HRP20050012A2

HRP20050012A2 - 2-heteroaryl carboxamides

Info

Publication number: HRP20050012A2
Application number: HR20050012A
Authority: HR
Inventors: Luithle Joachim; Böss Frank-Gerhard; Erb Christina; Hafner Frank-Thorsten; Schnitzler Katrin; Flesner Timo; Van Kampen Marja; Van Der Staay Franz-Josef
Original assignee: Bayer Healthcare Ag
Priority date: 2002-06-10
Filing date: 2005-01-07
Publication date: 2006-04-30
Also published as: DOP2003000657A; AR040261A1; TW200410967A; PE20040557A1; HN2003000166A

Abstract

Izum se odnosi na nove 2-heteroarilne karboksamide prema formuli (I), gdje R1 predstavlja l-aza-biciklo[2.2.2]okt-3-il, koji je opcijski supstituiran preko dušikovog atoma s nekim ostatkom odabranim iz skupine koju čine C1-C4-alkil, benzil i oksi, A predstavlja kisik ili sumpor, prsten B predstavlja benzo ili pirido, koji svaki može opcijski biti supstituiran ostatcima iz niza halogen, cijano, formil, trifluormetil, trifluormetoksi, nitro, amino, C1-C6-alkil i C1-C6-alkoksi, E predstavlja C≡C, aril i heteroaril, pri čemu aril i heteroaril mogu biti supstituirani ostatkom iz niza koji sadrži halogen, cijano, trifluormetil, trifluormetoksi, nitro, amino, C1-C6-alkoksi i C1-C6-alkil, kao i na solvate, te soli ili solvate soli tih spojeva. Izum obuhvaća i njihovu primjenu u pripravi lijekova za obradbu i/ili profilaksu bolesti i za poboljšanje sposobnosti opažanja, koncentracije, učenja i/ili pamćenja.The invention relates to novel 2-heteroaryl carboxamides of formula (I), wherein R1 represents l-aza-bicyclo [2.2.2] oct-3-yl, which is optionally substituted on a nitrogen atom with a moiety selected from the group consisting of C1 -C4-alkyl, benzyl and oxy, A represents oxygen or sulfur, ring B represents benzo or pyrido, which may each be optionally substituted by halogen, cyano, formyl, trifluoromethyl, trifluoromethoxy, nitro, amino, C1-C6-alkyl and C1-C6-alkoxy, E represents C≡C, aryl and heteroaryl, wherein the aryl and heteroaryl may be substituted by a halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C1-C6-alkoxy and C1- C6-alkyl, as well as solvates, and salts or solvates of these compounds. The invention also encompasses their use in the preparation of medicaments for the treatment and / or prophylaxis of diseases and for improving the ability to perceive, concentrate, learn and / or remember.

Description

Izum se odnosi na nove 2-heteroarilne karboksamide, postupke za njihovo pripravljanje, kao i njihovu primjenu u pripravljanju lijekova za obradbu i/ili profilaksu bolesti, te za poboljšanje sposobnosti opažanja, koncentracije, učenja i/ili pamćenja. The invention relates to new 2-heteroaryl carboxamides, procedures for their preparation, as well as their use in the preparation of drugs for the treatment and/or prophylaxis of diseases, and for improving the ability to observe, concentrate, learn and/or remember.

Nikotinski acetilkolinski receptori (nAChR) čine veliku skupinu ionskih kanala koji se aktiviraju kroz tijelu svojstveni transmiter acetilkolin (Galzi et al., Neuropharmacol. 1995, 34, 563-582). Djelotvorni nAChR sastoji se od 5 podjedinica koje mogu biti različite (određene kombinacije αl-9- ili β1-4,γ,δ,ε-podjedinica) ili jednake (α7-9). To dovodi do nastajanja mnoštva podtipova, koji se različito raspodjeljuju u muskulaturi, živčanom sustavu i drugim organima (McGehee et al., Annu. Rev. Physiol. 1995, 57, 521-546). Akitviranje nAChR dovodi do prodiranja kationa u stanice i do stimuliranja živčanih ili mišićnih stanica. Selektivno aktiviranje pojedinačnih podtipova nAChR ograničuje tu stimulaciju na one tipove stanica koji posjeduju odgovarajući podtip, te se na taj način mogu izbjeći neželjene nuspojave, kao što je primjerice stimulacija nAChR u muskulaturi. Klinički pokusi s nikotinom i pokusi na različitim životinjskim modelima ukazuju na ulogu središnjih nikotiskih acetilkolinskih receptora u procesima učenja i pamćenja (npr. Rezvani et al., Biol. Psychiatry 2001, 49, 258-267). Nikotinski acetilkolinski receptori podtipa alfa7 (α7-nAChR) imaju posebno visoku koncentraciju u dijelovima mozga bitnima za učenje i pamćenje, kao što su hipokampus i moždani korteks (Séguéla et al., 3. Neurosci. 1993r 13, 596-604). α7-nAChR posjeduje posebice visoku propusnost za kalcijeve ione, povisuje glutamatnu neurotransmisiju, utječe na rast neurita i na taj način modulira neuronalnu plastičnost (Broide et al., Mol. Neurobiol. 1999, 20, 1-16). Nicotinic acetylcholine receptors (nAChR) form a large group of ion channels that are activated by the body's inherent transmitter acetylcholine (Galzi et al., Neuropharmacol. 1995, 34, 563-582). An effective nAChR consists of 5 subunits that can be different (certain combinations of α1-9- or β1-4,γ,δ,ε-subunits) or the same (α7-9). This leads to the emergence of many subtypes, which are distributed differently in the musculature, nervous system and other organs (McGehee et al., Annu. Rev. Physiol. 1995, 57, 521-546). Activation of nAChR leads to penetration of cations into cells and stimulation of nerve or muscle cells. Selective activation of individual nAChR subtypes limits this stimulation to those cell types that possess the corresponding subtype, and thus unwanted side effects can be avoided, such as, for example, nAChR stimulation in the muscles. Clinical experiments with nicotine and experiments on various animal models indicate the role of central nicotinic acetylcholine receptors in learning and memory processes (eg Rezvani et al., Biol. Psychiatry 2001, 49, 258-267). Nicotinic acetylcholine receptors of the alpha7 subtype (α7-nAChR) have a particularly high concentration in parts of the brain essential for learning and memory, such as the hippocampus and cerebral cortex (Séguéla et al., 3. Neurosci. 1993r 13, 596-604). α7-nAChR has a particularly high permeability for calcium ions, increases glutamate neurotransmission, affects neurite growth and thus modulates neuronal plasticity (Broide et al., Mol. Neurobiol. 1999, 20, 1-16).

Određeni N-(l-aza-biciklo[2.2.2]okt-3-il)-heteroarilni karboksamidi za liječenje, među ostalim psihoza, opisani su u DE-A 37 24 059. Certain N-(1-aza-bicyclo[2.2.2]oct-3-yl)-heteroaryl carboxamides for the treatment of, inter alia, psychosis are described in DE-A 37 24 059.

N-(aza-bicikloalkil)-heteroarilni karboksamidi, posebice N-(l-aza-biciklo[2.2.2]okt-4-il)-benzotiofen-3-karboksamidi prikazani su u WO 93/15073, odnosno u EP-A 485 962, kao međuspojevi za sintezu farmaceutski djelotvornih spojeva. N-(aza-bicycloalkyl)-heteroaryl carboxamides, especially N-(1-aza-bicyclo[2.2.2]oct-4-yl)-benzothiophene-3-carboxamides are disclosed in WO 93/15073, respectively in EP-A 485 962, as intermediate compounds for the synthesis of pharmaceutically effective compounds.

Iz US 4,605,652 i EP-A 372 335 poznati su primjerice N-(l-aza-biciklo[2.2.2]okt-3-il)-tiofen-2-karboksamid i njegovo djelovanje na poboljšanje pamćenja. For example, N-(1-aza-bicyclo[2.2.2]oct-3-yl)-thiophene-2-carboxamide and its effect on improving memory are known from US 4,605,652 and EP-A 372,335.

U JP-A 14 030 084 opisani su 1-Azabicikloalkani koji se upotrebljavaju za liječenje, među ostalim, demencije, Attention Deficit Hyperactivity Disorder, te smetnja pri učenju i pamćenju. JP-A 14 030 084 describes 1-Azabicycloalkanes which are used for the treatment of, among others, dementia, Attention Deficit Hyperactivity Disorder, and learning and memory disorders.

Iz WO 02/44176, WO 02/085901, WO 01/60821, EP-A 1 231 212 i EP-A 1 219 622 poznati su drugi agonisti α7-nikotinskih acetilkolinskih receptora koji za liječenje bolesti središnjeg živčanog sustava. From WO 02/44176, WO 02/085901, WO 01/60821, EP-A 1 231 212 and EP-A 1 219 622, other α7-nicotinic acetylcholine receptor agonists are known for the treatment of diseases of the central nervous system.

Sadašnji izum odnosi se na spojeve formule The present invention relates to compounds of the formula

[image] [image]

u kojoj where

R1 predstavlja l-aza-biciklo[2.2.2]okt-3-il, opcijski supstituiran na dušikovom atomu ostatkom odabranim iz skupine C1-C4-alkil, benzil ili oksi, R1 represents 1-aza-bicyclo[2.2.2]oct-3-yl, optionally substituted on the nitrogen atom by a residue selected from the group C1-C4-alkyl, benzyl or oxy,

R2 predstavlja vodik ili C1-C6-alkil, R2 represents hydrogen or C1-C6-alkyl,

R3 predstavlja vodik, halogen ili C1-C6-alkil, R3 represents hydrogen, halogen or C1-C6-alkyl,

R4 predstavlja vodik, halogen, cijano, amino, trifluorometil, trifluorometoksi, C1-C6-alkil, C1-C6-alkilkarbonil, C1-C6-alkilamino, formil, hidroksikarbonil, C1-C6-alkoksi, C1-C6-alkoksikarbonil, C1-C6-alkiltio, C1-C6-alkilkarbonilamino, C1-C6-alkilaminokarbonil, C1-C4-alkilsulfonilamino, C3-C8-cikloalkil-karbonilamino, C3-C6-cikloalkilaminokarbonil, pirolil, C1-C6-alkilaminokarbonilamino, heterociklilkarbonil, heterociklil-karbonilamino, heteroarilkarbonilamino, hidroksi, fenil ili heterociklil, R 4 represents hydrogen, halogen, cyano, amino, trifluoromethyl, trifluoromethoxy, C1-C6-alkyl, C1-C6-alkylcarbonyl, C1-C6-alkylamino, formyl, hydroxycarbonyl, C1-C6-alkoxy, C1-C6- alkoxycarbonyl, C1- C6-alkylthio, C1-C6-alkylcarbonylamino, C1-C6-alkylaminocarbonyl, C1-C4-alkylsulfonylamino, C3-C8-cycloalkyl-carbonylamino, C3-C6-cycloalkylaminocarbonyl, pyrrolyl, C1-C6-alkylaminocarbonylamino, heterocyclylcarbonyl, heterocyclyl-carbonylamino, heteroarylcarbonylamino, hydroxy, phenyl or heterocyclyl,

pri čemu whereby

C1-C6-alkil opcijski može biti supstituiran s hidroksi, cijano, amino, C1-C6-alkilaminokarbonilamino, C1-C6-alkilamino-karboksilom, heterociklilom ili arilom, C1-C6-alkilaminokarbonil opcijski može biti supstituiran C1-C6-alkoksi ili C1-C6-alkilaminom, C1-C6-alkyl may optionally be substituted with hydroxy, cyano, amino, C1-C6-alkylaminocarbonylamino, C1-C6-alkylamino-carboxyl, heterocyclyl or aryl, C1-C6-alkylaminocarbonyl may optionally be substituted with C1-C6-alkoxy or C1 -C6-alkylamine,

C1-C6-alkilkarbonilamino opcijski može biti supstituiran C1-C6-alkoksi, a C1-C6-alkylcarbonylamino can optionally be substituted with C1-C6- alkoxy, and

heterociklil opcijski može biti supstituiran s okso, heterocyclyl can optionally be substituted with oxo,

A predstavlja kisik ili sumpor, A represents oxygen or sulfur,

prsten B predstavlja benzo ili pirido, također opcijski mogu biti supstituirani ostatkom iz niza koji sadrži halogen, cijano, formil, trifluormetil, trifluormetoksi, nitro, amino, C1-C6-alkil i C1-C6-alkoksi, ring B represents benzo or pyrido, they can also optionally be substituted by a residue from the series containing halogen, cyano, formyl, trifluoromethyl, trifluoromethoxy, nitro, amino, C1-C6-alkyl and C1-C6- alkoxy,

i and

E predstavlja C≡C, aril i heteroaril, pri čemu aril i heteroaril mogu biti supstituirani ostatkom iz niza koji sadrži halogen, cijano, trifluormetil, trifluormetoksi, nitro, amino, C1-C6-alkoksi i C1-C6-alkil, E represents C≡C, aryl and heteroaryl, wherein the aryl and heteroaryl can be substituted by a residue from the series containing halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C1-C6-alkoxy and C1-C6-alkyl,

i na solvate, te soli i solvate soli ovih spojeva. and to solvates, and salts and solvated salts of these compounds.

Solvatima se u okviru izuma smatraju oni oblici spojeva koji u krutom ili tekućem obliku koordinacijom s molekulama otapala tvore kompleks. Hidrati su poseban oblik solvata kod kojih se koordinacija odvija s vodom. In the context of the invention, solvates are those forms of compounds that, in solid or liquid form, form a complex by coordinating with solvent molecules. Hydrates are a special form of solvate in which coordination takes place with water.

Solima se u okviru izuma smatraju fiziološki prihvatljive soli spojeva prema izumu. Salts within the scope of the invention are considered to be physiologically acceptable salts of the compounds according to the invention.

Fiziološki prihvatljive soli spoja (I) mogu biti adicijske kiselinske soli spojeva s mineralnim kiselinama, karboksilnim kiselinama ili sulfonskim kiselinama. Ponajbolje su primjerice soli klorovodične kiseline, bromovodične kiseline, sumporne kiseline, fosforne kiseline, metansulfonske kiseline, etansulfonske kiseline, toluolsulfonske kiseline, benzolsulfonske kiseline, naftalindisulfonske kiseline, octene kiseline, propionske kiseline, oksalne kiseline, mliječne kiseline, vinske kiseline, limunske kiseline, fumarne kiseline, maleinske kiseline ili benzojeve kiseline. Physiologically acceptable salts of compound (I) can be acid addition salts of compounds with mineral acids, carboxylic acids or sulfonic acids. The best examples are the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalene sulfonic acid, acetic acid, propionic acid, oxalic acid, lactic acid, tartaric acid, citric acid, fumaric acid acid, maleic acid or benzoic acid.

Kao soli se mogu navesti i soli uobičajenih baza, kao što su primjerice soli alkalijskih metala (primjerice natrijeve i kalijeve soli), soli zemnoalkalijskih metala (primjerice kalcijeve i magnezijeve soli) ili amonijeve soli, izvedene iz amonijaka ili organskih amina kao što su primjerice monoetanolamin, dietanolamin, trietanolamin, arginin, lizin, dimetilaminoetanol, dietilamin, trietilamin, etildiizopropilamin, prokain, dibenzilamin, N-metilmorfolin, dihidroabietilamin, 1-efenamin ili metilpiperidin. As salts, salts of common bases can also be mentioned, such as, for example, salts of alkali metals (for example, sodium and potassium salts), salts of alkaline earth metals (for example, calcium and magnesium salts) or ammonium salts, derived from ammonia or organic amines, such as, for example, monoethanolamine , diethanolamine, triethanolamine, arginine, lysine, dimethylaminoethanol, diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabiethylamine, 1-ephenamine or methylpiperidine.

Spojevi prema izumu mogu postojati u stereoizomernim oblicima (enantiomeri, diastereomeri). Izum se odnosi i na enantiomere i na diastereomere, te na njihove smjese. Te smjese enantiomera i diastereomera mogu se na poznati način rastaviti na pojedinačne sastavne dijelove stereoizomera. The compounds according to the invention can exist in stereoisomeric forms (enantiomers, diastereomers). The invention relates to both enantiomers and diastereomers, and their mixtures. These mixtures of enantiomers and diastereomers can be separated into individual components of stereoisomers in a known manner.

U okviru prikazanog izuma imaju supstituenti općenito sljedeće značenje: Within the scope of the presented invention, substituents generally have the following meaning:

C1-C6- i C1-C4-alkoksi predstavljaju ravnolančani ili razgranati alkoksi ostatak sa 1 do 6, ponajprije sa 1 do 4, ponajbolje sa 1 do 3 ugljikova atoma. Neograničujući primjeri uključuju metoksi, etoksi, n-propoksi, izopropoksi, tert-butoksi, n-pentoksi i n-heksoksi. C1-C6- and C1-C4-Alkoxy represent a straight-chain or branched alkoxy residue with 1 to 6, preferably with 1 to 4, preferably with 1 to 3 carbon atoms. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

C1-C6- i C1-C4-alkil predstavljaju ravnolančani ili razgranati alkilni ostatak sa 1 do 6, ponajprije 1 do 4, ponajbolje 1 do 3 ugljikova atoma. Neograničujući primjeri uključuju metil, etil, n-propil, izopropil, tert-butil, n-pentil i n-heksil. C1-C6- and C1-C4-alkyl represent a straight-chain or branched alkyl residue with 1 to 6, preferably 1 to 4, preferably 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.

C1-C6- i C1-C4-alkilamino predstavlja ravnolančani ili razgranati mono- ili dialkilamino ostatak sa 1 do 6, ponajprije 1 do 4 ugljikova atoma po alkilnom ostatku. Neograničujući primjeri uključuju metilamino, dimetilamino, etilamino, dietilamino, n-propilamino, di-n-propilamino, izopropilamino, diizopropilamino, tert-butilamino, di-tert-butilamino, n-pentilamino, di-n-pentilamino, n-heksilamino, di-n-heksilamino, etilmetilamino, izopropilmetilamino, n-butiletilamino, n-heksil-i-pentilamino. C1-C6- and C1-C4-alkylamino represents a straight-chain or branched mono- or dialkylamino residue with 1 to 6, preferably 1 to 4 carbon atoms per alkyl residue. Non-limiting examples include methylamino, dimethylamino, ethylamino, diethylamino, n-propylamino, di-n-propylamino, isopropylamino, diisopropylamino, tert-butylamino, di-tert-butylamino, n-pentylamino, di-n-pentylamino, n-hexylamino, di -n-hexylamino, ethylmethylamino, isopropylmethylamino, n-butylethylamino, n-hexyl-i-pentylamino.

C1-C6- i C1-C4-alkilkarbonilamino predstavlja ravnolančani ili razgranati alkilkarbonilamino ostatak sa 1 do 6, ponajprije 1 do 4, a ponajbolje 1 do 3 ugljikova atoma. Neograničujući primjeri uključuju metilkarbonilamino, etilakrbonilamino, n-propilkarbonil-amino, izopropilkarbonilamino, tert-butilkarbonilamino, n-pentil-karbonilamino i n-heksilkarbonilamino. C1-C6- and C1-C4-alkylcarbonylamino represents a straight-chain or branched alkylcarbonylamino residue with 1 to 6, preferably 1 to 4, and preferably 1 to 3 carbon atoms. Non-limiting examples include methylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, isopropylcarbonylamino, tert-butylcarbonylamino, n-pentylcarbonylamino and n-hexylcarbonylamino.

C1-C6- i C1-C4-alkilaminokarboksil predstavlja ravnolančani ili razgranati mono- ili dialkilaminokarboksilni ostatak sa 1 do 6, ponajprije 1 do 4, a ponajbolje 1 do 3 ugljikova atoma po alkilnom ostatku. Neograničujući primjeri uključuju metilaminokarboksil, dimetilaminokarboksil, etilaminokarboksil, dietilaminokarboksil, n-propilaminokarboksil, di-n-propilaminokarboksil, izopropilamino-karboksil, diizopropilaminokarboksil, tert-butilaminokarboksil, di-tert-butilaminokarboksil, n-pentilaminokarboksil, di-n-pentilamino-karboksil, n-heksilaminokarboksil, di-n-heksilaminokarboksil, etilmetilaminokarboksil, izopropilmetilaminokarboksil, n-butiletil-aminokarboksil, n-heksil-i-pentilaminokarboksil. C1-C6- and C1-C4-alkylaminocarboxyl represents a straight-chain or branched mono- or dialkylaminocarboxyl residue with 1 to 6, preferably 1 to 4, and preferably 1 to 3 carbon atoms per alkyl residue. Non-limiting examples include methylaminocarboxyl, dimethylaminocarboxyl, ethylaminocarboxyl, diethylaminocarboxyl, n-propylaminocarboxyl, di-n-propylaminocarboxyl, isopropylaminocarboxyl, diisopropylaminocarboxyl, tert-butylaminocarboxyl, di-tert-butylaminocarboxyl, n-pentylaminocarboxyl, di-n-pentylaminocarboxyl, -hexylaminocarboxyl, di-n-hexylaminocarboxyl, ethylmethylaminocarboxyl, isopropylmethylaminocarboxyl, n-butylethylaminocarboxyl, n-hexyl-i-pentylaminocarboxyl.

C1-C6- i C1-C4-alkilaminokarbonil predstavlja ravnolančani ili razgranati mono- ili dialkilaminokarbonilni ostatak sa 1 do 6, ponajprije 1 do 4, a ponajbolje 1 do 3 ugljikova atoma po alkilnom ostatku. Neograničujući primjeri uključuju metilaminokarbonil, dimetilaminokarbonil, etilaminokarbonil, dietilaminokarbonil, n-propilaminokarbonil, di-n-propilaminokarbonil, izopropilamino-karbonil, diizopropilaminokarbonil, tert-butilaminokarbonil, di-tert-butilaminokarbonil, n-pentilaminokarbonil, di-n-pentilaminokarbonil, n-heksilaminokarbonil, di-n-heksilaminokarbonil, etilmetilamino-karbonil, izopropilmetilaminokarbonil, n-butiletilaminokarbonil, n-heksil-i-pentilaminokarbonil. C1-C6- and C1-C4-alkylaminocarbonyl represents a straight-chain or branched mono- or dialkylaminocarbonyl residue with 1 to 6, preferably 1 to 4, and preferably 1 to 3 carbon atoms per alkyl residue. Non-limiting examples include methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, diethylaminocarbonyl, n-propylaminocarbonyl, di-n-propylaminocarbonyl, isopropylaminocarbonyl, diisopropylaminocarbonyl, tert-butylaminocarbonyl, di-tert-butylaminocarbonyl, n-pentylaminocarbonyl, di-n-pentylaminocarbonyl, n-hexylaminocarbonyl. , di-n-hexylaminocarbonyl, ethylmethylamino-carbonyl, isopropylmethylaminocarbonyl, n-butylethylaminocarbonyl, n-hexyl-i-pentylaminocarbonyl.

C1-C6- i C1-C4-alkilaminokarbonilamino predstavlja ravnolančani ili razgranati mono- ili dialkilaminokarbonilamino ostatak sa 1 do 6, ponajprije 1 do 4, a ponajbolje 1 do 3 ugljikova atoma po alkilnom ostatku. Neograničujući primjeri uključuju metilaminokarbonilamino, dimetilaminokarbonilamino, etilaminokarbonilamino, dietilamino-karbonilamino, n-propilaminokarbonilamino, di-n-propilamino-karbonilamino, izopropilaminokarbonilamino, diizopropilamino-karbonilamino, tert-butilaminokarbonilamino, di-tert-butilamino-karbonilamino, n-pentilaminokarbonilamino, di-n-pentilamino-karbonilamino, n-heksilaminokarbonilamino, di-n-heksilamino-karbonilamino, etilmetilaminokarbonilamino, izopropilmetilamino-karbonilamino, n-butiletilaminokarbonilamino, n-heksil-i-pentil-aminokarbonilamino. C1-C6- and C1-C4-alkylaminocarbonylamino represents a straight-chain or branched mono- or dialkylaminocarbonylamino residue with 1 to 6, preferably 1 to 4, and preferably 1 to 3 carbon atoms per alkyl residue. Non-limiting examples include methylaminocarbonylamino, dimethylaminocarbonylamino, ethylaminocarbonylamino, diethylaminocarbonylamino, n-propylaminocarbonylamino, di-n-propylaminocarbonylamino, isopropylaminocarbonylamino, diisopropylaminocarbonylamino, tert-butylaminocarbonylamino, di-tert-butylaminocarbonylamino, n-pentylaminocarbonylamino, di-n -pentylamino-carbonylamino, n-hexylaminocarbonylamino, di-n-hexylamino-carbonylamino, ethylmethylaminocarbonylamino, isopropylmethylamino-carbonylamino, n-butylethylaminocarbonylamino, n-hexyl-i-pentyl-aminocarbonylamino.

C1-C6-alkilkarbonil predstavlja ravnolančani ili razgranati alkilkarbonilni ostatak sa 1 do 6, ponajprije 1 do 4 ugljikova atoma. Neograničujući primjeri uključuju acetil, etilkarbonil, propilkarbonil, izopropilkarbonil, butilkarbonil, izobutilkarbonil, tert-butilkarbonil, pentilkarbonil i heksilkarbonil. C1-C6-alkylcarbonyl represents a straight-chain or branched alkylcarbonyl residue with 1 to 6, preferably 1 to 4 carbon atoms. Non-limiting examples include acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, tert-butylcarbonyl, pentylcarbonyl and hexylcarbonyl.

C1-C4-alkilsulfonilamino predstavlja ravnolančani ili razgranati alkilsulfonilamino ostatak sa 1 do 4, ponajprije 1 do 3 ugljikova atoma. Kao primjeri se ponajprije navode metansulfonilamino, etansulfonilamino, n-propansulfonilamino, izopropansulfonilamino, tert-butansulfonilamino. C1-C4-alkylsulfonylamino represents a straight-chain or branched alkylsulfonylamino residue with 1 to 4, preferably 1 to 3 carbon atoms. Examples include methanesulfonylamino, ethanesulfonylamino, n-propanesulfonylamino, isopropanesulfonylamino, tert-butanesulfonylamino.

C1-C6- i C1-C4-alkoksikarbonil predstavlja ravnolančani ili razgranati alkoksikarbonilni ostatak sa 1 do 6, ponajprije 1 do 4, a ponajbolje 1 do 3 ugljikova atoma ugljika. Neograničujući primjeri uključuju metoksikarbonil, etoksikarbonil, n-propoksikarbonil, izopropoksi-karbonil i tert-butoksikarbonil. C1-C6- and C1-C4-Alkoxycarbonyl represents a straight-chain or branched alkoxycarbonyl residue with 1 to 6, preferably 1 to 4, and preferably 1 to 3 carbon atoms. Non-limiting examples include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.

C1-C6- i C1-C4-alkoksikarbonilamino predstavlja ravnolančani ili razgranati alkoksikarbonilamino ostatak sa 1 do 6, ponajprije 1 do 4, a ponajbolje 1 do 3 ugljikova atoma. Neograničujući primjeri uključuju metoksikarbonilamino, etoksikarbonilamino, n-propoksi-karbonilamino, izopropoksikarbonilamino, tert-butoksikarbonil-amino, n-pentoksikarbonilamino i n-heksoksikarbonilamino. C1-C6- and C1-C4-Alkoxycarbonylamino represents a straight-chain or branched Alkoxycarbonylamino residue with 1 to 6, preferably 1 to 4, and preferably 1 to 3 carbon atoms. Non-limiting examples include methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino, tert-butoxycarbonylamino, n-pentoxycarbonylamino and n-hexoxycarbonylamino.

C3-C6-cikloalkilaminokarbonil predstavlja cikloalkilaminokarbonilni ostatak sa 3 do 6, ponajprije 5 do 6 članova. Neograničujući primjeri uključuju ciklopropilaminokarbonil, ciklobutilaminokarbonil, ciklopentilaminokarbonil, cikloheksilaminokarbonil, cikloheptilamino-karbonil i ciklooktilaminokarbonil. C3-C6-cycloalkylaminocarbonyl represents a cycloalkylaminocarbonyl residue with 3 to 6, preferably 5 to 6 members. Non-limiting examples include cyclopropylaminocarbonyl, cyclobutylaminocarbonyl, cyclopentylaminocarbonyl, cyclohexylaminocarbonyl, cycloheptylaminocarbonyl, and cyclooctylaminocarbonyl.

C3-C8- i C5-C6-cikloalkilkarbonilamino predstavlja cikloalkilkarbonil-amino ostatak sa 3 do 8, ponajprije 5 do 6 članova. Neograničujući primjeri uključuju ciklopropilkarbonilamino, ciklobutilkarbonilamino, ciklopentilkarbonilamino, cikloheksilkarbonilamino, cikloheptil-karbonilamino i ciklooktilkarbonilamino. C3-C8- and C5-C6-cycloalkylcarbonylamino represents a cycloalkylcarbonylamino residue with 3 to 8, preferably 5 to 6 members. Non-limiting examples include cyclopropylcarbonylamino, cyclobutylcarbonylamino, cyclopentylcarbonylamino, cyclohexylcarbonylamino, cycloheptylcarbonylamino, and cyclooctylcarbonylamino.

Heterociklil predstavlja mono- ili policiklički, ponajprije mono- ili biciklički, nearomatski ostatak s obično 4 do 10, ponajprije 5 do 8 prstenskih atoma, te do 3, ponajprije do 2 heteroprstenska člana iz skupine N, O, S, SO, SO2. Heterociklilni ostatak može biti zasićen ili djelomično nezasićen. Neograničujući primjeri uključuju 5- do 8-člane monocikličke zasićene heterociklilne ostatke sa do dva heteroatoma u prstenu, odabranih između N, 0 i S, kao što su tetrahidrofuran-2-il, piperazinil, N-metilpiperazinil, pirolidin-2-il, pirolidin-3-il, pirolinil, piperidinil, morfolinil i perhidroazepinil. Heterocyclyl represents a mono- or polycyclic, preferably mono- or bicyclic, non-aromatic residue with usually 4 to 10, preferably 5 to 8 ring atoms, and up to 3, preferably up to 2 heteroring members from the group N, O, S, SO, SO2. The heterocyclyl residue can be saturated or partially unsaturated. Non-limiting examples include 5- to 8-membered monocyclic saturated heterocyclyl radicals with up to two ring heteroatoms selected from N, O and S, such as tetrahydrofuran-2-yl, piperazinyl, N-methylpiperazinyl, pyrrolidin-2-yl, pyrrolidine -3-yl, pyrrolinyl, piperidinyl, morpholinyl and perhydroazepinyl.

Heteroaril predstavlja aromatski, mono- ili biciklički ostatak sa 5 do 10 prstenska atoma, te do 5 heteroatoma iz skupine S, O, i/ili N. Ponajbolji su 5- do 6-člani heteroarili sa do 4 heteroatoma. Heteroarilni ostatak može biti vezan preko ugljikovog atoma ili preko heteroatoma. Neograničujući primjeri obuhvaćaju tienil, furil, pirolil, tiazolil, oksadiazolil, oksazolil, izoksazolil, imidazolil, tetrazolil, piridil, pirimidinil, piridazinil, indolil, indazolil, benzofuranil, benzotiofenil, kinolinil, izokinolinil. Heteroaryl represents an aromatic, mono- or bicyclic residue with 5 to 10 ring atoms, and up to 5 heteroatoms from the group S, O, and/or N. The best are 5- to 6-membered heteroaryls with up to 4 heteroatoms. The heteroaryl residue can be attached via a carbon atom or via a heteroatom. Non-limiting examples include thienyl, furyl, pyrrolyl, thiazolyl, oxadiazolyl, oxazolyl, isoxazolyl, imidazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl.

Heterociklilkarbonilamino predstavlja karbonilamino skupinu povezanu s nekim mono- ili policikličkim, ponajprije mono- ili bicikličkim, nearomatskim ostatkom, koji obično ima 4 do 10, ponajprije 5 do 8 prstenskih atoma i do 3, ponajprije do 2 heteroprstenska člana odabrana iz skupine N, O, S, SO, SO2. Heterociklilni ostatak može biti zasićen ili djelomično nezasićen. Neograničujući primjeri uključuju karbonilamino skupine spojene s 5- do 8-članim monocikličnim zasićenim heterociklilnim ostatcima sa do dva heteroatoma u prstenu odabrana između N, O i S, kao što su tetrahidrofuran-2-ilkarbonilamino, piperazinilkarbonilamino, N-metilpiperazinilkarbonilamino, pirolidin-2-ilkarbonilamino, pirolidin-3-ilkarbonilamino, pirolinilkarbonilamino, piperidinilkarbonilamino, morfolinilkarbonilamino i perhidroazepinilkarbonilamino. Heterocyclylcarbonylamino represents a carbonylamino group connected to some mono- or polycyclic, preferably mono- or bicyclic, non-aromatic residue, which usually has 4 to 10, preferably 5 to 8 ring atoms and up to 3, preferably up to 2 heteroring members selected from the group N, O, S, SO, SO2. The heterocyclyl residue can be saturated or partially unsaturated. Non-limiting examples include carbonylamino groups fused to 5- to 8-membered monocyclic saturated heterocyclic moieties with up to two ring heteroatoms selected from N, O, and S, such as tetrahydrofuran-2-ylcarbonylamino, piperazinylcarbonylamino, N-methylpiperazinylcarbonylamino, pyrrolidine-2- ylcarbonylamino, pyrrolidin-3-ylcarbonylamino, pyrrolinylcarbonylamino, piperidinylcarbonylamino, morpholinylcarbonylamino and perhydroazepinylcarbonylamino.

Heteroarilkarbonilamino predstavlja karbonilamino skupinu povezanu s aromatskim, mono- ili bicikličkim ostatkom sa 5 do 10 prstenskih atoma, te do 5 heteroatoma iz skupine S, O, i/ili N. Ponajbolji su 5- do 6-člani heteroarili sa do 4 heteroatoma. Heteroarilni ostatak može s karbonilamino skupinom biti vezan preko ugljikovog atoma ili preko heteroatoma. Neograničujući primjeri obuhvaćaju tienilkarbonilamino, furilkarbonilamino, pirolilkarbonilamino, tiazolilkarbonilamino, izoksazolilkarbonilamino, oksadiazolilkarbonilamino, oksazolilkarbonilamino, imidazolil-karbonilamino, tetrazolilkarbonilamino, piridilkarbonilamino, pirimidinilkarbonilamino, piridazinilkarbonilamino, indolilkarbonil-amino, indazolilkarbonilamino, benzofuranilkarbonilamino, benzotiofenilkarbonilamino, kinolinilkarbonilamino, izokinolinil-karbonilamino. Heteroarylcarbonylamino represents a carbonylamino group connected to an aromatic, mono- or bicyclic residue with 5 to 10 ring atoms, and up to 5 heteroatoms from the group S, O, and/or N. The best are 5- to 6-membered heteroaryls with up to 4 heteroatoms. The heteroaryl residue can be linked to the carbonylamino group via a carbon atom or via a heteroatom. Non-limiting examples include thienylcarbonylamino, furylcarbonylamino, pyrrolylcarbonylamino, thiazolylcarbonylamino, isoxazolylcarbonylamino, oxadiazolylcarbonylamino, oxazolylcarbonylamino, imidazolylcarbonylamino, tetrazolylcarbonylamino, pyridylcarbonylamino, pyrimidinylcarbonylamino, pyridazinylcarbonylamino, indolylcarbonylamino, indazolylcarbonylamino, benzofuranylcarbonylamino, benzothiophenylcarbonylamino, quinolinylcarbonylamino.

Heterociklilkarbonil predstavlja karbonilnu skupinu povezanu s mono- ili policikličkim, ponajprije mono- ili bicikličkim, nearomatskim ostatkom koji sadrži obično 4 do 10, ponajprije 5 do 8 prstenskih atoma i do 3, ponajprije do 2 heteroprstenska člana iz skupine N, O, S, SO, SO2. Heterociklilni ostatak može biti zasićen ili djelomično nezasićen. Neograničujući primjeri uključuju karbonilne skupine spojene s 5- do 8-članim monocikličkim zasićenim heterociklilnim ostatcima sa do dva heteroatoma u prstenu, odabrana između N, O i S, kao što su tetrahidrofuran-2-ilkarbonil, piperazinilkarbonil, N-metilpiperazinilkarbonil, pirolidin-2-ilkarbonil, pirolidin-3-ilkarbonil, pirolinilkarbonil, piperidinilkarbonil, morfolinil-karbonil i perhidroazepinilkarbonil. Heterocyclylcarbonyl represents a carbonyl group connected to a mono- or polycyclic, preferably mono- or bicyclic, non-aromatic residue containing usually 4 to 10, preferably 5 to 8 ring atoms and up to 3, preferably up to 2 heteroring members from the group N, O, S, SO , SO2. The heterocyclyl residue can be saturated or partially unsaturated. Non-limiting examples include carbonyl groups attached to 5- to 8-membered monocyclic saturated heterocyclic radicals with up to two ring heteroatoms selected from N, O and S, such as tetrahydrofuran-2-ylcarbonyl, piperazinylcarbonyl, N-methylpiperazinylcarbonyl, pyrrolidine-2 -ylcarbonyl, pyrrolidin-3-ylcarbonyl, pyrrolinylcarbonyl, piperidinylcarbonyl, morpholinylcarbonyl and perhydroazepinylcarbonyl.

Aril predstavlja mono- do triciklički aromatski karbociklički ostatak koji sadrži obično 6 do 10 ugljikovih atoma u prstenu. Neograničujući primjeri uključuju fenil i naftil. Aryl represents a mono- to tricyclic aromatic carbocyclic residue containing usually 6 to 10 carbon atoms in the ring. Non-limiting examples include phenyl and naphthyl.

Halogen predstavlja fluor, klor, brom i jod, ponajprije fluor, klor i brom, a ponajbolje fluor i klor. Halogen represents fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine, and preferably fluorine and chlorine.

C1-C6- i C1-C4-alkiltio predstavlja ravnolančani ili razgranati alkiltio ostatak sa 1 do 6, ponajprije 1 do 4, a ponajbolje 1 do 3 ugljikova atoma. Neograničujući primjeri uključuju metiltio, etiltio, n-propiltio, izopropiltio, tert-butiltio, n-pentiltio i n-heksiltio. C1-C6- and C1-C4-alkylthio represents a straight-chain or branched alkylthio residue with 1 to 6, preferably 1 to 4, and preferably 1 to 3 carbon atoms. Non-limiting examples include methylthio, ethylthio, n-propylthio, isopropylthio, tert-butylthio, n-pentylthio, and n-hexylthio.

Kad su ostaci u spojevima prema izumu opcijski supstituirani, oni mogu, ukoliko nije drugačije navedeno, biti jednako ili različito supstituirani, jedanput ili više puta. When the residues in the compounds according to the invention are optionally substituted, they can, unless otherwise stated, be equally or differently substituted, once or more.

U prednosti su oni spojevi formule (I) u kojima R1 predstavlja (3R)-1-aza-biciklo-[2.2.2]okt-3-il, a R2, R3, R4, A, E i prsten B imaju gore navedena značenja, te solvati, soli i solvati soli tih spojeva. Preference is given to those compounds of formula (I) in which R1 represents (3R)-1-aza-bicyclo-[2.2.2]oct-3-yl, and R2, R3, R4, A, E and ring B have the above meaning, and solvates, salts and solvates of salts of these compounds.

Isto tako su u prednosti oni spojevi formule (I) u kojima R2 predstavlja vodik ili metil, a R1, R3, R4, A, E i prsten B imaju gore navedena značenja, te solvati, soli i solvati soli tih spojeva. Those compounds of formula (I) in which R2 represents hydrogen or methyl, and R1, R3, R4, A, E and ring B have the above-mentioned meanings, and solvates, salts and solvates of salts of these compounds are also preferred.

Ponajbolji su oni spojevi formule (I) u kojima R2 predstavlja vodik, a R1, R3, R4, A, E i prsten B imaju gore navedena značenja, te solvati, soli i solvati soli tih spojeva. The best are those compounds of the formula (I) in which R2 represents hydrogen, and R1, R3, R4, A, E and ring B have the above meanings, as well as solvates, salts and solvates of salts of these compounds.

Isto tako su ponajbolji oni spojevi formule (I) u kojima R3 predstavlja vodik ili metil, a R1, R2, R4, A, E i prsten B imaju gore navedena značenja, te solvati, soli i solvati soli tih spojeva. Likewise, those compounds of formula (I) in which R3 represents hydrogen or methyl, and R1, R2, R4, A, E and ring B have the above-mentioned meanings, and solvates, salts and solvates of salts of these compounds are also the best.

Ponajbolji su oni spojevi formule (I) u kojima R3 predstavlja vodik, a R1, R2, R4, A, E i prsten B imaju gore navedena značenja, te solvati, soli i solvati soli tih spojeva. The best are those compounds of the formula (I) in which R3 represents hydrogen, and R1, R2, R4, A, E and ring B have the above meanings, as well as solvates, salts and solvates of salts of these compounds.

Isto tako su najbolji oni spojevi formule (I) u kojima R4 predstavlja vodik, fluor, klor, brom, trifluormetoksi, hidroksimetil, metoksi ili 6-člani heterociklil, a R1, R2, R3, A, E i prsten B imaju gore navedena značenja, te solvati, soli i solvati soli tih spojeva. Likewise, those compounds of formula (I) in which R4 represents hydrogen, fluorine, chlorine, bromine, trifluoromethoxy, hydroxymethyl, methoxy or 6-membered heterocyclyl are the best, and R1, R2, R3, A, E and ring B have the above meanings , and solvates, salts and solvates of salts of these compounds.

Isto tako su ponajbolji oni spojevi formule (I) u kojima A predstavlja sumporov atom, a R1, R2, R3, R4, E i prsten B imaju gore navedena značenja, te solvati, soli i solvati soli tih spojeva. Likewise, the best are those compounds of formula (I) in which A represents a sulfur atom, and R1, R2, R3, R4, E and ring B have the above-mentioned meanings, as well as solvates, salts and solvates of salts of these compounds.

Isto tako su ponajbolji oni spojevi formule (I) u kojima A predstavlja kisikov atom, a R1, R2, R3, R4, E i prsten B imaju gore navedena značenja, te solvati, soli i solvati soli tih spojeva. Likewise, the best are those compounds of formula (I) in which A represents an oxygen atom, and R1, R2, R3, R4, E and ring B have the above-mentioned meanings, as well as solvates, salts and solvates of salts of these compounds.

Isto tako su ponajbolji oni spojevi formule (I) u kojima prsten B predstavlja benzo, opcijski supstituiran sa 1 do 3 ostatka iz skupine halogen, cijano, trifluormetil i C1-C4-alkil, a R1, R2, R3, R4, A i E imaju gore navedena značenja, te solvati, soli i solvati soli tih spojeva. Likewise, those compounds of formula (I) in which ring B represents benzo, optionally substituted with 1 to 3 residues from the group halogen, cyano, trifluoromethyl and C1-C4-alkyl, and R1, R2, R3, R4, A and E are the best have the above meanings, and solvates, salts and solvates of salts of these compounds.

Isto tako su ponajbolji oni spojevi formule (I) u kojima E predstavlja fenil, opcijski supstituiran ostatkom iz skupine fluor, klor, brom, cijano, trifluormetoksi, C1-C6-alkil i C1-C6-alkoksi, a R1, R2, R3, R4, A i prsten B imaju gore navedena značenja, te solvati, soli i solvati soli tih spojeva. Likewise, those compounds of the formula (I) in which E represents phenyl, optionally substituted by a radical from the group fluorine, chlorine, bromine, cyano, trifluoromethoxy, C1-C6-alkyl and C1-C6-alkoxy, and R1, R2, R3, R4, A and ring B have the meanings given above, and solvates, salts and solvates of salts of these compounds.

Isto tako su u prednosti spojevi formule (I) u kojima Compounds of formula (I) in which

R1 predstavlja l-aza-biciklo[2.2.2]okt-3-il, R2 predstavlja vodik ili C1-C4-alkil, R1 represents 1-aza-bicyclo[2.2.2]oct-3-yl, R2 represents hydrogen or C1-C4-alkyl,

R3 predstavlja vodik, fluor, klor, brom ili C1-C4-alkil, R3 represents hydrogen, fluorine, chlorine, bromine or C1-C4-alkyl,

R4 predstavlja vodik, fluor, klor, brom, cijano, amino, trifluormetil, trifluormetoksi, C1-C4-alkil, C1-C4-alkilkarbonil, C1-C4-alkilamino, formil, hidroksikarbonil, C1-C4-alkoksi, C1-C4-alkoksikarbonil, C1-C4-alkiltio, C1-C4-alkilkarbonilamino, C1-C4-alkilaminokarbonil, C1-C4-alkilsulfonilamino, C3-C6-ciklo-alkilkarbonilamino, C3-C6-cikloalkilaminokarbonil, pirolil, C1-C4-alkilaminokarbonilamino, heterociklilkarbonil, heterociklil-karbonilamino, heteroarilkarbonilamino, hidroksi, fenil ili heterociklil, R4 represents hydrogen, fluorine, chlorine, bromine, cyano, amino, trifluoromethyl, trifluoromethoxy, C1-C4-alkyl, C1-C4-alkylcarbonyl, C1-C4-alkylamino, formyl, hydroxycarbonyl, C1-C4-alkoxy, C1-C4- alkoxycarbonyl, C1-C4-alkylthio, C1-C4-alkylcarbonylamino, C1-C4-alkylaminocarbonyl, C1-C4-alkylsulfonylamino, C3-C6-cyclo-alkylcarbonylamino, C3-C6-cycloalkylaminocarbonyl, pyrrolyl, C1-C4-alkylaminocarbonylamino, heterocyclylcarbonyl, heterocyclylcarbonylamino, heteroarylcarbonylamino, hydroxy, phenyl or heterocyclyl,

pri čemu C1-C4-alkil može biti opcijski supstituiran s hidroksi, cijano, amino, C1-C4-alkilaminokarbonilamino, C1-C4-alkilaminokarboksilom, heterociklilom ili arilom, C1-C4-alkilaminokarbonil može biti opcijski supstituiran s C1-C4-alkoksi ili C1-C4-alkilamino, C1-C4-alkilkarbonilamino može biti opcijski supstituiran s C1-C4-alkoksi, a heterociklil može biti opcijski supstituiran s okso, wherein C1-C4-alkyl may be optionally substituted with hydroxy, cyano, amino, C1-C4-alkylaminocarbonylamino, C1-C4-alkylaminocarboxyl, heterocyclyl or aryl, C1-C4-alkylaminocarbonyl may be optionally substituted with C1-C4-alkoxy or C1-C4-alkylamino, C1-C4-alkylcarbonylamino may be optionally substituted with C1-C4-alkoxy, and heterocyclyl may be optionally substituted with oxo,

A predstavlja kisik ili sumpor, A represents oxygen or sulfur,

prsten B predstavlja benzo ili pirido, koji su ponekad opcijski supstituirani ostatkom iz skupine halogen, cijano, trifluormetil, trifluormetoksi i C1-C4-alkil, ring B represents benzo or pyrido, which are sometimes optionally substituted with a radical from the group halogen, cyano, trifluoromethyl, trifluoromethoxy and C1-C4-alkyl,

i and

E predstavlja C≡C, aril i heteroaril, pri čemu aril i heteroaril mogu biti supstituirani ostatkom iz skupine halogen, cijano, trifluormetil, trifluormetoksi, nitro, amino, C1-C4-alkoksi i C1-C4-alkil, E represents C≡C, aryl and heteroaryl, whereby aryl and heteroaryl can be substituted by a radical from the group halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C1-C4-alkoxy and C1-C4-alkyl,

i solvati, te soli i solvati soli tih spojeva. and solvates, and salts and solvates of salts of these compounds.

Isto tako su u prednosti oni spojevi formule (I) u kojima Those compounds of formula (I) in which

R1 predstavlja l-aza-biciklo[2.2.2]okt-3-il, R1 represents l-aza-bicyclo[2.2.2]oct-3-yl,

R2 i R3 predstavljaju vodik, R2 and R3 represent hydrogen,

R4 predstavlja vodik, fluor, klor, brom, cijano, amino, trifluormetil, trifluormetoksi, C1-C4-alkil, C1-C4-alkilkarbonil, C1-C4-alkilamino, formil, hidroksikarbonil, C1-C4-alkoksi, C1-C4-alkoksikarbonil, C1-C6-alkiltio, C1-C4-alkilkarbonilamino, C1-C4-alkilaminokarbonil, C1-C4-alkilsulfonilamino, C3-C6-ciklo-alkilkarbonilamino, C3-C6-cikloalkilaminokarbonil, pirolil, C1-C4-alkilaminokarbonilamino, heterociklilkarbonil, heterociklil-karbonilamino, heteroarilkarbonilamino, hidroksi, fenil ili heterociklil, R4 represents hydrogen, fluorine, chlorine, bromine, cyano, amino, trifluoromethyl, trifluoromethoxy, C1-C4-alkyl, C1-C4-alkylcarbonyl, C1-C4-alkylamino, formyl, hydroxycarbonyl, C1-C4-alkoxy, C1-C4- alkoxycarbonyl, C1-C6-alkylthio, C1-C4-alkylcarbonylamino, C1-C4-alkylaminocarbonyl, C1-C4-alkylsulfonylamino, C3-C6-cyclo-alkylcarbonylamino, C3-C6-cycloalkylaminocarbonyl, pyrrolyl, C1-C4-alkylaminocarbonylamino, heterocyclylcarbonyl, heterocyclylcarbonylamino, heteroarylcarbonylamino, hydroxy, phenyl or heterocyclyl,

pri čemu C1-C4-alkil može biti opcijski supstituiran s hidroksi, cijano, amino, C1-C4-alkilaminokarbonilamino, C1-C4-alkilaminokarboksilom, heterociklilom ili arilom, C1-C4-alkilaminokarbonil može biti opcijski supstituiran s C1-C4-alkoksi ili C1-C4-alkilamino, wherein C1-C4-alkyl may be optionally substituted with hydroxy, cyano, amino, C1-C4-alkylaminocarbonylamino, C1-C4-alkylaminocarboxyl, heterocyclyl or aryl, C1-C4-alkylaminocarbonyl may be optionally substituted with C1-C4-alkoxy or C1-C4-alkylamino,

C1-C4-alkilkarbonilamino može biti opcijski supstituiran s C1-C4-alkoksi, a heterociklil može biti opcijski supstituiran s okso. C 1 -C 4 -alkylcarbonylamino may be optionally substituted with C 1 -C 4 -alkoxy, and heterocyclyl may be optionally substituted with oxo.

A predstavlja kisik, A represents oxygen,

prsten B predstavlja benzo ili pirido, koji su ponekad opcijski supstituirani s ostatkom iz skupine halogen, cijano, trifluorometil, trifluorometoksi i C1-C4-alkil, ring B represents benzo or pyrido, which are sometimes optionally substituted with a radical from the group halogen, cyano, trifluoromethyl, trifluoromethoxy and C1-C4-alkyl,

i and

E predstavlja C≡C, aril i heteroaril, pri čemu aril i heteroaril mogu biti opcijski supstituirani ostatkom iz skupine halogen, cijano, trifluormetil, trifluormetoksi, nitro, amino, C1-C4-alkoksi i C1-C4-alkil, E represents C≡C, aryl and heteroaryl, wherein aryl and heteroaryl can be optionally substituted by a radical from the group halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C1-C4-alkoxy and C1-C4-alkyl,

Isto tako su ponajbolji spojevi formule (I) u kojima Likewise, the best compounds of formula (I) in which

R2 predstavlja vodik ili C1-C6-alkil, R2 represents hydrogen or C1-C6-alkyl,

R4 predstavlja vodik, halogen, cijano, amino, trifluormetil, trifluormetoksi, C1-C6-alkil, C1-C6-alkilkarbonil, C1-C6-alkilamino, formil, hidroksikarbonil, C1-C6-alkoksi, C1-C6-alkoksikarbonil, C1-C6-alkiltio, C1-C6-alkilkarbonilamino, C1-C4-alkilsulfonilamino, C3-C8-cikloalkilkarbonilamino, pirolil, C1-C6-alkilaminokarbonilamino, heterociklilkarbonil, fenil ili heterociklil, R 4 represents hydrogen, halogen, cyano, amino, trifluoromethyl, trifluoromethoxy, C1-C6-alkyl, C1-C6-alkylcarbonyl, C1-C6-alkylamino, formyl, hydroxycarbonyl, C1-C6-alkoxy, C1-C6- alkoxycarbonyl, C1- C6-alkylthio, C1-C6-alkylcarbonylamino, C1-C4-alkylsulfonylamino, C3-C8-cycloalkylcarbonylamino, pyrrolyl, C1-C6-alkylaminocarbonylamino, heterocyclylcarbonyl, phenyl or heterocyclyl,

pri čemu C1-C6-alkil može biti opcijski supstituiran s hidroksi, amino, C1-C6-alkilaminokarbonilamino, C1-C6-alkilamino-karboksilom, heterociklilom ili arilom, wherein C1-C6-alkyl may be optionally substituted with hydroxy, amino, C1-C6-alkylaminocarbonylamino, C1-C6-alkylamino-carboxyl, heterocyclyl or aryl,

C1-C6-alkilkarbonilamino može biti opcijski supstituiran s C1-C6-alkoksi, a heterociklil može biti opcijski supstituiran s okso, C1-C6-alkylcarbonylamino may be optionally substituted with C1-C6-alkoxy, and heterocyclyl may be optionally substituted with oxo,

A predstavlja kisik ili sumpor, A represents oxygen or sulfur,

prsten B predstavlja benzo ili pirido, koji su ponekad opcijski supstituirani ostatkom iz skupine halogen cijano, formil, trifluormetil, trifluormetoksi, nitro, amino, C1-C6-alkil i C1-C6-alkoksi, ring B represents benzo or pyrido, which are sometimes optionally substituted with a radical from the halogen group cyano, formyl, trifluoromethyl, trifluoromethoxy, nitro, amino, C1-C6-alkyl and C1-C6-alkoxy,

i and

E predstavlja C≡C, aril i heteroaril, pri čemu aril i heteroaril mogu biti opcijski supstituirani ostatkom iz skupine halogen, cijano, trifluormetil, trifluormetoksi, nitro, amino, C1-C6-alkoksi i C1-C6-alkil, E represents C≡C, aryl and heteroaryl, wherein aryl and heteroaryl can be optionally substituted by a residue from the group halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C1-C6-alkoxy and C1-C6-alkyl,

Isto tako su najbolji oni spojevi formule (I) u kojima Likewise, those compounds of formula (I) in which

R2 predstavlja vodik ili C1-C6-alkil, R2 represents hydrogen or C1-C6-alkyl,

R4 predstavlja vodik, halogen, cijano, trifluormetil, trifluoro-metoksi, C1-C6-alkil, C1-C6-alkoksi ili heterociklil, pri čemu je alkil opcijski supstituiran hidroksi ostatkom, R4 represents hydrogen, halogen, cyano, trifluoromethyl, trifluoro-methoxy, C1-C6-alkyl, C1-C6-alkoxy or heterocyclyl, wherein the alkyl is optionally substituted with a hydroxy residue,

A predstavlja kisik ili sumpor, A represents oxygen or sulfur,

prsten B predstavlja benzo ili pirido, koji su ponekad opcijski supstituirani ostatkom iz skupine halogen, cijano, trifluormetil, trifluormetoksi, nitro, amino, C1-C6-alkil i C1-C6-alkoksi, ring B represents benzo or pyrido, which are sometimes optionally substituted with a radical from the group halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C1-C6-alkyl and C1-C6-alkoxy,

i and

E predstavlja C≡C, aril ili heteroaril, pri čemu aril i heteroaril mogu biti supstituirani ostatkom iz skupine halogen, cijano, trifluormetil, trifluormetoksi, nitro, amino, C1-C6-alkil i C1-C6-alkoksi, E represents C≡C, aryl or heteroaryl, whereby aryl and heteroaryl can be substituted by a radical from the group halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C1-C6-alkyl and C1-C6-alkoxy,

i solvati, te soli i solvati soli tih spojeva. Također su u prednosti spojevi formule and solvates, and salts and solvates of salts of these compounds. Compounds of the formula are also advantageous

[image] [image]

u kojima in which

R1 predstavlja (3R)-1-aza-biciklo[2.2.2]okt-3-il, R1 represents (3R)-1-aza-bicyclo[2.2.2]oct-3-yl,

R2 i R3 predstavljaju međusobno neovisno vodik ili metil, R2 and R3 independently represent hydrogen or methyl,

i and

RB predstavlja vodik, halogen, cijano, trifluormetil, trifluoro-metoksi, nitro, amino, C1-C6-alkil ili C1-C6-alkoksi, RB represents hydrogen, halogen, cyano, trifluoromethyl, trifluoro-methoxy, nitro, amino, C1-C6-alkyl or C1-C6-alkoxy,

Također su sasvim posebice u prednosti spojevi formule (Ia) gdje Compounds of formula (Ia) where

R2 i R3 predstavljaju vodik, R2 and R3 represent hydrogen,

R4 predstavlja vodik, fluor, klor, brom, trifluormetoksi, hidroksimetil, metoksi ili 6-člani heterociklil, R4 represents hydrogen, fluorine, chlorine, bromine, trifluoromethoxy, hydroxymethyl, methoxy or 6-membered heterocyclyl,

i and

RB predstavlja vodik, halogen, cijano, trifluormetil, trifluormetoksi ili C1-C4-alkil, RB represents hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy or C1-C4-alkyl,

Isto tako su ponajbolji spojevi formule Likewise, the best compounds are formulas

[image] [image]

gdje where

RB predstavlja vodik, halogen, cijano, trifluormetil, trifluoro-metoksi, nitro, amino, C1-C6-alkil i C1-C6-alkoksi, RB represents hydrogen, halogen, cyano, trifluoromethyl, trifluoro-methoxy, nitro, amino, C1-C6-alkyl and C1-C6-alkoxy,

Isto tako su ponajbolji oni spojevi formule (lb) u kojima R1 predstavlja (3R)-1-aza-biciklo[2.2.2]okt-3-il, R2 i R3 predstavljaju vodik, Likewise, the best are those compounds of formula (lb) in which R1 represents (3R)-1-aza-bicyclo[2.2.2]oct-3-yl, R2 and R3 represent hydrogen,

R4 predstavlja vodik, fluor, klor, brom, trifluormetoksi, hidroksi-metil, metoksi ili 6-člani heterociklil, a R4 represents hydrogen, fluorine, chlorine, bromine, trifluoromethoxy, hydroxymethyl, methoxy or 6-membered heterocyclyl, and

RB predstavlja vodik, halogen, cijano, trifluormetil, trifluoro-metoksi, ili C1-C4-alkil, RB represents hydrogen, halogen, cyano, trifluoromethyl, trifluoro-methoxy, or C1-C4-alkyl,

Također su u prednosti spojevi formule Compounds of the formula are also advantageous

[image] [image]

u kojoj where

E predstavlja fenilen, E represents phenylene,

R4 predstavlja C1-C6-alkoksi, aminometilen, hidroksikarbonil, C3-C8-cikloalkilkarbonilamino, skupinu formule R4 represents C1-C6-Alkoxy, aminomethylene, hydroxycarbonyl, C3-C8-cycloalkylcarbonylamino, a group of the formula

[image] [image]

pri čemu whereby

R5 predstavlja C1-C6-alkil, R5 represents C1-C6-alkyl,

n predstavlja nulu, 1, 2, 3 ili 4, n represents zero, 1, 2, 3 or 4,

ili or

5- do 6-člani heterociklil, opcijski supstituiran s okso, 5- to 6-membered heterocyclyl, optionally substituted with oxo,

A predstavlja sumpor ili kisik, A represents sulfur or oxygen,

Posebice se izum odnosi na one spojeve formule (I) u kojima In particular, the invention relates to those compounds of formula (I) in which

E predstavlja fenilen, E represents phenylene,

R4 predstavlja C1-C4-alkoksi, aminometilen, hidroksikarbonil, C3-C6-cikloalkilkarbonilamino, skupinu formule R4 represents C1-C4-Alkoxy, aminomethylene, hydroxycarbonyl, C3-C6-cycloalkylcarbonylamino, a group of the formula

[image] [image]

pri čemu whereby

R5 predstavlja C1-C4-alkil, R5 represents C1-C4-alkyl,

n predstavlja nulu, 1 ili 2, n represents zero, 1 or 2,

ili or

5- do 6-člani heterociklil, opcijski supstituiran s okso, A predstavlja sumpor ili kisik, i solvati, te soli i solvati soli tih spojeva. 5- to 6-membered heterocyclyl, optionally substituted with oxo, A represents sulfur or oxygen, and solvates, and salts and solvates of salts of these compounds.

Posebice se izum odnosi na spojeve sljedećih formula In particular, the invention relates to compounds of the following formulas

[image] [image]

i solvate, te soli i solvate soli tih spojeva. and solvates, and salts and solvated salts of these compounds.

Ponajbolje su kombinacije dvaju ili više gore navedenih prednostnih područja. Combinations of two or more of the above priority areas are best.

Izum se nadalje odnosi na postupak priprave spojeva prema izumu, po čemu spojevi formule The invention further relates to the process of preparing the compounds according to the invention, whereby the compounds of the formula

X1-E-R4 (II), X1-E-R4 (II),

u kojoj where

R4 ima gore navedena značenja, R 4 has the above meanings,

X1 u slučaju kada E predstavlja arilen ili heteroarilen, predstavlja -B(OH)2 ili X1 in the case where E represents arylene or heteroarylene, represents -B(OH)2 or

[image] [image]

a u slučaju kada E predstavlja -C≡C-, predstavlja vodik, reagiraju sa spojem formule and in the case when E represents -C≡C-, represents hydrogen, they react with the compound of the formula

[image] [image]

u kojoj where

R1, R2, R3, A i prsten B imaju gore navedena značenja, a R 1 , R 2 , R 3 , A and ring B have the above meanings, a

X2 predstavlja triflat ili halogen, ponajprije klor, brom ili jod, X2 represents triflate or halogen, preferably chlorine, bromine or iodine,

te se opcijski and optional

[A] rezultantni spojevi (I) alkiliraju s odgovarajućim reagensima za alkiliranje na dušikovom atomu kinuklidina, ili [A] the resulting compounds (I) are alkylated with suitable alkylating reagents at the quinuclidine nitrogen atom, or

[B] rezultantni spojevi (I) oksidiraju s prikladnim oksidacijskim sredstvima na dušikovom atomu kinuklidina, [B] the resulting compounds (I) are oxidized with suitable oxidizing agents on the quinuclidine nitrogen atom,

a rezultantni spojevi se (I) opcijski odgovarajućim (i) otapalima i/ili (ii) bazama ili kiselinama pretvore u svoje solvate, soli ili solvate soli. and the resulting compounds are (I) optionally converted into their solvates, salts or solvates of salts with appropriate (i) solvents and/or (ii) bases or acids.

Pretvorba spojeva (II) i (III) odvija se općenito u nekom inertnom otapalu uz prisutnost katalizatora od prijelaznog metala, uz prisutnost baze i opcijski uz prisutnost bakrovog(I) jodida. The conversion of compounds (II) and (III) generally takes place in some inert solvent in the presence of a transition metal catalyst, in the presence of a base and optionally in the presence of copper(I) iodide.

Ponajprije se postupak prema izumu odvija se u temperaturnom području od 70°C do 110°C pri normalnom tlaku. First of all, the process according to the invention takes place in the temperature range from 70°C to 110°C at normal pressure.

Inertna otapala su primjerice eteri kao što je dioksan, tetrahidrofuran ili 1,2-dimetoksietan, ugljikovodici kao što je benzol, ksilol ili toluol, nitroaromati kao što je nitrobenzol, opcijski N-alkilirani karboksamidi kao što je dimetilformamid, dimetilacetamid, alkilsulfoksidi kao što je dimetilsulfoksi ili ciklički laktami kao što je N-metilpirolidon. Ponajbolja su otapala iz skupine dimetilformamid, dimetilacetamid, dimetilsulfoksid i 1,2-dimetoksietan. Inert solvents are for example ethers such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, hydrocarbons such as benzene, xylene or toluene, nitroaromatics such as nitrobenzene, optionally N-alkylated carboxamides such as dimethylformamide, dimethylacetamide, alkylsulfoxides such as dimethylsulfoxy or cyclic lactams such as N-methylpyrrolidone. The best solvents are dimethylformamide, dimethylacetamide, dimethylsulfoxide and 1,2-dimethoxyethane.

Kao katalizatori od prijelaznih metala rabe se ponajprije spojevi paladija(0) ili paladija(II), posebice bis-(difenilfosfanferocenil)-paladijev(II) klorid, diklorbis(trifenilfosfin)-paladij ili tetrakis-(trifenilfosfin)-paladij(0). Palladium(0) or palladium(II) compounds, especially bis-(diphenylphosphaneferrocenyl)-palladium(II) chloride, dichlorobis(triphenylphosphine)-palladium or tetrakis-(triphenylphosphine)-palladium(0) are used as transition metal catalysts.

Kao baze u prednosti su alkalijski hidroksidi ili soli alkalijskih hidroksida kao što su kalijev acetat, natrijev hidroksid, natrijev hidrogenkarbonat ili natrijev karbonat, opcijski u obliku svojih vodenih otopina. Preferred bases are alkali hydroxides or salts of alkali hydroxides such as potassium acetate, sodium hydroxide, sodium bicarbonate or sodium carbonate, optionally in the form of their aqueous solutions.

Koraci priprave [A] i [B] mogu se provesti u inertnom otapalu pri temperaturama od -30°C do 50°C pri normalnom tlaku. Preparation steps [A] and [B] can be carried out in an inert solvent at temperatures from -30°C to 50°C at normal pressure.

Kao baze za korak priprave [A] mogu se dodati alkalijski hidridi kao što je kalijev ili natrijev hidrid, alkalijski hidroksidi kao što je natrijev ili kalijev hidroksid ili alkalijski karbonati kao što je natrijev ili kalijev karbonat. Alkali hydrides such as potassium or sodium hydride, alkali hydroxides such as sodium or potassium hydroxide, or alkali carbonates such as sodium or potassium carbonate may be added as bases for the preparation step [A].

Kao reagensi za alkiliranje u koraku priprave [A] mogu se dodati alikilhalogenidi kao što su metiljodid ili benzilhalogenidi kao što je benzilbromid. Alkyl halides such as methyl iodide or benzyl halides such as benzyl bromide may be added as alkylating reagents in the preparation step [A].

Kao oksidacijsko sredstvo u koraku priprave [B] posebno su prikladni vodikov peroksid ili metaklorperbenzojeva kiselina. As an oxidizing agent in the preparation step [B], hydrogen peroxide or metachloroperbenzoic acid are particularly suitable.

Reakcije katalizirane prijelaznim metalima mogu se provoditi analogno postupcima poznatima iz literature, primjerice pretvorba pomoću alkina: usp. N. Krause et al., J. Org. Chem. 1998. 63, 8551; ketona, aromata i alkena: usp. na pr. A. Suzuki, Acc. Chem. Res. 1982, 15, 178ff; Miyaura et al., 3. Am. Chem. Soc. 1989r 111, 314; J. K. Stille, Angew. Chem. 1986, 98, 504, te poomoću supstituiranih amina: usp. S. L. Buchwald et al., J. Organomet. Chem. 1999, 576, 125ff (vidjeti i J. Tsuji, Palladium Reagents and Catalysts, Wiley, NewYork, 1995). Reactions catalyzed by transition metals can be carried out analogously to procedures known from the literature, for example conversion using alkynes: cf. N. Krause et al., J. Org. Chem. 1998. 63, 8551; ketones, aromatics and alkenes: cf. for example A. Suzuki, Acc. Chem. Crisp. 1982, 15, 178ff; Miyaura et al., 3rd Am. Chem. Soc. 1989r 111, 314; J.K. Stille, Angew. Chem. 1986, 98, 504, and with the help of substituted amines: cf. S. L. Buchwald et al., J. Organomet. Chem. 1999, 576, 125ff (see also J. Tsuji, Palladium Reagents and Catalysts, Wiley, NewYork, 1995).

Spojevi (II) poznati su ili se mogu sintetizirati analogno poznatim postupcima iz odgovarajućih edukata. Compounds (II) are known or can be synthesized analogously by known procedures from the relevant studies.

Spojevi (III) mogu se pripraviti pretvorbom spojeva formule Compounds (III) can be prepared by converting compounds of the formula

R1R2NH (IV), R1R2NH (IV),

u kojoj R1 i R2 imaju gore navedena značenja, in which R1 and R2 have the above meanings,

sa spojem formule with the compound formula

[image] [image]

u kojoj where

R3, X2, A i prsten B imaju gore navedena značenja, a R 3 , X 2 , A and ring B have the above meanings, a

X3 predstavlja hidroksi ili halogen, ponajprije brom ili klor. X3 represents hydroxy or halogen, preferably bromine or chlorine.

Reakcija spojeva (IV) i (V) odvija se, ako X3 predstavlja halogen, općenito u inertnim otapalima, opcijski u prisutnosti baze, ponajprije pri temperaturi od 0°C do 50°C i normalnom tlaku. The reaction of compounds (IV) and (V) takes place, if X3 represents a halogen, generally in inert solvents, optionally in the presence of a base, preferably at a temperature of 0°C to 50°C and normal pressure.

Inertna otapala su primjerice halogeni ugljikovodici kao što su metilenklorid, triklormetan, tetraklormetan, trikloretan, tetraklor-etan, 1,2-dikloretan ili trikloretilen, eteri kao što su dietileter, metil-tert-butileter, dioksan, tetrahidrofuran, glikoldimetileter ili dietilenglikoldimetileter, ugljikovodici kao što su benzol, ksilol, toluol, heksan, cikloheksan ili naftne frakcije, nitroaromati kao što je nitrometan, esteri karboksilne kiseline kao što je etilacetat, ketoni kao što su aceton ili 2-butanon, opcijski N-alkilirani karboksamidi kao što su dimetilformamid ili dimetilacetamid, alkilsulfoksidi kao što je dimetilsulfoksid, nitrili karboksilne kiseline kao što je acetonitril ili heteroaromati kao što je piridin. Najbolji su dioksan, dimetilformamid ili metilenklorid. Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichloroethylene, ethers such as diethylether, methyl-tert-butylether, dioxane, tetrahydrofuran, glycoldimethylether or diethyleneglycoldimethylether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, nitroaromatics such as nitromethane, carboxylic acid esters such as ethyl acetate, ketones such as acetone or 2-butanone, optionally N-alkylated carboxamides such as dimethylformamide or dimethylacetamide, alkylsulfoxides such as dimethylsulfoxide, carboxylic acid nitriles such as acetonitrile or heteroaromatics such as pyridine. The best are dioxane, dimethylformamide or methylene chloride.

Baze su primjerice alkalijski hidroksidi kao što su natrijev ili kalijev hidroksid, alkalijski karbonati i hidrogenkarbonati kao što su cezijev karbonat, natrijev hidrogenkarbonat, natrijev ili kalijev karbonat, ili amidi kao što je litijev diizopropilamid, aliklamini kao što su trietilamin ili diizopropiletilamin, ponajprije diizopropilamin ili trietilamin, te druge baze kao što je DBU. Bases are, for example, alkali hydroxides such as sodium or potassium hydroxide, alkali carbonates and hydrogen carbonates such as cesium carbonate, sodium hydrogen carbonate, sodium or potassium carbonate, or amides such as lithium diisopropylamide, alkylamines such as triethylamine or diisopropylethylamine, preferably diisopropylamine or triethylamine, and other bases such as DBU.

Ako X3 predstavlja hidroksi, pretvorba se odvija općenito u inertnom otapalu, u prisutnosti kondenzacijskog sredstva, opcijski u prisutnosti baze, ponajprije pri temperaturi od 20°C do 50°C i normalnom tlaku. If X3 is hydroxy, the conversion generally takes place in an inert solvent, in the presence of a condensing agent, optionally in the presence of a base, preferably at a temperature of 20°C to 50°C and normal pressure.

Pojam "inertno otapalo" odnosi se, primjerice, na halogene ugljikovodike kao što su metilenklorid, triklormetan, tetraklormetan, trikloretan, tetrakloretan, 1,2-dikloretan ili trikloretilen, etere kao što su dietileter, metil-tert-butileter, dioksan, tetrahidrofuran, glikoldimetileter ili dietilenglikoldimetileter, ugljikovodike kao što su benzol, ksilol, toluol, heksan, cikloheksan ili naftne frakcije, nitroaromate kao što je nitrometan, estere karboksilne kiseline kao što je etilacetat, ketone kao što je aceton, opcijski N-alkilirane karboksamide kao što su dimetilformamid ili dimetilacetamid, alkilsulfokside kao što je dimetilsulfoksid, nitrile karboksilne kiseline kao što je acetonitril, te heteroaromate kao što je piridin. Najbolji su tetrahidrofuran, dimetilformamid, 1,2-dikloretan ili metilenklorid. The term "inert solvent" refers, for example, to halogenated hydrocarbons such as methylene chloride, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichloroethylene, ethers such as diethylether, methyl-tert-butylether, dioxane, tetrahydrofuran, glycoldimethylether or diethyleneglycoldimethylether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, nitroaromatics such as nitromethane, carboxylic acid esters such as ethyl acetate, ketones such as acetone, optionally N-alkylated carboxamides such as dimethylformamide or dimethylacetamide, alkylsulfoxides such as dimethylsulfoxide, carboxylic acid nitriles such as acetonitrile, and heteroaromatics such as pyridine. The best are tetrahydrofuran, dimethylformamide, 1,2-dichloroethane or methylene chloride.

Kondenzacijska sredstva u sklopu izuma su primjerice karbodiimidi, kao primjerice N,N'-dietil-, N,N'-dipropil-, N,N'-diizopropil, N,N'-dicikloheksilkarbodiimid, N-(3-dimetilaminoizopropil)-N'-etilkarbo-diimid-hidroklorid (EDC), N-cikloheksilkarbodiimid-N’-propiloksi-metil-polistirol (PS-karbodiimid); karbonilni spojevi kao što je karbodiimidazol; spojevi 1,2-oksazola kao što su 2-etil-5-fenil-l,2-oksazol-3-sulfat ili 2-tert-butil-5-metil-izooksazol-perklorat; acilamino spojevi kao što je 2-etoksi-1-etoksikarbonil-l,2-dihidro-kinolin; nadalje anhidrid propanfosfonske kiseline, izobutilklor-format, bis-(2-okso-3-oksazolidinil)-fosforilklorid, benzotriazoliloksi-tri(dimetilamino)fosfonheksafluorfosfat, O-(benzotriazol-1-il)-N,N,N',N'-tetrametiluron-heksafluorfosfat (HBTU), 2-(2-okso-1-(2H)-piridil)-1,1,3,3-tetrametiluron-tetrafluorborat (TPTU), 0-(7-azabenzotriazol-1-il)-N,N,N',N'-tetrametil-uron-heksafluorfosfat (HATU), benzotriazol-1-iloksitris(dimetilamino)-fosfon heksafluor-fosfat (BOP), te njihove smjese. Condensing agents within the scope of the invention are, for example, carbodiimides, such as N,N'-diethyl-, N,N'-dipropyl-, N,N'-diisopropyl, N,N'-dicyclohexylcarbodiimide, N-(3-dimethylaminoisopropyl)-N '-ethylcarbodiimide-hydrochloride (EDC), N-cyclohexylcarbodiimide-N'-propyloxy-methyl-polystyrene (PS-carbodiimide); carbonyl compounds such as carbodiimidazole; 1,2-oxazole compounds such as 2-ethyl-5-phenyl-1,2-oxazole-3-sulfate or 2-tert-butyl-5-methyl-isoxazole-perchlorate; acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydro-quinoline; further propanephosphonic acid anhydride, isobutylchloroformate, bis-(2-oxo-3-oxazolidinyl)-phosphoryl chloride, benzotriazolyloxy-tri(dimethylamino)phosphonhexafluorophosphate, O-(benzotriazol-1-yl)-N,N,N',N' -tetramethyluron-hexafluorophosphate (HBTU), 2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyluron-tetrafluoroborate (TPTU), 0-(7-azabenzotriazol-1-yl) -N,N,N',N'-tetramethyl-uron-hexafluorophosphate (HATU), benzotriazol-1-yloxytris(dimethylamino)-phosphone hexafluorophosphate (BOP), and their mixtures.

Opcijski može biti korisno upotrebljavati kondenzacijsko sredstvo u prisutnosti pomoćnog nukleofila kao što je, primjerice, 1-hidroksibenztriazol (HOBt). Optionally, it may be advantageous to use a condensing agent in the presence of an auxiliary nucleophile such as, for example, 1-hydroxybenztriazole (HOBt).

Baze su primjerice alkalijski karbonati i hidrogenkarbonati kao što su primjerice natrijev i kalijev karbonat ili hidrokgenkarbonat, organske baze kao što su alkilamini, primjerice trietilamin ili N-metilmorfolin, N-metilpiperidin, 4-dimetilaminopiridin ili diizopropiletilamin. Bases are, for example, alkali carbonates and hydrogen carbonates such as sodium and potassium carbonate or hydrogencarbonate, organic bases such as alkylamines, for example triethylamine or N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.

Ponajbolja je kombinacija N-(3-dimetilaminoizipropil)-N’-etilkarbo-diimid-hidroklorida (EDC), 1-hidroksibenzotriazola (HOBt) i trietilamina u dimetilformamidu ili O-(7-azabenzotriazol-1-il)-N,N,N',N'-tetrametil-uronheksafluorfosfata (HATU) i diizopropiletil-amina u dimetilformamidu. The best combination is N-(3-dimethylaminoisopropyl)-N'-ethylcarbo-diimide-hydrochloride (EDC), 1-hydroxybenzotriazole (HOBt) and triethylamine in dimethylformamide or O-(7-azabenzotriazol-1-yl)-N,N, of N',N'-tetramethyl-uronhexafluorophosphate (HATU) and diisopropylethylamine in dimethylformamide.

Spojevi (IV) i (V) poznati su ili se mogu sintetizirati analogno poznatim postupcima iz odgovarajućih edukata (usp. primjerice "Comprehensive Heterocydic Chemistry", Katrizki et al., Hrsg.; Elsevier, 1996). Compounds (IV) and (V) are known or can be synthesized analogously by known procedures from the relevant publications (cf. for example "Comprehensive Heterocydic Chemistry", Katrizki et al., Hrsg.; Elsevier, 1996).

Tako se primjerice supstituirane benzotiofen-2-karboksilne kiseline mogu dobiti iz odgovarajućih supstituiranih 2-halogenbenzaldehida reakcijom s metilnim esterom merkaptooctene kiseline (vidjeti primjerice A. J. Bridges et al., Tetrahedron Lett. 1992, 33, 7499) te odmah zatim saponifikacijom estera: Thus, for example, substituted benzothiophene-2-carboxylic acids can be obtained from corresponding substituted 2-halobenzaldehydes by reaction with the methyl ester of mercaptoacetic acid (see, for example, A. J. Bridges et al., Tetrahedron Lett. 1992, 33, 7499) and immediately afterwards by saponification of the ester:

Shema sinteze 1: Synthesis scheme 1:

[image] [image]

Sintezom odgovarajućih pirido derivata moguće je iz 2-halogenbenzonitrila reakcijom s metilnim esterom merkaptooctene kiseline dobiti estere 3-aminobenzotiofen-2-karboksilne kiseline: Through the synthesis of appropriate pyrido derivatives, it is possible to obtain esters of 3-aminobenzothiophene-2-carboxylic acid from 2-halobenzonitrile by reaction with methyl ester of mercaptoacetic acid:

Shema sinteze 2: Synthesis scheme 2:

[image] [image]

Atom dušika prikazan u prstenu može u aromatima zamijeniti CH-skupinu najednom od položaja 1 do 4. The nitrogen atom shown in the ring can replace the CH-group in aromatics at once from positions 1 to 4.

Amino funkcija može se odstraniti diazotizacijom. Napokon se ciljni spoj dobije saponifikacijom estera. The amino function can be removed by diazotization. Finally, the target compound is obtained by saponification of the ester.

Supstituirane benzofuran-2-karboksilne kiseline mogu se dobiti, primjerice, prema D. Bogdal et al., Tetrahedron, 2000, 56, 8769. Substituted benzofuran-2-carboxylic acids can be obtained, for example, according to D. Bogdal et al., Tetrahedron, 2000, 56, 8769.

Spojevi prema izumu prikladni su za uporabu kao lijekovi za obradbu i/ili profilaksu bolesti u ljudi i životinja. The compounds according to the invention are suitable for use as drugs for the treatment and/or prophylaxis of diseases in humans and animals.

Djeluju kao agonisti na α7-nAChR i pokazuju nepredvidljivi, vrijedan farmakološki spektar djelovanja. They act as α7-nAChR agonists and exhibit an unpredictable, valuable pharmacological spectrum of activity.

Spojevi prema izumu mogu se na temelju svojih farmakoloških svojstava sami ili u kombinaciji s drugim djelotvornim tvarima upotrijebiti za obradbu i/ili prevenciju kognitivnih smetnja, osobito Alzheimerove bolesti. Zbog svog selektivnog djelovanja kao agonisti α7-nAChR prikladni su posebice za poboljšanje opažanja, koncentracije, učenja i pamćenja, osobito kod kognitivnih smetnja, kao što su, primjerice, "blago kognitivno oštećenje", smetnje u učenju i pamćenju povezane sa starošću, gubitak pamćenja povezan sa starošću, vaskularna demencija, povreda lubanje i mozga, udar kapi, demencija koja nastupa nakon udara kapi ("post stroke dementia"), post-traumatska povreda lubanje i mozga, općenite smetnje koncentracije, smetnje koncentracije u djece s problemima učenja i pamćenja, smanjenje pozornosti zbog hiperaktivnosti («Attention deficit hyperactivity disorder»), Alzheimerova bolest, demencija s Lewy-tjelešcima, demencija s degeneracijom čeonog režnja uključujući Pickov sindrom, Parkinsonova bolest, progresivna nuklearna uzetost, demencija s kortikobazalnom degeneracijom, amiotropna lateralna skleroza (ALS), Huntingtonova bolest, multipla skleroza, degeneracija talamusa, Creuzfeld-Jacobova demencija, HIV-demencija, shizofrenija s demencijom ili pojava Korsakoffljeve psihoze. The compounds according to the invention can, on the basis of their pharmacological properties, be used alone or in combination with other active substances for the treatment and/or prevention of cognitive disorders, especially Alzheimer's disease. Due to their selective action as α7-nAChR agonists, they are particularly suitable for improving perception, concentration, learning and memory, especially in cognitive disorders, such as, for example, "mild cognitive impairment", age-related learning and memory disorders, memory loss age-related, vascular dementia, skull and brain injury, stroke, post-stroke dementia, post-traumatic skull and brain injury, general concentration disorders, concentration disorders in children with learning and memory problems , attention deficit hyperactivity disorder, Alzheimer's disease, dementia with Lewy bodies, dementia with frontal lobe degeneration including Pick's syndrome, Parkinson's disease, progressive nuclear involvement, dementia with corticobasal degeneration, amyotrophic lateral sclerosis (ALS) , Huntington's disease, multiple sclerosis, thalamic degeneration, Creuzfeld-Jacob dementia , HIV-dementia, schizophrenia with dementia or the onset of Korsakoff's psychosis.

Spojevi prema izumu mogu se sami ili u kombinaciji s drugim djelotvornim tvarima upotrijebiti za profilaksu i obradbu akutnih i/ili kroničnih bolova (za klasifikaciju vidjeti "Classification of Chronic Pain, Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms", 2. izd., Meskey und Begduk, Hrsg.; IASP-Press, Seattle, 1994), osobito za obradbu bolova uzrokovanih rakom i kroničnih neuropatskih bolova, kao primjerice kod dijabetičke neuropatije, postherpesne neuralgije, perifernih oštećenja živaca, centralnih bolova (primjerice kao posljedica cerebralne ishemije) i trigeminalne neuralgije, te kod drugih kroničnih bolova kao što su, primjerice, lumbago, bolovi u donjem dijelu leđa («low back pain») i drugih reumatskih bolova. Uz to, ove djelotvorne tvari prikladne su i za terapiju primarnih akutnih bolova svakog podrijetla te iz njih proizlazećih bolnih stanja, kao što je terapija nekad akutnih bolnih stanja koja su postala kronična. Spojevi prema izumu mogu se sami ili u kombinaciji s drugim djelatnim tvarima upotrijebiti za obradbu shizofrenije. The compounds according to the invention can be used alone or in combination with other active substances for the prophylaxis and treatment of acute and/or chronic pain (for classification, see "Classification of Chronic Pain, Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms", 2nd ed. , Meskey und Begduk, Hrsg.; IASP-Press, Seattle, 1994), especially for the treatment of pain caused by cancer and chronic neuropathic pain, such as diabetic neuropathy, postherpetic neuralgia, peripheral nerve damage, central pain (for example, as a result of cerebral ischemia) and trigeminal neuralgia, and in other chronic pains such as, for example, lumbago, low back pain and other rheumatic pains. In addition, these active substances are also suitable for the therapy of primary acute pain of any origin and the resulting pain conditions, such as the therapy of once acute pain conditions that have become chronic. The compounds according to the invention can be used alone or in combination with other active substances for the treatment of schizophrenia.

In-vitro djelovanje spojeva prema izumu može se pokazati sljedećim pokusima: The in-vitro action of the compounds according to the invention can be demonstrated by the following experiments:

1. Utvrđivanje afiniteta ispitivanih tvari prema α7-nAChR inhibicijom vezivanja [3H]metillikakonitina na moždane membrane štakora 1. Determining the affinity of the tested substances towards α7-nAChR by inhibiting the binding of [3H]methyllycaconitine to rat brain membranes

Ispitivanje vezivanja [3H]metillikakonitina modifikacija je metode koju su opisali Davies et al. u Neuropharmacol. 1999. 38, 679-690. The [3H]methyllycaconitine binding assay is a modification of the method described by Davies et al. in Neuropharmacol. 1999. 38, 679-690.

Moždano tkivo štakora (hipokampusa ili ukupnog mozga) homogenizira se u homogenizacijskom puferu (10 % wN’, 0.32 M sukroza, 1 mM EDTA, 0.1 mM fenilmetilsulfonilfluorid (PMSF), 0.01 % (w/v) NaN3, pH 7.4, 4°C) u staklenom homogenizatoru pri 600 okr/min. Homogenizat se centrifugira (1000 x g, 4°C, 10 min), te se ostatak ukloni. Peleta se ponovno suspendira (20 % w/v), te se suspenzija centrifugira (1000 x g, 4°C, 10 min). Oba ostatka se spoje i centrifugiraju (15000 x g, 4°C, 30 min). Tako dobivena peleta označi se kao P2-frakcija. Rat brain tissue (hippocampus or whole brain) is homogenized in homogenization buffer (10 % wN', 0.32 M sucrose, 1 mM EDTA, 0.1 mM phenylmethylsulfonyl fluoride (PMSF), 0.01 % (w/v) NaN3, pH 7.4, 4°C ) in a glass homogenizer at 600 rpm. The homogenate is centrifuged (1000 x g, 4°C, 10 min), and the residue is removed. The pellet is resuspended (20% w/v), and the suspension is centrifuged (1000 x g, 4°C, 10 min). Both residues are combined and centrifuged (15000 x g, 4°C, 30 min). The thus obtained pellet is designated as P2-fraction.

P2-peleta suspendira se dvaput u veznom puferu (50 mM tris-HCI, 1 mM MgCl2, 120 mM NaCI, 5 mM KCl, 2 mM CaCl2, pH 7.4), te se suspenzija centrifugira (15000 xg, 4°C, 30 min). The P2-pellet is suspended twice in binding buffer (50 mM Tris-HCl, 1 mM MgCl2, 120 mM NaCl, 5 mM KCl, 2 mM CaCl2, pH 7.4), and the suspension is centrifuged (15000 xg, 4°C, 30 min ).

Ostatak se resuspendira u veznom puferu i inkubira u volumenu od 250 μl (količina membranskih proteina 0.1-0.5 mg) u prisutnosti 1-5 nM [3H]-metillikakonitina 0.1 % (w/v) BSA (bovini serumalbumin) i različitih koncentracija ispitivane tvari kroz 2.5 h pri 21°C. Odmah potom inkubira se u prisutnosti 1 μM α-bungarotoksina ili 100 μM nikotina ili 10 μM MLA (metillikakonitin). The residue is resuspended in binding buffer and incubated in a volume of 250 μl (amount of membrane proteins 0.1-0.5 mg) in the presence of 1-5 nM [3H]-methyllycaconitine 0.1% (w/v) BSA (bovine serum albumin) and different concentrations of the test substance for 2.5 h at 21°C. Immediately afterwards, it is incubated in the presence of 1 μM α-bungarotoxin or 100 μM nicotine or 10 μM MLA (methyllycaconitine).

Inkubacija završava dodavanjem 4 ml PBS (20 mM Na2HPO4, 5 mM KH2PO4, 150 mM NaCl, pH 7.4, 4°C) i filtracijom preko filtara od staklenih vlakana tipa A/E (Gelman Sciences) koji su prethodno umetnuti u 0.3 % (v/v) polietilenimin (PEI) na 3 h. Filtri se dvaput isperu sa 4 ml PBS (4°C), a vezana radioaktivnost odredi se scintilacijskim mjerenjem. Svi testovi provedeni su kao trostruko određivanje. Konstanta disocijacije Ki ispitivane tvari određuje se jednadžbom Ki=IC50/(1 + L/KD) iz IC50-vrijednosti spojeva (koncentracija ispitivane tvari pri kojoj se istisne 50 % liganada vezanih na receptor), disocijacijske konstante Kd i koncentracije L [3H]metillikakonitina. Incubation is terminated by addition of 4 ml of PBS (20 mM Na2HPO4, 5 mM KH2PO4, 150 mM NaCl, pH 7.4, 4°C) and filtration through glass fiber filters type A/E (Gelman Sciences) pre-soaked in 0.3% (v /v) polyethyleneimine (PEI) for 3 h. The filters are washed twice with 4 ml of PBS (4°C), and the bound radioactivity is determined by scintillation measurement. All tests were performed in triplicate. The dissociation constant Ki of the test substance is determined by the equation Ki=IC50/(1 + L/KD) from the IC50 value of the compounds (the concentration of the test substance at which 50% of the ligands bound to the receptor are displaced), the dissociation constant Kd and the concentration of L [3H]methyllycaconitine .

Umjesto [3H]-metillikakonitina mogu se upotrijebiti i drugi α7-nAChR selektivni radioligandi kao što je primjerice [125I]-α-bungarotoksin ili neselektivni nAChR radioligandi zajedno s inhibitorima drugih nAChR. Instead of [3H]-methyllycaconitine, other α7-nAChR selective radioligands can be used, such as [125I]-α-bungarotoxin or non-selective nAChR radioligands together with inhibitors of other nAChRs.

Reprezentativni in-vitro radni podatci za spojeve prema izumu prikazani su u tablici A: Representative in vitro performance data for the compounds of the invention are shown in Table A:

Tablica A Table A

[image] [image]

Prikladnost spojeva prema izumu za obradbu kognitivnih smetnja može se pokazati na sljedećim životinjskim modelima: The suitability of the compounds according to the invention for the treatment of cognitive disorders can be demonstrated in the following animal models:

2. Ispitivanje prepoznavanja objekta 2. Examination of object recognition

Ispitivanje prepoznavanja objekta je ispitivanje pamćenja. Njime se ispituje sposobnost štakora (i miševa) za razlikovanje poznatih od nepoznatih objekata. The object recognition test is a memory test. It tests the ability of rats (and mice) to distinguish known from unknown objects.

Ispitivanje je opisano u Blokland et al., NeuroReport 1998, 9, 4205-4208; A. Ennaceur et al., Behav. Brain Res. 1988. 31, 47-59; A. Ennaceur et al., Psychopharmacology 1992, 109, 321-330; te Prickaerts et al., Eur. 3. Pharmacol. 1997, 337, 125-136. The test is described in Blokland et al., NeuroReport 1998, 9, 4205-4208; A. Ennaceur et al., Behav. Brain Res. 1988. 31, 47-59; A. Ennaceur et al., Psychopharmacology 1992, 109, 321-330; and Prickaerts et al., Eur. 3. Pharmacol. 1997, 337, 125-136.

U prvom prolazu se štakora, u inače praznom prostoru za promatranje, suoči sa dva identična objekta. Štakor će oba objekta detaljno ispitati, odnosno onjušiti i dotaknuti. U drugom prolazu, nakon razdoblja čekanja od 24 sata, štakora se ponovno postavi u prostor za promatranje. Sad se jedan poznati objekt postavi uz jedan novi, nepoznati. Kad štakor ponovno prepozna poznati objekt, on će prije svega ispitati nepoznati objekt. Nakon 24 sata štakor u pravilu već zaboravi koji objekt je ispitao već u prvom prolazu, te stoga oba objekta ispituje jednako. Davanje tvari koja djeluje na poboljšanje učenja i pamćenja može dovesti do toga da štakor ponovno prepozna objekt koji je vidio već 24 sata ranije u prvom prolazu. On će tada novi nepoznati objekt ispitati detaljnije nego već poznati. Ova sposobnost pamćenja izražava se diskriminacijskim indeksom. Diskriminacijski indeks nula znači da je štakor oba objekta, stari i novi, ispitivao jednako dugo, odnosno da nije prepoznao stari objekt i da je na oba reagirao kao da su novi. Diskriminacijski indeks veći od nule znači da je štakor novi objekt proučavao dulje nego stari, odnosno da je štakor ponovno prepoznao stari objekt. In the first pass, the rat, in an otherwise empty viewing area, is confronted with two identical objects. The rat will examine both objects in detail, i.e. smell and touch them. In the second passage, after a waiting period of 24 hours, the rat is again placed in the observation area. Now a known object is placed next to a new, unknown one. When a rat recognizes a familiar object again, it will first examine the unknown object. After 24 hours, the rat usually forgets which object it examined in the first pass, and therefore examines both objects equally. Administration of a substance that improves learning and memory can cause a rat to re-recognize an object that it saw 24 hours earlier in the first pass. He will then examine the new unknown object in more detail than the already known one. This ability to remember is expressed by the discrimination index. A discrimination index of zero means that the rat examined both objects, old and new, for the same amount of time, that is, it did not recognize the old object and reacted to both as if they were new. A discrimination index greater than zero means that the rat studied the new object longer than the old one, that is, that the rat recognized the old object again.

3. Ispitivanje socijalnog prepoznavanja 3. Examination of social recognition

Ispitivanje socijalnog prepoznavanja je ispitivanje djelovanja ispitivanih tvari na poboljšanje sposobnosti učenja ili pamćenja. The social recognition test is a test of the effect of test substances on improving the ability to learn or remember.

Odrasle štakore, koje se držalo u grupama, stavi se 30 minuta prije početka ispitivanja svakog pojedinačno u ispitne kaveze. Četiri minute prije početka ispitivanja ispitivana životinja donese se u kutiju za promatranje. Nakon tog razdoblja prilagodbe, mlada životinja dovede se ispitivanoj, te se mjeri vrijeme od dvije minute tijekom kojega odrasla životinja proučava mladu (Trial 1). Odrede se svi jasni načini ponašanja usmjereni prema mladoj životinji, tj. ano-genitalno proučavanje, tjeranje kao što je njega krzna, pri kojima je stara životinja udaljena najviše 1 cm od mlade. Nakon toga se mlada životinja izvadi, a odrasla ostavi u svom ispitnom kavezu (kod zadržavanja od 24 sata životinja se vrati natrag u kavez u kojem živi). Prije ili nakon prvog ispitivanja odrasla životinja se obradi ispitivanom tvari. Tek nakon vremenske točke obradbe može se ispitivanom tvari utjecati na učenje ili gomilanje informacija o mladoj životinji. Nakon određenog vremenskog razmaka (zadržavanje) ispitivanje se ponovi (Trial 2). Što je veća razlika između vremena proučavanja u Trial 1 i Trial 2, to se bolje odrasla životinja sjeća mlade. Adult rats, which were kept in groups, were placed 30 minutes before the start of the test, each individually in test cages. Four minutes before the start of the test, the test animal is brought to the observation box. After this period of adaptation, the young animal is brought to the examinee, and the time of two minutes during which the adult animal studies the young is measured (Trial 1). All clear behavior directed towards the young animal, i.e. ano-genital study, chasing such as grooming, where the old animal is no more than 1 cm away from the young, is determined. After that, the young animal is removed, and the adult is left in its test cage (in the case of a 24-hour stay, the animal is returned to the cage in which it lives). Before or after the first test, the adult animal is treated with the test substance. Only after the processing time point can the test substance affect the learning or accumulation of information about the young animal. After a certain time interval (detention), the test is repeated (Trial 2). The greater the difference between study times in Trial 1 and Trial 2, the better the adult animal remembers the young.

Spojevi prema izumu prikladni su za uporabu kao lijekovi za ljude i za životinje. The compounds of the invention are suitable for use as human and animal medicaments.

Sadašnjem izumu pripadaju i farmaceutski pripravci koji osim inertnih, neotrovnih, farmaceutski prihvatljivih pomoćnih i prijenosnih tvari sadrže jedan ili više spojeva prema izumu, ili koji se sastoje od jednog ili više spojeva prema izumu, kao i postupci za pripravu tih pripravaka. The present invention also includes pharmaceutical preparations which, in addition to inert, non-toxic, pharmaceutically acceptable excipients and carriers, contain one or more compounds according to the invention, or which consist of one or more compounds according to the invention, as well as methods for the preparation of these preparations.

Spojevi prema izumu trebaju u tim pripravama biti sadržani u koncentraciji od 0,1 do 99,5 masenih %, ponajprije od 0,5 do 95 masenih % u odnosu na ukupnu smjesu. The compounds according to the invention should be contained in these preparations in a concentration of 0.1 to 99.5% by mass, preferably from 0.5 to 95% by mass in relation to the total mixture.

Osim spojeva prema izumu farmaceutski pripravci mogu sadržavati i druge farmaceutske djelotvorne tvari. In addition to the compounds according to the invention, pharmaceutical preparations may also contain other pharmaceutical active substances.

Gore navedeni farmaceutski pripravci mogu se pripraviti na uobičajen način prema poznatim metodama. The above-mentioned pharmaceutical preparations can be prepared in the usual way according to known methods.

Nove djelotvorne tvari mogu se na poznate načine prenijeti u uobičajene formulacije, kao što su tablete, dražeje, pilule, granulati, aerosoli, sirupi, emuzije, suspenzije i otopine, uz uporabu inertnih, neotrovnih, farmaceutski prihvatljivih prijenosih tvari ili otapala. Pri tome bi se terapeutski djelotvoran spoj uvijek trebao nalaziti u koncentraciji od oko 0,5 do 90 masenih % formulacije, odnosno u količinama koje su dovoljne da bi se postiglo navedeno područje djelovanja doze. New active substances can be transferred in known ways into common formulations, such as tablets, dragees, pills, granulates, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically acceptable transfer substances or solvents. In doing so, the therapeutically effective compound should always be present in a concentration of about 0.5 to 90% by mass of the formulation, i.e. in amounts that are sufficient to achieve the stated area of effect of the dose.

Formulacije se pripravljaju primjerice spajanjem djelotvorne tvari s otapalima i/ili prijenosnim tvarima, opcijski uz uporabu emulgatora i/ili raspršivača, pri čemu se, primjerice u slučaju upotrebe vode kao razrjeđivača, opcijski mogu upotrijebiti organska otapala kao pomoćna otapala. Formulations are prepared, for example, by combining the active substance with solvents and/or transportable substances, optionally with the use of emulsifiers and/or dispersants, whereby, for example, in the case of using water as a diluent, organic solvents can optionally be used as auxiliary solvents.

Primjena se može provoditi na uobičajen način, osobito oralno, transdermalno ili parenteralno, ponajprije perlingvalno ili intravenozno. Može se provoditi i inhalacijom na usta ili nos, primjerice pomoću spreja, ili topički preko kože. Administration can be carried out in the usual way, especially orally, transdermally or parenterally, preferably perlingually or intravenously. It can also be administered by inhalation through the mouth or nose, for example using a spray, or topically through the skin.

Općenito se za postizanje djelotvornih rezultata pokazalo dobrim dati količinu od oko 0,001 do 10 mg/kg, kod oralne primjene ponajprije od oko 0,005 do 3 mg/kg tjelesne težine. In general, to achieve effective results, it has been shown to be good to give an amount of about 0.001 to 10 mg/kg, for oral administration preferably from about 0.005 to 3 mg/kg of body weight.

Ipak može opcijski biti neophodno odstupiti od navedenih količina, i to ovisno o tjelesnoj težini, odnosno načinu primjene, o individualnom reagiranju na lijek, odnosno načinu formuliranja i vremenskom trenutku odnosno intervalu nakon kojega slijedi davanje. Tako u nekim slučajevima može biti dovoljno upotrijebiti manje od navedene najmanje količine, dok u drugim slučajevima treba premašiti navedenu gornju granicu. U slučaju primjene većih količina može biti preporučljivo iste podijeliti na više pojedinačnih doza tijekom dana. However, it may optionally be necessary to deviate from the stated quantities, depending on body weight, i.e. the method of administration, individual reaction to the medicine, i.e. the method of formulation, and the moment in time, i.e. the interval after which the administration follows. Thus, in some cases it may be sufficient to use less than the specified minimum amount, while in other cases the specified upper limit should be exceeded. In case of application of larger amounts, it may be advisable to divide them into several individual doses during the day.

Ako nije drugačije navedeno, sve navedene količine odnose se na maseni postotak. Sadržaji otapala, razrjeđivača i navedene koncentracije otopina tekućina/tekućina odnose se na volumen. Izraz "w/v" znači masa/volumen ("weight/volume"). Tako primjerice "10 % w/v" znači da 100 ml otopine ili suspenzije sadrži 10 g tvari. Unless otherwise stated, all amounts given refer to mass percentage. The contents of solvents, thinners and stated concentrations of liquid/liquid solutions refer to volume. The term "w/v" means weight/volume. For example, "10% w/v" means that 100 ml of solution or suspension contains 10 g of the substance.

Kratice: Abbreviations:

DAD detektor s diodnom matricom DAD detector with diode matrix

DBU l,5-diazabiciklo[4.3.0]non-5-en DBU 1,5-diazabicyclo[4.3.0]non-5-ene

DCI direktna kemijska ionizacija (kod MS) DCI direct chemical ionization (at MS)

DMAP 4-N,N-dimetilaminopiridin DMAP 4-N,N-dimethylaminopyridine

DMF N,N-dimetilformamid DMF N,N-dimethylformamide

DMSO dimetilsulfoksid DMSO dimethylsulfoxide

teor. teorijski (kod iskorištenja) theor. theoretical (when used)

EDC N’-(3-dimetilaminopropil)-N-etilkarbodiimid x HCl EDC N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide x HCl

ekv. ekvivalent(i) eq. equivalent(s)

ESI elektrosprejna ionizacija (kod MS) ESI electrospray ionization (at MS)

HATU 0-(7-azabenzotriazol-1-il)-N’,N’,N’,N’-tetrametiluronijev heksafluorofosfat HATU 0-(7-azabenzotriazol-1-yl)-N',N',N',N'-tetramethyluronium hexafluorophosphate

HOBt 1-hidroksi-1H-benzotriazol x H2O HOBt 1-hydroxy-1H-benzotriazole x H2O

HPLC visokodjelotvorna tekuća kromatografija HPLC high-performance liquid chromatography

konc. koncentriran conc. concentrated

LC-MS tekućinskaa kromatografija s masenom spektroskopijom LC-MS liquid chromatography with mass spectroscopy

MS masena spektroskopija MS mass spectroscopy

NMR nuklearna magnetska rezonancija NMR nuclear magnetic resonance

PBS «phosphate buffered saline» (fosfatom puferirana solna otopina) PBS «phosphate buffered saline» (phosphate buffered saline solution)

PdCl2(dppf) bis-(difenilfosfanferocenil)-paladijev(II) klorid PdCl2(dppf) bis-(diphenylphosphaneferrocenyl)-palladium(II) chloride

PdCl2(PPh3)2 diklor-bis-(trifenilfosfin)-paladij PdCl2(PPh3)2 dichloro-bis-(triphenylphosphine)-palladium

Pd(PPh3)4 tetrakis-(trifenilfosfin)-paladij(0) Pd(PPh3)4 tetrakis-(triphenylphosphine)-palladium(0)

Ph fenil Ph phenyl

RT sobna temperatura RT room temperature

Rt vrijeme zadržavanja (kod HPLC) Rt retention time (for HPLC)

TBTU 0-(benzotriazol-1-il)-N’,N’,N’,N’-tetrametiluronijev tetrafluoroborat TBTU 0-(benzotriazol-1-yl)-N',N',N',N'-tetramethyluronium tetrafluoroborate

THF tetrahidrofuran THF tetrahydrofuran

TRIS tris-(hidroksimetil)aminometan TRIS tris-(hydroxymethyl)aminomethane

Metode HPLC i LC-MS: HPLC and LC-MS methods:

Metoda 1 (HPLC): Method 1 (HPLC):

Instrument: HP1100 s DAD-detekcijom; kolona: Kromasil RP-18, 60 mm x 2 mm, 3.5 μm; eluens: A = 5 mL HCIO4/L H2O, eluens B = acetonitril; gradijent: 0 min 2 % B, 0.5 min 2 % B, 4.5 min 90 % B, 6.5 min 90 % B; protok 0.75 mL/min; temperatura: 30°C; detekcija: UV 210 nm. Instrument: HP1100 with DAD-detection; column: Kromasil RP-18, 60 mm x 2 mm, 3.5 μm; eluent: A = 5 mL HCIO4/L H2O, eluent B = acetonitrile; gradient: 0 min 2 % B, 0.5 min 2 % B, 4.5 min 90 % B, 6.5 min 90 % B; flow rate 0.75 mL/min; temperature: 30°C; detection: UV 210 nm.

Metoda 2 (LC-MS): Method 2 (LC-MS):

Tip MS: Micromass ZQ; tip HPLC: Waters Alliance 2790; kolona: Symmetry C 18, 50 mm x 2.1 mm, 3.5 μm; eluens B: acetonitril + 0.05 % mravlje kiseline, eluens A: voda + 0.05 % mravlje kiseline; gradijent: 0 min 5 % B → 4.5 min 90 % B → 5.5 min 90 % B; peć: 50°C; protok: 1.0 mL/min; UV-detekcija: 210 nm. Type MS: Micromass ZQ; HPLC type: Waters Alliance 2790; column: Symmetry C 18, 50 mm x 2.1 mm, 3.5 μm; eluent B: acetonitrile + 0.05 % formic acid, eluent A: water + 0.05 % formic acid; gradient: 0 min 5 % B → 4.5 min 90 % B → 5.5 min 90 % B; oven: 50°C; flow rate: 1.0 mL/min; UV detection: 210 nm.

Metoda 3 (LC-MS): Method 3 (LC-MS):

Instrument: Micromass Platform LCZ, HP1100; kolona: Symmetry C18, 50 mm x 2.1 mm, 3.5 μm; eluens A: voda + 0.05 % mravlje kiseline, eluens B: acetonitril + 0.05 % mravlje kiseline; gradijent: 0 min 90 % A → 4.0 min 10 % A → 6.0 min 10 % A; peć: 40°C; protok: 0.5 mL/min; UV-detekcija: 208-400 nm. Instrument: Micromass Platform LCZ, HP1100; column: Symmetry C18, 50 mm x 2.1 mm, 3.5 μm; eluent A: water + 0.05 % formic acid, eluent B: acetonitrile + 0.05 % formic acid; gradient: 0 min 90 % A → 4.0 min 10 % A → 6.0 min 10 % A; oven: 40°C; flow rate: 0.5 mL/min; UV-detection: 208-400 nm.

Metoda 4 (LC-MS): Method 4 (LC-MS):

Tip MS: Micromass ZQ; tip HPLC: Waters Alliance 2790; kolona: Grom-Sil 120 ODS-4 HE, 50 mm x 2 mm, 3.0 μm; eluens B: acetonitril + 0.05 % mravlje kiseline, eluens A: voda + 0.05 % mravlje kiseline; gradijent: 0.0 min 5 % B → 2.0 min 40 % B → 4.5 min 90 % B →5.5 min 90 % B; peć: 45°C; protok: 0.0 min 0.75 mL/min → 4.5 min 0.75 mL/min → 5.5 min 1.25 mL/min; UV-detekcija: 210 nm. Type MS: Micromass ZQ; HPLC type: Waters Alliance 2790; column: Grom-Sil 120 ODS-4 HE, 50 mm x 2 mm, 3.0 μm; eluent B: acetonitrile + 0.05 % formic acid, eluent A: water + 0.05 % formic acid; gradient: 0.0 min 5 % B → 2.0 min 40 % B → 4.5 min 90 % B →5.5 min 90 % B; oven: 45°C; flow: 0.0 min 0.75 mL/min → 4.5 min 0.75 mL/min → 5.5 min 1.25 mL/min; UV detection: 210 nm.

Metoda 5 (LC-MS): Method 5 (LC-MS):

Instrument MS: Micromass TOF (LCT); instrument HPLC: prekapčanje između 2 kolone, Waters Alliance 2690; kolona: YMC-ODS-AQ, 50 mm x 4.6 mm, 3.0 μm; eluens A: voda + 0.1 % mravlje kiseline, eluens B: acetonitril + 0.1 % mravlje kiseline; gradijent: 0.0 min 100 % A → 0.2 min 95 % A → 1.8 min 25 % A → 1.9 min 10 % A → 3.2 min 10 % A; peć: 40°C; protok: 3.0 mL/min; UV-detekcija: 210 nm. Instrument MS: Micromass TOF (LCT); HPLC instrument: switching between 2 columns, Waters Alliance 2690; column: YMC-ODS-AQ, 50 mm x 4.6 mm, 3.0 μm; eluent A: water + 0.1 % formic acid, eluent B: acetonitrile + 0.1 % formic acid; gradient: 0.0 min 100 % A → 0.2 min 95 % A → 1.8 min 25 % A → 1.9 min 10 % A → 3.2 min 10 % A; oven: 40°C; flow rate: 3.0 mL/min; UV detection: 210 nm.

Metoda 6 (LC-MS): Method 6 (LC-MS):

«Flow-injection», instrument: Micromass Platform LCZ + Quattro LCZ; eluens A: voda + 0.05 % mravlje kiseline, eluens B: acetonitril + 0.05 % mravlje kiseline; gradijent: 0.0 min 30 % A → 1.0 min 30 % A; protok: 0.2-0.3 mL/min; HPLC: instrument HP1100; UV-detekcija: DAD. «Flow-injection», instrument: Micromass Platform LCZ + Quattro LCZ; eluent A: water + 0.05 % formic acid, eluent B: acetonitrile + 0.05 % formic acid; gradient: 0.0 min 30 % A → 1.0 min 30 % A; flow rate: 0.2-0.3 mL/min; HPLC: instrument HP1100; UV detection: DAD.

Metoda 7 (HPLC): Method 7 (HPLC):

Instrument: HP1100 s DAD-detekcijom; kolona: Kromasil RP-18, 60 mm x 2 mm, 3.5 nm; eluens A: 5 mL HCIO4/L H2O, eluens B: acetonitril; gradijent: 0 min 2 % B → 0.5 min 2 % B → 4.5 min 90 % B →> 9 min 90 % B; protok 0.75 mL/min; temperatura: 30°C; UV-detekcija: 210 nm. Instrument: HP1100 with DAD-detection; column: Kromasil RP-18, 60 mm x 2 mm, 3.5 nm; eluent A: 5 mL HCIO4/L H2O, eluent B: acetonitrile; gradient: 0 min 2 % B → 0.5 min 2 % B → 4.5 min 90 % B →> 9 min 90 % B; flow rate 0.75 mL/min; temperature: 30°C; UV detection: 210 nm.

Početni spojevi: Initial connections:

Općeniti radni propis A General work regulation A

Sinteza metilnoa estera 1-benzotiofen-2-karboksilne kiseline: Synthesis of 1-benzothiophene-2-carboxylic acid methyl ester:

[image] [image]

Stavi se 1.5 ekvivalenata natrijevog hidrida (60 %-tni u parafinskom ulju) pod argonskom atmosferom u apsolutni DMSO (0.60-1.26 M suspenzija). Pri sobnoj temperaturi reakcijskoj se smjesi polako dokapa 1.1 ekvivalent metilnog estera merkaptooctene kiseline, te se ostavi miješati do završetka razvijanja vodika (cea. 15 min). U apsolutnom DMSO otopi se (1.60-3.36 M otopina) 1.0 ekvivalent odgovarajućeg benzaldehida, te se doda rekacijskoj smjesi pri sobnoj temperaturi. Reakcijska smjesa miješa se do završetka reakcije (cea. 5-10 min), te se odmah potom ulije u ledenu vodu. Nastali talog se sakupi, preko noći osuši u vakuumu pri 40°C, te se sirov upotrebljava dalje. Place 1.5 equivalents of sodium hydride (60% in paraffin oil) under an argon atmosphere in absolute DMSO (0.60-1.26 M suspension). At room temperature, 1.1 equivalent of mercaptoacetic acid methyl ester is slowly added to the reaction mixture, and it is left to stir until the evolution of hydrogen is complete (about 15 min). 1.0 equivalent of the corresponding benzaldehyde is dissolved in absolute DMSO (1.60-3.36 M solution) and added to the reaction mixture at room temperature. The reaction mixture is stirred until the end of the reaction (cea. 5-10 min), and then immediately poured into ice water. The resulting precipitate is collected, dried overnight in a vacuum at 40°C, and used raw.

Općeniti radni propis B General work regulation B

Sinteza 1-benzotiofen-2-karboksilne kiseline: Synthesis of 1-benzothiophene-2-carboxylic acid:

[image] [image]

Odgovarajući metilni ester l-benzotiofen-2-karboksilne kiseline pomiješa se sa smjesom koja u jednakim dijelovima sadrži THF i 2 N vodenu otopinu kalijevog hidroksida (0.28-0.47 M otopina). Reakcijska smjesa ostavi se miješati preko noći pri sobnoj temperaturi. THF se ukloni u vakuumu, a vodena reakcijska smjesa se zakiseli koncentriranom solnom kiselinom. Dobiveni talog se sakupi i osuši u vakuumu pri 40°C. The corresponding methyl ester of 1-benzothiophene-2-carboxylic acid is mixed with a mixture containing equal parts of THF and 2 N aqueous potassium hydroxide solution (0.28-0.47 M solution). The reaction mixture is allowed to stir overnight at room temperature. The THF was removed in vacuo and the aqueous reaction mixture was acidified with concentrated hydrochloric acid. The precipitate obtained is collected and dried in a vacuum at 40°C.

Općeniti radni propis General work regulation

Amidno vezanie 3-kinuklidinamina i 2-benzotiofen-, odnosno 2-benzofurankarboksilne kiseline: Amide bond of 3-quinuclidinamine and 2-benzothiophene- or 2-benzofurancarboxylic acid:

1.0 ekv. odgovarajućeg enantiomera 3-kinuklidinaminskog klorovodika pomiješa se s 1 ekv. karboksilne kiseline i 1.2 ekv. HATU pri 0°C u DMF. Nakon dodavanja 1.2 ekv. N,N-diizopropiletilamina smjesa se miješa pri RT. Nakon 30 min doda se još 2.4 ekv. N,N-diizopropiletilamina i ponovno miješa preko noći pri RT. 1.0 eq. of the corresponding enantiomer of 3-quinuclidinamine hydrochloride is mixed with 1 eq. carboxylic acid and 1.2 equiv. HATU at 0°C in DMF. After adding 1.2 eq. The N,N-diisopropylethylamine mixture is stirred at RT. After 30 min, add another 2.4 equiv. of N,N-diisopropylethylamine and stirred again overnight at RT.

Primjer 1A Example 1A

6-brom-1-benzofuran-2-karboksilna kiselina 6-Bromo-1-benzofuran-2-carboxylic acid

[image] [image]

Pomiješa se 8.0 g (39.8 mmol) 4-brom-2-hidroksibenzaldehida i 1.47 g (3.98 mmol) tetra-n-butilamonijevog jodida sa 22 g (159.19 mmola) bezvodnog kalijevog karbonata. Doda se 9.07 g (83.57 mmola) metilnog estera kloroctene kiseline. Reakcijska smjesa grije se kroz 4 h na 130°C, te se odmah potom ohladi na 0°C u ledenoj kupelji. Doda se 100 mL THF i otopina od 13.4 g (238.8 mmola) kalijevog hidroksida u 50 mL vode, te se potom smjesa miješa preko noći pri RT. THF se ukloni pod sniženim tlakom. Zaostala vodena faza razrijedi se vodom i zakiseli koncentriranom solnom kiselinom. Dobiveni produkt se odfiltrira i osuši u visokom vakuumu. Do visoke čistoće pročisti se pomoću Kieselgel 60 (Merck, Darmstadt; eluens: toluol, toluol-octena kiselina 50:1, toluol-octena kiselina-metilni ester octene kiseline 35:1:5). Otapalo se ukloni pod sniženim tlakom. Napokon se posljednji ostatci otapala uklone u visokom vakuumu. Izolirano je 3.8 g (40 % od teor.) naslovnog spoja. 8.0 g (39.8 mmol) of 4-bromo-2-hydroxybenzaldehyde and 1.47 g (3.98 mmol) of tetra-n-butylammonium iodide are mixed with 22 g (159.19 mmol) of anhydrous potassium carbonate. 9.07 g (83.57 mmol) of chloroacetic acid methyl ester is added. The reaction mixture is heated to 130°C for 4 h, and immediately cooled to 0°C in an ice bath. 100 mL of THF and a solution of 13.4 g (238.8 mmol) of potassium hydroxide in 50 mL of water are added, and then the mixture is stirred overnight at RT. The THF was removed under reduced pressure. The remaining aqueous phase is diluted with water and acidified with concentrated hydrochloric acid. The obtained product is filtered off and dried in a high vacuum. It is purified to high purity using Kieselgel 60 (Merck, Darmstadt; eluent: toluene, toluene-acetic acid 50:1, toluene-acetic acid-acetic acid methyl ester 35:1:5). The solvent was removed under reduced pressure. Finally, the last remnants of the solvent are removed under high vacuum. 3.8 g (40% of theory) of the title compound was isolated.

1H-NMR (400 MHz, metanol-d4): δ = 7.91 (m, 1H), 7.61-7.51 (m,3H). 1H-NMR (400 MHz, methanol-d4): δ = 7.91 (m, 1H), 7.61-7.51 (m, 3H).

HPLC (metoda 1): Rt = 4.1 min. HPLC (method 1): Rt = 4.1 min.

MS (ESIpos): m/z = 258 (M+NH4)+. MS (ESIpos): m/z = 258 (M+NH4)+.

Primjer 2A Example 2A

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-6-brom-1-benzofuran-2-karboksamid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1-benzofuran-2-carboxamide

[image] [image]

Pomiješa se 3.8 g (15.77 mmola) 6-brombenzofuran-2-karboksilne kiseline (primjer 1A), 3.14 g (15.77 mmola) (R)-3-aminokinuklidin-dihidroklorida, 7.19 g (18.92 mmol) HATU, 7.34 g (56.76 mmola) N,N-diizopropiletilamina i 50 mL DMF, prema općenitom radnom propisu C. Sirovi produkt preuzme se u metanol, te se zajedno s kiselim ionskim izmjenjivačem (Dowex® WX2-200) potresa 20-ak minuta. Opterećeni ionski izmjenjivač ispere se metanolom, potom diklormetanom, te ponovno metanolom. Produkt se eluira metanol-trietilaminom 90:10. Otapalo se ukloni pod smanjenim tlakom na rotacijskom isparivaču. Napokon se posljednji ostaci otapala uklone u visokom vakuumu. Izolirano je 5.14 g (85 % od teor.). 3.8 g (15.77 mmol) of 6-bromobenzofuran-2-carboxylic acid (Example 1A), 3.14 g (15.77 mmol) of (R)-3-aminoquinuclidine dihydrochloride, 7.19 g (18.92 mmol) of HATU, 7.34 g (56.76 mmol) of ) of N,N-diisopropylethylamine and 50 mL of DMF, according to general procedure C. The crude product is taken up in methanol and shaken together with an acidic ion exchanger (Dowex® WX2-200) for about 20 minutes. The loaded ion exchanger is washed with methanol, then with dichloromethane, and again with methanol. The product is eluted with methanol-triethylamine 90:10. The solvent is removed under reduced pressure on a rotary evaporator. Finally, the last remnants of the solvent are removed under high vacuum. 5.14 g (85% of theory) was isolated.

Za analizu je mala količina prevedena u hidroklorid pomoću 4 N klorovodika u dioksanu. For analysis, a small amount was converted to the hydrochloride using 4 N hydrogen chloride in dioxane.

1H-NMR (200 MHz, DMSO-d6): δ = 10.55 (br. s, 1H), 9.22 (d, 1H), 8.05 (s, 1H), 7.75-7.55 (m, 3H), 4.43-4.29 (m, 1H), 3.70-3.55 (m, 1H), 3.45-3.10 (m, 5H), 2.25-2.00 (m, 2H), 1.98-1.82 (m, 2H), 1.80-1.60 (m, 1H). 1H-NMR (200 MHz, DMSO-d6): δ = 10.55 (no. s, 1H), 9.22 (d, 1H), 8.05 (s, 1H), 7.75-7.55 (m, 3H), 4.43-4.29 ( m, 1H), 3.70-3.55 (m, 1H), 3.45-3.10 (m, 5H), 2.25-2.00 (m, 2H), 1.98-1.82 (m, 2H), 1.80-1.60 (m, 1H).

HPLC (metoda 1): Rt = 3.9 min. HPLC (method 1): Rt = 3.9 min.

MS (ESIpos): m/z = 349 (M+H)+. MS (ESIpos): m/z = 349 (M+H) + .

LC-MS (metoda 2): Rt = 1.49 min. LC-MS (method 2): Rt = 1.49 min.

MS (ESIpos): m/z = 349 (M+H)+. MS (ESIpos): m/z = 349 (M+H) + .

Primjer 3A Example 3A

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-5-brom-1-benzofuran-2-karboksamid-hidro klorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-bromo-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Pomiješa se 240 mg (0.98 mmola) 5-brombenzofuran-2-karboksilne kiseline, 200 mg (0.98 mmola) (R)-3-aminokinuklidin-dihidro-klorida, 450 mg (1.18 mmola) HATU, 460 mg (3.54 mmola) N,N-diizorpropiletilamina i 2.0 mL DMF prema općenitom radnom propisu C. Reakcijska smjesa pročisti se preparativnom HPLC. Potom se produkt se pretvori sa suviškom 1 N klorovodične kiseline. Otapalo se ukloni pod sniženim tlakom. Izolirano je 202 mg (53 % od teor.) naslovnog spoja. 240 mg (0.98 mmol) of 5-bromobenzofuran-2-carboxylic acid, 200 mg (0.98 mmol) of (R)-3-aminoquinuclidine dihydrochloride, 450 mg (1.18 mmol) of HATU, 460 mg (3.54 mmol) of N ,N-diisopropylethylamine and 2.0 mL of DMF according to general procedure C. The reaction mixture is purified by preparative HPLC. Then the product is converted with an excess of 1 N hydrochloric acid. The solvent was removed under reduced pressure. 202 mg (53% of theory) of the title compound was isolated.

1H-NMR (200 MHz, DMSO-d6): δ = 9.38 (br. s, 1H), 8.88 (d, 1H), 7.60 (s, 1H), 7.38-7.20 (m, 2H), 7.09 (dd, 1H), 4.43-4.29 (m, 1H), 3.70-3.55 (m, 1H), 3.45-3.10 (m, 5H), 2.25-2.00 (m, 2H), 1.98-1.82 (m, 2H), 1.80-1.60 (m, 1H). MS (ESIpos): m/z = 349 (M+H)+(slobodna baza). 1H-NMR (200 MHz, DMSO-d6): δ = 9.38 (no. s, 1H), 8.88 (d, 1H), 7.60 (s, 1H), 7.38-7.20 (m, 2H), 7.09 (dd, 1H), 4.43-4.29 (m, 1H), 3.70-3.55 (m, 1H), 3.45-3.10 (m, 5H), 2.25-2.00 (m, 2H), 1.98-1.82 (m, 2H), 1.80- 1.60 (m, 1H). MS (ESIpos): m/z = 349 (M+H)+(free base).

LC-MS (metoda 3): Rt = 2.71 min. LC-MS (method 3): Rt = 2.71 min.

MS (ESIpos): m/z = 349 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 349 (M+H)+ (free base).

Primjer 4A Example 4A

7-brom-5-fluor-1-benzofuran-2-karboksilna kiselina 7-Bromo-5-fluoro-1-benzofuran-2-carboxylic acid

[image] [image]

Stavi se 1.0 g (5.24 mmola) 2-brom-4-fluorfenola u 4.0 mL trifluoroctene kiseline. Unutar 20 min doda se u obrocima 1.47 g (10.47 mmola) heksametilentetramina. Odmah potom se smjesa 28 sat kuha uz refluks. Pri RT se doda 6 mL vode i 3 mL 50 %-tne sumporne kiseline. Nakon 2 h ekstrahira se dvaput s ukupno 60 mL etilnog estera octene kiseline. Spojene organske faze isperu se četiri puta 1 N klorovodičnom kiselinom i jedanput vodom. Osuši se iznad magnezijevog sulfata, te se otapalo ukloni pod sniženim tlakom. Napokon se posljednji ostaci otapala uklone u visokom vakuumu. Sirovi produkt (bez daljnjeg pročišćavanja) i 0.19 g (0.52 mmola) tetra-n-butilamonijevog jodida pomiješa se sa 2.9 g (20.96 mmola) bezvodnog kalijevog karbonata. Doda se 1.19 g (11.0 mmola) metilnog estera kloroctene kiseline. Reakcijska smjesa grije se kroz 4 h na 130°C i odmah potom ohladi do 0°C pomoću ledene kupelji. Doda se 18 mL THF i otopina od 1.76 g (31.44 mmola) kalijevog hidroksida u 18 mL vode. Smjesa se miješa preko noći pri sobnoj temperaturi. Otapalo se ukloni pod sniženim tlakom. Smjesa se razrijedi vodom i zakiseli solnom kiselinom. Dvaput se ekstrahira etilnim esterom octene kiseline. Spojene organske faze osuše se iznad magnezijevog sulfata, te se otapalo ukloni pod sniženim tlakom na rotacijskom isparivaču. Pročisti se nad Kieselgel 60 (Merck, Darmstadt; eluens: toluol-octena kiselina 40:1). Otapalo se ukloni pod sniženim tlakom. Napokon se posljednji ostaci otapala uklone u visokom vakuumu. Izolirano je 257 mg (19 % od teor. tijekom oba stupnja) naslovnog spoja. 1.0 g (5.24 mmol) of 2-bromo-4-fluorophenol was added to 4.0 mL of trifluoroacetic acid. Within 20 min, 1.47 g (10.47 mmol) of hexamethylenetetramine is added in portions. Immediately afterwards, the mixture is refluxed for 28 hours. At RT, 6 mL of water and 3 mL of 50% sulfuric acid are added. After 2 h, it is extracted twice with a total of 60 mL of acetic acid ethyl ester. The combined organic phases are washed four times with 1 N hydrochloric acid and once with water. It is dried over magnesium sulfate, and the solvent is removed under reduced pressure. Finally, the last remnants of the solvent are removed under high vacuum. The crude product (without further purification) and 0.19 g (0.52 mmol) of tetra-n-butylammonium iodide were mixed with 2.9 g (20.96 mmol) of anhydrous potassium carbonate. 1.19 g (11.0 mmol) of chloroacetic acid methyl ester is added. The reaction mixture is heated to 130°C for 4 hours and immediately cooled to 0°C using an ice bath. 18 mL of THF and a solution of 1.76 g (31.44 mmol) of potassium hydroxide in 18 mL of water are added. The mixture is stirred overnight at room temperature. The solvent was removed under reduced pressure. The mixture is diluted with water and acidified with hydrochloric acid. It is extracted twice with ethyl acetate. The combined organic phases are dried over magnesium sulfate, and the solvent is removed under reduced pressure on a rotary evaporator. Purify over Kieselgel 60 (Merck, Darmstadt; eluent: toluene-acetic acid 40:1). The solvent was removed under reduced pressure. Finally, the last remnants of the solvent are removed under high vacuum. 257 mg (19% of theory during both steps) of the title compound was isolated.

1H-NMR (400 MHz, metanol-d4): δ = 7.60 (m, 1H), 7.48-7.35 (m,H). 1H-NMR (400 MHz, methanol-d4): δ = 7.60 (m, 1H), 7.48-7.35 (m,H).

HPLC (metoda 1): Rt = 4.1 min. HPLC (method 1): Rt = 4.1 min.

MS (ESIpos): m/z = 276 (M+NH4)+. MS (ESIpos): m/z = 276 (M+NH4)+.

Primjer 5A Example 5A

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-5-fluor-7-brom-1-benzofuran-2-karboksamid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-fluoro-7-bromo-1-benzofuran-2-carboxamide

[image] [image]

Pomiješa se 143 mg (0.55 mmola) 5-fluor-7-brom-1-benzofuran-2-karboksilne kiseline (primjer 4A), 100 mg (0.50 mmola) (fl)-3-aminokinuklidin-dihidroklorida, 229.14 mg (0.6 mmola) HATU, 234 mg (1.81 mmol) N,N-diizopropiletilamina i 2.0 mL DMF prema općenitom radnom propisu C. DMF se ukloni pod sniženim tlakom, a sirovi produkt se otopi u 1 N natrijeve lužine. Vodena faza ekstrahira se etilnim esterom octene kiseline i ispere zasićenom vodenom otopinom natrijevog klorida. Spojene organske faze osuše se iznad magnezijevog sulfata, a otapalo se odstrani pod sniženim tlakom na rotacijskom isparivaču. Sirovi produkt preuzme se u metanol te se zajedno s kiselim ionskim izmjenjivačem (Dowex® WX2-200) trese 20-ak minuta. Opterećeni ionski izmjenjivač ispere se triput sa po 30 mL metanola, potom vodom, ponovno metanolom, diklormetanom i napokom ponovno metanolom. Produkt se eluira metanol-tretilaminom 95:5. Otapalo se ukloni pod sniženim tlakom na rotacijskom isparivaču. Izolirano je 181 mg (98 % od teor.) naslovnog spoja. 143 mg (0.55 mmol) of 5-fluoro-7-bromo-1-benzofuran-2-carboxylic acid (Example 4A), 100 mg (0.50 mmol) of (fl)-3-aminoquinuclidine dihydrochloride, 229.14 mg (0.6 mmol) ) HATU, 234 mg (1.81 mmol) of N,N-diisopropylethylamine and 2.0 mL of DMF according to general procedure C. The DMF is removed under reduced pressure, and the crude product is dissolved in 1 N sodium hydroxide solution. The aqueous phase is extracted with ethyl acetate and washed with a saturated aqueous solution of sodium chloride. The combined organic phases are dried over magnesium sulfate, and the solvent is removed under reduced pressure on a rotary evaporator. The crude product is taken up in methanol and shaken together with an acidic ion exchanger (Dowex® WX2-200) for about 20 minutes. The loaded ion exchanger is washed three times with 30 mL of methanol, then with water, again with methanol, dichloromethane and finally with methanol again. The product is eluted with methanol-tertylamine 95:5. The solvent is removed under reduced pressure on a rotary evaporator. 181 mg (98% of theory) of the title compound was isolated.

1H-NMR (400 MHz, metanol-d4): δ = 7.59 (d, 1H), 7.53-7.46 (m, 2H), 4.24-4.18 (m, 1H), 3.34-3.29 (m, 1H), 3.07-2.97 (m, 1H), 2.93-2.77 (m, 4H), 2.13-2.05 (m, 1H), 1.98-1.86 (m, 1H), 1.84-1.75 (m, 2H), 1.63-1.53 (m, 1H). 1H-NMR (400 MHz, methanol-d4): δ = 7.59 (d, 1H), 7.53-7.46 (m, 2H), 4.24-4.18 (m, 1H), 3.34-3.29 (m, 1H), 3.07- 2.97 (m, 1H), 2.93-2.77 (m, 4H), 2.13-2.05 (m, 1H), 1.98-1.86 (m, 1H), 1.84-1.75 (m, 2H), 1.63-1.53 (m, 1H) ).

MS (ESIpos): m/z = 367 (M+H)+. MS (ESIpos): m/z = 367 (M+H) + .

LC-MS (metoda 3): Rt = 2.92 min. LC-MS (method 3): Rt = 2.92 min.

MS (ESIpos): m/z = 367 (M+H)+. MS (ESIpos): m/z = 367 (M+H) + .

Primjer 6A Example 6A

metilni ester 7-brom-1-benzotiofen-2-karboksilne kiseline 7-bromo-1-benzothiophene-2-carboxylic acid methyl ester

[image] [image]

Iz 27.8 g (137.1 mmol) 3-brom-2-flourbenzaldehida, 8.2 g (205.7 mmola) natrijevog hidrida (60 %-tni u parafinskom ulju) i 16.0 g (150.9 mmola) metilnog estera merkaptooctene kiseline dobije se 20.57 g smjese naslovnog spoja i odgovarajuće kiseline (cea. 1:1) postupkom prema općenitom radnom propisu A. From 27.8 g (137.1 mmol) of 3-bromo-2-fluorobenzaldehyde, 8.2 g (205.7 mmol) of sodium hydride (60% in paraffin oil) and 16.0 g (150.9 mmol) of methyl ester of mercaptoacetic acid, 20.57 g of the mixture of the title compound is obtained. and the appropriate acid (cea. 1:1) using the procedure according to the general working regulation A.

Primjer 7A Example 7A

7-brom-1-benzotiofen-2-karboksilna kiselina 7-Bromo-1-benzothiophene-2-carboxylic acid

[image] [image]

Iz 10.0 g (36.9 mmola) metilnog estera 7-brom-1-benzotiofen-2-karboksilne kiseline dobije se prema općem propisu za rad A 8.99 g (91.0 % teor.) željenog produkta. From 10.0 g (36.9 mmol) of 7-bromo-1-benzothiophene-2-carboxylic acid methyl ester, 8.99 g (91.0 % of theory) of the desired product is obtained according to the general procedure for work A.

lH-NMR (200 MHz, DMSO-d6): δ = 13.76 (br. s, 1H), 8.28 (s, 1H), 8.07 (d, 1H),7.78 (d, 1H), 7.46 (dd, 1H). 1H-NMR (200 MHz, DMSO-d6): δ = 13.76 (no. s, 1H), 8.28 (s, 1H), 8.07 (d, 1H), 7.78 (d, 1H), 7.46 (dd, 1H) .

HPLC (metoda 1): Rt = 4.4 min. HPLC (method 1): Rt = 4.4 min.

Primjer 8A Example 8A

N-(l-azabiciklo[2.2.2]okt-3-il)-7-brom-1-benzotiofen-2-karboksamid-hidroklorid N-(1-azabicyclo[2.2.2]oct-3-yl)-7-bromo-1-benzothiophene-2-carboxamide hydrochloride

[image] [image]

Pomiješa se 903.8 mg (3.52 mmola) 7-brom-1-benzotiofen-2-karboksilne kiseline (primjer 7A), 700 mg (3.52 mmola) (R)-3-aminokinuklidin-dihiroklorida, 1604.0 mg (4.22 mmola) HATU, 1635.7 mg (12.66 mmola) N,N-diizopropiletilamina i 7.0 mL DMF prema općenitom radnom propisu C. Reakcijska smjesa pročisti se preparativnom HPLC. Produkt se otopi u 1:1 smjesi 4 M klorovodika u dioksanu i 1 N solne kiseline, potom zgusne i osuši u visokom vakuumu. Dobije se 1087 mg (77 % od teor.) naslovnog spoja. 903.8 mg (3.52 mmol) of 7-bromo-1-benzothiophene-2-carboxylic acid (Example 7A), 700 mg (3.52 mmol) of (R)-3-aminoquinuclidine dihydrochloride, 1604.0 mg (4.22 mmol) of HATU, 1635.7 mg (12.66 mmol) of N,N-diisopropylethylamine and 7.0 mL of DMF according to general procedure C. The reaction mixture is purified by preparative HPLC. The product is dissolved in a 1:1 mixture of 4 M hydrogen chloride in dioxane and 1 N hydrochloric acid, then thickened and dried in a high vacuum. 1087 mg (77% of theory) of the title compound are obtained.

1H-NMR (200 MHz, DMSO-d6): δ = 10.01 (br. s, 1H), 9.15 (d, 1H), 8.47 (s, 1H), 8.02 (m, 1H), 7.74 (m, 1H), 7.43 (dd, 1H), 4.34 (m, 1H), 3.80-3.10 (m, 6H), 2.22 (m, 1H), 2.14 (m, 1H), 1.93 (m, 2H), 1.78 (m, 1H). 1H-NMR (200 MHz, DMSO-d6): δ = 10.01 (no. s, 1H), 9.15 (d, 1H), 8.47 (s, 1H), 8.02 (m, 1H), 7.74 (m, 1H) , 7.43 (dd, 1H), 4.34 (m, 1H), 3.80-3.10 (m, 6H), 2.22 (m, 1H), 2.14 (m, 1H), 1.93 (m, 2H), 1.78 (m, 1H ).

HPLC (metoda 1): Rt = 4.1 min. HPLC (method 1): Rt = 4.1 min.

MS (ESIpos): m/z = 365 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 365 (M+H)+ (free base).

Primjer 9A Example 9A

metilni ester 6-brom-1-benzotiofen-2-karboksilne kiseline 6-bromo-1-benzothiophene-2-carboxylic acid methyl ester

[image] [image]

Iz 6.54 g (32.2 mmola) 4-brom-2-fluorbenzaldehida, 1.93 g (48.3 mmola) natrijevog hidrida (60 %-tni u parafinskom ulju) i 3.76 g (35.5 mmola) metilnog estera merkaptooctene kiseline postupkom prema općenitomm radnom propisu A dobije se 4.06 g (46 % od teor.) naslovnog spoja. From 6.54 g (32.2 mmol) of 4-bromo-2-fluorobenzaldehyde, 1.93 g (48.3 mmol) of sodium hydride (60% strength in paraffin oil) and 3.76 g (35.5 mmol) of methyl ester of mercaptoacetic acid by the procedure according to the general work procedure, A is obtained with 4.06 g (46 % of theory) of the title compound.

1H-NMR (200 MHz, DMSO-d6): δ = 8.42 (d, 1H), 8.22 (s, 1H), 7.98 (d, 1H), 7.65 (dd, 1H), 3.90 (s, 3H). 1H-NMR (200 MHz, DMSO-d6): δ = 8.42 (d, 1H), 8.22 (s, 1H), 7.98 (d, 1H), 7.65 (dd, 1H), 3.90 (s, 3H).

HPLC (metoda 1): Rt = 5.3 min. HPLC (method 1): Rt = 5.3 min.

MS (ESIpos): m/z = 270 M+. MS (ESIpos): m/z = 270 M + .

Primjer 10A Example 10A

6-brom-1-benzotiofen-2-karboksilna kiselina 6-Bromo-1-benzothiophene-2-carboxylic acid

[image] [image]

Iz 4.0 g (14.8 mmola) metilnog estera 6-brom-1-benzotiofen-2-karboksilne kiseline (iz primjera 9A) postupkom prema općenitom radnom propisu B dobije se 3.55 g (94 % teor.) željenih produkata. From 4.0 g (14.8 mmol) of methyl ester of 6-bromo-1-benzothiophene-2-carboxylic acid (from Example 9A), 3.55 g (94 % of theory) of the desired products are obtained by the procedure according to general procedure B.

1H-NMR (400 MHz, DMSO-d6): δ = 13.48 (br. s, 1H), 8.38 (s, 1H), 8.22 (s, 1H),7.96 (d, 1H), 7.63 (m, 1H). 1H-NMR (400 MHz, DMSO-d6): δ = 13.48 (no. s, 1H), 8.38 (s, 1H), 8.22 (s, 1H), 7.96 (d, 1H), 7.63 (m, 1H) .

HPLC (metoda 1): Rt = 4.5 min. HPLC (method 1): Rt = 4.5 min.

Primjer 11A Example 11A

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-6-brom-1-benzotiofen-2-karboksamid-hidro klorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1-benzothiophene-2-carboxamide hydrochloride

[image] [image]

Pomiješa se 900.0 mg (3.50 mmola) 4-brom-1-benzotiofen-2-karboksilne kiseline (primjer 10A), 697.0 mg (3.50 mmola) (R)-3-aminokinuklidin-dihidroklorida, 1597.1 mg (4.20 mmola) HATU, 1628.7 mg (12.60 mmola) N,N-diizopropiletilamina i 8.0 mL DMF prema općenitomm radnom propisu C. Reakcijska smjesa pročisti se preparativnom HPLC. Produkt se otopi u smjesi 1:1 4 M klorovodika u dioksanu i 1 N solne kiseline, te se otopina odmah zatim zgusne. Kristalizacijom iz metanol/etanola (1:10) dobije se 594 mg (42 % od teor.) naslovnog spoja u obliku žuto-smeđih kristala. 900.0 mg (3.50 mmol) of 4-bromo-1-benzothiophene-2-carboxylic acid (Example 10A), 697.0 mg (3.50 mmol) of (R)-3-aminoquinuclidine dihydrochloride, 1597.1 mg (4.20 mmol) of HATU, 1628.7 mg (12.60 mmol) of N,N-diisopropylethylamine and 8.0 mL of DMF according to general procedure C. The reaction mixture is purified by preparative HPLC. The product is dissolved in a 1:1 mixture of 4 M hydrogen chloride in dioxane and 1 N hydrochloric acid, and the solution is immediately thickened. Crystallization from methanol/ethanol (1:10) gives 594 mg (42% of theory) of the title compound in the form of yellow-brown crystals.

1HNMR (300 MHz, DMSO-d6): δ = 9.81 (br. s, 1H), 8.76 (m, 1H), 8.33 (s, 1H), 8.22 (s, 1H), 7.91 (d, 1H), 7.59 (dd, 1H), 4.15 (m, 1H), 3.51-2.93 (m, 6H), 2.12-1.92 (m, 2H), 1.79 (m, 2H), 1.58 (m, 1H). 1HNMR (300 MHz, DMSO-d6): δ = 9.81 (no. s, 1H), 8.76 (m, 1H), 8.33 (s, 1H), 8.22 (s, 1H), 7.91 (d, 1H), 7.59 (dd, 1H), 4.15 (m, 1H), 3.51-2.93 (m, 6H), 2.12-1.92 (m, 2H), 1.79 (m, 2H), 1.58 (m, 1H).

HPLC (metoda 1): Rt = 4.1 min. HPLC (method 1): Rt = 4.1 min.

MS (ESIpos): m/z = 364 M+ (slobodna baza). MS (ESIpos): m/z = 364 M+ (free base).

Primjer 12A Example 12A

metilni ester 5-brom-1-benzotiofen-2-karboksilne kiseline 5-bromo-1-benzothiophene-2-carboxylic acid methyl ester

[image] [image]

Iz 2.99 g (14.7 mmol) 5-brom-2-fluorbenzaldehida, 0.88 g (22.1 mmol) natrijevog hidrida (60 %-tni) i 1.72 g (16.2 mmola) metilnog estera merkaptooctene kiseline postupkom prema općenitom radnom propisu A dobije se 2.76 g (69.1 % od teor.) naslovnog spoja. 2.76 g is obtained from 2.99 g (14.7 mmol) of 5-bromo-2-fluorobenzaldehyde, 0.88 g (22.1 mmol) of sodium hydride (60% alcohol) and 1.72 g (16.2 mmol) of methyl ester of mercaptoacetic acid by the procedure according to the general procedure A. (69.1 % of theory) of the title compound.

1H-NMR (200 MHz, DMSO-d6): δ = 8.29 (d, 1H), 8.18 (s, 1H), 8.08 (d, 1H), 7.69 (dd, 1H), 3.90 (s, 3H). 1H-NMR (200 MHz, DMSO-d6): δ = 8.29 (d, 1H), 8.18 (s, 1H), 8.08 (d, 1H), 7.69 (dd, 1H), 3.90 (s, 3H).

HPLC (metoda 1): Rt = 5.2 min. HPLC (method 1): Rt = 5.2 min.

MS (ESIpos): m/z = 270 (M+). MS (ESIpos): m/z = 270 (M + ).

Primjer 13A Example 13A

5-brom-1-benzotiofen-2-karboksilna kiselina 5-Bromo-1-benzothiophene-2-carboxylic acid

[image] [image]

Iz 2.7 g (9.96 mmola) metilnog estera 5-brom-1-benzotiofen-2-karboksilne kiseline (iz primjera 12A) dobije se postupkom prema općenitom radnom propisu B 2.41 g (94 % od teor.) željenog produkta. From 2.7 g (9.96 mmol) of methyl ester of 5-bromo-1-benzothiophene-2-carboxylic acid (from example 12A), 2.41 g (94% of theory) of the desired product is obtained by the procedure according to general procedure B.

1H-NMR (400 MHz, DMSO-d6): δ = 13.67 (br. s, 1H), 8.27 (m, 1H), 8.10 (s, 1H), 8.05 (d, 1H), 7.66 (dd, 1H). 1H-NMR (400 MHz, DMSO-d6): δ = 13.67 (no. s, 1H), 8.27 (m, 1H), 8.10 (s, 1H), 8.05 (d, 1H), 7.66 (dd, 1H) .

HPLC (metoda 1): Rt = 4.5 min. HPLC (method 1): Rt = 4.5 min.

Primjer 14A Example 14A

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-5-brom-1-benzotiofen-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-bromo-1-benzothiophene-2-carboxamide hydrochloride

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Pomiješa se 133.7 mg (0.52 mmola) 5-brom-1-benzotiofen-2-karboksilne kiseline (primjer 13A), 155.4 mg (0.78 mmola) (R)-3-aminokinuklidin-dihidroklorida, 296.7 mg (0.78 mmola) HATU, 369.8 mg (2.86 mmola) N,N-diizopropiletilamina i 1.5 mL DMF prema općenitom radnom propisu C. Reakcijska smjesa pročisti se preparativnom HPLC. Produkt se otopi u acetonitrilu i pretvoren sa suviškom 1 N solne kiseline. Potom se otapalo ukloni. Izolirano je 175 mg (84 % od teor.) naslovnog spoja. 133.7 mg (0.52 mmol) of 5-bromo-1-benzothiophene-2-carboxylic acid (Example 13A), 155.4 mg (0.78 mmol) of (R)-3-aminoquinuclidine dihydrochloride, 296.7 mg (0.78 mmol) of HATU, 369.8 mg (2.86 mmol) of N,N-diisopropylethylamine and 1.5 mL of DMF according to general procedure C. The reaction mixture is purified by preparative HPLC. The product is dissolved in acetonitrile and treated with an excess of 1 N hydrochloric acid. The solvent is then removed. 175 mg (84% of theory) of the title compound was isolated.

1H-NMR (200 MHz, DMSO-d6): δ = 9.44 (br. s, 1H), 8.95 (d, 1H), 8.30-8.10 (m, 2H), 8.03 (d, 1H), 7.60 (m, 1H), 4.38-4.20 (m, 1H), 3.80-3.55 (m, 1H), 3.42-3.05 (m, 5H), 2.25-2.00 (m, 2H), 1.98-1.62 (m, 3H). 1H-NMR (200 MHz, DMSO-d6): δ = 9.44 (no. s, 1H), 8.95 (d, 1H), 8.30-8.10 (m, 2H), 8.03 (d, 1H), 7.60 (m, 1H), 4.38-4.20 (m, 1H), 3.80-3.55 (m, 1H), 3.42-3.05 (m, 5H), 2.25-2.00 (m, 2H), 1.98-1.62 (m, 3H).

HPLC (metoda 1): Rt = 4.1 min. HPLC (method 1): Rt = 4.1 min.

MS (ESIpos): m/z = 365 (M + H)+ (slobodna baza). MS (ESIpos): m/z = 365 (M + H)+ (free base).

Primjer 15A Example 15A

4-(4-bromfenil)morfolin 4-(4-bromophenyl)morpholine

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Otopini od 20 g (122.5 mmola) N-fenilmorfolina u 170 mL octene kiseline polako se pri sobnoj temperaturi tijekom 40 min dokapava otopina od 6.94 mL (134.8 mmola) broma u 25 mL octene kiseline. Nakon 30 min miješanja pri sobnoj temperaturi reakcijska smjesa umiješa se u 750 mL vode i 45 %-tnom natrijevom lužinom ugodi na pH 11. Dobiveni talog se pokupi, ispere vodom i osuši u visokom vakuumu. Nakon kristalizacije iz etanola dobije se 18.6 g (62.9 % od teor.) naslovnog spoja. To a solution of 20 g (122.5 mmol) of N-phenylmorpholine in 170 mL of acetic acid, a solution of 6.94 mL (134.8 mmol) of bromine in 25 mL of acetic acid was slowly added dropwise at room temperature over 40 minutes. After stirring for 30 minutes at room temperature, the reaction mixture is mixed with 750 mL of water and adjusted to pH 11 with 45% sodium hydroxide solution. The resulting precipitate is collected, washed with water and dried in a high vacuum. After crystallization from ethanol, 18.6 g (62.9% of theory) of the title compound is obtained.

1H-NMR (200 MHz, DMSO-d6): δ = 7.37 (m, 2H), 6.89 (m, 2H), 3.73 (m, 4H), 3.08 (m, 4H). 1H-NMR (200 MHz, DMSO-d6): δ = 7.37 (m, 2H), 6.89 (m, 2H), 3.73 (m, 4H), 3.08 (m, 4H).

HPLC (metoda 1): Rt = 3.9 min. HPLC (method 1): Rt = 3.9 min.

MS (ESIpos): m/z = 242 (M+H)+. MS (ESIpos): m/z = 242 (M+H) + .

Primjer 16A Example 16A

4-(4-bromfenil)-3-morfolinon 4-(4-Bromophenyl)-3-morpholinone

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Otopini od 500 mg (2.07 mmola) 4-(4-bromfenil)morfolina (primjer 15A) u 10 mL diklormetana doda se 1.41 g (6.20 mmola) benziltrietilamonijevog klorida i 0.98 g (6.20 mmola) kalijevog permanganata. Nakon 5 sati pod refluksom sadržaj tikvice se zgusne u vakuumu, a ostatak se pročisti preparativnom HPLC. Zgusnuti produkt osuši se u visokom vakuumu. Dobije se 217 mg (35.7 % teor.) naslovnog spoja. 1.41 g (6.20 mmol) of benzyltriethylammonium chloride and 0.98 g (6.20 mmol) of potassium permanganate were added to a solution of 500 mg (2.07 mmol) of 4-(4-bromophenyl)morpholine (example 15A) in 10 mL of dichloromethane. After 5 hours under reflux, the contents of the flask are concentrated in vacuo, and the residue is purified by preparative HPLC. The thickened product is dried in a high vacuum. 217 mg (35.7 % of theory) of the title compound are obtained.

LC-MS (metoda 4): Rt = 2.9 min, m/z = 255 (M+). LC-MS (method 4): Rt = 2.9 min, m/z = 255 (M+).

Primjer 17A Example 17A

3-(4-morfolinil)fenil-trifluormetansulfonat 3-(4-morpholinyl)phenyl-trifluoromethanesulfonate

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Otopini od 1.54 g (8.6 mmola) 3-(4-morfolinil)-fenola i trietilamina u 10 mL diklormetana ohlađenoj na -10°C polako se dokapa 2.18 mL (12.9 mmola) anhidrida trifluormetansulfonske kiseline. Smjesa se miješa najprije 30 min pri -10°C, potom još 30 minuta pri 0°C. Ispere se 10 %-tnom otopinom natrijevog hidrogenkarbonata, potom vodom, te zasićenom otopinom kuhinjske soli, zgusne u vakuumu, te se ostatak osuši u visokom vakuumu. Dobije se 2.41 g (90.1 % od teor.) naslovnog spoja. To a solution of 1.54 g (8.6 mmol) of 3-(4-morpholinyl)-phenol and triethylamine in 10 mL of dichloromethane cooled to -10°C, 2.18 mL (12.9 mmol) of trifluoromethanesulfonic acid anhydride was slowly added dropwise. The mixture is first stirred for 30 minutes at -10°C, then for another 30 minutes at 0°C. It is washed with a 10% solution of sodium bicarbonate, then with water, and with a saturated solution of table salt, thickened in a vacuum, and the residue is dried in a high vacuum. 2.41 g (90.1 % of theory) of the title compound are obtained.

1H-NMR (200 MHz, CDCl3): δ = 7.28 (m, 1H), 6.88 (m, 1H), 6.73 (m, 2H),3.86 (m, 4H), 3.18 (m, 4H). 1H-NMR (200 MHz, CDCl3): δ = 7.28 (m, 1H), 6.88 (m, 1H), 6.73 (m, 2H), 3.86 (m, 4H), 3.18 (m, 4H).

HPLC (metoda 1): Rt = 4.8 min. HPLC (method 1): Rt = 4.8 min.

MS (ESIpos): m/z = 312 (M+H)+. MS (ESIpos): m/z = 312 (M+H) + .

Primjer 18A Example 18A

4-(4-morfolinilkarbonil)fenil-trifluormetansulfonat 4-(4-morpholinylcarbonyl)phenyl-trifluoromethanesulfonate

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Otopini 1.0 g (4.83 mmola) 4-(4-morfolinilkarbonil)fenola i 2.02 mL (14.48 mmola) trietilamina u 20 mL diklormetana ohlađenoj do -10°C polako se dokapa 1.23 mL (7.24 mmola) anhidrida trifluormetansulfonske kiseline. Smjesa se miješa najprije 30 min pri -10°C, potom još 30 min pri 0°C. Ispere se najprije 10 %-tnom otopinom natrijevog hidrogenkarbonata, potom vodom, te zasićenom otopinom kuhinjske soli, osuši iznad natrijevog sulfata, zgusne u vakuumu, te se ostatak osuši u visokom vakuumu. Dobije se 1.71 g (94.6 % od teor.) naslovnog spoja. To a solution of 1.0 g (4.83 mmol) of 4-(4-morpholinylcarbonyl)phenol and 2.02 mL (14.48 mmol) of triethylamine in 20 mL of dichloromethane cooled to -10°C, 1.23 mL (7.24 mmol) of trifluoromethanesulfonic acid anhydride was slowly added dropwise. The mixture is first stirred for 30 min at -10°C, then for another 30 min at 0°C. It is washed first with a 10% solution of sodium hydrogencarbonate, then with water, and with a saturated solution of table salt, dried over sodium sulfate, concentrated in a vacuum, and the rest is dried in a high vacuum. 1.71 g (94.6 % of theory) of the title compound is obtained.

1H-NMR (400 MHz, metanol-d4): δ = 7.62 (m, 2H), 7.49 (m, 2H), 3.86-3.34 (m,8H). 1H-NMR (400 MHz, methanol-d4): δ = 7.62 (m, 2H), 7.49 (m, 2H), 3.86-3.34 (m, 8H).

HPLC (metoda 1): Rt = 4.2 min. HPLC (method 1): Rt = 4.2 min.

MS (ESIpos): m/z = 357 (M+NH4)+. MS (ESIpos): m/z = 357 (M+NH4)+.

Primjer 19A Example 19A

metilni ester 7-[4-(4-morfolinil)fenil]-1-benzotiofen-2-karboksilnekiseline 7-[4-(4-morpholinyl)phenyl]-1-benzothiophene-2-carboxylic acid methyl ester

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Otopini od 619.1 mg (2.28 mmola) metilnog estera 7-brom-1-benzotiofen-2-karboksilne kiseline (primjer 6A) i 520 mg (2.51 mmol) 4-(4-morfolinil)fenilborne kiseline u 10 mL DMF doda se prvo 3.42 mL 2 M otopine natrijevog karbonata, potom 83.5 mg (0.11 mmola) PdCl2(dppf). Zagrijava se 16 h na 80°C. Nakon hlađenja filtrira se na silikagelu i pročisti preparativnom HPLC. Zgusnuti produkt se osuši u visokom vakuumu. Dobije se 146.7 mg (16.4 % teor.) naslovnog spoja. A solution of 619.1 mg (2.28 mmol) of 7-bromo-1-benzothiophene-2-carboxylic acid methyl ester (Example 6A) and 520 mg (2.51 mmol) of 4-(4-morpholinyl)phenylboronic acid in 10 mL of DMF was first added 3.42 mL of 2 M sodium carbonate solution, then 83.5 mg (0.11 mmol) of PdCl2(dppf). It is heated for 16 hours at 80°C. After cooling, it is filtered on silica gel and purified by preparative HPLC. The thickened product is dried in a high vacuum. 146.7 mg (16.4 % of theory) of the title compound is obtained.

HPLC (metoda 1): Rt = 4.6 min. HPLC (method 1): Rt = 4.6 min.

MS (ESIpos): m/z = 354 (M+H)+. MS (ESIpos): m/z = 354 (M+H) + .

Primjer 20A Example 20A

7-[4-(4-morfolinil)fenil]-1-benzotiofen-2-karboksilna kiselina 7-[4-(4-morpholinyl)phenyl]-1-benzothiophene-2-carboxylic acid

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Otopina od 330 mg (0.77 mmola) metilnog estera 7-[4-(4-morfolinil)fenil]-1-benzotiofen-2-karboksilne kiseline (primjer 19A) u 6 mL smjese 1:1 metanola i 2 N kalijeve lužine miješa se 2 h pri sobnoj temperaturi, te 1 h pri 50°C. Reakcijska smjesa zgusne se u vakuumu, pretvori s vodom i odmah potom zakiseli koncentriranom solnom kiselinom. Preostali talog se pokupi, dvaput ispere vodom i osuši u visokom vakuumu. Dobije se 292 mg sirovog produkta koji se dalje upotrebljava bez daljnjeg pročišćavanja. A solution of 330 mg (0.77 mmol) of 7-[4-(4-morpholinyl)phenyl]-1-benzothiophene-2-carboxylic acid methyl ester (Example 19A) in 6 mL of a mixture of 1:1 methanol and 2 N potassium hydroxide is mixed 2 h at room temperature, and 1 h at 50°C. The reaction mixture is concentrated in vacuo, converted with water and immediately acidified with concentrated hydrochloric acid. The remaining precipitate is collected, washed twice with water and dried under high vacuum. 292 mg of crude product is obtained, which is further used without further purification.

Primjer 21A Example 21A

7-(2-metoksifenil)-1-benzofuran-2-karboksilna kiselina 7-(2-Methoxyphenyl)-1-benzofuran-2-carboxylic acid

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Stavi se 5.0 g (20.7 mmola) 7-brom-1-benzofuran-2-karboksilne kiseline (primjer 29A) i 3.78 g (24.9 mmola) 2-metoksifenilborne kiseline u 50 ml DMF. Nakon dodatka 31.1 mL 2 M otopine natrijevog karbonata i 1.2 g (1.04 mmola) pd(PPh3)4 smjesa se zagrije na 90°C. Nakon 18 sati otapalo se odvoji destilacijom. Ostatak se razdijeli između 1N solne kiseline i etilnog estera octene kiseline i ekstrahira triput, svaki put sa po 200 mL etilnog estera octene kiseline. Organska faza se osuši iznad natrijevog sulfata i zgusne u vakuumu, Ostatak se pročisti flash-kromatografijom (silikagel, otapalo: diklormetan/metanol/octena kiselina 100:10:1). Nakon zgušnjavanja i sušenja u visokom vakuumu dobije se 2.97 g (53.2 % od teor.) naslovnog spoja. 5.0 g (20.7 mmol) of 7-bromo-1-benzofuran-2-carboxylic acid (Example 29A) and 3.78 g (24.9 mmol) of 2-methoxyphenylboronic acid were placed in 50 ml of DMF. After adding 31.1 mL of 2 M sodium carbonate solution and 1.2 g (1.04 mmol) of pd(PPh3)4, the mixture is heated to 90°C. After 18 hours, the solvent is separated by distillation. The residue is partitioned between 1N hydrochloric acid and ethyl acetate and extracted three times, each time with 200 mL of ethyl acetate. The organic phase is dried over sodium sulfate and concentrated in vacuo. The residue is purified by flash chromatography (silica gel, solvent: dichloromethane/methanol/acetic acid 100:10:1). After concentration and drying in high vacuum, 2.97 g (53.2 % of theory) of the title compound are obtained.

1H-NMR (300 MHz, DMSO-d6): δ =13.46.(s, 1H), 7.33 (dd, 1H), 7,59 (s, 1H), 7.48-7.33 (m, 4H), 7.20 (d, 1H), 7.09 (m, 1H), 3.75 (s, 1H). 1H-NMR (300 MHz, DMSO-d6): δ = 13.46.(s, 1H), 7.33 (dd, 1H), 7.59 (s, 1H), 7.48-7.33 (m, 4H), 7.20 (d , 1H), 7.09 (m, 1H), 3.75 (s, 1H).

HPLC (metoda 1): Rt = 4.5 min. HPLC (method 1): Rt = 4.5 min.

MS (ESIpos): m/z = 286 (M+H)+. MS (ESIpos): m/z = 286 (M+H) + .

Primjer 22A Example 22A

N-[(3S)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzotiofen-2-karboksamid-hidroklorid N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride

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Otopini od 4.0 g (15.6 mmola) 7-brom-1-benzotiofen-2-karboksilne kiseline (primjer 7A) i 3.10 g (15.6 mmol) (S)-3-aminokinuklidin-dihidroklorida u 50 mL DHF, ohlađenoj na 0°C, doda se 3.58 g (18.7 mmola) EDC, 2.52 g (18.7 mmol) HOBt i 7.8 mL (56 mmola) trietilamina. Miješa se pri sobnoj temperaturi kroz 18 h. Reakcija se prekine dodatkom 10 %-tne otopine natrijevog hidrogenkarbonata. Talog koji ostane nakon dodatka etilnog estera octene kiseline odvoji se filtracijom. Vodena faza ekstrahira se etilnim esterom octene kiseline, spojene organske faze osuše se iznad natrijevog sulfata, zgusnu, te se ostatak osuši u visokom vakuumu. Dobije se 4.70 g (68 % od teor.) naslovnog spoja. Solutions of 4.0 g (15.6 mmol) of 7-bromo-1-benzothiophene-2-carboxylic acid (Example 7A) and 3.10 g (15.6 mmol) of (S)-3-aminoquinuclidine dihydrochloride in 50 mL of DHF, cooled to 0°C , 3.58 g (18.7 mmol) of EDC, 2.52 g (18.7 mmol) of HOBt and 7.8 mL (56 mmol) of triethylamine are added. It is mixed at room temperature for 18 hours. The reaction is stopped by adding a 10% solution of sodium hydrogencarbonate. The precipitate that remains after the addition of acetic acid ethyl ester is separated by filtration. The aqueous phase is extracted with acetic acid ethyl ester, the combined organic phases are dried over sodium sulfate, concentrated, and the residue is dried under high vacuum. 4.70 g (68% of theory) of the title compound are obtained.

Spektroskopski podaci odgovaraju onima enantiomernog spoja (primjer 8A) gore. The spectroscopic data correspond to that of the enantiomeric compound (Example 8A) above.

Primjer 23A Example 23A

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-6-(4-formilfenil)-1-benzotiofen-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(4-formylphenyl)-1-benzothiophene-2-carboxamide hydrochloride

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Stavi se 200 mg (0.50 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-6-brom-1-benzotiofen-2-karboksamid-hidroklorida (primjer HA) i 74.6 mg (0.50 mmola) 4-formilfenilboronske kiseline u 2 mL DMF. Nakon dodatka 0.75 mL 2 M otopine natrijevog karbonata i 20.3 mg (0.02 mmola) PdCl2(dppf) smjesa se zagrije na 80°C. Nakon 18 h reakcijska smjesa se filtrira na silikagelu i pročisti preparativnom HPLC. Frakcije produkta se zgusnu, pretvore sa smjesom 5:1 metanola i 4 N klorovodika u dioksanu, te se ponovno zgusnu. Nakon sušenja u visokom vakuumu dobije se 163.8 mg (75 % od teor.) naslovnog spoja. 200 mg (0.50 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1-benzothiophene-2-carboxamide hydrochloride (example HA) and 74.6 mg (0.50 mmol) of 4-formylphenylboronic acid in 2 mL of DMF. After adding 0.75 mL of 2 M sodium carbonate solution and 20.3 mg (0.02 mmol) of PdCl2(dppf), the mixture was heated to 80°C. After 18 h, the reaction mixture is filtered on silica gel and purified by preparative HPLC. The product fractions were concentrated, reconstituted with a mixture of 5:1 methanol and 4 N hydrogen chloride in dioxane, and concentrated again. After drying in high vacuum, 163.8 mg (75% of theory) of the title compound is obtained.

1H-NMR (200 MHz, DMSO-d6): δ = 10.09 (s, 1H), 10.07 (br. s, 1H), 9.10 (d, 1H), 8.50 (m, 1H), 8.37 (s, 1H), 8.15-7.97 (m, 5H), 7.87 (dd, 1H), 4.33 (m, 1H), 3.68 (m, 1H), 3.45-3.12 (m, 5H), 2.23 (m, 1H), 2.16 (m, 1H), 1.91 (m, 2H), 1.76 (m, 1H). 1H-NMR (200 MHz, DMSO-d6): δ = 10.09 (s, 1H), 10.07 (no. s, 1H), 9.10 (d, 1H), 8.50 (m, 1H), 8.37 (s, 1H) , 8.15-7.97 (m, 5H), 7.87 (dd, 1H), 4.33 (m, 1H), 3.68 (m, 1H), 3.45-3.12 (m, 5H), 2.23 (m, 1H), 2.16 (m , 1H), 1.91 (m, 2H), 1.76 (m, 1H).

HPLC (metoda 1): Rt = 4.1 min. HPLC (method 1): Rt = 4.1 min.

MS (ESIpos): m/z = 391 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 391 (M+H)+ (free base).

Primjer 24A Example 24A

metilni ester 6-cijano-1-benzotiofen-2-karboksilne kiseline 6-cyano-1-benzothiophene-2-carboxylic acid methyl ester

[image] [image]

Zagrije se 4.08 g (23.2 mmola) 4-cijano-2-nitrobenzaldehida, 2.46 g (23.2 mmola) metilnog estera merkaptooctene kiseline i 6.46 mL (46.4 mmola) trietilamina tijekom 2.5 sati na 80°C u 12.3 mL DMSO. Reakcijska otopina doda se u 400 mL ledene vode. Nakon dodavanja 4 mL octene kiseline ukloni se preostali talog, dvaput ispere vodom i suši preko noći u vakuumu na 50°C. Dobije se 4.19 g (83.2 % od teor.) naslovnog spoja. 4.08 g (23.2 mmol) of 4-cyano-2-nitrobenzaldehyde, 2.46 g (23.2 mmol) of mercaptoacetic acid methyl ester and 6.46 mL (46.4 mmol) of triethylamine are heated for 2.5 hours at 80°C in 12.3 mL of DMSO. The reaction solution is added to 400 mL of ice water. After adding 4 mL of acetic acid, the remaining precipitate is removed, washed twice with water and dried overnight in a vacuum at 50°C. 4.19 g (83.2 % of theory) of the title compound are obtained.

1H-NMR (200 MHz, DMSO-d6): δ = 8.73 (d, 1H), 8.32 (s, 1H), 8.21 (d, 1H), 7.85 (dd, 1H), 3.92 (s, 3H). 1H-NMR (200 MHz, DMSO-d6): δ = 8.73 (d, 1H), 8.32 (s, 1H), 8.21 (d, 1H), 7.85 (dd, 1H), 3.92 (s, 3H).

HPLC (metoda 1): Rt = 4.4 min. HPLC (method 1): Rt = 4.4 min.

MS (ESIpos): m/z = 218 (M+H)+. MS (ESIpos): m/z = 218 (M+H) + .

Primjer 25A Example 25A

6-cijano-1-benzotiofen-2-karboksilna kiselina 6-Cyano-1-benzothiophene-2-carboxylic acid

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Iz 0.6 g (2.76 mmola) metilnog estera 6-cijano-1-benzotiofen-2-karboksilne kiseline (primjer 24A) dobije se u skladu s općenitim radnim propisom B 0.49 g (61.6 % od teor.) željenog produkta. From 0.6 g (2.76 mmol) of methyl ester of 6-cyano-1-benzothiophene-2-carboxylic acid (example 24A), 0.49 g (61.6 % of theory) of the desired product is obtained in accordance with general procedure B.

HPLC (metoda 1): Rt = 3.9 min. HPLC (method 1): Rt = 3.9 min.

MS (ESIpos): m/z = 222 (M+H)+. MS (ESIpos): m/z = 222 (M+H) + .

Primjer 26A Example 26A

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-6-cijano-1-benzotiofen-2-karboksamid-hidro klorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-cyano-1-benzothiophene-2-carboxamide hydrochloride

[image] [image]

Pomiješa se 320.8 mg (l.l mmol) 6-cijano-1-benzotiofen-2-karboksilna kiseline (primjer 25A), 200 mg (1.0 mmol) (R)-3-aminokinuklidin-dihidroklorida, 458.3 mg (1.21 mmol) HATU, 467.3 mg (3.62 mmola) A/,N-diizopropiletilamina i 4.0 mL DMF u skladu s općenitim radnim propisom C. Reakcijska smjesa se pročisti preparativnom HPLC. Produkt se otopi u smjesi metanola i 4 M klorovodika u dioksanu, odmah potom zgusne i osuši u visokom vakuumu. Dobije se 222.1 mg (64 % od teor.) naslovnog spoja. 320.8 mg (1.1 mmol) of 6-cyano-1-benzothiophene-2-carboxylic acid (Example 25A), 200 mg (1.0 mmol) of (R)-3-aminoquinuclidine dihydrochloride, 458.3 mg (1.21 mmol) of HATU, 467.3 mg (3.62 mmol) of A/,N-diisopropylethylamine and 4.0 mL of DMF in accordance with general procedure C. The reaction mixture is purified by preparative HPLC. The product is dissolved in a mixture of methanol and 4 M hydrogen chloride in dioxane, then immediately thickened and dried in a high vacuum. 222.1 mg (64% of theory) of the title compound is obtained.

HPLC (metoda 1): Rt = 3.6 min. HPLC (method 1): Rt = 3.6 min.

MS (ESIpos): m/z = 312 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 312 (M+H)+ (free base).

Primjer 27A Example 27A

6-[(Z)-amino(hidroksiimino)metil]-N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-1-benzotiofen-2-karboksamid-hidroklorid 6-[(Z)-amino(hydroxyimino)methyl]-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide hydrochloride

[image] [image]

Zagrije se 800 mg (2.0 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-6-cijano-1-benzotiofen-2-karboksamid-hidroklorida (primjer 26A), 278.1 mg (4.0 mmola) hidroksilamin-hidroklorida i 829.5 mg (6.0 mmola) kalijevog karbonata u 8 mL smjese 8:1 vode i etanola kroz 3 h na 80°C. Smjesa se pročisti kolonskom kromatografijom na silikagelu (otapalo: diklormetan/metanol/25 %-tna otopina amonijaka 100:20:4). Frakcije produkta spoje se, zgusnu, pretvore metanolom i 4 M klorovodikom u dioksanu, te odmah potom ponovno zgusnu i osuše u visokom vakuumu. Dobije se 447.3 mg (53.6 % od teor.) naslovnog spoja. Heat 800 mg (2.0 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-cyano-1-benzothiophene-2-carboxamide hydrochloride (Example 26A), 278.1 mg (4.0 mmol) of hydroxylamine hydrochloride and 829.5 mg (6.0 mmol) of potassium carbonate in 8 mL of a mixture of 8:1 water and ethanol for 3 h at 80°C. The mixture is purified by column chromatography on silica gel (solvent: dichloromethane/methanol/25% ammonia solution 100:20:4). The product fractions are combined, concentrated, converted to dioxane with methanol and 4 M hydrogen chloride, and immediately then concentrated again and dried in a high vacuum. 447.3 mg (53.6% of theory) of the title compound is obtained.

1H-NMR (200 MHz, DMSO-d6): δ = 11.15 (m, 1H), 10.22 (m, 1H), 9.36 (d, 1H), 8.52 (s, 1H), 8.46 (m, 1H), 8.14 (d, 1H), 7.73 (dd, 1H), 4.33 (m, 1H), 3.93-3.10 (m, 6H), 2.32-2.05 (m, 2H), 1.93 (m, 2H), 1.75 (m, 1H). 1H-NMR (200 MHz, DMSO-d6): δ = 11.15 (m, 1H), 10.22 (m, 1H), 9.36 (d, 1H), 8.52 (s, 1H), 8.46 (m, 1H), 8.14 (d, 1H), 7.73 (dd, 1H), 4.33 (m, 1H), 3.93-3.10 (m, 6H), 2.32-2.05 (m, 2H), 1.93 (m, 2H), 1.75 (m, 1H ).

HPLC (metoda 1): Rt = 2.9 min. HPLC (method 1): Rt = 2.9 min.

MS (ESIpos): m/z = 345 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 345 (M+H)+ (free base).

Primjer 28A Example 28A

3-brom-2-hidroksibenzaldehid 3-bromo-2-hydroxybenzaldehyde

[image] [image]

Stavi se 20.0 g (115.6 mmola) 2-bromfenola u 500 mL suhog acetonitrila. Tome se doda 16.84 g (176.87 mmola) suhog magnezijevog klorida, 23.4 g paraformaldehidnog granulata i 41.9 mL (300.6 mmola) trietilamina. Reakcijska smjesa zagrijava se 4 h pod refluksom, potom ohladi na 0°C i pretvori sa 300 mL 2 N solne kiseline. Vodena faza se ekstrahira triput sa po 200 mL dietiletera. Organska faza osuši se iznad magnezijevog sulfata, te se otapalo ukloni u vakuumu. Izolirano je 24 g (64 % od teor., sadržaj 62 % nakon HPLC) naslovnog spoja, koji se dalje upotrebljava bez daljnjeg pročišćavanja. Place 20.0 g (115.6 mmol) of 2-bromophenol in 500 mL of dry acetonitrile. 16.84 g (176.87 mmol) of dry magnesium chloride, 23.4 g of paraformaldehyde granules and 41.9 mL (300.6 mmol) of triethylamine are added to this. The reaction mixture is heated for 4 h under reflux, then cooled to 0°C and treated with 300 mL of 2 N hydrochloric acid. The aqueous phase is extracted three times with 200 mL of diethyl ether. The organic phase is dried over magnesium sulfate, and the solvent is removed in vacuo. 24 g (64% of theory, content 62% after HPLC) of the title compound was isolated, which was further used without further purification.

HPLC (metoda 1): Rt = 4.25 min. HPLC (method 1): Rt = 4.25 min.

MS (ESIpos): m/z = 202 (M+H)+. MS (ESIpos): m/z = 202 (M+H) + .

Primjer 29A Example 29A

7-brom-1-benzofuran-2-karboksilna kiselina 7-Bromo-1-benzofuran-2-carboxylic acid

[image] [image]

Zagrijava se 13.5 g (40.3 mmola) 3-brom-2-hidroksibenzaldehida (primjer 28A, sadržaj 62 %) zajedno sa 9.18 g (84.62 mmola) metilnog estera kloroctene kiseline, 1.49 g (4.03 mmola) tetra-n-butilamonijevog jodida i 22.28 g (161.18 mmola) kalijevog karbonata kroz 6 h na 130°C. Nakon hlađenja na RT doda se 100 mL vode i 100 mL THF, kao i 13.57 g (241.77 mmola) kalijevog hidroksida, te se preko noći miješa na RT. Otapalo se ukloni pod sniženim tlakom, a ostatak se preuzme u 400 mL vode i ispere četiri puta s ukupno 400 ml dietiletera. Uz hlađenje ledom ugodi se koncentriranom solnom kiselinom na pH 0 i pet puta ekstrahira s ukupno 700 mL etilnog estera octene kiseline. Organska faza opere se sa 100 mL zasićene otopine natrijevog klorida i odmah potom osuši iznad magnezijevog sulfata. Sirovi produkt se u visokom vakuumu u potpunosti oslobodi otapala i promiješa s 80 mL dietiletera. Produkt se odvoji filtracijom i ponovno opere s malo ledeno hladnog dietiletera. Izolirano je 4.8 g (47 % od teor.) naslovnog spoja. 13.5 g (40.3 mmol) of 3-bromo-2-hydroxybenzaldehyde (example 28A, content 62 %) is heated together with 9.18 g (84.62 mmol) of chloroacetic acid methyl ester, 1.49 g (4.03 mmol) of tetra-n-butylammonium iodide and 22.28 g (161.18 mmol) of potassium carbonate for 6 h at 130°C. After cooling to RT, add 100 mL of water and 100 mL of THF, as well as 13.57 g (241.77 mmol) of potassium hydroxide, and stir overnight at RT. The solvent is removed under reduced pressure, and the residue is taken up in 400 mL of water and washed four times with a total of 400 mL of diethyl ether. After cooling with ice, it is adjusted to pH 0 with concentrated hydrochloric acid and extracted five times with a total of 700 mL of ethyl acetic acid ester. The organic phase is washed with 100 mL of saturated sodium chloride solution and immediately dried over magnesium sulfate. The crude product is completely freed from the solvent in a high vacuum and mixed with 80 mL of diethyl ether. The product is separated by filtration and washed again with a little ice-cold diethyl ether. 4.8 g (47% of theory) of the title compound was isolated.

1H-NMR (200 MHz, DMSO-d6): δ = 13.5 (br. s, 1H), 7.86-7.72 (m, 2H), 7.79 (s, 1H), 7.31 (t, 1H). 1H-NMR (200 MHz, DMSO-d6): δ = 13.5 (no. s, 1H), 7.86-7.72 (m, 2H), 7.79 (s, 1H), 7.31 (t, 1H).

MS (DCI/NH3): m/z = 258 (M+NH4)+. MS (DCI/NH3): m/z = 258 (M+NH4)+.

Primjer 30A Example 30A

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzofuran-2-karboksamid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide

[image] [image]

Pomiješa se 5.20 g (21.57 mmola) 7-brombenzofuran-2-karboksilne kiseline (primjer 29A), 4.3 g (21.57 mmola) (K)-3-aminokinuklidin-dihidroklorida, 9.84 g (25.89 mmola) HATU, 13.53 mL (74.68 mmola) N,N-diizopropiletilamina i 21 mL DMF u skladu s općenitim radnim propisom C. Otapalo se ukloni pod sniženim tlakom, sirovi produkt se preuzme u 100 mL etilnog estera octene kiseline i petnaest puta ispere s ukupno 1.5 L 1 N natrijeve lužine. Organska faza osuši se iznad magnezijevog sulfata i oslobodi otapala. Izolirano je 5.2 g (69 % od teor.) naslovnog spoja. 5.20 g (21.57 mmol) of 7-bromobenzofuran-2-carboxylic acid (Example 29A), 4.3 g (21.57 mmol) of (K)-3-aminoquinuclidine dihydrochloride, 9.84 g (25.89 mmol) of HATU, 13.53 mL (74.68 mmol) of ) of N,N-diisopropylethylamine and 21 mL of DMF in accordance with general working regulation C. The solvent is removed under reduced pressure, the crude product is taken up in 100 mL of ethyl acetate and washed fifteen times with a total of 1.5 L of 1 N sodium hydroxide solution. The organic phase is dried over magnesium sulfate and freed from the solvent. 5.2 g (69% of theory) of the title compound was isolated.

1H-NMR (300 MHz, DMSO-d6): δ = 8.48 (d, 1H), 7.85-7.65 (m, 3H), 7.25 (t, 1H), 3.95 (m, 1H), 3.15 (m, 1H), 2.95 (m, 1H), 2.80-2.60 (m, 4H), 1.90 (m, 1H), 1.70 (m, 1H), 1.58 (m, 2H), 1.35 (m, 1H). 1H-NMR (300 MHz, DMSO-d6): δ = 8.48 (d, 1H), 7.85-7.65 (m, 3H), 7.25 (t, 1H), 3.95 (m, 1H), 3.15 (m, 1H) , 2.95 (m, 1H), 2.80-2.60 (m, 4H), 1.90 (m, 1H), 1.70 (m, 1H), 1.58 (m, 2H), 1.35 (m, 1H).

HPLC (metoda 1): Rt = 3.79 min. HPLC (method 1): Rt = 3.79 min.

MS (ESIpos): m/z = 349 (M+H)+. MS (ESIpos): m/z = 349 (M+H) + .

[α]2Od = 26.9° (c = 0.50, metanol). [α]2Od = 26.9° (c = 0.50, methanol).

U nekoliko izvedbenih primjera stavljen je odgovarajući hidroklorid, koji je dobiven pretvorbom naslovnog spoja sa smjesom 5:1 metanola i 1 N solne kiseline, te potom zgušnjavanjem i sušenjem u visokom vakuumu. In several exemplary embodiments, the appropriate hydrochloride was added, which was obtained by converting the title compound with a mixture of 5:1 methanol and 1 N hydrochloric acid, and then by concentration and drying in a high vacuum.

Primjer 31A Example 31A

N[(3S)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzofuran-2-karboksamid N[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide

[image] [image]

Pomiješa se 4.0 g (16.59 mmola) 7-brombenzofuran-2-karboksilne kiseline (primjer 29A), 3,3 g (16.59 mmola) (S)-3-aminokinuklidin-dihidroklorida, 7.57 g (19.91 mmol) HATU, 10.41 mL (59.74 mmola) N,N-diizopropiletilamina i 21 mL DMF u skladu s općenitim radnim propisom C. Otapalo se ukloni pod sniženim tlakom, sirovi produkt se preuzme u 100 mL etilnog estera octene kiseline i ispere s ukupno 1.5 L 1 N natrijeve lužine. Organska faza se osuši iznad magnezijevog sulfata i oslobodi otapala. Izoliralo se 5.0 g (85 % od teor.) naslovnog spoja. 4.0 g (16.59 mmol) of 7-bromobenzofuran-2-carboxylic acid (Example 29A), 3.3 g (16.59 mmol) of (S)-3-aminoquinuclidine dihydrochloride, 7.57 g (19.91 mmol) of HATU, 10.41 mL ( 59.74 mmol) of N,N-diisopropylethylamine and 21 mL of DMF in accordance with general procedure C. The solvent is removed under reduced pressure, the crude product is taken up in 100 mL of ethyl acetate and washed with a total of 1.5 L of 1 N sodium hydroxide solution. The organic phase is dried over magnesium sulfate and freed from the solvent. 5.0 g (85% of theory) of the title compound was isolated.

Analitički podatci slažu se s onima iz primjera 30A. Analytical data agree with those of Example 30A.

[α]20D = -28.0° (c = 0.1, metanol). [α]20D = -28.0° (c = 0.1, methanol).

Primjer 32A Example 32A

2-(4-morfolinil)fenil-trifluormetansulfonat 2-(4-morpholinyl)phenyl-trifluoromethanesulfonate

[image] [image]

Otopini 2 g (10.9 mmol) 2-(4-morfolinil)fenola i 4.57 mL (32.8 mmola) trietilamina u 15 mL diklormetana, ohlađenoj do -10°C, polagano se dokapa 2.78 mL (16.4 mmola) anhidrida trifluormetansulfonske kiseline. Potom se smjesa miješa 30 min pri -10°C, te još 30 min pri 0°C. Ispere se 10 %-tnom otopinom natrijevog hidrogenkarbonata, potom vodom, te zasićenom otopinom kuhinjske soli, osuši iznad natrijevog sulfata, zgusne u vakuumu, te se ostatak osuši u visokom vakuumu. Dobije se 3.48 g (87.6 % od teor.) naslovnog spoja. To a solution of 2 g (10.9 mmol) of 2-(4-morpholinyl)phenol and 4.57 mL (32.8 mmol) of triethylamine in 15 mL of dichloromethane, cooled to -10°C, 2.78 mL (16.4 mmol) of trifluoromethanesulfonic acid anhydride is slowly added dropwise. The mixture is then stirred for 30 min at -10°C, and another 30 min at 0°C. It is washed with a 10% solution of sodium bicarbonate, then with water, and with a saturated solution of table salt, dried over sodium sulfate, concentrated in a vacuum, and the residue is dried in a high vacuum. 3.48 g (87.6 % of theory) of the title compound are obtained.

HPLC (metoda 1): Rt = 4.9 min. HPLC (method 1): Rt = 4.9 min.

MS (ESIpos): m/z = 312 (M + H)+. MS (ESIpos): m/z = 312 (M + H) + .

Primjer 33A Example 33A

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-6-(3-formilfenil)-1-benzotiofen-2-karboksamid-hidroksid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(3-formylphenyl)-1-benzothiophene-2-carboxamide hydroxide

[image] [image]

Stavi se 200 mg (0.50 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-6-brom-1-benzotiofen-2-karboksamid-hidroklorida (primjer 11A) i 74.6 mg (0.50 mmola) 3-formilfenilboronske kiseline u 1 mL DMF. Nakon dodavanja 0.75 mL 2 M otopine natrijevog karbonata i 20.3 mg (0.02 mmola) PdCl2(dppf) smjesa se zagrijava na 80°C. Nakon 18 h reakcijska se smjesa filtrira na silikagelu i pročisti preparativnom HPLC. Frakcije produkta se zgusnu, pretvore smjesom 5:1 metanola i 4 N klorovodika u dioksanu, te ponovno zgusnu. Nakon sušenja u visokom vakuumu dobije se 92.4 mg (39.5 % teor.) naslovnog spoja. 200 mg (0.50 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 11A) and 74.6 mg (0.50 mmol) of 3-formylphenylboronic acid in 1 mL of DMF. After adding 0.75 mL of 2 M sodium carbonate solution and 20.3 mg (0.02 mmol) of PdCl2(dppf), the mixture is heated to 80°C. After 18 h, the reaction mixture is filtered on silica gel and purified by preparative HPLC. The product fractions are concentrated, reconstituted with a 5:1 mixture of methanol and 4 N hydrogen chloride in dioxane, and concentrated again. After drying in high vacuum, 92.4 mg (39.5 % of theory) of the title compound is obtained.

PLC (metoda 1): Rt = 4.11 min. PLC (method 1): Rt = 4.11 min.

MS (ESIpos): m/z = 391 (M + H)+ (slobodna baza). MS (ESIpos): m/z = 391 (M + H)+ (free base).

Izvedbeni primjeri Performance examples

Općeniti radni propis D: General work regulation D:

Otopi se 1.5 ekv. bis(pinakolato)dibora, 3.25 ekv. suhog kalijevog acetata, 1.3 ekv. supstituiranog halogenaromata ili supstituiranog ariltrifluormetasulfonata u DMF (cca. 1 mL/mmol halogenaromata, odnosno ariltrifluormetansulfonata). Tijekom 15 minuta se kroz reakcijsku smjesu provodi argon, odmah potom se ista pretvori s 0.05 ekv. PdCl2(dppf) i zagrijava 2 h na 90°C. Odmah potom se doda 1.0 ekv. odgovarajućeg bromom supstituiranog N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-benzotiofen-2-karboksamida ili N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-benzofuran-2-karboksamida, 5 ekv. 2 M vodene otopine natrijevog karbonata, te još 0.05 ekv. PdCl2(Cpddf). Rekcijska smjesa zagrijava se 6-12 h na 90°C. Pročišćavanje se provodi preparativnom HPLC. Dobiveni produkt (slobodna baza) otopi se u metanolu i pretvori sa suviškom 1 N solne kiseline. Otapalo se ukloni pod sniženim tlakom. Dissolve 1.5 equiv. bis(pinacolato)diboron, 3.25 eq. of dry potassium acetate, 1.3 eq. of substituted halogenaromatic or substituted aryltrifluoromethanesulfonate in DMF (approx. 1 mL/mmol of halogenaromatic or aryltrifluoromethanesulfonate). During 15 minutes, argon is passed through the reaction mixture, immediately afterwards it is converted with 0.05 equiv. PdCl2(dppf) and heated for 2 h at 90°C. Immediately afterwards, 1.0 eq. of the corresponding bromine-substituted N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-benzothiophene-2-carboxamide or N-[(3R)-1-azabicyclo[2.2.2]oct-3- yl]-benzofuran-2-carboxamide, 5 eq. 2 M aqueous solution of sodium carbonate, and another 0.05 equiv. PdCl2(Cpddf). The reaction mixture is heated for 6-12 h at 90°C. Purification is performed by preparative HPLC. The obtained product (free base) is dissolved in methanol and converted with an excess of 1 N hydrochloric acid. The solvent was removed under reduced pressure.

Općeniti radni propis E: General work regulation E:

Dokapa se 2 N otopini amina (0.23 mmola) u DMF otopina od 50 mg (0.11 mmol) hidroklorida 3-(2-{[(3R)-1-azabiciklo[2.2.2]okt-3-il-amino]karbonil}-1-benzotien-7-il)-benzojeve kiseline (primjer 75), 103 mg (0.27 mmola) HATU i 52.5 mg (0.41 mmol) N,N-diizopropiletilamina u 0.5 mL DMF. Nakon 16 h na sobnoj temperaturi, reakcijska smjesa pretvori se sa 0.1 mL vode, filtrira i pročisti preparativnom HPLC. Frakcije produkta se spoje, pretvore sa 2 mL 1 N solne kiseline, zgusnu u vakuumu i osuše u visokom vakuumu. A 2 N solution of amine (0.23 mmol) in DMF is added dropwise to a solution of 50 mg (0.11 mmol) of 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-yl-amino]carbonyl} hydrochloride -1-benzothien-7-yl)-benzoic acid (Example 75), 103 mg (0.27 mmol) HATU and 52.5 mg (0.41 mmol) N,N-diisopropylethylamine in 0.5 mL DMF. After 16 h at room temperature, the reaction mixture is converted with 0.1 mL of water, filtered and purified by preparative HPLC. The product fractions are combined, converted with 2 mL of 1 N hydrochloric acid, concentrated in vacuo and dried in high vacuum.

Općeniti radni propis F: General work regulation F:

Otopini od 50 mg (0.12 mmol) N-((3R)-kinuklidin-3-il)-[7-(3-aminofenil)benzo[b]tiofen-2-il]karboksamid-hidroklorida (primjer 21) u 0.5 mL DMF doda se 0.24 mmola kiselinskog klorida i 84 μL (0.60 mmol) trietilamina. Nakon jednog sata na sobnoj temperaturi reakcijska smjesa se pretvori s 0.5 mL 1 N natrijeve lužine i 15 mL etilnog estera octene kiseline i filtrira. Zgusnuta organska faza pročisti se preparativnom HPLC. Frakcije produkta se spoje, pretvore sa 1 N natrijevom lužinom, ponovno zgusnu u vakuumu i osuše u visokom vakuumu. Solutions of 50 mg (0.12 mmol) of N-((3R)-quinuclidin-3-yl)-[7-(3-aminophenyl)benzo[b]thiophen-2-yl]carboxamide hydrochloride (example 21) in 0.5 mL 0.24 mmol of acid chloride and 84 μL (0.60 mmol) of triethylamine were added to DMF. After one hour at room temperature, the reaction mixture is converted with 0.5 mL of 1 N sodium hydroxide solution and 15 mL of ethyl acetic acid ester and filtered. The concentrated organic phase is purified by preparative HPLC. The product fractions were combined, treated with 1 N sodium hydroxide solution, re-concentrated in vacuo and dried in high vacuum.

Primjer 1 Example 1

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-6-[2-(hidroksimetil)fenil]-1-benzofuran-2-karboksamid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-[2-(hydroxymethyl)phenyl]-1-benzofuran-2-carboxamide

[image] [image]

Smjesa od 130 mg (0.86 mmol) 2-(hidroksimetil)fenilborne kiseline, 200 mg (0.57 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-6-brom-1-benzofuran-2-karboksamida (primjer 2A), 1.72 mL (1.72 mmola) 1 N natrijeve lužine, 40 mg (0.06 mmola) 1,1'-bis(difenilfosfino)-ferocenpaladijevog(II) klorida i 2 mL DMF zagrijava se 18 h na 80-85°C. Otapalo se ukloni pod sniženim tlakom. Sirovi produkt pročisti se na Kieselgel 60 (Merck, Darmstadt; eluens: diklormetan, diklormetan-metanol 20:1, diklormetan-metanol-amonijak 80:20:2). Otapalo se ukloni pod sniženim tlakom. Konačno se posljednji ostatci otapala uklone u visokom vakuumu. Izolirano je 149 mg (63 % od teor.) naslovnog spoja. A mixture of 130 mg (0.86 mmol) 2-(hydroxymethyl)phenylboronic acid, 200 mg (0.57 mmol) N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1- benzofuran-2-carboxamide (example 2A), 1.72 mL (1.72 mmol) of 1 N sodium hydroxide solution, 40 mg (0.06 mmol) of 1,1'-bis(diphenylphosphino)-ferrocenepalladium(II) chloride and 2 mL of DMF are heated for 18 h at 80-85°C. The solvent was removed under reduced pressure. The crude product was purified on Kieselgel 60 (Merck, Darmstadt; eluent: dichloromethane, dichloromethane-methanol 20:1, dichloromethane-methanol-ammonia 80:20:2). The solvent was removed under reduced pressure. Finally, the last remnants of the solvent are removed under high vacuum. 149 mg (63% of theory) of the title compound was isolated.

1H-NMR (200 MHz, CDCl3): δ = 7.71-7.28 (m, 8H), 6.77 (d, 1H), 4.62 (s, 2H), 4.28-4.12 (m, 1H), 3.56-3.38 (m, 1H), 3.04-2.78 (m, 4H), 2.75-2.59 (m, 1H), 2.16-2.02 (m, 1H), 1.93-1.66 (m, 3H), 1.66-1.45 (m, 1H). 1H-NMR (200 MHz, CDCl3): δ = 7.71-7.28 (m, 8H), 6.77 (d, 1H), 4.62 (s, 2H), 4.28-4.12 (m, 1H), 3.56-3.38 (m, 1H), 3.04-2.78 (m, 4H), 2.75-2.59 (m, 1H), 2.16-2.02 (m, 1H), 1.93-1.66 (m, 3H), 1.66-1.45 (m, 1H).

HPLC (metoda 1): Rt = 3.6 min. HPLC (method 1): Rt = 3.6 min.

LC-MS (metoda 2): Rt = 1.49 min. LC-MS (method 2): Rt = 1.49 min.

MS (ESIpos): m/z = 377 (M+H)+. MS (ESIpos): m/z = 377 (M+H) + .

Primjer 2 Example 2

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-6-[3-(hidroksimetil)fenil]-1-benzofuran-2-karboksamid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-[3-(hydroxymethyl)phenyl]-1-benzofuran-2-carboxamide

[image] [image]

Smjesa od 130 mg (0.86 mmola) 3-(hidroksimetil)fenilborne kiseline, 200 mg (0.57 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-6-brom-1-benzofuran-2-karboksamida (primjer 2A), 1.72 mL (1.72 mmola) 1 N natrijeve lužine, 40 mg (0.06 mmola) 1,1'-bis(difenilfosfino)ferocenpaladijevog(II) klorida i 2 mL DMF zagrijava se 18 h na 80-85°C. Otapalo se ukloni pod sniženim tlakom. Sirovi produkt se pročisti na Kieselgel 60 (Merck, Darmstadt; eluens: diklormetan, diklormetan-metanol 20:1, diklormetan-metanol-amonijak 80:20:2). Otapalo se ukloni pod sniženim tlakom. Napokon se posljednji ostatci otapala odstrane u visokom vakuumu. Izolirano je 127 mg (54 % od teor.) naslovnog spoja. A mixture of 130 mg (0.86 mmol) 3-(hydroxymethyl)phenylboronic acid, 200 mg (0.57 mmol) N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1- benzofuran-2-carboxamide (example 2A), 1.72 mL (1.72 mmol) of 1 N sodium hydroxide solution, 40 mg (0.06 mmol) of 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride and 2 mL of DMF are heated for 18 h at 80-85°C. The solvent was removed under reduced pressure. The crude product was purified on Kieselgel 60 (Merck, Darmstadt; eluent: dichloromethane, dichloromethane-methanol 20:1, dichloromethane-methanol-ammonia 80:20:2). The solvent was removed under reduced pressure. Finally, the last remnants of the solvent are removed under high vacuum. 127 mg (54% of theory) of the title compound was isolated.

1H-NMR (200 MHz, CDCl3): δ = 7.86 (d, 1H), 7.72-7.28 (m, 7H), 6.77 (d, 1H), 4.62 (s, 2H), 4.28-4.12 (m, 1H), 3.56-3.38 (m, 1H), 3.04-2.78 (m, 4H), 2.75-2.59 (m, 1H), 2.16-2.02 (m, 1H), 1.93-1.66 (m, 3H), 1.66-1.45 (m, 1H). 1H-NMR (200 MHz, CDCl3): δ = 7.86 (d, 1H), 7.72-7.28 (m, 7H), 6.77 (d, 1H), 4.62 (s, 2H), 4.28-4.12 (m, 1H) , 3.56-3.38 (m, 1H), 3.04-2.78 (m, 4H), 2.75-2.59 (m, 1H), 2.16-2.02 (m, 1H), 1.93-1.66 (m, 3H), 1.66-1.45 ( m, 1H).

HPLC (metoda 1): Rt = 3.5 min. LC-MS (metoda 2): Rt = 1.50 min. MS (ESIpos): m/z = 377 (M+H)+. HPLC (method 1): Rt = 3.5 min. LC-MS (method 2): Rt = 1.50 min. MS (ESIpos): m/z = 377 (M+H) + .

Primjer 3 Example 3

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-6-[4-(hidroksimetil)fenil]-1-benzofuran-2-karboksamid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-[4-(hydroxymethyl)phenyl]-1-benzofuran-2-carboxamide

[image] [image]

Smjesa od 130 mg (0.86 mmola) 4-(hidroksimetil)fenilborne kiseline, 200 mg (0.57 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-6-brom-1-benzofuran-2-karboksamida (primjer 2A), 1.72 mL (1.72 mmola) 1 N natrijeve lužine, 40 mg (0.06 mmola) 1,1'-bis(difenilfosfino)ferocenpaladijevog(II) klorida i 2 mL DMF zagrijava se 18 h na 80-85°C. Otapalo se ukloni pod sniženim tlakom. Sirovi produkt se pročisti na Kieselgel 60 (Merck, Darmstadt; eluens: diklormetan, diklormetan-metanol 20:1, diklormetan-metanol-amonijak 80:20:2). Otapalo se ukloni pod sniženim tlakom. Konačno se posljednji ostatci otapala uklone u visokom vakuumu. Izolirano je 55 mg (23 % od teor.) naslovnog spoja. A mixture of 130 mg (0.86 mmol) 4-(hydroxymethyl)phenylboronic acid, 200 mg (0.57 mmol) N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1- benzofuran-2-carboxamide (example 2A), 1.72 mL (1.72 mmol) of 1 N sodium hydroxide solution, 40 mg (0.06 mmol) of 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride and 2 mL of DMF are heated for 18 h at 80-85°C. The solvent was removed under reduced pressure. The crude product was purified on Kieselgel 60 (Merck, Darmstadt; eluent: dichloromethane, dichloromethane-methanol 20:1, dichloromethane-methanol-ammonia 80:20:2). The solvent was removed under reduced pressure. Finally, the last remnants of the solvent are removed under high vacuum. 55 mg (23% of theory) of the title compound was isolated.

1H-NMR (200 MHz, CDCl3): δ = 7.83 (d, 1H), 7.69-7.28 (m, 7H), 6.77 (d, 1H), 4.62 (s, 2H), 4.28-4.12 (m, 1H), 3.56-3.38 (m, 1H), 3.04-2.78 (m, 4H), 2.75-2.59 (m, 1H), 2.16-2.02 (m, 1H), 1.93-1.66 (m, 3H), 1.66-1.45 (m, 1H). 1H-NMR (200 MHz, CDCl3): δ = 7.83 (d, 1H), 7.69-7.28 (m, 7H), 6.77 (d, 1H), 4.62 (s, 2H), 4.28-4.12 (m, 1H) , 3.56-3.38 (m, 1H), 3.04-2.78 (m, 4H), 2.75-2.59 (m, 1H), 2.16-2.02 (m, 1H), 1.93-1.66 (m, 3H), 1.66-1.45 ( m, 1H).

HPLC (metoda 1): Rt = 3.5 min. HPLC (method 1): Rt = 3.5 min.

LC-MS (metoda 2): Rt = 1.46 min. LC-MS (method 2): Rt = 1.46 min.

MS (ESIpos): m/z = 377 (M+H)+. MS (ESIpos): m/z = 377 (M+H) + .

Primjer 4 Example 4

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-6-[4-(4-morfolinil)-fenil]-1-benzofuran-2-karboksamid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-[4-(4-morpholinyl)-phenyl]-1-benzofuran-2-carboxamide

[image] [image]

Smjesa od 180 mg (0.86 mmola) 4-(4-morfolinil)fenilborne kiseline, 200 mg (0.57 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-6-brom-1-benzofuran-2-karboksamida (primjer 2A), 1.72 mL (1.72 mmola) 1 N natrijeve lužine, 40 mg (0.06 mmol) 1,1'-bis(difenilfosfino)-ferocenpaladijevog(II) klorida i 2 mL DMF zagrijava se 18 h na 80-85°C. Otapalo se ukloni pod sniženim tlakom. Sirovi produkt se pročisti na Kieselgel 60 (Merck, Darmstadt; eluens: diklormetan, diklormetan-metanol 20:1, diklormetan-metanol-amonijak 80:20:2). Otapalo se ukloni pod sniženim tlakom. Konačno se posljednji ostatci otapala odstrane u visokom vakuumu. Izolirano je 79 mg (32 % od teor.) naslovnog spoja. A mixture of 180 mg (0.86 mmol) 4-(4-morpholinyl)phenylboronic acid, 200 mg (0.57 mmol) N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo- 1-benzofuran-2-carboxamide (Example 2A), 1.72 mL (1.72 mmol) of 1 N sodium hydroxide solution, 40 mg (0.06 mmol) of 1,1'-bis(diphenylphosphino)-ferrocenepalladium(II) chloride and 2 mL of DMF are heated 18 h at 80-85°C. The solvent was removed under reduced pressure. The crude product was purified on Kieselgel 60 (Merck, Darmstadt; eluent: dichloromethane, dichloromethane-methanol 20:1, dichloromethane-methanol-ammonia 80:20:2). The solvent was removed under reduced pressure. Finally, the last remnants of the solvent are removed under high vacuum. 79 mg (32% of theory) of the title compound was isolated.

1H -NMR (200 MHz, CDCl3): δ = 7.84-7.29 (m, 7H), 6.99 (d, 1H), 6.84-6.70 (m, 1H), 4.28-4.13 (m, 1H), 3.97-3.83 (m, 2H), 3.59-3.36 (m, 1H), 3.29-3.13 (m, 2H), 3.04-2.78 (m, 4H), 2.75-2.59 (m, 1H), 2.16-2.02 (m, 1H), 1.93-1.66 (m, 3H), 1.66-1.45 (m, 1H). 1H-NMR (200 MHz, CDCl3): δ = 7.84-7.29 (m, 7H), 6.99 (d, 1H), 6.84-6.70 (m, 1H), 4.28-4.13 (m, 1H), 3.97-3.83 ( m, 2H), 3.59-3.36 (m, 1H), 3.29-3.13 (m, 2H), 3.04-2.78 (m, 4H), 2.75-2.59 (m, 1H), 2.16-2.02 (m, 1H), 1.93-1.66 (m, 3H), 1.66-1.45 (m, 1H).

HPLC (metoda 1): Rt = 3.5 min. HPLC (method 1): Rt = 3.5 min.

LC-MS (metoda 2): Rt = 1.74 min. LC-MS (method 2): Rt = 1.74 min.

MS (ESIpos): m/z = 432 (M+H)+. MS (ESIpos): m/z = 432 (M+H) + .

Primjer 5 Example 5

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-6-[4-(metoksi)-fenil]-1-benzofuran-2-karboksamid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-[4-(methoxy)-phenyl]-1-benzofuran-2-carboxamide

[image] [image]

Smjesa od 130 mg (0.86 mmola) 4-metoksifenilborne kiseline, 200 mg (0.57 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-6-brom-1-benzofuran-2-karboksamida (primjer 2A), 1.72 mL (1.72 mmola) 1 N natrijeve lužine, 40 mg (0.06 mmola) 1,1'-bis(difenilfosfino)-ferocenpaladijevog(II) klorida i 2 mL DMF zagrijava se 18 h na 80-85°C. Otapalo se ukloni pod sniženim tlakom. Sirovi produkt se pročisti na Kieselgel 60 (Merck, Darmstadt; eluens: diklormetan, diklormetan-metanol 20:1, diklormetan-metanol-amonijak 80:20:2). Otapalo se odstrani pod sniženim tlakom. Napokon se posljednji ostatci otapala uklone u visokom vakuumu. Izolirano je 160 mg (68 % od teor.) naslovnog spoja. A mixture of 130 mg (0.86 mmol) of 4-methoxyphenylboronic acid, 200 mg (0.57 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1-benzofuran-2 -carboxamide (example 2A), 1.72 mL (1.72 mmol) of 1 N sodium hydroxide solution, 40 mg (0.06 mmol) of 1,1'-bis(diphenylphosphino)-ferrocenepalladium(II) chloride and 2 mL of DMF is heated for 18 h at 80- 85°C. The solvent was removed under reduced pressure. The crude product was purified on Kieselgel 60 (Merck, Darmstadt; eluent: dichloromethane, dichloromethane-methanol 20:1, dichloromethane-methanol-ammonia 80:20:2). The solvent was removed under reduced pressure. Finally, the last remnants of the solvent are removed under high vacuum. 160 mg (68% of theory) of the title compound was isolated.

1H-NMR (200 MHz, CDCl3): δ = 7.84-7.75 (m, 1H), 7.62-7.45 (m, 5H), 6.99 (m, 2H), 6.84-6.70 (m, 1H), 4.28-4.13 (m, 1H), 3.87 (s, 3H), 3.59-3.36 (m, 1H), 3.04-2.78 (m, 4H), 2.75-2.59 (m, 1H), 2.16-2.02 (m, 1H), 1.93-1.66 (m, 3H), 1.66-1.45 (m, 1H). 1H-NMR (200 MHz, CDCl3): δ = 7.84-7.75 (m, 1H), 7.62-7.45 (m, 5H), 6.99 (m, 2H), 6.84-6.70 (m, 1H), 4.28-4.13 ( m, 1H), 3.87 (s, 3H), 3.59-3.36 (m, 1H), 3.04-2.78 (m, 4H), 2.75-2.59 (m, 1H), 2.16-2.02 (m, 1H), 1.93- 1.66 (m, 3H), 1.66-1.45 (m, 1H).

HPLC (metoda 1): Rt = 4.0 min. HPLC (method 1): Rt = 4.0 min.

LC-MS (metoda 3): Rt = 3.2 min. LC-MS (method 3): Rt = 3.2 min.

MS (ESIpos): m/z = 377 (M + H)+. MS (ESIpos): m/z = 377 (M + H) + .

Primjer 6 Example 6

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-6-[3-(metoksi)-fenil]-1-benzofuran-2-karboksamid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-[3-(methoxy)-phenyl]-1-benzofuran-2-carboxamide

[image] [image]

Smjesa od 130 mg (0.86 mmola) 3-metilfenilborne kiseline, 200 mg (0.57 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-6-brom-1-benzofuran-2-karboksamida (primjer 2A), 1.72 mL (1.72 mmola) 1 N natrijeve lužine, 40 mg (0.06 mmola) 1,l'-bis(difenilfosfino)-ferocenpaladijevog(II) klorida i 2 mL DMF zagrijava se 18 h na 80-85°C. Otapalo se ukloni pod sniženim tlakom. Sirovi produkt se pročisti na Kieselgel 60 (Merck, Darmstadt; eluens: diklormetan, diklormetan-metanol 20:1, diklormetan-metanol-amonijak 80:20:2). Otapalo se ukloni pod sniženim tlakom. Napokon se posljednji ostatci otapala uklone u visokom vakuumu. Izolirano je 151 mg (64 % od teor.) naslovnog spoja. A mixture of 130 mg (0.86 mmol) of 3-methylphenylboronic acid, 200 mg (0.57 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1-benzofuran-2 -carboxamide (example 2A), 1.72 mL (1.72 mmol) of 1 N sodium hydroxide solution, 40 mg (0.06 mmol) of 1,1'-bis(diphenylphosphino)-ferrocenepalladium(II) chloride and 2 mL of DMF is heated for 18 h at 80- 85°C. The solvent was removed under reduced pressure. The crude product was purified on Kieselgel 60 (Merck, Darmstadt; eluent: dichloromethane, dichloromethane-methanol 20:1, dichloromethane-methanol-ammonia 80:20:2). The solvent was removed under reduced pressure. Finally, the last remnants of the solvent are removed under high vacuum. 151 mg (64% of theory) of the title compound was isolated.

lH-NMR (200 MHz, CDCl3): δ = 7.90-7.80 (m, 1H), 7.72-7.08 (m, 5H), 6.95-6.85 (m, 1H), 6.84-6.70 (m, 1H), 4.28-4.13 (m, 1H), 3.87 (s, 3H), 3.59-3.36 (m, 1H), 3.04-2.78 (m, 4H), 2.75-2.59 (m, 1H), 2.16-2.02 (m, 1H), 1.93-1.66 (m, 3H), 1.66-1.45 (m, 1H). 1H-NMR (200 MHz, CDCl3): δ = 7.90-7.80 (m, 1H), 7.72-7.08 (m, 5H), 6.95-6.85 (m, 1H), 6.84-6.70 (m, 1H), 4.28- 4.13 (m, 1H), 3.87 (s, 3H), 3.59-3.36 (m, 1H), 3.04-2.78 (m, 4H), 2.75-2.59 (m, 1H), 2.16-2.02 (m, 1H), 1.93-1.66 (m, 3H), 1.66-1.45 (m, 1H).

HPLC (metoda 1): Rt = 4.0 min. HPLC (method 1): Rt = 4.0 min.

C-MS (metoda 2): Rt = 1.87 min. C-MS (method 2): Rt = 1.87 min.

MS (ESIpos): m/z = 377 (M+H)+. MS (ESIpos): m/z = 377 (M+H) + .

Primjer 7 Example 7

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-6-(4-fluorfenil)-1-benzofuran-2-karboksamid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(4-fluorophenyl)-1-benzofuran-2-carboxamide

[image] [image]

Smjesa od 120 mg (0.86 mmola) 4-fluorfenilborne kiseline, 200 mg (0.57 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-6-brom-1-benzofuran-2-karboksamida (primjer 2A), 1.72 mL (1.72 mmola) 1 N natrijeve lužine, 40 mg (0.06 mmola) 1,1'-bis(difenilfosfino)-ferocenpaladijevog(II) klorida i 2 mL DMF zagrijava se 18 h na 80-85°C. Otapalo se odstrani pod sniženim tlakom. Sirovi produkt se pročisti na Kieselgel 60 (Merck, Darmstadt; eluens: diklormetan, diklormetan-metanol 20:1, diklormetan-metanol-amonijak 80:20:2). Otapalo se odstrani pod sniženim tlakom. Napokon se posljednji ostatci otapala uklone u visokom vakuumu. Izolirano je 155 mg (68 % od teor.) naslovnog spoja. A mixture of 120 mg (0.86 mmol) of 4-fluorophenylboronic acid, 200 mg (0.57 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1-benzofuran-2 -carboxamide (example 2A), 1.72 mL (1.72 mmol) of 1 N sodium hydroxide solution, 40 mg (0.06 mmol) of 1,1'-bis(diphenylphosphino)-ferrocenepalladium(II) chloride and 2 mL of DMF is heated for 18 h at 80- 85°C. The solvent was removed under reduced pressure. The crude product was purified on Kieselgel 60 (Merck, Darmstadt; eluent: dichloromethane, dichloromethane-methanol 20:1, dichloromethane-methanol-ammonia 80:20:2). The solvent was removed under reduced pressure. Finally, the last remnants of the solvent are removed under high vacuum. 155 mg (68% of theory) of the title compound was isolated.

1H-NMR (200 MHz, CDCl3): δ = 7.99 (s, 1H), 7.64-7.46 (m, 5H), 7.22-7.07 (m, 2H), 6.84-6.70 (m, IH), 4.28-4.13 (m, IH), 3.59-3.36 (m, IH), 3.04-2.78 (m, 4H), 2.75-2.59 (m, 1H), 2.16-2.02 (m, 1H), 1.93-1.66 (m, 3H), 1.66-1.45 (m, 1H). HPLC (metoda 1): Rt = 4.1 min. 1H-NMR (200 MHz, CDCl3): δ = 7.99 (s, 1H), 7.64-7.46 (m, 5H), 7.22-7.07 (m, 2H), 6.84-6.70 (m, IH), 4.28-4.13 ( m, IH), 3.59-3.36 (m, IH), 3.04-2.78 (m, 4H), 2.75-2.59 (m, 1H), 2.16-2.02 (m, 1H), 1.93-1.66 (m, 3H), 1.66-1.45 (m, 1H). HPLC (method 1): Rt = 4.1 min.

LC-MS (metoda 2): Rt = 1.92 min. LC-MS (method 2): Rt = 1.92 min.

MS (ESIpos): m/z = 365 (M + H)+. MS (ESIpos): m/z = 365 (M + H) + .

Primjer 8 Example 8

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-6-(4-trifluormetoksifenil)-1-benzofuran-2-karboksamid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(4-trifluoromethoxyphenyl)-1-benzofuran-2-carboxamide

[image] [image]

Smjesa od 180 mg (0.86 mmola) 4-(trifluormetoksi)fenilborne kiseline, 200 mg (0.57 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-6-brom-1-benzofuran-2-karboksamida (primjer 2A), 1.72 ml_ (1.72 mmola) 1 N natrijeve lužine, 40 mg (0.06 mmola) 1,1'-bis(difenilfosfino)ferocenpaladijevog(II) klorida i 2 ml DMF zagrijava se 18 h na 80-85°C. Otapalo se odstrani pod sniženim tlakom. Sirovi produkt se pročisti na Kieselgel 60 (Merck, Darmstadt; eluens: diklormetan, diklormetan-metanol 20:1, diklormetan-metanol-amonijak 80:20:2). Otapalo se odstrani pod sniženim tlakom. Napokon se posljednji ostatci otapala uklone u visokom vakuumu. Izolirano je 155 mg (68 % od teor.) naslovnog spoja. A mixture of 180 mg (0.86 mmol) 4-(trifluoromethoxy)phenylboronic acid, 200 mg (0.57 mmol) N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1- benzofuran-2-carboxamide (example 2A), 1.72 ml_ (1.72 mmol) of 1 N sodium hydroxide solution, 40 mg (0.06 mmol) of 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride and 2 ml of DMF were heated for 18 h at 80-85°C. The solvent was removed under reduced pressure. The crude product was purified on Kieselgel 60 (Merck, Darmstadt; eluent: dichloromethane, dichloromethane-methanol 20:1, dichloromethane-methanol-ammonia 80:20:2). The solvent was removed under reduced pressure. Finally, the last remnants of the solvent are removed under high vacuum. 155 mg (68% of theory) of the title compound was isolated.

1H-NMR (200 MHz, CDCl3): δ = 7.82 (s, 1H), 7.72-7AS (m, 5H), 7.36-7.27 (m, 2H), 6.84-6.70 (m, 1H), 4.28-4.13 (m, IH), 3.59-3.36 (m, 1H), 3.04-2.78 (m, 4H), 2.75-2.59 (m, 1H), 2.16-2.02 (m, 1H), 1.93-1.66 (m, 3H), 1.66-1.45 (m, 1H). HPLC (metoda 1): Rt = 4.4 min. 1H-NMR (200 MHz, CDCl3): δ = 7.82 (s, 1H), 7.72-7AS (m, 5H), 7.36-7.27 (m, 2H), 6.84-6.70 (m, 1H), 4.28-4.13 ( m, 1H), 3.59-3.36 (m, 1H), 3.04-2.78 (m, 4H), 2.75-2.59 (m, 1H), 2.16-2.02 (m, 1H), 1.93-1.66 (m, 3H), 1.66-1.45 (m, 1H). HPLC (method 1): Rt = 4.4 min.

LC-MS (metoda 2): Rt = 2.22 min. LC-MS (method 2): Rt = 2.22 min.

MS (ESIpos): m/z = 431 (M + H)+. MS (ESIpos): m/z = 431 (M + H) + .

Primjer 9 Example 9

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-6-(3-hidroksi-l-propinil)-1-benzofuran-2-karboksamid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(3-hydroxy-1-propynyl)-1-benzofuran-2-carboxamide

[image] [image]

Smjesa od 289 mg (5.15 mmola) propargilnog alkohola, 150 mg (0.43 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-6-brom-1-benzofuran-2-karboksamid (primjer 2A), 1.6 mg (0.01 mmol) bakrovog (I) jodida, 15 mg (0.02 mmola) bis(trifenilfosfin)-paladijevog(II) klorida, 61 mg (0.86 mmola) piridina i 1 ml THF zagrijava se preko noći pod refluksom. Sirovi produkt pretvori se sa 10 ml 1 N natrijeve lužine i ekstrahira tri puta s ukupno 100 ml etilnog estera octene kiseline. Spojene organske faze osuše se iznad magnezijevog sulfata, a otapalo se odstrani pod sniženim tlakom. Sirovi produkt pročisti se na Kieselgel 60 (Merck, Darmstadt; eluens: diklormetan-trietilamin 100:1, potom diklormetan-metanot-trietilamin 100:1:1 do diklormetan-metanol-trietilamin 100:10:1). Otapalo se odstrani pod sniženim tlakom. Napokon se posljednji ostatci otapala uklone u visokom vakuumu. Izolirano je 40 mg (27 % od teor.) naslovnog spoja. A mixture of 289 mg (5.15 mmol) propargyl alcohol, 150 mg (0.43 mmol) N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1-benzofuran-2-carboxamide (Example 2A), 1.6 mg (0.01 mmol) of copper(I) iodide, 15 mg (0.02 mmol) of bis(triphenylphosphine)-palladium(II) chloride, 61 mg (0.86 mmol) of pyridine and 1 ml of THF were heated overnight under reflux. The crude product is converted with 10 ml of 1 N sodium hydroxide solution and extracted three times with a total of 100 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, and the solvent is removed under reduced pressure. The crude product was purified on Kieselgel 60 (Merck, Darmstadt; eluent: dichloromethane-triethylamine 100:1, then dichloromethane-methanot-triethylamine 100:1:1 to dichloromethane-methanol-triethylamine 100:10:1). The solvent was removed under reduced pressure. Finally, the last remnants of the solvent are removed under high vacuum. 40 mg (27% of theory) of the title compound was isolated.

HPLC (metoda 1): Rt = 3.3 min. HPLC (method 1): Rt = 3.3 min.

LC-MS (metoda 3): Rt = 2.6 min. LC-MS (method 3): Rt = 2.6 min.

MS (ESIpos): m/z = 325 (M+H)+. MS (ESIpos): m/z = 325 (M+H) + .

Primjer 10 Example 10

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-5-fluor-7-(4-fluorfenil)-1-benzofuran-2-karboksamid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-fluoro-7-(4-fluorophenyl)-1-benzofuran-2-carboxamide

[image] [image]

Smjesa od 40 mg (0.29 mmola) 4-fluorfenilborne kiseline, 70 mg (0.19 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-5-fluor-7-brom-1-benzofuran-2-karboksamida (primjer 5A), 0.57 mL (0.57 mmola) 1 N natrijeve lužine, 14 mg (0.02 mmola) 1,1'-bis(difenilfosfino)-ferocenpaladijevog(II) klorida i 2 mL DMF zagrijava se preko noći na 85°C. Otapalo se odstrani pod sniženim tlakom. Sirovi produkt pretvori se sa 1 N natrijevom lužinom i tri puta ekstrahira s ukupno 100 mL etilnog estera octene kiseline. Spojene organske faze osuše se iznad magnezijevog sulfata, a otapalo se ukloni pod sniženim tlakom. Sirovi produkt se preuzme u metanol i trese zajedno s kiselim ionskim izmjenjivačem (Dowex® WX2-200) 20-ak minuta. Opterećeni ionski izmjenjivač ispere se najprije tri puta sa po 30 mL metanola, potom vodom, ponovno metanolom, zatim diklormetanom, ponovno metanolom, zatim s THF, te na kraju još jedanput metanolom. Produkt se eluira metanol-trietilaminom 95:5. Otapalo se odstrani pod sniženim tlakom na rotacijskom isparivaču. Za fino pročišćavanje smjesa se pročisti na Kieselgel 60 (Merck, Darmstadt; eluens: diklormetan-trietilamin 100:1, zatim diklormetan-metanol-trietilamin 100:1:1 do diklormetan-metanol-trietilamin 100:10:1). Otapalo se odstrani pod sniženim tlakom. A mixture of 40 mg (0.29 mmol) 4-fluorophenylboronic acid, 70 mg (0.19 mmol) N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-fluoro-7-bromo-1 -benzofuran-2-carboxamide (Example 5A), 0.57 mL (0.57 mmol) of 1 N sodium hydroxide solution, 14 mg (0.02 mmol) of 1,1'-bis(diphenylphosphino)-ferrocenepalladium(II) chloride and 2 mL of DMF were heated over nights at 85°C. The solvent was removed under reduced pressure. The crude product is converted with 1 N sodium hydroxide solution and extracted three times with a total of 100 mL of acetic acid ethyl ester. The combined organic phases are dried over magnesium sulfate, and the solvent is removed under reduced pressure. The crude product is taken up in methanol and shaken together with an acidic ion exchanger (Dowex® WX2-200) for about 20 minutes. The loaded ion exchanger is first washed three times with 30 mL of methanol, then with water, again with methanol, then with dichloromethane, again with methanol, then with THF, and finally once more with methanol. The product is eluted with methanol-triethylamine 95:5. The solvent was removed under reduced pressure on a rotary evaporator. For fine purification, the mixture is purified on Kieselgel 60 (Merck, Darmstadt; eluent: dichloromethane-triethylamine 100:1, then dichloromethane-methanol-triethylamine 100:1:1 to dichloromethane-methanol-triethylamine 100:10:1). The solvent was removed under reduced pressure.

Napokon se posljednji ostatci otapala uklone u visokom vakuumu. Finally, the last remnants of the solvent are removed under high vacuum.

Izolirano je 51 mg (70 % od teor.) naslovnog spoja. 51 mg (70% of theory) of the title compound was isolated.

1H -NMR (400 MHz, metanol-d4): δ = 7.99-7.90 (m, 2H), 7.59 (s, 1H), 7.45-7.35 (m, 2H), 7.30-7.22 (m, 2H), 4.24-4.18 (m, 1H), 3.34-3.29 (m, 1H), 3.07-2.97 (m, 1H), 2.93-2.77 (m, 4H), 2.13-2.05 (m, 1H), 1.98-1.86 (m, 1H), 1.84-1.75 (m, 2H), 1.63-1.53 (m, 1H). 1H-NMR (400 MHz, methanol-d4): δ = 7.99-7.90 (m, 2H), 7.59 (s, 1H), 7.45-7.35 (m, 2H), 7.30-7.22 (m, 2H), 4.24- 4.18 (m, 1H), 3.34-3.29 (m, 1H), 3.07-2.97 (m, 1H), 2.93-2.77 (m, 4H), 2.13-2.05 (m, 1H), 1.98-1.86 (m, 1H) ), 1.84-1.75 (m, 2H), 1.63-1.53 (m, 1H).

HPLC (metoda 1): Rt = 4.3 min. HPLC (method 1): Rt = 4.3 min.

LC-MS (metoda 3): Rt = 3.08 min. LC-MS (method 3): Rt = 3.08 min.

MS (ESIpos): m/z = 383 (M+H)+. MS (ESIpos): m/z = 383 (M+H) + .

Primjer 11 Example 11

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-5-fluor-7-(4-trifluormetoksifenil)-1-benzofuran-2-karboksamid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-fluoro-7-(4-trifluoromethoxyphenyl)-1-benzofuran-2-carboxamide

[image] [image]

Smjesa od 40 mg (0.29 mmola) 4-(trifluormetoksi)fenilborne kiseline, 70 mg (0.19 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-5-fluor-7-brom-1-benzofuran-2-karboksamida (primjer 5A), 0.57 mL (0.57 mmola) 1 N natrijeve lužine, 14 mg (0.02 mmola) 1,1'-bis(difenilfosfino)ferocenpaladijevog(II) klorida i 2 mL DMF zagrijava se preko noći na 85°C. Otapalo se odstrani pod sniženim tlakom. Sirovi produkt pretvori se sa 1 N natrijevom lužinom i triput ekstrahira s ukupno 100 mL etilnog estera octene kiseline. Spojene organske faze osuše se iznad magnezijevog sulfata, a otapalo se ukloni pod sniženim tlakom. Sirovi produkt se preuzme u metanol i trese zajedno s kiselim ionskim izmjenjivačem (Dowex® WX2-200) 20-ak minuta. Opterećeni ionski izmjenjivač ispere se najprije tri puta sa po 30 mL metanola, potom vodom, ponovno metanolom, zatim diklormetanom, ponovno metanolom, zatim s THF, te na kraju još jedanput metanolom. Produkt se eluira metanol-trietilaminom 95:5. Otapalo se odstrani pod sniženim tlakom na rotacijskom isparivaču. Za fino pročišćavanje smjesa se pročisti na Kieselgel 60 (Merck, Darmstadt; eluens: diklormetan-trietilamin 100:1, zatim diklormetan-metanol-trietilamin 100:1:1 do diklormetan-metanol-trietilamin 100:10:1). Otapalo se odstrani pod sniženim tlakom. Napokon se posljednji ostatci otapala uklone u visokom vakuumu. Izolirano je 52 mg (61 % od teor.) naslovnog spoja. A mixture of 40 mg (0.29 mmol) 4-(trifluoromethoxy)phenylboronic acid, 70 mg (0.19 mmol) N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-fluoro-7- Bromo-1-benzofuran-2-carboxamide (Example 5A), 0.57 mL (0.57 mmol) of 1 N sodium hydroxide solution, 14 mg (0.02 mmol) of 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride and 2 mL of DMF are heated overnight at 85°C. The solvent was removed under reduced pressure. The crude product is converted with 1 N sodium hydroxide solution and extracted three times with a total of 100 mL of acetic acid ethyl ester. The combined organic phases are dried over magnesium sulfate, and the solvent is removed under reduced pressure. The crude product is taken up in methanol and shaken together with an acidic ion exchanger (Dowex® WX2-200) for about 20 minutes. The loaded ion exchanger is first washed three times with 30 mL of methanol, then with water, again with methanol, then with dichloromethane, again with methanol, then with THF, and finally once more with methanol. The product is eluted with methanol-triethylamine 95:5. The solvent was removed under reduced pressure on a rotary evaporator. For fine purification, the mixture is purified on Kieselgel 60 (Merck, Darmstadt; eluent: dichloromethane-triethylamine 100:1, then dichloromethane-methanol-triethylamine 100:1:1 to dichloromethane-methanol-triethylamine 100:10:1). The solvent was removed under reduced pressure. Finally, the last remnants of the solvent are removed under high vacuum. 52 mg (61% of theory) of the title compound was isolated.

1H-NMR (400 MHz, metanol-d4): δ = 8.08-8.00 (m, 2H), 7.59 (s, 1H), 7.49-7.41 (m, 4H), 4.24-4.18 (m, 1H), 3.34-3.29 (m, 1H), 3.07-2.97 (m, 1H), 2.93-2.77 (m, 4H), 2.13-2.05 (m, 1H), 1.98-1.86 (m, 1H), 1.84-1.75 (m, 2H), 1.63-1.53 (m, 1H). 1H-NMR (400 MHz, methanol-d4): δ = 8.08-8.00 (m, 2H), 7.59 (s, 1H), 7.49-7.41 (m, 4H), 4.24-4.18 (m, 1H), 3.34- 3.29 (m, 1H), 3.07-2.97 (m, 1H), 2.93-2.77 (m, 4H), 2.13-2.05 (m, 1H), 1.98-1.86 (m, 1H), 1.84-1.75 (m, 2H) ), 1.63-1.53 (m, 1H).

HPLC (metoda 1): Rt = 4.6 min. HPLC (method 1): Rt = 4.6 min.

LC-MS (metoda 3): Rt = 3.37 min. LC-MS (method 3): Rt = 3.37 min.

MS (ESIpos): m/z = 449 (M+H)+. MS (ESIpos): m/z = 449 (M+H) + .

Primjer 12 Example 12

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-5-fenil-1-benzotiofen-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-phenyl-1-benzothiophene-2-carboxamide hydrochloride

[image] [image]

Smjesi od 40 mg (0.10 mmol) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-5-brom-1-benzotiofen-2-karboksamid-hidroklorida (primjer 14A) i 12.1 mg (0.10 mmol) fenilborne kiseline u 1 mL DMF doda se 0.15 mL 2 M vodene otopine natrijevog karbonata i 4.1 mg (0.005 mmola) PdCl2(dppf). Reakcijska smjesa zagrijava se 14 h na 80°C, filtrira na silikagelu i zgusne do suhoga. Nakon pročišćavanja sirovog produkta preparativnom HPLC, pretvaranja sa 1 N solnom kiselinom i sušenja u visokom vakuumu dobije se 7.3 mg (18 % od teor.) naslovnog spoja. Mixtures of 40 mg (0.10 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 14A) and 12.1 mg (0.10 mmol) of phenylboronic acid in 1 mL of DMF is added to 0.15 mL of a 2 M aqueous solution of sodium carbonate and 4.1 mg (0.005 mmol) of PdCl2(dppf). The reaction mixture is heated for 14 h at 80°C, filtered on silica gel and concentrated to dryness. After purification of the crude product by preparative HPLC, conversion with 1 N hydrochloric acid and drying in high vacuum, 7.3 mg (18% of theory) of the title compound is obtained.

HPLC (metoda 1): Rt = 4.2 min. HPLC (method 1): Rt = 4.2 min.

LC-MS (metoda 2): Rt = 1.49 min. LC-MS (method 2): Rt = 1.49 min.

MS (ESIpos): m/z = 363 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 363 (M+H)+ (free base).

Primjer 13 Example 13

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-6-fenil-1-benzotiofen-2-karboksamid-hidroksid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-phenyl-1-benzothiophene-2-carboxamide hydroxide

[image] [image]

Smjesi od 40 mg (0.10 mmol) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-6-brom-1-benzotiofen-2-karboksamid-hidroklorida (primjer 11A) i 12.1 mg (0.10 mmol) fenilborne kiseline u 1 mL DMF doda se 0.15 mL 2 M vodene otopine natrijevog karbonata i 4.1 mg (0.005 mmola) PdCl2(dppf). Reakcijska smjesa zagrijava se 14 h na 80°C, filtrira na silikagelu i zgusne do suhoga. Nakon pročišćavanja sirovog produkta preparativnom HPLC, pretvaranja sa 1 N solnom kiselinom i sušenja u visokom vakuumu dobije se 14.5 mg (37 % od teor.) naslovnog spoja. Mixtures of 40 mg (0.10 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 11A) and 12.1 mg (0.10 mmol) of phenylboronic acid in 1 mL of DMF is added to 0.15 mL of a 2 M aqueous solution of sodium carbonate and 4.1 mg (0.005 mmol) of PdCl2(dppf). The reaction mixture is heated for 14 h at 80°C, filtered on silica gel and concentrated to dryness. After purification of the crude product by preparative HPLC, conversion with 1 N hydrochloric acid and drying in high vacuum, 14.5 mg (37% of theory) of the title compound are obtained.

1H -NMR (200 MHz, DMSO-d6): δ = 9.91 (m, 1H), 9.02 (d, 1H), 8.38 (m, 1H), 8.32 (m, 1H), 8.06 (d, 1H), 7.78 (m, 3H), 7.58-7.37 (m, 3H), 4.32 (m, 1H), 3.78-3.03 (m, 6H), 2.28-2.05 (m, 2H), 1.93 (m, 2H), 1.78 (m, 1H). 1H-NMR (200 MHz, DMSO-d6): δ = 9.91 (m, 1H), 9.02 (d, 1H), 8.38 (m, 1H), 8.32 (m, 1H), 8.06 (d, 1H), 7.78 (m, 3H), 7.58-7.37 (m, 3H), 4.32 (m, 1H), 3.78-3.03 (m, 6H), 2.28-2.05 (m, 2H), 1.93 (m, 2H), 1.78 (m , 1H).

HPLC (metoda 1): Rt = 4.2 min. HPLC (method 1): Rt = 4.2 min.

Primjer 14 Example 14

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-6-(3-metoksifenil)-1-benzotiofen-2-karboksamid-hidro klorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(3-methoxyphenyl)-1-benzothiophene-2-carboxamide hydrochloride

[image] [image]

Smjesi od 40 mg (0.10 mmol) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-6-brom-1-benzotiofen-2-karboksamid-hidroklorida (primjer 11A) i 15.1 mg (0.10 mmol) 3-metoksifenilborne kiseline u 1 mL DMF doda se 0.3 mL 2 M vodene otopine natrijevog karbonata i 4.1 mg (0.005 mmola) PdCl2(dppf). Reakcijska smjesa zagrijava se 14 h na 80°C, filtrira na silikagelu i zgusne do suhoga. Nakon pročišćavanja sirovog produkta preparativnom HPLC, pretvaranja sa 1 N solnom kiselinom i sušenja u visokom vakuumu dobije se 25.5 mg (57 % od teor.) naslovnog spoja. Mixtures of 40 mg (0.10 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 11A) and 15.1 mg (0.10 mmol) of 3-methoxyphenylboronic acid in 1 mL of DMF was added to 0.3 mL of 2 M aqueous sodium carbonate solution and 4.1 mg (0.005 mmol) of PdCl2(dppf). The reaction mixture is heated for 14 h at 80°C, filtered on silica gel and concentrated to dryness. After purification of the crude product by preparative HPLC, conversion with 1 N hydrochloric acid and drying in high vacuum, 25.5 mg (57% of theory) of the title compound are obtained.

1H-NMR (200 MHz, DMSO-d6): δ = 9.70 (s, 1H), 8.97 (d, 1H), 8.38 (m, 1H), 8.28 (m, 1H), 7.99 (m, 1H), 7.78 (m, 1H), 7.37 (m, 3H), 6.98 (m, 1H), 4.33 (m, 1H), 3.86 (s, 3H), 3.79-3.12 (m, 6H), 2.28-2.00 (m, 2H), 1.99-1.68 (m, 3H). 1H-NMR (200 MHz, DMSO-d6): δ = 9.70 (s, 1H), 8.97 (d, 1H), 8.38 (m, 1H), 8.28 (m, 1H), 7.99 (m, 1H), 7.78 (m, 1H), 7.37 (m, 3H), 6.98 (m, 1H), 4.33 (m, 1H), 3.86 (s, 3H), 3.79-3.12 (m, 6H), 2.28-2.00 (m, 2H ), 1.99-1.68 (m, 3H).

HPLC (metoda 1): Rt = 4.2 min. HPLC (method 1): Rt = 4.2 min.

MS (ESIpos): m/z = 393 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 393 (M+H)+ (free base).

Primjer 15 Example 15

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-6-(3-hidroksi-1-propinil)-1-benzotiofen-2-karboksamid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(3-hydroxy-1-propynyl)-1-benzothiophene-2-carboxamide

[image] [image]

Otopi se 120 mg (0.30 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-6-brom-1-benzotiofen-2-karboksamid-hidroklorida (primjer 11A), 10.5 mg (0.01 mmol) PdCl2(PPh3)2 i 4.6 mg (0.02 mmola) bakrovog(I) jodida pod argonom u 1.5 mL trietilamina/DMF (2:1) i miješa kroz 1 h pri 60°C. Nakon dodatka 25.1 mg (0.45 mmola) propargilnog alkohola smjesa se zagrijava još 16 h na 70°C. Nakon hlađenja filtrira se na silikagelu i pročisti preparativnom HPLC, zgusne, te se produkt osuši u vakuumu. Dobije se 12 mg (11 % od teor.) naslovnog spoja. Dissolve 120 mg (0.30 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 11A), 10.5 mg (0.01 mmol) PdCl2(PPh3)2 and 4.6 mg (0.02 mmol) copper(I) iodide under argon in 1.5 mL triethylamine/DMF (2:1) and stirred for 1 h at 60°C. After the addition of 25.1 mg (0.45 mmol) of propargyl alcohol, the mixture is heated for another 16 h at 70°C. After cooling, it is filtered on silica gel and purified by preparative HPLC, thickened, and the product is dried in a vacuum. 12 mg (11% of theory) of the title compound is obtained.

1H-NMR (200 MHz, DMSO-d6): δ = 8.73 (d, 1H), 8.20 (m, 2H), 7.96 (d, 1H), 7.46 (dd, 1H), 4.34 (s, 2H), 4.09 (m, 1H), 3.32 (m, 1H), 3.16-2.77 (m, 5H), 1.99 (m, 1H), 1.91 (m, 1H), 1.70 (m, 2H), 1.49 (m, 1H). 1H-NMR (200 MHz, DMSO-d6): δ = 8.73 (d, 1H), 8.20 (m, 2H), 7.96 (d, 1H), 7.46 (dd, 1H), 4.34 (s, 2H), 4.09 (m, 1H), 3.32 (m, 1H), 3.16-2.77 (m, 5H), 1.99 (m, 1H), 1.91 (m, 1H), 1.70 (m, 2H), 1.49 (m, 1H).

HPLC (metoda 1): Rt = 3.4 min. HPLC (method 1): Rt = 3.4 min.

MS (ESIpos): m/z = 341 (M+H)+. MS (ESIpos): m/z = 341 (M+H) + .

Primjer 16 Example 16

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-fenil-1-benzotiofen-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-phenyl-1-benzothiophene-2-carboxamide hydrochloride

[image] [image]

Smjesi od 56 mg (0.14 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzotiofen-2-karboksamid-hidroklorida (primjer 8A) i 18.7 mg (0.15 mmola) fenilborne kiseline u 1 mL DMF doda se 0.14 mL 2 M vodene otopine natrijevog karbonata i 5.7 mg (0.007 mmola) PdCl2(dppf). Reakcijska smjesa zagrijava se na 80°C. Nakon 3 h na toj temperaturi doda se još 5.7 mg (0.007 mmola) PdCl2(dppf), te se sve miješa još 12 h pri 80°C. Reakcijska smjesa filtrira se na silikagelu i zgusne do suhoga. Nakon pročišćavanja produkta preparativnom HPLC, pretvaranjem sa 1 N solnom kiselinom i sušenja u visokom vakuumu dobije se 10.6 mg (18 % od teor.) naslovnog spoja. Mixtures of 56 mg (0.14 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A) and 18.7 mg (0.15 mmol) of phenylboronic acid in 1 mL of DMF is added to 0.14 mL of a 2 M aqueous solution of sodium carbonate and 5.7 mg (0.007 mmol) of PdCl2(dppf). The reaction mixture is heated to 80°C. After 3 h at that temperature, another 5.7 mg (0.007 mmol) of PdCl2(dppf) is added, and everything is stirred for another 12 h at 80°C. The reaction mixture is filtered on silica gel and concentrated to dryness. After purification of the product by preparative HPLC, conversion with 1 N hydrochloric acid and drying in high vacuum, 10.6 mg (18% of theory) of the title compound is obtained.

HPLC (metoda 1): Rt = 4.2 min. HPLC (method 1): Rt = 4.2 min.

Primjer 17 Example 17

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-(3-metoksifenil)-1-benzotiofen-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-(3-methoxyphenyl)-1-benzothiophene-2-carboxamide hydrochloride

[image] [image]

Smjesi od 49 mg (0.10 mmol) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzotiofen-2-karboksamid-hidroklorida (primjer 8A) i 15.8 mg (0.10 mmol) 3-metoksifenilborne kiseline u 1 mL DMF doda se 0.16 mL 2 M vodene otopine natrijevog karbonata i 4.2 mg (0.005 mmola) PdCl2(dppf). Reakcijska smjesa zagrijava se 14 h na 80°C, filtrira na silikagelu i zgusne do suhoga. Nakon pročišćavanja produkta preparativnom HPLC, pretvorbe sa 1 N solnom kiselinom i sušenja u visokom vakuumu dobije se 8.0 mg (18 % od teor.) naslovnog spoja. Mixtures of 49 mg (0.10 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A) and 15.8 mg (0.10 mmol) of 3-methoxyphenylboronic acid in 1 mL of DMF was added to 0.16 mL of 2 M aqueous sodium carbonate solution and 4.2 mg (0.005 mmol) of PdCl2(dppf). The reaction mixture is heated for 14 h at 80°C, filtered on silica gel and concentrated to dryness. After purification of the product by preparative HPLC, conversion with 1 N hydrochloric acid and drying in high vacuum, 8.0 mg (18% of theory) of the title compound is obtained.

HPLC (metoda 1): Rt = 4.2 min. HPLC (method 1): Rt = 4.2 min.

Primjer 18 Example 18

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-(2-metoksifenil)-1-benzotiofen-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-(2-methoxyphenyl)-1-benzothiophene-2-carboxamide hydrochloride

[image] [image]

Smjesi od 60 mg (0.15 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzotiofen-2-karboksamid-hidroklorida (primjer 8A) i 22.7 mg (0.15 mmol) 2-metoksifenilborne kiseline u 1 mL DMF doda se 0.22 mL 2 M vodene otopine natrijevog karbonata i 6.1 mg (0.007 mmola) PdCI2(dppf). Reakcijska smjesa zagrijava se 14 h na 80°C, filtrira na silikagelu i zgusne do suhoga. Nakon pročišćavanja produkta preparativnom HPLC, pretvorbe sa 1 N solnom kiselinom i sušenja u visokom vakuumu dobije se 12.8 mg (18 % od teor.) naslovnog spoja. Mixtures of 60 mg (0.15 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A) and 22.7 mg (0.15 mmol) of 2-methoxyphenylboronic acid in 1 mL of DMF was added to 0.22 mL of 2 M aqueous sodium carbonate solution and 6.1 mg (0.007 mmol) of PdCl2(dppf). The reaction mixture is heated for 14 h at 80°C, filtered on silica gel and concentrated to dryness. After purification of the product by preparative HPLC, conversion with 1 N hydrochloric acid and drying in high vacuum, 12.8 mg (18% of theory) of the title compound are obtained.

HPLC (metoda 1): Rt = 4.2 min. HPLC (method 1): Rt = 4.2 min.

Primjer 19 Example 19

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[4-(4-morfolinil)fenil]-1-benzotiofen-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[4-(4-morpholinyl)phenyl]-1-benzothiophene-2-carboxamide hydrochloride

[image] [image]

Smjesi od 60 mg (0.15 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzotiofen-2-karboksamid-hidroklorida (primjer 8A) i 30.9 mg (0.15 mmola) 4-(4-morfolinil)-fenilborne kiseline u 1 mL DMF doda se 0.22 mL 2 M vodene otopine natrijevog karbonata i 6.1 mg (0.007 mmola) PdCl2(dppf). Reakcijska smjesa zagrijava se na 80°C. Nakon 4.5 h na toj temperaturi doda se još 6.1 mg (0.007 mmola) PdCl2(dppf). Nakon 12 h reakcijska smjesa filtrira se na silikagelu i zgusne do suhoga. Pročišćavanje produkta provodi se preparativnom HPLC. Produkt se otopi u metanolu i pretvori sa suviškom 4 N klorovodika u dioksanu. Nakon sušenja u visokom vakuumu dobije se 20.6 mg (25 % od teor.) naslovnog spoja. Mixtures of 60 mg (0.15 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A) and 30.9 mg (0.15 mmol) of 4-(4-morpholinyl)-phenylboronic acid in 1 mL of DMF was added to 0.22 mL of a 2 M aqueous solution of sodium carbonate and 6.1 mg (0.007 mmol) of PdCl2(dppf). The reaction mixture is heated to 80°C. After 4.5 h at that temperature, another 6.1 mg (0.007 mmol) of PdCl2(dppf) is added. After 12 h, the reaction mixture is filtered on silica gel and concentrated to dryness. Purification of the product is carried out by preparative HPLC. The product is dissolved in methanol and converted with an excess of 4 N hydrogen chloride in dioxane. After drying in high vacuum, 20.6 mg (25% of theory) of the title compound is obtained.

1H-NMR (300 MHz, metanol-d4): δ = 8.21 (s, 1H), 7.97 (m, 2H), 7.93 (s, 1H), 7.83 (m, 2H), 7.57 (dd, 1H), 7.52 (m, 1H), 4.46 (m, IH), 4.13 (m, 4H), 3.83 (m, 1H), 3.78 (m, 4H), 3.49 (m, 1H), 3.43-3.17 (m, 4H), 2.38 (m, 1H), 2.28 (m, 1H), 2.10 (m, 2H), 1.96 (m, 1H). 1H-NMR (300 MHz, methanol-d4): δ = 8.21 (s, 1H), 7.97 (m, 2H), 7.93 (s, 1H), 7.83 (m, 2H), 7.57 (dd, 1H), 7.52 (m, 1H), 4.46 (m, 1H), 4.13 (m, 4H), 3.83 (m, 1H), 3.78 (m, 4H), 3.49 (m, 1H), 3.43-3.17 (m, 4H), 2.38 (m, 1H), 2.28 (m, 1H), 2.10 (m, 2H), 1.96 (m, 1H).

HPLC (metoda 1): Rt = 4.3 min. HPLC (method 1): Rt = 4.3 min.

MS (ESIpos): m/z = 448 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 448 (M+H)+ (free base).

Primjer 20 Example 20

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[4-(hidroksimetil)fenil]-1-benzotiofen-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[4-(hydroxymethyl)phenyl]-1-benzothiophene-2-carboxamide hydrochloride

[image] [image]

Stavi se 60 mg (0.15 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzotiofen-2-karboksamid-hidroklorida (primjer 8A) i 22.7 mg (0.15 mmola) 4-(hidroksimetil)fenilborne kiseline u 1 mL DMF. Nakon dodatka 0.22 mL 2 M vodene otopine natrijevog karbonata i 6.1 mg (0.01 mmol) PdCl2(dppf), reakcijska smjesa se zagrijava na 80°C. Nakon 14 h reakcijska smjesa se filtrira na silikagelu i zgusne do suhoga. Pročišćavanje produkta provede se preparativnom HPLC. Produkt se otopi u metanolu i pretvori sa suviškom 4 N klorovodika u dioksanu. Nakon sušenja u visokom vakuumu dobije se 9 mg (9 % od teor.) naslovnog spoja. 60 mg (0.15 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (example 8A) and 22.7 mg (0.15 mmol) of 4-(hydroxymethyl)phenylboronic acid in 1 mL of DMF. After adding 0.22 mL of 2 M aqueous sodium carbonate solution and 6.1 mg (0.01 mmol) of PdCl2(dppf), the reaction mixture is heated to 80°C. After 14 h, the reaction mixture is filtered on silica gel and concentrated to dryness. Purification of the product is carried out by preparative HPLC. The product is dissolved in methanol and converted with an excess of 4 N hydrogen chloride in dioxane. After drying in high vacuum, 9 mg (9% of theory) of the title compound is obtained.

HPLC (metoda 1): Rt = 3.8 min. HPLC (method 1): Rt = 3.8 min.

Analogno se dobivaju spojevi navedeni u sljedećoj tablici: Analogously, the compounds listed in the following table are obtained:

Tablica 2: Table 2:

[image] [image]

Primjer 51 Example 51

7-[3-(acetilamino)fenil]-N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-1-benzotiofen-2-karboksamid-hidroklorid 7-[3-(acetylamino)phenyl]-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide hydrochloride

[image] [image]

Smjesi od 200 mg (0.50 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzotiofen-2-karboksamid-hidroklorida (primjer 8A) i 89.1 mg (0.50 mmola) 3-(acetamido)fenilborne kiseline u 2 mL DMF doda se 0.75 mL 2 M vodene otopine natrijevog karbonata i 20.3 mg (0.02 mmola) PdCl2(dppf). Reakcijska smjesa zagrijava se 17 h na 80°C. Potom se doda još 89.1 mg (0.50 mmola) 3-(acetamido)fenilborne kiseline, 1.5 mL 1 N natrijeve lužine i 81.3 mg (0.1 mmol) PdCl2(dppf), te se sve zagrijava još 18 h na 80°C. Nakon hlađenja smjesa se filtrira na silikagelu i pročisti preparativnom HPLC. Dobiveni sirovi produkt dalje se pročisti vakuumskom kromatografijom (otapalo: diklormetan/metanol/ amonijak 100:10:2). Frakcije produkta se zgusnu, preuzmu u smjesu 5:1 metanola i 1 N solne kiseline i ponovno zgusnu. Nakon sušenja u visokom vakuumu dobije se 243.2 mg (86.6 % od teor.) naslovnog spoja. Mixtures of 200 mg (0.50 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A) and 89.1 mg (0.50 mmol) of 3-(acetamido)phenylboronic acid in 2 mL of DMF was added to 0.75 mL of a 2 M aqueous solution of sodium carbonate and 20.3 mg (0.02 mmol) of PdCl2(dppf). The reaction mixture is heated for 17 h at 80°C. Then another 89.1 mg (0.50 mmol) of 3-(acetamido)phenylboronic acid, 1.5 mL of 1 N sodium hydroxide solution and 81.3 mg (0.1 mmol) of PdCl2(dppf) are added, and everything is heated for another 18 h at 80°C. After cooling, the mixture is filtered on silica gel and purified by preparative HPLC. The crude product obtained is further purified by vacuum chromatography (solvent: dichloromethane/methanol/ammonia 100:10:2). The product fractions are concentrated, taken up in a mixture of 5:1 methanol and 1 N hydrochloric acid and concentrated again. After drying in high vacuum, 243.2 mg (86.6% of theory) of the title compound is obtained.

1H-NMR (300 MHz, DMSO-d6): δ = 10.16 (s, 1H), 10.10 (br. s, 1H), 9.03 (d, 1H), 8.38 (s, 1H), 8.06 (m, 1H), 7.98 (dd, 1H), 7.65 (m, 1H), 7.59 (dd, 1H), 7.51 (m, 1H), 7.48 (m, 1H), 7.37 (m, 1H), 4.33 (m, 1H), 3.66 (m, 1H), 3.45-3.13 (m, 5H), 2.22 (m, 1H), 2.14 (m, 1H), 2.08 (s, 3H), 1.91 (m, 2H), 1.75 (m, 1H). 1H-NMR (300 MHz, DMSO-d6): δ = 10.16 (s, 1H), 10.10 (no. s, 1H), 9.03 (d, 1H), 8.38 (s, 1H), 8.06 (m, 1H) , 7.98 (dd, 1H), 7.65 (m, 1H), 7.59 (dd, 1H), 7.51 (m, 1H), 7.48 (m, 1H), 7.37 (m, 1H), 4.33 (m, 1H), 3.66 (m, 1H), 3.45-3.13 (m, 5H), 2.22 (m, 1H), 2.14 (m, 1H), 2.08 (s, 3H), 1.91 (m, 2H), 1.75 (m, 1H) .

HPLC (metoda 1): Rt = 3.9 min. HPLC (method 1): Rt = 3.9 min.

MS (ESIpos): m/z = 420 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 420 (M+H)+ (free base).

Primjer 52 Example 52

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-6-[4-(4-morfolinil)fenil]-1-benzotiofen-2-karboksamid-hidro klorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-[4-(4-morpholinyl)phenyl]-1-benzothiophene-2-carboxamide hydrochloride

[image] [image]

Stavi se 100 mg (0.25 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-6-brom-1-benzotiofen-2-karboksamid-hidroklorida (primjer 11A) i 51.5 mg (0.25 mmola) 4-morfolinofenilborne kiseline u 1 mL DMF. Nakon dodatka 0.37 mL 2 M otopine natrijevog karbonata i 10.2 mg (0.01 mmol) PdCl2(dppf) smjesa se zagrijava na 80°C. Nakon 16 h doda se još 51.5 mg (0.25 mmola) 4-morfolimofenilbome kiseline, 0.37 mL 2 M otopine natrijevog karbonata i 10.2 mg (0.01 mmol) PdCl2(dppf). Smjesa se zagrijava još 4 h. Nakon hlađenja reakcijska smjesa se filtrira na silikagelu i pročisti preparativnom HPLC. Frakcije produkta se zgusnu, pretvore smjesom 5:1 metanola i 4 M klorovodika u dioksanu i ponovno zgusnu. Nakon sušenja u visokom vakuumu dobije se 83 mg (69 % od teor.) naslovnog spoja. 100 mg (0.25 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 11A) and 51.5 mg (0.25 mmol) of 4-morpholinophenylboronic acid in 1 mL of DMF. After adding 0.37 mL of 2 M sodium carbonate solution and 10.2 mg (0.01 mmol) of PdCl2(dppf), the mixture is heated to 80°C. After 16 h, another 51.5 mg (0.25 mmol) of 4-morpholimophenylbomic acid, 0.37 mL of 2 M sodium carbonate solution and 10.2 mg (0.01 mmol) of PdCl2(dppf) are added. The mixture is heated for another 4 hours. After cooling, the reaction mixture is filtered on silica gel and purified by preparative HPLC. The product fractions were concentrated, reconstituted with a mixture of 5:1 methanol and 4 M hydrogen chloride in dioxane and concentrated again. After drying in a high vacuum, 83 mg (69% of theory) of the title compound are obtained.

1H-NMR (200 MHz, DMSO-d6): δ = 10.20 (br. s, 1H), 9.07 (d, 1H), 8.33 (s, 1H), 8.27 (s, 1H), 7.97 (d, 1H), 7.71 (m, 3H), 7.10 (m, 2H), 4.33 (m, 1H), 3.78 (m, 4H), 3.73-3.07 (m, 10H), 2.22 (m, 1H), 2.17 (m, 1H), 1.93 (m, 2H), 1.75 (m, 1H). 1H-NMR (200 MHz, DMSO-d6): δ = 10.20 (no. s, 1H), 9.07 (d, 1H), 8.33 (s, 1H), 8.27 (s, 1H), 7.97 (d, 1H) , 7.71 (m, 3H), 7.10 (m, 2H), 4.33 (m, 1H), 3.78 (m, 4H), 3.73-3.07 (m, 10H), 2.22 (m, 1H), 2.17 (m, 1H ), 1.93 (m, 2H), 1.75 (m, 1H).

HPLC (metoda 1): Rt = 3.8 min. HPLC (method 1): Rt = 3.8 min.

Primjer 53 Example 53

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-6-(5-metil-l,2,4-oksadiazol-3-il)-1-benzotiofen-2-karboksamid-hidro klorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(5-methyl-1,2,4-oxadiazol-3-yl)-1-benzothiophene-2-carboxamide- hydro chloride

[image] [image]

Otopi se 154 mg (0.37 mmola) 6-[amino(hidroksiimino)metil]-N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-1-benzotiofen-2-karboksamid-hidroklorida (primjer 27A) u 2 mL DMF i 0.75 mL THF. Smjesa se pretvori sa 250 mg molekularnog sita veličine 4 Å i miješa 30 min na sobnoj temperaturi. Nakon dodatka 44.4 mg (1.11 mmol) natrijevog hidrida (60 %-tna suspenzija u mineralnom ulju) smjesa se zagrijava 20 min na 60°C, te odmah potom ohladi do sobne temperature. Zatim se reakcijskoj smjesi doda otopina 90 μL (1.11 mmol) metilnog estera octene kiseline u 1 mL THF, te se sve potom zagrijava 14 h na 80°C. Nakon dodatka još 29.6 mg (0.74 mmol) natrijevog hidrida (60 %-tna suspenzija u mineralnom ulju) i 0.88 mL (11.1 mmol) metilnog estera octene kiseline u 1 mL THF smjesa se zagrijava još 24 h na 70°C. Reakcija se prekine dodatkom vode. Pročišćavanje se provede preparativnom HPLC. Frakcije produkta se zgusnu, pretvore sa smjesom 5:1 metanola i 4 N klorovodika u dioksanu, te ponovno zgusnu. Nakon sušenja u visokom vakuumu dobije se 41.9 mg (23.6 % od teor.) naslovnog spoja. 154 mg (0.37 mmol) of 6-[amino(hydroxyimino)methyl]-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide hydrochloride ( example 27A) in 2 mL DMF and 0.75 mL THF. The mixture was sieved with 250 mg of a 4 Å molecular sieve and stirred for 30 min at room temperature. After the addition of 44.4 mg (1.11 mmol) of sodium hydride (60% suspension in mineral oil), the mixture is heated for 20 min at 60°C, and immediately cooled to room temperature. Then, a solution of 90 μL (1.11 mmol) of acetic acid methyl ester in 1 mL of THF was added to the reaction mixture, and everything was then heated for 14 h at 80°C. After adding another 29.6 mg (0.74 mmol) of sodium hydride (60% suspension in mineral oil) and 0.88 mL (11.1 mmol) of acetic acid methyl ester in 1 mL of THF, the mixture is heated for another 24 h at 70°C. The reaction is stopped by the addition of water. Purification is performed by preparative HPLC. The product fractions are concentrated, reconstituted with a mixture of 5:1 methanol and 4 N hydrogen chloride in dioxane, and concentrated again. After drying in a high vacuum, 41.9 mg (23.6 % of theory) of the title compound is obtained.

1H-NMR (300 MHz, DMSO-d6): δ = 10.15 (br. s, 1H), 9.14 (d, 1H), 8.70 (m, 1H), 8.41 (s, 1H), 8.13 (d, 1H), 8.05 (m, 1H), 4.34 (m, 1H), 3.75-3.13 (m, 6H), 2.70 (s, 3H), 2.23 (m, 1H), 2.15 (m, 1H), 1.92 (m, 2H), 1.77 (m, 1H). 1H-NMR (300 MHz, DMSO-d6): δ = 10.15 (no. s, 1H), 9.14 (d, 1H), 8.70 (m, 1H), 8.41 (s, 1H), 8.13 (d, 1H) , 8.05 (m, 1H), 4.34 (m, 1H), 3.75-3.13 (m, 6H), 2.70 (s, 3H), 2.23 (m, 1H), 2.15 (m, 1H), 1.92 (m, 2H ), 1.77 (m, 1H).

HPLC (metoda 1): Rt = 3.8 min. HPLC (method 1): Rt = 3.8 min.

MS (ESIpos): m/z = 369 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 369 (M+H)+ (free base).

Primjer 54 Example 54

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-6-[2-(hidroksimetil)fenil]-1-benzotiofen-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-[2-(hydroxymethyl)phenyl]-1-benzothiophene-2-carboxamide hydrochloride

[image] [image]

Stavi se 100 mg (0.25 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-6-brom-1-benzotiofen-2-karboksamid-hidroklorida (primjer 11A) i 37.8 mg (0.25 mmola) 2(hidroksimetil)fenilborne kiseline u 1 mL DMF. Nakon dodatka 0.37 mL 2 M otopine natrijevog karbonata i 10.2 mg (0.01 mmol) PdCl2(dppf) smjesa se zagrijava na 80°C. Nakon 14 h reakcijska smjesa se filtrira na silikagelu i pročisti dvostrukim odjeljivanjem preparativnom HPLC. Frakcije produkta se zgusnu, pretvore smjesom 5:1 metanola i 4 N klorvodika u dioksanu, te ponovno zgusnu. Nakon sušenja u visokom vakuumu dobije se 27 mg (24.4 % od teor.) naslovnog spoja. 100 mg (0.25 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1-benzothiophene-2-carboxamide hydrochloride (example 11A) and 37.8 mg (0.25 mmol) of 2(hydroxymethyl)phenylboronic acid in 1 mL of DMF. After adding 0.37 mL of 2 M sodium carbonate solution and 10.2 mg (0.01 mmol) of PdCl2(dppf), the mixture is heated to 80°C. After 14 h, the reaction mixture is filtered on silica gel and purified by double separation by preparative HPLC. The product fractions are concentrated, reconstituted with a 5:1 mixture of methanol and 4 N hydrogen chloride in dioxane, and concentrated again. After drying in a high vacuum, 27 mg (24.4% of theory) of the title compound are obtained.

1H-NMR (200 MHz, DMSO-d6): δ = 10.10 (br. s, 1H), 9.06 (d, 1H), 8.36 (s, 1H), 8.02 (m, 2H), 7.61 (m, 1H), 7.54-7.36 (m, 4H), 4.43 (s, 2H), 4.33 (m, 1H), 3.67 (m, 1H), 3.55-3.12 (m, 5H), 2.23 (m, 1H), 2.16 (m, 1H), 1.92 (m, 2H), 1.77 (m, 1H). HPLC (metoda 1): Rt = 3.9 min. MS (ESIpos): m/z = 393 (M+H)+ (slobodna baza). 1H-NMR (200 MHz, DMSO-d6): δ = 10.10 (no. s, 1H), 9.06 (d, 1H), 8.36 (s, 1H), 8.02 (m, 2H), 7.61 (m, 1H) , 7.54-7.36 (m, 4H), 4.43 (s, 2H), 4.33 (m, 1H), 3.67 (m, 1H), 3.55-3.12 (m, 5H), 2.23 (m, 1H), 2.16 (m , 1H), 1.92 (m, 2H), 1.77 (m, 1H). HPLC (method 1): Rt = 3.9 min. MS (ESIpos): m/z = 393 (M+H)+ (free base).

Primjer 55 Example 55

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-6-(5-fenil-l,2,4-okadiazol-3-il)-1-benzotiofen-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(5-phenyl-1,2,4-okadiazol-3-yl)-1-benzothiophene-2-carboxamide- hydrochloride

[image] [image]

Otopi se 110 mg (0.26 mmola) 6-[amino(hidroksiimino)metil]-N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-1-benzotiofen-2-karboksamid-hidroklorida (primjer 27A) u 2 mL DMF i 0.75 mL THF. Smjesa se pretvori sa 250 mg molekularnog sita veličine 4 Å i miješa 30 min na sobnoj temperaturi. Nakon dodatka 31.2 mg (0.79 mmola) natrijevog hidrida (60 %-tna suspenzija u mineralnom ulju) smjesa se zagrijava 20 min na 60°C, te odmah potom ohladi do sobne temperature. Zatim se reakcijskoj smjesi doda otopina 100 μL (0.79 mmola) metilnog estera benzojeve kiseline u 1 mL THF, te se sve potom zagrijava 14 h na 80°C. Nakon dodavanja još 20.8 mg (0.52 mmola) natrijevog hidrida (60 %-tna suspenzija u mineralnom ulju) i 0.99 mL (7.91 mmol) metilnog estera benzojeve kiseline u 1 mL THF smjesa se zagrijava još 24 h na 70°C. Reakcija se prekine dodatkom vode. Pročišćavanje se provede preparativnom HPLC. Frakcije produkta se zgusnu, pretvore sa smjesom 5:1 metanola i 4 N klorovodika u dioksanu, te ponovno zgusnu. Nakon sušenja u visokom vakuumu dobije se 45.7 mg (32 % od teor.) naslovnog spoja. 110 mg (0.26 mmol) of 6-[amino(hydroxyimino)methyl]-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide hydrochloride ( example 27A) in 2 mL DMF and 0.75 mL THF. The mixture was sieved with 250 mg of a 4 Å molecular sieve and stirred for 30 min at room temperature. After adding 31.2 mg (0.79 mmol) of sodium hydride (60% suspension in mineral oil), the mixture is heated for 20 min at 60°C, and immediately cooled to room temperature. Then, a solution of 100 μL (0.79 mmol) of methyl ester of benzoic acid in 1 mL of THF was added to the reaction mixture, and everything was then heated for 14 h at 80°C. After adding another 20.8 mg (0.52 mmol) of sodium hydride (60% suspension in mineral oil) and 0.99 mL (7.91 mmol) of benzoic acid methyl ester in 1 mL of THF, the mixture was heated for another 24 h at 70°C. The reaction is stopped by the addition of water. Purification is performed by preparative HPLC. The product fractions are concentrated, reconstituted with a mixture of 5:1 methanol and 4 N hydrogen chloride in dioxane, and concentrated again. After drying in high vacuum, 45.7 mg (32% of theory) of the title compound is obtained.

HPLC (metoda 1): Rt = 4.5 min. HPLC (method 1): Rt = 4.5 min.

MS (ESIpos): m/z = 431 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 431 (M+H)+ (free base).

Primjer 56 Example 56

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-6-(5-benzil-l,2,4-oksadiazol-3-il)-1-benzotiofen-2-karboksamid-hidro klorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(5-benzyl-1,2,4-oxadiazol-3-yl)-1-benzothiophene-2-carboxamide- hydro chloride

[image] [image]

Otopi se 110 mg (0.26 mmola) 6-[amino(hidroksiimino)metil]-N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-1-benzotiofen-2-karboksamid-hidroklorida (primjer 27A) u 2 mL DMF i 0.75 mL THF. Smjesa se pretvori sa 250 mg molekularnog sita veličine 4 Å i miješa 30 min na sobnoj temperaturi. Nakon dodatka 31.2 mg (0.79 mmola) natrijevog hidrida (60 %-tna suspenzija u mineralnom ulju) smjesa se zagrijava 20 min na 60°C te odmah potom ohladi do sobne temperature. Zatim se reakcijskoj smjesi doda otopina 110 μL (0.79 mmola) metilnog estera feniloctene kiseline u 1 mL THF, te se sve potom zagrijava 14 h na 80°C. Nakon dodatka još 20.8 mg (0.52 mmola) natrijevog hidrida (60 %-tna suspenzija u mineralnom ulju) i 1.14 mL (7.91 mmol) metilnog estera feniloctene kiseline u 1 mL THF smjesa se zagrijava još 24 h na 70°C. Reakcija se prekine dodatkom vode. Pročišćavanje se provede preparativnom HPLC. Frakcije produkta se zgusnu, pretvore sa smjesom 5:1 metanola i 4 N klorovodika u dioksanu, te ponovno zgusnu. Nakon sušenja u visokom vakuumu dobije se 4.1 mg (3 % od teor.) naslovnog spoja. 110 mg (0.26 mmol) of 6-[amino(hydroxyimino)methyl]-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide hydrochloride ( example 27A) in 2 mL DMF and 0.75 mL THF. The mixture was sieved with 250 mg of a 4 Å molecular sieve and stirred for 30 min at room temperature. After adding 31.2 mg (0.79 mmol) of sodium hydride (60% suspension in mineral oil), the mixture is heated for 20 min at 60°C and immediately cooled to room temperature. Then, a solution of 110 μL (0.79 mmol) of methyl ester of phenylacetic acid in 1 mL of THF is added to the reaction mixture, and everything is then heated for 14 h at 80°C. After adding another 20.8 mg (0.52 mmol) of sodium hydride (60% suspension in mineral oil) and 1.14 mL (7.91 mmol) of phenylacetic acid methyl ester in 1 mL of THF, the mixture is heated for another 24 h at 70°C. The reaction is stopped by the addition of water. Purification is performed by preparative HPLC. The product fractions are concentrated, reconstituted with a mixture of 5:1 methanol and 4 N hydrogen chloride in dioxane, and concentrated again. After drying in a high vacuum, 4.1 mg (3% of theory) of the title compound is obtained.

1H-NMR (300 MHz, metanol-d4): δ = 8.63 (s, 1H), 8.11 (m, 2H), 8.04 (d, 1H), 7.43-7.27 (m, 5H), 4.47 (m, 1H), 4.38 (s, 2H), 3.87 (m, 1H), 3.52-3.20 (m, 5H), 2.40 (m, 1H), 2.28 (m, 1H), 2.11 (m, 2H), 1.97 (m, 1H). 1H-NMR (300 MHz, methanol-d4): δ = 8.63 (s, 1H), 8.11 (m, 2H), 8.04 (d, 1H), 7.43-7.27 (m, 5H), 4.47 (m, 1H) , 4.38 (s, 2H), 3.87 (m, 1H), 3.52-3.20 (m, 5H), 2.40 (m, 1H), 2.28 (m, 1H), 2.11 (m, 2H), 1.97 (m, 1H ).

HPLC (metoda 1): Rt = 4.4 min. HPLC (method 1): Rt = 4.4 min.

MS (ESIpos): m/z = 445 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 445 (M+H)+ (free base).

Primjer 57 Example 57

N-[(3R)-1-azabiciklo[2.2.2]okt-3HI]-6-[4-(4-morfolinilmetil)fenil]-1-benzotiofen-2-karboksamid-dihidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3HI]-6-[4-(4-morpholinylmethyl)phenyl]-1-benzothiophene-2-carboxamide dihydrochloride

[image] [image]

Otopini od 80 mg (0.19 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-6-(4-formilfenil)-1-benzotiofen-2-karboksamid-hidroklorida (primjer 23A) u 1.5 mL smjese 6:1 metanola i octene kiseline doda se jedno za drugim 330 mg (3.75 mmola) morfolina i 40 mg (0.56 mmola) natrijevog cijanoborhidrida. Nakon 2 h na sobnoj temperaturi i 6 h na 80°C smjesa se pročisti preparativnom HPLC. Frakcije produkta se zgusnu, pretvore sa smjesom 5:1 metanola i 1 N solne kiseline, te ponovno zgusnu. Nakon sušenja u visokom vakuumu dobije se 87.7 mg (88 % od teor.) naslovnog spoja. Solutions of 80 mg (0.19 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(4-formylphenyl)-1-benzothiophene-2-carboxamide hydrochloride (Example 23A ) in 1.5 mL of a mixture of 6:1 methanol and acetic acid, 330 mg (3.75 mmol) of morpholine and 40 mg (0.56 mmol) of sodium cyanoborohydride were added one after the other. After 2 h at room temperature and 6 h at 80°C, the mixture is purified by preparative HPLC. The product fractions are concentrated, converted with a mixture of 5:1 methanol and 1 N hydrochloric acid, and concentrated again. After drying in high vacuum, 87.7 mg (88% of theory) of the title compound are obtained.

1H -NMR (400 MHz, DMSO-d6): δ = 11.26 (br. s, 1H), 10.29 (br. s, 1H), 9.18 (d, 1H), 8.41 (m, 2H), 8.06 (d, 1H), 7.89 (m, 2H), 7.81 (d, 1H), 7.74 (m, 2H), 4.39 (m, 2H), 4.34 (m, 1H), 4.05-3.03 (m, 6H), 2.23 (m, 1H), 2.16 (m, 1H), 1.92 (m, 2H), 1.76 (m, 1H). 1H-NMR (400 MHz, DMSO-d6): δ = 11.26 (no. s, 1H), 10.29 (no. s, 1H), 9.18 (d, 1H), 8.41 (m, 2H), 8.06 (d, 1H), 7.89 (m, 2H), 7.81 (d, 1H), 7.74 (m, 2H), 4.39 (m, 2H), 4.34 (m, 1H), 4.05-3.03 (m, 6H), 2.23 (m , 1H), 2.16 (m, 1H), 1.92 (m, 2H), 1.76 (m, 1H).

HPLC (metoda 1): Rt = 3.5 min. HPLC (method 1): Rt = 3.5 min.

MS (ESIpos): m/z = 462 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 462 (M+H)+ (free base).

Primjer 58 Example 58

N-[(3R9-1-azabiciklo[2.2.2]okt-3-il]-7-[4-(dimetilamino)fenil]-1-benzotiofen-2-karboksamid-hidroklorid N-[(3R9-1-azabicyclo[2.2.2]oct-3-yl]-7-[4-(dimethylamino)phenyl]-1-benzothiophene-2-carboxamide hydrochloride

[image] [image]

Smjesi od 100 mg (0.22 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzotiofen-2-karboksamid-hidroklorida (primjer 8A) i 36.8 mg (0.22 mmola) 4-(dimetilamino)fenilborne kiseline u 1 mL DMF doda se 0.33 mL 2 M otopine natrijevog karbonata i 9.1 mg (0.01 mmol) PdCl2(dppf). Reakcijska smjesa zagrijava se 16 h na 80°C. Potom se doda se još 36.8 mg (0.22 mmola) 4-(dimetilamino)fenilborne kiseline, 36.5 mg (0.04 mmola) PdCl2(dppf) i 0.67 mL 1 N natrijeve lužine, te se sve zagrijava još 3 h na 80°C. Nakon hlađenja reakcijska smjesa se filtrira na silikagelu i pročisti preparativnom HPLC. Frakcije produkta se zgusnu, preuzmu u smjesu 5:1 metanola i 1 N solne kiseline, te ponovno zgusnu. Nakon sušenja u visokom vakuumu dobije se 50.6 mg (47 % od teor.) naslovnog spoja. Mixtures of 100 mg (0.22 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A) and 36.8 mg (0.22 mmol) of 4-(dimethylamino)phenylboronic acid in 1 mL of DMF was added to 0.33 mL of a 2 M sodium carbonate solution and 9.1 mg (0.01 mmol) of PdCl2(dppf). The reaction mixture is heated for 16 h at 80°C. Then another 36.8 mg (0.22 mmol) of 4-(dimethylamino)phenylboronic acid, 36.5 mg (0.04 mmol) of PdCl2(dppf) and 0.67 mL of 1 N sodium hydroxide solution are added, and everything is heated for another 3 h at 80°C. After cooling, the reaction mixture is filtered on silica gel and purified by preparative HPLC. The product fractions are concentrated, taken up in a mixture of 5:1 methanol and 1 N hydrochloric acid, and concentrated again. After drying in high vacuum, 50.6 mg (47% of theory) of the title compound is obtained.

1H-NMR (300 MHz, metanol-d4): 5 = 8.26 (s, 1H), 7.95 (m, 3H), 7.80 (m, 2H), 7.58 (dd, 1H), 7.53 (m, 1H), 4.46 (m, 1H), 3.82 (m, 1H), 3.51 (m, 1H), 3.45-3.16 (m, 10H), 2.37 (m, 1H), 2.29 (m, 1H), 2.10 (m, 2H), 1.95 (m, 1H). 1H-NMR (300 MHz, methanol-d4): δ = 8.26 (s, 1H), 7.95 (m, 3H), 7.80 (m, 2H), 7.58 (dd, 1H), 7.53 (m, 1H), 4.46 (m, 1H), 3.82 (m, 1H), 3.51 (m, 1H), 3.45-3.16 (m, 10H), 2.37 (m, 1H), 2.29 (m, 1H), 2.10 (m, 2H), 1.95 (m, 1H).

HPLC (metoda 1): Rt = 3.6 min. HPLC (method 1): Rt = 3.6 min.

MS (ESIpos): m/z = 406 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 406 (M+H)+ (free base).

Primjer 59 Example 59

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-(2-tienil)-1-benzotiofen-2-karboksamid-formijat N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-(2-thienyl)-1-benzothiophene-2-carboxamide-formate

[image] [image]

Stavi se 100 mg (0.25 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzotiofen-2-karboksamid-hidroklorida (primjer 8A) i 31.9 mg (0.25 mmola) 2-tiofenborne kiseline u 1.5 ml_DMF. Nakon dodatka 0.37 mL 2 M otopine natrijevog karbonata i 9.11 mg (0.01 mmol) PdCl2(dppf) smjesa se zagrijava na 85°C. Nakon 14 h reakcijska smjesa se filtrira na silikagelu i pročisti preparativnom HPLC (eluens A: acetonitril, eluens B: voda + 0.1 % mravlje kiseline; gradijent: 10 % A → 95 % A). Frakcije produkta se zgusnu i osuše u visokom vakuumu. Dobije se 30 mg (28 % od teor.) naslovnog spoja. 100 mg (0.25 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (example 8A) and 31.9 mg (0.25 mmol) of 2-thiophenboric acid in 1.5 ml_DMF. After adding 0.37 mL of 2 M sodium carbonate solution and 9.11 mg (0.01 mmol) of PdCl2(dppf), the mixture is heated to 85°C. After 14 h, the reaction mixture is filtered on silica gel and purified by preparative HPLC (eluent A: acetonitrile, eluent B: water + 0.1 % formic acid; gradient: 10 % A → 95 % A). The product fractions are concentrated and dried in high vacuum. 30 mg (28% of theory) of the title compound is obtained.

1H-NMR (200 MHz, DMSO-d6): δ = 8.80 (d, 1H), 8.33 (s, 1H), 8.23 (s, 1H), 7.97 (m, 1H), 7.72 (m, 3H), 7.55 (dd, 1H), 7.28 (dd, 1H), 4.12 (m, 1H), 3.36 (m, 1H), 3.18-2.80 (m, 5H), 2.03 (m, 1H), 1.95 (m, 1H), 1.74 (m, 2H), 1.52 (m, 1H). 1H-NMR (200 MHz, DMSO-d6): δ = 8.80 (d, 1H), 8.33 (s, 1H), 8.23 (s, 1H), 7.97 (m, 1H), 7.72 (m, 3H), 7.55 (dd, 1H), 7.28 (dd, 1H), 4.12 (m, 1H), 3.36 (m, 1H), 3.18-2.80 (m, 5H), 2.03 (m, 1H), 1.95 (m, 1H), 1.74 (m, 2H), 1.52 (m, 1H).

HPLC (metoda 1): Rt = 4.2 min. HPLC (method 1): Rt = 4.2 min.

Primjer 60 Example 60

7-(5-acetil-2-tienil)-N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-1-benzotiofen-2-karboksamid-hidroklorid 7-(5-acetyl-2-thienyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide hydrochloride

[image] [image]

Stavi se 100 mg (0.25 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzotiofen-2-karboksamid-hidroklorida (primjer 8A) i 42.3 mg (0.25 mmola) 5-acetil-2-tienilboronske kiseline u 1.5 mL DMF. Nakon dodavanja 0.37 mL 2M otopine natrijevog karbonata i 9.11 mg (0.01 mmol) PdCl2(dppf) smjesa se zagrijava na 85 °C. Nakon 15 h rekacijska smjesa se filtrira na silikagelu i pročisti preparativnom HPLC. Frakcije produkta se zgusnu, preuzmu u smjesu 5:1 metanola i 1 N solne kiseline i ponovno zgusnu i osuše u visokom vakuumu. Dobije se 52 mg (46 % od teor.) naslovnog spoja. 100 mg (0.25 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (example 8A) and 42.3 mg (0.25 mmol) of 5-acetyl-2-thienylboronic acid in 1.5 mL of DMF. After adding 0.37 mL of 2M sodium carbonate solution and 9.11 mg (0.01 mmol) of PdCl2(dppf), the mixture is heated to 85 °C. After 15 h, the reaction mixture is filtered on silica gel and purified by preparative HPLC. The product fractions are concentrated, taken up in a mixture of 5:1 methanol and 1 N hydrochloric acid and concentrated again and dried under high vacuum. 52 mg (46% of theory) of the title compound are obtained.

1H-NMR (200 MHz, DMSO-d6): δ = 10.25 (br. s, 1H), 9.23 (d, 1H), 8.49 (s, 1H), 8.08 (d, 1H), 8.06 (m, 1H), 7.89 (m, 1H), 7.82 (d, 1H), 7.61 (dd, 1H), 4.36 (m, 1H), 3.73-3.13 (m, 5H), 2.60 (s, 3H), 2.23 (m, 1H), 2.15 (m, 1H), 1.93 (m, 2H), 1.76 (m, 1H). 1H-NMR (200 MHz, DMSO-d6): δ = 10.25 (no. s, 1H), 9.23 (d, 1H), 8.49 (s, 1H), 8.08 (d, 1H), 8.06 (m, 1H) , 7.89 (m, 1H), 7.82 (d, 1H), 7.61 (dd, 1H), 4.36 (m, 1H), 3.73-3.13 (m, 5H), 2.60 (s, 3H), 2.23 (m, 1H ), 2.15 (m, 1H), 1.93 (m, 2H), 1.76 (m, 1H).

HPLC (metoda 1): Rt = 4.1 min. MS (ESIpos): HPLC (method 1): Rt = 4.1 min. MS (ESIpos):

m/z = 411 (M+H)+ (slobodna baza). m/z = 411 (M+H)+ (free base).

Primjer 61 Example 61

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[4-(6-okso-2-piperidinil)fenil]-1-benzotiofen-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[4-(6-oxo-2-piperidinyl)phenyl]-1-benzothiophene-2-carboxamide hydrochloride

[image] [image]

Prema općenitom radnom propisu D stavi se 123.4 mg (0.49 mmola) 6-(4-bromfenil)-2-piperidinona, 142.2 mg (0.56 mmola) bis(pinakolato)dibora, 146.6 mg (1.49 mmola) kalijevog acetata, 13.7 mg (0.02 mmola) PdCl2(dppf), 150 mg (0.37 mmola) N-[(3R)-l-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzotiofen-2-karboksamid-hidroklorida (primjer 8A), 0.93 ml_ 2 M otopine natrijevog karbonata, te još 13.7 mg (0.02 mmola) PdCl2(dppf) u 2 mL DMF. According to general procedure D, 123.4 mg (0.49 mmol) of 6-(4-bromophenyl)-2-piperidinone, 142.2 mg (0.56 mmol) of bis(pinacolato)diboron, 146.6 mg (1.49 mmol) of potassium acetate, 13.7 mg (0.02 mmol) PdCl2(dppf), 150 mg (0.37 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (example 8A), 0.93 ml of 2 M sodium carbonate solution, and another 13.7 mg (0.02 mmol) of PdCl2(dppf) in 2 mL of DMF.

Nakon sušenja u visokom vakuumu dobije se 7.3 mg (4 % od teor.) naslovnog spoja. After drying in a high vacuum, 7.3 mg (4% of theory) of the title compound is obtained.

HPLC (metoda 1): Rt = 3.9 min. HPLC (method 1): Rt = 3.9 min.

MS (ESIpos): m/z = 460 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 460 (M+H)+ (free base).

Primjer 62 Example 62

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[3-(hidroksimetil)fenil]-1-benzotiofen-2-karboksamid-hidro klorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[3-(hydroxymethyl)phenyl]-1-benzothiophene-2-carboxamide hydrochloride

[image] [image]

Stavi se 200 mg (0.45 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzotiofen-2-karboksamid-hidroklorida (primjer 8A) i 74.6 mg (0.49 mmola) 3-(hidroksimetil)fenilborne kiseline u 3 mL DMF. Nakon dodatka 0.67 mL 2 M otopine natrijevog karbonata i 18.2 mg (0.02 mmola) PdCI2(dppf) smjesa se zagrijava na 80 °C. Nakon 14 h reakcijska smjesa se filtrira na silikagelu i pročisti odjeljivanjem pomoću preparativne HPLC. Frakcije produkta se zgusnu, preuzmu u smjesu 5:1 metanola i 4 N klorovodika u dioksanu i ponovno zgusnu. Nakon sušenja u visokom vakuumu 200 mg (0.45 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (example 8A) and 74.6 mg (0.49 mmol) of 3-(hydroxymethyl)phenylboronic acid in 3 mL of DMF. After adding 0.67 mL of 2 M sodium carbonate solution and 18.2 mg (0.02 mmol) of PdCl2(dppf), the mixture is heated to 80 °C. After 14 h, the reaction mixture is filtered on silica gel and purified by separation using preparative HPLC. The product fractions are concentrated, taken up in a mixture of 5:1 methanol and 4 N hydrogen chloride in dioxane and concentrated again. After drying in high vacuum

dobije se 40 mg (19 % od teor.) naslovnog spoja. 40 mg (19% of theory) of the title compound is obtained.

1H-NMR (300 MHz, DMSO-d6): δ = 10.47 (br. s, 1H), 9.17 (d, 1H), 8.47 (s, 1H), 7.96 (d, 1H), 7.67 (s, 1H), 7.63-7.47 (m, 4H), 7.43 (d, 1H), 4.61 (s, 1H), 4.33 (m, 1H), 3.62 (m, 1H), 3.39 (m, 2H), 3.20 (m, 3H), 2.11 (m, 1H), 2.15 (m, 1H), 1.91 (m, 2H), 1.75 (m, 1H). 1H-NMR (300 MHz, DMSO-d6): δ = 10.47 (no. s, 1H), 9.17 (d, 1H), 8.47 (s, 1H), 7.96 (d, 1H), 7.67 (s, 1H) , 7.63-7.47 (m, 4H), 7.43 (d, 1H), 4.61 (s, 1H), 4.33 (m, 1H), 3.62 (m, 1H), 3.39 (m, 2H), 3.20 (m, 3H ), 2.11 (m, 1H), 2.15 (m, 1H), 1.91 (m, 2H), 1.75 (m, 1H).

HPLC (metoda 1): Rt = 3.9 min. HPLC (method 1): Rt = 3.9 min.

Primjer 63 Example 63

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[2-(4-morfolinil)fenil]-1-benzotiofen-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[2-(4-morpholinyl)phenyl]-1-benzothiophene-2-carboxamide hydrochloride

[image] [image]

Prema općenitom radnom propisu D stavi se 100 mg (0.41 mmol) 4-(2-bromfenil)-morfolina, 121.0 mg (0.48 mmola) bis(pinakolato)-dibora, 101.3 mg (1.03 mmola) kalijevog acetata, 11.6 mg (0.02 mmola) PdCl2(dppf), 127.6 mg (0.32 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzotiofen-2-karboksamid-hidroklorida (primjer 8A), 0.79 mL 2 M otopine natrijevog karbonata, te još 11.6 mg (0.02 mmola) PdCI2(dppf) u 2 mL DMF. Nakon sušenja u visokom vakuumu dobije se 38.9 mg (48 % od teor.) naslovnog spoja. According to general procedure D, 100 mg (0.41 mmol) of 4-(2-bromophenyl)-morpholine, 121.0 mg (0.48 mmol) of bis(pinacolato)-diboron, 101.3 mg (1.03 mmol) of potassium acetate, 11.6 mg (0.02 mmol) ) PdCl2(dppf), 127.6 mg (0.32 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A ), 0.79 mL of 2 M sodium carbonate solution, and another 11.6 mg (0.02 mmol) of PdCl2(dppf) in 2 mL of DMF. After drying in a high vacuum, 38.9 mg (48% of theory) of the title compound is obtained.

1H-NMR (300 MHz, DMSO-d6): δ = 10.20 (br. s, 1H), 9.04 (d, 1H), 8.36 (s, 1H), 7.93 (dd, 1H), 7.55 (m, 2H), 7.45 (d, 1H), 7.37 (dd, 1H), 7.17 (m, 2H), 4.32 (m, 1H), 3.62 (m, 1H), 3.48-3.10 (m, 9H), 2.69 (m, 4H), 2.19 (m, 1H), 2.10 (m, 1H), 1.90 (m, 2H), 1.73 (m, 1H). 1H-NMR (300 MHz, DMSO-d6): δ = 10.20 (no. s, 1H), 9.04 (d, 1H), 8.36 (s, 1H), 7.93 (dd, 1H), 7.55 (m, 2H) , 7.45 (d, 1H), 7.37 (dd, 1H), 7.17 (m, 2H), 4.32 (m, 1H), 3.62 (m, 1H), 3.48-3.10 (m, 9H), 2.69 (m, 4H ), 2.19 (m, 1H), 2.10 (m, 1H), 1.90 (m, 2H), 1.73 (m, 1H).

HPLC (metoda 1): Rt = 4.3 min. HPLC (method 1): Rt = 4.3 min.

Primjer 64 Example 64

2-(2-{[(3R)-1-azabiciklo[2.2.2]okt-3-ilamino]karbonil}-1-benzotien-7-il)-benziletilkarbamat-hidroklorid 2-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzothien-7-yl)-benzylethylcarbamate hydrochloride

[image] [image]

Suspenziji od 50 mg (0.12 mmol) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[2-(hidroksimetil)fenil]-1-benzotiofen-2-karboksamid-hidroklorida (primjer 131) u 1 mL smjese 5:1 THF i DMF doda se 32.5 nL (0.23 mmola) trietilamina i 16.6 mg (0.23 mmola) etilizocijanata. Nakon 18 h na sobnoj temperaturi doda se još 16.6 mg (0.23 mmola) etilizocijanata, kao i katalitička količina 4-N’,N-dimetilaminopiridina. Smjesa se miješa još 18 h na sobnoj temperaturi. Reakcijska smjesa se zgusne u vakuumu i pročisti preparativnom HPLC. Frakcije produkta se zgusnu, pretvore smjesom 5:1 metanola i 1 N solne kiseline i ponovno zgusnu. Nakon sušenja u visokom vakuumu dobije se 28 mg (47 % od teor.) naslovnog spoja. A suspension of 50 mg (0.12 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[2-(hydroxymethyl)phenyl]-1-benzothiophene-2-carboxamide hydrochloride (example 131) 32.5 nL (0.23 mmol) of triethylamine and 16.6 mg (0.23 mmol) of ethyl isocyanate are added to 1 mL of a 5:1 mixture of THF and DMF. After 18 h at room temperature, another 16.6 mg (0.23 mmol) of ethyl isocyanate was added, as well as a catalytic amount of 4-N',N-dimethylaminopyridine. The mixture is stirred for another 18 h at room temperature. The reaction mixture is concentrated in vacuo and purified by preparative HPLC. The product fractions are concentrated, reconstituted with a 5:1 mixture of methanol and 1 N hydrochloric acid and concentrated again. After drying in high vacuum, 28 mg (47% of theory) of the title compound are obtained.

HPLC (metoda 1): Rt = 4.2 min. HPLC (method 1): Rt = 4.2 min.

MS (ESIpos): m/z = 464 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 464 (M+H)+ (free base).

Primjer 65 Example 65

2-(2-{[(3R)-1-azabiciklo[2.2.2]okt-3-ilamino]karbonil}-1-benzotien-7-il)-benzilmetilkarbamat-hidroklorid 2-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzothien-7-yl)-benzylmethylcarbamate hydrochloride

[image] [image]

Suspenziji od 50 mg (0.12 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[2-(hidroksimetil)fenil]-1-benzotiofen-2-karboksamid-hidroklorida (primjer 131) u 1 mL smjese 5:1 THF i DMF doda se 32.5 μL (0.23 mmol) trietilamina i 13.3 mg (0.23 mmola) metilizocijanata. Nakon 18 h na sobnoj temperaturi doda se još 16.6 mg (0.23 mmola) metilizocijanata, kao i katalitička količina 4-N’,N-dimetilaminopiridina. Smjesa se miješa još 18 h na sobnoj temperaturi. Reakcijska smjesa se zgusne u vakuumu i pročisti preparativnom HPLC. Frakcije produkta se zgusnu, pretvore smjesom 5:1 metanola i 1 N solne kiseline i ponovno zgusnu. Nakon sušenja u visokom vakuumu dobije se 18 mg (30 % od teor.) naslovnog spoja. A suspension of 50 mg (0.12 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[2-(hydroxymethyl)phenyl]-1-benzothiophene-2-carboxamide hydrochloride (example 131) 32.5 μL (0.23 mmol) of triethylamine and 13.3 mg (0.23 mmol) of methyl isocyanate are added to 1 mL of a 5:1 mixture of THF and DMF. After 18 h at room temperature, another 16.6 mg (0.23 mmol) of methylisocyanate was added, as well as a catalytic amount of 4-N',N-dimethylaminopyridine. The mixture is stirred for another 18 h at room temperature. The reaction mixture is concentrated in vacuo and purified by preparative HPLC. The product fractions are concentrated, reconstituted with a mixture of 5:1 methanol and 1 N hydrochloric acid and concentrated again. After drying in a high vacuum, 18 mg (30% of theory) of the title compound are obtained.

1H-NMR (400 MHz, metanol-d4): δ = 8.18 (s, 1H), 7.95 (m, 1H), 7.63-7.42 (m, 4H), 7.38 (m, 2H), 4.42 (m, 1H), 3.81 (m, 1H), 3.47 (m, 1H), 3.40-3.25 (m, 4H), 2.57 (m, 3H), 2.37 (m, 1H), 2.26 (m, 1H), 2.09 (m, 2H), 1.94 (m, 1H). 1H-NMR (400 MHz, methanol-d4): δ = 8.18 (s, 1H), 7.95 (m, 1H), 7.63-7.42 (m, 4H), 7.38 (m, 2H), 4.42 (m, 1H) , 3.81 (m, 1H), 3.47 (m, 1H), 3.40-3.25 (m, 4H), 2.57 (m, 3H), 2.37 (m, 1H), 2.26 (m, 1H), 2.09 (m, 2H ), 1.94 (m, 1H).

LC-MS (metoda 4): Rt = 2.7 min, m/z = 464 (M+H)+ (slobodna baza). LC-MS (method 4): Rt = 2.7 min, m/z = 464 (M+H)+ (free base).

Primjer 66 Example 66

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[4-(2-okso-1-pirolidinil)fenil]-l-benzotiofen-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1-benzothiophene-2-carboxamide hydrochloride

[image] [image]

Prema općenitom radnom propisu D stavi se 116.5 mg (0.49 mmol) l-(4-bromfenil)-2-pirolidinona, 142.2 mg (0.56 mmola) bis-(pinakolato)dibora, 119.1 mg (1.21 mmol) kalijevog acetata, 13.7 mg (0.02 mmola) PdCl2(dppf), 150 mg (0.37 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzotiofen-2-karboksamid-hidroklorida (primjer 8A), 0.93 mL 2 M otopine natrijevog karbonata, te još 13.7 mg (0.02 mmola) PdCl2(dppf) u 2 mL DMF. According to general procedure D, 116.5 mg (0.49 mmol) of 1-(4-bromophenyl)-2-pyrrolidinone, 142.2 mg (0.56 mmol) of bis-(pinacolato)diboron, 119.1 mg (1.21 mmol) of potassium acetate, 13.7 mg ( 0.02 mmol) PdCl2(dppf), 150 mg (0.37 mmol) N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride ( example 8A), 0.93 mL of 2 M sodium carbonate solution, and another 13.7 mg (0.02 mmol) of PdCl2(dppf) in 2 mL of DMF.

Nakon sušenja u visokom vakuumu dobije se 71 mg (39 % od teor.) naslovnog spoja. After drying in a high vacuum, 71 mg (39% of theory) of the title compound are obtained.

1H-NMR (400 MHz, metanol-d4): δ = 8.16 (s, 1H), 7.91 (d, 1H), 7.80 (m, 2H), 7.75 (m, 2H), 7.54 (dd, 1H), 7.51 (dd, 1H), 4.46 (m, IH), 4.01 (m, 2H), 3.85 (m, 1H), 3.47 (m, 1H), 3.42-3.26 (m, 4H), 2.65 (m, 2H), 2.39 (m, 1H), 2.24 (m, 3H), 2.10 (m, 2H), 1.96 (m, 1H). 1H-NMR (400 MHz, methanol-d4): δ = 8.16 (s, 1H), 7.91 (d, 1H), 7.80 (m, 2H), 7.75 (m, 2H), 7.54 (dd, 1H), 7.51 (dd, 1H), 4.46 (m, 1H), 4.01 (m, 2H), 3.85 (m, 1H), 3.47 (m, 1H), 3.42-3.26 (m, 4H), 2.65 (m, 2H), 2.39 (m, 1H), 2.24 (m, 3H), 2.10 (m, 2H), 1.96 (m, 1H).

HPLC (metoda 1): Rt = 4.0 min. HPLC (method 1): Rt = 4.0 min.

MS (ESIpos): m/z = 446 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 446 (M+H)+ (free base).

Primjer 67 Example 67

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[4-(l-piperazinil)fenil]-1-benzotiofen-2-karboksamid-dihidro klorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[4-(1-piperazinyl)phenyl]-1-benzothiophene-2-carboxamide dihydro chloride

[image] [image]

Prema općenitom radnom propisu D stavi se 165.6 mg (0.49 mmola) tert-butil estera 4-(4-bromfenil)-1-piperazinkarboksilne kiseline, 142.2 mg (0.56 mmola) bis(pinakolato)dibora, 119.1 mg (1.21 mmol) kalijevog acetata, 13.7 mg (0.02 mmola) PdCl2(dppf), 150 mg (0.37 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzotiofen-2-karboksamid-hidroklorida (primjer 8A), 0.93 mL 2 M otopine natrijevog karbonata, te još 13.7 mg (0.02 mmola) PdCl2(dppf) u 2 mL DMF. Spoj pročišćen preparativnom HPLC otopi se u 3 mL metanola, pretvori sa 3 mL 4 M klorovodika u dioksanu i miješa 30 min pri sobnoj temperaturi. Sadržaj tikvice se zgusne u vakuumu, a ostatak se dvaput azeotropno destilira s toluolom. Nakon sušenja u visokom vakuumu dobije se 54 mg (28 % od teor.) naslovnog spoja. According to general procedure D, 165.6 mg (0.49 mmol) of tert-butyl ester of 4-(4-bromophenyl)-1-piperazinecarboxylic acid, 142.2 mg (0.56 mmol) of bis(pinacolato)diboron, 119.1 mg (1.21 mmol) of potassium acetate are added. , 13.7 mg (0.02 mmol) PdCl2(dppf), 150 mg (0.37 mmol) N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophen-2- of carboxamide hydrochloride (example 8A), 0.93 mL of 2 M sodium carbonate solution, and another 13.7 mg (0.02 mmol) of PdCl2(dppf) in 2 mL of DMF. The compound purified by preparative HPLC was dissolved in 3 mL of methanol, converted with 3 mL of 4 M hydrogen chloride in dioxane and stirred for 30 min at room temperature. The contents of the flask are concentrated in vacuo, and the residue is azeotropically distilled twice with toluene. After drying in high vacuum, 54 mg (28% of theory) of the title compound is obtained.

1H-NMR (300 MHz, metanol-d4): δ = 8.17 (s, 1H), 7.87 (dd, 1H), 7.66 (m, 2H), 7.52 (dd, 1H), 7.45 (dd, 1H), 7.18 (m, 2H), 4.45 (m, 1H), 3.83 (m, 1H), 3.75-3.13 (m, 13H), 2.38 (m, 1H), 2.28 (m, 1H), 2.10 (m, 2H), 1.95 (m, 1H). 1H-NMR (300 MHz, methanol-d4): δ = 8.17 (s, 1H), 7.87 (dd, 1H), 7.66 (m, 2H), 7.52 (dd, 1H), 7.45 (dd, 1H), 7.18 (m, 2H), 4.45 (m, 1H), 3.83 (m, 1H), 3.75-3.13 (m, 13H), 2.38 (m, 1H), 2.28 (m, 1H), 2.10 (m, 2H), 1.95 (m, 1H).

HPLC (metoda 1): Rt = 3.7 min. HPLC (method 1): Rt = 3.7 min.

MS (ESIpos): m/z = 447 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 447 (M+H)+ (free base).

Primjer 68 Example 68

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[4-(3-okso-4-morfolinil)fenil]-1-benzotiofen-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[4-(3-oxo-4-morpholinyl)phenyl]-1-benzothiophene-2-carboxamide hydrochloride

[image] [image]

Prema općenitom radnom propisu D stavi se 120 mg (0.39 mmola) 4-(4-bromfenil)-3-morfolinona, 115.3 mg (0.45 mmola) bis(pinakolato)dibora, 96.6 mg (0.98 mmola) kalijevog acetata, 11.1 mg (0.02 mmola) PdCl2(dppf), 121.6 mg (0.30 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzotiofen-2-karboksamid-hidroklorida (primjer 8A), 0.76 mL 2 M otopine natrijevog karbonata, te još 11.1 mg (0.02 mmola) PdCl2(dppf) u 2 mL DMF. Nakon sušenja u visokom vakuumu dobije se 24 mg (16 % od teor.) naslovnog spoja. According to general procedure D, 120 mg (0.39 mmol) of 4-(4-bromophenyl)-3-morpholinone, 115.3 mg (0.45 mmol) of bis(pinacolato)diboron, 96.6 mg (0.98 mmol) of potassium acetate, 11.1 mg (0.02 mmol) PdCl2(dppf), 121.6 mg (0.30 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (example 8A), 0.76 mL of 2 M sodium carbonate solution, and another 11.1 mg (0.02 mmol) of PdCl2(dppf) in 2 mL of DMF. After drying in a high vacuum, 24 mg (16% of theory) of the title compound are obtained.

1H-NMR (400 MHz, metanol-d4): δ = 8.17 (s, 1H), 7.93 (d, 1H), 7.80 (m, 2H), 7.55 (m, 4H), 4.46 (m, 1H), 4.33 (s, 2H), 4.09 (m, 2H), 3.88 (m, 2H), 3.84 (m, 1H), 3.47 (m, 1H), 3.41-3.26 (m, 4H), 2.39 (m, 1H), 2.28 (m, 1H), 2.10 (m, 2H), 1.95 (m, 1H). 1H-NMR (400 MHz, methanol-d4): δ = 8.17 (s, 1H), 7.93 (d, 1H), 7.80 (m, 2H), 7.55 (m, 4H), 4.46 (m, 1H), 4.33 (s, 2H), 4.09 (m, 2H), 3.88 (m, 2H), 3.84 (m, 1H), 3.47 (m, 1H), 3.41-3.26 (m, 4H), 2.39 (m, 1H), 2.28 (m, 1H), 2.10 (m, 2H), 1.95 (m, 1H).

HPLC (metoda 1): Rt = 3.8 min. HPLC (method 1): Rt = 3.8 min.

Primjer 69 Example 69

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[3-(l-pirolidinil)fenil]-1-benzotiofen-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[3-(1-pyrrolidinyl)phenyl]-1-benzothiophene-2-carboxamide hydrochloride

[image] [image]

Prema općenitom radnom propisu D stavi se 109.8 mg (0.49 mmola) l-(3-bromfenil)pirolidina, 142.2 mg (0.56 mmola) According to general procedure D, 109.8 mg (0.49 mmol) of l-(3-bromophenyl)pyrrolidine, 142.2 mg (0.56 mmol)

bis(pinakolato)dibora, 119.1 mg (1.21 mmol) kalijevog acetata, 13.7 mg (0.02 mmola) PdCh(dppf), 150 mg (0.37 mmola) N-[(3R)-l-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzotiofen-2-karboksamid-hidroklorida (primjer 8A), 0.93 mL 2 M otopine natrijevog karbonata, te još 13.7 mg (0.02 mmola) PdCl2(dppf) u 2 mL DMF. bis(pinacolato)diboron, 119.1 mg (1.21 mmol) potassium acetate, 13.7 mg (0.02 mmol) PdCh(dppf), 150 mg (0.37 mmol) N-[(3R)-l-azabicyclo[2.2.2]oct-3 -yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A), 0.93 mL of 2 M sodium carbonate solution, and another 13.7 mg (0.02 mmol) of PdCl2(dppf) in 2 mL of DMF.

Nakon sušenja u visokom vakuumu dobije se 88.4 mg (51 % od teor.) naslovnog spoja. After drying in a high vacuum, 88.4 mg (51% of theory) of the title compound is obtained.

1H-NMR (200 MHz, DMSO-d6): δ = 10.28 (br. s, 1H), 9.11 (d, 1H), 8.42 (s, 1H), 7.95 (dd, 1H), 7.55 (m, 2H), 7.36 (dd, 1H), 6.96 (d, 1H), 6.87 (s, 1H), 6.68 (m, 1H), 4.33 (m, 1H), 3.80-3.10 (m, 10H), 2.21 (m, 1H), 2.11 (m, 1H), 2.95 (m, 6H), 1.75 (m, 1H). 1H-NMR (200 MHz, DMSO-d6): δ = 10.28 (no. s, 1H), 9.11 (d, 1H), 8.42 (s, 1H), 7.95 (dd, 1H), 7.55 (m, 2H) , 7.36 (dd, 1H), 6.96 (d, 1H), 6.87 (s, 1H), 6.68 (m, 1H), 4.33 (m, 1H), 3.80-3.10 (m, 10H), 2.21 (m, 1H ), 2.11 (m, 1H), 2.95 (m, 6H), 1.75 (m, 1H).

HPLC (metoda 1): Rt = 4.2 min. HPLC (method 1): Rt = 4.2 min.

MS (ESIpos): m/z = 432 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 432 (M+H)+ (free base).

Primjer 70 Example 70

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[3-(4-morfolinil)fenil]-1-benzotiofen-2-karboksamid-hidro klorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[3-(4-morpholinyl)phenyl]-1-benzothiophene-2-carboxamide hydrochloride

[image] [image]

Prema općenitom radnom propisu D stavi se 151.1 mg (0.49 mmola) 3-(4-morfolinil)fenil-trifluormetansulfonata (primjer 17A), 142.2 mg (0.56 mmola) bis(pinakolato)dibora, 119.1 mg (1.21 mmol) kalijevog acetata, 13.7 mg (0.02 mmola) PdCbtdppf), 150.0 mg (0.37 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzotiofen-2-karboksamid-hidroklorida (primjer 8A), 0.93 mL 2 M otopine natrijevog karbonata, te još 13.7 mg (0.02 mmola) PdCl2(dppf) u 2 mL DMF. Nakon sušenja u visokom vakuumu dobije se 125.3 mg (68 % od teor.) naslovnog spoja. 1H-NMR (400 MHz, metanol-d4): δ = 8.26 (s, 1H), 7.99 (m, 2H), 7.86 (d, 1H), 7.75 (m, 2H), 7.59 (m, 2H), 4.47 (m, 1H), 4.10 (m, 4H), 3.83 (m, 1H), 3.76 (m, 4H), 3.73 (m, 1H), 3.52 (m, 1H), 3.37 (m, 3H), 2.38 (m, 1H), 2.29 (m, 1H), 2.10 (m, 2H), 1.96 (m, 1H). According to general procedure D, 151.1 mg (0.49 mmol) of 3-(4-morpholinyl)phenyl-trifluoromethanesulfonate (example 17A), 142.2 mg (0.56 mmol) of bis(pinacolato)diboron, 119.1 mg (1.21 mmol) of potassium acetate, 13.7 mg (0.02 mmol) PdCbtdppf), 150.0 mg (0.37 mmol) N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride ( example 8A), 0.93 mL of 2 M sodium carbonate solution, and another 13.7 mg (0.02 mmol) of PdCl2(dppf) in 2 mL of DMF. After drying in high vacuum, 125.3 mg (68% of theory) of the title compound is obtained. 1H-NMR (400 MHz, methanol-d4): δ = 8.26 (s, 1H), 7.99 (m, 2H), 7.86 (d, 1H), 7.75 (m, 2H), 7.59 (m, 2H), 4.47 (m, 1H), 4.10 (m, 4H), 3.83 (m, 1H), 3.76 (m, 4H), 3.73 (m, 1H), 3.52 (m, 1H), 3.37 (m, 3H), 2.38 ( m, 1H), 2.29 (m, 1H), 2.10 (m, 2H), 1.96 (m, 1H).

HPLC (metoda 1): Rt = 3.9 min. HPLC (method 1): Rt = 3.9 min.

Primjer 71 Example 71

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[4-(l-pirolidinil)fenil]-1-benzotiofen-2-karboksamid-dihidro klorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[4-(1-pyrrolidinyl)phenyl]-1-benzothiophene-2-carboxamide dihydro chloride

[image] [image]

Prema općenitom radnom propisu D stavi se 109.8 mg (0.49 mmola) l-(4-bromfenil)pirolidina, 142.2 mg (0.56 mmola) According to general procedure D, 109.8 mg (0.49 mmol) of l-(4-bromophenyl)pyrrolidine, 142.2 mg (0.56 mmol)

bis(pinakolato)dibora, 119.1 mg (1.21 mmol) kalijevog acetata, 13.7 mg (0.02 mmola) PdCI2(dppf), 150.0 mg (0.37 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzotiofen-2-karboksamid-hidroklorida (primjer 8A), 0.93 mL 2 M otopine natrijevog karbonata, te još 13.7 mg (0.02 mmola) PdCl2(dppf) u 2 mL DMF. Nakon sušenja u visokom vakuumu dobije se 24.8 mg (13 % od teor.) naslovnog spoja. bis(pinacolato)diboron, 119.1 mg (1.21 mmol) potassium acetate, 13.7 mg (0.02 mmol) PdCl2(dppf), 150.0 mg (0.37 mmol) N-[(3R)-1-azabicyclo[2.2.2]oct-3 -yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A), 0.93 mL of 2 M sodium carbonate solution, and another 13.7 mg (0.02 mmol) of PdCl2(dppf) in 2 mL of DMF. After drying in high vacuum, 24.8 mg (13% of theory) of the title compound is obtained.

1H-NMR (400 MHz, metanol-d4): δ = 8.26 (s, 1H), 7.98 (d, 1H), 7.92 (m, 2H), 7.75 (m, 2H), 7.58 (dd, 1H), 7.53 (d, 1H), 4.47 (m, 1H), 3.92-3.76 (m, 5H), 3.51 (m, 1H), 3.45-3.18 (m, 4H), 2.42-2.23 (m, 6H), 2.10 (m, 2H), 1.96 (m, 1H). 1H-NMR (400 MHz, methanol-d4): δ = 8.26 (s, 1H), 7.98 (d, 1H), 7.92 (m, 2H), 7.75 (m, 2H), 7.58 (dd, 1H), 7.53 (d, 1H), 4.47 (m, 1H), 3.92-3.76 (m, 5H), 3.51 (m, 1H), 3.45-3.18 (m, 4H), 2.42-2.23 (m, 6H), 2.10 (m , 2H), 1.96 (m, 1H).

HPLC (metoda 1): Rt = 4.1 min. HPLC (method 1): Rt = 4.1 min.

Primjer 72 Example 72

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[4-(4morfolinilkarbonil)fenil]-l-benzotiofen-2-karboksamid-hidro klorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[4-(4morpholinylcarbonyl)phenyl]-1-benzothiophene-2-carboxamide hydrochloride

[image] [image]

Prema općenitom radnom propisu D stavi se 164.7 mg (0.49 mmola) 4-(4-morfolinilkarbonil)fenil-trifluormetansulfonata, 142.2 mg (0.56 mmola) bis(pinakolato)dibora, 119.1 mg (1.21 mmol) kalijevog acetata, 13.7 mg (0.02 mmola) PdCl2(dppf), 150.0 mg (0.37 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzotiofen-2-karboksamid-hidroklorida (primjer 8A), 0.93 mL 2 M otopine natrijevog karbonata, te još 13.7 mg (0.02 mmola) PdCl2(dppf) u 2 mL DMF. Nakon prvog pročišćavanja preparativnom HPLC provede se kolonska kromatografija na silikagelu (otapalo: diklormetan-metanol-amonijak 90:9:1). Nakon sušenja u visokom vakuumu dobije se 24.8 mg (13 % od teor.) naslovnog spoja. According to general procedure D, 164.7 mg (0.49 mmol) of 4-(4-morpholinylcarbonyl)phenyl-trifluoromethanesulfonate, 142.2 mg (0.56 mmol) of bis(pinacolato)diboron, 119.1 mg (1.21 mmol) of potassium acetate, 13.7 mg (0.02 mmol) ) PdCl2(dppf), 150.0 mg (0.37 mmol) N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A ), 0.93 mL of 2 M sodium carbonate solution, and another 13.7 mg (0.02 mmol) of PdCl2(dppf) in 2 mL of DMF. After the first purification by preparative HPLC, column chromatography is performed on silica gel (solvent: dichloromethane-methanol-ammonia 90:9:1). After drying in high vacuum, 24.8 mg (13% of theory) of the title compound is obtained.

1H-NMR (400 MHz, metanol-d4): δ = 8.22 (s, 1H), 7.97 (d, 1H), 7.83 (m, 2H), 7.62 (m, 2H), 7.55 (m, 2H), 4.47 (m, 1H), 3.90-3.26 (m, 14H), 2.38 (m, 1H), 2.28 (m, 1H), 2.10 (m, 2H), 1.96 (m, 1H). 1H-NMR (400 MHz, methanol-d4): δ = 8.22 (s, 1H), 7.97 (d, 1H), 7.83 (m, 2H), 7.62 (m, 2H), 7.55 (m, 2H), 4.47 (m, 1H), 3.90-3.26 (m, 14H), 2.38 (m, 1H), 2.28 (m, 1H), 2.10 (m, 2H), 1.96 (m, 1H).

HPLC (metoda 1): Rt = 3.8 min. HPLC (method 1): Rt = 3.8 min.

MS (ESIpos): m/z = 476 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 476 (M+H)+ (free base).

Primjer 73 Example 73

7-[2-(aminometil)fenil]-N-[(3R)-1-azablciklo[2.2.2]okt-3-il]-1-benzotiofen-2-karboksamid-dihidro klorid 7-[2-(aminomethyl)phenyl]-N-[(3R)-1-azablcyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydro chloride

[image] [image]

Prema općenitom radnom propisu D stavi se 534.2 mg (1.87 mmola) tert-butil-2-brombenzilkarbamata, 474.1 mg (1.87 mmola) bis(pinakolato)dibora, 397.0 mg (4.04 mmola) kalijevog acetata, 45.5 mg (0.06 mmola) PdCl2(dppf), 500 mg (1.24 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzotiofen-2-karboksamid-hidroklorida (primjer 8A), 3.11 mL 2 M otopine natrijevog karbonata, te još 45.5 mg (0.06 mmola) PdCl2(dppf) u 6.0 mL DMF. Nakon pročišćavanja preparativnom HPLC spojene se frakcije produkta zgusnu, preuzmu u metanol, pretvore sa 1 N solne kiseline i miješaju 30 min pri sobnoj temperaturi. Nakon zgušnjavanja i sušenja u visokom vakuumu dobije se 121 mg (20 % od teor.) naslovnog spoja. According to general procedure D, 534.2 mg (1.87 mmol) of tert-butyl-2-bromobenzylcarbamate, 474.1 mg (1.87 mmol) of bis(pinacolato)diboron, 397.0 mg (4.04 mmol) of potassium acetate, 45.5 mg (0.06 mmol) of PdCl2( dppf), 500 mg (1.24 mmol) N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A), 3.11 mL of 2 M sodium carbonate solution, and another 45.5 mg (0.06 mmol) of PdCl2(dppf) in 6.0 mL of DMF. After purification by preparative HPLC, the combined product fractions are concentrated, taken up in methanol, converted with 1 N hydrochloric acid and mixed for 30 min at room temperature. After concentration and drying in high vacuum, 121 mg (20% of theory) of the title compound are obtained.

HPLC (metoda 1): Rt = 3.6 min. HPLC (method 1): Rt = 3.6 min.

MS (ESIpos): m/z = 392 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 392 (M+H)+ (free base).

Primjer 74 Example 74

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-{3-[(2,2-dimetilpropanoil)-amino]fenil}-1-benzotiofen-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-{3-[(2,2-dimethylpropanoyl)-amino]phenyl}-1-benzothiophene-2-carboxamide hydrochloride

[image] [image]

Prema općenitom radnom propisu D stavi se 143.5 mg (0.56 mmola) N-(3-bromfenil)-2,2-dimetilpropanamida, 142.2 mg (0.56 mmola) bis(pinakolato)dibora, 119.1 mg (1.21 mmol) kalijevog acetata, 13.7 mg (0.02 mmola) PdCl2(dppf), 150.0 mg (0.37 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzotiofen-2-karboksamid-hidroklorida (primjer 8A), 0.93 mL 2 M otopine natrijevog karbonata, te još 13.7 mg (0.02 mmola) PdCl2(dppf) u 2.0 mL DMF. Nakon prvog pročišćavanja preparativnom HPLC provede se kolonska kromatografija na silikagelu (otapalo: diklormetan-metanol-amonijak 90:9:1). Nakon sušenja u visokom vakuumu dobije se 32.4 mg (17 % od teor.) naslovnog spoja. According to general procedure D, 143.5 mg (0.56 mmol) of N-(3-bromophenyl)-2,2-dimethylpropanamide, 142.2 mg (0.56 mmol) of bis(pinacolato)diboron, 119.1 mg (1.21 mmol) of potassium acetate, 13.7 mg (0.02 mmol) PdCl2(dppf), 150.0 mg (0.37 mmol) N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (example 8A), 0.93 mL of 2 M sodium carbonate solution, and another 13.7 mg (0.02 mmol) of PdCl2(dppf) in 2.0 mL of DMF. After the first purification by preparative HPLC, column chromatography is performed on silica gel (solvent: dichloromethane-methanol-ammonia 90:9:1). After drying in high vacuum, 32.4 mg (17% of theory) of the title compound is obtained.

1H-NMR (400 MHz, metanol-d4): δ = 8.16 (s, 1H), 8.01 (m, 1H), 7.92 (m, 1H), 7.63-7.48 (m, 3H), 7.47 (m, 2H), 4.44 (m, 1H), 3.84 (m, 1H), 3.47 (m, 1H), 3.41-3.27 (m, 4H), 2.38 (m, 1H), 2.28 (m, 1H), 2.10 (m, 2H), 1.96 (m, 1H), 1.32 (s, 9H). 1H-NMR (400 MHz, methanol-d4): δ = 8.16 (s, 1H), 8.01 (m, 1H), 7.92 (m, 1H), 7.63-7.48 (m, 3H), 7.47 (m, 2H) , 4.44 (m, 1H), 3.84 (m, 1H), 3.47 (m, 1H), 3.41-3.27 (m, 4H), 2.38 (m, 1H), 2.28 (m, 1H), 2.10 (m, 2H ), 1.96 (m, 1H), 1.32 (s, 9H).

HPLC (metoda 1): Rt = 4.3 min. HPLC (method 1): Rt = 4.3 min.

Primjer 75 Example 75

hidroklorid 3-(2-{[(3R)-1-azabiciklo[2.2.2]okt-3-il-amino]karbonil}-1-benzotien-7-il)-benzojeve kiseline 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-yl-amino]carbonyl}-1-benzothien-7-yl)-benzoic acid hydrochloride

[image] [image]

Stavi se 200 mg (0.50 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzotiofen-2-karboksamid-hidroklorida (primjer 8A) i 82.6 mg (0.50 mmola) 3-karboksifenilborne kiseline u 1.5 mL DMF. Nakon dodatka 0.78 mL 2 M otopine natrijevog karbonata i 20.3 mg (0.02 mmola) PdCl2(dppf) smjesa se zagrijava na 60 °C. Nakon 18 h doda se još 20.3 mg (0.02 mmola) PdCl2(dppf), te se sve zagrijava još 18 h na 90 °C. Nakon hlađenja reakcijska smjesa se filtrira na silikagelu i pročisti preparativnom HPLC. Frakcije produkta se zgusnu, pretvore sa smjesom 3:1 acetonitrila i 1 N solne kiseline i ponovno zgusnu. Nakon sušenja u visokom vakuumu dobije se 103 mg (45 % od teor.) naslovnog spoja. 200 mg (0.50 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (example 8A) and 82.6 mg (0.50 mmol) of 3-carboxyphenylboronic acid in 1.5 mL of DMF. After adding 0.78 mL of 2 M sodium carbonate solution and 20.3 mg (0.02 mmol) of PdCl2(dppf), the mixture is heated to 60 °C. After 18 h, another 20.3 mg (0.02 mmol) of PdCl2(dppf) is added, and everything is heated for another 18 h at 90 °C. After cooling, the reaction mixture is filtered on silica gel and purified by preparative HPLC. The product fractions are concentrated, converted with a mixture of 3:1 acetonitrile and 1 N hydrochloric acid and concentrated again. After drying in a high vacuum, 103 mg (45% of theory) of the title compound is obtained.

1H-NMR (300 MHz, DMSO-d6): δ = 10.28 (br. s, 1H), 9.13 (d, 1H), 8.46 (s, 1H), 8.29 (m, 1H), 8.08-7.95 (m, 3H), 7.71 (dd, 1H), 7.60 (m, 2H), 4.33 (m, 1H), 3.85-3.12 (m, 6H), 2.22 (m, 1H), 2.15 (m, 1H), 1.91 (m, 2H), 1.75 (m, 1H). 1H-NMR (300 MHz, DMSO-d6): δ = 10.28 (no. s, 1H), 9.13 (d, 1H), 8.46 (s, 1H), 8.29 (m, 1H), 8.08-7.95 (m, 3H), 7.71 (dd, 1H), 7.60 (m, 2H), 4.33 (m, 1H), 3.85-3.12 (m, 6H), 2.22 (m, 1H), 2.15 (m, 1H), 1.91 (m , 2H), 1.75 (m, 1H).

HPLC (metoda 1): Rt = 3.9 min. HPLC (method 1): Rt = 3.9 min.

MS (ESIpos): m/z = 407 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 407 (M+H)+ (free base).

Primjer 76 Example 76

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[2-({[(metilamino)karbonil]-amino}metil)fenil]-1-benzotiofen-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[2-({[(methylamino)carbonyl]-amino}methyl)phenyl]-1-benzothiophene-2-carboxamide -hydrochloride

[image] [image]

Suspenziji od 85 mg (0.18 mmola) 7-[2-(aminometil)fenil]-N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-1-benzotiofen-2-karboksamid-dihidro-klorida (primjer 73) u 1 mL smjese 5:1 THF i DMF doda se 51.0 μL (0.37 mmola) trietilamina i 43.5 μL (0.73 mmola) metilizocijanata. Nakon 18 h na sobnoj temperaturi reakcijska se smjesa zgusne i pročisti preparativnom HPLC. Frakcije produkta se zgusnu, pretvore sa smjesom 5:1 metanola i 1 N solne kiseline, te se ponovno zgusnu. Nakon sušenja u visokom vakuumu dobije se 65.5 mg (74 % od teor.) naslovnog spoja. A suspension of 85 mg (0.18 mmol) of 7-[2-(aminomethyl)phenyl]-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide-dihydro -chloride (example 73) in 1 mL of a 5:1 mixture of THF and DMF, 51.0 μL (0.37 mmol) of triethylamine and 43.5 μL (0.73 mmol) of methyl isocyanate are added. After 18 h at room temperature, the reaction mixture is concentrated and purified by preparative HPLC. The product fractions are concentrated, reconstituted with a mixture of 5:1 methanol and 1 N hydrochloric acid, and concentrated again. After drying in a high vacuum, 65.5 mg (74% of theory) of the title compound is obtained.

1H-NMR (400 MHz, metanol-d4): δ = 8.18 (s, 1H), 7.94 (d, 1H), 7.58-7.44 (m, 3H), 7.43-7.29 (m, 3H), 4.43 (m, 1H), 4.15 (m, 2H), 3.82 (m, 1H), 3.47 (m, 1H), 3.41-3.27 (m, 4H), 2.62 (s, 3H), 2.37 (m, 1H), 2.26 (m, 1H), 2.08 (m, 2H), 1.94 (m, 1H). 1H-NMR (400 MHz, methanol-d4): δ = 8.18 (s, 1H), 7.94 (d, 1H), 7.58-7.44 (m, 3H), 7.43-7.29 (m, 3H), 4.43 (m, 1H), 4.15 (m, 2H), 3.82 (m, 1H), 3.47 (m, 1H), 3.41-3.27 (m, 4H), 2.62 (s, 3H), 2.37 (m, 1H), 2.26 (m , 1H), 2.08 (m, 2H), 1.94 (m, 1H).

HPLC (metoda 1): Rt = 3.8 min. HPLC (method 1): Rt = 3.8 min.

LC-MS (metoda 4): Rt = 2.5 min LC-MS (method 4): Rt = 2.5 min

Primjer 77 Example 77

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[3-(1H-pirol-1-il)fenil]-1-benzotiofen-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[3-(1H-pyrrol-1-yl)phenyl]-1-benzothiophene-2-carboxamide hydrochloride

[image] [image]

Prema općenitom radnom propisu D stavi se 124.4 mg (0.56 mmola) l-(3-bromfenil)-1H-pirola, 142.2 mg (0.56 mmola) bis(pinakolato)dibora, 119.1 mg (1.21 mmol) kalijevog acetata, 13.7 mg (0.02 mmola) PdCl2(dppf), 150.0 mg (0.37 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzotiofen-2-karboksamid-hidroklorida (primjer 8A), 0.93 mL 2 M otopine natrijevog karbonata, te još 13.7 mg (0.02 mmola) PdCl2(dppf) u 2.0 mL DMF. Nakon sušenja u visokom vakuumu dobije se 86.9 mg (48 % od teor.) naslovnog spoja. According to general procedure D, 124.4 mg (0.56 mmol) of l-(3-bromophenyl)-1H-pyrrole, 142.2 mg (0.56 mmol) of bis(pinacolato)diboron, 119.1 mg (1.21 mmol) of potassium acetate, 13.7 mg (0.02 mmol) PdCl2(dppf), 150.0 mg (0.37 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (example 8A), 0.93 mL of 2 M sodium carbonate solution, and another 13.7 mg (0.02 mmol) of PdCl2(dppf) in 2.0 mL of DMF. After drying in high vacuum, 86.9 mg (48% of theory) of the title compound is obtained.

1H-NMR (400 MHz, DMSO-d6): δ = 9.92 (br. s, 1H), 9.03 (d, 1H), 8.39 (m, 1H), 8.02 (m, 1H), 7.88 (s, 1H), 7.77-7.57 (m, 5H), 7.49 (m, 2H), 6.31 (m, 2H), 4.32 (m, 1H), 3.67 (m, 1H), 3.57-3.13 (m, 5H), 2.21 (m, 1H), 2.13 (m, 1H), 1.90 (m, 2H), 1.75 (m, 1H). 1H-NMR (400 MHz, DMSO-d6): δ = 9.92 (no. s, 1H), 9.03 (d, 1H), 8.39 (m, 1H), 8.02 (m, 1H), 7.88 (s, 1H) , 7.77-7.57 (m, 5H), 7.49 (m, 2H), 6.31 (m, 2H), 4.32 (m, 1H), 3.67 (m, 1H), 3.57-3.13 (m, 5H), 2.21 (m , 1H), 2.13 (m, 1H), 1.90 (m, 2H), 1.75 (m, 1H).

HPLC (metoda 1): Rt = 4.5 min. HPLC (method 1): Rt = 4.5 min.

MS (ESIpos): m/z = 428 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 428 (M+H)+ (free base).

Primjer 78 Example 78

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[3-(4-morfolinilkarbonil)fenil]-1-benzotiofen-2-karboksamid-hidro klorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[3-(4-morpholinylcarbonyl)phenyl]-1-benzothiophene-2-carboxamide hydrochloride

[image] [image]

Otopini od 50 mg (0.11) hidroklorida 3-(2-{[(3R)-1-azabiciklo-[2.2.2]okt-3-il-amino]karbonil}-1-benzotien-7-il)-benzojeve kiseline (primjer 75) i 19.7 nL (0.23 mmol) morfolina u 0.5 mL DMF doda se pri 0 °C 103 mg (0.27 mmol) HATU i 70.8 nL (0.41 mmol) N,N-diizopropiletilamina. Smjesa se miješa 18 h pri sobnoj temperaturi. Nakon pročišćavanja preparativnom HPLC frakcije produkta se zgusnu, pretvore sa smjesom 3:1 acetonitrila i 1 N solne kiseline, te ponovno zgusnu. Nakon sušenja u visokom vakuumu dobije se 43 mg (74 % od teor.) naslovnog spoja. Solutions of 50 mg (0.11) 3-(2-{[(3R)-1-azabicyclo-[2.2.2]oct-3-yl-amino]carbonyl}-1-benzothien-7-yl)-benzoic acid hydrochloride (Example 75) and 19.7 nL (0.23 mmol) morpholine in 0.5 mL DMF were added at 0 °C to 103 mg (0.27 mmol) HATU and 70.8 nL (0.41 mmol) N,N-diisopropylethylamine. The mixture is stirred for 18 h at room temperature. After purification by preparative HPLC, the product fractions are concentrated, converted with a mixture of 3:1 acetonitrile and 1 N hydrochloric acid, and concentrated again. After drying in high vacuum, 43 mg (74% of theory) of the title compound is obtained.

1H-NMR (200 MHz, DMSO-d6): δ = 10.66 (br. s, 1H), 9.33 (d, 1H), 8.56 (s, 1H), 7.99 (dd, 1H), 7.87-7.45 (m, 6H), 4.34 (m, 1H), 3.87-3.06 (m, 14H), 2.18 (m, 2H), 1.90 (m, 2H), 1.74 (m, 1H). 1H-NMR (200 MHz, DMSO-d6): δ = 10.66 (no. s, 1H), 9.33 (d, 1H), 8.56 (s, 1H), 7.99 (dd, 1H), 7.87-7.45 (m, 6H), 4.34 (m, 1H), 3.87-3.06 (m, 14H), 2.18 (m, 2H), 1.90 (m, 2H), 1.74 (m, 1H).

HPLC (metoda 1): Rt = 3.8 min. HPLC (method 1): Rt = 3.8 min.

MS (ESIpos): m/z = 476 (M + H)+ (slobodna baza). MS (ESIpos): m/z = 476 (M + H)+ (free base).

Primjer 79 Example 79

N-[(3S)-1-azabiciklo[2.2.2]okt-3-il]-7-[4-(4-morfolinil)fenil]-1-benzotiofen-2-karboksamid-hidro klorid N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-[4-(4-morpholinyl)phenyl]-1-benzothiophene-2-carboxamide hydrochloride

[image] [image]

Smjesi od 144.3 mg (0.72 mmola) S-3-aminokinuklidin-dihidro-klorida i 300 mg (0.72 mmola) 7-[4-(4-morfolinil)fenil]-1-benzotiofen-2-karboksilne kiseline (primjer 20A) u 3 mL DMF doda se pri 0 °C 330.7 mg (0.87 mmola) HATU i 112.4 mg (0.87 mmola) N,N-diizopropiletilamina. Nakon 30 min na 0 °C doda se još 224.8 mg (1.74 mmola) N’,N-diizopropiletilamina, te se smjesa miješa pri sobnoj temperaturi još 19 h. Reakcijska otopina se pretvori s nešto vode i acetonitrila i pročisti preparativnom HPLC. Frakcije produkta se zgusnu, pretvore smjesom 3:1 metanola i 1 N solne kiseline, te ponovno zgusnu. Nakon sušenja u visokom vakuumu dobije se 158 mg (45 % od teor.) naslovnog spoja. Mixtures of 144.3 mg (0.72 mmol) of S-3-aminoquinuclidine dihydrochloride and 300 mg (0.72 mmol) of 7-[4-(4-morpholinyl)phenyl]-1-benzothiophene-2-carboxylic acid (Example 20A) in 3 mL of DMF was added at 0 °C to 330.7 mg (0.87 mmol) of HATU and 112.4 mg (0.87 mmol) of N,N-diisopropylethylamine. After 30 min at 0 °C, another 224.8 mg (1.74 mmol) of N',N-diisopropylethylamine was added, and the mixture was stirred at room temperature for another 19 h. The reaction solution is taken up with some water and acetonitrile and purified by preparative HPLC. The product fractions are concentrated, converted with a 3:1 mixture of methanol and 1 N hydrochloric acid, and concentrated again. After drying in high vacuum, 158 mg (45% of theory) of the title compound are obtained.

Spektroskopski podatci odgovaraju onima enantiomernog spoja (primjer 19) gore. The spectroscopic data correspond to those of the enantiomeric compound (Example 19) above.

Primjer 80 Example 80

N-[(3R)-1-azabidklo[2.2.2]okt-3-il]-7-[3-(4-morfolinil)fenil]-1-benzofuran-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[3-(4-morpholinyl)phenyl]-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Prema općenitom radnom propisu D stavi se 151.1 mg (0.49 mmola) 3-(4-morfolinil)fenil-trifluormetansulfonat (primjer 17A), 142.2 mg (0.56 mmola) bis(pinakolato)dibora, 119.1 mg (1.21 mmol) kalijevog acetata, 13.7 mg (0.02 mmola) PdCl2(dppf), 144 mg (0.37 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzofuran-2-karboksamid-hidroklorida (primjer 30A), 0.93 mL 2 M otopine natrijevog karbonata, te još 13.7 mg (0.02 mmola) PdCl2(dppf) u 2 mL DMF. Nakon sušenja u visokom vakuumu dobije se 32 mg (18 % od teor.) naslovnog spoja. According to general procedure D, 151.1 mg (0.49 mmol) of 3-(4-morpholinyl)phenyl-trifluoromethanesulfonate (Example 17A), 142.2 mg (0.56 mmol) of bis(pinacolato)diboron, 119.1 mg (1.21 mmol) of potassium acetate, 13.7 mg (0.02 mmol) PdCl2(dppf), 144 mg (0.37 mmol) N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide- hydrochloride (example 30A), 0.93 mL of 2 M sodium carbonate solution, and another 13.7 mg (0.02 mmol) of PdCl2(dppf) in 2 mL of DMF. After drying in a high vacuum, 32 mg (18% of theory) of the title compound are obtained.

1H-NMR (300 MHz, DMSO-d6): δ = 10.27 (br. s, 1H), 8.96 (d, 1H), 7.85 (s, 1H), 7.78 (m, 1H), 7.68 (m, 1H), 7.62 (m, 1H), 7.43 (m, 3H), 7.17 (m, 1H), 4.36 (m, 1H), 3.82 (m, 4H), 3.63 (m, 1H), 3.44-3.10 (m, 9H), 2.22 (m, 1H), 2.12 (m, 1H), 1.91 (m, 2H), 1.75 (m, 1H). 1H-NMR (300 MHz, DMSO-d6): δ = 10.27 (no. s, 1H), 8.96 (d, 1H), 7.85 (s, 1H), 7.78 (m, 1H), 7.68 (m, 1H) , 7.62 (m, 1H), 7.43 (m, 3H), 7.17 (m, 1H), 4.36 (m, 1H), 3.82 (m, 4H), 3.63 (m, 1H), 3.44-3.10 (m, 9H ), 2.22 (m, 1H), 2.12 (m, 1H), 1.91 (m, 2H), 1.75 (m, 1H).

HPLC (metoda 1): Rt = 3.8 min. HPLC (method 1): Rt = 3.8 min.

Primjer 81 Example 81

7-(3-aminofenil)-N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]l-1-benzotiofen-2-karboksamid-hidroklorid 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]1-1-benzothiophene-2-carboxamide hydrochloride

[image] [image]

Stavi se 200 mg (0.50 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzotiofen-2-karboksamid-hidroklorida (primjer 8A) i 68.2 mg (0.50 mmola) 3-aminofenilborne kiseline u 1.5 mL DMF. Nakon dodatka 0.78 mL 2 M otopine natrijevog karbonata i 20.3 mg (0.02 mmola) PdCl2(dppf) smjesa se zagrijava 18 h na 60 °C. Nakon hlađenja reakcijska smjesa se filtrira na silikagelu i pročisti odvajanjem preparativnom HPLC. Frakcije produkta se zgusnu, pretvore sa smjesom 3:1 acetonitrila i 1 N solne kiseline i ponovno zgusnu. Nakon sušenja u visokom vakuumu dobije se 201 mg (98 % od teor.) naslovnog spoja. 200 mg (0.50 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (example 8A) and 68.2 mg (0.50 mmol) of 3-aminophenylboronic acid in 1.5 mL of DMF. After adding 0.78 mL of 2 M sodium carbonate solution and 20.3 mg (0.02 mmol) of PdCl2(dppf), the mixture is heated for 18 h at 60 °C. After cooling, the reaction mixture is filtered on silica gel and purified by separation by preparative HPLC. The product fractions are concentrated, converted with a mixture of 3:1 acetonitrile and 1 N hydrochloric acid and concentrated again. After drying in high vacuum, 201 mg (98% of theory) of the title compound are obtained.

1H-NMR (200 MHz, DMSO-d6): δ = 10.63 (br. s, 1H), 9.33 (d, 1H), 8.57 (s, 1H), 8.00 (dd, 1H), 7.76-7.58 (m, 4H), 7.55 (m, 1H), 7.43 (m, 1H), 4.34 (m, 1H), 3.62 (m, 1H), 3.42 (m, 2H), 3.19 (m, 3H), 2.19 (m, 2H), 1.90 (m, 2H), 1.73 (m, 1H). 1H-NMR (200 MHz, DMSO-d6): δ = 10.63 (no. s, 1H), 9.33 (d, 1H), 8.57 (s, 1H), 8.00 (dd, 1H), 7.76-7.58 (m, 4H), 7.55 (m, 1H), 7.43 (m, 1H), 4.34 (m, 1H), 3.62 (m, 1H), 3.42 (m, 2H), 3.19 (m, 3H), 2.19 (m, 2H ), 1.90 (m, 2H), 1.73 (m, 1H).

HPLC (metoda 1): Rt = 3.5 min. HPLC (method 1): Rt = 3.5 min.

MS (ESIpos): m/z = 378 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 378 (M+H)+ (free base).

Primjer 82 Example 82

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-{-3-[(metoksiacetil)amno]-fenil}-1-benzotiofen-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-{-3-[(methoxyacetyl)amino]-phenyl}-1-benzothiophene-2-carboxamide hydrochloride

[image] [image]

Otopini od 50 mg (0.12 mmola) 7-(3-aminofenil)-N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-1-benzotiofen-2-karboksamid-hidro klorida (primjer 81) i 18.5 nL (0.24 mmola) metoksioctene kiseline u 0.5 mL DMF doda se pri 0 °C i 96.4 mg (0.25 mmola) HATU i 71.5 μL (0.41 mmol) N,N-diizorpopiletilamina. Smjesa se miješa još 3 h na sobnoj temperaturi. Nakon pročišćavanja preparativnom HPLC frakcije produkta se zgusnu, pretvore smjesom 3:1 acetonitrila i 1 N solne kiseline i ponovno zgusnu. Nakon sušenja u visokom vakuumu dobije se 7 mg (11 % od teor.) naslovnog spoja. Solutions of 50 mg (0.12 mmol) 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide hydrochloride (example 81) and 18.5 nL (0.24 mmol) methoxyacetic acid in 0.5 mL DMF were added at 0 °C and 96.4 mg (0.25 mmol) HATU and 71.5 μL (0.41 mmol) N,N-diisopropylethylamine. The mixture is stirred for another 3 h at room temperature. After purification by preparative HPLC, the product fractions are concentrated, converted with a mixture of 3:1 acetonitrile and 1 N hydrochloric acid and concentrated again. After drying in high vacuum, 7 mg (11% of theory) of the title compound is obtained.

1H-NMR (300 MHz, DMSO-d6): δ = 10.13 (br. s, 1H), 9.97 (s, 1H), 9.04 (d, 1H), 8.39 (s, 1H), 8.13 (m, 1H), 7.98 (d, 1H), 7.76 (d, 1H), 7.58 (dd, 1H), 7.50 (m, 2H), 7.42 (m, 1H), 4.33 (m, 1H), 4.03 (s, 2H), 3.66 (m, 1H), 3.56-3.12 (m, 8H), 2.22 (m, 1H), 2.14 (m, 1H), 1.91 (m, 2H), 1.75 (m, 1H). 1H-NMR (300 MHz, DMSO-d6): δ = 10.13 (no. s, 1H), 9.97 (s, 1H), 9.04 (d, 1H), 8.39 (s, 1H), 8.13 (m, 1H) , 7.98 (d, 1H), 7.76 (d, 1H), 7.58 (dd, 1H), 7.50 (m, 2H), 7.42 (m, 1H), 4.33 (m, 1H), 4.03 (s, 2H), 3.66 (m, 1H), 3.56-3.12 (m, 8H), 2.22 (m, 1H), 2.14 (m, 1H), 1.91 (m, 2H), 1.75 (m, 1H).

HPLC (metoda 1): Rt = 4.0 min. HPLC (method 1): Rt = 4.0 min.

MS (ESIpos): m/z = 450 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 450 (M+H)+ (free base).

Primjer 83 Example 83

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[4-(2-okso-1-pirolidinil)fenil]-1-benzofuran-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Prema općenitom radnom propisu D stavi se 161.9 mg (0.67 mmola) l-(4-bromfenil)-2-pirolidinona, 197.5 mg (0.78 mmola) bis(pinakolato)dibora, 165.4 mg (1.69 mmola) kalijevog acetata, 19.0 mg (0.03 mmola) PdCl2(dppf), 200 mg (0.52 mmola) N-[(3R)-l-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzofuran-2-karboksamid-hidroklorida (primjer 30A), 1.30 mL 2 M otopine natrijevog karbonata, te još 19.0 mg (0.03 mmola) PdCl2(dppf) u 2.5 mL DMF. Nakon sušenja u visokom vakuumu dobije se 166.6 mg (65 % teor.) naslovnog spoja According to general procedure D, 161.9 mg (0.67 mmol) of 1-(4-bromophenyl)-2-pyrrolidinone, 197.5 mg (0.78 mmol) of bis(pinacolato)diboron, 165.4 mg (1.69 mmol) of potassium acetate, 19.0 mg (0.03 mmol) PdCl2(dppf), 200 mg (0.52 mmol) N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide hydrochloride (example 30A), 1.30 mL of 2 M sodium carbonate solution, and another 19.0 mg (0.03 mmol) of PdCl2(dppf) in 2.5 mL of DMF. After drying in a high vacuum, 166.6 mg (65 % of theory) of the title compound is obtained

1H-NMR (200 MHz, DMSO-d6): δ = 10.06 (br. s, 1H), 8.96 (d, 1H), 7.97 (m, 1H), 7.94 (s, 1H), 7.83 (m, 3H), 7.78 (dd, 1H), 7.69 (dd, 1H), 7.43 (dd, 1H), 4.33 (m, 1H), 4.00-3.75 (m, 2H), 3.66 (m, 1H), 3.49-3.10 (m, 5H), 2.55 (m, 2H), 2.23 (m, 1H), 2.10 (m, 3H), 1.91 (m, 2H), 1.75 (m, 1H). 1H-NMR (200 MHz, DMSO-d6): δ = 10.06 (no. s, 1H), 8.96 (d, 1H), 7.97 (m, 1H), 7.94 (s, 1H), 7.83 (m, 3H) , 7.78 (dd, 1H), 7.69 (dd, 1H), 7.43 (dd, 1H), 4.33 (m, 1H), 4.00-3.75 (m, 2H), 3.66 (m, 1H), 3.49-3.10 (m , 5H), 2.55 (m, 2H), 2.23 (m, 1H), 2.10 (m, 3H), 1.91 (m, 2H), 1.75 (m, 1H).

HPLC (metoda 1): Rt = 4.0 min. HPLC (method 1): Rt = 4.0 min.

MS (ESIpos): m/z = 430.5 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 430.5 (M+H)+ (free base).

Primjer 84 Example 84

7-[3-(acetilamino)fenil]-N-[(3S)-1-azabiciklo[2.2.2]okt-3-il]-1-benzotiofen-2-karboksamid-hidro klorid 7-[3-(acetylamino)phenyl]-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide hydrochloride

[image] [image]

Smjesi od 200 mg (0.45 mmola) N-[(3S)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzotiofen-2-karboksamid-hidroklorida (primjer 22A) i 80.2 mg (0.45 mmola) 3-(acetamido)fenilborne kiseline u 2 mL DMF stavi se 0.67 mL 2 M otopine natrijevog karbonata i 18.3 mg (0.02 mmola) PdCl2(dppf). Reakcijska smjesa zagrijava se 17 h na 80 °C. Doda se još 40.1 mg (0.22 mmol) 3-(acetamido)-fenilborne kiseline, 1.34 mL 1 N natrijeve lužine, te 73.2 mg (0.09 mmola) PdCl2(dppf) te se sve zagrjiava još 18 h na 70 °C. Nakon hlađenja smjesa se filtrira na silikagelu i pročisti preparativnom HPLC. Frakcije produkta se zgusnu, preuzmu u smjesu 5:1 metanola i 1 N solne kiseline i ponovno zgusnu. Nakon sušenja u visokom vakuumu dobije se 124.5 mg (59 % od teor.) naslovnog spoja. Spektroskopski podatci odgovaraju onima enantiomerng spoja (primjer 51) gore. Mixtures of 200 mg (0.45 mmol) of N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 22A) and 80.2 mg (0.45 mmol) of 3-(acetamido)phenylboronic acid in 2 mL of DMF was added to 0.67 mL of a 2 M sodium carbonate solution and 18.3 mg (0.02 mmol) of PdCl2(dppf). The reaction mixture is heated for 17 h at 80 °C. Another 40.1 mg (0.22 mmol) of 3-(acetamido)-phenylboronic acid, 1.34 mL of 1 N sodium hydroxide solution, and 73.2 mg (0.09 mmol) of PdCl2(dppf) are added, and everything is heated for another 18 h at 70 °C. After cooling, the mixture is filtered on silica gel and purified by preparative HPLC. The product fractions are concentrated, taken up in a mixture of 5:1 methanol and 1 N hydrochloric acid and concentrated again. After drying in high vacuum, 124.5 mg (59% of theory) of the title compound is obtained. The spectroscopic data correspond to those of the enantiomerng compound (Example 51) above.

Primjer 85 Example 85

N-[(3S)-1-azabiciklo[2.2.2]okt-3-il]-7-(3-metoksifenil)-1-benzotiofen-2-karboksamid-hidro klorid N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-(3-methoxyphenyl)-1-benzothiophene-2-carboxamide hydrochloride

[image] [image]

Smjesi od 200 mg (0.45 mmola) N-[(3S)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzotiofen-2-karboksamid-hidroklorida (primjer 22A) i 68.1 mg (0.45 mmola) 3-metoksifenilbome kiseline u 2 mL DMF doda se 0.67 mL 2 M vodene otopine natrijevog karbonata i 18.3 mg (0.02 mmola) PdCl2(dppf). Reakcijska smjesa zagrijava se 17 h na 80 °C, filtrira na silikagelu i zgusne do suhoga. Nakon pročišćavanja produkta preparativnom HPLC, provede se kolonska kromatografija na silikagelu (otapalo: doklormetan-metanol-amonijak 90:9:1). Frakcije produkta se zgusnu, preuzmu u smjesu 5:1 metanola i 1 N solne kiseline i ponovno zgusnu. Nakon sušenja u visokom vakuumu dobije se 97.7 mg (48 % od teor.) naslovnog spoja. Mixtures of 200 mg (0.45 mmol) of N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 22A) and 68.1 mg (0.45 mmol) of 3-methoxyphenylbomic acid in 2 mL of DMF was added to 0.67 mL of 2 M aqueous sodium carbonate solution and 18.3 mg (0.02 mmol) of PdCl2(dppf). The reaction mixture is heated for 17 h at 80 °C, filtered on silica gel and concentrated to dryness. After purification of the product by preparative HPLC, column chromatography is performed on silica gel (solvent: dichloromethane-methanol-ammonia 90:9:1). The product fractions are concentrated, taken up in a mixture of 5:1 methanol and 1 N hydrochloric acid and concentrated again. After drying in high vacuum, 97.7 mg (48% of theory) of the title compound is obtained.

1H-NMR (200 MHz, DMSO-d6): δ = 10.25 (br. s, 1H), 9.11 (d, 1H), 8.42 (s, 1H), 7.97 (dd, 1H), 7.56 (m, 2H), 7.47 (d, 1H), 7.30 (d, 3H), 7.24 (m, 1H), 7.06 (m, 1H), 4.32 (m, 1H), 3.83 (s, 3H), 3.63 (m, 1H), 3.49-3.10 (m, 5H), 2.20 (m, 1H), 2.13 (m, 1H), 1.90 (m, 2H), 1.74 (m, 1H). 1H-NMR (200 MHz, DMSO-d6): δ = 10.25 (no. s, 1H), 9.11 (d, 1H), 8.42 (s, 1H), 7.97 (dd, 1H), 7.56 (m, 2H) , 7.47 (d, 1H), 7.30 (d, 3H), 7.24 (m, 1H), 7.06 (m, 1H), 4.32 (m, 1H), 3.83 (s, 3H), 3.63 (m, 1H), 3.49-3.10 (m, 5H), 2.20 (m, 1H), 2.13 (m, 1H), 1.90 (m, 2H), 1.74 (m, 1H).

Analitički podatci odgovaraju onima enantiomernog spoja (primjer 17) gore. The analytical data correspond to those of the enantiomeric compound (Example 17) above.

Primjer 86 Example 86

hidroklorid 4-(2-{[(3R)-1-azabiciklo[2.2.2]okt-3-il-amino]karbonil}-1-benzofuran-7-il)-benzojeve kiseline 4-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-yl-amino]carbonyl}-1-benzofuran-7-yl)-benzoic acid hydrochloride

[image] [image]

Stavi se 150 mg (0.43 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzofuran-2-karboksamid-hidroklorida (primjer 30A) i 71.3 mg (0.43 mmola) 4-karboksifenilborne kiseline u 1.5 mL DMF. Nakon dodatka 0.64 mL 2 M otopine natrijevog karbonata i 17.5 mg (0.02 mmola) PdCI2(dppf) smjesa se zagrijava 18 h na 80 °C. Nakon hlađenja reakcijska smjesa se filtrira na silikagelu, filtrat se zgusne i raspodijeli između vode i etilnog estera octene kiseline. Vodena faza se ispere etilnim esterom octene kiseline i potom zgusne. Sirovi produkt pročisti se preparativnom HPLC. Frakcije produkta se spoje, zgusnu, pretvore sa smjesom 3:1 acetonitrila i 1 N solne kiseline i ponovno zgusnu. Sirovi produkt se pomiješa s acetonitrilom. Nakon sakupljanja taloga i sušenja u visokom vakuumu dobije se 37 mg (20 % od teor.) naslovnog spoja. 150 mg (0.43 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide hydrochloride (Example 30A) and 71.3 mg (0.43 mmol) of 4-carboxyphenylboronic acid in 1.5 mL of DMF. After adding 0.64 mL of 2 M sodium carbonate solution and 17.5 mg (0.02 mmol) of PdCl2(dppf), the mixture is heated for 18 h at 80 °C. After cooling, the reaction mixture is filtered on silica gel, the filtrate is concentrated and distributed between water and ethyl acetate. The aqueous phase is washed with ethyl acetate and then concentrated. The crude product is purified by preparative HPLC. The product fractions are combined, concentrated, converted with a mixture of 3:1 acetonitrile and 1 N hydrochloric acid and concentrated again. The crude product is mixed with acetonitrile. After collection of the precipitate and drying in a high vacuum, 37 mg (20% of theory) of the title compound are obtained.

1H-NMR (300 MHz, DMSO-d6): δ = 10.37 (br. s, 1H), 9.15 (d, 1H), 8.08 (m, 4H), 7.93 (s, 1H), 7.85 (dd, 1H), 7.76 (dd, 1H), 7.47 (dd, 2H), 4.36 (m, 1H), 3.77-3.32 (m, 3H), 3.32 (m, 3H), 2.23 (m, 1H), 2.12 (m, 1H), 1.92 (m, 2H), 1.76 (m, 1H). 1H-NMR (300 MHz, DMSO-d6): δ = 10.37 (no. s, 1H), 9.15 (d, 1H), 8.08 (m, 4H), 7.93 (s, 1H), 7.85 (dd, 1H) , 7.76 (dd, 1H), 7.47 (dd, 2H), 4.36 (m, 1H), 3.77-3.32 (m, 3H), 3.32 (m, 3H), 2.23 (m, 1H), 2.12 (m, 1H ), 1.92 (m, 2H), 1.76 (m, 1H).

HPLC (metoda 1): Rt = 3.9 min. HPLC (method 1): Rt = 3.9 min.

Primjer 87 Example 87

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[3-(trifluormetoksi)fenil]-1-benzofuran-2-karboksamid-hidro klorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[3-(trifluoromethoxy)phenyl]-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Stavi se 200 mg (0.52 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzofuran-2-karboksamid-hidroklorida (primjer 30A) i 106.8 mg (0.52 mmola) 3-(trifluormetoksi)fenilborne kiseline u 2.0 mL DMF. Nakon dodatka 0.78 mL 2 M otopine natrijevog karbonata i 21.2 mg (0.03 mmola) PdCl2(dppf) smjesa se zagrijava 17 h na 70 °C. Nakon hlađenja reakcijska smjesa se filtrira na silikagelu i pročisti preparativnom HPLC. Frakcije produkta se spoje, zgusnu, pretvore smjesom 5:1 metanola i 1 N solne kiseline i ponovno zgusnu. Nakon sušenja u visokom vakuumu dobije se 48.8 mg (20 % od teor.) naslovnog spoja. 200 mg (0.52 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide hydrochloride (Example 30A) and 106.8 mg (0.52 mmol) of 3-(trifluoromethoxy)phenylboronic acid in 2.0 mL of DMF. After adding 0.78 mL of 2 M sodium carbonate solution and 21.2 mg (0.03 mmol) of PdCl2(dppf), the mixture is heated for 17 h at 70 °C. After cooling, the reaction mixture is filtered on silica gel and purified by preparative HPLC. The product fractions were combined, concentrated, reconstituted with a 5:1 mixture of methanol and 1 N hydrochloric acid and concentrated again. After drying in high vacuum, 48.8 mg (20% of theory) of the title compound is obtained.

1H-NMR (200 MHz, DMSO-d6): δ = 10.18 (br. s, 1H), 9.00 (d, 1H), 7.95 (m, 2H), 7.89 (s, 1H), 7.86 (m, 1H), 7.77 (m, 1H), 7.68 (m, 1H), 7.47 (m, 2H), 4.34 (m, 1H), 3.65 (m, 1H), 3.35 (m, 2H), 3.23 (m, 3H), 2.22 (m, 1H), 2.12 (m, 1H), 1.92 (m, 2H), 1.76 (m, 1H). 1H-NMR (200 MHz, DMSO-d6): δ = 10.18 (no. s, 1H), 9.00 (d, 1H), 7.95 (m, 2H), 7.89 (s, 1H), 7.86 (m, 1H) , 7.77 (m, 1H), 7.68 (m, 1H), 7.47 (m, 2H), 4.34 (m, 1H), 3.65 (m, 1H), 3.35 (m, 2H), 3.23 (m, 3H), 2.22 (m, 1H), 2.12 (m, 1H), 1.92 (m, 2H), 1.76 (m, 1H).

HPLC (metoda 1): Rt = 4.5 min. HPLC (method 1): Rt = 4.5 min.

Primjer 88 Example 88

N-[(3S)-1-azabiciklo[2.2.2]okt-3-il]-7-(2-metoksifenil)-1-benzotiofen-2-karboksamid-hidroklorid N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-(2-methoxyphenyl)-1-benzothiophene-2-carboxamide hydrochloride

[image] [image]

Smjesi od 200 mg (0.45 mmola) N-[(3S)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzotiofen-2-karboksamid-hidroklorida (primjer 22A) i 68.1 mg (0.45 mmola) 2-metoksifenilborne kiseline u 2 ml DMF doda se 0.67 mL 2M otopine natrijevog karbonata i 18.3 mg (0.02 mmola) PdCl2(dppf). Reakcijska smjesa zagrijava se 17 h na 70 °C, nakon hlađenja filtrira na silikagelu i pročisti preparativnom HPLC. Frakcije produkta se zgusnu, preuzmu u smjesu 5:1 metanola i 1 N solne kiseline i ponovno zgusnu. Nakon sušenja u visokom vakuumu dobije se 112 mg (58 % od teor.) naslovnog spoja. Mixtures of 200 mg (0.45 mmol) of N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 22A) and 68.1 mg (0.45 mmol) of 2-methoxyphenylboronic acid in 2 ml of DMF was added to 0.67 ml of 2M sodium carbonate solution and 18.3 mg (0.02 mmol) of PdCl2(dppf). The reaction mixture is heated for 17 h at 70 °C, after cooling it is filtered on silica gel and purified by preparative HPLC. The product fractions are concentrated, taken up in a mixture of 5:1 methanol and 1 N hydrochloric acid and concentrated again. After drying in a high vacuum, 112 mg (58% of theory) of the title compound are obtained.

1H-NMR (400 MHz, DMSO-d6): δ = 10.38 (br. s, 1H), 9.07 (d, 1H), 8.38 (s, 1H), 7.95 (m, 1H), 7.50 (dd, 1H), 7.47 (m, 1H), 7.37 (m, 2H), 7.20 (d, 1H), 7.09 (dd, 1H), 4.31 (m, 1H), 3.73 (s, 3H), 3.62 (m, 1H), 3.35 (m, 2H), 3.19 (m, 3H), 2.19 (m, 1H), 2.13 (m, 1H), 1.90 (m, 2H), 1.73 (m, 1H). 1H-NMR (400 MHz, DMSO-d6): δ = 10.38 (no. s, 1H), 9.07 (d, 1H), 8.38 (s, 1H), 7.95 (m, 1H), 7.50 (dd, 1H) , 7.47 (m, 1H), 7.37 (m, 2H), 7.20 (d, 1H), 7.09 (dd, 1H), 4.31 (m, 1H), 3.73 (s, 3H), 3.62 (m, 1H), 3.35 (m, 2H), 3.19 (m, 3H), 2.19 (m, 1H), 2.13 (m, 1H), 1.90 (m, 2H), 1.73 (m, 1H).

Preostali analitički podatci odgovaraju onima enantiomernog spoja (primjer 18) gore. The remaining analytical data correspond to those of the enantiomeric compound (Example 18) above.

Primjer 89 Example 89

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[3-(hidroksimetil)fenil]-1-benzofuran-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[3-(hydroxymethyl)phenyl]-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Stavi se 150 mg (0.43 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzofuran-2-karboksamid-hidroklorida (primjer 30A) i 65.3 mg (0.43 mmola) 3-(hidroksimetil)fenilborne kiseline u 1.5 mL DMF. Nakon dodatka 0.64 mL 2 M otopine natrijevog karbonata i 17.5 mg (0.02 mmola) PdCl2(dppf) smjesa se zagrijava 18 h na 60 °C. Doda se još 17.5 mg (0.02 mmola) PdCl2(dppf) i miješa još 18 h na 90 °C. Nakon hlađenja reakcijska smjesa se filtrira na silikagelu. Nakon prvog pročišćavanja preparativnom HPLC provede se kolonska kromatografija na silikagelu (otapalo: diklormetan-metanol-amonijak 90:9:1). Frakcije produkta se spoje, zgusnu, pretvore smjesom 5:1 metanola i 4 N klorovodika u dioksanu i ponovno zgusnu. Nakon sušenja u visokom vakuumu dobije se 45 mg (24 % od teor.) naslovnog spoja. 150 mg (0.43 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide hydrochloride (Example 30A) and 65.3 mg (0.43 mmol) of 3-(hydroxymethyl)phenylboronic acid in 1.5 mL of DMF. After adding 0.64 mL of 2 M sodium carbonate solution and 17.5 mg (0.02 mmol) of PdCl2(dppf), the mixture is heated for 18 h at 60 °C. Another 17.5 mg (0.02 mmol) of PdCl2(dppf) was added and stirred for another 18 h at 90 °C. After cooling, the reaction mixture is filtered on silica gel. After the first purification by preparative HPLC, column chromatography is performed on silica gel (solvent: dichloromethane-methanol-ammonia 90:9:1). The product fractions were combined, concentrated, reconstituted with a mixture of 5:1 methanol and 4 N hydrogen chloride in dioxane and concentrated again. After drying in a high vacuum, 45 mg (24% of theory) of the title compound is obtained.

1H-NMR (400 MHz, metanol-d4): δ = 7.98 (m, 1H), 7.74 (m, 2H), 7.65 (m, 2H), 7.55 (dd, 1H), 7.42 (m, 2H), 4.72 (s, 2H), 4.51 (m, 1H), 3.87-3.26 (m, 6H), 2.39 (m, 1H), 2.23 (m, 1H), 2.10 (m, 2H), 1.95 (m, 1H). 1H-NMR (400 MHz, methanol-d4): δ = 7.98 (m, 1H), 7.74 (m, 2H), 7.65 (m, 2H), 7.55 (dd, 1H), 7.42 (m, 2H), 4.72 (s, 2H), 4.51 (m, 1H), 3.87-3.26 (m, 6H), 2.39 (m, 1H), 2.23 (m, 1H), 2.10 (m, 2H), 1.95 (m, 1H).

HPLC (metoda 1): Rt = 3.9 min. HPLC (method 1): Rt = 3.9 min.

MS (ESIpos): m/z = 377 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 377 (M+H)+ (free base).

Primjer 90 Example 90

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[4-(3-okso-4-morfolinil)fenil]-1-benzofuran-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[4-(3-oxo-4-morpholinyl)phenyl]-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Prema općenitom radnom propisu D stavi se 205.4 mg (0.70 mmola) 4-(4-bromfenil)-3-morfolinona (primjer 16A), 204.4 mg (0.81 mmol) bis(pinakolato)dibora, 171.2 mg (1.74 mmola) kalijevog acetata, 19.6 mg (0.03 mmola) PdCl2(dppf), 207 mg (0.54 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzofuran-2-karboksamid-hidroklorida (primjer 30A), 1.34 mL 2 M otopine natrijevog karbonata, te još 19.6 mg (0.03 mmola) PdCl2(dppf) u 2 mL DMF. Nakon sušenja u visokom vakuumu dobije se 233 mg (85 % od teor.) naslovnog spoja. According to general procedure D, 205.4 mg (0.70 mmol) of 4-(4-bromophenyl)-3-morpholino (example 16A), 204.4 mg (0.81 mmol) of bis(pinacolato)diboron, 171.2 mg (1.74 mmol) of potassium acetate, 19.6 mg (0.03 mmol) PdCl2(dppf), 207 mg (0.54 mmol) N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide -hydrochloride (example 30A), 1.34 mL of 2 M sodium carbonate solution, and another 19.6 mg (0.03 mmol) of PdCl2(dppf) in 2 mL of DMF. After drying in high vacuum, 233 mg (85% of theory) of the title compound are obtained.

1H-NMR (200 MHz, DMSO-d6): δ = 10.32 (br. s, 1H), 9.07 (d, 1H), 7.95 (m, 3H), 7.80 (dd, 1H), 7.70 (dd, 1H), 7.59 (m, 2H), 7.44 (dd, 1H), 4.33 (m, 1H), 4.26 (s, 2H), 4.02 (m, 2H), 3.83 (m, 2H), 3.64 (m, 1H), 3.37 (m, 2H), 3.21 (m, 3H), 2.23 (m, 1H), 2.11 (m, 3H), 1.91 (m, 2H), 1.74 (m, 1H). 1H-NMR (200 MHz, DMSO-d6): δ = 10.32 (no. s, 1H), 9.07 (d, 1H), 7.95 (m, 3H), 7.80 (dd, 1H), 7.70 (dd, 1H) , 7.59 (m, 2H), 7.44 (dd, 1H), 4.33 (m, 1H), 4.26 (s, 2H), 4.02 (m, 2H), 3.83 (m, 2H), 3.64 (m, 1H), 3.37 (m, 2H), 3.21 (m, 3H), 2.23 (m, 1H), 2.11 (m, 3H), 1.91 (m, 2H), 1.74 (m, 1H).

HPLC (metoda 1): Rt = 4.5 min. HPLC (method 1): Rt = 4.5 min.

MS (ESIpos): m/z = 446 (M + H)+ (slobodna baza). MS (ESIpos): m/z = 446 (M + H)+ (free base).

Primjer 91 Example 91

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[2-(4-morfolinil)fenil]-1-benzofuran-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[2-(4-morpholinyl)phenyl]-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Prema općenitom radnom propisu D stavi se 225 mg (0.93 mmola) 2-(4-morfolinil)fenil-trifluormetansulfonata (primjer 32A), 272 mg (1.07 mmol) bis(pinakolato)dibora, 228 mg (2.33 mmola) kalijevog acetata, 26 mg (0.04 mmola) PdCl2(dppf), 250 mg (0.72 mmola) N- [(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzofuran-2-karboksamid-hidroklorida (primjer 30A), 1.8 mL 2 M otopine natrijevog karbonata, te još 26 mg (0.04 mmol) PdCl2(dppf) u 2 mL DMF. Nakon sušenja u visokom vakuumu dobije se 82 mg (24 % od teor.) naslovnog spoja. According to general procedure D, 225 mg (0.93 mmol) of 2-(4-morpholinyl)phenyl-trifluoromethanesulfonate (Example 32A), 272 mg (1.07 mmol) of bis(pinacolato)diboron, 228 mg (2.33 mmol) of potassium acetate, 26 mg (0.04 mmol) PdCl2(dppf), 250 mg (0.72 mmol) N- [(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide- hydrochloride (example 30A), 1.8 mL of 2 M sodium carbonate solution, and another 26 mg (0.04 mmol) of PdCl2(dppf) in 2 mL of DMF. After drying in a high vacuum, 82 mg (24% of theory) of the title compound are obtained.

1H-NMR (400 MHz, DMSO-d6): δ = 9.76 (s, 1H), 8.82 (d, 1H), 7.79 (s, 1H), 7.77 (d, 1H), 7.55 (d, 1H), 7.46-7.37 (m, 3H), 7.23-7.14 (m, 2H), 4.33 (m, 1H), 3.83-3.04 (m, 6H), 3.55 (s, 4H), 2.68 (s, 4H), 2.16 (m, 1H), 2.04 (m, 1H), 1.95-1.84 (m, 2H), 1.79-1.67 (m, 1H). 1H-NMR (400 MHz, DMSO-d6): δ = 9.76 (s, 1H), 8.82 (d, 1H), 7.79 (s, 1H), 7.77 (d, 1H), 7.55 (d, 1H), 7.46 -7.37 (m, 3H), 7.23-7.14 (m, 2H), 4.33 (m, 1H), 3.83-3.04 (m, 6H), 3.55 (s, 4H), 2.68 (s, 4H), 2.16 (m , 1H), 2.04 (m, 1H), 1.95-1.84 (m, 2H), 1.79-1.67 (m, 1H).

HPLC (metoda 1): Rt = 4.1 min. HPLC (method 1): Rt = 4.1 min.

Primjer 92 Example 92

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[4-(4-morfolinil)fenil]-1-benzofuran-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[4-(4-morpholinyl)phenyl]-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Smjesi od 500 mg (0.143 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzofuran-2-karboksamid-hidroklorida (primjer 30A) i 105 mg (0.14 mmola) PdCl2(dppf) u 5 mL DMF stavi se 444 mg (2.15 mmola) 4-(4-morfolinil)fenilboronske kiseline i 4.3 mL 1 N natrijeve lužine. Reakcijska smjesa zagrijeva se preko noći na 100 °C. Otapalo se odstrani pod sniženim tlakom, te se sirovi produkt preuzme u metanol i filtrira na silikagelu. Pročišćavanje se provede preparativnom HPLC. Frakcije produkta se zgusnu, otope u metanolu i pretvore sa suviškom 1 N solne kiseline. Otapalo se ukloni pod sniženim tlakom. Nakon sušenja u visokom vakuumu dobije se 393 mg (59 % od teor.) naslovnog spoja. Mixtures of 500 mg (0.143 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide hydrochloride (Example 30A) and 105 mg (0.14 mmol) of PdCl2(dppf) in 5 mL of DMF was added to 444 mg (2.15 mmol) of 4-(4-morpholinyl)phenylboronic acid and 4.3 mL of 1 N sodium hydroxide solution. The reaction mixture is heated to 100 °C overnight. The solvent is removed under reduced pressure, and the crude product is taken up in methanol and filtered on silica gel. Purification is performed by preparative HPLC. The product fractions are concentrated, dissolved in methanol and converted with an excess of 1 N hydrochloric acid. The solvent was removed under reduced pressure. After drying in high vacuum, 393 mg (59% of theory) of the title compound are obtained.

1H-NMR (200 MHz, DMSO-d6): δ = 10.45 (s, 1H), 9.10 (d, 1H), 7.91 (s, 1H), 7.87 (d, 1H), 7.75-7.55 (m, 2H), 7.40 (t, 1H), 7.18 (d, 2H), 4.40 (m, 1H), 3.80 (m, 4H), 3.75-3.00 (m, 6H), 3.20 (m, 4H), 2.30-2.02 (m, 2H), 2.00-1.62 (m, 3H). HPLC (metoda 1): Rt = 3.79 min. 1H-NMR (200 MHz, DMSO-d6): δ = 10.45 (s, 1H), 9.10 (d, 1H), 7.91 (s, 1H), 7.87 (d, 1H), 7.75-7.55 (m, 2H) , 7.40 (t, 1H), 7.18 (d, 2H), 4.40 (m, 1H), 3.80 (m, 4H), 3.75-3.00 (m, 6H), 3.20 (m, 4H), 2.30-2.02 (m , 2H), 2.00-1.62 (m, 3H). HPLC (method 1): Rt = 3.79 min.

Primjer 93 Example 93

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-5-[4-(4-morfolinil)fenil]-1-benzofuran-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-[4-(4-morpholinyl)phenyl]-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Smjesi od 250 mg (0.72 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-5-brom-1-benzofuran-2-karboksamid-hidroklorida (primjer 3A) i 52 mg (0.07 mmola) PdCl2(dppf) u 3 mL DMF doda se 177 mg (0.86 mmola) 4-(4-morfolinil)fenilborne kiseline i 2.15 mL 1 N natrijeve lužine. Reakcijska smjesa zagrijava se preko noći na 90 °C. Otapalo se odstrani pod sniženim tlakom, te se sirovi produkt preuzme u metanol i filtrira na silikagelu. Pročišćavanje se provede preparativnom HPLC. Frakcije produkta se zgusnu, otope u acetonitril/vodi i pretvore sa suviškom 1 N solne kiseline. Otapalo se ukloni pod sniženim tlakom. Nakon sušenja u visokom vakuumu dobije se 23 mg (7 % od teor.) naslovnog spoja. Mixtures of 250 mg (0.72 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-bromo-1-benzofuran-2-carboxamide hydrochloride (Example 3A) and 52 mg (0.07 mmol) of PdCl2(dppf) in 3 mL of DMF was added to 177 mg (0.86 mmol) of 4-(4-morpholinyl)phenylboronic acid and 2.15 mL of 1 N sodium hydroxide solution. The reaction mixture is heated to 90 °C overnight. The solvent is removed under reduced pressure, and the crude product is taken up in methanol and filtered on silica gel. Purification is performed by preparative HPLC. The product fractions are concentrated, dissolved in acetonitrile/water and treated with an excess of 1 N hydrochloric acid. The solvent was removed under reduced pressure. After drying in a high vacuum, 23 mg (7% of theory) of the title compound are obtained.

1H-NMR (200 MHz, DMSO-d6): δ = 10.40 (s, 1H), 9.15 (d, 1H), 7.98 (s, 1H), 7.76-7.68 (m, 2H), 7.67-7.58 (m, 2H), 7.20-7.10 (d, 2H), 4.45 (m, 1H), 3.80 (m, 4H), 3.75-3.30 (m, 6H), 3.20 (m, 4H), 2.30-2.02 (m, 2H), 2.00-1.62 (m, 3H). HPLC (metoda 1): Rt = 3.52 min. 1H-NMR (200 MHz, DMSO-d6): δ = 10.40 (s, 1H), 9.15 (d, 1H), 7.98 (s, 1H), 7.76-7.68 (m, 2H), 7.67-7.58 (m, 2H), 7.20-7.10 (d, 2H), 4.45 (m, 1H), 3.80 (m, 4H), 3.75-3.30 (m, 6H), 3.20 (m, 4H), 2.30-2.02 (m, 2H) , 2.00-1.62 (m, 3H). HPLC (method 1): Rt = 3.52 min.

MS (ESIpos): m/z = 432 (M + H)+ (slobodna baza). MS (ESIpos): m/z = 432 (M + H)+ (free base).

Primjer 94 Example 94

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-5-[4-(hidroksimetil)fenil]-1-benzofuran-2-karboksamid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-[4-(hydroxymethyl)phenyl]-1-benzofuran-2-carboxamide

[image] [image]

Smjesi od 170 mg (0.49 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-5-brom-1-benzofuran-2-karboksamida (primjer 3A) i 35 mg (0.05 mmola) PdCl2(dppf) u 2 mL DMF doda se 110 mg (0.73 mmola) 4-(hidroksimetil)fenilboronske kiseline i 1.46 mL 1 N natrijeve lužine. Reakcijska smjesa zagrijava se preko noći na 85 °C. Otapalo se odstrani pod sniženim tlakom. Nakon dodatka smjese 1 N natrijeve lužine i etilnog estera octene kiseline u refluks, vodena se faza ekstrahira etilnim esterom octene kiseline. Spojene organske faze isperu se dvaput s otopinom 1 N natrijeve lužine i zasićenom otopinom natrijevog klorida, osuše iznad magnezijevog sulfata i zgusnu pod sniženim tlakom na rotacijskom isparivaču. Sirovi produkt se preuzme u metanolu i trese zajedno s kiselim ionskim izmjenjivačem (Dowex® WX2-200) 20-ak minuta. Opterećeni ionski izmjenjivač ispere se prvo tri puta sa po 30 mL metanola, potom DMF, ponovno metanolom, zatim diklormetanom, ponovno metanolom, zatim vodom, te na kraju još jednom metanolom. Produkt se eluira metanol-trietilaminom 95:5. Otapalo se ukloni pod sniženim tlakom na rotacijskom isparivaču. Izolirano je 148 mg (80 % od teor.) naslovnog spoja. Mixtures of 170 mg (0.49 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-bromo-1-benzofuran-2-carboxamide (Example 3A) and 35 mg (0.05 mmol) of PdCl2(dppf) in 2 mL of DMF, 110 mg (0.73 mmol) of 4-(hydroxymethyl)phenylboronic acid and 1.46 mL of 1 N sodium hydroxide solution are added. The reaction mixture is heated to 85 °C overnight. The solvent was removed under reduced pressure. After adding a mixture of 1 N sodium hydroxide solution and ethyl acetic acid to the reflux, the aqueous phase is extracted with ethyl acetic acid. The combined organic phases are washed twice with 1 N sodium hydroxide solution and saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure on a rotary evaporator. The crude product is taken up in methanol and shaken together with an acidic ion exchanger (Dowex® WX2-200) for about 20 minutes. The loaded ion exchanger is washed first three times with 30 mL of methanol, then DMF, again with methanol, then with dichloromethane, again with methanol, then with water, and finally with methanol again. The product is eluted with methanol-triethylamine 95:5. The solvent is removed under reduced pressure on a rotary evaporator. 148 mg (80% of theory) of the title compound was isolated.

1H-NMR (200 MHz, CDCl3): δ = 7.85 (s, 1H), 7.70-7.35 (m, 7H), 6.77 (d, 1H), 4.62 (s, 2H), 4.28-4.12 (m, 1H), 3.56-3.38 (m, 1H), 3.04-2.78 (m, 4H), 2.75-2.59 (m, 1H), 2.16-2.02 (m, 1H), 1.93-1.66 (m, 3H), 1.66-1.50 (m, 1H). 1H-NMR (200 MHz, CDCl3): δ = 7.85 (s, 1H), 7.70-7.35 (m, 7H), 6.77 (d, 1H), 4.62 (s, 2H), 4.28-4.12 (m, 1H) , 3.56-3.38 (m, 1H), 3.04-2.78 (m, 4H), 2.75-2.59 (m, 1H), 2.16-2.02 (m, 1H), 1.93-1.66 (m, 3H), 1.66-1.50 ( m, 1H).

HPLC (metoda 1): Rt = 3.65 min. HPLC (method 1): Rt = 3.65 min.

MS (ESIpos): m/z = 377 (M+H)+. MS (ESIpos): m/z = 377 (M+H) + .

Primjer 95 Example 95

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-5-[2-(hidroksimetil)fenil]-1-benzofuran-2-karboksamid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-[2-(hydroxymethyl)phenyl]-1-benzofuran-2-carboxamide

[image] [image]

Smjesi od 170 mg (0.49 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-5-brom-1-benzofuran-2-karboksamida (primjer 3A) i 35 mg (0.05 mmola) PdCl2(dppf) u 2 mL DMF doda se 110 mg (0.73 mmola) 2-(hidroksimetil)fenilborne kiseline i 1.46 mL 1 N natrijeve lužine. Reakcijska smjesa zagrijava se preko noći na 85 °C. Otapalo se odstrani pod sniženim tlakom. Nakon dodavanja smjese 1 N natrijeve lužine i etilnog estera octene kiseline u refluks vodena se faza ekstrahira etilnim esterom octene kiseline. Spojene organske faze isperu se dvaput otopinom 1 N natrijeve lužine i zasićenom otopinom natrijevog klorida, osuše iznad magnezijevog sulfata i zgusnu pod sniženim tlakom na rotacijskom isparivaču. Sirovi produkt se preuzme u metanolu i trese zajedno s kiselim ionskim izmjenjivačem (Dowex® WX2-200) 20-ak minuta. Opterećeni ionski izmjenjivač ispere se prvo tri puta sa po 30 mL metanola, potom DMF, ponovno metanolom, zatim diklormetanom, ponovno metanolom, zatim vodom, te na kraju još jednom metanolom. Produkt se eluira metanol-trietilaminom 95:5. Otapalo se ukloni pod sniženim tlakom na rotacijskom isparivaču. Izoliralo se 140 mg (76 % od teor.) naslovnog spoja. Mixtures of 170 mg (0.49 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-bromo-1-benzofuran-2-carboxamide (Example 3A) and 35 mg (0.05 mmol) of PdCl2(dppf) in 2 mL of DMF was added to 110 mg (0.73 mmol) of 2-(hydroxymethyl)phenylboronic acid and 1.46 mL of 1 N sodium hydroxide solution. The reaction mixture is heated to 85 °C overnight. The solvent was removed under reduced pressure. After adding a mixture of 1 N sodium hydroxide solution and acetic acid ethyl ester to the reflux, the aqueous phase is extracted with acetic acid ethyl ester. The combined organic phases are washed twice with 1 N sodium hydroxide solution and saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure on a rotary evaporator. The crude product is taken up in methanol and shaken together with an acidic ion exchanger (Dowex® WX2-200) for about 20 minutes. The loaded ion exchanger is washed first three times with 30 mL of methanol, then DMF, again with methanol, then with dichloromethane, again with methanol, then with water, and finally with methanol again. The product is eluted with methanol-triethylamine 95:5. The solvent is removed under reduced pressure on a rotary evaporator. 140 mg (76% of theory) of the title compound was isolated.

1H-NMR (300 MHz, CDCl3): δ = 7.70-7.25 (m, 8H), 6.75 (d, 1H), 4.62 (s, 2H), 4.28-4.12 (m, 1H), 3.56-3.38 (m, 1H), 3.04-2.78 (m, 4H), 2.75-2.59 (m, 1H), 2.16-2.02 (m, 1H), 1.93-1.66 (m, 3H), 1.66-1.50 (m, 1H). 1H-NMR (300 MHz, CDCl3): δ = 7.70-7.25 (m, 8H), 6.75 (d, 1H), 4.62 (s, 2H), 4.28-4.12 (m, 1H), 3.56-3.38 (m, 1H), 3.04-2.78 (m, 4H), 2.75-2.59 (m, 1H), 2.16-2.02 (m, 1H), 1.93-1.66 (m, 3H), 1.66-1.50 (m, 1H).

HPLC (metoda 1): Rt = 3.76 min. HPLC (method 1): Rt = 3.76 min.

MS (ESIpos): m/z = 377 (M+H)+. MS (ESIpos): m/z = 377 (M+H) + .

Primjer 96 Example 96

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-5-[4-(dimetilamino)fenil]-1-benzofuran-2-karboksamid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-[4-(dimethylamino)phenyl]-1-benzofuran-2-carboxamide

[image] [image]

Smjesi od 170 mg (0.49 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-5-brom-1-benzofuran-2-karboksamida (primjer 3A) i 35 mg (0.05 mmola) PdCl2(dppf) u 2 mL DMF doda se 120 mg (0.73 mmola) 4-(dimetilamino)fenilboronske kiseline i 1.46 mL 1 N natrijeve lužine. Reakcijska smjesa zagrijava se preko noći na 85 °C. Otapalo se odstrani pod sniženim tlakom. Nakon dodavanja smjese 1 N natrijeve lužine i etilnog estera octene kiseline u refluks vodena se faza ekstrahira etilnim esterom octene kiseline. Spojene organske faze isperu se dvaput otopinom 1 N natrijeve lužine i zasićenom otopinom natrijevog klorida, osuše iznad magnezijevog sulfata i zgusnu pod sniženim tlakom na rotacijskom isparivaču. Sirovi produkt se preuzme u metanol i trese zajedno s kiselim ionskim izmjenjivačem (Dowex® WX2-200) 20-ak minuta. Opterećeni ionski izmjenjivač ispere se prvo tri puta sa po 30 mL metanola, potom DMF, ponovno metanolom, zatim diklormetanom, ponovno metanolom, zatim vodom, te na kraju još jednom metanolom. Produkt se eluira metanol-trietilaminom 95:5. Otapalo se ukloni pod sniženim tlakom na rotacijskom isparivaču. Izolirano je 138 mg (73 % od teor.) naslovnog spoja. Mixtures of 170 mg (0.49 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-bromo-1-benzofuran-2-carboxamide (Example 3A) and 35 mg (0.05 mmol) of PdCl2(dppf) in 2 mL of DMF, 120 mg (0.73 mmol) of 4-(dimethylamino)phenylboronic acid and 1.46 mL of 1 N sodium hydroxide solution were added. The reaction mixture is heated to 85 °C overnight. The solvent was removed under reduced pressure. After adding a mixture of 1 N sodium hydroxide solution and acetic acid ethyl ester to the reflux, the aqueous phase is extracted with acetic acid ethyl ester. The combined organic phases are washed twice with 1 N sodium hydroxide solution and saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure on a rotary evaporator. The crude product is taken up in methanol and shaken together with an acidic ion exchanger (Dowex® WX2-200) for about 20 minutes. The loaded ion exchanger is washed first three times with 30 mL of methanol, then DMF, again with methanol, then with dichloromethane, again with methanol, then with water, and finally with methanol again. The product is eluted with methanol-triethylamine 95:5. The solvent is removed under reduced pressure on a rotary evaporator. 138 mg (73% of theory) of the title compound was isolated.

1H-NMR (200 MHz, CDCl3): δ = 7.78 (d, 1H), 7.70-7.39 (m, 4H), 6.88-6.75 (m, 3H), 4.28-4.12 (m, 1H), 3.56-3.38 (m, 1H), 3.04-2.78 (m, 4H), 3.00 (s, 6H), 2.75-2.59 (m, 1H), 2.16-2.02 (m, 1H), 1.93-1.66 (m, 3H), 1.66-1.50 (m, 1H). HPLC (metoda 1): Rt = 3.36 min. 1H-NMR (200 MHz, CDCl3): δ = 7.78 (d, 1H), 7.70-7.39 (m, 4H), 6.88-6.75 (m, 3H), 4.28-4.12 (m, 1H), 3.56-3.38 ( m, 1H), 3.04-2.78 (m, 4H), 3.00 (s, 6H), 2.75-2.59 (m, 1H), 2.16-2.02 (m, 1H), 1.93-1.66 (m, 3H), 1.66- 1.50 (m, 1H). HPLC (method 1): Rt = 3.36 min.

MS (ESIpos): m/z = 390 (M+H)+. MS (ESIpos): m/z = 390 (M+H) + .

Primjer 97 Example 97

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-5-[4-(metoksi)fenil]-1-benzofuran-2-karboksamid-hidro klorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-[4-(methoxy)phenyl]-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Smjesi od 250 mg (0.72 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-5-brom-1-benzofuran-2-karboksamid-hidroklorida (primjer 3A) i 52 mg (0.07 mmola) PdCl2(dppf) u 3 mL DMF doda se 130 mg (0.86 mmola) 4-(metoksi)fenilborne kiseline i 2.15 mL 1 N natrijeve lužine. Reakcijska smjesa zagrijava se preko noći na 90 °C. Otapalo se odstrani pod sniženim tlakom, te se sirovi produkt preuzme u metanol i filtrira na silikagelu. Pročišćavanje se provede preparativnom HPLC. Frakcije produkta se pretvore sa suviškom 1 N solne kiseline. Otapalo se ukloni pod sniženim tlakom. Nakon sušenja u visokom vakuumu dobije se 127 mg (39 % od teor.) naslovnog spoja. Mixtures of 250 mg (0.72 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-bromo-1-benzofuran-2-carboxamide hydrochloride (Example 3A) and 52 mg (0.07 mmol) of PdCl2(dppf) in 3 mL of DMF was added to 130 mg (0.86 mmol) of 4-(methoxy)phenylboronic acid and 2.15 mL of 1 N sodium hydroxide solution. The reaction mixture is heated to 90 °C overnight. The solvent is removed under reduced pressure, and the crude product is taken up in methanol and filtered on silica gel. Purification is performed by preparative HPLC. The product fractions are converted with an excess of 1 N hydrochloric acid. The solvent was removed under reduced pressure. After drying in a high vacuum, 127 mg (39% of theory) of the title compound are obtained.

1H-NMR (200 MHz, DMSO-d6): δ = 9.90 (s, 1H), 9.10 (d, 1H), 7.95 (m, 2H), 7.75-7.60 (m, 4H), 7.10-7.02 (m, 2H), 4.40 (m, 1H), 3.85 (m, 3H), 3.75-3.00 (m, 6H), 3.20 (m, 4H), 2.30-2.02 (m, 2H), 2.00-1.62 (m, 3H). 1H-NMR (200 MHz, DMSO-d6): δ = 9.90 (s, 1H), 9.10 (d, 1H), 7.95 (m, 2H), 7.75-7.60 (m, 4H), 7.10-7.02 (m, 2H), 4.40 (m, 1H), 3.85 (m, 3H), 3.75-3.00 (m, 6H), 3.20 (m, 4H), 2.30-2.02 (m, 2H), 2.00-1.62 (m, 3H) .

HPLC (metoda 1): Rt = 4.15 min. HPLC (method 1): Rt = 4.15 min.

Primjer 98 Example 98

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-5-[3-(metoksi)fenil]-1-benzofuran-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-[3-(methoxy)phenyl]-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Smjesi od 250 mg (0.72 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-5-brom-1-benzofuran-2-karboksamid-hidroklorida (primjer 3A) i 52 mg (0.07 mmola) PdCl2(dppf) u 3 mL DMF doda se 130 mg (0.86 mmola) 3-(metoksi)fenilboronske kiseline i 2.15 mL 1 N natrijeve lužine. Reakcijska smjesa zagrijava se preko noći na 90 °C. Otapalo se odstrani pod sniženim tlakom, te se sirovi produkt preuzme u metanol i filtrira na silikagelu. Pročišćavanje se provede preparativnom HPLC. Frakcije produkta se pretvore sa suviškom 1 N solne kiseline. Otapalo se ukloni pod sniženim tlakom. Nakon sušenja u visokom vakuumu dobije se 208 mg (63 % od teor.) naslovnog spoja. Mixtures of 250 mg (0.72 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-bromo-1-benzofuran-2-carboxamide hydrochloride (Example 3A) and 52 mg (0.07 mmol) of PdCl2(dppf) in 3 mL of DMF was added to 130 mg (0.86 mmol) of 3-(methoxy)phenylboronic acid and 2.15 mL of 1 N sodium hydroxide solution. The reaction mixture is heated to 90 °C overnight. The solvent is removed under reduced pressure, and the crude product is taken up in methanol and filtered on silica gel. Purification is performed by preparative HPLC. The product fractions are converted with an excess of 1 N hydrochloric acid. The solvent was removed under reduced pressure. After drying in high vacuum, 208 mg (63% of theory) of the title compound are obtained.

1H-NMR (300 MHz, DMSO-d6): δ = 10.0 (s, 1H), 9.10 (d, 1H), 8.05 (s, 1H), 7.80-7.65 (m, 3H), 7.42-7.18 (m, 3H), 6.93 (m, 1H), 4.35 (m, 1H), 3.85 (s, 3H), 3.75-3.00 (m, 6H), 3.20 (m, 4H), 2.30-2.02 (m, 2H), 2.00-1.62 (m, 3H). 1H-NMR (300 MHz, DMSO-d6): δ = 10.0 (s, 1H), 9.10 (d, 1H), 8.05 (s, 1H), 7.80-7.65 (m, 3H), 7.42-7.18 (m, 3H), 6.93 (m, 1H), 4.35 (m, 1H), 3.85 (s, 3H), 3.75-3.00 (m, 6H), 3.20 (m, 4H), 2.30-2.02 (m, 2H), 2.00 -1.62 (m, 3H).

HPLC (metoda 1): Rt = 4.19 min. HPLC (method 1): Rt = 4.19 min.

MS (ESIpos): m/z = 377 (M + H)+ (slobodna baza). MS (ESIpos): m/z = 377 (M + H)+ (free base).

Primjer 99 Example 99

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[4-(metoksi)fenil]-1-benzofuran-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[4-(methoxy)phenyl]-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Smjesi od 300 mg (0.86 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzofuran-2-karboksamida (primjer 30A) i 63 mg (0.09 mmola) PdCl2(dppf) u 4 mL DMF doda se 130 mg (0.86 mmola) 4-(metoksi)fenilborne kiseline i 2.58 mL 1 N natrijeve lužine. Reakcijska smjesa zagrijava se preko noći na 95 °C. Otapalo se odstrani pod sniženim tlakom, te se sirovi produkt preuzme u metanol i filtrira na silikagelu. Pročišćavanje se provede preparativnom HPLC. Frakcije produkta se pretvore sa suviškom 1 N solne kiseline. Otapalo se ukloni pod sniženim tlakom. Nakon sušenja u visokom vakuumu dobije se 165 mg (47 % od teor.) naslovnog spoja. Mixtures of 300 mg (0.86 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide (Example 30A) and 63 mg (0.09 mmol) of PdCl2(dppf) in 4 mL of DMF, 130 mg (0.86 mmol) of 4-(methoxy)phenylboronic acid and 2.58 mL of 1 N sodium hydroxide solution were added. The reaction mixture is heated to 95 °C overnight. The solvent is removed under reduced pressure, and the crude product is taken up in methanol and filtered on silica gel. Purification is performed by preparative HPLC. The product fractions are converted with an excess of 1 N hydrochloric acid. The solvent was removed under reduced pressure. After drying in high vacuum, 165 mg (47% of theory) of the title compound is obtained.

1H-NMR (300 MHz, DMSO-d6): δ = 10.4 (s, 1H), 9.00 (d, 1H), 8.05 (s, 1H), 7.90-7.82 (m, 3H), 7.75 (d, 1H), 7.62 (d, 1H), 7.40 (t, 1H), 7.15-7.05 (m, 2H), 4.35 (m, 1H), 3.85 (s, 3H), 3.65 (m, 1H), 3.48-3.30 (m, 2H), 3.25-3.10 (m, 3H), 2.25 (m, 1H), 2.18-2.05 (m, 1H), 1.98-1.88 (m, 2H), 1.80-1.63 (m, 1H). 1H-NMR (300 MHz, DMSO-d6): δ = 10.4 (s, 1H), 9.00 (d, 1H), 8.05 (s, 1H), 7.90-7.82 (m, 3H), 7.75 (d, 1H) , 7.62 (d, 1H), 7.40 (t, 1H), 7.15-7.05 (m, 2H), 4.35 (m, 1H), 3.85 (s, 3H), 3.65 (m, 1H), 3.48-3.30 (m , 2H), 3.25-3.10 (m, 3H), 2.25 (m, 1H), 2.18-2.05 (m, 1H), 1.98-1.88 (m, 2H), 1.80-1.63 (m, 1H).

HPLC (metoda 1): Rt = 4.18 min. HPLC (method 1): Rt = 4.18 min.

Primjer 100 Example 100

N-[(3S)-1-azabiciklo[2.2.2]okt-3-il]-7-(2-metoksifenil)-1-l-benzofuran-2-karboksamid-hidro klorid N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-(2-methoxyphenyl)-1-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Smjesi od 890 mg (4.47 mmola) S-3-aminokinuklidin-dihidroklorida i 1000 mg (3.73 mmola) 7-(2-metoksifenil)-1-benzofuran-2-karboksilne kiseline (primjer 21A) u 10 mL DMF doda se pri 0 °C 3.4 g (8.95 mmola) HATU i 2.34 mL (13.42 mmola) N,N-diizopropiletilamina. Nakon 18 h miješanja pri sobnoj temperaturi reakcijska se smjesa pročisti preparativnom HPLC. Frakcije produkta se zgusnu, pretvore sa 5 mL 1 N solne kiseline i ponovno zgusnu. Nakon sušenja u visokom vakuumu dobije se 209 mg (13.6 % od teor.) naslovnog spoja. A mixture of 890 mg (4.47 mmol) of S-3-aminoquinuclidine dihydrochloride and 1000 mg (3.73 mmol) of 7-(2-methoxyphenyl)-1-benzofuran-2-carboxylic acid (Example 21A) in 10 mL of DMF was added at 0 °C 3.4 g (8.95 mmol) HATU and 2.34 mL (13.42 mmol) N,N-diisopropylethylamine. After stirring for 18 hours at room temperature, the reaction mixture was purified by preparative HPLC. The product fractions are concentrated, converted with 5 mL of 1 N hydrochloric acid and concentrated again. After drying in a high vacuum, 209 mg (13.6 % of theory) of the title compound are obtained.

Analitički podatci odgovaraju onima enantiomernog spoja (primjer 102). Analytical data correspond to those of the enantiomeric compound (example 102).

Primjer 101 Example 101

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[3-(metoksi)fenil]-1-benzofuran-2-karboksamid-hidro klorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[3-(methoxy)phenyl]-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Smjesi od 150 mg (0.43 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzofuran-2-karboksamida (primjer 30A) i 31 mg (0.04 mmola) PdCl2(dppf) u 2 mL DMF doda se 98 mg (0.64 mmola) 3-(metoksi)fenilboronske kiseline i 1.29 mL 1 N natrijeve lužine. Reakcijska smjesa zagrijava se preko noći na 90 °C. Otapalo se odstrani pod sniženim tlakom, te se sirovi produkt preuzme u metanol i filtrira na silikagelu. Pročišćavanje se provede preparativnom HPLC. Produkt se otopi u metanolu i pretvori sa suviškom 1 N solne kiseline. Otapalo se ukloni pod sniženim tlakom, te se ostatak kristalizira iz malo izopropanola. Nakon sušenja u visokom vakuumu dobije se 159 mg (85 % od teor.) naslovnog spoja. Mixtures of 150 mg (0.43 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide (Example 30A) and 31 mg (0.04 mmol) of PdCl2(dppf) in 2 mL of DMF was added to 98 mg (0.64 mmol) of 3-(methoxy)phenylboronic acid and 1.29 mL of 1 N sodium hydroxide solution. The reaction mixture is heated to 90 °C overnight. The solvent is removed under reduced pressure, and the crude product is taken up in methanol and filtered on silica gel. Purification is performed by preparative HPLC. The product is dissolved in methanol and converted with an excess of 1 N hydrochloric acid. The solvent is removed under reduced pressure, and the residue is crystallized from a little isopropanol. After drying in a high vacuum, 159 mg (85% of theory) of the title compound are obtained.

1H-NMR (400 MHz, DMSO-d6): δ = 10.05 (s, 1H), 8.95 (d, 1H), 7.85 (s, 1H), 7.80 (d, 1H), 7.70 (d, 1H), 7.50-7.40 (m, 4H), 7.00 (m, 1H), 4.35 (m, 1H), 3.85 (s, 3H), 3.65 (m, 1H), 3.48-3.30 (m, 2H), 3.25-3.15 (m, 3H), 2.25 (m, 1H), 2.18-2.05 (m, 1H), 1.98-1.88 (m, 2H), 1.80-1.63 (m, 1H). 1H-NMR (400 MHz, DMSO-d6): δ = 10.05 (s, 1H), 8.95 (d, 1H), 7.85 (s, 1H), 7.80 (d, 1H), 7.70 (d, 1H), 7.50 -7.40 (m, 4H), 7.00 (m, 1H), 4.35 (m, 1H), 3.85 (s, 3H), 3.65 (m, 1H), 3.48-3.30 (m, 2H), 3.25-3.15 (m , 3H), 2.25 (m, 1H), 2.18-2.05 (m, 1H), 1.98-1.88 (m, 2H), 1.80-1.63 (m, 1H).

HPLC (metoda 1): Rt = 4.21 min. HPLC (method 1): Rt = 4.21 min.

Primjer 102 Example 102

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[2-(metoksi)fenil]-1-benzofuran-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[2-(methoxy)phenyl]-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Metoda a): Method a):

Smjesi od 150 mg (0.43 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzofuran-2-karboksamida (primjer 30A) i 31 mg (0.04 mmola) PdCl2(dppf) u 2 mL DMF doda se 98 mg (0.64 mmola) 2-(metoksi)fenilborne kiseline i 1.29 mL 1 N natrijeve lužine. Reakcijska smjesa zagrijava se preko noći na 85 °C. Otapalo se odstrani pod sniženim tlakom, te se sirovi produkt preuzme u metanol i filtrira na silikagelu. Daljnje pročišćavanje se provede preparativnom HPLC. Produkt se otopi u metanolu i pretvori sa suviškom 1 N solne kiseline. Otapalo se ukloni pod sniženim tlakom, te se ostatak kristalizira iz malo izopropanola. Nakon sušenja u visokom vakuumu dobije se 100 mg (62 % od teor.) naslovnog spoja. Mixtures of 150 mg (0.43 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide (Example 30A) and 31 mg (0.04 mmol) of PdCl2(dppf) in 2 mL of DMF was added to 98 mg (0.64 mmol) of 2-(methoxy)phenylboronic acid and 1.29 mL of 1 N sodium hydroxide solution. The reaction mixture is heated to 85 °C overnight. The solvent is removed under reduced pressure, and the crude product is taken up in methanol and filtered on silica gel. Further purification is carried out by preparative HPLC. The product is dissolved in methanol and converted with an excess of 1 N hydrochloric acid. The solvent is removed under reduced pressure, and the residue is crystallized from a little isopropanol. After drying in high vacuum, 100 mg (62% of theory) of the title compound is obtained.

1H-NMR (400 MHz, DMSO-d6): δ = 10.08 (s, 1H), 8.91 (d, 1H), 7.87 (s, 1H), 7.84-7.74 (m, 2H), 7.53-7.33 (m, 3H), 7.25-7.00 (m, 2H), 4.35 (m, 1H), 3.75 (s, 3H), 3.65 (m, 1H), 3.48-3.30 (m, 2H), 3.25-3.15 (m, 3H), 2.25 (m, 1H), 2.18-2.05 (m, 1H), 1.98-1.88 (m, 2H), 1.80-1.63 (m, 1H). 1H-NMR (400 MHz, DMSO-d6): δ = 10.08 (s, 1H), 8.91 (d, 1H), 7.87 (s, 1H), 7.84-7.74 (m, 2H), 7.53-7.33 (m, 3H), 7.25-7.00 (m, 2H), 4.35 (m, 1H), 3.75 (s, 3H), 3.65 (m, 1H), 3.48-3.30 (m, 2H), 3.25-3.15 (m, 3H) , 2.25 (m, 1H), 2.18-2.05 (m, 1H), 1.98-1.88 (m, 2H), 1.80-1.63 (m, 1H).

HPLC (metoda 1): Rt = 4.16 min. HPLC (method 1): Rt = 4.16 min.

Metoda b): Method b):

Otopini 2.92 g (10.9 mmola) 7-(2-metoksifenil)-1-benzofuran-2-karboksilne kiseline (primjer 21A) i 2.17 g (10.9 mmola) (R)-3-aminokinuklidin-dihidroklorida u 35 mL DMF doda se pri 0 °C 2.51 g (13.1 mmol) EDC, 1.77 g (13.1 mmol) HOBt i 5.47 mL (39.2 mmola) trietilamina. Nakon 18-satnog miješanja pri sobnoj temperaturi doda se još 434 mg (2.2 mmola) (R)-3-aminokinuklidin-dihidroklorida te 418 mg (2.2 mmola) EDC. Nakon 2 h na 55 °C reakcijska se smjesa zgusne, te se ostatak raspodijeli između po 200 mL etilnog estera octene kiseline i 2 N natrijeve lužine. Organska faza se ispere 15 puta sa po 100 ml 2 N natrijeve lužine. Spojene vodene faze se reekstrahiraju s 250 mL etilnog estera octene kiseline. Spojene organske faze osuše se iznad natrijevog sulfata, zgusnu, ostatak se pretvori smjesom 5:1 metanola i 1 N solne kiseline, ponovno zgusne i osuši u visokom vakuumu. Nakon kristalizacije ostatka iz 10 mL smjese 10:1 izopropanola i etanola dobije se 2.73 g (60.5 % od teor.) naslovnog spoja. A solution of 2.92 g (10.9 mmol) of 7-(2-methoxyphenyl)-1-benzofuran-2-carboxylic acid (Example 21A) and 2.17 g (10.9 mmol) of (R)-3-aminoquinuclidine dihydrochloride in 35 mL of DMF was added at 0 °C 2.51 g (13.1 mmol) EDC, 1.77 g (13.1 mmol) HOBt and 5.47 mL (39.2 mmol) triethylamine. After stirring for 18 hours at room temperature, another 434 mg (2.2 mmol) of (R)-3-aminoquinuclidine dihydrochloride and 418 mg (2.2 mmol) of EDC were added. After 2 h at 55 °C, the reaction mixture thickens, and the residue is distributed between 200 mL each of acetic acid ethyl ester and 2 N sodium hydroxide solution. The organic phase is washed 15 times with 100 ml of 2 N sodium hydroxide solution. The combined aqueous phases are re-extracted with 250 mL of ethyl acetate. The combined organic phases are dried over sodium sulfate, concentrated, the residue is converted with a mixture of 5:1 methanol and 1 N hydrochloric acid, concentrated again and dried under high vacuum. After crystallization of the residue from 10 mL of a 10:1 mixture of isopropanol and ethanol, 2.73 g (60.5% of theory) of the title compound is obtained.

Primjer 103 Example 103

N-[(3R)-1-azabidklo[2.2.2]okt-3-il]-7-[4-(metoksi)-3-piridinil]-1-benzofuran-2-karboksamid-hidro klorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[4-(methoxy)-3-pyridinyl]-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Smjesi od 100 mg (0.29 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzofuran-2-karboksamida (primjer 30A) i 21 mg (0.03 mmola) PdCl2(dppf) u 2 mL DMF doda se 98 mg (0.64 mmola) 4-metoksi-3-piridinilboronske kiseline i 0.86 mL 1 N natrijeve lužine. Reakcijska smjesa zagrijava se preko noći na 85 °C. Otapalo se odstrani pod sniženim tlakom, te se sirovi produkt preuzme u metanol i filtrira na silikagelu. Pročišćavanje se provede preparativnom HPLC. Frakcije produkta pretvore se sa suviškom 1 N solne kiseline. Otapalo se ukloni pod sniženim tlakom. Nakon sušenja u visokom vakuumu dobije se 58 mg (49 % od teor.) naslovnog spoja. Mixtures of 100 mg (0.29 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide (Example 30A) and 21 mg (0.03 mmol) of PdCl2(dppf) in 2 mL of DMF, 98 mg (0.64 mmol) of 4-methoxy-3-pyridinylboronic acid and 0.86 mL of 1 N sodium hydroxide solution were added. The reaction mixture is heated to 85 °C overnight. The solvent is removed under reduced pressure, and the crude product is taken up in methanol and filtered on silica gel. Purification is performed by preparative HPLC. Product fractions are converted with an excess of 1 N hydrochloric acid. The solvent was removed under reduced pressure. After drying in a high vacuum, 58 mg (49% of theory) of the title compound are obtained.

1H-NMR (400 MHz, DMSO-d6): δ = 10.55 (s, 1H), 9.20 (d, 1H), 9.05 (s, 1H), 8.95 (d, 1H), 7.96-7.89 (m, 2H), 7.82 (d, 1H), 7.65 (d, 1H), 7.50 (t, 1H), 4.35 (m, 1H), 4.10 (s, 3H), 3.65-3.15 (m, 6H), 2.20 (m, 1H), 2.18-2.05 (m, 1H), 1.98-1.88 (m, 2H), 1.80-1.63 (m, 1H). 1H-NMR (400 MHz, DMSO-d6): δ = 10.55 (s, 1H), 9.20 (d, 1H), 9.05 (s, 1H), 8.95 (d, 1H), 7.96-7.89 (m, 2H) , 7.82 (d, 1H), 7.65 (d, 1H), 7.50 (t, 1H), 4.35 (m, 1H), 4.10 (s, 3H), 3.65-3.15 (m, 6H), 2.20 (m, 1H ), 2.18-2.05 (m, 1H), 1.98-1.88 (m, 2H), 1.80-1.63 (m, 1H).

HPLC (metoda 1): Rt = 3.35 min. HPLC (method 1): Rt = 3.35 min.

Primjer 104 Example 104

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[4-(4-morfolinilkarbonil)fenil]-1-benzofuran-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[4-(4-morpholinylcarbonyl)phenyl]-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Prema općenitom radnom propisu D stavi se 631 mg (1.43 mmola) 4-(4-morfolinilkarbonil)fenil-trifluormetansulfonata (primjer 18A), 545 mg (2.15 mmola) bis(pinakolato)dibora, 456 mg (4.65 mmola) kalijevog acetata, 52 mg (0.07 mmola) PdCbtdppf), 500 mg (1.43 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzofuran-2-karboksamid-hidroklorida (primjer 30A), 3.6 mL 2 M otopine natrijevog karbonata, te još 52 mg (0.07 mmola) PdCl2(dppf) u 8 mL DMF. Nakon sušenja u visokom vakuumu dobije se 455 mg (61 % od teor.) naslovnog spoja. According to general procedure D, 631 mg (1.43 mmol) of 4-(4-morpholinylcarbonyl)phenyl-trifluoromethanesulfonate (Example 18A), 545 mg (2.15 mmol) of bis(pinacolato)diboron, 456 mg (4.65 mmol) of potassium acetate, 52 mg (0.07 mmol) PdCbtdppf), 500 mg (1.43 mmol) N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide hydrochloride ( example 30A), 3.6 mL of 2 M sodium carbonate solution, and another 52 mg (0.07 mmol) of PdCl2(dppf) in 8 mL of DMF. After drying in high vacuum, 455 mg (61% of theory) of the title compound is obtained.

1H-NMR (400 MHz, DMSO-d6): δ = 10.45 (s, 1H), 9.10 (d, 1H), 8.02-7.92 (m, 3H), 7.78 (d, 1H), 7.71 (d, 1H), 7.60 (d, 2H), 7.45 (t, 1H), 4.35 (m, 1H), 3.75-3.35 (m, 1H), 3.25-3.15 (m, 3H), 2.25 (m, 1H), 2.18-2.05 (m, 1H), 1.98-1.88 (m, 2H), 1.80-1.63 (m, 1H). 1H-NMR (400 MHz, DMSO-d6): δ = 10.45 (s, 1H), 9.10 (d, 1H), 8.02-7.92 (m, 3H), 7.78 (d, 1H), 7.71 (d, 1H) , 7.60 (d, 2H), 7.45 (t, 1H), 4.35 (m, 1H), 3.75-3.35 (m, 1H), 3.25-3.15 (m, 3H), 2.25 (m, 1H), 2.18-2.05 (m, 1H), 1.98-1.88 (m, 2H), 1.80-1.63 (m, 1H).

HPLC (metoda 1): Rt = 3.79 min. HPLC (method 1): Rt = 3.79 min.

Primjer 105 Example 105

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[3-(l-piperidinil)fenil]-1-benzofuran-2-karboksamid-dihidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[3-(1-piperidinyl)phenyl]-1-benzofuran-2-carboxamide dihydrochloride

[image] [image]

Smjesi od 300 mg (0.86 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzofuran-2-karboksamida (primjer 30A) i 63 mg (0.09 mmola) PdCl2(dppf) u 4 mL DMF doda se 311 mg (1.29 mmola) 3-(l-piperidinil)fenilborne kiseline i 3.44 mL 1 N natrijeve lužine. Reakcijska smjesa zagrijava se preko noći na 95 °C. Otapalo se odstrani pod sniženim tlakom, te se sirovi produkt preuzme u metanol i filtrira na silikagelu. Pročišćavanje se provede preparativnom HPLC. Produkt se otopi u metanolu i pretvori sa suviškom 1 N solne kiseline. Otapalo se ukloni pod sniženim tlakom. Nakon sušenja u visokom vakuumu dobije se 164 mg (41 % od teor.) naslovnog spoja. Mixtures of 300 mg (0.86 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide (Example 30A) and 63 mg (0.09 mmol) of PdCl2(dppf) in 4 mL of DMF was added to 311 mg (1.29 mmol) of 3-(1-piperidinyl)phenylboronic acid and 3.44 mL of 1 N sodium hydroxide solution. The reaction mixture is heated to 95 °C overnight. The solvent is removed under reduced pressure, and the crude product is taken up in methanol and filtered on silica gel. Purification is performed by preparative HPLC. The product is dissolved in methanol and converted with an excess of 1 N hydrochloric acid. The solvent was removed under reduced pressure. After drying in high vacuum, 164 mg (41% of theory) of the title compound is obtained.

1H-NMR (200 MHz, DMSO-d6): δ = 10.55 (s, 1H), 9.10 (d, 1H), 8.75 (s, 1H), 7.95-7.63 (m, 7H), 7.45 (t, 1H), 4.35 (m, 1H), 4.13-3.40 (m, 7H), 3.35-3.10 (m, 3H), 2.15-1.50 (m, 1H). 1H-NMR (200 MHz, DMSO-d6): δ = 10.55 (s, 1H), 9.10 (d, 1H), 8.75 (s, 1H), 7.95-7.63 (m, 7H), 7.45 (t, 1H) , 4.35 (m, 1H), 4.13-3.40 (m, 7H), 3.35-3.10 (m, 3H), 2.15-1.50 (m, 1H).

HPLC (metoda 1): Rt = 3.72 min. HPLC (method 1): Rt = 3.72 min.

MS (ESIpos): m/z = 430 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 430 (M+H)+ (free base).

Primjer 106 Example 106

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-(3-piridinil)-1-benzofuran-2-karboksamid-dihidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-(3-pyridinyl)-1-benzofuran-2-carboxamide dihydrochloride

[image] [image]

Smjesi od 100 mg (0.86 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzofuran-2-karboksamida (primjer 30A) i 63 mg (0.09 mmola) PdCl2(dppf) u 4 mL DMF doda se 70 mg (0.57 mmola) 3-piridinborne kiseline i 0.86 mL 1 N natrijeve lužine. Reakcijska smjesa zagrijava se preko noći na 95 °C. Otapalo se odstrani pod sniženim tlakom, te se sirovi produkt preuzme u metanol i filtrira na silikagelu. Pročišćavanje se provede preparativnom HPLC. Produkt se otopi u metanolu i pretvori sa suviškom 1 N solne kiseline. Otapalo se ukloni pod sniženim tlakom. Nakon sušenja u visokom vakuumu dobije se 49 mg (45 % od teor.) naslovnog spoja. Mixtures of 100 mg (0.86 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide (Example 30A) and 63 mg (0.09 mmol) of PdCl2(dppf) in 4 mL of DMF, 70 mg (0.57 mmol) of 3-pyridineboric acid and 0.86 mL of 1 N sodium hydroxide solution were added. The reaction mixture is heated to 95 °C overnight. The solvent is removed under reduced pressure, and the crude product is taken up in methanol and filtered on silica gel. Purification is performed by preparative HPLC. The product is dissolved in methanol and converted with an excess of 1 N hydrochloric acid. The solvent was removed under reduced pressure. After drying in a high vacuum, 49 mg (45% of theory) of the title compound is obtained.

1H-NMR (300 MHz, DMSO-d6): δ = 10.55 (s, 1H), 9.51 (s, 1H), 9.30 (d, 1H), 9.20 (s, 1H), 8.94-8.80 (m, 2H), 8.07-7.80 (m, 4H), 7.55 (t, 1H), 4.35 (m, 1H), 3.65-3.15 (m, 6H), 2.20 (m, 1H), 2.18-2.05 (m, 1H), 1.98-1.88 (m, 2H), 1.80-1.63 (m, 1H). 1H-NMR (300 MHz, DMSO-d6): δ = 10.55 (s, 1H), 9.51 (s, 1H), 9.30 (d, 1H), 9.20 (s, 1H), 8.94-8.80 (m, 2H) , 8.07-7.80 (m, 4H), 7.55 (t, 1H), 4.35 (m, 1H), 3.65-3.15 (m, 6H), 2.20 (m, 1H), 2.18-2.05 (m, 1H), 1.98 -1.88 (m, 2H), 1.80-1.63 (m, 1H).

HPLC (metoda 1): Rt = 3.27 min. HPLC (method 1): Rt = 3.27 min.

MS (ESIpos): m/z = 348 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 348 (M+H)+ (free base).

Primjer 107 Example 107

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-(3-{[(metilamino)karbonil]-amino}fenil)-1-benzofuran-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-(3-{[(methylamino)carbonyl]-amino}phenyl)-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Zagrijava se 63 mg (0.18 mmola) 7-(3-aminofenil)-N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-1-benzofuran-2-karboksamida (primjer 114), 40 mg (0.70 mmola) metilizocijanata i 0.12 mL (0.88 mmola) trietilamina preko noći na 40 °C u 3 mL THF/DMF (1:1). Doda se još 40 mg (0.70 mmola) metilizocijanata i katalitička količina DMAP, te se smjesa zagrijava preko noći na 50 °C. Nakon hlađenja smjesa se pretvori vodom, filtrira, te se otapalo ukloni pod sniženim tlakom. Pročišćavanje se provede preparativnom HPLC. Produkt se otopi u metanolu i pretvori sa suviškom 1 N solne kiseline. Otapalo se ukloni pod sniženim tlakom. Nakon sušenja u visokom vakuumu dobije se 18 mg (23 % od teor.) naslovnog spoja. Heat 63 mg (0.18 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide (Example 114), 40 mg (0.70 mmol) methylisocyanate and 0.12 mL (0.88 mmol) triethylamine overnight at 40 °C in 3 mL THF/DMF (1:1). Another 40 mg (0.70 mmol) of methyl isocyanate and a catalytic amount of DMAP are added, and the mixture is heated overnight at 50 °C. After cooling, the mixture is diluted with water, filtered, and the solvent is removed under reduced pressure. Purification is performed by preparative HPLC. The product is dissolved in methanol and converted with an excess of 1 N hydrochloric acid. The solvent was removed under reduced pressure. After drying in a high vacuum, 18 mg (23% of theory) of the title compound are obtained.

1H-NMR (400 MHz, DMSO-d6): δ = 9.98 (s, 1H), 8.85 (s, 1H), 8.63 (d, 1H), 8.15 (s, 1H), 7.80 (m, 2H), 7.65 (d, 1H), 7.45 (t, 1H), 7.38 (s, 2H), 6.20 (m, 1H), 4.35 (m, 1H), 3.75-3.63 (m, 1H), 3.60-3.15 (m, 5H), 2.65 (s, 3H), 2.30 (m, 1H), 2.18-2.05 (m, 1H), 1.98-1.88 (m, 2H), 1.80-1.63 (m, 1H). 1H-NMR (400 MHz, DMSO-d6): δ = 9.98 (s, 1H), 8.85 (s, 1H), 8.63 (d, 1H), 8.15 (s, 1H), 7.80 (m, 2H), 7.65 (d, 1H), 7.45 (t, 1H), 7.38 (s, 2H), 6.20 (m, 1H), 4.35 (m, 1H), 3.75-3.63 (m, 1H), 3.60-3.15 (m, 5H ), 2.65 (s, 3H), 2.30 (m, 1H), 2.18-2.05 (m, 1H), 1.98-1.88 (m, 2H), 1.80-1.63 (m, 1H).

HPLC (metoda 1): Rt = 3.89 min. HPLC (method 1): Rt = 3.89 min.

MS (ESIpos): m/z = 419 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 419 (M+H)+ (free base).

Primjer 108 Example 108

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-(3-{[(etilamino)karbonil]-amino}fenil)-1-benzofuran-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-(3-{[(ethylamino)carbonyl]-amino}phenyl)-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Zagrijava se 63 mg (0.18 mmola) 7-(3-aminofenil)-N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-1-benzofuran-2-karboksamida (primjer 114), 50 mg (0.70 mmola) etilizocijanata i 0.12 mL (0.88 mmola) trietilamina preko noći na 40 °C u 3 mL THF/DMF (1:1). Doda se još 50 mg (0.70 mmola) etilizocijanata i katalitička količina DMAP, te se smjesa zagrijava preko noći na 50 °C. Nakon hlađenja smjesa se pretvori vodom, filtrira, te se otapalo ukloni pod sniženim tlakom. Pročišćavanje se provede preparativnom HPLC. Produkt se otopi u metanolu i pretvori sa suviškom 1 N solne kiseline. Otapalo se ukloni pod sniženim tlakom. Nakon sušenja u visokom vakuumu dobije se 15 mg (18 % od teor.) naslovnog spoja. Heat 63 mg (0.18 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide (Example 114), 50 mg (0.70 mmol) ethyl isocyanate and 0.12 mL (0.88 mmol) triethylamine overnight at 40 °C in 3 mL THF/DMF (1:1). Another 50 mg (0.70 mmol) of ethyl isocyanate and a catalytic amount of DMAP are added, and the mixture is heated overnight at 50 °C. After cooling, the mixture is diluted with water, filtered, and the solvent is removed under reduced pressure. Purification is performed by preparative HPLC. The product is dissolved in methanol and converted with an excess of 1 N hydrochloric acid. The solvent was removed under reduced pressure. After drying in a high vacuum, 15 mg (18% of theory) of the title compound is obtained.

1H-NMR (400 MHz, DMSO-d6): δ = 9.80 (s, 1H), 8.74 (s, 1H), 8.63 (d, 1H), 8.10 (s, 1H), 7.80 (m, 2H), 7.60 (d, 1H), 7.45 (t, 1H), 7.38 (s, 2H), 6.20 (m, 1H), 4.35 (m, 1H), 3.75-3.63 (m, 1H), 3.60-3.15 (m, 5H), 3.10 (m, 2H), 2.65 (s, 3H), 2.30 (m, 1H), 2.18-2.05 (m, 1H), 1.98-1.88 (m, 2H), 1.80-1.63 (m, 1H), 1.05 (t, 3H). HPLC (metoda 1): Rt = 4.01 min. MS (ESIpos): m/z = 433 (M+H)+ (slobodna baza). 1H-NMR (400 MHz, DMSO-d6): δ = 9.80 (s, 1H), 8.74 (s, 1H), 8.63 (d, 1H), 8.10 (s, 1H), 7.80 (m, 2H), 7.60 (d, 1H), 7.45 (t, 1H), 7.38 (s, 2H), 6.20 (m, 1H), 4.35 (m, 1H), 3.75-3.63 (m, 1H), 3.60-3.15 (m, 5H ), 3.10 (m, 2H), 2.65 (s, 3H), 2.30 (m, 1H), 2.18-2.05 (m, 1H), 1.98-1.88 (m, 2H), 1.80-1.63 (m, 1H), 1.05 (t, 3H). HPLC (method 1): Rt = 4.01 min. MS (ESIpos): m/z = 433 (M+H)+ (free base).

Primjer 109 Example 109

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[3-({[(l-metiletil)amino]-karbonil}amino)fenil]-1-benzofuran-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[3-({[(1-methylethyl)amino]-carbonyl}amino)phenyl]-1-benzofuran-2 -carboxamide hydrochloride

[image] [image]

Zagrijava se 50 mg (0.14 mmola) 7-(3-aminofenil)-N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-1-benzofuran-2-karboksamida (primjer 114), 47 mg (0.55 mmola) izopropilizocijanata i 0.12 mL (0.88 mmola) trietilamina preko noći na 40 °C u 3 mL THF/DMF (1:1). Doda se još 47 mg (0.55 mmola) izopropilizocijanata i katalitička količina DMAP, te se smjesa zagrijava preko noći na 50 °C. Nakon hlađenja smjesa se pretvori vodom, filtrira, te se otapalo ukloni pod sniženim tlakom. Pročišćavanje se provede preparativnom HPLC. Produkt se otopi u metanolu i pretvori sa suviškom 1 N solne kiseline. Otapalo se ukloni pod sniženim tlakom. Nakon sušenja u visokom vakuumu dobije se 13 mg (18 % od teor.) naslovnog spoja. Heat 50 mg (0.14 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide (Example 114), 47 mg (0.55 mmol) isopropylisocyanate and 0.12 mL (0.88 mmol) triethylamine overnight at 40 °C in 3 mL THF/DMF (1:1). Another 47 mg (0.55 mmol) of isopropyl isocyanate and a catalytic amount of DMAP are added, and the mixture is heated overnight at 50 °C. After cooling, the mixture is diluted with water, filtered, and the solvent is removed under reduced pressure. Purification is performed by preparative HPLC. The product is dissolved in methanol and converted with an excess of 1 N hydrochloric acid. The solvent was removed under reduced pressure. After drying in a high vacuum, 13 mg (18% of theory) of the title compound is obtained.

1H-NMR (400 MHz, DMSO-d6): δ = 9.80 (s, 1H), 8.70 (d, 1H), 8.65 (s, 1H), 8.05 (s, 1H), 7.80 (m, 2H), 7.60 (d, 1H), 7.45 (t, 1H), 7.38 (s, 2H), 6.20 (m, 1H), 4.35 (m, 1H), 3.80-3.72 (m, 1H), 3.70-3.63 (m, 1H), 3.50-3.05 (m, 5H), 2.30 (m, 1H), 2.18-2.05 (m, 1H), 1.98-1.88 (m, 2H), 1.80-1.63 (m, 1H), 1.10 (d, 6H). 1H-NMR (400 MHz, DMSO-d6): δ = 9.80 (s, 1H), 8.70 (d, 1H), 8.65 (s, 1H), 8.05 (s, 1H), 7.80 (m, 2H), 7.60 (d, 1H), 7.45 (t, 1H), 7.38 (s, 2H), 6.20 (m, 1H), 4.35 (m, 1H), 3.80-3.72 (m, 1H), 3.70-3.63 (m, 1H ), 3.50-3.05 (m, 5H), 2.30 (m, 1H), 2.18-2.05 (m, 1H), 1.98-1.88 (m, 2H), 1.80-1.63 (m, 1H), 1.10 (d, 6H ).

HPLC (metoda 1): Rt = 4.12 min. HPLC (method 1): Rt = 4.12 min.

Primjer 110 Example 110

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[3-({[(l,l-dimetiletil)amino]-karbonil}amino)fenil]-1-benzofuran-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[3-({[(1,1-dimethylethyl)amino]-carbonyl}amino)phenyl]-1-benzofuran -2-carboxamide hydrochloride

[image] [image]

Zagrijava se 63 mg (0.14 mmola) 7-(3-aminofenil)-N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-1-benzofuran-2-karboksamida (primjer 114), 69 mg (0.70 mmola) tert-butilizocijanata i 0.12 mL (0.88 mmola) trietilamina preko noći na 40 °C u 3 mL THF/DMF (1:1). Doda se još 69 mg (0.70 mmola) tert-butilizocijanata i katalitička količina DMAP, te se smjesa zagrijava preko noći na 50 °C. Nakon hlađenja smjesa se pretvori vodom, filtrira, te se otapalo ukloni pod sniženim tlakom. Pročišćavanje se provede preparativnom HPLC. Produkt se otopi u metanolu i pretvori sa suviškom 1 N solne kiseline. Otapalo se ukloni pod sniženim tlakom. Nakon sušenja u visokom vakuumu dobije se 8 mg (9 % od teor.) naslovnog spoja. 63 mg (0.14 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide (example 114) are heated, 69 mg (0.70 mmol) of tert-butylisocyanate and 0.12 mL (0.88 mmol) of triethylamine overnight at 40 °C in 3 mL of THF/DMF (1:1). Another 69 mg (0.70 mmol) of tert-butyl isocyanate and a catalytic amount of DMAP are added, and the mixture is heated overnight at 50 °C. After cooling, the mixture is diluted with water, filtered, and the solvent is removed under reduced pressure. Purification is performed by preparative HPLC. The product is dissolved in methanol and converted with an excess of 1 N hydrochloric acid. The solvent was removed under reduced pressure. After drying in high vacuum, 8 mg (9% of theory) of the title compound is obtained.

1H-NMR (400 MHz, DMSO-d6): δ = 9.70 (s, 1H), 8.80 (d, 1H), 8.55 (s, 1H), 7.85 (s, 1H), 7.80 (m, 2H), 7.65 (d, 1H), 7.45 (t, 1H), 7.38 (s, 2H), 6.10 (m, 1H), 4.35 (m, 1H), 3.70-3.63 (m, 1H), 3.50-3.05 (m, 5H), 2.30 (m, 1H), 2.18-2.05 (m, 1H), 1.98-1.88 (m, 2H), 1.80-1.63 (m, 1H), 1.30 (s, 9H). 1H-NMR (400 MHz, DMSO-d6): δ = 9.70 (s, 1H), 8.80 (d, 1H), 8.55 (s, 1H), 7.85 (s, 1H), 7.80 (m, 2H), 7.65 (d, 1H), 7.45 (t, 1H), 7.38 (s, 2H), 6.10 (m, 1H), 4.35 (m, 1H), 3.70-3.63 (m, 1H), 3.50-3.05 (m, 5H ), 2.30 (m, 1H), 2.18-2.05 (m, 1H), 1.98-1.88 (m, 2H), 1.80-1.63 (m, 1H), 1.30 (s, 9H).

HPLC (metoda 1): Rt = 4.27 min. HPLC (method 1): Rt = 4.27 min.

MS (ESIpos): m/z = 461 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 461 (M+H)+ (free base).

Primjer 111 Example 111

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-{3-[(metilsulfonil)arnino]-fenil}-1-benzofuran-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-{3-[(methylsulfonyl)amino]-phenyl}-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Zagrijava se 73 mg (0.20 mmola) 7-(3-aminofenil)-N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-1-benzofuran-2-karboksamida (primjer 114), 69 mg (0.61 mmol) klorida metansulfonske kiseline i 0.14 mL (1.01 mmol) trietilamina preko noći na 50 °C u 3 mL THF/DMF (1:1). Nakon hlađenja smjesa se pretvori vodom, filtrira, te se otapalo ukloni pod sniženim tlakom. Pročišćavanje se provede preparativnom HPLC. Produkt se otopi u metanolu i pretvori sa suviškom 1 N solne kiseline. Otapalo se ukloni pod sniženim tlakom. Nakon sušenja u visokom vakuumu dobije se 16 mg (14 % od teor.) naslovnog spoja. 73 mg (0.20 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide (Example 114) is heated. 69 mg (0.61 mmol) methanesulfonic acid chloride and 0.14 mL (1.01 mmol) triethylamine overnight at 50 °C in 3 mL THF/DMF (1:1). After cooling, the mixture is diluted with water, filtered, and the solvent is removed under reduced pressure. Purification is performed by preparative HPLC. The product is dissolved in methanol and converted with an excess of 1 N hydrochloric acid. The solvent was removed under reduced pressure. After drying in a high vacuum, 16 mg (14% of theory) of the title compound is obtained.

1H-NMR (300 MHz, DMSO-d6): δ = 10.15 (s, 1H), 9.90 (s, 1H), 8.76 (d, 1H), 7.90 (s, 1H), 7.85-7.75 (m, 2H), 7.66-7.60 (m, 2H), 7.55-7.53 (m, 2H), 7.25 (m, 1H), 4.37 (m, 1H), 3.70-3.63 (m, 1H), 3.45-3.05 (m, 5H), 3.10 (s, 3H), 2.30 (m, 1H), 2.18-2.05 (m, 1H), 1.98-1.88 (m, 2H), 1.80-1.63 (m, 1H). 1H-NMR (300 MHz, DMSO-d6): δ = 10.15 (s, 1H), 9.90 (s, 1H), 8.76 (d, 1H), 7.90 (s, 1H), 7.85-7.75 (m, 2H) , 7.66-7.60 (m, 2H), 7.55-7.53 (m, 2H), 7.25 (m, 1H), 4.37 (m, 1H), 3.70-3.63 (m, 1H), 3.45-3.05 (m, 5H) , 3.10 (s, 3H), 2.30 (m, 1H), 2.18-2.05 (m, 1H), 1.98-1.88 (m, 2H), 1.80-1.63 (m, 1H).

HPLC (metoda 1): Rt = 3.97 min. HPLC (method 1): Rt = 3.97 min.

MS (ESIpos): m/z = 440 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 440 (M+H)+ (free base).

Primjer 112 Example 112

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-{2-[(ciklobutilkarbonil)-amino]fenil}-1-benzofuran-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-{2-[(cyclobutylcarbonyl)-amino]phenyl}-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Zagrijava se 60 mg (0.15 mmola) 7-(2-aminofenil)-N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-1-benzofuran-2-karboksamida (primjer 132), 26 mg (0.22 mmola) klorida ciklobutankarboksilne kiseline i 0.06 mL (0.44 mmola) trietilamina preko noći na RT u 2 mL THF/DMF (1:1). Otapalo se ukloni pod sniženim tlakom. Pročišćavanje se provede preparativnom HPLC. Produkt se otopi u metanolu i pretvori sa suviškom 1 N solne kiseline. Otapalo se ukloni pod sniženim tlakom. Nakon sušenja u visokom vakuumu dobije se 39 mg (56 % od teor.) naslovnog spoja. Heat 60 mg (0.15 mmol) of 7-(2-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide (example 132), 26 mg (0.22 mmol) cyclobutanecarboxylic acid chloride and 0.06 mL (0.44 mmol) triethylamine overnight at RT in 2 mL THF/DMF (1:1). The solvent was removed under reduced pressure. Purification is performed by preparative HPLC. The product is dissolved in methanol and converted with an excess of 1 N hydrochloric acid. The solvent was removed under reduced pressure. After drying in high vacuum, 39 mg (56% of theory) of the title compound are obtained.

1H-NMR (300 MHz, DMSO-d6): δ = 10.15 (s, 1H), 9.05 (s, 1H), 8.40 (d, 1H), 7.95 (s, 1H), 7.80-7.70 (m, 2H), 7.55-7.30 (m, 6H), 4.32 (m, 1H), 3.70-3.63 (m, 1H), 3.45-3.05 (m, 5H), 2.98-2.88 (m, 1H), 2.30 (m, 1H), 2.18-2.05 (m, 1H), 1.98-1.55 (m, 9H). 1H-NMR (300 MHz, DMSO-d6): δ = 10.15 (s, 1H), 9.05 (s, 1H), 8.40 (d, 1H), 7.95 (s, 1H), 7.80-7.70 (m, 2H) , 7.55-7.30 (m, 6H), 4.32 (m, 1H), 3.70-3.63 (m, 1H), 3.45-3.05 (m, 5H), 2.98-2.88 (m, 1H), 2.30 (m, 1H) , 2.18-2.05 (m, 1H), 1.98-1.55 (m, 9H).

HPLC (metoda 1): Rt = 3.95 min. HPLC (method 1): Rt = 3.95 min.

MS (ESIpos): m/z = 444 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 444 (M+H)+ (free base).

Primjer 113 Example 113

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-5-(5-pirimidinil)-1-benzofuran-2-karboksamid-hidro klorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-(5-pyrimidinyl)-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Smjesi od 250 mg (0.72 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-5-brom-1-benzofuran-2-karboksamid-hidroklorida (primjer 3A) i 52 mg (0.07 mmola) PdCl2(dppf) u 3 mL DMF doda se 177 mg (0.86 mmola) 5-(4,4,5,5-tetrametil-l,3,2-dioksaborolan-2-il)-pirimidina i 2.15 mL 1 N natrijeve lužine. Reakcijska smjesa zagrijava se preko noći na 90 °C. Otapalo se odstrani pod sniženim tlakom, te se sirovi produkt preuzme u metanol i filtrira na silikagelu. Pročišćavanje se provede preparativnom HPLC. Produkt se otopi u metanolu i pretvori sa suviškom 1 N solne kiseline. Otapalo se ukloni pod sniženim tlakom. Nakon kristaliziranja ostatka iz izopropanola i sušenja u visokom vakuumu dobije se 28 mg (10 % od teor.) naslovnog spoja. Mixtures of 250 mg (0.72 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-bromo-1-benzofuran-2-carboxamide hydrochloride (example 3A) and 52 mg (0.07 mmol) of PdCl2(dppf) in 3 mL of DMF was added to 177 mg (0.86 mmol) of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrimidine and 2.15 mL 1 N sodium hydroxide solution. The reaction mixture is heated to 90 °C overnight. The solvent is removed under reduced pressure, and the crude product is taken up in methanol and filtered on silica gel. Purification is performed by preparative HPLC. The product is dissolved in methanol and converted with an excess of 1 N hydrochloric acid. The solvent was removed under reduced pressure. After crystallization of the residue from isopropanol and drying in high vacuum, 28 mg (10% of theory) of the title compound are obtained.

1H-NMR (300 MHz, DMSO-d6): δ = 10.30 (s, 1H), 9.22-9.13 (m, 4H), 8.24 (m, 1H), 7.93-7.81 (m, 3H), 4.39 (m, 1H), 3.68-3.48 (m, 1H), 3.45-3.13 (m, 5H), 2.28-2.20 (m, 1H), 2.18-2.07 (m, 1H), 1.97-1.88 (m, 2H), 1.80-1.57 (m, 1H). HPLC (metoda 1): Rt = 3.26 min. 1H-NMR (300 MHz, DMSO-d6): δ = 10.30 (s, 1H), 9.22-9.13 (m, 4H), 8.24 (m, 1H), 7.93-7.81 (m, 3H), 4.39 (m, 1H), 3.68-3.48 (m, 1H), 3.45-3.13 (m, 5H), 2.28-2.20 (m, 1H), 2.18-2.07 (m, 1H), 1.97-1.88 (m, 2H), 1.80- 1.57 (m, 1H). HPLC (method 1): Rt = 3.26 min.

Primjer 114 Example 114

7-(3-aminofenil)-N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-1-benzofuran-2-karboksamid-hidroklorid 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Metoda a): Method a):

Smjesi od 978 mg (2.80 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzofuran-2-karboksamida (primjer 30A) i 205 mg (0.28 mmola) PdCl2(dppf) u 15 mL DMF doda se 622 mg (1.68 mmola) hemisulfata 3-aminofenilboronske kiseline i 11.2 mL 1 N natrijeve lužine. Reakcijska smjesa zagrijava se preko noći na 95 °C. Sirovi produkt se filtrira na silikagelu, potom ispere s DMF i pod sniženim tlakom oslobodi otapala. Ostatak se pretvori s 200 mL 1 N natrijeve lužine i 200 mL etilnog estera octene kiseline. Nakon odvajanja faza organska se faza još dvaput ispere s po 100 mL 1 N natrijeve lužine, te potom još jednom sa 100 mL zasićene otopine kuhinjske soli. Nakon sušenja iznad magnezijevog sulfata provede se pročišćavanje sirovog produkta preparativnom HPLC. Nakon uklanjanja otapala na rotacijskom isparivaču može se pretvaranjem dva puta diklormetanom i ponovnim zgušnjavanjem dobiti 875 mg (73 % od teor.) naslovnog spoja u obliku bijele pjene. Mixtures of 978 mg (2.80 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide (Example 30A) and 205 mg (0.28 mmol) of PdCl2(dppf) in 15 mL of DMF, 622 mg (1.68 mmol) of 3-aminophenylboronic acid hemisulfate and 11.2 mL of 1 N sodium hydroxide solution are added. The reaction mixture is heated to 95 °C overnight. The crude product is filtered on silica gel, then washed with DMF and freed from the solvent under reduced pressure. The residue is converted with 200 mL of 1 N sodium hydroxide solution and 200 mL of ethyl acetate. After separating the phases, the organic phase is washed two more times with 100 mL of 1 N sodium lye, and then once more with 100 mL of a saturated table salt solution. After drying over magnesium sulfate, the crude product is purified by preparative HPLC. After removing the solvent on a rotary evaporator, 875 mg (73% of theory) of the title compound can be obtained in the form of a white foam by converting twice with dichloromethane and re-concentrating.

1H-NMR (300 MHz, DMSO-d6): δ = 8.48 (d, 1H), 8.21 (s, 1H), 7.76-7.69 (m, 1H), 7.54 (d, 1H), 7.45-7.37 (m, 1H), 7.20-7.00 (m, 3H), 6.67-6.61 (m, 1H), 4.13-4.06 (m, 1H), 3.48-3.26 (m, 1H), 3.10-3.01 (m, 1H), 2.93-2.79 (m, 4H), 2.03 (m, 1H), 2.00-1.88 (m, 1H), 1.79-1.67 (m, 2H), 1.58-1.42 (m, 1H). 1H-NMR (300 MHz, DMSO-d6): δ = 8.48 (d, 1H), 8.21 (s, 1H), 7.76-7.69 (m, 1H), 7.54 (d, 1H), 7.45-7.37 (m, 1H), 7.20-7.00 (m, 3H), 6.67-6.61 (m, 1H), 4.13-4.06 (m, 1H), 3.48-3.26 (m, 1H), 3.10-3.01 (m, 1H), 2.93- 2.79 (m, 4H), 2.03 (m, 1H), 2.00-1.88 (m, 1H), 1.79-1.67 (m, 2H), 1.58-1.42 (m, 1H).

HPLC (metoda 1): Rt = 3.46 min. HPLC (method 1): Rt = 3.46 min.

MS (ESIpos): m/z = 362 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 362 (M+H)+ (free base).

Metoda b): Method b):

Smjesi od 660 mg (1.89 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzofuran-2-karboksamida (primjer 30A) i 138 mg (0.19 mmola) PdCl2(dppf) u 8 mL DMF doda se 419 mg (1.13 mmola) bis[3-(dihidroksiboranil)-benzolaminij]sulfata I 7.56 mL 1 N natrijeve lužine. Reakcijska smjesa zagrijava se preko noći na 95 °C. Otapalo se odstrani pod sniženim tlakom, te se sirovi produkt preuzme u metanol i filtrira na silikagelu. Daljnje pročišćavanje se provede preparativnom HPLC. Otapalo se iz frakcija produkta ukloni pod sniženim tlakom. Nakon kristaliziranja ostatka iz izopropanola i sušenja u visokom vakuumu dobije se 485 mg (71 % od teor.) naslovnog spoja. Mixtures of 660 mg (1.89 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide (Example 30A) and 138 mg (0.19 mmol) of PdCl2(dppf) in 8 mL of DMF was added to 419 mg (1.13 mmol) of bis[3-(dihydroxyboranyl)-benzolaminium]sulfate and 7.56 mL of 1 N sodium hydroxide solution. The reaction mixture is heated to 95 °C overnight. The solvent is removed under reduced pressure, and the crude product is taken up in methanol and filtered on silica gel. Further purification is carried out by preparative HPLC. The solvent was removed from the product fractions under reduced pressure. After crystallization of the residue from isopropanol and drying in high vacuum, 485 mg (71% of theory) of the title compound are obtained.

1H-NMR (300 MHz, DMSO-d6): δ = 8.48 (d, 1H), 8.21 (s, 1H), 7.70 (s, 1H), 7.55 (m, 1H), 7.40 (t, 1H), 7.18 (t, 1H), 7.10-7.00 (m, 2H), 6.66 (m, 1H), 4.20 (br. s, 2H), 4.05 (m, 1H), 3.25 (m, 1H), 3.05 (m, 1H), 2.90-2.70 (m, 4H), 2.05 (m, 1H), 1.70 (m, 1H), 1.65 (m, 2H), 1.45 (m, 1H). 1H-NMR (300 MHz, DMSO-d6): δ = 8.48 (d, 1H), 8.21 (s, 1H), 7.70 (s, 1H), 7.55 (m, 1H), 7.40 (t, 1H), 7.18 (t, 1H), 7.10-7.00 (m, 2H), 6.66 (m, 1H), 4.20 (no. s, 2H), 4.05 (m, 1H), 3.25 (m, 1H), 3.05 (m, 1H ), 2.90-2.70 (m, 4H), 2.05 (m, 1H), 1.70 (m, 1H), 1.65 (m, 2H), 1.45 (m, 1H).

HPLC (metoda 1): Rt = 3.50 min. HPLC (method 1): Rt = 3.50 min.

Primjer 115 Example 115

7-[3-(acetilamino)fenil]-N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-1-benzofuran-2-karboksamid-hidroklorid 7-[3-(acetylamino)phenyl]-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Miješa se 75 mg (0.16 mmola) 7-(3-aminofenil)-N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-1-benzofuran-2-karboksamida (primjer 114), 18 nL (0.24 mmola) acetilklorida i 68 nL (0.49 mmola) trietilamina preko noći na RT u 2 mL THF. Otapalo se ukloni pod sniženim tlakom. Pročišćavanje se provede preparativnom HPLC. Produkt se otopi u metanolu i pretvori sa suviškom 1 N solne kiseline. Nakon uklanjanja otapala pod sniženim tlakom i sušenja u visokom vakuumu dobije se 51 mg (72 % od teor.) naslovnog spoja. Mix 75 mg (0.16 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide (example 114), 18 nL (0.24 mmol) acetyl chloride and 68 nL (0.49 mmol) triethylamine overnight at RT in 2 mL THF. The solvent was removed under reduced pressure. Purification is performed by preparative HPLC. The product is dissolved in methanol and converted with an excess of 1 N hydrochloric acid. After removing the solvent under reduced pressure and drying in a high vacuum, 51 mg (72% of theory) of the title compound is obtained.

1H-NMR (300 MHz, DMSO-d6): δ = 10.37 (s, 1H), 10.30 (br. s, 1H), 8.67-8.59 (m, 2H), 7.82-7.68 (m, 3H), 7.58-7.41 (m, 4H), 4.40 (m, 1H), 3.73-3.60 (m, 1H), 3.48-3.37 (m, 1H), 3.78-3.15 (m, 4H), 2.29 (m, 1H), 2.19-2.09 (m, 1H), 2.13 (s, 3H), 1.98-1.90 (m, 2H), 1.81-1.69 (m, 1H). 1H-NMR (300 MHz, DMSO-d6): δ = 10.37 (s, 1H), 10.30 (No. s, 1H), 8.67-8.59 (m, 2H), 7.82-7.68 (m, 3H), 7.58- 7.41 (m, 4H), 4.40 (m, 1H), 3.73-3.60 (m, 1H), 3.48-3.37 (m, 1H), 3.78-3.15 (m, 4H), 2.29 (m, 1H), 2.19- 2.09 (m, 1H), 2.13 (s, 3H), 1.98-1.90 (m, 2H), 1.81-1.69 (m, 1H).

HPLC (metoda 1): Rt = 4.04 min. HPLC (method 1): Rt = 4.04 min.

MS (ESIpos): m/z = 404 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 404 (M+H)+ (free base).

Primjer 116 Example 116

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-{3-[(ciklopropilkarbonil)-amino]fenil}-1-benzofuran-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-{3-[(cyclopropylcarbonyl)-amino]phenyl}-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Miješa se 75 mg (0.21 mmol) 7-(3-aminofenil)-N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-1-benzofuran-2-karboksamida (primjer 114), 28 μL (0.31 mmol) klorida ciklopropilkarboksilne kiseline i 87 μL (0.62 mmola) trietilamina preko noći na RT u 2 mL THF. Nakon pretvaranja vodom otapalo se ukloni pod sniženim tlakom. Pročišćavanje se provede preparativnom HPLC. Produkt se otopi u metanolu i pretvori sa suviškom 1 N solne kiseline. Nakon uklanjanja otapala pod sniženim tlakom i sušenja u visokom vakuumu dobije se 55 mg (57 % od teor.) naslovnog spoja. Mix 75 mg (0.21 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide (example 114), 28 μL (0.31 mmol) cyclopropylcarboxylic acid chloride and 87 μL (0.62 mmol) triethylamine overnight at RT in 2 mL THF. After conversion with water, the solvent is removed under reduced pressure. Purification is performed by preparative HPLC. The product is dissolved in methanol and converted with an excess of 1 N hydrochloric acid. After removing the solvent under reduced pressure and drying in a high vacuum, 55 mg (57% of theory) of the title compound is obtained.

1H-NMR (300 MHz, DMSO-d6): δ = 10.53 (s, 1H), 10.08 (br. s, 1H), 8.83 (m, 1H), 8.28 (s, 1H), 7.82-7.75 (m, 2H), 7.71 (d, 1H), 7.62 (d, 1H), 7.58-7.50 (m, 1H), 7.48-7.41 (m, 2H), 4.38 (m, 1H), 3.71-3.60 (m, 1H), 3.50-3.15 (m, 5H), 2.27 (m, 1H), 2.21-2.11 (m, 1H), 1.99-1.82 (m, 3H), 1.80-1.71 (m, 1H), 0.88-0.77 (m, 4H). 1H-NMR (300 MHz, DMSO-d6): δ = 10.53 (s, 1H), 10.08 (no. s, 1H), 8.83 (m, 1H), 8.28 (s, 1H), 7.82-7.75 (m, 2H), 7.71 (d, 1H), 7.62 (d, 1H), 7.58-7.50 (m, 1H), 7.48-7.41 (m, 2H), 4.38 (m, 1H), 3.71-3.60 (m, 1H) , 3.50-3.15 (m, 5H), 2.27 (m, 1H), 2.21-2.11 (m, 1H), 1.99-1.82 (m, 3H), 1.80-1.71 (m, 1H), 0.88-0.77 (m, 4H).

HPLC (metoda 1): Rt = 4.07 min. HPLC (method 1): Rt = 4.07 min.

Primjer 117 Example 117

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-(3-{[(metoksi)acetil]amino}-fenil)-1-benzofuran-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-(3-{[(methoxy)acetyl]amino}-phenyl)-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Miješa se 75 mg (0.21 mmol) 7-(3-aminofenil)-N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-1-benzofuran-2-karboksamida (primjer 114), 21 μL (0.31 mmol) klorida metoksioctene kiseline i 87 μL (0.62 mmol) trietilamina preko noći na RT u 2 mL THF. Nakon pretvaranja vodom otapalo se ukloni pod sniženim tlakom. Pročišćavanje se provede preparativnom HPLC. Produkt se otopi u metanolu i pretvori sa suviškom 1 N solne kiseline. Nakon uklanjanja otapala pod sniženim tlakom i sušenja u visokom vakuumu dobije se 56 mg (55 % od teor.) naslovnog spoja. Mix 75 mg (0.21 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide (example 114), 21 μL (0.31 mmol) methoxyacetic acid chloride and 87 μL (0.62 mmol) triethylamine overnight at RT in 2 mL THF. After conversion with water, the solvent is removed under reduced pressure. Purification is performed by preparative HPLC. The product is dissolved in methanol and converted with an excess of 1 N hydrochloric acid. After removing the solvent under reduced pressure and drying in high vacuum, 56 mg (55% of theory) of the title compound are obtained.

1H-NMR (300 MHz, DMSO-d6): δ = 10.17 (br. s, 1H), 10.10 (s, 1H), 8.63-8.55 (m, 2H), 7.82-7.68 (m, 3H), 7.64-7.57 (m, 2H), 7.52-7.41 (m, 2H), 4.39 (m, 1H), 4.10 (s, 2H), 3.71-3.61 (m, 1H), 3.49-3.14 (m, 5H), 3.41 (s, 3H), 2.29 (m, 1H), 2.19-2.05 (m, 1H), 1.99-1.89 (m, 2H), 1.80-1.69 (m, 1H). 1H-NMR (300 MHz, DMSO-d6): δ = 10.17 (No. s, 1H), 10.10 (s, 1H), 8.63-8.55 (m, 2H), 7.82-7.68 (m, 3H), 7.64- 7.57 (m, 2H), 7.52-7.41 (m, 2H), 4.39 (m, 1H), 4.10 (s, 2H), 3.71-3.61 (m, 1H), 3.49-3.14 (m, 5H), 3.41 ( s, 3H), 2.29 (m, 1H), 2.19-2.05 (m, 1H), 1.99-1.89 (m, 2H), 1.80-1.69 (m, 1H).

HPLC (metoda 1): Rt = 4.07 min. HPLC (method 1): Rt = 4.07 min.

MS (ESIpos): m/z = 434 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 434 (M+H)+ (free base).

Primjer 118 Example 118

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-{3-[(ciklobutilkarbonil)-amino]fenil}-1-benzofuran-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-{3-[(cyclobutylcarbonyl)-amino]phenyl}-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Miješa se 75 mg (0.21 mmol) 7-(3-aminofenil)-N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-1-benzofuran-2-karboksamida (primjer 114), 37 mg (0.31 mmol) klorida ciklobutankarboksilne kiseline i 87 μL (0.62 mmola) trietilamina preko noći na RT u 2 mL THF. Nakon pretvaranja vodom otapalo se ukloni pod sniženim tlakom. Pročišćavanje se provede preparativnom HPLC. Produkt se otopi u metanolu i pretvori sa suviškom 1 N solne kiseline. Nakon uklanjanja otapala pod sniženim tlakom i sušenja u visokom vakuumu dobije se 57 mg (57 % od teor.) naslovnog spoja. 75 mg (0.21 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide (example 114) are mixed, 37 mg (0.31 mmol) cyclobutanecarboxylic acid chloride and 87 μL (0.62 mmol) triethylamine overnight at RT in 2 mL THF. After conversion with water, the solvent is removed under reduced pressure. Purification is performed by preparative HPLC. The product is dissolved in methanol and converted with an excess of 1 N hydrochloric acid. After removing the solvent under reduced pressure and drying in high vacuum, 57 mg (57% of theory) of the title compound are obtained.

1H-NMR (300 MHz, DMSO-d6): δ = 10.14 (br. s, 1H), 10.07 (s, 1H), 8.82 (d, 1H), 8.35 (s, 1H), 7.80-7.78 (m, 2H), 7.74-7.61 (m, 2H), 7.57-7.41 (m, 3H), 4.36 (m, 1H), 3.70-3.61 (m, 1H), 3.45-3.13 (m, 5H), 2.30-1.67 (m, 12H). 1H-NMR (300 MHz, DMSO-d6): δ = 10.14 (no. s, 1H), 10.07 (s, 1H), 8.82 (d, 1H), 8.35 (s, 1H), 7.80-7.78 (m, 2H), 7.74-7.61 (m, 2H), 7.57-7.41 (m, 3H), 4.36 (m, 1H), 3.70-3.61 (m, 1H), 3.45-3.13 (m, 5H), 2.30-1.67 ( m, 12H).

HPLC (metoda 1): Rt = 4.22 min. HPLC (method 1): Rt = 4.22 min.

Primjer 119 Example 119

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-{2-[(ciklopropilkarbonil)-amino]fenil}-1-benzofuran-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-{2-[(cyclopropylcarbonyl)-amino]phenyl}-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Miješa se 60 mg (0.15 mmola) 7-(2-aminofenil)-N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-1-benzofuran-2-karboksamida (primjer 132), 20 μL (0.31 mmol) klorida ciklopropilkarboksilne kiseline i 87 μL (0.62 mmola) trietilamina preko noći na RT u 2 mL THF/DMF (1:1). Nakon pretvaranja vodom otapalo se ukloni pod sniženim tlakom. Pročišćavanje se provede preparativnom HPLC. Produkt se otopi u metanolu i pretvori sa suviškom 1 N solne kiseline. Nakon uklanjanja otapala pod sniženim tlakom i sušenja u visokom vakuumu dobije se 27 mg (40 % od teor.) naslovnog spoja. Mix 60 mg (0.15 mmol) of 7-(2-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide (example 132), 20 μL (0.31 mmol) cyclopropylcarboxylic acid chloride and 87 μL (0.62 mmol) triethylamine overnight at RT in 2 mL THF/DMF (1:1). After conversion with water, the solvent is removed under reduced pressure. Purification is performed by preparative HPLC. The product is dissolved in methanol and converted with an excess of 1 N hydrochloric acid. After removing the solvent under reduced pressure and drying in a high vacuum, 27 mg (40% of theory) of the title compound are obtained.

1H-NMR (300 MHz, DMSO-d6): δ = 10.07 (br. s, 1H), 9.48 (s, 1H), 8.84 (d, 1H), 7.83-7.77 (m, 1H), 7.72 (m, 1H), 7.54-7.31 (m, 6H), 4.30 (m, 1H), 3.70-3.61 (m, 1H), 3.37-3.03 (m, 5H), 2.23 (m, 1H), 2.14-2.03 (m, 1H), 1.95-1.83 (m, 2H), 1.79-1.68 (m, 1H), 1.53 (m, 1H), 1.31-1.15 (m, 4H). 1H-NMR (300 MHz, DMSO-d6): δ = 10.07 (no. s, 1H), 9.48 (s, 1H), 8.84 (d, 1H), 7.83-7.77 (m, 1H), 7.72 (m, 1H), 7.54-7.31 (m, 6H), 4.30 (m, 1H), 3.70-3.61 (m, 1H), 3.37-3.03 (m, 5H), 2.23 (m, 1H), 2.14-2.03 (m, 1H), 1.95-1.83 (m, 2H), 1.79-1.68 (m, 1H), 1.53 (m, 1H), 1.31-1.15 (m, 4H).

HPLC (metoda 1): Rt = 3.85 min. HPLC (method 1): Rt = 3.85 min.

MS (ESIpos): m/z = 430 (M + H)+ (slobodna baza). MS (ESIpos): m/z = 430 (M + H)+ (free base).

Primjer 120 Example 120

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-(2-{[(metoksi)acetil]amino}-fenil)-1-benzofuran-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-(2-{[(methoxy)acetyl]amino}-phenyl)-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Miješa se 60 mg (0.15 mmola) 7-(2-aminofenil)-N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-1-benzofuran-2-karboksamida (primjer 132), 20 μL (0.22 mmola) klorida metoksioctene kiseline i 61 μL (0.44 mmola) trietilamina preko noći na RT u 2 mL THF/DMF (1:1). Nakon pretvaranja vodom otapalo se ukloni pod sniženim tlakom. Pročišćavanje se provede preparativnom HPLC. Produkt se otopi u metanolu i pretvori sa suviškom 1 N solne kiseline. Nakon uklanjanja otapala pod sniženim tlakom i sušenja u visokom vakuumu dobije se 29 mg (40 % od teor.) naslovnog spoja. XH-NMR (300 MHz, DMSO-d6): δ = 10.15 (br. s, 1H), 9.05 (s, 1H), 8.53 (d, 1H), 7.88-7.73 (m, 3H), 7.52-7.34 (m, 5H), 4.33 (m, 1H), 3.77 (s, 2H), 3.69-3.59 (m, 1H), 3.44-3.14 (m, 5H), 3.04 (s, 3H), 2.22 (m, 1H), 2.18-2.05 (m, 1H), 1.96-1.84 (m, 2H), 1.80-1.67 (m, 1H). Mix 60 mg (0.15 mmol) of 7-(2-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide (example 132), 20 μL (0.22 mmol) methoxyacetic acid chloride and 61 μL (0.44 mmol) triethylamine overnight at RT in 2 mL THF/DMF (1:1). After conversion with water, the solvent is removed under reduced pressure. Purification is performed by preparative HPLC. The product is dissolved in methanol and converted with an excess of 1 N hydrochloric acid. After removing the solvent under reduced pressure and drying in a high vacuum, 29 mg (40% of theory) of the title compound are obtained. XH-NMR (300 MHz, DMSO-d6): δ = 10.15 (no. s, 1H), 9.05 (s, 1H), 8.53 (d, 1H), 7.88-7.73 (m, 3H), 7.52-7.34 ( m, 5H), 4.33 (m, 1H), 3.77 (s, 2H), 3.69-3.59 (m, 1H), 3.44-3.14 (m, 5H), 3.04 (s, 3H), 2.22 (m, 1H) , 2.18-2.05 (m, 1H), 1.96-1.84 (m, 2H), 1.80-1.67 (m, 1H).

HPLC (metoda 1): Rt = 3.84 min. HPLC (method 1): Rt = 3.84 min.

Primjer 121 Example 121

N-[(3S)-1-azabiciklo[2.2.2]okt-3-il]-7-[4-(4-morfolinil)fenil]-1-benzofuran-2-karboksamid-hidroklorid N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-[4-(4-morpholinyl)phenyl]-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Smjesi od 150 mg (0.43 mmol) N-[(3S)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzofuran-2-karboksamida (primjer 31A) i 35 mg (0.04 mmola) PdCl2(dppf) u 4 mL DMF doda se 107 mg (0.52 mmola) 4-morfolinofenilborne kiseline i 1.72 mL 1 N natrijeve lužine. Reakcijska smjesa zagrijava se preko noći na 95 °C. Sirovi produkt se filtrira na silikagelu, ispere s DMF, te se otapalo odstrani pod sniženim tlakom. Da bi se odvojio posljednji ostatak katalizatora, još se jednom filtrira na silikagelu i ispere diklormetanom i metanolom. Pročišćavanje sirovog produkta se provede preparativnom HPLC. Produkt se otopi u metanolu i pretvori sa suviškom 1 N solne kiseline. Nakon uklanjanja otapala pod sniženim tlakom i sušenja u visokom vakuumu dobije se 84 mg (42 % od teor.) naslovnog spoja. Mixtures of 150 mg (0.43 mmol) of N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide (Example 31A) and 35 mg (0.04 mmol) of PdCl2(dppf) in 4 mL of DMF, 107 mg (0.52 mmol) of 4-morpholinophenylboronic acid and 1.72 mL of 1 N sodium hydroxide solution were added. The reaction mixture is heated to 95 °C overnight. The crude product is filtered on silica gel, washed with DMF, and the solvent is removed under reduced pressure. To separate the last residue of the catalyst, it is once again filtered on silica gel and washed with dichloromethane and methanol. Purification of the crude product is carried out by preparative HPLC. The product is dissolved in methanol and converted with an excess of 1 N hydrochloric acid. After removing the solvent under reduced pressure and drying in high vacuum, 84 mg (42% of theory) of the title compound are obtained.

1H-NMR (300 MHz, DMSO-d6): δ = 10.48 (br. s, 1H), 9.05 (d, 1H), 7.90-7.82 (m, 3H), 7.70 (d, 1H), 7.63 (d, 1H), 7.42-7.35 (m, 1H), 7.20-7.12 (m, 2H), 4.40-4.31 (m, 1H), 3.84-3.77 (m, 4H), 3.69-3.57 (m, 1H), 3.48-3.12 (m, 9H), 2.22 (m, 1H), 2.28-2.20 (m, 1H), 2.19-2.08 (m, 1H), 1.96-1.85 (m, 2H), 1.80-1.71 (m, 1H). 1H-NMR (300 MHz, DMSO-d6): δ = 10.48 (no. s, 1H), 9.05 (d, 1H), 7.90-7.82 (m, 3H), 7.70 (d, 1H), 7.63 (d, 1H), 7.42-7.35 (m, 1H), 7.20-7.12 (m, 2H), 4.40-4.31 (m, 1H), 3.84-3.77 (m, 4H), 3.69-3.57 (m, 1H), 3.48- 3.12 (m, 9H), 2.22 (m, 1H), 2.28-2.20 (m, 1H), 2.19-2.08 (m, 1H), 1.96-1.85 (m, 2H), 1.80-1.71 (m, 1H).

HPLC (metoda 1): Rt = 3.82 min. HPLC (method 1): Rt = 3.82 min.

MS (ESIpos): m/z = 432 (M+H)+. MS (ESIpos): m/z = 432 (M+H) + .

Primjer 122 Example 122

N-[(3S)-1-azabiciklo[2.2.2]okt-3-il]-7-[2-(hidroksimetil)fenil]-1-benzofuran-2-karboksamid N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-[2-(hydroxymethyl)phenyl]-1-benzofuran-2-carboxamide

[image] [image]

Smjesi od 150 mg (0.43 mmol) N-[(3S)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzofuran-2-karboksamida (primjer 31A) i 35 mg (0.04 mmola) PdCl2(dppf) u 3 mL DMF doda se 78 mg (0.52 mmola) 2-(hidroksimetil)fenilboronske kiseline i 1.72 mL 1 N natrijeve lužine. Reakcijska smjesa zagrijava se preko noći na 95 °C. Sirovi produkt se filtrira na silikagelu, ispere s DMF, te se otapalo odstrani pod sniženim tlakom. Da bi se odvojio posljednji ostatak katalizatora, još se jednom filtrira na silikagelu i ispere diklormetanom i metanolom. Pročišćavanje sirovog produkta se provede preparativnom HPLC. Produkt se otopi u metanolu i pretvori sa suviškom 1 N solne kiseline. Nakon uklanjanja otapala pod sniženim tlakom i sušenja u visokom vakuumu dobije se 81 mg (46 % od teor.) naslovnog spoja. Mixtures of 150 mg (0.43 mmol) of N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide (Example 31A) and 35 mg (0.04 mmol) of PdCl2(dppf) in 3 mL of DMF, 78 mg (0.52 mmol) of 2-(hydroxymethyl)phenylboronic acid and 1.72 mL of 1 N sodium hydroxide solution are added. The reaction mixture is heated to 95 °C overnight. The crude product is filtered on silica gel, washed with DMF, and the solvent is removed under reduced pressure. To separate the last residue of the catalyst, it is once again filtered on silica gel and washed with dichloromethane and methanol. Purification of the crude product is carried out by preparative HPLC. The product is dissolved in methanol and converted with an excess of 1 N hydrochloric acid. After removing the solvent under reduced pressure and drying in high vacuum, 81 mg (46% of theory) of the title compound are obtained.

1H-NMR (300 MHz, DMSO-d6): δ = 10.12 (br. s, 1H), 8.94 (d, 1H), 7.91-7.79 (m, 3H), 7.69 (d, 1H), 7.53-7.32 (m, 5H), 4.33-4.22 (m, 3H), 3.68-3.57 (m, 1H), 3.48-3.12 (m, 5H), 2.19 (m, 1H), 2.15-2.04 (m, 1H), 1.94-1.83 (m, 2H), 1.79-1.67 (m, 1H). 1H-NMR (300 MHz, DMSO-d6): δ = 10.12 (no. s, 1H), 8.94 (d, 1H), 7.91-7.79 (m, 3H), 7.69 (d, 1H), 7.53-7.32 ( m, 5H), 4.33-4.22 (m, 3H), 3.68-3.57 (m, 1H), 3.48-3.12 (m, 5H), 2.19 (m, 1H), 2.15-2.04 (m, 1H), 1.94- 1.83 (m, 2H), 1.79-1.67 (m, 1H).

HPLC (metoda 1): Rt = 3.87 min. HPLC (method 1): Rt = 3.87 min.

MS (ESIpos): m/z = 377 (M+H)+. MS (ESIpos): m/z = 377 (M+H) + .

Primjer 123 Example 123

N-[(3S)-1-azabiciklo[2.2.2]okt-3-il]-7-(3-piridinil)-1-benzofuran-2-karboksamid-hidro klorid N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-(3-pyridinyl)-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Smjesi od 150 mg (0.43 mmola) N-[(3S)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzofuran-2-karboksamida (primjer 31A) i 35 mg (0.04 mmola) PdCl2(dppf) u 4 mL DMF doda se 63 mg (0.57 mmola) 3-piridinborne kiseline i 1.72 mL 1 N natrijeve lužine. Reakcijska smjesa zagrijava se preko noći na 95 °C. Otapalo se odstrani pod sniženim tlakom, te se sirovi produkt preuzme u metanol i filtrira na silikagelu. Da bi se odvojio posljednji ostatak katalizatora, još se jednom filtrira na silikagelu i ispere diklormetanom i metanolom. Pročišćavanje se provede preparativnom HPLC. Produkt se otopi u metanolu i pretvori sa suviškom 1 N solne kiseline. Otapalo se ukloni pod sniženim tlakom. Nakon sušenja u visokom vakuumu dobije se 76 mg (42 % od teor.) naslovnog spoja. Mixtures of 150 mg (0.43 mmol) of N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide (Example 31A) and 35 mg (0.04 mmol) of PdCl2(dppf) in 4 mL of DMF, 63 mg (0.57 mmol) of 3-pyridineboric acid and 1.72 mL of 1 N sodium hydroxide solution were added. The reaction mixture is heated to 95 °C overnight. The solvent is removed under reduced pressure, and the crude product is taken up in methanol and filtered on silica gel. To separate the last residue of the catalyst, it is once again filtered on silica gel and washed with dichloromethane and methanol. Purification is performed by preparative HPLC. The product is dissolved in methanol and converted with an excess of 1 N hydrochloric acid. The solvent was removed under reduced pressure. After drying in a high vacuum, 76 mg (42% of theory) of the title compound are obtained.

1H-NMR (300 MHz, DMSO-d6): δ = 10.49 (s, 1H), 9.51 (s, 1H), 9.30 (d, 1H), 8.94-8.80 (m, 2H), 8.07-7.80 (m, 4H), 7.55 (t, 1H), 4.35 (m, 1H), 3.65-3.15 (m, 6H), 2.20 (m, 1H), 2.18-2.05 (m, 1H), 1.98-1.88 (m, 2H), 1.80-1.63 (m, 1H). HPLC (metoda 1): Rt = 3.30 min. 1H-NMR (300 MHz, DMSO-d6): δ = 10.49 (s, 1H), 9.51 (s, 1H), 9.30 (d, 1H), 8.94-8.80 (m, 2H), 8.07-7.80 (m, 4H), 7.55 (t, 1H), 4.35 (m, 1H), 3.65-3.15 (m, 6H), 2.20 (m, 1H), 2.18-2.05 (m, 1H), 1.98-1.88 (m, 2H) , 1.80-1.63 (m, 1H). HPLC (method 1): Rt = 3.30 min.

Primjer 124 Example 124

N-[(3S)-1-azabiciklo[2.2.2]okt-3-il]-7-[4-(metoksi)fenil]-1-benzofuran-2-karboksamid-hidroklorid N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-[4-(methoxy)phenyl]-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Smjesi od 150 mg (0.43 mmola) N-[(3S)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzofuran-2-karboksamida (primjer 31A) i 35 mg (0.04 mmola) PdCl2(dppf) u 4 mL DMF doda se 78 mg (0.52 mmola) 4-(metoksi)fenilboronske kiseline i 1.72 mL 1 N natrijeve lužine. Reakcijska smjesa zagrijava se preko noći na 95 °C. Otapalo se odstrani pod sniženim tlakom, te se sirovi produkt preuzme u metanolu i filtrira na silikagelu. Da bi se odvojio posljednji ostatak katalizatora, još se jednom filtrira na silikagelu i ispere diklormetanom i metanolom. Pročišćavanje se provede preparativnom HPLC. Frakcije produkta pretvore se sa suviškom 1 N solne kiseline. Otapalo se ukloni pod sniženim tlakom. Nakon sušenja u visokom vakuumu dobije se 27 mg (15 % od teor.) naslovnog spoja. Mixtures of 150 mg (0.43 mmol) of N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide (Example 31A) and 35 mg (0.04 mmol) of PdCl2(dppf) in 4 mL of DMF, 78 mg (0.52 mmol) of 4-(methoxy)phenylboronic acid and 1.72 mL of 1 N sodium hydroxide solution were added. The reaction mixture is heated to 95 °C overnight. The solvent is removed under reduced pressure, and the crude product is taken up in methanol and filtered on silica gel. To separate the last residue of the catalyst, it is once again filtered on silica gel and washed with dichloromethane and methanol. Purification is performed by preparative HPLC. Product fractions are converted with an excess of 1 N hydrochloric acid. The solvent was removed under reduced pressure. After drying in a high vacuum, 27 mg (15% of theory) of the title compound are obtained.

Analitički podatci odgovaraju onima enantiomernog spoja (primjer 99). Analytical data correspond to those of the enantiomeric compound (example 99).

Primjer 125 Example 125

N-[(3S)-1-azabiciklo[2.2.2]okt-3-il]-7-[3-(metoksi)fenil]-1-benzofuran-2-karboksamid-hidro klorid N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-[3-(methoxy)phenyl]-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Smjesi od 150 mg (0.43 mmola) N-[(3S)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzofuran-2-karboksamida (primjer 31A) i 35 mg (0.04 mmola) PdCl2(dppf) u 3 mL DMF doda se 78 mg (0.52 mmola) 3-(metoksi)fenilborne kiseline i 1.72 mL 1 N natrijeve lužine. Reakcijska smjesa zagrijava se preko noći na 95 °C. Otapalo se odstrani pod sniženim tlakom, te se sirovi produkt preuzme u metanolu i filtrira na silikagelu. Da bi se odvojio posljednji ostatak katalizatora, još se jednom filtrira na silikagelu i ispere diklormetanom i metanolom. Pročišćavanje se provede preparativnom HPLC. Frakcije produkta pretvore se sa suviškom 1 N solne kiseline. Otapalo se ukloni pod sniženim tlakom. Nakon sušenja u visokom vakuumu dobije se 23 mg (13 % od teor.) naslovnog spoja. Mixtures of 150 mg (0.43 mmol) of N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide (Example 31A) and 35 mg (0.04 mmol) of PdCl2(dppf) in 3 mL of DMF was added to 78 mg (0.52 mmol) of 3-(methoxy)phenylboronic acid and 1.72 mL of 1 N sodium hydroxide solution. The reaction mixture is heated to 95 °C overnight. The solvent is removed under reduced pressure, and the crude product is taken up in methanol and filtered on silica gel. To separate the last residue of the catalyst, it is once again filtered on silica gel and washed with dichloromethane and methanol. Purification is performed by preparative HPLC. Product fractions are converted with an excess of 1 N hydrochloric acid. The solvent was removed under reduced pressure. After drying in a high vacuum, 23 mg (13% of theory) of the title compound is obtained.

Analitički podatci odgovaraju onima enantiomernog spoja (primjer 101). Analytical data correspond to those of the enantiomeric compound (example 101).

Primjer 126 Example 126

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[2-({[(l-metiletil)amino]-karbonil}amino)fenil]-1-benzofuran-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[2-({[(1-methylethyl)amino]-carbonyl}amino)phenyl]-1-benzofuran-2 -carboxamide hydrochloride

[image] [image]

Zagrijava se 75 mg (0.16 mmola) 7-(2-aminofenil)-N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-1-benzofuran-2-karboksamida (primjer 132), 65 μL (0.66 mmola) izopropilizocijanata i 114 μL (0.82 mmola) trietilamina 48 h na 50 °C u 3 mL THF/DMF (1:1). Nakon hlađenja smjesa se pretvori vodom i filtrira, te se otapalo ukloni pod sniženim tlakom. Pročišćavanje se provede preparativnom HPLC. Produkt se otopi u metanolu i pretvori sa suviškom 1 N solne kiseline. Otapalo se ukloni pod sniženim tlakom. Nakon sušenja u visokom vakuumu dobije se 21 mg (26 % od teor.) naslovnog spoja. Heat 75 mg (0.16 mmol) of 7-(2-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide (example 132), 65 μL (0.66 mmol) isopropylisocyanate and 114 μL (0.82 mmol) triethylamine for 48 h at 50 °C in 3 mL THF/DMF (1:1). After cooling, the mixture is diluted with water and filtered, and the solvent is removed under reduced pressure. Purification is performed by preparative HPLC. The product is dissolved in methanol and converted with an excess of 1 N hydrochloric acid. The solvent was removed under reduced pressure. After drying in high vacuum, 21 mg (26% of theory) of the title compound is obtained.

1H-NMR (300 MHz, DMSO-d6): δ = 10.09 (br. s, 1H), 8.60 (d, 1H), 7.95 (s, 1H), 7.88-7.77 (m, 3H), 7.46-7.33 (m, 3H), 7.29 (dd, 1H), 7.19-7.10 (m, 1H), 6.22 (br. s, 1H), 4.29 (m, 1H), 3.75-3.54 (m, 2H), 3.39-3.13 (m, 5H), 2.22 (m, 1H), 2.15-2.02 (m, 1H), 1.96-1.86 (m, 2H), 1.80-1.69 (m, 1H), 0.96 (d, 6H). 1H-NMR (300 MHz, DMSO-d6): δ = 10.09 (no. s, 1H), 8.60 (d, 1H), 7.95 (s, 1H), 7.88-7.77 (m, 3H), 7.46-7.33 ( m, 3H), 7.29 (dd, 1H), 7.19-7.10 (m, 1H), 6.22 (no. s, 1H), 4.29 (m, 1H), 3.75-3.54 (m, 2H), 3.39-3.13 ( m, 5H), 2.22 (m, 1H), 2.15-2.02 (m, 1H), 1.96-1.86 (m, 2H), 1.80-1.69 (m, 1H), 0.96 (d, 6H).

HPLC (metoda 1): Rt = 3.92 min. HPLC (method 1): Rt = 3.92 min.

Primjer 127 Example 127

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-(2-{[(etilamino)karbonil]-amino}fenil)-1-benzofuran-2-karboksamid-hidro klorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-(2-{[(ethylamino)carbonyl]-amino}phenyl)-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Zagrijava se 75 mg (0.16 mmola) 7-(2-aminofenil)-N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-1-benzofuran-2-karboksamida (primjer 132), 50 μL (0.66 mmola) etilizocijanata i 110 μL (0.82 mmola) trietilamina zajedno s katalitičkom količinom DMAP kroz 48 h na 50 °C u 3 mL THF/DMF (1:1). Nakon hlađenja smjesa se pretvori vodom i filtrira, te se otapalo ukloni pod sniženim tlakom. Pročišćavanje se provede preparativnom HPLC. Produkt se otopi u metanolu i pretvori sa suviškom 1 N solne kiseline. Otapalo se ukloni pod sniženim tlakom. Nakon sušenja u visokom vakuumu dobije se 10 mg (12 % od teor.) naslovnog spoja. Heat 75 mg (0.16 mmol) of 7-(2-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide (example 132), 50 μL (0.66 mmol) ethyl isocyanate and 110 μL (0.82 mmol) triethylamine together with a catalytic amount of DMAP for 48 h at 50 °C in 3 mL THF/DMF (1:1). After cooling, the mixture is diluted with water and filtered, and the solvent is removed under reduced pressure. Purification is performed by preparative HPLC. The product is dissolved in methanol and converted with an excess of 1 N hydrochloric acid. The solvent was removed under reduced pressure. After drying in a high vacuum, 10 mg (12% of theory) of the title compound is obtained.

1H-NMR (300 MHz, DMSO-d6): δ = 10.41 (br. s, 1H), 9.30 (d, 1H), 8.69 (d, 1H), 7.96-7.78 (m, 3H), 7.59-7.11 (m, 4H), 4.30 (m, 1H), 3.69-3.54 (m, 1H), 3.40-3.13 (m, 5H), 2.99 (q, 2H), 2.24-2.19 (m, 1H), 2.17-2.04 (m, 1H), 1.96-1.84 (m, 2H), 1.80-1.64 (m, 1H), 0.92 (t, 3H). 1H-NMR (300 MHz, DMSO-d6): δ = 10.41 (no. s, 1H), 9.30 (d, 1H), 8.69 (d, 1H), 7.96-7.78 (m, 3H), 7.59-7.11 ( m, 4H), 4.30 (m, 1H), 3.69-3.54 (m, 1H), 3.40-3.13 (m, 5H), 2.99 (q, 2H), 2.24-2.19 (m, 1H), 2.17-2.04 ( m, 1H), 1.96-1.84 (m, 2H), 1.80-1.64 (m, 1H), 0.92 (t, 3H).

HPLC (metoda 1): Rt = 3.86 min. HPLC (method 1): Rt = 3.86 min.

MS (ESIpos): m/z = 433 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 433 (M+H)+ (free base).

Primjer 128 Example 128

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-(2-{[(metilamino)karbonil]-amino}fenil)-1-benzofuran-2-karboksamid-hidro klorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-(2-{[(methylamino)carbonyl]-amino}phenyl)-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Zagrijava se 75 mg (0.16 mmola) 7-(2-aminofenil)-N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-1-benzofuran-2-karboksamida (primjer 132), 37 mg (0.66 mmola) metilizocijanata i 110 μL (0.82 mmola) trietilamina zajedno s katalitičkom količinom DMAP preko noći na 50 °C u 3 mL THF/DMF (1:1). Nakon hlađenja smjesa se pretvori vodom i filtrira, te se otapalo ukloni pod sniženim tlakom. Pročišćavanje se provede preparativnom HPLC. Produkt se otopi u metanolu i pretvori sa suviškom 1 N solne kiseline. Otapalo se ukloni pod sniženim tlakom. Nakon sušenja u visokom vakuumu dobije se 29 mg (35 % od teor.) naslovnog spoja. Heat 75 mg (0.16 mmol) of 7-(2-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide (example 132), 37 mg (0.66 mmol) methylisocyanate and 110 μL (0.82 mmol) triethylamine together with a catalytic amount of DMAP overnight at 50 °C in 3 mL THF/DMF (1:1). After cooling, the mixture is diluted with water and filtered, and the solvent is removed under reduced pressure. Purification is performed by preparative HPLC. The product is dissolved in methanol and converted with an excess of 1 N hydrochloric acid. The solvent was removed under reduced pressure. After drying in high vacuum, 29 mg (35% of theory) of the title compound are obtained.

1H-NMR (300 MHz, DMSO-d6): δ = 10.22 (br. s, 1H), 8.60 (d, 1H), 8.69 (d, 1H), 7.86-7.74 (m, 3H), 7.51-7.28 (m, 5H), 7.18-7.11 (m, 1H), 6.21 (br. s, 1H), 4.29 (m, 1H), 3.69-3.58 (m, 1H), 3.38-3.13 (m, 5H), 2.51 (s, 3H), 2.28-2.22 (m, 1H), 2.18-2.04 (m, 1H), 1.99-1.87 (m, 2H), 1.82-1.68 (m, 1H). 1H-NMR (300 MHz, DMSO-d6): δ = 10.22 (no. s, 1H), 8.60 (d, 1H), 8.69 (d, 1H), 7.86-7.74 (m, 3H), 7.51-7.28 ( m, 5H), 7.18-7.11 (m, 1H), 6.21 (No. s, 1H), 4.29 (m, 1H), 3.69-3.58 (m, 1H), 3.38-3.13 (m, 5H), 2.51 ( s, 3H), 2.28-2.22 (m, 1H), 2.18-2.04 (m, 1H), 1.99-1.87 (m, 2H), 1.82-1.68 (m, 1H).

HPLC (metoda 1): Rt = 3.72 min. HPLC (method 1): Rt = 3.72 min.

Primjer 129 Example 129

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[2-({[(l,l-dimetiletil)amino]-karbonil}amino)fenil]-1-benzofuran-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[2-({[(1,1-dimethylethyl)amino]-carbonyl}amino)phenyl]-1-benzofuran -2-carboxamide hydrochloride

[image] [image]

Zagrijava se 75 mg (0.16 mmola) 7-(2-aminofenil)-N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-1-benzofuran-2-karboksamida (primjer 132), 65 mg (0.66 mmola) (1,1-dimetiletil)izocijanata i 110 μL (0.82 mmola) trietilamina zajedno s katalitičkom količinom DMAP preko noći na 50 °C u 3 mLTHF/DMF (1:1). Nakon hlađenja smjesa se pretvori vodom i filtrira, te se otapalo ukloni pod sniženim tlakom. Pročišćavanje se provede preparativnom HPLC. Produkt se otopi u metanolu i pretvori sa suviškom 1 N solne kiseline. Otapalo se ukloni pod sniženim tlakom. Nakon sušenja u visokom vakuumu dobije se 10 mg (12 % od teor.) naslovnog spoja. Heat 75 mg (0.16 mmol) of 7-(2-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide (example 132), 65 mg (0.66 mmol) of (1,1-dimethylethyl)isocyanate and 110 μL (0.82 mmol) of triethylamine together with a catalytic amount of DMAP overnight at 50 °C in 3 mLTHF/DMF (1:1). After cooling, the mixture is diluted with water and filtered, and the solvent is removed under reduced pressure. Purification is performed by preparative HPLC. The product is dissolved in methanol and converted with an excess of 1 N hydrochloric acid. The solvent was removed under reduced pressure. After drying in a high vacuum, 10 mg (12% of theory) of the title compound is obtained.

HPLC (metoda 1): Rt = 4.06 min. MS (ESIpos): m/z = 461 (M + H)+ (slobodna baza). HPLC (method 1): Rt = 4.06 min. MS (ESIpos): m/z = 461 (M + H)+ (free base).

Primjer 130 Example 130

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[2-(metoksi)fenil]-1-benzofuran-2-karboksamid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[2-(methoxy)phenyl]-1-benzofuran-2-carboxamide

[image] [image]

Otopi se 600 mg (1.45 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[2-(metoksi)fenil]-1-benzofuran-2-karboksamid-hidroklorida (primjer 102) u 15 mL etilnog estera octene kiseline i ekstrahira triput sa 1 N natrijevom lužinom. Organska faza se osuši iznad natrijevog sulfata i odmah potom zgusne. Nakon sušenja u visokom vakuumu dobije se 534 mg (97.6 % od teor.) naslovnog spoja. Dissolve 600 mg (1.45 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[2-(methoxy)phenyl]-1-benzofuran-2-carboxamide hydrochloride (example 102) in 15 mL of ethyl acetate and extracted three times with 1 N sodium hydroxide solution. The organic phase is dried over sodium sulfate and immediately concentrated. After drying in high vacuum, 534 mg (97.6% of theory) of the title compound is obtained.

1H -NMR (200 MHz, DMSO-d6): δ = 8.34 (d, 1H), 7.72 (dd, 1H), 7.70 (s, 1H), 7.50-7.30 (m, 4H), 7.20 (m, 1H), 7.08 (m, 1H), 3.93 (m, 1H), 3.76 (s, 3H), 3.11 (m, 1H), 2.86 (m, 1H), 2.69 (m, 4H), 1.86 (m, 1H), 1.75 (m, 1H), 1.58 (m, 2H), 1.32 (m, 1H). 1H-NMR (200 MHz, DMSO-d6): δ = 8.34 (d, 1H), 7.72 (dd, 1H), 7.70 (s, 1H), 7.50-7.30 (m, 4H), 7.20 (m, 1H) , 7.08 (m, 1H), 3.93 (m, 1H), 3.76 (s, 3H), 3.11 (m, 1H), 2.86 (m, 1H), 2.69 (m, 4H), 1.86 (m, 1H), 1.75 (m, 1H), 1.58 (m, 2H), 1.32 (m, 1H).

HPLC (metoda 1): Rt = 4.1 min. HPLC (method 1): Rt = 4.1 min.

MS (ESIpos): m/z = 377 (M+H)+. MS (ESIpos): m/z = 377 (M+H) + .

Primjer 131 Example 131

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[2-(hidroksimetil)fenil]-1-benzotiofen-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[2-(hydroxymethyl)phenyl]-1-benzothiophene-2-carboxamide hydrochloride

[image] [image]

Stavi se 200 mg (0.45 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzotiofen-2-karboksamid-hidroklorida (primjer 8A) i 67.9 mg (0.45 mmola) 2-(hidroksimetil)fenilborne kiseline u 2 ml DMF. Nakon dodavanja 0.67 mL 2 M otopine natrijevog karbonata i 18.2 mg (0.02 mmola) PdCl2(dppf) smjesa se zagrijava na 80 °C. Nakon 18 h reakcijska smjesa filtrira se na silikagelu i pročisti odvajanjem preparativnom HPLC. Frakcije produkta se zgusnu, pretvore smjesom 5:1 metanola i 4 N klorovodika u dioksanu i ponovno zgusnu. Nakon sušenja u visokom vakuumu dobije se 148 mg (72 % od teor.) naslovnog spoja. 200 mg (0.45 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A) and 67.9 mg (0.45 mmol) of 2-(hydroxymethyl)phenylboronic acid in 2 ml of DMF. After adding 0.67 mL of 2 M sodium carbonate solution and 18.2 mg (0.02 mmol) of PdCl2(dppf), the mixture is heated to 80 °C. After 18 h, the reaction mixture is filtered on silica gel and purified by preparative HPLC separation. The product fractions were concentrated, reconstituted with a mixture of 5:1 methanol and 4 N hydrogen chloride in dioxane and concentrated again. After drying in high vacuum, 148 mg (72% of theory) of the title compound are obtained.

1H-NMR (300 MHz, DMSO-d6): δ = 10.30 (br. s, 1H), 9.10 (d, 1H), 8.47 (s, 1H), 8.07 (d, 1H), 7.78 (d, 1H), 7.68-7.54 (m, 2H), 7.52-7.39 (m, 3H), 4.40 (m, 1H), 4.36 (s, 2H), 3.72 (m, 1H), 3.53-3.20 (m, 5H), 2.29 (m, 1H), 2.21 (m, 1H), 2.00 (m, 2H), 1.82 (m, 1H). 1H-NMR (300 MHz, DMSO-d6): δ = 10.30 (no. s, 1H), 9.10 (d, 1H), 8.47 (s, 1H), 8.07 (d, 1H), 7.78 (d, 1H) , 7.68-7.54 (m, 2H), 7.52-7.39 (m, 3H), 4.40 (m, 1H), 4.36 (s, 2H), 3.72 (m, 1H), 3.53-3.20 (m, 5H), 2.29 (m, 1H), 2.21 (m, 1H), 2.00 (m, 2H), 1.82 (m, 1H).

HPLC (metoda 1): Rt = 3.9 min. HPLC (method 1): Rt = 3.9 min.

MS (ESIpos): m/z = 393 (M + H)+ (slobodna baza). MS (ESIpos): m/z = 393 (M + H)+ (free base).

Primjer 132 Example 132

7-(2-aminofenil)-N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-1-benzofuran-2-karboksamid 7-(2-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide

[image] [image]

Smjesi od 1.0 g (2.86 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzofuran-2-karboksamida (primjer 30A) i 234 mg (0.29 mmola) PdCl2(dppf) u 15 mL DMF doda se 752 mg (3.44 mmola) 2-(4,4,5,5-tetrametil-l,3,2-dioksaborolan-2-il)fenilamina i 11.45 mL 1 N natrijeve lužine. Reakcijska smjesa zagrijava se preko noći na 95 °C i potom filtrira na silikagelu. Odmah zatim otapalo se odstrani pod sniženim tlakom, te se ostatak preuzme u 100 mL etilnog estera octene kiseline i 100 mL 1 N natrijeve lužine. Organska faza ispere se dvaput sa 1 N natrijevom lužine i jednom zasićenom otopinom natrijevog klorida. Spojene organske faze osuše se iznad magnezijevog sulfata, te se otapalo odvoji filtracijom pod sniženim tlakom na rotacijskom isparivaču. Sirovi produkt se preuzme u metanol i trese zajedno s kiselim ionskim izmjenjivačem (Dowex® WX2-200) 30-ak minuta. Opterećeni ionski izmjenjivač ispere se prvo tri puta s po 30 mL metanola, potom DMF. Potom se ispere metanolom, diklormetanom, metanolom, vodom, metanolom, diklormetanom, metanolom, THF, te na kraju još jednom metanolom. Produkt se eluira metanol-trietilaminom 95:5. Otapalo se odstrani pod sniženim tlakom na rotacijskom isparivaču. Nakon sušenja u visokom vakuumu dobije se 601 mg (48 % od teor.) naslovnog spoja čistoće dovoljne za daljnju uporabu. Mixtures of 1.0 g (2.86 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide (Example 30A) and 234 mg (0.29 mmol) of PdCl2(dppf) in 15 mL of DMF, 752 mg (3.44 mmol) of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine and 11.45 mL of 1 N sodium alkalis. The reaction mixture is heated overnight at 95 °C and then filtered on silica gel. Immediately afterwards, the solvent was removed under reduced pressure, and the residue was taken up in 100 mL of acetic acid ethyl ester and 100 mL of 1 N sodium hydroxide solution. The organic phase is washed twice with 1 N sodium hydroxide solution and once with saturated sodium chloride solution. The combined organic phases are dried over magnesium sulfate, and the solvent is separated by filtration under reduced pressure on a rotary evaporator. The crude product is taken up in methanol and shaken together with an acidic ion exchanger (Dowex® WX2-200) for about 30 minutes. The charged ion exchanger is washed first three times with 30 mL of methanol each, then with DMF. It is then washed with methanol, dichloromethane, methanol, water, methanol, dichloromethane, methanol, THF, and finally with methanol again. The product is eluted with methanol-triethylamine 95:5. The solvent was removed under reduced pressure on a rotary evaporator. After drying in a high vacuum, 601 mg (48% of theory) of the title compound of sufficient purity for further use are obtained.

HPLC (metoda 1): Rt = 3.51 min. HPLC (method 1): Rt = 3.51 min.

MS (ESIpos): m/z = 362 (M + H)+. MS (ESIpos): m/z = 362 (M + H) + .

Primjer 133 Example 133

N-[(3S)-1-azabiciklo[2.2.2]okt-3-il]-7-[4-(4morfolinilkarbonil)fenil]-1-benzotiofen-2-karboksamid-hidroklorid N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-[4-(4morpholinylcarbonyl)phenyl]-1-benzothiophene-2-carboxamide hydrochloride

[image] [image]

Prema općenitom radnom propisu D stavi se 244.0 mg (0.65 mmola) 4-(4-morfolinilkarbonil)fenil-trifluormetansulfonata (primjer 18A), 189.6 mg (0.75 mmola) bis(pinakolato)dibora, 158.8 mg (1.62 mmola) kalijevog acetata, 18.2 mg (0.02 mmola) PdCl2(dppf), 200.0 mg (0.50 mmola) N-[(3S)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzotiofen-2-karboksamid-hidroklorida (primjer 22A), 1.24 mL 2 M otopine natrijevog karbonata, te još 18.2 mg (0.02 mmola) PdCl2(dppf) u 2.5 mL DMF. Nakon sušenja u visokom vakuumu dobije se 76.8 mg (30.1 % od teor.) naslovnog spoja. Spektroskopski podatci odgovaraju onima enantiomernog spoja (primjer 72). According to the general procedure D, 244.0 mg (0.65 mmol) of 4-(4-morpholinylcarbonyl)phenyl-trifluoromethanesulfonate (example 18A), 189.6 mg (0.75 mmol) of bis(pinacolato)diboron, 158.8 mg (1.62 mmol) of potassium acetate, 18.2 mg (0.02 mmol) PdCl2(dppf), 200.0 mg (0.50 mmol) N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide- hydrochloride (example 22A), 1.24 mL of 2 M sodium carbonate solution, and another 18.2 mg (0.02 mmol) of PdCl2(dppf) in 2.5 mL of DMF. After drying in high vacuum, 76.8 mg (30.1 % of theory) of the title compound is obtained. The spectroscopic data correspond to those of the enantiomeric compound (Example 72).

Primjer 134 Example 134

N-[(3S)-1-azabiciklo[2.2.2]okt-3-il]-7-[3-(4-morfolinil)fenil]-1-benzotiofen-2-karboksamid-hidro klorid N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-[3-(4-morpholinyl)phenyl]-1-benzothiophene-2-carboxamide hydrochloride

[image] [image]

Prema općenitom radnom propisu D stavi se 143.3 mg (0.49 mmola) 3-(4-morfolinil)fenil-trifluormetansulfonata (primjer 17A), 142.2 mg (0.56 mmola) bis(pinakolato)dibora, 119.1 mg (1.21 mmol) kalijevog acetata, 13.7 mg (0.02 mmola) PdCl2(dppf), 150 mg (0.37 mmola) N-[(3S)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzotiofen-2-karboksamid-hidroklorida (primjer 22A), 0.93 mL 2 M otopine natrijevog karbonata, te još 13.7 mg (0.02 mmola) PdCl2(dppf) u 2.0 mL DMF. Nakon sušenja u visokom vakuumu dobije se 67 mg (37.1 % od teor.) naslovnog spoja. Spektroskopski podatci odgovaraju onima enantiomernog spoja (primjer 70). According to general procedure D, 143.3 mg (0.49 mmol) of 3-(4-morpholinyl)phenyl-trifluoromethanesulfonate (example 17A), 142.2 mg (0.56 mmol) of bis(pinacolato)diboron, 119.1 mg (1.21 mmol) of potassium acetate, 13.7 mg (0.02 mmol) PdCl2(dppf), 150 mg (0.37 mmol) N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide- hydrochloride (example 22A), 0.93 mL of 2 M sodium carbonate solution, and another 13.7 mg (0.02 mmol) of PdCl2(dppf) in 2.0 mL of DMF. After drying in a high vacuum, 67 mg (37.1 % of theory) of the title compound is obtained. The spectroscopic data correspond to those of the enantiomeric compound (Example 70).

Primjer 135 Example 135

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-{3-[(ciklopropilamino)-karbonil]fenil}-1-benzotiofen-2-karboksamid-hidro klorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-{3-[(cyclopropylamino)-carbonyl]phenyl}-1-benzothiophene-2-carboxamide hydrochloride

[image] [image]

Prema općenitom propisu E pomiješa se 50 mg (0.11 mmola) hidroklorida 3-(2-{[(3R)-1-azabiciklo[2.2.2]okt-3-il]karbonil}-1-benzotiofen-1-il)-benzojeve kiseline (primjer 75) i 12.9 mg (0.23 mmola) ciklopropilamina. Dobije se 17.6 mg (31.1 % od teor.) naslovnog spoja. According to general formula E, 50 mg (0.11 mmol) of 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-yl]carbonyl}-1-benzothiophen-1-yl)-hydrochloride are mixed of benzoic acid (example 75) and 12.9 mg (0.23 mmol) of cyclopropylamine. 17.6 mg (31.1 % of theory) of the title compound is obtained.

1H-NMR (400 MHz, metanol-d4): 5 = 8.18 (s, 1H), 8.15 (s, 1H), 7.93 (d, 1H), 7.88 (m, 2H), 7.62 (dd, 1H), 7.56 (m, 2H), 4.45 (m, 1H), 3.84 (m, 1H), 3.48 (m, 1H), 3.42-3.27 (m, 4H), 2.89 (m, 1H), 2.38 (m, 1H), 2.28 (m, 1H), 2.10 (m, 2H), 1.96 (m, 1H), 0.82 (m, 2H), 0.67 (m, 2H). 1H-NMR (400 MHz, methanol-d4): δ = 8.18 (s, 1H), 8.15 (s, 1H), 7.93 (d, 1H), 7.88 (m, 2H), 7.62 (dd, 1H), 7.56 (m, 2H), 4.45 (m, 1H), 3.84 (m, 1H), 3.48 (m, 1H), 3.42-3.27 (m, 4H), 2.89 (m, 1H), 2.38 (m, 1H), 2.28 (m, 1H), 2.10 (m, 2H), 1.96 (m, 1H), 0.82 (m, 2H), 0.67 (m, 2H).

HPLC (metoda 1): Rt = 3.95 min. HPLC (method 1): Rt = 3.95 min.

LC-MS (metoda 6): Rt = 3.36 min; m/z = 445 (M+H)+ (slobodna baza). LC-MS (method 6): Rt = 3.36 min; m/z = 445 (M+H)+ (free base).

Primjer 136 Example 136

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-(3-{[etil(metil)amino]-karbonil}fenil)-1-benzotiofen-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-(3-{[ethyl(methyl)amino]-carbonyl}phenyl)-1-benzothiophene-2-carboxamide hydrochloride

[image] [image]

Prema općenitom radnom propisu E pomiješa se 50 mg (0.11 mmola) hidroklorida 3-(2-{[(3R)-1-azabiciklo[2.2.2]okt-3- According to general procedure E, 50 mg (0.11 mmol) of 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-) hydrochloride is mixed

il]karbonil}-1-benzotiofen-1-il)-benzojeve kiseline (primjer 75) i 13.3 mg (0.23 mmola) etilmetilamina. Dobije se 20.1 mg (36.8 % od teor.) naslovnog spoja. yl]carbonyl}-1-benzothiophen-1-yl)-benzoic acid (Example 75) and 13.3 mg (0.23 mmol) of ethylmethylamine. 20.1 mg (36.8% of theory) of the title compound is obtained.

1H-NMR (400 MHz, metanol-d4): δ = 8.19 (s, 1H), 7.95 (d, 1H), 7.82 (d, 1H), 7.73 (m, 1H), 7.64 (dd, 1H), 7.60-7.46 (m, 3H), 4.45 (m, 1H), 3.83 (m, 1H), 3.61 (m, 1H), 3.51-3.28 (m, 6H), 3.10 (m, 3H), 2.39 (m, 1H), 2.28 (m, 1H), 2.10 (m, 2H), 1.96 (m, 1H), 1.23 (m, 3H). 1H-NMR (400 MHz, methanol-d4): δ = 8.19 (s, 1H), 7.95 (d, 1H), 7.82 (d, 1H), 7.73 (m, 1H), 7.64 (dd, 1H), 7.60 -7.46 (m, 3H), 4.45 (m, 1H), 3.83 (m, 1H), 3.61 (m, 1H), 3.51-3.28 (m, 6H), 3.10 (m, 3H), 2.39 (m, 1H ), 2.28 (m, 1H), 2.10 (m, 2H), 1.96 (m, 1H), 1.23 (m, 3H).

HPLC (metoda 1): Rt = 4.00 min. HPLC (method 1): Rt = 4.00 min.

LC-MS (metoda 6): Rt = 3.40 min; m/z = 447 (M+H)+ (slobodna baza). LC-MS (method 6): Rt = 3.40 min; m/z = 447 (M+H)+ (free base).

Primjer 137 Example 137

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[3-(2,5-dihidro-1H-pirol-1-ilkarbonil)fenil]-1-benzotiofen-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[3-(2,5-dihydro-1H-pyrrol-1-ylcarbonyl)phenyl]-1-benzothiophene-2 -carboxamide hydrochloride

[image] [image]

il]karbonil}-1-benzotiofen-1-il)-benzojeve kiseline (primjer 75) i 15.6 mg (0.23 mmola) 3-pirolina. Dobije se 20 mg (35.9 % od teor.) naslovnog spoja. yl]carbonyl}-1-benzothiophen-1-yl)-benzoic acid (Example 75) and 15.6 mg (0.23 mmol) of 3-pyrroline. 20 mg (35.9% of theory) of the title compound is obtained.

HPLC (metoda 1): Rt = 4.00 min. HPLC (method 1): Rt = 4.00 min.

LC-MS (metoda 6): Rt = 3.40 min; m/z = 457 (M+H)+ (slobodna baza). LC-MS (method 6): Rt = 3.40 min; m/z = 457 (M+H)+ (free base).

Primjer 138 Example 138

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-(3-{[(3-metoksipropil)-amino]karbonil}fenil)-1-benzotiofen-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-(3-{[(3-methoxypropyl)-amino]carbonyl}phenyl)-1-benzothiophene-2-carboxamide- hydrochloride

[image] [image]

il]karbonil}-1-benzotiofen-1-il)-benzojeve kiseline (primjer 75) i 20.1 mg (0.23 mmola) 3-metoksipropilamina. Dobije se 29.2 mg (49.8 % od teor.) naslovnog spoja. HPLC (metoda 1): Rt = 3.94 min. yl]carbonyl}-1-benzothiophen-1-yl)-benzoic acid (Example 75) and 20.1 mg (0.23 mmol) of 3-methoxypropylamine. 29.2 mg (49.8% of theory) of the title compound is obtained. HPLC (method 1): Rt = 3.94 min.

LC-MS (metoda 6): Rt = 3.37 min; m/z = 477 (M + H)+ (slobodna baza). LC-MS (method 6): Rt = 3.37 min; m/z = 477 (M + H)+ (free base).

Primjer 139 Example 139

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-(3-{[(2-metoksietil)(metil)-amino]karbonil}fenil)-1-benzotiofen-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-(3-{[(2-methoxyethyl)(methyl)-amino]carbonyl}phenyl)-1-benzothiophene-2 -carboxamide hydrochloride

[image] [image]

Prema općenitom radnom propisu E pomiješa se 50 mg (0.11 mmola) hidroklorida 3-(2-{[(3R)-1-azabiciklo[2.2.2]okt-3-il]karbonil}-1-benzotiofen-1-il)-benzojeve kiseline (primjer 75) i 20.1 mg (0.23 mmola) (2-metoksietil)metilamina. Dobije se 20.5 mg (31.8 % od teor.) naslovnog spoja. According to general procedure E, 50 mg (0.11 mmol) of 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-yl]carbonyl}-1-benzothiophen-1-yl) hydrochloride is mixed -benzoic acid (example 75) and 20.1 mg (0.23 mmol) of (2-methoxyethyl)methylamine. 20.5 mg (31.8% of theory) of the title compound is obtained.

HPLC (metoda 1): Rt = 3.93 min. HPLC (method 1): Rt = 3.93 min.

LC-MS (metoda 6): Rt = 3.35 min; m/z = 477 (M+H)+ (slobodna baza). LC-MS (method 6): Rt = 3.35 min; m/z = 477 (M+H)+ (free base).

Primjer 140 Example 140

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-(3-{[(3-etoksipropil)amino]-karbonil}fenil)-1-benzotiofen-2-karboksamid-hidro klorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-(3-{[(3-ethoxypropyl)amino]-carbonyl}phenyl)-1-benzothiophene-2-carboxamide- hydro chloride

[image] [image]

il]karbonil}-1-benzotiofen-1-il)-benzojeve kiseline (primjer 75) i 20.1 mg (0.23 mmola) 3-etoksipropilamina. Dobije se 23.4 mg (37.1 % od teor.) naslovnog spoja. yl]carbonyl}-1-benzothiophen-1-yl)-benzoic acid (Example 75) and 20.1 mg (0.23 mmol) of 3-ethoxypropylamine. 23.4 mg (37.1% of theory) of the title compound is obtained.

1H-NMR (400 MHz, metanol-d4): δ = 8.18 (s, 1H), 8.15 (s, 1H), 7.94 (d, 1H), 7.89 (m, 2H), 7.64 (dd, 1H), 7.56 (m, 2H), 4.45 (m, 1H), 3.84 (m, 1H), 3.55 (m, 2H), 3.53-3.25 (m, 9H), 2.39 (m, 1H), 2.28 (m, 1H), 2.10 (m, 2H), 1.96 (m, 1H), 1.91 (m, 2H), 1.17 (m, 3H). 1H-NMR (400 MHz, methanol-d4): δ = 8.18 (s, 1H), 8.15 (s, 1H), 7.94 (d, 1H), 7.89 (m, 2H), 7.64 (dd, 1H), 7.56 (m, 2H), 4.45 (m, 1H), 3.84 (m, 1H), 3.55 (m, 2H), 3.53-3.25 (m, 9H), 2.39 (m, 1H), 2.28 (m, 1H), 2.10 (m, 2H), 1.96 (m, 1H), 1.91 (m, 2H), 1.17 (m, 3H).

HPLC (metoda 1): Rt = 4.07 min. HPLC (method 1): Rt = 4.07 min.

LC-MS (metoda 6): Rt = 3.46 min; m/z = 491 (M+H)+ (slobodna baza). LC-MS (method 6): Rt = 3.46 min; m/z = 491 (M+H)+ (free base).

Primjer 141 Example 141

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-{3-[(4-metil-1-piperazinil)-karbonil]fenil}-1-benzotiofen-2-karboksamid-dihidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-{3-[(4-methyl-1-piperazinyl)-carbonyl]phenyl}-1-benzothiophene-2-carboxamide -dihydrochloride

[image] [image]

Prema općenitomm radnom propisu E pomiješa se 50 mg (0.11 mmola) hidroklorida 3-(2-{[(3R)-1-azabiciklo[2.2.2]okt-3-il]karbonil}-1-benzotiofen-1-il)-benzojeve kiseline (primjer 75) i 22.6 mg (0.23 mmola) N-metilpiperazina. Dobije se 4.2 mg (6.6 % od teor.) naslovnog spoja. According to general procedure E, 50 mg (0.11 mmol) of 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-yl]carbonyl}-1-benzothiophen-1-yl) hydrochloride is mixed -benzoic acid (example 75) and 22.6 mg (0.23 mmol) of N-methylpiperazine. 4.2 mg (6.6% of theory) of the title compound is obtained.

1H-NMR (400 MHz, metanol-d4): δ = 8.23 (s, 1H), 7.79 (dd, 1H), 7.88 (m, 2H), 7.69 (m, 1H), 7.57 (m, 3H), 4.46 (m, 1H), 3.84 (m, 1H), 3.50 (m, 1H), 3.46-3.25 (m, 12H), 2.97 (s, 3H), 2.39 (m, 1H), 2.29 (m, 1H), 2.10 (m, 2H), 1.96 (m, 1H). 1H-NMR (400 MHz, methanol-d4): δ = 8.23 (s, 1H), 7.79 (dd, 1H), 7.88 (m, 2H), 7.69 (m, 1H), 7.57 (m, 3H), 4.46 (m, 1H), 3.84 (m, 1H), 3.50 (m, 1H), 3.46-3.25 (m, 12H), 2.97 (s, 3H), 2.39 (m, 1H), 2.29 (m, 1H), 2.10 (m, 2H), 1.96 (m, 1H).

HPLC (metoda 1): Rt = 3.62 min. HPLC (method 1): Rt = 3.62 min.

LC-MS (metoda 6): Rt = 2.94 min; m/z = 488 (M+H)+ (slobodna baza). LC-MS (method 6): Rt = 2.94 min; m/z = 488 (M+H)+ (free base).

Primjer 142 Example 142

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-{3-[(dklobutilkarbonll)-amino]fenil}-1-benzotiofen-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-{3-[(dichlorobutylcarbonyl)-amino]phenyl}-1-benzothiophene-2-carboxamide hydrochloride

[image] [image]

Prema općenitom radnom propisu F pomiješa se 50 mg (0.12 mmola) hidroklorida 7-(3-aminofenil)-N-[(3R)-1-azabiciklo[2.2.2]-okt-3-il]-1-benzotiofen-2-karboksamid-hidroklorida (primjer 21) i 28.6 mg (0.24 mmola) klorida ciklobutankarboksilne kiseline. Dobije se 38 mg (61.3 % teor.) naslovnog spoja. According to general procedure F, 50 mg (0.12 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]-oct-3-yl]-1-benzothiophene-2 hydrochloride are mixed -carboxamide hydrochloride (example 21) and 28.6 mg (0.24 mmol) cyclobutanecarboxylic acid chloride. 38 mg (61.3 % of theory) of the title compound are obtained.

HPLC (metoda 1): Rt = 4.22 min. HPLC (method 1): Rt = 4.22 min.

MS (ESIpos): m/z = 460 (M + H)+ (slobodna baza). MS (ESIpos): m/z = 460 (M + H)+ (free base).

Primjer 143 Example 143

N-[3-(2-{[(3R)-1-azabiciklo[2.2.2]okt-3-ilamino]karbonil}-1-benzotien-7-il)-fenil]-5-izoksazolkarboksamid-hidro klorid N-[3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzothien-7-yl)-phenyl]-5-isoxazolecarboxamide hydrochloride

[image] [image]

Prema općenitom radnom propisu F pomiješa se 50 mg (0.12 mmola) hidroklorida 7-(3-aminofenil)-N-[(3R)-1-azabidklo[2.2.2]-okt-3-il]-1-benzotiofen-2-karboksamid-hidroklorida (primjer 21) i 31.8 mg (0.24 mmola) klorida izoksazol-5-karboksilne kiseline. Dobije se 44.4 mg (72.6 % od teor.) naslovnog spoja. According to general procedure F, 50 mg (0.12 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]-oct-3-yl]-1-benzothiophene-2 hydrochloride are mixed -carboxamide hydrochloride (example 21) and 31.8 mg (0.24 mmol) of isoxazole-5-carboxylic acid chloride. 44.4 mg (72.6% of theory) of the title compound is obtained.

1H-NMR (400 MHz, metanol-d4): δ = 8.58 (d, 1H), 8.18 (s, 2H), 7.93 (dd, 1H), 7.79 (m, 1H), 7.55 (m, 4H), 7.13 (m, 1H), 4.45 (m, 1H), 3.83 (m, 1H), 3.48 (m, 1H), 3.42-3.27 (m, 4H), 2.39 (m, 1H), 2.28 (m, 1H), 2.10 (m, 2H), 1.96 (m, 1H). 1H-NMR (400 MHz, methanol-d4): δ = 8.58 (d, 1H), 8.18 (s, 2H), 7.93 (dd, 1H), 7.79 (m, 1H), 7.55 (m, 4H), 7.13 (m, 1H), 4.45 (m, 1H), 3.83 (m, 1H), 3.48 (m, 1H), 3.42-3.27 (m, 4H), 2.39 (m, 1H), 2.28 (m, 1H), 2.10 (m, 2H), 1.96 (m, 1H).

HPLC (metoda 1): Rt = 4.12 min. HPLC (method 1): Rt = 4.12 min.

MS (ESIpos): m/z = 473 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 473 (M+H)+ (free base).

Primjer 144 Example 144

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-{3-[(ciklopentilkarbonil)-amino]fenil}-1-benzotiofen-2-karboksamid-hidro klorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-{3-[(cyclopentylcarbonyl)-amino]phenyl}-1-benzothiophene-2-carboxamide hydrochloride

[image] [image]

Prema općenitom radnom propisu F pomiješa se 50 mg (0.12 mmola) hidroklorida 7-(3-aminofenil)-N-[(3R)-1-azabiciklo[2.2.2]-okt-3-il]-1-benzotiofen-2-karboksamid-hidroklorida (primjer 21) i 32 mg (0.24 mmola) klorida ciklopentilkarboksilne kiseline. Dobije se 30.5 mg (52.8 % od teor.) naslovnog spoja. According to general procedure F, 50 mg (0.12 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]-oct-3-yl]-1-benzothiophene-2 hydrochloride are mixed -carboxamide hydrochloride (example 21) and 32 mg (0.24 mmol) of cyclopentylcarboxylic acid chloride. 30.5 mg (52.8% of theory) of the title compound is obtained.

1H-NMR (400 MHz, metanol-d4): δ = 8.17 (s, 1H), 8.03 (m, 1H), 7.91 (dd, 1H), 7.60 (m, 1H), 7.57-7.38 (m, 4H), 4.45 (m, 1H), 3.83 (m, 1H), 3.48 (m, 1H), 3.42-3.27 (m, 4H), 2.86 (m, 1H), 2.38 (m, 1H), 2.28 (m, 1H), 2.10 (m, 2H), 1.96 (m, 3H), 1.90-1.72 (m, 4H), 1.66 (m, 2H). 1H-NMR (400 MHz, methanol-d4): δ = 8.17 (s, 1H), 8.03 (m, 1H), 7.91 (dd, 1H), 7.60 (m, 1H), 7.57-7.38 (m, 4H) , 4.45 (m, 1H), 3.83 (m, 1H), 3.48 (m, 1H), 3.42-3.27 (m, 4H), 2.86 (m, 1H), 2.38 (m, 1H), 2.28 (m, 1H ), 2.10 (m, 2H), 1.96 (m, 3H), 1.90-1.72 (m, 4H), 1.66 (m, 2H).

HPLC (metoda 1): Rt = 4.40 min. HPLC (method 1): Rt = 4.40 min.

MS (ESIpos): m/z = 4740 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 4740 (M+H)+ (free base).

Primjer 145 Example 145

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-{3-[(cikloheksilkarbonil)-amino]fenil}-1-benzotiofen-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-{3-[(cyclohexylcarbonyl)-amino]phenyl}-1-benzothiophene-2-carboxamide hydrochloride

[image] [image]

Prema općenitom radnom propisu F pomiješa se 50 mg (0.12 mmola) hidroklorida 7-(3-aminofenil)-N-[(3R)-1-azabiciklo[2.2.2]-okt-3-il]-1-benzotiofen-2-karboksamid-hidroklorida (primjer 21) i 35.4 mg (0.24 mmola) klorida cikloheksilkarboksilne kiseline. Dobije se 9.8 mg (16.2 % od teor.) naslovnog spoja. According to general procedure F, 50 mg (0.12 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]-oct-3-yl]-1-benzothiophene-2 hydrochloride are mixed -carboxamide hydrochloride (example 21) and 35.4 mg (0.24 mmol) cyclohexylcarboxylic acid chloride. 9.8 mg (16.2% of theory) of the title compound is obtained.

HPLC (metoda 1): Rt = 4.51 min. HPLC (method 1): Rt = 4.51 min.

MS (ESIpos): m/z = 488 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 488 (M+H)+ (free base).

Primjer 146 Example 146

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-{3-[(tetrahidro-2-furanil-karbonil)amino]fenil}-1-benzotiofen-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-{3-[(tetrahydro-2-furanyl-carbonyl)amino]phenyl}-1-benzothiophene-2-carboxamide- hydrochloride

[image] [image]

Prema općenitom radnom propisu F pomiješa se 50 mg (0.12 mmola) hidroklorida 7-(3-aminofenil)-N-[(3R)-1-azabiciklo[2.2.2]-okt-3-il]-1-benzotiofen-2-karboksamid-hidroklorida (primjer 21) i 32.5 mg (0.24 mmola) klorida tetrahidrofuran-2-karboksilne kiseline. Dobije se 40.9 mg (68.1 % od teor.) naslovnog spoja. According to general procedure F, 50 mg (0.12 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]-oct-3-yl]-1-benzothiophene-2 hydrochloride are mixed -carboxamide hydrochloride (example 21) and 32.5 mg (0.24 mmol) tetrahydrofuran-2-carboxylic acid chloride. 40.9 mg (68.1% of theory) of the title compound is obtained.

1H-NMR (400 MHz, metanol-d4): δ = 8.17 (s, 1H), 8.04 (s, 1H), 7.91 (d, 1H), 7.61 (m, 1H), 7.58-7.40 (m, 4H), 4.46 (m, 1H), 4.04 (dd, 1H), 3.92 (m, 2H), 3.83 (m, 2H), 3.48 (m, 1H), 3.42-3.27 (m, 4H), 3.23 (m, 1H), 2.38 (m, 1H), 2.28 (m, 1H), 2.22 (m, 2H), 2.10 (m, 2H), 1.96 (m, 1H). 1H-NMR (400 MHz, methanol-d4): δ = 8.17 (s, 1H), 8.04 (s, 1H), 7.91 (d, 1H), 7.61 (m, 1H), 7.58-7.40 (m, 4H) , 4.46 (m, 1H), 4.04 (dd, 1H), 3.92 (m, 2H), 3.83 (m, 2H), 3.48 (m, 1H), 3.42-3.27 (m, 4H), 3.23 (m, 1H ), 2.38 (m, 1H), 2.28 (m, 1H), 2.22 (m, 2H), 2.10 (m, 2H), 1.96 (m, 1H).

HPLC (metoda 1): Rt = 3.99 min. HPLC (method 1): Rt = 3.99 min.

Primjer 147 Example 147

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[3-(izobutirilamino)fenil]-1-benzotiofen-2-karboksamid-hidro klorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[3-(isobutyrylamino)phenyl]-1-benzothiophene-2-carboxamide hydrochloride

[image] [image]

Prema općenitom radnom propisu F pomiješa se 50 mg (0.12 mmola) hidroklorida 7-(3-aminofenil)-N-[(3R)-1-azabiciklo[2.2.2]-okt-3-il]-1-benzotiofen-2-karboksamid-hidroklorida (primjer 21) i 25.7 mg (0.24 mmol) klorida izomaslačne kiseline. Dobije se 35.1 mg (64.9 % od teor.) naslovnog spoja. According to general procedure F, 50 mg (0.12 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]-oct-3-yl]-1-benzothiophene-2 hydrochloride are mixed -carboxamide hydrochloride (example 21) and 25.7 mg (0.24 mmol) of isobutyric acid chloride. 35.1 mg (64.9% of theory) of the title compound is obtained.

1H-NMR (400 MHz, metanol-d4): δ = 8.17 (s, 1H), 8.03 (s, 1H), 7.90 (d, 1H), 7.61 (m, 1H), 7.57-7.40 (m, 4H), 4.45 (m, 1H), 3.83 (m, 1H), 3.48 (m, 1H), 3.42-3.27 (m, 4H), 2.68 (m, 1H), 2.38 (m, 1H), 2.28 (m, 1H), 2.10 (m, 2H), 1.96 (m, 1H), 1.21 (d, 6H). 1H-NMR (400 MHz, methanol-d4): δ = 8.17 (s, 1H), 8.03 (s, 1H), 7.90 (d, 1H), 7.61 (m, 1H), 7.57-7.40 (m, 4H) , 4.45 (m, 1H), 3.83 (m, 1H), 3.48 (m, 1H), 3.42-3.27 (m, 4H), 2.68 (m, 1H), 2.38 (m, 1H), 2.28 (m, 1H ), 2.10 (m, 2H), 1.96 (m, 1H), 1.21 (d, 6H).

HPLC (metoda 1): Rt = 4.19 min. HPLC (method 1): Rt = 4.19 min.

Primjer 148 Example 148

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[3-(2-furoilamino)fenil]-1-benzotiofen-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[3-(2-furoylamino)phenyl]-1-benzothiophene-2-carboxamide hydrochloride

[image] [image]

Prema općenitom radnom propisu F pomiješa se 50 mg (0.12 mmola) hidroklorida 7-(3-aminofenil)-N-[(3R)-1-azabiciklo[2.2.2]-okt-3-il]-1-benzotiofen-2-karboksamid-hidroklorida (primjer 21) i 31.5 mg (0.24 mmola) klorida furan-2-karboksilne kiseline. Dobije se 29.1 mg (51.1 % od teor.) naslovnog spoja. According to general procedure F, 50 mg (0.12 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]-oct-3-yl]-1-benzothiophene-2 hydrochloride are mixed -carboxamide hydrochloride (example 21) and 31.5 mg (0.24 mmol) furan-2-carboxylic acid chloride. 29.1 mg (51.1 % of theory) of the title compound is obtained.

1H-NMR (400 MHz, metanol-d4): δ = 8.17 (s, 2H), 7.91 (d, 1H), 7.74 (m, 2H), 7.58-7.47 (m, 4H), 7.29 (d, 1H), 6.65 (m, 1H), 4.44 (m, 1H), 3.83 (m, 1H), 3.47 (m, 1H), 3.42-3.27 (m, 4H), 2.38 (m, 1H), 2.28 (m, 1H), 2.10 (m, 2H), 1.96 (m, 1H). 1H-NMR (400 MHz, methanol-d4): δ = 8.17 (s, 2H), 7.91 (d, 1H), 7.74 (m, 2H), 7.58-7.47 (m, 4H), 7.29 (d, 1H) , 6.65 (m, 1H), 4.44 (m, 1H), 3.83 (m, 1H), 3.47 (m, 1H), 3.42-3.27 (m, 4H), 2.38 (m, 1H), 2.28 (m, 1H ), 2.10 (m, 2H), 1.96 (m, 1H).

HPLC (metoda 1): Rt = 4.19 min. HPLC (method 1): Rt = 4.19 min.

MS (ESIpos): m/z = 472 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 472 (M+H)+ (free base).

Primjer 149 Example 149

hidroklorid 3-(2-{[(3R)-1-azabiciklo[2.2.2]okt-3-il-amino]karbonil}-1-benzofuran-7-il)-benzojeve kiseline 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-yl-amino]carbonyl}-1-benzofuran-7-yl)-benzoic acid hydrochloride

[image] [image]

Smjesi od 1104 mg (2.86 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzofuran-2-karboksamid-hidroklorida (primjer 30A) i 475 mg (2.86 mmola) 3-karboksifenilboronske kiseline u 10 mL DMF doda se 4.3 mL 2 M vodene otopine natrijevog karbonata i 116.9 mg (0.14 mmola) PdCl2(dppf). Reakcijska smjesa zagrijava se 18 h na 90 °C, potom se filtrira na silikagelu i zgusne do suhoga. Nakon pročišćavanja sirovog produkta preparativnom HPLC, pretvaranja smjesom 3:1 acetonitrila i 1 N solne kiseline, zgušnjavanja i sušenja u visokom vakuumu dobije se 724 mg (59.2 % od teor.) naslovnog spoja. Mixtures of 1104 mg (2.86 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide hydrochloride (Example 30A) and 475 mg (2.86 mmol) of 3-carboxyphenylboronic acid in 10 mL of DMF was added to 4.3 mL of 2 M aqueous sodium carbonate solution and 116.9 mg (0.14 mmol) of PdCl2(dppf). The reaction mixture is heated for 18 h at 90 °C, then filtered on silica gel and concentrated to dryness. After purification of the crude product by preparative HPLC, conversion with a mixture of 3:1 acetonitrile and 1 N hydrochloric acid, concentration and drying in high vacuum, 724 mg (59.2% of theory) of the title compound are obtained.

1H-NMR (200 MHz, metanol-d4): δ = 8.62 (s, 1H), 8.11 (d, 1H), 8.08 (d, 1H), 7.76 (d, 1H), 7.73-7.61 (m, 3H), 7.46 (dd, 1H), 4.49 (m, 1H), 3.83 (m, 1H), 3.48 (m, 1H), 3.43-3.27 (m, 4H), 2.40 (m, 1H), 2.28 (m, 1H), 2.10 (m, 2H), 1.96 (m, 1H). 1H-NMR (200 MHz, methanol-d4): δ = 8.62 (s, 1H), 8.11 (d, 1H), 8.08 (d, 1H), 7.76 (d, 1H), 7.73-7.61 (m, 3H) , 7.46 (dd, 1H), 4.49 (m, 1H), 3.83 (m, 1H), 3.48 (m, 1H), 3.43-3.27 (m, 4H), 2.40 (m, 1H), 2.28 (m, 1H ), 2.10 (m, 2H), 1.96 (m, 1H).

HPLC (metoda 1): Rt = 3.89 min. HPLC (method 1): Rt = 3.89 min.

Primjer 150 Example 150

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[2-(hidroksimetil)fenil]-1-benzofuran-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[2-(hydroxymethyl)phenyl]-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Smjesi od 150 mg (0.43 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzofuran-2-karboksamid-hidroklorida (primjer 30A) i 65.3 mg (0.43 mmola) 2-(hidroksimetil)fenilboronske kiseline u 1.5 mL DMF doda se 0.64 mL 2 M vodene otopine natrijevog karbonata i 17.5 mg (0.02 mmola) PdCl2(dppf). Reakcijska smjesa zagrijava se 18 h na 90 °C, potom se filtrira na silikagelu i zgusne do suhoga. Nakon pročišćavanja sirovog produkta preparativnom HPLC, pretvaranja smjesom 3:1 acetonitrila i 1 N solne kiseline, zgušnjavanja i sušenja u visokom vakuumu dobije se 13 mg (7.1 % od teor.) naslovnog spoja. Mixtures of 150 mg (0.43 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide hydrochloride (Example 30A) and 65.3 mg (0.43 mmol) of 2-(hydroxymethyl)phenylboronic acid in 1.5 mL of DMF was added to 0.64 mL of 2 M aqueous sodium carbonate solution and 17.5 mg (0.02 mmol) of PdCl2(dppf). The reaction mixture is heated for 18 h at 90 °C, then filtered on silica gel and concentrated to dryness. After purification of the crude product by preparative HPLC, conversion with a mixture of 3:1 acetonitrile and 1 N hydrochloric acid, concentration and drying in high vacuum, 13 mg (7.1 % of theory) of the title compound are obtained.

HPLC (metoda 1): Rt = 3.87 min. HPLC (method 1): Rt = 3.87 min.

Primjer 151 Example 151

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-(2,5-dimetoksifenil)-1-benzofuran-2-karboksamid-hidro klorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-(2,5-dimethoxyphenyl)-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Smjesi od 200 mg (0.52 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzofuran-2-karboksamid-hidroklorida (primjer 30A) i 94.4 mg (0.52 mmola) 2,5-dimetoksifenilboronske kiseline u 2 mL DMF doda se 0.78 mL 2 M vodene otopine natrijevog karbonata i 21.2 mg (0.03 mmola) PdCl2(dppf). Reakcijska smjesa zagrijava se 17 h na 70 °C, potom se filtrira na silikagelu i zgusne do suhoga. Nakon pročišćavanja sirovog produkta preparativnom HPLC, pretvaranja smjesom 3:1 acetonitrila i 1 N solne kiseline, zgušnjavanja i sušenja u visokom vakuumu dobije se 75 mg (31.7 % od teor.) naslovnog spoja. Mixtures of 200 mg (0.52 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide hydrochloride (Example 30A) and 94.4 mg (0.52 mmol) of 2,5-dimethoxyphenylboronic acid in 2 mL of DMF was added to 0.78 mL of 2 M aqueous sodium carbonate solution and 21.2 mg (0.03 mmol) of PdCl2(dppf). The reaction mixture is heated for 17 h at 70 °C, then filtered on silica gel and concentrated to dryness. After purification of the crude product by preparative HPLC, conversion with a mixture of 3:1 acetonitrile and 1 N hydrochloric acid, concentration and drying in high vacuum, 75 mg (31.7 % of theory) of the title compound is obtained.

HPLC (metoda 1): Rt = 4.15 min. HPLC (method 1): Rt = 4.15 min.

Primjer 152 Example 152

7-[2-(aminometil)fenil]-N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-1-benzofuran-2-karboksamid-dihidroklorid 7-[2-(aminomethyl)phenyl]-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide dihydrochloride

[image] [image]

Prema općenitom radnom propisu D stavi se 500 mg (1.75 mmola) tert-butil-2-brombenzilkarbamata, 512 mg (2.02 mmola) bis-(pinakolato)dibora, 428.7 mg (4.37 mmola) kalijevog acetata, 49.2 mg (0.07 mmola) PdCI2(dppf), 518.4 mg (1.34 mmol) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzofuran-2-karboksamid-hidroklorida (primjer 30A), 3.36 mL 2 M otopine natrijevog karbonata, te još 49.2 mg (0.07 mmola) PdCl2(dppf) u 5 mL DMF. Sirovi produkt osušen u visokom vakuumu miješa se 2 h pri sobnoj temperaturi u 8 mL smjese 1:1 metanola i 4 M klorovodika u dioksanu. Reakcijska otopina se zgusne, te se dobiveni sirovi produkt pročisti preparativnom HPLC. Frakcije produkta se zgusnu, pretvore smjesom 3:1 metanola I 1 N solne kiseline, ponovno zgusnu i osuše u visokom vakuumu. Dobije se 245.5 mg (44.5 % od teor.) naslovnog spoja. According to general procedure D, 500 mg (1.75 mmol) of tert-butyl-2-bromobenzylcarbamate, 512 mg (2.02 mmol) of bis-(pinacolato)diboron, 428.7 mg (4.37 mmol) of potassium acetate, 49.2 mg (0.07 mmol) of PdCl2 are added. (dppf), 518.4 mg (1.34 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide hydrochloride (Example 30A), 3.36 mL of 2 M sodium carbonate solution, and another 49.2 mg (0.07 mmol) of PdCl2(dppf) in 5 mL of DMF. The crude product, dried in a high vacuum, was mixed for 2 h at room temperature in 8 mL of a 1:1 mixture of methanol and 4 M hydrogen chloride in dioxane. The reaction solution is concentrated, and the resulting crude product is purified by preparative HPLC. The product fractions are concentrated, converted with a 3:1 mixture of methanol and 1 N hydrochloric acid, concentrated again and dried in a high vacuum. 245.5 mg (44.5% of theory) of the title compound is obtained.

1H-NMR (200 MHz, DMSO-d6): δ = 10.48 (br. s, 1H), 9.26 (d, 1H), 8.47 (br. s, 3H), 8.05 (s, 1H), 7.88 (dd, 1H), 7.80 (d, 1H), 7.62-7.40 (m, 5H), 4.31 (m, 1H), 3.86 (m, 2H), 3.48 (m, 1H), 3.51-3.10 (m, 5H), 2.18 (m, 1H), 2.11 (m, 3H), 1.90 (m, 2H), 1.71 (m, 1H). 1H-NMR (200 MHz, DMSO-d6): δ = 10.48 (no. s, 1H), 9.26 (d, 1H), 8.47 (no. s, 3H), 8.05 (s, 1H), 7.88 (dd, 1H), 7.80 (d, 1H), 7.62-7.40 (m, 5H), 4.31 (m, 1H), 3.86 (m, 2H), 3.48 (m, 1H), 3.51-3.10 (m, 5H), 2.18 (m, 1H), 2.11 (m, 3H), 1.90 (m, 2H), 1.71 (m, 1H).

HPLC (metoda 1): Rt = 3.55 min. HPLC (method 1): Rt = 3.55 min.

MS (ESIpos): m/z = 376 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 376 (M+H)+ (free base).

Primjer 153 Example 153

hidroklorid 3-(2-{[(3S)-1-azabiciklo[2.2.2]okt-3-il-amino]karbonil}-1-benzofuran-7-il)-benzojeve kiseline 3-(2-{[(3S)-1-azabicyclo[2.2.2]oct-3-yl-amino]carbonyl}-1-benzofuran-7-yl)-benzoic acid hydrochloride

[image] [image]

Smjesi od 1000 mg (2.59 mmola) N-[(3S)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzofuran-2-karboksamid-hidroklorida (slobodna baza: primjer 31A) i 430.2 mg (2.59 mmola) 3-karboksi-fenilboronske kiseline u 8 ml DMF doda se 3.89 mL 2 M vodene otopine natrijevog karbonata i 105.9 mg (0.13 mmola) PdCl2(dppf). Reakcijska smjesa zagrijava se 18 h na 70 °C, potom se filtrira na silikagelu i zgusne do suhoga. Nakon pročišćavanja sirovog produkta preparativnom HPLC, pretvorbe smjesom 3:1 acetonitrila i 1 N solne kiseline, zgušnjavanja i sušenja u visokom vakuumu dobije se 142.5 mg (12 % od teor.), te još 627.9 mg (80 %-tne čistoće) naslovnog spoja. Mixtures of 1000 mg (2.59 mmol) N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide hydrochloride (free base: Example 31A) and 430.2 mg (2.59 mmol) of 3-carboxy-phenylboronic acid in 8 ml of DMF, 3.89 ml of 2 M aqueous sodium carbonate solution and 105.9 mg (0.13 mmol) of PdCl2(dppf) were added. The reaction mixture is heated for 18 h at 70 °C, then filtered on silica gel and concentrated to dryness. After purification of the crude product by preparative HPLC, conversion with a mixture of 3:1 acetonitrile and 1 N hydrochloric acid, concentration and drying in a high vacuum, 142.5 mg (12% of theory) and another 627.9 mg (80% purity) of the title compound are obtained .

Spektroskopski podatci odgovaraju onima enantiomernog spoja (primjer 149). The spectroscopic data correspond to those of the enantiomeric compound (Example 149).

Primjer 154 Example 154

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-{3-[(ciklopropilamino)-karbonil]fenil}-1-benzofuran-2-karboksamid-hidro klorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-{3-[(cyclopropylamino)-carbonyl]phenyl}-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Prema općenitom radnom propisu E pomiješa se 50 mg (0.12 mmola) hidroklorida 3-(2-{[(3R)-1-azabiciklo[2.2.2]okt-3-il-amino]karbonil}-1-benzofuran-7-il)-benzojeve kiseline (primjer 149) i 13.4 mg (0.23 mmola) ciklopropilamina. Dobije se 20 mg (23.2 % od teor.) naslovnog spoja. According to general procedure E, 50 mg (0.12 mmol) of hydrochloride 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-yl-amino]carbonyl}-1-benzofuran-7- yl)-benzoic acid (Example 149) and 13.4 mg (0.23 mmol) of cyclopropylamine. 20 mg (23.2% of theory) of the title compound is obtained.

HPLC (metoda 1): Rt = 3.93 min. HPLC (method 1): Rt = 3.93 min.

LC-MS (metoda 6): Rt = 3.33 min; m/z = 429 (M+H)+ (slobodna baza). LC-MS (method 6): Rt = 3.33 min; m/z = 429 (M+H)+ (free base).

Primjer 155 Example 155

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-(3-{[etil(metil)amino]-karbonil}fenil)-1-benzofuran-2-karboksamid-hidro klorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-(3-{[ethyl(methyl)amino]-carbonyl}phenyl)-1-benzofuran-2-carboxamide-hydro chloride

[image] [image]

Prema općenitom radnom propisu E pomiješa se 50 mg (0.12 mmola) hidroklorida 3-(2-{[(3R)-1-azabiciklo[2.2.2]okt-3-il-amino]karbonil}-1-benzofuran-7-il)-benzojeve kiseline (primjer 149) i 13.9 mg (0.23 mmola) metiletilamina. Dobije se 19.8 mg (29.4 % od teor.) naslovnog spoja. HPLC (metoda 1): Rt = 4.03 min. According to general procedure E, 50 mg (0.12 mmol) of hydrochloride 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-yl-amino]carbonyl}-1-benzofuran-7- yl)-benzoic acid (Example 149) and 13.9 mg (0.23 mmol) of methylethylamine. 19.8 mg (29.4% of theory) of the title compound is obtained. HPLC (method 1): Rt = 4.03 min.

LC-MS (metoda 6): Rt = 3.38 min; m/z = 431 (M+H)+ (slobodna baza). LC-MS (method 6): Rt = 3.38 min; m/z = 431 (M+H)+ (free base).

Primjer 156 Example 156

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-{3-[(butilamino)karbonil]-fenil}-1-benzofuran-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-{3-[(butylamino)carbonyl]-phenyl}-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Prema općenitom radnom propisu E pomiješa se 50 mg (0.12 mmola) hidroklorida 3-(2-{[(3R)-1-azabiciklo[2.2.2]okt-3-il-amino]karbonil}-1-benzofuran-7-il)-benzojeve kiseline (primjer 149) i 17.1 mg (0.23 mmola) n-butilamina. Dobije se 15.2 mg (26.2 % od teor.) naslovnog spoja. According to general procedure E, 50 mg (0.12 mmol) of hydrochloride 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-yl-amino]carbonyl}-1-benzofuran-7- yl)-benzoic acid (Example 149) and 17.1 mg (0.23 mmol) of n-butylamine. 15.2 mg (26.2% of theory) of the title compound is obtained.

HPLC (metoda 1): Rt = 4.21 min. HPLC (method 1): Rt = 4.21 min.

LC-MS (metoda 6): Rt = 3.49 min; m/z = 445 (M+H)+ (slobodna baza). LC-MS (method 6): Rt = 3.49 min; m/z = 445 (M+H)+ (free base).

Primjer 157 Example 157

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-{3-[(izobutilamino)karbonil]-fenil}-1-benzofuran-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-{3-[(isobutylamino)carbonyl]-phenyl}-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Prema općenitom radnom propisu E pomiješa se 50 mg (0.12 mmola) hidroklorida 3-(2-{[(3R)-1-azabiciklo[2.2.2]okt-3-il-amino]karbonil}-1-benzofuran-7-il)-benzojeve kiseline (primjer 149) i 17.1 mg (0.23 mmola) /zo-butilamina. Dobije se 15.2 mg (26.9 % od teor.) naslovnog spoja. According to general procedure E, 50 mg (0.12 mmol) of hydrochloride 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-yl-amino]carbonyl}-1-benzofuran-7- yl)-benzoic acid (Example 149) and 17.1 mg (0.23 mmol) of / iso -butylamine. 15.2 mg (26.9% of theory) of the title compound is obtained.

HPLC (metoda 1): Rt = 4.18 min. HPLC (method 1): Rt = 4.18 min.

Primjer 158 Example 158

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[3-(l-piperidinilkarbonil)-fenil]-1-benzofuran-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[3-(1-piperidinylcarbonyl)-phenyl]-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Prema općenitom radnom propisu E pomiješa se 50 mg (0.12 mmola) hidroklorida 3-(2-{[(3R)-1-azabiciklo[2.2.2]okt-3-il-amino]karbonil}-1-benzofuran-7-il)-benzojeve kiseline (primjer 149) i 20.0 mg (0.23 mmola) piperidina. Dobije se 16.4 mg (27.6 % od teor.) naslovnog spoja. According to general procedure E, 50 mg (0.12 mmol) of hydrochloride 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-yl-amino]carbonyl}-1-benzofuran-7- yl)-benzoic acid (Example 149) and 20.0 mg (0.23 mmol) of piperidine. 16.4 mg (27.6% of theory) of the title compound is obtained.

HPLC (metoda 1): Rt = 4.22 min. HPLC (method 1): Rt = 4.22 min.

LC-MS (metoda 6): Rt = 3.51 min; m/z = 457 (M+H)+ (slobodna baza). LC-MS (method 6): Rt = 3.51 min; m/z = 457 (M+H)+ (free base).

Primjer 159 Example 159

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[3-({[2-(dimetilamino)etil]-amino}karbonil)fenil]-1-benzofuran-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[3-({[2-(dimethylamino)ethyl]-amino}carbonyl)phenyl]-1-benzofuran-2 -carboxamide hydrochloride

[image] [image]

Prema općenitom radnom propisu E pomiješa se 50 mg (0.12 mmola) hidroklorida 3-(2-{[(3R)-1-azabiciklo[2.2.2]okt-3-il-amino]karbonil}-1-benzofuran-7-il)-benzojeve kiseline (primjer 149) i 20.7 mg (0.23 mmola) N-(2-aminoetil)-N’,N-dimetilamina. Dobije se 17.4 mg (24.8 % od teor.) naslovnog spoja. According to general procedure E, 50 mg (0.12 mmol) of hydrochloride 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-yl-amino]carbonyl}-1-benzofuran-7- yl)-benzoic acid (Example 149) and 20.7 mg (0.23 mmol) of N-(2-aminoethyl)-N',N-dimethylamine. 17.4 mg (24.8% of theory) of the title compound is obtained.

HPLC (metoda 1): Rt = 3.64 min. HPLC (method 1): Rt = 3.64 min.

LC-MS (metoda 6): Rt = 2.93 min; m/z = 460 (M+H)+ (slobodna baza). LC-MS (method 6): Rt = 2.93 min; m/z = 460 (M+H)+ (free base).

Primjer 160 Example 160

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-(3-{[(3-metoksipropil)-amino]karbonil}fenil)-1-benzofuran-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-(3-{[(3-methoxypropyl)-amino]carbonyl}phenyl)-1-benzofuran-2-carboxamide- hydrochloride

[image] [image]

Prema općenitom radnom propisu E pomiješa se 50 mg (0.12 mmola) hidroklorida 3-(2-{[(3R)-1-azabiciklo[2.2.2]okt-3-il-amino]karbonil}-1-benzofuran-7-il)-benzojeve kiseline (primjer 149) i 20.9 mg (0.23 mmola) 3-metoksipropilamina. Dobije se 22.7 mg (36.4 % od teor.) naslovnog spoja. According to general procedure E, 50 mg (0.12 mmol) of hydrochloride 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-yl-amino]carbonyl}-1-benzofuran-7- yl)-benzoic acid (Example 149) and 20.9 mg (0.23 mmol) of 3-methoxypropylamine. 22.7 mg (36.4% of theory) of the title compound is obtained.

HPLC (metoda 1): Rt = 3.93 min. HPLC (method 1): Rt = 3.93 min.

LC-MS (metoda 6): Rt = 3.36 min; m/z = 461 (M+H)+ (slobodna baza). LC-MS (method 6): Rt = 3.36 min; m/z = 461 (M+H)+ (free base).

Primjer 161 Example 161

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-(3-{[(2-metoksietil)(metil)-amino]karbonil}fenil)-1-benzofuran-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-(3-{[(2-methoxyethyl)(methyl)-amino]carbonyl}phenyl)-1-benzofuran-2 -carboxamide hydrochloride

[image] [image]

Prema općenitom radnom propisu E pomiješa se 50 mg (0.12 mmola) hidroklorida 3-(2-{[(3R)-1-azabiciklo[2.2.2]okt-3-il-amino]karbonil}-1-benzofuran-7-il)-benzojeve kiseline (primjer 149) i 20.9 mg (0.23 mmola) N-(2-metoksietil)-N-metilamina. Dobije se 20.4 mg (31.3 % od teor.) naslovnog spoja. According to general procedure E, 50 mg (0.12 mmol) of hydrochloride 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-yl-amino]carbonyl}-1-benzofuran-7- yl)-benzoic acid (Example 149) and 20.9 mg (0.23 mmol) of N-(2-methoxyethyl)-N-methylamine. 20.4 mg (31.3% of theory) of the title compound is obtained.

HPLC (metoda 1): Rt = 3.96 min. HPLC (method 1): Rt = 3.96 min.

LC-MS (metoda 6): Rt = 3.34 min; m/z = 461 (M+H)+ (slobodna baza). LC-MS (method 6): Rt = 3.34 min; m/z = 461 (M+H)+ (free base).

Primjer 162 Example 162

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-(3-{[(3-etoksipropil)amino]-karbonil}fenil)-1-benzofuran-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-(3-{[(3-ethoxypropyl)amino]-carbonyl}phenyl)-1-benzofuran-2-carboxamide- hydrochloride

[image] [image]

Prema općenitom radnom propisu E pomiješa se 50 mg (0.12 mmola) hidroklorida 3-(2-{[(3R)-1-azabiciklo[2.2.2]okt-3-il-amino]karbonil}-1-benzofuran-7-il)-benzojeve kiseline (primjer 149) i 24.2 mg (0.23 mmola) 3-etoksipropilamina. Dobije se 17.8 mg (28.9 % od teor.) naslovnog spoja. According to general procedure E, 50 mg (0.12 mmol) of hydrochloride 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-yl-amino]carbonyl}-1-benzofuran-7- yl)-benzoic acid (Example 149) and 24.2 mg (0.23 mmol) of 3-ethoxypropylamine. 17.8 mg (28.9% of theory) of the title compound is obtained.

HPLC (metoda 1): Rt = 4.06 min. HPLC (method 1): Rt = 4.06 min.

LC-MS (metoda 6): Rt = 3.43 min; m/z = 475 (M+H)+ (slobodna baza). LC-MS (method 6): Rt = 3.43 min; m/z = 475 (M+H)+ (free base).

Primjer 163 Example 163

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-{3-[(4-metil-1-piperazinil)-karbonil]fenil}-1-benzofuran-2-karboksamid-dihidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-{3-[(4-methyl-1-piperazinyl)-carbonyl]phenyl}-1-benzofuran-2-carboxamide -dihydrochloride

[image] [image]

Prema općenitom radnom propisu E pomiješa se 50 mg (0.12 mmola) hidroklorida 3-(2-{[(3R)-1-azabiciklo[2.2.2]okt-3-il-amino]karbonil}-1-benzofuran-7-il)-benzojeve kiseline (primjer 149) i 23.5 mg (0.23 mmola) N-metilpiperazina. Dobije se 29.6 mg (41.9 % od teor.) naslovnog spoja. According to general procedure E, 50 mg (0.12 mmol) of hydrochloride 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-yl-amino]carbonyl}-1-benzofuran-7- yl)-benzoic acid (Example 149) and 23.5 mg (0.23 mmol) of N-methylpiperazine. 29.6 mg (41.9% of theory) of the title compound is obtained.

HPLC (metoda 1): Rt = 3.60 min. HPLC (method 1): Rt = 3.60 min.

LC-MS (metoda 6): Rt = 2.91 min; m/z = 472 (M+H)+ (slobodna baza). LC-MS (method 6): Rt = 2.91 min; m/z = 472 (M+H)+ (free base).

Primjer 164 Example 164

N-[(3S)-1-azabiciklo[2.2.2]okt-3-il]-7-(3-{[etil(metil)amino]-karbonil}fenil)-1-benzofuran-2-karboksamid-hidroklorid N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-(3-{[ethyl(methyl)amino]-carbonyl}phenyl)-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Prema općenitom radnom propisu E pomiješa se 50 mg (0.12 mmola) hidroklorida 3-(2-{[(3S)-1-azabiciklo[2.2.2]okt-3-il-amino]karbonil}-1-benzofuran-7-il)-benzojeve kiseline (primjer 153) i 13.9 mg (0.23 mmola) metiletilamina. Dobije se 50.1 mg (91.4 % od teor.) naslovnog spoja. According to general procedure E, 50 mg (0.12 mmol) of 3-(2-{[(3S)-1-azabicyclo[2.2.2]oct-3-yl-amino]carbonyl}-1-benzofuran-7-hydrochloride is mixed yl)-benzoic acid (Example 153) and 13.9 mg (0.23 mmol) of methylethylamine. 50.1 mg (91.4% of theory) of the title compound is obtained.

Spektroskopski podatci odgovaraju onima enantiomerskog spoja (primjer 155). The spectroscopic data correspond to those of the enantiomeric compound (Example 155).

Primjer 165 Example 165

N-[(3S)-1-azabiciklo[2.2.2]okt-3-il]-7-{3-[(butilamino)karbonil]-fenil}-1-benzofuran-2-karboksamid-hidroklorid N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-{3-[(butylamino)carbonyl]-phenyl}-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Prema općenitom radnom propisu E pomiješa se 50 mg (0.12 mmola) hidroklorida 3-(2-{[(3S)-1-azabiciklo[2.2.2]okt-3-il-amino]karbonil}-1-benzofuran-7-il)-benzojeve kiseline (primjer 153) i 17.1 mg (0.23 mmola) n-butilamina. Dobije se 49.4 mg (87.5 % od teor.) naslovnog spoja. According to general procedure E, 50 mg (0.12 mmol) of 3-(2-{[(3S)-1-azabicyclo[2.2.2]oct-3-yl-amino]carbonyl}-1-benzofuran-7-hydrochloride is mixed yl)-benzoic acid (Example 153) and 17.1 mg (0.23 mmol) of n-butylamine. 49.4 mg (87.5% of theory) of the title compound is obtained.

Spektroskopski podatci odgovaraju onima enantiomerskog spoja (primjer 156). The spectroscopic data correspond to those of the enantiomeric compound (Example 156).

Primjer 166 Example 166

N-[(3S)-1-azabiciklo[2.2.2]okt-3-il]-7-{3-[(izobutilamino)karbonil]-fenil}-1-benzofuran-2-karboksamid-hidroklorid N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-{3-[(isobutylamino)carbonyl]-phenyl}-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Prema općenitom radnom propisu E pomiješa se 50 mg (0.12 mmola) hidroklorida 3-(2-{[(3S)-1-azablciklo[2.2.2]okt-3-il-amino]karbonil}-1-benzofuran-7-il)-benzojeve kiseline (primjer 153) i 17.1 mg (0.23 mmola) izo-butilamina. Dobije se 40.3 mg (71.4 % od teor.) naslovnog spoja. According to general procedure E, 50 mg (0.12 mmol) of 3-(2-{[(3S)-1-azablcyclo[2.2.2]oct-3-yl-amino]carbonyl}-1-benzofuran-7- yl)-benzoic acid (Example 153) and 17.1 mg (0.23 mmol) of iso-butylamine. 40.3 mg (71.4% of theory) of the title compound is obtained.

Spektroskopski podatci odgovaraju onima enantiomernog spoja (primjer 157). The spectroscopic data correspond to those of the enantiomeric compound (Example 157).

Primjer 167 Example 167

N-[(3S)-1-azabiciklo[2.2.2]okt-3-il]-7-[3-(l-piperidinilkarbonil)-fenil]-1-benzofuran-2-karboksamid-hidroklorid N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-[3-(1-piperidinylcarbonyl)-phenyl]-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Prema općenitom radnom propisu E pomiješa se 50 mg (0.12 mmola) hidroklorida 3-(2-{[(3S)-1-azabiciklo[2.2.2]okt-3-il-amino]karbonil}-1-benzofuran-7-il)-benzojeve kiseline (primjer 149) i 20.0 mg (0.23 mmola) piperidina. Dobije se 29.7 mg (49.9 % od teor.) naslovnog spoja. According to general procedure E, 50 mg (0.12 mmol) of 3-(2-{[(3S)-1-azabicyclo[2.2.2]oct-3-yl-amino]carbonyl}-1-benzofuran-7-hydrochloride is mixed yl)-benzoic acid (Example 149) and 20.0 mg (0.23 mmol) of piperidine. 29.7 mg (49.9% of theory) of the title compound is obtained.

Spektroskopski podatci odgovaraju onima enantiomernog spoja (primjer 158). The spectroscopic data correspond to those of the enantiomeric compound (Example 158).

Primjer 168 Example 168

N-[(3S)-1-azabiciklo[2.2.2]okt-3-il]-7-[3-({[2-(dimetilamino)etil]-amino}karbonil)fenil]-1-benzofuran-2-karboksamid-hidroklorid N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-[3-({[2-(dimethylamino)ethyl]-amino}carbonyl)phenyl]-1-benzofuran-2 -carboxamide hydrochloride

[image] [image]

Prema općenitom radnom propisu E pomiješa se 50 mg (0.12 mmola) hidroklorida 3-(2-{[(3S)-1-azabiciklo[2.2.2]okt-3-il-amino]karbonil}-1-benzofuran-7-il)-benzojeve kiseline (primjer 153) i 20.7 mg (0.23 mmola) N-(2-aminoetil)-N’,N-dimetilamina. Dobije se 42.5 mg (64.5 % od teor.) naslovnog spoja. Spektroskopski podatci odgovaraju onima enantiomernog spoja (primjer 159). According to general procedure E, 50 mg (0.12 mmol) of 3-(2-{[(3S)-1-azabicyclo[2.2.2]oct-3-yl-amino]carbonyl}-1-benzofuran-7-hydrochloride is mixed yl)-benzoic acid (Example 153) and 20.7 mg (0.23 mmol) of N-(2-aminoethyl)-N',N-dimethylamine. 42.5 mg (64.5% of theory) of the title compound is obtained. The spectroscopic data correspond to those of the enantiomeric compound (Example 159).

Primjer 169 Example 169

N-[(3S)-1-azabiciklo[2.2.2]okt-3-il]-7-(3-{[(3-metoksipropil)-amino]karbonil}fenil)-1-benzofuran-2-karboksamid-hidroklorid N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-(3-{[(3-methoxypropyl)-amino]carbonyl}phenyl)-1-benzofuran-2-carboxamide- hydrochloride

[image] [image]

Prema općenitom radnom propisu E pomiješa se 50 mg (0.12 mmola) hidroklorida 3-(2-{[(3S)-1-azabiciklo[2.2.2]okt-3-il-amino]karbonil}-1-benzofuran-7-il)-benzojeve kiseline (primjer 153) i 20.9 mg (0.23 mmola) 3-metoksipropilamina. Dobije se 29.8 mg (44.5 % od teor.) naslovnog spoja. According to general procedure E, 50 mg (0.12 mmol) of 3-(2-{[(3S)-1-azabicyclo[2.2.2]oct-3-yl-amino]carbonyl}-1-benzofuran-7-hydrochloride is mixed yl)-benzoic acid (Example 153) and 20.9 mg (0.23 mmol) of 3-methoxypropylamine. 29.8 mg (44.5% of theory) of the title compound is obtained.

Spektroskopski podatci odgovaraju onima enantiomernog spoja (primjer 160). The spectroscopic data correspond to those of the enantiomeric compound (Example 160).

Primjer 170 Example 170

N-[(3S)-1-azabiciklo[2.2.2]okt-3-il]-7-(3-{[(2-metoksietil)(metil)-amino]karbonil}fenil)-1-benzofuran-2-karboksamid-hidroklorid N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-(3-{[(2-methoxyethyl)(methyl)-amino]carbonyl}phenyl)-1-benzofuran-2 -carboxamide hydrochloride

[image] [image]

Prema općenitom radnom propisu E pomiješa se 50 mg (0.12 mmola) hidroklorida 3-(2-{[(3S)-1-azabiciklo[2.2.2]okt-3-il-amino]karbonil}-1-benzofuran-7-il)-benzojeve kiseline (primjer 153) i 20.9 mg (0.23 mmola) N-(2-metoksietil)-N-metilamina. Dobije se 22.1 mg (35.1 % od teor.) naslovnog spoja. Spektroskopski podatci odgovaraju onima enantiomernog spoja (primjer 161). According to general procedure E, 50 mg (0.12 mmol) of 3-(2-{[(3S)-1-azabicyclo[2.2.2]oct-3-yl-amino]carbonyl}-1-benzofuran-7-hydrochloride is mixed yl)-benzoic acid (Example 153) and 20.9 mg (0.23 mmol) of N-(2-methoxyethyl)-N-methylamine. 22.1 mg (35.1% of theory) of the title compound is obtained. The spectroscopic data correspond to those of the enantiomeric compound (Example 161).

Primjer 171 Example 171

N-[(3S)-1-azabiciklo[2.2.2]okt-3-il]-7-(3-{[(3-etoksipropil)-amino]karbonil}fenil)-1-benzofuran-2-karboksamid-hidro klorid N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-(3-{[(3-ethoxypropyl)-amino]carbonyl}phenyl)-1-benzofuran-2-carboxamide- hydro chloride

[image] [image]

Prema općenitom radnom propisu E pomiješa se 50 mg (0.12 mmola) hidroklorida 3-(2-{[(3S)-1-azabiciklo[2.2.2]okt-3-il-amino]karbonil}-1-benzofuran-7-il)-benzojeve kiseline (primjer 153) i 24.2 mg (0.23 mmola) 3-etoksipropilamina. Dobije se 23.6 mg (36.9 % od teor.) naslovnog spoja. According to general procedure E, 50 mg (0.12 mmol) of 3-(2-{[(3S)-1-azabicyclo[2.2.2]oct-3-yl-amino]carbonyl}-1-benzofuran-7-hydrochloride is mixed yl)-benzoic acid (Example 153) and 24.2 mg (0.23 mmol) of 3-ethoxypropylamine. 23.6 mg (36.9% of theory) of the title compound is obtained.

Spektroskopski podatci odgovaraju onima enantiomernog spoja (primjer 162). The spectroscopic data correspond to those of the enantiomeric compound (Example 162).

Primjer 172 Example 172

N-[(3S)-1-azabiciklo[2.2.2]okt-3-il]-7-{3-[(4-metil-1-piperazinil)-karbonil]fenil}-1-benzofuran-2-karboksamid-dihidro klorid N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-{3-[(4-methyl-1-piperazinyl)-carbonyl]phenyl}-1-benzofuran-2-carboxamide -dihydro chloride

[image] [image]

Prema općenitom radnom propisu E pomiješa se 50 mg (0.12 mmola) hidroklorida 3-(2-{[(3S)-1-azabiciklo[2.2.2]okt-3-il-amino]karbonil}-1-benzofuran-7-il)-benzojeve kiseline (primjer 153) i 23.5 mg (0.23 mmola) N-metilpiperazina. Dobije se 9.2 mg (15.4 % od teor.) naslovnog spoja. According to general procedure E, 50 mg (0.12 mmol) of 3-(2-{[(3S)-1-azabicyclo[2.2.2]oct-3-yl-amino]carbonyl}-1-benzofuran-7-hydrochloride is mixed yl)-benzoic acid (Example 153) and 23.5 mg (0.23 mmol) of N-methylpiperazine. 9.2 mg (15.4% of theory) of the title compound is obtained.

Spektroskopski podatci odgovaraju onima enantiomernog spoja (primjer 163). The spectroscopic data correspond to those of the enantiomeric compound (Example 163).

Primjer 173 Example 173

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[3-(l-pirolidinil)fenil]-1-benzofuran-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[3-(1-pyrrolidinyl)phenyl]-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Prema općenitom radnom propisu D stavi se 114.3 mg (0.51 mmol)l-(3-bromfenil)pirolidina, 148.1 mg (0.58 mmola) bis(pinakolato)-dibora, 124.1 mg (1.26 mmola) kalijevog acetata, 14.2 mg (0.02 mmola) PdCl2(dppf), 150 mg (0.39 mmola) N-[(3R)-1-azabiciklo-[2.2.2]okt-3-il]-7-brom-1-benzofuran-2-karboksamid-hidroklorida (primjer 30A), 0.97 mL 2 M otopine natrijevog karbonata, te još 14.2 mg (0.02 mmol) PdCl2(dppf) u 2.0 mL DMF. Nakon sušenja u visokom vakuumu dobije se 95.6 mg (54.4 % od teor.) naslovnog spoja. According to general procedure D, 114.3 mg (0.51 mmol) 1-(3-bromophenyl)pyrrolidine, 148.1 mg (0.58 mmol) bis(pinacolato)-diboron, 124.1 mg (1.26 mmol) potassium acetate, 14.2 mg (0.02 mmol) PdCl2(dppf), 150 mg (0.39 mmol) N-[(3R)-1-azabicyclo-[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide hydrochloride (Example 30A ), 0.97 mL of 2 M sodium carbonate solution, and another 14.2 mg (0.02 mmol) of PdCl2(dppf) in 2.0 mL of DMF. After drying in high vacuum, 95.6 mg (54.4% of theory) of the title compound is obtained.

HPLC (metoda 1): Rt = 3.85 min. HPLC (method 1): Rt = 3.85 min.

MS (ESIpos): m/z = 416 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 416 (M+H)+ (free base).

Primjer 174 Example 174

7-[2-(aminometil)fenil]-N-[(3S)-1-azabiciklo[2.2.2]okt-3-il]-1-benzofuran-2-karboksamid-dihidroklorid 7-[2-(aminomethyl)phenyl]-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide dihydrochloride

[image] [image]

Prema općenitom radnom propisu D stavi se 500 mg (1.75 mmola) tert-butil-2-brombenzilkarbamata, 512 mg (2.02 mmola) bis(pinakolato)dibora, 428.7 mg (4.37 mmola) kalijevog acetata, 49.2 mg (0.07 mmola) PdCl2(dppf), 518.4 mg (1.34 mmola) N-[(3S)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzofuran-2-karboksamid-hidroklorida (slobodna baza: primjer 31A), 3.36 mL 2 M otopine natrijevog karbonata, te još 49.2 mg (0.07 mmola) PdCl2(dppf) u 5 mL DMF. Sirovi produkt osušen u visokom vakuumu miješa se 2 h pri sobnoj temperaturi u 4 mL smjese 1:1 metanola i 4 M klorovodika u dioksanu. Reakcijska otopina se zgusne, te se dobiveni sirovi produkt pročisti preparativnom HPLC. Frakcije produkta se zgusnu, pretvore smjesom 3:1 metanola i 1 N solne kiseline, ponovno zgusnu i osuše u visokom vakuumu. Dobije se 121.6 mg (22.4 % od teor.) naslovnog spoja. Spektroskopski podatci odgovaraju onima enantiomemog spoja (primjer 152). According to general procedure D, 500 mg (1.75 mmol) of tert-butyl-2-bromobenzylcarbamate, 512 mg (2.02 mmol) of bis(pinacolato)diboron, 428.7 mg (4.37 mmol) of potassium acetate, 49.2 mg (0.07 mmol) of PdCl2( dppf), 518.4 mg (1.34 mmol) of N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide hydrochloride (free base: Example 31A ), 3.36 mL of 2 M sodium carbonate solution, and another 49.2 mg (0.07 mmol) of PdCl2(dppf) in 5 mL of DMF. The crude product, dried in a high vacuum, was mixed for 2 h at room temperature in 4 mL of a 1:1 mixture of methanol and 4 M hydrogen chloride in dioxane. The reaction solution is concentrated, and the resulting crude product is purified by preparative HPLC. The product fractions are concentrated, converted with a mixture of 3:1 methanol and 1 N hydrochloric acid, concentrated again and dried in a high vacuum. 121.6 mg (22.4% of theory) of the title compound is obtained. The spectroscopic data correspond to those of the enantiomeric compound (Example 152).

Primjer 175 Example 175

N-[(3R)-1-azabidklo[2.2.2]okt-3-il]-7-[2-({[(metilamino)karbonil]-amino}metil)fenil]-1-benzofuran-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[2-({[(methylamino)carbonyl]-amino}methyl)phenyl]-1-benzofuran-2-carboxamide -hydrochloride

[image] [image]

Otopini od 100 mg (0.22 mmola) 7-[2-(aminometil)fenil]-N-[(3R)-l-azabiciklo[2.2.2]okt-3-il]-1-benzofuran-2-karboksamid-dihidroklorida (primjer 152) u 1 mL smjese 5:1 THF i DMF doda se 62.2 nL (0.45 mmola) trietilamina i 53 μL (0.89 mmola) metilizocijanata. Nakon 18 h pri sobnoj temperaturi reakcijska smjesa se zgusne i pročisti preparativnom HPLC. Frakcije produkta se zgusnu, pretvore smjesom 3:1 metanola i 1 N solne kiseline, ponovno zgusnu i osuše u visokom vakuumu. Dobije se 75 mg (66 % od teor.) naslovnog spoja. Solutions of 100 mg (0.22 mmol) 7-[2-(aminomethyl)phenyl]-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide dihydrochloride (example 152) 62.2 nL (0.45 mmol) of triethylamine and 53 μL (0.89 mmol) of methyl isocyanate are added to 1 mL of a 5:1 mixture of THF and DMF. After 18 h at room temperature, the reaction mixture is concentrated and purified by preparative HPLC. The product fractions are concentrated, converted with a mixture of 3:1 methanol and 1 N hydrochloric acid, concentrated again and dried in a high vacuum. 75 mg (66% of theory) of the title compound are obtained.

1H-NMR (400 MHz, metanol-d4): δ = 7.78 (m, 1H), 7.68 (s, 1H), 7.52-7.30 (m, 6H), 4.47 (m, 1H), 4.23 (m, 2H), 3.77 (m, 1H), 3.53-3.25 (m, 5H), 2.69 (s, 3H), 2.37 (m, 1H), 2.20 (m, 1H), 2.08 (m, 2H), 1.88 (m, 1H). 1H-NMR (400 MHz, methanol-d4): δ = 7.78 (m, 1H), 7.68 (s, 1H), 7.52-7.30 (m, 6H), 4.47 (m, 1H), 4.23 (m, 2H) , 3.77 (m, 1H), 3.53-3.25 (m, 5H), 2.69 (s, 3H), 2.37 (m, 1H), 2.20 (m, 1H), 2.08 (m, 2H), 1.88 (m, 1H ).

HPLC (metoda 1): Rt = 3.78 min. HPLC (method 1): Rt = 3.78 min.

Primjer 176 Example 176

N-[(3S)-1-azabidklo[2.2.2]okt-3-il]-7-[2-({[(metilamino)karbonil]-amino}metil)fenil]-1-benzofuran-2-karboksamid-hidroklorid N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-[2-({[(methylamino)carbonyl]-amino}methyl)phenyl]-1-benzofuran-2-carboxamide -hydrochloride

[image] [image]

Otopini od 57.9 mg (0.13 mmola) 7-[2-(aminometil)fenil]-N-[(3S)-1-azabiciklo[2.2.2]okt-3-il]-1-benzofuran-2-karboksamid-dihidroklorida (primjer 174) u 0.7 mL smjese 5:1 THF i DMF doda se 36 nL (0.26 mmola) trietilamina i 29.5 nL (0.52 mmola) metilizocijanata. Nakon 18 h pri sobnoj temperaturi reakcijska smjesa se zgusne i pročisti preparativnom HPLC. Frakcije produkta se zgusnu, pretvore smjesom 3:1 metanola i 1 N solne kiseline, ponovno zgusnu i osuše u visokom vakuumu. Dobije se 49.2 mg (81.2 % od teor.) naslovnog spoja. Solutions of 57.9 mg (0.13 mmol) 7-[2-(aminomethyl)phenyl]-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide dihydrochloride (example 174) 36 nL (0.26 mmol) of triethylamine and 29.5 nL (0.52 mmol) of methyl isocyanate are added to 0.7 mL of a 5:1 mixture of THF and DMF. After 18 h at room temperature, the reaction mixture is concentrated and purified by preparative HPLC. The product fractions are concentrated, converted with a mixture of 3:1 methanol and 1 N hydrochloric acid, concentrated again and dried in a high vacuum. 49.2 mg (81.2% of theory) of the title compound is obtained.

Spektroskopski podatci odgovaraju onima enantiomernog spoja (primjer 175). The spectroscopic data correspond to those of the enantiomeric compound (Example 175).

Primjer 177 Example 177

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-{3-[(2,2-dimetilpropanoil)-amino]fenil}-1-benzofuran-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-{3-[(2,2-dimethylpropanoyl)-amino]phenyl}-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Prema općenitom radnom propisu F pomiješa se 50 mg (0.14 mmola) hidroklorida 7-(3-aminofenil)-N-[(3R)-1-azabiciklo[2.2.2]-okt-3-il]-1-benzofuran-2-karboksamida (primjer 114) i 33.4 mg (0.28 mmola) klorida pivalinske kiseline. Dobije se 15.2 mg (20.7 % od teor.) naslovnog spoja. According to general procedure F, 50 mg (0.14 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]-oct-3-yl]-1-benzofuran-2 hydrochloride are mixed -carboxamide (example 114) and 33.4 mg (0.28 mmol) pivalic acid chloride. 15.2 mg (20.7% of theory) of the title compound is obtained.

HPLC (metoda 1): Rt = 4.30 min. HPLC (method 1): Rt = 4.30 min.

Primjer 178 Example 178

N-[3-(2-{[(3R)-1-azabiciklo[2.2.2]okt-3-ilamino]karbonil}-1-benzofuran-7-il)fenil]-5-izoksazolkarboksamid-hidro klorid N-[3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzofuran-7-yl)phenyl]-5-isoxazolecarboxamide hydrochloride

[image] [image]

Prema općenitom radnom propisu F pomiješa se 50 mg (0.14 mmola) hidroklorida 7-(3-aminofenil)-N-[(3R)-1-azabiciklo[2.2.2]-okt-3-il]-1-benzofuran-2-karboksamida (primjer 114) i 36.4 mg (0.28 mmola) klorida 5-izoksazolkarboksilne kiseline. Dobije se 39.6 mg (53.3 % od teor.) naslovnog spoja. According to general procedure F, 50 mg (0.14 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]-oct-3-yl]-1-benzofuran-2 hydrochloride are mixed -carboxamide (example 114) and 36.4 mg (0.28 mmol) of 5-isoxazolecarboxylic acid chloride. 39.6 mg (53.3% of theory) of the title compound is obtained.

HPLC (metoda 1): Rt = 4.18 min. HPLC (method 1): Rt = 4.18 min.

MS (ESIpos): m/z = 457 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 457 (M+H)+ (free base).

Primjer 179 Example 179

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-{3-[(ciklopentilkarbonil)-amino]fenil}-1-benzofuran-2-karboksamid-hidro klorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-{3-[(cyclopentylcarbonyl)-amino]phenyl}-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Prema općenitom radnom propisu F pomiješa se 50 mg (0.14 mmola) hidroklorida 7-(3-aminofenil)-N-[(3R)-1-azabiciklo[2.2.2]-okt-3-il]-1-benzofuran-2-karboksamida (primjer 114) i 36.7 mg (0.28 mmola) klorida ciklopentankarboksilne kiseline. Dobije se 33.2 mg (45.1 % od teor.) naslovnog spoja. According to general procedure F, 50 mg (0.14 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]-oct-3-yl]-1-benzofuran-2 hydrochloride are mixed -carboxamide (example 114) and 36.7 mg (0.28 mmol) cyclopentanecarboxylic acid chloride. 33.2 mg (45.1% of theory) of the title compound is obtained.

HPLC (metoda 1): Rt = 4.38 min. HPLC (method 1): Rt = 4.38 min.

MS (ESIpos): m/z = 458 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 458 (M+H)+ (free base).

Primjer 180 Example 180

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[3-(izobutirilamino)fenil]-1-benzofuran-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[3-(isobutyrylamino)phenyl]-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Prema općenitom radnom propisu F pomiješa se 50 mg (0.14 mmola) hidroklorida 7-(3-aminofenil)-N-[(3R)-1-azabiciklo[2.2.2]-okt-3-il]-1-benzofuran-2-karboksamida (primjer 114) i 29.5 mg (0.28 mmola) klorida izomaslačne kiseline. Dobije se 12.8 mg (19.5 % od teor.) naslovnog spoja. According to general procedure F, 50 mg (0.14 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]-oct-3-yl]-1-benzofuran-2 hydrochloride are mixed -carboxamide (example 114) and 29.5 mg (0.28 mmol) of isobutyric acid chloride. 12.8 mg (19.5% of theory) of the title compound is obtained.

HPLC (metoda 1): Rt = 4.19 min. HPLC (method 1): Rt = 4.19 min.

Primjer 181 Example 181

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[3-(2-furoilamino)fenil]-1-benzofuran-2-karboksamid-hidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[3-(2-furoylamino)phenyl]-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Prema općenitom radnom propisu F pomiješa se 50 mg (0.14 mmola) hidroklorida 7-(3-aminofenil)-N-[(3R)-1-azabiciklo[2.2.2]-okt-3-il]-1-benzofuran-2-karboksamida (primjer 114) i 36.1 mg (0.28 mmola) klorida furan-2-karboksilne kiseline. Dobije se 7.4 mg (10.6 % od teor.) naslovnog spoja. According to general procedure F, 50 mg (0.14 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]-oct-3-yl]-1-benzofuran-2 hydrochloride are mixed -carboxamide (example 114) and 36.1 mg (0.28 mmol) furan-2-carboxylic acid chloride. 7.4 mg (10.6% of theory) of the title compound is obtained.

HPLC (metoda 1): Rt = 4.27 min. HPLC (method 1): Rt = 4.27 min.

MS (ESIpos): m/z = 456 (M + H)+ (slobodna baza). MS (ESIpos): m/z = 456 (M + H)+ (free base).

Primjer 182 Example 182

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-(2-metoksifenil)-1-benzofuran-2-karboksamid-acetat N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-(2-methoxyphenyl)-1-benzofuran-2-carboxamide-acetate

[image] [image]

Otopi se 95.9 mg (0.25 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-(2-metoksifenil)-1-benzofuran-2-karboksamida (primjer 130) u 2 mL metanola. Nakon dodatka 15.3 mg (0.25 mmola) octene kiseline smjesa se zgusne, te se ostatak osuši u vakuumu. Dobije se 114.9 mg (99.7 % od teor.) naslovnog spoja. Dissolve 95.9 mg (0.25 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-(2-methoxyphenyl)-1-benzofuran-2-carboxamide (Example 130) in 2 mL of methanol. After the addition of 15.3 mg (0.25 mmol) of acetic acid, the mixture thickens, and the residue is dried in a vacuum. 114.9 mg (99.7% of theory) of the title compound is obtained.

1H-NMR (200 MHz, DMSO-d6): δ = 8.37 (d, 1H), 7.74 (dd, 1H), 7.71 (s, 1H), 7.50-7.33 (m, 4H), 7.20 (d, 1H), 7.08 (m, 1H), 3.93 (m, 1H), 3.76 (s, 3H), 3.10 (m, 1H), 2.87 (m, 1H), 2.78-2.60 (m, 4H), 1.90 (s, 3H), 1.87 (m, 1H), 1.75 (m, 1H), 1.58 (m, 2H), 1.33 (m, 1H). 1H-NMR (200 MHz, DMSO-d6): δ = 8.37 (d, 1H), 7.74 (dd, 1H), 7.71 (s, 1H), 7.50-7.33 (m, 4H), 7.20 (d, 1H) , 7.08 (m, 1H), 3.93 (m, 1H), 3.76 (s, 3H), 3.10 (m, 1H), 2.87 (m, 1H), 2.78-2.60 (m, 4H), 1.90 (s, 3H ), 1.87 (m, 1H), 1.75 (m, 1H), 1.58 (m, 2H), 1.33 (m, 1H).

Primjer 183 Example 183

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-(2-metoksifenil)-1-benzofuran-2-karboksamid-tosilat N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-(2-methoxyphenyl)-1-benzofuran-2-carboxamide-tosylate

[image] [image]

Otopi se 95.9 mg (0.25 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-(2-metoksifenil)-1-benzofuran-2-karboksamida (primjer 130) u 2 mL metanola. Nakon dodatka 49.2 mg (0.25 mmola) p-toluolsulfonske kiseline smjesa se zgusne, te se ostatak osuši u vakuumu. Dobije se 143 mg (99.4 % od teor.) naslovnog spoja. Dissolve 95.9 mg (0.25 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-(2-methoxyphenyl)-1-benzofuran-2-carboxamide (Example 130) in 2 mL of methanol. After the addition of 49.2 mg (0.25 mmol) of p-toluenesulfonic acid, the mixture thickens, and the residue is dried in a vacuum. 143 mg (99.4% of theory) of the title compound is obtained.

1H-NMR (200 MHz, DMSO-d6): δ = 9.34 (br. s, 1H), 8.70 (d, 1H), 7.77 (dd, 1H), 7.72 (s, 1H), 7.52-7.35 (m, 6H), 7.21 (d, 1H), 7.15-7.04 (m, 3H), 4.30 (m, 1H), 3.76 (s, 3H), 3.68 (m, 1H), 3.33-3.11 (m, 5H), 2.29 (s, 3H), 2.19 (m, 1H), 2.07 (m, 1H), 1.91 (m, 2H), 1.74 (m, 1H). 1H-NMR (200 MHz, DMSO-d6): δ = 9.34 (no. s, 1H), 8.70 (d, 1H), 7.77 (dd, 1H), 7.72 (s, 1H), 7.52-7.35 (m, 6H), 7.21 (d, 1H), 7.15-7.04 (m, 3H), 4.30 (m, 1H), 3.76 (s, 3H), 3.68 (m, 1H), 3.33-3.11 (m, 5H), 2.29 (s, 3H), 2.19 (m, 1H), 2.07 (m, 1H), 1.91 (m, 2H), 1.74 (m, 1H).

Primjer 184 Example 184

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-(2-metoksifenil)-1-benzofuran-2-karboksamid-fumarat N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-(2-methoxyphenyl)-1-benzofuran-2-carboxamide fumarate

[image] [image]

Otopi se 95.9 mg (0.25 mmol) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-(2-metoksifenil)-1-benzofuran-2-karboksamida (primjer 130) u 1.5 mL acetona. Nakon dodavanja 29.6 mg (0.25 mmola) fumarne kiseline u 1 mL vrućeg izopropanola smjesa se miješa 30 min na 50 °C, potom zgusne, te se ostatak osuši u vakuumu. Dobije se 124.2 mg (99 % od teor.) naslovnog spoja. Dissolve 95.9 mg (0.25 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-(2-methoxyphenyl)-1-benzofuran-2-carboxamide (Example 130) in 1.5 mL of acetone. After adding 29.6 mg (0.25 mmol) of fumaric acid to 1 mL of hot isopropanol, the mixture was stirred for 30 min at 50 °C, then thickened, and the residue was dried in a vacuum. 124.2 mg (99% of theory) of the title compound is obtained.

1H-NMR (200 MHz, DMSO-d6): δ = 8.62 (d, 1H), 7.76 (dd, 1H), 7.72 (s, 1H), 7.49-7.33 (m, 4H), 7.21 (d, 1H), 7.09 (m, 1H), 6.50 (s, 2H), 4.16 (m, 1H), 3.76 (s, 3H), 3.38 (m, 1H), 3.11 (m, 1H), 3.06-2.85 (m, 4H), 2.03 (m, 1H), 1.92 (m, 1H), 1.76 (m, 2H), 1.56 (m, 1H). 1H-NMR (200 MHz, DMSO-d6): δ = 8.62 (d, 1H), 7.76 (dd, 1H), 7.72 (s, 1H), 7.49-7.33 (m, 4H), 7.21 (d, 1H) , 7.09 (m, 1H), 6.50 (s, 2H), 4.16 (m, 1H), 3.76 (s, 3H), 3.38 (m, 1H), 3.11 (m, 1H), 3.06-2.85 (m, 4H ), 2.03 (m, 1H), 1.92 (m, 1H), 1.76 (m, 2H), 1.56 (m, 1H).

Primjer 185 Example 185

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-(2-metoksifenil)-1-benzofuran-2-karboksamid-oksalat N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-(2-methoxyphenyl)-1-benzofuran-2-carboxamide-oxalate

[image] [image]

Otopi se 95.9 mg (0.25 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-(2-metoksifenil)-1-benzofuran-2-karboksamida (primjer 130) u 1.5 mL acetona. Nakon dodavanja 22.9 mg (0.25 mmola) oksalne kiseline u 1 mL vrućeg izopropanola smjesa se miješa 30 min na 50 °C, potom zgusne, te se ostatak osuši u vakuumu. Dobije se 117.6 mg (99 % od teor.) naslovnog spoja. Dissolve 95.9 mg (0.25 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-(2-methoxyphenyl)-1-benzofuran-2-carboxamide (Example 130) in 1.5 mL of acetone. After adding 22.9 mg (0.25 mmol) of oxalic acid to 1 mL of hot isopropanol, the mixture was stirred for 30 min at 50 °C, then thickened, and the residue was dried in a vacuum. 117.6 mg (99% of theory) of the title compound are obtained.

1H-NMR (200 MHz, DMSO-d6): δ = 8.75 (d, 1H), 7.77 (dd, 1H), 7.72 (s, 1H), 7.50-7.33 (m, 4H), 7.20 (d, 1H), 7.09 (m, 1H), 4.28 (m, 1H), 3.75 (s, 3H), 3.62 (m, 1H), 3.32-3.08 (m, 5H), 2.17 (m, 1H), 2.04 (m, 1H), 1.89 (m, 2H), 1.71 (m, 1H). 1H-NMR (200 MHz, DMSO-d6): δ = 8.75 (d, 1H), 7.77 (dd, 1H), 7.72 (s, 1H), 7.50-7.33 (m, 4H), 7.20 (d, 1H) , 7.09 (m, 1H), 4.28 (m, 1H), 3.75 (s, 3H), 3.62 (m, 1H), 3.32-3.08 (m, 5H), 2.17 (m, 1H), 2.04 (m, 1H ), 1.89 (m, 2H), 1.71 (m, 1H).

Primjer 186 Example 186

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-(2-hidroksifenil)-1-benzofuran-2-karboksamid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-(2-hydroxyphenyl)-1-benzofuran-2-carboxamide

[image] [image]

Suspenziji od 200 mg (0.48 mmol) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-(2-metoksifenil)-1-benzofuran-2-karboksamid-hidroklorida (primjer 102) u 8 mL diklormetana, ohlađenoj na -20 °C, doda se 2.42 mL 1 M otopine bortribromida u diklormetanu. Nakon 2 h reakcija se prekine dodatkom dietiletera. Smjesa se miješa 30 min pri sobnoj temperaturi, potom se pretvori vodom i dovede do neutralnosti 1 N natrijevom lužinom. Ekstrahira se etilnim esterom octene kiseline, organske faze se spoje i osuše iznad natrijevog sulfata. Nakon zgušnjavanja i sušenja u visokom vakuumu dobije se 125.9 mg (71.1 % od teor.) naslovnog spoja. A suspension of 200 mg (0.48 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-(2-methoxyphenyl)-1-benzofuran-2-carboxamide hydrochloride (example 102 ) in 8 mL of dichloromethane, cooled to -20 °C, add 2.42 mL of a 1 M solution of boron tribromide in dichloromethane. After 2 h, the reaction is stopped by the addition of diethyl ether. The mixture is stirred for 30 min at room temperature, then diluted with water and brought to neutrality with 1 N sodium hydroxide solution. It is extracted with ethyl acetate, the organic phases are combined and dried over sodium sulfate. After concentration and drying in high vacuum, 125.9 mg (71.1% of theory) of the title compound is obtained.

HPLC (metoda 1): Rt = 3.84 min. MS (ESIpos): m/z = 363 (M+H)+. HPLC (method 1): Rt = 3.84 min. MS (ESIpos): m/z = 363 (M+H) + .

Primjer 187 Example 187

(3R)-3-({[7-(2-metoksifenil)-1-benzofuran-2-il]karbonil}amino)-1-metil-1-azoniabiciklo[2.2.2]oktan-klorid (3R)-3-({[7-(2-methoxyphenyl)-1-benzofuran-2-yl]carbonyl}amino)-1-methyl-1-azoniabicyclo[2.2.2]octane chloride

[image] [image]

Otopini od 250 mg (0.61 mmol) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-(2-metoksifenil)-1-benzofuran-2-karboksamid-hidroklorida (primjer 102) u 2.5 mL diklormetana, ohlađenoj na -20 °C, doda se 60.5 mg (1.51 mmol) natrijevog hidrida (60 %-tna suspenzija u mineralnom ulju). Nakon 30 min na sobnoj temperaturi i hlađenja na -20 °C doda se 33.9 μL (0.54 mmola) jodometana. Nakon 18 h na sobnoj temperaturi reakcija se prekine dodatkom vode. Smjesa se pročisti preparativnom HPLC. Frakcije produkta se zgusnu, kodestiliraju sa 1 N solnom kiselinom, ponovno zgusnu i osuše u visokom vakuumu. Dobije se 206 mg (79.7 % teor.) naslovnog spoja. Solutions of 250 mg (0.61 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-(2-methoxyphenyl)-1-benzofuran-2-carboxamide hydrochloride (Example 102 ) in 2.5 mL of dichloromethane, cooled to -20 °C, add 60.5 mg (1.51 mmol) of sodium hydride (60% suspension in mineral oil). After 30 min at room temperature and cooling to -20 °C, 33.9 μL (0.54 mmol) of iodomethane was added. After 18 h at room temperature, the reaction is stopped by the addition of water. The mixture is purified by preparative HPLC. The product fractions are concentrated, co-distilled with 1 N hydrochloric acid, concentrated again and dried under high vacuum. 206 mg (79.7 % of theory) of the title compound are obtained.

1H-NMR (200 MHz, DMSO-d6): δ = 9.23 (d, 1H), 8.02 (s, 1H), 7.77 (d, 1H), 7.46 (dd, 1H), 7.39 (m, 3H), 7.20 (d, 1H), 7.09 (dd, 1H), 4.32 (m, 1H), 3.83 (m, 1H), 3.75 (s, 3H), 3.63 (m, 1H), 3.49-3.33 (m, 4H), 2.96 (s, 3H), 2.27 (m, 1H), 2.20 (m, 1H), 1.97 (m, 2H), 1.83 (m, 1H). 1H-NMR (200 MHz, DMSO-d6): δ = 9.23 (d, 1H), 8.02 (s, 1H), 7.77 (d, 1H), 7.46 (dd, 1H), 7.39 (m, 3H), 7.20 (d, 1H), 7.09 (dd, 1H), 4.32 (m, 1H), 3.83 (m, 1H), 3.75 (s, 3H), 3.63 (m, 1H), 3.49-3.33 (m, 4H), 2.96 (s, 3H), 2.27 (m, 1H), 2.20 (m, 1H), 1.97 (m, 2H), 1.83 (m, 1H).

HPLC (metoda 1): Rt = 4.19 min. HPLC (method 1): Rt = 4.19 min.

MS (ESIpos): m/z = 391 (M+H)+. MS (ESIpos): m/z = 391 (M+H) + .

Primjer 188 Example 188

(3R)-1-benzil-3-({[7-(2-metoksifneil)-1-benzofuran-2-il]karbonil}arnino)-1-metil-1-azoniabiciklo[2.2.2]oktan-bromid (3R)-1-benzyl-3-({[7-(2-methoxyphenyl)-1-benzofuran-2-yl]carbonyl}arnino)-1-methyl-1-azoniabicyclo[2.2.2]octane bromide

[image] [image]

Otopini od 500 mg (1.21 mmol) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-(2-metoksifenil)-1-benzofuran-2-karboksamid-hidroklorida (primjer 102) u 12.5 mL DMF doda se 288 μL (2.42 mmola) benzilbromida i 502 mg (3.63 mmola) kalijevog karbonata. Nakon 20 h na 50 °C reakcijska smjesa se pročisti preparativnom HPLC. Frakcije produkta se zgusnu, pretvore 50 %-tnom bromovodičnom kiselinom, ponovno zgusnu i osuše u visokom vakuumu. Kristalizacija iz cikloheksan/acetona daje 537 mg (77 % od teor.) naslovnog spoja. Solutions of 500 mg (1.21 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-(2-methoxyphenyl)-1-benzofuran-2-carboxamide hydrochloride (Example 102 ) 288 μL (2.42 mmol) of benzyl bromide and 502 mg (3.63 mmol) of potassium carbonate are added to 12.5 mL of DMF. After 20 h at 50 °C, the reaction mixture is purified by preparative HPLC. The product fractions are concentrated, treated with 50% hydrobromic acid, concentrated again and dried in a high vacuum. Crystallization from cyclohexane/acetone afforded 537 mg (77% of theory) of the title compound.

HPLC (metoda 1): Rt = 4.44 min. HPLC (method 1): Rt = 4.44 min.

MS (ESIpos): m/z = 467 (M+H)+. MS (ESIpos): m/z = 467 (M+H) + .

Primjer 189 Example 189

(3R)-3-[{[7-(2-metoksifenil)-1-benzofuran-2-il]karbonil}(metil)-amino]-1-metil-1-azoniabiciklo[2.2.2]oktan-klorid (3R)-3-[{[7-(2-methoxyphenyl)-1-benzofuran-2-yl]carbonyl}(methyl)-amino]-1-methyl-1-azoniabicyclo[2.2.2]octane chloride

[image] [image]

Otopini od 250 mg (0.61 mmol) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-(2-metoksifenil)-1-benzofuran-2-karboksamid-hidroklorida (primjer 102) u 2.5 mL DMF, ohlađenoj na -20 °C, doda se 84.8 mg (2.12 mmola) natrijevog hidrida (60 %-tna suspenzija u mineralnom ulju). Nakon 30 min na sobnoj temperaturi i ponovnog hlađenja na -20 °C doda se 94.2 μL (1.51 mmol) jodometana. Nakon 18 h na sobnoj temperaturi reakcija se prekine dodavtkom vode. Smjesa se pročisti preparativnom HPLC. Frakcije produkta se zgusnu, kodestiliraju sa smjesom 1:1 metanola i 4 M klorovodika u dioksanu, ponovno zgusnu i osuše u visokom vakuumu. Dobije se 58 mg (21.7 % od teor.) naslovnog spoja. Solutions of 250 mg (0.61 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-(2-methoxyphenyl)-1-benzofuran-2-carboxamide hydrochloride (Example 102 ) in 2.5 mL of DMF, cooled to -20 °C, add 84.8 mg (2.12 mmol) of sodium hydride (60% suspension in mineral oil). After 30 min at room temperature and cooling again to -20 °C, 94.2 μL (1.51 mmol) of iodomethane was added. After 18 h at room temperature, the reaction is stopped by adding water. The mixture is purified by preparative HPLC. The product fractions are concentrated, co-distilled with a 1:1 mixture of methanol and 4 M hydrogen chloride in dioxane, concentrated again and dried under high vacuum. 58 mg (21.7% of theory) of the title compound is obtained.

HPLC (metoda 1): Rt = 4.17 min. HPLC (method 1): Rt = 4.17 min.

MS (ESIpos): m/z = 405 (M+H)+. MS (ESIpos): m/z = 405 (M+H) + .

Primjer 190 Example 190

7-(2-metoksifenil)-N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-1-benzofuran-2-karboksamid 7-(2-methoxyphenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide

[image] [image]

Otopini od 110 mg N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-[2-(metoksi)fenil]-1-benzofuran-2-karboksamida (primjer 130) u 2 mL metanola, ohlađenoj na 0 °C, doda se 35.8 μL (0.35 mmola) 30 %-tnog vodikovog peroksida. Nakon 18 h na sobnoj temperaturi doda se još 35.8 μL (0.35 mmola) 30 %-tnog vodikovog peroksida. Nakon još 18 h na sobnoj temperaturi reakcijska se otopina zgusne, te se ostatak osuši u visokom vakuumu. Dobije se 111.5 (97.2 % od teor.) naslovnog spoja. Solutions of 110 mg of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[2-(methoxy)phenyl]-1-benzofuran-2-carboxamide (Example 130) in 2 mL of methanol, cooled to 0 °C, add 35.8 μL (0.35 mmol) of 30% hydrogen peroxide. After 18 h at room temperature, another 35.8 μL (0.35 mmol) of 30% hydrogen peroxide is added. After another 18 h at room temperature, the reaction solution thickens, and the residue is dried in a high vacuum. 111.5 (97.2 % of theory) of the title compound is obtained.

1H-NMR (400 MHz, metanol-d4): δ = 7.69 (d, 1H), 7.59 (s, 1H), 7.41 (m, 3H), 7.37 (dd, 1H), 7.16 (d, 1H), 7.08 (dd, 1H), 4.57 (m, 1H), 3.78 (s, 3H), 3.75 (m, 1H), 3.43-3.30 (m, 5H), 2.22 (m, 2H), 2.13 (m, 2H), 1.99 (m, 2H). 1H-NMR (400 MHz, methanol-d4): δ = 7.69 (d, 1H), 7.59 (s, 1H), 7.41 (m, 3H), 7.37 (dd, 1H), 7.16 (d, 1H), 7.08 (dd, 1H), 4.57 (m, 1H), 3.78 (s, 3H), 3.75 (m, 1H), 3.43-3.30 (m, 5H), 2.22 (m, 2H), 2.13 (m, 2H), 1.99 (m, 2H).

HPLC (metoda 1): Rt = 4.18 min. HPLC (method 1): Rt = 4.18 min.

MS (ESIpos): m/z = 393 (M+H)+. MS (ESIpos): m/z = 393 (M+H) + .

Primjer 191 Example 191

N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-6-[3-(4-morfolinilmetil)fenil]-1-benzotiofen-2-karboksamid-dihidroklorid N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-[3-(4-morpholinylmethyl)phenyl]-1-benzothiophene-2-carboxamide dihydrochloride

[image] [image]

Otopini od 80 mg (0.17 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-6-(3-formilfenil)-1-benzotiofen-2-karboksamid-hidroksida (primjer 33A) u 1.0 mL smjese 6:1 metanola i octene kiseline doda se 290 mg (3.32 mmola) morfolina, potom 31 mg (0.50 mmola) natrijevog cijanoborhidrida. Nakon 18 h na 80 °C smjesa se pročisti preparativnom HPLC. Frakcije produkta se zgusnu, pretvore smjesom 5:1 metanola i 1 N solne kiseline i ponovno zgusnu. Nakon sušenja u visokom vakuumu dobije se 47 mg (49.8 % od teor.) naslovnog spoja. Solutions of 80 mg (0.17 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(3-formylphenyl)-1-benzothiophene-2-carboxamide hydroxide (Example 33A ) in 1.0 mL of a mixture of 6:1 methanol and acetic acid, 290 mg (3.32 mmol) of morpholine, then 31 mg (0.50 mmol) of sodium cyanoborohydride are added. After 18 h at 80 °C, the mixture is purified by preparative HPLC. The product fractions are concentrated, reconstituted with a mixture of 5:1 methanol and 1 N hydrochloric acid and concentrated again. After drying in high vacuum, 47 mg (49.8% of theory) of the title compound is obtained.

HPLC (metoda 1): Rt = 3.64 min. HPLC (method 1): Rt = 3.64 min.

Primjer 192 Example 192

7-(5-acetil-2-tienil)-N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-1-benzofuran-2-karboksamid-hidro klorida 7-(5-acetyl-2-thienyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide hydrochloride

[image] [image]

Smjesi od 150 mg (0.39 mmola) N-[(3R)-1-azabiciklo[2.2.2]okt-3-il]-7-brom-1-benzofuran-2-karboksamid-hidroklorida (primjer 30A) i 66.1 mg (0.39 mmola) 5-acetil-2-tienilboronske kiseline u 2 mL DMF doda se 0.58 mL 2 M vodene otopine natrijevog karbonata i 15.9 mg (0.02 mmola) PdCl2(dppf). Reakcijska smjesa se zagrijava 18 h na 70 °C, filtrira na silikagelu, i zgusne do suhoga. Nakon pročišćavanja sirovog produkta preparativnom HPLC, potom pretvaranja smjesom 1:1 metanola i 1 N solne kiseline, zgušnjavanja i sušenja u visokom vakuumu dobije se 83.6 mg (49.9 % od teor.) naslovnog spoja. Mixtures of 150 mg (0.39 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide hydrochloride (Example 30A) and 66.1 mg (0.39 mmol) of 5-acetyl-2-thienylboronic acid in 2 mL of DMF was added to 0.58 mL of 2 M aqueous sodium carbonate solution and 15.9 mg (0.02 mmol) of PdCl2(dppf). The reaction mixture is heated for 18 h at 70 °C, filtered on silica gel, and concentrated to dryness. After purification of the crude product by preparative HPLC, then conversion with a mixture of 1:1 methanol and 1 N hydrochloric acid, concentration and drying in high vacuum, 83.6 mg (49.9 % of theory) of the title compound are obtained.

1H-NMR (400 MHz, DMSO-d6): δ = 10.29 (br. s, 1H), 9.10 (d, 1H), 8.07 (m, 2H), 7.95 (m, 1H), 7.93 (d, 1H), 7.87 (d, 1H), 7.46 (dd, 1H), 4.38 (m, 1H), 3.63 (m, 1H), 3.40 (m, 2H), 3.23 (m, 3H), 2.60 (s, 3H), 2.27 (m, 1H), 2.16 (m, 1H), 1.94 (m, 2H), 1.77 (m, 1H). 1H-NMR (400 MHz, DMSO-d6): δ = 10.29 (no. s, 1H), 9.10 (d, 1H), 8.07 (m, 2H), 7.95 (m, 1H), 7.93 (d, 1H) , 7.87 (d, 1H), 7.46 (dd, 1H), 4.38 (m, 1H), 3.63 (m, 1H), 3.40 (m, 2H), 3.23 (m, 3H), 2.60 (s, 3H), 2.27 (m, 1H), 2.16 (m, 1H), 1.94 (m, 2H), 1.77 (m, 1H).

HPLC (metoda 1): Rt = 3.99 min. HPLC (method 1): Rt = 3.99 min.

MS (ESIpos): m/z = 495 (M+H)+ (slobodna baza). MS (ESIpos): m/z = 495 (M+H)+ (free base).

Claims

1. Spojevi formule [image] naznačeni time, da u njoj R1 predstavlja 1-aza-biciklo [2.2.2] okt-3-il, koji je opcijski supstituiran preko dušikovog atoma s nekim ostatkom dabranim iz skupine koju čine C1-C4-alkil, benzil i oksi, R predstavlja vodik ili C1-C6-alkil, R3 predstavlja vodik, halogen ili C1-C6-alkil, R4predstavlja vodik, halogen, cijano, amino, trifluormetil, trifluormetoksi, C1-C6-alkil, C1-C6-alkilkarbonil, C1-C6-alkilamino, formil, hidroksikarbonil, C1-C6-alkoksi, C1-C6-alkoksikarbonil, C1-C6-alkiltio, C1-C6-alkilkarbonilamino, C1-C6-alkilaminokarbonil, C1-C4-alkilsulfonilamino, C3-C8-cikloalkilkarbonilamino, C3-C6-cikloalkilaminokarbonil, pirolil, C1-C6-alkilaminokarbonilamino, heterociklil-karbonil, heterociklilkarbonilamino, heteroarilkarbonil-amino, hidroksi, fenil ili heterociklil, pri čemu C1-C6-alkil može opcijski biti supstituiran s hidroksi, cijano, amino, C1-C6-alkilaminokarbonilamino, C1-C6-alkilamino-karboksil, heterociklil ili aril, C1-C6-alkilarninokarbonil opcijski s C1-C6-alkoksi ili C1-C6-alkilamino, C1-C6-alkilkarbonilamino opcijski s C1-C6-alkoksi i heterociklil opcijski s okso, A predstavlja kisik ili sumpor, prsten B predstavlja benzo ili pirido, koji svaki može opcijski biti supstituiran ostatcima iz niza halogen, cijano, formil, trifluormetil, trifluormetoksi, nitro, amino, C1-C6-alkil i C1-C6-alkoksi, a predstavlja C≡C, aril i heteroaril, pri čemu aril i heteroaril mogu biti supstituirani ostatkom iz niza koji sadrži halogen, cijano, trifluormetil, trifluormetoksi, nitro, amino, C1-C6-alkoksi i C1-C6-alkil, kao i solvati, te soli i solvati soli ovih spojeva.1. Compounds of the formula [image] indicated by the fact that in it R1 represents 1-aza-bicyclo [2.2.2] oct-3-yl, which is optionally substituted via the nitrogen atom with a radical selected from the group consisting of C1-C4-alkyl, benzyl and oxy, R represents hydrogen or C1-C6-alkyl, R3 represents hydrogen, halogen or C1-C6-alkyl, R4represents hydrogen, halogen, cyano, amino, trifluoromethyl, trifluoromethoxy, C1-C6-alkyl, C1-C6-alkylcarbonyl, C1-C6-alkylamino, formyl, hydroxycarbonyl, C1-C6-alkoxy, C1-C6-alkoxycarbonyl, C1-C6 -alkylthio, C1-C6-alkylcarbonylamino, C1-C6-alkylaminocarbonyl, C1-C4-alkylsulfonylamino, C3-C8-cycloalkylcarbonylamino, C3-C6-cycloalkylaminocarbonyl, pyrrolyl, C1-C6-alkylaminocarbonylamino, heterocyclyl-carbonyl, heterocyclylcarbonylamino, heteroarylcarbonyl-amino , hydroxy, phenyl or heterocyclyl, wherein C1-C6-alkyl may optionally be substituted with hydroxy, cyano, amino, C1-C6-alkylaminocarbonylamino, C1-C6-alkylamino-carboxyl, heterocyclyl or aryl, C1-C6-alkylarninocarbonyl optionally with C1-C6-alkoxy or C1-C6-alkylamino, C1-C6-alkylcarbonylamino optionally with C1-C6-alkoxy and heterocyclyl optionally with oxo, A represents oxygen or sulfur, ring B represents benzo or pyrido, each of which may be optionally substituted with radicals from the group consisting of halogen, cyano, formyl, trifluoromethyl, trifluoromethoxy, nitro, amino, C1-C6-alkyl and C1-C6-alkoxy, and represents C≡C, aryl and heteroaryl, wherein the aryl and heteroaryl can be substituted by a radical from the series containing halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C1-C6-alkoxy and C1-C6-alkyl, as well as solvates, and salts and solvates of salts of these compounds.

2. Spojevi prema zahtjevu 1, formule (I), naznačeni time, da u njoj R1 predstavlja l-aza-biciklo[2.2.2]okt-3-il, R2 predstavlja vodik ili C1-C4-alkil, R3 predstavlja vodik, fluor, klor, brom ili C1-C4-alkil, R4 predstavlja vodik, fluor, klor, brom, cijano, amino, trifluormetil, trifluormetoksi, C1-C4-alkil, C1-C4-alkilkarbonil, C1-C4-alkilamino, formil, hidroksikarbonil, C1-C4-alkoksi, C1-C4-alkoksikarbonil, C1-C4-alkiltio, C1-C4-alkilkarbonilamino, C1-C4-alkilaminokarbonil, C1-C4-alkilsulfonilamino, C3-C6-ciklo-alkilkarbonilamino, C3-C6-cikloalkilaminokarbonil, pirolil, C1-C4-alkilaminokarbonil-amino, heterociklilkarbonil, heterociklilkarbonilamino, heteroarilkarbonilamino, hidroksi, fenil ili heterociklil, pri čemu C1-C4-alkil može biti opcijski supstituiran s hidroksi, cijano, amino, C1-C4-alkilaminokarbonil-amino, C1-C4-alkilaminokarboksilom, hetero-ciklilom ili arilom, C1-C4-alkilaminokarbonil može biti opcijski supstituiran s C1-C4-alkoksi ili C1-C4-alkilamino, C1-C4-alkilkarbonilamino može biti opcijski supstituiran s C1-C4-alkoksi, a heterociklil može biti opcijski supstituiran s okso, A predstavlja kisik ili sumpor, prsten B predstavlja benzo ili pirido, koji su ponekad opcijski supstituirani ostatkom iz skupine halogen, cijano, trifluormetil, trifluormetoksi i C1-C4-alkil, i E predstavlja C≡C, aril i heteroaril, pri čemu aril i heteroaril mogu biti supstituirani ostatkom iz skupine halogen, cijano, trifluormetil, trifluormetoksi, nitro, amino, C1-C4-alkoksi i C1-C4-alkil, i solvati, te soli i solvati soli tih spojeva.2. Compounds according to claim 1, formula (I), characterized in that in it R1 represents l-aza-bicyclo[2.2.2]oct-3-yl, R2 represents hydrogen or C1-C4-alkyl, R3 represents hydrogen, fluorine, chlorine, bromine or C1-C4-alkyl, R4 represents hydrogen, fluorine, chlorine, bromine, cyano, amino, trifluoromethyl, trifluoromethoxy, C1-C4-alkyl, C1-C4-alkylcarbonyl, C1-C4-alkylamino, formyl, hydroxycarbonyl, C1-C4-alkoxy, C1-C4- Alkoxycarbonyl, C1-C4-alkylthio, C1-C4-alkylcarbonylamino, C1-C4-alkylaminocarbonyl, C1-C4-alkylsulfonylamino, C3-C6-cyclo-alkylcarbonylamino, C3-C6-cycloalkylaminocarbonyl, pyrrolyl, C1-C4-alkylaminocarbonyl-amino, heterocyclylcarbonyl, heterocyclylcarbonylamino, heteroarylcarbonylamino, hydroxy, phenyl or heterocyclyl, wherein C1-C4-alkyl may be optionally substituted with hydroxy, cyano, amino, C1-C4-alkylaminocarbonyl-amino, C1-C4-alkylaminocarboxyl, hetero-cyclyl or aryl, C1-C4-alkylaminocarbonyl may be optionally substituted with C1-C4-alkoxy or C1-C4-alkylamino, C1-C4-alkylcarbonylamino may be optionally substituted with C1-C4-alkoxy, and heterocyclyl may be optionally substituted with oxo, A represents oxygen or sulfur, ring B represents benzo or pyrido, which are sometimes optionally substituted with a radical from the group halogen, cyano, trifluoromethyl, trifluoromethoxy and C1-C4-alkyl, and E represents C≡C, aryl and heteroaryl, whereby aryl and heteroaryl can be substituted by a radical from the group halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C1-C4-alkoxy and C1-C4-alkyl, and solvates, and salts and solvates of salts of these compounds.

3. Spojevi prema zahtjevima 1 i 2, formule (I), naznačeni time, da u njoj R1 predstavlja l-aza-biciklo[2.2.2]okt-3-il, R2 i R3 predstavljaju vodik, R4 predstavlja vodik, fluor, klor, brom, cijano, amino, trifluormetil, trifluormetoksi, C1-C4-alkil, C1-C4-alkilkarbonil, C1-C4-alkilamino, formil, hidroksikarbonil, C1-C4-alkoksi, C1-C4-alkoksikarbonil, C1-C6-alkiltio, C1-C4-alkilkarbonilamino, C1-C4-alkilaminokarbonil, C1-C4-alkilsulfonilamino, C3-C6-ciklo-alkilkarbonilamino, C3-C6-cikloalkilaminokarbonil, pirolil, C1-C4-alkilaminokarbonil-amino, heterociklilkarbonil, heterociklilkarbonilamino, heteroarilkarbonilamino, hidroksi, fenil ili heterociklil, pri čemu C1-C4-alkil može biti opcijski supstituiran s hidroksi, cijano, amino, C1-C4-alkilaminokarbonil-amino, C1-C4-alkilaminokarboksilom, hetero-ciklilom ili arilom, C1-C4-alkilaminokarbonil može biti opcijski supstituiran s C1-C4-alkoksi ili C1-C4-alkilamino, C1-C4-alkilkarbonilamino može biti opcijski supstituiran s C1-C4-alkoksi, a heterociklil može biti opcijski supstituiran s okso. A predstavlja kisik, prsten B predstavlja benzo ili pirido, koji su ponekad opcijski supstituirani s ostatkom iz skupine halogen, cijano, trifluorometil, trifluorometoksi i C1-C4-alkil, i E predstavlja C≡C, aril i heteroaril, pri čemu aril i heteroaril mogu biti opcijski supstituirani ostatkom iz skupine halogen, cijano, trifluormetil, trifluormetoksi, nitro, amino, C1-C4-alkoksi i C1-C4-alkil, te solvati, soli i solvati soli tih spojeva.3. Compounds according to claims 1 and 2, formula (I), characterized by the fact that therein R1 represents l-aza-bicyclo[2.2.2]oct-3-yl, R2 and R3 represent hydrogen, R4 represents hydrogen, fluorine, chlorine, bromine, cyano, amino, trifluoromethyl, trifluoromethoxy, C1-C4-alkyl, C1-C4-alkylcarbonyl, C1-C4-alkylamino, formyl, hydroxycarbonyl, C1-C4-alkoxy, C1-C4- Alkoxycarbonyl, C1-C6-alkylthio, C1-C4-alkylcarbonylamino, C1-C4-alkylaminocarbonyl, C1-C4-alkylsulfonylamino, C3-C6-cyclo-alkylcarbonylamino, C3-C6-cycloalkylaminocarbonyl, pyrrolyl, C1-C4-alkylaminocarbonyl-amino, heterocyclylcarbonyl, heterocyclylcarbonylamino, heteroarylcarbonylamino, hydroxy, phenyl or heterocyclyl, wherein C1-C4-alkyl may be optionally substituted with hydroxy, cyano, amino, C1-C4-alkylaminocarbonyl-amino, C1-C4-alkylaminocarboxyl, hetero-cyclyl or aryl, C1-C4-alkylaminocarbonyl may be optionally substituted with C1-C4-alkoxy or C1-C4-alkylamino, C1-C4-alkylcarbonylamino may be optionally substituted with C1-C4-alkoxy, and heterocyclyl may be optionally substituted with oxo. A represents oxygen, ring B is benzo or pyrido, which are sometimes optionally substituted with a radical from the group halogen, cyano, trifluoromethyl, trifluoromethoxy and C1-C4-alkyl, and E represents C≡C, aryl and heteroaryl, wherein aryl and heteroaryl can be optionally substituted by a radical from the group halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C1-C4-alkoxy and C1-C4-alkyl, and solvates, salts and solvates of salts of these compounds.

4. Spojevi prema zahtjevima 1 do 3, formule (I), naznačeni time, da u njoj R1 predstavlja l-aza-biciklo[2.2.2]okt-3-il, R2predstavlja vodik ili C1-C6-alkil, R3 predstavlja vodik, halogen ili C1-C6-alkil, R4 predstavlja vodik, halogen, cijano, amino, trifluormetil, trifluormetoksi, C1-C6-alkil, C1-C6-alkilkarbonil, C1-C6-alkilamino, formil, hidroksikarbonil, C1-C6-alkoksi, C1-C6-alkoksikarbonil, C1-C6-alkiltio, C1-C6-alkilkarbonilamino, C1-C4-alkilsulfonilamino, C3-C8-cikloalkilkarbonilamino, pirolil, C1-C6-alkilaminokarbonilamino, heterociklil-karbonil, fenil ili heterociklil, pri čemu C1-C6-alkil može biti opcijski supstituiran s hidroksi, amino, C1-C6-alkilaminokarbonilamino, C1-C6-alkilamino-karboksilom, heterociklilom ili arilom, C1-C6-alkilkarbonilamino može biti opcijski supstituiran s C1-C6-alkoksi, a heterociklil može biti opcijski supstituiran s okso, A predstavlja kisik ili sumpor, prsten B predstavlja benzo ili pirido, koji su ponekad opcijski supstituirani ostatkom iz skupine halogen cijano, formil, trifluormetil, trifluormetoksi, nitro, amino, C1-C6-alkil i C1-C6-alkoksi, i E predstavlja C≡C, aril i heteroaril, pri čemu aril i heteroaril mogu biti opcijski supstituirani ostatkom iz skupine halogen, cijano, trifluormetil, trifluormetoksi, nitro, amino, C1-C6-alkoksi i C1-C6-alkil, i solvati, te soli i solvati soli tih spojeva.4. Compounds according to claims 1 to 3, formula (I), characterized in that in it R1 represents l-aza-bicyclo[2.2.2]oct-3-yl, R2 represents hydrogen or C1-C6-alkyl, R3 represents hydrogen, halogen or C1-C6-alkyl, R 4 represents hydrogen, halogen, cyano, amino, trifluoromethyl, trifluoromethoxy, C1-C6-alkyl, C1-C6-alkylcarbonyl, C1-C6-alkylamino, formyl, hydroxycarbonyl, C1-C6-alkoxy, C1-C6- alkoxycarbonyl, C1- C6-alkylthio, C1-C6-alkylcarbonylamino, C1-C4-alkylsulfonylamino, C3-C8-cycloalkylcarbonylamino, pyrrolyl, C1-C6-alkylaminocarbonylamino, heterocyclyl-carbonyl, phenyl or heterocyclyl, wherein C1-C6-alkyl may be optionally substituted with hydroxy, amino, C1-C6-alkylaminocarbonylamino, C1-C6-alkylamino-carboxyl, heterocyclyl or aryl, C1-C6-alkylcarbonylamino may be optionally substituted with C1-C6-alkoxy, and heterocyclyl may be optionally substituted with oxo, A represents oxygen or sulfur, ring B represents benzo or pyrido, which are sometimes optionally substituted with a radical from the group halogeno cyano, formyl, trifluoromethyl, trifluoromethoxy, nitro, amino, C1-C6-alkyl and C1-C6-alkoxy, and E represents C≡C, aryl and heteroaryl, wherein aryl and heteroaryl can be optionally substituted by a radical from the group halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C1-C6-alkoxy and C1-C6-alkyl, and solvates, and salts and solvates of salts of these compounds.

5. Spojevi formule (I) prema zahtjevima 1 do 4, naznačeni time, da u njoj R1 predstavlja l-aza-biciklo[2.2.2]okt-3-il, R2 predstavlja vodik ili C1-C6-alkil, R3 predstavlja vodik, halogen ili C1-C6-alkil, R4 predstavlja vodik, halogen, cijano, trifluormetil, trifluorometoksi, C1-C6-alkil, C1-C6-alkoksi ili heterociklil, pri čemu je alkil opcijski supstituiran hidroksi ostatkom, A predstavlja kisik ili sumpor, prsten B predstavlja benzo ili pirido, koji su ponekad opcijski supstituirani ostatkom iz skupine halogen, cijano, trifluormetil, trifluormetoksi, nitro, amino, C1-C6-alkil i C1-C6-alkoksi, i E predstavlja C≡C, aril ili heteroaril, pri čemu aril i heteroaril mogu biti supstituirani ostatkom iz skupine halogen, cijano, trifluormetil, trifluormetoksi, nitro, amino, C1-C6-alkil i C1-C6-alkoksi, te solvati, soli i solvati soli tih spojeva.5. Compounds of formula (I) according to claims 1 to 4, characterized in that in it R1 represents l-aza-bicyclo[2.2.2]oct-3-yl, R2 represents hydrogen or C1-C6-alkyl, R3 represents hydrogen, halogen or C1-C6-alkyl, R4 represents hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, C1-C6-alkyl, C1-C6-alkoxy or heterocyclyl, wherein the alkyl is optionally substituted by a hydroxy residue, A represents oxygen or sulfur, ring B is benzo or pyrido, which are sometimes optionally substituted with a radical from the group halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C1-C6-alkyl and C1-C6-alkoxy, and E represents C≡C, aryl or heteroaryl, whereby aryl and heteroaryl can be substituted by a radical from the group halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C1-C6-alkyl and C1-C6-alkoxy, and solvates, salts and solvates of salts of these compounds.

6. Spojevi prema zahtjevima 1 do 5, formule [image] naznačeni time, da u njoj R1predstavlja (3R)-1-aza-biciklo [2.2.2] okt-3-il, R2 i R3 međusobno nezavisno predstavljaju vodik ili metil, R4 predstavlja vodik, halogen, cijano, trifluormetil, trifluormetoksi, C1-C6-alkil, C1-C6-alkoksi ili heterociklil, pri čemu je alkil opcijski supstituiran hidroksi ostatkom, i RB predstavlja vodik, halogen, cijano, trifluormetil, trifluormetoksi, nitro, amino, C1-C6-alkil ili C1-C6-alkoksi, kao i solvati, te soli ili solvati soli tih spojeva. 6. Compounds according to claims 1 to 5, formulas [image] indicated by the fact that in it R1 represents (3R)-1-aza-bicyclo [2.2.2] oct-3-yl, R2 and R3 independently represent hydrogen or methyl, R4 represents hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, C1-C6-alkyl, C1-C6-alkoxy or heterocyclyl, wherein the alkyl is optionally substituted with a hydroxy residue, and RB represents hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C1-C6-alkyl or C1-C6-alkoxy, as well as solvates, and salts or solvates of salts of these compounds.

7. Spojevi prema zahtjevima 1 do 6, formule [image] naznačeni time, da u njoj R1 predstavlja (3R)-1-aza-biciklo[2.2.2]okt-3-il, R2 i R3 predstavljaju međusobno nezavisno vodik ili metil, R4 predstavlja vodik, halogen, cijano, trifluormetil, trifluorometoksi, C1-C6-alkil, C1-C6-alkoksi ili heterociklil, pri čemu je alkil opcijski supstituiran hidroksi ostatkom, RB predstavlja vodik, halogen, cijano, trifluormetil, trifluorometoksi, nitro, amino, C1-C6-alkil i C1-C6-alkoksi, i solvati, te soli i solvati soli tih spojeva.7. Compounds according to claims 1 to 6, formulas [image] indicated by the fact that in it R1 represents (3R)-1-aza-bicyclo[2.2.2]oct-3-yl, R2 and R3 independently represent hydrogen or methyl, R4 represents hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, C1-C6-alkyl, C1-C6-alkoxy or heterocyclyl, wherein the alkyl is optionally substituted by a hydroxy residue, RB represents hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C1-C6-alkyl and C1-C6-alkoxy, and solvates, and salts and solvates of salts of these compounds.

8. Spojevi prema zahtjevima 1 do 7, naznačeni time, da u njima R1 predstavlja (3R)-1-aza-biciklo[2.2.2]okt-3-il, R2 i R3 predstavljaju vodik, R4 predstavlja vodik, fluor, klor, brom, trifluormetoksi, hidroksimetil, metoksi ili 6-člani heterociklil, a RB predstavlja vodik, halogen, cijano, trifluormetil, trifluorometoksi, ili C1-C4-alkil, te solvati, soli i solvati soli tih spojeva.8. Compounds according to claims 1 to 7, characterized in that in them R1 represents (3R)-1-aza-bicyclo[2.2.2]oct-3-yl, R2 and R3 represent hydrogen, R4 represents hydrogen, fluorine, chlorine, bromine, trifluoromethoxy, hydroxymethyl, methoxy or 6-membered heterocyclyl, and RB represents hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, or C1-C4-alkyl, and solvates, salts and solvates of salts of these compounds.

9. Spojevi prema zahtjevima 1 do 8, formule [image] naznačeni time, da u njoj E predstavlja fenilen, R4 predstavlja C1-C6-alkoksi, aminometilen, hidroksi-karbonil, C3-C8-cikloalkilkarbonilamino, skupinu formule [image] pri čemu R5 predstavlja C1-C6-alkil, n predstavlja nulu, 1, 2, 3 ili 4, ili 5- do 6-člani heterociklil, opcijski supstituiran s okso, A predstavlja sumpor ili kisik, i solvati, te soli i solvati soli tih spojeva.9. Compounds according to claims 1 to 8, formulas [image] characterized by the fact that in it E represents phenylene, R4 represents C1-C6-Alkoxy, aminomethylene, hydroxy-carbonyl, C3-C8-cycloalkylcarbonylamino, a group of the formula [image] whereby R5 represents C1-C6-alkyl, n represents zero, 1, 2, 3 or 4, or 5- to 6-membered heterocyclyl, optionally substituted with oxo, A represents sulfur or oxygen, and solvates, and salts and solvate salts of these compounds.

10. Spojevi prema zahtjevima 1 do 9, formule (Ic), naznačeni time, da u njoj E predstavlja fenilen, R4 predstavlja C1-C4-alkoksi, aminometilen, hidroksikarbonil, C3-C6-cikloalkilkarbonil-amino, skupinu formule [image] pri čemu R5 predstavlja C1-C4-alkil, n predstavlja nulu, 1 ili 2, ili 5- do 6-člani heterociklil, opcijski supstituiran s okso, A predstavlja sumpor ili kisik, i solvati, te soli i solvati soli tih spojeva.10. Compounds according to claims 1 to 9, formula (Ic), characterized in that in it E represents phenylene, R4 represents C1-C4-Alkoxy, aminomethylene, hydroxycarbonyl, C3-C6-cycloalkylcarbonyl-amino, a group of the formula [image] whereby R5 represents C1-C4-alkyl, n represents zero, 1 or 2, or 5- to 6-membered heterocyclyl, optionally substituted with oxo, A represents sulfur or oxygen, and solvates, and salts and solvate salts of these compounds.

11. Spojevi prema zahtjevima 1 do 10, naznačeni time, da su sljedećih formula [image] i solvati, te soli i solvati soli tih spojeva.11. Compounds according to claims 1 to 10, characterized in that they are of the following formula [image] and solvates, and salts and solvates of salts of these compounds.

12. Postupak priprave spojeva formule (I), naznačen time, da spojevi formule Xl-E-R4 (II) u kojoj R4 ima gore navedena značenja, X1 u slučaju kada E predstavlja arilen ili heteroarilen, predstavlja -B(OH)2 ili [image] a u slučaju kada E predstavlja -C≡C-, predstavlja vodik, reagiraju sa spojem formule [image] u kojoj R1, R2, R3, A i prsten B imaju u zahtjevu 1 navedena značenja, a X2 predstavlja triflat ili halogen, ponajprije klor, brom ili jod, te se opcijski [A] rezultantni spojevi (I) alkiliraju s odgovarajućim reagensima za alkiliranje na dušikovom atomu kinuklidina, ili [B] rezultantni spojevi (I) oksidiraju s prikladnim oksidacijskim sredstvima na dušikovom atomu kinuklidina, a rezultantni spojevi se (I) opcijski odgovarajućim (i) otapalima i/ili (ii) bazama ili kiselinama pretvore u svoje solvate, soli ili solvate soli.12. Process for preparing compounds of formula (I), characterized in that compounds of formula Xl-E-R4 (II) where R 4 has the above meanings, X1 in the case where E represents arylene or heteroarylene, represents -B(OH)2 or [image] and in the case when E represents -C≡C-, represents hydrogen, they react with the compound of the formula [image] where R1, R2, R3, A and ring B have the meanings specified in claim 1, a X2 represents triflate or halogen, preferably chlorine, bromine or iodine, and optional [A] the resulting compounds (I) are alkylated with suitable alkylating reagents at the quinuclidine nitrogen atom, or [B] the resulting compounds (I) are oxidized with suitable oxidizing agents on the quinuclidine nitrogen atom, and the resulting compounds are (I) optionally converted into their solvates, salts or solvates of salts with suitable (i) solvents and/or (ii) bases or acids.

13. Postupak priprave spojeva prema izumu, naznačen time, da spojevi formule formule X1-E-R4 (II), u kojoj R4 ima u zahtjevu 1 navedena značenja, X1 u slučaju kada E predstavlja arilen ili heteroarilen, predstavlja -B(OH)2 ili [image] a u slučaju kada E predstavlja -C≡C-, predstavlja vodik, reagiraju sa spojem formule [image] u kojoj R1, R2, R3, A i prsten B imaju u zahtjevu 1 navedena značenja, a X2 predstavlja triflat ili halogen, ponajprije klor, brom ili jod, te se rezultantni spojevi (I) opcijski s odgovarajućim (i) otapalima i/ili (ii) bazama ili kiselinama pretvore u svoje solvate, te soli ili solvate soli.13. Process for the preparation of compounds according to the invention, characterized in that the compounds of the formula X1-E-R4 (II), where R4 has the meanings specified in claim 1, X1 in the case where E represents arylene or heteroarylene, represents -B(OH)2 or [image] and in the case where E represents -C≡C-, it represents hydrogen, react with a compound of the formula [image] where R1, R2, R3, A and ring B have the meanings specified in claim 1, a X2 represents triflate or halogen, preferably chlorine, bromine or iodine, and the resulting compounds (I) are optionally converted with appropriate (i) solvents and/or (ii) bases or acids into their solvates, and salts or solvates of salts.

14. Spojevi prema nekom od zahtjeva 1 do 11, naznačeni time, da su za obradbu i/ili profilaksu bolesti.14. Compounds according to one of the claims 1 to 11, characterized in that they are for the treatment and/or prophylaxis of diseases.

15. Lijekovi, naznačeni time, da sadrže barem jedan spoj prema nekom od zahtjeva 1 do 11 i barem jedan farmaceutski podnošljiv neotrovan nosač ili ekscipijent.15. Medicines, characterized in that they contain at least one compound according to one of claims 1 to 11 and at least one pharmaceutically acceptable non-toxic carrier or excipient.

16. Primjena spojeva prema nekom od zahtjeva 1 do 11, naznačena time, da je za pripravu sredstva za poboljšanje sposobnosti opažanja, koncentracije, učenja i/ili pamćenja.16. Use of compounds according to one of claims 1 to 11, characterized in that it is for the preparation of means for improving the ability to perceive, concentrate, learn and/or remember.

17. Primjena spojeva prema nekom od zahtjeva 1 do 11, naznačena time, da je za pripravu lijeka za obradbu i/ili profilaksu smetnja sposobnosti opažanja, koncentracije, učenja i/ili pamćenja.17. Application of compounds according to one of claims 1 to 11, characterized in that it is for the preparation of a medicine for the treatment and/or prophylaxis of impaired perception, concentration, learning and/or memory.

18. Lijek prema zahtjevu 15, naznačen time, da je za obradbu i/ili profilaksu smetnja sposobnosti opažanja, koncentracije, učenja i/ili pamćenja.18. The drug according to claim 15, characterized in that it is for the treatment and/or prophylaxis of impaired perception, concentration, learning and/or memory.