HRP20080507A2 - Substituted morpholine and thiomorpholine derivates - Google Patents

Substituted morpholine and thiomorpholine derivates Download PDF

Info

Publication number
HRP20080507A2
HRP20080507A2 HR20080507A HRP20080507A HRP20080507A2 HR P20080507 A2 HRP20080507 A2 HR P20080507A2 HR 20080507 A HR20080507 A HR 20080507A HR P20080507 A HRP20080507 A HR P20080507A HR P20080507 A2 HRP20080507 A2 HR P20080507A2
Authority
HR
Croatia
Prior art keywords
phenyl
morpholin
alk
acetamide
cyclopentyl
Prior art date
Application number
HR20080507A
Other languages
Croatian (hr)
Inventor
Wenzel Tornoe Christian
Rottlander Mario
Khanzhin Nikolay
Ritzen Andreas
Patrick Watskon Wiliam
Original Assignee
H. Lundbeck A/S
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by H. Lundbeck A/S filed Critical H. Lundbeck A/S
Priority to HR20080507A priority Critical patent/HRPK20080507B3/en
Publication of HRP20080507A2 publication Critical patent/HRP20080507A2/en
Publication of HRPK20080507B3 publication Critical patent/HRPK20080507B3/en

Links

Abstract

Ovaj izum se odnosi na supstituirane derivate morfolina i tiomorfolina koji imaju opću formulu I ili na njihove farmaceutski prihvatljive soli te na njihovu uporabu.The present invention relates to substituted morpholine and thiomorpholine derivatives having the general formula I or their pharmaceutically acceptable salts and their use.

Description

Područje izuma Field of invention

Ovaj izum se odnosi na nove supstituirane derivate morfolina i tiomorfolina koji otvaraju kalijeve ionske kanale roda KCNQ. Ti su spojevi korisni u liječenju poremećaja i bolesti uslijed kojih dolazi do otvaranja kalijevih ionskih kanala roda KCNQ, od kojih je jedna takva bolest epilepsija. This invention relates to new substituted morpholine and thiomorpholine derivatives that open potassium ion channels of the KCNQ family. These compounds are useful in the treatment of disorders and diseases that lead to the opening of KCNQ potassium ion channels, one such disease being epilepsy.

Prethodno stanje struke Previous state of the profession

Ionski kanali su stanični proteini koji reguliraju kolanje iona, uključujući kalij, kalcij, klor i natrij, u stanice i iz njih. Ti se kanali nalaze u životinjskim i ljudskim stanicama i djeluju na različite procese, uključujući transmisiju neurona, grčenje mišića i staničnu sekreciju. Ion channels are cellular proteins that regulate the flow of ions, including potassium, calcium, chlorine, and sodium, into and out of cells. These channels are found in animal and human cells and affect a variety of processes, including neuronal transmission, muscle contraction, and cellular secretion.

Ljudi imaju preko 70 gena koji kodiraju podtipove kalijevih kanala (Jentsch, Nature Reviews Neuroscience 2000., 1, 21-30) koji su vrlo različiti s obzirom ne samo na strukturu nego i na funkciju. Neuronski kalijevi kanali, koji se nalaze u mozgu, prije svega su odgovorni za održavanje negativnog potencijala mirujuće membrane, kao i za kontrolu repolarizacije membrane nakon djelatnog potencijala. Humans have over 70 genes encoding subtypes of potassium channels (Jentsch, Nature Reviews Neuroscience 2000, 1, 21-30) that are very different not only in structure but also in function. Neuronal potassium channels, located in the brain, are primarily responsible for maintaining the negative potential of the resting membrane, as well as for controlling membrane repolarization after an action potential.

Jedna podvrsta gena kalijevih kanala je rod KCNQ. Pokazalo se da mutacije u četiri od pet KCNQ gena uzrokuju bolesti koje uključuju srčane aritmije, gluhoću i epilepsiju (Jentsch, Nature Reviews Neuroscience 2000., 1, 21-30).Smatra se da gen KCNQ kodira korelat kanala kalija koji se nalazi u vanjskim dlakavim stanicama kohleje i u dlakavim stanicama tipa I vestibularnog aparata, u kojem mutacije mogu dovesti do jednog oblika nasljedne gluhoće. One subtype of potassium channel genes is the KCNQ genus. Mutations in four of the five KCNQ genes have been shown to cause diseases that include cardiac arrhythmias, deafness, and epilepsy (Jentsch, Nature Reviews Neuroscience 2000, 1, 21-30). The KCNQ gene is thought to encode a potassium channel correlate found in the outer hair cells of the cochlea and in type I hair cells of the vestibular apparatus, in which mutations can lead to one form of hereditary deafness.

KCNQ1 (KvLQT1) skupljen je zajedno s proizvodom gena KCNE1 (minimalni K(+)-kanalni protein) u srcu i stvara kardijalno usporenu struju (K+) sličnu ispravljaču. Mutacije u tom kanalu mogu uzrokovati jedan oblik nasljednog dugog QT sindroma tipa 1 (LQT1), a može imati veze i s jednim oblikom gluhoće (Robbins, Pharmacol Ther 2001., 90, 1-19). KCNQ1 (KvLQT1) is clustered together with the KCNE1 (minimal K(+)-channel protein) gene product in the heart and generates a rectifier-like cardiac slow current (K+). Mutations in this channel can cause one form of hereditary long QT syndrome type 1 (LQT1), and may be associated with one form of deafness (Robbins, Pharmacol Ther 2001, 90, 1-19).

Geni KCNQ2 i KCNQ3 otkriveni su 1988. godine i izgleda da su mutirani u nasljednom obliku epilepsije poznate kao benigne obiteljske neonatalne konvulzije (Rogawski, Trends in Neurosciences 2000., 23, 393-398). Proteini koje kodiraju geni KCNQ2 i KCNQ3 lokalizirani su u piramidalnim neuronima ljudskog korteksa i hipokampusa, područja mozga koje se povezuje s nastankom i razvojem napadaja (Cooper i sur., Proceedings National Academy of Science USA 2000., 97, 4914-4919). The KCNQ2 and KCNQ3 genes were discovered in 1988 and appear to be mutated in an inherited form of epilepsy known as benign familial neonatal convulsions (Rogawski, Trends in Neurosciences 2000, 23, 393-398). The proteins encoded by the KCNQ2 and KCNQ3 genes are localized in pyramidal neurons of the human cortex and hippocampus, an area of the brain associated with the onset and development of seizures (Cooper et al., Proceedings National Academy of Science USA 2000, 97, 4914-4919).

KCNQ2 i KCNQ3 su dvije podjedinice kalijevog kanala koje prikazane in vitro tvore "M-struje". M-struja je ne-onesposobljujuća kalijeva struja koja se nalazi u mnogim stanicama neuronskog tipa. U svakom tipu stanice ona je dominantna u kontroli podraživosti membrane budući da je jedina trajna struja u području aktiviranja potencijala djelovanja (Marrion, Annual Review Physiology 1997., 59, 483-504). Modulacija M-struje snažno djeluje na podraživost neurona, na primjer aktiviranje struje će smanjiti podraživost neurona. Otvarači tih KCNQ. kanala ili aktivatori M-struje smanjit će prekomjerno djelovanje neurona i tako mogu biti korisni u liječenju napadaja i drugih bolesti i poremećaja koje karakterizira pretjerano djelovanje neurona, poput neuronske hiperpodraživosti uključujući konvulzivne poremećaje, epilepsiju i neuropatske bolove. KCNQ2 and KCNQ3 are two potassium channel subunits that have been shown to form "M-currents" in vitro. The M-current is a non-inactivating potassium current found in many neuronal-type cells. In each cell type, it is dominant in controlling membrane excitability since it is the only permanent current in the area of action potential activation (Marrion, Annual Review Physiology 1997, 59, 483-504). Modulation of the M-current has a strong effect on the excitability of the neuron, for example activating the current will reduce the excitability of the neuron. The openers of those KCNQ. channel or M-current activators will reduce neuronal overactivity and thus may be useful in the treatment of seizures and other diseases and disorders characterized by neuronal overactivity, such as neuronal hyperexcitability including seizure disorders, epilepsy and neuropathic pain.

Retigabin (D-23129; N-(2-amino-4-4-fluorobenzilamina)-fenil) etil ester karbamatske kiseline) i njemu analogni spojevi opisani su u EP554543. Retigabin je antikonvulzivni spoj širokog spektra i jakih antikonvulzivnih svojstava, in vitro kao i in vivo. On djeluje nakon oralne ili intraperitonealne primjene kod štakora i miševa u rasponu antikonvulzivnih testova koji uključuju: napadaje inducirane električnom strujom, napadaje inducirane kemijski pomoću pentilentetrazola, pikrotoksina i N-metil-D-aspartata (NMDA), te kod genetskog životinjskog modela, DBA/2 miša (Rostock i sur., Epilepsy Research 1996., 23, 211-223). Osim toga, retigabin djeluje u modelu poticanja amigdale kompleksnih djelomičnih napadaja, što pokazuje da ovaj spoj ima potencijala za antikonvulzivnu terapiju. U kliničkim pokusima retigabin se nedavno pokazao učinkovitim u smanjenju učestalosti napadaja kod epileptičara (Bialer i sur., Epilepsy Research 2002., 51, 31-71). Pokazalo se da retigabin aktivira K(+) struju u neuronskim stanicama, a farmakologija toga je zaključila da se iskazane struje podudaraju s objavljenom farmakologijom M-kanala, koja je nedavno dovedena u vezu s heteromultimerom kanala KCNQ2/3 K(+). To ukazuje na to da bi aktiviranje kanala KCNQ2/3 moglo biti odgovorno za neke od antikonvulzivnih djelovanja tog agensa (Wickenden i sur., Molecular Pharmacology 2000., 58, 591-600) i da bi drugi agensi koji djeluju prema jednakom mehanizmu mogli imati sličnu primjenu. Retigabine (D-23129; N-(2-amino-4-4-fluorobenzylamine)-phenyl) carbamatic acid ethyl ester) and analogous compounds are described in EP554543. Retigabine is a broad-spectrum anticonvulsant compound with strong anticonvulsant properties, both in vitro and in vivo. It acts after oral or intraperitoneal administration in rats and mice in a range of anticonvulsant tests including: electrically induced seizures, chemically induced seizures using pentylenetetrazol, picrotoxin and N-methyl-D-aspartate (NMDA), and in a genetic animal model, DBA/ 2 mice (Rostock et al., Epilepsy Research 1996, 23, 211-223). In addition, retigabine works in an amygdala stimulation model of complex partial seizures, indicating that this compound has potential for anticonvulsant therapy. In clinical trials, retigabine has recently been shown to be effective in reducing the frequency of seizures in epileptics (Bialer et al., Epilepsy Research 2002, 51, 31-71). Retigabine has been shown to activate a K(+) current in neuronal cells, and the pharmacology of this has concluded that the currents shown match the published M-channel pharmacology, which has recently been linked to the KCNQ2/3 K(+) channel heteromultimer. This suggests that activation of KCNQ2/3 channels may be responsible for some of the anticonvulsant effects of this agent (Wickenden et al., Molecular Pharmacology 2000, 58, 591-600) and that other agents acting by the same mechanism may have similar application.

Također je opisano da kanali KCNQ2 i 3 mogu biti regulirani na više kod modela neuropatskih bolova Wickenden i sur., Society for Neuroscience Abstracts 2002., 454.7), a za modulatore kalijevih kanala pretpostavlja se da djeluju i kod neuropatskih bolova i kod epilepsije (Schroder i sur., Neuropharmacology 2001., 40, 888-898). It has also been described that KCNQ2 and 3 channels can be up-regulated in neuropathic pain models (Wickenden et al., Society for Neuroscience Abstracts 2002, 454.7), and potassium channel modulators are hypothesized to act in both neuropathic pain and epilepsy (Schroder et al., Neuropharmacology 2001, 40, 888-898).

Retigabin se pokazao korisnim i kod životinjskih modela neuropatskih bolova (Blackburn-Munro i Jensen, European Journal of Pharmacology 2003., 460, 109-116), te se tako predlaže da se otvarači kanala KCNQ koriste u liječenju poremećaja bolova uključujući neuropatske bolove. Retigabine has also been shown to be useful in animal models of neuropathic pain (Blackburn-Munro and Jensen, European Journal of Pharmacology 2003, 460, 109-116), thus suggesting that KCNQ channel openers be used in the treatment of pain disorders including neuropathic pain.

Opisana je lokalizacija KCNQ kanala mRNA u područjima mozga i ostalog centralnog živčanog sustava povezana s bolom (Goldstein i sur., Society of Neuroscience Abstracts 2003., 53.8). Osim uloge kod neuropatskih bolova, pojava mRNA za KCNQ 2-5 u ganglijima trigeminatnog i dorzalnog korijena te u trigeminalnom nucleusu caudalisu znači da otvarači tih kanala mogu također djelovati na osjetilno razvijanje bolova kod migrene (Goldstein i sur., Society for Neuroscience Abstracts 2003., 53.8). Localization of KCNQ channel mRNA in areas of the brain and other central nervous system associated with pain has been described (Goldstein et al., Society of Neuroscience Abstracts 2003, 53.8). In addition to the role in neuropathic pain, the appearance of mRNA for KCNQ 2-5 in the trigeminal and dorsal root ganglia and in the trigeminal nucleus caudalis means that openers of these channels may also act on the sensory development of migraine pain (Goldstein et al., Society for Neuroscience Abstracts 2003. , 53.8).

Najnoviji izvještaji pokazuju da se mRNA za KCNQ 3 i 5, uz onaj za KCNQ2, nalaze u astrocitima i glialnim stanicama. Tako kanali KCNQ2, 3 i 5 mogu biti od pomoći u modulaciji sinaptičke aktivnosti u centralnom živčanom sustavu i pridonijeti neuroprotektivnom učinku otvarača kanala KCNQ (Noda i sur., Society for neuroscience Abstracts 2003., 53.9). Recent reports indicate that mRNA for KCNQ 3 and 5, in addition to that for KCNQ2, is found in astrocytes and glial cells. Thus, KCNQ2, 3 and 5 channels may be helpful in modulating synaptic activity in the central nervous system and contribute to the neuroprotective effect of KCNQ channel openers (Noda et al., Society for neuroscience Abstracts 2003, 53.9).

Retigabin i drugi modulatori KCNQ mogu, dakle, predstavljati zaštitu od neurodegenerativnih aspekata epilepsije, jer se pokazalo da retigabin sprječava limbičku neurodegeneraciju i izražavanje markera apoptoze nakon epileptičkog stanja izazvanog kainskom kiselinom kod štakora (Ebert i sur., Epilepsia 2002., 43. Suppl 5, 86-95). To može biti relevantno u sprječavanju napredovanja epilepsije kod bolesnika, tj. biti anti-epileptogeno. Pokazalo se također da retigabin usporava napredovanje poticanja hipokampusa kod štakora, daljnjeg modela razvoja epilepsije (Tober i sur., European Journal of Pharmacology 1996., 303, 163-169). Retigabine and other KCNQ modulators may therefore represent protection against neurodegenerative aspects of epilepsy, as retigabine has been shown to prevent limbic neurodegeneration and the expression of apoptosis markers following kainic acid-induced status epilepticus in rats (Ebert et al., Epilepsia 2002, 43 Suppl 5 , 86-95). This may be relevant in preventing the progression of epilepsy in patients, i.e. being anti-epileptogenic. Retigabine has also been shown to slow the progression of hippocampal stimulation in rats, a further model of epilepsy development (Tober et al., European Journal of Pharmacology 1996, 303, 163-169).

Prema tome se smatra da bi ta svojstva retigabina i drugih modulatora KCNQ mogla spriječiti oštećenja neurona uzrokovana pretjeranim neuroskim djelovanjem i da bi ti spojevi mogli biti korisni u liječenju neurodegenerativnih bolesti i biti modifikatori bolesti (ili antiepileptogeni) kod epileptičara. Pod pretpostavkom da se antikonvulzivni spojevi poput benzodiazepina i klormetiazola klinički rabe u liječenju sindroma ukidanja etanola te da su drugi antikonvulzivni spojevi, npr. gabapentin, vrlo učinkoviti kod životinjskih modela tog sindroma (Watson i sur., Neuropharmacology 1997., 36, 1369-1375), očekujemo da će prema tome i drugi antikonvulzivni spojevi poput otvarača KCNQ biti djelotvorni kod tog stanja. Therefore, it is believed that these properties of retigabine and other KCNQ modulators could prevent neuronal damage caused by excessive neural activity and that these compounds could be useful in the treatment of neurodegenerative diseases and be disease modifiers (or antiepileptogens) in epileptics. Assuming that anticonvulsant compounds such as benzodiazepines and chlormethiazole are clinically used in the treatment of ethanol withdrawal syndrome and that other anticonvulsant compounds, eg gabapentin, are very effective in animal models of this syndrome (Watson et al., Neuropharmacology 1997, 36, 1369-1375 ), we therefore expect that other anticonvulsant compounds such as KCNQ openers will also be effective in this condition.

mRNA za podjedinice KCNQ 2 i 3 nađen je u područjima mozga povezanima s tjeskobom i emocionalnim ponašanjima poput bipolamog poremećaja npr. hipokampus i amigdala (Saganich i sur., Journal of Neuroscience 2001., 21, 4609-4624), a retigabin je opisan kao učinkovit kod nekih životinjskih modela ponašanja sličnog tjeskobi (Hartz i sur., Journal of Psychopharmacology 2003., 17 Suppl. 3, A 28, B 16), dok se drugi antikonvulzivni spojevi klinički rabe u liječenju bipolamog poremećaja. Dakle, otvarači KCNQ mogli bi biti korisni za liječenje poremećaja tjeskobe i bipolamog poremećaja. mRNA for KCNQ subunits 2 and 3 has been found in brain areas associated with anxiety and emotional behaviors such as bipolar disorder eg the hippocampus and amygdala (Saganich et al., Journal of Neuroscience 2001, 21, 4609-4624), and retigabine has been described as effective in some animal models of anxiety-like behavior (Hartz et al., Journal of Psychopharmacology 2003, 17 Suppl. 3, A 28, B 16), while other anticonvulsant compounds are clinically used in the treatment of bipolar disorder. Thus, KCNQ openers may be useful for the treatment of anxiety disorders and bipolar disorder.

WO 200196540 opisuje uporabu modulatora M-struje nastalih izražavanjem gena KCNQ2 i KCNQ3 za nesanicu, dok WO 2001092526 otkriva da se modulatori KCNQ mogu rabiti za liječenje poremećaja spavanja. WO 200196540 describes the use of M-current modulators generated by expression of the KCNQ2 and KCNQ3 genes for insomnia, while WO 2001092526 discloses that KCNQ modulators can be used to treat sleep disorders.

WO 01/022953 opisuje uporabu retigabina za profilaksu i liječenje neuropatskih bolova poput alodinije, hiperalgezičnih bolova, fantomskih bolova, neuropatskih bolova u vezi s dijabetičkom neuropatijom i neuropatskih bolova u vezi s migrenom. WO 01/022953 describes the use of retigabine for the prophylaxis and treatment of neuropathic pain such as allodynia, hyperalgesic pain, phantom pain, neuropathic pain associated with diabetic neuropathy and neuropathic pain associated with migraine.

WO 02/049628 opisuje uporabu retigabina za liječenje poremećaja tjeskobe poput tjeskobe, poremećaja opće tjeskobe, paničnog straha, opsesivno kompulzivnog poremećaja, socijalne fobije, treme, poremećaja post traumatskog stresa, akutne reakcije na stres, poremećaja prilagodbe, hipohondrijakalnih poremećaja, poremećaja straha od razdvajanja, agorafobije i specifičnih fobija. WO 97/15300 opisuje uporabu retigabina za liječenje neurodegenerativnih poremećaja poput Alzheimerove bolesti, Huntingtonove horeje, skleroze poput multiple skleroze i amiotropne lateralne skleroze, Creutzfeld-Jakobove bolesti, Parkinsonove bolesti, encefalopatije uslijed AIDS-a i drugih encefalopatija u vezi s infekcijama uzrokovanih virusima rubeole, virusa herpesa, borelije i nepoznatih patogena, neurodegeneracija uzrokovanih traumom, stanja neuronske hiperpodraživosti poput onih kod ukidanja lijekova ili intoksikacije te neurodegenerativnih poremećaja perifernog živčanog sustava poput polineuropatija i polineuritisa. WO 02/049628 describes the use of retigabine for the treatment of anxiety disorders such as anxiety, generalized anxiety disorder, panic disorder, obsessive compulsive disorder, social phobia, stage fright, post traumatic stress disorder, acute stress reaction, adjustment disorder, hypochondriacal disorder, separation anxiety disorder , agoraphobia and specific phobias. WO 97/15300 describes the use of retigabine for the treatment of neurodegenerative disorders such as Alzheimer's disease, Huntington's chorea, sclerosis such as multiple sclerosis and amyotrophic lateral sclerosis, Creutzfeld-Jakob disease, Parkinson's disease, encephalopathy due to AIDS and other encephalopathies associated with infections caused by rubella viruses , herpes viruses, Borrelia and unknown pathogens, neurodegeneration caused by trauma, states of neuronal hyperexcitability such as those caused by drug withdrawal or intoxication, and neurodegenerative disorders of the peripheral nervous system such as polyneuropathies and polyneuritis.

Dakle, vrlo su poželjni novi spojevi koji su snažni otvarači roda KCNQ kalijevih kanala. Također su poželjni novi spojevi s poboljšanim svojstvima u odnosu na poznate spojeve koji otvaraju kalijeve kanale roda KCNQ, poput retigabina. Poželjno je poboljšanje jednog ili više sljedećih parametara: Thus, new compounds that are potent openers of the KCNQ family of potassium channels are highly desirable. Also desirable are new compounds with improved properties compared to known compounds that open potassium channels of the KCNQ family, such as retigabine. It is desirable to improve one or more of the following parameters:

vrijeme poluraspadanja, bistrenje, selektivnost, interakcije s drugim lijekovima, biološka učinkovitost, djelovanje, mogućnost formuliranja, kemijska stabilnost, metabolička stabilnost, membranska propusnost, topivost i terapeutski indeks. Poboljšanje tih parametara može dovesti do poboljšanja poput: half-life, clearance, selectivity, interactions with other drugs, biological efficacy, activity, formability, chemical stability, metabolic stability, membrane permeability, solubility and therapeutic index. Improving these parameters can lead to improvements such as:

• poboljšanog režima doziranja kroz smanjivanje broja potrebnih dnevnih doza, • improved dosing regimen by reducing the number of required daily doses,

• lakše primjene kod bolesnika koji primaju više lijekova, • easier application in patients receiving multiple medications,

• smanjenog broja nuspojava, • reduced number of side effects,

• proširenog terapeutskog indeksa, • extended therapeutic index,

• poboljšanog podnošenja ili • improved submission or

• poboljšane privole. • improved permissions.

Kratki opis izuma Brief description of the invention

Jedna svrha ovog izuma je pribaviti nove spojeve koji su snažni otvarači kalijevih kanala roda KCNQ. One purpose of the present invention is to provide novel compounds that are potent openers of potassium channels of the KCNQ family.

Spojevi prema ovom izumu su supstituirani derivati morfolina i tiomorfolina opće formule I ili njihove soli The compounds according to the present invention are substituted morpholine and thiomorpholine derivatives of the general formula I or their salts

[image] [image]

gdje su q, W, X, Z, R1, R2, R3, R4, R5, R6 i R7 prema definiciji koja slijedi. where q, W, X, Z, R1, R2, R3, R4, R5, R6 and R7 are as defined below.

Ovaj izum nudi spoj formule I za uporabu kao lijek. The present invention provides a compound of formula I for use as a medicament.

Ovaj izum se nadalje odnosi na farmaceutsku smjesu koja sadrži spoj formule I i njezinu primjenu. This invention further relates to a pharmaceutical composition containing a compound of formula I and its use.

Ovaj izum prema tome nudi farmaceutsku smjesu koja sadrži spoj formule I i farmaceutski prihvatljiv nositelj ili diluent. The present invention accordingly provides a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier or diluent.

Ovaj izum nudi uporabu spoja formule I za pripravu lijeka za liječenje poremećaja napadaja, poremećaja tjeskobe, poremećaja neuropatskih bolova i bolova zbog migrene ili neurodegenerativnih poremećaja. This invention provides the use of a compound of formula I for the preparation of a medicament for the treatment of seizure disorders, anxiety disorders, neuropathic pain disorders and migraine pain or neurodegenerative disorders.

Detaljni opis izuma Detailed description of the invention

Ovaj izum se odnosi na supstituirane derivate morfolina i tiomorfolina koji su snažni otvarači kalijevih kanala KCNQ. This invention relates to substituted derivatives of morpholine and thiomorpholine which are potent KCNQ potassium channel openers.

Prema tome, ovaj izum se odnosi na supstituirane derivate morfolina i tiomorfolina opće formule I Accordingly, this invention relates to substituted morpholine and thiomorpholine derivatives of the general formula I

[image] [image]

u kojoj where

q znači 0 ili 1; q means 0 or 1;

W je O ili S; W is O or S;

X je CO; X is CO;

Z je O; Z is O;

R1 je odabran iz grupe koja se sastoji od halogena, cijana, C1-6-alk(en/in)ila, C3-8-cikloalk(en)ila, C3-8-cikloalk(en)il-C1-6-alk(en/in)ila, halo-C1-6-alk(en/in)ila, halo-C3-8-cikloalk(en)ila, halo-C3-8-cikloalk(en)il-C1-6-alk/en/in)ila, C1-6-alk(en/in)iloksi, C3-8-cikloalk(en)iloksi i C3-8-cikloalk(en)il-C1-6-alk(en(in)iloksi; R1 is selected from the group consisting of halogen, cyano, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk (en/yn)yl, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C1-6-alk /en/yn)yl, C1-6-alk(en/yn)yloxy, C3-8-cycloalk(en)yloxy and C3-8-cycloalk(en)yl-C1-6-alk(en(yn)yloxy ;

R2 je odabran iz grupe koja se sastoji od halogena, cijana, C1-6-alk(en/in)ila, C3-8-cikloalk(en)ila, C3-8-cikloalk(en)il-C1-6-alk(en/in)ila, halo-C1-6-alk(en/in)ila, halo-C3-8-cikloalk(en)ila, halo-C3-8-cikloalk(en)il-C1-6-alk(en/in)ila, C1-6-alk(en/in)iloksi, C3-8-cikloalk(en)iloksi, C3-8-cikloalk(en)il-C1-6-alk(en/in)iloksi, opcionalno supstituiranog fenila i opcionalno supstituiranog piridila; pri čemu su fenil i piridil opcionalno supstituirani s jednim ili više supstituenata koji su neovisno halogen, C1-6-alk(en/in)il, C3-8-cikloalk(en)il ili C3-8-cikloalk(en)il-C1-6-alk(en/in)il; R2 is selected from the group consisting of halogen, cyano, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk (en/yn)yl, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C1-6-alk (en/yn)yl, C1-6-alk(en/yn)yloxy, C3-8-cycloalk(en)yloxy, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yloxy , optionally substituted phenyl and optionally substituted pyridyl; wherein phenyl and pyridyl are optionally substituted with one or more substituents which are independently halogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl or C3-8-cycloalk(en)yl- C1-6-alk(en/yn)yl;

R3 je C3-8-cikloalk(en)il-C1-6-alk(en/in)il; a R3 is C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl; And

svaki od R4, R5, R6 i R7 je neovisno odabran iz grupe koja se sastoji od vodika i Ar; Ar je odabran iz grupe koja se sastoji od opcionalno supstituiranog fenila, opcionalno supstituiranog naftila, opcionalno supstituiranog piridina, opcionalno supstituiranog tiofena, opcionalno supstituiranog furana, opcionalno supstituiranog tiazola, opcionalno supstituiranog kvinolina, opcionalno supstituiranog indola, opcionalno supstituiranog 2,3-dihidro-benzofurana, opcionalno supstituiranog pirimidina, opcionalno supstituiranog pirola, opcionalno supstituiranog oksazola; pri čemu su supstituenti neovisno halogen, C1-6-alk(en/in)il, C3-8-cikloalk(en)il, C3-8-cikloalk(en)il-C1-6-alk(en/in)il, halo-C1-6-alk(en/in)il, C1-6-alk(en/in)iloksi, C3-8-alk(en/in)iloksi; each of R 4 , R 5 , R 6 and R 7 is independently selected from the group consisting of hydrogen and Ar; Ar is selected from the group consisting of optionally substituted phenyl, optionally substituted naphthyl, optionally substituted pyridine, optionally substituted thiophene, optionally substituted furan, optionally substituted thiazole, optionally substituted quinoline, optionally substituted indole, optionally substituted 2,3-dihydro-benzofuran , optionally substituted pyrimidine, optionally substituted pyrrole, optionally substituted oxazole; wherein the substituents are independently halogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl , halo-C1-6-alk(ene/yne)yl, C1-6-alk(ene/yne)yloxy, C3-8-alk(ene/yne)yloxy;

kao njihova slobodna baza ili sol. as their free base or salt.

U jednoj verziji spoja formule I q je 0; u drugoj verziji spoja formule I q je 1. In one version of the compound of formula I, q is 0; in the second version of the compound of formula I, q is 1.

U daljnjoj verziji spoja formule I W je atom kisika; u drugoj verziji je W atom sumpora. In a further version of the compound of formula I, W is an oxygen atom; in the second version, W is a sulfur atom.

U daljnjoj verziji spoja formule I, R1 je odabran iz grupe koja se sastoji od C3-8-cikloalk(en)ila, C3-8-cikloak(en)il-C1-6-alk(en/in)ila, halo-C3-8-cikloalk(en)ila, halo-C3-8-cikloalk(en)il-C1-6-alk(en/in)ila, C3-8-cikloalk(en)iloksi i C3-8-cikloalk(en)il-C1-6-alk(en/in)il iloksi; In a further version of the compound of formula I, R1 is selected from the group consisting of C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, halo- C3-8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yloxy and C3-8-cycloalk( en)yl-C1-6-alk(en/yn)ylyloxy;

u još jednoj verziji R1 je odabran iz grupe koja se sastoji od halogena, halo-C1-6-alk(en/in)ila, C1-6-alk(en/in)ila i cijana. in another embodiment, R 1 is selected from the group consisting of halogen, halo-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yl and cyano.

Obično je R1 odabran iz grupe koja se sastoji od halogena, cijana, C1-6-alk(en/in)ila, halo-C1-6-alk(en/in)ila i C1-6-alk(en/in)iloksi. Typically R1 is selected from the group consisting of halogen, cyano, C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl and C1-6-alk(en/yn) iloxy.

Za daljnju ilustraciju bez ograničavanja ovog izuma jedna verzija R1 je halogen; druga verzija R1 je cijan, još jedna verzija R1 je C1-6-alk(en/in)il; To further illustrate without limiting the present invention, one version of R1 is halogen; another version of R1 is cyano, another version of R1 is C1-6-alk(en/yn)yl;

daljnja verzija R1 je halo-C1-6-alk(en/in)il; a further version of R1 is halo-C1-6-alk(en/yn)yl;

još jedna verzija R1 je C1-6-alk(en/in)iloksi. another version of R1 is C1-6-alk(en/yn)yloxy.

U daljnjoj verziji spoja formule I R2 je odabran iz grupe koja se sastoji od C3-8-cikloalk(en)ila, C3-8-cikloalk(en)il-C1-6-alk(en/in)ila, halo-C3-8-cikloalk(en)ila, halo-C3-8-cikloalk(en)il-C1-6-alk(en/ln)ila, C3-8-cikloalk(en)iloksi i C3-8-cikloalk(en)il-C1-6-alk(en/in)iloksi; u drugoj verziji R2 je odabran iz grupe koja se sastoji od halogena, halo-C1-6-alk(en/in)la, C1-6-alk(en/in)ila i cijana. In a further version of the compound of formula I, R2 is selected from the group consisting of C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, halo-C3 -8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C1-6-alk(en/ln)yl, C3-8-cycloalk(en)yloxy and C3-8-cycloalk(ene )yl-C 1-6 -alk(ene/yn)yloxy; in another embodiment, R2 is selected from the group consisting of halogen, halo-C1-6-alk(en/yn)la, C1-6-alk(en/yn)yl and cyano.

Obično je R2 odabran iz grupe koja se sastoji od halogena, cijana, C1-6-alk(en/in)ila, halo-C1-6-alk(en/in)ila, C1-6-alk(en/in)iloksi, opcionalno supstituiranog fenila i opcionalno supstituiranog piridila. Typically, R2 is selected from the group consisting of halogen, cyano, C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, C1-6-alk(en/yn) yloxy, optionally substituted phenyl and optionally substituted pyridyl.

Za daljnju ilustraciju bez ograničavanja ovog izuma jedna verzija R2 je halogen; druga verzija R2 je cijan; To further illustrate without limiting the present invention, one version of R 2 is halogen; the second version of R2 is cyan;

još jedna verzija R2 je C1-6-alk(en/in)il; another version of R 2 is C 1-6 -alk(en/yn)yl;

još jedna verzija R2 je halo-C1-6-alk(en/in)il; another version of R2 is halo-C1-6-alk(en/yn)yl;

još jedna verzija R2 je C1-6-alk(en/in)iloksi; another version of R 2 is C 1-6 -alk(ene/yn)yloxy;

još jedna verzija R2 je opcionalno supstituirani fenil; another version of R 2 is optionally substituted phenyl;

još jedna verzija R2 je opcionalno supstituirani piridil. another version of R 2 is optionally substituted pyridyl.

U daljnjoj verziji spoja R2 opcionalno supstituirani fenil i opcionalno supstituirani piridil mogu biti supstituirani s jednim ili više supstituenata odabranih iz grupe koja se sastoji od halogena ili C1-6-alk(en/in)ila; In a further version of the compound R2 optionally substituted phenyl and optionally substituted pyridyl can be substituted with one or more substituents selected from the group consisting of halogen or C1-6-alk(en/yn)yl;

u daljnjoj verziji R2 fenil i piridil nisu supstituirani; in a further version R2 phenyl and pyridyl are not substituted;

u još jednoj verziji R2 opcionalno supstituirani fenil i opcionalno supstituirani piridil supstituirani su s jednim supstituentom; in yet another embodiment R 2 optionally substituted phenyl and optionally substituted pyridyl are substituted with one substituent;

u još jednoj verziji R2 opcionalno supstituirani fenil i opcionalno supstituirani piridil supstituirani su s dva supstituenta; in yet another embodiment R2 optionally substituted phenyl and optionally substituted pyridyl are substituted with two substituents;

u još jednoj verziji R2 opcionalno supstituirani fenil i opcionalno supstituirani piridil supstituirani su s tri supstituenta. in another embodiment R2 optionally substituted phenyl and optionally substituted pyridyl are substituted with three substituents.

U daljnjoj verziji spoja formule I Ar je odabran iz grupe koja se sastoji od opcionalno supstituiranog furana, opcionalno supstituiranog tiazola, opcionalno supstituiranog kvinolina, opcionalno supstituiranog indola, opcionalno supstituiranog pirimidina, opcionalno supstituiranog pirola i opcionalno supstituiranog oksazola; In a further version of the compound of formula I Ar is selected from the group consisting of optionally substituted furan, optionally substituted thiazole, optionally substituted quinoline, optionally substituted indole, optionally substituted pyrimidine, optionally substituted pyrrole and optionally substituted oxazole;

u daljnjoj verziji je Ar odabran iz grupe koja se sastoji od opcionalno supstituiranog fenila, opcionalno supstituiranog tiofena i opcionalno supstituiranog naftila; in a further embodiment, Ar is selected from the group consisting of optionally substituted phenyl, optionally substituted thiophene, and optionally substituted naphthyl;

u daljnjoj verziji Ar je odabran iz grupe koja se sastoji od opcionalno supstituiranog fenila, opcionalno supstituiranog tiofena, opcionalno supstituiranog naftila, opcionalno supstituiranog 2,3-dihidro-benzofurana; in a further embodiment, Ar is selected from the group consisting of optionally substituted phenyl, optionally substituted thiophene, optionally substituted naphthyl, optionally substituted 2,3-dihydro-benzofuran;

u još jednoj verziji Ar je odabran iz grupe koja se sastoji od opcionalno supstituiranog fenila i opcionalno supstituiranog piridina in another embodiment Ar is selected from the group consisting of optionally substituted phenyl and optionally substituted pyridine

U jednoj verziji ovog izuma Ar predstavlja opcionalno supstituirani fenil, opcionalno supstituirani naftil, opcionalno supstituirani tiofen ili opcionalno supstituirani 2,3-dihidro-benzofuran. In one embodiment of this invention, Ar represents optionally substituted phenyl, optionally substituted naphthyl, optionally substituted thiophene, or optionally substituted 2,3-dihydro-benzofuran.

Obično je Ar odabran iz grupe koja se sastoji od opcionalno supstituiranog fenila, opcionalno supstituiranog naftila, opcionalno supstituiranog piridina, opcionalno supstituiranog 2,3-dihidro-benzofurana i opcionalno supstituiranog tiofena. Za daljnju ilustraciju bez ograničavanja ovog izuma jedna verzija Ar je opcionalno supstituirani fenil; Typically, Ar is selected from the group consisting of optionally substituted phenyl, optionally substituted naphthyl, optionally substituted pyridine, optionally substituted 2,3-dihydro-benzofuran, and optionally substituted thiophene. To further illustrate without limiting the present invention one version of Ar is optionally substituted phenyl;

daljnja verzija Ar je opcionalno supstituirani naftil; a further version of Ar is optionally substituted naphthyl;

daljnja verzija Ar je opcionalno supstituirani piridin; a further version of Ar is an optionally substituted pyridine;

daljnja verzija Ar je opcionalno supstituirani 2,3-dihidro-benzofurab; a further version of Ar is an optionally substituted 2,3-dihydro-benzofurab;

daljnja verzija Ar je opcionalno supstituirani tiofen. a further version of Ar is an optionally substituted thiophene.

Gornji supstituenti u opcionalno supstituiranom Ar su neovisno halogen, C1-6-alk(en/in)il, C3-8-cikloalk(en)il, C3-8-cikloalk(en)il-C1-6-alk(en/in)il, halo-C1-6-alk(en/in)il, C1-6-alk(en/in)iloksi ili C3-8-alk(en)iloksi. The above substituents in optionally substituted Ar are independently halogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/ yn)yl, halo-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy or C3-8-alk(en)yloxy.

U još jednoj verziji Ar je opcionalno supstituiran s jednim ili više supstituenata koji su neovisno halogen ili halo-C1-6-alk(en/in)il. U daljnjoj verziji ovog izuma Ar je supstituiran s jednim ili više supstituenata koji su neovisno halogen, C1-6-alk(en/in)il, halo-C1-6-alk(en/in)il, C1-6-alk(en/in)iloksi. In yet another embodiment, Ar is optionally substituted with one or more substituents which are independently halogen or halo-C1-6-alk(en/yn)yl. In a further version of this invention Ar is substituted with one or more substituents which are independently halogen, C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, C1-6-alk( en/yn)yloxy.

Za daljnju ilustraciju bez ograničavanja ovog izuma, verzija Ar je supstituirana halogenom; To further illustrate without limiting the present invention, the Ar version is substituted with halogen;

još jedna verzija Ar je supstituirana s C1-6-alk(en/in)ilom; another version of Ar is substituted with C1-6-alk(en/yn)yl;

još jedna verzija Ar je supstituirana s halo-C1-6-alk(en/in)ilom; another version of Ar is substituted with halo-C1-6-alk(en/yn)yl;

još jedna verzija Ar je supstituirana s C1-6-alk(en/in)iloksi; another version of Ar is substituted with C1-6-alk(en/yn)yloxy;

još jedna verzija Ar je nesupstituirana; another version of Ar is unsubstituted;

još jedna verzija Ar je supstituirana jednim supstituentom; another version of Ar is substituted with one substituent;

još jedna verzija Ar je supstituirana s 2 supstituenta; another version of Ar is substituted with 2 substituents;

još jedna verzija Ar je supstituirana s 3 supstituenta. another version of Ar is substituted with 3 substituents.

Jedna verzija se odnosi na spojeve opće formule I u kojoj bar jedan od R4 i R5 nije Ar. One version relates to compounds of general formula I in which at least one of R4 and R5 is not Ar.

Druga verzija se odnosi na spojeve opće formule I u kojoj bar jedan od R6 i R7 nije Ar. The second version refers to compounds of the general formula I in which at least one of R6 and R7 is not Ar.

Još jedna verzija se odnosi na spojeve opće formule I u kojoj bar tri od R4, R5, R6 i R7 nisu Ar. Another version relates to compounds of the general formula I in which at least three of R4, R5, R6 and R7 are not Ar.

Još jedna verzija se odnosi na spojeve opće formule I u kojoj najviše jedan od R4, R5, R6 i R7 sadrži Ar; Another version relates to compounds of the general formula I in which at most one of R4, R5, R6 and R7 contains Ar;

još jedna verzija se odnosi na spojeve opće formule I u kojoj najviše dva od R4, R5, R6 i R7 sadrže Ar; another version relates to compounds of the general formula I in which at most two of R4, R5, R6 and R7 contain Ar;

još jedna verzija se odnosi na spojeve opće formule I u kojoj najviše tri od R4, R5, R6 i R7 sadrže Ar; another version relates to compounds of the general formula I in which at most three of R4, R5, R6 and R7 contain Ar;

još jedna verzija se odnosi na spojeve opće formule I u kojoj R4 ne sadrži Ar; another version relates to compounds of general formula I in which R 4 does not contain Ar;

još jedna verzija se odnosi na spojeve opće formule I u kojoj R5 ne sadrži Ar; another version relates to compounds of general formula I in which R 5 does not contain Ar;

još jedna verzija se odnosi na spojeve opće formule I u kojoj R6 ne sadrži Ar; another version relates to compounds of general formula I in which R 6 does not contain Ar;

još jedna verzija se odnosi na spojeve opće formule I u kojoj R7 ne sadrži Ar. another version refers to compounds of general formula I in which R7 does not contain Ar.

Jedna verzija se odnosi na spojeve opće formule I u kojoj je stereo konfiguracija na atomu ugljika s kojim su vezani R4 i R5 S-konfiguracija. One version relates to compounds of general formula I in which the stereo configuration at the carbon atom to which R4 and R5 are attached is the S-configuration.

Još jedna verzija se odnosi na spojeve opće formule I u kojoj je stereo konfiguracija na atomu ugljika s kojim su vezani R4 i R5 R-konfiguracija. Another version relates to compounds of the general formula I in which the stereo configuration on the carbon atom to which R4 and R5 are bonded is the R-configuration.

Još jedna verzija se odnosi na spojeve opće formule I u kojoj je stereo konfiguracija na atomu ugljika s kojim su vezani R6 i R7 S-konfiguracija. Another version relates to compounds of general formula I in which the stereo configuration on the carbon atom to which R6 and R7 are bonded is the S-configuration.

Još jedna verzija se odnosi na spojeve opće formule I u kojoj je stereo konfiguracija na atomu ugljika s kojim su vezani R6 i R7 R-konfiguracija. Another version refers to compounds of the general formula I in which the stereo configuration on the carbon atom to which R6 and R7 are bonded is the R-configuration.

Još jedna verzija se odnosi na spojeve opće formule I u kojoj je stereo konfiguracija na atomu ugljika s kojim su vezani R4 i R5 jedna ka stereo konfiguraciji na atomu ugljika s kojim su vezani R6 i R7. Another version relates to compounds of general formula I in which the stereo configuration on the carbon atom to which R4 and R5 are bonded is the same as the stereo configuration on the carbon atom to which R6 and R7 are bonded.

Još jedna verzija se odnosi na spojeve opće formule I u kojoj je stereo konfiguracija na atomu ugljika s kojim su vezani R4 i R5 različita od stereo konfiguracije na atomu ugljika s kojim su vezani R6 i R7. Another version relates to compounds of general formula I in which the stereo configuration on the carbon atom to which R4 and R5 are bonded is different from the stereo configuration on the carbon atom to which R6 and R7 are bonded.

Spojevi sa sljedećeg popisa i njihove soli primjeri su ovog izuma, s time da taj popis ni u kojem slučaju ne treba smatrati ograničavajućim: The compounds from the following list and their salts are examples of this invention, with the fact that this list should in no way be considered limiting:

2-ciklopentil-N-(2-bromo-6-trifluorometil-4-morfolin-4-il-fenil)-acetamid, 2-cyclopentyl-N-(2-bromo-6-trifluoromethyl-4-morpholin-4-yl-phenyl)-acetamide,

N-(2-bromo-4-morfolin-4-il-6-trifluorometil-fenil)-3-ciklopentil-propionamid, N-(2-bromo-4-morpholin-4-yl-6-trifluoromethyl-phenyl)-3-cyclopentyl-propionamide,

N-(2-kloro-6-cijano-4-morfolin-4-il-fenil)-3-cikloheksil-propionamid, N-(2-chloro-6-cyano-4-morpholin-4-yl-phenyl)-3-cyclohexyl-propionamide,

2-ciklopentil-N-(2,6-dimetil-4-tiomorfolin-4-il-fenil)-acetamid, 2-cyclopentyl-N-(2,6-dimethyl-4-thiomorpholin-4-yl-phenyl)-acetamide,

2-ciklopentil-N-[2,6-dimetil-4-(2-fenil-morfolin-4-il)-fenil]-acetamid, 2-cyclopentyl-N-[2,6-dimethyl-4-(2-phenyl-morpholin-4-yl)-phenyl]-acetamide,

2-ciklopentil-N-[2,6-dimetil-4-(2-fenil-tiomorfolin-4-il)-fenil]-acetamid, 2-cyclopentyl-N-[2,6-dimethyl-4-(2-phenyl-thiomorpholin-4-yl)-phenyl]-acetamide,

2-ciklopentil-N-[2,6-dimetil-4-(3-piridin-3-il-tiomorfolin-4-il)-fenil]-acetamid, 2-cyclopentyl-N-[2,6-dimethyl-4-(3-pyridin-3-yl-thiomorpholin-4-yl)-phenyl]-acetamide,

2-ciklopentil-N-{2,6-dimetil-4-[2-(4-trifluorometil-fenil)-tiomorfolin-4-il]-fenil}-acetamid, 2-cyclopentyl-N-{2,6-dimethyl-4-[2-(4-trifluoromethyl-phenyl)-thiomorpholin-4-yl]-phenyl}-acetamide,

N-{4-[2-(2-kloro-fenil)-tiomorfolin-4-il]-2,6-dimetil-fenil}-2-ciklopentil-acetamid, N-{4-[2-(2-chloro-phenyl)-thiomorpholin-4-yl]-2,6-dimethyl-phenyl}-2-cyclopentyl-acetamide,

2-biciklo[2.2.1]hept-1-lN-(2,6-dimetil-4-morfolin-4-il-fenil)-acetamid, 2-bicyclo[2.2.1]hept-1-1N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-acetamide,

2-cikloheksil-N-(2,6-dimetil-4-morfolin-4-il-fenil)-acetamid, 2-cyclohexyl-N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-acetamide,

2-cikloheksil-N-(2,6-dimetil-4-morfolin-4-il-fenil)-acetamid, 2-cyclohexyl-N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-acetamide,

3-cikloheksil-N-(2,6-dimetil-4-morfolin-4-il-fenil)-propionamid, 3-cyclohexyl-N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-propionamide,

3-ciklopentil-N-(2,6-dimetil-4-morfolin-4-il-fenil)-propionamid, 3-cyclopentyl-N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-propionamide,

2-cikloheptil-N-(2,6-dimetil-4-morfolin-4-il-fenil)-acetamid, 2-cycloheptyl-N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-acetamide,

N-(2-bromo-4-morfolin-4-il-6-trifluorometil-fenil)-3-cikloheksil-propionamid, N-(2-bromo-4-morpholin-4-yl-6-trifluoromethyl-phenyl)-3-cyclohexyl-propionamide,

N-(2-kloro-4-il-morfolin-4-il-6-trifluorometil-fenil)-2-ciklopentil-acetamid, N-(2-chloro-4-yl-morpholin-4-yl-6-trifluoromethyl-phenyl)-2-cyclopentyl-acetamide,

2-ciklopentil-N-{2,6-dimetil-4-[2-(4-trifluorometil-fenil)-morfolin-4-il]-fenil}-acetamid, 2-cyclopentyl-N-{2,6-dimethyl-4-[2-(4-trifluoromethyl-phenyl)-morpholin-4-yl]-phenyl}-acetamide,

N{4-[2-(2-kloro-fenil)-morfolin-4-il]-2,6-dimetil}-2-ciklopentil-acetamid, N{4-[2-(2-chloro-phenyl)-morpholin-4-yl]-2,6-dimethyl}-2-cyclopentyl-acetamide,

2-ciklopentil-N{-4-[2-(4-fluoro-fenil)-morfolin-4-il]-2,6-dimetil-fenil}-acetamid, 2-cyclopentyl-N{-4-[2-(4-fluoro-phenyl)-morpholin-4-yl]-2,6-dimethyl-phenyl}-acetamide,

2-ciklopentil-N-(4-morfolin-4-il-2-piridin-3-il-6-trifluorometil-fenil)-acetamid, 2-cyclopentyl-N-(4-morpholin-4-yl-2-pyridin-3-yl-6-trifluoromethyl-phenyl)-acetamide,

2-ciklopentil-N-(5-morfolin-4-il-3-trifluorometil-bifenil-2-il)-acetamid, 2-cyclopentyl-N-(5-morpholin-4-yl-3-trifluoromethyl-biphenyl-2-yl)-acetamide,

2-ciklopentil-N-(4'-fluoro-5-morfolin-4-il-3-trifluorometil-bifenil-2-il)-acetamid, 2-cyclopentyl-N-(4'-fluoro-5-morpholin-4-yl-3-trifluoromethyl-biphenyl-2-yl)-acetamide,

2-ciklopentil-N-(4'-metil-5-morfolin-4-il-3-trifluorometil-bifenil-2-il)-acetamid, 2-cyclopentyl-N-(4'-methyl-5-morpholin-4-yl-3-trifluoromethyl-biphenyl-2-yl)-acetamide,

2-ciklopentil-N-(3'-metil-5-morfolin-4-il-3-trifluorometil-bifenil-2-il)-acetamid, 2-cyclopentyl-N-(3'-methyl-5-morpholin-4-yl-3-trifluoromethyl-biphenyl-2-yl)-acetamide,

2-ciklopentil-N-(3,4'-difluoro-5-morfolin-4-il-3-trifluorometil-bifenil-2-il)-acetamid, 2-cyclopentyl-N-(3,4'-difluoro-5-morpholin-4-yl-3-trifluoromethyl-biphenyl-2-yl)-acetamide,

2-ciklopentil-N-(2,6-dietil-4-morfolin-4-il-fenil)-acetamid, 2-cyclopentyl-N-(2,6-diethyl-4-morpholin-4-yl-phenyl)-acetamide,

2-ciklopentil-N-(2,6-diizopropil-4-morfolin-4-il-fenil)-acetamid, 2-cyclopentyl-N-(2,6-diisopropyl-4-morpholin-4-yl-phenyl)-acetamide,

2-ciklopentil-N-(2,6-difluoro-4-morfolin-4-il-fenil)-acetamid, 2-cyclopentyl-N-(2,6-difluoro-4-morpholin-4-yl-phenyl)-acetamide,

2-ciklopent-2-enil-N-(2,6-difluoro-4-morfolin-4-il-fenil)-acetamid, 2-cyclopent-2-enyl-N-(2,6-difluoro-4-morpholin-4-yl-phenyl)-acetamide,

2-biciklo[2.2.1]hept-2-il-N-(2,6-difluoro-4-morfolin-4-il-fenil)-acetamid, 2-bicyclo[2.2.1]hept-2-yl-N-(2,6-difluoro-4-morpholin-4-yl-phenyl)-acetamide,

2-biciklo[2.2.1]hept-2-il-N-(2-metil-4-morfolin-4-il-6-trifluorometil-fenil)-acetamid 2-bicyclo[2.2.1]hept-2-yl-N-(2-methyl-4-morpholin-4-yl-6-trifluoromethyl-phenyl)-acetamide

2-ciklopent-2-enil-N-(-2-metil-4-morfolin-4-il-6-trifluorometil-fenil)-acetamid, 2-cyclopent-2-enyl-N-(-2-methyl-4-morpholin-4-yl-6-trifluoromethyl-phenyl)-acetamide,

2-ciklopentil-N-(2-metil-4-morfolin-4-il-6-trifluorometil-fenil)-acetamid, 2-cyclopentyl-N-(2-methyl-4-morpholin-4-yl-6-trifluoromethyl-phenyl)-acetamide,

2-ciklopentil-N-(2-metoksi-6-metil-4-morfolin-4-il-fenil)-acetamid 2-cyclopentyl-N-(2-methoxy-6-methyl-4-morpholin-4-yl-phenyl)-acetamide

2-ciklopent-2-enil-N-(-2-metoksi-6-metil-4-morfolin-4-il-fenil)-acetamid, 2-cyclopent-2-enyl-N-(-2-methoxy-6-methyl-4-morpholin-4-yl-phenyl)-acetamide,

2-biciklo[2.2.1]hept-2-il-N-(2-metoksi-6-metil-4-morfolin-4-il-fenil)-acetamid i 2-bicyclo[2.2.1]hept-2-yl-N-(2-methoxy-6-methyl-4-morpholin-4-yl-phenyl)-acetamide and

N-(2-kloro-6-metil-4-morfolin-4-il-fenil)-2-ciklopentil-acetamid N-(2-chloro-6-methyl-4-morpholin-4-yl-phenyl)-2-cyclopentyl-acetamide

kao slobodna baza ili njezina sol. Svaki od ovih spojeva smatra se posebnom verzijom i mogao bi predstavljati pojedinačni patentni zahtjev. as a free base or its salt. Each of these compounds is considered a separate version and could represent a separate patent claim.

Ovaj izum podrazumijeva i soli spojeva prema ovom izumu, obično farmaceutski prihvatljive soli. This invention also includes salts of compounds according to this invention, usually pharmaceutically acceptable salts.

Soli prema ovom izumu uključuju kiselinske soli, metalne soli, soli amonijaka i alkiliranog amonijaka. Salts of the present invention include acid salts, metal salts, ammonia salts, and alkylated ammonia salts.

Soli prema ovom izumu su preferirano kiselinske soli. Kiselinske soli prema ovom izumu preferirano su farmaceutski prihvatljive soli spojeva prema ovom izumu dobivene s netoksičnim kiselinama. The salts of this invention are preferably acid salts. The acid salts of the present invention are preferably pharmaceutically acceptable salts of the compounds of the present invention obtained with non-toxic acids.

Kiselinske soli uključuju soli anorganskih kiselina kao i organskih. Primjeri prikladnih anorganskih kiselina su solna, bromovodična, jodovodična, fosforna, sumporna, sulfaminska, dušična kiselina i slične. Primjeri prikladnih organskih kiselina su mravlja, octena trikloroctena, trifluoroctena, propionska, benzojeva, cinamična, limunska, fumarna, glikolna, itakonska, mliječna, metansulfonska, maleinska, jabučna, malonska, bademova, oksalna, ptkrična, piruvinska, salicilna, sukcinska, metan sulfonska, etansulfonska, vinska, askorbinska, pamoična, bimetilensalicilna, etandisulfonska, glukonska, citrakonska, asparaginska, stearinska, palmitinska, EDTA, glikolna, p-aminobenzojeva, glutaminska, benzensulfonska, p-toluensulfonska kiselina, teofilinske octene kiseline, kao i 8-haloteofilini, na primjer 8-bromoteofilin i slično. Daljnji primjeri farmaceutski prihvatljivih anorganskih ili organskih kiselinskih soli uključuju farmaceutski prihvatljive soli navedene u J. Pharm. Sci. 1977., 66, 2, koji je ovdje uključen kao referenca. Acid salts include salts of inorganic as well as organic acids. Examples of suitable inorganic acids are hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, sulfamic, nitric acid and the like. Examples of suitable organic acids are formic, acetic trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconic, lactic, methanesulfonic, maleic, malic, malonic, mandelic, oxalic, pturic, pyruvic, salicylic, succinic, methanesulfonic , ethanesulfonic, tartaric, ascorbic, pamoic, bimethylenesalicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acid, theophylline acetic acids, as well as 8-halotheophylline, for example 8-bromotheophylline and the like. Further examples of pharmaceutically acceptable inorganic or organic acid salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference.

Kao kiselinske soli su određeni i hidrati koje mogu tvoriti spojevi prema ovom izumu. The hydrates that can be formed by the compounds according to this invention are defined as acid salts.

Primjeri metalnih soli su soli litija, natrija, kalija, magnezija i slične. Examples of metal salts are salts of lithium, sodium, potassium, magnesium and the like.

Primjeri soli amonijaka i alkiliranog amonijaka su amonijeve, metil-, dimetil-, trimetil-, etil-, hidroksietil-, dietil-, n-butil-, sek-butil-, tert-butil-, tetrametilamonijeve soli i slične. Examples of ammonium salts and alkylated ammonia are ammonium, methyl-, dimethyl-, trimethyl-, ethyl-, hydroxyethyl-, diethyl-, n-butyl-, sec-butyl-, tert-butyl-, tetramethylammonium salts and the like.

Nadalje, spojevi prema ovom izumu mogu biti u neotopljenim kao i u otopljenim oblicima s farmaceutski prihvatljivim otapalima poput vode, etanola i sličnog. Općenito, za svrhu ovog izuma otopljeni oblici se smatraju ekvivalentnima neotopljenim oblicima. Further, the compounds of the present invention may be in undissolved as well as dissolved forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, for the purposes of this invention, the dissolved forms are considered equivalent to the undissolved forms.

Spojevi prema ovom izumu mogu imati jedan ili više asimetričnih centara, a namjera je da svi optički izomeri (tj. enantiomeri ili dijastereomeri), kao separirani, čisti ili djelomično pročišćeni optički izomeri i njihove mješavine uključujući racemične mješavine, tj. mješavinu stereoizomera, budu uključeni u opseg ovog izuma. The compounds of this invention may have one or more asymmetric centers, and all optical isomers (ie enantiomers or diastereomers), as separated, pure or partially purified optical isomers and mixtures thereof including racemic mixtures, ie a mixture of stereoisomers, are intended to be included. within the scope of this invention.

Racemični oblici mogu se na poznate načine pretvoriti u optičke antipode, na primjer separacijom njihovih dijastereomernih soli s optički aktivnom kiselinom i oslobađanjem optički aktivnog spoja amina tretiranjem bazom. Drugi način pretvaranja racemata u optičke antipode temelji se na kromatografiji na optički aktivnoj matrici. Racemični spojevi prema ovom izumu mogu se pretvoriti u svoje optičke antipode npr. frakcionalnom kristalizacijom. Spojevi prema ovom izumu mogu biti pretvoreni i stvaranjem dijastereomerskih derivata. Mogu se rabiti i drugi, struci poznati, načini pretvaranja optičkih izomera. Među te načine idu i oni opisani u J. Jaques, A. Collet i S. Willen u "Enantiomers, Racemates and Resolutions", John Wiley and Sons, New York (1981.). Optički aktivni spojevi mogu se pripraviti i iz optički aktivnih polaznih supstanca ili stereoselektivnom sintezom. Racemic forms can be converted to optical antipodes in known ways, for example by separating their diastereomeric salts with an optically active acid and releasing the optically active amine compound by treatment with a base. Another way of converting racemates into optical antipodes is based on chromatography on an optically active matrix. The racemic compounds of this invention can be converted into their optical antipodes, for example, by fractional crystallization. The compounds according to this invention can also be converted by the formation of diastereomeric derivatives. Other ways of converting optical isomers known to the art can be used. Among these methods are those described in J. Jaques, A. Collet and S. Willen in "Enantiomers, Racemates and Resolutions", John Wiley and Sons, New York (1981). Optically active compounds can be prepared from optically active starting substances or by stereoselective synthesis.

Nadalje, kad je u molekuli prisutna dvostruka veza ili puni ili djelomično zasićeni sustav prstenova mogu se oblikovati geometrijski izomeri. Namjera je da svi geometrijski izomeri, kao separirani, čisti ili djelomično pročišćeni geometrijski izomeri ili njihove mješavine budu uključeni u obujam ovog izuma. Jednako, geometrijske izomere mogu tvoriti molekule koje imaju vezu s ograničenom rotacijom. Namjera je i njih uključiti u obujam ovog izuma. Furthermore, when a double bond or a full or partially saturated ring system is present in the molecule, geometric isomers can be formed. All geometric isomers, as separated, pure or partially purified geometric isomers or mixtures thereof, are intended to be included within the scope of this invention. Equally, geometric isomers can form molecules that have a rotation-restricted bond. It is intended to include them within the scope of this invention.

Nadalje, neki od spojeva prema ovom izumu mogu postojati u različitim tautomerijskim oblicima i namjera je da svi tautomerijski oblici koje spojevi mogu tvoriti budu uključeni u obujam ovog izuma. Furthermore, some of the compounds of this invention may exist in various tautomeric forms, and all tautomeric forms that the compounds may form are intended to be included within the scope of this invention.

Ovaj izum obuhvaća i predlijekove prema ovim spojevima, koji prilikom primjene prolaze kroz kemijsku pretvorbu uslijed metaboličkih procesa prije no što postanu farmakološki djelatne tvari. This invention also includes prodrugs according to these compounds, which, when applied, go through a chemical transformation due to metabolic processes before they become pharmacologically active substances.

Općenito, takvi predlijekovi će biti funkcionalni derivati spojeva formule I, koji se jednostavno in vivo pretvaraju u traženi spoj formule I. Uobičajeni postupci za odabir i pripravu prikladnog derivata predlijeka opisani su npr. u "Design of Prodrugs", izd. H. Bundgaard, Elsevier, 1985. In general, such prodrugs will be functional derivatives of compounds of formula I, which are easily converted in vivo to the desired compound of formula I. Conventional procedures for the selection and preparation of a suitable prodrug derivative are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

Jedan aspekt ovog izuma nudi spoj formule I ili njegovu sol za uporabu kao lijek. One aspect of the present invention provides a compound of formula I or a salt thereof for use as a medicament.

U jednoj verziji ovaj izum se odnosi na uporabu jednog ili više spojeva prema ovom izumu za izradu lijeka za liječenje poremećaja ili bolesti odgovornih za povećani protok iona u kalijevom kanalu poput kalijevih ionskih kanala roda KCNQ. Takav poremećaj ili bolest je preferirano poremećaj ili bolest centralnog živčanog sustava. In one version, the present invention relates to the use of one or more compounds according to the present invention for the manufacture of a medicament for the treatment of disorders or diseases responsible for increased flow of ions in a potassium channel such as potassium ion channels of the KCNQ genus. Such disorder or disease is preferably a disorder or disease of the central nervous system.

U još jednoj verziji ovaj izum nudi farmaceutsku smjesu koja sadrži jedan ili više farmaceutski prihvatljivih nositelja ili diluenata i jedan ili više spojeva formule I ili njihove soli. In another version, the present invention offers a pharmaceutical composition containing one or more pharmaceutically acceptable carriers or diluents and one or more compounds of formula I or their salts.

Daljnja verzija ovog izuma odnosi se na uporabu spoja formule I ili njegove soli za pripravu farmaceutske smjese za liječenje bolesti ili poremećaja u kojoj je koristan otvarač kalijevog kanala KCNQ poput otvarača kalijevog kanala KCNQ2. Obično je takav poremećaj ili bolest odabran iz grupe koja se sastoji od poremećaja napadaja, poremećaja tjeskobe, poremećaja neuropatskih bolova i bolova uslijed migrene ili neurodegenerativnih poremećaja. A further version of this invention relates to the use of a compound of formula I or a salt thereof for the preparation of a pharmaceutical composition for the treatment of a disease or disorder in which a KCNQ potassium channel opener such as the KCNQ2 potassium channel opener is useful. Typically, such disorder or disease is selected from the group consisting of seizure disorders, anxiety disorders, neuropathic pain disorders, migraine pain disorders, or neurodegenerative disorders.

U jednoj verziji spojevi prema ovom izumu mogu se primjenjivati kao jedini terapeutski učinkovit spoj. In one version, the compounds of the present invention may be administered as the sole therapeutically effective compound.

U još jednoj verziji spojevi prema ovom izumu mogu se primjenjivati kao dio kombinirane terapije, tj. spojevi prema ovom izumu mogu se primjenjivati u kombinaciji s drugim terapeutski učinkovitim spojevima koji imaju npr. antikonvulzivna svojstva. Učinak takvih drugih spojeva koji imaju antikonvulzivna svojstva mogu uključivati, ali ne i biti ograničeni na, djelovanje na: In another version, the compounds according to the present invention can be administered as part of a combination therapy, i.e. the compounds according to the present invention can be administered in combination with other therapeutically effective compounds having, for example, anticonvulsant properties. The effect of such other compounds having anticonvulsant properties may include, but not be limited to, effects on:

• ionske kanale poput kanala natrija, kalija ili kalcija • ion channels such as sodium, potassium or calcium channels

• podražajne amino kiselinske sustave, npr. blokadu ili modulaciju NMDA receptora • stimulating amino acid systems, eg blockade or modulation of NMDA receptors

• inhibicijske neurotransmisijske sustave, npr. poticanje otpuštanja GABA ili blokadu ponovne pohrane GABA ili • inhibitory neurotransmission systems, eg stimulation of GABA release or blockade of GABA reuptake or

• učinke stabilizacije membrane. • membrane stabilization effects.

Postojeći antikonvulzivni lijekovi uključuju, ali nisu ograničeni na, tiagabin, karbamazepin, natrijev valproat, lamotrigin, gabapeptin, pregabalin, etosumiksid, levetiracetam, fenitoin, topiramat, zonisamid, kao i članove klase benzodiazepina i barbiturata. Existing anticonvulsant drugs include, but are not limited to, tiagabine, carbamazepine, sodium valproate, lamotrigine, gabapeptin, pregabalin, ethosumicide, levetiracetam, phenytoin, topiramate, zonisamide, as well as members of the benzodiazepine and barbiturate classes.

Spojevi prema ovom izumu smatraju se korisnima za poboljšanje protoka iona u o naponu ovisnom kalijevom kanalu kod sisavaca poput ljudi. Dakle, ti se spojevi smatraju korisnima u liječenju poremećaja ili bolesti odgovornih za povećani protok iona u o naponu ovisnom kalijevom kanalu, poput kalijevih ionskih kanala roda KCNQ Takav poremećaj ili bolest je preferirano bolest ili poremećaj centralnog živčanog sustava. The compounds of the present invention are considered useful for enhancing ion flux in a voltage-gated potassium channel in mammals such as humans. Thus, these compounds are considered useful in the treatment of disorders or diseases responsible for increased ion flow in a voltage-gated potassium channel, such as potassium ion channels of the KCNQ family. Such disorder or disease is preferably a disease or disorder of the central nervous system.

U jednoj verziji, poremećaj ili bolest su odabrani iz grupe koja se sastoji od poremećaja napadaja, poput akutnih napadaja, konvulzija, status epilepticusa i epilepsije poput epileptičkih sindroma ili epileptičkih napadaja, posebno konvulzija, epilepsije i status epilepticusa. In one version, the disorder or disease is selected from the group consisting of seizure disorders, such as acute seizures, convulsions, status epilepticus, and epilepsy like epileptic syndromes or epileptic seizures, especially convulsions, epilepsy, and status epilepticus.

U još jednoj verziji poremećaj ili bolest su odabrani iz grupe koja se sastoji od poremećaja neuropatskih bolova i bolova uslijed migrene, poput alodinije, hiperalgezičnih bolova, fantomskih bolova, neuropatskih bolova u vezi s dijabetičkom neuropatijom, neuropatskih bolova u vezi s trigeminalnom neuralgijom i neuropatskih bolova u vezi s migrenom; posebno alodinije, hiperalgezičnih bolova, fantomskih bolova, neuropatskih bolova u vezi s dijabetičkom neuropatijom i neuropatskih bolova u vezi s migrenom. In another embodiment, the disorder or disease is selected from the group consisting of neuropathic pain disorders and migraine pain, such as allodynia, hyperalgesic pain, phantom pain, neuropathic pain associated with diabetic neuropathy, neuropathic pain associated with trigeminal neuralgia, and neuropathic pain related to migraine; especially allodynia, hyperalgesic pain, phantom pain, neuropathic pain associated with diabetic neuropathy and neuropathic pain associated with migraine.

U još jednoj verziji poremećaj ili bolest su odabrani iz grupe koja se sastoji od poremećaja tjeskobe, poput straha te poremećaja i bolesti u vezi s napadajima panike, agorafobije, poremećaja panike s agorafobijom, poremećaja panike bez agorafobije, agorafobije bez povijesti poremećaja panike, specifične fobije, društvene fobije i drugi specifičnih fobija, opsesivno kompulzivnog poremećaja, poremećaja post traumatskog stresa, poremećaja akutnog stresa, poremećaja opće tjeskobe, poremećaja tjeskobe uzrokovane općim zdravstvenim stanjem, poremećaja tjeskobe uzrokovane primjenom neke supstance, poremećaja tjeskobe zbog razdvajanja, poremećaja prilagodbe, treme, hipohondrijskih poremećaja, poremećaja tjeskobe uzrokovane općim zdravstvenim stanjem i poremećaja tjeskobe uzorkovane primjenom neke supstance te poremećaja neodređene tjeskobe; posebno straha, općeg poremećaja tjeskobe, paničnog straha, opsesivno kompulzivnog poremećaja, socijalne fobije, treme, poremećaja post traumatskog stresa, akutne reakcije na stres, poremećaje prilagodbe, hipohondrijskog poremećaja, poremećaja tjeskobe zbog razdvajanja, agorafobije, specifičnih fobija, poremećaja tjeskobe uzrokovane općim zdravstvenim stanjem i poremećaja tjeskobe uzrokovane primjenom neke supstance. In another embodiment, the disorder or disease is selected from the group consisting of anxiety disorders, such as fear and disorders and diseases related to panic attacks, agoraphobia, panic disorder with agoraphobia, panic disorder without agoraphobia, agoraphobia without a history of panic disorder, specific phobia , social phobias and other specific phobias, obsessive compulsive disorder, post-traumatic stress disorder, acute stress disorder, general anxiety disorder, anxiety disorder caused by a general health condition, anxiety disorder caused by the use of a substance, separation anxiety disorder, adjustment disorder, stage fright, hypochondria disorders, anxiety disorders caused by a general health condition and anxiety disorders sampled by the use of a substance and unspecified anxiety disorders; especially fear, generalized anxiety disorder, panic fear, obsessive compulsive disorder, social phobia, stage fright, post-traumatic stress disorder, acute stress reaction, adjustment disorder, hypochondriacal disorder, separation anxiety disorder, agoraphobia, specific phobias, anxiety disorder caused by general health condition and anxiety disorder caused by the use of a substance.

U još jednoj verziji poremećaj ili bolest su izabrani iz grupe koja se sastoji iz neurodegenerativnih poremećaja, poput Alzheimerove bolesti, Huntingtonove horeje, multiple skleroze, amiotropne lateralne skleroze, Creutzfeld-Jakobove bolesti, Parkinskonove bolesti, encefalopatija uzrokovanih AIDS-om ili infenkcijom virusa rubele, virusa herpesa, borelije i nepoznatih patogena, neurodegeneracija uzrokovanih traumom, stanja neuronske hiperpodraživosti kao kod ukidanja lijeka ili uslijed intoksikacije i neurodegenerativnih bolesti perifernog živčanog sustava poput polineuropatija i polineuritisa; posebno Alzeimerove bolesti, Huntingtonove horeje, multiple skleroze, amiotropne lateralne skleroze, encefalopatije uzrokovane AIDS-om i drugih encefalopatija uzrokovanih infekcijom virusom rubele, virusom herpesa, borelije i nepoznatih patogena, Creutzfeld-Jakobove bolesti, Parkinsobove bolesti, neurodegeneracija uzrokovanih traumom. U još jednoj verziji poremećaj ili bolest su odabrani iz grupe koja se sastoji od stanja neuronske hiperpodraživosti kao kod ukidanja lijeka ili uslijed intoksikacije. In another embodiment, the disorder or disease is selected from the group consisting of neurodegenerative disorders, such as Alzheimer's disease, Huntington's chorea, multiple sclerosis, amyotrophic lateral sclerosis, Creutzfeld-Jakob disease, Parkinson's disease, encephalopathies caused by AIDS or rubella virus infection, herpes virus, borrelia and unknown pathogens, neurodegeneration caused by trauma, states of neuronal hyperexcitability such as when drug withdrawal or intoxication and neurodegenerative diseases of the peripheral nervous system such as polyneuropathies and polyneuritis; especially Alzheimer's disease, Huntington's chorea, multiple sclerosis, amyotrophic lateral sclerosis, encephalopathy caused by AIDS and other encephalopathies caused by infection with the rubella virus, herpes virus, Borrelia and unknown pathogens, Creutzfeld-Jakob disease, Parkinson's disease, neurodegeneration caused by trauma. In yet another embodiment, the disorder or disease is selected from the group consisting of states of neuronal hyperexcitability such as drug withdrawal or intoxication.

U još jednoj verziji poremećaj ili bolest su odabrani iz grupe koja se sastoji od poremećaja spavanja kao kod nesanice. In yet another embodiment, the disorder or disease is selected from the group consisting of sleep disorders such as insomnia.

Ovdje korišteni izraz "liječenje" u vezi s bolešću ili poremećajima uključuje i prevenciju, inhibiciju i poboljšanje, ovisno o odnosnom slučaju. As used herein, the term "treatment" in relation to a disease or disorder includes prevention, inhibition and amelioration, as the case may be.

U jednoj verziji spojevi prema ovom izumu su se pokazali učinkovitima na kalijeve kanale roda KCNQ, posebno podjedinice KCNQ2. Ovaj izum nudi spojeve koji su pokazali učinak u jednom ili više od sljedećih testova: In one embodiment, the compounds of the present invention have been shown to be effective on potassium channels of the KCNQ family, particularly the KCNQ2 subunit. The present invention provides compounds that have demonstrated efficacy in one or more of the following tests:

• "Relativno istjecanje kroz kanal KCNQ2" • "Relative efflux through the KCNQ2 channel"

što je mjera za djelovanje spoja na ciljani kanal which is a measure of the effect of a compound on the target channel

• "Maksimalni elektrošok" • "Maximum electroshock"

što je mjera za napadaje uzrokovane nespecifičnom stimulacijom CŽS električnom strujom which is a measure for seizures caused by non-specific stimulation of the CNS with electric current

• "Napadaji uzrokovani pilokarpinom" • "Pilocarpine-induced seizures"

Napadaji uzrokovani pilokarpinom često se teško liječe mnogim postojećim lijekovima protiv napadaja i tako odražavaju model "napadaja otpornih na lijekove" Seizures induced by pilocarpine are often difficult to treat with many existing antiseizure drugs and thus reflect the "drug-resistant seizure" model.

• "Električni testovi praga napadaja" i "Kemijski testovi praga napadaja" • "Electrical seizure threshold tests" and "Chemical seizure threshold tests"

Ti modeli mjere prag na kojem započinju napadaji, pa su to modeli koji otkrivaju mogu li spojevi odgoditi početak napadaja. These models measure the threshold at which seizures begin, so they are models that reveal whether compounds can delay the onset of seizures.

• "Poticanje amigdale" • "Stimulating the amygdala"

koji se rabi kao mjera napredovanja bolesti, jer kod zdravih životinja napadaji postaju jači kako životinja prima jaču stimulaciju which is used as a measure of the progression of the disease, because in healthy animals the seizures become stronger as the animal receives stronger stimulation

• "Elektrofiziološko snimanje uklještenja komadića u CHO stanicama" i "elektrofiziološko snimanje kanala KCNQ2, KCNQ2/KCNQ3 ili KCNQ5 u oocitima" • "Electrophysiological imaging of patch-clamping in CHO cells" and "Electrophysiological imaging of KCNQ2, KCNQ2/KCNQ3 or KCNQ5 channels in oocytes"

U tim testovima snimaju se struje KCNQ2, KCNQ2/KCNQ3 ili KCNQ5 izazvane naponom. In these assays, voltage-evoked currents of KCNQ2, KCNQ2/KCNQ3, or KCNQ5 are recorded.

U jednoj verziji spojevi su KCNQ2 aktivni s EC50 manjim od 15000 nM poput manjim od 10000 nM izmjerenih testom "Relativno istjecanje kroz kanal KCNQ2". U drugoj verziji spojevi su KCNQ2 aktivni s EC50 manjim od 2000 nM izmjerenih testom "Relativno istjecanje kroz kanal KCNQ2". U još jednoj verziji spojevi su KCNQ2 aktivni s EC50 manjim od 200 nM poput manjih od 150 nM izmjerenih testom "Relativno istjecanje kroz kanal KCNQ2". Test "Relativno istjecanje kroz kanal KCNQ2" opisan je u nastavku. In one embodiment, the compounds are KCNQ2 active with an EC50 of less than 15,000 nM such as less than 10,000 nM as measured by the "Relative efflux through the KCNQ2 channel" assay. In another embodiment, the compounds are KCNQ2 active with an EC50 of less than 2000 nM as measured by the "Relative efflux through the KCNQ2 channel" assay. In another embodiment, the compounds are KCNQ2 active with an EC50 of less than 200 nM such as less than 150 nM as measured by the "Relative efflux through the KCNQ2 channel" assay. The "Relative efflux through the KCNQ2 channel" assay is described below.

U jednoj verziji spojevi imaju ED50 manji od 15 mg/kg u testu "Maksimalni elektrošok". U drugoj verziji spojevi imaju ED50 manji od 5 mg/kg u testu "Maksimalni elektrošok". Test "Maksimalni elektrošok" opisan je u nastavku. In one version, the compounds have an ED50 of less than 15 mg/kg in the "Maximum Electroshock" test. In another version, the compounds have an ED50 of less than 5 mg/kg in the "Maximum Electroshock" test. The "Maximum Electroshock" test is described below.

U jednoj verziji spojevi imaju ED50 manji od 5 mg/kg u "Električnom testu praga napadaja" i "Kemijskom testu praga napadaja" koji su opisani u nastavku. In one embodiment, the compounds have an ED50 of less than 5 mg/kg in the "Electrical Seizure Threshold Test" and the "Chemical Seizure Threshold Test" described below.

Neki spojevi imaju malobrojne ili klinički beznačajne nuspojave. Tako su neki spojevi testirani na modelima neželjenih sedativnih, hipotermičkih i ataksičkih djelovanja spojeva. Some compounds have few or clinically insignificant side effects. Thus, some compounds were tested on models of unwanted sedative, hypothermic and ataxic effects of the compounds.

Neki od spojeva imaju široki terapeutski indeks između antikonvulzivnog učinka i nuspojava poput popuštanja lokomotorne aktivnosti ili ataksičkih učinaka prema mjerenju na rotirajućoj sipki. Takve spojeve će očekivano dobro podnositi bolesnici koji dozvole primjenu velikih doza prije očitovanja nuspojava. Stoga se očekuje dobar pristanak na terapiju i dozvola za primjenu visokih doza, što će učiniti učinkovitijim liječenje bolesnika koji bi inače uz druge lijekove osjećali nuspojave. Some of the compounds have a wide therapeutic index between anticonvulsant effect and side effects such as relaxation of locomotor activity or ataxic effects as measured on a rotating rod. Such compounds are expected to be well tolerated by patients who allow the use of large doses before side effects appear. Therefore, good consent to the therapy and permission to use high doses is expected, which will make the treatment of patients who would otherwise experience side effects with other drugs more effective.

Neograničavajući aspekt ovog izuma tiče se spojeva prema verzijama 1-10 koje slijede: A non-limiting aspect of the present invention relates to compounds according to versions 1-10 of the following:

1. Supstituirani derivat morfolina ili tiomorfolina opće formule I 1. Substituted morpholine or thiomorpholine derivative of general formula I

[image] [image]

u kojoj where

q znači 0 ili 1, q means 0 or 1,

W znači O ili S, W stands for O or S,

X znači CO, X stands for CO,

Z znači O, Z stands for O,

R1 i R2 su neovisno odabrani iz grupe koja se sastoji od halogena, halo-C1-6-alk(en/in)ila, C1-6-alk(en/in)ila i cijana, R1 and R2 are independently selected from the group consisting of halogen, halo-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yl and cyano,

R3 je C3-8-cikloalk(en)il-C1-6-alk(en/in)il, a R3 is C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, and

R4, R5, R6 i R7 su neovisno odabrani iz grupe koja se sastoji od vodika ili Ar, R 4 , R 5 , R 6 and R 7 are independently selected from the group consisting of hydrogen or Ar,

kao njihova slobodna baza ili sol. as their free base or salt.

2. Spoj prema verziji 1, pri čemu je spoj odabran iz grupe koja se sastoji od: 2. A compound according to version 1, wherein the compound is selected from the group consisting of:

2-ciklopentil-N-(2-bromo-6-trifluorometil-4-morfolin-4-il-fenil)-acetamida, 2-cyclopentyl-N-(2-bromo-6-trifluoromethyl-4-morpholin-4-yl-phenyl)-acetamide,

N-(2-bromo-4-morfolin-4-il-6-trifluorometil-fenil)-3-ciklopentil-propionamida, N-(2-bromo-4-morpholin-4-yl-6-trifluoromethyl-phenyl)-3-cyclopentyl-propionamide,

N-(2-kloro-6-cijano-4-morfolin-4-il-fenil)-3-cikloheksil-propionamida, N-(2-chloro-6-cyano-4-morpholin-4-yl-phenyl)-3-cyclohexyl-propionamide,

2-ciklopentil-N-(2,6-dimetil-4-tiomorfolin-4-il-fenil)-acetamida, 2-cyclopentyl-N-(2,6-dimethyl-4-thiomorpholin-4-yl-phenyl)-acetamide,

2-ciklopentil-N-[-2,6-dimetil-4-(2-fenil-morfolin-4-il)-fenil]-acetamida, 2-cyclopentyl-N-[-2,6-dimethyl-4-(2-phenyl-morpholin-4-yl)-phenyl]-acetamide,

2-ciklopentil-N-[2,6-dimetil-4-(2-fenil-tiomorfolin-4-il)-fenil]-acetamida, 2-cyclopentyl-N-[2,6-dimethyl-4-(2-phenyl-thiomorpholin-4-yl)-phenyl]-acetamide,

2-ciklopentil-N-[2,6-dimetil-4-(3-piridin-3-il-tiomorfolin-4-il)-fenil]-acetamida, 2-cyclopentyl-N-[2,6-dimethyl-4-(3-pyridin-3-yl-thiomorpholin-4-yl)-phenyl]-acetamide,

2-ciklopentil-N-{2,6-dimetil-[2-(4-trifluorometil-fenil)-tiomorfolin-4-il]-fenil}-acetamida, 2-cyclopentyl-N-{2,6-dimethyl-[2-(4-trifluoromethyl-phenyl)-thiomorpholin-4-yl]-phenyl}-acetamide,

N-{4-[2-(2-kloro-fenil)-tiomorfolin-4-il]-2,6-dimetil-fenil}-2-ciklopentil-acetamida, N-{4-[2-(2-chloro-phenyl)-thiomorpholin-4-yl]-2,6-dimethyl-phenyl}-2-cyclopentyl-acetamide,

2-biciklo[2.2.1]hept-2-il-N-(2,6-dimetil-4-morfolin-4-il-fenil)-acetamida, 2-bicyclo[2.2.1]hept-2-yl-N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-acetamide,

2-cikloheksil-N-(2,6-dimetil-4-morfolin-4-il-fenil)-acetamida, 2-cyclohexyl-N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-acetamide,

2-ciklopentil-N-(2,6-dimetil-4-morfolin-4-il-fenil)-acetamida, 2-cyclopentyl-N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-acetamide,

3-cikloheksil-N-(2,6-dimetil-4-morfolin-4-il-fenil)-propionamida, 3-cyclohexyl-N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-propionamide,

3-ciklopentil-N-(2,6-dimetil-4-morfolin-4-il-fenil)-propionamida i 3-cyclopentyl-N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-propionamide and

2-cikloheptil-N-(2,6-dimetil-4-morfolin-4-il-fenil)-acetamida. 2-cycloheptyl-N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-acetamide.

3. Farmaceutska smjesa koja sadrži jedan ili više farmaceutski prihvatljivih nositelja ili diluenata i jedan ili više spojeva prema jednoj od verzija 1 i 2. 3. Pharmaceutical mixture containing one or more pharmaceutically acceptable carriers or diluents and one or more compounds according to one of versions 1 and 2.

4. Primjena farmaceutske smjese prema verziji 3 za izradu lijeka za povećanje protoka iona u o naponu ovisnom kalijevom kanalu kod sisavaca kao što su ljudi. 4. Use of the pharmaceutical composition according to version 3 for the manufacture of a medicament for increasing the flow of ions in a voltage-gated potassium channel in mammals such as humans.

5. Primjena prema verziji 4 u liječenju poremećaja ili bolesti odgovornih za povećan protok iona u o naponu ovisnom kalijevom kanalu, pri čemu su takav poremećaj ili bolest preferirano poremećaj ili bolesti centralnog živčanog sustava. 5. Use according to version 4 in the treatment of a disorder or disease responsible for increased ion flow in a voltage-gated potassium channel, wherein such disorder or disease is preferably a disorder or disease of the central nervous system.

6. Primjena prema verziji 5 naznačena time da su poremećaj ili bolest odabrani iz grupe koja se sastoji od poremećaja napadaja poput konvulzija, epilepsije i status epilepticusa. 6. Use according to version 5 characterized in that the disorder or disease is selected from the group consisting of seizure disorders such as convulsions, epilepsy and status epilepticus.

7. Primjena prema verziji 5 naznačena time da su poremećaj ili bolest odabrani iz grupe koja se sastoji od poremećaja neuropatskih bolova i bolova uslijed migrene poput alodinije, hiperalgezičnih bolova, fantomskih bolova, neuropatskih bolova u vezi s dijabetičkom neuropatijom i neuropatskih bolova u vezi s migrenom. 7. The use of version 5 wherein the disorder or disease is selected from the group consisting of neuropathic pain disorders and migraine pain disorders such as allodynia, hyperalgesic pain, phantom pain, neuropathic pain associated with diabetic neuropathy, and neuropathic pain associated with migraine .

8. Primjena prema verziji 5 naznačena time da su poremećaj ili bolest odabrani iz grupe koja se sastoji od poremećaja tjeskobe poput straha, poremećaja opće tjeskobe, paničnog straha, opsesivno kompulzivnog poremećaja, socijalne fobije, treme, poremećaja post traumatskog stresa, akutne reakcije na stres, poremećaja prilagodbe, hipohondrijakalnih poremećaja, poremećaja straha od razdvajanja, agorafobije, specifičnih fobija, poremećaj tjeskobe uzrokovane općim zdravstvenim stanjem i poremećaj tjeskobe izazvane primjenom neke supstance. 8. Use according to version 5 characterized in that the disorder or disease is selected from the group consisting of anxiety disorders such as fear, generalized anxiety disorder, panic fear, obsessive compulsive disorder, social phobia, stage fright, post traumatic stress disorder, acute stress reaction , adjustment disorders, hypochondriacal disorders, separation anxiety disorder, agoraphobia, specific phobias, anxiety disorder caused by a general health condition and anxiety disorder caused by the use of a substance.

9. Primjena prema verziji 5 naznačena time da su poremećaj ili bolest odabrani iz grupe koja se sastoji od neurodegenerativnih poremećaja poput Alzheimerove bolesti, Huntingtonove horeje, multiple skleroze, amiotropne lateralne skleroze, encefalopacije uslijed AIDS-a i drugih encefalopatija uslijed infekcije uzrokovane virusom rubele, virusom herpesa, borelije ili nepoznatih patogena, Creutzfeld-Jakobove bolesti, Parkinsonove bolesti, neudegeneracija izazvanih traumom. 9. Use according to version 5 characterized in that the disorder or disease is selected from the group consisting of neurodegenerative disorders such as Alzheimer's disease, Huntington's chorea, multiple sclerosis, amyotrophic lateral sclerosis, encephalopathy due to AIDS and other encephalopathies due to infection caused by the rubella virus, herpes virus, Borrelia or unknown pathogens, Creutzfeld-Jakob disease, Parkinson's disease, non-degeneration caused by trauma.

10. Primjena prema verziji 5 naznačena time da su poremećaj ili bolest odabrani iz grupe koja se sastoji od stanja neuronske hiperpodraživosti poput onog uzrokovanog ukidanjem lijeka ili intoksikacijom. 10. Use according to version 5 characterized in that the disorder or disease is selected from the group consisting of a state of neuronal hyperexcitability such as that caused by drug withdrawal or intoxication.

Definicije Definitions

Izraz heteroatom odnosi se na atom dušika, kisika ili sumpora. The term heteroatom refers to a nitrogen, oxygen or sulfur atom.

Halogen znači fluor, klor, brom ili jod. Halogen means fluorine, chlorine, bromine or iodine.

Izraz C1-6-alk(en/in)il znači C1-6-alkilnu, C2-6-alkenilnu ili C2-6-alkinilnu grupu. Izraz C1-6-alkil odnosi se na razgranatu ili nerazgranatu alkilnu grupu koja ima jedan do uključivo šest atoma ugljika, uključujući ali ne ograničujući se na metil, etil, 1-propil, 2-propil, 1-butil, 2-butil, 2-metil-2-propil i 2-metil-1-propil. Slično tome, C2-6-alkenil odnosno C2-6-alkinil označavaju takve grupe koje imaju dva do šest atoma ugljika, uključujući jednu dvostruku vezu odnosno jednu trostruku vezu, uključujući ali ne ograničavajući se na etenil, propenil, butenil, etinil, propinil i butinil. The term C1-6-alk(en/yn)yl means a C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl group. The term C1-6-alkyl refers to a branched or unbranched alkyl group having one to six carbon atoms inclusive, including but not limited to methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2 -methyl-2-propyl and 2-methyl-1-propyl. Similarly, C2-6-alkenyl and C2-6-alkynyl mean such groups having two to six carbon atoms, including one double bond and one triple bond, respectively, including but not limited to ethenyl, propenyl, butenyl, ethynyl, propynyl and butynyl.

Izraz C1-10-alk(en/in)il znači C1-10-alkilnu, C2-10-alkenilnu ili C2-10-alkinilnu grupu. Izraz C1-10-alkil odnosi se na razgranatu ili nerazgranatu alkilnu grupu koja ima jedan do uključivo šest atoma ugljika, uključujući ali ne ograničujući se na metil, etil, 1-propil, 2-propil, 1-butil, 2-butil, 1-pentil, 1-heksil, 1-heptil, 1-oktil, 1-nonil, 1-decil, 2-metil-2-propil i 2-metil-1-propil. Slično tome, C2-10-alkenil odnosno C2-10-alkinil označavaju takve grupe koje imaju dva do šest atoma ugljika, uključujući jednu dvostruku vezu odnosno jednu trostruku vezu, uključujući ali ne ograničavajući se na etenil, propenil, butenil, pentenil, heksenil, heptenil, oktenil, nonenil, decenil, etinil, propinil, butinil, pentinil, heksinil, heptinil, oktinil, noninil i decinil. The term C1-10-alk(en/yn)yl means a C1-10-alkyl, C2-10-alkenyl or C2-10-alkynyl group. The term C1-10-alkyl refers to a branched or unbranched alkyl group having one to six carbon atoms inclusive, including but not limited to methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 1 -pentyl, 1-hexyl, 1-heptyl, 1-octyl, 1-nonyl, 1-decyl, 2-methyl-2-propyl and 2-methyl-1-propyl. Similarly, C2-10-alkenyl and C2-10-alkynyl mean such groups having two to six carbon atoms, including one double bond and one triple bond, respectively, including but not limited to ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octinyl, nonynyl and decinyl.

Izraz C3-8-cikloalk(en)il znači C3-8-cikloalkilnu ili cikoalkenilnu grupu. Izraz C3-8-cikloalkil označava monociklički ili biciklički karboprsten koji ima tri do osam atoma C, uključujući ali ne ograničavajući se na ciklopropil, ciklopentil, cikloheksil, cikloheptil, ciklooktil, [1.1.1]biciklopentil, biciklo[2.2.1]heptil, [2.2.2]biciklooktil i [3.3.0]biciklooktil itd. Izraz C3-8-cikloalkenil označava monociklični ili biciklični karboprsten koji ima tri do osam atoma C i uključuje jednu dvostruku vezu. The term C3-8-cycloalk(en)yl means a C3-8-cycloalkyl or cycloalkenyl group. The term C3-8-cycloalkyl means a monocyclic or bicyclic carboring having three to eight carbon atoms, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, [1.1.1]bicyclopentyl, bicyclo[2.2.1]heptyl, [2.2.2]bicyclooctyl and [3.3.0]bicyclooctyl etc. The term C3-8-cycloalkenyl means a monocyclic or bicyclic carboring having three to eight carbon atoms and including one double bond.

Izraz halo-C1-6-alk(en/in)il označava C1-6-alk(en/in)il supstituiran s jednim ili više atoma halogena, uključujući ali ne ograničujući se na trifluorometil. Slično tome, halo-C3-8-cikloalk(en)il označava C3-8-cikloalk(en)il supstituiran s jednim ili više atoma halogena. The term halo-C1-6-alk(en/yn)yl means C1-6-alk(en/yn)yl substituted with one or more halogen atoms, including but not limited to trifluoromethyl. Similarly, halo-C3-8-cycloalk(en)yl means C3-8-cycloalk(en)yl substituted with one or more halogen atoms.

U izrazu halo-C3-8-ciktoalk(en)il-C1-6-alk(en/in)il izrazi C1-6-alk(en/in)il i halo-C3-8-cikloalk(en)il su prema gornjoj definiciji. In the term halo-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, the terms C1-6-alk(en/yn)yl and halo-C3-8-cycloalk(en)yl are according to the above definition.

Kad dva susjedna supstituenta zajedno s aromatskom grupom s kojom su vezani tvore 4-8-člani prsten, koji opcionalno sadrži jedan, dva ili tri heteroatoma, onda se sustav prstena tvori pomoću 4-8 atoma odabranih iz 4-8 atoma ugljika i 0-3 heteroatoma odabranih iz N, S ili O. Tako dva susjedna supstituenta mogu zajedno tvoriti: -CH2)a-CH2-, -CH=CH-(CH2)b-, -CH2-CH=CH-(CH2)c, -CH=CH-CH=CH-, -CH2)a-O-, -O-(CH2)b-O-, -CH2-O-(CH2)c-O-, -CH2-O-CH2-O-CH2-, -(CH2)a-S-, -S-(CH2)b-S-, -CH2-S-(CH2)c-S-, CH2-S-CH2-S-CH2-, -(CH2)a-NH-, -NH-(CH2)b-NH, -CH2-NH-(CH2)c-NH- ili -O-(CH2)c-NH-CH2-, -S-(CH2)b-NH-, -N=CH-NH-, -N=CH-O- ili N=CH-S- ili -N=N-NH-, When two adjacent substituents together with the aromatic group to which they are attached form a 4-8 membered ring, which optionally contains one, two or three heteroatoms, then the ring system is formed by means of 4-8 atoms selected from 4-8 carbon atoms and 0- 3 heteroatoms selected from N, S or O. Thus, two adjacent substituents can together form: -CH2)a-CH2-, -CH=CH-(CH2)b-, -CH2-CH=CH-(CH2)c, - CH=CH-CH=CH-, -CH2)a-O-, -O-(CH2)b-O-, -CH2-O-(CH2)c-O-, -CH2-O-CH2-O-CH2-, -(CH2 )a-S-, -S-(CH2)b-S-, -CH2-S-(CH2)c-S-, CH2-S-CH2-S-CH2-, -(CH2)a-NH-, -NH-(CH2) b-NH, -CH2-NH-(CH2)c-NH- or -O-(CH2)c-NH-CH2-, -S-(CH2)b-NH-, -N=CH-NH-, - N=CH-O- or N=CH-S- or -N=N-NH-,

gdje b znači 1, 2 ili 3, c znači 2, 3 ili 4, a c znači 1 ili 2. where b means 1, 2, or 3, c means 2, 3, or 4, and c means 1 or 2.

Primjeri AR grupa su opcionalno supstituirani fenil, opcionalno supstituirani naftil, opcionalno supstituirani piridin, opcionalno supstituirani tiofen, opcionalno supstituirani furan, opcionalno supstituirani tiazol, opcionalno supstituirani kvinolin, opcionalno supstituirani indol, opcionalno supstituirani 2,3-dihidro-benzofuran, opcionalno supstituirani, pirimidin, opcionalno supstituirani pirol i opcionalno supstituirani oksazol. Ar može biti supstituiran s jednim ili više supstituenata koji su neovisno halogen, C1-6-alk(en/in)il, C3-8-cikloalk(en)il, C3-8-cikloalk(en)il-C1-6-alk(en/in)il, halo-C1-6-alk(en/in)il, C1-6-alk(en/in) iloksi i C3-8-alk(en/in)iloksi. Examples of AR groups are optionally substituted phenyl, optionally substituted naphthyl, optionally substituted pyridine, optionally substituted thiophene, optionally substituted furan, optionally substituted thiazole, optionally substituted quinoline, optionally substituted indole, optionally substituted 2,3-dihydro-benzofuran, optionally substituted, pyrimidine , optionally substituted pyrrole and optionally substituted oxazole. Ar may be substituted with one or more substituents which are independently halogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6- alk(ene/yne)yl, halo-C1-6-alk(ene/yne)yl, C1-6-alk(ene/yne)yloxy and C3-8-alk(ene/yne)yloxy.

Izraz acil odnosi se na formil, C1-6-alk(en/in)ilkarbonil, C3-8-cikloalk(en)ilkarbonil, Ar-karbonil, Ar-C1-6-alk(en/in)ilkarbonil ili C3-8-cikloalk(en)il-C1-6-alk(en/in)il-karbonilnu grupu, gdje su C1-6-alk(en/in)il, C3-8-cikloalk(en)il i Ar definirani kao gore. The term acyl refers to formyl, C1-6-alk(en/yn)ylcarbonyl, C3-8-cycloalk(en)ylcarbonyl, Ar-carbonyl, Ar-C1-6-alk(en/yn)ylcarbonyl or C3-8 -cycloalk(en)yl-C1-6-alk(en/yn)yl-carbonyl group, where C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl and Ar are defined as above .

Izrazi C3-8-cikloalk(en)il-C1-6-alk(en/in)il, Ar-C1-6-alk(en/in)il, C1-6-alk(en/in)iloksi i C3-8-cikloalk(en)iloksi označavaju takve grupe u kojima su C1-6-alk(en/in)il, C3-8-cikloalk(en)il i Ar definirani kao gore. The terms C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, Ar-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy and C3 -8-cycloalk(en)yloxy means such groups in which C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl and Ar are defined as above.

Slično tome, C3-8-cikloalk(en)il-C1-6-alk(en/in)iloksi označavaju takve grupe u kojima su C3-8-cikloalk(en)il i C1-6-alk(en/in)iloksi definirani kao gore. Similarly, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yloxy means those groups in which C3-8-cycloalk(en)yl and C1-6-alk(en/yn) yloxy defined as above.

Izrazi Ar-C3-8-cikloalk(en)il i Ar-C3-8-cikloalk(en)il-C1-6-alk(en/in)il označavaju takve grupe u kojima su C1-6-alk(en(in)il, C3-8-cikloalk(en)il i Ar definirani kao gore. The terms Ar-C3-8-cycloalk(en)yl and Ar-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl denote such groups in which C1-6-alk(en( yn)yl, C3-8-cycloalk(en)yl and Ar as defined above.

Farmaceutske smjese Pharmaceutical mixtures

Ovaj izum se također odnosi na farmaceutske smjese. Spojevi prema ovom izumu ili njihove soli mogu se primjenjivati sami ili u kombinaciji s farmaceutski prihvatljivim nositeljima ili diluentima, bilo u jednoj bilo u više doza. Farmaceutski spojevi prema ovom izumu mogu se formulirati s farmaceutski prihvatljivim nositeljima ili diluentima, kao i sa svim drugim poznatim pomoćnim tvarima i ekscipijentima u skladu s konvencionalnom tehnikom prema opisu u Remington: The Science and Practice of Pharmacy, 19 Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995. This invention also relates to pharmaceutical compositions. The compounds according to the present invention or their salts can be administered alone or in combination with pharmaceutically acceptable carriers or diluents, either in one or more doses. The pharmaceutical compounds of this invention may be formulated with pharmaceutically acceptable carriers or diluents, as well as with any other known excipients and excipients, in accordance with conventional techniques as described in Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.

Farmaceutske smjese mogu biti specifično formulirane za primjenu bilo kojim putem kao što je oralni, rektalni, nazalni, pulmonalni, kroz usta (uključujući usnu šupljinu i pod jezikom), transdermalni, intracistemalni, intraperitonealni, vaginalni i parenteralni (uključujući potkožni, intramuskularni, intratekalni, intravenozni i intradermalni), s time da se preferira oralni put. Treba uzeti u obzir da će preferirani put ovisiti o općem stanju i dobi osobe koja će se liječiti, prirodi poremećaja ili bolesti koja se liječi i odabrano] djelatnoj tvari. Pharmaceutical compositions may be specifically formulated for administration by any route such as oral, rectal, nasal, pulmonary, buccal (including oral and sublingual), transdermal, intracystic, intraperitoneal, vaginal, and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal), with the oral route being preferred. It should be considered that the preferred route will depend on the general condition and age of the person to be treated, the nature of the disorder or disease being treated, and the selected] active substance.

Farmaceutske smjese nastale kombinacijom spoja prema ovom izumu i farmaceutski prihvatljivih nositelja potom se primjenjuju u raznim oblicima doziranja prikladnim za odabrani put primjene. Formulacije mogu prikladno biti predstavljene u jediničnim dozama na načine poznate struci. Spojevi prema ovom izumu općenito se rabe kao slobodna supstanca ili njezina farmaceutski prihvatljiva sol. Jedan primjer je kiselinska sol spoja koja djeluje kao slobodna baza. Kad spoj prema ovom izumu sadrži slobodnu bazu takve se soli pripravljaju na konvencionalan način tretiranjem otopine ili suspenzije slobodne baze prema ovom izumu kemijskim ekvivalentom farmaceutski prihvatljive kiseline. Naprijed su spomenuti reprezentativni primjerci. Farmaceutske smjese za oralnu primjenu mogu biti krute ili tekuće. Kruti oblici doziranja za oralnu primjenu uključuju npr. kapsule, tablete, dražeje, pilule, pastile, praške, granule i tablete npr. stavljene u kapsulu od tvrde želatine ili u oblik kuglice ili npr. u oblik okrugle ili duguljaste pastile. Kad je prikladno farmaceutske smjese za oralnu primjenu mogu biti pripravljene s oblogom poput enteričkih obloga ili mogu biti formulirane tako da omoguće kontrolirano otpuštanje djelatne tvari, poput usporenog ili produženog otpuštanja, prema struci dobro poznatim načinima. Tekući oblici doziranja za oralnu primjenu uključuju npr. otopine, emulzije, suspenzije, sirupe i eliksire. Formulacije prema ovom izumu prikladne za oralnu primjenu mogu biti u obliku promišljenih jedinica poput kapsula ili tableta, od kojih svaka sadrži predodređenu količinu djelatne tvari, a mogu sadržavati i prikladni ekscipijent. Nadalje, formulacije za oralnu primjenu mogu biti u obliku praška ili granula, otopine ili suspenzije u vodenoj ili bezvodnoj tekućini ili emulziji ulje-u-vodi ili voda-u-ulju. Prikladni farmaceutski nositelji su inertni kruti diluenti ili punila, sterilna vodena otopina i razna organska otapala. Primjeri nositelja u krutom obliku su laktoza, terra alba, sukroza, ciklodekstrin, talk, želatina, agar, pektin, akacija, magnezijev stearat, stearinska kiselina, niži alkilni eteri celuloze, kukuruzni škrob, krumpirov škrob, smole i slično. Primjeri tekućih nositelja su sirup, ulje kikirikija, maslinovo ulje, fosfo lipidi, masne kiseline, amini masnih kiselina, polioksietilen i voda. Nositelj ili diluent može uključivati bilo koji materijal s usporenim otpuštanjem poznat struci, poput gliceril monostearata ili gliceril distearata, samog ili pomiješanog s voskom. Mogu se upotrebljavati sve pomoćne tvari ili aditivi koji se obično rabe u te svrhe, poput boja, aroma, konzervansa itd. pod uvjetom da su kompatibilni s djelatnom tvari. Količina nositelja u krutom obliku može varirati, ali će obično biti od oko 25 mg do oko 1 g. Ako se rabi tekući nositelj, pripravak može biti u obliku sirupa, emulzije, meke želatinske kapsule ili sterilne tekućina za ubrizgavanje poput vodene ili bezvodne tekuće suspenzije ili otopine. The pharmaceutical mixtures formed by the combination of the compound according to the present invention and pharmaceutically acceptable carriers are then applied in various dosage forms suitable for the chosen route of administration. The formulations may conveniently be presented in unit doses in ways known in the art. The compounds of this invention are generally used as the free substance or a pharmaceutically acceptable salt thereof. One example is an acid salt of a compound that acts as a free base. When the compound according to the present invention contains a free base, such salts are prepared in a conventional manner by treating a solution or suspension of the free base according to the present invention with a chemical equivalent of a pharmaceutically acceptable acid. Representative examples are mentioned above. Pharmaceutical mixtures for oral administration can be solid or liquid. Solid dosage forms for oral administration include, for example, capsules, tablets, dragees, pills, lozenges, powders, granules and tablets, for example placed in a hard gelatin capsule or in the form of a ball or, for example, in the form of a round or oblong lozenge. When appropriate, pharmaceutical compositions for oral administration may be prepared with a coating such as enteric coatings or may be formulated to provide controlled release of the active ingredient, such as sustained or sustained release, by methods well known in the art. Liquid dosage forms for oral administration include, for example, solutions, emulsions, suspensions, syrups and elixirs. Formulations according to the present invention suitable for oral administration can be in the form of calculated units such as capsules or tablets, each of which contains a predetermined amount of active substance, and can also contain a suitable excipient. Furthermore, formulations for oral administration may be in the form of powders or granules, solutions or suspensions in an aqueous or anhydrous liquid or an oil-in-water or water-in-oil emulsion. Suitable pharmaceutical carriers are inert solid diluents or fillers, sterile aqueous solution and various organic solvents. Examples of carriers in solid form are lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, lower alkyl cellulose ethers, corn starch, potato starch, resins and the like. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water. The carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. All auxiliary substances or additives that are usually used for these purposes can be used, such as colors, aromas, preservatives, etc., provided that they are compatible with the active substance. The amount of solid carrier may vary, but will typically be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule, or sterile injectable liquid such as an aqueous or anhydrous liquid suspension. or solutions.

Tablete se mogu pripravljati miješanjem djelatne tvari s uobičajenim pomoćnim tvarima ili diluentima i potom komprimiranjem te mješavine u konvencionalnom stroju za tabletiranje. Tablets can be prepared by mixing the active substance with the usual excipients or diluents and then compressing the mixture in a conventional tableting machine.

Farmaceutske smjese za parenteralnu primjenu uključuju sterilne vodene ili bezvodne otopine za ubrizgavanje, disperzije, suspenzije ili emulzije kao i sterilne praške koji će se prije uporabe rekonstruirati u sterilnim otopinama ili disperzijama za ubrizgavanje. Formulacije za ubrizgavanje s usporenim otpuštanjem također se razmatraju u okviru ovog izuma. Pharmaceutical mixtures for parenteral administration include sterile aqueous or anhydrous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders that will be reconstituted in sterile injectable solutions or dispersions before use. Sustained release injectable formulations are also contemplated within the scope of this invention.

Za parenteralnu primjenu mogu se rabiti otopine spoja prema ovom izumu u sterilnoj vodenoj otopini, vodenoj otopini propilen glikola, vodenoj otopini vitamina E ili ulju sezama ili kikirikija. Takve vodene otopine moraju biti po potrebi puferirane, a tekući diluent pretvoren u izotonični pomoću dovoljne količine fiziološke otopine ili glukoze. Vodene otopine su posebno prikladne za intravenoznu, intramuskularnu, supkutanu i intraperitonealnu primjenu. Korišteni vodeni mediji su svi raspoloživi prema standardnoj tehnici poznatoj struci. For parenteral administration, solutions of the compound according to this invention in sterile aqueous solution, aqueous propylene glycol solution, aqueous vitamin E solution or sesame or peanut oil can be used. Such aqueous solutions must be buffered if necessary, and the liquid diluent converted to isotonic using a sufficient amount of saline or glucose. Aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The aqueous media used are all available according to standard techniques known in the art.

Otopine za ubrizgavanje mogu se pripravljati otapanjem djelatne tvari i eventualnih aditiva u dijelu otapala za ubrizgavanje, preferirano sterilne vode, uz podešavanje otopine na željeni volumen, sterilizaciju otopine i njezino punjenje u prikladne ampule ili bočice. Može se dodati svaki prikladan aditiv koji obično struka rabi poput agensa toničnosti, konzervansa, antioksidansa itd. Solutions for injection can be prepared by dissolving the active substance and possible additives in part of the solvent for injection, preferably sterile water, adjusting the solution to the desired volume, sterilizing the solution and filling it into suitable ampoules or bottles. Any suitable additive commonly used in the art such as tonicity agents, preservatives, antioxidants, etc. can be added.

Drugi prikladni oblici primjene uključuju supozitorije, sprejeve, masti, kreme, gelove, inhalante, kožne flastere, implante i sl. Other suitable forms of administration include suppositories, sprays, ointments, creams, gels, inhalants, skin patches, implants, and the like.

Tipično doziranje za oralnu primjenu kreće se u rasponu od oko 0,001 do oko 100 mg/kg tjelesne težine dnevno, preferirano od oko 0,01 do oko 50 mg/kg tjelesne težine dnevno, a još više preferirano od oko 0,05 do oko 10 mg/kg tjelesne težine dnevno primijenjeno u jednoj ili više doza, kao 1 do 3 doze. Točno doziranje će ovisiti o učestalosti i načinu primjene, spolu, dobi, tjelesnoj težini i općem stanju osobe koja će se liječiti, prirodi i stupnju liječenog poremećaja ili bolesti i ostalim istovremeno liječenim bolestima te ostalim faktorima očitima stručnjacima. A typical dosage for oral administration ranges from about 0.001 to about 100 mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kg body weight per day, and even more preferably from about 0.05 to about 10 mg/kg of body weight per day administered in one or more doses, as 1 to 3 doses. The exact dosage will depend on the frequency and method of administration, sex, age, body weight and general condition of the person to be treated, the nature and degree of the disorder or disease being treated and other simultaneously treated diseases and other factors obvious to experts.

Formulacije mogu prikladno biti predstavljene u obliku jedinične doze na načine poznate stručnjacima. Tipičan oblik jediničnog doziranja za oralnu primjenu jednom ili više puta dnevno, kao 1 do 3 puta dnevno, može sadržavati od 0,01 do oko 1000 mg, kao oko 0,01 do 200 mg, preferirano od oko 0,05 do oko 500 mg, a još više preferirano od oko 0,5 do oko 200 mg. The formulations may conveniently be presented in unit dosage form in ways known to those skilled in the art. A typical unit dosage form for oral administration once or more times a day, such as 1 to 3 times a day, may contain from 0.01 to about 1000 mg, such as about 0.01 to 200 mg, preferably from about 0.05 to about 500 mg. , and more preferably from about 0.5 to about 200 mg.

Za parenteralnu primjenu poput intravenozne, intratekalne, intramuskularne i slične primjene, uobičajene doze su u redu veličine od oko polovice doze od one za oralnu primjenu. For parenteral administration such as intravenous, intrathecal, intramuscular and similar administration, usual doses are on the order of about half the dose for oral administration.

Tipični primjeri recepata za formulaciju prema ovom izumu su: Typical examples of formulation recipes according to the present invention are:

1) Tablete koje sadrže 5,0 mg spoja prema ovom izumu računatog kao slobodna baza: 1) Tablets containing 5.0 mg of the compound according to this invention calculated as free base:

Spoj koji ima formulu I 5,0 mg A compound having the formula I 5.0 mg

Laktoza 60 mg Lactose 60 mg

Kukuruzni škrob 30 mg Corn starch 30 mg

Hidroksipropilceluloza 2,4 mg Hydroxypropylcellulose 2.4 mg

Mikrokristalna celuloza 19,2 mg Microcrystalline cellulose 19.2 mg

Kroskarmelozni natrij tipa A 2,4 mg Croscarmellose sodium type A 2.4 mg

Magnezijev stearat 0,84 mg Magnesium stearate 0.84 mg

2) Tablete koje sadrže 0,5 mg spoja prema ovom izumu računatog kao slobodna baza: 2) Tablets containing 0.5 mg of the compound according to this invention calculated as free base:

Spoj koji ima formulu I 0,5 mg A compound having the formula I 0.5 mg

Laktoza 46,9 mg Lactose 46.9 mg

Kukuruzni škrob 23,5 mg Corn starch 23.5 mg

Povidon 1,8 mg Povidone 1.8 mg

Mikrokristalna celuloza 14,4 mg Microcrystalline cellulose 14.4 mg

Kroskarmelozni natrij tipa A 1,8 mg Croscarmellose sodium type A 1.8 mg

Magnezijev stearat 0,63 mg Magnesium stearate 0.63 mg

3) Sirup sa sadržajem po mililitru: 3) Syrup with contents per milliliter:

Spoj koji ima formulu I 25 mg A compound having the formula I 25 mg

Sorbitol 500 mg Sorbitol 500 mg

Hidroksipropilceluloza 15 mg Hydroxypropylcellulose 15 mg

Glicerol 50 mg Glycerol 50 mg

Metil-paraben 1 mg Methyl-paraben 1 mg

Propil-paraben 0,1 mg Propyl-paraben 0.1 mg

Etanol 0,005 mL Ethanol 0.005 mL

Aroma 0,05 mg Aroma 0.05 mg

Saharin natrij 0,5 mg Saccharin sodium 0.5 mg

Voda do 1 mL Water up to 1 mL

4) Otopina za ubrizgavanje sa sadržajem po mililitru: 4) Solution for injection with contents per milliliter:

Spoj koji ima formulu I 0,5 mg A compound having the formula I 0.5 mg

Sorbitol 5,1 mg Sorbitol 5.1 mg

Octena kiselina 0,05 mg Acetic acid 0.05 mg

Saharin natrij 0,5 mg Saccharin sodium 0.5 mg

Voda do 1 mL Water up to 1 mL

Izraz spoj prema ovom izumu podrazumijeva bilo koju od verzija formule I kao što je već naprijed opisano. The term compound of the present invention includes any of the versions of formula I as described above.

U daljnjem aspektu ovaj izum se odnosi na način priprave spoja prema ovom izumu prema opisu u nastavku. In a further aspect, this invention relates to the method of preparing the compound according to this invention as described below.

Priprava spojeva prema ovom Izumu Preparation of compounds according to this invention

Spojevi prema ovom izumu opće formule I, u kojoj su q, W, X, Z, R1, R2, R3, R4, R5, R6 i R7 definirani kao gore mogu se pripravljati na načine predstavljene u shemama i opisima u nastavku: Compounds of the present invention of general formula I, wherein q, W, X, Z, R1, R2, R3, R4, R5, R6 and R7 are as defined above may be prepared in the manners presented in the schemes and descriptions below:

Shema 1 Scheme 1

[image] [image]

Shema 2 Scheme 2

[image] [image]

[image] [image]

[image] [image]

[image] [image]

[image] [image]

[image] [image]

U spojevima opće formule I - XV In compounds of the general formula I - XV

q, W, X, Z, R1, R2, R3, R4, R5, R6, i R7 su definirani kao za formulu I. q, W, X, Z, R1, R2, R3, R4, R5, R6, and R7 are defined as for formula I.

Spojevi općih formula II, III, VI, VIII i XI su ili dobiveni iz komercijalnih izvora ili pripravljeni na standardne načine poznate kemičarima od struke. Compounds of general formulas II, III, VI, VIII and XI are either obtained from commercial sources or prepared by standard methods known to skilled chemists.

Alternativno, spojevi opće formule III, gdje je R2 halogen poput Cl, Br ili I (shema 1), dobiveni su pomoću regioselektivne aromatske supstitucije, dobro poznate kemičarima od struke, s odgovarajućim elektrofilima poput N-klorosukcinimida, N-bromosukcinimida, bromina, jodina ili jodoklorida u prikladnom otapalu poput octene kiseline, prema opisu u "Electrophilic halogenations" autora P.B.D. de la Mare, Cambridge University Press, Cambridge, 1976. Alternatively, compounds of the general formula III, where R 2 is a halogen such as Cl, Br or I (Scheme 1), are obtained by means of regioselective aromatic substitution, well known to chemists skilled in the art, with appropriate electrophiles such as N-chlorosuccinimide, N-bromosuccinimide, bromine, iodine or iodochloride in a suitable solvent such as acetic acid, as described in "Electrophilic halogenations" by P.B.D. de la Mare, Cambridge University Press, Cambridge, 1976.

Nitro grupa u spojevima općih formula III, IX i XIII (sheme 1, 4 i 6) može se reducirati prikladnim reducirajućim agensima poput cinka ili željeznog praha uz prisutnost kiseline poput octene kiseline ili vodene otopine solne kiseline ili vodikovog plina ili amonijevog formiata uz prisutnost odgovarajućeg katalizatora hidrogenacije poput paladija na aktivnom ugljenu u prikladnim otapalima poput metanola, etanola ili tetrahidrofurana, na odgovarajućim temperaturama ili uz ultrazvučno zračenje, kako bi se dobili anilini opće formule IV, V odnosno XIV. Alternativno, kao reducirajući agensi mogu se koristiti kositreni (II) klorid ili natrijev ditionit u uvjetima dobro poznatima kemičarima od struke. The nitro group in compounds of general formulas III, IX and XIII (Schemes 1, 4 and 6) can be reduced with suitable reducing agents such as zinc or iron powder in the presence of an acid such as acetic acid or aqueous hydrochloric acid or hydrogen gas or ammonium formate in the presence of a suitable hydrogenation catalysts such as palladium on activated carbon in suitable solvents such as methanol, ethanol or tetrahydrofuran, at appropriate temperatures or with ultrasonic radiation, in order to obtain anilines of the general formula IV, V or XIV. Alternatively, stannous (II) chloride or sodium dithionite can be used as reducing agents under conditions well known to chemists skilled in the art.

Spojevi općih formula I i VII (sheme 1, 2, 3 i 4) mogu se pripraviti reakcijom spojeva općih formula V odnosno VI s prikladnim elektrofilnim reagensima poput, ali bez ograničenja na njih, prikladno supstituiranih klorida karboksilne kiseline, bromida karboksilne kiseline, jodida karboksilne kiseline, anhidrida karboksilne kiseline, aktivnih estera, kloro formata i sa dodavanjem ili bez dodavanja baza poput piridina, trialkil amina, kalijevog karbonata, magnezijevog oksida ili litijevih, natrijevih ili kalijevih alkoholata, u prikladnom otapalu poput etil acetata, dioksana, tetrahidrofurana, acetonitrita ili dietil etera, na prikladnoj temperaturi poput sobne temperature ili temperature refluksa. Alternativno, spojevi općih formula I i V (sheme 2 i 3) mogu se pripraviti paladijem kataliziranom reakcijom koja tvori C-N-vezu između prikladno supstituiranih spojeva općih formula VII i VI i prikladno supstituiranih morfolina ili tiomorfolina, prema opisu u S.L. Buchwald i sur. (M.C. Harris, X. Hang i S.L. Buchwald, Organic Letters, 2002., 4, 2885). Compounds of general formulas I and VII (Schemes 1, 2, 3 and 4) can be prepared by reacting compounds of general formulas V and VI with suitable electrophilic reagents such as, but not limited to, suitably substituted carboxylic acid chlorides, carboxylic acid bromides, carboxylic acid iodides acids, carboxylic acid anhydrides, active esters, chloroformate and with or without the addition of bases such as pyridine, trialkyl amines, potassium carbonate, magnesium oxide or lithium, sodium or potassium alcoholates, in a suitable solvent such as ethyl acetate, dioxane, tetrahydrofuran, acetonitrite or of diethyl ether, at a suitable temperature such as room temperature or reflux temperature. Alternatively, compounds of general formulas I and V (Schemes 2 and 3) can be prepared by a palladium-catalyzed C-N-bond forming reaction between suitably substituted compounds of general formulas VII and VI and suitably substituted morpholines or thiomorpholines, as described in S.L. Buchwald et al. (M.C. Harris, X. Hang and S.L. Buchwald, Organic Letters, 2002, 4, 2885).

Spojevi općih formula V i XV (sheme 1 i 6) mogu se pripraviti reakcijom spojeva općih formula IV i XIV s prikladno supstituiranim bis-(2-haloetil)eterima i s dodavanjem ili bez dodavanja baza poput trialkil amina, kalijevog karbonata ili litijevih, natrijevih ili kalijevih alkoholata, u prikladnom otapalu poput dimetil sulfoksida ili N,N-dimetilformamida, na prikladnoj temperaturi poput sobne temperature ili temperature refluksa. Alternativno, spojevi opće formule V (shema 3) mogu se pripraviti reakcijom spojeva opće formule VI s prikladno supstituiranim derivatima morfolina ili tiomorfolina uz prisutnost paladijevog katalizatora poput bis(dibenzilidneaceton)paladija uz dodavanje prikladnog fosfinskog liganda poput (t)-2,2'-bis(difenilfosfino)-1,1'-binaftila uz prisutnost baze poput kalijevog karbonata ili litijevih, natrijevih ili kalijevih alkoholata, u prikladnom otapalu poput toluena ili tetrahidrofurana, na prikladnoj temperaturi poput sobne temperature ili temperature refluksa. Compounds of general formulas V and XV (Schemes 1 and 6) can be prepared by reacting compounds of general formulas IV and XIV with suitably substituted bis-(2-haloethyl)ethers and with or without the addition of bases such as trialkyl amines, potassium carbonate or lithium, sodium or of potassium alcoholates, in a suitable solvent such as dimethyl sulfoxide or N,N-dimethylformamide, at a suitable temperature such as room temperature or reflux temperature. Alternatively, compounds of general formula V (Scheme 3) can be prepared by reacting compounds of general formula VI with suitably substituted morpholine or thiomorpholine derivatives in the presence of a palladium catalyst such as bis(dibenzylideneacetone)palladium with the addition of a suitable phosphine ligand such as (t)-2,2'- bis(diphenylphosphino)-1,1'-binaphthyl in the presence of a base such as potassium carbonate or lithium, sodium or potassium alcoholates, in a suitable solvent such as toluene or tetrahydrofuran, at a suitable temperature such as room temperature or reflux temperature.

Spojevi opće formule IX (shema 4) mogu se pripraviti reakcijom spojeva opće formule VIII s prikladno supstituiranim morfolinima ili tiomorfolinima i s dodavanjem ili bez dodavanja baze poput kalijevog karbonata, u prikladnom otapalu poput dimetil sulfoksida ili N,N-dimetilformamida, na prikladnoj temperaturi poput sobne temperature ili temperature refluksa. Compounds of general formula IX (Scheme 4) can be prepared by reacting compounds of general formula VIII with suitably substituted morpholines or thiomorpholines and with or without the addition of a base such as potassium carbonate, in a suitable solvent such as dimethyl sulfoxide or N,N-dimethylformamide, at a suitable temperature such as room temperature temperature or reflux temperature.

Spojevi opće formule I, u kojoj je R2 Ar ili Het (shema 5) mogu se pripraviti iz spojeva opće formule X, pomoću križno kopulirajućih reakcija poznatih kemičarima od struke, poput Suzuki kopuliranja, Stille kopuliranja ili drugih križno kopulirajućih reakcija kataliziranih prijelaznim metalima (D.W. Knight, "Coupling reactions between sp2 carbon centers" u Comprehensive Organic Synthesis, sv. 3, str. 481-520, Pergamon Press, 1991). Compounds of general formula I, wherein R 2 is Ar or Het (Scheme 5) can be prepared from compounds of general formula X by cross-coupling reactions known to chemists skilled in the art, such as Suzuki coupling, Stille coupling, or other transition metal-catalyzed cross-coupling reactions (D.W. Knight, "Coupling reactions between sp2 carbon centers" in Comprehensive Organic Synthesis, vol. 3, pp. 481-520, Pergamon Press, 1991).

Spojevi opće formule VI (shema 7) mogu se pripraviti iz spojeva opće formule XI pomoću elektrofilne aromatske supstitucije dobro poznate kemičarima od struke, s odgovarajući elektrofilima poput N-bromosukcinimida ili bromina u prikladnom otapalu poput octene kiseline, prema opisu u P.B.D. de la Mare i J.H. Ridd, "Preparative methods of aromatic halogenation" u Aromatic supstitutions, str. 105-115, Butterworths ScientificPublications, London, 1959. Spojevi opće formule XII (shema 6) mogu se pripraviti reakcijom spojeva opće formule XI s p-toluensulfonil kloridom s dodavanjem ili bez dodavanja baza poput piridina, trialkil amina, kalijevog karbonata, natrijevog hidro karbonata, magnezijevog oksida ili litijevih, natrijevih ili kalijevih alkoholata, u prikladnom otapalu poput piridina, etil acetata, dioksana, tetrahidrofurana, acetonitrila ili dietil etera, na prikladnim temperaturama poput sobne temperature ili temperature refluksa. Spojevi opće formule XIII (shema 6) mogu se pripraviti iz spojeva opće formule XII nitracijskim reakcijama poznatima kemičarima od struke, poput reakcije s koncentriranom nitričnom kiselinom, natrijevim nitritom ili natrijevim nitratom, u prikladnom otapalu poput leden octene kiseline, octenog anhidrida, trifluoroctene kiseline, koncentrirane sumporne kiseline ili njihove mješavine, na prikladnim temperaturama, na primjer prema opisu u P.B.D. de la Mare i J.H.Ridd, "Preparative methods of nitration" u Aromatic Substitutions, str. 48-56, Butterworths Scientific Publications, London, 1959. Compounds of general formula VI (Scheme 7) can be prepared from compounds of general formula XI by electrophilic aromatic substitution well known to chemists skilled in the art, with appropriate electrophiles such as N-bromosuccinimide or bromine in a suitable solvent such as acetic acid, as described in P.B.D. de la Mare and J.H. Ridd, "Preparative methods of aromatic halogenation" in Aromatic substitutions, p. 105-115, Butterworths ScientificPublications, London, 1959. Compounds of general formula XII (Scheme 6) can be prepared by reacting compounds of general formula XI with p-toluenesulfonyl chloride with or without the addition of bases such as pyridine, trialkyl amines, potassium carbonate, sodium hydrogen carbonate , magnesium oxide or lithium, sodium or potassium alcoholates, in a suitable solvent such as pyridine, ethyl acetate, dioxane, tetrahydrofuran, acetonitrile or diethyl ether, at suitable temperatures such as room temperature or reflux temperature. Compounds of general formula XIII (Scheme 6) can be prepared from compounds of general formula XII by nitration reactions known to chemists skilled in the art, such as reaction with concentrated nitric acid, sodium nitrite or sodium nitrate, in a suitable solvent such as glacial acetic acid, acetic anhydride, trifluoroacetic acid, concentrated sulfuric acid or mixtures thereof, at suitable temperatures, for example as described in P.B.D. de la Mare and J.H.Ridd, "Preparative methods of nitration" in Aromatic Substitutions, p. 48-56, Butterworths Scientific Publications, London, 1959.

Spojevi opće formule V (shema 6) mogu se pripravljati tretiranjem spojeva opće formule XV u jakim kiselim uvjetima poput vodene otopine sumporne kiseline ili vodene otopine solne kiseline, na prikladnim temperaturama, poput sobne temperature ili temperature refluksa. Compounds of general formula V (Scheme 6) can be prepared by treating compounds of general formula XV under strongly acidic conditions, such as aqueous sulfuric acid or aqueous hydrochloric acid, at suitable temperatures, such as room temperature or reflux temperature.

Primjeri Examples

Analitički LC-MS podaci dobiveni su na instrumentu PE SciexAPI 150EX opremljenom foto ionizacijom pri atmosferskom tlaku i Shimadzu LC-8A/SLC-1OA LC sustavom. Kolona: 30 x 4,6 mm Waters Symetry C 18 kolona s veličinom čestica 3,5 μm; sustav otapala: A = voda/trifluoroctema kiselina (100:0,05) i B= voda/a ceton itri l/t rifl u o rode na kiselina (5:95:0,03); metoda: linearna gradijentna elucija s 90% A do 100% B za 4 minute s protokom od 2 mL/minuti. čistoća je određena integracijom UV (254 nm) i ELSD traga. Vremena retencije (to) izražena su u minutama. Pripremno LC-MS pročišćavanje obavljeno je na istom instrumentu s kemijskom ionizacijom pri atmosferskom tlaku. Kolona: 50 x 20 m YMC ODS-A s veličinom čestica 5 μm; način: linearna gradijentna elucija s 80% A do 100% B za 7 minuta i s protokom od 22,7 mL/min. Prikupljanje frakcije obavljano je split-flow MS detekcijom. Analytical LC-MS data were obtained on a PE SciexAPI 150EX instrument equipped with photo ionization at atmospheric pressure and a Shimadzu LC-8A/SLC-1OA LC system. Column: 30 x 4.6 mm Waters Symmetry C 18 column with particle size 3.5 μm; solvent system: A = water/trifluoroacetic acid (100:0.05) and B= water/a ketone itri l/t rifl u o rode na acid (5:95:0.03); method: linear gradient elution from 90% A to 100% B in 4 minutes at a flow rate of 2 mL/minute. purity was determined by integrating the UV (254 nm) and ELSD traces. Retention times (to) are expressed in minutes. Preliminary LC-MS purification was performed on the same instrument with chemical ionization at atmospheric pressure. Column: 50 x 20 m YMC ODS-A with particle size 5 μm; method: linear gradient elution from 80% A to 100% B in 7 minutes and with a flow rate of 22.7 mL/min. Fraction collection was performed by split-flow MS detection.

Analitički LC-MS-TOF (TOF = prolazno vrijeme) podaci su dobiveni na instrumentu Micromass LCT 4-ways MUX opremljenom detektorskim sustavom Waters 2488/Sedex 754. Kolona: 30 × 4,6 mm Waters Symetry C 18 kolona s veličinom čestica 3,5 μm; sustav otapala: A = voda/fluoroctena kiselina (100:0,05) i B = voda/acetonitril/trifluoroctena kiselina (5:95:0,03); metoda: linearna gradijentna elucija s 90% A do 100% B za 4 minute i s protokom od 2 mL/min. čistoća je određena integracijom UV (254 nm) i ELSD traga. Vremena retencije (tr) su izražena u minutama. Analytical LC-MS-TOF (TOF = time of transit) data were obtained on a Micromass LCT 4-ways MUX instrument equipped with a Waters 2488/Sedex 754 detector system. Column: 30 × 4.6 mm Waters Symmetry C 18 column with particle size 3, 5 μm; solvent system: A = water/fluoroacetic acid (100:0.05) and B = water/acetonitrile/trifluoroacetic acid (5:95:0.03); method: linear gradient elution with 90% A to 100% B in 4 minutes and with a flow rate of 2 mL/min. purity was determined by integrating the UV (254 nm) and ELSD traces. Retention times (tr) are expressed in minutes.

GC-MS podaci su dobiveni na plinskom kromatografu Varian CP 3800 opremljenom Phenomenex kolonom (Zebron ZB-5, dužina: 15 metara, unutrašnji promjer: 0,25 mm) spojenom s Varian Saturn 2000 iontrap mass spektrometrom. Metoda: trajanje 15 minuta, protok kroz kolonu 1,4 mL/min (plin nositelj je bio helij), gradijent peći: 0-1 minuta, 60°C; 1-13 minuta, 60-300°C; 13-15 minuta, 300°C. 1H NMR spektri su zabilježeni na 500,13 MHz na instrumentu Bruker Avance DRX500. Kao otapala su upotrebljeni deuterizirani kloroform (99,8%D) ili dimetil sulfoksid (99,8%D). TNS je korišten kao unutrašnji referentni standard. Vrijednosti kemijskih pomaka izražene su u ppm-vrijednostima. Za mnoštvo NMR signala rabe se sljedeće kratice: s = singlet, d - dublet, t = triplet. q = kvartet, qui = kvintet, h = heptet, dd = dvostruki dublet, ddd = dvostruki dvostruki dublet, dt = dvostruki triplet, dq = dvostruki kvartet, tt = trostruki triplet, m = multiplet i b = široki singlet. Mikrovalni pokusi su obavljani postupkom hermetički zatvorenih bočica ili reaktora pomoću instrumenata Emrys Synthesizer ili Emrys Optimizer proizvođača Personal Chemistry ili instrumenta Milestone Microsynt proizvođača Milestone. Kad je reakcija zagrijana u mikrovalnom instrumentu, prije slijedeće faze postupka je ohlađena na 25°C. GC-MS data were obtained on a Varian CP 3800 gas chromatograph equipped with a Phenomenex column (Zebron ZB-5, length: 15 meters, inner diameter: 0.25 mm) connected to a Varian Saturn 2000 iontrap mass spectrometer. Method: duration 15 minutes, flow through the column 1.4 mL/min (carrier gas was helium), oven gradient: 0-1 minute, 60°C; 1-13 minutes, 60-300°C; 13-15 minutes, 300°C. 1H NMR spectra were recorded at 500.13 MHz on a Bruker Avance DRX500 instrument. Deuterated chloroform (99.8%D) or dimethyl sulfoxide (99.8%D) were used as solvents. TNS was used as an internal reference standard. Chemical shift values are expressed in ppm-values. The following abbreviations are used for many NMR signals: s = singlet, d - doublet, t = triplet. q = quartet, qui = quintet, h = heptet, dd = double doublet, ddd = double doublet, dt = double triplet, dq = double quartet, tt = triplet triplet, m = multiplet, and b = broad singlet. Microwave experiments were performed using hermetically sealed vials or reactors using the Emrys Synthesizer or Emrys Optimizer instruments manufactured by Personal Chemistry or the Milestone Microsynt instrument manufactured by Milestone. When the reaction was heated in a microwave instrument, it was cooled to 25°C before the next stage of the procedure.

Pripravljanje intermediera Preparation of intermediates

2,6-dimetil-4-morfolin-4-il-fenilamin 2,6-dimethyl-4-morpholin-4-yl-phenylamine

Bis(dibenzilidenaceton)paladij (2,88 g) i (+)-2,2'-bis(difenilfosfino)-1,1'-binaftil (4,69 g) dodani su suhom toluenu (175 mL očišćenih argonom) i 15 minuta miješani u atmosferi argona. Potom su dodani kalijev tert-butoksid (7,06 g), morfolin (8,7 mL) i 4-bromo-2,6-dimetilanilin (10,03 g). Reakcijska mješavina je 16 sati grijana do refluksa u atmosferi argona, ohlađena i filtrirana kroz siliciju (200 g). Dodan je matični lug (250 mL) i mješavina je ekstrahirana etil acetatom (3×200 mL). Kombinirane organske faze su osušene na magnezijevom sulfatu i koncentrirane in vacuo. Sirovi proizvod je otopljen u dietil eteru (250 mL), filtriran kroz siliciju (200 g) i koncentriran in vacuo te se dobilo 8,5 g (iskorištenje 41%) naslovnog spoja u obliku tamnog ulja. Proizvod je upotrijebljen bez daljnjeg pročišćavanja. GC-MS (m/z) 206 (M+); tR = 6,90. 1H NMR (500 MHz, CDCl3): 2,18 (s, 6H), 3,02 (m, 4H), 3,85 (m, 4H), 6.62 (b, 2H). Bis(dibenzylideneacetone)palladium (2.88 g) and (+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (4.69 g) were added to dry toluene (175 mL purged with argon) and 15 minutes mixed in an argon atmosphere. Potassium tert-butoxide (7.06 g), morpholine (8.7 mL) and 4-bromo-2,6-dimethylaniline (10.03 g) were then added. The reaction mixture was heated to reflux in an argon atmosphere for 16 hours, cooled and filtered through silica (200 g). Mother liquor (250 mL) was added and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic phases were dried over magnesium sulfate and concentrated in vacuo. The crude product was dissolved in diethyl ether (250 mL), filtered through silica (200 g) and concentrated in vacuo to give 8.5 g (41% yield) of the title compound as a dark oil. The product was used without further purification. GC-MS (m/z) 206 (M+); tR = 6.90. 1 H NMR (500 MHz, CDCl 3 ): 2.18 (s, 6H), 3.02 (m, 4H), 3.85 (m, 4H), 6.62 (b, 2H).

N-(4-bromo-2,6-dimetil-fenil)-2-ciklopentil-acetamid N-(4-bromo-2,6-dimethyl-phenyl)-2-cyclopentyl-acetamide

4-bromo-2,6-dimetilanilin (5,92 g) i ciklopentilacetil klorid (4,87 mL) su otopljeni u acetonitrilu (26 mL) i 10 minuta zagrijavani na 150°C u mikrovalnom postupku hermetički zatvorene bočice. Reakcija je ohlađena na 0°C, proizvod filtriran i ispran hladnim acetonitrilom (50 mL) te se dobilo 8,43 g (iskorištenje 92%) naslovnog spoja u obliku smeđe krutine. Sirovi proizvod je upotrijebljen bez daljnjeg pročišćavanja. LC-MS (m/z) 312 (MH+); tR = 3,10. (UV, ELSD) 89%. 99%. 1HNMR (500 MHz, CDCl3): 1,22 (m, 2H), 1,52 (m, 2H), 1,63 (m, 2H), 1,77 (m, 2H), 2,06 (2, 6H), 2,31 (m, 1H), 2.64 (d, 2H), 7,15 (s, 2H), 9,98 (b, 1H). 4-bromo-2,6-dimethylaniline (5.92 g) and cyclopentylacetyl chloride (4.87 mL) were dissolved in acetonitrile (26 mL) and heated at 150°C for 10 minutes in a microwave-sealed vial. The reaction was cooled to 0°C, the product was filtered and washed with cold acetonitrile (50 mL) to give 8.43 g (92% yield) of the title compound as a brown solid. The crude product was used without further purification. LC-MS (m/z) 312 (MH+); tR = 3.10. (UV, ELSD) 89%. 99%. 1HNMR (500 MHz, CDCl 3 ): 1.22 (m, 2H), 1.52 (m, 2H), 1.63 (m, 2H), 1.77 (m, 2H), 2.06 (2, 6H), 2.31 (m, 1H), 2.64 (d, 2H), 7.15 (s, 2H), 9.98 (b, 1H).

2-bromo-4-nitro-6-trifluorometil-fenilamin 2-bromo-4-nitro-6-trifluoromethyl-phenylamine

Bromin (0,60 mL) otopljen u octenoj kiselini (11 mL) dodan je kap po kap otopini 4-nitro-2-trifluorometil-fenilamina (2,4 g) u octenoj kiselini (12 mL). Reakcijska mješavina je 21⁄2 sata grijana do 120°C, izlivena u vodu (400 mL) i filtrirana. Prikupljena krutina isprana je vodom (200 mL) i osušena in vacuo te se dobilo 3,03 g (iskorištenje 91%) naslovnog spoja u obliku žute krutine. 1H NMR (500 MHz, DMSO-d6): 78,08 (s, 2H), 8,23 (d, 1H), 8,51 (d, 1H). Bromine (0.60 mL) dissolved in acetic acid (11 mL) was added dropwise to a solution of 4-nitro-2-trifluoromethyl-phenylamine (2.4 g) in acetic acid (12 mL). The reaction mixture was heated to 120°C for 21⁄2 hours, poured into water (400 mL) and filtered. The collected solid was washed with water (200 mL) and dried in vacuo to give 3.03 g (91% yield) of the title compound as a yellow solid. 1H NMR (500 MHz, DMSO-d 6 ): 78.08 (s, 2H), 8.23 (d, 1H), 8.51 (d, 1H).

2-bromo-6-trifluorometil-benzen-1,4-diamin 2-bromo-6-trifluoromethyl-benzene-1,4-diamine

Vodena otopina solne kiseline (2M, 45 mL) polako je dodana mješavini cinkove prašine (8,6 g) i 2-bromo-4-nitro-6-trifluorometil-fenilamina (2,5 g) u tetrahidrofuranu (50 mL). Reakcijska mješavina je miješana 1 sat, filtrirana i neutralizirana zasićenom vodenom otopinom natrijevog bikarbonata (100 mL). Dodana je voda (100 mL) i mješavina je ekstrahirana etil acetatom (2×100 mL). Kombinirane organske faze isprane su vodom (2×200 ml) i matičnim lugom (200 mL), osušene na natrijevom sulfatu i koncentrirane in vacuo te se dobilo 2,22 g (iskorištenje 98%) naslovnog spoja u obliku crvene krutine. 1H NMR (500 MHz, DMCO-d6): 4,55 (s. 2H), 4,91 (s, 2H), 6,76 (d, 1H), 7,01 (d, 1H). Aqueous hydrochloric acid (2M, 45 mL) was slowly added to a mixture of zinc dust (8.6 g) and 2-bromo-4-nitro-6-trifluoromethyl-phenylamine (2.5 g) in tetrahydrofuran (50 mL). The reaction mixture was stirred for 1 hour, filtered and neutralized with a saturated aqueous solution of sodium bicarbonate (100 mL). Water (100 mL) was added and the mixture was extracted with ethyl acetate (2×100 mL). The combined organic phases were washed with water (2×200 mL) and mother liquor (200 mL), dried over sodium sulfate and concentrated in vacuo to give 2.22 g (98% yield) of the title compound as a red solid. 1H NMR (500 MHz, DMCO-d6): 4.55 (s. 2H), 4.91 (s, 2H), 6.76 (d, 1H), 7.01 (d, 1H).

2-bromo-4-morfolin-4-il-6-trifluorometil-fenilamin 2-bromo-4-morpholin-4-yl-6-trifluoromethyl-phenylamine

2-bromo-6-trifluorometil-benzen-1,4-diamin (2,21 g), bis-(2-bromoetil)eter (1,30 mL) i N,N diizopropil-etilamin (4,64 mL) miješani su u N,N-dimetilformamidu (19 mL) i 30 minuta grijani do 180°C u mikrovalnom postupku hermetički zatvorene bočice. Dodana je zasićena vodena otopina bikarbonata (100 mL) i sirova mješavina je ekstrahirana etil acetatom (100 mL). Organska faza je isprana vodom (100 mL) i matičnim lugom (100 mL), osušena na natrijevom sulfatu i koncentrirana in vacuo. Sirovi proizvod je pročišćen flash kromatografijom te se dobilo 1,78 g (63%) naslovnog spoja u obliku žute krutine. LC-MS (mh) 326 (MH+); tR = 2,55, (UV, ELSD) 83%, 75%. 1H NMR (500 MHz, DMSO-d6): 2,99 (m, 4H), 3,70 (m, 4H), 5,00 (s, 2H), 7,00 (d, 1H), 7,38 (d, 1H). 2-Bromo-6-trifluoromethyl-benzene-1,4-diamine (2.21 g), bis-(2-bromoethyl)ether (1.30 mL) and N,N diisopropylethylamine (4.64 mL) were mixed were in N,N-dimethylformamide (19 mL) and heated to 180°C for 30 minutes in a microwave procedure in a hermetically sealed vial. Saturated aqueous bicarbonate solution (100 mL) was added and the crude mixture was extracted with ethyl acetate (100 mL). The organic phase was washed with water (100 mL) and mother liquor (100 mL), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography to give 1.78 g (63%) of the title compound as a yellow solid. LC-MS (mh) 326 (MH+); tR = 2.55, (UV, ELSD) 83%, 75%. 1H NMR (500 MHz, DMSO-d6): 2.99 (m, 4H), 3.70 (m, 4H), 5.00 (s, 2H), 7.00 (d, 1H), 7.38 (d, 1H).

2,5-diamino-3-kloro-benzonitril 2,5-diamino-3-chloro-benzonitrile

Vodena otopina solne kiseline (12 M, 5,3 mL) polako je dodana mješavini cinkove prašine (2,01 g) i 2-amino-3-kloro-5-nitro-benzonitrila (0,50 g) u tetrahidrofuranu (40 mL). Reakcijska mješavina je miješana 2 sata, neutralizirana zasićenom vodenom otopinom natrijevog karbonata (50 mL) i ekstrahirana etil acetatom (3×50 mL). Kombinirane organske faze osušene su na natrijevom sulfatu i koncentrirane in vacuo te se dobilo 0,42 g (iskorištenje 99%) naslovnog spoja u obliku crvene krutine. 1H NMR (500 MHz, DMSO-d6): 4,89 (s, 2H), 5,13 (s, 2H), 6,64 (d, 1H), 6,89 (d, 1H). Aqueous hydrochloric acid (12 M, 5.3 mL) was slowly added to a mixture of zinc dust (2.01 g) and 2-amino-3-chloro-5-nitro-benzonitrile (0.50 g) in tetrahydrofuran (40 mL). ). The reaction mixture was stirred for 2 hours, neutralized with saturated aqueous sodium carbonate solution (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic phases were dried over sodium sulfate and concentrated in vacuo to give 0.42 g (99% yield) of the title compound as a red solid. 1H NMR (500 MHz, DMSO-d6): 4.89 (s, 2H), 5.13 (s, 2H), 6.64 (d, 1H), 6.89 (d, 1H).

2-amino-3-kloro-5-morfolin-4-il-benzonitril 2-amino-3-chloro-5-morpholin-4-yl-benzonitrile

2,5-diamino-3-kloro-benzonitril (387 mg), bis-(2-bromoetil)eter (0,35 mL) i N,N-diizopropil-etilamin (1,25 mL) izmiješani su u N,N-dimetiltormamidu (4 mL) i 30 minuta grijani do 180°C u mikrovalnom postupku hermetički zatvorene bočice. Dodana je zasićena vodena otopina bikarbonata (20 mL) i sirova mješavina je ekstrahirana etil acetatom (20 mL). Organska faza je isprana vodom (20 mL) i matičnim lugom (20 mL), osušena na natrijevom sulfatu i koncentrirana in vacuo te se dobilo 0,50 g (91%) naslovnog spoja u obliku smeđe krutine. LC-MS (m/z) 238 (MH+); tR = 2,31, (UV, ELSD) 85%, 95%. 1H NMR (500 MHz, DMSO-d6): 2,97 (m, 4H), 3,69 (m, 4H), 5,59 (s, 2H), 7,04 (d, 1H), 7,29 (d, 1H). 2,5-Diamino-3-chloro-benzonitrile (387 mg), bis-(2-bromoethyl)ether (0.35 mL) and N,N-diisopropylethylamine (1.25 mL) were mixed in N,N -dimethyltormamide (4 mL) and heated for 30 minutes to 180°C in a microwave procedure in a hermetically sealed vial. A saturated aqueous bicarbonate solution (20 mL) was added and the crude mixture was extracted with ethyl acetate (20 mL). The organic phase was washed with water (20 mL) and mother liquor (20 mL), dried over sodium sulfate and concentrated in vacuo to give 0.50 g (91%) of the title compound as a brown solid. LC-MS (m/z) 238 (MH+); tR = 2.31, (UV, ELSD) 85%, 95%. 1H NMR (500 MHz, DMSO-d6): 2.97 (m, 4H), 3.69 (m, 4H), 5.59 (s, 2H), 7.04 (d, 1H), 7.29 (d, 1H).

[2-(4-fluoro-fenil)-2-hidroksi-etil]-karbamska kiselina tert-butil ester [2-(4-fluoro-phenyl)-2-hydroxy-ethyl]-carbamic acid tert-butyl ester

U miješanu otopinu karbamske kiseline tert-butil estera (0,22 g) u acetonitrilu (6 mL) dodavani su jedan za drugim na 0°: natrijev hidroksid (52 mg) u vodi (5 mL), nakon 2 minute tert-butil hipoklorit (139 μL), nakon 10 minuta kalijev osmat (VI)dihidrat (9 mg) u vodi (1 mL), nakon jedne minute hidrokvinin (antrakvinon-1,4-diil)dieter (26 mg) u acetonitrilu (4 mL), nakon 3 minute acetonitril (6,7 mL) i fosfatni pufer (3,3, mL, 0,5 M pH 7,65), nakon 5 minuta dovoljno natrijevog bifosfata da se postigne pH = 7,65, te konačno 4-fluorostiren. Reakcija je ugašena nakon što je 3 sata miješana na 25°C s natrijevim sulfitom (0,20 g) u vodi (2 mL) na 0°C. Faze su separirane i vodeni sloj je ekstrahiran etil acetatom (3×20 mL). Kombinirane organske faze su isprane vodom (1×50 mL), osušene na natrijevom sulfatu, koncentrirane in vacuo i pročišćene flash kromatografijom te se dobilo 90 mg (57%) naslovnog spoja u obliku bezbojnog ulja. 1H NMR (500 MHz, CDCl3): 1,45 (s, 9H), 3.18 (m, 1H), 3,23 (m, 1H), 3,44 (m, 1H), 4,83 (m, 1H), 4,92 (b, 1H), 7,04 (1, 2H), 7,43 (m, 2H), To a mixed solution of carbamic acid tert-butyl ester (0.22 g) in acetonitrile (6 mL) were added one after the other at 0°: sodium hydroxide (52 mg) in water (5 mL), after 2 minutes tert-butyl hypochlorite (139 μL), after 10 minutes potassium osmate (VI) dihydrate (9 mg) in water (1 mL), after one minute hydroquinine (anthraquinone-1,4-diyl)diether (26 mg) in acetonitrile (4 mL), after 3 minutes acetonitrile (6.7 mL) and phosphate buffer (3.3 mL, 0.5 M pH 7.65), after 5 minutes enough sodium biphosphate to reach pH = 7.65, and finally 4-fluorostyrene . The reaction was quenched after stirring at 25°C for 3 hours with sodium sulfite (0.20 g) in water (2 mL) at 0°C. The phases were separated and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with water (1×50 mL), dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography to give 90 mg (57%) of the title compound as a colorless oil. 1H NMR (500 MHz, CDCl3): 1.45 (s, 9H), 3.18 (m, 1H), 3.23 (m, 1H), 3.44 (m, 1H), 4.83 (m, 1H ), 4.92 (b, 1H), 7.04 (1, 2H), 7.43 (m, 2H),

Analogno su pripravljeni sljedeći spojevi: Analogously, the following compounds were prepared:

[2-hidroksi-2-(4-trifluorometil-fenil)-etil]-karbamska kiselina tert-butil ester [2-hydroxy-2-(4-trifluoromethyl-phenyl)-ethyl]-carbamic acid tert-butyl ester

Iskorištenje: 82%. 1H NMR (500 MHz, CDCI3): 1,44 (s, 9H), 3,26 (m, 1H), 3,52 (m, 2H), 4,40 (b, 1H), 4,92 (b, 1H), 7,49 (d, 2H), 7,61 (d.2H). Utilization: 82%. 1H NMR (500 MHz, CDCl 3 ): 1.44 (s, 9H), 3.26 (m, 1H), 3.52 (m, 2H), 4.40 (b, 1H), 4.92 (b , 1H), 7.49 (d, 2H), 7.61 (d, 2H).

[2-(2-klorofenil)-2-hidroksi-etil]-karbamska kiselina tert-butil ester [2-(2-Chlorophenyl)-2-hydroxy-ethyl]-carbamic acid tert-butyl ester

Iskorištenje: 61%. 1H NMR (500 MHz, CDCl3): 1,44 (s, 9H), 3,32 (m, 1H), 3,51 (m, 1H), 4,23 (m, 1H), 5,08 (b, 1H), 5,19 (b, 1H), 7,20 (m, 1H), 7,29 (m, 1H), 7,59 (m, 1H). Utilization: 61%. 1H NMR (500 MHz, CDCl3): 1.44 (s, 9H), 3.32 (m, 1H), 3.51 (m, 1H), 4.23 (m, 1H), 5.08 (b , 1H), 5.19 (b, 1H), 7.20 (m, 1H), 7.29 (m, 1H), 7.59 (m, 1H).

2-(4-fluoro-fenil)-rnorfolin 2-(4-Fluoro-phenyl)-norpholine

Otopina [2-(4-fluoro-fenil)-2-hidroksi-etil]-karbamska kiselina tert-butil estera (90 mg) u diklormetanu (1 mL) i trifluoroctenoj kiselini (1 mL) 1 sat je miješana na 25°C i potom koncentrirana in vacuo. Talog je razdijeljen između etil acetata (5 mL) i zasićene vodene otopine kalijevog karbonata (5 mL). Organska faza je osušena na natrijevom sulfatu, koncentrirana in vacuo i ponovno otopljena u suhom tetrahidrofuranu (3 mL) i trietilaminu (54 μL). Kap po kap je dodan kloroacetil klorid (31 μL) u suhom tetrahidrofuranu (1 mL) na 0°C. Nakon 30 minuta reakcija je razrijeđena etil acetatom (10 mL) i isprana vodom/matičnim lugom (1:1, 3×10 mL). Organska faza je osušena na natrijevom sulfatu, koncentrirana in vacuo i ponovno otopljena u tert-butanolu (5 mL). Dodan je kalijev tert-butoksid (79 mg) i reakcija je 1,5 sat miješana na 25°C. Reakcija je ugašena zasićenom vodenom otopinom amonijevog klorida (30 mL) i ekstrahirana etil acetatom (2×30 mL). Kombinirane organske faze su osušene na natrijevom sulfatu, koncentrirane in vacuo i zajedno uparene s toluenom (2×5 mL). Talog je otopljen u suhom toluenu (5 mL) u atmosferi argona i kap po kap tretiran natrijevim bis(2-metoksietoksi)aluminijevim hidridom (70% u toluenu, 20 μL) te miješan 5 sati na 25°C. Reakcija je ugašena na 0°C 10%-tnom vodenom otopinom natrijevog hidroksida (5 mL), a mješavina je ekstrahirana dietil eterom (2×15 mL). Kombinirane organske faze su osušene na natrijevom sulfatu i koncentrirane in vacuo te se dobilo 60 mg (94%) naslovnog spoja u obliku bezbojnog ulja. LC-MS (m/z) 182 (MH+); tR = 1,06, (UV, ELSD) 78%, 98%. A solution of [2-(4-fluoro-phenyl)-2-hydroxy-ethyl]-carbamic acid tert-butyl ester (90 mg) in dichloromethane (1 mL) and trifluoroacetic acid (1 mL) was stirred at 25°C for 1 hour and then concentrated in vacuo. The precipitate was partitioned between ethyl acetate (5 mL) and saturated aqueous potassium carbonate (5 mL). The organic phase was dried over sodium sulfate, concentrated in vacuo and redissolved in dry tetrahydrofuran (3 mL) and triethylamine (54 μL). Chloroacetyl chloride (31 μL) in dry tetrahydrofuran (1 mL) was added dropwise at 0°C. After 30 minutes, the reaction was diluted with ethyl acetate (10 mL) and washed with water/mother liquor (1:1, 3×10 mL). The organic phase was dried over sodium sulfate, concentrated in vacuo and redissolved in tert-butanol (5 mL). Potassium tert-butoxide (79 mg) was added and the reaction was stirred for 1.5 hours at 25°C. The reaction was quenched with saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (2×30 mL). The combined organic phases were dried over sodium sulfate, concentrated in vacuo and co-evaporated with toluene (2×5 mL). The precipitate was dissolved in dry toluene (5 mL) in an argon atmosphere and treated dropwise with sodium bis(2-methoxyethoxy)aluminum hydride (70% in toluene, 20 μL) and stirred for 5 hours at 25°C. The reaction was quenched at 0°C with 10% aqueous sodium hydroxide solution (5 mL), and the mixture was extracted with diethyl ether (2×15 mL). The combined organic phases were dried over sodium sulfate and concentrated in vacuo to give 60 mg (94%) of the title compound as a colorless oil. LC-MS (m/z) 182 (MH + ); tR = 1.06, (UV, ELSD) 78%, 98%.

Analogno su pripravljeni sljedeći spojevi: Analogously, the following compounds were prepared:

2-(4-trifluoro-fenil)-morfolin 2-(4-trifluoro-phenyl)-morpholine

Iskorištenje: 85%. LC-MS (m/z) 232 (MH+); tR = 1,59, (UV, ELSD) 79%, 99%. Utilization: 85%. LC-MS (m/z) 232 (MH + ); tR = 1.59, (UV, ELSD) 79%, 99%.

2-(2-kloro-fenil)-morfolin 2-(2-chloro-phenyl)-morpholine

Iskorištenje: 86%. LC-MS (m/z) 198 (MH+); tR = 1,21, (UV, ELSD) 66%, 99%. Utilization: 86%. LC-MS (m/z) 198 (MH + ); tR = 1.21, (UV, ELSD) 66%, 99%.

4-bromo-2-metoksi-6-metil-fenilamin 4-bromo-2-methoxy-6-methyl-phenylamine

2-metoksi-6-metil-fenilaminu (10,0 g) otopljenom u acetonitrilu (100 mL) dodan je M-bromosukcinimid (14,3 g) i reakcijska mješavina je 15 minuta grijana do 145°C u mikrovalnom postupku hermetički zatvorene posude. Sirova mješavina je filtrirana kroz celit, razrijeđena dietil eterom (200 mL) i isprana natrijevim hidroksidom (1 M, 2×100 mL) i matičnim lugom (1×100 mL). Organska faza je osušena na magnezijevom sulfatu, koncentrirana in vacuo i pročišćena flash kromatografijom te se dobilo 3,4 g (26%) naslovnog spoja u obliku crne krutine. 1H NMR (500 MHz, DMSO-d6): 2,06 (s, 3H), 3,77 (s, 3H), 4,55 (s, 2H), 6,78 (d, 1H), 6,82 (d, 1H). M-bromosuccinimide (14.3 g) was added to 2-methoxy-6-methyl-phenylamine (10.0 g) dissolved in acetonitrile (100 mL) and the reaction mixture was heated to 145°C in a hermetically sealed container in a microwave oven for 15 minutes. . The crude mixture was filtered through celite, diluted with diethyl ether (200 mL) and washed with sodium hydroxide (1 M, 2×100 mL) and mother liquor (1×100 mL). The organic phase was dried over magnesium sulfate, concentrated in vacuo and purified by flash chromatography to give 3.4 g (26%) of the title compound as a black solid. 1H NMR (500 MHz, DMSO-d6): 2.06 (s, 3H), 3.77 (s, 3H), 4.55 (s, 2H), 6.78 (d, 1H), 6.82 (d, 1H).

Analogno je pripravljen sljedeći spoj: Analogously, the following compound was prepared:

4-bromo-2-metil-6-trifluorometil-fenilamin 4-bromo-2-methyl-6-trifluoromethyl-phenylamine

Iskorištenje: 80%. GC-MS (m/z) 254 (M+); tR = 3,73. Utilization: 80%. GC-MS (m/z) 254 (M+); tR = 3.73.

2-metoksi-6-metil-4-morfolin-4-il-fenilamin 2-Methoxy-6-methyl-4-morpholin-4-yl-phenylamine

Bis(dibenzilidenaceton)paladij (0,63 g) i (2'-dicikloheksilfosfanil-bifenil-2-il)-dimetil-amin (0,68 g) dodani su suhom toluenu (100 mL očišćenih argonom) i miješani 15 minuta u atmosferi argona. Potom su dodani kalijev tert-butoksid (3,70 g), morfolin (4,0 mL) i 4-bromo-2-metoksi-6-metil-fenilamin (3,40 g). Reakcijska mješavina je 16 sati grijana do refluksa u atmosferi argona, ohlađena i filtrirana kroz siliciju (50 g). Dodan je natrijev hidroksid (2M, 200 mL) i mješavina je ekstrahirana etil acetatom (3-200 mL). Kombinirane organske faze su isprane matičnim lugom (1×200 mL), osušene na magnezijevom sulfatu i koncentrirane in vacuo. Sirovi proizvod je pročišćen flash kromatografijom te se dobilo 1,0 g (iskorištenje 29%) naslovnog spoja u obliku crnog ulja. 1H NMR (500 MHz, DMSO-d6): 2,05 (s, 3H), 2,91 (t, 4H), 3,69 (t, 4H), 3,74 (s, 3H), 3,95 (s, 2H), 6,23 (d, 1H) 6,39 (d, 1H). Bis(dibenzylideneacetone)palladium (0.63 g) and (2'-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethylamine (0.68 g) were added to dry toluene (100 mL purged with argon) and stirred for 15 min under atmosphere argon. Potassium tert-butoxide (3.70 g), morpholine (4.0 mL) and 4-bromo-2-methoxy-6-methyl-phenylamine (3.40 g) were then added. The reaction mixture was heated to reflux in an argon atmosphere for 16 hours, cooled and filtered through silica (50 g). Sodium hydroxide (2M, 200 mL) was added and the mixture was extracted with ethyl acetate (3-200 mL). The combined organic phases were washed with mother liquor (1×200 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography to give 1.0 g (29% yield) of the title compound as a black oil. 1H NMR (500 MHz, DMSO-d6): 2.05 (s, 3H), 2.91 (t, 4H), 3.69 (t, 4H), 3.74 (s, 3H), 3.95 (s, 2H), 6.23 (d, 1H) 6.39 (d, 1H).

Analogno je pripravljen sljedeći spoj: Analogously, the following compound was prepared:

2-metil-4-morfolin-4-il-6-trifluorometil-fenilamin 2-methyl-4-morpholin-4-yl-6-trifluoromethyl-phenylamine

Iskorištenje: 28%. 1H NMR (500 MHz, DMSO-d6): 2,13 (s, 3H), 2,93 (t, 4H), 3,70 (t, 4H), 4,67 (s, 2H),6,75(d, 1H), 6,99 (d, 1H), Utilization: 28%. 1H NMR (500 MHz, DMSO-d6): 2.13 (s, 3H), 2.93 (t, 4H), 3.70 (t, 4H), 4.67 (s, 2H), 6.75 (d, 1H), 6.99 (d, 1H),

4-(3,5-difluoro-4-nitro-fenil)-morfolin 4-(3,5-difluoro-4-nitro-phenyl)-morpholine

2,4,6-trifluoronitrobenzen (4,95 g) i kalijev karbonat (4,63 g) su izmiješani u suhom dimetil sulfoksidu (40 mL) i u atmosferi argona ohlađeni na 10°C. Dodan je morfolin (2,56 mL) te je reakcijska mješavina ostavljena da se ugrije na 25°C i u atmosferi argona miješana 16 sati. Reakcijska mješavrma je koncentrirana in vacuo. Dodan je matični lug (50 mL) i proizvod je ekstrahiran etil acetatom (3×50 mL). Kombinirane organske faze su osušene na magnezijevom sulfatu i koncentrirane in vacuo. Sirovi materijal je pročišćen flash kromatografijom te se dobilo 2,49 g (iskorištenje 37%) naslovnog spoja u obliku žute krutine. 1H NMR (500 MHz, DMSO-d6): 3,43 (t, 4H), 3,69 (t, 4H), 6,87 (d, 2H). 2,4,6-trifluoronitrobenzene (4.95 g) and potassium carbonate (4.63 g) were mixed in dry dimethyl sulfoxide (40 mL) and cooled to 10°C under an argon atmosphere. Morpholine (2.56 mL) was added and the reaction mixture was allowed to warm to 25°C and stirred under an argon atmosphere for 16 hours. The reaction mixture was concentrated in vacuo. Mother liquor (50 mL) was added and the product was extracted with ethyl acetate (3×50 mL). The combined organic phases were dried over magnesium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography to give 2.49 g (37% yield) of the title compound as a yellow solid. 1 H NMR (500 MHz, DMSO-d 6 ): 3.43 (t, 4H), 3.69 (t, 4H), 6.87 (d, 2H).

2,6-difluoro-4-morfolin-4-il-fenilamin 2,6-difluoro-4-morpholin-4-yl-phenylamine

Koncentrirana solna kiselina (4,2 mL) je polako dodavana mješavini cinkove prašine (3,3 g) i 4-(3,5-difluoro-4-nitro-fenil)-morfolinu (2,49 g) u tetrafuranu (40 mL) ohlađenoj na 0°C. Reakcijska mješavina je potom 1 sat miješana na 0°C i 2 sata ne 25'C. Reakcijska mješavina je filtrirana kroz celit (10 g), koncentrirana in vacuo i pročišćena flash kromatografijom te se dobilo 1,96 g (iskorištenje 90%) naslovnog spoja u obliku bijele krutine. GC-MS (m/z) 214 (M+); tR = 5.84. 1H NMR (500 MZh, DMSO-d6): 2,94 (t, 4H). 3,69 (t, 4H), 4,53 (s, 2H), 6,57 (m, 2H). Concentrated hydrochloric acid (4.2 mL) was slowly added to a mixture of zinc dust (3.3 g) and 4-(3,5-difluoro-4-nitro-phenyl)-morpholine (2.49 g) in tetrafuran (40 mL ) cooled to 0°C. The reaction mixture was then stirred at 0°C for 1 hour and at 25°C for 2 hours. The reaction mixture was filtered through celite (10 g), concentrated in vacuo and purified by flash chromatography to give 1.96 g (90% yield) of the title compound as a white solid. GC-MS (m/z) 214 (M+); tR = 5.84. 1 H NMR (500 MZh, DMSO-d 6 ): 2.94 (t, 4H). 3.69 (t, 4H), 4.53 (s, 2H), 6.57 (m, 2H).

2-kloro-4-nitro-6-trifluorometil-fenilamin 2-chloro-4-nitro-6-trifluoromethyl-phenylamine

Napravljena je suspenzija 4-nitro-2-trifluorometil-fenilamina (5,6 g) i N-klorosukcinimida (4,0 g) u acetonitrilu (15 mL) i 10 minuta grijana na 150°C u mikrovalnom postupku hermeticki zatvorene bočice. Dodan je etil acetat (80 mL) i organska faza je isprana s 5%-tnom vodenom otopinom NaOH (2×50 mL), vodom (2×50 mL) i matičnim lugom (2×50 mL). Organska faza je osušena na magnezijevom sulfatu i koncentrirana in vacuo. Sirovi proizvod je pročišćen flash kromatografijom te se dobilo 4,9 g (iskorištenje 75%) naslovnog spoja u obliku žute krutine. 1H NMR (500 MHz. CDCl3): 5,35 (b, 2H), 8,35 (b, 1H), 8,37 (b, 1H). A suspension of 4-nitro-2-trifluoromethyl-phenylamine (5.6 g) and N-chlorosuccinimide (4.0 g) in acetonitrile (15 mL) was prepared and heated for 10 minutes at 150°C in a microwave process in a hermetically sealed vial. Ethyl acetate (80 mL) was added and the organic phase was washed with 5% aqueous NaOH (2×50 mL), water (2×50 mL) and mother liquor (2×50 mL). The organic phase was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography to give 4.9 g (75% yield) of the title compound as a yellow solid. 1 H NMR (500 MHz. CDCl 3 ): 5.35 (b, 2H), 8.35 (b, 1H), 8.37 (b, 1H).

Analogno je pripravljen sljedeći spoj: Analogously, the following compound was prepared:

2-kloro-6-metil-4-nitro-fenilamin 2-chloro-6-methyl-4-nitro-phenylamine

Iskorištenje: 95%. 1H NMR (500 MHz, DMSO-d6): 2,22 (s, 3H), 6,56 (b, 2H), 7,89 (d, 1H), 8,00 (d, 1H). Utilization: 95%. 1H NMR (500 MHz, DMSO-d6): 2.22 (s, 3H), 6.56 (b, 2H), 7.89 (d, 1H), 8.00 (d, 1H).

N-(2-kloro-6-metit-4-nitm-fenil)-2-ciklopentil-acetamid N-(2-chloro-6-methyl-4-nitrophenyl)-2-cyclopentyl-acetamide

2-kloro-6-metil-4-nitro-fenilamin (6,0 g) i ciklopentilacetil klorid (5,1 g) otopljeni su u acetonitrilu (45 mL) i 20 minuta grijani do 150°C u mikrovalnom postupku hermeticki zatvorene posude. Reakcijska mješavina je ohlađena na 0°C, a istaloženi proizvod prikupljen filtriranjem i ispran hladnim acetonitrilom te se dobilo 5,5 g (58%) naslovnog spoja u obliku žute krutine. 1H NMR (500 MHz, DMSO-d6) 1,24 (m, 2H), 1,58 (m, 4H), 1,78 (m, 2H). 2,27 (m, 1H), 2,30 (s, 3H), 2,38 (d, 2H), 8,15 (d, 1H),8,18(d, 1H), 9,83 (s, 1H). 2-Chloro-6-methyl-4-nitro-phenylamine (6.0 g) and cyclopentylacetyl chloride (5.1 g) were dissolved in acetonitrile (45 mL) and heated to 150°C for 20 minutes in a microwave oven in a hermetically sealed container. . The reaction mixture was cooled to 0°C, and the precipitated product was collected by filtration and washed with cold acetonitrile to give 5.5 g (58%) of the title compound as a yellow solid. 1 H NMR (500 MHz, DMSO-d 6 ) 1.24 (m, 2H), 1.58 (m, 4H), 1.78 (m, 2H). 2.27 (m, 1H), 2.30 (s, 3H), 2.38 (d, 2H), 8.15 (d, 1H), 8.18 (d, 1H), 9.83 (s , 1H).

Analogno je pripravljen sljedeći spoj: Analogously, the following compound was prepared:

N-(2-kloro-6-metil-4-nitro-fenil)-2-(3-fluoro-fenil)-acetamid N-(2-chloro-6-methyl-4-nitro-phenyl)-2-(3-fluoro-phenyl)-acetamide

Iskorištenje: 72%. 1H NMR (500 MHz, DMSO-d6): 2,24 (s, 3H), 3,77 (s, 2H), 7,10 (dt, 1H), 7,21 (m, 2H), 7,39 (m, 1H), 8,14 (d, 1H), 8,19 (d, 1H), 10,15 (s, 1H). Utilization: 72%. 1H NMR (500 MHz, DMSO-d6): 2.24 (s, 3H), 3.77 (s, 2H), 7.10 (dt, 1H), 7.21 (m, 2H), 7.39 (m, 1H), 8.14 (d, 1H), 8.19 (d, 1H), 10.15 (s, 1H).

2-kloro-6-trifluorometil-benzen-1,4-diamin 2-chloro-6-trifluoromethyl-benzene-1,4-diamine

Octena kiselina (13 mL) je polako dodana mješavini cinkove prašine (12,4 g) i 2-kloro-4-nitro-6-trifluorometil-fenilamina (4 g) u tetrahidrofuranu (40 nL). Reakcijska mješavina je miješana 1 sat, filtrirana kroz siliciju i koncentrirana in vacuo. Sirovi proizvod je pročišćen flash kromatografijom te se dobilo 2,9 g (83%) naslovnog spoja u obliku crne krutine. 1H NMR (500 MHz, CDCl3): 3,44 (b, 2H), 4,16 (b,2H), 6,77 (d, 1H), 6,86 (d, 1H). Acetic acid (13 mL) was slowly added to a mixture of zinc dust (12.4 g) and 2-chloro-4-nitro-6-trifluoromethyl-phenylamine (4 g) in tetrahydrofuran (40 nL). The reaction mixture was stirred for 1 hour, filtered through silica and concentrated in vacuo. The crude product was purified by flash chromatography to give 2.9 g (83%) of the title compound as a black solid. 1 H NMR (500 MHz, CDCl 3 ): 3.44 (b, 2H), 4.16 (b, 2H), 6.77 (d, 1H), 6.86 (d, 1H).

Analogno su pripravljeni sljedeći spojevi: Analogously, the following compounds were prepared:

N-(4-amino-2-kloro-6-metil-fenil)-2-ciklopentil-acetamid N-(4-amino-2-chloro-6-methyl-phenyl)-2-cyclopentyl-acetamide

Iskorištenje: 69%. 1H NMR (500 MHz, DMSO-d6): 1,21 (m, 2H), 1,57 (m, 4H), 1.76 (m, 2H), 2,00 (s, 3H), 2,23 (d, 2H), 2.26 (m, 1H), 5.23 (s. 2H), 6,36 (d, 1H), 6,48 (d, 1H), 8,98 (s, 1H). Utilization: 69%. 1H NMR (500 MHz, DMSO-d6): 1.21 (m, 2H), 1.57 (m, 4H), 1.76 (m, 2H), 2.00 (s, 3H), 2.23 (d , 2H), 2.26 (m, 1H), 5.23 (s. 2H), 6.36 (d, 1H), 6.48 (d, 1H), 8.98 (s, 1H).

N-(4-amino-2-kloro-6-metil-fenil)-2-(3-fIuoro-fenil)-acetamid N-(4-amino-2-chloro-6-methyl-phenyl)-2-(3-fluoro-phenyl)-acetamide

Iskorištenje; 88%. 1H NMR (500 MHz, DMS0-d6); 1.90 (s, 3H), 3,62 (s, 2H), 5.26 (s, 2H), 6 35 (d, 1H), 6,49 (d, 1H), 7,07 (dt, 1H), 7,20 (m, 2H), 7, 37 (m, 1H), 9,34 (s, 1H). Utilization; 88%. 1H NMR (500 MHz, DMS0-d6); 1.90 (s, 3H), 3.62 (s, 2H), 5.26 (s, 2H), 6 35 (d, 1H), 6.49 (d, 1H), 7.07 (dt, 1H), 7 .20 (m, 2H), 7.37 (m, 1H), 9.34 (s, 1H).

2-kloro-4-morfolin-4-it-6-trifluorometil-fenilamin 2-chloro-4-morpholin-4-yl-6-trifluoromethyl-phenylamine

2-kloro-6-trifluorometil-benzen-1,4-diamin (2,9 g), bis-(2-kloroetil)eter (1,72 mL) i natrijev jodid (516 mg) pomiješani su u acetonitrilu (45 mL) i 1 sat grijani do 165°C u mikrovalnom postupku hermetički zatvorene posude. Sirova mješavina je koncentrirana in vacuo, ponovno otopljena u etil acetatu (100 mL) te isprana vodom (2×100 mL) i matičnim lugom (1×100 mL). Organska faza je osušena na magnezijevom sulfatu i koncentrirana in vacuo. Sirovi proizvod je pročišćen flash kromatografijom te se dobilo 940 mg (24%) naslovnog spoja u obliku crnog ulja. 1H NMR (500 MHz, CDCl3): 3,02 (m, 4H), 3,84 (m, 4H), 4,30 (b, 2H), 6,97 (d, 1H), 7,06 (d, 1H). 2-Chloro-6-trifluoromethyl-benzene-1,4-diamine (2.9 g), bis-(2-chloroethyl)ether (1.72 mL) and sodium iodide (516 mg) were mixed in acetonitrile (45 mL ) and heated to 165°C for 1 hour in a microwave oven in a hermetically sealed container. The crude mixture was concentrated in vacuo, redissolved in ethyl acetate (100 mL) and washed with water (2×100 mL) and mother liquor (1×100 mL). The organic phase was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography to give 940 mg (24%) of the title compound as a black oil. 1H NMR (500 MHz, CDCl3): 3.02 (m, 4H), 3.84 (m, 4H), 4.30 (b, 2H), 6.97 (d, 1H), 7.06 (d , 1H).

N-(2,6-diizopropil-4-nitro-fenil)-4-metil-benzensulfonamid N-(2,6-diisopropyl-4-nitro-phenyl)-4-methyl-benzenesulfonamide

2,6-diizopropil-fenilamin (1,80 mL) i para-toluensulfonil klorid (2,00 g) otopljeni su u piridinu (4 mL) i 10 minuta grijani do 160°C u mikrovalnom postupku hermetički zatvorene bočice. Dobivena kaša je otopljena etil acetatom (10 mL) te isprana solnom kiselinom (2M, 10 mL) i matičnim lugom (10 mL). Organska faza je osušena na natrijevom sulfatu, koncentrirana in vacuo te je napravljena suspenzija 65%-tne dušične kiseline (15 mL) i vode (60 mL). Postupno su dodavani octena kiselina (60 mL) i natrijev nitrit (0,99 g) te je reakcijska mješavina 12 sati grijana do 100°C. Mješavina je ohlađena na 25°C, izlivena na ledenu vodu (200 mL) i filtrirana te se dobilo 2,07 g (58%) naslovnog spoja u obliku žute krutine. 1H NMR (500 MHz, CDCl3): 1,06 (d, 12H), 2,43 (s, 3H), 3,19 (m, 2H), 6,29 (s, 1H), 7,28 (d, 2H), 7,59 (d, 2H), 7,97 (s, 2H). 2,6-diisopropyl-phenylamine (1.80 mL) and para-toluenesulfonyl chloride (2.00 g) were dissolved in pyridine (4 mL) and heated to 160°C for 10 minutes in a microwave oven in a hermetically sealed vial. The resulting slurry was dissolved in ethyl acetate (10 mL) and washed with hydrochloric acid (2M, 10 mL) and mother liquor (10 mL). The organic phase was dried over sodium sulfate, concentrated in vacuo and a suspension of 65% nitric acid (15 mL) and water (60 mL) was made. Acetic acid (60 mL) and sodium nitrite (0.99 g) were gradually added, and the reaction mixture was heated to 100°C for 12 hours. The mixture was cooled to 25°C, poured onto ice water (200 mL) and filtered to give 2.07 g (58%) of the title compound as a yellow solid. 1H NMR (500 MHz, CDCl3): 1.06 (d, 12H), 2.43 (s, 3H), 3.19 (m, 2H), 6.29 (s, 1H), 7.28 (d , 2H), 7.59 (d, 2H), 7.97 (s, 2H).

N-(4-amino-2,6-diizopropil-fenil)-4-metil-benzen sulfonamid N-(4-amino-2,6-diisopropyl-phenyl)-4-methyl-benzene sulfonamide

U suspenziju N-(2,6-diizopropil-4-nitro-fenil)-4-metil-benzensulfonamida (3,72 g) u etanolu (50 mL) dodan je kositreni (II) klorid dihidrat (11,2 g) te je mješavina 1,5 sat grijana do 80°C. Potom je izlivena na led (300 mL), jako zalužena krutim natrijevim hidroksidom (20 g) i otopljena etil acetatom (100 mL). Suspenzija je filtrirana i ekstrahirana etil acetatom (3×100 mL). Kombinirane organske faze su isprane natrijevim sulfatom i koncentrirane in vacuo. Sirovi proizvod je pročišćen flash kromatografijom te se dobilo 2,60 g (76%) naslovnog spoja u obliku prljavobijele krutine 1H NMR (500 MHz, CDCl3): 0,95 (d, 12 H), 2,40 (s, 3H), 3,02 (m, 2H), 3,68 (b, 2h), 5,74 (s, 1H), 6,39 (s, 2H), 7,23 (d, 2H), 7,60 (d, 2H). Tin (II) chloride dihydrate (11.2 g) was added to a suspension of N-(2,6-diisopropyl-4-nitro-phenyl)-4-methyl-benzenesulfonamide (3.72 g) in ethanol (50 mL) and the mixture is heated to 80°C for 1.5 hours. It was then poured onto ice (300 mL), made very alkaline with solid sodium hydroxide (20 g) and dissolved in ethyl acetate (100 mL). The suspension was filtered and extracted with ethyl acetate (3×100 mL). The combined organic phases were washed with sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography to give 2.60 g (76%) of the title compound as an off-white solid 1H NMR (500 MHz, CDCl3): 0.95 (d, 12 H), 2.40 (s, 3H) , 3.02 (m, 2H), 3.68 (b, 2h), 5.74 (s, 1H), 6.39 (s, 2H), 7.23 (d, 2H), 7.60 ( d, 2H).

2,6-diizopropil-4-morfolin-4-il-fenilamin 2,6-diisopropyl-4-morpholin-4-yl-phenylamine

Mješavina N-(4-amino-2,6-diizopropil-fenil)-4-metil-benzensulfonamid (346 mg), bis-(2-bromoetil) eter (151 μL), N,N-diizopropil-etilamina (0,53 mL) N-metilpirolidina (1,0 mL) 20 minuta je grijana do 180°C u mikrovalnom postupku hermetički zatvorene bočice. Mješavina je otopljena etil acetatom (20 mL), isprana matičnim lugom (30 mL) i zasićenom vodenom otopinom kalijevog karbonata (30 mL) te osušena na natrijevom sulfatu. Organska faza je koncentrirana in vacuo i ponovno otopljena u mješavini sumporne kiseline (1,9 mL) i vode (0,1 mL) te 3 sata miješana na 40°C. Dodani su led (30 mL) i voda (30 mL) te je mješavina zalužena krutim kalijevim karbonatom. Mješavina je ekstrahirana etil acetatom (3×20 mL), a kombinirane organske faze su osušene na natrijevom sulfatu i koncentrirane in vacuo te se dobilo 260 mg (99%) naslovnog spoja u obliku bijele krutine. 1H NMR (500 MHz, CDCl3): 1.26 (d. 12H), 2,95 (m, 2H), 3,06 (m, 4H), 3,49 (b, 2H). 3,87 (m, 4H), 6,69 (s, 2H). A mixture of N-(4-amino-2,6-diisopropyl-phenyl)-4-methyl-benzenesulfonamide (346 mg), bis-(2-bromoethyl) ether (151 μL), N,N-diisopropyl-ethylamine (0, 53 mL) of N-methylpyrrolidine (1.0 mL) was heated to 180°C for 20 minutes in a microwave oven in a hermetically sealed vial. The mixture was dissolved in ethyl acetate (20 mL), washed with mother liquor (30 mL) and saturated aqueous potassium carbonate solution (30 mL) and dried over sodium sulfate. The organic phase was concentrated in vacuo and redissolved in a mixture of sulfuric acid (1.9 mL) and water (0.1 mL) and stirred at 40°C for 3 hours. Ice (30 mL) and water (30 mL) were added and the mixture basified with solid potassium carbonate. The mixture was extracted with ethyl acetate (3×20 mL), and the combined organic phases were dried over sodium sulfate and concentrated in vacuo to give 260 mg (99%) of the title compound as a white solid. 1H NMR (500 MHz, CDCl 3 ): 1.26 (d. 12H), 2.95 (m, 2H), 3.06 (m, 4H), 3.49 (b, 2H). 3.87 (m, 4H), 6.69 (s, 2H).

N-(2,6-dietil-4-nitro-fenil)-4-metil-benzensulfonamid N-(2,6-diethyl-4-nitro-phenyl)-4-methyl-benzenesulfonamide

2,6-dietil-fenilamin (1,57 mL) i para-toluensulfonil klorid (2,00 g) otopljeni su u piridinu (4 mL) i 10 minuta grijani do 160°C u mikrovalnom postupku hermetički zatvorene bočice. Dobivena kaša je otopljena etil acetatom (10 mL) te isprana solnom kiselinom (2M, 10 mL) i matičnim lugom (10 mL). Organska faza je osušena na natrijevom sulfatu, koncentrirana in vacuo te je napravljena suspenzija od 65%-tne dušične kiseline (15 mL) i vode (60 mL). Postupno su dodani octena kiselina (60 mL) i natrijev nitrit (0,99 g) te je reakcijska mješavina 12 sati grijana do 100°C. Mješavina je ohlađena na 25°C i izlivena u ledenu vodu (200 mL), zalužena krutim natrijevim hidroksidom i ekstrahirana etil acetatom (3×50 mL). Kombinirane organske faze su isprane matičnim lugom (1×100 mL), osušene na natrijevom sulfatu i koncentrirane in vacuo te se dobilo 0,31 g (9%) naslovnog spoja u obliku žutog sirupa. 1H NMR (500 MHz, DMSO-d6): 0,98 (t, 6H), 2,34 (s, 3H), 3,30 (m, 4H), 7,25 (d, 2H), 7,52 (d, 2H), 7,80 (s, 2H). 2,6-diethyl-phenylamine (1.57 mL) and para-toluenesulfonyl chloride (2.00 g) were dissolved in pyridine (4 mL) and heated to 160°C for 10 minutes in a microwave oven in a hermetically sealed vial. The resulting slurry was dissolved in ethyl acetate (10 mL) and washed with hydrochloric acid (2M, 10 mL) and mother liquor (10 mL). The organic phase was dried over sodium sulfate, concentrated in vacuo and a suspension of 65% nitric acid (15 mL) and water (60 mL) was made. Acetic acid (60 mL) and sodium nitrite (0.99 g) were gradually added, and the reaction mixture was heated to 100°C for 12 hours. The mixture was cooled to 25°C and poured into ice water (200 mL), basified with solid sodium hydroxide and extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with mother liquor (1×100 mL), dried over sodium sulfate and concentrated in vacuo to give 0.31 g (9%) of the title compound as a yellow syrup. 1H NMR (500 MHz, DMSO-d6): 0.98 (t, 6H), 2.34 (s, 3H), 3.30 (m, 4H), 7.25 (d, 2H), 7.52 (d, 2H), 7.80 (s, 2H).

N-(4-amino-2,6-dietil-fenil)-4-metil-benzensulfonamid N-(4-amino-2,6-diethyl-phenyl)-4-methyl-benzenesulfonamide

Otopina natrijevog ditionita (772 mg) u vodi (6 mL) dodana je otopini N-(2,6-detil-nitro-fenil)-4-metil-benzensulfonamida (309 mg) u tetrahidrofuranu (6 mL) te je dobivena mješavina 20 sati miješana na 50°C. Nakon hlađenja, voda je zasićena kalijevim karbonatom i ekstrahirana etil acetatom (2×10 mL). Kombinirane organske faze osušene su na natrijevom sulfatu, koncentrirane in vacuo i pročišćene flash kromatografijom te se dobilo 70 mg (25%) naslovnog spoja u obliku prljavobijele krutine. Proizvod je upotrijebljen izravno u sljedećoj reakciji bez spektralne karakterizacije. A solution of sodium dithionite (772 mg) in water (6 mL) was added to a solution of N-(2,6-dethyl-nitro-phenyl)-4-methyl-benzenesulfonamide (309 mg) in tetrahydrofuran (6 mL) to give a mixture of 20 hours stirred at 50°C. After cooling, the water was saturated with potassium carbonate and extracted with ethyl acetate (2×10 mL). The combined organic phases were dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography to give 70 mg (25%) of the title compound as an off-white solid. The product was used directly in the next reaction without spectral characterization.

N-(2,6-dietil-4-morfolin-4-ilfenil)-4-metil-benzensulfonamid N-(2,6-diethyl-4-morpholin-4-ylphenyl)-4-methyl-benzenesulfonamide

Mješavina N-(4-amino-2,6-dietil-fenil)-4-metil-benzensulfonamida (70 mg), bis-(2-bromoetil)etera (33 μL), N,N-dizopropil-etilamina (115 μL) i N-metilpirolidina (0,3 mL) 20 minuta je grijana do 180°C u mikrovalnom postupku hermetički zatvorene bočice. Mješavina je razrijeđena etil acetatom (20 mL), isprana matičnim lugom (30 mL) i zasićenom vodenom otopinom kalijevog karbonata (30 mL) te osušena na natrijevom sulfatu. Organska faza je koncentrirana in vacuo te se dobilo 78 mg (91%) naslovnog spoja. LC-MS (m/z) 389 (MH+); tR = 2,77, (UV, ELSD) 57%, 98%. Sirovi proizvod je upotrijebljen bez daljnjeg pročišćavanja. A mixture of N-(4-amino-2,6-diethyl-phenyl)-4-methyl-benzenesulfonamide (70 mg), bis-(2-bromoethyl)ether (33 μL), N,N-diisopropyl-ethylamine (115 μL ) and N-methylpyrrolidine (0.3 mL) was heated to 180°C for 20 minutes in a microwave oven in a hermetically sealed bottle. The mixture was diluted with ethyl acetate (20 mL), washed with mother liquor (30 mL) and saturated aqueous potassium carbonate solution (30 mL) and dried over sodium sulfate. The organic phase was concentrated in vacuo to give 78 mg (91%) of the title compound. LC-MS (m/z) 389 (MH + ); tR = 2.77, (UV, ELSD) 57%, 98%. The crude product was used without further purification.

(3,4-difluoro-fenil)-acetil klorid (3,4-difluoro-phenyl)-acetyl chloride

U (3,4-difluor-fenil)-octenu kiselinu (2,0 g) otopljenu u 1,2-dikloroetanu (5 mL) dodan je tionil klorid (5 mL) te je mješavina bila 16 sati u refluksu u atmosferi argona. Sirova mješavina je koncentrirana in vacuo te se dobilo 2,2 g (100%) naslovnog spoja u obliku žutog ulja. 1H NMR (500 MHz, CDCl6): 4,10 (s, 2H), 7,00 (m, 1H), 7,11 (m, 1H), 7,17 (m, 1H). Thionyl chloride (5 mL) was added to (3,4-difluoro-phenyl)-acetic acid (2.0 g) dissolved in 1,2-dichloroethane (5 mL) and the mixture was refluxed in an argon atmosphere for 16 hours. The crude mixture was concentrated in vacuo to give 2.2 g (100%) of the title compound as a yellow oil. 1H NMR (500 MHz, CDCl 6 ): 4.10 (s, 2H), 7.00 (m, 1H), 7.11 (m, 1H), 7.17 (m, 1H).

Analogno je pripravljen sljedeći spoj: Analogously, the following compound was prepared:

(3-fluoro-fenil)-acetil klorid (3-fluoro-phenyl)-acetyl chloride

Iskorištenje: 99%. 1H NMR (500 MHz, CD Cl3): 4,13 (s, 2H), 6,92 (m, 1H), 7,01 (m. 2H), 7,34 (m, 1H). Utilization: 99%. 1 H NMR (500 MHz, CD Cl 3 ): 4.13 (s, 2H), 6.92 (m, 1H), 7.01 (m. 2H), 7.34 (m, 1H).

Spojevi prema ovom izumu Compounds of the present invention

Kiselinske soli spojeva prema ovom izumu mogu se jednostavno dobiti na načine poznate kemičaru od struke. The acid salts of the compounds of the present invention can be readily obtained by methods known to a chemist skilled in the art.

Primjer 1 (Referenca) Example 1 (Reference)

1a N-(2-bromo-4-morfolin-4-il-6-trifluorometil-fenil)-2-(4-fluoro-fenil)-acetamid 1a N-(2-bromo-4-morpholin-4-yl-6-trifluoromethyl-phenyl)-2-(4-fluoro-phenyl)-acetamide

2-bromo-4-morfolin4-il-6-trifluorometil-fenilamin (0,236 g) i 4-fluorofenilacetil klorid (0,105 mL) otopljeni su u acetonitrilu (5 mL) i 10 minuta grijani do 150°C u mikrovalnom postupsku hermetićki zatvorene bočice. Dodana je voda (25 mL) i proizvod je ekstrahiran etil acetatom (3×25 mL). Organske faze su isprane matičnim lugom (50 mL), osušene na magnezijevom sulfatu i koncentrirane in vacuo. Sirovi proizvod je pročišćen flash kromatografijom te se dobilo 0,027 g (9%) naslovnog spoja u obliku prljavobijele krutine. LC-MS (m/z) 462 (MH+); tR = 2,84, (UV, ELSD) 96%, 100%. 1H NMR (500 MHz, DMSO-d6): 3,23 (m, 4H), 3,62 (s, 2H), 3,72 (m, 4H), 7,14 (dd, 2H), 7,19 (d, 1H), 7,35 (dd, 2H), 7,46 (d, 1H), 9,78 (s, 1H). 2-bromo-4-morpholin4-yl-6-trifluoromethyl-phenylamine (0.236 g) and 4-fluorophenylacetyl chloride (0.105 mL) were dissolved in acetonitrile (5 mL) and heated to 150°C for 10 minutes in a microwave-assisted hermetically sealed vial. . Water (25 mL) was added and the product was extracted with ethyl acetate (3×25 mL). The organic phases were washed with mother liquor (50 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography to give 0.027 g (9%) of the title compound as an off-white solid. LC-MS (m/z) 462 (MH + ); tR = 2.84, (UV, ELSD) 96%, 100%. 1H NMR (500 MHz, DMSO-d6): 3.23 (m, 4H), 3.62 (s, 2H), 3.72 (m, 4H), 7.14 (dd, 2H), 7.19 (d, 1H), 7.35 (dd, 2H), 7.46 (d, 1H), 9.78 (s, 1H).

Analogno su pripravljeni sljedeći spojevi: Analogously, the following compounds were prepared:

1b 2-ciklopentil-N-(2-bromo-6-trifluorometil-4-morfolin-4-il-fenil)-acetamid 1b 2-cyclopentyl-N-(2-bromo-6-trifluoromethyl-4-morpholin-4-yl-phenyl)-acetamide

Iskorištenje: 22%. LC-MS (m/z) 436 (MH+); tR = 2,95, (UV, ELSD) 97%, 98%. 1H NMR (500 MHz, DMSO-d6): 1,20 (m, 2H), 1,50 (m, 2H), 1.60 (m, 2H), 1,77 (m, 2H), 2,24 (m, 1H), 2,26 (d, 2H), 3,23 (m, 4H), 3,72 (m, 4H), 7,19 (d, 1H), 7,46 (d, 1H), 9,46 (s, 1H). Utilization: 22%. LC-MS (m/z) 436 (MH+); tR = 2.95, (UV, ELSD) 97%, 98%. 1H NMR (500 MHz, DMSO-d6): 1.20 (m, 2H), 1.50 (m, 2H), 1.60 (m, 2H), 1.77 (m, 2H), 2.24 (m , 1H), 2.26 (d, 2H), 3.23 (m, 4H), 3.72 (m, 4H), 7.19 (d, 1H), 7.46 (d, 1H), 9 .46 (s, 1H).

1c N-(2-bromo-4-morfolin-4-il'6'trifluorometil-fenil)-3-ciklopentil-propionamid 1c N-(2-bromo-4-morpholin-4-yl'6'trifluoromethyl-phenyl)-3-cyclopentyl-propionamide

Iskorištenje: 20%. Lc-MS (m/z) 450 (MH+); tR = 3,20, (UV, ELSD) 99%, 98%. 1H NMR (500 MHz, DMSO-d5): 1,09 (m, 2H), 1,49 (m, 2H), 1,59 (m,4H), 1,76 (m,2H), 1,80 (m, 1H), 2,27 (t, 2H), 3,22 (m, 4H), 3,72 (m, 4H), 7,18 (d, 1H), 7,46 (d, 1H), 9,48 (s, 1H). Utilization: 20%. Lc-MS (m/z) 450 (MH + ); tR = 3.20, (UV, ELSD) 99%, 98%. 1H NMR (500 MHz, DMSO-d5): 1.09 (m, 2H), 1.49 (m, 2H), 1.59 (m, 4H), 1.76 (m, 2H), 1.80 (m, 1H), 2.27 (t, 2H), 3.22 (m, 4H), 3.72 (m, 4H), 7.18 (d, 1H), 7.46 (d, 1H) , 9.48 (s, 1H).

1d N-(2-kloro-6-cijano-4-morfolin-4-il-fenil)-3-cikloheksil-propionamid 1d N-(2-chloro-6-cyano-4-morpholin-4-yl-phenyl)-3-cyclohexyl-propionamide

Iskorištenje: 24%. LC-MS (m/z) 376 (MH+); tR = 3.10, (UV, ELSD) 98%, 100%. 1H NMR (500 MHz, DMSO-d6): 0,90 (m,2H), 1,23 (m,4H), 1,51 (m, 2H). 1,64 (m, 1H), 1,70 (m, 4H), 2,33 (m, 4H) 3 71 (m, 4H), 7,37 (s, 2H), 9,79 (s, 1H). Utilization: 24%. LC-MS (m/z) 376 (MH + ); tR = 3.10, (UV, ELSD) 98%, 100%. 1H NMR (500 MHz, DMSO-d6): 0.90 (m,2H), 1.23 (m,4H), 1.51 (m,2H). 1.64 (m, 1H), 1.70 (m, 4H), 2.33 (m, 4H) 3 71 (m, 4H), 7.37 (s, 2H), 9.79 (s, 1H ).

1e N-(2-bromo-4-morfolin-4-il-6-trifluorometil-fenil)-3-cikloheksil-propionamid 1e N-(2-bromo-4-morpholin-4-yl-6-trifluoromethyl-phenyl)-3-cyclohexyl-propionamide

Iskorištenje: 19%. LC-NS (m/z) 464 (MH+); tR = 3,38, (UV, ELSD) 97%, 99%. 1H NMR (500 MHz, DMSO-d6): 0, 86 (dq, 2H), 1.16 (m, 3H), 1,27 (m, 1H), 1,48 (q. 2H), 1,61 (m, 1H), 1,70 (m,4H), 2,27 (t, 2H), 3,23 (m, 4H), 3,72 (m, 4H), 7,18 (d, 1H), 7,46 (d, 1H), 9,47 (s, 1H). Utilization: 19%. LC-NS (m/z) 464 (MH + ); tR = 3.38, (UV, ELSD) 97%, 99%. 1H NMR (500 MHz, DMSO-d6): 0.86 (dq, 2H), 1.16 (m, 3H), 1.27 (m, 1H), 1.48 (q. 2H), 1.61 (m , 1H), 1.70 (m, 4H), 2.27 (t, 2H), 3.23 (m, 4H), 3.72 (m, 4H), 7.18 (d, 1H), 7 .46 (d, 1H), 9.47 (s, 1H).

1f N-(2-bromo-4-morfolin-4-il-6-trifluorometil-fenil)-2-(3-fluoro-fenil)-acetamid 1f N-(2-bromo-4-morpholin-4-yl-6-trifluoromethyl-phenyl)-2-(3-fluoro-phenyl)-acetamide

Iskorištenje: 44%. LC-MS (m/z) 462 (MH4); tR = 2,85, (UV, ELSD) 98%, 99%. 1H NMR (500 MHz, DMSO-d6): 3,23 (m, 4H), 3,67 (s. 2H), 3,72 (m, 4H), 7,10 (m, 2H). 7,18 (m, 2h), 7,36 (m, 1H), 7,46 (m, 1H), 9,82 (s, 1H). Utilization: 44%. LC-MS (m/z) 462 (MH4); tR = 2.85, (UV, ELSD) 98%, 99%. 1H NMR (500 MHz, DMSO-d6): 3.23 (m, 4H), 3.67 (s. 2H), 3.72 (m, 4H), 7.10 (m, 2H). 7.18 (m, 2h), 7.36 (m, 1H), 7.46 (m, 1H), 9.82 (s, 1H).

1g N-(2-bromo-4-morfolin-4-il-6-trifluorometil-fenil)-propionamid 1g N-(2-bromo-4-morpholin-4-yl-6-trifluoromethyl-phenyl)-propionamide

Iskorištenje: 41%. LC-MS (mfr) 382 (MH+); tR = 2,16, (UV, ELSD) 99%, 99%. 1H NMR (500 MHz, DMSO-d6): 1,09 (1, 3H), 2,27 (q,2H), 3,23 (m, 4H), 3,72 (m, 4H), 7,19 (d, 1H), 7,47 (d, 1H) 946 (s, 1H). Utilization: 41%. LC-MS (mfr) 382 (MH + ); tR = 2.16, (UV, ELSD) 99%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.09 (1, 3H), 2.27 (q, 2H), 3.23 (m, 4H), 3.72 (m, 4H), 7.19 (d, 1H), 7.47 (d, 1H) 946 (s, 1H).

1h N-(2-bromo-4-morfolin-4-il-6-trifluorometil-fenil)-butiramid 1h N-(2-bromo-4-morpholin-4-yl-6-trifluoromethyl-phenyl)-butyramide

Iskorištenje: 76%. LC-MS (m/z) 396 (MH+); tR = 2,43, (UV, ELSD) 99%, 96%. 1H NMR (500 MHz, DMSO-d6): 0,93 (t, 3H), 1,60 (m, 2H), 2,24 (t, 2H), 3,23 (m, 4H), 3,72 (m, 4H), 7,18 (d, 1H). 9,45 (s, 1H). Utilization: 76%. LC-MS (m/z) 396 (MH + ); tR = 2.43, (UV, ELSD) 99%, 96%. 1H NMR (500 MHz, DMSO-d6): 0.93 (t, 3H), 1.60 (m, 2H), 2.24 (t, 2H), 3.23 (m, 4H), 3.72 (m, 4H), 7.18 (d, 1H). 9.45 (s, 1H).

1i N-(2-kloro-4-morfolin-4-il-6-trifluorometil-fenil)-2-(3-fluoro-fenil)-acetamid 1i N-(2-chloro-4-morpholin-4-yl-6-trifluoromethyl-phenyl)-2-(3-fluoro-phenyl)-acetamide

Iskorištenje: 21%. LC-MS (m/z) 417 (MH+); tR = 2,84, (UV, ELSD) 97%, 99%. 1H NMR (500 MHz, DMSO-d6): 3,23 (m, 4H), 3,67 (s, 2H), 3,72 (m, 4H), 7,07 (dt, 1H), 7,15 (m, 3H), 7,32 (d, 1H), 7,36 (m, 1H),9,76(s, 1H). Utilization: 21%. LC-MS (m/z) 417 (MH+); tR = 2.84, (UV, ELSD) 97%, 99%. 1H NMR (500 MHz, DMSO-d6): 3.23 (m, 4H), 3.67 (s, 2H), 3.72 (m, 4H), 7.07 (dt, 1H), 7.15 (m, 3H), 7.32 (d, 1H), 7.36 (m, 1H), 9.76 (s, 1H).

1j N-(2-kloro-4-morfolin-4-il-6-trifluorometil-fenil)-2-ciklopentil-acetamid 1j N-(2-chloro-4-morpholin-4-yl-6-trifluoromethyl-phenyl)-2-cyclopentyl-acetamide

Iskorištenje: 76%. LC-MS (m/z) 391 (MH+); tR = 2,97, (UV, ELSD) 99%, 99%. 1H NMR (500 MHz, DMSO-d6): 1,19 (m,2H), 1,50 (m,2H), 1,60 (m,2H), 1,76 (m, 2H), 2,23 (m, 1H), 2,26 (d, 2H), 3,23 (m, 4H), 3,72 (m,4H), 7,15 (d, 1H), 7.32 (d, 1H),9,40(s, 1H). Utilization: 76%. LC-MS (m/z) 391 (MH+); tR = 2.97, (UV, ELSD) 99%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.19 (m,2H), 1.50 (m,2H), 1.60 (m,2H), 1.76 (m,2H), 2.23 (m, 1H), 2.26 (d, 2H), 3.23 (m, 4H), 3.72 (m, 4H), 7.15 (d, 1H), 7.32 (d, 1H), 9 , 40 (s, 1H).

Primjer 2 Example 2

2a 2-Ciklopentil-N-(2,6-dimetil-4-tiomorfolin-4-il-fenil)-acetamid 2a 2-Cyclopentyl-N-(2,6-dimethyl-4-thiomorpholin-4-yl-phenyl)-acetamide

Bis(dibenzilidenaceton)paladij (37 mg) i (2'-dicikloheksilfosfanil-bifenil-2-il)-dimetil-amin (38 mg) miješani su 5 minuta u suhom otplinjenom toluenu (2 mL) u atmosferi argona. Toj mješavini su dodani N-(4-bromo-2,6-dimetilfenil)-2-ciklopentil-acetamid (200 mg), kalijev terf-butoksid (90 mg) i tiomorfolin (80 mg) te je reakcijska mješavina u hermetski zatvorenoj bočici od 4 mL 16 sati grijana do 90°C u atmosferi argona, ohlađena i filtrirana kroz siliciju (2 g). Dodana je voda/matični lug (1:1, ukupno 4 mL) te je mješavina ekstrahirana etil acetatom (3×2 mL). Kombinirane organske faze su osušene na magnezijevom sulfatu i koncentrirane in vacuo. Siromi proizvod pročišćen je preparativnom LC-MS te se dobilo 5,6 mg (iskorištenje 3%) naslovnog spoja. LC-MS-TOF (m/z) 333 (MH+); tR = 2,03, (UV, ELSD) 98%, 100%. Bis(dibenzylideneacetone)palladium (37 mg) and (2'-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethylamine (38 mg) were stirred for 5 min in dry degassed toluene (2 mL) under an argon atmosphere. N-(4-bromo-2,6-dimethylphenyl)-2-cyclopentyl-acetamide (200 mg), potassium tert-butoxide (90 mg) and thiomorpholine (80 mg) were added to this mixture, and the reaction mixture was in a hermetically sealed vial. of 4 mL heated to 90°C for 16 hours in an argon atmosphere, cooled and filtered through silica (2 g). Water/mother liquor (1:1, total 4 mL) was added and the mixture was extracted with ethyl acetate (3×2 mL). The combined organic phases were dried over magnesium sulfate and concentrated in vacuo. The poor product was purified by preparative LC-MS to give 5.6 mg (3% yield) of the title compound. LC-MS-TOF (m/z) 333 (MH+); tR = 2.03, (UV, ELSD) 98%, 100%.

Analogno su pripravljeni sljedeći spojevi: Analogously, the following compounds were prepared:

2b2-ciklopentil-N-[2,6-dimetil-4-(2-fenil-morfolin-4-il)-fenil]-acetamid 2b2-cyclopentyl-N-[2,6-dimethyl-4-(2-phenyl-morpholin-4-yl)-phenyl]-acetamide

Iskorištenje: 3%. LC-MS-TOF (m/z) 393 (MH+); tR = 3,11, (UV, ELSD) 96%, 98%. Utilization: 3%. LC-MS-TOF (m/z) 393 (MH+); tR = 3.11, (UV, ELSD) 96%, 98%.

2c 2-ciklopentil-N-[2,6~dimetil-4-(2-fenil-tiomorfolin-4-H)-fenil)-acetamid 2c 2-cyclopentyl-N-[2,6~dimethyl-4-(2-phenyl-thiomorpholine-4-H)-phenyl)-acetamide

Iskorištenje: 4%. Lc-MS-TOF (m/z) 409 (MH+); tR = 3,30, (UV, ELSD) 99%, 98%. Utilization: 4%. Lc-MS-TOF (m/z) 409 (MH+); tR = 3.30, (UV, ELSD) 99%, 98%.

2d 2-cikopentil-N-[2,6-dimetil-4-(3-piridin-3-il-tiomorfolin-4-il)-fenil]-ecetamid 2d 2-cyclopentyl-N-[2,6-dimethyl-4-(3-pyridin-3-yl-thiomorpholin-4-yl)-phenyl]-acetamide

Iskorištenje: 12%. LC-MS-TOF (m/z) 410 (MH+); tR = 2,00, (UV, ELSD) 99%, 100%. Utilization: 12%. LC-MS-TOF (m/z) 410 (MH+); tR = 2.00, (UV, ELSD) 99%, 100%.

2e 2-ciklopentil-N-{2,6-dimetil-4-[2-(4-trifluorometil-fenil)-tiomorfolin-4-il]-fenil}-acetamid 2e 2-cyclopentyl-N-{2,6-dimethyl-4-[2-(4-trifluoromethyl-phenyl)-thiomorpholin-4-yl]-phenyl}-acetamide

Iskorištenje: 6%. LC-MS (m/z) Ali (MH+); tR = 3,64, (UV, ELSD) 95%, 100%. Utilization: 6%. LC-MS (m/z) Ali (MH+); tR = 3.64, (UV, ELSD) 95%, 100%.

2f N-{2-[2-(2-kloro-fenil)-tiomorfolin-4-il]-2,6-dimetil-fenil}-2-ciklopentil-acetamid 2f N-{2-[2-(2-chloro-phenyl)-thiomorpholin-4-yl]-2,6-dimethyl-phenyl}-2-cyclopentyl-acetamide

Iskorištenje: 20%. LC-MS-TOF (m/z) 444 (MH+); tR = 3,59, (UV, ELSD) 89%, 100%. Utilization: 20%. LC-MS-TOF (m/z) 444 (MH+); tR = 3.59, (UV, ELSD) 89%, 100%.

2g 2-ciklopentil-N-{2,6-dimetil-4-[2-(4-trifluommetil-fenil)-morfolin-4-il]-fenil}-acetamid 2g 2-cyclopentyl-N-{2,6-dimethyl-4-[2-(4-trifluoromethyl-phenyl)-morpholin-4-yl]-phenyl}-acetamide

Iskorištenje: 26%. LC-MS (m/z) 461 (MH+); tR = 3,55, <UV, ELSD= 90%, 95%. Utilization: 26%. LC-MS (m/z) 461 (MH+); tR = 3.55, <UV, ELSD= 90%, 95%.

2h N-(4-[2-(2-kloro-fenil)-morfolin-4-il]-1,6-dimetil-fenil}-2-ciklopentil-acetamid 2h N-(4-[2-(2-chloro-phenyl)-morpholin-4-yl]-1,6-dimethyl-phenyl}-2-cyclopentyl-acetamide

Iskorištenje: 35%. LC-MS (m/z) 427 (MH+); tR = 3,44, (UV, ELSD) 77%, 95%. Utilization: 35%. LC-MS (m/z) 427 (MH+); tR = 3.44, (UV, ELSD) 77%, 95%.

2i 2-ciklopentil-N-{4-[-2-(4-fluoro-fenil)-morfolin-4-il]-2,6-dimetil-fenil}-acetamid 2i 2-cyclopentyl-N-{4-[-2-(4-fluoro-phenyl)-morpholin-4-yl]-2,6-dimethyl-phenyl}-acetamide

Iskorištenje: 17%. LC-MS (m/z) (MH+); 1R = 3,17, (UV, ELSD) 98%, 99%. Utilization: 17%. LC-MS (m/z) (MH+); 1R = 3.17, (UV, ELSD) 98%, 99%.

Primjer 3 Example 3

3a 2-biciklo[2.2.1]hept-2-il-N-(2,6-dimetil-4-morfolin-4-il-fenil)-acetamid 3a 2-bicyclo[2.2.1]hept-2-yl-N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-acetamide

Biciklo[2.2.1]hept-il-octena kiselina (0,41 g) je 2 sata grijana do 50°C u atmosferi argona u 1:1 mješavini tionil klorida i 1,2-dikloroetana (ukupno 10 mL). Otapala su uklonjena in vacuo a dobiveni kiseli klorid je ponovno otopljen u acetonitrilu (5 mL) i dodan je 2,6-dimetil-4-morfolin-4-il-fenilamin (0,50 g). Reakcijska mješavina je 10 minuta grijana do 150°C u mikrovalnom postupku hermetski zatvorene bočice. Dodana je voda (25 mL) i proizvod je ekstrahiran etil acetatom (3×25 mL). Kombinirane organske faze su isprane matičnim lugom (50 mL), osušene na magnezijevom sulfatu i koncentrirane in vacuo. Sirovi proizvod je pročišćen flash kromatografijom te se dobilo 0,074 g (9%) naslovnog spoja u obliku prljavobijele krutine. LC-MS-TOF (m/z) 343 (MH+); tR = 2,21, (UV, ELSD) 98%, 100%. 1H NMR (500 MHz, DMSO-d6): 1,14 (m, 4H), 1,41 (m, 4H), 1,90 (m 1H), 2,02 (m, 1H), 2,06 (s, 6H), 2,10 (m, 1H), 2,20 (m, 2H), 3,05 (m, 4H), 3,71 (m, 4H), 6,62 (s. 2H), fi,92 (sa, 1H). Bicyclo[2.2.1]hept-yl-acetic acid (0.41 g) was heated for 2 hours to 50°C under an argon atmosphere in a 1:1 mixture of thionyl chloride and 1,2-dichloroethane (total 10 mL). The solvents were removed in vacuo and the resulting acid chloride was redissolved in acetonitrile (5 mL) and 2,6-dimethyl-4-morpholin-4-yl-phenylamine (0.50 g) was added. The reaction mixture was heated to 150°C for 10 minutes in a microwave oven in a hermetically sealed bottle. Water (25 mL) was added and the product was extracted with ethyl acetate (3×25 mL). The combined organic phases were washed with mother liquor (50 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography to give 0.074 g (9%) of the title compound as an off-white solid. LC-MS-TOF (m/z) 343 (MH+); tR = 2.21, (UV, ELSD) 98%, 100%. 1H NMR (500 MHz, DMSO-d6): 1.14 (m, 4H), 1.41 (m, 4H), 1.90 (m 1H), 2.02 (m, 1H), 2.06 ( s, 6H), 2.10 (m, 1H), 2.20 (m, 2H), 3.05 (m, 4H), 3.71 (m, 4H), 6.62 (s. 2H), fi, 92 (with, 1H).

Analogno su pripravljeni sljedeći spojevi: Analogously, the following compounds were prepared:

3b 2-ciktoheksil-N-(2,6-dimetil-4-morfolin-4-it-fenil)-acetamid 3b 2-cyclohexyl-N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-acetamide

Iskorištenje; 19%. LC-MS-TOF (m/z) 331 (MH+); tR = 2,21, (UV, ELSD) 97%, 100%. 1H NMR (500 MHz, DMSO-d6): 0,98 (m, 2H), 1,22 (m, 4H), 1,68 (m, 6H), 2,07 (s, 6H), 2,15 (d, 2H), 3,05 (m, 4H9, 3,71 (m, 4H), 6,63 (as, 2H), 8,93 (s, 1H). Utilization; 19%. LC-MS-TOF (m/z) 331 (MH+); tR = 2.21, (UV, ELSD) 97%, 100%. 1H NMR (500 MHz, DMSO-d6): 0.98 (m, 2H), 1.22 (m, 4H), 1.68 (m, 6H), 2.07 (s, 6H), 2.15 (d, 2H), 3.05 (m, 4H9, 3.71 (m, 4H), 6.63 (as, 2H), 8.93 (s, 1H).

Primjer 4 Example 4

4a 2-ciklopentil-N-(2,6-dimetil-4-morfolin-4-il-fenil)-acetamid 4a 2-cyclopentyl-N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-acetamide

2,6-dimetil-4-morfolin-4-il-fenilamin (0,50 g) i ciklopentilacetil klorid (0,53 mL) otopljeni su u acetonitrilu (5 mL) i 10 minuta grijani do 150°C u mikrovalnom postupku hermetički zatvorene bočice. Dodana je voda (25 mL) i proizvod je ekstrahiran etil acetatom (3×25 mL). Organske faze su isprane matičnim lugom (50 mL), osušene na magnezijevom sulfatu i koncentrirane in vacuo. Sirovi proizvod je pročišćen flash kromatografijom te se dobilo 0,138 g (20%) naslovnog spoja u obliku proljavobijele krutine. LC-MS-TOF (m/z) 317 (MH+); tR = 1,93, (UV, ELSD) 95%, 100%. 1H NMR (500 MHz, DMSO-d6): 1,21 (m, 2H), 1,52 (m, 2H), 1,61 (m, 2H), 1,76 (m, 2H), 2,07 (s, 6H), 2,11 (m, 1H), 2,25 (d, 2H), 3,05 (dd, 4H), 3,71 (dd, 4H), 6,63 (s, 2H), 8,94 (s, 1H). 2,6-dimethyl-4-morpholin-4-yl-phenylamine (0.50 g) and cyclopentylacetyl chloride (0.53 mL) were dissolved in acetonitrile (5 mL) and heated to 150°C in the microwave hermetically for 10 minutes closed bottles. Water (25 mL) was added and the product was extracted with ethyl acetate (3×25 mL). The organic phases were washed with mother liquor (50 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography to give 0.138 g (20%) of the title compound as an off-white solid. LC-MS-TOF (m/z) 317 (MH+); tR = 1.93, (UV, ELSD) 95%, 100%. 1H NMR (500 MHz, DMSO-d6): 1.21 (m, 2H), 1.52 (m, 2H), 1.61 (m, 2H), 1.76 (m, 2H), 2.07 (s, 6H), 2.11 (m, 1H), 2.25 (d, 2H), 3.05 (dd, 4H), 3.71 (dd, 4H), 6.63 (s, 2H) , 8.94 (s, 1H).

Analogno su pripravljeni sljedeći spojevi: Analogously, the following compounds were prepared:

4e 3-cikloheksil-N-(2,6-dimetil-4-morfolin-4-il-fenil)-propionamid 4e 3-cyclohexyl-N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-propionamide

Iskorištenje: 8%. LC-MS-TOF (m/z) 345 (MH+); tR = 2,21, (UV, ELSD) 97%, 98%. 1H NMR (500 MHz, DMSO-d6): 0,88 (m, 2H), 1,16 (m,2H), 1,25 (m, 2H), 1,49 (q, 2H). 1,63 (m, 1H), 1,69 (m, 4H), 2,06 (s, 6H), 2,27 (t, 2H), 3,05 (dd, 4H), 3,71 (dd, 4H), 6,63 (s, 2H), 8,95 (s, 1H). Utilization: 8%. LC-MS-TOF (m/z) 345 (MH+); tR = 2.21, (UV, ELSD) 97%, 98%. 1H NMR (500 MHz, DMSO-d6): 0.88 (m, 2H), 1.16 (m, 2H), 1.25 (m, 2H), 1.49 (q, 2H). 1.63 (m, 1H), 1.69 (m, 4H), 2.06 (s, 6H), 2.27 (t, 2H), 3.05 (dd, 4H), 3.71 (dd , 4H), 6.63 (s, 2H), 8.95 (s, 1H).

Primjer 5 Example 5

5a 2-cikloheptil-N-(2,6-dimetil-4-morfolin-4-il-fenil)-acetamid 5a 2-cycloheptyl-N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-acetamide

Cikloheptil-octena kiselina (0,45 g) i jedna kap N,N-dimetilformamida miješani su 2 sata na 25°C u atmosferi argona u mješavini 1:1 oksalil klorida (2M u diklorometanu) i 1,2-dikloroetana (ukupno 12 mL). Otapala su uklonjena in vacuo i dobiveni kiseli klorid je ponovno otopljen u acetonitrilu (8 mL) te su dodani 2,6,-dimetil-4-morfolin-4-il-fenilamin (0,50 g) i magnezijev oksid (0,20 g). Reakcijsla mješavina je 16 sati miješana na 25°C u atmosferi argona i potom filtrirana kroz celit (10 g). Organska faza je koncentrirana in vacuo, a sirovi proizvod je pročišćen flash kromatografijom te se dobilo 0,133 g (16%) naslovnog spoja u obliku prljavobijele krutine. LC-MS (m/z) 345 (MH+); tR = 2,36, (UV;ELSD=97%, 100%. 1H NMR (500 MHz, DMSO-d6): 1.23 (m, 2H), 1,44 (m, 4 H), 1,60 (m, 4H), 1,73 (m, 2H), 1,99 (m, 1H), 2,07 (s, 6H), 2,18 (d, 2H), 3,05 (m, 4H), 3,71 (m, 4H), 6,63 (s, 2H), 8,94 (s, 1H). Cycloheptyl-acetic acid (0.45 g) and one drop of N,N-dimethylformamide were mixed for 2 hours at 25°C under an argon atmosphere in a 1:1 mixture of oxalyl chloride (2M in dichloromethane) and 1,2-dichloroethane (a total of 12 mL). The solvents were removed in vacuo and the resulting acid chloride was redissolved in acetonitrile (8 mL) and 2,6,-dimethyl-4-morpholin-4-yl-phenylamine (0.50 g) and magnesium oxide (0.20 Mr). The reaction mixture was stirred for 16 hours at 25°C in an argon atmosphere and then filtered through celite (10 g). The organic phase was concentrated in vacuo and the crude product was purified by flash chromatography to give 0.133 g (16%) of the title compound as an off-white solid. LC-MS (m/z) 345 (MH+); tR = 2.36, (UV; ELSD=97%, 100%. 1H NMR (500 MHz, DMSO-d6): 1.23 (m, 2H), 1.44 (m, 4H), 1.60 (m , 4H), 1.73 (m, 2H), 1.99 (m, 1H), 2.07 (s, 6H), 2.18 (d, 2H), 3.05 (m, 4H), 3 .71 (m, 4H), 6.63 (s, 2H), 8.94 (s, 1H).

Primjer 6 (Referenca) Example 6 (Reference)

6a (2,6-dimetil-4-morfolin-4-il-fenil)-karbamska kiselina benzil ester 6a (2,6-dimethyl-4-morpholin-4-yl-phenyl)-carbamic acid benzyl ester

Benzil kloroformat (32 mg) je dodan otopini 0,15 M 2,6-dimetil-4-morfolin-4-il-fenilamina i 0,30 M N,N-duzopropil-etilamina u 1,2,-dikloroetanu (1 mL). Bočica je tresena 16 sati i koncentrirana in vacuo. Dodana je vodena otopina natrijevog hidroksida (1M, 2 ml) i sirova mješavina je ekstrahirana izopropil acetatom/tetrahidrofuranom (4:1, 2,5 mL). Organska faza je koncentrirana in vacuo i ponovno otopljena u dimetil sulfoksidu (0,5 mL) od čega je 0,2 mL podvrgnuto preprativnom LC-MS pročišćavanju te se dobilo 9,5 mg naslovnog spoja u obliku ulja. LC-MS (m/z) 341 (MH+); tR = 2,28, (UV, ELSD) 100%. 100%. Benzyl chloroformate (32 mg) was added to a solution of 0.15 M 2,6-dimethyl-4-morpholin-4-yl-phenylamine and 0.30 M N,N-dusopropyl-ethylamine in 1,2,-dichloroethane (1 mL). . The vial was shaken for 16 hours and concentrated in vacuo. Aqueous sodium hydroxide solution (1M, 2 mL) was added and the crude mixture was extracted with isopropyl acetate/tetrahydrofuran (4:1, 2.5 mL). The organic phase was concentrated in vacuo and redissolved in dimethyl sulfoxide (0.5 mL) of which 0.2 mL was subjected to preliminary LC-MS purification to give 9.5 mg of the title compound as an oil. LC-MS (m/z) 341 (MH+); tR = 2.28, (UV, ELSD) 100%. 100%.

Primjer 7 (Referenca) Example 7 (Reference)

7a 2-(3,4-dikloro-fenil)-N-(2,6-dimetil-4-morfolin-4-il-fenil)-acetamid 7a 2-(3,4-dichloro-phenyl)-N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-acetamide

3,4-diklorofeniloctena kiselina (39 mg) je 2 sata miješana na 25°C u atmosferi argona u 1:1 mješavini oksalil klorida (2M u diklorometanu) i 1,2-dikloroetana (ukupno 1M). Otapala su uklonjena in vacuo i dobivenom kiselom kloridu je dodana otopina 0,25 M 2,6-dimetil-4-morfolin-4-il-fenilamina i 0,30 M N,N-duzopropil-etilamina u 1,2-dikloroetanu (1 mL). Bočica je tresena 16 sati i koncentrirana in vacuo. Dodana je vodena otopina natrijevog hidroksida (1 M, 2 mL) te je sirova mješavina ekstrahirana izopropil acetatom/tetrahidrofuranom (4:1, 2,5 mL). Organske faze su koncentrirane in vacuo i ponovno otopljene u dimetil sulfoksidu (0,5 mL) od čega je 0,2 mL podvrgnuto preparativnom LC-MS pročišćavanju te se dobilo 2,7 mg (iskorištenje 11%) naslovnog spoja u obliku ulja. LC-MS (m/z) 394 (MH+); tR = 2,40, (UV, ELSD) 80%, 100%. 3,4-Dichlorophenylacetic acid (39 mg) was stirred for 2 hours at 25°C under an argon atmosphere in a 1:1 mixture of oxalyl chloride (2M in dichloromethane) and 1,2-dichloroethane (total 1M). The solvents were removed in vacuo and to the resulting acid chloride was added a solution of 0.25 M 2,6-dimethyl-4-morpholin-4-yl-phenylamine and 0.30 M N,N-dusopropyl-ethylamine in 1,2-dichloroethane (1 mL). The vial was shaken for 16 hours and concentrated in vacuo. Aqueous sodium hydroxide solution (1 M, 2 mL) was added and the crude mixture was extracted with isopropyl acetate/tetrahydrofuran (4:1, 2.5 mL). The organic phases were concentrated in vacuo and redissolved in dimethyl sulfoxide (0.5 mL), of which 0.2 mL was subjected to preparative LC-MS purification to give 2.7 mg (11% yield) of the title compound in the form of an oil. LC-MS (m/z) 394 (MH + ); tR = 2.40, (UV, ELSD) 80%, 100%.

Analogno su pripravljeni sljedeći spojevi: Analogously, the following compounds were prepared:

7p 2-ciklopen-2-enil-N-(2,6-dimetil-4-morfolin-4-il-fenil)-acetamid 7p 2-cyclopen-2-enyl-N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-acetamide

Iskorištenje: 69%. LC-MS (m/z) 315 (MH+); tR = 1,82, (UV, ELSD) 97%, 99%. 1H NMR (500 MHz, DMSO-d6); 1,51 (m, 2H), 2,06 (m, 1H), 2,08 (s, 6H), 2,23 (m, 1H), 2,29 (m, 1H), 2,34 (m, 2H), 3,05 (m, 4H), 3,72 (m, 4H). 5,73 (m, 1H), 5,76 (m, 1H), 6,63 (s, 2H), 8,98 (s, 1H). Utilization: 69%. LC-MS (m/z) 315 (MH + ); tR = 1.82, (UV, ELSD) 97%, 99%. 1H NMR (500 MHz, DMSO-d6); 1.51 (m, 2H), 2.06 (m, 1H), 2.08 (s, 6H), 2.23 (m, 1H), 2.29 (m, 1H), 2.34 (m , 2H), 3.05 (m, 4H), 3.72 (m, 4H). 5.73 (m, 1H), 5.76 (m, 1H), 6.63 (s, 2H), 8.98 (s, 1H).

Primjer 8 Example 8

8a 2-ciklopentil-N-(4-morfolin-4-il-2-piridin-3-il-6-trifluorometil-fenil)-acetamid 8a 2-cyclopentyl-N-(4-morpholin-4-yl-2-pyridin-3-yl-6-trifluoromethyl-phenyl)-acetamide

2-ciklopentil-N-(2-bromo-6-trifluorometil-4-morfolin-4-il-fenil)-acetamid (1b, 15mg), 3-piridilboronska kiselina (21 mg), vodena otopina kalijevog karbonata (5 M, 90 uL) i paladijev(II) acetat (1 mg) miješani su u acetonu (2 mL) i 20 minuta grijani do 130°C i mikrovalnom postupku hermetički zatvorene bočice. Reakcijska mješavina je filtrirana kroz siliciju (500 mg), koncentrirana in vacuo, ponovno otopljena u dimetil sulfoksidu (0,5 mL) i podvrgnuta preparativnom LC-MS pročišćavanju te se dobilo 2,7 mg (iskorištenje 18 %) naslovnog spoja u obliku bezbojnog ulja. LC-MS (m/z) 434 (MH+); tR = 1,89, (UV, ELSD) 99%, 99%. 2-cyclopentyl-N-(2-bromo-6-trifluoromethyl-4-morpholin-4-yl-phenyl)-acetamide (1b, 15mg), 3-pyridylboronic acid (21mg), aqueous potassium carbonate solution (5M, 90 µL) and palladium(II) acetate (1 mg) were mixed in acetone (2 mL) and heated for 20 minutes to 130°C and microwaved in a hermetically sealed vial. The reaction mixture was filtered through silica (500 mg), concentrated in vacuo, redissolved in dimethyl sulfoxide (0.5 mL) and subjected to preparative LC-MS purification to give 2.7 mg (18% yield) of the title compound as a colorless oil. LC-MS (m/z) 434 (MH + ); tR = 1.89, (UV, ELSD) 99%, 99%.

Analogno su pripravljeni sljedeći spojevi: Analogously, the following compounds were prepared:

8b 2-ciklopentil-N-(5-morfolin-4-il-3-trifluorometil-bifenil-2-il)-acetamid 8b 2-cyclopentyl-N-(5-morpholin-4-yl-3-trifluoromethyl-biphenyl-2-yl)-acetamide

Iskorištenje: &4%. LC-MS (m/z) 433 (MH+); tR = 3,16, (UV, ELSD) 96%, 99%. Utilization: &4%. LC-MS (m/z) 433 (MH+); tR = 3.16, (UV, ELSD) 96%, 99%.

8c 2-ciklopentil-N-(4'-fluoro-5-morfolin-4-il-3-trifluorometil-bifenil-2-il)-acetamid 8c 2-cyclopentyl-N-(4'-fluoro-5-morpholin-4-yl-3-trifluoromethyl-biphenyl-2-yl)-acetamide

Iskorištenje: 20%. LC-MS (m/z) 451 (MH+); tR = 3,28, (UV, ELSD) 99%, 099%. Utilization: 20%. LC-MS (m/z) 451 (MH+); tR = 3.28, (UV, ELSD) 99%, 099%.

8d 2-ciklopentil-N-(4'-metil-5-morfolin-4-il-3-frifluorometil-bifenil-2-il)-acetamid 8d 2-cyclopentyl-N-(4'-methyl-5-morpholin-4-yl-3-frifluoromethyl-biphenyl-2-yl)-acetamide

Iskorištenje: 51 %. LC-MS (m/z) 447 (MH+), tR = 3,32, (UV, ELSD) 97%, 99%. Utilization: 51 %. LC-MS (m/z) 447 (MH + ), tR = 3.32, (UV, ELSD) 97%, 99%.

8e 2-ciklofenil-N-(3'-metil-morfolin-4-il-3-trifluorometil-bifenil-2-il)-acetamid 8e 2-cyclophenyl-N-(3'-methyl-morpholin-4-yl-3-trifluoromethyl-biphenyl-2-yl)-acetamide

Iskorištenje: 37%. LC-MS (m/z) 447 (MH+); tR = 3,33, (UV, ELSD) 99%, 99% Utilization: 37%. LC-MS (m/z) 447 (MH + ); tR = 3.33, (UV, ELSD) 99%, 99%

8f 2-ciklopentil-N-(3'-4'-fluoro-5-morfolin-4-il-3-trifluorometil-bifenil-2-il)-acetamid 8f 2-cyclopentyl-N-(3'-4'-fluoro-5-morpholin-4-yl-3-trifluoromethyl-biphenyl-2-yl)-acetamide

Iskorištenje: 51%. LC-MS (m/z) 469 (MH+); tR = 3,29, (UV, ELSD) 99%, 99%. Utilization: 51%. LC-MS (m/z) 469 (MH + ); tR = 3.29, (UV, ELSD) 99%, 99%.

Primjer 9 Example 9

9a 2-ciklopentil-N-(2,6-dietil-4-morfolin-4-il-fenil)-acetamid 9a 2-cyclopentyl-N-(2,6-diethyl-4-morpholin-4-yl-phenyl)-acetamide

N-(2,6-dietil 4-morfolin-4-il-fenil)-4-melil-benzensulfonamid (78 mg), sumporna kiselina (0,95 mL) i voda (50 μL) miješani su 3 sala na 40°C. Dodani su led (30 mL) i voda (30 mL) te je mješavina zalužena krutim kalijevim karbonatom. Mješavina je ekstrahirana etil acetatom (3×20 mL), kombinirane organske faze su osušene na natrijevom sulfatu i koncentrirane in vacuo. Talog je ponovno otopljen u tetrahidrofuranu (1 mL) i pomiješan s piridinom (49 μL) i ciklopentilacetil kloridom (44 μL). Mješavina je 1 sat miješana na 25°C, razrijeđena etil acetatom (20 mL) i isprana 10%-tnom vodenom otopinom natrijevog bikarbonata (20 mL) i matičnim lugom (20 mL). Organska faza je osušena na natrijevom sulfatu, koncentrirana in vacuo i pročišćena flash kromatografijom te se dobilo 35 mg (51%) naslovnog spoja u obliku žućkastosmeđe krutine. LC-MS (m/z) 345 (MH+); ts = 2,27, (UV, ELSD) 84%, 98%. N-(2,6-diethyl 4-morpholin-4-yl-phenyl)-4-melyl-benzenesulfonamide (78 mg), sulfuric acid (0.95 mL) and water (50 μL) were mixed for 3 hours at 40° C. Ice (30 mL) and water (30 mL) were added and the mixture basified with solid potassium carbonate. The mixture was extracted with ethyl acetate (3×20 mL), the combined organic phases were dried over sodium sulfate and concentrated in vacuo. The precipitate was redissolved in tetrahydrofuran (1 mL) and mixed with pyridine (49 μL) and cyclopentylacetyl chloride (44 μL). The mixture was stirred for 1 hour at 25°C, diluted with ethyl acetate (20 mL) and washed with 10% aqueous sodium bicarbonate solution (20 mL) and mother liquor (20 mL). The organic phase was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography to give 35 mg (51%) of the title compound as a tan solid. LC-MS (m/z) 345 (MH+); ts = 2.27, (UV, ELSD) 84%, 98%.

9b 2-ciktopentil-N-(2,6-diizopropil-4-morfolin-45-il-fenil)-acetanil 9b 2-cyclopentyl-N-(2,6-diisopropyl-4-morpholin-45-yl-phenyl)-acetanyl

U otopinu 2,6-diizopropil-4-morfolin-4-il-fenilamina (279 mg) i piridina (245 μL) dodan je ciklopentilacetil klorid (210 μL) te je mješavina 1 sat miješana na 25°C. Reakcijska mješavina je razrijeđena etil acetatom (20 mL) i isprana 10%-tnom vodenom otopinom natrijevog bikarbonata (20 mL) i matičnim lugom (20 mL). Organska faza je osušena na natrijevom sulfetu, koncentrirana in vacuo i pročišćena flash kromatografijom. Rekristalizacija sirovog smeđeg materijala iz vrućeg acetata/heptana dala je 122 mg (33%) naslovnog spoja u obliku bijele krutine. LC-MS (m/z) 373 (MH+); tR = 2,58, (UV, ELSD) 98%, 99%. 1H NMR (500 MHz. CDCl3): 1.19 (d, 12 H), 1,27 (m,2H), 1,60 (m, 2H), 1,68 (m, 2H), 1,93 (m, 2H), 2,40 (m, 1H), 2,41 (m, 2H), 3,05 (m, 2H), 3,17 (m, 4H), 3,87 (m, 4H), 6,49 (s, 1H), 6,70 (s, 2H). Cyclopentylacetyl chloride (210 μL) was added to a solution of 2,6-diisopropyl-4-morpholin-4-yl-phenylamine (279 mg) and pyridine (245 μL) and the mixture was stirred for 1 hour at 25°C. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with 10% aqueous sodium bicarbonate solution (20 mL) and mother liquor (20 mL). The organic phase was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography. Recrystallization of the crude brown material from hot acetate/heptane afforded 122 mg (33%) of the title compound as a white solid. LC-MS (m/z) 373 (MH + ); tR = 2.58, (UV, ELSD) 98%, 99%. 1H NMR (500 MHz. CDCl3): 1.19 (d, 12 H), 1.27 (m, 2H), 1.60 (m, 2H), 1.68 (m, 2H), 1.93 (m, 2H), 2.40 (m, 1H), 2.41 (m, 2H), 3.05 (m, 2H), 3.17 (m, 4H), 3.87 (m, 4H), 6, 49 (s, 1H), 6.70 (s, 2H).

Primjer 10 Example 10

10a 2-ciklopentil-N-(2,6-difluoro-4-rnorfolin-4-il-fenil)-acetamid 10a 2-cyclopentyl-N-(2,6-difluoro-4-norpholin-4-yl-phenyl)-acetamide

2,6-difluoro-4-morfolin-4-il-fenilamin (0,10 g) i ciklopentilacetil klorid (149 μL) otopljeni su u actonitrilu (4 mL) i 10 minuta grijani na 150°C u mikrovalnom postupku hermetički zatvorene bočice. Reakcijska mješavina je koncentrirana in vacuo i pročišćena flash kromatografijom te se dobilo 228 mg (75%9 naslovnog spoja u obliku bijele krutine. LC-MS (m/z) 325 (MH+); tR = 2,61, (UV, ELSD) 99%, 99%. 1H NMR (500 MHz, DMSO-d6): 1,19 (m, 2H), 1,51 (m, 2H), 1,60 (m, 2H), 2,19 (m, 1H), 2,26 (d, 2H), 3,14 (m, 4 H), 3,70 (m, 4H), 6,68 (d, 2H), 9,20 (s, 1H). 2,6-difluoro-4-morpholin-4-yl-phenylamine (0.10 g) and cyclopentylacetyl chloride (149 μL) were dissolved in actonitrile (4 mL) and heated at 150°C for 10 minutes in a microwave-sealed vial. . The reaction mixture was concentrated in vacuo and purified by flash chromatography to give 228 mg (75%9) of the title compound as a white solid. LC-MS (m/z) 325 (MH+); tR = 2.61, (UV, ELSD) 99%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.19 (m, 2H), 1.51 (m, 2H), 1.60 (m, 2H), 2.19 (m, 1H), 2.26 (d, 2H), 3.14 (m, 4H), 3.70 (m, 4H), 6.68 (d, 2H), 9.20 (s, 1H).

Analogno su pripravljeni sljedeći spojevi: Analogously, the following compounds were prepared:

10 e 2-ciklopent-2-enil-N-(2,6-difluoro-4-morfolin-4-il-fenil)-acetamid 10 e 2-cyclopent-2-enyl-N-(2,6-difluoro-4-morpholin-4-yl-phenyl)-acetamide

Ciklopent-2-eniloctena kiselina (0,17 mL), N,N-diizopropil-etilamin (0,50 mL) i N-[(dimetilamino)-1 H-1,2,3-triazolo-[4,5-b]piridin-1-il-metilen]-N-metil-metanaminij heksafluoro-fosfat N-oksid (0,55 g) izmiješani su u suhom N,N-dimetilformamidu (3 mL) i 2 minute miješani u atmosferi argona. 2,6-difluoro-4-morfolin-4-il-fenilamin (0,20 g) otopljen u suhom N,N-dimetilformamidu (2 mL) dodan je u reakcijsku mješavinu koja je 16 sati miješana na 25°C u atmosferi argona. Dodan je etil acetat (20 mL) te je organska faza isprana zasićenom vodenom otopinom amonijevog klorida/vode (1:1, 20 mL), vodom (20 mL), matičnim lugom/vodom (1:1, 20 mL), osušena na magnezijevom sulfatu, koncentrirana in vacuo i pročišćena flash kromatografijom te se dobilo 0,21 g (iskorištenje 21%) naslovnog spoja u obliku bijele krutine. LC-MS (m/z) 323 (MH+); tR = 2,49, (UV, ELSD) 96%, 99%. 1H NMR (500 MHz, DMSO-d6): 1,48 (m, 1H), 2,02 (m, 1H), 2,29 (m, 4H), 3,03 (m, 1H), 3,14 (t, 4H), 3,71 (t, 4H), 5,71 (m, 1H), 5,76 (m, 1H), 6,68 (d, 2H), 9,25 (s, 1H). Cyclopent-2-enylacetic acid (0.17 mL), N,N-diisopropyl-ethylamine (0.50 mL) and N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5- b]pyridin-1-yl-methylene]-N-methyl-methanaminium hexafluoro-phosphate N-oxide (0.55 g) was mixed in dry N,N-dimethylformamide (3 mL) and stirred under an argon atmosphere for 2 minutes. 2,6-difluoro-4-morpholin-4-yl-phenylamine (0.20 g) dissolved in dry N,N-dimethylformamide (2 mL) was added to the reaction mixture which was stirred for 16 hours at 25°C under argon atmosphere . Ethyl acetate (20 mL) was added and the organic phase was washed with saturated aqueous ammonium chloride/water (1:1, 20 mL), water (20 mL), mother liquor/water (1:1, 20 mL), dried on magnesium sulfate, concentrated in vacuo and purified by flash chromatography to give 0.21 g (21% yield) of the title compound as a white solid. LC-MS (m/z) 323 (MH + ); tR = 2.49, (UV, ELSD) 96%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.48 (m, 1H), 2.02 (m, 1H), 2.29 (m, 4H), 3.03 (m, 1H), 3.14 (t, 4H), 3.71 (t, 4H), 5.71 (m, 1H), 5.76 (m, 1H), 6.68 (d, 2H), 9.25 (s, 1H) .

Analogno je pripravljen sljedeći spoj: Analogously, the following compound was prepared:

10f 2-biciklo[2.2.1]hept-2-il-N-(2,6-difluoro-4-morfolin-4-il-fenil)-acetamid 10f 2-bicyclo[2.2.1]hept-2-yl-N-(2,6-difluoro-4-morpholin-4-yl-phenyl)-acetamide

Iskorištenje: 56%. LC-MS (m/z) 351 (MH+); tR = 2,90, (UV, ELSD) 98%, 99%. 1H MNR (500 MHz, DMSO-d6): 1.11 (m,4H), 1,43 (m, 4H), 1,85 (m, 1H), 2,00 (m, 1H), 2,11 (m, 1H), 2,21 (m, 2H), 3,14 (t, 4H), 3,71 (t, 4H), 6,67 (d, 2H), 9,19 (s. 1H). Utilization: 56%. LC-MS (m/z) 351 (MH+); tR = 2.90, (UV, ELSD) 98%, 99%. 1H MNR (500 MHz, DMSO-d6): 1.11 (m, 4H), 1.43 (m, 4H), 1.85 (m, 1H), 2.00 (m, 1H), 2.11 (m , 1H), 2.21 (m, 2H), 3.14 (t, 4H), 3.71 (t, 4H), 6.67 (d, 2H), 9.19 (s. 1H).

Primjer 11 Example 11

11a 2-biciklo[2.21]hept-2-il-N-(2-metil-4-morfolin-4-il-6-trifluorometilfenil)-acetamid 11a 2-bicyclo[2.21]hept-2-yl-N-(2-methyl-4-morpholin-4-yl-6-trifluoromethylphenyl)-acetamide

Biciklo[2.2.1]hept-2-il-octena kiselina (160 mg), N,N-duzopropil-etilamin (0,44 mL) i N-[(dimetilamino)-1H-1,2,3-triazolo-[4,5-b]piridin-1-il-metilen]-N-metil-metanaminij heksafluoro-fosfat N-oksid (0,47 g) izmiješani su u suhom N,N-dimetllformamidu (3 mL) i 2 minule miješani u atmosferi argona. 2-metil-4-morfolin-4-il-6-trifluorometil-fenilamin (0,18 g) otopljen u suhom N,N-dimetilformamidu (2 mL) dodan je reakcijskoj mješavini, koja je 16 sati miješana na 25°C u atmosferi argona. Dodan je etil acetat (20 mL) i organska faza je isprana zasićenom otopinom amonijevog klorida/vode (1:1, 20 mL), vodom (20 mL), matičnim lugom/vodom (1:1, 20 mL), osušena na magnezijevom sulfatu, koncentrirana in vacuo i pročišćena flash kromatografijom te se dobilo 16 mg (iskorištenje 6%) naslovnog spoja u obliku bijele krutine. LC-MS (m/z) 397 (MH+); tR = 3,12, (UV, ELSD) 91%, 98%. Bicyclo[2.2.1]hept-2-yl-acetic acid (160 mg), N,N-dusopropyl-ethylamine (0.44 mL) and N-[(dimethylamino)-1H-1,2,3-triazolo- [4,5-b]pyridin-1-yl-methylene]-N-methyl-methanaminium hexafluoro-phosphate N-oxide (0.47 g) was mixed in dry N,N-dimethylformamide (3 mL) and stirred for 2 minutes in an argon atmosphere. 2-Methyl-4-morpholin-4-yl-6-trifluoromethyl-phenylamine (0.18 g) dissolved in dry N,N-dimethylformamide (2 mL) was added to the reaction mixture, which was stirred for 16 hours at 25°C in argon atmosphere. Ethyl acetate (20 mL) was added and the organic phase was washed with saturated ammonium chloride/water (1:1, 20 mL), water (20 mL), mother liquor/water (1:1, 20 mL), dried over magnesium sulfate, concentrated in vacuo and purified by flash chromatography to give 16 mg (6% yield) of the title compound as a white solid. LC-MS (m/z) 397 (MH+); tR = 3.12, (UV, ELSD) 91%, 98%.

11d 2-ciklopent-2-enil-N-(2-metil-4-morfolin-4-il-6-trifluorometil-fenil)-acetamid 11d 2-cyclopent-2-enyl-N-(2-methyl-4-morpholin-4-yl-6-trifluoromethyl-phenyl)-acetamide

Iskorištenje: 25%. LC-MS (m/z) 369 (MH+); tR = 2,70, (UV, ELSD) 96%, 99%. 1H NMR (500 MHz, DMSO-d6): 1,48 (m, 1H), 2,04 (m, 1H), 2,25 (m, 2H), 2,34 (m, 2H), 3,06 (m. 1 H),m 3,16 (t, 4H), 3,74 (t, 4H), 5,71 (m, 1H), 5,76 (m, 1H), 7,00 (m, 1H), 7,13 (m, 1H), 9,23 (s, 1H). Utilization: 25%. LC-MS (m/z) 369 (MH + ); tR = 2.70, (UV, ELSD) 96%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.48 (m, 1H), 2.04 (m, 1H), 2.25 (m, 2H), 2.34 (m, 2H), 3.06 (m. 1 H), m 3.16 (t, 4H), 3.74 (t, 4H), 5.71 (m, 1H), 5.76 (m, 1H), 7.00 (m, 1H), 7.13 (m, 1H), 9.23 (s, 1H).

11e 2-ciklopentil-N-(2-metil-4-morfolin-4-il-6-trifluorometil-fenil)-acetamid 11e 2-cyclopentyl-N-(2-methyl-4-morpholin-4-yl-6-trifluoromethyl-phenyl)-acetamide

2-metil-4-morfolin-4-il-6-trifluorometil-fenilamin (0,18 g) i ciklopentilacetil klorid (112 g) su otopljeni u acetonitrilu (4 mL) i 10 minuta grijani do 150°C u mikrovalnom postupku hermetički zatvorene bočice. Reakcijska mješavina je razrijeđena etil acetatom (20 mL) i isprana vodom (2×20 mL) i matičnim lugom (1×20 mL). Organska faza je osušena na magnezijevom sulfatu, koncentrirana in vacuo i pročišćena flash kromatografijom te se dobilo 132 mg (52%) naslovnog spoja u obliku bijele krutine. LC-MS (m/z) 371 (MH+); tR = 2,87, (UV, ELSD) 99%, 99%. 1H NMR (500 MHz, DMSO-d6): 1,20 (m, 2H), 1,51 (m, 2H), 1,60 (m, 2H), 1,76 (m, 2H), 2,11 (s, 3H), 2,24 (m, 1H), 2,26 (d, 2H), 3,16 (t, 4H), 3,73 (t, 4H), 7,00 (d, 1H), 7,12 (d, 1H), 9,16 (s, 1H). 2-methyl-4-morpholin-4-yl-6-trifluoromethyl-phenylamine (0.18 g) and cyclopentylacetyl chloride (112 g) were dissolved in acetonitrile (4 mL) and heated to 150°C in a microwave hermetically for 10 minutes closed bottles. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (2×20 mL) and mother liquor (1×20 mL). The organic phase was dried over magnesium sulfate, concentrated in vacuo and purified by flash chromatography to give 132 mg (52%) of the title compound as a white solid. LC-MS (m/z) 371 (MH + ); tR = 2.87, (UV, ELSD) 99%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.20 (m, 2H), 1.51 (m, 2H), 1.60 (m, 2H), 1.76 (m, 2H), 2.11 (s, 3H), 2.24 (m, 1H), 2.26 (d, 2H), 3.16 (t, 4H), 3.73 (t, 4H), 7.00 (d, 1H) , 7.12 (d, 1H), 9.16 (s, 1H).

Analogno su pripravljeni sljedeći spojevi: Analogously, the following compounds were prepared:

11f Heksanoična kiselina (2-metil-4-morfolin-4-il-6-trifluorometil-fenil)-amid 11f Hexanoic acid (2-methyl-4-morpholin-4-yl-6-trifluoromethyl-phenyl)-amide

Iskorištenje: 64%. LC-MS (m/z) 359 (MH+); tR = 2,86, (UV, ELSD) 95%, 99%. 1H NMR (500 MHz; DMSO-d6): 0,88 (t, 3H), 1,30 (m,4H), 1,58 (qui, 2H), 2,11 (s, 3H), 2,26 (t, 2H), 3,16 (t, 4H), 3,73 (t, 4H),6,99 (d, 1H), 7,11 (d. 1H). 9,17 (s, 1H). Utilization: 64%. LC-MS (m/z) 359 (MH + ); tR = 2.86, (UV, ELSD) 95%, 99%. 1H NMR (500 MHz; DMSO-d6): 0.88 (t, 3H), 1.30 (m, 4H), 1.58 (qui, 2H), 2.11 (s, 3H), 2.26 (t, 2H), 3.16 (t, 4H), 3.73 (t, 4H), 6.99 (d, 1H), 7.11 (d. 1H). 9.17 (s, 1H).

11j 2-ciklopentil-N-(2-metoksi-6-metil-4-morfolin-4-il-fenil)-acetamid 11j 2-cyclopentyl-N-(2-methoxy-6-methyl-4-morpholin-4-yl-phenyl)-acetamide

Iskorištenje: 81%. Lc-MS (m/z) 333 (MH+); tR = 2,06, (UV, ELSD) 99%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.21 (m, 2H), 1,51 (m, 2H), 1,60 (m, 2H), 1,75 (m, 2H), 2,05 (s, 3H), 2,21 (m, 1H), 2,23 (d, 2H), 3,17 (m, 4H), 3,71 (s, 3H), 3,77 (m, 4H), 6,48 (b, 1H), 8.80 (s, 1H). Utilization: 81%. Lc-MS (m/z) 333 (MH + ); tR = 2.06, (UV, ELSD) 99%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.21 (m, 2H), 1.51 (m, 2H), 1.60 (m, 2H), 1.75 (m, 2H), 2.05 (s , 3H), 2.21 (m, 1H), 2.23 (d, 2H), 3.17 (m, 4H), 3.71 (s, 3H), 3.77 (m, 4H), 6 .48 (b, 1H), 8.80 (s, 1H).

11m 2-ciklopent-2-enil-N-(2-metoksi-6-metil-4-morfolin-4-il-fenil)-acetamid 11m 2-cyclopent-2-enyl-N-(2-methoxy-6-methyl-4-morpholin-4-yl-phenyl)-acetamide

Iskorištenje: 27%. LC-MS (m/z) 331 (MH+); tR =1,91, (UV, ELSD) 96%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.51 (m, 1H), 2,04 (m, 1H), 2,05 (s, 3H), 2,22 (m, 2H), 2,29(m, 2H), 3,04 (m, 1H); 3,13 (t, 4H), 3,71 (s, 3H), 3,75 (t, 4H), 5,74 (m, 2H), 6,43 (b, 1H), 6,49 (b. 1H), 8,82 (s, 1H). Utilization: 27%. LC-MS (m/z) 331 (MH+); tR =1.91, (UV, ELSD) 96%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.51 (m, 1H), 2.04 (m, 1H), 2.05 (s, 3H), 2.22 (m, 2H), 2.29(m , 2H), 3.04 (m, 1H); 3.13 (t, 4H), 3.71 (s, 3H), 3.75 (t, 4H), 5.74 (m, 2H), 6.43 (b, 1H), 6.49 (b .1H), 8.82 (s, 1H).

11o 2-biciklo[2.2.1]hept-2-il-N-(2-metoksi-6-metil-4-morfolin-4-il-fenil)-acetamid 11o 2-bicyclo[2.2.1]hept-2-yl-N-(2-methoxy-6-methyl-4-morpholin-4-yl-phenyl)-acetamide

Biciklo[2.2.1]hept-2-il-octena kiselina (0,17 g) otopljena u oksalil kloridu (1M u diklorometanu, 0,7 mL) miješana je 2 sata na 25°C u atmosferi argona. Otapala su uklonjena in vacuo, a dobiveni kiselin klorid je ponovno otopljen u acetonitrilu (4 mL) i dodano je 2-metoksi-6-metil-morfolin-4-il- fenilamina (50 mg). Reakcijska mješavina je 10 minuta grijana do 150°C u mikrovalnom postupku hermetički zatvorene bočice i potom razrijeđena etil acetatom (20 mL) i isprana vodom (2×20 mL) i matičnim lugom (1×20 mL). Organska faza je osušena na magnezijevom sulfatu, koncentrirana in vacuo i proččišćena plash kromatografijom te se dobilo 20 mg (25%) naslovnog spoja u obliku bijele krutine. LC-MS (m/z) 359 (MH+); tR = 2,30, (UV, ELSD) 99%, 99%. 1H NMR (500 MHz, DMSO-d6): 1,14(m,4H), 1,43 (m,4H), 1,86 (m, 1H), 2,03 (s, 3H), 2,06 (m, 2H), 2,19 (m, 2H), 3,11 (t, 4H), 3,70 (s, 3H), 3,74 (t, 4H), 6,38 (b, 1H), 6,45 (b, 1H), 8,74 (s, 1H). Bicyclo[2.2.1]hept-2-yl-acetic acid (0.17 g) dissolved in oxalyl chloride (1M in dichloromethane, 0.7 mL) was stirred for 2 hours at 25°C under an argon atmosphere. The solvents were removed in vacuo, and the resulting acid chloride was redissolved in acetonitrile (4 mL) and 2-methoxy-6-methyl-morpholin-4-yl-phenylamine (50 mg) was added. The reaction mixture was heated to 150°C for 10 minutes in a microwave oven in a hermetically sealed bottle and then diluted with ethyl acetate (20 mL) and washed with water (2×20 mL) and mother liquor (1×20 mL). The organic phase was dried over magnesium sulfate, concentrated in vacuo and purified by flash chromatography to give 20 mg (25%) of the title compound as a white solid. LC-MS (m/z) 359 (MH + ); tR = 2.30, (UV, ELSD) 99%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.14 (m, 4H), 1.43 (m, 4H), 1.86 (m, 1H), 2.03 (s, 3H), 2.06 (m, 2H), 2.19 (m, 2H), 3.11 (t, 4H), 3.70 (s, 3H), 3.74 (t, 4H), 6.38 (b, 1H) , 6.45 (b, 1H), 8.74 (s, 1H).

Primjer 12 Example 12

12b N-(2-kloro-6-metil-4-morfolin-4-il-fenil)-2-ciklopentil-acetamid 12b N-(2-chloro-6-methyl-4-morpholin-4-yl-phenyl)-2-cyclopentyl-acetamide

N-(4-amino-2-kloro-6-mettl-fenil)-2-ciklopentil-acetamid (830 mg). bis-(2-kloroetil)eter (3, 35 mL) i kalijev jodid (470 mg) miješani su u apsolutnom etanolu (33 mL) i 1 sati grijani do 170× u mikrovalnom postupku hermetički zatvorene bočice. Sirova mješavine je koncentrirana in vacuo i pročišćena flash komatografijom te se dobilo 390 mg (41%) naslovnog spoja u obliku bijele krutine. N-(4-amino-2-chloro-6-methyl-phenyl)-2-cyclopentyl-acetamide (830 mg). bis-(2-chloroethyl)ether (3.35 mL) and potassium iodide (470 mg) were mixed in absolute ethanol (33 mL) and heated to 170× in a hermetically sealed vial microwave process for 1 hour. The crude mixture was concentrated in vacuo and purified by flash chromatography to give 390 mg (41%) of the title compound as a white solid.

LC-MS (mfr) 337 (MH+); tr = 2,61. (UV, ELSD) 97%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.22 (m. 2H), 1,51 (m, 2H), 1,61 (m. 2H), 1,77 (m, 2H), 2,11 (s, 3H), 2,25 (m, 1H), 2,26 (m, 2H), 3,10 (m, 4H), 3,71 (m, 4H), 6,80 (d,1H), 6,84 (d, 1H), 9.18 (s, 1H). LC-MS (mfr) 337 (MH + ); tr = 2.61. (UV, ELSD) 97%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.22 (m. 2H), 1.51 (m, 2H), 1.61 (m. 2H), 1.77 (m, 2H), 2.11 (s , 3H), 2.25 (m, 1H), 2.26 (m, 2H), 3.10 (m, 4H), 3.71 (m, 4H), 6.80 (d, 1H), 6 .84 (d, 1H), 9.18 (s, 1H).

Tablica 1. Reagensi korišteni za pripravu spojeva u primjerima 1-12 Table 1. Reagents used for the preparation of compounds in examples 1-12

[image] [image] [image] [image]

Ispitivanje in vitro i in vivo Testing in vitro and in vivo

Spojevi prema ovo izumu ispitani su i njihov učinak je prikazan u jednom ili više modela koji slijede: The compounds of this invention have been tested and their performance demonstrated in one or more of the following models:

Relativno istjecanje kroz kanal KCNQ2 Relative efflux through the KCNQ2 channel

To je primjer protokola snimanja KCNQ2 radi ocjene spojeva prema ovom izumu. Taj pokus mjeri relativno istjecanje kroz kanal KCNQ2, a provedeno je prema metodi opisanoj u Tang i sur. (Tang, W. i sur., J. Biomol. Screen. 2001., 6, 325-331) za hERG kalijeve kanale s niže opisanim modifikacijama. It is an example of a KCNQ2 imaging protocol to evaluate compounds of the present invention. This experiment measures the relative efflux through the KCNQ2 channel, and was performed according to the method described in Tang et al. (Tang, W. et al., J. Biomol. Screen. 2001, 6, 325-331) for hERG potassium channels with the modifications described below.

Adekvatan broj CHO stanica koje izražavaju naponom poticane KCNQ2 kanale postavljene su na ploču u gustoći dovoljnoj da na dan pokusa stvori mono-konfluentni sloj. Stanice su stavljene dan prije pokusa i preko noći napunjene 1 μCi/ml [86^Rb], Na dan pokusa stanice su isprane puferom koji je sadržavao HBSS. Stanice su predinkubirane lijekom tijekom 30 minuta i 86Rb+ istjecanje je potaknuto submaksimalnom koncentracijom 15 mM KCl uz stalnu prisutnost lijeka tijekom 30 minuta. Nakon prikladnog perioda inkubacije plivajući materijal je uklonjen i prebrojen u liquid scintillation brojaču (Tricaro). Stanice su lizirane s 2 mM NaOH i prebrojena je količina 86Rb+. Relativno istjecanje je izračunato (CPMsuper/(CPMsuper + CPMstanica))cmpd/(CPMsuper/(CPMsuper + CPMstanica))15mM KCl) 100-100. Adequate numbers of CHO cells expressing voltage-gated KCNQ2 channels were plated at a density sufficient to form a mono-confluent layer on the day of the experiment. The cells were plated the day before the experiment and loaded with 1 μCi/ml [86^Rb] overnight. On the day of the experiment, the cells were washed with a buffer containing HBSS. Cells were preincubated with the drug for 30 min and 86Rb+ efflux was induced by a submaximal concentration of 15 mM KCl in the constant presence of the drug for 30 min. After an appropriate incubation period, the floating material was removed and counted in a liquid scintillation counter (Tricaro). Cells were lysed with 2 mM NaOH and the amount of 86Rb+ was counted. Relative efflux was calculated as (CPMsuper/(CPMsuper + CPMstation))cmpd/(CPMsuper/(CPMsuper + CPMstation))15mM KCl) 100-100.

Spojevi prema ovom izumu imaju EC50 manji od 20000 nM, u većini slučajeva manji od 2000 nM, a u mnogim slučajevima manji od 200 nM. Prema tome, spojevi prema ovom izumu smatraju se korisnima u liječenju bolesti povezanih s kalijevim kanalima roda KCNQ. The compounds of the present invention have an EC50 of less than 20000 nM, in most cases less than 2000 nM, and in many cases less than 200 nM. Accordingly, the compounds of the present invention are considered useful in the treatment of diseases associated with potassium channels of the KCNQ family.

Elektrofiziološko snimanje uklještenja komadića u CHO stanicama Electrophysiological recording of fragment entrapment in CHO cells

Naponom poticane KCNQ2 struje iz CHO stanica sisavaca snimane su konvencionalnom tehnikom snimanja uklještenja komadića u konfiguraciji uklještenja komadića čitave stanice. (Hamill OP i sur., Pflugers Arch 1981., 391, 85-100). CHO stanice sa stabilnim izražajem naponom poticanih KCNQ2 kanala uzgajane su u normalnim uvjetima uzgoja stanica u CO2 inkubatorima i korištene za elektrofiziološko snimanje 1-7 dana nakon postavljanja. KCNQ2 kalijevi kanali aktivirani su postepenim naponima do + 90 mV s porastima od 2-50 mV (ili s uzlaznim protokolom) od podržavajućeg potencijala membrane između - 100 mV i - 40 mV (Tatulian L. i sur., J. Neuroscience 2001., 21 (25): 5535-5545). Elektrofiziološko djelovanje spojeva ocjenjivano je prema različitim parametrima naponom potaknutih KCNQ2 struja. Posebno je proučavano djelovanje na prag poticanja za struju i na maksimalnu induciranu struju. Voltage-evoked KCNQ2 currents from mammalian CHO cells were recorded using a conventional patch-clamp recording technique in a whole-cell patch-clamp configuration. (Hamill OP et al., Pflugers Arch 1981, 391, 85-100). CHO cells with stable expression of voltage-gated KCNQ2 channels were grown under normal cell culture conditions in CO2 incubators and used for electrophysiological recording 1-7 days after plating. KCNQ2 potassium channels are voltage-gated up to + 90 mV with 2-50 mV increments (or with a step-up protocol) from a supporting membrane potential between - 100 mV and - 40 mV (Tatulian L. et al., J. Neuroscience 2001., 21 (25): 5535-5545). The electrophysiological effects of compounds were evaluated according to different parameters of voltage-evoked KCNQ2 currents. The effect on the stimulation threshold for the current and on the maximum induced current was studied in particular.

Neki od spojeva prema ovom izumu ispitani su ovim testom. Očekuje se da pomak ulijevo praga poticanja ili povećanje maksimalne inducirane kalijeve struje smanjuje aktivnost u neuronskoj mreži te time čini spojeve korisnima kod bolesti s povećanom neuronskom aktivnošću - poput epilepsije. Some of the compounds of the present invention were tested by this test. A shift to the left of the stimulation threshold or an increase in the maximal induced potassium current is expected to reduce the activity in the neuronal network, thus making the compounds useful in diseases with increased neuronal activity - such as epilepsy.

Elektrofiziološko snimanje KCNQ2, KCNQ2/KCNQ3 ili KCNQ5 kanala u oocitima Electrophysiological recording of KCNQ2, KCNQ2/KCNQ3 or KCNQ5 channels in oocytes

Naponom poticane KCNQ2, KCNQ2/KCNQ3 ili KCNQ5 struje snimane su iz Xenopus oocvtes u koje je ubrizgan mRNA kod za ionske kanale KCNQ2, KCNQ2+KCNQ3 ili KCNQ5 (Wang i sur., Science 1009., 282, 1890-1893; Lerche i sur., J. Biol. Chem. 2000., 175, 22359-400). Kalijevi kanali KCNQ2, KCNQ2/KCNQ3 ili KCNQ5 poticani su postepenim naponom od potencijala održavanja membrane (između -100 mV i -40 mV) do + 40 mV u povišenjima od 5-10 mV (ili s uzlaznim protokolom). Ocijenjeno je elektrofiziološko djelovanje uzrokovano ovim spojevima na različitim parametrima naponom potaknutih KCNQ2, KCNQ2/KCNQ3 ili KCNQ5 struja. Posebno je proučavano djelovanje na prag poticanja za struju i na maksimalnu iduciranu struju. Također je ispitano hiperpolarizirajuće djelovanje nekih spojeva izravno na potencijal membrane tijekom uklještenja struje. Voltage-gated KCNQ2, KCNQ2/KCNQ3, or KCNQ5 currents were recorded from Xenopus oocvtes injected with mRNA coding for KCNQ2, KCNQ2+KCNQ3, or KCNQ5 ion channels (Wang et al., Science 1009, 282, 1890-1893; Lerche et al. ., J. Biol. Chem. 2000., 175, 22359-400). KCNQ2, KCNQ2/KCNQ3, or KCNQ5 potassium channels were voltage-gated from the holding membrane potential (between −100 mV and −40 mV) to + 40 mV in 5–10 mV increments (or with a step-up protocol). The electrophysiological effects caused by these compounds on different parameters of voltage-evoked KCNQ2, KCNQ2/KCNQ3 or KCNQ5 currents were evaluated. The effect on the stimulation threshold for the current and on the maximum induced current was studied in particular. The hyperpolarizing effect of some compounds directly on the membrane potential during current clamping was also examined.

Maksimalni elektrošok Maximum electroshock

Ispitivanje je provedeno kod skupina mužjaka miševa pomoću komealnih elektroda i primjenom pravokutnog impulsnog napona od 26 mA tijekom 0,4 sekunde kako bi se izazvalo grčenje koje karakterizira toničko istezanje stražnjih udova (Wlaz i sur., Epilepsy Research 1, 1998., 30, 219-229.) The test was performed in groups of male mice using comeal electrodes and applying a rectangular pulse voltage of 26 mA for 0.4 seconds to induce a convulsion characterized by tonic stretching of the hindlimbs (Wlaz et al., Epilepsy Research 1, 1998, 30, 219 -229.)

Napadaji izazvani pilokarpinom Seizures induced by pilocarpine

Napadaji uzrokovani pilokarpinom izazivaju se intraperitonealnim ubrizgavanjem 250 mg/kg pilokarpina skupini mužjaka miševa i promatranjem djelovanja napadaja uslijed kojih dolazi do gubitka uspravnog položaja tijela u roku od 30 minuta (Starr i sur., Pharmacology Biochemistry and Benavior. 1993., 45, 321-325.) Pilocarpine-induced seizures are induced by intraperitoneally injecting 250 mg/kg pilocarpine into a group of male mice and observing the effects of seizures resulting in loss of upright body position within 30 minutes (Starr et al., Pharmacology Biochemistry and Benavior. 1993, 45, 321- 325.)

Ispitivanje praga električkog izazivanja napadaja Electrical seizure threshold testing

Za određivanje srednjeg praga izazivanja toničkog istezanja stražnjih udova kao odgovor na kornealni elektrošok kod skupine mužjaka miševa korištena je modifikacija metode porasta i pada (Kimhall i sur, Radiation Research, 1957., 1-12). Prvi miš iz svake grupe primio je elektrošok od 14 mA (0,4 s, 50 Hz) te je promatran zbog djelovanja napadaja. Ako je napadaj primijećen, struja je kod sljedećeg miša smanjena za 1 mA, međutim, ako napadaj nije primijećen, struja je povećana za 1 mA. Taj postupak je ponavljan na svih 15 miševa u ispitnoj skupini. A modification of the rise and fall method (Kimhall et al, Radiation Research, 1957, 1-12) was used to determine the mean threshold for inducing tonic stretching of the hind limbs in response to corneal electroshock in a group of male mice. The first mouse from each group received a 14 mA electroshock (0.4 s, 50 Hz) and was observed for seizure activity. If a seizure was observed, the current was decreased by 1 mA in the next mouse, however, if a seizure was not observed, the current was increased by 1 mA. This procedure was repeated on all 15 mice in the test group.

Ispitivanje praga kemijskog izazivanja napadaja Examining the chemical seizure threshold

Doza praga pentilentetrazola potrebna za izazivanje kloničkog grčenja mjerena je vremenski mjerenom infuzijom pentilentetrazola (5 mg/mL kod 0,5 mL) u lateralnoj repnoj veni skupine mužjaka miševa (Nutt i sur., J. Pharmacy and Pharmacology 1986., 38, 697-698). The threshold dose of pentylenetetrazole required to induce clonic convulsion was measured by timed infusion of pentylenetetrazole (5 mg/mL in 0.5 mL) into the lateral tail vein of a group of male mice (Nutt et al., J. Pharmacy and Pharmacology 1986, 38, 697- 698).

Poticanje amigdale Amygdala stimulation

Štakori su podvrgnuti kirurškom zahvatu kojim su im u dorzolateralnu amigdalu ugrađena tropolne elektrode. Nakon zahvata životinje su ostavljena da se oporave, a potom su primile ili različite doze ispitivanog spoja ili nositelja lijeka. Životinje su poticane svojim početnim pragom nakon pražnjenja + 25 μA dnevno tijekom 3-5 tjedana i svaki put su bilježene jačine napadaja, trajanje napadaja i električnog trajanja nakon pražnjenja. (Račine. Electroencephalography and Clinical Neurophysiology 1972., 32, 281-294). Rats were subjected to a surgical procedure in which three-pole electrodes were implanted in their dorsolateral amygdala. After the procedure, the animals were allowed to recover, and then they received either different doses of the tested compound or the drug carrier. Animals were stimulated at their baseline after-discharge threshold + 25 μA daily for 3–5 weeks and seizure magnitudes, seizure durations, and electrical after-discharge durations were recorded each time. (Račine. Electroencephalography and Clinical Neurophysiology 1972., 32, 281-294).

Nuspojave Side effects

Nuspojave centralnog živčanog sustava mjerene su bilježenjem vremena za vrijeme kojega bi miševi ostali na rotarod uređaju (Capacio i sur., Drug and Chemical Toxicology 1992., 15, 177-201) ili bilježenjem njihove lokomotorne aktivnosti preko brojanja prelazaka kroz infracrvene zrake u ispitnom kavezu (Watson i sur., Neuropharmacology 1997., 36, 1369-1375). Hipotermičko djelovanje spoja na tjelesnu temperaturu životinja mjereno je ili rektalno ili pomoću ugrađenih radio-telemetrijskih odašiljača koji su u stanju mjeriti temperaturu (Keeney i sur., Physiology and Behaviour 2001., 74,177.184). Central nervous system side effects were measured by recording the time the mice remained on the rotarod device (Capacio et al., Drug and Chemical Toxicology 1992, 15, 177-201) or by recording their locomotor activity by counting crossings through infrared rays in the test cage. (Watson et al., Neuropharmacology 1997, 36, 1369-1375). The hypothermic effect of the compound on the body temperature of the animals was measured either rectally or using embedded radio-telemetry transmitters capable of measuring temperature (Keeney et al., Physiology and Behavior 2001, 74,177,184).

Farmakokinetici Pharmacokinetics

Farmakokinetička svojstva spoja određena su preko i.v. i p.o. doza koje su primili Spraque Dawiey štakori i, potom, uzimanjem uzoraka njihove krvi tijekom 20 sati. Koncentracije plazme određene su pomoću LC/MS/MS. Pharmacokinetic properties of the compound were determined via i.v. and a half. dose received by Spraque Dawiey rats and, subsequently, by taking their blood samples for 20 hours. Plasma concentrations were determined by LC/MS/MS.

Claims (26)

1. Supstituirani derivat morfolina ili tiomorfolina naznačen time da ima opću formulu I [image] u kojoj q znači 0 ili 1, W znači O ili S, X znači CO, Z znači O, R1 je odabran iz grupe koja se sastoji od halogena, cijana, C1-6-alk(en/in)ila, C3-8-cikloalk(en)ila, C3-8-cikloalk(en)il-C1-6-alk(en/in)ila, halo-C1-6-alk(en/in)ila, halo-C3-8-cikloalk(en)ila, halo-C3-8-cikloalk(en)il-C1-6-alk(en/in)ila, C1-6-alk(en/in)iloksi, C3-8-cikloalk(en)iloksi i C3-8-cikloalk(en)il-C1-6-alk(en/in)iloksi, R2 je odabran iz grupe koja se sastoji od halogena, cijana, C1-6-alk(en/in)ila, C3-8-cikloalk(en)ila, C3-8-cikloalk(en)il-C1-6-alk(en/in)ila, halo-C1-6-alk(en/in)ila, halo-C3-8-cikloalk(en)ila, halo-C3-8-cikloalk(en)il-C1-6-alk(en/in)ila, -C1-6-alk(en/in)iloksi, C3-8-cikloalk(en)iloksi, C3-8-cikloalk(en)il-C1-6-alk(en/in)iloksi, opcionalno supstituiranog fenila i opcionalno supstituiranog piridila, pri čemu su fenil i piridil opcionalno supstituirani s jednim ili više supstituenata koji su neovisno halogen, C1-6-alk(en/in)il, C3-8-cikloanlk(en)il ili C3-8-cikloalk(en)il-C1-6-alk(en/in)il, R3 je C3-8-cikloalk(en)il-C1-6-alk(en/in)il, svaki od R4, R5, R6 i R7 je neovisno odabran iz grupe koja se sastoji od vodika ili Ar, Ar je odabran iz grupe koja se sastoji od opcionalno supstituiranog fenila, opcionalno supstituiranog naftila, opcionalno supstituiranog piridina, opcionalno supstituiranog tiofena, opcionalno supstituiranog furana, opcionalno supstituiranog tiazola, opcionalno supstituiranog kvinolina, opcionalno supstituiranog indola, opcionalno supstituiranog 2,3-dihidro-benzofurana, opcionalno supstituiranog pirimidina, opcionalno supstituiranog pirola i opcionalno supstituiranog oksazola, pri čemu su supstituenti neovisno halogen, C1-6-alk(en/in)il, C3-8-cikloak(en)il, C3-8-cikloalk(en)il-C1-6-alk(en/in)il, halo-C1-6-alk(en/in)il, C1-6-alk(en(in)iloksi, C3-8-alk(en/in)iloksi, kao slobodna baza ili njezine soli.1. A substituted morpholine or thiomorpholine derivative characterized by having the general formula I [image] where q means 0 or 1, W stands for O or S, X stands for CO, Z stands for O, R1 is selected from the group consisting of halogen, cyano, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk (en/yn)yl, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C1-6-alk (en/yn)yl, C1-6-alk(en/yn)yloxy, C3-8-cycloalk(en)yloxy and C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yloxy , R2 is selected from the group consisting of halogen, cyano, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk (en/yn)yl, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C1-6-alk (en/yn)yl, -C1-6-alk(en/yn)yloxy, C3-8-cycloalk(en)yloxy, C3-8-cycloalk(en)yl-C1-6-alk(en/yn) yloxy, optionally substituted phenyl and optionally substituted pyridyl, wherein the phenyl and pyridyl are optionally substituted with one or more substituents which are independently halogen, C1-6-alk(en/yn)yl, C3-8-cycloalnk(en)yl or C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, R3 is C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, each of R 4 , R 5 , R 6 and R 7 is independently selected from the group consisting of hydrogen or Ar, Ar is selected from the group consisting of optionally substituted phenyl, optionally substituted naphthyl, optionally substituted pyridine, optionally substituted thiophene, optionally substituted furan, optionally substituted thiazole, optionally substituted quinoline, optionally substituted indole, optionally substituted 2,3-dihydro-benzofuran , optionally substituted pyrimidine, optionally substituted pyrrole and optionally substituted oxazole, wherein the substituents are independently halogen, C1-6-alk(en/yn)yl, C3-8-cycloalkyl(en)yl, C3-8-cycloalk(en) yl-C1-6-alk(ene/yne)yl, halo-C1-6-alk(ene/yne)yl, C1-6-alk(ene(yne)yloxy, C3-8-alk(ene/yne) iloxy, as the free base or its salts. 2. Spoj prema patentnom zahtjevu 1 naznačen time da je Ar odabran iz grupe koja se sastoji od opcionalno supstituiranog fenila, opcionalno supstituiranog naftila, opcionalno supstituiranog piridina, opcionalno supstituiranog 2,3-dihidro-benzofurana ili opcionalno supstituiranog tiofena.2. The compound according to claim 1 characterized in that Ar is selected from the group consisting of optionally substituted phenyl, optionally substituted naphthyl, optionally substituted pyridine, optionally substituted 2,3-dihydro-benzofuran or optionally substituted thiophene. 3. Spoj prema bilo kojem od patentnih zahtjeva 1-2 naznačen time da svaki Ar može biti supstituiran s jednim ili više supstituenata koji je neovisno halogen, C1-6-alk(en/in)il, halo-C1-6-alk(en/in)il ili C1-6-alk(en/in)iloksi.3. A compound according to any of claims 1-2 characterized in that each Ar can be substituted with one or more substituents which are independently halogen, C1-6-alk(en/yn)yl, halo-C1-6-alk( en/yn)yl or C1-6-alk(en/yn)yloxy. 4. Spoj prema bilo kojem od patentnih zahtjeva 1-3 naznačen time da q znači 0.4. A compound according to any one of claims 1-3 characterized in that q means 0. 5. Spoj prema bilo kojem od patentnih zahtjeva 1-3 naznačen time da q znači 1.5. A compound according to any one of claims 1-3 characterized in that q means 1. 6. Spoj prema bilo kojem od patentnih zahtjeva 1-5 naznačen time da je W atom kisika.6. A compound according to any one of claims 1-5 characterized in that W is an oxygen atom. 7. Spoj prema bilo kojem od patentnih zahtjeva 1-5 naznačen time da je W atom sumpora.7. A compound according to any one of claims 1-5 characterized in that W is a sulfur atom. 8. Spoj prema bilo kojem od patentnih zahtjeva 1-7 naznačen time da je R1 odabran iz grupe koja se sastoji od halogena, cijana, C1-6-alk(en/in)ila, halo-C1-6-alk(en/in)ila i C1-6-alk(en/in)iloksi.8. A compound according to any one of claims 1-7 characterized in that R1 is selected from the group consisting of halogen, cyano, C1-6-alk(en/yn)yl, halo-C1-6-alk(en/ yn)yl and C1-6-alk(en/yn)yloxy. 9. Spoj prema patentnom zahtjevu 8 naznačen time da je R1 C1-6-alk(en/in)il.9. Compound according to patent claim 8 characterized in that R1 is C1-6-alk(en/yn)yl. 10. Spoj prema bilo kojem od patentnih zahtjeva 1-6 naznačen time da je R2 odabran iz grupe koja se sastoji od halogena, cijana, C1-6-alk(en/in)ila, halo-C1-6-alk(en/in)ila, C1-6-alk(en/in)iloksi, opcionalno supstituiranog fenila i opcionalno supstituiranog piridila.10. A compound according to any one of claims 1-6 characterized in that R2 is selected from the group consisting of halogen, cyano, C1-6-alk(en/yn)yl, halo-C1-6-alk(en/ yn)yl, C1-6-alk(en/yn)yloxy, optionally substituted phenyl and optionally substituted pyridyl. 11. Spoj prema patentnom zahtjevu 10 naznačen time da je R2 C1-6-alk(en/in)il.11. Compound according to patent claim 10 characterized in that R2 is C1-6-alk(en/yn)yl. 12. Spoj prema patentnom zahtjevu 10 naznačen time da opcionalno supstituirani fenil i opcionalno supstituirani piridil mogu biti supstituirani s jednim ili više supstituenata koji su neovisno halogen ili C1-6-alk(en/in)il.12. The compound according to patent claim 10 characterized in that optionally substituted phenyl and optionally substituted pyridyl can be substituted with one or more substituents which are independently halogen or C1-6-alk(en/yn)yl. 13. Spoj prema bilo kojem od patentnih zahtjeva 1-12 naznačen time da R4 ne sadrži Ar.13. Compound according to any one of claims 1-12 characterized in that R4 does not contain Ar. 14. Spoj prema bilo kojem od patentnih zahtjeva 1-13 naznačen time da R5 ne sadrži Ar.14. The compound according to any one of claims 1-13 characterized in that R5 does not contain Ar. 15. Spoj prema bilo kojem od patentnih zahtjeva 1-14 naznačen time da R6 ne sadrži Ar.15. Compound according to any one of claims 1-14 characterized in that R6 does not contain Ar. 16. Spoj prema bilo kojem od patentnih zahtjeva 1-15 naznačen time da R7 ne sadrži Ar.16. A compound according to any one of claims 1-15 characterized in that R7 does not contain Ar. 17. Supstituirani derivat morfolina prema patentnom zahtjevu 1 naznačen time da u njemu q znači 0 ili 1, W znači O ili S, X znači CO, Z znači O, R1 i R2 su neovisno odabrani iz grupe koja se sastoji od halogena, halo-C1-6-alk(en/in)ila, C1-6-alk(en/in)ila i cijana, R3 znači C3-8-cikloalk(en)il-C1-6-alk(en/in)il, a R4, R5, R6 i R7 su neovisno odabrani iz grupe koja se sastoji od vodika i Ar, ili njihovih soli.17. Substituted morpholine derivative according to patent claim 1 characterized in that in it q means 0 or 1, W stands for O or S, X stands for CO, Z stands for O, R1 and R2 are independently selected from the group consisting of halogen, halo-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yl and cyano, R3 means C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, and R4, R5, R6 and R7 are independently selected from the group consisting of hydrogen and Ar, or their salts. 18. Spoj prema bilo kojem od patentnih zahtjeva 1-17, naznačen time da je rečeni spoj odabran iz grupe koja se sastoji od: 2-ciklopentil-N-(2-bromo-6-trifluorometil-4-morfolin-4-il-fenil)-acetamida, N-(2-bromo-4-morfolin-4-il-6-trifluorometil-fenil)-3-ciklopentil-propionamida, N-(2-kloro-6-cijano-4-morfolifr4-il-fenil)-3-cikloheksil-propionamida, 2-ciklopentil-N-(2,6-dimetil-4-tiomorfolin-4-il-fenil)-acetamida, 2-ciklopentil-N-[2,6-dimetil-4-(2-fenil-morfolin-4-il)-fenil]-acetamida, 2-ciklopentil-N-[2,6-dimetil-4-(3-piridin-3-il-tiomorfolin-4-il)-fenil]-acetamida, 2-ciklopentil-N-{2,6-dimetil-4-[2-(4-trifluorometil-fenil)-tiomorfolin-4-il]-fenil}-acetamida, N-{4-[2-(2-kloro-fenil)-tiomorfolin-4-il]-2,6-dimetil-fenil}-2-ciklopentil-acetamida, 2-biciklo[2.2.1]hept-2-il-N-(2,6-dimetil-4-morfolin-4-il-fenil)-acetamida, 2-cikloheksil-N-(2,6-dimetil-4-morfolin-4-il-fenil)-acetamida, 2-ciklopentil-N-(2,6-dimetil-4-morfolin-4-il-fenil)-acetamida, 3-cikloheksil-N-(2,6-dimetil-4-morfolin-4-il-fenil)-propionamida, 3-ciklopentil-N-(2,6-dimetil-4-morfolin-4-il-fenil)-propionamida, 2-cikloheptil-N-(2,6-dimetil-4-morfolin-4-il-fenil)-acetamida, N-(2-bromo-4-morfolin-4-il-6-trifluorometil-fenil)-3-cikloheksil-propionamida N-(2-kloro-4-morfolin-4-il-6-trifluorometil-fenil)-2-ciklopentil-acetamida, 2-ciklopentil-N{2,6-dimetil-4-[2-(4-trifluorometil-fenil)-morfolin-4-il]-fenil}-acetamida, N-{4-[2-(2-kloro-fenil)-morfolin-4-il]-2,6-dimetil-fenil}-2-ciklopentil-acetamida, 2-ciklopentil-N-{4-[2-(4-fluoro-fenil)-morfolin-4-il]-2,6-dimetil-fenil)-acetamida, 2-ciklopentil-2-enil-N-(2,6-dimetil-4-morfolin-4-il-fenil)-acetamida, 2-ciklopentil-N-(4-morfolin-4-il-piridin-3-il-fenil)-acetamida, 2-ciklopentil-N-(5-morfolin-4-il-3-trifluorometil-bifenil-2-il)-acetamida, 2-ciklopentil-N-(4'-fluoro-5-morfolin-4-il-3-trifluorometil-bifenil-2-il)-acetamida, 2-ciklopentil-N-(4'-metil-5-morfolin-4-il-3-trifluorometil-bifenil-2-il)-acetamida, 2-ciklopentil-N-(3'-metil-5-morfolin-4-il-3-trifluorometil-bifenil-2-il)-acetamida, 2-ciklopentil-N-(3',4'-difluoro-5-morfolin-4-il-3-trifluorometil-bifenil-2-il)-acetamida, 2-ciklopentil-N-(2,6-dietil-4-morfolin-4-il-fenil)-acetamida, 2-ciklopentil-N-(2,6-diizopropil-4-morfolin-4-il-fenil)-acetamida, 2-ciklopentil-N-(2,6-difluoro-4-morfolin-4-il-fenil)-acetamida, 2-ciklopent-2-enil-N-(2,6-difluoro-4-morfolin-4-il-fenil)-acetamida, 2-biciklo[2.2.1]hept-2-il-N-(2,6-difluoro-4-morfolin-4-il-fenil)-acetamida, 2-biciklo[2.2.1]hept-2-il-N-(2-metil-4-morfolin-4-il-6-trifluorometil-fenil)-acetamida, 2-ciklopent-2-enil-N-(2-metil-4-morfolin-4-il-6-trifluorometil-fenil)-acetamida, 2-ciklopentil-N-(2-metil-4-morfolin-4-il-6-trifluorometil-fenil)-acetamida, 2-ciklopentil-N-(2-metoksi-6-metil-4-morfolin-4-il-fenil)-acetamida, 2-ciklopent-2-enil-N-(2-metoksi-6-metil-4-morfolin-4'il-fenil)-acetamida, 2-biciklo[2.2.1]hept-2-il-N-(2-metoksi-6-metil-4-morfolin-4-il-fenil)-acetamida i N-(2-kloro-6-metil-4-morfolin-4-il-fenil)-2-ciklopentil-acetamida.18. A compound according to any of claims 1-17, characterized in that said compound is selected from the group consisting of: 2-cyclopentyl-N-(2-bromo-6-trifluoromethyl-4-morpholin-4-yl-phenyl)-acetamide, N-(2-bromo-4-morpholin-4-yl-6-trifluoromethyl-phenyl)-3-cyclopentyl-propionamide, N-(2-chloro-6-cyano-4-morphol-4-yl-phenyl)-3-cyclohexyl-propionamide, 2-cyclopentyl-N-(2,6-dimethyl-4-thiomorpholin-4-yl-phenyl)-acetamide, 2-cyclopentyl-N-[2,6-dimethyl-4-(2-phenyl-morpholin-4-yl)-phenyl]-acetamide, 2-cyclopentyl-N-[2,6-dimethyl-4-(3-pyridin-3-yl-thiomorpholin-4-yl)-phenyl]-acetamide, 2-cyclopentyl-N-{2,6-dimethyl-4-[2-(4-trifluoromethyl-phenyl)-thiomorpholin-4-yl]-phenyl}-acetamide, N-{4-[2-(2-chloro-phenyl)-thiomorpholin-4-yl]-2,6-dimethyl-phenyl}-2-cyclopentyl-acetamide, 2-bicyclo[2.2.1]hept-2-yl-N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-acetamide, 2-cyclohexyl-N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-acetamide, 2-cyclopentyl-N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-acetamide, 3-cyclohexyl-N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-propionamide, 3-cyclopentyl-N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-propionamide, 2-cycloheptyl-N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-acetamide, N-(2-bromo-4-morpholin-4-yl-6-trifluoromethyl-phenyl)-3-cyclohexyl-propionamide N-(2-chloro-4-morpholin-4-yl-6-trifluoromethyl-phenyl)-2-cyclopentyl-acetamide, 2-cyclopentyl-N{2,6-dimethyl-4-[2-(4-trifluoromethyl-phenyl)-morpholin-4-yl]-phenyl}-acetamide, N-{4-[2-(2-chloro-phenyl)-morpholin-4-yl]-2,6-dimethyl-phenyl}-2-cyclopentyl-acetamide, 2-cyclopentyl-N-{4-[2-(4-fluoro-phenyl)-morpholin-4-yl]-2,6-dimethyl-phenyl)-acetamide, 2-cyclopentyl-2-enyl-N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-acetamide, 2-cyclopentyl-N-(4-morpholin-4-yl-pyridin-3-yl-phenyl)-acetamide, 2-cyclopentyl-N-(5-morpholin-4-yl-3-trifluoromethyl-biphenyl-2-yl)-acetamide, 2-cyclopentyl-N-(4'-fluoro-5-morpholin-4-yl-3-trifluoromethyl-biphenyl-2-yl)-acetamide, 2-cyclopentyl-N-(4'-methyl-5-morpholin-4-yl-3-trifluoromethyl-biphenyl-2-yl)-acetamide, 2-cyclopentyl-N-(3'-methyl-5-morpholin-4-yl-3-trifluoromethyl-biphenyl-2-yl)-acetamide, 2-cyclopentyl-N-(3',4'-difluoro-5-morpholin-4-yl-3-trifluoromethyl-biphenyl-2-yl)-acetamide, 2-cyclopentyl-N-(2,6-diethyl-4-morpholin-4-yl-phenyl)-acetamide, 2-cyclopentyl-N-(2,6-diisopropyl-4-morpholin-4-yl-phenyl)-acetamide, 2-cyclopentyl-N-(2,6-difluoro-4-morpholin-4-yl-phenyl)-acetamide, 2-cyclopent-2-enyl-N-(2,6-difluoro-4-morpholin-4-yl-phenyl)-acetamide, 2-bicyclo[2.2.1]hept-2-yl-N-(2,6-difluoro-4-morpholin-4-yl-phenyl)-acetamide, 2-bicyclo[2.2.1]hept-2-yl-N-(2-methyl-4-morpholin-4-yl-6-trifluoromethyl-phenyl)-acetamide, 2-cyclopent-2-enyl-N-(2-methyl-4-morpholin-4-yl-6-trifluoromethyl-phenyl)-acetamide, 2-cyclopentyl-N-(2-methyl-4-morpholin-4-yl-6-trifluoromethyl-phenyl)-acetamide, 2-cyclopentyl-N-(2-methoxy-6-methyl-4-morpholin-4-yl-phenyl)-acetamide, 2-cyclopent-2-enyl-N-(2-methoxy-6-methyl-4-morpholin-4'yl-phenyl)-acetamide, 2-bicyclo[2.2.1]hept-2-yl-N-(2-methoxy-6-methyl-4-morpholin-4-yl-phenyl)-acetamide and N-(2-chloro-6-methyl-4-morpholin-4-yl-phenyl)-2-cyclopentyl-acetamide. 19. Spoj prema bilo kojem od patentnih zahtjeva 1-18 naznačen time da je za uporabu kao lijek.19. A compound according to any one of claims 1-18, characterized in that it is for use as a medicine. 20. Farmaceutska smjesa naznačena time da sadrži jedan ili više farmaceutski prihvatljivih nositelja ili diluenata i jedan ili više spojeva prema bilo kojem od patentnih zahtjeva 1-19.20. Pharmaceutical mixture characterized in that it contains one or more pharmaceutically acceptable carriers or diluents and one or more compounds according to any of claims 1-19. 21. Uporaba spoja prema bilo kojem od patentnih zahtjeva 1-19 naznačena time da je za je za izradu farmaceutskih spojeva za liječenje poremećaja ili bolesti koji su odgovorni za povećani protok iona u kalijevom kanalu, a taj poremećaj ili bolest je preferirano poremećaj ili bolest centralnog živčanog sustava.21. The use of the compound according to any one of patent claims 1-19, characterized in that it is for the preparation of pharmaceutical compounds for the treatment of disorders or diseases that are responsible for the increased flow of ions in the potassium channel, and this disorder or disease is preferably a disorder or disease of the central nervous system. 22. Uporaba prema patentnom zahtjevu 21 naznačena time da je poremećaj ili bolest koji će se liječiti odabrana iz grupe koja se sastoji od poremećaja napadajem poremećaja tjeskobe, neuropatskih bolova i bolova uslijed migrene te neurodegenerativnih poremećaja.22. Use according to patent claim 21 characterized in that the disorder or disease to be treated is selected from the group consisting of anxiety disorder, neuropathic pain and migraine pain, and neurodegenerative disorders. 23. Uporaba prema patentnom zahtjevu 22 naznačena time da su poremećaji napadaja odabrani iz grupe koja se sastoji od akutnih napadaja, konvulzija, status epilepticusa poput epileptičkih sindroma i epileptičkih napadaja.23. Use according to patent claim 22 characterized in that seizure disorders are selected from the group consisting of acute seizures, convulsions, status epilepticus such as epileptic syndromes and epileptic seizures. 24. Uporaba prema patentnom zahtjevu 22 naznačena time da su poremećaji tjeskobe odabrani iz grupe koja se sastoji od poremećaja tjeskobe te poremećaja i bolesti u vezi s napadajima panike, agorafobijom, poremećaj panike s agorafobijom, poremećaj panike bez agorafobije, agorafobija bez povijesti poremećaja panike, specifične fobije, socijalne fobije i drugih specifičnih fobija, opsesivno kompulzivnog poremećaja, poremećaja post traumatskog stresa, poremećaji akutnog stresa, poremećaj tjeskobe zbog općeg zdravstvenog stanja, poremećaj tjeskobe uzrokovan nekom supstancom, poremećaj tjeskobe zbog razdvajanja, poremećaji prilagodbe, trema, hipohondrijski poremećaji, poremećaj tjeskobe zbog općeg zdravstvenog stanja i poremećaj tjeskobe uzrokovan nekom supstancom te neodređeni poremećaj tjeskobe.24. Use according to patent claim 22 characterized in that the anxiety disorders are selected from the group consisting of anxiety disorders and disorders and diseases related to panic attacks, agoraphobia, panic disorder with agoraphobia, panic disorder without agoraphobia, agoraphobia without a history of panic disorder, specific phobias, social phobias and other specific phobias, obsessive compulsive disorder, post-traumatic stress disorder, acute stress disorders, anxiety disorder due to a general health condition, anxiety disorder caused by a substance, separation anxiety disorder, adjustment disorders, stage fright, hypochondriac disorders, anxiety due to a general health condition and anxiety disorder caused by a substance and unspecified anxiety disorder. 25. Uporaba prema patentnom zahtjevu 22 naznačena time da su neuropatski bolovi i bolovi uslijed migrene odabrani iz grupe koja se sastoji od alodinije, hiperalgezičnih bolova, fantomskih bolova, neuropatskih bolova u vezi s dijabetičkom neuropatijom, neuropatskih bolova u vezi s trigeminalnom neuralgijom i neuropatkis bolova u vezi s migrenom.25. Use according to claim 22 characterized in that neuropathic pain and migraine pain are selected from the group consisting of allodynia, hyperalgesic pain, phantom pain, neuropathic pain associated with diabetic neuropathy, neuropathic pain associated with trigeminal neuralgia and neuropathic pain related to migraine. 26. Uporaba prema patentnom zahtjevu 22 naznačena time da su neurodegeneratvini poremećaji odabrani iz grupe koja se sastoji od Alzheimerove bolesti, Huntingtinive horeje, multiple skleroze, amiotropne lateralne skleroze, Creutzfeld-Jakobove bolesti, Parkinsovone bolesti, encefalopatija uzrokovanih AIDS-om ili infekcijom virusa rubele, virusa herpesa, borelije ili nepoznatih patogena, neurodegeneracija izazvanih traumom, stanja neuronske hiperpodraživosti poput ukidanja lijeka ili intoksikacije te neurodegenerativnih bolesti perifernog živčanog sustava poput polineuropalija i polineuritisa.26. Use according to patent claim 22 characterized in that the neurodegenerative disorders are selected from the group consisting of Alzheimer's disease, Huntingtin's chorea, multiple sclerosis, amyotrophic lateral sclerosis, Creutzfeld-Jakob disease, Parkinson's disease, encephalopathies caused by AIDS or rubella virus infection , herpes viruses, Borrelia or unknown pathogens, neurodegeneration caused by trauma, states of neuronal hyperexcitability such as drug withdrawal or intoxication, and neurodegenerative diseases of the peripheral nervous system such as polyneuropathy and polyneuritis.
HR20080507A 2008-10-14 2008-10-14 Substituted morpholine and thiomorpholine derivates HRPK20080507B3 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
HR20080507A HRPK20080507B3 (en) 2008-10-14 2008-10-14 Substituted morpholine and thiomorpholine derivates

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
HR20080507A HRPK20080507B3 (en) 2008-10-14 2008-10-14 Substituted morpholine and thiomorpholine derivates

Publications (2)

Publication Number Publication Date
HRP20080507A2 true HRP20080507A2 (en) 2010-04-30
HRPK20080507B3 HRPK20080507B3 (en) 2011-06-30

Family

ID=42113258

Family Applications (1)

Application Number Title Priority Date Filing Date
HR20080507A HRPK20080507B3 (en) 2008-10-14 2008-10-14 Substituted morpholine and thiomorpholine derivates

Country Status (1)

Country Link
HR (1) HRPK20080507B3 (en)

Also Published As

Publication number Publication date
HRPK20080507B3 (en) 2011-06-30

Similar Documents

Publication Publication Date Title
JP5006184B2 (en) Substituted morpholine and thiomorpholine derivatives
JP5705249B2 (en) Substituted pyridine derivatives
US20060264496A1 (en) Substituted indoline and indole derivatives
JP2009507052A (en) Pyrimidine derivatives and their use as KCNQ potassium channel openers
HRP20080507A2 (en) Substituted morpholine and thiomorpholine derivates
NZ541999A (en) Substituted indoline and indole derivatives
IL185113A (en) Substituted pyridine derivatives, pharmaceutical compositions comprising same and use thereof for preparation of medicaments
MXPA06010329A (en) Substituted morpholine and thiomorpholine derivatives

Legal Events

Date Code Title Description
A1OB Publication of a patent application
AKOB Publication of a request for the grant of a patent not including a substantive examination of a patent application (a consensual patent)
PKB1 Consensual patent granted
ODRP Renewal fee for the maintenance of a patent

Payment date: 20130911

Year of fee payment: 6

PBKO Lapse due to non-payment of renewal fee for consensual patent

Effective date: 20141014