HRP940337A2

HRP940337A2 - Spyro-substituted azacycles as neurokinin antagonists

Info

Publication number: HRP940337A2
Application number: HR08/072,904A
Authority: HR
Inventors: Malcolm Maccoss; Sander G Mills; Shrenik K Shah; Yuan-Ching P Chiang; Patrick T Dunn; Hiroo Koyama; Paul E Finke; Hangbo Qi; Albert J Robichaud
Original assignee: Merck & Co Inc
Priority date: 1993-06-07
Filing date: 1994-06-06
Publication date: 1997-04-30
Also published as: IL109836A0; ZA943946B; WO1994029309A1; AU680020B2; EP0702681A1; AU7201194A; JPH08511522A; CA2163995A1

Description

Izum opisan ovdje usmjeren je na izvjesne spirosupstituirane azaciklične spojeve kao antagoniste receptora tahikinina, spojevi opisani ovdje su antagonisti receptora neurokinina. The invention described herein is directed to certain spiro-substituted azacyclic compounds as tachykinin receptor antagonists, the compounds described herein being neurokinin receptor antagonists.

Tahikinini, supstanca P (SP, neurokinin A (NKA) i neurokinin B (NKB) su strukturno slični članovi familije neuropeptida. Svaki od ovih je agonist receptorskog tipa, neurokinin-1 receptor (NK-1), neurokini-2 receptor (NK-2) i neurokinin-3 receptor (NK-3), koji su tako definirani prema njihovim relativnim sposobnostima da vežu tahikinine sa visokim afinitetom i da se aktiviraju prirodnim agonistima SP, NKA i odnosno NKB. The tachykinins, substance P (SP), neurokinin A (NKA), and neurokinin B (NKB) are structurally similar members of the neuropeptide family. Each of these is a receptor-type agonist, the neurokinin-1 receptor (NK-1), the neurokinin-2 receptor (NK- 2) and neurokinin-3 receptor (NK-3), which are thus defined according to their relative ability to bind tachykinins with high affinity and to be activated by natural agonists SP, NKA and NKB respectively.

Tahikinini se razlikuju sačuvanom karboksil-terminalnom sekvencom Phe-X-Gly-Leu-Met-NH2. Određenije, supstanca P je farmakološki-aktivan neuropeptid koji se proizvodi u sisavcima i ima karakterističnu amino kiselinsku sekvencu: Tachykinins are distinguished by the conserved carboxyl-terminal sequence Phe-X-Gly-Leu-Met-NH2. More specifically, substance P is a pharmacologically active neuropeptide that is produced in mammals and has a characteristic amino acid sequence:

Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2

Neurokinin A ima slijedeću aminokiselinsku sekvencu: Neurokinin A has the following amino acid sequence:

His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met-NH2. His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met-NH2.

Neurokinin B ima slijedeću amino kiselinsku sekvencu: Neurokinin B has the following amino acid sequence:

Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met-NH2. Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met-NH2.

(Chang i surad., Nature New Biol. 232, 86 (1971); D.F. Veber i surad., U.S. Patent No. 4,680,283). (Chang et al., Nature New Biol. 232, 86 (1971); D.F. Veber et al., U.S. Patent No. 4,680,283).

Receptori neurokinina su široko rasprostranjeni kroz nervni sistem sisavaca (naročito mozak i spinalne ganglie), cirkulatorni sistem i periferna tkiva (naročito duodenum i jejunum) su uključeni u reguliranje niza različitih bioloških procesa. Ovo uključuje osjetilno opažanje mirisa, vida, sluha i bola, kontrolu pokreta, gastričnu pokretljivost, vazodilataciju, salivaciju (lučenje pljuvačke), i mikturiciju (mokrenje) (B. Pernow, Pharmacol. Rev., 1983, 35, 85- 141). Nkl i Nk2 receptorski podtipovi su sadržani u sinaptičkoj transmisiji (Laneuville i surad., Life Sci., 42: 1295-1305 (1988)). Neurokinin receptors are widely distributed throughout the nervous system of mammals (especially brain and spinal ganglia), circulatory system and peripheral tissues (especially duodenum and jejunum) are involved in regulating a number of different biological processes. These include sensory perception of smell, sight, hearing, and pain, control of movement, gastric motility, vasodilation, salivation (secretion of saliva), and micturition (urination) (B. Pernow, Pharmacol. Rev., 1983, 35, 85-141). Nk1 and Nk2 receptor subtypes are involved in synaptic transmission (Laneuville et al., Life Sci., 42: 1295-1305 (1988)).

Supstanca P djeluje kao vazodilatator, depresant, stimulira salivaciju i proizvodi povećanu kapilarnu permeabilnost. Također je sposobna da proizvede i analgeziju i hiperalgeziju kod životinja, u ovisnosti od doze i osjećaja bola kod životinje (vidjeti R.C.A. Frederickson i surad., Science, 199. 1359 (1978); P. Oehme i surad., Science, 208, 305 (1980)) i igra ulogu u osjetilnoj transmisiji i opažanju bola (T.M. Jessell, Advan. Biochem. Psyhopharmacol. 28, 189 (1981)). Pokazalo se da je naročito supstanca P uključena u transmisiju bola kod migrene (vidjeti B.E.B., Sandberg i surad.. Journal of Medicinal Chemistry, 25, 1009 (1982)), i artritisa (Levine i surad., Science, (1984) 226, 547-549). Substance P acts as a vasodilator, depressant, stimulates salivation and produces increased capillary permeability. It is also capable of producing both analgesia and hyperalgesia in animals, depending on the dose and pain sensation of the animal (see R.C.A. Frederickson et al., Science, 199, 1359 (1978); P. Oehme, et al., Science, 208, 305 (1980)) and plays a role in sensory transmission and perception of pain (T.M. Jessell, Advan. Biochem. Psyhopharmacol. 28, 189 (1981)). Substance P in particular has been shown to be involved in pain transmission in migraine (see B.E.B., Sandberg et al.. Journal of Medicinal Chemistry, 25, 1009 (1982)), and arthritis (Levine et al., Science, (1984) 226, 547-549).

Kod dišnih puteva, je pokazano da su NK1 receptori povezani sa mikrovaskularnim propuštanjem i sekrecijom mukusa, dok NK2 receptori reguliraju kontrakciju glatkih mišića. Također, je pokazano da su obje supstance i supstanca P i neurokinin efikasne u izazivanju sužavanja dišnih puteva i edema. Na osnovu ovih saznanja, vjeruje se da supstanca P i neurokinin A mogu biti povezani sa patogenezom neurogene inflamacije, uključujući alergične bolesti kao što je astma. (Frossard i surad., Life Sci., 49, 1941-1953 (1991); Advenier, i surad., Biochem. Biophys. Res. Comm., 184(3), 1418-1424 (1992). In the airways, NK1 receptors have been shown to be associated with microvascular leakage and mucus secretion, while NK2 receptors regulate smooth muscle contraction. Also, it has been shown that both substances and substance P and neurokinin are effective in causing airway narrowing and edema. Based on these findings, it is believed that substance P and neurokinin A may be related to the pathogenesis of neurogenic inflammation, including allergic diseases such as asthma. (Frossard et al., Life Sci., 49, 1941-1953 (1991); Advenier, et al., Biochem. Biophys. Res. Comm., 184(3), 1418-1424 (1992).

U eksperimentalnim studijama, senzorni neuropeptidi, naročito tahikinini kao što su supstanca P i neurokinin A, mogu da dovedu do mnogih patofizioloških karakteristika astme. Neurokinin A je veoma snažan konstriktor humanih dišnih puteva in vitro, a supstanca P izaziva sekreciju mukusa u dišnim putevima. (Barnes P. J., Lancet, str. 242-44 (1986); Rogers D.R., Aursudkij B., Barnes P.J., Euro J. Pharmacol, 174, 283-86 (1989)). In experimental studies, sensory neuropeptides, especially tachykinins such as substance P and neurokinin A, can lead to many pathophysiological features of asthma. Neurokinin A is a very strong constrictor of human airways in vitro, and substance P causes mucus secretion in the airways. (Barnes P. J., Lancet, p. 242-44 (1986); Rogers D. R., Aursudkij B., Barnes P. J., Euro J. Pharmacol, 174, 283-86 (1989)).

Inhalacija bradikinina izaziva bronhokonstrikciju (stezanje bronhija) kod astmatičnih pacijenata ali ne i kod normalnih subjekata. (Fuller R.W., Dixon C.M.S., Cuss F.M.C., Barnes P.J., Am. Rev. Respir Dis, 135, 176-80 (1987)). Pošto je bradikininom izazvana bronhokonstrikcija djelomično suzbijena antikolinergičnim sredstvima i pošto je bradikinin samo slab konstriktor humanih dišnih puteva in vitro, predloženo je da bronho-sužavajući (brongokonstrikcijski) odgovor djelomično posredovan nervnim refleksom. Bradikinin stimulira vagalna (plućno želudačna) dovodna C vlakna i izaziva bronhokonstrikciju (suženje bronhija) kod pasa (Kaufman M.P., Coleridge H.M., Coleridge J.C.G., Baker D.G., J. Appl. Physio., 48, 511-17 (1980)). U dišnim putevima zamorčića, bradikinin izaziva bronho-konstrikcijsku reakciju na način holinergičnog i senzorno-nervno-posredovanih mehanizama (Ichinoe M., Belvisi M.G., Barnes P.J., J. Pharmacol. Exp. Ther., 253, 594-99 (1990). Bradikininom - izazvana bronhokonstrikcija u humanim dišnim putevima može stoga biti djelomično uslijed tahikinina odlobođenog iz senzornih nervnih terminala preko akson refleks mehanizama. Klinički eksperimeti su pokazali da dvostruki NK-1/NK-2 antagonist (kao što je FK-224) štiti od bradikininom izazvane bronhokonstrikcije kod astmatičnih pacijenata (Ichinoe, M. i surad., Lancet, vol. 340, str. 1248-1251 (1992)). Inhalation of bradykinin causes bronchoconstriction in asthmatic patients but not in normal subjects. (Fuller R.W., Dixon C.M.S., Cuss F.M.C., Barnes P.J., Am. Rev. Respir Dis, 135, 176-80 (1987)). Since bradykinin-induced bronchoconstriction is partially prevented by anticholinergic agents and since bradykinin is only a weak constrictor of human airways in vitro, it has been proposed that the bronchoconstrictor response is partially mediated by a neural reflex. Bradykinin stimulates vagal (pulmonary-gastric) afferent C fibers and causes bronchoconstriction (narrowing of the bronchi) in dogs (Kaufman M.P., Coleridge H.M., Coleridge J.C.G., Baker D.G., J. Appl. Physio., 48, 511-17 (1980)). In the airways of guinea pigs, bradykinin causes a bronchoconstriction reaction by way of cholinergic and sensory-nerve-mediated mechanisms (Ichinoe M., Belvisi M.G., Barnes P.J., J. Pharmacol. Exp. Ther., 253, 594-99 (1990). Bradykinin-induced bronchoconstriction in human airways may therefore be partially due to tachykinin released from sensory nerve terminals via axon reflex mechanisms.Clinical experiments have shown that a dual NK-1/NK-2 antagonist (such as FK-224) protects against bradykinin-induced bronchoconstriction. bronchoconstriction in asthmatic patients (Ichinoe, M. et al., Lancet, vol. 340, pp. 1248-1251 (1992)).

Tahikinini su također upleteni u gastrointestinalne (GI) poremećaje i bolesti GI trakta, kao što je inflamatorna crijevna bolest, ulcerativni kolitis i "Crohn-ova" bolest, itd. (vidjeti Mantyh i surad., Neuroscience, 25 (3), 817-37 (1988) i D. Regoli u 'Trends in Cluster Headache" Izd. F. Sicuteri i surad., Elsevier Scientific Publishers, Amsterdam, 1987, str. 85-95). Tachykinins have also been implicated in gastrointestinal (GI) disorders and diseases of the GI tract, such as inflammatory bowel disease, ulcerative colitis and Crohn's disease, etc. (see Mantyh et al., Neuroscience, 25(3), 817- 37 (1988) and D. Regoli in 'Trends in Cluster Headache" Ed. F. Sicuteri et al., Elsevier Scientific Publishers, Amsterdam, 1987, pp. 85-95).

Također je postavljena hipoteza da postoji neurogeni mehanizam za artritis u kome supstanca P može imati ulogu (ECdd i surad., "A. Neurogenic Mechanism for Symmetric Arthritis" The Lancet, 11 studeni 1989 i Gronblad i surad., "Neuropeptides in Synovium of Patients with Rheumatoid Arthritis and Osteoarthritis u J. Rheumatol. (1988) 15 (12) 1807-10). Stoga se vjeruje da je supstanca P uključena u inframatornu reakciju u bolestima kao što je reumatodni artritis i osteoartritis (O'Byrne i surad, u Arthritis and Rheumatism (1990) 33, 1023-8). Druga područja bolesti gdje se vjeruje da antagonisti tahikinina mogu biti korisni su alergijska stanja (Mahelet i surad., Can. J. Pharmacol. Physiol. (1988) 66, 1361-8-), imunoregulacija (Lotz i surad., Science (1988) 241, 1218-21, Kimball i surad., J. Immunol. (1988) 141 (10 3564-9 i A. Perianin i surad., Buiochem. Biophys. Res. Commun. 161, 520 (1989)) vazodilatacija, bronhospazam, refleks ili nervna kontrola utrobe (Mantyh i surad., PNAS (1988) 85, 3235-9) i, moguće za sprečavanje ili usporavanje α-amiloidno posredovanih neurodegenerativnih promjena (Yankner i surad., Science, (1990) 250, 279-82) u senilnoj demenciji Alzeheimer-ovog tipa, Alzheimer-ovoj bolesti i Down-ovog sindroma. Supstanca P može također igrati ulogu u demielinaciji bolesti kao što su multipla skleroza i amiotropna lateralna skleroza (J. Luber-Narod i surad., poster prezentiran na C.I.N.P. XVIII-tom kongresu, 28-mog lipnja- 2-gog srpnja, 1992). It has also been hypothesized that there is a neurogenic mechanism for arthritis in which substance P may play a role (ECdd et al., "A. Neurogenic Mechanism for Symmetric Arthritis" The Lancet, November 11, 1989 and Gronblad et al., "Neuropeptides in Synovium of Patients with Rheumatoid Arthritis and Osteoarthritis in J. Rheumatol. (1988) 15 (12) 1807-10).Therefore, substance P is believed to be involved in the inflammatory response in diseases such as rheumatoid arthritis and osteoarthritis (O'Byrne et al., in Arthritis and Rheumatism (1990) 33, 1023-8).Other disease areas where tachykinin antagonists are believed to be useful are allergic conditions (Mahelet et al., Can. J. Pharmacol. Physiol. (1988) 66, 1361-8 -), immunoregulation (Lotz et al., Science (1988) 241, 1218-21, Kimball et al., J. Immunol. (1988) 141 (10 3564-9 and A. Perianin et al., Buiochem. Biophys. Res. Commun. 161, 520 (1989)) vasodilatation, bronchospasm, reflex or nervous control of the gut (Mantyh et al., PNAS (1988) 85, 3235-9) and, possibly for preventing or retarding α-amyloid-mediated neurodegenerative changes (Yankner et al., Science, (1990) 250, 279-82) in senile dementia of the Alzheimer's type, Alzheimer's disease and Down's syndrome. Substance P may also play a role in demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis (J. Luber-Narod et al., poster presented at C.I.N.P. XVIII Congress, June 28-July 2, 1992).

Antagonisti selektivni za supstancu P i/ili neurokinin A Receptor može biti koristan u tretiranju asmatičnih bolesti (Frossard i surad., Life Sci., 49, 1941-1953 (1991); Advenier, i surad., Biochem. Biophys. Res. Comm., 184(3), 1418-1424 (1992)). Antagonists selective for the substance P and/or neurokinin A receptor may be useful in the treatment of asthmatic diseases (Frossard et al., Life Sci., 49, 1941-1953 (1991); Advenier, et al., Biochem. Biophys. Res. Comm ., 184(3), 1418-1424 (1992)).

Ovaj izum se odnosi na spojeve formule I. This invention relates to compounds of formula I.

[image] [image]

Izum se odnosi također na farmaceutske formulacije sa ovim novim spojevima kao aktivnih komponentama i na upotrebu novih spojeva i njihovih formulacija u tretiranju izvjesnih poremećaja. The invention also relates to pharmaceutical formulations with these new compounds as active components and to the use of the new compounds and their formulations in the treatment of certain disorders.

Spojevi prema ovom izumu su antagonisti receptori tahikinina i korisna su u tretiranju inflamatornih bolesti, bola ili migrene i astme. The compounds according to this invention are tachykinin receptor antagonists and are useful in the treatment of inflammatory diseases, pain or migraine and asthma.

Ovaj izum je usmjeren na spojeve formule I. This invention is directed to compounds of formula I.

[image] [image]

ili njihove farmaceutske soli, or their pharmaceutical salts,

gdje je dušik izrično prikazan gore opcijski kvaterniziran sa C1-4 alkil ili fenil C1-4 alkil ili je opcijski prisutan kao N-oksid (N+O-), i gdje su: wherein the nitrogen explicitly shown above is optionally quaternized with C1-4 alkyl or phenyl C1-4 alkyl or is optionally present as N-oxide (N+O-), and where:

1 i m svaki neovisno, 0, 1, 2, 3, 4, ili 5, pod uvjetom da je 1 and m each independently, 0, 1, 2, 3, 4, or 5, provided that

1 + m jednako sa 1, 2, 3, 4 ili 5; 1 + m equals 1, 2, 3, 4 or 5;

R1 je odabran iz grupe koja se sastoji od: R1 is selected from the group consisting of:

(1) vodika, (1) hydrogen,

(2) linearnog ili razgranatog C1-8 alkil, linearnog ili razgranatog C2-8 alkenil, ili linearnog ili razgranatog C2-8 alkinil, gdje je C1-8 alkil, C2-8 alkenil ili C2-8 alkinil opcijski mono, di, tri ili tetra supstituiran, a supstituenti su neovisno odabrani od (2) linear or branched C1-8 alkyl, linear or branched C2-8 alkenyl, or linear or branched C2-8 alkynyl, where C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl is optionally mono, di, tri or tetra substituted, and the substituents are independently selected from

(a) hikdroksi (a) hydroxy

(b) okso, (b) oxo,

(c) cijano, (c) cyano,

(d) halogena koji je definiran da obuhvaća Br, Cl, I, i F, (d) halogen, which is defined to include Br, Cl, I, and F,

(e) trifluorometil, (e) trifluoromethyl,

(f) fenil ili mono, di ili trisupstituiranog fenil, a supstituenti su neovisno odabrani od (f) phenyl or mono, di or trisubstituted phenyl, the substituents being independently selected from

(1) fenil (1) phenyl

(2) hidroksi, (2) hydroxy,

(3) C1-3 alkil, (3) C1-3 alkyl,

(4) cijano, (4) cyano,

(5) halogena, (5) halogen,

(6) trifluorometil, (6) trifluoromethyl,

(7) -NR6COR7, gdje su R6 i R7 neovisno odabrani od: (7) -NR6COR7, where R6 and R7 are independently selected from:

(a) vodika, (a) hydrogen,

(b) C1-6 alkil, ili mono ili disupstituiranog C1-6 alkil, a supstituenti su neovisno odabrani od (b) C1-6 alkyl, or mono- or disubstituted C1-6 alkyl, and the substituents are independently selected from

(1) fenil, nesupstituiranog ili supstituiranog sa hidroksi, C1-3 alkil, cijano, halogenom, trifluorometil ili C1-4 alkoksi, (1) phenyl, unsubstituted or substituted with hydroxy, C1-3 alkyl, cyano, halogen, trifluoromethyl or C1-4 alkoxy,

(2) hidroksi, (2) hydroxy,

(3) okso, (3) oxo,

(4) cijano, (4) cyano,

(5) halogena, (5) halogen,

(6) trifluorometil (6) trifluoromethyl

(c) fenil, piridinil, ili tiofen ili mono, di ili trisupstituirani fenil, piridinil ili tiofen, a supstituenti su neovisno odabrani od (c) phenyl, pyridinyl, or thiophene or mono, di, or trisubstituted phenyl, pyridinyl, or thiophene, the substituents being independently selected from

(1) hidroksi, (1) hydroxy,

(2) C1-4 alkil, (2) C1-4 alkyl,

(3) cijano, (3) cyano,

(4) halogena, (4) halogen,

(5) trifluorometil, (5) trifluoromethyl,

(d) C1-3 alkiloksi, (d) C1-3 alkyloxy,

ili or

R6 i R7 su spojeni međusobno tako da tvore 5-to, 6-to, ili 7-mo člani monociklični zasićen prsten koji sadrži 1 ili 2 heteroatoma nezavisno odabrana od dušika, kisika, sumpora, i u kome je prsten nesupstituiran ili mono ili disupstituiran, a supstituenti su nezavisno odabrani od R6 and R7 are joined together to form a 5-, 6-, or 7-membered monocyclic saturated ring containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and in which the ring is unsubstituted or mono- or disubstituted, and the substituents are independently selected from

(a) hidroksi, (a) hydroxy,

(b) okso, (b) oxo,

(c) cijano, (c) cyano,

(d) halogena, (d) halogens,

(e) trifluorometil (e) trifluoromethyl

(8) -NR6CO2R7 (8) -NR6CO2R7

(9) -NR6CO2R7, (9) -NR6CO2R7,

(10) -NR6S(O)jR7 gdje je j 1 ili 2, (10) -NR6S(O)jR7 where j is 1 or 2,

(11) -CONR6R7, (11) -CONR6R7,

(12) -COR6, (12) -COR6,

(13) -CO2R6, (13) -CO2R6,

(14) -OR6, (14) -OR6,

(15) -S(O)kR6, gdje je k 0,1 ili 2 (15) -S(O)kR6, where k is 0.1 or 2

(16) heteroaril, gdje je heteroaril odabran iz grupe koja se sastoji od: (16) heteroaryl, wherein heteroaryl is selected from the group consisting of:

(1) benzimidazolil, (1) benzimidazolyl,

(2) benzofuranil, (2) benzofuranil,

(3) benzoksazolil, (3) benzoxazolyl,

(4) furanil, (4) furanyl,

(5) imidazolil, (5) imidazolyl,

(6) indolil, (6) indolyl,

(7) izoksazolil, (7) isoxazolyl,

(8) izotiazolil, (8) isothiazolyl,

(9) oksadiazolil, (9) oxadiazolyl,

(10) oksazolil, (10) oxazolyl,

(11) pirazinil, (11) pyrazinyl,

(12) pirazolil, (12) pyrazolyl,

(13) piridil, (13) pyridyl,

(14) pirimidil, (14) pyrimidyl,

(15) pirolil, (15) pyrrolyl,

(16) hinolil, (16) quinolyl,

(17) tetrazolil, (17) tetrazolyl,

(18) tiadiazolil, (18) thiadiazolyl,

(19) tiazolil, (19) thiazolyl,

(20) tienil, i (20) thienyl, i

(21) triazolil, (21) triazolyl,

gdje je heteroaril nesupstituiran ili mono, di, ili trisupstituiran, a supstituenti su neovisno odabrani od, wherein the heteroaryl is unsubstituted or mono, di, or trisubstituted, and the substituents are independently selected from,

(a) hidroksi, (a) hydroxy,

(b) okso, (b) oxo,

(c) cijano, (c) cyano,

(d) halogena, (d) halogens,

(e) trifluorometil, (e) trifluoromethyl,

(g) -NR6R7, (g) -NR6R7,

(h) -NR6COR7, (h) -NR6COR7,

(i) -NR6CO2R7, (i) -NR6CO2R7,

(j) -NR6CONHR7, (j) -NR6CONHR7,

(k) -NR6S(Oj)R7, (k) -NR6S(Oj)R7,

(l) -CONR6R7, (l) -CONR6R7,

(m) -COR6, (m) -COR6,

(n) -CO2R6, (n) -CO2R6,

(o) -OR6, (o) -OR6,

(p) -S(O)kR6, (p) -S(O)kR6,

(q) heteroaril, gdje je heteroaril odabran iz grupe koja se sastoji od: (q) heteroaryl, wherein heteroaryl is selected from the group consisting of:

(1) benzimidazolil, (1) benzimidazolyl,

(2) benzofuranil, (2) benzofuranil,

(3) benzoksazolil, (3) benzoxazolyl,

(4) furanil, (4) furanyl,

(5) imidazolil, (5) imidazolyl,

(6) indolil, (6) indolyl,

(7) izoksazolil, (7) isoxazolyl,

(8) izotiazolil, (8) isothiazolyl,

(9) oksadiazolil, (9) oxadiazolyl,

(10) oksazolil, (10) oxazolyl,

(11) pirazinil, (11) pyrazinyl,

(12) pirazolil, (12) pyrazolyl,

(13) piridil, (13) pyridyl,

(14) pirimidil, (14) pyrimidyl,

(15) pirolil, (15) pyrrolyl,

(16) hinolil, (16) quinolyl,

(17) tetrazolil, (17) tetrazolyl,

(18) tiadiazolil, (18) thiadiazolyl,

(19) tiazolil, (19) thiazolyl,

(20) tienil, (20) thienyl,

(21) triazolil, (21) triazolyl,

gdje je heteroaril nesupstituiran ili mono, di, ili trisupstituiran, a supstituenti su neovisno odabrani od wherein the heteroaryl is unsubstituted or mono, di, or trisubstituted, and the substituents are independently selected from

(1) fenil, (1) phenyl,

(2) hidroksi, (2) hydroxy,

(3) okso, (3) oxo,

(4) cijano, (4) cyano,

(5) halogena, (5) halogen,

(6) trifluorometil, (6) trifluoromethyl,

gdje je dušik iz definicije R1 2(g) kao što je definiran gore opcijski kvaterniziran sa C1-4 alkil ili fenil C1-4 alkil ili je opcijski prisutan kao N-oksid (N+O-) wherein the nitrogen of the definition of R1 2(g) as defined above is optionally quaternized with C1-4 alkyl or phenyl C1-4 alkyl or is optionally present as N-oxide (N+O-)

W je odabran iz grupe koja se sastoji od W is selected from the group consisting of

(1) kovalentne veze (1) covalent bonds

(2) C1-3 alkil, nesupstituiranog ili supstituiranog sa (2) C1-3 alkyl, unsubstituted or substituted with

(a) okso, (a) oxo,

(b) hidroksi, (b) hydroxy,

(c) OR6, (c) OR6,

(d) halogena, (d) halogens,

(e) trifiuorometil (e) trifluoromethyl

(f) fenil ili mono, di, ili trisupstituiranog fenil, a supstituenti su neovisno odabrani od (f) phenyl or mono, di, or trisubstituted phenyl, the substituents being independently selected from

(1) hidroksi, (1) hydroxy,

(2) cijano, (2) cyano,

(3) halogena, (3) halogen,

(4) trif1uorometil, (4) trifluoromethyl,

(3) S(O)k, (3) S(O)k,

(4) (C1-3 alkil)-S(O)k, (4) (C1-3 alkyl)-S(O)k,

(5) S(O)k-(C1-2 alkil), (5) S(O)k-(C1-2 alkyl),

(6) S(O)k-NH, (6) S(O)k-NH,

(7) S(O)j-NH(C1-2alkil), (7) S(O)j-NH(C1-2alkyl),

(8) S(O)j-NR6, (8) S(O)j-NR6,

(9) S(O)j-NR6-(C1-2 alkil), (9) S(O)j-NR6-(C1-2 alkyl),

(10) CONH, (10) CONH,

(11) CONH-(C1-2alkil), (11) CONH-(C1-2alkyl),

(12) CONR6, (12) CONR6,

(13) CONR6-(C1-2alkil), (13) CONR6-(C1-2alkyl),

(14) CO2, (14) CO2,

(15) CO2-(C1-2 alkil); (15) CO2-(C1-2 alkyl);

Q = NR2, O, S, S(O), ili SO2 pod uvjetom da kada je W kovalentna veza i X je C1-3 alkil, tada Q mora biti NR2; Q = NR 2 , O, S, S(O), or SO 2 provided that when W is a covalent bond and X is C 1-3 alkyl, then Q must be NR 2 ;

R2 je odabran iz grupe koja se sastoji od: R2 is selected from the group consisting of:

(1) vodika, (1) hydrogen,

(2) C1-8 linearnog ili razgranatog alkil, supstituiranog ili multi supstituiranog sa (2) C1-8 linear or branched alkyl, substituted or multi-substituted with

(a) -OR6, (a) -OR6,

(b) =O, (b) =O,

(c) -NHCOR6, (c) -NHCOR6,

(d) -NR6R7, (d) -NR6R7,

(e) -CN, (e) -CN,

(f) -halogena, (f) -halogen,

(g) -CF3, (g) -CF3,

(h) -fenil, nesupstituiranog ili supstituiranog, gdje su supstituenti odabrani iz grupe koja se sastoji od (h) -phenyl, unsubstituted or substituted, wherein the substituents are selected from the group consisting of

(1) hidroksi, (1) hydroxy,

(2) cijano, (2) cyano,

(3) halogena, (3) halogen,

(4) trifluorometil, (4) trifluoromethyl,

(3) S(O)R8, gdje je R8 C1-6 linearni ili razgranati alkil, nesupstituiran, mono, di ili trisupstituiran sa (3) S(O)R8, where R8 is C1-6 linear or branched alkyl, unsubstituted, mono, di or trisubstituted with

(a) hidroksi, (a) hydroxy,

(b) okso, (b) oxo,

(c) cijano, (c) cyano,

(d) -OR6, (d) -OR6,

(e) -NR6R7, (e) -NR6R7,

(f) -N R6COR7, (f) -N R6COR7,

(g) -halogenom, (g) -halogen,

(h) -CF3, (h) -CF3,

(i) -fenil ili mono, di ili trisupstituiranim fenil, a supstituenti su neovisno odabrani od (i) -phenyl or mono, di or trisubstituted phenyl, the substituents being independently selected from

(1) hidroksi, (1) hydroxy,

(2) okso, (2) oxo,

(3) cijano, (3) cyano,

(4) -NHR6, (4) -NHR6,

(5) -NR6R7, (5) -NR6R7,

(6) -NR6COR7, (6) -NR6COR7,

(7) halogena, (7) halogen,

(8) -CF3, i (8) -CF3, i

(9) C1-3 alkil, (9) C1-3 alkyl,

(4) SO2R8, ili (4) SO2R8, or

(5) COR8, (5) COR8,

(6) CO2R8, (6) CO2R8,

(7) CONR7R8; (7) CONR7R8;

X je odabran iz grupe koja se sastoji od X is selected from the group consisting of

(1) kovalentne veze (1) covalent bonds

(a) okso, (a) oxo,

(b) OR6, (b) OR6,

(c) halogena, (c) halogens,

(d) trifluorometil, (d) trifluoromethyl,

(e) fenil ili mono, di ili trisupstituiranog fenil, a supstituenti su neovisno odabrani od (e) phenyl or mono, di or trisubstituted phenyl, the substituents being independently selected from

(1) OR6 (1) OR6

(2) halogena, i (2) halogens, i

(3) trifuorometil, (3) trifluoromethyl,

(3) S(O)k, (3) S(O)k,

(4) C1-3 alkil)S(O)k, (4) C1-3 alkyl)S(O)k,

(5) S(O)k(C1-2 alkil), (5) S(O)k(C1-2 alkyl),

(6) NHS(O)j, (6) NHS(O)j,

(7) NH(C1-2 alkil)S(O)j, (7) NH(C1-2 alkyl)S(O)j,

(8) S(O)jNR6, (8) S(O)jNR6,

(9) S(O)j-NR6-(C1-2 alkil), (9) S(O)j-NR6-(C1-2 alkyl),

(10) NHCO, (10) NHCO,

(11) NHCO-(C1-2 alkil), (11) NHCO-(C1-2 alkyl),

(12) NR6CO, (12) NR6CO,

(13) NR6-(C1-2 alkil)CO, (13) NR6-(C1-2 alkyl)CO,

(14) O(CO), i (14) O(CO), i

(15) (C1-2 alkil)O(CO), (15) (C1-2 alkyl)O(CO),

Y-Z promatrani zajedno su 2 pripojena atoma prstena. Y-Z viewed together are 2 attached ring atoms.

[image] [image]

a navedeni prsten je fenil, naftil ili heteroaril grupa, sa heteroarilima odabranim iz grupe koja se sastoji od: and said ring is a phenyl, naphthyl or heteroaryl group, with heteroaryls selected from the group consisting of:

(1) benzimidazolil, (1) benzimidazolyl,

(2) benzofuranil, (2) benzofuranil,

(3) benzoksazolil, (3) benzoxazolyl,

(4) furanil, (4) furanyl,

(5) imidazolil, (5) imidazolyl,

(6) indolil, (6) indolyl,

(7) izoksazolil, (7) isoxazolyl,

(8) izotiazolil, (8) isothiazolyl,

(9) oksadiazolil, (9) oxadiazolyl,

(10) oksazolil, (10) oxazolyl,

(11) pirazinil, (11) pyrazinyl,

(12) pirazolil, (12) pyrazolyl,

(13) piridil, (13) pyridyl,

(14) pirimidil, (14) pyrimidyl,

(15) pirolil, (15) pyrrolyl,

(16) hinolil, (16) quinolyl,

(17) tetrazolil, (17) tetrazolyl,

(18) tiaziazolil, (18) thiaziazolyl,

(19) tiazolil, (19) thiazolyl,

(20) tienil, (20) thienyl,

(21) triazolil, (21) triazolyl,

i gdje je aril ili heteroaril grupa nesupstituirana, mono, di ili tri supstituirana, a supstituenti su odabrani od: and where the aryl or heteroaryl group is unsubstituted, mono, di or tri substituted, and the substituents are selected from:

(a) vodika, (a) hydrogen,

(b) C1-6 alkil, razgranatog ili nerazgranatog, nesupstituiranog ili mono ili disupstituiranog, a supstituenti su odabrani od vodika i hidroksi, (b) C1-6 alkyl, branched or unbranched, unsubstituted or mono- or disubstituted, and the substituents are selected from hydrogen and hydroxy,

(c) okso, (c) oxo,

(d) OR6, gdje je R6 kao što je definirano odmah gore, (d) OR 6 , where R 6 is as defined immediately above,

(e) halogena, (e) halogen,

(f) trifluorometil, (f) trifluoromethyl,

(g) nitro, (g) nitro,

(h) cijano, (h) cyano,

(i) NHR6, (i) NHR6,

(j) NR6R7, (j) NR6R7,

(k) NHCOR6, (k) NHCOR6,

(l) NR6COR7, (l) NR6COR7,

(m) NHCO2R6, (m) NHCO2R6,

(n) NR6CO2R7, (n) NR6CO2R7,

(o) NHS(O)jR6. (o) NHS(O)jR6.

(p) NR6S(O)jR7, (p) NR6S(O)jR7,

(q) CONR6R7, (q) CONR6R7,

(r) COR6, (r) COR6,

(s) CO2R6, (s) CO2R6,

(t) S(O)jR6, (t) S(O)jR6,

(u) heteroaril, gdje je heteroaril odabran iz grupe koja se sastoji od: (u) heteroaryl, wherein heteroaryl is selected from the group consisting of:

(a) benzimidazolil, (a) benzimidazolyl,

(b) benzofuranil, (b) benzofuranil,

(c) benzoksazolil, (c) benzoxazolyl,

(d) furanil, (d) furanyl,

(e) imidazolil, (e) imidazolyl,

(f) indolil, (f) indolyl,

(g) izoksazolil, (g) isoxazolyl,

(h) izotiazolil, (h) isothiazolyl,

(i) oksadiazolil, (i) oxadiazolyl,

(j) oksazolil, (j) oxazolyl,

(k) pirazinil, (k) pyrazinyl,

(l) pirazolil, (l) pyrazolyl,

(m) piridil, (m) pyridyl,

(n) pirimidil, (n) pyrimidyl,

(o) pirolil, (o) pyrrolyl,

(p) hinolil, (p) quinolyl,

(q) tetrazolil, (q) tetrazolyl,

(r) tiadiazolil, (r) thiadiazolyl,

(s) tiazolil, (s) thiazolyl,

(t) tienil, (t) thienyl,

(u) triazolil, (u) triazolyl,

i gdje je heteroaril nesupstituiran mono ili di supstituiran, a supstituenti su odabrani od and wherein the heteroaryl is unsubstituted mono or di substituted, and the substituents are selected from

(1) vodika, (1) hydrogen,

(2) C1-6 alkil, razgranatog ili nerazgranatog, nesupstituiranog ili mono ili di supstituiranog ili mono ili di supstituiranog, a supstituenti su odabrani od vodika i hidroksi, (2) C1-6 alkyl, branched or unbranched, unsubstituted or mono or di substituted or mono or di substituted, and the substituents are selected from hydrogen and hydroxy,

(3) okso, (3) oxo,

(4) OR6, (4) OR6,

(5) trifluorometil, (5) trifluoromethyl,

(6) nitro, (6) nitro,

(7) cijano, (7) cyano,

(8) NHR6, (8) NHR6,

(9) NR6R7, (9) NR6R7,

(10) NHCOR6, (10) NHCOR6,

(11) NR6COR7, (11) NR6COR7,

(12) NHCO2R6, (12) NHCO2R6,

(13) NR6CO2R7, (13) NR6CO2R7,

(14) NHS(O)jR6, (14) NHS(O)jR6,

(15) NR6S(O)jR7, (15) NR6S(O)jR7,

(16) CONR6R7, (16) CONR6R7,

(17) COR6, (17) COR6,

(18) C02R6, (18) C02R6,

(19) S(O)jR6, i (19) S(O)jR6, i

(20) fenil. (20) phenyl.

Jedna podklasa ovog izuma sastoji se od struktura navedenih niže vezanih za R1 (kao što je dano detaljno odmah gore) preko izlomljene veze, i opcijski supstituiranih na položajima označenim brojevima 1-8 sa One subclass of this invention consists of the structures listed below linked to R1 (as detailed immediately above) via a broken bond, and optionally substituted at positions numbered 1-8 with

(a) hidroksi, (a) hydroxy,

(b) okso, (b) oxo,

(c) cijano, (c) cyano,

(d) -NR6R7, (d) -NR6R7,

(e) -NHCOR6R7, (e) -NHCOR6R7,

(f) -halogena, (f) -halogen,

(g) -CF3, (g) -CF3,

(h) -fenil ili mono, di, ili trisupstituiranog fenil, a supstituenti su neovisno odabrani od (a) do (g) i C1-3 alkil; navedene strukture su (h) -phenyl or mono, di, or trisubstituted phenyl, the substituents being independently selected from (a) to (g) and C1-3 alkyl; the listed structures are

[image] [image]

Kao što je jasno iz primjera i šema, obilježavanje: As is clear from the examples and schemes, marking:

[image] [image]

u formuli I je izmjenjivo sa (CH2)1 ili odnosno (CH2)m. Kao što je jasno stručnjacima, halogen (halo) kao što je upotrijebljeno ovdje, namijenjeno je da obuhvaća klor (kloro), fluor (fluoro), brom (bromo) i jod (jodo). in formula I is interchangeable with (CH2)1 or (CH2)m. As will be appreciated by those skilled in the art, halogen (halo) as used herein is intended to include chlorine (chloro), fluorine (fluoro), bromine (bromo), and iodine (iodo).

Kao primjer ovog pronalaska služe spojevi iz primjera koji obuhvaćaju grupu koja se sastoji od As an example of this invention, the compounds from the examples that comprise the group consisting of

(a) 1'-(3-(S)-(3,4-diklorofenil)-4-(N-t-butoksikarbonil)(metilamino))butil)-1-metansulfonil-spiro(indolin -3,4'-piperidina); (a) 1'-(3-(S)-(3,4-dichlorophenyl)-4-(N-t-butoxycarbonyl)(methylamino))butyl)-1-methanesulfonyl-spiro(indoline-3,4'-piperidine) ;

(b) 1'-(3-((S)-(3,4-diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil)-1-metan-sulfonil-spiro (indolin-3,4'-piperidina); (b) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)-1-methane-sulfonyl-spiro ( indoline-3,4'-piperidine);

(c) 1'-(3-((S)-(3,4-diklorofenil))-4-(N-(benzoil)-(metil-amino))butil)-1-metansulfonil-spiro-(indolin-3,4'-piperidina); (c) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(benzoyl)-(methyl-amino))butyl)-1-methanesulfonyl-spiro-(indoline- 3,4'-piperidine);

(d) 1'-(3-((S)-(3,4-diklorofenil)-4-(N-(3,5-bistrifluoro-metilbenzoil) (metilamino))butil)-1-metansulfonil (d) 1'-(3-((S)-(3,4-dichlorophenyl)-4-(N-(3,5-bistrifluoro-methylbenzoyl)(methylamino))butyl)-1-methanesulfonyl

-spiro)indolin-3,4'-piperidina); -spiro)indoline-3,4'-piperidine);

(e) 1'(3-((S)-(3,4-diklorofenil))-4-(N-(3-metilbenzoil)(metilamino))butil)-1-metansulfonil-spiro(indolin (e) 1'(3-((S)-(3,4-dichlorophenyl))-4-(N-(3-methylbenzoyl)(methylamino))butyl)-1-methanesulfonyl-spiro(indoline

-3,4'-piperidina); -3,4'-piperidine);

(f) 1'-(3-((S)-(3,4-diklorofenil))-4-(N-(3-klorobenzoil)(metilamino)butil)-1-metansulfonil-spiro(indolin (f) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3-chlorobenzoyl)(methylamino)butyl)-1-methanesulfonyl-spiro(indoline

-3,4'-piperidina); -3,4'-piperidine);

(g) 1'-(3-((S)-(3,4-diklorofenil))-4-(N-(3-trifluorometil-benzoil) (metilamino))butil)-1-metansulfonil-spiro (g) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3-trifluoromethyl-benzoyl)(methylamino))butyl)-1-methanesulfonyl-spiro

(indolin-3,4'-piperidina); (indoline-3,4'-piperidine);

(h) 1'-(3-((S)-(3,4-diklorofenil))-4-(N-(3,5-diklorobenzoil)(metilamino))butil)1-metan-sulfonil-spiro (h) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dichlorobenzoyl)(methylamino))butyl)1-methanesulfonyl-spiro

(indolin-3,4'-piperidina); (indoline-3,4'-piperidine);

(i) 1'-(3-((S)-(3,4-diklorofenil))-4-(N-(3-trifluorometilfenilacetil) (metilamino))butil)-1-metansulfonil (i) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3-trifluoromethylphenylacetyl) (methylamino))butyl)-1-methanesulfonyl

-spiro(indolin-3,4'piperidina); -spiro(indoline-3,4'piperidine);

(j) 1'-(3-((S)-(3,4-diklorofenil))-4-(N-(3-izopropiloksi-fenilacetil)(metilamino))butil)-1-metansulfonil (j) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3-isopropyloxy-phenylacetyl)(methylamino))butyl)-1-methanesulfonyl

-spiro(indolin-3,4'- piperidina); -spiro(indoline-3,4'-piperidine);

(k) 1'-(3-((S)-(3,4-diklorofenil))-4-(N-(benzolsulfonil)(metilamino))butil)-1-metansulfonil-spiro(indolin (k) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(benzenesulfonyl)(methylamino))butyl)-1-methanesulfonyl-spiro(indoline

-3,4'-piperidina); -3,4'-piperidine);

(l) 1'-(3-((S)-(3,4-diklorofenil)-4-(N-(3,5-dimetilbenzoil)(metilamino))butil)-1-benziloksi-karbonil (l) 1'-(3-((S)-(3,4-dichlorophenyl)-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)-1-benzyloxy-carbonyl

-spiro(indolin-3,4'-piperidina); -spiro(indoline-3,4'-piperidine);

(m) 1'-(3-((S)-(3,4-diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil)-spiro(indolin-3,4'-piperidina); (m) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)-spiro(indoline-3,4' - piperidine);

(n) 1'-(3-((S)-(3,4-dikloroenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil)-1-propionil-spiro(indolin (n) 1'-(3-((S)-(3,4-dichloroenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)-1-propionyl-spiro(indoline

-3,4'- piperidina); -3,4'- piperidine);

(o) 1'-(3-((S)-3,4-diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil)-1-formil-spiro(indolin (o) 1'-(3-((S)-3,4-dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)-1-formyl-spiro(indoline

-3,4'piperidina); -3,4'piperidine);

(p) 1'-(3-((S)-(3,4-diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil)-1-t-butil-karbonil (p) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)-1-t-butyl-carbonyl

-spiro(indolin-3,4'-piperidina; -spiro(indoline-3,4'-piperidine;

(q) 1'-(3-((S-(3,4-diklorofenil))-4-(N-3,5-dimetilbenzoil)(metilamino))butil)-1-metil-aminokarbonil (q) 1'-(3-((S-(3,4-dichlorophenyl))-4-(N-3,5-dimethylbenzoyl)(methylamino))butyl)-1-methyl-aminocarbonyl

-spiro(indolin-3,4'-piperidina); -spiro(indoline-3,4'-piperidine);

(r) 1'-(3-((S)-(3,4-diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino)jbutil)-1-etoksi-karbonil-spiro (r) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino)jbutyl)-1-ethoxy-carbonyl-spiro

(indolin-3,4'-piperidina; (indoline-3,4'-piperidine;

(s) 1'-(3-((S)-(3,4-diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil)-1-etan-sulfonil-spiro (s) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)-1-ethanesulfonyl-spiro

(indolin-3,4'-piperidina); (indoline-3,4'-piperidine);

(t) 1'-(3((S)-(3,4-diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil)-1-i-propansulfonil-spiro (t) 1'-(3((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)-1-i-propanesulfonyl-spiro

(indolin-3,4'piperidina); (indoline-3,4'piperidine);

(u) 1'-(3((S)-(3,4-diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil)1'-metil-1-metansulfonil (u) 1'-(3((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)1'-methyl-1-methanesulfonyl

-spiro-indolin-3,4'-piperidinijum jodida; -spiro-indoline-3,4'-piperidinium iodide;

(v) 1'-(3-(S)-(3,4-diklorofenil)-4-(N-(R ili S)-(3-metilbenzoil)(metilamino))pentil)-1-metan-sulfonil-spiro (v) 1'-(3-(S)-(3,4-dichlorophenyl)-4-(N-(R or S)-(3-methylbenzoyl)(methylamino))pentyl)-1-methanesulfonyl- spiro

(indolin-3,4'piperidina); (indoline-3,4'piperidine);

(w) 1'-(3-(S)-(3,4-diklorofenil)-4-(N-(R ili S)-(3,5-bis(trifloorometil)benzoil) (metilamino))-pentil)-1 (w) 1'-(3-(S)-(3,4-dichlorophenyl)-4-(N-(R or S)-(3,5-bis(trifluoromethyl)benzoyl)(methylamino))-pentyl) -1

-metansulfonilspiro(indolin-3,4'-piperidina); -methanesulfonylspiro(indoline-3,4'-piperidine);

(x) 1'-(3)-(S)-(3,4-diklorofenil)-4-(N-(R ili S)-(3,5-dimetilbenzoil) (metilamino))pentil)-1-metansulfonil (x) 1'-(3)-(S)-(3,4-dichlorophenyl)-4-(N-(R or S)-(3,5-dimethylbenzoyl)(methylamino))pentyl)-1-methanesulfonyl

-spiro(indolin-3,4'piperidina); -spiro(indoline-3,4'piperidine);

(y) 1'-(3-(S)-(3,4-diklorofenil)-4-(N-(R ili S)-(3,5-diklorobenzoil) (metilamino))pentil)-1-metansulfonil (y) 1'-(3-(S)-(3,4-dichlorophenyl)-4-(N-(R or S)-(3,5-dichlorobenzoyl)(methylamino))pentyl)-1-methanesulfonyl

-spiro(indolin-3,4'piperidina); -spiro(indoline-3,4'piperidine);

(a) 1'-(3-((S)-(3,4-diklorofenil))-4-(N-(3,5-difluorobenzoil) (metilamino))butil)-1-metansuffonil-spiro (a) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-difluorobenzoyl)(methylamino))butyl)-1-methanesulfonyl-spiro

(indolin-3,4'piperidina); (indoline-3,4'piperidine);

(ab) 1'-(3-((S)-(3,4-diklorofenil))-4-(N-(3-fluoro-5-(trifluorometil)benzoil)(metilamino))butil-1 (ab) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3-fluoro-5-(trifluoromethyl)benzoyl)(methylamino))butyl-1

-metansulfonil-spiro(indolin3,4'piperidina); -methanesulfonyl-spiro(indoline3,4'piperidine);

(ac) 1'-(3-((S)-(3,4-diklorofenil))-4-(N-(1-naftoil)(metilamino))butil)-1-metansulfonil-spiro(indolin-3,4' (ac) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(1-naphthoyl)(methylamino))butyl)-1-methanesulfonyl-spiro(indoline-3, 4'

-piperidina); - piperidine);

(ad) 1'-(3-((S)-(3,4-diklorofenil))-4-(N-(2-klorofenilsulfonil)(metilamino))butil)-1-metil-sulfonil-spiro (ad) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(2-chlorophenylsulfonyl)(methylamino))butyl)-1-methyl-sulfonyl-spiro

(indolin-3,4'-piperidina); (indoline-3,4'-piperidine);

(ae) 1'-(3-((S)-(3,4-diklorofenil))-4-(N-(3-klorofenilsulfonil)(metilamino))butil)-1-metilsulfonil-spiro (ae) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3-chlorophenylsulfonyl)(methylamino))butyl)-1-methylsulfonyl-spiro

(indolin-3,4'-piperidina); (indoline-3,4'-piperidine);

(af) 1'-(3-((S)-(3,4-diklorofenil))-4-(N-(4-klorofenilsulfonil)(metilamino))butil)-1-metilsulfonil-spiro (af) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(4-chlorophenylsulfonyl)(methylamino))butyl)-1-methylsulfonyl-spiro

(indolin-3,4'-piperidina); (indoline-3,4'-piperidine);

(ag) 1'-(3-((S)-(3,4-diklorofenil))-4-(N-(3,5-diklorofenilsulfonil)(metilamino))butil)-1-metilsulfonil-spiro (ag) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dichlorophenylsulfonyl)(methylamino))butyl)-1-methylsulfonyl-spiro

(indolin-3,4'-piperidina); (indoline-3,4'-piperidine);

(ah) 1'-(3-((S)-(3,4-dikloroenil))-4-(N-(3-fluoro-5-(trifuorometil)benzoil)(metilamino))-butil)-1-acetil (ah) 1'-(3-((S)-(3,4-dichloroenyl))-4-(N-(3-fluoro-5-(trifluoromethyl)benzoyl)(methylamino))-butyl)-1- acetyl

-spiro(indolin-3,4'piperidina); -spiro(indoline-3,4'piperidine);

(ai) 1'-(3-((S)-(3,4-diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil)1-acetilspiro(indolin-3,4'-piperidina; (ai) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)1-acetylspiro(indoline-3,4 '-piperidine;

(aj) (1'-(3-((S)-(3,4-diklorofenil))-4-(N-(3-brom-5-metilbenzoil)(metilamino))butil)-1-metansulfonil (aj) (1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3-bromo-5-methylbenzoyl)(methylamino))butyl)-1-methanesulfonyl

-spiro(indolin-3,4'piperidina); -spiro(indoline-3,4'piperidine);

(ak) 1'-(3-((S)-(3,4-diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil)1-(2-aminoacetil)-spiro (indolin-3,4'-piperidina); (ak) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)1-(2-aminoacetyl)-spiro (indoline-3,4'-piperidine);

(al) 1'(3-((S)-(3,4-diklorofenil))-4-(N-3,5-dimetilbenzoil)(metilamino))butil)-1- metil-spiro(indol-2-on-3,4'-piperidina); (al) 1'(3-((S)-(3,4-dichlorophenyl))-4-(N-3,5-dimethylbenzoyl)(methylamino))butyl)-1- methyl-spiro(indole-2- on-3,4'-piperidine);

(am) 1'-(3-((S)-(3,4-diklorofenil))-4-(N-(3,5-diklorobenzoil)(metilamino))butil)1-metil-spiro(izoindol-1-on -3,4'-piperidina); (am) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dichlorobenzoyl)(methylamino))butyl)1-methyl-spiro(isoindole-1 -one -3,4'-piperidine);

(an) 1'-(3-((S)-(3,4- diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino)) butil)spiro (2-okso- tetrahidro hinolin-4,4'- piperidina; (an) 1'-(3-((S)-(3,4- dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino)) butyl)spiro (2-oxo-tetrahydro quinoline- 4,4'-piperidine;

(ao) 1'-(3-((S)-(3,4-diklorofenil))-4-(N-(3,5-diklorobenzoil)(metilamino))butil)1-metil-spiro(2-okso (ao) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dichlorobenzoyl)(methylamino))butyl)1-methyl-spiro(2-oxo

-tetrahidrohinolin-4,4'-piperidina); -tetrahydroquinoline-4,4'-piperidine);

U jednoj alternativnoj realizaciji gornji spojevi se mogu ko-primjenjivati sa 2-agonistom kao što je Bambuterol, US 4,419,364 izdanog firmi Draco 6/12/83; Bitofterol mezilat, US 4,138,581 izdanog firmi Sterling 6/2/79; Carbuterol, US 3,763,232 izdanog firmi SmithKline 2/10/73; Clenbuterol, US 3,536,712 izdanog firmi Boehringer Ingelheim 27/10/70; Dopexamine, US 4,645,768 izdanog firmi Fisons 24/2/87; Formoterol, US 3,994,974 izdatog firmi Yamanouchi 30/11 /76; Mabuterol, US 4,119,710 izdanog firmi Boehringer Ingelheim 10/10/78; Pirbuterol hidroklorid US 3,700,681 izdanog firmi Pfizer 24/10/72; Procterol hidroklorid US 4,026,897 izdanog firmi Otsuka 31 /5/77; Ritodrin hidroklorid US 3,410,944 izdanog firmi North American Philips 12/11 /68; Brosaterol, US 4,276,299 izdanog firmi Zambon 30/6/81 i US 4,520,200 izdanog firmi Zambon 28/5/85; Cimaterol, US 4,407,819 izdanog firmi American Gyanamid 4/10/83; Docarpamin, US 4,228,183 izdanog firmi Tanabe 14/10/80; Salmeterol, US 4,992,474 izdanog firmi Glaxo 21 /2/91 i US 5,091,422 izdanog firmi Glaxo 25/2/92. In an alternative embodiment, the above compounds can be co-administered with a 2-agonist such as Bambuterol, US 4,419,364 issued to Draco 6/12/83; Bitofterol mesylate, US 4,138,581 issued to Sterling 6/2/79; Carbuterol, US 3,763,232 issued to SmithKline 2/10/73; Clenbuterol, US 3,536,712 issued to Boehringer Ingelheim 10/27/70; Dopexamine, US 4,645,768 issued to Fisons 2/24/87; Formoterol, US 3,994,974 issued to Yamanouchi 11/30/76; Mabuterol, US 4,119,710 issued to Boehringer Ingelheim 10/10/78; Pirbuterol hydrochloride US 3,700,681 issued to Pfizer 10/24/72; Procterol hydrochloride US 4,026,897 issued to Otsuka on 5/31/77; Ritodrine hydrochloride US 3,410,944 issued to North American Philips 12/11/68; Brosaterol, US 4,276,299 issued to Zambon 6/30/81 and US 4,520,200 issued to Zambon 5/28/85; Cimaterol, US 4,407,819 issued to American Gyanamid 4/10/83; Docarpamine, US 4,228,183 issued to Tanabe 10/14/80; Salmeterol, US 4,992,474 issued to Glaxo on 2/21/91 and US 5,091,422 issued to Glaxo on 2/25/92.

Spojevi formule I su naročito korisni u tretiranju bolesti ili stanja koja se pogodno tretiraju sa pratećim antagonizmom za oba i NK1 i NK2 receptora ili NK1, NK2 i NK3 receptore. Ove bolesti uključuju neuropatiju, kao što je dijabetična ili periferalna neuropatija i kemoterapijom-izazvana neuropatija; astma; osteoartritis; reumatoidni artritis; i migrena. Compounds of formula I are particularly useful in the treatment of diseases or conditions that are conveniently treated with concomitant antagonism for both NK1 and NK2 receptors or NK1, NK2 and NK3 receptors. These diseases include neuropathy, such as diabetic or peripheral neuropathy and chemotherapy-induced neuropathy; asthma; osteoarthritis; rheumatoid arthritis; and migraine.

U drugoj alternativnoj realizaciji, spojevi formule I mogu se ko-primjenjivati sa jednim drugim NK1 ili NK2 kao što su oni opisani u Prijavi No. DO-139125, podnijetoj 08-lipnja-78, objavljenoj 12-prosinca-79; Prijavi No. EP-82568, podnijetoj 22-prosinca-81, objavljenoj 29-lipnja-83; Prijavi No. EP490379, podnijetoj 13-prosinca-90 objavljenoj 17-lipnja-92. Prijavi No. EP-353732, podnijetoj 05-kolovoza-88, objavljenoj 07-veljače-90; Prijavi No. EP161007, podnijetoj 13-siječnja-84, objavljenoj 13-studenog-85; Prijavi No. EP385-43, podnijetoj 28-veljače-89, objavljenoj 05-rujna-90; Prijavi No. W08301251, podnijetoj 09-listopada-81, objavljenoj 14-travnja-83; Prijavi No. BE-894602, podnijetoj 09-listopada-81, objavljenoj 31-siječnja-83. Prijavi No. DE3205991, podnijetoj 19-veljače-82; objavljenoj 01-rujna-83; Prijavi No. EP327009, podnijetoj 02-veljače-88, objavljenoj 09-kolovoza-89; Prijava No. EP336230, podnijetoj 05-travnja-88, objavljenoj 11-listopada-89; Prijavi No. 394989, podnijetoj 28-travnja-89, objavljenoj 31-listopada-90; Prijavi No. AU9068010, podnijetoj 22-prosinca-89, objavljenoj 27-lipnja-91; Prijavi No. EP482539, podnijetoj 24-listopada-90, objavljenoj 29-travnja-92; Prijava No. EP443132, podnijetoj 10-prosinca-90, objavljenoj 28-kolovoza-91; Prijavi No. EP498069, podnijetoj 21-prosinca-90, objavljenoj 12-kolovoza-92; Prijavi No. W09222569, podnijetoj 19-lipnja-91, objavljenoj 23-prosinca-92; Prijavi No. J04297492, podnijetoj 24-listopada-91, objavljenoj 21-listopada-92; Prijavi No. U54997853, podnijetoj 02-prosinca-88, objavljenoj 05-ožujka-91; Prijava No. EP-272929, podnijetoj 24-prosinca-86, objavljenoj 29-lipnja-88; Prijavi No. EP360390, podnijetoj 25-srpnja-88, objavljenoj 28-ožujka-90; Prijavi No. U53862114, podnijetoj 22-studenog-71, objavljenoj 21-siječnja-75; Prijavi No. EP-219258, podnijetoj 30-rujna-85, objavljenoj 22-travnja-87; Prijava No. U54742156, podnijetoj 30-rujna-85, objavljenoj 03-svibnja-88; Prijavi No. EP401177, podnijetoj 29-svibnja-89, objavljenoj 05-prosinca-90; Prijavi No. W09202546, podnijetoj 03-kolovoza-90, objavljenoj 20-veljače-92; Prijavi No. EP-17643fi, podnijetoj 26-rujna-84, objavljenoj 02-travnja-86; Prijavi No. U54680283, podnijetoj 26-rujna-84, objavljenoj 14-srpnja-87; Prijavi No. W09220661, podnijetoj 22-svibnja-91, objavljenoj 26-studenog-92; Prijavi No. EP-520555, podnijetoj 24-lipnja-91, objavljenoj 30-prosinca-92; Prijavi No. EP347802, podnijetoj 20-lipnja-88, objavljenoj 27-prosinca-89; Prijavi No. EP412542, podnijetoj 10-kolovoza-89, objavljenoj 13-veljače-91; Prijavi No. W09005729, podnijetoj 23-studenog-88, objavljenoj 31-svibnja-90; Prijavi No. W09005525, podnijetoj 23-studenog-88, objavljenoj 31-svibnja-90; Prijavi No. EP-436334, podnijetoj 04-siječnja-90, objavljenoj 10-srpnja-91; Prijavi No. W09118878, podnijetoj 31-svibnja-90, objavljenoj 12-prosinca-91; Prijavi W09118899, podnijetoj 01-lipnja-90, objavljenoj 12-prosinca 91; Prijavi No. W09201688, podnijetoj 23-srpnja-90, objavljenoj 06-veljače-92; Prijavi No. W09206079, podnijetoj 28-rujna-90, objavljenoj 16-travnja-92; Prijavi No. W09212152, podnijetoj 03-siječnja-91, objavljenoj 23-srpnja-92; Prijavi No. W09212151, podnijetoj 10-siječnja-91, objavljenoj 23-srpnja-92; WO 9215585, podnijetoj 01-ožujka-91, objavljenoj 29-travnja-92, Prijavi No. W0022-676, podnijetoj 22-svibnja-91, objavljenoj 26-studenog-92; Prijavi No. W09221677, podnijetoj 31-svibnja-91, objavljenoj 10-prosinca-92; Prijavi No. W0930031, podnijetoj 20-lipnja-91, objavljenoj 07-lipnja-93; Prijavi No. W00300330, podnijetoj 21-lipnja-91, objavljenoj 07-siječnja-93; Prijava No. W09109844, podnijetoj 11-srpnja-91, objavljenoj 11-srpnja-91; Prijavi No. EP-429366, podnijetoj 23-studenog-89, objavljenoj 29-svibnja-91; Prijavi No. EP-430771, podnijetoj 23-studenog-89, objavljenoj 05-lipnja-91; Prijavi No. EP-514274, podnijetoj 17-svibnja-91, objavljenoj 19-studenog-92; Prijavi No. EP-514276, podnijetoj 17-svibnja-91, objavljenoj 19-studenog-92; Prijavi No. EP-514275, podnijetoj 17-svibnja-91, objavljenoj 19-studenog-92; Prijavi No. EP-514273, podnijetoj 17-svibnja-91, objavljenoj 19-studenog-92; Prijavi No. EP-428434, podnijetoj 06-studenog-89, objavljenoj 22-svibnja-91; Prijavi No. EP-474561, podnijetoj 09-svibnja-90, objavljenoj 11-ožujka-92; Prijavi EP-512901, podnijetoj 03-svibnja-91, objavljenoj 11-studenog-92; Prijavi No. EP-512902, podnijetoj 03-svibnja-91, objavljenoj 25-studenog-92; Prijavi No. U54472305, podnijetoj 17-svibnja-83, objavljenoj 18-rujna-84; Prijavi No. U54839465, podnijetoj 20- siječnja-87, objavljenoj 13-lipnja-89; Prijavi No. EP-101929, podnijetoj 28- srpnja-82, objavljenoj 07-ožujka-84; Prijavi No. W09102745, podnijetoj 16- kolovoza-89, objavljenoj 07-ožujka-91; Prijavi No. U53912711, podnijetoj 03- srpnja-72, objavljenoj 14-listopada-75; Prijavi No. U54059693, podnijetoj 11- lipnja-76, objavljenoj 22-studenog-77; Prijavi No. U54481139, podnijetoj 13- travnja-83, objavljenoj 06-studenog-84; Prijavi No. U57358073, podnijetoj 24-listopada-88, objavljenoj 19-prosinca-89; Prijavi No. U57261627, podnijetoj 24- listopada-88, objavljenoj 19-prosinca-89; Prijavi No. U57261627, podnijetoj 24- listopada-88, objavljenoj 07-ožujka-89 koje su ovdje inkorporirane referencom. In another alternative embodiment, the compounds of formula I can be co-administered with another NK1 or NK2 as described in Application No. DO-139125, filed 08-Jun-78, published 12-Dec-79; Report No. EP-82568, filed 22-Dec-81, published 29-Jun-83; Report No. EP490379, filed 13-Dec-90 published 17-Jun-92. Report No. EP-353732, filed 05-Aug-88, published 07-Feb-90; Report No. EP161007, filed 13-Jan-84, published 13-Nov-85; Report No. EP385-43, filed 28-Feb-89, published 05-Sep-90; Report No. W08301251, filed 09-Oct-81, published 14-Apr-83; Report No. BE-894602, filed 09-Oct-81, published 31-Jan-83. Report No. DE3205991, filed 19-Feb-82; published 01-Sep-83; Report No. EP327009, filed 02-Feb-88, published 09-Aug-89; Application no. EP336230, filed 05-Apr-88, published 11-Oct-89; Report No. 394989, filed 28-Apr-89, published 31-Oct-90; Report No. AU9068010, filed 22-Dec-89, published 27-Jun-91; Report No. EP482539, filed 24-Oct-90, published 29-Apr-92; Application no. EP443132, filed 10-Dec-90, published 28-Aug-91; Report No. EP498069, filed 21-Dec-90, published 12-Aug-92; Report No. W09222569, filed 19-Jun-91, published 23-Dec-92; Report No. J04297492, filed 24-Oct-91, published 21-Oct-92; Report No. U54997853, filed 02-Dec-88, published 05-Mar-91; Application no. EP-272929, filed 24-Dec-86, published 29-Jun-88; Report No. EP360390, filed 25-Jul-88, published 28-Mar-90; Report No. U53862114, filed 22-Nov-71, published 21-Jan-75; Report No. EP-219258, filed 30-Sep-85, published 22-Apr-87; Application no. U54742156, filed 30-Sep-85, published 03-May-88; Report No. EP401177, filed 29-May-89, published 05-Dec-90; Report No. W09202546, filed 03-Aug-90, published 20-Feb-92; Report No. EP-17643fi, filed 26-Sep-84, published 02-Apr-86; Report No. U54680283, filed 26-Sep-84, published 14-Jul-87; Report No. W09220661, filed 22-May-91, published 26-Nov-92; Report No. EP-520555, filed 24-Jun-91, published 30-Dec-92; Report No. EP347802, filed 20-Jun-88, published 27-Dec-89; Report No. EP412542, filed 10-Aug-89, published 13-Feb-91; Report No. W09005729, filed 23-Nov-88, published 31-May-90; Report No. W09005525, filed 23-Nov-88, published 31-May-90; Report No. EP-436334, filed 04-Jan-90, published 10-Jul-91; Report No. W09118878, filed 31-May-90, published 12-Dec-91; Report W09118899, filed 01-Jun-90, published 12-Dec-91; Report No. W09201688, filed 23-Jul-90, published 06-Feb-92; Report No. W09206079, filed 28-Sep-90, published 16-Apr-92; Report No. W09212152, filed 03-Jan-91, published 23-Jul-92; Report No. W09212151, filed 10-Jan-91, published 23-Jul-92; WO 9215585, filed 01-Mar-91, published 29-Apr-92, Application No. W0022-676, filed 22-May-91, published 26-Nov-92; Report No. W09221677, filed 31-May-91, published 10-Dec-92; Report No. W0930031, filed 20-Jun-91, published 07-Jun-93; Report No. W00300330, filed 21-Jun-91, published 07-Jan-93; Application no. W09109844, filed 11-Jul-91, published 11-Jul-91; Report No. EP-429366, filed 23-Nov-89, published 29-May-91; Report No. EP-430771, filed 23-Nov-89, published 05-Jun-91; Report No. EP-514274, filed 17-May-91, published 19-Nov-92; Report No. EP-514276, filed 17-May-91, published 19-Nov-92; Report No. EP-514275, filed 17-May-91, published 19-Nov-92; Report No. EP-514273, filed 17-May-91, published 19-Nov-92; Report No. EP-428434, filed 06-Nov-89, published 22-May-91; Report No. EP-474561, filed 09-May-90, published 11-Mar-92; Report EP-512901, filed 03-May-91, published 11-Nov-92; Report No. EP-512902, filed 03-May-91, published 25-Nov-92; Report No. U54472305, filed 17-May-83, published 18-Sep-84; Report No. U54839465, filed 20-Jan-87, published 13-Jun-89; Report No. EP-101929, filed 28-Jul-82, published 07-Mar-84; Report No. W09102745, filed 16-Aug-89, published 07-Mar-91; Report No. U53912711, filed 03-Jul-72, published 14-Oct-75; Report No. U54059693, filed 11-Jun-76, published 22-Nov-77; Report No. U54481139, filed 13-Apr-83, published 06-Nov-84; Report No. U57358073, filed 24-Oct-88, published 19-Dec-89; Report No. U57261627, filed 24-Oct-88, published 19-Dec-89; Report No. U57261627, filed 24-Oct-88, published 07-Mar-89 which are incorporated herein by reference.

Spojevi formule I su korisni u prevenciji i tretiranju veoma različitih kliničkih stanja (kao što je detaljno dano u ovoj specifikaciji) koja se karakteriziraju prekomjernom stimulacijom tahikinin receptora, naročito NK1, NK2 i NK3. The compounds of formula I are useful in the prevention and treatment of a wide variety of clinical conditions (as detailed in this specification) characterized by overstimulation of tachykinin receptors, particularly NK1, NK2 and NK3.

Ova stanja mogu obuhvatiti poremećaje centralnog nervnog sustava kao što su anksioznost, depresija, psihoze i shizofrenija; neurodegenerativni poremećaji kao što su SIDI srodna demencija, senilna demencija Alzeheimerovog tipa, Alzeheimerova bolest i Down-sov sindrom; demielinecijske bolesti kao što su multipla skleroza i amiotropna lateralna skleroza i drugi neuropatološki poremećaji kao što je dijabetička i periferalna neuropadija. SIDI srodna neuropatija, kemoterapijom izazvana neuropatija, i neuralgija; respiratorne bolesti, kao što je kronična obstruktivna bolest dišnih puteva, bronhopneumonija, bronhospazam i astma; inflamatorne bolesti kao što je inflamatorna bolest utrobe, psorijaza, fibrozitis, osteoartritis i reumatoidni artritis; alergije kao što su ekcem i rinitis; hipersenzitivni poremećaji kao što je otrovni bršljan; oftalamičke bolesti kao što je konjuktivitis, proljetni konjuktivitis, i slično; kožne bolesti kao što su kontaktni dermatitis, atipični dermatitis, urtikarija, i drugi eksematoidni dermatitis; adikcijski poremećaji (poremećaji navike) kao što je alkoholizam; somatični poremećaji povezani sa stresom; refleksna simpatetična distrofija kao što je rame/ruka sindrom; distimični poremećaji; nepovoljne imunološke reakcije kao što je odbacivanje transplantiranih tkiva, i poremećaji povezani sa imunim povećanjem ili supresijom kao što je sistemski lupus eritematosis; gastrointestinalni (GI) poremećaji i poremećaji GI trakta kao što su poremećaji povezani sa neurološkom kontrolom utrobe, kao što je ulcerativni kolitis, Crohn-ova bolest i inkontinencija; poremećaji funkcije mjehura; bolesti fibroze i kolagena kao što su skleroderma i eosinofilična fascioliaza; poremećaji toka krvi izazvani vazodilatacijom i vazospastične bolesti kao što je angina, migrena i Reynaudova bolest; i bol ili nocicepcija, na primjer, koja se može pripisati na ili je povezana sa bilo kojim od prethodnih stanja, naročito transmisiji bola kod migrene. Stoga se, ovi spojevi lako adaptiraju na terapeutsku upotrebu za tretiranje fizioloških poremećaja povezanih sa prekomjernom stimulacijom receptora tahikinina, naročito NK1, NK2 i NK3. These conditions may include central nervous system disorders such as anxiety, depression, psychoses and schizophrenia; neurodegenerative disorders such as AIDS-related dementia, senile dementia of the Alzheimer type, Alzheimer's disease and Down's syndrome; demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis and other neuropathological disorders such as diabetic and peripheral neuropathy. AIDS-related neuropathy, chemotherapy-induced neuropathy, and neuralgia; respiratory diseases, such as chronic obstructive airways disease, bronchopneumonia, bronchospasm and asthma; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis and rheumatoid arthritis; allergies such as eczema and rhinitis; hypersensitivity disorders such as poison ivy; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like; skin diseases such as contact dermatitis, atypical dermatitis, urticaria, and other eczematoid dermatitis; addictive disorders (habit disorders) such as alcoholism; somatic disorders related to stress; reflex sympathetic dystrophy such as shoulder/arm syndrome; dysthymic disorders; adverse immune reactions such as rejection of transplanted tissues, and disorders associated with immune enhancement or suppression such as systemic lupus erythematosis; gastrointestinal (GI) disorders and disorders of the GI tract such as disorders associated with neurological bowel control, such as ulcerative colitis, Crohn's disease and incontinence; bladder function disorders; fibrosis and collagen diseases such as scleroderma and eosinophilic fascioliasis; blood flow disorders caused by vasodilation and vasospastic diseases such as angina, migraine and Reynaud's disease; and pain or nociception, for example, attributable to or associated with any of the foregoing conditions, particularly migraine pain transmission. Therefore, these compounds are easily adapted to therapeutic use for the treatment of physiological disorders associated with excessive stimulation of tachykinin receptors, especially NK1, NK2 and NK3.

Spojevi prema ovom izumu su naročito pogodni u tretiranju bola ili nocicepcije i/ili inflamaciji i poremećajima povezanim sa ovim kao što su, na primjer: neuropatija, kao što je dijabetička ili periferijalna neuropatija i kemoterapijom izazvana neuropatija; astma; osteoartritis; reumatoidni artritis; i migrena. The compounds of the present invention are particularly useful in the treatment of pain or nociception and/or inflammation and disorders associated therewith such as, for example: neuropathy, such as diabetic or peripheral neuropathy and chemotherapy-induced neuropathy; asthma; osteoarthritis; rheumatoid arthritis; and migraine.

Za tretiranje bilo koje od ovih bolesti, spojevi formule I mogu se primjenjivati oralno, lokalno, parenteralno, ICV, inhalacijom spreja ili rektalno u jediničnim dozama formulacija koje sadrže ne-toksične farmaceutski prihvatljive nosače, adjuvane i prenosioce. Izraz parenteralno, kao što je upotrijebljen ovdje. Obuhvaća subcutane injekcije, intravenske, intramuskularne, intracisternalne injekcije ili infuzione tehnike. Pored tretiranja toplokrvnih životinja kao što su miševi, štakori, konji, stoka, ovce, psi, mačke, itd., spojevi prema ovom izumu su efikasni u tretiranju ljudi. For the treatment of any of these diseases, the compounds of formula I may be administered orally, topically, parenterally, ICV, by inhalation spray or rectally in unit dose formulations containing non-toxic pharmaceutically acceptable carriers, adjuvants and carriers. The term parenteral, as used herein. It includes subcutaneous injections, intravenous, intramuscular, intracisternal injections or infusion techniques. In addition to treating warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, etc., the compounds of this invention are effective in treating humans.

Farmaceutske kompozicije koje sadrže aktivnu komponentu, mogu biti u obliku pogodnom za oralnu upotrebu, na primjer, kao tablete, trošeje, lozenge, vodene ili uljane suspenzije, praškovi koji se mogu dispergirati ili granule, emulzije, tvrde ili meke kapsule, ili sirupi ili eliksiri. Kompozicije namijenjene za oralnu upotrebu mogu se dobiti prema bilo kojem postupku poznatom u tehnici za proizvodnju farmaceutskih kompozicija i takve kompozicije mogu sadržavati jedno ili više sredstava odabranih iz grupe koja se sastoji od sredstava za zaslađivanje, sredstava za davanje ukusa, sredstava za bojenje i konzervansi u cilju da se dobiju farmaceutski elegantni i ukusni preparati. Tablete sadrže aktivnu komponentu u smjesi sa netoksičnim farmaceutski prihvatljivim ekscipijentima koji su pogodni za proizvodnju tableta. Ovi ekscipijenti mogu na primjer, biti inertni razblaživači, kao što su kalcij karbonat, natrij karbonat, laktoza, kalcij fosfat ili natrij fosfat, sredstva za granuliranje i dezintegracijska sredstva, na primjer, kukuruzni škrob, ili alginska kiselina; vezivna sredstva, naprimjer škrob, želatin ili akacija, i sredstva za podmazivanje, na primjer, magnezij stearat, stearinska kiselina ili talk. Tablete mogu biti neobložene ili mogu biti obložene poznatim tehnikama da bi se odložila dezintegracija i apsorpcija u gastrointestinalnom traktu, i da se na taj način osigura neprekidno djelovanje tokom dužeg perioda. Na primjer, mogu se upotrijebiti materijali koji vremenski odlažu djelovanja, kao što su gliceril monostearat ili gliceril distearat. Tablete se mogu obložiti tehnikama opisanim u U.S. Patentima 4,256,108; 4,166,452; i 4,265,874 da bi se dobile osmotske terapeutske tablete sa kontroliranim oslobađanjem. Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. . Compositions intended for oral use may be obtained by any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservatives in with the goal of obtaining pharmaceutical elegant and tasty preparations. Tablets contain the active component in a mixture with non-toxic pharmaceutically acceptable excipients suitable for the production of tablets. These excipients can be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating agents and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, and thus ensure continuous action over a longer period. For example, time-delayed materials such as glyceryl monostearate or glyceryl distearate can be used. Tablets can be coated using techniques described in U.S. Pat. Patents 4,256,108; 4,166,452; and 4,265,874 to provide controlled release osmotic therapeutic tablets.

Formulacije za oralnu upotrebu mogu također biti kao tvrde želatinske kapsule, gdje se aktivna komponenta miješa sa inertnim čvrstim razblaživačem, na primjer, kalcij karbonatom, kalcij fosfatom ili kaolinom, ili kao meke želatinske kapsule gdje se aktivna komponenta pomiješa sa vodenim ili uljanim medijem, na primjer kikiriki uljem, tekućim parafinom, ili maslinovim uljem. Formulations for oral use can also be as hard gelatin capsules, where the active component is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules where the active component is mixed with an aqueous or oily medium, on example with peanut oil, liquid paraffin, or olive oil.

Vodene suspenzije sadrže aktivne materijale u smjesi sa ekscipijentima pogodnim za proizvodnju vodenih suspenzijska sredstva, na primjer natrij suspenzija. Takvi ekscipijenti su karboksimetilceluloza, metilceluloza, hidroksi-propilmetilceluloza, natrij alginat, polivinil-pirolidon, tragakant guma i akacija guma; disperzijska sredstva ili sredstva za kvašenje mogu biti prirodni fosfatidi, na primjer lecitin ili kondenzacijski proizvodi alkilen oksida sa masnim kiselinama, na primjer polioksietilen stearat, ili kondenzacijski proizvodi etilen oksida sa alifatičnim alkoholima dugačkog niza, na primjer heptadekaetilenoksicetanol, ili kondenzacijski proizvodi etilen oksida sa parcijalnim esterima izvedenim iz masnih kiselina i heksitola kao što je polioksietilen sorbitol monooleat, ili kondenzacijski proizvodi etilen oksida sa parcijalnim esterima izvedenim iz masnih kiselina i heksitol anhidrida, na primjer polietilen sorbiton monooleat. Vodene suspenzije mogu također sadržati jedan ili više konzervansa, na primjer etil, ili n-propil, p-hidroksibenzoat, jedno ili više sredstava za bojenje, jedan ili više začina, i jedno ili više sredstava za zaslađivanje, kao što su saharoza ili saharin. Aqueous suspensions contain active materials in admixture with excipients suitable for the production of aqueous suspension agents, for example sodium suspension. Such excipients are carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing agents or wetting agents can be natural phosphatides, for example lecithin or condensation products of alkylene oxides with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example heptadecaethyleneoxyethanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydride, for example polyethylene sorbitol monooleate. Aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more spices, and one or more sweetening agents, such as sucrose or saccharin.

Uljane suspenzije mogu se formulirati suspendiranjem aktivne komponente u biljnom ulju, na primjer arahis ulju, maslinovom ulju, sezamovom ulju ili kokosovom ulju, ili u mineralnom ulju kao što je tekući parafin. Uljane suspenzije mogu sadržavati sredstvo za zgrušnjavanje, na primjer pčelinji vosak, tvrdi parafin ili cetil alkohol. Sredstva za zaslađivanje kao što su ona navedena gore, i začini se mogu dodavati da bi se osigurao ukusan oralni preparat. Ove kompozicije se mogu konzervirati dodatkom anti-oksidanta kao što je askorbinska kiselina. Oil suspensions can be formulated by suspending the active component in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oil suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those listed above, and spices may be added to provide a palatable oral preparation. These compositions can be preserved by the addition of antioxidants such as ascorbic acid.

Praškovi koji se mogu dispergirati i granule pogodni za dobivanje vodene suspenzije dodatkom vode osiguravaju aktivnu komponentu u smjesi sa disperzijskim sredstvom i jednim ili više konzervansa. Pogodna sredstva za dispergiranje ili kvašenje i suspenzijska sredstva su dana primjerima koji su već spomenuti gore. Također mogu biti prisutni dodatni ekscipijenti, na primjer sredstva za zaslađivanje, začini i sredstva za bojenje. Dispersible powders and granules suitable for obtaining an aqueous suspension by the addition of water provide the active component in a mixture with a dispersing agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are given by the examples already mentioned above. Additional excipients may also be present, for example sweetening agents, spices and coloring agents.

Farmaceutske kompozicije prema izumu mogu također biti u obliku ulje-u-vodi emulzijama. Uljana faza može biti biljno ulje, na primjer maslinovo ulje, ili arahinsko ulje, ili mineralno ulje, na primjer tekući parafin ili njihove smjese. Pharmaceutical compositions according to the invention can also be in the form of oil-in-water emulsions. The oily phase can be vegetable oil, for example olive oil, or arachin oil, or mineral oil, for example liquid paraffin or mixtures thereof.

Pogodni emulgatori mogu biti prirodne gume, na primjer akacija guma ili tragakant guma, prirodni fosfatidi, na primjer soja, lecitin, i esteri ili parcijalni esteri izvedeni iz masnih kiselina i heksitol anhidrida, na primjer sorbitan monooleat, i kondenzacijski proizvodi navedenih parcijalnih estera sa etilen oksidom, na primjer polioksietilen sorbitan monooleat. Emulzije mogu sadržati sredstva za zaslađivanje i začine. Suitable emulsifiers can be natural gums, for example gum acacia or gum tragacanth, natural phosphatides, for example soya, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydride, for example sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. Emulsions may contain sweeteners and spices.

Sirupi i eliksiri mogu se formulirati sa sredstvima za zaslađivanje, na primjer glicerin, propilen glikol, sorbit ili saharoza. Takve formulacije mogu također sadržavati sredstvo za umirenje (smanjenje nadražaja), konzervans i sredstva za davanje ukusa i za bojenje. Farmaceutske kompozicije mogu biti u obliku sterilnih injekcijskih vodenih ili uljanih suspenzija. Ova suspenzija može se formulirati prema poznatim tehnikama upotrebljavajući ona pogodna disperzijska sredstva i sredstva za kvašenje i suspenzijska sredstva koja su spomenuta gore. Sterilni injekcijski preparat može također biti sterilna injekcijska otopina ili suspenzija u ne-toksičnom parenteralno prihvatljivom razblaživaču ili otapalu, na primjer kao otopina u 1,3-butan diolu. Među prihvatljivim prenosiocima i otapalima koji se mogu upotrijebiti su voda, Ringer-ova otepina i izotonični natrij kloridna otopina. Pored toga, konvencionalno se upotrebljavaju sterilna neisparljiva ulja, kao otapalo ili suspenzijski medij. U ovu svrhu može se upotrijebiti bilo koja smjesa neisparljivog ulja uključujući sintetske mono- ili digliceride. Pored toga, masne kiseline kao što je oleinska kiselina nalaze primjenu u dobivanju preparata za injekcije. Syrups and elixirs can be formulated with sweetening agents, for example glycerin, propylene glycol, sorbitol or sucrose. Such formulations may also contain a sedative (reduction of irritation), a preservative, and flavoring and coloring agents. Pharmaceutical compositions can be in the form of sterile injectable aqueous or oily suspensions. This suspension may be formulated according to known techniques using those suitable dispersing and wetting agents and suspending agents mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile non-volatile oils are conventionally used as a solvent or suspension medium. Any fixed oil mixture including synthetic mono- or diglycerides can be used for this purpose. In addition, fatty acids such as oleic acid are used in the preparation of injectable preparations.

Spojevi formule I mogu se također primjenjivati u obliku supozitorija za rektalnu primjenu lijeka. Ove kompozicije mogu se dobiti miješanjem lijeka sa pogodnim ne-iritirajućim ekscipijentom koji je čvrst na normalnim temperaturama, ali tekuć na rektalnoj temperaturi i stoga će se otopiti u rektumu, pri čemu se oslobađa lijek. Takvi materijali su kakao maslac i polietilen glikoli. The compounds of formula I can also be administered in the form of suppositories for rectal administration of the drug. These compositions can be obtained by mixing the drug with a suitable non-irritating excipient which is solid at normal temperatures but liquid at rectal temperature and will therefore dissolve in the rectum, releasing the drug. Such materials are cocoa butter and polyethylene glycols.

Za lokalnu upotrebu, upotrebljavaju se kreme, masti, želeji, otopine ili suspenzije, itd. suspenzije, itd., koje sadrže spojeve formule I (Za svrhe ove prijave, lokalna primjena treba obuhvatiti otopine za pranje usta i ispiranje grla). For topical use, creams, ointments, jellies, solutions or suspensions, etc. suspensions, etc., containing compounds of formula I are used (For the purposes of this application, topical application should include mouth washes and gargles).

U tretiranju stanja povezanih sa viškom tahikinina, pogodan nivo doze će uglavnom biti oko 0.001 do 50 mg na kg tjelesne težine pacijenta na dan koja se može primjeniti u jediničnoj ili višestrukoj dozi. Prvenstveno nivo doze će biti oko 0.01 do oko 25 mg/kg na dana; još pogodnije oko 0.05 do oko 10 mg/kg na dan. Pogodan nivo doze može biti oko 0.001 do 25 mg/kg na dan, oko 0.005 do 10 mg/kg na dan, ili oko 0.005 do 5 mg/kg na dan. U ovom području doza može biti 0.005 do 0.05, 0.05 do 0.5 ili 0.5 do 5.0 mg/kg na dan. Spojevi se mogu primjenjivati režimom od 1 do 4 puta na dan, prvenstveno jednom ili dva puta na dan. In the treatment of conditions associated with excess tachykinin, a suitable dosage level will generally be about 0.001 to 50 mg per kg of the patient's body weight per day, which can be administered in single or multiple doses. Primarily the dose level will be about 0.01 to about 25 mg/kg per day; more preferably about 0.05 to about 10 mg/kg per day. A suitable dosage level may be about 0.001 to 25 mg/kg per day, about 0.005 to 10 mg/kg per day, or about 0.005 to 5 mg/kg per day. In this area, the dose can be 0.005 to 0.05, 0.05 to 0.5 or 0.5 to 5.0 mg/kg per day. The compounds can be applied in a regimen of 1 to 4 times a day, preferably once or twice a day.

ANALIZA ANTAGONIZMA TAHIKININA ANALYSIS OF TAHYKININ ANTAGONISM

Spojevi prema ovom izumu su korisni za antagoniziranje tahikinina, naročito supstance P i neurokinina A u tretiranju gastrointestinalnih poremećaja, poremećaja centralnog nervnog sistema, inflamatornih bolesti, bola ili migrene i astme kod sisavaca kome je potreban takav tretman. Ova aktivnost se može prikazati slijedećom analizom. The compounds of this invention are useful for antagonizing tachykinin, especially substance P and neurokinin A in the treatment of gastrointestinal disorders, central nervous system disorders, inflammatory diseases, pain or migraine and asthma in mammals in need of such treatment. This activity can be shown by the following analysis.

A. Ekspresija receptora u COS A. Receptor expression in COS

Da bi se ekspresioniziralo klonirani neurokinin-1-receptor (NK1 R) prijelazno u COS, cDNK za humani NK1 R se klonira u ekspresijski vektor pCDOM9 koji se izvodi iz pCDM8 (INVITROGEN) ubacivanjem rezistentnog gena za ampicilin (nukleotid 1973 do 2964 iz BLUESCRIPT SK+) u Sac II položaj. Transfekcija 20 μg plazmidne DNK u 10 milijuna COS stanica koje se postiže elektroporacijom u 800 μl transfekcijskog pufera (135 mM NaCl, 1.2 mM CaCl2, 1.2 mM MgCl2, 2.4 mM K2HPO4, 0.6 mM KH2PO4, 10 mM glukoze, 10 mM HEPES pH 7.4) na 260 V i 950 uF upotrebljavajući IBI Genezapper (IBI, New Haven, CT). Stanice se inkubiraju u 10% fetalnom telećem serumu, 1 mM glutamina, 100 U/ml penicilina-streptomicina, i 90% DMEM medija (GIBCO, Grand Island, NY) u 5% CO2 na 37°C tri dana prije analize vezivanja. Slični postupci su upotrijebljeni za ekspresioniranje NK2 receptora. To transiently express the cloned neurokinin-1 receptor (NK1 R) in COS, the cDNA for human NK1 R was cloned into the pCDOM9 expression vector derived from pCDM8 (INVITROGEN) by inserting the ampicillin resistance gene (nucleotide 1973 to 2964 from BLUESCRIPT SK+ ) in the Sac II position. Transfection of 20 μg of plasmid DNA into 10 million COS cells is achieved by electroporation in 800 μl of transfection buffer (135 mM NaCl, 1.2 mM CaCl2, 1.2 mM MgCl2, 2.4 mM K2HPO4, 0.6 mM KH2PO4, 10 mM glucose, 10 mM HEPES pH 7.4) at 260 V and 950 uF using an IBI Genezapper (IBI, New Haven, CT). Cells were incubated in 10% fetal calf serum, 1 mM glutamine, 100 U/ml penicillin-streptomycin, and 90% DMEM medium (GIBCO, Grand Island, NY) in 5% CO2 at 37°C for three days prior to binding assay. Similar procedures were used to express the NK2 receptor.

B. Stabilna ekspresija u CHO B. Stable expression in CHO

Da bi se uspostavila stabilna stanična linija koja ekspresionira klonirani humani NF1R, cDNK se subklonira u vektor pRcCMV (INVITROGEN). Transfekcija 20 μg plazmidne DNK u CHO stanice postiže se elektroporacijom u 800 μl transfekcijskog pufera dopunjenog sa 0.625 mg/ml IBI GENEZAPPER (IBI). Transfektirane stanice se inkubiraju u CHO mediju (10% fetalnog telećeg seruma, 100 U/ml penicilina-streptomicina, 2 mM glutamina, 1/500 hipoksantin-timidina (ATCC), 90% IMDM medija (JRH BIOSCIENCES, Lenexa, KS), 0.7 mg/ml g418 (GIBCO) u 5% CO2 na 37°C sve dok kolonije ne postanu vidljive. Svaka kolonija se odvaja i razvija. Stanični klon sa najvišim brojem humanog NK1 R se selektira za naredne primjene kao što je pretraživanje lijeka. To establish a stable cell line expressing the cloned human NF1R, the cDNA was subcloned into the pRcCMV vector (INVITROGEN). Transfection of 20 μg of plasmid DNA into CHO cells is achieved by electroporation in 800 μl of transfection buffer supplemented with 0.625 mg/ml IBI GENEZAPPER (IBI). Transfected cells were incubated in CHO medium (10% fetal calf serum, 100 U/ml penicillin-streptomycin, 2 mM glutamine, 1/500 hypoxanthine-thymidine (ATCC), 90% IMDM medium (JRH BIOSCIENCES, Lenexa, KS), 0.7 mg/ml g418 (GIBCO) in 5% CO2 at 37°C until colonies become visible. Each colony is detached and grown. The cell clone with the highest number of human NK1 R is selected for further applications such as drug discovery.

Slični postupci su upotrebljeni za ekspresioniranje NK2 NK2 receptora. Similar procedures were used to express the NK2 NK2 receptor.

C. Protokol analize koji koristi COS ili CHO C. Analysis protocol using COS or CHO

Analiza vezivanja humanog NK1R ekspresioniranog bilo u COS ili CHO stanicama zasniva se na upotrebi 125l-supstance P(125l-SP, od firme DU PONT, Boston, MA) kao radioaktivno obilježenog liganda, koji se nadmeće sa neobilježenom supstancom P ili bilo kojim drugim ligandom za vezivanje za humani NK1R. Monoslojne stanične kulture COS ili CHO se dislociraju sa neenzimatskom otopinom (SPECIALTY MEDIA, Lavallette, NJ) i ponovno suspendiraju u pogodnoj zapremnini vezujućeg pufera (50 mM Tris pH 7.5, 5 mM MnCl2, 150 mM NaCl, 0.04 mg/ml bacitracina, 0.004 mg/ml leupeptina, 0.02 mg/ml BSA, 0.01 mM fosforamidona) tako da će 200 μl stanične suspenzije dati oko 10,000 cpm specifičnog 125l-SP vezivanja (približno 50,000 do 200,000 stanica). U analizi vezivanja, 500 μl stanica se dodaju u epruvetu koja sadrži 20 μl 1.5 do 0.25 nM 125l-SP i 5 μl neobilježene supstance P ili bilo kojeg drugog test spoja u DMSO. Epruvete se inkubiraju na 4°C ili na sobnoj temperaturi 1 sat uz blago mućkanje. Vezana radioaktivnost se odvaja od nevezane radioaktivnosti pomoću GF/C filtra (BRANDEL, Gaithersurg, MD), koji se prethodno pokvasi sa 0.1 % polietilenimida, Filter se pere sa 3 ml pufera za pranje (50 mM Tris pH 7.5, 5 mM MnCl2, 150 mM NaCl) tri puta i njegova radioaktivnost se određuje gama brojačem. Slična analiza je upotrijebljena za NK2 osim što je 125l-NKA upotrijebljen kao ligand. The binding assay of human NK1R expressed in either COS or CHO cells is based on the use of 125l-substance P (125l-SP, from DU PONT, Boston, MA) as a radiolabeled ligand, which competes with unlabeled substance P or any other ligand. for binding to human NK1R. COS or CHO monolayer cell cultures are dislodged with a nonenzymatic solution (SPECIALTY MEDIA, Lavallette, NJ) and resuspended in a suitable volume of binding buffer (50 mM Tris pH 7.5, 5 mM MnCl2, 150 mM NaCl, 0.04 mg/ml bacitracin, 0.004 mg /ml leupeptin, 0.02 mg/ml BSA, 0.01 mM phosphoramidon) so that 200 μl of cell suspension will give about 10,000 cpm of specific 125 I-SP binding (approximately 50,000 to 200,000 cells). In the binding assay, 500 μl of cells are added to a tube containing 20 μl of 1.5 to 0.25 nM 125l-SP and 5 μl of unlabeled substance P or any other test compound in DMSO. The test tubes are incubated at 4°C or at room temperature for 1 hour with gentle shaking. Bound radioactivity is separated from unbound radioactivity using a GF/C filter (BRANDEL, Gaithersurg, MD), which is pre-wetted with 0.1% polyethyleneimide. The filter is washed with 3 ml of wash buffer (50 mM Tris pH 7.5, 5 mM MnCl2, 150 mM NaCl) three times and its radioactivity is determined with a gamma counter. A similar analysis was used for NK2 except that 125 I -NKA was used as the ligand.

Aktivacija fosfolipaze C pomoću NK1R može se također mjeriti u CHO stanicama koje ekspresioniraju humani NK1R određivanjem akumulacije inozitol monofosfata koji je degradacijski proizvod IP3. CHO stanice se zasijavaju u ploče sa 12 udubljenja pri 250,000 stanica po udubljenju. Poslije inkubacije u CHO mediju 4 dana, stanice se opterećuju sa 0.025 uCi/ml 3H mioinozitola inkubacijom preko noći. Ekstracelularna radioaktivnost se uklanja pranjem sa fosfatom puferiranim slanom otopinom. U udubljenje se dodaje LiCl pri finalnoj koncentraciji od 0.1 mM sa ili bez test spoja, i inkubiranje se nastavlja na 37�C 15 minuta. Dodaje se supstanca P u udubljenje pri finalnoj koncentraciji od 0.3 nM da bi se aktivirao humani NK1R. Poslije 30 minuta inkubacije na 37°C, uklanja se medij i dodaje se 0.1 N HCI. Svako udubljenje se tretira ultrazvukom na 4°C i ekstrahira se sa CHCl3/metanolom (1:1). Vodena faza se nanosi na 1 ml Dowex AG 1 XS iono izmjenjivačku kolonu. Kolona se pere sa 0.1 N mravljom kiselinom, a zatim sa 0.025 M amonij formijatom-0.1 N mravljom kiselinom. Inozitol monofosfat seeluira sa 0.2 M amonij formijatom-0.1 N mravljom kiselinom i određuje se kvantitativno pomoću beta brojača. Slični postupci su upotrebljeni da se odredi antagonizam na NK2 receptor, osim što je NKA upotrijebljen kao stimulacijski agonist. Activation of phospholipase C by NK1R can also be measured in CHO cells expressing human NK1R by determining the accumulation of inositol monophosphate, a degradation product of IP3. CHO cells are seeded in 12-well plates at 250,000 cells per well. After incubation in CHO medium for 4 days, the cells are loaded with 0.025 uCi/ml 3H myoinositol by overnight incubation. Extracellular radioactivity is removed by washing with phosphate buffered saline. LiCl is added to the well at a final concentration of 0.1 mM with or without test compound, and incubation is continued at 37°C for 15 minutes. Substance P is added to the well at a final concentration of 0.3 nM to activate the human NK1R. After 30 minutes of incubation at 37°C, the medium is removed and 0.1 N HCl is added. Each well was sonicated at 4°C and extracted with CHCl3/methanol (1:1). The aqueous phase is applied to a 1 ml Dowex AG 1 XS ion exchange column. The column is washed with 0.1 N formic acid and then with 0.025 M ammonium formate-0.1 N formic acid. Inositol monophosphate is eluted with 0.2 M ammonium formate-0.1 N formic acid and determined quantitatively using a beta counter. Similar procedures were used to determine antagonism at the NK2 receptor, except that NKA was used as the stimulatory agonist.

Spojevi formule I kao što su dani u PRIMJERIMA niže, nađeno je da se premješta radioaktivni ligand za NK-1 receptor, pri području koncentracije od 0.01 nM do 1.0 um, za NK-2 receptor, 0.01 nM do 5 uM, i za NK-3 receptor, 1.0 nM do 10 um. Compounds of formula I as given in the EXAMPLES below were found to displace the radioactive ligand for the NK-1 receptor, at a concentration range of 0.01 nM to 1.0 µM, for the NK-2 receptor, 0.01 nM to 5 µM, and for the NK- 3 receptor, 1.0 nM to 10 um.

Nekoliko postupaka za dobivanje spoja prema izumu ilustrirano je u slijedećim Šemama i Primjerima. Several processes for obtaining the compound of the invention are illustrated in the following Schemes and Examples.

Spojevi prema ovom izumu se dobivaju alkiliranjem azacikličnog spoja 1, gdje je R1 = H, pod pogodnim uvjetima (Šema 1). Potrebni azaciklični spojevi, polazni materijali dobivaju se koristeći postupke opisane u literaturi; kao što je opisano u Ong, H.J. i surad., Journal of Medicinal Chemistry, 1983, 26, 981-986, i Nargund, R. i surad., USSN 08/147,226 (3-studeni, 1993), EP 93309867.5 ovdje inkorporiranih referencom. Ni jedan od spojeva u ovim referencama nije zaštićen kao neurokinin antagonisti neurokinina. The compounds according to this invention are obtained by alkylating the azacyclic compound 1, where R1 = H, under suitable conditions (Scheme 1). The necessary azacyclic compounds, starting materials are obtained using procedures described in the literature; as described in Ong, H.J. et al., Journal of Medicinal Chemistry, 1983, 26, 981-986, and Nargund, R. et al., USSN 08/147,226 (November 3, 1993), EP 93309867.5 incorporated herein by reference. None of the compounds in these references are patented as neurokinin antagonists.

Prema tome, azaciklični spoj 1 (R1 = H) se sjedinjava sa pogodnim aldehidom i intermedijarni imin se reducira do tercijarnog amida, kemijski /na pr. upotrebljavajući natrij cijanoborhidrid) ili katalitički na pr., upotrebljavajući vodik i paladij na ugljenu ili Raney nikl katalizator) (Šema 1). Aldehid, potreban za ovu reakciju može se dobiti postupcima uglavnom poznatim u kemijskoj literaturi; za svrhe ovog izuma, dobivanje reprezentativnih aldehida je opisan u Hale, J.J.; Finke, P.E.; MacCoss, M. Bioorganic & Medicinal Chemistry Letters 1993, 3, 319-322. Accordingly, the azacyclic compound 1 (R1 = H) is combined with a suitable aldehyde and the intermediate imine is reduced to the tertiary amide, chemically/e.g. using sodium cyanoborohydride) or catalytically, for example, using hydrogen and palladium on carbon or a Raney nickel catalyst) (Scheme 1). Aldehyde, required for this reaction can be obtained by procedures mostly known in the chemical literature; for purposes of this invention, the preparation of representative aldehydes is described in Hale, J.J.; Finke, P.E.; MacCoss, M. Bioorganic & Medicinal Chemistry Letters 1993, 3, 319-322.

U jednoj alternativnoj realizaciji ovog izuma, azaciklični spoj 1 (R1 = H) može se alkilirati sa alkil halogenidom ili alkil sulfonatom esterom (sa ili bez dodate baze da se neutralizira mineralna kiselina ili sulfo kiselina, nus proizvodi reakcije), pri čemu se dobiva željeni spoj (Šema 1). Alkil halogenid ili alkil sulfonat potrebni za ovu reakciju, mogu se dobiti postupcima opće poznatim u kemijskoj literaturi; za svrhe ovog izuma aldehid dobiven kao što je prikazano gore, može se reducirati do alkohola sa natrij borhidridom, dizobutilaluminij hidridom ili litij aluminij hidridom, i proizvod, alkohol se konvertira bilo u alkil halogenid koristeći postupke opisane u March J. "Advanced Organic Chemistry", 3-će izd., John Wiley & Sons, New York, str. 382-384 (1985), ili alkil sulfonatni ester koristeći postupke opisane u March J. "Advanced Organic Chemistry, 3-će izd., John Wiley & Sons, New York, str., 444 (1985). In an alternative embodiment of the present invention, the azacyclic compound 1 (R1 = H) can be alkylated with an alkyl halide or alkyl sulfonate ester (with or without added base to neutralize the mineral acid or sulfo acid, non-reaction products), to give the desired compound (Scheme 1). Alkyl halide or alkyl sulfonate required for this reaction can be obtained by procedures generally known in the chemical literature; for the purposes of this invention the aldehyde obtained as shown above can be reduced to the alcohol with sodium borohydride, diisobutylaluminum hydride or lithium aluminum hydride, and the product, the alcohol converted either to an alkyl halide using procedures described in March J. "Advanced Organic Chemistry" , 3rd ed., John Wiley & Sons, New York, p. 382-384 (1985), or an alkyl sulfonate ester using the procedures described in March J. "Advanced Organic Chemistry, 3rd ed., John Wiley & Sons, New York, p. 444 (1985).

U jednoj alternativnoj realizaciji ovog izuma 1 (R1 = H) može se acilirati, pri čemu se dobiva tercijarni amid i zatim se reducira sa jakim redukcijskim sredstvom (npr., diboran uključujući boran dimetilsulfid; i, litij aluminij hidrid), pri čemu se dobiva željeni spoj (Šema 1). Sredstvo za aciliranje potrebno za ovu reakciju može se dobiti postupcima opće poznatim u kemijskoj literaturi; za svrhe ovog izuma, aldehid, dobiven kao što je opisano gore, može se oksidirati upotrebljavajući takve uobičajeno upotrebljavane reagense kao permanganat u kiselini ili srebro oksid, i dobivena kiselina se aktivira kao kiselinski klorid ili mješoviti anhidrid koji se može upotrijebiti da se acilira I (R1 = H). Proizvod, amid može sam i po sebi biti neurokinin antagonist ili se može reducirati sa jakim redukcijskim sredstvom, kao što je diboran ili litij aluminij hidrid, pri čemu se dobiva tercijarni amin. In an alternative embodiment of this invention, 1 (R1 = H) can be acylated, yielding a tertiary amide, and then reduced with a strong reducing agent (eg, diborane including borane dimethylsulfide; and, lithium aluminum hydride), yielding the desired compound (Scheme 1). The acylating agent required for this reaction can be obtained by procedures generally known in the chemical literature; for the purposes of this invention, the aldehyde obtained as described above can be oxidized using such commonly used reagents as permanganate in acid or silver oxide, and the resulting acid activated as an acid chloride or mixed anhydride which can be used to acylate I ( R1 = H). The product amide can be a neurokinin antagonist by itself, or it can be reduced with a strong reducing agent, such as diborane or lithium aluminum hydride, to give a tertiary amine.

Opcijski spoj I tvoren u stupnju alkiliranja može se dalje modificirati u slijedećim reakcijama. U jednoj ilustraciji takvog prilaza, aldehidni fragment sadrži t-butoksikarbonilamino grupu (Primjer 2). Poslije reduktivne aminacije, 1-butoksikarbonil zaštitna grupa se uklanja tretiranjem sa jakom kiselinom kao što je trifluoroctena kiselina ili mravlja kiselina i dobiveni amin se acilira da bi se dobili željeni spojevi (Primjer 3). Alternativno, zaštitna grupa može također biti prisutna u azaciklo dijelu kao što je ilustrirano sa benziloksikarbonil grupom u Primjeru 6. Prema tome, azaciklični spoj koji sadrži benziloksikarbonilindolin (dobiven u Primjeru 4) se alkilira sa aldehidom u prisustvu redukcijskog sredstva. Zatim se uklanja zaštitna grupa da bi se oslobodio slobodan amin (Primjer 7) i amin dalje reagira da bi se dobili dodatni analozi (Primjer 8). The optional compound I formed in the alkylation step can be further modified in the following reactions. In one illustration of such an approach, the aldehyde fragment contains a t-butoxycarbonylamino group (Example 2). After reductive amination, the 1-butoxycarbonyl protecting group is removed by treatment with a strong acid such as trifluoroacetic acid or formic acid and the resulting amine is acylated to give the desired compounds (Example 3). Alternatively, a protecting group may also be present in the azacyclo moiety as illustrated with the benzyloxycarbonyl group in Example 6. Accordingly, an azacyclic compound containing benzyloxycarbonylindoline (obtained in Example 4) is alkylated with an aldehyde in the presence of a reducing agent. The protecting group is then removed to release the free amine (Example 7) and the amine is further reacted to provide additional analogs (Example 8).

ŠEMA 1 SCHEME 1

[image] [image]

U alternativnoj realizaciji ovog izuma, alil kiselina 2 (opisana u Hale i surad; vidjeti gore) može se konvertirati u N-metil metoksi amid 3, koji se zatim tretira sa alkil ili aril metalnim reagensom, na primjer sa metillitijem ili butillitijem, pri čemu se dobiva keton 4 (Šema 2). Keton se može konvertirati u imin koji se tada može reducirati do sekundarnog amina 5, kamijski (na pr., upotrebljavajući natrij cijanoborhidrid ili natrij borhidrid), ili katalitički (na pr. upotrebljavajući vodik i paladij na ugljenu ili Raney nikl katalizator). Aciliranje pod standardnim uvjetima, na primjer sa kiselinskim kloridom, osigurava amid 6. Alil grupa u 6 može se oksidativno cijepati do aldehida 7 sa osmij tetroksidom, a zatim sa natrij perjodatom ili sa ozonom na niskoj temperaturi. Reduktivno aminiranje aldehida 7 sa azacikličnim spojem 1 tada se može izvesti pod uvjetima opisanim gore. In an alternative embodiment of the present invention, the allylic acid 2 (described in Hale et al.; see above) can be converted to the N-methyl methoxy amide 3, which is then treated with an alkyl or aryl metal reagent, for example methyllithium or butyllithium, wherein ketone 4 is obtained (Scheme 2). The ketone can be converted to an imine which can then be reduced to the secondary amine 5, chemically (eg using sodium cyanoborohydride or sodium borohydride), or catalytically (eg using hydrogen and palladium on carbon or Raney nickel catalyst). Acylation under standard conditions, for example with acid chloride, provides amide 6. The allyl group in 6 can be oxidatively cleaved to aldehyde 7 with osmium tetroxide and then with sodium periodate or with ozone at low temperature. Reductive amination of aldehyde 7 with azacyclic compound 1 can then be carried out under the conditions described above.

Supstituirani spiro(indolin-3,4' piperidin) derivati se mogu dobiti kao što je prikazano u Šemi 3 polazeći od pogodno supstituiranih fenilhidrazina. Radeći prema Fischer-ovoj indolnoj reakciji i redukcijom intermetijarnog imina sa blagim redukcijskim sredstvom kao što je natrij borhidrid, dušik indolina može reagirati sa elektrofilom kao što je acil klorid ili sulfonil klorid. Zaštitna grupa, se može ukloniti tretiranjem sa vodikom u prisustvu paladija na ugljenu ili izlaganjem trimetilsilil jodidu, pri čemu se dobiva oslobođen zaštite supstituirani apiro)indolin-3,4' piperidin). Substituted spiro(indoline-3,4' piperidine) derivatives can be prepared as shown in Scheme 3 starting from suitably substituted phenylhydrazines. Working according to the Fischer indole reaction and reducing the intermediate imine with a mild reducing agent such as sodium borohydride, the indoline nitrogen can react with an electrophile such as an acyl chloride or sulfonyl chloride. The protecting group can be removed by treatment with hydrogen in the presence of palladium on charcoal or by exposure to trimethylsilyl iodide, whereby a deprotected substituted apiro)indoline-3,4' piperidine is obtained.

ŠEMA 2 SCHEME 2

[image] [image]

ŠEMA 3 SCHEME 3

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Dobivanje spiro(2,3-dihidrobenzotiofen-3,4'-piperidin) derivata prikazano je u Šemi 4. Reakcija N-Boc zaštićenog 4-piperidona sa litijevom soli metil fenil sulfoksida a zatim bazom posredovano eliminacijsko premještanje i bazno osiguranje navedeni alilni alkohol. Alkohol se može konvertirati u premješteni alilni klorid sa tionil kloridom u toluolu u prisustvu 2,6- lutidina kao skupljača protona. Premještanje klorida sa funkcionaliziranim 2-bromtiofenolom osigurava alilni sulfid, koji se može ciklizirati pod radikalnim uvjetima, pri čemu se dobiva ilustrirani spiro(2,3-dihidrobenzotiofen-3,4'-piperidin). Cijepanje tbutoksikarbonil grupe pod standardnim uvjetima, kao što je trifluoroctena kiselina, tada osigurava željeni spirociklični spoj. Obtaining the spiro(2,3-dihydrobenzothiophene-3,4'-piperidine) derivative is shown in Scheme 4. Reaction of N-Boc protected 4-piperidone with the lithium salt of methyl phenyl sulfoxide followed by base-mediated elimination displacement and base securing of the mentioned allylic alcohol. The alcohol can be converted to the displaced allyl chloride with thionyl chloride in toluene in the presence of 2,6-lutidine as a proton collector. Displacement of the chloride with a functionalized 2-bromothiophenol affords the allylic sulfide, which can be cyclized under radical conditions to give the illustrated spiro(2,3-dihydrobenzothiophene-3,4'-piperidine). Cleavage of the t-butoxycarbonyl group under standard conditions, such as trifluoroacetic acid, then provides the desired spirocyclic compound.

ŠEMA 4 SCHEME 4

[image] [image]

Spiro(2,3-dihidrobenzofuran-3,4'-piperidin) derivati mogu se dobiti kao što je ilustrirano u Šemi 5. Tretiranje pogodno supstituiranog estera 2-fluorofenilacetata sa mekloretamin hidrokloridom pod baznim uvjetima osigurava piperidinski proizvod, koji tretiranjem sa jakim redukcijskim sredstvom kao što je litij aluminij hidrid daje odgovarajući 4-(hidroksimetil) spoj. Ciklizacija sa bazom osigurava benzofuran derifat, a cijepanje N-metil grupe se tada može izvršiti upotrebljavajući 1-kloretil klorformijat ili drugo pogodno N-demetilirajuće sredstvo. Spiro(2,3-dihydrobenzofuran-3,4'-piperidine) derivatives can be obtained as illustrated in Scheme 5. Treatment of an appropriately substituted 2-fluorophenylacetate ester with mechlorethamine hydrochloride under basic conditions affords the piperidine product, which upon treatment with a strong reducing agent such as lithium aluminum hydride gives the corresponding 4-(hydroxymethyl) compound. Cyclization with a base affords the benzofuran derivative, and cleavage of the N-methyl group can then be accomplished using 1-chloroethyl chloroformate or another suitable N-demethylating agent.

ŠEMA 5 SCHEME 5

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Spojevi sa alternativnim rasporedima amidne veze mogu se dobiti kao što je prikazano u Šemi 6. Ilustrirana kiselina može se homologirati pod ArndtEistert uvjetima, pri čemu se dobiva kiselina sa produženim lancem, koja se može derivatizirati pod standardnim uvjetima aciliranja sa, na primjer, anilin derivatom, pri čemu se dobiva odgovarajući amid. Oksidativno cijepanje olefina sa osmij tetroksidom ili ozonom tada osigurava aldehidni intermedijar pogodan zakupliranje kao što je ranije opisano. Compounds with alternative arrangements of the amide bond can be obtained as shown in Scheme 6. The illustrated acid can be homologated under ArndtEistert conditions, yielding an extended-chain acid, which can be derivatized under standard acylation conditions with, for example, an aniline derivative , whereby the corresponding amide is obtained. Oxidative cleavage of the olefin with osmium tetroxide or ozone then provides an aldehyde intermediate suitable for coupling as described earlier.

ŠEMA 6 SCHEME 6

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Pored toga ketonski derivati mogu se dobiti proširivanjem kemije date gore, kao što je prikazano u Šemi 7. Drugo Arndt-Eistert produžavanje landa osigurava prikazani derivat heptenske kiseline, koji poslije konverzije u njegov N-metoksi-N-metil amid, može reagirati sa aril organometalnim reagensom, kao što je aril magnezij bromid, pri čemu se dobiva keton. Tada, rutinsko oksidativno cijepanje daje željeni aldehid, koji se može kuplirati sa spiropiperidin derivatom kao što je opisano gore. In addition, ketone derivatives can be obtained by extending the chemistry given above, as shown in Scheme 7. A second Arndt-Eistert extension of the land provides the shown heptenoic acid derivative, which, after conversion to its N-methoxy-N-methyl amide, can react with aryl with an organometallic reagent, such as aryl magnesium bromide, yielding a ketone. Then, routine oxidative cleavage affords the desired aldehyde, which can be coupled to the spiropiperidine derivative as described above.

ŠEMA 7 SCHEME 7

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Alkohol koji sadrži antagoniste može se dobiti prema postupcima danim u Šemi 8. Tvorba N-metil-N-metoksi amida prikazane kiseline, a zatim oksidativno cjepanje olefina osigurava intermedijarni aldehid. Kupliranje sa spiro(indolin-3,4'-piperidin) derivatom, a zatim adicijom organometalnog reagensa na amid, osigurava prikazani keton. Tretiranje sa hidridnim redukcijskim sredstvom, kao što je natrij borhidrid, tada daje željene alkoholne derivate. An alcohol containing antagonists can be obtained according to the procedures given in Scheme 8. Formation of the N-methyl-N-methoxy amide of the acid shown, followed by oxidative cleavage of the olefin provides the intermediate aldehyde. Coupling with a spiro(indoline-3,4'-piperidine) derivative, followed by addition of an organometallic reagent to the amide, provides the shown ketone. Treatment with a hydride reducing agent, such as sodium borohydride, then gives the desired alcohol derivatives.

ŠEMA 8 SCHEME 8

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Tvorba heterociklično supstituiranih antagonista može se izvršiti prema postupku danom u Šemi 9 za supstituirane imidazole. Redukcija alil kiseline sa jakim redukcijskim sredstvom kao što je litij aluminij hidrid, a zatim tvorbom in situ trifluorometansulfonata tvorenog alkohola omogućava premještanje triflata sa nukleofilom kao što je 2-fenilimidazol. Oksidativno cijepanje pod standardnim uvjetima osigurava prikazani aldehid koji se tada može kuplirati pod uvjetima opisanim gore do pogodnog spiro derivata. The formation of heterocyclic substituted antagonists can be carried out according to the procedure given in Scheme 9 for substituted imidazoles. Reduction of the allyl acid with a strong reducing agent such as lithium aluminum hydride, followed by in situ formation of the trifluoromethanesulfonate of the formed alcohol, enables displacement of the triflate with a nucleophile such as 2-phenylimidazole. Oxidative cleavage under standard conditions provides the aldehyde shown which can then be coupled under the conditions described above to the appropriate spiro derivative.

ŠEMA 9 SCHEME 9

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Spiro(2-okso-1,2,3,4-tetrahidrohinolin-4,4'-piperidin) i spiro(1-okso-1,2,3,4,tetrahidroizohinolin-4,4'piperidin) mogu se dobiti kao što je prikazano u Šemi 10. Polazeći od prikazanog spiro(2-oksoindan-3,4'-piperidina (opisanog u Cleremon, D.A. i surad., European Patent 0 431 943 943 A2, Evans, B.E. i surad., U.S. Patent 4,420,485 koji su svi inkorporirani referencom, i Parham i surad., Journal of Organic Chemistry, 41 2628 (1976) oslobađanje od zaštite dušika piperidina izvodi se tretiranjem sa kiselinom, na primjer trifluoroctenom kiselinom, a zatim zaštitom kao trifluoracetamid, i proizvod se izlaže dušikovodičnoj kiselini u prisustvu sumporne kiseline. Zagrijavanje ove smjese izaziva Schmidt-ovo premještanje, pri čemu se dobivaju i tetrahidrohinolin i tetrahidroizohinolin derivati. Ovi spiro spojevi mogu se dana odvojiti i kuplirati na funkcionalizirane aldehide metodologijom danom gore. Spiro(2-oxo-1,2,3,4-tetrahydroquinoline-4,4'-piperidine) and spiro(1-oxo-1,2,3,4,tetrahydroisoquinoline-4,4'piperidine) can be obtained as as shown in Scheme 10. Starting from the shown spiro(2-oxoindane-3,4'-piperidine (described in Cleremon, D.A. et al., European Patent 0 431 943 943 A2, Evans, B.E. et al., U.S. Patent 4,420,485 all of which are incorporated by reference, and Parham et al., Journal of Organic Chemistry, 41 2628 (1976) deprotection of the piperidine nitrogen is accomplished by treatment with an acid, for example trifluoroacetic acid, followed by protection as trifluoroacetamide, and the product is exposed to hydrochloric acid in the presence of sulfuric acid. Heating this mixture causes a Schmidt shift, yielding both tetrahydroquinoline and tetrahydroisoquinoline derivatives. These spiro compounds can be isolated and coupled to functionalized aldehydes by the methodology given above.

ŠEMA 10 SCHEME 10

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Neurokinin antagonisti sa bilo kojim supstituentima mogu se također dobiti na način prikazan u Šemi 11. Prema tome, alil kiselina prodiskutirana ranije može se reducirati u odgovarajući alkohol sa, na primjer, litij aluminij hidridom. Ovaj alkohol može se alkilirati pomoću Williamson-ove etarske sinteze, deprotonacijom sa jakom bazom kao što je natrij hidrid ili natrij heksametildisiazid a zatim reakcijom sa benzil halogenidom kao što je benzil bromid. Proizvod se može obraditi preko stupnjeva oksidativnog cijepanja opisanih ranije, pri čemu se osigurava aldehid koji se dana može kuplirati sa spirocikl kunder reduktivnim uvjetima aminacije ili drukčije redukcijom u odgovarajući alkohol i konverzijom u bromid, bromid se tada može upotrijebiti da se alkilira spirociklično spoj pod uvjetima detaljno opisanim gore. Neurokinin antagonists with any substituents can also be prepared as shown in Scheme 11. Accordingly, the allyl acid discussed earlier can be reduced to the corresponding alcohol with, for example, lithium aluminum hydride. This alcohol can be alkylated using the Williamson ether synthesis, deprotonation with a strong base such as sodium hydride or sodium hexamethyldisiazide and then reaction with a benzyl halide such as benzyl bromide. The product can be processed via the oxidative cleavage steps described earlier, providing the aldehyde which can then be coupled to the spirocycle under reductive amination conditions or alternatively by reduction to the corresponding alcohol and conversion to the bromide, the bromide can then be used to alkylate the spirocycle under conditions described in detail above.

ŠEMA 11 SCHEME 11

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Prema tome, u jednom drugom aspektu izum obuhvaća postupak za dobivanje spoja formule I Accordingly, in another aspect, the invention includes a process for obtaining a compound of formula I

[image] [image]

kao što je definirana gore, koji obuhvaća stupnjeve: as defined above, which includes degrees:

(a) reakciju spoja formule A (a) reaction of a compound of formula A

[image] [image]

u pogodnom otapalu kao što je acetonitril ili dimetilacetimid sa spojem formule R1-X1 gdje je X1 grupa koja se udaljava kao što je brom (bromo, klor (kloro), tozil ili mezil opcijski u prisustvu pogodne baze kao što je trialkilamin; ili in a suitable solvent such as acetonitrile or dimethylacetimide with a compound of formula R1-X1 where X1 is a leaving group such as bromo (bromo, chloro(chloro), tosyl or mesyl optionally in the presence of a suitable base such as trialkylamine; or

(b) reakciju spoja formule A u drugom pogodnom otapalu kao što je metanol ili etanol sa spojem formule R-CH(O), gdje je R-CH2 = R1 kao što je definirano gore, u prisustvu redukcijskog sredstva kao što je natrij cijanoborhidrid ili vodik i paladij na ugljenu kao katalizator; ili (b) reacting a compound of formula A in another suitable solvent such as methanol or ethanol with a compound of formula R-CH(O), where R-CH2 = R1 as defined above, in the presence of a reducing agent such as sodium cyanoborohydride or hydrogen and palladium on coal as a catalyst; or

(c) c) reakciju spoja formule A u halogenougljikovodičnom otapalu kao što je metilen klorid sa spojem formule R-C(O)X2 gdje je X pogodna grupa koja se udaljava kao što je brom (bromo) ili klor (kloro) u prisustvu pogodne baze kao što je trialkilamin, (c) c) reaction of a compound of formula A in a halogenated hydrocarbon solvent such as methylene chloride with a compound of formula R-C(O)X2 where X is a suitable leaving group such as bromine (bromo) or chlorine (chloro) in the presence of a suitable base as what is trialkylamine

pri čemu se dobiva spoj formule I. whereby the compound of formula I is obtained.

Primjer 1 Example 1

3-(S)-(3,4-diklorofenil)-4-(N-(t-butoksikarbonil)metilamino)butanal 3-(S)-(3,4-dichlorophenyl)-4-(N-(t-butoxycarbonyl)methylamino)butanal

Otopina od 10 g (41 mmola) 3-(S)-(3,4-diklorofenil)-4-metilamino-1-pentena u 100 ml CH2Cl2 ohladi se u kupaonici sa ledom i tretira se sa 5.8 ml (41 mmola) trietilamina (Et3N) i 9 g (41 mmola) di-t-butil dikarbonata. Hladna kupaonica se uklanja poslije 5 minuta i miješanje se nastavlja 1 sat. Reakcijska smjesa se razblažuje sa CH2Cl2 i pere se sa vodom, 1.2 N HCl, zasićenom otopinom NaHCO3 i slanom otopinom. Otopina se suši preko Na2SO4 i koncentrira, pri čemu se dobiva 14.58 preostalog ulja. A solution of 10 g (41 mmol) of 3-(S)-(3,4-dichlorophenyl)-4-methylamino-1-pentene in 100 ml of CH2Cl2 is cooled in an ice bath and treated with 5.8 ml (41 mmol) of triethylamine. (Et3N) and 9 g (41 mmol) of di-t-butyl dicarbonate. The cold bath is removed after 5 minutes and mixing is continued for 1 hour. The reaction mixture is diluted with CH2Cl2 and washed with water, 1.2 N HCl, saturated NaHCO3 solution and brine. The solution is dried over Na2SO4 and concentrated to give 14.58 g of residual oil.

1H NMR (CDCl3 ppm granice su date zbog rotomjera amida i širenja linije) 1.36 (s, 9H), 2.33 (m, 2H), 2.60 & 2.70 (2s, 3H), 2.8-3.6 (m, 3H), 4.94 (m, 2H), 5.59 (m, 1H), 6.9-7.4 (m, 3H). 1H NMR (CDCl3 ppm limits given due to amide rotometer and line broadening) 1.36 (s, 9H), 2.33 (m, 2H), 2.60 & 2.70 (2s, 3H), 2.8-3.6 (m, 3H), 4.94 (m , 2H), 5.59 (m, 1H), 6.9-7.4 (m, 3H).

Ostatak se otapa u 80 ml acetona, 40 ml t-butanola i 40 ml vode. U ovu otopinu se dodaje 1 ml osmij tetroksida (4% otopina u vodi) i 5.15 g (44 mmola) 4-metilmorfolin N-oksida. Poslije miješanja u toku 26 sati, reakcija se zaustavlja sa približno 5 g Na2SO3 i koncentrira se do 25% od originalne zapremnine. Ostatak se raspodjeljuje između vode i 1:1 etera (Et2O), etil acetata (EtOAc), i slojevi se odvajaju i vodeni sloj se ekstrahira sa Et21O:EtOAc. Svaki organski sloj se pere sa vodom, slanom otopinom i suši se filtriranjem kroz Na2SO4. Filtrat se koncentrira, pri čemu se dobiva sirovi diol. The residue is dissolved in 80 ml of acetone, 40 ml of t-butanol and 40 ml of water. 1 ml of osmium tetroxide (4% solution in water) and 5.15 g (44 mmol) of 4-methylmorpholine N-oxide are added to this solution. After stirring for 26 hours, the reaction is stopped with approximately 5 g of Na2SO3 and concentrated to 25% of the original volume. The residue was partitioned between water and 1:1 ether (Et2O), ethyl acetate (EtOAc), and the layers were separated and the aqueous layer was extracted with Et21O:EtOAc. Each organic layer is washed with water, brine and dried by filtration through Na2SO4. The filtrate is concentrated to give the crude diol.

Otopina diola u 120 ml tetrahidrofurana (THF) i 40 ml vode tretira se sa 9.42 g (44 mmola) natrij perjodata. Poslije miješanja u toku 2 sata, reakcija se razblažuje sa Et2O:EtOAc i pere se sa vodom i slanom otopinom. Organski sloj se suši (Na2SO4) i filtrat se koncentrira. Ostatak se pročišćava preparativnom kromatografijom upotrebljavajući 30% EtOAc/heksan da bi se dobilo 11.74 g (83% prinos za tri stupnja) naslovnog spoja u obliku gustog ulja. A solution of the diol in 120 ml of tetrahydrofuran (THF) and 40 ml of water is treated with 9.42 g (44 mmol) of sodium periodate. After stirring for 2 hours, the reaction was diluted with Et2O:EtOAc and washed with water and brine. The organic layer is dried (Na2SO4) and the filtrate is concentrated. The residue was purified by preparative chromatography using 30% EtOAc/hexane to give 11.74 g (83% yield over three steps) of the title compound as a thick oil.

1H NMR (CDCl3, ppm granice su date zbog rotamera amida i širenja linije) δ 1.38 (s, 9H), 2.69 & 2.75 (2s, 3H), 2.6-3.65 (m, 5H), 6.95-7.4 (m, 3H), 9.67 (s, 1H). 1H NMR (CDCl3, ppm limits given due to amide rotamer and line broadening) δ 1.38 (s, 9H), 2.69 & 2.75 (2s, 3H), 2.6-3.65 (m, 5H), 6.95-7.4 (m, 3H) , 9.67 (s, 1H).

Primjer 2 Example 2

1'-(3-(S)-(3,4-diklorofenil)-4-(N-t-butoksikarbonil)-(metilamino))butil-1-metansulfonilspiro(indolin-3,4'-piperidin) 1'-(3-(S)-(3,4-dichlorophenyl)-4-(N-t-butoxycarbonyl)-(methylamino))butyl-1-methanesulfonylspiro(indoline-3,4'-piperidine)

U otopinu od 0.76 g (2.2 mmola) 3-(S)-(3,4-diklorofenil)-4-(N-(t-butoksikarbonil)-metilamino)butanala (iz Primjera 1) u ml metanola, dodaje se 0.608 g (2 mmola) 1-metan-sulfonil-spiro(indolin- 3,4'-piperidin) hidroklorida i 0.6 g sprašenih 4 A molekularnih sita. Poslije 15 minuta dodaje se ukapavanjem otopina od 0.554 g (8.8 mmola) NaCNBH3 u 8 ml THF. Promatrano je nešto razvijanja plina. Poslije 2 sata kada je reakcija završena, određeno pomoću TLC (tankoslojne kromatografije), smjesa se filtrira kroz sloj celita, reakcijski balon i sloj celita se ispiru sa metanolom. Filtrat se koncentrira do približno 5 ml i ostatak se raspodjeljuje između zasićenih otopina NaHCO3 i Et2:EtOAc. Organski sloj se pere sa vodom, slanom otopinom i suši preko Na2SO4. Filtrat se koncentrira i ostatak se kromatografira na fleš koloni upotrebljavajući gradijent od 49:49;2 do 74:24:2 EtOAc:heksan:trietilamin pri čemu se dobiva 0.94 g (72%) naslovnog spoja u obliku pjene. In a solution of 0.76 g (2.2 mmol) of 3-(S)-(3,4-dichlorophenyl)-4-(N-(t-butoxycarbonyl)-methylamino)butanal (from Example 1) in ml of methanol, add 0.608 g (2 mmol) of 1-methane-sulfonyl-spiro(indoline-3,4'-piperidine) hydrochloride and 0.6 g of powdered 4 A molecular sieves. After 15 minutes, a solution of 0.554 g (8.8 mmol) of NaCNBH3 in 8 ml of THF is added dropwise. Some gas evolution was observed. After 2 hours when the reaction is complete, as determined by TLC (thin layer chromatography), the mixture is filtered through a pad of celite, the reaction flask and the pad of celite are washed with methanol. The filtrate was concentrated to approximately 5 ml and the residue was partitioned between saturated NaHCO 3 and Et 2 :EtOAc solutions. The organic layer is washed with water, brine and dried over Na2SO4. The filtrate was concentrated and the residue was chromatographed on a flash column using a gradient of 49:49:2 to 74:24:2 EtOAc:hexane:triethylamine to give 0.94 g (72%) of the title compound as a foam.

1H NMR (CDCl3), ppm granice su date zbog rotamera amida i širenja linije) δ 1.37 (s, 9H), 1.6-3.6 (m, 15H), 2.61 & 2.72 (2s, 3H), 2.86 (s, 3H), 3.74 (s, 2H), 6.95-7.4 (m, 7H). 1H NMR (CDCl3), ppm limits given due to amide rotamer and line broadening) δ 1.37 (s, 9H), 1.6-3.6 (m, 15H), 2.61 & 2.72 (2s, 3H), 2.86 (s, 3H), 3.74 (s, 2H), 6.95-7.4 (m, 7H).

Primjer 3 Example 3

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil)-1-metansulfonil-spiro(indolin-3,4' 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)-1-methanesulfonyl-spiro(indoline-3,4 '

-piperidin) -piperidine)

Stupanj A: Grade A:

1,3(3-((S)-(3,4-diklorofenil))-4-(metilamino)-butil)-1-metansulfonil-spiro(indolin-3,4'-piperidin) 1,3(3-((S)-(3,4-dichlorophenyl))-4-(methylamino)-butyl)-1-methanesulfonyl-spiro(indoline-3,4'-piperidine)

Hladna trifluorooctena kiselina (TFA, 4 ml) i 0.2 ml anizola se dodaju u 0.94 g (1.57 mmola) 1'-(3-(S)-(3-4-diklorofenil)-4- (N-(t-butoksikarbonil)(metilamino))butil)-1-metansulfonil-spiro(indolin-3,4'-piperidina) i smjesa se u kupaonici s ledom sve dok se ne otopi sva pjena. Poslije miješanja smjese na sobnoj temperaturi u toku 30 minuta, ona se koncentrira u vakuumu. Ostatak se raspodjeljuje između 0.5 N NaOH i CH2Cl2 i odvoje se slojevi. Organski sloj se pere sa slanom otopinom, suši preko Na2SO4 i koncentrira, pri čemu se dobiva 0.7 g pjene koja se upotrebljava u slijedećem stupnju bez pročišćavanja. Cold trifluoroacetic acid (TFA, 4 ml) and 0.2 ml of anisole were added to 0.94 g (1.57 mmol) of 1'-(3-(S)-(3-4-dichlorophenyl)-4-(N-(t-butoxycarbonyl) (methylamino)butyl)-1-methanesulfonyl-spiro(indoline-3,4'-piperidine) and mixed in an ice bath until all the foam had dissolved. After stirring the mixture at room temperature for 30 minutes, it is concentrated in a vacuum. The residue is partitioned between 0.5 N NaOH and CH2Cl2 and the layers are separated. The organic layer is washed with brine, dried over Na2SO4 and concentrated, whereby 0.7 g of foam is obtained, which is used in the next step without purification.

1H NMR (CDCl3, ppm granice su date zbog rotomera amida i širenja linije) δ 1.7-2.7 (m, 10H), 2.64 (s, 3H), 2.88 (s, 3H), 2.9-3.4 (m, 5H), 3.70 (s, 2H), 6.8-7.4 (m, 7H). 1H NMR (CDCl3, ppm limits given due to amide rotomer and line broadening) δ 1.7-2.7 (m, 10H), 2.64 (s, 3H), 2.88 (s, 3H), 2.9-3.4 (m, 5H), 3.70 (s, 2H), 6.8-7.4 (m, 7H).

Stupanj B: Grade B:

-piperidin) -piperidine)

Otopina od 0.12 g (0.52 mmola) 3,5-dimetilbenzoeve kiseline u 2 ml CH2Cl2 koji sadrži 1 kap DMF tretira se sa 85 μl oksalil klorida. (Pažnja razvijanje plina). Poslije 20 minuta otopina se koncentrira u vakuumu i ostatak se pomiješa sa 0.2 g (0.4 mmola) 1'-(3-((S)-(3,4-diklorofenil))-4-(metilamino)butil)-1-metan-sulfonil-spiro-(indolin-3,4'-piperidina) dobivenog iz Stupnja A, i 0.14 ml (1 mmola) Et3N u 2 ml CH2Cl2. Poslije 1 sata, reakcijska smjesa se razblažuje sa CH2Cl2 i pere se sa zasićenom otopinom NaHCO3, vodom, i slanom otopinom. A solution of 0.12 g (0.52 mmol) of 3,5-dimethylbenzoic acid in 2 ml of CH2Cl2 containing 1 drop of DMF is treated with 85 μl of oxalyl chloride. (Caution gas evolution). After 20 minutes, the solution was concentrated in vacuo and the residue was mixed with 0.2 g (0.4 mmol) of 1'-(3-((S)-(3,4-dichlorophenyl))-4-(methylamino)butyl)-1-methane. -sulfonyl-spiro-(indoline-3,4'-piperidine) obtained from Step A, and 0.14 ml (1 mmol) of Et3N in 2 ml of CH2Cl2. After 1 hour, the reaction mixture was diluted with CH2Cl2 and washed with saturated NaHCO3 solution, water, and brine.

CH2Cl2 otopina se suši preko Na2SO4, filtrira i koncentrira. Pročišćavanjem ostatka pomoću preparativne TLC (tankoslojne kromatografije) upotrebljavajući 2% Et3N/EtOAc dobiva se 0.238 g (93% prinos) naslovnog spoja u obliku pjene. 1H NMR (CDCl3, ppm granice su date zbog rotamera amida i širenja linije) δ 1.6-2.4 (m, 10H), 2.27 (s, 6H), 2.6-3.9 (m, 10H), 2.86 (s, 3H), 6.6-7.5 (m, 10H). The CH2Cl2 solution is dried over Na2SO4, filtered and concentrated. Purification of the residue by preparative TLC (thin layer chromatography) using 2% Et3N/EtOAc gave 0.238 g (93% yield) of the title compound as a foam. 1H NMR (CDCl3, ppm limits given due to amide rotamer and line broadening) δ 1.6-2.4 (m, 10H), 2.27 (s, 6H), 2.6-3.9 (m, 10H), 2.86 (s, 3H), 6.6 -7.5 (m, 10H).

Slijedeći spojevi se dobivaju zamjenjujući 3,5-dimetilbenzoil klorid u Stupnju B sa željenim kloridom kiseline. The following compounds are obtained by replacing 3,5-dimethylbenzoyl chloride in Step B with the desired acid chloride.

1'-(3-((S)-(3,4-diklorofenil))-4-(N-(benzoil)(metilamino))-butil)-1-metansulfonil-spiro(indolin-3,4'-piperidin). 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(benzoyl)(methylamino))-butyl)-1-methanesulfonyl-spiro(indoline-3,4'-piperidine ).

Maseni spektar (FAB) 602 (37Cl+35Cl izotop), 600 (35Cl+35Cl izotop). Mass spectrum (FAB) 602 (37Cl+35Cl isotope), 600 (35Cl+35Cl isotope).

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-3,5-bistrifluorometilbenzoil)(metilamino))butil)-1-metansulfonil-spiro(indolin-3,4'-piperidin). 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-3,5-bistrifluoromethylbenzoyl)(methylamino))butyl)-1-methanesulfonyl-spiro(indoline-3,4' -piperidine).

Maseni spektar (FAB) 738 (37Cl + 35Cl izotop), 746 (35Cl + 35Cl izotop). Mass spectrum (FAB) 738 (37Cl + 35Cl isotope), 746 (35Cl + 35Cl isotope).

1'(3-((S)-(3,4-Diklorofenil))-4-(N-(3-metilbenzoil)(metilamino))-butil)-1-metansulfonil- spiro(indolin-3,4'-piperidin). 1'(3-((S)-(3,4-Dichlorophenyl))-4-(N-(3-methylbenzoyl)(methylamino))-butyl)-1-methanesulfonyl- spiro(indoline-3,4'- piperidine).

1H NMR (CDCl3, ppm granice su date zbog rotamera amida i širenja linije) δ 1.6-2.4 (m, 10H), 2.32 (s, 3H), 2.6-3.9 (m, 10H), 2.86 (s, 3H), 6.75-7.5 (m, 11H). 1H NMR (CDCl3, ppm limits given due to amide rotamers and line broadening) δ 1.6-2.4 (m, 10H), 2.32 (s, 3H), 2.6-3.9 (m, 10H), 2.86 (s, 3H), 6.75 -7.5 (m, 11H).

Maseni spektar (FAB) 616 (37CI + 35Cl izotop), 614 (35Cl + 35Cl izotop). Mass spectrum (FAB) 616 (37Cl + 35Cl isotope), 614 (35Cl + 35Cl isotope).

1'-(3-((S)-(3,4-Diklorofenil)-4-(N-(3-klorobenzoil)(metilamino))-butil)-1-metansulfonil-spiro(indolin-3,4'-piperidin). 1'-(3-((S)-(3,4-Dichlorophenyl)-4-(N-(3-chlorobenzoyl)(methylamino))-butyl)-1-methanesulfonyl-spiro(indoline-3,4'- piperidine).

1H NMR (CDCl3. ppm granice su date zbog rotamera amida i širenja linije) δ 1.6-2.4 (m, 10H), 2.6-3.9 (m, 10H), 2.86 (s, 3H), 6.75-7.5 (m, 11H). Maseni spektar (FAB) 635 1H NMR (CDCl3. ppm limits given due to amide rotamers and line broadening) δ 1.6-2.4 (m, 10H), 2.6-3.9 (m, 10H), 2.86 (s, 3H), 6.75-7.5 (m, 11H) . Mass spectrum (FAB) 635

37Cl + 35Cl izotop), 633 (35Cl + 35Cl izotop). 37Cl + 35Cl isotope), 633 (35Cl + 35Cl isotope).

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(3-trifluorometilbenzoil)(metilamino))butil)-1-metansulfonil-spiro(indolin-3,4'-piperidin). 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(3-trifluoromethylbenzoyl)(methylamino))butyl)-1-methanesulfonyl-spiro(indoline-3,4'- piperidine).

Maseni spektar (FAB) 669 (37Cl + 35Cl izotop), 667 (35Cl + 35Cl izotop). Mass spectrum (FAB) 669 (37Cl + 35Cl isotope), 667 (35Cl + 35Cl isotope).

1'-(3-((S)-(3,4-Diklorofenil)-4-(N-(3,5-diklorobenzoil)(metilamino))-butil-1-metansulfonil-spiro(indolin-3,4'-piperidin). 1'-(3-((S)-(3,4-Dichlorophenyl)-4-(N-(3,5-dichlorobenzoyl)(methylamino))-butyl-1-methanesulfonyl-spiro(indoline-3,4' -piperidine).

1H NMR (CDCl3, ppm granice su date zbog rotamera amida i širenja linije) δ 1.6-2.4 (m, 10H), 2.6-3.9 (m, 10H), 2.86 (s, 3H), 6.75-7.5 (10H). Maseni spektar (FAB) 671 (37Cl + 35Cl izotop), 669 (35Cl + 35Cl izotop). 1H NMR (CDCl3, ppm limits given due to amide rotamer and line broadening) δ 1.6-2.4 (m, 10H), 2.6-3.9 (m, 10H), 2.86 (s, 3H), 6.75-7.5 (10H). Mass spectrum (FAB) 671 (37Cl + 35Cl isotope), 669 (35Cl + 35Cl isotope).

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(3-trifluorometilfenilacetil)(metilamino))butil)-1-metansulfonil-spiro(indolin-3,4'-piperidin). 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(3-trifluoromethylphenylacetyl)(methylamino))butyl)-1-methanesulfonyl-spiro(indoline-3,4'- piperidine).

Maseni spektar (FAB) 684 (37Cl + 35Cl izotop), 682 (35Cl + 35Cl izotop). Mass spectrum (FAB) 684 (37Cl + 35Cl isotope), 682 (35Cl + 35Cl isotope).

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(3-izopropiloksifenilacetil)(metilamino))butil)-1-metansulfonil-spiro(indolin-3,4'-piperidin). 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(3-isopropyloxyphenylacetyl)(methylamino))butyl)-1-methanesulfonyl-spiro(indoline-3,4'- piperidine).

1'-(3((S)-(3,4-Diklorofenil))-4-(N-(benzolsuifonil)(metilamino))-butil)-1-metansulfonil-spiro(indolin-3,4'-piperidin) 1'-(3((S)-(3,4-Dichlorophenyl))-4-(N-(benzenesulfonyl)(methylamino))-butyl)-1-methanesulfonyl-spiro(indoline-3,4'-piperidine)

1H NMR (CDCl3, ppm granice su date zbog rotamera amida i širenja linije) δ 1.65 (m, 3H), 1.8-2.3 (m, 7H), 2.62 (s, 3H), 2.7-3.05 (m, 4H), 2.86 (s, 3H), 3.3 (m, 2H), 3.74 (s, 2H), 7.0-7.7 (m, 12H). 1H NMR (CDCl3, ppm limits given due to amide rotamers and line broadening) δ 1.65 (m, 3H), 1.8-2.3 (m, 7H), 2.62 (s, 3H), 2.7-3.05 (m, 4H), 2.86 (s, 3H), 3.3 (m, 2H), 3.74 (s, 2H), 7.0-7.7 (m, 12H).

Maseni spektar (FAB) 637 (37Cl + 35Cl izotop), 635 (35Cl + 35Cl izotop). Mass spectrum (FAB) 637 (37Cl + 35Cl isotope), 635 (35Cl + 35Cl isotope).

Slijedeći spojevi se također dobivaju upotrebljavajući pogodan klorid kiseline pod uvjetima danim u Stupnju B gore: The following compounds are also obtained using the appropriate acid chloride under the conditions given in Step B above:

1'-(3-((S)-(3,4-diklorofenil))-4-(N-(3,5-difluorobenzoil)(metilamino))butil)-1-metansulfonil-spiro(indolil-3,4'-piperidin). 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-difluorobenzoyl)(methylamino))butyl)-1-methanesulfonyl-spiro(indolyl-3,4 '-piperidine).

Maseni spektar (FAB) 638 (37Cl + 35Cl izotop), 636 (35Cl + 35Cl izotop). Mass spectrum (FAB) 638 (37Cl + 35Cl isotope), 636 (35Cl + 35Cl isotope).

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(3,5-difluorobenzoil)(metilamino))butil)-1-metansulfonil-spiro-(indolin-3,4'piperidin) 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(3,5-difluorobenzoyl)(methylamino))butyl)-1-methanesulfonyl-spiro-(indoline-3, 4'piperidine)

Maseni spektar (Cl) 688 (37Cl + 35Cl izotop), 686 (35Cl + 35Cl izotop). Mass spectrum (Cl) 688 (37Cl + 35Cl isotope), 686 (35Cl + 35Cl isotope).

1'(3-((S)-(3,4-Diklorofenil))-4-(N-(1-n aftoil)(metilamino))-butil)-1-metansulfonil-spiro(indolin-3,4'-piperidin) 1'(3-((S)-(3,4-Dichlorophenyl))-4-(N-(1-n aphthoyl)(methylamino))-butyl)-1-methanesulfonyl-spiro(indoline-3,4' -piperidine)

1H NMR (CDCl3, ppm granice su date zbog rotamera amida i širenja linije) d 1H NMR (CDCl3, ppm limits are given due to amide rotamers and line broadening) d

Maseni spektar (FAB) (37Cl + 35Cl izotop), (35Cl + 35Cl izotop). Mass spectrum (FAB) (37Cl + 35Cl isotope), (35Cl + 35Cl isotope).

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(2-klorofenilsulfonil)-(metilamino))butil)-1-metilsutfonil-spiro(indolin-3,4'-piperidin). 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(2-chlorophenylsulfonyl)-(methylamino))butyl)-1-methylsutphonyl-spiro(indoline-3,4' -piperidine).

Maseni spektar: 200, 202, 228, 230, 279, 308, 310, 494, 496, 670, 672 (grupa). Mass spectrum: 200, 202, 228, 230, 279, 308, 310, 494, 496, 670, 672 (group).

1'-(3-((S)-(3,4-Diklorofenil)-1-(N-(3-klorofenilsulfonil)-(metilamino))-4-butil)-1-metilsulfonil-spiro(indolin-3,4'-piperidin). 1'-(3-((S)-(3,4-Dichlorophenyl)-1-(N-(3-chlorophenylsulfonyl)-(methylamino))-4-butyl)-1-methylsulfonyl-spiro(indoline-3, 4'-piperidine).

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(4-klorofenilsulfonil)-(metilamino))butil)1-metilsulfonil-spiro(indolin-3,4'-piperidin). 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(4-chlorophenylsulfonyl)-(methylamino))butyl)1-methylsulfonyl-spiro(indoline-3,4'- piperidine).

Maseni spektar: 200, 228, 230, 279, 494, 496, 669 (grupa). Mass spectrum: 200, 228, 230, 279, 494, 496, 669 (group).

1'-(3.((S)-(3,4-Diklorofenil))-4-(N-(3,5-diklorofenilsulfonil)-(metilamino))butil)-metilsulfonil-spiro(indolin-3,4'-piperidin) 1'-(3.((S)-(3,4-Dichlorophenyl))-4-(N-(3,5-dichlorophenylsulfonyl)-(methylamino))butyl)-methylsulfonyl-spiro(indoline-3,4' -piperidine)

Maseni spektar: 228, 230, 279, 494, 496, 703, 705 (grupa). Mass spectrum: 228, 230, 279, 494, 496, 703, 705 (group).

Primjer 4 Example 4

1-Benziloksikarbonil-spiro(indolin-3.4'-piperidinijev hidroklorid 1-Benzyloxycarbonyl-spiro(indoline-3,4'-piperidinium hydrochloride

Otopina od 99 g (489 mmola) 1'-metilspiro(indolil-3,4'-piperidina /dobivenog prema Ong-u, H, H, i surad., J. Med. Chem., 1983, 26, 981-986) u 1 litru CH2Cl2 i 82 ml (539 mmola) Et3N se ohladi do 0-5°C sa kupaonicom sa ledom i dodaje se 77 ml (539 mmola) i benzil kloroformijata u toku 30 minuta održavajući reakcijsku temperaturu ispod 10°C. Poslije miješanja u toku 2 sata, dodaje se 19 ml (136 mmola) Et3N i 15 ml (105 mmola) benzil klorformijata pošto je reakcija nekompletna i miješa se 2 sata. U tom trenutku, dodaje se dodatnih 19 ml (136 mmola) Et3N i 15 ml (105 mmola) benzil klorformijata. Poslije 1 sata kada TLC pokaže da je reakcija završena, otopina se koncentrira u vakuumu i ostatak se raspodjeljuje između etera i zasićene otopine NaHCO3. Odvajaju se slojevi, i organski sloj se pere sa zasićenom otopinom NaHCO3 i slanom otopinom, i suši se preko MgSO4. A solution of 99 g (489 mmol) of 1'-methylspiro(indolyl-3,4'-piperidine) prepared according to Ong, H, H, et al., J. Med. Chem., 1983, 26, 981-986 ) in 1 liter of CH2Cl2 and 82 ml (539 mmol) Et3N is cooled to 0-5°C with an ice bath and 77 ml (539 mmol) and benzyl chloroformate are added over 30 minutes keeping the reaction temperature below 10°C. After stirring for 2 hours, 19 ml (136 mmol) of Et3N and 15 ml (105 mmol) of benzyl chloroformate were added since the reaction was incomplete and stirred for 2 hours. At this point, an additional 19 ml (136 mmol) of Et 3 N and 15 ml (105 mmol) of benzyl chloroformate were added. After 1 hour when TLC indicated that the reaction was complete, the solution was concentrated in vacuo and the residue was partitioned between ether and saturated NaHCO3 solution. The layers were separated, and the organic layer was washed with saturated NaHCO 3 and brine, and dried over MgSO 4 .

Filtrat se koncentrira i ostatak se kromatografira na 2 kg silika gela upotrebljavajući 1-5% MeOH/CH2Cl2 pri čemu se dobiva 117 g (71 %) benziloksikarbonil-1'-metil-spiro(indolin-3,4'-piperidin) kao žuto ulje. The filtrate was concentrated and the residue was chromatographed on 2 kg of silica gel using 1-5% MeOH/CH2Cl2 to give 117 g (71%) of benzyloxycarbonyl-1'-methyl-spiro(indoline-3,4'-piperidine) as a yellow oil.

Žuto ulje se otapa u 800 ml 1,2-dikloretan i ohladi se u kupaonici sa ledom kada se dodaje 50 ml (463 mmola) 1-kloretil kloroformijata održavajući temperaturu ispod 10°C. Dobivena otopina se zagrijava do refluksa. Kada je temperatura dostigla 70-75°C zapaženo je razvijanje plina. Poslije 1 sata otopina se ohladi, koncentrira se do oko 250 ml u vakuumu i dodaje se 700 ml metanola. Smjesa se refluksira 1.5 sati i uočava se razvijanje plina. Reakcija se ohladi do sobne temperature i koncentrira u vakuumu do vlažne krute tvari. Kruta tvar se suspendira sa hladnim metanolom, kruta tvar se filtrira, pere se sa hladnim metanolom i suši. Filtrati i tekućine od pranja se sjedinjavaju i koncentriraju do mrke pjene. Mrka pjena i profiltrirana kruta tvar se suspendiraju u CH2Cl2, pere se sa 2.5 N NaOH i CH2Cl2, metanol, NH4OH, pri čemu se izolira 91.3 g slobodne baze u obliku mrkog ulja. The yellow oil is dissolved in 800 ml of 1,2-dichloroethane and cooled in an ice bath when 50 ml (463 mmol) of 1-chloroethyl chloroformate is added maintaining the temperature below 10°C. The resulting solution is heated to reflux. When the temperature reached 70-75°C, gas evolution was observed. After 1 hour, the solution is cooled, concentrated to about 250 ml in vacuo and 700 ml of methanol is added. The mixture is refluxed for 1.5 hours and the evolution of gas is observed. The reaction was cooled to room temperature and concentrated in vacuo to a wet solid. The solid is suspended with cold methanol, the solid is filtered, washed with cold methanol and dried. Filtrates and washing liquids are combined and concentrated to a dark foam. The dark foam and the filtered solid are suspended in CH2Cl2, washed with 2.5 N NaOH and CH2Cl2, methanol, NH4OH, whereby 91.3 g of the free base is isolated in the form of a brown oil.

Ulje se otapa u 1 lit EtOAc dodavanjem metanola (oko 10 ml) i HCl plin se provodi kroz otopinu. Poslije miješanja kisele otopine 10 minuta, on se koncentrira do pjene. Pjena se triturira sa eterom i kruta tvar se filtrira, pere se sa još etera i suši, pri čemu se dobiva 91,5 g (73%) naslovnog spoja u obliku svijetlo žute čvrste tvari. The oil is dissolved in 1 liter of EtOAc by adding methanol (ca. 10 ml) and HCl gas is passed through the solution. After stirring the acid solution for 10 minutes, it is concentrated to foam. The foam was triturated with ether and the solid was filtered, washed with more ether and dried to give 91.5 g (73%) of the title compound as a light yellow solid.

Primjer 5 Example 5

3-((S)-(3,4-Diklorofenil))-4-(3,5-dimetilbenzoil)metilamino)-butanal 3-((S)-(3,4-Dichlorophenyl))-4-(3,5-dimethylbenzoyl)methylamino)-butanal

Naslovni spoj se dobiva upotrebljavajući postupke opisane u Primjeru 1, ali zamjenjujući di-t-butil dikarbonat sa 3,5-dimetilbenzoil kloridom. The title compound is obtained using the procedures described in Example 1, but replacing di-t-butyl dicarbonate with 3,5-dimethylbenzoyl chloride.

1H NMR (CDCl3, ppm granice su date zbog rotamera amida i širenja linije a 2.27 (s, 6H), 2.6-3.9 (m, 8H), 6.5-7.5 (m, 6H), 9.73 (s, 1 H). 1H NMR (CDCl3, ppm limits are given due to amide rotamer and line broadening a 2.27 (s, 6H), 2.6-3.9 (m, 8H), 6.5-7.5 (m, 6H), 9.73 (s, 1H).

Primjer 6 Example 6

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil)-1-benzoiloksikarbonil-spiro(indolin-3,4'-piperidin 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)-1-benzoyloxycarbonyl-spiro(indoline-3,4 '-piperidine

Naslovni spoj se dobiva iz 3-((S)-(3,4-diklorofenil))-4-((3,5-dimetilbenzoil)metilamino)butanala (Primjer 5) i 1-benziloksi karbonil-spiro(indolin-3,4'-piperidinij) hidroklorida (Primjer 4) radeći prema postupku iz Primjera 2. The title compound is obtained from 3-((S)-(3,4-dichlorophenyl))-4-((3,5-dimethylbenzoyl)methylamino)butanal (Example 5) and 1-benzyloxycarbonyl-spiro(indoline-3, 4'-piperidinium) hydrochloride (Example 4) working according to the procedure from Example 2.

1H NMR (CDCl3, ppm granice su date zbog rotamera amida i širenja linije) 1.6-2.35 (m, 10H), 2.27 (s, 6H), 2.6-3.9 (m, 10H), 5.23 & 5.3 (2s, 2H), 6.6-7.6 (m, 15H). 1H NMR (CDCl3, ppm limits given due to amide rotamer and line broadening) 1.6-2.35 (m, 10H), 2.27 (s, 6H), 2.6-3.9 (m, 10H), 5.23 & 5.3 (2s, 2H), 6.6-7.6 (m, 15H).

Maseni spektar (FAB) 686 (37Cl + 35Cl izotop), 684 (35Cl + 35Cl izotop). Mass spectrum (FAB) 686 (37Cl + 35Cl isotope), 684 (35Cl + 35Cl isotope).

Primjer 7 Example 7

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil)-spiro(indolin-3,4'-piperidin) 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)-spiro(indoline-3,4'-piperidine)

Otopina od 1.23 g (1.8 mmola) 1'-(3-((S)-(3,4-diklorofenil))-4-(3,5- dimetilbenzoil(metilamino))butil)- 1-benzoiloksi karbonil-spiro(indolin-3,4'-piperidina) (Primjer 6) u 10 ml etanola i 0.8 ml octene kiseline (HOAc), dodaje se 0.15 g 10% Pd/C. Dobivena smjesa se hidrogenizira na Parr-ovoj aparaturi 20 sati. Katalizator se filtrira i pere se EtOH. Sjedinjeni filtrat se koncentrira u vakuumu i ostatak se otapa u CH2Cl2. CH2Cl2 otopina se pere sa razrijeđenom otopinom (oko 0.5 N) NaOH i slanom otopinom, i suši se filtracijom kroz Na2SO4. Filtrat se koncentrira, pri čemu se dobiva 1.03 g (kvantitativno) naslovnog spoja u obliku pjene, koja se upotrebljava u slijedećoj reakciji bez pročišćavanja. A solution of 1.23 g (1.8 mmol) of 1'-(3-((S)-(3,4-dichlorophenyl))-4-(3,5- dimethylbenzoyl(methylamino))butyl)- 1-benzoyloxycarbonyl-spiro( indolin-3,4'-piperidine) (Example 6) in 10 ml of ethanol and 0.8 ml of acetic acid (HOAc), 0.15 g of 10% Pd/C is added. The resulting mixture is hydrogenated on Parr's apparatus for 20 hours. The catalyst is filtered off and washed with EtOH. The combined filtrate is concentrated in vacuo and the residue is dissolved in CH2Cl2. The CH2Cl2 solution is washed with a dilute solution (about 0.5 N) of NaOH and brine, and dried by filtration through Na2SO4. The filtrate is concentrated, whereby 1.03 g (quantitatively) of the title compound is obtained in the form of a foam, which is used in the next reaction without purification.

1H NMR (CDCl3, ppm granice su date zbog rotamera amida i širenja linije) 1.6-2.45 (m, 10H), 2.27 (s, 6H), 2.6-3.9 (m, 10H), 6.5-7.5 (m, 10H). 1H NMR (CDCl3, ppm limits given due to amide rotamer and line broadening) 1.6-2.45 (m, 10H), 2.27 (s, 6H), 2.6-3.9 (m, 10H), 6.5-7.5 (m, 10H).

Maseni spektar (FAB) 552 (37Cl + 35Cl izotop), 550 (35Cl + 35Cl izotop). Mass spectrum (FAB) 552 (37Cl + 35Cl isotope), 550 (35Cl + 35Cl isotope).

Primjer 8 Example 8

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil-1-acetil-spiro(indolin-3,4'-piperidin) 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl-1-acetyl-spiro(indoline-3,4' -piperidine)

Acetil klorid (16 ul) se dodaje u otopinu od 0.1 g (0.18 mmola) 1'-(3-((S)-(3,4-diklorofenil))-4-(N-(3,5- dimetil benzoil) (metilamino))butil)-spiro(indolin-3,4'-piperidina (Primjer 7) u 4 ml CH2Cl2 koji sadrži 30 ml piridina. Poslije miješanja 2 sata, reakcijska smjesa se razrjeđuje sa CH2Cl2 i pere se sa zasićenom otopinom NaHCO3, vodom, slanom otopinom i suši. Ostatak poslije koncentriranja filtrira se pročišćava pomoću preparativne TLC kromatografije upotrebljavajući 5% Et3N/EtOAc kao eluent, pri čemu se dobiva 90 mg (84%) naslovnog spoja. Acetyl chloride (16 µl) was added to a solution of 0.1 g (0.18 mmol) of 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5- dimethyl benzoyl) (methylamino))butyl)-spiro(indoline-3,4'-piperidine (Example 7) in 4 ml of CH2Cl2 containing 30 ml of pyridine. After stirring for 2 hours, the reaction mixture was diluted with CH2Cl2 and washed with saturated NaHCO3 solution, water, brine and dried The residue after concentration was filtered and purified by preparative TLC chromatography using 5% Et3N/EtOAc as eluent to give 90 mg (84%) of the title compound.

1H NMR (CDCl3, ppm granice su date zbog rotamera amida i širenja linije) ° 1.55-2.5 (m, 10H), 2.22 (s, 3H), 2.27 (s, 6H)- 2.6-3.9 (m, 10H), 6.6-7.5 (m, 9H), 8.17 (d, 1H, J = 12 Hz). 1H NMR (CDCl3, ppm limits given due to amide rotamers and line broadening) ° 1.55-2.5 (m, 10H), 2.22 (s, 3H), 2.27 (s, 6H)- 2.6-3.9 (m, 10H), 6.6 -7.5 (m, 9H), 8.17 (d, 1H, J = 12 Hz).

Maseni spektar (FAB) 594 (37Cl + 35Cl izotop), 592 (35Cl + 35Cl izotop). Mass spectrum (FAB) 594 (37Cl + 35Cl isotope), 592 (35Cl + 35Cl isotope).

Slijedeći analozi se dobivaju zamjenjujući acetil klorid sa pogodnim sredstvom za aciliranje u gorenjem postupku. The following analogs are obtained by replacing acetyl chloride with a suitable acylating agent in the above procedure.

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(3,5-dimetilbenzoil)-(metilamino))butil)-1-propionil-spiro(indolin-3,4'-piperidin). 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)-(methylamino))butyl)-1-propionyl-spiro(indoline-3, 4'-piperidine).

Maseni spektar (FAB) 608 (37Cl + 35Cl izotop), 606 (35Cl + 35Cl izotop). Mass spectrum (FAB) 608 (37Cl + 35Cl isotope), 606 (35Cl + 35Cl isotope).

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))-butil)-1-formil-spiro(indolin-3,4'-piperidin). 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))-butyl)-1-formyl-spiro(indoline-3, 4'-piperidine).

Maseni spektar (FAB) 580 (37Cl + 35Cl izotop), 578 (35Cl + 35Cl izotop). Mass spectrum (FAB) 580 (37Cl + 35Cl isotope), 578 (35Cl + 35Cl isotope).

1'-(3-((S)-3,4-Diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil)-1-t-butilkarbonil-spiro(indolin-3,4'-piperidin). 1'-(3-((S)-3,4-Dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)-1-t-butylcarbonyl-spiro(indoline-3, 4'-piperidine).

Maseni spektar (FAB) 636 (37Cl + 35Cl izotop), 634 (35Cl + 35Cl izotop). Mass spectrum (FAB) 636 (37Cl + 35Cl isotope), 634 (35Cl + 35Cl isotope).

1'-(3-((S)-(3,4-Diklorofenil))-4-(n-(3,5-dimetilbenzoil)(metilamino)butil)-1-metilaminokarbonil-spiro(indolin-3,4'-piperidin). 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(n-(3,5-dimethylbenzoyl)(methylamino)butyl)-1-methylaminocarbonyl-spiro(indoline-3,4' -piperidine).

Maseni spektar (FAB) 609 (M+H, 37Cl + 35Cl izotop), 607 (M+H, 35Cl + 35Cl izotop). Mass spectrum (FAB) 609 (M+H, 37Cl + 35Cl isotope), 607 (M+H, 35Cl + 35Cl isotope).

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil)-1-etoksikarbonil-spiro(indolin-3,4'-piperidin). 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)-1-ethoxycarbonyl-spiro(indoline-3,4 '-piperidine).

Maseni spektar (FAB) 624 (37Cl + 35Cl izotop), 622 (35Cl + 35Cl izotop). Mass spectrum (FAB) 624 (37Cl + 35Cl isotope), 622 (35Cl + 35Cl isotope).

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil)-1-etansulfonil-spiro(indolin-3,4'-piperidin). 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)-1-ethanesulfonyl-spiro(indoline-3,4 '-piperidine).

Maseni spektar (FAB) 643 (37Cl + 35Cl izotop), 641 (35Cl + 35Cl izotop). Mass spectrum (FAB) 643 (37Cl + 35Cl isotope), 641 (35Cl + 35Cl isotope).

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil)-1-i-propansulfonil-spiro(indolin-3,4'-piperidin). 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)-1-i-propanesulfonyl-spiro(indoline-3 ,4'-piperidine).

Maseni spektar (FAB) 657 (37Cl + 35Cl izotop), 655 (35Cl + 35Cl izotop). Mass spectrum (FAB) 657 (37Cl + 35Cl isotope), 655 (35Cl + 35Cl isotope).

Slijedeći spojevi mogu se također dobiti pod uvjetima danim gore: The following compounds can also be obtained under the conditions given above:

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(3-fluoro-5-(trifluorometil)-(benzoil)(metilamino))butil)-1-acetil-spiro(indolin-3,4'-piperidin) 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(3-fluoro-5-(trifluoromethyl)-(benzoyl)(methylamino))butyl)-1-acetyl- spiro(indoline-3,4'-piperidine)

Maseni spektar (FAB) (Cl) 652 (37Cl + 35Cl izotop), 650 (35Cl + 35Cl izotop). Mass spectrum (FAB) (Cl) 652 (37Cl + 35Cl isotope), 650 (35Cl + 35Cl isotope).

Alternativni postupak (postupak B) je dan niže: An alternative procedure (procedure B) is given below:

1' (3-((S)-(3,4-Diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil)-1-acetil-spiro(indolin-3,4'-piperidin) 1' (3-((S)-(3,4-Dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)-1-acetyl-spiro(indoline-3,4' -piperidine)

1-Acetil-spiro(indolin-3,4'-piperidin) 1-Acetyl-spiro(indoline-3,4'-piperidine)

Acetil (1.4 ml, 19.9 mmola) se dodaje u otopinu od 5.35 g (16.6 mmola) 1'-benziloksi karbonil-spiro(indolin-3,4'-piperidina) u 33 ml CH2Cl2 i 3.2 ml (23.2 mmola) Et3N, održavajući temperaturu između 0-5°C hlađenjem u kupaonici sa ledom. Poslije 10 minuta hladna kupaonica se uklanja i reakcija se miješa 30 minuta u kom trenutku TLC pokazuje završenu reakciju. Otopina se razrjeđuje sa CH2Cl2 i pere se sa vodom, slanom otopinom i suši preko Na2SO4. Filtrat se koncentrira do gustog ulja i ulje se otapa u 40 ml EtOH. U otopinu se dodaju octena kiselina (3 ml) i 0.8 g 10% Pd/C i dobivena smjesa se hidrogenizira na Parr-ovoj aparaturi 3 sata. Katalizator se filtrira i pere se sa EtOAc i sjedinjeni filtrat se koncentrira. Ostatak se raspodjeljuje između CH2Cl2 i vode i 2N NaOH se dodaje u tu smjesu sve dok vodeni sloj ne bude bazan. Slojevi se odvajaju i vodeni sloj se ekstrahira sa CH2Cl2. Sjedinjeni organski sloj se pere sa slanom otopinom, suši preko Na2SO4 i filtrat se koncentrira, pri čemu se dobiva 2.93 g (77%) naslovnog spoja dovoljno čistog za upotrebu u slijedećoj reakciji. Acetyl (1.4 mL, 19.9 mmol) was added to a solution of 5.35 g (16.6 mmol) of 1'-benzyloxycarbonyl-spiro(indoline-3,4'-piperidine) in 33 mL of CH2Cl2 and 3.2 mL (23.2 mmol) of Et3N, maintaining temperature between 0-5°C by cooling in an ice bath. After 10 minutes the cold bath is removed and the reaction is stirred for 30 minutes at which point TLC indicates the reaction is complete. The solution is diluted with CH2Cl2 and washed with water, brine and dried over Na2SO4. The filtrate was concentrated to a thick oil and the oil was dissolved in 40 ml of EtOH. Acetic acid (3 ml) and 0.8 g of 10% Pd/C are added to the solution and the resulting mixture is hydrogenated on a Parr apparatus for 3 hours. The catalyst was filtered off and washed with EtOAc and the combined filtrate was concentrated. The residue is partitioned between CH2Cl2 and water and 2N NaOH is added to the mixture until the aqueous layer is basic. The layers are separated and the aqueous layer is extracted with CH2Cl2. The combined organic layer was washed with brine, dried over Na2SO4 and the filtrate was concentrated to give 2.93 g (77%) of the title compound sufficiently pure for use in the next reaction.

1'-(3-((S)-(3,4-Diklorofenil)-4-(N-(3,5-dimetilbenzoil)(metilamino)) butil)-1-acetil-spiro(indolin-3.4'-piperidin) 1'-(3-((S)-(3,4-Dichlorophenyl)-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)-1-acetyl-spiro(indoline-3,4'-piperidine )

U otopinu od 0.284 g (0.75 mmola) 3-((S)-(3,4-diklorofenil))-4-(N-(3,5- dimetilbenzoil)(metilamino))butanala (Primjer 5) u 2 ml MeOH, dodaju se 0.166 g (0.72 mmola) 1-acetil-spiro(indolin-3,4'piperidina), 0.5 g sprašenih 4 A molekularnih sita i 10 kapi (oko 0.1 ml) octene kiseline. Poslije miješanja smjese 1.5 sati dodaje se otopina od 0.189 g (3 mmola) NaCNBH3 u 3 ml THF. Uočeno je nešto razvijanja plina. Poslije 30 minuta kada je reakcija završena prema TLC smjesa se filtrira kroz sloj celita, reakcijski balon i sloj celita se ispiru sa MeOH. Filtrat se koncentrira do približno 3 ml i ostatak se razrijeđuje sa EtOAc. EtOAc otopina se pere sa vodom slanom otopinom, i suši se preko Na2SO4. Filtrat se koncentrira i ostatak se kromatografira na "fleš" koloni upotrebljavajući 50% EtOAc-heksan a zatim sa 2% Et3N-EtOAc i na kraju 93:5:2 EtOAc: MeOH: Et3N da bi se izoliralo 0.317 g (74%) naslovnog spoja u obliku bijele pjene. In a solution of 0.284 g (0.75 mmol) of 3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butanal (Example 5) in 2 ml of MeOH , 0.166 g (0.72 mmol) of 1-acetyl-spiro(indoline-3,4'piperidine), 0.5 g of powdered 4 A molecular sieves and 10 drops (about 0.1 ml) of acetic acid are added. After stirring the mixture for 1.5 hours, a solution of 0.189 g (3 mmol) of NaCNBH3 in 3 ml of THF was added. Some gas evolution was observed. After 30 minutes, when the reaction is complete according to TLC, the mixture is filtered through a celite layer, the reaction flask and the celite layer are washed with MeOH. The filtrate was concentrated to approximately 3 ml and the residue was diluted with EtOAc. The EtOAc solution is washed with brine, and dried over Na2SO4. The filtrate was concentrated and the residue was chromatographed on a flash column using 50% EtOAc-hexane followed by 2% Et3N-EtOAc and finally 93:5:2 EtOAc:MeOH:Et3N to isolate 0.317 g (74%) of the title compound. compound in the form of white foam.

Primjer 9 Example 9

1'-(3-((S)-(3,4-Diklorofenil))-4-(3,5-dimetilbenzoil(metilamino)) butil)-1'-metil-metansulfonil-spiroi(indolin 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(3,5-dimethylbenzoyl(methylamino))butyl)-1'-methyl-methanesulfonyl-spiro(indoline

-3,4'-piperidinij jodid -3,4'-piperidinium iodide

Otopina od 53 mg (0.084 mmola) 1'-(3-((S)-(3,4-diklorofenil))-4-(3,5- dimetilbenzoil (metil amino))butil)-1- metan sulfonil-spiro(indolin-3,4' piperidina) u 5 kapi MeOH se razrijedi sa 1 ml etera i dodaje se 0.5 ml metil jodida. A solution of 53 mg (0.084 mmol) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(3,5- dimethylbenzoyl (methyl amino))butyl)-1- methane sulfonyl-spiro (indoline-3,4' piperidine) in 5 drops of MeOH is diluted with 1 ml of ether and 0.5 ml of methyl iodide is added.

Reakcijska smjesa se miješa preko noći dok se tvori kruta tvar. Žućkasta kruta tvar se ostavi da se staloži i gornji sloj tekućine se uklanja. Kruta tvar se pere sa eterom i suši, pri čemu se dobiva 51 mg (78%) naslovnog spoja. The reaction mixture was stirred overnight as a solid formed. The yellowish solid is allowed to settle and the upper liquid layer is removed. The solid was washed with ether and dried to give 51 mg (78%) of the title compound.

Primjer 10 Example 10

1'-(3-(S)-(3,4-Diklorofenil)-4-(N-(R ili S)-(3-metilbenzoil)(metilamino))pentil)-1-metansulfonil-spiro(indolin-3,4' piperidin) 1'-(3-(S)-(3,4-Dichlorophenyl)-4-(N-(R or S)-(3-methylbenzoyl)(methylamino))pentyl)-1-methanesulfonyl-spiro(indoline-3 ,4' piperidine)

Stupanj 1: Level 1:

N-Metoksi-N-metil-2-(S)-(3,4-diklorofenil)-4-pentenamid N-Methoxy-N-methyl-2-(S)-(3,4-dichlorophenyl)-4-pentenamide

Smjesa od 306 mg (1.25 mmola) (2S)-(3,4-diklorofenil)-4-pentenove kiseline (dobivene prema postupku Hale-a, J.J.; Finke-a, P.E.; MacCross-a, M. Bioorganic 6 Medicinal Chemistry Letters 1993, 3, 319-322) i 202 mg (1.50 mmola) 1-hidroksibenzotriazol hidrata u 10 ml metilen klorida se ohladi do 0°C i tretira sa 287 mg (1.50 mmola) 1-(3-dimetil-aminopropil)-3-etilkarbodiimida. Kupaonica za hlađenje se uklanja poslije 45 minuta kroz cjevčicu dodaje otopina od 365 mg (3.75 mmola) trietilamina u 10 ml metilen klorida. Smjesa se tada miješa na 22°C 4 sata, a zatim se zaustavlja sa 10 ml vode i razrješuje se sa 8 ml metilen klorida. Odvajaju se slojevi i vodeni sloj se ekstrahira sa metilen kloridom (2 x 10 ml). Sjedinjeni organski slojevi se peru sa 10 ml slane otopine, suši se preko anhidriranog natrij sulfata, filtrira, i koncentrira u vakuumu. "Fleš" kromatografijom na 75 g silika gela upotrebljavajući 1:9 v/v etil acetata/heksana kao eluent dobiva se 319 mg (89%) naslovnog spoja u obliku bistrog ulja. A mixture of 306 mg (1.25 mmol) of (2S)-(3,4-dichlorophenyl)-4-pentenoic acid (obtained according to the procedure of Hale, J.J.; Finke, P.E.; MacCross, M. Bioorganic 6 Medicinal Chemistry Letters 1993, 3, 319-322) and 202 mg (1.50 mmol) of 1-hydroxybenzotriazole hydrate in 10 ml of methylene chloride were cooled to 0°C and treated with 287 mg (1.50 mmol) of 1-(3-dimethyl-aminopropyl)- 3-Ethylcarbodiimide. The cooling bath is removed after 45 minutes and a solution of 365 mg (3.75 mmol) of triethylamine in 10 ml of methylene chloride is added through a tube. The mixture is then stirred at 22°C for 4 hours, then quenched with 10 ml of water and quenched with 8 ml of methylene chloride. The layers were separated and the aqueous layer was extracted with methylene chloride (2 x 10 ml). The combined organic layers are washed with 10 ml of brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography on 75 g of silica gel using 1:9 v/v ethyl acetate/hexane as eluent afforded 319 mg (89%) of the title compound as a clear oil.

1H NMR (400 MHz, CDCl3) δ 2.40 (pentet, 1H), 2.75 (pentet, 1H), 3.13 (s, 3H), 3.52 (s, 3H), 3.99-4.01 (m, 1H), 4.96-5.05 (m, 2H), 5.63-5.70 (m, 1H), 7.15 (dd, 1H), 7.35 (d, 1H), 7.41 (d, 1H). 1H NMR (400 MHz, CDCl3) δ 2.40 (pentet, 1H), 2.75 (pentet, 1H), 3.13 (s, 3H), 3.52 (s, 3H), 3.99-4.01 (m, 1H), 4.96-5.05 ( m, 2H), 5.63-5.70 (m, 1H), 7.15 (dd, 1H), 7.35 (d, 1H), 7.41 (d, 1H).

Maseni spektar (FAB): m/z 290 (M+H, 37Cl + 35Cl izotop, 50%), 288 (M+H, 37Cl + 37Cl izotop, 100%). Mass spectrum (FAB): m/z 290 (M+H, 37Cl + 35Cl isotope, 50%), 288 (M+H, 37Cl + 37Cl isotope, 100%).

Stupanj 2: Stage 2:

3-(S)-(3,4-diklorofenil)-5-heksen-2-on 3-(S)-(3,4-Dichlorophenyl)-5-hexen-2-one

Otopina od 319 mg (1.11 mmola) N-metoksi-N-metil-2-(S)-(3,4-diklorofenil)-4-pentenamida (iz Stupnja 1 gore) u 10 ml suhog tetrahidrofurana se ohladi do -70°C i tretira se sa 1.0 ml (1.40 mmola) metillitija i miješa se između -70°C do -40°C. Poslije 3 sata, reakcija se zaustavlja sa 5 ml vode, i razrijeđuje se sa 10 ml etil acetata. Odvajaju se slojevi i organski sloj se pere sa vodom (3 x 10 ml). Vodeni slojevi ekstrahiraju sa 10 ml etil acetata. Sjedinjeni organski slojevi se peru sa 10 ml zasićene vodene otopine natrij klorida, suši se preko anhidriranog natrij sulfata, filtrira, i koncentrira u vakuumu. "Fleš" kromatografijom na 44 g silika gela upotrebljavajući 1:3 v/v etil acetat/heksan kao eluant dobiva se 250 mg (93%) naslovnog spoja kao bistro ulje. A solution of 319 mg (1.11 mmol) of N-methoxy-N-methyl-2-(S)-(3,4-dichlorophenyl)-4-pentenamide (from Step 1 above) in 10 ml of dry tetrahydrofuran is cooled to -70° C and treated with 1.0 ml (1.40 mmol) methyllithium and stirred between -70°C to -40°C. After 3 hours, the reaction is stopped with 5 ml of water, and diluted with 10 ml of ethyl acetate. The layers are separated and the organic layer is washed with water (3 x 10 ml). The aqueous layers were extracted with 10 ml of ethyl acetate. The combined organic layers are washed with 10 ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography on 44 g of silica gel using 1:3 v/v ethyl acetate/hexane as eluent afforded 250 mg (93%) of the title compound as a clear oil.

1H NMR (400 MHz, CDCl3) δ 2.07 (s, 3H), 2.36 (pentet, 1H), 2.72 (pentet, 1H), 3.64 (t, 1H), 4.95-5.01 (m, 2H), 5.55-5.65 (m, 1H), 7.03 (dd, 1H), 7.30 (d, 1H), 7.39 (d, 1H). 1H NMR (400 MHz, CDCl3) δ 2.07 (s, 3H), 2.36 (pentet, 1H), 2.72 (pentet, 1H), 3.64 (t, 1H), 4.95-5.01 (m, 2H), 5.55-5.65 ( m, 1H), 7.03 (dd, 1H), 7.30 (d, 1H), 7.39 (d, 1H).

Maseni spektar (FAB): m/z 245 (M+H, 37Cl + 35Cl izotop, 30%), 243 (M+H, 37Cl + 37Cl izotop, 50%), 155 (60%), 119 (100%). Mass spectrum (FAB): m/z 245 (M+H, 37Cl + 35Cl isotope, 30%), 243 (M+H, 37Cl + 37Cl isotope, 50%), 155 (60%), 119 (100%) .

Stupanj 3: Level 3:

N-Metil-3-(S)-(3,4-diklorofenil)-5-heksen-2-(RS)-amin N-Methyl-3-(S)-(3,4-dichlorophenyl)-5-hexen-2-(RS)-amine

Smjesa od 102 mg (0.42 mmola) 3-(S)-(3,4-diklorofenil)-5-heksen-2-ona (iz Stupnja 2 gore), 170 mg (2.52 mmola) metilamin hidroklorida, i 234 μl (1.68 mmola) trietilamina u 4.0 ml metanola se tretira sa 16 mg (0.25 mmola) natrij cijanborhidridom i miješa se na 22°C 20 sati. Dodaje se zasićena vodena otopina natrij bikarbonata (1.0 ml) i dobivena mliječna kaša se razrjeđuje sa 5.0 ml etil acetata i 5.0 ml vode. Odvajaju se slojevi i organski sloj se pere sa vodom (3 x 5 ml). Vodeni slojevi se ekstrahiraju sa 10 ml etil acetata. Sjedinjeni organski slojevi se peru s 10 ml zasićene vodene otopine natrij klorida, suše se preko anhidriranog natrij sulfata, filtrira se, i koncentrira u vakuumu. "Fleš" kromatografijom na 42 g silika gela upotrebljavajući 10:1 v/v etera/heksana kao eluant daje 64 mg izomera sa višom Rf vrijednošću (Izomer A) i 22 mg izomera sa nižom Rf vrijednošću (Izomer B), oba u obliku žutih ulja. A mixture of 102 mg (0.42 mmol) 3-(S)-(3,4-dichlorophenyl)-5-hexen-2-one (from Step 2 above), 170 mg (2.52 mmol) methylamine hydrochloride, and 234 μl (1.68 mmol) of triethylamine in 4.0 ml of methanol is treated with 16 mg (0.25 mmol) of sodium cyanoborohydride and stirred at 22°C for 20 hours. A saturated aqueous solution of sodium bicarbonate (1.0 ml) is added and the obtained milk slurry is diluted with 5.0 ml of ethyl acetate and 5.0 ml of water. The layers are separated and the organic layer is washed with water (3 x 5 ml). The aqueous layers are extracted with 10 ml of ethyl acetate. The combined organic layers are washed with 10 ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. "Flash" chromatography on 42 g of silica gel using 10:1 v/v ether/hexane as eluant gives 64 mg of the higher Rf isomer (Isomer A) and 22 mg of the lower Rf isomer (Isomer B), both as yellow solids. oil.

1H NMR (400 MHz, CDCl3); Izomer A; δ 1.04 (d, 3H), 2.29-2.35 (m, 4H), 2.50-2.68 (m, 3H), 4.86-4.95 (m, 2H), 5.48-5.56 (m, 1H), 7.01 (dd, 1H), 7.26 (d, 1H), 7.34 (d, 1H); Izomer B: 0.86 (d, 3H), 2.32-2.50 (m, 4H), 2.51-2.53 (m, 1H), 2.68-2.73 (m, 2H), 4.88-4.98 (m, 2H), 5.54-5.61 (m, 1H), 6.97 (dd, 1H), 7.22 (d, 1H), 7.33 (d, 1H). 1H NMR (400 MHz, CDCl3); Isomer A; δ 1.04 (d, 3H), 2.29-2.35 (m, 4H), 2.50-2.68 (m, 3H), 4.86-4.95 (m, 2H), 5.48-5.56 (m, 1H), 7.01 (dd, 1H) , 7.26 (d, 1H), 7.34 (d, 1H); Isomer B: 0.86 (d, 3H), 2.32-2.50 (m, 4H), 2.51-2.53 (m, 1H), 2.68-2.73 (m, 2H), 4.88-4.98 (m, 2H), 5.54-5.61 ( m, 1H), 6.97 (dd, 1H), 7.22 (d, 1H), 7.33 (d, 1H).

Maseni spektar (Izomer A) (FAB): m/z 260 (M+H, 37Cl + 35Cl izotop, 70%), 258 (M+H, 35Cl + 35Cl izotop, 100%). Mass spectrum (Isomer A) (FAB): m/z 260 (M+H, 37Cl + 35Cl isotope, 70%), 258 (M+H, 35Cl + 35Cl isotope, 100%).

Stupanj 4: Stage 4:

N-Metil-N-t-butoksikarbonil-3-(S)-(3,4-dikloroenil)-5-heksen-2-(RS)-amin N-Methyl-N-t-butoxycarbonyl-3-(S)-(3,4-dichloroenyl)-5-hexen-2-(RS)-amine

Otopina od 1.1 g (4.1 mmola) N-metil-3-(S)-(3,4-diklorofenil)-5-heksen-2-(R ili S)-amina (Izomer B iz Stupnja 3 gore) u 10 ml suhog metilen klorida se ohladi do 0°C i tretira se sa 690 μl (5.0 mmola) trietilamina i 1.2 g (5.3 mmola) di-terc-butil dikarbonata. Kupaonica za hlađenje se uklanja i reakcija se miješa na 22°C 20 sati. Reakcija se zaustavlja sa 10 ml vode i razrjeđuje se sa 25 ml metilen klorida. Odvoje se slojevi i vodeni sloj se ekstrahira sa metilen kloridom (2 x 10 ml). Sjedinjeni organski slojevi se peru sa 15 ml slane otopine, suše se preko anhidriranog natrij sulfata, filtrira se, i koncentrira u vakuumu. "Fleš" kromatografijom na 72 g silika gela upotrebljavajući 1:3 v/v etil acetata/heksana kao eluant dobiva se 1.4 g (95%) naslovnog spoja u obliku žutog ulja. A solution of 1.1 g (4.1 mmol) of N-methyl-3-(S)-(3,4-dichlorophenyl)-5-hexen-2-(R or S)-amine (Isomer B from Step 3 above) in 10 ml of dry methylene chloride is cooled to 0°C and treated with 690 μl (5.0 mmol) of triethylamine and 1.2 g (5.3 mmol) of di-tert-butyl dicarbonate. The cooling bath is removed and the reaction is stirred at 22°C for 20 hours. The reaction is stopped with 10 ml of water and diluted with 25 ml of methylene chloride. The layers were separated and the aqueous layer was extracted with methylene chloride (2 x 10 ml). The combined organic layers are washed with 15 ml of brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. "Flash" chromatography on 72 g of silica gel using 1:3 v/v ethyl acetate/hexane as eluant afforded 1.4 g (95%) of the title compound as a yellow oil.

1H NMR (400 MHz, CDCl3, granice su date zbog rotamera amida i širenja linije) δ 1.24-5.70 (22H), 6.88-7.40 (3H), 1.50(s, 3H, N-CH3). 1H NMR (400 MHz, CDCl3, limits given due to amide rotamers and line broadening) δ 1.24-5.70 (22H), 6.88-7.40 (3H), 1.50(s, 3H, N-CH3).

Maseni spektar (FAB): m/z 358 (M+H, 37Cl + 35Cl izotop, 30%), 302 (100%). Mass spectrum (FAB): m/z 358 (M+H, 37Cl + 35Cl isotope, 30%), 302 (100%).

Stupanj 5 Grade 5

N-Metil-N-t-butoksikarbonil-3-(S)-(3,4-diklorofenil)-4-(RS)-amino-pentanal N-Methyl-N-t-butoxycarbonyl-3-(S)-(3,4-dichlorophenyl)-4-(RS)-amino-pentanal

Otopina od 1.4 g (3.9 mmola) N-metil-N-t-butoksikarbonil-3-(S)-(3,4-diklorofenil)-5-heksen-2-(RS)-amina (iz Stupnja 4 gore) u 20 ml 2:1:1 v/v/v acetona/t-butanola/vode tretira se sa 30 mg (0.12 mmola) osmij tetroksida. Poslije 5 minuta dodaje se 691 mg (5.90 mmola) N-metilmorfolin N-oksida i dobivena smjesa se miješa na 22°C 4 sata. Reakcija se zaustavlja sa 491 mg natrij bisulfita i koncentrira se u vakuumu do 25% od originalne zapremine. Ostatak se raspodjeljuje između 20 ml metilen klorida i 10 ml vode i odvoje se slojevi. Vodeni sloj se ekstrahira sa metilen kloridom (2 x 10 ml). Sjedinjeni organski slojevi se suše preko anhidriranog natrij sulfata, filtriraju, i koncentriraju u vakuumu. A solution of 1.4 g (3.9 mmol) of N-methyl-N-t-butoxycarbonyl-3-(S)-(3,4-dichlorophenyl)-5-hexen-2-(RS)-amine (from Step 4 above) in 20 ml 2:1:1 v/v/v acetone/t-butanol/water is treated with 30 mg (0.12 mmol) of osmium tetroxide. After 5 minutes, 691 mg (5.90 mmol) of N-methylmorpholine N-oxide was added and the resulting mixture was stirred at 22°C for 4 hours. The reaction is quenched with 491 mg of sodium bisulfite and concentrated in vacuo to 25% of the original volume. The residue is partitioned between 20 ml of methylene chloride and 10 ml of water and the layers are separated. The aqueous layer was extracted with methylene chloride (2 x 10 ml). The combined organic layers are dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo.

Otopina od sirovog diola u 24 ml 3:1 v/v tetrahidrofurana/vode se tretira sa 1.1 g (5.1 mmola) natrij perjodata i miješa se na 22�C 20 sati. Reakcijska smjesa se raspodjeljuje između 20 ml etil etera i 10 ml vode i odvoje se slojevi. Organski sloj se pere sa vodom (2 x 15 ml), suši se preko anhidriranog natrij sulfata, filtrira, i koncentrira u vakuumu. "Fleš" kromatografijom na 68 g silika gela upotrebljavajući 4:1 v/v etil etera/heksana kao eluant dobiva se 372 mg izomera sa višom vrijednošću Rf (Izomer A) i 879 mg izomera sa nižom vrijednošću Rf (Izomer B) oba u obliku žućkastog ulja. A solution of the crude diol in 24 ml of 3:1 v/v tetrahydrofuran/water was treated with 1.1 g (5.1 mmol) of sodium periodate and stirred at 22°C for 20 hours. The reaction mixture is partitioned between 20 ml of ethyl ether and 10 ml of water and the layers are separated. The organic layer is washed with water (2 x 15 ml), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. "Flash" chromatography on 68 g of silica gel using 4:1 v/v ethyl ether/hexane as eluant gives 372 mg of the isomer with a higher Rf value (Isomer A) and 879 mg of the isomer with a lower Rf value (Isomer B), both in the form yellowish oil.

1H NMR (400 MHz, CDCl3) Izomer B: δ 1.19-1.34 (m, 13H), 2.45 (s, 3H, N-CH3), 2.68-281 (m, 2H), 3.28-3.34 (m, 1H), 4.20-4.50 (m, 1H), 6.98-7.32 (m, 3H), 9.60 (s, 1H, -CHO). 1H NMR (400 MHz, CDCl3) Isomer B: δ 1.19-1.34 (m, 13H), 2.45 (s, 3H, N-CH3), 2.68-281 (m, 2H), 3.28-3.34 (m, 1H), 4.20-4.50 (m, 1H), 6.98-7.32 (m, 3H), 9.60 (s, 1H, -CHO).

Maseni spektar (Izomer B) (Fab): m/z 360 (M+H, 37Cl + 35Cl izotop, 20%), 242 (100%). Mass spectrum (Isomer B) (Fab): m/z 360 (M+H, 37Cl + 35Cl isotope, 20%), 242 (100%).

Stupanj 6: Level 6:

1'-(3-(S)-(3,4-diklorofenil)-4-(N-(R ili S)-(t-butoksikarbonil)(metilamino))pentil)-1-metansulfonil-spiro 1'-(3-(S)-(3,4-dichlorophenyl)-4-(N-(R or S)-(t-butoxycarbonyl)(methylamino))pentyl)-1-methanesulfonyl-spiro

(indolin-3,4'-piperidin) (indoline-3,4'-piperidine)

Smjesa od 217 mg (0.60 mmola) N-metil-N-t-butoksikarbonil-3-(S)-(3,4-diklorofenil)-4-(RS)amino-pentanala (iz Stupnja 5 gore) i 262 mg (0.86 mmola) 1-metansulfonil-spiro(indolin-3,4'-piperidin) hidroklorida u 13 ml metanola tretira se sa 115 (1.83 mmola) natrij cijanoborhidrida i miješa se na 22°C 20 sati. Dodaje se zasićena vodena otopina natrij bikarbonata (1.0 ml) i dobivena mliječna smjesa se koncentrira do 50% od njene originalne zapremnine. Ostatak se raspodjeljuje između 25 ml etil acetata i 15 ml vode i odvajaju se slojevi. Organski sloj se pere sa vodom (3 x 10 ml). Vodeni slojevi se ekstrahiraju sa 20 ml etil acetata. Sjedinjeni organski slojevi se peru sa 15 ml slane otopine, suši se preko anhidriranog natrij sulfata, filtrira, i koncentrira u vakuumu. "Fleš" kromatografijom na 42 g silika gela upotrebljavajući 5:95 v/v metanola/metilen klorida kao eluant dobiva se 329 mg (89%) naslovnog spoja kao bijela pjena. A mixture of 217 mg (0.60 mmol) of N-methyl-N-t-butoxycarbonyl-3-(S)-(3,4-dichlorophenyl)-4-(RS)amino-pentanal (from Step 5 above) and 262 mg (0.86 mmol ) of 1-methanesulfonyl-spiro(indoline-3,4'-piperidine) hydrochloride in 13 ml of methanol is treated with 115 (1.83 mmol) of sodium cyanoborohydride and stirred at 22°C for 20 hours. A saturated aqueous solution of sodium bicarbonate (1.0 ml) is added and the resulting milk mixture is concentrated to 50% of its original volume. The residue is partitioned between 25 ml of ethyl acetate and 15 ml of water and the layers are separated. The organic layer is washed with water (3 x 10 ml). The aqueous layers are extracted with 20 ml of ethyl acetate. The combined organic layers are washed with 15 ml of brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography on 42 g of silica gel using 5:95 v/v methanol/methylene chloride as eluant afforded 329 mg (89%) of the title compound as a white foam.

1H NMR (400 MHz, CDCl3, granice su date zbog rotamera amida i širenja linije) δ 1.20-2.90 (31 H), 3.74 (s, 3H, N-SO2CH3), 7.05-7.41 (m, 8H). 1H NMR (400 MHz, CDCl3, limits given due to amide rotamer and line broadening) δ 1.20-2.90 (31 H), 3.74 (s, 3H, N-SO2CH3), 7.05-7.41 (m, 8H).

Maseni spektar (FAB): m/z 612 (M+H, 37Cl + 37Cl izotop, 100%). Mass spectrum (FAB): m/z 612 (M+H, 37Cl + 37Cl isotope, 100%).

Stupanj 7: Level 7:

1'-(3(S)-(3,4-Diklorofenil)-4-(N-(R ili S)-(metilamino))pentil-1-metansulfonil-spiro(indolin-3,4'-piperidin). 1'-(3(S)-(3,4-Dichlorophenyl)-4-(N-(R or S)-(methylamino))pentyl-1-methanesulfonyl-spiro(indoline-3,4'-piperidine).

U otopinu od 329 mg (0.54 mmola) 1'-(3-(S)-(3,4-diklorofenil)-4-N(R ili S)-(t-butoksikarbonil)(metil-amino)) pentil)-1- metansulfonil-spiro(indolin-3,4'-piperidina) (iz Stupnja 6 gore) u 8 ml suhog metilen klorida na 0°C dodaje se 117 μl (1.1 mmola) anizola i 2.0 ml trifloroctene kiseline. Kupaonica za hlađenje se uklanja i reakcija se miješa na 22°C 20 minuta. Reakcija se koncentrira u vakuumu. In a solution of 329 mg (0.54 mmol) 1'-(3-(S)-(3,4-dichlorophenyl)-4-N(R or S)-(t-butoxycarbonyl)(methyl-amino))pentyl)- 1- methanesulfonyl-spiro(indoline-3,4'-piperidine) (from Step 6 above) in 8 ml of dry methylene chloride at 0°C, 117 μl (1.1 mmol) of anisole and 2.0 ml of trifluoroacetic acid are added. The cooling bath is removed and the reaction is stirred at 22°C for 20 minutes. The reaction is concentrated in vacuo.

Ostatak se raspodjeljuje između 10 ml metilen klorida i 5.0 ml vode. Organski sloj se pere sa 2N NaOH (3 x 5 ml), suši se preko anhidriranog natrij sulfata, filtrira, i koncentrira u vakuumu. "Fleš" kromatografijom na 42 g silika gela upotrebljavajući 5:95:0.5 v/v/v metanola/metilen klorida/amonij hidroksida kao eluant dobiva se 221 mg (80%) naslovnog spoja u obliku bistrog ulja. The residue is partitioned between 10 ml of methylene chloride and 5.0 ml of water. The organic layer is washed with 2N NaOH (3 x 5 ml), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography on 42 g of silica gel using 5:95:0.5 v/v/v methanol/methylene chloride/ammonium hydroxide as eluant afforded 221 mg (80%) of the title compound as a clear oil.

1H NMR (400 MHz, CDCl3) δ 1.05 (d, 3H, J = 6.2Hz), 1.62-2.85 (m, 17H), 2.30 (s, 3H, N-CH3), 7.03-7.37 (m, 7H). 1H NMR (400 MHz, CDCl3) δ 1.05 (d, 3H, J = 6.2Hz), 1.62-2.85 (m, 17H), 2.30 (s, 3H, N-CH3), 7.03-7.37 (m, 7H).

Maseni spektar (FAB): m/z 512 (M+H, 37Cl + 35Cl izotop, 70%), 510 (M+H, 37Cl + 37Cl izotop, 100%). Mass spectrum (FAB): m/z 512 (M+H, 37Cl + 35Cl isotope, 70%), 510 (M+H, 37Cl + 37Cl isotope, 100%).

Stupanj 8: Level 8:

1'(3-(S)-(3,4-Diklorofenil)-4-(N-(R ili S)-(3-metilbenzoil)(metilamino))pentil)-1-metansulfonil-spiro(indolin 1'(3-(S)-(3,4-Dichlorophenyl)-4-(N-(R or S)-(3-methylbenzoyl)(methylamino))pentyl)-1-methanesulfonyl-spiro(indoline

-3,4'-piperidin) -3,4'-piperidine)

Naslovni spoj se dobiva iz 1'-(3-(S)-(3,4-diklorofenil)-4-(R ili S)(metilamino)pentil)-1-metansulfonil-spiro (indolin-3,4'- piperidin) (iz stupnja 7 gore) upotrebljavajući postupak identičan sa Primjerom 3, Stupanj (b), zamjenjujući 3,5-dimetilbenzoil klorid sa m-toluoil kloridom. The title compound is obtained from 1'-(3-(S)-(3,4-dichlorophenyl)-4-(R or S)(methylamino)pentyl)-1-methanesulfonyl-spiro (indoline-3,4'-piperidine ) (from Step 7 above) using a procedure identical to Example 3, Step (b), substituting m-toluoyl chloride for 3,5-dimethylbenzoyl chloride.

1H NMR (400 MHz, CDCl3, granice su date zbog rotamera amida i širenja linije) δ 1.42 (3H, J = 6.7Hz), 1.60-2.30 (16H), 2.54 (s, 3H, ph-CH3), 2.87 (s, 3H, N-CH3), 3.74 (s, 3H, N-SO2CH3), 7.05-7.79 (m, 11H). 1H NMR (400 MHz, CDCl3, limits given due to amide rotamers and line broadening) δ 1.42 (3H, J = 6.7Hz), 1.60-2.30 (16H), 2.54 (s, 3H, ph-CH3), 2.87 (s , 3H, N-CH3), 3.74 (s, 3H, N-SO2CH3), 7.05-7.79 (m, 11H).

Maseni spektar (FAB): m/z 630 (M+H, 37Cl + 35Cl izotop, 70%) 628 (M+H, 37Cl + 37Cl izotop, 100%). Mass spectrum (FAB): m/z 630 (M+H, 37Cl + 35Cl isotope, 70%) 628 (M+H, 37Cl + 37Cl isotope, 100%).

Primjer 11 Example 11

1'-(3-(S)-(3,4-Diklorofenil)-4-(N-(R ili S)-(3,5-bis(trifluorometil)-benzoil)(metilamino)pentil)-1-metansulfonil –spiro (indolin-3,4'-piperidin 1'-(3-(S)-(3,4-Dichlorophenyl)-4-(N-(R or S)-(3,5-bis(trifluoromethyl)-benzoyl)(methylamino)pentyl)-1-methanesulfonyl –spiro (indoline-3,4'-piperidine

Naslovni spoj se dobiva iz 1'-(3-(S)-(3,4-diklorofenil)-4-(r ili S)-(metilamino)pentil)-1-metansulfonil- spiro (indolin- 3,4'-piperidina) (iz Primjera 1, Stupanj 7 gore) upotrebljavajući postupak identičan sa Primjerom 3, Stupanj (b9, zamjenjujući 3,5-dimetilbenzoil klorid sa 3,5-bis(trifluorometil)benzoil kloridom. The title compound is obtained from 1'-(3-(S)-(3,4-dichlorophenyl)-4-(r or S)-(methylamino)pentyl)-1-methanesulfonyl- spiro (indolin- 3,4'- piperidine) (from Example 1, Step 7 above) using a procedure identical to Example 3, Step (b9, replacing 3,5-dimethylbenzoyl chloride with 3,5-bis(trifluoromethyl)benzoyl chloride.

1H NMR (400 MHz, CDCl3, granice su date zbog rotamera amida i širenja linije) δ 1.38-3.00 (22H), 3.74 (s, 3H, N-SO2CH3), 6.40-7.41 (m, 10H). 1H NMR (400 MHz, CDCl3, limits given due to amide rotamer and line broadening) δ 1.38-3.00 (22H), 3.74 (s, 3H, N-SO2CH3), 6.40-7.41 (m, 10H).

Maseni spektar (FAB): m/z 752 (M+H, 37Cl + 35Cl izotop, 40%), 750 (M+H), 37Cl + 37Cl izotop, 60%), 241 (100%). Mass spectrum (FAB): m/z 752 (M+H, 37Cl + 35Cl isotope, 40%), 750 (M+H), 37Cl + 37Cl isotope, 60%), 241 (100%).

Primjer 12 Example 12

1'(3-(S)-(3,4-Diklorofenil)-4-(R ili S)-(3,5-dimetilbenzoil(metilamino))pentil)-1-metansulfonil-spiro(indolin-3,4' 1'(3-(S)-(3,4-Dichlorophenyl)-4-(R or S)-(3,5-dimethylbenzoyl(methylamino))pentyl)-1-methanesulfonyl-spiro(indoline-3,4'

-piperidin) -piperidine)

Naslovni spoj se dobiva iz 1'-(3-(S)-(3,4-diklorofenil)-4-(R ili S)(metilamino)pentil)-1-metansulfonil-spiro (indolin-3,4'- piperidina) (iz Primjera 1, Stupanj 7 gore) upotrebljavajući postupak identičan sa onim Primjerom 3, Stupanj (B). 1H NMR (400 MHz, CDCl3, granice su date zbog rotamera amida i širenja linije) δ 1.37-2.86 (28H), 3.74 (s, 3H, N-SO2CH3), 6.24-7.41 (m, 10H). The title compound is obtained from 1'-(3-(S)-(3,4-dichlorophenyl)-4-(R or S)(methylamino)pentyl)-1-methanesulfonyl-spiro (indoline-3,4'-piperidine ) (from Example 1, Step 7 above) using a procedure identical to that of Example 3, Step (B). 1H NMR (400 MHz, CDCl3, limits given due to amide rotamers and line broadening) δ 1.37-2.86 (28H), 3.74 (s, 3H, N-SO2CH3), 6.24-7.41 (m, 10H).

Maseni spektar (FAB): m/z 642 (M+H, 37Cl + 35Cl izotop, 70%), 644 (M+H, 37Cl + 37Cl izotop, 100%). Mass spectrum (FAB): m/z 642 (M+H, 37Cl + 35Cl isotope, 70%), 644 (M+H, 37Cl + 37Cl isotope, 100%).

Primjer 13 Example 13

(1'-(3-(S)-(3,4-Diklorofenil)-4-(R ili S)-(3,5-diklorobenzoil)metilamino)) pentil-1-metansulfonil-spiro(indolin-3,4' (1'-(3-(S)-(3,4-Dichlorophenyl)-4-(R or S)-(3,5-dichlorobenzoyl)methylamino))pentyl-1-methanesulfonyl-spiro(indoline-3,4 '

-piperidin) -piperidine)

Naslovni spoj se dobiva iz 1'-(3-(S)-(3,4-diklorofenil)-4-(R ili S)(metilamino)pentil)-1-metansulfonil- spiro(indolin- 3,4'piperidin) (iz Primjera 1, Stupanj 7 gore) upotrebljavajući postupak identičan sa Primjerom 3, Stupanj (b), zamjenjujući 3,5-dimetilbenzoilklorid sa 3,5-diklorobenzoil kloridom. 1H NMR (400 MHz, CDCl3, granice su date zbog rotamera amida i širenja linije) δ 1.38-2.93 (22H), 3.73 (s, 3H, N-SO2CH3), 6.53-7.42 (m, 10H). The title compound is obtained from 1'-(3-(S)-(3,4-dichlorophenyl)-4-(R or S)(methylamino)pentyl)-1-methanesulfonyl-spiro(indoline-3,4'piperidine) (from Example 1, Step 7 above) using a procedure identical to Example 3, Step (b), substituting 3,5-dichlorobenzoyl chloride for 3,5-dimethylbenzoyl chloride. 1H NMR (400 MHz, CDCl3, limits given due to amide rotamers and line broadening) δ 1.38-2.93 (22H), 3.73 (s, 3H, N-SO2CH3), 6.53-7.42 (m, 10H).

Maseni spektar (FAB): m/z 684 (M+H, 37Cl + 35Cl izotop, 70%), 686 (M+H, 37Cl + 37Cl izotop, 100%). Mass spectrum (FAB): m/z 684 (M+H, 37Cl + 35Cl isotope, 70%), 686 (M+H, 37Cl + 37Cl isotope, 100%).

Primjer 14 Example 14

1'-(3-((S)-(3,4-diklorofenil))-4-(N-(3-brom-5-metilbenzoil)-(metilamino))butil)-1-metansulfonil-spiro(indolin-3,4' 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3-bromo-5-methylbenzoyl)-(methylamino))butyl)-1-methanesulfonyl-spiro(indoline- 3.4'

-piperidin - piperidine

Stupanj A: Grade A:

3-Brom-5-metilbenzoeva kiselina 3-Bromo-5-methylbenzoic acid

U Otopinu od 0.38 g (1.44 mmola) 3-brom-5-metilbenzil bromida (dobivenog pomoću NBS bromiranja 3,5-dimetilbromo benzola) u 22 ml MeCN i 50 ml vode, dodaje se 7.8 ml (28.8 mmola) vodene otopine natrij hipoklorita (13% aktivnog Cl). Smjesa se ostavi da stoji u ultrazvučnoj kupaonici za čišćenje 14 sati. Reakcija se zakišeljava sa HCl do pH 3 i ekstrahira se sa CH2Cl2. Organski sloj se pere sa vodom, slanom otopinom i suši se sa Na2SO4. Filtrat se koncentrira i ostatak koji je smjesa željene kiseline i aldehida se otapa u 3 ml acetona. Otopina se tretira sa 6N Jones-ovim reagensom sve dok narandžasta boja ne ostane postojana. Poslije miješanja od 20 minuta višak reagensa se razara dodatkom nekoliko kapi iPrOH. Otopina se razblažuje sa vodom i ekstrahira sa CH2Cl2 sloj se pere sa slanom otopinom, suši i filtrat se koncentrira. Ostatak se pročišćava preparativnom tankoslojnom kromatografijom (TLC) upotrebljavajući 0.5:30:69.5 HOAc:EtOAc-heksana, pri čemu se izolira 0.14 g (45% 3-brom-5-metilbenzoeve kiseline). To a solution of 0.38 g (1.44 mmol) of 3-bromo-5-methylbenzyl bromide (obtained by NBS bromination of 3,5-dimethylbromobenzene) in 22 ml of MeCN and 50 ml of water, 7.8 ml (28.8 mmol) of an aqueous solution of sodium hypochlorite is added (13% active Cl). The mixture is left to stand in the ultrasonic cleaning bath for 14 hours. The reaction is acidified with HCl to pH 3 and extracted with CH2Cl2. The organic layer is washed with water, brine and dried with Na2SO4. The filtrate is concentrated and the residue, which is a mixture of the desired acid and aldehyde, is dissolved in 3 ml of acetone. The solution is treated with 6N Jones reagent until the orange color remains constant. After stirring for 20 minutes, the excess reagent is destroyed by the addition of a few drops of iPrOH. The solution is diluted with water and extracted with CH2Cl2, the layer is washed with brine, dried and the filtrate is concentrated. The residue is purified by preparative thin layer chromatography (TLC) using 0.5:30:69.5 HOAc:EtOAc-hexane, whereby 0.14 g (45% 3-bromo-5-methylbenzoic acid) is isolated.

Stupanj B: Grade B:

1'-(3-((S)-(3,4-diklorofenil))-4-(N-(3-brom-5-metilbenzoil)(metilamino))butil)-1-metansulfonil-spiro(indolin-3,4' 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3-bromo-5-methylbenzoyl)(methylamino))butyl)-1-methanesulfonyl-spiro(indoline-3 ,4'

-piperidin) -piperidine)

3-Brom-5-metilbenzoeva kiselina se upotrebljava u reakciji aciliranja prema postupku u Primjeru 3, Stupanj B, pri čemu se dobiva naslovni spoj. Maseni spektar (Cl) 696 (37Cl + 35Cl izotop), 694 (35Cl + 35Cl izotop). 3-Bromo-5-methylbenzoic acid is used in the acylation reaction according to the procedure in Example 3, Step B, whereby the title compound is obtained. Mass spectrum (Cl) 696 (37Cl + 35Cl isotope), 694 (35Cl + 35Cl isotope).

Primjer 15 Example 15

1'(3-((S)-(3,4-Diklorofenil))-4-(N-(3,5-dimetilbenzoil)-(metilamino))butil)-1-(2-aminoacetil)-spiro(indolin-3,4' 1'(3-((S)-(3,4-Dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)-(methylamino))butyl)-1-(2-aminoacetyl)-spiro(indoline -3.4'

-piperidin) -piperidine)

Otopina od 65 mg (0.31 mmola) karbobenziloksiglicina u 3 ml CH2Cl2 se tretira sa 82 mg (0.41 mmola)1-etil-3-(3- dimetilaminopropil)karbodiimida i 56 mg (0.41 mmola) 1-hidroksibenzotriazola i 42 mg (0.41 mmola) N-metilmorfolina. Poslije 10 minuta 123 mg (0.21 mmola) 1'-(3-((S)-(3,4-diklorofenil))-4-(N- (3,5- dimetil benzoil)- (metil amino))- butil)-spiro(indolin-3,4'-piperidina (Primjer 7) se dodaje i reakcija se miješa 2 sata. Smjesa se razblažuje sa CH2Cl2 i pere se sa vodom, slanom otopinom, suši i koncentrira, pri čemu se dobiva 0.184 g ostatka. Ostatak u 10 kapi HOAc se otapa u 3 ml EtOH i otopina se hidrogenizira na Parr-ovoj aparaturi 16 sati. Katalizator se filtrira i pere sa EtOAc. Filtrat se pere sa 10% Na2CO3, slanom otopinom i koncentrira. Ostatak se pročišćava pomoću preparativne TLC upotrebljavajući 30% MeOH-EtOAc, pri čemu se dobiva 80 mg (69%) naslovnog spoja. A solution of 65 mg (0.31 mmol) carbobenzyloxyglycine in 3 ml CH2Cl2 is treated with 82 mg (0.41 mmol) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 56 mg (0.41 mmol) 1-hydroxybenzotriazole and 42 mg (0.41 mmol) ) N-methylmorpholine. After 10 minutes, 123 mg (0.21 mmol) of 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethyl benzoyl)-(methyl amino))-butyl )-spiro(indolin-3,4'-piperidine (Example 7) is added and the reaction is stirred for 2 hours. The mixture is diluted with CH2Cl2 and washed with water, brine, dried and concentrated to give 0.184 g of a residue . The residue in 10 drops of HOAc is dissolved in 3 ml of EtOH and the solution is hydrogenated on a Parr apparatus for 16 hours. The catalyst is filtered and washed with EtOAc. The filtrate is washed with 10% Na2CO3, brine and concentrated. The residue is purified using preparative TLC using 30% MeOH-EtOAc gave 80 mg (69%) of the title compound.

Maseni spektar (Cl) 651 (37Cl + 35Cl izotop), 649 (35Cl + 35Cl izotop). Mass spectrum (Cl) 651 (37Cl + 35Cl isotope), 649 (35Cl + 35Cl isotope).

Primjer 16 Example 16

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(3,5-dimetiibenzoil)-(metilamino))butil)-1-metil-spiroi(indol-2-on-3,4' 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)-(methylamino))butyl)-1-methyl-spiro(indole-2- on-3,4'

-piperidin) -piperidine)

Stupanj A: Grade A:

1,1'-Dimetil-spiro(indol-2-on-3,4'-piperidin) 1,1'-Dimethyl-spiro(indol-2-one-3,4'-piperidine)

Otopina od 0.1 g (0.68 mmola) N-metil-2-oksoindola u 2 ml THF se dodaje u dobro miješanu suspenziju od 0.14 g (3,4 mmola) NaH u 2 ml THF sa hlađenjem u kupaonici od leda. Pošto je prestalo razvijanje plina kupaonica za hlađenje se uklanja i smjesa se zagrijava u kupaonici od 50°C još 15 minuta. Reakcija se ostavi da se ohladi do sobne temperature i dodaje se 0.68 ml DMSO i uočava se još razvijanja plina. Poslije miješanja 10 minuta, reakcijska smjesa se ohladi u kupaonici sa ledom i dodaje se 0.144 g mekloretamin hidroklorida. Smjesa se zagrijava do sobne temperature i miješa se preko noći. Slijedećeg jutra, reakcija se zaustavlja sa vodom i ekstrahira se sa EtOAc. EtOAc ekstrakt se pere sa slanom otopinom, suši se preko Na2SO4 i filtrira. Filtrat se koncentrira i ostatak se pročišćava preparativnom TLC upotrebljavajući 89:10:1 EtOAc:MeOH-Et3N, pri čemu se dobiva 25 mg (15) naslovnog spoja. A solution of 0.1 g (0.68 mmol) of N-methyl-2-oxoindole in 2 ml of THF was added to a well-stirred suspension of 0.14 g (3.4 mmol) of NaH in 2 ml of THF with cooling in an ice bath. After the evolution of gas has stopped, the cooling bath is removed and the mixture is heated in a bath at 50°C for another 15 minutes. The reaction is allowed to cool to room temperature and 0.68 ml of DMSO is added and further gas evolution is observed. After stirring for 10 minutes, the reaction mixture was cooled in an ice bath and 0.144 g of mechlorethamine hydrochloride was added. The mixture is warmed to room temperature and stirred overnight. The next morning, the reaction was quenched with water and extracted with EtOAc. The EtOAc extract is washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated and the residue was purified by preparative TLC using 89:10:1 EtOAc:MeOH-Et3N to give 25 mg (15) of the title compound.

Stupanj B: Grade B:

1-Metil-spiro(indol-2-on-3,4'-piperidin) 1-Methyl-spiro(indol-2-one-3,4'-piperidine)

Otopina od 25 mg (0.11 mmola) 1,1'-dimetil-spiro(indol-2-on-3,4'-piperidina) (iz Stupnja A gore) u 1 ml suhog dikloretana se tretira sa 0.023 ml (0.22 mmola) 1-kloretil kloroformijata (ACECI) pod atmosferom suhog N2. Poslije 30 minuta na sobnoj temperaturi, otopina se drži u kupaonici od 50°C 30 minuta. Reakcijska smjesa se ohladi do sobne temperature, dodaje se 2 ml MeOH i ponovno zagrije do 60°C. Poslije 30 minuta otopina se ohladi i koncentrira u vakuumu. Ostatak se raspodjeljuje između vode i EtOAc i pH vodene faze se podesi na pH 9 dodatkom 1 N otopine NaOH. Odvajaju se slojevi i sjedinjena EtOAc otopina se pere sa slanom otopinom i suši. Filtrat poslije koncentriranja daje 34 mg ostatka, koji je smjesa željenog spoja i polaznog materijala; ali je dovoljno čist da se upotrijebi u slijedećoj reakciji. A solution of 25 mg (0.11 mmol) of 1,1'-dimethyl-spiro(indol-2-one-3,4'-piperidine) (from Step A above) in 1 ml of dry dichloroethane is treated with 0.023 ml (0.22 mmol) of 1-chloroethyl chloroformate (ACECI) under a dry N2 atmosphere. After 30 minutes at room temperature, the solution is kept in a 50°C bath for 30 minutes. The reaction mixture was cooled to room temperature, 2 ml of MeOH was added and reheated to 60°C. After 30 minutes, the solution is cooled and concentrated in vacuo. The residue is partitioned between water and EtOAc and the pH of the aqueous phase is adjusted to pH 9 by addition of 1 N NaOH solution. The layers are separated and the combined EtOAc solution is washed with brine and dried. After concentration, the filtrate gives 34 mg of a residue, which is a mixture of the desired compound and the starting material; but it is pure enough to be used in the next reaction.

Stupanj C: Grade C:

1'-(3-((S)-3,4-Diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil)-1-metil-spiro(indol-2-on-3,4'-piperidin) 1'-(3-((S)-3,4-Dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)-1-methyl-spiro(indol-2-one- 3,4'-piperidine)

Reakcija od 49 mg (0.13 mmola) 3-((S)-(3,4-diklorofenil))-4-(N-(3,5- dimetilbenzoil)-metilamino)butanala (Primjer 5) sa 34 mg nečistog 1-metil-spiro(indol-2-on-3,4'-piperidina) (iz Stupnja B) prema postupku iz Primjera 8, postupak B, daje poslije pročišćavanja sa preparativnom TLC 32 mg naslovnog spoja. Reaction of 49 mg (0.13 mmol) of 3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)-methylamino)butanal (Example 5) with 34 mg of impure 1- methyl-spiro(indol-2-one-3,4'-piperidine) (from Step B) according to the procedure of Example 8, procedure B, gives after purification by preparative TLC 32 mg of the title compound.

Maseni spektar (Cl) 580 (37Cl + 35Cl izotop), 578 (35Cl + 35Cl izotop). Mass spectrum (Cl) 580 (37Cl + 35Cl isotope), 578 (35Cl + 35Cl isotope).

Primjer 17 Example 17

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(3,5-diklorobenzoil)-(metilamino))butil)-1-metil-spiro(izoindol-1-on-3,4' 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(3,5-dichlorobenzoyl)-(methylamino))butyl)-1-methyl-spiro(isoindole-1- on-3,4'

-piperidin - piperidine

Maseni spektar (Cl) 622 (37Cl + 35Cl izotop), 620 (35Cl + 35Cl izotop). Mass spectrum (Cl) 622 (37Cl + 35Cl isotope), 620 (35Cl + 35Cl isotope).

Primjer 18 Example 18

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(3,5-dimetilbenzoil)-(metilamino))butil)-spiro((2-okso-tetrahidrohinolin-4,4' 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)-(methylamino))butyl)-spiro((2-oxo-tetrahydroquinoline-4 ,4'

-piperidin) -piperidine)

Stupanj A: Grade A:

1'-Trifluoroacetil-spiro(1-indanon-3,4'-piperidin) 1'-Trifluoroacetyl-spiro(1-indanone-3,4'-piperidine)

Hladna trifluorooctena kiselina (15 ml) i 0.6 ml anizola se dodaju u 2 g (6.6 mmola) 1'-t-butoksi- karbonil- spiro(1-indanon-3,4'-piperidina) i dobivena otopina se miješa u kupaonici sa ledom 1 sat. Reakcijska smjesa se koncentrira u vakuumu i ostatak se raspodjeljuje između CH2Cl2 i 0,5N NaOH. Organski sloj se pere sa slanom otopinom, suši sa Na2SO4 i koncentrira. Preostalo narandžasto ulje se otapa u 10 ml CH2Cl2 i dodaje se 1.92 ml (13.7 mmola (Et3N, 1 ml (7.1 mmola) anhidrida trifluorooctene kiseline i 3 kristala DMAP. Poslije miješanja od 4 sata, reakcijska smjesa se razblažuje sa CH2Cl2 i pere se sa vodom, slanom otopinom i suši. Otopina se filtrira i filtrat se koncentrira, pri čemu se dobiva 2.0 g (kvantitativno) željenog proizvoda u obliku čvrste supstance. Cold trifluoroacetic acid (15 ml) and 0.6 ml of anisole are added to 2 g (6.6 mmol) of 1'-t-butoxy-carbonyl-spiro(1-indanone-3,4'-piperidine) and the resulting solution is stirred in a bath with with ice for 1 hour. The reaction mixture was concentrated in vacuo and the residue was partitioned between CH2Cl2 and 0.5N NaOH. The organic layer is washed with brine, dried with Na2SO4 and concentrated. The remaining orange oil is dissolved in 10 ml of CH2Cl2 and 1.92 ml (13.7 mmol) of (Et3N, 1 ml (7.1 mmol) of trifluoroacetic anhydride and 3 crystals of DMAP are added. After stirring for 4 hours, the reaction mixture is diluted with CH2Cl2 and washed with water, brine and dried The solution was filtered and the filtrate was concentrated to give 2.0 g (quantitative) of the desired product as a solid.

1H NMR (CDCl3) δ 1.65 (d, 2H, J=14Hz), 2.05 (m, 2H), 2.67 (ABq, 2H), 2.89 (m, 1H), 3.28 (m, 1H), 4.11 (d, 1H, J=14Hz), 4.67 (dt, 1H, J=14 i 2 Hz), 7.5-7.8 (m, 4H). 1H NMR (CDCl3) δ 1.65 (d, 2H, J=14Hz), 2.05 (m, 2H), 2.67 (ABq, 2H), 2.89 (m, 1H), 3.28 (m, 1H), 4.11 (d, 1H , J=14Hz), 4.67 (dt, 1H, J=14 and 2 Hz), 7.5-7.8 (m, 4H).

Stupanj B: Grade B:

1'-Trifluoroacetil-spiro-(2-okso-1,2,3,4-tetrahidro-hinolin-4,4'-piperidin) i 1'-Trifluoroacetyl-spiro-(2-oxo-1,2,3,4-tetrahydro-quinoline-4,4'-piperidine) and

1'1'-trifluoroacetil-spiro-(1-okso-1,2,3,4-tetrahidroizohinolin-4,4'-piperidin 1'1'-trifluoroacetyl-spiro-(1-oxo-1,2,3,4-tetrahydroisoquinoline-4,4'-piperidine

U smjesu od 1.09 g (16.8 mmola) natrij azida u 1.2 ml vode i 6.6 ml CHCl3 dodaje se 0.46 ml koncentrirane H2SO4 (36 N) održavajući temperaturu između 0-5°C (Pažnja!). Poslije 10 minuta hladna kupaonica se uklanja i reakcija se miješa 3 sata, kada se CHCl3 sloj odvaja od vodenog sloja. CHCl3 sloj koji sadrži HN3 se suši i filtrat se dodaje u otopinu od 2 g (6.7 mmola) 1'-trifluoroacetil-spiro(1-indanon-3,4'-piperidina) (iz Stupnja A) u 7 ml CHCl3. Dodaje se koncentrirana H2SO4 (1.8 ml u ovu otopinu i dopusti se da reakcija stari 30 minuta. Smjesa se zagrijava u kupaonici na 45°C 45 minuta i zatim se miješa na sobnoj temperaturi 16 sati. Slijedećeg jutra, reakcijska smjesa se sipa u led i odvoje se slojevi. Vodeni sloj se neutralizira sa vodenom otopinom NaOH i ekstrahira se sa EtOAc. Sjedinjene organske faze se peru sa slanom otopinom, suše i koncentriraju. Ostatak se kromatografira upotrebljavajući 50-80% EtOAc-CH2Cl2, pri čemu se izolira 0.34 g (16%) 1'-trifluoro acetil- spiro(2- okso-1,2,3,4-tetrahidroinolin-4,4'-piperidina) i 0.13 g 1'-trifluoroacetil-spiro(1- okso-1,2,3,4-tetrahidro izohinolin-4,4'- piperidina). Pored toga, regenerira se 0.72 g (36%) polaznog indanona. 0.46 ml of concentrated H2SO4 (36 N) is added to a mixture of 1.09 g (16.8 mmol) of sodium azide in 1.2 ml of water and 6.6 ml of CHCl3, maintaining the temperature between 0-5°C (Caution!). After 10 minutes, the cold bath is removed and the reaction is stirred for 3 hours, when the CHCl3 layer separates from the aqueous layer. The CHCl 3 layer containing HN 3 is dried and the filtrate is added to a solution of 2 g (6.7 mmol) 1'-trifluoroacetyl-spiro(1-indanone-3,4'-piperidine) (from Step A) in 7 ml CHCl 3 . Concentrated H2SO4 (1.8 ml) was added to this solution and the reaction was allowed to stand for 30 minutes. The mixture was heated in a bath at 45°C for 45 minutes and then stirred at room temperature for 16 hours. The next morning, the reaction mixture was poured into ice and The layers were separated. The aqueous layer was neutralized with aqueous NaOH and extracted with EtOAc. The combined organic phases were washed with brine, dried and concentrated. The residue was chromatographed using 50-80% EtOAc-CH2Cl2, isolating 0.34 g ( 16%) 1'-trifluoroacetyl-spiro(2-oxo-1,2,3,4-tetrahydroinoline-4,4'-piperidine) and 0.13 g of 1'-trifluoroacetyl-spiro(1-oxo-1,2, 3,4-tetrahydro isoquinoline-4,4'-piperidine).In addition, 0.72 g (36%) of the starting indanone is regenerated.

1H NMR (CDCl3) Izomer A: 1.82 (m, 2H), 1.96 (m, 2H), 2.75 (ABq, 2H, J=14Hz), 3.16 (t, 1H), 3.46 (t, 1H), 3.9 (d, 1H), 4.42 (d, 1H), 6.8-87.3 (m, 4H), 8.49 (širok s, 1H); 1H NMR (CDCl3) Isomer A: 1.82 (m, 2H), 1.96 (m, 2H), 2.75 (ABq, 2H, J=14Hz), 3.16 (t, 1H), 3.46 (t, 1H), 3.9 (d , 1H), 4.42 (d, 1H), 6.8-87.3 (m, 4H), 8.49 (broad s, 1H);

Izomer B: 1.9-2.1 (m, 4H), 3.09 (t, 1H), 3.42 (m, 1H), 3.61 (ABq, 2H), 3.94 (d, 1H), 4.45 (d, 1H), 6.72 (širok s, 1H), 7.3-7.6 (m, 3H), 8.11 (d, 1H). Isomer B: 1.9-2.1 (m, 4H), 3.09 (t, 1H), 3.42 (m, 1H), 3.61 (ABq, 2H), 3.94 (d, 1H), 4.45 (d, 1H), 6.72 (broad s, 1H), 7.3-7.6 (m, 3H), 8.11 (d, 1H).

Stupanj C: Grade C:

Spiro-(2-okso-1,2,3,4-tetrahidrohinolin-4,4'-piperidin Spiro-(2-oxo-1,2,3,4-tetrahydroquinoline-4,4'-piperidine).

U otopinu od 0.3 g (0.97 mmola) 1'-trifluoroacetil-spiro-(2-okso-1,2,3,4-tetrahidrohinolin-4,4'-piperidina) (iz Stupnja B) u 4 ml MeOH, dodaje se 0.16 g (2.9 mmola) KOH u 1 ml vode. Poslije miješanja reakcije 16 sati otopina se koncentrira i ostatak se raspodjeljuje između EtOAc i vode. EtOAc sloj se pere sa slanom otopinom, suši sa Na2SO4 i koncentrira, pri čemu se dobiva 0.16 g (76%) naslovnog spoja u obliku bijele čvrste supstance. To a solution of 0.3 g (0.97 mmol) of 1'-trifluoroacetyl-spiro-(2-oxo-1,2,3,4-tetrahydroquinoline-4,4'-piperidine) (from Step B) in 4 ml of MeOH, is added 0.16 g (2.9 mmol) of KOH in 1 ml of water. After stirring the reaction for 16 h, the solution was concentrated and the residue was partitioned between EtOAc and water. The EtOAc layer was washed with brine, dried over Na2SO4 and concentrated to give 0.16 g (76%) of the title compound as a white solid.

1H NMR (CDCl3) δ 1.6-2.0 (m, 4H), 2.72 (s, 2H), 2.95 (m, 4H), 6.7-7.4 (m, 4H), 8.4 (širok s, 1H). 1H NMR (CDCl3) δ 1.6-2.0 (m, 4H), 2.72 (s, 2H), 2.95 (m, 4H), 6.7-7.4 (m, 4H), 8.4 (broad s, 1H).

Stupanj D: Grade D:

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil)-spiro-(2-okso-tetrahidrohinolin-4-4' 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)-spiro-(2-oxo-tetrahydroquinoline-4- 4'

-piperidin) -piperidine)

Naslovni spoj se dobiva reduktivnom aminacijom 3-((S)-(3,4-diklorofenil))-4-(3,5- dimetilbenzoil)metilamino)-butanala (Primjer 5) pomoću spiro-(2-okso-1,2,3,4- tetrahidrohinolin-4-4'-piperidina) dobivenog u Stupnju C prema postupku iz Primjera 8, postupak B. The title compound is obtained by reductive amination of 3-((S)-(3,4-dichlorophenyl))-4-(3,5-dimethylbenzoyl)methylamino)-butanal (Example 5) using spiro-(2-oxo-1,2 ,3,4-tetrahydroquinoline-4-4'-piperidine) obtained in Step C according to the procedure from Example 8, procedure B.

Primjer 19 Example 19

1'-(3-((S)-3,4-Diklorofenil))-4-(N-(3,5-diklorobenzoil)-(metilamino))butil)-1-metil-spiro(2-okso-tetrahidrohinolin-4,4'-piperidin) 1'-(3-((S)-3,4-Dichlorophenyl))-4-(N-(3,5-dichlorobenzoyl)-(methylamino))butyl)-1-methyl-spiro(2-oxo-tetrahydroquinoline -4,4'-piperidine)

Stupanj A: Grade A:

1-Metil-spiro-(2-okso-1,2,3,4-tetrahidrohinolin-4,4'-piperidin) 1-Methyl-spiro-(2-oxo-1,2,3,4-tetrahydroquinoline-4,4'-piperidine)

U otopinu od 0.15 g (0.48 mmola) 1'-trifluoroacetil-spiro(2-okso-1,2,3,4-tetrahidrohinolin-4,4'-piperidina) (iz Primjera 18, Stupanj B) u 1.7 ml DMF, dodaje se 19 mg (0.77 mmola) 95% NaH na 0°C. Poslije 15 minuta dodaje se 0.063 ml (1 mmol) metil jodida i dopusti se da se reakcija zagrije do sobne temperature. Poslije miješanja 16 sati, reakcija nije bila završena, tako da se dodaje dodatnih 0.015 ml metil jodida i otopina se zagrije u kupaonici na 45°C. Poslije 2 sata reakcija se ohladi do sobne temperature i raspodjeljuje se između EtOAc i vode. EtOAc sloj se pere sa slanom otopinom, suši i filtrat se koncentrira. Ostatak se pročišćava preparativnom TLC upotrebljavajući 33% EtOAc-heksana, pri čemu se dobiva 1-metil -1'trifluoro acetil-spiro-(2-okso-1,2,3,4-tetrahidrohinolin-4-4'-piperidin). Hidrolizom ovog trifluoroacetamida kao što je opisano u Primjeru 55, Stupanj C dobiva se 71 mg (64% naslovnog spoja. In a solution of 0.15 g (0.48 mmol) of 1'-trifluoroacetyl-spiro(2-oxo-1,2,3,4-tetrahydroquinoline-4,4'-piperidine) (from Example 18, Step B) in 1.7 ml of DMF, 19 mg (0.77 mmol) of 95% NaH are added at 0°C. After 15 minutes, 0.063 ml (1 mmol) of methyl iodide was added and the reaction was allowed to warm to room temperature. After stirring for 16 hours, the reaction was not complete, so an additional 0.015 ml of methyl iodide was added and the solution was heated in a bath to 45°C. After 2 hours, the reaction was cooled to room temperature and partitioned between EtOAc and water. The EtOAc layer was washed with brine, dried and the filtrate was concentrated. The residue is purified by preparative TLC using 33% EtOAc-hexane to give 1-methyl-1'trifluoroacetyl-spiro-(2-oxo-1,2,3,4-tetrahydroquinoline-4-4'-piperidine). Hydrolysis of this trifluoroacetamide as described in Example 55, Step C afforded 71 mg (64%) of the title compound.

1H NMR (CDCl3) δ 1.61 (d, 2H), 1.92 (m, 2H), 2.74 (s, 2H), 2.98 (m, 4H), 3.36 (s, 3H), 7.0-7.4 (m, 4H). 1H NMR (CDCl3) δ 1.61 (d, 2H), 1.92 (m, 2H), 2.74 (s, 2H), 2.98 (m, 4H), 3.36 (s, 3H), 7.0-7.4 (m, 4H).

Stupanj B: Grade B:

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(3,5-diklorobenzoil)(metilamino))butil)-1-metil-spiro(2-okso-tetrahidrohinolin-4,4'-piperidin 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(3,5-dichlorobenzoyl)(methylamino))butyl)-1-methyl-spiro(2-oxo-tetrahydroquinoline -4,4'-piperidine

Naslovni spoj se dobiva reakcijom amina iz Stupnja A i 3-((S)-(3,4-diklorofenil))-4-((3,5-diklorobenzoil)-metilamino)butanala, kao što je opisano u Primjeru 18, Stupanj D. The title compound is obtained by reacting the amine from Step A and 3-((S)-(3,4-dichlorophenyl))-4-((3,5-dichlorobenzoyl)-methylamino)butanal, as described in Example 18, Step D.

Maseni spektar (Cl) 636 (37Cl + 35Cl izotop), 634 (35Cl + 35Cl izotop). Mass spectrum (Cl) 636 (37Cl + 35Cl isotope), 634 (35Cl + 35Cl isotope).

Primjer 20 Example 20

4-Brom-2-(S)-(4-fluorofenil)i-1-(3,5-bistrifluorometilbenzoil)metilamino)butan 4-Bromo-2-(S)-(4-fluorophenyl)i-1-(3,5-bistrifluoromethylbenzoyl)methylamino)butane

Stupanj A: Grade A:

3-(S)-(4-Fluorofenil)-4-(N-(3,5-bistrifluorometil)benzoilmetilamino)butanol 3-(S)-(4-Fluorophenyl)-4-(N-(3,5-bistrifluoromethyl)benzoylmethylamino)butanol

Otopina od 1.67 g (3.84 mmola) 3-((S)-(4-fluorofenil)-4-(N-(3,5- (bistrifluorometil)benzoil)(metilamino))butanala (dobivenog iz 4-fluorofeniloctene kiseline kao što su opisali J. Hale i surad., Bioorganic & Medicinal Chemistry Letters 1993, 3, 319-322) u 16 ml apsolutnog etanola na 0°C, tretira se sa 172 mg (4.55 mmola) natrij borhidrida. Poslije miješanja od 1 sata na sobnoj temperaturi, reakcija se zaustavlja sa zasićenom otopinom NH4Cl i ekstrahira se dva puta sa etil acetatom. Sjedinjeni organski slojevi se peru sa slanom otopinom, suše (MgSO4) i uparavaju, pri čemu se dobiva 1.59 preostalog ulja. Pročišćavanjem na silika gel fleš koloni (30:70 tada 50:50 etil acetata: heksana) osigurava se 1.21 g (72%) naslovnog spoja u obliku viskoznog ulja. Maseni spektar (Cl/NH3) M+H=438. A solution of 1.67 g (3.84 mmol) of 3-((S)-(4-fluorophenyl)-4-(N-(3,5- (bistrifluoromethyl)benzoyl)(methylamino))butanal (obtained from 4-fluorophenylacetic acid as described by J. Hale et al., Bioorganic & Medicinal Chemistry Letters 1993, 3, 319-322) in 16 ml of absolute ethanol at 0°C, treated with 172 mg (4.55 mmol) of sodium borohydride. After stirring for 1 hour at at room temperature, the reaction was quenched with saturated NH4Cl and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4) and evaporated to give 1.5 g of a residual oil. Purification on a silica gel flash column ( 30:70 then 50:50 ethyl acetate:hexane) provided 1.21 g (72%) of the title compound as a viscous oil.Mass spectrum (Cl/NH3) M+H=438.

Stupanj B: Grade B:

4-Brom-2-(S)-(4-fluorofenil)-1-(N-(3,5-bistrifluorometilbenzoil) metilamino)butan 4-Bromo-2-(S)-(4-fluorophenyl)-1-(N-(3,5-bistrifluoromethylbenzoyl)methylamino)butane

U otopinu od 1.19 g (2.72 mmola) 3-(S)-(4-fluorofenil)-4-(N-(3,5- bistrifluorometilbenzoil)metilamino)-butanola u 20 ml acetonitrila, dodaje se 1.49 g (3.53 mmola) trifenilfosfin dibromida. Poslije 1.5 sati reakcija se raspodjeljuje između etil acetata i vode. Organski sloj se pere sa slanom otopinom, suši (MgSO4) i koncentrira, pri čemu se dobiva 2.33 g sirove bijele čvrste supstance. Pročišćavanjem na silika gel fleš koloni (30:70 etil acetata:heksana) dobiva se 944 mg (69%) željenog bromida u obliku viskoznog ulja. To a solution of 1.19 g (2.72 mmol) of 3-(S)-(4-fluorophenyl)-4-(N-(3,5- bistrifluoromethylbenzoyl)methylamino)-butanol in 20 ml of acetonitrile, 1.49 g (3.53 mmol) is added. triphenylphosphine dibromide. After 1.5 hours, the reaction is partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4) and concentrated to give 2.33 g of a crude white solid. Purification on a silica gel flash column (30:70 ethyl acetate:hexane) gives 944 mg (69%) of the desired bromide in the form of a viscous oil.

Maseni spektar (Cl/NH3) M+H=500, 502 (79,81Br izotop). Mass spectrum (Cl/NH3) M+H=500, 502 (79.81Br isotope).

Primjer 21 Example 21

1'-(3-(S)-(4-Fluorofenil)-4-(N-(3,5-bistrifluorometil-benzoil)-(metilamino))butil)-1-acetil-spiro(indolin-3,4' 1'-(3-(S)-(4-Fluorophenyl)-4-(N-(3,5-bistrifluoromethyl-benzoyl)-(methylamino))butyl)-1-acetyl-spiro(indoline-3,4'

-piperidin) -piperidine)

U 40 mg (0.08 mmola) bromida dobivenog u Primjeru 20, Stupanj B i 0.21 μl (0.12 mmola) n,N-diizopropiletilamina u 0.5 ml acetonitrila, dodaje se 37 mg (0.16 mmola) 1-acetil-spiro(indolin-3,4'-piperidina). Dobivena smjesa se zagrijava u dobro zatvorenoj ampuli na 50°C četiri dana. Otapalo se uparava i ostatak se pročišćava na preparativnoj ploči od 1000 mikrova silika gela (93:5:2 etil acetata:metanola:trietilamina), pri čemu se dobiva 46.6 mg (90%) naslovnog spoja u obliku bijele pjene. 37 mg (0.16 mmol) of 1-acetyl-spiro(indolin-3, 4'-piperidine). The resulting mixture is heated in a tightly closed ampoule at 50°C for four days. The solvent is evaporated and the residue is purified on a preparative 1000 micron silica gel plate (93:5:2 ethyl acetate:methanol:triethylamine) to give 46.6 mg (90%) of the title compound as a white foam.

Maseni spektar (Cl/NH3) M+H=650. Mass spectrum (Cl/NH3) M+H=650.

Spojevi u Primjerima 22-26 se dobivaju kao u Primjeru 21 iz potrebnog bromida, dobivenog iz odgovarajuće feniloctene kiseline kao što je opisano u Primjeru 20, i željenog 1-supstituiranog-spiro(indolin-3,4'-piperidina). The compounds of Examples 22-26 are prepared as in Example 21 from the required bromide, obtained from the appropriate phenylacetic acid as described in Example 20, and the desired 1-substituted-spiro(indoline-3,4'-piperidine).

Primjer 22 Example 22

1'-(3-(S)-(3-klorofenil)-4-(N-(3,5-bistrifluorometilbenzoil)-(metilamino))butil-1-acetil-spiro(indolin-3,4'-piperidin) 1'-(3-(S)-(3-chlorophenyl)-4-(N-(3,5-bistrifluoromethylbenzoyl)-(methylamino))butyl-1-acetyl-spiro(indoline-3,4'-piperidine)

Maseni spektar (Cl/NH3) M+H=666, 668 (35,37Cl-izotop). Mass spectrum (Cl/NH3) M+H=666, 668 (35.37Cl-isotope).

Primjer 23 Example 23

1'-(3-(S)-(4-klorofenil)-4-(N-(3,5-bistrifluorometilbenzoil)-(metilamino))butil)-1-acetil-spiro(indolin-3,4'-piperidin) 1'-(3-(S)-(4-chlorophenyl)-4-(N-(3,5-bistrifluoromethylbenzoyl)-(methylamino))butyl)-1-acetyl-spiro(indoline-3,4'-piperidine )

Primjer 24 Example 24

1'(3-(S)-(3,4-Difluorofenil)-4-(N-(3,5-bistrifluorometilbenzoil)-(metilamino))butil)-1-acetil-spiro(indolin-3,4'-piperidin) 1'(3-(S)-(3,4-Difluorophenyl)-4-(N-(3,5-bistrifluoromethylbenzoyl)-(methylamino))butyl)-1-acetyl-spiro(indoline-3,4'- piperidine)

Maseni spektar (Cl/NH3) M+H=668. Mass spectrum (Cl/NH3) M+H=668.

Primjer 25 Example 25

1'-(3-(S)-(3,4-Metilendioksifenil)-4-(3,5-bistrifluorometilbenzoil)-(metilamino))butil-1-metansulfonil-spiro-(indolin-3,4'-piperidin) 1'-(3-(S)-(3,4-Methylenedioxyphenyl)-4-(3,5-bistrifluoromethylbenzoyl)-(methylamino))butyl-1-methanesulfonyl-spiro-(indoline-3,4'-piperidine)

Maseni spektar (Cl/NH3) M+H=712. Mass spectrum (Cl/NH3) M+H=712.

Primjer 26 Example 26

1'-((3-(RS)-(3,5-Diklorofenil)-4-(N-(3,5-bistrifluorometilbenzoil)-(metilamino))butil)-1-metansulfonil-spiro (indolin-3,4'-piperidin) 1'-((3-(RS)-(3,5-Dichlorophenyl)-4-(N-(3,5-bistrifluoromethylbenzoyl)-(methylamino))butyl)-1-methanesulfonyl-spiro (indoline-3,4 '-piperidine)

Maseni spektar (Cl/NH3) M+H=736, 738 (35,37Cl-izotop). Mass spectrum (Cl/NH3) M+H=736, 738 (35.37Cl-isotope).

Primjer 27 Example 27

1'(3-(S)-(4-klorofenil)-4-(N-(3,5-bistrifluorometilbenzoil)-(metilamino))butil)-spiro(2,3-dihidrobenzotiofen-3,4'-piperidin) 1'(3-(S)-(4-chlorophenyl)-4-(N-(3,5-bistrifluoromethylbenzoyl)-(methylamino))butyl)-spiro(2,3-dihydrobenzothiophene-3,4'-piperidine)

Naslovni spoj se dobiva kao u Primjeru 21 iz 4-brom-2-(S)-(4-klorofenil)-1-(N- (3,5-bistrifluoro metilbenzoil)- metilamino) butana i spiro(2,3-dihidrobenzotiofen-3,4'-piperidin) hidroklorida osim što je upotrijebljeno 3 ekviv. diizopropiletilamina. The title compound is obtained as in Example 21 from 4-bromo-2-(S)-(4-chlorophenyl)-1-(N-(3,5-bistrifluoromethylbenzoyl)-methylamino)butane and spiro(2,3-dihydrobenzothiophene -3,4'-piperidine) hydrochloride except that 3 equiv. diisopropylethylamine.

Maseni spektar (Cl/NH3) M+H=641, 643 (35,37Cl-izotop). Mass spectrum (Cl/NH3) M+H=641, 643 (35.37Cl-isotope).

Primjer 28 Example 28

1'-(3-(RS)-(4-Piridil)-4-(N-(3,5-bistrifluorometilbenzoil)-(metilamino))butil)-1-acetil-spiro(indolin-3,4-piperidin) 1'-(3-(RS)-(4-Pyridyl)-4-(N-(3,5-bistrifluoromethylbenzoyl)-(methylamino))butyl)-1-acetyl-spiro(indoline-3,4-piperidine)

Naslovni spoj se dobiva iz 3-(S)-(4-piridil)-4-(N-(3,5-bistrifluorometilbenzoil)metilamino)butanala (dobivenog iz 4-piridiloctene kiseline kao što su opisali J. Hale i surad., Bioorganic & Medicinal Chemistry Letters 1993, 3, 319-322) reduktivnim aminiranjem kao što je opisano u Primjeru 2. The title compound is obtained from 3-(S)-(4-pyridyl)-4-(N-(3,5-bistrifluoromethylbenzoyl)methylamino)butanal (obtained from 4-pyridylacetic acid as described by J. Hale et al., Bioorganic & Medicinal Chemistry Letters 1993, 3, 319-322) by reductive amination as described in Example 2.

Maseni spektar (Cl/NH3) M+H=633. Mass spectrum (Cl/NH3) M+H=633.

Primjer 29 Example 29

1'-(3-(S)-(3,4-Diklorofenil)-4-(N-(3,5-dimetilbenzoil)-(etilamino))butil)-1-metansulfonil-spiro(indolin-3,4'-piperidin) 1'-(3-(S)-(3,4-Dichlorophenyl)-4-(N-(3,5-dimethylbenzoyl)-(ethylamino))butyl)-1-methanesulfonyl-spiro(indoline-3,4' -piperidine)

Stupanj A: Grade A:

4-Brom-2-(S)-(3,4-diklorofenil)-1-(N-(3,5-dimetilbenzoil)metilamino)butan 4-Bromo-2-(S)-(3,4-dichlorophenyl)-1-(N-(3,5-dimethylbenzoyl)methylamino)butane

Naslovni spoj se dobiva kao u Primjeru 20, Stupnjevi A i B iz 3-(S)-(3,4-diklorofenil)-4-(N-(3,5-dimetilbenzoil) etilamino)butanala (dobivenog iz 3,4-diklorofeniloctene kiseline kao što su opisali J. Hale i surad., (Bioorganic & Medicinal Chemistry Letters 1993, 3, 319-322) upotrebljavajući etilamin prije nego metilamin da bi se dobio intermedijarni amid). The title compound is obtained as in Example 20, Steps A and B from 3-(S)-(3,4-dichlorophenyl)-4-(N-(3,5-dimethylbenzoyl)ethylamino)butanal (obtained from 3,4- of dichlorophenylacetic acid as described by J. Hale et al., (Bioorganic & Medicinal Chemistry Letters 1993, 3, 319-322) using ethylamine rather than methylamine to give the intermediate amide).

Maseni spektar (Cl/NH3) M = 454, 456 (79,81Br izotop). Mass spectrum (Cl/NH3) M = 454, 456 (79.81Br isotope).

Stupanj B: Grade B:

1'-(3-(S)-(3,4-Diklorofenil)-4-(N-(3,5-dimetilbenzoil)-(etilamino))butil-1-metansulfonil-spiro(indolin-3,4'-piperidin). 1'-(3-(S)-(3,4-Dichlorophenyl)-4-(N-(3,5-dimethylbenzoyl)-(ethylamino))butyl-1-methanesulfonyl-spiro(indoline-3,4'- piperidine).

Naslovni spoj se dobiva iz bromida dobivenog u Stupnju i 1-acetil-spiro(indolin-3,4'-piperidina) kao što je opisano u Primjeru 21. The title compound is obtained from the bromide obtained in Step 1 and 1-acetyl-spiro(indoline-3,4'-piperidine) as described in Example 21.

Primjer 30 Example 30

5-Fluoro-spiro(2,3-dihidrobenzofuran-3,4'-piperidin)hidrokloridna sol 5-Fluoro-spiro(2,3-dihydrobenzofuran-3,4'-piperidine) hydrochloride salt

Stupanj 1: Level 1:

4-(2,5-Difluorofenil)-4-metoksikarbonil-1-metilpiperidin 4-(2,5-Difluorophenyl)-4-methoxycarbonyl-1-methylpiperidine

Metil 2,5-difluorofenilacetat (4.8 g, 26 mmola) i mekloretilamin hidroklorid (5.0 g, 26 mmola) u DMSO 615 ml) i THF (50 ml) na 0°C se pažljivo tretiraju sa NaH (2.5 g, 104 mmola). Reakcija se postupno zagrijava do refluksa u toku 1 sata i refluksira daljnjih 1 sat. Reakcija se ohladi do 0°C, i lagano se dodaje 6N HCl (25 ml). Reakcija se razblažuje sa 1N HCl (200 ml) i pere se sa heksanom (200 ml). Vodeni sloj se ohladi do 0°C i podesi se na pH 12 sa čvrstim K2CO3. Proizvod se ekstrahira sa etil acetatom (200 ml), pere se sa slanom otopinom (100 ml), suši (MgSO4), i koncentrira do 4.1 g (59%) naslovnog spoja kao ulje. Methyl 2,5-difluorophenylacetate (4.8 g, 26 mmol) and mechlorethylamine hydrochloride (5.0 g, 26 mmol) in DMSO (615 ml) and THF (50 ml) at 0°C are carefully treated with NaH (2.5 g, 104 mmol) . The reaction was gradually heated to reflux over 1 hour and refluxed for an additional 1 hour. The reaction was cooled to 0°C, and 6N HCl (25 mL) was slowly added. The reaction was diluted with 1N HCl (200 ml) and washed with hexane (200 ml). The aqueous layer was cooled to 0°C and adjusted to pH 12 with solid K2CO3. The product was extracted with ethyl acetate (200 ml), washed with brine (100 ml), dried (MgSO 4 ), and concentrated to 4.1 g (59%) of the title compound as an oil.

1H NMR (400 MHz, CDCl3) δ 7.34 (dkvar., 1H), 6.88 (m, 1H), (ddd, 1H), 6.69 (minor NMe invertomer, dm), 6.59 (minor NMe invertomer, dd), 3.69 (s, 3H), 3.80 (minor invertomer, s), 2.71 (d, 2H), 2.48 (d, 2H), 2.38 (t, 2H), 2.25 (s, 3H), 2.10 (t, 2H) ppm. 1H NMR (400 MHz, CDCl3) δ 7.34 (dquar., 1H), 6.88 (m, 1H), (ddd, 1H), 6.69 (minor NMe invertomer, dm), 6.59 (minor NMe invertomer, dd), 3.69 ( s, 3H), 3.80 (minor invertomer, s), 2.71 (d, 2H), 2.48 (d, 2H), 2.38 (t, 2H), 2.25 (s, 3H), 2.10 (t, 2H) ppm.

Stupanj 2: Stage 2:

4-(2,5-Difluorofenil)-4-hidroksimetil-1-metilpiperidin 4-(2,5-Difluorophenyl)-4-hydroxymethyl-1-methylpiperidine

EtOH (5.1 ml, 86 mmola) se dodaje u 0.5 M LiA1H4 u glimu (CH3OC2H4OCH3) (82 ml, 41 mmola) na 0�C. Dodaje se 4-(2,5-difluorofenil)-4-metoksikarbonil-1-metil-piperidin (3.45 g, 12.8 mmola) u glimu (4 ml). EtOH (5.1 ml, 86 mmol) was added to 0.5 M LiA1H4 in glyme (CH3OC2H4OCH3) (82 ml, 41 mmol) at 0°C. Add 4-(2,5-difluorophenyl)-4-methoxycarbonyl-1-methyl-piperidine (3.45 g, 12.8 mmol) in glyme (4 mL).

Zajedno sa celtirom (10 g) dodaje se zasićena vodena otopina natrij kalij tartarat (50 ml) i smjesa se miješa mehanički 1 sat na sobnoj temperaturi. Suspenzija se filtrira, organski sloj se ekstrahira sa 1N HCl. HCl se pere sa EtOAc i zatim se zaalkilira sa 3N NaOH. Proizvod se ekstrahira sa CH2Cl2, pere se sa 20% slanom otopinom, suši (MgSO4) i koncentrira do sirove čvrste tvari, koja se prekristalizira (EtOAc), pri čemu se dobiva 1.46 g (52% naslovnog spoja kao bezbojni kristali). A saturated aqueous solution of sodium potassium tartrate (50 ml) is added together with Celtir (10 g) and the mixture is mechanically stirred for 1 hour at room temperature. The suspension is filtered, the organic layer is extracted with 1N HCl. The HCl is washed with EtOAc and then alkylated with 3N NaOH. The product was extracted with CH2Cl2, washed with 20% brine, dried (MgSO4) and concentrated to a crude solid, which was recrystallized (EtOAc) to give 1.46 g (52% of the title compound as colorless crystals).

1H NMR (400 MHz, CDCl3) δ 7.28 (dt, 1H, J = 7.9 Hz), 6.88 (ddd, 1H, J = 3,9,9, Hz), 6.81 (ddd, J=3,9,13 Hz), 3.76 (s, 2H), 2.59 (m, 2H), 2.32-2.20 (m, 4H), 2.23 (s, 3H), 1.96 (t, 2H, J=5 Hz) ppm. 1H NMR (400 MHz, CDCl3) δ 7.28 (dt, 1H, J = 7.9 Hz), 6.88 (ddd, 1H, J = 3,9,9, Hz), 6.81 (ddd, J=3,9,13 Hz ), 3.76 (s, 2H), 2.59 (m, 2H), 2.32-2.20 (m, 4H), 2.23 (s, 3H), 1.96 (t, 2H, J=5 Hz) ppm.

Stupanj 3: Level 3:

5-Fluoro-1'metil-spiro82,3-diklorobenzofuan-3,4'-piperidin) 5-Fluoro-1'methyl-spiro82,3-dichlorobenzofuan-3,4'-piperidine)

NaH (158 mg, 6.56 mmola) se dodaje u 4-(2,5-difluorofenil)-4-hidroksimetil-1-metilpiperidin (1.45 g, 6.56 mmola) u DMF (20 ml). Suspenzija se zagrijava do 90°C 6 sati. Reakcija se razblažuje sa heksanom (200 ml), pere se sa vodom (200 ml), slanom otopinom (50 ml), suše (MgSO4), i koncentriraju, pri čemu se dobiva 1.21 g (92%) naslovnog spoja u obliku bijele kristalne tvari; NaH (158 mg, 6.56 mmol) was added to 4-(2,5-difluorophenyl)-4-hydroxymethyl-1-methylpiperidine (1.45 g, 6.56 mmol) in DMF (20 mL). The suspension is heated to 90°C for 6 hours. The reaction was diluted with hexane (200 ml), washed with water (200 ml), brine (50 ml), dried (MgSO4), and concentrated to give 1.21 g (92%) of the title compound as a white crystalline solid. substances;

1H NMR (400 MHz, CDCl3) δ 6.98 (dd, 1H), 6.54 (dt, 1H), 6.48 (dd, 1H), 4.37 (s, 2H), 2.84 (m, 2H), 2.31 (s, 3H), 1.97 (4H, pentuplet), 1.71 (m, 2H) ppm. 1H NMR (400 MHz, CDCl3) δ 6.98 (dd, 1H), 6.54 (dt, 1H), 6.48 (dd, 1H), 4.37 (s, 2H), 2.84 (m, 2H), 2.31 (s, 3H) , 1.97 (4H, pentuplet), 1.71 (m, 2H) ppm.

Stupanj 4: Stage 4:

5-Fluoro-spiro(2,3-dihidrobenzofuran-3,4'-piperidin) hidrokloridna sol 5-Fluoro-spiro(2,3-dihydrobenzofuran-3,4'-piperidine) hydrochloride salt

5-Fluor-1'-metil-spiro(2,3-dihidrobenzofuran-3,4'-piperidin) (1.21 g, 5.48 mmola) u 1,2-dikloretanu (12 ml) tretira se na sobnoj temperaturi sa 2-kloretil klorformijatom (1 ml, 9 mmola). Tvori se bijeli talog, i reakcija se refluksira 2 sata. Dodaje se MeOH (12 ml) i refluksiranje se nastavlja 2 sata. Reakcija se koncentrira do sirove čvrste tvari, koja se triturira sa EtOAc (5 ml) i filtrira, pri čemu se dobiva 1.27 g (95%) naslovnog spoja kao bijela kristalna čvrsta tvar. 5-Fluoro-1'-methyl-spiro(2,3-dihydrobenzofuran-3,4'-piperidine) (1.21 g, 5.48 mmol) in 1,2-dichloroethane (12 ml) was treated at room temperature with 2-chloroethyl with chloroformate (1 ml, 9 mmol). A white precipitate forms, and the reaction is refluxed for 2 hours. MeOH (12 mL) was added and reflux was continued for 2 h. The reaction was concentrated to a crude solid, which was triturated with EtOAc (5 mL) and filtered to give 1.27 g (95%) of the title compound as a white crystalline solid.

1H NMR (400 MHz, d6-DMSO) δ 9.12 (s, 1H), 9.04 (s, 1H), 7.11 (dd, 1H), 7.74-7.66 (m, 2H), 4.53 (s, 2H), 3.26 (d, 2H), 2.95 (t, 2H), 2.08 (t, 2H), 1.79 (d, 2H) ppm. 1H NMR (400 MHz, d6-DMSO) δ 9.12 (s, 1H), 9.04 (s, 1H), 7.11 (dd, 1H), 7.74-7.66 (m, 2H), 4.53 (s, 2H), 3.26 ( d, 2H), 2.95 (t, 2H), 2.08 (t, 2H), 1.79 (d, 2H) ppm.

Reakcija 5-fluoro-spiro(2,3-dihidrobenzofuran-3,4'-piperidin) hidroklorida sa 3-((S)-(3,4-diklorofenil))-4-(N-(t- butiksi karbonil-(metilamino)butanalom prema postupku datom u Primjeru 8, postupak B daje 1'-(3-((S)-(3,4- diklorofenil)) -4-(N-(t- butoksikarbonil)-(metilamino))butil)-5-fluoro-spiro(2,3-dihidrobenzofuran-3,4'piperidin). Reaction of 5-fluoro-spiro(2,3-dihydrobenzofuran-3,4'-piperidine) hydrochloride with 3-((S)-(3,4-dichlorophenyl))-4-(N-(t-butoxycarbonyl-( with methylamino)butanal according to the procedure given in Example 8, procedure B gives 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(t-butoxycarbonyl)-(methylamino))butyl) -5-fluoro-spiro(2,3-dihydrobenzofuran-3,4'piperidine).

Uklanjanje BOC grupe i tvorba benzamida prema postupku datom u Primjeru 3, Stupnjevi A i B daju spojeve nabrojane u Primjerima 31-36. Removal of the BOC group and benzamide formation according to the procedure given in Example 3, Steps A and B gives the compounds listed in Examples 31-36.

Primjer 31 Example 31

1'(3-((S)-(3,4-Diklorofenil))-4-(N-(3,5-diklorobenzoil)-(metilamino))butil)-5-fluoro-spiro(2,3-dihidrobenzofuran 1'(3-((S)-(3,4-Dichlorophenyl))-4-(N-(3,5-dichlorobenzoyl)-(methylamino))butyl)-5-fluoro-spiro(2,3-dihydrobenzofuran

-3,4'-piperidin) -3,4'-piperidine)

Maseni spektar (Cl): m/z = 611.2 (35Cl + 35Cl izotop + H+), 613.2 (37Cl + 35Cl izotop + H+). Mass spectrum (Cl): m/z = 611.2 (35Cl + 35Cl isotope + H+), 613.2 (37Cl + 35Cl isotope + H+).

Primjer 32 Example 32

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(4-fluoro-1-naftoil)-(metilamino))butil9-5-fluoro-spiro(2,3-dihidrobenzofuran 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(4-fluoro-1-naphthoyl)-(methylamino))butyl9-5-fluoro-spiro(2,3 -dihydrobenzofuran

-3,4'-piperidin) -3,4'-piperidine)

Maseni spektar (Cl): m/z = 609.3 (35Cl + 35Cl izotop + H+), 611.3 (37Cl + 35Cl izotop + H+). Mass spectrum (Cl): m/z = 609.3 (35Cl + 35Cl isotope + H+), 611.3 (37Cl + 35Cl isotope + H+).

Primjer 33 Example 33

1'-(3-((S)-(3,4-Diklorofenil)-4-(N-(3-klorbenzoil)-(metilamino))butil)-5-fluoro-spiro(2,3-dihidrobenzofuran-3,4' 1'-(3-((S)-(3,4-Dichlorophenyl)-4-(N-(3-chlorobenzoyl)-(methylamino))butyl)-5-fluoro-spiro(2,3-dihydrobenzofuran-3 ,4'

-piperidin) -piperidine)

Maseni spektar (Cl): m/z = 575.2 (35Cl + 35Cl izotop + H+), 577.2 (37Cl + 37Cl izotop + H+). Mass spectrum (Cl): m/z = 575.2 (35Cl + 35Cl isotope + H+), 577.2 (37Cl + 37Cl isotope + H+).

Primjer 34 Example 34

1'-(3-((S)-(3,4-Diklorofenil)-4-(N-(3,5-dimetilbenzoil)-(metilamino))butil)-5-fluoro-spiro(2,3-dihidrobenzofuran 1'-(3-((S)-(3,4-Dichlorophenyl)-4-(N-(3,5-dimethylbenzoyl)-(methylamino))butyl)-5-fluoro-spiro(2,3-dihydrobenzofuran

-3,4'-piperidin) -3,4'-piperidine)

Maseni spektar (Cl): m/z = 569.3 (35Cl + 35Cl izotop + H+), 571.3 (37Cl + 35Cl izotop + H+). Mass spectrum (Cl): m/z = 569.3 (35Cl + 35Cl isotope + H+), 571.3 (37Cl + 35Cl isotope + H+).

Primjer 35 Example 35

1'(3-((S)-(3,4-Diklorofenil)-4-(N-(3-metilbenzoil)-(metilamino))butil)-5-fluoro-spiro(2,3-dihidrobenzofuran-3,4' 1'(3-((S)-(3,4-Dichlorophenyl)-4-(N-(3-methylbenzoyl)-(methylamino))butyl)-5-fluoro-spiro(2,3-dihydrobenzofuran-3, 4'

-piperidin) -piperidine)

Maseni spektar (Cl): m/z = 555.3 (35Cl + 35Cl izotop + H+), 557.3 (37Cl + 35Cl izotop + H+). Mass spectrum (Cl): m/z = 555.3 (35Cl + 35Cl isotope + H+), 557.3 (37Cl + 35Cl isotope + H+).

Primjer 36 Example 36

1'-(3-((S)-(3,4-diklorofenil))-4-(N-(benzoil)-(metilamino)-butil)-5-fluoro-spiro(2,3- dihidrobenzofuran-3,4' 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(benzoyl)-(methylamino)-butyl)-5-fluoro-spiro(2,3-dihydrobenzofuran-3, 4'

-piperidin) -piperidine)

Maseni spektar (Cl): m/z = 541.3 (35Cl + 35Cl izotop + H+), 543.3 (37Cl + 35Cl izotop + H+). Mass spectrum (Cl): m/z = 541.3 (35Cl + 35Cl isotope + H+), 543.3 (37Cl + 35Cl isotope + H+).

Dobivanje spiro(2,3-dihidrobenzofuran-3,4'-piperidin) hidroklorida izvodi se analogno sa postupkom iznijetim u Primjeru 30, polazeći sa metil 2-fluorofenilacetatom. Reakcija spiro(2,3-dihidrobenzofuran-3,4'-piperidin) hidroklorida sa 3-(S)-(3,4- diklorfenil)-4-(t-butoksikarbonil-metilamino)-butanalom prema postupku iznijetom u Primjeru 8, Stupanj B, daje 1'-(3-((S)-(3,4-diklorofenil))-4-(N-(t-butoksikarbonil)-(metilamino))butil)-spiro(2,3-dihidrobenzofuran-3,4'-piperidin). Uklanjanje BOC grupe i tvorba benzamida prema postupku iznijetom u Primjeru 3, Stupnjevi A i B daju spojeve navedene u Primjerima 37-43. Obtaining spiro(2,3-dihydrobenzofuran-3,4'-piperidine) hydrochloride is carried out analogously to the procedure outlined in Example 30, starting with methyl 2-fluorophenylacetate. Reaction of spiro(2,3-dihydrobenzofuran-3,4'-piperidine) hydrochloride with 3-(S)-(3,4-dichlorophenyl)-4-(t-butoxycarbonyl-methylamino)-butanal according to the procedure outlined in Example 8, Step B gives 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(t-butoxycarbonyl)-(methylamino))butyl)-spiro(2,3-dihydrobenzofuran- 3,4'-piperidine). Removal of the BOC group and benzamide formation according to the procedure outlined in Example 3, Steps A and B afforded the compounds listed in Examples 37-43.

Primjer 37 Example 37

1'-(3-((S)-(3,4-diklorofenil)-4-(N-(benzoil)-(metilamino))-butil)-spiro(2,3-dihidrobenzofuran-3,4'-piperidin) 1'-(3-((S)-(3,4-dichlorophenyl)-4-(N-(benzoyl)-(methylamino))-butyl)-spiro(2,3-dihydrobenzofuran-3,4'-piperidine )

Maseni spektar (Cl): m/z = 523.1 (35Cl + 35Cl izotop + H+). Mass spectrum (Cl): m/z = 523.1 (35Cl + 35Cl isotope + H+).

Primjer 38 Example 38

1'-(3-((S)-(4,3-diklorofenil))-4-(N-(3-metilbenzoil)-(metilamino))butil-spiro(2,3-dihidrobenzofuran-3,4'-piperidin) 1'-(3-((S)-(4,3-dichlorophenyl))-4-(N-(3-methylbenzoyl)-(methylamino))butyl-spiro(2,3-dihydrobenzofuran-3,4'- piperidine)

Maseni spektar (Cl): m/z = 537.2 (35Cl + 35Cl izotop + H+), 539.2 (37Cl + 35Cl izotop + H+). Mass spectrum (Cl): m/z = 537.2 (35Cl + 35Cl isotope + H+), 539.2 (37Cl + 35Cl isotope + H+).

Primjer 39 Example 39

1'-(3-((S)-(3,4-diklorfenil))-4.N-(3,5-dimetilbenzoil)-(metilamino))butil)-spiro(2,3- dihidrobenzoruran-3,4'-piperidin) 1'-(3-((S)-(3,4-dichlorophenyl))-4.N-(3,5-dimethylbenzoyl)-(methylamino))butyl)-spiro(2,3-dihydrobenzorurane-3,4 '-piperidine)

Maseni spektar (Cl): m/z = 551.2 (35Cl + 35Cl izotop + H+), 553.2 (37Cl + 35Cl izotop + H+). Mass spectrum (Cl): m/z = 551.2 (35Cl + 35Cl isotope + H+), 553.2 (37Cl + 35Cl isotope + H+).

Primjer 40 Example 40

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(3-klorobenzoil)-(metilamino))butil)-spiro(2,3-dihidrobenzofuran-3,4'-piperidin) 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(3-chlorobenzoyl)-(methylamino))butyl)-spiro(2,3-dihydrobenzofuran-3,4' -piperidine)

Maseni spektar (Cl): m/z = 557.0 (35Cl + 35Cl izotop + H+). Mass spectrum (Cl): m/z = 557.0 (35Cl + 35Cl isotope + H+).

Primjer 41 Example 41

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(3,5-diklorobenzoil)-(metilamino))butil)-spiro(2,3-dihidrobenzofuran-3,4'-piperidin) 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(3,5-dichlorobenzoyl)-(methylamino))butyl)-spiro(2,3-dihydrobenzofuran-3, 4'-piperidine)

Maseni spektar (Cl): m/z = 591.0 (35Cl + 35Cl izotop + H+), 593.1 (37Cl + 35Cl izotop + H+). Mass spectrum (Cl): m/z = 591.0 (35Cl + 35Cl isotope + H+), 593.1 (37Cl + 35Cl isotope + H+).

Primjer 42 Example 42

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(4-fluoro-1-naftoil)-(metilamino))butil)-spiro(2,3-dihidrobenzofuran-3,4'-piperidin). 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(4-fluoro-1-naphthoyl)-(methylamino))butyl)-spiro(2,3-dihydrobenzofuran- 3,4'-piperidine).

Maseni spektar (Cl): m/z = 591.3 (35Cl + 35Cl izotop + H+), 593.2 (37Cl + 35Cl izotop + H+). Mass spectrum (Cl): m/z = 591.3 (35Cl + 35Cl isotope + H+), 593.2 (37Cl + 35Cl isotope + H+).

Primjer 44 Example 44

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(t-butoksikarbonil)-(metilamino))butil)-spiro(2,3-dihidrobenzotiofen-3,4'-piperidin) 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(t-butoxycarbonyl)-(methylamino))butyl)-spiro(2,3-dihydrobenzothiophene-3,4' -piperidine)

Stupanj 1: Level 1:

1-t-Butoksikarbonil-3-hidroksi-4-metilen-piperidin 1-t-Butoxycarbonyl-3-hydroxy-4-methylene-piperidine

U otopinu diizopropilamina (3.32 ml, 23.7 mmola) u THF (15 ml) na -78°C dodaje se otopina n-butil litij (9.57 ml, 2.45 M u heksanu, 23.7 mmola). Poslije 30 minuta na -78°C dodaje se metil fenil suffoksid (3.32 g, 23.7 mmola) u THF (4 ml). Otopina se zagrijava do 0°C i ohladi se ponovno do -78°C. Dodaje se 1-t-butoksikarbonil-4-piperidinon (4.69 g, 23.7 mmola) u THF (20 ml). Reakcija se zagrijava do sobne temperature, zaustavi se dodatkom čvrstog NH4Cl, koncentrira se u vakuumu i raspodjeljuje se između H2O (100 ml) i EtOAc (100 ml). Organski sloj se pere sa H2O (50 ml), slanom otopinom (50 ml), suši (MgSO4) i koncentrira u vakuumu. Dobiveno ulje se zagrijava na 80°C u t-butanolu (50 ml) sa kalij t-butoksidom (3.4 g, 30 mmola) 2 sata. Dodaje se čvrst NH4Cl, i reakcija se koncentrira u vakuumu i raspodjeljuje između H2O (100 ml) i EtOAc (100 ml). EtOAc se pere sa salnom otopinom (50 ml), suši (MgSO4), koncentrira u vakuumu i pročišćava kromatografijom na koloni (silika gel 60, 0-50% EtOAc/heksan), pri čemu se dobiva 4.47 g (79% naslovnog spoja kao kristalna čvrsta tvar). A solution of n-butyl lithium (9.57 ml, 2.45 M in hexane, 23.7 mmol) was added to a solution of diisopropylamine (3.32 ml, 23.7 mmol) in THF (15 ml) at -78°C. After 30 minutes at -78°C, methyl phenyl sulfoxide (3.32 g, 23.7 mmol) in THF (4 ml) was added. The solution is heated to 0°C and cooled again to -78°C. 1-t-Butoxycarbonyl-4-piperidinone (4.69 g, 23.7 mmol) in THF (20 mL) was added. The reaction was warmed to room temperature, quenched with solid NH 4 Cl, concentrated in vacuo and partitioned between H 2 O (100 mL) and EtOAc (100 mL). The organic layer was washed with H 2 O (50 ml), brine (50 ml), dried (MgSO 4 ) and concentrated in vacuo. The obtained oil is heated at 80°C in t-butanol (50 ml) with potassium t-butoxide (3.4 g, 30 mmol) for 2 hours. Solid NH 4 Cl was added, and the reaction was concentrated in vacuo and partitioned between H 2 O (100 mL) and EtOAc (100 mL). EtOAc was washed with brine (50 ml), dried (MgSO4), concentrated in vacuo and purified by column chromatography (silica gel 60, 0-50% EtOAc/hexane) to give 4.47 g (79% of the title compound as crystalline solid).

1H NMR (400 MHz, DMSO-d6) δ 5.21 (d, 1H), 4.96 (s, 1H), 4.77 (s, 1H), 3.82 (t, 2H), 3.67 (dt, 1H), 2.83 (dt, 1H), 2.77-2.50 (širok d, 1H), 2.26 (dt, 1H), 2.01 (ddd, 1H), 1.38 (s, 9H) ppm. 1H NMR (400 MHz, DMSO-d6) δ 5.21 (d, 1H), 4.96 (s, 1H), 4.77 (s, 1H), 3.82 (t, 2H), 3.67 (dt, 1H), 2.83 (dt, 1H), 2.77-2.50 (broad d, 1H), 2.26 (dt, 1H), 2.01 (ddd, 1H), 1.38 (s, 9H) ppm.

Stupanj 2: Stage 2:

1-t-Butoksikarbonil-3,4-didehidro-4-(klorometil)piperidin 1-t-Butoxycarbonyl-3,4-didehydro-4-(chloromethyl)piperidine

U 1-t-butoksikarbonil-3-hidroksi-4-metilen-piperidina (5.329 g, 25.1 mmola) u toluolu (120 ml) i 2,6-lutidina (3.1 ml, 26mmola) na 0°C, dodaje se SOC12 (2.0 ml, 26 mmola). Reakcija se zagrijava na 40°C 30 minuta, ohladi se do 0°C, pere sa 0°C 1N HCl (100 ml), 0.1 N HCl (100 ml), H2O (100 ml), slanom otopinom (50 ml), suši (MgSO4), i koncentrira u vakuumu, pri čemu se dobiva 5.18 g (89%) alilnog klorida kao žuto ulje. To 1-t-butoxycarbonyl-3-hydroxy-4-methylene-piperidine (5.329 g, 25.1 mmol) in toluene (120 mL) and 2,6-lutidine (3.1 mL, 26 mmol) at 0°C, SOC12 ( 2.0 ml, 26 mmol). The reaction is heated to 40°C for 30 minutes, cooled to 0°C, washed with 0°C 1N HCl (100 ml), 0.1 N HCl (100 ml), H2O (100 ml), brine (50 ml), dried (MgSO4), and concentrated in vacuo to give 5.18 g (89%) of allyl chloride as a yellow oil.

1H NMR (400 MHz, CDCl3) δ 5.78 (s, 1H), 4.04 (s, 2H), 3.95 (s, 2H), 3.55 (t, 2H, J = 6 Hz), 2.24 (s, 2H), 1.45 (s, 9H) ppm. 1H NMR (400 MHz, CDCl3) δ 5.78 (s, 1H), 4.04 (s, 2H), 3.95 (s, 2H), 3.55 (t, 2H, J = 6 Hz), 2.24 (s, 2H), 1.45 (s, 9H) ppm.

Stupanj 3: Level 3:

1-t-Butoksikarbonil-4-((2-bromofenil)tio)-metil-1,2,5,6-tetrahidropiridin 1-t-Butoxycarbonyl-4-((2-bromophenyl)thio)-methyl-1,2,5,6-tetrahydropyridine

Alilni Klorid (330 mg, 1.43 mmola) se otapa u acetonu (10 ml) i dodaje se 2-bromotiofenol (172 ml, 1.43 mmola) i K2CO3 (390 mg, 2.86 mmola). Reakcijska smjesa se zagrijava do 60°C 1 sat, a zatim se filtrira kroz silika gel (eter). Organski sloj se koncentrira u vakuumu i pročišćava kromatografijom na koloni (silika gel, 60, heksani/etil acetat 10/1), pri čemu se dobiva naslovni spoj u 84% prinosu (460 mg). Allyl chloride (330 mg, 1.43 mmol) was dissolved in acetone (10 ml) and 2-bromothiophenol (172 ml, 1.43 mmol) and K2CO3 (390 mg, 2.86 mmol) were added. The reaction mixture is heated to 60°C for 1 hour and then filtered through silica gel (ether). The organic layer is concentrated in vacuo and purified by column chromatography (silica gel, 60, hexanes/ethyl acetate 10/1), whereby the title compound is obtained in 84% yield (460 mg).

Stupanj 4: Stage 4:

1'-t-Butoksikarbonil-spiro(2,3-dihidrobenzotiofen-3,4'-piperidin) 1'-t-Butoxycarbonyl-spiro(2,3-dihydrobenzothiophene-3,4'-piperidine)

Intermedijarni adukt (proizvod pripajanja) iz Stupnja 3 gore (450 mg 1.17 mmola) se otapa u benzolu (60 ml) i dodaju se AIBN (10 mg) i tributilkalaj hidrid (644 ml, 2.39 mmola). Smjesa se refluksira 2 sata i koncentrira. Ostatak se otapa u Et2O i dodaje se Br2 sve dok reakcijska otopina ne postane mrke boje. U ovu mrku otopinu na sobnoj temperaturi se dodaju DBU (650 ml) ukapavanjem. Dobivena zamućena otopina se filtrira kroz silika gel i pere se sa Et2O. Et2O otopina se koncentrira i ostatak se pročišćava radijalnom kromatografijom (silika gel 60, 10/1 heksani/EtOAc), pri čemu se dobiva naslovni spoj (157 mg) u 43% prinosu. The intermediate adduct (coupling product) from Step 3 above (450 mg 1.17 mmol) was dissolved in benzene (60 mL) and AIBN (10 mg) and tributyltin hydride (644 mL, 2.39 mmol) were added. The mixture is refluxed for 2 hours and concentrated. The residue is dissolved in Et2O and Br2 is added until the reaction solution becomes dark in color. DBU (650 ml) was added dropwise to this dark solution at room temperature. The resulting cloudy solution is filtered through silica gel and washed with Et2O. The Et 2 O solution was concentrated and the residue was purified by radial chromatography (silica gel 60, 10/1 hexanes/EtOAc) to give the title compound (157 mg) in 43% yield.

1H NMR (400 MHz, CDCl3) δ 7.18 (d, 7Hz, 1H), 7.12 (t, 7Hz, 1H), 7.06 (m, 2H), 4.11 (m, 2H), 3.30 (s, 3H), 2.89 (m, 2H), 1.79 (m, 4H), 1.47 (s, 9H) ppm. 1H NMR (400 MHz, CDCl3) δ 7.18 (d, 7Hz, 1H), 7.12 (t, 7Hz, 1H), 7.06 (m, 2H), 4.11 (m, 2H), 3.30 (s, 3H), 2.89 ( m, 2H), 1.79 (m, 4H), 1.47 (s, 9H) ppm.

Uklanjanje BOC grupe prema postupku izloženom u Primjeru 3, Stupanj A, a zatim reakcijom sa 3-((S)-(3,4- diklorofenil))-4-(N-(t-butoksikarbonil)-(metilamino))-butanalom prema postupku izloženom u Primjeru 8, Postupak B daje 1'-(3-((S)-(3,4-diklorofenil))-4-(N-(t-butoksikarbonil)-(metilamino))-butil)-spiro(2,3-dihidrobenzotiofen-3,4'-piperidin). Removal of the BOC group according to the procedure set forth in Example 3, Step A, followed by reaction with 3-((S)-(3,4-dichlorophenyl))-4-(N-(t-butoxycarbonyl)-(methylamino))-butanal according to the procedure set forth in Example 8, Procedure B provides 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(t-butoxycarbonyl)-(methylamino))-butyl)-spiro (2,3-dihydrobenzothiophene-3,4'-piperidine).

Uklanjanje BOC grupe i tvorba benzamida prema postupku opisanom u Primjeru 3, Stupnjevi A i B daje spojeve navedene u Primjerima 45-46: Removal of the BOC group and benzamide formation according to the procedure described in Example 3, Steps A and B gives the compounds listed in Examples 45-46:

Primjer 45 Example 45

1'-(3-((S)-(3,4-Diklorofenil)-4-(N-(3,5-dimetilbenzoil)-(metilamino))butil)-spiro(2,3-dihidrobentotiofen-3,4'-piperidin) 1'-(3-((S)-(3,4-Dichlorophenyl)-4-(N-(3,5-dimethylbenzoyl)-(methylamino))butyl)-spiro(2,3-dihydrobentothiophene-3,4 '-piperidine)

Maseni spektar (Cl): m/z = 567.2 (35Cl + 35Cl izotop + H+), 569.2 (37Cl + 35Cl izotop + H+). Mass spectrum (Cl): m/z = 567.2 (35Cl + 35Cl isotope + H+), 569.2 (37Cl + 35Cl isotope + H+).

Primjer 46 Example 46

1'(3-((S)-(4-Klorofenil))-4-(N-(3,5-dimetilbenzoil)-(metilamino))butil)-spiro(2,3- dihidrobenzotiofen-3,4'-piperidin) 1'(3-((S)-(4-Chlorophenyl))-4-(N-(3,5-dimethylbenzoyl)-(methylamino))butyl)-spiro(2,3-dihydrobenzothiophene-3,4'- piperidine)

Maseni spektar (Cl): m/z = 533 (35Cl + 35Cl izotop + H+), 535 (37Cl + 35Cl izotop + H+). Mass spectrum (Cl): m/z = 533 (35Cl + 35Cl isotope + H+), 535 (37Cl + 35Cl isotope + H+).

Primjer 47 Example 47

1'-(3-((S)-(3,4-Diklorofenil)-4-(N-(6-butoksikarbonil)-(metilamino)butil)spiro(2,3-dihidrobenzotioen-3,4'-piperidin)-1-oksid 1'-(3-((S)-(3,4-Dichlorophenyl)-4-(N-(6-butoxycarbonyl)-(methylamino)butyl)spiro(2,3-dihydrobenzothioene-3,4'-piperidine) -1-oxide

1'-(3-((S)-(3,4-Diklorofenil))-4-(n-(t-butoksikarbonil)-(metilamino))butil)-spiro(2,3-dihidrobenzotiofen-3,4'-piperidin) (222 mg, 415 mmola) u CH2Cl2 (500 ul) na -78�C tretira se sa otopinom m-klorperbenzoeve kiseline (86 mg, 498 mola) u CH2Cl2 (1 ml). Reakcija se izruči u zasićenu otopinu NaHSO3 na 0°C. Organski sloj se pere zasićenom vodenom otopinom NaHCO3 (1 ml), slanom otopinom (1 ml), suši (MgSO4), koncentrira u vakuumu i pročišćava kromatografijom na koloni (silika gel 60, 0-100% acetona/CH2Cl2), pri čemu se dobiva 54.3 mg (24%) naslovnog spoja u obliku bijele pjene. 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(n-(t-butoxycarbonyl)-(methylamino))butyl)-spiro(2,3-dihydrobenzothiophene-3,4' -piperidine) (222 mg, 415 mmol) in CH2Cl2 (500 ul) at -78°C is treated with a solution of m-chloroperbenzoic acid (86 mg, 498 mol) in CH2Cl2 (1 ml). The reaction was poured into saturated NaHSO3 solution at 0°C. The organic layer is washed with saturated aqueous NaHCO3 solution (1 ml), brine (1 ml), dried (MgSO4), concentrated in vacuo and purified by column chromatography (silica gel 60, 0-100% acetone/CH2Cl2), whereby yields 54.3 mg (24%) of the title compound as a white foam.

1H NMR (500 MHz, CDCl3) δ 7.84 (d, 1H, J = 7.5 Hz), 7.60 (t, 1H, J = 7.5 Hz), 7.48 (t, 1H, J=7.5 Hz), 7.44 (m, 1H), 7.39 (dd, 1H, J=2.0, 8.5 Hz), 7.32 (m, 1H), 7.10-7.04 (multipleti rotamera, 1H), 3.6-3.2 (m, 2H), 3.34, 3.32 (dva dubleta jednog dijastereoizomera, 1H), 3.16, 3.14 (dva dubleta drugog dijastereoizomera, 1H), 3.1-2.8 (m, 3H), 2.75-2.65 (singleti rotamera, 3H), 2.3-1.7 (m, 10H), 1.42 (s, 9H) ppm. 1H NMR (500 MHz, CDCl3) δ 7.84 (d, 1H, J = 7.5 Hz), 7.60 (t, 1H, J = 7.5 Hz), 7.48 (t, 1H, J=7.5 Hz), 7.44 (m, 1H ), 7.39 (dd, 1H, J=2.0, 8.5 Hz), 7.32 (m, 1H), 7.10-7.04 (multiplets of rotamers, 1H), 3.6-3.2 (m, 2H), 3.34, 3.32 (two doublets of one diastereoisomer , 1H), 3.16, 3.14 (two doublets of the second diastereoisomer, 1H), 3.1-2.8 (m, 3H), 2.75-2.65 (singlets of the rotamer, 3H), 2.3-1.7 (m, 10H), 1.42 (s, 9H) ppm.

Primjer 48 Example 48

1'-(3-((S)-(3,4-Diklorofenil)-4-(N-(4-fluoro-1-naftilmetil)-(metilamino))butil)-spiro(2,3- dihidrobenzotiofen-3,4' 1'-(3-((S)-(3,4-Dichlorophenyl)-4-(N-(4-fluoro-1-naphthylmethyl)-(methylamino))butyl)-spiro(2,3-dihydrobenzothiophene-3 ,4'

-piperidin)-1-oksid -piperidine)-1-oxide

Naslovni spoj se dobiva oksidacijom 1'-(3-((S)-(3,4-diklorofenil))-4-(N-(6- butoksikarbonil)- (metil amino))butil)- spiro(2,3-dihidrobenzotiofen-3,4'-piperidina) kao što je opisano u Primjeru 47 gore, a zatim uklanjanjem BOC grupe i N-benzoiliranjem prema postupcima danim u Primjeru 3, Stupnjevi A i B. The title compound is obtained by oxidation of 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(6-butoxycarbonyl)-(methylamino))butyl)-spiro(2,3- dihydrobenzothiophene-3,4'-piperidine) as described in Example 47 above, followed by removal of the BOC group and N-benzoylation according to the procedures given in Example 3, Steps A and B.

Maseni spektar (Cl): m/z = 623.1 (35Cl + 35Cl izotop H+). Mass spectrum (Cl): m/z = 623.1 (35Cl + 35Cl isotope H+).

Primjer 49 Example 49

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(t-butoksikarbonil)-(metilamino))butil)-spiro(2,3-dihidrobenzotiofen-3,4' 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(t-butoxycarbonyl)-(methylamino))butyl)-spiro(2,3-dihydrobenzothiophene-3,4'

-piperidin)-1,1-dioksid -piperidine)-1,1-dioxide

U 1'-(3-((S)-(3,4-diklorofenil))-4-(N-(t-butoksikarbonil)-(metilamino))butil)-spiro(2,3-dihidro-benzotiofen-3,4'-piperidina) (102 mg, 191 mmola) u MeOH (0.8 ml) na 0°C, dodaje se "Oxon" (176 mg, 287 mola) u vodi (0.4 ml). Poslije 30 minuta na sobnoj temperaturi, reakcija se filtrira kroz sloj silika gela i koncentrira, pri čemu se dobiva 39.5 mg (36%) od naslovnog spoja kao bijela pjena. In 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(t-butoxycarbonyl)-(methylamino))butyl)-spiro(2,3-dihydro-benzothiophene-3 ,4'-piperidine) (102 mg, 191 mmol) in MeOH (0.8 ml) at 0 °C, "Oxon" (176 mg, 287 mol) in water (0.4 ml) was added. After 30 min at room temperature, the reaction was filtered through a pad of silica gel and concentrated to give 39.5 mg (36%) of the title compound as a white foam.

1H NMR (500 MHz, CDCl3) δ 7.72 (d, 1H, J=7.5 Hz), 7.66 (t, 1H, J=7.5 Hz), 7.51 (t, 1H, J=7.3 Hz), 7.39 (t, 1H, J=8.3 Hz), 3.65-3.25 (m, 2H), 3.38 (s, 2H), 3.15-2.85 (m, 3H), 2.76-2.66 (singleti rotamera, 3H), 2.25 (m, 2H), 2.15-1.95 (m, 3H), 1.95-1.65 (m, 5H), 1.40 (s, 9H) ppm. 1H NMR (500 MHz, CDCl3) δ 7.72 (d, 1H, J=7.5 Hz), 7.66 (t, 1H, J=7.5 Hz), 7.51 (t, 1H, J=7.3 Hz), 7.39 (t, 1H , J=8.3 Hz), 3.65-3.25 (m, 2H), 3.38 (s, 2H), 3.15-2.85 (m, 3H), 2.76-2.66 (rotamer singlets, 3H), 2.25 (m, 2H), 2.15 -1.95 (m, 3H), 1.95-1.65 (m, 5H), 1.40 (s, 9H) ppm.

Primjer 50 Example 50

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(3,5-dimetilbenzoil)-(metilamino))butil)-spiro(2,3- dihidrobenzotiofen-3,4'- piperidin)- 1.1-dioksid. 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)-(methylamino))butyl)-spiro(2,3-dihydrobenzothiophene-3, 4'-piperidine)-1.1-dioxide.

Naslovni spoj se dobiva uklanjanjem BOC grupe i N-benzoiliranjem (prema postupcima danim u Primjeru 3, Stupnjevi A i B) proizvoda iz Primjera 49. The title compound is obtained by removal of the BOC group and N-benzoylation (according to the procedures given in Example 3, Steps A and B) of the product of Example 49.

Maseni spektar (Cl): m/z = 639.1 (35Cl + 35Cl izotop + H+). Mass spectrum (Cl): m/z = 639.1 (35Cl + 35Cl isotope + H+).

Primjer 51 Example 51

1'-(3-((S)-(3,4-Diklorofenil))-4-N-(3,5-dimetilbenzoil)-(metilamino))butil)-spiro(2,3- dihidrobenzotiofen-3,4' -piperidin)- 1,1-dioksid 1'-(3-((S)-(3,4-Dichlorophenyl))-4-N-(3,5-dimethylbenzoyl)-(methylamino))butyl)-spiro(2,3-dihydrobenzothiophene-3,4 '-piperidine)-1,1-dioxide

U 1'-(3-((S)-(3,4-diklorofenil))-4-(N-(3,5-dimetil-benzoil)(metilamino))butil-spiro(2,3-dihidrobenzotiofen-3,4'-piperidina) (10 mg, 20 mmola) u MeOH (0.1 ml) na 0°C dodaje se 0.4 M vodena otopina "Oxona" (75 ul, 30 mmola). Reakcija se zagrijava do sobne temperature i miješa se preko noći. Reakcija se koncentrira u vakuumu, raspodjeljuje se između 1N NaOH (1 ml) i CH2Cl2 (1 ml). Organski sloj se koncentrira i pročišćava kromatografijomna koloni (silika gel 60, 0-100% acetona/CH2Cl2), pri čemu se dobiva 9.0 mg (90%) naslovnog spoja kao bezbojan film. In 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethyl-benzoyl)(methylamino))butyl-spiro(2,3-dihydrobenzothiophene-3 ,4'-piperidine) (10 mg, 20 mmol) in MeOH (0.1 ml) at 0°C was added a 0.4 M aqueous solution of "Oxon" (75 µl, 30 mmol). The reaction was warmed to room temperature and stirred over overnight. The reaction was concentrated in vacuo, partitioned between 1N NaOH (1 ml) and CH2Cl2 (1 ml). The organic layer was concentrated and purified by column chromatography (silica gel 60, 0-100% acetone/CH2Cl2) to give 9.0 mg (90%) of the title compound as a colorless film.

Maseni spektar (Cl): m/z = 599.1 (35Cl + 35Cl izotop + H+), 601.1 (37Cl + 35Cl izotop + H+). Mass spectrum (Cl): m/z = 599.1 (35Cl + 35Cl isotope + H+), 601.1 (37Cl + 35Cl isotope + H+).

Primjer 52 Example 52

1'-(3-((S)-(4-Klorofenil))-4-(N-(3,5-dimetilbenzoil)-(metilamino))butil-spiro(2,3- dihidrobenzotiofen-3,4' 1'-(3-((S)-(4-Chlorophenyl))-4-(N-(3,5-dimethylbenzoyl)-(methylamino))butyl-spiro(2,3-dihydrobenzothiophene-3,4'

-piperidin)-1,1-dioksid. -piperidine)-1,1-dioxide.

Ovaj spoj se dobiva prema postupku danom u Primjeru 51 gore. This compound is obtained according to the procedure given in Example 51 above.

Maseni spektar (Cl): m/z = 567 (35Cl + 35Cl izotop + H+), 565 (37Cl + 35Cl izotop + H+). Mass spectrum (Cl): m/z = 567 (35Cl + 35Cl isotope + H+), 565 (37Cl + 35Cl isotope + H+).

Primjer 53 Example 53

1'-(3-((S)-(4-Klorofenil)-4-(N-(3,5-dimetilbenzoil)-(metilamino))butil9-spiro(2,3-dihidrobenzotiofen)-3,4' 1'-(3-((S)-(4-Chlorophenyl)-4-(N-(3,5-dimethylbenzoyl)-(methylamino))butyl9-spiro(2,3-dihydrobenzothiophene)-3,4'

-piperidin)-1-oksid. -piperidine)-1-oxide.

U 1'-(3-((S)-(4-klorofenil)))-4-(N-(3,5-dimetilbenzoil)-(metilamino))-butil)-spiro(2,3-dihidrobenzotiofen-3,4'-piperidina)(25 mg, 47 mmola) u MeOH (1.0 ml) na 0°C, dodaje se otopina "Oxona" (38 mg, 61 mmola) u H2O (1.0 ml). Reakcija se miješa 2 minute i zaustavlja se sa 10% vodenom otopinom natrij bisulfita. Reakcijska smjesa se razblažuje sa H2O (10 ml), neutralizira se zasićenom vodenom otopinom NaHCO3 (15 ml), ekstrahira se sa CH2Cl2 (3 x 25 ml) pere se sa salnom otopinom (10 ml), suši (Na2SO2), koncentrira u vakuumu, i pročišćava kromatografijom na koloni (silika gel 60, 5-8% MeOH/CH2Cl2), pri čemu se dobiva 25 mg (99%) bezbojne čvrste tvari. In 1'-(3-((S)-(4-chlorophenyl)))-4-(N-(3,5-dimethylbenzoyl)-(methylamino))-butyl)-spiro(2,3-dihydrobenzothiophene-3 ,4'-piperidine)(25 mg, 47 mmol) in MeOH (1.0 ml) at 0°C, a solution of "Oxon" (38 mg, 61 mmol) in H2O (1.0 ml) was added. The reaction is stirred for 2 minutes and stopped with 10% aqueous sodium bisulfite solution. The reaction mixture is diluted with H2O (10 ml), neutralized with saturated aqueous NaHCO3 solution (15 ml), extracted with CH2Cl2 (3 x 25 ml), washed with brine (10 ml), dried (Na2SO2), concentrated in vacuo , and purified by column chromatography (silica gel 60, 5-8% MeOH/CH2Cl2), yielding 25 mg (99%) of a colorless solid.

Maseni spektar (CL): m/z = 549 (35Cl + 35Cl izotop + H+), 551 (37Cl + 35Cl izotop + H+). Mass spectrum (CL): m/z = 549 (35Cl + 35Cl isotope + H+), 551 (37Cl + 35Cl isotope + H+).

Primjer 54 Example 54

1'-(3-((S)-(4-klorofenil)-4-(N-(3,5-bistrifluorometilbenzoil)-(metilamino))butil)spiro(2,3-dihidrobenzotiofen-3,4'-piperidin), 1 oksid. 1'-(3-((S)-(4-chlorophenyl)-4-(N-(3,5-bistrifluoromethylbenzoyl)-(methylamino))butyl)spiro(2,3-dihydrobenzothiophene-3,4'-piperidine ), 1 oxide.

Naslovni spoj se dobiva postupkom oksidacije "Oxonom" opisanim u Primjeru 53. The title compound is obtained by the "Oxon" oxidation process described in Example 53.

Maseni spektar (Cl/NH3) M+H = 657, 659 (35,37Cl izotop). Mass spectrum (Cl/NH3) M+H = 657, 659 (35.37Cl isotope).

Primjer 55 Example 55

1'-(3-(S)-(4-Klorofenil)-4-(N-(3,5-bistrifluorometilbenzoil)-(metilamino))butil-spiro(2,3-dihidrobenzotioen-3,4'-piperidin), 1,1-dioksid 1'-(3-(S)-(4-Chlorophenyl)-4-(N-(3,5-bistrifluoromethylbenzoyl)-(methylamino))butyl-spiro(2,3-dihydrobenzothioene-3,4'-piperidine) , 1,1-dioxide

Naslovni spoj se dobiva postupkom oksidacije "Oxonom" opisanim u Primjeru 51. The title compound is obtained by the "Oxon" oxidation process described in Example 51.

Maseni spektar (Cl/NH3) M+H = 673, 675 (35, 37Cl-izotop). Mass spectrum (Cl/NH3) M+H = 673, 675 (35, 37Cl-isotope).

Supstituirani indolinspiropiperidin derivati se dobivaju upotrebljavajući supstituirane fenil hidrazine i 1-benziloksi karbonilpiperidin-4-karboksialdehid u Fisher-ovoj sintezi indola. Kada se tvore regionalni izomeri, oni se razdvajaju kao 1'-benzoiloksikarbonil-1-metan-sulfonil-spiro(indolin-3,4'-piperidin) derivat kromatografijom (silika gel 60, THF/heksan). Dobivanje reprezantno supstituiranog spiro(indolin-3,4'-piperidinij) hidroklorida je opisano niže: Substituted indoline spiropiperidine derivatives are obtained using substituted phenyl hydrazines and 1-benzyloxy carbonylpiperidine-4-carboxyaldehyde in Fisher's indole synthesis. When regional isomers are formed, they are separated as the 1'-benzoyloxycarbonyl-1-methanesulfonyl-spiro(indoline-3,4'-piperidine) derivative by chromatography (silica gel 60, THF/hexane). The preparation of representatively substituted spiro(indoline-3,4'-piperidinium) hydrochloride is described below:

Primjer 56 Example 56

1'-Benziloksikarboni-5-fluoro-spiro(indolin-3,4'-piperidin) 1'-Benzyloxycarbons-5-fluoro-spiro(indoline-3,4'-piperidine)

Suspenzija 4-fluorofenilhidrazin hidroklorida (6.504 g, 40 mmola), piridina (6.56 ml, 80 mmola), toluola (360 ml), acetonitrila (40 ml) i N-benzilkarboksi-4-piperidin karboksialdehida (9.88 g, 40 mmola) se održava na 0°C 1 sat. Dodaje se trifluorooctena kiselina (18.5 ml, 240 mmola), i reakcija se zagrijava 20 sati na 60°C. Reakcija se ohladi do 0°C i dodaje se metanol (40 ml) a zatim NaBH4 (1.51 g, 40 mmola). Kupaonica za hlađenje se uklanja i dodaje se 30% vodena otopina NH4OH (100 ml). Odvaja se organski sloj, pere sa 5% vodenom otopinom NH4OH (100 ml) slanom otopinom (50 ml), suši (MgSO4), i koncentrira do sirovog ulja, koje se pročišćava kromatografijom na koloni (SG 60 silicij dioksid, 0-5% acetona/CH2Cl2), pri čemu se dobiva 6.48 g (48%) naslovnog spoja kao bistro ulje. A suspension of 4-fluorophenylhydrazine hydrochloride (6.504 g, 40 mmol), pyridine (6.56 ml, 80 mmol), toluene (360 ml), acetonitrile (40 ml) and N-benzylcarboxy-4-piperidine carboxyaldehyde (9.88 g, 40 mmol) was maintained at 0°C for 1 hour. Trifluoroacetic acid (18.5 ml, 240 mmol) was added, and the reaction was heated at 60°C for 20 hours. The reaction was cooled to 0°C and methanol (40 ml) was added followed by NaBH4 (1.51 g, 40 mmol). The cooling bath is removed and 30% aqueous NH 4 OH (100 ml) is added. The organic layer is separated, washed with 5% aqueous NH4OH solution (100 ml), brine (50 ml), dried (MgSO4), and concentrated to a crude oil, which is purified by column chromatography (SG 60 silica, 0-5% acetone/CH2Cl2), giving 6.48 g (48%) of the title compound as a clear oil.

1H NMR (400 MHz, CDCl3): δ 7.23-7.36 (m, 5H), 6.76-6-71 (m, 2H), 6.58 (dd, 1H, J=4.4, 8.0 Hz), 5.14 (s, 2H), 4.12 (širok s, 2H), 3.49 (s, 2H), 2.95 (širok s, 2H), 1.73 (širok s, 3H) ppm. 1H NMR (400 MHz, CDCl3): δ 7.23-7.36 (m, 5H), 6.76-6-71 (m, 2H), 6.58 (dd, 1H, J=4.4, 8.0 Hz), 5.14 (s, 2H) , 4.12 (broad s, 2H), 3.49 (s, 2H), 2.95 (broad s, 2H), 1.73 (broad s, 3H) ppm.

Primjer 57 Example 57

Stupanj 1) Level 1)

1'-Benziloksikarbonil-5-fluoro-1-metansulfonil-spiro(indolin-3,4'-piperidin) 1'-Benzyloxycarbonyl-5-fluoro-1-methanesulfonyl-spiro(indoline-3,4'-piperidine)

U otopinu 1'-benziloksikarbonil-5-fluoro-spiro(indolin-3,4'-piperidina)(6.48 g, 19.0 mmola) u CH2Cl2 (19 ml) i piridina (38 mmola, 3.1 ml) na 0°C dodaje se metansulfonil klorid (19 mmola, 1.52 ml). Reakcija se zagrijava do sobne temperature, razblažuje se sa etil acetatom (200 ml), pere se sa 1N vodenom otopinom HCl (100 ml), zasićenom vodenom otopinom NaHCO3 (100 ml), slanom otopinom (50 ml), suši (MgSO4), i koncentrira do 7,81 g (98%) naslovnog spoja kao crvena pjena. To a solution of 1'-benzyloxycarbonyl-5-fluoro-spiro(indoline-3,4'-piperidine) (6.48 g, 19.0 mmol) in CH2Cl2 (19 ml) and pyridine (38 mmol, 3.1 ml) at 0°C is added methanesulfonyl chloride (19 mmol, 1.52 ml). The reaction is warmed to room temperature, diluted with ethyl acetate (200 ml), washed with 1N aqueous HCl (100 ml), saturated aqueous NaHCO3 (100 ml), brine (50 ml), dried (MgSO4), and concentrated to 7.81 g (98%) of the title compound as a red foam.

1H NMR (400 MHz, CDCl3) δ 7.35 (m, 5H), 7.32 (dd, 1H), J = 4.2, 9.0 Hz), 6.90 (dt, 1H, J=2.7, 8.8 Hz), 6.81 (1H, dd J=2.6, 8.2 Hz), 5.14 (s, 2H), 4.22 (širok s, 2H), 3.84 (s, 2H), 2.92 (širok s, 2H), 2.88 (s, 3H), 1.79 (širok s, 2H), 1.69 (d, 2H, 13 Hz), ppm. 1H NMR (400 MHz, CDCl3) δ 7.35 (m, 5H), 7.32 (dd, 1H), J = 4.2, 9.0 Hz), 6.90 (dt, 1H, J=2.7, 8.8 Hz), 6.81 (1H, dd J=2.6, 8.2 Hz), 5.14 (s, 2H), 4.22 (broad s, 2H), 3.84 (s, 2H), 2.92 (broad s, 2H), 2.88 (s, 3H), 1.79 (broad s, 2H), 1.69 (d, 2H, 13 Hz), ppm.

Stupanj 2) Level 2)

5-Fluoro-1-metansulfonil-spiro(indolin-3,4'-piperidin) hidrokloridna sol 5-Fluoro-1-methanesulfonyl-spiro(indoline-3,4'-piperidine) hydrochloride salt

U 1'-benziloksikarbonil-5-fluoro-1-metansulfonil-spiro(indolin-3,4'-piperidin) (7.81 g, 18.7 mmola) u CHCl3 (18 ml) na sobnoj temperaturi, dodaje se trimeetilsilil jodid (20.5 mmola, 2.93 ml). Poslije 5 minuta, reakcijska smjesa se ohladi do 0°C i dodaje se 5 M otopina HCl u metanolu/metil acetatu uz snažno miješanje. HCl otopina se dobiva dodavanjem acetil klorida (190 mmola, 14 ml) u metanol (20 ml) na 0°C. Dodaje se 40 ml EtOAc, i suspenzija se snažno miješa na 0°C 4 sata. Čvrsta supstanca se profiltrira pod atmosferom suhog dušika, pere se sa etil acetatom na 0°C (10 ml) i zatim sa heksanom (10 ml), i suši pod vakuumom, pri čemu se dobiva 4.77 g (80%) naslovnog spoja u obliku svijetlo ružičaste čvrste tvari. To 1'-benzyloxycarbonyl-5-fluoro-1-methanesulfonyl-spiro(indoline-3,4'-piperidine) (7.81 g, 18.7 mmol) in CHCl3 (18 mL) at room temperature, was added trimethylsilyl iodide (20.5 mmol, 2.93 ml). After 5 minutes, the reaction mixture was cooled to 0°C and a 5 M solution of HCl in methanol/methyl acetate was added with vigorous stirring. The HCl solution was prepared by adding acetyl chloride (190 mmol, 14 ml) to methanol (20 ml) at 0°C. 40 ml EtOAc was added, and the suspension was vigorously stirred at 0°C for 4 hours. The solid was filtered under dry nitrogen, washed with ethyl acetate at 0°C (10 ml) and then with hexane (10 ml), and dried under vacuum to give 4.77 g (80%) of the title compound as light pink solid.

1H NMR (400 MHz, DMSO-d6) δ 8.85 (širok s, 1H), 8.77 (širok s, 1H), 7.26 (dd, 1H, J=4.4, 8.8 Hz), 7.11 (dt, 1H, J=2.8, 8.8 Hz), 7.02 (dd, 1H, J=2.8, 8.4 Hz), 3.97 (s, 3H), 3.30 (m, 2H), 3.06 (m, 2H), 3.06 (s, 3H), 2.04 (m, 2H), 1.83 (d, 2H, J=14 Hz) ppm. 1H NMR (400 MHz, DMSO-d6) δ 8.85 (broad s, 1H), 8.77 (broad s, 1H), 7.26 (dd, 1H, J=4.4, 8.8 Hz), 7.11 (dt, 1H, J=2.8 , 8.8 Hz), 7.02 (dd, 1H, J=2.8, 8.4 Hz), 3.97 (s, 3H), 3.30 (m, 2H), 3.06 (m, 2H), 3.06 (s, 3H), 2.04 (m , 2H), 1.83 (d, 2H, J=14 Hz) ppm.

Supstituirani 1-metansulfonil-spiro(indolin-3,4'-piperidinij) hidroktoridi mogu se reduktivno aminirati sa 3-(S)-(3,4- diklorofenil)-4-(t-butoksikarbonilmetilamino)butanalom prema postupku opisanom u Primjeru 8, Postupak B. Uklanjanje BOC grupe postupkom danim u Primjeru 3, Stupanj A osigurava intermedijarne spojeve sekundarne amine opisane niže koji se mogu benzolirati pod uvjetima iznijetim u Primjeru 3, Stupanj B, pri čemu se dobiva naznačeni benzamidni derivat. Substituted 1-methanesulfonyl-spiro(indoline-3,4'-piperidinium) hydrides can be reductively aminated with 3-(S)-(3,4-dichlorophenyl)-4-(t-butoxycarbonylmethylamino)butanal according to the procedure described in Example 8 , Procedure B. Removal of the BOC group by the procedure given in Example 3, Step A provides the secondary amine intermediates described below which can be benzolylated under the conditions outlined in Example 3, Step B, to give the indicated benzamide derivative.

Primjer 58 Example 58

1'-(3-((S)-(3,4-Diklorofenil)-4-(metilamino)butil)-1-metansulfonil-5-metoksi-spiro(indolin-3,4'-piperidin) 1'-(3-((S)-(3,4-Dichlorophenyl)-4-(methylamino)butyl)-1-methanesulfonyl-5-methoxy-spiro(indoline-3,4'-piperidine)

1H NMR (CDCl3, 400 MHz) δ 7.37 (d, 1H, J=8.2 Hz), 7.29 (d, 1H), 7.25 (d, 1H), 7.04 (dd, 1H, J=2.1, 8.3 Hz), 6.72 (m, 2H), 3.76 (s, 3H), 3.73 (s, 2H), 2.87 (m, 2H), 2.82 (s, 3H), 2.78 (d, 2H, J=7.1 Hz), 2.41 (s, 3H), 2.32-2.18 (m, 2H), 2.05-1.85 (m, 5H), 1.7 (m, 3H) ppm. 1H NMR (CDCl3, 400 MHz) δ 7.37 (d, 1H, J=8.2 Hz), 7.29 (d, 1H), 7.25 (d, 1H), 7.04 (dd, 1H, J=2.1, 8.3 Hz), 6.72 (m, 2H), 3.76 (s, 3H), 3.73 (s, 2H), 2.87 (m, 2H), 2.82 (s, 3H), 2.78 (d, 2H, J=7.1 Hz), 2.41 (s, 3H), 2.32-2.18 (m, 2H), 2.05-1.85 (m, 5H), 1.7 (m, 3H) ppm.

Primjer 59 Example 59

1'-(3-((S)-(3,4-Diklorofenil))-4-(metilamino)butil)-1-metansulfonil-5-metil-spiro(indolin-3,4'-piperidin). 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(methylamino)butyl)-1-methanesulfonyl-5-methyl-spiro(indoline-3,4'-piperidine).

1H NMR (CDCl3, 400 MHz) δ 7.37 (d, 1H, J=6.2 Hz), 7.30 (d, 1H, J=2.0 Hz), 7.24 (d, 1H, J=10 Hz), 7.05 (dd, 1H, J=2.0, 8.2 Hz), 7.00 (d, 1H, 1=8.8 Hz), 6.95 (s, 1H), 3.71 (dd, 2H, J=16= 5.4 Hz), 2.9 (m, 3H), 2.84 (s, 3H), 2.79 (d, 2H, J=7.4 Hz), 2.43 (s, 3H), 2.30 (s, 3H), 2.24 (m, 1H), 2.05- 1.85 (m, 5H), 1.75-1.60 (m, 3H) ppm. 1H NMR (CDCl3, 400 MHz) δ 7.37 (d, 1H, J=6.2 Hz), 7.30 (d, 1H, J=2.0 Hz), 7.24 (d, 1H, J=10 Hz), 7.05 (dd, 1H , J=2.0, 8.2 Hz), 7.00 (d, 1H, 1=8.8 Hz), 6.95 (s, 1H), 3.71 (dd, 2H, J=16= 5.4 Hz), 2.9 (m, 3H), 2.84 (s, 3H), 2.79 (d, 2H, J=7.4 Hz), 2.43 (s, 3H), 2.30 (s, 3H), 2.24 (m, 1H), 2.05- 1.85 (m, 5H), 1.75- 1.60 (m, 3H) ppm.

Primjer 60 Example 60

5-Kloro-1'-(3-((S)-(3,4-diklorofenil))-4-(metilamino)butil)-1-metansulfonil-spiro(indolin-3,4'-piperidin) 5-Chloro-1'-(3-((S)-(3,4-dichlorophenyl))-4-(methylamino)butyl)-1-methanesulfonyl-spiro(indoline-3,4'-piperidine)

1H NMR (CDCl3, 400 MHz) δ 7.39 (d, 1H, J=8.2 Hz), 7.29 (d, 1H, J=2.1 ), 7.24 (s, 1H), 7.17 (dd, 1H, J=2.2, 8.5 Hz), 7.11 (d, 1H, J=2.1 Hz), 7.05 (dd, 1H, J=2.0, 8.3 Hz), 3.76 (dd, 2H, J=4.5, 25 Hz), 3.18 (p, 1H), 2.10- 2.85 (m, 4H), 2.87 (s, 3H), 2.61 (s, 3H), 2.47 (m, 1H), 2.34 (m, 1H), 2.15 (t, 1H), 2.04 (m, 2H), 1.95-1.70 (m, 5H) ppm. 1H NMR (CDCl3, 400 MHz) δ 7.39 (d, 1H, J=8.2 Hz), 7.29 (d, 1H, J=2.1 ), 7.24 (s, 1H), 7.17 (dd, 1H, J=2.2, 8.5 Hz), 7.11 (d, 1H, J=2.1 Hz), 7.05 (dd, 1H, J=2.0, 8.3 Hz), 3.76 (dd, 2H, J=4.5, 25 Hz), 3.18 (p, 1H), 2.10- 2.85 (m, 4H), 2.87 (s, 3H), 2.61 (s, 3H), 2.47 (m, 1H), 2.34 (m, 1H), 2.15 (t, 1H), 2.04 (m, 2H) , 1.95-1.70 (m, 5H) ppm.

Primjer 61 Example 61

1'-(3((S)-3,4-Diklorofenil)-4-(metilamino)butil)-5-fluor-1-metansulfonil-spiro(indolin-3,4'-piperidin) 1'-(3((S)-3,4-Dichlorophenyl)-4-(methylamino)butyl)-5-fluoro-1-methanesulfonyl-spiro(indoline-3,4'-piperidine)

1H NMR (CDCl3, 400 MHz) δ 7.38 (d, 1H), 7.3 (m, 2H), 7.05 (dd, 1H), 7.91-7.85 (m, 2H), 3.75 (dd, 2H), 3.0-2.8 (m, 3H), 2.81 (d, 2H), 2.43 (s, 3H), 2.42 (m, 1 H), 2.34 (m, 1H), 2.1-1.8 (m, 5H), 1.7 (m, 3H) ppm. 1H NMR (CDCl3, 400 MHz) δ 7.38 (d, 1H), 7.3 (m, 2H), 7.05 (dd, 1H), 7.91-7.85 (m, 2H), 3.75 (dd, 2H), 3.0-2.8 ( m, 3H), 2.81 (d, 2H), 2.43 (s, 3H), 2.42 (m, 1H), 2.34 (m, 1H), 2.1-1.8 (m, 5H), 1.7 (m, 3H) ppm .

Primjer 62 Example 62

1'-(3-((S)-(3,4-Diklorofenil))-4-(metilamino)butil)-7-fluor-1-metansulfonil-spiro(indolin-3,4'-piperidin) 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(methylamino)butyl)-7-fluoro-1-methanesulfonyl-spiro(indoline-3,4'-piperidine)

1H NMR (CDCl3, 400 MHz) δ 7.38 (d, 1H), 7.29 (d, 1H), 7.05 (m, 2H), 6.95 (m, 2H), 3.99 (dd, 2H), 3.25 (s, 3H), 2.9 (m, 2H), 2.81 (t, 1H), 2.45 (s, 3H), 2.38 (m, 1H), 2.28 (m, 1H), 2.1-1.8 (m, 5H), 1.75 (m, 3H) ppm. 1H NMR (CDCl3, 400 MHz) δ 7.38 (d, 1H), 7.29 (d, 1H), 7.05 (m, 2H), 6.95 (m, 2H), 3.99 (dd, 2H), 3.25 (s, 3H) , 2.9 (m, 2H), 2.81 (t, 1H), 2.45 (s, 3H), 2.38 (m, 1H), 2.28 (m, 1H), 2.1-1.8 (m, 5H), 1.75 (m, 3H ) ppm.

Primjer 63 Example 63

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(3,5-dimetilbenzoil)-(metilamino))butil)-1-metansulfonil-5-metil-spiro(indolin 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)-(methylamino))butyl)-1-methanesulfonyl-5-methyl-spiro( indoline

-3,4'-piperidin) -3,4'-piperidine)

Maseni spektar (FAB): m/z 642.0 (35Cl + 35Cl izotop + H+). Mass spectrum (FAB): m/z 642.0 (35Cl + 35Cl isotope + H+).

Primjer 64 Example 64

5-Klor-1'-(3-((S)-(3,4-diklorofenil))-4-(N-(3-metilbenzoil)-(metilamino))butil)-1-metansulfonil-spiro(indolin-3,4'-piperidin) 5-Chloro-1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3-methylbenzoyl)-(methylamino))butyl)-1-methanesulfonyl-spiro(indoline- 3,4'-piperidine)

Maseni spektar (FAB): m/z = 648.1 (35Cl + 35Cl izotop + H+). Mass spectrum (FAB): m/z = 648.1 (35Cl + 35Cl isotope + H+).

Primjer 65 Example 65

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-3,5-dimetilbenzoil)-(metilamino))butil)-1-metanosulfonil-5-metoksi-spiro (indolin-3,4'- piperidin) 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-3,5-dimethylbenzoyl)-(methylamino))butyl)-1-methanesulfonyl-5-methoxy-spiro (indoline -3,4'- piperidine)

Maseni spektar (FAB): m/z = 658 (35Cl + 35Cl izotop + H+). Mass spectrum (FAB): m/z = 658 (35Cl + 35Cl isotope + H+).

Primjer 66 Example 66

1'-(3-((S)-(3,4-Dikloorofenil))-4-(N-(3-metilbenzoil)-(metilamino))butil)-5-fluoro-1-metansulfonil-spiro(indolin-3,4'-piperidin) 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(3-methylbenzoyl)-(methylamino))butyl)-5-fluoro-1-methanesulfonyl-spiro(indoline- 3,4'-piperidine)

Maseni spektar (Cl): m/z = 632.2 (35Cl + 35Cl izotop + H+), 634.2 (37Cl + 35Cl + izotop + H+). Mass spectrum (Cl): m/z = 632.2 (35Cl + 35Cl isotope + H+), 634.2 (37Cl + 35Cl + isotope + H+).

Primjer 67 Example 67

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(3,5-diklorofenzoil)-(metilamino))butil)-5-fluor-1-metansulfonil-spiroi(indolin-3,4'-piperidin). 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(3,5-dichlorophenzoyl)-(methylamino))butyl)-5-fluoro-1-methanesulfonyl-spiro( indoline-3,4'-piperidine).

Maseni spektar (FAB): m/z = 688.0 (37Cl + 35Cl izotop + 35Cl + 35Cl izotop + H+). Mass spectrum (FAB): m/z = 688.0 (37Cl + 35Cl isotope + 35Cl + 35Cl isotope + H+).

Primjer 68 Example 68

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(3,5-dimetilbenzoil)-(metilamino))butil)-5-fluoro-1-metansulfonil-spiro(indolin-3,4'-piperidin) 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)-(methylamino))butyl)-5-fluoro-1-methanesulfonyl-spiro( indoline-3,4'-piperidine)

Maseni spektar: (Cl): m/z = 646.1 (35Cl + 35Cl izotop + H+), 648.1 (37Cl + 35Cl izotop + H+). Mass spectrum: (Cl): m/z = 646.1 (35Cl + 35Cl isotope + H+), 648.1 (37Cl + 35Cl isotope + H+).

Primjer 69 Example 69

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(3-klorbenzoil)-(metilamino))butil)-5-fluor-1-metansulfonil-spiro(indolin-3,4'-piperidin) 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(3-chlorobenzoyl)-(methylamino))butyl)-5-fluoro-1-methanesulfonyl-spiro(indoline- 3,4'-piperidine)

Maseni spektar (Cl): m/z = 652.2 (35Cl + 35Cl izotop + 35Cl + 35Cl izotop + H+), 656.2 (37Cl + 35Cl izotop + 35Cl + 657.2 (37Cl + 37Cl izotop + 37Cl + 35Cl izotop + H+), 658.2 (37Cl + 37Cl izotop + 37Cl + 37Cl izotop + H+). Mass spectrum (Cl): m/z = 652.2 (35Cl + 35Cl isotope + 35Cl + 35Cl isotope + H+), 656.2 (37Cl + 35Cl isotope + 35Cl + 657.2 (37Cl + 37Cl isotope + 37Cl + 35Cl isotope + H+), 658.2 (37Cl + 37Cl isotope + 37Cl + 37Cl isotope + H+).

Primjer 70 Example 70

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(3,5-bis(trifluorometil)benzoil)-(metilamino))butil)-5-fluor-1-metansulfonil-spiro(indolin-3,4'-piperidin) 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(3,5-bis(trifluoromethyl)benzoyl)-(methylamino))butyl)-5-fluoro-1- methanesulfonyl-spiro(indoline-3,4'-piperidine)

Maseni spektar (Cl): m/z = 754.1 (35Cl + 35Cl izotop + H+), 756.1 (37Cl + 35Cl izotop + H+). Mass spectrum (Cl): m/z = 754.1 (35Cl + 35Cl isotope + H+), 756.1 (37Cl + 35Cl isotope + H+).

Primjer 71 Example 71

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(3,5-dimetilbenzoil)-(metilamino))butil)-7-fluor-1-metansulfonil-spiro(indolin-3,4'-piperidin) 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)-(methylamino))butyl)-7-fluoro-1-methanesulfonyl-spiro( indoline-3,4'-piperidine)

Maseni spektar (Cl): m/z = 646.1 (35Cl + 35Cl izotop + H+), 648.1 (37Cl + 35Cl izotop + H+). Mass spectrum (Cl): m/z = 646.1 (35Cl + 35Cl isotope + H+), 648.1 (37Cl + 35Cl isotope + H+).

Primjer 72 Example 72

1-Acetil-1'-(3((S)-(3,4-diklorofenil))-4-(N-t-butoksi-karbonil)-(metilamino))butil)-5-fluor-spiro(indollin-3,4,'-piperidin) 1-Acetyl-1'-(3((S)-(3,4-dichlorophenyl))-4-(N-t-butoxy-carbonyl)-(methylamino))butyl)-5-fluoro-spiro(indolline-3, 4,'-piperidine)

U 1'-(3-((S)-(3,4-diklorofenil))-4-(N-t-butoksikarbonil)-(metilamino))butil)-5-fluor-1-metan-sulfonil-spiro(indolin-3,4'-piperidin)(1.32 g, 2.15 mmola) u toluolu (5 ml) na 0°C dodaje se 3.4 M crvenog-Al/toluola (5.7 ml, 17.2 mmola). Poslije 4 sata na sobnoj temperaturi reakcija se ohladi na 0°C i zaustavlja se pažljivim dodavanjem 1N vodene otopine NaOH (2 ml). Dodaje se zasićena vodena otopina natrij kalij tartarata (30 ml), dvofazna smjesa se miješa mehanički na 0°C 1 sat. Proizvod se ekstrahira sa toluolom (3 x 10 ml), pere se sa 50% zasićenom otopinom natrij kalij tartarata (10 ml), H2O (10 ml), slanom otopinom (10 ml), suši (MgSO4), i koncentrira do grubo 5 ml zapremnine, i ohladi se do 0°C. Dodaju se piridin (705 ul, 8.6 mmola) i anhidrid octene kiseline (410 ul, 4.3 mmola). Poslije 16 sati na sobnoj temperaturi, reakcija se koncentrira i pročišćava se kromatografijom na koloni (silika gel 60, 0-50% acetona/CH2Cl2), pri čemu se dobija 830 mg (72%) naslovnog spoja kao bijela pjena. In 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-t-butoxycarbonyl)-(methylamino))butyl)-5-fluoro-1-methane-sulfonyl-spiro(indoline- 3,4'-piperidine) (1.32 g, 2.15 mmol) in toluene (5 ml) at 0°C was added 3.4 M red-Al/toluene (5.7 ml, 17.2 mmol). After 4 hours at room temperature, the reaction was cooled to 0°C and quenched by the careful addition of 1N aqueous NaOH solution (2 ml). A saturated aqueous solution of sodium potassium tartrate (30 ml) is added, the two-phase mixture is stirred mechanically at 0°C for 1 hour. The product is extracted with toluene (3 x 10 ml), washed with 50% saturated sodium potassium tartrate solution (10 ml), H2O (10 ml), brine (10 ml), dried (MgSO4), and concentrated to a crude ml volume, and cool to 0°C. Add pyridine (705 µl, 8.6 mmol) and acetic anhydride (410 µl, 4.3 mmol). After 16 hours at room temperature, the reaction was concentrated and purified by column chromatography (silica gel 60, 0-50% acetone/CH2Cl2), yielding 830 mg (72%) of the title compound as a white foam.

1H NMR (400 MHz, CDCl3) δ 8.14 (dd, 1H), 7.37 (d, 1H), 7.28 (m, 1H), 7.1- 7-0 (m, 1H), 6.87 (m, 2H), 3.95, 3.81 (singleti rotamera, 2H), 3.53 (m, 1H), 3.36 (m, 2H), 3.22 (m, 1H), 3.01 (m, 1H), 2.90 (m, 1H), 2.82 (m, 1H), 2.74, 2.63 (singleti rotamera, 3H), 2.39, 2.20 (singleti rotamera, 3H), 1.89 (m, 4H), 1.65 (m, 4H) ppm. 1H NMR (400 MHz, CDCl3) δ 8.14 (dd, 1H), 7.37 (d, 1H), 7.28 (m, 1H), 7.1-7-0 (m, 1H), 6.87 (m, 2H), 3.95, 3.81 (rotamer singlets, 2H), 3.53 (m, 1H), 3.36 (m, 2H), 3.22 (m, 1H), 3.01 (m, 1H), 2.90 (m, 1H), 2.82 (m, 1H), 2.74, 2.63 (rotamer singlets, 3H), 2.39, 2.20 (rotamer singlets, 3H), 1.89 (m, 4H), 1.65 (m, 4H) ppm.

Odgovarajuća 1-acetil-spiro(indolin-3,4'-piperidin) spojevi se dobivaju selektivnim uklanjanjem metansulfonil grupe sa crvenim-Al i zatim tretiranjem sa anhidridom octene kiseline/piridinom u stadiju kada je metilamino grupa zaštićena sa BOC; reprezentativni postupak je dat u Primjeru 72 gore. BOC grupa može se ukloniti upotrebljavajući postupak dat u Primjeru 3, Stupanj A, pri čemu se dobivaju intermedijarna metilamina spojevi koji se benzoliraju prema Primjeru 3, Stupanj B, pri čemu se dobivaju spojevi u Primjerima 73-90. The corresponding 1-acetyl-spiro(indoline-3,4'-piperidine) compounds are obtained by selective removal of the methanesulfonyl group with red-Al and then treatment with acetic anhydride/pyridine at the stage when the methylamino group is protected with BOC; a representative procedure is given in Example 72 above. The BOC group can be removed using the procedure given in Example 3, Step A, yielding intermediate methylamine compounds which are benzolated according to Example 3, Step B, yielding the compounds in Examples 73-90.

Primjer 73 Example 73

1-Acetil-5-klor-1'-(3-((S)-(3,4-diklorofenil))-4-(metilamino)butil)-spiro(indolin-3,4'-piperidin) 1-Acetyl-5-chloro-1'-(3-((S)-(3,4-dichlorophenyl))-4-(methylamino)butyl)-spiro(indoline-3,4'-piperidine)

1H NMR (CDCl3, 400 MHz) δ 7.83 (d, 1H, J=6.6 Hz), 7.12 (d, 1H, J=5.2 Hz), 7.09 (d, 1H, J=2.0 Hz), 6.87 (dd, 2H), J=2.0, 10.0 Hz), 6.84 (s, 1H), 2.81 (p, 1H), 2.75-2.55 (m, 4H), 2.27 (s, 3H), 2.12 (m, 1H), 2.04 (m, 1H), 1.95 (s, 3H), 1.9-1.7 (m, 3H), 1.6 (t, 2H), 1.5-1.4 (m, 3H) ppm. 1H NMR (CDCl3, 400 MHz) δ 7.83 (d, 1H, J=6.6 Hz), 7.12 (d, 1H, J=5.2 Hz), 7.09 (d, 1H, J=2.0 Hz), 6.87 (dd, 2H ), J=2.0, 10.0 Hz), 6.84 (s, 1H), 2.81 (p, 1H), 2.75-2.55 (m, 4H), 2.27 (s, 3H), 2.12 (m, 1H), 2.04 (m , 1H), 1.95 (s, 3H), 1.9-1.7 (m, 3H), 1.6 (t, 2H), 1.5-1.4 (m, 3H) ppm.

Primjer 74 Example 74

1-Acetil-1'-(3-((S)-(3,4-diklorofenil))-4-(metilamino)butil)-5-metil-spiro(indolin-3,4'-piperidin) 1-Acetyl-1'-(3-((S)-(3,4-dichlorophenyl))-4-(methylamino)butyl)-5-methyl-spiro(indoline-3,4'-piperidine)

1H NMR (CDCl3, 400 MHz) δ 8.05 (d, 1H), 7.38 (d, 1H), 7.30 (d, 1H), 7.05 (dd, 1H), 7.00 (d, 1H), 6.92 (s, 1H), 3.79 (s, 2H), 3.01 (p, 2H), 2.9 (m, 3H), 2.52 (s, 3H), 2.5-2.1 (m, 2H), 2.29 (s, 3H), 2.20 (s, 3H), 2.1-1.7 (m, 6H), 1.65 (m, 2H) ppm. 1H NMR (CDCl3, 400 MHz) δ 8.05 (d, 1H), 7.38 (d, 1H), 7.30 (d, 1H), 7.05 (dd, 1H), 7.00 (d, 1H), 6.92 (s, 1H) , 3.79 (s, 2H), 3.01 (p, 2H), 2.9 (m, 3H), 2.52 (s, 3H), 2.5-2.1 (m, 2H), 2.29 (s, 3H), 2.20 (s, 3H ), 2.1-1.7 (m, 6H), 1.65 (m, 2H) ppm.

Primjer 75 Example 75

1-Acetil-1'-(3-((S)-(3,4-diklorofenil))-4-(metilamino)butil)-5-fluor-spiro(indolin-3,4'-piperidin) 1-Acetyl-1'-(3-((S)-(3,4-dichlorophenyl))-4-(methylamino)butyl)-5-fluoro-spiro(indoline-3,4'-piperidine)

1H NMR (CDCl3, 400 MHz) δ 8.14 (dd, 1H), 7.38 (d, 1H), 7.24 (s, 1H), 7.05 (dd, 1H), 6.88 (dt, 1H), 6.82 (dd, 1H), 3.93 3.83 (singleti rotamera, 2H), 3.13 (p, 1H), 3.04 (dd, 2H), 2.92 (dd, 2H), 2.69, 2.66 (singleti rotamera, 3H), 2.50 (p, 1H), 2.33 (p, 1H), 2.38, 2.20 (singleti rotamera, 3H), 2.13 (t, 1H), 2.05 (m, 1H), 1.7 (m, 4H), 1.73 (dd, 2H), ppm. 1H NMR (CDCl3, 400 MHz) δ 8.14 (dd, 1H), 7.38 (d, 1H), 7.24 (s, 1H), 7.05 (dd, 1H), 6.88 (dt, 1H), 6.82 (dd, 1H) , 3.93 3.83 (rotamer singlets, 2H), 3.13 (p, 1H), 3.04 (dd, 2H), 2.92 (dd, 2H), 2.69, 2.66 (rotamer singlets, 3H), 2.50 (p, 1H), 2.33 ( p, 1H), 2.38, 2.20 (rotamer singlets, 3H), 2.13 (t, 1H), 2.05 (m, 1H), 1.7 (m, 4H), 1.73 (dd, 2H), ppm.

Primjer 76 Example 76

1-Acetil-1'-(3-((S)-(3,4-diklorofenil))-4-(metilamino)-butil)-6-fluor-spiro(indolin-3,4'-piperidin) 1-Acetyl-1'-(3-((S)-(3,4-dichlorophenyl))-4-(methylamino)-butyl)-6-fluoro-spiro(indoline-3,4'-piperidine)

1H NMR (DMSO-d6, 500 MHz) δ 7.76 (dd, 1H), 7.58-7.53 (m, 2H), 7.26 (dd, 1H), 7.21 (dd, 1H), 6.80 (dt, 1H), 3.93 (s, 2H), 2.98-2.86 (m, 3H), 2.82 (d, 1H), 2.65 (d, 1H), 2.38 (s, 3H), 2.19 (m, 1H), 2.16 (s, 3H), 2.09 (m, 1H), 2.05 (t, 1H), 1.90 (t, 2H), 1.78-1.60 (m, 3H), 1.6-1.5 (m, 2H) ppm. 1H NMR (DMSO-d6, 500 MHz) δ 7.76 (dd, 1H), 7.58-7.53 (m, 2H), 7.26 (dd, 1H), 7.21 (dd, 1H), 6.80 (dt, 1H), 3.93 ( s, 2H), 2.98-2.86 (m, 3H), 2.82 (d, 1H), 2.65 (d, 1H), 2.38 (s, 3H), 2.19 (m, 1H), 2.16 (s, 3H), 2.09 (m, 1H), 2.05 (t, 1H), 1.90 (t, 2H), 1.78-1.60 (m, 3H), 1.6-1.5 (m, 2H) ppm.

Primjer 77 Example 77

1-Acetil-1'-(3-((S)-(3,4-diklorofenil))-4-(metilamino)-butil)-4-fluor-spiro(indolin-3,4'piperidin 1-Acetyl-1'-(3-((S)-(3,4-dichlorophenyl))-4-(methylamino)-butyl)-4-fluoro-spiro(indoline-3,4'piperidine

1H NMR (DMSO-d6, 500 MHz) δ 7.88 (d, 1H), 7.63-7.58 (m, 2H), 7.29 (dd, 1H), 7.19 (kvar, 1H), 6.79 (t, 1H), 3.86 (s, 2H), 3.23-3-13 (m, 3H), 2.97 (m, 1H), 2.72 (m, 1H), 2.52 (s, 3H), 2.26 (m, 1H), 2.16 (s, 3H), 2.09 (t, 4H), 1.97 (p, 2H), 1.76-1.62 (m, 3H) ppm. 1H NMR (DMSO-d6, 500 MHz) δ 7.88 (d, 1H), 7.63-7.58 (m, 2H), 7.29 (dd, 1H), 7.19 (kvar, 1H), 6.79 (t, 1H), 3.86 ( s, 2H), 3.23-3-13 (m, 3H), 2.97 (m, 1H), 2.72 (m, 1H), 2.52 (s, 3H), 2.26 (m, 1H), 2.16 (s, 3H) , 2.09 (t, 4H), 1.97 (p, 2H), 1.76-1.62 (m, 3H) ppm.

Primjer 78 Example 78

1-Acetil-1'-(3-((S)-(3,4-diklorofenil))-4-(N-(benzoil)-(metilamino))butil)-4-fluor-spiro(indolin-3,4'-piperidin) 1-Acetyl-1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(benzoyl)-(methylamino))butyl)-4-fluoro-spiro(indoline-3, 4'-piperidine)

Maseni spektar (Cl): m/z = 588.2 (35Cl + 35Cl izotop + H+). Mass spectrum (Cl): m/z = 588.2 (35Cl + 35Cl isotope + H+).

Primjer 79 Example 79

1-Acetil-1'-(3-((S)-(3,4-diklorofenil))-4-(N-(3,5-dimetilbenzoil)-(metilamino))butil)-6-fluoro-spiro(indolin-3,4'-piperidin) 1-Acetyl-1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)-(methylamino))butyl)-6-fluoro-spiro( indoline-3,4'-piperidine)

Maseni spektar (Cl): m/z = 610.2 (35Cl + 35Cl izotop + H+), 612.2 (37Cl + 35Cl izotop + H+). Mass spectrum (Cl): m/z = 610.2 (35Cl + 35Cl isotope + H+), 612.2 (37Cl + 35Cl isotope + H+).

Primjer 80 Example 80

1-Acetil-l'-(3-((S)-(3,4-diklorofenil))-4-(N-(benzoil)-(metilamino))butil)-6-fluor-spiro(indolin-3,4'-piperidin) 1-Acetyl-1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(benzoyl)-(methylamino))butyl)-6-fluoro-spiro(indoline-3, 4'-piperidine)

Maseni spektar (Cl): m/z = 582.3 (35Cl + 35Cl izotop + H+). Mass spectrum (Cl): m/z = 582.3 (35Cl + 35Cl isotope + H+).

Primjer 81 Example 81

1-Acetil-1'-(3-((S)-(3,4-diklorofenil))-4-(N-(3,5-dimetil-benzoil)-(metilamino))butil)-4-fluor-spiro(indolin-3,4'-piperidin) 1-Acetyl-1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethyl-benzoyl)-(methylamino))butyl)-4-fluoro- spiro(indoline-3,4'-piperidine)

Maseni spektar (Cl): m/z = 610.3 (35Cl + 35Cl izotop + H+). Mass spectrum (Cl): m/z = 610.3 (35Cl + 35Cl isotope + H+).

Primjer 82 Example 82

1-Acetil-1'-(3-((S)-(3,4-diklorofenil))-4-(N-(benzoil)-(metilamino))butil)-5-fluor-spiro(indolin-3,4'-piperidin) 1-Acetyl-1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(benzoyl)-(methylamino))butyl)-5-fluoro-spiro(indoline-3, 4'-piperidine)

Maseni spektar (Cl): m/z = 582.2 (35Cl + 35Cl izotop + H+). Mass spectrum (Cl): m/z = 582.2 (35Cl + 35Cl isotope + H+).

Primjer 83 Example 83

1-Acetil-1'-5-klor-(3-((S)-(3,4-diklorofenil))-4-(N-(3,5-dimetilbenzoil)-(metilamino))butil)-spiro(indolin-3,4'-piperidin) 1-Acetyl-1'-5-chloro-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)-(methylamino))butyl)-spiro( indoline-3,4'-piperidine)

Maseni spektar (FAB): m/z = 626.0 (35Cl + 35Cl izotop + H+), 628.1 (37Cl + 35Cl izotop + H+). Mass spectrum (FAB): m/z = 626.0 (35Cl + 35Cl isotope + H+), 628.1 (37Cl + 35Cl isotope + H+).

Primjer 84 Example 84

1-A etil-1'-(3-((S)-(3,4-diklorofenil))-4-(N-(3-klorbenzoil)-(metilamino))butil)-5-fluor-spiro(indolin-3,4'-piperidin) 1-A ethyl-1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3-chlorobenzoyl)-(methylamino))butyl)-5-fluoro-spiro(indoline -3,4'-piperidine)

Maseni spektar (Cl): m/z = 616.2 (35Cl + 35Cl izotop + H+). Mass spectrum (Cl): m/z = 616.2 (35Cl + 35Cl isotope + H+).

Primjer 85 Example 85

1-Acetil-1'-(3-((S)-(3,4-diklorofenil))-4-(N-(3,5-diklorbenzoil)-(metilamino))butil)-5-fluor-spiro(indolin-3,4'-piperidin) 1-Acetyl-1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dichlorobenzoyl)-(methylamino))butyl)-5-fluoro-spiro( indoline-3,4'-piperidine)

Maseni spektar (Cl): m/z = 650.1 (35Cl + 35Cl izotop + H+). Mass spectrum (Cl): m/z = 650.1 (35Cl + 35Cl isotope + H+).

Primjer 86 Example 86

1-Acetil-1'-(3-((S)-(3,4-diklorofenil))-4-(N-(3-metilbenzoil)-(metilamino))butil)-5-fluor-spiro(indolin-3,4'-piperidin) 1-Acetyl-1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3-methylbenzoyl)-(methylamino))butyl)-5-fluoro-spiro(indoline- 3,4'-piperidine)

Maseni spektar (Cl): m/z = 596.2 (35Cl + 35Cl izotop + H+), 598.3 (37Cl + 35Cl izotop + H+). Mass spectrum (Cl): m/z = 596.2 (35Cl + 35Cl isotope + H+), 598.3 (37Cl + 35Cl isotope + H+).

Primjer 87 Example 87

1-Acetil-1'-(3-((S)-(3,4-diklorofenil))-4-(N-(3,5-dimetil-benzoil)-(metilamino))butil-5-fluor-spiro(indolin-3,4'-piperidin) 1-Acetyl-1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethyl-benzoyl)-(methylamino))butyl-5-fluoro-spiro (indoline-3,4'-piperidine)

Maseni spektar (Cl): m/z = 610.2 (35Cl + 35Cl izotop + H+). Mass spectrum (Cl): m/z = 610.2 (35Cl + 35Cl isotope + H+).

Primjer 88 Example 88

1-Acetil-1'-(3-((S)-(3,4-diklorfenil)-4-(N-(3-izopropoksibenzoil)-(metilamino))butil)-5-fluor-spiro(indolin-3,4'-piperidin) 1-Acetyl-1'-(3-((S)-(3,4-dichlorophenyl)-4-(N-(3-isopropoxybenzoyl)-(methylamino))butyl)-5-fluoro-spiro(indoline-3 ,4'-piperidine)

Maseni spektar (Cl): m/z = 640.3 (35Cl + 35Cl izotop + H+), 642.3 (37Cl + 35Cl izotop + H+). Mass spectrum (Cl): m/z = 640.3 (35Cl + 35Cl isotope + H+), 642.3 (37Cl + 35Cl isotope + H+).

Primjer 89 Example 89

1-Acetil-1'-(3-((S)-(3,4-diklorofenil)-4-(N-(3,5-bis(trifluorometil)-(metilamino))butil)-5-fluor-spiro(indolin-3,4'-piperidin) 1-Acetyl-1'-(3-((S)-(3,4-dichlorophenyl)-4-(N-(3,5-bis(trifluoromethyl)-(methylamino))butyl)-5-fluoro-spiro (indoline-3,4'-piperidine)

Maseni spektar (Cl): m/z = 718.2 (35Cl + 35Cl izotop + H+), 720.2 (37Cl + 35Cl izotop + H+). Mass spectrum (Cl): m/z = 718.2 (35Cl + 35Cl isotope + H+), 720.2 (37Cl + 35Cl isotope + H+).

Primjer 90 Example 90

1-Acetil-1'-(3-((S)-(3,4-diklorofenil))-4-(N-(3,5-dimetilbenzoil)-(metilamino))butil)-5-metil-spiro(indolin-3,4'-piperidin). 1-Acetyl-1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)-(methylamino))butyl)-5-methyl-spiro( indoline-3,4'-piperidine).

Maseni spektar (FAB): m/z = 606.1 (35Cl + 35Cl izotop + H+), 608.2 (37Cl + 35Cl izotop + H+). Mass spectrum (FAB): m/z = 606.1 (35Cl + 35Cl isotope + H+), 608.2 (37Cl + 35Cl isotope + H+).

N-Naftoil-metilamino derivati (Primjeri 91-101) se dobivaju analogno sa benzoil derivatima, upotrebljavajući komercijalno dostupne 1-naftoil kloride umjesto benzoil klorida: N-Naphtoyl-methylamino derivatives (Examples 91-101) are obtained analogously to benzoyl derivatives, using commercially available 1-naphthoyl chlorides instead of benzoyl chloride:

Primjer 91 Example 91

1-Acetil-1'-(3-((S)-(3,4-diklorofenil))-4-(N-(4-fluor-1-naftoil)-(metilamino))butil)-5-fluor-spiro(indolin-3,4'-piperidin) 1-Acetyl-1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(4-fluoro-1-naphthoyl)-(methylamino))butyl)-5-fluoro- spiro(indoline-3,4'-piperidine)

Maseni spektar (Cl): m/z = 650.3 (35Cl + 35Cl izotop + H+). Mass spectrum (Cl): m/z = 650.3 (35Cl + 35Cl isotope + H+).

Primjer 92 Example 92

1-Acetil-1'-(3-((S)-(3,4-diklorofenil))-4-(N-(1-naftoil)-(metilamino))butil)-5-fluor-spiro(indolin-3,4'-piperidin) 1-Acetyl-1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(1-naphthoyl)-(methylamino))butyl)-5-fluoro-spiro(indoline- 3,4'-piperidine)

Maseni spektar (Cl): m/z = 632.2 (35Cl + 35Cl izotop + H+), 634.2 (37Cl + 35Cl izotop + H+). Mass spectrum (Cl): m/z = 632.2 (35Cl + 35Cl isotope + H+), 634.2 (37Cl + 35Cl isotope + H+).

Primjer 93 Example 93

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(1-naftoil)-(metilamino))butil)-5-fluor-1-metansulfonil-spiro(indolin-3,4'-piperidin) 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(1-naphthoyl)-(methylamino))butyl)-5-fluoro-1-methanesulfonyl-spiro(indoline- 3,4'-piperidine)

Maseni spektar (Cl): m/z = 668.2 (35Cl + 35Cl izotop + H+). Mass spectrum (Cl): m/z = 668.2 (35Cl + 35Cl isotope + H+).

Primjer 94 Example 94

1'-(3-(S)-(3,4-Diklorofenil))-4-(N-(4-fluor-1-naftoil)-(metilamino)butil)-5-fluor-1-metansulfonil-spiro(indolin-3,4'-piperidin) 1'-(3-(S)-(3,4-Dichlorophenyl))-4-(N-(4-fluoro-1-naphthoyl)-(methylamino)butyl)-5-fluoro-1-methanesulfonyl-spiro( indoline-3,4'-piperidine)

Maseni spektar (Cl); m/z = 668.2 (35Cl + 35Cl izotop + H+). Mass spectrum (Cl); m/z = 668.2 (35Cl + 35Cl isotope + H+).

Primjer 95 Example 95

1'-(3-((S)-3,4-Dikloroenil))-4-(N-(4-fluor-1-naftoil)-(metilamino))butil)-spiro(2,3-dihidrobenzotiofen-3,4'-piperidin 1'-(3-((S)-3,4-Dichloroenyl))-4-(N-(4-fluoro-1-naphthoyl)-(methylamino))butyl)-spiro(2,3-dihydrobenzothiophene-3 ,4'-piperidine

Maseni spektar (Cl): m/z = 607.2 (35Cl + 35Cl izotop + H+). Mass spectrum (Cl): m/z = 607.2 (35Cl + 35Cl isotope + H+).

Primjer 96 Example 96

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(4-fluor-1-naftoil)-(metilamino))butil)-spiro(2,3-dihidrobenzotiofen-3,4'-piperidin) sulfon 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(4-fluoro-1-naphthoyl)-(methylamino))butyl)-spiro(2,3-dihydrobenzothiophene- 3,4'-piperidine) sulfone

Primjer 97 Example 97

1'-(3-((S)-(3,4-Diklorofenil)-4-(N-(4-fluor-1-naftoil)-(metilamino))butil)-spiro(2,3-dihidrobenzotiofen-3,4'-piperidin) 1'-(3-((S)-(3,4-Dichlorophenyl)-4-(N-(4-fluoro-1-naphthoyl)-(methylamino))butyl)-spiro(2,3-dihydrobenzothiophene-3 ,4'-piperidine)

Maseni spektar (Cl): m/z = 623.1 (35Cl + 35Cl izotop + H+). Mass spectrum (Cl): m/z = 623.1 (35Cl + 35Cl isotope + H+).

Primjer 98 Example 98

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(4-fluor-1-naftoil)-(metilamino))butil-5-fluor-spiro(2,3-dihidrobenzofuran-3,4' 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(4-fluoro-1-naphthoyl)-(methylamino))butyl-5-fluoro-spiro(2,3 -dihydrobenzofuran-3,4'

-piperidin) -piperidine)

Primjer 99 Example 99

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(4-fluor-1-naftoil)-(metilamino))butil-spiro(2,3-dihidrobenzofuran-3,4'-piperidin). 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(4-fluoro-1-naphthoyl)-(methylamino))butyl-spiro(2,3-dihydrobenzofuran-3 ,4'-piperidine).

Maseni spektar (Cl): m/z = 591.3 (35Cl + 35Cl izotop + H+), 593.3 (37Cl + 35Cl izotop + H+). Mass spectrum (Cl): m/z = 591.3 (35Cl + 35Cl isotope + H+), 593.3 (37Cl + 35Cl isotope + H+).

Primjer 100 Example 100

1-Acetil-1'-(3-((S)-(3,4-diklorofenil))-4-(N-(4-fluor-1-naftoil)-(metilamino))butil)-6-fluor-spiro(indolin-3,4'-piperidin) 1-Acetyl-1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(4-fluoro-1-naphthoyl)-(methylamino))butyl)-6-fluoro- spiro(indoline-3,4'-piperidine)

Primjer 101 Example 101

1-Acetil-1'-(3-((S)-(3,4-diklorofenil))-4-(N-(4-fluoro-1-naftoil)-(metilamino))butil)-4-fluor-spiro(indolin-3,4'-piperidin). 1-Acetyl-1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(4-fluoro-1-naphthoyl)-(methylamino))butyl)-4-fluoro- spiro(indoline-3,4'-piperidine).

Maseni spektar (Cl): m/z = 650.3 (35Cl + 35Cl izotop + H+) Mass spectrum (Cl): m/z = 650.3 (35Cl + 35Cl isotope + H+)

Benzilamin derivati mogu se sintetizirati redukcijom benzamida 1-metansulfonil-spiro(indolin-3,4'-piperidin derivata opisanih u nekim od Primjera. Metansulfonil grupa se može ukloniti zagrijavanjem sa HBr/octenom kiselinom/fenolom a zatim da se zamijeni sa acetil grupom tretiranjem sa anhidridom octene kiseline/piridinom. Reprezentativni postupci i spojevi su dati u Primjerima 102 i 103 niže: Benzylamine derivatives can be synthesized by reduction of the benzamide 1-methanesulfonyl-spiro(indoline-3,4'-piperidine derivatives described in some of the Examples. The methanesulfonyl group can be removed by heating with HBr/acetic acid/phenol and then replaced with an acetyl group by treatment with acetic anhydride/pyridine Representative procedures and compounds are given in Examples 102 and 103 below:

Primjer 102 Example 102

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(4-fluoro-1-naftil-metil)-(metilamino))butil-5-fluoro-1-metansulfonil-spiro-(indolin-3,4'-piperidin). 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(4-fluoro-1-naphthyl-methyl)-(methylamino))butyl-5-fluoro-1-methanesulfonyl -spiro-(indoline-3,4'-piperidine).

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(4-fluoro-1-naftoil)-(metilamino))butil-5-fluoro-1-metansulfonil-spiro(indolin-3,4'-piperidina) (96 mg) se otapa u 1M Dibal-u-H u toluolu (160 ul). Poslije 1/2 sata dodaje se zasićena vodena otopina natrij kalij tartarata (5 ml) i EtOAc (5 ml) i miješa se snažno 2 sata. Organski sloj se pere sa H2O (5 ml), slanom otopinom (5 ml), suši (MgSO4), i koncentrira se do sirovog ulja, koje se pročišćava kromatografijom na koloni (silika gel 60, 0-10% acetona/CH2Cl2) pri čemu se dobiva 55 mg (59%) naslovnog spoja u obliku bijele pjene; 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(4-fluoro-1-naphthoyl)-(methylamino))butyl-5-fluoro-1-methanesulfonyl-spiro (indoline-3,4'-piperidine) (96 mg) was dissolved in 1M Dibal-u-H in toluene (160 µl). After 1/2 hour a saturated aqueous solution of sodium potassium tartrate (5 ml) and EtOAc (5 ml ) and stirred vigorously for 2 h. The organic layer was washed with H2O (5 mL), brine (5 mL), dried (MgSO4), and concentrated to a crude oil, which was purified by column chromatography (silica gel 60.0 -10% acetone/CH2Cl2) to give 55 mg (59%) of the title compound as a white foam;

1H NMR (400 MHz, CDCl3) δ 8.09 (d, 1H, J=8.5 Hz), 7.91 (d, 1H, J=8.5 Hz), 7.53 (t, 1H, J=7.5 Hz), 7.38 (t, 1H, J=7.5 Hz), 7.33 (dd, 1H, J=4.3, 8.8 Hz), 7.22 (dd, 1H, J=5.8, 7.8 Hz), 7.18 (d, 1H, J=8.5 Hz), 7.09 (d, J=2.0 Hz), 7.04 (dd, 1H, J=7.5, 10.0 Hz), 6.92 (dt, 1H, J=2.5, 8.5 Hz), 6.88 (d, 1H), 6.77 (dd, 1H, J=1.8, 8.3 Hz), 3.85 (dd, 1H, J=8.0 Hz), 3.76 (s, 2H), 3.75 (dd, 1H, J=8.0 Hz), 2.88 (s, 3H), 2.80-2.66 (m, 3H), 2.62 (dd, 1H, J=8.8, 12.3 Hz), 2.51 (dd, 1H, J=6.5, 12.5 Hz), 2.28 (s, 3H), 2.18-2.06 (m, 2H), 1.88-1.80 (m, 4H), 1.65 (d, 2H, J=10.5 Hz) ppm; 1H NMR (400 MHz, CDCl3) δ 8.09 (d, 1H, J=8.5 Hz), 7.91 (d, 1H, J=8.5 Hz), 7.53 (t, 1H, J=7.5 Hz), 7.38 (t, 1H , J=7.5 Hz), 7.33 (dd, 1H, J=4.3, 8.8 Hz), 7.22 (dd, 1H, J=5.8, 7.8 Hz), 7.18 (d, 1H, J=8.5 Hz), 7.09 (d , J=2.0 Hz), 7.04 (dd, 1H, J=7.5, 10.0 Hz), 6.92 (dt, 1H, J=2.5, 8.5 Hz), 6.88 (d, 1H), 6.77 (dd, 1H, J= 1.8, 8.3 Hz), 3.85 (dd, 1H, J=8.0 Hz), 3.76 (s, 2H), 3.75 (dd, 1H, J=8.0 Hz), 2.88 (s, 3H), 2.80-2.66 (m, 3H), 2.62 (dd, 1H, J=8.8, 12.3 Hz), 2.51 (dd, 1H, J=6.5, 12.5 Hz), 2.28 (s, 3H), 2.18-2.06 (m, 2H), 1.88-1.80 (m, 4H), 1.65 (d, 2H, J=10.5 Hz) ppm;

Maseni spektar (Cl): m/z = 672.4 (35Cl + 35Cl izotop + H+). Mass spectrum (Cl): m/z = 672.4 (35Cl + 35Cl isotope + H+).

Primjer 103 Example 103

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(4-fluoro-1-naftilmetil)-(metilamino))butil)-5-fluoro-spiro(indolin-3,4'-piperidin) 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(4-fluoro-1-naphthylmethyl)-(methylamino))butyl)-5-fluoro-spiro(indoline- 3,4'-piperidine)

1'-(3-((S)-(3,4-diklorofenil))-4-(N-(4-fluoro-1-naftimetil)-(metilamino))butil)-5-fluoro-1-metansulfonil-spiro(indolin-3,4'-piperidina) (45.6 mg) i fenola (19 mg) u 30% HBr/HOAc (270 ul) zagrijavaju se na 70°C 6 sati u zatopljenoj posudi. Reakcija se koncentrira i raspodjeljuje se između CH2Cl2 (1 ml) i 1N NaOH (2 ml). Organski sloj se eluira kroz sloj od 3 x 3 cm silika gela sa 0-100% acetona/CH2Cl2, pri čemu se dobiva 30 mg (74%) naslovnog spoja u obliku žutog ulja. 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(4-fluoro-1-naphthymethyl)-(methylamino))butyl)-5-fluoro-1-methanesulfonyl- spiro(indoline-3,4'-piperidine) (45.6 mg) and phenol (19 mg) in 30% HBr/HOAc (270 µl) were heated at 70°C for 6 hours in a heated vessel. The reaction was concentrated and partitioned between CH 2 Cl 2 (1 mL) and 1N NaOH (2 mL). The organic layer was eluted through a 3 x 3 cm pad of silica gel with 0-100% acetone/CH2Cl2 to give 30 mg (74%) of the title compound as a yellow oil.

1H NMR (400 MHz, CDCl3) δ 8.09 (d, 1H, J=8.0 Hz), 7.93 (d, 1H), J=8.5 HZ), 7.52 (t, 1H, J=7.5 Hz), 7.43 (t, 1H, J=7.3 Hz), 7.22 (dd, 1H, J=5.5, 7.5 Hz), 7.17 (d, 1H, J=8.5 Hz), 7.06 (dd, 1H, J=8.8, 10.3 Hz), 7.02 (d, 1H, J=1.5 Hz), 6.87 (d, 1H, J=3.5 Hz), 6.78 (dd, 1H, J=2.3, 8.3 Hz), 6.75 (dd, 1H, J=2.3, 7.8 Hz), 6.56 (dd, 1H, J=4.0, 8.5 Hz) ppm; 1H NMR (400 MHz, CDCl3) δ 8.09 (d, 1H, J=8.0 Hz), 7.93 (d, 1H), J=8.5 Hz), 7.52 (t, 1H, J=7.5 Hz), 7.43 (t, 1H, J=7.3 Hz), 7.22 (dd, 1H, J=5.5, 7.5 Hz), 7.17 (d, 1H, J=8.5 Hz), 7.06 (dd, 1H, J=8.8, 10.3 Hz), 7.02 ( d, 1H, J=1.5 Hz), 6.87 (d, 1H, J=3.5 Hz), 6.78 (dd, 1H, J=2.3, 8.3 Hz), 6.75 (dd, 1H, J=2.3, 7.8 Hz), 6.56 (dd, 1H, J=4.0, 8.5 Hz) ppm;

Maseni spektar (Cl): m/z = 594.3 (35Cl + 35Cl izotop + H+), 596.3 (37Cl + 35Cl izotop + H+). Mass spectrum (Cl): m/z = 594.3 (35Cl + 35Cl isotope + H+), 596.3 (37Cl + 35Cl isotope + H+).

Primjer 104 Example 104

1-Acetil-1'-(3-((S)-(3,4-dikloroenil))-4-(N-(4-fluoro-1-naftimetil)-(metilamino))butil)-5-fluoro-spiro(indolin-3,4'-piperidin) 1-Acetyl-1'-(3-((S)-(3,4-dichloroenyl))-4-(N-(4-fluoro-1-naphthymethyl)-(methylamino))butyl)-5-fluoro- spiro(indoline-3,4'-piperidine)

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(4-fluoro-1-naftilmetil)-(metilamino))butil-5-fluoro-spiro(indolin-3,4'piperidina) (10 mg) u CH2Cl2 (100 ul) se tretira sa jednom kapi anhidrida octene kiseline i 1 kapi piridina. Poslije 30 minuta, reakcija se eluira kroz 1 x 2 cm kolonu od silika gela upotrebljavajući 0-100% acetona/CH2Cl2 plus 1% NH4OH, pri čemu se dobiva 10 mg (93%) naslovnog spoja kao bistar film. 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(4-fluoro-1-naphthylmethyl)-(methylamino))butyl-5-fluoro-spiro(indoline-3 ,4'piperidine) (10 mg) in CH2Cl2 (100 µl) is treated with 1 drop of acetic anhydride and 1 drop of pyridine. After 30 min, the reaction is eluted through a 1 x 2 cm column of silica gel using 0-100% acetone /CH2Cl2 plus 1% NH4OH to give 10 mg (93%) of the title compound as a clear film.

1H NMR (CDCl3) δ 8.17 (dd, 1H, J=4.3, 8.8 Hz), 8.09 (d, 1H, J=8.5 Hz), 7.91 (d, 1H, J=8.0 Hz), 7.52 (t, 1H, 7.3 Hz), 7.38 (t, 1H, J=7.3 Hz), 7.22 (dd, 1H, 6.8, 7.09 Hz), 7.18 (d, 1H, J=8.8 Hz), 7.07 (d, 1H, J=2.0 Hz), 7.04 (dd, 1H, J=8.0, 10.5 Hz), 6.91 (dt, 1H, J=2.0, 9.0 Hz), 6.86 (dd, 1H, J=2.0, 7.5 Hz), 6.76 (dd, 1H, J=2.0, 8.5) Hz, 3.96, 3.81 1H, J=2.0, 7.5 Hz), 6.76 (dd, 1H, J=2.0, 8.5 Hz), 3.96, 3.81 (singleti rotamera, 3H), 3.85 (d, 1H, J=13 Hz), 3.75 (d, 1H, J=13 Hz), 2.84 (m, 2H), 2.74 (m, 1H), 2.61 (dd, 1H, J=8.5, 13 Hz), 2.51 (dd, 1H, J=7.0, 13 Hz), 2.43, 2.35 (singleti rotamera, 3H), 2.24 (s, 3H), 2.3-2.2 (m, 3H), 2.0-1.85 (m, 4H), 1.65 (m, 2H), 1.50 (m, 1H) ppm; 1H NMR (CDCl3) δ 8.17 (dd, 1H, J=4.3, 8.8 Hz), 8.09 (d, 1H, J=8.5 Hz), 7.91 (d, 1H, J=8.0 Hz), 7.52 (t, 1H, 7.3 Hz), 7.38 (t, 1H, J=7.3 Hz), 7.22 (dd, 1H, 6.8, 7.09 Hz), 7.18 (d, 1H, J=8.8 Hz), 7.07 (d, 1H, J=2.0 Hz ), 7.04 (dd, 1H, J=8.0, 10.5 Hz), 6.91 (dt, 1H, J=2.0, 9.0 Hz), 6.86 (dd, 1H, J=2.0, 7.5 Hz), 6.76 (dd, 1H, J=2.0, 8.5) Hz, 3.96, 3.81 1H, J=2.0, 7.5 Hz), 6.76 (dd, 1H, J=2.0, 8.5 Hz), 3.96, 3.81 (rotamer singlets, 3H), 3.85 (d, 1H , J=13 Hz), 3.75 (d, 1H, J=13 Hz), 2.84 (m, 2H), 2.74 (m, 1H), 2.61 (dd, 1H, J=8.5, 13 Hz), 2.51 (dd , 1H, J=7.0, 13 Hz), 2.43, 2.35 (rotamer singlets, 3H), 2.24 (s, 3H), 2.3-2.2 (m, 3H), 2.0-1.85 (m, 4H), 1.65 (m, 2H), 1.50 (m, 1H) ppm;

Maseni spektar (Cl): m/z = 636,4 (35Cl + 35Cl izotop + H+), 638.4 (37Cl + 35Cl izotop + H+). Mass spectrum (Cl): m/z = 636.4 (35Cl + 35Cl isotope + H+), 638.4 (37Cl + 35Cl isotope + H+).

Primjer 105 Example 105

1'-(5-Fluoroindolil-3-(3-etanoil))-1-metansultonil-spiro-(indolin-3,4'-piperidin) 1'-(5-Fluoroindolyl-3-(3-ethanoyl))-1-methanesultonyl-spiro-(indoline-3,4'-piperidine)

U otopinu 1-metansulfonil-spiro(indolin-3,4'-piperidin) hidroklorida (373 mg, 1.23 mmola), 5-fluoroindol-3-octene kiseline (500 mg, 2.59 mmola) u DMF (15 ml) na sobnoj temperaturi, dodaje se N-metil-morfolin (261 mg, 2.59 mmola), hidroksibenzotriazol (381 mg, 2.82 mmola) i (1-(3-dimetilaminopropil)-3-etilkarbodiimid (473 mg, 2.47 mmola). Reakcija se miješa 48 sati, razblažuje se sa H2O (250 ml), ekstrahira se sa EtOAc (3 x 100 ml), pere se sa H2O (2 x 150 ml), slanom otopinom (150 ml), suši (Na2SO4), koncentrira u vakuumu i pročišćava se kromatografijom na koloni (SG 60 silicij dioksid, 5% MeOH/CH2Cl2), pri čemu se dobiva 486 mg (89%) naslovnog spoja kao bezbojno ulje. In a solution of 1-methanesulfonyl-spiro(indoline-3,4'-piperidine) hydrochloride (373 mg, 1.23 mmol), 5-fluoroindole-3-acetic acid (500 mg, 2.59 mmol) in DMF (15 ml) at room temperature , N-methyl-morpholine (261 mg, 2.59 mmol), hydroxybenzotriazole (381 mg, 2.82 mmol) and (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (473 mg, 2.47 mmol)) were added. The reaction was stirred for 48 hours. , diluted with H2O (250 ml), extracted with EtOAc (3 x 100 ml), washed with H2O (2 x 150 ml), brine (150 ml), dried (Na2SO4), concentrated in vacuo and purified column chromatography (SG 60 silica, 5% MeOH/CH2Cl2) to give 486 mg (89%) of the title compound as a colorless oil.

1H NMR (500 MHz, CDCl3) δ 8.39 (širok s, 1H), 7.37 (d, 1H, J=8.2 Hz), 7.34 (dd, 1H, J=9.6, 2.3 Hz), 7.29 (dd, 1H, J=8.9, 4.4 (Hz), 7.23 (dt, 1H, J=7.8, 1.2 Hz), 7.14 (d, 1H, J=2.3 Hz), 7.03 (t, 1H, J=7.3 Hz), 6.98 (dt, 1H, J=8.9, 2.5 Hz), 6.87 (d, 1H, J=7.5 Hz), 4.73 (d, 1H, J=13.7 Hz), 3.96 (d, 1H, J=13.4 Hz), 2.91 (s, 3H), 2.73 (t, 1H, J=13.5 Hz), 1.83 (dt, 1H, J=13.5, 4.4 Hz), 1.65-1.75 (m, 2H), 1.52-1.58 (m, 1H), 1.40 (dt, 1H, J=13.0, 4.3 Hz) ppm; 1H NMR (500 MHz, CDCl3) δ 8.39 (broad s, 1H), 7.37 (d, 1H, J=8.2 Hz), 7.34 (dd, 1H, J=9.6, 2.3 Hz), 7.29 (dd, 1H, J =8.9, 4.4 (Hz), 7.23 (dt, 1H, J=7.8, 1.2 Hz), 7.14 (d, 1H, J=2.3 Hz), 7.03 (t, 1H, J=7.3 Hz), 6.98 (dt, 1H, J=8.9, 2.5 Hz), 6.87 (d, 1H, J=7.5 Hz), 4.73 (d, 1H, J=13.7 Hz), 3.96 (d, 1H, J=13.4 Hz), 2.91 (s, 3H), 2.73 (t, 1H, J=13.5 Hz), 1.83 (dt, 1H, J=13.5, 4.4 Hz), 1.65-1.75 (m, 2H), 1.52-1.58 (m, 1H), 1.40 (dt , 1H, J=13.0, 4.3 Hz) ppm;

Maseni spektar (Cl): m/z 44a (M+H). Mass spectrum (Cl): m/z 44a (M+H).

Primjer 106 Example 106

1'-(2-(3-(5-Fluoroindolil))etil))-1-metansulfonil-spiro-indolin-3,4'-piperidin) 1'-(2-(3-(5-Fluoroindolyl))ethyl))-1-methanesulfonyl-spiro-indoline-3,4'-piperidine)

U otopinu 1'-(5-fluoroindolil-3-(2-etanoil))-1-metansulfonil-spiro(indolin-3,4'piperidina (100 mg, .226 mmola) u CH2Cl2 (8 ml) na -70�C dodaje se Dibal-H (1M u THF, 0.91 ml, .0906 mmola). Poslije 2,5 sati smjesa se zaustavlja dodatkom 1M NaOH (20 ml), razblažuje se sa CH2Cl2) i miješa se snažno 15 minuta. Smjesa se ekstrahira sa CH2Cl2 (Na2SO4), koncentrira u vakuumu i pročišćava kromatografijom na koloni (SG 60 silicij dioksid, 5% MeOH/CH2Cl2), pri čemu se dobiva 66 mg (68%) naslovnog spoja kao bezbojna čvrsta tvar. In a solution of 1'-(5-fluoroindolyl-3-(2-ethanoyl))-1-methanesulfonyl-spiro(indoline-3,4'piperidine (100 mg, .226 mmol) in CH2Cl2 (8 ml) at -70� Dibal-H (1M in THF, 0.91 ml, .0906 mmol) was added C. After 2.5 hours, the mixture was quenched by addition of 1M NaOH (20 ml), diluted with CH2Cl2) and stirred vigorously for 15 minutes. The mixture was extracted with CH2Cl2 (Na2SO4), concentrated in vacuo and purified by column chromatography (SG 60 silica, 5% MeOH/CH2Cl2) to give 66 mg (68%) of the title compound as a colorless solid.

1H NMR (500 MHz, CDCl3) δ 8.20 (širok s, 1H), 7.42 (d, 1H, J=8.0 Hz), 7.20-7.30 (m, 4H), 7.06-7.14 (m, 2H), 6.93-6.97 (m, 1H), 3.84 (s, 2H), 3.08 (d, 2H, J=11.7 Hz), 2.94-3.00 (m, 2H), 2.93 (s, 3H), 2.71-2.77 (m, 2H), 2.19 (t, 2H, J=12.3 Hz), 2.07 (dt, 2H, J=13.2, 3.9 Hz), 1.75 (d, 2H, J=13.0 Hz) ppm; 1H NMR (500 MHz, CDCl3) δ 8.20 (broad s, 1H), 7.42 (d, 1H, J=8.0 Hz), 7.20-7.30 (m, 4H), 7.06-7.14 (m, 2H), 6.93-6.97 (m, 1H), 3.84 (s, 2H), 3.08 (d, 2H, J=11.7 Hz), 2.94-3.00 (m, 2H), 2.93 (s, 3H), 2.71-2.77 (m, 2H), 2.19 (t, 2H, J=12.3 Hz), 2.07 (dt, 2H, J=13.2, 3.9 Hz), 1.75 (d, 2H, J=13.0 Hz) ppm;

Maseni spektar (Cl) m/z 428 (M+H). Mass spectrum (Cl) m/z 428 (M+H).

Primjer 107 Example 107

4-Fluor-3,5-dimetilbenzoeva kiselina 4-Fluoro-3,5-dimethylbenzoic acid

Stupanj 1) Level 1)

1-Brom-4-fluor-3.5-dimetilbenzol 1-Bromo-4-fluoro-3,5-dimethylbenzene

U smjesu 4-brom-2,6-dimetilaniline (8.3 g, 42 mmola) na 5°C i H2O (50 ml), dodaje se koncentrirana H2SO4 (6.25 ml). NaNO2 (4.1 g) se dodaje u porcijama sve dok se ne pokaže višak pomoću škrob jodidnog papira. Dodaje se voda (30 ml) da bi se dobila homogena smjesa. Poslije prebacivanja u plastičnu posudu, dodaje se ukapavanjem uz miješanje, HBF4 (50%, 13.7 g). Dobiven bijeli talog se sakuplja filtracijom u vakuumu, pere se sa H2O (30 ml), MeOH (30 ml), i Et2O (60 ml) i suši se preko P2O5 pod vakuumom u toku 16 sati. Čvrsta supstanca se zagrijava u staklenom balonu sa otvorenim plamenom sve dok se čvrsta supstanca ne raspadne. Preostala tekućina se razblažuje sa Et2O (50 ml) i 0.5 M NaOH (25 ml). Organski sloj se odvaja, pere se sa 0.5 M NaOH (25 ml), H2O (25 ml), slanom otopinom (25 ml), suši (MgSO4) i koncentrira u vakuumu, pri čemu se dobiva 6,06 g (72%) 1-brom-4-fluoro-3,5-dimetilbenzola kao svijetlo žuta tekućina. To a mixture of 4-bromo-2,6-dimethylaniline (8.3 g, 42 mmol) at 5°C and H2O (50 ml), was added concentrated H2SO4 (6.25 ml). NaNO2 (4.1 g) is added in portions until an excess is indicated by starch iodide paper. Water (30 ml) is added to obtain a homogeneous mixture. After transferring to a plastic container, HBF4 (50%, 13.7 g) is added dropwise with stirring. The resulting white precipitate is collected by vacuum filtration, washed with H2O (30 ml), MeOH (30 ml), and Et2O (60 ml) and dried over P2O5 under vacuum for 16 hours. The solid is heated in a glass flask with an open flame until the solid decomposes. The remaining liquid was diluted with Et2O (50 ml) and 0.5 M NaOH (25 ml). The organic layer is separated, washed with 0.5 M NaOH (25 ml), H2O (25 ml), brine (25 ml), dried (MgSO4) and concentrated in vacuo to give 6.06 g (72%) 1-Bromo-4-fluoro-3,5-dimethylbenzene as a light yellow liquid.

1NMR (500 MHz, CDCl3) δ 7.17 (d, 2H, J=6.2 Hz), 2.21 (s, 6H) ppm. 1NMR (500 MHz, CDCl3) δ 7.17 (d, 2H, J=6.2 Hz), 2.21 (s, 6H) ppm.

Stupanj B) Grade B)

4-Fluor-3,5-dimetilbenzoeva kiselina 4-Fluoro-3,5-dimethylbenzoic acid

U smjesu opiljaka magnezija (120 mg, 4.92 mmola) u THF (2 ml), dodaje se kristal joda a zatim se lagano dodaje otopina bromida (1.0 g, 4.92 mmola) u THF (3 ml). Reakcijska smjesa se zagrijava do refluksa 1 sat, a zatim se ohladi do sobne temperature, i dodaje se CO2 (višak), miješa se 1 sat i zaustavi se reakcija dodatkom 1 M HCl (10 ml). Smjesa se ekstrahira sa Et2O (3 x 25 ml), pere se sa slanom otopinom (25 ml), suši MgSO4), i koncentrira u vakuumu, pri čemu se dobiva 0.82 g (99%) naslovnog spoja kao svijetlo žuta čvrsta tvar. To a mixture of magnesium filings (120 mg, 4.92 mmol) in THF (2 ml), a crystal of iodine is added and then a solution of bromide (1.0 g, 4.92 mmol) in THF (3 ml) is slowly added. The reaction mixture was heated to reflux for 1 hour, then cooled to room temperature, and CO2 (excess) was added, stirred for 1 hour, and the reaction was quenched by the addition of 1 M HCl (10 mL). The mixture was extracted with Et 2 O (3 x 25 mL), washed with brine (25 mL), dried with MgSO 4 , and concentrated in vacuo to give 0.82 g (99%) of the title compound as a light yellow solid.

1H NMR (500 MHz, CDCl3) δ 7.81 (d, 2H, J=6.7 Hz), 2.36 (s, 6H) ppm; 1H NMR (500 MHz, CDCl3) δ 7.81 (d, 2H, J=6.7 Hz), 2.36 (s, 6H) ppm;

Maseni spektar (Cl) m/z 168 (M-H). Mass spectrum (Cl) m/z 168 (M-H).

Spojevi iz Primjera 108-120 se dobivaju prema Primjeru 3 Stupanj B, upotrebljavajući prethodno dobivene amine i pogodne benzoeve i naftalinkarbonske kiseline: The compounds from Examples 108-120 are obtained according to Example 3 Stage B, using previously obtained amines and suitable benzoic and naphthalene carboxylic acids:

Primjer 108 Example 108

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(3-klor-4-fluoro-benzoil)-(metilamino))butil)-1-metansulfonil-spiro(indolin-3,4'-piperidin 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(3-chloro-4-fluoro-benzoyl)-(methylamino))butyl)-1-methanesulfonyl-spiro( indoline-3,4'-piperidine

Maseni spektar (Cl) 656 (37Cl + 35Cl izotop + H+), 654 (35Cl + 35Cl izotop + H+). Mass spectrum (Cl) 656 (37Cl + 35Cl isotope + H+), 654 (35Cl + 35Cl isotope + H+).

Primjer 109 Example 109

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(3-klor-4-fluoro-benzoil)-(metilamino))butil-5-fluor-1- metansulfonil- spiro-(indolin-3,4'- piperidin). 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(3-chloro-4-fluoro-benzoyl)-(methylamino))butyl-5-fluoro-1-methanesulfonyl - spiro-(indoline-3,4'-piperidine).

Maseni spektar (Cl) 674 (37Cl + 35Cl izotop + H+), 672 (35Cl + 35Cl izotop + H+). Mass spectrum (Cl) 674 (37Cl + 35Cl isotope + H+), 672 (35Cl + 35Cl isotope + H+).

Primjer 110 Example 110

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(4-fluorobenzoil)-(metilamino))butil)-1-metansulfonil-spiro(indolin-3,4'-piperidin) 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(4-fluorobenzoyl)-(methylamino))butyl)-1-methanesulfonyl-spiro(indoline-3,4' -piperidine)

Maseni spektar (Cl) 620 (37Cl + 35Cl izotop + H+), 618 (35Cl + 35Cl izotop + H+). Mass spectrum (Cl) 620 (37Cl + 35Cl isotope + H+), 618 (35Cl + 35Cl isotope + H+).

Primjer 111 Example 111

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(4-fluorobenzoil)-(metilamino))butil)-5-fluoro-1-acetil-spiro(indolin-3,4'-piperidin) 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(4-fluorobenzoyl)-(methylamino))butyl)-5-fluoro-1-acetyl-spiro(indoline- 3,4'-piperidine)

Maseni spektar (Cl) 618 (37Cl + 35Cl izotop + H+), 616 (35Cl + 35Cl izotop + H+). Mass spectrum (Cl) 618 (37Cl + 35Cl isotope + H+), 616 (35Cl + 35Cl isotope + H+).

Primjer 112 Example 112

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(3-klor-4-fluorobenzoil)-(metilamino)butil)-5-fluoro1-acetil-spiro-(indolin-3,4'-piperidin) 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(3-chloro-4-fluorobenzoyl)-(methylamino)butyl)-5-fluoro1-acetyl-spiro-( indoline-3,4'-piperidine)

Maseni spektar (Cl) 636 (37Cl + 35Cl izotop + H+), 634 (35Cl + 35Cl izotop + H+). Mass spectrum (Cl) 636 (37Cl + 35Cl isotope + H+), 634 (35Cl + 35Cl isotope + H+).

Primjer 113 Example 113

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(4-fluoro-3,5-dimetil-benzoil)-(metilamino))butil)-5-fluoro-1-acetil-spiro-(indolin-3,4'-piperidin) 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(4-fluoro-3,5-dimethyl-benzoyl)-(methylamino))butyl)-5-fluoro- 1-acetyl-spiro-(indoline-3,4'-piperidine)

Maseni spektar (Cl) 636 (37Cl + 35Cl izotop + H+), 628 (35Cl + 35Cl izotop + H+). Mass spectrum (Cl) 636 (37Cl + 35Cl isotope + H+), 628 (35Cl + 35Cl isotope + H+).

Primjer 114 Example 114

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(4-fluoro-3,5-dimetilbenzoil)-(metilamino))butil)-1-metansulfonil-spiro-(indolin-3,4'-piperidin) 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(4-fluoro-3,5-dimethylbenzoyl)-(methylamino))butyl)-1-methanesulfonyl-spiro- (indoline-3,4'-piperidine)

Maseni spektar (Cl) 648 (37Cl + 35Cl izotop + H+), 646 (35Cl + 35Cl izotop + H+). Mass spectrum (Cl) 648 (37Cl + 35Cl isotope + H+), 646 (35Cl + 35Cl isotope + H+).

Primjer 115 Example 115

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(4-fluoro-3-trifluorometilbenzoil)-(metilamino))butil)-1-metansulfonil-spiro-(indolin-3,4'-piperidin) 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(4-fluoro-3-trifluoromethylbenzoyl)-(methylamino))butyl)-1-methanesulfonyl-spiro-(indoline -3,4'-piperidine)

Maseni spektar (Cl) 688 (37Cl + 35Cl izotop + H+), 686 (35Cl + 35Cl izotop + H+). Mass spectrum (Cl) 688 (37Cl + 35Cl isotope + H+), 686 (35Cl + 35Cl isotope + H+).

Primjer 116 Example 116

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(4-fluoro-3,5-dimetilbenzoil)-(metilamino))butil)-1-acetil-spiro(indolin-3,4'-piperidin) 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(4-fluoro-3,5-dimethylbenzoyl)-(methylamino))butyl)-1-acetyl-spiro( indoline-3,4'-piperidine)

Maseni spektar (Cl) 612 (37Cl + 35Cl izotop + H+), 610 (35Cl + 35Cl izotop + H+). Mass spectrum (Cl) 612 (37Cl + 35Cl isotope + H+), 610 (35Cl + 35Cl isotope + H+).

Primjer 117 Example 117

1'-(3-((S)-(3,4-Diklorofenil))-4-)N-(4-fluoro-3-trifluorometilbenzoil)-(metilamino))butil)-1-acetil-spiro(indolin-3,4'-piperidin) 1'-(3-((S)-(3,4-Dichlorophenyl))-4-)N-(4-fluoro-3-trifluoromethylbenzoyl)-(methylamino))butyl)-1-acetyl-spiro(indoline- 3,4'-piperidine)

Maseni spektar (Cl) 652 (37Cl + 35Cl izotop + H+), 650 (35Cl + 35Cl izotop + H+). Mass spectrum (Cl) 652 (37Cl + 35Cl isotope + H+), 650 (35Cl + 35Cl isotope + H+).

Primjer 118 Example 118

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(4-fluoro-1-naftoil)-(metilamino))butil)-1-acetil-spiro(indolin-3,4'-piperidin) 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(4-fluoro-1-naphthoyl)-(methylamino))butyl)-1-acetyl-spiro(indoline- 3,4'-piperidine)

Maseni spektar (Cl) 634 (37Cl + 35Cl izotop + H+), 632 (35Cl + 35Cl + H+). Mass spectrum (Cl) 634 (37Cl + 35Cl isotope + H+), 632 (35Cl + 35Cl + H+).

Primjer 119 Example 119

1'-(3-((S)-(3,4-Dikloroenil))-4-(N-(4-fluoro-1-naftoil)-(metilamino))butil)-1-metansulfonil-spiro(indolin-3,4'-piperidin) 1'-(3-((S)-(3,4-Dichloroenyl))-4-(N-(4-fluoro-1-naphthoyl)-(methylamino))butyl)-1-methanesulfonyl-spiro(indoline- 3,4'-piperidine)

Maseni spektar (Cl) 670 (37Cl + 35Cl izotop + H+), 668 (35Cl + 35Cl izotop + H+). Mass spectrum (Cl) 670 (37Cl + 35Cl isotope + H+), 668 (35Cl + 35Cl isotope + H+).

Primjer 120 Example 120

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(1-naftoil)-metilamino))butil)-1-acetil-spiro(indolin-3,4'-piperidin) 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(1-naphthoyl)-methylamino))butyl)-1-acetyl-spiro(indoline-3,4'- piperidine)

Maseni spektar (Cl) 616 (37Cl + 35Cl izotop + H+), 614 (35Cl + 35Cl izotop + H+). Mass spectrum (Cl) 616 (37Cl + 35Cl isotope + H+), 614 (35Cl + 35Cl isotope + H+).

Primjer 121 Example 121

1'-(3-((S)-(3,4-Diklorofenil))-4-(N-(3,5-dimetilbenzoil)-(metilamino)-4-fenil-butil)-1-metansulfonil-spiro(indolin-3,4'-piperidin) 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)-(methylamino)-4-phenyl-butyl)-1-methanesulfonyl-spiro( indoline-3,4'-piperidine)

Naslovni spoj se dobiva u 6 stupnjeva iz 2-(S)-(3,4-diklorofenil)-4-pentenove kiseline upotrebljavajući postupak identičan sa onim u Primjeru 10 zamjenjujući metillitij u Primjeru 10 Stupanj 2, sa fenillitijem. The title compound is prepared in 6 steps from 2-(S)-(3,4-dichlorophenyl)-4-pentenoic acid using a procedure identical to that of Example 10 replacing methyllithium in Example 10 Step 2, with phenyllithium.

Maseni spektar (FAB): m/z 704 (M+H, 37Cl + 35Cl izotop, 100%), 706 (M+H, 37Cl + 37Cl izotop, 80%). Mass spectrum (FAB): m/z 704 (M+H, 37Cl + 35Cl isotope, 100%), 706 (M+H, 37Cl + 37Cl isotope, 80%).

Primjer 122 Example 122

1'-(4-(N-(3,5-Dimetilbenzoil)-(metilamino))-4-(fenil)butil)-1-acetil-spiro(indolin-3,4'piperidin) 1'-(4-(N-(3,5-Dimethylbenzoyl)-(methylamino))-4-(phenyl)butyl)-1-acetyl-spiro(indoline-3,4'piperidine)

Naslovni spoj se dobiva u 6 stupnjeva iz 4-pentenove kiseline upotrebljavajući postupak identičan sa onim u Primjeru 10, zamjenjujući metillitij u Primjeru 10, Stupanj 2, sa fenillitijem. The title compound is prepared in 6 steps from 4-pentenoic acid using a procedure identical to that of Example 10, replacing methyllithium in Example 10, Step 2, with phenyllithium.

Maseni spektar (FAB): m/z 524 (M+H, 37Cl + 35Cl izotop, 100%), 526 (M+H, 37Cl + 37Cl izotop, 50%). Mass spectrum (FAB): m/z 524 (M+H, 37Cl + 35Cl isotope, 100%), 526 (M+H, 37Cl + 37Cl isotope, 50%).

Primjer 123 Example 123

1'-(3-((S)-(3,4-Diklorofenil))-4-(1-(2-fenilimidazo))butil)-1-metansulfonil-spiro(indolin-3,4'-piperidin) 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(1-(2-phenylimidazo))butyl)-1-methanesulfonyl-spiro(indoline-3,4'-piperidine)

Stupanj 1) Level 1)

1-(2-Fenilimidazolo)-2-((S)-(3,4-diklorofenil)-4-penten 1-(2-Phenylimidazolo)-2-((S)-(3,4-dichlorophenyl)-4-pentene

U otopinu od 0.178 g (0.77 mmola) 2-((S)-(3,4-diklorofenil))-4-penten-1-ola (dobivenog u Primjeru 136, Stupanj A) i 0.099 ml (0.85 mmola) 2,6-lutidina u 1.5 ml metilen klorida na -53°C pod dušikom, dodaje se 0.136 ml (0.81 mmola) anhidrida trifluorometansulfonske kiseline. Otopina se miješa na temperaturi između -30°C i -40°C 15 minuta, kada se dodaje 0.333 g (2.31 mmola) 2-fenilimidazola. Ostavi se da se zagrije do -20°C kratkotrajno, i smjesa se zatim ohladi do -60°C, miješa se na toj temperaturi 1 sat, miješa se na -20°C 2 sata i zatim drži na 4°C 16 sati. Poslije miješanja na sobnoj temperaturi 8 sati, smjesa se tretira sa 10 ml zasićene otopine natrij karbonata i 10 ml etil acetata i odvoje se slojevi. Vodena faza se ekstrahira sa 2 x 15 ml etil acetata i sjedinjeni vodeni slojevi se suše preko natrij sulfata, filtriraju i koncentriraju u vakuumu. Ostatak se djelomično pročišćava fleš kromatografjom na 36 g sililcij dioksida eluiranjem sa 500 ml 3:100 metanola:metilen klorida, zatim sa 300 ml 5:100:0.1 metanola: metilen klorida: amonijačnom vodom. Djelomično pročišćene frakcije proizvoda se fleš kromatografiraju na 66 g silicij dioksida eluiranjem sa 1.2 litre 83 : 17 metilen klorida:etil acetata, pri čemu se dobiva 85 mg (31 %) ulja. In a solution of 0.178 g (0.77 mmol) of 2-((S)-(3,4-dichlorophenyl))-4-penten-1-ol (obtained in Example 136, Step A) and 0.099 ml (0.85 mmol) of 2, 6-lutidine in 1.5 ml of methylene chloride at -53°C under nitrogen, 0.136 ml (0.81 mmol) of trifluoromethanesulfonic acid anhydride is added. The solution was stirred at a temperature between -30°C and -40°C for 15 minutes, when 0.333 g (2.31 mmol) of 2-phenylimidazole was added. Allow to warm to -20°C briefly, and the mixture is then cooled to -60°C, stirred at that temperature for 1 hour, stirred at -20°C for 2 hours and then held at 4°C for 16 hours. After stirring at room temperature for 8 hours, the mixture is treated with 10 ml of saturated sodium carbonate solution and 10 ml of ethyl acetate and the layers are separated. The aqueous phase is extracted with 2 x 15 ml of ethyl acetate and the combined aqueous layers are dried over sodium sulfate, filtered and concentrated in vacuo. The residue is partially purified by flash chromatography on 36 g of silica eluting with 500 ml of 3:100 methanol:methylene chloride, then with 300 ml of 5:100:0.1 methanol:methylene chloride:ammonia water. Partially purified fractions of the product are flash chromatographed on 66 g of silica eluting with 1.2 liters of 83:17 methylene chloride:ethyl acetate, whereby 85 mg (31%) of oil is obtained.

1H BNR (400 MHz, CDCl3) δ 2.26 (app, t, 2H), 2.85 (pentet 1H), 4.08 (dd, 1H), 4.27 (dd, 1H), 4.9-5.0 (m, 2H), 5.45-5.55 (m, 1H), 6.59 (dd, 1H), 6.79 (s, 1H), 6.85 (d, 1H), 7.18 (d, 1H), 7.23-7.30 (m, 2H), 7.35-7.43 (m, 3H). 1H BNR (400 MHz, CDCl3) δ 2.26 (app, t, 2H), 2.85 (pentet 1H), 4.08 (dd, 1H), 4.27 (dd, 1H), 4.9-5.0 (m, 2H), 5.45-5.55 (m, 1H), 6.59 (dd, 1H), 6.79 (s, 1H), 6.85 (d, 1H), 7.18 (d, 1H), 7.23-7.30 (m, 2H), 7.35-7.43 (m, 3H ).

Maseni spektar (FAB): m/z 359 (M+H, 65%), 357 (M+H, 100%), 145 (7%). Mass spectrum (FAB): m/z 359 (M+H, 65%), 357 (M+H, 100%), 145 (7%).

Stupanj 2) Level 2)

1'(2-((S)-(3,4-Diklorofenil))-1-(1-(2-fenilimidazolo))-4-butil)-1-metansulfonil)spiro(indolin-3,4'-piperidin) 1'(2-((S)-(3,4-Dichlorophenyl))-1-(1-(2-phenylimidazolo))-4-butyl)-1-methanesulfonyl)spiro(indoline-3,4'-piperidine )

Naslovni spoj se dobiva upotrebljavajući kemizam izložen u Primjerima 1 i 2, upotrebljavajući 1-(2-fenilimidazolo) -2- ((S) - (3,4-diklorofenil))-3-buten umjesto 3-(S)-3,4-diklorofenil)-4-metilamino-1-pentena, a polazeći sa stupnjem sa osmij tetroksidom. The title compound is obtained using the chemistry set forth in Examples 1 and 2, using 1-(2-phenylimidazolo)-2-((S)-(3,4-dichlorophenyl))-3-butene instead of 3-(S)-3, 4-dichlorophenyl)-4-methylamino-1-pentene, and starting with the step with osmium tetroxide.

1H-NMR (400 MHz, CDCl3) δ 1.55-2 (m, 8H), 2.08 (t, J=7.3, 2H), 2.63 (širok d, J=11, 1H), 2.70 (širok d, J=8.3, 1H), 2.86 (s, 3H) 2.9-3.0 (m, 1H), 3.71 (s, 2H), 4.13 (dd, J=14, 8.8, 1H), 4.25 (dd, J=14, 6.2, 1H), 6.66 (dd, J=6.2, 2.1, 1H), 6.79 (d, J=1.3, 1H), 6.94 (d, J=2.1, 1H), 7.03 (d, J01.3, 1H), 7.05 (d, J=6.4, 1H), 7.15 (d, J=6.5, 1H), 7.15-7.25 (m, 2H), 7.35-7.45 (m, 6H). 1H-NMR (400 MHz, CDCl3) δ 1.55-2 (m, 8H), 2.08 (t, J=7.3, 2H), 2.63 (broad d, J=11, 1H), 2.70 (broad d, J=8.3 , 1H), 2.86 (s, 3H) 2.9-3.0 (m, 1H), 3.71 (s, 2H), 4.13 (dd, J=14, 8.8, 1H), 4.25 (dd, J=14, 6.2, 1H ), 6.66 (dd, J=6.2, 2.1, 1H), 6.79 (d, J=1.3, 1H), 6.94 (d, J=2.1, 1H), 7.03 (d, J01.3, 1H), 7.05 ( d, J=6.4, 1H), 7.15 (d, J=6.5, 1H), 7.15-7.25 (m, 2H), 7.35-7.45 (m, 6H).

Maseni spektar (FAB): m/z 609 (M+H, 25%), 279 (100%), 267 (50%), 212 (30%), 187 (35%). Mass spectrum (FAB): m/z 609 (M+H, 25%), 279 (100%), 267 (50%), 212 (30%), 187 (35%).

Primjer 124 Example 124

1'-(3-((S)-(3,4-diklorofenil))-4-((N-(R ili S)-(3,5-dimetil-benzoil)-(metilamino))pentil)-1-acetil-spiro(indolin-3,4'-piperidin) 1'-(3-((S)-(3,4-dichlorophenyl))-4-((N-(R or S)-(3,5-dimethyl-benzoyl)-(methylamino))pentyl)-1 -acetyl-spiro(indoline-3,4'-piperidine)

Naslovni spoj se dobiva u 6 stupnjeva iz (2S)-(3,4-diklorofenil)-4-pentenove kiseline upotrebljavajući postupke identične sa onima u Primjeru 10, zamjenjujući 1-metansulfonil-spiro(indolin-3,4'-piperidin) u Primjeru 10, Stupanj 6 sa 1-acetil- spiro (indolin-3,4'-piperidinom). The title compound was prepared in 6 steps from (2S)-(3,4-dichlorophenyl)-4-pentenoic acid using procedures identical to those of Example 10, substituting 1-methanesulfonyl-spiro(indoline-3,4'-piperidine) in Example 10, Step 6 with 1-acetyl-spiro (indoline-3,4'-piperidine).

Maseni spektar (FAB): m/z 606 (M+H, 37Cl + 35Cl izotop, 100%), 608 (M+H, 37Cl + 37Cl izotop, 80%). Mass spectrum (FAB): m/z 606 (M+H, 37Cl + 35Cl isotope, 100%), 608 (M+H, 37Cl + 37Cl isotope, 80%).

Primjer 125 Example 125

1'-(3-((S)-(3,4-Diklorofenil))-4-((N-(R ili S)-(4-fluoro-1-naftil)-(metilamino))pentil)-1-acetil-spiro(indolin-3,4'-piperidin). 1'-(3-((S)-(3,4-Dichlorophenyl))-4-((N-(R or S)-(4-fluoro-1-naphthyl)-(methylamino))pentyl)-1 -acetyl-spiro(indoline-3,4'-piperidine).

Naslovni spoj se dobiva u 6 stupnjeva iz (2S)-(3,4-diklorofenil)-4-pentenove kiseline upotrebljavajući postupke identične sa onima u Primjeru 10, zamjenjujući 1-metansulfonil-spiro(indolin-3,4'piperidin) u Primjeru 10, Stupanj 6 sa 1-acetil-spiro (indolin-3,4'-piperidinom), i zamjenjujući benzoil klorid sa 4-fluor-1-naftoil kloridom. The title compound is prepared in 6 steps from (2S)-(3,4-dichlorophenyl)-4-pentenoic acid using procedures identical to those of Example 10, substituting 1-methanesulfonyl-spiro(indoline-3,4'piperidine) in Example 10, Step 6 with 1-acetyl-spiro(indoline-3,4'-piperidine), and replacing the benzoyl chloride with 4-fluoro-1-naphthoyl chloride.

Maseni spektar (FAB): m/z 646 (M+H, 37Cl + 35Cl izotop, 30%), 204 (100%). Mass spectrum (FAB): m/z 646 (M+H, 37Cl + 35Cl isotope, 30%), 204 (100%).

Slijedeći spojevi opisani u Primjerima 126-129 dobivaju se postupkom opisanim u Šemi II i u Primjeru 10, osim što se u Stupnju 2 etilmagnezij klorid ili propil-magnezij klorid upotrebljavaju na sobnoj temperaturi umjesto metillitij na -78°C. The following compounds described in Examples 126-129 are obtained by the process described in Scheme II and in Example 10, except that in Step 2 ethylmagnesium chloride or propylmagnesium chloride is used at room temperature instead of methyllithium at -78°C.

Primjer 126 Example 126

1'-(3-((S)-(3,4-Diklorofenil))-4-(R ili S)-(N-(3,5-dimetilbenzoil)-(metilamino))heksil)-1-acetil-spiro(indolin-3,4'-piperidin) 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(R or S)-(N-(3,5-dimethylbenzoyl)-(methylamino))hexyl)-1-acetyl- spiro(indoline-3,4'-piperidine)

1H NMR (400 MHz, CDCl3) δ 0.97 (t, 3H), 2.20 (s, 6H), 2.21 (s, 3H), 2.42-2.46 (S+m, 4H), 6.23 (s, 2H), 6.89 (s, 1H), 7.04 (t, 1H), 7.15-7.21 (m, 3H), 7.39 (t, 2H), 8.18 (d, 1H). 1H NMR (400 MHz, CDCl3) δ 0.97 (t, 3H), 2.20 (s, 6H), 2.21 (s, 3H), 2.42-2.46 (S+m, 4H), 6.23 (s, 2H), 6.89 ( s, 1H), 7.04 (t, 1H), 7.15-7.21 (m, 3H), 7.39 (t, 2H), 8.18 (d, 1H).

Maseni spektar (FAB) m/z 620 (m+). Mass spectrum (FAB) m/z 620 (m+).

Primjer 127 Example 127

1'-(3-((S)-(3,4-Diklorofenil))-4-(R ili S)-N-(3,5-dimetilbenzoil)-(metilamino))heksil)-1-acetil-5-fluoro-spiro -(indolin-3,4'- piperidin). 1'-(3-((S)-(3,4-Dichlorophenyl))-4-(R or S)-N-(3,5-dimethylbenzoyl)-(methylamino))hexyl)-1-acetyl-5 -fluoro-spiro -(indoline-3,4'-piperidine).

1H-NMR (400 MHz, CDCl3) δ 0.96 (t, 3H), 2.20 (s, 9H), 2.45 (s, 3H), 3.81 (s, 2H), 6.24 (s, 2H), 6.84-6.89 (m, 3H), 7.19 (dd, 1H), 7.39 (5, 2H), 8.13 (dd, 1H). 1H-NMR (400 MHz, CDCl3) δ 0.96 (t, 3H), 2.20 (s, 9H), 2.45 (s, 3H), 3.81 (s, 2H), 6.24 (s, 2H), 6.84-6.89 (m , 3H), 7.19 (dd, 1H), 7.39 (5, 2H), 8.13 (dd, 1H).

Maseni spektar (FAB) m/z 638 (m+). Mass spectrum (FAB) m/z 638 (m+).

Primjer 128 Example 128

1'-(3-((S)-(3,4-Diklorofenil)-4-(R ili S)-(N-(3,5-dimetilbenzoil)-(metilamino))heptil)-1-acetil-spiro(indolin-3,4'-piperidin) 1'-(3-((S)-(3,4-Dichlorophenyl)-4-(R or S)-(N-(3,5-dimethylbenzoyl)-(methylamino))heptyl)-1-acetyl-spiro (indoline-3,4'-piperidine)

1H-NMR (400 MHz, CDCl3) δ 0.96 (t, 3H), 2.20 (s, 6H), 2.21 (s, 3H), 2.41-2.45 (s+m, 4H), 3.78 (s, 2H), 6.22 (s, 2H), 6.89 (s, 1H), 7.03 (t, 1H), 7.15-7.21 (m, 3H), 7.39 (t, 2H), 8.18 (d, 1H). 1H-NMR (400 MHz, CDCl3) δ 0.96 (t, 3H), 2.20 (s, 6H), 2.21 (s, 3H), 2.41-2.45 (s+m, 4H), 3.78 (s, 2H), 6.22 (s, 2H), 6.89 (s, 1H), 7.03 (t, 1H), 7.15-7.21 (m, 3H), 7.39 (t, 2H), 8.18 (d, 1H).

Maseni spektar (FAB): m/z 634 (m+). Mass spectrum (FAB): m/z 634 (m+).

Primjer 129 Example 129

1'-(3-((S)-(3,4-Diklorofenil)-4-(R ili S)-(N-(3,5-dimetil-benzoil)-(metilamino))heptil)-1-acetil-5-fluoro-spiro -(indolin-3,4'- piperidin) 1'-(3-((S)-(3,4-Dichlorophenyl)-4-(R or S)-(N-(3,5-dimethyl-benzoyl)-(methylamino))heptyl)-1-acetyl -5-fluoro-spiro -(indoline-3,4'-piperidine)

1H-NMR (400 MHz, CDCl3) δ 0.97 (t, 3H), 2.20 (s, 9H), 2.44 (s, 3H), 3.81 (s, 2H), 6.22 (s, 2H), 6.83-6.88 (m, 3H), 7.18 (dd, 1H), 7.38 (t, 2H), 8.13 (dd, 1H). 1H-NMR (400 MHz, CDCl3) δ 0.97 (t, 3H), 2.20 (s, 9H), 2.44 (s, 3H), 3.81 (s, 2H), 6.22 (s, 2H), 6.83-6.88 (m , 3H), 7.18 (dd, 1H), 7.38 (t, 2H), 8.13 (dd, 1H).

Maseni spektar (FAB) m/z 652 (m+). Mass spectrum (FAB) m/z 652 (m+).

Primjer 130 Example 130

1'-(3((S)-(3,4-Diklorofenil))-4-(R ili S)-hidroksi-5-(3,5-dimetilfenil)pentil)-1-metan-sulfonil-spiro(indolin-3,4'-piperidin) 1'-(3((S)-(3,4-Dichlorophenyl))-4-(R or S)-hydroxy-5-(3,5-dimethylphenyl)pentyl)-1-methane-sulfonyl-spiro(indoline -3,4'-piperidine)

U THF (3 ml) otopinu 3,5-dimetilbenzilmagnezij klorida (dobivenog iz 290 mg (1.9 mmola) 3,5-dimetilbenzilklorida i 53 mg (2.2 mola) magnezij u THF), dodaje se lagano 1'-(3-((S)-(3,4-diklorofenil))-3-(N-metoksi-N- metilaminokarbonil) propil)-1- metansulfonil-spiro(indolin-3,4'-piperidina)(100 mg, 0.19 mmola, dobivenog reakcijom proizvoda dobivenog u Primjeru 10, Stupanj 1 pod uvjetima oksidativnog cijepanja datim u Primjeru 1, a zatim postupkom kupliranja datim u Primjeru 2) u 1 ml THF. Reakcijska smjesa se miješa na 60°C 40 minuta i lijeva se u 20 ml 1N HCl. Otopina se ekstrahira sa 3 x 10 ml EtOAc. Organski ekstrakti se sjedinjavaju, suše i koncentriraju. Proizvod se pročišćava preparativnom TLC (30% EtOAc u CH2Cl2), pri čemu se dobiva 20 mg ketona. 1'-(3-(( S)-(3,4-dichlorophenyl))-3-(N-methoxy-N-methylaminocarbonyl)propyl)-1-methanesulfonyl-spiro(indoline-3,4'-piperidine) (100 mg, 0.19 mmol, obtained by reaction of the product obtained in Example 10, Step 1 under the oxidative cleavage conditions given in Example 1, followed by the coupling procedure given in Example 2) in 1 ml of THF. The reaction mixture was stirred at 60°C for 40 minutes and poured into 20 ml of 1N HCl. The solution was extracted with 3 x 10 ml EtOAc. Organic extracts are combined, dried and concentrated. The product is purified by preparative TLC (30% EtOAc in CH 2 Cl 2 ), yielding 20 mg of the ketone.

U MeOH (3 ml) otopina ketona (19.4 mg) dodaje se otopina natrij borhidrida (7 mg). Smjesa se miješa na 55°C 1 sat i koncentrira. Ostatak se pročišćava preparativnom TLC (4% MeOH u CH2Cl2), pri čemu se dobiva 15 mg izomera sa višom vrijednošću Rf (Izomer A) i 4 mg izomera sa nižom vrijednošću Rf (Izomer B). A solution of sodium borohydride (7 mg) was added to a ketone solution (19.4 mg) in MeOH (3 ml). The mixture is stirred at 55°C for 1 hour and concentrated. The residue is purified by preparative TLC (4% MeOH in CH2Cl2), yielding 15 mg of the isomer with a higher Rf value (Isomer A) and 4 mg of the isomer with a lower Rf value (Isomer B).

1H-NMR (400 MHz, CDCl3), Izomer A: d 1.71 (d, 2H), 1.92-2.12 (m, 6H), 2.23-2.29 (s+m, 9H), 2.50-2.60 (m, 2H), 2.72-2.76 (m, 1H), 2.88 (s, 3H), 2.95 (d, 2H), 3.76 (s, 2H), 4.00-4.06 (m, 1H), 6.69 (s, 2H), 6.83 (s, 1H), 7.05 (d, 1H), 7.19-7.24 (m, 3H), 7.37 (t, 2H), 7.44 (s, 1H). 1H-NMR (400 MHz, CDCl3), Isomer A: d 1.71 (d, 2H), 1.92-2.12 (m, 6H), 2.23-2.29 (s+m, 9H), 2.50-2.60 (m, 2H), 2.72-2.76 (m, 1H), 2.88 (s, 3H), 2.95 (d, 2H), 3.76 (s, 2H), 4.00-4.06 (m, 1H), 6.69 (s, 2H), 6.83 (s, 1H), 7.05 (d, 1H), 7.19-7.24 (m, 3H), 7.37 (t, 2H), 7.44 (s, 1H).

Maseni spektar (FAB) Izomer A, m/z 601 (m+), 603 (m++ 2). Mass spectrum (FAB) Isomer A, m/z 601 (m+), 603 (m++ 2).

1H-NMR (400 MHz, CDCl3), Izomer B: d 1.69 (d, 2H), 1.74-1.79 (m, 1H), 1.83-1.90 (m, 1H), 1.93-2.05 (m, 2H), 2.07-2.20 (m, 2H), 2.24-2.36 (s+m, 8H), 2.42-2.47 (m, 1H), 2.55-2.58 (dd, 1H), 2.66-2.72 (d+dd, 2H), 2.87 (s, 3H), 2.86-3.00 (m, 2H), 3.76 (s, 2H), 3.91-3.95 (m, 1H), 6.72 (s, 2H), 6.82 (s, 2H), 7.13-7.19 (m, 2H), 7.18-7.21 (m, 2H), 7.36 (t, 2H). 1H-NMR (400 MHz, CDCl3), Isomer B: d 1.69 (d, 2H), 1.74-1.79 (m, 1H), 1.83-1.90 (m, 1H), 1.93-2.05 (m, 2H), 2.07- 2.20 (m, 2H), 2.24-2.36 (s+m, 8H), 2.42-2.47 (m, 1H), 2.55-2.58 (dd, 1H), 2.66-2.72 (d+dd, 2H), 2.87 (s , 3H), 2.86-3.00 (m, 2H), 3.76 (s, 2H), 3.91-3.95 (m, 1H), 6.72 (s, 2H), 6.82 (s, 2H), 7.13-7.19 (m, 2H ), 7.18-7.21 (m, 2H), 7.36 (t, 2H).

Maseni spektar (FAB) Izomer B, m/z 601 (m+) 603 (m++ 2). Mass spectrum (FAB) Isomer B, m/z 601 (m+) 603 (m++ 2).

Primjer 131 Example 131

1'-(3-(R)-(3,4-Diklorofenil)-5-(N-3,5-dimetilfenil-metilamino)-5-okso-pentil)-1-metansulfonil-spiro(indolin-3,4'-piperidin) 1'-(3-(R)-(3,4-Dichlorophenyl)-5-(N-3,5-dimethylphenyl-methylamino)-5-oxo-pentyl)-1-methanesulfonyl-spiro(indoline-3,4 '-piperidine)

Stupanj 1) Level 1)

Dijazometil-(2-(S)-(3,4-diklorofenil)-pent-4-en-il)-keton Diazomethyl-(2-(S)-(3,4-dichlorophenyl)-pent-4-en-yl)-ketone

U otopinu od 2-(S)-(3,4-diklorfenil)-pent-4-nove kiseline (5.04 g, 20.6 mmola) u 60 ml diklormetana, dodaje se oksalil klorid 2.15 ml (24.6 mmola) i dimetilformamid (0.1 ml) uz hlađenje u kupaonici od ledene vode. Tada se uklanja kupaonica za hlađenje i reakcijska smjesa se miješa na sobnoj temperaturi preko noći. Otapalo se uklanja pod smanjenim tlakom. Dobiveni materijal se razblažuje u etil acetatu i koncentrira se u vakuumu, da bi se uklonila preostala HCl. Preostali sirovi klorid kiseline se otapa u 70 ml etera i lagano se dodaje u 100 ml eterske otopine dijazometana (77 mmola). Poslije miješanja 2 sata na sobnoj temperaturi, otapalo se uklanja pod vakuumom. Dobiveno žuto ulje se kromatografira na koloni od silika gela eluiranjem sa gradijentom od heksana : etil acetata = 20 : 1 do 3 : 1, pri čemu se dobiva 4.66 g (84%) dijazometil-(2-(S)-(3,4- diklorofenil)- pent-4-en-il)-ketona. Oxalyl chloride 2.15 ml (24.6 mmol) and dimethylformamide (0.1 ml ) with cooling in an ice water bath. The cooling bath is then removed and the reaction mixture is stirred at room temperature overnight. The solvent is removed under reduced pressure. The resulting material was diluted in ethyl acetate and concentrated in vacuo to remove the remaining HCl. The remaining crude acid chloride is dissolved in 70 ml of ether and slowly added to 100 ml of an ethereal solution of diazomethane (77 mmol). After stirring for 2 hours at room temperature, the solvent is removed under vacuum. The obtained yellow oil is chromatographed on a silica gel column eluting with a gradient of hexane : ethyl acetate = 20 : 1 to 3 : 1, whereby 4.66 g (84%) of diazomethyl-(2-(S)-(3,4 - dichlorophenyl)-pent-4-en-yl)-ketone.

1H-NMR (CDCl3 400 MHz): δ 2.44 (app. kvintet 1H), 2.82 (app. kvintet, 1H), 3.43 (širok s, 1H), 4.98 & 5.02 (d iz AB kvarteta, 2H), 5.16 (širok s, 1H), 5.63 (m, 1H), 7.09 (dd, J=2.2 Hz, 8.3 Hz, 1H), 7.34 (d, J=2.2 Hz, 1H), 7.38 (d J=8.3 Hz). 1H-NMR (CDCl3 400 MHz): δ 2.44 (app. quintet 1H), 2.82 (app. quintet, 1H), 3.43 (broad s, 1H), 4.98 & 5.02 (d from AB quartet, 2H), 5.16 (broad s, 1H), 5.63 (m, 1H), 7.09 (dd, J=2.2 Hz, 8.3 Hz, 1H), 7.34 (d, J=2.2 Hz, 1H), 7.38 (d J=8.3 Hz).

Stupanj 2) Level 2)

3-(R)-(3,4-Diklorofenil)heks-4-enska kiselina 3-(R)-(3,4-Dichlorophenyl)hex-4-enoic acid

U otopinu gornjeg dijazoketona 4.56 g (17.0 mmola) u 340 ml tetrahidrofurana, dodaje se 170 ml vodene otopine srebro nitrata 3.02 g (17.8 mmola). Poslije miješanja na sobnoj temperaturi preko noći, tetrahidrofuran se uklanja pod smanjenim tlakom. Preostali vodeni sloj se ekstrahira sa dvije porcije od po 100 ml diklormetana. Sjedinjene organske faze se peru sa slanom otopinom, suše se preko anhidriranog magnezij suffata, filtriraju, i koncentriraju. Dobiveni materijal se pročišćava kromatografijom na koloni od silika gela. Eluiranjem sa diklormetanom : metanolom = 10 : 1, dobiva se 3.94 g (90%) 3-(R) - (3,4-diklorofenil)-heks-4-enska kiselina. To a solution of the above diazoketone 4.56 g (17.0 mmol) in 340 ml of tetrahydrofuran, 170 ml of an aqueous solution of silver nitrate 3.02 g (17.8 mmol) is added. After stirring at room temperature overnight, the tetrahydrofuran is removed under reduced pressure. The remaining aqueous layer is extracted with two portions of 100 ml each of dichloromethane. The combined organic phases are washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The obtained material is purified by chromatography on a silica gel column. Elution with dichloromethane : methanol = 10 : 1 gives 3.94 g (90%) of 3-(R)-(3,4-dichlorophenyl)-hex-4-enoic acid.

Stupanj 3) Level 3)

(N-(3,5-Dimetilfenil)-N-metil)-((3-(R)-(3,4-diklorofenil)-heks-5-en-il)amid (N-(3,5-Dimethylphenyl)-N-methyl)-((3-(R)-(3,4-dichlorophenyl)-hex-5-en-yl)amide

Karboksilna kiselina iz Stupnja 2 (300 mg, 1.16 mmola) se otapa u 5 ml diklorometana. U ovu otopinu se dodaje 0.131 ml (1.50 mmola) oksalil klorida, a zatim se dodaje kap dimetilformamida uz hlađenje u kupaonici sa ledenom vodom. Kupaonica za hlađenje se uklanja i reakcijska smjesa se miješa na sobnoj temperaturi 2 sata. Otapalo i preostala HCl se uklanjaju kao što je opisano gore. Dobiveni sirovi klorid kiseline se tada otapa u 5 ml diklormetana. U ovu otopinu se dodaje N-metil-3,5-dimetilanilin 313 mg (3.32 mmola) (Dobiven iz 3,5-dimetilanilina prema postupku Berlueng-a J., Bayon-a A. M., i Asensio-a G. J. Chem. Soc. Chem. Comm. 1984 1334), a zatim dodavanjem trietilamina 0.5 ml (3.6 mmola) uz hlađenje u kupaonici sa ledenom vodom. Zatim se uklanja kupaonica zahlađenje i reakcijska smjesa se miješa na sobnoj temperaturi preko noći. Otapalo se uklanja pod smanjenim tlakom. Preostali čvrst materijal se otapa u 15 ml etil acetata i 5 ml vode. Organska faza se odvaja i vodena faza se ekstrahira sa dvije porcije od po 7 ml etil acetata. Sjedinjene organske faze se peru sa slanom otopinom, suše preko anhidriranog magnezij sulfata, filtriraju, i koncentriraju. Sirovi materijal se kromatografira na silika gelu, eluiranjem sa gradijentom od 10 : 1 do 3 : 1 heksana-etil acetata, pri čemu se dobiva 386 mg (N-(3,5-dimetil fenil)-N- metil)-((3-(R)-(3,4-diklorofenil)heks-5-en-il)-amid (88%). The carboxylic acid from Step 2 (300 mg, 1.16 mmol) was dissolved in 5 ml of dichloromethane. 0.131 ml (1.50 mmol) of oxalyl chloride is added to this solution, and then a drop of dimethylformamide is added while cooling in an ice water bath. The cooling bath is removed and the reaction mixture is stirred at room temperature for 2 hours. The solvent and residual HCl are removed as described above. The obtained crude acid chloride is then dissolved in 5 ml of dichloromethane. N-methyl-3,5-dimethylaniline 313 mg (3.32 mmol) is added to this solution (obtained from 3,5-dimethylaniline according to the procedure of Berlueng J., Bayon A. M., and Asensio G. J. Chem. Soc. Chem. Comm. 1984 1334), and then adding triethylamine 0.5 ml (3.6 mmol) while cooling in an ice water bath. Then the cooling bath is removed and the reaction mixture is stirred at room temperature overnight. The solvent is removed under reduced pressure. The remaining solid material is dissolved in 15 ml of ethyl acetate and 5 ml of water. The organic phase is separated and the aqueous phase is extracted with two portions of 7 ml each of ethyl acetate. The combined organic phases are washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude material is chromatographed on silica gel, eluting with a gradient of 10 : 1 to 3 : 1 hexane-ethyl acetate, whereby 386 mg of (N-(3,5-dimethyl phenyl)-N-methyl)-((3 -(R)-(3,4-dichlorophenyl)hex-5-en-yl)-amide (88%).

1H NMR (CDCl3 400 MHz) δ 2.15-2.35 (m, 4H), 2.29 (s, 6H), 3.09 (s, 3H), 3.26 (kvintet, J=7.2 Hz, 1H), 4.88 (d, J=7.6 Hz, 1H), 4.92 (s, 1H), 5.5 (m, 1H), 6.45 (s, 2H), 6.91 (dd, J=2 Hz, 7 Hz, 1H), 6.93 (s, 1H), 7.30 (d, J=8.3 Hz, 1H). 1H NMR (CDCl3 400 MHz) δ 2.15-2.35 (m, 4H), 2.29 (s, 6H), 3.09 (s, 3H), 3.26 (quintet, J=7.2 Hz, 1H), 4.88 (d, J=7.6 Hz, 1H), 4.92 (s, 1H), 5.5 (m, 1H), 6.45 (s, 2H), 6.91 (dd, J=2 Hz, 7 Hz, 1H), 6.93 (s, 1H), 7.30 ( d, J=8.3 Hz, 1H).

Stupanj 4) Level 4)

3-(R)-(3,4-Diklorofenil)-5-(N-(3,5-dimetilfenil)-metilamino)-5-okso-pentanal 3-(R)-(3,4-Dichlorophenyl)-5-(N-(3,5-dimethylphenyl)-methylamino)-5-oxo-pentanal

386 mg (1.03 mmola) proizvoda iz prethodnog stupnja se oksidira sa osmij tetroksidom do odgovarajućeg diola kao što je opisano u Primjeru 1, pri čemu se dobiva 413 mg sirovog diola. 381 mg ovog materijala se tada otapa u 10 ml benzola. U ovu otopinu se dodaje olovo tetraacetat 452 mg (1.02 mmola). Poslije miješanja 1 sat na sobnoj temperaturi, dodaje se 5 ml vode da bi se zaustavila reakcija. Reakcijska smjesa se ekstrahira sa dvije porcije od po 10 ml etil acetata. Sjedinjene organske faze se suše preko anhidriranog magnezij sulfata, filtriraju, i koncentriraju. Sirovi materijal se kromatografira na silika gelu eluiranjem sa heksanom : etil acetatom = 2 : 1, pri čemu se dobiva 329 mg 3-(R)-(3,4-diklorofenil)-5-(N-(3,5- dimetilfenil) metilamino)- 5- okso-pentanal (94% iz dva stupnja). 386 mg (1.03 mmol) of the product from the previous step is oxidized with osmium tetroxide to the corresponding diol as described in Example 1, yielding 413 mg of the crude diol. 381 mg of this material is then dissolved in 10 ml of benzene. Lead tetraacetate 452 mg (1.02 mmol) is added to this solution. After stirring for 1 hour at room temperature, 5 ml of water was added to stop the reaction. The reaction mixture is extracted with two portions of 10 ml each of ethyl acetate. The combined organic phases are dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude material is chromatographed on silica gel eluting with hexane:ethyl acetate = 2:1, whereby 329 mg of 3-(R)-(3,4-dichlorophenyl)-5-(N-(3,5-dimethylphenyl) methylamino)-5-oxo-pentanal (94% from two stages).

Stupanj 5) Grade 5)

Radeći prema postupku opisnom u Primjeru 2, 107 mg (0.287 mmola) ovog aldehida se tretira sa 1-metansulfonil-spiro (indolin-3,4'-piperidin) hidrokloridom, pri čemu se dobiva 103 mg (58% prinos) naslovnog spoja. Working according to the procedure described in Example 2, 107 mg (0.287 mmol) of this aldehyde is treated with 1-methanesulfonyl-spiro (indoline-3,4'-piperidine) hydrochloride to give 103 mg (58% yield) of the title compound.

1H-NMR (CDCl3 400 MHz): δ 2.23 (s, 6H), 2.86 (s, 3H), 3.09 (s, 3H), 3.72 (s, 2H), 6.49 (s, 2H), 6.9-7.2 (s, 8H). 1H-NMR (CDCl3 400 MHz): δ 2.23 (s, 6H), 2.86 (s, 3H), 3.09 (s, 3H), 3.72 (s, 2H), 6.49 (s, 2H), 6.9-7.2 (s , 8H).

MS(Cl): 628 (Mg + 1: 35Cl x 2), 630 (M++1: 35Cl & 37Cl). MS(Cl): 628 (Mg + 1: 35Cl x 2), 630 (M++1: 35Cl & 37Cl).

Primjer 132 Example 132

1'-(3-(R)-(3,-4-Diklorofenil)-5-(3,5-dimetilfenil)-5-oksopentil)-1-metansulfonil-spiroi(indolin-3,4'-piperidin) 1'-(3-(R)-(3,-4-Dichlorophenyl)-5-(3,5-dimethylphenyl)-5-oxopentyl)-1-methanesulfonyl-spiro(indoline-3,4'-piperidine)

Stupanj 1) Level 1)

(N-Metoksi-N-metil)-3-(R)-(3,4-diklorofenil)-4-heksenil)-amid (N-Methoxy-N-methyl)-3-(R)-(3,4-dichlorophenyl)-4-hexenyl)-amide

U otopinu 3-(R)-(3,4-dikloroenil)-5-heksenske kiseline (Primjer 132, Stupanj 1) 744 mg (2.87 mmola), dodaje se 1-hidroksibenzotriazol hidrat 465 mg (3.44 mmola) i 1-(3-dimetilaminopropil)-3-etilkarbodiimid hidroklorid 660 mg (3.44 mmola uz hlađenje u kupaonici sa ledenom vodom. Kupaonica za hlađenje se tada uklanja. Poslije miješanja na sobnoj temperaturi 1 sat, dodaje se 5 ml diklormetanske suspenzije N,O-dimetilhidroksil amin hidroklorida 840 mg (8.61 mmola) i trietilamina 1.2 (8.6 mmola). Poslije miješanja preko noći, uklanja se otapalo pod vakuumom, razblažuje se sa etil acetatom i vodom. Organska faza se odvaja. Vodena faza se ekstrahira dva puta sa etil acetatom. Sjedinjene organske faze se peru sa slanom otopinom, suše se preko anhidriranog magnezij sulfata, filtriraju i koncentriraju, kromatografiraju na silika gelu eluiranjem na gradijentu heksana: etil acetata = 5 : 1 do 2 : 1, pri čemu se dobiva 762 mg (88%)(N-metoksi-N-metil) -(3-(R)-(3,4-diklorofenil)-4-heksenil)-amida. To a solution of 3-(R)-(3,4-dichloroenyl)-5-hexenoic acid (Example 132, Step 1) 744 mg (2.87 mmol), 1-hydroxybenzotriazole hydrate 465 mg (3.44 mmol) and 1-( 3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 660 mg (3.44 mmol) with cooling in an ice water bath. The cooling bath is then removed. After stirring at room temperature for 1 hour, 5 ml of a dichloromethane suspension of N,O-dimethylhydroxyl amine hydrochloride is added 840 mg (8.61 mmol) and triethylamine 1.2 (8.6 mmol). After stirring overnight, the solvent is removed under vacuum, diluted with ethyl acetate and water. The organic phase is separated. The aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed with saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated, chromatographed on silica gel eluting with a gradient of hexane: ethyl acetate = 5 : 1 to 2 : 1, whereby 762 mg (88%) (N -methoxy-N-methyl)-(3-(R)-(3,4-dichlorophenyl)-4-hexenyl)-amide.

1H-NMR (CDCl3 400 MHz): δ 2.34 (m, 1H), 2.69 (App. d, 2H), 3.09 (s, 3H), 3.23 (kvintet J=7.3 Hz, 1H), 3.56 (s, 3H), 4.95 (s, 1H), 4.98 (app. d, 1H), 5.6 (m, 1H), 7.0 (dd, J=2.1 Hz, 8.4 Hz, 1H), 7.28 (d, J=2.1 Hz, 1H), 7.32 (d, J=8.3 Hz, 1H). 1H-NMR (CDCl3 400 MHz): δ 2.34 (m, 1H), 2.69 (App. d, 2H), 3.09 (s, 3H), 3.23 (quintet J=7.3 Hz, 1H), 3.56 (s, 3H) , 4.95 (s, 1H), 4.98 (app. d, 1H), 5.6 (m, 1H), 7.0 (dd, J=2.1 Hz, 8.4 Hz, 1H), 7.28 (d, J=2.1 Hz, 1H) , 7.32 (d, J=8.3 Hz, 1H).

Stupanj 2) Level 2)

3-(R)-(3,4-Diklorofenil)-(N-metoksi-metilamino)-5-okso-pentanal 3-(R)-(3,4-Dichlorophenyl)-(N-methoxy-methylamino)-5-oxo-pentanal

Ovaj gornji materijal se podvrgava oksidaciji sa osmij tetroksidom u odgovarajući diol kao što je opisano u Primjeru 1. Sirovi proizvod se tada tretira sa 1.23 g (2.77 mmola) olovo tetraacetata kao što je opisano u Primjeru 131, Stupanj 4. Kromatografskim pročišćavanjem na silika gelu (eluant; diklorometan : etil acetat = 5 : 1 ) dobiva se 618 mg (81% iz dva stupnja) 3-(R)-(3,4-diklorofenil)-(N-metoksi-metilamino)-5-okso-pentanala. This above material is subjected to oxidation with osmium tetroxide to the corresponding diol as described in Example 1. The crude product is then treated with 1.23 g (2.77 mmol) of lead tetraacetate as described in Example 131, Step 4. Chromatographic purification on silica gel (eluent; dichloromethane : ethyl acetate = 5 : 1 ) 618 mg (81% from two steps) of 3-(R)-(3,4-dichlorophenyl)-(N-methoxy-methylamino)-5-oxo-pentanal are obtained .

Stupanj 3) Level 3)

1'-(3-(R)-(3,4-Diklorofenil)-5-(N-metoksi-metilamino)-5-okso-pentil)-1-metansulfonil-spiro(indolin-3,4'-piperidin) 1'-(3-(R)-(3,4-Dichlorophenyl)-5-(N-methoxy-methylamino)-5-oxo-pentyl)-1-methanesulfonyl-spiro(indoline-3,4'-piperidine)

Uzorak od 332 mg (1.09 mmola) aldehida iz Stupnja 2 gore podvrgava se reduktivnoj aminaciji sa 1-metansulfonil- spiro(indolin-3,4'-piperidin) hidroklorida kao što je opisano u Primjeru 2, pri čemu se dobiva 369 mg (61%) 1'-(3-(R)-(3,4-diklorofenil)-5-(N-metoksi)-N-(metil)-amino)-5-okso-pentil)-1-metansulfonil-spiro(indolin-3,4'-piperidina). A sample of 332 mg (1.09 mmol) of the aldehyde from Step 2 above was subjected to reductive amination with 1-methanesulfonyl-spiro(indoline-3,4'-piperidine) hydrochloride as described in Example 2 to give 369 mg (61 %) 1'-(3-(R)-(3,4-dichlorophenyl)-5-(N-methoxy)-N-(methyl)-amino)-5-oxo-pentyl)-1-methanesulfonyl-spiro( indoline-3,4'-piperidine).

1H-NMR (CDCl3 400 MHz): δ 2.87 (s, 3H), 3.10 (s, 3H), 360 (s, 3H), 7.0-7.4 (m, 7H). 1 H-NMR (CDCl 3 400 MHz): δ 2.87 (s, 3H), 3.10 (s, 3H), 360 (s, 3H), 7.0-7.4 (m, 7H).

Stupanj 4) Level 4)

1'-(3-(R)-(3,4-Diklorofenil))-5-(3,5-dimetilfenil)-5-okso-pentil)-1-metansulfonil-spiro(indolin-3,4'-piperidin) 1'-(3-(R)-(3,4-Dichlorophenyl))-5-(3,5-dimethylphenyl)-5-oxo-pentyl)-1-methanesulfonyl-spiro(indoline-3,4'-piperidine )

U 1.2 ml THF otopine amida iz Stupnja 3 gore (73 mg, 0.13 mmola), dodaje se 1.1 ml 0.7 M otopine 3,5-dimetilfenilmagnezij bromida u THF (dobiven iz 5-brom-m-ksilola i otpiljaka magnezij u THF). Reakcijska smjesa se zagrijava do 50�C. Poslije miješanja 1.5 sati, ostavi se da se reakcijska smjesa ohladi do sobne temperature i reakcija se zaustavlja zasićenom vodenom otopinom NH4CI. THF se uklanja pod smanjenim tlakom, razblažuje se sa etil acetatom. Odvaja se organska faza i vodena faza se ekstrahira dva puta sa etil acetatom. Sjedinjene organske faze se suše preko anhidriranog magnezij sulfata, filtriraju, koncentriraju, kromatografiraju na silika gelu eluiranjem sa gradijentom od diklorometana: etil acetata = 10 : 1 do 1 : 1, pri čemu se dobiva 55 mg /70%) naslovnog spoja. To 1.2 ml of a THF solution of the amide from Step 3 above (73 mg, 0.13 mmol), is added 1.1 ml of a 0.7 M solution of 3,5-dimethylphenylmagnesium bromide in THF (obtained from 5-bromo-m-xylene and magnesium sawdust in THF). The reaction mixture is heated to 50�C. After stirring for 1.5 hours, the reaction mixture was allowed to cool to room temperature and the reaction was quenched with a saturated aqueous solution of NH4Cl. THF is removed under reduced pressure, diluted with ethyl acetate. The organic phase is separated and the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are dried over anhydrous magnesium sulfate, filtered, concentrated, chromatographed on silica gel eluting with a gradient of dichloromethane: ethyl acetate = 10:1 to 1:1, whereby 55 mg/70%) of the title compound is obtained.

1H-NMR (CDCl3 400 MHz): δ 2.34 (s, 6H), 2.86 (s, 3H), 3.23 (m, 2H), 3.74 (s, 2H), 7.0-7.5 (m, 10H). 1H-NMR (CDCl3 400 MHz): δ 2.34 (s, 6H), 2.86 (s, 3H), 3.23 (m, 2H), 3.74 (s, 2H), 7.0-7.5 (m, 10H).

MS (Cl): 599 (M++1: 35Cl x 2), 601 (M++1: 35Cl & 37Cl). MS (Cl): 599 (M++1: 35Cl x 2), 601 (M++1: 35Cl & 37Cl).

Primjer 133 Example 133

1'-(3-(R)-(3,4-diklorofenil)-6-(3,5-dimetilfenil)-5-oksoheksil)-1-metansulfonil-spiroi(indolin-3,4'-piperidin) 1'-(3-(R)-(3,4-dichlorophenyl)-6-(3,5-dimethylphenyl)-5-oxohexyl)-1-methanesulfonyl-spiro(indoline-3,4'-piperidine)

70 mg (0.126 mmola) 1'-(3-(R)-(3,4-diklorofenil)-5-(N-metoksi)-N- (metil)amino)-5- okso-pentil)-1- metan sulfonil- spiro (indolin-3,4'-piperidina) (PRimjer 132, Stupanj 3) tretira se sa 0.8 M THF otopinom 3,5-dimetil benzilmagnezij klorida kao u slučaju Primjera 132. Sirovi materijal se kromatografira na silika gelu u istom sistemu otapala, pri čemu se dobiva 33 mg naslovnog spoja (43%). 70 mg (0.126 mmol) 1'-(3-(R)-(3,4-dichlorophenyl)-5-(N-methoxy)-N-(methyl)amino)-5-oxo-pentyl)-1-methane sulfonyl-spiro (indoline-3,4'-piperidine) (Example 132, Step 3) is treated with a 0.8 M THF solution of 3,5-dimethyl benzylmagnesium chloride as in the case of Example 132. The crude material is chromatographed on silica gel in the same system solvent, yielding 33 mg of the title compound (43%).

1H-NMR (CDCl3 400 MHz): δ 2.24 (s, gH), 2.86 (s, 3H), 3.47 (s, 2H), 3.72 (s, 2H), 6.64 (s, 2H), 6.8-7.4 (m, 8H). 1H-NMR (CDCl3 400 MHz): δ 2.24 (s, gH), 2.86 (s, 3H), 3.47 (s, 2H), 3.72 (s, 2H), 6.64 (s, 2H), 6.8-7.4 (m , 8H).

MS (Cl): 613 (M++1: 35Cl x 2), 615 (M++1: 35Cl & 37Cl). MS (Cl): 613 (M++1: 35Cl x 2), 615 (M++1: 35Cl & 37Cl).

Primjer 134 Example 134

1'-(3-(S)-(3,4-Diklorofenil)-6-(3,5-dimetilfenil)-6-oksoheksil)-1-metansulfonil-spiro(indolin-3,4'-piperidin) 1'-(3-(S)-(3,4-Dichlorophenyl)-6-(3,5-dimethylphenyl)-6-oxohexyl)-1-methanesulfonyl-spiro(indoline-3,4'-piperidine)

3-(R)-(3,4-Diklorofenil)-4-heksenska kiselina (Primjer 131, Stupanj 2) se konvertira u 4-(S)-(3,4-Diklorofenil)-5-heptensku kiselinu kao u Primjeru 131, Stupnjevi 1 i 2. 4-(S)-(3,4-diklorofenil)-4-heptenska kiselina se konvertira u (N-metoksi-N- metil)-(4-(S)-(3,4-diklorofenil)-6-heptenil)-amid a zatim se tretira sa 3,5-dimetilfenil-magnezij bromidom kao što je opisano u Primjeru 132, Stupanj 4, pri čemu se dobiva naslovni spoj. 3-(R)-(3,4-Dichlorophenyl)-4-hexenoic acid (Example 131, Step 2) is converted to 4-(S)-(3,4-Dichlorophenyl)-5-heptenoic acid as in Example 131 , Steps 1 and 2. 4-(S)-(3,4-dichlorophenyl)-4-heptenoic acid is converted to (N-methoxy-N-methyl)-(4-(S)-(3,4-dichlorophenyl) )-6-heptenyl)-amide and then treated with 3,5-dimethylphenyl-magnesium bromide as described in Example 132, Step 4, to give the title compound.

1H-NMR (CDCl3 400 MHz): δ 2.32 (s, 6H), 2.80 (s, 3H), 3.74 (s, 3H), 7.0-7.4 (m, 10H). 1H-NMR (CDCl3 400 MHz): δ 2.32 (s, 6H), 2.80 (s, 3H), 3.74 (s, 3H), 7.0-7.4 (m, 10H).

Primjer 135 Example 135

1'-(3-(S)-(3,4-Diklorofenil)-6-(3,5-dimetilfenil)-5-(RS)-metil-6-okso-heksil)-1-metansulfonil-spiro(indolin-3,4'-piperidin) 1'-(3-(S)-(3,4-Dichlorophenyl)-6-(3,5-dimethylphenyl)-5-(RS)-methyl-6-oxo-hexyl)-1-methanesulfonyl-spiro(indoline -3,4'-piperidine)

Stupanj 1) Level 1)

4-(S)-(3,4-Diklorofenil)-1-(3,5-dimetilfenil)-hept-6-en-1-on 4-(S)-(3,4-Dichlorophenyl)-1-(3,5-dimethylphenyl)-hept-6-en-1-one

1.42 g (4.50 mmola) (N-Metoksi-N-metil)-4-(S)-(3,4-diklorofenil)-6-heptenil)-amida (dobivenog u Primjeru 134) otapa se u 20 ml suhog THF. U ovu otopinu se dodaje 10 ml THF otopine 3,5-dimetilfenilmagnezij bromida dobivenog iz 1.8 g (9.6 mmola) 5-brom-m-ksilola i 463 mg otpiljaka magnezija. Poslije miješanja 2 sata na sobnoj temperaturi, reakcija se zaustavlja sa zasićenom vodenom otopinom amonij klorida. THF se uklanja pod smanjenim tlakom. Preostali materijal se razblažuje sa etil acetatom. Organska faza se odvaja, a vodena faza se ekstrahira dva puta sa etil acetatom. Sjedinjene organske faze se peru sa slanom otopinom, suše preko anhidriranog magnezij sulfata, filtriraju i koncentriraju, kromatografiranjem na silika gelu eluiranjem sa gradijentom heksana : etil acetata = 10 : 1 do 5 : 1 dobiva se 1.57 g (4-(S)-(3,4-diklorofenil)-1-(3,5- dimetilfenil)- hept-6-en-1-ona (97%). 1.42 g (4.50 mmol) of (N-Methoxy-N-methyl)-4-(S)-(3,4-dichlorophenyl)-6-heptenyl)-amide (obtained in Example 134) was dissolved in 20 ml of dry THF. 10 ml of a THF solution of 3,5-dimethylphenylmagnesium bromide obtained from 1.8 g (9.6 mmol) of 5-bromo-m-xylene and 463 mg of magnesium filings are added to this solution. After stirring for 2 hours at room temperature, the reaction is stopped with a saturated aqueous solution of ammonium chloride. The THF is removed under reduced pressure. The remaining material is diluted with ethyl acetate. The organic phase is separated, and the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated, by chromatography on silica gel eluting with a gradient of hexane : ethyl acetate = 10 : 1 to 5 : 1, 1.57 g of (4-(S)-( 3,4-dichlorophenyl)-1-(3,5-dimethylphenyl)-hept-6-en-1-one (97%).

Stupanj 2) Level 2)

4-(R)-(3,4-Diklorofenil)-1-(3,5-dimetilfenil)-2-(RS)-metil-hept-6-en-1-on 4-(R)-(3,4-Dichlorophenyl)-1-(3,5-dimethylphenyl)-2-(RS)-methyl-hept-6-en-1-one

Heksametildisilazan (0.108 ml, 0.512 mmola), i 0.089 ml heksametilfosforamida otapaju se u 2 ml suhog THF. U ovu otopinu se dodaje 0.306 ml (0.49 mmola) n-butillitij (1.6 M otopina u heksanu) poslije hlađenja u kupaonici sa ledenom vodom. Poslije miješanja od 20 minuta, kupaonrca sa ledenom vodom se zamjenjuje sa kupaonicom sa duhim ledom-acetonom i dodaje se kroz cjevčicu 2 ml THF otopina 4-(S)-(3,4-diklorofenil)-1-(3,5-dimetilfenil)-hept-6-en-1-ona (154 mg, 0.426 mmola). Poslije miješanja od 1 sata dodaje se 0.066 ml (1.06 mmola) metiljodida. Kupaonica zahlađenje se uklanja i smjesa se miješa na sobnoj temperaturi preko noći. Tada se uklanja otapalo pod smanjenim tlakom i preostali materijal se razblažuje u etil acetatu i vodi. Odvaja se organska faza. Vodena faza se ekstrahira dva puta sa etil acetatom. Sjedinjene organske faze se peru sa slanom otopinom, suše se preko anhidriranog magnezij sulfata, filtriraju, koncentriraju, i kromatografiraju na silika gelu eluiranjem sa gradijentom od heksana : etil acetata = 10 : 1 do 7 : 1, pri čemu se dobiva 150 mg 4-(R)-(3,4-diklorofenil)- 1-(3,5- dimetilfenil)-2-(R & S)-metil-hept-6-en-1-on (94%). Ovo je 1 prema 1 smjesa dva dijastereoizomera kao što je utvrđeno protonskom NMR. Hexamethyldisilazane (0.108 ml, 0.512 mmol), and 0.089 ml of hexamethylphosphoramide were dissolved in 2 ml of dry THF. 0.306 ml (0.49 mmol) of n-butyllithium (1.6 M solution in hexane) is added to this solution after cooling in an ice water bath. After stirring for 20 minutes, the ice water bath is replaced by a dry ice-acetone bath and 2 ml of THF solution 4-(S)-(3,4-dichlorophenyl)-1-(3,5-dimethylphenyl) is added through a tube. )-hept-6-en-1-one (154 mg, 0.426 mmol). After stirring for 1 hour, 0.066 ml (1.06 mmol) of methyl iodide is added. The cooling bath is removed and the mixture is stirred at room temperature overnight. The solvent is then removed under reduced pressure and the remaining material is diluted in ethyl acetate and water. The organic phase is separated. The aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed with brine, dried over anhydrous magnesium sulfate, filtered, concentrated, and chromatographed on silica gel eluting with a gradient of hexane : ethyl acetate = 10 : 1 to 7 : 1, whereby 150 mg of 4- (R)-(3,4-dichlorophenyl)-1-(3,5-dimethylphenyl)-2-(R & S)-methyl-hept-6-en-1-one (94%). This is a 1 to 1 mixture of two diastereoisomers as determined by proton NMR.

1H-NMR (CDCl3 400 MHz): δ 1.06 (d, J=7 Hz, 1.5H), 1.14 (d, J=6.7 Hz, 1.5H), 2.30, 2.31 (s, 6H), 2.5 (m, 0.5H), 2.6 (m, 0.5H), 3.1-3.2 (m, 1H), 4.9 (m, 2H), 5.5 (m, 1H), 6.8-7.4 (m, 6H). 1H-NMR (CDCl3 400 MHz): δ 1.06 (d, J=7 Hz, 1.5H), 1.14 (d, J=6.7 Hz, 1.5H), 2.30, 2.31 (s, 6H), 2.5 (m, 0.5 H), 2.6 (m, 0.5H), 3.1-3.2 (m, 1H), 4.9 (m, 2H), 5.5 (m, 1H), 6.8-7.4 (m, 6H).

Stupanj 3) Level 3)

3-(S)-(3,4-Diklorofenil)-5-(RS)-metil-6-(3,5-dimetilfenil)-6-okso-heksanal 3-(S)-(3,4-Dichlorophenyl)-5-(RS)-methyl-6-(3,5-dimethylphenyl)-6-oxo-hexanal

Proizvod iz Stupnja 2 gore podvrgava se oksidaciji sa osmij tetroksidom a zatim se tretira sa natrij perjodatom kao što je opisano u Primjeru 1, pri čemu se dobiva 3-(S)-(3,4-diklorofenil)-5-(RS)-metil-6-(3,5-dimetilfenil)-6-okso-heksanal. The product from Step 2 above is subjected to oxidation with osmium tetroxide and then treated with sodium periodate as described in Example 1 to give 3-(S)-(3,4-dichlorophenyl)-5-(RS)- methyl-6-(3,5-dimethylphenyl)-6-oxo-hexanal.

Stupanj 4) Level 4)

1'-(3-(S)-(3,4-Diklorofenil)-6-(3,5-dimetil-fenil)-5-(RS)-metil-6-okso-heksil)-1-metansulfonil-spiro(indolin-3,4'-piperidin) 1'-(3-(S)-(3,4-Dichlorophenyl)-6-(3,5-dimethyl-phenyl)-5-(RS)-methyl-6-oxo-hexyl)-1-methanesulfonyl-spiro (indoline-3,4'-piperidine)

Proizvod iz Stupnja 3 gore, podvrgava se reduktivnoj aminaciji sa 1-metansulfonil-spiro(indolin-3,4'-piperidinom) kao što je opisano u Primjeru 2, pri čemu se dobiva naslovni spoj. The product from Step 3 above is subjected to reductive amination with 1-methanesulfonyl-spiro(indoline-3,4'-piperidine) as described in Example 2 to give the title compound.

1H-NMR (CDCl3 400 MHz). δ 1.05 (d, J=7Hz), 1.08 (d, J=6.7 Hz), 2.30 & 2.32 (s, 6H), 2.89 (s, 3H), 3.72 (s, 2H), 6.8-7.0 (m, 10H). 1H-NMR (CDCl3 400 MHz). δ 1.05 (d, J=7Hz), 1.08 (d, J=6.7 Hz), 2.30 & 2.32 (s, 6H), 2.89 (s, 3H), 3.72 (s, 2H), 6.8-7.0 (m, 10H ).

MS (Cl): 627 (M++1: 35Cl x 2), 629 (M++1: 35Cl & 37Cl). MS (Cl): 627 (M++1: 35Cl x 2), 629 (M++1: 35Cl & 37Cl).

Primjer 136 Example 136

1-(3-(S)-(3,4-Diklorofenil)-4-(3,5-(bistrifluorometil)-benziloksi)-1-acetil-spiro(indolin-3,4'-piperidin) 1-(3-(S)-(3,4-Dichlorophenyl)-4-(3,5-(bistrifluoromethyl)-benzyloxy)-1-acetyl-spiro(indoline-3,4'-piperidine)

Stupanj A: Grade A:

2-(S)-(3,4-Diklorofenil)-4-penten-1-ol 2-(S)-(3,4-Dichlorophenyl)-4-penten-1-ol

U otopinu 2-(S)-(3,4-diklorofenil)-4-pentenske kiseline (7.0 mg) (dobivene kao što su opisali J. Hale i surad. Bioorganic & Medicinal Chemistry Letters 1993, 3, 319-322) u eteru (50 ml) na sobnoj temperaturi dodaje se u procijama u toku 5 minuta čvrst litij aluminij hidrid (700 mg). Reakcija se zagrijava za 40°C 3 sata i zatim se miješa na sobnoj temperaturi 16 sati. Reakcija se izruči u vodu koja sadrži 25 ml 2N NaOH i ekstrahira se dva puta sa eterom. Eterski slojevi se peru sa slanom otopinom, sjedinjavaju i suše preko Na2SO4. Fleš kromatografijom se dobiva naslovni spoj (4.5 gm) kao ulje. /α/d = +14 (EtOH,c = 1.5). In a solution of 2-(S)-(3,4-dichlorophenyl)-4-pentenoic acid (7.0 mg) (obtained as described by J. Hale et al. Bioorganic & Medicinal Chemistry Letters 1993, 3, 319-322) in solid lithium aluminum hydride (700 mg) is added in portions to ether (50 ml) at room temperature over 5 minutes. The reaction was heated at 40°C for 3 hours and then stirred at room temperature for 16 hours. The reaction was poured into water containing 25 ml of 2N NaOH and extracted twice with ether. The ether layers are washed with brine, combined and dried over Na2SO4. Flash chromatography afforded the title compound (4.5 gm) as an oil. /α/d = +14 (EtOH, c = 1.5).

Stupanj B: Grade B:

2-(S)-(3,4-Diklorofenil)-1-(3,5-(bistrifluorometil)benziloksi)-4-penten 2-(S)-(3,4-Dichlorophenyl)-1-(3,5-(bistrifluoromethyl)benzyloxy)-4-pentene

U otopinu 2-(S)-(3,4-diklorofenil)-4-penten-1-ola (1.0 gm) u DMF (25 ml) dodaje se natrij hidrid (175 mg) dok se hladi u kupaonici sa ledom. Poslije 1 minute, dodaje se 3,5-(bistrifluorometil)benzil bromid (2.0 gm), a zatim druga porcija natrij hidrida (175 mg). Poslije 1 sata, reakcija se izruči u vodu i ekstrahira se dva puta sa eterom. Eterski slojevi se peru sa slanom otopinom, sjedinjavaju i suše preko Na2SO4. Fleš kromatografijom (heksani, zatim 2 i 5% etil acetata/heksana) dobiva se naslovni spoj (2.0 gm) kao ulje. To a solution of 2-(S)-(3,4-dichlorophenyl)-4-penten-1-ol (1.0 gm) in DMF (25 ml) was added sodium hydride (175 mg) while cooling in an ice bath. After 1 minute, 3,5-(bistrifluoromethyl)benzyl bromide (2.0 gm) was added, followed by a second portion of sodium hydride (175 mg). After 1 hour, the reaction was poured into water and extracted twice with ether. The ether layers are washed with brine, combined and dried over Na2SO4. Flash chromatography (hexanes, then 2 and 5% ethyl acetate/hexanes) gave the title compound (2.0 gm) as an oil.

NMR (CDCl3): δ 2.30-2.40 i 2.50-2.60 (2m, 2H), 2.90-3.00 (m, 1H), 3.55-3.65 (d od AB q, 2H, J=6 i 9 Hz), 4.54 (AB q, 2H, J=13 Hz), 4.90-5.00 (m, 2H), 5.55-5.70 (m, 1H), 7.04 (dd, 1H, J=2 i 8 Hz), 7.32 (d, 1 h, J=2 Hz), 7.36 (d, 1 h, J=8 Hz), 7.65 (s, 2H), 7.76 (s, 1H). NMR (CDCl3): δ 2.30-2.40 and 2.50-2.60 (2m, 2H), 2.90-3.00 (m, 1H), 3.55-3.65 (d of AB q, 2H, J=6 and 9 Hz), 4.54 (AB q, 2H, J=13 Hz), 4.90-5.00 (m, 2H), 5.55-5.70 (m, 1H), 7.04 (dd, 1H, J=2 and 8 Hz), 7.32 (d, 1 h, J =2 Hz), 7.36 (d, 1 h, J=8 Hz), 7.65 (s, 2H), 7.76 (s, 1H).

Stupanj D Degree D

4-Brom-2-(S)-(3,4-diklorofenil)-1-(3,5-(bistrifluorometil)benziloksi)butan 4-Bromo-2-(S)-(3,4-dichlorophenyl)-1-(3,5-(bistrifluoromethyl)benzyloxy)butane

3-(S)-(3,4-Diklorofenil)-4-(3,5-bistrifluorometil)benziloksi)butan-1-ol iz Stupnja C (500 mg) se konvertira u naslovni spoj (530 mg) sa Ph3P-Br2 kao što je opisano u Primjeru 20, Stupanj B. 3-(S)-(3,4-Dichlorophenyl)-4-(3,5-bistrifluoromethyl)benzyloxy)butan-1-ol from Step C (500 mg) was converted to the title compound (530 mg) with Ph3P-Br2 as described in Example 20, Step B.

Stupanj E: Grade E:

1'-(3-(S)-(3,4-Diklorofenil)-4-(3,5-(bistrifluorometil)benziloksi)-1-acetil-spiro-(indolin-3,4'-piperidin). 1'-(3-(S)-(3,4-Dichlorophenyl)-4-(3,5-(bistrifluoromethyl)benzyloxy)-1-acetyl-spiro-(indoline-3,4'-piperidine).

4-Brom-2-(S)-(3,4-diklorofenil)-1-(3,5-(bistrifluorometil)benziloksi)butan (30 mg) iz Stupnja D se konvertira u naslovni spoj (42 mg) kao što je opisano u Primjeru 20, Stupanj C. 4-Bromo-2-(S)-(3,4-dichlorophenyl)-1-(3,5-(bistrifluoromethyl)benzyloxy)butane (30 mg) from Step D was converted to the title compound (42 mg) as described in Example 20, Step C.

NMR (CDCl3): δ1.48-2.05 (m, 10H), 2.14 i 2.34 (2 s, 3H), 2.10-2.25 (m, 2H), 2.70-2.85 (m, 2H), 2.90 (m, 1H), 3.48 - 3.58 (m, 2 H), 3.70 i 3.84 (2 s, 2H), 4.55 (AB q, 2H, J = 13 Hz), 6.90-7.15 (m, 4h), 7.33 (d, 1h, J = 2 Hz), 7.37 (d, 1h, J = 8 Hz), 7.66 (s, 2h), 7.76 (s, 1H), 8.18 (d, 1h, 8Hz). NMR (CDCl3): δ1.48-2.05 (m, 10H), 2.14 and 2.34 (2 s, 3H), 2.10-2.25 (m, 2H), 2.70-2.85 (m, 2H), 2.90 (m, 1H) , 3.48 - 3.58 (m, 2 H), 3.70 and 3.84 (2 s, 2H), 4.55 (AB q, 2H, J = 13 Hz), 6.90-7.15 (m, 4h), 7.33 (d, 1h, J = 2 Hz), 7.37 (d, 1h, J = 8 Hz), 7.66 (s, 2h), 7.76 (s, 1H), 8.18 (d, 1h, 8Hz).

Claims

1. Spoj formule I [image] ili njegova farmaceutski prihvatljiva sol, naznačen time, što je dušik izrično prikazan gore opcijski kvaterniziran sa C1-4 alkil ili je opcijski prisutan kao N-oksid N+O- i gdje su: l i m svaki neovisno 0, 1, 2, 3, 4 ili 5, pod uvjetom da je l + m jednako sa 1, 2, 3, 4, ili 5; R1 je odabran iz grupe koja se sastoji od: (1) vodika, (2) linearnog ili razgranatog C1-8 alkil, linearnog ili razgranatog C2-8 alkenil, ili linearnog ili razgranatog C2-8 alkinil, gdje je C1-8 alkil, C2-8 alkenil ili C2-8 alkinil di ili tri ili tetra supstituiran, a supstituenti su nezavisno odabrani od: (a) hidroksi, (b) okso, (c) cijano, (d) halogena koji je definiran da obuhvaća Br, Cl, l, i F, (e) trifluorometil, (f) fenil ili mono, di ili trisupstituiranog fenil, a supstituenti su neovisno odabrani od (1) fenil, (2) hidroksi, (3) C1-3 alkil, (4) cijano, (5) halogena, (6) trifluorometil, (7) -NR6COR7, gdje su R6 i R7 neovisno odabrani od: (a) vodika, (b) C1-6 alkil, ili mono ili disupstituiranog C1-6 alkil, a supstituenti su neovisno odabrani od (1) fenil, nesuptituiranog ili supstituiranog sa hidroksi C1-3 alkil, cijano, halogenom, trifluorometil ili C1-4 alkoksi, (2) hidroksi, (3) okso, (4) cijano, (5) halogena, (6) trifluorometil, (c) fenil, piridinil, ili tiofen ili mono, di ili trisupstituirani fenil, piridinil ili tiofen, a supstituenti su neovisno odabrani od (1) hidroksi, (2) C1-4 alkil, (3) cijano, (4) halogena, (5) trrfluorometil, (d) C1-3 alkiloksi, ili R6 i R7 su spojeni međusobno tako da tvore 5-to, 6-to, ili 7-mo člani monociklični zasićen prsten koji sadrži 1 ili 2 heteroatoma neovisno odabrana od dušika, kisika, sumpora, i u kome je prsten nesupstituiran ili mono ili disupstituiran, a supstituenti su neovisno odabrani od (a) hidroksi, (b) okso, (c) cijano, (d) halogena, (e) trifluorometil, (8) -NR6CO2R7, (9) -NR6CONHR7, (10) -NR6S(O)jR7 gdje je j 1 ili 2, (11) -CONR6R7, (12) -COR6, (13) -CO2R6 (14) -OR6, (15) -S(O)kR6, gdje je k 0, 1 ili 2 (16) heteroaril, gdje je heteroaril odabran iz grupe koja se sastoji od: (1) benzimidazolil, (2) benzofuranil, (3) benzoksazolil, (4) furanil, (5) imidazolil, (6) indolil, (7) izoksazolil, (8) izotiazolil, (9) oksadiazolil, (10) oksazolil, (11) pirazinil, (12) pirazolil, (13) piridil, (14) pirimidil, (15) pirolil, (16) hinolil, (17) tetrazolil, (18) tiadiazolil, (19) tiazolil, (20) tienil, i (21) triazolil, gdje je heteroaril nesupstituiran ili mono, di, ili trisupstituiran, a supstituenti su neovisno odabrani od, (a) hidroksi, (b) okso, (c) cijano, (d) halogena, (e) trifluorometil, (g) -NR6R7, (h) -NR6COR7, (i) -NR6CO2R7, (j) -NR6CONHR7, (k) -NR6S(Oj)R7, (l) -CONR6R7, (m) -COR6, (n) -CO2R6, (o) -OR6, (p) -S(O)kR6, (q) heteroaril, gdje je heteroaril odabran iz grupe koja se sastoji od: (1) benzimidazolil, (2) benzofuranil, (3) benzoksazolil, (4) furanil, (5) imidazolil, (6) indolil, (7) izoksazolil, (8) izotiazolil, (9) oksadiazolil, (10) oksazolil, (11) pirazinil, (12) pirazolil, (13) piridil, (14) pirimidil, (15) pirolil, (16) hinolil, (17) tetrazolil, (18) tiadiazolil, (19) tiazolil, (20) tienil, (21) triazolil, gdje je heteroaril nesupstituiran ili mono, di, ili trisupstituiran, a supstituenti su neovisno odabrani od (1) fenil, (2) hidroksi, (3) okso, (4) cijano, (5) halogena, (6) trifluorometil, gdje je dušik iz definicije R1 2(g) kao što je definiran gore opcijski kvaterniziran sa C1-4 alkil ili fenil C1-4 alkil ili je opcijski prisutan kao N-oksid (N+O-); W je odabran iz grupe koja se sastoji od (1) kovalentne veze (2) C1-3 alkil, nesupstituiranog ili supstituiranog sa (a) okso, (b) OR6, (c) halogena, (d) trifluorometil (e) fenil ili mono, di, ili trisupstituiranog fenol, a supstituenti su neovisno odabrani od (1) hidroksi, (2) cijano, (3) halogena, (4) trifluorometil, (3) S(O)k, (4) (C1-3akil)-S(O)k, (5) S(O)k-(C1-2 alkil), (6) S(O)k-NH, (7) S(O)j-NH(C1-2 alkil), (8) S(O)j-NR6, (9) S(O)j-NR6-(C1-2 alkil), (10) CONH, (11) CONH-(C1-2 alkil), (12) CONR6, (13) CONR6-(C1-2 alkil), (14) CO2, (15) CO2-(C1-2 alkil); Q = NR2, O, S, S(O), ili SO2, pod uvjetom da kada je W kovalentna veza i X je C1-3 alkil, tada Q mora biti NR2; R2 je odabran iz grupe koja se sastoji od: (1) vodika, (2) C1-8 linearnog ili razgranatog alkil, nesupstituiranog, mono supstituiranog ili multi supstituiranog sa (a) -OR6, (b) =O, (c) -NHCOR6, (d) -NR6R7, (e) -CN, (f) -halogena, (g) -CF3, (i) -fenil, nesupstituiranog ili supstituiranog, gdje su supstituenti odabrani iz grupe koja se sastoji od (1) hidroksi, (2) cijano, (3) halogena, (4) trifluorometil, (3) S(O)R8, gdje je R8 C1-6 linearni ili razgranati alkil, nesupstituiran, mono, di ili trisupstituiran sa (a) hidroksi, (b) okso, (c) cijano, (d) -OR6, (e) -NR6R7, (f) -NR6COR7, (g) -halogenom, i (h) -CF3, (i) -fenil ili mono, di ili trisupstituiranim fenil, a supstituenti su neovisno odabrani od (1) hidroksi, (2) okso, (3) cijano, (4) -NHR6, (5) NR6R7, (6) -NR6COR7, (7) halogena, (8) -CF3, i (9) C1-3 alkil, (4) SO2R8, ili (5) COR8, (6) CO2R8; (7) CONR7R8; X je odabran iz grupe koja se sastoji od (1) kovalentne veze (2) C1-3 alkil, nesupstituiranog ili supstituiranog sa (a) okso, (b) OR6, (c) halogena, (d) trifluorometil, (e) fenil ili mono, di ili trisupstituiranog fenil, a supstituienti su neovisno odabrani od (1) hidroksi, (2) OR6, (3) halogena, i (4) trifluorometil, (3) S(O)k, (4) (C1-3 alkil)S(O)k, (5) S(O)k(C1-2 alkil), (6) NHS(O)j, (7) NH(C1-2 alkil)S(O)j, (8) S(O)jNR6, (9) S(O)j-NR6-(C1-2 alkil), (10) NHCO, (11) NHCO-(C1-2 alkil), (12) NR6CO, (13) NR6-(C1-2 alkil)CO, (14) O(CO), i (15) (C1-2 alkil)O(CO), Y-Z promatrani zajedno su 2 pripojena atoma prstena [image] a navedeni prsten je fenil, naftil ili heteroaril grupa, sa heteroarilima odabranim iz grupe koja se sastoji od: (1) benzimidazolil, (2) benzofuranil, (3) benzoksazolil, (4) furanil, (5) imidazolil, (6) indolil, (7) izoksazolil, (8) izotiazolil, (9) oksadiazolil, (10) oksazolil, (11) pirazinil, (12) pirazolil, (13) piridil, (14) pirimidil, (15) pirolil, (16) hinolil, (17) tetrazolil, (18) tiadiazolil, (19) tiazolil, (20) tienil, (21) triazolil, i gdje je aril ili heteroaril grupa nesupstituirana, mono, di ili tri supstitirana, a supstituenti su odabrani od: (a) vodika (b) C1-6 alkil, razgranatog ili nerazgranatog, nesupstituiranog ili mono ili di supstituiranog, a supstituenti su odabrani od vodika i hidroksi, (c) okso, (d) OR6, gdje je R6 kao što je definirano odmah gore, (e) halogena, (f) trifluorometil, (g) nitro, (h) cijano, (i) NR6R7, (j) NR6COR7, (k) NR6CO2R7, (l) NHS(O)jR7, (n) COR6R7, (o) COR6, (p) CO2R6, (q) S(O)jR6, (r) heteroaril, gdje je heteroaril odabran iz grupe koja se sastoji od: (a) benzimidazolil, (b) benzofuranil, (c) benzoksazolil, (d) furanil, (e) imidazolil, (f) indolil, (g) izoksazolil, (h) izotiazolil, (i) oksadiazolil, (j) oksazolil, (k) pirazinil, (l) pirazolil, (m) piridil, (n) pirimidil, (o) pirolil, (p) hinolil, (q) tetrazolil, (r) tiadiazolil, (s) tiazolil, (t) tienil, (u) triazolil, i gdje je heteroaril nesupstituiran, mono ili di supstituiran, a supstituenti su odabrani od (1) vodika, (2) C1-6 alkil, razgranatog ili nerazgranatog, nesupstituiranog ili mono ili disupstituiranog, a supstituenti su odabrani od vodika i hidroksi, (3) okso, (4) OR6, (5) trifluorometil, (6) nitro, (7) cijano, (8) NR6R7, (9) NR6COR7, (10) NR6CO2R7, (11) NHS(O)jR6, (12) NR6S(O)jR7, (18) CONR6R7, (19) COR6, (20) CO2R6, (21) S(O)jR6, i (22) fenil.1. Compound of formula I [image] or a pharmaceutically acceptable salt thereof, characterized in that the nitrogen explicitly shown above is optionally quaternized with C1-4 alkyl or is optionally present as N-oxide N+O- and where: l and m each independently 0, 1, 2, 3, 4 or 5, provided that l + m equal to 1, 2, 3, 4, or 5; R1 is selected from the group consisting of: (1) hydrogen, (2) linear or branched C1-8 alkyl, linear or branched C2-8 alkenyl, or linear or branched C2-8 alkynyl, where C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl is di or tri or tetra substituted , and the substituents were independently selected from: (a) hydroxy, (b) oxo, (c) cyano, (d) halogen, which is defined to include Br, Cl, I, and F, (e) trifluoromethyl, (f) phenyl or mono, di or trisubstituted phenyl, the substituents being independently selected from (1) phenyl, (2) hydroxy, (3) C1-3 alkyl, (4) cyano, (5) halogen, (6) trifluoromethyl, (7) -NR6COR7, where R6 and R7 are independently selected from: (a) hydrogen, (b) C1-6 alkyl, or mono- or disubstituted C1-6 alkyl, and the substituents are independently selected from (1) phenyl, unsubstituted or substituted with hydroxy C1-3 alkyl, cyano, halogen, trifluoromethyl or C1-4 alkoxy, (2) hydroxy, (3) oxo, (4) cyano, (5) halogen, (6) trifluoromethyl, (c) phenyl, pyridinyl, or thiophene or mono, di, or trisubstituted phenyl, pyridinyl, or thiophene, the substituents being independently selected from (1) hydroxy, (2) C1-4 alkyl, (3) cyano, (4) halogen, (5) trifluoromethyl, (d) C1-3 alkyloxy, or R6 and R7 are joined together to form a 5-, 6-, or 7-membered monocyclic saturated ring containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and in which the ring is unsubstituted or mono- or disubstituted, and the substituents are independently selected from (a) hydroxy, (b) oxo, (c) cyano, (d) halogens, (e) trifluoromethyl, (8) -NR6CO2R7, (9) -NR6CONHR7, (10) -NR6S(O)jR7 where j is 1 or 2, (11) -CONR6R7, (12) -COR6, (13) -CO2R6 (14) -OR6, (15) -S(O)kR6, where k is 0, 1 or 2 (16) heteroaryl, wherein heteroaryl is selected from the group consisting of: (1) benzimidazolyl, (2) benzofuranil, (3) benzoxazolyl, (4) furanyl, (5) imidazolyl, (6) indolyl, (7) isoxazolyl, (8) isothiazolyl, (9) oxadiazolyl, (10) oxazolyl, (11) pyrazinyl, (12) pyrazolyl, (13) pyridyl, (14) pyrimidyl, (15) pyrrolyl, (16) quinolyl, (17) tetrazolyl, (18) thiadiazolyl, (19) thiazolyl, (20) thienyl, i (21) triazolyl, wherein the heteroaryl is unsubstituted or mono, di, or trisubstituted, and the substituents are independently selected from, (a) hydroxy, (b) oxo, (c) cyano, (d) halogens, (e) trifluoromethyl, (g) -NR6R7, (h) -NR6COR7, (i) -NR6CO2R7, (j) -NR6CONHR7, (k) -NR6S(Oj)R7, (l) -CONR6R7, (m) -COR6, (n) -CO2R6, (o) -OR6, (p) -S(O)kR6, (q) heteroaryl, wherein heteroaryl is selected from the group consisting of: (1) benzimidazolyl, (2) benzofuranil, (3) benzoxazolyl, (4) furanyl, (5) imidazolyl, (6) indolyl, (7) isoxazolyl, (8) isothiazolyl, (9) oxadiazolyl, (10) oxazolyl, (11) pyrazinyl, (12) pyrazolyl, (13) pyridyl, (14) pyrimidyl, (15) pyrrolyl, (16) quinolyl, (17) tetrazolyl, (18) thiadiazolyl, (19) thiazolyl, (20) thienyl, (21) triazolyl, wherein the heteroaryl is unsubstituted or mono, di, or trisubstituted, and the substituents are independently selected from (1) phenyl, (2) hydroxy, (3) oxo, (4) cyano, (5) halogen, (6) trifluoromethyl, wherein the nitrogen of the definition of R1 2(g) as defined above is optionally quaternized with C1-4 alkyl or phenyl C1-4 alkyl or is optionally present as N-oxide (N+O-); W is selected from the group consisting of (1) covalent bonds (2) C1-3 alkyl, unsubstituted or substituted with (a) oxo, (b) OR6, (c) halogens, (d) trifluoromethyl (e) phenyl or mono, di, or trisubstituted phenol, wherein the substituents are independently selected from (1) hydroxy, (2) cyano, (3) halogen, (4) trifluoromethyl, (3) S(O)k, (4) (C1-3alkyl)-S(O)k, (5) S(O)k-(C1-2 alkyl), (6) S(O)k-NH, (7) S(O)j-NH(C1-2 alkyl), (8) S(O)j-NR6, (9) S(O)j-NR6-(C1-2 alkyl), (10) CONH, (11) CONH-(C1-2 alkyl), (12) CONR6, (13) CONR6-(C1-2 alkyl), (14) CO2, (15) CO2-(C1-2 alkyl); Q = NR 2 , O, S, S(O), or SO 2 , provided that when W is a covalent bond and X is C 1-3 alkyl, then Q must be NR 2 ; R2 is selected from the group consisting of: (1) hydrogen, (2) C1-8 linear or branched alkyl, unsubstituted, mono-substituted or multi-substituted with (a) -OR6, (b) =O, (c) -NHCOR6, (d) -NR6R7, (e) -CN, (f) -halogen, (g) -CF3, (i) -phenyl, unsubstituted or substituted, wherein the substituents are selected from the group consisting of (1) hydroxy, (2) cyano, (3) halogen, (4) trifluoromethyl, (3) S(O)R8, where R8 is C1-6 linear or branched alkyl, unsubstituted, mono, di or trisubstituted with (a) hydroxy, (b) oxo, (c) cyano, (d) -OR6, (e) -NR6R7, (f) -NR6COR7, (g) -halogen, i (h) -CF3, (i) -phenyl or mono, di or trisubstituted phenyl, the substituents being independently selected from (1) hydroxy, (2) oxo, (3) cyano, (4) -NHR6, (5) NR6R7, (6) -NR6COR7, (7) halogen, (8) -CF3, i (9) C1-3 alkyl, (4) SO2R8, or (5) COR8, (6) CO2R8; (7) CONR7R8; X is selected from the group consisting of (1) covalent bonds (2) C1-3 alkyl, unsubstituted or substituted with (a) oxo, (b) OR6, (c) halogens, (d) trifluoromethyl, (e) phenyl or mono, di or trisubstituted phenyl, the substituents being independently selected from (1) hydroxy, (2) OR6, (3) halogens, i (4) trifluoromethyl, (3) S(O)k, (4) (C1-3 alkyl)S(O)k, (5) S(O)k(C1-2 alkyl), (6) NHS(O)j, (7) NH(C1-2 alkyl)S(O)j, (8) S(O)jNR6, (9) S(O)j-NR6-(C1-2 alkyl), (10) NHCO, (11) NHCO-(C1-2 alkyl), (12) NR6CO, (13) NR6-(C1-2 alkyl)CO, (14) O(CO), i (15) (C1-2 alkyl)O(CO), Y-Z viewed together are 2 attached ring atoms [image] and said ring is a phenyl, naphthyl or heteroaryl group, with heteroaryls selected from the group consisting of: (1) benzimidazolyl, (2) benzofuranil, (3) benzoxazolyl, (4) furanyl, (5) imidazolyl, (6) indolyl, (7) isoxazolyl, (8) isothiazolyl, (9) oxadiazolyl, (10) oxazolyl, (11) pyrazinyl, (12) pyrazolyl, (13) pyridyl, (14) pyrimidyl, (15) pyrrolyl, (16) quinolyl, (17) tetrazolyl, (18) thiadiazolyl, (19) thiazolyl, (20) thienyl, (21) triazolyl, and wherein the aryl or heteroaryl group is unsubstituted, mono, di or tri substituted, and the substituents are selected from: (a) hydrogen (b) C1-6 alkyl, branched or unbranched, unsubstituted or mono- or di-substituted, and the substituents are selected from hydrogen and hydroxy, (c) oxo, (d) OR 6 , where R 6 is as defined immediately above, (e) halogen, (f) trifluoromethyl, (g) nitro, (h) cyano, (i) NR6R7, (j) NR6COR7, (k) NR6CO2R7, (l) NHS(O)jR7, (n) COR6R7, (o) COR6, (p) CO2R6, (q) S(O)jR6, (r) heteroaryl, wherein heteroaryl is selected from the group consisting of: (a) benzimidazolyl, (b) benzofuranil, (c) benzoxazolyl, (d) furanyl, (e) imidazolyl, (f) indolyl, (g) isoxazolyl, (h) isothiazolyl, (i) oxadiazolyl, (j) oxazolyl, (k) pyrazinyl, (l) pyrazolyl, (m) pyridyl, (n) pyrimidyl, (o) pyrrolyl, (p) quinolyl, (q) tetrazolyl, (r) thiadiazolyl, (s) thiazolyl, (t) thienyl, (u) triazolyl, and wherein the heteroaryl is unsubstituted, mono or di substituted, and the substituents are selected from (1) hydrogen, (2) C1-6 alkyl, branched or unbranched, unsubstituted or mono or disubstituted, and the substituents are selected from hydrogen and hydroxy, (3) oxo, (4) OR6, (5) trifluoromethyl, (6) nitro, (7) cyano, (8) NR6R7, (9) NR6COR7, (10) NR6CO2R7, (11) NHS(O)jR6, (12) NR6S(O)jR7, (18) CONR6R7, (19) COR6, (20) CO2R6, (21) S(O)jR6, i (22) phenyl.

2. Spojevi prema zahtjevu 1, naznačeni time, što je: 1 + m jednako sa 2, 3 ili 4; Y i Z su svaki nezavisno atom ugljika; R1 je odabran iz grupe koja se sastoji od: C1, C2, C3, C4, C5, C6, C7 ili C8 linearnog ili razgranatog alkil, di, tri ili tetra supstituiranog, a supstituenti su neovisno odabrani od: (a) hidroksi, (b) Cl ili F, (c) trifluorometil, (d) fenil ili mono, di ili trisupstituirani fenil, a supstituenti su neovisno odabrani od (1) fenil, (2) hidroksi, (3) C1-3 alkil, (4) cijano, (5) halogena, (6) trifluorometil, (7) -NR6COR7, gdje su R6 i R7 neovisno odabrani od: (a) vodika, (b) C1-6 alkil, ili mono ili disupstituiranog C1-6 alkil, a supstituenti su neovisno odabrani od (1) fenil, nesupstituiranog ili supstituiranog sa hidroksi, C1-3 alkil, cijano, halogenom, trifluorometil ili C1-4 alkoksi, (2) hidroksi, (3) okso, (4) cijano, (5) halogena, (6) trifluorometil, (c) fenil, piridil ili tiofen ili mono, di ili trisupstituiran fenil, piridinil ili tiofen, a supstituenti su neovisno odabrani od (1) hidroksi, (2) C1-4 alkil, (3) cijano, (4) halogena, (5) trifluorometil, (d) C1-3 alkiloksi, ili R6 i R7 su spojeni međusobno tako da tvore 5-to, 6-to, ili 7-mo člani monociklični zasićen prsten koji sadrži 1 ili 2 heteroatoma nezavisno odabrana od dušika, kisika i sumpora, i u kome je prsten nesupstituiran ili mono ili disupstituiran, a supstituenti su neovisno odabrani od (a) hidroksi, (b) okso, (c) cijano, (d) halogena, (e) trifluorometil (8) -NR6CO2R7, (9) -NR6CONHR7, (10) -NR6S(O)jR7, gdje je j = 1 ili 2, (11) -CONR6R7, (12) -COR6, (13) -CO2R6, (14) -OR6, (15) -S(O)kR6, (16) heteroaril, gdje je heteroaril odabran iz grupe koja se sastoji od: (a) pirazinil, (b) pirazolil, (c) piridil, (d) pirimidil, i (e) tienil, gdje je heteroaril nesupstituiran ili mono, di ili trisupstituiran, a supstituenti su neovisno odabrani od, (a) hidroksi, (b) okso, (c) cijano, (d) halogena, (e) trifluorometil, (e) -NR6COR7, (f) -NR6CO2R7, (g) -NR6CONHR7, (h) -NHS(O)jR6, (i) -COR6 (j) -OR6, (k) heteroaril, gdje je heteroaril odabran iz grupe koja se sastoji od: (1) pirazinil, (2) pirazolil, (3) piridil, (4) pirimidil, i (5) tienil gdje je heteroaril nesupstituiran ili mono, di ili trisupstituiran, a supstituenti su neovisno odabrani od (a) fenil, (b) hidroksi, (c) okso, (d) cijano, (e) halogena, i (f) trifluorometil, W je odabran iz grupe koja se sastoji od (1) kovalentne veze, (2) C1-3 alkil, nesupstituiranog ili supstituiranog sa okso, i (3) S(O)2; Q = NR2, S, S(O) ili SO2, pod uvjetima da kada je W kovalentna veza i X je C1-3 alkil, tada Q mora biti NR2; R2 je odabran iz grupe koja se sastoji od: (1) vodika, (2) C1, C2, C3, C4, C5, C6, C7 ili C8 linearnog ili razgranatog alkil, nesupstituiranog, monosupstituiranog ili multi supstituiranog sa (a) -OR6, (b) =O, (c) -NR6R7, (3) SO2R8, gdje je R8 C1-4 linearni ili razgranati alkil, nesupstituiran, mono ili disupstituiran sa (a) -OR6, (b) -NHCOR6, (c) -NR6R7, (d) -halogenom, (e) -fenil; (4) COR8 ili (5) CO2R8; (6) CONR7R8, X je odabran iz grupe koja se sastoji od (1) kovalentne veze, i (2) C1-3 alkil; Y-Z promatrani zajedno su dva pripojena atoma prstena [image] a navedeni prsten je fenil, naftil ili heteroaril, sa heteroarilom odabranim od (1) pirazinil, (2) pirazolil, (3) piridil, (4) pirimidil, i (5) tienil.2. Compounds according to claim 1, characterized in that: 1 + m equals 2, 3 or 4; Y and Z are each independently a carbon atom; R1 is selected from the group consisting of: C1, C2, C3, C4, C5, C6, C7 or C8 linear or branched alkyl, di, tri or tetra substituted, and the substituents are independently selected from: (a) hydroxy, (b) Cl or F, (c) trifluoromethyl, (d) phenyl or mono, di or trisubstituted phenyl, the substituents being independently selected from (1) phenyl, (2) hydroxy, (3) C1-3 alkyl, (4) cyano, (5) halogen, (6) trifluoromethyl, (7) -NR6COR7, where R6 and R7 are independently selected from: (a) hydrogen, (b) C1-6 alkyl, or mono- or disubstituted C1-6 alkyl, and the substituents are independently selected from (1) phenyl, unsubstituted or substituted with hydroxy, C1-3 alkyl, cyano, halogen, trifluoromethyl or C1-4 alkoxy, (2) hydroxy, (3) oxo, (4) cyano, (5) halogen, (6) trifluoromethyl, (c) phenyl, pyridyl or thiophene or mono, di or trisubstituted phenyl, pyridinyl or thiophene, the substituents being independently selected from (1) hydroxy, (2) C1-4 alkyl, (3) cyano, (4) halogen, (5) trifluoromethyl, (d) C1-3 alkyloxy, or R6 and R7 are joined together to form a 5-, 6-, or 7-membered monocyclic saturated ring containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and in which the ring is unsubstituted or mono- or disubstituted, and the substituents are independently selected from (a) hydroxy, (b) oxo, (c) cyano, (d) halogens, (e) trifluoromethyl (8) -NR6CO2R7, (9) -NR6CONHR7, (10) -NR6S(O)jR7, where j = 1 or 2, (11) -CONR6R7, (12) -COR6, (13) -CO2R6, (14) -OR6, (15) -S(O)kR6, (16) heteroaryl, wherein heteroaryl is selected from the group consisting of: (a) pyrazinyl, (b) pyrazolyl, (c) pyridyl, (d) pyrimidyl, i (e) thienyl, wherein the heteroaryl is unsubstituted or mono, di or trisubstituted, and the substituents are independently selected from, (a) hydroxy, (b) oxo, (c) cyano, (d) halogens, (e) trifluoromethyl, (e) -NR6COR7, (f) -NR6CO2R7, (g) -NR6CONHR7, (h) -NHS(O)jR6, (i) -COR6 (j) -OR6, (k) heteroaryl, wherein heteroaryl is selected from the group consisting of: (1) pyrazinyl, (2) pyrazolyl, (3) pyridyl, (4) pyrimidyl, i (5) thienyl wherein the heteroaryl is unsubstituted or mono, di or trisubstituted, and the substituents are independently selected from (a) phenyl, (b) hydroxy, (c) oxo, (d) cyano, (e) halogens, i (f) trifluoromethyl, W is selected from the group consisting of (1) covalent bonds, (2) C1-3 alkyl, unsubstituted or substituted with oxo, i (3) S(O)2; Q = NR 2 , S, S(O) or SO 2 , provided that when W is a covalent bond and X is C 1-3 alkyl, then Q must be NR 2 ; R2 is selected from the group consisting of: (1) hydrogen, (2) C1, C2, C3, C4, C5, C6, C7 or C8 linear or branched alkyl, unsubstituted, monosubstituted or multi-substituted with (a) -OR6, (b) =O, (c) -NR6R7, (3) SO2R8, where R8 is C1-4 linear or branched alkyl, unsubstituted, mono- or disubstituted with (a) -OR6, (b) -NHCOR6, (c) -NR6R7, (d) -halogen, (e) -phenyl; (4) COR8 or (5) CO2R8; (6) CONR7R8, X is selected from the group consisting of (1) covalent bonds, i (2) C1-3 alkyl; Y-Z viewed together are two attached ring atoms [image] and said ring is phenyl, naphthyl or heteroaryl, with heteroaryl selected from (1) pyrazinyl, (2) pyrazolyl, (3) pyridyl, (4) pyrimidyl, i (5) thienyl.

3. Spoj prema zahtjevu 2, naznačen time, što je 1 + m jednako 2, 3 ili 4; R1 je odabran iz grupe koja se sastoji od: C1, C2, C3, C4, C5 ili C6 linearnog ili razgranatog alkil, di ili tri supstituiranog, a supstituenti su neovisno odabrani od (a) hidroksi, (b) Cl ili F, (c) fenil ili mono, di ili trisupstituiranog fenil, a supstituenti su neovisno odabrani od (1) fenil, (2) hidroksi, (3) C1-3 alkil, (4) cijano, (5) halogena, (6) trifluorometil, (d) -NR6COR7, gdje je R6 vodik ili C1-3 alkil i R7 je fenil, piridinil ili tiofen, fenil-C1-3 alkil, piridinilC1-3 alkil ili tiofen-C1-3 alkil, gdje su fenil, piridinil ili tiofen, fenil C1-3 alkil, piridinil C1-3alkil, ili tiofen C1-3 alkil, opcijski supstiturani sa Cl, F, CF3 ili C1-3 alkil, (e) -NHS(O)jR6, (f) -COR6, (g) -OR6, W je odabran iz grupe koja se sastoji od (1) kovalentne veze, i (2) C1-3 alkil, nesupstituiranog ili supstituiranog sa, okso; Q je NR2, S, S(O) ili S(O)2; R2 je odabran iz grupe koja se sastoji od: (1) vodika, (2) C1, C2, C3 ili C4 linearnog ili razgranatog alkil, nesupstituiranog, monosupstituiranog ili disupstituiranog sa okso, OR6, NR6R7 ili fenil, (3) SO2R8 (4) COR8 ili (5) CO2R8, (6) CONR7R8; X je odabran iz grupe koja se sastoji od (1) kovalentne veze, i (2) metilen ili 1-etilen ili 2-etilen; Y-Z razmatrani zajedno su dva pripojena atoma prstena [image] a navedeni prsten je fenil. 3. Compound according to claim 2, characterized in that it is 1 + m equals 2, 3 or 4; R1 is selected from the group consisting of: C1, C2, C3, C4, C5 or C6 linear or branched alkyl, di or tri substituted, and the substituents are independently selected from (a) hydroxy, (b) Cl or F, (c) phenyl or mono, di or trisubstituted phenyl, the substituents being independently selected from (1) phenyl, (2) hydroxy, (3) C1-3 alkyl, (4) cyano, (5) halogen, (6) trifluoromethyl, (d) -NR6COR7, where R6 is hydrogen or C1-3 alkyl and R7 is phenyl, pyridinyl or thiophene, phenyl-C1-3 alkyl, pyridinylC1-3 alkyl or thiophene-C1-3 alkyl, where phenyl, pyridinyl or thiophene , phenyl C1-3 alkyl, pyridinyl C1-3 alkyl, or thiophene C1-3 alkyl, optionally substituted with Cl, F, CF3 or C1-3 alkyl, (e) -NHS(O)jR6, (f) -COR6, (g) -OR6, W is selected from the group consisting of (1) covalent bonds, i (2) C1-3 alkyl, unsubstituted or substituted with, oxo; Q is NR 2 , S, S(O) or S(O) 2 ; R2 is selected from the group consisting of: (1) hydrogen, (2) C1, C2, C3 or C4 linear or branched alkyl, unsubstituted, monosubstituted or disubstituted with oxo, OR6, NR6R7 or phenyl, (3) SO2R8 (4) COR8 or (5) CO2R8, (6) CONR7R8; X is selected from the group consisting of (1) covalent bonds, i (2) methylene or 1-ethylene or 2-ethylene; Y-Z considered together are two attached ring atoms [image] and said ring is phenyl.

4. Spoj prema zahtjevu 3, naznačen time, što je 1 + m jednako 2 ili 3; R1 je odabran iz grupe koja se sastoji od: C1, C2, C3, C4, C5 ili C6 linearnog ili razgranatog alkil, di ili tri supstituiranog, a supstituenti su odabrani neovisno do (a) hidroksi, (b) Cl ili F, (c) fenil ili mono, di ili trisupstituiranog fenil, a supstituenti su neovisno odabrani od (1) fenil, (2) hidroksi, (3) metil ili etil, (4) cijano, (5) halogena, (6) trifluorometil, (d) -NR6COR7, gdje je R6 metil a R7 je fenil, piridinil ili tiofen, fenil C1-3 alkil, piridinil C1-3 alkil, ili tiofen C1-3 alkil, gdje su fenil, piridinil ili tiofen, fenil C1-3 alkil, piridinil C1-3 alkil ili tioen C1-3 alkil, opcijski supstituirani sa Cl, F, CF3 ili C1-3 alkil, W je odabran iz grupe koja se sastoji od (1) kovalentne veze, i (2) C1-3 alkil, nesupstituiranog ili supstituiranog sa okso, i Q je NR2; R2 je odabran iz grupe koja se sastoji od: (1) vodika, (2) C1, C2, C3 ili C4 linearnog ili razgranatog alkil, nesupstituiranog, monosupstituiranog ili multisupstituiranog sa okso, OR6, NR6R7 i fenil, (3) SO2R8, (4) COR8, ili (5) CO2R8: (6) CONR7R8; X je odabran iz grupe koja se sastoji od (1) kovalentne veze, i (2) metilen ili 1-etilen ili 2-etilen; Y-Z promatrani zajedno su 2 pripojena atoma prstena [image] a navedeni prsten je fenil.4. Compound according to claim 3, characterized in that it is 1 + m equals 2 or 3; R1 is selected from the group consisting of: C1, C2, C3, C4, C5 or C6 linear or branched alkyl, di or tri substituted, and the substituents are independently selected up to (a) hydroxy, (b) Cl or F, (c) phenyl or mono, di or trisubstituted phenyl, the substituents being independently selected from (1) phenyl, (2) hydroxy, (3) methyl or ethyl, (4) cyano, (5) halogen, (6) trifluoromethyl, (d) -NR6COR7, where R6 is methyl and R7 is phenyl, pyridinyl or thiophene, phenyl C1-3 alkyl, pyridinyl C1-3 alkyl, or thiophene C1-3 alkyl, where phenyl, pyridinyl or thiophene, phenyl C1-3 alkyl, pyridinyl C1-3 alkyl or thioene C1-3 alkyl, optionally substituted with Cl, F, CF3 or C1-3 alkyl, W is selected from the group consisting of (1) covalent bonds, i (2) C1-3 alkyl, unsubstituted or substituted with oxo, i Q is NR 2 ; R2 is selected from the group consisting of: (1) hydrogen, (2) C1, C2, C3 or C4 linear or branched alkyl, unsubstituted, monosubstituted or multisubstituted with oxo, OR6, NR6R7 and phenyl, (3) SO2R8, (4) COR8, or (5) CO2R8: (6) CONR7R8; X is selected from the group consisting of (1) covalent bonds, i (2) methylene or 1-ethylene or 2-ethylene; Y-Z viewed together are 2 attached ring atoms [image] and said ring is phenyl.

5. Spoj prema zahtjevu, naznačen time, što je 1 + m = 3. R1 je [image] gdje je B: (a) fenil ili mono, di ili trisupstituirani fenil, gdje su supstituenti neovisno klor, metil, fenil ili CF3; (b) -CH2 fenil ili mono ili disupstituirani -CH2 fenil gdje su supstituenti neovisno klor, metil, fenil ili CF3; (c) piridil ili mono, di ili trisupstituirani piridil gdje su supstituenti neovisno klor, metil, fenil ili CF3; i (d) tiofen ili mono ili disupstituirani tiofen gdje su supstituenti neovisno odabrani od klor, metil, fenil ili CF3.5. The compound according to the claim, characterized in that it is 1 + m = 3. R1 is [image] where B is: (a) phenyl or mono, di or trisubstituted phenyl, where the substituents are independently chlorine, methyl, phenyl or CF3; (b) -CH2 phenyl or mono or disubstituted -CH2 phenyl where the substituents are independently chlorine, methyl, phenyl or CF3; (c) pyridyl or mono, di or trisubstituted pyridyl where the substituents are independently chlorine, methyl, phenyl or CF3; and (d) thiophene or mono- or disubstituted thiophene wherein the substituents are independently selected from chlorine, methyl, phenyl or CF3.

6. Spoj prema zahtjevu 5, naznačen time, što je B: (a) fenil ili mono, di ili trisupstituirani fenil, gdje su supstituenti neovisno klor, metil, fenil ili CF3.6. Compound according to claim 5, characterized in that B: (a) phenyl or mono, di or trisubstituted phenyl, wherein the substituents are independently chlorine, methyl, phenyl or CF3.

7. Spoj formule I prema zahtjevu 1, [image] naznačen time, što je grupa [image] opcijski mono, di ili trisupstituirana grupa odabrana od: [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] opcijski supstituenti se nalaze na nesupstituiranim položajima 1, 2 ili 3 na gornjim grupama, a supstituenti su odabrani iz grupe koja se sastoji od (a) hidroksi, (b) okso, (c) cijano, (d) -NR6R7, (e) -NHCOR6R7, (f) halogena, (g) -CF3, (h) -fenil, mono, di ili trisupstituiranog fenil, a supstituenti su neovisno odabrani od (1) hidroksi, (2) okso, (3) cijano, (4) -NR6R7, (5) -NHCOR6R7, (6) -halogena, (7) -CF3, i (8) -C1-3 alkil.7. Compound of formula I according to claim 1, [image] indicated by what the group is [image] an optionally mono, di or trisubstituted group selected from: [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] optional substituents are at unsubstituted positions 1, 2 or 3 on the above groups, and the substituents are selected from the group consisting of (a) hydroxy, (b) oxo, (c) cyano, (d) -NR6R7, (e) -NHCOR6R7, (f) halogens, (g) -CF3, (h) -phenyl, mono, di or trisubstituted phenyl, and the substituents are independently selected from (1) hydroxy, (2) oxo, (3) cyano, (4) -NR6R7, (5) -NHCOR6R7, (6) -halogen, (7) -CF3, i (8) -C1-3 alkyl.

8. Spoj prema zahtjevu 7, naznačen time, što je: R1 odabran iz grupe koja se sastoji od: C1, C2, C3, C4, C5, C6, C7 ili C8 linearnog ili razgranatog alkil, di, tri, ili tetra supstituiranog, a supstituenti su neovisno odabrani od: (a) hidroksi, (b) Cl ili F, (c) trifluorometil, (d) fenil ili mono, di ili trisupstituirani fenil, a supstituienti su neovisno odabrani od (1) fenil, (2) hidroksi, (3) C1-3 alkil, (4) cijano, (5) halogena, (6) trifluorometil, (7) -NR6COR7, gdje su R6 i R7 neovisno odabrani od: (a) vodika, (b) C1-6 alkil, ili mono ili disupstituiranog C1-6 alkil, a supstituenti su neovisno odabrani od (1) fenil, nesupstituiranog ili supstituiranog sa hidroksi, C1-3 alkil, cijano, halogenom, trifluorometil ili C1-4 alkoksi, (2) hidroksi, (3) okso, (4) cijano, (5) halogena, (6) trifluorometil, (c) fenil, piridinil ili tiofen ili mono, di ili trisupstituiranog fenil, piridinil ili tiofen, a supstituenti su neovisno odabrani od (1) hidroksi, (2) C1-4 alkil (3) cijano, (4) halogena, (5) trifluorometil, (d) C1-3 alkiloksi, ili R6 i R7 su spojeni međusobno tako da tvore 5-to, 6-to, ili 7-mo člani monociklični prsten koji sadrži 1 ili 2 heteroatoma neovisno odabrana od dušika, kisika ili sumpora, a u kome je prsten nesupstituiran ili mono ili disupstituiran, a supstituenti su odabrani od (a) hidroksi, (b) okso, (c) cijano, (d) halogena, (e) trifluorometil, (8) -NR6CO2R7, (9) -NR6CONHR7, (10) -NR6S(O)jR7, gdje je j = 1 ili 2, (11) -CONR6R7, (12) -COR6, (13) -CO2R6, (14) -OR6, (15) -S(O)kR6, (16) heteroaril, gdje je heteroaril odabran iz grupe koja se sastoji od: (a) pirazinil, (b) pirazolil, (c) piridil, (d) pirimidil, i (e) tienil, gdje je heteroaril nesupstituiran ili mono, di ili trisupstituiran, a supstituenti su neovisno odabrani od, (a) hidroksi, (b) okso, (c) cijano, (d) halogena, (e) trifluorometil, (e) -NR6COR7, (f) -NR6CO2R7, (g) -NR6CONHR7, (h) -NHS(O)jR6, (i) -COR6, (j) -OR6, (k) heteroaril, gdje je heteroaril odabran iz grupe koja se sastoji od: (1) pirazinil, (2) pirazolil, (3) piridil, (4) pirimidil, i (5) tienil, gdje je heteroaril nesupstituiran ili mono, di ili trisupstituiran, a supstituenti su neovisno odabrani od (a) fenil, (b) hidroksi, (c) okso, (d) cijano, (e) halogena, i (f) trif1uorometil.8. Compound according to claim 7, characterized in that: R1 selected from the group consisting of: C1, C2, C3, C4, C5, C6, C7 or C8 linear or branched alkyl, di, tri, or tetra substituted, and the substituents are independently selected from: (a) hydroxy, (b) Cl or F, (c) trifluoromethyl, (d) phenyl or mono, di or trisubstituted phenyl, the substituents being independently selected from (1) phenyl, (2) hydroxy, (3) C1-3 alkyl, (4) cyano, (5) halogen, (6) trifluoromethyl, (7) -NR6COR7, where R6 and R7 are independently selected from: (a) hydrogen, (b) C1-6 alkyl, or mono- or disubstituted C1-6 alkyl, and the substituents are independently selected from (1) phenyl, unsubstituted or substituted with hydroxy, C1-3 alkyl, cyano, halogen, trifluoromethyl or C1-4 alkoxy, (2) hydroxy, (3) oxo, (4) cyano, (5) halogen, (6) trifluoromethyl, (c) phenyl, pyridinyl or thiophene or mono, di or trisubstituted phenyl, pyridinyl or thiophene, the substituents being independently selected from (1) hydroxy, (2) C1-4 alkyl (3) cyano, (4) halogen, (5) trifluoromethyl, (d) C1-3 alkyloxy, or R6 and R7 are joined together to form a 5-, 6-, or 7-membered monocyclic ring containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and in which the ring is unsubstituted or mono- or disubstituted, and substituents are selected from (a) hydroxy, (b) oxo, (c) cyano, (d) halogens, (e) trifluoromethyl, (8) -NR6CO2R7, (9) -NR6CONHR7, (10) -NR6S(O)jR7, where j = 1 or 2, (11) -CONR6R7, (12) -COR6, (13) -CO2R6, (14) -OR6, (15) -S(O)kR6, (16) heteroaryl, wherein heteroaryl is selected from the group consisting of: (a) pyrazinyl, (b) pyrazolyl, (c) pyridyl, (d) pyrimidyl, i (e) thienyl, wherein the heteroaryl is unsubstituted or mono, di or trisubstituted, and the substituents are independently selected from, (a) hydroxy, (b) oxo, (c) cyano, (d) halogens, (e) trifluoromethyl, (e) -NR6COR7, (f) -NR6CO2R7, (g) -NR6CONHR7, (h) -NHS(O)jR6, (i) -COR6, (j) -OR6, (k) heteroaryl, wherein heteroaryl is selected from the group consisting of: (1) pyrazinyl, (2) pyrazolyl, (3) pyridyl, (4) pyrimidyl, i (5) thienyl, wherein the heteroaryl is unsubstituted or mono, di or trisubstituted, and the substituents are independently selected from (a) phenyl, (b) hydroxy, (c) oxo, (d) cyano, (e) halogens, i (f) trifluoromethyl.

9. Spoj prema zahtjevu 8, naznačen time, što je: R1 odabran iz grupe koja se sastoji od: C1, C2, C3, C4, C5 ili C6 linearnog ili razgranatog alkil, di ili tri supstituiranog, a supstituenti .su neovisno odabrani od: (a) hidroksi, (b) Cl ili F, (c) fenil ili mono, di ili trisupstituiranog fenil, a supstituenti su neovisno odabrani od (1) fenil, (2) hidroksi, (3) C1-3 alkil, (4) cijano, (5) halogena, (6) trifluorometil, (d) -NR6COR7, gdje je R6 vodik ili C1-3 alkil, i R7 je fenil, piridinil ili tiofe)(N-(3,5-dimetilbenzoil) -(metil amino))butil-5-fluoro-1-metansulfonil-spiro(indolin-3,4'-piperidina), (e) –NHS(O)jR6 (f) –COR6 (g) –OR69. Compound according to claim 8, characterized in that: R1 selected from the group consisting of: C1, C2, C3, C4, C5 or C6 linear or branched alkyl, di or tri substituted, and the substituents are independently selected from: (a) hydroxy, (b) Cl or F, (c) phenyl or mono, di or trisubstituted phenyl, the substituents being independently selected from (1) phenyl, (2) hydroxy, (3) C1-3 alkyl, (4) cyano, (5) halogen, (6) trifluoromethyl, (d) -NR6COR7, where R6 is hydrogen or C1-3 alkyl, and R7 is phenyl, pyridinyl or thiophene)(N-(3,5-dimethylbenzoyl)-(methylamino))butyl-5-fluoro-1-methanesulfonyl -spiro(indoline-3,4'-piperidine), (e) –NHS(O)jR6 (f) –COR6 (g) –OR6

10. Spoj prema zahtjevu 9, naznačen time, što je grupa [image] je opcijski mono, di ili trisupstituirana grupa odabrana od [image] supstituenti se nalaze na 1, 2 ili 3 položajima od 1, 2, 3, 4, 5, 6 ili 7 položaja gornjih grupa, a supstituenti su odabrani iz grupe koja se sastoji od (a) hidroksi (b) okso, (c) cijano, (d) –NHR6, (e) –NR6R7, (f) –NHCOR6R7 (g) –halogena, (h) –CF3, (i) –fenil, ili mono, di ili trisupstituiranog fenil, a suspstituenti su neovisno odabrani od (1) hidroksi, (2) okso, (3) cijano, (4) –NHR6, (5) –NR6R7 (6) –-NHCOR6R7, (7) –halogena, (8) –CF3, i (9) –C1-3 alkil.10. A compound according to claim 9, characterized in that it is a group [image] is an optionally mono, di or trisubstituted group selected from [image] the substituents are located at 1, 2, or 3 positions of the 1, 2, 3, 4, 5, 6, or 7 positions of the above groups, and the substituents are selected from the group consisting of (a) hydroxy (b) oxo, (c) cyano, (d) –NHR6, (e) –NR6R7, (f) -NHCOR6R7 (g) –halogen, (h) –CF3, (i) -phenyl, or mono, di or trisubstituted phenyl, the substituents being independently selected from (1) hydroxy, (2) oxo, (3) cyano, (4) –NHR6, (5) –NR6R7 (6) –-NHCOR6R7, (7) –halogen, (8) –CF3, i (9) –C1-3 alkyl.

11. Spoj prema zahtjevu 10, naznačen time, što je: R1 odabran iz grupe koja se sastoji od: C2, C3, C4 ili C5 linearnog ili razgranatog alkil, di ili trisupstituiranog, a supstituenti su neovisno odabranai od: (a) hidroksi, (b) Cl ili F, (c) fenil ili mono, di ili trisupstituirani fenil, a supstituenti su neovisno odabrani od (1) fenil, (2) hidroksi, (3) metil ili etil, (4) cijano, (5) halogena, (6) trifluorometil, (d) -NR6COR7, gdje je R6 metil, a R7 je fenil, piridinil, ili tiofen, fenil C1-3 alkil, piridinil C1-3 alkil ili tiofenel C1-3 alkil, gdje su fenil, piridinil, ili tiofen, fenil C1-3 alkil, piridinil C1-3 alkil ili tiofenel C1-3 alkil, opcijski supstituirani sa Cl, F, CF3 ili C1-3 alkil.11. Compound according to claim 10, characterized in that: R1 selected from the group consisting of: C2, C3, C4 or C5 linear or branched alkyl, di or trisubstituted, and the substituents are independently selected from: (a) hydroxy, (b) Cl or F, (c) phenyl or mono, di or trisubstituted phenyl, the substituents being independently selected from (1) phenyl, (2) hydroxy, (3) methyl or ethyl, (4) cyano, (5) halogen, (6) trifluoromethyl, (d) -NR6COR7, where R6 is methyl and R7 is phenyl, pyridinyl, or thiophene, phenyl C1-3 alkyl, pyridinyl C1-3 alkyl, or thiophenel C1-3 alkyl, where phenyl, pyridinyl, or thiophene, phenyl C1-3 -3 alkyl, pyridinyl C1-3 alkyl or thiophenel C1-3 alkyl, optionally substituted with Cl, F, CF3 or C1-3 alkyl.

12. Spoj prema zahtjevu 11, naznačen time, što je R1 [image] gdje je B (a) fenil ili mono, di ili trisupstituirani fenil, gdje su supstituenti neovisno kloro, metil, fenil ili CF3; (b) -CH2-fenil ili mono ili disupstituirani CH2-fenil, gdje su supstituenti neovisno kloro, metil, fenil ili CF3 (c) piridil ili mono, di ili trisupstituirani piridil, gdje su supstituenti neovisno kloro, metil, fenil ili CF3; (d) tiofen ili mono ili disupstituirani tiofen, gdje su supstituenti neovisno kloro, metil, fenil ili CF3.12. Compound according to claim 11, characterized in that R1 [image] where is B (a) phenyl or mono, di or trisubstituted phenyl, where the substituents are independently chloro, methyl, phenyl or CF3; (b) -CH2-phenyl or mono or disubstituted CH2-phenyl, where the substituents are independently chloro, methyl, phenyl or CF3 (c) pyridyl or mono, di or trisubstituted pyridyl, where the substituents are independently chloro, methyl, phenyl or CF3; (d) thiophene or mono- or disubstituted thiophene, wherein the substituents are independently chloro, methyl, phenyl or CF3.

13. Spoj prema zahtjevu 12, naznačen time, što je B fenil ili mono, di ili trisupstituirani fenil gdje su supstituenti neovisno kloro, metil, fenil ili CF3.13. Compound according to claim 12, characterized in that B is phenyl or mono, di or trisubstituted phenyl where the substituents are independently chloro, methyl, phenyl or CF3.

14. Spoj prema zahtjevu 1, naznačen time, što je odabrano iz grupe koja se sastoji od (a) 1’-(3-(S)-(3,4-diklorofenil)-4-(N-t-butoksikarbonil)(metilamino)butil)-1-metansulfonil-spiro (indolin-3,4’-piperidina); (b) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil-1-metan-sulfonil-spiro (indolin-3,4’-piperidina); (c) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(benzoil)-(metil-amino))-butil)-1-metansulfonil-spiro-(indolin-3,4’-piepridina); (d) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(3,5-bistrifluorometilbenzoil)(metilamino))butil-1-metansulfonil-spiro(indolin-3,4-piperidina); (e) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(3-metilbenzoil)(metilamino))butil)-1-metansulfonila-spiro (indolin-3,4’-piperidina); (f) 1’-(3-((S)-(3,4-diklorfenil))-4-(N-(3-klorobenzoil)(metilamino))butil)-1-metansulfonil-spiro(indolin-3,4’-piperidinil); (g) 1’-(s((S)-(3,4-diklorofenil)-4-(N-(3-trifluorometil-benzoil)(metilamino))butil)-1-metansulfonil-spiro (indolin-3,4’-piperidina); (h) 1’-(3((S)-(3,4-diklorofenil))-4-(N-(3,5-diklorobenzoil)(metilamino))butil)-1-metansulfonil-spiro (indolin-3,4’-piperidina); (i) 1’-(3((S)-(3,4-diklorofenil))-4-(N-(3-trifluorometil-fenilacetil)metilamino))butil)-1-metansulfonil-spiro(indolin-3,4’-piperidina); (j) 1’-(3((S)-(3,4-diklorofenil))-4-(N-(3-izopropiloksi-fenilacetil)(metilamino))butil)-1-metansulfonil-spiro(indolin-3,4’-piperidina); (k) 1’-(3((S)-(3,4-diklorofenil))-4-(N-(benzolsulfonil)(metilamino))butil)-1-metansulfonil-spiro(indolin-3,4’-piperidina); (l) 1’-(3((S)-(3,4-diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil)-1-benziloksikarbonil-spiro (indolin-3,4’-piperidina); (m) 1’-(3((S)-(3,4-diklorofenil))-4-(N-(3,5-diemtilbenzoil)(metilamino))butil)-spiro(indolin-3,4’-piperidina); (n) 1’-(3((S)-(3,4-diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil)-1-propionil-spiro(indolin-3,4’-piperidina); (o) 1’-(3((S)-(3,4-diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamn+ino))butil)-1-formil-spiro(indolin-3,4’-piperidina); (p) 1’-(3((S)-(3,4-diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil)-1-t-butilkarbonil-spiro (indolin-3,4’-piperidina); (q) 1’-(s((S)-(3,4-diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil)-1-metilaminokarbonil-spiro(indolin-3,4’-piperidina); (r) 1’-(3((S)-(3,4-diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil)-1-etoksikarbonil-spiro (indolin-3,4’-piperidina); (s) 1’-(3((S)-(3,4-diklorofenil)))-4-(N-(3,5-dimetilbenzoil)(metilamino)butil)-1-etansulfonil-spiro(indolin-3,4’-piperidina); (t) 1’-(3((S)-(3,4-diklorofenil))-4-(N-(3,5dimetilbenzoil)(metilamino))butil)-1-i-propansulfonil-spiro (indolin-3,4’-piperidina); (u) 1’-(S((S)-(3,4-diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil)-1’-metil-1-metansulfonil-spiro-indolin-3,4’-piperidinijum jodida; (v) 1’-(3(S)-(3,4-diklorofenil)-4-(N-(R ili S)-(3-metilbenzoil)(metilamino))pentil)-1-metan-sulfonil-spiro (indolin-3,4’-piperidina); (w) 1’-(3(S)-(3,4-diklorofenil)-4-(N-(R ili S)-(3,5-bis(trifluorometil)benzoil)(metilamino))-pentil-1 -metansulfonil-spiro(indolin-3,4’-piperidina); (x) 1’-(3)-(S)-(3,4-diklorofenil)-4-(N-(R ili S)-(3,5-dimetilbenzoil)(metilamino))pentil)-1-metansulfonil-spiro(indolin-3,4’-piperidina); (y) 1’-(3)-(S)-(3,4-diklorofenil)-4-(N-((R ili S)-(3,5-diklorobenzoil)(metilamino))pentil)-1-metansulfonil-spiro(indolin-3,4’-piperidina); (aa) 1’-(3((S)-(3,4-diklorofenil))-4-(N-(3,5-difluorobenzoil)(metilamino))butil)-1-metansulfonil-spiro(indolin-3,4’-piperidina); (ab) 1’-(3((S)-(3,4-diklorofenil))-4-(N-(3-fluoro-5-(trifluormetil)benzoil)(metilamino))butil-1 -metansulfonil-spiro(indolin-3,4’-piperidina); (ac) 1’-(3((S)-(3,4-diklorofenil))-4-(N-(1.naftoil)(metilamino))butil)-1-metansulfonil-spiro(indolin-3,4’-piperidina); (ad) 1’-(3((S)-(3,4-diklorofenil))-4-(N-(2-klorofenilsulfonil)-(metilamino))butil)-1-metilsulfonil-spiro (indolin-3,4’-piepridina); (ae) 1’-(3((S)-(3,4-diklorofenil))-4-(N-(3-klorofenilsulfonil)-(metilamino))butil)-1-metilsulfonil-spiro (indolin-3,4’-piperidina); (af) 1’-(3((S)-(3,4-diklorofenil))-4-(N-(4-klorofenilsulfonil)-(metilamino))butil)-1-metilsulfonil-spiro (indolin-3,4’-piperidina); (ag) 1’-(3((S)-(3,4-diklorofenil))-4-(N-(3,5-diklorofenilsulfonil)-(metilamino))butil)-1-metilsulfonil-spiro (indolin-3,4’-piperidina); (ah) 1’-(3((S)-(3,4-diklorofenil))-4-(N-(3-fluoro-5-(trifluorometil) benzoil)(metilamino))-butil)- 1-acetil- spiro(indolin-3,4’-piperidina); (ai) 1’-(3((S)-(3,4-diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil)-1-acetil-spiro(indolin-3,4’ -piperidina); (aj) 1’-(3((S)-(3,4-diklorofenil))-4-(N-(3-brom-5-metilbenzoil)metilamino))butil)-1-metansulfonil-spiro (indolin-3,4’-piperidina); (ak) 1’-(3((S)-(3,4-diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil)-1-(2-aminoacetil)-spiro (indolin-3,4’-piperidina); (al) 1’-(3((S)-(3,4-diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil)-1-metil-spiro(indolin-3,4’ -piperidina); (am) 1’-(3((S)-(3,4-diklorofenil))-4-(N-(3,5-diklorobenzoil)(metilamino))butil)-1-metil-spiro(indolin-3,4’ -piperidina); (an) 1’-(3((S)-(3,4-diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metil amino))butil)-spiro-(2- okso-tetrahidro hinolin-4,4’-piperidina); i (ao) 1’-(3((S)-(3,4-diklorofenil))-4-(N-(3,5-dilorobenzoil)(metilamino)) butil)-1-metil-spiro (2-okso-tetrahidro hinolin-4,4’-piperidina);14. A compound according to claim 1, characterized in that it is selected from the group consisting of (a) 1'-(3-(S)-(3,4-dichlorophenyl)-4-(N-t-butoxycarbonyl)(methylamino)butyl)-1-methanesulfonyl-spiro (indoline-3,4'-piperidine); (b) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl-1-methane-sulfonyl-spiro (indoline -3,4'-piperidine); (c) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(benzoyl)-(methyl-amino))-butyl)-1-methanesulfonyl-spiro-(indoline -3,4'-piepridine); (d) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-bistrifluoromethylbenzoyl)(methylamino))butyl-1-methanesulfonyl-spiro(indoline-3 ,4-piperidine); (e) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3-methylbenzoyl)(methylamino))butyl)-1-methanesulfonyl-spiro (indoline-3, 4'-piperidine); (f) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3-chlorobenzoyl)(methylamino))butyl)-1-methanesulfonyl-spiro(indoline-3, 4'-piperidinyl); (g) 1'-(s((S)-(3,4-dichlorophenyl)-4-(N-(3-trifluoromethyl-benzoyl)(methylamino))butyl)-1-methanesulfonyl-spiro (indoline-3, 4'-piperidine); (h) 1'-(3((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dichlorobenzoyl)(methylamino))butyl)-1-methanesulfonyl-spiro (indoline-3 ,4'-piperidine); (i) 1'-(3((S)-(3,4-dichlorophenyl))-4-(N-(3-trifluoromethyl-phenylacetyl)methylamino))butyl)-1-methanesulfonyl-spiro(indoline-3, 4'-piperidine); (j) 1'-(3((S)-(3,4-dichlorophenyl))-4-(N-(3-isopropyloxy-phenylacetyl)(methylamino))butyl)-1-methanesulfonyl-spiro(indoline-3 ,4'-piperidine); (k) 1'-(3((S)-(3,4-dichlorophenyl))-4-(N-(benzenesulfonyl)(methylamino))butyl)-1-methanesulfonyl-spiro(indoline-3,4'- piperidine); (l) 1'-(3((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)-1-benzyloxycarbonyl-spiro (indoline-3 ,4'-piperidine); (m) 1'-(3((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)-spiro(indoline-3,4'- piperidine); (n) 1'-(3((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)-1-propionyl-spiro(indoline-3 ,4'-piperidine); (o) 1'-(3((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)-1-formyl-spiro(indoline -3,4'-piperidine); (p) 1'-(3((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)-1-t-butylcarbonyl-spiro (indoline -3,4'-piperidine); (q) 1'-(s((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)-1-methylaminocarbonyl-spiro(indoline-3 ,4'-piperidine); (r) 1'-(3((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)-1-ethoxycarbonyl-spiro (indoline-3 ,4'-piperidine); (s) 1'-(3((S)-(3,4-dichlorophenyl)))-4-(N-(3,5-dimethylbenzoyl)(methylamino)butyl)-1-ethanesulfonyl-spiro(indoline-3 ,4'-piperidine); (t) 1'-(3((S)-(3,4-dichlorophenyl))-4-(N-(3,5dimethylbenzoyl)(methylamino))butyl)-1-i-propanesulfonyl-spiro (indoline-3 ,4'-piperidine); (u) 1'-(S((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)-1'-methyl-1-methanesulfonyl- spiro-indoline-3,4'-piperidinium iodide; (v) 1'-(3(S)-(3,4-dichlorophenyl)-4-(N-(R or S)-(3-methylbenzoyl)(methylamino))pentyl)-1-methanesulfonyl-spiro (indoline-3,4'-piperidine); (w) 1'-(3(S)-(3,4-dichlorophenyl)-4-(N-(R or S)-(3,5-bis(trifluoromethyl)benzoyl)(methylamino))-pentyl-1 -methanesulfonyl-spiro(indoline-3,4'-piperidine); (x) 1'-(3)-(S)-(3,4-dichlorophenyl)-4-(N-(R or S)-(3,5-dimethylbenzoyl)(methylamino))pentyl)-1-methanesulfonyl -spiro(indoline-3,4'-piperidine); (y) 1'-(3)-(S)-(3,4-dichlorophenyl)-4-(N-((R or S)-(3,5-dichlorobenzoyl)(methylamino))pentyl)-1- methanesulfonyl-spiro(indoline-3,4'-piperidine); (aa) 1'-(3((S)-(3,4-dichlorophenyl))-4-(N-(3,5-difluorobenzoyl)(methylamino))butyl)-1-methanesulfonyl-spiro(indoline-3 ,4'-piperidine); (ab) 1'-(3((S)-(3,4-dichlorophenyl))-4-(N-(3-fluoro-5-(trifluoromethyl)benzoyl)(methylamino))butyl-1-methanesulfonyl-spiro (indoline-3,4'-piperidine); (ac) 1'-(3((S)-(3,4-dichlorophenyl))-4-(N-(1.naphthoyl)(methylamino))butyl)-1-methanesulfonyl-spiro(indoline-3,4 '-piperidine); (ad) 1'-(3((S)-(3,4-dichlorophenyl))-4-(N-(2-chlorophenylsulfonyl)-(methylamino))butyl)-1-methylsulfonyl-spiro (indoline-3, 4'-piepridine); (ae) 1'-(3((S)-(3,4-dichlorophenyl))-4-(N-(3-chlorophenylsulfonyl)-(methylamino))butyl)-1-methylsulfonyl-spiro (indoline-3, 4'-piperidine); (af) 1'-(3((S)-(3,4-dichlorophenyl))-4-(N-(4-chlorophenylsulfonyl)-(methylamino))butyl)-1-methylsulfonyl-spiro (indoline-3, 4'-piperidine); (ag) 1'-(3((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dichlorophenylsulfonyl)-(methylamino))butyl)-1-methylsulfonyl-spiro (indoline- 3,4'-piperidine); (ah) 1'-(3((S)-(3,4-dichlorophenyl))-4-(N-(3-fluoro-5-(trifluoromethyl)benzoyl)(methylamino))-butyl)-1-acetyl - spiro(indoline-3,4'-piperidine); (ai) 1'-(3((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)-1-acetyl-spiro(indoline-3 ,4'-piperidine); (aj) 1'-(3((S)-(3,4-dichlorophenyl))-4-(N-(3-bromo-5-methylbenzoyl)methylamino))butyl)-1-methanesulfonyl-spiro (indoline- 3,4'-piperidine); (ak) 1'-(3((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)-1-(2-aminoacetyl)-spiro (indoline-3,4'-piperidine); (al) 1'-(3((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)-1-methyl-spiro(indoline-3 ,4'-piperidine); (am) 1'-(3((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dichlorobenzoyl)(methylamino))butyl)-1-methyl-spiro(indoline-3 ,4'-piperidine); (an) 1'-(3((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methyl amino))butyl)-spiro-(2- oxo-tetrahydro quinoline-4,4'-piperidine); and (ao) 1'-(3((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dilorobenzoyl)(methylamino))butyl)-1-methyl-spiro (2-oxo -tetrahydro quinoline-4,4'-piperidine);

15. Spojevi prema zahtjevu 1, naznačeni time, što su odabrani od (a) 1’-(3-(S)-4-fluorofenil)-4-(N-(3,5-bistrifluorometilbenzoil)(metilamino))-butil)-1-acetil-spiro(indolin-3,4’-piperidina), (b) 1’-(3-(S)-(3-klorofenil)-4-(N-(3,5-bistrifluorometilbenzoil)(metilamino))butil)-1acetil-spiro(indolin-3,4’-piperidina), (c) 1’-(3-(S)-(4-klorofenil)-4-(N-(3,5-bistrifluorometilbenzoil)(metilamino))butil)-1-acetil-spiro(indolin-3,4’-piperidina), (d) 1’-(3-(S)-(3,4-difluorofenil)-4-(N-(3,5-bistrifluorometilbenzoil)(metilamino))butil)-1-acetil-spiro (indolin-3,4’-piperidina), (e) 1’-(3-(S)-(3,4-metilendioksifenil)-4-(N-(3,5-bistrifluorometilbenzoil)(metilamino))butil)-1-metansulfonil-spiro(indolin-3,4’-piperidina), (f) 1’-(3-(RS)-(3,5-diklorofenil)-4-(N-(3,5-bistrifluorometilbenzoil)(metilamino))butil)-1-metansulfonil-spiro(indolin-3,4’-piperidina), (g) 1’-(3-(S)-(4-klorofenil)-4-(N-(3,5-bistrifluorometilbenzoil)(metilamino))butil-spiro (dihidrobenzotiofen-3,4’-piperidina), (h) 1’-(3-(RS)-(4-piridil)-4-(N-(3,5-bistrifluorometilbenzoil)(metilamino))butil)-1-acetil-spiro(indolin-3,4’-piperidina), (i) 1’-(3-(S)-(3,4-diklorofenil)-4-(N-(3,5-dimetilbenzoil)(etilamino))butil)-1-metansulfonil-spiro (indolin-3,4’-piperidina), (j) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-3,5-diklorobenzoil)(metilamino))butil)-5-fluoro-spiro(indolin-3,4’-piperidina), (k) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(3-klorbenzoil)(metilamino))butil-5-fluoro-spiro(2,3-dihidrobenzofuran-3,4’-piperidina), (l) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil)-5-fluoro-spiro(2,3-dihidrobenzofuran-3,4’-piperidina), (m) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(3-metilbenzoil)(metilamino))butil)-5-fluoro-spiro(2,3-dihidrobenzofuran-3,4’-piperidina), (n) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(benzoil)(metilamino))butil-5-fluoro-spiro(2,3-dihidrobenzofuran-3,4’-piperidina), (o) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(benzoil)(metilamino))butil-spiro(2,3-dihidrobenzofuran-3,4’-piperidina), (p) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(3-metilbenzoil)(metilamino))butil)-spiro(2,3-dihidrobenzofuran-3,4’piperidina), (q) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil-spiro(2,3-dihidrobenzofuran-3,4’piperidina), (r) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(3-klorbenzoil)(metilamino))butil)-spiro(2,3-dihidrobenzofuran-3,4’-piperidina), (s) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(3,5-diklorobenzoil)(metilamino))butil)-spiro(2,3-dihidrobenzofuran-3,4’-piperidina), (t) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(4-fluoro-1-naftoil)(metilamino))butil)-spiro(2,3-dihidrobenzofuran-3,4’-piperidina), (u) 1’-(3-((S)-(3,4-dikloroenil))-4-(N-(t-butoksikarbonil)(metilamino))butil)-spiro-(2,3-dihidrobenzotiofen-3,4’-piperidina), (v) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil)-spiro(2,3-dihidrobenzotiofen-3,4’-piperidina), (w) 1’-(3-((S)-(4-klorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil-spiro(2,3-dihidrobenzotiofen-3,4’piperidina), (x) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-t-butoksikarbonil)(metilamino))butil)-spiro(2,3-dihidrobenzotiofen-3,4’-piperidina), (y) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(4-fluor-1-naftilmetil)(metilamino))-buti)-spiro(2,3-dihidrobenzotiofen-3,4’-piperidin)-1-oksida, (``) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(t-butoksikarbonil)(metilamino))butil)-spiro(2,3dihidrobenzotiofen-3,4’-piperidin)-1,1-dioksida, (aa) 1’-(3-((S)-(3,4-diklorofenil))-butil-spiro(2,3-dihidrobenzotiofen-3,4’-piperidin)-1,1-dioksida, (ab) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(3,5-dimetilbenzoil) (metilamino))butil)-spiro(dihidro benzotiofen-3,4’- piperidin)-1,1-dioksida, (ac) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil)-spiro(2,3 -dihidrobenzotiofen)-3,4’-piperidin)-1,1-dioksida, (ad) 1’-(3-((S)-(4-klorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil)-spiro-(2,3-dihidrobenzotiofen -3,4’-piperidin)-1-oksida, (ae) 1’-(3-(S)-(4-klorofenil)-4-(N-(3,5-bistrifluorometilbenzoil)(metilamino))butil)-spiro(2,3 -dihidrobenzotiofen-3,4’piperidin)-1-oksid, (af) 1’-(3-(S)-(4-klorofenil)-4-(N-(3,5-bistrifluorometilbenzoil)(metilamino))butil)-spiro(2,3 -dihidrobenzotiofen-3,4’piperidin)-1,1-dioksid, (ag) 1’-benziloksikarbonil-5-fluor-1-metansulfonil-spiro(indolin-3,4’piperidina), (ah) 1’-(3-((S)-(3,4-diklorofenil))-4-(metilamino))butil)-1-metansulfonil.5.metoksi-spiro(indolin-3,4’-piperidina), (ai) 1’-(3-((S)-(3,4-diklorofenil))-4-(metilamino)butil)-1-metansulfonil-5-metil-spiro(indolin-3,4’-piperidina), (ak) 1’-(3-((S)-(3,4-diklorofenil))-4-(metilamino)butil)-5-fluoro-1-metansulfonil-spiro(indolin-3,4’-piperidina), (al) 1’-(3-((S)-(3,4-diklorofenil))-4-(metilamino)butil)-7-fluoro-1-metansulfonil-spiro(indolin-3,4’-piperidina), (am) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil)-1-metansulfonil-5-metil -spiro(indolin-3,4’-piperidina), (an) 5-klor-1’-(3-((S)-(3,4-diklorofenil))-4-(N-(3-metilbenzoil)(metilamino))butil-1-metansulfonil-spiro (indolin-3,4’-piperidina), (ao) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil)-1-metansulfonil-5-metoksi -spiro(indolin-3,4’-piperidina), (ap) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(3-metilbenzoil)(metilamino))butil-5-fluoro-1-metansulfonil-spiro (indolin-3,4’-piperidina), (aq) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(3,5-diklorobenzoil)(metilamino))butil)-5-fluoro-1-metansulfonil -spiro(indolin-3,4’piperidina), (ar) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil-5-fluoro-1-metansulfonil -spiro(indolin-3,4’-piperidina), (as) 1'-(3-((S)-(3,4-dikloroenil))-4-(N-(3-klorbenzoil)(metilamino))butil)-5-fluoro-1-metansulfonil-spiro (indolin-3,4'-piperidina), (at) 1'-(3-((S)-(3,4-diklorofenil))-4-(N-(3,5-bis(trifluorometil)benzoil)-(metilamino))butil-5-fluoro-1 -metansulfonil-spiro(indolin-3,4'-piperidina), (au) 1'-(3-((S)-(3,4-diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino)) butil)-7- fluoro-1- metan sulfonil-spiro(indolin-3,4’-piperidina), (av) 1-acetil-1’-(3-((S)-(3,4-diklorofenil))-4-(N-t-butoksikarbonil)(metilamino))butil)-5-fluoro-spiro (indolin-3,4’-piperidin), (aw) 1-acetil-5-klor-1’-(3-((S)-(3,4-diklorofenil))-4-(metilamino)butil)-spiro(indolin-3,4’-piperidina), (ax) 1-acetil-1’-(3-((S)-(3,4-diklorofenil))-4-((metilamino)butil)-5-metil-spiro(indolin-3,4’-piperidina), (ay) 1-acetil-1’-(3-((S)-(3,4-diklorofenil))-4-((metilamino)butil)-5-fluoro-spiro(indolin-3,4’-piperidina), (az) 1-acetil-1’-(3-((S)-(3,4-diklorofenil))-4-(metilamino))butil)-6-fluoro-spiro(indolin-3,4’-piperidina), (ba) 1-acetil-1’-(3-((S)-(3,4-diklorofenil))-4-(metilamino)butil)-4-fluoro-spiro(indolin-3,4’-piperidina), (bb) 1-acetil-1’-(3-((S)-(3,4-diklorofenil)))-4-(N-(benzoil)(metilamino))butil)-4-fluoro-spiro(indolin-3,4’ -piperidina), (bc) 1-acetil-1’-(3-((S)-(3,4-diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil)-6-fluoro-spiro (indolin-3,4’-piperidina), (bd) 1-acetil-1’-(3-((S)-(3,4-diklorofenil))-4-(N-(benzoil)(metilamino))butil)-6-fluoro-spiro(indolin-3,4’-piperidina), (be) 1-acetil-1’-(3-((S)-(3,4-diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil)-4-fluoro-spiro (indolin-3,4’-piperidina), (bf) 1-acetil-1’-(3-((S)-(3,4-diklorofenil))-4-(N-(benzoil)(metilamino))butil)-5-fluoro-spiro(indolin-3,4’-piperidina), (bg) 1-acetil-1’-5-kloro-(3-((S)-(3,4-diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil)-spiro (indolin-3,4’-piperidina), (bh) 1-acetil-1’-(3-((S)-(3,4-diklorofenil))-4-(N-(3-klorobenzoil)(metilamino))butil)-5-fluoro-spiro(idolin -3,4’-piperidina), (bi) 1-acetil-1’-(3-((S)-(3,4-diklorofenil))-4-(N-(3,5-diklorbenzoil)(metilamino))butil)-5-fluoro-spiro (indolin-3,4’-piperidina), (bj) 1-acetil-1’-(3-((S)-(3,4-diklorofenil))-4-(N-(3-metilbenzoil)(metilamino))butil)-5-fluoro-spiro(indolin -3,4’-piperidina), (bk) 1-acetil-1’-(3-((S)-(3,4-diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil)-5-fluoro-spiro (indolin-3,4’-piperidina), (bl) 1-acetil-1’-(3-((S)-(3,4-diklorofenil))-4-(N-(3-izopropoksibenzoil)(metilamino))butil)-5-fluoro-spiro (indolin-3,4’-piperidina), (bm) 1-acetil-1’-(3-((S)-(3,4-diklorofenil))-4-(N-(3,5-bis(trifluorometil)(metilamino))-butil)-5-fluoro-spiro (indolin-3,4’-piperidina), (bn) 1-acetil-1’-(3-((S)-(3,4-diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))butil)-5-metil-spiro (indolin-3,4’-piperidina), (bo) 1-acetil-1’-(3-((S)-(3,4-diklorofenil))-4-(N-(4-fluoro-1-naftoil))metilamino))butil)-5-fluoro-spiro (indolin-3,4’-piperidina), (bp) 1-acetil-1’-(3-((S)-(3,4-diklorofenil))-4-(N-(1-naftoil)(metilamino))butil)-5-fluoro-spiro(indolin-3,4’ -piperidina), (bq) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(1-naftoil)(metilamino))butil)-5-fluoro-1-metansulfonil-spiro (indolin-3,4’-piperidina), (br) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(4-fluoro-1-naftoil)(metilamino))butil)-5-fluoro-1-metansulfonil -spiro(indolin-3,4’-piperidina), (bs) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(4-fluoro-1-naftoil)(metilamino))butil)-spiro (2,3dihidrobenzotiofen)-3,4’-piperidina), (bt) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(4-fluoro-1-naftoil)(metilamino))butil)-spiro(2,3 -dihidrobenzotiofen-3,4’-piperidin)sulfona, (bu) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(4-fluoro-1-naftoil)(metilamino))butil)-spiro(2,3 -dihidrobenzotiofen-3,4’-piperidina), (bv) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(4-fluoro-1-naftoil)(metilamino))butil)-5-fluoro-spiro-(2,3 -dihidrobenzofuran-3,4’-piperidina), (bw) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(4-fluoro-1-naftoil)(metilamino))butil)-spiro(2,3-dihidrobenzofuran -3,4’-piperidina), (bx) 1-acetil-1’-(3-((S)-(3,4-diklorofenil))-4-(N-(4-fluoro-1-naftoil)(metilamino))butil-6-fluoro-spiro (indolin-3,4’-piperidina), (by) 1-acetil-1’-(3-((S)-(3,4-diklorofenil))-4-(N-(4-fluoro-1- naftoil)(metil amino))butil)-4-fluoro- spiro(indolin- 3,4’-piperidina), (bz) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(4-fluoro-1-naftilmetil)(metilamino))butil)-5-1-metansulfonil-spiro (indolin-3,4’-piperidina), (ca) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(4-fluoro-1-naftilmetil)(metilamino))butil)-5-fluoro-spiro(indolin -3,4’-piperidina), (cb) 1-acetil-1’-(3-((S)-(3,4-diklorofenil))-4-(N-(4-fluoro-1-naftilmetil)(metilamino))butil)-5-fluoro-spiro (indolin-3,4’-piperidina), (cd) 1’-(5-fluoroindolil-3-(2-etanoil))-1-metansulfonil-spiro(indolin-3,4’-piperidina), (ce) 1’-(2-(3-(5-fluoroindolil))etil))-1-metansulfonil-spiro(indolin-3,4’-piperidina), (cf) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(3-klor-4-fluorobenzoil)(metilamino))butil)-1-metansulfonil-spiro (indolin-3,4’-piperidina), (cg) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(3-klor-4-fluorobenzoil)(metilamino))butil-5-fluoro-1 -metansulfonil-spiro-(indolin-3,4’-piperidina), (ch) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(4-fluorobenzoil)(metilamino))butil)-1-metansulfonil-spiro(indolin -3,4’-piperidina), (ci) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(4-fluorobenzoil)(metilamino))butil)-5-fluor-1-acetil-spiro(indolin-3,4’-piperidina), (cj) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(3-klor-4-fluorobenzoil)(metilamino))butil)-5-fluoro-1-acetil-spiro (indolin-3,4’-piperidina), (ck) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(4-fluoro-3,5-dimetilbenzoil)(metilamino))butil)-5-fluoro-1-acetil -spiro(indolin-3,4’-piperidina), (cl) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(4-fluoro-3,5-dimetilbenzoil)(metilamino))-butil)-1-metansulfonil-spiro(indolin-3,4’-piperidina), (cm) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(4-fluoro-3-trifluorometilbenzoil)(metilamino))butil)-1-metansulfonil-spiro(indolin-3,4’-piperidina), (cn) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(4-fluoro-3,5-dimetilbenzoil)(metilamino))butil)-1-metansulfonil -spiro(indolin-3,4’-piperidina), (co) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(4-fluoro-3-trifluorometilbenzoil)(metilamino))-butil)-1-acetil-spiro (indolin-3,4’-piperidina), (cp) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(4-fluoro-1-naftoil)(metilamino))butil)-1-acetil-spiro(indolin-3,4’-piperidin), (cq) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(4-fluoro-1-naftoil)(metilamino))butil)-1-metansulfonil-spiro (indolin-3,4’-piperidina), (cr) 1’-(3-((S)-(3,4-diklorofenil))-4-(N-(1-naftoil)(metilamino))butil)-1-acetil-spiro(indolin-3,4’-piperidina), (cs) 1’-(3((S)-(3,4-diklorofenil))-4-(N-(3,5-dimetilbenzoil)(metilamino))-4-fenil-butil)-1-metansulfonil -spiro(indolin-3,4’-piperidina), (ct) 1’-(4-N-(3,5-dimetilbenzoil)(metilamino))-4-(fenil)butil)-1-acetil-spiro(indolin-3,4’-piperidina), (cu) 1’-(3-((S)-(3,4-diklorofenil))-4-(1-(2-fenilimidazolo))butil)-1-metansulfonil-spiro(indolin-3,4’-piperidina), (cv) 1’-(3-((S)-(3,4-diklorofenil))-4-((N-(3,5-dimetilbenzoil)(metilamino))-4-(metil)butil)-1-acetil-spiro (indolin-3,4’-piperidina), (cw) 1’-(3-((S)-(3,4-diklorofenil))-4-((N-(4-fluoro-1-naftil)(metilamino))-4-(metil)butil)-1-acetil-spiro (indolin-3,4’-piperidina), (cx) 1’-(3-((S)-(3,4-diklorofenil))-4-(R i S)-(N-(3,5-dimetilbenzoil)(metilamino))heksil)-1-acetil-spiro (indolin-3,4’-piperidina), (cy) 1’-(3-((S)-(3,4-diklorofenil))-4-(R i S)-(N-(3,5-dimetilbenzoil)(metilamino))heksil)-1-acetil-5-fluoro -spiro(indolin-3,4’-piperidina), (cz) 1’-(3-((S)-(3,4-diklorofenil)-4-(R i S)-(N-(3,5-dimetilbenzoil)(metilamino))heptil)-1-acetil-spiro (indolin-3,4’-piperidina), (da) 1’-(3-((S)-(3,4-diklorofenil)-4-(R i S)-(N-(3,5-dimetilbenzoil)(metilamino))heptil)-1-acetil-5-fluoro -spiro(indolin-3,4’-piperidina), (db) 1’-(3-((S)-(3,4-diklorofenil))-4-(R i S)-hidroksi-5-(3,5-dimetilbenzoil)pentil)-1-metansulfonil-spiro (indolin-3,4’-piperidina), (dc) 1’-(3-(R)-(3,4-diklorofenil)-5-(N-(3,5-dimetilbenzoil)(metilamino))-5-okso-pentil)-1-metansulfonil -spiro(indolin-3,4’-piperidina), (dd) 1’-(3-(R)-(3,4-diklorofenil))-5-(3,5-dimetilfenil)-5-okso-pentil)-1-metansulfonil-spiro(indolin-3,4’-piperidina), (de) 1’-(3-(R)-(3,4-diklorofenil)-6-(3,5-dimetilfenil)-5-okso-heksil)metansulfonil-spiro(indolin-3,4’-piperidina), (df) 1’-(3-(S)-(3,4-diklorofenil)-6-(3,5-dimetilfenil)-6-okso-heksil)-1-metansulfonil-spiro(indolin-3,4’-piperidina), (dg) 1’-(3-(S)-(3,4-diklorofenil)-6-(3,5-dimetilfenil)-5-(R i S)-metil-6-okso-heksil)-1-metansulfonil-spiro (indolin-3,4’-piperidina), (dh) 1’-(3-(S)-(3,4-diklorofenil)-4-(3,5-(bistrifluorometil)benziloksi)-1-acetil-spiro(indolin-3,4’-piperidina),15. Compounds according to claim 1, characterized in that they are selected from (a) 1'-(3-(S)-4-fluorophenyl)-4-(N-(3,5-bistrifluoromethylbenzoyl)(methylamino))-butyl)-1-acetyl-spiro(indoline-3,4' -piperidine), (b) 1'-(3-(S)-(3-chlorophenyl)-4-(N-(3,5-bistrifluoromethylbenzoyl)(methylamino))butyl)-1acetyl-spiro(indoline-3,4'-piperidine ), (c) 1'-(3-(S)-(4-chlorophenyl)-4-(N-(3,5-bistrifluoromethylbenzoyl)(methylamino))butyl)-1-acetyl-spiro(indoline-3,4' -piperidine), (d) 1'-(3-(S)-(3,4-difluorophenyl)-4-(N-(3,5-bistrifluoromethylbenzoyl)(methylamino))butyl)-1-acetyl-spiro (indoline-3, 4'-piperidine), (e) 1'-(3-(S)-(3,4-methylenedioxyphenyl)-4-(N-(3,5-bistrifluoromethylbenzoyl)(methylamino))butyl)-1-methanesulfonyl-spiro(indoline-3, 4'-piperidine), (f) 1'-(3-(RS)-(3,5-dichlorophenyl)-4-(N-(3,5-bistrifluoromethylbenzoyl)(methylamino))butyl)-1-methanesulfonyl-spiro(indoline-3, 4'-piperidine), (g) 1'-(3-(S)-(4-chlorophenyl)-4-(N-(3,5-bistrifluoromethylbenzoyl)(methylamino))butyl-spiro (dihydrobenzothiophene-3,4'-piperidine), (h) 1'-(3-(RS)-(4-pyridyl)-4-(N-(3,5-bistrifluoromethylbenzoyl)(methylamino))butyl)-1-acetyl-spiro(indoline-3,4' -piperidine), (i) 1'-(3-(S)-(3,4-dichlorophenyl)-4-(N-(3,5-dimethylbenzoyl)(ethylamino))butyl)-1-methanesulfonyl-spiro (indoline-3, 4'-piperidine), (j) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-3,5-dichlorobenzoyl)(methylamino))butyl)-5-fluoro-spiro(indoline-3 ,4'-piperidine), (k) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3-chlorobenzoyl)(methylamino))butyl-5-fluoro-spiro(2,3-dihydrobenzofuran -3,4'-piperidine), (l) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)-5-fluoro-spiro(2, 3-dihydrobenzofuran-3,4'-piperidine), (m) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3-methylbenzoyl)(methylamino))butyl)-5-fluoro-spiro(2,3- dihydrobenzofuran-3,4'-piperidine), (n) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(benzoyl)(methylamino))butyl-5-fluoro-spiro(2,3-dihydrobenzofuran-3 ,4'-piperidine), (o) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(benzoyl)(methylamino))butyl-spiro(2,3-dihydrobenzofuran-3,4'- piperidine), (p) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3-methylbenzoyl)(methylamino))butyl)-spiro(2,3-dihydrobenzofuran-3, 4'piperidine), (q) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl-spiro(2,3-dihydrobenzofuran-3 ,4'piperidine), (r) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3-chlorobenzoyl)(methylamino))butyl)-spiro(2,3-dihydrobenzofuran-3, 4'-piperidine), (s) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dichlorobenzoyl)(methylamino))butyl)-spiro(2,3-dihydrobenzofuran- 3,4'-piperidine), (t) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(4-fluoro-1-naphthoyl)(methylamino))butyl)-spiro(2,3- dihydrobenzofuran-3,4'-piperidine), (u) 1'-(3-((S)-(3,4-dichloroenyl))-4-(N-(t-butoxycarbonyl)(methylamino))butyl)-spiro-(2,3-dihydrobenzothiophene-3 ,4'-piperidine), (v) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)-spiro(2,3-dihydrobenzothiophene- 3,4'-piperidine), (w) 1'-(3-((S)-(4-chlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl-spiro(2,3-dihydrobenzothiophene-3,4 'piperidine), (x) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-t-butoxycarbonyl)(methylamino))butyl)-spiro(2,3-dihydrobenzothiophene-3,4'- piperidine), (y) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(4-fluoro-1-naphthylmethyl)(methylamino))-buty)-spiro(2,3 -dihydrobenzothiophene-3,4'-piperidine)-1-oxide, (``) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(t-butoxycarbonyl)(methylamino))butyl)-spiro(2,3dihydrobenzothiophene-3,4 '-piperidine)-1,1-dioxide, (aa) 1'-(3-((S)-(3,4-dichlorophenyl))-butyl-spiro(2,3-dihydrobenzothiophene-3,4'-piperidine)-1,1-dioxide, (ab) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)-spiro(dihydro benzothiophene-3,4 '-piperidine)-1,1-dioxide, (ac) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)-spiro(2,3-dihydrobenzothiophene) -3,4'-piperidine)-1,1-dioxide, (ad) 1'-(3-((S)-(4-chlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)-spiro-(2,3-dihydrobenzothiophene-3 ,4'-piperidine)-1-oxide, (ae) 1'-(3-(S)-(4-chlorophenyl)-4-(N-(3,5-bistrifluoromethylbenzoyl)(methylamino))butyl)-spiro(2,3-dihydrobenzothiophene-3,4' piperidine)-1-oxide, (af) 1'-(3-(S)-(4-chlorophenyl)-4-(N-(3,5-bistrifluoromethylbenzoyl)(methylamino))butyl)-spiro(2,3-dihydrobenzothiophene-3,4' piperidine)-1,1-dioxide, (ag) 1'-benzyloxycarbonyl-5-fluoro-1-methanesulfonyl-spiro(indoline-3,4'piperidine), (ah) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(methylamino))butyl)-1-methanesulfonyl.5.methoxy-spiro(indoline-3,4'-piperidine ), (ai) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(methylamino)butyl)-1-methanesulfonyl-5-methyl-spiro(indoline-3,4'-piperidine) , (ak) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(methylamino)butyl)-5-fluoro-1-methanesulfonyl-spiro(indoline-3,4'-piperidine) , (al) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(methylamino)butyl)-7-fluoro-1-methanesulfonyl-spiro(indoline-3,4'-piperidine) , (am) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)-1-methanesulfonyl-5-methyl - spiro(indoline-3,4'-piperidine), (an) 5-chloro-1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3-methylbenzoyl)(methylamino))butyl-1-methanesulfonyl-spiro (indoline -3,4'-piperidine), (ao) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)-1-methanesulfonyl-5-methoxy - spiro(indoline-3,4'-piperidine), (ap) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3-methylbenzoyl)(methylamino))butyl-5-fluoro-1-methanesulfonyl-spiro (indoline -3,4'-piperidine), (aq) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dichlorobenzoyl)(methylamino))butyl)-5-fluoro-1-methanesulfonyl - spiro(indoline-3,4'piperidine), (ar) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl-5-fluoro-1-methanesulfonyl-spiro (indoline-3,4'-piperidine), (as) 1'-(3-((S)-(3,4-dichloroenyl))-4-(N-(3-chlorobenzoyl)(methylamino))butyl)-5-fluoro-1-methanesulfonyl-spiro ( indoline-3,4'-piperidine), (at) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-bis(trifluoromethyl)benzoyl)-(methylamino))butyl-5-fluoro- 1-methanesulfonyl-spiro(indoline-3,4'-piperidine), (au) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)-7-fluoro-1-methanesulfonyl -spiro(indoline-3,4'-piperidine), (av) 1-acetyl-1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-t-butoxycarbonyl)(methylamino))butyl)-5-fluoro-spiro (indoline-3 ,4'-piperidine), (aw) 1-acetyl-5-chloro-1'-(3-((S)-(3,4-dichlorophenyl))-4-(methylamino)butyl)-spiro(indoline-3,4'-piperidine) , (ax) 1-acetyl-1'-(3-((S)-(3,4-dichlorophenyl))-4-((methylamino)butyl)-5-methyl-spiro(indoline-3,4'-piperidine) ), (ay) 1-acetyl-1'-(3-((S)-(3,4-dichlorophenyl))-4-((methylamino)butyl)-5-fluoro-spiro(indoline-3,4'-piperidine ), (az) 1-acetyl-1'-(3-((S)-(3,4-dichlorophenyl))-4-(methylamino))butyl)-6-fluoro-spiro(indoline-3,4'-piperidine ), (ba) 1-acetyl-1'-(3-((S)-(3,4-dichlorophenyl))-4-(methylamino)butyl)-4-fluoro-spiro(indoline-3,4'-piperidine) , (bb) 1-acetyl-1'-(3-((S)-(3,4-dichlorophenyl)))-4-(N-(benzoyl)(methylamino))butyl)-4-fluoro-spiro(indoline -3,4'-piperidine), (bc) 1-acetyl-1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)-6-fluoro- spiro (indoline-3,4'-piperidine), (bd) 1-acetyl-1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(benzoyl)(methylamino))butyl)-6-fluoro-spiro(indoline- 3,4'-piperidine), (be) 1-acetyl-1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)-4-fluoro- spiro (indoline-3,4'-piperidine), (bf) 1-acetyl-1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(benzoyl)(methylamino))butyl)-5-fluoro-spiro(indoline- 3,4'-piperidine), (bg) 1-acetyl-1'-5-chloro-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)- spiro (indoline-3,4'-piperidine), (bh) 1-acetyl-1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3-chlorobenzoyl)(methylamino))butyl)-5-fluoro-spiro( idolin-3,4'-piperidine), (bi) 1-acetyl-1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dichlorobenzoyl)(methylamino))butyl)-5-fluoro- spiro (indoline-3,4'-piperidine), (bj) 1-acetyl-1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3-methylbenzoyl)(methylamino))butyl)-5-fluoro-spiro( indoline-3,4'-piperidine), (bk) 1-acetyl-1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)-5-fluoro- spiro (indoline-3,4'-piperidine), (bl) 1-acetyl-1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3-isopropoxybenzoyl)(methylamino))butyl)-5-fluoro-spiro ( indoline-3,4'-piperidine), (bm) 1-acetyl-1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-bis(trifluoromethyl)(methylamino))-butyl)-5 -fluoro-spiro (indoline-3,4'-piperidine), (bn) 1-acetyl-1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))butyl)-5-methyl- spiro (indoline-3,4'-piperidine), (bo) 1-acetyl-1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(4-fluoro-1-naphthoyl))methylamino))butyl)-5- fluoro-spiro (indoline-3,4'-piperidine), (bp) 1-acetyl-1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(1-naphthoyl)(methylamino))butyl)-5-fluoro-spiro( indoline-3,4'-piperidine), (bq) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(1-naphthoyl)(methylamino))butyl)-5-fluoro-1-methanesulfonyl-spiro ( indoline-3,4'-piperidine), (br) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(4-fluoro-1-naphthoyl)(methylamino))butyl)-5-fluoro-1- methanesulfonyl-spiro(indoline-3,4'-piperidine), (bs) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(4-fluoro-1-naphthoyl)(methylamino))butyl)-spiro (2,3dihydrobenzothiophene) -3,4'-piperidine), (bt) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(4-fluoro-1-naphthoyl)(methylamino))butyl)-spiro(2,3 - dihydrobenzothiophene-3,4'-piperidine) sulfone, (bu) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(4-fluoro-1-naphthoyl)(methylamino))butyl)-spiro(2,3 - dihydrobenzothiophene-3,4'-piperidine), (bv) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(4-fluoro-1-naphthoyl)(methylamino))butyl)-5-fluoro-spiro- (2,3-dihydrobenzofuran-3,4'-piperidine), (bw) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(4-fluoro-1-naphthoyl)(methylamino))butyl)-spiro(2,3- dihydrobenzofuran-3,4'-piperidine), (bx) 1-acetyl-1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(4-fluoro-1-naphthoyl)(methylamino))butyl-6-fluoro -spiro (indoline-3,4'-piperidine), (by) 1-acetyl-1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(4-fluoro-1-naphthoyl)(methyl amino))butyl)-4 -fluoro-spiro(indoline-3,4'-piperidine), (bz) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(4-fluoro-1-naphthylmethyl)(methylamino))butyl)-5-1-methanesulfonyl- spiro (indoline-3,4'-piperidine), (ca) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(4-fluoro-1-naphthylmethyl)(methylamino))butyl)-5-fluoro-spiro( indoline-3,4'-piperidine), (cb) 1-acetyl-1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(4-fluoro-1-naphthylmethyl)(methylamino))butyl)-5- fluoro-spiro (indoline-3,4'-piperidine), (cd) 1'-(5-fluoroindolyl-3-(2-ethanoyl))-1-methanesulfonyl-spiro(indoline-3,4'-piperidine), (ce) 1'-(2-(3-(5-fluoroindolyl))ethyl))-1-methanesulfonyl-spiro(indoline-3,4'-piperidine), (cf) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3-chloro-4-fluorobenzoyl)(methylamino))butyl)-1-methanesulfonyl-spiro ( indoline-3,4'-piperidine), (cg) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3-chloro-4-fluorobenzoyl)(methylamino))butyl-5-fluoro-1-methanesulfonyl -spiro-(indoline-3,4'-piperidine), (ch) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(4-fluorobenzoyl)(methylamino))butyl)-1-methanesulfonyl-spiro(indoline-3, 4'-piperidine), (ci) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(4-fluorobenzoyl)(methylamino))butyl)-5-fluoro-1-acetyl-spiro( indoline-3,4'-piperidine), (cj) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3-chloro-4-fluorobenzoyl)(methylamino))butyl)-5-fluoro-1- acetyl-spiro (indoline-3,4'-piperidine), (ck) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(4-fluoro-3,5-dimethylbenzoyl)(methylamino))butyl)-5-fluoro- 1-acetyl-spiro(indoline-3,4'-piperidine), (cl) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(4-fluoro-3,5-dimethylbenzoyl)(methylamino))-butyl)-1-methanesulfonyl -spiro(indoline-3,4'-piperidine), (cm) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(4-fluoro-3-trifluoromethylbenzoyl)(methylamino))butyl)-1-methanesulfonyl-spiro( indoline-3,4'-piperidine), (cn) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(4-fluoro-3,5-dimethylbenzoyl)(methylamino))butyl)-1-methanesulfonyl - spiro(indoline-3,4'-piperidine), (co) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(4-fluoro-3-trifluoromethylbenzoyl)(methylamino))-butyl)-1-acetyl-spiro (indoline-3,4'-piperidine), (cp) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(4-fluoro-1-naphthoyl)(methylamino))butyl)-1-acetyl-spiro( indoline-3,4'-piperidine), (cq) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(4-fluoro-1-naphthoyl)(methylamino))butyl)-1-methanesulfonyl-spiro ( indoline-3,4'-piperidine), (cr) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(1-naphthoyl)(methylamino))butyl)-1-acetyl-spiro(indoline-3, 4'-piperidine), (cs) 1'-(3((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)(methylamino))-4-phenyl-butyl)-1-methanesulfonyl - spiro(indoline-3,4'-piperidine), (ct) 1'-(4-N-(3,5-dimethylbenzoyl)(methylamino))-4-(phenyl)butyl)-1-acetyl-spiro(indoline-3,4'-piperidine), (cu) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(1-(2-phenylimidazolo))butyl)-1-methanesulfonyl-spiro(indoline-3,4'- piperidine), (cv) 1'-(3-((S)-(3,4-dichlorophenyl))-4-((N-(3,5-dimethylbenzoyl)(methylamino))-4-(methyl)butyl)-1 -acetyl-spiro (indoline-3,4'-piperidine), (cw) 1'-(3-((S)-(3,4-dichlorophenyl))-4-((N-(4-fluoro-1-naphthyl)(methylamino))-4-(methyl)butyl) -1-acetyl-spiro (indoline-3,4'-piperidine), (cx) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(R and S)-(N-(3,5-dimethylbenzoyl)(methylamino))hexyl)-1- acetyl-spiro (indoline-3,4'-piperidine), (cy) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(R and S)-(N-(3,5-dimethylbenzoyl)(methylamino))hexyl)-1- acetyl-5-fluoro-spiro(indoline-3,4'-piperidine), (cz) 1'-(3-((S)-(3,4-dichlorophenyl)-4-(R and S)-(N-(3,5-dimethylbenzoyl)(methylamino))heptyl)-1-acetyl -spiro (indoline-3,4'-piperidine), (da) 1'-(3-((S)-(3,4-dichlorophenyl)-4-(R and S)-(N-(3,5-dimethylbenzoyl)(methylamino))heptyl)-1-acetyl -5-fluoro-spiro(indoline-3,4'-piperidine), (db) 1'-(3-((S)-(3,4-dichlorophenyl))-4-(R and S)-hydroxy-5-(3,5-dimethylbenzoyl)pentyl)-1-methanesulfonyl-spiro (indoline-3,4'-piperidine), (dc) 1'-(3-(R)-(3,4-dichlorophenyl)-5-(N-(3,5-dimethylbenzoyl)(methylamino))-5-oxo-pentyl)-1-methanesulfonyl-spiro (indoline-3,4'-piperidine), (dd) 1'-(3-(R)-(3,4-dichlorophenyl))-5-(3,5-dimethylphenyl)-5-oxo-pentyl)-1-methanesulfonyl-spiro(indoline-3,4 '-piperidine), (de) 1'-(3-(R)-(3,4-dichlorophenyl)-6-(3,5-dimethylphenyl)-5-oxo-hexyl)methanesulfonyl-spiro(indoline-3,4'-piperidine) , (df) 1'-(3-(S)-(3,4-dichlorophenyl)-6-(3,5-dimethylphenyl)-6-oxo-hexyl)-1-methanesulfonyl-spiro(indoline-3,4' -piperidine), (dg) 1'-(3-(S)-(3,4-dichlorophenyl)-6-(3,5-dimethylphenyl)-5-(R and S)-methyl-6-oxo-hexyl)-1- methanesulfonyl-spiro (indoline-3,4'-piperidine), (dh) 1'-(3-(S)-(3,4-dichlorophenyl)-4-(3,5-(bistrifluoromethyl)benzyloxy)-1-acetyl-spiro(indoline-3,4'-piperidine),

16. Farmaceutska kompozicija za antagoniziranje efekta supstance P kod pacijenta kome je potreban takav tretman, naznačena time, što obuhvaća farmaceutski prihvatljiv nosač i ne-toksičnu terapeutski efikasnu količinu spojeva prema zahtjevu 1.16. A pharmaceutical composition for antagonizing the effect of substance P in a patient who needs such treatment, characterized in that it comprises a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of compounds according to claim 1.

17. Farmaceutska kompozicija za antagoniziranje efekta neurokinina A, kod pacijenta kome je potreban takav tretman, naznačena time, što obuhvaća farmaceutski prihvatljiv nosač i ne-toksičnu terapeutski efikasnu količinu spojeva prema zahtjevu 1.17. A pharmaceutical composition for antagonizing the effect of neurokinin A, in a patient in need of such treatment, characterized in that it comprises a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of compounds according to claim 1.

18. Postupak za antagoniziranje efekta supstance P kod pacijenta kome je potrebno takvo antagoniziranje, naznačen time, što obuhvaća primjenu na pacijentu ne-toksične terapeutski efikasne količine spojeva prema zahtjevu 1.18. A method for antagonizing the effect of substance P in a patient who needs such antagonism, indicated by the fact that it comprises the application to the patient of a non-toxic therapeutically effective amount of compounds according to claim 1.

19. Postupak za antagoniziranje efekta neurokinina A kod pacijenta kome je potrebno takvo antagoniziranje, naznačen time, što obuhvaća primjenu na pacijentu ne-toksične terapeutski efikasne količine spojeva prema zahtjevu 1.19. A method for antagonizing the effect of neurokinin A in a patient who needs such antagonism, characterized in that it comprises the application to the patient of a non-toxic therapeutically effective amount of compounds according to claim 1.

20. Postupak za tretiranje i prevenciju astme kod pacijenta kome je to potrebno, naznačen time, što obuhvaća primjenu na pacijenta ne-toksične terapeutski efikasne količine spojeva prema zahtjevu 1.20. A method for the treatment and prevention of asthma in a patient who needs it, characterized in that it comprises the application to the patient of a non-toxic therapeutically effective amount of compounds according to claim 1.

21. Postupak za dobivanje spoja formule I prema zahtjevima 1 do 14, [image] naznačen time, što obuhvaća stupnjeve: (a) reakciju spoja A [image] u pogodnom otapalu sa spojem formule R1-X1 gdje je X1 grupa koja se udaljava, opcijski u prisustvu pogodne baze kao što je trialkilamin; ili (b) reakcija spoja formule A u drugom pogodnom otapalu sa spojem formula R-CH(O), gdje je R-CH2=R1 kao što je definirano gore, u prisustvu redukcijskog sredstva; ili (c) reakciju spoja formule A u halogeno ugljikovodičnom otapalu sa spojem formule R-C(O)X2, gdje je X2 pogodna grupa koja se udaljava kao što je brom ili klor u prisustvu pogodne baze; pri čemu se dobiva spoj formule I.21. Process for obtaining the compound of formula I according to claims 1 to 14, [image] characterized by the fact that it includes degrees: (a) reaction of compound A [image] in a suitable solvent with a compound of the formula R 1 -X 1 where X 1 is a leaving group, optionally in the presence of a suitable base such as trialkylamine; or (b) reacting a compound of formula A in another suitable solvent with a compound of formula R-CH(O), where R-CH2=R1 as defined above, in the presence of a reducing agent; or (c) reacting a compound of formula A in a halohydrocarbon solvent with a compound of formula R-C(O)X 2 , wherein X 2 is a suitable leaving group such as bromine or chlorine in the presence of a suitable base; whereby the compound of formula I is obtained.