NO324953B1 - Nye forbindelser, farmasoytiske preparat inneholdende slike, fremgangsmate for deres fremstilling samt anvendelser av nevnte forbindelser - Google Patents
Nye forbindelser, farmasoytiske preparat inneholdende slike, fremgangsmate for deres fremstilling samt anvendelser av nevnte forbindelser Download PDFInfo
- Publication number
- NO324953B1 NO324953B1 NO20032892A NO20032892A NO324953B1 NO 324953 B1 NO324953 B1 NO 324953B1 NO 20032892 A NO20032892 A NO 20032892A NO 20032892 A NO20032892 A NO 20032892A NO 324953 B1 NO324953 B1 NO 324953B1
- Authority
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- Norway
- Prior art keywords
- chlorophenyl
- preparation
- formula
- phenyl
- compound
- Prior art date
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- NONOKGVFTBWRLD-UHFFFAOYSA-N isocyanatosulfanylimino(oxo)methane Chemical class O=C=NSN=C=O NONOKGVFTBWRLD-UHFFFAOYSA-N 0.000 description 1
- 238000005567 liquid scintillation counting Methods 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- BQPIGGFYSBELGY-UHFFFAOYSA-N mercury(2+) Chemical class [Hg+2] BQPIGGFYSBELGY-UHFFFAOYSA-N 0.000 description 1
- CYEBJEDOHLIWNP-UHFFFAOYSA-N methanethioamide Chemical class NC=S CYEBJEDOHLIWNP-UHFFFAOYSA-N 0.000 description 1
- SDDKIZNHOCEXTF-UHFFFAOYSA-N methyl carbamimidothioate Chemical compound CSC(N)=N SDDKIZNHOCEXTF-UHFFFAOYSA-N 0.000 description 1
- LOWNRGJMVVHOEY-UHFFFAOYSA-N n-(4-chlorophenyl)sulfonyl-4-phenyl-n'-propan-2-yl-5-pyridin-4-yl-3,4-dihydropyrazole-2-carboximidamide Chemical compound C1C(C=2C=CC=CC=2)C(C=2C=CN=CC=2)=NN1C(=NC(C)C)NS(=O)(=O)C1=CC=C(Cl)C=C1 LOWNRGJMVVHOEY-UHFFFAOYSA-N 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 208000027753 pain disease Diseases 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- UCQFSGCWHRTMGG-UHFFFAOYSA-N pyrazole-1-carboximidamide Chemical compound NC(=N)N1C=CC=N1 UCQFSGCWHRTMGG-UHFFFAOYSA-N 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- JZCPYUJPEARBJL-UHFFFAOYSA-N rimonabant Chemical group CC=1C(C(=O)NN2CCCCC2)=NN(C=2C(=CC(Cl)=CC=2)Cl)C=1C1=CC=C(Cl)C=C1 JZCPYUJPEARBJL-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- QFNFDHNZVTWZED-UHFFFAOYSA-N tert-butyl n-[[(2-methylpropan-2-yl)oxycarbonylamino]-pyrazol-1-ylmethylidene]carbamate Chemical compound CC(C)(C)OC(=O)NC(=NC(=O)OC(C)(C)C)N1C=CC=N1 QFNFDHNZVTWZED-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D231/08—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with oxygen or sulfur atoms directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Description
Den foreliggende oppfinnelsen vedrører en gruppe av nye enantiomerer av 4,5-dihydro-lH-pyrazolderivater med S-konfigurasjon på 4-posisjonen i deres 4,5-dihydropyrazolring, fremgangsmåte for fremstilling av disse forbindelser og farmasøytiske sammensetninger inneholdende en eller flere av disse forbindelser som en aktiv komponent. Videre vedrører oppfinnelsen anvendelsen av en forbindelse ifølge foreliggende oppfinnelse for fremstilling av et preparat for behandling av ulike tilstander.
De ovenfor nevnte (4S)-4,5-dihydro-lH-pyrazoler er kraftige Cannabis-1 (CBi) reseptorantagonister nyttige for behandling av psykiatriske og neurologiske forstyrrelser.
Cannabinoider er tilstede i den indiske hampen Cannabis Sativa L. og er blitt anvendt som medisinske midler i århundreder (Mechoulam, R.; Feigenbaum, J.J. Prog. Med. Chem. 1987,24,159). Imidlertid kun innenfor de siste tiårene har forskningen innenfor cannabinoid-området avslørt vesentlig informasjon om cannabinoid reseptorer og deres (endogene) agonister og antagonister. Oppdagelsen og den etterfølgende kloning av to forskjellige undertyper av Cannabinoid reseptorer (CBi og CB2) stimulerte søket etter nye cannabinoid-reseptorantagonister (Munro, S.; Thomas, K.L.; Abu-Shaar, M. Nature 1993, 365, 61. Matsuda, L.A.; Bonner, T.I. Cannabinoid Receptors, Pertwee, R.G. Ed. 1995,117, Academic Press, London). I tillegg ble farmasøytiske bedrifter interessert i utviklingen av cannabinoidmedikamenter for behandlingen av sykdommer forbundet med forstyrrelser i cannabinoidsystemet. Den brede fordelingen av CBi reseptorer i hjernen kombinert med den sterkt perifere lokalisering av CB2 reseptoren gjør CBi reseptoren til et meget interessant molekylært mål for CNS-rettet medikament oppdagelse innenfor områdene både psykiatriske og neurologiske forstyrrelser (Consroe, P. Neurobiology ofDisease 1998, 5, 534. Pop, E. Curr. Opin. In CPNS Investigational Drugs, 1999,1, 587. Greenberg, D.A. Drug News Perspect. 1999, 12, 458). Inntil nå kjennes tre distinkte typer av CB] reseptor-antagonister. Sanofi angir at deres diarylpyrazol passer som selektive CBi reseptorantagonister. Et representativt eksempel er SR-141716A, som i dag går gjennom fase II klinisk utvikling for psykotiske forstyrrelser (Dutta, A.K.; Sard, H.; Ryan, W.; Razdan, R.K., Compton, D.R.; Martin, B.R. Med. Chem. Res. 1994, 5, 54. Lan, R.; Liu, Q.; Fan, P.; Lin, S.; Fernando, S.R.; McCallion, D.; Pertwee, R.; Makriyannis, A. J. Med. Chem. 1999,42, 769. Nakamura-Palacios, E.M.; Moerschbaecher, J.M.; Barker, L.A. CNS Drug Rev. 1999, 5, 43). Aminoalkylindoler er blitt angitt som CBi reseptorantagonister. Et representativt eksempel er iodopravadolin (AM-630), som ble introdusert i 1195. AM-630 er en CBi reseptorantagonist, men oppfører seg noen ganger som en svak delvis agonist (Hosohata, K.; Quock, R.M.; Hosohata, Y.; Burkey, T.H.; Makriyannis, A.; Consroe, P.; Roeske, W.R.; Yamamura, H.I. Life Sc. 1997,61, PLI 15). Mer nylig har forskere fra Eli Lilly beskrevet aryl-aroyl substituerte benzofuraner som selektive CBi reseptorantagonister (for eksempel LY-320135) (Felder, CC; Joyce, K.E.; Briley, E.J.; Glass, M.; Mackie, K.P.; Fahey, K.J.; Cullinan, G.J.; Hunden, D.C; Johnson, D.W.; Chaney, M.O.; Koppel, G.A.; Brownstein, M. J. Pharmacol. Exp. Ther. 1998, 284, 291). Nylig ble 3-alkyl-5,5'-difenylimidazolidinioner beskrevet som cannabinoid reseptorligander som ble indikert å være cannabinoid antagonister (Kanyonyo, M.; Govaerts, S.J.; Hermans, E.; Poupaert, J.H., Lambert, D.M. Biorg. Med. Chem. Lett. 1999, 9, 2233). Interessant nok er mange CBi reseptorantagonister rapportert å oppføre seg som motsatte agonister in vitro (Landsman, R.S.; Burkey, T.H.; Consroe, P.; Roeske, W.R.; Yamamura, H.I. Eur. J. Pharmacol. 1997, 334, RI). Nylig gjennomganger gir et godt overblikk over den nåværende status innen cannabinoid forskningsområdet (Mechoulam, R.; Hanus, L.; Fride, E. Prog. Med. Chem. 1998, 35, 199. Lambert D.M. Curr. Med. Chem. 1999, 6, 635. Mechoulam, R.; Fride, E.; Di Marzo, V. Eur. J. Pharmacol. 1998, 359, 1).
Et første aspekt ved oppfinnelsen vedrører enantiomere med S-konfigurasjon på 4-posisjonen til dens 4,5-dihydropyrazolring av en forbindelse av formel (I),
hvor
- R og Ri er like eller forskjellige og representerer 3-pyridyl eller 4-pyridyl, eller fenyl som kan være substituert med halogen eller metoksy, - R2 og R3 er like eller forskjellige og representerer hydrogen, alkyl (1-3 C) eller dimetylamino, - Pm representerer fenyl som kan være substituert med 1,2 eller 3 substituenter valgt blant gruppen halogenatomer, trifluormetyl, metoksy og alkyl (1-3 C)
og tautomerer, og salter derav.
Forbindelsene ifølge det første aspekt ved oppfinnelsen er nå overraskende blitt funnet å være vesentlig mer potente og selektive antagonister av cannabis CBi-reseptoren enn de tilsvarende R-enantiomerene.
En utførelsesform ifølge oppfinnelsen vedrører forbindelsene ifølge det første aspekt ved oppfinnelsen hvor R gruppen er 4-klorfenyl, Ri er fenyl, R2 er hydrogen, R3 er metyl og R4 representerer 4-klorfenyl og salter derav.
På grunn av den potente CBi antagonistiske virkningen er forbindelsene ifølge oppfinnelsen egnet for bruk i behandling av psykiatriske forstyrrelser slik som psykose, angst, depressjon, oppmerksomhetsmangler, hukommelsesforstyrrelser og apetittforstyrrelser, fedme, neurologiske forstyrrelser slik som demens, distoni, Parkinson's sykdom, Alzheimers sykdom, epilepsi, Huntington's sykdom, Tourette's syndrom, cerebral ischaemia, så vel som behandlingen av smerteforstyrrelser og andre CNS-sykdommer som involverer cannabinoid neurotransmissjon og ved behandlingen av gastrointestinal forstyrrelser og kardiovaskulære forstyrrelser.
Virkningen av forbindelsene ifølge oppfinnelsen på cannabinoid CBi reseptorer ble bestemt anvendende membranpreparater av kinesisk hamster eggstokk (CHO) celler i hvilke den humane cannabis CBi reseptoren er stabil transferert i forbindelse med [3H]CP-55,940 som radioligand. Etter inkubasjon av et ferskt fremstilt cellemembran preparat med [3H]-liganden, med eller uten tilsetning av forbindelser ifølge oppfinnelsen, ble separasjon av bundet og fri ligand utført ved filtrering over glassfiberfiltrer. Radioaktiviteten på filteret ble målt ved væskescintillasjonstelling.
Den cananbinoide CBi antagonistiske virkningen av forbindelser ifølge oppfinnelsen ble bestemt ved funksjonelle studier anvendende CHO celler i hvilke human cannabinoid CBi reseptorer ble uttrykt stabilt. Adenylyl cyklase ble stimulert anvendende forskolin og målt ved kvantifisering av mengden av akkumulert syklisk AMP. Concomitant aktivering av CBi reseptorer ved CBi reseptorantagonister (for eksempel CP-55,940 eller (RR)-WIN-55,212-2) kan svekke den forskolin-induserte akkumulering av cAMP på en konsentrasjonsavhengig måte. Denne CBi reseptor-medierte respons kan antagoniseres med CBi reseptorantagonister slik som forbindelsene ifølge oppfinnelsen.
Oppfinnelsen vedrører både E-isomeren, Z-isomeren og E/Z-blandingene av forbindelsene av formel (I).
Et andre aspekt ved foreliggende oppfinnelse vedrører et farmasøytisk preparat som inneholder minst en forbindelse ifølge det første aspekt ved oppfinnelsen som en aktiv komponent.
Et tredje aspekt ved oppfinnelsen vedrører en fremgangsmåte for fremstilling av nevnte farmasøytiske preparat, kjennetegnet ved at en forbindelse ifølge det første aspekt ved oppfinnelsen bringes på en for administrering egnet form.
Et fjerde aspekt ved oppfinnelsen vedrører en fremgangsmåte for fremstilling av forbindelsene ifølge det første aspekt ved oppfinnelsen, kjennetegnet ved at den racemiske blandingen av en forbindelse av formel I adskilles i de levorotatoriske og dekstrorotatoriske enantiomerene.
Et femte aspekt ved oppfinnelsen vedrører anvendelse av en forbindelse ifølge det første aspekt ved oppfinnelsen for fremstillingen av et preparat til behandling av psykiatriske forstyrrelser slik som psykose, angst, depressjon, oppmerksomhetsmangler, hukommelsesforstyrrelser og apetittforstyrrelser, fedme, neurologiske forstyrrelser slik som Parkinson's sykdom, demens, distoni, Alzheimers sykdom, epilepsi, Huntington's sykdom, Tourette's syndrom, ischaemia, smerte, andre CNS-forstyrrelser som involverer cannabinoid neurotransmissjon, gastrointestinal forstyrrelser involverende cannabinoid neurotransmissjon og kardiovaskulære forstyrrelser involverende cannabinoid neurotransmissjon.
Forbindelsene ifølge oppfinnelsen av formelen (III) (vide infra) kan oppnås ifølge fremgangsmåtene kjent for eksempel fra: a) EP 0021506; b) DE 2529689.
En passende syntese for de racemiske forbindelsene ifølge den foreliggende oppfinnelsen er den følgende:
S<y>ntesevei A
Trinn 1 i vei A
Reaksjon av en forbindelse av formel (III)
med en forbindelse av formel (IV) hvor R5 representerer en lavere alkylgruppe slik som for eksempel 2-metyl-2-tiopseudourea eller med en egnet saltform derav i nærvær av en base. Denne reaksjon gir et 4,5-dihydro-lH-pyrazol-l-karboksamidderivat av formel (V)
hvor symbolene har betydningen som nevnt over. Forbindelser av formel (V) hvor R, Ri, R2 og R3 har betydningene som beskrevet heri ovenfor for forbindelse (I) er nye.
Alternativt reageres en forbindelse av formel (III) med et såkalt guanyleringsmiddel. Eksempler på slike guanyleringsmidler er lH-pyrazol-l-karboksamidin og dets salter
(for eksempel hydrokloirdsaltet) og 3,5-dimetyl-lH-pyrazol-l-karboksamidin og dets salter (for eksempel nitratsaltet) og lignende. Denne reaksjonen gir et karboksamidin-derivat av formel (V).
Alternativt reageres en forbindelse av formel (III) med et såkalt beskyttet guanyleringsmiddel. Eksempler på slike beskyttede guanyleringsmidler er N-(benzyloksykarbonyl)-1 H-pyrazol-1 -karboksamidin og N,N'-bis(tert-butoksykarbonyl)-lH-pyrazol-l-karboksamidin og lignende. Denne reaksjonen gir etter avbeskyttelse en forbindelse av formel (V).
Trinn 2 i vei A
Forbindelsen av formel (V) reageres med en eventuelt substituert forbindelse av formel R4-SO2X, hvor R4 har den ovenfor nevnte betydning og X representerer et halogenatom. Denne reaksjon utføres fortrinnsvis i nærvær av en base slik som trietylamin i et aprotisk løsemiddel slik som acetonitril.
Syntesevei Al
Trinn 1 i vei Al
Reaksjon av en forbindelse av formel (III)
med et tioisocyanatderivat av formel (VI).
Denne reaksjonen utføres fortrinnsvis i et inert organisk løsemiddel slik som acetonitril.
Denne reaksjon gir et tiokarboksamidderivat av formel (VII). Forbindelser av formel (VII) hvor R, Ri og R4 har betydninger som beskrevet heri ovenfor for forbindelse (I) er nye.
Trinn 2 i vei Al
Reaksjon av en forbindelse av formel (VII) med et amin i nærvær av et kvikksølv (II) salt slik som for eksempel HgCk gir en forbindelse av formel (I). Denne reaksjon utføres fortrinnsvis i et polært organisk løsemiddel slik som for eksempel acetonitril.
Svntesevei A2
i Trinn 1 i vei A2
Reaksjon av en forbindelse av formel III
med et karbamatesterderivat av formel (VIII).
)
hvor R.6 representerer en lavere alkylgruppe for eksempel metyl.
Denne reaksjon utføres fortrinnsvis i et inert organisk løsemiddel slik som for eksempel 1,4-dioksan.
Denne reaksjon gir et 4,5-dihydropyrazol-l-karboksamidderivat med formel (IX). Forbindelser av formel (IX) hvor R, R] og R4 har betydninger som beskrevet heri ovenfor for forbindelse (I) er nye.
Trinn 2 i vei A2
Reaksjon av en forbindelse av formel (IX) med et halogeneirngsmiddel slik som for eksempel PCI5 gir et 4,5-dihydropyrazol-l-karboksimidoylhalogenidderivat av formel
(X)
hvor R7 representerer et halogenatom slik som for eksempel klor. Denne reaksjon utføres fortrinnsvis i et inert organisk løsemiddel slik som for eksempel klorbenzen.
Forbindelser av formel (X) hvor R, Ri og R4 har betydningen som beskrevet heri ovenfor for forbindelse (I) og hvor R7 representerer et halogenatom er nye.
Trinn 3 i vei A2
Reaksjon av en forbindelse av formel (X) med et amin gir en forbindelse av formel (I). Denne reaksjon utføres fortrinnsvis i et inert organisk løsemiddel slik som for eksempel diklormetan.
Svntesevei A3
Trinn 1 i vei A3
Reaksjon av en forbindelse av formel III
med et ditioimidokarbonesterderivat av formel (XI)
hvor Rg representerer en Ci-3-alkylgruppe.
Denne reaksjon utføres fortrinnsvis i et polært organisk løsemiddel slik som for eksempel acetonitril.
Denne reaksjon gir et karboksimidotioesterderivat av formel (XII).
Forbindelser av formel (XII) hvor R, Ri og R4 har betydninger som beskrevet heri ovenfor for forbindelse (I) og hvor R% representerer en Ci-3-alkylgruppe er nye.
Trinn 2 i vei A3
Reaksjon av en forbindelse av formel (XII) med et amin gir en forbindelse av formel (I).
Denne reaksjon utføres fortrinnsvis i et polært organisk løsemiddel slik som for eksempel metanol.
Eksempel 1
3-(4-klorfenyl)-4,5-dihydro-N-((4-fluorfenyl)sulfonyl)-4-fenyl-lH-pyrazol-l-karboksamidin
Del A: En omrørt blanding av 3-(4-klorfenyl)-4,5-dihydro-4-fenyl-lH-pyrazol (5,13 g, 20,0 mmol), 2-metyl-2-tiopseudoureahydrojodid (5,00 g, 23,0 mmol) og pyridin (10 ml) oppvarmes til 110°C i 1 time. Etter å ha stått en natt ved romtemperatur tilsettes dietyleter og precipitatet oppsamles ved filtrering. Dette precipitat vaskes tre ganger med dietyleterporsjoner for å tilveiebringe et faststoff (9 g). Smeltepunkt: ~230°C. Dette faste stoffet oppløses i metanol (20 ml). Til den resulterende oppløsningen tilsettes i rekkefølge en 2N natriumhydroksidoppløsning (12 ml) og vann (200 ml). Det dannede precipitat oppsamles ved filtrering, vaskes to ganger med dietyleter og suksessivt med diisopropyleter. Det resulterende faste stoffet tørkes i vakuum for å oppnå 3-(4-klorfenyl)-4,5-dihydro-4-fenyl-lH-pyrazol-l-karboksamidin (5,1 g, 88% utbytte. Smeltepunkt: 187-189°C.
Del B: Til en omrørt blanding av 3-(4-klorfenyl)-4,5-dihydro-4-fenyl-lH-pyrazol (0,50 g, 1,68 mmol) og 4-fluorfenylsulfonylklorid (0,34 g, 1,75 mmol) i acetonitril (10 ml) tilsettes N,N-dimetyl-4-aminopyridin (0,020 g, 0,175 mmol) og trietylamin (1 ml). Den resulterende oppløsningen omrøres ved romtemperatur i 30 min. Etter tilsetning av en 2N natriumhydroksidoppløsning og ekstraksjon med etylacetat (400 ml), konsentreres etylacetatsjiktet i vakuum. Den resulterende rå resten renses ytterligere ved hjelp av flashkromatografi (petroleumeter/dietyleter = l/l(volum/volum), etterfulgt av etylacetat). Etterfølgende konsentrasjon i vakuum tilveiebringer fast 3-(4-klorfenyl)-4,5-dihydro-N-((4-fluorfenyl)sulfonyl)-4-fenyl-lH-pyrazol-l-karboksamidin (0,55 g, 72% utbytte. Smeltepunkt: 214-215°C.
På en analog måte er forbindelsene av formel (I) anført nedenfor blitt fremstilt: 4,5-dihydro-N-((4-fluorfenyl)sulfonyl)-3-(4-metoksyfenyl)-4-(4-metoksyfenyl-lH-pyrazol-l-karboksamidin: Smeltepunkt: 155-156°C.
4,5-dihydro-3-(4-metoksyfenyl)-4-(4-metoksyfenyl)-N-((4-metoksyfenyl)sulfonyl-lH-pyrazol-l-karboksamidin: Smeltepunkt: 148-150°C.
3-(4-klorfenyl)-4,5-dihydro-4-fenyl-N-((2,4,6-trimetylfenyl)sulfonyl)-lH-pyrazol-l-karboksamidin: Smeltepunkt: 221-222°C.
Eksempel II
N<1>,N<l->dimetyl-N<2->((4-klorfenyl)sulfonyl)-3-(4-klorfenyl)-4,5-dihydro-4-fenyl-lH-pyrazol-l-karboksamidin
Del A: En omrørt blanding av 3-(4-klorfenyl)-4,5-dihydro-4-fenyl-lH-pyrazol (12,0 g, 46,8 mmol), [(4-klorfenylsulfonyl]ditioimidakarbonsyredimetylester (CAS: 13068-12-7) (9,20 g, 31,1 mmol) og trietylamin (15 ml) i acetonitril (200 ml) oppvarmes ved tilbakeløpstemperatur i 20 timer. En ytterligere porsjon 3-(4-klorfenyl)-4,5-dihydro-4-fenyl-lH-pyrazol (12,0 g, 46,8 mmol) tilsettes og den resulterende blandingen oppvarmes til tilbakeløpstemperatur i ytterligere 16 timer. Etter konsentrasjon i vakuum tilsettes diklormetan og den resulterende oppløsningen vaskes to ganger med vann og tørkes over vannfritt Na2SC<4. Etter filtrering og inndamping i vakuum renses resten ytterligere ved flashkromatografi (dietyleter/petroleumeter = 1/1 (volum/volum) for å oppnå 3-(4-klorfenyl)-N-((4-klorfenyl)sulfonyl)-4,5-dihydro-4-fenyl-1 H-pyrazol-1 - karboksimidosvovelsyremetylester (12,5 g, 80% utbytte basert på [(4-klorfenyl)sulfonyl]ditioimidokarbonsyredimetylester) som et amorf faststoff.
Del B: Til en omrørt blanding av 3-(4-klorfenyl)-N-((4-klorfenyl)sulfonyl-4,5-dihydro-4-fenyl-lH-pyrazol-1-karboksimidosvovelsyremetylester (4,20 g, 8,30 mmol) i metanol (75 ml) tilsettes dimetylamin (10 ml) og diklormetan (75 ml) og den resulterende oppløsningen omrøres ved romtemperatur i 6 timer. Fordampning i vakuum og etterfølgende flashkromatografisk rensing (dietyleter/petroleumeter = 1/1 (volum/volum), etterfulgt av dietyleter) gir et faststoff som renses ytterligere ved rekrystallisasjon fra diisopropyleter for å oppnå N -dimetyl-N -((4-klor-fenyl)sulfonyl)-3-(4-klorfenyl)-4,5-dihydro-4-fenyl-lH-pyrazol-1-karboksamidin (2,63 g, 63% utbytte). Smeltepunkt: 182°C.
På en analog måte er forbindelsene av formel (I) anført nedenfor blitt fremstilt: N-metyl-N'-((4-klorfenyl)sulfonyl)-3-(4-klorfenyl)-4,5-dihydro-4-(3-pyridyl)-lH-pyrazol-1-karboksamidin. Smeltepunkt: 101-105°C. N-metyl-N'-((4-klorfenyl)sulfonyl)-3-(4-klorfenyl)-4,5-dihydro-4-(4-pyridyl)-lH-pyrazol-1-karboksamidin. Smeltepunkt: 112-115°C.
Eksempel III
. N-metyl-N'-((4-klorfenyl)sulfonyl)-3-(4-klorfenyl)-4,5-dihydro-4-fenyl-lH-pyrazol-1-karboksamidin
Del A: Til en oppløsning av N-((4-klorfenyl)sulfonyl)karbaminsyremetylester (CAS: 34543-04-9) (2,99 g, 12,0 mmol) og pyridin (4 ml) i 1,4-dioksan (20 ml) tilsettes 3-(4-klorfenyl)-4,5-dihydro-4-fenyl-lH-pyrazol (3,39 g, 13,2 mmol) og den resulterende blandingen omrøres i 4 timer ved 100°C. Etter konsentrasjon i vakuum oppløses resten i diklormetan, og vaskes suksessivt med vann, IN HC1 og vann, tørkes over vannfritt Na2S04, filtreres og konsentreres i vakuum til et volum på 20 ml. Metyl-tert-butyleter (60 ml) tilsettes og den resulterende oppløsningen konsentreres til et volum på 20 ml. De dannede krystaller oppsamles ved filtrering og rekrystallisasjon fra metyl-tert-butyleter for å oppnå 3-(4-klorfenyl)-N-((4-klorfenyl)sulfonyl)-4,5-dihydro-4-fenyl-lH-pyrazol-l-karboksamid (4,75 g, 76% utbytte). Smeltepunkt: 211-214°C.
Del B: En blanding av 3-(4-klorfenyl)-N-((4-klorfenyl)sulfonyl-4,5-dihydro-4-fenyl-lH-pyrazol-l-karboksamid (3,67 g, 7,75 mmol) og fosforpentaklorid (1,69 g, 8,14 mmol) i klorbenzen (40 ml) oppvarmes i tilbakeløp i 1 time. Etter grundig konsentrering i vakuum suspenderes det dannede N-((4-klorfenyl)sulfonyl)-3-(4-klorfenyl)-4,5-dihydro-4-fenyl-lH-pyrazol-l-karboksimidoylklorid i diklormetan og reageres med kald metylamin (1,5 ml). Etter omrøring i romtemperatur i 1 time konsentreres blandingen i vakuum. Resten krystalliseres fra dietyleter for å oppnåN-metyl-N'-((4-klorfenyl)sulfonyl)-3-(4-klorfenyl)-4,5-dihydro-4-fenyl-lH-pyrazol-l-karboksamidin (22,9 g, 61% utbytte). Smeltepunkt: 96-98°C (nedbrytning).
På en analog måte ble forbindelsene av formel (I) anført nedenfor fremstilt: N-metyl-N'-((3-klorfenyl)sulfonyl)-3-(4-klorfenyl)-4,5-dihydro-4-fenyl-lH-pyrazol-l-karboksamidin. Smeltepunkt: 156-160°C.
i N-propyl-N'-((4-klorfenyl)sulfonyl)-3-(4-klorfenyl)-4,5-dihydro-4-fenyl-lH-pyrazol-l-karboksamidin. Smeltepunkt: 129-138°C.
N-(2-propyl)-N'-((4-klorfenyl)sulfonyl)-3-(4-klorfenyl)-4,5-dihydro-4-fenyl-lH-pyrazol-1-karboksamidin. Smeltepunkt: 110-112°C.
N-(2-propyl)-N'-((4-klorfenyl)sulfonyl)-3-(4-pyridyl)-4,5-dihydro-4-fenyl-lH-pyrazol-i 1-karboksamidin. Smeltepunkt: Amorf.
N<1->etyl-N<1->metyl-N<2->((4-klorfenyl)sulfonyl)-3-(4-klorfenyl)-4,5-dihydro-4-fenyl-lH-pyrazol-l-karboksamidin. Smeltepunkt: 184°C. N1-etyl-N1-metyl-N2-((4-kto pyrazol-1-karboksamidin. Smeltepunkt: 173-176°C.
N1,N1-dimetyl-N2-((4-trifluormetyl)sulfonyl)-3-(4-klorfenyl)-4,5-dihydro-4-fenyl-lH-pyrazol-1-karboksamidin. Smeltepunkt: 195-196°C.
; N<1>,N<1->dimetyl-N<2->((3-metylfenyl)sulfonyl)-3-(4-klorfenyl)-4,5-dihydro-4-fenyl-lH-pyrazol-1-karboksamidin. Smeltepunkt: 195-198°C.
N<1>,N<1->dimetyl-N<2->((3-metoksyfentyl)sulfonyl)-3-(4-klorfenyl)-4,5-dihydro-4-fenyl-lH-pyrazol-1-karboksamidin. Smeltepunkt: 204-206°C.
N-etyl-N'-((4-klorfenyl)sulfonyl)-3-(4-klorfenyl)-4,5-dihydro-4-fenyl-lH-pyrazol-l-i karboksamidin. Smeltepunkt: Amorf.
N-dimetylamino-N'-((4-klorfenyl)sulfonyl)-3-(4-klorfenyl)-4,5-dihydro-4-fenyl-lH-pyrazol-1-karboksamidin. Smeltepunkt: 155-159°C.
N-metyl-N'-((4-trifluormetyl)fenyl)sulfonyl)-3-(4-klorfenyl)-4,5-dihydro-4-fenyl-lH-pyrazol-1-karboksamidin. Smeltepunkt: Amorf,
i N1 .N1 -dimetyl-N2-((2-metylfentyl)sulfonyl)-3-(4-klorfenyl)-4,5-dihydro-4-fenyl-lH-pyrazol-1-karboksamidin. Smeltepunkt: 148-151°C.
N-metyl-N'-((2,4-difluorfenyl)sulfonyl)-3-(4-klorfenyl)-4,5-dihydro-4-fenyl-lH-pyrazol-1-karboksamidin. Smeltepunkt: 85°C.
Eksempel IV (.).(4S)-N-metyl-N'-((4-klorfeny])sulfonyl)-3-(4-klorfenyl)-4,5-dihydro-4-fenyl-lH-pyrazol-l-karboksamidin (-)-(4S)-N-metyl-N'-((4-klorfenyl)sulfonyl)-3-(4-klorfenyl)-4,5-dihydro-4-fenyl-lH-5 pyrazol-1-karboksamidin (7,16 g, 0,0147 mol) ([a<25>D] = 150°, C = 0,01, MeOH) (smeltepunkt: 169-170°C) ble oppnådd via kiral kromatografisk separasjon av racemisk N-metyl-N'-((4-klorfenyl)sulfonyl)-3-(4-klorfenyl)-4,5-dihydro-4-fenyl-1 H-pyrazol-1 - karboksamidin (18 g, 0,037 mol) anvendende en Chiralpak AD, 20 um kiral stasjonær
fase. Den mobile fasen besto av en blanding av heksan/etanol (80/20 (volum/volum)) og ) 0,1% ammoniumhydroksid (25% vandig oppløsning).
På en analog måte ble de optisk rene forbindelsene anført nedenfor fremstilt fra de tilsvarende racematene: (-)-(4S)-N-etyl-N'-((4-klorfenyl)sulfonyl)-3-(4-klorfenyl)-4,5-dihydro-4-fenyl-lH-pyrazol-1-karboksamidin ([a<2S>D] = -126°, c = 0,01, CHC13); Smeltepunkt: 172-175°C). Stasjonær fase: Chiracel OD. Mobil fase: En blanding av heptan/2-propanol (85/15 (volum/volum)). (-)-(4S)-N-dimetylamino-N'-((4-klorfenyl)sulfonyl)-3-(4-klorfenyl)-4,5-dihydro-4-fenyl-lH-pyrazol-l-karboksamidin ([a<25>D] = -132°, c = 0,01, CHCI3); Smeltepunkt: 218-224°C). Stasjonær fase: Chiracel OD. Mobil fase: En blanding av heptan/2-propanol (85/15 (volum/volum)). (-)-(4S)-N-metyl-N'-((4-klorfenyl)sulfonyl)-3-(4-klorfenyl)-4,5-dihydro-4-fenyl-lH-pyrazol-1-karboksamidin ([oc<25>D] = -131°, c = 0,01, CHC13); Smeltepunkt: 157-160°C). Stasjonær fase: Chiracel OD. Mobil fase: En blanding av heptan/2-propanol (85/15 (volum/volum)). (-)-(4S)-N,,N'-dimetyl-N<2->((2-metylfenyl)sulfonyl)-3-(4-klorfenyl)-4,5-dihydro-4-fenyl-lH-pyrazol-l-karboksamidin ([a<25>D] = -88°, c = 0,01, MeOH); Smeltepunkt: Amorf. Stasjonær fase: Chiracel AD. Mobil fase: Etanol. (-)-(4S)-N-metyl-N'-((2,4-difluorfenyl)sulfonyl)-3-(4-klorfenyl)-4,5-dihydro-4-fenyl-lH-pyrazol-l-karboksamidin ([a<25>D] = -129°, c = 0,01, MeOH); Smeltepunkt: Amorf. Stasjonær fase: Chiracel AD. Mobil fase: Metanol.
Claims (8)
1.
Enantiomer med S-konfigurasjon på 4-posisjonen til dens 4,5-dihydropyrazolring av en forbindelse av formel (I),
hvor - R og R] er like eller forskjellige og representerer 3-pyridyl eller 4-pyridyl, eller fenyl som kan være substituert med halogen eller metoksy, - R2 og R3 er like eller forskjellige og representerer hydrogen, alkyl (1-3 C) eller dimetylamino, - R4 representerer fenyl som kan være substituert med 1, 2 eller 3 substituenter
valgt blant gruppen halogenatomer, trifluormetyl, metoksy og alkyl (1-3 C) og tautomerer, og salter derav.
2.
Forbindelse av formel (I) ifølge krav 1, karakterisert ved at R er gruppen 4-klorfenyl, R\ er fenyl, R2 er hydrogen, R3 er metyl og R4 representerer 4-klorfenyl og salter derav.
3.
Farmasøytisk preparat inneholdende minst en forbindelse ifølge krav 1 som en aktiv komponent.
4.
Fremgangsmåte for fremstilling av farmasøytiske preparater, karakterisert ved at en forbindelse ifølge krav 1 bringes på en for administrering egnet form.
5.
Fremgangsmåte for fremstilling av forbindelser av formel I, karakterisert ved at den racemiske blandingen av en forbindelse av formel I adskilles i de levorotatoriske og dekstrorotatoriske enantiomerene.
6.
Anvendelse av en forbindelse ifølge krav 1 for fremstillingen av et preparat til behandling av psykiatriske forstyrrelser slik som psykose, angst, depressjon, oppmerksomhetsmangler, hukommelsesforstyrrelser og apetittforstyrrelser, fedme, neurologiske forstyrrelser slik som Parkinson's sykdom, demens, distoni, Alzheimers sykdom, epilepsi, Huntington's sykdom, Tourette's syndrom, ischaemia, smerte og andre CNS-forstyrrelser som involverer cannabinoid neurotransmissjon.
7.
Anvendelse av en forbindelse ifølge krav 1 for fremstilling av et preparat for behandling av gastrointestinal forstyrrelser involverende cannabinoid neurotransmissjon.
8.
Anvendelse av en forbindelse ifølge krav 1 for fremstilling av et preparat for behandling av kardiovaskulære forstyrrelser involverende cannabinoid neurotransmissjon.
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| NL158178B (nl) * | 1974-07-12 | 1978-10-16 | Philips Nv | Werkwijze ter bereiding van insekticide preparaten die een pyrazolinederivaat bevatten, aldus verkregen gevormde preparaten, en werkwijze ter bereiding van pyrazolinederivaten met insekticide werking. |
| DE3431926A1 (de) * | 1984-08-30 | 1986-03-06 | Bayer Ag, 5090 Leverkusen | Amidinoazole |
| FR2692575B1 (fr) | 1992-06-23 | 1995-06-30 | Sanofi Elf | Nouveaux derives du pyrazole, procede pour leur preparation et compositions pharmaceutiques les contenant. |
| MXPA02009258A (es) * | 2000-03-23 | 2005-04-19 | Solvay Pharm Bv | Derivados de 4,5-dihidro-1h-pirazol que tienen actividad antagonistica de cannabis-1. |
| PE20021046A1 (es) * | 2000-09-30 | 2002-12-14 | Gruenenthal Chemie | Sulfonilguanidina que tiene afinidad al punto de fijacion de gabapentina |
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