DK2477983T3 - (4-phenyl-piperidin-1-yl)-[5-1h-pyrazol-4yl)-thiophen-3-yl]-methanonforbindelser og deres anvendelse - Google Patents

(4-phenyl-piperidin-1-yl)-[5-1h-pyrazol-4yl)-thiophen-3-yl]-methanonforbindelser og deres anvendelse Download PDF

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DK2477983T3
DK2477983T3 DK10755215.0T DK10755215T DK2477983T3 DK 2477983 T3 DK2477983 T3 DK 2477983T3 DK 10755215 T DK10755215 T DK 10755215T DK 2477983 T3 DK2477983 T3 DK 2477983T3
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Scott Peter Webster
Jonathan Robert Seckl
Brian Robert Walker
Peter Ward
Thomas David Pallin
Hazel Joan Dyke
Trevor Robert Perrior
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Univ Edinburgh
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Claims (25)

1. Forbindelse udvalgt fra forbindelser med følgende formel og farmaceutisk acceptable salte, hydrater og solvater deraf:
hvor: - W uafhængigt er -Y; - Y uafhængigt er -Y1, -Y2, -Y3, -Y4 eller -Y5; - Y1 uafhængigt er -OH; - Y2 uafhængigt er Y2A, - -Y2B eller -Y2c; - Y3 uafhængigt er -Y3A, -Y3B eller -Y3C; - Y4 uafhængigt er -F, -Cl, -Br eller -I; - Y5 uafhængigt er -CN; hvor: - Y2A uafhængigt er -ORYA; - Y2B uafhængigt er -ORYB; - Y2C uafhængigt er -ORYC; - Y3A uafhængigt er -RYA; - Y3B uafhængigt er -RYB; - Y3C uafhængigt er -RYC; hvor: hvert -Rya uafhængigt er mættet alifatisk Ci_6alkyl; hvert -Ryb uafhængigt er mættet alifatisk halogen-Ci_6alkyl; hvert -RYC uafhængigt er mættet alifatisk hydroxy-Ci_6alkyl; og hvor: hvert af-J1, -J2, -J3 og -J4 er-H; eller hvert af -J2 og -J4 er -H; og -J1 og -J3 sammen danner -CH2- eller -CH2CH2-; eller hvert af -J1 og -J3 er -H; og -J2 og -J4 sammen danner -CH2- eller -CH2CH2-; eller hvert af -J2 og -J3 er -H; og -J1 og -J4 sammen danner -CH2- eller - CH2CH2-; og hvor: - Rn uafhængigt er -H eller -RNN; - Rnn uafhængigt er mættet alifatisk Ci_6alkyl; og hvor: - RB1 uafhængigt er -H eller -RBB; - RB2 uafhængigt er -H eller -RBB; hvor: hvert -Rbb uafhængigt er -RBB1, -RBB2 eller -RBB3; hvor: hvert -RBB1 uafhængigt er mættet alifatisk Ci_6alkyl og eventuelt er substitueret med en eller flere substituenter udvalgt fra -F, -OH, -ORBBB, -OCH2F, -OCHF2, -OCF3, -NH2, -NHRbbb og -NRbbb2; hvor hvert -RBBB uafhængigt er mættet alifatisk Ci_4alkyl; hvert -RBB2 uafhængigt er -F, -Cl, -Br eller -I; hvert-RBB3 uafhængigt er -CN; og hvor: n uafhængigt er 0, 1,2, 3, 4 eller 5; hvert -Rf uafhængigt er -Rz, -F, -Cl, -Br, -I, -CF3, -OH, -ORz, -OCF3, -SRZ, -S(=0)2Rz eller -CN; og hvert -Rz uafhængigt er mættet alifatisk Ci_6alkyl og eventuelt er substitueret med en eller flere substituenter udvalgt fra -F, -Cl, -OH, -ORzz, -OCH2F, -OCHF2 og -OCF3; hvor hvert -Rzz uafhængigt er mættet alifatisk Ci-4alkyl.
2. Forbindelse ifølge krav 1, hvor -Y uafhængigt er -Y1.
3. Forbindelse ifølge krav 1, hvor -Y uafhængigt er -Y2.
4. Forbindelse ifølge krav 1, hvor -Y uafhængigt er -Y3.
5. Forbindelse ifølge krav 1, hvor -Y uafhængigt er -Y4.
6. Forbindelse ifølge krav 1, hvor -Y uafhængigt er -Y5.
7. Forbindelse ifølge et af kravene 1 til 6, hvor -Y2, hvis til stede, uafhængigt er -Y2A
8. Forbindelse ifølge et af kravene 1 til 7, hvor -Y3, hvis til stede, uafhængigt er -Y3A
9. Forbindelse ifølge et af kravene 1 til 8, hvor -Y3, hvis til stede, uafhængigt er -Y3c.
10. Forbindelse ifølge et af kravene 1 til 9, hvor -Y4, hvis til stede, uafhængigt er-F.
11. Forbindelse ifølge et af kravene 1 til 10, hvor hvert -RYA, hvis til stede, uafhængigt er -Me.
12. Forbindelse ifølge et af kravene 1 til 11, hvor hvert -RYC, hvis til stede, uafhængigt er -CFI2OFI.
13. Forbindelse ifølge et af kravene 1 til 12, hvor hvert af-J1, -J2, -J3 og -J4 er -H.
14. Forbindelse ifølge et af kravene 1 til 12, hvor hvert af -J2 og -J4 er -H; og -J1 og -J3 sammen danner -CFI2CFI2-.
15. Forbindelse ifølge et af kravene 1 til 12, hvor hvert af-J1 og -J3 er -H; og -J2 og -J4 sammen danner -CFI2CFI2-.
16. Forbindelse ifølge et af kravene 1 til 15, hvor -RN uafhængigt er -H.
17. Forbindelse ifølge et af kravene 1 til 16, hvor: - RB1 uafhængigt er -H; og - RB2 uafhængigt er -H.
18. Forbindelse ifølge et af kravene 1 til 17, hvor n uafhængigt er 0, 1,2 eller 3.
19. Forbindelse ifølge et af kravene 1 til 18, hvor hvert -RF, hvis til stede, uafhængigt er -F, -Cl, -Me, -Et, -OFI, -OMe, -OEt, -CF3, -OCF3 eller -CN.
20. Forbindelse ifølge krav 1 udvalgt fra forbindelser med følgende formler og farmaceutiskacceptable salte, hydrater og solvater deraf:
(AA-01),
(AA-02),
(AA-03),
(AA-04),
(AA-05),
(AA-06),
(AA-07),
(AA-08),
(AA-09),
(AA-10),
(AA-11),
(AA-12),
(AA-13),
(AA-14),
(AA-15),
(AA-16),
(AA-17),
(AA-18),
(AA-19),
(AA-20),
(AA-21),
(AA-22),
(AA-23),
(AA-24),
(AA-25),
(AA-26),
(AA-27),
(AA-28),
(AA-29),
(AA-30),
(AA-31),
(AA-32),
(AA-33),
(AA-34),
(AA-35),
(AA-36),
(AA-37),
(AA-38),
(AA-39),
(AA-40), and
(AA-41).
21. Farmaceutisk sammensætning omfattende en forbindelse ifølge et af kravene 1 til 20 og en farmaceutisk acceptabel bærer eller et fortyndingsmiddel.
22. Fremgangsmåde til inhibering af 11 β-hydroxysteroiddehydrogenase type 1 funktion i en celle, in vitro, hvilken fremgangsmåde omfatter det at bringe cellen i kontakt med en virksom mængde af en forbindelse ifølge et af kravene 1 til 20.
23. Forbindelse ifølge et af kravene 1 til 20 til anvendelse ved behandling af menneske- eller dyrekroppen ved terapi.
24. Forbindelse ifølge et af kravene 1 til 20 til anvendelse ved behandling eller forebyggelse af: en lidelse i menneske- eller dyrekroppen, som bedres ved inhibering af 11 β-hydroxysteroiddehydrogenase type 1 ved terapi; eller: (1) Cushings syndrom; (2) type 2 diabetes og nedsat glukosetolerance; (3) insulinmodstandssyndromer såsom myotonisk dystrofi, Prader Willi, lipo-dystrofier, polycystisk ovariesyndrom, gastrointestinal diabetes, osv.; (4) obesitet og overvægt; (5) lipidlidelser, herunder dyslipidæmi; (6) aterosklerose og dens følgesygdomme, herunder myokardieinfarkt og perifer vaskulær sygdom; (7) metabolisk syndrom; (8) steatohepatitis/fedtlever og ikke-alkoholisk fedtleversygdom; (9) kognitiv svækkelse i diabetes type 2, glukoseintolerance og ældning og ved psykotiske lidelser og præ-skizofreni; (10) demens såsom Alzheimers sygdom, multi-infarkt-demens, demens med Lewylegemer, frontotemporal demens (herunder Picks sygdom), progressiv supranukleær lammelse, Korsakoffs syndrom, Binswangers sygdom, HIV-associeret demens, Creutzfeldt-Jakob-sygdom (CJD), multipel sklerose, mo-torneuronsygdom, Parkinsons sygdom, Huntingtons sygdom, Niemann-Pick-sygdom type C, normaltrykshydrocephalus og Downs syndrom; (11) let kognitiv svækkelse (kognitiv svækkelse uden demens); (12) β-celle-dysfunktion ved pancreaslidelse; (13) glaukom; (14) angst; (15) depression og andre affektive lidelser; typisk (melankolsk) og atypisk depression; dystymi; efterfødselsdepression; bipolær affektiv lidelse; medicininducerede affektive lidelser; angst; posttraumatisk stresslidelse; panik; fobier; (16) delirium og akut sindsforvirring; (17) inflammatorisk sygdom; (18) osteoporose; (19) myokardieinfarkt, f.eks. til forebyggelse af venstre ventrikulær dysfunktion efter myokardieinfarkt; eller (20) slagtilfælde, f.eks. til begrænsning af iskæmisk neurontab efter kardio- vaskulær ulykke; eller: (1) hypercalcæmi; (2) glukoseintolerance og nedsat glukosetolerance; (3) insulinmodstand; (4) hyperlipidæmi; (5) hypertriglyceridæmi; (6) hyperkolesterolæmi; (7) lave HDL-niveauer; (8) høje LDL-niveauer; (9) vaskulær restenose; (10) abdominal obesitet; (11) neurodegenerativ sygdom; (12) retinopati; (13) neuropati; (14) blodtryksforhøjelse; eller (15) andre sygdomme, hvor insulinmodstand er en komponent; eller: en bivirkning af glukocorticoider, der anvendes til behandling af inflammatoriske sygdomme såsom astma, kronisk obstruktiv lungesygdom, hudsygdomme, reumatoid artritis og andre arthropatier, inflammatorisk tarmsygdom og kæmpecellearteritis/polymyalgia rheumatica; eller: metabolisk syndrom, som indbefatter lidelser som diabetes type 2 og obesitet og associerede lidelser, herunder insulinmodstand, blodtryksforhøjelse, lipid-lidelser og kardiovaskulære lidelser såsom iskæmisk (koronar) hjertesygdom; eller: en CNS-lidelse såsom let kognitiv svækkelse og tidlig demens, herunder Alz-heimers sygdom.
25. Anvendelse af en forbindelse ifølge et af kravene 1 til 20 ved fremstilling af et medikament til behandling eller forebyggelse af: en lidelse i menneske- eller dyrekroppen, som bedres ved inhibering af 11 β-hydroxysteroiddehydrogenase type 1; eller: (1) Cushings syndrom; (2) type 2 diabetes og nedsat glukosetolerance; (3) insulinmodstandssyndromer såsom myotonisk dystrofi, Prader Willi, lipo-dystrofier, polycystisk ovariesyndrom, gastrointestinal diabetes, osv.; (4) obesitet og overvægt; (5) lipidlidelser, herunder dyslipidæmi; (6) aterosklerose og dens følgesygdomme, herunder myokardieinfarkt og perifer vaskulær sygdom; (7) metabolisk syndrom; (8) steatohepatitis/fedtlever og ikke-alkoholisk fedtleversygdom; (9) kognitiv svækkelse i diabetes type 2, glukoseintolerance og ældning og ved psykotiske lidelser og præ-skizofreni; (10) demens såsom Alzheimers sygdom, multi-infarkt-demens, demens med Lewylegemer, frontotemporal demens (herunder Picks sygdom), progressiv supranukleær lammelse, Korsakoffs syndrom, Binswangers sygdom, HIV-associeret demens, Creutzfeldt-Jakob-sygdom (CJD), multipel sklerose, mo-torneuronsygdom, Parkinsons sygdom, Huntingtons sygdom, Niemann-Pick-sygdom type C, normaltrykshydrocephalus og Downs syndrom; (11) let kognitiv svækkelse (kognitiv svækkelse uden demens); (12) β-celle-dysfunktion ved pancreaslidelse; (13) glaukom; (14) angst; (15) depression og andre affektive lidelser; typisk (melankolsk) og atypisk depression; dystymi; efterfødselsdepression; bipolær affektiv lidelse; medicininducerede affektive lidelser; angst; posttraumatisk stresslidelse; panik; fobier; (16) delirium og akut sindsforvirring; (17) inflammatorisk sygdom; (18) osteoporose; (19) myokardieinfarkt, f.eks. til forebyggelse af venstre ventrikulær dysfunktion efter myokardieinfarkt; eller (20) slagtilfælde, f.eks. til begrænsning af iskæmisk neurontab efter kardio-vaskulær ulykke; eller: (1) hypercalcæmi; (2) glukoseintolerance og nedsat glukosetolerance; (3) insulinmodstand; (4) hyperlipidæmi; (5) hyperthglyceridæmi; (6) hyperkolesterolæmi; (7) lave HDL-niveauer; (8) høje LDL-niveauer; (9) vaskulær restenose; (10) abdominal obesitet; (11) neurodegenerativ sygdom; (12) retinopati; (13) neuropati; (14) blodtryksforhøjelse; eller (15) andre sygdomme, hvor insulinmodstand er en komponent; eller: en bivirkning af glukocorticoider, der anvendes til behandling af inflammatoriske sygdomme såsom astma, kronisk obstruktiv lungesygdom, hudsygdomme, reumatoid artritis og andre arthropatier, inflammatorisk tarmsygdom og kæmpecellearteritis/polymyalgia rheumatica; eller: metabolisk syndrom, som indbefatter lidelser som diabetes type 2 og obesitet og associerede lidelser, herunder insulinmodstand, blodtryksforhøjelse, lipid-lidelser og kardiovaskulære lidelser såsom iskæmisk (koronar) hjertesygdom; eller: en CNS-lidelse såsom let kognitiv svækkelse og tidlig demens, herunder Alz-heimers sygdom.
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