AU2010319400B2 - Spiropiperidine compounds as ORL-1 receptor antagonists - Google Patents

Info

Publication number

AU2010319400B2

AU2010319400B2 AU2010319400A AU2010319400A AU2010319400B2 AU 2010319400 B2 AU2010319400 B2 AU 2010319400B2 AU 2010319400 A AU2010319400 A AU 2010319400A AU 2010319400 A AU2010319400 A AU 2010319400A AU 2010319400 B2 AU2010319400 B2 AU 2010319400B2

Authority

AU

Australia

Prior art keywords

methyl

piperidine

pyran

pyrazol

chloro

Prior art date

2009-11-16

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Ceased

Links

• Espacenet
• Global Dossier
• Discuss

• 108010020615 nociceptin receptor Proteins 0.000 title abstract description 24
• 229940044551 receptor antagonist Drugs 0.000 title abstract description 4
• 239000002464 receptor antagonist Substances 0.000 title abstract description 4
• JUXAVSAMVBLDKO-UHFFFAOYSA-N 1-(1-azabicyclo[2.2.2]octan-3-yl)-3-[3-(1h-indol-3-yl)-1-oxo-1-spiro[1,2-dihydroindene-3,4'-piperidine]-1'-ylpropan-2-yl]urea Chemical class C1N(CC2)CCC2C1NC(=O)NC(C(=O)N1CCC2(C3=CC=CC=C3CC2)CC1)CC1=CNC2=CC=CC=C12 JUXAVSAMVBLDKO-UHFFFAOYSA-N 0.000 title description 3
• 150000001875 compounds Chemical class 0.000 claims abstract description 224
• 238000011282 treatment Methods 0.000 claims abstract description 38
• 238000000034 method Methods 0.000 claims abstract description 24
• 208000008589 Obesity Diseases 0.000 claims abstract description 15
• 235000020824 obesity Nutrition 0.000 claims abstract description 15
• 206010033307 Overweight Diseases 0.000 claims abstract description 12
• 208000019695 Migraine disease Diseases 0.000 claims abstract description 10
• OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 169
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 153
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 95
• FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 73
• -1 chloro, cyano, cyanomethyl Chemical group 0.000 claims description 69
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 60
• 150000003839 salts Chemical class 0.000 claims description 49
• 125000003003 spiro group Chemical group 0.000 claims description 39
• 125000001153 fluoro group Chemical group F* 0.000 claims description 30
• 229940095064 tartrate Drugs 0.000 claims description 26
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 24
• 125000004353 pyrazol-1-yl group Chemical group [H]C1=NN(*)C([H])=C1[H] 0.000 claims description 18
• 239000001257 hydrogen Substances 0.000 claims description 17
• 229910052739 hydrogen Inorganic materials 0.000 claims description 17
• 241000124008 Mammalia Species 0.000 claims description 16
• JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 15
• YYNOJCBVROUTEB-UHFFFAOYSA-N 2-chloro-4,4-difluorospiro[5h-thieno[2,3-c]pyran-7,4'-piperidine] Chemical compound C1=2SC(Cl)=CC=2C(F)(F)COC21CCNCC2 YYNOJCBVROUTEB-UHFFFAOYSA-N 0.000 claims description 14
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 13
• BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 12
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 11
• 150000002431 hydrogen Chemical group 0.000 claims description 10
• 239000008194 pharmaceutical composition Substances 0.000 claims description 10
• KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 9
• 239000003814 drug Substances 0.000 claims description 9
• 206010027599 migraine Diseases 0.000 claims description 9
• 239000003085 diluting agent Substances 0.000 claims description 7
• 239000003937 drug carrier Substances 0.000 claims description 7
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
• MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 claims description 6
• HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 claims description 6
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
• 238000004519 manufacturing process Methods 0.000 claims description 6
• 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 6
• 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 claims description 6
• IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 5
• 125000004289 pyrazol-3-yl group Chemical group [H]N1N=C(*)C([H])=C1[H] 0.000 claims description 5
• 239000012896 selective serotonin reuptake inhibitor Substances 0.000 claims description 5
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 4
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 4
• 125000000217 alkyl group Chemical group 0.000 claims description 4
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
• 230000001225 therapeutic effect Effects 0.000 claims description 4
• 239000004615 ingredient Substances 0.000 claims description 3
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
• 235000020825 overweight Nutrition 0.000 claims description 3
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
• 125000001305 1,2,4-triazol-3-yl group Chemical group [H]N1N=C([*])N=C1[H] 0.000 claims description 2
• ALDFBAMFJCZMRT-UHFFFAOYSA-N 1-[2-[4-[(2-chloro-4,4-difluorospiro[5h-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methylpyrazol-1-yl]-3-fluorophenyl]ethanone Chemical compound CC(=O)C1=CC=CC(F)=C1N1N=C(C)C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)=C1 ALDFBAMFJCZMRT-UHFFFAOYSA-N 0.000 claims description 2
• XZPLGWDRMOMJEQ-UHFFFAOYSA-N 2-chloro-1'-[[1-(2,6-dimethylphenyl)-3-methylpyrazol-4-yl]methyl]-4,4-difluorospiro[5h-thieno[2,3-c]pyran-7,4'-piperidine] Chemical compound C1=C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)C(C)=NN1C1=C(C)C=CC=C1C XZPLGWDRMOMJEQ-UHFFFAOYSA-N 0.000 claims description 2
• LFJUFKLBEDBJPR-UHFFFAOYSA-N 2-chloro-4,4-difluoro-1'-[[3-methyl-1-(2-methylphenyl)pyrazol-4-yl]methyl]spiro[5h-thieno[2,3-c]pyran-7,4'-piperidine] Chemical compound C1=C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)C(C)=NN1C1=CC=CC=C1C LFJUFKLBEDBJPR-UHFFFAOYSA-N 0.000 claims description 2
• GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 2
• 125000004849 alkoxymethyl group Chemical group 0.000 claims description 2
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
• IGQNOFOHZUSKIL-UHFFFAOYSA-N methyl n-methylcarbamate Chemical compound [CH2]NC(=O)OC IGQNOFOHZUSKIL-UHFFFAOYSA-N 0.000 claims description 2
• 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 claims description 2
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
• CCWFXIZOSUQHPT-LREBCSMRSA-N (2R,3R)-2,3-dihydroxybutanedioic acid 1-[3-fluoro-2-[3-methyl-4-[(2,4,4-trifluorospiro[5H-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]pyrazol-1-yl]phenyl]-N,N-dimethylmethanamine Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.CN(C)CC1=CC=CC(F)=C1N1N=C(C)C(CN2CCC3(CC2)C=2SC(F)=CC=2C(F)(F)CO3)=C1 CCWFXIZOSUQHPT-LREBCSMRSA-N 0.000 claims 1
• NNOVVEMYYNWICL-UHFFFAOYSA-N 1-[2-[4-[(2-chloro-4,4-difluorospiro[5h-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methylpyrazol-1-yl]-3-fluorophenyl]-n,n-dimethylmethanamine Chemical compound CN(C)CC1=CC=CC(F)=C1N1N=C(C)C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)=C1 NNOVVEMYYNWICL-UHFFFAOYSA-N 0.000 claims 1
• WODKTBZTGZUTGA-UHFFFAOYSA-N 1-[2-[4-[(2-chloro-4,4-difluorospiro[5h-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methylpyrazol-1-yl]-3-methoxyphenyl]-n-methylmethanamine Chemical compound CNCC1=CC=CC(OC)=C1N1N=C(C)C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)=C1 WODKTBZTGZUTGA-UHFFFAOYSA-N 0.000 claims 1
• UXQWNFPSOYECDK-LREBCSMRSA-N 2-chloro-4,4-difluoro-1'-[[1-[2-(methoxymethyl)phenyl]-3-methylpyrazol-4-yl]methyl]spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine] (2R,3R)-2,3-dihydroxybutanedioic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.COCC1=CC=CC=C1N1N=C(C)C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)=C1 UXQWNFPSOYECDK-LREBCSMRSA-N 0.000 claims 1
• NDESORITPQFVQC-UHFFFAOYSA-N 2-chloro-4,4-difluoro-1'-[[1-[2-fluoro-6-(1h-1,2,4-triazol-5-yl)phenyl]-3-methylpyrazol-4-yl]methyl]spiro[5h-thieno[2,3-c]pyran-7,4'-piperidine] Chemical compound C1=C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)C(C)=NN1C1=C(F)C=CC=C1C=1N=CNN=1 NDESORITPQFVQC-UHFFFAOYSA-N 0.000 claims 1
• QVICWXVSKJDHLP-LREBCSMRSA-N 2-chloro-4,4-difluoro-1'-[[3-methyl-1-(2-propan-2-ylphenyl)pyrazol-4-yl]methyl]spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine] (2R,3R)-2,3-dihydroxybutanedioic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.CC(C)C1=CC=CC=C1N1N=C(C)C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)=C1 QVICWXVSKJDHLP-LREBCSMRSA-N 0.000 claims 1
• IGJYNRJBRWKKKT-UHFFFAOYSA-N 4,4-difluorospiro[5H-thieno[2,3-c]pyran-7,4'-piperidine] Chemical compound FC1(C2=C(SC=C2)C2(CCNCC2)OC1)F IGJYNRJBRWKKKT-UHFFFAOYSA-N 0.000 claims 1
• NLPQEJNUWGRTSY-LREBCSMRSA-N OC(=O)[C@H](O)[C@@H](O)C(O)=O.CNCC1=CC=CC(F)=C1N1N=C(C)C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)=C1 Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.CNCC1=CC=CC(F)=C1N1N=C(C)C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)=C1 NLPQEJNUWGRTSY-LREBCSMRSA-N 0.000 claims 1
• RLFLBNZJFJOODD-LREBCSMRSA-N OC(=O)[C@H](O)[C@@H](O)C(O)=O.COC(=O)N(C)C1=CC=CC(F)=C1N1N=C(C)C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)=C1 Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.COC(=O)N(C)C1=CC=CC(F)=C1N1N=C(C)C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)=C1 RLFLBNZJFJOODD-LREBCSMRSA-N 0.000 claims 1
• HAWROUUMJVBNIU-LREBCSMRSA-N OC(=O)[C@H](O)[C@@H](O)C(O)=O.COCC1=CC=CC(F)=C1N1N=C(C)C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)=C1 Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.COCC1=CC=CC(F)=C1N1N=C(C)C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)=C1 HAWROUUMJVBNIU-LREBCSMRSA-N 0.000 claims 1
• ZWJYBMRHLQSTPN-LREBCSMRSA-N OC(=O)[C@H](O)[C@@H](O)C(O)=O.FC1=CC=CC(F)=C1N1N=CC(CN2CCC3(CC2)C=2SC(Cl)=CC=2CCO3)=C1 Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.FC1=CC=CC(F)=C1N1N=CC(CN2CCC3(CC2)C=2SC(Cl)=CC=2CCO3)=C1 ZWJYBMRHLQSTPN-LREBCSMRSA-N 0.000 claims 1
• UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims 1
• 238000002360 preparation method Methods 0.000 abstract description 60
• 239000005557 antagonist Substances 0.000 abstract description 19
• 238000012423 maintenance Methods 0.000 abstract description 8
• 208000020401 Depressive disease Diseases 0.000 abstract description 7
• 238000010171 animal model Methods 0.000 abstract description 5
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 200
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 159
• 239000000203 mixture Substances 0.000 description 128
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 113
• 239000000243 solution Substances 0.000 description 101
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 90
• 239000002904 solvent Substances 0.000 description 74
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 58
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• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 54
• 239000012071 phase Substances 0.000 description 46
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• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 39
• 239000012044 organic layer Substances 0.000 description 37
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
• 238000004587 chromatography analysis Methods 0.000 description 36
• 102000005962 receptors Human genes 0.000 description 31
• 230000002829 reductive effect Effects 0.000 description 30
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 29
• 238000006243 chemical reaction Methods 0.000 description 29
• 108020003175 receptors Proteins 0.000 description 29
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 29
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 28
• 235000017557 sodium bicarbonate Nutrition 0.000 description 28
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 28
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• PULGYDLMFSFVBL-SMFNREODSA-N nociceptin Chemical compound C([C@@H](C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)[C@@H](C)O)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 PULGYDLMFSFVBL-SMFNREODSA-N 0.000 description 27
• 239000007787 solid Substances 0.000 description 27
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 26
• 229910052938 sodium sulfate Inorganic materials 0.000 description 26
• 235000011152 sodium sulphate Nutrition 0.000 description 26
• 238000012360 testing method Methods 0.000 description 26
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• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 17
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