MX2007012233A - Moduladores canabinoides de tetrahidrotiopirano pirazol. - Google Patents

Info

Publication number

MX2007012233A

MX2007012233A MX2007012233A MX2007012233A MX2007012233A MX 2007012233 A MX2007012233 A MX 2007012233A MX 2007012233 A MX2007012233 A MX 2007012233A MX 2007012233 A MX2007012233 A MX 2007012233A MX 2007012233 A MX2007012233 A MX 2007012233A

Authority

MX

Mexico

Prior art keywords

phenyl

tetrahydro

thiopyran

pyrazole

carboxylic acid

Prior art date

2005-03-31

Links

• Espacenet
• Global Dossier
• Discuss

• 229930003827 cannabinoid Natural products 0.000 title description 75
• 239000003557 cannabinoid Substances 0.000 title description 75
• UBEXPFAJZMPWAL-UHFFFAOYSA-N 1,2,3,3a-tetrahydrothiopyrano[3,2-c]pyrazole Chemical compound C1=CSC2CNNC2=C1 UBEXPFAJZMPWAL-UHFFFAOYSA-N 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 308
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 238
• 208000035475 disorder Diseases 0.000 claims abstract description 123
• 201000010099 disease Diseases 0.000 claims abstract description 115
• 208000011580 syndromic disease Diseases 0.000 claims abstract description 111
• 230000001404 mediated effect Effects 0.000 claims abstract description 71
• 102000005962 receptors Human genes 0.000 claims abstract description 66
• 108020003175 receptors Proteins 0.000 claims abstract description 66
• -1 -NR8R9 Chemical group 0.000 claims description 352
• KOPFEFZSAMLEHK-UHFFFAOYSA-N 1h-pyrazole-5-carboxylic acid Chemical compound OC(=O)C=1C=CNN=1 KOPFEFZSAMLEHK-UHFFFAOYSA-N 0.000 claims description 288
• 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 claims description 152
• 239000000203 mixture Substances 0.000 claims description 115
• 125000000217 alkyl group Chemical group 0.000 claims description 100
• 125000003118 aryl group Chemical group 0.000 claims description 77
• 229910052736 halogen Inorganic materials 0.000 claims description 76
• 150000002367 halogens Chemical class 0.000 claims description 76
• 125000003545 alkoxy group Chemical group 0.000 claims description 72
• 239000002253 acid Substances 0.000 claims description 68
• 125000000623 heterocyclic group Chemical group 0.000 claims description 59
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 55
• 125000004289 pyrazol-3-yl group Chemical group [H]N1N=C(*)C([H])=C1[H] 0.000 claims description 40
• 125000002947 alkylene group Chemical group 0.000 claims description 37
• 229910052739 hydrogen Inorganic materials 0.000 claims description 37
• 239000001257 hydrogen Substances 0.000 claims description 37
• 239000003433 contraceptive agent Substances 0.000 claims description 33
• WXSMREPXSXVZGV-UHFFFAOYSA-N N-(3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl)-1H-pyrazole-5-carboxamide Chemical compound C1N(CC2C1CCC2)NC(=O)C1=NNC=C1 WXSMREPXSXVZGV-UHFFFAOYSA-N 0.000 claims description 30
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 30
• 239000001961 anticonvulsive agent Substances 0.000 claims description 30
• 239000003814 drug Substances 0.000 claims description 30
• 239000000556 agonist Substances 0.000 claims description 29
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 29
• 230000000694 effects Effects 0.000 claims description 29
• 108010073366 CB1 Cannabinoid Receptor Proteins 0.000 claims description 27
• 102000009132 CB1 Cannabinoid Receptor Human genes 0.000 claims description 27
• 229940124558 contraceptive agent Drugs 0.000 claims description 26
• 150000003839 salts Chemical class 0.000 claims description 26
• UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 claims description 24
• 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 23
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 22
• NIJJYAXOARWZEE-UHFFFAOYSA-N di-n-propyl-acetic acid Natural products CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 claims description 22
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 22
• 101710187010 Cannabinoid receptor 1 Proteins 0.000 claims description 21
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• 208000008589 Obesity Diseases 0.000 claims description 21
• 235000020824 obesity Nutrition 0.000 claims description 21
• 229940125425 inverse agonist Drugs 0.000 claims description 19
• IBBLKSWSCDAPIF-UHFFFAOYSA-N thiopyran Chemical compound S1C=CC=C=C1 IBBLKSWSCDAPIF-UHFFFAOYSA-N 0.000 claims description 19
• KJADKKWYZYXHBB-XBWDGYHZSA-N Topiramic acid Chemical group C1O[C@@]2(COS(N)(=O)=O)OC(C)(C)O[C@H]2[C@@H]2OC(C)(C)O[C@@H]21 KJADKKWYZYXHBB-XBWDGYHZSA-N 0.000 claims description 18
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 18
• 230000036528 appetite Effects 0.000 claims description 17
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• 108010073376 CB2 Cannabinoid Receptor Proteins 0.000 claims description 16
• 102000009135 CB2 Cannabinoid Receptor Human genes 0.000 claims description 16
• 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 16
• 125000004104 aryloxy group Chemical group 0.000 claims description 16
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 16
• 125000006284 3-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(F)=C1[H])C([H])([H])* 0.000 claims description 15
• 230000004060 metabolic process Effects 0.000 claims description 15
• 229960003965 antiepileptics Drugs 0.000 claims description 14
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 14
• 229960004394 topiramate Drugs 0.000 claims description 14
• 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 13
• 230000001773 anti-convulsant effect Effects 0.000 claims description 13
• 206010012601 diabetes mellitus Diseases 0.000 claims description 12
• LWMPFIOTEAXAGV-UHFFFAOYSA-N piperidin-1-amine Chemical compound NN1CCCCC1 LWMPFIOTEAXAGV-UHFFFAOYSA-N 0.000 claims description 12
• 239000000651 prodrug Substances 0.000 claims description 12
• 229940002612 prodrug Drugs 0.000 claims description 12
• RQEUFEKYXDPUSK-ZETCQYMHSA-N (1S)-1-phenylethanamine Chemical compound C[C@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-ZETCQYMHSA-N 0.000 claims description 11
• 229960002870 gabapentin Drugs 0.000 claims description 11
• PYZRQGJRPPTADH-UHFFFAOYSA-N lamotrigine Chemical compound NC1=NC(N)=NN=C1C1=CC=CC(Cl)=C1Cl PYZRQGJRPPTADH-UHFFFAOYSA-N 0.000 claims description 11
• 230000015654 memory Effects 0.000 claims description 11
• 230000036407 pain Effects 0.000 claims description 11
• 229960000604 valproic acid Drugs 0.000 claims description 11
• 208000002193 Pain Diseases 0.000 claims description 10
• 125000001118 alkylidene group Chemical group 0.000 claims description 10
• 239000005557 antagonist Substances 0.000 claims description 10
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 10
• 230000002254 contraceptive effect Effects 0.000 claims description 10
• 229960001848 lamotrigine Drugs 0.000 claims description 10
• 229940124597 therapeutic agent Drugs 0.000 claims description 10
• 206010010904 Convulsion Diseases 0.000 claims description 9
• FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 claims description 9
• 230000019771 cognition Effects 0.000 claims description 9
• CBYXIIFIKSBHEY-UHFFFAOYSA-N 2,2,4-trimethylbicyclo[2.2.1]heptan-3-amine Chemical compound C1CC2(C)C(N)C(C)(C)C1C2 CBYXIIFIKSBHEY-UHFFFAOYSA-N 0.000 claims description 8
• 229960000623 carbamazepine Drugs 0.000 claims description 8
• 230000013016 learning Effects 0.000 claims description 8
• 239000002207 metabolite Substances 0.000 claims description 8
• 208000011117 substance-related disease Diseases 0.000 claims description 8
• RQEUFEKYXDPUSK-SSDOTTSWSA-N (1R)-1-phenylethanamine Chemical compound C[C@@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-SSDOTTSWSA-N 0.000 claims description 7
• 208000007101 Muscle Cramp Diseases 0.000 claims description 7
• 208000005392 Spasm Diseases 0.000 claims description 7
• 230000004410 intraocular pressure Effects 0.000 claims description 7
• 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 7
• 210000000056 organ Anatomy 0.000 claims description 7
• 201000009032 substance abuse Diseases 0.000 claims description 7
• 231100000736 substance abuse Toxicity 0.000 claims description 7
• 229910052717 sulfur Inorganic materials 0.000 claims description 7
• XBWOPGDJMAJJDG-ZETCQYMHSA-N (1s)-1-cyclohexylethanamine Chemical compound C[C@H](N)C1CCCCC1 XBWOPGDJMAJJDG-ZETCQYMHSA-N 0.000 claims description 6
• 208000010412 Glaucoma Diseases 0.000 claims description 6
• 208000019022 Mood disease Diseases 0.000 claims description 6
• CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 claims description 6
• 230000010261 cell growth Effects 0.000 claims description 6
• 230000008602 contraction Effects 0.000 claims description 6
• OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 claims description 6
• 125000002541 furyl group Chemical group 0.000 claims description 6
• 230000033001 locomotion Effects 0.000 claims description 6
• 208000023504 respiratory system disease Diseases 0.000 claims description 6
• 125000001544 thienyl group Chemical group 0.000 claims description 6
• XBWOPGDJMAJJDG-SSDOTTSWSA-N (1r)-1-cyclohexylethanamine Chemical compound C[C@@H](N)C1CCCCC1 XBWOPGDJMAJJDG-SSDOTTSWSA-N 0.000 claims description 5
• 238000004519 manufacturing process Methods 0.000 claims description 5
• UOCYIXGKOTWCPB-SECBINFHSA-N n-[(1r)-1-phenylethyl]-1h-pyrazole-5-carboxamide Chemical compound N([C@H](C)C=1C=CC=CC=1)C(=O)C=1C=CNN=1 UOCYIXGKOTWCPB-SECBINFHSA-N 0.000 claims description 5
• 229960002036 phenytoin Drugs 0.000 claims description 5
• 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
• RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical class C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 claims description 4
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
• 125000004494 ethyl ester group Chemical group 0.000 claims description 4
• 208000026278 immune system disease Diseases 0.000 claims description 4
• 229940127234 oral contraceptive Drugs 0.000 claims description 4
• 239000003539 oral contraceptive agent Substances 0.000 claims description 4
• 239000000583 progesterone congener Substances 0.000 claims description 4
• 239000000779 smoke Substances 0.000 claims description 4
• 239000011593 sulfur Substances 0.000 claims description 4
• PDNHLCRMUIGNBV-ZCFIWIBFSA-N (1r)-1-pyridin-2-ylethanamine Chemical compound C[C@@H](N)C1=CC=CC=N1 PDNHLCRMUIGNBV-ZCFIWIBFSA-N 0.000 claims description 3
• NKBWMBRPILTCRD-UHFFFAOYSA-N 2-Methylheptanoic acid Chemical compound CCCCCC(C)C(O)=O NKBWMBRPILTCRD-UHFFFAOYSA-N 0.000 claims description 3
• 102000018208 Cannabinoid Receptor Human genes 0.000 claims description 3
• 108050007331 Cannabinoid receptor Proteins 0.000 claims description 3
• OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 claims description 3
• 229960000304 folic acid Drugs 0.000 claims description 3
• 235000019152 folic acid Nutrition 0.000 claims description 3
• 239000011724 folic acid Substances 0.000 claims description 3
• JFFOUICIRBXFRC-RFZPGFLSSA-N (1r,2r)-2-aminocyclopentan-1-ol Chemical compound N[C@@H]1CCC[C@H]1O JFFOUICIRBXFRC-RFZPGFLSSA-N 0.000 claims description 2
• LOPKSXMQWBYUOI-DTWKUNHWSA-N (1r,2s)-1-amino-2,3-dihydro-1h-inden-2-ol Chemical compound C1=CC=C2[C@@H](N)[C@@H](O)CC2=C1 LOPKSXMQWBYUOI-DTWKUNHWSA-N 0.000 claims description 2
• LOPKSXMQWBYUOI-BDAKNGLRSA-N (1s,2r)-1-amino-2,3-dihydro-1h-inden-2-ol Chemical compound C1=CC=C2[C@H](N)[C@H](O)CC2=C1 LOPKSXMQWBYUOI-BDAKNGLRSA-N 0.000 claims description 2
• BWSIKGOGLDNQBZ-LURJTMIESA-N (2s)-2-(methoxymethyl)pyrrolidin-1-amine Chemical compound COC[C@@H]1CCCN1N BWSIKGOGLDNQBZ-LURJTMIESA-N 0.000 claims description 2
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 2
• WOXFMYVTSLAQMO-UHFFFAOYSA-N 2-Pyridinemethanamine Chemical compound NCC1=CC=CC=N1 WOXFMYVTSLAQMO-UHFFFAOYSA-N 0.000 claims description 2
• WWMSVGAAJKSNPI-UHFFFAOYSA-N N-(2,6-dimethylpiperidin-1-yl)-1H-pyrazole-5-carboxamide Chemical compound CC1N(C(CCC1)C)NC(=O)C1=NNC=C1 WWMSVGAAJKSNPI-UHFFFAOYSA-N 0.000 claims description 2
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
• 229940011871 estrogen Drugs 0.000 claims description 2
• 239000000262 estrogen Substances 0.000 claims description 2
• 208000027866 inflammatory disease Diseases 0.000 claims description 2
• 230000004112 neuroprotection Effects 0.000 claims description 2
• SBMSLRMNBSMKQC-UHFFFAOYSA-N pyrrolidin-1-amine Chemical compound NN1CCCC1 SBMSLRMNBSMKQC-UHFFFAOYSA-N 0.000 claims description 2
• SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical group [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 2
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims 28
• 150000002431 hydrogen Chemical group 0.000 claims 16
• 102100031151 C-C chemokine receptor type 2 Human genes 0.000 claims 2
• 101710149815 C-C chemokine receptor type 2 Proteins 0.000 claims 2
• PQMCFTMVQORYJC-PHDIDXHHSA-N (1r,2r)-2-aminocyclohexan-1-ol Chemical compound N[C@@H]1CCCC[C@H]1O PQMCFTMVQORYJC-PHDIDXHHSA-N 0.000 claims 1
• BWSIKGOGLDNQBZ-ZCFIWIBFSA-N (2r)-2-(methoxymethyl)pyrrolidin-1-amine Chemical compound COC[C@H]1CCCN1N BWSIKGOGLDNQBZ-ZCFIWIBFSA-N 0.000 claims 1
• 230000003137 locomotive effect Effects 0.000 claims 1
• MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 claims 1
• 238000000034 method Methods 0.000 abstract description 100
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 98
• 239000000243 solution Substances 0.000 description 81
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 78
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• 239000000047 product Substances 0.000 description 58
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 49
• 235000019439 ethyl acetate Nutrition 0.000 description 49
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 47
• 239000012044 organic layer Substances 0.000 description 43
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• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 39
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• 239000012298 atmosphere Substances 0.000 description 27
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 23
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• 101710187022 Cannabinoid receptor 2 Proteins 0.000 description 17
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• YPWFISCTZQNZAU-UHFFFAOYSA-N Thiane Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 description 15
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• 235000011152 sodium sulphate Nutrition 0.000 description 15
• 238000012360 testing method Methods 0.000 description 15
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• 125000004188 dichlorophenyl group Chemical group 0.000 description 12
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• 125000001424 substituent group Chemical group 0.000 description 12
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• 241001465754 Metazoa Species 0.000 description 7
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