JP5376942B2 - 置換されたスピロ化合物及び医薬の製造へのその使用 - Google Patents

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Publication number

JP5376942B2

JP5376942B2 JP2008511621A JP2008511621A JP5376942B2 JP 5376942 B2 JP5376942 B2 JP 5376942B2 JP 2008511621 A JP2008511621 A JP 2008511621A JP 2008511621 A JP2008511621 A JP 2008511621A JP 5376942 B2 JP5376942 B2 JP 5376942B2

Authority

JP

Japan

Prior art keywords

phenyl

butyl

group

tert

oxa

Prior art date

2005-05-19

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.)

Expired - Fee Related

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• 239000003814 drug Substances 0.000 title claims description 45
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• 238000004519 manufacturing process Methods 0.000 title claims description 12
• -1 benzo[b]-furanyl Chemical group 0.000 claims abstract description 534
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 105
• 125000001424 substituent group Chemical group 0.000 claims abstract description 80
• 239000000203 mixture Substances 0.000 claims abstract description 77
• 125000004076 pyridyl group Chemical group 0.000 claims abstract description 76
• 125000002098 pyridazinyl group Chemical group 0.000 claims abstract description 47
• 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 38
• 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 38
• 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 abstract description 30
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims abstract description 30
• 125000000335 thiazolyl group Chemical group 0.000 claims abstract description 29
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 27
• 125000000714 pyrimidinyl group Chemical group 0.000 claims abstract description 24
• 150000003839 salts Chemical class 0.000 claims abstract description 24
• 125000002541 furyl group Chemical group 0.000 claims abstract description 23
• 125000001624 naphthyl group Chemical group 0.000 claims abstract description 23
• 230000000694 effects Effects 0.000 claims abstract description 20
• 125000001041 indolyl group Chemical group 0.000 claims abstract description 19
• 229910052760 oxygen Inorganic materials 0.000 claims abstract description 19
• 229910052717 sulfur Inorganic materials 0.000 claims abstract description 18
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims abstract description 16
• 102100029613 Transient receptor potential cation channel subfamily V member 1 Human genes 0.000 claims abstract description 13
• 239000012453 solvate Substances 0.000 claims abstract description 13
• 108050004388 Transient receptor potential cation channel subfamily V member 1 Proteins 0.000 claims abstract description 12
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
• 238000002360 preparation method Methods 0.000 claims abstract description 5
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• 150000001875 compounds Chemical class 0.000 claims description 85
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 71
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 71
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 67
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 67
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 66
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 64
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 58
• 239000002904 solvent Substances 0.000 claims description 58
• 229910052801 chlorine Inorganic materials 0.000 claims description 57
• 229910052794 bromium Inorganic materials 0.000 claims description 56
• 229910052731 fluorine Inorganic materials 0.000 claims description 56
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 54
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• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 34
• YKPUWZUDDOIDPM-SOFGYWHQSA-N capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 claims description 32
• 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 32
• 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 29
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• 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 28
• 229910052740 iodine Inorganic materials 0.000 claims description 25
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• 125000004122 cyclic group Chemical group 0.000 claims description 22
• 239000012429 reaction media Substances 0.000 claims description 22
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• OHPSBNXNFPTYFO-UHFFFAOYSA-N 3-phenyl-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carboxylic acid Chemical compound C1CC(C(=O)O)CCC11ON=C(C=2C=CC=CC=2)C1 OHPSBNXNFPTYFO-UHFFFAOYSA-N 0.000 claims description 18
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 17
• 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 17
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 16
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 16
• 235000017663 capsaicin Nutrition 0.000 claims description 16
• 229960002504 capsaicin Drugs 0.000 claims description 16
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 16
• 239000001301 oxygen Substances 0.000 claims description 16
• 208000007848 Alcoholism Diseases 0.000 claims description 15
• 208000007271 Substance Withdrawal Syndrome Diseases 0.000 claims description 15
• 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 15
• 238000000034 method Methods 0.000 claims description 15
• 239000011593 sulfur Substances 0.000 claims description 15
• 125000004193 piperazinyl group Chemical group 0.000 claims description 14
• 230000002265 prevention Effects 0.000 claims description 13
• 239000000556 agonist Substances 0.000 claims description 12
• 125000004429 atom Chemical group 0.000 claims description 12
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• 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 11
• 125000002757 morpholinyl group Chemical group 0.000 claims description 11
• 230000004770 neurodegeneration Effects 0.000 claims description 11
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• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 11
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• 208000009722 Overactive Urinary Bladder Diseases 0.000 claims description 9
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• 206010046543 Urinary incontinence Diseases 0.000 claims description 8
• 208000005298 acute pain Diseases 0.000 claims description 8
• 208000010877 cognitive disease Diseases 0.000 claims description 8
• 208000027866 inflammatory disease Diseases 0.000 claims description 8
• ZJOWVJQKUXFWJL-UHFFFAOYSA-N spiro[1H-naphthalene-2,5'-4H-1,2-oxazole] Chemical compound C1C2(C=CC3=CC=CC=C13)CC=NO2 ZJOWVJQKUXFWJL-UHFFFAOYSA-N 0.000 claims description 8
• 125000000464 thioxo group Chemical group S=* 0.000 claims description 8
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 7
• XNRZKFATEKTIRA-UHFFFAOYSA-N 8-tert-butyl-n-(2,3-dihydro-1,4-benzodioxin-5-yl)-1-oxa-2-azaspiro[4.5]dec-2-ene-3-carboxamide Chemical compound C1CC(C(C)(C)C)CCC11ON=C(C(=O)NC=2C=3OCCOC=3C=CC=2)C1 XNRZKFATEKTIRA-UHFFFAOYSA-N 0.000 claims description 7
• 208000030814 Eating disease Diseases 0.000 claims description 7
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• 239000003153 chemical reaction reagent Substances 0.000 claims description 7
• 235000014632 disordered eating Nutrition 0.000 claims description 7
• 229940079593 drug Drugs 0.000 claims description 7
• DACPYRNCOYJTKC-UHFFFAOYSA-N n-[5-[bis(methylsulfonyl)amino]-2-fluorophenyl]-8-tert-butyl-1-oxa-2-azaspiro[4.5]dec-2-ene-3-carboxamide Chemical compound C1CC(C(C)(C)C)CCC11ON=C(C(=O)NC=2C(=CC=C(C=2)N(S(C)(=O)=O)S(C)(=O)=O)F)C1 DACPYRNCOYJTKC-UHFFFAOYSA-N 0.000 claims description 7
• IYMKEGIJVNYNHI-UHFFFAOYSA-N n-[[3-fluoro-4-(methanesulfonamido)phenyl]methyl]-8-(2-methylbutan-2-yl)-1-oxa-2-azaspiro[4.5]dec-2-ene-3-carboxamide Chemical compound C1CC(C(C)(C)CC)CCC11ON=C(C(=O)NCC=2C=C(F)C(NS(C)(=O)=O)=CC=2)C1 IYMKEGIJVNYNHI-UHFFFAOYSA-N 0.000 claims description 7
• 208000023504 respiratory system disease Diseases 0.000 claims description 7
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• OUEKLNJUMVZULZ-UHFFFAOYSA-N 2-[4-(2-aminoethoxy)-3-methoxyphenyl]-n-[3-(3,4-dimethylphenyl)propyl]acetamide;hydron;chloride Chemical compound Cl.C1=C(OCCN)C(OC)=CC(CC(=O)NCCCC=2C=C(C)C(C)=CC=2)=C1 OUEKLNJUMVZULZ-UHFFFAOYSA-N 0.000 claims description 6
• HCAWEHRMIMYHAX-UHFFFAOYSA-N 8-tert-butyl-n-(4-tert-butylphenyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-3-carboxamide Chemical compound C1CC(C(C)(C)C)CCC11ON=C(C(=O)NC=2C=CC(=CC=2)C(C)(C)C)C1 HCAWEHRMIMYHAX-UHFFFAOYSA-N 0.000 claims description 6
• VJBDJDUSVRLFQK-UHFFFAOYSA-N 8-tert-butyl-n-(7-hydroxynaphthalen-1-yl)-1-oxa-2-azaspiro[4.5]dec-2-ene-3-carboxamide Chemical compound C1CC(C(C)(C)C)CCC11ON=C(C(=O)NC=2C3=CC(O)=CC=C3C=CC=2)C1 VJBDJDUSVRLFQK-UHFFFAOYSA-N 0.000 claims description 6
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• 230000008878 coupling Effects 0.000 claims description 6
• 238000010168 coupling process Methods 0.000 claims description 6
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• 125000005959 diazepanyl group Chemical group 0.000 claims description 6
• 230000005764 inhibitory process Effects 0.000 claims description 6
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• MHMQYFMTOFLJNG-UHFFFAOYSA-N n-(2,3-dihydro-1,4-benzodioxin-5-yl)-8-(2-methylbutan-2-yl)-1-oxa-2-azaspiro[4.5]dec-2-ene-3-carboxamide Chemical compound C1CC(C(C)(C)CC)CCC11ON=C(C(=O)NC=2C=3OCCOC=3C=CC=2)C1 MHMQYFMTOFLJNG-UHFFFAOYSA-N 0.000 claims description 6
• YOJQHRHKJMJSTK-UHFFFAOYSA-N n-[4-[bis(methylsulfonyl)amino]-3-fluorophenyl]-8-tert-butyl-1-oxa-2-azaspiro[4.5]dec-2-ene-3-carboxamide Chemical compound C1CC(C(C)(C)C)CCC11ON=C(C(=O)NC=2C=C(F)C(N(S(C)(=O)=O)S(C)(=O)=O)=CC=2)C1 YOJQHRHKJMJSTK-UHFFFAOYSA-N 0.000 claims description 6
• FGSKYUOFKOOOAY-UHFFFAOYSA-N 2-ethylidene-N-[[4-(methanesulfonamido)phenyl]methyl]nonanamide Chemical compound CS(=O)(=O)NC1=CC=C(CNC(=O)C(=CC)CCCCCCC)C=C1 FGSKYUOFKOOOAY-UHFFFAOYSA-N 0.000 claims description 5
• FCHQKGREPXBCFE-UHFFFAOYSA-N 8-tert-butyl-n-[2-fluoro-5-(methanesulfonamido)phenyl]-1-oxa-2-azaspiro[4.5]dec-2-ene-3-carboxamide Chemical compound C1CC(C(C)(C)C)CCC11ON=C(C(=O)NC=2C(=CC=C(NS(C)(=O)=O)C=2)F)C1 FCHQKGREPXBCFE-UHFFFAOYSA-N 0.000 claims description 5
• 208000024827 Alzheimer disease Diseases 0.000 claims description 5
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• IOMAPSSJBLQYEE-UHFFFAOYSA-N FC=1C=C(CNC(=O)C(=CC)CCCCCCC)C=CC1NS(=O)(=O)C Chemical compound FC=1C=C(CNC(=O)C(=CC)CCCCCCC)C=CC1NS(=O)(=O)C IOMAPSSJBLQYEE-UHFFFAOYSA-N 0.000 claims description 5
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• OPZKBPQVWDSATI-KHPPLWFESA-N N-Vanillyloleamide Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)NCC1=CC=C(O)C(OC)=C1 OPZKBPQVWDSATI-KHPPLWFESA-N 0.000 claims description 5
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• OPZKBPQVWDSATI-UHFFFAOYSA-N oleoyl vanillylamide Natural products CCCCCCCCC=CCCCCCCCC(=O)NCC1=CC=C(O)C(OC)=C1 OPZKBPQVWDSATI-UHFFFAOYSA-N 0.000 claims description 5
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• 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 5
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• RLWGDRLXZSLGHV-UHFFFAOYSA-N 1-[[4-(2-aminoethoxy)-3-methoxyphenyl]methyl]-3-[(4-tert-butylphenyl)methyl]urea Chemical compound C1=C(OCCN)C(OC)=CC(CNC(=O)NCC=2C=CC(=CC=2)C(C)(C)C)=C1 RLWGDRLXZSLGHV-UHFFFAOYSA-N 0.000 claims description 4
• JPQCRDHFVMEWOX-UHFFFAOYSA-N 2-ethylidene-N-(pyridin-4-ylmethyl)nonanamide Chemical compound N1=CC=C(C=C1)CNC(=O)C(=CC)CCCCCCC JPQCRDHFVMEWOX-UHFFFAOYSA-N 0.000 claims description 4
• YFHIMTPTPQAPPA-UHFFFAOYSA-N 2-ethylidene-N-[(4-hydroxy-3-methoxyphenyl)methyl]nonanamide Chemical compound CCCCCCCC(=CC)C(=O)NCC1=CC=C(O)C(OC)=C1 YFHIMTPTPQAPPA-UHFFFAOYSA-N 0.000 claims description 4
• XONMZPOMEPGILK-UHFFFAOYSA-N 3,8-diphenyl-1-oxa-2-azaspiro[4.5]dec-2-ene Chemical compound C1C(C=2C=CC=CC=2)=NOC1(CC1)CCC1C1=CC=CC=C1 XONMZPOMEPGILK-UHFFFAOYSA-N 0.000 claims description 4
• GWVNXUZBJMOSIW-UHFFFAOYSA-N 3-(3-methoxyphenyl)-n-[[4-(trifluoromethoxy)phenyl]methyl]-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carboxamide Chemical compound COC1=CC=CC(C=2CC3(ON=2)CCC(CC3)C(=O)NCC=2C=CC(OC(F)(F)F)=CC=2)=C1 GWVNXUZBJMOSIW-UHFFFAOYSA-N 0.000 claims description 4
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• VNCYOSRYGBXZJS-UHFFFAOYSA-N 3-(4-tert-butylphenyl)-8-(2-methylbutan-2-yl)-1-oxa-2-azaspiro[4.5]dec-2-ene Chemical compound C1CC(C(C)(C)CC)CCC11ON=C(C=2C=CC(=CC=2)C(C)(C)C)C1 VNCYOSRYGBXZJS-UHFFFAOYSA-N 0.000 claims description 4
• YFYFRSFQWDOKSZ-UHFFFAOYSA-N 3-(4-tert-butylphenyl)-8-ethyl-1-oxa-2-azaspiro[4.5]dec-2-ene Chemical compound C1CC(CC)CCC11ON=C(C=2C=CC(=CC=2)C(C)(C)C)C1 YFYFRSFQWDOKSZ-UHFFFAOYSA-N 0.000 claims description 4
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• 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 4
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