JP5232143B2 - モチリン受容体アンタゴニストとしてのベンジルピペラジン誘導体 - Google Patents
モチリン受容体アンタゴニストとしてのベンジルピペラジン誘導体 Download PDFInfo
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- JP5232143B2 JP5232143B2 JP2009514801A JP2009514801A JP5232143B2 JP 5232143 B2 JP5232143 B2 JP 5232143B2 JP 2009514801 A JP2009514801 A JP 2009514801A JP 2009514801 A JP2009514801 A JP 2009514801A JP 5232143 B2 JP5232143 B2 JP 5232143B2
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- Prior art keywords
- methyl
- phenyl
- amino
- formula
- piperidinecarboxamide
- Prior art date
- 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.)
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- 102000057413 Motilin receptors Human genes 0.000 title description 7
- 108700040483 Motilin receptors Proteins 0.000 title description 7
- IQXXEPZFOOTTBA-UHFFFAOYSA-N 1-benzylpiperazine Chemical class C=1C=CC=CC=1CN1CCNCC1 IQXXEPZFOOTTBA-UHFFFAOYSA-N 0.000 title description 2
- 239000002464 receptor antagonist Substances 0.000 title 1
- 229940044551 receptor antagonist Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 191
- 238000000034 method Methods 0.000 claims abstract description 60
- 238000002360 preparation method Methods 0.000 claims abstract description 14
- 230000008569 process Effects 0.000 claims abstract description 6
- 150000003839 salts Chemical class 0.000 claims description 40
- -1 (piperazinyl) methylene substituent Chemical group 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 25
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 16
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- VAHGCBIEHWKWMD-IBGZPJMESA-N 4-(3-fluoroanilino)-n-methyl-n-[4-[[(3s)-3-methylpiperazin-1-yl]methyl]phenyl]piperidine-1-carboxamide Chemical compound C1CN[C@@H](C)CN1CC1=CC=C(N(C)C(=O)N2CCC(CC2)NC=2C=C(F)C=CC=2)C=C1 VAHGCBIEHWKWMD-IBGZPJMESA-N 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 238000006268 reductive amination reaction Methods 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 5
- 230000009467 reduction Effects 0.000 claims description 5
- 238000006722 reduction reaction Methods 0.000 claims description 5
- 239000012453 solvate Substances 0.000 claims description 5
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 4
- CBGQNRZLQSNQNS-FQEVSTJZSA-N 4-(3-cyanophenyl)-n-methyl-n-[4-[[(3s)-3-methylpiperazin-1-yl]methyl]phenyl]piperidine-1-carboxamide Chemical compound C1CN[C@@H](C)CN1CC1=CC=C(N(C)C(=O)N2CCC(CC2)C=2C=C(C=CC=2)C#N)C=C1 CBGQNRZLQSNQNS-FQEVSTJZSA-N 0.000 claims description 4
- QEJHPRPCSRIROF-SFHVURJKSA-N 4-(3-fluoroanilino)-n-methyl-n-[6-[[(3s)-3-methylpiperazin-1-yl]methyl]pyridin-3-yl]piperidine-1-carboxamide Chemical compound C1CN[C@@H](C)CN1CC1=CC=C(N(C)C(=O)N2CCC(CC2)NC=2C=C(F)C=CC=2)C=N1 QEJHPRPCSRIROF-SFHVURJKSA-N 0.000 claims description 4
- ZMIHIMYJXRASEQ-IBGZPJMESA-N 4-(3-fluorophenyl)-n-methyl-n-[4-[[(3s)-3-methylpiperazin-1-yl]methyl]phenyl]piperidine-1-carboxamide Chemical compound C1CN[C@@H](C)CN1CC1=CC=C(N(C)C(=O)N2CCC(CC2)C=2C=C(F)C=CC=2)C=C1 ZMIHIMYJXRASEQ-IBGZPJMESA-N 0.000 claims description 4
- OJJXMMVVELBULF-IBGZPJMESA-N 4-(4-fluorophenyl)-n-methyl-n-[4-[[(3s)-3-methylpiperazin-1-yl]methyl]phenyl]piperidine-1-carboxamide Chemical compound C1CN[C@@H](C)CN1CC1=CC=C(N(C)C(=O)N2CCC(CC2)C=2C=CC(F)=CC=2)C=C1 OJJXMMVVELBULF-IBGZPJMESA-N 0.000 claims description 4
- 150000001299 aldehydes Chemical class 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- UGSIGXWFIZZAAR-FQEVSTJZSA-N 4-(3-fluoroanilino)-n-methyl-n-[3-methyl-4-[[(3s)-3-methylpiperazin-1-yl]methyl]phenyl]piperidine-1-carboxamide Chemical compound C1CN[C@@H](C)CN1CC1=CC=C(N(C)C(=O)N2CCC(CC2)NC=2C=C(F)C=CC=2)C=C1C UGSIGXWFIZZAAR-FQEVSTJZSA-N 0.000 claims description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- AEMCAHYRZPQHGI-IBGZPJMESA-N 4-(2-carbamoylanilino)-n-methyl-n-[4-[[(3s)-3-methylpiperazin-1-yl]methyl]phenyl]piperidine-1-carboxamide Chemical compound C1CN[C@@H](C)CN1CC1=CC=C(N(C)C(=O)N2CCC(CC2)NC=2C(=CC=CC=2)C(N)=O)C=C1 AEMCAHYRZPQHGI-IBGZPJMESA-N 0.000 claims description 2
- NOOCUGDSASZTIW-FQEVSTJZSA-N 4-(2-cyanoanilino)-n-methyl-n-[4-[[(3s)-3-methylpiperazin-1-yl]methyl]phenyl]piperidine-1-carboxamide Chemical compound C1CN[C@@H](C)CN1CC1=CC=C(N(C)C(=O)N2CCC(CC2)NC=2C(=CC=CC=2)C#N)C=C1 NOOCUGDSASZTIW-FQEVSTJZSA-N 0.000 claims description 2
- RVEDDKMAENNWSJ-IBGZPJMESA-N 4-(2-fluoroanilino)-n-methyl-n-[4-[[(3s)-3-methylpiperazin-1-yl]methyl]phenyl]piperidine-1-carboxamide Chemical compound C1CN[C@@H](C)CN1CC1=CC=C(N(C)C(=O)N2CCC(CC2)NC=2C(=CC=CC=2)F)C=C1 RVEDDKMAENNWSJ-IBGZPJMESA-N 0.000 claims description 2
- POTIXHFLOMRIPL-UHFFFAOYSA-N 4-(3-cyanoanilino)-n-methyl-n-[4-(piperazin-1-ylmethyl)phenyl]piperidine-1-carboxamide Chemical compound C=1C=C(CN2CCNCC2)C=CC=1N(C)C(=O)N(CC1)CCC1NC1=CC=CC(C#N)=C1 POTIXHFLOMRIPL-UHFFFAOYSA-N 0.000 claims description 2
- YTEWUWUUWKZUEH-FQEVSTJZSA-N 4-(3-cyanoanilino)-n-methyl-n-[4-[[(3s)-3-methylpiperazin-1-yl]methyl]phenyl]piperidine-1-carboxamide Chemical compound C1CN[C@@H](C)CN1CC1=CC=C(N(C)C(=O)N2CCC(CC2)NC=2C=C(C=CC=2)C#N)C=C1 YTEWUWUUWKZUEH-FQEVSTJZSA-N 0.000 claims description 2
- WMSXCTMDOXKYEK-IBGZPJMESA-N 4-(3-fluoro-4-methoxyanilino)-n-methyl-n-[4-[[(3s)-3-methylpiperazin-1-yl]methyl]phenyl]piperidine-1-carboxamide Chemical compound C1=C(F)C(OC)=CC=C1NC1CCN(C(=O)N(C)C=2C=CC(CN3C[C@H](C)NCC3)=CC=2)CC1 WMSXCTMDOXKYEK-IBGZPJMESA-N 0.000 claims description 2
- GBDNMGFJZHEWJK-UHFFFAOYSA-N 4-(3-fluoroanilino)-n-methyl-n-[4-(piperazin-1-ylmethyl)phenyl]piperidine-1-carboxamide Chemical compound C=1C=C(CN2CCNCC2)C=CC=1N(C)C(=O)N(CC1)CCC1NC1=CC=CC(F)=C1 GBDNMGFJZHEWJK-UHFFFAOYSA-N 0.000 claims description 2
- VAHGCBIEHWKWMD-LJQANCHMSA-N 4-(3-fluoroanilino)-n-methyl-n-[4-[[(3r)-3-methylpiperazin-1-yl]methyl]phenyl]piperidine-1-carboxamide Chemical compound C1CN[C@H](C)CN1CC1=CC=C(N(C)C(=O)N2CCC(CC2)NC=2C=C(F)C=CC=2)C=C1 VAHGCBIEHWKWMD-LJQANCHMSA-N 0.000 claims description 2
- MHWVNOWZAYMLBI-IBGZPJMESA-N 4-(3-fluorophenoxy)-n-methyl-n-[4-[[(3s)-3-methylpiperazin-1-yl]methyl]phenyl]piperidine-1-carboxamide Chemical compound C1CN[C@@H](C)CN1CC1=CC=C(N(C)C(=O)N2CCC(CC2)OC=2C=C(F)C=CC=2)C=C1 MHWVNOWZAYMLBI-IBGZPJMESA-N 0.000 claims description 2
- VBSRCXCGKMBKIV-FQEVSTJZSA-N 4-(4-cyanoanilino)-n-methyl-n-[4-[[(3s)-3-methylpiperazin-1-yl]methyl]phenyl]piperidine-1-carboxamide Chemical compound C1CN[C@@H](C)CN1CC1=CC=C(N(C)C(=O)N2CCC(CC2)NC=2C=CC(=CC=2)C#N)C=C1 VBSRCXCGKMBKIV-FQEVSTJZSA-N 0.000 claims description 2
- FQQOBLHOKLMWSN-IBGZPJMESA-N 4-(4-fluoro-3-methoxyanilino)-n-methyl-n-[4-[[(3s)-3-methylpiperazin-1-yl]methyl]phenyl]piperidine-1-carboxamide Chemical compound C1=C(F)C(OC)=CC(NC2CCN(CC2)C(=O)N(C)C=2C=CC(CN3C[C@H](C)NCC3)=CC=2)=C1 FQQOBLHOKLMWSN-IBGZPJMESA-N 0.000 claims description 2
- PDPFEGLNWDJQTL-UHFFFAOYSA-N 4-(4-fluoroanilino)-n-methyl-n-[4-(piperazin-1-ylmethyl)phenyl]piperidine-1-carboxamide Chemical compound C=1C=C(CN2CCNCC2)C=CC=1N(C)C(=O)N(CC1)CCC1NC1=CC=C(F)C=C1 PDPFEGLNWDJQTL-UHFFFAOYSA-N 0.000 claims description 2
- OKKIPMUUMQAQDL-IBGZPJMESA-N 4-(4-fluoroanilino)-n-methyl-n-[4-[[(3s)-3-methylpiperazin-1-yl]methyl]phenyl]piperidine-1-carboxamide Chemical compound C1CN[C@@H](C)CN1CC1=CC=C(N(C)C(=O)N2CCC(CC2)NC=2C=CC(F)=CC=2)C=C1 OKKIPMUUMQAQDL-IBGZPJMESA-N 0.000 claims description 2
- 239000004202 carbamide Substances 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- LOZWNVRRUMVRHD-BGYRXZFFSA-N n-[4-[[(3s,5r)-3,5-dimethylpiperazin-1-yl]methyl]phenyl]-4-(3-fluoroanilino)-n-methylpiperidine-1-carboxamide Chemical compound C1[C@@H](C)N[C@@H](C)CN1CC1=CC=C(N(C)C(=O)N2CCC(CC2)NC=2C=C(F)C=CC=2)C=C1 LOZWNVRRUMVRHD-BGYRXZFFSA-N 0.000 claims description 2
- 101001132878 Homo sapiens Motilin receptor Proteins 0.000 abstract description 21
- 102100033818 Motilin receptor Human genes 0.000 abstract description 21
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 6
- 230000001404 mediated effect Effects 0.000 abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 139
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 129
- 239000000243 solution Substances 0.000 description 53
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 52
- 239000000203 mixture Substances 0.000 description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 43
- 239000002904 solvent Substances 0.000 description 41
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 38
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 32
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- 238000004440 column chromatography Methods 0.000 description 28
- 235000019439 ethyl acetate Nutrition 0.000 description 26
- 239000010410 layer Substances 0.000 description 23
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- 239000007787 solid Substances 0.000 description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 21
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 20
- 239000012044 organic layer Substances 0.000 description 20
- 239000003921 oil Substances 0.000 description 19
- 235000019198 oils Nutrition 0.000 description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- 239000003643 water by type Substances 0.000 description 18
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
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- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 14
- 239000000556 agonist Substances 0.000 description 14
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 13
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 13
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 13
- 229920006395 saturated elastomer Polymers 0.000 description 13
- 239000011734 sodium Substances 0.000 description 13
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
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- 101800002372 Motilin Proteins 0.000 description 11
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- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- 229910052708 sodium Inorganic materials 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
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- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 8
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
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- OLIDKJBMRLAXQA-UHFFFAOYSA-N n-(3-fluorophenyl)piperidin-4-amine Chemical compound FC1=CC=CC(NC2CCNCC2)=C1 OLIDKJBMRLAXQA-UHFFFAOYSA-N 0.000 description 6
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 6
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- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 5
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- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
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- OLAMWIPURJGSKE-UHFFFAOYSA-N et2o diethylether Chemical compound CCOCC.CCOCC OLAMWIPURJGSKE-UHFFFAOYSA-N 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- OCLXJTCGWSSVOE-UHFFFAOYSA-N ethanol etoh Chemical compound CCO.CCO OCLXJTCGWSSVOE-UHFFFAOYSA-N 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 1
- 230000002964 excitative effect Effects 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 230000004634 feeding behavior Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 238000002825 functional assay Methods 0.000 description 1
- 125000003838 furazanyl group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000003324 growth hormone secretagogue Substances 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 229940077716 histamine h2 receptor antagonists for peptic ulcer and gord Drugs 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 210000000111 lower esophageal sphincter Anatomy 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 150000002678 macrocyclic compounds Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 230000003880 negative regulation of appetite Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 238000002610 neuroimaging Methods 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000002687 nonaqueous vehicle Substances 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 229960002700 octreotide Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- BCIIMDOZSUCSEN-UHFFFAOYSA-N piperidin-4-amine Chemical compound NC1CCNCC1 BCIIMDOZSUCSEN-UHFFFAOYSA-N 0.000 description 1
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 1
- 230000001817 pituitary effect Effects 0.000 description 1
- 210000003635 pituitary gland Anatomy 0.000 description 1
- 102000054765 polymorphisms of proteins Human genes 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 208000037821 progressive disease Diseases 0.000 description 1
- 230000001141 propulsive effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 239000000612 proton pump inhibitor Substances 0.000 description 1
- 229940126409 proton pump inhibitor Drugs 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000003369 serotonin 5-HT3 receptor antagonist Substances 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- DATRVIMZZZVHMP-MRVPVSSYSA-N tert-butyl (2r)-2-methylpiperazine-1-carboxylate Chemical compound C[C@@H]1CNCCN1C(=O)OC(C)(C)C DATRVIMZZZVHMP-MRVPVSSYSA-N 0.000 description 1
- FJIBTJVKKCLUBL-UHFFFAOYSA-N tert-butyl 4-(2-fluoroanilino)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1NC1=CC=CC=C1F FJIBTJVKKCLUBL-UHFFFAOYSA-N 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N tert-butyl alcohol Substances CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- PHCBRBWANGJMHS-UHFFFAOYSA-J tetrasodium;disulfate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O PHCBRBWANGJMHS-UHFFFAOYSA-J 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- 150000003555 thioacetals Chemical class 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
-
- 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
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- 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
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- 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
- A61P1/10—Laxatives
-
- 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
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Diabetes (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Nutrition Science (AREA)
- Hospice & Palliative Care (AREA)
- Otolaryngology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Aは、ハロゲン、C(1−4)アルキルまたはC(1−4)アルコキシで置換されていてもよいフェニルまたは6員のヘテロアリール環であり;
R1およびR2は、独立して、HまたはC(1−4)アルキルであり;
R3は、置換されていてもよいフェニルまたは置換されていてもよい5もしくは6員のヘテロアリールであり;
Yは、NH、O、CH2または結合であり;
R4は、C(1−4)アルキルまたはC(1−4)アルコキシC(1−4)アルキルである]
で示される化合物またはその医薬上許容される塩または誘導体を提供する。
本発明の一の具体例において、R1は水素またはメチルである。
本発明の一の具体例において、R2は水素またはメチルである。
本発明の一の具体例において、R3は置換されていてもよいフェニルである。
本発明の一の具体例において、Yは、NH、Oまたは結合である。
本発明の一の具体例において、R4はメチルである。
Aはフェニルまたはピリジルであり;および/または
R1は水素またはメチルであり;および/または
R2は水素またはメチルであり;および/または
R3は置換されていてもよいフェニルであり;および/または
YはNH、Oまたは結合であり;および/または
R4はメチルである。
R3が置換されたフェニルである場合、それは、フルオロ、シアノ、アミノカルボニルおよびメトキシから選択される1〜2個の置換基で置換されていてもよい。
本発明のさらなる具体例において、(ピペラジニル)メチレン置換基および(−NR4−)は、環Aを挟んで互いにパラ位にある。
4−[(3−フルオロフェニル)アミノ]−N−メチル−N−(4−{[(3S)−3−メチル−1−ピペラジニル]メチル}フェニル)−1−ピペリジンカルボキサミド(E1)、
4−[(4−フルオロフェニル)アミノ]−N−メチル−N−(4−{[(3S)−3−メチル−1−ピペラジニル]メチル}フェニル)−1−ピペリジンカルボキサミド(E2)、
4−[(3−シアノフェニル)アミノ]−N−メチル−N−(4−{[(3S)−3−メチル−1−ピペラジニル]メチル}フェニル)−1−ピペリジンカルボキサミド(E3)、
4−[(2−フルオロフェニル)アミノ]−N−メチル−N−(4−{[(3S)−3−メチル−1−ピペラジニル]メチル}フェニル)−1−ピペリジンカルボキサミド(E4)、
4−[(4−シアノフェニル)アミノ]−N−メチル−N−(4−{[(3S)−3−メチル−1−ピペラジニル]メチル}フェニル)−1−ピペリジンカルボキサミド(E5)、
4−{[2−(アミノカルボニル)フェニル]アミノ}−N−メチル−N−(4−{[(3S)−3−メチル−1−ピペラジニル]メチル}フェニル)−1−ピペリジンカルボキサミド(E6)、
4−[(3−フルオロフェニル)オキシ]−N−メチル−N−(4−{[(3S)−3−メチル−1−ピペラジニル]メチル}フェニル)−1−ピペリジンカルボキサミド(E7)、
4−[(2−シアノフェニル)アミノ]−N−メチル−N−(4−{[(3S)−3−メチル−1−ピペラジニル]メチル}フェニル)−1−ピペリジンカルボキサミド(E8)、
4−{[3−フルオロ−4−(メチルオキシ)フェニル]アミノ}−N−メチル−N−(4−{[(3S)−3−メチル−1−ピペラジニル]メチル}フェニル)−1−ピペリジンカルボキサミド(E9)、
4−{[4−フルオロ−3−(メチルオキシ)フェニル]アミノ}−N−メチル−N−(4−{[(3S)−3−メチル−1−ピペラジニル]メチル}フェニル)−1−ピペリジンカルボキサミド(E10)、
4−[(3−フルオロフェニル)アミノ]−N−メチル−N−(4−{[(3R)−3−メチル−1−ピペラジニル]メチル}フェニル)−1−ピペリジンカルボキサミド(E11)、
N−(4−{[(3R,5S)−3,5−ジメチル−1−ピペラジニル]メチル}フェニル)−4−[(3−フルオロフェニル)アミノ]−N−メチル−1−ピペリジンカルボキサミド(E12)、
4−[(3−シアノフェニル)アミノ]−N−メチル−N−[4−(1−ピペラジニルメチル)フェニル]−1−ピペリジンカルボキサミド(E13)、
4−[(3−フルオロフェニル)アミノ]−N−メチル−N−[4−(1−ピペラジニルメチル)フェニル]−1−ピペリジンカルボキサミド(E14)、
4−[(4−フルオロフェニル)アミノ]−N−メチル−N−[4−(1−ピペラジニルメチル)フェニル]−1−ピペリジンカルボキサミド(E15)、
4−(4−フルオロフェニル)−N−メチル−N−(4−{[(3S)−3−メチル−1−ピペラジニル]メチル}フェニル)−1−ピペリジンカルボキサミド(E16)、
4−(3−フルオロフェニル)−N−メチル−N−(4−{[(3S)−3−メチル−1−ピペラジニル]メチル}フェニル)−1−ピペリジンカルボキサミド(E17)、
4−(3−シアノフェニル)−N−メチル−N−(4−{[(3S)−3−メチル−1−ピペラジニル]メチル}フェニル)−1−ピペリジンカルボキサミド(E18)、
4−[(3−フルオロフェニル)アミノ]−N−メチル−N−(3−メチル−4−{[(3S)−3−メチル−1−ピペラジニル]メチル}フェニル)−1−ピペリジンカルボキサミド(E19)、
4−[(3−フルオロフェニル)アミノ]−N−メチル−N−(6−{[(3S)−3−メチル−1−ピペラジニル]メチル}−3−ピリジニル)−1−ピペリジンカルボキサミド(E20)、
4−{[4−(アミノカルボニル)フェニル]アミノ}−N−メチル−N−(4−{[(3S)−3−メチル−1−ピペラジニル]メチル}フェニル)−1−ピペリジンカルボキサミド(E21)、
4−[(4−シアノフェニル)アミノ]−N−メチル−N−[4−(1−ピペラジニルメチル)フェニル]−1−ピペリジンカルボキサミド(E22)
である。
で示される化合物またがその医薬上許容される塩または溶媒和物の製法であって、式(II):
で示される化合物を式(III):
で示される化合物と、尿素形成に適当な反応条件を用いて、例えば、ホスゲンまたはカルボニルジイミダゾールおよび適当な塩基、例えば、トリエチルアミンの存在下、適当な溶媒、例えば、1,2−ジクロロエタンまたはジクロロメタン中で反応させることを特徴とする製法を提供する。
1.式(I)の1の化合物の式(I)の他の化合物への変換;
2.いずれかの保護基の除去;
3.かくして形成された化合物の適当な医薬上許容される塩または溶媒和物の形成
の1以上を行ってもよいことを特徴とする。
で示される化合物と適当なアルデヒドまたはケトンとを、還元的アミノ化に適当な条件を用いて、例えば、水素化ホウ素ナトリウムなどの適当な還元剤の存在下、メタノールなどの適当な溶媒中、所望によりナトリウムメトキシドなどの適当な塩基の存在下で反応させて、R4を提供する反応によって調製されうる。
で示される化合物を、還元に適当な条件を用いて、例えば、QがBOCである場合、炭上のパラジウムまたは炭上の白金などの適当な触媒の存在下、メタノールなどの適当な溶媒中、および水酸化カリウムまたはトリエチルアミンなどの適当な塩基の存在下における水素化を用いて反応させることによって調製されうる。別法では、QがBOCまたはCBZである場合、還元は、塩化アンモニウムなどの適当なプロトン供給源の存在下、水性メタノールなどの適当な溶媒中、鉄粉などの適当な金属還元剤を用いて行ってもよい。
で示される化合物を式(VII):
で示される化合物と、還元的アミノ化に適当な反応条件を用いて、例えば、ジクロロメタンまたは1,2−ジクロロエタンなどの適当な溶媒中におけるトリ(アセトキシ)水素化ホウ素ナトリウムなどの還元剤の存在下で反応することによって調製されうる。
で示される化合物との、上記のような還元的アミノ化に適当な条件下での反応を含む。
で示される化合物と、式R4NHQ1(式中、R4は、式(I)の定義とおりであり、Q1は、tert−ブチルオキシカルボニル(BOC)などの適当な窒素保護基である]
で示される化合物との、トリス(ジベンジリデンアセトン)ジパラジウム(0)/キサントホス(Xantphos)などの適当な遷移金属触媒系の存在下、炭酸セシウムなどの適当な塩基の存在下、ジオキサンなどの適当な溶媒中における反応、次いで、適当な脱保護工程によって調製されうる。
で示される化合物とを、上記のような還元的アミノ化に適当な条件下で反応させ、次いで、適当な脱保護工程によってQ1を除去することを含む。
(I)
ハードウェア
Agilent 1100勾配プンプ
Agilent 1100オートサンプラー
Agilent 1100DAD検出器
Agilent 1100脱気器
Agilent 1100オーブン
Agilent 1100コントローラー
Waters ZQ質量分析計
Sedere Sedex 55、Sedere Sedex 85またはPolymer Labs PL−ELS−2100
ソフトウェア
Waters MassLynxバージョン4.0SP2
カラム
使用されるカラムは、寸法4.6mm x 50mmのWaters Atlantisである。固定相粒子サイズは、3μmである。
溶媒
A:水性溶媒=水+0.05%ギ酸
B:有機溶媒=アセトニトリル+0.05%ギ酸
方法
使用される一般的な方法は、5分実行時間を有する。
時間/分 %B
0 3
0.1 3
4 97
4.8 97
4.9 3
5.0 3
流速
上記の方法は、3ml/分の流速を有する。
ハードウェア
Waters Acquity二成分溶媒マネージャー
Waters Acquityサンプルマネージャー
Waters Acquity PDA
Waters ZQ質量分析計
Sedere Sedex 85、Sedere Sedex 75、Polymer Labs PL−ELS−2100
ソフトウェア
Waters MassLynxバージョン4.1
カラム
使用されるカラムは、寸法2.1mm x 50mmのWaters Acquity BEH UPLC C18である。固定相粒子サイズは、1.7μmである。
溶媒
A:水性溶媒=水+0.05%ギ酸
B:有機溶媒=アセトニトリル+0.05%ギ酸
弱洗浄=1:1 メタノール:水
強洗浄=水
方法
使用される一般的な方法は、2分の実行時間を有する。
時間/分 %B
0 3
0.1 3
1.5 97
1.9 97
2.0 3
上記の方法は、1ml/分の流速を有する。
一般的な方法の注入量は、0.5μlである。
カラム温度は40度である。
UV検出範囲は、220〜330nmである。
(I)
ハードウェア
下記からなるオープン・アクセス・マス・ディレクテッド・オート・プレプ装置:
1 Waters 600勾配ポンプ
1 Waters 2767インジェクト/コレクター
1 Waters試薬マネージャー
1 MicroMass ZQ質量分析計
1 Gilson Aspec−廃棄物コレクター
1 Gilson 115分画後UV検出器
1 コンピューターシステム
ソフトウェア
MicroMass MassLynx v4.0
カラム
使用されるカラムは、典型的には、内径20mm長さ100mmの寸法のSupelco LCABZ++カラムである。固定相粒子サイズは、5μmである。
A:水性溶媒=水+0.1%ギ酸
B:有機溶媒=MeCN:水 95:5+0.05%ギ酸
メイクアップ用溶媒=MeOH:水 80:20+50mMol酢酸アンモニウム
ニードルリンス用溶媒=MeOH:水:DMSO 80:10:10
方法
目的の化合物の分析保持時間によって、5方法のうち1つを用いてもよい。
全て、15分の実行時間を有し、10分の勾配、次いで、5分のカラム洗浄(flush)、および再平衡化工程を含む。
MDP 1.5−2.2=0−30%B
MDP 2.0−2.8=5−30%B
MDP 2.5−3.0=15−55%B
MDP 2.8−4.0=30−80%B
MDP 3.8−5.5=50−90%B
流速
上記の方法は全て、20ml/分の流速を有する。
ハードウェア
Waters 2525二成分勾配モジュール
Waters 515メイクアップポンプ
Watersポンプコントロールモジュール
Waters 2767インジェクト・コレクト
Watersカラム・フルーディックス・マネージャー
Waters 2996フォトダイオードアレイ検出器
Waters ZQ質量分析計
Gilson 202フラクションコンレクター
Gilson Aspec廃棄物コレクター
ソフトウェア
Waters MassLynxバージョン4 SP2
カラム
使用されるカラムは、19mm x 100mm(小規模)および30mm x 100mm(大規模)の寸法のWaters Atlantisである。固定相粒子サイズは、5μmである。
溶媒
A:水性溶媒=水+0.1%ギ酸
B:有機溶媒=アセトニトリル+0.1%ギ酸
メイクアップ用溶媒=メタノール:水 80:20
ニードルリンス用溶媒=メタノール
方法
目的の化合物の分析保持時間によって、使用される5つの方法がある。それらは、13.5分の実行時間を有し、10分の勾配、次いで、3.5分のカラム洗浄および再平衡化工程からなる。
大/小規模 1.0−1.5=5−30%B
大/小規模 1.5−2.2=15−55%B
大/小規模 2.2−2.9=30−85%B
大/小規模 2.9−3.6=50−99%B
大/小規模 3.6−5.0=80−99%B(6分で、次いで、7.5分の洗浄および再平衡化)
流速
上記MDAP法の全ては、20mls/分(小規模)または40mls/分(大規模)のいずれかの流速を有する。
浅い勾配
大 1.5〜2.3分=13−29%B
大 1.9〜2.3分=25−41%B
大 2.3〜2.6分=37−53%B
大 2.6〜3.1分=49−65%B
大 3.1〜3.6分=61−77%B
ハードウェア
Bruker 400MHzウルトラシールド
Bruker B−ACS60オートサンプラー
Bruker Advance 400コンソール
Bruker DPX250
Bruker AVANCE 500
Bruker DRX600
ソフトウェア
ユーザーインターフェース−NMR Kiosk
コントローリングソフトウェア−XWin NMRバージョン3.0
クロマトグラフィー
別記しないかぎり、全てのカラムクロマトグラフィーは、シリカカラムを用いて行った。
BINAP−(±)−2,2’−ビス(ジフェニルホスフィノ)−1,1’−ビナフタレン
tBuOH−tert−ブタノール
CDCl3−ジュウテリオクロロホルム
CD3OD−メタノール−d4
1,2−DCE−1,2−ジクロロエタン
DCM−ジクロロメタン
DMSO−d6−ジメチルスルホキシド−d6
Et2O−ジエチルエーテル
EtOAc−酢酸エチル
EtOH−エタノール
HCl−塩酸、塩化水素
IMS−工業用メチル化スピリット
KOH−水酸化カリウム
MeOH−メタノール
MgSO4−硫酸マグネシウム
MnO2−二酸化マンガン
NaCl−塩化ナトリウム
NaHCO3−炭酸水素ナトリウム
NaOH−水酸化ナトリウム
Na2SO4−硫酸ナトリウム
NH3−アンモニア
Pd/C−炭上のパラジウム
Pt/C−炭上の白金
SCX−強カチオン交換体
TFA−トリフルオロ酢酸
THF−テトラヒドロフラン
キサントホス(Xantphos)−4,5−ビス(ジフェニルホスフィノ)−9,9−ジメチルキサンセン
4−[(4−フルオロフェニル)アミノ]−1−ピペリジンカルボン酸1,1−ジメチルエチル(D1)
δH(CDCl3,250MHz)6.88(2H,t),6.54(2H,dd),4.04(2H,m),3.35(1H,m),2.91(2H,m),2.02(2H,m),1.46(9H,s),1.30(2H,m)
N−(4−フルオロフェニル)−4−ピペリジンアミン(D2)
δH(CDCl3,250MHz)6.88(2H,t),6.54(2H,dd),3.30(1H,m),3.20(2H,m),2.70(2H,m),2.05(2H,m),1.69(2H,br),1.29(2H,m)
4−[(3−フルオロフェニル)アミノ]−1−ピペリジンカルボン酸1,1−ジメチルエチル(D3)
δH(CDCl3,250MHz)7.08(1H,q),6.35(3H,m),4.04(1H,br s),3.65(1H,br s),3.38(1H,m),2.92(2H,m),2.02(2H,m),1.47(9H,s),1.34(2H,m)
N−(3−フルオロフェニル)−4−ピペリジンアミン(D4)
δH(CDCl3,250MHz)7.07(1H,q),6.33(3H,m),3.83(1H,br s),3.33(1H,br s),3.12(2H,m),2.71(2H,m),2.04(2H,m),1.30(2H,m)
N−(3−フルオロフェニル)−4−ピペリジンアミン塩酸塩(D4a)
3−フルオロアニリン(28.38ml,0.296mol)を4−オキソ−1−ピペリジンカルボキシレート(60g,0.302mol)の1,2−DCE(600ml)中溶液に加え、該混合物を15分間攪拌した。トリ(アセトキシ)水素化ホウ素ナトリウム(83g,0.392mol)を5分かけて徐々に加え、該混合物を5.5時間攪拌し、次いで、2M HCl(100ml)、水(200ml)および氷(1l)の混合物中に注ぎ入れた。相を分離し、水相をDCM(200ml)で抽出した。合わせた有機相をMgSO4で乾燥させ、濃縮して、薄黄色固体を得、それをMeOH(400ml)中に溶解し、2M HCl(100ml)で処理した。得られた溶液を60℃で一晩攪拌した。5M HCl(100ml)を加え、加熱をさらに7時間続けた。反応混合物を真空下で濃縮して、黄色油性固体を得た。これをMeOH/EtOAcから再結晶化して、2バッチの標題化合物を得た(42.6gおよび17.0g)。これらのバッチを次いで、IMS/EtOAcから再結晶化し、得られたバッチを真空下、50℃で乾燥させて、標題化合物を得た(全部で49.0g)。
δH(CD3OD,250MHz)7.54(1H,q),7.24(2H,m),7.15(1H,t),3.89(1H,m),3.54(2H,d),3.11(2H,t),2.24(2H,d),2.01(2H,m)
4−[(3−シアノフェニル)アミノ]−1−ピペリジンカルボン酸1,1−ジメチルエチル(D5)
δH(CDCl3,250MHz)7.22(1H,t),6.95(1H,dd),6.77(2H,m),4.07(2H,m),3.77(1H,m),3.41(1H,m),2.93(2H,m),2.03(2H,m),1.47(9H,s),1.34(2H,m)。MS(ES):MH+302
3−(4−ピペリジニルアミノ)ベンゾニトリル(D6)
δH(CDCl3,250MHz)7.21(2H,t),6.93(1H,m),6.77(2H,m),3.78(1H,m),3.35(1H,m),3.14(2H,m),2.73(2H,m),2.06(2H,m),1.34(2H,m)
MS(ES):MH+202
4−[(4−シアノフェニル)アミノ]−1−ピペリジンカルボン酸1,1−ジメチルエチル(D7)
4−(4−ピペリジニルアミノ)ベンゾニトリル(D8)
4−{[4−フルオロ−3−(メチルオキシ)フェニル]アミノ}−1−ピペリジンカルボン酸1,1−ジメチルエチル(D9)
δH(CDCl3,400MHz)6.89(1H,dd),6.22(1H,dd),6.09(1H,m),4.03(2H,br s),3.84(3H,s),3.36(1H,br s),2.92(2H,m),2.03(2H,m),1.46(9H,s),1.32(2H,m)
N−[4−フルオロ−3−(メチルオキシ)フェニル]−4−ピペリジンアミン(D10)
δH(DMSO−d6,400MHz)6.86(1H,dd),6.33(1H,dd),6.03(1H,m),5.32(1H,d),3.74(3H,s),3.33(1H,br s),3.18(1H,m),2.92(2H,m),2.51(2H,m),1.83(2H,m),1.17(2H,m)
MS(ES):MH+225
4−[(3−フルオロフェニル)オキシ]−1−ピペリジンカルボン酸1,1−ジメチルエチル(D11)
δH(CDCl3,250MHz)1.47(9H,s),1.76(2H,m),1.92(2H,m),3.35(2H,ddd),3.69(2H,ddd),4.44(1H,m),6.65(3H,m),7.20(1H,m)
4−[(3−フルオロフェニル)オキシ]ピペリジン(D12)
δH(CDCl3,250MHz)1.66(2H,m),2.01(2H,m),2.73(2H,m),3.14(2H,m),4.34(1H,m),6.68(3H,m),7.19(1H,m),MS(ES):MH+196
これを全てMeOHで希釈し、Et2O中における1M HClで処理して、標題化合物の塩酸塩を得た(8.0g)。
4−{[3−フルオロ−4−(メチルオキシ)フェニル]アミノ}−1−ピペリジンカルボン酸1,1−ジメチルエチル(D13)
N−[3−フルオロ−4−(メチルオキシ)フェニル]−4−ピペリジンアミン(D14)
4−[(2−フルオロフェニル)アミノ]−1−ピペリジンカルボン酸1,1−ジメチルエチル(D15)
N−(2−フルオロフェニル)−4−ピペリジンアミン(D16)
4−[(2−シアノフェニル)アミノ]−1−ピペリジンカルボン酸1,1−ジメチルエチル(D17)
2−(4−ピペリジニルアミノ)ベンゾニトリル(D18)
4−{[2−(アミノカルボニル)フェニル]アミノ}−1−ピペリジンカルボン酸1,1−ジメチルエチル(D19)
δH(CDCl3,250MHz)7.96(1H,br d),7.40(1H,m),7.31(1H,m),6.71(1H,d),6.57(1H,t),5.80(2H,br s),3.93(2H,m),3.53(1H,m),3.06(2H,m),1.99(2H,m),1.50(2H,m),1.47(9H,s)
MS(ES):MH+320
2−(4−ピペリジニルアミノ)ベンズアミド(D20)
(2S)−2−メチル−4−[(4−ニトロフェニル)メチル]−1−ピペラジンカルボン酸1,1−ジメチルエチル(D21)
δH(CDCl3,400MHz)8.19(2H,d),7.53(2H,d),4.21(1H,br.s),3.83(1H,d),3.62(1H,d),3.50(1H,d),3.13(1H,td),2.74(1H,m),2.54(1H,m),2.20(1H,dd),2.08(1H,m),1.46(9H,s),1.25(3H,d)
(2S)−2−メチル−4−[(4−ニトロフェニル)メチル]−1−ピペラジンカルボン酸1,1−ジメチルエチル(D21)
4−ニトロベンズアルデヒド(30.22g,0.2mol)、(2S)−2−メチル−1−ピペラジンカルボン酸1−ジメチルエチル(40.06g,0.2mol)およびトリ(アセトキシ)水素化ホウ素ナトリウム(85g,0.4mol)の1,2−DCE(1L)中混合物を週末にかけて室温で攪拌した。反応混合物を〜2時間かけて、NaHCO3溶液(400mL)で少しずつ処理した。さらに30分後、有機層を分離し、ブラインで洗浄し、乾燥させ、濃縮して、粘性薄黄色油を得た。0%、10%、次いで、20%のEtOAc/ヘキサンで溶出するカラムクロマトグラフィーにって精製して、標題化合物を黄色結晶性固体として得た(61.1g)。
(2S)−4−[(4−アミノフェニル)メチル]−2−メチル−1−ピペラジンカルボン酸1,1−ジメチルエチル(D22)
δH(CDCl3,400MHz)7.10(2H,d),6.64(2H,d),4.16(1H,br.s),3.78(1H,d),3.62(2H,s),3.42(1H,d),3.28(1H,d),3.08(1H,td),2.74(1H,m),2.58(1H,m),2.06(1H,dd),1.95(1H,m),1.46(9H,s),1.21(3H,d)
(2S)−4−[(4−アミノフェニル)メチル]−2−メチル−1−ピペラジンカルボン酸1,1−ジメチルエチル(D22)
水酸化カリウム(16.5g,0.29mol)の水(35mL)中溶液に、乾燥10%Pd/C触媒(10g)を加えた。MeOH(150mL)を加え、混合物を室温および大気圧下で15−20分間水素化した。MeOH(165mL)中における(2S)−2−メチル−4−[(4−ニトロフェニル)メチル]−1−ピペラジンカルボン酸1,1−ジメチルエチル(D21)(10g,29.8mmol)を加え、反応物を全部で5時間水素化した。触媒を濾過によって除去し、MeOHおよび水で洗浄し、濾液/洗浄液を真空下で濃縮した。残渣をDCMおよび水の間に分配し、水層をさらにDCMで抽出した。合わせた有機層をブラインで洗浄し、乾燥させ、濃縮して、標題化合物を無色ゴムとして得(8.49g)、それをさらに精製することなく次工程に用いた。
(2S)−4−[(4−アミノフェニル)メチル]−2−メチル−1−ピペラジンカルボン酸1,1−ジメチルエチル(D22)
(2S)−2−メチル−4−[(4−ニトロフェニル)メチル]−1−ピペラジンカルボン酸1,1−ジメチルエチル(D21)(21.62g,0.0644mol)、トリエチルアミン(40mL)および5%Pt/C触媒(21g,56%w/w水)のMeOH(400mL)中混合物を室温および大気圧下で一晩水素化した。触媒を濾過によって除去し、さらなるMeOHで洗浄した。濾液を真空下で濃縮し、DCM(200mL)中に再溶解し、2M NaOH溶液で洗浄した。水性洗浄液をDCM(x2,100mL)で再抽出し、全ての有機相を合わせ、ブラインで洗浄し、乾燥させ、濃縮して、標題化合物を得(19.53g)、それをさらに精製することなく次工程に用いた。
(2S)−4−[(4−アミノフェニル)メチル]−2−メチル−1−ピペラジンカルボン酸1,1−ジメチルエチル(D22)
MeOH(150mL)および水(150mL)中における(2S)−2−メチル−4−[(4−ニトロフェニル)メチル]−1−ピペラジンカルボン酸1,1−ジメチルエチル(D21)(15g,44.8mol)に、80℃にて、塩化アンモニウム(11.9g,0.224mol)および鉄粉(7.5g,0.134mol)を勢い良く攪拌しながら加えた。反応物を80℃で2時間攪拌した後、熱いままセライトR(登録商標)で濾過し、濾過ケークをさらなるDCMで洗浄した。濾液層を分離し、水層をDCM(x3)で洗浄した。DCM層を合わせ、乾燥させ(Na2SO4)、濃縮して粗生成物を得、それをカラムクロマトグラフィーによって精製した。20−70%EtOAc/石油エーテルでの溶出により、標題化合物を白色固体として得た(9.46g)。
(2S)−2−メチル−4−{[4−(メチルアミノ)フェニル]メチル}−1−ピペラジンカルボン酸1,1−ジメチルエチル(D23)
δH(CDCl3,400MHz)7.13(2H,d),6.57(2H,d),4.16(1H,br.s),3.78(1H,d),3.67(1H,br.s),3.42(1H,d),3.30(1H,d),3.08(1H,td),2.83(3H,s),2.75(1H,m),2.59(1H,m),2.06(1H,dd),1.94(1H,m),1.45(9H,s),1.21(3H,d)
(2S)−2−メチル−4−{[4−(メチルアミノ)フェニル]メチル}−1−ピペラジンカルボン酸1,1−ジメチルエチル(D23)
(2S)−4−[(4−アミノフェニル)メチル]−2−メチル−1−ピペラジンカルボン酸1,1−ジメチルエチル(D22)(7.45g,24.43mmol)、パラホルムアルデヒド(2.202g,73.28mmol)およびナトリウムメトキシド(6.597g,122.13mmol)のMeOH(150mL)中混合物をアルゴン雰囲気下、50℃で週末にかけて加熱した。冷却後、水素化ホウ素ナトリウム(1.848g,48.85mmol)を加え、反応混合物を50℃で1時間加熱後、室温に冷却した。泡立ちが観察されなくなるまでアセトンを加え、次いで、混合物を濃縮した。残渣をDCMおよび水の間に分配し、水層をDCMで再抽出した。合わせた有機相をMeOH(約20mL)で希釈して溶解性を助け、乾燥させ、濃縮して、標題化合物をオフホワイト色固体として得た(7.77g)。
(2R)−2−メチル−4−[(4−ニトロフェニル)メチル]−1−ピペラジンカルボン酸1,1−ジメチルエチル(D24)
MS(ES):[M−(CH2=CMe2)]H+ 280.2,[M−(CH2=CMe2)−CO2]H+ 236.3,分子イオンなし
(2R)−4−[(4−アミノフェニル)メチル]−2−メチル−1−ピペラジンカルボン酸1,1−ジメチルエチル(D25)
MS(ES):MH+306.2,MNa+328.2
(2R)−2−メチル−4−{[4−(メチルアミノ)フェニル]メチル}−1−ピペラジンカルボン酸1,1−ジメチルエチル(D26)
δH(CDCl3,400MHz)7.13(2H,d),6.57(2H,d),4.16(1H,m),3.78(1H,d),3.42(1H,d),3.29(1H,d),3.08(1H,td),2.83(3H,s),2.75(1H,m),2.59(1H,m),2.07(1H,dd),1.94(1H,m),1.45(9H,s),1.21(3H,d)
MS(ES):342.3(MNa+),分子イオン(MH+)観察されず。
(2R,6S)−2,6−ジメチル−4−[(4−ニトロフェニル)メチル]−1−ピペラジンカルボン酸1,1−ジメチルエチル(D27)
(2R,6S)−2,6−ジメチル−4−[(4−ニトロフェニル)メチル]−1−ピペラジンカルボン酸1,1−ジメチルエチル(D27)
(3R,5S)−1−[(4−ニトロフェニル)メチル]−3,5−ジメチルピペラジン(D57)(4.278g,17.17mmol)をジオキサン(180mL)中に溶解し、Boc無水物(7.494g,34.34mmol)および飽和水性NaHCO3溶液(60mL)を加えた。混合物を室温で一晩攪拌し、混合物を濾過し、濾過ケークをDCMで洗浄した。濾液を真空下で濃縮し、残渣をDCMおよび水の間に分配した。DCM層を分離し、水層をDCM(x2)で抽出した。DCM層を合わせ、乾燥させて、黄色油を生成した(9.614g)。混合物をSCXカートリッジに通すことによって精製して黄色油を生成し(4.787g)、それが標題化合物および未反応D82の混合物であった。これを全てDCM(60mL)中に溶解し、トリエチルアミン(2.936mL)を加え、次いでBoc無水物(4.612g,21.13mmol)を加えた。混合物をアルゴン下、室温で一晩攪拌した。PS−トリスアミン樹脂(6g)を加え、混合物を30分間攪拌させ、ポリマーを濾去し、溶媒を除去して黄色油を生成した(6.5621g)。0−50% Et2O/石油エーテルで溶出するカラムクロマトグラフィーによる精製によって、薄黄色固体を得た(5.245g)。該固体をMeOH中に溶解し、SCXカートリッジ(70g)に通し、それをMeOH、次いでMeOH中における2M NH3で洗い流した。溶媒を除去して黄色固体を生成し(3.833g)、それをさらにカラムクロマトグラフィーによって精製した。0−50% Et2O/石油エーテルでの溶出により、標題化合物を白っぽいクリーム色固体として得た(2.624g)。
MS(ES):294.3,+250.3,分子イオン(MH+)観察されず。
(2R,6S)−4−[(4−アミノフェニル)メチル]−2,6−ジメチル−1−ピペラジンカルボン酸1,1−ジメチルエチル(D28)
δH(CDCl3,400MHz)7.12(2H,d),6.64(2H,d),4.05(2H,m),3.64(2H,br.s),3.36(2H,s),2.59(2h,d),2.06(2H,dd),1.46(9H,s),1.27(6H,d)
MS(ES):MH+320.3,MNa+342.3
(2R,6S)−2,6−ジメチル−4−{[4−(メチルアミノ)フェニル]メチル}−1−ピペラジンカルボン酸1,1−ジメチルエチル(D29)
δH(CDCl3,400MHz)7.16(2H,d),6.57(2H,d),4.05(2H,m),3.70(1H,br s),3.36(2H,s),2.82(3H,s),2.59(2H,d),2.06(2H,dd),1.49(9H,s),1.27(6H,d)
MS(ES):356.3,(MNa+),234.3,分子イオン(MH+)観察されず。
4−[(4−ニトロフェニル)メチル]−1−ピペラジンカルボン酸1,1−ジメチルエチル(D30)
MS(ES):266.1,222.2,分子イオン(MH+)観察されず。
4−[(4−アミノフェニル)メチル]−1−ピペラジンカルボン酸1,1−ジメチルエチル(D31)
MS(ES):MH+292.1,MNa+314.2
4−{[4−(メチルアミノ)フェニル]メチル}−1−ピペラジンカルボン酸1,1−ジメチルエチル(D32)
δH(CDCl3,400MHz)7.11(2H,d),6.57(2H,d),3.69(1H,br.s),3.40(6H,m),2.83(3H,s),2.36(4H,m),1.45(9H,s)[スペクトル上0.58ppmにて不正確な標準TMSに対して補正されたδ値]
MS(ES):206.2,分子イオン(MH+)観察されず
(2S)−4−({4−[({4−[(3−フルオロフェニル)アミノ]−1−ピペリジニル}カルボニル)(メチル)アミノ]フェニル}メチル)−2−メチル−1−ピペラジンカルボン酸1,1−ジメチルエチル(D33)
δH(CDCl3,400MHz)7.29(2H,d),7.04(3H,m),6.32(2H,m),6.21(1H,m),4.18(1H,br s),3.80(3H,m),3.60(1H,m),3.49(1H,d),3.37(1H,d),3.28(1H,m),3.21(3H,s),3.10(1H,td),2.75(3H,m),2.56(1H,d),2.12(1H,dd),2.01(1H,td),1.87(2H,m),1.47(9H,s),1.23(3H,d),1.17(2H,m)
MS(ES):MH+540
(2S)−4−({4−[({4−[(3−フルオロフェニル)アミノ]−1−ピペリジニル}カルボニル)(メチル)アミノ]フェニル}メチル)−2−メチル−1−ピペラジンカルボン酸1,1−ジメチルエチル(D33)
乾燥DCM(100mL)中における(2S)−2−メチル−4−{[4−(メチルアミノ)フェニル]メチル}−1−ピペラジンカルボン酸1,1−ジメチルエチル(D23)(4.255g,13.319mmol)に、飽和水性NaHCO3溶液(100mL)を加え、混合物を氷浴中で冷却しながら10分間、勢い良く攪拌した。層を分離し、次いで、トルエン中におけるホスゲン溶液(20%,1.85M,12.813mL,24.216mmol)を直接、有機層に加えた。混合物を10分間、勢い良く攪拌した後、有機相を分離し、水層をDCMで2回抽出した。合わせた有機抽出物を乾燥させ、濃縮して、白色固体を得た。該物質を1,2−ジクロロエタン(80mL)中に溶解し、N−(3−フルオロフェニル)−4−ピペリジンアミン(D4)(2.352g,12.108mmol)を加え、次いで、トリエチルアミン(1.685mL,12.108mmol)を加えた。反応混合物を2時間熱還流した後、室温に冷却し、アルゴン下で一晩静置した。次いで、混合物をPS−トリスアミン樹脂(4.16g)で処理し、室温で30分間攪拌した。ポリマーを濾過によって除去し、濾液を濃縮して、粗生成物を黄色ゴムとして得た(10.375g)。該物質を、同規模で平行して行った第2の調製から得られた粗生成物(10.499g)と合わせた。合わせた粗生成物を、0−80% EtOAc/石油エーテルで溶出するカラムクロマトグラフィーによって精製して、標題化合物をクリーム色泡沫状ゴムとして得た(8.281g)。質量スペクトルおよび1H NMRスペクトル分析データは、記載例33由来の生成物に関して以前に得られたデータと一致した。
化合物は、一般構造式:
を有する。
(2S)−4−({4−[{[4−(4−フルオロフェニル)−1−ピペリジニル]カルボニル}(メチル)アミノ]フェニル}メチル)−2−メチル−1−ピペラジンカルボン酸1,1−ジメチルエチル(D48)
MS(ES):MH+525.3
(2S)−4−({4−[{[4−(3−フルオロフェニル)−1−ピペリジニル]カルボニル}(メチル)アミノ]フェニル}メチル)−2−メチル−1−ピペラジンカルボン酸1,1−ジメチルエチル(D49)
(2S)−4−({4−[{[4−(3−シアノフェニル)−1−ピペリジニル]カルボニル}(メチル)アミノ]フェニル}メチル)−2−メチル−1−ピペラジンカルボン酸1,1−ジメチルエチル(D50)
N−[4−(ヒドロキシメチル)−3−メチルフェニル]アセトアミド(D51)
δH(CD3OD,400MHz)7.36(2H,d),7.25(1H,d),4.57(2H,s),2.31(3H,s),2.10(3H,s)
MH+180.2
N−(4−ホルミル−3−メチルフェニル)アセトアミド(D52)
δH(CDCl3,400MHz)10.27(1H,s),7.79(1H,d),7.50(1H,d),7.45(1H,s),7.35(1H,br.s),2.66(3H,s),2.20(3H,s)
MH+178.2
(2S)−4−{[4−(アセチルアミノ)−2−メチルフェニル]メチル}−2−メチル−1−ピペラジンカルボン酸1,1−ジメチルエチル(D53)
δH(CDCl3,400MHz)7.27(2H,m),7.16(1H,d),7.11(1H,br.s),4.17(1H,m),3.78(1H,m),3.36(2H,s),3.02(1H,m),2.70(1H,m),2.56(1H,m),2.36(3H,s),2.17(4H,m),1.95(1H,m),1.45(9H,s),1.18(3H,d)
MH+362.3
(2S)−4−[(4−アミノ−2−メチルフェニル)メチル]−2−メチル−1−ピペラジンカルボン酸1,1−ジメチルエチル(D54)
δH(CDCl3,400MHz)6.97(1H,d),6.52(1H,d),6.46(1H,dd),4.17(1H,br.s),3.76(1H,d),3.57(2H,br.s),3.29(2H,m),3.01(1H,td),2.70(1H,d),2.56(1H,d),2.30(3H,s),2.10(1H,dd),1.90(1H,m),1.45(9H,s),1.18(3H,d)
MS(AP+):342.3(MNa+),分子イオン(MH+)観察されず。
(2S)−2−メチル−4−{[2−メチル−4−(メチルアミノ)フェニル]メチル}−1−ピペラジンカルボン酸1,1−ジメチルエチル(D55)
δH(CDCl3,400MHz)7.00(1H,d),6.45(1H,d),6.39(1H,dd),4.17(1H,br.s),3.76(1H,d),3.57(1H,br.s),3.33(1H,d),3.27(1H,d),3.01(1H,td),2.82(3H,s),2.71(1H,d),2.58(1H,d),2.32(3H,s),2.11(1H,dd),1.90(1H,m),1.45(9H,s),1.17(3H,d)
MS(AP+):356.2(MNa+),234.2,分子イオン(MH+)観察されず。
(2S)−4−({4−[({4−[(3−フルオロフェニル)アミノ]−1−ピペリジニル}カルボニル)(メチル)アミノ]−2−メチルフェニル}メチル)−2−メチル−1−ピペラジンカルボン酸1,1−ジメチルエチル(D56)
MS(ES):MNa+576.2,MH+554.3
(3R,5S)−1−[(4−ニトロフェニル)メチル]−3,5−ジメチルピペラジン(D57)
MS(ES):MH+250.2
メチルカルバミン酸1,1−ジメチルエチル(D58)
δH(CDCl3,400MHz)4.58(1H,br.s),2.73(3H,d),1.44(9H,s)
(6−ホルミル−3−ピリジニル)メチルカルバミン酸1,1−ジメチルエチル(D59)
δH(CDCl3,400MHz)10.01(1H,s),8.79(1H,d),7.94(1H,d),7.86(1H,dd),3.40(3H,s),1.53(9H,s)
MS(ES):259.1(MNa+),181.2,分子イオン(MH+)観察されず。
5−(メチルアミノ)−2−ピリジンカルバルデヒドおよび6−[ビス(メチルオキシ)メチル]−N−メチル−3−ピリジンアミン(D60)
MS(ES+):アルデヒド−137(MH+);アセタール−151.MS(AP+):アルデヒド−137(MH+);アセタール−205(MNa+),151.
(2S)−2−メチル−4−{[5−(メチルアミノ)−2−ピリジニル]メチル}−1−ピペラジンカルボン酸1,1−ジメチルエチル(D61)
δH(CDCl3,400MHz)7.96(1H,d),7.23(1H,d),6.88(1H,dd),4.17(1H,br.s),3.80(2H,d),3.58(1H,d),3.45(1H,d),3.12(1H,td),2.86(3H,s),2.76(1H,m),2.58(1H,m),2.18(1H,dd),2.07(1H,m),1.45(9H,s),1.23(3H,d)
MS(ES):MH+321.4
(2S)−4−({5−[({4−[(3−フルオロフェニル)アミノ]−1−ピペリジニル}カルボニル)(メチル)アミノ]−2−ピリジニル}メチル)−2−メチル−1−ピペラジンカルボン酸1,1−ジメチルエチル(D62)
MS(ES):MH+541.4
4−[(3−フルオロフェニル)アミノ]−N−メチル−N−(4−{[(3S)−3−メチル−1−ピペラジニル]メチル}フェニル)−1−ピペリジンカルボキサミド(E1)
δH(CDCl3,400MHz)7.27(2H,d),7.05(3H,m),6.34(1H,m),6.29(1H,m),6.21(1H,m),3.77(2H,d),3.62(1H,d),3.47(2H,m),3.38(1H,m),3.21(3H,s),2.93(3H,m),2.75(3H,m),2.20(1H+H2O,br.s),2.05(1H,td),1.85(2H,m),1.72(1H,m),1.16(2H,m),1.04(3H,d)
MS(ES):MH+440.2
これを全てDCM中に溶解し、Et2O中における1M HCl(100μl)で処理した。溶媒を真空下で除去して、標題化合物の塩酸塩を白色固体として得た(47mg)。
MS(ES):MH+440.2
4−[(3−フルオロフェニル)アミノ]−N−メチル−N−(4−{[(3S)−3−メチル−1−ピペラジニル]メチル}フェニル)−1−ピペリジンカルボキサミド(E1)
(2S)−4−({4−[({4−[(3−フルオロフェニル)アミノ]−1−ピペリジニル}カルボニル)(メチル)アミノ]フェニル}メチル)−2−メチル−1−ピペラジンカルボン酸1,1−ジメチルエチル(D33)(9.337g,17.322mmol)をDCM(144mL)中に溶解し、氷浴中で冷却した。TFA(36mL)をゆっくりと加え、混合物をアルゴン下で2.5時間攪拌した。溶媒を真空下で除去し、残渣をDCMおよび飽和水性NaHCO3の間に分配した。有機層を分離し、水層をDCMで2回抽出した。合わせた有機抽出物を乾燥させ、濃縮して、標題化合物をクリーム色の泡沫として得た(7.82g)。
MS(ES):MH+440.3.
δH(CD3OD,400MHz)7.55(2H,d),7.22(2H,d),7.16(1H,dd),6.62(1H,d),6.49−6.57(2H,m),4.19(2H,s),3.30(2H,d),3.69(1H,m),3.59(1H,m),3.45(4H,m),3.20(3H,s),3.10(1H,m),2.91(1H,m),2.83(2H,t),1.85(2H,d),1.35(3H,d),1.30(2H,m)
4−(4−フルオロフェニル)−N−メチル−N−(4−{[(3S)−3−メチル−1−ピペラジニル]メチル}フェニル)−1−ピペリジンカルボキサミド(E16)
δH(CDCl3,400MHz)7.29(2H,d),7.06(4H,m),6.95(2H,m),3.95(2H,m),3.46(2H,s),3.23(3H,s),2.82−2.97(3H,m),2.74(2H,d),2.65(2H,m),2.52(1H,m),2.02(1H,td),1.69(1H,m),1.82(1H+H2O,br.s),1.62(2H,d),1.40(2H,m),0.98(3H,d)
MS(ES):MH+425.2
これを全てMeOH中に溶解し、Et2O中における1M HCl(0.24ml)で処理して、標題化合物の塩酸塩を薄黄色油として得た(92.5mg)。
MS(ES):MH+425.3
4−(3−フルオロフェニル)−N−メチル−N−(4−{[(3S)−3−メチル−1−ピペラジニル]メチル}フェニル)−1−ピペリジンカルボキサミド(E17)
MS(ES):MH+425.2
4−(3−シアノフェニル)−N−メチル−N−(4−{[(3S)−3−メチル−1−ピペラジニル]メチル}フェニル)−1−ピペリジンカルボキサミド(E18)
MS(ES):MH+432.1
4−[(3−フルオロフェニル)アミノ]−N−メチル−N−(3−メチル−4−{[(3S)−3−メチル−1−ピペラジニル]メチル}フェニル)−1−ピペリジンカルボキサミド(E19)
MS(ES):MH+454.3
4−[(3−フルオロフェニル)アミノ]−N−メチル−N−(6−{[(3S)−3−メチル−1−ピペラジニル]メチル}−3−ピリジニル)−1−ピペリジンカルボキサミド(E20)
MS(ES)MH+441.3
これを全てDCM中に溶解し、Et2O中における1M HCl(545μl)で処理した。溶媒を真空下で除去して、標題化合物の塩酸塩を白色固体として得た(261mg)。
MS(ES):MH+441.3
アッセイの24時間前に、GPR38受容体を安定に発現しているCHO−K1細胞をポリ−D−リジンコートした384ウェル黒壁透明底マイクロタイタープレート(Greiner)中に播種した(10,000細胞/ウェル)。アッセイの日に、細胞洗浄器を用いて培地を細胞プレートから吸引した(10μlの培地を残す)。すぐに、細胞にローディングバッファー[Tyrodes(Elga水+145mM NaCl+5mM KCl+20mM HEPES+10mMグルコース+1mM MgCl2)+1.5mM CaCl2+0.714mg/mlプロベニシド(Probenicid)(1M NaOH中に予め溶解した)+0.25mMブリリアント・ブラック+2μM Fluo4ダイ]を負荷し、37.5℃で1時間インキュベートした。
次いで、プレートを蛍光イメージングプレートリーダー(FLIPR,Molecular Devices)上でアッセイした。
マスター化合物プレートを100%DMSO中で調製した。最高濃度3mMを用い(アッセイ中、12μM最終濃度をもたらす)、これを1:4で連続希釈した。、マスタープレート由来の1μlを娘プレートに移し、そこに50μlの化合物希釈バッファー(Tyrodes+1mg/ml BSA+1.5mM CaCl2)を加えた。FLIPRにおいて、10μlの試験化合物を細胞に加え、1分の時間枠で蛍光変化を測定した。ベースラインを超える最大の蛍光変化を用いて、アゴニスト応答を決定し、4−パラメータロジスティック方程式を用いて濃度応答曲線を構築した。
別のプロトコールにおいて、ローディングバッファーは、HBSS{Elga水+137mM NaCl+5mM KCl+0.41mMa KH2PO4(無水)+20mM HEPES+5mMグルコース+0.81mM MgSO4(無水)+1.3mM CaCl2+4.16mM NaHCO3}+0.25mMブリリアント・ブラック+2μM Fluo4ダイおよびであり、CHO−K1細胞を冷凍アリコートから解凍し、アッセイの24時間前に播種した。
Claims (8)
- Aがフェニルまたはピリジルであり;および/または
R1が水素またはメチルであり;および/または
R2が水素またはメチルであり;および/または
R3が置換されていてもよいフェニルであり;および/または
YがNH、Oまたは結合であり;および/または
R4がメチルである、請求項1記載の式(I)の化合物またはその医薬上許容される塩。 - (ピペラジニル)メチレン置換基および−NR4が環Aを挟んで互いにパラ位にある請求項1または2記載の化合物またはその塩。
- 4−[(3−フルオロフェニル)アミノ]−N−メチル−N−(4−{[(3S)−3−メチル−1−ピペラジニル]メチル}フェニル)−1−ピペリジンカルボキサミド、
4−[(4−フルオロフェニル)アミノ]−N−メチル−N−(4−{[(3S)−3−メチル−1−ピペラジニル]メチル}フェニル)−1−ピペリジンカルボキサミド、
4−[(3−シアノフェニル)アミノ]−N−メチル−N−(4−{[(3S)−3−メチル−1−ピペラジニル]メチル}フェニル)−1−ピペリジンカルボキサミド、
4−[(2−フルオロフェニル)アミノ]−N−メチル−N−(4−{[(3S)−3−メチル−1−ピペラジニル]メチル}フェニル)−1−ピペリジンカルボキサミド、
4−[(4−シアノフェニル)アミノ]−N−メチル−N−(4−{[(3S)−3−メチル−1−ピペラジニル]メチル}フェニル)−1−ピペリジンカルボキサミド、
4−{[2−(アミノカルボニル)フェニル]アミノ}−N−メチル−N−(4−{[(3S)−3−メチル−1−ピペラジニル]メチル}フェニル)−1−ピペリジンカルボキサミド、
4−[(3−フルオロフェニル)オキシ]−N−メチル−N−(4−{[(3S)−3−メチル−1−ピペラジニル]メチル}フェニル)−1−ピペリジンカルボキサミド、
4−[(2−シアノフェニル)アミノ]−N−メチル−N−(4−{[(3S)−3−メチル−1−ピペラジニル]メチル}フェニル)−1−ピペリジンカルボキサミド、
4−{[3−フルオロ−4−(メチルオキシ)フェニル]アミノ}−N−メチル−N−(4−{[(3S)−3−メチル−1−ピペラジニル]メチル}フェニル)−1−ピペリジンカルボキサミド、
4−{[4−フルオロ−3−(メチルオキシ)フェニル]アミノ}−N−メチル−N−(4−{[(3S)−3−メチル−1−ピペラジニル]メチル}フェニル)−1−ピペリジンカルボキサミド、
4−[(3−フルオロフェニル)アミノ]−N−メチル−N−(4−{[(3R)−3−メチル−1−ピペラジニル]メチル}フェニル)−1−ピペリジンカルボキサミド、
N−(4−{[(3R,5S)−3,5−ジメチル−1−ピペラジニル]メチル}フェニル)−4−[(3−フルオロフェニル)アミノ]−N−メチル−1−ピペリジンカルボキサミド、
4−[(3−シアノフェニル)アミノ]−N−メチル−N−[4−(1−ピペラジニルメチル)フェニル]−1−ピペリジンカルボキサミド、
4−[(3−フルオロフェニル)アミノ]−N−メチル−N−[4−(1−ピペラジニルメチル)フェニル]−1−ピペリジンカルボキサミド、
4−[(4−フルオロフェニル)アミノ]−N−メチル−N−[4−(1−ピペラジニルメチル)フェニル]−1−ピペリジンカルボキサミド、
4−(4−フルオロフェニル)−N−メチル−N−(4−{[(3S)−3−メチル−1−ピペラジニル]メチル}フェニル)−1−ピペリジンカルボキサミド、
4−(3−フルオロフェニル)−N−メチル−N−(4−{[(3S)−3−メチル−1−ピペラジニル]メチル}フェニル)−1−ピペリジンカルボキサミド、
4−(3−シアノフェニル)−N−メチル−N−(4−{[(3S)−3−メチル−1−ピペラジニル]メチル}フェニル)−1−ピペリジンカルボキサミド、
4−[(3−フルオロフェニル)アミノ]−N−メチル−N−(3−メチル−4−{[(3S)−3−メチル−1−ピペラジニル]メチル}フェニル)−1−ピペリジンカルボキサミド、
4−[(3−フルオロフェニル)アミノ]−N−メチル−N−(6−{[(3S)−3−メチル−1−ピペラジニル]メチル}−3−ピリジニル)−1−ピペリジンカルボキサミド
から選択される化合物またはその塩。 - 4−[(3−フルオロフェニル)アミノ]−N−メチル−N−(4−{[(3S)−3−メチル−1−ピペラジニル]メチル}フェニル)−1−ピペリジンカルボキサミドである、請求項1記載の式(I)の化合物またはその塩。
- Aが置換されていてもよいフェニルまたは置換されていてもよいピリジルであるときの請求項1〜5のいずれか1項記載の化合物またはその医薬上許容される塩:
(a)式(II):
で示される化合物および式(III):
で示される化合物を、尿素形成に適当な反応条件を用いて、反応させ、
(b)その後、下記の反応:
いずれかの保護基の除去;
かくして形成された化合物の適当な医薬上許容される塩または溶媒和物の形成
の1以上を行ってもよい
ことを特徴とする製法。
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2006
- 2006-06-15 GB GBGB0611907.7A patent/GB0611907D0/en not_active Ceased
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2007
- 2007-06-14 US US12/304,539 patent/US8012981B2/en not_active Expired - Fee Related
- 2007-06-14 EP EP07765418A patent/EP2029538B1/en active Active
- 2007-06-14 AT AT07765418T patent/ATE542795T1/de active
- 2007-06-14 JP JP2009514801A patent/JP5232143B2/ja not_active Expired - Fee Related
- 2007-06-14 WO PCT/EP2007/055890 patent/WO2007144400A1/en active Application Filing
- 2007-06-14 ES ES07765418T patent/ES2379658T3/es active Active
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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US9142971B2 (en) | 2006-03-07 | 2015-09-22 | Server Technology, Inc. | Power distribution, management, and monitoring systems and methods |
US9952261B2 (en) | 2009-03-04 | 2018-04-24 | Server Technology, Inc. | Monitoring power-related parameters in a power distribution unit |
Also Published As
Publication number | Publication date |
---|---|
US20110275815A1 (en) | 2011-11-10 |
ATE542795T1 (de) | 2012-02-15 |
ES2379658T3 (es) | 2012-04-30 |
EP2029538A1 (en) | 2009-03-04 |
EP2029538B1 (en) | 2012-01-25 |
US8236953B2 (en) | 2012-08-07 |
GB0611907D0 (en) | 2006-07-26 |
US8012981B2 (en) | 2011-09-06 |
US20090131453A1 (en) | 2009-05-21 |
JP2009539938A (ja) | 2009-11-19 |
WO2007144400A1 (en) | 2007-12-21 |
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