TWI421070B - 螺化合物及其醫藥用途 - Google Patents
螺化合物及其醫藥用途 Download PDFInfo
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- TWI421070B TWI421070B TW097140805A TW97140805A TWI421070B TW I421070 B TWI421070 B TW I421070B TW 097140805 A TW097140805 A TW 097140805A TW 97140805 A TW97140805 A TW 97140805A TW I421070 B TWI421070 B TW I421070B
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- Prior art keywords
- spiro
- compound
- group
- ring
- pharmaceutically acceptable
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- 150000003413 spiro compounds Chemical class 0.000 title claims description 71
- 150000001875 compounds Chemical class 0.000 claims description 374
- 238000002360 preparation method Methods 0.000 claims description 143
- 150000003839 salts Chemical class 0.000 claims description 120
- 125000003003 spiro group Chemical group 0.000 claims description 71
- 206010012601 diabetes mellitus Diseases 0.000 claims description 48
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 47
- 125000004432 carbon atom Chemical group C* 0.000 claims description 45
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 43
- 239000008103 glucose Substances 0.000 claims description 43
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 39
- 229910052799 carbon Inorganic materials 0.000 claims description 36
- 239000003795 chemical substances by application Substances 0.000 claims description 31
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims description 28
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- 125000001424 substituent group Chemical group 0.000 claims description 24
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 22
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- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 22
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 20
- 239000008194 pharmaceutical composition Substances 0.000 claims description 18
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- 229910052717 sulfur Inorganic materials 0.000 claims description 17
- DGENZVKCTGIDRZ-UHFFFAOYSA-N 3-[4-[(3-phenoxyphenyl)methylamino]phenyl]propanoic acid Chemical compound C1=CC(CCC(=O)O)=CC=C1NCC1=CC=CC(OC=2C=CC=CC=2)=C1 DGENZVKCTGIDRZ-UHFFFAOYSA-N 0.000 claims description 16
- 229940125827 GPR40 agonist Drugs 0.000 claims description 16
- 208000002705 Glucose Intolerance Diseases 0.000 claims description 16
- 125000005842 heteroatom Chemical group 0.000 claims description 16
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 16
- 125000004434 sulfur atom Chemical group 0.000 claims description 16
- 201000001421 hyperglycemia Diseases 0.000 claims description 15
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 14
- 102000004877 Insulin Human genes 0.000 claims description 14
- 108090001061 Insulin Proteins 0.000 claims description 14
- 229940125396 insulin Drugs 0.000 claims description 14
- 230000003914 insulin secretion Effects 0.000 claims description 14
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 12
- 230000002159 abnormal effect Effects 0.000 claims description 12
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 11
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 11
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 10
- 239000004480 active ingredient Substances 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 239000003472 antidiabetic agent Substances 0.000 claims description 8
- 229940126904 hypoglycaemic agent Drugs 0.000 claims description 8
- 125000000468 ketone group Chemical group 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 4
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- 125000004429 atom Chemical group 0.000 claims description 2
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- 230000001771 impaired effect Effects 0.000 claims 1
- 239000011593 sulfur Substances 0.000 claims 1
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- 239000000243 solution Substances 0.000 description 239
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 134
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- 239000012453 solvate Substances 0.000 description 66
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 47
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- 238000000034 method Methods 0.000 description 45
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- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 38
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- 238000004440 column chromatography Methods 0.000 description 35
- 229920006395 saturated elastomer Polymers 0.000 description 32
- 238000004519 manufacturing process Methods 0.000 description 31
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 24
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 24
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 13
- 239000012279 sodium borohydride Substances 0.000 description 13
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- PZRRDICPFGUDED-QWAKEFERSA-N (3s)-3-[4-(spiro[5.5]undecan-4-ylmethoxy)phenyl]hex-4-ynoic acid Chemical compound C1=CC([C@H](CC(O)=O)C#CC)=CC=C1OCC1CC2(CCCCC2)CCC1 PZRRDICPFGUDED-QWAKEFERSA-N 0.000 description 7
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Classifications
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- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
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- C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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- C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
- C07C235/76—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
- C07C235/78—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing rings
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
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- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
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- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
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- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
- C07D277/34—Oxygen atoms
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/07—Optical isomers
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
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| AU2008314933B2 (en) * | 2007-10-26 | 2013-05-02 | Japan Tobacco Inc. | Spiro-ring compound and use thereof for medical purposes |
| EP2289868B1 (en) * | 2008-06-25 | 2014-08-13 | Daiichi Sankyo Company, Limited | Carboxylic acid compound |
| JP5749261B2 (ja) * | 2009-06-29 | 2015-07-15 | メルツ・ファルマ・ゲーエムベーハー・ウント・コ・カーゲーアーアー | 3,3,5,5−テトラメチルシクロヘキサノンを調製する方法 |
| JP5749259B2 (ja) | 2009-06-29 | 2015-07-15 | メルツ・ファルマ・ゲーエムベーハー・ウント・コ・カーゲーアーアー | 1−クロロアセトアミド−1,3,3,5,5−ペンタメチルシクロヘキサンを調製する方法 |
| PL2448910T3 (pl) * | 2009-06-29 | 2013-10-31 | Merz Pharma Gmbh & Co Kgaa | Sposób wytwarzania nerameksanu |
| EP2289881A1 (de) * | 2009-08-06 | 2011-03-02 | Boehringer Ingelheim International GmbH | Verfahren zur stereoselektiven Synthese bicyclischer Heterocyclen |
| AR078522A1 (es) * | 2009-10-15 | 2011-11-16 | Lilly Co Eli | Compuesto de espiropiperidina, composicion farmaceutica que lo comprende, su uso para preparar un medicamento util para tratar diabetes y compuesto intermediario para su sintesis |
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| TW201221505A (en) | 2010-07-05 | 2012-06-01 | Sanofi Sa | Aryloxyalkylene-substituted hydroxyphenylhexynoic acids, process for preparation thereof and use thereof as a medicament |
| TW201215388A (en) | 2010-07-05 | 2012-04-16 | Sanofi Sa | (2-aryloxyacetylamino)phenylpropionic acid derivatives, processes for preparation thereof and use thereof as medicaments |
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