TWI333855B - Benzamide compounds, process for preparation thereof, and pharmaceutical compositions for treating or preventing a disease or medical condition mediated through glucokinase (glk) comprising same - Google Patents
Benzamide compounds, process for preparation thereof, and pharmaceutical compositions for treating or preventing a disease or medical condition mediated through glucokinase (glk) comprising same Download PDFInfo
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- TWI333855B TWI333855B TW097137990A TW97137990A TWI333855B TW I333855 B TWI333855 B TW I333855B TW 097137990 A TW097137990 A TW 097137990A TW 97137990 A TW97137990 A TW 97137990A TW I333855 B TWI333855 B TW I333855B
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- 238000000034 method Methods 0.000 title claims description 61
- 238000002360 preparation method Methods 0.000 title claims description 41
- 201000010099 disease Diseases 0.000 title claims description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 9
- 230000008569 process Effects 0.000 title claims description 5
- 102000030595 Glucokinase Human genes 0.000 title description 79
- 108010021582 Glucokinase Proteins 0.000 title description 79
- 230000001404 mediated effect Effects 0.000 title description 2
- 150000003936 benzamides Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 234
- 125000000217 alkyl group Chemical group 0.000 claims description 215
- -1 Hexahydropyridinyl Chemical group 0.000 claims description 125
- 125000000623 heterocyclic group Chemical group 0.000 claims description 56
- 150000003839 salts Chemical class 0.000 claims description 52
- 229910052739 hydrogen Inorganic materials 0.000 claims description 47
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 39
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 39
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 38
- 125000005843 halogen group Chemical group 0.000 claims description 37
- 239000001257 hydrogen Substances 0.000 claims description 37
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 32
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 29
- 238000011282 treatment Methods 0.000 claims description 28
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 27
- 239000012453 solvate Substances 0.000 claims description 25
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 24
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 23
- 238000006243 chemical reaction Methods 0.000 claims description 21
- 206010012601 diabetes mellitus Diseases 0.000 claims description 18
- 125000003118 aryl group Chemical group 0.000 claims description 17
- 125000006239 protecting group Chemical group 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- 125000003342 alkenyl group Chemical group 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 14
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 14
- 208000008589 Obesity Diseases 0.000 claims description 13
- 235000020824 obesity Nutrition 0.000 claims description 13
- 125000001424 substituent group Chemical group 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 9
- 125000004076 pyridyl group Chemical group 0.000 claims description 9
- 230000002265 prevention Effects 0.000 claims description 8
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 7
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 7
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 claims description 6
- 238000006467 substitution reaction Methods 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 5
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 5
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 4
- 238000010511 deprotection reaction Methods 0.000 claims description 4
- 125000001475 halogen functional group Chemical group 0.000 claims description 4
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 4
- 125000003386 piperidinyl group Chemical group 0.000 claims description 4
- 230000001105 regulatory effect Effects 0.000 claims description 4
- 125000000565 sulfonamide group Chemical group 0.000 claims description 4
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 4
- 230000001225 therapeutic effect Effects 0.000 claims description 4
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical group [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 3
- 125000003282 alkyl amino group Chemical group 0.000 claims description 3
- 125000004122 cyclic group Chemical group 0.000 claims description 3
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical group C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 3
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 3
- 125000005505 thiomorpholino group Chemical group 0.000 claims description 3
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical group O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 5
- KLSJWNVTNUYHDU-UHFFFAOYSA-N Amitrole Chemical group NC1=NC=NN1 KLSJWNVTNUYHDU-UHFFFAOYSA-N 0.000 claims 1
- 229920000858 Cyclodextrin Polymers 0.000 claims 1
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 claims 1
- 238000002648 combination therapy Methods 0.000 claims 1
- 229930003658 monoterpene Natural products 0.000 claims 1
- 125000002299 monoterpene group Chemical group 0.000 claims 1
- 235000002577 monoterpenes Nutrition 0.000 claims 1
- 125000004673 propylcarbonyl group Chemical group 0.000 claims 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims 1
- 125000004306 triazinyl group Chemical group 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 192
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 138
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 98
- 235000019439 ethyl acetate Nutrition 0.000 description 84
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 63
- 239000000243 solution Substances 0.000 description 61
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 59
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 56
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 54
- 239000002585 base Substances 0.000 description 49
- 239000000203 mixture Substances 0.000 description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 47
- 229910001868 water Inorganic materials 0.000 description 43
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
- 239000011541 reaction mixture Substances 0.000 description 38
- 239000007787 solid Substances 0.000 description 32
- 238000005160 1H NMR spectroscopy Methods 0.000 description 30
- 239000002253 acid Substances 0.000 description 30
- 239000000651 prodrug Substances 0.000 description 30
- 229940002612 prodrug Drugs 0.000 description 30
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 29
- 229910052786 argon Inorganic materials 0.000 description 27
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 26
- 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 description 23
- 239000008103 glucose Substances 0.000 description 23
- 239000007789 gas Substances 0.000 description 21
- 239000000725 suspension Substances 0.000 description 21
- 150000002431 hydrogen Chemical group 0.000 description 20
- 239000007858 starting material Substances 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 230000000694 effects Effects 0.000 description 18
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 18
- 239000002904 solvent Substances 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 150000002148 esters Chemical class 0.000 description 16
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 15
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 15
- 230000003993 interaction Effects 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 14
- 230000007062 hydrolysis Effects 0.000 description 14
- 238000006460 hydrolysis reaction Methods 0.000 description 14
- 125000006327 phenyl hydrazinyl group Chemical group [H]N(*)N([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- MWKFXSUHUHTGQN-UHFFFAOYSA-N decan-1-ol Chemical compound CCCCCCCCCCO MWKFXSUHUHTGQN-UHFFFAOYSA-N 0.000 description 12
- 238000001704 evaporation Methods 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
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- 239000012267 brine Substances 0.000 description 11
- 230000008020 evaporation Effects 0.000 description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
- 239000007921 spray Substances 0.000 description 11
- 235000021419 vinegar Nutrition 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 238000005804 alkylation reaction Methods 0.000 description 10
- 229910052799 carbon Inorganic materials 0.000 description 10
- 230000008878 coupling Effects 0.000 description 10
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 10
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 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 10
- 239000000052 vinegar Substances 0.000 description 10
- VZXTWGWHSMCWGA-UHFFFAOYSA-N 1,3,5-triazine-2,4-diamine Chemical compound NC1=NC=NC(N)=N1 VZXTWGWHSMCWGA-UHFFFAOYSA-N 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 9
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- 230000029936 alkylation Effects 0.000 description 9
- 125000000304 alkynyl group Chemical group 0.000 description 9
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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 9
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 9
- 238000000159 protein binding assay Methods 0.000 description 9
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 8
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- 238000005481 NMR spectroscopy Methods 0.000 description 8
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- 101150041968 CDC13 gene Proteins 0.000 description 7
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 7
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- GZVHEAJQGPRDLQ-UHFFFAOYSA-N 6-phenyl-1,3,5-triazine-2,4-diamine Chemical class NC1=NC(N)=NC(C=2C=CC=CC=2)=N1 GZVHEAJQGPRDLQ-UHFFFAOYSA-N 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
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- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
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- 125000001425 triazolyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
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- 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
- XOTGRWARRARRKM-UHFFFAOYSA-N uranium hydride Chemical compound [UH3] XOTGRWARRARRKM-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
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- C07D213/00—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
- 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
- C07D213/72—Nitrogen atoms
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- 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D213/82—Amides; Imides in position 3
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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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
- C07D213/85—Nitriles in position 3
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole 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
- C07D231/38—Nitrogen atoms
- C07D231/40—Acylated on said nitrogen atom
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
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- C07D233/48—Nitrogen atoms not forming part of a nitro radical with acyclic hydrocarbon or substituted acyclic hydrocarbon radicals, attached to said nitrogen atoms
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- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
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- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having 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
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- C—CHEMISTRY; METALLURGY
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
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- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
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- C—CHEMISTRY; METALLURGY
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- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
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| RU2005113713A (ru) | 2002-10-03 | 2006-01-20 | Новартис АГ (CH) | Замещенные (тиазол-2-ил)амиды или сульфонамиды в качестве активаторов глюкокиназы, которые могут применяться при лечении диабета типа 2 |
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| PL378117A1 (pl) | 2003-02-11 | 2006-03-06 | Prosidion Limited | Tricyklopodstawione związki amidowe |
| AU2004220234C1 (en) | 2003-02-13 | 2013-01-17 | Msd K.K. | Novel 2-pyridinecarboxamide derivatives |
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| DE602004016992D1 (de) * | 2003-05-02 | 2008-11-20 | Elan Pharm Inc | 4-bromo-5-(2-chloro-benzoylamino)-1h-pyrazol-3-carbonsäureamid-derivate und verwandte verbindungen als bradykinin b1 rezeptor antagonisten zur behandlung von entzündlichen erkrankungen |
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| ATE390922T1 (de) * | 2003-06-20 | 2008-04-15 | Hoffmann La Roche | 2-aminobenzothiazole als cb1 rezeptor inverse agonisten |
| ES2222822B1 (es) * | 2003-07-28 | 2005-12-16 | Laboratorios Farmaceuticos Rovi, S.A. | Diamidas de aminoacidos en posicion no alfa utiles como adyuvantes para la administracion de agentes biologicos activos. |
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| US20080312207A1 (en) * | 2004-02-18 | 2008-12-18 | Craig Johnstone | Compounds |
| ES2322709T3 (es) * | 2004-02-18 | 2009-06-25 | Astrazeneca Ab | Derivados de benzamida y su uso como agentes activadores de la glucocinasa. |
| US20080125403A1 (en) | 2004-04-02 | 2008-05-29 | Merck & Co., Inc. | Method of Treating Men with Metabolic and Anthropometric Disorders |
| WO2005095417A1 (en) | 2004-04-02 | 2005-10-13 | Novartis Ag | Thiazolopyridine derivates, pharmaceutical conditions containing them and methods of treating glucokinase mediated conditions |
| ATE524479T1 (de) | 2004-04-02 | 2011-09-15 | Novartis Ag | Sulfonamidthiazolpyridinderivate als zur behandlung von typ-2-diabetes geeignete glucokinaseaktivatoren |
| TW200600086A (en) * | 2004-06-05 | 2006-01-01 | Astrazeneca Ab | Chemical compound |
| RU2403246C2 (ru) * | 2004-06-05 | 2010-11-10 | Астразенека Аб | Гетероарилбензамидные производные для применения в качестве активаторов глюкокиназы (glk) в лечении диабета |
| KR100739367B1 (ko) * | 2004-07-14 | 2007-07-16 | 크리스탈지노믹스(주) | 설파마이드 유도체 및 이를 함유하는 지방대사 촉진용약학적 조성물 |
| AU2005293343B2 (en) | 2004-10-16 | 2009-03-19 | Astrazeneca Ab | Process for making phenoxy benzamide compounds |
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| US7576099B2 (en) | 2005-02-28 | 2009-08-18 | Renovis, Inc. | Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same |
| AU2006250354A1 (en) * | 2005-05-23 | 2006-11-30 | Japan Tobacco Inc. | Pyrazole compound and therapeutic agent for diabetes comprising the same |
| US20110059941A1 (en) * | 2005-05-24 | 2011-03-10 | Peter William Rodney Caulkett | 2-phenyl substituted imidazol [4,5b] pyridine/pyrazine and purine derivatives as glucokinase modulators |
| TW200714597A (en) * | 2005-05-27 | 2007-04-16 | Astrazeneca Ab | Chemical compounds |
| GB0510852D0 (en) * | 2005-05-27 | 2005-07-06 | Astrazeneca Ab | Chemical compounds |
| EP1910350A1 (en) * | 2005-07-09 | 2008-04-16 | AstraZeneca AB | 2 -heterocyclyloxybenzoyl amino heterocyclyl compounds as modulators of glucokinase for the treatment of type 2 diabetes |
| RU2415141C2 (ru) * | 2005-07-09 | 2011-03-27 | Астразенека Аб | Производные гетероарилбензамида для применения в качестве активаторов glk в лечении диабета |
| BRPI0622261A2 (pt) * | 2005-07-09 | 2011-08-09 | Astrazeneca Ab | composto, composição farmacêutica, uso de um composto ou um sal farmaceuticamente aceitável do mesmo, e, processo para a preparação de um composto |
| EP2027113A1 (en) * | 2005-07-09 | 2009-02-25 | AstraZeneca AB | Heteroaryl benzamide derivatives for use as glk activators in the treatment of diabetes |
| GB0514173D0 (en) * | 2005-07-09 | 2005-08-17 | Astrazeneca Ab | Chemical compounds |
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| GT200600428A (es) | 2005-09-30 | 2007-05-21 | Compuestos organicos | |
| GT200600429A (es) | 2005-09-30 | 2007-04-30 | Compuestos organicos | |
| JP5198280B2 (ja) | 2005-11-17 | 2013-05-15 | イーライ リリー アンド カンパニー | グルカゴン受容体アンタゴニスト、並びにその調製及び治療への使用 |
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| CL2007003061A1 (es) | 2006-10-26 | 2008-08-01 | Astrazeneca Ab | Compuestos derivados de 3,5-dioxi-benzamida; proceso de preparacion; composicion farmaceutica que comprende a dichos compuestos; y su uso para tratar una enfermedad mediada a traves de glk, tal como la diabetes tipo 2. |
| RU2009121756A (ru) | 2006-12-21 | 2011-01-27 | Астразенека Аб (Se) | Новое кристаллическое соединение, полезное в качестве активатора глюкокиназы (glk) |
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