UA73781C2 - Dicyclic pyrolylamides as inhibitors of glucogenphosphorylase - Google Patents
Dicyclic pyrolylamides as inhibitors of glucogenphosphorylase Download PDFInfo
- Publication number
- UA73781C2 UA73781C2 UA2003021026A UA2003021026A UA73781C2 UA 73781 C2 UA73781 C2 UA 73781C2 UA 2003021026 A UA2003021026 A UA 2003021026A UA 2003021026 A UA2003021026 A UA 2003021026A UA 73781 C2 UA73781 C2 UA 73781C2
- Authority
- UA
- Ukraine
- Prior art keywords
- pyrrole
- dichloro
- carbamoyl
- alkyl
- thieno
- Prior art date
Links
- 239000003112 inhibitor Substances 0.000 title description 7
- 125000002619 bicyclic group Chemical group 0.000 title description 3
- -1 Heterocyclic amide Chemical class 0.000 claims abstract description 271
- 150000003839 salts Chemical class 0.000 claims abstract description 39
- 150000002148 esters Chemical class 0.000 claims abstract description 31
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 11
- 238000004519 manufacturing process Methods 0.000 claims abstract description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 849
- 125000000217 alkyl group Chemical group 0.000 claims description 238
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 183
- 150000001875 compounds Chemical class 0.000 claims description 164
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 77
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 70
- 125000000623 heterocyclic group Chemical group 0.000 claims description 58
- 125000005843 halogen group Chemical group 0.000 claims description 51
- 229910052799 carbon Inorganic materials 0.000 claims description 48
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 48
- 125000003118 aryl group Chemical group 0.000 claims description 45
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 45
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 41
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 37
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 36
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 33
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 30
- 229910052739 hydrogen Inorganic materials 0.000 claims description 30
- 239000001257 hydrogen Substances 0.000 claims description 29
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 28
- 229910052757 nitrogen Inorganic materials 0.000 claims description 27
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 24
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 21
- 241001465754 Metazoa Species 0.000 claims description 17
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 16
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 16
- 125000001072 heteroaryl group Chemical group 0.000 claims description 15
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 15
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 125000005002 aryl methyl group Chemical group 0.000 claims description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 13
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 13
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 12
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 12
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 12
- 125000004130 indan-2-yl group Chemical group [H]C1=C([H])C([H])=C2C(=C1[H])C([H])([H])C([H])(*)C2([H])[H] 0.000 claims description 12
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 11
- 125000006125 ethylsulfonyl group Chemical group 0.000 claims description 11
- 150000002431 hydrogen Chemical class 0.000 claims description 11
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 11
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 125000003107 substituted aryl group Chemical group 0.000 claims description 8
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 7
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 7
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 7
- 125000004174 2-benzimidazolyl group Chemical group [H]N1C(*)=NC2=C([H])C([H])=C([H])C([H])=C12 0.000 claims description 6
- 230000003301 hydrolyzing effect Effects 0.000 claims description 6
- 239000002245 particle Substances 0.000 claims description 6
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- 150000002829 nitrogen Chemical class 0.000 claims description 5
- 229910052698 phosphorus Inorganic materials 0.000 claims description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 239000011593 sulfur Substances 0.000 claims description 5
- 125000001589 carboacyl group Chemical group 0.000 claims description 4
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 150000003950 cyclic amides Chemical class 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 125000006413 ring segment Chemical group 0.000 claims description 2
- 102000009097 Phosphorylases Human genes 0.000 claims 1
- 108010073135 Phosphorylases Proteins 0.000 claims 1
- 238000012876 topography Methods 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 160
- 238000011282 treatment Methods 0.000 abstract description 18
- 108010046163 Glycogen Phosphorylase Proteins 0.000 abstract description 17
- 102000007390 Glycogen Phosphorylase Human genes 0.000 abstract description 17
- 230000000694 effects Effects 0.000 abstract description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 7
- 201000010099 disease Diseases 0.000 abstract description 6
- 230000008569 process Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 197
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 175
- 239000000203 mixture Substances 0.000 description 131
- 239000000243 solution Substances 0.000 description 122
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 116
- 238000005481 NMR spectroscopy Methods 0.000 description 83
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 76
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 76
- 125000003277 amino group Chemical group 0.000 description 75
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 69
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 61
- 239000007787 solid Substances 0.000 description 54
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 48
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 47
- 239000011541 reaction mixture Substances 0.000 description 47
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 43
- 230000002829 reductive effect Effects 0.000 description 39
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 38
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 38
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 37
- 235000019341 magnesium sulphate Nutrition 0.000 description 37
- 150000001721 carbon Chemical group 0.000 description 31
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 31
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- 125000001424 substituent group Chemical group 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 26
- 125000004093 cyano group Chemical group *C#N 0.000 description 26
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 23
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- 239000003480 eluent Substances 0.000 description 22
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- 241000282414 Homo sapiens Species 0.000 description 21
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- 230000005764 inhibitory process Effects 0.000 description 18
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- 150000001412 amines Chemical class 0.000 description 17
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical group C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 16
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- 238000010992 reflux Methods 0.000 description 14
- 125000002252 acyl group Chemical group 0.000 description 13
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- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 13
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 12
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- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 125000001721 carboxyacetyl group Chemical group 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
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- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 238000000451 chemical ionisation Methods 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 1
- 229940106681 chloroacetic acid Drugs 0.000 description 1
- 238000010549 co-Evaporation Methods 0.000 description 1
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- 229910052802 copper Inorganic materials 0.000 description 1
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- 230000008025 crystallization Effects 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- 208000033679 diabetic kidney disease Diseases 0.000 description 1
- 125000005117 dialkylcarbamoyl group Chemical group 0.000 description 1
- FDKCTEWMJWRPDS-UHFFFAOYSA-N dialuminum;trimagnesium;trisilicate Chemical compound [Mg+2].[Mg+2].[Mg+2].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-].[O-][Si]([O-])([O-])[O-].[O-][Si]([O-])([O-])[O-] FDKCTEWMJWRPDS-UHFFFAOYSA-N 0.000 description 1
- IUNMPGNGSSIWFP-UHFFFAOYSA-N dimethylaminopropylamine Chemical compound CN(C)CCCN IUNMPGNGSSIWFP-UHFFFAOYSA-N 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
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- 125000004185 ester group Chemical group 0.000 description 1
- BEGBSFPALGFMJI-UHFFFAOYSA-N ethene;sodium Chemical group [Na].C=C BEGBSFPALGFMJI-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000006627 ethoxycarbonylamino group Chemical group 0.000 description 1
- FDLDWKIEWAWOSL-UHFFFAOYSA-N ethyl acetate;2-methylpentane Chemical compound CCCC(C)C.CCOC(C)=O FDLDWKIEWAWOSL-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000006260 ethylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
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- 235000013305 food Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
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- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 150000002485 inorganic esters Chemical class 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
- VDBNYAPERZTOOF-UHFFFAOYSA-N isoquinolin-1(2H)-one Chemical compound C1=CC=C2C(=O)NC=CC2=C1 VDBNYAPERZTOOF-UHFFFAOYSA-N 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 150000002689 maleic acids Chemical class 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 125000006626 methoxycarbonylamino group Chemical group 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- RXYCUKSOYJWGPE-UHFFFAOYSA-N methyl 2-azidoacetate Chemical compound COC(=O)CN=[N+]=[N-] RXYCUKSOYJWGPE-UHFFFAOYSA-N 0.000 description 1
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 1
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 1
- 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 101150093855 msh1 gene Proteins 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000003431 oxalo group Chemical group 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000000538 pentafluorophenyl group Chemical group FC1=C(F)C(F)=C(*)C(F)=C1F 0.000 description 1
- 238000005897 peptide coupling reaction Methods 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 108091000115 phosphomannomutase Proteins 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- 125000005633 phthalidyl group Chemical group 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
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000000291 postprandial effect Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- GKKCIDNWFBPDBW-UHFFFAOYSA-M potassium cyanate Chemical compound [K]OC#N GKKCIDNWFBPDBW-UHFFFAOYSA-M 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- 229910052832 pyrope Inorganic materials 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000003893 regulation of appetite Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 201000001370 sclerosteosis 1 Diseases 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 125000006633 tert-butoxycarbonylamino group Chemical group 0.000 description 1
- 125000004187 tetrahydropyran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 1
- 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- 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
- A61P3/04—Anorexiants; Antiobesity agents
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Diabetes (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Child & Adolescent Psychology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pyrrole Compounds (AREA)
- Indole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Enzymes And Modification Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB0021831.3A GB0021831D0 (en) | 2000-09-06 | 2000-09-06 | Chemical compounds |
| PCT/SE2001/001880 WO2002020530A1 (en) | 2000-09-06 | 2001-08-31 | Bicyclic pyrrolyl amides as glucogen phosphorylase inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| UA73781C2 true UA73781C2 (en) | 2005-09-15 |
Family
ID=9898927
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| UA2003021026A UA73781C2 (en) | 2000-09-06 | 2001-08-31 | Dicyclic pyrolylamides as inhibitors of glucogenphosphorylase |
Country Status (31)
| Country | Link |
|---|---|
| US (1) | US20030232875A1 (de) |
| EP (1) | EP1317459B1 (de) |
| JP (1) | JP2004508376A (de) |
| KR (1) | KR100802369B1 (de) |
| CN (2) | CN1264846C (de) |
| AT (1) | ATE263772T1 (de) |
| AU (2) | AU2001282833B2 (de) |
| BG (1) | BG107624A (de) |
| BR (1) | BR0113606A (de) |
| CA (1) | CA2417594A1 (de) |
| CZ (1) | CZ2003616A3 (de) |
| DE (1) | DE60102710T2 (de) |
| DK (1) | DK1317459T3 (de) |
| EE (1) | EE200300083A (de) |
| ES (1) | ES2217183T3 (de) |
| GB (1) | GB0021831D0 (de) |
| HK (1) | HK1055299A1 (de) |
| HU (1) | HUP0400784A3 (de) |
| IL (1) | IL154291A0 (de) |
| IS (1) | IS2110B (de) |
| MX (1) | MXPA03001512A (de) |
| NO (1) | NO20031024D0 (de) |
| NZ (1) | NZ524011A (de) |
| PL (1) | PL361024A1 (de) |
| PT (1) | PT1317459E (de) |
| RU (1) | RU2003104013A (de) |
| SK (1) | SK2592003A3 (de) |
| TR (1) | TR200401659T4 (de) |
| UA (1) | UA73781C2 (de) |
| WO (1) | WO2002020530A1 (de) |
| ZA (1) | ZA200301013B (de) |
Families Citing this family (64)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CO5271699A1 (es) | 2000-01-24 | 2003-04-30 | Pfizer Prod Inc | Procedimiento para el tratamiento de cardiomiopatia utilizando inhibidores de la glucogeno fosforilasa |
| PE20020856A1 (es) | 2001-02-13 | 2002-11-11 | Aventis Pharma Gmbh | 1,2,3,4-tetrahidronaftil aminas aciladas |
| TWI243164B (en) | 2001-02-13 | 2005-11-11 | Aventis Pharma Gmbh | Acylated indanyl amines and their use as pharmaceuticals |
| GB0205175D0 (en) | 2002-03-06 | 2002-04-17 | Astrazeneca Ab | Chemical compounds |
| GB0205162D0 (en) | 2002-03-06 | 2002-04-17 | Astrazeneca Ab | Chemical compounds |
| GB0205166D0 (en) * | 2002-03-06 | 2002-04-17 | Astrazeneca Ab | Chemical compounds |
| GB0205170D0 (en) | 2002-03-06 | 2002-04-17 | Astrazeneca Ab | Chemical compounds |
| GB0205165D0 (en) * | 2002-03-06 | 2002-04-17 | Astrazeneca Ab | Chemical compounds |
| GB0205176D0 (en) | 2002-03-06 | 2002-04-17 | Astrazeneca Ab | Chemical compounds |
| IL164249A0 (en) * | 2002-04-11 | 2005-12-18 | Aventis Pharma Gmbh | Acyl-3-carboxphenylurea derivatives, processes forpreparing them and their use |
| DE10215908B4 (de) * | 2002-04-11 | 2005-08-18 | Aventis Pharma Deutschland Gmbh | Acyl-3-carboxyphenyl-harnstoffderivate und deren Verwendung als Arzneimittel |
| US7057046B2 (en) * | 2002-05-20 | 2006-06-06 | Bristol-Myers Squibb Company | Lactam glycogen phosphorylase inhibitors and method of use |
| DE10225635C1 (de) * | 2002-06-07 | 2003-12-24 | Aventis Pharma Gmbh | N-Benzoylureido-Zimtsäurederivate, Verfahren zu deren Herstellung und deren Verwendung |
| DE50311954D1 (de) * | 2002-06-17 | 2009-11-12 | Saltigo Gmbh | Verfahren zur Herstellung von mono-N-sulfonylierten Diaminen |
| MXPA05000055A (es) * | 2002-07-11 | 2005-04-08 | Aventis Pharma Gmbh | Acilureas sustituidas con urea y uretano, metodos para su produccion y su uso. |
| EP1388535A1 (de) * | 2002-08-07 | 2004-02-11 | Aventis Pharma Deutschland GmbH | Acylierte Arylcycloalkylamine und ihre Anwendung als Arzneimittelwirkstoff |
| US7186735B2 (en) | 2002-08-07 | 2007-03-06 | Sanofi-Aventis Deutschland Gmbh | Acylated arylcycloalkylamines and their use as pharmaceuticals |
| GB0222909D0 (en) | 2002-10-03 | 2002-11-13 | Astrazeneca Ab | Novel process and intermediates |
| GB0222912D0 (en) * | 2002-10-03 | 2002-11-13 | Astrazeneca Ab | Novel process and intermediates |
| BR0316099A (pt) * | 2002-11-07 | 2005-09-27 | Pfizer Prod Inc | Agentes antidiabéticos |
| WO2004092158A1 (en) | 2003-04-17 | 2004-10-28 | Pfizer Products Inc. | Carboxamide derivatives as anti-diabetic agents |
| US7405210B2 (en) | 2003-05-21 | 2008-07-29 | Osi Pharmaceuticals, Inc. | Pyrrolopyridine-2-carboxylic acid amide inhibitors of glycogen phosphorylase |
| NZ543482A (en) * | 2003-05-21 | 2009-02-28 | Prosidion Ltd | Pyrrolopyridine-2-carboxylic acid amide inhibitors of glycogen phoshorylase |
| WO2004113345A1 (ja) * | 2003-06-20 | 2004-12-29 | Japan Tobacco Inc. | 縮合ピロール化合物及びその医薬用途 |
| GB0318464D0 (en) * | 2003-08-07 | 2003-09-10 | Astrazeneca Ab | Chemical compounds |
| GB0318463D0 (en) * | 2003-08-07 | 2003-09-10 | Astrazeneca Ab | Chemical compounds |
| GB0319759D0 (en) * | 2003-08-22 | 2003-09-24 | Astrazeneca Ab | Chemical compounds |
| GB0319690D0 (en) * | 2003-08-22 | 2003-09-24 | Astrazeneca Ab | Chemical compounds |
| WO2005020985A1 (en) * | 2003-08-29 | 2005-03-10 | Astrazeneca Ab | Indolamide derivatives which possess glycogen phosphorylase inhibitory activity |
| WO2005020986A1 (en) * | 2003-08-29 | 2005-03-10 | Astrazeneca Ab | Heterocyclic amide derivatives which posses glycogen phosphorylase inhibitory activity |
| GB0320422D0 (en) * | 2003-08-30 | 2003-10-01 | Astrazeneca Ab | Chemical compounds |
| CN1922149A (zh) | 2003-12-29 | 2007-02-28 | 塞普拉科公司 | 吡咯和吡唑daao抑制剂 |
| US7453002B2 (en) | 2004-06-15 | 2008-11-18 | Bristol-Myers Squibb Company | Five-membered heterocycles useful as serine protease inhibitors |
| WO2006055462A1 (en) * | 2004-11-15 | 2006-05-26 | Bristol-Myers Squibb Company | 2-amino-4-functionalized tetralin derivatives and related glycogen phosphorylase inhibitors |
| WO2006055435A1 (en) | 2004-11-15 | 2006-05-26 | Bristol-Myers Squibb Company | 2-aminonaphthalene derivatives and related glycogen phosphorylase inhibitors |
| US7365061B2 (en) | 2004-11-15 | 2008-04-29 | Bristol-Myers Squibb Company | 2-Amino-3-functionalized tetralin derivatives and related glycogen phosphorylase inhibitors |
| US7214704B2 (en) | 2004-11-15 | 2007-05-08 | Bristol-Myers Squibb Company | 2-Amino-1-functionalized tetralin derivatives and related glycogen phosphorylase inhibitors |
| WO2006059165A1 (en) * | 2004-12-02 | 2006-06-08 | Prosidion Limited | Pyrrolopyridine-2-carboxylic acid amide derivative useful as inhibitor of glycogen phosphorylase |
| WO2006059163A1 (en) * | 2004-12-02 | 2006-06-08 | Prosidion Limited | Treatment of diabetes with glycogen phosphorylase inhibitors |
| ATE506951T1 (de) * | 2005-01-19 | 2011-05-15 | Merck Sharp & Dohme | Als inhibitoren von beta-secretase aktive tertiäre carbinamine mit substituierten heterocyclen zur behandlung der alzheimer- krankheit |
| US20100137397A1 (en) * | 2005-02-05 | 2010-06-03 | Astrazeneca Ab | Chemical Compounds |
| EP1848693A1 (de) * | 2005-02-05 | 2007-10-31 | AstraZeneca AB | Indanamidderivate mit glykogenphosphorylase hemmender wirkung |
| NZ569630A (en) | 2006-01-06 | 2011-09-30 | Sepracor Inc | Cycloalkylamines as monoamine reuptake inhibitors |
| CA2636275C (en) | 2006-01-06 | 2013-02-12 | Sepracor Inc. | Tetralone-based monoamine reuptake inhibitors |
| DK2013835T3 (en) | 2006-03-31 | 2015-12-14 | Sunovion Pharmaceuticals Inc | Preparation of chiral amides and AMINES |
| PE20080251A1 (es) | 2006-05-04 | 2008-04-25 | Boehringer Ingelheim Int | Usos de inhibidores de dpp iv |
| US7884124B2 (en) | 2006-06-30 | 2011-02-08 | Sepracor Inc. | Fluoro-substituted inhibitors of D-amino acid oxidase |
| EP2298772A1 (de) * | 2006-10-18 | 2011-03-23 | Takeda Pharmaceutical Company Limited | Kondensierte heterozyklische Verbindungen |
| US7902252B2 (en) | 2007-01-18 | 2011-03-08 | Sepracor, Inc. | Inhibitors of D-amino acid oxidase |
| KR101581289B1 (ko) | 2007-05-31 | 2015-12-31 | 세프라코 아이엔시. | 모노아민 재흡수 억제제로서 페닐 치환된 시클로알킬아민 |
| US8969514B2 (en) | 2007-06-04 | 2015-03-03 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases |
| US20100152200A1 (en) * | 2008-11-17 | 2010-06-17 | The Regents Of The University Of Michigan | Alphavirus inhibitors and uses thereof |
| WO2012027331A1 (en) | 2010-08-27 | 2012-03-01 | Ironwood Pharmaceuticals, Inc. | Compositions and methods for treating or preventing metabolic syndrome and related diseases and disorders |
| US9616097B2 (en) | 2010-09-15 | 2017-04-11 | Synergy Pharmaceuticals, Inc. | Formulations of guanylate cyclase C agonists and methods of use |
| PL3004138T3 (pl) | 2013-06-05 | 2024-07-29 | Bausch Health Ireland Limited | Ultra-oczyszczeni agoniści peptydowi cyklazy guanylanowej C, sposób ich uzyskiwania i ich zastosowanie |
| MX2017002610A (es) | 2014-08-29 | 2017-10-11 | Tes Pharma S R L | INHIBIDORES DE ACIDO A-AMINO-ß-CARBOXIMUCONICO SEMIALDEHIDO DESCARBOXILASA. |
| TWI763630B (zh) * | 2015-07-02 | 2022-05-11 | 瑞士商赫孚孟拉羅股份公司 | 雙環內醯胺及其使用方法 |
| JP6974331B2 (ja) * | 2016-02-05 | 2021-12-01 | デナリ セラピューティクス インコーポレイテッドDenali Therapeutics Inc. | 化合物、組成物及び方法 |
| BR112019007543A2 (pt) | 2016-10-14 | 2019-07-02 | Tes Pharma S R L | inibidores de ácido alfa-amino-beta-carboximuconico semialdeido decarboxilase |
| EP3526219B1 (de) | 2016-10-17 | 2021-12-15 | F. Hoffmann-La Roche AG | Bicyclische pyridonlactame und verfahren zur verwendung davon |
| US11072607B2 (en) | 2016-12-16 | 2021-07-27 | Genentech, Inc. | Inhibitors of RIP1 kinase and methods of use thereof |
| CN112074519B (zh) | 2018-04-20 | 2024-08-02 | 豪夫迈·罗氏有限公司 | 作为rip1激酶抑制剂用于治疗例如肠易激综合征(ibs)的化合物 |
| WO2020104456A1 (en) | 2018-11-20 | 2020-05-28 | Tes Pharma S.R.L | INHIBITORS OF α-AMINO-β-CARBOXYMUCONIC ACID SEMIALDEHYDE DECARBOXYLASE |
| CA3163206A1 (en) * | 2019-11-27 | 2021-06-03 | Riken | G9a inhibitor |
Family Cites Families (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3706810A (en) * | 1970-09-15 | 1972-12-19 | American Cyanamid Co | N-morpholinoalkyl-thieno(3,2-b)pyrrole-5-carboxamides |
| US4692522A (en) * | 1985-04-01 | 1987-09-08 | Merck & Co., Inc. | Benzofused lactams useful as cholecystokinin antagonists |
| US4668769A (en) * | 1985-08-02 | 1987-05-26 | Hoover Dennis J | Oxa- and azahomocyclostatine polypeptides |
| US4599198A (en) * | 1985-08-02 | 1986-07-08 | Pfizer Inc. | Intermediates in polypeptide synthesis |
| US4720503A (en) * | 1985-08-02 | 1988-01-19 | Merck & Co., Inc. | N-substituted fused-heterocyclic carboxamide derivatives as dual cyclooxygenase and lipoxygenase inhibitors |
| FR2601368B1 (fr) * | 1986-07-08 | 1989-04-07 | Synthelabo | Derives de nitrofuranne, leur preparation et leur application en therapeutique. |
| DE3629545A1 (de) * | 1986-08-30 | 1988-03-10 | Bayer Ag | Dihydropyridinverbindungen, verfahren zu ihrer herstellung und ihre verwendung |
| US4751231A (en) * | 1987-09-16 | 1988-06-14 | Merck & Co., Inc. | Substituted thieno[2,3-b]pyrrole-5-sulfonamides as antiglaucoma agents |
| ES2081747B1 (es) * | 1993-09-07 | 1997-01-16 | Esteve Labor Dr | Amidas derivadas de tienopirroles, su preparacion y su aplicacion como medicamentos. |
| US5863903A (en) * | 1994-03-09 | 1999-01-26 | Novo Nordisk A/S | Use of hydroxy alkyl piperidine and pyrrolidine compounds to treat diabetes |
| FR2723739B1 (fr) * | 1994-08-19 | 1997-02-14 | Sanofi Sa | Derives de glycinamide, procedes pour leur preparation et medicaments les contenant. |
| WO1996039384A1 (en) * | 1995-06-06 | 1996-12-12 | Pfizer, Inc. | Substituted n-(indole-2-carbonyl)-glycinamides and derivatives as glycogen phosphorylase inhibitors |
| US5952322A (en) * | 1996-12-05 | 1999-09-14 | Pfizer Inc. | Method of reducing tissue damage associated with non-cardiac ischemia using glycogen phosphorylase inhibitors |
| US5998463A (en) * | 1998-02-27 | 1999-12-07 | Pfizer Inc | Glycogen phosphorylase inhibitors |
| JP2002506073A (ja) * | 1998-03-12 | 2002-02-26 | ノボ ノルディスク アクティーゼルスカブ | プロテイン・チロシン・ホスファターゼ（ＰＴＰａｓｅｓ）のモジュレーター |
| PT1088824E (pt) * | 1999-09-30 | 2004-04-30 | Pfizer Prod Inc | Pirrolil-amidas biciclicas como inibidores de glicogenio-fosforilase |
| CO5271699A1 (es) * | 2000-01-24 | 2003-04-30 | Pfizer Prod Inc | Procedimiento para el tratamiento de cardiomiopatia utilizando inhibidores de la glucogeno fosforilasa |
| US6555569B2 (en) * | 2000-03-07 | 2003-04-29 | Pfizer Inc. | Use of heteroaryl substituted N-(indole-2-carbonyl-) amides for treatment of infection |
| US7057046B2 (en) * | 2002-05-20 | 2006-06-06 | Bristol-Myers Squibb Company | Lactam glycogen phosphorylase inhibitors and method of use |
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