DE60315886T2 - Substituierte pyrazin- oder pyridin-derivate als glukokinase-aktivatoren - Google Patents
Substituierte pyrazin- oder pyridin-derivate als glukokinase-aktivatoren Download PDFInfo
- Publication number
- DE60315886T2 DE60315886T2 DE60315886T DE60315886T DE60315886T2 DE 60315886 T2 DE60315886 T2 DE 60315886T2 DE 60315886 T DE60315886 T DE 60315886T DE 60315886 T DE60315886 T DE 60315886T DE 60315886 T2 DE60315886 T2 DE 60315886T2
- Authority
- DE
- Germany
- Prior art keywords
- cyclopentyl
- phenyl
- propionamide
- chloro
- methanesulfonyl
- 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.)
- Expired - Lifetime
Links
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical class C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 title claims description 75
- 239000012190 activator Substances 0.000 title description 4
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical class C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 471
- -1 nitro, cyano, methyl Chemical group 0.000 claims description 366
- 229920006395 saturated elastomer Polymers 0.000 claims description 106
- 125000001424 substituent group Chemical group 0.000 claims description 74
- 239000000203 mixture Substances 0.000 claims description 72
- 229910052799 carbon Inorganic materials 0.000 claims description 69
- 229940080818 propionamide Drugs 0.000 claims description 65
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 61
- 125000003118 aryl group Chemical group 0.000 claims description 46
- 125000000217 alkyl group Chemical group 0.000 claims description 43
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 39
- 150000001721 carbon Chemical group 0.000 claims description 38
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 37
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 35
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 35
- 150000003839 salts Chemical class 0.000 claims description 32
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 31
- 125000004432 carbon atom Chemical group C* 0.000 claims description 30
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 30
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 27
- 239000001257 hydrogen Substances 0.000 claims description 27
- 229910052739 hydrogen Inorganic materials 0.000 claims description 27
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 26
- 125000001072 heteroaryl group Chemical group 0.000 claims description 24
- 125000000623 heterocyclic group Chemical group 0.000 claims description 24
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 19
- 229910052757 nitrogen Inorganic materials 0.000 claims description 19
- 229910052760 oxygen Chemical group 0.000 claims description 19
- 229910052717 sulfur Inorganic materials 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 18
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 16
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical class 0.000 claims description 16
- 125000005842 heteroatom Chemical group 0.000 claims description 16
- 239000001301 oxygen Chemical group 0.000 claims description 16
- 239000011593 sulfur Chemical group 0.000 claims description 16
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 13
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- 230000008569 process Effects 0.000 claims description 11
- SXHFVJNXGCUJRL-YHVXIASJSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-(5-methylsulfinylpyrazin-2-yl)propanamide Chemical compound C1=NC(S(=O)C)=CN=C1NC(=O)[C@@H](C=1C=C(Cl)C(=CC=1)S(C)(=O)=O)CC1CCCC1 SXHFVJNXGCUJRL-YHVXIASJSA-N 0.000 claims description 10
- ZRXYEXRHPSYMDY-MRXNPFEDSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-(dimethoxymethyl)pyrazin-2-yl]propanamide Chemical compound C1=NC(C(OC)OC)=CN=C1NC(=O)[C@@H](C=1C=C(Cl)C(=CC=1)S(C)(=O)=O)CC1CCCC1 ZRXYEXRHPSYMDY-MRXNPFEDSA-N 0.000 claims description 10
- DVSOMGQPQXDSTH-UHFFFAOYSA-N 2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-(5-formylpyrazin-2-yl)propanamide Chemical compound C1=C(Cl)C(S(=O)(=O)C)=CC=C1C(C(=O)NC=1N=CC(C=O)=NC=1)CC1CCCC1 DVSOMGQPQXDSTH-UHFFFAOYSA-N 0.000 claims description 10
- 206010012601 diabetes mellitus Diseases 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- XHGUXJHPFQFDCQ-OAHLLOKOSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-(5-methylsulfanylpyrazin-2-yl)propanamide Chemical compound C1=NC(SC)=CN=C1NC(=O)[C@@H](C=1C=C(Cl)C(=CC=1)S(C)(=O)=O)CC1CCCC1 XHGUXJHPFQFDCQ-OAHLLOKOSA-N 0.000 claims description 9
- UILCYGKPSXGBPC-MRXNPFEDSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-(2-hydroxyethylsulfanyl)pyrazin-2-yl]propanamide Chemical compound C1=C(Cl)C(S(=O)(=O)C)=CC=C1[C@H](C(=O)NC=1N=CC(SCCO)=NC=1)CC1CCCC1 UILCYGKPSXGBPC-MRXNPFEDSA-N 0.000 claims description 9
- BMOGJRFSZYYMPK-HXUWFJFHSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-[3-(dimethylamino)propyl]pyrazin-2-yl]propanamide Chemical compound C1=NC(CCCN(C)C)=CN=C1NC(=O)[C@@H](C=1C=C(Cl)C(=CC=1)S(C)(=O)=O)CC1CCCC1 BMOGJRFSZYYMPK-HXUWFJFHSA-N 0.000 claims description 9
- NESMGVQBWDEZAO-CQSZACIVSA-N chembl2337925 Chemical compound C1=C(Cl)C(S(=O)(=O)C)=CC=C1[C@H](C(=O)NC=1N=CC(=NC=1)C(\N)=N/O)CC1CCCC1 NESMGVQBWDEZAO-CQSZACIVSA-N 0.000 claims description 9
- LFQVDCHGADGOPL-NCQSQGRDSA-N chembl2337926 Chemical compound C1=NC(C(=N\O)/C)=CN=C1NC(=O)[C@@H](C=1C=C(Cl)C(=CC=1)S(C)(=O)=O)CC1CCCC1 LFQVDCHGADGOPL-NCQSQGRDSA-N 0.000 claims description 9
- BPUNDRVIOJADLI-UHFFFAOYSA-N n-(5-acetylpyrazin-2-yl)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentylpropanamide Chemical compound C1=NC(C(=O)C)=CN=C1NC(=O)C(C=1C=C(Cl)C(=CC=1)S(C)(=O)=O)CC1CCCC1 BPUNDRVIOJADLI-UHFFFAOYSA-N 0.000 claims description 9
- BFPODEUMNZELOT-GOSISDBHSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-(3-hydroxyprop-1-ynyl)pyrazin-2-yl]propanamide Chemical compound C1=C(Cl)C(S(=O)(=O)C)=CC=C1[C@H](C(=O)NC=1N=CC(=NC=1)C#CCO)CC1CCCC1 BFPODEUMNZELOT-GOSISDBHSA-N 0.000 claims description 8
- CMQOYBOIWRLMTL-MRXNPFEDSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-(dimethylamino)pyrazin-2-yl]propanamide Chemical compound C1=NC(N(C)C)=CN=C1NC(=O)[C@@H](C=1C=C(Cl)C(=CC=1)S(C)(=O)=O)CC1CCCC1 CMQOYBOIWRLMTL-MRXNPFEDSA-N 0.000 claims description 8
- ZKPYUNODMMMMTM-GOSISDBHSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-(dimethylamino)pyridin-2-yl]propanamide Chemical compound N1=CC(N(C)C)=CC=C1NC(=O)[C@@H](C=1C=C(Cl)C(=CC=1)S(C)(=O)=O)CC1CCCC1 ZKPYUNODMMMMTM-GOSISDBHSA-N 0.000 claims description 8
- KFAOCUVRWMNQHM-QGZVFWFLSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-(methanesulfonamido)pyridin-2-yl]propanamide Chemical compound N1=CC(NS(=O)(=O)C)=CC=C1NC(=O)[C@@H](C=1C=C(Cl)C(=CC=1)S(C)(=O)=O)CC1CCCC1 KFAOCUVRWMNQHM-QGZVFWFLSA-N 0.000 claims description 8
- BCTONCKQOYIUPK-CQSZACIVSA-N (2r)-n-[5-(5-amino-1,2,4-oxadiazol-3-yl)pyrazin-2-yl]-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentylpropanamide Chemical compound C1=C(Cl)C(S(=O)(=O)C)=CC=C1[C@H](C(=O)NC=1N=CC(=NC=1)C=1N=C(N)ON=1)CC1CCCC1 BCTONCKQOYIUPK-CQSZACIVSA-N 0.000 claims description 8
- MLHOQMZPSCAVOH-UHFFFAOYSA-N 2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]pyrazin-2-yl]propanamide Chemical compound C1=C(Cl)C(S(=O)(=O)C)=CC=C1C(C(=O)NC=1N=CC(CC2C(NC(=O)S2)=O)=NC=1)CC1CCCC1 MLHOQMZPSCAVOH-UHFFFAOYSA-N 0.000 claims description 8
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- UKAVSLAMXUQZRD-SECBINFHSA-N (2R)-N-[5-(N'-hydroxycarbamimidoyl)pyrazin-2-yl]-2-(4-methylsulfonylphenyl)propanamide Chemical compound ONC(=N)C=1N=CC(=NC1)NC([C@H](C)C1=CC=C(C=C1)S(=O)(=O)C)=O UKAVSLAMXUQZRD-SECBINFHSA-N 0.000 claims description 7
- FKOMCYQVYFWGPV-IERDGZPVSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-[(1s)-1,2-dihydroxy-2-methylpropyl]pyrazin-2-yl]propanamide Chemical compound C1=NC([C@H](O)C(C)(O)C)=CN=C1NC(=O)[C@@H](C=1C=C(Cl)C(=CC=1)S(C)(=O)=O)CC1CCCC1 FKOMCYQVYFWGPV-IERDGZPVSA-N 0.000 claims description 7
- RSWSKYSBRPWBFL-NNJIEVJOSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-n-[5-[cyano(hydroxy)methyl]pyrazin-2-yl]-3-cyclopentylpropanamide Chemical compound C1=C(Cl)C(S(=O)(=O)C)=CC=C1[C@H](C(=O)NC=1N=CC(=NC=1)C(O)C#N)CC1CCCC1 RSWSKYSBRPWBFL-NNJIEVJOSA-N 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- MGXHZTQMLYFNMR-CRAIPNDOSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-[(1s)-1,2-dihydroxyethyl]pyrazin-2-yl]propanamide Chemical compound C1=C(Cl)C(S(=O)(=O)C)=CC=C1[C@H](C(=O)NC=1N=CC(=NC=1)[C@H](O)CO)CC1CCCC1 MGXHZTQMLYFNMR-CRAIPNDOSA-N 0.000 claims description 6
- OJWKFRQGNQMXJY-HXUWFJFHSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-[3-(dimethylamino)prop-1-ynyl]pyrazin-2-yl]propanamide Chemical compound C1=NC(C#CCN(C)C)=CN=C1NC(=O)[C@@H](C=1C=C(Cl)C(=CC=1)S(C)(=O)=O)CC1CCCC1 OJWKFRQGNQMXJY-HXUWFJFHSA-N 0.000 claims description 6
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 238000011282 treatment Methods 0.000 claims description 6
- HSLLSJONPLQLGR-MRXNPFEDSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrazin-2-yl]propanamide Chemical compound CC1=NOC(C=2N=CC(NC(=O)[C@H](CC3CCCC3)C=3C=C(Cl)C(=CC=3)S(C)(=O)=O)=NC=2)=N1 HSLLSJONPLQLGR-MRXNPFEDSA-N 0.000 claims description 5
- BPMWWFLXYFMFCH-MRXNPFEDSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-(n'-hydroxycarbamimidoyl)pyridin-2-yl]propanamide Chemical compound C1=C(Cl)C(S(=O)(=O)C)=CC=C1[C@H](C(=O)NC=1N=CC(=CC=1)C(\N)=N/O)CC1CCCC1 BPMWWFLXYFMFCH-MRXNPFEDSA-N 0.000 claims description 5
- VFRFXGJYDITECZ-GOSISDBHSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-[(dimethylamino)methyl]pyrazin-2-yl]propanamide Chemical compound C1=NC(CN(C)C)=CN=C1NC(=O)[C@@H](C=1C=C(Cl)C(=CC=1)S(C)(=O)=O)CC1CCCC1 VFRFXGJYDITECZ-GOSISDBHSA-N 0.000 claims description 5
- ZYABJVQMTAQRIB-QGZVFWFLSA-N (2r)-3-cyclopentyl-n-(5-methylsulfanylpyrazin-2-yl)-2-(4-methylsulfonylphenyl)propanamide Chemical compound C1=NC(SC)=CN=C1NC(=O)[C@@H](C=1C=CC(=CC=1)S(C)(=O)=O)CC1CCCC1 ZYABJVQMTAQRIB-QGZVFWFLSA-N 0.000 claims description 5
- RGCOLBLUBXBSDY-UHFFFAOYSA-N 2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-(2-methylpropanoyl)pyrazin-2-yl]propanamide Chemical compound C1=NC(C(=O)C(C)C)=CN=C1NC(=O)C(C=1C=C(Cl)C(=CC=1)S(C)(=O)=O)CC1CCCC1 RGCOLBLUBXBSDY-UHFFFAOYSA-N 0.000 claims description 5
- LKHZSMIUTBLQBD-UHFFFAOYSA-N 2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-[(2,5-dioxoimidazolidin-4-yl)methyl]pyrazin-2-yl]propanamide Chemical compound C1=C(Cl)C(S(=O)(=O)C)=CC=C1C(C(=O)NC=1N=CC(CC2C(NC(=O)N2)=O)=NC=1)CC1CCCC1 LKHZSMIUTBLQBD-UHFFFAOYSA-N 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 125000000524 functional group Chemical group 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 5
- BNAMDSLGAAEBSX-GOSISDBHSA-N (2R)-3-cyclopentyl-N-[5-(N-hydroxy-C-methylcarbonimidoyl)pyrazin-2-yl]-2-(4-methylsulfonylphenyl)propanamide Chemical compound C1=NC(C(=NO)C)=CN=C1NC(=O)[C@@H](C=1C=CC(=CC=1)S(C)(=O)=O)CC1CCCC1 BNAMDSLGAAEBSX-GOSISDBHSA-N 0.000 claims description 4
- BAFMKRODEYFKSI-MRXNPFEDSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-(dimethylsulfamoyl)pyrazin-2-yl]propanamide Chemical compound C1=NC(S(=O)(=O)N(C)C)=CN=C1NC(=O)[C@@H](C=1C=C(Cl)C(=CC=1)S(C)(=O)=O)CC1CCCC1 BAFMKRODEYFKSI-MRXNPFEDSA-N 0.000 claims description 4
- MHHLRNDLIDHPMN-QGZVFWFLSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-(methylsulfanylmethyl)pyrazin-2-yl]propanamide Chemical compound C1=NC(CSC)=CN=C1NC(=O)[C@@H](C=1C=C(Cl)C(=CC=1)S(C)(=O)=O)CC1CCCC1 MHHLRNDLIDHPMN-QGZVFWFLSA-N 0.000 claims description 4
- BPUNDRVIOJADLI-MRXNPFEDSA-N (2r)-n-(5-acetylpyrazin-2-yl)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentylpropanamide Chemical compound C1=NC(C(=O)C)=CN=C1NC(=O)[C@@H](C=1C=C(Cl)C(=CC=1)S(C)(=O)=O)CC1CCCC1 BPUNDRVIOJADLI-MRXNPFEDSA-N 0.000 claims description 4
- CCXZTCBMMQQVHU-CQSZACIVSA-N chembl2338349 Chemical compound C1=C(Cl)C(S(=O)(=O)C)=CC=C1[C@H](C(=O)NC=1N=CC(=NC=1)C(=O)NO)CC1CCCC1 CCXZTCBMMQQVHU-CQSZACIVSA-N 0.000 claims description 4
- 125000004043 oxo group Chemical group O=* 0.000 claims description 4
- XNEHGKJPSHBDRO-MRXNPFEDSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-(1,3-dioxolan-2-yl)pyrazin-2-yl]propanamide Chemical compound C1=C(Cl)C(S(=O)(=O)C)=CC=C1[C@H](C(=O)NC=1N=CC(=NC=1)C1OCCO1)CC1CCCC1 XNEHGKJPSHBDRO-MRXNPFEDSA-N 0.000 claims description 3
- PIBVOMAOFIPNJU-OAHLLOKOSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-(methanesulfonamido)pyrazin-2-yl]propanamide Chemical compound C1=NC(NS(=O)(=O)C)=CN=C1NC(=O)[C@@H](C=1C=C(Cl)C(=CC=1)S(C)(=O)=O)CC1CCCC1 PIBVOMAOFIPNJU-OAHLLOKOSA-N 0.000 claims description 3
- PVZZCNBROJBJHG-OAHLLOKOSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-(methylsulfamoyl)pyrazin-2-yl]propanamide Chemical compound C1=NC(S(=O)(=O)NC)=CN=C1NC(=O)[C@@H](C=1C=C(Cl)C(=CC=1)S(C)(=O)=O)CC1CCCC1 PVZZCNBROJBJHG-OAHLLOKOSA-N 0.000 claims description 3
- WUBYGXHOAJQAQK-OYGDXLDBSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-(methylsulfinylmethyl)pyrazin-2-yl]propanamide Chemical compound C1=NC(CS(=O)C)=CN=C1NC(=O)[C@@H](C=1C=C(Cl)C(=CC=1)S(C)(=O)=O)CC1CCCC1 WUBYGXHOAJQAQK-OYGDXLDBSA-N 0.000 claims description 3
- DHTQDLARMJZTRI-MJTSIZKDSA-N (2r)-n-[5-(2-amino-1-hydroxy-2-oxoethyl)pyrazin-2-yl]-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentylpropanamide Chemical compound C1=C(Cl)C(S(=O)(=O)C)=CC=C1[C@H](C(=O)NC=1N=CC(=NC=1)C(O)C(N)=O)CC1CCCC1 DHTQDLARMJZTRI-MJTSIZKDSA-N 0.000 claims description 3
- ALRUAKYXLTVWEZ-UHFFFAOYSA-N 2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-(1-hydroxy-2-methylpropyl)pyrazin-2-yl]propanamide Chemical compound C1=NC(C(O)C(C)C)=CN=C1NC(=O)C(C=1C=C(Cl)C(=CC=1)S(C)(=O)=O)CC1CCCC1 ALRUAKYXLTVWEZ-UHFFFAOYSA-N 0.000 claims description 3
- LPTXOARRBIFFCR-UHFFFAOYSA-N 2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-(1-hydroxyethyl)pyrazin-2-yl]propanamide Chemical compound C1=NC(C(O)C)=CN=C1NC(=O)C(C=1C=C(Cl)C(=CC=1)S(C)(=O)=O)CC1CCCC1 LPTXOARRBIFFCR-UHFFFAOYSA-N 0.000 claims description 3
- MHHLRNDLIDHPMN-UHFFFAOYSA-N 2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-(methylsulfanylmethyl)pyrazin-2-yl]propanamide Chemical compound C1=NC(CSC)=CN=C1NC(=O)C(C=1C=C(Cl)C(=CC=1)S(C)(=O)=O)CC1CCCC1 MHHLRNDLIDHPMN-UHFFFAOYSA-N 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
- TZQZTAAKWYSXKV-OAQYLSRUSA-N (2r)-2-(3-chloro-2-methylsulfonylphenyl)-3-cyclopentyl-n-[5-(3-methoxyphenyl)pyrazin-2-yl]propanamide Chemical compound COC1=CC=CC(C=2N=CC(NC(=O)[C@H](CC3CCCC3)C=3C(=C(Cl)C=CC=3)S(C)(=O)=O)=NC=2)=C1 TZQZTAAKWYSXKV-OAQYLSRUSA-N 0.000 claims description 2
- LKRYWWFJGDPNAI-QGZVFWFLSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-(5-thiophen-2-ylpyrazin-2-yl)propanamide Chemical compound C1=C(Cl)C(S(=O)(=O)C)=CC=C1[C@H](C(=O)NC=1N=CC(=NC=1)C=1SC=CC=1)CC1CCCC1 LKRYWWFJGDPNAI-QGZVFWFLSA-N 0.000 claims description 2
- MGXHZTQMLYFNMR-NNJIEVJOSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-[5-(1,2-dihydroxyethyl)pyrazin-2-yl]propanamide Chemical compound C1=C(Cl)C(S(=O)(=O)C)=CC=C1[C@H](C(=O)NC=1N=CC(=NC=1)C(O)CO)CC1CCCC1 MGXHZTQMLYFNMR-NNJIEVJOSA-N 0.000 claims description 2
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- CQXDYHPBXDZWBA-UHFFFAOYSA-N tert-butyl 2,2,2-trichloroethanimidate Chemical compound CC(C)(C)OC(=N)C(Cl)(Cl)Cl CQXDYHPBXDZWBA-UHFFFAOYSA-N 0.000 description 1
- JDLBHMJRNCTQMG-PDYUXYPTSA-N tert-butyl n-[(2s)-1-[(2e)-2-[(2-chloro-7-methylquinolin-3-yl)methylidene]hydrazinyl]-4-methylsulfanyl-1-oxobutan-2-yl]carbamate Chemical compound C1=C(C)C=C2N=C(Cl)C(/C=N/NC(=O)[C@@H](NC(=O)OC(C)(C)C)CCSC)=CC2=C1 JDLBHMJRNCTQMG-PDYUXYPTSA-N 0.000 description 1
- XBXCNNQPRYLIDE-UHFFFAOYSA-N tert-butylcarbamic acid Chemical compound CC(C)(C)NC(O)=O XBXCNNQPRYLIDE-UHFFFAOYSA-N 0.000 description 1
- AWDBHOZBRXWRKS-UHFFFAOYSA-N tetrapotassium;iron(6+);hexacyanide Chemical compound [K+].[K+].[K+].[K+].[Fe+6].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] AWDBHOZBRXWRKS-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000004149 thio group Chemical group *S* 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- LWNCDBSQZPDFOG-UHFFFAOYSA-N tributyl(2-methylprop-1-enyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C=C(C)C LWNCDBSQZPDFOG-UHFFFAOYSA-N 0.000 description 1
- ZQMLPLBDZBCQCV-UHFFFAOYSA-N tributyl(3,4-dihydro-2h-pyran-6-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CCCCO1 ZQMLPLBDZBCQCV-UHFFFAOYSA-N 0.000 description 1
- QIWRFOJWQSSRJZ-UHFFFAOYSA-N tributyl(ethenyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C=C QIWRFOJWQSSRJZ-UHFFFAOYSA-N 0.000 description 1
- YLGRTLMDMVAFNI-UHFFFAOYSA-N tributyl(prop-2-enyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)CC=C YLGRTLMDMVAFNI-UHFFFAOYSA-N 0.000 description 1
- ISPSHPOFLYFIRR-UHFFFAOYSA-N trihexylsilicon Chemical compound CCCCCC[Si](CCCCCC)CCCCCC ISPSHPOFLYFIRR-UHFFFAOYSA-N 0.000 description 1
- 239000012178 vegetable wax Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
-
- 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
- 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
- C07D213/76—Nitrogen atoms to which a second hetero atom is attached
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D213/78—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
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-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
- C07D241/20—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-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
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Diabetes (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Emergency Medicine (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyridine Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (5)
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| US43280602P | 2002-12-12 | 2002-12-12 | |
| US432806P | 2002-12-12 | ||
| US52453103P | 2003-11-24 | 2003-11-24 | |
| US524531P | 2003-11-24 | ||
| PCT/EP2003/014055 WO2004052869A1 (en) | 2002-12-12 | 2003-12-11 | 5-substituted-pyrazine or pyridine glucokinase activators |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE60315886D1 DE60315886D1 (de) | 2007-10-04 |
| DE60315886T2 true DE60315886T2 (de) | 2008-05-15 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE60315886T Expired - Lifetime DE60315886T2 (de) | 2002-12-12 | 2003-12-11 | Substituierte pyrazin- oder pyridin-derivate als glukokinase-aktivatoren |
Country Status (26)
| Country | Link |
|---|---|
| US (1) | US7132425B2 (enExample) |
| EP (1) | EP1572670B1 (enExample) |
| JP (1) | JP4490285B2 (enExample) |
| KR (1) | KR100743890B1 (enExample) |
| AR (1) | AR046244A1 (enExample) |
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| AU (1) | AU2003292229B2 (enExample) |
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| CA (1) | CA2506441C (enExample) |
| CY (1) | CY1106989T1 (enExample) |
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| DK (1) | DK1572670T3 (enExample) |
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| MY (1) | MY141521A (enExample) |
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| UY (1) | UY28121A1 (enExample) |
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Families Citing this family (90)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE0102299D0 (sv) | 2001-06-26 | 2001-06-26 | Astrazeneca Ab | Compounds |
| SE0102764D0 (sv) | 2001-08-17 | 2001-08-17 | Astrazeneca Ab | Compounds |
| JP2006509774A (ja) | 2002-10-03 | 2006-03-23 | ノバルティス アクチエンゲゼルシャフト | 2型糖尿病の処置において有用なグルコキナーゼアクチベーターとしての置換(チアゾール−2−イル)−アミドまたはスルホンアミド |
| GB0226931D0 (en) | 2002-11-19 | 2002-12-24 | Astrazeneca Ab | Chemical compounds |
| GB0226930D0 (en) | 2002-11-19 | 2002-12-24 | Astrazeneca Ab | Chemical compounds |
| US7262196B2 (en) * | 2003-02-11 | 2007-08-28 | Prosidion Limited | Tri(cyclo) substituted amide glucokinase activator compounds |
| JP2007530631A (ja) | 2004-04-02 | 2007-11-01 | ノバルティス アクチエンゲゼルシャフト | チアゾロピリジン誘導体、それを含む医薬組成物およびグルコキナーゼ介在性状態の処置法 |
| ATE524479T1 (de) | 2004-04-02 | 2011-09-15 | Novartis Ag | Sulfonamidthiazolpyridinderivate als zur behandlung von typ-2-diabetes geeignete glucokinaseaktivatoren |
| JP2008521864A (ja) | 2004-12-03 | 2008-06-26 | トランステック・ファーマ、インコーポレイテッド | ヘテロ芳香族グルコキナーゼ活性化剤 |
| NZ575512A (en) | 2005-07-09 | 2009-11-27 | Astrazeneca Ab | Heteroaryl benzamide derivatives for use as GLK activators in the treatment of diabetes |
| BRPI0615236A2 (pt) * | 2005-08-31 | 2011-05-10 | Astellas Pharma Inc | derivado de tiazol |
| JP2007063225A (ja) * | 2005-09-01 | 2007-03-15 | Takeda Chem Ind Ltd | イミダゾピリジン化合物 |
| EP1931337B1 (en) | 2005-09-29 | 2013-10-23 | Sanofi | Phenyl- and pyridinyl- 1, 2 , 4 - oxadiazolone derivatives, processes for their preparation and their use as pharmaceuticals |
| GT200600428A (es) * | 2005-09-30 | 2007-05-21 | Compuestos organicos | |
| GT200600429A (es) * | 2005-09-30 | 2007-04-30 | Compuestos organicos | |
| JP2009515997A (ja) * | 2005-11-18 | 2009-04-16 | タケダ サン ディエゴ インコーポレイテッド | グルコキナーゼ活性剤 |
| JP5302012B2 (ja) | 2006-03-08 | 2013-10-02 | タケダ カリフォルニア インコーポレイテッド | グルコキナーゼ活性剤 |
| US8211925B2 (en) * | 2006-04-28 | 2012-07-03 | Transtech Pharma, Inc. | Benzamide glucokinase activators |
| PE20080251A1 (es) | 2006-05-04 | 2008-04-25 | Boehringer Ingelheim Int | Usos de inhibidores de dpp iv |
| JP5386350B2 (ja) | 2006-05-31 | 2014-01-15 | タケダ カリフォルニア インコーポレイテッド | グルコキナーゼ活性剤としての、インダゾールおよびイソインドール誘導体 |
| FR2903985B1 (fr) | 2006-07-24 | 2008-09-05 | Sanofi Aventis Sa | Derives de n-(amino-heteroaryl)-1h-indole-2-carboxamides, leur preparation et leur application en therapeutique |
| AU2007278261A1 (en) | 2006-07-24 | 2008-01-31 | F. Hoffmann-La Roche Ag | Pyrazoles as glucokinase activators |
| FR2904316B1 (fr) | 2006-07-31 | 2008-09-05 | Sanofi Aventis Sa | Derives de n-(amino-heteroaryl)-1h-indole-2-carboxamides, leur preparation et leur application en therapeutique. |
| US20080107725A1 (en) * | 2006-10-13 | 2008-05-08 | Albano Antonio A | Pharmaceutical Solid Dosage Forms Comprising Amorphous Compounds Micro-Embedded in Ionic Water-Insoluble Polymers |
| US7902248B2 (en) * | 2006-12-14 | 2011-03-08 | Hoffmann-La Roche Inc. | Oxime glucokinase activators |
| WO2008079787A2 (en) | 2006-12-20 | 2008-07-03 | Takeda San Diego, Inc. | Glucokinase activators |
| WO2008074694A1 (en) * | 2006-12-20 | 2008-06-26 | F. Hoffmann-La Roche Ag | Crystallization of glucokinase activators |
| TW200831081A (en) * | 2006-12-25 | 2008-08-01 | Kyorin Seiyaku Kk | Glucokinase activator |
| FR2910473B1 (fr) | 2006-12-26 | 2009-02-13 | Sanofi Aventis Sa | Derives de n-(amino-heteroaryl)-1h-pyrrolopyridine-2- carboxamides, leur preparation et leur application en therapeutique. |
| EP2105435A4 (en) * | 2007-01-10 | 2011-06-15 | Mitsubishi Tanabe Pharma Corp | Hydrazone derivative |
| KR20170085615A (ko) | 2007-02-09 | 2017-07-24 | 메타베이시스 테라퓨틱스, 인크. | 글루카곤 수용체의 길항제 |
| AU2008225613B2 (en) * | 2007-03-07 | 2012-06-14 | Kyorin Pharmaceutical Co., Ltd. | Glucokinase activator |
| US8173645B2 (en) * | 2007-03-21 | 2012-05-08 | Takeda San Diego, Inc. | Glucokinase activators |
| CN101641447A (zh) | 2007-04-04 | 2010-02-03 | 霍夫曼-拉罗奇有限公司 | 乙酰氧基酮的微生物还原 |
| EP2148878A4 (en) * | 2007-04-20 | 2011-08-10 | Merck Canada Inc | NEW HETEROAROMATIC COMPOUNDS AS INHIBITORS OF STEAROYL-COENZYME-A-DELTA-9-DESATURASE |
| WO2009022179A2 (en) * | 2007-08-14 | 2009-02-19 | Astrazeneca Ab | Glucokinase activators in the treatment of osteoarthritis |
| JP5580201B2 (ja) * | 2007-10-08 | 2014-08-27 | アドビヌス・セラピューティクス・プライベート・リミテッド | グルコキナーゼアクチベータとしてのアセトアミド誘導体、その製法及び医薬応用 |
| MX2010007853A (es) | 2008-01-18 | 2010-10-06 | Astellas Pharma Inc | Derivado de fenilacetamida. |
| US7741327B2 (en) | 2008-04-16 | 2010-06-22 | Hoffmann-La Roche Inc. | Pyrrolidinone glucokinase activators |
| US8258134B2 (en) * | 2008-04-16 | 2012-09-04 | Hoffmann-La Roche Inc. | Pyridazinone glucokinase activators |
| MX2010011778A (es) | 2008-04-28 | 2010-11-30 | Kyorin Seiyaku Kk | Derivados de ciclopentil acrilamida. |
| EP2799428B1 (en) | 2008-08-13 | 2016-11-16 | Metabasis Therapeutics, Inc. | Glucagon antagonists |
| UA104742C2 (uk) * | 2008-12-19 | 2014-03-11 | Эли Лилли Энд Компани | Похідні арилциклопропілацетаміду, застосовні як активатори глюкокінази |
| US20110021570A1 (en) * | 2009-07-23 | 2011-01-27 | Nancy-Ellen Haynes | Pyridone glucokinase activators |
| US20110040091A1 (en) | 2009-08-13 | 2011-02-17 | Stephan Bachmann | Process for the preparation of (r)-2-phenyl propionic acid derivatives |
| US20110054174A1 (en) | 2009-08-28 | 2011-03-03 | Stephan Bachmann | Process for the preparation of a glucokinase activator compound |
| US8962627B2 (en) | 2009-10-30 | 2015-02-24 | Prestwick Chemical, Inc. | Oxime derivatives and their use as allosteric modulators of metabotropic glutamate receptors |
| US8222416B2 (en) | 2009-12-14 | 2012-07-17 | Hoffmann-La Roche Inc. | Azaindole glucokinase activators |
| AU2011235212B2 (en) | 2010-03-31 | 2014-07-31 | The Scripps Research Institute | Reprogramming cells |
| CN102971313A (zh) | 2010-04-14 | 2013-03-13 | 百时美施贵宝公司 | 新颖的葡糖激酶激活剂及其使用方法 |
| US8178689B2 (en) | 2010-06-17 | 2012-05-15 | Hoffman-La Roche Inc. | Tricyclic compounds |
| AR082590A1 (es) | 2010-08-12 | 2012-12-19 | Hoffmann La Roche | Inhibidores de la tirosina-quinasa de bruton |
| NZ710405A (en) * | 2010-11-16 | 2017-04-28 | Acetylon Pharmaceuticals Inc | Pyrimidine hydroxy amide compounds as protein deacetylase inhibitors and methods of use thereof |
| US8470866B2 (en) | 2011-05-03 | 2013-06-25 | Hoffmann-La Roche Inc. | Isoindolinone derivatives |
| US9630929B2 (en) | 2011-10-31 | 2017-04-25 | Xenon Pharmaceuticals Inc. | Benzenesulfonamide compounds and their use as therapeutic agents |
| RU2014121983A (ru) | 2011-10-31 | 2015-12-10 | Ксенон Фармасьютикалз Инк. | Биарильные простоэфирные сульфонамиды и их применение в качестве терапевтических средств |
| US8952169B2 (en) | 2012-05-22 | 2015-02-10 | Xenon Pharmaceuticals Inc. | N-substituted benzamides and methods of use thereof |
| CN104797555B (zh) * | 2012-07-06 | 2017-12-22 | 基因泰克公司 | N‑取代的苯甲酰胺及其使用方法 |
| HK1213476A1 (zh) | 2013-03-14 | 2016-07-08 | 基因泰克公司 | 取代的三唑並吡啶及其使用方法 |
| CA2898680A1 (en) | 2013-03-15 | 2014-09-18 | Genentech,Inc. | Substituted benzoxazoles and methods of use thereof |
| KR20160045863A (ko) | 2013-08-23 | 2016-04-27 | 패리온 사이언스 인코퍼레이티드 | 디티올 점액 용해제 |
| ES2929576T3 (es) | 2013-10-08 | 2022-11-30 | Acetylon Pharmaceuticals Inc | Combinaciones de inhibidores de histona deacetilasa 6 y el inhibidor de Her2 lapatinib para el uso en el tratamiento del cáncer de mama |
| EP3055299B1 (en) | 2013-10-10 | 2021-01-06 | Acetylon Pharmaceuticals, Inc. | Pyrimidine hydroxy amide compounds as histone deacetylase inhibitors |
| US10660890B2 (en) | 2013-10-24 | 2020-05-26 | National Institutes Of Health (Nih), U.S. Dept. Of Health And Human Services (Dhhs), U.S. Government Nih Division Of Extramural Inventions And Technology Resources (Deitr) | Treatment of polycystic diseases with an HDAC6 inhibitor |
| CA2931732A1 (en) | 2013-11-27 | 2015-06-04 | Genentech, Inc. | Substituted benzamides and methods of use thereof |
| EP2878339A1 (en) | 2013-12-02 | 2015-06-03 | Siena Biotech S.p.A. | SIP3 antagonists |
| KR20160092018A (ko) | 2013-12-03 | 2016-08-03 | 에이스틸론 파마수티컬스 인코포레이티드 | 히스톤 탈아세틸화효소 저해제 및 면역조절 약물의 조합 |
| US9464073B2 (en) | 2014-02-26 | 2016-10-11 | Acetylon Pharmaceuticals, Inc. | Pyrimidine hydroxy amide compounds as HDAC6 selective inhibitors |
| EP3154956A4 (en) | 2014-06-12 | 2018-01-17 | Ligand Pharmaceuticals, Inc. | Glucagon antagonists |
| AU2015288060A1 (en) | 2014-07-07 | 2017-02-09 | Acetylon Pharmaceuticals, Inc. | Treatment of leukemia with histone deacetylase inhibitors |
| WO2016007534A1 (en) | 2014-07-07 | 2016-01-14 | Genentech, Inc. | Therapeutic compounds and methods of use thereof |
| RS58592B1 (sr) | 2014-08-27 | 2019-05-31 | Prexton Therapeutics Sa | Novi derivat hromon oksima i njegova upotreba kao alosterni modulator metabotropnih glutamatnih receptora |
| AU2015356779A1 (en) | 2014-12-05 | 2017-07-13 | University of Modena and Reggio Emilia | Combinations of histone deacetylase inhibitors and bendamustine for use in the treatment of lymphoma |
| CN112321472A (zh) * | 2015-01-30 | 2021-02-05 | 帕里昂科学公司 | 新型单硫醇粘液溶解剂 |
| JP2018520986A (ja) | 2015-04-30 | 2018-08-02 | パリオン・サイエンシィズ・インコーポレーテッド | ジチオール粘液溶解剤の新規なプロドラッグ |
| PE20180575A1 (es) | 2015-05-22 | 2018-04-04 | Genentech Inc | Benzamidas sustituidas y metodos para utilizarlas |
| US10272084B2 (en) | 2015-06-01 | 2019-04-30 | Regenacy Pharmaceuticals, Llc | Histone deacetylase 6 selective inhibitors for the treatment of cisplatin-induced peripheral neuropathy |
| RS59651B1 (sr) | 2015-08-27 | 2020-01-31 | Prexton Therapeutics Sa | Derivat hromonoksima koji prodire u mozak u svrhu terapije diskinezije uzrokovane levodopom |
| MA42683A (fr) | 2015-08-27 | 2018-07-04 | Genentech Inc | Composés thérapeutiques et leurs méthodes utilisation |
| BR112018006189A2 (pt) | 2015-09-28 | 2018-10-09 | Genentech Inc | compostos da fórmula, composição farmacêutica, métodos de tratamento de uma doença, de diminuição do fluxo de íons e de tratamento de prurido em um mamífero, método para tratamento de dores em um mamífero e uso de um composto |
| JP2018535234A (ja) | 2015-11-25 | 2018-11-29 | ジェネンテック, インコーポレイテッド | ナトリウムチャネル遮断薬として有用な置換ベンズアミド |
| CN109071426A (zh) | 2016-03-30 | 2018-12-21 | 基因泰克公司 | 取代的苯甲酰胺及其使用方法 |
| EP3445364A4 (en) | 2016-04-19 | 2019-11-27 | Acetylon Pharmaceuticals, Inc. | HDAC INHIBITORS, ONLY OR IN COMBINATION WITH BTK INHIBITORS, FOR THE TREATMENT OF CHRONIC LYMPHOCYTIC LEUKEMIA |
| EP3487862A1 (en) | 2016-07-22 | 2019-05-29 | Bristol-Myers Squibb Company | Glucokinase activators and methods of using same |
| WO2018072602A1 (en) | 2016-10-17 | 2018-04-26 | Genentech, Inc. | Therapeutic compounds and methods of use thereof |
| JP2020511511A (ja) | 2017-03-24 | 2020-04-16 | ジェネンテック, インコーポレイテッド | ナトリウムチャネル阻害剤としての4−ピペリジン−n−(ピリミジン−4−イル)クロマン−7−スルホンアミド誘導体 |
| CN111954560A (zh) | 2018-02-13 | 2020-11-17 | 配体药物公司 | 胰高血糖素受体拮抗剂 |
| EP3759098A1 (en) | 2018-02-26 | 2021-01-06 | Genentech, Inc. | Pyridine-sulfonamide compounds and their use against pain and related conditions |
| US10947251B2 (en) | 2018-03-30 | 2021-03-16 | Genentech, Inc. | Therapeutic compounds and methods of use thereof |
| TW202003490A (zh) | 2018-05-22 | 2020-01-16 | 瑞士商赫孚孟拉羅股份公司 | 治療性化合物及其使用方法 |
Family Cites Families (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE249241C (enExample) | 1910-05-01 | 1912-07-13 | ||
| US3431301A (en) | 1966-03-24 | 1969-03-04 | Hoffmann La Roche | Process for producing methylhydrazine derivatives |
| US3776917A (en) | 1972-06-05 | 1973-12-04 | Schering Corp | 2-amino-6-phenalkyl-aminopyridines and derivatives thereof |
| ES419319A1 (es) | 1973-10-04 | 1976-03-01 | Gallardo Antonio Sa | Un procedimiento para la obtencion de derivados de acidos 3-benzoilfenilalcanoicos. |
| GB8909574D0 (en) | 1989-04-26 | 1989-06-14 | Ici Plc | Chemical process |
| US5169951A (en) | 1990-04-23 | 1992-12-08 | Ciba-Geigy Corporation | Process for preparing nematicidal compositions |
| DE69322118T2 (de) | 1992-04-17 | 1999-05-20 | Hodogaya Chemical Co., Ltd., Tokio/Tokyo | Amino-Thiazolderivate und ihre Anwendung als Fungizide |
| US5556859A (en) | 1994-12-22 | 1996-09-17 | Dowelanco | N-(4-pyrimidinyl)amide pesticides |
| FR2766183B1 (fr) * | 1997-07-17 | 1999-08-27 | Rhone Poulenc Rorer Sa | Medicaments contenant des polyhydroxybutylpyrazines, les polyhydroxybutylpyrazines nouvelles et leur preparation |
| GB9823871D0 (en) | 1998-10-30 | 1998-12-23 | Pharmacia & Upjohn Spa | 2-Amino-thiazole derivatives, process for their preparation, and their use as antitumour agents |
| US6610846B1 (en) | 1999-03-29 | 2003-08-26 | Hoffman-La Roche Inc. | Heteroaromatic glucokinase activators |
| MXPA01009814A (es) * | 1999-03-29 | 2002-04-24 | Hoffmann La Roche | Activadores de la glucoquinasa. |
| US6320050B1 (en) | 1999-03-29 | 2001-11-20 | Hoffmann-La Roche Inc. | Heteroaromatic glucokinase activators |
| RU2242469C2 (ru) | 1999-03-29 | 2004-12-20 | Ф.Хоффманн-Ля Рош Аг | Активаторы глюкокиназы |
| US6353111B1 (en) | 1999-12-15 | 2002-03-05 | Hoffmann-La Roche Inc. | Trans olefinic glucokinase activators |
| MXPA02010746A (es) * | 2000-05-03 | 2003-03-10 | Hoffmann La Roche | Activadores de la glucocinasa que contienen hidantoina. |
| KR100502033B1 (ko) | 2000-05-03 | 2005-07-25 | 에프. 호프만-라 로슈 아게 | 알키닐 페닐 헤테로방향족 글루코키나제 활성제 |
| DK1282611T3 (da) | 2000-05-08 | 2005-02-14 | Hoffmann La Roche | Substituerede phenylacetatamider og anvendelse deraf som glucokinaseaktivatorer |
| US6489485B2 (en) | 2000-05-08 | 2002-12-03 | Hoffmann-La Roche Inc. | Para-amine substituted phenylamide glucokinase activators |
| PT1305301E (pt) | 2000-07-20 | 2005-09-30 | Hoffmann La Roche | Benzeno-acetamidas alfa-acilo e alfa-heteroatomo-substituidas activadoras da glucocinase |
| US6369232B1 (en) | 2000-08-15 | 2002-04-09 | Hoffmann-La Roche Inc. | Tetrazolyl-phenyl acetamide glucokinase activators |
| AU2002221902B2 (en) | 2000-12-06 | 2006-11-23 | F. Hoffmann-La Roche Ag | Fused heteroaromatic glucokinase activators |
| US6433188B1 (en) | 2000-12-06 | 2002-08-13 | Wendy Lea Corbett | Fused heteroaromatic glucokinase activators |
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