HRP20010716A2 - Aminopyrimidines as sorbitol dehydrogenase inhibitors - Google Patents
Aminopyrimidines as sorbitol dehydrogenase inhibitors Download PDFInfo
- Publication number
- HRP20010716A2 HRP20010716A2 HR20010716A HRP20010716A HRP20010716A2 HR P20010716 A2 HRP20010716 A2 HR P20010716A2 HR 20010716 A HR20010716 A HR 20010716A HR P20010716 A HRP20010716 A HR P20010716A HR P20010716 A2 HRP20010716 A2 HR P20010716A2
- Authority
- HR
- Croatia
- Prior art keywords
- alkyl
- optionally substituted
- hydroxy
- alkoxy
- fluorines
- Prior art date
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- 239000003112 inhibitor Substances 0.000 title claims description 29
- 108010009384 L-Iditol 2-Dehydrogenase Proteins 0.000 title claims description 11
- 102100026974 Sorbitol dehydrogenase Human genes 0.000 title claims description 10
- 150000005005 aminopyrimidines Chemical class 0.000 title 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 920
- 150000001875 compounds Chemical class 0.000 claims description 473
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 432
- -1 vinylenylcarbonyl Chemical group 0.000 claims description 429
- 235000019000 fluorine Nutrition 0.000 claims description 418
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 416
- 125000001153 fluoro group Chemical group F* 0.000 claims description 409
- 239000000651 prodrug Substances 0.000 claims description 379
- 229940002612 prodrug Drugs 0.000 claims description 379
- 229910052739 hydrogen Inorganic materials 0.000 claims description 264
- 239000001257 hydrogen Substances 0.000 claims description 264
- 150000003839 salts Chemical class 0.000 claims description 192
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 186
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 173
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 159
- 125000005843 halogen group Chemical group 0.000 claims description 141
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 135
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 127
- 125000004076 pyridyl group Chemical group 0.000 claims description 95
- 125000001424 substituent group Chemical group 0.000 claims description 94
- VOPWNXZWBYDODV-UHFFFAOYSA-N Chlorodifluoromethane Chemical compound FC(F)Cl VOPWNXZWBYDODV-UHFFFAOYSA-N 0.000 claims description 72
- 125000004193 piperazinyl group Chemical group 0.000 claims description 65
- 125000002757 morpholinyl group Chemical group 0.000 claims description 63
- 241000124008 Mammalia Species 0.000 claims description 60
- 238000000034 method Methods 0.000 claims description 58
- 125000005466 alkylenyl group Chemical group 0.000 claims description 56
- 125000003386 piperidinyl group Chemical group 0.000 claims description 56
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 56
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 55
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 53
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 53
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 52
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 51
- 125000000335 thiazolyl group Chemical group 0.000 claims description 50
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 47
- 229910052731 fluorine Inorganic materials 0.000 claims description 47
- 239000011737 fluorine Substances 0.000 claims description 47
- 125000002971 oxazolyl group Chemical group 0.000 claims description 47
- 229910052757 nitrogen Chemical group 0.000 claims description 46
- 229920006395 saturated elastomer Polymers 0.000 claims description 46
- 125000002947 alkylene group Chemical group 0.000 claims description 45
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 43
- 125000002541 furyl group Chemical group 0.000 claims description 42
- 125000001544 thienyl group Chemical group 0.000 claims description 42
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 40
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 37
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 claims description 36
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 35
- 150000002431 hydrogen Chemical group 0.000 claims description 34
- 125000002785 azepinyl group Chemical group 0.000 claims description 33
- 125000002393 azetidinyl group Chemical group 0.000 claims description 32
- 208000002249 Diabetes Complications Diseases 0.000 claims description 31
- 206010012655 Diabetic complications Diseases 0.000 claims description 31
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 31
- 229910052717 sulfur Inorganic materials 0.000 claims description 30
- 125000002883 imidazolyl group Chemical group 0.000 claims description 27
- OBNCKNCVKJNDBV-UHFFFAOYSA-N butanoic acid ethyl ester Natural products CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 claims description 26
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 claims description 24
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 24
- 108091006647 SLC9A1 Proteins 0.000 claims description 24
- 102100030980 Sodium/hydrogen exchanger 1 Human genes 0.000 claims description 24
- 229910052760 oxygen Inorganic materials 0.000 claims description 24
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 23
- 125000001624 naphthyl group Chemical group 0.000 claims description 23
- 239000011593 sulfur Chemical group 0.000 claims description 23
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 22
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 21
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 20
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 20
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 20
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 20
- 206010012601 diabetes mellitus Diseases 0.000 claims description 20
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 20
- 125000005493 quinolyl group Chemical group 0.000 claims description 20
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 20
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 19
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 125000002619 bicyclic group Chemical group 0.000 claims description 18
- 150000003254 radicals Chemical group 0.000 claims description 18
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 17
- 125000005842 heteroatom Chemical group 0.000 claims description 17
- 239000001301 oxygen Substances 0.000 claims description 17
- 125000001425 triazolyl group Chemical group 0.000 claims description 17
- 239000003288 aldose reductase inhibitor Substances 0.000 claims description 16
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 16
- 125000004432 carbon atom Chemical group C* 0.000 claims description 15
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 15
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 14
- 229940118148 Aldose reductase inhibitor Drugs 0.000 claims description 14
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 14
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 14
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 14
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 14
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 14
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 14
- 125000004306 triazinyl group Chemical group 0.000 claims description 14
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 13
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 13
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 13
- HNAGHMKIPMKKBB-UHFFFAOYSA-N 1-benzylpyrrolidine-3-carboxamide Chemical compound C1C(C(=O)N)CCN1CC1=CC=CC=C1 HNAGHMKIPMKKBB-UHFFFAOYSA-N 0.000 claims description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 125000002950 monocyclic group Chemical group 0.000 claims description 12
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 12
- 125000005090 alkenylcarbonyl group Chemical group 0.000 claims description 11
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 10
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 10
- 125000005153 alkyl sulfamoyl group Chemical group 0.000 claims description 10
- 125000005554 pyridyloxy group Chemical group 0.000 claims description 10
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 9
- 208000028867 ischemia Diseases 0.000 claims description 9
- 125000004043 oxo group Chemical group O=* 0.000 claims description 9
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 8
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 claims description 8
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 8
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims description 7
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 7
- 125000004399 C1-C4 alkenyl group Chemical group 0.000 claims description 7
- 239000004305 biphenyl Substances 0.000 claims description 7
- 235000010290 biphenyl Nutrition 0.000 claims description 7
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 7
- 238000005342 ion exchange Methods 0.000 claims description 7
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 7
- 101001043818 Mus musculus Interleukin-31 receptor subunit alpha Proteins 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 150000002222 fluorine compounds Chemical class 0.000 claims description 6
- MNQZXJOMYWMBOU-UHFFFAOYSA-N glyceraldehyde Chemical compound OCC(O)C=O MNQZXJOMYWMBOU-UHFFFAOYSA-N 0.000 claims description 6
- 125000001041 indolyl group Chemical group 0.000 claims description 6
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 claims description 6
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 6
- 125000004588 thienopyridyl group Chemical group S1C(=CC2=C1C=CC=N2)* 0.000 claims description 6
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 5
- 125000004414 alkyl thio group Chemical group 0.000 claims description 5
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
- NLUNLVTVUDIHFE-UHFFFAOYSA-N cyclooctylcyclooctane Chemical group C1CCCCCCC1C1CCCCCCC1 NLUNLVTVUDIHFE-UHFFFAOYSA-N 0.000 claims description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 claims description 4
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 4
- 230000002401 inhibitory effect Effects 0.000 claims description 4
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 4
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 claims description 4
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 4
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 claims description 4
- 125000006085 pyrrolopyridyl group Chemical group 0.000 claims description 4
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 4
- PRNRUOJLUPUJDN-UHFFFAOYSA-N 4-piperidin-4-ylpiperidine Chemical group C1CNCCC1C1CCNCC1 PRNRUOJLUPUJDN-UHFFFAOYSA-N 0.000 claims description 3
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- QQWLEMDZDOOMGE-CQSZACIVSA-N [(1r)-1-[4-(4-quinoxalin-2-ylpiperazin-1-yl)pyrimidin-2-yl]ethyl] acetate Chemical compound CC(=O)O[C@H](C)C1=NC=CC(N2CCN(CC2)C=2N=C3C=CC=CC3=NC=2)=N1 QQWLEMDZDOOMGE-CQSZACIVSA-N 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 2
- 229940093499 ethyl acetate Drugs 0.000 claims description 2
- 235000019439 ethyl acetate Nutrition 0.000 claims description 2
- 230000005764 inhibitory process Effects 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 198
- ROJNYKZWTOHRNU-UHFFFAOYSA-N 2-chloro-4,5-difluoro-n-[[2-methoxy-5-(methylcarbamoylamino)phenyl]carbamoyl]benzamide Chemical compound CNC(=O)NC1=CC=C(OC)C(NC(=O)NC(=O)C=2C(=CC(F)=C(F)C=2)Cl)=C1 ROJNYKZWTOHRNU-UHFFFAOYSA-N 0.000 claims 12
- CKJNUZNMWOVDFN-UHFFFAOYSA-N methanone Chemical compound O=[CH-] CKJNUZNMWOVDFN-UHFFFAOYSA-N 0.000 claims 4
- 238000006243 chemical reaction Methods 0.000 claims 3
- 239000012442 inert solvent Substances 0.000 claims 3
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 2
- AEOZCEMLLBCHQZ-UHFFFAOYSA-N 2-hydroxypropanimidamide;hydrochloride Chemical compound Cl.CC(O)C(N)=N AEOZCEMLLBCHQZ-UHFFFAOYSA-N 0.000 claims 2
- CEIPQQODRKXDSB-UHFFFAOYSA-N ethyl 3-(6-hydroxynaphthalen-2-yl)-1H-indazole-5-carboximidate dihydrochloride Chemical compound Cl.Cl.C1=C(O)C=CC2=CC(C3=NNC4=CC=C(C=C43)C(=N)OCC)=CC=C21 CEIPQQODRKXDSB-UHFFFAOYSA-N 0.000 claims 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 2
- 102000016912 Aldehyde Reductase Human genes 0.000 claims 1
- 108010053754 Aldehyde reductase Proteins 0.000 claims 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims 1
- NINSPLAPBBAHEW-ONEGZZNKSA-N ethyl (e)-3-hydroxyprop-2-enoate Chemical compound CCOC(=O)\C=C\O NINSPLAPBBAHEW-ONEGZZNKSA-N 0.000 claims 1
- SXQFCVDSOLSHOQ-UHFFFAOYSA-N lactamide Chemical compound CC(O)C(N)=O SXQFCVDSOLSHOQ-UHFFFAOYSA-N 0.000 claims 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- 125000006239 protecting group Chemical group 0.000 claims 1
- 159000000000 sodium salts Chemical class 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 157
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 14
- 238000002360 preparation method Methods 0.000 description 7
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 4
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 4
- 206010012689 Diabetic retinopathy Diseases 0.000 description 4
- 208000033679 diabetic kidney disease Diseases 0.000 description 4
- XINQFOMFQFGGCQ-UHFFFAOYSA-L (2-dodecoxy-2-oxoethyl)-[6-[(2-dodecoxy-2-oxoethyl)-dimethylazaniumyl]hexyl]-dimethylazanium;dichloride Chemical compound [Cl-].[Cl-].CCCCCCCCCCCCOC(=O)C[N+](C)(C)CCCCCC[N+](C)(C)CC(=O)OCCCCCCCCCCCC XINQFOMFQFGGCQ-UHFFFAOYSA-L 0.000 description 3
- 208000003790 Foot Ulcer Diseases 0.000 description 3
- 229930091371 Fructose Natural products 0.000 description 3
- 239000005715 Fructose Substances 0.000 description 3
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 3
- 206010040943 Skin Ulcer Diseases 0.000 description 3
- 230000002526 effect on cardiovascular system Effects 0.000 description 3
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 3
- 208000031225 myocardial ischemia Diseases 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 3
- 150000003230 pyrimidines Chemical class 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- 229940123934 Reductase inhibitor Drugs 0.000 description 2
- 229940123659 Sorbitol dehydrogenase inhibitor Drugs 0.000 description 2
- 229940090865 aldose reductase inhibitors used in diabetes Drugs 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 description 1
- 208000032781 Diabetic cardiomyopathy Diseases 0.000 description 1
- 206010063547 Diabetic macroangiopathy Diseases 0.000 description 1
- 206010054044 Diabetic microangiopathy Diseases 0.000 description 1
- 102000050381 Na+/H+ exchanger Human genes 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 108091006672 Sodium–hydrogen antiporter Proteins 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 125000005092 alkenyloxycarbonyl group Chemical group 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 201000009101 diabetic angiopathy Diseases 0.000 description 1
- 125000005067 haloformyl group Chemical group 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000002207 retinal effect Effects 0.000 description 1
- 208000037816 tissue injury Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
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Publication number | Priority date | Publication date | Assignee | Title |
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CA2366858A1 (fr) * | 1999-04-01 | 2000-10-12 | Margaret Yuhua Chu-Moyer | Inhibiteurs de sorbitol deshydrogenase |
WO2002032411A2 (fr) * | 2000-10-18 | 2002-04-25 | Pfizer Products Inc. | Combinaison de statines et d'inhibiteurs de sorbitol-deshydrogenase |
SE0003795D0 (sv) | 2000-10-20 | 2000-10-20 | Astrazeneca Ab | Pharmaceutically useful compounds |
CA2430298A1 (fr) | 2000-11-30 | 2002-06-06 | Banavara Lakshman Mylari | Combinaison d'agonistes gaba et d'inhibiteurs de la sorbitol-deshydrogenase (sdi) |
CA2433090A1 (fr) * | 2000-12-27 | 2002-07-04 | Kyowa Hakko Kogyo Co., Ltd. | Inhibiteur de dipeptidyl peptidase iv |
IL147696A0 (en) * | 2001-01-25 | 2002-08-14 | Pfizer Prod Inc | Combination therapy |
EP1247809A3 (fr) * | 2001-03-30 | 2003-12-17 | Pfizer Products Inc. | Dérivés de triazine et leur application comme inhibiteurs de sorbitol-déhydrogénase |
IL158941A0 (en) | 2001-05-22 | 2004-05-12 | Neurogen Corp | Melanin concentrating hormone receptor ligands: substituted 1-benzyl-4-aryl piperazine analogues |
GB0127929D0 (en) * | 2001-11-21 | 2002-01-16 | Celltech R&D Ltd | Chemical compounds |
US7067517B2 (en) * | 2001-12-14 | 2006-06-27 | Nero Nordisk A/S | Use of compounds for decreasing activity of hormone-sensitive lipase |
AU2003249369A1 (en) | 2002-06-21 | 2004-01-06 | Cellular Genomics, Inc. | Certain amino-substituted monocycles as kinase modulators |
US7582635B2 (en) | 2002-12-24 | 2009-09-01 | Purdue Pharma, L.P. | Therapeutic agents useful for treating pain |
MY150088A (en) | 2003-05-19 | 2013-11-29 | Irm Llc | Immunosuppressant compounds and compositions |
BRPI0410746A (pt) * | 2003-05-19 | 2006-06-27 | Irm Llc | compostos e composições imunossupressoras |
EP1636189A1 (fr) * | 2003-06-12 | 2006-03-22 | Novo Nordisk A/S | Derives de 1-aryl-4-(aryloxycarbonyl)-piperazine utilises en tant qu'inhibiteurs de la lipase hormonosensible |
AU2004257289A1 (en) * | 2003-07-16 | 2005-01-27 | Neurogen Corporation | Biaryl piperazinyl-pyridine analogues |
TWI290140B (en) * | 2003-08-25 | 2007-11-21 | Schering Corp | 2-Substituted benzimidazole derivatives as selective melanin concentrating hormone receptor antagonists for thr treatment of obesity and related disorders |
BRPI0414541B8 (pt) | 2003-09-17 | 2021-05-25 | Janssen Pharmaceutica Nv | compostos heterocíclicos fundidos tendo atividade de modulação de receptor de serotonina, método de preparação de compostos intermediários |
WO2005037284A1 (fr) * | 2003-10-15 | 2005-04-28 | Pfizer Products Inc. | Inhibiteur de la sorbitol-deshydrogenase et associations d'agents antihypertenseurs |
US8455489B2 (en) * | 2003-11-10 | 2013-06-04 | Exelixis, Inc. | Substituted pyrimidine compositions and methods of use |
US20050239791A1 (en) * | 2004-04-07 | 2005-10-27 | Hutchison Alan J | Substituted 1-heteroaryl-4-substituted piperazine and piperidine analogues |
WO2005110982A2 (fr) * | 2004-04-07 | 2005-11-24 | Neurogen Corporation | Analogues substitues 1-benzyl-4-substitues piperazine |
TW200609219A (en) * | 2004-06-17 | 2006-03-16 | Neurogen Corp | Aryl-substituted piperazine derivatives |
MY145822A (en) * | 2004-08-13 | 2012-04-30 | Neurogen Corp | Substituted biaryl piperazinyl-pyridine analogues |
GB0420831D0 (en) | 2004-09-17 | 2004-10-20 | Glaxo Group Ltd | Novel compounds |
US20060128710A1 (en) * | 2004-12-09 | 2006-06-15 | Chih-Hung Lee | Antagonists to the vanilloid receptor subtype 1 (VR1) and uses thereof |
RU2408580C2 (ru) * | 2005-02-17 | 2011-01-10 | Астеллас Фарма Инк. | Пиридильное неароматическое азотсодержащее гетероцикло-1-карбоксилатное производное |
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