CZ20013465A3 - Aminopyrimidiny jako inhibitory sorbitoldehydrogenasy - Google Patents
Aminopyrimidiny jako inhibitory sorbitoldehydrogenasy Download PDFInfo
- Publication number
- CZ20013465A3 CZ20013465A3 CZ20013465A CZ20013465A CZ20013465A3 CZ 20013465 A3 CZ20013465 A3 CZ 20013465A3 CZ 20013465 A CZ20013465 A CZ 20013465A CZ 20013465 A CZ20013465 A CZ 20013465A CZ 20013465 A3 CZ20013465 A3 CZ 20013465A3
- Authority
- CZ
- Czechia
- Prior art keywords
- alkyl
- optionally substituted
- group
- alkoxy
- hydroxy
- Prior art date
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- 239000003112 inhibitor Substances 0.000 title claims abstract description 37
- 108010009384 L-Iditol 2-Dehydrogenase Proteins 0.000 title claims abstract description 12
- 102100026974 Sorbitol dehydrogenase Human genes 0.000 title claims abstract description 11
- 150000005005 aminopyrimidines Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 522
- 238000000034 method Methods 0.000 claims abstract description 86
- 241000124008 Mammalia Species 0.000 claims abstract description 60
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 48
- 102100030980 Sodium/hydrogen exchanger 1 Human genes 0.000 claims abstract description 26
- 108010093115 growth factor-activatable Na-H exchanger NHE-1 Proteins 0.000 claims abstract description 26
- 239000003288 aldose reductase inhibitor Substances 0.000 claims abstract description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 17
- 229940118148 Aldose reductase inhibitor Drugs 0.000 claims abstract description 15
- MNQZXJOMYWMBOU-UHFFFAOYSA-N glyceraldehyde Chemical compound OCC(O)C=O MNQZXJOMYWMBOU-UHFFFAOYSA-N 0.000 claims abstract description 9
- 208000002249 Diabetes Complications Diseases 0.000 claims abstract description 6
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 6
- 230000015572 biosynthetic process Effects 0.000 claims abstract 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 817
- -1 vinylenylcarbonyl Chemical group 0.000 claims description 718
- 125000001153 fluoro group Chemical group F* 0.000 claims description 469
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 379
- 239000000651 prodrug Substances 0.000 claims description 377
- 229940002612 prodrug Drugs 0.000 claims description 377
- 229910052739 hydrogen Inorganic materials 0.000 claims description 274
- 239000001257 hydrogen Substances 0.000 claims description 274
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 250
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 214
- 150000003839 salts Chemical class 0.000 claims description 192
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 168
- 125000000217 alkyl group Chemical group 0.000 claims description 150
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 146
- 229910052736 halogen Inorganic materials 0.000 claims description 136
- 150000002367 halogens Chemical class 0.000 claims description 136
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 124
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 116
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 90
- 125000004076 pyridyl group Chemical group 0.000 claims description 87
- VOPWNXZWBYDODV-UHFFFAOYSA-N Chlorodifluoromethane Chemical compound FC(F)Cl VOPWNXZWBYDODV-UHFFFAOYSA-N 0.000 claims description 72
- 125000001424 substituent group Chemical group 0.000 claims description 71
- 125000004193 piperazinyl group Chemical group 0.000 claims description 68
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical group FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 62
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 61
- 125000005466 alkylenyl group Chemical group 0.000 claims description 60
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical group FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 58
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 57
- 125000002757 morpholinyl group Chemical group 0.000 claims description 56
- 229910052757 nitrogen Chemical group 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
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 49
- 229920006395 saturated elastomer Polymers 0.000 claims description 49
- 125000000335 thiazolyl group Chemical group 0.000 claims description 48
- 125000002971 oxazolyl group Chemical group 0.000 claims description 47
- 125000002947 alkylene group Chemical group 0.000 claims description 46
- 125000001544 thienyl group Chemical group 0.000 claims description 45
- 125000002541 furyl group Chemical group 0.000 claims description 44
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 43
- 125000002785 azepinyl group Chemical group 0.000 claims description 43
- 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 42
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 40
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 40
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 38
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 37
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 35
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 claims description 35
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 34
- 125000002883 imidazolyl group Chemical group 0.000 claims description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 31
- 125000003545 alkoxy group Chemical group 0.000 claims description 31
- 125000002393 azetidinyl group Chemical group 0.000 claims description 30
- 125000003386 piperidinyl group Chemical group 0.000 claims description 30
- 229910052717 sulfur Inorganic materials 0.000 claims description 30
- 125000004432 carbon atom Chemical group C* 0.000 claims description 28
- 125000005936 piperidyl group Chemical group 0.000 claims description 28
- 125000001624 naphthyl group Chemical group 0.000 claims description 25
- 229910052760 oxygen Inorganic materials 0.000 claims description 25
- 150000003254 radicals Chemical class 0.000 claims description 25
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 24
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 22
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 22
- 125000001425 triazolyl group Chemical group 0.000 claims description 22
- 125000004429 atom Chemical group 0.000 claims description 21
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 21
- OBNCKNCVKJNDBV-UHFFFAOYSA-N butanoic acid ethyl ester Natural products CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 claims description 21
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 21
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 21
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 20
- 125000005493 quinolyl group Chemical group 0.000 claims description 20
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 19
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 19
- 239000011593 sulfur Chemical group 0.000 claims description 19
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 18
- 125000002619 bicyclic group Chemical group 0.000 claims description 18
- 125000005842 heteroatom Chemical group 0.000 claims description 18
- 239000001301 oxygen Substances 0.000 claims description 18
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 17
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 16
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 16
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 16
- 229910052799 carbon Inorganic materials 0.000 claims description 15
- 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 15
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 14
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 14
- 125000004306 triazinyl group Chemical group 0.000 claims description 14
- 125000005843 halogen group Chemical group 0.000 claims description 13
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 13
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 13
- 125000005090 alkenylcarbonyl group Chemical group 0.000 claims description 12
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 12
- 125000005153 alkyl sulfamoyl group Chemical group 0.000 claims description 12
- 229910052731 fluorine Inorganic materials 0.000 claims description 12
- 239000011737 fluorine Substances 0.000 claims description 12
- 125000002950 monocyclic group Chemical group 0.000 claims description 12
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 12
- 238000006467 substitution reaction Methods 0.000 claims description 12
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 11
- 125000005554 pyridyloxy group Chemical group 0.000 claims description 11
- HNAGHMKIPMKKBB-UHFFFAOYSA-N 1-benzylpyrrolidine-3-carboxamide Chemical compound C1C(C(=O)N)CCN1CC1=CC=CC=C1 HNAGHMKIPMKKBB-UHFFFAOYSA-N 0.000 claims description 10
- 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 10
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 10
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 10
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 10
- YTMHZXYXPHNWMA-UHFFFAOYSA-N 1-pyrimidin-2-ylethanol Chemical compound CC(O)C1=NC=CC=N1 YTMHZXYXPHNWMA-UHFFFAOYSA-N 0.000 claims description 9
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 9
- 208000028867 ischemia Diseases 0.000 claims description 9
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 8
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 8
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 8
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 8
- 125000006085 pyrrolopyridyl group Chemical group 0.000 claims description 8
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 7
- 238000005342 ion exchange Methods 0.000 claims description 7
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 6
- 125000004605 1,2,3,4-tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 claims description 6
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 6
- 125000003282 alkyl amino group Chemical group 0.000 claims description 6
- 125000004414 alkyl thio group Chemical group 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000001041 indolyl group Chemical group 0.000 claims description 6
- 125000004043 oxo group Chemical group O=* 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 125000006168 tricyclic group Chemical group 0.000 claims description 6
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims description 5
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 5
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 claims description 5
- 125000004399 C1-C4 alkenyl group Chemical group 0.000 claims description 5
- 101001043818 Mus musculus Interleukin-31 receptor subunit alpha Proteins 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
- 125000006267 biphenyl group Chemical group 0.000 claims description 5
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 5
- 125000004588 thienopyridyl group Chemical group S1C(=CC2=C1C=CC=N2)* 0.000 claims description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- 150000001721 carbon Chemical group 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
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 4
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 claims description 4
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 claims description 4
- 125000004434 sulfur atom Chemical group 0.000 claims description 4
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 4
- CSDSSGBPEUDDEE-UHFFFAOYSA-N 2-formylpyridine Chemical compound O=CC1=CC=CC=N1 CSDSSGBPEUDDEE-UHFFFAOYSA-N 0.000 claims description 3
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 claims description 3
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 3
- 238000011282 treatment Methods 0.000 claims description 3
- 125000006727 (C1-C6) alkenyl group Chemical group 0.000 claims description 2
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 claims description 2
- 125000004317 1,3,5-triazin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=N1 0.000 claims description 2
- 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
- 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
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000005390 cinnolyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 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
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims 4
- 102000007390 Glycogen Phosphorylase Human genes 0.000 claims 3
- 108010046163 Glycogen Phosphorylase Proteins 0.000 claims 3
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims 3
- 201000010099 disease Diseases 0.000 claims 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 3
- 239000012442 inert solvent Substances 0.000 claims 3
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 claims 3
- 235000010290 biphenyl Nutrition 0.000 claims 2
- 239000004305 biphenyl Substances 0.000 claims 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 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
- 230000035484 reaction time Effects 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
- HLGDWKWUYZNZIF-UWTATZPHSA-N (2r)-2-hydroxypropanimidamide Chemical compound C[C@@H](O)C(N)=N HLGDWKWUYZNZIF-UWTATZPHSA-N 0.000 claims 1
- SXQFCVDSOLSHOQ-UWTATZPHSA-N (R)-(+)-Lactamide Chemical compound C[C@@H](O)C(N)=O SXQFCVDSOLSHOQ-UWTATZPHSA-N 0.000 claims 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 1
- 241001465754 Metazoa Species 0.000 claims 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims 1
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 claims 1
- BNIPQHDMPLVAIY-UHFFFAOYSA-N ethyl 3-hydroxyprop-2-enoate;sodium Chemical compound [Na].CCOC(=O)C=CO BNIPQHDMPLVAIY-UHFFFAOYSA-N 0.000 claims 1
- 125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 claims 1
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 claims 1
- 150000002916 oxazoles Chemical class 0.000 claims 1
- 125000006239 protecting group Chemical group 0.000 claims 1
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
- 125000000147 tetrahydroquinolinyl group Chemical class N1(CCCC2=CC=CC=C12)* 0.000 claims 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 abstract description 5
- 206010012655 Diabetic complications Diseases 0.000 abstract description 5
- 208000007342 Diabetic Nephropathies Diseases 0.000 abstract description 4
- 208000033679 diabetic kidney disease Diseases 0.000 abstract description 4
- 208000032781 Diabetic cardiomyopathy Diseases 0.000 abstract description 2
- 206010063547 Diabetic macroangiopathy Diseases 0.000 abstract description 2
- 206010054044 Diabetic microangiopathy Diseases 0.000 abstract description 2
- 201000009101 diabetic angiopathy Diseases 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 abstract 2
- 208000031229 Cardiomyopathies Diseases 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 13
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- 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 5
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- 210000005036 nerve Anatomy 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 239000000600 sorbitol Substances 0.000 description 5
- 102000016912 Aldehyde Reductase Human genes 0.000 description 4
- 108010053754 Aldehyde reductase Proteins 0.000 description 4
- 206010012689 Diabetic retinopathy Diseases 0.000 description 4
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- 208000005230 Leg Ulcer Diseases 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- GPRLSGONYQIRFK-UHFFFAOYSA-N hydron Chemical group [H+] GPRLSGONYQIRFK-UHFFFAOYSA-N 0.000 description 3
- 125000005412 pyrazyl group Chemical group 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
- 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
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- 210000001519 tissue Anatomy 0.000 description 2
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 description 1
- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 description 1
- CQZCBLLPJONWCZ-UHFFFAOYSA-N 2,2-dimethylpiperazine-1-carboxylic acid Chemical compound CC1(C)CNCCN1C(O)=O CQZCBLLPJONWCZ-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- MUQNGPZZQDCDFT-JNQJZLCISA-N Halcinonide Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CCl)[C@@]1(C)C[C@@H]2O MUQNGPZZQDCDFT-JNQJZLCISA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 241000131972 Sphingomonadaceae Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- LKDRXBCSQODPBY-ZXXMMSQZSA-N alpha-D-fructopyranose Chemical compound OC[C@]1(O)OC[C@@H](O)[C@@H](O)[C@@H]1O LKDRXBCSQODPBY-ZXXMMSQZSA-N 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229940028332 halog Drugs 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 230000003680 myocardial damage Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 210000001525 retina Anatomy 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
Classifications
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- 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
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- C04B35/00—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
- C04B35/622—Forming processes; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
- C04B35/626—Preparing or treating the powders individually or as batches ; preparing or treating macroscopic reinforcing agents for ceramic products, e.g. fibres; mechanical aspects section B
- C04B35/63—Preparing or treating the powders individually or as batches ; preparing or treating macroscopic reinforcing agents for ceramic products, e.g. fibres; mechanical aspects section B using additives specially adapted for forming the products, e.g.. binder binders
- C04B35/632—Organic additives
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- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- 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
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- 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
- C07D405/14—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 three or more hetero rings
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- 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
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- C07D409/12—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 linked by a chain containing hetero atoms as chain links
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- 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
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- C07D413/12—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 linked by a chain containing hetero atoms as chain links
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- 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
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- C07D451/06—Oxygen atoms
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Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US12743799P | 1999-04-01 | 1999-04-01 | |
| PCT/IB2000/000296 WO2000059510A1 (en) | 1999-04-01 | 2000-03-16 | Aminopyrimidines as sorbitol dehydrogenase inhibitors |
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| CZ20013465A3 true CZ20013465A3 (cs) | 2002-10-16 |
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| CZ20013465A CZ20013465A3 (cs) | 1999-04-01 | 2000-03-16 | Aminopyrimidiny jako inhibitory sorbitoldehydrogenasy |
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| EA004656B1 (ru) * | 1999-04-01 | 2004-06-24 | Пфайзер Продактс Инк. | Аминопиримидины в качестве ингибиторов сорбитолдегидрогеназы |
| JP2004517053A (ja) * | 2000-10-18 | 2004-06-10 | ファイザー・プロダクツ・インク | スタチン類とソルビトールデヒドロゲナーゼ阻害薬の併用 |
| SE0003795D0 (sv) * | 2000-10-20 | 2000-10-20 | Astrazeneca Ab | Pharmaceutically useful compounds |
| WO2002043762A2 (en) | 2000-11-30 | 2002-06-06 | Pfizer Products Inc. | Combination of gaba agonists and sorbitol dehydrogenase inhibitors |
| CA2433090A1 (en) * | 2000-12-27 | 2002-07-04 | Kyowa Hakko Kogyo Co., Ltd. | Dipeptidyl peptidase iv inhibitor |
| IL147696A0 (en) * | 2001-01-25 | 2002-08-14 | Pfizer Prod Inc | Combination therapy |
| EP1247809A3 (en) | 2001-03-30 | 2003-12-17 | Pfizer Products Inc. | Triazine compounds useful as sorbitol dehydrogenase inhibitors |
| EP1389189A2 (en) | 2001-05-22 | 2004-02-18 | Neurogen Corporation | 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 |
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| DE3905364A1 (de) * | 1989-02-22 | 1990-08-23 | Hoechst Ag | Substituierte pyrimidin-derivate, verfahren zu ihrer herstellung und ihre verwendung als tool |
| DE4025387A1 (de) * | 1990-08-10 | 1992-02-13 | Hoechst Ag | Substituierte pyrimidin-derivate, verfahren zu ihrer herstellung und ihre verwendung als reagenzien |
| NZ254550A (en) * | 1992-09-28 | 1997-08-22 | Pfizer | Use of nitrogen-substituted pyrimidines to prepare medicaments useful for treatment or prevention of diabetic complications |
| DK0791355T3 (da) * | 1996-02-29 | 2002-06-17 | Pfizer | Fremgangsmåde til reduktion af vævsbeskadigelse forbundet med iskæmi |
| IT1285601B1 (it) | 1996-03-08 | 1998-06-18 | Bonfiglioli Riduttori Spa | Riduttore angolare a piu' stadi |
| EA004656B1 (ru) * | 1999-04-01 | 2004-06-24 | Пфайзер Продактс Инк. | Аминопиримидины в качестве ингибиторов сорбитолдегидрогеназы |
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