UA71951C2 - Pyrimidines as sorbitol dehydrogenase inhibitors, a pharmaceutical composition containing them, intermediate compounds and a method for the preparation of intermediate compound - Google Patents
Pyrimidines as sorbitol dehydrogenase inhibitors, a pharmaceutical composition containing them, intermediate compounds and a method for the preparation of intermediate compound Download PDFInfo
- Publication number
- UA71951C2 UA71951C2 UA2001096634A UA2001096634A UA71951C2 UA 71951 C2 UA71951 C2 UA 71951C2 UA 2001096634 A UA2001096634 A UA 2001096634A UA 2001096634 A UA2001096634 A UA 2001096634A UA 71951 C2 UA71951 C2 UA 71951C2
- Authority
- UA
- Ukraine
- Prior art keywords
- alkyl
- pyrimidin
- ethanol
- compound
- dimethylpiperazin
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 721
- 238000000034 method Methods 0.000 title claims abstract description 147
- 108010009384 L-Iditol 2-Dehydrogenase Proteins 0.000 title claims abstract description 18
- 102100026974 Sorbitol dehydrogenase Human genes 0.000 title claims abstract description 17
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 16
- 150000003230 pyrimidines Chemical class 0.000 title claims description 10
- 239000003112 inhibitor Substances 0.000 title abstract description 42
- 238000002360 preparation method Methods 0.000 title description 5
- 208000002249 Diabetes Complications Diseases 0.000 claims abstract description 33
- 206010012655 Diabetic complications Diseases 0.000 claims abstract description 33
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 24
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 18
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 12
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims abstract description 10
- 208000033679 diabetic kidney disease Diseases 0.000 claims abstract description 10
- 208000032131 Diabetic Neuropathies Diseases 0.000 claims abstract description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 616
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 446
- 239000000651 prodrug Substances 0.000 claims description 313
- 229940002612 prodrug Drugs 0.000 claims description 313
- -1 4,6-dimethylpyrimid-2-yl Chemical group 0.000 claims description 208
- 150000003839 salts Chemical class 0.000 claims description 159
- 239000001257 hydrogen Substances 0.000 claims description 156
- 229910052739 hydrogen Inorganic materials 0.000 claims description 156
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 133
- 125000003545 alkoxy group Chemical group 0.000 claims description 125
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 119
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 105
- 229910052736 halogen Inorganic materials 0.000 claims description 93
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 93
- 150000002367 halogens Chemical class 0.000 claims description 92
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 75
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 56
- 239000012442 inert solvent Substances 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 49
- 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 39
- 125000002757 morpholinyl group Chemical group 0.000 claims description 36
- 125000005466 alkylenyl group Chemical group 0.000 claims description 33
- 125000004193 piperazinyl group Chemical group 0.000 claims description 32
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 26
- 125000006239 protecting group Chemical group 0.000 claims description 26
- 125000002883 imidazolyl group Chemical group 0.000 claims description 21
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 14
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 12
- 125000001425 triazolyl group Chemical group 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- 125000004306 triazinyl group Chemical group 0.000 claims description 9
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 230000003993 interaction Effects 0.000 claims description 6
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 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 description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 2
- 150000003840 hydrochlorides Chemical class 0.000 claims description 2
- 159000000000 sodium salts Chemical class 0.000 claims description 2
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 claims 3
- 239000012971 dimethylpiperazine Substances 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
- 238000012876 topography Methods 0.000 claims 1
- 241000124008 Mammalia Species 0.000 abstract description 56
- 239000003288 aldose reductase inhibitor Substances 0.000 abstract description 32
- 229940118148 Aldose reductase inhibitor Drugs 0.000 abstract description 21
- 210000002216 heart Anatomy 0.000 abstract description 20
- MNQZXJOMYWMBOU-UHFFFAOYSA-N glyceraldehyde Chemical compound OCC(O)C=O MNQZXJOMYWMBOU-UHFFFAOYSA-N 0.000 abstract description 9
- 239000000543 intermediate Substances 0.000 abstract description 8
- 208000032781 Diabetic cardiomyopathy Diseases 0.000 abstract description 4
- 206010063547 Diabetic macroangiopathy Diseases 0.000 abstract description 4
- 206010054044 Diabetic microangiopathy Diseases 0.000 abstract description 4
- 201000009101 diabetic angiopathy Diseases 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 102100030980 Sodium/hydrogen exchanger 1 Human genes 0.000 abstract description 2
- 108010093115 growth factor-activatable Na-H exchanger NHE-1 Proteins 0.000 abstract description 2
- 230000008569 process Effects 0.000 abstract description 2
- 208000031229 Cardiomyopathies Diseases 0.000 abstract 1
- 125000001153 fluoro group Chemical group F* 0.000 description 264
- 238000006243 chemical reaction Methods 0.000 description 135
- 125000001424 substituent group Chemical group 0.000 description 73
- 239000002904 solvent Substances 0.000 description 69
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 54
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- 125000004076 pyridyl group Chemical group 0.000 description 46
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 45
- 150000001412 amines Chemical class 0.000 description 39
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 38
- 239000002585 base Substances 0.000 description 38
- 125000002785 azepinyl group Chemical group 0.000 description 35
- 101100419015 Hordeum vulgare RPS27 gene Proteins 0.000 description 33
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 32
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 32
- 229910052799 carbon Inorganic materials 0.000 description 31
- 229910052757 nitrogen Chemical group 0.000 description 31
- 230000035484 reaction time Effects 0.000 description 31
- 125000003386 piperidinyl group Chemical group 0.000 description 30
- 229920006395 saturated elastomer Polymers 0.000 description 30
- 238000009835 boiling Methods 0.000 description 29
- 150000002431 hydrogen Chemical class 0.000 description 29
- 239000000203 mixture Substances 0.000 description 29
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 28
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- 239000002253 acid Substances 0.000 description 27
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 27
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 26
- 125000002947 alkylene group Chemical group 0.000 description 25
- 239000003795 chemical substances by application Substances 0.000 description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 23
- 125000002971 oxazolyl group Chemical group 0.000 description 23
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 23
- 125000000335 thiazolyl group Chemical group 0.000 description 23
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 22
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 21
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 21
- 201000010099 disease Diseases 0.000 description 21
- 229910052796 boron Inorganic materials 0.000 description 20
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 description 20
- 125000001544 thienyl group Chemical group 0.000 description 20
- 210000001519 tissue Anatomy 0.000 description 20
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- 125000002393 azetidinyl group Chemical group 0.000 description 18
- 125000002541 furyl group Chemical group 0.000 description 18
- 208000028867 ischemia Diseases 0.000 description 18
- 238000006467 substitution reaction Methods 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 17
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 17
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 17
- 239000001301 oxygen Substances 0.000 description 17
- 229910052760 oxygen Inorganic materials 0.000 description 17
- 239000011593 sulfur Chemical group 0.000 description 17
- 229910052717 sulfur Inorganic materials 0.000 description 17
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 16
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 16
- 239000003054 catalyst Substances 0.000 description 16
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 16
- 235000019000 fluorine Nutrition 0.000 description 16
- 229960004198 guanidine Drugs 0.000 description 16
- 125000004429 atom Chemical group 0.000 description 15
- 239000003153 chemical reaction reagent Substances 0.000 description 15
- 230000000694 effects Effects 0.000 description 15
- 125000005090 alkenylcarbonyl group Chemical group 0.000 description 14
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 14
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 14
- 150000008282 halocarbons Chemical class 0.000 description 14
- 239000002609 medium Substances 0.000 description 14
- 125000004433 nitrogen atom Chemical group N* 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- 230000004224 protection Effects 0.000 description 14
- 229910052709 silver Inorganic materials 0.000 description 14
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 14
- 229930091371 Fructose Natural products 0.000 description 13
- 239000005715 Fructose Substances 0.000 description 13
- 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 13
- 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 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 13
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 13
- 229910052731 fluorine Inorganic materials 0.000 description 13
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- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 13
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- 150000003254 radicals Chemical class 0.000 description 13
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- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 12
- 125000002619 bicyclic group Chemical group 0.000 description 12
- 239000000460 chlorine Substances 0.000 description 12
- 150000002170 ethers Chemical class 0.000 description 12
- 125000005842 heteroatom Chemical group 0.000 description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 12
- 239000000600 sorbitol Substances 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- 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 description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 11
- 229940090865 aldose reductase inhibitors used in diabetes Drugs 0.000 description 11
- 239000012038 nucleophile Substances 0.000 description 11
- 229940083542 sodium Drugs 0.000 description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 11
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 10
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- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 10
- 229910052801 chlorine Inorganic materials 0.000 description 10
- 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 description 10
- 208000010125 myocardial infarction Diseases 0.000 description 10
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- 238000006722 reduction reaction Methods 0.000 description 10
- 239000011734 sodium Substances 0.000 description 10
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- 210000000056 organ Anatomy 0.000 description 9
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- 125000003282 alkyl amino group Chemical group 0.000 description 8
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- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 8
- 125000005956 isoquinolyl group Chemical group 0.000 description 8
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- 125000006530 (C4-C6) alkyl group Chemical group 0.000 description 7
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- 239000010949 copper Substances 0.000 description 7
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- 125000002950 monocyclic group Chemical group 0.000 description 7
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- 108010053754 Aldehyde reductase Proteins 0.000 description 6
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- 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 6
- 241000282414 Homo sapiens Species 0.000 description 6
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- 239000000010 aprotic solvent Substances 0.000 description 6
- 239000012736 aqueous medium Substances 0.000 description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 6
- 229910052794 bromium Inorganic materials 0.000 description 6
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- 230000000875 corresponding effect Effects 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 6
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- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 6
- 238000005342 ion exchange Methods 0.000 description 6
- 150000002576 ketones Chemical class 0.000 description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 6
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- 230000035939 shock Effects 0.000 description 6
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- 239000007858 starting material Substances 0.000 description 6
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 5
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 5
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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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 |
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