JPH0253788A - Pyrimidine derivative - Google Patents
Pyrimidine derivativeInfo
- Publication number
- JPH0253788A JPH0253788A JP20345488A JP20345488A JPH0253788A JP H0253788 A JPH0253788 A JP H0253788A JP 20345488 A JP20345488 A JP 20345488A JP 20345488 A JP20345488 A JP 20345488A JP H0253788 A JPH0253788 A JP H0253788A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound
- expressed
- derivative
- pyrimidine
- 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.)
- Pending
Links
- 150000003230 pyrimidines Chemical class 0.000 title claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- -1 aminocarboxylic acid ester Chemical class 0.000 abstract description 32
- 150000001875 compounds Chemical class 0.000 abstract description 16
- 239000002904 solvent Substances 0.000 abstract description 15
- 150000007514 bases Chemical class 0.000 abstract description 8
- 239000012948 isocyanate Substances 0.000 abstract description 7
- 150000002513 isocyanates Chemical class 0.000 abstract description 7
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 abstract description 6
- 230000002401 inhibitory effect Effects 0.000 abstract description 6
- 150000001323 aldoses Chemical class 0.000 abstract description 5
- 150000001412 amines Chemical class 0.000 abstract description 5
- 206010012601 diabetes mellitus Diseases 0.000 abstract description 5
- 125000000217 alkyl group Chemical group 0.000 abstract description 4
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 abstract description 2
- 230000003449 preventive effect Effects 0.000 abstract description 2
- 208000017667 Chronic Disease Diseases 0.000 abstract 1
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 abstract 1
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 238000005886 esterification reaction Methods 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 239000000203 mixture Substances 0.000 description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- 150000001340 alkali metals Chemical class 0.000 description 6
- 102000016912 Aldehyde Reductase Human genes 0.000 description 5
- 108010053754 Aldehyde reductase Proteins 0.000 description 5
- 229910052783 alkali metal Inorganic materials 0.000 description 5
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 5
- 229920005862 polyol Polymers 0.000 description 5
- 150000003077 polyols Chemical class 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 150000001342 alkaline earth metals Chemical class 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- 102000004316 Oxidoreductases Human genes 0.000 description 3
- 108090000854 Oxidoreductases Proteins 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000007257 deesterification reaction Methods 0.000 description 3
- 238000000921 elemental analysis Methods 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- WRMCZHYLTVSDQU-UHFFFAOYSA-N pyrimidin-1-ium;acetate Chemical class CC(O)=O.C1=CN=CN=C1 WRMCZHYLTVSDQU-UHFFFAOYSA-N 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 150000001242 acetic acid derivatives Chemical class 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 2
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 2
- 150000004703 alkoxides Chemical class 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 150000004292 cyclic ethers Chemical class 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 2
- 239000001095 magnesium carbonate Substances 0.000 description 2
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 2
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 2
- 239000000347 magnesium hydroxide Substances 0.000 description 2
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 2
- CRGZYKWWYNQGEC-UHFFFAOYSA-N magnesium;methanolate Chemical compound [Mg+2].[O-]C.[O-]C CRGZYKWWYNQGEC-UHFFFAOYSA-N 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229910052987 metal hydride Inorganic materials 0.000 description 2
- 150000004681 metal hydrides Chemical class 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- RLTFBWCBGIZCDQ-UHFFFAOYSA-N (4-bromo-2-fluorophenyl)methanamine Chemical compound NCC1=CC=C(Br)C=C1F RLTFBWCBGIZCDQ-UHFFFAOYSA-N 0.000 description 1
- 125000006507 2,4-difluorobenzyl group Chemical group [H]C1=C(F)C([H])=C(F)C(=C1[H])C([H])([H])* 0.000 description 1
- 125000006280 2-bromobenzyl group Chemical group [H]C1=C([H])C(Br)=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000006282 2-chlorobenzyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000004847 2-fluorobenzyl group Chemical group [H]C1=C([H])C(F)=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000006481 2-iodobenzyl group Chemical group [H]C1=C([H])C(I)=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000006512 3,4-dichlorobenzyl group Chemical group [H]C1=C(Cl)C(Cl)=C([H])C(=C1[H])C([H])([H])* 0.000 description 1
- 125000006279 3-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(Br)=C1[H])C([H])([H])* 0.000 description 1
- 125000003852 3-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(Cl)=C1[H])C([H])([H])* 0.000 description 1
- 125000006284 3-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(F)=C1[H])C([H])([H])* 0.000 description 1
- 125000006482 3-iodobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(I)=C1[H])C([H])([H])* 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 125000006281 4-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Br)C([H])([H])* 0.000 description 1
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 1
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 description 1
- 125000006483 4-iodobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1I)C([H])([H])* 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010007749 Cataract diabetic Diseases 0.000 description 1
- 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 1
- 208000002249 Diabetes Complications Diseases 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- 206010012655 Diabetic complications Diseases 0.000 description 1
- 206010012689 Diabetic retinopathy Diseases 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
- 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 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 101100177665 Rattus norvegicus Hipk3 gene Proteins 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- SXDBWCPKPHAZSM-UHFFFAOYSA-N bromic acid Chemical compound OBr(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-N 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 210000000695 crystalline len Anatomy 0.000 description 1
- 201000007025 diabetic cataract Diseases 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- XTLNYNMNUCLWEZ-UHFFFAOYSA-N ethanol;propan-2-one Chemical compound CCO.CC(C)=O XTLNYNMNUCLWEZ-UHFFFAOYSA-N 0.000 description 1
- XNASJEQIJMDBQN-UHFFFAOYSA-N ethyl 2-amino-1-benzothiophene-3-carboxylate Chemical compound C1=CC=C2C(C(=O)OCC)=C(N)SC2=C1 XNASJEQIJMDBQN-UHFFFAOYSA-N 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- MNQZXJOMYWMBOU-UHFFFAOYSA-N glyceraldehyde Chemical compound OCC(O)C=O MNQZXJOMYWMBOU-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 201000008383 nephritis Diseases 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
産業上の利用分野
本発明は、新規なピリミジン誘導体及びその薬理学的に
許容し得る塩に関するものである。DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to novel pyrimidine derivatives and pharmacologically acceptable salts thereof.
本発明化合物は、アルドース・リダクターゼ阻害作用を
有し、糖尿病に伴う種々の慢性症状や合併症を予防し、
治療するための医薬として有用である。The compound of the present invention has an aldose reductase inhibitory effect, prevents various chronic symptoms and complications associated with diabetes,
It is useful as a medicine for treatment.
従来の技術
糖尿病合併症（例えば糖尿病性白内障、糖尿病性神経症
、糖尿病性腎炎もしくは糖尿病性網膜症等）の発症、進
展には、木下らによりアルドース・リダクターゼが関与
していることが明らかにされている（ジエイ、エイチ、
キノシタ０．Ｈ。Conventional technology Kinoshita et al. revealed that aldose reductase is involved in the onset and progression of diabetic complications (e.g., diabetic cataracts, diabetic neuropathy, diabetic nephritis, diabetic retinopathy, etc.). (Jei, H,
Kinoshita 0. H.
Ｋ １ｎｏｓｈｉｔａ）等、ジャーナル オブ ジ ア
メリカン アソシエイション（Ｊ ｏｕｒｎａｌ ｏｆ
ｔｈｅＡｍｅｒｉｃａｎ Ａｓ５ｏｃｉａｔｉｏｎ）
２４６．２５７（１９８１））。アルすドース拳リダ
クターゼはグルコースやガラクトースなどのアルドース
類をソルビトールの様なポリオールに還元するが、生成
したポリオールは比較的安定で細胞外へほとんど移行せ
ず、アルドース・リダクターゼの活性が元進するため、
ポリオールが水晶体、神経組織、血管組織などに異常蓄
積する。その結果、これらの組織の細胞内では浸透圧が
上昇し、細胞の膨潤が引き起こされて、細胞機能が損な
われ、組織障害をきたす。そこで、このような全身的障
害をきたすポリオールの生成を抑制すること、即ち、ア
ルドース・リダクターゼを阻害し、細胞内ポリオールの
異常蓄積を回避することにより、糖尿病に合併して生ず
る諸疾患を治療し、予防する為に、優れたアルドース・
リダクターゼ阻害作用を有し、医薬として有用な化合物
の開発が要望されている。Journal of the American Association, etc.
the American Association)
246.257 (1981)). Aldose fist reductase reduces aldoses such as glucose and galactose to polyols such as sorbitol, but the generated polyols are relatively stable and hardly migrate outside the cell, and the activity of aldose reductase is accelerated. ,
Polyols accumulate abnormally in the crystalline lens, nervous tissue, vascular tissue, etc. As a result, osmotic pressure increases within the cells of these tissues, causing cell swelling, impairing cell function and causing tissue damage. Therefore, by suppressing the production of polyols that cause such systemic disorders, that is, by inhibiting aldose reductase and avoiding abnormal accumulation of intracellular polyols, it is possible to treat various diseases that occur as a complication of diabetes. , an excellent aldose to prevent
There is a need for the development of compounds that have a reductase inhibitory effect and are useful as pharmaceuticals.
問題点を解決するだめの手段
本発明者は、上記従来技術の問題点に鑑みて鋭意研究を
重ねた結果、下記一般式（Ｉ）で表される新規なピリミ
ジン誘導体及びその塩が優れたアルドース・リダクター
ゼ阻害活性を有し、医薬として有用であることを見出し
、本発明を完成した。Means to Solve the Problems As a result of extensive research in view of the problems of the prior art described above, the present inventors have discovered that a novel pyrimidine derivative represented by the following general formula (I) and its salts are excellent aldoses. - It was discovered that it has reductase inhibitory activity and is useful as a medicine, and the present invention was completed.
即ち本発明は、下記一般式（Ｉ）
ＣＨ２Ｃ００Ｈ
（式中Ｒ２は水素またはハロゲン原子を示し、Ｘ及びＹ
の何れか一方は直接結合しており、他方は５ＳＮ−ＣＨ
３又はＮ−ＣＨ２Ｃ６Ｈ５を示し、Ｒ２はベンジル又は
ハロゲン置換ベンジル基を示す。）で表されるピリミジ
ン誘導体及びその薬理学的に許容し得る塩に係わる。That is, the present invention provides the following general formula (I) CH2C00H (wherein R2 represents hydrogen or a halogen atom, and X and Y
Either one is directly bonded, and the other is 5SN-CH
3 or N-CH2C6H5, and R2 represents benzyl or a halogen-substituted benzyl group. ) and its pharmacologically acceptable salts.
上記一般式（Ｉ）においてＲ１で定義されるノ１０ゲン
原子としては、フッ素、塩素、臭素、沃素を、Ｒ２で定
義されるハロゲン置換ベンジル基としてはフッ素、塩素
、臭素、沃素がフェニル環状に１〜２個置換した２−フ
ルオロベンジル、３−フルオロベンジル、４−フルオロ
ベンジル、２−クロロベンジル、３−クロロベンジル、
４−クロロベンジル、２−ブロモベンジル、３−ブロモ
ベンジル、４−ブロモベンジル、２−ヨードベンジル、
３−ヨードベンジル、４−ヨードベンジル、２．４−ジ
フルオロベンジル、２，４−ジクロロベンジル、２，６
−ジクロロベンジル、３，４−ジクロロベンジル、４−
ブロモ−２−フルオロベンジル基等を例示することがで
きる。In the above general formula (I), fluorine, chlorine, bromine, and iodine are used as the 10-gen atom defined by R1, and fluorine, chlorine, bromine, and iodine are used as the halogen-substituted benzyl group defined in R2 in the form of a phenyl ring. 1-2 substituted 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-chlorobenzyl, 3-chlorobenzyl,
4-chlorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 2-iodobenzyl,
3-iodobenzyl, 4-iodobenzyl, 2,4-difluorobenzyl, 2,4-dichlorobenzyl, 2,6
-dichlorobenzyl, 3,4-dichlorobenzyl, 4-
Examples include bromo-2-fluorobenzyl group.
また、前記一般式（Ｉ）で表される本発明化合物の塩と
しては、例えばナトリウム、カリウム等のアルカリ金属
塩、カルシウム、マグネシウム等のアルカリ土類金属塩
、リジン、アルギニン等の塩基性アミノ酸塩、トリス（
ハイドロキシメチル）アミノメタン等の有機塩基塩等の
医薬として許容される塩が例示できる。Examples of the salts of the compound of the present invention represented by the general formula (I) include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, and basic amino acid salts such as lysine and arginine. , Tris (
Examples include pharmaceutically acceptable salts such as organic base salts such as hydroxymethyl)aminomethane.
本発明のピリミジン誘導体ＣＩ）は、下記反応工程式に
示す方法に従い製造することができる。The pyrimidine derivative CI) of the present invention can be produced according to the method shown in the following reaction scheme.
反応工程式 （Ｂ工程） （Ｃ工程） ＣＨ２ＣＯＯＲａ ↓ ＣＲ２Ｃ００ＲＡ ＣＨ２ＣＯＯＨ （式中、ＲＩ 、Ｒ２及びＸＳＹは、前記に同じ。reaction process formula (B process) (C process) CH2COORa ↓ CR2C00RA CH2COOH (In the formula, RI, R2 and XSY are the same as above.
Ｒ３は低級アルキル基、Ｒ４はカルボギシ保護基を示す
。）
上記反応工程式における各工程は、より詳細には以下の
ごとくして実施される。R3 represents a lower alkyl group, and R4 represents a carboxyprotecting group. ) Each step in the above reaction scheme is carried out in more detail as follows.
Ａ工程
Ａ工程中、Ｒ３で表される低級アルキル基としては（Ｖ
）から（Ｖｌ）への合成の際に容易に脱離するアルキル
基であれば特に限定されないが、通常炭素数１〜６の低
級アルキル基であればよく、具体的にはメチル、エチル
、プロピル、１ｓｏ−プロピル、ブチル、１ｓｏ−ブチ
ル、ｔｅｒｔ−ブチル、ペンチル、ヘキシル基等である
。一般式（ＩＩ）で表されるアミノカルボン酸エステル
誘導体にホスゲンまたはトリクロロメチルクロロフォル
メイト（ＴＣＰ）を適当な溶媒中で反応させることによ
り、一般式（ｍ）で表されるイソシアネー）・誘導体を
得、これを触媒の存在下または不存在下に、一般式
％式％（）
（式中、Ｒ２は前記に同じ。）で表されるアミン誘導体
と適当な溶媒中で反応させ、得られた一般式（Ｖ）で表
されるウレイド化合物を適当な溶媒中にて塩基性化合物
と反応させることにより、一般式（Ｖｌ）で表されるピ
リミジン化合物を得る。Step A In step A, the lower alkyl group represented by R3 is (V
) is not particularly limited as long as it is an alkyl group that is easily eliminated during the synthesis from , 1so-propyl, butyl, 1so-butyl, tert-butyl, pentyl, hexyl group, etc. By reacting the aminocarboxylic acid ester derivative represented by general formula (II) with phosgene or trichloromethylchloroformate (TCP) in an appropriate solvent, the isocyanate derivative represented by general formula (m) is prepared. This was reacted in the presence or absence of a catalyst with an amine derivative represented by the general formula % (in which R2 is the same as above) in a suitable solvent. A pyrimidine compound represented by general formula (Vl) is obtained by reacting a ureido compound represented by general formula (V) with a basic compound in a suitable solvent.
アミノカルボン酸エステル誘導体（ｎ）とホスゲンまた
はＴＣＰとの反応における溶媒としては、本反応に関与
しないものであれば特に限定されないが、例えばエチル
エーテル、ジオキサン、テトラヒドロフラン等のエーテ
ル類、ジクロロメタン、クロロホルム、四塙化炭素等の
ハロゲン化炭化水素類またはこれらの混合溶媒等が好適
に使用される。アミノカルボン酸エステル誘導体（ｎ）
とホスゲンまたはＴＣＦの使用割合は適宜選択できるが
、通常アミノカルボン酸エステル誘導体（ｎ）に対しホ
スゲンまたはＴＣＰを２〜１０倍モル程度使用するのが
好ましい。反応は、通常室温から溶媒の還流温度で行わ
れる。得られたイソシアネート誘導体（ＩＩ［）はその
まま或いは単離して、次の反応に使用できる。The solvent for the reaction of the aminocarboxylic acid ester derivative (n) with phosgene or TCP is not particularly limited as long as it does not participate in the reaction, but examples include ethers such as ethyl ether, dioxane, and tetrahydrofuran, dichloromethane, chloroform, Halogenated hydrocarbons such as carbon tetrahydride, mixed solvents thereof, and the like are preferably used. Aminocarboxylic acid ester derivative (n)
The ratio of phosgene or TCF to be used can be selected as appropriate, but it is usually preferable to use phosgene or TCP in an amount of about 2 to 10 times the molar amount of the aminocarboxylic acid ester derivative (n). The reaction is usually carried out at room temperature to the reflux temperature of the solvent. The obtained isocyanate derivative (II[) can be used as it is or after isolation for the next reaction.
イソシアネート誘導体（ｍ）とアミン誘導体（ＩＶ）と
の反応における溶媒としては、本反応に関与しないもの
であれば特に限定はされないが、例えばエチルエーテル
、ジオキサン、テトラヒドロフラン等のエーテル類、ベ
ンゼン、トルエン、キシレン等の芳香族炭化水素類が好
適に使用される。この反応に使用される触媒としてはナ
トリウムメトキサイド、ナトリウムエトキサイド、マグ
ネシウムメトキサイド等のアルカリ金属またはアルカリ
土類金属のアルコキサイド、ナトリウムハイドライド等
の金属水素化物、ナトリウムアミド等の金属アミド化合
物等が用いられる。触媒は、イソシアネート誘導体（Ｉ
ＩＩ）に対し０．１〜３．０倍モル程度使用するのが好
ましい。イソシアネート誘導体（Ｉ［Ｉ）とアミン誘導
体（ＩＶ）の使用割合は適宜選択できるが、通常イソシ
アネート誘導体（Ｉ［）に対しアミン誘導体（ＩＶ）を
１．０〜２．０倍モル程度使用するのが好ましい。反応
は、通常室温から溶媒の還流温度で行われる。得られた
ウレイド化合物（Ｖ）はそのまま或いは単離して次の反
応に使用できる。The solvent for the reaction between the isocyanate derivative (m) and the amine derivative (IV) is not particularly limited as long as it does not participate in the reaction, but examples include ethers such as ethyl ether, dioxane, and tetrahydrofuran, benzene, toluene, Aromatic hydrocarbons such as xylene are preferably used. Catalysts used in this reaction include alkoxides of alkali metals or alkaline earth metals such as sodium methoxide, sodium ethoxide, and magnesium methoxide, metal hydrides such as sodium hydride, and metal amide compounds such as sodium amide. It will be done. The catalyst is an isocyanate derivative (I
It is preferable to use about 0.1 to 3.0 times the mole of II). The ratio of the isocyanate derivative (I[I) and the amine derivative (IV) to be used can be selected as appropriate, but usually the amine derivative (IV) is used at about 1.0 to 2.0 times the mole of the isocyanate derivative (I[). is preferred. The reaction is usually carried out at room temperature to the reflux temperature of the solvent. The obtained ureido compound (V) can be used as it is or after isolation for the next reaction.
ウレイド化合物（Ｖ）と塩基性化合物との反応における
溶媒としては、反応に関与しないものであれば特に限定
はされないが、例えばメタノール、エタノール等アルコ
ール類、ベンゼン、トルエン、キシレン等の芳香族炭化
水素類、ジメチルホルムアミド、ジメチルスルホキサイ
ド等が好適に使用される。また、塩基性化合物としては
、上記の化合物（ｍ）と化合物（ＩＶ）の反応において
使用された触媒でよい。塩基性化合物は、ウレイド化合
物（Ｖ）に対し１．０〜３．０倍モル程度使用するのが
好ましい。反応は、通常室温から溶媒の還流温度で行わ
れる。The solvent for the reaction between the ureido compound (V) and the basic compound is not particularly limited as long as it does not participate in the reaction, but examples include alcohols such as methanol and ethanol, and aromatic hydrocarbons such as benzene, toluene, and xylene. etc., dimethylformamide, dimethyl sulfoxide, etc. are preferably used. Moreover, as the basic compound, the catalyst used in the reaction of the above compound (m) and compound (IV) may be used. The basic compound is preferably used in an amount of about 1.0 to 3.0 times the molar amount of the ureido compound (V). The reaction is usually carried out at room temperature to the reflux temperature of the solvent.
Ｂ工程
一般式（ＶＩ）で表されるピリミジン化合物と一般式
％式％（）
（式中Ｒ４は前記に同じ。ｈａΩは、塩素原子、臭素原
子又はヨウ素原子を示す。）
で表される酢酸エステル誘導体を、適当な溶媒中で塩基
性化合物の存在下に反応させることにより、一般式（■
）で表されるピリミジン酢酸エステル誘導体を得る。Step B: A pyrimidine compound represented by the general formula (VI) and an acetic acid represented by the general formula % (in the formula, R4 is the same as above. haΩ represents a chlorine atom, a bromine atom, or an iodine atom) By reacting the ester derivative in the presence of a basic compound in a suitable solvent, the general formula (■
) to obtain a pyrimidine acetate derivative.
溶媒としては、反応に関与しないものであれば特に限定
はないが、例えばエチルエーテル、テトラヒドロフラン
、ジオキサン等のエーテル類、ベンゼン、トルエン、キ
シレン等の芳香族炭化水素類、ジメチルホルムアミド、
ジメチルスルホキサイド等が好適に用いられる。The solvent is not particularly limited as long as it does not participate in the reaction, but examples include ethers such as ethyl ether, tetrahydrofuran, and dioxane, aromatic hydrocarbons such as benzene, toluene, and xylene, dimethylformamide,
Dimethyl sulfoxide and the like are preferably used.
塩基性化合物としては、ナトリウムメトキサイド、ナト
リウムエトキサイド、マグネシウムメトキサイド等のア
ルカリ金属またはアルカリ土類金属のアルコキサイド、
ナトリウムハイドライド等の金属水素化物、ナトリウム
アミド等の金属アミド化合物、水酸化ナトリウム、水酸
化カリウム、水酸化マグネシウム等のアルカリ金属また
はアルカリ土類金属の水酸化物、炭酸ナトリウム、炭酸
カリウム、炭酸マグネシウム等のアルカリ金属またはア
ルカリ土類金属の炭酸塩等が例示される。Basic compounds include alkoxides of alkali metals or alkaline earth metals such as sodium methoxide, sodium ethoxide, and magnesium methoxide;
Metal hydrides such as sodium hydride, metal amide compounds such as sodium amide, alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, sodium carbonate, potassium carbonate, magnesium carbonate, etc. Examples include carbonates of alkali metals or alkaline earth metals.
塩基性化合物は、ピリミジン化合物（ＶＩ）に対し１．
０〜３．０倍モル程度使用するのが好ましい。またピリ
ミジン化合物（ＶＩ）と酢酸エステル誘導体（■）の使
用割合は適宜選択できるが、通常ピリミジン化合物（Ｖ
Ｉ）に対し酢酸エステル誘導体（■）を１．０〜３．０
倍モル程度使用するのが好ましい。反応温度は、特に限
定されないが、通常は室温乃至冷却下に行われる。The basic compound has a 1.
It is preferable to use about 0 to 3.0 times the mole amount. In addition, the ratio of the pyrimidine compound (VI) and the acetate derivative (■) can be selected as appropriate, but usually the pyrimidine compound (V
1.0 to 3.0 of the acetate derivative (■) to I)
It is preferable to use about twice the molar amount. The reaction temperature is not particularly limited, but it is usually carried out at room temperature or under cooling.
Ｃ工程
上記で得られた一般式（■）で表されるピリミジン酢酸
エステル誘導体は、そのまま或いはＢ工程の反応系より
単離して、脱エステル反応に供し、一般式（Ｉ）で表さ
れるピリミジン誘導体を得る。Step C The pyrimidine acetate derivative represented by the general formula (■) obtained above is subjected to a deesterification reaction either as it is or isolated from the reaction system of the step B, to obtain the pyrimidine acetate derivative represented by the general formula (I). Obtain the derivative.
脱エステルの方法としては酸または塩基を使用する公知
の方法が適用できる。例えばカルボキシ保護基がメチル
、エチル、プロピル、ｐ−メトキジベンジル、ｔｅｒｔ
−ブチル、トリチル、ジフェニルメチル、メトキシメチ
ル、テトラヒドロピラニル等の場合は酸による方法が、
メチル、エチル、プロピル、ベンジル等の場合は塩基に
よる方法をも採用される。As a method for deesterification, a known method using an acid or a base can be applied. For example, the carboxy protecting group is methyl, ethyl, propyl, p-methoxydibenzyl, tert
- In the case of butyl, trityl, diphenylmethyl, methoxymethyl, tetrahydropyranyl, etc., the acid method is
In the case of methyl, ethyl, propyl, benzyl, etc., a method using a base is also adopted.
酸による脱エステルの方法の際に用いられる酸としては
、蟻酸、酢酸等の低級脂肪酸、トリクロロ酢酸、トリフ
ルオロ酢酸等のトリハロ酢酸、塩酸、臭素酸、フッ化水
素酸等のハロゲン化水素酸、ｐ−トルエンスルホン酸、
トリフルオロメタンスルホン酸等の有機スルホン酸、ま
たはこれらの混合物等が例示される。酸を用いる上記反
応は、液体の酸を使用するときは特に他の溶媒を必要と
しないが、ジクロロメタン、クロロホルム等のハロゲン
化炭化水素類、テトラヒドロフラン、ジオキサン等の環
状エーテル類、ジメチルホルムアミド、アセトン、水ま
たはこれらの混合溶媒等のこの反応に関与しない溶媒を
使用して実施することも可能である。Examples of acids used in the acid deesterification method include lower fatty acids such as formic acid and acetic acid, trihaloacetic acids such as trichloroacetic acid and trifluoroacetic acid, hydrohalic acids such as hydrochloric acid, bromic acid, and hydrofluoric acid; p-toluenesulfonic acid,
Examples include organic sulfonic acids such as trifluoromethanesulfonic acid, and mixtures thereof. The above reaction using an acid does not require any other solvent when using a liquid acid, but halogenated hydrocarbons such as dichloromethane and chloroform, cyclic ethers such as tetrahydrofuran and dioxane, dimethylformamide, acetone, It is also possible to carry out the reaction using a solvent that does not participate in this reaction, such as water or a mixed solvent thereof.
また塩基としては、水酸化ナトリウム、水酸化カリウム
、水酸化マグネシウム等のアルカリ金属またはアルカリ
土類金属の水酸化物、炭酸ナトリウム、炭酸カリウム、
炭酸マグネシウム等のアルカリ金属またはアルカリ土類
金属の炭酸塩、モルホリン、１，８−ジアザビシクロ（
５，４，０）−７−ウンデセン等が例示される。Bases include alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, sodium carbonate, potassium carbonate,
Carbonates of alkali metals or alkaline earth metals such as magnesium carbonate, morpholine, 1,8-diazabicyclo(
Examples include 5,4,0)-7-undecene and the like.
溶媒としては、メタノール、エタノール等のアルコール
類、テトラヒドロフラン、ジオキサン等の環状エーテル
類、ジメチルホルムアミドまたはこれらの混合物及び水
との混合物等の反応に関与しないものが用いられる。As the solvent, those that do not participate in the reaction, such as alcohols such as methanol and ethanol, cyclic ethers such as tetrahydrofuran and dioxane, dimethylformamide, or a mixture thereof and a mixture with water, are used.
上記反応により生成した本発明の新規ピリミジン誘導体
（Ｉ）は、通常の分離手段、例えば再結晶、カラムクロ
マトグラフィー等により容易に精製できる。The novel pyrimidine derivative (I) of the present invention produced by the above reaction can be easily purified by conventional separation means such as recrystallization, column chromatography, etc.
かくして得られた本発明化合物は優れたアルドース・リ
ダクターゼ阻害作用を示し、糖尿病に伴う種々の慢性症
状や合併症の予防及び治療剤として有用である。The thus obtained compounds of the present invention exhibit excellent aldose reductase inhibitory activity and are useful as preventive and therapeutic agents for various chronic symptoms and complications associated with diabetes.
実施例
次に、参考例及び実施例を挙げて本発明をより具体的に
説明する。EXAMPLES Next, the present invention will be explained in more detail by referring to reference examples and examples.
参考例１
ジオキサン３０厳とホスゲン含有四塩化炭素溶液（２，
７２Ｍ溶液）１０−との混液に、２−アミノ−３−エト
キシカルボニルベンゾチオフェン２ｇをジオキサン１０
顧に溶解したものを、室温で滴下した。滴下後３時間還
流した後、反応液を濃縮し、残渣をジオキサン３０ｍＱ
で抽出した。ジオキサン５０厳と６０％水素化ナトリウ
ム０．５２ｇとの混合物に、４−ブロモ−２−フルオロ
ベンジルアミン２．２ｇを水冷下に滴下後、さらに」二
足ジオキサン抽出溶液を滴下した。反応液を室温で一夜
撹拌後、濃縮した。残渣をメタノール１００ｍＱに溶解
し、ナトリウムメトキサイド１．３ｇを加えて、４時間
還流した。放冷後、反応液に希塩酸を加え酸性とし、析
出物を沖取した。Reference Example 1 Dioxane 30% and phosgene-containing carbon tetrachloride solution (2,
72M solution) 10-, 2-amino-3-ethoxycarbonylbenzothiophene 2g was added to dioxane 10-
The solution was added dropwise at room temperature. After refluxing for 3 hours after the dropwise addition, the reaction solution was concentrated and the residue was dissolved in dioxane 30mQ.
Extracted with. To a mixture of 50% dioxane and 0.52 g of 60% sodium hydride, 2.2 g of 4-bromo-2-fluorobenzylamine was added dropwise while cooling with water, and then a dioxane extraction solution was further added dropwise. The reaction solution was stirred at room temperature overnight and then concentrated. The residue was dissolved in 100 mQ of methanol, 1.3 g of sodium methoxide was added, and the mixture was refluxed for 4 hours. After cooling, dilute hydrochloric acid was added to the reaction solution to make it acidic, and the precipitate was scraped off.
枦取した結晶をエタノール−アセトンで再結晶し、３−
（４−ブロモ−２−フルオロベンジル）ベンゾチェノ
（２，３−ｄ） ピリミジン−２，４（ＩＨ，３Ｈ）ジ
オン（化合物■−１）を２．Ｏｇ（収率５５％）得た。The collected crystals were recrystallized with ethanol-acetone, and 3-
(4-bromo-2-fluorobenzyl)benzocheno
(2,3-d) pyrimidine-2,4(IH,3H)dione (compound ■-1) in 2. Og (yield 55%) was obtained.
ｍ、Ｉ）、３０１〜３０３℃
Ｍａｓｓ［Ｍ＋コ４０４
元素分析（Ｃ１７ＨＩＤ Ｎ２０２ Ｓ Ｆ Ｂ ｒと
して）ＣＨＮ
計算値（％） ５０．３９ ２．４９ ６．９１実測
値（％”） ５０．６４ ２． ６６ ６． ７９参
考例２
参考例１と同様な方法により第１表に示す化合物ＶＩ−
２〜ＶＩ−９を合成した。m, I), 301-303℃ Mass [M+Co404 Elemental analysis (as C17HID N202 SF Br) CHN Calculated value (%) 50.39 2.49 6.91 Actual value (%”) 50.64 2 .66 6.79 Reference Example 2 Compound VI- shown in Table 1 was prepared in the same manner as in Reference Example 1.
2 to VI-9 were synthesized.
参考例３
参考例１で得た化合物（ＶＩ−１）Ｉｇを無水ジメチル
ホルムアミド１０厳と６０％水素化ナトリウム０．１５
ｇとの混液に水冷下に加え、室温で］１時間撹拌した。Reference Example 3 Compound (VI-1) Ig obtained in Reference Example 1 was mixed with 10% of anhydrous dimethylformamide and 0.15% of 60% sodium hydride.
The mixture was added to the mixture with g under water cooling and stirred at room temperature for 1 hour.
つぎにブロム酢酸エチル０．５ｇを加えて、室温で２日
間撹拌後濃縮した。残渣に希塩酸を加え析出物を炉底し
た。枦取した結晶をエタノールで再結晶し、３−（４−
ブロモ−２−フルオロベンジル）−１−工ｌ・キシカル
ボニルメチルベンゾチェノ（２，３−ｄ〕ピリミジン−
２，４（ＩＨ，３Ｈ）−ジオン（化合物■−１）を０．
７ｇ（収率５８％）得た。Next, 0.5 g of ethyl bromoacetate was added, and the mixture was stirred at room temperature for 2 days and then concentrated. Dilute hydrochloric acid was added to the residue and the precipitate was drained to the bottom of the furnace. The collected crystals were recrystallized with ethanol to give 3-(4-
Bromo-2-fluorobenzyl)-1-oxycarbonylmethylbenzocheno(2,3-d]pyrimidine-
2,4(IH,3H)-dione (compound ■-1) at 0.
7 g (yield 58%) was obtained.
ｍ、ｐ、１６６〜１６８℃
ＭａｓｓＣＭ＋コ４９２
元素分析（Ｃ２１Ｈ，８Ｎ２０４８ＦＢｒとして）ＣＨ
Ｎ
計算値（％’＞ ５１． ３３ ３．２８ ５．７０
実測値（％）５１．２２ Ｂ、２２ ５．７２参考例
４
参考例３と同様な方法により第２表に示す化合物■−２
〜■−９を合成した。m, p, 166-168℃ MassCM+ko492 Elemental analysis (as C21H, 8N2048FBr) CH
N Calculated value (%'> 51. 33 3.28 5.70
Actual value (%) 51.22 B, 22 5.72 Reference Example 4 Compound ■-2 shown in Table 2 was prepared in the same manner as Reference Example 3.
-■-9 was synthesized.
実施例１
参考例３で得た化合物（■−１）０．７ｇを酢酸３０顧
と濃塩酸１０−との混液に加え、２時間還流した。濃塩
酸３−を追加し、さらに２時間還流した。反応液を濃縮
し、残渣にメタノールを加えた後、沖過した。枦取した
結晶をメタノールで再結晶し、３−（４−ブロモ−２−
フルオロベンジル）−１−カルボキシメチルベンゾチェ
ノ〔２゜３−ｄ〕ピリミジン−２，４（ＩＨ，３Ｈ）−
ジオン（化合物ニー１）を０．５ｇ（収率７６％）得た
。Example 1 0.7 g of the compound (■-1) obtained in Reference Example 3 was added to a mixed solution of 30% acetic acid and 10% concentrated hydrochloric acid, and the mixture was refluxed for 2 hours. Concentrated hydrochloric acid 3- was added and the mixture was further refluxed for 2 hours. The reaction solution was concentrated, methanol was added to the residue, and the mixture was filtered. The collected crystals were recrystallized with methanol to give 3-(4-bromo-2-
fluorobenzyl)-1-carboxymethylbenzocheno[2゜3-d]pyrimidine-2,4(IH,3H)-
0.5 g (yield 76%) of dione (compound 1) was obtained.
ｍ、ｐ、２６５〜２６６℃
Ｍ ａｓｓ ［Ｍ ＋］ ４６４
元素分析（ＣＴ９Ｈ１２Ｎ２０４５ＢｒＦとして）ＣＨ
Ｎ
計算値（％）４９． ２６ ２．６１ ６．０５実測値
（％）４９．４３ ２．７１ ５．９８実施例２
実施例１と同様な方法により第３表に示す化合物Ｉ−２
〜Ｉ−９を合成した。m, p, 265-266°C M ass [M +] 464 Elemental analysis (as CT9H12N2045BrF) CH
N Calculated value (%) 49. 26 2.61 6.05 Actual value (%) 49.43 2.71 5.98 Example 2 Compound I-2 shown in Table 3 was prepared in the same manner as in Example 1.
~I-9 was synthesized.
手続補正書 （自発） 事件の表示 昭和６３年特許願第２０３４５４号 大鵬薬品工業株式会社Procedural amendment (spontaneous) Display of incidents 1988 Patent Application No. 203454 Taiho Pharmaceutical Co., Ltd.
Claims (1)
Ｙの何れか一方は直接結合しており、他方はＳ、Ｎ−Ｃ
Ｈ＿３又はＮ−ＣＨ＿２Ｃ＿６Ｈ＿５を示し、Ｒ＿２は
ベンジル又はハロゲン置換ベンジル基を示す。）で表さ
れるピリミジン誘導体及びその薬理学的に許容される塩
。[Claims] [1] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1 represents hydrogen or a halogen atom, one of X and Y is directly bonded, and the other is S , N-C
It represents H_3 or N-CH_2C_6H_5, and R_2 represents benzyl or a halogen-substituted benzyl group. ) Pyrimidine derivatives and pharmacologically acceptable salts thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP20345488A JPH0253788A (en) | 1988-08-16 | 1988-08-16 | Pyrimidine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP20345488A JPH0253788A (en) | 1988-08-16 | 1988-08-16 | Pyrimidine derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0253788A true JPH0253788A (en) | 1990-02-22 |
Family
ID=16474388
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP20345488A Pending JPH0253788A (en) | 1988-08-16 | 1988-08-16 | Pyrimidine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0253788A (en) |
-
1988
- 1988-08-16 JP JP20345488A patent/JPH0253788A/en active Pending
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