JPS63246377A - Pyrazolopyrimidines - Google Patents
PyrazolopyrimidinesInfo
- Publication number
- JPS63246377A JPS63246377A JP62081578A JP8157887A JPS63246377A JP S63246377 A JPS63246377 A JP S63246377A JP 62081578 A JP62081578 A JP 62081578A JP 8157887 A JP8157887 A JP 8157887A JP S63246377 A JPS63246377 A JP S63246377A
- Authority
- JP
- Japan
- Prior art keywords
- group
- alkyl group
- phenyl
- lower alkyl
- carbon atoms
- 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
- APXRHPDHORGIEB-UHFFFAOYSA-N 1H-pyrazolo[4,3-d]pyrimidine Chemical class N1=CN=C2C=NNC2=C1 APXRHPDHORGIEB-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 101
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 74
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 31
- -1 ACO2R<3> Chemical group 0.000 claims abstract description 25
- 125000001931 aliphatic group Chemical group 0.000 claims abstract description 16
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 9
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims abstract description 9
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims abstract description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 52
- 125000005843 halogen group Chemical group 0.000 claims description 31
- 239000000126 substance Substances 0.000 claims description 24
- 125000002947 alkylene group Chemical group 0.000 claims description 15
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 15
- 229920006395 saturated elastomer Polymers 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 150000003230 pyrimidines Chemical class 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 239000003524 antilipemic agent Substances 0.000 claims description 3
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 claims description 3
- 230000002140 halogenating effect Effects 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- IHYNKGRWCDKNEG-UHFFFAOYSA-N n-(4-bromophenyl)-2,6-dihydroxybenzamide Chemical compound OC1=CC=CC(O)=C1C(=O)NC1=CC=C(Br)C=C1 IHYNKGRWCDKNEG-UHFFFAOYSA-N 0.000 claims description 2
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 claims description 2
- ZOCLAPYLSUCOGI-UHFFFAOYSA-M potassium hydrosulfide Chemical compound [SH-].[K+] ZOCLAPYLSUCOGI-UHFFFAOYSA-M 0.000 claims description 2
- DSKLYHDHQJANOE-UHFFFAOYSA-N pyrazolo[4,3-d]pyrimidine Chemical class C1=NC=N[C]2C=NN=C21 DSKLYHDHQJANOE-UHFFFAOYSA-N 0.000 claims description 2
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 claims description 2
- 101100378191 Caenorhabditis elegans aco-2 gene Proteins 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 26
- 229910052736 halogen Inorganic materials 0.000 abstract 2
- 150000002367 halogens Chemical class 0.000 abstract 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 abstract 1
- 229910052794 bromium Inorganic materials 0.000 abstract 1
- OGEBRHQLRGFBNV-RZDIXWSQSA-N chembl2036808 Chemical class C12=NC(NCCCC)=NC=C2C(C=2C=CC(F)=CC=2)=NN1C[C@H]1CC[C@H](N)CC1 OGEBRHQLRGFBNV-RZDIXWSQSA-N 0.000 abstract 1
- QPJDMGCKMHUXFD-UHFFFAOYSA-N cyanogen chloride Chemical compound ClC#N QPJDMGCKMHUXFD-UHFFFAOYSA-N 0.000 abstract 1
- 239000011630 iodine Substances 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 48
- 238000006243 chemical reaction Methods 0.000 description 27
- 239000000203 mixture Substances 0.000 description 26
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- 239000002904 solvent Substances 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 17
- 150000004820 halides Chemical class 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- 238000001228 spectrum Methods 0.000 description 14
- 239000003921 oil Substances 0.000 description 13
- 235000019198 oils Nutrition 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 12
- 239000002994 raw material Substances 0.000 description 12
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 238000000034 method Methods 0.000 description 10
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 238000004809 thin layer chromatography Methods 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 230000001315 anti-hyperlipaemic effect Effects 0.000 description 9
- 238000001816 cooling Methods 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
- 230000008034 disappearance Effects 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- 235000019341 magnesium sulphate Nutrition 0.000 description 6
- 210000002966 serum Anatomy 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- RTEXIPZMMDUXMR-UHFFFAOYSA-N benzene;ethyl acetate Chemical compound CCOC(C)=O.C1=CC=CC=C1 RTEXIPZMMDUXMR-UHFFFAOYSA-N 0.000 description 5
- MDHYEMXUFSJLGV-UHFFFAOYSA-N beta-phenethyl acetate Natural products CC(=O)OCCC1=CC=CC=C1 MDHYEMXUFSJLGV-UHFFFAOYSA-N 0.000 description 5
- 235000012000 cholesterol Nutrition 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 235000011181 potassium carbonates Nutrition 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-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
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 4
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 239000002808 molecular sieve Substances 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 239000000829 suppository Substances 0.000 description 4
- 150000003512 tertiary amines Chemical class 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- 208000031226 Hyperlipidaemia Diseases 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 3
- KNHUKKLJHYUCFP-UHFFFAOYSA-N clofibrate Chemical compound CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 KNHUKKLJHYUCFP-UHFFFAOYSA-N 0.000 description 3
- 229960001214 clofibrate Drugs 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 238000005658 halogenation reaction Methods 0.000 description 3
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 150000003335 secondary amines Chemical class 0.000 description 3
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 3
- ZZKDGABMFBCSRP-UHFFFAOYSA-N 3-ethyl-2-methylpyridine Chemical compound CCC1=CC=CN=C1C ZZKDGABMFBCSRP-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229940110456 cocoa butter Drugs 0.000 description 2
- 235000019868 cocoa butter Nutrition 0.000 description 2
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 2
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 230000026030 halogenation Effects 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 235000008390 olive oil Nutrition 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000003495 polar organic solvent Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 229920001592 potato starch Polymers 0.000 description 2
- 150000003141 primary amines Chemical class 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 230000006824 pyrimidine synthesis Effects 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007901 soft capsule Substances 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- JFZSDNLQDTYVEE-UHFFFAOYSA-N 1,4-dihydropyrazolo[4,3-d]pyrimidin-7-one Chemical compound O=C1N=CNC2=C1NN=C2 JFZSDNLQDTYVEE-UHFFFAOYSA-N 0.000 description 1
- XMBHGEAQFMUJMX-UHFFFAOYSA-N 2,4-dihydro-1h-pyrazolo[4,3-d]pyrimidine-3,5-dione Chemical class N1=C(O)N=C2C(O)=NNC2=C1 XMBHGEAQFMUJMX-UHFFFAOYSA-N 0.000 description 1
- CUHRIRXNRTVEOH-UHFFFAOYSA-N 2-aminoacetic acid;chloroethane Chemical compound CCCl.NCC(O)=O CUHRIRXNRTVEOH-UHFFFAOYSA-N 0.000 description 1
- HHENWMDMGFNJEO-UHFFFAOYSA-N 7-chloro-1h-pyrazolo[4,3-d]pyrimidine Chemical compound ClC1=NC=NC2=C1NN=C2 HHENWMDMGFNJEO-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 102100022006 Cell division cycle protein 123 homolog Human genes 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 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 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical class S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- KIWBPDUYBMNFTB-UHFFFAOYSA-N Ethyl hydrogen sulfate Chemical compound CCOS(O)(=O)=O KIWBPDUYBMNFTB-UHFFFAOYSA-N 0.000 description 1
- 206010016825 Flushing Diseases 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 101000897353 Homo sapiens Cell division cycle protein 123 homolog Proteins 0.000 description 1
- 206010020772 Hypertension Diseases 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
- 239000004166 Lanolin Substances 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 150000004996 alkyl benzenes Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- RUDATBOHQWOJDD-BSWAIDMHSA-N chenodeoxycholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-BSWAIDMHSA-N 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- IOLQWGVDEFWYNP-UHFFFAOYSA-N ethyl 2-bromo-2-methylpropanoate Chemical compound CCOC(=O)C(C)(C)Br IOLQWGVDEFWYNP-UHFFFAOYSA-N 0.000 description 1
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000002474 experimental method 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
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 208000001130 gallstones Diseases 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 150000002366 halogen compounds Chemical class 0.000 description 1
- RXHIZFMFPLHZDT-UHFFFAOYSA-N hexadecyl 4-methylbenzenesulfonate Chemical compound CCCCCCCCCCCCCCCCOS(=O)(=O)C1=CC=C(C)C=C1 RXHIZFMFPLHZDT-UHFFFAOYSA-N 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 description 1
- 239000002960 lipid emulsion Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 230000005976 liver dysfunction Effects 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 239000011812 mixed powder Substances 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 208000013465 muscle pain Diseases 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 description 1
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 description 1
- PZHNNJXWQYFUTD-UHFFFAOYSA-N phosphorus triiodide Chemical compound IP(I)I PZHNNJXWQYFUTD-UHFFFAOYSA-N 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- CBPYOHALYYGNOE-UHFFFAOYSA-M potassium;3,5-dinitrobenzoate Chemical compound [K+].[O-]C(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1 CBPYOHALYYGNOE-UHFFFAOYSA-M 0.000 description 1
- CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical compound [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 238000006748 scratching Methods 0.000 description 1
- 230000002393 scratching effect Effects 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- NRHMKIHPTBHXPF-TUJRSCDTSA-M sodium cholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 NRHMKIHPTBHXPF-TUJRSCDTSA-M 0.000 description 1
- HYHCSLBZRBJJCH-UHFFFAOYSA-M sodium hydrosulfide Chemical compound [Na+].[SH-] HYHCSLBZRBJJCH-UHFFFAOYSA-M 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (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〕
本発明は新規なピラゾロ〔4,3〜d〕ピリミジン誘導
体、その製造法およびこれらを含む抗高脂血剤およびこ
れらの中間体とその製造法に関する。Detailed Description of the Invention [Field of Industrial Application] The present invention relates to novel pyrazolo[4,3-d]pyrimidine derivatives, their production methods, antihyperlipidemic agents containing them, intermediates thereof, and their production. Regarding the law.
高脂血症は、高血圧、糖尿病、喫煙と共に、動脈硬化、
冠動脈疾患の主要な危険因子であることが認識されてお
り、この高脂血症の治療、予防のために多数の薬剤が研
究されてきた。この分野の薬剤は、疾患の性格上、使用
が長期間にわたる可能性があり、安全性の高いものが要
求されている。しかしながら、従来から抗高脂血剤とし
て広く使用されているニコチン酸およびその誘導体、ま
たはクロフィブレートおよびその誘導体については種々
の副作用が報告されており、満足できる薬剤とはいえな
い、たとえば、ニコチン酸およびその誘導体は、顔面紅
潮、胃腸障害等の報告がある。また、クロフィブレート
およびその誘導体では筋肉痛、肝機能障害のほか、胆石
発生の可能性が高いことが知られている。また、クロフ
ィブレートについては、動物実験では肝臓癌の発生もあ
ることが報告されている。CD、J、5voboda
and D、L。Hyperlipidemia, along with hypertension, diabetes, and smoking, causes arteriosclerosis,
It has been recognized that hyperlipidemia is a major risk factor for coronary artery disease, and a number of drugs have been studied to treat and prevent hyperlipidemia. Due to the nature of the disease, drugs in this field may be used for long periods of time, and therefore are required to be highly safe. However, various side effects have been reported for nicotinic acid and its derivatives, or clofibrate and its derivatives, which have been widely used as antihyperlipidemic agents, and they cannot be said to be satisfactory drugs. Acids and their derivatives have been reported to cause facial flushing, gastrointestinal disorders, etc. In addition, clofibrate and its derivatives are known to cause muscle pain, liver dysfunction, and a high possibility of gallstone formation. Furthermore, clofibrate has been reported to cause liver cancer in animal experiments. CD, J, 5voboda
and D, L.
八zarnoff、Cancer Res、、 3
9.3419(1979) ) 。8zarnoff, Cancer Res, 3
9.3419 (1979)).
本発明者らは既に特開昭60−231679号において
ピラゾロ(4,3−dlピリミジン類が抗高脂血作用を
有することを明らかにしており、今回さらに新たに本発
明の新規なピラゾロ〔4,3〜d〕ピリミジン誘導体を
合成し、それらがすぐれた抗高脂血作用を有することを
見出し、本発明を完成した。The present inventors have already revealed in JP-A No. 60-231679 that pyrazolo (4,3-dl pyrimidines) have an antihyperlipidemic effect, and now we have further disclosed that the novel pyrazolo [4,3-dl pyrimidines] of the present invention have an antihyperlipidemic effect. , 3-d] and have synthesized pyrimidine derivatives and found that they have excellent antihyperlipidemic effects, thereby completing the present invention.
本発明に関する抗高脂血作用をもつ新規のピラゾロ(4
,3−d)ピリミジン類は、下記の一般式〔式中、R1
は炭素数1から4までのアルキル基、 フェニル基、ま
たは低級アルキル基、低級アルコキシ基またはハロゲン
原子で置換されたフェニル基を示し、R2は炭素数2か
ら20の飽和または不飽和の、直鎖状または分岐鎖状脂
肪族基、フェニル低級アルキル基、フェニル基が低級ア
ルキル基、低級アルコキシ基またはハロゲン原子で置換
されたフェニル低級アルキル基またはACO□R’(A
は置換されていない、または炭素数1から3のアルキル
基によって置換されたメチレン鎖数1から3のアルキレ
ンを示し、R3は炭素数1から4の低級アルキル基を示
す。)を示し、XはOR’ (R’は炭素数1から20
までの直鎖状または分岐鎖状脂肪族基、フェニル基、低
級アルキル基、低級アルコキシ基またはハロゲン原子で
置換されたフェニル基、ACO□R,(A、R’は前述
と同、!味である)、ピリジルメチル基または低級アル
キル基で置換されたピリジルメチル基を示す)、SH,
NR’R’ (R’、R’はそれぞれ水素原子、低級
アルキル基、フェニル基、低級アルキル基あるいは低級
アルコキシ基で置換されたフェニル基またはBCOJ’
(Bは置換されていない、またはメチル基、エチル基
、プロピル基、ブチル基またはイソブチル基によって置
換されたメチレン鎖数1から3のアルキレンを示し
R?は水素原子、低級アルキル基を示す。)を示す。)
、シアノ基、塩素原子、臭素原子、沃素原子またはHC
R”R9(R’。Novel pyrazolo (4) with antihyperlipidemic effect related to the present invention
, 3-d) Pyrimidines are represented by the following general formula [wherein R1
represents an alkyl group having 1 to 4 carbon atoms, a phenyl group, a lower alkyl group, a lower alkoxy group, or a phenyl group substituted with a halogen atom, and R2 is a saturated or unsaturated linear chain having 2 to 20 carbon atoms. or a branched aliphatic group, a phenyl lower alkyl group, a phenyl lower alkyl group in which a phenyl group is substituted with a lower alkyl group, a lower alkoxy group, or a halogen atom, or ACO□R'(A
represents an alkylene having 1 to 3 methylene chains which is unsubstituted or substituted with an alkyl group having 1 to 3 carbon atoms, and R3 represents a lower alkyl group having 1 to 4 carbon atoms. ), X is OR'(R' is a carbon number of 1 to 20
Straight-chain or branched aliphatic group, phenyl group, lower alkyl group, lower alkoxy group or phenyl group substituted with a halogen atom, ACO□R, (A, R' are the same as above, ! taste) ), pyridylmethyl group or pyridylmethyl group substituted with a lower alkyl group), SH,
NR'R'(R' and R' are each a hydrogen atom, a lower alkyl group, a phenyl group, a phenyl group substituted with a lower alkyl group or a lower alkoxy group, or BCOJ'
(B represents an alkylene having 1 to 3 methylene chains that is unsubstituted or substituted with a methyl group, ethyl group, propyl group, butyl group, or isobutyl group)
R? represents a hydrogen atom or a lower alkyl group. ) is shown. )
, cyano group, chlorine atom, bromine atom, iodine atom or HC
R”R9(R'.
R9はそれぞれシアノ基または炭素数1から4の低級ア
ルキルオキシカルボニル基を示す。)を示す。〕によっ
て表される化合物である。一般式(I)で表わされるピ
ラゾロ(4,3−d)ピリミジン類は、下記の反応式に
従って合成される。R9 each represents a cyano group or a lower alkyloxycarbonyl group having 1 to 4 carbon atoms. ) is shown. ] is a compound represented by Pyrazolo(4,3-d)pyrimidines represented by general formula (I) are synthesized according to the following reaction formula.
([) (r−(X・0H))
(1(X=Ilal))
(I −(X=OR’))
(以下、余白)
(1−(X=NR’R’))
H
(I −(X=SI+))
(1−(X=SH) ”)
N
(1−(X=CN))
〔反応式中、Halは塩素原子、臭素原子、沃素原子な
どのハロゲン原子を示し、Yはハロゲン原子、低級アル
キルスルホニルオキシ、無置換または炭素数1から3の
アルキル基または塩素によって置換すれたフェニルスル
ホニルオキシなどの脱離基を示し、Mはナトリウム、カ
リウムまたはカルシウム(1/2原子分)を示す。R’
、R”、R’ps、 R6,R?、R8およびR9は上
述の一般式(I)の説明と同意味である。〕
工程1は3.7−シヒドロキシピラゾロ(4,3−d)
ピリミジンの3位ヒドロキシ基をアルキル化する工程で
あり、各種ハロゲン化合物、低級アルキルスルホニルオ
キシ化合物、無置換あるいは炭素数1から3のアルキル
基または塩素によって置換されたフェニルスルホニルオ
キシ化合物との反応により行なうことが出来る。これら
アルキル化剤は、化合物=(II)”に対して1.0〜
1.5倍モル好ましくは1.01〜1.2倍モル使用す
る。([) (r-(X・0H))
(1(X=Ilal)) (I - (X=OR')) (Hereafter, margin) (1-(X=NR'R')) H (I - (X=SI+)) (1-(X =SH) ") N (1-(X=CN)) It represents a leaving group such as an alkyl group having 1 to 3 carbon atoms or phenylsulfonyloxy substituted with chlorine, and M represents sodium, potassium or calcium (1/2 atom).R'
. )
This is a process of alkylating the hydroxyl group at the 3-position of pyrimidine, and is carried out by reaction with various halogen compounds, lower alkylsulfonyloxy compounds, unsubstituted or alkyl groups having 1 to 3 carbon atoms, or phenylsulfonyloxy compounds substituted with chlorine. I can do it. These alkylating agents are 1.0 to 1.0 to
The amount used is 1.5 times the mole, preferably 1.01 to 1.2 times the mole.
この反応は、塩基存在下、不活性の溶媒中好ましくはジ
メチルホルムアミド、ジメチルアセトアミド、ジメチル
スルホキシド、ヘキサメチルホスホリックトリアミドな
どの非プロトン性極性溶媒中、室温ないし溶媒の沸点中
好ましくは50″Cから100°Cの加熱下で進行し、
これら好ましい条件(溶媒、温度等)下では、特に円滑
に進行する。This reaction is carried out in the presence of a base in an inert solvent, preferably in an aprotic polar solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethylphosphoric triamide, at room temperature to the boiling point of the solvent, preferably at 50°C. Proceed under heating from to 100°C,
Under these preferable conditions (solvent, temperature, etc.), the process proceeds particularly smoothly.
塩基としては通常のカセイソーダ、カセイカリ、炭酸ソ
ーダ、炭酸カリ、ナトリウムアルコキシドあるいはカリ
ウムアルコキシドの脱酸剤を使用できるが、これらの塩
基とジヒドロキシピラゾロピリミジンはしばしば有機溶
媒に非常に難溶の塩を作るため、反応系から析出しやす
く反応を円滑に進行させるためには多量の溶媒を必要と
することか多い。一方トリメチルアミン、トリエチルア
ミン、ピリジン、メチルエチルピリジンのごとき三級ア
ミンを使用すると、これらの塩は溶解度が大きいので、
系から析出することなく、相対的に少量の溶媒中でも反
応が円滑に進行する。これら塩基の使用量は、少なくと
も反応により生成する酸を中和するのに充分な量を必要
とする。即ち、化合物(n)に対して1.0〜2.0倍
モル量を必要とする。As bases, the usual deoxidizing agents such as caustic soda, caustic potash, sodium carbonate, potassium carbonate, sodium alkoxides or potassium alkoxides can be used, but these bases and dihydroxypyrazolopyrimidines often form salts that are very sparingly soluble in organic solvents. Therefore, it is easy to precipitate from the reaction system, and a large amount of solvent is often required for the reaction to proceed smoothly. On the other hand, when using tertiary amines such as trimethylamine, triethylamine, pyridine, and methylethylpyridine, these salts have high solubility, so
The reaction proceeds smoothly even in a relatively small amount of solvent without precipitation from the system. The amount of these bases used must be at least sufficient to neutralize the acid produced by the reaction. That is, a molar amount of 1.0 to 2.0 times that of compound (n) is required.
工程2は各種ハロゲン化剤による7位ヒドロキシ基のハ
ロゲン化反応であり、塩基の存在下あるいは非存在下に
おいて室温下あるいは100°Cまで加熱することによ
り進行する。ハロゲン化剤としてオキシ塩化リン、オキ
シ臭化リン、チオニルクロリド、チオニルプロミドまた
は三沃化リンを、無溶媒下・化合物(1−(X・0H)
)に対して5〜10倍モル量を用いるか、テトラリンの
ような不活性の芳香属炭化水素系の有機溶媒(塩素化ベ
ンゼン類または低級アルキルベンゼン類)の存在下・化
合物(1−(X=O11) )に対して5〜10倍量を
用いて反応せしめる。Step 2 is a halogenation reaction of the 7-position hydroxy group using various halogenating agents, and proceeds by heating at room temperature or up to 100°C in the presence or absence of a base. As a halogenating agent, phosphorus oxychloride, phosphorus oxybromide, thionyl chloride, thionyl bromide, or phosphorus triiodide was added to the compound (1-(X・0H)
), or in the presence of an inert aromatic hydrocarbon organic solvent (chlorinated benzenes or lower alkylbenzenes) such as tetralin. The reaction is carried out using 5 to 10 times the amount of O11).
また塩基としては通常のハロゲン化に用いる三級アミン
類例えばジメチルアニリン、トリエチルアミン、メチル
エチルピリジンまたはピリジンが用いられる。これら塩
基の使用量は、少なくとも反応により生成する酸を中和
するのに充分な量を必要とする。即ち、化合物(1−(
X=OI+))に対して1.0〜2.0倍モル量を必要
とする。As the base, tertiary amines commonly used in halogenation, such as dimethylaniline, triethylamine, methylethylpyridine or pyridine, are used. The amount of these bases used must be at least sufficient to neutralize the acid produced by the reaction. That is, the compound (1-(
1.0 to 2.0 times the molar amount is required relative to X=OI+)).
工程3は塩基存在下でのハロゲン化物(1−(X=ll
al)) とアルコール類との反応であり、塩基として
炭酸カリウム、炭酸ナトリウム、カリウム−も−ブトキ
シドなどを用いることが出来る。アルコール類はハロゲ
ン化物(1(X=IIal))に対し1.1倍モル量以
上であって、好ましくは使用するハロゲン化物(r −
(X=tlal))を溶解するのに充分な量、塩基はハ
ロゲン化物(1−(X=Hal))に対し1〜3倍モル
量好ましくは1〜1.5倍モル量を用いる。溶媒として
は、置換反応させようとするアルコール類のほか、不活
性の極性有機溶媒たとえばジメチルホルムアミド、ジメ
チルアセトアミド、ジメチルスルホキシド、テトラヒド
ロフランまたはジオキサンを用いることが出来る。Step 3 is the formation of a halide (1-(X=ll) in the presence of a base.
al)) and alcohol, and potassium carbonate, sodium carbonate, potassium butoxide, etc. can be used as the base. The alcohol is used in an amount of 1.1 times or more molar amount or more relative to the halide (1(X=IIal)), and is preferably used in the amount of the halide (r-
(X=tlal)), the base is used in an amount of 1 to 3 times the molar amount, preferably 1 to 1.5 times the molar amount of the halide (1-(X=Hal)). As the solvent, in addition to the alcohol to be subjected to the substitution reaction, inert polar organic solvents such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, or dioxane can be used.
また先に置換により導入しようとするアルコールと、カ
リウム−t−ブトキシドまたはナトリウムヒドリドから
ハロゲン化物(1−(X=Flal)) ニ対して1〜
2倍モル量のアルコキシドを作っておき、これとハロゲ
ン化物を反応させることも出来る。温度は水冷下(約−
5°C)から80″Cまでを用いることが出来る。In addition, the alcohol to be introduced by substitution and the halide (1-(X=Fal)) from potassium t-butoxide or sodium hydride are 1 to 1.
It is also possible to prepare twice the molar amount of alkoxide and react it with the halide. The temperature is under water cooling (approximately -
5°C) to 80″C can be used.
工程4はハロゲン化物(1−(X=Ilal)) と第
1級あるいは第2級アミンとの反応であり、無溶媒ある
いはジメチルホルムアミド、ジメチルアセトアミド、ジ
メチルスルホキシド、あるいは各種不活性溶媒を用いて
行なうことが出来る。脱酸剤としては、この反応で導入
される第1級あるいは第2級アミン類自体を2倍モル以
上用いて行うか、あるいはトリエチルアミンのような第
3級アミンあるいは炭酸カリウムなどの無機塩を用いて
、水冷下0°C〜−5°C次いで約80°Cまでに加熱
して反応させる。脱酸剤として第3級アミンあるいは無
機塩基を用いて行うときは、アミノ化に用いる第1級ま
たは第2級アミンをハロゲン化物(1−(X=Hal)
)に対して1〜2.0倍モル量用いる。Step 4 is a reaction between a halide (1-(X=Ilal)) and a primary or secondary amine, and is carried out without a solvent or using dimethylformamide, dimethylacetamide, dimethylsulfoxide, or various inert solvents. I can do it. As a deoxidizing agent, use twice or more of the primary or secondary amine itself introduced in this reaction, or use a tertiary amine such as triethylamine or an inorganic salt such as potassium carbonate. Then, the reaction mixture is heated to 0°C to -5°C under water cooling, and then heated to about 80°C. When using a tertiary amine or an inorganic base as a deoxidizing agent, the primary or secondary amine used for amination is a halide (1-(X=Hal)
) is used in a molar amount of 1 to 2.0 times.
工程5は、ハロゲン化物(I (X=Hal))と
水硫化カリあるいは水硫化ナトリウムとの反応による7
−メルカプト体の合成である。これらの水硫化物はハロ
ゲン化物(1−(X=Hal))に対し1〜5倍モル量
用いる。この反応は水、アルコール、ジメチルスルホキ
シドなどの溶媒中で、水冷下(約−5°C)から80
’Cまでの反応温度の下で行なうことが出来る。Step 5 involves the reaction of a halide (I (X=Hal)) with potassium hydrosulfide or sodium hydrosulfide.
-Synthesis of mercapto compound. These hydrosulfides are used in an amount of 1 to 5 times the molar amount of the halide (1-(X=Hal)). This reaction is carried out in a solvent such as water, alcohol, dimethyl sulfoxide, etc. under water cooling (approximately -5°C) to 80°C.
It can be carried out at reaction temperatures up to 'C.
工程6は、7−位の水酸基のハロゲン化を経ない直接の
メルカプト化反応でありピリジン、ピコリン、メチルエ
チルピリジンなどのピリジン系溶媒中、化合物(1−(
X=OH))に対して1〜3倍モル量の五二硫化リンあ
るいはいわゆるローソン試薬(Lawesson’s
Reagent:2,4−bis(4−methoxy
phenyl)−1+ 3−di thia−2+ 4
−diphosphetane−2+ 4−d isu
If 1de)と共に室温下から約80°Cまで加熱
することにより進行させることが出来る。Step 6 is a direct mercaptization reaction without halogenation of the 7-position hydroxyl group, in which the compound (1-(
1 to 3 times the molar amount of phosphorus pentasulfide or so-called Lawesson's reagent (X=OH))
Reagent: 2,4-bis(4-methoxy)
phenyl)-1+ 3-di thia-2+ 4
-diphosphetane-2+ 4-d isu
It can be advanced by heating from room temperature to about 80°C together with If 1de).
工程7は、ハロゲン化物(I −(X=Hal))とシ
アノアニオンとの反応による7−シアノ体の合成であり
、ジメチルスルホキシド、ジメチルホルムアミド、ヘキ
サメチルホスホリックトリアミドなどの非プロトン性掻
性溶媒中、ハロゲン化物(■−(x・l1al))に対
し1.0〜10倍モル量好ましくは1,5〜3倍モル量
のシアン化ソーダ、シアン化カリなどを用いて、室温か
ら80°Cまでの温度で行なうことができる。Step 7 is the synthesis of 7-cyano compound by reaction of a halide (I-(X=Hal)) with a cyano anion, and aprotic scratching agents such as dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, etc. Using sodium cyanide, potassium cyanide, etc. in a solvent in an amount of 1.0 to 10 times the molar amount, preferably 1.5 to 3 times the molar amount of the halide (■-(x・l1al)), It can be carried out at temperatures up to °C.
工程8は、ハロゲン化物(1−(X=Ilal))
とカルボアニオンとの反応であリジメチルホルムアミド
、ジメチルスルホキシド、ヘキサメチルホスホリックト
リアミドのような不活性の非プロトン性極性有機溶媒中
でナトリウムヒドリド、カリウム−1−ブトキシドなど
の強塩基によって、酸性プロトンをもった化合物、たと
えばマロン酸ジメチルエステル、シアノ酢酸エチルエス
テルなどからカルボアニオンを発生させ、これとハロゲ
ン化物とを反応させて目的物を得る。発生させるカルボ
アニオンの量はハロゲン化物(r (X=Hal)
) ニ対して1.0〜2.0倍モル量好ましくは1.0
1〜1.5倍モル量である。Step 8 is a halide (1-(X=Ilal))
The reaction with the carbanion is acidified by a strong base such as sodium hydride, potassium-1-butoxide in an inert aprotic polar organic solvent such as lydimethylformamide, dimethylsulfoxide, or hexamethylphosphoric triamide. A carbanion is generated from a compound having a proton, such as dimethyl malonate or ethyl cyanoacetate, and the target product is obtained by reacting this with a halide. The amount of carbanion generated is halide (r (X=Hal)
) 1.0 to 2.0 times the molar amount, preferably 1.0
The amount is 1 to 1.5 times the molar amount.
使用する酸性プロトンをもった化合物の1は、ハロゲン
化物(1−(X=Ilal))に対して1.0〜3.0
倍モル量である。1 of the compound with an acidic proton used is 1.0 to 3.0 with respect to the halide (1-(X=Ilal))
This is twice the molar amount.
反応温度は、水冷下(約−5°C)から100°Cまで
を選ぶことができる。The reaction temperature can be selected from water cooling (approximately -5°C) to 100°C.
本発明の化合物は、後述の試験結果により示されたよう
に顕著な抗高脂血作用を有しており、抗高脂置割または
抗動脈硬化剤として有用である。The compound of the present invention has a remarkable antihyperlipidemic effect as shown by the test results described below, and is useful as an antihyperlipidemic or antiarteriosclerotic agent.
この活性成分はその投与経路により種々の型の製剤化が
可能である。The active ingredient can be formulated into various types depending on the route of administration.
本発明に従う薬学組成物は、本発明化合物自体あるいは
適宜の薬理的に許容される結合剤(シロップ、アラビア
ゴム、ゼラチン、ソルビット、トラガント、ポリビニル
ピロリドンなど)、賦形剤(乳糖、砂糖、コーンスター
チ、リン酸カルシウム、ソルビット、グリシンなど)、
滑沢剤(ステアリン酸マグネシウム、タルク、ポリエチ
レングリコール、シリカなど)、崩壊剤(じゃがいも澱
粉など)と混合し、粉末、顆粒、錠剤またはカプセル剤
などの形態をとることができ、経口的に投与することが
望ましい。しかしながら、もちろんこれだけに限定され
るものではなく、非経口投与の可能性もある。たとえば
、カカオ脂、ポリエチレングリコール、ラノリン、脂肪
酸トリグリセライド等の油脂性基材を用いた坐剤として
の投与の可能性もある。The pharmaceutical composition according to the present invention includes the compound of the present invention itself or a suitable pharmacologically acceptable binder (syrup, gum arabic, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone, etc.), excipients (lactose, sugar, corn starch, calcium phosphate, sorbitol, glycine, etc.),
It can be mixed with lubricants (magnesium stearate, talc, polyethylene glycol, silica, etc.) and disintegrants (potato starch, etc.) and taken in the form of powder, granules, tablets, or capsules, and is administered orally. This is desirable. However, it is of course not limited to this, and parenteral administration is also possible. For example, there is also the possibility of administration as a suppository using an oily base such as cocoa butter, polyethylene glycol, lanolin, or fatty acid triglyceride.
成人を治療する場合の投与量は、−日当たり0.01〜
2.0g、好ましくは0.1〜1.5gで、−日1〜3
回投薬されるが、年齢、体重、症状などにより投与量が
増減する。The dosage for treating adults is -0.01 per day to
2.0g, preferably 0.1-1.5g, -days 1-3
The drug is administered in multiple doses, but the dosage may vary depending on age, weight, symptoms, etc.
[実施例(試験例、毒性試験、実施例、製剤例)〕以下
、本発明の化合物の抗高脂血作用試験例、合成例、およ
び製剤例を記述した。なお、本発明はこれらによって限
定されるものではない。[Examples (Test Examples, Toxicity Tests, Examples, Formulation Examples)] Below, antihyperlipidemic effect test examples, synthesis examples, and formulation examples of the compounds of the present invention are described. Note that the present invention is not limited to these.
試験例1.急性毒性
ddY系マウス(一群5匹)を用いて検体のCMC懸濁
液を経口投与して、3日後の生死により象、性毒性値を
求めた。実施例2.15および23の本発明化合物は、
300■/kgを経口投与しても、死亡率は0%であっ
た。Test example 1. The CMC suspension of the specimen was orally administered to acutely toxic ddY mice (5 mice per group), and the sexual toxicity value was determined based on whether they were alive or dead after 3 days. The compounds of the invention of Examples 2.15 and 23 are
Even when 300 μ/kg was orally administered, the mortality rate was 0%.
試験例2.リピッドエマルジゴン投与高脂血症ラットに
おける作用
4a令の雄性SD系ラットを一群5〜6匹とし、毎日午
前10時に薬物を0.5%CMC懸濁液として4.0m
l/kgずつ、薬物投与量が300 mg/kgとなる
ように経口投与し、30分後指肪乳濁液(コレステロー
ル22.5g、コール酸ナトリウム10g1シヨ糖90
g、オリーブオイル150gに水を加え、全量300m
1とした混合乳濁液)をラット当たり2.5ml経口投
与した。3日間の試験期間中この他ラット用固形飼料を
自由に与えた。Test example 2. Effect of Lipid Emuldigone Administration on Hyperlipidemic Rats A group of 5 to 6 male SD rats aged 4a were administered the drug as a 0.5% CMC suspension at 10 am every day.
The drug was orally administered at a dose of 300 mg/kg, and after 30 minutes, a finger emulsion (22.5 g of cholesterol, 10 g of sodium cholate, 90 g of sucrose,
g, add water to 150g of olive oil, total volume 300m
2.5 ml of the mixed emulsion (mixed emulsion 1) was orally administered to each rat. In addition, chow for rats was given ad libitum during the 3-day test period.
一夜絶食後、翌朝工大静脈から採血し、血清中の総コレ
ステロールとトリグリセライドを定■した。コントロー
ル群には、脂肪乳濁液とCMC水溶液のみを与えた。After an overnight fast, blood was collected from the vena cava the next morning, and serum total cholesterol and triglyceride were determined. The control group received only the fat emulsion and CMC aqueous solution.
血清中のコレステロールは和光純薬製コレステロール測
定キット(コレステロールC−テストフコ−)を用いて
渭1定した。トリグリセライドは和光純薬製トリグリセ
ライド測定キット(トリグリセライドCテストワコー)
を用いて測定した。Cholesterol in serum was determined using a cholesterol measurement kit (Cholesterol C-Test Fuco) manufactured by Wako Pure Chemical Industries. For triglyceride, use Wako Pure Chemical's triglyceride measurement kit (Triglyceride C Test Wako)
Measured using
以下の記述においてはコレステロールをChol。In the following description, cholesterol is referred to as Chol.
トリグリセライドをTGと略記する。Triglyceride is abbreviated as TG.
**Chol低下率は、次式により算出した。**Chol reduction rate was calculated using the following formula.
A:コントロール群の血清Chol量(mg/a)B:
本発明化合物投与群の血清Chol量(mg/dり*)
kTG低下率は、次式により算出した。A: Serum Chol amount of control group (mg/a) B:
Serum Chol amount (mg/d*) of the group administered with the compound of the present invention
The kTG reduction rate was calculated using the following formula.
Carントロール群の血清TGffi (mg/dl)
D:本発明化合物投与群の血清TGffl (mg/C
Iり試験結果を表1に示した。(以下、余白)表1.
ピラゾロ(4,3−d)ピリミジン誘導体の抗高脂血
作用
23 NHCl1tCOtEt
−51−2524HELM −19−35
150Cill+s−n −21−2330”
C+1Hs3峠 NHCll2COIEt −16−
64〃−C(Me)x−COzEt Of(−13−
405N CIhC,II、 011
−4 −619 Ca1ls n−C+z
llzs Oll −3−468〃−C
(Me)z−COzEt OH−13−40” C1
5lhff”リルイル(Iinoleyl)実施例1.
2−メチル−3−リルイルオキシ−7−ヒドロキシー
ピラゾ口(4,3−d)ピリミジン
2−メチル−3,7−シヒドロキシーピラゾロ〔4,3
−d)ピリミジン16.6g(0,1モル)をジメチル
スルホキシド100mj!に懸濁させ、更にトリエチル
アミン20.2g(0,2モル)を加えて均一溶液とし
た。窒素雰囲気下で80°Cに加熱し、撹拌しながらリ
ルイルトシレート46.2g(0゜11モル)を滴下し
た。更に80°Cで4.5時間加熱撹拌した。薄層クロ
マトグラフィーで原料トシレートの消失を確認後、反応
液を氷冷し、クロロホルム、食塩水、希塩酸水を加えて
、溶液のpHを2とした。クロロホルム層を水洗後、無
水硫酸マグネシウムで脱水した。溶媒をエバポレータ、
ついで真空ポンプで減圧留去し、残留オイルをメタノー
ルから再結晶した。淡褐色粉末、20.4g(49,5
%)、再結晶母液について溶媒を留去し、シリカゲルカ
ラムクロマトグラフィーにかけることにより(溶離液;
ベンゼン−酢酸エチル)、更に6.6g(16%)の目
的物を得た。Serum TGffi (mg/dl) of Car control group
D: Serum TGffl (mg/C
The test results are shown in Table 1. (Hereafter, blank space) Table 1.
Antihyperlipidemic effect of pyrazolo(4,3-d)pyrimidine derivatives 23 NHCl1tCOtEt
-51-2524HELM -19-35 150Cill+s-n -21-2330"
C+1Hs3 Pass NHCll2COIEt -16-
64〃-C(Me)x-COzEtOf(-13-
405N CIhC, II, 011
-4 -619 Ca1ls n-C+z
llzs Oll -3-468〃-C
(Me)z-COzEt OH-13-40” C1
5lhff”Iinoleyl Example 1.
2-Methyl-3-lylyloxy-7-hydroxy-pyrazo(4,3-d)pyrimidine 2-methyl-3,7-hydroxy-pyrazolo[4,3
-d) 16.6 g (0.1 mol) of pyrimidine and 100 mj of dimethyl sulfoxide! 20.2 g (0.2 mol) of triethylamine was added to form a homogeneous solution. The mixture was heated to 80°C under a nitrogen atmosphere, and 46.2 g (0°11 mol) of rillyl tosylate was added dropwise while stirring. The mixture was further heated and stirred at 80°C for 4.5 hours. After confirming the disappearance of the raw material tosylate by thin layer chromatography, the reaction solution was cooled with ice, and chloroform, brine, and dilute hydrochloric acid were added to adjust the pH of the solution to 2. After washing the chloroform layer with water, it was dehydrated with anhydrous magnesium sulfate. evaporator the solvent,
The residue was then distilled off under reduced pressure using a vacuum pump, and the remaining oil was recrystallized from methanol. Light brown powder, 20.4 g (49.5
%), the recrystallization mother liquor was distilled off from the solvent and subjected to silica gel column chromatography (eluent;
Benzene-ethyl acetate), and further obtained 6.6 g (16%) of the desired product.
ps+r(CDCII s中)
δppm ; 11.58 (br、s、IH,OR
)、 7.68 (s、III。ps+r (in CDCII s) δppm; 11.58 (br, s, IH, OR
), 7.68 (s, III.
pyrimidin−11)、 5.42〜5.25
(m、4H)。pyrimidin-11), 5.42-5.25
(m, 4H).
4.75 (t、211.J=6Hz)、 3.88
(s、311)。4.75 (t, 211.J=6Hz), 3.88
(s, 311).
2.4〜1.15 (m、2411)、 0.96〜0
.76(m、3H)
実施例2.2−メチル−3−n−ヘキサデシルオキシ−
7−ヒドロキシ−ピラゾロ〔
4,3−d)ピリミジン
実施例1においてリルイルトシレートのかわりにn−ヘ
キサデシルトシレートを用い実施例1と同様に反応、処
理して表記化合物を得た。収率94.9%、白色粉末、
mp’ 133−134.5°Cp酊スペクトル(CD
Cl s中)
δ(ppm);11.67 (m、LH)、 7.71
(s、LH)、 4.75 (t。2.4-1.15 (m, 2411), 0.96-0
.. 76(m, 3H) Example 2.2-Methyl-3-n-hexadecyloxy-
7-Hydroxy-pyrazolo[4,3-d)pyrimidine In Example 1, n-hexadecyl tosylate was used instead of lylyl tosylate, and the reaction and treatment were carried out in the same manner as in Example 1 to obtain the title compound. Yield 94.9%, white powder,
mp' 133-134.5°Cp drunkenness spectrum (CD
Cl s) δ (ppm); 11.67 (m, LH), 7.71
(s, LH), 4.75 (t.
2H,0CHz、J=6flz)、3.89 (s、3
!I、N−C11s)。2H, 0CHz, J=6flz), 3.89 (s, 3
! I, N-C11s).
0.7〜2.1 (n+、 3111)MS(m/e)
;390 (M”)、166 (M”−C+611iz
)実施例3. 2−メチル−3−エトキシー7−ヒドロ
キシ−ピラゾロ(4,3−d)ピリミジン
合成例1o(方法Aとする)
実施例1のリルイルトシレートのかわりにエチル硫酸を
用い、実施例と同様に反応させて目的物を得た。収率1
5%。0.7-2.1 (n+, 3111) MS (m/e)
;390 (M”), 166 (M”-C+611iz
) Example 3. 2-Methyl-3-ethoxy7-hydroxy-pyrazolo(4,3-d)pyrimidine Synthesis Example 1o (method A) Using ethyl sulfate instead of lylyl tosylate in Example 1, the same procedure as in Example 1 was carried out. The target product was obtained by reaction. Yield 1
5%.
合成例2.(方法Bとする)
2−メチル−3−ヒドロキシ−7−エチルチオーピラゾ
ロ(4,3−d)ピリミジンをジメチルホルムアミド溶
液中で炭酸カリウム存在下に60°Cで加熱することに
より得られた反応混合物をシリカゲルカラムクロマトグ
ラフィーにより分離し、2−メチル−3−エトキシ−7
−エチルチオーピラゾロ(4,3−d)ピリミジンを得
た。mp 250°C(分解)。Synthesis example 2. (Method B) 2-Methyl-3-hydroxy-7-ethylthiopyrazolo(4,3-d)pyrimidine is obtained by heating at 60°C in the presence of potassium carbonate in a dimethylformamide solution. The reaction mixture was separated by silica gel column chromatography, and 2-methyl-3-ethoxy-7
-Ethylthiopyrazolo(4,3-d)pyrimidine was obtained. mp 250°C (decomposition).
得られた7−ニチルチオ体0.46’ gを氷酢酸5m
lにとかし、30%過酸化水素水を0.5mff1加え
、室温で2日間放置した。FIJiクロマトグラフィー
で原料が消失したことを確認した°後、水を加え、クロ
ロホルムで抽出した。クロロホルム層を硫酸マグネシウ
ムで乾燥後、乾固、メタノールから再結晶することによ
り無色の結晶を得た。0.25g(64%)
mp 255〜257°C
pmrスペクトル(CDCI 、中)
δ(ppm);8.31 (s、IH)、 4.93
(q、2H,J=711z)、 4.64(q、 21
1.J=7tlz)、 3.93 (s、311)、
1.52(t。0.46' g of the obtained 7-nitylthio compound was added to 5 m of glacial acetic acid.
1 of 30% hydrogen peroxide was added thereto, and the mixture was left at room temperature for 2 days. After confirming that the raw materials had disappeared by FIJi chromatography, water was added and the mixture was extracted with chloroform. The chloroform layer was dried over magnesium sulfate, dried to dryness, and recrystallized from methanol to obtain colorless crystals. 0.25g (64%) mp 255-257°C pmr spectrum (CDCI, middle) δ (ppm); 8.31 (s, IH), 4.93
(q, 2H, J=711z), 4.64(q, 21
1. J=7tlz), 3.93 (s, 311),
1.52 (t.
3H,J=7tlz)、 1.51 (t、3H,J=
7tlz)MS(m/e);222 (M”)、194
(M”−Cztli)、166 (M”−C!114
x2)
実施例4.2−メチル−3−(1−メチル−1−エトキ
シカルボニル−エトキシ)−
7−ヒドロキシ−ピラゾロC4,3−d )ピリミジン
合成例1. (方法A)
2−メチル−3,7−シヒドロキシーピラゾロピリミジ
ン13.28 g (0,08モル)をジメチルスルホ
キシド280mj!にとかし、無水の粉末炭酸カリとエ
チルブロモイソブチレート18 g (0,092モル
)を加えかきまぜながら2日間60に加熱した。その後
塩酸水を加えて酸性とし、クロロホルムにより抽出した
。クロロホルム層を水洗した後、無水硫酸マグネシウム
で乾燥し、さらに活性炭処理した。溶媒を留去した後、
残留オイルにアセトンを加えふりまぜることにより結晶
化した。粗結晶をアセトンから再結晶することにより純
粋な標記化合物を得た。3H, J=7tlz), 1.51 (t, 3H, J=
7tlz) MS (m/e); 222 (M”), 194
(M”-Cztli), 166 (M”-C!114
x2) Example 4.2-Methyl-3-(1-methyl-1-ethoxycarbonyl-ethoxy)-7-hydroxy-pyrazoloC4,3-d) Pyrimidine Synthesis Example 1. (Method A) 13.28 g (0.08 mol) of 2-methyl-3,7-cyhydroxy-pyrazolopyrimidine was added to 280 mj of dimethyl sulfoxide! Then, anhydrous powdered potassium carbonate and 18 g (0,092 mol) of ethyl bromoisobutyrate were added and heated to 60°C for 2 days with stirring. Thereafter, the mixture was made acidic by adding aqueous hydrochloric acid, and extracted with chloroform. The chloroform layer was washed with water, dried over anhydrous magnesium sulfate, and further treated with activated carbon. After distilling off the solvent,
The residual oil was crystallized by adding acetone and stirring. The pure title compound was obtained by recrystallizing the crude crystals from acetone.
mp 161〜162℃
pmrスペクトル(CDCl W中)
δppm ; 11.44 (br、s、IH)、 7
.72 (s、18)、 4.23(q、 211.J
=7Hz)、 3.95 (s、3H)、 1.78(
s。mp 161-162°C PMR spectrum (in CDCl W) δppm; 11.44 (br, s, IH), 7
.. 72 (s, 18), 4.23 (q, 211.J
=7Hz), 3.95 (s, 3H), 1.78(
s.
6H)、 1.25 (t、3H,J=7Hz)合成例
2.(方法B)
下記のpmrスペクトルを示した2−メチル−3−(l
−メチル−1−エトキシカルボニル−エトキシ)−7−
エチルチオーピラゾロ[4,3−d)ピリミジン
pmrスペクトル(CDC123中)
δppm ;8,50 (s、111)、 4.23
(q、2H,J=7Hz)。6H), 1.25 (t, 3H, J=7Hz) Synthesis Example 2. (Method B) 2-Methyl-3-(l
-methyl-1-ethoxycarbonyl-ethoxy)-7-
Ethylthiopyrazolo[4,3-d)pyrimidine PMR spectrum (in CDC123) δppm; 8,50 (s, 111), 4.23
(q, 2H, J=7Hz).
4.02(s、3H)、 3.37 (q、2H,J=
7Hz)、 1.83(s、6H)、 1.46 (t
、3H,J−7tlz)、 1.23 (t。4.02 (s, 3H), 3.37 (q, 2H, J=
7Hz), 1.83 (s, 6H), 1.46 (t
, 3H, J-7tlz), 1.23 (t.
3H,J・7Hz)
を実施例3の合成例2と同様の酢酸、過酸イヒ水素法に
より目的物を得た。収率75%
実施例5〜11゜
実施例1〜4と同様にして方法Aあるし)番よ方法Bに
より表2に示した化合物を得た・
(以下、余白)
9 Ph n−C+ tllzs
MS(m/e) : 381 (M’15) 、22
6 (M”−C+ Jlza)実施例12.2−メチル
−3−リルイルオキシ=7−クロロ−ピラゾロ(4,3
−d)ピリミジン
2−メチル−3−リルイルオキシ−7−ヒドロキシーピ
ラゾロ(4,3−d)ピリミジン4.97gをオキシ塩
化リン30gに懸濁させ、窒素雰囲気下で90°Cに加
熱撹拌した。約10分で溶解し、淡褐色の溶液となった
後、更に3時間加熱撹拌した。薄層クロマトグラフで原
料の消失を確認後、真空ポンプでオキシ塩化リンを減圧
留去し、残留オイルをクロロホルム抽出した。食塩水で
洗浄後無水硫酸マグネシウムで脱水した。溶媒をエバポ
レーター、次いで真空ポンプで減圧留去し、残留オイル
をヘキサン溶液とし、活性炭処理を行なった。溶媒をエ
バポレーター、次いで真空ポンプで減圧留去し褐色オイ
ルの目的物を4.91 g (94,6%)得た。3H,J・7Hz) was subjected to the same acetic acid/hydrogen peroxide method as in Synthesis Example 2 of Example 3 to obtain the desired product. Yield: 75% Examples 5 to 11 The compounds shown in Table 2 were obtained using Method A or Method B in the same manner as Examples 1 to 4.
MS (m/e): 381 (M'15), 22
6 (M”-C+ Jlza) Example 12.2-Methyl-3-lylyloxy 7-chloro-pyrazolo(4,3
-d) Pyrimidine 4.97 g of 2-methyl-3-lylyloxy-7-hydroxy-pyrazolo(4,3-d) pyrimidine was suspended in 30 g of phosphorus oxychloride, and the mixture was heated and stirred at 90°C under a nitrogen atmosphere. . After dissolving in about 10 minutes and becoming a light brown solution, the mixture was heated and stirred for an additional 3 hours. After confirming the disappearance of the raw materials using thin layer chromatography, phosphorus oxychloride was distilled off under reduced pressure using a vacuum pump, and the remaining oil was extracted with chloroform. After washing with saline, it was dehydrated with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure using an evaporator and then a vacuum pump, and the remaining oil was made into a hexane solution and treated with activated carbon. The solvent was distilled off under reduced pressure using an evaporator and then a vacuum pump to obtain 4.91 g (94.6%) of the desired product as a brown oil.
pmrスペクトル(CDCf 、中)
δ(ppm);8.51 (s、111)、 5.2〜
5.5 (m、 411) 、 4.93(t、28,
0CI(z、J=6Hz)、 4.02(s、3!(、
N−C84)。pmr spectrum (CDCf, medium) δ (ppm); 8.51 (s, 111), 5.2 ~
5.5 (m, 411), 4.93 (t, 28,
0CI(z, J=6Hz), 4.02(s, 3!(,
N-C84).
0.7 〜2.9 (+n、27H)MS(m/e)
;432 (M”)、 184(M”−C+5H3
z)実施例13.2−メチル−3−n−ヘキサデシルオ
キシ−7−クロロ−ピラゾロ(4,3−d〕ピリミジン
実施例12における2−メチル−3−リルイルオキシ−
7−ヒドロキシーピラゾロ(4,3−d)ピリミジンの
かわりに2−メチル−3−n−ヘキサデシルオキシ−ピ
ラゾロ(4,3−d)ピリミジンを用い実施例12と同
様に反応処理して目的物を得た。収率96.3%、白色
結晶 mp 64−66°Cpmrスペクトル(CDC
I!、中)
δ(ppm);8.51 (s、IH)、 4.93
(t、2H,0Ctlz、J=6Hz)。0.7 ~ 2.9 (+n, 27H) MS (m/e)
;432 (M”), 184 (M”-C+5H3
z) Example 13. 2-Methyl-3-n-hexadecyloxy-7-chloro-pyrazolo(4,3-d]pyrimidine 2-methyl-3-lylyloxy- in Example 12
The reaction was carried out in the same manner as in Example 12 using 2-methyl-3-n-hexadecyloxy-pyrazolo(4,3-d)pyrimidine instead of 7-hydroxy-pyrazolo(4,3-d)pyrimidine. Obtained the object. Yield 96.3%, white crystals mp 64-66°Cpmr spectrum (CDC
I! , medium) δ (ppm); 8.51 (s, IH), 4.93
(t, 2H, 0Ctlz, J=6Hz).
4.02(s、311.N−CHz)、0.7〜2.1
(m、318)MS(m/e);408 (M’)、
184(M”−C+Jzz)実施例14.2−メチル
−3〔1−メチル−1−エトキシカルボニル−エトキシ
)−7
−クロロ−ピラゾロ(4,3−d)ピリミジン
2−メチル−3−(1−メチル−1−エトキシカルボニ
ル−エトキシ)−7−ヒトロキシービラゾロ(4,3−
d)ピリミジン1gをオキシ塩化リン5 ml中に加え
、更にジエチルアニリン1 mlを加えた。70°Cで
4時間加熱撹拌した後、オキシ塩化リン、ジエチルアニ
リンを留去した。残留オイルに氷水とクロロホルムを加
えふりまぜた後、クロロホルム層を分離水洗した。乾燥
、活性炭処理後溶媒を留去し、残留した黒褐色オイルを
ヘキサンから再結晶することにより無色針状結晶を得た
。4.02 (s, 311.N-CHz), 0.7-2.1
(m, 318) MS (m/e); 408 (M'),
184(M”-C+Jzz) Example 14.2-Methyl-3[1-methyl-1-ethoxycarbonyl-ethoxy)-7-chloro-pyrazolo(4,3-d)pyrimidine 2-methyl-3-(1 -methyl-1-ethoxycarbonyl-ethoxy)-7-hydroxyvirazolo(4,3-
d) 1 g of pyrimidine was added to 5 ml of phosphorus oxychloride, followed by 1 ml of diethylaniline. After heating and stirring at 70°C for 4 hours, phosphorus oxychloride and diethylaniline were distilled off. After adding ice water and chloroform to the residual oil and shaking it, the chloroform layer was separated and washed with water. After drying and treatment with activated carbon, the solvent was distilled off, and the remaining dark brown oil was recrystallized from hexane to obtain colorless needle crystals.
収率75%
mp 93〜94°C
pmrスペクトル(CDC1、中)
δppn+ ;8.52 (s、IH)、 4.23
(q、2H,J=7t(z)、4.10(s、3H)、
1.85 (s、6H)、1.23 (t、311.J
=7tlz)実施例15.2−メチル−3−ヘキサデシ
ルオキシ−7−ヘキシルオキシ−ピラゾロ
(4,3−d )ピリミジン
n−ヘキサノール5gに金属ナトリウム83mgを溶解
したものを室温下で撹拌した。これに、2−メチル−3
−ヘキサデシルオキシ−7−クロロピラゾロ(4,3−
d)ピリミジン1.23 gを加え、室温下で3時間撹
拌した。薄層クロマトグラフィーで原料の消失を確認後
、真空ポンプにて過剰のヘキサノールを減圧留去した。Yield 75% mp 93-94°C pmr spectrum (CDC1, medium) δppn+; 8.52 (s, IH), 4.23
(q, 2H, J=7t(z), 4.10(s, 3H),
1.85 (s, 6H), 1.23 (t, 311.J
=7tlz) Example 15. 2-Methyl-3-hexadecyloxy-7-hexyloxy-pyrazolo(4,3-d)pyrimidine A solution of 83 mg of sodium metal in 5 g of n-hexanol was stirred at room temperature. To this, 2-methyl-3
-hexadecyloxy-7-chloropyrazolo(4,3-
d) 1.23 g of pyrimidine was added and stirred at room temperature for 3 hours. After confirming the disappearance of the raw materials by thin layer chromatography, excess hexanol was distilled off under reduced pressure using a vacuum pump.
残渣をクロロホルム抽出し、水洗後、硫酸マグネシウム
で乾燥した。The residue was extracted with chloroform, washed with water, and then dried over magnesium sulfate.
溶媒を減圧留去して得られた粗生成物をカラムクロマト
グラフィーにかけて、(?容雛液;ベンゼンー酢酸エチ
ル)目的物を単離した。The crude product obtained by evaporating the solvent under reduced pressure was subjected to column chromatography (? volume stock solution; benzene-ethyl acetate) to isolate the desired product.
収率 1.35g(94,9%)、無色粉末 mp 4
3−44.5°C
pmrスペクトル(CDCg 、中)
8.31 (s、LH)、 4.87 (t、2tl、
J=711zL4.56(t、21+、J=7Hz)、
3.96(s、311)、 0.8〜2.1(m、4
21()
MS(m/e); 474(M”)、 250(M”−
C+6H3z)、 166(250−caHt□ν
実施例16.2−メチル−3−(1−メチル−1−エト
キシカルボニル−エトキシ)−
7−(3−ピリジルメチルオキシ)−
ピラゾロ(4,3−d)ピリミジン
3−ヒドロキシメチルピリジン125a+gをテトラヒ
ドロフラン6 ml中に溶かし、氷冷しながらナトリウ
ムヒドリド351■を加えた。生成したゼラチン状態?
Q液に2−メチル−3−(1−メチル−1−エトキシカ
ルボニル−エトキシ)−7−クロロピラゾロ(4,3−
d〕ピリミジン300■を加え、5時間室温で撹拌した
。原料のクロリドが完全に消失ごとを薄層クロマトグラ
フィーで確認した後、溶媒を留去し、クロロホルムと重
ソウ水を加え振りまぜた。クロロホルム層を硫酸マグネ
シウムで乾燥した後、乾固し、残留オイルをカラムクロ
マトグラフィーにかけて(溶離液1〜2%メタノール−
クロロホルム)目的物を単離した。収率1B8mg(5
1%)、無色オイル
pmrスペクトル(CDCl s中)
δ ppm;8.85〜7.35 (m、4fl)、
8.34 (s、LH)、5.68(s、2H) 4.
25 (q、2H,J=711z)、 4.02(s、
311)。Yield 1.35g (94.9%), colorless powder mp 4
3-44.5°C pmr spectrum (CDCg, medium) 8.31 (s, LH), 4.87 (t, 2tl,
J=711zL4.56 (t, 21+, J=7Hz),
3.96 (s, 311), 0.8-2.1 (m, 4
21 () MS (m/e); 474 (M”), 250 (M”-
C+6H3z), 166(250-caHt□ν Example 16.2-Methyl-3-(1-methyl-1-ethoxycarbonyl-ethoxy)-7-(3-pyridylmethyloxy)-pyrazolo(4,3-d ) 125a+g of pyrimidine 3-hydroxymethylpyridine was dissolved in 6ml of tetrahydrofuran, and 351cm of sodium hydride was added while cooling on ice.The gelatin state formed?
2-Methyl-3-(1-methyl-1-ethoxycarbonyl-ethoxy)-7-chloropyrazolo(4,3-
d] 300 μm of pyrimidine was added and stirred at room temperature for 5 hours. After confirming by thin layer chromatography that the raw material chloride had completely disappeared, the solvent was distilled off, and chloroform and sodium hydrogen aqueous solution were added and mixed. After drying the chloroform layer with magnesium sulfate and drying, the remaining oil was subjected to column chromatography (eluent: 1-2% methanol-
(Chloroform) The desired product was isolated. Yield 1B8mg (5
1%), colorless oil PMR spectrum (in CDCl s) δ ppm; 8.85-7.35 (m, 4fl),
8.34 (s, LH), 5.68 (s, 2H) 4.
25 (q, 2H, J=711z), 4.02 (s,
311).
1.83 (s、6H)、 1.24 (t、3t(、
J=BHz)MS(m/e); 37HM”L 298
.257(Base peak)実施例17〜22゜
実施例15と同様にして対応するクロリドとアルコール
あるいはフェノールから表3に示した化合物を合成した
。(以下、余白)
(以下、余白)
実施例23.2−メチル−3−n−ヘキサデシルオキシ
−7−エトキシカルボニルメチ
ルアミノ−ピラゾロ(4,3−d)ピリミジン
ナトリウムヒドリド0.33gをヘキサンで洗浄し、モ
レキュラーシーブ脱水ジメチルホルムアミド10mJに
懸濁させた。これに水冷下、塩酸グリシンエチルエステ
ル1.05gを加え撹拌した。1.83 (s, 6H), 1.24 (t, 3t(,
J=BHz)MS(m/e); 37HM”L 298
.. 257 (Base peak) Examples 17 to 22 In the same manner as in Example 15, the compounds shown in Table 3 were synthesized from the corresponding chloride and alcohol or phenol. (Hereinafter, blank) (Hereinafter, blank) Example 23. 0.33 g of 2-methyl-3-n-hexadecyloxy-7-ethoxycarbonylmethylamino-pyrazolo(4,3-d)pyrimidine sodium hydride in hexane. It was washed and suspended in 10 mJ of molecular sieve dehydrated dimethylformamide. To this was added 1.05 g of glycine ethyl hydrochloride under water cooling, and the mixture was stirred.
更に2−メチル−3−n−ヘキサデシルオキシ−7−ク
ロロ−ピラゾロ(4,3−d)ピリミジン0.61gを
ジメチルホルムアミド10m1に溶解したものを加え室
温下で約1週間撹拌した。薄層クロマトグラフィーで原
料の消失を確認後、反応液にクロロホルム、氷水、希塩
酸を加え液性をpH2とした。クロロホルム層を食塩水
で洗浄し、硫酸マグネシウムで乾燥後、溶媒を留去し、
残留オイルをシリカゲルりロマトグラフィーにかけて(
?容離ン夜2%メタノール−クロロホルム)、粗目的物
を単離した。更に、ヘキサンで再結晶する事により目的
物を得た。収率0.56g(78,6%)、淡黄色粉末
、mp 60−63°C
pmrスペクトル(CDCI! x中)δppm ;
8.1B (s、1tl)、 6.1〜6.4 (m、
III)、 4.80(t、2H,J=6Hz)、4.
3−4.5 (m、2H)、 4.24(q、2H,J
=711z)、 3.88 (s、3H)、 0.5〜
2.0 (m、34H)
MS(m/e);475(M”)、 372(M”−N
HzCIIzCOJt)、251(M”−C+bHzz
)+ 180
実施例24.2−メチル−3−n−ヘキサデシルオキシ
−7−ジエチルアミノ−ピラゾ
ロ(4,3−d)ピリミジン
ナトリウムヒドリド0.76gをヘキサンで洗浄し、モ
レキュラーシーブ脱水ジメチルホルムアミド10mfに
懸濁させた。これに塩酸ジエチルアミン1.37gを加
え氷冷した。2−メチル−3−n−ヘキサデシルオキシ
−7−クロロ−ピラゾロ(4,3−d )ピリミジン1
.02gをジメチルホルムアミド20mj2に溶解させ
たものを加え、室温下で撹拌した。約2.5時間後、薄
層クロマトグラフィーで原料のクロリドが完全に消失し
たことを確認後、反応液にクロロホルムと氷水を加え分
液した。クロロホルム層を水洗し、硫酸マグネシウムで
乾燥した後、溶媒を留去し、残留オイルをシリカゲルカ
ラムクロマトグラフィーにかけて(?容離液ベンゼンー
酢酸エチル)目的物を単離した。Furthermore, a solution of 0.61 g of 2-methyl-3-n-hexadecyloxy-7-chloro-pyrazolo(4,3-d)pyrimidine dissolved in 10 ml of dimethylformamide was added, and the mixture was stirred at room temperature for about one week. After confirming the disappearance of the raw materials by thin layer chromatography, chloroform, ice water, and dilute hydrochloric acid were added to the reaction solution to adjust the pH to 2. The chloroform layer was washed with brine, dried over magnesium sulfate, and the solvent was distilled off.
The residual oil was chromatographed on silica gel (
? The crude target product was isolated by distillation (2% methanol-chloroform). Furthermore, the desired product was obtained by recrystallizing with hexane. Yield 0.56 g (78,6%), pale yellow powder, mp 60-63 °C pmr spectrum (in CDCI! x) δppm;
8.1B (s, 1tl), 6.1~6.4 (m,
III), 4.80 (t, 2H, J=6Hz), 4.
3-4.5 (m, 2H), 4.24 (q, 2H, J
=711z), 3.88 (s, 3H), 0.5~
2.0 (m, 34H) MS (m/e); 475 (M"), 372 (M"-N
HzCIIzCOJt), 251(M”-C+bHz
) + 180 Example 24. 0.76 g of 2-methyl-3-n-hexadecyloxy-7-diethylamino-pyrazolo(4,3-d) pyrimidine sodium hydride was washed with hexane and added to 10 mf of molecular sieve dehydrated dimethylformamide. suspended. 1.37 g of diethylamine hydrochloride was added to this and cooled on ice. 2-Methyl-3-n-hexadecyloxy-7-chloro-pyrazolo(4,3-d)pyrimidine 1
.. A solution of 02 g of 0.02 g dissolved in 20 mj2 of dimethylformamide was added, and the mixture was stirred at room temperature. After about 2.5 hours, it was confirmed by thin layer chromatography that the raw material chloride had completely disappeared, and then chloroform and ice water were added to the reaction solution to separate the reaction mixture. After washing the chloroform layer with water and drying over magnesium sulfate, the solvent was distilled off, and the remaining oil was subjected to silica gel column chromatography (eluent: benzene-ethyl acetate) to isolate the desired product.
収率 0.81g (72,8%)、無色粉末、mp3
9−40 ’(pmrスペクトル(CDCl 3中)
δppm ;8.20 (s、LH)、 4.80 (
t、2H,J=611z)、3.7〜4.2 (m、4
H)、 3.87(s、3H)、 0.7〜2.0(m
、 37H)
MS(m/e);445(M”)、 220M”−C+
aLz)実施例23と同様にして相当するクロリドとア
ミン類から表4に示した化合物を得た。Yield 0.81g (72.8%), colorless powder, mp3
9-40' (pmr spectrum (in CDCl3) δppm; 8.20 (s, LH), 4.80 (
t, 2H, J=611z), 3.7-4.2 (m, 4
H), 3.87 (s, 3H), 0.7-2.0 (m
, 37H) MS (m/e); 445 (M"), 220M"-C+
aLz) In the same manner as in Example 23, the compounds shown in Table 4 were obtained from the corresponding chlorides and amines.
(以下、余白)
38 Me −C(門e)gcOJt NlI
C+Jzs−n オイル39 1’le −C(
yle)z%F、t NlIC6111t−n
オイル似下、余白)
実施例40.2−メチル−3−リルイルオキシ−7−メ
ルカブトービラゾロ(4,3−dlピリミジン
2−メチル−3−リルイルオキシ−7−クロロピラゾロ
(4,3−d)ピリミジン0.87gを、モレキュラー
シーブ脱水ジメチルホルムアミド10mflに溶解させ
、氷冷した。これに市販の70%水硫化ソーダ0.32
gを加え、窒素雰囲気下で水冷2時間撹拌した。更に
室温下で2時間撹拌し、薄層クロマトグラフィーで原料
の消失を確認後、反応液にクロロホルム、氷水、希塩酸
水を加えて溶液のpHを2とした。クロロホルム層を水
洗後、無水硫酸マグネシウムで脱水した。溶媒をエバポ
レーター、ついで真空ポンプで減圧留去し、残留オイル
をシリカゲルクロマトグラフィーにかけることにより(
溶離液;ベンゼン−酢酸エチル)褐色のロウ状物質を得
た、更にメタノール再結晶により、黄褐色粉末の目的物
質を0.17g(19,8%)得た。mp 68−7
0℃
実施例41.2−メチル−3−リルイルオキシ−7−メ
ルカプト−ピラゾロ(4,3−d)ピリミジン
2−メチル−3,7−シヒドロキシービラゾロ(4,3
−d)ピリミジン2.07gとローソン試薬1.07g
をモレキュラーシーブ脱水ベンゼン20m1に懸濁した
。窒素雰囲気下で60’Cに加熱撹拌し、約1.5時間
で黄橙色の溶液となった。薄層クロマトグラフで原料の
消失を確認後、反応液を氷冷しクロロホルム、食塩水、
を加えて分液した。(Hereafter, blank space) 38 Me -C (gate e) gcOJt NlI
C+Jzs-n oil 39 1'le -C(
yle)z%F,tNlIC6111t-n
Example 40. 2-Methyl-3-lylyloxy-7-merkabutovirazolo (4,3-dl pyrimidine 2-methyl-3-lylyloxy-7-chloropyrazolo (4,3-d) 0.87 g of pyrimidine was dissolved in 10 mfl of molecular sieve dehydrated dimethylformamide and cooled on ice.To this was added 0.32 g of commercially available 70% sodium bisulfide.
g was added thereto, and the mixture was stirred for 2 hours while cooling with water under a nitrogen atmosphere. After further stirring at room temperature for 2 hours and confirming the disappearance of the raw materials by thin layer chromatography, chloroform, ice water, and dilute hydrochloric acid were added to the reaction solution to adjust the pH of the solution to 2. After washing the chloroform layer with water, it was dehydrated with anhydrous magnesium sulfate. The solvent was removed under reduced pressure using an evaporator and then a vacuum pump, and the remaining oil was subjected to silica gel chromatography (
Eluent: benzene-ethyl acetate) A brown waxy substance was obtained, and recrystallization with methanol yielded 0.17 g (19.8%) of the desired substance as a yellowish brown powder. mp68-7
0°C Example 41.2-Methyl-3-lylyloxy-7-mercapto-pyrazolo(4,3-d)pyrimidine 2-methyl-3,7-cyhydroxy-virazolo(4,3-d)
-d) 2.07g of pyrimidine and 1.07g of Lawson's reagent
was suspended in 20 ml of molecular sieve dehydrated benzene. The mixture was heated and stirred at 60'C under a nitrogen atmosphere to become a yellow-orange solution in about 1.5 hours. After confirming the disappearance of the raw materials using thin layer chromatography, the reaction solution was cooled on ice and mixed with chloroform, brine,
was added and separated.
クロロホルム層を更に食塩水で洗浄した後、無水硫酸マ
グネシウムで脱水した。溶媒をエバポレーターで減圧留
去し、残留ロウ状物質をシリカゲルカラムクロマトグラ
フィーにかけることにより(溶離液;ベンゼン−酢酸エ
チル)、黄色ロウ状の目的物2.01 g (93,5
%)を得た。The chloroform layer was further washed with brine and then dehydrated with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure using an evaporator, and the remaining waxy substance was subjected to silica gel column chromatography (eluent: benzene-ethyl acetate) to obtain 2.01 g (93,5
%) was obtained.
pmrスペクトル(CDCA 、中)
δppm ; 0.6〜2.2 (2511,m、C1
1zX11+CHiX1)。pmr spectrum (CDCA, middle) δppm; 0.6 to 2.2 (2511, m, C1
1zX11+CHiX1).
2.5〜2.8 (2H,m、Ctlz) 、3.93
(3H,s、N−CD5)14.77 (2H1t、
0CIh+J=61(z)、5.1〜5.5 (4H,
m、olef)、 7.75 (IH,s、ring−
II)、15.8〜15.6 (III、broad
m、NH,(千オン型構造を示す))
MS(m/e);430(M+)、 397(M+−5
R)、 183mp 80−84.5°C
実施例42.2−メチル−3−エトキシ−7=(ビス−
メトキシカルボニル−メチル)ピラゾロ(4,3−d)
ピリミジン
2−メチル−3−エトキシ−7−クロロ−ピラゾロ(4
,3−d)ピリミジン440■とジメチルマロネート4
00mgをジメチルホルムアミド10mJに加え均一に
溶解させた。この溶液に水冷下でナトリウムヒドリド5
0mgを加えた後、室温で一昼夜かきまぜた。薄層クロ
マトグラフィーで原料が゛消失したことを確認した後、
クロロホルムと水を加えふりまぜた。クロロホルム層を
水洗した後、硫酸マグネシウムで乾燥し、溶媒を留去、
残留物をシリカゲルクロマトグラフィーにより精製した
。2.5-2.8 (2H, m, Ctlz), 3.93
(3H,s,N-CD5)14.77 (2H1t,
0CIh+J=61(z), 5.1~5.5 (4H,
m, olef), 7.75 (IH, s, ring-
II), 15.8-15.6 (III, broad
m, NH, (indicates a thousand-on type structure)) MS (m/e); 430 (M+), 397 (M+-5
R), 183mp 80-84.5°C Example 42.2-Methyl-3-ethoxy-7=(bis-
methoxycarbonyl-methyl)pyrazolo(4,3-d)
Pyrimidine 2-methyl-3-ethoxy-7-chloro-pyrazolo (4
, 3-d) Pyrimidine 440■ and dimethylmalonate 4
00 mg was added to 10 mJ of dimethylformamide and uniformly dissolved. Add 5 sodium hydride to this solution under water cooling.
After adding 0 mg, the mixture was stirred at room temperature overnight. After confirming that the raw material has disappeared by thin layer chromatography,
Chloroform and water were added and mixed. After washing the chloroform layer with water, drying with magnesium sulfate and distilling off the solvent,
The residue was purified by silica gel chromatography.
(溶離液;0.4%メタノール−クロホルム)白色結晶
、収ffi 140 nv、 mp 194−196
″CplTlrスペクトル(CDCff 3中)δ p
pm ;7.52 (d、LH,J=3Hz)、
4.74(q、2H,J=711z)3.78 (s
、3H)、3.77 (s、3H)、 3.48
(d。(Eluent: 0.4% methanol-chloroform) White crystals, collected ffi 140 nv, mp 194-196
"CplTlr spectrum (in CDCff 3) δ p
pm; 7.52 (d, LH, J=3Hz),
4.74 (q, 2H, J=711z) 3.78 (s
, 3H), 3.77 (s, 3H), 3.48
(d.
11LJ=611z)、 1.44 (t、38.
J=7Hz)実施例43.2−メチル−3−(1−メチ
ル−1−エトキシカルボニル−エトキシ)−
7−ジアツーピラゾロ(4,3−d )ピリミジン
2−メチル−3−(1−メチル−1−エトキシカルボニ
ル−エトキシ)−7−クロロ−ピラゾロ(4,3−d)
ピリミジン300■をジメチルスルホキシド5 mlに
とかし、次いでシアン化ソーダ100■を加えた。室温
で1時間、更に40°Cで30分間かきまぜた後、薄層
クロマトグラフィーで原料の消失を確認した。(原料は
無色で紫外線ランプの照射により青白色螢光を発し、生
成物は黄色スポットで同じく螢光を発する。)反応液に
クロロホルムと食塩水を加え振りまぜた後、クロロホル
ム層を更に水洗、乾燥後、溶媒を完全に留去した。残留
物をカラムクロマトグラフィーにより精製した。黄色オ
イル(徐々に結晶化した。)pmrスペクトル(CDC
j! z中)δppm ; 8.91(s、IH)、
4.20 (q、2H,J=7Hz)、4.13(s、
311)、 1.87(s、611)、 1.21 (
t、31LJ=7[1z)
MS(m/e);289(M”)、 216(M”−C
OzEt)1175(M”−C(Me) zcOzEt
−1) 、 115. 87次に本発明の抗高脂血化合
物を含有する製剤の例を示す。11LJ=611z), 1.44 (t, 38.
J=7Hz) Example 43.2-Methyl-3-(1-methyl-1-ethoxycarbonyl-ethoxy)-7-diatwopyrazolo(4,3-d)pyrimidine 2-methyl-3-(1-methyl-1 -ethoxycarbonyl-ethoxy)-7-chloro-pyrazolo(4,3-d)
300 μm of pyrimidine was dissolved in 5 ml of dimethyl sulfoxide, and then 100 μm of sodium cyanide was added. After stirring at room temperature for 1 hour and further at 40°C for 30 minutes, disappearance of the raw materials was confirmed by thin layer chromatography. (The raw material is colorless and emits blue-white fluorescence when irradiated with an ultraviolet lamp, and the product also emits fluorescence with yellow spots.) After adding chloroform and saline to the reaction solution and shaking, the chloroform layer is further washed with water. After drying, the solvent was completely distilled off. The residue was purified by column chromatography. Yellow oil (slowly crystallized) PMR spectrum (CDC
j! z) δppm; 8.91 (s, IH),
4.20 (q, 2H, J=7Hz), 4.13 (s,
311), 1.87 (s, 611), 1.21 (
t, 31LJ=7[1z) MS (m/e); 289 (M”), 216 (M”-C
OzEt) 1175(M”-C(Me)zcOzEt
-1), 115. 87 Next, examples of formulations containing the antihyperlipidemic compound of the present invention will be shown.
製剤例1z錠剤
成分(4,000錠)
組 成 重 量実施例N11
23(7)化合物 500(g)じゃがいも澱粉
334
カルボキシメチルセルロース 87.5ポリビニルア
ルコール 61
ステアリン酸マグネシウム 17.51.000
上記成分分量を計り、■型混合機に入れ、均一に混合す
る。この混合粉末を直接打錠法で錠剤とした。−錠当た
りの重量は250■であった。Formulation Example 1z Tablet components (4,000 tablets) Composition Weight Example N11
23(7) Compound 500 (g) Potato starch 334 Carboxymethylcellulose 87.5 Polyvinyl alcohol 61 Magnesium stearate 17.51.000 Weigh the amounts of the above ingredients, put them in a type mixer, and mix them uniformly. This mixed powder was made into tablets by direct compression. -The weight per tablet was 250 μ.
製剤例2:軟カプセル剤
成分(1,000カプセル)
組 成 重 量
実施例階23の化合物 250(g)オリーブ油
250
上記成分分量を計り、均一に混合し、500mgずつ軟
カプセルに充填、乾燥した。Formulation Example 2: Soft capsule ingredients (1,000 capsules) Composition Weight Compound of Example 23 250 (g) Olive oil
250 The amounts of the above ingredients were measured, mixed uniformly, filled into soft capsules of 500 mg each, and dried.
製剤例3:顆粒剤
成分(1,000包)
組 成 重 量実施例隘23
の化合物 10100(無水ケイ酸
80
結晶セルロース 180
乳糖 130
ステアリン酸マグネシウム 10
上記成分分量を計り、均一に混合した後、顆粒とし、−
色光たり500■となるように分包した。Formulation example 3: Granule ingredients (1,000 packets) Composition Weight Example 23
Compound 10100 (silicic anhydride
80 Crystalline Cellulose 180 Lactose 130 Magnesium Stearate 10 Weigh out the amounts of the above ingredients, mix them uniformly, make them into granules, and -
It was divided into 500 square bags.
製剤例4:坐剤
成分(1,000個)
組成 重量
実施例11m23の化合物 200 (g)カカ
オ脂 1.000
1.200
上記成分分量を計り、38°Cで均一に融解させ、予め
僅かに冷却しておいた坐剤鋳型へ注いだ。Formulation example 4: Suppository components (1,000 pieces) Composition Weight Compound of Example 11m23 200 (g) Cocoa butter 1.000 1.200 Weigh out the amounts of the above ingredients, melt them uniformly at 38°C, and add a little Pour into cooled suppository molds.
坐剤1個当たりの重量は1.2gであった。The weight of each suppository was 1.2 g.
特許出願人 日産化学工業株式会社Patent applicant: Nissan Chemical Industries, Ltd.
Claims (10)
ェニル基、または低級アルキル基、低級アルコキシ基ま
たはハロゲン原子で置換されたフェニル基を示し、R^
2は炭素数2から20の飽和または不飽和の、直鎖状ま
たは分岐鎖状脂肪族基、フェニル低級アルキル基、フェ
ニル基が低級アルキル基、低級アルコキシ基またはハロ
ゲン原子で置換されたフェニル低級アルキル基またはA
CO_2R^3(Aは置換されていない、または炭素数
1から3のアルキル基によって置換されたメチレン鎖数
1から3のアルキレンを示し、R^3は炭素数1から4
の低級アルキル基を示す。)を示し、XはOR^4(R
^4は炭素数1から20までの直鎖状または分岐鎖状脂
肪族基、フェニル基、低級アルキル基、低級アルコキシ
基またはハロゲン原子で置換されたフェニル基、ACO
_2R^3(A、R^3は前述と同意味である)、ピリ
ジルメチル基または低級アルキル基で置換されたピリジ
ルメチル基を示す。)、SH、NR^5R^6(R^5
、R^6はそれぞれ水素原子、低級アルキル基、フェニ
ル基、低級アルキル基または低級アルコキシ基で置換さ
れたフェニル基またはBCO_2R^7(Bは置換され
ていない、またはメチル基、エチル基、プロピル基、ブ
チル基またはイソブチル基によって置換されたメチレン
鎖数1から3のアルキレン基を示し、R^7は水素原子
、低級アルキル基を示す。)を示す。)、シアノ基、塩
素原子、臭素原子、沃素原子またはHCR^8R^9(
R^8、R^9はそれぞれシアノ基または炭素数1から
4の低級アルキルオキシカルボニル 基を示す。)を示す。〕により表されるピラゾロ〔4,
3−d〕ピリミジン誘導体。(1) General formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R^1 is an alkyl group with 1 to 4 carbon atoms, a phenyl group, a lower alkyl group, or a lower alkoxy group. or a phenyl group substituted with a halogen atom, R^
2 is a saturated or unsaturated linear or branched aliphatic group having 2 to 20 carbon atoms, a phenyl lower alkyl group, a phenyl lower alkyl group in which the phenyl group is substituted with a lower alkyl group, a lower alkoxy group, or a halogen atom; group or A
CO_2R^3 (A is unsubstituted or substituted with an alkyl group having 1 to 3 carbon atoms and has 1 to 3 methylene chains; R^3 is an alkylene group having 1 to 4 carbon atoms;
represents a lower alkyl group. ), and X is OR^4(R
^4 is a linear or branched aliphatic group having 1 to 20 carbon atoms, a phenyl group, a lower alkyl group, a lower alkoxy group, or a phenyl group substituted with a halogen atom, ACO
_2R^3 (A and R^3 have the same meanings as above), which represents a pyridylmethyl group or a pyridylmethyl group substituted with a lower alkyl group. ), SH, NR^5R^6 (R^5
, R^6 is a hydrogen atom, a lower alkyl group, a phenyl group, a phenyl group substituted with a lower alkyl group or a lower alkoxy group, or BCO_2R^7 (B is unsubstituted, or a methyl group, ethyl group, propyl group) , represents an alkylene group having 1 to 3 methylene chains substituted with a butyl group or an isobutyl group, and R^7 represents a hydrogen atom or a lower alkyl group). ), cyano group, chlorine atom, bromine atom, iodine atom or HCR^8R^9(
R^8 and R^9 each represent a cyano group or a lower alkyloxycarbonyl group having 1 to 4 carbon atoms. ) is shown. ] pyrazolo [4,
3-d] pyrimidine derivative.
ェニル基、または低級アルキル基、低級アルコキシ基ま
たはハロゲン原子で置換されたフェニル基を示し、R^
2は炭素数2から20の飽和または不飽和の、直鎖状ま
たは分岐鎖状脂肪族基、フェニル低級アルキル基、フェ
ニル基が低級アルキル基、低級アルコキシ基またはハロ
ゲン原子で置換されたフェニル低級アルキル基、ACO
_2R^3(Aは置換されていない、または炭素数1か
ら3のアルキル基によって置換されたメチレン鎖数1か
ら3のアルキレンを示し、R^3は炭素数1から4の低
級アルキル基を示す。)を示し、XはOR^4(R^4
は炭素数1から20までの直鎖状または分岐鎖状脂肪族
基、フェニル基、低級アルキル基、低級アルコキシ基ま
たはハロゲン原子で置換されたフェニル基、ACO_2
R^3(A、R^3は前述と同意味である)、ピリジル
メチル基または低級アルキル基で置換されたピリジルメ
チル基を示す。)、SH、NR^5R^6(R^5、R
^6はそれぞれ水素原子、低級アルキル基、フェニル基
、低級アルキル基あるいは低級アルコキシ基で置換され
たフェニル基またはBCO_2R^7(Bは置換されて
いない、またはメチル基、エチル基、プロピル基、ブチ
ル基、イソブチル基によって置換されたメチレン鎖数1
から3のアルキレンを示し、R^7は水素原子、低級ア
ルキル基を示す)を示す。)、シアノ基、塩素原子、臭
素原子、沃素原子またはHCR^8R^9(R^8、R
^9はそれぞれシアノ基または炭素数1から4の低級ア
ルキルオキシカルボニル基を示す。)を示す。〕により
表されるピラゾロ〔4,3−d〕ピリミジン誘導体の一
種以上を含有することを特徴とする抗高脂血剤。(2) General formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R^1 is an alkyl group with 1 to 4 carbon atoms, a phenyl group, a lower alkyl group, or a lower alkoxy group. or a phenyl group substituted with a halogen atom, R^
2 is a saturated or unsaturated linear or branched aliphatic group having 2 to 20 carbon atoms, a phenyl lower alkyl group, a phenyl lower alkyl group in which the phenyl group is substituted with a lower alkyl group, a lower alkoxy group, or a halogen atom; Group, ACO
_2R^3 (A represents an alkylene having 1 to 3 methylene chains that is unsubstituted or substituted with an alkyl group having 1 to 3 carbon atoms, and R^3 represents a lower alkyl group having 1 to 4 carbon atoms. ), and X is OR^4(R^4
is a linear or branched aliphatic group having 1 to 20 carbon atoms, a phenyl group, a lower alkyl group, a lower alkoxy group, or a phenyl group substituted with a halogen atom, ACO_2
R^3 (A and R^3 have the same meanings as above) represents a pyridylmethyl group or a pyridylmethyl group substituted with a lower alkyl group. ), SH, NR^5R^6 (R^5, R
^6 is a hydrogen atom, a lower alkyl group, a phenyl group, a phenyl group substituted with a lower alkyl group or a lower alkoxy group, or BCO_2R^7 (B is unsubstituted, or a methyl group, ethyl group, propyl group, butyl group) 1 methylene chain substituted by isobutyl group
3 represents alkylene, and R^7 represents a hydrogen atom or a lower alkyl group). ), cyano group, chlorine atom, bromine atom, iodine atom or HCR^8R^9 (R^8, R
^9 each represents a cyano group or a lower alkyloxycarbonyl group having 1 to 4 carbon atoms. ) is shown. ] An antihyperlipidemic agent characterized by containing one or more pyrazolo[4,3-d]pyrimidine derivatives represented by the following.
ェニル基、または低級アルキル基、低級アルコキシ基ま
たはハロゲン原子で置換されたフェニル基を示す。〕で
表わされるピラゾロ〔4,3−d〕ピリミジン誘導体を
塩基の存在下、R^2Y(Yはハロゲン原子、低級アル
キルスルホニルオキシ、無置換または任意に置換された
フェニルスルホニルオキシなどの脱離基を示し、R^2
は炭素数2から20の飽和または不飽和の、直鎖状また
は分岐鎖状脂肪族基、フェニル低級アルキル基、フェニ
ル基が低級アルキル基、低級アルコキシ基またはハロゲ
ン原子で置換されたフェニル低級アルキル基またはAC
O_2R^3(Aは置換されていない、または炭素数1
から3のアルキル基によって置換されたメチレン鎖数1
から3のアルキレンを示し、R^3は炭素数1から4の
低級アルキル基を示す。)を示す。 〕を反応させることを特徴とする、一般式( I −(X
=OH)) ▲数式、化学式、表等があります▼( I −(X=OH
)) 〔式中、R^1、R^2は前述と同意味である。〕で表
わされるピラゾロ〔4,3−d〕ピリミジン誘導体の製
造法。(3) General formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (II) [In the formula, R^1 is an alkyl group with 1 to 4 carbon atoms, a phenyl group, a lower alkyl group, or a lower alkoxy group. Or it represents a phenyl group substituted with a halogen atom. ] in the presence of a base, R^2Y (Y is a leaving group such as a halogen atom, lower alkylsulfonyloxy, unsubstituted or optionally substituted phenylsulfonyloxy) and R^2
is a saturated or unsaturated linear or branched aliphatic group having 2 to 20 carbon atoms, a phenyl lower alkyl group, a phenyl lower alkyl group in which the phenyl group is substituted with a lower alkyl group, a lower alkoxy group, or a halogen atom. or AC
O_2R^3 (A is unsubstituted or has 1 carbon number
1 methylene chain substituted by 3 alkyl groups
to 3 alkylene, and R^3 represents a lower alkyl group having 1 to 4 carbon atoms. ) is shown. ] is reacted with the general formula (I − (X
=OH)) ▲There are mathematical formulas, chemical formulas, tables, etc.▼( I −(X=OH
)) [In the formula, R^1 and R^2 have the same meanings as above. ] A method for producing a pyrazolo[4,3-d]pyrimidine derivative.
)) 〔式中、R^1は炭素数1から4までのアルキル基、フ
ェニル基、または低級アルキル基、低級アルコキシ基ま
たはハロゲン原子で置換されたフェニル基を示し、R^
2は炭素数2から20の飽和または不飽和の、直鎖状ま
たは分岐鎖状脂肪族基、フェニル低級アルキル基、フェ
ニル基が低級アルキル基、低級アルコキシ基またはハロ
ゲン原子で置換されたフェニル低級アルキル基またはA
CO_2R^3(Aは置換されていない、または炭素数
1から3のアルキル基によって置換されたメチレン鎖数
1から3のアルキレンを示し、R^3は炭素数1から4
の低級アルキル基を示す。)を示す。〕で表わされるピ
ラゾロ〔4,3−d〕ピリミジン誘導体に各種ハロゲン
化剤を作用させることによる一般式( I −(X=Ha
l)) ▲数式、化学式、表等があります▼( I −(X=Ha
l)) 〔式中、R^1、R^2は前述と同意味であり、Hal
はハロゲン原子を示す、〕で表わされるピラゾロ〔4,
3−d〕ピリミジン誘導体の製造法。(4) General formula ( I − (X=OH)) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( I − (X=OH)
)) [In the formula, R^1 represents an alkyl group having 1 to 4 carbon atoms, a phenyl group, a lower alkyl group, a lower alkoxy group, or a phenyl group substituted with a halogen atom, and R^
2 is a saturated or unsaturated linear or branched aliphatic group having 2 to 20 carbon atoms, a phenyl lower alkyl group, a phenyl lower alkyl group in which the phenyl group is substituted with a lower alkyl group, a lower alkoxy group, or a halogen atom; group or A
CO_2R^3 (A is unsubstituted or substituted with an alkyl group having 1 to 3 carbon atoms and has 1 to 3 methylene chains; R^3 is an alkylene group having 1 to 4 carbon atoms;
represents a lower alkyl group. ) is shown. ] By reacting various halogenating agents to the pyrazolo[4,3-d]pyrimidine derivative represented by the general formula ( I -(X=Ha
l)) ▲There are mathematical formulas, chemical formulas, tables, etc.▼( I − (X=Ha
l)) [In the formula, R^1 and R^2 have the same meanings as above, and Hal
represents a halogen atom, pyrazolo[4,
3-d] Method for producing a pyrimidine derivative.
l)) 〔式中、R^1は炭素数1から4までのアルキル基、フ
ェニル基、または低級アルキル基、低級アルコキシ基ま
たはハロゲン原子で置換されたフェニル基を示し、R^
2は炭素数2から20の飽和または不飽和の、直鎖状ま
たは分岐鎖状脂肪族基、フェニル低級アルキル基、フェ
ニル基が低級アルキル基、低級アルコキシ基またはハロ
ゲン原子で置換されたフェニル低級アルキル基またはA
CO_2R^3(Aは置換されていない、または炭素数
1から3のアルキル基によって置換されたメチレン鎖数
1から3のアルキレンを示し、R^3は炭素数1から4
のアルキル基を意味する。)を意味する。〕で表わされ
るピラゾロ〔4,3−d〕ピリミジン誘導体にHNR^
5R^6(R^5、R^6はそれぞれ水素原子、低級ア
ルキル基、フェニル基、低級アルキル基または低級アル
コキシ基で置換されたフェニル基またはBCO_2R^
7(Bは置換されていない、またはメチル基、エチル基
、プロピル基、ブチル基、イソブチル基によって置換さ
れたメチレン鎖数1から3のアルキレンを示し、R^7
は水素原子、低級アルキル基を示す。)を示す。)で表
わされるアミンを反応させることによる一般式 I −(
X=NR^5R^6)▲数式、化学式、表等があります
▼( I −(X=NR^5R^6)) 〔式中、R^1、R^2、R^5、R^6は前述と同意
味である。〕で表わされるピラゾロ〔4,3−d〕ピリ
ミジン誘導体の製造法。(5) General formula ( I − (X=Hal)) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( I − (X = Ha
l)) [In the formula, R^1 represents an alkyl group having 1 to 4 carbon atoms, a phenyl group, a lower alkyl group, a lower alkoxy group, or a phenyl group substituted with a halogen atom, and R^
2 is a saturated or unsaturated linear or branched aliphatic group having 2 to 20 carbon atoms, a phenyl lower alkyl group, a phenyl lower alkyl group in which the phenyl group is substituted with a lower alkyl group, a lower alkoxy group, or a halogen atom; group or A
CO_2R^3 (A is unsubstituted or substituted with an alkyl group having 1 to 3 carbon atoms and has 1 to 3 methylene chains; R^3 is an alkylene group having 1 to 4 carbon atoms;
means an alkyl group. ) means. ] HNR^ to the pyrazolo[4,3-d]pyrimidine derivative represented by
5R^6 (R^5 and R^6 are each a hydrogen atom, a lower alkyl group, a phenyl group, a phenyl group substituted with a lower alkyl group or a lower alkoxy group, or BCO_2R^
7 (B represents an alkylene having 1 to 3 methylene chains that is unsubstituted or substituted with a methyl group, ethyl group, propyl group, butyl group, or isobutyl group, R^7
represents a hydrogen atom or a lower alkyl group. ) is shown. ) by reacting the amine represented by the general formula I −(
X=NR^5R^6) ▲There are mathematical formulas, chemical formulas, tables, etc.▼( I - (X=NR^5R^6)) [In the formula, R^1, R^2, R^5, R^6 has the same meaning as above. ] A method for producing a pyrazolo[4,3-d]pyrimidine derivative.
l)) 〔式中、R^1は炭素数1から4までのアルキル基、フ
ェニル基、または低級アルキル基、低級アルコキシ基ま
たはハロゲン原子で置換されたフェニル基を示し、R^
2は炭素数2から20の飽和または不飽和の、直鎖状ま
たは分岐鎖状脂肪族基、フェニル低級アルキル基、フェ
ニル基が低級アルキル基、低級アルコキシ基またはハロ
ゲン原子で置換されたフェニル低級アルキル基またはA
CO_2R^3(Aは置換されていない、または炭素数
1から3のアルキル基によって置換されたメチレン鎖数
1から3のアルキレンを示し、R^3は炭素数1から4
のアルキル基を意味する。)を意味する。〕で表わされ
るピラゾロ〔4,3−d〕ピリミジン誘導体に、塩基の
存在下、R^4OH(R^4は炭素数1から20までの
直鎖状または分岐鎖状脂肪族基、フェニル基、低級アル
キル基、低級アルコキシ基またはハロゲン原子で置換さ
れたフェニル基、ACO_2R^3(A、R^3は前述
と同意味である。)、ピリジルメチル基または低級アル
キル基で置換されたピリジルメチル基を示す。)で表わ
されるアルコール類またはフェノール類を反応させるこ
とを特徴とする一般式( I −(X=OR^4)) ▲数式、化学式、表等があります▼( I −(X=OR
^4)) 〔式中、R^1、R^2、R^4は上述と同意味である
。〕で表わされるピラゾロ〔4,3−d〕ピリミジン誘
導体の製造法。(6) General formula ( I - (X=Hal)) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( I - (X = Ha
l)) [In the formula, R^1 represents an alkyl group having 1 to 4 carbon atoms, a phenyl group, a lower alkyl group, a lower alkoxy group, or a phenyl group substituted with a halogen atom, and R^
2 is a saturated or unsaturated linear or branched aliphatic group having 2 to 20 carbon atoms, a phenyl lower alkyl group, a phenyl lower alkyl group in which the phenyl group is substituted with a lower alkyl group, a lower alkoxy group, or a halogen atom; group or A
CO_2R^3 (A is unsubstituted or substituted with an alkyl group having 1 to 3 carbon atoms and has 1 to 3 methylene chains; R^3 is an alkylene group having 1 to 4 carbon atoms;
means an alkyl group. ) means. ] to the pyrazolo[4,3-d]pyrimidine derivative represented by R^4OH (R^4 is a linear or branched aliphatic group having 1 to 20 carbon atoms, a phenyl group, Lower alkyl group, lower alkoxy group or phenyl group substituted with a halogen atom, ACO_2R^3 (A and R^3 have the same meanings as above), pyridylmethyl group or pyridylmethyl group substituted with a lower alkyl group ▲There are mathematical formulas, chemical formulas, tables, etc.▼( I - (X=OR
^4)) [In the formula, R^1, R^2, and R^4 have the same meanings as above. ] A method for producing a pyrazolo[4,3-d]pyrimidine derivative.
)) 〔式中、R^1は炭素数1から4までのアルキル基、フ
ェニル基、または低級アルキル基、低級アルコキシ基ま
たはハロゲン原子で置換されたフェニル基を示し、R^
2は炭素数2から20の飽和または不飽和の、直鎖状ま
たは分岐鎖状脂肪族基、フェニル低級アルキル基、フェ
ニル基が低級アルキル基、低級アルコキシ基またはハロ
ゲン原子で置換されたフェニル低級アルキル基またはA
CO_2R^3(Aは置換されていない、または炭素数
1から3のアルキル基によって置換されたメチレン鎖数
1から3のアルキレンを示し、R^3は炭素数1から4
のアルキル基を意味する。)を意味する。〕で表わされ
るピラゾロ〔4,3−d〕ピリミジン誘導体に五二硫化
リンあるいはいわゆるローソン試薬と呼ばれる硫化剤を
反応させることを特徴とする一般式( I −(X=SH
)) ▲数式、化学式、表等があります▼( I −(X=SH
) 〔式中、R^1、R^2は前述と同意味である。〕で表
わされるピラゾロ〔4,3−d〕ピリミジン誘導体の製
造法。(7) General formula I - (X=OH) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( I - (X=OH
)) [In the formula, R^1 represents an alkyl group having 1 to 4 carbon atoms, a phenyl group, a lower alkyl group, a lower alkoxy group, or a phenyl group substituted with a halogen atom, and R^
2 is a saturated or unsaturated linear or branched aliphatic group having 2 to 20 carbon atoms, a phenyl lower alkyl group, a phenyl lower alkyl group in which the phenyl group is substituted with a lower alkyl group, a lower alkoxy group, or a halogen atom; group or A
CO_2R^3 (A is unsubstituted or substituted with an alkyl group having 1 to 3 carbon atoms and has 1 to 3 methylene chains; R^3 is an alkylene group having 1 to 4 carbon atoms;
means an alkyl group. ) means. ] The pyrazolo[4,3-d]pyrimidine derivative represented by the general formula (I - (X=SH
)) ▲There are mathematical formulas, chemical formulas, tables, etc.▼( I −(X=SH
) [In the formula, R^1 and R^2 have the same meanings as above. ] A method for producing a pyrazolo[4,3-d]pyrimidine derivative.
l)) 〔式中、R^1は炭素数1から4までのアルキル基、フ
ェニル基、または低級アルキル基、低級アルコキシ基ま
たはハロゲン原子で置換されたフェニル基を示し、R^
2は炭素数2から20の飽和または不飽和の、直鎖状ま
たは分岐鎖状脂肪族基、フェニル低級アルキル基、フェ
ニル基が低級アルキル基、低級アルコキシ基またはハロ
ゲン原子で置換されたフェニル低級アルキル基またはA
CO_2R^3(Aは置換されていない、または炭素数
1から3のアルキル基によって置換されたメチレン鎖数
1から3のアルキレンを示し、R^3は炭素数1から4
のアルキル基を意味する。)を示し、Halはハロゲン
原子を示す。〕で表わされるピラゾロ〔4,3−d〕ピ
リミジン誘導体に水硫化ソーダ、水硫化カリを反応させ
ることを特徴とする一般式( I −(X=SH)) ▲数式、化学式、表等があります▼( I −(X=SH
)) 〔式中、R^1、R^2は前述と同意味である。〕で表
わされるピラゾロ〔4,3−d〕ピリミジン誘導体の製
造法。(8) General formula ( I − (X=Hal)) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( I − (X = Ha
l)) [In the formula, R^1 represents an alkyl group having 1 to 4 carbon atoms, a phenyl group, a lower alkyl group, a lower alkoxy group, or a phenyl group substituted with a halogen atom, and R^
2 is a saturated or unsaturated linear or branched aliphatic group having 2 to 20 carbon atoms, a phenyl lower alkyl group, a phenyl lower alkyl group in which the phenyl group is substituted with a lower alkyl group, a lower alkoxy group, or a halogen atom; group or A
CO_2R^3 (A is unsubstituted or substituted with an alkyl group having 1 to 3 carbon atoms and has 1 to 3 methylene chains; R^3 is an alkylene group having 1 to 4 carbon atoms;
means an alkyl group. ), and Hal represents a halogen atom. General formula characterized by reacting a pyrazolo[4,3-d]pyrimidine derivative represented by ] with sodium bisulfide and potassium bisulfide (I - (X=SH)) ▲ Contains mathematical formulas, chemical formulas, tables, etc. ▼(I −(X=SH
)) [In the formula, R^1 and R^2 have the same meanings as above. ] A method for producing a pyrazolo[4,3-d]pyrimidine derivative.
l)) 〔式中、R^1は炭素数1から4までのアルキル基、フ
ェニル基、または低級アルキル基、低級アルコキシ基ま
たはハロゲン原子で置換されたフェニル基を示し、R^
2は炭素数2から20の飽和または不飽和の、直鎖状ま
たは分岐鎖状脂肪族基、フェニル低級アルキル基、フェ
ニル基が低級アルキル基、低級アルコキシ基またはハロ
ゲン原子で置換されたフェニル低級アルキル基またはA
CO_2R^3(Aは置換されていない、または炭素数
1から3のアルキル基によって置換されたメチレン鎖数
1から3のアルキレンを示し、R^3は炭素数1から4
のアルキル基を意味する。)を示し、Halはハロゲン
原子を示す。〕で表わされるピラゾロ〔4,3−d〕ピ
リミジン誘導体にシアン化カリ、シアン化ソーダを反応
させることを特徴とする一般式( I −(X=CN)) ▲数式、化学式、表等があります▼( I −(X=CN
)) 〔式中、R^1、R^2は前述と同意味である。〕で表
わされるピラゾロ〔4,3−d)ピリミジン誘導体の製
造法。(9) General formula ( I - (X=Hal)) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( I - (X = Ha
l)) [In the formula, R^1 represents an alkyl group having 1 to 4 carbon atoms, a phenyl group, a lower alkyl group, a lower alkoxy group, or a phenyl group substituted with a halogen atom, and R^
2 is a saturated or unsaturated linear or branched aliphatic group having 2 to 20 carbon atoms, a phenyl lower alkyl group, a phenyl lower alkyl group in which the phenyl group is substituted with a lower alkyl group, a lower alkoxy group, or a halogen atom; group or A
CO_2R^3 (A is unsubstituted or substituted with an alkyl group having 1 to 3 carbon atoms and has 1 to 3 methylene chains; R^3 is an alkylene group having 1 to 4 carbon atoms;
means an alkyl group. ), and Hal represents a halogen atom. ] A general formula characterized by reacting a pyrazolo[4,3-d]pyrimidine derivative with potassium cyanide and sodium cyanide (I - (X=CN)) ▲Contains mathematical formulas, chemical formulas, tables, etc. ▼(I −(X=CN
)) [In the formula, R^1 and R^2 have the same meanings as above. ] A method for producing a pyrazolo[4,3-d)pyrimidine derivative.
l)) 〔式中、R^1は炭素数1から4までのアルキル基、フ
ェニル基、または低級アルキル基、低級アルコキシ基ま
たはハロゲン原子で置換されたフェニル基を示し、R^
2は炭素数2から20の飽和または不飽和の、直鎖状ま
たは分岐鎖状脂肪族基、フェニル低級アルキル基、フェ
ニル基が低級アルキル基、低級アルコキシ基またはハロ
ゲン原子で置換されたフェニル低級アルキル基またはA
CO_2R^3(Aは置換されていない、または炭素数
1から3のアルキル基によって置換されたメチレン鎖数
1から3のアルキレンを示し、R^3は炭素数1から4
のアルキル基を意味する。)を示し、Halはハロゲン
原子を示す。〕で表わされるピラゾロ〔4,3−d〕ピ
リミジン誘導体に、水素原子を活性化する能力のある塩
基(例えば、ナトリウムヒドリドまたはナトリウムアル
コキシド等)の存在下、H_2CR^8R^9(R^8
、R^9はそれぞれシアノ基、炭素数1から4の低級ア
ルキルオキシカルボニル基を示す。)で表される活性メ
チレン化合物を反応させることを特徴とする一般式(
I −(X=HCR^8R^9))▲数式、化学式、表等
があります▼( I −(X=HCR^8R^9)) 〔式中、R^1、R^2、R^8およびR^9は前述と
同意味である。〕で表わされるピラゾロ〔4,3−d〕
ピリミジン誘導体の製造法。(10) General formula (I - (X=Hal)) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I - (X=Ha
l)) [In the formula, R^1 represents an alkyl group having 1 to 4 carbon atoms, a phenyl group, a lower alkyl group, a lower alkoxy group, or a phenyl group substituted with a halogen atom, and R^
2 is a saturated or unsaturated linear or branched aliphatic group having 2 to 20 carbon atoms, a phenyl lower alkyl group, a phenyl lower alkyl group in which the phenyl group is substituted with a lower alkyl group, a lower alkoxy group, or a halogen atom; group or A
CO_2R^3 (A is unsubstituted or substituted with an alkyl group having 1 to 3 carbon atoms and has 1 to 3 methylene chains; R^3 is an alkylene group having 1 to 4 carbon atoms;
means an alkyl group. ), and Hal represents a halogen atom. ] H_2CR^8R^9 (R^8
, R^9 represent a cyano group and a lower alkyloxycarbonyl group having 1 to 4 carbon atoms, respectively. ) is characterized by reacting an active methylene compound represented by the general formula (
I - (X=HCR^8R^9)) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( I - (X = HCR^8R^9)) [In the formula, R^1, R^2, R^8 and R^9 have the same meanings as above. ] pyrazolo [4,3-d]
Method for producing pyrimidine derivatives.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP62081578A JPS63246377A (en) | 1987-04-02 | 1987-04-02 | Pyrazolopyrimidines |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP62081578A JPS63246377A (en) | 1987-04-02 | 1987-04-02 | Pyrazolopyrimidines |
Publications (1)
Publication Number | Publication Date |
---|---|
JPS63246377A true JPS63246377A (en) | 1988-10-13 |
Family
ID=13750190
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP62081578A Pending JPS63246377A (en) | 1987-04-02 | 1987-04-02 | Pyrazolopyrimidines |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS63246377A (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006126718A1 (en) * | 2005-05-27 | 2006-11-30 | Tanabe Seiyaku Co., Ltd. | Pyrazolopyrimidine derivative |
-
1987
- 1987-04-02 JP JP62081578A patent/JPS63246377A/en active Pending
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006126718A1 (en) * | 2005-05-27 | 2006-11-30 | Tanabe Seiyaku Co., Ltd. | Pyrazolopyrimidine derivative |
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