JPH0528719B2 - - Google Patents
Info
- Publication number
- JPH0528719B2 JPH0528719B2 JP28005784A JP28005784A JPH0528719B2 JP H0528719 B2 JPH0528719 B2 JP H0528719B2 JP 28005784 A JP28005784 A JP 28005784A JP 28005784 A JP28005784 A JP 28005784A JP H0528719 B2 JPH0528719 B2 JP H0528719B2
- Authority
- JP
- Japan
- Prior art keywords
- purine
- pyridyl
- piperazinyl
- methyl
- melting point
- 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.)
- Expired - Lifetime
Links
- -1 1-pyrrolidinylmethyl Chemical group 0.000 claims description 39
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 150000002431 hydrogen Chemical group 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 claims description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000005505 thiomorpholino group Chemical group 0.000 claims description 2
- 125000000561 purinyl group Chemical class N1=C(N=C2N=CNC2=C1)* 0.000 claims 1
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 68
- 238000002844 melting Methods 0.000 description 52
- 230000008018 melting Effects 0.000 description 52
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 150000001875 compounds Chemical class 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- 150000003212 purines Chemical class 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 description 4
- 230000003110 anti-inflammatory effect Effects 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 230000000202 analgesic effect Effects 0.000 description 3
- 230000001754 anti-pyretic effect Effects 0.000 description 3
- 239000002221 antipyretic Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 235000008504 concentrate Nutrition 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 229920000137 polyphosphoric acid Polymers 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 3
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-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
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000003266 anti-allergic effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000002158 endotoxin Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 229920006008 lipopolysaccharide Polymers 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000004570 mortar (masonry) Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 229940083251 peripheral vasodilators purine derivative Drugs 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 125000006030 1-methyl-3-butenyl group Chemical group 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- RLQZIECDMISZHS-UHFFFAOYSA-N 2-phenylcyclohexa-2,5-diene-1,4-dione Chemical compound O=C1C=CC(=O)C(C=2C=CC=CC=2)=C1 RLQZIECDMISZHS-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 1
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- ZZLCFHIKESPLTH-UHFFFAOYSA-N 4-Methylbiphenyl Chemical compound C1=CC(C)=CC=C1C1=CC=CC=C1 ZZLCFHIKESPLTH-UHFFFAOYSA-N 0.000 description 1
- SXIFAEWFOJETOA-UHFFFAOYSA-N 4-hydroxy-butyl Chemical group [CH2]CCCO SXIFAEWFOJETOA-UHFFFAOYSA-N 0.000 description 1
- BYVYXBSURBOLSI-UHFFFAOYSA-N 4-n,4-n-diethylpyrimidine-4,5,6-triamine Chemical compound CCN(CC)C1=NC=NC(N)=C1N BYVYXBSURBOLSI-UHFFFAOYSA-N 0.000 description 1
- ABTLCEHFUKRNJG-UHFFFAOYSA-N 6-(4-methylpiperazin-1-yl)-2-phenylpyrimidine-4,5-diamine Chemical compound C1CN(C)CCN1C1=NC(C=2C=CC=CC=2)=NC(N)=C1N ABTLCEHFUKRNJG-UHFFFAOYSA-N 0.000 description 1
- INSCOECCGXYLOS-UHFFFAOYSA-N 6-(4-methylpiperazin-1-yl)pyrimidine-4,5-diamine Chemical compound C1CN(C)CCN1C1=NC=NC(N)=C1N INSCOECCGXYLOS-UHFFFAOYSA-N 0.000 description 1
- BTEXVXIBCAQRES-UHFFFAOYSA-N 6-methylsulfanyl-8-pyridin-4-yl-7h-purine Chemical compound N1C=2C(SC)=NC=NC=2N=C1C1=CC=NC=C1 BTEXVXIBCAQRES-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- DEVFVVLSBJSUNB-UHFFFAOYSA-N 7h-purine;hydrochloride Chemical compound Cl.N1=CNC2=NC=NC2=C1 DEVFVVLSBJSUNB-UHFFFAOYSA-N 0.000 description 1
- GDGONIPBXFORCU-UHFFFAOYSA-N 8-pyridin-4-yl-7H-purine Chemical compound c1cc(ccn1)-c1nc2ncncc2[nH]1 GDGONIPBXFORCU-UHFFFAOYSA-N 0.000 description 1
- 208000000104 Arthus reaction Diseases 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 241000588832 Bordetella pertussis Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 208000009386 Experimental Arthritis Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 206010018367 Glomerulonephritis chronic Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- YDFRXRVSVNGWLE-UHFFFAOYSA-N N1=CC=C(C=C1)C1=NC=C2NC=NC2=N1 Chemical compound N1=CC=C(C=C1)C1=NC=C2NC=NC2=N1 YDFRXRVSVNGWLE-UHFFFAOYSA-N 0.000 description 1
- 206010030124 Oedema peripheral Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 206010053614 Type III immune complex mediated reaction Diseases 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 108010093894 Xanthine oxidase Proteins 0.000 description 1
- 102100033220 Xanthine oxidase Human genes 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000003529 anticholesteremic agent Substances 0.000 description 1
- 229940125716 antipyretic agent Drugs 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 description 1
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 description 1
- 201000001155 extrinsic allergic alveolitis Diseases 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000005067 haloformyl group Chemical group 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 208000022098 hypersensitivity pneumonitis Diseases 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- UEXOHHQENZNYBY-UHFFFAOYSA-N n,n-diethyl-2-methyl-8-pyridin-4-yl-7h-purin-6-amine Chemical compound N1C=2C(N(CC)CC)=NC(C)=NC=2N=C1C1=CC=NC=C1 UEXOHHQENZNYBY-UHFFFAOYSA-N 0.000 description 1
- OBUNQEAKJSQBAM-UHFFFAOYSA-N n-ethyl-8-pyridin-4-yl-7h-purin-6-amine Chemical compound N1C=2C(NCC)=NC=NC=2N=C1C1=CC=NC=C1 OBUNQEAKJSQBAM-UHFFFAOYSA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 229920006316 polyvinylpyrrolidine 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
- 238000011160 research Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 206010040400 serum sickness Diseases 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000829 suppository 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
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】
産業上の利用分野
本発明は、新規かつ医薬として有用なプリン誘
導体に関する。DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to novel and pharmaceutically useful purine derivatives.
従来の技術
英国特許第1201997号明細書には、抗腫瘍活性
を有する８−（２−，３−，および４−ピリジン）
プリン化合物が、Journal of Medicinal
Chemistry，vol.11，p.656，1968には、キサンチ
ンオキシダーゼ阻害作用を有する８−フエニルア
デニン化合物が、ベルギー特許第737949号明細書
には、低コレステロール血症剤として有用な９−
プリニルヒドロキシアルカン酸誘導体が開示され
ている。Prior Art British Patent No. 1201997 discloses that 8-(2-, 3-, and 4-pyridine) has antitumor activity.
Purine compounds have been published in the Journal of Medicinal
Chemistry, vol. 11, p. 656, 1968 describes the 8-phenyladenine compound which has a xanthine oxidase inhibitory effect, and Belgian Patent No. 737949 describes the 9-phenyladenine compound useful as a hypocholesterolemic agent.
Purinylhydroxyalkanoic acid derivatives are disclosed.
しかしながら、これらを含む先行技術には、抗
炎症、鎮痛、解熱作用、抗アレルギー作用、血小
板凝集抑制作用を有するプリン誘導体は知られて
いない。 However, in the prior art including these, purine derivatives having anti-inflammatory, analgesic, antipyretic, anti-allergic, and platelet aggregation-inhibiting effects are not known.
従つて、本発明の目的は抗炎症、鎮痛、解熱作
用、抗アレルギー作用、血小板凝集抑制作用を有
する新規プリン誘導体を提供することである。 Therefore, an object of the present invention is to provide a novel purine derivative having anti-inflammatory, analgesic, antipyretic, anti-allergic, and platelet aggregation-inhibiting effects.
問題点を解決するための手段
本発明者らは、上記の点に鑑み、鋭意研究を重
ねた結果、本発明を完成した。すなわち、本発明
は一般式
で表わされるプリン誘導体またはその医薬上許容
しうる酸付加塩に関し、当該プリン誘導体はその
水和物をも含むものである。Means for Solving the Problems In view of the above points, the present inventors have completed the present invention as a result of extensive research. That is, the present invention is based on the general formula With regard to the purine derivative represented by the formula or its pharmaceutically acceptable acid addition salt, the purine derivative also includes its hydrate.
上記一般式（）中、Ｒは水素、アルキルまた
は置換基としてハロゲン、低級アルキルもしくは
低級アルコキシの少なくとも１個以上を有してい
てもよいフエニルを示し、R1、R2は同一または
異なつて、水素、アルキル、シクロアルキル、ヒ
ドロキシアルキル、ジアルキルアミノアルキル、
１−ピロジニルメチル、２−（１−ピロリジニル）
エチル、２−ピペリジノエチル、２−モルホリノ
エチル、３−チオモルホリノプロピル、２−（１
−ピペラジニル）エチル、２−（４−メチル−１
−ピペラジニル）エチル、２−〔４−（２−ヒドロ
キシエチル）−１−ピペラジニル〕エチル、２−
（４−メチル−１−ホモピペラジニル）エチル、
アルケニルまたはアラルキルを示すか、R1、R2
が隣接する窒素原子と結合して１−ピロリジニ
ル、ピペリジノ、１−ピペラジニル、４−メチル
−１−ピペラジニル、４−エチル−１−ピペラジ
ニル、４−（２−ヒドロキシエチル）−１−ピペラ
ジニル、１−ホモピペラジニル、４−メチル−１
−ホモピペラジニル、モルホリノ、チオモルホリ
ノを形成する基を示し、R3、R4は同一または異
なつて、水素または低級アルキルを示す。 In the above general formula (), R represents hydrogen, alkyl, or phenyl which may have at least one of halogen, lower alkyl, or lower alkoxy as a substituent, and R 1 and R 2 are the same or different, Hydrogen, alkyl, cycloalkyl, hydroxyalkyl, dialkylaminoalkyl,
1-pyrrolidinylmethyl, 2-(1-pyrrolidinyl)
Ethyl, 2-piperidinoethyl, 2-morpholinoethyl, 3-thiomorpholinopropyl, 2-(1
-piperazinyl)ethyl, 2-(4-methyl-1
-piperazinyl)ethyl, 2-[4-(2-hydroxyethyl)-1-piperazinyl]ethyl, 2-
(4-methyl-1-homopiperazinyl)ethyl,
Represents alkenyl or aralkyl, R 1 , R 2
is bonded to the adjacent nitrogen atom to form 1-pyrrolidinyl, piperidino, 1-piperazinyl, 4-methyl-1-piperazinyl, 4-ethyl-1-piperazinyl, 4-(2-hydroxyethyl)-1-piperazinyl, 1- Homopiperazinyl, 4-methyl-1
- Represents a group forming homopiperazinyl, morpholino, or thiomorpholino, and R 3 and R 4 are the same or different and represent hydrogen or lower alkyl.
本明細書において、アルキルとは炭素数１〜８
個の直鎖状または分枝状のアルキルを意味し、た
とえば、メチル、エチル、プロピル、イソプロピ
ル、ブチル、イソブチル、第３級ブチル、ペンチ
ル、ヘキシル、オクチルがあげられる。ハロゲン
は、フツ素、塩素、臭素、ヨウ素を意味する。低
級アルキルは炭素数１〜４個の直鎖状または分枝
状のアルキルを意味し、たとえば、メチル、エチ
ル、プロピル、イソプロピル、ブチル、イソブチ
ル、第３級ブチルがあげられる。低級アルコキシ
とは炭素数１〜４個の直鎖状または分枝状のアル
コキシを意味し、たとえば、メトキシ、エトキ
シ、プロポキシ、イソプロポキシ、ブトキシ、第
３級ブトキシがあげられる。シクロアルキルとは
炭素数３〜７個の環状飽和炭化水素基であり、シ
クロプロピル、シクロブチル、シクロペンチル、
シクロヘキシル、シクロヘプチルがあげられる。
ヒドロキシアルキルとはアルキル部分の炭素数が
１〜８個であり、たとえば、２−ヒドロキシエチ
ル、２−ヒドロキシプロピル、３−ヒドロキシプ
ロピル、４−ヒドロキシブチルがあげられる。ジ
アルキルアミノアルキルとは各アルキル部分の炭
素数が１〜８個であり、たとえば、２−ジメチル
アミノエチル、２−ジエチルアミノエチル、３−
ジメチルアミノプロピル、４−ジメチルアミノブ
チルなどがあげられる。アルケニルとは炭素数１
〜８個の直鎖状または分枝状のアルケニルを意味
し、たとえば、ビニル、アリル、イソプロペニ
ル、ブテニル、ペンテニル、１−メチル−３−ブ
テニル、ヘキセニルがあげられる。アラルキルと
はアリールアルキルを意味し、たとえばベンジ
ル、２−フエニルエチル、３−フエニルプロピル
があげられる。 In this specification, alkyl means carbon number 1 to 8.
It means straight-chain or branched alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and octyl. Halogen means fluorine, chlorine, bromine, and iodine. Lower alkyl means a straight or branched alkyl having 1 to 4 carbon atoms, and includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tertiary butyl. Lower alkoxy means a straight or branched alkoxy having 1 to 4 carbon atoms, and includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tertiary butoxy. Cycloalkyl is a cyclic saturated hydrocarbon group having 3 to 7 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl,
Examples include cyclohexyl and cycloheptyl.
Hydroxyalkyl has 1 to 8 carbon atoms in the alkyl moiety, and includes, for example, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, and 4-hydroxybutyl. Dialkylaminoalkyl has 1 to 8 carbon atoms in each alkyl moiety, for example, 2-dimethylaminoethyl, 2-diethylaminoethyl, 3-diethylaminoethyl.
Examples include dimethylaminopropyl and 4-dimethylaminobutyl. Alkenyl has 1 carbon number
It means a linear or branched alkenyl having ~8 members, such as vinyl, allyl, isopropenyl, butenyl, pentenyl, 1-methyl-3-butenyl, and hexenyl. Aralkyl means arylalkyl, and includes, for example, benzyl, 2-phenylethyl, and 3-phenylpropyl.
本発明の一般式（）の化合物は、たとえば、
次の方法により製造することができる。 The compound of the general formula () of the present invention is, for example,
It can be manufactured by the following method.
(1) 一般式
（式中、各記号は前記と同義である）
で表わされる化合物と一般式
式中、Ｘはカルボキシル、低級アルコキシカル
ボニル、シアノ、ハロホルミルまたはチオアミド
を示し、R4は前記と同義である）
で表わされる化合物とを反応させる方法。(1) General formula (In the formula, each symbol has the same meaning as above.) Compounds represented by and general formula (wherein, X represents carboxyl, lower alkoxycarbonyl, cyano, haloformyl or thioamide, and R 4 has the same meaning as above).
反応は、一般式（）の化合物の置換基Ｘの種
類により適宜進行するが、好ましくは、ポリリン
酸、ポリリン酸エステル、オキシ塩化リン、ｐ−
トルエンスルホン酸、塩化水素酸、臭化水素酸、
リン酸、塩化チオニル、五酸化リン、ナトリウム
エトキシド、カリウム第３級ブトキシドなどの縮
合剤の存在下、必要に応じて、ベンゼン、トルエ
ン、キシレン、ピリジン、エタノール、イソプロ
パノール、エチレングリコール、ジエチレングリ
コールジメチルエーテル、ジメチルホルムアミ
ド、ジオキサンなどの反応に不活性な溶媒中、０
〜250℃の温度で進行する。 The reaction proceeds appropriately depending on the type of substituent X in the compound of general formula (), but preferably polyphosphoric acid, polyphosphoric acid ester, phosphorus oxychloride, p-
Toluenesulfonic acid, hydrochloric acid, hydrobromic acid,
Benzene, toluene, xylene, pyridine, ethanol, isopropanol, ethylene glycol, diethylene glycol dimethyl ether, In a reaction-inert solvent such as dimethylformamide or dioxane, 0
Proceeds at temperatures of ~250°C.
(2) 一般式
（式中、Ｙはハロゲンまたはメチルチオ、エチ
ルチオなどの低級アルキルチオを示し、他の記号
は前記と同義である）
で表わされる化合物と一般式
（式中、各記号は前記と同義である）
で表わされる化合物とを反応させる方法。(2) General formula (In the formula, Y represents halogen or lower alkylthio such as methylthio or ethylthio, and the other symbols have the same meanings as above.) (In the formula, each symbol has the same meaning as above.) A method of reacting with a compound represented by:
反応は、無溶媒または好ましくは水、トルエ
ン、キシレン、ピリジン、エタノール、イソプロ
パノール、ジメチルホルムアミドなどの反応に不
活性な溶媒中、還流下または耐圧容器内で50〜
250℃の温度で進行する。 The reaction is carried out without a solvent or preferably in a reaction-inert solvent such as water, toluene, xylene, pyridine, ethanol, isopropanol, dimethylformamide, etc., under reflux or in a pressure vessel for 50 to 50 minutes.
Proceed at a temperature of 250°C.
本発明の一般式（）で示されるプリン誘導体
は、遊離塩基または酸付加塩あるいは水和物とし
て、医薬に供し得る。酸付加塩としては医薬上許
容されるものであつて、塩酸、硫酸、臭化水素
酸、リン酸、ギ酸、酢酸、シユウ酸、フマール
酸、マレイン酸、クエン酸、酒石酸、リンゴ酸、
マンデル酸、メタンスルホン酸、トルエンスルホ
ン酸などの無機酸、有機酸の塩があげられる。 The purine derivative represented by the general formula () of the present invention can be used as a medicine as a free base, an acid addition salt, or a hydrate. Pharmaceutically acceptable acid addition salts include hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, formic acid, acetic acid, oxalic acid, fumaric acid, maleic acid, citric acid, tartaric acid, malic acid,
Examples include salts of inorganic acids and organic acids such as mandelic acid, methanesulfonic acid, and toluenesulfonic acid.
作用及び効果
本発明の一般式（）の化合物、その医薬上許
容しうる酸付加塩または水和物は、たとえば、ウ
インターらのカラゲニン足浮腫法、ヘンダーシヨ
ツトらのフエニルキノンライズイング法により、
また小林らのリポポリサツカライド（LPS）発熱
モルモツトにおいて抗炎症、鎮痛、解熱作用を示
す。Actions and Effects The compound of the general formula () of the present invention, its pharmaceutically acceptable acid addition salt or hydrate, can be prepared by, for example, the carrageenan foot edema method of Winter et al., or the phenylquinone rising method of Hendershot et al.
Kobayashi et al.'s lipopolysaccharide (LPS) also shows anti-inflammatory, analgesic, and antipyretic effects in feverish guinea pigs.
本発明の化合物は、アスピリンなどの酸性非ス
テロイド抗炎症薬と異なり、潰瘍惹起作用が認め
られず、副作用の少ない抗炎症、鎮痛、解熱薬と
して有用である。 The compounds of the present invention, unlike acidic nonsteroidal anti-inflammatory drugs such as aspirin, do not exhibit ulcer-inducing effects and are useful as anti-inflammatory, analgesic, and antipyretic agents with few side effects.
また、ニユーボールドらのラツトアジユバント
関節炎を抑制し、慢性関節リウマチ、変形性関節
症などの治療に有用性を示し、さらにプラムらの
方法によるReverse Passive Arthus反応を抑制
することから、慢性関節リウマチを含め、全身性
エリテマトーデス、血清病、過敏性肺臓炎、慢性
糸球体腎炎などの型アレルギー反応に起因する
疾患の治療に有用性を示す。更に、デイ・ロザら
の方法を一部改良して行つた試験で、ラツト腹腔
白血球の百日咳菌貧食に伴うSRS−Ａの産生を抑
制し、気管支喘息治療薬としての有用性を示す。 In addition, it suppresses the rat adjuvant arthritis of Newbold et al., and has shown usefulness in the treatment of rheumatoid arthritis, osteoarthritis, etc. Furthermore, it suppresses the reverse passive Arthus reaction according to the method of Plumb et al. It is useful in the treatment of diseases caused by type allergic reactions, including rheumatism, systemic lupus erythematosus, serum sickness, hypersensitivity pneumonitis, and chronic glomerulonephritis. Furthermore, in a test conducted by partially modifying the method of Dei Rosa et al., it suppressed the production of SRS-A in rat peritoneal leukocytes due to the ingestion of Bordetella pertussis, demonstrating its usefulness as a therapeutic agent for bronchial asthma.
さらに、本発明の化合物は、血小板凝集を抑制
することから、循環機能改善薬としても有用であ
る。 Furthermore, since the compound of the present invention suppresses platelet aggregation, it is also useful as a circulatory function improving drug.
本発明の化合物は、経口でも非経口でも投与さ
れるが、経口の場合、適宜医薬上許容される添加
剤（（担体、賦形剤、希釈剤など）と混合し、散
剤、錠剤、カプセル剤、トローチ、水剤、シロツ
プ剤、顆粒剤として用いられる。非経口の場合、
水溶液もしくは非水性懸濁剤として、静注、筋
注、皮下注射などの注射剤、または坐剤、クリー
ム状軟膏剤として用いられる。 The compound of the present invention can be administered orally or parenterally, but in the case of oral administration, it is mixed with appropriate pharmaceutically acceptable additives (carriers, excipients, diluents, etc.) and formulated into powders, tablets, and capsules. , used as troches, solutions, syrups, and granules.For parenteral administration,
It is used as an aqueous solution or non-aqueous suspension, an injection such as intravenous injection, intramuscular injection, or subcutaneous injection, or a suppository or cream ointment.
投与量は患者の症状、体重、年令などにより変
わりうるが、通常成人１回あたり0.1〜10mg／Kg
体重が適当である。 The dosage may vary depending on the patient's symptoms, weight, age, etc., but it is usually 0.1 to 10 mg/Kg per dose for adults.
Appropriate weight.
実施例
以下に実施例をあげて本発明をより一層具体的
に説明するが、本発明はこれらに限定されるもの
ではない。EXAMPLES The present invention will be explained in more detail with reference to Examples below, but the present invention is not limited thereto.
実施例 １
４，５−ジアミノ−６−ジエチルアミノピリミ
ジン５ｇおよびイソコチン酸3.4ｇを乳鉢中で均
一に混合粉砕したものをオキシ塩化リン110mlに
撹拌下加え、３時間加熱還流する。反応液を濃縮
し残油状物に水180mlを加え溶解し、アンモニア
水で中和し析出する結晶を濾取し、水洗後メタノ
ールから再結晶すると、融点260〜262℃の６−ジ
エチルアミノ−８−（４−ピリジル）プリン3.4ｇ
が得られる。Example 1 5 g of 4,5-diamino-6-diethylaminopyrimidine and 3.4 g of isocotinic acid were uniformly mixed and ground in a mortar and added to 110 ml of phosphorus oxychloride under stirring, and heated under reflux for 3 hours. The reaction solution was concentrated, and the remaining oil was dissolved in 180 ml of water, neutralized with aqueous ammonia, and the precipitated crystals were collected by filtration, washed with water, and then recrystallized from methanol. (4-pyridyl)purine 3.4g
is obtained.
実施例 ２
４，５−ジアミノ−６−（４−メチル−１−ピ
ペラジニル）ピリミジン３ｇ、イソニコチン酸
1.8ｇおよびポリリン酸45ｇを窒素気流中、160〜
170℃で４時間撹拌後、水200mlを加え溶解し、つ
いでアンモニア水で中和し、析出する結晶を濾取
水洗後、メタノールから再結晶すると、融点333
〜335℃の６−（４−メチル−１−ピペラジニル）
−８−（４−ピリジル）プリン1.5ｇが得られる。Example 2 4,5-diamino-6-(4-methyl-1-piperazinyl)pyrimidine 3g, isonicotinic acid
1.8g and 45g of polyphosphoric acid in a nitrogen stream at 160~
After stirring at 170℃ for 4 hours, 200ml of water was added to dissolve, then neutralized with aqueous ammonia, and the precipitated crystals were filtered, washed with water, and recrystallized from methanol, resulting in a melting point of 333.
6-(4-methyl-1-piperazinyl) at ~335°C
1.5 g of -8-(4-pyridyl)purine is obtained.
実施例 ３
４，５−ジアミノ−６−ジエチルアミノ−２−
メチルピリジン５ｇおよびイソニコチン酸3.2ｇ
を乳鉢中で均一に混合粉砕したものをオキシ塩化
リン110mlに撹拌下加え、３時間加熱還流する。
反応液を濃縮し残油状物に水180mlを加え溶解し、
アンモニア水で中和し析出する結晶を濾取し、シ
リカゲルカラムクロマトグラフイー（溶出：クロ
ロホルム：メタノール＝10：１）で精製し、メタ
ノールから再結晶すると、融点228〜230℃の６−
ジエチルアミノ−２−メチル−８−（４−ピリジ
ル）プリン2.3ｇが得られる。Example 3 4,5-diamino-6-diethylamino-2-
Methylpyridine 5g and isonicotinic acid 3.2g
The mixture was uniformly mixed and ground in a mortar, added to 110 ml of phosphorus oxychloride under stirring, and heated under reflux for 3 hours.
Concentrate the reaction solution and dissolve the remaining oil by adding 180 ml of water.
After neutralization with ammonia water, the precipitated crystals were collected by filtration, purified by silica gel column chromatography (elution: chloroform:methanol = 10:1), and recrystallized from methanol.
2.3 g of diethylamino-2-methyl-8-(4-pyridyl)purine are obtained.
実施例 ４
４，５−ジアミノ−６−（４−メチル−１−ピ
ペラジニル）−２−フエニルピリミジン４ｇおよ
びイソニコチン酸1.7ｇをオキシ塩化リン80mlに
加え、撹拌下、６時間加熱還流する。反応液を濃
縮し、残油状物に、水700mlを加え溶解させ、ア
ンモニア水で中和し析出する結晶を濾取し、水洗
後、クロロホルム：メタノール＝２：１の混合溶
媒より再結晶すると、融点333〜337℃の６−（４
−メチル−１−ピペラジニル）−２−フエニル−
８−（４−ピリジル）プリン2.7ｇが得られる。Example 4 4 g of 4,5-diamino-6-(4-methyl-1-piperazinyl)-2-phenylpyrimidine and 1.7 g of isonicotinic acid are added to 80 ml of phosphorus oxychloride, and the mixture is heated under reflux for 6 hours with stirring. Concentrate the reaction solution, add 700 ml of water to the residual oil, dissolve it, neutralize with aqueous ammonia, collect the precipitated crystals by filtration, wash with water, and recrystallize from a mixed solvent of chloroform:methanol = 2:1. 6-(4) with a melting point of 333-337℃
-Methyl-1-piperazinyl)-2-phenyl-
2.7 g of 8-(4-pyridyl)purine are obtained.
実施例 ５
６−メチルチオ−８−（４−ピリジル）プリン
６ｇ、70％エチルアミン水溶液30mlおよび水30ml
の混合物をオートクレーブに移し、150℃で10時
間加熱撹拌する。反応液を濃縮後、メタノールに
溶解し、活性炭を約３ｇ加えよく振り混ぜた後、
濾過し濃縮する。得られた結晶をエタノール：水
＝１：１の混合溶媒より再結晶すると、融点308
〜310℃の６−エチルアミノ−８−（４−ピリジ
ル）プリン1.7ｇが得られる。Example 5 6-methylthio-8-(4-pyridyl)purine 6g, 70% ethylamine aqueous solution 30ml and water 30ml
Transfer the mixture to an autoclave and heat and stir at 150°C for 10 hours. After concentrating the reaction solution, it was dissolved in methanol, about 3 g of activated carbon was added, and after shaking well,
Filter and concentrate. When the obtained crystals are recrystallized from a mixed solvent of ethanol:water = 1:1, the melting point is 308.
1.7 g of 6-ethylamino-8-(4-pyridyl)purine are obtained at ~310°C.
上記実施例及び明細書記載の方法により、次の
化合物が得られる。 The following compounds can be obtained by the methods described in the above examples and specification.
◎６−ジメチルアミノ−８−（３−ピリジル）プ
リン、融点325〜326℃
◎６−ジメチルアミノ−８−（４−ピリジル）プ
リン、融点335〜336℃
◎６−ジエチルアミノ−８−（２−ピリジル）プ
リン、融点239〜241℃
◎６−ジエチルアミノ−８−（３−ピリジル）プ
リン、融点260〜262℃
◎６−ジイソプロピルアミノ−２−メチル−８−
（４−ピリジル）プリン、融点213〜215℃
◎６−ジイソプロピルアミノ−２−メチル−８−
（３−ピリジル）プリン、融点234〜236℃
◎６−モルホリノ−８−（４−ピリジル）プリン、
融点358〜360℃
◎２−メチル−６−モルホリノ−８−（３−ピリ
ジル）プリン、融点306〜307℃
◎２−メチル−６−モルホリノ−８−（４−ピリ
ジル）プリン、融点311〜313℃
◎６−アミノ−９−エチル−２−メチル−８−
（２−ピリジル）プリン、融点243〜245℃
◎２−メチル−６−ピペリジノ−８−（３−ピリ
ジル）プリン、融点293〜295℃
◎２−メチル−６−ピペリジノ−８−（４−ピリ
ジル）プリン、融点273〜279℃
◎８−（４−ピリジル）−６−（１−ピロリジニル）
プリン、融点345〜350℃
◎８−（３−ピリジル）−６−（１−ピロリジニル）
プリン、融点324〜325℃
◎２−メチル−８−（４−ピリジル）−６−（１−
ピロリジニル）プリン、融点304〜305℃
◎６−ジエチルアミノ−２，９−ジメチル−８−
（４−ピリジル）プリン、融点130〜131℃
◎２，９−ジメチル−６−ピペリジノ−８−（４
−ピリジル）プリン、融点151〜153℃
◎６−ジエチルアミノ−９−メチル−８−（４−
ピリジル）プリン、融点109〜110℃
◎６−ジエチルアミノ−２−フエニル−８−（４
−ピリジル）プリン、融点314〜316℃
◎２−フエニル−６−ピペリジノ−８−（４−ピ
リジル）プリン、融点360℃以上
◎２−フエニル−８−（４−ピリジル）−６−（１
−ピロリジニル）プリン、融点360℃以上
◎２−（４−メチルフエニル）−６−モルホリノ−
８−（３−ピリジル）プリン、融点318〜320℃
◎２−（４−フルオロフエニル）−６−ピペリジノ
−８−（４−ピリジル）プリン、融点360℃以上
◎２−（４−フルオロフエニル）−８−（４−ピリ
ジル）−６−（１−ピロリジニル）プリン、融点
350℃以上
◎６−〔〔Ｎ−メチル−Ｎ−（２−ジメチルアミノ
エチル）アミノ〕−８−（４−ピリジル）プリ
ン、融点221〜223℃
◎６−ジブチルアミノ−８−（４−ピリジル）プ
リン、融点236〜237℃
◎６−ジエチルアミノ−２−（４−メトキシフエ
ニル）８−（４−ピリジル）プリン、融点250〜
252℃
◎２−メチル−６−（４−メチル−１−ピペラジ
ニル）−８−（４−ピリジル）プリン、融点276
〜278℃（分解）
◎６−（４−メチル−１−ピペラジニル）−２−
（４−メチルフエニル）−８−（４−ピリジル）
プリン、融点301〜305℃（分解）
◎６−〔Ｎ−（２−ヒドロキシエチル）−Ｎ−メチ
ルアミノ〕−８−（４−ピリジル）プリン、融点
286〜289℃
◎６−シクロヘキシルアミノ−８−（４−ピリジ
ル）プリン、融点317〜319℃
◎６−（２−フエニルエチル）アミノ−８−（４−
ピリジル）プリン、融点290〜292℃
◎２−（４−フルオロフエニル）−６−（４−メチ
ル−１−ピペラジニル）−８−（４−ピリジル）
プリン、融点320〜330℃（分解）
◎６−〔４−（２−ヒドロキシエチル）−１−ピペ
ラジニル〕−８−（４−ピリジル）プリン、融点
302〜306℃
◎６−（２−モルホリノエチルアミノ）−８−（４
−ピリジル）プリン、融点268〜271℃
◎２−（３，４−ジメトキシフエニル）−６−（４
−メチル−１−ピペラジニル）−８−（４−ピリ
ジル）プリン、融点281〜283℃
◎６−（４−メチル−１−ホモピペラジニル）−２
−フエニル−８−（４−ピリジル）プリン、融
点318〜321℃
◎６−〔Ｎ，Ｎ−ビス（２−ヒドロキシエチル）
アミノ〕−８−（４−ピリジル）プリン、融点
243〜248℃
◎６−オクチルアミノ−８−（４−ピリジル）プ
リン、融点245〜246℃
◎２−イソプロピル−８−（４−ピリジル）−６−
（１−ピロリジニル）プリン、融点305〜307℃
◎２−イソプロピル−６−（４−メチル−１−ピ
ペラジニル）−８−（４−ピリジル）プリン、融
点271〜273℃
◎２−（４−クロロフエニル）−６−（４−メチル
−１−ピペラジニル）−８−（４−ピリジル）プ
リン、融点306〜310℃
◎２−メチル−６−ピペリジノ−８−（５−エチ
ル−２−ピリジル）プリン、融点196〜198℃
◎６−〔４−（２−ヒドロキシエチル）−１−ピペ
ラジニル〕−２−フエニル−８−（４−ピリジ
ル）プリン、融点324〜326℃
◎６−〔Ｎ−（３−ジメチルアミノプロピル）−Ｎ
−メチルアミノ〕２−フエニル−８−（４−ピ
リジル）プリン、融点278〜281℃
◎６−〔（１−メチル−３−ブテン−１−イル）ア
ミノ〕−８−（４−ピリジル）プリン、融点290
〜293℃
◎２−（４−クロロフエニル）−６−（４−メチル
−１−ピペラジニル）−８−（３−ピリジル）プ
リン、融点312〜315℃
◎２−（４−クロロフエニル）−６−（４−メチル
−１−ピペラジニル）−８−（２−ピリジル）プ
リン・塩酸塩、融点328〜331℃（分解）
◎６−（４−エチル−１−ピペラジニル）−２−
（４−クロロフエニル）−８−（４−ピリジル）
プリン、融点305〜310℃
◎２−（４−クロロフエニル）−６−（４−メチル
−１−ホモピペラジニル）−８−（４−ピリジ
ル）プリン、融点280〜283℃
◎６−（４−エチル−１−ピペラジニル）−２−
（４−メトキシフエニル）−８−（４−ピリジル）
プリン、融点270〜275℃
製剤処方例
化合物（）50.0mgを含有する錠剤は次の処方
により調製することができる。◎6-dimethylamino-8-(3-pyridyl)purine, melting point 325-326℃ ◎6-dimethylamino-8-(4-pyridyl)purine, melting point 335-336℃ ◎6-diethylamino-8-(2- pyridyl) purine, melting point 239-241℃ ◎6-diethylamino-8-(3-pyridyl)purine, melting point 260-262℃ ◎6-diisopropylamino-2-methyl-8-
(4-pyridyl)purine, melting point 213-215℃ ◎6-diisopropylamino-2-methyl-8-
(3-pyridyl)purine, melting point 234-236℃ ◎6-morpholino-8-(4-pyridyl)purine,
Melting point 358-360℃ ◎2-Methyl-6-morpholino-8-(3-pyridyl)purine, melting point 306-307℃ ◎2-Methyl-6-morpholino-8-(4-pyridyl)purine, melting point 311-313 °C ◎6-amino-9-ethyl-2-methyl-8-
(2-pyridyl)purine, melting point 243-245℃ ◎2-Methyl-6-piperidino-8-(3-pyridyl)purine, melting point 293-295℃ ◎2-Methyl-6-piperidino-8-(4-pyridyl) ) Purine, melting point 273-279℃ ◎8-(4-pyridyl)-6-(1-pyrrolidinyl)
Purine, melting point 345-350℃ ◎8-(3-pyridyl)-6-(1-pyrrolidinyl)
Purine, melting point 324-325℃ ◎2-Methyl-8-(4-pyridyl)-6-(1-
pyrrolidinyl) purine, melting point 304-305℃ ◎6-diethylamino-2,9-dimethyl-8-
(4-pyridyl)purine, melting point 130-131℃ ◎2,9-dimethyl-6-piperidino-8-(4
-pyridyl)purine, melting point 151-153℃ ◎6-diethylamino-9-methyl-8-(4-
6-diethylamino-2-phenyl-8-(4
-pyridyl) purine, melting point 314-316°C ◎2-phenyl-6-piperidino-8-(4-pyridyl)purine, melting point 360°C or higher ◎2-phenyl-8-(4-pyridyl)-6-(1
-pyrrolidinyl) purine, melting point 360℃ or higher◎2-(4-methylphenyl)-6-morpholino-
8-(3-pyridyl)purine, melting point 318-320℃ ◎2-(4-fluorophenyl)-6-piperidino-8-(4-pyridyl)purine, melting point 360℃ or higher enyl)-8-(4-pyridyl)-6-(1-pyrrolidinyl)purine, melting point
350℃ or higher◎6-[[N-methyl-N-(2-dimethylaminoethyl)amino]-8-(4-pyridyl)purine, melting point 221-223℃◎6-dibutylamino-8-(4-pyridyl) ) Purine, melting point 236~237℃ ◎6-diethylamino-2-(4-methoxyphenyl)8-(4-pyridyl)purine, melting point 250~
252℃ ◎2-Methyl-6-(4-methyl-1-piperazinyl)-8-(4-pyridyl)purine, melting point 276
~278℃ (decomposition) ◎6-(4-methyl-1-piperazinyl)-2-
(4-methylphenyl)-8-(4-pyridyl)
Purine, melting point 301-305℃ (decomposition) ◎6-[N-(2-hydroxyethyl)-N-methylamino]-8-(4-pyridyl)purine, melting point
286-289℃ ◎6-cyclohexylamino-8-(4-pyridyl)purine, melting point 317-319℃ ◎6-(2-phenylethyl)amino-8-(4-
2-(4-fluorophenyl)-6-(4-methyl-1-piperazinyl)-8-(4-pyridyl)
Purine, melting point 320-330℃ (decomposition) ◎6-[4-(2-hydroxyethyl)-1-piperazinyl]-8-(4-pyridyl)purine, melting point
302～306℃ ◎6-(2-morpholinoethylamino)-8-(4
-pyridyl)purine, melting point 268-271℃ ◎2-(3,4-dimethoxyphenyl)-6-(4
-Methyl-1-piperazinyl)-8-(4-pyridyl)purine, melting point 281-283℃ ◎6-(4-methyl-1-homopiperazinyl)-2
-Phenyl-8-(4-pyridyl)purine, melting point 318-321℃ ◎6-[N,N-bis(2-hydroxyethyl)
Amino]-8-(4-pyridyl)purine, melting point
243-248℃ ◎6-octylamino-8-(4-pyridyl)purine, melting point 245-246℃ ◎2-isopropyl-8-(4-pyridyl)-6-
(1-pyrrolidinyl)purine, melting point 305-307℃ ◎2-isopropyl-6-(4-methyl-1-piperazinyl)-8-(4-pyridyl)purine, melting point 271-273℃ ◎2-(4-chlorophenyl )-6-(4-methyl-1-piperazinyl)-8-(4-pyridyl)purine, melting point 306-310°C ◎2-Methyl-6-piperidino-8-(5-ethyl-2-pyridyl)purine, Melting point 196-198℃ ◎6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-phenyl-8-(4-pyridyl)purine, melting point 324-326℃ ◎6-[N-(3- dimethylaminopropyl)-N
-Methylamino]2-phenyl-8-(4-pyridyl)purine, melting point 278-281℃ ◎6-[(1-methyl-3-buten-1-yl)amino]-8-(4-pyridyl)purine , melting point 290
~293℃ ◎2-(4-chlorophenyl)-6-(4-methyl-1-piperazinyl)-8-(3-pyridyl)purine, melting point 312-315℃ ◎2-(4-chlorophenyl)-6-( 4-Methyl-1-piperazinyl)-8-(2-pyridyl)purine hydrochloride, melting point 328-331℃ (decomposition) ◎6-(4-ethyl-1-piperazinyl)-2-
(4-chlorophenyl)-8-(4-pyridyl)
Purine, melting point 305-310℃ ◎2-(4-chlorophenyl)-6-(4-methyl-1-homopiperazinyl)-8-(4-pyridyl)purine, melting point 280-283℃ ◎6-(4-ethyl- 1-piperazinyl)-2-
(4-methoxyphenyl)-8-(4-pyridyl)
Purine, melting point 270-275°C Pharmaceutical formulation example A tablet containing 50.0 mg of compound () can be prepared according to the following formulation.
化合物（） 50.0mg
乳 糖 68.5mg
トウモロコシデンプン 30.0mg
結晶セルロース 20.0mg
ポリビニルピロリドンＫ−30 2.0mg
タルク 4.0mg
ステアリン酸マグネシウム 0.5mg
175.0mg
化合物（）をアトマイザーにより粉砕し、平
均粒子径10μ以下の微粉とする。化合物（）、
乳糖、トウモロコシデンプンおよび結晶セルロー
スを、練合機中で混合したのち、ポリビニルピロ
リドン糊液を加えて、20分間練合する。練合物を
200メツシユの篩を通して造粒し、50℃の熱風乾
燥機中で、水分３〜４％となるまで乾燥し、24メ
ツシユの篩を通したのち、タルクおよびステアリ
ン酸マグネシウムを混合し、ロータリー式打錠機
により、直径８mmの平面杵を用いて打錠する。Compound () 50.0mg Lactose 68.5mg Corn starch 30.0mg Crystalline cellulose 20.0mg Polyvinylpyrrolidone K-30 2.0mg Talc 4.0mg Magnesium stearate 0.5mg 175.0mg Compound () is ground with an atomizer to form a fine powder with an average particle size of 10μ or less shall be. Compound(),
Lactose, corn starch and crystalline cellulose are mixed in a kneader, then polyvinylpyrrolidone paste is added and kneaded for 20 minutes. Mixture
Granulated through a 200 mesh sieve, dried in a hot air dryer at 50°C until the moisture content was 3-4%, passed through a 24 mesh sieve, mixed with talc and magnesium stearate, and granulated using a rotary pulverizer. Compress into tablets using a tablet machine using a flat punch with a diameter of 8 mm.
本発明を上述の明細書および包含される実施例
で十分に説明したが、本発明の精神と範囲に反す
ることなく種々に変更、修飾することができる。 Although the present invention has been fully described in the foregoing specification and included examples, various changes and modifications can be made without departing from the spirit and scope of the invention.
Claims (1)
しうる酸付加塩。 上記式中、Ｒは水素、アルキルまたは置換基と
してハロゲン、低級アルキルもしくは低級アルコ
キシの少なくとも１個以上を有していてもよいフ
エニルを示し、R1、R2は同一または異なつて、
水素、アルキル、シクロアルキル、ヒドロキシア
ルキル、ジアルキルアミノアルキル、１−ピロリ
ジニルメチル、２−（１−ピロリジニル）エチル、
２−ピペリジノエチル、２−モルホリノエチル、
３−チオモルホリノプロピル、２−（１−ピペラ
ジニル）エチル、２−（４−メチル−１−ピペラ
ジニル）エチル、２−〔４−（２−ヒドロキシエチ
ル）−１−ピペラジニル〕エチル、２−（４−メチ
ル−１−ホモピペラジニル）エチル、アルケニル
またはアラルキルを示すか、R1、R2が隣接する
窒素原子と結合して１−ピロリジニル、ピペリジ
ノ、１−ピペラジニル、４−メチル−１−ピペラ
ジニル、４−エチル−１−ピペラジニル、４−
（２−ヒドロキシエチル）−１−ピペラジニル、１
−ホモピペラジニル、４−メチル−１−ホモピペ
ラジニル、モルホリノ、チオモルホリノを形成す
る基を示し、R3、R4は同一または異なつて、水
素または低級アルキルを示す。[Claims] 1. General formula A purine derivative represented by or a pharmaceutically acceptable acid addition salt thereof. In the above formula, R represents hydrogen, alkyl, or phenyl which may have at least one of halogen, lower alkyl, or lower alkoxy as a substituent, and R 1 and R 2 are the same or different,
Hydrogen, alkyl, cycloalkyl, hydroxyalkyl, dialkylaminoalkyl, 1-pyrrolidinylmethyl, 2-(1-pyrrolidinyl)ethyl,
2-piperidinoethyl, 2-morpholinoethyl,
3-thiomorpholinopropyl, 2-(1-piperazinyl)ethyl, 2-(4-methyl-1-piperazinyl)ethyl, 2-[4-(2-hydroxyethyl)-1-piperazinyl]ethyl, 2-(4 -Methyl-1-homopiperazinyl) ethyl, alkenyl or aralkyl, or R 1 and R 2 are bonded to adjacent nitrogen atoms to represent 1-pyrrolidinyl, piperidino, 1-piperazinyl, 4-methyl-1-piperazinyl, 4- Ethyl-1-piperazinyl, 4-
(2-hydroxyethyl)-1-piperazinyl, 1
- represents a group forming homopiperazinyl, 4-methyl-1-homopiperazinyl, morpholino, and thiomorpholino, and R 3 and R 4 are the same or different and represent hydrogen or lower alkyl.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP28005784A JPS61158983A (en) | 1984-12-28 | 1984-12-28 | Purine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP28005784A JPS61158983A (en) | 1984-12-28 | 1984-12-28 | Purine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS61158983A JPS61158983A (en) | 1986-07-18 |
| JPH0528719B2 true JPH0528719B2 (en) | 1993-04-27 |
Family
ID=17619700
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP28005784A Granted JPS61158983A (en) | 1984-12-28 | 1984-12-28 | Purine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS61158983A (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU3196900A (en) * | 1999-03-25 | 2000-10-16 | Welfide Corporation | Preventives/remedies for interstitial pneumonia and pulmonary fibrosis |
| WO2001002400A1 (en) * | 1999-07-02 | 2001-01-11 | Eisai Co., Ltd. | Fused imidazole compounds and remedies for diabetes mellitus |
| EP1751159A2 (en) * | 2004-04-28 | 2007-02-14 | Cv Therapeutics, Inc. | Purine derivatives as a1 adenosine receptor antagonists |
-
1984
- 1984-12-28 JP JP28005784A patent/JPS61158983A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS61158983A (en) | 1986-07-18 |
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