JPH083165A - New pyridopyrimidine derivative - Google Patents
New pyridopyrimidine derivativeInfo
- Publication number
- JPH083165A JPH083165A JP6159324A JP15932494A JPH083165A JP H083165 A JPH083165 A JP H083165A JP 6159324 A JP6159324 A JP 6159324A JP 15932494 A JP15932494 A JP 15932494A JP H083165 A JPH083165 A JP H083165A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- group
- pyrimidine
- dione
- butyl
- 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
- 150000008518 pyridopyrimidines Chemical class 0.000 title 1
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 44
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 19
- 239000000126 substance Substances 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 13
- 125000003277 amino group Chemical group 0.000 claims description 10
- 150000003230 pyrimidines Chemical class 0.000 claims description 9
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 125000004442 acylamino group Chemical group 0.000 claims description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 3
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 claims 7
- 208000006673 asthma Diseases 0.000 abstract description 17
- 239000003814 drug Substances 0.000 abstract description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 abstract description 12
- 230000003266 anti-allergic effect Effects 0.000 abstract description 8
- 208000030603 inherited susceptibility to asthma Diseases 0.000 abstract description 8
- 239000013078 crystal Substances 0.000 abstract description 7
- 238000001914 filtration Methods 0.000 abstract description 5
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 abstract description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 3
- LXBBKPIEZIXNCQ-UHFFFAOYSA-N 1-benzyl-5-chloropyrido[2,3-d]pyrimidine-2,4-dione Chemical compound O=C1NC(=O)C=2C(Cl)=CC=NC=2N1CC1=CC=CC=C1 LXBBKPIEZIXNCQ-UHFFFAOYSA-N 0.000 abstract description 2
- YOHMVGIQQNQDAW-UHFFFAOYSA-N 5-amino-1,3-diethyl-7-methylpyrido[2,3-d]pyrimidine-2,4-dione Chemical compound CC1=CC(N)=C2C(=O)N(CC)C(=O)N(CC)C2=N1 YOHMVGIQQNQDAW-UHFFFAOYSA-N 0.000 abstract description 2
- 230000003182 bronchodilatating effect Effects 0.000 abstract description 2
- 230000003449 preventive effect Effects 0.000 abstract description 2
- 239000002244 precipitate Substances 0.000 abstract 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- 230000002035 prolonged effect Effects 0.000 abstract 1
- 238000002844 melting Methods 0.000 description 34
- 230000008018 melting Effects 0.000 description 34
- 150000001875 compounds Chemical class 0.000 description 29
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 22
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 20
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 14
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 14
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 14
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 14
- 125000004432 carbon atom Chemical group C* 0.000 description 13
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 13
- -1 ethoxy, propoxy Chemical group 0.000 description 11
- 229940079593 drug Drugs 0.000 description 10
- 159000000018 pyrido[2,3-d]pyrimidines Chemical class 0.000 description 9
- 239000000243 solution Substances 0.000 description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 229940124630 bronchodilator Drugs 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 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
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 229940125782 compound 2 Drugs 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- JXLAUBBYDHROLD-UHFFFAOYSA-N 5-(benzylamino)-1h-pyrido[2,3-d]pyrimidine-2,4-dione Chemical compound C=12C(=O)NC(=O)NC2=NC=CC=1NCC1=CC=CC=C1 JXLAUBBYDHROLD-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 208000026935 allergic disease Diseases 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
- 229940126214 compound 3 Drugs 0.000 description 3
- 230000008602 contraction Effects 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 229960001340 histamine Drugs 0.000 description 3
- 229960004931 histamine dihydrochloride Drugs 0.000 description 3
- PPZMYIBUHIPZOS-UHFFFAOYSA-N histamine dihydrochloride Chemical compound Cl.Cl.NCCC1=CN=CN1 PPZMYIBUHIPZOS-UHFFFAOYSA-N 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 210000002460 smooth muscle Anatomy 0.000 description 3
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 2
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 2
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 2
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 2
- JQPYINKVAWEQDQ-UHFFFAOYSA-N 1h-pyrido[2,3-d]pyrimidine-2,4-dione Chemical compound C1=CC=C2C(=O)NC(=O)NC2=N1 JQPYINKVAWEQDQ-UHFFFAOYSA-N 0.000 description 2
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 2
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 2
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 2
- LBOFRSMUBPRAMX-UHFFFAOYSA-N 5-chloro-1,3-diethylpyrido[2,3-d]pyrimidine-2,4-dione Chemical compound C1=CC(Cl)=C2C(=O)N(CC)C(=O)N(CC)C2=N1 LBOFRSMUBPRAMX-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 229940126657 Compound 17 Drugs 0.000 description 2
- 229940126639 Compound 33 Drugs 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
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- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
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- 241000700159 Rattus Species 0.000 description 2
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- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
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- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- OTZKQQGMSWSZBY-UHFFFAOYSA-N n'-(1,3-diethyl-2,4-dioxopyrido[2,3-d]pyrimidin-5-yl)-n,n-dimethylmethanimidamide Chemical compound C1=CC(N=CN(C)C)=C2C(=O)N(CC)C(=O)N(CC)C2=N1 OTZKQQGMSWSZBY-UHFFFAOYSA-N 0.000 description 1
- PGQJNWDPWSWYRR-UHFFFAOYSA-N n-(1,3-diethyl-2,4-dioxopyrido[2,3-d]pyrimidin-5-yl)benzamide Chemical compound C=12C(=O)N(CC)C(=O)N(CC)C2=NC=CC=1NC(=O)C1=CC=CC=C1 PGQJNWDPWSWYRR-UHFFFAOYSA-N 0.000 description 1
- HZJZJNKNGOXJGF-UHFFFAOYSA-N n-(1,3-dimethyl-2,4-dioxopyrido[2,3-d]pyrimidin-5-yl)acetamide Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CC=C2NC(=O)C HZJZJNKNGOXJGF-UHFFFAOYSA-N 0.000 description 1
- BEJGGKAPTIJCIH-UHFFFAOYSA-N n-(1,3-dimethyl-2,4-dioxopyrido[2,3-d]pyrimidin-5-yl)benzamide Chemical compound C=12C(=O)N(C)C(=O)N(C)C2=NC=CC=1NC(=O)C1=CC=CC=C1 BEJGGKAPTIJCIH-UHFFFAOYSA-N 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
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- 230000000069 prophylactic effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- 208000017520 skin disease Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 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
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
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- 239000000080 wetting agent Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、医薬として有用な新規
ピリド〔２，３−ｄ〕ピリミジン誘導体及びその薬学的
に許容しうる塩に関する。TECHNICAL FIELD The present invention relates to a novel pyrido [2,3-d] pyrimidine derivative useful as a medicine and a pharmaceutically acceptable salt thereof.
【０００２】[0002]
【従来の技術】現代社会においては、例えば自動車の増
加に伴う粉塵等の影響により気管支喘息患者は増え続け
ている。気管支喘息とは、発作時に気管支平滑筋の攣縮
が起こる疾患であり、発作時は大変苦しい呼吸困難の状
態に陥る。発作を起こす誘因によってアトピー型、感染
型及び混合型に分類されているが、一般には化学伝達物
質やその他の因子に対する気道過敏性の亢進等の体質的
素因に後天的な因子が加わり、いわゆる喘息準備状態が
成立し、これに抗原刺激等の誘因が加わって発症するも
のと考えられている。2. Description of the Related Art In the modern society, the number of patients with bronchial asthma continues to increase due to the influence of dust and the like as the number of automobiles increases. Bronchial asthma is a disease in which bronchial smooth muscle spasms occur during an attack, and during an attack, a person suffers from extremely difficult breathing. It is classified into atopic type, infectious type, and mixed type depending on the trigger of seizure, but in general, acquired factors are added to constitutional factors such as increased airway hyperresponsiveness to chemical transmitters and other factors, so-called asthma. It is considered that a preparatory state is established, and in addition to this, inducing factors such as antigen stimulation are added to develop the condition.
【０００３】気管支喘息に対する薬剤としては、収縮し
た気管支に対して直接的に作用して弛緩させる気管支拡
張剤の他に抗アレルギー剤、去痰剤、副腎皮質ステロイ
ド剤及び抗不安剤等が用いられている。例えば、汎用さ
れている薬剤の一つである抗アレルギー剤とは、アレル
ギーに関与するヒスタミン等の化学伝達物質の遊離又は
合成を阻害し、或いはそれらに拮抗する作用機序によっ
て、化学伝達物質が関与する喘息症状の発症を予防する
薬剤として使用されている。従って、即効的な気管支拡
張作用を有し、且つ喘息症状の発症を抑え予防的に作用
する抗アレルギー作用を併せ有するような薬剤は、気管
支喘息に対する薬剤として非常に有用性が高いものであ
る。As drugs for bronchial asthma, antiallergic agents, expectorants, corticosteroids, anti-anxiety agents and the like are used in addition to bronchodilators that directly act on and relax the contracted bronchi. There is. For example, an anti-allergic agent, which is one of the widely used drugs, means that a chemical mediator is a mechanism that acts by inhibiting the release or synthesis of chemical mediators such as histamine, which is involved in allergy, or by antagonizing them. It is used as a drug to prevent the development of related asthma symptoms. Therefore, a drug having an immediate bronchodilatory action and an antiallergic action that suppresses the onset of asthma symptoms and acts prophylactically is extremely useful as a drug for bronchial asthma.
【０００４】ある種のピリド〔２，３−ｄ〕ピリミジン
誘導体について、ヒスタミン等の化学伝達物質の遊離抑
制作用や拮抗作用に基づく抗アレルギー作用を有するこ
とが知られている（特開昭６３−４５２７９号公報）。
本発明者らは、即効的な気管支拡張作用並びに予防的な
抗アレルギー作用を併せ有する物質に関して研究を続け
た結果、優れた両薬理作用を有する新規なピリド〔２，
３−ｄ〕ピリミジン誘導体を見い出し、本発明を完成し
た。It is known that certain pyrido [2,3-d] pyrimidine derivatives have an antiallergic action based on the inhibitory action or antagonistic action of the release of chemical mediators such as histamine (Japanese Patent Laid-Open No. 63-63). 45279).
The inventors of the present invention continued to study a substance having both an immediate bronchodilator action and a prophylactic anti-allergic action, and as a result, a novel pyrido [2,2] having both excellent pharmacological actions was obtained.
The present invention was completed by finding a 3-d] pyrimidine derivative.
【０００５】[0005]
【発明が解決しようとする課題】本発明の目的は、気管
支拡張作用並びに抗アレルギー作用を併せ有し、各種の
アレルギー疾患や気管支喘息等に対する治療・予防剤と
して有用な新規ピリド〔２，３−ｄ〕ピリミジン誘導体
を提供することにある。DISCLOSURE OF THE INVENTION The object of the present invention is to provide a novel pyrido [2,3-, which has both bronchodilator action and antiallergic action and is useful as a therapeutic / preventive agent for various allergic diseases and bronchial asthma. d] Providing a pyrimidine derivative.
【０００６】[0006]
【課題を解決するための手段】本発明ピリド〔２，３−
ｄ〕ピリミジン誘導体は、次の一般式（Ｉ）乃至（VII)
で表される化合物である。The present invention pyrido [2,3-
d] pyrimidine derivatives have the following general formulas (I) to (VII)
Is a compound represented by.
【化８】 〔式中、Ｒa1及びＲb1は各々同一若しくは異なってアル
キル基を表し、Ｒc1はアミノ基又はアルキルアミノ基を
表し、Ｒe1はアルキル基を表す。〕Embedded image [In the formula, Ra 1 and Rb 1 are the same or different and each represents an alkyl group, Rc 1 represents an amino group or an alkylamino group, and Re 1 represents an alkyl group. ]
【０００７】[0007]
【化９】 〔式中、Ｒa2及びＲb2は各々同一若しくは異なってアル
キル基を表し、Ｒc2はアルコキシカルボニル基を表
す。〕[Chemical 9] [In the formula, Ra 2 and Rb 2 are the same or different and each represents an alkyl group, and Rc 2 represents an alkoxycarbonyl group. ]
【０００８】[0008]
【化１０】 〔式中、Ｒc3はアミノ基、アルキルアミノ基又はベンジ
ルアミノ基を表す。〕[Chemical 10] [In the formula, Rc 3 represents an amino group, an alkylamino group or a benzylamino group. ]
【０００９】[0009]
【化１１】 〔式中、Ｒa4及びＲb4は一方が水素でかつ他方がアルキ
ル基を表し、Ｒc4はアミノ基又はアルキルアミノ基を表
す。〕[Chemical 11] [In the formula, one of Ra 4 and Rb 4 is hydrogen and the other is an alkyl group, and Rc 4 is an amino group or an alkylamino group. ]
【００１０】[0010]
【化１２】 〔式中、Ｒa5及びＲb5は各々異なったアルキル基を表
し、Ｒc5はアミノ基又はアルキルアミノ基を表す。〕[Chemical 12] [In the formula, Ra 5 and Rb 5 represent different alkyl groups, and Rc 5 represents an amino group or an alkylamino group. ]
【００１１】[0011]
【化１３】 〔式中、Ｒa6は水素又はアルキル基を表し、Ｒc6はアミ
ノ基、アルキルアミノ基又はベンジルアミノ基を表
す。〕[Chemical 13] [In the formula, Ra 6 represents hydrogen or an alkyl group, and Rc 6 represents an amino group, an alkylamino group, or a benzylamino group. ]
【００１２】[0012]
【化１４】 〔式中、Ｒa7及びＲb7は各々同一若しくは異なってアル
キル基を表し、Ｒc7はアシルアミノ基、アルキルアミノ
基、ベンジルアミノ基又はジアルキルアミノメチレンア
ミノ基を表す。〕Embedded image [In the formula, Ra 7 and Rb 7 are the same or different and each represents an alkyl group, and Rc 7 represents an acylamino group, an alkylamino group, a benzylamino group or a dialkylaminomethyleneamino group. ]
【００１３】上記一般式（Ｉ）中、Ｒa1又はＲb1におけ
るアルキル基としては、メチル、エチル、プロピル、イ
ソプロピル、ブチル、イソブチル、ｓｅｃ−ブチル、ｔ
−ブチル等の直鎖又は分枝状の炭素数１乃至４のアルキ
ル基が挙げられる。Ｒc1におけるアルキルアミノ基中の
アルキル基としては、エチル、プロピル、イソプロピ
ル、ブチル、イソブチル、ｓｅｃ−ブチル、ｔ−ブチル
等の直鎖又は分枝状の炭素数１乃至４のアルキル基が挙
げらる。Ｒe1におけるアルキル基としては、メチル、エ
チル、プロピル、イソプロピル、ブチル、イソブチル、
ｓｅｃ−ブチル、ｔ−ブチル等の直鎖又は分枝状の炭素
数１乃至４のアルキル基が挙げらる。In the general formula (I), the alkyl group for Ra 1 or Rb 1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t.
-A straight-chain or branched alkyl group having 1 to 4 carbon atoms such as butyl. Examples of the alkyl group in the alkylamino group for Rc 1 include linear or branched alkyl groups having 1 to 4 carbon atoms such as ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butyl. It Examples of the alkyl group in Re 1 include methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
Examples thereof include linear or branched alkyl groups having 1 to 4 carbon atoms such as sec-butyl and t-butyl.
【００１４】上記一般式（II）中、Ｒa2又はＲb2におけ
るアルキル基としては、メチル、エチル、プロピル、イ
ソプロピル、ブチル、イソブチル、ｓｅｃ−ブチル、ｔ
−ブチル等の直鎖又は分枝状の炭素数１乃至４のアルキ
ル基が挙げられる。Ｒd2におけるアルコキシカルボニル
基中のアルコキシ基としては、エトキシ、プロポキシ、
イソプロポキシ、ブトキシ、イソブトキシ、ｓｅｃ−ブ
トキシ、ｔ−ブトキシ等の直鎖又は分枝状の炭素数１乃
至４のアルコキシ基が挙げらる。In the above general formula (II), the alkyl group for Ra 2 or Rb 2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t.
-A straight-chain or branched alkyl group having 1 to 4 carbon atoms such as butyl. As the alkoxy group in the alkoxycarbonyl group for Rd 2 , ethoxy, propoxy,
Examples thereof include linear or branched C1-C4 alkoxy groups such as isopropoxy, butoxy, isobutoxy, sec-butoxy, and t-butoxy.
【００１５】上記一般式（III)中、Ｒc3におけるアルキ
ルアミノ基中のアルキル基としては、エチル、プロピ
ル、イソプロピル、ブチル、イソブチル、ｓｅｃ−ブチ
ル、ｔ−ブチル等の直鎖又は分枝状の炭素数１乃至４の
アルキル基が挙げらる。In the above general formula (III), the alkyl group in the alkylamino group represented by Rc 3 is linear or branched such as ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl. Examples thereof include an alkyl group having 1 to 4 carbon atoms.
【００１６】上記一般式（IV）中、Ｒa4又はＲb4におけ
るアルキル基としては、メチル、エチル、プロピル、イ
ソプロピル、ブチル、イソブチル、ｓｅｃ−ブチル、ｔ
−ブチル等の直鎖又は分枝状の炭素数１乃至４のアルキ
ル基が挙げられる。Ｒc4におけるアルキルアミノ基中の
アルキル基としては、エチル、プロピル、イソプロピ
ル、ブチル、イソブチル、ｓｅｃ−ブチル、ｔ−ブチル
等の直鎖又は分枝状の炭素数１乃至４のアルキル基が挙
げらる。In the above general formula (IV), the alkyl group for Ra 4 or Rb 4 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t.
-A straight-chain or branched alkyl group having 1 to 4 carbon atoms such as butyl. Rc The alkyl group in the alkylamino group in the 4, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, straight-chain or branched et al includes an alkyl group having 1 to 4 carbon atoms, such as t- butyl It
【００１７】上記一般式（Ｖ）中、Ｒa5又はＲb5におけ
るアルキル基としては、メチル、エチル、プロピル、イ
ソプロピル、ブチル、イソブチル、ｓｅｃ−ブチル、ｔ
−ブチル等の直鎖又は分枝状の炭素数１乃至４のアルキ
ル基が挙げられる。Ｒc5におけるアルキルアミノ基中の
アルキル基としては、エチル、プロピル、イソプロピ
ル、ブチル、イソブチル、ｓｅｃ−ブチル、ｔ−ブチル
等の直鎖又は分枝状の炭素数１乃至４のアルキル基が挙
げらる。In the general formula (V), the alkyl group for Ra 5 or Rb 5 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t.
-A straight-chain or branched alkyl group having 1 to 4 carbon atoms such as butyl. Examples of the alkyl group in the alkylamino group for Rc 5 include linear or branched alkyl groups having 1 to 4 carbon atoms such as ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butyl. It
【００１８】上記一般式（VI）中、Ｒa6におけるアルキ
ル基としては、メチル、エチル、プロピル、イソプロピ
ル、ブチル、イソブチル、ｓｅｃ−ブチル、ｔ−ブチル
等の直鎖又は分枝状の炭素数１乃至４のアルキル基が挙
げられる。Ｒc6におけるアルキルアミノ基中のアルキル
基としては、エチル、プロピル、イソプロピル、ブチ
ル、イソブチル、ｓｅｃ−ブチル、ｔ−ブチル等の直鎖
又は分枝状の炭素数１乃至４のアルキル基が挙げらる。In the above general formula (VI), the alkyl group for Ra 6 is a linear or branched carbon number 1 such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or t-butyl. To 4 alkyl groups. Examples of the alkyl group in the alkylamino group for Rc 6 include linear or branched alkyl groups having 1 to 4 carbon atoms such as ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butyl. It
【００１９】上記一般式（VII)中、Ｒa7又はＲb7におけ
るアルキル基としては、メチル、エチル、プロピル、イ
ソプロピル、ブチル、イソブチル、ｓｅｃ−ブチル、ｔ
−ブチル等の直鎖又は分枝状の炭素数１乃至４のアルキ
ル基が挙げられる。Ｒc7におけるアシルアミノ基中のア
シル基としては、ホルミル、アセチル、プロピオニル、
ブチリル、イソブチリル、ｔ−ブチリル等の直鎖又は分
枝状の炭素数１乃至４のアシル基及びベンゾイル基が挙
げられ、アルキルアミノ基中のアルキル基としては、エ
チル、プロピル、イソプロピル、ブチル、イソブチル、
ｓｅｃ−ブチル、ｔ−ブチル等の直鎖又は分枝状の炭素
数１乃至４のアルキル基が挙げられ、ジアルキルアミノ
メチレンアミノ基中のアルキル基としては、エチル、プ
ロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ−
ブチル、ｔ−ブチル等の直鎖又は分枝状の炭素数１乃至
４のアルキル基が挙げられる。In the above general formula (VII), the alkyl group for Ra 7 or Rb 7 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t.
-A straight-chain or branched alkyl group having 1 to 4 carbon atoms such as butyl. Examples of the acyl group in the acylamino group for Rc 7 include formyl, acetyl, propionyl,
Examples thereof include linear or branched C1 to C4 acyl groups such as butyryl, isobutyryl, and t-butyryl, and benzoyl groups. Examples of the alkyl group in the alkylamino group include ethyl, propyl, isopropyl, butyl, and isobutyl. ,
Examples thereof include linear or branched alkyl groups having 1 to 4 carbon atoms such as sec-butyl and t-butyl. Examples of the alkyl group in the dialkylaminomethyleneamino group include ethyl, propyl, isopropyl, butyl, isobutyl, sec-
Examples thereof include linear or branched alkyl groups having 1 to 4 carbon atoms such as butyl and t-butyl.
【００２０】本発明化合物中、特に好ましい化合物は以
下の通りである。 ・５−アミノ−１，３−ジエチル−７−メチルピリド
〔２，３−ｄ〕ピリミジン−２，４−ジオン（化合物
１） ・１，３−ジエチル−５−イソプロピルアミノ−７−メ
チルピリド〔２，３−ｄ〕ピリミジン−２，４−ジオン
（化合物２） ・７−アミノ−１，３−ジエチル−６−エトキシカルボ
ニルピリド〔２，３−ｄ〕ピリミジン−２，４−ジオン
（化合物３） ・５−アミノピリド〔２，３−ｄ〕ピリミジン−２，４
−ジオン（化合物４） ・５−イソプロピルアミノピリド〔２，３−ｄ〕ピリミ
ジン−２，４−ジオン（化合物５）Among the compounds of the present invention, particularly preferable compounds are as follows. 5-amino-1,3-diethyl-7-methylpyrido [2,3-d] pyrimidine-2,4-dione (Compound 1) 1,3-diethyl-5-isopropylamino-7-methylpyrido [2,2] 3-d] pyrimidine-2,4-dione (Compound 2) 7-amino-1,3-diethyl-6-ethoxycarbonylpyrido [2,3-d] pyrimidine-2,4-dione (Compound 3) -5-aminopyrido [2,3-d] pyrimidine-2,4
-Dione (compound 4) -5-isopropylaminopyrido [2,3-d] pyrimidine-2,4-dione (compound 5)
【００２１】・５−ベンジルアミノピリド〔２，３−
ｄ〕ピリミジン−２，４−ジオン（化合物６） ・５−アミノ−３−メチルピリド〔２，３−ｄ〕ピリミ
ジン−２，４−ジオン（化合物７） ・５−アミノ−３−エチルピリド〔２，３−ｄ〕ピリミ
ジン−２，４−ジオン（化合物８） ・５−アミノ−１−メチルピリド〔２，３−ｄ〕ピリミ
ジン−２，４−ジオン（化合物９） ・５−アミノ−１−エチルピリド〔２，３−ｄ〕ピリミ
ジン−２，４−ジオン（化合物１０） ・５−イソプロピルアミノ−３−メチルピリド〔２，３
−ｄ〕ピリミジン−２，４−ジオン（化合物１１） ・３−エチル−５−イソプロピルアミノピリド〔２，３
−ｄ〕ピリミジン−２，４−ジオン（化合物１２） ・５−イソプロピルアミノ−１−メチルピリド〔２，３
−ｄ〕ピリミジン−２，４−ジオン（化合物１３） ・１−エチル−５−イソプロピルアミノピリド〔２，３
−ｄ〕ピリミジン−２，４−ジオン（化合物１４） ・５−アミノ−３−エチル−１−メチルピリド〔２，３
−ｄ〕ピリミジン−２，４−ジオン（化合物１５）5-benzylaminopyrido [2,3-
d] pyrimidine-2,4-dione (compound 6) -5-amino-3-methylpyrido [2,3-d] pyrimidine-2,4-dione (compound 7) -5-amino-3-ethylpyrido [2,2 3-d] pyrimidine-2,4-dione (compound 8) -5-amino-1-methylpyrido [2,3-d] pyrimidine-2,4-dione (compound 9) -5-amino-1-ethylpyrido [ 2,3-d] pyrimidine-2,4-dione (Compound 10) .5-isopropylamino-3-methylpyrido [2,3
-D] pyrimidine-2,4-dione (Compound 11) 3-ethyl-5-isopropylaminopyrido [2,3
-D] pyrimidine-2,4-dione (Compound 12) -5-isopropylamino-1-methylpyrido [2,3
-D] pyrimidine-2,4-dione (compound 13). 1-ethyl-5-isopropylaminopyrido [2,3
-D] pyrimidine-2,4-dione (compound 14) .5-amino-3-ethyl-1-methylpyrido [2,3
-D] pyrimidine-2,4-dione (Compound 15)
【００２２】・５−アミノ−１−エチル−３−メチルピ
リド〔２，３−ｄ〕ピリミジン−２，４−ジオン（化合
物１６） ・３−エチル−５−イソプロピルアミノ−１−メチルピ
リド〔２，３−ｄ〕ピリミジン−２，４−ジオン（化合
物１７） ・１−エチル−５−イソプロピルアミノ−３−メチルピ
リド〔２，３−ｄ〕ピリミジン−２，４−ジオン（化合
物１８） ・５−アミノ−１−ベンジルピリド〔２，３−ｄ〕ピリ
ミジン−２，４−ジオン（化合物１９） ・５−アミノ−１−ベンジル−３−メチルピリド〔２，
３−ｄ〕ピリミジン−２，４−ジオン（化合物２０） ・５−アミノ−１−ベンジル−３−エチルピリド〔２，
３−ｄ〕ピリミジン−２，４−ジオン（化合物２１） ・１−ベンジル−５−イソプロピルアミノピリド〔２，
３−ｄ〕ピリミジン−２，４−ジオン（化合物２２） ・１−ベンジル−５−イソプロピルアミノ−３−メチル
ピリド〔２，３−ｄ〕ピリミジン−２，４−ジオン（化
合物２３） ・１−ベンジル−３−エチル−５−イソプロピルアミノ
ピリド〔２，３−ｄ〕ピリミジン−２，４−ジオン（化
合物２４） ・１−ベンジル−５−ベンジルアミノピリド〔２，３−
ｄ〕ピリミジン−２，４−ジオン（化合物２５）5-Amino-1-ethyl-3-methylpyrido [2,3-d] pyrimidine-2,4-dione (Compound 16) 3-Ethyl-5-isopropylamino-1-methylpyrido [2,3] -D] pyrimidine-2,4-dione (Compound 17) -1 -ethyl-5-isopropylamino-3-methylpyrido [2,3-d] pyrimidine-2,4-dione (Compound 18) -5-amino- 1-benzylpyrido [2,3-d] pyrimidine-2,4-dione (Compound 19) 5-amino-1-benzyl-3-methylpyrido [2,2
3-d] pyrimidine-2,4-dione (Compound 20) 5-amino-1-benzyl-3-ethylpyrido [2,2]
3-d] pyrimidine-2,4-dione (Compound 21) 1-benzyl-5-isopropylaminopyrido [2,2]
3-d] pyrimidine-2,4-dione (Compound 22). 1-benzyl-5-isopropylamino-3-methylpyrido [2,3-d] pyrimidine-2,4-dione (Compound 23). -3-Ethyl-5-isopropylaminopyrido [2,3-d] pyrimidine-2,4-dione (Compound 24) 1-benzyl-5-benzylaminopyrido [2,3-
d] Pyrimidine-2,4-dione (Compound 25)
【００２３】・５−ベンジルアミノ−１，３−ジエチル
ピリド〔２，３−ｄ〕ピリミジン−２，４−ジオン（化
合物２６） ・１，３−ジエチル−５−イソプロピルアミノピリド
〔２，３−ｄ〕ピリミジン−２，４−ジオン（化合物２
７） ・５−アセチルアミノ−１，３−ジメチルピリド〔２，
３−ｄ〕ピリミジン−２，４−ジオン（化合物２８） ・５−ベンゾイルアミノ−１，３−ジメチルピリド
〔２，３−ｄ〕ピリミジン−２，４−ジオン（化合物２
９） ・１，３−ジメチル−５−ジメチルアミノメチレンアミ
ノピリド〔２，３−ｄ〕ピリミジン−２，４−ジオン
（化合物３０） ・５−アセチルアミノ−１，３−ジエチルピリド〔２，
３−ｄ〕ピリミジン−２，４−ジオン（化合物３１） ・５−ベンゾイルアミノ−１，３−ジエチルピリド
〔２，３−ｄ〕ピリミジン−２，４−ジオン（化合物３
２） ・１，３−ジエチル−５−ジメチルアミノメチレンアミ
ノピリド〔２，３−ｄ〕ピリミジン−２，４−ジオン
（化合物３３） ・１，３−ジエチル−５−ホルムアミドピリド〔２，３
−ｄ〕ピリミジン−２，３−ｄ〕ピリミジン−２，４−
ジオン（化合物３４）5-benzylamino-1,3-diethylpyrido [2,3-d] pyrimidine-2,4-dione (compound 26) 1,3-diethyl-5-isopropylaminopyrido [2,3- d] pyrimidine-2,4-dione (compound 2
7) ・ 5-Acetylamino-1,3-dimethylpyrido [2,
3-d] pyrimidine-2,4-dione (Compound 28) 5-benzoylamino-1,3-dimethylpyrido [2,3-d] pyrimidine-2,4-dione (Compound 2)
9) 1,3-Dimethyl-5-dimethylaminomethyleneaminopyrido [2,3-d] pyrimidine-2,4-dione (Compound 30) 5-Acetylamino-1,3-diethylpyrido [2,2]
3-d] pyrimidine-2,4-dione (Compound 31) 5-benzoylamino-1,3-diethylpyrido [2,3-d] pyrimidine-2,4-dione (Compound 3
2) 1,3-diethyl-5-dimethylaminomethyleneaminopyrido [2,3-d] pyrimidine-2,4-dione (compound 33) 1,3-diethyl-5-formamidopyrido [2,2] Three
-D] pyrimidine-2,3-d] pyrimidine-2,4-
Dione (compound 34)
【００２４】本発明新規ピリド〔２，３−ｄ〕ピリミジ
ン誘導体は、前記一般式（Ｉ）乃至（VII)で表される化
合物の薬学的に許容される塩を包含し、例えば、塩酸、
硫酸、硝酸、臭化水素酸、リン酸、過塩素酸、チオシア
ン酸、ホウ酸、ギ酸、酢酸、ハロ酢酸、プロピオン酸、
グリコール酸、クエン酸、酒石酸、コハク酸、グルコン
酸、乳酸、マロン酸、フマール酸、アントラニル酸、安
息香酸、ケイ皮酸、ｐ−トルエンスルホン酸、ナフタレ
ンスルホン酸、スルファニル酸等との酸付加塩、或いは
ナトリウム、カリウム等のアルカリ金属、カルシウム、
マグネシウム等のアルカリ土類金属又はアルミニウム等
の金属との塩を挙げることができる。The novel pyrido [2,3-d] pyrimidine derivatives of the present invention include pharmaceutically acceptable salts of the compounds represented by the above general formulas (I) to (VII), for example, hydrochloric acid,
Sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, perchloric acid, thiocyanic acid, boric acid, formic acid, acetic acid, haloacetic acid, propionic acid,
Acid addition salts with glycolic acid, citric acid, tartaric acid, succinic acid, gluconic acid, lactic acid, malonic acid, fumaric acid, anthranilic acid, benzoic acid, cinnamic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, sulfanilic acid, etc. , Or alkali metals such as sodium and potassium, calcium,
Examples thereof include salts with alkaline earth metals such as magnesium or metals such as aluminum.
【００２５】本発明新規ピリド〔２，３−ｄ〕ピリミジ
ン誘導体は、その金属錯化合物を包含し、例えば、亜
鉛、ニッケル、コバルト、銅、鉄等との錯化合物が挙げ
られる。これらの塩若しくは金属錯化合物は公知の方法
により、遊離の本発明ピリド〔２，３−ｄ〕ピリミジン
誘導体より製造でき或いは相互に変換できる。また本発
明化合物においてシス−トランス異性体、光学異性体、
配座異性体等の立体異性体が存在する場合、或いは水和
物の状態で存在する場合においても、本発明はそのいず
れの立体異性体及び水和物をも包含する。The novel pyrido [2,3-d] pyrimidine derivative of the present invention includes its metal complex compound, and examples thereof include complex compounds with zinc, nickel, cobalt, copper, iron and the like. These salts or metal complex compounds can be produced from the free pyrido [2,3-d] pyrimidine derivative of the present invention or converted into each other by a known method. Further, in the compound of the present invention, cis-trans isomer, optical isomer,
When stereoisomers such as conformational isomers exist or exist in the state of hydrates, the present invention includes any stereoisomers and hydrates thereof.
【００２６】本発明化合物の製造方法に関しては、特開
昭６３−４５２７９号公報記載の方法に従って、或いは
それに準じて製造することができるが、さらに具体的に
本発明化合物の製造方法について、以下の実施例におい
て詳細に示した。Regarding the method for producing the compound of the present invention, it can be produced according to the method described in JP-A-63-45279 or in accordance therewith. More specifically, the method for producing the compound of the present invention will be described below. Details are shown in the examples.
【００２７】[0027]
実施例１． （１）３ｇの１−ベンジル−５−クロロピリド〔２，３
−ｄ〕ピリミジン−２，４−ジオンと１ｇのアジ化ナト
リウムをジメチルホルムアミド（ＤＭＦ）３０ｍｌに溶
解し、室温で１０時間攪拌した。反応液を４００ｍｌの
水に加え、析出した結晶を濾取して、乾燥後、１５０ｍ
ｌのメタノールに溶解し、０．５ｇの１０％パラジウム
−炭素を加え、水素雰囲気下、室温で１５時間攪拌し
た。触媒を除去し、濾液を濃縮後、残渣を１Ｎ塩酸に溶
解し、クロロホルムで洗浄後水層を２０％水酸化ナトリ
ウムで中和した。析出した結晶をクロロホルムにて抽出
し、有機層を濃縮後、得られた結晶をエチルアセテート
から再結晶して１．５ｇの化合物１９を得た。 融点: 291.5-292 ℃ NMR(DMSO-d6): 5.30(s,2H), 6.40(d,1H), 7.16-7.32(m,
5H), 7.62(bs,1H), 7.90(d,1H), 8.19(bs,1H), 11.45(b
s,1H).Example 1. (1) 3 g of 1-benzyl-5-chloropyrido [2,3
-D] Pyrimidine-2,4-dione and 1 g of sodium azide were dissolved in 30 ml of dimethylformamide (DMF), and the mixture was stirred at room temperature for 10 hours. The reaction solution was added to 400 ml of water, and the precipitated crystals were collected by filtration, dried, and dried to 150 m.
It was dissolved in 1 l of methanol, 0.5 g of 10% palladium-carbon was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 15 hours. The catalyst was removed, the filtrate was concentrated, the residue was dissolved in 1N hydrochloric acid, washed with chloroform, and the aqueous layer was neutralized with 20% sodium hydroxide. The precipitated crystals were extracted with chloroform, the organic layer was concentrated, and the obtained crystals were recrystallized from ethyl acetate to obtain 1.5 g of compound 19. Melting point: 291.5-292 ° C NMR (DMSO-d 6 ): 5.30 (s, 2H), 6.40 (d, 1H), 7.16-7.32 (m,
5H), 7.62 (bs, 1H), 7.90 (d, 1H), 8.19 (bs, 1H), 11.45 (b
s, 1H).
【００２８】１−置換−、３−置換−又は１，３−ジ置
換−５−クロロピリド〔２，３−ｄ〕ピリミジン−２，
４−ジオンを同様に処理して、以下の化合物を得た。 （化合物９） 融点: >300℃ NMR(DMSO-d6): 3.38(s,3H), 6.39(d,1H), 7.58(bs,1H),
7.94(d,1H), 8.16(bs,1H), 11.33(bs,2H). （化合物１０） 融点: >300℃ NMR(DMSO-d6): 1.13(t,3H), 4.12(q,2H), 6.39(d,1H),
7.57(bs,1H), 7.95(d,1H), 8.17(bs,1H), 11.32(bs,1
H). （化合物１５） 融点: 211-212 ℃ NMR(DMSO-d6): 1.14(t,3H), 3.46(s,3H), 3.91(q,2H),
6.42(d,1H), 7.62(bs,1H), 7.95(d,1H), 8.26(bs,1H). （化合物１６） 融点: 246-247 ℃ NMR(DMSO-d6): 1.16(t,3H), 3.24(s,3H), 4.20(q,2H),
6.42(d,1H), 7.60(bs,1H), 7.96(d,1H), 8.25(bs,1H). （化合物２０） 融点: 187-188 ℃ NMR(DMSO-d6): 3.26(s,3H), 5.37(s,2H), 6.44(d,1H),
7.16-7.33(m,5H), 7.66(bs,1H), 7.92(d,1H), 8.23(bs,
1H). （化合物２１） 融点: 187-188 ℃ NMR(DMSO-d6): 1.15(t,3H), 3.93(q,2H), 5.37(s,2H),
6.45(d,1H), 7.16-7.3(m,5H), 7.68(bs,1H), 7.90(d,1
H), 8.29(bs,1H).1-substituted-, 3-substituted- or 1,3-disubstituted-5-chloropyrido [2,3-d] pyrimidine-2,
The 4-dione was similarly treated to give the following compound. (Compound 9) Melting point:> 300 ° C NMR (DMSO-d 6 ): 3.38 (s, 3H), 6.39 (d, 1H), 7.58 (bs, 1H),
7.94 (d, 1H), 8.16 (bs, 1H), 11.33 (bs, 2H). (Compound 10) Melting point:> 300 ° C NMR (DMSO-d 6 ): 1.13 (t, 3H), 4.12 (q, 2H) ), 6.39 (d, 1H),
7.57 (bs, 1H), 7.95 (d, 1H), 8.17 (bs, 1H), 11.32 (bs, 1
H). (Compound 15) Melting point: 211-212 ° C. NMR (DMSO-d 6 ): 1.14 (t, 3H), 3.46 (s, 3H), 3.91 (q, 2H),
6.42 (d, 1H), 7.62 (bs, 1H), 7.95 (d, 1H), 8.26 (bs, 1H). (Compound 16) Melting point: 246-247 ° C NMR (DMSO-d 6 ): 1.16 (t, 3H), 3.24 (s, 3H), 4.20 (q, 2H),
6.42 (d, 1H), 7.60 (bs, 1H), 7.96 (d, 1H), 8.25 (bs, 1H). (Compound 20) Melting point: 187-188 ° C NMR (DMSO-d 6 ): 3.26 (s, 3H), 5.37 (s, 2H), 6.44 (d, 1H),
7.16-7.33 (m, 5H), 7.66 (bs, 1H), 7.92 (d, 1H), 8.23 (bs,
1H). (Compound 21) Melting point: 187-188 ° C NMR (DMSO-d 6 ): 1.15 (t, 3H), 3.93 (q, 2H), 5.37 (s, 2H),
6.45 (d, 1H), 7.16-7.3 (m, 5H), 7.68 (bs, 1H), 7.90 (d, 1
H), 8.29 (bs, 1H).
【００２９】（２）５ｇの５−クロロ−１，３−ジエチ
ルピリド〔２，３−ｄ〕ピリミジン−２，４−ジオンと
３．５ｇのイソプロピルアミンをＤＭＦ７０ｍｌに溶解
し、室温で１２時間攪拌した。反応液を氷水に加え、析
出した結晶を濾取して、乾燥後、シリカゲルカラムで精
製して４．９ｇの化合物２７を得た。 融点: 118-119 ℃ NMR(DMSO-d6): 1.12(t,3H), 1.18 (t,3H), 1.22(d,6H),
3.75-3.88(m,1H), 3.85(q,2H), 4.21(q,2H), 6.41(d,1
H), 7.96(d,1H), 8.91(d,1H), 11.47(bs,1H).(2) 5 g of 5-chloro-1,3-diethylpyrido [2,3-d] pyrimidine-2,4-dione and 3.5 g of isopropylamine were dissolved in 70 ml of DMF and stirred at room temperature for 12 hours. . The reaction solution was added to ice water, and the precipitated crystals were collected by filtration, dried and purified with a silica gel column to obtain 4.9 g of compound 27. Melting point: 118-119 ° C NMR (DMSO-d 6 ): 1.12 (t, 3H), 1.18 (t, 3H), 1.22 (d, 6H),
3.75-3.88 (m, 1H), 3.85 (q, 2H), 4.21 (q, 2H), 6.41 (d, 1
H), 7.96 (d, 1H), 8.91 (d, 1H), 11.47 (bs, 1H).
【００３０】１−置換−、３−置換−又は１，３−ジ置
換−５−クロロピリド〔２，３−ｄ〕ピリミジン−２，
４−ジオンと種々の置換アミン類を反応させ、同様の方
法で以下の化合物を得た。 （化合物２６） 融点: 111-112 ℃ NMR(DMSO-d6): 1.15(t,3H), 1.17(t,3H), 3.93(q,2H),
4.21(q,2H), 4.56(d,2H), 6.45(d,1H), 7.2-7.4(m,5H),
8.05(d,1H), 9.57(t,1H). （化合物１３） 融点: 215.8-216.6 ℃ NMR(DMSO-d6): 1.22(d,6H), 3.39(s,3H), 3.81(dq,1H),
6.48(d,1H), 8.06(d,1H), 8.99(d,1H), 11.45(bs,1H). （化合物１４） 融点: 227-228 ℃ NMR(DMSO-d6): 1.14(t,3H), 1.21(d,6H), 3.82(dq,1H),
4.13(q,2H), 6.48(d,1H), 8.07(d,1H), 9.00(d,1H), 1
1.43(bs,1H). （化合物１７） 融点: 141.0-141.5 ℃ NMR(DMSO-d6): 1.14(t,3H), 1.23(d,6H), 3.47(s,3H),
3.84(dq,1H), 3.92(q,2H), 6.52(d,1H), 8.08(d,1H),
9.10(d,1H). （化合物１８） 融点: 95-96.5 ℃ NMR(DMSO-d6): 1.16(t,3H), 1.23(d,6H), 3.24(s,3H),
3.84(dq,1H), 4.21(q,2H), 6.51(d,1H), 8.08(d,1H),
9.10(d,1H).1-substituted-, 3-substituted- or 1,3-disubstituted-5-chloropyrido [2,3-d] pyrimidine-2,
4-dione was reacted with various substituted amines to obtain the following compound by the same method. (Compound 26) Melting point: 111-112 ° C NMR (DMSO-d 6 ): 1.15 (t, 3H), 1.17 (t, 3H), 3.93 (q, 2H),
4.21 (q, 2H), 4.56 (d, 2H), 6.45 (d, 1H), 7.2-7.4 (m, 5H),
8.05 (d, 1H), 9.57 (t, 1H). (Compound 13) Melting point: 215.8-216.6 ° C NMR (DMSO-d 6 ): 1.22 (d, 6H), 3.39 (s, 3H), 3.81 (dq, 1H),
6.48 (d, 1H), 8.06 (d, 1H), 8.99 (d, 1H), 11.45 (bs, 1H). (Compound 14) Melting point: 227-228 ° C NMR (DMSO-d 6 ): 1.14 (t, 3H), 1.21 (d, 6H), 3.82 (dq, 1H),
4.13 (q, 2H), 6.48 (d, 1H), 8.07 (d, 1H), 9.00 (d, 1H), 1
1.43 (bs, 1H). (Compound 17) Melting point: 141.0-141.5 ° C NMR (DMSO-d 6 ): 1.14 (t, 3H), 1.23 (d, 6H), 3.47 (s, 3H),
3.84 (dq, 1H), 3.92 (q, 2H), 6.52 (d, 1H), 8.08 (d, 1H),
9.10 (d, 1H). (Compound 18) Melting point: 95-96.5 ° C. NMR (DMSO-d 6 ): 1.16 (t, 3H), 1.23 (d, 6H), 3.24 (s, 3H),
3.84 (dq, 1H), 4.21 (q, 2H), 6.51 (d, 1H), 8.08 (d, 1H),
9.10 (d, 1H).
【００３１】（化合物２２） 融点: 205-206 ℃ NMR(DMSO-d6): 1.22(d,6H), 3.82(m,1H), 5.31(s,2H),
6.49(d,1H), 7.16-7.33(m,5H), 8.02(d,1H), 9.01(d,1
H), 11.56(bs,1H). （化合物２３） 融点: 128-129 ℃ NMR(DMSO-d6): 1.23(d,6H), 3.26(s,3H), 3.84(dq,1H),
5.39(s,2H), 6.52(d,1H), 7.15-7.33(m,5H), 8.04(d,1
H), 9.12(d,1H). （化合物２４） 融点: 136-137 ℃ NMR(DMSO-d6): 1.15(t,3H), 1.23(d,6H), 3.84(dq,1H),
3.94(q,2H), 5.39(s,2H), 6.52(d,1H), 7.15-7.3(m,5
H), 8.03(d,1H), 9.13(d,1H). （化合物２５） 融点: 223.4-224.6 ℃ NMR(DMSO-d6): 4.57(d,2H), 5.31(s,2H), 6.44(d,1H),
7.16-7.42(m,10H), 7.99(d,1H), 9.49(t,1H), 11.59(b
s,1H).(Compound 22) Melting point: 205-206 ° C. NMR (DMSO-d 6 ): 1.22 (d, 6H), 3.82 (m, 1H), 5.31 (s, 2H),
6.49 (d, 1H), 7.16-7.33 (m, 5H), 8.02 (d, 1H), 9.01 (d, 1
H), 11.56 (bs, 1H). (Compound 23) Melting point: 128-129 ° C. NMR (DMSO-d 6 ): 1.23 (d, 6H), 3.26 (s, 3H), 3.84 (dq, 1H),
5.39 (s, 2H), 6.52 (d, 1H), 7.15-7.33 (m, 5H), 8.04 (d, 1
H), 9.12 (d, 1H). (Compound 24) Melting point: 136-137 ° C. NMR (DMSO-d 6 ): 1.15 (t, 3H), 1.23 (d, 6H), 3.84 (dq, 1H),
3.94 (q, 2H), 5.39 (s, 2H), 6.52 (d, 1H), 7.15-7.3 (m, 5
(H), 8.03 (d, 1H), 9.13 (d, 1H). (Compound 25) Melting point: 223.4-224.6 ° C NMR (DMSO-d 6 ): 4.57 (d, 2H), 5.31 (s, 2H), 6.44 (d, 1H),
7.16-7.42 (m, 10H), 7.99 (d, 1H), 9.49 (t, 1H), 11.59 (b
s, 1H).
【００３２】（化合物２８） 融点: 196-197 ℃. （化合物２９） 融点: 243-244 ℃. （化合物３０） 融点: 149-150 ℃. （化合物３１） 融点: 141-142 ℃. （化合物３２） 融点: 191-192 ℃. （化合物３３） 融点: 100-101 ℃. （化合物３４） 融点: 163-164 ℃.(Compound 28) Melting point: 196-197 ° C. (Compound 29) Melting point: 243-244 ° C. (Compound 30) Melting point: 149-150 ° C. (Compound 31) Melting point: 141-142 ° C. (Compound 32 ) Melting point: 191-192 ℃. (Compound 33) Melting point: 100-101 ℃. (Compound 34) Melting point: 163-164 ℃.
【００３３】実施例２．７．５ｇの化合物４６と１ｇの
１０％パラジウム−炭素を６００ｍｌの酢酸に加え、５
０℃で１５時間攪拌した。反応液に活性炭を加え、３０
分間加熱還流後、不溶物を濾過し、濾液を濃縮した。残
渣にエタノールを加え、結晶を濾取し乾燥して５ｇの化
合物５を得た。 融点: >300℃ NMR(DMSO-d6): 1.21(d,6H), 3.78(dq,1H), 6.39(d,1H),
7.94(d,1H), 8.79(d,1H), 11.18(bs,2H).Example 2.7.5 g of compound 46 and 1 g of 10% palladium on carbon were added to 600 ml of acetic acid and 5
The mixture was stirred at 0 ° C for 15 hours. Activated carbon is added to the reaction mixture,
After heating under reflux for 1 minute, the insoluble material was filtered off and the filtrate was concentrated. Ethanol was added to the residue, and the crystals were collected by filtration and dried to obtain 5 g of compound 5. Melting point:> 300 ° C NMR (DMSO-d 6 ): 1.21 (d, 6H), 3.78 (dq, 1H), 6.39 (d, 1H),
7.94 (d, 1H), 8.79 (d, 1H), 11.18 (bs, 2H).
【００３４】化合物１９、２０、２１、２３、２４及び
２５を同様に処理して、以下の化合物を得た。 （化合物４） 融点: >300℃ NMR(DMSO-d6): 6.30(d,1H), 7.50(bs,1H), 7.84(d,1H),
8.01(bs,1H), 11.69(bs,2H). （化合物７） 融点: >300℃ NMR(DMSO-d6): 3.17(s,3H), 6.34(d,1H), 7.55(bs,1H),
7.83(d,1H), 8.09(bs,1H). （化合物８） 融点 :>300℃ NMR(DMSO-d6): 1.11(t,3H), 3.85(q,2H), 6.33(d,1H),
7.55(bs,1H), 7.83(d,1H), 8.10(bs,1H), 11.38(bs,1
H). （化合物１１） 融点: 240.5-241 ℃ NMR(DMSO-d6): 1.22(d,6H), 3.17(s,3H), 3.81(dq,1H),
6.41(d,1H), 7.96(d,1H), 8.90(d,1H), 11.48(bs,1H). （化合物１２） 融点: 249.5-250 ℃ NMR(DMSO-d6): 1.16(t,3H), 1.22(d,6H), 3.8(dq,1H),
3.85(q,2H), 6.41(d,1H), 7.96(d,1H), 8.9(d,1H). （化合物６） 融点: >300℃ NMR(DMSO-d6): 4.54(d,2H), 6.34(d,1H), 7.22-7.42(m,
5H), 7.92(d,1H), 9.27(t,1H), 11.21(bs,1H), 11.25(b
s,1H).Compounds 19, 20, 21, 23, 24 and 25 were similarly treated to give the following compounds. (Compound 4) Melting point:> 300 ° C NMR (DMSO-d 6 ): 6.30 (d, 1H), 7.50 (bs, 1H), 7.84 (d, 1H),
8.01 (bs, 1H), 11.69 (bs, 2H). (Compound 7) Melting point:> 300 ° C NMR (DMSO-d 6 ): 3.17 (s, 3H), 6.34 (d, 1H), 7.55 (bs, 1H ),
7.83 (d, 1H), 8.09 (bs, 1H). (Compound 8) Melting point:> 300 ° C NMR (DMSO-d 6 ): 1.11 (t, 3H), 3.85 (q, 2H), 6.33 (d, 1H) ),
7.55 (bs, 1H), 7.83 (d, 1H), 8.10 (bs, 1H), 11.38 (bs, 1
H). (Compound 11) Melting point: 240.5-241 ° C NMR (DMSO-d 6 ): 1.22 (d, 6H), 3.17 (s, 3H), 3.81 (dq, 1H),
6.41 (d, 1H), 7.96 (d, 1H), 8.90 (d, 1H), 11.48 (bs, 1H). (Compound 12) Melting point: 249.5-250 ° C NMR (DMSO-d 6 ): 1.16 (t, 3H), 1.22 (d, 6H), 3.8 (dq, 1H),
3.85 (q, 2H), 6.41 (d, 1H), 7.96 (d, 1H), 8.9 (d, 1H). (Compound 6) Melting point:> 300 ° C NMR (DMSO-d 6 ): 4.54 (d, 2H) ), 6.34 (d, 1H), 7.22-7.42 (m,
5H), 7.92 (d, 1H), 9.27 (t, 1H), 11.21 (bs, 1H), 11.25 (b
s, 1H).
【００３５】実施例３． （１）前記の実施例１（１）における１−ベンジル−５
−クロロピリド〔２，３−ｄ〕ピリミジン−２，４−ジ
オンの代わりに、１，３−ジエチル−７−メチル−５−
（ｐ−トルエンスルホニルオキシ）ピリド〔２，３−
ｄ〕ピリミジン−２，４−ジオンを用いて、実施例１
（１）と同様の反応を行って化合物１を得た。 融点: 198.5-199.0 ℃ NMR(DMSO-d6): 1.13(t,3H), 1.16(t,3H), 2.27(s,3H),
3.91(q,2H), 4.19(q,2H), 6.28(s,1H), 7.48(bs,1H),
8.16(bs,1H).Example 3. (1) 1-benzyl-5 in the above-mentioned Example 1 (1)
-Chloropyrido [2,3-d] pyrimidine-2,4-dione instead of 1,3-diethyl-7-methyl-5-
(P-Toluenesulfonyloxy) pyrido [2,3-
d] pyrimidine-2,4-dione, Example 1
The same reaction as in (1) was performed to obtain compound 1. Melting point: 198.5-199.0 ° C NMR (DMSO-d 6 ): 1.13 (t, 3H), 1.16 (t, 3H), 2.27 (s, 3H),
3.91 (q, 2H), 4.19 (q, 2H), 6.28 (s, 1H), 7.48 (bs, 1H),
8.16 (bs, 1H).
【００３６】（２）前記の実施例１（２）において、５
−クロロ−１，３−ジエチルピリド〔２，３−ｄ〕ピリ
ミジン−２，４−ジオンの代わりに、１，３−ジエチル
−７−メチル−５−（ｐ−トルエンスルホニルオキシ）
ピリド〔２，３−ｄ〕ピリミジン−２，４−ジオンを用
いて、実施例１（２）と同様の反応を行って化合物２を
得た。 融点: 92-93 ℃ NMR(DMSO-d6): 1.13(t,3H), 1.16(t,3H), 1.22(d,6H),
2.34(s,3H), 3.82(dq,1H), 3.91(q,2H), 4.20(q,2H),
6.40(s,1H), 8.99(d,1H).(2) In the above-mentioned Embodiment 1 (2), 5
-Chloro-1,3-diethylpyrido [2,3-d] pyrimidine-2,4-dione instead of 1,3-diethyl-7-methyl-5- (p-toluenesulfonyloxy)
Using pyrido [2,3-d] pyrimidine-2,4-dione, the same reaction as in Example 1 (2) was performed to give compound 2. Melting point: 92-93 ° C NMR (DMSO-d 6 ): 1.13 (t, 3H), 1.16 (t, 3H), 1.22 (d, 6H),
2.34 (s, 3H), 3.82 (dq, 1H), 3.91 (q, 2H), 4.20 (q, 2H),
6.40 (s, 1H), 8.99 (d, 1H).
【００３７】実施例４．３．０ｇの６−アミノ−１，３
−ジエチルウラシルと３．４ｇのエチル２−エトキシメ
チレン−２−シアノアセテートを、アルゴン雰囲気下１
７０℃で１時間攪拌した。冷却後メタノールを加え結晶
を濾取し、乾燥して得られた混合物をフラシュカラムで
精製した後エタノールから再結晶して化合物３を得た。 融点: 203-204.5 ℃ NMR(DMSO-d6): 1.13(t,3H), 1.20(t,3H), 1.34(t,3H),
3.89(q,2H), 4.16(q,2H), 4.29(q,2H), 7.98(bs,1H),
8.12(bs,1H), 8.52(s,1H).Example 4. 3.0 g of 6-amino-1,3
-Diethyluracil and 3.4 g of ethyl 2-ethoxymethylene-2-cyanoacetate under argon atmosphere 1
The mixture was stirred at 70 ° C for 1 hour. After cooling, methanol was added, the crystals were collected by filtration, dried, and the resulting mixture was purified by a flash column and recrystallized from ethanol to obtain compound 3. Melting point: 203-204.5 ° C NMR (DMSO-d 6 ): 1.13 (t, 3H), 1.20 (t, 3H), 1.34 (t, 3H),
3.89 (q, 2H), 4.16 (q, 2H), 4.29 (q, 2H), 7.98 (bs, 1H),
8.12 (bs, 1H), 8.52 (s, 1H).
【００３８】[0038]
【作用】次に本発明新規ピリド〔２，３−ｄ〕ピリミジ
ン誘導体の薬理作用について詳細に説明する。 （１）気管支拡張作用 モルモットを放血致死させ、気管を摘出し、気管軟骨に
沿って切開した幅約１ｍｍの気管切片の４つを絹糸にて
連結したものを気管平滑筋標本とした。標本はタイロー
ド液を満たし、酸素９５％と二酸化炭素５％の混合ガス
を通気した５mlのマグヌス槽内（３１℃）に約０．５ｇ
の張力を負荷して懸垂した。０．５〜１時間放置してベ
ースラインが安定となった後、ヒスタミン二塩酸塩を作
用させ、その等張性収縮をアイソトニック・トランスデ
ューサーを介して記録した。Next, the pharmacological action of the novel pyrido [2,3-d] pyrimidine derivative of the present invention will be described in detail. (1) Bronchodilation action A guinea pig was exsanguinated and killed, the trachea was extracted, and four tracheal sections with a width of about 1 mm, which were cut along the tracheal cartilage, were connected with silk thread to prepare a tracheal smooth muscle sample. Approximately 0.5g of the sample was filled with Tyrode's solution and placed in a 5ml Magnus tank (31 ° C), which was aerated with a mixed gas of 95% oxygen and 5% carbon dioxide.
Suspended by applying the tension of. After allowing the baseline to stabilize for 0.5-1 hour, histamine dihydrochloride was applied and its isotonic contractions were recorded via isotonic transducers.
【００３９】被験薬の気管支拡張作用の検討は、収縮剤
による持続的収縮反応に対する弛緩作用を指標にした。
すなわち、１０-4Ｍのヒスタミン二塩酸塩による平滑筋
の持続的収縮反応が一定に達した後、被験薬を１０-5Ｍ
濃度で作用させ、持続的収縮高に対する弛緩率を求め、
この弛緩率の強さで活性を評価した。ヒスタミン二塩酸
塩を作用させたときの収縮気管支平滑筋の長さで、被験
薬を作用させ弛緩した長さを除した値を弛緩率とした。In the examination of the bronchodilator effect of the test drug, the relaxing effect on the continuous contractile response by the contractile agent was used as an index.
That is, after the continuous contraction reaction of smooth muscle by 10 −4 M histamine dihydrochloride reached a certain level, the test drug was treated with 10 −5 M.
It acts at a concentration to determine the relaxation rate for continuous contraction height,
The activity was evaluated by the strength of this relaxation rate. The relaxation rate was defined as the value obtained by dividing the length of the contracted bronchial smooth muscle when the histamine dihydrochloride was allowed to act and the length of the relaxed effect of the test drug.
【００４０】以下の表１に実験結果の一例を示す。Table 1 below shows an example of the experimental results.
【表１】 [Table 1]
【００４１】（２）抗アレルギー作用 本発明化合物の抗アレルギー作用をラット受身皮膚アナ
フィラキシー（ＰＣＡ）反応により評価した。背部を刈
毛した一群６匹のウイスター系雄性ラット（６週令）の
背部皮内４カ所に、生理食塩水で希釈した抗ＤＮＰ−Ａ
ｓｃ溶液を投与することにより受動感作した。被検薬を
経口投与した１時間後、ＤＮＰ−Ａｓｃ溶液（５ｍｇ／
ｍｌ）と２％エバンスブルー溶液の当量混合物を静脈内
投与してＰＣＡ反応を惹起させた。３０分後に断頭放血
して屠殺し、青色斑部分を切取り、その漏出色素量を測
定した。即ち、２Ｎ水酸化カリウム水溶液で皮膚を溶解
させ、２Ｎリン酸水溶液、アセトンを加えて遠心分離
後、得られた上清の６２０ｎｍにおける吸光度により色
素量を測定し、色素漏出の抑制率を求めた。その結果、
本発明化合物２０ｍｇ／ｋｇの経口投与群において、対
照群と比較して有為な色素漏出の抑制作用が観察され
た。(2) Antiallergic action The antiallergic action of the compound of the present invention was evaluated by the rat passive cutaneous anaphylaxis (PCA) reaction. A group of 6 Wistar male rats (6 weeks old) with shaved backs were treated with anti-DNP-A diluted in physiological saline at 4 intradermal sites on the back.
Passive sensitization was performed by administering sc solution. One hour after oral administration of the test drug, a DNP-Asc solution (5 mg /
(ml) and an equivalent mixture of 2% Evans blue solution were intravenously administered to induce a PCA reaction. Thirty minutes later, the blood was decapitated and sacrificed, the blue spot was cut off, and the amount of the leaked pigment was measured. That is, the skin was dissolved with 2N potassium hydroxide aqueous solution, 2N phosphoric acid aqueous solution and acetone were added, and after centrifugation, the dye amount was measured by the absorbance of the obtained supernatant at 620 nm to obtain the dye leakage inhibition rate. . as a result,
In the oral administration group of the compound of the present invention 20 mg / kg, a significant inhibitory effect on dye leakage was observed as compared with the control group.
【００４２】[0042]
【効果】以上の薬理実験の結果から明らかなように、本
発明新規ピリド〔２，３−ｄ〕ピリミジン誘導体は優れ
た気管支拡張作用及び抗アレルギー作用を併せ有する。
このように本発明化合物は、ヒスタミン等の化学伝達物
質が関与する喘息症状の発症を抑え予防できることに加
え、収縮した気管平滑筋に直接的に作用して弛緩させ、
喘息発作時の呼吸困難症状をやわらげる即効的な治療に
も用いることができ、アレルギー性喘息のみならず、内
因性喘息、外因性喘息、塵埃喘息等の種々の気管支喘息
の治療に用いることができる。従って、本発明ピリド
〔２，３−ｄ〕ピリミジン誘導体は、アレルギー性鼻
炎、アレルギー性結膜炎、蕁麻疹、アレルギー性皮膚疾
患等の各種アレルギー疾患や気管支喘息等に対する薬剤
として非常に有用性が高いものである。[Effect] As is clear from the results of the above-mentioned pharmacological experiments, the novel pyrido [2,3-d] pyrimidine derivative of the present invention has both excellent bronchodilator action and antiallergic action.
Thus, the compound of the present invention, in addition to being able to suppress and prevent the development of asthma symptoms involving chemical mediators such as histamine, directly acting on the contracted tracheal smooth muscle to relax,
It can be used for immediate treatment to relieve dyspnea symptoms during asthma attack, and can be used not only for allergic asthma but also for various bronchial asthma such as intrinsic asthma, extrinsic asthma, dust asthma, etc. . Therefore, the pyrido [2,3-d] pyrimidine derivative of the present invention is very useful as a drug for allergic diseases such as allergic rhinitis, allergic conjunctivitis, urticaria, and allergic skin diseases and bronchial asthma. Is.
【００４３】[0043]
【実施例】本発明化合物は、適当な医薬用の担体若しく
は希釈剤と組み合わせて医薬とすることができ、通常の
如何なる方法によっても製剤化でき、経口又は非経口投
与するための固体、半固体、液体又は気体の剤形に処方
することができる。処方にあたっては、本発明化合物を
その薬学的に許容しうる塩の形で用いてもよく、本発明
化合物を単独で若しくは適宜組み合わせて用いることが
でき、又、他の医薬活性成分との配合剤としてもよい。EXAMPLES The compound of the present invention can be made into a medicine by combining it with a suitable pharmaceutical carrier or diluent, and can be formulated by any ordinary method. It can be solid or semisolid for oral or parenteral administration. , Liquid or gas dosage forms. In formulating, the compound of the present invention may be used in the form of a pharmaceutically acceptable salt thereof, the compound of the present invention can be used alone or in an appropriate combination, or a combination with another pharmaceutically active ingredient. It may be.
【００４４】経口投与製剤としては、そのまま或いは適
当な添加剤、例えば乳糖、マンニット、トウモロコシデ
ンプン、バレイショデンプン等の慣用の賦形剤と共に、
結晶セルロース、セルロース誘導体、アラビアゴム、ト
ウモロコシデンプン、ゼラチン等の結合剤、トウモロコ
シデンプン、バレイショデンプン、カルボキシメチルセ
ルロースカリウム等の崩壊剤、タルク、ステアリン酸マ
グネシウム等の滑沢剤、その他増量剤、湿潤化剤、緩衝
剤、保存剤、香料等を適宜組み合わせて錠剤、散剤、顆
粒剤或いはカプセル剤とすることができる。As an oral administration preparation, as it is or together with suitable additives, for example, conventional excipients such as lactose, mannitol, corn starch and potato starch,
Crystalline cellulose, cellulose derivatives, gum arabic, corn starch, gelatin and other binders, corn starch, potato starch, carboxymethyl cellulose potassium and other disintegrants, talc, magnesium stearate and other lubricants, other extenders, wetting agents Tablets, powders, granules or capsules can be prepared by appropriately combining buffers, preservatives, perfumes and the like.
【００４５】注射剤としては、水性溶剤又は非水性溶
剤、例えば注射用蒸溜水、生理食塩水、リンゲル液、植
物油、合成脂肪酸グリセリド、高級脂肪酸エステル、プ
ロピレングリコール等の溶液若しくは懸濁液とすること
ができる。また患者の状態や疾患の種類に応じて、その
治療に最適な上記以外の剤形、例えば吸入剤、エアゾー
ル剤、坐剤、軟膏、パップ剤、点眼剤等に適宜製剤化す
ることが可能である。The injection may be an aqueous solvent or a non-aqueous solvent such as distilled water for injection, physiological saline, Ringer's solution, vegetable oil, synthetic fatty acid glyceride, higher fatty acid ester, propylene glycol solution or suspension. it can. Further, depending on the patient's condition and the type of disease, it is possible to appropriately formulate a dosage form other than the above which is most suitable for the treatment, for example, an inhalant, an aerosol, a suppository, an ointment, a poultice, an eye drop, etc. is there.
【００４６】本発明化合物の望ましい投与量は、投与対
象、剤形、投与方法、投与期間等によって変わるが、所
望の効果を得るには、一般の成人に対して通常１日に１
乃至１０００ｍｇ、好ましくは５乃至５００ｍｇを１回
乃至数回に分けて経口投与することができる。また注射
剤等の非経口投与の場合、吸収等の影響により、前記経
口投与量の３乃至１０分の１の用量レベルの投与量が好
ましい。The desirable dose of the compound of the present invention varies depending on the administration subject, dosage form, administration method, administration period, etc.
To 1000 mg, preferably 5 to 500 mg, can be orally administered in one to several divided doses. In the case of parenteral administration of injections and the like, a dose level of 3 to 1/10 of the above oral dose is preferable due to the influence of absorption and the like.
Claims (7)
−ｄ〕ピリミジン誘導体及びその薬学的に許容される
塩。 【化１】 〔式中、Ｒa1及びＲb1は各々同一若しくは異なってアル
キル基を表し、Ｒc1はアミノ基又はアルキルアミノ基を
表し、Ｒe1はアルキル基を表す。〕1. A pyrido [2,3] represented by the general formula (I).
-D] Pyrimidine derivatives and pharmaceutically acceptable salts thereof. Embedded image [In the formula, Ra 1 and Rb 1 are the same or different and each represents an alkyl group, Rc 1 represents an amino group or an alkylamino group, and Re 1 represents an alkyl group. ]
−ｄ〕ピリミジン誘導体及びその薬学的に許容される
塩。 【化２】 〔式中、Ｒa2及びＲb2は各々同一若しくは異なってアル
キル基を表し、Ｒd2はアルコキシカルボニル基を表
す。〕2. A pyrido represented by the general formula (II) [2,3
-D] Pyrimidine derivatives and pharmaceutically acceptable salts thereof. Embedded image [In the formula, Ra 2 and Rb 2 are the same or different and each represents an alkyl group, and Rd 2 represents an alkoxycarbonyl group. ]
−ｄ〕ピリミジン誘導体及びその薬学的に許容される
塩。 【化３】 〔式中、Ｒc3はアミノ基、アルキルアミノ基又はベンジ
ルアミノ基を表す。〕3. A pyrido [2,3 represented by the general formula (III).
-D] Pyrimidine derivatives and pharmaceutically acceptable salts thereof. Embedded image [In the formula, Rc 3 represents an amino group, an alkylamino group or a benzylamino group. ]
−ｄ〕ピリミジン誘導体及びその薬学的に許容される
塩。 【化４】 〔式中、Ｒa4及びＲb4は一方が水素でかつ他方がアルキ
ル基を表し、Ｒc4はアミノ基又はアルキルアミノ基を表
す。〕4. A pyrido [2,3] represented by the general formula (IV):
-D] Pyrimidine derivatives and pharmaceutically acceptable salts thereof. [Chemical 4] [In the formula, one of Ra 4 and Rb 4 is hydrogen and the other is an alkyl group, and Rc 4 is an amino group or an alkylamino group. ]
−ｄ〕ピリミジン誘導体及びその薬学的に許容される
塩。 【化５】 〔式中、Ｒa5及びＲb5は各々異なったアルキル基を表
し、Ｒc5はアミノ基又はアルキルアミノ基を表す。〕5. A pyrido represented by the general formula (V) [2,3
-D] Pyrimidine derivatives and pharmaceutically acceptable salts thereof. Embedded image [In the formula, Ra 5 and Rb 5 represent different alkyl groups, and Rc 5 represents an amino group or an alkylamino group. ]
−ｄ〕ピリミジン誘導体及びその薬学的に許容される
塩。 【化６】 〔式中、Ｒa6は水素又はアルキル基を表し、Ｒc6はアミ
ノ基、アルキルアミノ基又はベンジルアミノ基を表
す。〕6. A pyrido [2,3 represented by the general formula (VI).
-D] Pyrimidine derivatives and pharmaceutically acceptable salts thereof. [Chemical 6] [In the formula, Ra 6 represents hydrogen or an alkyl group, and Rc 6 represents an amino group, an alkylamino group, or a benzylamino group. ]
−ｄ〕ピリミジン誘導体及びその薬学的に許容される
塩。 【化７】 〔式中、Ｒa7及びＲb7は各々同一若しくは異なってアル
キル基を表し、Ｒc7はアシルアミノ基、アルキルアミノ
基、ベンジルアミノ基又はジアルキルアミノメチレンア
ミノ基を表す。〕7. A pyrido represented by the general formula (VII) [2,3
-D] Pyrimidine derivatives and pharmaceutically acceptable salts thereof. [Chemical 7] [In the formula, Ra 7 and Rb 7 are the same or different and each represents an alkyl group, and Rc 7 represents an acylamino group, an alkylamino group, a benzylamino group or a dialkylaminomethyleneamino group. ]
Priority Applications (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6159324A JPH083165A (en) | 1994-06-17 | 1994-06-17 | New pyridopyrimidine derivative |
| US08/490,297 US5776942A (en) | 1994-06-17 | 1995-06-14 | Bronchodilating pyrido 2,3-d!pyrimidine derivatives |
| CA002151971A CA2151971A1 (en) | 1994-06-17 | 1995-06-16 | Remedy for bronchial asthma |
| EP95109391A EP0696590A1 (en) | 1994-06-17 | 1995-06-16 | Pyrido[2,3-d]pyrimidine derivatives, their preparation and their use as anti-asthma agents |
| CN 95107046 CN1120436A (en) | 1994-06-17 | 1995-06-16 | A remedy for bronchial asthma |
| KR1019950016049A KR960000225A (en) | 1994-06-17 | 1995-06-16 | Bronchial Asthma Treatment |
| AU21752/95A AU694958B2 (en) | 1994-06-17 | 1995-06-16 | A remedy for bronchial asthma |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6159324A JPH083165A (en) | 1994-06-17 | 1994-06-17 | New pyridopyrimidine derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH083165A true JPH083165A (en) | 1996-01-09 |
Family
ID=15691324
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP6159324A Pending JPH083165A (en) | 1994-06-17 | 1994-06-17 | New pyridopyrimidine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH083165A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100377787B1 (en) * | 2000-12-29 | 2003-03-26 | 씨제이 주식회사 | Novel pyridopyrimidine derivatives, preparing process thereof and pharmaceutical composition containing the same |
| KR100377788B1 (en) * | 2000-12-29 | 2003-03-26 | 씨제이 주식회사 | Novel pyridopyrimidine derivatives, preparing process thereof and pharmaceutical composition containing the same |
-
1994
- 1994-06-17 JP JP6159324A patent/JPH083165A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100377787B1 (en) * | 2000-12-29 | 2003-03-26 | 씨제이 주식회사 | Novel pyridopyrimidine derivatives, preparing process thereof and pharmaceutical composition containing the same |
| KR100377788B1 (en) * | 2000-12-29 | 2003-03-26 | 씨제이 주식회사 | Novel pyridopyrimidine derivatives, preparing process thereof and pharmaceutical composition containing the same |
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