CA1120475A - Derives d'acide 7,8-dihydro-2,5,8-trisubst.- 7-oxo-pyrido(2,3-d)-pyrimidine-6-carboxylique - Google Patents

Derives d'acide 7,8-dihydro-2,5,8-trisubst.- 7-oxo-pyrido(2,3-d)-pyrimidine-6-carboxylique

Info

Publication number: CA1120475A
Authority: CA; Canada
Prior art keywords: pyrimidine; carboxylic acid; oxo; dihydro; ethyl ester
Prior art date: 1979-04-18
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

Application number

CA000350056A

Other languages

English (en)

Inventor

Arthur A. Santilli

Anthony C. Scotese

Robert L. Morris

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Wyeth LLC

Original Assignee

American Home Products Corp

Priority date (The priority date 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 date listed.)

1979-04-18

Filing date

1980-04-17

Publication date

1982-03-23

1979-04-18 Priority claimed from US06/031,256 external-priority patent/US4215216A/en

1980-01-28 Priority claimed from US06/116,123 external-priority patent/US4245094A/en

1980-02-28 Priority claimed from US06/125,620 external-priority patent/US4301281A/en

1980-04-17 Application filed by American Home Products Corp filed Critical American Home Products Corp

1982-03-23 Application granted granted Critical

1982-03-23 Publication of CA1120475A publication Critical patent/CA1120475A/fr

Status Expired legal-status Critical Current

Links

-1 7,8-dihydro-2,5,8-trisubstituted-7-oxo-pyrido [2,3-d]-pyrimidine-6-carboxylic acid Chemical class 0.000 title claims abstract description 59
238000000034 method Methods 0.000 claims abstract description 94
230000008569 process Effects 0.000 claims abstract description 86
150000001875 compounds Chemical class 0.000 claims abstract description 70
125000000217 alkyl group Chemical group 0.000 claims abstract description 43
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 23
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 22
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 16
239000001257 hydrogen Substances 0.000 claims abstract description 16
125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 16
125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims abstract description 14
125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims abstract description 13
125000004414 alkyl thio group Chemical group 0.000 claims abstract description 11
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 11
125000004663 dialkyl amino group Chemical group 0.000 claims abstract description 11
125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims abstract description 10
125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims abstract description 10
125000003282 alkyl amino group Chemical group 0.000 claims abstract description 9
229960005235 piperonyl butoxide Drugs 0.000 claims abstract description 9
125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 claims abstract description 9
125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims abstract description 8
125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims abstract description 8
125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims abstract description 7
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 317
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 103
125000004432 carbon atom Chemical group C* 0.000 claims description 55
239000000203 mixture Substances 0.000 claims description 50
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 49
150000003839 salts Chemical class 0.000 claims description 49
239000000126 substance Substances 0.000 claims description 42
239000011734 sodium Substances 0.000 claims description 36
238000010992 reflux Methods 0.000 claims description 31
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 30
230000020477 pH reduction Effects 0.000 claims description 30
DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 25
229910052708 sodium Inorganic materials 0.000 claims description 25
IPOVOSHRRIJKBR-UHFFFAOYSA-N 2-ethylpropanedioyl dichloride Chemical compound CCC(C(Cl)=O)C(Cl)=O IPOVOSHRRIJKBR-UHFFFAOYSA-N 0.000 claims description 21
DWRWSNAREGLUHZ-UHFFFAOYSA-N ethyl pyrimidine-4-carboxylate Chemical compound CCOC(=O)C1=CC=NC=N1 DWRWSNAREGLUHZ-UHFFFAOYSA-N 0.000 claims description 19
LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 claims description 18
239000002253 acid Substances 0.000 claims description 18
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 17
229910000029 sodium carbonate Inorganic materials 0.000 claims description 15
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 13
125000004494 ethyl ester group Chemical group 0.000 claims description 13
RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 12
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
125000003545 alkoxy group Chemical group 0.000 claims description 11
ASUDFOJKTJLAIK-UHFFFAOYSA-N 2-methoxyethanamine Chemical compound COCCN ASUDFOJKTJLAIK-UHFFFAOYSA-N 0.000 claims description 7
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 7
150000001412 amines Chemical class 0.000 claims description 6
125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims description 6
238000004519 manufacturing process Methods 0.000 claims description 6
159000000000 sodium salts Chemical class 0.000 claims description 6
OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 claims description 5
229910052783 alkali metal Inorganic materials 0.000 claims description 5
150000001340 alkali metals Chemical class 0.000 claims description 5
RFMSOJTVKIEULZ-UHFFFAOYSA-N ethyl 5-chloro-8-ethyl-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxylate Chemical compound N1=C2N(CC)C(=O)C(C(=O)OCC)=C(Cl)C2=CN=C1C1=CC=CC=C1 RFMSOJTVKIEULZ-UHFFFAOYSA-N 0.000 claims description 5
HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 4
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 claims description 4
150000003230 pyrimidines Chemical class 0.000 claims description 4
BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 claims description 3
125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 3
HKSQZEGSMBFHGC-UHFFFAOYSA-N pyrimidine-4-carboxamide Chemical compound NC(=O)C1=CC=NC=N1 HKSQZEGSMBFHGC-UHFFFAOYSA-N 0.000 claims description 3
PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 2
125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 2
NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 2
GGKUZJDSFNXJIF-UHFFFAOYSA-N 7-phenyl-1-prop-2-enylpyrimido[4,5-d][1,3]oxazine-2,4-dione Chemical compound N=1C=C2C(=O)OC(=O)N(CC=C)C2=NC=1C1=CC=CC=C1 GGKUZJDSFNXJIF-UHFFFAOYSA-N 0.000 claims description 2
229910021529 ammonia Inorganic materials 0.000 claims description 2
150000007514 bases Chemical class 0.000 claims description 2
KMGBZBJJOKUPIA-UHFFFAOYSA-N butyl iodide Chemical compound CCCCI KMGBZBJJOKUPIA-UHFFFAOYSA-N 0.000 claims description 2
HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
TUEPAOXQYKBBBN-UHFFFAOYSA-N ethyl 2-methylsulfanyl-4-(propylamino)pyrimidine-5-carboxylate Chemical compound CCCNC1=NC(SC)=NC=C1C(=O)OCC TUEPAOXQYKBBBN-UHFFFAOYSA-N 0.000 claims description 2
VDDZMXQAZJMGPK-UHFFFAOYSA-N ethyl 4-(methylamino)-2-methylsulfanylpyrimidine-5-carboxylate Chemical compound CCOC(=O)C1=CN=C(SC)N=C1NC VDDZMXQAZJMGPK-UHFFFAOYSA-N 0.000 claims description 2
229910052736 halogen Inorganic materials 0.000 claims description 2
238000010438 heat treatment Methods 0.000 claims description 2
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
235000013350 formula milk Nutrition 0.000 claims 17
125000004356 hydroxy functional group Chemical group O* 0.000 claims 7
229940001593 sodium carbonate Drugs 0.000 claims 5
235000017550 sodium carbonate Nutrition 0.000 claims 5
OMCDJZRKPLNPJC-UHFFFAOYSA-N ethyl 5-hydroxy-8-(2-methoxyethyl)-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxylate Chemical compound N1=C2N(CCOC)C(=O)C(C(=O)OCC)=C(O)C2=CN=C1C1=CC=CC=C1 OMCDJZRKPLNPJC-UHFFFAOYSA-N 0.000 claims 4
OVMFULNMNOXRRW-UHFFFAOYSA-N ethyl 5-amino-2-methyl-7-oxo-8h-pyrido[2,3-d]pyrimidine-6-carboxylate Chemical compound N1=C(C)N=C2NC(=O)C(C(=O)OCC)=C(N)C2=C1 OVMFULNMNOXRRW-UHFFFAOYSA-N 0.000 claims 2
SQKIAZZCKMOZGL-UHFFFAOYSA-N ethyl 5-hydroxy-7-oxo-2-phenyl-8-propylpyrido[2,3-d]pyrimidine-6-carboxylate Chemical compound N=1C=C2C(O)=C(C(=O)OCC)C(=O)N(CCC)C2=NC=1C1=CC=CC=C1 SQKIAZZCKMOZGL-UHFFFAOYSA-N 0.000 claims 2
DYADCDHHJJBFRO-UHFFFAOYSA-N ethyl 5-hydroxy-8-methyl-2-methylsulfanyl-7-oxopyrido[2,3-d]pyrimidine-6-carboxylate Chemical compound N1=C(SC)N=C2N(C)C(=O)C(C(=O)OCC)=C(O)C2=C1 DYADCDHHJJBFRO-UHFFFAOYSA-N 0.000 claims 2
JKTDSASHUAOKCB-UHFFFAOYSA-N ethyl 5-hydroxy-8-methyl-2-methylsulfonyl-7-oxopyrido[2,3-d]pyrimidine-6-carboxylate Chemical compound N1=C(S(C)(=O)=O)N=C2N(C)C(=O)C(C(=O)OCC)=C(O)C2=C1 JKTDSASHUAOKCB-UHFFFAOYSA-N 0.000 claims 2
230000001590 oxidative effect Effects 0.000 claims 2
DHCFTQRFUAPIGP-UHFFFAOYSA-N 1,7-diphenylpyrimido[4,5-d][1,3]oxazine-2,4-dione Chemical compound O=C1OC(=O)C2=CN=C(C=3C=CC=CC=3)N=C2N1C1=CC=CC=C1 DHCFTQRFUAPIGP-UHFFFAOYSA-N 0.000 claims 1
HWRQVBMQPCTMMC-UHFFFAOYSA-N 1-(1,3-benzodioxol-5-ylmethyl)-7-methylsulfanylpyrimido[4,5-d][1,3]oxazine-2,4-dione Chemical compound C1=C2OCOC2=CC(CN2C=3C(C(OC2=O)=O)=CN=C(N=3)SC)=C1 HWRQVBMQPCTMMC-UHFFFAOYSA-N 0.000 claims 1
BLSDODAIMSRMBK-UHFFFAOYSA-N 1-(2-methoxyethyl)-7-methylsulfanylpyrimido[4,5-d][1,3]oxazine-2,4-dione Chemical compound CSC1=NC=C2C(=O)OC(=O)N(CCOC)C2=N1 BLSDODAIMSRMBK-UHFFFAOYSA-N 0.000 claims 1
PVENCEDSKVTUAC-UHFFFAOYSA-N 1-(2-methoxyethyl)-7-phenylpyrimido[4,5-d][1,3]oxazine-2,4-dione Chemical compound N=1C=C2C(=O)OC(=O)N(CCOC)C2=NC=1C1=CC=CC=C1 PVENCEDSKVTUAC-UHFFFAOYSA-N 0.000 claims 1
FWYWLPAKWPFFCN-UHFFFAOYSA-N 1-[(4-methoxyphenyl)methyl]-7-phenylpyrimido[4,5-d][1,3]oxazine-2,4-dione Chemical compound C1=CC(OC)=CC=C1CN1C(=O)OC(=O)C2=CN=C(C=3C=CC=CC=3)N=C21 FWYWLPAKWPFFCN-UHFFFAOYSA-N 0.000 claims 1
BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical group CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 claims 1
UFDLPEYMZWMSTJ-UHFFFAOYSA-N 4-(2-methoxyethylamino)-2-phenylpyrimidine-5-carbonitrile Chemical compound C1=C(C#N)C(NCCOC)=NC(C=2C=CC=CC=2)=N1 UFDLPEYMZWMSTJ-UHFFFAOYSA-N 0.000 claims 1
QJIXSBMCEJHGFU-UHFFFAOYSA-N 4-amino-2-(n-methylanilino)pyrimidine-5-carbonitrile Chemical compound N=1C=C(C#N)C(N)=NC=1N(C)C1=CC=CC=C1 QJIXSBMCEJHGFU-UHFFFAOYSA-N 0.000 claims 1
YBPNIILOUYAGIF-UHFFFAOYSA-N 4-amino-2-methylpyrimidine-5-carbonitrile Chemical compound CC1=NC=C(C#N)C(N)=N1 YBPNIILOUYAGIF-UHFFFAOYSA-N 0.000 claims 1
IYSIKDDDIYNDMB-UHFFFAOYSA-N 5-hydroxy-n,8-bis(2-methoxyethyl)-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxamide Chemical compound N1=C2N(CCOC)C(=O)C(C(=O)NCCOC)=C(O)C2=CN=C1C1=CC=CC=C1 IYSIKDDDIYNDMB-UHFFFAOYSA-N 0.000 claims 1
XHIMXDLDGFQIRM-UHFFFAOYSA-N 7-methylsulfanyl-1-propan-2-ylpyrimido[4,5-d][1,3]oxazine-2,4-dione Chemical compound CC(C)N1C(=O)OC(=O)C=2C1=NC(SC)=NC=2 XHIMXDLDGFQIRM-UHFFFAOYSA-N 0.000 claims 1
BKDOXAQGEXTYOQ-UHFFFAOYSA-N 7-phenyl-1-propylpyrimido[4,5-d][1,3]oxazine-2,4-dione Chemical compound N=1C=C2C(=O)OC(=O)N(CCC)C2=NC=1C1=CC=CC=C1 BKDOXAQGEXTYOQ-UHFFFAOYSA-N 0.000 claims 1
CJKRXEBLWJVYJD-UHFFFAOYSA-N N,N'-diethylethylenediamine Chemical compound CCNCCNCC CJKRXEBLWJVYJD-UHFFFAOYSA-N 0.000 claims 1
125000004390 alkyl sulfonyl group Chemical group 0.000 claims 1
230000002152 alkylating effect Effects 0.000 claims 1
ZRNOFRPDIVVAMC-UHFFFAOYSA-N ethyl 2-methylsulfanyl-4-(prop-2-enylamino)pyrimidine-5-carboxylate Chemical compound CCOC(=O)C1=CN=C(SC)N=C1NCC=C ZRNOFRPDIVVAMC-UHFFFAOYSA-N 0.000 claims 1
AJZCIGSQFBVLKC-UHFFFAOYSA-N ethyl 2-phenyl-4-(prop-2-ynylamino)pyrimidine-5-carboxylate Chemical compound N1=C(NCC#C)C(C(=O)OCC)=CN=C1C1=CC=CC=C1 AJZCIGSQFBVLKC-UHFFFAOYSA-N 0.000 claims 1
ZNHMNBQAVPCQIS-UHFFFAOYSA-N ethyl 2-phenyl-4-(propylamino)pyrimidine-5-carboxylate Chemical compound C1=C(C(=O)OCC)C(NCCC)=NC(C=2C=CC=CC=2)=N1 ZNHMNBQAVPCQIS-UHFFFAOYSA-N 0.000 claims 1
OIOXOKAYWBQYTN-UHFFFAOYSA-N ethyl 4-(ethylamino)-2-phenylpyrimidine-5-carboxylate Chemical compound C1=C(C(=O)OCC)C(NCC)=NC(C=2C=CC=CC=2)=N1 OIOXOKAYWBQYTN-UHFFFAOYSA-N 0.000 claims 1
KDZMKRYHCBBPAG-UHFFFAOYSA-N ethyl 5-(diethylamino)-8-ethyl-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxylate Chemical compound N1=C2N(CC)C(=O)C(C(=O)OCC)=C(N(CC)CC)C2=CN=C1C1=CC=CC=C1 KDZMKRYHCBBPAG-UHFFFAOYSA-N 0.000 claims 1
HUUSAJBVJDLFRF-UHFFFAOYSA-N ethyl 5-amino-2-(n-methylanilino)-7-oxo-8h-pyrido[2,3-d]pyrimidine-6-carboxylate Chemical compound N1=C2NC(=O)C(C(=O)OCC)=C(N)C2=CN=C1N(C)C1=CC=CC=C1 HUUSAJBVJDLFRF-UHFFFAOYSA-N 0.000 claims 1
WGUUTUFRAUJNSD-UHFFFAOYSA-N ethyl 5-amino-8-(2-methoxyethyl)-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxylate Chemical compound N1=C2N(CCOC)C(=O)C(C(=O)OCC)=C(N)C2=CN=C1C1=CC=CC=C1 WGUUTUFRAUJNSD-UHFFFAOYSA-N 0.000 claims 1
XAIKKTVBORJPLE-UHFFFAOYSA-N ethyl 5-amino-8-butyl-2-methyl-7-oxopyrido[2,3-d]pyrimidine-6-carboxylate Chemical compound CC1=NC=C2C(N)=C(C(=O)OCC)C(=O)N(CCCC)C2=N1 XAIKKTVBORJPLE-UHFFFAOYSA-N 0.000 claims 1
HCCKGVYMTRZCGB-UHFFFAOYSA-N ethyl 5-amino-8-ethyl-2-methyl-7-oxopyrido[2,3-d]pyrimidine-6-carboxylate Chemical compound N1=C(C)N=C2N(CC)C(=O)C(C(=O)OCC)=C(N)C2=C1 HCCKGVYMTRZCGB-UHFFFAOYSA-N 0.000 claims 1
SWRSLTKKIGSKJI-UHFFFAOYSA-N ethyl 5-amino-8-ethyl-7-oxo-2-propylpyrido[2,3-d]pyrimidine-6-carboxylate Chemical compound NC1=C(C(=O)OCC)C(=O)N(CC)C2=NC(CCC)=NC=C21 SWRSLTKKIGSKJI-UHFFFAOYSA-N 0.000 claims 1
QVPYFEMDBJEGCP-UHFFFAOYSA-N ethyl 5-chloro-8-(2-methoxyethyl)-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxylate Chemical compound N1=C2N(CCOC)C(=O)C(C(=O)OCC)=C(Cl)C2=CN=C1C1=CC=CC=C1 QVPYFEMDBJEGCP-UHFFFAOYSA-N 0.000 claims 1
MUEXBLMEJCDDCM-UHFFFAOYSA-N ethyl 5-hydroxy-2-methylsulfanyl-7-oxo-8-prop-2-enylpyrido[2,3-d]pyrimidine-6-carboxylate Chemical compound N1=C(SC)N=C2N(CC=C)C(=O)C(C(=O)OCC)=C(O)C2=C1 MUEXBLMEJCDDCM-UHFFFAOYSA-N 0.000 claims 1
BPKZALDCHAXRIT-UHFFFAOYSA-N ethyl 5-hydroxy-2-methylsulfanyl-7-oxo-8-propan-2-ylpyrido[2,3-d]pyrimidine-6-carboxylate Chemical compound N1=C(SC)N=C2N(C(C)C)C(=O)C(C(=O)OCC)=C(O)C2=C1 BPKZALDCHAXRIT-UHFFFAOYSA-N 0.000 claims 1
RKBWKNDYYVDLAD-UHFFFAOYSA-N ethyl 5-hydroxy-2-methylsulfanyl-7-oxo-8-propylpyrido[2,3-d]pyrimidine-6-carboxylate Chemical compound CSC1=NC=C2C(O)=C(C(=O)OCC)C(=O)N(CCC)C2=N1 RKBWKNDYYVDLAD-UHFFFAOYSA-N 0.000 claims 1
AWVZOUBPHJFHCQ-UHFFFAOYSA-N ethyl 5-hydroxy-7-oxo-2,8-diphenylpyrido[2,3-d]pyrimidine-6-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(O)C2=CN=C(C=3C=CC=CC=3)N=C2N1C1=CC=CC=C1 AWVZOUBPHJFHCQ-UHFFFAOYSA-N 0.000 claims 1
CEEHFWSNEHHQPJ-UHFFFAOYSA-N ethyl 5-hydroxy-7-oxo-2-phenyl-8-prop-2-enylpyrido[2,3-d]pyrimidine-6-carboxylate Chemical compound N1=C2N(CC=C)C(=O)C(C(=O)OCC)=C(O)C2=CN=C1C1=CC=CC=C1 CEEHFWSNEHHQPJ-UHFFFAOYSA-N 0.000 claims 1
KDJVVVXTIIPSCB-UHFFFAOYSA-N ethyl 5-hydroxy-8-(4-morpholin-4-ylphenyl)-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(O)C2=CN=C(C=3C=CC=CC=3)N=C2N1C(C=C1)=CC=C1N1CCOCC1 KDJVVVXTIIPSCB-UHFFFAOYSA-N 0.000 claims 1
DYZHXXGPLYBENT-UHFFFAOYSA-N ethyl 5-hydroxy-8-[(4-methoxyphenyl)methyl]-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(O)C2=CN=C(C=3C=CC=CC=3)N=C2N1CC1=CC=C(OC)C=C1 DYZHXXGPLYBENT-UHFFFAOYSA-N 0.000 claims 1
QZBMJVYPYJBPKZ-UHFFFAOYSA-N ethyl 8-(1,3-benzodioxol-5-ylmethyl)-5-hydroxy-2-methylsulfanyl-7-oxopyrido[2,3-d]pyrimidine-6-carboxylate Chemical compound C1=C2OCOC2=CC(CN2C3=NC(SC)=NC=C3C(O)=C(C2=O)C(=O)OCC)=C1 QZBMJVYPYJBPKZ-UHFFFAOYSA-N 0.000 claims 1
TWNGGJBAYKSWIV-UHFFFAOYSA-N ethyl 8-(2-methoxyethyl)-5-(2-methoxyethylamino)-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxylate Chemical compound N1=C2N(CCOC)C(=O)C(C(=O)OCC)=C(NCCOC)C2=CN=C1C1=CC=CC=C1 TWNGGJBAYKSWIV-UHFFFAOYSA-N 0.000 claims 1
FPSQFBLSEBYEOQ-UHFFFAOYSA-N ethyl 8-benzyl-5-hydroxy-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(O)C2=CN=C(C=3C=CC=CC=3)N=C2N1CC1=CC=CC=C1 FPSQFBLSEBYEOQ-UHFFFAOYSA-N 0.000 claims 1
MUMWFBIMKPSHMR-UHFFFAOYSA-N ethyl 8-ethyl-5-hydroxy-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxylate Chemical compound N1=C2N(CC)C(=O)C(C(=O)OCC)=C(O)C2=CN=C1C1=CC=CC=C1 MUMWFBIMKPSHMR-UHFFFAOYSA-N 0.000 claims 1
XNBNORODBRCYJI-UHFFFAOYSA-N ethyl 8-ethyl-7-oxo-2-phenyl-5-pyrrolidin-1-ylpyrido[2,3-d]pyrimidine-6-carboxylate Chemical compound C12=CN=C(C=3C=CC=CC=3)N=C2N(CC)C(=O)C(C(=O)OCC)=C1N1CCCC1 XNBNORODBRCYJI-UHFFFAOYSA-N 0.000 claims 1
125000005843 halogen group Chemical group 0.000 claims 1
230000002140 halogenating effect Effects 0.000 claims 1
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
XVRCWGVHAICWOW-UHFFFAOYSA-N pyrido[2,3-d]pyrimidine-6-carboxylic acid Chemical compound N1=CN=CC2=CC(C(=O)O)=CN=C21 XVRCWGVHAICWOW-UHFFFAOYSA-N 0.000 claims 1
238000006798 ring closing metathesis reaction Methods 0.000 claims 1
230000003266 anti-allergic effect Effects 0.000 abstract description 22
125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 12
239000002731 stomach secretion inhibitor Substances 0.000 abstract description 6
239000000543 intermediate Substances 0.000 abstract description 5
230000000694 effects Effects 0.000 abstract description 3
125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 abstract 3
125000004848 alkoxyethyl group Chemical group 0.000 abstract 1
159000000018 pyrido[2,3-d]pyrimidines Chemical class 0.000 abstract 1
229960004756 ethanol Drugs 0.000 description 94
235000019441 ethanol Nutrition 0.000 description 94
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 61
239000000243 solution Substances 0.000 description 56
239000000047 product Substances 0.000 description 49
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
239000007787 solid Substances 0.000 description 45
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 43
238000006243 chemical reaction Methods 0.000 description 35
239000000706 filtrate Substances 0.000 description 32
239000011541 reaction mixture Substances 0.000 description 25
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 23
239000002244 precipitate Substances 0.000 description 20
238000000746 purification Methods 0.000 description 19
230000001262 anti-secretory effect Effects 0.000 description 17
229960000583 acetic acid Drugs 0.000 description 16
229940093499 ethyl acetate Drugs 0.000 description 16
235000019439 ethyl acetate Nutrition 0.000 description 16
238000001953 recrystallisation Methods 0.000 description 15
229940083542 sodium Drugs 0.000 description 14
235000015424 sodium Nutrition 0.000 description 14
125000004429 atom Chemical group 0.000 description 12
238000007912 intraperitoneal administration Methods 0.000 description 12
239000003208 petroleum Substances 0.000 description 12
241001465754 Metazoa Species 0.000 description 11
235000011054 acetic acid Nutrition 0.000 description 11
IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 11
229910000041 hydrogen chloride Inorganic materials 0.000 description 11
238000001914 filtration Methods 0.000 description 10
RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 9
QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 9
CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 8
241000700159 Rattus Species 0.000 description 8
208000026935 allergic disease Diseases 0.000 description 8
239000008096 xylene Substances 0.000 description 8
206010020751 Hypersensitivity Diseases 0.000 description 7
230000002496 gastric effect Effects 0.000 description 7
VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 6
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 6
230000000172 allergic effect Effects 0.000 description 6
208000010668 atopic eczema Diseases 0.000 description 6
229910052799 carbon Inorganic materials 0.000 description 6
229960000443 hydrochloric acid Drugs 0.000 description 6
235000011167 hydrochloric acid Nutrition 0.000 description 6
230000005764 inhibitory process Effects 0.000 description 6
150000002500 ions Chemical class 0.000 description 6
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
238000012360 testing method Methods 0.000 description 6
CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 5
239000000043 antiallergic agent Substances 0.000 description 5
125000004093 cyano group Chemical group *C#N 0.000 description 5
VXWYTPARKVGWFX-UHFFFAOYSA-N ethyl 4-chloro-2-phenylpyrimidine-5-carboxylate Chemical compound N1=C(Cl)C(C(=O)OCC)=CN=C1C1=CC=CC=C1 VXWYTPARKVGWFX-UHFFFAOYSA-N 0.000 description 5
239000012065 filter cake Substances 0.000 description 5
239000012362 glacial acetic acid Substances 0.000 description 5
238000003756 stirring Methods 0.000 description 5
238000011282 treatment Methods 0.000 description 5
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
208000008469 Peptic Ulcer Diseases 0.000 description 4
239000000538 analytical sample Substances 0.000 description 4
230000015572 biosynthetic process Effects 0.000 description 4
150000002148 esters Chemical class 0.000 description 4
UKFXDFUAPNAMPJ-UHFFFAOYSA-N ethylmalonic acid Chemical compound CCC(C(O)=O)C(O)=O UKFXDFUAPNAMPJ-UHFFFAOYSA-N 0.000 description 4
239000000463 material Substances 0.000 description 4
208000011906 peptic ulcer disease Diseases 0.000 description 4
239000012258 stirred mixture Substances 0.000 description 4
239000000725 suspension Substances 0.000 description 4
101100134925 Gallus gallus COR6 gene Proteins 0.000 description 3
239000000427 antigen Substances 0.000 description 3
102000036639 antigens Human genes 0.000 description 3
108091007433 antigens Proteins 0.000 description 3
150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
239000003795 chemical substances by application Substances 0.000 description 3
239000012043 crude product Substances 0.000 description 3
229940079593 drug Drugs 0.000 description 3
239000003814 drug Substances 0.000 description 3
SNNHLSHDDGJVDM-UHFFFAOYSA-N ethyl 4-chloro-2-methylsulfanylpyrimidine-5-carboxylate Chemical compound CCOC(=O)C1=CN=C(SC)N=C1Cl SNNHLSHDDGJVDM-UHFFFAOYSA-N 0.000 description 3
239000007788 liquid Substances 0.000 description 3
229910052943 magnesium sulfate Inorganic materials 0.000 description 3
235000019341 magnesium sulphate Nutrition 0.000 description 3
125000000719 pyrrolidinyl group Chemical group 0.000 description 3
230000036647 reaction Effects 0.000 description 3
239000000523 sample Substances 0.000 description 3
QJWAMNAUVIOHQN-UHFFFAOYSA-N 4-(2-methoxyethylamino)-2-phenylpyrimidine-5-carboxylic acid Chemical compound C1=C(C(O)=O)C(NCCOC)=NC(C=2C=CC=CC=2)=N1 QJWAMNAUVIOHQN-UHFFFAOYSA-N 0.000 description 2
GHSCYYSXTRXNJV-UHFFFAOYSA-N 5-chloro-6h-pyrido[3,2-d]pyrimidine Chemical class C1=NC=C2N(Cl)CC=CC2=N1 GHSCYYSXTRXNJV-UHFFFAOYSA-N 0.000 description 2
PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
206010003645 Atopy Diseases 0.000 description 2
VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
241000286819 Malo Species 0.000 description 2
BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
108010058846 Ovalbumin Proteins 0.000 description 2
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
206010045240 Type I hypersensitivity Diseases 0.000 description 2
230000029936 alkylation Effects 0.000 description 2
238000005804 alkylation reaction Methods 0.000 description 2
230000007815 allergy Effects 0.000 description 2
238000005937 allylation reaction Methods 0.000 description 2
150000001408 amides Chemical class 0.000 description 2
WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
208000002352 blister Diseases 0.000 description 2
230000037396 body weight Effects 0.000 description 2
150000001721 carbon Chemical group 0.000 description 2
238000001816 cooling Methods 0.000 description 2
239000013078 crystal Substances 0.000 description 2
PYRZPBDTPRQYKG-UHFFFAOYSA-N cyclopentene-1-carboxylic acid Chemical compound OC(=O)C1=CCCC1 PYRZPBDTPRQYKG-UHFFFAOYSA-N 0.000 description 2
125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 2
NNJZBCZCRSDRBM-UHFFFAOYSA-N ethyl 2-phenyl-4-(prop-2-enylamino)pyrimidine-5-carboxylate Chemical compound N1=C(NCC=C)C(C(=O)OCC)=CN=C1C1=CC=CC=C1 NNJZBCZCRSDRBM-UHFFFAOYSA-N 0.000 description 2
PJFXDPZWCVXNQZ-UHFFFAOYSA-N ethyl 3-oxo-1,2-dihydropyrazole-4-carboxylate Chemical group CCOC(=O)C1=CNNC1=O PJFXDPZWCVXNQZ-UHFFFAOYSA-N 0.000 description 2
YCWDQAKDVQNVAR-UHFFFAOYSA-N ethyl pyrimidine-5-carboxylate Chemical compound CCOC(=O)C1=CN=CN=C1 YCWDQAKDVQNVAR-UHFFFAOYSA-N 0.000 description 2
VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
230000003647 oxidation Effects 0.000 description 2
238000007254 oxidation reaction Methods 0.000 description 2
238000002360 preparation method Methods 0.000 description 2
238000011321 prophylaxis Methods 0.000 description 2
WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
UDJFFSGCRRMVFH-UHFFFAOYSA-N pyrido[2,3-d]pyrimidine Chemical class N1=CN=CC2=CC=CN=C21 UDJFFSGCRRMVFH-UHFFFAOYSA-N 0.000 description 2
KAOCIOXBABYFMP-UHFFFAOYSA-N pyrimido[4,5-e]oxazine-3,4-dione Chemical compound N1=CN=C2C(=O)C(=O)NOC2=C1 KAOCIOXBABYFMP-UHFFFAOYSA-N 0.000 description 2
230000003248 secreting effect Effects 0.000 description 2
239000011343 solid material Substances 0.000 description 2
239000012265 solid product Substances 0.000 description 2
239000002195 soluble material Substances 0.000 description 2
239000007858 starting material Substances 0.000 description 2
230000001629 suppression Effects 0.000 description 2
KPDWWEJAIPSECL-UHFFFAOYSA-N 1,4-diphenyl-1,2,4,5-tetrazine Chemical compound C1=NN(C=2C=CC=CC=2)C=NN1C1=CC=CC=C1 KPDWWEJAIPSECL-UHFFFAOYSA-N 0.000 description 1
IDPURXSQCKYKIJ-UHFFFAOYSA-N 1-(4-methoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C=C1 IDPURXSQCKYKIJ-UHFFFAOYSA-N 0.000 description 1
OEICGMPRFOJHKO-UHFFFAOYSA-N 2-(ethoxymethylidene)propanedinitrile Chemical compound CCOC=C(C#N)C#N OEICGMPRFOJHKO-UHFFFAOYSA-N 0.000 description 1
125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
IPIYOTSHMSSGLY-UHFFFAOYSA-N 2-methylsulfanyl-4-(propan-2-ylamino)pyrimidine-5-carboxylic acid Chemical compound CSC1=NC=C(C(O)=O)C(NC(C)C)=N1 IPIYOTSHMSSGLY-UHFFFAOYSA-N 0.000 description 1
SHASOVNNKCSWPT-UHFFFAOYSA-N 2h-pyrido[2,3-e]oxazine Chemical compound C1=CN=C2C=CNOC2=C1 SHASOVNNKCSWPT-UHFFFAOYSA-N 0.000 description 1
IRLMNFMZCDNKAW-UHFFFAOYSA-N 4-(ethylamino)-2-phenylpyrimidine-5-carboxylic acid Chemical compound C1=C(C(O)=O)C(NCC)=NC(C=2C=CC=CC=2)=N1 IRLMNFMZCDNKAW-UHFFFAOYSA-N 0.000 description 1
FGBGOOGXKLPYJI-UHFFFAOYSA-N 4-[(4-methoxyphenyl)methylamino]-2-phenylpyrimidine-5-carboxylic acid Chemical compound C1=CC(OC)=CC=C1CNC1=NC(C=2C=CC=CC=2)=NC=C1C(O)=O FGBGOOGXKLPYJI-UHFFFAOYSA-N 0.000 description 1
BVPWJMCABCPUQY-UHFFFAOYSA-N 4-amino-5-chloro-2-methoxy-N-[1-(phenylmethyl)-4-piperidinyl]benzamide Chemical compound COC1=CC(N)=C(Cl)C=C1C(=O)NC1CCN(CC=2C=CC=CC=2)CC1 BVPWJMCABCPUQY-UHFFFAOYSA-N 0.000 description 1
WBXWTYBRTMXVCN-UHFFFAOYSA-N 4-anilino-2-phenylpyrimidine-5-carboxylic acid Chemical compound OC(=O)C1=CN=C(C=2C=CC=CC=2)N=C1NC1=CC=CC=C1 WBXWTYBRTMXVCN-UHFFFAOYSA-N 0.000 description 1
MYNMNRVNVCHWIT-UHFFFAOYSA-N 4-chloro-2-methylsulfanylpyrimidine-5-carboxylic acid Chemical compound CSC1=NC=C(C(O)=O)C(Cl)=N1 MYNMNRVNVCHWIT-UHFFFAOYSA-N 0.000 description 1
PHNDZBFLOPIMSM-UHFFFAOYSA-N 4-morpholin-4-ylaniline Chemical compound C1=CC(N)=CC=C1N1CCOCC1 PHNDZBFLOPIMSM-UHFFFAOYSA-N 0.000 description 1
206010003497 Asphyxia 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
101800004538 Bradykinin Proteins 0.000 description 1
CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
COXVTLYNGOIATD-HVMBLDELSA-N CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O Chemical compound CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O COXVTLYNGOIATD-HVMBLDELSA-N 0.000 description 1
101100516572 Caenorhabditis elegans nhr-8 gene Proteins 0.000 description 1
241000283707 Capra Species 0.000 description 1
BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
241000861718 Chloris <Aves> Species 0.000 description 1
241000518994 Conta Species 0.000 description 1
241000699800 Cricetinae Species 0.000 description 1
QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
241000283073 Equus caballus Species 0.000 description 1
241000282326 Felis catus Species 0.000 description 1
241000699694 Gerbillinae Species 0.000 description 1
QXZGBUJJYSLZLT-UHFFFAOYSA-N H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH Natural products NC(N)=NCCCC(N)C(=O)N1CCCC1C(=O)N1C(C(=O)NCC(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CO)C(=O)N2C(CCC2)C(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CCCN=C(N)N)C(O)=O)CCC1 QXZGBUJJYSLZLT-UHFFFAOYSA-N 0.000 description 1
LELOWRISYMNNSU-UHFFFAOYSA-N Hydrocyanic acid Natural products N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 1
208000001718 Immediate Hypersensitivity Diseases 0.000 description 1
102100035792 Kininogen-1 Human genes 0.000 description 1
241000699666 Mus <mouse, genus> Species 0.000 description 1
241001494479 Pecora Species 0.000 description 1
241000009328 Perro Species 0.000 description 1
YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 1
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
OURRXQUGYQRVML-AREMUKBSSA-N [4-[(2s)-3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl]phenyl]methyl 2,4-dimethylbenzoate Chemical compound CC1=CC(C)=CC=C1C(=O)OCC1=CC=C([C@@H](CN)C(=O)NC=2C=C3C=CN=CC3=CC=2)C=C1 OURRXQUGYQRVML-AREMUKBSSA-N 0.000 description 1
150000007513 acids Chemical class 0.000 description 1
239000000654 additive Substances 0.000 description 1
239000002671 adjuvant Substances 0.000 description 1
238000005905 alkynylation reaction Methods 0.000 description 1
238000000540 analysis of variance Methods 0.000 description 1
238000004458 analytical method Methods 0.000 description 1
208000010216 atopic IgE responsiveness Diseases 0.000 description 1
230000009286 beneficial effect Effects 0.000 description 1
239000008280 blood Substances 0.000 description 1
210000004369 blood Anatomy 0.000 description 1
239000001045 blue dye Substances 0.000 description 1
238000009835 boiling Methods 0.000 description 1
QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 1
150000001768 cations Chemical class 0.000 description 1
238000005660 chlorination reaction Methods 0.000 description 1
125000004803 chlorobenzyl group Chemical group 0.000 description 1
DDKMFOUTRRODRE-UHFFFAOYSA-N chloromethanone Chemical compound Cl[C]=O DDKMFOUTRRODRE-UHFFFAOYSA-N 0.000 description 1
229960000265 cromoglicic acid Drugs 0.000 description 1
239000013058 crude material Substances 0.000 description 1
238000002425 crystallisation Methods 0.000 description 1
230000008025 crystallization Effects 0.000 description 1
230000002939 deleterious effect Effects 0.000 description 1
RCJVRSBWZCNNQT-UHFFFAOYSA-N dichloridooxygen Chemical compound ClOCl RCJVRSBWZCNNQT-UHFFFAOYSA-N 0.000 description 1
235000005911 diet Nutrition 0.000 description 1
230000037213 diet Effects 0.000 description 1
239000012895 dilution Substances 0.000 description 1
238000010790 dilution Methods 0.000 description 1
VLARUOGDXDTHEH-UHFFFAOYSA-L disodium cromoglycate Chemical compound [Na+].[Na+].O1C(C([O-])=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C([O-])=O)O2 VLARUOGDXDTHEH-UHFFFAOYSA-L 0.000 description 1
HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 description 1
ADXNMWBLJLAMNG-UHFFFAOYSA-N ethyl 2-phenylpyrimidine-5-carboxylate Chemical compound N1=CC(C(=O)OCC)=CN=C1C1=CC=CC=C1 ADXNMWBLJLAMNG-UHFFFAOYSA-N 0.000 description 1
RJMASKLJMAXODL-UHFFFAOYSA-N ethyl 4-(4-morpholin-4-ylanilino)-2-phenylpyrimidine-5-carboxylate Chemical compound CCOC(=O)C1=CN=C(C=2C=CC=CC=2)N=C1NC(C=C1)=CC=C1N1CCOCC1 RJMASKLJMAXODL-UHFFFAOYSA-N 0.000 description 1
VDVNMLOCJBXZTB-UHFFFAOYSA-N ethyl 4-[(4-methoxyphenyl)methylamino]-2-phenylpyrimidine-5-carboxylate Chemical compound CCOC(=O)C1=CN=C(C=2C=CC=CC=2)N=C1NCC1=CC=C(OC)C=C1 VDVNMLOCJBXZTB-UHFFFAOYSA-N 0.000 description 1
OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
PYFMAAFCQDFHJX-UHFFFAOYSA-N ethyl pyrimidine-2-carboxylate Chemical compound CCOC(=O)C1=NC=CC=N1 PYFMAAFCQDFHJX-UHFFFAOYSA-N 0.000 description 1
125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
229960003699 evans blue Drugs 0.000 description 1
238000001704 evaporation Methods 0.000 description 1
230000008020 evaporation Effects 0.000 description 1
230000001747 exhibiting effect Effects 0.000 description 1
210000003608 fece Anatomy 0.000 description 1
239000012530 fluid Substances 0.000 description 1
ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 1
239000007789 gas Substances 0.000 description 1
210000004211 gastric acid Anatomy 0.000 description 1
229960004198 guanidine Drugs 0.000 description 1
230000026030 halogenation Effects 0.000 description 1
238000005658 halogenation reaction Methods 0.000 description 1
150000002367 halogens Chemical group 0.000 description 1
229960001340 histamine Drugs 0.000 description 1
210000003630 histaminocyte Anatomy 0.000 description 1
XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
239000005457 ice water Substances 0.000 description 1
238000002329 infrared spectrum Methods 0.000 description 1
238000002350 laparotomy Methods 0.000 description 1
230000010534 mechanism of action Effects 0.000 description 1
229910052751 metal Inorganic materials 0.000 description 1
239000002184 metal Substances 0.000 description 1
125000000896 monocarboxylic acid group Chemical group 0.000 description 1
229940066827 pertussis vaccine Drugs 0.000 description 1
XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 1
TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
230000000069 prophylactic effect Effects 0.000 description 1
GALGARMYOZAHQP-UHFFFAOYSA-N pyrido[2,3-e]oxazine-3,4-dione Chemical compound C1=CN=C2C(=O)C(=O)NOC2=C1 GALGARMYOZAHQP-UHFFFAOYSA-N 0.000 description 1
YPOXGDJGKBXRFP-UHFFFAOYSA-N pyrimidine-4-carboxylic acid Chemical compound OC(=O)C1=CC=NC=N1 YPOXGDJGKBXRFP-UHFFFAOYSA-N 0.000 description 1
IIVUJUOJERNGQX-UHFFFAOYSA-N pyrimidine-5-carboxylic acid Chemical compound OC(=O)C1=CN=CN=C1 IIVUJUOJERNGQX-UHFFFAOYSA-N 0.000 description 1
239000000376 reactant Substances 0.000 description 1
230000009467 reduction Effects 0.000 description 1
238000007363 ring formation reaction Methods 0.000 description 1
IOVGROKTTNBUGK-SJCJKPOMSA-N ritodrine Chemical compound N([C@@H](C)[C@H](O)C=1C=CC(O)=CC=1)CCC1=CC=C(O)C=C1 IOVGROKTTNBUGK-SJCJKPOMSA-N 0.000 description 1
239000002002 slurry Substances 0.000 description 1
239000011780 sodium chloride Substances 0.000 description 1
239000008279 sol Substances 0.000 description 1
239000002904 solvent Substances 0.000 description 1
238000012453 sprague-dawley rat model Methods 0.000 description 1
210000002784 stomach Anatomy 0.000 description 1
238000000967 suction filtration Methods 0.000 description 1
BGRJTUBHPOOWDU-UHFFFAOYSA-N sulpiride Chemical compound CCN1CCCC1CNC(=O)C1=CC(S(N)(=O)=O)=CC=C1OC BGRJTUBHPOOWDU-UHFFFAOYSA-N 0.000 description 1
238000004448 titration Methods 0.000 description 1
238000001665 trituration Methods 0.000 description 1
238000005406 washing Methods 0.000 description 1

Landscapes

Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

CA000350056A 1979-04-18 1980-04-17 Derives d'acide 7,8-dihydro-2,5,8-trisubst.- 7-oxo-pyrido(2,3-d)-pyrimidine-6-carboxylique Expired CA1120475A (fr)

Applications Claiming Priority (7)

Application Number	Priority Date	Filing Date	Title
US06/031,256 US4215216A (en)	1979-04-18	1979-04-18	7,8-Dihydro-2,5,8-trisubstituted-7-oxo-pyrido[2,3-d]pyrimidine-6-carboxylic acid derivatives
US31,256		1979-04-18
US06/089,013 US4236004A (en)	1979-04-18	1979-10-29	2-Alkylsulphonyl-7,8-dihydro-5-hydroxy-7-oxo-pyrido[2,3-d]pyrimidine-6-carboxylic acid derivatives
US116,123		1980-01-28
US06/116,123 US4245094A (en)	1980-01-28	1980-01-28	5-Amino-2,8-dialkyl-7,8-dihydro-7-oxo-pyrido-[2,3-d]pyrimidine-6 carboxylic acid derivatives
US125,620		1980-02-28
US06/125,620 US4301281A (en)	1979-04-18	1980-02-28	7,8-Dihydro-2,5,8-trisubstituted-7-oxo-pyrido[2,3-d]-pyrimidine-6-carboxylic acid amides

Publications (1)

Publication Number	Publication Date
CA1120475A true CA1120475A (fr)	1982-03-23

Family

ID=27487881

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
CA000350056A Expired CA1120475A (fr)	1979-04-18	1980-04-17	Derives d'acide 7,8-dihydro-2,5,8-trisubst.- 7-oxo-pyrido(2,3-d)-pyrimidine-6-carboxylique

Country Status (1)

Country	Link
CA (1)	CA1120475A (fr)

1980
- 1980-04-17 CA CA000350056A patent/CA1120475A/fr not_active Expired

Legal Events

Date	Code	Title	Description
1999-03-23	MKEX	Expiry

Publication	Publication Date	Title
CA1115272A (fr)	1981-12-29	Derives de la 4-amino-3-carboxy ou cyano-1,2-dihydro- 2-oxo-1,8-naphtyridine
US4083980A (en)	1978-04-11	Derivatives of quinazolone
EP0018139B1 (fr)	1983-05-04	Dérivés de la pyrido (2,3-d) pyrimidine, compositions pharmaceutiques les contenant et procédés pour leur préparation
CA1074793A (fr)	1980-04-01	Acides 8-alkyl-5-oxo-5,8-dihydro-pyrido(2,3-d) pyrimidine-6-carboxyliques; leur preparation
US3257401A (en)	1966-06-21	5-hydroxy-2-methylcycloalkyl[d] imidazo[1, 2-a]pyrimidines
Rosowsky et al.	1974	Pyrimido [4, 5-c] isoquinolines. 2. Synthesis and biological evaluation of some 6-alkyl-, 6-aralkyl-, and 6-aryl-1, 3-diamino-7, 8, 9, 10-tetrahydropyrimido [4, 5-c] isoquinolines as potential folate antagonists
CA1120475A (fr)	1982-03-23	Derives d'acide 7,8-dihydro-2,5,8-trisubst.- 7-oxo-pyrido(2,3-d)-pyrimidine-6-carboxylique
Degraw et al.	1982	An alternate synthesis of 6‐substituted‐5‐deazapteridines
Roth et al.	1951	Analogs of pteroylglutamic acid. VII. 2-Alkylamino derivatives
US4301281A (en)	1981-11-17	7,8-Dihydro-2,5,8-trisubstituted-7-oxo-pyrido[2,3-d]-pyrimidine-6-carboxylic acid amides
Taylor et al.	1964	Synthesis of Some [1, 2, 3] Thiadiazolo [5, 4-d] pyrimidines and Pyrimido [4, 5-b][1, 4] thiazines1
US3412094A (en)	1968-11-19	5-alkyl-2-amino-4-azido-6-phenylpyrimidines and congeners
Abdel-Rahman et al.	2000	SYNTHESIS OF SOME NEW THIENO [2, 3-b] PYRIDINES, PYRIDO [3′, 2′: 4, 5]-THIENO [3, 2-d] PYRIMIDINES AND PYRIDO [3′, 2′: 4, 5] THIENO [3, 2-d][1, 2, 3]-TRIAZINES
NISHIGAKI et al.	1970	Synthetic Antibacterials. II. Synthesis of Pyrido [2, 3-d] pyrimidine Derivatives.(1)
US4066645A (en)	1978-01-03	Derivatives of pyrazolo [1,5-a]pyrido[3,4-e]pyrimidine
Sauter et al.	1996	New hetero-annelation reactions using N-[bis-(methylthio)-methylene]-amino and related reagents
IE42746B1 (en)	1980-10-08	Fused pyrimidine-4-(3h)-ones and preparation thereof
US4255568A (en)	1981-03-10	2H-Pyrimido[4,5-d][1,3]oxazine-2,4(1H)-dione derivatives
Abdehamid et al.	1984	New heterocyclic syntheses from hydrazidoyl halides. Convenient syntheses of fused pyrimidines, pyridazines, and quinazolines
Habib et al.	1984	Ylides of heterocycles. VII.. I‐, N‐, P‐and S‐ylides of pyrimidones
US4233446A (en)	1980-11-11	5-Chloro-7,8-dihydro-7-oxo-pyrido[2,3-d]pyrimidine-6-carboxylic acid derivatives
WEISS et al.	1960	Potential Purine Antagonists. XXIII. Synthesis of Some 7-Substituted Amino-v-triazolo (d) pyrimidines1
El‐Reedy et al.	1989	Azolopyrimidines and pyrimidoquinazolines from 4‐chloropyrimidines
US3127402A (en)	1964-03-31	Y-oxopteridine derivatives
NO129744B (fr)	1974-05-20