EP0000383B1 - Pyrimido (4,5-c) pyridazines, their use in pharmaceutical preparations, and process for their preparation - Google Patents
Pyrimido (4,5-c) pyridazines, their use in pharmaceutical preparations, and process for their preparation Download PDFInfo
- Publication number
- EP0000383B1 EP0000383B1 EP78100331A EP78100331A EP0000383B1 EP 0000383 B1 EP0000383 B1 EP 0000383B1 EP 78100331 A EP78100331 A EP 78100331A EP 78100331 A EP78100331 A EP 78100331A EP 0000383 B1 EP0000383 B1 EP 0000383B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- group
- formula
- compound
- optionally substituted
- phenyl ring
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 238000000034 method Methods 0.000 title claims description 21
- 238000002360 preparation method Methods 0.000 title claims description 10
- UVGCYMVPDRDDDT-UHFFFAOYSA-N pyrimido[4,5-c]pyridazine Chemical class N1=CN=C2N=NC=CC2=C1 UVGCYMVPDRDDDT-UHFFFAOYSA-N 0.000 title description 9
- 239000000825 pharmaceutical preparation Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 63
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 26
- -1 phenacyl group Chemical group 0.000 claims description 21
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 10
- 125000005042 acyloxymethyl group Chemical group 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 238000006460 hydrolysis reaction Methods 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 230000007062 hydrolysis Effects 0.000 claims description 6
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 6
- 125000006301 indolyl methyl group Chemical group 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000001041 indolyl group Chemical group 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 241000282414 Homo sapiens Species 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 230000003301 hydrolyzing effect Effects 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 8
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
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- 239000007787 solid Substances 0.000 description 15
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 238000000921 elemental analysis Methods 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- WBFYVDCHGVNRBH-UHFFFAOYSA-N 7,8-dihydropteroic acid Chemical compound N=1C=2C(=O)NC(N)=NC=2NCC=1CNC1=CC=C(C(O)=O)C=C1 WBFYVDCHGVNRBH-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- AESGJYVQDCJVQY-UHFFFAOYSA-N 2-amino-6-[amino(methyl)amino]-1h-pyrimidin-4-one Chemical compound CN(N)C1=CC(=O)N=C(N)N1 AESGJYVQDCJVQY-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
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- IPKMHRDOJWVZQT-UHFFFAOYSA-N 7-amino-1,3-dimethyl-8h-pyrimido[4,5-c]pyridazine-4,5-dione Chemical compound NC1=NC(O)=C2C(=O)C(C)=NN(C)C2=N1 IPKMHRDOJWVZQT-UHFFFAOYSA-N 0.000 description 4
- 108700016256 Dihydropteroate synthases Proteins 0.000 description 4
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 4
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- 229960004050 aminobenzoic acid Drugs 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- WRFWAYDBNCOWRA-UHFFFAOYSA-N 3,4-dichloro-1-(6-iodo-4-oxo-2-thiophen-2-ylquinazolin-3-yl)pyrrole-2,5-dione Chemical class O=C1C(Cl)=C(Cl)C(=O)N1N1C(=O)C2=CC(I)=CC=C2N=C1C1=CC=CS1 WRFWAYDBNCOWRA-UHFFFAOYSA-N 0.000 description 3
- QCODOZCHMUXAJB-UHFFFAOYSA-N 5,7-diamino-1,3-dimethylpyrimido[4,5-c]pyridazin-4-one Chemical compound NC1=NC(N)=C2C(=O)C(C)=NN(C)C2=N1 QCODOZCHMUXAJB-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
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- 239000006227 byproduct Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
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- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 125000004043 oxo group Chemical group O=* 0.000 description 3
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- 125000001424 substituent group Chemical group 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- MSTNYGQPCMXVAQ-RYUDHWBXSA-N (6S)-5,6,7,8-tetrahydrofolic acid Chemical compound C([C@H]1CNC=2N=C(NC(=O)C=2N1)N)NC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 MSTNYGQPCMXVAQ-RYUDHWBXSA-N 0.000 description 2
- CQQNNQTXUGLUEV-UHFFFAOYSA-N 2-amino-6-(hydroxymethyl)-7,8-dihydropteridin-4-ol Chemical compound N1CC(CO)=NC2=C1N=C(N)NC2=O CQQNNQTXUGLUEV-UHFFFAOYSA-N 0.000 description 2
- RWZDEGYOEZDNHX-UHFFFAOYSA-N 6-[amino(methyl)amino]pyrimidine-2,4-diamine Chemical compound CN(N)C1=CC(N)=NC(N)=N1 RWZDEGYOEZDNHX-UHFFFAOYSA-N 0.000 description 2
- BKXXMVKZQYELEY-UHFFFAOYSA-N 7,8-dihydropteridin-2-ylmethanol Chemical compound N1=CCNC2=NC(CO)=NC=C21 BKXXMVKZQYELEY-UHFFFAOYSA-N 0.000 description 2
- 102000003960 Ligases Human genes 0.000 description 2
- 108090000364 Ligases Proteins 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000011724 folic acid Substances 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 125000001841 imino group Chemical group [H]N=* 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- CWKLZLBVOJRSOM-UHFFFAOYSA-N methyl pyruvate Chemical compound COC(=O)C(C)=O CWKLZLBVOJRSOM-UHFFFAOYSA-N 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
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- 239000000376 reactant Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
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- 238000000967 suction filtration Methods 0.000 description 2
- 239000005460 tetrahydrofolate Substances 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- NLDLOHKVQMKTII-UHFFFAOYSA-N (7-amino-1,2-dimethyl-4,5-dioxo-3,6-dihydropyrimido[4,5-c]pyridazin-3-yl) acetate Chemical compound NC=1N=C(C2=C(N(N(C(C2=O)OC(C)=O)C)C)N=1)O NLDLOHKVQMKTII-UHFFFAOYSA-N 0.000 description 1
- UKWANYOYRCYDNC-UHFFFAOYSA-N (7-amino-1-methyl-2H-pyrimido[4,5-c]pyridazin-3-yl)methanol Chemical compound NC=1N=CC2=C(N(NC(=C2)CO)C)N=1 UKWANYOYRCYDNC-UHFFFAOYSA-N 0.000 description 1
- OCOJMRFCWDNSBJ-UHFFFAOYSA-N (7-amino-1-methyl-2H-pyrimido[4,5-c]pyridazin-3-yl)methyl acetate Chemical compound NC=1N=CC2=C(N(NC(=C2)COC(C)=O)C)N=1 OCOJMRFCWDNSBJ-UHFFFAOYSA-N 0.000 description 1
- LNAHHHVNKALHNW-UHFFFAOYSA-N 2-(5,7-diamino-1-methyl-4-oxopyrimido[4,5-c]pyridazin-3-yl)oxyacetic acid Chemical compound C(=O)(O)COC=1C(C2=C(N(N=1)C)N=C(N=C2N)N)=O LNAHHHVNKALHNW-UHFFFAOYSA-N 0.000 description 1
- JTIRAEJJWJLRJY-UHFFFAOYSA-N 2-(7-amino-1-methyl-2H-pyrimido[4,5-c]pyridazin-3-yl)propanoic acid Chemical compound NC=1N=CC2=C(N(NC(=C2)C(C)C(=O)O)C)N=1 JTIRAEJJWJLRJY-UHFFFAOYSA-N 0.000 description 1
- SXZORYSZYIGPEA-UHFFFAOYSA-N 2-(7-amino-1-methyl-4,5-dioxo-8h-pyrimido[4,5-c]pyridazin-3-yl)-2-methoxyacetic acid Chemical compound NC1=NC(O)=C2C(=O)C(C(C(O)=O)OC)=NN(C)C2=N1 SXZORYSZYIGPEA-UHFFFAOYSA-N 0.000 description 1
- QWIGIULIWQYMLS-UHFFFAOYSA-N 2-(7-amino-1-methyl-4,5-dioxo-8h-pyrimido[4,5-c]pyridazin-3-yl)-3-(3,4,5-trimethoxyphenyl)propanenitrile Chemical compound COC1=C(OC)C(OC)=CC(CC(C#N)C=2C(C=3C(=O)N=C(N)NC=3N(C)N=2)=O)=C1 QWIGIULIWQYMLS-UHFFFAOYSA-N 0.000 description 1
- XUKTUWRGSZSUGO-UHFFFAOYSA-N 2-(7-amino-1-methyl-4,5-dioxo-8h-pyrimido[4,5-c]pyridazin-3-yl)propanoic acid Chemical compound NC1=NC(O)=C2C(=O)C(C(C(O)=O)C)=NN(C)C2=N1 XUKTUWRGSZSUGO-UHFFFAOYSA-N 0.000 description 1
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- NUWHKWFUYSANPY-UHFFFAOYSA-N 3-morpholin-4-yl-5h-pyrimido[4,5-e][1,2,4]triazine-6,8-dione Chemical compound N=1N=C2C(=O)NC(=O)NC2=NC=1N1CCOCC1 NUWHKWFUYSANPY-UHFFFAOYSA-N 0.000 description 1
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- ONPGOSVDVDPBCY-CQSZACIVSA-N 6-amino-5-[(1r)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-n-[4-(4-methylpiperazine-1-carbonyl)phenyl]pyridazine-3-carboxamide Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NN=1)N)=CC=1C(=O)NC(C=C1)=CC=C1C(=O)N1CCN(C)CC1 ONPGOSVDVDPBCY-CQSZACIVSA-N 0.000 description 1
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- HXAOMTKPSXAOAG-UHFFFAOYSA-N 7-amino-1-methyl-2H-pyrimido[4,5-c]pyridazine-3-carboxylic acid Chemical compound NC=1N=CC2=C(N(NC(=C2)C(=O)O)C)N=1 HXAOMTKPSXAOAG-UHFFFAOYSA-N 0.000 description 1
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- 241000282412 Homo Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
- UPLKWSHKQOQMKA-UHFFFAOYSA-N NC=1N=CC2=C(N(NC(=C2)C(C)C(=O)OCC)C)N=1 Chemical compound NC=1N=CC2=C(N(NC(=C2)C(C)C(=O)OCC)C)N=1 UPLKWSHKQOQMKA-UHFFFAOYSA-N 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- XAKBSHICSHRJCL-UHFFFAOYSA-N [CH2]C(=O)C1=CC=CC=C1 Chemical group [CH2]C(=O)C1=CC=CC=C1 XAKBSHICSHRJCL-UHFFFAOYSA-N 0.000 description 1
- QBJRFHRDZABKOX-UHFFFAOYSA-N [N]NN Chemical group [N]NN QBJRFHRDZABKOX-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000000287 crude extract Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- GYOZYWVXFNDGLU-XLPZGREQSA-N dTMP Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)C1 GYOZYWVXFNDGLU-XLPZGREQSA-N 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- OQOCQBJWOCRPQY-UHFFFAOYSA-N diethyl 2-methyl-3-oxosuccinate Chemical compound CCOC(=O)C(C)C(=O)C(=O)OCC OQOCQBJWOCRPQY-UHFFFAOYSA-N 0.000 description 1
- DBKKFIIYQGGHJO-UHFFFAOYSA-N diethyl 2-oxopropanedioate Chemical compound CCOC(=O)C(=O)C(=O)OCC DBKKFIIYQGGHJO-UHFFFAOYSA-N 0.000 description 1
- OZRNSSUDZOLUSN-LBPRGKRZSA-N dihydrofolic acid Chemical compound N=1C=2C(=O)NC(N)=NC=2NCC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OZRNSSUDZOLUSN-LBPRGKRZSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 150000002148 esters Chemical group 0.000 description 1
- UVJQQYMWMAISMQ-UHFFFAOYSA-N ethyl 2,4-dioxo-4-phenylbutanoate Chemical compound CCOC(=O)C(=O)CC(=O)C1=CC=CC=C1 UVJQQYMWMAISMQ-UHFFFAOYSA-N 0.000 description 1
- WFPZQWFVWDABRP-UHFFFAOYSA-N ethyl 2-(4,5-dioxo-6H-pyrimido[4,5-c]pyridazin-1-yl)propanoate Chemical compound C(C)OC(=O)C(C)N1N=CC(C2=C1N=CN=C2O)=O WFPZQWFVWDABRP-UHFFFAOYSA-N 0.000 description 1
- ARRGJCSOUZZOJA-UHFFFAOYSA-N ethyl 2-(7-amino-1-methyl-4,5-dioxo-8h-pyrimido[4,5-c]pyridazin-3-yl)acetate Chemical compound N1=C(N)NC(=O)C2=C1N(C)N=C(CC(=O)OCC)C2=O ARRGJCSOUZZOJA-UHFFFAOYSA-N 0.000 description 1
- 229940014144 folate Drugs 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 150000002224 folic acids Chemical class 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 150000007857 hydrazones Chemical class 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 230000001050 lubricating effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- UMCVKCJVDJEVQF-UHFFFAOYSA-N methyl 3-acetyloxy-2-oxopropanoate Chemical compound COC(=O)C(=O)COC(C)=O UMCVKCJVDJEVQF-UHFFFAOYSA-N 0.000 description 1
- FTPSUNCBLUXIAA-UHFFFAOYSA-N methyl 4-(2,5-dimethoxyphenyl)-2,4-dioxobutanoate Chemical compound COC(=O)C(=O)CC(=O)C1=CC(OC)=CC=C1OC FTPSUNCBLUXIAA-UHFFFAOYSA-N 0.000 description 1
- SWGYTCCANCNTOL-UHFFFAOYSA-N methyl 5,7-diamino-1-methyl-2H-pyrimido[4,5-c]pyridazine-3-carboxylate Chemical compound C(=O)(OC)C1=CC2=C(N(N1)C)N=C(N=C2N)N SWGYTCCANCNTOL-UHFFFAOYSA-N 0.000 description 1
- SRADWVLXZAEHIR-UHFFFAOYSA-N methyl 5,7-diamino-1-methyl-4-oxopyrimido[4,5-c]pyridazine-3-carboxylate Chemical compound NC1=NC(N)=C2C(=O)C(C(=O)OC)=NN(C)C2=N1 SRADWVLXZAEHIR-UHFFFAOYSA-N 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 238000004816 paper chromatography Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000000561 purinyl group Chemical class N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 150000004892 pyridazines Chemical class 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 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
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/50—Three nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Definitions
- lower as used herein in conjunction with an alkyl, alkoxy or acyl group is indicative of the fact that such groups have from 1 to 6 carbon atoms arranged in a straight or branched chain.
- phenacyl group however is used to denote solely a C 6 H 5 COCH 2 ⁇ group.
- the above compounds of formula (II) inhibit the enzyme dihydropteroate synthetase which enables microorganisms to synthesize an essential intermediate in the production of tetrahydrofolate co-factors.
- Most of these co-factors are one-carbon adducts of tetrahydrofilic acid and they are essential metabolites in cells for the biosynthesis of purines, thymidylic acid, serine, and several other biologically important compounds.
- Man and other higher animals are unable to synthesise folic acid and therefore they have to obtain them from food which contains the required preformed folates.
- the hydrolysis of the lower acyloxymethyl group will preferably take place under alkaline conditions, for example, by using aqueous sodium hydroxide.
- the hydrolysis will be carried out at a non extreme temperature, i.e. between 10° and 100°C, and preferably at room temperature.
- the compounds of formula (VII) can be prepared preferably in situ, by condensing a 2 - amino - 4 - imino - 6 - hydrazinopyrimidine of formula (VIII), or a tautomer thereof, with an a-keto ester of formula (V).
- Humans an other animals suffering from microbial infections may be treated by administering a non-toxic effective antimicrobial treatment amount of a compound of formula (II), or preferably administering a pharmaceutical formulation comprising the said amount of a compound of formula (II) and a pharmaceutically acceptable carrier, to the infected human or other animal.
- the 3 ⁇ CH(OCH 3 )CO 2 H compound (disodium salt) was prepared in a manner similar to that of 6A from the 3 ⁇ CH(OCH 3 )CO 2 C 2 H 5 starting material, yield 69%.
- Calcd. for C 10 H 9 N 5 Na 2 O 5 C, 36.93%; H, 2.79%; N, 21.54%; Na, 14.14%. Found: C, 36.70%; H, 2.92%; N, 21.38%; Na, 14.01%.
- the reactions are followed by determining the amount of 14 C in H 2 pteroate after separation from the substrate, p-aminobenzoate-7- 14 C, by paper chromatography.
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB2876577 | 1977-07-08 | ||
| GB2876577 | 1977-07-08 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP0000383A1 EP0000383A1 (en) | 1979-01-24 |
| EP0000383B1 true EP0000383B1 (en) | 1982-10-13 |
Family
ID=10280798
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP78100331A Expired EP0000383B1 (en) | 1977-07-08 | 1978-07-07 | Pyrimido (4,5-c) pyridazines, their use in pharmaceutical preparations, and process for their preparation |
Country Status (4)
| Country | Link |
|---|---|
| US (6) | US4225710A (enrdf_load_stackoverflow) |
| EP (1) | EP0000383B1 (enrdf_load_stackoverflow) |
| JP (1) | JPS5419996A (enrdf_load_stackoverflow) |
| DE (1) | DE2862102D1 (enrdf_load_stackoverflow) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4225710A (en) * | 1977-07-08 | 1980-09-30 | Burroughs Wellcome Co. | Pyrimido(4,5-c)pyridazines |
| JPS5422393A (en) * | 1977-07-20 | 1979-02-20 | Wellcome Found | Novel heterocyclic compound and preparation and compositions thereof |
| US4260758A (en) * | 1979-09-17 | 1981-04-07 | Burroughs Wellcome Co. | Pyrazolo (3,4-d) pyrimidines and methods of making |
| US5365624A (en) * | 1993-03-02 | 1994-11-22 | Berns Michael S | Apparatus for automatic and simultaneous caring for teeth and gums |
| ES2216817T3 (es) * | 1993-06-10 | 2004-11-01 | Karlin Technology, Inc. | Dispositivo protector con primero y segundo pasos para cirugia del espacio intervertebral. |
| CN1311665A (zh) * | 1998-08-03 | 2001-09-05 | 新生制药公司 | 一种新的止痛、抗炎和创伤治疗剂 |
| GB2353330B (en) | 1999-08-04 | 2003-05-28 | Pet Mate Ltd | Pond pump |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2130358A (en) * | 1937-04-07 | 1938-09-20 | Eastman Kodak Co | Azo compounds and process for coloring therewith |
| US2328956A (en) * | 1942-08-18 | 1943-09-07 | Gen Electric | Diazine derivatives |
| US2435203A (en) * | 1942-08-26 | 1948-02-03 | Gen Electric | Acylhydrazino amino derivatives |
| DK113716B (da) * | 1960-07-30 | 1969-04-21 | Takeda Chemical Industries Ltd | Fremgangsmåde til fremstilling af 1-[pyrimidinyl-(2)]-guanazolforbindelser eller salte deraf. |
| US3382247A (en) * | 1965-11-01 | 1968-05-07 | Upjohn Co | 6-amino-1, 2-dihydro-1-hydroxy-2-imino-4-phenoxypyrimidines |
| US3464987A (en) * | 1966-02-21 | 1969-09-02 | Upjohn Co | 1,2-dihydro-1-hydroxy-2-imino-6-(lower alkyl)pyrimidines |
| US3947442A (en) * | 1969-11-20 | 1976-03-30 | The Sherwin-Williams Company | Method for producing heterocyclic acid anhydrides and pyrimidinediones |
| US3998827A (en) * | 1971-04-07 | 1976-12-21 | The Upjohn Company | 6-amino-4-(substituted piperidino)-1,2-dihydro-1-hydroxy-2-iminopyrimidines |
| US4225710A (en) * | 1977-07-08 | 1980-09-30 | Burroughs Wellcome Co. | Pyrimido(4,5-c)pyridazines |
| EP0000382B1 (en) * | 1977-07-08 | 1982-10-06 | The Wellcome Foundation Limited | Pyrimido (4,5-c)pyridazines, compositions containing them and processes for their preparation |
| JPS5422393A (en) * | 1977-07-20 | 1979-02-20 | Wellcome Found | Novel heterocyclic compound and preparation and compositions thereof |
| US4235909A (en) * | 1979-04-19 | 1980-11-25 | Eli Lilly And Company | Octahydro-2H-pyrrolo[3,4-g]quinolines |
-
1978
- 1978-07-07 US US05/922,545 patent/US4225710A/en not_active Expired - Lifetime
- 1978-07-07 EP EP78100331A patent/EP0000383B1/en not_active Expired
- 1978-07-07 DE DE7878100331T patent/DE2862102D1/de not_active Expired
- 1978-07-07 JP JP8286978A patent/JPS5419996A/ja active Granted
-
1980
- 1980-05-13 US US06/149,255 patent/US4329362A/en not_active Expired - Lifetime
- 1980-05-27 US US06/153,058 patent/US4302587A/en not_active Expired - Lifetime
- 1980-05-27 US US06/153,061 patent/US4303789A/en not_active Expired - Lifetime
- 1980-05-27 US US06/153,060 patent/US4303790A/en not_active Expired - Lifetime
- 1980-05-27 US US06/153,059 patent/US4323679A/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| EP0000383A1 (en) | 1979-01-24 |
| US4302587A (en) | 1981-11-24 |
| DE2862102D1 (en) | 1982-11-18 |
| US4303789A (en) | 1981-12-01 |
| US4225710A (en) | 1980-09-30 |
| JPS5419996A (en) | 1979-02-15 |
| US4323679A (en) | 1982-04-06 |
| US4303790A (en) | 1981-12-01 |
| JPS6339597B2 (enrdf_load_stackoverflow) | 1988-08-05 |
| US4329362A (en) | 1982-05-11 |
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Legal Events
| Date | Code | Title | Description |
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