CA2063177A1 - Mixed pyridine-2,4- and -2,5-dicarboxamides, a process for preparing them, the use thereof and pharmaceuticals based on these compounds - Google Patents
Mixed pyridine-2,4- and -2,5-dicarboxamides, a process for preparing them, the use thereof and pharmaceuticals based on these compoundsInfo
- Publication number
- CA2063177A1 CA2063177A1 CA002063177A CA2063177A CA2063177A1 CA 2063177 A1 CA2063177 A1 CA 2063177A1 CA 002063177 A CA002063177 A CA 002063177A CA 2063177 A CA2063177 A CA 2063177A CA 2063177 A1 CA2063177 A1 CA 2063177A1
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- formula
- unsubstituted
- phenyl
- compound
- 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.)
- Abandoned
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 38
- 239000003814 drug Substances 0.000 title claims abstract description 11
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 5
- 102000004079 Prolyl Hydroxylases Human genes 0.000 claims abstract description 11
- 108010043005 Prolyl Hydroxylases Proteins 0.000 claims abstract description 11
- 230000005764 inhibitory process Effects 0.000 claims abstract description 8
- 102000008490 2-Oxoglutarate 5-Dioxygenase Procollagen-Lysine Human genes 0.000 claims abstract description 5
- 108010020504 2-Oxoglutarate 5-Dioxygenase Procollagen-Lysine Proteins 0.000 claims abstract description 5
- 229960003444 immunosuppressant agent Drugs 0.000 claims abstract description 5
- 239000003018 immunosuppressive agent Substances 0.000 claims abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
- -1 cyano, amino, carboxyl Chemical group 0.000 claims description 15
- 108010035532 Collagen Proteins 0.000 claims description 12
- 102000008186 Collagen Human genes 0.000 claims description 12
- 229920001436 collagen Polymers 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 230000004060 metabolic process Effects 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- 238000006467 substitution reaction Methods 0.000 claims description 5
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 4
- 230000001861 immunosuppressant effect Effects 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 125000006710 (C2-C12) alkenyl group Chemical group 0.000 claims description 3
- 125000006711 (C2-C12) alkynyl group Chemical group 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 125000001072 heteroaryl group Chemical group 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 238000011282 treatment Methods 0.000 claims description 3
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 208000035475 disorder Diseases 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001041 indolyl group Chemical group 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 5
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 claims 1
- 125000005392 carboxamide group Chemical group NC(=O)* 0.000 abstract description 2
- 150000003140 primary amides Chemical class 0.000 abstract 1
- 239000002253 acid Substances 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 7
- 239000003112 inhibitor Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 5
- 210000004185 liver Anatomy 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 5
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 150000003254 radicals Chemical class 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 102000004266 Collagen Type IV Human genes 0.000 description 3
- 108010042086 Collagen Type IV Proteins 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 3
- 239000004472 Lysine Substances 0.000 description 3
- 102000008109 Mixed Function Oxygenases Human genes 0.000 description 3
- 108010074633 Mixed Function Oxygenases Proteins 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- OOXOXZVOZIURRD-UHFFFAOYSA-N pyridine-2,4-dicarboxamide Chemical compound NC(=O)C1=CC=NC(C(N)=O)=C1 OOXOXZVOZIURRD-UHFFFAOYSA-N 0.000 description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- CPLXHLVBOLITMK-UHFFFAOYSA-N Magnesium oxide Chemical compound [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 230000036570 collagen biosynthesis Effects 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 208000030159 metabolic disease Diseases 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical group N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 102000001187 Collagen Type III Human genes 0.000 description 1
- 108010069502 Collagen Type III Proteins 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 108010050808 Procollagen Proteins 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 244000166490 Tetrameles nudiflora Species 0.000 description 1
- 231100000644 Toxic injury Toxicity 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000010775 animal oil Substances 0.000 description 1
- 150000005840 aryl radicals Chemical class 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229950005499 carbon tetrachloride Drugs 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000024203 complement activation Effects 0.000 description 1
- 150000001879 copper Chemical class 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 150000001470 diamides Chemical class 0.000 description 1
- KQNSKAOKCLMGFC-UHFFFAOYSA-N dibenzyl pyridine-2,4-dicarboxylate Chemical compound C=1C=NC(C(=O)OCC=2C=CC=CC=2)=CC=1C(=O)OCC1=CC=CC=C1 KQNSKAOKCLMGFC-UHFFFAOYSA-N 0.000 description 1
- 125000004989 dicarbonyl group Chemical group 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- WJJMNDUMQPNECX-UHFFFAOYSA-N dipicolinic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=N1 WJJMNDUMQPNECX-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 229960002591 hydroxyproline Drugs 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- MJIVRKPEXXHNJT-UHFFFAOYSA-N lutidinic acid Chemical compound OC(=O)C1=CC=NC(C(O)=O)=C1 MJIVRKPEXXHNJT-UHFFFAOYSA-N 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- 235000012245 magnesium oxide Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- HCTVWSOKIJULET-LQDWTQKMSA-M phenoxymethylpenicillin potassium Chemical compound [K+].N([C@H]1[C@H]2SC([C@@H](N2C1=O)C([O-])=O)(C)C)C(=O)COC1=CC=CC=C1 HCTVWSOKIJULET-LQDWTQKMSA-M 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 108010016297 plasmin drug combination deoxyribonuclease Proteins 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000005412 pyrazyl group Chemical group 0.000 description 1
- 125000005495 pyridazyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 230000036647 reaction Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Immunology (AREA)
- Pulmonology (AREA)
- Biomedical Technology (AREA)
- Physical Education & Sports Medicine (AREA)
- Gastroenterology & Hepatology (AREA)
- Transplantation (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Photoreceptors In Electrophotography (AREA)
- Hydrogenated Pyridines (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Indole Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Abstract of the disclosure Mixed pyridine-2,4- and -2,5-dicarboxamides, a process for preparing them, the use thereof and pharmaceuticals based on these compounds The invention relates to mixed pyridine-2,4- and -2,5-dicarboxamides where the carboxamide group in position 2 is a primary amide. The said compounds are suitable for the inhibition of proline hydroxylase and lysine hydroxylase and are used as fibrosuppressants and immunosuppressants.
Description
%~fi3177 HOECHST AKTIENGESELLSCH~FT HOE 91/F 079 Dr.FI/pl Description Mixed pyridine-2,4- and -2,5-dicarboxamides, a process for preparing them, the use thereof and pharmaceuticals based on these compounds Compounds which inhibit proline hydroxyla~e ~nd lysine hydroxyla~e effect a very selective inhibition of collagen biosynthesis due to influencing collagen-~pecific hydroxylation reactions. In the course thereof,protein-bound proline or lysine is hydroxylated by the enz~mes proline hydroxylase or lysine hydro~ylase respectively. If this reaction is snppre~sed by inhibitors, the resulting collagen molecule is unable to function, is insufficiently hydroxylated and can be released by the cells only in small ~mounts into the ex~racellular space. The insufficiently hydroxylated collagen cannot, moreover, be incorporated in the collagen matrix and i8 VQry easily broken down by ~0 proteolysis. The conseque~ce of these ef~ects i8 an overall reduction in the amount of collagen deposited in the extracellular ~pace.
It is known that inhibition of proline hydroxylase by known inhibitors such as ~ dipyridyl result~ in inhibition of Clg biosynthe~is by macrophages (W. Muller et al., FEBS Lett. 90 (1978), 218; Immunobiology 155 t1978), 47~. This results in the classical pathway of complement activation becG~ing inoperative. Hence inhibitors of proline hydroxylase act as immunosuppres-sants, for example in immune complex disea~es.
It is known that proline hydroxylase can be effectivelyinhibited by pyridine-2,4- and -2,5-dicarboxylic acids (K. Mayama et al., Eur. J. Biochem. 138 (1984) 239-245).
However, in cell culture, these compounds are effective inhibitors only in very high concentrations (Tschank, G.
It is known that inhibition of proline hydroxylase by known inhibitors such as ~ dipyridyl result~ in inhibition of Clg biosynthe~is by macrophages (W. Muller et al., FEBS Lett. 90 (1978), 218; Immunobiology 155 t1978), 47~. This results in the classical pathway of complement activation becG~ing inoperative. Hence inhibitors of proline hydroxylase act as immunosuppres-sants, for example in immune complex disea~es.
It is known that proline hydroxylase can be effectivelyinhibited by pyridine-2,4- and -2,5-dicarboxylic acids (K. Mayama et al., Eur. J. Biochem. 138 (1984) 239-245).
However, in cell culture, these compounds are effective inhibitors only in very high concentrations (Tschank, G.
2~3~77 et al., ~iochem. J. 238 tl987) 625-633).
DE-A 34 32 094 describes pyridine-2,4- and -2,5-dicarboxylic disesters with 1-6 carbon atoms in the ester alkyl moiety as pharmaceutical~ for the inhibition of 5 proline hydroxylase ~nd ly~ins hydroxylasa.
These lower al~ylated die~ters have ~he disadvantage, however, that they are too rapidly clsaved in the body to the acid~ and do not reach their site of action in the cell in sufficiently high concentration and thus are less suitable for poqsible admini~tration a~ pharmaceuticals.
DE-~ 37 03 959, DE-A 37 03 362 and DE-A 37 03 963 describe in a general form mixed estexsJ~mides, higher alkylated dies~ers and diamides of pyridine-2,4- and -2,5-dicarbo~ylic acids which are effec~ive inhibitors of collagen biosynthesi~ in animal models.
Thus, DE-~ 37 03 959 describes, inter alia, the ~ynthesis of N~ N '-bis(2-methoxyeth~l~pyridine-2,4-dicarboxamideand N,N'-bi~3-isopropoxypropyl)pyridine-2,4-dicarboxamide.
German Patent Application~ P 38 26 471.4 and P 38 28 140.6 propose an improved process for preparing N,N'-bis~2-methoxyethyl)pyridine-2,4-dicarboxamide. Germa~ Patent Application P 39 24 093.2 proposes novel N,N'-bis(alkoxyalkyl)pyridine-2,4~dicarboxamides.
The object to be achieved was thus to find compound which are suitable in a much improved manner than those hitherto disclosed for the inhibition of proline hydroxy-la~e and lysine hydroxylase. The ob~ect has been achieved by pyridine-2,g- and -2,5-dicarboxamides of the formula O
R -N-~- ~
Rl N tI) ~-N~2 2 ~
in whicA
Rl is Cl Cl2-alkyl, C2~C12~alkenyl or C2-Cl2-alkynyl, which are un~ubstituted or ~ubsti~uted once or, in the case of the C2-C12-alkyls, C2-C12-alkenyls and C2-C12-alkynyls, al80 several times by halogen, hydroxyl, cyano, amino, carboxyl, alko~y, alkoxycarbonyl, alkylcarbonyloxy, alkyl-or dialkylam~no, where the alkyl radicals have 1-4 carbon atoms, or b~
indolyl or phenyl, which is unsubstituted or subs~ituted once, twice or three times by halo-gen, ni~ro, Cl-C4-alkyl or Cl-C4-alkoxy, it al~o baing possible in the case of multiple substitu-tions for the substituents to be independently different from one another, or R1 i~ saturated C5-C7-c~cloalkyl which i5 option-ally benzo-fused, : or R1 i8 aryl or heteroaryl, which i~ unsubstitu~ed or in turn 3ubstituted once, twice or three times by halo~en, nitro, cyano, C~-C4-alkyl or Cl-C4-alkoxy, it also being possible in the ca~e of multiple substitutions for the substituents to be independently dif~erent from one another, or provided that R2 is H, R1 is amino which is unsubstituted or mono- or disubstituted by Cl-C4-alkyl, phenyl or Cl-C3-alkylcarbonyl, and R2 is hydrogen or R1, where R2 and Rl are identical or different, :
20~3.~7~
or where the radicals Rl and R2 form, ~ogether with the nitrog~n atom~ a radical of the fonmula ~ R3 -N\ ~ X
(CH2)n in which n is 1 to 3 and X is 0, S, CH2 or N-R3, where R3 is ~ydrogen, phenyl or Cl-C6-alkyl, C2-C~-alkeIIyl or C2-C6-alkynyl, where these phenyl, alkyl, alkenyl and alkynyl radicals are unsubstitu~ed or sub~ti~uted one or more tlmes by:
phenyl which in turn i~ unsub~tituted or substituked one or more times by one or more substituents selected from: halogen, nitro, cyanot carboxyl, hydroxyl" methyl, ethyl, methoxy, e~hoxy and trifluoromethyl, or N(R4~2, where R4 is H or C1-C3-alkyl, or CoGR5, where R5 is H or C,-C3-alkyl, or CON ( R6 ) 2 or CONHR6, where R8 is H or Cl-C3 alkyll or where (R6)2 is a C4-C
~$~
alkylene chain in which zero or one CH2 group which is not directly ad;acent to the nitrogen atom is replaced by O, S or N-R4, or where R3 is C~-C4-alkoxycarbonyl or C3-C7-cycloalkyl, and the physiologically tolerated salts, which likewise effectively inhibit lysinP hydroxylase and prolin~
hydroxylase in animal models.
The invention particularly relates to pyridine-2,4- and -2,5-dicarboxamides of ~he formula I in which Rl is Cl-Cl2-alkyl which is unsubstituted or substitllted once or, in the case of the C2-Cl2-alkyls, 180 several times by phenyl, hydro~yl, alkoxy, amino, alkoxycarbonyl, lS alkyl- or dialkylamino, where the alkyl radicals have 1-3 carbon atoms, or R1 is phenyl which is unsubstituted or in turn substituted once by halogen, nitro, cyano, methyl or methoxy, or, provided that R2 is H, Rl is amino which i8 unsubstituted or mono~ubstituted ~y Cl-C3-alkyl, phenyl or Cl-C3 alkylcarbonyl, - and R2 i8 hydrogen, or where the radicals R1 and RZ form, together with the nitrogen atom, a radical of the formula r~
-N X
6 2~3~77 in which X is O, CH2 or N-R3, where R3 is hydrogen, or Cl-C3-alkyl, and the physiologically tolerated salts.
The meanings of halogen are fluorine, chlorine, bromine and iodine, those of aryl are, phenyl and naphthyl, and those of heteroaryl are 5- and 6-membered aromatic rings with l, 2 or 3 nitrogen and~or oxygen and/or sulfur atoms, which can also be benzo-fused where appropriate, the heteroaryl radicals are~ in particular, pyridyl, pyridazyl, pyrimidyl, pyrazyl, 1,3~5-triazyl, pyrrolyl, pyrazolyl~ imidazolyl,~ tria 701yl ~ thienyl, oxazolyl and thiazolyl radicals and, where appropriate, the benzo-fused compounds thereof.
"Substituted several times~ means hereinbefore andhPreinafter that at least 2~ not more than 4, hydrogen atoms present in the alkyl, alkenyl, alk~nyl, het roaryl and aryl radicals are replaced by the ~ubstituents mentloned. In the case of multiple substitutions the substituents can also be independently different from one another.
All alkyl and alkenyl radicals mentioned with more than 2 carbon atoms and all alkynyl radicals with more than 3 carbon atoms can be ~oth ~traight-chain and branched.
~he invention further relates to the compounds of the formula I for use as pharmaceuticals. The invention additional~.y relates to the compounds of the formula I
for use as fibrosuppressants and immunosuppressant~ and for the inhibition of proline hydroxylase and lysine hydroxylase and for influencing the metabolism of 2 ~ s7 7 collagen and collagen-like substances and the biosynthesis of Clq. Inhibitors cE proline hydroxylase are sui~able tools in the therapy of diseases in which the deposition of collagens makes a crucial contribution to the clinical picture. The~e include, inter alia, fibroses of the lungs, liver and skin (scleroderma) and ~therosclerosis.
The pyridine-2,4- and -2,5-dicarboxamides o~ the formula I which are substituted exclusively in position ~ or S in the amide group show a considarable and surpri~ing improved activity in inhibiting proline hydroxylase and lysina hydroxylase in animal experiments comparad with the pyridine-2,4-dicarboxamides substituted in position 5 also by carboxamide groups from ~E-A-3 707 429 and compared with the pyridine-2,4- and -2,5-dicarbo~clmides substituted in both amide groups of DE-A 37 039 59.
The invention furthsr relates to a process for the preparation of compounds of tha formula I, which com-prises reacting ~0 a compound of the formula II' \ c5~
(II') with a compound of the formula III
~,1 H-N (III) where R1 and R~ have the meanings indicated for formula I, and Y is halogen, especially chloriney and subsequently converting the resulting compound of the formula IV
2~$317~
C - N RlR2 (IV) 1, ll ~l with ~H3 into a compound of the formula I
- N RlR2 N ~1 - NH2 followed, where appxopriate, by co~ersion into its ph~siologically tolera~ed salts.
The following reaction diagram shows the preparation : route ~tages 5 and 6), including the synthesi~ of the precursors (1 to 4) 2~63 ~ 7rl Reaction diagram Stage 2 C02CH2~ C02CH2~
;; NC2CH3 N CO2H
:~ Staye 4 C02H CONRlR2 Stage 5 : . ¦ (II) ~ ¦ (IV) - ~ ~ C02CH3 H~Rl NC2CH3 N~3/
MeOH Stage 6 ~ ~ .
CONRlR2 ( I
2 ~ 7 7 In ~tage 1, commerclally availabls pyridine-2,4-dicarboxylic acid is converted into its dicarbonyl dihalide, preferably its dichlorid~, and reaoted with an optionally ~ubstituted benzyl alcohol to give dibenzyl pyridine-2,4-dicarboxylate.
In stage 2, the diester is ~electlvely hydrolyzed in position 2, for example in the presence of a copper salt as described by Delaxge, J.: Phar. Acta. Helv. ~4 ~10), 637 (1969).
The free acid functionality in position 2 i~ subseguently converted in stage 3 into the corresponding acid chloride and reacted with an alcohol such as, for example, methyl or ethyl alcohol to give the corre~ponding 2-carboxylic e~ter.
The remaining benzyl protective group in position 4 is elLminated by hydrogenolysiR in stage 4 tor example with H2/Pd, Houben-Weyl- Vol. IV/lc (1980), pp. 381 ~ 82).
The free acid in position 4 (foxmula II) is converted into its acid halide, preferably chloride. ~he acid chloride can now be convQrted with the amine of the foxmula (III) into the mixed pyridine-4-carboxamide-2-carboxylic ester (IV).
The mixed diamide of the formula (I) is prepaxed from the 2-carboxylic ester (IV) with alcoholic ammonia ~olution (for example in methanol).
The said process, which has been described in the reac-tion diagram for the compounds substituted in position 4, also applies to the compounds correspondingly sub~tituted in position S.
It is possible where appropriate for the products to be worked up, for example, by extraction or by chromato-graphy, for example on silica gel. The isolated products can be recry~tallized and, wher~ appropriate, reacted with a suitable acid ~o give a physiologically tolerated salt. Examplas of ~uitable acids are:
mineral acids such as hydrochloric and hydrobromic acid 5 and sulfuric, pho~phoric, nitric or perchloric acid or organic acids such as formic, acetic, prop~onic, succinic, glycolic, lactic, malic, tartaric, citric, maleic, fumaric, phe~ylacetic, benzoic, methane~ulfonic, toluenesulfonic, oxalic, 4-aminobenzoic, naphthalene-1,5-disulfonic or ~scorbic acid.
The starting compounds of the formula ~III) which cannotbe bought can be synthesized s~raightforwardly (for example Organikum, Organisch Chemisches Grundpra~tikum, 15th edition, VEB Deutscher Verlag der Wi~senschaften, 1976; a summary of the various possibilities is to be found in the me~hods index, p. 822).
The compounds of the formula I according to the invention have valuable pharmacological properties and, in parti-cular, display activity as inhibitors of proline hydroxy-lase and lysine hydroxylase, as fibrosuppressant and immunosuppressant.
The activity of the fibrogenase can be determined by ; radioimmunological determination of the N-terminal propeptide of collagen type III or of the N- or C-terminal crossl~nking domain of collagen type IV (7s collagen or type IV collagen NCl) in ~erum.
For this purpose, the hydroxyproline, procollagen III
peptide, 7s collagen and type IV collagen NC
concentrations were measured ln the liver of a) untreated rats (control) b) rats given tetrachloromethane (CCl4 control) c) rats given first CCl4 and then a compound according to the invention (this test method is described by Rouiller, C., 3~ experimental toxic injury of the liver; in The '7 7 Liver, C. Rouiller, Vol. 2, pp. 335-476, New York, Academic Pre~s, 1964).
By reason of these pha~macological propertie~ the compounds according to the invention are suitable for the treatment of di~orders of the metabolism of collagen and collagen-like substances and for ~he trea~ment of dis-orders of the biosynthesis of Clg.
The invention therefore further relates to the use of the compounds of the formula I according to the in~ention, and of the physiologically tolerated salts thereof, for the treatment of the abovementioned metabolic disorders.
The compounds can be used a~ pharmaceuticals either alone or mixed with physiologically tolera~ed auxiliari~s or vahicles. They can be administered for this purpose orally in doses of 0.01 ~ 25.0 mg/kg~day, preferably 0.01 - 5.0 mgfkg/day or parenterally in dose~ of 0.001 - 5 mg/kg/day/ preferably 0.001 - 2.5 mg/kg/day, especially to 0.005 - 1.0 mg/kg/day. It is also possible ~o increase the dosage in severe cases. However, lower do~es al~o suffice in many cases. These data relate to an adult weighing about 75 kg.
The invention also embraces the use of the compounds according to the invention for preparing pharmaceutical~
which are employed for the ~reatment and prophylaxis of the abovementioned metabolic disorders.
The invention addit onally relates to pharmaceuticals which contain one or more compounds of the formula I
according to the invention and/or their physiologically tolerated salts.
The pharmaceuticals are producing by processes known per se and familiar to the person skilled in the art. As pharmaceuticals, the pharmacologically active compounds (= active substance) according to the invention are 2 ~ 7 ~
employed either as ~uch or, preferably, in combination with suitable pharmaceutical auxiliaries or vehicles in the f Qrm of tabletR, coated tablets, capsule~, suppositories, emulsions, suspensions or solutions, where S the content of active substance is up to 95 %
advantageou~ly between 10 to 7S ~.
Suitable auxiliaries and vehicle~ for the required pharmaceutical formulation are, for example, besides solvents, gel formers, suppo~itory bases, tableting auxiliaries and other active ~ubstancQ vehicles, also antioxidant6, ~ispersants,` emulsifiers, foxm suppressants, f~avorings, preservatives, solubili2ers or colorants.
The active substances can be administered orally, parenterally or rectslly.
~ha active compounds are mixed with tha additives suitable for this, such as vehicles, ~abilizers or lner diluents, and converted by the usual methods into suitable ~osage forms such as tablets, coa~ed tablets, hard gelatin capsules, aqueous alcoholic or oily suspen~ions or aqueous or oily solutions. Examples of inert vehicles which can be used are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or ~tarch, especially corn starchn The preparation can be carried out either as dry or as wet granules. Examples o~ suitable oily vehicles or solvents are vegetable or animal oils, such as ~unflower oil or fish liver oil.
For subcutaneous or intravenous administxation, the active compounds are, if required, converted into a solution, suspension or emulsion with the substances suitable for this purpose, such as solubilizers, emulsifiers or other auxiliaries. Examples of suitable solvents are physiological saline or alcohols, for example ethanol, propanol, glycerol, as well as sugar ~ v ~ ~ ~
solutions ~uch a~ glucose or mannitol ~olution~, or el3e a mixture oP the various solvent mentioned.
The inventien i8 explained in more detail hereinafter by means of example~.
General procedure for the preparation of the compounds 1 mmol of methyl pyridine-4~carboxam1de-2-carboxylate (IV) is di~solved in 30 ml of sa~urated methanolic ammonia solution and tirred at room temperature for 2 hours. The solution is concentrated and the residue i5 stirred with diisopropyl ether and filtered off with suction.
Example 1 4-N-Ethylpyridine-2-carboxamide-4-carboxamide ~elting point: 197C
Exampl~ 2 4-Norpholinocarbonylpyridine 2-carbox~mide Melting point: 12BC
Example 3 4-N,N-Diethylpyridine-2-carboxamide-4-carboxamide Oil, MS = 222 ~M + H+) molecular mass C11~15N302 (221) Example 4 4-N-(2-methoxypropyl)pyridine-2-carboxamide-4-carboxamids ~elting point: 116 - 120C
- 15 - ~ 7~
Example 5 4-N-~3-methoxypropyl)pyridine-2-carboxamide-4-carboxamide Melting point: 14~C
~xampl~ 6 4-N-(3-hydroxypropyl)pyridine-2-carbox~mide-4-~arboxamide ~eltin~ point~ 154 - 156C
Example 7 4-N-alanylp~idine-2-carboxamide-4-carboxamide Melting point: 124 - 125C
Example 8 4-N-(O-benzylalanyl~pyridine-2-carboxamide-4-carboxamide Melting point: 138 - 140C
DE-A 34 32 094 describes pyridine-2,4- and -2,5-dicarboxylic disesters with 1-6 carbon atoms in the ester alkyl moiety as pharmaceutical~ for the inhibition of 5 proline hydroxylase ~nd ly~ins hydroxylasa.
These lower al~ylated die~ters have ~he disadvantage, however, that they are too rapidly clsaved in the body to the acid~ and do not reach their site of action in the cell in sufficiently high concentration and thus are less suitable for poqsible admini~tration a~ pharmaceuticals.
DE-~ 37 03 959, DE-A 37 03 362 and DE-A 37 03 963 describe in a general form mixed estexsJ~mides, higher alkylated dies~ers and diamides of pyridine-2,4- and -2,5-dicarbo~ylic acids which are effec~ive inhibitors of collagen biosynthesi~ in animal models.
Thus, DE-~ 37 03 959 describes, inter alia, the ~ynthesis of N~ N '-bis(2-methoxyeth~l~pyridine-2,4-dicarboxamideand N,N'-bi~3-isopropoxypropyl)pyridine-2,4-dicarboxamide.
German Patent Application~ P 38 26 471.4 and P 38 28 140.6 propose an improved process for preparing N,N'-bis~2-methoxyethyl)pyridine-2,4-dicarboxamide. Germa~ Patent Application P 39 24 093.2 proposes novel N,N'-bis(alkoxyalkyl)pyridine-2,4~dicarboxamides.
The object to be achieved was thus to find compound which are suitable in a much improved manner than those hitherto disclosed for the inhibition of proline hydroxy-la~e and lysine hydroxylase. The ob~ect has been achieved by pyridine-2,g- and -2,5-dicarboxamides of the formula O
R -N-~- ~
Rl N tI) ~-N~2 2 ~
in whicA
Rl is Cl Cl2-alkyl, C2~C12~alkenyl or C2-Cl2-alkynyl, which are un~ubstituted or ~ubsti~uted once or, in the case of the C2-C12-alkyls, C2-C12-alkenyls and C2-C12-alkynyls, al80 several times by halogen, hydroxyl, cyano, amino, carboxyl, alko~y, alkoxycarbonyl, alkylcarbonyloxy, alkyl-or dialkylam~no, where the alkyl radicals have 1-4 carbon atoms, or b~
indolyl or phenyl, which is unsubstituted or subs~ituted once, twice or three times by halo-gen, ni~ro, Cl-C4-alkyl or Cl-C4-alkoxy, it al~o baing possible in the case of multiple substitu-tions for the substituents to be independently different from one another, or R1 i~ saturated C5-C7-c~cloalkyl which i5 option-ally benzo-fused, : or R1 i8 aryl or heteroaryl, which i~ unsubstitu~ed or in turn 3ubstituted once, twice or three times by halo~en, nitro, cyano, C~-C4-alkyl or Cl-C4-alkoxy, it also being possible in the ca~e of multiple substitutions for the substituents to be independently dif~erent from one another, or provided that R2 is H, R1 is amino which is unsubstituted or mono- or disubstituted by Cl-C4-alkyl, phenyl or Cl-C3-alkylcarbonyl, and R2 is hydrogen or R1, where R2 and Rl are identical or different, :
20~3.~7~
or where the radicals Rl and R2 form, ~ogether with the nitrog~n atom~ a radical of the fonmula ~ R3 -N\ ~ X
(CH2)n in which n is 1 to 3 and X is 0, S, CH2 or N-R3, where R3 is ~ydrogen, phenyl or Cl-C6-alkyl, C2-C~-alkeIIyl or C2-C6-alkynyl, where these phenyl, alkyl, alkenyl and alkynyl radicals are unsubstitu~ed or sub~ti~uted one or more tlmes by:
phenyl which in turn i~ unsub~tituted or substituked one or more times by one or more substituents selected from: halogen, nitro, cyanot carboxyl, hydroxyl" methyl, ethyl, methoxy, e~hoxy and trifluoromethyl, or N(R4~2, where R4 is H or C1-C3-alkyl, or CoGR5, where R5 is H or C,-C3-alkyl, or CON ( R6 ) 2 or CONHR6, where R8 is H or Cl-C3 alkyll or where (R6)2 is a C4-C
~$~
alkylene chain in which zero or one CH2 group which is not directly ad;acent to the nitrogen atom is replaced by O, S or N-R4, or where R3 is C~-C4-alkoxycarbonyl or C3-C7-cycloalkyl, and the physiologically tolerated salts, which likewise effectively inhibit lysinP hydroxylase and prolin~
hydroxylase in animal models.
The invention particularly relates to pyridine-2,4- and -2,5-dicarboxamides of ~he formula I in which Rl is Cl-Cl2-alkyl which is unsubstituted or substitllted once or, in the case of the C2-Cl2-alkyls, 180 several times by phenyl, hydro~yl, alkoxy, amino, alkoxycarbonyl, lS alkyl- or dialkylamino, where the alkyl radicals have 1-3 carbon atoms, or R1 is phenyl which is unsubstituted or in turn substituted once by halogen, nitro, cyano, methyl or methoxy, or, provided that R2 is H, Rl is amino which i8 unsubstituted or mono~ubstituted ~y Cl-C3-alkyl, phenyl or Cl-C3 alkylcarbonyl, - and R2 i8 hydrogen, or where the radicals R1 and RZ form, together with the nitrogen atom, a radical of the formula r~
-N X
6 2~3~77 in which X is O, CH2 or N-R3, where R3 is hydrogen, or Cl-C3-alkyl, and the physiologically tolerated salts.
The meanings of halogen are fluorine, chlorine, bromine and iodine, those of aryl are, phenyl and naphthyl, and those of heteroaryl are 5- and 6-membered aromatic rings with l, 2 or 3 nitrogen and~or oxygen and/or sulfur atoms, which can also be benzo-fused where appropriate, the heteroaryl radicals are~ in particular, pyridyl, pyridazyl, pyrimidyl, pyrazyl, 1,3~5-triazyl, pyrrolyl, pyrazolyl~ imidazolyl,~ tria 701yl ~ thienyl, oxazolyl and thiazolyl radicals and, where appropriate, the benzo-fused compounds thereof.
"Substituted several times~ means hereinbefore andhPreinafter that at least 2~ not more than 4, hydrogen atoms present in the alkyl, alkenyl, alk~nyl, het roaryl and aryl radicals are replaced by the ~ubstituents mentloned. In the case of multiple substitutions the substituents can also be independently different from one another.
All alkyl and alkenyl radicals mentioned with more than 2 carbon atoms and all alkynyl radicals with more than 3 carbon atoms can be ~oth ~traight-chain and branched.
~he invention further relates to the compounds of the formula I for use as pharmaceuticals. The invention additional~.y relates to the compounds of the formula I
for use as fibrosuppressants and immunosuppressant~ and for the inhibition of proline hydroxylase and lysine hydroxylase and for influencing the metabolism of 2 ~ s7 7 collagen and collagen-like substances and the biosynthesis of Clq. Inhibitors cE proline hydroxylase are sui~able tools in the therapy of diseases in which the deposition of collagens makes a crucial contribution to the clinical picture. The~e include, inter alia, fibroses of the lungs, liver and skin (scleroderma) and ~therosclerosis.
The pyridine-2,4- and -2,5-dicarboxamides o~ the formula I which are substituted exclusively in position ~ or S in the amide group show a considarable and surpri~ing improved activity in inhibiting proline hydroxylase and lysina hydroxylase in animal experiments comparad with the pyridine-2,4-dicarboxamides substituted in position 5 also by carboxamide groups from ~E-A-3 707 429 and compared with the pyridine-2,4- and -2,5-dicarbo~clmides substituted in both amide groups of DE-A 37 039 59.
The invention furthsr relates to a process for the preparation of compounds of tha formula I, which com-prises reacting ~0 a compound of the formula II' \ c5~
(II') with a compound of the formula III
~,1 H-N (III) where R1 and R~ have the meanings indicated for formula I, and Y is halogen, especially chloriney and subsequently converting the resulting compound of the formula IV
2~$317~
C - N RlR2 (IV) 1, ll ~l with ~H3 into a compound of the formula I
- N RlR2 N ~1 - NH2 followed, where appxopriate, by co~ersion into its ph~siologically tolera~ed salts.
The following reaction diagram shows the preparation : route ~tages 5 and 6), including the synthesi~ of the precursors (1 to 4) 2~63 ~ 7rl Reaction diagram Stage 2 C02CH2~ C02CH2~
;; NC2CH3 N CO2H
:~ Staye 4 C02H CONRlR2 Stage 5 : . ¦ (II) ~ ¦ (IV) - ~ ~ C02CH3 H~Rl NC2CH3 N~3/
MeOH Stage 6 ~ ~ .
CONRlR2 ( I
2 ~ 7 7 In ~tage 1, commerclally availabls pyridine-2,4-dicarboxylic acid is converted into its dicarbonyl dihalide, preferably its dichlorid~, and reaoted with an optionally ~ubstituted benzyl alcohol to give dibenzyl pyridine-2,4-dicarboxylate.
In stage 2, the diester is ~electlvely hydrolyzed in position 2, for example in the presence of a copper salt as described by Delaxge, J.: Phar. Acta. Helv. ~4 ~10), 637 (1969).
The free acid functionality in position 2 i~ subseguently converted in stage 3 into the corresponding acid chloride and reacted with an alcohol such as, for example, methyl or ethyl alcohol to give the corre~ponding 2-carboxylic e~ter.
The remaining benzyl protective group in position 4 is elLminated by hydrogenolysiR in stage 4 tor example with H2/Pd, Houben-Weyl- Vol. IV/lc (1980), pp. 381 ~ 82).
The free acid in position 4 (foxmula II) is converted into its acid halide, preferably chloride. ~he acid chloride can now be convQrted with the amine of the foxmula (III) into the mixed pyridine-4-carboxamide-2-carboxylic ester (IV).
The mixed diamide of the formula (I) is prepaxed from the 2-carboxylic ester (IV) with alcoholic ammonia ~olution (for example in methanol).
The said process, which has been described in the reac-tion diagram for the compounds substituted in position 4, also applies to the compounds correspondingly sub~tituted in position S.
It is possible where appropriate for the products to be worked up, for example, by extraction or by chromato-graphy, for example on silica gel. The isolated products can be recry~tallized and, wher~ appropriate, reacted with a suitable acid ~o give a physiologically tolerated salt. Examplas of ~uitable acids are:
mineral acids such as hydrochloric and hydrobromic acid 5 and sulfuric, pho~phoric, nitric or perchloric acid or organic acids such as formic, acetic, prop~onic, succinic, glycolic, lactic, malic, tartaric, citric, maleic, fumaric, phe~ylacetic, benzoic, methane~ulfonic, toluenesulfonic, oxalic, 4-aminobenzoic, naphthalene-1,5-disulfonic or ~scorbic acid.
The starting compounds of the formula ~III) which cannotbe bought can be synthesized s~raightforwardly (for example Organikum, Organisch Chemisches Grundpra~tikum, 15th edition, VEB Deutscher Verlag der Wi~senschaften, 1976; a summary of the various possibilities is to be found in the me~hods index, p. 822).
The compounds of the formula I according to the invention have valuable pharmacological properties and, in parti-cular, display activity as inhibitors of proline hydroxy-lase and lysine hydroxylase, as fibrosuppressant and immunosuppressant.
The activity of the fibrogenase can be determined by ; radioimmunological determination of the N-terminal propeptide of collagen type III or of the N- or C-terminal crossl~nking domain of collagen type IV (7s collagen or type IV collagen NCl) in ~erum.
For this purpose, the hydroxyproline, procollagen III
peptide, 7s collagen and type IV collagen NC
concentrations were measured ln the liver of a) untreated rats (control) b) rats given tetrachloromethane (CCl4 control) c) rats given first CCl4 and then a compound according to the invention (this test method is described by Rouiller, C., 3~ experimental toxic injury of the liver; in The '7 7 Liver, C. Rouiller, Vol. 2, pp. 335-476, New York, Academic Pre~s, 1964).
By reason of these pha~macological propertie~ the compounds according to the invention are suitable for the treatment of di~orders of the metabolism of collagen and collagen-like substances and for ~he trea~ment of dis-orders of the biosynthesis of Clg.
The invention therefore further relates to the use of the compounds of the formula I according to the in~ention, and of the physiologically tolerated salts thereof, for the treatment of the abovementioned metabolic disorders.
The compounds can be used a~ pharmaceuticals either alone or mixed with physiologically tolera~ed auxiliari~s or vahicles. They can be administered for this purpose orally in doses of 0.01 ~ 25.0 mg/kg~day, preferably 0.01 - 5.0 mgfkg/day or parenterally in dose~ of 0.001 - 5 mg/kg/day/ preferably 0.001 - 2.5 mg/kg/day, especially to 0.005 - 1.0 mg/kg/day. It is also possible ~o increase the dosage in severe cases. However, lower do~es al~o suffice in many cases. These data relate to an adult weighing about 75 kg.
The invention also embraces the use of the compounds according to the invention for preparing pharmaceutical~
which are employed for the ~reatment and prophylaxis of the abovementioned metabolic disorders.
The invention addit onally relates to pharmaceuticals which contain one or more compounds of the formula I
according to the invention and/or their physiologically tolerated salts.
The pharmaceuticals are producing by processes known per se and familiar to the person skilled in the art. As pharmaceuticals, the pharmacologically active compounds (= active substance) according to the invention are 2 ~ 7 ~
employed either as ~uch or, preferably, in combination with suitable pharmaceutical auxiliaries or vehicles in the f Qrm of tabletR, coated tablets, capsule~, suppositories, emulsions, suspensions or solutions, where S the content of active substance is up to 95 %
advantageou~ly between 10 to 7S ~.
Suitable auxiliaries and vehicle~ for the required pharmaceutical formulation are, for example, besides solvents, gel formers, suppo~itory bases, tableting auxiliaries and other active ~ubstancQ vehicles, also antioxidant6, ~ispersants,` emulsifiers, foxm suppressants, f~avorings, preservatives, solubili2ers or colorants.
The active substances can be administered orally, parenterally or rectslly.
~ha active compounds are mixed with tha additives suitable for this, such as vehicles, ~abilizers or lner diluents, and converted by the usual methods into suitable ~osage forms such as tablets, coa~ed tablets, hard gelatin capsules, aqueous alcoholic or oily suspen~ions or aqueous or oily solutions. Examples of inert vehicles which can be used are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or ~tarch, especially corn starchn The preparation can be carried out either as dry or as wet granules. Examples o~ suitable oily vehicles or solvents are vegetable or animal oils, such as ~unflower oil or fish liver oil.
For subcutaneous or intravenous administxation, the active compounds are, if required, converted into a solution, suspension or emulsion with the substances suitable for this purpose, such as solubilizers, emulsifiers or other auxiliaries. Examples of suitable solvents are physiological saline or alcohols, for example ethanol, propanol, glycerol, as well as sugar ~ v ~ ~ ~
solutions ~uch a~ glucose or mannitol ~olution~, or el3e a mixture oP the various solvent mentioned.
The inventien i8 explained in more detail hereinafter by means of example~.
General procedure for the preparation of the compounds 1 mmol of methyl pyridine-4~carboxam1de-2-carboxylate (IV) is di~solved in 30 ml of sa~urated methanolic ammonia solution and tirred at room temperature for 2 hours. The solution is concentrated and the residue i5 stirred with diisopropyl ether and filtered off with suction.
Example 1 4-N-Ethylpyridine-2-carboxamide-4-carboxamide ~elting point: 197C
Exampl~ 2 4-Norpholinocarbonylpyridine 2-carbox~mide Melting point: 12BC
Example 3 4-N,N-Diethylpyridine-2-carboxamide-4-carboxamide Oil, MS = 222 ~M + H+) molecular mass C11~15N302 (221) Example 4 4-N-(2-methoxypropyl)pyridine-2-carboxamide-4-carboxamids ~elting point: 116 - 120C
- 15 - ~ 7~
Example 5 4-N-~3-methoxypropyl)pyridine-2-carboxamide-4-carboxamide Melting point: 14~C
~xampl~ 6 4-N-(3-hydroxypropyl)pyridine-2-carbox~mide-4-~arboxamide ~eltin~ point~ 154 - 156C
Example 7 4-N-alanylp~idine-2-carboxamide-4-carboxamide Melting point: 124 - 125C
Example 8 4-N-(O-benzylalanyl~pyridine-2-carboxamide-4-carboxamide Melting point: 138 - 140C
Claims (11)
1. A pyridine-2,4- or -2,5-dicarboxamide of the formula I
(I) in which R1 is C1-C12-alkyl, C2-C12-alkenyl or C2-C12-alkynyl, which are unsubstituted or substituted once or, in the case of the C2-C12-alkyls, C2-C12-alkenyls and C2-C12-alkynyls, also several times by halogen, hydroxyl, cyano, amino, carboxyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyl-ox dialkylamino, where the alkyl radicals have 1-4 carbon atoms, or by indolyl or phenyl, which is unsubstituted or substituted once, twice or three times by halo-gen, nitro, C1-C4-alkyl or C1-C4-alkoxy, it also being possible in the case of multiple substitu-tions for the substituents to be independently different from one another, or R1 is saturated C5-C7-cycloalkyl which is option-ally benzo-fused, or R1 is aryl or heteroaryl, which is unsubstituted or in turn substituted once, twice or three times by halogen, nitro, cyano, C1-C4-alkyl or C1-C4-alkoxy, it also being possible in the case of multiple substitutions for the substituents to be independently different from one another, or provided that R2 is H, R1 is amino which is unsubstituted or mono° or disubstituted by C1-C4-alkyl, phenyl or C1-C3-alkylcarbonyl, and R2 is hydrogen or R1, where R2 and R1 are identical or different, or where the radicals R1 and R2 form, together with the nitrogen atom, a radical of the formula in which n is 1 to 3 and X is O, S, CH2 or N-R3, where R3 is hydrogen, phenyl or C1-C6-alkyl, C2-C6-alkenyl or C2-C6-alkynyl, where the phenyl, alkyl, alkenyl and alkynyl radicals are unsubstituted or substituted one or more times by:
phenyl which in turn is unsubstituted or substituted one or more times by one or more substituents selected from: halogen, nitro, cyano, carboxyl, hydroxyl, methyl, ethyl, methoxy, ethoxy and trifluoromethyl, or N(R4)2, where R4 is H or C1-C3-alkyl, or COOR5, where R5 is H or C1-C3-alkyl, or CON(R6)2 or CONHR6, where R6 is H or C1-C3-alkyl, or where (R6)2 is a C4-C6-alkylene chain in which zero or one CH2 group which is not directly adjacent to the nitrogen atom is replaced by O, S or N-R4, or where R3 is C1-C4-alkoxycarbonyl or C3-C7-cycloalkyl, and the physiologically tolerated salts.
(I) in which R1 is C1-C12-alkyl, C2-C12-alkenyl or C2-C12-alkynyl, which are unsubstituted or substituted once or, in the case of the C2-C12-alkyls, C2-C12-alkenyls and C2-C12-alkynyls, also several times by halogen, hydroxyl, cyano, amino, carboxyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyl-ox dialkylamino, where the alkyl radicals have 1-4 carbon atoms, or by indolyl or phenyl, which is unsubstituted or substituted once, twice or three times by halo-gen, nitro, C1-C4-alkyl or C1-C4-alkoxy, it also being possible in the case of multiple substitu-tions for the substituents to be independently different from one another, or R1 is saturated C5-C7-cycloalkyl which is option-ally benzo-fused, or R1 is aryl or heteroaryl, which is unsubstituted or in turn substituted once, twice or three times by halogen, nitro, cyano, C1-C4-alkyl or C1-C4-alkoxy, it also being possible in the case of multiple substitutions for the substituents to be independently different from one another, or provided that R2 is H, R1 is amino which is unsubstituted or mono° or disubstituted by C1-C4-alkyl, phenyl or C1-C3-alkylcarbonyl, and R2 is hydrogen or R1, where R2 and R1 are identical or different, or where the radicals R1 and R2 form, together with the nitrogen atom, a radical of the formula in which n is 1 to 3 and X is O, S, CH2 or N-R3, where R3 is hydrogen, phenyl or C1-C6-alkyl, C2-C6-alkenyl or C2-C6-alkynyl, where the phenyl, alkyl, alkenyl and alkynyl radicals are unsubstituted or substituted one or more times by:
phenyl which in turn is unsubstituted or substituted one or more times by one or more substituents selected from: halogen, nitro, cyano, carboxyl, hydroxyl, methyl, ethyl, methoxy, ethoxy and trifluoromethyl, or N(R4)2, where R4 is H or C1-C3-alkyl, or COOR5, where R5 is H or C1-C3-alkyl, or CON(R6)2 or CONHR6, where R6 is H or C1-C3-alkyl, or where (R6)2 is a C4-C6-alkylene chain in which zero or one CH2 group which is not directly adjacent to the nitrogen atom is replaced by O, S or N-R4, or where R3 is C1-C4-alkoxycarbonyl or C3-C7-cycloalkyl, and the physiologically tolerated salts.
2. A pyridine-2,4- or -2,5-dicarboxamide of the formula I as claimed in claim 1, in which R1 is C1-C12-alkyl which is unsubstituted or substituted once or, in the case of the C2-C12-alkyls, also several times by phenyl, hydroxyl, alkoxy, alkoxycarbonyl, or dialkylamino, where the alkyl radicals have 1-3 carbon atoms, or R1 is phenyl which is unsubstituted or in turn substituted once by halogen, nitro, cyano, methyl or methoxy, or, provided that R2 is H, R1 is amino which is unsubstituted or monosubstituted by C1-C3-alkyl, phenyl or C1-C3-alkylcarbonyl, and R2 is hydrogen, or where the radicals R1 and R2 form, together with the nitrogen atom, a radical of the formula in which X is O, CH2 or N-R3, where R3 is hydrogen, or C1-C3-alkyl, and the physiologically tolerated salts.
3. A pyridine-2,4- or -2,5-dicarboxamide of the formula I as claimed in claim 1, in which R1 is C1-C12-alkyl which is unsubstituted or substituted once or, in the case of the C2-C12-alkyls, also several times by phenyl, hydroxyl, alkoxy, alkoxycarbonyl, or dialkylamino, where the alkyl radicals have 1-3 carbon atoms, or R1 is phenyl, or, provided that R2 is H, R1 is amino which is unsubstituted or monosubstituted by methyl-carbonyl, and R2 is hydrogen, or where the radicals R1 and R2 form, together with the nitrogen atom, a radical of the formula in which X is O, CH2 or N-R3, where R3 is hydrogen, or methyl, and the physiologically tolerated salts.
4. A process for the preparation of compounds of the formula I, which comprises reacting a compound of the formula II' (II') with a compound of the formula III
(III) where R1 and R2 have the meanings indicated for formula I, and Y is halogen, especially chlorine, and subsequently converting the resulting compound of the formula IV
(IV) with NH3 into a compound of the formula I and into its physiologically tolerated salts.
(III) where R1 and R2 have the meanings indicated for formula I, and Y is halogen, especially chlorine, and subsequently converting the resulting compound of the formula IV
(IV) with NH3 into a compound of the formula I and into its physiologically tolerated salts.
5. A compound as claimed in one or more of claims 1 to 3 for use as pharmaceuticals.
6. A compound as claimed in one or more of claims 1 to 3 for the inhibition of proline hydroxylase and lysine hydroxylase.
7. A compound as claimed in one or more of claims 1 to 3 for use as fibrosuppressant and immunosuppressant.
8. A pharmaceutical containing a compound of the formula I with compatible pharmaceutical vehicles.
9. The use of compound of the formula I for influenc-ing the metabolism of collagen and collagen-like substan-ces and the biosynthesis of Clq.
10. The use of compounds of the formula I for the treatment of disorders of the metabolism of collagen and collagen-like substances and of the biosynthesis of Clq.
11. A process for the production of pharmaceuticals for influencing the metabolism of collagen and collagen-like substances and the biosynthesis of Clq, which comprises incorporating a compound of the formula I in the pharma-ceutical.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE4108824 | 1991-03-18 | ||
DEP4108824.7 | 1991-03-18 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2063177A1 true CA2063177A1 (en) | 1992-09-19 |
Family
ID=6427597
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002063177A Abandoned CA2063177A1 (en) | 1991-03-18 | 1992-03-17 | Mixed pyridine-2,4- and -2,5-dicarboxamides, a process for preparing them, the use thereof and pharmaceuticals based on these compounds |
Country Status (22)
Country | Link |
---|---|
EP (1) | EP0504799B1 (en) |
JP (1) | JP3121428B2 (en) |
KR (1) | KR100243959B1 (en) |
AT (1) | ATE154929T1 (en) |
AU (1) | AU645668B2 (en) |
CA (1) | CA2063177A1 (en) |
CZ (1) | CZ282298B6 (en) |
DE (1) | DE59208651D1 (en) |
DK (1) | DK0504799T3 (en) |
ES (1) | ES2104758T3 (en) |
FI (1) | FI101701B (en) |
GR (1) | GR3024309T3 (en) |
HR (1) | HRP940835A2 (en) |
HU (1) | HU217809B (en) |
IE (1) | IE920843A1 (en) |
IL (1) | IL101257A (en) |
MX (1) | MX9201156A (en) |
NO (1) | NO178859C (en) |
NZ (1) | NZ241968A (en) |
TW (1) | TW199147B (en) |
YU (1) | YU48156B (en) |
ZA (1) | ZA921945B (en) |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3703959A1 (en) * | 1987-02-10 | 1988-08-18 | Hoechst Ag | PYRIDINE-2,4- AND 2,5-DICARBONIC ACID AMIDES, METHOD FOR THE PRODUCTION THEREOF, USE OF THE SAME AND MEDICINAL PRODUCTS BASED ON THESE COMPOUNDS |
DE58908519D1 (en) * | 1988-08-04 | 1994-11-24 | Hoechst Ag | Improved process for the preparation of N, N-bis (alkoxyalkyl) pyridine -2,4-dicarboxylic acid diamides. |
DE3924093A1 (en) * | 1989-07-20 | 1991-02-07 | Hoechst Ag | N, N'-BIS (ALKOXY-ALKYL) -PYRIDINE-2,4-DICARBONESAUREDIAMIDES, METHOD FOR THE PRODUCTION AND USE THEREOF |
DE3928144A1 (en) * | 1989-08-25 | 1991-02-28 | Hoechst Ag | CYCLIC PYRIDINE-2,4- AND -2,5-DICARBONIC ACIDEDIAMIDES, METHOD FOR THE PRODUCTION AND USE THEREOF |
DE3938805A1 (en) * | 1989-11-23 | 1991-05-29 | Hoechst Ag | PYRIDINE-2,4- AND 2,5-DICARBONIC ACID DIAMOND, METHOD FOR THE PRODUCTION AND USE THEREOF |
DE4030999A1 (en) * | 1990-10-01 | 1992-04-09 | Hoechst Ag | 4- OR 5-SUBSTITUTED PYRIDINE-2-CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MEDICINAL PRODUCT |
-
1991
- 1991-09-20 TW TW080107458A patent/TW199147B/zh active
-
1992
- 1992-03-12 YU YU24692A patent/YU48156B/en unknown
- 1992-03-16 IL IL101257A patent/IL101257A/en not_active IP Right Cessation
- 1992-03-16 IE IE084392A patent/IE920843A1/en unknown
- 1992-03-16 NZ NZ241968A patent/NZ241968A/en unknown
- 1992-03-16 FI FI921119A patent/FI101701B/en active
- 1992-03-17 KR KR1019920004320A patent/KR100243959B1/en not_active IP Right Cessation
- 1992-03-17 CZ CS92803A patent/CZ282298B6/en unknown
- 1992-03-17 ZA ZA921945A patent/ZA921945B/en unknown
- 1992-03-17 MX MX9201156A patent/MX9201156A/en unknown
- 1992-03-17 EP EP92104584A patent/EP0504799B1/en not_active Expired - Lifetime
- 1992-03-17 AU AU12967/92A patent/AU645668B2/en not_active Ceased
- 1992-03-17 AT AT92104584T patent/ATE154929T1/en not_active IP Right Cessation
- 1992-03-17 NO NO921025A patent/NO178859C/en not_active IP Right Cessation
- 1992-03-17 CA CA002063177A patent/CA2063177A1/en not_active Abandoned
- 1992-03-17 ES ES92104584T patent/ES2104758T3/en not_active Expired - Lifetime
- 1992-03-17 JP JP04060053A patent/JP3121428B2/en not_active Expired - Fee Related
- 1992-03-17 DE DE59208651T patent/DE59208651D1/en not_active Expired - Fee Related
- 1992-03-17 HU HU9200891A patent/HU217809B/en not_active IP Right Cessation
- 1992-03-17 DK DK92104584.5T patent/DK0504799T3/en active
-
1994
- 1994-10-26 HR HRP-246/92A patent/HRP940835A2/en not_active Application Discontinuation
-
1997
- 1997-07-30 GR GR970401958T patent/GR3024309T3/en unknown
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US5130317A (en) | Pyrimidine-4,6-dicarboxylic acid diamides, processes for the use thereof, and pharmaceuticals based on these compounds | |
AU599746B2 (en) | Pyridine-2,4- and -2,5-dicarboxylic acid amides, processes for their preparation, the use thereof, and medicaments based on these compounds | |
DE60306934T2 (en) | Use of nitrile compounds as medicaments | |
NZ238701A (en) | 2,4- and 2,5-substituted pyridine-n-oxides and pharmaceutical compositions | |
KR960011371B1 (en) | 2,4-and 2,5-pyridine-dicarboxylic-acid derivatives, process for their preparation, their use and medicines based on these compounds | |
EP1455790A1 (en) | Use of pyridine-2,4-dicarboxylic acid diamides and of pyrimidine-4,6-dicarboxylic acid diamides for selective collagenase inhibition | |
AU614074B2 (en) | Substituted pyridine-2,4-dicarboxylic acid derivatives, processes for their preparation, the use thereof and medicaments based on these compounds | |
JPH04247070A (en) | 4- or 5-substituted pyridine-2-carboxylic acid, process for producing same and use thereof as medicine | |
CA2063177A1 (en) | Mixed pyridine-2,4- and -2,5-dicarboxamides, a process for preparing them, the use thereof and pharmaceuticals based on these compounds | |
US5658923A (en) | Azepine derivatives and use thereof | |
US5240921A (en) | Cyclic pyridine-2,4- and -2,5-dicarboxylic acid diamides, processes for their preparation and their use | |
US5512586A (en) | Medicaments based on pyridine-2,4- and 2,5-dicarboxylic acid amides | |
US5153208A (en) | Pyridine-2,4- and -2,5-dicarboxylic acid amides and their medicinal compositions and methods of use | |
US5364873A (en) | Pyridine-2,4- and dicarboxylic acid derivatives, the use thereof and pharmaceutical composition based on these compounds | |
EP0661271B1 (en) | Azepine derivatives, production thereof, and use thereof as sigma-receptor ligands | |
KR100214797B1 (en) | 2,4-and 2,5-bis-(tetrazolyl)pyridines process for their preparation and their use as medicines | |
IE904233A1 (en) | Pyridine-2,4- and 2,5-dicarboxamides, a process for the¹preparation thereof, and the use thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
EEER | Examination request | ||
FZDE | Discontinued |