IE902642A1 - N,N'-Bis(alkoxyalkyl)-pyridine-2,4-dicarboxylic acid diamides, preparation and their use - Google Patents
N,N'-Bis(alkoxyalkyl)-pyridine-2,4-dicarboxylic acid diamides, preparation and their useInfo
- Publication number
- IE902642A1 IE902642A1 IE264290A IE264290A IE902642A1 IE 902642 A1 IE902642 A1 IE 902642A1 IE 264290 A IE264290 A IE 264290A IE 264290 A IE264290 A IE 264290A IE 902642 A1 IE902642 A1 IE 902642A1
- Authority
- IE
- Ireland
- Prior art keywords
- compound
- formula
- pyridine
- conh
- dicarboxylic acid
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims description 11
- 125000004183 alkoxy alkyl group Chemical group 0.000 title claims description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 60
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- -1 pyridine-2,4-dicarboxylic acid diamides Chemical class 0.000 claims abstract description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 11
- 239000001257 hydrogen Substances 0.000 claims abstract description 11
- JUCNGMPTCXPMNB-UHFFFAOYSA-N 2-n,4-n-bis(2-methoxyethyl)pyridine-2,4-dicarboxamide Chemical compound COCCNC(=O)C1=CC=NC(C(=O)NCCOC)=C1 JUCNGMPTCXPMNB-UHFFFAOYSA-N 0.000 claims abstract description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229960003444 immunosuppressant agent Drugs 0.000 claims abstract description 3
- 239000003018 immunosuppressive agent Substances 0.000 claims abstract description 3
- NCSNKLYQUVNTRG-UHFFFAOYSA-N 2-n,4-n-bis(2-hydroxyethyl)pyridine-2,4-dicarboxamide Chemical compound OCCNC(=O)C1=CC=NC(C(=O)NCCO)=C1 NCSNKLYQUVNTRG-UHFFFAOYSA-N 0.000 claims abstract 3
- MJIVRKPEXXHNJT-UHFFFAOYSA-N lutidinic acid Chemical compound OC(=O)C1=CC=NC(C(O)=O)=C1 MJIVRKPEXXHNJT-UHFFFAOYSA-N 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 14
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 13
- 239000000126 substance Substances 0.000 claims description 13
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical class OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 12
- 229920001436 collagen Polymers 0.000 claims description 11
- 230000015572 biosynthetic process Effects 0.000 claims description 10
- 102000008186 Collagen Human genes 0.000 claims description 9
- 108010035532 Collagen Proteins 0.000 claims description 9
- 230000005764 inhibitory process Effects 0.000 claims description 9
- 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 claims description 8
- 102000004079 Prolyl Hydroxylases Human genes 0.000 claims description 8
- 108010043005 Prolyl Hydroxylases Proteins 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 102000008490 2-Oxoglutarate 5-Dioxygenase Procollagen-Lysine Human genes 0.000 claims description 6
- 108010020504 2-Oxoglutarate 5-Dioxygenase Procollagen-Lysine Proteins 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 150000004820 halides Chemical class 0.000 claims description 5
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 230000002140 halogenating effect Effects 0.000 claims description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 3
- MBPFVJIPLPCUGE-UHFFFAOYSA-N 2-phenylmethoxycarbonylpyridine-4-carboxylic acid Chemical compound OC(=O)C1=CC=NC(C(=O)OCC=2C=CC=CC=2)=C1 MBPFVJIPLPCUGE-UHFFFAOYSA-N 0.000 claims description 2
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims 1
- 230000001861 immunosuppressant effect Effects 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 claims 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Chemical compound OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 abstract description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract description 3
- 102000008109 Mixed Function Oxygenases Human genes 0.000 abstract description 3
- 108010074633 Mixed Function Oxygenases Proteins 0.000 abstract description 3
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 abstract description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 150000001408 amides Chemical class 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- 210000002966 serum Anatomy 0.000 description 7
- 101150041968 CDC13 gene Proteins 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 210000004185 liver Anatomy 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- FAXDZWQIWUSWJH-UHFFFAOYSA-N 3-methoxypropan-1-amine Chemical compound COCCCN FAXDZWQIWUSWJH-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 3
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 239000003054 catalyst 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
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229960002591 hydroxyproline Drugs 0.000 description 3
- 238000007912 intraperitoneal administration Methods 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- ASUDFOJKTJLAIK-UHFFFAOYSA-N 2-methoxyethanamine Chemical compound COCCN ASUDFOJKTJLAIK-UHFFFAOYSA-N 0.000 description 2
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 2
- ABKKZPBEHVFPTE-UHFFFAOYSA-N 2-n,4-n-bis(3-propan-2-yloxypropyl)pyridine-2,4-dicarboxamide Chemical compound CC(C)OCCCNC(=O)C1=CC=NC(C(=O)NCCCOC(C)C)=C1 ABKKZPBEHVFPTE-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 2
- 241000700157 Rattus norvegicus Species 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 230000036570 collagen biosynthesis Effects 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 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 2
- 150000005690 diesters Chemical class 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- NXMXETCTWNXSFG-UHFFFAOYSA-N 1-methoxypropan-2-amine Chemical compound COCC(C)N NXMXETCTWNXSFG-UHFFFAOYSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- IBZKBSXREAQDTO-UHFFFAOYSA-N 2-methoxy-n-(2-methoxyethyl)ethanamine Chemical compound COCCNCCOC IBZKBSXREAQDTO-UHFFFAOYSA-N 0.000 description 1
- PYZREYKDAGXBQO-UHFFFAOYSA-N 3-(3-propan-2-yloxypropyl)pyridine-2,4-dicarboxamide Chemical compound C(C)(C)OCCCC=1C(=NC=CC=1C(=O)N)C(=O)N PYZREYKDAGXBQO-UHFFFAOYSA-N 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
- SOYBEXQHNURCGE-UHFFFAOYSA-N 3-ethoxypropan-1-amine Chemical compound CCOCCCN SOYBEXQHNURCGE-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 208000024781 Immune Complex disease Diseases 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
- 239000004472 Lysine Substances 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-N Metaphosphoric acid Chemical compound OP(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 241000978776 Senegalia senegal Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 231100000644 Toxic injury Toxicity 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 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
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 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
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000012320 chlorinating reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000024203 complement activation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 150000004699 copper complex Chemical class 0.000 description 1
- OMZSGWSJDCOLKM-UHFFFAOYSA-N copper(II) sulfide Chemical compound [S-2].[Cu+2] OMZSGWSJDCOLKM-UHFFFAOYSA-N 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 150000001470 diamides Chemical class 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
- 229940079593 drug Drugs 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
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- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
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- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
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- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
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- 230000003204 osmotic effect Effects 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
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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
- C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/56—Amides
-
- 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
- C07D213/82—Amides; Imides in position 3
-
- 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
Abstract
N,N'-bis(alkoxyalkyl)pyridine-2,4-dicarboxylic acid diamides of the formula I <IMAGE> where R<1> is linear or branched C1-C4-alkanediyl, R<2> is unbranched C1-C4-alkyl or hydrogen and n is 1 or 2 and R<1'>, R<2'> and n' have the same meanings as R<1>, R<2> and n, where R<1> and R<1'>, R<2> and R<2'>, and n and n' are identical or different, and their physiologically acceptable salts with the exception of N,N'-bis(2-methoxyethyl)pyridine-2,4-dicarboxylic acid diamide and N,N'-bis(2-hydroxyethyl)pyridine-2,4-dicarboxylic acid diamide. The compounds of the formula I inhibit prolin hydroxylase and lysin hydroxylase and are suitable as fibrosuppressants and immunosuppressants.
Description
HOECHST AKTIENGESELLSCHAFT Dr.SW/fe HOE 89/F 241 Description N,N'-Bis (alkoxyalkyl)-pyridine-2,4-dicarboxylic acid diamides, preparation and their use Compounds which inhibit proline hydroxylase and lysine hydroxylase cause a very selective inhibition of collagen biosynthesis by influencing the collagen-specific hydroxylation reactions. In the course of these, proteinbound proline or lysine is hydroxylated by the enzymes proline hydroxylase or lysine hydroxylase. If this reaction is suppressed by inhibitors, a non-functional, hypohydroxylated collagen molecule is formed, which can be released by the cells into the extracellular space in only a small amount. The hypohydroxylated collagen also cannot be incorporated into the collagen matrix and is very easily degraded by proteolysis. As a consequence of these effects, the amount of extracellularly deposited collagen overall is reduced.
It is known that the inhibition of proline hydroxylase by known inhibitors, such as α,a'-dipyridyl, leads to an inhibition of the Clq biosynthesis of macrophages (W. Muller et al., FEBS Lett. 90 (1978), 218; and Immunbiology 155 (1978) 47). This results in a failure of the classical route of complement activation. Inhibitors of proline hydroxylase therefore also act as immunosuppressants, for example in cases of immune complex diseases.
It is known that proline hydroxylase is inhibited effectively by pyridine-2,4- and -2,5-dicarboxylic acid (K. Ma jama a et al., Eur. J. Biochem. 138 (1984) 239-245).
However, in the cell culture these compounds are effective as inhibitors only in very high concentrations (Tschank, G. et al., Biochem. J. 238, 625-633, 1987).
German Patent A-3,432,094 describes pyridine-2,4- and -2,5-dicarboxylic acid diesters having 1-6 carbon atoms - 2 in the ester alkyl part as pharmaceuticals for inhibition of proline hydroxylase and lysine hydroxylase.
However, these lower alkylated diesters have the disadvantage that they are split too rapidly in the organism to give the acids and do not arrive at their site of action in the cell in a sufficiently high concentration, and are therefore of little suitability for possible administration as pharmaceuticals.
German Patent A-3,703,959, German Patent A-3,703,962 and 10 German Patent A-3,703,963 describe, in general form, mixed ester/amides, higher alkylated diesters and diamides of pyridine-2,4- and -2,5-dicarboxylic acid which effectively inhibit collagen biosynthesis in the animal model.
German Patent A-3,703,959 thus describes, inter alia, the synthesis of N,N'-bis(2-methoxyethyl)-pyridine-2,4dicarboxylic acid diamide (III) CONH- CH2- CH2- 0- CH3 (III) CONH- CH2 - CH2 - 0- CH3 and N,N'-bis (3-isopropoxypropyl)-pyridine-2,4-dicarboxylic acid diamide (IV) CH, CONH- CH,-CH,- CH,- 0- CH < 2 2 2 ch3 ch3 (IV) CONH- CH2- CH2- CH2- 0- CH CH, An improved process for the preparation of N,N'-bis(2methoxyethyl)-pyridine-2,4-dicarboxylic acid diamide (HI) is proposed in German Patent Applications P 38 26 471.4 and P 38 28 140.6. - 3 The enteral absorbability of many of the compounds described in German Patent A-3,703,959 is still unsatisfactory, however, so that there is a need to provide compounds which effectively inhibit proline hydroxylase and lysine hydroxylase after oral administration even in low dosages.
It has been found that compounds of the formula I CONH-(R1)-(0R2)nr 2, W JLcONH-tR1 )-(0RZ )n«, N wherein R1 denotes linear or branched C^-C^-alkanediyl, R2 denotes unbranched Ci-C^-alkyl or hydrogen, n denotes 1 or 2 and R1', R2' and n' have the same meanings as R1, R2 and n, R1 and R1', and R2 and R2’ and n and n' being identical or different, and physiologically tolerated salts thereof, excluding Ν,Ν'-bis(2-methoxyethyl)-pyridine-2,4-dicarboxylic acid diamide and Ν,Ν'-bis(2-hydroxyethyl)-pyridine-2,4-dicarboxylic acid diamide, achieve the abovementioned object.
In comparison with the compounds Ν,Ν'-bis(2-methoxyethyl) -pyridine-2, 4 -dicarboxylic acid diamide and Ν,Ν'bis (3-isopropoxypropyl)-pyridine-2,4-dicarboxylic acid diamide described in German Patent A-3,703,959, the compounds of the formula I have both a better pharmaco25 logical activity and a better enteral absorbability.
The invention furthermore relates to a process for the preparation of N,N'-bis-(alkoxyalkyl)-pyridine-2,4dicarboxylic acid diamides of the formula I CONH-(R1).,.(OR2)n Ο J_ CONH-(R1·)-(OR2')_.
(I) - 4 wherein R1 denotes linear or branched Ci-C^-alkanediyl, R2 denotes unbranched C1-C4-alkyl or hydrogen, n denotes 1 or 2 and R1', R2' and n' have the same meanings as R1, R2 and n, R1 and R1’, and R2 and R2' and n and n' being identical or different, excluding N,N'bis (2-methoxyethyl) -pyridine-2,4-dicarboxylic acid diamide and N,N'-bis(210 hydroxyethyl) -pyridine-2,4-dicarboxylic acid diamide, which comprises reacting a pyridine-2,4-dicarboxylic acid halide with an alkoxyalkylamine or hydroxyalkylamine.
The invention likewise relates to a process for the 15 preparation of N,N'-bis-(alkoxyalkyl)-pyridine-2,4dicarboxylic acid diamides of the formula I CONH-(R1)-(0R2)n (I) CONH-(R1’)-(OR2*)n» wherein R1 denotes linear or branched Cx-C^-alkanediyl, R2 denotes unbranched C1-C4-alkyl or hydrogen, n denotes 1 or 2 and R1’, R2’ and n' have the same meanings as R1, R2 and n, R1 and R1’, and R2 and R2’ and n and n' being identical or different, which comprises first A) 1. adding at least two equivalents of a halogenating agent to pyridine-2,4-dicarboxylic acid and 2. dissolving at least 2 equivalents of a hydroxyalkyl30 amine or alkoxyalkylamine of the formula II or II' H2N-(R1) - (0Rz)„ (II) H2N-(Rv)-(OR2’)n.
(II') in which R1 and R1' denote linear or branched Ci-C^-alkanediyl, R2 and R2’ denote unbranched Cx-(L-alkyl or hydrogen, n and n' denote 1 or 2 and R1 and R1’, R2 and R2’ and n and n' are identical or different, but II and II' are different, in a solvent and then reacting the solution prepared according to 1. with the solution prepared according to 2., or B) converting the resulting N,N'-bis(alkoxyalkyl)-pyridine-2 ,4-dicarboxylic acid diamide into the bis(hydroxyalkyl) compound, or C) reacting the pyridine-2,4-dicarboxylic acid halide prepared according to A) 1. with a substituted or unsub15 stituted benzyl alcohol to give the benzyl pyridine-2,4dicarboxylate, hydrolyzing the benzyl ester selectively in the 2-position of the pyridine, converting the free carboxylic acid in the 2-position into the acid halide again in accordance with process variant A) 1. and adding a solution prepared according to A) 2. using a compound of the formula II' to the compound thus obtained, a pyridine-4-(carboxylic acid benzyl ester)-2-carboxylic acid amide being formed, and then splitting off the benzyl protective group in the 4-position by hydrogenoly25 sis, converting the free carboxylic acid into the acid chloride again in accordance with process variant A) 1., and subsequently adding a solution prepared according to A) 2. using a compound of the formula II, an unsymmetrically substituted compound of the formula I being formed, and if appropriate then converting the resulting compound of the formula I into its physiologically tolerated salt.
In the process for the preparation of the compounds of the formula I, the pyridine-2,4-dicarboxylic acid commercially available as a starting substance is suspended in a solvent, such as toluene, and a halogenating agent, preferably a chlorinating agent, such as, for example, SOC12, is added at room temperature. 2-3 equivalents, preferably 2.5 equivalents, of a halogenating agent, - 6 based on the molar amount of pyridine-2/4-dicarboxylic acid employed, are used. The resulting reaction mixture is heated at 90-110’C, preferably at 100°C/ until no further evolution of gas is to be observed and a clear solution has formed. 10% of the solution is then evaporated off - preferably under a high vacuum (down to about 10‘3 mm Hg) - and the resulting carboxylic acid halide is reacted further. 2-4 times the molar amount of commercially available 10 alkoxyalkylamine or hydroxyalkylamine, based on the molar amount of pyridine-2,4-dicarboxylic acid employed, is now dissolved in a solvent, such as toluene, and 2-4 times the molar amount of a base, such as triethylamine, is preferably added. The carboxylic acid halide is reacted with the alkoxyalkylamine or the hydroxyalkylamine. This is preferably done by adding the solution of the alkylamine mentioned dropwise to the dissolved pyridine-2,4dicarboxylic acid halide. However, it is also possible to add the solution of the carboxylic acid halide dropwise to the solution of the alkoxyalkylamine or hydroxyalkylamine. The addition is carried out at a temperature of -5 to +5°C, preferably at 0’C. The reaction mixture can then be after-reacted, for example, by warming it to room temperature and subsequently stirring it for a further 225 5 hours, preferably 3 hours. The resulting product is then acidified in order to remove excess hydroxy- or alkoxyalkylamine from the desired product. The acidification can be carried out, for example, with 0.2 molar citric acid. The organic phase is then separated off and washed with water. The organic phase is subsequently dried - preferably over magnesium sulfate - and finally freed from the solvent. On removal of the solvent, the product is obtained as a white solid or as an oil.
To prepare the N,N'-bis(hydroxyalkyl)-pyridine-2,435 dicarboxylic acid diamides, a procedure is preferably followed in which a corresponding bis(alkoxyalkyl)diamide, preferably bis(methoxyalkyl)diamide, is converted - 7 into the corresponding bis(hydroxyalkyl)diamide by processes which are known from the literature, for example using boron tribromide.
Unsymmetrically substituted compounds of the formula I 5 can be synthesized, for example, as follows: reaction of a pyridine-2,4-dicarboxylic acid halide, preferably the chloride, with substituted or unsubstituted benzyl alcohol to give benzyl pyridine-2,4-diearboxylate, subsequent selective hydrolysis of the ester in the 210 position (for example in the presence of a copper catalyst, Acta Helv. 44, 1963, page 637), conversion of the free acid in the 2-position into the acid halide, reaction with a compound of the formula (II') to give the pyridine-4-(carboxylic acid benzyl ester)-2-carboxylie acid amide, splitting off of the remaining benzyl protective group by hydrogenolysis (for example with H2/Pd, see Houben-Weyl Volume IV/lc (1980), pages 381-82) and subsequent conversion of the free acid in the 4-position of the pyridine ring into the acid halide.
The acid halide can now be converted into the mixed diamide (I) with an amine II (see equation).
If appropriate, the products can be worked up, for example, by extraction or by chromatography, for example over silica gel. The product isolated can be recrystal25 lized and if appropriate reacted with a suitable acid to give a physiologically tolerated salt. Examples of possible suitable acids are: mineral acids, such as hydrochloric and hydrobromic acid as well as sulfuric, phosphoric, nitric or perchloric acid, or organic acids, such as formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, maleic, fumaric, phenylacetic, benzoic, methanesulfonic, toluenesulfonic, oxalic, 4-aminobenzoic, naphthalene-1,4-disulfonic or ascorbic acid.
The compounds of the formula I can be used as medicaments in the form of pharmaceutical preparations which contain - 8 them, if appropriate together with tolerated pharmaceutical excipients. The compounds can be used as medicines, for example in the form of pharmaceutical preparations which contain these compounds as a mixture with a pharmaceutical, organic or inorganic excipient suitable for enteral, percutaneous or parenteral administration, such as, for example, water, gum arabic, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, vaseline and the like.
The pharmaeutical preparations can be in solid form, for example as tablets, coated tablets, suppositories or capsules; in semi-solid form, for example as ointments, or in liquid form, for example as solutions, suspensions or emulsions. If appropriate, they are sterilized and/or contain auxiliaries, such as preservatives, stabilizers, wetting agents or emulsifiers, salts for modifying the osmotic pressure or buffers. They can also additionally contain other therapeutically active substances.
It has been found that the compounds of the formula I have exceptionally good enteral absorbabilities. The absorbability was investigated on Wistar rats to which the compounds according to the invention were administered intragastrally. The serum level dropped in the first hours after administration of the substance, and after about 5 hours reached a plateau which still fell only slightly. The good absorbability of the substances can be concluded from the initially very high serum level directly after administration of the substances.
The invention is illustrated in more detail below with the aid of examples. - 9 Example 1 Pyridine-2,4-dicarboxylic acid bis-Ν,Ν'-(methoxypropyl)amide g of pyridine-2,4-dicarboxylic acid are initially 5 introduced into 50 ml of toluene and 1 ml of dimethylformamide, and 2.7 ml of thionyl chloride are added dropwise to the solution. The mixture is heated until no further evolution of gas is to be observed (about 2.5 hours). It is cooled, 5 ml of toluene are distilled off and 4.6 ml of 3-methoxypropylamine and 5 ml of triethylamine are added dropwise to the solution. After the solution has been stirred at room temperature for 4 hours, it is evaporated, the residue is taken up in water and the mixture is extracted 4 times with methylene chloride. The combined organic phases are dried over magnesium sulfate and evaporated. The crude product is chromatographed with silica gel (solvent: ethyl acetate). Yield: 4.3 g; oil ^-NMR (CDC13) : δ = 1.6-2.3 (4H, m); 3.2-3.8 (14H, m); 7.8-8.0 (1H, m); 8.3-8.5 (1H, m); 8.68.8 (1H, m).
Example 2 Pyridine-2,4-dicarboxylic acid bis-Ν,Ν'-(ethoxypropyl)amide For instructions see Example 1; amine component: ethoxypropylamine Yield: 4.5 g, melting point: 46-48eC. hl-NMR (CDC13): 6 = 1.3 (6H, tr); 1.7-2.1 (4H, m); 3.3-3.8 (12H, m); 7.8-8.0 (1H, m); 8.4-8.5 (1H, m); 8.5-8.8 (1H, m). - 10 Example 3 Pyridine-2,4-dicarboxylic acid bis-N,N'-(2-dimethoxyethyl) amide For instructions see Example 1; amine component: 25 dimethoxyethylamine Yield: 1.6 g (from 3 g of pyridine-2,4-dicarboxylic acid), oil 1H-NMR (CDC13): δ = 3.4 (12H, s); 3.7 (4H, m); 4.5 (2H, m)? 7.9-8.0 (IH, m); 8.4-8.5 (IH, m); 8.7-8.8 (IH, m).
Example 4 Pyridine-2,4-dicarboxylic acid bis-N,N'-(2-methoxyisopropyl) amide For instructions see Example 1; amine component: 215 methoxyisopropylamine; Yield: 3.3 g (from 3 g of pyridine-2,4-dicarboxylic acid), oil XH-NMR (CDCI3): δ = 1.3 (6H, d); 3.2 (6H, s); 3.5 (4H, d); 4.4 (2H, m); 7.9-8.0 (IH, m); 8.4-8.5 (IH, m); 8.7-8.8 (IH, m).
Example 5 Pyridine-2,4-dicarboxylic acid bis-N,N'-(2-ethoxyethyl)amide For instructions see Example 1; amine component: ethoxy25 ethylamine, Yield: 7.8 g (from 10 g of pyridine-2,4-dicarboxylic acid), melting point: 42-44eC 1H-NMR (CDCI3): δ = 1.2 (3H, tr); 3.3-3.8 (12H, qu. and m); 7.9 (IH, m); 8.4-8.5 (IH, m); 8.78.8 (IH, m). - 11 Example 6 Pyridine-2,4 -dicarboxylic acid bis-Ν,Ν' - (3-hydroxyethyl) amide 0.5 g of pyridine-2,4-dicarboxylic acid bis-N,N'-(35 methoxyethyl) amide are dissolved in 10 ml of methylene chloride, and boron tribromide (11 ml, 1 molar solution in methylene chloride) is added dropwise at -78°C. When the addition has ended, the mixture is allowed to come to room temperature and is subsequently stirred for 3 hours.
It is poured onto 100 ml of saturated bicarbonate solution and extracted 3 times with ethyl acetate. The combined organic phases are dried with magnesium sulfate and evaporated. The crude product is chromatographed on silica gel.
Yield: 0.45 g; oil ^-NMR (CDC13): 5 = 1.5-2.2 (4H, m) -, 3.4 (4H, m); 3.6 (4H, m); 7.9-8.0 (IH, m); 8.4-8.5 (IH, m); 8.7-8.8 (IH, m).
Example 7a Pyridine-2,4-dicarboxylic acid dibenzyl ester 30g of pyridine-2,4-dicarboxylic acid are converted into the acid chloride using 30 ml of thionyl chloride analogously to Example 1 and the acid chloride is reacted with 43.8 g of benzyl alcohol. The product is recrystallized from diisopropyl ether.
Yield: 42.1 g Melting point 63-65’C Example 7b Pyridine-2-(carboxylic acid)-4-carboxylic acid benzyl ester 40 g of pyridine-2,4-dicarboxylic acid dibenzyl ester from Example 7a are added to a suspension of 27.8 g of - 12 copper-II nitrate in 700 ml of methanol. The mixture is boiled under reflux for one hour and, after cooling, the copper complex is filtered off. The complex is suspended in dioxane and carbon disulfide is passed in. The copper sulfide which has precipitated is filtered off and the organic phase is concentrated. The product is stirred with petroleum ether.
Yield: 25.3 g Melting point 113-115’C Example 7c Pyridine-2-[(3-methoxypropyl)-carboxylic acid amide]-4carboxylic acid benzyl ester 3.9 g of pyridine-2-(carboxylic acid)-4-carboxylic acid benzyl ester from Example 7b are converted into the acid chloride using 1.2 ml of thionyl chloride analogously to Example 1 and the acid chloride is reacted with 3-methoxypropy1amine to give the amide. For purification, the product is chromatographed over silica gel using a mixture of cyclohexane/ethyl acetate (1:1).
Yield: 4.3 g Oil Example 7d Pyridine-4-(carboxylic acid)-2-(3-methoxypropyl)-carboxylic acid amide 4.3 g of the compound from Example 7c are dissolved in 100 ml of dioxane and hydrogenated using 500 mg of palladium/charcoal (10% strength) catalyst under normal pressure for 4 hours. When the uptake of hydrogen has ended, the catalyst is filtered off with suction and the solvent is stripped off.
Yield: 3.5 g Melting point 124-126’C - 13 Example 7e Pyridine-4-[carboxylic acid-(2-methoxyethyl)-amide]-2carboxy1ic acid (3-methoxypropyl)-amide 1.8 g of the compound from Example 7d are converted into 5 the acid chloride using 0.6 ml of thionyl chloride in accordance with Example 1 and the acid chloride is then reacted with 2-methoxyethylamine. For purification, the product is chromatographed over silica gel using a mixture of methylene chloride/methanol (20:1).
Yield: 1.0 g Oil hl-NMR (CDC13): 5 = 1.9-2.0 (2H, qui); 3.4 (6H, s); 3.53.7 (8H, m); 6.9 (1H, s, br); 8.0 (1H, dd); 8.4 (1H, s, br)? 8.5 (1H, s); 8.7 (1H, d).
Example 8 Pyridine-2-[carboxylic acid-(2-methoxyethyl)-amide]-4carboxylic acid (3-methoxypropyl)-amide The compound according to Example 8 is prepared analogously to Examples 7a-e by using 2-methoxyethylamine in the reaction step of Example 7c and 3-methoxypropylamine in the reaction step of Example 7e.
Melting point: 69-72eC ^-NMR (CDC13): δ = 1.9-2.0 (2H, qui); 3.4 (3H, s); 3.45 (3H, s); 3.6-3.7 (8H, m); 7.4 (1H, br); 7.9 (1H, dd); 8.3 (1H, br); 8.4 (1H, d); 8.7 (1H, d).
Example 9 Enteral absorbability Female Wistar rats of about 150 g body weight are given an intragastral administration of 50 mg/kg of the substance under investigation by means of a stomach probe. - 14 In each case 4 rats are anesthetized after 5; 10; 15; 30; 60; 120; 180 and 240 minutes and exsanguinated via the Vena Cava. The blood is centrifuged immediately and the compound administered is extracted from the serum using ether. After the ether has been evaporated, the residue is taken up in 100 ml of mobile phase. The mobile phase consists of 0.05 M phosphoric acid and acetonitrile (4:1). 50 μΐ of this sample are injected into a high performance liquid chromatography column. Detection is performed under UV of 200 nm with a retention time of 2.2 minutes. The results are documented in Table 1.
Table 1: Serum levels of the compounds according to the invention from Examples 1-3 after administration of 50 mg/kg perorally Time (minutes) Substance from Example 1 Substance from Example 2 Substance from Example 3 X SD X SD X SD 5 45.3 ± 15.4 51.4 ± 11.2 8.9 + 3.1 10 49.8 ± 3.6 39.2 ± 4.0 11.5 ± 0.6 15 39.9 ± 11.0 29.4 ± 6.7 14.7 ± 1.9 30 28.1 ± 3.2 15.2 + 5.6 10.7 + 1.9 60 9.4 ± 5.5 1.4 ± 1.0 11.3 ± 1.5 120 0.3 ± 0.3 5.5 i 0.9 180 2.9 ± 0.5 240 1.7 ± 0.4 x = mean value of 4 measurements 30 SD = standard deviation Example 10 Pharmacological activity To demonstrate the effective inhibition of proline 35 hydroxylase and lysine hydroxylase by the compounds - 15 according to the invention, the hydroxyproline concentrations in the liver and the 7s-(IV)-collagen concentrations in the serum of a) untreated rats (control) b) rats to which carbon tetrachloride had been administered (CC14 control) c) rats to which first CC14 and then a compound according to the invention had been administered were measured (this test method is described by Rouiller, C., experimental toxic injury of the liver; in The Liver, C. Rouiller, Volume 2, pages 335-476, New York, Academic Press, 1964).
The action potency of the compounds according to the invention was determined as the percentage inhibition of the liver hydroxyproline synthesis and serum 7s-(IV)collagen synthesis following oral administration in comparison with control animals to which only carbon tetrachloride had been administered (CC14 control). The results are shown in Table 2. The compounds from Examples 2 and 3 of German Patent A-3,703,959 (N,N'-bis(2-methoxyethyl)-pyridine-2,4-dicarboxylic acid diamide and N,N'bis(3-isopropoxypropyl)-pyridine-2,4-dicarboxylic acid diamide) are likewise also shown as comparison substances. Surprisingly, the compounds according to the inven25 tion show a better activity, even after oral administration, than the intraperitoneally administered compound from Example 2 of German Patent A-3,703,959. - 16 Table 2: Substance from Example Dosage Liver hydroxyproline [ % inhibition] Serum 7s- (IV)-collagen [% inhibition] Adminis- tration 1 2x2 mg 62 28 p.o. 2x10 mg 90 67 p.o. 2 2x2 mg 25 2 p.o. 2x10 mg 60 35 p.o. 2 (from DE-A-3,703,959) 2x25 mg 55 48 i.p. 3 (from DE-A-3,703,959] 2x25 mg 49 11 p.o. p.o. = peroral i.p. = intraperitoneal
Claims (25)
1. 1. HOE 89/F 241 An N,N'-bis (alkoxyalkyl)-pyridine-2,4-dicarboxylic acid diamide of the formula I (I) 2.
2. 3.
3. 4.
4. wherein R 1 denotes linear or branched Cx-C^-alkanediyl, R 2 denotes unbranched Ci-C^-alkyl or hydrogen, n denotes 1 or 2 and R 1 ', R 2 ' and n' have the same meanings as R 1 , R 2 and n, R 1 and R 1 ’, and R 2 and R 2 ’ and n and n' being identical or different, or a physiologically tolerated salt thereof, excluding N,N'-bis (2-methoxyethyl)-pyridine-2,4-dicarboxylic acid diamide and N,N'-bis(2-hydroxyethyl)pyridine-2,4-dicarboxylic acid diamide. A compound of the formula I as claimed in claim 1, in which in each case R 1 and R 1 ’, R 2 and R 2 ' and n and n' have the same meaning. A compound of the formula I as claimed in claim 1, in which the substituents -(R 1 )-(OR z )n and -(R 1 )(0R 2 ’)n' are different. A compound of the formula I as claimed in any one of claims 1, 2 and 3, in which R 1 denotes linear or branched Ci-Cg-alkyl and R 2 denotes unbranched Ci-Ca-alkyl or hydrogen. The compound of the formula CONH- CH 2 -CH 2 -CH 2 -O-CH 3 n< ^ x conh- ch 2 - ch 2 - ch 2 - 0- ch 3 - 18 or one of its physiologically tolerated salts
5. 6. The compound of the formula CONH- CH 2 - CH 2 - CH 2 - 0- C 2 H 5 CONH- CH 2 - CH 2 - CH 2 - 0- C 2 H 5 or one of its physiologically tolerated salts
6. 7. The compound of the formula P-ch 3 C0NH-CH 2 -CH x conh-ch 2 -ch. 0-CH3 O-CH“ ^0-CH 3 · or one of its physiologically tolerated
7. 8. The compound of the formula ch 3 conh-ch-ch 2 -och 3 salts CONH- CH- CH 2 - 0CH 3 ch 3 or one of its physiologically tolerated
8. 9. The compound of the formula CONH-CH 2 -CH 2 -0-C 2 H 5 CONH- CH 2 -CH 2 -0- C 2 H 5 salts or one of its physiologically tolerated salts - 19
9. 10. The compound of the formula CONH- CH 2 - CH 2 - CH 2 - OH Cl CONH- CH 2 - CH 2 - CH 2 - OH or one of its physiologically tolerated salts.
10. 11. The compound of the formula CONH- CH 2 - CH 2 - OCH 3 CONH-(CH 2 ) 3 -OCH 3 or one of its physiologically tolerated salts,
11. 12. The compound of the formula CONH(CH 2 ) 3 OCH 3 N conh(ch 2 ) 2 och 3 or one of its physiologically tolerated salts.
12. 13. A process for the preparation of an N,N'-bis(alkoxyalkyl) -pyridine-2,4-dicarboxylic acid diamide of the formula I CONH-(R 1 )-(0R 2 ) n (I) c°t ipLcONH- (R 1 ’)- (OR 2 ’ ) n , wherein R 1 denotes linear or branched Ci-C^-alkanediyl, R 2 denotes unbranched Cj-C A -alkyl or hydrogen, n denotes 1 or 2 and R 1 ', R 2 ’ and n' have the same meanings as R 1 , R 2 and n, R 1 and R 1 ', and R 2 and R 2 ’ and n and n' - 20 being identical or different, excluding N,N'-bis (2-methoxyethyl)-pyridine-2,4dicarboxylic acid diamide and N,N'bis (2-hydroxyethyl) -pyridine-2,4-dicarboxylic acid diamide, which comprises reacting a pyridine-2,4-dicarboxylic acid halide with an alkoxyalkylamine or hydroxyalkylamine.
13. 14. A process for the preparation of an N,N'-bis(alkoxyalkyl) -pyridine-2,4-dicarboxylic acid diamide of the formula I CONH-(R 1 )-(OR 2 )n [^^LcONH- (R 1 ’ )-(OR 2 ')n« (I) wherein R 1 denotes linear or branched C x -C 4 -alkanediyl, R 2 denotes unbranched Ci-C^-alkyl or hydrogen, n denotes 1 or 2 and R 1 ’, R 2 ' and n' have the same meanings as R 1 , R 2 and n, R 1 and R 1 ', and R 2 and R 2 ’ and n and n' being identical or different, which comprises first A) 1. adding at least two equivalents of a halogenating agent to pyridine-2,4-dicarboxylic acid and 2. dissolving at least 2 equivalents of a hydroxyalkylamine or alkoxyalkylamine of the formula II or II' H 2 N-(R 1 )-(OR 2 ) n (II) H 2 N-(R r ) - (OR 2 ’)„. (II') in which R 1 and R 1 ’ denote linear or branched C 1 -C 4 -alkanediyl, R 2 and R 2 ’ denote unbranched C^C^-alkyl or hydrogen, n and n' denote 1 or 2 and - 21 R 1 and R 1 ', R 2 and R 2 ' and n and n' are identical or different, but II and II' are different, in a solvent and then reacting the solution prepared according to 1. with the solution prepared according to 2., or B) converting the resulting Ν,Ν'-bis(alkoxyalkyl)pyridine-2,4-dicarboxylic acid diamide into the bis(hydroxyalkyl) compound, or C) reacting the pyridine-2,4-dicarboxylic acid halide prepared according to A) 1. with a substituted or unsubstituted benzyl alcohol to give the benzyl pyridine-2,4-dicarboxylate, hydrolyzing the benzyl ester selectively in the 2-position of the pyridine, converting the free carboxylic acid in the 2-position into the acid halide again in accordance with process variant A) 1. and adding a solution prepared according to A) 2. using a compound of the formula II' to the compound thus obtained, a pyridine-4 -( carboxylic acid benzyl ester)-carboxylic acid amide being formed, and then splitting off the benzyl protective group in the 4-position by hydrogenolysis, converting the free carboxylic acid into the acid chloride again in accordance with process variant A) 1., and subsequently adding a solution prepared according to A) 2. using a compound of the formula II, an unsymmetrically substituted compound of the formula I being formed, and if appropriate then converting the resulting compound of the formula I into its physiologically tolerated salt.
14. 15. A compound as claimed in any one of claims 1 to 12 for inhibition of proline hydroxylase and lysine hydroxylase.
15. 16. A compound as claimed in any one of claims 1 to 12 for use as a fibrosuppressant and immunosuppressant.
16. 17. A pharmaceutical containing a compound of the formula I as claimed in any one of claims 1-12 - 22 and/or one of its physiologically tolerated salts with tolerated pharmaceutical excipients.
17. 18. The use of a compound of the formula I as claimed in any one of claims 1-12 and/or a physiologically tolerated salt thereof for influencing the biosynthesis of collagen and collagen-like substances or the biosynthesis of Cl q .
18.
19. The use of a compound of the formula I as claimed in any one of claims 1-12 and/or a physiologically tolerated salt thereof for the treatment of disturbances in the biosynthesis of collagen and collagenlike substances or the biosynthesis of Cl q .
20. A process for the preparation of pharmaceuticals for influencing the biosynthesis of collagen and collagen-like substances or the biosynthesis of Cl q , which comprises incorporating a compound of the formula I as claimed in any one of claims 1-12 and/or a physiologically tolerated salt of this compound into the pharmaceutical.
21. A compound as claimed in claim 1, substantially as hereinbefore described and exemplified.
22. A process for the preparation of a compound as claimed in claim 1, substantially as hereinbefore described .
23. A compound as claimed in claim 1, whenever prepared by a process claimed in any one of claims 13, 14 or 22.
24. A pharmaceutical according to claim 17, substantially as hereinbefore described.
25. Use according to claim 18 or 19, substantially as hereinbefore described.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE3924093A DE3924093A1 (en) | 1989-07-20 | 1989-07-20 | N, N'-BIS (ALKOXY-ALKYL) -PYRIDINE-2,4-DICARBONESAUREDIAMIDES, METHOD FOR THE PRODUCTION AND USE THEREOF |
Publications (2)
Publication Number | Publication Date |
---|---|
IE902642A1 true IE902642A1 (en) | 1991-02-27 |
IE64438B1 IE64438B1 (en) | 1995-08-09 |
Family
ID=6385494
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IE264290A IE64438B1 (en) | 1989-07-20 | 1990-07-19 | N, N'-bis(alkoxyalkyl)-pyridine-2, 4-dicarboxylic acid diamides preparation and their use |
Country Status (26)
Country | Link |
---|---|
EP (1) | EP0409119B1 (en) |
JP (1) | JPH0776213B2 (en) |
KR (1) | KR0181945B1 (en) |
AT (1) | ATE104280T1 (en) |
AU (1) | AU624978B2 (en) |
CA (1) | CA2021529C (en) |
CY (1) | CY1997A (en) |
CZ (1) | CZ280129B6 (en) |
DD (1) | DD300429A5 (en) |
DE (2) | DE3924093A1 (en) |
DK (1) | DK0409119T3 (en) |
ES (1) | ES2052112T3 (en) |
FI (1) | FI94630C (en) |
HU (1) | HU218274B (en) |
IE (1) | IE64438B1 (en) |
IL (1) | IL95121A (en) |
LT (1) | LT3798B (en) |
LV (1) | LV10430B (en) |
NO (1) | NO177187C (en) |
NZ (1) | NZ234563A (en) |
PL (1) | PL166307B1 (en) |
PT (1) | PT94779B (en) |
RU (1) | RU1836350C (en) |
SK (1) | SK279199B6 (en) |
UA (1) | UA19056A (en) |
ZA (1) | ZA905680B (en) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3707429A1 (en) * | 1987-03-07 | 1988-09-15 | Hoechst Ag | SUBSTITUTED PYRIDINE-2,4-DICARBONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, USE OF THE SAME AND MEDICINAL PRODUCTS BASED ON THESE COMPOUNDS |
ES2065355T3 (en) * | 1988-08-04 | 1995-02-16 | Hoechst Ag | IMPROVED PROCEDURE FOR THE PREPARATION OF N, N'-BIS (ALCOXIALKYL) -DIAMIDES OF PIRIDINE-2,4-DICARBOXYLIC ACIDS. |
DE4020570A1 (en) | 1990-06-28 | 1992-01-02 | Hoechst Ag | 2,4- AND 2,5-SUBSTITUTED PYRIDINE-N-OXIDES, 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 |
YU9492A (en) * | 1991-02-05 | 1995-03-27 | Hoechst Ag. | 2,4- and 2,5-BIS-TETRAZOLYL pyridines and the process for their preparation |
TW199147B (en) * | 1991-03-18 | 1993-02-01 | Hoechst Ag | |
EP0541042A1 (en) * | 1991-11-05 | 1993-05-12 | Hoechst Aktiengesellschaft | 2,4- and 2,5-pyridine-dicarboxylic acid derivatives, process for their preparation and their use |
TW222585B (en) * | 1992-09-11 | 1994-04-21 | Hoechst Ag | |
DOP2002000332A (en) | 2001-02-14 | 2002-08-30 | Warner Lambert Co | MATRIX METALOPROTEINAS PYRIDINE INHIBITORS |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3432094A1 (en) | 1984-08-31 | 1986-03-06 | Hoechst Ag, 6230 Frankfurt | ESTER OF PYRIDINE-2,4- AND -2,5-DICARBONIC ACID AS A MEDICINAL PRODUCT FOR INHIBITING PROLIN AND LYSINE HYDROXYLASE |
DE3703963A1 (en) | 1987-02-10 | 1988-08-18 | Hoechst Ag | PYRIDINE-2,4- AND 2,, 5-DICARBONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, USE THEREOF, AND MEDICINAL PRODUCTS BASED ON THESE COMPOUNDS |
DE3703962A1 (en) * | 1987-02-10 | 1988-08-18 | Hoechst Ag | PYRIDINE-2,4- AND 2,5-DICARBONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, USE OF THE SAME AND MEDICINAL PRODUCTS BASED ON THESE COMPOUNDS |
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 |
DE3826471A1 (en) | 1988-08-04 | 1990-02-22 | Hoechst Ag | Improved process for the preparation of N,N'-bis(alkoxyalkyl)pyridine-2,4-dicarboximides |
ES2065355T3 (en) * | 1988-08-04 | 1995-02-16 | Hoechst Ag | IMPROVED PROCEDURE FOR THE PREPARATION OF N, N'-BIS (ALCOXIALKYL) -DIAMIDES OF PIRIDINE-2,4-DICARBOXYLIC ACIDS. |
DE3828140A1 (en) | 1988-08-19 | 1990-03-01 | Hoechst Ag | Improved process for the preparation of N,N'-bis(alkoxyalkyl)pyridine-2,4-dicarboxamides and use of these compounds for the preparation of orally administrable medicaments |
-
1989
- 1989-07-20 DE DE3924093A patent/DE3924093A1/en not_active Withdrawn
-
1990
- 1990-07-14 ES ES90113528T patent/ES2052112T3/en not_active Expired - Lifetime
- 1990-07-14 AT AT90113528T patent/ATE104280T1/en not_active IP Right Cessation
- 1990-07-14 DK DK90113528.5T patent/DK0409119T3/en active
- 1990-07-14 DE DE59005328T patent/DE59005328D1/en not_active Expired - Fee Related
- 1990-07-14 EP EP90113528A patent/EP0409119B1/en not_active Expired - Lifetime
- 1990-07-18 CZ CS903576A patent/CZ280129B6/en not_active IP Right Cessation
- 1990-07-18 FI FI903624A patent/FI94630C/en not_active IP Right Cessation
- 1990-07-18 IL IL9512190A patent/IL95121A/en not_active IP Right Cessation
- 1990-07-18 DD DD342874A patent/DD300429A5/en not_active IP Right Cessation
- 1990-07-18 SK SK3576-90A patent/SK279199B6/en unknown
- 1990-07-18 NZ NZ234563A patent/NZ234563A/en unknown
- 1990-07-19 NO NO903235A patent/NO177187C/en not_active IP Right Cessation
- 1990-07-19 RU SU904830947A patent/RU1836350C/en active
- 1990-07-19 JP JP2189620A patent/JPH0776213B2/en not_active Expired - Lifetime
- 1990-07-19 HU HU549/90A patent/HU218274B/en not_active IP Right Cessation
- 1990-07-19 UA UA4830947A patent/UA19056A/en unknown
- 1990-07-19 ZA ZA905680A patent/ZA905680B/en unknown
- 1990-07-19 CA CA002021529A patent/CA2021529C/en not_active Expired - Fee Related
- 1990-07-19 AU AU59144/90A patent/AU624978B2/en not_active Ceased
- 1990-07-19 KR KR1019900010938A patent/KR0181945B1/en not_active IP Right Cessation
- 1990-07-19 PL PL90286132A patent/PL166307B1/en unknown
- 1990-07-19 IE IE264290A patent/IE64438B1/en not_active IP Right Cessation
- 1990-07-20 PT PT94779A patent/PT94779B/en not_active IP Right Cessation
-
1993
- 1993-05-07 LV LVP-93-301A patent/LV10430B/en unknown
- 1993-11-12 LT LTIP1462A patent/LT3798B/en not_active IP Right Cessation
-
1997
- 1997-09-05 CY CY199797A patent/CY1997A/en unknown
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MM4A | Patent lapsed |