CA2045868A1 - 2,4- and 2,5-substituted pyridine-n-oxides, processes for their preparation and their use - Google Patents
2,4- and 2,5-substituted pyridine-n-oxides, processes for their preparation and their useInfo
- Publication number
- CA2045868A1 CA2045868A1 CA002045868A CA2045868A CA2045868A1 CA 2045868 A1 CA2045868 A1 CA 2045868A1 CA 002045868 A CA002045868 A CA 002045868A CA 2045868 A CA2045868 A CA 2045868A CA 2045868 A1 CA2045868 A1 CA 2045868A1
- Authority
- CA
- Canada
- Prior art keywords
- radicals
- different
- phenyl
- formula
- alkyl
- 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
- 238000000034 method Methods 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 40
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical class [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 claims abstract description 12
- 108010035532 Collagen Proteins 0.000 claims abstract description 10
- 102000008186 Collagen Human genes 0.000 claims abstract description 10
- 229920001436 collagen Polymers 0.000 claims abstract description 10
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 5
- 239000000126 substance Substances 0.000 claims abstract description 5
- 230000001506 immunosuppresive effect Effects 0.000 claims abstract description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 3
- 208000035475 disorder Diseases 0.000 claims abstract description 3
- 230000004060 metabolic process Effects 0.000 claims abstract 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 34
- -1 nitro, nitroxy, amino, carboxyl Chemical group 0.000 claims description 26
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- 150000002367 halogens Chemical class 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 17
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 102000004079 Prolyl Hydroxylases Human genes 0.000 claims description 10
- 108010043005 Prolyl Hydroxylases Proteins 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000001041 indolyl group Chemical group 0.000 claims description 6
- 230000005764 inhibitory process Effects 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 150000002500 ions Chemical class 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 150000001204 N-oxides Chemical class 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 102000008490 2-Oxoglutarate 5-Dioxygenase Procollagen-Lysine Human genes 0.000 claims description 3
- 108010020504 2-Oxoglutarate 5-Dioxygenase Procollagen-Lysine Proteins 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 8
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 5
- 125000001424 substituent group Chemical group 0.000 claims 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 4
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical class CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims 3
- 125000004494 ethyl ester group Chemical group 0.000 claims 3
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 2
- 125000006710 (C2-C12) alkenyl group Chemical group 0.000 claims 2
- 125000006711 (C2-C12) alkynyl group Chemical group 0.000 claims 2
- 125000003545 alkoxy group Chemical group 0.000 claims 2
- 125000004076 pyridyl group Chemical group 0.000 claims 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims 1
- 125000004663 dialkyl amino group Chemical group 0.000 claims 1
- 229940125721 immunosuppressive agent Drugs 0.000 abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 241000700159 Rattus Species 0.000 description 8
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 7
- OOXOXZVOZIURRD-UHFFFAOYSA-N pyridine-2,4-dicarboxamide Chemical compound NC(=O)C1=CC=NC(C(N)=O)=C1 OOXOXZVOZIURRD-UHFFFAOYSA-N 0.000 description 7
- 238000004587 chromatography analysis Methods 0.000 description 6
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- 239000003112 inhibitor Substances 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 4
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 4
- 239000004472 Lysine Substances 0.000 description 4
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- 238000001953 recrystallisation Methods 0.000 description 4
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
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- WJJMNDUMQPNECX-UHFFFAOYSA-N dipicolinic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=N1 WJJMNDUMQPNECX-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
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- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 2
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 2
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
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- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
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- KPZGRMZPZLOPBS-UHFFFAOYSA-N 1,3-dichloro-2,2-bis(chloromethyl)propane Chemical compound ClCC(CCl)(CCl)CCl KPZGRMZPZLOPBS-UHFFFAOYSA-N 0.000 description 1
- RGEWNDVBCQKERB-UHFFFAOYSA-N 2-N,4-N-bis[(3-chlorophenyl)methyl]-2-N-hydroxypyridine-2,4-dicarboxamide Chemical compound C=1C(C(=O)NCC=2C=C(Cl)C=CC=2)=CC=NC=1C(=O)N(O)CC1=CC=CC(Cl)=C1 RGEWNDVBCQKERB-UHFFFAOYSA-N 0.000 description 1
- ICNFFLWLYLRSMC-UHFFFAOYSA-N 2-N-hydroxy-2-N,4-N-bis(4-hydroxybutyl)pyridine-2,4-dicarboxamide Chemical compound OCCCCNC(=O)C1=CC=NC(C(=O)N(O)CCCCO)=C1 ICNFFLWLYLRSMC-UHFFFAOYSA-N 0.000 description 1
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- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 108010016297 plasmin drug combination deoxyribonuclease Proteins 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940093916 potassium phosphate Drugs 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- 150000003222 pyridines Chemical class 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
- 239000003381 stabilizer Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 229950011008 tetrachloroethylene Drugs 0.000 description 1
- 229960002415 trichloroethylene Drugs 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
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- 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
- C07D213/89—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 with hetero atoms directly attached to the ring nitrogen atom
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- 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
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
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- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
Abstract of the disclosure 2,4- and 2,5-substituted pyridine N-oxides, processes for their preparation and their use 2,4- and 2,5-substituted pyridine-N-oxides are provided which are effective as fibrosuppressives and immuno-suppressives. Said compounds are also suitable for the treatment of disorders of the metabolism of collagen and collagen-like substances or the biosynthesis of C1q.
Description
~58~8 HOECHST ARTIENGESELLSCHAFT HOE 90/F 192 Dr. Fi/PP
Description 2,4- and 2,5-substituted pyridine-N-oxide~, proce~ses for their preparation and their U8e Compounds which inhibi~ the enzymes proline hydroxylase and lysine hydroxyla~e cau~0 ~ very selective inhibition of collagen biosynthesis by in~luencing collagen-~pecific hydroxylation reactions. In the course thereof, protein-bound proline or lysine i~ hydroxylat~d by the enzymes proline hydroxylase or lysine hydroxyla~e. If this reaction i5 suppressed by inhibitors, a non-functional, underhydroxylated collagen molecule i~ formed, which can be released into the extracellular ~pace by the cell~
only to a small e~tent. In addition, th~ underhydroxy-lated collagen cannot be inoorporated into the collagenmatrix and is ve~y easily degraded by prot~olysi3. As a result of these effects, the amount of collagen stored extracellularly is on the whole reduced.
Inh~bitor~ of prolyl hydroxylase are th~re~ore ~uitable substances in the treatment of disorders in which the storage of collagens contrlhutes decisively to the symptoms. These include, inter alia, $i.bros~s of the lungs, liver and skin (~cleroderma~ and atherosclerosis.
It is known that the inhibition of proline hydroxylase by known inhibitors such a ~ dipyridyl leads to an inhibition o~ Clq biosynthesis by macroph~es (W. ~ller et al., FEBS Lett. 90 (1978), 218; Immunbiology 155 (1978), 47). As a result, a failure of the classical route of complemen~ activation occur~. Inhibitors of proline hydroxyla~e therefore also act a~ immunosuppres-sives, for example in immune complex diseases.
It is known that the enzyme proline hydroxylase is effectively inhibited by pyridine-2,4 and -2,5-dicarboxylic acid (R. Ma~amaa et al., 2~45~8 Eur. J. Biochem. 138 (1984) 239-245). However, ~hese compounds are effec~ive in cell culkure as inhibitors only in very high concentrations (Tschank, G. et al., Biochem. J. 238 (1987) 625-633).
DE-~ 3,432,0g4 dascribes pyridine-2,4- and -2,5-dicar-boxylic acid diesters haring 1-6 carbon atoms in the ester al~yl moiety as pharmsceutical~ for the inhibition of proline hydroxylase and lysine hydroxyla~e.
However, these lower-alkylated diestexs have the disad-vanta~e tha~ ~hey are cleaved ~o the acid~ too rapidly in ~he organism and do not reach their ~ite of action in the cell in sufficiently high concentration and are therefore le ~ suitable for possibl admini~tration a8 pharmaceuti-cals.
DE-A 3J703~959~ DE-A 3,703,962 and DE A 3,703,963 dQS-cribe in general form mixed e~ter/amide6, higher alky-lated diesters and diamides of pyridine-2,4- and _2,5-dicarboxylic acid, which effsctively inhibit, collagen biosynthesis in the animal model. ~hus, DE-A 3,703,959, inter alia, de~cribes the synthesi~ of N,N'-bis(2-methoxyethyl)pyridin2-2,4-d~carboxamide and N,N'-bis(3-isopropoxypropyl)pyridine-2,4-dicarboxamide.
An improved process for the preparation of N,N~-bis(2-methoxyethyl)pyridine-2,4-dicarbo~amide i8 propo~ed in Genman Patent Application~ P 38 26 471.4 and P 38 28 1~0.6.
German Patent Application P 39 24 093.2 proposes ~ovel N,N~-bistslko~yalkyl)pyridine-2,4-dicarboxamides.
German Patent ~pplication P 40 01 00~.3 describes the use of N,N'-(nitroxyalkyl)pyridine-2,4- and -2,5-dicarbox-amides for the preparation of pharmaceuticals inhibiting proline hydroxyla~e and lysine hydroxylase.
Both pyridine-2,4- and -2,5-dicarboxamide - 3 - ~ ~4~8~
(Hirakata et al., J~ pharm. Soc. Japan 77 (1957) 219 and Haring et al., ~elv. 37 ~195~ 7, 153) and pyridine-2,4- and -2,5-dicarboxylic acid dihydrazide ~It~i et al. r Bl. nation. hyg. ~abor. Tokyo, 74 ~1956) 115, 117 and Shinohara et al., Chem. High Polymer~ Japan, 15 (1958) 839) are already known as antituberculosi~ agent~.
JP 53/28175 (78/28175) de~cribes N,N'-bis~2-nitrooxy-ethyl)pyridine~2,4- and -2,5-dicarbox~mides as 6ubstance~
having vasodilatory action.
Surprisingly, i~ ha~ now been found that 2,4- and 2,5-substituted pyridine-N oxides of the general formula I
indicated below and the phy~iolo~ically tolerable ~alts effectively inhibit ly~ine hydroxylase and p:roline hydroxylase in the animal model.
The invention accordingly relates to 2,4 and 2,5-~ub-stituted pyridine N-oxides of the general formula I
R2_ o in which R1 is -C(o)-X-R3, where X is O or -N(R3)~ and R3 is hydrogen, Cl-C12-alkyl, C2-Cl2-alkenyl, C2-Cl2-alkynyl, non-benzo-fu~ed or benzo-fused C5-C7-cycloalkyl, aryl or heteroaryl, where the6e radicals mentioned for R3 are unsub9tituted or ~5 are sub~tituted by one or more identical or different radicals R4, where R4 is halogen, hydroxyl, cyano, nitro, _ 4 _ 2~
nitroxy, amino, carboxyl, C,-C4-alkoxy, C~-C4-alkoxycarbonyl, Cl~C~-al~yl- or -dialkylamino, indolyl or phenyl, where the indolyl or phenyl radical i8 unsub-~tituted or monosubstituted t dlsub~tituted or tri~ub~tituted by halogen, nitro, C1--C4-alkyl or C~-C4-alkoxy~ ~here, in the case of poly~ubsti~ution, the radicals are idenkical or different or R3, if X is -~(R3), i8 a radical -N(R5) (R6)~ in which Rs and R6 are identical or dif ferent and are hydrogen, C,-C4-alkyl, C1-C3-alkylcarbonyl or phenyl and R3 has the meaning of R3, where the radicals R3 and R3 are identical or diffarent ox R3 and R3, together with the nitrogen atom to which ~0 they are bonded, are a radical of the formula II
r~
_ N ~ (II) (CH2)n in which n is l to 3 and A is 0, S, CHa or -N~R')-, where R7 i~ hydrogen, phenyl, Cl-C6-alkyl, C2 CB-alkenyl 2~8~
or C2-C6~al~ynyl, whera these mentioned radical3 are uns~bstituted or substituted by phenyl which, for it~ part, i8 un~ubstltuted, or monosub~ uted or poly~ubsti~ted by one or more identical or differen~ ~ub-~tituent~ ~elect0d from the group com-prisings halogen, nitro, cyano, carbo~yl, hydro~yl, methyl, ethy:L, methoxy, ~thoxy and trifluor~ethyl or -N~R~)z, where R8 is hydragen or C~-C3-alkyl or -COOR~
or -CON~R~)2 or CoNHR7, where R9 has ~he meaning of ~8 or where (R9) 2 is a C4~C6~alkylene chain in which no CH2 ~roup or a CH2 group which is not directly ad~acent to the ni~rogen atom is xeplaced by O, S or N-R8 or where R7 is Cl-C4-alkoxycarbonyl or C3-C,-cycloalkyl and in which R2 has the meaning of R1, where the radicals Rl and R2 2~86~
are identical or diffsrent or R2 i8 vnly present in the 4-position, and one of the radicals R3 or R4 is in the 5-po~ition and the physiologically tolerable salts, where the compound~ of the general formula I are excluded in which Rl and R2 are identical or different and are carboxyl, it~
methyl or ethyl e~ters and its diethylamidas.
The invention furthermore relates ~o the use of compound~
of the ~eneral formula I and the physiologically tolerable salts for ~he production of a pharmaceutical inhibiting proline hydroxylase and ly~ine hydroxylase.
Finally, the invPntion relate~ to the compounds of the general formu~a I for use as pharmaceuticals.
The invention relates in particular to the campounds of the formula I for use as fibrosuppressives and immuno-suppressives and also for the inhibition of proline hydro~ylase and ly~ine hydroxylase and for influencing the metab~lism of collagPn and collagen-like sub~tances or the biosyntha6is of Clq.
All said alkyl radicals having more than 2 carbon atoms can be either straight-chain or branched.
The invention furthermore relate~ to a process for the preparation of compound~ of the general for~ula I.
The compounds according to the invention are mo~t 6imply prepared by adding oxidants such as, for example, hydro-gen peroxide or p~racids such as peracetic ~cid, per-fluoroacetic acid, perbenzoic acid or metachloroper-benzoic acid in ~olvents such as chlorinated hydro-carbons, such as, for example, methylene chloride, chloroform, tri- or tetrachloroethylene, benzene or toluene, to the pyridine compounds to be oxidized, which 2l~8~
~ 7 --can likewise be dissolved in the abovementioned ~olvents, and stirring at a temperature betw~en -30 and +40C, praferably between 0 and ~5C, ~or betwean 30 minutes and 3 days. Completion of the reaction can ~e determined, for example, by means of thin layer chromatography. The compound~ according to ~he invention can pre~erably be prepared by employing the pyridine deriYative and the oxidant in equimolar amoun~s or up to an about 5-fold excess of oxidant.
If appropriate, an exceRs of peracid ean al80 be elimin-ated by introducing, for example, gaseou~ ~mmonia into the reaction solution and separating the resulting pr~cipitate from the reac$ion sslutiQn by filtration.
I~ appropriate, the products can be worked up, for example, by extraction or by chromatography, for ex,ample by means of silica gel. The isolated product can be recrystallized.
A general procedure for this oxidation method i8 also deRcribed, Por example, in "E. ~ingsberg, Pyridine and its Derivatives, Interscience Publi6hers, Mew York, 1961, Par~ 2, 93".
Oxidation with hydrogen peroxide i~ described, for example, in "E. Ochiai, J. Org. Chem. 18, 534 (1953)".
The preparation of the dif~erent pyridine derivati~es necessary for the oxidation described is set out in the Patent Applications already cited as prior art. ~hose which may be mentioned are German Patent Applications P 38 26 471.4, 38 28 140.6, 39 24 093.2, 40 01 002.3 and DE-A-3,703,959, 3,703,962 and 3,703,963.
The compounds of the formula I according to the invention have useful pharmacological properties and in particular show activity as inhibitors of proline hydroxylase and lysine hydroxylase, as a fibro~uppressive, - 8 - 2~g~
immunosuppres~ive and antiatherosclerotic.
The antifibrotic action can be detarmined in the ~arbon tetrachloride-induced liver fibrosis model. For this purpose, rats ~re treated twice weakly with CCl4 ~1 ~l/kg) - di solved in olive oil. The te~t su~stance i~ ~dminl~-tered daily, if appropriate even ~wi~e daily, orally or intraperitoneally - dissolved in a 3ui~ab1e tolerable solvent. The extent of liver fibro~ 8 i~ determined histologically and the proportion of collagen in the li~er i8 analyzed by hydroxyproline det~rmination a~
described in ~ivirikko et al. (~nal. Biochem. 19, 249 et seq. tl967)). The fibrogenesis activity can be determined by radioLmmunological determination of collagen fragmants and procollagen peptides in the ~erum~ The co~pounds according to the invention are effective in this model in concen~rations of 1 - 100 mg/kg.
The fibro~enesis activity can be determined by radio-immunological determination of the N-terminal propeptide of type III collagen or of the N- or C-terminal cross-linking domain of type IV ~ollagen (7s colla~en or typeIV collagen-NCl) in the serum.
For thi~ purpose, the hydroxyproline, procollagen III
peptide, 7s~collagen and type IV collaqen-NCl concentra-tions in the 1 tver of a) untreated rats ~control~
b) rats to which carbon ~etrachloride was admini~tered ~CCl4 control) c) rats to which first CCl4 and then a compound accor-ding to the invention was administered were measured ~this test method is described by Rouiller, C., experime~tal toxic in~ury o~ the liver; in The ~iver, C. Rouiller, ~ol. ~, pp. 335-476, New York, Academic Pressr 1964).
Another model for the evaluation of antifibrotic action is bleomycin-induced lung fibrosis as described in 9 2~8~
Xelley et al. (J. ~ab. Clin~ Med. 96, 954, (1980)). The cotton pellet granuloma model, as described in ~eier et al. J Experientia 6, 469 (1~50) can be u~ed to evaluate the action of the compounds according to the invention in the granulation tissue.
The compounds of the formula ~ can be used a8 mediCamentB
in the form of pharmaceu~ical preparations which contain them, if appropriate together with tolerable pharmaceuti-cal carriers. The compounds can be u~0d as medic~ments, for example in thP form of pharmaceutical preparation , which contain these compounds in a mixture with a pharma-ceu~ical organic or inorganic carrier suitable for enteral, percutaneous or parenteral administrationg such as, for example, water, gum ~rabic, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, poly-alkylene glycols, petroleum ~elly etc.
For this purpose, they can be administered orally in doses cf 0.1 - 25 mg/kg/day, preferably 1 - 5 mg/kg/day or parenterally in doses of O.Dl - 5 mg/kg~day, pre-ferably 0.01 - 2.S mg/kg/day, in particular 0.5 1.0 mg/kg/day. ~n severe ca~e~, the do6l~ge can also be increased. In many caaes, however, lower dose~ are also sufficient. This information relate~ to an adult weighing about 75 kg.
The invention furthermore includes the use of the com-pounds according to the invention in the production of pharmaceuticals which are employed ~or the treatment and prophyla~is of the abovementioned metabolic disorders.
The invention further relates to pharmaceutical~ which contain one or more compound~ of the formula ~ according to the invention snd/or their physiologically tolerable ~alts.
The pharmaceuticals axe prepared by processes which are known per se and which are familiar to the person skilled 20~58~
in the art. As pharmacautical~, ~he pharmacologically active compounds according to the invention are employed either as such or preferably in combination with suitable pharmaceutical auxiliarias or exoipient~ in the fo~m of tablets, coated tablets, capsule6, ~uppositorie~, emul-sions, su~pension~ or solu~ions, ~e active compound content being up to about 95~, advantageously b~tween 10 and 75~.
In addition to solvent~ gel-forming agen~s, ~uppoaitory bases, tablet auxiliaries and o~her active compound carriers, ~uitable auxiliaries or excipients for the desired pharmaceutical formulation are al60, for example, antioxidants, dispersants, emulsifiers, antifoams, flavor correctants, preservatiYes, solubilizers or colorantsO
The active compounds can be administered orally, paren-terally or r~ctally.
~he active compounds are mixed with the additives suitable for this purpose, such a~ excipients, stabi-lizers or inert diluents and brought into suitable adminis~ration form6~ ~uch as ~ablet~, coated tablets, hard gelatin capsules, agueous alcoholic or oily ~uspen-sions or aqueous or oily &olutions, by the customary methods.
Inert excipient~ which can be u~ed are, for example, gum arabic, magnesiaf magnesium carbonate, potassium phos-phate, lactose, glucose or ~tarch, in particular corn starch. In thi~ case, preparation can be carried out both as dry and as moist granules- Possible oily excipient~ or ~olvents are, for example, vegetable or animal oils, such as sunflower oil or cod liver oil.
For ~ubcutaneous or intravenous administration, the active compounds are brought into solution, fiu~pension or emulsion, if desired usin~ the substances suitable for this such as solubilizers, emulsifier6 or other 8 6 ~
auxiliarie~. Suitable ~olvents are, for examp}e, phy~io-logical ~aline solution or alcohol , for example ethanol, propanol or glycerol, and in a~dition al~o ~ugar ~olu-tion~ such as gluco~e or mannitol 801ution~, or, altarna-tively, a mixture of the variou~ solvent~ mentioned.
The invention i8 illu~trated in more detail below by Exzmples.
Genaral procedure for ~he preparatiorl of the compound~
1 equivalent of p~ridine derivative tfor preparation see description~ is initially introduced in met~yl2ne chloride and 1 equivalent of metachloroperbenzoic acid (~CPBA), dissolved in methylene chloxide~ dded dropwise at room temperature. The mixture i8 s~irred at room temperature. ~fter completion of the reaction, gaseous ammonia is blown into the solution with ice-: cooling until a precipitate is no longer formed. The precipitate is filtered off, and the filtrate i~ dried with magnesium sulfate and concentrated.
~he crude product i8 recrystallized or p~ri~ied by means of thin layer chromatography.
The compounds mentioned in the fol~owing Examples areprepared according to ~his general procedure.
~Emple 1 N,N'~Di-(2-methoxyethyl)pyridine-2,4-dicarbo~amide N-oxide From 1 g of N,N'-di-~2-methoxyethyl)pyridine-2,4-dicar-boxamide and 0~62 g o~ ~CPBA.
Yield: 620 mg (chromatography. ethyl acetate/methanol 5:1) M.p.: 10~C
1~ 2`~8~8 E~ample 2 N~N'-Di-(3-methoxypropyl~pyridine-2,4-dicarboxamide N-oxide From 1 g of N,N~-di-(3-methoxypropyl)pyridine-2,4-dicarb-oxamide and 1.2 g of ~CPBA.
Yield: 0.58 g (recrystallization: ethanol~
M.p.: 90C
~ample 3 Pyridine-2,4-dic~rboxamide N-oxide From 1 g of pyridine-2,4-dicarboxamide and 1.2 g of MCPBAO
Yield: 0.8 g (recrystallization: ethanol) M.p.: 260C
~æample 4 15 N,N'-Di-(2-dimethoxyethyl)pyridine-2,4-dicaxboxamide N-oxide From 1 g of N,N'-di-(2 dimethoxyethyl)pyridine-2,4-dicar-boxamide and l.l g of MCP~A.
Yield: 0.5 g (chromatography: ethyl acetate/methanol 5:1) ~.p.: 8~~
- 13 ~ ~0~58~
~;e~ple S
N, N ' -Di- ( 3 -e~hoxypropyl ) pyridine -2, 4-dicarboxamide N-oxide From 1 g of N, N ' -di- ( 3-ethoxypropyl ) pyridine~2, 4 -dicarb-oxamide and 1. 5 g of NCP33A.
Yield: O . 34 g (chromatography~ ethyl acetate/methanol 5 s 1 ) M.p.: ~1C
Example 6 N, N ' -Di- ( 2-methoxyethyl ) pyridine-2, 5-dicarboxamide N-oxide From 1 g of ~, N ' -di- ( 2-methoxyethyl ) pyridine-2, 4 -dicarb-oxamide and 1. 3 g of MCPBA.
Yield: 0.4 g (recrys allization: ethanol) M.p.: 137~C
~ample 7 Di-(2-methoxyethyl) pyridine-2,4-dicarboxylate N-oxide From 1 g of di-(2-methoxye~hyl) pyridine-2,~-dicarboxy-late and 1.3 g of MCPBA.
2Q Yield: O.2 g ~chromatography: ethyl acetate) M.p.: oil 2~5868 ~ample 8 N, N '-Diethylpyridine-2~5-dicarboxamide ~-oxide From 1 g of N,N~-diethylpyridine-2,5-dicarboxamide and 1.8 g of ~CPB~.
Yield: 0.4 g (recrystallization: e~hanol~
.p.: 1~8C
E~a~pl~ 9 N,N'-Di-(3-methoxypropyl)pyridine-2,5-dicarbo~amide ~-oxide From 1 g of N,N' di-(3-methoxypropyl3~yri~ine-2,5-dicar boxamide and 1.2 g of ~CPBA.
Yield: O.3 g (recrystallization: diethyl ether/methanol) M.p.: 123C
~ample 10 2,4-Di-[(morpholin-l yl)carbonyl]pyridine N oxide Fro~ 1 g of 2,4-di-[(morpholin-1-yl)carbonyl~pyridine ~nd 1,2 g of ~CP~A.
Yield: 0.5 g ~chromatography: ethyl acetate/methanol 5/1 M.p.: oil 4 ~ 8 13xample 11 N,N'-Di-(4-hydroxybutyl)pyridine-2,4-dicarboxamide N-oxide From 1 g of N,N~-di-(4~hydro~ybutyl) pyridine-2,4-dicarb-oxamide and 0.8 g of ~CP~A.
Yield: 0.82 g (ethanol) M.p.: ~8C
~xam~le 12 N,N'-Dicyclohe~ylpyridine-2,4-dicarboxamide N-oxide From 1 g of N,N~-dicyclohexylpyridine-2,4-dicarbo~nide and 0 g of MCPBA.
Yield: 0.59 g (ethanol) M.p.: 153C
~am~le 13 N,N'-Di-(3-chlorobenzyl)pyridine-2,4-dicarboxamide N-oxide From 1 g of N,N'-di-(3-chlorobenzyl)pyridine-2,4-dicarb-oxamide and 0.65 g of MCPBA.
Yield: 0.76 g (toluene~
M.p.: 112C
2~ 8 E~ample 14 N t N~-Di-(4-methylbenzyl)pyridine-2~ 4-dicar~oxamide N-oxide From 1 g o N,N'-di-~4-methylbenzyl)p~ridine-2,4-dicarb-S oxamide and ~.2 g of MCP~.
Yield: 0.7~ g (toluene) M.p.: 153C
~xample 15 Di-(4-chlorobutyl) pyridine-2,4-dicarboxylate N-oxide From 1 g of di- ( 4-chlorobutyl ) pyridine-2, 4-dicarboxy~ ate and 0.75 g of MCPBA.
Yield: 0.83 g (ethanol) ~,p.: 98C
~ample 16 Dicyclohexyl pyridine 2,4-dicarboxylate N-oxide From 1 g of dicyclohexyl pyridine-2,4-dicarboxylate and 0.75 g of ~CPBA.
Yield: 0.87 g Oil, MS - 348 (M~H) molec~lar weight 347 2 ~
~xample 17 Di-(methoxycarbonylmethyl) pyridine-2,4-dicarboxylate N-oxide From 1 ~ of di-(methoxycarbonylmethyl~ pyridine-2,4-di-S carboxylate and 1.1 g of ~CP~.
Yield: 0.81 g Oil, MS = 328 (M~H~ molecular wei~ht 327 Example 18 Pharmacological activity In order to show the efficient inhibit:ion of proline hydroxylase and ly~ine hydroxylase by the ~ompounds according to the inven~ion, the concentrations of bili-rubin, bile acids and gamma GT in the serum of a) untreated rats ~control), b) rats treated with CCl4, c) rats to which first CCl4 and then a compound accor-ding to the invention have been given, are measured. (The method i5 described by Roailler, C.~
Experimental toxic in~ury of the liver; in The Liver, C. Rouiller, Vol. 2, pages 335-476, New York, Academic Press 1964).
The result~ are summarized in Table 1.
2 0 ~ 8 Table 1:
Action of prolyl hydroxylase inhibitor~3 on CCl4-induced liver fibxosi3 in rats ~rreatment Dose~ R~lirubin Bile ~CidB G~na n~ N ~n _ U/L
51.76 ~ 0.27 26 ~ 6.8 2 0 CCl4 - 224.98 + 1.06 Bl ~ 8.7 5.3 + 1.4 Exs~le 1 20 12 6.30 + 5.497 ~ 76 4.3 ~ 3.1 (0) (0) ~27) Ea~ple 2 20 11 2.90 t 0.94*71 + 42 3.3 + 2.2*
(~5) (18) ~5~) The re~ults are me~n value~ ~ 6tandard deviation, *p ~0 . 05 fox CCl4 treatment, values in brackets are the percentage improve~nent c:om-pared to an exclusive CCl4 treatment.
a: tutal daily oral àose.
Description 2,4- and 2,5-substituted pyridine-N-oxide~, proce~ses for their preparation and their U8e Compounds which inhibi~ the enzymes proline hydroxylase and lysine hydroxyla~e cau~0 ~ very selective inhibition of collagen biosynthesis by in~luencing collagen-~pecific hydroxylation reactions. In the course thereof, protein-bound proline or lysine i~ hydroxylat~d by the enzymes proline hydroxylase or lysine hydroxyla~e. If this reaction i5 suppressed by inhibitors, a non-functional, underhydroxylated collagen molecule i~ formed, which can be released into the extracellular ~pace by the cell~
only to a small e~tent. In addition, th~ underhydroxy-lated collagen cannot be inoorporated into the collagenmatrix and is ve~y easily degraded by prot~olysi3. As a result of these effects, the amount of collagen stored extracellularly is on the whole reduced.
Inh~bitor~ of prolyl hydroxylase are th~re~ore ~uitable substances in the treatment of disorders in which the storage of collagens contrlhutes decisively to the symptoms. These include, inter alia, $i.bros~s of the lungs, liver and skin (~cleroderma~ and atherosclerosis.
It is known that the inhibition of proline hydroxylase by known inhibitors such a ~ dipyridyl leads to an inhibition o~ Clq biosynthesis by macroph~es (W. ~ller et al., FEBS Lett. 90 (1978), 218; Immunbiology 155 (1978), 47). As a result, a failure of the classical route of complemen~ activation occur~. Inhibitors of proline hydroxyla~e therefore also act a~ immunosuppres-sives, for example in immune complex diseases.
It is known that the enzyme proline hydroxylase is effectively inhibited by pyridine-2,4 and -2,5-dicarboxylic acid (R. Ma~amaa et al., 2~45~8 Eur. J. Biochem. 138 (1984) 239-245). However, ~hese compounds are effec~ive in cell culkure as inhibitors only in very high concentrations (Tschank, G. et al., Biochem. J. 238 (1987) 625-633).
DE-~ 3,432,0g4 dascribes pyridine-2,4- and -2,5-dicar-boxylic acid diesters haring 1-6 carbon atoms in the ester al~yl moiety as pharmsceutical~ for the inhibition of proline hydroxylase and lysine hydroxyla~e.
However, these lower-alkylated diestexs have the disad-vanta~e tha~ ~hey are cleaved ~o the acid~ too rapidly in ~he organism and do not reach their ~ite of action in the cell in sufficiently high concentration and are therefore le ~ suitable for possibl admini~tration a8 pharmaceuti-cals.
DE-A 3J703~959~ DE-A 3,703,962 and DE A 3,703,963 dQS-cribe in general form mixed e~ter/amide6, higher alky-lated diesters and diamides of pyridine-2,4- and _2,5-dicarboxylic acid, which effsctively inhibit, collagen biosynthesis in the animal model. ~hus, DE-A 3,703,959, inter alia, de~cribes the synthesi~ of N,N'-bis(2-methoxyethyl)pyridin2-2,4-d~carboxamide and N,N'-bis(3-isopropoxypropyl)pyridine-2,4-dicarboxamide.
An improved process for the preparation of N,N~-bis(2-methoxyethyl)pyridine-2,4-dicarbo~amide i8 propo~ed in Genman Patent Application~ P 38 26 471.4 and P 38 28 1~0.6.
German Patent Application P 39 24 093.2 proposes ~ovel N,N~-bistslko~yalkyl)pyridine-2,4-dicarboxamides.
German Patent ~pplication P 40 01 00~.3 describes the use of N,N'-(nitroxyalkyl)pyridine-2,4- and -2,5-dicarbox-amides for the preparation of pharmaceuticals inhibiting proline hydroxyla~e and lysine hydroxylase.
Both pyridine-2,4- and -2,5-dicarboxamide - 3 - ~ ~4~8~
(Hirakata et al., J~ pharm. Soc. Japan 77 (1957) 219 and Haring et al., ~elv. 37 ~195~ 7, 153) and pyridine-2,4- and -2,5-dicarboxylic acid dihydrazide ~It~i et al. r Bl. nation. hyg. ~abor. Tokyo, 74 ~1956) 115, 117 and Shinohara et al., Chem. High Polymer~ Japan, 15 (1958) 839) are already known as antituberculosi~ agent~.
JP 53/28175 (78/28175) de~cribes N,N'-bis~2-nitrooxy-ethyl)pyridine~2,4- and -2,5-dicarbox~mides as 6ubstance~
having vasodilatory action.
Surprisingly, i~ ha~ now been found that 2,4- and 2,5-substituted pyridine-N oxides of the general formula I
indicated below and the phy~iolo~ically tolerable ~alts effectively inhibit ly~ine hydroxylase and p:roline hydroxylase in the animal model.
The invention accordingly relates to 2,4 and 2,5-~ub-stituted pyridine N-oxides of the general formula I
R2_ o in which R1 is -C(o)-X-R3, where X is O or -N(R3)~ and R3 is hydrogen, Cl-C12-alkyl, C2-Cl2-alkenyl, C2-Cl2-alkynyl, non-benzo-fu~ed or benzo-fused C5-C7-cycloalkyl, aryl or heteroaryl, where the6e radicals mentioned for R3 are unsub9tituted or ~5 are sub~tituted by one or more identical or different radicals R4, where R4 is halogen, hydroxyl, cyano, nitro, _ 4 _ 2~
nitroxy, amino, carboxyl, C,-C4-alkoxy, C~-C4-alkoxycarbonyl, Cl~C~-al~yl- or -dialkylamino, indolyl or phenyl, where the indolyl or phenyl radical i8 unsub-~tituted or monosubstituted t dlsub~tituted or tri~ub~tituted by halogen, nitro, C1--C4-alkyl or C~-C4-alkoxy~ ~here, in the case of poly~ubsti~ution, the radicals are idenkical or different or R3, if X is -~(R3), i8 a radical -N(R5) (R6)~ in which Rs and R6 are identical or dif ferent and are hydrogen, C,-C4-alkyl, C1-C3-alkylcarbonyl or phenyl and R3 has the meaning of R3, where the radicals R3 and R3 are identical or diffarent ox R3 and R3, together with the nitrogen atom to which ~0 they are bonded, are a radical of the formula II
r~
_ N ~ (II) (CH2)n in which n is l to 3 and A is 0, S, CHa or -N~R')-, where R7 i~ hydrogen, phenyl, Cl-C6-alkyl, C2 CB-alkenyl 2~8~
or C2-C6~al~ynyl, whera these mentioned radical3 are uns~bstituted or substituted by phenyl which, for it~ part, i8 un~ubstltuted, or monosub~ uted or poly~ubsti~ted by one or more identical or differen~ ~ub-~tituent~ ~elect0d from the group com-prisings halogen, nitro, cyano, carbo~yl, hydro~yl, methyl, ethy:L, methoxy, ~thoxy and trifluor~ethyl or -N~R~)z, where R8 is hydragen or C~-C3-alkyl or -COOR~
or -CON~R~)2 or CoNHR7, where R9 has ~he meaning of ~8 or where (R9) 2 is a C4~C6~alkylene chain in which no CH2 ~roup or a CH2 group which is not directly ad~acent to the ni~rogen atom is xeplaced by O, S or N-R8 or where R7 is Cl-C4-alkoxycarbonyl or C3-C,-cycloalkyl and in which R2 has the meaning of R1, where the radicals Rl and R2 2~86~
are identical or diffsrent or R2 i8 vnly present in the 4-position, and one of the radicals R3 or R4 is in the 5-po~ition and the physiologically tolerable salts, where the compound~ of the general formula I are excluded in which Rl and R2 are identical or different and are carboxyl, it~
methyl or ethyl e~ters and its diethylamidas.
The invention furthermore relates ~o the use of compound~
of the ~eneral formula I and the physiologically tolerable salts for ~he production of a pharmaceutical inhibiting proline hydroxylase and ly~ine hydroxylase.
Finally, the invPntion relate~ to the compounds of the general formu~a I for use as pharmaceuticals.
The invention relates in particular to the campounds of the formula I for use as fibrosuppressives and immuno-suppressives and also for the inhibition of proline hydro~ylase and ly~ine hydroxylase and for influencing the metab~lism of collagPn and collagen-like sub~tances or the biosyntha6is of Clq.
All said alkyl radicals having more than 2 carbon atoms can be either straight-chain or branched.
The invention furthermore relate~ to a process for the preparation of compound~ of the general for~ula I.
The compounds according to the invention are mo~t 6imply prepared by adding oxidants such as, for example, hydro-gen peroxide or p~racids such as peracetic ~cid, per-fluoroacetic acid, perbenzoic acid or metachloroper-benzoic acid in ~olvents such as chlorinated hydro-carbons, such as, for example, methylene chloride, chloroform, tri- or tetrachloroethylene, benzene or toluene, to the pyridine compounds to be oxidized, which 2l~8~
~ 7 --can likewise be dissolved in the abovementioned ~olvents, and stirring at a temperature betw~en -30 and +40C, praferably between 0 and ~5C, ~or betwean 30 minutes and 3 days. Completion of the reaction can ~e determined, for example, by means of thin layer chromatography. The compound~ according to ~he invention can pre~erably be prepared by employing the pyridine deriYative and the oxidant in equimolar amoun~s or up to an about 5-fold excess of oxidant.
If appropriate, an exceRs of peracid ean al80 be elimin-ated by introducing, for example, gaseou~ ~mmonia into the reaction solution and separating the resulting pr~cipitate from the reac$ion sslutiQn by filtration.
I~ appropriate, the products can be worked up, for example, by extraction or by chromatography, for ex,ample by means of silica gel. The isolated product can be recrystallized.
A general procedure for this oxidation method i8 also deRcribed, Por example, in "E. ~ingsberg, Pyridine and its Derivatives, Interscience Publi6hers, Mew York, 1961, Par~ 2, 93".
Oxidation with hydrogen peroxide i~ described, for example, in "E. Ochiai, J. Org. Chem. 18, 534 (1953)".
The preparation of the dif~erent pyridine derivati~es necessary for the oxidation described is set out in the Patent Applications already cited as prior art. ~hose which may be mentioned are German Patent Applications P 38 26 471.4, 38 28 140.6, 39 24 093.2, 40 01 002.3 and DE-A-3,703,959, 3,703,962 and 3,703,963.
The compounds of the formula I according to the invention have useful pharmacological properties and in particular show activity as inhibitors of proline hydroxylase and lysine hydroxylase, as a fibro~uppressive, - 8 - 2~g~
immunosuppres~ive and antiatherosclerotic.
The antifibrotic action can be detarmined in the ~arbon tetrachloride-induced liver fibrosis model. For this purpose, rats ~re treated twice weakly with CCl4 ~1 ~l/kg) - di solved in olive oil. The te~t su~stance i~ ~dminl~-tered daily, if appropriate even ~wi~e daily, orally or intraperitoneally - dissolved in a 3ui~ab1e tolerable solvent. The extent of liver fibro~ 8 i~ determined histologically and the proportion of collagen in the li~er i8 analyzed by hydroxyproline det~rmination a~
described in ~ivirikko et al. (~nal. Biochem. 19, 249 et seq. tl967)). The fibrogenesis activity can be determined by radioLmmunological determination of collagen fragmants and procollagen peptides in the ~erum~ The co~pounds according to the invention are effective in this model in concen~rations of 1 - 100 mg/kg.
The fibro~enesis activity can be determined by radio-immunological determination of the N-terminal propeptide of type III collagen or of the N- or C-terminal cross-linking domain of type IV ~ollagen (7s colla~en or typeIV collagen-NCl) in the serum.
For thi~ purpose, the hydroxyproline, procollagen III
peptide, 7s~collagen and type IV collaqen-NCl concentra-tions in the 1 tver of a) untreated rats ~control~
b) rats to which carbon ~etrachloride was admini~tered ~CCl4 control) c) rats to which first CCl4 and then a compound accor-ding to the invention was administered were measured ~this test method is described by Rouiller, C., experime~tal toxic in~ury o~ the liver; in The ~iver, C. Rouiller, ~ol. ~, pp. 335-476, New York, Academic Pressr 1964).
Another model for the evaluation of antifibrotic action is bleomycin-induced lung fibrosis as described in 9 2~8~
Xelley et al. (J. ~ab. Clin~ Med. 96, 954, (1980)). The cotton pellet granuloma model, as described in ~eier et al. J Experientia 6, 469 (1~50) can be u~ed to evaluate the action of the compounds according to the invention in the granulation tissue.
The compounds of the formula ~ can be used a8 mediCamentB
in the form of pharmaceu~ical preparations which contain them, if appropriate together with tolerable pharmaceuti-cal carriers. The compounds can be u~0d as medic~ments, for example in thP form of pharmaceutical preparation , which contain these compounds in a mixture with a pharma-ceu~ical organic or inorganic carrier suitable for enteral, percutaneous or parenteral administrationg such as, for example, water, gum ~rabic, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, poly-alkylene glycols, petroleum ~elly etc.
For this purpose, they can be administered orally in doses cf 0.1 - 25 mg/kg/day, preferably 1 - 5 mg/kg/day or parenterally in doses of O.Dl - 5 mg/kg~day, pre-ferably 0.01 - 2.S mg/kg/day, in particular 0.5 1.0 mg/kg/day. ~n severe ca~e~, the do6l~ge can also be increased. In many caaes, however, lower dose~ are also sufficient. This information relate~ to an adult weighing about 75 kg.
The invention furthermore includes the use of the com-pounds according to the invention in the production of pharmaceuticals which are employed ~or the treatment and prophyla~is of the abovementioned metabolic disorders.
The invention further relates to pharmaceutical~ which contain one or more compound~ of the formula ~ according to the invention snd/or their physiologically tolerable ~alts.
The pharmaceuticals axe prepared by processes which are known per se and which are familiar to the person skilled 20~58~
in the art. As pharmacautical~, ~he pharmacologically active compounds according to the invention are employed either as such or preferably in combination with suitable pharmaceutical auxiliarias or exoipient~ in the fo~m of tablets, coated tablets, capsule6, ~uppositorie~, emul-sions, su~pension~ or solu~ions, ~e active compound content being up to about 95~, advantageously b~tween 10 and 75~.
In addition to solvent~ gel-forming agen~s, ~uppoaitory bases, tablet auxiliaries and o~her active compound carriers, ~uitable auxiliaries or excipients for the desired pharmaceutical formulation are al60, for example, antioxidants, dispersants, emulsifiers, antifoams, flavor correctants, preservatiYes, solubilizers or colorantsO
The active compounds can be administered orally, paren-terally or r~ctally.
~he active compounds are mixed with the additives suitable for this purpose, such a~ excipients, stabi-lizers or inert diluents and brought into suitable adminis~ration form6~ ~uch as ~ablet~, coated tablets, hard gelatin capsules, agueous alcoholic or oily ~uspen-sions or aqueous or oily &olutions, by the customary methods.
Inert excipient~ which can be u~ed are, for example, gum arabic, magnesiaf magnesium carbonate, potassium phos-phate, lactose, glucose or ~tarch, in particular corn starch. In thi~ case, preparation can be carried out both as dry and as moist granules- Possible oily excipient~ or ~olvents are, for example, vegetable or animal oils, such as sunflower oil or cod liver oil.
For ~ubcutaneous or intravenous administration, the active compounds are brought into solution, fiu~pension or emulsion, if desired usin~ the substances suitable for this such as solubilizers, emulsifier6 or other 8 6 ~
auxiliarie~. Suitable ~olvents are, for examp}e, phy~io-logical ~aline solution or alcohol , for example ethanol, propanol or glycerol, and in a~dition al~o ~ugar ~olu-tion~ such as gluco~e or mannitol 801ution~, or, altarna-tively, a mixture of the variou~ solvent~ mentioned.
The invention i8 illu~trated in more detail below by Exzmples.
Genaral procedure for ~he preparatiorl of the compound~
1 equivalent of p~ridine derivative tfor preparation see description~ is initially introduced in met~yl2ne chloride and 1 equivalent of metachloroperbenzoic acid (~CPBA), dissolved in methylene chloxide~ dded dropwise at room temperature. The mixture i8 s~irred at room temperature. ~fter completion of the reaction, gaseous ammonia is blown into the solution with ice-: cooling until a precipitate is no longer formed. The precipitate is filtered off, and the filtrate i~ dried with magnesium sulfate and concentrated.
~he crude product i8 recrystallized or p~ri~ied by means of thin layer chromatography.
The compounds mentioned in the fol~owing Examples areprepared according to ~his general procedure.
~Emple 1 N,N'~Di-(2-methoxyethyl)pyridine-2,4-dicarbo~amide N-oxide From 1 g of N,N'-di-~2-methoxyethyl)pyridine-2,4-dicar-boxamide and 0~62 g o~ ~CPBA.
Yield: 620 mg (chromatography. ethyl acetate/methanol 5:1) M.p.: 10~C
1~ 2`~8~8 E~ample 2 N~N'-Di-(3-methoxypropyl~pyridine-2,4-dicarboxamide N-oxide From 1 g of N,N~-di-(3-methoxypropyl)pyridine-2,4-dicarb-oxamide and 1.2 g of ~CPBA.
Yield: 0.58 g (recrystallization: ethanol~
M.p.: 90C
~ample 3 Pyridine-2,4-dic~rboxamide N-oxide From 1 g of pyridine-2,4-dicarboxamide and 1.2 g of MCPBAO
Yield: 0.8 g (recrystallization: ethanol) M.p.: 260C
~æample 4 15 N,N'-Di-(2-dimethoxyethyl)pyridine-2,4-dicaxboxamide N-oxide From 1 g of N,N'-di-(2 dimethoxyethyl)pyridine-2,4-dicar-boxamide and l.l g of MCP~A.
Yield: 0.5 g (chromatography: ethyl acetate/methanol 5:1) ~.p.: 8~~
- 13 ~ ~0~58~
~;e~ple S
N, N ' -Di- ( 3 -e~hoxypropyl ) pyridine -2, 4-dicarboxamide N-oxide From 1 g of N, N ' -di- ( 3-ethoxypropyl ) pyridine~2, 4 -dicarb-oxamide and 1. 5 g of NCP33A.
Yield: O . 34 g (chromatography~ ethyl acetate/methanol 5 s 1 ) M.p.: ~1C
Example 6 N, N ' -Di- ( 2-methoxyethyl ) pyridine-2, 5-dicarboxamide N-oxide From 1 g of ~, N ' -di- ( 2-methoxyethyl ) pyridine-2, 4 -dicarb-oxamide and 1. 3 g of MCPBA.
Yield: 0.4 g (recrys allization: ethanol) M.p.: 137~C
~ample 7 Di-(2-methoxyethyl) pyridine-2,4-dicarboxylate N-oxide From 1 g of di-(2-methoxye~hyl) pyridine-2,~-dicarboxy-late and 1.3 g of MCPBA.
2Q Yield: O.2 g ~chromatography: ethyl acetate) M.p.: oil 2~5868 ~ample 8 N, N '-Diethylpyridine-2~5-dicarboxamide ~-oxide From 1 g of N,N~-diethylpyridine-2,5-dicarboxamide and 1.8 g of ~CPB~.
Yield: 0.4 g (recrystallization: e~hanol~
.p.: 1~8C
E~a~pl~ 9 N,N'-Di-(3-methoxypropyl)pyridine-2,5-dicarbo~amide ~-oxide From 1 g of N,N' di-(3-methoxypropyl3~yri~ine-2,5-dicar boxamide and 1.2 g of ~CPBA.
Yield: O.3 g (recrystallization: diethyl ether/methanol) M.p.: 123C
~ample 10 2,4-Di-[(morpholin-l yl)carbonyl]pyridine N oxide Fro~ 1 g of 2,4-di-[(morpholin-1-yl)carbonyl~pyridine ~nd 1,2 g of ~CP~A.
Yield: 0.5 g ~chromatography: ethyl acetate/methanol 5/1 M.p.: oil 4 ~ 8 13xample 11 N,N'-Di-(4-hydroxybutyl)pyridine-2,4-dicarboxamide N-oxide From 1 g of N,N~-di-(4~hydro~ybutyl) pyridine-2,4-dicarb-oxamide and 0.8 g of ~CP~A.
Yield: 0.82 g (ethanol) M.p.: ~8C
~xam~le 12 N,N'-Dicyclohe~ylpyridine-2,4-dicarboxamide N-oxide From 1 g of N,N~-dicyclohexylpyridine-2,4-dicarbo~nide and 0 g of MCPBA.
Yield: 0.59 g (ethanol) M.p.: 153C
~am~le 13 N,N'-Di-(3-chlorobenzyl)pyridine-2,4-dicarboxamide N-oxide From 1 g of N,N'-di-(3-chlorobenzyl)pyridine-2,4-dicarb-oxamide and 0.65 g of MCPBA.
Yield: 0.76 g (toluene~
M.p.: 112C
2~ 8 E~ample 14 N t N~-Di-(4-methylbenzyl)pyridine-2~ 4-dicar~oxamide N-oxide From 1 g o N,N'-di-~4-methylbenzyl)p~ridine-2,4-dicarb-S oxamide and ~.2 g of MCP~.
Yield: 0.7~ g (toluene) M.p.: 153C
~xample 15 Di-(4-chlorobutyl) pyridine-2,4-dicarboxylate N-oxide From 1 g of di- ( 4-chlorobutyl ) pyridine-2, 4-dicarboxy~ ate and 0.75 g of MCPBA.
Yield: 0.83 g (ethanol) ~,p.: 98C
~ample 16 Dicyclohexyl pyridine 2,4-dicarboxylate N-oxide From 1 g of dicyclohexyl pyridine-2,4-dicarboxylate and 0.75 g of ~CPBA.
Yield: 0.87 g Oil, MS - 348 (M~H) molec~lar weight 347 2 ~
~xample 17 Di-(methoxycarbonylmethyl) pyridine-2,4-dicarboxylate N-oxide From 1 ~ of di-(methoxycarbonylmethyl~ pyridine-2,4-di-S carboxylate and 1.1 g of ~CP~.
Yield: 0.81 g Oil, MS = 328 (M~H~ molecular wei~ht 327 Example 18 Pharmacological activity In order to show the efficient inhibit:ion of proline hydroxylase and ly~ine hydroxylase by the ~ompounds according to the inven~ion, the concentrations of bili-rubin, bile acids and gamma GT in the serum of a) untreated rats ~control), b) rats treated with CCl4, c) rats to which first CCl4 and then a compound accor-ding to the invention have been given, are measured. (The method i5 described by Roailler, C.~
Experimental toxic in~ury of the liver; in The Liver, C. Rouiller, Vol. 2, pages 335-476, New York, Academic Press 1964).
The result~ are summarized in Table 1.
2 0 ~ 8 Table 1:
Action of prolyl hydroxylase inhibitor~3 on CCl4-induced liver fibxosi3 in rats ~rreatment Dose~ R~lirubin Bile ~CidB G~na n~ N ~n _ U/L
51.76 ~ 0.27 26 ~ 6.8 2 0 CCl4 - 224.98 + 1.06 Bl ~ 8.7 5.3 + 1.4 Exs~le 1 20 12 6.30 + 5.497 ~ 76 4.3 ~ 3.1 (0) (0) ~27) Ea~ple 2 20 11 2.90 t 0.94*71 + 42 3.3 + 2.2*
(~5) (18) ~5~) The re~ults are me~n value~ ~ 6tandard deviation, *p ~0 . 05 fox CCl4 treatment, values in brackets are the percentage improve~nent c:om-pared to an exclusive CCl4 treatment.
a: tutal daily oral àose.
Claims (12)
1. A 2,4- or 2,5-substituted pyridine N-oxide of the formula I
(I) in which R1 is -C(O)-X-R3, where X is O or N(R3')- and R3 is hydrogen, C1-C12-alkyl, C2-C12-alkenyl, C2-C12-alkynyl, non-benzo-fused or benzo-fused C5-C7-cycloalkyl, aryl or heteroaryl, where these radicals mentioned for R3 are unsubstituted or are substituted by one or more identical or different radicals R4, where R4 is halogen, hydroxyl; cyano, nitro, nitroxy, amino, carboxyl, C1-C4-alkoxy, C1-C4-alkoxycarbonyl, C1-C4-alkyl- or -dialkylamino, indolyl or phenyl, where the indolyl or phenyl radical is unsub-stituted or monosubstituted, disubstituted or trisubstitutbd by halogen, nitro, C1-C4-alkyl or C1-C4-alkoxy, where, in the case of polysubstitution, the radicals are identical or different or R3, if X is -N(R3), is a radical -N(R5)(R6), in which R5 and R6 are identical or different and are hydrogen, C1-C4-alkyl, C1-C3-alkylcarbonyl or phenyl and R3 has the meaning of R3, where the radicals R3 and R3 are identical or different or R3 and R3, together with the nitrogen atom to which they are bonded, are a radical of the formula II
(II) in which n is 1 to 3 and A is O, S, CH2 or -N(R7)-, where R7 is hydrogen, phenyl, C1-C6-alkyl, C2-C6-alkenyl or C2-C6-alkynyl, where these mentioned radicals are unsubstituted or substituted by phenyl which, for its part, is unsubstituted, or monosubstituted or polysubstituted by one or more identical or different sub-stituents selected from the group compri-sing: halogen, nitro, cyano, carboxyl, hydroxyl, methyl, ethyl, methoxy, ethoxy and trifluoromethyl or -N(R8)2, where R8 is hydrogen or C1-C3-alkyl or or -CON(R9)2 or COHNR7, where R9 has the meaning of R6 or where (R9)2 is a C4-C6-alkylene chain in which no CH2 group or a CH2 group which is not directly adjacent to the nitrogen atom is replaced by O, S or N-R6 or where R7 is C1-C4 alkoxycarbonyl or C3-C7-cycloalkyl and in which R2 has the meanlng of R1, where the radicals R1 and R2 are identical or different or R2 is only present in the 4-position, and one of the radicals R3 or R4 is in the 5-position and the physiologically tolerable salts, where the compounds of the general formula I are excluded in which R1 and R2 are identical or different and are carboxyl, its methyl or ethyl esters and its diethylamides.
(I) in which R1 is -C(O)-X-R3, where X is O or N(R3')- and R3 is hydrogen, C1-C12-alkyl, C2-C12-alkenyl, C2-C12-alkynyl, non-benzo-fused or benzo-fused C5-C7-cycloalkyl, aryl or heteroaryl, where these radicals mentioned for R3 are unsubstituted or are substituted by one or more identical or different radicals R4, where R4 is halogen, hydroxyl; cyano, nitro, nitroxy, amino, carboxyl, C1-C4-alkoxy, C1-C4-alkoxycarbonyl, C1-C4-alkyl- or -dialkylamino, indolyl or phenyl, where the indolyl or phenyl radical is unsub-stituted or monosubstituted, disubstituted or trisubstitutbd by halogen, nitro, C1-C4-alkyl or C1-C4-alkoxy, where, in the case of polysubstitution, the radicals are identical or different or R3, if X is -N(R3), is a radical -N(R5)(R6), in which R5 and R6 are identical or different and are hydrogen, C1-C4-alkyl, C1-C3-alkylcarbonyl or phenyl and R3 has the meaning of R3, where the radicals R3 and R3 are identical or different or R3 and R3, together with the nitrogen atom to which they are bonded, are a radical of the formula II
(II) in which n is 1 to 3 and A is O, S, CH2 or -N(R7)-, where R7 is hydrogen, phenyl, C1-C6-alkyl, C2-C6-alkenyl or C2-C6-alkynyl, where these mentioned radicals are unsubstituted or substituted by phenyl which, for its part, is unsubstituted, or monosubstituted or polysubstituted by one or more identical or different sub-stituents selected from the group compri-sing: halogen, nitro, cyano, carboxyl, hydroxyl, methyl, ethyl, methoxy, ethoxy and trifluoromethyl or -N(R8)2, where R8 is hydrogen or C1-C3-alkyl or or -CON(R9)2 or COHNR7, where R9 has the meaning of R6 or where (R9)2 is a C4-C6-alkylene chain in which no CH2 group or a CH2 group which is not directly adjacent to the nitrogen atom is replaced by O, S or N-R6 or where R7 is C1-C4 alkoxycarbonyl or C3-C7-cycloalkyl and in which R2 has the meanlng of R1, where the radicals R1 and R2 are identical or different or R2 is only present in the 4-position, and one of the radicals R3 or R4 is in the 5-position and the physiologically tolerable salts, where the compounds of the general formula I are excluded in which R1 and R2 are identical or different and are carboxyl, its methyl or ethyl esters and its diethylamides.
2. A 2,4- or 2,5-substituted pyridine-N-oxide of the formula I
(I) in which R1 is -C(O)-X-R3, where X is O or -N(R3')- and R3 is hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6 alkynyl, C5-C7-cycloallyl, aryl. or heteroaryl, where these radicals mentioned for R3 are unsubstituted or are substituted by one or two identical or different radicals R4, where R4 is halogen, hydroxyl, cyano, amino, carboxyl, C1-C4-alkoxy, C1-C4-alkoxy-carbonyl, C1-C4-alkyl- or-dialkylamino, or phenyl, where the phenyl radical is unsubstituted or monosubstituted by halogen, C1-C2-alkyl or C1-C2-alkoxy, and R3' has the meaning of R3, where the radicals R3 and R3' are identical or different or R3 and R3', together with the nitrogen atom to which they are bonded, are a radical of the formula II
(II) in which n is 1 to 3 and A is O, CH2 or -N(R7)-, where R7 is hydrogen, phenyl or C1-C5-alkyl, where these mentioned radicals are unsubstituted or sub-stituted by phenyl which, for its part, is unsubstituted, or monosubstituted or polysubstituted by one or more identical or different sub-stituents selected from the group compri-sing: halogen, nitro, cyano, carboxyl, hydroxyl, methyl, ethyl, methoxy, ethoxy and trifluoromethyl R7 is C1-C4-alkoxycarbonyl or C3-C7-cycloalkyl and in which R2 has the meaning of R1, where the radicals R1 and R2 are identical or different or R2 is only present in the 4-position, and one of the radicals R3 or R4 is in the 5-position and the physiologically tolerable salts, where the compounds of the general formula I are excluded in which R1 and R2 are identical or different and are carboxyl, its methyl or ethyl esters and its diethylamides.
(I) in which R1 is -C(O)-X-R3, where X is O or -N(R3')- and R3 is hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6 alkynyl, C5-C7-cycloallyl, aryl. or heteroaryl, where these radicals mentioned for R3 are unsubstituted or are substituted by one or two identical or different radicals R4, where R4 is halogen, hydroxyl, cyano, amino, carboxyl, C1-C4-alkoxy, C1-C4-alkoxy-carbonyl, C1-C4-alkyl- or-dialkylamino, or phenyl, where the phenyl radical is unsubstituted or monosubstituted by halogen, C1-C2-alkyl or C1-C2-alkoxy, and R3' has the meaning of R3, where the radicals R3 and R3' are identical or different or R3 and R3', together with the nitrogen atom to which they are bonded, are a radical of the formula II
(II) in which n is 1 to 3 and A is O, CH2 or -N(R7)-, where R7 is hydrogen, phenyl or C1-C5-alkyl, where these mentioned radicals are unsubstituted or sub-stituted by phenyl which, for its part, is unsubstituted, or monosubstituted or polysubstituted by one or more identical or different sub-stituents selected from the group compri-sing: halogen, nitro, cyano, carboxyl, hydroxyl, methyl, ethyl, methoxy, ethoxy and trifluoromethyl R7 is C1-C4-alkoxycarbonyl or C3-C7-cycloalkyl and in which R2 has the meaning of R1, where the radicals R1 and R2 are identical or different or R2 is only present in the 4-position, and one of the radicals R3 or R4 is in the 5-position and the physiologically tolerable salts, where the compounds of the general formula I are excluded in which R1 and R2 are identical or different and are carboxyl, its methyl or ethyl esters and its diethylamides.
3. A 2,4- or 2,5-substituted pyridine-N-oxide of the formula I
(I) - 23a -in which R1 is -C(O)-X-R3, where X is O or -N(R3')- and R3 is hydrogen, C1-C5-alkyl, C6-cycloalkyl, phenyl or pyridyl, where these radicals mentioned for R3 are unsubstituted or are substituted by one or two identical radicals R4, where R4 is hydroxyl, amino, carboxyl, C1-C4-alkoxy, C1-C4-alkoxycarbonyl or phenyl, where the phenyl radical is unsubstituted or mono-substituted by methyl or methoxy and R3' has the meaning of R3, where the radicals R3 and R3' are identical or different or R3 and R3', together with the nitrogen atom to which they are bonded, are a radical of the formula II
(II) in which n is 2 and A is O or CH2, and in which R2 has the meaning of R1, where the radicals R1 and R2 are identical or different or R2 is only present in the 4-position, and one of the radicals R3 or R4 is in the 5-position and the physiologically tolerable salts, where the compounds of the general formula I are excluded in which R1 and R2 are identical or different and are carboxyl, its methyl or ethyl esters and its diethylamides.
(I) - 23a -in which R1 is -C(O)-X-R3, where X is O or -N(R3')- and R3 is hydrogen, C1-C5-alkyl, C6-cycloalkyl, phenyl or pyridyl, where these radicals mentioned for R3 are unsubstituted or are substituted by one or two identical radicals R4, where R4 is hydroxyl, amino, carboxyl, C1-C4-alkoxy, C1-C4-alkoxycarbonyl or phenyl, where the phenyl radical is unsubstituted or mono-substituted by methyl or methoxy and R3' has the meaning of R3, where the radicals R3 and R3' are identical or different or R3 and R3', together with the nitrogen atom to which they are bonded, are a radical of the formula II
(II) in which n is 2 and A is O or CH2, and in which R2 has the meaning of R1, where the radicals R1 and R2 are identical or different or R2 is only present in the 4-position, and one of the radicals R3 or R4 is in the 5-position and the physiologically tolerable salts, where the compounds of the general formula I are excluded in which R1 and R2 are identical or different and are carboxyl, its methyl or ethyl esters and its diethylamides.
4. A process for the preparation of compounds of the formula I as claimed in claim 1, which comprises a) reacting a compound of the formula III
(III) in which Y is halogen, hydroxyl or alkoxy, with a compound of the formula IV
H-X-R3 (IV) in which X and R3 have the meanings indicated in claim 1, or b) reacting a compound of the formula V
(V) in which Y is halogen, hydroxyl or alkoxy, with a compound of the formula VI
H-X-R3 (VI) in which X and R3 have the meanings indicated in claim 1, if desired introducing a further substituent into the side chain R3 and then converting the compound thus obtained into the N-oxide and if desired then converting the compound thus obtained into a physiologically tolerable salt.
(III) in which Y is halogen, hydroxyl or alkoxy, with a compound of the formula IV
H-X-R3 (IV) in which X and R3 have the meanings indicated in claim 1, or b) reacting a compound of the formula V
(V) in which Y is halogen, hydroxyl or alkoxy, with a compound of the formula VI
H-X-R3 (VI) in which X and R3 have the meanings indicated in claim 1, if desired introducing a further substituent into the side chain R3 and then converting the compound thus obtained into the N-oxide and if desired then converting the compound thus obtained into a physiologically tolerable salt.
5. A 2,4- or 2,5-substituted pyridine-N-oxide of the formula I
(I) in which R1 is -C(O)-X-R3, where X is O or -N(R3)- and R3 is hydrogen, C1-C12-alkyl, C2-C12-alkenyl, C2-C12-alkynyl, non-benzo-fused or banzo-fused C5-C7-cycloalkyl, aryl or heteroaryl, where these radicals mentioned for R3 are unsubstituted or Are substituted by one or more identical or different radicals R4, where R4 is halogen hydroxyl cyano, nitro, nitroxy, amino, carboxyl, C1-C4-alkoxy, C1-C4-alkoxycarbonyl, C1-C4-alkyl- or -dialkylamino, indolyl or phenyl, where the indolyl or phenyl radical is unsub-stituted or monosubstituted, disubstituted or trisubstituted by halogen, nitro, C1-C4-alkyl or C1-C4-alkoxy, where, in the case of polysubstitution, the radicals are identical or different or R3, if X is -N(R3'), is a radical -N(R5)(R6), in which R5 and R6 are identical or different and are hydrogen, C3-C4-alkyl, C1-C3-alkylcarbonyl or phenyl and R3 has the meaning of R3, where the radicals R3 and R3 are identical or different or R3 and R3', together with the nitrogen atom to which they are bonded, are a radical of the formula II
(II) in which n is 1 to 3 and A is O, S, CH2 or -N(R7)-, where R7 is hydrogen, phenyl, C1-C6-alkyl, C2-C6-alkenyl or C2-C6-alkynyl, where these mentioned radicals are unsubstituted or substituted by phenyl which, for its part, is unsubstituted, or monosubstituted or polysubstituted by one or more identical or different sub-stituents selected from the group compri-sing: halogen, nitro, cyano, carboxyl, hydroxyl, methyl, ethyl, methoxy, ethoxy and trifluoromethyl or -N(R8)2, where R8 is hydrogen or C1-C3-alkyl or or -CON(R9)2 or CONHR7, where R9 has the meaning of R8 or where (R9)2 is a C4-C6-alkylene chain in which no CH2 group or a CH2 group which is not dircetly adjacent to the nitrogen atom is replaced by O, S or N-R8 or where R7 is C1-C4-alkoxycarbonyl or C3-C7-cycloalkyl and in which R2 has the meaning of R1, where the radicals R1 and R2 are identical or different or R2 is only present ion the 4-position, and one of the radicals R3 or R4 is in the 5-position and the physiologically tolerable salts for use as medicaments.
(I) in which R1 is -C(O)-X-R3, where X is O or -N(R3)- and R3 is hydrogen, C1-C12-alkyl, C2-C12-alkenyl, C2-C12-alkynyl, non-benzo-fused or banzo-fused C5-C7-cycloalkyl, aryl or heteroaryl, where these radicals mentioned for R3 are unsubstituted or Are substituted by one or more identical or different radicals R4, where R4 is halogen hydroxyl cyano, nitro, nitroxy, amino, carboxyl, C1-C4-alkoxy, C1-C4-alkoxycarbonyl, C1-C4-alkyl- or -dialkylamino, indolyl or phenyl, where the indolyl or phenyl radical is unsub-stituted or monosubstituted, disubstituted or trisubstituted by halogen, nitro, C1-C4-alkyl or C1-C4-alkoxy, where, in the case of polysubstitution, the radicals are identical or different or R3, if X is -N(R3'), is a radical -N(R5)(R6), in which R5 and R6 are identical or different and are hydrogen, C3-C4-alkyl, C1-C3-alkylcarbonyl or phenyl and R3 has the meaning of R3, where the radicals R3 and R3 are identical or different or R3 and R3', together with the nitrogen atom to which they are bonded, are a radical of the formula II
(II) in which n is 1 to 3 and A is O, S, CH2 or -N(R7)-, where R7 is hydrogen, phenyl, C1-C6-alkyl, C2-C6-alkenyl or C2-C6-alkynyl, where these mentioned radicals are unsubstituted or substituted by phenyl which, for its part, is unsubstituted, or monosubstituted or polysubstituted by one or more identical or different sub-stituents selected from the group compri-sing: halogen, nitro, cyano, carboxyl, hydroxyl, methyl, ethyl, methoxy, ethoxy and trifluoromethyl or -N(R8)2, where R8 is hydrogen or C1-C3-alkyl or or -CON(R9)2 or CONHR7, where R9 has the meaning of R8 or where (R9)2 is a C4-C6-alkylene chain in which no CH2 group or a CH2 group which is not dircetly adjacent to the nitrogen atom is replaced by O, S or N-R8 or where R7 is C1-C4-alkoxycarbonyl or C3-C7-cycloalkyl and in which R2 has the meaning of R1, where the radicals R1 and R2 are identical or different or R2 is only present ion the 4-position, and one of the radicals R3 or R4 is in the 5-position and the physiologically tolerable salts for use as medicaments.
6. A 2,4- or 2,5-substituted pyridine-N-oxide of the formula I
(I) in which R1 is -C(O)-X-R3, where X is O or -N(R3+)- and R3 is hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C5-C7-cycloalkyl, aryl or hexeroaxyl, where these radicals mentioned for R3 are unsubstituted or are substituted by one or two identical or different radicals R4, where R4 is halogen, hydroxyl, cyano, amino, carbonyl, C1-C4-alkoxy, C1-C4-alkoxy-carbonyl, C1-C4-alkyl or dialkylamino, or phenyl, where the phenyl radical is unsubstituted or monosubstituted by halogen, C1-C2-alkyl or C1-C2-alkoxy, and R3' has the meaning of R3, where the radicals R3 and R3' are identical or different or R3 and R3, together with the nitrogen atom to which they are bonded, are a radical of the formula II
(II) in which n is 1 to 3 and A is O, CH2 or -N(R7)-, where R7 is hydrogen, phenyl or C1-C6-alkyl, where these mentioned radicals are unsubstituted or sub-stituted by phenyl which, for its part, is unsubstituted, or monosubstituted or polysubstituted by one or more identical or different sub-stituents selected from the group compri-sing: halogen, nitro, cyano, carboxyl, hydroxyl, methyl, ethyl, methoxy, ethoxy and trifluoromethyl R7 is C1-C4-alkoxycarbonyl or C3-C7-cycloalkyl and in which R2 has the meaning of R1, where the radicals R1 and R2 are identical or different or R2 is only present in the 4-position, and one of the radicals R3 or R4 is in the 5-position and the physiologically tolerable salts, for the inhibi-tion of proline hydroxylase and lysine hydroxylase.
(I) in which R1 is -C(O)-X-R3, where X is O or -N(R3+)- and R3 is hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C5-C7-cycloalkyl, aryl or hexeroaxyl, where these radicals mentioned for R3 are unsubstituted or are substituted by one or two identical or different radicals R4, where R4 is halogen, hydroxyl, cyano, amino, carbonyl, C1-C4-alkoxy, C1-C4-alkoxy-carbonyl, C1-C4-alkyl or dialkylamino, or phenyl, where the phenyl radical is unsubstituted or monosubstituted by halogen, C1-C2-alkyl or C1-C2-alkoxy, and R3' has the meaning of R3, where the radicals R3 and R3' are identical or different or R3 and R3, together with the nitrogen atom to which they are bonded, are a radical of the formula II
(II) in which n is 1 to 3 and A is O, CH2 or -N(R7)-, where R7 is hydrogen, phenyl or C1-C6-alkyl, where these mentioned radicals are unsubstituted or sub-stituted by phenyl which, for its part, is unsubstituted, or monosubstituted or polysubstituted by one or more identical or different sub-stituents selected from the group compri-sing: halogen, nitro, cyano, carboxyl, hydroxyl, methyl, ethyl, methoxy, ethoxy and trifluoromethyl R7 is C1-C4-alkoxycarbonyl or C3-C7-cycloalkyl and in which R2 has the meaning of R1, where the radicals R1 and R2 are identical or different or R2 is only present in the 4-position, and one of the radicals R3 or R4 is in the 5-position and the physiologically tolerable salts, for the inhibi-tion of proline hydroxylase and lysine hydroxylase.
7. A 2,4- or 2,5-substituted pyridine-N-oxide of the formula I
(I) - 30a -in which R1 is -C(O)-X-R3, where X is O or -N(R3') and R3 is hydrogen, C1-C5-alkyl, C6-cycloalkyl, phenyl or pyridyl, where these radicals mentioned for R3 are unsubstituted or are substituted by one or two identical radicals R4, where R4 is hydroxyl, amino, carboxyl, C1-C4-alkoxy, C1-C4-alkoxycarbonyl or phenyl, where the phenyl radical is unsubstituted or mono-substituted by methyl or methoxy and R3 has the meaning of R3, where the radicals R3 and R3' are identical or different or R3 and R3', together with the nitrogen atom to which they are bonded, are a radical of the formula II
(II) in which n is 2 and A is O or CH2, and in which R2 has the meaning of R1, where the radicals R1 and R2 are identical or different or R2 is only present in the 4-position, and one of the radicals R3 or R4 is in the 5-position and the physiologically tolerable salts, for use as fibrosuppressives and immunosuppresives.
(I) - 30a -in which R1 is -C(O)-X-R3, where X is O or -N(R3') and R3 is hydrogen, C1-C5-alkyl, C6-cycloalkyl, phenyl or pyridyl, where these radicals mentioned for R3 are unsubstituted or are substituted by one or two identical radicals R4, where R4 is hydroxyl, amino, carboxyl, C1-C4-alkoxy, C1-C4-alkoxycarbonyl or phenyl, where the phenyl radical is unsubstituted or mono-substituted by methyl or methoxy and R3 has the meaning of R3, where the radicals R3 and R3' are identical or different or R3 and R3', together with the nitrogen atom to which they are bonded, are a radical of the formula II
(II) in which n is 2 and A is O or CH2, and in which R2 has the meaning of R1, where the radicals R1 and R2 are identical or different or R2 is only present in the 4-position, and one of the radicals R3 or R4 is in the 5-position and the physiologically tolerable salts, for use as fibrosuppressives and immunosuppresives.
8. A pharmaceutical composition containing a compound of the formula I as claimed in claim 5 and a pharmaceutically tolerable carrier.
9. The use of compounds of the formula I as claimed in claim 5 for influencing the metabolism of collagen and collagen-like substances or the biosynthesis of Clq.
10. The use of compounds of the formula I as claimed in claim 5 for the treatment of disorders of the metobolism of collagen and collagen-like substances or the bio-synthesis of Clq.
11. A process for the production of a pharmaceutical composition as claimed in claim 8, which comprises converting a compound of the formula I as claimed in claim 1 and a pharmaceutically tolerable carrier into suitable administration form.
12. A 2,4- or 2,5-substituted pyridine-N-oxide as claimed in claim 1 and substantially as described herein.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4020570.3 | 1990-06-28 | ||
| DE4020570A DE4020570A1 (en) | 1990-06-28 | 1990-06-28 | 2,4- AND 2,5-SUBSTITUTED PYRIDINE-N-OXIDES, METHOD FOR THE PRODUCTION AND USE THEREOF |
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|---|---|
| CA2045868A1 true CA2045868A1 (en) | 1991-12-29 |
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| CA002045868A Abandoned CA2045868A1 (en) | 1990-06-28 | 1991-06-27 | 2,4- and 2,5-substituted pyridine-n-oxides, processes for their preparation and their use |
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| JP (1) | JPH0832687B2 (en) |
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| AU (1) | AU636990B2 (en) |
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| CA (1) | CA2045868A1 (en) |
| CZ (1) | CZ283782B6 (en) |
| DE (2) | DE4020570A1 (en) |
| DK (1) | DK0463592T3 (en) |
| EG (1) | EG19851A (en) |
| ES (1) | ES2061118T3 (en) |
| FI (1) | FI101070B (en) |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5607954A (en) * | 1992-03-24 | 1997-03-04 | Hoechst Aktiengesellschaft | Sulfonamido- and sulfonamidocarbonylpyridine-2-carboxamides and their pyridine-n-oxides, process for their preparation and their use as pharmaceuticals |
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|---|---|---|---|---|
| YU9492A (en) * | 1991-02-05 | 1995-03-27 | Hoechst Ag. | 2,4- and 2,5-BIS-TETRAZOLYL pyridines and the process for their preparation |
| CA2085954A1 (en) * | 1991-12-24 | 1993-06-25 | Klaus Weidmann | Substituted pyridine n-oxides, processes for their preparation, and their use |
| TW222585B (en) * | 1992-09-11 | 1994-04-21 | Hoechst Ag | |
| DE4233124A1 (en) * | 1992-10-02 | 1994-04-07 | Hoechst Ag | Acylsulfonamido and sulfonamidopyridine-2-carboxylic acid esters and their pyridine N-oxides, processes for their preparation and their use as medicaments |
| DE19624659A1 (en) | 1996-06-20 | 1998-01-08 | Klinge Co Chem Pharm Fab | New pyridylalkene and pyridylalkanoic acid amides |
| US6451816B1 (en) | 1997-06-20 | 2002-09-17 | Klinge Pharma Gmbh | Use of pyridyl alkane, pyridyl alkene and/or pyridyl alkine acid amides in the treatment of tumors or for immunosuppression |
| DE19624704A1 (en) | 1996-06-20 | 1998-01-08 | Klinge Co Chem Pharm Fab | New pyridylalkanoic acid amides |
| FR2766187B1 (en) * | 1997-07-17 | 2000-06-02 | Rhone Poulenc Rorer Sa | PYRAZINE DERIVATIVES, THEIR PREPARATION AND THE MEDICINES CONTAINING THEM |
| US6903118B1 (en) | 1997-12-17 | 2005-06-07 | Klinge Pharma Gmbh | Piperazinyl-substituted pyridylalkane, alkene and alkine carboxamides |
| DE19756212A1 (en) | 1997-12-17 | 1999-07-01 | Klinge Co Chem Pharm Fab | New cyclic imide-substituted pyridylalkane, alkene and alkyarboxylic acid amides |
| DE19756235A1 (en) | 1997-12-17 | 1999-07-01 | Klinge Co Chem Pharm Fab | New piperidinyl-substituted pyridylalkane alkene and alkane carboxylic acid amides |
| DE19756261A1 (en) | 1997-12-17 | 1999-07-01 | Klinge Co Chem Pharm Fab | New aryl-substituted pyridylalkane, alkene and alkyarboxylic acid amides |
| EP1031564A1 (en) | 1999-02-26 | 2000-08-30 | Klinge Pharma GmbH | Inhibitors of cellular nicotinamide mononucleotide formation and their use in cancer therapy |
| JP2004518723A (en) | 2001-02-14 | 2004-06-24 | ワーナー−ランバート・カンパニー、リミテッド、ライアビリティ、カンパニー | Pyrimidine matrix metalloproteinase inhibitors |
| DOP2002000332A (en) | 2001-02-14 | 2002-08-30 | Warner Lambert Co | MATRIX METALOPROTEINAS PYRIDINE INHIBITORS |
| DOP2002000333A (en) | 2001-02-14 | 2002-09-30 | Warner Lambert Co | DERIVATIVES OF ISOFTALIC ACID AS INHIBITORS OF METALOPROTEINASES OF THE MATRIX |
| US6924276B2 (en) | 2001-09-10 | 2005-08-02 | Warner-Lambert Company | Diacid-substituted heteroaryl derivatives as matrix metalloproteinase inhibitors |
| BR0213233A (en) | 2001-10-12 | 2005-01-04 | Warner Lambert Co | Matrix metalloproteinase inhibitor alkynes |
| US6933298B2 (en) | 2001-12-08 | 2005-08-23 | Aventis Pharma Deutschland Gmbh | Pyridine-2,4-dicarboxylic acid diamides and pyrimidine-4,6-dicarboxylic acid diamides and the use thereof for selectively inhibiting collagenases |
| DE10160357A1 (en) * | 2001-12-08 | 2003-06-18 | Aventis Pharma Gmbh | Use of pyridine-2,4-dicarboxylic acid diamides and pyrimidine-4,6-dicarboxylic acid diamides for the selective inhibition of collagenases |
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| JPS5623987B2 (en) * | 1972-02-04 | 1981-06-03 | ||
| JPS6052702B2 (en) | 1976-08-27 | 1985-11-20 | 中外製薬株式会社 | Pyridine derivatives and their manufacturing method |
| JPS57109792A (en) * | 1980-12-26 | 1982-07-08 | Banyu Pharmaceut Co Ltd | Penicillin derivative and salt thereof |
| 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 |
| JP2512924B2 (en) * | 1987-01-21 | 1996-07-03 | 萬有製薬株式会社 | Hair restorer |
| 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 |
| 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 |
| 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 |
| JP2600786B2 (en) * | 1988-04-12 | 1997-04-16 | 萬有製薬株式会社 | Hair restorer |
| DE3826471A1 (en) | 1988-08-04 | 1990-02-22 | Hoechst Ag | Improved process for the preparation of N,N'-bis(alkoxyalkyl)pyridine-2,4-dicarboximides |
| 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 |
| ZA91291B (en) | 1990-01-16 | 1991-09-25 | Hoechst Ag | Di(nitroxyalkyl)amides of pyridine-2,4-and-2,5-dicarboxylic acids,a process for the preparation thereof,and the use thereof |
-
1990
- 1990-06-28 DE DE4020570A patent/DE4020570A1/en not_active Withdrawn
-
1991
- 1991-06-22 ES ES91110343T patent/ES2061118T3/en not_active Expired - Lifetime
- 1991-06-22 DK DK91110343.0T patent/DK0463592T3/en active
- 1991-06-22 EP EP91110343A patent/EP0463592B1/en not_active Expired - Lifetime
- 1991-06-22 DE DE59102547T patent/DE59102547D1/en not_active Expired - Fee Related
- 1991-06-22 AT AT91110343T patent/ATE110059T1/en not_active IP Right Cessation
- 1991-06-26 NZ NZ238701A patent/NZ238701A/en unknown
- 1991-06-26 IL IL9862991A patent/IL98629A/en not_active IP Right Cessation
- 1991-06-26 CZ CS911959A patent/CZ283782B6/en not_active IP Right Cessation
- 1991-06-26 FI FI913118A patent/FI101070B/en active IP Right Grant
- 1991-06-26 MY MYPI91001142A patent/MY107573A/en unknown
- 1991-06-26 EG EG39291A patent/EG19851A/en active
- 1991-06-27 CN CN91104308A patent/CN1038585C/en not_active Expired - Fee Related
- 1991-06-27 IE IE225391A patent/IE65300B1/en unknown
- 1991-06-27 CA CA002045868A patent/CA2045868A1/en not_active Abandoned
- 1991-06-27 JP JP3156562A patent/JPH0832687B2/en not_active Expired - Lifetime
- 1991-06-27 HU HU912158A patent/HU214627B/en not_active IP Right Cessation
- 1991-06-27 MX MX2641591A patent/MX26415A/en unknown
- 1991-06-27 YU YU113391A patent/YU113391A/en unknown
- 1991-06-27 NO NO912541A patent/NO178026C/en not_active IP Right Cessation
- 1991-06-27 AU AU79356/91A patent/AU636990B2/en not_active Ceased
- 1991-06-27 ZA ZA914958A patent/ZA914958B/en unknown
- 1991-06-27 MA MA22469A patent/MA22191A1/en unknown
- 1991-06-27 BR BR919102699A patent/BR9102699A/en not_active Application Discontinuation
- 1991-06-27 PT PT98108A patent/PT98108B/en not_active IP Right Cessation
- 1991-06-28 KR KR1019910010858A patent/KR920000724A/en not_active Withdrawn
-
1993
- 1993-11-12 LT LTIP1464A patent/LT3918B/en not_active IP Right Cessation
-
1994
- 1994-10-19 HR HRP-1133/91A patent/HRP940701B1/en not_active IP Right Cessation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5607954A (en) * | 1992-03-24 | 1997-03-04 | Hoechst Aktiengesellschaft | Sulfonamido- and sulfonamidocarbonylpyridine-2-carboxamides and their pyridine-n-oxides, process for their preparation and their use as pharmaceuticals |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |