IL98629A - 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
- IL98629A IL98629A IL9862991A IL9862991A IL98629A IL 98629 A IL98629 A IL 98629A IL 9862991 A IL9862991 A IL 9862991A IL 9862991 A IL9862991 A IL 9862991A IL 98629 A IL98629 A IL 98629A
- Authority
- IL
- Israel
- Prior art keywords
- radicals
- different
- phenyl
- formula
- unsubstituted
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 14
- 238000002360 preparation method Methods 0.000 title claims description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 43
- 229920001436 collagen Polymers 0.000 claims abstract description 14
- 108010035532 Collagen Proteins 0.000 claims abstract description 13
- 102000008186 Collagen Human genes 0.000 claims abstract description 13
- 239000000126 substance Substances 0.000 claims abstract description 8
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical class [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000011282 treatment Methods 0.000 claims abstract description 7
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 6
- 230000004060 metabolic process Effects 0.000 claims abstract description 4
- -1 nitro, nitroxy, amino, carboxyl Chemical group 0.000 claims description 36
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 18
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 18
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- 150000002367 halogens Chemical class 0.000 claims description 17
- 102000004079 Prolyl Hydroxylases Human genes 0.000 claims description 15
- 108010043005 Prolyl Hydroxylases Proteins 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 13
- 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
- 150000003839 salts Chemical class 0.000 claims description 11
- 102000008490 2-Oxoglutarate 5-Dioxygenase Procollagen-Lysine Human genes 0.000 claims description 10
- 108010020504 2-Oxoglutarate 5-Dioxygenase Procollagen-Lysine Proteins 0.000 claims description 10
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 7
- 230000005764 inhibitory process Effects 0.000 claims description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 125000001041 indolyl group Chemical group 0.000 claims description 6
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims description 5
- 150000003222 pyridines Chemical class 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical class CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 4
- 125000004494 ethyl ester group Chemical group 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
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- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 125000006711 (C2-C12) alkynyl group Chemical group 0.000 claims description 2
- 150000001204 N-oxides Chemical class 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
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- 125000003545 alkoxy group Chemical group 0.000 claims 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 2
- 125000004076 pyridyl group Chemical group 0.000 claims 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 1
- 125000006710 (C2-C12) alkenyl group Chemical group 0.000 claims 1
- 125000004663 dialkyl amino group Chemical group 0.000 claims 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims 1
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
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- 229920000642 polymer Polymers 0.000 description 1
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- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
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- 238000011321 prophylaxis Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 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
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002511 suppository base 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
- 239000000814 tuberculostatic agent Substances 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
- 230000003442 weekly effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
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- 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
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- 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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- Obesity (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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- Preparation Of Compounds By Using Micro-Organisms (AREA)
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- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
2,4- and 2,5-substituted pyridine N-oxides which have fibrosuppressive and immunosuppressive activity are presented. The said compounds are likewise suitable for the treatment of disturbances of the metabolism of collagen and collagen-like substances and of the biosynthesis of C1q.
Description
2,4- AND 2,5-SUBSTITUTED PYRIDINE-N-OXIDES, PROCESSES FOR THEI PREPARATION AND THEIR USE enn'e i wa:>n¾ ΪΙ Ο>Β ,ηηοηιο -s,2-i -4,2 nmamv- N -ιπη>ο HOECHST AKTIENGESELLSCHAFT HOE 90/F 192 Dr. Fi/PP Description 2,4- and 2 ,5-substituted pyridine-N-oxides, processes for their preparation and their use Compounds which inhibit the enzymes proline hydroxylase and lysine hydroxylase cause a very selective inhibition of collagen biosynthesis by influencing collagen-specific hydroxylation reactions. In the course thereof, protein-bound proline or lysine is hydroxylated by the enzymes proline hydroxylase or lysine hydroxylase. If this reaction is suppressed by inhibitors, a non-functional, underhydroxylated collagen molecule is formed, which can be released into the extracellular space by the cells only to a small extent. In addition, the underhydroxylated collagen cannot be incorporated into the collagen matrix and is very easily degraded by proteolysis. As a result of these effects, the amount of collagen stored extracellularly is on the whole reduced.
Inhibitors of prolyl hydroxylase are therefore suitable substances in the treatment of disorders in which the storage of collagens contributes decisively to the symptoms. These include, inter alia, fibroses of the lungs, liver and skin (scleroderma) and atherosclerosis.
It is known that the inhibition of proline hydroxylase by known inhibitors such as α , a '-dipyridyl leads to an inhibition of CI, biosynthesis by macrophages (W. Miiller et al., FEBS Lett. 90 (1978), 218; Immunbiology 155 (1978), 47). As a result, a failure of the classical route of complement activation occurs. Inhibitors of proline hydroxylase therefore also act as immunosuppressives, 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 ( . Majamaa et al., - 2 - 98629/2 Eur. J. Biochem. 138 (1984) 239-245). However, these compounds are effective in cell culture as inhibitors only in very high concentrations (Tschank, G. et al., Biochem. J. 238 (1987) 625-633).
DE-A 3, 32 , 094 describes pyridine-2, 4- and -2,5-dicar-boxylic acid diesters having 1-6 carbon atoms in the ester alkyl moiety as pharmaceuticals for the inhibition of proline hydroxylase and lysine hydroxylase.
However, these lower-alkylated diesters have the disadvantage that they are cleaved to the acids too rapidly in the organism and do not reach their site of action in the cell in sufficiently high concentration and are therefore less suitable for possible administration as pharmaceuticals .
DE-A 3,703,959, corresponding to IL 85362, DE-A 3,703,962 corresponding to IL 85360 and DE-A 3,703,963, corresponding to IL 85361 describe in general form mixed ester/amides , igher alky lated diesters and diamides of pyridine-2, - and -2,5-dicarboxylic acid, which effectively inhibit, collagen biosynthesis in the animal model. Thus, DE-A 3,703,959, inter alia, describes the synthesis of N,N ' -bis ( 2-methoxyethyl )pyridine-2 , 4-dicarboxamide and N,N ' -bis ( 3-isopropoxypropyl )pyridine-2 , 4-dicarboxamide .
An improved process for the preparation of Ν,Ν' -bis ( 2-methoxyethyl )pyridine-2 , 4-dicarboxamide is proposed in German Patent Applications P 38 26 471.4 and p38 28 140.6 corresponding to IL 91185.
German Patent Application P 39 24 093.2 proposes novel N, N ' -bis ( alkoxyalkyl )pyridine-2 , 4-dicarboxamides .
German Patent Application P 40 01 002.3 describes the use of N,N'-(nitroxyalkyl)pyridine-2,4- and -2 , 5-dicarbox-amides for the preparation of pharmaceuticals inhibiting proline hydroxylase and lysine hydroxylase.
Both pyridine-2 , - and -2 , 5-dicarboxamide (Hirakata et al., J. pharm. Soc. Japan 77 (1957) 219 and HSring et al., Helv. 37 (1954) 147, 153) and pyridine-2,4- and -2 ,5-dicarboxylic acid dihydrazide (Itai et al., Bl. nation, hyg. Labor. Tokyo, 74 (1956) 115, 117 and Shinohara et al., Chem. High Polymers Japan, 15 (1958) 839) are already known as antituberculosis agents.
JP 53/28175 (78/28175) describes N,N'-bis(2-nitrooxy-ethyl)pyridine-2,4- and -2,5-dicarboxamides as substances having vasodilatory action.
Surprisingly, it has now been found that 2,4- and 2,5-substituted pyridine-N-oxides of the general formula I indicated below and the physiologically tolerable salts effectively inhibit lysine hydroxylase and proline hydroxylase in the animal model.
The invention accordingly relates to 2,4- and 2,5-sub-stituted pyridine-N-oxides of the general formula I -C(0)-X-R3, where is 0 or -N(R3' ) - and is hydrogen, Cj-Cjj-alkyl, 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 R*, where is halogen, hydroxy!, cyano, nitro, nitroxy, amino, carboxyl, Cx-C^-alkoxy, -dialkylamino, indolyl or phenyl, where the indolyl or phenyl radical is unsub- stituted or monosubstituted, disubstituted or trisubstituted by halogen, nitro, C--C*- alkyl or where, in the case of polyeubstitution, 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, Cx-CA-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 in which n is 1 to 3 and A is 0, S, CH2 or -N(R7)-, where R7 is hydrogen, phenyl, Ci-Ce-alkyl, C2-C6-alkenyl or C2-C6-alkynyl/ where these mentioned alkyl, alkenyl or alkynyl radicals are unsubstituted or substituted by phenyl which phenyl is unsubstituted, or monosubstituted or polysubstituted by one or more identical or different substituents selected from the groups comprising: halogen, nitro, cyano, carboxyl, hydroxyl, methyl, ethyl, methoxy, ethoxy and trifluoromethyl , or R7 designates: -N(R8)2, where R8 is hydrogen or C].-C3-alkyl; or-C00R8 or -CON (R$)2 or C0NHR7, where R9 has the meaning of R8 or where (R9)2 s a C4-Ce-alkylene chain in which no CH2 group or a CH2 group which is not directly adjacent to the nitrogen atom is replaced by 0, S or N-R8; or where R7 is C1-C^-alkoxycarbonyl or C3-C7-cycloalkyl and in which has the meaning of R1, where the radicals R1 and - O - ¾8629/2 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, excluding pyridine-2-carboxyl-4-octyl-carbox amide-N-oxide 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.
The invention furthermore relates to the use of compounds of the general formula I and the physiologically tolerable salts for the production of a pharmaceutical inhibiting proline hydroxylase and lysine hydroxylase.
Finally, the invention relates to the compounds of the general formula I for use as pharmaceuticals.
The invention relates in particular to the compounds of the formula I for use as fibrosuppressives and immunosuppressives and also for the inhibition of proline hydroxylase and lysine hydroxylase and for influencing the metabolism of collagen and collagen-like substances or the biosynthesis of Clg.
All said alkyl radicals having more than 2 carbon atoms can be either straight-chain or branched.
The invention furthermore relates to a process for the preparation of compounds of the general formula I.
The compounds according to the invention are most simply prepared by adding oxidants such as, for example, hydrogen peroxide or peracids such as peracetic acid, per-fluoroacetic acid, perbenzoic acid or metachloroper-benzoic acid in solvents such as chlorinated hydrocarbons, such as, for example, methylene chloride, chloroform, tri- or tetrachloroethylene, benzene or toluene, to the pyridine compounds to be oxidized, which can likewise be dissolved in the abovementioned solvents, and stirring at a temperature between -30 and +40eC, preferably between 0 and +25°C, for between 30 minutes and 3 days. Completion of the reaction can be determined, for example, by means of thin layer chromatography. The compounds according to the invention can preferably be prepared by employing the pyridine derivative and the oxidant in eguimolar amounts or up to an about 5-fold excess of oxidant.
If appropriate, an excess of peracid can also be eliminated by introducing, for example, gaseous ammonia into the reaction solution and separating the resulting precipitate from the reaction solution by filtration.
If appropriate, the products can be worked up, for example, by extraction or by chromatography, for example by means of silica gel. The isolated product can be recrystallized.
A general procedure for this oxidation method is also described, for example, in "E. Lingsberg, Pyridine and its Derivatives, Interscience Publishers, New Tork, 1961, Part 2, 93".
Oxidation with hydrogen peroxide is described, for example, in "E. Ochiai, J. Org. Chem. 18, 534 (1953)".
The preparation of the different pyridine derivatives necessary for the oxidation described is set out in the Patent Applications already cited as prior art. Those 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 fibrosuppressive, immunosuppressive and antiatherosclerotic.
The antifibrotic action can be determined in the carbon tetrachloride-induced liver fibrosis model. For this purpose, rats are treated twice weekly with CC14 (1 ml/kg) - dissolved in olive oil. The test substance is administered daily, if appropriate even twice daily, orally or intraperitoneally - dissolved in a suitable tolerable solvent. The extent of liver fibrosis is determined histologically and the proportion of collagen in the liver is analyzed by hydroxyproline determination - as described in Kivirikko et al. (Anal. Biochem. 19, 249 et seq. (1967)). The fibrogenesis activity can be determined by radioimmunological determination of collagen fragments and procollagen peptides in the serum. The compounds according to the invention are effective in this model in concentrations of 1 - 100 mg/kg.
The fibrogenesis activity can be determined by radioimmunological determination of the N-terminal propeptide of type III collagen or of the N- or C-terminal cross-linking domain of type IV collagen (7s collagen or type IV collagen-NCx) in the serum.
For this purpose, the hydroxyproline, procollagen III peptide, 7s-collagen and type IV collagen-NC^ concentrations in the liver of a) untreated rats (control) b) rats to which carbon tetrachloride was administered (CC14 control) c) rats to which first CC14 and then a compound according to the invention was administered were measured (this test method is described by Rouiller, C, experimental toxic injury of the liver; in The Liver, C. Rouiller, Vol. 2, pp. 335-476, New Tork, Academic Press, 1964).
Another model for the evaluation of antifibrotic action is bleomycin-induced lung fibrosis as described in Kelley et al. (J. Lab. Clin. Med. 96, 954, (1980)). The cotton pellet granuloma model, as described in Meier et al., Experientia 6, 469 (1950) can be used to evaluate the action of the compounds according to the invention in the granulation tissue.
The compounds of the formula I can be used as medicaments in the form of pharmaceutical preparations which contain them, if appropriate together with tolerable pharmaceutical carriers. The compounds can be used as medicaments, for example in the form of pharmaceutical preparations, which contain these compounds in a mixture with a pharmaceutical organic or inorganic carrier suitable for enteral, percutaneous or parenteral administration, such as, for example, water, gum arabic, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, poly-alkylene glycols, petroleum jelly etc.
For this purpose, they can be administered orally in doses of 0.1 - 25 mg/kg/day, preferably 1 - 5 mg/kg/day or parenterally in doses of 0.01 - 5 mg/kg/day, pre-ferably 0.01 - 2.5 mg/kg/day, in particular 0.5 -1.0 mg/kg/day. In severe cases, the dosage can also be increased. In many cases, however, lower doses are also sufficient. This information relates to an adult weighing about 75 kg.
The invention furthermore includes the use of the compounds according to the invention in the production of pharmaceuticals which are employed for the treatment and prophylaxis of the abovementioned metabolic disorders.
The invention further relates to pharmaceuticals which contain one or more compounds of the formula I according to the invention and/or their physiologically tolerable salts .
The pharmaceuticals are prepared by processes which are known per se and which are familiar to the person skilled in the art. As pharmaceuticals, the pharmacologically active compounds according to the invention are employed either as such or preferably in combination with suitable pharmaceutical auxiliaries or excipients in the form of tablets, coated tablets, capsules, suppositories, emulsions, suspensions or solutions, the active compound content being up to about 95%, advantageously between 10 and 75%.
In addition to solvents, gel-forming agents, suppository bases, tablet auxiliaries and other active compound carriers, suitable auxiliaries or excipients for the desired pharmaceutical formulation are also, for example, antioxidants, dispersants, emulsifiers, antifoams, flavor correctants, preservatives, solubilizers or colorants.
The active compounds can be administered orally, paren-terally or rectally.
The active compounds are mixed with the additives suitable for this purpose, such as excipients, stabilizers or inert diluents and brought into suitable administration forms, such as tablets, coated tablets, hard gelatin capsules, aqueous alcoholic or oily suspensions or aqueous or oily solutions, by the customary methods .
Inert excipients which can be used are, for example, gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. In this case, preparation can be carried out both as dry and as moist granules. Possible oily excipients or solvents are, for example, vegetable or animal oils, such as sunflower oil or cod liver oil.
For subcutaneous or intravenous administration, the active compounds are brought into solution, suspension or emulsion, if desired using the substances suitable for this such as solubilizers, emulsifiers or other auxiliaries. Suitable solvents are, for example, physiological saline solution or alcohols, for example ethanol, propanol or glycerol, and in addition also sugar solutions such as glucose or mannitol solutions, or, alterna-tively, a mixture of the various solvents mentioned.
The invention is illustrated in more detail below by Examples .
General procedure for the preparation of the compounds 1 equivalent of pyridine derivative (for preparation see description) is initially introduced in methylene chloride and 1 equivalent of metachloroperbenzoic acid (MCPBA) , dissolved in methylene chloride, is added dropwise at room temperature. The mixture is stirred at room temperature. After 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 is dried with magnesium sulfate and concentrated.
The crude product is recrystallized or purified by means of thin layer chromatography.
The compounds mentioned in the following Examples are prepared according to this general procedure.
Example 1 N , N ' -Di- ( 2-methoxyethyl ) pyridine-2 , 4-dicarboxamide N-oxide From 1 g of N,N'-di-(2-methoxyethyl)pyridine-2,4-dicarboxamide and 0.62 g of MCPBA.
Yield: 620 mg (chromatography: ethyl acetate/methanol 5:1) M.p.: 102eC Example 2 , N ' -Di- ( 3-methoxypropyl )pyridine-2 , 4-dicarboxamide N-oxide From 1 g of Ν,Ν'-di-( 3-methoxypropyl)pyridine-2 ,4-dicarb-oxamide and 1.2 g of MCPBA.
Yield: 0.58 g (recrystallization: ethanol) M.p.: 90eC Example 3 Pyridine-2, 4-dicarboxamide N-oxide From 1 g of pyridine-2, 4-dicarboxamide and 1.2 g of MCPBA.
Yield: 0.8 g (recrystallization: ethanol) M.p.: 260eC Example 4 N,N ' -Di- ( 2-dimethoxyethyl )pyridine-2 , 4-dicarboxamide N-oxide From 1 g of N, ' -di- (2-dimethoxyethyl)pyridine-2 ,4-dicarboxamide and 1.1 g of MCPBA.
Yield: 0.5 g (chromatography: ethyl acetate/methanol 5:1) M.p.: 86eC Example 5 N , N ' -Di- ( 3-ethoxypropyl ) pyridine-2 , 4-dicarboxamide N-oxide From 1 g of N,N'-di-(3-ethoxypropyl)pyridine-2,4-dicarboxamide and 1.5 g of MCPBA.
Tield: 0.34 g (chromatographyt ethyl acetate/methanol 5.1) M.p.: 81eC Example 6 , N ' -Di- ( 2-methoxyethyl ) pyridine-2 , 5-dicarboxamide N-oxide From 1 g of N,N'-di-( 2-methoxyethyl)pyridine- 2 ,4-dicarboxamide and 1.3 g of MCPBA.
Yield: 0.4 g (recrystallization: ethanol) M.p.: 137eC Example 7 Di-( 2-methoxyethyl) pyridine-2,4-dicarboxylate N-oxide From 1 g of di-(2-methoxyethyl) pyridine-2,4-dicarboxy-late and 1.3 g of MCPBA.
Yield: 0.2 g (chromatography: ethyl acetate) M.p.: oil From 1 g of N,N'-diethylpyridine-2,5-dicarboxamide and 1.8 g of MCPBA.
Yield: 0.4 g (recrystallization: ethanol) M.p.: 128eC Example 9 N,N ' -Di- ( 3-methoxypropyl)pyridine-2 ,5-dicarboxamide N- oxide From 1 g of N,N'-di-(3-methoxypropyl)pyridine-2,5-dicarboxamide and 1.2 g of MCPBA.
Yield: 0.3 g (recrystallization: diethyl ether/methanol) M.p.: 123eC Example 10 2,4-Di-[ (morpholin-l-yl)carbonyl]pyridine N-oxide From 1 g of 2 , 4-di-[ (morpholin-l-yl)carbonyl]pyridine and 1,2 g of MCPBA.
Yield: 0.5 g (chromatography: ethyl acetate/methanol 5/1) M.p.: oil Example 11 Μ,Ν' -Di- (4-hydroxybutyl ) pyridine-2 , 4-dicarboxamide N-oxide Prom 1 g of Ν,Ν' -di-(4-hydroxybutyl)pyridine-2,4-dicarb-oxamide and 0.8 g of MCPBA.
Yield: 0.82 g (ethanol) M.p.: 88eC Example 12 Ν,Ν' -Dicyclohexylpyridine-2,4-dicarboxamide N-oxide From 1 g of Ν,Ν' -dicyclohexylpyridine-2,4-dicarboxamide and 0 g of MCPBA.
Yield: 0.59 g (ethanol) M.p.: 153eC Example 13 , ' -Di- ( 3-chlorobenzyl ) pyridine-2 , 4-dicarboxamide N-oxide From 1 g of N,N'-di-( 3-chlorobenzyl)pyridine-2,4-dicarboxamide and 0.65 g of MCPBA.
Yield: 0.76 g (toluene) M.p.: 112eC Example 17 Di- (methoxycarbonylmethyl) pyridine-2 ,4-dicarboxylate N-oxide From 1 g of di-(methoxycarbonylmethyl) pyridine-2,4-di-carboxylate and 1.1 g of MCPBA.
Yield: 0.81 g Oil, MS = 328 (M+H) molecular weight 327 Example 18 Pharmacological activity In order to show the efficient inhibition of proline hydroxylase and lysine hydroxylase by the compounds according to the invention, the concentrations of bilirubin, bile acids and gamma 6T in the serum of a) untreated rats (control ) , b) rats treated with CC14, c) rats to which first CC1 and then a compound according to the invention have been given, are measured. (The method is described by Rouiller, C, Experimental toxic injury of the liver; in The Liver, C. Rouiller, Vol. 2, pages 335-476, New York, Academic Press 1964).
The results are summarized in Table 1.
Table I t Action of prolyl hydroxylase inhibitors on CCl -induced liver fibrosis in rats Treatment Dose* Bilirubin Bile acids fl-wrtmw GT Control 5 1.76 ± 0.27 26 ± 6.8 2 ± 0 CC1, - 22 4.98 ± 1.06 81 ± 8.7 5.3 ± 1.4 Example 1 20 12 6.30 1 5.4 97 ± 76 4.3 i 3.1 (0) (0) (27) Example 2 20 11 2.90 ± 0.94* 71 ± 42 3.3 ± 2.2* (65) ( 18) (59) The results are mean values ± standard deviation, *p <0 . 05 for CC1A treatment , values in brackets are the percentage improvement compared to an exclusive CCl* treatment , a : total daily oral dose .
Claims (10)
1. A 2,4- or 2,5-substituted pyridine-N-oxide of the formula I C(0)-X-R3, where is 0 or -N(R3' )- and is hydrogen, Cj-Cig-elkyl, ^-C^—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 R*, where R* is halogen, hydroxyl, cyano, nitro, nitroxy, amino, carboxyl, -dialkylamino, indolyl or phenyl, where the indolyl or phenyl radical is unsubstituted or monosubstituted, disubstituted or trisubstituted by halogen, nitro, C^-C^- alkyl or where, in the case of polysubstitution, the radicals are identical or different or if X is -N(R3'), is a radical -N(R3)(R6), which R5 and R6 are identical or different and are hydrogen, Cx-C^-alkyl, Cx-Ca-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 in which n is 1 to 3 and A is 0, S, CH2 or -N(R7)-, where R7 is hydrogen, phenyl, Cx-Ce-alkyl, C2-Ce-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 comprising: halogen, nitro, cyano, carboxyl, hydroxyl, methyl, ethyl, methoxy, ethoxy and trifluoro ethyl or -N(R8)2, where - 21 - 98629/2 R8 is hydrogen or Ci-Ca-alJc l or -COOR8 or -CON(Re)2 or CONHR7, where Re has the meaning of R8 or where (R9)2 is a C«-C6-alkylene chain in which no CH2 group or a CH2 group which is not directly adjacent to the nitrogen atom is replaced by 0, S or N-R8 or where R7 is 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, excluding pyridine-2-carboxyl-4-octyl-carbox amide-N-oxide and the physiologically tolerable salts, were 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 in which R1 is -C(0)-X-R3, where X is 0 or -N(R3' )- and R3 is hydrogen, Cj-Ce-alkyl, C2-Ce-alkenyl, C2-C6- alkynyl, C5-C7-cycloalkyl, aryl or heteroaryl, where these radicals mentioned for R3 are unsubstituted or are substituted by one or two identical or different radicals R*, where R* is halogen, hydroxy1, cyano, amino, carboxyl, Cj-C^-alkoxy, Cj-C^-alkoxy- carbonyl, 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) 98629/2 in which n is 1 to 3 and A is 0, CH2 or -N ( R7 ) - where R7 is hydrogen, phenyl or Ci-Ce-alkyl, 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 comprising: halogen, nitro, cyano, carboxyl, hydroxyl, methyl, ethyl, raethoxy, ethoxy and trifluoromethyl R7 is or C3-C7-cycloalkyl and in which R2 has the meaning of Rl, where the radicals R1 and R2 are identical or different where R2 is either in the 4- or 5-position, and if R2 is in position 4, one of the substituents R3 or R4 may be a substituent on the moiety on the pyridine ring in position 5, resulting in a triple substituted pyridine moeity in positions 2, 4 (R1 or R2), and 5 (R3 or R4) . and the physiologicail'y 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 0 is -C(0)-X-R3, where X is 0 or -N(R3' ) - and R3 is hydrogen, Cj-Cs-alkyl, Ce-cycloalkyl, phenyl or pyridyl, where these radicals mentioned for R3 are unsubstituted or are substituted by one or two identical radicals R*, where R* is hydroxyl, amino, carboxyl, C1-C4-alkoxy, Cj-C^-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 / \ -\ (ID <∞2>η in which n is 2 and A is 0 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 R* 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 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 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 in which R1 is -C(0)-X-R3, where X is 0 or -N(R3')- and R3 is hydrogen, Ci-Cxa-alkyl, C2-C12-alkenyl, C2-C12- alkynyl, non-benzo-fused or benzo-fused C3-C7- cycloalkyl, aryl or heteroaryl, where these radicals mentioned for R3 are unsubstituted or are substituted by one or more identical or different radicals RA, where R* is halogen, hydroxyl, cyano, nitro, nitroxy, amino, carboxyl, Ci-C^-alkoxycarbonyl, Cj-C^-alkyl- or -dialkylamino, indolyl or phenyl, where the indolyl or phenyl radical is unsubstituted or monosubstituted, disubstituted or trisubstituted by halogen, nitro, Cx-C^- alkyl or Cx-Ct-alko y, where, in the case of polysubstitution, the radicals are identical or different or R3, if X is -N(R3' ) , is a radical -N(R5)(Re), in which Rs and R6 are identical or different and are hydrogen, d-C^-alkyl, C1-Ca-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 (CH2)n in which n is 1 to 3 and A is 0, S, CH2 or -N(R7)-, where R7 is hydrogen, phenyl, Cx-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 monosubstltuted or polysubstituted by one or more identical or different sub- stituents selected from the group comprising: halogen, nitro, cyano, carboxyl, hydroxyl, methyl, ethyl, methoxy, ethoxy and trifluoromethyl or -N(R8)2, where R8 is hydrogen or Ci-Ca-alkyl or -COOR8 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 directly adjacent to the nitrogen atom is replaced by 0, S or N-R8 or where R7 is Cj-Ci.-alkoxycarbonyl or C3-C7-cycloalkyl and in which R2 has the meaning of Rl, 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 R* 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 in which R1 is -C(0)-X-R3, where X is 0 or -N(R3')- and R3 is hydrogen, Cx-Ce-alkyl, C2-C6-alkenyl, C2-C6- alkynyl, C5-C7-cycloalkyl, aryl or heteroaryl, where these radicals mentioned for R3 are unsubstituted or are substituted by one or two identical or different radicals R, where R* is halogen, hydroxyl, cyano, amino, carboxyl, C1-C4-alkoxy- carbonyl, dialkylamino, or phenyl, where the phenyl radical is unsubstituted or monosubstituted by halogen, Ci-Ca-alkyl or Ci-Ca-alko , 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 — in which n is 1 to 3 and A is 0, CH2 or -N(R7)-, where R7 is hydrogen, phenyl or Ci-Ce-alkyl, 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 comprising: halogen, nitro, cyano, carboxyl, hydroxyl, methyl, ethyl, methoxy, ethoxy and trifluoromethyl R7 is Cj-C^-alkoxycarbonyl or C3-C7-cycloalkyl and in which R2 has the meaning of R1, where the radicals Rl and R2 are identical or different or R2 is only present in the 4-position, and one of the radicals R3 or R* is in the 5-position and the physiologically tolerable salts, for the inhibition of proline hydroxylase and lysine hydroxylase.
7. A 2,4- or 2 , 5-substituted pyridine-N-oxide of the formula I is -C(0)-X-R3, where X is 0 or -N(R3' ) - and R3 is hydrogen, Cj-Cj-alkyl, C8-cycloalkyl, phenyl - 31 - or pyridyl, where these radicals mentioned for R3 are unsubstituted or are substituted by one or two identical radicals R*, where R* is hydroxyl, amino, carboxyl, 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 in which n is 2 and A is 0 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 R* is in the 5-position and the physiologically tolerable salts, for use as fibrosuppressives and immunosuppressives. 98629/3 -32- 98629/2
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 in the preparation of a medicament for influencing the metabolism of collagen and collagen-like substances or the biosynthesis of Clq., as hereinbefore described.
10. The use of compounds of the formula I as claimed in claim 5 in the preparation of a medicament for the treatment of disorders of the metabolism of collagen and collagenlike, substances or the bio synthesis of Clq., as hereinbefore described. 1 1. 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 a suitable administration form.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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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| Publication Number | Publication Date |
|---|---|
| IL98629A0 IL98629A0 (en) | 1992-07-15 |
| IL98629A true IL98629A (en) | 1996-05-14 |
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| IL9862991A IL98629A (en) | 1990-06-28 | 1991-06-26 | 2,4- and 2,5-substituted pyridine-n-oxides processes for their preparation and their use |
Country Status (27)
| Country | Link |
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| EP (1) | EP0463592B1 (en) |
| JP (1) | JPH0832687B2 (en) |
| KR (1) | KR920000724A (en) |
| CN (1) | CN1038585C (en) |
| AT (1) | ATE110059T1 (en) |
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| BR (1) | BR9102699A (en) |
| 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) |
| HR (1) | HRP940701B1 (en) |
| HU (1) | HU214627B (en) |
| IE (1) | IE65300B1 (en) |
| IL (1) | IL98629A (en) |
| LT (1) | LT3918B (en) |
| MA (1) | MA22191A1 (en) |
| MX (1) | MX26415A (en) |
| MY (1) | MY107573A (en) |
| NO (1) | NO178026C (en) |
| NZ (1) | NZ238701A (en) |
| PT (1) | PT98108B (en) |
| YU (1) | YU113391A (en) |
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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 |
| EP0548883A1 (en) * | 1991-12-24 | 1993-06-30 | Hoechst Aktiengesellschaft | Substituted pyridine-N-oxides, process for their preparation and their use as medicines |
| TW352384B (en) * | 1992-03-24 | 1999-02-11 | Hoechst Ag | Sulfonamido- or sulfonamidocarbonylpyridine-2-carboxamides, process for their preparation and their use as pharmaceuticals |
| 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 |
| DE19624704A1 (en) * | 1996-06-20 | 1998-01-08 | Klinge Co Chem Pharm Fab | New 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 |
| DE19624659A1 (en) | 1996-06-20 | 1998-01-08 | Klinge Co Chem Pharm Fab | New pyridylalkene and pyridylalkanoic acid amides |
| FR2766187B1 (en) | 1997-07-17 | 2000-06-02 | Rhone Poulenc Rorer Sa | PYRAZINE DERIVATIVES, THEIR PREPARATION AND THE MEDICINES CONTAINING THEM |
| DE19756212A1 (en) | 1997-12-17 | 1999-07-01 | Klinge Co Chem Pharm Fab | New cyclic imide-substituted pyridylalkane, alkene and alkyarboxylic acid amides |
| US6903118B1 (en) | 1997-12-17 | 2005-06-07 | Klinge Pharma Gmbh | Piperazinyl-substituted pyridylalkane, alkene and alkine carboxamides |
| 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 |
| DOP2002000333A (en) | 2001-02-14 | 2002-09-30 | Warner Lambert Co | DERIVATIVES OF ISOFTALIC ACID AS INHIBITORS OF METALOPROTEINASES OF THE MATRIX |
| DOP2002000332A (en) * | 2001-02-14 | 2002-08-30 | Warner Lambert Co | MATRIX METALOPROTEINAS PYRIDINE INHIBITORS |
| WO2002064571A1 (en) | 2001-02-14 | 2002-08-22 | Warner-Lambert Company Llc | Pyrimidine matrix metalloproteinase inhibitors |
| US6924276B2 (en) | 2001-09-10 | 2005-08-02 | Warner-Lambert Company | Diacid-substituted heteroaryl derivatives as matrix metalloproteinase inhibitors |
| EP1434585A1 (en) | 2001-10-12 | 2004-07-07 | Warner-Lambert Company LLC | Alkyne matrix metalloproteinase inhibitors |
| 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 |
| 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 |
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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 |
| 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 |
| 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 |
| 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 METHOD FOR PRODUCING N, N'-BIS (ALKOXYALKYL) -PYRIDINE-2,4-DICARBONIC ACIDEDIAMIDES |
| 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 |
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1990
- 1990-06-28 DE DE4020570A patent/DE4020570A1/en not_active Withdrawn
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1991
- 1991-06-22 ES ES91110343T patent/ES2061118T3/en not_active Expired - Lifetime
- 1991-06-22 EP EP91110343A patent/EP0463592B1/en not_active Expired - Lifetime
- 1991-06-22 DK DK91110343.0T patent/DK0463592T3/en active
- 1991-06-22 AT AT91110343T patent/ATE110059T1/en not_active IP Right Cessation
- 1991-06-22 DE DE59102547T patent/DE59102547D1/en not_active Expired - Fee Related
- 1991-06-26 CZ CS911959A patent/CZ283782B6/en not_active IP Right Cessation
- 1991-06-26 IL IL9862991A patent/IL98629A/en not_active IP Right Cessation
- 1991-06-26 MY MYPI91001142A patent/MY107573A/en unknown
- 1991-06-26 EG EG39291A patent/EG19851A/en active
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- 1991-06-26 FI FI913118A patent/FI101070B/en active IP Right Grant
- 1991-06-27 HU HU912158A patent/HU214627B/en not_active IP Right Cessation
- 1991-06-27 JP JP3156562A patent/JPH0832687B2/en not_active Expired - Lifetime
- 1991-06-27 MX MX2641591A patent/MX26415A/en unknown
- 1991-06-27 PT PT98108A patent/PT98108B/en not_active IP Right Cessation
- 1991-06-27 MA MA22469A patent/MA22191A1/en unknown
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- 1991-06-27 CN CN91104308A patent/CN1038585C/en not_active Expired - Fee Related
- 1991-06-27 CA CA002045868A patent/CA2045868A1/en not_active Abandoned
- 1991-06-27 ZA ZA914958A patent/ZA914958B/en unknown
- 1991-06-27 AU AU79356/91A patent/AU636990B2/en not_active Ceased
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- 1991-06-27 BR BR919102699A patent/BR9102699A/en not_active Application Discontinuation
- 1991-06-28 KR KR1019910010858A patent/KR920000724A/en not_active Withdrawn
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