IE65300B1 - 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
- IE65300B1 IE65300B1 IE225391A IE225391A IE65300B1 IE 65300 B1 IE65300 B1 IE 65300B1 IE 225391 A IE225391 A IE 225391A IE 225391 A IE225391 A IE 225391A IE 65300 B1 IE65300 B1 IE 65300B1
- Authority
- IE
- Ireland
- Prior art keywords
- compound
- formula
- meaning
- collagen
- radicals
- Prior art date
Links
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical class [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 title claims abstract description 9
- 238000000034 method Methods 0.000 title claims description 17
- 238000002360 preparation method Methods 0.000 title claims description 11
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- 229920001436 collagen Polymers 0.000 claims abstract description 14
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- 102000008186 Collagen Human genes 0.000 claims abstract description 13
- 239000000126 substance Substances 0.000 claims abstract description 8
- 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
- 102000004079 Prolyl Hydroxylases Human genes 0.000 claims description 15
- 108010043005 Prolyl Hydroxylases Proteins 0.000 claims description 15
- 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
- 150000003839 salts Chemical class 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 230000002401 inhibitory effect Effects 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 2
- 208000035475 disorder Diseases 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 4
- 125000003545 alkoxy group Chemical group 0.000 claims 2
- 229910052736 halogen Inorganic materials 0.000 claims 2
- 125000005843 halogen group Chemical group 0.000 claims 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 2
- 241001484259 Lacuna Species 0.000 claims 1
- 150000001204 N-oxides Chemical class 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 claims 1
- 230000001506 immunosuppresive effect Effects 0.000 abstract description 2
- 239000003814 drug Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
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- -1 3 -isopropoxypropyl Chemical group 0.000 description 6
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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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- NUKJWCDZSPKZIF-UHFFFAOYSA-N 2-n,4-n-bis(3-ethoxypropyl)pyridine-2,4-dicarboxamide Chemical compound CCOCCCNC(=O)C1=CC=NC(C(=O)NCCCOCC)=C1 NUKJWCDZSPKZIF-UHFFFAOYSA-N 0.000 description 1
- HLSXICGBWKECLM-UHFFFAOYSA-N 2-n,4-n-bis(3-methoxypropyl)pyridine-2,4-dicarboxamide Chemical compound COCCCNC(=O)C1=CC=NC(C(=O)NCCCOC)=C1 HLSXICGBWKECLM-UHFFFAOYSA-N 0.000 description 1
- LXZKYTKXZYSEOZ-UHFFFAOYSA-N 3-(2-methoxyethyl)pyridine-2,4-dicarboxamide Chemical compound COCCC1=C(C(N)=O)C=CN=C1C(N)=O LXZKYTKXZYSEOZ-UHFFFAOYSA-N 0.000 description 1
- YNJSNEKCXVFDKW-UHFFFAOYSA-N 3-(5-amino-1h-indol-3-yl)-2-azaniumylpropanoate Chemical compound C1=C(N)C=C2C(CC(N)C(O)=O)=CNC2=C1 YNJSNEKCXVFDKW-UHFFFAOYSA-N 0.000 description 1
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- OOXOXZVOZIURRD-UHFFFAOYSA-N pyridine-2,4-dicarboxamide Chemical compound NC(=O)C1=CC=NC(C(N)=O)=C1 OOXOXZVOZIURRD-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/89—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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Immunology (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Obesity (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Transplantation (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicinal Preparation (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (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-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, proteinbound 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 a,a'-dipyridyl leads to an inhibition of Clq biosynthesis by macrophages (W. Muller et al., FEBS Lett. 90 (1978), 218; Immunbiology 155 (1976), 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 (K. Majamaa et al., 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 3,432,094 describes pyridine-2,4- and -2,5-dicarboxylic 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, DE-A 3,703,962 and DE-A 3,703,963 describe in general form mixed ester/amides, higher alkylated diesters and diamides of pyridine-2,4- and -2,5-dicarboxylic acid, which effectively inhibit, collagen biosynthesis in the animal model. 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) pyr idine-2,4-dicarboxamide.
An improved process for the preparation of N,N'-bis25 (2-methoxyethyl)pyridine-2,4-dicarboxamide is proposed in German Patent Applications P 38 26 471.4 and P 38 28 140.6.
German Patent Application P 39 24 093.2 proposes novel N,N' -bis (alkoxyalkyl) pyr idine-2,4-dicarboxamides.
German Patent Application P 40 01 002.3 describes the use of N,N'- (nitroxyalkyl)pyridine-2,4 and 2,5-dicarboxamides for the preparation of pharmaceuticals inhibiting proline hydroxylase and lysine hydroxylase. r_r ~T Both pyridine-2,4- and -2,5-dicarboxamide (Hirakata et al., J. pharm. Soc. Japan 77 (1957) 219 and Haring et al., Helv. 37 (1954) 147, 153) and pyridine-2,4- and -2,5-dicarboxylic acid dihydrazide (Itai et al., BI. 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-nitrooxyethy1)pyridine-2,4- and -2,5-dicarboxamides as substances having vasodilatory action.
Surprisingly, it has now been found that 2,4- and 2,5substituted pyridine-N-oxides of the 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-substituted pyridine-N-oxides of the formula I R (I) in which R1 is -C(O)-X-R3, where X is -N(R3')- and R3 is hydrogen or C2 and C3-alkyl, where the alkyl radical is substituted by one or more identical Cxor C2-alkoxy radicals and -«—r R3 has the meaning of R3, R2 has the meaning of R1, where the radicals R1 and R2 are identical or different and the physiologically tolerable salts.
The invention furthermore relates to the use of compounds of the 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 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 Clq.
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 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, perfluoroacetic acid, perbenzoic acid or metachloroperbenzoic 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 +40®C, preferably between 0 and +25°C, for between 30 minutes T 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 equimolar 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 York, 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 crosslinking domain of type IV collagen (7s collagen or type IV collagen-NC^ in the serum.
For this purpose, the hydroxyproline, procollagen III peptide, 7s-collagen and type IV collagen-NCx 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 York, Academic Press, 1964).
Another model for the evaluation of antibiotic 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., Experimentia 6, 469 (1950) can be used to evaluate the T action of the compounds according to the invention in the granulation tissue. The invention is illustrated in more detail below by Examples.
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, polyalkylene 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, preferably 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 hy processes which are known per se and which are familiar to the person skilled in the art. As pharmaceuticals, the pharmacologically Tty 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, parenterally 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 com 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, alternatively, 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 equivalent of pyridine derivative (for preparation see description) are 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 icecooling 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 N2 5 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 Σ I— Example 2 N,Ν' -Di-(3-methoxypropyl)pyridine-2,4-dicarboxamide N-oxide From 1 g of N,N' -di-(3-methoxypropyl)pyridine-2,4-dicarboxamide and 1.2 g of MCPBA.
Yield: 0.58 g (recrystallization: ethanol) M. p.: 90°C Example 3 N, N'-Di-(2-dimethoxyethyl)pyridine-2,4-dicarboxamide N-oxide From 1 g of N,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.: 86°C Example 4 N, Ν' - 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.
Yield: 0.34 g (chromatography: ethyl acetate/methanol 5:1) M.p.: 81°C Example 5 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 GT in the serum of a) untreated rats (control), b) rats treated with CC14, c) rats to which first CC14 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 1: Action of prolyl hydroxylase inhibitors on CCl4-induced 15 liver fibrosis in rats Treatment Dose* Bilirubin /un Bile acids Gamma GT D/L mg/kg N Control 5 1.76 ± 0.27 26 * 6.8 2 ± 0 CC14 - 22 4.98 ± 1.06 81 ± 8·7 5.3 ± 1.4 Example 1 20 12 6.30 i 5.4 (0) 97 ± 76 (0) 4.3 i 3.1 (27) Example 2 20 11 2.90 ± 0.94* (65) 71 ± 42 (18) 3.3 ± 2.2* (59) The results are mean values ± standard deviation, *p <0.05 for CC14 treatment, values in brackets are the percentage improvement compared to an exclusive CC14 treatment, a: total daily oral dose.
Claims (17)
1. 1. A 2,4-substituted pyridine-N-oxide of the formulae I R 2 5 in which R 1 is -C(O)-X-R 3 , where X is -N(R 3 ')- and R 3 is hydrogen or C x -C 5 -alkyl, where the alkyl radical is substituted by one or 10 two identical C x - or C 2 -alkoxy radicals and R 3 ' has the meaning of R 3 , R 2 has the meaning of R 1 , where the radicals R 1 and R 2 are identical or different 15 or the physiologically tolerable salts.
2. 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 (ΙΠ) in which Y is halogen, hydroxyl or alkoxy, with a compound of the formula IV H-X-R 3 (IV) in which X and R 3 have the meanings indicated in claim 1, or (V) in which Y is halogen, hydroxyl or alkoxy, with a compound of the formula VI H-X-R 3 (VI) in which X and R 3 have the meanings indicated in claim 1, optionally introducing a further substituent into the βide chain R 3 and then converting the compound thus obtained to the N-oxide and optionally then converting the compound thus obtained to a physiologically tolerable salt. A 2,4-substituted pyridine-N-oxide of the formula I (I) R 2 in which R 1 is -C(O)-X-R 3 , where X is -N(R 3 ')- and R 3 is hydrogen or C 2 - or C 3 -alkyl, where 5 the alkyl radical is substituted by one or two identical C 1 - or C 2 -alkoxyradicals and R 3 ' has the meaning of R 3 , 10 R 2 has the meaning of R 1 , where the radicals R 1 and R 2 are identical or different or the physiologically tolerable salts, for use as a pharmaceutical.
3. 4. A 2,4-substituted pyridine-N-oxide of the formulae 15 I and 1' R 2 (I) in which I T R 1 is -C(O)-X-R 3 , where X is -N(R 3 ')- and R 3 is hydrogen or C 2 - or C 3 -alkyl, where the alkyl radical is substituted by
4. 5 one or two identical Cj-C^-alkoxy radicals and R 3 ' has the meaning of R 3 , R 2 has the meaning of R 1 , where the radicals R 1 10 and R 2 are identical or different or the physiologically tolerable salts, for inhibiting proline hydroxylase and lysine hydroxylase. 5. A 2,4-substituted pyridine-N-oxide of the formulae I and I' R 2 15 in which R 1 is -C(O)-X-R 3 , where X is -N(R 3 ')- and R 3 is hydrogen or C 2 - or C 3 -alkyl, where [lacuna] is substituted by one or two 2 0 identical C x or C 2 -alkoxy radicals and R 3 ' has the meaning of R 3 , R 2 has the meaning of R 1 , where the radicals R 1 and R 2 are identical or different or the physiologically tolerable salts, for use as fibrosuppressants and immunisuppressants.
5. 6. A pharmaceutical composition, containing a compound of the formula I as claimed in claim 3, and a pharmaceutically tolerable excipient.
6. 7. The use of compounds of the formula I as claimed in claim 3 for affecting the metabolism of collagen and collagen-like substances or the biosynthesis of Cl q .
7. 8. The use of compounds of the formula I as claimed in claim 3 for the treatment of disorders of the metabolism of collagen and collagen-like substances or the biosynthesis of Cl q .
8.
9. A process for the production of a pharmaceutical composition as claimed in claim 6, which comprises converting a compound of the formula I as claimed in claim 1 and a pharmaceutically tolerable excipient into a suitable administration form.
10. A compound as claimed in claim 1, substantially as hereinbefore described and exemplified.
11. A process for the preparation of a compound as claimed in claim 1, substantially as hereinbefore described and exemplified.
12. A compound as claimed in claim 1, whenever prepared by a process claimed in claim 2 or 11. —.....17
13. A pharmaceutical composition as claimed in claim 6, substantially as hereinbefore described.
14. Use as claimed in claim 7, substantially as hereinbefore described.
15. Use as claimed in claim 8, substantially as hereinbefore described.
16. A process for the production of a pharmaceutical composition as claimed in claim 6, substantially as hereinbefore described and exemplified. 10
17. A pharmaceutical composition as claimed in claim 6, whenever produced by a process claimed in claim 9 or 16.
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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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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 |
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 |
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 |
DE19756261A1 (en) | 1997-12-17 | 1999-07-01 | Klinge Co Chem Pharm Fab | New aryl-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 |
DE19756212A1 (en) | 1997-12-17 | 1999-07-01 | Klinge Co Chem Pharm Fab | New cyclic imide-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 |
WO2002064571A1 (en) | 2001-02-14 | 2002-08-22 | Warner-Lambert Company Llc | Pyrimidine matrix metalloproteinase inhibitors |
DOP2002000332A (en) | 2001-02-14 | 2002-08-30 | Warner Lambert Co | MATRIX METALOPROTEINAS PYRIDINE INHIBITORS |
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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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 |
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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 |
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DE3826471A1 (en) | 1988-08-04 | 1990-02-22 | Hoechst Ag | Improved process for the preparation of N,N'-bis(alkoxyalkyl)pyridine-2,4-dicarboximides |
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- 1991-06-26 CZ CS911959A patent/CZ283782B6/en not_active IP Right Cessation
- 1991-06-27 JP JP3156562A patent/JPH0832687B2/en not_active Expired - Lifetime
- 1991-06-27 CA CA002045868A patent/CA2045868A1/en not_active Abandoned
- 1991-06-27 MX MX2641591A patent/MX26415A/en unknown
- 1991-06-27 HU HU912158A patent/HU214627B/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 IE IE225391A patent/IE65300B1/en unknown
- 1991-06-27 BR BR919102699A patent/BR9102699A/en not_active Application Discontinuation
- 1991-06-27 YU YU113391A patent/YU113391A/en unknown
- 1991-06-27 MA MA22469A patent/MA22191A1/en unknown
- 1991-06-27 NO NO912541A patent/NO178026C/en not_active IP Right Cessation
- 1991-06-27 CN CN91104308A patent/CN1038585C/en not_active Expired - Fee Related
- 1991-06-27 PT PT98108A patent/PT98108B/en not_active IP Right Cessation
- 1991-06-28 KR KR1019910010858A patent/KR920000724A/en not_active Application Discontinuation
-
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
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