IE913436A1 - 4- or 5-substituted pyridine-2-carboxylic acids, a process¹for the preparation thereof and the use thereof as¹pharmaceuticals - Google Patents
4- or 5-substituted pyridine-2-carboxylic acids, a process¹for the preparation thereof and the use thereof as¹pharmaceuticalsInfo
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- IE913436A1 IE913436A1 IE343691A IE343691A IE913436A1 IE 913436 A1 IE913436 A1 IE 913436A1 IE 343691 A IE343691 A IE 343691A IE 343691 A IE343691 A IE 343691A IE 913436 A1 IE913436 A1 IE 913436A1
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/65—One oxygen atom attached in position 3 or 5
- C07D213/66—One oxygen atom attached in position 3 or 5 having in position 3 an oxygen atom and in each of the positions 4 and 5 a carbon atom bound to an oxygen, sulphur, or nitrogen atom, e.g. pyridoxal
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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
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
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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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
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- Animal Behavior & Ethology (AREA)
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Abstract
The invention relates to pyridine-2-carboxylic acids substituted in the 4- or 5-position with carboxyl groups and to their use as medicaments. In particular, the action of the compounds for inhibiting proline hydroxylase and lysine hydroxylase and for treating disorders of the biosynthesis of collagen and collagen-like substances is described.
Description
HOECHST AKTIENGESELLSCHAFT HOE 90/F 296 Dr. Fi/Le
Description
4- or 5-substituted pyridine-2-carboxylic acids, a process for the preparation thereof and the use thereof as pharmaceuticals
Compounds which inhibit the enzymes proline hydroxylase and lysine hydroxylase effect very selective inhibition of collagen biosynthesis due to influencing collagenspecific hydroxylation reactions. In the course thereof, protein-bound proline or lysine is hydroxylated by the enzymes proline hydroxylase or lysine hydroxylase respectively. If this reaction is suppressed by inhibitors, the resulting collagen molecule is unable to function, is insufficiently hydroxylated and can be released by the cells only in small amounts into the extracellular space. The insufficiently hydroxylated collagen is unable, moreover, to be incorporated in the collagen matrix and is very easily broken down by proteolysis. The consequence of these effects is an overall reduction in the amount of collagen deposited in the extracellular space.
It is known that inhibition of proline hydroxylase by known inhibitors such as a, a'-dipyridyl results in inhibition of Clq biosynthesis by macrophages (W. Muller et al., FEBS Lett. 90 (1978), 218; Immunobiology 155 (1978), 47). This results in the classical pathway of complement activation becoming inoperative. Hence, inhibitors of proline hydroxylase also act as immunosuppressants, for example in immune complex diseases.
It is known that the enzyme proline hydroxylase is effi30 ciently inhibited by pyridine-2,4- and -2,5-dicarboxylic acids (K. Ma jama a et al., Eur. J. Biochem. 138 (1984) 239-245). However, in cell culture, these compounds are effective inhibitors only in very high concentrations (Tschank, G. et al., Biochem. J. 248 (1987) 625-633).
- 2 DE-A 34 32 094 describes pyridine-2,4- and -2,5-dicarboxylic diesters with 1-6 carbon atoms in the ester alkyl moiety as pharmaceuticals for inhibition of proline hydroxylase and lysine hydroxylase.
These lower alkylated diesters have the disadvantage, however, that they are too rapidly cleaved in the body to the acids and do not reach their site of action in the cell in sufficiently high concentration and thus are relatively little suited for possible administration as pharmaceuticals.
DE-A 37 03 959, DE-A 37 03 962 and DE-A 37 03 963 describe in a general form mixed esters/amides, higher alkylated diesters and diamides of pyridine-2,4- and -2,5-dicarboxylic acids which are effective inhibitors of collagen biosynthesis in animal models. Thus, DE-A 37 03 959 describes, inter alia, the synthesis of N,N'-bis (2-methoxyethyl)pyridine-2,4-dicarboxamide and N,N'-bis (3-isopropoxypropyl)pyridine-2,4-dicarboxamide.
German Patent Applications P 38 26 471.4 and
P 38 28 140.6 describe an improved process for preparing N,N'-bis (2-methoxyethyl)pyridine-2,4-dicarboxamide.
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 describee the use of di(nitroxyalkyl)amides of pyridine-2,4- and -2,5dicarboxylic acids for preparing pharmaceuticals inhibiting proline hydroxylase and lysine hydroxylase.
Both pyridine-2,4- and -2,5-dicarboxamide (Hirakata et al., J. Pharm. Soc. Japan 77 (1957) 219 and H&ring et al., Helv. 37 (1954) 147, 153) and pyridine-2,4- and -2,5-dicarbohydrazide (Itai et al., BI. Nation. Hyg. Labor. Tokyo, 74 (1956) 115, 117 and Shinohara et al., Chem. High Polymers Japan, 15 (1958) 839) have already been disclosed as agents for tuberculosis.
JP 53/28175 (78/28175) describes N,N'-bis(2-nitroxyethyl)pyridine-2,4- and -2,5-dicarboxamides as substances with a vasodilator action.
German Patent Application P (HOE 90/F 192) describes the use of 2,4- and 2,5-substituted pyridine Noxides for preparing pharmaceuticals inhibiting proline hydroxylase and lysine hydroxylase.
It has now been found, surprisingly, that 4- or 5-substituted pyridine-2-carboxylic acids of the formula I indicated below, and the physiologically tolerated salts thereof, effectively inhibit lysine hydroxylase and proline hydroxylase in animal models.
Thus the invention claims compounds of the formula I
in which
R1 is Ci-C^-alkyl, C2-C12-alkenyl, C2-C12-alkynyl, nonbenzo-fused or benzo-fused C5-C7-cycloalkyl, aryl or heteroaryl, where this radical mentioned for R1 is unsubstituted or substituted by one or more identical or different radicals R2, where
R2 is halogen, hydroxyl, cyano, nitro, nitroxy, amino, carboxyl, Cx-C^-alkoxy, Ci-C^-alkoxycarbonyl, Cj-C^alkyl- or -dialkylamino, indolyl or phenyl, where the indolyl and phenyl radical is unsubstituted or substituted once, twice or three times by halogen, nitro, Cx-C4-alkyl or Cx-C4-alkoxy, where in the case of multiple substitution the radicals are identical or different, and the physiologically tolerated salts, where the 4-methyl and -benzyl esters of
- 4 2,4-and the 5-methyl and -benzyl esters of 2,5-pyridinedicarboxylie acid are excepted.
Particularly preferred compounds of the formula I are those in which
R1 is Cx-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C5-C7cycloalkyl, aryl or heteroaryl, where these radicals mentioned for R1 are unsubstituted or substituted by one or two identical or different radicals R2, where
R2 is halogen, hydroxyl, cyano, amino, carboxyl, Cx-C410 alkoxy, Cx-C4-alkoxycarbonyl, Cx-C4-alkyl- or dialkylamino, or phenyl, where the phenyl radical is unsubstituted or substituted once by halogen, Cx-C2alkyl or Cx-C2-alkoxy, and the physiologically tolerated salts, where the 4-methyl and -benzyl esters of 2,4- and the 5-methyl and -benzyl esters of 2,5-pyridinedicarboxylic acid are excepted.
Especially preferred compounds of the formula I are those in which
R1 is Cx-C3-alkyl, C6-cycloalkyl, phenyl or pyridyl, 20 where these radicals mentioned for R1 are unsubstituted or substituted by one or two identical radicals R2, where
R2 is hydroxyl, amino, carboxyl, Cx-C*-alkoxy, CX-CAalkoxycarbonyl or phenyl, where the phenyl radical is unsubstituted or substituted once by methyl or methoxy, and the physiologically tolerated salts, where the 4-methyl and -benzyl esters of 2,4- and the 5-methyl and -benzyl esters of 2,5-pyridinedicarboxylic acid are excepted.
Said 4-methyl and -benzyl esters of 2,4- and 5-methyl and -benzyl esters of 2,5-pyridinedicarboxylic acid are described by Thums, L: J. Pharm. Biolog. 24 (1-2). 3-21 (1969) and Delarge, Js Pharm. Acta. Helv. 44 (10),
637-43 (1969). The corresponding 4-benzyl esters are disclosed in P ......... (HOE 89/F 241) and the 5-benzyl esters are disclosed in DE-A 37 03 963.
- 5 Halogen means fluorine, chlorine, bromine and iodine, aryl means phenyl and naphthyl, and heteroaryl means 5and 6-membered aromatic rings with 1, 2 or 3 nitrogen and/or oxygen and/or sulphur atoms, which can also optionally be benzo-fused; the heteroaryl radicals are, in particular, pyridyl, pyridazyl, pyrimidyl, pyrazyl,
1,3,5-triazyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thienyl, oxazolyl and thiazolyl radicals and optionally their benzo-fused compounds.
Substituted more than once means hereinbefore and hereinafter that at least 2 and at most all of the hydrogen atoms present in the alkyl radicals are replaced by said substituents. In this connection there is preferably one substituent per methyl or methylene group.
In the case of multiple substitutions, the substituents can also be different independently of one another.
The invention also relates to the use of compounds of the formula I plus the 4-methyl and -benzyl esters of 2,4and the 5-methyl and -benzyl esters of 2,5-pyridinedicar20 boxylic acid and the physiologically tolerated salts thereof for producing a pharmaceutical inhibiting proline hydroxylase and lysine hydroxylase.
Finally, the invention relates to the compounds of the formula I plus the 4-methyl and -benzyl esters of 2,425 and the 5-methyl and -benzyl esters of 2,5-pyridinedicarboxylic acid for use as pharmaceuticals.
The invention particularly relates to the compounds of the formula I plus the 4-methyl and -benzyl esters of
2,4- and the 5-methyl and -benzyl esters of 2,5-pyridine30 dicarboxylic acid for use as fibrosuppressants and immunosuppressants and for inhibiting proline hydroxylase and lysine hydroxylase and for influencing the metabolism of collagen and collagen-like substances and the biosynthesis of Clg.
All said alkyl radicals with more than 2 carbon atoms can be either straight-chain or branched.
The invention also relates to a process for preparing compounds of the formula I plus the 4-methyl and -benzyl esters of 2,4- and the 5-methyl and -benzyl esters of
2,5-pyridinedicarboxylic acid, which comprises reacting a compound of the formula II
H
in which Z is halogen, especially chlorine or bromine, hydroxyl or alkoxy, especially (C1-C6)-alkoxy, with a compound of the formula III
HO-R1 (III) in which R1 has the meaning indicated in claim 1, and, in a second reaction stage, selectively hydrolyzing in position 2 the diester of the formula IV
(IV) resulting therefrom.
The selective hydrolysis of an ester, for example in the 20 presence of a copper catalyst, is described by
Delarge, J. in: Pharm. Acta. Helv. 44 (101. 637 (1969).
Said process is disclosed for the preparation of the corresponding benzyl esters In DE-A 37 03 963.
The compounds of the formula I according to the invention have valuable pharmacological properties and show, In particular, activity as inhibitors of proline hyroxylase and lysine hydroxylase, as fibrosuppressant and immunosuppressant.
The activity of the fibrogenase can be determined by 5 radioimmunological determination of the N-terminal propeptide of collagen type III or of the N- or Cterminal crosslinking domain of collagen type IV (7s collagen or type IV collagen NCX) in serum.
For this purpose, the hydroxyproline, procollagen III peptide, 7s collagen and type IV collagen NCX concentrations were measured in the liver of
a) untreated rats (control)
b) rats given tetrachloromethane (CC14 control)
c) rats given first CC14 and then a compound according to the invention (this test method is described by Roullier, C., experimental toxic injury of the liver; in The Liver,
C. Roullier, Vol. 2, pp. 335-476, New York, Academic Press, 1964).
The compounds of the formula I plus the 4-methyl and
-benzyl esters of 2,4- and the 5-methyl and -benzyl esters of 2,5-pyridinedicarboxylic acid can be used as medicaments in the form of pharmaceutical products which contain them where appropriate together with tolerated pharmaceutical vehicles. The compounds can be used as medicines, for example in the form of pharmaceutical products which contain these compounds mixed with a pharmaceutical, organic or inorganic vehicle suitable for enteral, percutaneous or parenteral administration, such as, for example, water, gum arabic, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, vaseline etc.
They can be administered for this purpose orally in doses of 0.01 - 25.0 mg/kg/day, preferably 0.01 - 5.0 mg/kg/day or parenterally in doses of 0.001 - 5 mg/kg/day,
- 8 preferably 0.001 - 2.5 mg/kg/day, especially 0.005 1.0 mg/kg/day. It is also possible to increase the dosage in severe cases. However, lower doses also suffice in many cases. These data relate to an adult weighing about
75 kg.
The invention also embraces the use of the compounds according to the invention for preparing pharmaceuticals which are employed for the treatment and prophylaxis of the abovementioned metabolic disorders.
The invention additionally relates to pharmaceuticals which contain one or more compounds of the formula I according to the invention, and/or their physiologically tolerated salts, plus the 4-methyl and -benzyl esters of
2,4- and the 5-methyl and -benzyl esters of 2,5-pyridine15 dicarboxylic acid.
The pharmaceuticals are produced by processes known per se and familiar to the person skilled in the art. As pharmaceuticals, the pharmacologically active compounds (= active substance) according to the invention are 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, where the content of active substance is up to about 95 %, advant25 ageously between 10 and 75 %.
Suitable auxiliaries and excipients for the required pharmaceutical formulation are, for example, besides solvents, gel formers, suppository bases, tableting auxiliaries and other active substance vehicles, also antioxidants, dispersants, emulsifiers, foam suppressants, flavorings, preservatives, solubilizers or colorants.
The active substances can be administered orally, parenterally or rectally.
- 9 The active compounds are mixed with the additives suitable for this, such as excipients, stabilizers or inert diluents, and converted by the usual methods into suitable dosage forms such as tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily suspensions or aqueous or oily solutions.
Examples of inert excipients which can be used are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, especially corn starch. The preparation can be carried out either as dry or as wet granules. Examples of suitable oily excipients or solvents are vegetable or animal oils, such as sunflower oil or fish liver oil.
For subcutaneous or intravenous administration, the active compounds are, if required, converted into a solution, suspension or emulsion with the substances suitable for this purpose, such as solubilizers, emulsifiers or other auxiliaries. Examples of suitable solvents are physiological saline or alcohols, for example eth20 anol, propanol, glycerol, as well as sugar solutions such as glucose or mannitol solutions, or else a mixture of the various solvents mentioned.
The invention is explained in more detail hereinafter by means of examples.
General procedure for the preparation of compounds according to the invention.
0.1 mol of copper nitrate (X 3 H2O) is introduced into 700 ml of methanol, and 0.1 mol of a pyridine-2,4- or -2,5-dicarboxylic ester of the formula IV is added. The mixture is heated under reflux for 3 hours, cooled, and the resulting copper complex is filtered off with suction and washed with diethyl ether. 0.1 mol of the copper complex is introduced into 400 ml of dioxane. Hydrogen sulfide is passed in at room temperature over a period of hours. The precipitated copper sulfide is filtered off and the filter is washed with a little dioxane. The filtrate is concentrated, the residue is triturated with petroleum ether and the crystalline residue is filtered off.
Example 1
Benzyl 2-carboxypyridine-4-carboxylate
Yield: 77% melting point: 113-115’C
Example 2
Benzyl 2-carboxypyridine-5-carboxylate
Yield: 75% melting point: 132eC
Example 3
Ethyl 2-carboxypyridine-4-carboxylate
Yield: 96% melting point: 149-153°C
Example 4
Methyl 2-carboxypyridine-5-carboxylate
Yield: 60% melting point: 185°C
Example 5
Butyl 2-carboxypyridine-4-carboxylate 20 Yield: 41% melting point: 102’C
Example 6
Butyl 2-carboxypyridine-5-carboxylate
Yield: 51% melting point: 104*C
Example 7
3-Methoxybutyl 2-carboxypyridine-4-carboxylate
Yield: 63% melting point: 77’C
Example 8
3-Methoxybutyl 2-carboxypyridine-5-carboxy1ate Yield: 25% melting point: 163*C
Claims (12)
1. A 4- or 5-substituted pyridine-2-carboxylic acid of the formula I R 1 O(O)C•Ν' COOH (I) in which R 1 is C x -C 12 -alkyl, C 2 -C 12 -alkenyl, C 2 -C 12 -alkynyl, nonbenzo-fused or benzo-fused C 5 -C 7 -cycloalkyl, aryl or heteroaryl, where this radical mentioned for R 1 is unsubstituted or substituted by one or more identical or different radicals R 2 , where R 2 is halogen, hydroxyl, cyano, nitro, nitroxy, amino, carboxyl, C x -C*-alkoxy, Cx-C 4 -alkoxycarbonyl, C x -C 4 alkyl- or -dialkylamino, indolyl or phenyl, where the indolyl and phenyl radical is unsubstituted or substituted once, twice or three times by halogen, nitro, Cx-C 4 -alkyl or Ci-C 4 -alkoxy, where in the case of multiple substitution the radicals are identical or different, and the physiologically tolerated salts, where the 4-methyl and -benzyl esters of 2,4and the 5-methyl and -benzyl esters of 2,5-pyridinedicarboxylic acid are excepted.
2. A compound as claimed in claim 1, in which R 1 is Cx-C 6 -alkyl, C 2 -C B -alkenyl, C 2 -C 6 -alkynyl, C 5 -C 7 cycloalkyl, aryl or heteroaryl, where these radicals mentioned for R 1 are unsubstituted or substituted by one or two identical or different radicals R 2 , where R 2 is halogen, hydroxyl, cyano, amino, carboxyl, Cx-C 4 alkoxy, Ci-C 4 -alkoxycarbonyl, Cx-C 4 -alkyl- or dialkylamino, or phenyl, where the phenyl radical is unsubstituted or substituted once by halogen, C x -C 2 alkyl or Cx-C 2 -alkoxy, and the physiologically tolerated salts, where the 4-methyl and -benzyl esters of 2,4- and the 5-methyl and -benzyl esters of 2,5-pyridinedicarboxylic acid are excepted.
3. A compound as claimed In claim 1, In which R 1 is Ci-Cj-alkyl, C 6 -cycloalkyl, phenyl or pyridyl, where these radicals mentioned for R 1 are unsubstituted or substituted by one or two identical radicals R 2 , where R 2 is hydroxyl, amino, carboxyl, Cx-C A -alkoxy, 0χ-0 Α alkoxycarbonyl or phenyl, where the phenyl radical is unsubstituted or substituted once by methyl or methoxy, and the physiologically tolerated salts, where the 4-methyl and -benzyl esters of 2,4- and the 5-methyl and -benzyl esters of 2,5-pyridinedicarboxylic acid are excepted.
4. A process for preparing 4- or 5-substituted pyridine2-carboxylic acids of the formula I and their physiologically tolerated salts plus the 4-methyl and -benzyl esters of 2,4- and the 5-methyl and -benzyl esters of 2,5-pyridinedicarboxylic acid, which comprises reacting a compound of the formula II is halogen, especially chlorine or bromine, hydroxyl or alkoxy, especially (C X -C B )-alkoxy, preferably (ϋχ-ϋ Α )-alkoxy, with a compound of the formula III HO-R 1 (III) has the meaning indicated in claim 1, and, in a second reaction stage, selectively hydrolyzing In position 2 the diester of the formula IV in which Z in which R (IV) resulting therefrom.
5. A compound as claimed in claim 4 for inhibiting proline hydroxylase and lysine hydroxylase.
6. A compound as claimed in claim 4 for use as fibrosup5 pressant and immunosuppressant.
7. A pharmaceutical containing a compound as claimed in claim 4 and/or its physiologically tolerated salts for the treatment of disturbances of the biosynthesis of collagen and collagen-like substances and of the biosyn10 thesis of Clq.
8. A process for producing pharmaceuticals for influencing the biosynthesis of collagen and collagen-like substances and the biosynthesis of Clq, which comprises incorporating into the pharmaceutical a compound of the 15 formula I as claimed in claim 4 and/or a physiologically tolerated salt of this compound.
9. A 4- or 5-substituted pyridine-2-carboxylic acid of the formula I given and defined in claim 1 and the physiologically tolerated salts, where the 4-methyl and -benzyl esters of 2,4- and the 5-methyl and -benzyl esters of 2,5-pyridinedicarboxylic acid are excepted, substantially as hereinbefore described and exemplified.
10. A process according to claim 4 for preparing 4- or 5-substituted pyridine-2-carboxylic acids of the formula I given and defined in claim 1 and their physiologically tolerated salts plus the 4-methyl and -benzyl esters of 2.4- and the 5-methyl and -benzyl esters of 2,5-pyridinedicarboxylic acid, substantially as hereinbefore described and exemplified.
11. 4- or 5-Substituted pyridine-2-carboxylic acids of the formula I given and defined in claim 1 and their physiologically tolerated salts plus the 4-methyl and -benzyl esters of 2,4- and the 5-methyl and -benzyl esters of 2.5- pyridinedicarboxylic acid, whenever prepared by a process claimed in claim 4 or 10.
12. A pharmaceutical according to claim 7, substantially as hereinbefore described.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4030999A DE4030999A1 (en) | 1990-10-01 | 1990-10-01 | 4- OR 5-SUBSTITUTED PYRIDINE-2-CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MEDICINAL PRODUCT |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| IE913436A1 true IE913436A1 (en) | 1992-04-08 |
Family
ID=6415344
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE343691A IE913436A1 (en) | 1990-10-01 | 1991-09-30 | 4- or 5-substituted pyridine-2-carboxylic acids, a process¹for the preparation thereof and the use thereof as¹pharmaceuticals |
Country Status (19)
| Country | Link |
|---|---|
| EP (1) | EP0479178A3 (en) |
| JP (1) | JPH072777A (en) |
| KR (1) | KR920008000A (en) |
| CN (1) | CN1060464A (en) |
| AU (1) | AU8485191A (en) |
| BR (1) | BR9104204A (en) |
| CA (1) | CA2052509A1 (en) |
| CS (1) | CS299091A3 (en) |
| DE (1) | DE4030999A1 (en) |
| FI (1) | FI914557A (en) |
| HU (1) | HUT59101A (en) |
| IE (1) | IE913436A1 (en) |
| IL (1) | IL99606A0 (en) |
| MA (1) | MA22312A1 (en) |
| MX (1) | MX9101348A (en) |
| NO (1) | NO913833L (en) |
| PL (1) | PL291880A1 (en) |
| PT (1) | PT99133A (en) |
| ZA (1) | ZA917806B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW199147B (en) * | 1991-03-18 | 1993-02-01 | Hoechst Ag | |
| CN108884047B (en) * | 2016-03-25 | 2022-03-08 | 沈阳三生制药有限责任公司 | Intermediates for the synthesis of aryl or heteroaryl substituted 5-hydroxy-1, 7-naphthyridine compounds and methods for their preparation |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3432094A1 (en) * | 1984-08-31 | 1986-03-06 | Hoechst Ag, 6230 Frankfurt | ESTER OF PYRIDINE-2,4- AND -2,5-DICARBONIC ACID AS A MEDICINAL PRODUCT FOR INHIBITING PROLIN AND LYSINE HYDROXYLASE |
| DE3703963A1 (en) * | 1987-02-10 | 1988-08-18 | Hoechst Ag | PYRIDINE-2,4- AND 2,, 5-DICARBONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, USE THEREOF, AND MEDICINAL PRODUCTS BASED ON THESE COMPOUNDS |
| DE3707429A1 (en) * | 1987-03-07 | 1988-09-15 | Hoechst Ag | SUBSTITUTED PYRIDINE-2,4-DICARBONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, USE OF THE SAME AND MEDICINAL PRODUCTS BASED ON THESE COMPOUNDS |
| 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 |
-
1990
- 1990-10-01 DE DE4030999A patent/DE4030999A1/en not_active Withdrawn
-
1991
- 1991-09-27 FI FI914557A patent/FI914557A/en not_active Application Discontinuation
- 1991-09-27 IL IL99606A patent/IL99606A0/en unknown
- 1991-09-30 BR BR919104204A patent/BR9104204A/en unknown
- 1991-09-30 CN CN91109397A patent/CN1060464A/en active Pending
- 1991-09-30 AU AU84851/91A patent/AU8485191A/en not_active Abandoned
- 1991-09-30 KR KR1019910017065A patent/KR920008000A/en not_active Application Discontinuation
- 1991-09-30 IE IE343691A patent/IE913436A1/en not_active Application Discontinuation
- 1991-09-30 CS CS912990A patent/CS299091A3/en unknown
- 1991-09-30 PL PL29188091A patent/PL291880A1/en unknown
- 1991-09-30 ZA ZA917806A patent/ZA917806B/en unknown
- 1991-09-30 NO NO91913833A patent/NO913833L/en unknown
- 1991-09-30 HU HU913120A patent/HUT59101A/en unknown
- 1991-09-30 CA CA002052509A patent/CA2052509A1/en not_active Abandoned
- 1991-09-30 MX MX9101348A patent/MX9101348A/en unknown
- 1991-09-30 JP JP3250720A patent/JPH072777A/en active Pending
- 1991-09-30 EP EP19910116633 patent/EP0479178A3/en not_active Withdrawn
- 1991-10-01 PT PT99133A patent/PT99133A/en not_active Application Discontinuation
- 1991-10-01 MA MA22592A patent/MA22312A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CA2052509A1 (en) | 1992-04-02 |
| DE4030999A1 (en) | 1992-04-09 |
| FI914557A0 (en) | 1991-09-27 |
| MX9101348A (en) | 1992-06-05 |
| NO913833L (en) | 1992-04-02 |
| CN1060464A (en) | 1992-04-22 |
| PT99133A (en) | 1992-08-31 |
| ZA917806B (en) | 1992-05-27 |
| CS299091A3 (en) | 1992-04-15 |
| HUT59101A (en) | 1992-04-28 |
| BR9104204A (en) | 1992-06-02 |
| FI914557A (en) | 1992-04-02 |
| EP0479178A2 (en) | 1992-04-08 |
| JPH072777A (en) | 1995-01-06 |
| MA22312A1 (en) | 1992-07-01 |
| AU8485191A (en) | 1992-04-02 |
| KR920008000A (en) | 1992-05-27 |
| EP0479178A3 (en) | 1992-10-28 |
| HU913120D0 (en) | 1992-01-28 |
| PL291880A1 (en) | 1992-06-26 |
| NO913833D0 (en) | 1991-09-30 |
| IL99606A0 (en) | 1992-08-18 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FC9A | Application refused sect. 31(1) |