IE920843A1

IE920843A1 - Mixed pyridine-2,4- and -2,5-dicarboxamides, a process for¹preparing them, the use thereof and pharmaceuticals based on¹these compounds

Info

Publication number: IE920843A1
Application number: IE084392A
Authority: IE
Inventors: Ekkehard Baader; Martin Bickel; Volkmar Guenzler-Pukall; Manfred Volz
Original assignee: Hoechst Ag
Priority date: 1991-03-18
Filing date: 1992-03-16
Publication date: 1992-09-23
Also published as: KR100243959B1; DE59208651D1; TW199147B; NZ241968A; JPH0586032A; EP0504799A1; NO921025L; HU9200891D0; GR3024309T3; JP3121428B2; ATE154929T1; CA2063177A1; YU24692A; HU217809B; CZ282298B6; CS80392A3; FI921119A0; FI101701B1; DK0504799T3; MX9201156A

Abstract

The invention relates to mixed pyridine-2,4- and -2,5-dicarboxylic acid diamides, the carboxylic acid amide group in position 2 being a primary acid amide. The said compounds are suitable for the inhibition of proline hydroxylase and lysine hydroxylase and are used as fibrosuppressants and immunosuppressants.

Description

Description Mixed pyridine-2,4- and -2,5-dicarboxamides, a process 5 for preparing them, the use thereof and pharmaceuticals based on these compounds Compounds which inhibit proline hydroxylase and lysine hydroxylase effect a very selective inhibition of collagen biosynthesis due to influencing collagen10 specific 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 cannot, moreover, 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 act as immunosuppres30 sants, for example in immune complex diseases.

It is known that proline hydroxylase can be effectively inhibited by pyridine-2,4- and -2,5-dicarboxylic acids (K. Mayama 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. 238 (1987) 625-633).

DE-A 34 32 094 describes pyridine-2,4- and -2,5dicarboxylic disesters with 1-6 carbon atoms in the ester alkyl moiety as pharmaceuticals for the 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 less suitable for possible administration as pharmaceuticals.

DE-A 37 03 959, DE-A 37 03 362 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 20 propose an improved process for preparing N,N'-bis(2methoxyethyl)pyridine-2,4-dicarboxamide. German Patent Application P 39 24 093.2 proposes novel N,N'bis(alkoxyalkyl)pyridine-2,4-dicarboxamides.

The object to be achieved was thus to find compounds 25 which are suitable in a much improved manner than those hitherto disclosed for the inhibition of proline hydroxylase and lysine hydroxylase. The object has been achieved by pyridine-2,4- and -2,5-dicarboxamldes of the formula (I) in which R1 is Ci-C^-alkyl, C2-C12-alkenyl or C2-C12-alkynyl, which are unsubstituted or substituted once or, in the case of the C2-C12-alkyls, C2-C12-alkenyls and C2-C125 alkynyls, also several times by halogen, hydroxyl, cyano, amino, carboxyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkylor dialkylamino, where the alkyl radicals have 14 carbon atoms, or by indolyl or phenyl, which is unsubstituted or substituted once, twice or three times by halogen, nitro, Ci-C^-alkyl or Ci-C^-alkoxy, it also being possible in the case of multiple substitutions for the substituents to be independently different from one another, or R1 is saturated C5-C7-cycloalkyl which is optionally benzo-fused, or R1 is aryl or heteroaryl, which is unsubstituted or in turn substituted once, twice or three times by halogen, nitro, cyano, Cx-C^-alkyl or Cj-C*alkoxy, it also being possible in the case of multiple substitutions for the substituents to be independently different from one another, or provided that R2 is H, R1 is amino which is unsubstituted or mono- or disubstituted by Ci-C^alkyl, phenyl or C1-C3-alkylcarbonyl, and R2 is hydrogen or R1, where R2 and R1 are identical or different, or where the radicals R1 and R2 form, together with the nitrogen atom, a radical of the formula (CH2)n in which n is 1 to 3 and X is 0, S, CH2 or N-R3, where R3 is hydrogen, phenyl or Ci-Ce-alkyl, C2-C6-alkenyl or C2-C6-alkynyl, where these phenyl, alkyl, alkenyl and 10 alkynyl radicals are unsubstituted or substituted one or more times by: phenyl which in turn is unsubstituted or substituted one or more times by one or more substituents selected from: halogen, nitro, cyano, carboxyl, hydroxyl, methyl, ethyl, methoxy, ethoxy and trifluoromethyl, or N(R*)2/ where R* is H or Cx-Ca-alkyl, or COOR5, where R5 is H or Cx-Cg-alkyl, or CON(R6)2 or CONHR6, where R6 is H or Ci-Cg-alkyl, or where (R6)2 is a C4-C625 alkylene chain in which zero or one CH2 group which is not directly adjacent to the nitrogen atom is replaced by 0, S or N-R*, or where R3 is Ci-C^-alkoxycarbonyl or C3-C7-cycloalkyl, and the physiologically tolerated salts, which likewise effectively inhibit lysine hydroxylase and proline hydroxylase in animal models.

The invention particularly relates to pyridine-2,4- and 10 -2,5-dicarboxamides of the formula I in which R1 is C1-C12-alkyl which is unsubstituted or substituted once or, in the case of the C2-C12-alkyls, also several times by phenyl, hydroxyl, alkoxy, amino, alkoxycarbonyl, 15 alkyl- or dialkylamino, where the alkyl radicals have 1-3 carbon atoms, or R1 is phenyl which is unsubstituted or in turn substituted once by halogen, nitro, cyano, methyl or methoxy, or, provided that R2 is H, R1 is amino which is unsubstituted or monosubstituted by Cx-Cg-alkyl, phenyl or Cx-Ca-alkylcarbonyl, and R2 is hydrogen, or where the radicals R1 and R2 form, together with the nitrogen atom, a radical of the formula -N X in which X is 0, CH2 or N-R3, where R3 is hydrogen, or Cx-Ca-alkyl, and the physiologically 5 tolerated salts.

The meanings of halogen are fluorine, chlorine, bromine and iodine, those of aryl are, phenyl and naphthyl, and those of heteroaryl are 5- and 6-membered aromatic rings with 1, 2 or 3 nitrogen and/or oxygen and/or sulfur atoms, which can also be benzo-fused where appropriate; the heteroaryl radicals are, in particular, pyridyl, pyridazyl, pyrimidyl, pyrazyl, 1,3,5-triazyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thienyl, oxazolyl and thiazolyl radicals and, where appropriate, the benzo15 fused compounds thereof.

Substituted several times means hereinbefore and hereinafter that at least 2, not more than 4, hydrogen atoms present in the alkyl, alkenyl, alkynyl, heteroaryl and aryl radicals are replaced by the substituents mentioned. In the case of multiple substitutions the substituents can also be independently different from one another.

All alkyl and alkenyl radicals mentioned with more than 2 carbon atoms and all alkynyl radicals with more than 3 carbon atoms can be both straight-chain and branched.

The invention further relates to the compounds of the formula I for use as pharmaceuticals. The invention additionally relates to the compounds of the formula I for use as fibrosuppressants and immunosuppressants and for the inhibition of proline hydroxylase and lysine hydroxylase and for influencing the metabolism of - 7 collagen and collagen-like substances and the biosynthesis of Clq. Inhibitors of proline hydroxylase are suitable tools in the therapy of diseases in which the deposition of collagens makes a crucial contribution to the clinical picture. These include, inter alia, fibroses of the lungs, liver and skin (scleroderma) and atherosclerosis.

The pyridine-2,4- and -2,5-dicarboxamides of the formula I which are substituted exclusively in position 4 or 5 in the amide group show a considerable and surprising improved activity in inhibiting proline hydroxylase and lysine hydroxylase in animal experiments compared with the pyridine-2,4-dicarboxamides substituted in position 5 also by carboxamide groups from DE-A-3 707 429 and compared with the pyridine-2,4- and -2,5-dicarboxamides substituted in both amide groups of DE-A 37 039 59.

The invention further relates to a process for the preparation of compounds of the formula I, which comprises reacting a compound of the formula II' \z <7 (II') N CO2CH3 with a compound of the formula III (III) and subsequently converting the resulting compound of the formula IV where R1 and R2 have the meanings indicated for formula I, and Y is halogen, especially chlorine, Ο Ii 12 C - N RXRZ (IV) N C02CH3 with NH3 into a compound of the formula I followed, where appropriate, by conversion into its 5 physiologically tolerated salts.

The following reaction diagram shows the preparation route (stages 5 and 6), including the synthesis of the precursors (1 to 4) - 9 Reaction diagram co2h CONFER2 (IV) co2h Stage 5 (II) co2ch3 NH3/ MeOH Stage 6 CONH- (I) In stage 1, commercially available pyridine-2,4dicarboxylie acid is converted into its dicarbonyl dihalide, preferably its dichloride, and reacted with an optionally substituted benzyl alcohol to give dibenzyl pyridine-2,4-dicarboxylate.

In stage 2, the diester is selectively hydrolyzed in position 2, for example in the presence of a copper salt as described by Delarge, J.: Phar. Acta. Helv. 44 (10), 637 (1969).

The free acid functionality in position 2 is subsequently converted in stage 3 into the corresponding acid chloride and reacted with an alcohol such as, for example, methyl or ethyl alcohol to give the corresponding 2-carboxylic ester.

The remaining benzyl protective group in position 4 is eliminated by hydrogenolysis in stage 4 (for example with H2/Pd, Houben-Weyl: Vol. IV/lc (1980), pp. 381 - 82).

The free acid in position 4 (formula II) is converted into its acid halide, preferably chloride. The acid chloride can now be converted with the amine of the formula (III) into the mixed pyridine-4-carboxamide-2carboxylic ester (IV).

The mixed diamide of the formula (I) is prepared from the 2-carboxylic ester (IV) with alcoholic ammonia solution (for example in methanol).

The said process, which has been described in the reaction diagram for the compounds substituted in position 4, also applies to the compounds correspondingly substituted in position 5.

It is possible where appropriate for the products to be worked up, for example, by extraction or by chromatography, for example on silica gel. The isolated products can be recrystallized and, where appropriate, reacted with a suitable acid to give a physiologically tolerated salt. Examples of suitable acids are: mineral acids such as hydrochloric and hydrobromic acid 5 and sulfuric, phosphoric, nitric or perchloric acid or organic acids such as formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, maleic, fumaric, phenylacetic, benzoic, methanesulfonic, toluenesulfonic, oxalic, 4-aminobenzoic, naphthalene-1,510 disulfonic or ascorbic acid.

The starting compounds of the formula (III) which cannot be bought can be synthesized straightforwardly (for example Organikum, Organisch Chemisches Grundpraktikum, 15th edition, VEB Deutscher Verlag der Wissenschaften, 1976; a summary of the various possibilities is to be found in the methods index, p. 822).

The compounds of the formula I according to the invention have valuable pharmacological properties and, in particular, display activity as inhibitors of proline hydroxy20 lase and lysine hydroxylase, as fibrosuppressant and immunosuppressant.

The activity of the fibrogenase can be determined by radioimmunological determination of the N-terminal propeptide of collagen type III or of the N- or C25 terminal 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 NCj 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 Rouiller, C., 35 experimental toxic injury of the liver; in The Liver, C. Rouiller, Vol. 2, pp. 335-476, New York, Academic Press, 1964).

By reason of these pharmacological properties, the compounds according to the invention are suitable for the treatment of disorders of the metabolism of collagen and collagen-like substances and for the treatment of disorders of the biosynthesis of Clq.

The invention therefore further relates to the use of the compounds of the formula I according to the invention, and of the physiologically tolerated salts thereof, for the treatment of the abovementioned metabolic disorders.

The compounds can be used as pharmaceuticals either alone or mixed with physiologically tolerated auxiliaries or vehicles. 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, preferably 0.001 - 2.5 mg/kg/day, especially to 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.

The pharmaceuticals are producing 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 - 13 employed either as such or, preferably, in combination with suitable pharmaceutical auxiliaries or vehicles in the form of tablets, coated tablets, capsules, suppositories, emulsions, suspensions or solutions, where the content of active substance is up to 95 % advantageously between 10 to 75 %.

Suitable auxiliaries and vehicles 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, form suppressants, flavorings, preservatives, solubilizers or colorants.

The active substances can be administered orally, parenterally or rectally.

The active compounds are mixed with the additives suitable for this, such as vehicles, stabilizers or iner diluents, and converted by the usual methods into suitable dosage forms such as tablets, coated tablets, hard gelatin capsules, agueous alcoholic or oily suspensions or agueous or oily solutions. Examples of inert vehicles 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 vehicles 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 ethanol, 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 the compounds mmol of methyl pyridine-4-carboxamide-2-carboxylate (IV) is dissolved in 30 ml of saturated methanolic ammonia solution and stirred at room temperature for 2 hours. The solution is concentrated and the residue is stirred with diisopropyl ether and filtered off with suction.

Example 1 4-N-Ethylpyridine-2-carboxamide-4-carboxamide Melting point: 197°C Example 2 4-Morpho1inocarbonylpyridine-2-carboxamide Melting point: 128°C Example 3 4-N,N-Diethylpyridine-2-carboxamide-4-carboxamide Oil, MS = 222 (M + H+) molecular mass C11H15N302 (221) Example 4 4-N- (2-methoxypropyl)pyridine-2-carboxamide-4-carboxamide Melting point: 116 - 120°C Example 5 4-N- (3-methoxypropyl)pyridine-2-carboxamide-4-carboxamide Melting point: 149°C Example 6 4-N- (3-hydroxypropyl)pyridine-2-carboxamide-4-carboxamide Melting point: 154 - 156°C Example 7 4-N-alanylpyridine-2-carboxamide-4-carboxamide Melting point: 124 - 125eC Example 8 4-N- (O-benzylalanyl) pyridine-2-carboxamide-4-carboxamide Melting point: 138 - 140°C

Claims

1. Patent Claims:

1. A pyridine-2,4- or -2,5-dicarboxamide of the formula I 5 in which R 1 is Cj-Cu-alkyl, C 2 -C 12 -alkenyl or C 2 -C 12 -alkynyl, which are unsubstituted or substituted once or, in the case of the C 2 -C 12 -alkyls, C 2 -C 12 -alkenyls and C 2 -C 12 alkynyls, also several times by 10 halogen, hydroxyl, cyano, amino, carboxyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkylor dialkylamino, where the alkyl radicals have 14 carbon atoms, or by indolyl or phenyl, which is unsubstituted or 15 substituted once, twice or three times by halogen, nitro, Cj-C 4 -alkyl or Ci-C^-alkoxy, it also being possible in the case of multiple substitutions for the substituents to be independently different from one another, 20 or R 1 is saturated C 5 -C 7 -cycloalkyl which is optionally benzo-fused, or R 1 is aryl or heteroaryl, which is unsubstituted or in turn substituted once, twice or three times by halogen, nitro, cyano, C 1 -C 4 -alkyl or Ci-C,,25 alkoxy, it also being possible in the case of multiple substitutions for the substituents to be independently different from one another, - 17 or provided that R 2 is H, R 1 is amino which is unsubstituted or mono- or disubstituted by Ci-C*alkyl, phenyl or C 1 -C 3 -alkylcarbonyl, and 5 R 2 is hydrogen or R 1 , where R 2 and R 1 are identical or different, or where the radicals R 1 and R 2 form, together with the nitrogen atom, a radical of the formula R 3 ’ \ / (CH 2 ) n 10 in which n is 1 to 3 and X is 0, S, CH 2 or N-R 3 , where R 3 is hydrogen, phenyl or Ci-Ce-alkyl, C 2 -C 6 -alkenyl or 15 C 2 -C 6 -alkynyl, where the phenyl, alkyl, alkenyl and alkynyl radicals are unsubstituted or substituted one or more times by: phenyl which in turn is unsubstituted or substituted one or more times by one or more substituents 20 selected from: halogen, nitro, cyano, carboxyl, hydroxyl, methyl, ethyl, methoxy, ethoxy and trifluoromethyl, or N(R*) 2 , where 25 R* is H or Ci-Ca-alkyl, or - 18 COOR 5 , where R 5 is H or Ci-Cg-alkyl, or CON(R 5 ) 2 or CONHR®, where 5 R 6 is H or Ci-Cg-alkyl, or where (R®) 2 is a C 4 -C 6 alkylene chain in which zero or one CH 2 group which is not directly adjacent to the nitrogen atom is replaced by 0, S or N-R 4 , or where 10 R 3 is Ci-C^-alkoxycarbonyl or C 3 -C 7 -cycloalkyl, and the physiologically tolerated salts.

2. A pyridine-2,4- or -2,5-dicarboxamide of the formula I as claimed in claim 1, in which R 1 is C 1 -C 12 -alkyl which is unsubstituted or substituted 15 once or, in the case of the C 2 -C 12 -alkyls, also several times by phenyl, hydroxyl, alkoxy, alkoxycarbonyl, or dialkylamino, where the alkyl radicals have 1-3 carbon atoms, 20 or R 1 is phenyl which is unsubstituted or in turn substituted once by halogen, nitro, cyano, methyl or methoxy, or, provided that R 2 is H, R 1 is amino which is unsubstituted or monosubstituted by C^Ca-alkyl, 25 phenyl or C 1 -C 3 -alkylcarbonyl, and R 2 is hydrogen, IS or where the radicals R 1 and R 2 form, together with the nitrogen atom, a radical of the formula in which 5 X is 0, CH 2 or N-R 3 , where R 3 is hydrogen, or C 1 -C 3 -alkyl, and the physiologically tolerated salts.

3. A pyridine-2,4- or -2,5-dicarboxamide of the formula 10 I as claimed in claim 1, in which R 1 is Cj-C^-alkyl which is unsubstituted or substituted once or, in the case of the C 2 -C 12 -alkyls, also several times by phenyl, hydroxyl, alkoxy, alkoxycarbonyl, or 15 dialkylamino, where the alkyl radicals have 1-3 carbon atoms, or R 1 is phenyl, or, provided that R 2 is H, R 1 is amino which is unsubstituted or monosubstituted by methyl20 carbonyl, and R 2 is hydrogen, or where the radicals R 1 and R 2 form, together with the nitrogen atom, a radical of the formula - 20 -Ν V_7 in which X is O, CH 2 or N-R 3 , where 5 R 3 is hydrogen, or methyl, and the physiologically tolerated salts.

4. A process for the preparation of compounds of the formula I, which comprises reacting a compound of the formula II' with a compound of the formula III (HI) where R 1 and R 2 have the meanings indicated for formula I, and Y is halogen, especially chlorine, and subsequently converting the resulting compound of the formula IV (IV) with NH 3 into a compound of the formula I and into its physiologically tolerated salts. - 21 5. A compound as claimed in one or more of claims 1 to 3 for use as pharmaceuticals. 6. A compound as claimed in one or more of claims 1 to 3 for the inhibition of proline hydroxylase and lysine

5. Hydroxy1ase.

6. 7. A compound as claimed in one or more of claims 1 to 3 for use as fibrosuppressant and immunosuppressant.

7. 8. A pharmaceutical containing a compound of the formula I with compatible pharmaceutical vehicles.

8. 10 9. The use of compounds of the formula I for influencing the metabolism of collagen and collagen-like substances and the biosynthesis of Cl q . 10. The use of compounds of the formula I for the treatment of disorders of the metabolism of collagen and 15 collagen-like substances and of the biosynthesis of Cl q .

9. 11. A process for the production of pharmaceuticals for influencing the metabolism of collagen and collagen-like substances and the biosynthesis of Cl q , which comprises incorporating a compound of the formula I in the pharma20 ceutical. -2212. A pyridine -2,4- or -2,5- dicarboxamide as claimed in claim 1, substantially as hereinbefore described and exemplified.

10. 13. A process for the preparation of a pyridine -2,4- or -2,5dicarboxamide as claimed in claim 1, substantially as hereinbefore described and exemplified.

11. 14. A pyridine -2,4- or -2,5- dicarboxamide as claimed in claim 1, whenever prepared by a process claimed in claim 4 or claim 13.

12. 15. A pharmaceutical according to claim 8, substantially as hereinbefore described.

13. 16. Use according to claim 9, substantially as hereinbefore described.

14. 17. Use according to claim 10, substantially as hereinbefore described.

15. 18. A process for the production of a pharmaceutical according to claim 8, substantially as hereinbefore described.

16. 19. A pharmaceutical according to claim 8, whenever produced by a process claimed in claim 11 or 18.