NZ236766A

NZ236766A - Di(nitroxyalkyl)amides of pyridine-2,4- and -2,5-dicarboxylic acids and their use in pharmaceutical compositions

Info

Publication number: NZ236766A
Application number: NZ236766A
Authority: NZ
Inventors: Ekkehard Baader
Original assignee: Hoechst Ag
Priority date: 1990-01-16
Filing date: 1991-01-14
Publication date: 1993-08-26
Also published as: ZA91291B; PT96493A; HUT59102A; CA2034206A1; AU6936691A; MX24143A; JPH04330060A; MA22041A1; KR910014352A; IE910126A1; IL96941A0; NO910163D0; CN1053606A; BR9100159A; AU631285B2; FI910177A; DE4001002A1; FI910177A0; NO910163L; HU910109D0

Description

<div id="description" class="application article clearfix"> New Zealand Paient Spedficaiion for Paient Number £36766 Henry Hughes Ltd 236 7 6 6 Patents Form 5 Priority Del;?,: Jk.K'SQ Caiiip.o^ £■■. y.i'. r '.ioi"! r;. co~nQZ&h.i;Ww-. Publics'! ;,n Date: P.O. Journal, No: J%1X f! % ^ •• t M '< A I$ jfp f\ * /S; m an u y y\i N.Z. No. NEW ZEALAND Patents Act 1953 COMPLETE SPECIFICATION PI(NITROXYALKYL)AMIDES OF PYRIDINE-2.A- AND -2.5-DICARBOXYLIC ACIDS. A PROCESS FOR THE PREPARATION THEREOF. AND THE USE THEREOF We, HOECHST AKTIENGESELLSHAFT, a Corporation organized under the laws of the Federal Republic of Germany, of D-6230 Frankfurt am Main 80, Federal Republic of Germany, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement - 1 - (Followed by 1A) f !,Z. PATEi'iT 14 JAN 1991 REcsivro SQSCggT1 ilKTSSII^BLLS^HAFT HOE 00/? CIO Dr. CW/^ p. .•'vi ?<m 'A Di(nitroxyalkyl)amides of pyridine-2,4- and -2,5-dicarboxylic acids, a process for the preparation there-5 of, and the use thereof Compounds which inhibit the enzymes proline hydroxylase and lysine hydroxylase bring about a very selective inhibition of collagen biosynthesis by influencing the collagen-specific hydroxylation reactions. In the course 10 thereof, protein-bound proline or lysine is hydroxylated by the enzymes proline hydroxylase or lysine hydroxylase. If this reaction is suppressed by inhibitors, the result is an insufficiently hydroxylated collagen molecule which is unable to function and can be released by the cells 15 into the extracellular space only in a small amount. Moreover, the insufficiently hydroxylated collagen cannot be incorporated in the collagen matrix and very readily undergoes proteolytic degradation. The consequence of these effects is an overall reduction in the amount of 20 collagen deposited outside the cells. It is known that the inhibition of proline hydroxylase by known inhibitors such as a, a' -dipyridyl results in inhibition of Clq biosynthesis by macrophages (W. Miiller et al., FEBS Lett. 90 (1978), 218; Immunobiology 155 25 (1978), 47). This leads to the classical pathway of complement activation becoming inoperative. Thus, inhibitors of proline hydroxylase also act as immunosuppressants, for example in immune complex diseases. It is known that the enzyme proline hydroxylase is 30 efficiently inhibited by pyridine-2,4- and -2,5-dicarb-oxylic acids (K. Ma jama a et al., Eur. J. Biochem. 138 (1984) 239-245). These compounds are, however, effective inhibitors in cell culture only in very high concentrations (Tschank, G. et al., Biochem. J. 238 (1987) 625-35 633). • 5 US 4,717,727 gives a description of diesters of pyri-dine-2,4- and -2,5-dicarboxylic acids with 1-6 carbon atoms in the ester alkyl moiety as pharmaceuticals for inhibiting proline hydroxylase and lysine hydroxylase. These lower alkyl diesters have the disadvantage, however, that in the body they are too rapidly cleaved to the acids and do not reach their site of action in the cell in sufficiently high concentration and thus are poorly suited for possible administration as pharmaceuticals . NZ 223433, US 5,037,839 and NZ 223431 describe in a general form mixed ester/amides, higher alkyl diesters and diamides of pyridine-2,4- and -2,5-dicar-boxylic acids, which are effective inhibitors of collagen biosynthesis in animal models. Thus, NZ 223433 and US 5,037,839 describe, inter alia, the synthesis of N, N' -bis (2 -methoxyethyl) pyridine-2,4-dicarboxamide and N, N' -bis (3 - is opropoxypr opyl) pyridine-2,4-dicarboxamide. AU-A-89/39263 proposes an improved process for the preparation of N,N'-bis(2-methcxyethyl)pyridine-2,4-dicarboxamide. CA 2021529 proposes new N,N'-bis(alkoxyalkyl)pyridine-2,4-dicarboxamides. Both pyridine-2,4- and -2,5-dicarboxamides (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-dicarbohydrazides (Itai et al., Bl. 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. 5 10 15 — i — o n n ^ n J it oo I OU I It has now been found, surprisingly, that di(nitroxy-alkyl)amides of pyridine-2,4- and -2,5-dicarboxylic acids, of the formula I 02n0-r-hn0c— tx (I) conh-r-ono2 in which R is Cj-C^-alkanediyl, and the physiologically tolerated salts, effectively inhibit lysine hydroxylase and proline hydroxylase in animal models. Accordingly, the invention relates to a) the use of compounds of the formula I o2no-r-hnoc— (I) c0nh-r-0n02 cx in which R is Cj-C^-alkanediyl, and the physiologically tolerated salts, for the preparation of a pharmaceutical which inhibits proline hydroxylase and lysine hydroxylase. The invention additionally relates to b) the compounds of the formula I in which R is methylene, propylene or butylene, and the physiologically tolerated salts, for use as pharmaceuticals. - 4 - i~ oo ( t>() I The invention additionally -relates to c) the compounds of the formula I ( in which R is methylene, propylene or butylene, 5 and the physiologically tolerated salts thereof. The invention particularly relates to the compounds of the formula I defined in a), b) and c) for use as fibro-suppressants and immunosuppressants and for the inhibition of proline hydroxylase and lysine hydroxylase and 10 for influencing the metabolism of collagen and collagenlike substances and the biosynthesis of Clg. All the said alkyl radicals with more than 2 carbon atoms can be both straight-chain and branched. The invention additionally relates to a process for the 15 preparation of compounds of the formula I, which comprises reacting a compound of the formula II 0 « Y- C— rp, (II) Dl N C-Y « O with a compound of the formula III h2n-r-0n02 (xii> where R has the meaning specified for formula I, and T is halogen, hydroxyl or C1-CA-alkoxy, or forms together with 20 the carbonyl group an active ester or a mixed anhydride. XjteivSS r . .. . - 5 - 236 7 ho-r-hnoc— fx & (IV) CONH-R-OH in which R is as defined above, and subsequently converting the reaction products where appropriate into their physiologically tolerated salts. 5 The preparation of compounds of the formula I and the preparation of those starting substances required for this which cannot be bought is described in detail hereinafter. The compounds according to the invention are prepared 10 most straightforwardly by the two components, the pyridine derivative of the formula (II) and the amine of the formula (III), being mixed in equimolar amounts or with an up to about 5-fold excess of III and reacted at temperatures between -30 and 150 °C, preferably at 20 to 15 100°C, until the reaction is complete. The completion of the reaction can be determined, for example, by thin-layer chromatography. One variant of this process comprises using a suitable solvent such as diethyl ether or dimethoxyethane or tetrahydrofuran, chlorinated hydro-20 carbons such as methylene chloride, chloroform, tri- or tetrachloroethylene, benzene, toluene or else polar solvents such as dimethylformamide, acetone, alcohols such as methanol or ethanol or dimethyl sulfoxide. It is also possible in this case to use an excess of amine of 25 the formula (III), which can be up to about 5-fold amounts. The temperatures for this reaction are between room temperature and the boiling point of the solvent, with temperatures in the range from room temperature to 130°C being particularly preferred. 30 The reaction can likewise be carried out via a mixed 236766 anhydride such as ethyl chloro formate or via an actiyai+^d ester such as paranitrophenyl ester (Y= C1CH2-C00 or N02-C6H4-0). Appropriate methods are described in the literature. 5 It is also possible, where appropriate, for the reaction to be carried out in the presence of bases. Examples of suitable additional bases are carbonates or bicarbonates such as sodium or potassium carbonate or sodium or potassium bicarbonate, or tertiary amines such as tri-10 ethylamine, tributylamine, e t hy 1 di i s opr opy 1 amine or heterocyclic amines such as N-alkylmorpholine, pyridine, quinoline or dialkylanilines. One variant for the preparation of the compounds of the formula I comprises nitration of the corresponding 15 hydroxyalkyldiamides of pyridine-2,4- or -2,5-dicarboxylic acid (IV). This entails adding concentrated nitric acid to the corresponding hydroxyalkyldiamides at reaction temperatures from -20#C to +10"C, preferably at -10°C to -5°C. The reaction time in this case is 20 10-240 min, preferably 20-90 min. The reaction product is subsequently neutralized where appropriate. Where appropriate the products can be worked up, for example, by extraction or by chromatography, for example on silica gel. The isolated product can be recrystallized 25 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, and sulfuric, phosphoric, nitric or perchloric acid or 30 organic acids such as formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, maleic, fumaric, phenylacetic, benzoic, methanesulfonic, toluene-sulfonic, oxalic, 4-aminobenzoic, naphthalene-l,5-disulf-onic or ascorbic acid. 10 15 20 25 30 _7_ 23 6 766 Those starting compounds of the formula (III) which cannot be bought can be synthesized by processes known from the literature. The starting compounds of the formula (II) are obtained, for example, by converting pyridine-2,4- or -2,5-dicarboxylic acid into the corresponding pyridine-2,4- or -2,5-dicarbonyl halide, preferably chloride (by processes known from the literature), preferably in the presence of a catalyst such as dimethyl form amide. This acid halide can then be reacted, for example, either with a suitable alcohol, for example paranitrobenzyl alcohol, to give the corresponding active ester, or else with lower alcohols such as methanol or ethanol to give the corresponding esters. It is likewise also possible for the pyridine-2,4- or -2,5-dicarboxylic acid initially to be converted by addition of a suitable carboxylic acid or of a carb-oxylic ester such as ethyl chloroformate into a mixed anhydride which is then reacted with the amines (III) to give the products according to the invention. An appropriate method is likewise described in the literature. The starting compounds of the formula (IV) are obtained, for example, by reacting corresponding N,N'-bis(alkoxy-alkyl)pyridine-2,4- or -2,5-dicarboxamides, preferably the bis (methoxyalkyl)diamide by processes known from the literature, for example with boron tribromide. The preparation of the bis (alkoxyalkyl) diamides is Jaiown and described, for example, in NZ 223433 and US 5,037,839. This entails reacting a reactive pyridinedicarboxylic acid derivative, for example the pyridinedicarbonyl chloride, with an alkoxyalkylamine. The compounds of the formula I according to the invention have valuable pharmacological properties and display, in particular, activity as inhibitors of proline hydroxylase t w { and lysine hydroxylase, as fibrosuppressant and ixnmuna- ^ suppr e s s ant. v x-.* f X'~ <" * - 8 - 236766 Because of these pharmacological properties, the compounds according to the invention are suitable for the treatment of disturbances of the metabolism of collagen and collagen-like substances and for the treatment of disturbances of the biosynthesis of Clg. Hence the invention furthermore 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 excipients. 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, in particular 0.005 - 1.0 mg/kg/day. The dose can also be increased in severe cases. However, in many cases, lower doses are also sufficient. These data relate to adults weighing about 75 kg. The invention additionally embraces the use of the compounds according to the invention for the preparation of pharmaceuticals which are employed for the treatment and prophylaxis of the abovementioned metabolic disorders . The invention furthermore relates to pharmaceuticals which contain one or more compounds of the formula I according to the invention and/or the physiologically tolerated salts thereof. The pharmaceuticals are prepared by processes which core known per se and familiar to those skilled in the art. The pharmacologically active compounds (= active substance) according to the invention are employed as pharmaceuticals either as such or, preferably, in combination with suitable pharmaceutical auxiliaries or -9 - *Z3&766 exclpients in the form of tablets, coated tablets, capsules, suppositories, emulsions, suspensions or solutions, in which the content of active substance is up to about 95%, advantageously between 10 and 75%. 5 Examples of suitable auxiliaries or excipients for the desired pharmaceutical formulation are, besides solvents, gel-formers, suppository bases, tablet auxiliaries and other active substance vehicles, also antioxidants, dispersing agents, emulsifiers, antifoam agents, flavor 10 correctives, preservatives, solubilizers and colorants. The active substances can be administered orally, paren-terally or rectally. The active compounds are mixed with the additives suitable for this purpose, such as excipients, stabilizers or 15 inert diluents, and converted by customary 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 20 arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, especially com starch. This preparation can be carried out both as dry and as wet granules. Examples of suitable oily excipients or solvents are vegetable or animal oils, such as sun-25 flower oil or fish liver oil. For subcutaneous or intravenous administration, the active compounds are converted into solution, suspension or emulsion, if desired with the substances suitable for this purpose, such as solubilizers, emulsifiers or other 30 auxiliaries. Examples of suitable solvents are physiological saline or alcohols, for example ethanol, propan-ol, glycerol, as well as sugar solutions such as glucose or mannitol solutions, or else a mixture of the various solvents mentioned. — 10 — O O f-J '"> P id ob/ob t The invention is explained in detail hereinafter by means of examples. Precursor 1: bis-N,N' - (Methoxyethyl) amide of pyridine-2,4-dicarboxylic 5 acid CONH-CH2-CH2.OCH3 cV N CONH-CH2-CH2-OCH3 3 g of pyridine-2,4-dicarboxylic acid are introduced into 50 ml of toluene and 1 ml of DMF, and 2.7 ml of thionyl chloride are added dropwise to the solution. The mixture is heated until no further evolution of gas is evident 10 (about 2.5 h). The mixture is cooled, 5 ml of toluene are distilled out, and 4.6 ml of 2-methoxyethylamine and 5 ml of triethylamine are added dropwise to the solution. The solution is stirred at room temperature for 4 h and then evaporated, the residue is taken up in water and ex-15 tracted 4 x with methylene chloride. The combined organic phases are dried over magnesium sulfate and evaporated. The crude product is chromatographed on silica gel (solvent ethyl acetate). Melting point: 42 - 44"C 20 ^-NMR (CDCI3) z 5 = 1.2 (3H, tr); 3.3-3.8 (12H, qu. and m); 7.9 (1H, m); 8.4-8.5 (1H, m); - 11 ' *J.'L>Ujl 2 S bis-N,N'-(2-Hydroxyethyl)amide of pyridine-2,4-dicarboxylic acid conh-ch2-ch2-oh A — conh-ch2-ch2-oh 0.5 g of bis-(N,N'-(2-methoxyethyl)amide of pyridine-2,4-dicarboxylic acid (precursor 1) is dissolved in 10 ml of dichloromethane and, at -78°C, boron tribromide (11 ml, 1 molar solution in dichloromethane) is added dropwise. After addition is complete, allow to reach room temperature and then stir for 3 hours. Pour into 100 ml of saturated bicarbonate solution and extract 3 x with ethyl acetate. The combined organic solvents are dried with magnesium sulfate and evaporated. The crude product is chromatographed on silica gel. ^-NMR (CDC13): 5 = 1.5-2.2 (4H, m); 3.4 (4H, m); 3.6 (4H, m); 7.9-8.0 (1H, m); 8.4-8.5 (1H, m); 8.7-8.8 (1H, m) Example 1 N, N' -Di (2-nitroxyethyl) amide of pyridine-2,4-dicarboxylic acid conh- chj. ch?-onoo dx conh-ch2-ch2-ono2 1 g of di( 2-hydroxy ethyl) amide of pyridine-2,4-di-carboxylic acid (precursor 2) is added at -10°C to -5°C 0 7 C -9 u j V / </div>

Claims

<div id="claims" class="application article clearfix printTableText"> 23B7o'G '■ - 12 - 1 to 5ml concentrated nitric acid. The mixture is allowed to warm to 2"C and then stirred for 40 minutes. It is poured into ice/water and neutralized with sodium carbonate. The solution is extracted three times with dichloromethane, and the organic phases are dried over magnesium sulfate and evaporated. The residue crystallizes from ether. Yield: 750 mg Melting point: 85 - 88"C VX R 7 fi R _ 13 _ V I w V WHAT WE CLAIM IS:

1. The use of di(nitroxyalkyl) amides of pyridine-2,4- and -2,5-dicarboxylic acids, of the formula I o2ko-r-hnoc— ftL ^ n ^ conh- r- 0n02 in which R is linear or branched Cj-C^-alkanediyl but excluding ethylene, and the physiologically tolerated salts thereof, for the preparation of pharmaceuticals which inhibit proline hydroxylase and lysine hydroxylase.

2. The use as claimed in claim 1, wherein R is propylene.

3. A compound of the formula I 0,no-r-hnoc- j-, c0nh-r-0n02 a (I) in which R is methylene, propylene or butylene, and the physiologically tolerated salts thereof.

4. A compound of the formula I as claimed in claim 3, wherein R is methylene or n-propylene.

5. A compound as claimed in claim 3 or 4, for use as a - •' » pharmaceutical. A process for the preparation of compounds of trie * " ^;AT C7fi;14 - & O - V /• U;formula I as claimed in claim 3, which comprises reacting a compound of the formula II;O;n y-c-;tx;(ID;n c-y a O;with a compound of the formula III;h2n-r-ono2 (hi);where R is as defined in claim 3, and Y is halogen, hydroxyl or Ci-C^-alkoxy, or forms together with the carbonyl group an active ester or a mixed anhydride, or comprises nitrating a compound of the formula IV;IX.;ho-r-hnoc—;iv conh-r-oh in which r is as defined in claim 3, and subsequently converting the reaction products where appropriate into their physiologically tolerated salts.;A compound as claimed in claim 3 or 4 for inhibiting proline hydroxylase and lysine hydroxylase.;Use of a compound of the formula I as defined in any one of claims 1 to 4 for the preparation of an agent for use as a fibrosuppressant or an immunosuppressant.;A pharmaceutical containing a compound of the formula I as claimed in claim 3 or 4 with tolerated pharmaceutical;23 67 6;/;15;10. The use of compounds of the formula I or the physiologically tolerated salts thereof as defined in any one of claims 1 - 4 for the preparation of an agent for influencing the metabolism of collagen and collagen-like substances and the biosynthesis of Clq.;11. The use of compounds of the formula I or the physiologically tolerated salts thereof as defined in any one of claims 1 - 4 for the preparation of an agent for the treatment of disturbances of the metabolism of collagen and collagen-like substances and the biosynthesis of Clq.;12. A. process for the preparation of pharmaceuticals for influencing the metabolism of collagen and collagen-like substances and the biosynthesis of Clq, which comprises adding a compound of the formula I or the physiologically tolerated salts thereof as defined in any one of claims 1 to 4 to the pharmaceutical.;13. A compound according to claim 3 substantially as herein described or exemplified.;14. A process according to claim 6 substantially as herein described or exemplified.;15. A pharmaceutical according to claim 9 substantially as herein described or exemplified.;16. A process according to claim 12 substantially as herein described or exemplified.;HOECHST /AKTIENGESELLSCHAFr* </div>