IE880350L - Pyridine-2,4- and -2,5-dicarboxylic acid derivatives,¹process for their preparation, the use thereof and¹medicaments based on these compounds - Google Patents
Pyridine-2,4- and -2,5-dicarboxylic acid derivatives,¹process for their preparation, the use thereof and¹medicaments based on these compoundsInfo
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- IE880350L IE880350L IE880350A IE35088A IE880350L IE 880350 L IE880350 L IE 880350L IE 880350 A IE880350 A IE 880350A IE 35088 A IE35088 A IE 35088A IE 880350 L IE880350 L IE 880350L
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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
- A61P3/00—Drugs for disorders of the metabolism
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- 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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- 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
- C07D213/81—Amides; Imides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Abstract
Pyridine-2,4- and -2,5-dicarboxylic acid derivatives of the formula I <IMAGE> in which R<1>, R<2> and X have the meanings indicated, are used in particular for influencing the metabolism of collagen and collagen- like substances or the biosynthesis of C1q.
[EP0278452A2]
Description
67446 - i - Compounds which inhibit proline hydroxylase and lysine hydroxylase effect very selective inhibition of collages, biosynthesis by influencing collagen-specific hydroxy- lation reactions- In fchs course of these, protein-bonded 9 5 proline or lysine is hydroseylated by the enzymes proline hydroxylase and lysine hydroxylase- If this reaction is j, suppressed by inhibitors„ a hypo-hydroxylated collagen molecule which is not capable of functioning arid can be released by the cell into the extracellular space in only 10 a small amount is formed. The hypo-hydroxylated collagen also cannot be incorporated into the collagen matrix and is very readily degraded proteolytieally. As a consequence of these effects, the total amount of extracellular ly deposited collagen is reduced, 15 It is known that inhibition of proline hydroxylase by known inhibitors, such as a„ a' -dipyridy 1, leads to an inhibition of the Cl^-biosyn thesis of macrophages (W. Muller at al., FEBS Lett. 90 (1978), 218; limxxmx-biology 155 (1978) 47) . There is thus a loss of the 20 classical route of complement activation- Inhibitors of proline hydroxylase therefore also act as immunosuppressants, for example in immunity complex diseases.
It is known that proline hydro^cylase is inhibited effectively by pyridine-2,4- and -2,5-dicarboxylic acid 25 (X» Mayama et al.# Eur- J- Biochem. 138 (1984) 239-245) . However, these compounds are active ass inhibitors in the cell culture only in very high concentrations (v\ Gunsler at al» Collagen and Rel. Research 3, 71 1983) .
DE-A 3,432,094 describes pyridine-2,4- and -2,5-dicar-3 0 boxylic acid diesters with 1-6 carbon atoms in the ester alkyl part as pharmaceuticals for inhibiting proline: hydroxy1ase and lysine hydroxylase.
Hoseirer,, these lower alkyl dies tars have the disadvantage that they are split too rapidly in the organism to give 35 the acids and do not arrive at their site of action in - 2 - the cell -in a sufficiently high concentration, and therefore are not particularly suitable for possible administration as pharmaceuticals.
Surprisingly, it has so**' been found that the mixed 5 ester/amides of pyridine-2,4- and -2,5-dicarboxylic acid and likewise the higher alkylated diesters are excellent inhibitors of collagen biosynthesis in the animal model.
The actual active compound, the pyridine-2,4- or -2,5-dicarboxylic acid, is first farmed in the cell by 10 hydrolysis of the esters or ester/amides. On the basis of their higher lipophilic!ty and the fact that, surprisingly , they are hydrolyzed only very slowly during transportation,, the asters and ester/abides can be transported into the cells. Only here is the actual active compound^ 15 pyridine-2,4- or -2,5-dicarboxylic acid, released.
The invention thus relates to: 1. Pyridine-2,4- and -2, 5-dicarboacylic acid derivatives of the formula X 9 in R--0-C- "f*1 (I) C-X-R R 0 in which 20 R1 denotes branched or unbranched C1~C12 -alkyl which is monosubstitutad or else, in the cas<& ot the C2-C12~alkyl radicals , polysubs t i-tut ed by halogen ? hydroxyl, cyano, carboxyl, alkoxy, alkoxycarboayl, alkylcarbonylorsy or alkyl- or 25 dxalkylamino, the alkyl radicals coatainiag 1-4 carbon atoms and, in the case of the C3- aa,d C4-alkyl radicals,, it also bsdng possible for them to be branched, phenyl, which is in tuna - 3 ~ optionally mono-, di- or t r i s ub s t i t u t e d by halogen^ nitro, C1-C4-alkyl or C^-C^-alkoxy, it also being possible, in the case of poly-substitution, for the substituents to differ 5 independently of one another and it also being possible, in the case of the C3- and C4-alkyl radicals, for these to be branched, or R1 denotes saturated Cs-C7 -cycloalkyl, which is optionally benzo-fused, 10 or R1 denotes phenyls n&phthyl or a 5~ or 6-meabered aromatic ring having 1, 2 or 3 nitrogen and/or oxygen and/or sulfur atoms „ which in turn is optionally a.ono-t, di- or trisubstituted by halogen, C^-C^-alkyl ox- Cx-CA-alko3cy, it also 15 being possible, in the case of polysubstitution, for the substifcuents to differ independently of one another and it also ha lag possible, in the case of the C3- and CA-alkyl radicals , for these to be branched, 20 or R1 denotes 2-oxo-l, 3-dioxolylmethyl, which is optionally also methyl-substituted, or R1, if 2 is nitrogen, denotes hydrogen* and R2 independently of R1 is hydrogen or R1, it alsio 25 being possible for R2 to be identical to R1, and X denotes oxygen or R3-substituted nitrogen, in which R3 is hydrogen or C^-Cg-alkyl or optionally together with R1 fionss a heterocyclic saturated 30 5-, 6- or 7-membered ring,, it also being possible for the heterocyclic ring to include a second nitrogen atom and it being possible for the heterocyclic ring in turn to be substituted by phenyl or pheny 1 -Cx - C3 - alkyl, 35 and physiologically tolerated salts thereof for use as phaxxoaeeuticals.
The invention particularly relates to pyridine-2,4- and -2,5-dicarboxyllc a,cid derivatives of formula X, in which ~ 4 _ R1 denotes branched or unbrsnched C^-C^-alkyl %-hich is monosubsticuted or else,, in the case of the C3- and C4-alkyl radicals,, polysubs tituted by C1-C3-alkoxy and/or C1"C3-alkoxycarbanyl, it also 5 being possible for the C3-alkyl radicals to be branched, and/or phenyl, or R1 denotes C5» or Cs-cycloalkyl? which is optionally benzo-fused, or R1 denotes phenyl, which is optionally mono-, di- or 10 trisubstituted by nitro, or R1 denotes 2-, 3- or 4-pyridyl, naphthyl, 2- or 3-thienyl, pyrazolyl, imidazolyl or thiazolyl, or R1 denotes 5-methyl-2-o3co-l,3-dioaeol-4-yl-methyl and 15 R2 independently of K1 is hydrogen or R1, it also being possible for R2 to be identical to R1, and X denotes oxygen or R3-substituted nitrogen, in which R3 is hydrogen or Ci-C3-alkyl or optionally 2 0 together with E1 forms a heterocyclic saturated 6-memta®red ring,'it also being possible for the heterocyclic 6 -mexnbered ring to include a second nitrogen ato^ and to be substituted in turn by phenyl or phenyl -C^-Cg- alkyl, 25 and physiologically tolerated salts thereof„ for use as pharmaceuticals.
The invention also relates to pyridine-2,4- and -2,5-dicarboacylic acid derivatives of the formula I" 0 0» II R (I' ) 18 C - X" - R1 n 0 Cl in which 3 0 R1' denotes branched or unbranched alkyl which is- mono substituted or else, in the ease of C2-C12-alkyl, polysubstituted by halogen, hydroacyl, cyan© , carboxyl, alkoxy, alkoxy-carbonyl, alkylcarbonyloxy or alkyl- or dialkyl-aiaino, the alkyl radicals containing 1-4 carbon atoms and it also being possible, in the case of the C3- and C4-alkyl radicals, for these to ba branched, phenyl, which is in turn optionally mono-;, di- or trisubstituted by halogen, C1-C4-alkoxy or C^-C^-alkyl, it also being possible for the C3- and C4-alkyl radicals mentioned to be branched and it also being possible, in the case of polysubs ti tut ion , for the substituents to differ independently of one another, denotes saturated C5-C7-cycloalkyl, which is optionally benzo"fused, denotes phenyl, naphthyl or a 5- or 6-membered aromatic ring having 1,, 2 or 3 nitrogen and/or oxygen and/or sulfur atoms, which is in turn optionally mono - L, di- or trisubstituted by halogen, nitro, C^-C^-alkyl or Cx-C4 -alkoxy, it also being possible, in the case of poly-substitution,, for the substituents to differ independently of one another and it also being possible, in the case of the C3~ and C4»alkyl radicals, for these to be branched, denotes 2-oxo-l,3 -dioscolylmethyl, which is optionally methyl-substituted, if X' is nitrogen,, denotes hydrogen, independently of R1' is hydrogen or R1', it also being possible for R2' to ba identical to R1 , denotes oxygen or R3'-substituted nitrogen,, in which R3' is hydrogen or Cx-Cs~ alkyl or, optionally together with R1', fors&s a heterocyclic,, saturated 5-, a- or 7-me3J!bsred ring,, it also being possible for the heterocyclic ring to include a second nitrogen atom and it - S - being possible for the heterocyclic ring in turn to be substituted by phenyl or phenyl-Cx-C3-alkyl, and physiologically tolerated salts thereof, 5 excluding the compounds in which I' denotes oscygen and R1' and R2' are methyl or ethyl which is substituted by chlorine, hydroxy 1 or phenyl, and di (4-methoxyphen.yl) pyridine-2, S-dicarboscylate.
Preferred pyridine-2,4- and -2,5-dicarboxylic acid 10 derivatives of formula Is are those in which R1' denotes branched or unbranched C1-C4-alkyl, which is monosuhstituted or else, in the case of the C2-C4-alkyl radicals, polysubstituted by alkoxy or alkoacycarbonyl, the alkyl radicals containing 15 1-3 carbon atoms and it also being possible, in the case of the C3-alkyl compounds, for these to be branched,, or phenyl or E1' denotes cyclopentyl or cyclohexyl, which are 2 0 optionally benzo-fused, or R1' denotes phenyl, which is optionally substituted by 1, 2 or 3 nitro groups, or naphthyl, or R1' denotes 2-, 3- or 4-pyridyl, 3-thienyl, pyrazolyl, imidasolyl or thiazolyl, 25 or R1' denotes 5~methyl-2-oaeo-l, 3~dioxol-4-yl~methyl and R2' independently or R1' is hydrogen or R1', it also being possible for R2' to be identical to R3"'^ and 30 X' denotes oxygen or R3' - substituted nitrogen,, xxx which R3' is hydrogen or C^-Cg-alkyl or optionally together with R1' foxsas a heterocyclic, saturated S-membered ring,, it also being possible for the heterocyclic S-^esabered ring to include 3 5 a second nitrogen atom and in turn to be sub stituted by phenyl or phenyl-Cx-C3-alkyl „ and physiologically tolerated salts thereof, - 7 - excluding -the compounds in %?hich X' denotes oxygen and R1' and R2' are methyl or ethyl which is substituted by chlorine, hydro.iq/1 or phenyl, arid di (4-methoxypheiiyl) pyridine-2,5-dicarboacylate. 5 Particularly preferred pyridine-2„4- and -2,5-dicarboacylie acid derivatives of the formula I7 are those in which R1' is branched or unbranched C1-C4-alkyl, which is stabs tituted by alkoacycarbonyl, the alkyl radicals containing 1-3 carbon atoms and it also being possible, 10 in the case of the C3-alkyl radicals, for these to be branched, and R2' independently of R1' is hydrogen or E1', it also being possible for R2' to be identical to R1', and X' denotes oxygen, and physiologically tolerated salts thereof. 15 These compounds have, inter alia, a particular activity on oral administration, as do the especially preferred pyridine-2,4- and -2,5-dicarboxylic acid derivatives of the foxinula 1*' in which E1' and R2' are l-isopropoaey-carbonylethyl groups and X' denotes oxygen (such as, for 20 example, bis (l-isoproposcyearbonylethyl) pyridine-2,5-dicarboacylata (Example 3) or bis (1-isopropoxycarbonylethyl) pyridine-2,4-dicarboxylate (Example 30)), and physiologically tolerated salts thereof. 25 By halogan there are understood fluorine, chlorine, bromine and iodine, by aryl there are understood phenyl and naphthyl and by heteroaryl there are understood 5-and 6-membered aromatic rings having 1, 2 or 3 nitrogen and/or oxygen and/or sulfur atoms and can optionally also 30 be benzo-fused? the heteroaryl radicals- are, in particular,,, pyridyl pyrxdazyl, pyrimidyl, pyrazyl, 1,3,5-triasyl, pyrolyl, pyrazolyl, imxdazolyl, triazolyl, thienyl, oaca^olyl and thiazolyl radicals and where appropriate benzo-fused compounds thereof., 35 "Polysubstituted"' above and below means that at least 2 - 8 - and at most all of the hydrogen, atoms present in the alkyl radicals are replaced by the substituents mentioned. It is preferably a matter here of one substituent per methyl or methylene group. 5 In the case of polysubstitution, the substituents can also differ independently of one another.
The invention furthermore relates to a process for the preparation of compounds of the formula Xe, which comprises 10 a) reacting a conipotxad of the formula II C-Y ii 0 with a compound of the formula XII EE' -R1' (III) in which R1', R2' and X' have the meanings given in the ease of formula Is and Y is halogen or hydroucyl, 15 or b) reacting a compound of the form-sal®, IV Z"C~~>p a (IV) C-X'-R1' %?ith a compound of the formula V HO-R2' (T) in which R1', R2' and Xs have the meanings given in 20 the case of forssila I* and % is halogen, or ~ 9 c) reacting a compound of the formula "ST. 0 8 z-c- CVT) c-z » 0 with an alcohol HO-R2' or an alcohol of the formula VI X HO-R1' (VXD 5 in, which R1' and R2' have the aiaanings given in the case of formula I" and Z is halogen, or d) reacting an alkali metal aalt of pyridine-2,4- or -2,5-dicarboxylic acid with a halide of the formula VIII 10 R1' -Z (VIII) in which R1' has the meanings gives, in the case of formula I* and Z is halogen, and, if appropriate, converting the reaction products into their physiologically tolerated salts. 15 The preparation of compounds according to formula I and the preparation of the starting substances required for this - where they are not commercially available - are described in more detail below.
The compounds according to the invention are moat easily 20 prepared by mixing the ewo components, the pyridine derivative according to formula (XI), (IV) or (VI) and the amine or alcohol according to formula (XXX)„ (V) or (VII), in equimolar sanounts or with up to an approximately 5-fold excess of XIX, V or VIX, and 25 reacting them at temperatures between -30 to 150 °Ce preferably at 20 to 100°C» until the reaction has ended. The end of the reaction can be determined by means of thin layer chromatography (TLC control) . One variant of this process comprises carrying out the reaction in a 10 - suitable • solvent, such as diethyl ether or disiethoxyethane or tetrahydrofuran, chlorinated hydrocarbons, such as methylene chloride, chloroform or trior tatrachloroethvlene, bensssne, toluene or polar 5 solvents, such as dimethyl formamide or acetone or dimethyl sulfoxide. Mx excess of amine/alcohol according to formula (III) , (V) or (VII) , *«*hich can be up to 5 times the amounts, can also be used here. The reaction temperatures here are between room temperature and the 10 boiling point of the solvent, temperatures in the range from room temperature to 130 °C being particularly preferred.
If appropriate, the reaction can also be carried out in the presence of bases. Possible additional bases are 15 inorganic acid-trapping agents, such as carbonates or bicarbonatas, for example sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate, or organic acid-trapping agents, such as tertiary amines, such as triethylamiaa, tributvlamine or ethyl diiso-2 0 propylamine, or heterocyclic amines t. such as M-alkyl-morpholine, pyridine, eruinoline or dialkylanilines.
The reaction of the compounds according to formula (II) with alcohols according to formula (III) (X'= O) is preferably carried out with the addition of a dehydrating 25 agent, such as a dialkylcarbodiimide, the alkyl radicals containing 1 to 8 carbon atoms and it also being possible, in the case of the C3 ~ C8 - compounds „ for these to be branched or cyclic? dicyclohexylcarbodiinide is preferably used. A corresponding method is described ia 30 Houben-Weyl, Volume XV/2, pages 103-111',,, Methoden der Organischen Chemie (Methods of Organic Chemistry) , 4th edition, Georg Thieme Verlag, Stuttgart, 1974 - If appropriate, the products can be worked up, for example by attraction or by chromatography, for example 35 over silica gel. The isolated products can be recrystallizad and if appropriate reacted with a suitable - 11 - acid to give a physiologically tolerated salt. Examples of possible suitable acids ares mineral acids„ such, as hydrochloric and hydrobramic acid, as well as sulfuric, phosphoric, nitric or perchloric acid, or organic acids, 5 such as formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric f citric, Hialeic, fuiaarie, phanyl&eetic, bensoic, methanesulfonie, toluenesulfonic, oxalic, 4-aminobenzoic, naphthalene-1,5-disulfonic or ascorbic acid. 10 The starting compounds of the formula (III) , (V) and (VII), where they are not commercially available, can ba synthesized in a simple manner (for example Organikum, Organisch Chemisches Grundp r ak t i kum (Basic Practical Organic Chemistry), 15th edition, VEB Deutsehar Verlag 15 der Wissenschaften, 1976; a review of the various possibilities is to h@ found in the method register; Alcohols: page 821e Amines: page 822).
The starting compounds of the formula (II) are obtained, for ..example, by converting pyridine-2,4- or -2,5-20 diearboxylic acid into the corresponding pyridine-2,4- or -2,5-dicarboxylic acid halide (VI) , preferably the chloride (by processes which are known from the literature, for example Organikmn, Organisch Chemisches Grundpraktikum (Basic Practical Organic Chemistry), 15th 25 edition,, VEB Deutseher Verlag der Wissenschaften, 1976, page 595 efc seg.), which is then reacted with an alcohol of the formula R2' -OH (V) to give the corresponding 2,4-or 2„5-diester. Selective hydrolysis of the ester in the 2-position of the pyridine derivative (for example by a 30 copper complex, see Ph&rm,, Acta Eelv. 44'1969, page 637) or partial alkaline hydrolysis (see J. Org. Chem. 3J[ (B) 1974, page 1158) gives the pyridine-4- or -5-carboxylic acid ester-2-carboxylic acid, which is either used directly (II„ Y-OH) or can be converted into the acid 35 halide (II, Y=C1, Br or I) „ preferably the acid chloride.
The starting compounds of the formula (IV) can be - 12 - synthesized, for example, as follows; Reaction of the pyridine-2„4- or -2,5-dicarboxylic acid halide, preferably the chloride, with benzyl alcohol to give pyridine-2,4- or -2, 5-dicarboxylic acid bensyl 5 ester; subsequent selective hydrolysis of the ester in the 2-position (for example in the presence of a copper catalyst, Loc„cit,Phara, Acta Helv.), conversion of the free acid in the 2-position into the aeid halide, reaction with a compound of the formula HX" -R1' (III) to 10 give the pyridine-4- or 5-carboxylic acid benzyl ester-2~ carboxylic acid (R1') ester or ~02ui.de, hydrogenolytic splitting off of the bansyl protective group which remains (for example with H2/Ptf see Houben-Weyl Volume XV/Ic (1980), pages 381«62) and subsequent conversion of 15 the free acid in the 4- or 5-position of the pyridine ring into the acid halide (XV).
The pyridine-2,4- or -2,5-dicarboxylic acid halide according to formula VI can be obtained by known methods, for example by reaction of pyridine-2,4- or -2,5- 2 0 dicarboxylic acid with a phosphorus trihalide (see, for example„ Organikum, Organisch Chemisches Grundpraktikum (Basic Practical Organic Chemistry),, 15th edition,, VEB Deutscher Verlag dar Wissenschaften, 197S, pages 527 and 595 st seq.). 25 The reaction of alkali metal salts of the pyridine-2,4-or -2,5-dicarboxylic aeid with a halide of the formula VIII is carried out by processes which are known from the literature (sse; for example, Organikum, Organisch. Chemisches Grundpraktikum (Basic Practical Organic 30 Chemistry) „ 15th edition, VEB Deutscher Verlag der Wissenschaften, 1976, page 255 et seq.).
The compounds of the formula I and If according to the. invention have useful pharmacological properties, and in particular show an activity as inhibitors of proline 3 5 hydroxylase and lysine hydroxylase and as - 13 - fihrosupprassailts and isssvunosuppressants« The activity of the fibrogsnase can be determined by radioimmunological assay of the H~ terminal propeptide of collagen type 111 or the N- or C-terminal cross linking 5 domains of collagen type IV (7s-collagen or type IV collagen-NC^) in the serum.
For this purpose, the hydroacyproline, procollagen. Ill, peptide, 7s-collagen and type IV collagen concentrations in the liver of 10 a) untreated rats (control) b) rats to which carbon tetrachloride had been administered (CCl4 control) c) rats to which first CC1* and then a compound according to the invention had been administered 15 were measured (this test method is described by Rouiller, C„, experimental toxic injury of the liver; in The Liver, C„ Rouiller, Volume 2, pages 335-476, Mew York, Academic Press, 1964) .
The pharmacological activity of the substances according 20 to the invention has been investigated in a series of experiments (see Table 1) . A clear inhibition of proline hydroxylase and lysine hydroxylase was thereby found.
Table 1 25 Subiafcasqi! Ssrosa Eiinsapl® Doaa&gis Hydrosqr-psroliae jsg/isg of. lives PsroeolX&gss III p&pfcida ag/sal 73-COlXliigaiE eg/si Typo ry collsigan-KCl ng/sal 30 CC14 control control 2 x 25 ssg 0.482 0.773 0*289 37.2 73.5 11.1 121.4 308.7 22. S 100.3 1S8 „ 4 23.5 The compounds of the formula, I and 1* can b© used as medicaments in the fom of pharmaceutical preparations - 14 - which contain them, if appropriate together with tolerated pharmaceutical excipients. The compounds can be used as medicines, for example in the fiona of pharmaceutical preparations which contain these compounds as a 5 mixture with a pharmaceutical organic or inorganic exci-pient suitable for enteral? percutaneous or parenteral administration, such as, for example, "®"ater, gum arabic, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, vaseline and the like. 10 The pharmaceutical preparations can be in the solid form,, for example as tablets, coated tablets, suppositories or capsules? in the semi-solid form, for example as ointments, or in the liquid form, for example as solutions, suspensions or emulsions.. If appropriate, 15 they are sterilised and/or contain auxiliaries, such as preservatives, stabilisers, wetting agents or emulsifying agents, salts for modifying the osmotic pressure or buffers. They can furthermore also contain other therapeutically active substances. 20 The invention is illustrated in more detail with the aid of examples below: Examples 1. Bis(1-methoxycarbonylethyl) pyridine-2,5-dicarboxy- late 25 35 30 10 g of pyridine-2,5~dicarboxylic acid are taken in 60 ml of dry methylene chloride, and 80 ml of freshly distilled thionyl chloride and 2 ml of dry dime thy lformamide are added. The mixture ia boiled under reflux for three hours, the excess thionyl chloride and the methylene chloride are then distilled off and the residue is evaporated, with fuming,, once with dry toluene, A solution of 12.5 g of methyl lactate, dissolved in methylene chloride, is added dropwise to the reaction mixture at -30 to -20°C. The mixture is allowed to warm slowly to - 15 - room -temperature and ia stirred overnight at room temperature and the solution is washed with sodium bicarbonate solution™ After drying* the organic phase is freed from the solvent and chromatographad over silica gal with athyl acetate as the mobile phase. The product is recrystallized from isopropanol.
Melting point 78°C; yield 7.2 g Bi s (1 - a thoacycarbonyl e thyl) pyr i dine-2,5-dicarboxy - late 10 g of pyridine-2,5-dicarboxylic acid are taken ia SO ml of dry methylene chloride, and 80 sal of freshly distilled thionyl chloride and 2 sal of dry dime thyl forxaasiide are added. The mixture is boiled under reflux for three hours, the excess thionyl chloride and the methylene chloride are then distilled off and the residue is evaporated,, with rusting, once with dry toluene. A solution of 14.1 g of ethyl lactate, dissolved in 1 1 of methylene chloride, is added dropwise to the reaction mixture at «30 to -20°C- The mixture is allowed to warm slowly to roonst temperature and is stirred overnight at room temperature and the solution is washed with sodium bicarbonate solution. After drying, the organic phase is freed from the solvent and chrosiatographed over silica gel with athyl acetate as the mobile phase. The product is obtained as an oil.
Yield 16.6 g Bis(1-isopropoxycarbonylethyl) pyridine-2,5 -dicarboacylate 10 g of pyridine-2,5-diearboscylic acid are taken in 60 ml of dry methylene chloride, and 80 ml of freshly distilled thionyl chloride and 2 ml of dry dixaethylforxaazai de are added. The mixture is boiled under• reflux for three hours, the excess thionyl chloride and the me thylana chloride are then distilled off and the residue is evaporated, with fuming, once B«*ith dry toluene. A solution of IS. 8 g of isopropyl lactate, dissolved in 100 ml of methylene chloride, is added dropwise to the reaction mixture at -30 to -20°C» The mixture is allowed to v?arm slowly to room temperature and is stirred overnight at room temperature and the solution is washed with sodium bicarbonate solution.™ After drying, the organic phase is freed from the solvent and stirred ■with diisopropyl ether. The aonoaster is separated off and the mother liquor is chromatographed over silica gel with a miseture of four parts of toluene and one part of ethyl acetate as the mobile phase. The oily product slowly crystallizes completely.
Melting point 52 - 53°C Yield 13.5 gr Bis (2 -metho:?eycarbonyl-2,2 -dime thyl ethyl) pyridine-2,5-dicarboxylate 10 g of pyridine-2,5-dicarboxylic acid are taken in SO sal of dry methylene chloride,, and 80 nil of freshly distilled thionyl chloride and 2 ml of dry dimethylformamide are added. The mixture is boiled under reflux for three hours, the excess thionyl chloride and the methylene chloride are then distilled off and the residue ia evaporated, with fuming, once with dry toluene. A solution of 15-8 g of methyl 2, 2-dimethyl-3 -hydroxypropionate, dissolved in 100 ml of methylene chloride, is added to the reaction mixture at -30 to -2G°C~ The mixture is allowed to warm slowly to room temperature and is stirred overnight at room temperature and the solution is washed with sodium bicarbonate solution. After drying, the organic phase is freed from the solvent and the product is recrystallized from isopropanol.
Melting point 114-5°C Yield 18.6 g Bis (2-methoxycarbonyl-2, 2-dime thyl a thyl) pyridine-2 , 4-dicarhoxylate 7-5 g of pyridine-2, 4-dicarboxylie acid are taken in 45 ml of dry methylene chloride, and 60 ia! of freshly distilled thionyl chloride and 2 ml of dry dimethyl formaiaide are added. The mixture is boiled under reflux for three hours, the excess thionyl chloride and the methylene chloride are then distilled off and the residue is evaporated, with fuming, once with dry toluene. A solution of 11.9 g of methyl 2,2-dimethyl-3-hydroxypropionate, dissolved in 100 ml of methylene chloride, is added to tha reaction mixture at -30 to -2Q°C. The mixture is allowed to warm slowly to room temperature and is stirred overnight at room temperature and the solution is washed with sodium bicarbonate solution. After drying, the organic phase is freed from the solvent and chromatographed over silica gel with ethyl acetate as the mobile phase. The product is obtained as an oil. Yield 6.7 g.
Bis(1-ethoxyearbonylathyl) pyridine-2, 4-dicarboxylate 7„5 g of pyridine-2,4-dicarboxylic aeid are taken in 45 ml of dry methylene chloride, and 60 ml of freshly distilled thionyl chloride and 2 xal of dry diaaethylfonaainide are. added. The mixture is boiled for three hours,, the excess thionyl chloride and the methylene chloride are then distilled off and tha residue is evaporated,, with fuming,, once with dry toluene. A solution, o£ 10.6 g of ethyl lactate, dissolved in 100 ml of methylene chloride, is added dropwise to the reaction mixture at -30 to -20°C. The mixture is allowed to warm slowly to room temperature and is stirred overnight at room - 18 - temperature and the solution is washed with, sodims, bicarbonate solution. After drying, the organic phase is freed from the solvent and chromatographed over silica gel with ethyl acetate as the mobile phase. The product is obtained as an oil, which slowly crystallises completely.
Melting point 59 - 60°C Yield 3.7 g.
Bis (5-xaethyl~2-03£0"l^ 3-dioxol-4-ylmethyl) pyridine- 2.4 -dicarboxylate 6.3 g of pyridine-2,4-dicarboxylic acid sodium salt are boiled under reflux with 14.3 g of 5-methyl-2-Gseo-l, 3 -dio3eol-4-yl-methyl bromide and 4.5 g of potassium earbonate in 125 ml of dry acetone for 40 hours. The carbonate is filtered off and the solution is chromatographed over silica gel with a 4:1 mixture of toluene and ethyl acetate.
Melting point 113°C Yield 2.6 g Methyl 2-(4-(2-phenylsthyl)piperasinocarbonyl)-pyridine - 5 - carboaeylate 1.5 g of diethyl pyridine-2 - (carboxylic acid) - 5- carboxylate are heated under reflux with 22.5 ml of freshly distilled thionyl chloride until a clear solution has formed. The solution is subsequently stirred at room temperatures for oaa hour and tha thionyl chloride is distilled off completely. The residue is taken up in 15 sal of dry methylene chloride,, the mixture is added dropwise to a solution of 3.IS g of 1-(2-phenylethyl)-piperazine in 8 ml of methylene chloride and the components are subsequently stirred at room temperature for five minutes and freed from the solvent. The residue is recrystallized from isopropanol,, with the addition of a little active charcoal. The product is obtained as tha hydrochloride.
Melting point 201 - 203°C Yield 2.6 g - 19 - Methyl 2 -bensylaminoearbonyl-pyridine-5-earboxylate 1.5 g of methyl pyridine-2-(carboscylic acid)-5-carboxylate are heated under refluse with 22.5 ml of freshly distilled thionyl chloride until a clear solution, has formed. The solution is subsequently stirred at room temperature for one hour and the thionyl chloride is distilled off completely. The residue is taken up in 15 sal of dry methylene chloride, the mixture is added dropwise to a solution, of 1.15 g of henzylamine in 8 ml of methylene chloride and the components are subsequently stirred at room temperature for five minutes and freed froa the solvent. The residue is recrystallized from isopropanol, with the addition, of a .little active charcoal.
Melting point 215 - 216°C Yield 1.9 g Methyl 2- (N-benzyl-N-methylaminocarbonyl) -pyridines' carboacylate 1.5 g of methyl pyridine-2 - (c&rboxylie acid) - 5-carboxylate are heated under reflux with 22.5 ml of freshly distilled thionyl chloride until a clear solution has formed. The solution is subsequently stirred at room temperature for one hour and tha thionyl chloride is distilled off completely. The residua ia taken up in 15 ml of dry methylene chloride, the mixture is added dropwise to a solution of 2.0 g of N-methylbenzylamine in 8 ml of methylene chloride. and the components are subsequently stirred at room temperature for five minutes and freed from the solvent. The-residue is chromatographed over silica gel with a mixture of 7 parts o£ methylene chloride and 3 parts of acetone. The product is obtained as an oil. - 20 - Methyl 2-banzyloxycarbonylpyridine-5-carhoxylate 1.5 g of methyl pyridine-2-(carboxylic acid)~5- carboxylate are heated under reflux with 22.5 ml of freshly distilled thionyl chloride ■until a clear solution has formed. The solution is subsequently stirred at room temperature for one hour and the thionyl chloride is distilled off completely. The residue is taken up in 15 ml of dry methylene chloride, the mixture is added dropwise to a solution of 1.79 g of benziylalcohol in 8 ml of methylene chloride and the components are subsequently stirred at room temperature for five minutes and freed from the solvent. The residue is recrystallized from isopropanol, with the addition of a little active charcoal.
Melting point 104°C Yield 1.5 g Methyl 2-phenylaminocarbonylpyridine-5-carboxylate 1.5 g of methyl pyridine-2-(carboxylic aeid)-5- carboxylate are heated under reflux with 22.5 sal of freshly distilled thionyl chloride until a clear solution has formed. The solution is subsequently stirred at room temperature for one hour and the thionyl chloride is distilled off completely. The residue is taken up in 15 ml of dry methylene chloridethe mixture, is added dropwise to a solution of 1.54 g of .aniline in 8 ml of methylene chloride and the components are subsequently stirred at room temperature for five minutes and freed from the solvent. The residue is recrystallized from isopropanol,. with the addition of a Xit-tle active charcoal.
Melting point 167°C Yield 1.5 g - 21 - 13 . Methyl 2 - (2, 2 -diphenylethylamino) carbonylpyridine-5-aarhosrylata 1.5 g of methyl pyridine-2-(carboxylic acid)-5-carboxylate are heated under reflux with 22.5 sal of 5 freshly distilled thionyl chloride until a clear solution has fonasd„ The solution is subsequently stirred at room temperature for one hour and the thionyl chloride is distilled off completely. The residue is taken up in 15 ml of dry methylene 10 chloride, the mixture is added dropwise to a solu tion of 3.27 g of diphany 1 a thy 1 amine in 8 ml of methylene chloride and the components are subsequently stirred at room temperature for five minutes and freed firas. the solvent. The residue is 15 recrystallized fros isopropanol, ■with the addition of a little active charcoal.
Melting point 147°C Yield 1.8 g 14. Methyl 2-(N-methyl-N-phenylamino) carbonylpyridine-5- earboxylate 20 25.5 g of methyl pyridine-2- (carboxylic acid) -5- carboacylate are heated under reflux with 380 ml of freshly distilled thionyl chloride until a clear solution has formed- The solution is subsequently stirred at room temperature for one hour and the 25 thionyl chloride ia distilled off completely. The residue is taken up in 250 ml of dry methylene chloride, the mixture is added dropwise to a solution of 3 0 g of N-inefchylaniline in 150 ml of methylene chloride and the components are 30 subsequently stirred at room tesperature for five minutes and freed from the solvent. The residue is recrystallized from isopropanol„ with the addition of a little active charcoal.
Malting point 123°C Yield 30 g - 22 - Methyl 2-N-propylamino-carbonylpyridine-5-carboxy-late 15 g of methyl pyridine-2 - (carboxylic aeid)-5-carboxylata srs heated under reflux with 225 ml of freshly distilled thionyl chloride until a clear solution has forced. The solution is subsequently stirred at roon temperature for one hour and the thionyl chloride is distilled off completely. The residue is taken up in 70 ail of dry methylene chloride, the mixture is added dropwise to a solution of 13.7 g of propylamine in 150 ml of methylene chloride and the components are subsequently stirred at room temperature for five minutes and freed from the solvent. Tha residue is chromatographed over silica gel with a fixture of 7 parts of methylene chloride and 3 parts of acetone as the mobile phase. Melting point 88°C Yield 12.6 g Di(4-nitro-phenyl) pvridine-2,5-earbaxylate IS.7 g of pyridine-2,5~dicarboxylic acid are taken in 100 ml of dry methylene chloride# and 135 ml of freshly distilled thionyl chloride and 3 al of dry dimethylsormamide are added. The mixture is boiled under reflux for three hours, fcxxe excess thionyl chloride and the methylene chloride are then distilled off and the residue is evaporated, with fuming, once with dry toluene. A solution of 27.8 g of 4-nitrophenol in 50 ml of pyridine is added drop-wise to the reaction.mixture at -30 to -20#C. The mixture is allowed to warm slowly to room temperature and is stirred overnight at room temperature and the solution is washed with sodium bicarbonate solution. After drying, the organic phase is freed from the solvent and chromat©graphed over silica gel with ethyl acetate as tha mobile phase.
Melting point 190°C Yield 12.5 g - 23 - Bis (5 -me thyl - 2 - oxo -1,3 » dicxol - 4 -yl -methyl) pyridine-2,5-dicarboxylate Analogously to Example 1, 6-3 g of pyridine-2,5~ dicarboxylie acid sodium salt are reacted with. 14.3 g of 5-methyl-2-oxo-l#3-dioxol-4-yl-siethyl bromide and the mixture is boiled under reflux in acetone for 2„5 hours. After chromatography over silica gal with ethyl acetate as the mobile phase, the product is recrystallized from hot ethyl acetate.
Melting point 118°C Yield 0.23 g Di- (es-saethoxycarbonylbenzyl) pyridine = 2,5- dicarboxylats Analogously to Example 1„ 10 g of pyridine-2»5-dicarboxylic acid are converted into the acid chloride and this is reacted with 19.9 g of methyl (+)-mandelate. After extraction,, working up is carried out by chromatography over silica gel with a mixture of toluene and ethyl acetate as the mobile phase.
Melting point 125°C Yield 0.5 g Methyl pyridine - 2 - carboxsmide - 5 - carboscy la t e 20 g of aethyl pyridine-2~(carboxylic acid)-5-carboxylase are converted into the acid chloride ■with 200 g of thionyl chloride as described in Example 8. The acid chloride is dissolved in chloroform, and ammonia gas is passed over the suspension, with vigorous stirring. The mixture is left to stand for two days and the product is filtered off with, suction and washed 'with '«ater.
Melting point 195-197°C Yield 15.6 g - 24 - 20. Dibenssyl pyridine-2, 5-dicarboxylata .Analogously to Example 1, 20 g of pyridine-2,5-dicarboxylic acid are converted into the acid chloride with ISO ml of thionyl chloride and this is 5 reacted with 25.9 g of benzyl alcohol. The product is recrystallized from ethyl acetate, with the addition of active charcoal.
Melting point 110"C Yield 20.4 g 21. Benzyl pyridine-2-(carboxylic acid)-5-carboxylate 10 17 g of dibenzyl pyridine-2,5-dicarboacylate are suspended in methanol and the suspension is added to a suspension of 12.1 g of copper(XX) nitrate. The isixture is boiled under reflux for one hour and, after cooling, the copper complex is filtered off. 15 The complex is suspended in dioxane, and hydrogen sulfide is passed in up to a weight increase of 4 g. The copper sulfide is separated off and the organic phase is concentrated. The product is recrystallized from toluene. 20 Melting point 132°C Yield 10.2 g 22 . Benzyl pyridine-2 - (3-isopropoxy-propyl) carboxamide~ 5-carboxylate Analogously to Example 8, 8 g of 5-benzyl pyridine-2-carboxylate are converted into tha acid chloride 25 with 90 ml of thionyl chloride and this is reacted with 3 -isopropoxy-propylamine to give the amide.
For purification,, the product is "ehroma.tograpb.ed over silica gel with a mixture of cyclohexane/etbyl acetate (1:1)» 30 Melting point 41°C Yield 6.4 g - 25 - 23. Pyridine-5-carboxylic acid 2-(3-isopropoxy-propyl)-carboxamide 5.3 g of pyridine—2- (3-iaopropoxy-propyl) -sjaida 5-benzyl aster are hydrogensted in dioxane under 5 normal pressure in the presence of a palladium-on- chareoal catalyst for five hours. When the uptake of hydrogen has ended, the catalyst is filtered off with suction and tha solvent is stripped off. Melting point 129°C Yield 2.4 g 10 24. Benzyl pyridine-2-(3-isopropoxy-propyl)carhoxamide-5-carboxylate In accordance with Example 8, 1 g of pyridine-5-carboxylic acid 2-(3-isopropoxy-propyl) amide are converted into the acid chloride (20 ml of thionyl 15 chloride) and this is then reacted with 2 ml of benzyl alcohol fco give the pyridine-2-(isopropoxy-propyl) amide 5-benzyl ester. For purification, the .product is chromatographed over silica .gel with a mixture of cyclohexane/ethyl acetate (IsI). 20 Melting point 41°C Yield 0-9 g 25. Di (5-methyl"2-nitro-benzyl) pyridine-2, 5-carboxylate Analogously to Example 1, S g of pyridine-2,5-dicarboxylic acid are converted into the acid chloride with 40 ml of thionyl chloride in 30 ml of 25 methylene chloride and this is reacted with 10 g of S-methyl-Z-nitro-bensyl alcohol in 50 ml of methylene chloride. The reaction mixture is stirred overnight at room temperature,, sodium bicarbonate solution is than added, the mixture is extracted 30 with methylene chloride and the organic phase is dried. After the solvent has been stripped off«, the, residue is stirred with ethyl acetate, filtered off with suction and recrystallized twice from methylene chloride. - 26 - Melting point 182°C Yield 2.9 g 26. Bis(2-ethoxy-ethyl) pyridine-2r5-dicarboxylate Analogously to Example 1, 10 g of pyridine-2,5-dicarboxylic acid are converted into the acid 5 chloride with 80 xal of thionyl chloride in 60 ml of methylene chloride and this is reacted with 10.78 g of ethylene glycol monomethyl ether in 100 ml of methylene chloride. Working up is by adding sodium bicarbonate solution, separating off the organic 10 phase and stripping off the solvent. The product is ehrosnat ©graphed twice over silica gel i??ith ethyl acetate and dissolved in hot athyl acetate, and the solution is clarified with active charcoal and freed from the solvent. The product is obtained as an 15 oil.
Yield 7,2 g 27. Bis(2-methoxy-ethyl) pyridine-2,5-dicarboxylate Analogously to Example 26, 10 g of pyridine-2,5-dicarboxylic acid are converted into the acid 2 0 chloride and this is reacted with 9.1 g of ethylene glycol monosiethyl ether. Working up is carried out in accordance with Example 26. The product is obtained as an oil.
Yield 6.5 g 25 28. Bis(2-ethoxy-ethyl) pyridine-2,4-dicarboacylate As described in. Example 26, 10 g of pyridine-2,4-dicarboxylic acid are reacted with ethylene glycol xnonoethyl ether via, the acid chloride. The reaction mixture is worked up analogously to E^aarple 26. Tha 3 0 product is obtained as an oil.
Yield 7.2 g -Ills. 2 -Methoxycarhonyl-2-methyl-propyl pyridine- 5 -carboxylate-2 -N~(3-isopropoxy-propyl)carboxamide 1 g of pyridine-5-carboxylic acid 2~(3~ isopropoxvpropyl)amide are boiled under reflux in 5 20 nil of thionyl chloride until a solution is obtained. The solution is left to stand at room temperature for one hour, the thionyl chloride is distilled off,, the residue is dissolved in 10 ml of dry methylene chloride and a solution of 0.5 g of 10 methyl 2a2-dimethyl-3-hydroxypropionate in 20 ml of dry methylene chloride is added dropwise. When the reaction has ended, the solvent is stripped off and the prodtiet is chroma,tographed over silica gel with ethyl acetate. 15 Yield 0.15 g 30. Bis (1 - isopropoxycarbonylethyl) pyridine-2,4-dic&rboxylate 10 g of pyridine-2,4-dicarboxylic acid are taken in 60 ml of dry methylene chloridet, and 80 ml of .20 freshly distilled thionyl chloride and 2 ml of dry dime thy Iformaamida are added. The mixture is boiled under reflux for three hours, tha excess thionyl chloride and the methylene chloride are then distilled off and the residue is evaporated, with 25 fusing„ once with dry toluene™ A solution of 15. 8 g of isopropyl lactate dissolved in 100 ml of methylene chloride is added dropwise to the reaction mixture at -30 to -20°C. The mixture is allowed to warm slowly to room temperature and is stirred 30 overnight at room temperature and the solution is washed with sodium bicarbonate solution. After drying,, the organic phase is freed froia the solvent and stirred with diisopropyl ether. The monoestar is separated off and the mother liquor is chromato-35 graphed over silica gel with a mixture of four parts of toluene and one part of ethyl acetate as tha - 28 - siobile phase. The product is obtained as an oil Yield: 11.2 g
Claims (1)
1. - 29 - PATENT CLAIMS 1. A pyridine-2,4- or -2,5-dicarboxylic aeid derivative of tha formula I 0 o t R--0-C (I) N-"\ . C-X-R1 B 0 5 in which R1 denotes branched or unbranched C1-C12- alkyl which is monosubstituted or else, in the ease of the C2-C12-alkyl radicals, polysubstituted by halogen, hydroxy1 , cyano, carboacyl, alkoxy, 10 alkoacycarbonyl, alkylcarbonyloacy or alkyl- or dialkylamino, the alkyl radicals containing 1-4 carbon atoms and, in the case of the C3- and C4-alkyl radicals, it also being possible for them to h»3 branched, phenyl * which is in turn 15 optionally mono-, di- or trisubstituted by halogen, nitro* C1-C4-alkyl or C,-C4~alkoxy, it also being possible, in the case of polysubs titution, for the substituents to differ independently of one another and it also being 20 possible, in the case of the C3- and CA-alkyl radicals, for these to be branched, or R1 denotes saturated Cs-C7-eyeloalkyl„ which is optionally benso-fused,, or R1 denotes phenyl, naphthyl or a S- or 6-25 membered aromatic ring having 1> 2 or 3 nitrogen and/or oxygen and/or sulfur atosas,, which in turn are optionally mono- e di- or trisubstituted by halogen, C-, -C4-alkyl or C1-CA-alkoxy, it also being possible, in the case of 30 polysubstitufcion, for the substituents to differ independently of one another and it - 30 - - also being possible, ia the case of the C3-and C4-alkyl radicals, for these to ba branched, or R1 denotes 2-oxo-1,3 -dioxolyImethyl, which is optionally also methyl-substituted, or R1,if X is nitrogen, denotes hydrogen, and R2 independently of R1 is hydrogen or R1, it also being possible for R2 to be identical to R1, and X denotes oxygen or R3 -substituted nitrogen, in which R3 is hydrogen or C1-C6~alkyl or optionally together with R1 forsis a heterocyclic saturated 5-, 6- or 7-meaherad ring, it also being possible for the heterocyclic ring to include a second nitrogen atom and it being possible fox- the heterocyclic ring in turn to be substituted by phenyl or phenyl - C3 - C3 -alkyl, or a physiologically tolerated salt thereof for use as a pharsaacautieal „ A pyridine-2,4- or -2, 5-dicarboxylic acid derivative of formula I as claimed in claim 1„ in which R1 denotes branched or unbranched C-j-C^-alkyl which is XBLonosubsfcituted or else, in the caaa of the C3~ and -alkyl radicals, polysubstituted by C-, -C3-alkoxy and/or -C3 -alkoxy-carbonyl, it also being possible for the C3-alkyl radicals to be branched, and/or phenyl, or R1 denotes C5- or C6-cycloalkyl, which is optionally benzo-fused, or R1 denotes phenyl, which is optionally mono-„ di- or trisubstitufced by nitro,. or E1 denotes 2-„ 3- or 4 -pyridyl t, naphtbyl, 2-or 3-thisnyl, pyrazolyl, is&idasolyl or thiassolyl, or R1 denotes 5-methyl-2-oa:o-l,3-dioxol-4-yl- methyl - 31 - and R2 independently of R1 is hydrogen or R1, it also being possible for R2 to be identical to R1, and X denotes oxygen or R3-substituted nitrogen, in which R3 is hydrogen or €,-€3-alkyl or optionally together with R1 forms a heterocyclic saturated 6 -membered ring, it also being possible for the heterocyclic 6-aastbered ring to include a second nitrogen atom and to be substituted in turn by phenyl or phenyl -C-jl -C3" alkyl, or a physiologically tolerated salt thereof, for use as a pharmaceutical. A pyridine-2,4- or -2„5-diearbo3tylie acid derivative of the formula I* (I?) C - X' - R II 0 1 , in which R1' denotes branched or unbranched C^-C^-alkyl which ia monosubstituted or else, in the case of C2~C12-alkyl, polysubstituted by halogen,, hydroxy1, cyano, carboaeyl,, alkoscy, alkoaey-carbonyl„ alkylcarbonyloxy or alkyl- or di-alkylamino* the alkyl radicals containing 1-4 carbon a touts and it also being possible, in the case o£ the C3~ and C4 - alley 1 radicals,, for these to be branched, phenyl, which, is in turn optionally mono-, di- or trisubsfcituted by halogen, C1-C4-alkoxy or C1-C4-alkjrl1, it also being possible for the C3- and C4-alkyl radicals mentioned to be branched and it also - 32 - •being possible, in the case of polysubstitu-tion, for the substituents to differ independently of one another, or R1' denotes saturated C s - C7 - eye 1 o al ky 1, which is optionally bensso-fused, or R1' denotes phenyl,, naphfchyl or a 5- or S-memberad sroaxatie ring having 1, 2 or 3 nitrogen and/or oacygen and/or sulfur atoms, which is in turn optionally aono-f di- or trisubstituted by halogen,, nitro, C.,-C4-alkyl or C1-C4-alkoxy, it also being possible, in the case of palysuh s ti tution e for the substituents to differ independently of one another and it also being possible, in tha case of the C3- and C4~alkyl radicals, for these to be branched, or R1' denotes 2-oxo-l, 3~dioxolylmethyl, which is op t ional ly me thyl - sub stituted, or R1', if X' is nitrogen, denotes hydrogen, and R2' independently of R1' is hydrogen or R1', it also being possible for R2' to be identical to R1', and X' denotes oxygen or R3'-substituted nitrogen, in which R3' is hydrogen or C1-Cs-alkyl or, optionally together with R1', forms a heterocyclic, saturated 5-, 6- or 7-aiesifaered ring, it also being possible for the heterocyclic riag to include a second nitrogen atom and it being possible for the heterocyclic ring in tara to be subs titu ted by phenyl or phenyl -C^-Cg- alkyl, - or a physiologically tolerated salt thereof,, excluding the compounds in which X' denotes oxygen and R1' and R2' are methyl or ethyl which is substituted by chlorine, hydroxyl or phenyl, and di(4-methoscyphenyl) pyridine-2,5-dicarboacylate., - 33 - A pyridine-2, 4- or -2, 5-diearboxylic acid derivative of formula I* as claimed in claim 3, in which R1' denotes branched or unbranched C1-C4-alkyls which is mono sub s t i tu t ed or else, in the cass of the C2-C4-alkyl radicals, polysubstituted by alkoxy or alkoxycarbonyl, the alkyl radicals containing 1-3 carbon atoms and it also being possible, in tha casa of tha C3~ alkyl compounds* for these to be branched, or phenyl or R1' denotes cyclopentyl or cyclohexyl, which are optionally bengo-fused,, or R1' denotes phenyl, %'hich is optionally substituted by 1, 2 or 3 nitro groups , or naphthyl, or R1' denotes 2-e 3- or 4-pyridyl,, 3-thienyl, pyrazolyl, imidazolyl or thiazolyl, or R1' denotes 5-iaethyl-2-oxa-l»3-dioxol-4-yl- methyl and R2' independently- of R1" is hydrogen or R1', it also being possible for R2' to be identical to R1', and Xf denotes oxygen or R3' -substituted nitrogen? in which R3' is hydrogen or Ci-Cg- alkyl or optionally together with R1' forms a heterocyclic, saturated 6-membered ring, it also being possible for the heterocyclic 6-membered ring to include a second nitrogen atom and in turn to be substituted by phenyl or phenyl-alkyl, or a physiologically tolerated salt thereof, excluding the compounds in ■which 3E? denotes oxygen and H1' and E2" are methyl or ethyl which is substituted by chlorine, hydroxy1 or phenyl, and di- (4-methoxypheny 1) pyridine-2, S-dicarboxylate. A process for the preparation of a compound of the - 34 - formula I' as claimed in claim 3, •ws'hich comprises a) reacting a compound of tha formula XI with a cojapoimd of tha formula III HX'-R1' (TTT) in which R1', R2' and X' have the meanings given in 5 the case of formula. I' and Y is halogen or hydroxy1, or 3b) reacting a compound of the forsaula X"v 0 * u 0 with a compound of the formula V HO-R2' (V) 10 in which R1' £. R2' and 2S* have tha meanings given in the case of formula I' and Z is halogen, or c) reacting a compound of the. forassala VI 0 ii 0 - 35 - with an alcohol HO-R2' or an alcohol of the formula ¥11 HO-R1' (vXI) ia which R1' and E2' have tha meanings given in tha case of formula Ie and Z is halogen, or d) reacting an alkali metal salt of pyridine-2,4- or -2, S-dieariboxylic acid with a halide of the formula VIII R1' -2 (VIII) in which R1' has the meanings given in the case of formula Xs and % is halogen, and, if appropriate,, converting tha reaction product into one of its physiologically tolerated salts. Tha process as claimed in claim 5, wherein, in process variant a), the reaction is carried out with simultaneous addition of a dialkylearhodiiiaide, the dialkyl radicals containing 1 to 8 carbon atoms and it also being possible, in the case of the C3-C8 compounds„ for these to be branched or cyclic. A compound, as claimed in one of claims 1 to 4 for inhibiting proline hydroxylase and lysine hydroxylase. A compound as claimed in claim 1 to 4 for use as a fibroauppressant and immunosuppressant - A pharmaceutical containing a compound of the formula I or I" as claimed in claim 1 or 3 with, tolerated pharmaceutical excipients. A process for the preparation of a pharmaceutical for influencing the metabolism of collagen and collagen-like substances or the biosynthesis of C,!ag which comprises incorporating a compound of the formula I or Ie as claimed ia claim 1 or 3 into the pharmaceutical. - 3S - 11. A pyridine-2,4- or -2,5-dicarboxylic acid derivative of the formula. I' as claimed in claim 3, ia which R1' is branched or unbranched C1-C4-alkyl, which is substituted by alkoxycarbonyl, tha alkyl radicals 5 containing 1-3 carbon atoms and it also being possible,, in the ease of the C3-alkyl radicals, for these to be branched, and R2" independently of R1' is hydrogen as R1', it also being possible for R2' to be identical to S1", and X' denotes oxygen, 1© o>r a physiologically tolerated salt thereof. 12. A pyridine-2,4- or -2, 5-dicarboxylic acid derivative of the foranila IfJ as claimed in elaiss 3, is which R1' and R2' are 1-isopropoxycarbonylethyl groups and X' denotes oxygen,, or a physiologically tolerated IS salt thereof. 13. A compound as claimed in claim 3, substantially as hereinbefore described and exemplified. 2 fi 14. A process for the preparation of a compound as claimed in claim 3, substantially as hereinbefore described and exemplified. 15. A compound as claimed in claim 3, whenever prepared 2 S by a process claimed in any one oi claims 5s 6 or 14. 16. A pharmaceutical as claimed in claim 9, substantially as hereinbefore described and exemplified. 30 17. A process for the preparation of a pharmaceutical as claimed in claim 9, substantially as hereinbefore described and exemplified. 18. A pharmaceutical as claimed in claim 9, whenever prepared by a process claimed in claim 10 or 17. F.R. KELLY & CO., AGENTS FOR THE APPLICANTS.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19873703963 DE3703963A1 (en) | 1987-02-10 | 1987-02-10 | PYRIDINE-2,4- AND 2,, 5-DICARBONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, USE THEREOF, AND MEDICINAL PRODUCTS BASED ON THESE COMPOUNDS |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE880350L true IE880350L (en) | 1988-08-10 |
| IE67446B1 IE67446B1 (en) | 1996-04-03 |
Family
ID=6320593
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE35088A IE67446B1 (en) | 1987-02-10 | 1988-02-09 | Pyridine-2,4- and -2,5-dicarboxylic acid derivatives processes for their preparation the use thereof and medicaments based on these compounds |
Country Status (17)
| Country | Link |
|---|---|
| EP (1) | EP0278452B1 (en) |
| JP (1) | JPS63216870A (en) |
| KR (1) | KR960011371B1 (en) |
| AR (1) | AR247816A1 (en) |
| AT (1) | ATE123022T1 (en) |
| AU (1) | AU600084B2 (en) |
| DE (2) | DE3703963A1 (en) |
| DK (2) | DK168379B1 (en) |
| ES (1) | ES2073393T3 (en) |
| FI (1) | FI91524C (en) |
| HU (1) | HU207295B (en) |
| IE (1) | IE67446B1 (en) |
| IL (1) | IL85361A (en) |
| NO (1) | NO173184C (en) |
| NZ (1) | NZ223431A (en) |
| PT (1) | PT86734B (en) |
| ZA (1) | ZA88897B (en) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| HU202516B (en) * | 1987-10-02 | 1991-03-28 | Egyt Gyogyszervegyeszeti Gyar | Process for producing (2-thenyl)-thiourea derivatives and yield increasing agents comprising such 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 |
| DE3938805A1 (en) * | 1989-11-23 | 1991-05-29 | Hoechst Ag | PYRIDINE-2,4- AND 2,5-DICARBONIC ACID DIAMOND, METHOD FOR THE PRODUCTION AND USE THEREOF |
| US5260323A (en) * | 1990-06-28 | 1993-11-09 | Hoechst Aktiengesellschaft | 2,4- and 2,5-substituted pyridine-N-oxides, processes for their preparation and their use |
| DE4020570A1 (en) * | 1990-06-28 | 1992-01-02 | Hoechst Ag | 2,4- AND 2,5-SUBSTITUTED PYRIDINE-N-OXIDES, METHOD FOR THE PRODUCTION AND USE THEREOF |
| DE4030999A1 (en) * | 1990-10-01 | 1992-04-09 | Hoechst Ag | 4- OR 5-SUBSTITUTED PYRIDINE-2-CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MEDICINAL PRODUCT |
| YU9492A (en) * | 1991-02-05 | 1995-03-27 | Hoechst Ag. | 2,4- and 2,5-BIS-TETRAZOLYL pyridines and the process for their preparation |
| CA2085954A1 (en) * | 1991-12-24 | 1993-06-25 | Klaus Weidmann | Substituted pyridine n-oxides, processes for their preparation, and their use |
| 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 |
| EP1027351B1 (en) * | 1997-10-24 | 2003-12-03 | Fibrogen, Inc. | Phenanthroline derivatives |
| KR100579792B1 (en) * | 1998-05-13 | 2006-05-12 | 동화약품공업주식회사 | Novel 2,5-pyridinedicarboxylic acid derivatives |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4093622A (en) * | 1975-05-19 | 1978-06-06 | Zoecon Corporation | Pyridine esters of cyclopropane-carboxylic acid |
| EP0123700A1 (en) * | 1983-04-27 | 1984-11-07 | Byk Gulden Lomberg Chemische Fabrik GmbH | Substituted picolinic acids, processes for their preparation, their use, and pharmaceutical preparations containing them |
| 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 |
| US4757071A (en) * | 1984-12-14 | 1988-07-12 | Nisshin Flour Milling Co., Ltd. | 1,4-dihydropyridine derivatives, and pharmaceutical compositions containing same, useful for treating cardiovascular diseases |
| US4691018A (en) * | 1985-05-23 | 1987-09-01 | Chugai Seiyaku Kabushiki Kaisha | Pyridine derivatives and their use as anti-allergic agents |
| GB8702890D0 (en) * | 1987-02-10 | 1987-03-18 | Zyma Sa | Heterocyclic compounds |
| EP0353668B1 (en) * | 1988-08-04 | 1994-10-19 | Hoechst Aktiengesellschaft | Process for the preparation of N,N-bis(alkoxyalkyl) diamides of pyridine-2,4-dicarboxylic acid |
-
1987
- 1987-02-10 DE DE19873703963 patent/DE3703963A1/en not_active Withdrawn
-
1988
- 1988-02-08 ES ES88101791T patent/ES2073393T3/en not_active Expired - Lifetime
- 1988-02-08 IL IL85361A patent/IL85361A/en not_active IP Right Cessation
- 1988-02-08 DE DE3853839T patent/DE3853839D1/en not_active Expired - Fee Related
- 1988-02-08 FI FI880554A patent/FI91524C/en not_active IP Right Cessation
- 1988-02-08 NZ NZ223431A patent/NZ223431A/en unknown
- 1988-02-08 EP EP88101791A patent/EP0278452B1/en not_active Expired - Lifetime
- 1988-02-08 AT AT88101791T patent/ATE123022T1/en not_active IP Right Cessation
- 1988-02-08 AR AR88310032A patent/AR247816A1/en active
- 1988-02-09 DK DK066088A patent/DK168379B1/en active
- 1988-02-09 ZA ZA880897A patent/ZA88897B/en unknown
- 1988-02-09 KR KR1019880001198A patent/KR960011371B1/en active IP Right Grant
- 1988-02-09 JP JP63026721A patent/JPS63216870A/en active Pending
- 1988-02-09 IE IE35088A patent/IE67446B1/en not_active IP Right Cessation
- 1988-02-09 AU AU11450/88A patent/AU600084B2/en not_active Ceased
- 1988-02-09 PT PT86734A patent/PT86734B/en not_active IP Right Cessation
- 1988-02-09 NO NO880556A patent/NO173184C/en unknown
- 1988-02-10 HU HU88612A patent/HU207295B/en not_active IP Right Cessation
-
1992
- 1992-07-10 DK DK090992A patent/DK170245B1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| JPS63216870A (en) | 1988-09-09 |
| FI880554A0 (en) | 1988-02-08 |
| AU600084B2 (en) | 1990-08-02 |
| IL85361A (en) | 1993-01-31 |
| NO880556L (en) | 1988-08-11 |
| KR960011371B1 (en) | 1996-08-22 |
| NZ223431A (en) | 1990-07-26 |
| DE3703963A1 (en) | 1988-08-18 |
| FI91524B (en) | 1994-03-31 |
| IE67446B1 (en) | 1996-04-03 |
| DK66088A (en) | 1988-08-11 |
| AR247816A1 (en) | 1995-04-28 |
| NO173184B (en) | 1993-08-02 |
| DK170245B1 (en) | 1995-07-17 |
| FI91524C (en) | 1994-07-11 |
| DK90992D0 (en) | 1992-07-10 |
| ZA88897B (en) | 1988-08-09 |
| ES2073393T3 (en) | 1995-08-16 |
| HUT47249A (en) | 1989-02-28 |
| DK66088D0 (en) | 1988-02-09 |
| PT86734B (en) | 1992-05-29 |
| FI880554A (en) | 1988-08-11 |
| EP0278452A2 (en) | 1988-08-17 |
| DE3853839D1 (en) | 1995-06-29 |
| DK90992A (en) | 1992-07-10 |
| NO880556D0 (en) | 1988-02-09 |
| EP0278452B1 (en) | 1995-05-24 |
| NO173184C (en) | 1993-11-10 |
| KR880009935A (en) | 1988-10-05 |
| EP0278452A3 (en) | 1989-10-18 |
| IL85361A0 (en) | 1988-07-31 |
| HU207295B (en) | 1993-03-29 |
| ATE123022T1 (en) | 1995-06-15 |
| DK168379B1 (en) | 1994-03-21 |
| PT86734A (en) | 1988-03-01 |
| AU1145088A (en) | 1988-08-11 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Patent lapsed |