CA2052510A1 - 4- or 5-substituted pyridine-2-carboxylic acids, a process for the preparation thereof and the use thereof as pharmaceuticals - Google Patents

4- or 5-substituted pyridine-2-carboxylic acids, a process for the preparation thereof and the use thereof as pharmaceuticals

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Publication number
CA2052510A1
CA2052510A1 CA002052510A CA2052510A CA2052510A1 CA 2052510 A1 CA2052510 A1 CA 2052510A1 CA 002052510 A CA002052510 A CA 002052510A CA 2052510 A CA2052510 A CA 2052510A CA 2052510 A1 CA2052510 A1 CA 2052510A1
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alkyl
radicals
phenyl
hydrogen
pyridine
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Ekkehard Baader
Martin Bickel
Volkmar Gunzler-Pukall
Manfred Volz
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Hoechst AG
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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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D213/82—Amides; Imides in position 3

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  • Organic Chemistry (AREA)
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  • Health & Medical Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Immunology (AREA)
  • Transplantation (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
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  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

ABSTRACT OF THE DISCLOSURE

4- or 5-substituted pyridine-2-carboxylic acids, a process for the preparation thereof and the use thereof as pharmaceuticals The invention relates to pyridine-2-carboxylic acids substituted in position 4 or 5 by amino groups and to the use thereof as pharmaceuticals. In particular, the action of the compounds for inhibiting proline hydroxylase and lysine hydroxylase and for treating disturbances of the biosynthesis of collagen and collagen-like substances are described.

Description

2 ~3~ t~

HOECHST ~XTIENGESELLSCHAFT HOE 90~F 295 Dr. FI/rh Description 4- or 5-sub~tituted pyridine-2-carboxylic acids, a proce~s for the preparstion thereof and the U8Q thereof a~ pharmaceuticals Compounds which inhibit the enzymes proline hydroxylase and lysine hydroxyla~e effect very æelecti~e inhibition sf collagen biosynthesis due to influencin~ ~ollagen-specific hydroxylation reactions. In the course thereof, protein-bound proline or ly~ine i-s hydro*ylated b~ the enzymes proline hydroxyla~e or lysine hydro~ylase respec-tively. 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 spase.
The insufficiently hydroxylated collagen i5 unable, moreover, to be incorporated ln ~he collagen matrix and is ve~y easily broken down by proteolysis. The conse-~uence of these effects is an overall reduction in the amount o~ collagen deposited in the extracellular spase.

It is known that inhibition of proline hydr~xyla~e ~y known inhihitor~ ~uch as ~ dipyridyl results în inhibition of Clq biosynthesis by macrophages (W. Muller et al., FEBS Lett. 90 (1978), 218; Immunobiolo~y 155 2S (1978), 47~. This results in the classical pathway of complement activation becoming inoperative. Hence in-hibitors of proline hydroxylase act as immunosuppres-sants, for example in Lmmune complex disea~e~.

It is known that the enzyme proline hydroxylase can be efficiently inhibited by pyridine-2,4- and -2,5-dicar-boxylic acids (K. Majamaa et al., Eur. J. Biochem. 138 (1984) 239-245). However, in cell culture, these com-pounds are effective inhibitors only in very high concen-trations (Tschank, G. et al., Biochem. J. 248 (1987) 2 ~ ~ 2 3~. ~J

625-633).

DE-A 34 32 094 de6cribes pyridine-2,4- and -2,5-dicar~
boxylic diesters with 1-6 carbon atoms in the ester alkyl moiety as pharmaceuticals for inhibition of proline hydroxylase and lysin~ hydroxylase.

These lower alkylate~ diesters h~ve the disadvanta~e, however, that hey are rapidly cleaved in the body to the acids and do not reach their ~ite of action in the cell in suf~iciently high concentration and thus are relatively little suited ~or pos~ible administxation a~
pharmaceuticals~ -DE-A 37 03 959, DE-A 37 03 952 and DE-~ 37 03 963 de-scribe in a general form mixed estersJamidas, higher alkylated diesters and diamides of pyridine-2~4- and -2,5 dicarbo~ylic acids which are effective inhibitor~ of collagen biosynthe~is in animal models. Thus~
DE-A 37 03 959 de~cribe~, inter alia, the ~ynthesi~ of N,N~-bis~2-methoxyethyl)pyridine-2,4-dicarboxamide and N,N'-bi~(3-i~opropoxypropyl)pyridine-2,4-dicaxhoxamide.

German Paten~ Applications P 38 26 471.4 and P 38 28 140.6 describe an Lmproved pro~e~s for preparing N,~-bis(2-methoxyethyl)pyridine-2~4-dicarboxamide.

German Pate~t Application P 39 24 093.2 proposes novel N,N'-bi~(alkoxyalkyl)pyridine-2,4-dicar~oxamides.

German Patent Application P 40 01 002.3 describes the u~e of di(nitroxyalkyl)amides of pyridina-2,4- and -~,5-dicarboxylic acids for preparing pharmaceuticals inhibit-ing proline hydroxylase and lysine hydroxylase.

Both pyridine-2,4- and -2,5-dicarboxamide (Hirakata et al.~ J. Pharm. Soc. Japan 77 ~1957) 219 and Haring et al., Helv. 37 (1954) 147, 153) and pyridine-2,4- and -2,5-dicarbohydrazide (Itai et al., Bl. Nation. Hyg.

Lahor. ~okyo, 74 tl956) 115, 117 and Shin~har~ et al., Chem. High Polymers Japan, i5 (1~5~) 839) have already heen disclosed as agents for tuberculosis.

JP 53/28175 (78/28175) de~cribes N,N'-~is(2-nitroxy-ethyl)pyridlne-2,4- and ~,5 dicarboxEm~des a~ ~ubstances with a vasodilator actios~.

German Patent Application P .. .. . ~ . (HOE 90/F 192 ) describes the u~e of 2,4- and 2,5-sub~tituted pyridine N-oxides for preparing pharmaceuticals :inhibiting proline hydxoxylase and lysine hydroxylase.

It has now been found, surprisingly, that 4- or 5-~ubsti-tuted pyridine~2-carboxylic acids of the formula I
indicated below/ and the physiologically tolerated ~alts thereof, effec~ively inhibit lysine hydroxylase and proline hydroxyla~e in animal models.

Thus the invention claims compounds of the formula I

R1R2N(O)C-(I) N COOH

in which Rl and R2 are, independently of one another, hydrogen, C1-Cl2-alkyl, C2-Cl2~alkenyl, C2-Cl2-alkynyl, non-benzo-fused or benzo-~u~ed C5 C7-cycloalkyl, aryl or hetero-aryl, where these radicals mentioned for R1 and R2 are unsubstituted or su~stituted by one or more identical or different radicals R3, where R3 is halogen, hydroxyl, cyano, nitro, nitroxy, amino, carboxyl, Cl-C4-alkoxy, Cl-C4-alkoxycarbonyl, C1-C4-alkyl~ or -dialkylamino, indolyl or phenyl, where the indolyl and phenyl radical is unsubstituted or substi-tuted once, twice or three times by halogen, nitro, C1-C4-alkyl or C1-C4-alkoxy, where in the case o~
3 ~

multiple sub~titution the radicals are identical or di~ferent, or, if Rl is hydro~en, R2 is a radical -N~R4)(R53 in which R4 and R5 are identical or different and are ~ydrogen, C~-Cb-alkyl, C1-3-alkylcar~onyl ox phenyl, or, if ~1 i8 hydrogen, R2 is a residue of an ~-~mino acid, ~-amino acid alkyl ester, ~-amino amide, ~-amino alkyl-or dialkylamide, which i8 bonded via the N terminuæ~
where said al~yl radical~ have 1 to 4 carbon atoms and are optionally monosubstituted by phenyl, and whare the C3- and C4~alkyl radical~ can also be branched, or, if R1 is hydrogent R2 i~ a residue of a di- or tripeptide which is bonded via the N terminus, where ~Iresic1ue~
means the particular ~-amino acid and the derivati~e~
thereof or the di- or tripeptide, in each case lacking the N texminus, and Rl has the meaning of R2~ where tha radicalfi R1 and R2 are identical or different, or Rl and R2 are, together with the nitrogen at~m to which they are bo~ded, a radical of the formula II

~ (II) -N A
(CH2)n in which n i~ 1 to 3 and A is O, S, CH2 or N(R6)-, where R6 i8 hydrogen, phenyl, C~-C6-alkyl, C2-C6 alkenyl or C2-C6-alkynyl, where these said radicals are unsub-stituted or substituted by phenyl which in turn is unsubstituted or substituted once or more than once by one or more identical or different substituents selected from: halogen, nitro, cyano, carboxyl, - 5 _ 2 ~

hydroxyl, methyl, ethyl, methoxy, ethoxy and trifluoromethyl, or -N(R7)2 where R7 is hydrogen or Cl-C3-alkyl, or -CooR7 or -CON(Ra)2 or -CONHRB, where R3 has the meaning of R7 or wherQ (Ra)2 is a C4-C~-alkylene chain in which zero or one CHa group which is not directly adjacent to the nltrogen atom i~
replaced by U, S or N-R7, or where ~ is Cl-C4-alko~ycarbonyl or C3-C7-cycloalkyl, and the physiologically tolerated 8alt8, where pyridine-4- and -5-carboxamide-2-caxboxylic acid are excepted.

Particularly preferred compounds of the formula I are tho~e in which R1 and R2 are, independently of one another, hydrogen, Cl-C~;-al3cyl, C2-C6-alkenyl, C2-C6-alkynyl, C5-C7-cyclo-alkyl, aryl or heteroaryl, where these radicals mentioned for Rl and R2 are unsubstituted or substi-tuted by one or two identical or different radi~als R3, where R3 is halogen, hydroxyl, cyano, amino, car~oxyl, Cl-C4-alkoxy, C1-C4-alkoxycarbonyl~ Cl-C4-alkyl- or -dialkyl-amino, or phenyl~ where the phenyl radical i8 un~ub-~tituted or ~ubstituted once by halogen, Cl-C2-alkyl or Cl-C2-alkoxy, or, if Rl iS hydrOgell/ R2 i8 a radical -N(R4)(R5~ in which R4 and R5 are identical or different and are hydrogen or Cl-C3-alkyl, or, if Rl is hydrogen, R2 is a residue of an ~-amino ~cid or ~-amino acid alkyl ester bonded via the N terminus, where the alkyl radical has 1 to 3 carbon atoms and is - 6 ~ ~ ~32 opt~onally monosubstituted hy phenyl, and where the C3-alkyl radical can al80 b~ branched, and Rl ha~ the meaning of R2, where the radicals R1 and R2 are 5identical or dif~erent, or Rl and R~ are, together with the nitrogen atom to which they are bonded, a radical of the fonmula II

-N A (I~
(GH2)n in which lOn is 1 to 3, and A is 0, CH2 or -N(R5)-, where R6 is hydrogen, phenyl, C1-C6-alkyl, where these said radicals are unsub tituted or substituted by C1-C4-alkoxycarbonyl or C3-C,-cycloalkyl, and the physiologically tolerated salts, where pyridine-4- and -5-caxboxamide-2-carboxylic acid are excepted.

Especially preerrad compounds of the formula I are those in which R1 and R2 are, independently of one another, hydro~en, Cl-C6-alkyl, especially ~-C3-alkyl, C~-cycloal~qyl, phenyl, or pyridyl, where these radicals mentioned for Rl and R2 are unsubstituted or ~ubstituted by one or two identical radicals R3, where R3 is hydroxyl, amino, carboxylr Cl-C4-alkoxy, especially methoxy, C1-C4-alkoxycarbonyl, nr phenyl, where the phenyl radical is unsubstituted or substituted once by methyl or metho~y, and Rl has the meaning of R2/ where the radicals R1 and R2 are identical or different, or and R2 are, together with the nitrogen atom to which they are bonded, a radical of the formula II

(II) -N A
(CH2)n in which n i8 2 and ~ i8 0 or CH2, 5 and the physiologically tolerated salts, where pyrldine-4- and ~5 carbox~mide-2-carboxylic acid are excepted.

Said compounds pyridine-4- and ~-~-carbox~mide-2-car-boxylic acid have already been described as such in Thums, L.J. Pharm. Belg. 24 (1-2), 3~ 69~ and Delar~e, J.: Pharm. ~cta. Helv. 44 (10), 637-43 (1969).

Halogen means fluorine, chlorine, br~mine and iodine, aryl means phenyl and naphthyl, and heteroaryl mesns 5-and 6-member~d aromatic rings with 1, 2 or 3 nitrogen and~or oxygen and/or sulphur atoms~ which can al~o optionally be benzo-~used; the he~eroaryl radlcals are, in particular, pyridyl, pyridazyl, pyrimidyl, pyrazyl, 1,3,5-triazyl, pyrrolyl, pyrazolyl, imidazolyl, tri-azolyl, tetrazolyl, thienyl, oxazolyl and thia~olyl radicals and optionally ~hair benzo-fu~ed compounds.

"Substituted more than once`' means herein~efora and hereinafter that at least 2 and at mo~t all the hydrogen atoms present in the alkyl radicals are replaced by ~aid substituents. In this connection there is preferably one sub6tituent per methyl ~r m~thylene gxoup.

In the ca~e of multiple substitutions, the substituent~
can also be independent of one another.

The invention also relates to the use of compounds of the formula I and to the physiologically tolerated salts plus pyridine-4- and -5-carboxamide-2-carboxylic acid for producinq a pharmaceutical inhibiting proline hydroxylase and lysin~ hydroxylase.

Finally, the invention relates to ~he compounds of ~he formula I plus pyridine-4- and -5-carboxamide-2-car~ox-S ylic acid for use as pharmaceuticals.

The in~ention particularly r21ates to ~he compounds of the formula I plus pyridine-4- and -5-carboxamide-2-carboxylic acid for use as fibrosuppressants and immuno-suppressant~ and for inhibiting proline hydroxylase.and lysine hydroxylase and for influencing the metaboli~m of collag~n and collagen-like substances and the biosynthe-si~ of Clq.

All said alkyl radicals with more than 2 carbon atoms can be either straight-chain or branched.

lS The invention al~o relates to a process for preparing compounds of the foxmula I plus pyridine-4- or -5-carbox-amide-2-carboxylic acids.

The process according to the invention is illustrated hereinafter taking the example of pyridine 2,4-dicar-boxylic acid. The process of compounds according to theinven~ion with 2,5-substitution is carried out in an analogous manner.

2~ . {j Reaction scheme 23 8 0zCH

Stage 21 ~H2~ _ ~H2 CO2CH3 S tage 3 N O~H

¦ Stufe 4 CO2H CONR I R~

~II) e~l C~2C~i3 ¦ S t a g e 6 .

CON~1R~

(I') ~02H

In Stage 1, pyridine-2,4~dicarboxy1ic acid, which can be 2t~ ,? 1 1 ~

bought~ i8 converted into its dicarbonyl dihalide, preferably it~ dichloride, and reacted with an optionally substituted benzyl alcohol to give the dibenzyl pyridine-2,4-dicarboxylate.

In Stage 2, the diester is selectively hydrolyzed in position 2, for example in th~ presence of a copper cataly~t as described by Delarge, ~.s Phar. Acta.
H~lv. 44 (10), 637 (1969~.

The free acid functionality in position 2 i5 sub~eguent-lyr in Stage 3, converted into the corresponding acid chloride and converted with an ~lcohol ~uch a~, for example, methyl or ethyl alcohol into the corresponding 2~arbo~ylic e~ter.

~ he remaining ben~yl protective group in positio~ 4 iiB in Stage 4 eliminated by hydrogenolysis (for example with H2~Pd, Houben-Weyl: Vol. IV/lc (1980~, pp. 381-82)/ and the free acid in position 4 is converted into its acid chloride.

The acid chloride can now be converted with the amine of the formula III in which Rl and R~ have the meaning a~ in the compounds of the formula I into the mixed py.ridine-4-carboxamide-2-carboxylic ester.

~he 2-carboxylic ester can now finally (Sta~e 6) be converted with alcoholic alkali (for example sodium hydroxide solution in ethanol) first into tha salt of the 2-carboxylic acid, which is then converted with mineral acids (such a~, for example, hydrochloric acid) into the compound of the formula I' according to the invention.

Said process which has been described according to the reaction scheme for the compounds substituted in position 4 also applies to the compounds which are correspondingly substituted in position 5.

~ ~3 $ ~ J

The compounds of tha formula I plus pyridine-4- and -5-carboxamide-2-carboxylic acid have valuable pharmaco-logical propertie~ an~ ~how, in particular, activ~ty a~
inhibitor~ o~ ~roline hydroxylase and lysine hydroxylase, as fibrosuppres~ant and immunosuppressant.

The activity of the ~ibrogenase can ~e de~e~mined by radioimmunological determination of the N-terminal propeptide of collagen type III or of the N- or C-terminal cros~linking domain of collagen typa IV t7s collagen or type I~ collagen ~Cl) in ~erum.

For this purpose, the hydroxyproline, procollagen III
peptide~ 7s collagen and type IV collagen NCl concentra-tion~ were measured in the liver of a~ untreated rats ~control) b) rats given tetrachloromethane ( CC14 cont~ol3 c) rats given first CC14 and then a compound according to the invention (this test method is described by Rouiller, C., experi-mental toxic in~ury o~ the liver; in The Liver, 2~ C. Rouiller, Vol. 2, pp. 335-476, New York, Academic Press, 1964).

The compounds of the fonmula I plus pyridina-4- and -5-carboxamide 2-carboxylic acid can be used as medicament~
in the form of pharmaceutical products which contain them where appropriate together with tolerated pharmaceutical vehicles. The compounds can be used as medi~ine~, ~or example in the form of pharmaceutical products which contain these compounds mixed with a pharmaceutical, organic or inorganic vehicle suitable for enteral, percutaneous or parenteral administration, such as~ for example, water, gum arabic, gelatin, lactose, ~tarch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, vaseline etc.

They can be administered for this purpo6e orally in dose6 of 0.01 - 25.0 mg/kg/day, preferably 0.01 - 5.0 mg/kg/day . Y.

or parenterally in doses of 0~001 - 5 mg/kg/day, prefer-ably 0.001 - 2.5 mg/kg~day, ~pecially 0.005 1.0 mg/kg/day. It is also possible to increase the dosage in sevexe ca~eR. However, lower dose~ also 6uffice in S many ca~es. These data relate to an adult weighing about 75 ~g.

The invention also embraces the use of the compounds according to the invention ~or preparing pharmaceuticals which are employed for ~he 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 invPntîon and/or their physiologically tolerated salts, plus the pyridine-4- and -S-carboxam:ide-2-carboxylic acids.

The pharmaceuticals are produced by processes Xnown per se and familiar to the person skilled iYl the art. As pharmaceuticals, the pharmacologically active compounds (= active ^~ubstance) according to the invention are employed either as such or, preferably, in combinati~n with suitable pharmaceutical auxiliaries or excipients i~
the form of tablets, coated tablets, capsules, supposit-ories, emulsions, suspen~ions or solutions, where the content of acti~e substance is up to about 95 %, advant-ageously between 10 and 75 %~

Suitable auxiliaries and excipients for the reguiredpharmaceutical formulation are, for example, besides solvents, gel former~, suppository bases, tableting auxiliaries and other active substance vehicles, also antioxidants, disper6ants, emulsifier6, foam suppres-sants, flavorin~s, preservativeæ, solubilizers or colorants.

The active substances can be administered orally, parent-erally or rectally.

r ~ r J 3 The active compounds are mixed with the additives ~uit-able for this r such as excipients, stabilizers or inert diluents, and converted by the usual methods into ~uit-able dosage forms such as tablets, coated tablets, hard S gelatin capsulesl aqueou~ alcoholic or oily suspen~ions or aqueous or oily solutions.

Examples of inert excipients which can be used are ~um arabicJ magnesia, magnesium carbonate, potassium pho~-phate, lactose, glucose or starch, especially corn starch. The preparation can be carried out either a~ dry or as wet granules. ~xamples of suitable oily excip~ents or solvents are vegetable or animal oils~ ~uch a8 ~un-flower oil or fish liver oil.

For subcutaneous or intravenous administration, the active compounds are, if required, converted into a solution, suspQnsion or emulsion with the sub~tances suitable for this purpose, such as solubilizers, emulsi-fiers or other auxiliaries~ Examples of suitable solvents are physiological saline or alcohols, for example eth-ano~, propanol, glycerol, as well as ~ugar solutions ~uchas glucose or mannitol solutions, or else a mixture of the various solvents mentioned.

The invention is explained in ~ore de~ail hereinafter by means of examples.

Example 1 Dibenæyl pyridine-2~4-dicarboxylate (Stage 1) 30 g of pyridine-2t4-dicarboxylic acid are converted with 30 ml of thionyl chloride into the acid chloride and reacted with 43.8 g of ben%yl alcohol. The product i~
recrystallized from diisopropyl ether.
Yield: 42.1 g melting point 63 - 65C

~ A~ $ S) 1-,`; A~, r3 Example 2 Pyridine-2,4-dicarboxylic acid 4-benzyl ester (Stage 2) 40 g of dibenzyl pyridina-~,4-~icarboxylate from Ex-ample 1 are ad~ed to a suspension of 27.8 g of copper(II) nitrate in 700 ml of methanol. ~he mixture is ~o~led under reflux for one hour and, after cooling, the copper complex is remo~ed by filtra~ion. The complex is ~uspend ed in dioxane, and hydrogen sulfide is pa~sed in. The precipitated coppex sulide is filtered off and the organic phase is concentrated. The product is stirred with petroleum ether.
Yield: 25.3 g melting point 113 - 115C

Example 3 4-Benzyl 2-methyl pyridine-2,4-dicarboxylate (Stage 3) 34 g of the compound from Example 2 are introduced into l l of tetrah~drofuran. The mixt~re is cooled to ODC and, at this temperature, 250 ml of a diazomethane ~olution are 910~1y added dropwise. The mixture i allowed to reach room temperature and is stirred for 12 hours. The 20 solution is concentrated and the crude product is chroma-tographed (silica g~l, mobile pha~e ethyl acetate).
Yield: 26 g melting point: 58DC

Exampl~ 4 Pyridine-2,4-dicarboxylic a~id 2-methyl ester (Stage 4~

26 g of the compound from Example 3 are dissolved in 1 l of dioxane at room temperature. 500 mg of palladium/car-bon (10 ~) catalyst are added to the solution, and hydrogenation is carried out under atmospheric pressure for 4 hours. After hydrogen uptake ceases, the catalyst is filtered off with suction and the solvent iB ~tripped off~

Yield: 15.3 g melting point 241 - 243C

Example 5a Pyridine-2,4-dicarboxylic acid 2-methyl es~er 4-(2-methoxyethyl)amide ~Staqe 5) ll g of the compound from Example 4 are converted in analogy to Example 1 with 4.8 ml o~ thionyl chloride into the acid chloride and reacted with S.~ ml of 2-methoxy-ethylamine to give the amide. The crude product is triturated with diisopropyl ether and filtered off with suction.
Yield: 9.5 g melting point: 74 - 76C

Example 5b Pyridine-2~4-dicarboxylic acid 2-methyl ester 4-(3-mekhoxypropyl)amide ~Stage S) In analogy to Example 5a, 3 g of the compound from Example 4 are converted with 1.2 ml of thionyl chloride into the acid chloride and reacted with 1.7 ml o 3-methoxypropylamine to give the amide. ~he crude product i8 chromatographed (ethyl acetateJmethanol 15~1).
Yield: 2.6 g oil Example 6a Pyridine-2,4-dicarboxylic acid 4-(2-methoxyethyl)amide (Stage 6) 2.3 g of sodium hydro~ide ~pellets) Are dissolved in 70 ml of ethanol at room temperature. A solution of 9 g of the compound from Example 5a in 30 ml of ethanol is added dropwise at this temperature. After 4 hours, the mixture is evaporated to dryness, the residue is taken up in a little water and the solution is slowly acidified with concentrated hydrochloric acid. The solution i3 ~ ~ è3 ~ ~? ,3 ,~i evaporated and the product is recrys~allized from hot ethanol.
Yield: 8 g melting point~ 130 - 135C

Example 6b Pyridine-~,4-dicarboxylic acid 4-(3-methoxypropyl)ami~e (Stage 6) The compou~d is prepared in analogy to ~xample Xa from 3 g of the e~er fr~m Example 5b.
Yield: 2.6 g melting point: 118 - 1224C

Claims (8)

1. A 4- or 5 substituted pyridine 2-carboxylic acid of the formula I

(I) in which R1 and R2 are, independently of one another, hydrogen, C1-C12-alkyl, C2-C12-alkenyl, C2-C12-alkynyl, non-benzo-fused or benzo-fused C5-C7-cycloalkyl, aryl or hetero-aryl, where these radicals mentioned for R1 and R2 are unsubstituted or substituted by one or more identical or different radicals R3, where R3 is halogen, hydroxyl, cyano, nitro, nitroxy, amino, carboxyl, C1-C4-alkoxy, C1-C4-alkoxycarbonyl, Cl-C4-alkyl- or -dialkylamino, indolyl or phenyl, where the indolyl and phenyl radical is unsubstituted or substi-tuted once, twice or three times by halogen, nitro, C1-C4,-alkyl or C1-C4 alkoxy, where in the case of multiple e substitution the radicals are identical or different, or, if R1 is hydrogen, R2 is a radical -N(R4)(R5) in which R4 and R5 are identical or different and are hydrogen, C1-C4-alkyl, C1-C3-alkylcarbonyl or phenyl, or, if R1 is hydrogen, R2 is a residue of an .alpha.-amino acid, .alpha.-amino acid alkyl ester, .alpha.-amino amide, .alpha.-amino alkyl-or dialkylamide, which is bonded via the N terminus, where said alkyl radicals have 1 to 4 carbon atoms and are optionally monosubstituted by phenyl, and where the C3- and C4-alkyl radicals can also be branched, or, if R1 is hydrogen, R2 is a residue of a di- or tripeptide which is bonded via the N terminus, where "residue"
means the particular .alpha.-amino acid and the derivatives thereof or the di- or tripeptide, in each case lacking the N terminus, and R1 has the meaning of R2, where the radicals R1 and R2 are identical or different, or R1 and R2 are, together with the nitrogen atom to which they are bonded, a radical of the formula II

(II) , in which n is l to 3 and A is O, S, CH2 or -N(R6)-, where R6 is hydrogen, phenyl, C1-C6-alkyl, C2-C8-alkenyl or C2-C6-alkynyl, where these said radicals are unsub-stituted or substituted by phenyl which in turn is unsubstituted or substituted once or more than once by one or more identical or different substituents selected from: halogen, nitro, cyano, carboxyl, hydroxyl, methyl, ethyl, methoxy, ethoxy and trifluoromethyl, or -N(R7)2 where R7 is hydrogen or C1-C3-alkyl, or or -CON (R8) 2 or -CONHR6, where R8 has the meaning of R7 or where (R8)2 is a C4-C6-alkylene chain in which zero or one CH2 group which is not directly adjacent to the nitrogen atom is replaced by O, S or N-R7, or where R6 is C1-C4-alkoxycarbonyl or C3-C7-cycloalkyl, and the physiologically tolerated salts, where pyridine-4- and -5-carboxamide-2-caxboxylic acid are excepted.
2. A compound as claimed in claim 1, in which R1 and R2 are, independently of one another, hydrogen, C1-C6-alkyl, C2-C6-alkenyl,C2-C6-alkynyl, C5-C7-cyclo-alkyl, aryl or heteroaryl, where these radicals mentioned for R1 and R2 are unsubstituted or substi-tuted by one or two identical or different radicals R3 , where R3 is halogen, hydroxyl, cyano, amino, carboxyl, C1-C4-alkoxy, C1-C4-alkoxycarbonyl, C1-C4-alkyl or -dialkyl-amino, or phenyl, where the phenyl radical is unsub-stituted or substituted once by halogen, C1-C2-alkyl or C1-C2 alkoxy, or, if R1 is hydrogen, R2 is a radical -N(R4)(R5) in which R4 and R5 are identical or different and are hydrogen or C1-C3-alkyl, or, if is hydrogen, R2 is a residue of an .alpha.-amino acid or .alpha.-amino acid alkyl ester bonded via the N terminus, where the alkyl radical has 1 to 3 carbon atoms and is optionally monosubstituted by phenyl, and where the C3-alkyl radical can also be branched, and R1 has the meaning of R2, where the radicals R1 and R2 are identical or different, or R1 and R2 are, together with the nitrogen atom to which they are bonded, a radical of the formula II

(II) in which n is 1 to 3, and A is 0, CH2 or -N(R6)-, where R6 is hydrogen, phenyl C1-C6-alkyl, where these said radicals are unsubstituted or substituted by C1-C4-alkoxycarbonyl or C3-C7-cycloalkyl, and the physiologically tolerated salts, where pyridine-4- and -5-carboxamide-2-carboxylic acid are excepted.
3. A compound as claimed in claim 1, in which R1 and R2 are, independently of one another, hydrogen, C1-C5-alkyl, especially C1-C3-alkyl, C6-cycloalkyl, phenyl, or pyridyl, where these radicals mentioned for R1 and R2 are unsubstituted or substituted by one or two identical radicals R3, where R3 is hydroxyl, amino, carboxyl, C1-C4-alkoxy, especially methoxy, C1-C4-alkoxycarbonyl, or phenyl, where the phenyl radical is unsubstituted or substituted once by methyl or methoxy, and R1 has the meaning of R2, where the radicals R1 and R2 are identical or different, or R1 and R2 axe, together with the nitrogen atom to which they are bonded, a radical of the formula II

(II) in which n is 2 and A is V or CH2, and the physiologically tolerated salts, where pyridine-
4- and -5-carboxamide-2-carboxylic acid are excepted.

4. A process for preparing 4- or 5-substituted pyridine-2-carboxylic acids of the formula I and their physio-logically tolerated salts plus pyridine-4- and -5-carbox-amide-2-carboxylic acids, where - pyridine-2,4-dicarboxylic acid is converted into its dihalide, - the dihalide is converted into the dibenzyl ester, - the dibenzyl ester is selectively hydrolyzed in position 2, - the monobenzyl ester resulting therefrom is converted at the free acid functionality into the corresponding acid chloride and converted with an alcohol, which does not correspond to benzyl alcohol, into the corresponding 2-carboxylic ester, - the benzyl protective group in position 4 or 5 is eliminated by hydrogenolysis and the resulting free acid in position 4 or 5 is converted into the cor-responding acid chloride, which comprises - the acid chloride from the previous stage being converted with an amine of the formula III

HNR1R2 (III) where R1 and R2 have a meaning indicated in formula I, into the mixed pyridine-dicarboxylic acid 4- or 5-amide 2-ester, and - finally said 2-carboxylic ester being converted with mineral acid into the free acid in position 2.
5. A compound as claimed in claim 4 for inhibiting proline hydroxylase and lysine hydroxylase.
6. A compound as claimed in claim 4 for use as fibrosup-pressant and immunosuppressant.
7. A pharmaceutical containing a compound as claimed in claim 4 and/or its physiologically tolerated salts for the treatment of disturbances of the biosynthesis of collagen and collagen-like substances and of the biosyn-thesis of Clq.
8. A process for producing pharmaceuticals for influenc-ing the biosynthesis of collagen and collagen-like substances and the biosynthesis of Clq, which comprises incorporating into the pharmaceutical a compound of the formula I as claimed in claim 4 and/or a physiologically tolerated salt of this compound.
CA002052510A 1990-10-01 1991-09-30 4- or 5-substituted pyridine-2-carboxylic acids, a process for the preparation thereof and the use thereof as pharmaceuticals Abandoned CA2052510A1 (en)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7592343B2 (en) 2004-09-20 2009-09-22 Xenon Pharmaceuticals Inc. Pyridazine-piperazine compounds and their use as stearoyl-CoA desaturase inhibitors
US7767677B2 (en) 2004-09-20 2010-08-03 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors
US7777036B2 (en) 2004-09-20 2010-08-17 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as therapeutic agents
US7829712B2 (en) 2004-09-20 2010-11-09 Xenon Pharmaceuticals Inc. Pyridazine derivatives for inhibiting human stearoyl-CoA-desaturase
US7919496B2 (en) 2004-09-20 2011-04-05 Xenon Pharmaceuticals Inc. Heterocyclic derivatives for the treatment of diseases mediated by stearoyl-CoA desaturase enzymes
US7951805B2 (en) 2004-09-20 2011-05-31 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as mediators of stearoyl-CoA desaturase
US8071603B2 (en) 2004-09-20 2011-12-06 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors
US8541457B2 (en) 2005-06-03 2013-09-24 Xenon Pharmaceuticals Inc. Aminothiazole derivatives as human stearoyl-CoA desaturase inhibitors

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* Cited by examiner, † Cited by third party
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EP0617020A1 (en) * 1992-04-02 1994-09-28 Shudo, Koichi, Prof. Dr. Carboxylic acid derivatives having retinoic acid-like activity
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

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DE3703962A1 (en) * 1987-02-10 1988-08-18 Hoechst Ag PYRIDINE-2,4- AND 2,5-DICARBONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, USE OF THE SAME AND MEDICINAL PRODUCTS BASED ON THESE COMPOUNDS
DE3703959A1 (en) * 1987-02-10 1988-08-18 Hoechst Ag PYRIDINE-2,4- AND 2,5-DICARBONIC ACID AMIDES, METHOD FOR THE PRODUCTION THEREOF, USE OF THE SAME AND MEDICINAL PRODUCTS BASED ON THESE 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

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7592343B2 (en) 2004-09-20 2009-09-22 Xenon Pharmaceuticals Inc. Pyridazine-piperazine compounds and their use as stearoyl-CoA desaturase inhibitors
US7767677B2 (en) 2004-09-20 2010-08-03 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors
US7777036B2 (en) 2004-09-20 2010-08-17 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as therapeutic agents
US7829712B2 (en) 2004-09-20 2010-11-09 Xenon Pharmaceuticals Inc. Pyridazine derivatives for inhibiting human stearoyl-CoA-desaturase
US7919496B2 (en) 2004-09-20 2011-04-05 Xenon Pharmaceuticals Inc. Heterocyclic derivatives for the treatment of diseases mediated by stearoyl-CoA desaturase enzymes
US7951805B2 (en) 2004-09-20 2011-05-31 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as mediators of stearoyl-CoA desaturase
US8026360B2 (en) 2004-09-20 2011-09-27 Xenon Pharmaceuticals Inc. Substituted pyridazines as stearoyl-CoA desaturase inhibitors
US8071603B2 (en) 2004-09-20 2011-12-06 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors
US8541457B2 (en) 2005-06-03 2013-09-24 Xenon Pharmaceuticals Inc. Aminothiazole derivatives as human stearoyl-CoA desaturase inhibitors

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