AU637848B2 - Pyridine-2,4- and 2,5-dicarboxamides, a process for the preparation thereof, and the use thereof - Google Patents
Pyridine-2,4- and 2,5-dicarboxamides, a process for the preparation thereof, and the use thereof Download PDFInfo
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- AU637848B2 AU637848B2 AU66895/90A AU6689590A AU637848B2 AU 637848 B2 AU637848 B2 AU 637848B2 AU 66895/90 A AU66895/90 A AU 66895/90A AU 6689590 A AU6689590 A AU 6689590A AU 637848 B2 AU637848 B2 AU 637848B2
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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
- C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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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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- 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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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyridine Compounds (AREA)
Description
COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952-69 COMPLETE SPECIFICATION
(ORIGINAL)
Class I nt. Class Application Number: Lodged: 3 tomplete Specification Lodged: 9..Accepted: Published: ~Priority Related Art N'ame of Applicant *Goo33* A ddress of Applicant: -A~ctual Inventor Address for Service HOECHST AITIENGESELLSCHAFT 50 Bruningstrasse, D-6230 Frankfurt/Main of Germany 80, Federal Republic EKKEHARD BAADER, MARTIN BICKEL and VOLKMAR GUNZLER-PUKALL WATERMARK PATENT TRADEMARK ATTORNEYS.
LOCKED BAG NO. 5, HAWTHORN, VICTORIA 3122, AUSTRALIA Complete Specification for the invention entitled: PYRIDINE-2,4- AND 2,5-DICARBOXAMIDES, A PROCESS FOR THE PREPARATION THEREOF, AND THE USE THEREOF The following statement is a full description of this invention, including the best method of performing it known to us HOECHST AKTIENGESELLSCHAFT HOE 89/F 369 Dr.SW7/PP Description Pyridine-2,4- and 2,5-dicarboxamides, a process for the preparation thereof, and the use thereof Compounds which inhibit the enzymes proline hydroxylase and lysine hydroxylase bring about a very selective inhibition of collagen biosynthesis by influencing the collagen-specific hydroxylation reactions. In the course thereof, protein-bound proline or lysine is hydroxylated **10 by the enzymes proline hydroxylase or lysine hydroxylase.
If this reaction is suppressed by inhibitors, the result .is an insufficiently hydroxylated collagen molecule which is unable to function and can be released by the cells o into the extracellular space only in a small amount.
Moreover, the insufficiently hydroxylated collagen cannot be incorporated in the collagen matrix and very readily undergoes proteolytic degradation. The consequence of these effects is an overall reduction in the amount of collagen deposited outside the cells.
It is known that the inhibition of proline hydroxylase by known inhibitors such as a,a'-dipyridyl results in inhibition of Clq biosynthesis by macrophages Muller et al., FEBS Lett. 90 (1978), 218; Immunobiology 155 S"(1978), 47). This leads to the classical pathway of *25 complement activation becoming inoperative. Thus, inhibitors of proline hydroxylase also act as immunosuppressants, for example in immune complex diseases.
It is known that the enzyme proline hydroxylase is efficiently inhibited by pyridine-2,4- and oxylic acids Majamaa et al., Eur. J. Biochem. 138 (1984) 239-245). These compounds are, however, effective inhibitors in cell culture only in very high concentrations (Tschank, G. et al., Biochem, J. 238 (1987) 625- 633).
2 DE-A 34 32 094 gives a description of diesters of pyridine-2,4- and -2,5-dicarboxylic acids with 1-6 carbon atoms in the ester alkyl moiety as pharmaceuticals for inhibiting proline hydroxylase and lysine hydroxylase.
These lower alkyl diesters have the disadvantage, however, that in the body they are rapidly cleaved to the acids and do not reach their site of action in the cell in sufficiently high concentration and thus are poorly suited for possible administration as pharmaceuticals.
,10 DE-A 37 03 959, DE-A 37 03 962 and DE-A 37 03 963 describe in a general form mixed ester/amides, higher alkyl diesters and diamides of pyridine-2,4- and boxylic acids, which are effective inhibitors of collagen biosynthesis in animal models.
Thus, DE-A 37 03 959 describes, inter alia, the synthesis of N, N' -bis (2-methoxyethyl) pyridine-2,4-dicarboxamide and N,N'-bis(3-isopropoxypropyl)pyridine-2,4-dicarboxamide.
German Patent Applications P 38 26 471.4 and P 38 28 140.6 propose an improved process for the preparation of 20 N,N'-bis(2-methoxyethyl)pyridine-2,4-dicarboxamide.
German Patent Application P 3924093.2 proposes new N,N'bis(alkoxyalkyl)pyridine-2,4-dicarboxamides.
Both pyridine-2,4- and -2,5-dicarboxamides (Hirakata et al., J. pharm. Soc. Japan 77 (1957) 219 and Haring et al., Helv. 37 (1954) 147, 153) and pyridine-2,4- and (Itai et al., Bl. nation. hyg.
Labor. Tokyo, 74 (1956) 115, 117 and Shinohara et al., Chem. High Polymers Japan, 15 (1958) 839) have already been disclosed as agents for tuberculosis, It has now been found, surprisingly, that substituted pyridine-2,4- and 2,5-dicarboxamides of the formula I 3
R
1
HNOC
(I)
N CONH- R 1 in which
R
1 is hydrogen or NR 3 where R 2 and R 3 are identical or different and are hydrogen, Ci-C 4 -alkyl, phenyl or Ci-C 3 -alkylcarbonyl, and the physiologically tolerated salts, are likewise effective inhibitors of lysine hydroxylase and proline hydroxylase in animal models.
Accordingly, the invention relates to a) the use of *10 compounds of the formula I
RIHNOC
(I)
CONH- R 1 in which R is hydrogen or
N
-R
3 where R 2 and R 3 are identical or different and are hydrogen, Ci-C 4 -alkyl, phenyl or Ci-C 3 -alkylcarbonyl,
C
and the physiologically tolerated salts, for the preparation of a pharmaceutical inhibiting proline hydroxylase and lysine hydroxylase.
The invention furthermore relates to b) the compounds of the formula I in which
R
1 is
N
R
3 where R 2 is hydrogen, C 1
-C
4 -alkyl, phenyl or Ci-C 3 -alkylcarb:nyl, and R 3 has the meaning of R 2 apart from hydrogen, 4 and the physiologically tolerated salts, for use as pharmaceuticals.
The invention furthermore relates to c) the compounds of the formula I in which 2
R
1 is NR3 where R 2 is hydrogen, Ci-C 4 -alkyl, phenyl or Ci-C 3 -alkylcarbonyl, and R 3 has the meaning 0e of R 2 apart from hydrogen, and the physiologically tolerated salts thereof.
In particular, the invention relates to the compounds of the formula I defined in b) and c) for use as fibrosuppressants and immunosuppressants and for inhibiting proline hydroxylase and lysine hydroxylase and for influencing the metabolism of collagen and collagen-like substances and the biosynthesis of Clq.
S
All the said alkyl radicals with more than 2 carbon atoms can be both straight-chain and branched.
The invention furthermore relates to a process for the preparation of compounds of the formula I, which comprises reacting a compound of the formula II 0
Y-C-
SC-Y
0 with a compound of the formula III
R
2
R
2
(III)
R3 where R and R 3 have the meanings specified for formula I, /f where R 2 and R 3 have the meanings specified for formula I, 5 and Y is halogen, hydroxyl or Ci-C 4 -alkoxy, or forms together with the carbonyl group an active ester or a mixed anhydride, or comprises first reacting the compound of the formula II in which Y is as defined above with a compound of the formula III in which R 2 =R and subsequently reacting the reaction product with a compound of the f-omula IV Y-C -Ci-C 3 -alkyl (IV) where Y is as defined above, and subsequently converting 10 the reaction products into the physiologically tolerated salts thereof where appropriate.
The preparation of compounds of the formula I and the preparation of those starting substances required for this which cannot be bought is described in detail hereinafter.
The compounds according to the invention are prepared o' most straightforwardly by the two components, the pyridine derivative of the formula (II) and the amine of the formula (III), being mixed in equimolar amounts or with 20 an up to about 5-fold excess of III and reacted at
S
temperatures between -30 and 150"C, preferably at 20 to 100°C, until the reaction is complete. The completion of the reaction can be determined, for example, by thinlayer chromatography. One variant of this process comprises using a suitable solvent such as diethyl ether or dimethoxyethane or tetrahydrofuran, chlorinated hydrocarbons such as methylene chloride, chloroform, tri- or tetrachloroethylene, benzene, toluene or else polar advents such as dimethylformamide, acetone, alcohols such as methanol or ethanol or dimethyl sulfoxide. It is also possible in this case to use an excess of amine of the formula (III), which can be up to about amounts. The temperatures for this reaction are between room temperature and the boiling point of the solvent, with temperatures in the range from room temperature to 6 130"C being particularly preferred.
The reaction can likewise be carried out via a mixed anhydride such as ethyl chloroformate or via an activated ester such as paranitrophenyl ester CICH 2 -COO or
NO
2
-C
6
H
4 Appropriate methods are described in the literature.
It is also possible, where appropriate, for the reaction to be carried out in the presence of bases. Examples of suitable additional bases are carbonates or bicarbonates 10 such as sodium or potassium carbonate or sodium or S potassium bicarbonate, or tertiary amines such as triethylamine, tributylamine, ethyldiisopropylamine or S heterocyclic amines such as N-alkylmorpholine, pyridine, S* quinoline or dialkylanilines.
One variant for the preparation of the compounds with
R=C
1
-C
3 -alkylcarbonyl comprises componds with R 2
=R
3
H
•II* being prepared as described above and then mixed with 0. Ci-C 3 -alkanoyl chlorides in equimolar amounts or with an up to about 5-fold excess of acid chloride, and reacted 0 at temperatures between -30" and 150"C, preferably at to 100 0 C, until the reaction is complete. It is also possible to use a suitable solvent such as dimethylformamide, acetone, alcohols such as methanol or ethanol or dimethyl sulfoxide. The reaction can also, where appropriate, be carried ct in the presence of bases. Examples of suitable additional bases are carbonates or bicarbonates such as sodium or potassium carbonate or sodium or potassium bicarbonate, or tertiary amines such as triethylamine, tributylamine, ethyldiisopropylamine, or heterocyclic amines such as N-alkylmorpholine, pyridine, quinoline or dialkylanilines.
Where appropriate the products can be worked up, for example, by extraction or by chromatography, for example on silica gel. The isolated product can be recrystallized and, where appropriate, reacted with a suitable acid to 7give a physiologically tolerated salt. Examples of suitable acids are: mineral acids such as hydrochloric and hydrobromic acid, and sulfuric, phosphoric, nitric or perchloric acid or organic acids such as formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, maleic, fumaric, phenylacetic, benzoic, methanesulfonic, toluenesulfonic, oxalic, 4-aminobenzoic, onic or ascorbic acid.
:.10 Those starting compounds of the formula (III) which 6* cannot be bought can be synthesized by processes known from the literature.
09 The starting compounds of the formula (II) are obtained, for example, by converting pyridine-2,4- or oxylic acid into the corresponding pyridine-2,4- or dicarbonyl halide, preferably chloride (by processes known from the literature), preferably in the presence of a catalyst such as dimethylformamide. This acid halide can then be reacted, for example, either with a suitable alcohol, for example paranitrobenzyl alcohol, to give the corresponding active ester, or else with lower alcohols such as methanol or ethanol to give the corresponding esters. It is likewise also possible for the pyridine- S 2,4- or 2,5-dicarboxylic acid initially to be converted by addition of a suitable carboxylic acid or of a carboxylic ester such as ethyl chloroformate into a mixed anhydride which is then reacted with the amines (III) to give the products according to the invention. An appropriate method is likewise described in the literature.
The compounds of the formula I according to the invention have valuable pharmacological properties and display, in particular, activity as inhibitors of proline hydroxylase and lysine hydroxylase, as fibrosuppressant and immunosuppressant.
8 Because of these pharmacological properties, the compounds according to the invention are suitable for the treatment of disturbances of the metabolism of collagen and collagen-like substances and for the treatment of disturbances of the biosynthesis of Clq.
Hence the invention furthermore relates to the use of the compounds of the formula I according to the invention and of the physiologically tolerated salts thereof for the treatment of the abovementioned metabolic disorders.
The compounds can be used as pharmaceuticals either alone or mixed with physiologically tolerated auxiliaries or S* excipients. They can be administered for this purpose orally in doses of 0.01 25.0 mg/kg/day, preferably 0.01 5.0 mg/kg/day or parenterally in doses of 0.001 5 mg/ kg/day, preferably 0.001 2.5 mg/kg/day, in particular 0.005 1.0 mg/kg/day. The dose can also be increased in severe cases. However, in many cases, lower doses are also sufficient. These data relate to adults weighing about 75 kg.
The invention additionally embraces the use of the compounds according to the invention for the preparation of pharmaceuticals which are employed for the treatment and prophylaxis of the abovementioned metabolic disorders.
The invention furthermore relates to pharmaceuticals which contain one or more compounds of the formula I according to the invention and/or the physiologically tolerated salts thereof.
The pharmaceuticals are prepared by processes which are known per se and familiar to those skilled in the art.
The pharmacologically active compounds active substance) according to the invention are employed as pharmaceuticals either as such or, preferably, in combination with suitable pharmaceutical auxiliaries or 9 excipients in the form of tablets, coated tablets, capsules, suppositories, emulsions, suspensions or solutions, in which the content of active substance is up to about 95%, preferably between 10 and Examples of suitable auxiliaries or excipients for the desired pharmaceutical formulation are, besides solvents, gel-formers, suppository bases, tablet auxiliaries and other active substance vehicles, also antioxidants, dispersing agents, emulsifiers, antifoam agents, flavor correctives, preservatives, solubilizers and colorants.
The active substances can be administered orally, parenterally or rectally.
The active compounds are mixed with the additives zuitable for this purpose, such as excipients, stabilizers or inert diluents, and converted by customary methods into suitable dosage forms such as tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily suspensions or aqueous or oily solutions.
*6 Examples of inert excipients which can be used are gum 0 arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, especially corn starch. This preparation can be carried out both as dry and as wet granules. Examples of suitable oily excipients or solvents are vegetable or animal oils, such as sunflower oil or fish liver oil.
For subcutaneous or intravenous administration, the active compounds are converted into solution, suspension or r on, if desired with the substances suitable for this purpose, such as solubilizers, emulsifiers or other auxiliaries. Examples of suitable solvents are physiological saline or alcohols, for example ethanol, propanol, glycerol, as well as sugar solutions such as glucose or mannitol solutions, or else a mixture of the various solvents mentioned.
t The invention is explained in detail hereinafter by means of examples.
Example 1: 2 ,4-Bis (2-acetylhydrazinocarbonyl)pyridine (Formula I: R 1 NII-C (O)CH 3 12.6 g of pyridine-2,4-dicarbohydrazide are suspended in 750 ml of dichioromethane. To this are adde.i at room I:temperature 7.9 g of N,N-diniethylaminopyridine and ev a* 32.4 ml of acetic anhydride.
10The mi~xture is stirred at this temperature for 36 h, concentrated and evaporated 3 times with toluene. The residue is chromatographed on silica gel (mobile phase: cyclohexane/ethyl acetate 1/4).
Yield: 5.6 g Melting point: 136-137*C Ei;ample 2: fee**: 2,5-Bis (2-methylhydrazinocarbonyl)pyridina (Formula I: R' NH-CH 3 Dixnethyl pyridine-2,5-dicarboxylate are dissolved in 100 ml of methanol, and 0.5 g of methylhydrazine is 020 added. The T.nix- -tre is stirred under ref lux for 4 hours and concentrated, and the residue is stirred with diisopropyl ether and filtered off with suction.
Yield: 0.75 g Melting point: 202 0
C
Example 31.
Pharmacologic~L activity To demonstrate the efficient inhibition of proline hydroxylase and lysine hydroxylase by the compounds 11 according to the invention, the hydroxyproline concentrations in the liver and the procollagen III peptide concentrations in the serum of a) untreated rats (control) b) rats given tetrachloromethane (CCI4 control) c) rats given first CCl 4 and then a compound according to the invention were measured (this test method is described by Rouiller, experimental toxic injury of the liver; in The Liver, C. Rouiller, Vol. 2, pages 335-476, New York, Academic Press, 1964).
The potency of the compounds according to the invention was determined as the percentage inhibition of liver hydroxyproline and procollagen III peptide synthesis ".15 after oral administration compared with control animals which were given only tetrachloromethane (CC1 4 control).
The results are listed in Table 1.
0 se 6 *0 12 Table 1: Ef fect of prolyl hydroxylase inhibitors on CCd 4 induced liver fibrosis in rats, 8-week treatment Compound Dose a mg/kg N Bilirubinb
AM
PulIpU ng/ml Hyp d pUg/mi Control 1.9 11 0.056 CC1 4 Increase a. Diainide 10 Increase' Decreasef S.....Mean" Examnple 1 06 Increase' Decreasef Mean" 4.
2.
3.
1.
54 3.
1 58 5 32 6 21 1 25 2 14 35 (42 6 0 29 1 18 14 (33 13 0.228 0 .172 0 .163 0.107 38 0.181 0.125 27 sees
C
6 0 e *0 S 6 daily oral dose bilirubin in serumri (total) prccollagen III N-peptide in serum hydroxyproline content in the liver increase (absolute) compared with control percentage decrease compared with CC1 4 treatment total content of bilirtibin, PIIlP and Hyp, deviation
Claims (9)
1. A compound of the formula I R 1 HNOC N CONH-R 1 in which R 2 R' is N where R is hydrogen, C 1 -C 4 -alkyl, SR 3 phenyl or C 1 -Cs-alkylcarbonyl, and R3 has the meaning of R2 apart from hydrogen, and the physiologically tolerated salts thereof.
2. A compound of the formula I as claimed in claim 1, wherein R2 is hydrogen, and R3 is C--C 2 -alkyl, phenyl or C 1 -C 2 -alkylcarbonyl.
3. A compound of the formula I as claimed in claim 1 or 2, wherein R2 is hydrogen, and R3 is C 3 -C 4 -alkyl or acetyl.
4. A process for the preparation of compounds of the formula I as claimed in claim 1, which comprises reacting a compound of the formula II N C-Y I II C-Y S" with a compound of the formula III HN N R 2 H2N-N -(lI) 14 where R2 and R3 have the meanings specified for formula I in claim 1, and Y is halogen, hydroxyl or C1-C4-alkoxy, or forms together with the carbonyl group an active ester or a mixed anhydride, or comprises first reacting the compound of the formula II in which Y is as defined above with a compound of the formula III in which R2=R3=H, and subsequently reacting the reaction product with a compound of the formula IV Y-C(O)-C1-C3-alkyl (V where Y is as defined above, and subsequently converting the reaction products into the physiologically tolerated salts thereof where appropriate. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula I as claimed in claim 1 in adjunct with pharmacologically acceptable excipients or carriers.
6. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula I as claimed in claim 2 in adjunct with pharmacologically acceptable excipients or carriers.
7. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula I as claimed in claim 3 in adjunct with pharmacologically acceptable excipients or carriers.
8. A method of inhibiting proline hydroxylase and lysine hydroxylase comprising administering to a patient requiring such treatment an effective amount of the compound as claimed in one or more of claims 1 to 3.
9. A method of treating fibrosuppression or immunosuppression comprising administering to a patient requiring such treatment an effective amount of the compound as claimed in one or more of claims 1 to 3. ••go A method of influencing the metabolism of collagen and collagen-like substances and the biosynthesis of Clq comprising administering to a patient requiring such treatment an eflective amount of the compound as claimed in one or more of claims 1 to 3,
11. A method of treating disturbaes -of- tho metabolism of collagen--an collagen-like substances and of the bios l th q comprising administering to_ a nng such treatment an effective amount of the R.peu -as claimed ino.,,r o fclams 1 to- 3,oel VL SA method of preparation of a medicament having proline hydroxylase and lysine hydroxylase inhibiting activity comprising admixing in a pharmacologically acceptable ratio an effective amount of the compound as claimed in claim 1 with suitable pharmaceutically acceptable carriers or excipients. The method as claimed in claim 12, wherein R1 is amino which is unsubstituted or monosubstituted by C 1 -C 3 -alkyl, phenyl or C 1 -C3-alkyl-carbonyl. 3. The method as claimed in claim 12, wherein SR1 is amino which is unsubstituted or monosubstituted by acetyl. o 16 A process for the preparation of pharmaceuticals for influencing the metabolism of collagen and collagen-like substances and of the biosynthesis of C q, which comprises incorporating a compound of the formula I as claimed in one or more of claims 1 tr 3 into the pharmaceutical. DATED this 22nd day of February, 1993 HOECHST AKTIENGESELLSCHAFT WATERMARIK PATENT TRADEMARK ATTORNEYS THE ATRIUM 290 BURWOOD ROAD HAWTHORN VICTORIA 3122 AUSTRALIA DB/J:A U6950WCEO.0 Ar S A '1 7>;
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3938805 | 1989-11-23 | ||
| DE3938805A DE3938805A1 (en) | 1989-11-23 | 1989-11-23 | PYRIDINE-2,4- AND 2,5-DICARBONIC ACID DIAMOND, METHOD FOR THE PRODUCTION AND USE THEREOF |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU6689590A AU6689590A (en) | 1991-05-30 |
| AU637848B2 true AU637848B2 (en) | 1993-06-10 |
Family
ID=6394045
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU66895/90A Ceased AU637848B2 (en) | 1989-11-23 | 1990-11-22 | Pyridine-2,4- and 2,5-dicarboxamides, a process for the preparation thereof, and the use thereof |
Country Status (15)
| Country | Link |
|---|---|
| EP (1) | EP0430029A3 (en) |
| JP (1) | JPH03170461A (en) |
| KR (1) | KR910009662A (en) |
| AU (1) | AU637848B2 (en) |
| CA (1) | CA2030633A1 (en) |
| DE (1) | DE3938805A1 (en) |
| FI (1) | FI905745A (en) |
| HU (1) | HU208528B (en) |
| IE (1) | IE904233A1 (en) |
| IL (1) | IL96430A0 (en) |
| NO (1) | NO905063L (en) |
| PL (1) | PL287884A1 (en) |
| PT (1) | PT95956A (en) |
| RU (1) | RU1836349C (en) |
| ZA (1) | ZA909374B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU645668B2 (en) * | 1991-03-18 | 1994-01-20 | Hoechst Aktiengesellschaft | Mixed pyridine-2,4-and-2,5-dicarboxamides, a process for preparing them, the use thereof and pharmaceuticals based on these compounds |
Families Citing this family (1)
| 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 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3781286A (en) * | 1969-11-21 | 1973-12-25 | Montedison Spa | Process for the preparation of amides of nitrogen heterocyclic compounds |
| DE2803592A1 (en) * | 1978-01-27 | 1979-08-02 | Scott Eugene J Van | Psoriasis topical treatment compsns. - contg. non-allergenic pyrazinamide and nicotinamide derivs. |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3432094A1 (en) * | 1984-08-31 | 1986-03-06 | Hoechst Ag, 6230 Frankfurt | ESTER OF PYRIDINE-2,4- AND -2,5-DICARBONIC ACID AS A MEDICINAL PRODUCT FOR INHIBITING PROLIN AND LYSINE HYDROXYLASE |
| 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 |
| DE3703963A1 (en) * | 1987-02-10 | 1988-08-18 | Hoechst Ag | PYRIDINE-2,4- AND 2,, 5-DICARBONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, USE THEREOF, AND MEDICINAL PRODUCTS BASED ON THESE COMPOUNDS |
| 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 |
-
1989
- 1989-11-23 DE DE3938805A patent/DE3938805A1/en not_active Withdrawn
-
1990
- 1990-11-20 EP EP19900122159 patent/EP0430029A3/en not_active Withdrawn
- 1990-11-21 FI FI905745A patent/FI905745A/en not_active Application Discontinuation
- 1990-11-21 RU SU904831767A patent/RU1836349C/en active
- 1990-11-21 KR KR1019900018859A patent/KR910009662A/en not_active Application Discontinuation
- 1990-11-21 IL IL96430A patent/IL96430A0/en unknown
- 1990-11-22 PT PT95956A patent/PT95956A/en not_active Application Discontinuation
- 1990-11-22 AU AU66895/90A patent/AU637848B2/en not_active Ceased
- 1990-11-22 ZA ZA909374A patent/ZA909374B/en unknown
- 1990-11-22 CA CA002030633A patent/CA2030633A1/en not_active Abandoned
- 1990-11-22 NO NO90905063A patent/NO905063L/en unknown
- 1990-11-22 PL PL28788490A patent/PL287884A1/en unknown
- 1990-11-22 JP JP2315715A patent/JPH03170461A/en active Pending
- 1990-11-22 IE IE423390A patent/IE904233A1/en unknown
- 1990-11-23 HU HU907627A patent/HU208528B/en not_active IP Right Cessation
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3781286A (en) * | 1969-11-21 | 1973-12-25 | Montedison Spa | Process for the preparation of amides of nitrogen heterocyclic compounds |
| DE2803592A1 (en) * | 1978-01-27 | 1979-08-02 | Scott Eugene J Van | Psoriasis topical treatment compsns. - contg. non-allergenic pyrazinamide and nicotinamide derivs. |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU645668B2 (en) * | 1991-03-18 | 1994-01-20 | Hoechst Aktiengesellschaft | Mixed pyridine-2,4-and-2,5-dicarboxamides, a process for preparing them, the use thereof and pharmaceuticals based on these compounds |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0430029A3 (en) | 1991-11-13 |
| JPH03170461A (en) | 1991-07-24 |
| EP0430029A2 (en) | 1991-06-05 |
| HUT56348A (en) | 1991-08-28 |
| DE3938805A1 (en) | 1991-05-29 |
| RU1836349C (en) | 1993-08-23 |
| NO905063D0 (en) | 1990-11-22 |
| FI905745A0 (en) | 1990-11-21 |
| IE904233A1 (en) | 1991-06-05 |
| PT95956A (en) | 1991-09-13 |
| PL287884A1 (en) | 1992-02-10 |
| KR910009662A (en) | 1991-06-28 |
| ZA909374B (en) | 1991-08-28 |
| CA2030633A1 (en) | 1991-05-24 |
| HU907627D0 (en) | 1991-06-28 |
| FI905745A (en) | 1991-05-24 |
| AU6689590A (en) | 1991-05-30 |
| IL96430A0 (en) | 1991-08-16 |
| HU208528B (en) | 1993-11-29 |
| NO905063L (en) | 1991-05-24 |
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