IE910126A1 - Di(nitroxyalkyl)amides of pyridine-2,4- and¹-2,5-dicarboxylic acids, a process for the preparation¹thereof, and the use thereof - Google Patents
Di(nitroxyalkyl)amides of pyridine-2,4- and¹-2,5-dicarboxylic acids, a process for the preparation¹thereof, and the use thereofInfo
- Publication number
- IE910126A1 IE910126A1 IE012691A IE12691A IE910126A1 IE 910126 A1 IE910126 A1 IE 910126A1 IE 012691 A IE012691 A IE 012691A IE 12691 A IE12691 A IE 12691A IE 910126 A1 IE910126 A1 IE 910126A1
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- IE
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- Prior art keywords
- formula
- compound
- collagen
- pyridine
- compounds
- Prior art date
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Classifications
-
- 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
- C07D213/26—Radicals substituted by halogen atoms or nitro radicals
-
- 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
-
- 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
Abstract
The invention relates to pyridine-2,4- and -2,5-dicarboxydi(nitroxyalkyl)amides of the formula I in which R has the meanings indicated. The compounds according to the invention inhibit the enzymes proline hydroxylase and lysine hydroxylase and can therefore be employed as fibrosuppressants and immunosuppressants.
Description
Di (nitroxyalkyl) amides of pyridine-2,4- and -2,5dicarboxylic acids, a process for the preparation there5 of, and the use thereof
Compounds which inhibit the enzymes proline hydroxylase and lysine hydroxylase bring about a very selective inhibition of collagen biosynthesis by influencing the collagen-specific hydroxylation reactions. In the course thereof, protein-bound proline or lysine is hydroxylated by the enzymes proline hydroxylase or lysine hydroxylase. If this reaction is suppressed by inhibitors, the result is an insufficiently hydroxylated collagen molecule which is unable to function and can be released by the cells 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 (W. Muller et al., FEBS Lett. 90 (1978), 218; Immunobiology 155 (1978), 47). This leads to the classical pathway of complement activation becoming inoperative. Thus, inhibitors of proline hydroxylase also act as immunosuppressants, for example in immune complex diseases.
It is known that the enzyme proline hydroxylase is efficiently inhibited by pyridine-2,4- and -2,5-dicarboxylic acids (K. Ma jama a et al., Eur. J. Biochem. 138 (1984) 239-245). These compounds are, however, effective inhibitors in cell culture only in very high concentrations (Tschank, G. et al., Biochem. J. 238 (1987) 62535 633).
IE 91126 —--------------- - 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 too rapidly cleaved to the acids and do not reach their site of action in the cell in sufficiently high concentration and thus are poorly suited for possible administration as pharmaceuti10 cals.
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 -2,5-dicarboxylic acids, which are effective inhibitors of collagen biosynthesis in animal models.
Thus, DE-A 37 03 959 describes, inter alia, the synthesis of Ν, N * -bis (2-methoxyethyl) pyridine-2,4-dicarboxamide and Μ,N'-bis (3-isopropoxypropyl)pyridine-2,4-dicarboxamide.
German Patent Applications P 38 26 471.4 and P 38 28 20 140.6 propose an improved process for the preparation of
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 25 al., J. pharm. Soc. Japan 77 (1957) 219 and Haring et al., Helv. 37 (1954) 147, 153) and pyridine-2,4- and
-2,5-dicarbohydrazides (Itai et al., BI. 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.
JP 53/28175 (78/28175) describes N,N'-bis(2-nitroxyethyl)pyridine-2,4- and -2,5-dicarboxamides as substances with a vasodilator action.
IE 91126
- 3 It has now been found, surprisingly, that di(nitroxyalkyl)amides of pyridine-2,4- and -2,5-dicarboxylic acids, of the formula I
O9NO-R-HNOC—,x<
tx (I)
C0NH-R-0N02 in which
R is Cx-Ct-alkanediyl, and the physiologically tolerated salts, effectively inhibit lysine hydroxylase and proline hydroxylase in animal models.
Accordingly, the invention relates to a) the use of 10 compounds of the formula I o2no-r-hnoc—
TX (I) conh-r-ono2 in which
R is Cx-C4-alkanediyl, and the physiologically tolerated salts, for the preparation of a pharmaceutical which inhibits proline hy15 droxylase and lysine hydroxylase.
The invention additionally relates to b) the compounds of the formula I in which
R is methylene, propylene or butylene, and the physiologically tolerated salts, for use as pharmaceuticals.
IE 91126
--------- - 4 The invention additionally relates to c) the compounds of the formula I in which
R is methylene, propylene or butylene, and the physiologically tolerated salts thereof.
The invention particularly relates to the compounds of the formula I defined in a), b) and c) for use as fibrosuppressants and immunosuppressants and for the inhibition of proline hydroxylase and lysine hydroxylase and for influencing the metabolism of collagen and collagenlike substances and the biosynthesis of Clq.
All the said alkyl radicals with more than 2 carbon atoms can be both straight-chain and branched.
The invention additionally relates to a process for the 15 preparation of compounds of the formula I, which comprises reacting a compound of the formula II
O «
ι with a compound of the formula III
H2N-R-ONO2 CIII) where R has the meaning specified for formula I, and Y is halogen, hydroxyl or Cx-CA-alkoxy, or forms together with the carbonyl group an active ester or a mixed anhydride, or comprises nitrating a compound of the formula IV
IE 91126 ho-r-hnoc— (IV)
CONH-R-OH in which
R is as defined above, and subsequently converting the reaction products where appropriate into their physiologically tolerated salts.
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 most straightforwardly by the two components, the pyridine derivative of the formula (II) and the amine of the formula (III), being mixed in equimolar amounts or with an up to about 5-fold excess of III and reacted at temperatures between -30 and 150°C, preferably at 20 to 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 solvents such as dimethylformamide, acetone, alcohols such as methanol or ethanol or dimethyl sulfoxide. It is also possible in this case to use an excess of amine of the formula (III), which can be up to about 5-fold amounts. The temperatures for this reaction are between room temperature and the boiling point of the solvent, with temperatures in the range from room temperature to 130C being particularly preferred.
The reaction can likewise be carried out via a mixed
IE91126 -βanhydride such as ethyl chloroformate or via an activated ester such as paranitrophenyl ester (Y= C1CH2-COO or NO2-C6H4-O). 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 such as sodium or potassium carbonate or sodium or potassium bicarbonate, or tertiary amines such as tri10 ethylamine, tributyl amine, ethyldiisopropylamine or heterocyclic amines such as M-alkylmorpholine, pyridine, quinoline or dialkylanilines.
One variant for the preparation of the compounds of the formula I comprises nitration of the corresponding hydroxyalkyldiamides of pyridine-2,4- or -2,5-dicarboxylie acid (IV). This entails adding concentrated nitric acid to the corresponding hydroxyalkyldiamides at reaction temperatures from -20*C to +10“C, preferably at -10’C to -5 °C. The reaction time in this case is
-240 min, preferably 20-90 min. The reaction product is subsequently neutralized where appropriate.
Where appropriate the products can be worked up, for example, by extraction or by chromatography, for example on silica gel. The isolated product can be recrystallized and, where appropriate, reacted with a suitable acid to give a physiologically tolerated salt. Examples of suitable acids are:
mineral acids such as hydrochloric and hydrobromic acid, and sulfuric, phosphoric, nitric or perchloric acid or organic acids such as formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, maleic, fumaric, phenylacetic, benzoic, methanesulfonic, toluenesulfonic, oxalic, 4-aminobenzoic, naphthalene-1,5-disulfonic or ascorbic acid.
IE 91126
---- - 7 Those starting compounds of the formula (III) which cannot be bought can be synthesized by processes known from the literature.
The starting compounds of the formula (II) are obtained, 5 for example, by converting pyridine-2,4- or -2,5-dicarboxylic acid into the corresponding pyridine-2,4- or -2,5dicarbonyl 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 pyridine15 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 approp20 riate method is likewise described in the literature.
The starting compounds of the formula (IV) are obtained, for example, by reacting corresponding N,N'-bis(alkoxyalkyl) pyridine-2, 4- or -2,5-dicarboxamides, preferably the bis(methoxyalkyl)diamide by processes known from the literature, for example with boron tribromide. The preparation of the bis(alkoxyalkyl)diamides is known and described, for example, in DE-A 3,703,959. This entails reacting a reactive pyridinedicarboxylic acid derivative, for example the pyridinedicarbonyl chloride, with an alkoxyalkylamine.
The compounds of the formula I according to the invention have valuable pharmacological properties and display, in particular, activity as inhibitors of proline hydroxylase and lysine hydroxylase, as fibrosuppressant and immuno35 suppressant.
IE 91126
Because of these pharmacological properties, the compounds according to the invention are suitable for the treatment of disturbances of the metabolism of collagen and collagen-like substances and for the treatment of disturbances of the biosynthesis of Clg.
Hence the invention furthermore relates to the use of the compounds of the formula I according to the invention and of the physiologically tolerated salts thereof for the treatment of the abovementioned metabolic disorders.
The compounds can be used as pharmaceuticals either alone or mixed with physiologically tolerated auxiliaries or excipients. They can be administered for this purpose orally in doses of 0.01 - 25.0 mg/kg/day, preferably 0.01 - 5.0 mg/kg/day or parenterally In doses of 0.001 - 5 mg/ kg/day, preferably 0.001 - 2.5 mg/kg/day, in particular 0.005 -, 1.0 mg/kg/day. The dose can also be increased in severe cases. However, in many cases, lower doses are also sufficient. These data relate to adults weighing about 75 kg.
The invention additionally embraces the use of the compounds according to the invention for the preparation of pharmaceuticals which are employed for the treatment and prophylaxis of the abovementioned metabolic disorders .
The invention furthermore relates to pharmaceuticals which contain one or more compounds of the formula I according to the invention and/or the physiologically tolerated salts thereof.
The pharmaceuticals are prepared by processes which 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
IE 91126
- 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%, advantageously between 10 and 75%.
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 suitable 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, agueous alcoholic or oily suspensions or agueous or oily solutions.
Examples of inert excipients which can be used are gum 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 sun25 flower oil or fish liver oil.
For subcutaneous or intravenous administration, the active compounds are converted into solution, suspension or emulsion, if desired with the substances suitable for this purpose, such as solubilizers, emulsifiers or other 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.
IE 91126
The invention is explained in detail hereinafter by means of examples.
Precursor 1:
bis-N, N' - (Methoxyethyl) amide of pyridine-2,4-dicarboxylic 5 acid conh-ch2-ch2-och3 cl
CONH-CH2-CH2-OCH3 g of pyridine-2,4-dicarboxylic acid are introduced into 50 ml of toluene and 1 ml of DMF, and 2.7 ml of thionyl chloride are added dropwise to the solution. The mixture is heated until no further evolution of gas is evident (about 2.5 h). The mixture is cooled, 5 ml of toluene are distilled out, and 4.6 ml of 2-methoxyethylamine and 5 ml of triethylamine are added dropwise to the solution. The solution is stirred at room temperature for 4 h and then evaporated, the residue is taken up in water and ex15 tracted 4 x with methylene chloride. The combined organic phases are dried over magnesium sulfate and evaporated. The crude product is chromatographed on silica gel (solvent ethyl acetate).
Melting point: 42 - 44*C hl-NMR (CDC13): 6 - 1.2 (3H, tr); 3.3-3.8 (12H, qu. and
m); 7.9 (IH, m); 8.4-8.5 (IH, m); 8.7-8.8 (IH, m);
IE 91126
----------- - ii Precursor 2:
bis-N,N'-(2-Hydroxyethyl) amide of pyridine-2,4dicarboxylic acid
CONH-CH2-CH2-OH
Λ
--C0NH-CH2-CH2-0H
0.5 g of bis-(N,N'-(2-methoxyethyl) amide of pyridine-2,45 dicarboxylic acid (precursor 1) is dissolved in 10 ml of dichloromethane and, at -78°C, boron tribromide (11 ml, molar solution in dichloromethane) is added dropwise. After addition is complete, allow to reach room temperature and then stir for 3 hours. Pour into 100 ml of saturated bicarbonate solution and extract 3 x with ethyl acetate. The combined organic solvents are dried with magnesium sulfate and evaporated. The crude product is chromatographed on silica gel.
Tl-NMR (CDC13): 5 = 1.5-2.2 (4H, m); 3.4 (4H, m); 3.6 (4H, m); 7.9-8.0 (1H, m); 8.4-8.5 (1H, m); 8.7-8.8 (1H, m)
Example 1
N,N' -Di (2-nitroxyethyl) amide of pyridine-2,4-dicarboxylic acid
CONH- CH,-CH5-ONO, (X conh-ch2-ch2-ono2 g of di(2-hydroxyethyl) amide of pyridine-2,4-dicarboxylic acid (precursor 2) is added at -10 °C to -5*C
IE 91126 ________ - 12 to5ml of concentrated nitric acid. The mixture is allowed to warm to 2°C and then stirred for 40 minutes. It is poured into ice/water and neutralized with sodium carbonate. The solution is extracted three times with dichloromethane, and the organic phases are dried over magnesium sulfate and evaporated. The residue crystallizes from ether.
Yield: 750 mg
Melting point: 85 - 88°C
JE 91126
HOE 90/F 010
Claims (17)
1. The use of di (nitroxyalkyl) amides of pyridine-2,4- and -2,5-dicarboxylic acids, of the formula 1 0,N0- R- HNOC—zy. (X (I) C0NH-R-0N0 2 in which R is linear or branched Cj-C^-alkanediyl, and the physiologically tolerated salts, for the preparation of pharmaceuticals which inhibit proline hydroxylase and lysine hydroxylase.
2. The use as claimed in claim 1, wherein R is ethylene or propylene.
3. A compound of the formula I NO-R-HNOC (I) conh-r-ono 2 in which R is methylene, propylene or butylene, and the physiologically tolerated salts.
4. A compound of the formula I as claimed in claim 3, wherein R is methylene or n-propylene.
5. A compound as claimed in claim 3 or 4, for use as a pharmaceutical.
6. A process for the preparation of compounds of the formula I as claimed in claim 3, which comprises reacting a compound of the formula II IE 91126 (II) with a compound of the formula III where R has the meanings specified in claim 3, and Y is halogen, hydroxyl or Cj-C^-alkoxy, or forms together with the carbonyl group an active ester or a mixed anhydride, or comprises nitrating a compound of the formula IV HO-R-HNOC IV CONH- R- OH 7.
7. 8.
8. 9.
9. in which R is as defined in claim 3, and subsequently converting the reaction products where appropriate into their physiologically tolerated salts. A compound as claimed in claim 3 or 4 for inhibiting proline hydroxylase and lysine hydroxylase. A compound as claimed in one or more of claims 1 to 4 for use as fibrosuppressants and immunosuppressants. A pharmaceutical containing a compound of the formula I as claimed in claim 3 or 4 with tolerated pharmaceutical vehicles. IE 91126 15
10. The use of compounds of the formula I or the salts thereof as claimed in one or more of claims 1 to 4 for influencing the metabolism of collagen and collagen-like substances and the biosynthesis of Clg.
11. The use of compounds of the formula I or the salts thereof as claimed in one or more of claims 1 to 4 for the treatment of disturbances of the metabolism of collagen and collagen-like substances and of the biosynthesis of Clg.
12. A process for the preparation of pharmaceuticals for influencing the metabolism of collagen and collagen-like substances and the biosynthesis of Clg, which comprises adding a compound of the formula I or the salts thereof as claimed in one or more of claims 1 to 4 to the pharmaceutical. IE 91126
13. Use as claimed in claim 1, substantially as hereinbefore described.
14. A compound as claimed in claim 3, substantially as hereinbefore described and exemplified.
15. A process for the preparation of a compound as claimed in claim 3, substantially as hereinbefore described and exemplified.
16. A compound as claimed in claim 3, whenever prepared by a process claimed in claim 6 or 15.
17. A pharmaceutical as claimed in claim 9, substantially as hereinbefore described.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4001002A DE4001002A1 (en) | 1990-01-16 | 1990-01-16 | N'N'-di:(nitroxyalkyl) pyridine-2,4- and -2,5-di:carboxamide derivs. - used as proline and lysine hydroxylase inhibitors for use a immuno:suppressive, fibro-suppressive and collagen biosynthesis inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| IE910126A1 true IE910126A1 (en) | 1991-07-17 |
Family
ID=6398117
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE012691A IE910126A1 (en) | 1990-01-16 | 1991-01-15 | Di(nitroxyalkyl)amides of pyridine-2,4- and¹-2,5-dicarboxylic acids, a process for the preparation¹thereof, and the use thereof |
Country Status (19)
| Country | Link |
|---|---|
| EP (1) | EP0438795A1 (en) |
| JP (1) | JPH04330060A (en) |
| KR (1) | KR910014352A (en) |
| CN (1) | CN1053606A (en) |
| AU (1) | AU631285B2 (en) |
| BR (1) | BR9100159A (en) |
| CA (1) | CA2034206A1 (en) |
| CS (1) | CS7591A2 (en) |
| DE (1) | DE4001002A1 (en) |
| FI (1) | FI910177A (en) |
| HU (1) | HUT59102A (en) |
| IE (1) | IE910126A1 (en) |
| IL (1) | IL96941A0 (en) |
| MA (1) | MA22041A1 (en) |
| MX (1) | MX24143A (en) |
| NO (1) | NO910163L (en) |
| NZ (1) | NZ236766A (en) |
| PT (1) | PT96493A (en) |
| ZA (1) | ZA91291B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| YU9492A (en) * | 1991-02-05 | 1995-03-27 | Hoechst Ag. | 2,4- and 2,5-BIS-TETRAZOLYL pyridines and the process for their preparation |
| EP0533130A1 (en) * | 1991-09-19 | 1993-03-24 | Hoechst Aktiengesellschaft | 2-Hydroxymethylpyridines, the corresponding pyridine-N-oxides and derivatives thereof, process for their preparation and their use |
| EP0541042A1 (en) * | 1991-11-05 | 1993-05-12 | Hoechst Aktiengesellschaft | 2,4- and 2,5-pyridine-dicarboxylic acid derivatives, process for their preparation and their use |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK145608C (en) * | 1976-04-02 | 1983-07-11 | Chugai Pharmaceutical Co Ltd | ANALOGY PROCEDURE FOR PREPARING THE NICKETIC ACID ESTER OF N- (2-HYDROXYETHYL) NICOTINAMIDE |
| 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 |
-
1990
- 1990-01-15 ZA ZA91291A patent/ZA91291B/en unknown
- 1990-01-16 DE DE4001002A patent/DE4001002A1/en not_active Withdrawn
- 1990-12-28 EP EP90125638A patent/EP0438795A1/en not_active Withdrawn
-
1991
- 1991-01-14 KR KR1019910000412A patent/KR910014352A/en not_active Application Discontinuation
- 1991-01-14 FI FI910177A patent/FI910177A/en unknown
- 1991-01-14 JP JP3069547A patent/JPH04330060A/en active Pending
- 1991-01-14 IL IL96941A patent/IL96941A0/en unknown
- 1991-01-14 NZ NZ236766A patent/NZ236766A/en unknown
- 1991-01-15 BR BR919100159A patent/BR9100159A/en unknown
- 1991-01-15 CN CN91100222A patent/CN1053606A/en active Pending
- 1991-01-15 MX MX2414391A patent/MX24143A/en unknown
- 1991-01-15 CS CS9175A patent/CS7591A2/en unknown
- 1991-01-15 CA CA002034206A patent/CA2034206A1/en not_active Abandoned
- 1991-01-15 AU AU69366/91A patent/AU631285B2/en not_active Ceased
- 1991-01-15 NO NO91910163A patent/NO910163L/en unknown
- 1991-01-15 HU HU91109A patent/HUT59102A/en unknown
- 1991-01-15 IE IE012691A patent/IE910126A1/en unknown
- 1991-01-16 PT PT96493A patent/PT96493A/en not_active Application Discontinuation
- 1991-01-16 MA MA22314A patent/MA22041A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CS7591A2 (en) | 1991-09-15 |
| AU631285B2 (en) | 1992-11-19 |
| HUT59102A (en) | 1992-04-28 |
| NZ236766A (en) | 1993-08-26 |
| MA22041A1 (en) | 1991-10-01 |
| KR910014352A (en) | 1991-08-31 |
| IL96941A0 (en) | 1992-03-29 |
| EP0438795A1 (en) | 1991-07-31 |
| ZA91291B (en) | 1991-09-25 |
| JPH04330060A (en) | 1992-11-18 |
| CA2034206A1 (en) | 1991-07-17 |
| NO910163L (en) | 1991-07-17 |
| HU910109D0 (en) | 1991-08-28 |
| DE4001002A1 (en) | 1991-07-18 |
| BR9100159A (en) | 1991-10-22 |
| MX24143A (en) | 1993-05-01 |
| AU6936691A (en) | 1991-07-18 |
| NO910163D0 (en) | 1991-01-15 |
| PT96493A (en) | 1991-10-15 |
| FI910177A0 (en) | 1991-01-14 |
| FI910177A (en) | 1991-07-17 |
| CN1053606A (en) | 1991-08-07 |
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