AU624978B2 - N,n'-bis(alkoxyalkyl)-pyridine-2,4-dicarboxylic acid diamides, preparation and their use - Google Patents
N,n'-bis(alkoxyalkyl)-pyridine-2,4-dicarboxylic acid diamides, preparation and their use Download PDFInfo
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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
- C07D213/56—Amides
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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
- C07D213/82—Amides; Imides in position 3
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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
Abstract
N,N'-bis(alkoxyalkyl)pyridine-2,4-dicarboxylic acid diamides of the formula I <IMAGE> where R<1> is linear or branched C1-C4-alkanediyl, R<2> is unbranched C1-C4-alkyl or hydrogen and n is 1 or 2 and R<1'>, R<2'> and n' have the same meanings as R<1>, R<2> and n, where R<1> and R<1'>, R<2> and R<2'>, and n and n' are identical or different, and their physiologically acceptable salts with the exception of N,N'-bis(2-methoxyethyl)pyridine-2,4-dicarboxylic acid diamide and N,N'-bis(2-hydroxyethyl)pyridine-2,4-dicarboxylic acid diamide. The compounds of the formula I inhibit prolin hydroxylase and lysin hydroxylase and are suitable as fibrosuppressants and immunosuppressants.
Description
62 x1 I~ Form COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952-69 COMPLETE SPECIFICATION
(ORIGINAL)
Class Int. Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: S Priority Related Art ca Name of Applicant Address of Applicant Actual Inventor: Address for Service HOECHST AKTIENGESELLSCHAFT 50 Bruningstrasse, D-6230 Frankfurt/Main of Germany 80, Federal Repubic EKKEHARD EAADER, MARTIN BICKEL and VOLKMAR GUNZLER-PUKALL WATERMARK PATENT TRADEMARK ATTORNEYS.
LOCKED BAG NO. 5, HAWTHORN, VICTORIA 3122, AUSTRALIA Complete Specification for the invention entitled: N,N'-BIS(ALKOXYALKYL)-PYRIDINE-2,4-DICARBOXYLIC ACID DIAMIDES, PREPARATION AND THEIR USE The following statement is a full description of this invention, including the best method of performing it known to us HOECHST AKTIENGESELLSCHAFT Dr.SW/fe HOE 89/F 241 Description N,N'-Bis(alkoxyalkyl)-pyridine-2,4-dicarboxylic acid diamides, preparation and their use Compounds which inhibit proline hydroxylase and lysine hydroxylase cause a very selective inhibition of collagen biosynthesis by influencing the collagen-specific hydrox-ylation reactions. In the course of these, proteinbound proline or lysine is hydroxylated by the enzymes proline hydroxylase or lysine hydroxylase. If this reaction is suppressed by inhibitors, a non-functional, hypohydroxylated collagen molecule is formed, which can be released by the cells into the extracellular space in °o only a small amount. The hypohydroxylated collagen also cannot be incorporated into the collagen matrix and is very easily degraded by proteolysis. As a consequence of o 0 0 u these effects, the amount of extracellularly deposited collagen overall is reduced.
It is known that the inhibition of proline hydroxylase by known inhibitors, such as a,a'-dipyridyl, leads to an inhibition of the Clq biosynthesis of macrophages .oo Muller et al., FEBS Lett. 90 (1978), 218; and Immunbiology 155 (1978) 47). This results in a failure of the classical route of complement activation. Inhibitors of 00 o 25 proline hydroxylase therefore also act as immunosuppressants, for example in cases of immune complex diseases.
It is known that proline hydroxylase is inhibited effeco oj tively by pyridine-2,4- and -2,5-dicarboxylic acid Majamaa et al., Eur. J. Biochem. 138 (1984) 23' -245).
However, in the cell culture these compounds are effective as inhibitors only in very high concentrations (Tschank, G. et al., Biochem. J. 238, 625-633, 1987).
German Patent A-3,432,094 describes pyridine-2,4- and acid diesters having 1-6 carbon atoms 2 in the ester alkyl part as pharmaceuticals for inhibition of proline hydroxylase and lysine hydroxylase.
However, these lower alkylated diesters have the disadvantage that they are split too rapidly in the organism to give the acids and do not arrive at their site of action in the cell in a sufficiently high concentration, and are therefore of little suitability for possible administration as pharmaceuticals.
German Patent A-3,703,959, German Patent A-3,703,962 and German Patent A-3,703,963 describe, in general form, mixed ester/amides, higher alkylated diesters and diamides of pyridine-2,4- and -2,5-dicarboxylic acid which effectively inhibit collagen biosynthesis in the animal model.
1i5 German Patent A-3,703,959 thus describes, inter alia, the synthesis of N,N'-bis(2-methoxyethyl)-pyridine-2,4dicarboxylic acid diamide (III)
CONH-CH
2
CH
2
-O-CH
3 CONH-CH2-CH2-O-CH 3 and N,N'-bis(3-isopropoxypropyl)-pyridine-2,4-dicarboxylic acid diamide (IV)
SCH
3
CONH-CH
2
-CH
2
-CH
2 -0-CH
CH
3 CH.
(IV)
S CONH-CH 2
-CH
2
-CH
2
-O-CH
CH3 An improved process for the preparation of N,N'-bis(2methoxyethyl)-pyridine-2,4-dicarboxylic acid diamide (III) is proposed in German Patent Applications P 38 26 471.4 and P 38 28 140.6.
r- 3- The enteral absorbability of many of the compounds described in German Patent A-3,703,959 is still unsatisfactory, however, so that there is a need to provide compounds which effectively inhibit pro!ine hydroxylase and lysine hydroxylase after oral administration even in low dosages.
It has been found that compounds of the formula I CONH-(R
(OR
2 )n 2
(I)
I CONH- (R 1 )-(OR2
N
wherein
R
1 denotes linear or branched Ci-C 4 -alkanediyl, R 2 denotes unbranched C 1
-C
4 -alkyl or hydrogen, n denotes 1 or 2 and R' R 2 and n' have the same meanings as R 1
R
2 and n, R 1 and R 1 1 and R 2 and R 2 and n and n' being identical or different, and physiologically tolerated salts thereof, excluding N,N'-bis(2-methoxyethyl)-pyridine-2,4-dicarboxylic acid diamide and N,N'-bis(2-hydroxyethyl)-pyridine-2,4-dicarboxylic acid diamide, achieve the abovementioned object.
In comparison with the compounds N,N'-bis(2-methoxyethyl)-pyridine-2,4-dicarboxylic acid diamide and N,N'bis(3-isopropoxypropyl)-pyridine-2,4-dicarboxylic acid diamide described in German Patent A-3,703,959, the compounds of the formula I have both a better pharmacological activity and a better enteral absorbability.
The invention furthermore relates to a process for the preparation of N,N'-bis-(alkoxyalkyl)-pyridine-2,4dicarboxylic acid diamides of the formula I CONH-(R1).-(OR2)n CONH-(R (OR2 0 CONH-(R')-(OR 2
N
I_
4 wherein
R
1 denotes linear or branched Ci-C 4 -alkanediyl,
R
2 denotes unbranched Ci-C 4 -alkyl or hydrogen, n denotes 1 or 2 and
R
1
R
2 and n' have the same meanings as R 1
R
2 and n, R 1 and R 1 and R 2 and R 2 and n and n' being identical or different, excluding N,N'bis(2-methoxyethyl)-pyridine-2,4-dicarboxylic acid diamide and N,N'-bis(2hydroxyethyl)-pyridine-2,4-dicarboxylic acid diamide, which comprises reacting a pyridine-2,4-dicarboxylic acid halide with an alkoxyalkylamine or hydroxyalkylamine.
The invention likewise relates to a process for the preparation of N,N'-bis-(alkoxyalkyl)-pyridine-2,4dicarboxylic acid diamides of the formula I
CONH-(R
1
)-(OR
2 )n
(I)
0°CONH-(R 1 2 ')n wherein o R 1 denotes linear or branched Cl-C 4 -alkanediyl, 1,°20 R 2 denotes unbranched Ci-C 4 -alkyl or hydrogen, n denotes 1 or 2 and
SR
1
R
2 and n' have the same meanings as R 1
R
2 and n, R 1 and R 1 and R 2 and R 2 and n and n' being identical or different, which comprises first
A)
1. adding at least two equivalents of a halogenating agent to pyridine-2,4-dicarboxylic acid and 2. dissolving at least 2 equivalents of a hydroxyalkylamine or alkoxyalkylamine of the formula II or II'
HN-(R
1 (OR2)
(II)
H2N- (OR 1)n'
(II')
-5 5 in which
R
1 and R 1 denote linear or branched C-C4-alkanediyl,
R
2 and R 2 denote unbranched C 1
-C
4 -alkyl or hydrogen, n and n' denote 1 or 2 and
R
1 and R 1
R
2 and R 2 and n and n' are identical or different, but II and II' are different, in a solvent and then reacting the solution prepared according to 1.
with the solution prepared according to or B) converting the resulting N,N'-bis(alkoxyalkyl)-pyridine-2,4-dicarboxylic acid diamide into the bis(hydroxyalkyl) compound, or C) reacting the pyridine-2,4-dicarboxylic acid halide prepared according to A) 1. with a substituted or unsub- 15 stituted benzyl alcohol to give the benzyl pyridine-2,4dicarboxylate, hydrolyzing the benzyl ester selectively in the 2-position of the pyridine, converting the free carboxylic acid in the 2-position into the acid halide again in accordance with process variant A) 1. and adding a solution prepared according to A) 2. using a compound of the formula II' to the compound thus obtained, a pyridine-4-(carboxylic acid benzyl ester)-2-carboxylic acid amide being formed, and then splitting off the benzyl protective group in the 4-position by hydrogenoly- 25 sis, converting the free carboxylic acid into the acid S chloride again in accordance with process variant A) 1., and subsequently adding a solution prepared according to A) 2. using a compound of the formula II, an unsymmetrically substituted compound of the formula I being formed, 3 .30 and if a ropriate then converting the resulting compound of the >rmula I into its physiologically tolerated salt.
In the process for the preparation of the compounds of the formula I, the pyridine-2,4-dicarboxylic acid commercially available as a starting substance is suspended in a solvent, such as toluene, and a halogenating agent, preferably a chlorinating agent, such as, for example, SOC1 2 is added at room temperature. 2-3 equivalents, preferably 2.5 equivalents, of a halogenating agent, 6 based on the molar amount of pyridine-2,4-dicarboxylic acid employed, are used. The resulting reaction mixture is heated at 90-110C, preferably at 100 0 C, until no further evolution of gas is to be observed and a clear solution has formed. 10% of the solution is then evaporated off preferably under a high vacuum (down to about 3 mm Hg) and the resulting carboxylic acid halide is reacted further.
2-4 times the molar amount of commercially available alkoxyalkylamine or hydroxyalkylamine, based on the molar amount of pyridine-2,4-dicarboxylic acid employed, is now dissolved in a solvent, such as toluene, and 2-4 times the molar amount of a base, such as triethylamine, is preferably added. The carboxylic acid halide is reacted with the alkoxyalkylamine or the hydroxyalkylamine. This is preferably done by adding the solution of the alkylamine mentioned dropwise to the dissolved pyridine-2,4dicarboxylic acid halide. However, it is also possible to 0 add the solution of the carboxylic acid halide dropwise to the solution of the alkoxyalkylamine or hydroxyalkylamine. The addition is carried out at a temperature of to preferably at 0°C. The reaction mixture can o" then be after-reacted, for example, by warming it to room temperature and subsequently stirring it for a further 2- 5 hours, preferably 3 hours. The resulting product is then acidified in order to remove excess hydroxy- or alkoxyalkylamine from the desired product. The acidification can be carried out, for example, with 0.2 molar citric acid. The organic phase is then separated off and washed with water. The organic phase is subsequently dried preferably over magnesium sulfate and finally freed from the solvent. On removal of the solvent, the product is obtained as a white solid or as an oil.
To prepare the N,N'-bis(hydroxyalkyl)-pyridine-2,4dicarboxylic acid diamides, a procedure is preferably followed in which a corresponding bis(alkoxyalkyl)diamide, preferably bis(methoxyalkyl)diamide, is converted -7 intr the corresponding bis(hydroxyalkyl)diamide by processes which are known from the literature, for example using boron tribromide.
Unsymmetrically substituted compounds of the formula I can be synthesized, for example, as follows: reaction of a pyridine-2,4-dicarboxylic acid halide, preferably the chloride, with substituted or unsubstituted benzyl alcohol to give benzyl pyridine-2,4-dicarboxylate, subsequent selective hydrolysis of the ester in the 2position (for example in the presence of a copper catalyst, Acta Helv. 44, 1963, page 637), conversion of the free acid in the 2-position into the acid halide, reaction with a compound of the formula to give the pyridine-4-(carboxylic acid benzyl ester)-2-carboxylic acid amide, splitting off of the remaining benzyl protective group by hydrogenolysis (for example with Hz/Pd, see Houben-Weyl Volume IV/lc (1980), pages 381-82) and subsequent conversion of the free acid in the 4-position of the pyridine ring into the acid halide.
The acid halide can now be converted into the mixed diamide with an amine II (see equation).
If appropriate, the products can be worked up, for example, by extraction or by chromatography, for example over silica gel. The product isolated can be recrystallized and if appropriate reacted with a suitable acid to give a physiologically tolerated salt. Examples of possible suitable acids are: mineral acids, such as hydrochloric and hydrobromic acid as well as 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-l,4-disulfonic or ascorbic acid.
The compounds of the formula I can be used as medicaments in the form of pharmaceutical preparations which contain c 1 li_ 8 them, if appropriate together with tolerated pharmaceutical excipients. The compounds can be used as medicines, for example in the form of pharmaceutical preparations which contain these compounds as a mixture with a pharmaceutical, organic or inorganic excipient suitable for enteral, percutaneous or parenteral administration, such as, for example, water, gum arabic, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, vaseline and the like.
The pharmaeutical preparations can be in solid form, for example as tablets, coated tablets, suppositories or capsules; in semi-solid form, for example as ointments, or in liquid form, for example as solutions, suspensions or emulsions. If appropriate, they are sterilized and/or contain auxiliaries, such as preservatives, stabilizers, wetting agents or emulsifiers; salts for modifying the osmotic pressure or buffers. They can also additionally contain other therapeutically active substances.
It has been found that the compounds of the formula I have exceptionally good enteral absorbabilities. The absorbability was investigated on Wistar rats to which the compounds according to the invention were administered intragastrally. The serum level dropped in the first hours after administration of the substance, and after about 5 hours reached a plateau which still fell only slightly. The good absorbability of the substances can be concluded from the initially very high serum level directly after administration of the substances.
The invention is illustrated in more detail below with the aid of examples.
9 Example 1 Pyridine-2,4-dicarboxylic acid bis-N,N'-(methoxypropyl)amide 3 g of pyridine-2,4-dicarboxylic acid are initially introduced into 50 ml of toluene and 1 ml of dimethylformamide, and 2.7 ml of thionyl chloride are added dropwise to the solution. The mixture is heated until no further evolution of gas is to be observed (about hours). It is cooled, 5 ml of toluene are distilled off and 4.6 ml of 3-methoxypropylamine and 5 ml of triethylamine are added dropwise to the solution. After the solution has been stirred at room temperature for 4 hours, it is evaporated, the residue is taken up in water and the mixture is extracted 4 times with methylene chloride. The combined organic phases are dried over magnesium sulfate and evaporated. The crude product is chromatographed with silica gel (solvent: ethyl acetate).
Yield: 4.3 g; oil 1H-NMR (CDCl 3 6 1,6-2.3 (4H, 3.2-3.8 (14H, m); 7.8-8.0 (1H, 8.3-8.5 (1H, 8.6- 8.8 (1H, m).
Example 2 Pyridine-2,4-dicarboxylic acid bis-N,N'-(ethoxypropyl)amide For instructions see Example 1; amine component: ethoxypropylamine Yield: 4.5 g, melting point: 46-48°C.
1 H-NMR (CDC13): 6 1.3 (6H, tr); 1.7-2.1 (4H, 3.3-3.8 (12H, 7.8-8.0 (1H, 8.4-8.5 (1H, 8.5-8.8 (1H, m).
10 Example 3 Pyridine-2, 4 -dicarboxylic acid bis-N,N'-(2-dimethoxyethyl) amide For instructions see Example 1; amine component: 2diinetb oxyethyl aiine Yield: 1.6 g (from 3 g of pyridine-2,4-dicarboxylic acid), oil 1 H-NMR (CDCl 3 6 =3.4 (12H, 3.7 (4H, in); 4.5 (2H, mn); 7.9-8.0 (1H1, in); 8.4-8.5 (1Hi, m); 8.7-8.8 (1H, in).
Example 4 Pyridine-2 ,4-dicarboxylic acid bis-N,N' -(2-inethoxyisopropyl)anide For instructions see Example 1; amine component: 2methoxyisopropyl amine; Yield.# 3,3 g (from 3 g of pyridine-2,4-dicarboxylic acid), oil H1-NMR (CDCl 3 6 3 (6H, 3.2 (6H, s) 3.5 (4H, d); 4.4 (2H, in); 7.9-8.0 (1H, in); 8.4-8.5 (1H, in); 8.7-8.8 (1N, in).
Example Plyridine-2 ,4-dicarboxylic acid bis-N,N'-(2-ethoxyethyl) ainide For instructions see Example 1L; amine component: ethoxyethylanine, Yield: 7.8 g (from 10 g of pyridine-2,4-dicarboxyIlic acid), melting point: 4 -44 0
C
'H-NI4R (CDCl 3 6 1.2 (3H, tr); 3.3-3.8 (12H, qu. and in); 7.9 (iN, mn); 8.4-8.5 (1H1, mn); 8.7- 8.8 (iN, mn).
11 Example 6 Pyridine,. 2,4-dicarboxylic acid bis-N,N'- (3-hydroxyethyl) amide g of pyridine-2,4-dicarboxylic acid bis-N,N'-(3methoxyethyl)amide are dissolved in 10 ml of methylene chloride, and boron tribromide (11 ml, 1 molar solution in methylene chloride) is added dropwise at -78C. When the addition has ended, the mixture is allowed to come to room temperature and is subsequently stirred for 3 hours.
It is poured onto 100 ml of saturated bicarbonate solution and extracted 3 times with ethyl acetate. The combined organic phases are dried with magnesium sulfate and. evaporated. The crude product is chromatographed on silica gel.
Yield: 0.45 g; oil 1 H-NMR (CDC1 3 6 1.5-2.2 (4H, 3.4 (4H, 3.6 (4H, 7.9-8.0 (1H, 8.4-8.5 (1H, m); 8.7-8.8 (1H, m).
Example 7a Pyridine-2,4-dicarboxylic acid dibenzyl ester of pyridine-2,4-dicarboxylic acid are converted into the acid chloride using 30 ml of thionyl chloride analogously to Example 1 and the acid chloride is reacted with 43.8 g of benzyl alcohol. The product is recrystallized from diisopropyl ether.
Yield: 42.1 g Melting point 63-65°C Example 7b Pyridine-2-(carboxylic acid)-4-carboxylic acid benzyl ester 40 g of pyridine-2,4-dicarboxylic acid dibenzyl ester from Example 7a are added to a suspension of 27.8 g of i 12 copper-II nitrate in 700 ml of methanol. The mixture is boiled under reflux for one hour and, after cooling, the copper complex is filtered off. The complex is suspended in dioxane a'id carbon disulfide is passed in. The copper sulfide which has precipitated is filtered off and the organic phase is concentrated. The product is stirred with petroleum ether.
Yield: 25.3 g Melting point 113-115°C Example 7c Pyridine-2-[(3-methoxypropyl)-carboxylic acid amide]-4carboxylic acid benzyl ester 3.9 g of pyridine-2-(carboxylic acid)-4-carboxylic acid benzyl ester from Example 7b are converted into the acid Schloride using 1.2 ml of thionyl chloride analogously to 1 Example 1 and the acid chloride is reacted with 3-methoxypropylamine to give the amide. For purification, the product is chromatographed over silica gel using a mixture of cyclohexane/ethyl acetate Yleld: 4.3 g Oil Example 7d Pyridine-4-(carboxylic acid)-2-(3-methoxypropyl)-carboxylic acid amide 4.3 g of the compound from Example 7c are dissolved in S100 ml of dioxane and hydrogenated using 500 mg of palladium/charcoal (10% strength) catalyst under normal pressure for 4 hours. When the uptake of hydrogen has ended, the catalyst is filtered off with suction and the solvent is stripped off.
Yield: 3.5 g Melting point 124-126°C
_-L---III~~LI
13 Example 7e Pyridine-4- [carboxylic acid- (2-methoxyethvl) -amide -2carboxylic acid (3-methoxypropyl)-amide 1.8 g of the compound from Example 7d are converted into the acid chloride using 0.6 ml of thionyl chloride in accordance with Example 1 and the acid chloride is then reacted with 2-methoxyethylamine. For purification, the product is chromatographed over silica gel using a mixture of methylene chloride/methanol (20:1).
Yield: 1.0 g Oil 1H-NMR (CDCl 3 6 1.9-2.0 (2H, qui); 3.4 (6H, 3.7 (8H, 6.9 (1H, s, br); 8.0 (1H, dd); 8.4 (1H, s, br); 8.5 (1H, 8.7 (1H, d).
Example 8 Pyridine-2-[carboxylic acid-(2-mochoxyethyl) -amide]-4carboxylic acid (3-methoxypropyl)-amide The compound according to Example 8 is prepared analogously to Examples 7a-e by using 2-methoxyethylamine in the reaction step of Example 7c and 3-methoxypropylamine in the reaction step of Example 7e.
Melting point: 69-72 0
C
1 H-NMR (CDC13): 6 1.9-2.0 (2H, qui); 3.4 (3H, 3.45 (3H, 3.6-3.7 (8H, 7.4 (1H, br); 7.9 (1H, dd); 8.3 (1H, br); 8.4 (1H, 8.7 (1H, d).
Example 9 Enteral absorbability Female Wistar rats of about 150 g body weight are given an intragastral alinistration of 50 mg/kg of the substance under investigation by means of a stomach probe.
c_ i 14 In each case 4 rats are anesthetized after 5; 10; 15; 120; 180 and 240 minutes and exsanguinated via the Vena Cava. The blood is centrifuged immediately and the compound administered is extracted from the serum using ether. After the ether has been evaporated, the residue is taken up in 100 ml of mobile phase. The mobile phase consists of 0.05 M phosphoric acid and acetonitrile 50 pl of this sample are injected into a high performance liquid chromatography column. Detection is performed under UV of 200 nm with a retention time of 2.2 minutes. The results are documented in Table 1.
Table 1: Serum levels of the compounds according to the invention from Examples 1-3 after administration of 50 mg/kg perorally Time Substance from Substance from Substance from minutes) Example 1 Example 2 Example 3 x SD x SD x SD 5 45.3 15.4 51.4 11.2 8.9 3.1 49.8 3.6 39.2 4.0 11.5 0.6 39.9 13.0 29.4 6.7 14.7 1.9 28.1 3,2 15.2 5.6 10.7 1.9 9.4 5.5 1.4 1.0 11.3 120 0.3 0.3 <DL 5.5 0.9 180 <DL <DL 2.9 240 <DL <DL 1.7 0.4 x mean value of 4 measurements SD standard deviation <DL below the detection limit Example Pharmacological activity To demonstrate the effective inhibition of proline hydroxylase and lysine hydroxylase by the compounds 1IJ 15 according to the invention, the hydroxyproline concentrations in the liver and the 7s-(IV)-collagen concentrations in the serum of a) untreated rats (control) b) rats to which carbon tetrachloride had been administered (CC1 4 control) c) rats to which first CCl 4 and then a compound according to the invention had been administered were measured (this test method is described by Rouiller, experimental toxic injury of the liver; in The Liver, C. Rouiller, Volume 2, pages 335-476, New York, Academic Press, 1964).
The action potency of the compounds according to the invention was determined as the percentage inhibition of the liver hydroxyproline synthesis and serum 7s-(IV)collagen synthesis following oral administration in comparison with control animals to which only carbon tetrachloride had been administered (CC1 control). The results are shown in Table 2. The compounds from Examples 2 and 3 of German Patent A-3,703,959 (N,N'-bis(2-methoxyethyl)-pyridine-2,4-dicarboxylic acid diamide and N,N'bis(3-isopropoxypropyl)-pyridine-2,4-dicarboxylic acid diamide) are likewise also shown as comparison substances. Surprisingly, the compounds according to the invention show a better activity, even after oral administration, than the intraperitoneally administered compound from Example 2 of German Patent A-3,703,959.
16 Table 2: Substance Dosage Liver Serum 7s- Adminisfrom hydroxy- (IV) -collagen tration Example proline inhibition] inhibition] 1 2x2 mg 62 28 P.O.
2x10 mg 90 67 P.O.
2 2x2 mg 25 2 P.O.
2x10 mg 60 35 P.O.
2 (from 2x25 mg 55 48 i.p.
DE-A-3, 703,959: 3 (from 2x25 mg 49 11 P.O.
DE-A-3,7 03,959: p.o. peroral i.p. intraperitoneal
I.'U
Claims (16)
1. An N,N'-bis(alkoxyalkyl)-pyridine-2,4-dicarboxylic acid diamide of the formula I CONH- (R 1 )-(OR 2 n I 'N CONH-(R 1 )-(OR 2 n'' wherein R 1 denotes linear or branched Ci-C 4 -alkanediyl, R 2 denotes unbranched Ci-C 4 -alkyl or hydrogen, n denotes 1 or 2 and R 1 R 2 and n' have the same meanings as R 1 R 2 and n, R 1 and R 1 and R 2 and R 2 and n and n' being identical or different, or a physiologically tolerated salt thereof, exclud- ing N,N'-bis(2-methoxyethyl)-pyridine-2,4-dicar- boxylic acid diamide and N,N'-bis(2-hydroxyethyl)- pyridine-2,4-dicarboxylic acid diamide.
2. A compound of the formula I as claimed in claim 1, in which in each case R 1 and R 1 R 2 and R 2 and n and n' have the same meaning.
3. A compound of the formula I as claimed in claim 1, in which the substituents 2 )n and -(R 1 (OR are different.
4. A compound of the formula I as claimed in any one of claims 1, 2 and 3, in which R 1 denotes linear or branched C 1 -C 3 -alkyl and R 2 denotes unbranched C 1 -C 2 -alkyl or hydrogen. The compound of the formula CONH- CH 2 -CH 2 -CH 2 -O-CH 3 N \CONH-CH 2 -CH 2 CH 2 -O-CH 3 18 or one of its physiologically tolerated salts.
6. The compound of the formula CONH- CH 2 -CH 2 -CH 2 -O-C 2 H l CONH-CH 2 CH 2 CH 2 C 2 H or one of its physiologically tolerated salts.
7. The compound of the formula Q-CH 3 -0-CH3 CONH-CH CH- NO- CH O-CH3 1 LCONH-CH2 -CH< O-CH3 N 2 "-0-CH3 or one of its physiologically tolerated salts.
8. The compound of the formula CH 3 CONH-CH-CH 2 -OCH 3 N CONH-CH-CH 2 -OCH 3 CH 3 I or one of its physiologically tolerated salts.
9. The compound of the formula CONH- CH 2 -CH 2 0-C 2 H CONH-CH 2 -CH 2 -0-C 2 H or one of its physiologically tolerated salts. 19 The compound of the formula CONH- CH 2 CH 2 -CH 2 OH N nW CNH- CH 2 -CH 2 -CH 2 -OH or one of its physiologically tolerated salts.
11. The compound of the £,rmula CONH- CH 2 CH 2 OCH 3 -CONH-(CH 2 3 -OCH 3 N3 or one of its physiologically tolerated salts.
12. The compound of the formula CONE (CE 2 3 0CH 3 N CONH(CH 2 2 0CH 3 or one of its physiologically tolerated salts.
13. A process for the prePration of an N,N'-bis- (alkoxyalkyl) -pyridine-2 ,4-dicarboxylic acid diamide of the formula I CONH- (R 1 (OR 2 )n N CONE- (R 1 (OR 2 n wherein R' denotes linear or branched C,-C 4 -al'kanediyl, R 2 denotes unbranched C 1 -C 4 -alkyl or h~ydrogen, n denotes 1 or 2 and R 1 R 2 and n' have the same meanings as R 2 and n, R 1 and R" t and R 2 and R 2 and n and n' 20 being identical or different, excluding N,N'-bis(2-methoxyethyl)-pyridine-2,4- dicarboxylic acid diamide and N,N'- bis (2-hydroxyethyl) -pyridine-2,4-dicar- boxylic acid diamide, which comprises reacting a pyridine-2,4-dicarboxylic acid halide with an alkoxyalkylamine or hydroxy- alkylamine.
14. A process for the preparation of an N,N'-bis- (alkoxyalkyl) -pyridine-2,4-dicarboxylic acid diamide of the formula I CONH- (OR 2 )n CONH- (R 1 (OR 2 )n' wherein R 1 denotes linear or branched Ci-C 4 -alkanediyl, R 2 denotes unbranched Ci-C 4 -alkyl or hydrogen, n denotes 1 or 2 and R 1 R 2 and n' have the same meanings as R 1 R 2 and n, R 1 and and R 2 and R 2 and n and n' being identical or different, which comprises first A) 1. adding at least two equivalents of a halogenating agent to pyridine-2,4-dicarboxylic acid and 2. dissolving at least 2 equivalents of a hydroxy- alkylamine or alkoxyalkylamine of the formula II or II' HzN- (R)-(OR2)n (II) H2N-(R 1 )-(OR 2 )n (I in which R 1 and R 1 denote linear or branched Ci-C 4 -alkanediyl, R 2 and R 2 z denote unbranched Ci-C 4 -alkyl or hydrogen, n and n' denote 1 or 2 and i (3- 21 R 1 and R 1 R 2 and R 2 and n and n' are identical or different, but II and II' are different, in a solvent and then reacting the solution prepared according to 1. with the solution prepared according to or B) converting the resulting N,N'-bis(alkoxyalkyl)- pyridine-2,4-dicarboxylic acid diamide into the bis(hydroxyalkyl) compound, or C) reacting the pyridine-2,4-dicarboxylic acid halide prepared according to A) 1. with a substitu- ted or unsubstituted benzyl alcohol to give the benzyl pyridine-2,4-dicarboxylate, hydrolyzing the benzyl ester selectively in the 2-position of the pyridine, converting the free carboxylic acid in the 2-position into the acid halide again in accordance with process variant A) 1. and adding a solution prepared according to A) 2. using a compound of the formula II' to the compound thus obtained, a pyri- dine-4-(carboxylic acid benzyl ester)-carboxylic acid amide being formed, and then splitting off the benzyl protective group in the 4-position by hydro- genolysis, converting the free carboxylic acid into the acid chloride again in accordance with process variant A) and subsequently adding a solution prepared according to A) 2. using a compound of the formula II, an unsynimetrically substituted compound of the formula I being formed, and if appropriate then converting the resulting compound of the formula I into its physiologically tolerated salt. A compound as la-imed in a-ny-nc -of claims- I t for inhibition of proline hydroxylase and 1 l e hydroxylase.
16. A compound as claimed a-ny one of claims 1 to 12 for use as a fib uppressant and immunosuppressant.
17. pharmaceutical containing a compound of the f:-i1mrl.a I as- claimed- in-any--ne- of- lais-- 1 -2 Iv'Vb W I~sJ 4 22 A method of inhibition of proline hydroxylase and lysine hydroxylase comprising administering to a patient requiring such treatment anr effective amount of a compound as claimed in any one of claims 1 to 12. 16. A method of fibrosuppression and immunosuppression comprising administering to a patient requiring such treatment an effective amount of a compound as claimed in any one of claims 1 to 12. 17. A pharmaceutical containing a compound of the formula I as claimed in any one of claims 1-12 and/or one of its physiologically tolerated salts with tolerated pharmaceutical excipienis.
18. A method of influencing the biosynthesis of collagen and collagen-like substances oo or the biosynthesis of Clq comprising administering to a patient requiring such treatment an effective amount of a compound of the formula I as claimed in any one of claims 1-12 and/or a physiologically tolerated salt thereof. o 0 0 o 1 9. A method of treatment of disturbances in the biosynthesis of collagen and collagen- like substances or the biosynthesis of Clq comprising administering to a patient requiring such treatment an effective amount of a compound of the formula I as claimed in any one of claims 1-12 and/or a physiologically tolerated salt thereof.
20. A process for the preparation of pharmaceuticals for influencing the biosynthesis of collagen and collagen-like substances or the biosynthesis of CIq, which comprises incorporating a compound of the formula I as claimed in any one of claims 1-12 and/or a physiologically tolerated salt of this compound into the pharmaceutical. DATED this 18th day of March 1992 HOECHST AKTIENGESELLSCHAFT WATERMARK PATENT TRADEMARK ATTORNEYS THE ATRIUM 290 BURWOOD ROAD HAWTHORN VICTORIA 3122 AUSTRALIA A4 y T ?y'
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3924093A DE3924093A1 (en) | 1989-07-20 | 1989-07-20 | N, N'-BIS (ALKOXY-ALKYL) -PYRIDINE-2,4-DICARBONESAUREDIAMIDES, METHOD FOR THE PRODUCTION AND USE THEREOF |
| DE3924093 | 1989-07-20 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU5914490A AU5914490A (en) | 1991-01-24 |
| AU624978B2 true AU624978B2 (en) | 1992-06-25 |
Family
ID=6385494
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU59144/90A Ceased AU624978B2 (en) | 1989-07-20 | 1990-07-19 | N,n'-bis(alkoxyalkyl)-pyridine-2,4-dicarboxylic acid diamides, preparation and their use |
Country Status (26)
| Country | Link |
|---|---|
| EP (1) | EP0409119B1 (en) |
| JP (1) | JPH0776213B2 (en) |
| KR (1) | KR0181945B1 (en) |
| AT (1) | ATE104280T1 (en) |
| AU (1) | AU624978B2 (en) |
| CA (1) | CA2021529C (en) |
| CY (1) | CY1997A (en) |
| CZ (1) | CZ280129B6 (en) |
| DD (1) | DD300429A5 (en) |
| DE (2) | DE3924093A1 (en) |
| DK (1) | DK0409119T3 (en) |
| ES (1) | ES2052112T3 (en) |
| FI (1) | FI94630C (en) |
| HU (1) | HU218274B (en) |
| IE (1) | IE64438B1 (en) |
| IL (1) | IL95121A (en) |
| LT (1) | LT3798B (en) |
| LV (1) | LV10430B (en) |
| NO (1) | NO177187C (en) |
| NZ (1) | NZ234563A (en) |
| PL (1) | PL166307B1 (en) |
| PT (1) | PT94779B (en) |
| RU (1) | RU1836350C (en) |
| SK (1) | SK357690A3 (en) |
| UA (1) | UA19056A (en) |
| ZA (1) | ZA905680B (en) |
Families Citing this family (9)
| 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 |
| DE58908519D1 (en) * | 1988-08-04 | 1994-11-24 | Hoechst Ag | Improved process for the preparation of N, N-bis (alkoxyalkyl) pyridine -2,4-dicarboxylic acid diamides. |
| DE4020570A1 (en) | 1990-06-28 | 1992-01-02 | Hoechst Ag | 2,4- AND 2,5-SUBSTITUTED PYRIDINE-N-OXIDES, METHOD FOR THE PRODUCTION AND USE THEREOF |
| DE4030999A1 (en) * | 1990-10-01 | 1992-04-09 | Hoechst Ag | 4- OR 5-SUBSTITUTED PYRIDINE-2-CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MEDICINAL PRODUCT |
| YU9492A (en) * | 1991-02-05 | 1995-03-27 | Hoechst Ag. | 2,4- and 2,5-BIS-TETRAZOLYL pyridines and the process for their preparation |
| TW199147B (en) * | 1991-03-18 | 1993-02-01 | Hoechst Ag | |
| 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 |
| TW222585B (en) * | 1992-09-11 | 1994-04-21 | Hoechst Ag | |
| DOP2002000332A (en) | 2001-02-14 | 2002-08-30 | Warner Lambert Co | MATRIX METALOPROTEINAS PYRIDINE INHIBITORS |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU604293B2 (en) * | 1987-02-10 | 1990-12-13 | Hoechst Aktiengesellschaft | Pyridine-2,4- and 2,5-dicarboxylic acid derivatives, a process for their preparation, the use thereof, and medicaments based on these compounds |
| AU615324B2 (en) * | 1988-08-04 | 1991-09-26 | Hoechst Aktiengesellschaft | An improved process for the preparation of n,n'-bis- (alkoxyalkyl)-pyridine-2,4-dicarboxamides |
Family Cites Families (5)
| 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 |
| 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 |
| 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 |
| DE3828140A1 (en) | 1988-08-19 | 1990-03-01 | Hoechst Ag | Improved process for the preparation of N,N'-bis(alkoxyalkyl)pyridine-2,4-dicarboxamides and use of these compounds for the preparation of orally administrable medicaments |
| DE3826471A1 (en) | 1988-08-04 | 1990-02-22 | Hoechst Ag | Improved process for the preparation of N,N'-bis(alkoxyalkyl)pyridine-2,4-dicarboximides |
-
1989
- 1989-07-20 DE DE3924093A patent/DE3924093A1/en not_active Withdrawn
-
1990
- 1990-07-14 DE DE59005328T patent/DE59005328D1/en not_active Expired - Fee Related
- 1990-07-14 ES ES90113528T patent/ES2052112T3/en not_active Expired - Lifetime
- 1990-07-14 DK DK90113528.5T patent/DK0409119T3/en active
- 1990-07-14 EP EP90113528A patent/EP0409119B1/en not_active Expired - Lifetime
- 1990-07-14 AT AT90113528T patent/ATE104280T1/en not_active IP Right Cessation
- 1990-07-18 NZ NZ234563A patent/NZ234563A/en unknown
- 1990-07-18 IL IL9512190A patent/IL95121A/en not_active IP Right Cessation
- 1990-07-18 FI FI903624A patent/FI94630C/en not_active IP Right Cessation
- 1990-07-18 SK SK3576-90A patent/SK357690A3/en unknown
- 1990-07-18 CZ CS903576A patent/CZ280129B6/en not_active IP Right Cessation
- 1990-07-18 DD DD342874A patent/DD300429A5/en not_active IP Right Cessation
- 1990-07-19 HU HU549/90A patent/HU218274B/en not_active IP Right Cessation
- 1990-07-19 KR KR1019900010938A patent/KR0181945B1/en not_active IP Right Cessation
- 1990-07-19 AU AU59144/90A patent/AU624978B2/en not_active Ceased
- 1990-07-19 RU SU904830947A patent/RU1836350C/en active
- 1990-07-19 UA UA4830947A patent/UA19056A/en unknown
- 1990-07-19 CA CA002021529A patent/CA2021529C/en not_active Expired - Fee Related
- 1990-07-19 PL PL90286132A patent/PL166307B1/en unknown
- 1990-07-19 JP JP2189620A patent/JPH0776213B2/en not_active Expired - Lifetime
- 1990-07-19 IE IE264290A patent/IE64438B1/en not_active IP Right Cessation
- 1990-07-19 NO NO903235A patent/NO177187C/en not_active IP Right Cessation
- 1990-07-19 ZA ZA905680A patent/ZA905680B/en unknown
- 1990-07-20 PT PT94779A patent/PT94779B/en not_active IP Right Cessation
-
1993
- 1993-05-07 LV LVP-93-301A patent/LV10430B/en unknown
- 1993-11-12 LT LTIP1462A patent/LT3798B/en not_active IP Right Cessation
-
1997
- 1997-09-05 CY CY199797A patent/CY1997A/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU604293B2 (en) * | 1987-02-10 | 1990-12-13 | Hoechst Aktiengesellschaft | Pyridine-2,4- and 2,5-dicarboxylic acid derivatives, a process for their preparation, the use thereof, and medicaments based on these compounds |
| AU615324B2 (en) * | 1988-08-04 | 1991-09-26 | Hoechst Aktiengesellschaft | An improved process for the preparation of n,n'-bis- (alkoxyalkyl)-pyridine-2,4-dicarboxamides |
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Legal Events
| Date | Code | Title | Description |
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| MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |