HRP920948A2 - Nitratoalkanecarbone acid derivatives, process for the preparation thereof, the use of the same and drugs containing them - Google Patents

Abstract

Nitratoalkanoic acid derivatives of the general formula (I), in particular containing N-acylamino acids or N-acylpeptides, of the general formula (I) <IMAGE> in which the symbols have the meanings mentioned in the claims. They are distinguished by advantageous physicochemical properties and good physiological tolerability for active substances already preventing known nitrate tolerance or weakening a tolerance which has already set in. The compounds are used in medicaments for the treatment of circulatory disorders, high blood pressure, cardiac insufficiency and for dilating the peripheral vessels.

Description

The field of technology

This invention is from the field of organic and pharmaceutical chemistry. According to the International Patent Classification, it belongs to sections and subsections C 07 C 327/34, A 61 K 31/21, A 61 K 32/195, A 61 K 37/02 and C 07 K 5/06.

Technical problem

The object of the present invention is to provide new compounds which are suitable in medicaments for the treatment of blood flow diseases, high blood pressure, heart failure and for the dilation of peripheral blood vessels.

The invention relates to derivatives of nitratoalkanecarboxylic acids, the process for obtaining them, their use and medicines containing them.

State of the art

Organic nitrates (nitric acid esters) have been proven in the treatment of heart diseases.

They develop their action both by relieving the heart, lowering the pre-afterload, and by improving the oxygen supply to the heart, by expanding the coronary vessels.

Certainly in previous years, it has been established that the organic nitrates used so far in therapy, such as trinitroglycerin (tng), isosorbide-5-mononitrate or isosorbide dinitrate, with high and continuous intake into the body, show a significant decrease in action, nitrate tolerance in the course of a relatively short time . Numerous experiments have shown that the presence of sulfhydryl groups prevents the formation of nitrate tolerance and can weaken already formed tolerance. The mechanism of creating tolerance is today interpreted in the following way:

According to the current state of knowledge, the pharmacological action of organic nitro compounds depends on the presence of cysteine. This organic nitrate creates a common precursor step, the decomposition of which also releases NO-radicals, which then activate the target enzyme, soluble guanylate cyclase, a class of smooth muscle cells. Further, by creating cGMP-induced alternating reactions, they then lead to the relaxation or expansion of blood vessels.

The reactive and short-lived, so far still hypothetical intermediate product can be a nitric acid tiester or a thionitrate. By intramolecular rearrangement and further and alternating reactions, which have not yet been clarified, it is postulated that a single nitrosothiol is finally formed, from which nitrogen monoxide or nitrite ions are then released. Degradation that depends on enzymes, by means of GSH-reductase, must not have any influence on the pharmacological action, however, because it only leads to the formation of nitrite ions. Non-enzymatic degradation needs, as described, cysteine, and in this way it is exhaustible (exhaustion of SH-groups), so that enough NO is permanently no longer created as an inherent activator of guanylcyclase, and the effect is clinically weakened.

In EP 89 116 700.9, specifically constructed compounds consisting of nitrofatty acids (nitratoalkanecarboxylic acids) and sulfur-containing amino acids or peptides are described. The presence of sulfhydryl groups must prevent or reduce nitrate tolerance or an already established tolerance.

Also listed are compounds containing sulfur-containing amino acids, such as cysteine or methionine in the form of their methyl, ethyl or propyl esters. Finally, SH groups of cysteine can be esterified with lower alkanecarboxylic acids with 2 to 8 carbon atoms.

Although these compounds have significant pharmacological properties in relation to the avoidance of nitrate tolerance, that is, the prevention or weakening of already formed tolerance, they also have disadvantages. They have low melting points, have low solubility in water and create difficulties in obtaining them in pure form.

The task of this invention is therefore to obtain new organic compounds and to make them available to the expert, which avoid the above-mentioned disadvantages.

Description of the solution

This task was solved in such a way that the compounds according to the invention are derivatives of nitratoalkanecarboxylic acids of the general formula (I)

[image]

in which it is

R hydroxy, lower alkoxy, lower alkenoxy, di-lower alkyl-amino-lower alkoxy, acylamino-lower alkoxy, acyloxy-lower alkoxy, aryloxy, aryl-lower alkyloxy, substituted aryloxy or substituted aryl lower alkoxy, where the substituent is methyl, halogen or methoxy; amino, lower alkylamino, di-lower alkylamino, aryl lower alkylamino, hydroxy lower alkylamino or amino acid residues via a peptide bond,

R1 hydrogen, alkyl with 1 to 6 carbon atoms, substituted lower alkyl, where the substituent is halogen, hydroxy, lower alkoxy, aryloxy, amino, lower alkylamino, acylamino, acyloxy, arylamino, mercapto, lower alkylthio, arylthio,

R2 represents as R1 hydrogen or lower alkyl,

R3 is hydrogen or lower alkyl,

R4 is hydrogen, lower alkyl, phenyl, methoxyphenyl, phenyl lower alkyl, methoxy-phenyl-lower alkyl, hydroxyphenyl-lower alkyl, hydroxy lower alkyl, alkoxy lower alkyl, amino-lower alkyl, acylamino lower alkyl, mercapto-lower alkyl or lower alkylthio-lower alkyl,

R5 denotes S-acyl compounds of a lower alkyl thiol, especially their amino acid thioesters, N-acylamino acid thioesters, peptide thioesters or N-acyl peptide thioesters with 2-5 peptide-bound amino acid residues,

R and R4 can be linked together to form an ester or amide,

R 3 and R 4 may be bonded together to form one alkylene bridge of 2 to 4 carbon atoms, one alkylene bridge of 2 to 3 carbon atoms and one sulfur atom of one alkylene bridge of 3 to 4 carbon atoms containing one double bond or an alkylene bridge as above, substituted with hydroxy, lower alkoxy, lower alkyl or di-lower alkyl,

m, n and o represent the numbers 0-10 as well as their physiologically tolerable salts.

According to a further embodiment of the invention, parts of nitrofatty acids have a chain length of C2 to C6; they can be normal, branched, racemic or optical isomers.

Primarily, derivatives of nitratoalkanecarboxylic acids according to the invention of the general formula (I) contain, from a series of sulfur-containing amino acids, the amino acids cysteine, methionine or homocysteine.

According to a further embodiment of the invention, the amino acids are in the stereochemical L-form.

Sulfur-containing amino acids can be esterified at the C-terminal end.

According to one preferred embodiment according to the invention, the amino acids cysteine and/or methionine are present as a methyl, ethyl or propyl ester, in particular

N-Nitratopivaloyl-S-(N-acetylglycyl)-L-cysteine ethyl ester,

N-Nitratopivaloyl-S-(N-acetylalanyl)-L-cysteine ethyl ester as well as

N-Nitratopivaloyl-S-(N-acetylleucyl)-L-cysteine ethyl ester in terms of the invention is primary.

The compounds according to the invention of the general formula (I) can be obtained in a known manner, such as the compound of the general formula (II)

[image]

in which it is

R hydroxy, lower alkoxy, lower alkenoxy, di-lower alkyl-amino-lower alkoxy, acylamino-lower alkoxy, acyloxy-lower alkoxy, aryloxy, ayl-lower alkyloxy, substituted aryloxy or substituted aryl lower alkoxy, where the substituent is methyl, halogen or methoxy; amino, lower alkylamino, di-lower alkylamino, aryl lower alkylamino, hydroxy lower alkylamino or amino acid residues linked via a peptide bond,

R1 hydrogen, alkyl with 1 to 6 carbon atoms, substituted lower alkyl, where the substituent is halogen, hydroxy, lower alkoxy, aryloxy, amino, lower alkylamino, acylamino, acyloxy, arylamino, mercapto, lower alkylthio, arylthio,

R2 represents as R1 hydrogen or lower alkyl,

R3 is hydrogen or lower alkyl,

R4 is hydrogen, lower alkyl, phenyl, methoxyphenyl, phenyl lower alkyl, methoxy-phenyl-lower alkyl, hydroxyphenyl-lower alkyl, hydroxy lower alkyl, alkoxy lower alkyl, amino-lower alkyl, acylamino lower alkyl, mercapto-lower alkyl or lower alkylthio-lower alkyl,

R and R4 can be linked together to form an ester or amide,

R3 and R4 can be bonded together to form one alkylene bridge of 2 to 4 carbon atoms, one alkylene bridge of 2 to 3 carbon atoms and one sulfur atom, one alkylene bridge of 3 to 4 carbon atoms containing one double bond, or one alkylene bridge as above, substituted with hydroxy, lower alkoxy, lower alkyl or di-lower alkyl,

R 6 represents a lower alkylthiol

according to one known reaction for obtaining thioesters by subjecting amino acids, N-acylamino acids, peptides or N-acyl peptides to a reaction with 2-5 peptide-bound esters of amino acids. Compounds of the general formula (II) can be obtained in the manner described in EP 89 116 700.9.

Then the nitrofatty acids of the general formula (A) can be

[image]

in which R1, R and m have the meanings given above, in the form of their free acids, reactive acid chlorides, acid azides, esters and acid anhydrides to be used with the compound of the general formula (B)

[image]

in which the meanings for R, R3, R4, R6, n and o are as given above, the obtained amino acids and/or peptides are converted with the formation of compounds of the general formula (II)

To convert the compounds of the general formula (I) into their pharmacologically harmless salts, these are treated in an organic or aqueous organic solvent, with an equivalent amount of an inorganic or organic acid in the given case. Examples include hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, formic acid, acetic acid, propionic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, adipic acid, benzoic acid, salicylic acid, O- acetoxybenzoic acid, cinnamic acid, naphthoenic acid, mandelic acid, citric acid, malic acid, tartaric acid, aspartic acid, glutamic acid, methanesulfonic acid or p-toluenesulfonic acid.

The new compounds according to the invention of the general formula (I) and their salts can be administered in liquid or solid form enterally or parenterally.

As an injection medium, primarily water is used, which contains the usual additives for injection solutions, such as stabilizers, solubility-improving agents or buffers. Such additives are, for example, tartrate and citrate buffers, ethanol, a complexing agent (ethylenediaminetetraacetic acid and its non-toxic salts), high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation. Solid fillers are, for example, starches, lactose, mannitol, methylcellulose, talc, highly dispersed silica gel acids, gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats, and solid high-molecular polymers (such as polyethylene glycols); preparations suitable for oral administration may, in the desired case, contain substances to give taste and sweet substances.

According to a further embodiment of the invention, the drugs contain one and/or a mixture of compounds according to the invention.

These drugs can be used to treat blood flow diseases, for example as coronary dilators, as a means of treating high blood pressure, heart failure and to dilate peripheral blood vessels including the blood vessels of the brain and kidneys.

Pharmaceutical preparations, which contain a previously calculated amount of one or more compounds according to the invention, can be given once a day in the form of retarded preparations or several times a day at regular intervals (2-3 times a day). The usual amounts of active substances per day are 20-300 mg per day, in relation to a body weight of 75 kg. In the form of injections, the compounds according to the invention can be given 1-8 times a day in or in the form of continuous infusions. In normal cases, amounts from 5 to 200 mg/day are sufficient.

One typical tablet may have the following composition:

1) N-Nitratopivaloyl-S-(N-acetylglycyl)-L-cysteine ethyl ester 25 mg

2) Starch, U.S.P. 57 mg

3) Lactose, U.S.P. 73 mg

4) Talc, U.S.P. 9 mg

5) Stearic acid 6 mg

Substances 1, 2 and 3 are sieved, granulated, mixed with 4 and 5 and finally tableted. Exemplary embodiments, without being limited to them, illuminate the invention.

Examples

Example 1

Preparation of N-Nitratopivaloyl-S-(N-acetylglycyl)-L-cysteine ethyl ester

48 g (0.41 mol) of N-acetylglycine are suspended at room temperature in 300 ml of methyl chloride (CH2Cl2) with stirring, and cooled to 10 °C. With stirring, a solution of 109.8 g (0/373 mol) of N-nitratopivaloyl-L-cysteine ethyl ester in 300 ml of CH2Cl2 is added with a slightly exothermic reaction. The reaction mixture is cooled to 5°C with stirring and a solution of 84.6 g (0.41 mol) of dicyclohexylcarbodiimide (DCC) in 200 ml of CH2Cl2 is slowly added dropwise with stirring, so that the temperature lies in the range between 5°C and 10° C. After heating to room temperature, it is mixed for 4 days at room temperature. The DCC-urea is suctioned off and washed twice with 100 ml of CH 2 Cl.

The combined CH2Cl2 phases are washed one after the other each time, once with 200 ml of 9% NaHCO3 solution, 300 ml of 1 n HCl and 300 ml of distilled water. Finally, the methylene chloride phase is dried over anhydrous sodium sulfate and evaporated to dryness on a rotary vacuum evaporator (RotavaporR, Buchl).

The yield was 162.9 g (theoretical 146/74 g) of N-nitratopivaloyl-S-(B-acetylphlicyl)-L-cysteine ethyl ester as a light yellow oil.

162/9 g of N-nitratopivaloyl-S-(B-acetylphenyl)-L-cysteine ethyl ester are dissolved in 470 ml of ethyl acetate at room temperature. After stirring for 15 minutes at room temperature, the undissolved white precipitate is filtered. The clear light yellow filtrate is treated slowly at room temperature with stirring with 390 ml of n-hexane.

Grafting crystals are added to this solution and mixed at room temperature overnight. The precipitated crystals are filtered and washed twice with 100 ml of a mixture of 20 ml of ethyl acetate and 80 ml of n-hexane at room temperature.

The crystals are dried in a vacuum oven at room temperature, vacuum 2 torr to constant weight.

The yield was 85/5 g (theoretical 146.74 g) of N-nitratopivaloyl-S-(B-acetylphlicyl)-L-cysteine ethyl ester. T.t. 71.8°C.

Example 2

Preparation of N-nitratopivaloyl-S-(N-acetylalanyl)-L-cysteine ethyl ester

53/8 g (0.41 mol) of N-acetylalanine is suspended with stirring at room temperature in 300 ml of methylene chloride (CH2Cl2) and cooled to 10°C. With stirring, a solution of 109/8 g (0.373 mol) of N-nitratopivaloyl-L-cysteine ethyl ester in 300 ml of CH2Cl2 is added with a slightly exothermic reaction. The reaction mixture is cooled to 5°C with stirring, a solution of 84/6 g (0.41 mol) of dicyclohexylcarbodiimide solution (DCC) in 200 ml of CH2Cl2 is added dropwise with stirring at 5°C, so that the temperature lies in the range between 5° C and 10°C. After heating to room temperature, it is stirred at room temperature for four days.

DCC-urea is suctioned and washed twice with 100 ml of CH2Cl2 each.

The combined methylene chloride phases are washed one after the other each time with 200 ml of 9% NaHCO3 solution, 300 ml of 1 n HCl and 300 ml of distilled water. Finally, the methylene chloride phase is dried over anhydrous sodium sulfate and evaporated on a rotary vacuum evaporator (RotavaporR, Buchl) to constant weight.

The yield was 160.5 g (theoretical 151.84) of N-nitratopivaloyl-S-(N-acetylalanyl)-L-cysteine ethyl ester as a light yellow oil.

160/5 g of N-nitratopivaloyl-S-(N-acetylalanyl)-L-cysteine ethyl ester is dissolved in 345 ml of ethyl acetate at room temperature. After 15 minutes of mixing at room temperature, the undissolved precipitate is filtered. The clear light yellow filtrate is treated slowly with stirring at room temperature with 345 ml of n-hexane.

Grafting crystals are added to this solution and stirred at room temperature overnight. The precipitated crystals are suctioned and washed twice with 100 ml each of a mixture of 20 ml ethyl acetate and 80 ml n-hexane at room temperature.

The crystals are dried in a vacuum oven at room temperature, vacuum 2 torr, to constant weight.

The yield was 78/2 g (theoretical 151/84 g) of N-nitratopivaloyl-S-(N-acetylalanyl)-L-cysteine ethyl ester. T.t. 76/6oC.

Example 3

Preparation of N-nitratopivaloyl-S-(N-acetylleucyl)-L-cysteine ethyl ester

0.02 mol = 6 g of acid cysteine ethyl ester nitratopivalin is dissolved in 100 ml of dichloromethane. At 10°C and with nitrogen supply, 0.03 mol = 5.19 g of N-acetyl leucine and 0.1 g (DMAP) of dimethylaminopyridine are added slowly. Finally, 0.03 mol = 6.15 g of dichlorohexylcarbodiimide (DCC), dissolved in 80 ml of dichloromethane, is added dropwise. It is mixed overnight at room temperature.

Processing

The mixture is vacuumed. The solution is washed successively with equivalent amounts of 0.1 N HCl and solution, saturated with NaHCO 3 solution and extracted with distilled water. Finally, the solvent is evaporated on a rotary vacuum evaporator (RotavaporR, Buchl). 10 g of carbon residue remains.

Recrystallization

10 g of the oily substance is dissolved with gentle heating in 45 ml of ethanol and 40 ml of H2O dist. Leave the substance overnight in the refrigerator to crystallize. The crystals are filtered and dried in a vacuum oven.

Mass spectrum confirmed the structure.

Melting point: 91.4°C

GPLC analysis: 98.7%

Yield: 5 g = 0.012 mol = 57.4& theoretical

Claims (11)

1. Compounds of general formula (I) [image] indicated by what is R hydroxy, lower alkoxy, lower alkenoxy, di-lower alkyl-amino-lower alkoxy, acylamino-lower alkoxy, acyloxy-lower alkoxy, aryloxy, ait-lower alkyloxy, substituted aryloxy or substituted aryl lower alkoxy, where the substituent is methyl, halogen or methoxy; amino, lower alkylamino, di-lower alkylamino, aryl lower alkylamino, hydroxy lower alkylamino or amino acid residues via a peptide bond, R1 hydrogen, alkyl with 1 to 6 carbon atoms, substituted lower alkyl, where the substituent is halogen, hydroxy, lower alkoxy, aryloxy, amino, lower alkylamino, acylamino, acyloxy, arylamino, mercapto, lower alkylthio, arylthio, R2 represents as R1 radicals lower alkyl, R3 is hydrogen or lower alkyl, R4 is hydrogen, lower alkyl, phenyl, methoxyphenyl, phenyl lower alkyl, methoxy-phenyl-lower alkyl, hydroxyphenyl-lower alkyl, hydroxy lower alkyl, alkoxy lower alkyl, amino-lower alkyl, acylamino lower alkyl, mercapto-lower alkyl or lower alkylthio-lower alkyl, R5 denotes S-acyl compounds of a lower alkyl thiol, especially their thioesters of amino acids, thioesters of N-acylamino acids, thioesters of peptides or thioesters of N-acyl peptides with 2-5 peptide-bound amino acid residues, R and R4 can be linked together to form an ester or amide, R 3 and R 4 may be bonded together to form one alkylene bridge of 2 to 4 carbon atoms, one alkylene bridge of 2 to 3 carbon atoms and one sulfur atom of one alkylene bridge of 3 to 4 carbon atoms containing one double bond or an alkylene bridge as above, substituted with hydroxy, lower alkoxy, lower alkyl or di-lower alkyl, m, n and o represent the numbers 0-10 as well as their physiologically tolerable salts. 2. Compounds according to claim 1, characterized in that their components of nitrofatty acids have a chain length of C2 to C6, and that they are normal, branched, racemic or optical isomers. 3. Compounds according to claims 1 and 2, characterized in that the sulfur-containing amino acids are primarily cysteine, methionine or homocysteine. 4. Compounds according to claims 1 to 3, characterized in that the amino acids are in the stereochemical L form. 5. Compounds according to claims 1 to 4, characterized in that the sulfur-containing amino acids are esterified at the C-terminal end. 6. Compounds according to claims 1 to 5, characterized in that the amino acids cysteine and/or methionine are in the form of methyl, ethyl or propyl esters. 7. Compounds according to claims 1 to 6, characterized in that they are a) N-Nitratopivaloyl-S-(N-acetylglycyl)-L-cysteine ethyl ester b) N-Nitratopivaloyl-S-(N-acetylalanyl)-L-cysteine ethyl ester c) B-Nitratopivaloyl-S-(N-acetylleucyl)-L-cysteine ethyl ester. 8. Process for obtaining derivatives of nitratoalkanecarboxylic acids of the general formula (I) [image] R hydroxy, lower alkoxy, lower alkenoxy, di-lower alkyl-amino-lower alkoxy, acylamino-lower alkoxy, acyloxy-lower alkoxy, aryloxy, ad-1-lower alkyloxy, substituted aryloxy or substituted aryl lower alkoxy, where the substituent is methyl, halogen or methoxy; amino, lower alkylamino, di-lower alkylamino, aryl lower alkylamino, hydroxy lower alkylamino or amino acid residues via a peptide bond, R1 hydrogen, alkyl with 1 to 6 carbon atoms, substituted lower alkyl, where the substituent is halogen, hydroxy, lower alkoxy, aryloxy, amino, lower alkylamino, acylamino, acyloxy, arylamino, mercapto, lower alkylthio, arylthio, R2 represents as R1 radicals lower alkyl, R3 is hydrogen or lower alkyl, R4 is hydrogen, lower alkyl, phenyl, methoxyphenyl, phenyl lower alkyl, methoxy-phenyl-lower alkyl, hydroxyphenyl-lower alkyl, hydroxy lower alkyl, alkoxy lower alkyl, amino-lower alkyl, acylamino lower alkyl, mercapto-lower alkyl or lower alkylthio-lower alkyl, R5 denotes S-acyl compounds of a lower alkyl thiol, especially their amino acid thioesters, N-acylamino acid thioesters, peptide thioesters or N-acyl peptide thioesters with 2-5 peptide-bound amino acid residues, R and R4 can be linked together to form an ester or amide, R 3 and R 4 may be bonded together to form one alkylene bridge of 2 to 4 carbon atoms, one alkylene bridge of 2 to 3 carbon atoms and one sulfur atom of one alkylene bridge of 3 to 4 carbon atoms containing one double bond or an alkylene bridge as above, substituted with hydroxy, lower alkoxy, lower alkyl or di-lower alkyl, m, n and o represent the numbers 0-10, as well as their physiologically acceptable salts, indicated by the fact that compounds of the general formula (II) are combined in a known manner [image] in which it is R hydroxy, lower alkoxy, lower alkenoxy, di-lower alkyl-amino-lower alkoxy, acylamino-lower alkoxy, acyloxy-lower alkoxy, aryloxy, adt lower alkyloxy, substituted aryloxy or substituted aryl lower alkoxy, where the substituent is methyl, halogen or methoxy; amino, lower alkylamino, di-lower alkylamino, aryl lower alkylamino, hydroxy lower alkylamino or amino acid residues linked via a peptide bond, R1 hydrogen, alkyl with 1 to 6 carbon atoms, substituted lower alkyl, where the substituent is halogen, hydroxy, lower alkoxy, aryloxy, amino, lower alkylamino, acylamino, acyloxy, arylamino, mercapto, lower alkylthio, arylthio, R2 represents as R1 radicals lower alkyl, R3 is hydrogen or lower alkyl, R4 is hydrogen, lower alkyl, phenyl, methoxyphenyl, phenyl lower alkyl, methoxy-phenyl-lower alkyl, hydroxyphenyl-lower alkyl, hydroxy lower alkyl, alkoxy lower alkyl, amino-lower alkyl, acylamino lower alkyl, mercapto-lower alkyl or lower alkylthio-lower alkyl, R and R4 can be linked together to form an ester or amide, R3 and R4 can be bonded together to form one alkylene bridge of 2 to 4 carbon atoms, one alkylene bridge of 2 to 3 carbon atoms and one sulfur atom, one alkylene bridge of 3 to 4 carbon atoms containing one double bond, or one alkylene bridge as above, substituted with hydroxy, lower alkoxy, lower alkyl or di-lower alkyl, R 6 represents a lower alkylthiol are obtained according to one known reaction for obtaining thioesters by subjecting amino acids, N-acylamino acids, peptides or N-acyl peptides to a reaction with 2-5 peptide-bound esters of amino acids and finally subjecting the obtained compounds to their pharmacologically harmless salts as desired. 9. Medicines according to claims 1 to 8, characterized by the fact that they contain one or more compounds, as well as usual fillers and auxiliary substances. 10. Use of compounds according to claims 1 to 8, characterized by the fact that they serve to obtain drugs for the prophylaxis of heart and blood flow diseases. 11. Compounds according to claims 1 to 7, characterized by the fact that they serve to obtain drugs for the prophylaxis of diseases of the heart and blood vessels.