FI111074B - Process for the preparation of nitratoalkanecarboxylic acid derivatives - 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

111074

A process for the preparation of nitrate alkane carboxylic acid derivatives r

The invention relates to a process for the preparation of nitrate alkane carboxylic acid derivatives.

Organic nitrates (nitric acid esters) have proven to be good in the treatment of heart disease.

10 They exert their effects through both reduction of cardiac strain by reduction of pre- and post-strain and improvement of oxygen supply to the heart by dilation of the coronary arteries.

However, over the past few years, it has been shown that organic nitrates such as glycerolitrinitrate (GTN), isosorbide-5-mononitrate or isosorbide dinitrate, used hitherto in therapy, exhibit a marked reduction in activity, nitrates, over a relatively short period of time. Numerous experiments suggest that the presence of sulfhydryl groups may prevent the formation of nitrate titol tolerance and may impair the already established tolerance.

20

The mechanism of tolerance formation is now understood as:

According to current knowledge, the pharmacological activity of organic nitro compounds depends on the presence of cysteine. Organic nitrate forms with this. 25 second precursors, which are liberated, e.g. NO radicals that activate the target enzyme, soluble guanylate cyclase in smooth muscle. Other effects triggered by the formation of cGMP then lead to relaxation or vasodilation.

30 A reactive and short-lived, hitherto hypothetical intermediate would be: thioester or thionitrate of nitric acid. Through intramolecular rearrangement and other ensuing reactions, the formation of the last nitrosothiol is assumed, which then releases nitric oxide or nitrite ions. Conversely, enzyme-dependent degradation by GSH reductase would have no significant pharmacological effect since it results exclusively in the formation of nitrite ions. Non-enzymatic degradation also requires, as described, cysteine and is dose dependent depletion (depletion of the total number of SH groups) such that, over time, it is no longer possible to convert enough NO into the actual guanyl cyclase activator, and clinically becomes less effective. .

EP-A-89116700.9 mentions specifically formed compounds consisting of nitrate fatty acids (nitrate alkane carboxylic acids) and sulfur-containing amino acids or peptides. The presence of sulfhydryl groups is said to inhibit or weaken the nitrate tolerance or the onset of tolerance.

Mentioned e.g. compounds containing sulfur-containing amino acids such as cysteine or methionine in the form of their methyl, ethyl or propyl esters. Finally, the SH group of cysteine may be esterified with lower alkanecarboxylic acid of 2 to 8 carbon atoms.

Although these compounds already possess valuable pharmacological properties for the avoidance of nitrate thiol-15 or the inhibition or attenuation of the already formed tolerance, they have drawbacks. They have low melting points, low solubility in water and difficulties in producing a pure product.

Thus, it is an object of the invention to make and make available to a person skilled in the art new or-20 organic compounds which avoid the above-mentioned disadvantages.

This object was solved by the nitrate alkane carboxylic acid derivatives of the general formula I obtained according to the invention.

25 CH30 H R1 O

I III I II

02N-O-CH2-C-C-N-CC-R (I) ch3 h wherein: R is hydroxy, amino or methoxy, ethoxy or propoxy and R1 is a group -XSY wherein X is an alkylene residue having one or two carbon atoms and Y is an N-acetylamino acid residue wherein the amino acid is glycine, alanine or leucine, as well as their physiologically acceptable salts.

35

According to a further development of the invention, the nitrate fatty acid moieties have a chain length of C2-C6; they may be straight-chain, branched, racemic or optical isomers.

3, 111074

The nitrate alkane carboxylic acid derivatives v of the general formula I according to the invention contain from the sulfur-containing amino acids cysteine, methionine or homocysteine.

5

According to a further development of the invention, the amino acids exist in stereochemically L-form.

The sulfur-containing amino acids may be esterified at the C-terminal end.

10

According to a preferred further development of the invention, the amino acids cysteine and / or methionine are in the form of methyl, ethyl or propyl ester.

In particular, N-nitrate pivaloyl S- (N-acetylglycyl) -L-cysteine ethyl ester, N-nitrate pivaloyl S- (N-acetylalanyl) -L-cysteine ethyl ester as well as N-nitrate pivaloyl S- (N-acetyl leucyl) -L-cysteine ester are preferred according to the invention.

Compounds of general formula I may be prepared in a manner known per se such that a compound of general formula Π or Π '

CH3 O H CH2 — SH O

iiii / 25 Ο, Ν-O-CHr-CC-N-CC (II) II \ ch3 hr ch3 oh ch2-ch2-sh o 30 ..... / 02N-O-CH2-CC-N-CC ( Wherein R is as above, is reacted with N-acetylglycine, N-acetylalanine or N-acetylleucine, and the resulting compound is then converted, if desired, into its pharmacologically acceptable salt.

4, 111074

The compound of general formula II may be prepared as described in EP 89116700.9.

Subsequently, nitrate fatty acids 5 of the general formula (A) may be used

R1 O

II

O 2 N-O-CH 2 -C- (CH 2) m C-O H (A) R 2 wherein R 1, R 2 and m are as defined above, in the form of their free acids, reactive acid halides, acid azides, esters and acid anhydrides; B)

R3 R4 O

I I II

HN- (CH 2) n -C- (CH) O-C-R (B) 20 R 6 wherein R, R 3, R 4, R 6, n and o are as defined above, including amino acids and / or peptides to form compounds of formula Π.

In order to convert the compounds of general formula (I) into their pharmacologically acceptable salts, they are reacted, in particular in an organic or aqueous organic solvent, with an equivalent amount of an optionally inorganic or organic acid. Any relevant hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, formic acid, acetic acid, propionihap-30 acid, oxalic acid, fumaric acid, maleic acid, succinic acid, adipic acid, benzoic acid, salicylic acid, o-acetoxybenzoic acid, cinnamic acid, naphthoic acid, mandelic acid, citric acid, malic acid, tartaric acid , aspartic acid, glutamic acid, methanesulfonic acid or p-toluenesulfonic acid.

The novel compounds of general formula (I) and salts thereof may be administered enterally or parenterally in liquid or solid form.

Injection medium is, in particular, water containing the usual additives for injection solutions, such as a stabilizer, a solubilizing agent or a buffer. Such additives include, for example, tartrate and citrate buffer, ethanol, complexing agent (such as ethylenediaminetetraacetic acid and its non-toxic salts), high molecular weight polymers (such as liquid polyethylene oxide) for viscosity control.

Solid media include, for example, starch, lactose, mannitol, methylcellulose, talc, ultra-fine silicas, high molecular weight fatty acids (such as stearic acid), gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and plant ); preparations suitable for oral administration may, if desired, contain flavoring and sweetening agents.

10

According to a further development of the invention, the drugs contain one compound and / or a mixture thereof obtained according to the invention.

These drugs can be used to treat circulatory disorders, for example as se-15 coronary dilators, as agents for the treatment of hypertension and heart failure, and to dilate peripheral blood vessels, including the cerebral and renal blood vessels.

Pharmaceutical preparations containing a predetermined amount of one or more compounds of the invention may be administered once daily in the form of sustained release formulations or several times daily at regular intervals (2-3 times daily). The usual daily amounts of drug are 20-300 mg / day / 75 kg body weight. In the form of injections, the compounds of the invention may be administered 1 to 8 times daily or by continuous infusion. Normally sufficient ..: 25 amounts of 5-200 mg / day.

A typical tablet may have the following composition: 1) N-nitrate-pivaloyl-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 35 Substances 1, 2 and 3 are screened, granulated, mixed homogeneously with substances 4 and 5 and tableted next.

3 6 111074

The examples illustrate the invention without limiting it.

Example 1 Preparation of N-nitrate pivaloyl-S- (N-acetylglycyl) -L-cysteine ethyl ester 5g (0.41 mol) of N -acetylglycine was suspended at room temperature in 300 ml of methylene chloride (CH 2 Cl 2) and cooled to 10 ° C. A solution of 109.8 g (0.373 mol) of N-nitrate-pivaloyl L-cysteine ethyl ester in 300 mL of CH 2 Cl 2 was added with stirring in a slightly exothermic reaction. The reaction mixture was cooled to 5 ° C with stirring and a solution of 84.6 g (0.41 mol) of dicyclohexylcarbodiimide (DCC) in 200 ml of CH 2 Cl 2 was added dropwise with stirring, keeping the temperature within between 5 and 10 ° C. After warming to room temperature, the mixture was stirred for 4 days at room temperature. The DCC urea was filtered off with a suction flask and washed twice with 100 mL of CH 2 Cl 2 each.

15

The combined CH2Cl2 phases were washed sequentially with 200 ml of 9% NaHCO3 solution, 300 ml of 1 N HCl and 300 ml of distilled water each time. Finally, the methylene chloride phase was dried over anhydrous sodium sulfate and concentrated to constant weight on a rotary evaporator (Rotavapor®, Biichi).

20

The yield was 162.9 g (theoretically 146.74 g) of N-nitrate-pivaloyl-S- (N-acetylglycyl) -L-cysteine ethyl ester as a pale yellow oil.

162.9 g of N-nitrate pivaloyl-S- (N-acetylglycyl) -L-cysteine ethyl ester was dissolved in 470 ml of ethyl acetate at room temperature. After stirring for 15 minutes at room temperature, the white precipitate was filtered off. To the clear pale yellow filtrate, 390 ml of n-hexane was slowly added with stirring at room temperature.

Seed crystals were added to this solution and stirred at room temperature overnight. The precipitated crystals were filtered off with suction and washed twice at room temperature with 100 mL each of a mixture of 20 mL of ethyl acetate and 80 mL of n-hexane.

The crystals were dried to constant weight in a vacuum oven at room temperature, vacuum 267 Pa.

7, 111074

The yield was 85.4 g (theoretically 146.74 g) of N-nitrate pivaloyl-S- (N-acetylglycyl) -L-cysteine ethyl ester.

Mp: 71.8 ° C

Example 2 Preparation of N-nitrate pivaloyl-S- (N-acetylalanyl) -L-cysteine ethyl ester 53.8 g (0.41 mol) of N-acetylalanine were suspended in 300 ml of methylene chloride (CH 2 Cl 2) at room temperature and cooled to 10 ° C: C. A solution of 109.8 g (0.373 mol) of N-nitrate-pivaloyl-L-cysteine ethyl ester in 300 ml of CH 2 Cl 2 was added with stirring. The reaction mixture was cooled to 5 ° C with stirring and a solution of 84.6 g (0.41 mol) of dicyclohexylcarbodiimide (DCC) in 200 mL of CH 2 Cl 2 was added dropwise with stirring so that the temperature was between 5 and 10 ° C. After warming to room temperature, stirring was continued for 4 days at room temperature. The DCC urea was filtered off with a suction flask and washed twice with 100 mL of CH 2 Cl 2 each.

The combined methylene chloride phases were washed successively once with 200 mL of 9% NaHCO 3 solution, 300 mL of 1N HCl and 300 mL of distilled water. Finally, the methylene chloride phase was dried over anhydrous sodium sulfate and concentrated to constant weight on a rotary evaporator (Rotavapor®, Btichi).

The yield was 160.5 g (theoretically 151.84 g) of N-nitrate pivaloyl S- (N-acetylalanyl) -L-cysteine ethyl ester as a pale yellow oil.

160.5 g of N-nitrate pivaloyl-S- (N-acetylalanyl) -L-cysteine ethyl ester were dissolved in 345 ml of ethyl acetate at room temperature. After stirring for 15 minutes at room temperature, the insoluble precipitate was filtered off. 345 ml of n-30 hexane was slowly added to the clear pale yellow filtrate with stirring at room temperature.

* * * To this solution, seed crystals were added and stirred at room temperature overnight. The precipitated crystals were filtered off with suction and washed twice at room temperature with 100 mL each of 20 mL of ethyl acetate and 80 mL of n-hex-35.

5 8 111074

The crystals were dried to constant weight in a vacuum oven at room temperature, vacuum 267 Pa.

The yield was 78.2 g (theoretically 151.84 g) of N-nitrate pivaloyl-S- (N-acetylalanyl-5L) -L-cysteine ethyl ester.

Mp: 76.6 ° C

Example 3 Preparation of N-nitrate pivaloyl-S- (N-acetylleucyl) -L-cysteine ethyl ester 10 0.02 mol = 6 g of nitrate pivalic acid cysteine ethyl ester was dissolved in 100 ml of methylene chloride. At 10 ° C and with nitrogen addition, 0.03 mol = 5.19 g N-acetyl leucine and 0.1 g dimethylaminopyridine (DMAP) were added slowly. Next, 0.03 mol = 6.15 g of dicyclohexylcarbodiimide (DCC) dissolved in 80 ml of methylene chloride was added dropwise. Stir overnight at room temperature.

Subsequent treatment:

Filter the precipitate by suction. The solution is extracted successively with equal volumes of 0.1 N HCl solution, saturated NaHCO 3 solution and distilled H 2 O. Next, shark-20 is degassed on a rotary evaporator (Rotavapor®, Buchi). 10 g of an oily residue remain.

Recrystallization: 10 g of oily substance are dissolved gently with warming in 45 ml of ethanol and 25 ml of distilled H 2 O. The substance may crystallize overnight in the refrigerator. The crystals are suction filtered and dried in a vacuum oven.

The mass spectrum supports the structure.

Melting point: 91.4 ° C

30 HPLC analysis: 98.7%

Yield: 5 g = 0.012 mol = 57.4% of theory.

Claims (2)

9 111074 A process for the preparation of the pharmaceutical nitrate alkane carboxylic acid derivatives of the general formula (I) 5 CH 3 O 1 H 2 O 2 N-O-CH 2 -C-C-N-C-C-R (I) CH3 H wherein R is hydroxy, amino or methoxy, ethoxy or propoxy and R1 is a group -XSY wherein X is an alkylene residue of one or two carbon atoms and Y is an N-acetylamino acid residue wherein the amino acid is glycine, alanine or leuc -15in, as well as for the preparation of their physiologically acceptable acid addition salts, characterized in that the compound of general formula II or ΙΓ CH3 OH CH2-SH O 20. II I I / 02N-O-CH2-C-C-N-C-C (II) I I \ ch3 h r Wherein R is as above, is reacted with N-acetylglycine, N-acetylalanine or N-acetylleucine, and thereafter, if desired, converting the resulting compound into its pharmacologically acceptable salt. 35 Process according to claim 1, characterized in that a) N-nitrate pivaloyl-S- (N-acetylglycyl) -L-cysteine ethyl ester, b) N-nitrate pivaloyl S- (N-acetylalanyl) -L-cysteine ethyl ester, or c ) N-nitrate pivaloyl-S- (N-acetylleucyl) -L-cysteine ethyl ester. 40 10 111074