GB2283238A

GB2283238A - Nitric esters of propionic acid derivatives

Info

Publication number: GB2283238A
Application number: GB9320599A
Authority: GB
Inventors: Soldato Piero Del
Original assignee: HCT HEALTH CARE TRADING Ltd
Current assignee: HCT HEALTH CARE TRADING Ltd
Priority date: 1993-10-06
Filing date: 1993-10-06
Publication date: 1995-05-03
Anticipated expiration: 2013-10-06
Also published as: GB2283238B; GB9320599D0; HK1004916A1

Abstract

Compounds of the formula: <IMAGE> where: A and B are hydrogen or optionally substituted alkyl; R is <IMAGE> Y is oxygen, NH or NR1, where R1 is alkyl; and n is 1 - 10, have pharmaceutical uses, e.g. as anti-inflammatory agents.

Description

OBJECT OF THE INVENTION The present invention refers to nitric esters of derivatives of propionic acid, their pharmaceutical utilization and the process for their preparation.

PRIOR ART Some derivatives of propionic acid, such as, for instance, 2-(6-methoxy-2-naphtyl)propionic acid 2-(4isobutylphenyl)propionic acid or alpha-Methyl-4-1(2- oxocyclopentyl) methyl] benzeneacetic acid, have been used for a long time in the pharmaceutical field for their anti-inflammatory activity and have been present for many years on the different world markets. The process for the preparation of 2-(6-methoxy-2naphtyl)propionic acid has been described in the South African Patent N06707,597, in the German Patent NO 1,934,460, corresponding to the US Patent N03,637,767 and also in C.A.71,91162j (1969); HARRISON et al.

J.Med.Chem. 13,203 (1970); the process for the preparation of 2-(4-isobutylphenyl)propionic acid has been described in Patents GB N0971,700, US N03,228,831 and US N03,385,886, and also in T. SHIORI, N. KAWAI, J.Org.

Chem. 43,2936 (1978); J.T. PINHEY, B.A. ROWE, Tetrahedron Letters 21, 965 (1980);while the process for the preparation of alpha-methyl-4-t(2-oxocyclopentyl)met- hyl]benzenacetic acid has been described in the German Patent N02,814,556 and in US Patent N04,161,538.

In the case of 2-(6-methoxy-2-naphtyl)propionic acid, the pharmacological profile is described in ROSZKOWSKI et al. J. Pharmacol. Exp. Ther. 179,114 (1971), while the pharmacological profile of isobutylphenyl)propionic acid is reported in ADAMS et al. Arch. Pharmacodyn. Ther. 178,115 (1969).

The utilization of these derivatives of propionic acid as anti-inflammatory agents involves, as known, extremely severe adverse reactions affecting, for instance, the gastrointestinal system, as well as damages to liver and kidneys. There are many experimental evidences (S. MONCADA, R.M.J. PALMER, E.A. HIGGS, Pharmacological Reviews, 43 (2), 109-142 (1991); T.F. LUSHER, C.M. BOULANGER, Y. DOHI, Z. YANG, Hypertension, 19,117130 (1992)], on which basis the integrity of vasal endothelium is assumed to constitute a basic protection barrier against the onset of pathological processes in different organs and systems.

Such protection barrier, and therefore the integrity of vasal endothelium, is ensured on the physiological plane, by the presence of nitric oxide and prostacyclin.

The treatment with non steroidal drugs having an antiinflammatory activity, such as, for instance, 2-(6 methoxy-2-naphtyl)propionic acid or 2-(4-isobutylphenyl)propionic acid, causes the inhibition of cyclooxygenase, an enzyme which synthesizes the precursor of prostacyclin.

As a consequence, the production of prostacyclin being so inhibited, the tissue reserve of same is markedly depauperated and therefore the integrity of vasal endothelium is compromised.

As said, because of this endothelial damage due to the reduction of prostacyclin, diffuse pathological processes break out which affect the gastrointestinal system, the renal system and the liver.

Furthermore, as known, during inflammatory processes, new enzyme proteins, such as for example, nitric oxide synthetase, are induced; these enzyme proteins are partially responsible for the supporting of the inflammation [T.I.P.S. 14,287(1993)].

OBJECTS OF THE INVENTION Object of the present invention is that of providing a product which, while assuring at least the maintenance of the pharmacological activity which is characteristic of the known anti-inflammatory agents, is capable of eliminating the adverse reactions brought about by the treatment with said agents.

Another object of the present invention is that of realizing a process for the preparation of derivatives of propionic acid having an anti-inflammatory activity and exempt from the adverse reactions that are typical of anti-inflammatory agents.

DESCRIPTION OF THE INVENTION These and still further objects and associated advantages which shall clearly result from the following description, are reached by derivatives of propionic acid which, according to the present invention, have the following general formula:

where: A and B are chosen among hydrogen, linear or branched, substituted or non substituted alkyl chains, while R is chosen among:

Y is chosen among oxygen, NH, NR1, where R1 is a linear or branched alkyl group, and n is comprised between 1 and 10.

In fact, it has been observed that the introduction of a group such as a terminal nitric ester in the derivatives of propionic acid as in (I) permits to mantain the pharmacological activity which is characteristic of anti-inflammatory non steroidal agents, while eliminating the adverse reactions caused by the treatment with such drugs. Furthermore, the introduction of a terminal nitric ester in the derivatives of propionic acid as in (I), permits to potentiate the anti-inflammatory effect compared with the well known non-steroidal antiinflammatory drugs; such increase is made by the terminal nitrio ester group, which can be considered as a source of nitric oxide and which can exert additional anti-inflammatory effects.

It has been also observed that the derivatives (I) are useful in the treatment of different unhealthy conditions, such as, for instance, rheumatic diseases in general, disorders of an immunologic nature, and they can also alleviate moderate-medium painful states of any kind.

Moreover, the derivatives (I) subject matter of this invention, are useful in the treatment of the illnesses of the cardiovascular system, and in particular in the treatment of myocardial and brain ischemiae, as well as in some cases of arterial thrombosis.

Always according to this invention, a nitric ester of a derivative of propionic acid (I) proved to be particularly advantageous, where: hydrogen is chosen as A and B, as R is chosen:

NH is chosen as Y, and n is equal to four, according to the following formula:

A nitric ester of a derivative of propionic acid (I) has also proved to be particularly advantageous according to this invention, where: hydrogen is chosen as A and B, as R is chosen:

oxygen is chosen as Y, an n is equal to four, according to the following formula:

Also the nitric esters of derivatives of 2-(4isobutylphenyl)propionic acid have proved to be particularly advantageous according to this invention, having the following formulae:

Always according to the present invention, nitric esters of derivatives of propionic acid (I) have proved to be particularly advantageous, having the following formulae:

For the preparation of nitric esters of derivatives (I) of propionic acid subject matter of the present invention, a first process has proved to be particularly advantageous which, according to the present invention, includes the following steps: - Preparation of sodium salt of derivatives of propionic acid having the following general formula::

where R is chosen among the following structures:

or preparation of derivatives (VI) of propionic acid functionalized to the carboxylic group as acylic chlorides, anhydrides or the like; - Reaction between the sodium salt of said derivatives (VI) of propionic acid or of said derivatives (VI) of propionic acid functionalized to the carboxylic group, with a composition having the following general formula:

where:: R4 is chosen among chlorine, bromine, NHR with R hydrogen, linear or branched alkyl chain, A and B are chosen among hydrogen, linear or branched, substituted or non substitutes alkyl chains, R3 is chosen among chlorine, bromine and iodine, and n is comprised between 1 and 10, with ensuing production of the relevant monomeric esters or the relevant amides; - Reaction of said monomeric esters or said amides with a nitrating agent such as AgNO3 or the like, with ensuing production of nitric esters of derivatives of propionic acid (I).

A second process has also proved to be particularly advantageous which, always according to the present invention,-includes the following steps: - Preparation of sodium salt of derivatives of propionic acid having the following general formula:

where R is chosen among the following structures:

or preparation of derivatives (VI) of propionic acid functionalized to the carboxylic group, such as acylic chlorides, anhydrides or the like; - Reaction between the sodium salt of said derivatives (VI) of propionic acid or of said derivatives (VI) of propionic ,acid functionalized to the carboxylic group, with a composition having the following general formula::

where; R4 is chosen among chlorine, bromine, NHR with R hydrogen, linear or branched alkyl chains, A and B are chosen among hydrogen, linear or branched, substituted or non substituted alkyl chains, and n is comprised between 1 and 10, with ensuing production of the relevant monomeric esters or the relevant amides; - Reaction of said monomeric esters or said amides with an halogenating composition such as PBr3 or the like, with ensuing prouction of said monomeric esters or said amides characterized by the presence of a terminal halogen group; - Reaction of said monomeric esters or said amides characterized by the presence of a terminal halogen group, with a nitrating agent such as AgNO3 or the like, with ensuing production of nitric esters of derivatives of propionic acid (I).

The solvents which are utilized in the processes subject matter of the present invention are preferably chosen among chloroform, methylene chloride, acetonitrile, dimethylformamide, tetrahydrofuran, 1, 4-dioxane and the like.

Such processes for the preparation of derivatives of propionic acid (I), subject matter of the present invention, consist of a limited number of steps, which permits to obtain in a short time the products which derive from these processes, with satisfactory yields and in high amounts, also on the industrial level. According to the processes subject matter of this invention, the preparation of a nitric ester derived from propionic acid has -proved to be particularly advantageous, having the following formula:

which is prepared as described in the example that is given hereunder as a mere indication and which does not limit in any way the protection scope of the invention.

EXAMPLE 1 a) 0.59 g'of EtONa dissolved in 10 ml of ethyl alcohol were added, by slow dripping, to a solution of 2 g of 2-(6-methoxy-2-naphtyl)propionic acid, dissolved in 20 ml of ethyl alcohol. The reaction mixture was stirred for 5 minutes at room temperature, then the solvent was evaporated at a reduced pressure, obtaining 2.1 g of sodium salt of 2-(6-methoxy-2-naphtyl)propionic acid.

The 2.1 g of sodium salt of 2-(6-methoxy-2-naphtyl) propionic acid so obtained were disperded in 40 ml of dimethylformamide and 1.5 g of l-Br-4-Cl-butane dissol ved in 30 ml of dimethylformamide were added by dripping to this dispersion. The reaction mixture was stirred for 12 hours at room temperature, then diluted with water and extracted with methylene chloride. The organic phase so extracted was anhydrified on sodium sulfate and the solvent was evaporated at a reduced pressure until a dry residue of 2 g was obtained.

The residue was purified by chromatography on silica gel, utilizing an eluting mixture constituted by hexane/ether 7/3 (v/v).

The head fractions were collected, the solvent was evaporated at a reduced pressure and 1 g of 2-(6-methoxy-2-naphtyl)propionate of 4-chlorobutyl (IX) was obtained.

IR(cm1) :C=0,1669.

1H-NMR(300MHz) (CDCl3): 1.6ppm (d,3H); 1.75ppm (m, 4H); 3.45ppm (m, 2H); 3.88ppm (q,lH); 3.91ppm (1,3H); 4.lppm (m, 2H); 7.1-7-7.7ppm (m, aromatics).

Mass spectrometry (i.e.): M+. 320.

b) 0.79 g of AgNO3 dissolved in 1.3 ml of acetonitrile were dripped to 1 g of (IX) obtained as described in a), dissolved in 4,5 ml of acetonitrile. The reaction mixture was stirred for 12 hours at a temperature of 850C and then filtered.

From the resulting solution, the solvent was evaporated at a reduced pressure, and a residue was obtained to which 10 ml of methylene chloride were added. The mix so obtained was filtered once again, the organic phase was washed with water and then anhydrified on sodium sulfate. The solvent was evaporated under reduced pressure and 1.8 g of a dry residue was obtained, which was purified by chromatography on silica gel, utilizing an eluting mixture constituted by hexane/ether 7/3 (v/v). The fractions containing the product were collected, the solvent was evaporated at a reduced pressure and 1.5 g of nitric ester of 2-(6-methoxy-2-naphtyl)propionate of 4-hydroxy-butyl (V) were obtained.

IR(cm1): C=0,1733; ONO2, 1637.

1H-NMR(300MHz) (CDCL3): 1.6ppm (d,3H); 1.65ppm (m, 4H); 3.8ppm (q, lH); 3.9ppm (s,3H); 4.lppm (m, 2H); 4.3ppm (m, 2H); 71-7.7ppm (m, aromatics).

Mass spectometry (i.e.) M±347.

Always according to the processes subject matter of the present invention, also the preparation of å nitric ester derivated from prop ionic acid proved to be particularly advantageous, having the following formula:

which is prepared as described in the following example, that is given hereunder as a mere indication and which does not limit in any way the protection scope of this invention.

EXAMPLE 2 a) 23.9 g of potassium-phtalimide dispersed into 200 ml of anhydrous dimethylformamide were added to a solution of 55.7 g of 1,4-di bromo-butane dissolved in 300 ml of anhydrous dimethylformamide.

The reaction mixture was agitated for 12 hours at room temperature, then diluted with water and extracted with methylene chloride. The methylene chloride was evaporated from the organic phase so obtained at a reduced pressure and then the dimethylformamide was removed by distillation at the pressure of 10 mm Hg.

The residue was regained with water and extracted with methylene chloride.

Tha organic phase so obtained was anhydrified and the solvent was evaporated at a reduced pressure until 14.8 g of l-phtalimide-4-bromo-butane were obtained, which were treated with isopropyl ether and then essiccated.

m.p. = 77"C b) 32 ml of hydriodic acid were cautiously added to 8.25 g of 1-phtalimido-4-bromo-butane; the mixture was then submitted to heating and kept in ebullition for 24 hours.

After cooling, the mixture was diluted with water and after filtration the solvent was evaporated at a reduced pressure, obtaining a residue which, once crystallized by ethyl ether, produced 6 g of 4-iodine-butylammonium iodide.

m.p. = 103"C c) 7 ml of thionyl chloride were cautiously added to a solution of 2.3 g of 2-(6-methoxy-2-naphtyl)propionic acid in 15 ml of anhydrous chloroform. The reaction mixture was stirred for 40 minutes at room temperature and then the solvent was evaporated at a reduced pressure, obtaining 2.23 g of 2-(6-methoxy-2-naphtyl)propionylchloride.

2.3 g od 2-(6-methoxy-2-naphtyl)propionylchloride were dissolved in pyridine and the solution was cooled at the temperature of OOC.

3.27 g of 4-iodobutylammonium iodide were added to this solution and the mixture so obtained was agitated for 1 hour at OOC and then diluted with water and extracted with methylene chloride.

The organic phase so obtained was washed initially with a 10% solution of hydrochloric acid and afterward with a saturated solution of sodium bicarbonate, then the solvent was evaporated at a reduced pressure, obtaining 3.2 g of a dry residue. The residue was purified by chromatography on silica gel, utilizing methylene chloride as eluent.

The intermediate fractions were collected, the solvent was evaporated at a reduced pressure and 1.6 g of 2-(6methoxy-2-naphtyl)-4-iodobutyl propionamide (XX) were obtained.

IR (cm 1): NH, 3294; C=0,1651.

1H-NMR(300MHz) (CDC13): 1.1-1.75 ppm (m, 4H); 1.6ppm (d, 3H); 3.lppm (t, 2H); 3.2ppm (q, 2H); 3.7ppm (q, lH); 3.9ppm (s, 3H); 5.35ppm (m, NH); 7.1-7.75ppm (m, aromatics).

d) A suspension of 1.6 g of 2-(6-methoxy-2-naphtyl)-4iodobutyl propionamide in 20 ml of acetonitrile was heated at a temperature of about 400C and stirred until a solution was obtained to which 1.0 g of AgNO3 were added.

The mixture was stirred for 1 hour at room temperature, then filtered and the solvent was evaporated at a reduced pressure. The residue obtained was regained with methylene choride, the resulting mixture was filtered and the solvent was evaporated at a reduced pressure, and 0,8 g of dry residue were obtained which were purified by chromatography on silica gel, utilizing an eluting mixture constituted by methylene chlo ride/ethyl acetate 9/1 (v/v).

The head fractions were collected, the solvent was evaporated at a reduced pressure and 0-.75 g of nitric ester of 2-(6-methoxy-2-naphtyl)-4-hydroxybutyl propionamide (IV) were obtained.

IR(cm1): C=0,1672; NH, 3294; ONO2, 1637 Mass spectometry (i.e.) M±346.

1H-NMR(80mhz) (CDCl3): 1.3ppm-1.6ppm (m, 4H); 1.7ppm (d, 3H); 3.lppm (q, 2H); 3.7ppm (q, 1H); 3.9ppm (s, 3H); 4.3ppm (m, 2H); 5.6ppm (m, NH); 7.05-7.8ppm (m, aromatics).

Through biological assays the anti-inflammatory and analgesic activity were determined, for instance of nitric esters of derivatives of propionic acid (I) having the following formulae:

The anti-inflammatory activity of said nitric esters of derivatives of prop ionic acid was determined in Wistar rats utilizing the method of carrageenan edema, as reported in C.A. WINTER, E. RISLEY, G.W. NUSS, Proc.

Soc. Exp. Biol. Med. 111,544-547 (1962), while the analgesic activity of said derivatives was determined in Swiss mice as reported by L.C. HENDERSHOT, J. FOR SAITH, J.Pharmacol. Exp. Ter. 125,237-249 (1959).

The anti-inflammatory and analgesic activity of said derivatives resulted to be comparable to 2-(6-methoxy-2-naphtyl)propionic acid taken as a reference.

Then, the acute toxicity of said derivatives (IV) and (V) was evaluated by oral administration of a single dose of each composition (IV) and (V), utilizing groups of 10 Swiss mice for each derivative.

The incidence of lethality and the onset of a toxic symptomatology were reported for an observation period of 14 days.

Even after the administration of a dose of 750 mg/kg of composition (IV) or composition (V) no apparent toxicity simptoms were observed in the treated animals.

Further biological as says were carried out in order to define the pharmaco-toxicological profile of the stu died compounds, in particular of composition (V) compared with 2- (6-methoxy-2-naphtyl) propionic acid taken as reference.

A. PHARMACODYNAMIC ACTIVITY ACUTE MODELS Rat carrageenan paw edema. On the basis of preliminary experiments, the compound (V) and 2-(6-methoxy-2-naphtyl)propionic acid prove to have a comparable efficacy; the effective dose is comprised in the range from 1 to 10 mg/kg p.o.

SUBACUTE MODELS Rat adjuvant arthritis. The animals treated for 19 running days (from the 3rd to the 20th day after the inducing injection) with composition (V) or with 2-(6methoxy-2-naphtyl)propionic acid, both of them at doses of 3 mg/kg p.o., showed a significant and comparable reduction in arthritic symptomatology compared with controls.

B. GASTROINTESTINAL TOLERABILITY Damage to the gastric mucosa of the rat. The compound (V) was studied in comparison with 2-(6-methoxy-2naphtyl)propionic acid taken as reference, both of them at doses comprised between 3 and 30 mg/kg p.o.; the compound (V) proved to be significantly better tolerated than 2- (6-methoxy-2-naphtyl) propionic acid. 2-(6 methoxy-2-naphtyl)propionic acid already at 3 mg/kg caused gastric damages, and such effects resulted to be dose-dependent, while the compound (v) proved to be well tolerated even at doses of 30 mg/kg.

C. GENERAL PHARMACOLOGY A secondary pharmacological evaluation of compound (V) was carried out in comparison with 2-(6-methoxy-2naphtyl)propionic acid. No considerable additional effects with respect to the primary pharmacological activity were observed on central nervous system, on the autonomous system, on the cardiovascular, respiratory and gastrointestinal systems.

D. TOXICOLOGY Acute toxicity in rodents. Preliminary studies were carried out in rodents, utilizing two administration routes. No simptoms of apparent toxicity were observed in animals treated with oral or intraperitoneal doses of 300 mg/kg.

Maximum tolerated dose in non-rodents. Preliminary studies have indicated that compound (V) was very well tolerated in the dog, an animal species which is known to be particularly sensitive to the ulcerogenic activity of anti-inflammatory agents in general. The animals received increasing oral doses of compound (V) up to 30 mg/kg and no apparent symptoms were observed. In compa rison, 2-(6-methoxy-2-naphtyl)propionic acid, administered at doses of 10 mg/kg, caused the death of the animals.

Claims

1. Derivatives of propionic acid characterized in that they have the following general formula:

where: A and B are chosen among hydrogen, linear or branched, substituted or non substituted alkyl chains, R is chosen among:

2. Derivative of propionic acid according to claim 1, characterized in that R is:

A and B are equal to hydrogen, Y is equal to oxygen, and n is equal to four.

3. Derivative of propionic acid according to claim 1, characterized in that R is:

A and B are equal to hydrogen, Y is equal to NH, and n is equal to four.

4. Derivatives of propionic acid according to claim 1, characterized in that R is equal to:

Y is equal to oxygen, A and B are equal to hydrogen, and n is equal to four.

5. Derivative of propionic acid according to claim 1, characterized in that R is equal to:

Y is equal to NH, A and B are equal to hydrogen, and n is equal to four.

6. Derivative of propionic acid, according to claim 1, characterized in that R is equal to

A and B are equal to hydrogen, y is equal to oxygen and n is equal to four.

7. Derivative of propionic acid according to claim 1, characterized in that R is equal to

A and B are equal to hydrogen, y is equal to NH and n is equal to four.

8. Derivatives of propionic acid according to claim 1, characterized in that they are utilizable in the pharmaceutical field as anti-inflammatory agents.

9. Derivatives of propionic acid according to claim 1, characterized in that they are utilizable in the treatment of rheumatic illnesses, in the treatment of disorders of an immunologic nature and of the moderate to medium painful states.

10. Derivatives of propionic acid according to claim 1, characterized in that they are utilizable in the treatment of the diseases of the cardiovascular system, in the treatment of miocardial and brain ischemiae and in cases of arterial thrombosis.

11. Process for the preparation of derivatives of prop ionic acid according to claim 1 and having the following general formula:

where A and B are chosen among hydrogen, linear or branched, substituted or non substituted alkyl chains, R is chosen among:

Y is chosen among oxygen, NH, NR1, where R1 is a linear or branched alkyl group, and n is comprised between 1 and 10, characterized in that it comprises the following steps: - Preparation of sodium salt of derivatives of propionic acid having the following general formula:

where R is chosen among the following structures::

or preparation of derivatives (VI) of propionic acid functionalized to the carboxylic group, such as acylic chlorides, anhydrides or the like; - Reaction between the sodium salt of said derivatives (VI) of propionic acid or of said derivatives (VI) of propionic acid functionalized to the carboxylic group, with a compound having the following general formula:

where:: R4 is chosen among chlorine, bromine, NHR with R hydrogen, linear or branched alkyd chain, A and B are chosen among hydrogen, linear or branched, substituted or non substituted alkyl chains, R3 is chosen among chlorine, bromine and iodine, and n is comprised between 1 and 10, with ensuing production of the relevant monomeric esters or the relevant amides; - Reaction of said monomeric esters or said amides with a nitrating agent such as AgNO3 or the like, with ensuing production of nitric esters of derivatives of propionc acid (I).

12. Process for the preparation of derivatives of propionic acid according to claim 1 and having the following general formula:

where: A and B are chosen among hydrogen, linear or branched, substituted or non substitured alkyl chains, R is chosen among:

Y is chosen among oxygen, NH, NR1, where R1 is a linear or branched alkyl group, and n is comprised between 1 and 10, characterized in that it comprises the following steps: - Preparation of sodium salt of deriyatives of propionic acid having the following general formula:

where R is chosen among the following structures::

or preparation of derivatives (VI) of propionic acid functionalized to the carboxylic group, such as acylic chorides, anhydrides or the like; - Reaction between the sodium salt of said derivatives (VI) of propionic acid or of said derivatives (VI) of propionic acid functionalized to the carboxylic group, with a composition having the following general formula:

where:: R4 is chosen among chlorine, bromine, NHR with R hydrogen, linear or branched alkyl chain, A and B are chosen among hydrogen, linear or branched, substituted or non substituted alkyl chains, and n is comprised between 1 and 10, with ensuing production of the relevant monomeric esters or the relevant amides; - Reaction of said monomeric esters or said amides with an halogenating compound such as PBr3 or the like, with ensuing production of said monomeric esters or said amides, characterized by the presence of a terminal halogen group; - Reaction of said monomeric esters or of said amides, characterized by the presence of a terminal halogen group with a nitrating agent such as AgNo3 or the like, with ensuing production of nitric esters of derivatives of propionic acid (I).

13. A derivative of propionic acid as claimed in Claim 1 substantially as herein described with reference to the Example.

14. A process as claimed in Claim 11 substantially as herein described with reference to the Example.