GB2053912A - Acylaminobenzoic acid derivatives - Google Patents

Abstract

Acylaminobenzoic acid derivatives of the formula:- <IMAGE> [wherein R<1> represents a hydrogen atom, an alkyl group containing from 1 to 6 carbon atoms (which may be substituted by one or more than one of the same type of substituent selected from the hydroxy group, alkenyl groups containing from 2 to 5 carbon atoms and alkanoyloxy groups containing from 2 to 7 carbon atoms), R<o> represents a hydrogen atom or a group of the formula -COR<2>, and R<2> represents an alkyl group containing from 2 to 20 carbon atoms], which are new compounds, possess pharmacological properties and are useful inter alia in the prevention or treatment of atherosclerosis.

Description

SPECIFICATION Acyla minobenzoic acid derivatives This invention relates to new therapeuticaliy useful acylaminobenzoic acid derivatives, to processes for preparing them, and to pharmaceutical compositions containing them.

The acylaminobenzoic acid derivates of the present invention are those compounds of the general formula:

wherein R7 represents a hydrogen atom or a straight- or branched-chain alkyl group containing from 1 to 6 carbon atoms (which may be substituted by one or more than one of the same type of substituents selected from the hydroxy group, alkenyl groups containing from 2 to 5 carbon atoms and alkanoyloxy groups containing from 2 to 7 carbon atoms), preferably a methyl group, RO represents a hydrogen atom or a group of the formula --COR2, and R2 represents a straight- or branched-chain alkyl group, preferably a straight-chain alkyl group, containing from 2 to 20 (preferably from 7 to 16) carbon atoms, and pharmaceutically acceptable salts thereof.When R1 is a substituted alkyl group it may be, for example, a 2,3-dihydroxyprop-l -yl, allyl or pivaloyloxymethyl group.

It will be understood by those skilled in the art that in certain cases the substituents R1 and R2 contribute to optical isomerism. Ail such forms are embraced by the present invention.

By the term "pharmaceutically acceptable sait" is meant a salt formed, when RO represents a hydrogen atom, by reaction with an acid or, when R1 represents a hydrogen atom, by reaction with a base, so that the anion (in the case of an acid addition salt) or the cation (in the case of salt formed by a compound of general formula I wherein R1 represents a hydrogen atom) is relatively innocuous to the animal organism when used in therapeutic doses so that the beneficial pharmacological properties of the parent compound of general formula I are not vitiated by side-effects ascribable to the said anion or cation.

Suitable acid addition salts of those compounds of general formula I wherein RO represents a hydrogen atom include salts derived from inorganic acids, for example hydrochlorides, hydrobromides, phosphates, sulphates and nitrates, and organic acids, for example methanesulphonates, 2hydroxyethanesulphonates, oxalates, lactates, tartrates, acetates, salicylates, citrates propionates, succinates, fu ma rates, maleates, methylene-bis-P-hydroxynaphthoates, gentisates and didi-ptoluoyltartrates.

Suitable salts formed by compounds of general formula I wherein R1 represents a hydrogen atom include the alkali metal (e.g. sodium and potassium) alkaline earth metal (e.g. calcium and magnesium) and ammonium salts, and salts of amines known in the art to be pharmaceutically acceptable, e.g.

ethylenediamine, choline, diethanolamine, triethanolamine, octadecylamine, diethylamine, triethylamine, 2-amino-2-(hydroxymethyl)propane-1 ,3-diol and 1 -(3,4-dihydroxyphenyl)-2-isopropylaminoethanol.

It is to be understood that, where in this specification reference is made to compounds of general formula I, it is intended to refer to their pharmaceutically acceptable salts, where the context so permits.

The compounds of general formula I possess useful pharmacological properties. For example, they reduce the proliferation of arterial smooth muscle cells which is a major feature of atheromatous plaques. Furthermore, they inhibit the accumulation of cholesteryl ester and the incorporation of cholesteryl oleate in total cholesteryl ester and other complex lipids characteristic of the enzyme fatty acyl CoA:cholesterol acyl transferase. The stimulation of this enzyme in the presence of hyperlipaemic plasma occurs in the development of atheromatous lesions. The compounds of general formula I also suppress lymphocyte transformation as do anti-rheumatic drugs.Thus they are of utility in the prevention or treatment of atherosclerosis, and of associated conditions such as angina, myocardial infarction, cerebral vascular occlusion, arterial aneurism and peripheral vascular disease; as well as arthritis, immunological disease, cancer and graft rejection.

Compounds of general formula I which are of particular interest include the following compounds, and when appropriate, their optically active forms and their salts:methyl 4-amino-3-(n-hexadecanamido)benzoate A methyl 4-amino-3-(n-dodecanamido)benzoate B methyl 4-amino-3-(n-tetradecanamido)benzoate C methyl 4-amino-3-(n-tridecanamido)benzoate D 3,4-bis(n-hexadecanamido)benzoic acid E methyl 3,4-bis(n-hexadeca na m ido)benzoate F methyl 3,4-bis(n-undecanamido)benzoate G methyl 4-amino-3-(n-decanamido)benzoate H methyl 3,4-bis(n-octanamido)benzoate 3,4-bis(n-pentadecanamido)benzoic acid J methyl 3,4-bis(n-nonanamido)benzoate K 3,4-bis(n-heptadecanamido)benzoic acid L 3,4-bis(n-heneicosanamido)benzoic acid M 3,4-bis(n-eicosanamido)benzoic acid N 4-amino-3-(n-nonadecanamido)benzoic acid 0 (BS)(BS)-3,4-bis(2-methyltetradecanamido)-benzoic acid P 4-amino-3-(2-hexyloctanamido)benzoic acid Q (BS)-4-amino-3-(2-ethyldodecanamido)benzoic acid R (RS)-4-amino-3-(2-butyidecanamido)benzoic acid S 2,3-bis(n-tetradecanamido)benzoic acid T3-amino-4-(n-hexadecanamido)benzoic acid U 4-amino-3-(n-octanamido)benzoic acid V 4-amino-3-(n-dodecanamido)benzoic acid W 4-amino-3-(n-octadecanamido)benzoic acid X methyl 4-amino-3-(n-octanamido)benzoate Y methyl 3,4-bis(n-dodecanamido)benzoate Z methyl 3 A-bis(n-trideca na mido)benzoate AA methyl 3,4-bis(n-tetradecanamido)benzoate BB methyl 3,4-bis(n-octadecanamido)benzoate CC methyl 3-amino-4-(n-octanamido)benzoate DD 3-amino-4-(n-octanamido)benzoic acid EE 3-amino-4-(n-dodecanamido)benzoic acid FF methyl 3,4-bis(n-decanamido)benzoate GG 3,4-bis(n-dodecanamido)benzoic acid HH 3,4-bis(n-octanamido)benzoic acid II 3,4-bis(n-tetradecanamido)benzoic acid JJ methyl 3-amino-4-(n-dodecanamido)benzoate KK methyl 3-amino-4-(n-hexadecanamido)benzoate LL methyl 3-amino-4-(n-decanamido)benzoate MM 4-amino-3-(n-hexa-decanamido)benzoic acid NN 3,4-bis(n-decanamido)benzoic acid 00 3,4-bis(n-tridecanamido)benzoic acid PP 3,4-bis(n-octadecanamido)benzoic acid QQ 2,3-bis(n-hexadecanamido)benzoic acid and BB methyl 4-amino-3-(n-heptanamido)benzoate SS The letters A to SS are assigned to the compounds for easy reference later in the specification, for example in the Tables.

The properties of the compounds of general formula I were demonstrated in the following tests: Aortic smooth muscle cell proliferation inhibiting activity Smooth muscle cells were grown in culture from explants of pig thoracic aorta, using Dulbecco's Modified Eagles (DME) Medium containing 20% foetal calf serum (FCS) and antibiotics. The cells were incubated at 370C in an atmosphere of 95% air and 5% carbon dioxide. At confluency the cells were routinely subcultured by trypsinising and replating at approximately one third of their confluent density in DME Medium containing 10% FCS and antibiotics.

The smooth muscle cells were plated out at densities of 100,000-200,000 cells per 35 x 10 mm Falcon dish in 2 ml DME Medium containing 10% FCS and antibiotics. After 24 hours, when the cells had attached to the dishes, the medium was replaced with 2 ml DME Medium containing 1% FCS and antibiotics. The cultures were incubated for a further three days to allow the cells to become quiescent (i.e. no longer undergoing cell division). The medium was then replaced by 2 ml control or test medium. The test medium consisted of DME Medium (containing 10% FCS and antibiotics) and the compound to be tested at a concentration of 5 Mg/ml medium. The compounds were pre-dissolved in acetone such that the final concentration of acetone in the medium was 0.2% (v/v). The control medium consisted of DME Medium (containing 10% FCS and antibiotics) and acetone at 0.2% (v/v) concentration. After three days incubation in test or control medium, the medium was replaced with fresh test or control medium and the cells incubated for a further three or four days. At the end of the six or seven day incubation period cell numbers were determined by trypsinising the cells and counting the cell suspension in a Coulter counter.

All results in Table I hereinafter represent the mean value for four dishes of cells. Percentage inhibition of proliferation was calculated using the following formula: Percentage inhibition of proliferation

= 100 - T--s x 100 C - S Where S = Mean cell number per dish at start of experiment (upon addition of control or test medium).

T = Mean cell number per dish in test cultures at completion of experiment.

C = Mean cell number per dish in control cultures at completion of experiment.

TABLE I

Compound % inhibition Y 59, 76, 84, 56, 32, 40, 41, 55 B 51, 52 D 61, 61 C 54, 48 A 71, 76, 47, 40 KK 24, 47 I I Aortic smooth muscle cell cholesteryl ester accumulation inhibiting activity Aortic smooth muscle cells as hereinbefore described at subculture No. 8 were grown to confluence in Dulbecco's Modified Eagle's (DME) Medium containing 10% foetal calf serum (FSC) and antibiotics.

Four replicate dishes of smooth muscle cells ere incubated for 24 hours in DME medium containing 10% v/v hyperlipaemic rabbit serum, 3H-oleate complexed with defatted bovine serum albumin (molar ratio of free fatty acid (FFA): albumin = 0.862; concentration of oleate in medium 0.155 mM), antibiotics (penicillin G 100 I.U./ml, streptomycin 100 yg/ml and kanamycin 100 ,ug/ml) and the test compound at a concentration of 100 ssg/ml medium. Control dishes without test compound and control dishes with 10% v/v FCS in place of hyperlipaemic rabbit serum were also incubated.

The sera were heat-inactivated before use and contained 933 mg/dl or 26 mg/dl of total cholesterol respectively.

After incubation the cells were washed with Hanks solution, trypsinised and centrifuged and the pellet was sonicated in 0.27 mM EDTA. Cellular concentrations of free and esterified cholesterol and the incorporation of 3H-labelled cholesteryl oleate in total cholesteryl ester and other complex lipids were determined, with comparison with the controls.

All results in Tables II and Ill hereafter represent the mean value for four dishes of cells.

TABLE II

% reduction in concentration compared with control with hyperlipaemic serum Free Cholesteryl Compound Solvent cholesterol ester Y ethanol 16.2 31 A ethanol 32 27 TABLE Ill

% reduction of FFA incorporation compared with control of same solvent and serum Cholesteryl Total Compound Phospholipid Triglycerides ester lipid Y 13.1 77,3 55,7 45.2 A 11.5 73.9 52.5 53.9 Mitogen-stimulated lymph node cell lymphocyte transformation inhibiting activity in Guinea Pigs.

Guinea pigs were sensitised to Mycobacterium tuberculosum by footpad injections of Freund's Complete Adjuvant (FCA) (0.05 ml; 0.5 mglml of 50% v/v FCA solution in sterile physiological saline).

After 14 days lymph node cells were obtained and suspended in Eagles Minimal Essential (EMI) Medium, containing 10% foetal calf serum (FCS) and buffered with Earle's salts, at a concentration of 2.5 x 106 cells/ml.

For 24 hours, 0.1 ml of cell suspension was incubated at 370C in an atmosphere of 95% air and 5% carbon dioxide in the presence of 0.1 5 ml of mitogen or mitogen and the compound to b tested in EME Medium (containing 10% FCS and buffered with Earle's salts).

Eighteen hours before harvesting, 3H-thymidine ( 1 of or 100 ,mCi/ml solution in 09% sterile saline) was added.

As an index of DNA synthesis, the level of 3H-thymidine incorporation by the cells was measured with comparison with the mitogen control.

The results are given hereafter in Table IV.

TABLE IV

% inhibition of 3H-thymidine Dose in incorporation into cell DNA incubation compared with mitogen control medium Compound gg/ml (i) (ii) (iii) v 3 5 17 14 10 60 59 61 30 94 97 96 H 3 21 10 76 30 90 B 3 27 10- 46 30 71 D 3 35 10 51 30 76 C 3 12 10 37 30 62 A 3 4 10 10 30 15 The utility of the compounds is enhanced by the fact that they are of only very low toxicity, as demonstrated in the following test: Oral Toxicity in Mice Groups of mice were dosed orally with graded doses of the test compound (in a 0.5% w/v aqueous suspension of tragacanth mucilage) and observed for 3 days thereafter. The percentages of animals which died during that period at each dose level were used to construct a graph, from which the LD50, that is to say the dose in mg/kg animal body weight, necessary to kill 50% of the mice, was calculated.

Compounds of general formula I specified in the list above were tested and the LDso of each compound was greater than 1000 mg/kg animal body weight.

Preferred compounds of the invention are those hereinbefore identified by the letters Y, A, B, D and C.

The compounds of general formula I can be prepared by application or adaptation of known methods (i.e. methods heretofore used or described in the chemical literature), for example end hereinafter identified.

(A) According to a feature of the present invention, the compounds of general formula I, wherein RO represents a hydrogen atom, are prepared by the reduction of a compound of the general formula:

(wherein R1 and R2 are as hereinbefore defined) by known methods for the reduction of a nitro group to a primary amino group, for example by catalytic hydrogenation, preferably using palladium on charcoal as catalyst.

(B) According to another feature of the present invention, the compounds of general formula I, wherein RO represents a group of the formula --COR2 (R2 being as hereinbrfore defined), or the substituent group -NH-COB2 (R2 being as hereinbefore defined is meta to the substitutent group -COOB1 (R1 being as hereinbefore defined) and R" represents a hydrogen atom, are prepared by the reaction of a compound of the general formula:

(wherein R1 is as hereinbefore defined) with an acylating agent of the general formula: R2COX1 IV wherein R2 is as hereinbefore defined, and X1 represents a halogen (preferably chlorine) atom or a hydroxy group.

Particularly suitable conditions are as follows:- (i) Compounds of general formula I, wherein RO represents a group of the formula --COR2 (wherein R2 is as hereinbefore defined), are prepared by the reaction of a compound of general formula Ill (wherein R' is as hereinbefore defined) with an acyl halide of general formula IV (wherein R2 is as hereinbefore defined, and X1 represents a halogen, preferably chlorine, atom) in an inert organic solvent, for example dichloromethane or dimethylformamide, preferably under anhydrous conditions and preferably in the presence of an acid binding agent, for example a trialkylamine, (e.g. triethylamine), or an alkali metal carbonate or bicarbonate (e.g. anhydrous sodium or potassium carbonate), at a temperature which may be greater than ambient, for example at between 100 and 500C.

(ii) Compounds of general formula I in which the substituent group -NH-COB2 (R2 being as hereinbefore defined) is meta to the substituent group -COOB1 (R1 being as hereinbefore defined) and RO represents a hydrogen atom, are prepared by the reaction of a compound of general formula III (especially those wherein R1 represents a straight- or branched-chain alkyl group containing from 1 to 6 carbon atoms) with an acyl halide of general formula IV (wherein R2 is as hereinbefore defined and X' represents a halogen, preferably chlorine, atom), under conditions similar to those described hereinbefore under (i) but using a lesser quantity of the acyl halide and controlling the temperature, preferably at between OOC and room temperature.

(C) According to a further feature of the present invention, the compounds of general formula I, wherein RO represents a group of the formula --COR2 (R2 being as hereinbefore defined), are prepared from a corresponding compound of general formula I (wherein RO represents a hydrogen atom) by reaction with a compound of general formula IV, according to known methods.

Compounds of general formula II may be prepared by the reaction of a compound of the general formula

(wherein R1 is as hereinbefore defined) with a compound of general formula IV in a similar manner to that hereinbefore described in method B(i).

The compounds of general formula V can be prepared by known methods.

(D) According to a further feature of the present invention, the compounds of general formula I, wherein R1 represents a straight- or branched-chain alkyl group containing from 1 to 6 carbon atoms (which may be substituted by one or more than one of the same type of substituent selected from the hydroxy group, alkenyl groups containing from 2 to 5 carbon atoms or alkanoyloxy groups containing from 2 to 7 carbon atoms), are prepared by esterification of a corresponding compound of general formula I wherein R1 represents a hydrogen atom by the application or adaptation of known methods, for example by reaction with the corresponding diazoalkane in the presence of an inert organic solvent.

(E) According to yet a further feature of the present invention, the compounds of general formula I, wherein R1 represents a hydrogen atom, are prepared by alkaline hydrolysis of a corresponding ester of general formula I wherein R1 represents a straight- or branched-chain alkyl group containing from 1 to 6 carbon atoms (which may be substituted by one or more than one of the same type of substituent selected from the hydroxy group, alkenyl groups containing from 2 to 5 carbon atoms or alkanoyloxy groups containing from 2 to 7 carbon atoms), for example, by treatment with an alkali metal hydroxide in an aqueous organic solvent system and at an elevated temperature.

(F) According to a further feature of the present invention, compounds of general formula I, wherein R1 represents a hydrogen atom and/or RO represents a hydrogen atom, are converted to their pharmaceutically acceptable salts, and vica versa, by the application or adaptation of known methods.

As well as being useful in itself, this procedure is useful for the purification of compounds of general formula I and their salts by taking advantage of differences in solubility in water and various organic solvents of the compounds and their salts and of any impurities present, by means of known methods such as crystallisation.

(i) Compounds of general formula I wherein R1 represents a hydrogen atom (RO and R2 being as hereinbefore defined) may be converted to their salts of pharmaceutically acceptable bases, for example, by reaction with the appropriate base, for example the appropriate amine or a compound of the general formula: M1oR3 VI (wherein M1 represents an alkali metal, e.g. sodium or potassium, atom and R3 represents an alkyl group containing up to 4 carbon atoms, e.g. methyl or ethyl, or a hydrogen atom) in a suitable solvent, e.g. methanol or ethanol, or a mixture of water and acetone, followed if necessary by evaporation of parts or all of the solvent, and collection of the solid salt.

These salts may be re-converted to the parent compounds of general formula 1, for example by reaction with a suitable acid, e.g. glacial acetic acid, in solution in a suitable solvent, e.g. water or ethanol, followed if necessary by evaporation of part or all of the solvent, and collection of the solid compound of general formula I.

(i) Compounds of general formula I wherein RO represents a hydrogen atom may be converted to their pharmaceutically acceptable acid addition salts, for example, by reaction with the appropriate acid in solution or suspension in a suitable solvent, e.g. acetone, methanol or ethanol, followed if necessary by evaporation of part or all of the solvent, and collection of the solid salt.

The acid addition salts may be re-converted to the parent compounds of general formula I, for example by reaction with aqueous ammonia in the presence of a suitable solvent, e.g. ethanol, followed by treatment with a weak acid, for example glacial acetic acid.

The compounds of general formula I are also of use as starting materials for the preparation of therapeutically useful benzimidazole derivatives of the general formula:

(wherein R1 is as hereinbefore defined, and R2 represents a straight- or branched-chain alkyl group containing from 7 to 20 carbon atoms), the group B1OOC being attached to the 4 or 5-position of the benzimidazole ring system, into which they may be converted by the application of known methods of cyclisation.

For example, (i) when RO in general formula I is a group of the formula -COB2 (R2 being as hereinbefore defined), cyclisation to form a benzimidazole derivative of general formula VII can be effected at an elevated temperature, for example between 600 and 1 000C, by reaction with an inorganic acid, for example hydrochloric acid, in the presence of water and in an organic solvent, for example an alcohol such as methanol or ethanol, or a ketone such as acetone or methyl ethyl ketone, or (ii) when RO in general formula I is a hydrogen atom, cyclisation can be effected either under conditions similar to those described hereinbefore under (i) or, alternatively, by reaction with an organic acid (e.g.

p-toluenesulphonic acid) in water or an organic solvent (e.g. toluene), preferably at an elevated temperature, for example between 60 and 1 00 C, or (iii) cyclisation can be effected in the absence of solvent and at elevated temperatures (for example at between 1 500 and 2500C, or in the presence of water and an inorganic acid (for example hydrochloric acid) and in a suitable solvent, for example diglyme.

It will be understood by those skilled in the art that in the performance of the processes above and of the present invention it may be desirable to introduce chemical protecting groups into the reactants in order to avoid secondary reactions taking place, for example in the method of preparation of benzomidazoles hereinbefore described hydroxy groups in the substituent R' depicted in general formula I may have been converted into benzyloxy groups before reaction as described with subsequent removal of the benzyl group.

The benzimidazole derivatives of general formula VII are of utility in the prevention or treatment of diabetes mellitus, hyperlopoproteinaemic states, of atherosclerosic, and of associated conditions such as angina, myocardial infarcdon, cerebral vascular occlusion, arterial aneurism, peripheral vascular diease, recurrent pancreatitis and xanthomas; as well as arthritis, immunological disease, cancer and graft rejection.

The following Examples illustrate the preparation of the compounds of the present invention.

EXAMPLE 1 Compound Methyl 4-amino-3-(n-hexadecanamido)benzoate was prepared by either of the following methods: (i) A stirred solution of methyl 3,4-diaminobenzoate (35 g) in dry dimethylformamide (1200 ml), containing anhydrous sodium carbonate (11.8 g), was treated dropwise with n-hexadecanoyl chloride (58 g) during one hour. The rate of addition of the n-hexadecanoyl chloride was such as to allow the temperature of the reaction mixture to rise from an initial value of 1 00C to room temperature. The mixture was then stirred at room temperature for a further period of 3 hours and was then poured into water (5 litres). The resulting solid was collected and was boiled in acetone (1000 ml) and the boiling mixture was then filtered.The filtrate was cooled to OOC and the resulting buff solid was filtered off, to give methyl 4-amino-3-(n-hexadecanamido)benzoate (48.2 g), m.p. 1120--1140C.

(ii) A stirring solution of methyl 3,4-diaminobenzoate (16.6 g) in dry dichloromethane (270 ml), containing triethylamine (10.3 g), was treated dropwise with a solution of n-hexadecanoyl chloride (27.5 g) in dry dichoromethane (30 ml) during 45 minutes. The temperature during the addition was maintained between 1 60 and 200 C. The mixture was stirred for a further period of 2 hours. The resulting solid was then collected and boiled in a mixture of acetone (1000 ml) and methanol (1 50 ml) and the insoluble material was removed by filtration. The filtrate was cooled to 250C and treated with water (800 ml) to give methyl 4-amino-3-(n-hexadecanamido)benzoate in the form of a buff solid, m.p.

1120--1140C.

EXAMPLE 2 Compound B A solution of methyl 3,4-diaminobenzoate (25.0 g) in dry dimethylformamide (1120 ml), containing anhydrous sodium carbonate (7.7 g), was treated with n-dodecanoyl chloride (30.5 g)in a manner similar to that hereinbefore described in Example 1 (i) to give crude methyl 4-amino-3-(ndodecanamido)benzoate (41 g) in the form of a buff solid.

EXAMPLE 3 Compound C A stirred solution of methyl 3,4-diaminobenzoate (25.0 g) in dry dichloromethane (500 ml), containing triethylamine (15.5 g), was treated dropwise with a solution of n-tetradecanoyl chloride (37.12 g) in dry dichloromethane (50 ml) in a manner similar to that described hereinbefore in Example 1 (ii) to give a crude methyl 4-amino-3-(n-tetradecanamido)benzoate (40 g) in the form of a buff solid.

EXAMPLE 4 Compound A solution of methyl 3,4-diaminobenzoate (17.8 g) in dichloromethane (350 ml) containing triethylamine (10.8 g) was treated with n-tridecanoyl chloride (25 g) in a manner similar to that described hereinbefore in Example 1 (ii) to give crude methyl 4-amino-3-(n-tridecanamido)benzoate (40 9).

EXAMPLE 5 Compound E A solution of 3,4-diaminobenzoic acid (7.5 g) in dichloromethane (100 ml) containing triethylamine (1 5 g) was treated with n-hexadecanoyl chloride (27.5 g) in a manner similar to that described hereinbefore in Example 1 (ii). A solid was collected and was recrystallised from glacial acetic acid and was then recrystallised from methyl ethyl ketone (with filtration of the hot solution) to give 3,4bis(n-hexadecanamido)benzoic acid (20 g) in the form of a buff solid, m.p. 1 980--2020C.

EXAMPLE 6 Compound F A solution of methyl 3,4-diaminobenzoate (5.0 g) in dichloromethane (50 ml), containing triethylamine (6.2 g), was treated with n-hexadecanoyl chloride (1 6.5 g) in a manner similar to that described hereinbefore in Example 1 (ii) (the temperature of the reaction mixture during the addition being allowed to rise from 200 to 300 C). A solid was collected and recrystallized from chloroform to give methyl 3,4-bis(n-hexadecanamido)-benzoate (14.9 g) in the form of a white solid, m.p.

1290--1320C.

EXAMPLE 7 Compound G A solution of methyl 3,4-diaminobenzoate (17.9 g) in dichloromethane (300 ml) containing triethylamine (21.8 g) was treated with n-undecanoyl chloride (44.3 g) in an manner similar to that described hereinbefore in Example 6. A solid was collected and recrystallised twice from ethanol (with filtration of the hot solution) to give methyl 3,4-bis(n-undecanamido)benzoate (40.2 g) in the form of a white solid, m.p. 1390--1410C.

EXAMPLE 8 Compound H A stirred solution of methyl 3,4-diaminobenzoate (16.6 g) in dry dimethylformamide (600 ml) containing anhydrous sodium carbonate (5.3 g) was treated dropwise with n-decanoyl chloride (19.1 g) in a manner similar to that described hereinbefore in Example 1 (i) to give methyl 4-amino-3-(ndecanamido)-benzoate (18.8 g) in the form of a buff solid, m.p. 96 0--980C.

EXAMPLE 9 Compoundl A solution of methyl 3,4-diaminobenzoate (41.2 g) in dichloromethane (412 ml) containing triethylamine (51.0 g) was treated with a solution of n-octanoyl chloride (80.6 g) in dichloromethane (330 ml) in a manner similar to that described hereinbefore in Example 6, recrystallising from methanol (with treatment with charcoal), to give methyl 3,4-bis(n-octanamido)benzoate (81.8 g) in the form of white solid, m.p. 1380--1400C.

EXAMPLE 10 Compounds A solution of 3,4-diaminobenzoic acid (13.85 g) in dimethylformamide (180 ml) containing triethylamine (27.6 g) was treated with n-pentadecanoyl chloride (47.4 g) in a manner similar to that described hereinbefore in Example 1(i). The resulting solid was collected and recrystallised from methyl ethyl ketone (with treatment with charcoal and with filtration of the hot solution) to give 3,4-bis(npentadecanamido)benzoic acid (49.3 g) m.p. 1780--1800C.

EXAMPLE 11 Compound E A stirred solution of 3,4-diaminobenzoic acid (152 g) in dimethylformamide (1500 ml), containing triethylamine (303 g), was treated dropwise with n-hexadecanoyl chloride (549.0 g) during 1.5 hours.

The rate of addition of n-hexadecanoyl chloride was such as to allow the temperature of the reaction mixture to rise from room temperature to 350--400C. The mixture was then stirred at room temperature for a further period of 2 hours and was then poured into hot water (10 litres kept at 700C), containing concentrated hydrochloric acid (150 ml of strength 36.5% w/v). The resulting solid was collected and gave crude 3,4-bis(N-hexadecanamido)benzoic acid (600 g) in the form of a buff solid, m.p. 1800-1900C.

EXAMPLE 12 Compound A stirred solution of methyl 3,4-diaminobenzoate (20 g) in dry dichloromethane (250 ml), containing triethylamine (24.2 g), was treated dropwise with a solution of nonanoyl chloride (44.12 g) in dry dichloromethane (50 ml) in a manner similar to that described hereinbefore in Example 1 (ii) to give a pink solid, which was recrystallised from methanol, with treatment with charcoal, to give methyl 3,4-bis(n-nonanamido)benzoate (30.3 g) in the form of a white solid, m.p. 1 42 0--1 45 OC.

EXAMPLE 13 Compound A stirred solution of 3,4-diaminobenzoic acid (45.6 g) in dimethylformamide (400 ml), containing triethylamine (75.8 g), was treated dropwise with n-heptadecanoyl chloride (130 g) in a manner similar to that described hereinbefore in Example 11 to give crude 3,4-bis(n-heptadecanamido)benzoic acid (140 g) in the form of a pink solid.

EXAMPLE 14 Compounds A stirred solution of 3,4-diaminobenzoic acid (21.9 g) in dimethylformamide (175 ml), containing triethylamine (43.6 g), was treated dropwise with n-heneicosanoyl chloride (99.2 g) in a manner similar to that described hereinbefore in Example 11 to give crude 3,4-bis(n-heneicosanamido)benzoic acid (126.5 g) in the form of a light brown solid.

EXAMPLE 1 5 Compound N A stirred solution of 3,4-diaminobenzoic acid (18.3 g) in dimethylformamide (200 ml), containing triethylamine (36.5 g), was treated dropwise with n-eicosanoyl chloride (79.4 g) in a similar manner to that described hereinbefore in Example 11 to give crude 3,4-bis(n-eicosanamido)benzoic acid (93 g) in the form of a pale brown solid, m.p. 1 60C1 700C.

EXAMPLE 1 6 Compound O A stirred solution of 3,4-diaminobenzoic acid (38 g) in dimethylformamide (500 ml), containing triethylamine (50.5 g), was treated dropwise with n-nonadecanoyl chloride (79.1 g) in a similar manner to that described hereinbefore in Example 11 to give an orange solution, which was poured into water (3000 ml), containing concentrated hydrochloric acid (100 ml, of strength 36.5% w/v). The solid was collected, washed with water (2 x 100 ml) and then dried to give crude 4-amino-3-(n nonadecanamido)benzoic acid (107 g), m.p. 10301 130C.

EXAMPLE 17 Compound P A stirred solution of 3,4-diaminobenzoic acid (17.5 g) in dimethylformamide (140 ml), containing triethylamine (34.8 g), was treated dropwise with pentadecan-2-oyl chloride (59.7 g) in a similar manner to that described hereinbefore in Example II to give crude (RS)(RS)-3,4-bis(2 methyltetradecanamido)-benzoic acid (68 g).

EXAMPLE 18 Compound Q A stirred solution of 3,4-diaminobenzoic acid (20.7 g) in dimethylformamide (165 ml), containing triethylamine (56.5 ml), was treated dropwise with 2-hexyloctanoyl chloride (67 g) in a similar manner to that described hereinbefore in Example 11. The waxy solid was collected and dissolved in diethyl ether (500 ml) and the ether solution was dried and evaporated to give a red brown oil. This oil was extracted with hot methanol, using a continuous extraction apparatus, for 5 hours. The methanol solution was evaporated on a rotary evaporator to give a brown solid, which was recrystallised from acetone to give 4-amino-3-(2-hexyloctanamido)benzoic acid (1 5.2 g) in the form of a white solid, m.p.

2190--2210C.

EXAMPLE 1 9 Compound A stirred solution of 3,4-diaminobenzoic acid (22.8 g) in dimethylformamide (200 ml), containing triethylamine (22.7 g), was treated dropwise with 2-ethyldodecanoyl chloride (37 g) in a similar manner to that described hereinbefore in Example 11. After working up the reaction product as herebefore described in Example 18, a solid was obtained, which was recrystallised from ethyl acetate with treatment with charcoal to give (RS)-4-amino-3-(2-ethyidodecanamido)benzoic acid (22.2 g) in the form of a white solid, m.p. 1880--191 OC.

EXAMPLE 20 Compound S A stirred solution of 3,4-diaminobenzoic acid (15.8 g) in dimethylformamide (130 ml), containing triethylamine (43.4 g), was treated dropwise with 2-butyldecanoyl chloride (51.4 g) in a similar manner to that described hereinbefore in Example 11. After working up the reaction product as described hereinbefore in Example 18, (RS)-4-amino-3-(2-butyidecanamido)-benzoic acid (9.8 g) was obtained in the form of a white solid, m.p. 1 7801 82cC.

EXAMPLE 21 Compound A solution of 2,3-diaminobenzoic acid (20 g)) in dimethylformamide (200 ml), containing triethylamine (39.9 g), was treated with n-tetradecanoyl chloride (65.0 g). The rate of addition of the ntetradecanoyl chloride was such as to allow the temperature of the reaction mixture to rise from room temperature to 45050CC. The mixture was then stirred for a further 2 hours and allowed to stand at room temperature overnight. Methanol (20 ml) was added to the mixture, and the resulting mixture was stirred for 20 minutes and afterwards treated with concentrated hydrochloric acid (strength 36.5% w/v) until the pH was 2.The resultant mixture was poured into water (1000 ml) and the black solid was collected, washed with water (2 x 500 ml) and then with hot light petroleum (b.p. 600--800C; 500 ml), and was finally recrystallised from ethanol, with treatment with charcoal, to give 2,3-bis(ntetradecanamido)benzoic acid (17.7 g) in the form of a buff solid, m.p. 1500--1580C.

EXAMPLE 22 Compound U 3-Nitro-4-(n-hexadecanamido)benzoic acid (22 g) dissolved in n-butanol (500 ml) was hydrogenated by shaking in the presence of 5% w/w palladium on charcoal (2.5 g) at 700C and atmospheric pressure for 6 hours. The mixture was filtered hot and the filtrate allowed to cool. The resulting solid was collected and washed with ethanol (100 ml) to give 3-amino-4 (hexadecanamido)benzoic acid (11.6 g) in the form of a cream solid, m.p. 1 60C1 620C.

The 3-nitro-4-(n-hexadecanamido)benzoic acid, used as starting material, was prepared as follows:- A solution of 4-amino-3-nitrobenzoic acid (18.2 g) and n-hexadecanoyl chloride (33.0 g) in dry dimethyiformamide (100 ml) was heated for 90 minutes at 970C. The solution was cooled and then poured onto crushed ice (300 g). The resulting solid was collected, washed with water (3 x 100 ml), dried and recrystallised from a mixture of acetone and water (5:1) (with treatment with charcoal) to give 3-nitro-4-(N-hexadecanamido)benzoic acid (31.7 g) in the form of a pale yellow solid, m.p.

1530--1540C.

EXAMPLE 23 Compound V By proceeding in a similar manner to that hereinbefore described in Example 1 6 for the preparation of 4-amino-3-(n-nonadecanamido)benzoic acid but replacing n-nonadecanoyl chloride by noctanoyl chloride, there was prepared 4-amino-3-(n-octanamido)benzoic acid in the form of an offwhite solid, m.p. 2020--2030C after recrystallisation from methanol.

EXAMPLE 24 Compound W By proceeding in a similar manner to that hereinbefore described in Example 1 6 for the preparation of 4-amino-3-(n-nonadecanamido)benzoic acid but replacing n-nonadecanoyl chloride by ndodecanoyl chloride, there was prepared 4-amino-3-(n-dodecanamido)-benzoic acid in the form of a white solid, m.p. 1830-1850C.

EXAMPLE 25 Compound By proceeding in a similar manner to that hereinbefore described in Example 16 for the preparation of 4-amino-3-(n-nonadecanamido)benzoic acid but replacing n-nonadecanoyl chloride by noctadecanoyl chloride, there was prepared 4-amino-3-(n-octadecanamido)benzoic acid in the form of a light brown solid, m.p. 1850--1870C after recrystallisation from methyl ethyl ketone.

EXAMPLE 26 Compound Y A solution of methyl 3,4-diaminobenzoate (83.1 g) in dry dimethylformamide (900 ml) containing triethylamine (50.8 g), was treated dropwise with n-octanoyl chloride (81.3 g) during 30 minutes at a temperature maintained between 50 and 80C. The mixture was stirred for a further period of 2 hours.

The solid was removed by filtration and the filtrate was poured into water (8000 ml). The resulting solid was collected and was recrystallised twice from methanol to give methyl 4-amino-3-(n-octanamido)benzoate (65.5 g) in the form of a white solid, m.p. 1 200C.

EXAMPLE 27 Compound 8 By proceeding in a similar manner to that hereinbefore described in Example 26 for the preparation of methyl 4-amino-3-(n-octanamido)benzoate but replacing n-octanoyl chloride by ndodecanoyl chloride, there was prepared methyl 4-amino-3-(n-dodecanamido)-benzoate in the form of an off-white solid, m.p. 1 02o1 050C after recrystallisation from methanol.

EXAMPLE 28 Compound D By proceeding in a similar manner to that hereinbefore described in Example 26 for the preparation of methyl 4-amino-3-(n-octanamido)benzoate but replacing n-octanoyl chloride by ntridecanoyl chloride, there was prepared methyl 4-amino-3-(n-tridecanamido)benzoate in the form of a light brown solid, m.p. 101 o1 040C after recrystallisation from methanol.

EXAMPLE 29 Compound C By proceeding in a similar manner to that hereinbefore described in Example 26 for the preparation of methyl 4-amino-3-(n-octanamido)benzoate but replacing n-octanoyl chloride by ntetradecanoyl chloride, there was prepared methyl 4-amino-3-(n-tridecanamido)benzoate in the form of a light brown solid, m.p. 1 08a1 090C after recrystallisation from methanol.

EXAMPLE 30 Compound A By proceeding in a similar manner to that hereinbefore described in Example 26 for the preparation of methyl 4-amino-3-(n-octanamido)benzoate but replacing n-octanoyl chloride by nhexadecanoyl chloride, there was prepared methyl 4-amino-3-(n-hexadecanamido)benzoate in the form of a white solid, m.p. 1 09 0--1 1 OOC after recrystallisation from methanol.

EXAMPLE 31 Compound F A stirred solution of methyl 3,4-diaminobenzoate (5 g) in dry dimethylformamide (50 ml), containing triethylamine (6.1 g), was treated dropwise with a solution of n-hexadecanoyl chloride (16.54 g) in dry dimethylformamide (40 ml) during 5 minutes. The temperature was allowed to rise from 200C to 500 C. The mixture was stirred for a further period of 3 hours. The resulting suspension was poured into water (800 ml) containing hydrochloric acid (10 ml, 36.5% w/v). The resulting solid was collected and recrystallised from a mixture of chloroform and acetone (1 :1) to give methyl 3,4bis(n-hexadecanamido)benzoate (12.1 g) in the form of a white solid, m.p. 1290-1320C, which is identical to the product of Example 6.

EXAMPLE 32 Compound By proceeding in a similar manner to that hereinbefore described in Example 31 for the preparation of methyl 3,4-bis(n-hexadecanamido)-benzoate but replacing n-hexadecanoyl chloride bv nnoctanoyl chloride, there was prepared methyl 3,4-bis(n-octanido)benzoate in the form of a white solid, m.p. 1 45o1 470C after recrystallisation from acetone.

EXAMPLE 33 Compound By proceeding in a similar manner to that hereinbefore described in Example 31 for the preparation of methyl 3,4-bis(n-hexadecanamido)benzoate but replacing n-hexadecanoyl chloride by ndodecanoyl chloride, there was prepared methyl 3,4-bis(n-dodecanamido)benzoate in the form of an off-white solid, m.p. 1290--131 OC after recrystallisation from acetone.

EXAMPLE 34 Compound By proceeding in a similar manner to that hereinbefore described in Example 31 for the preparation of methyl 3,4-bis(n-hexadecanamido)benzoate but replacing n-hexadecanoyl chloride by ntridecanlyl chloride, there was prepared methyl 3,4-bis(n-tridecanamido)benzoate in the form of a white solid, m.p. 1320--1340C after recrystallisation from acetone.

EXAMPLE 35 Compound By proceeding in a similar manner to that hereinbefore described in Example 31 for the preparation of methyl 3,4-bis(n-hexadecanamido)benzoate but replacing n-hexadecanoyl chloride by ntetradecanoyl chloride, there was prepared methyl 3,4-bis(n-tetradecanamido)benzoate in the form of a white solid, m.p. 1320--1330C after recrystallisation from acetone.

EXAMPLE 36 Compound CC By proceeding in a similar manner to that hereinbefore described in Example 31 for the preparation of methyl 3,4-bis(n-hexadecanamido)benzoate but replacing n-hexadecanoyl chloride by noctadecanoyl chloride, there was prepared methyl 3,4-bis(n-octadecanamido)benzoate in the form of a white solid, m.p. 1 200C after recrystallisation from a mixture of acetone and methanol (1:1).

EXAMPLE 37 Compound 3-Amino-4-(n-octanamido)benzoic acid (12.1 g) in methanol (200 ml) was treated with ethereai diazomethane until the reaction had gone to completion (as shown by thin layer chromatography on silica, using methanol: chloroform:glacial acetic acid; 10:90:0.5). Acetic acid (0.2 ml) was then added and the reaction mixture concentrated under reduced pressure. The resulting solid was recrystallised from ethyl acetate to give methyl 3-amino-4-(n-octanamido)benzoate (9.2 g) in the form of a cream solid, m.p. 1280--1310C.

EXAMPLE 38 CompoundEE 3-Nitro-4-(n-octanamido)benzoic acid (25 g) dissolved in ethanol (500 ml) at 500C was hydrogenated by shaking in the presence of 5% w/w palladium on charcoal (2.5 g) at 500C and atmospheric pressure for 3 hours. The mixture was filtered hot and the filtrate was evaporated in vacua.

The residue was recrystallised from a mixture of ethanol and water (1:1) to give 3-amino-4-(n octanamido)benzoic acid (8 g) in the form of a yellow solid, m.p. 1550--1560C.

The 3-nitro-4-(n-octanamido)benzoic acid, used as starting material, was prepared as follows:- A solution of 4-amino-3-nitrobenzoic acid (18.2 g) and n-octanoyl chloride (19.4 g) in dry dimethylformamide (100 ml) was treated for 90 minutes at 970C. The solution was cooled and poured onto ice (300 g). The resulting solid was collected and washed with water (3 x 100 ml), dried and recrystallised from a mixture of methanol and water (8:1) (with treatment with charcoal) to give 3-nitro 4-(n-octanamido)benzoic acid (22 g) in the form of a pale yellow solid, m.p. 1 53 0--1 540 C.

EXAMPLE 39 Compound 3-Nitro-4-(n-dodecanamido)benzoic acid (21 9) dissolved in ethyl acetate (500 ml) was hydrogenated by shaking in the presence of 5% w/w palladium on charcoal (2.5 g) at 500C and atmospheric pressure. The resulting mixture was filtered hot to yield a cream solid on cooling. This product was recrystallised from methanol to give 3-amino-4-(n-dodecanamido)benzoic acid (7.4 g) as a beige solid, m.p. 1580--1600C.

EXAMPLE 40 Compound H By proceeding in a similar manner to that hereinbefore described in Example 26 for the preparation of methyl 4-amino-3-(n-octanamido)benzoate but replacing n-octanoyl chloride by n decanoyl chloride, there was prepared methyl 4-amino-3-(n-decanamido)benzoate in the form of a white solid, m.p. 960--1000C.

EXAMPLE 41 Compound By proceeding in a similar manner to that hereinbefore described in Example 31 for the preparation of methyl 3,4-bis(n-hexadecanamido)benzoate but replacing n-hexadecanoyl chloride by ndecanoyl chloride, there was prepared methyl 3,4-bis(n-decanamidobenzoate in the form of a white solid, m.p. 1390--141 OC after recrystallisation from ethanol.

EXAMPLE 42 Compound A stirred solution of 3,4-diaminobenzoic acid (10 g) in dry dimethylformamide (100 ml) containing potassium carbonate (28 g) was treated dropwise with a solution of n-dodecanoyl chloride (33.1 g) in dry dimethylformamide (30 ml) during 5 minutes. The temperature was allowed to rise from 200 to 500 C. The mixture was stirred for a further period of 3 hours. The resulting suspension was filtered and the filtrate poured into water (700 ml) containing hydrochloric acid (10 ml, 36.5% w/v).The resulting solid was collected and recrystallised from glacial acetic acid; the product was then washed with water and recrystallised from methyl ethyl ketone to give 3,4-bis(n-dodecanamido)benzoic acid (12.5 g) in the form of a white solid, m.p. 1 95 0--1 97QC.

EXAMPLE 43 Compound E By proceeding in a similar manner to that hereinbefore described in Example 42 for the preparation of 3,4-bis(n-dodecanamido)benzoic acid but replacing n-dodecanoyl chloride by nhexadecanoyl chloride and potassium carbonate by sodium carbonate, there was prepared 3,4-bis(nhexadecanamido)benzoic acid in the form of a white solid, m.p. 1980--2020C after successive recrystallisation from glacial acetic acid and methyl ethyl ketone.

EXAMPLE 44 Compoundll By proceeding in a similar manner to that hereinbefore described in Example 42 for the preparation of 3,4-bis(n-dodecanamido)benzoic acid but replacing n-dodecanoyl chloride by noctanoyl chloride there was prepared 3,4-bis(n-octanamido)benzoic acid in the form of a white solid, m.p. 1 95 0--1 97 OC after successive recrystallisation from glacial acetic acid and methyl ethyl ketone.

EXAMPLE 45 Compound JJ By proceeding in a similar manner to that hereinbefore described in Example 42 for the preparation of 3,4-bis(n-dodecanamido)benzoic acid but replacing n-didecanoyl chloride by ntetradecanoyl chloride, there was prepared 3,4-bis(n-tetradecanamido)benzoic acid in the form of a white solid, m.p. 201 0--2060C after successive recrystallisation from glacial acetic acid and methyl ethyl ketone.

EXAMPLE 46 Compound KK Methyl 4-(n-dodecanamido)-3-nitrobenzoate (21 g) dissolved in warm ethyl acetate (500 ml) (500--550C) was hydrogenated by shaking in the presence of 5% w/w palladium on charcoal (2.0 g) at 600C and atmospheric pressure for 2 hours. The mixture was filtered hot and the filtrate was allowed to cool. The solid was collected to give methyl 3-amino-4-(n-dodecanamido)benzoate (14.1 g) in the form a white solid, m.p. 1340--1370C.

The methyl 4-(n-dodecanamido)-3-nitrobenzoate, used as starting material, was prepared as follows L Methyl 4-amino-3-nitrobenzoate (19.6 g) and n-dodecanoyl chloride (23 g) in dimethylformamide (100 ml) were heated for 2 1/2 hours at 970C with occasional shaking. The resulting solution was poured onto crushed ice (300 g) and the solid collected and recrystallised from a mixture of methanol an chloroform (5:1) to give methyl 4-(n-dodecanamido)-3-nitrobenzoate (31 g) in the form of a yellow solid m.p. 780--800C.

The methyl 4-amino-3-nitrobenzoate was prepared as follows:- 4-Amino-3-nitrobenzoic acid (70 g) was added to a solution of anhydrous hydrogen chloride in methanol [made from acetyl chloride (78 g) and dry methanol (300 ml)j. The resulting mixture was refluxed for 10 hours, cooled in ice and the solid collected to give methyl 4-amino-3-nitrobenzoate (62 g) in the form of yellow solid, m.p. 1 93 0--1 95 OC.

EXAMPLE 47 Compound LL By proceeding in a similar manner to that hereinbefore described in Example 46 for the preparation of methyl 3-amino4-(n-dodecanamido)benzoate but replacing methyl 4-(n-dodecanamido)- 3-nitrobenzoate by methyl 4-(n-hexadecanamido)-3-nitrobenzoate, there was prepared methyl 3amino-4-(n-hexadecanamido)benzoate in the form of a white solid, m.p. 135-1 370C.

EXAMPLE 48 Compound MM By proceeding in a similar manner to that hereinbefore described in Example 46 for the preparation of methyl 3-amino-4-(n-dodecanamido)benzoate but replacing methyl 4-(n-dodecanamido)3-nitrobenzoate by methyl 4-(n-decanamido)-3-nitrobenzoate, there was prepared methyl 3-amino-4 (n-decanamido)benzoate in the form of a white solid, m.p. 131 0--1 33 0 C.

EXAMPLE 49 Compound NN A stirred solution of 3,4-diaminobenzoic acid (8.4 g) in dry dimethylformamide (100 ml) containing potassium carbonate (15.27 g) was treated dropwise with a solution of n-hexadecanoyl chloride (15.17 g) in dry dimethylformamide (30 ml) during 30 minutes at 00--50C. The mixture was stirred for a further 2 hours at 00--50C and allowed to warm to room temperature in 30 minutes.

The solution was then poured into water (700 ml) containing hydrochloric acid (10 ml, 36.5% w/v). the solid was collected, heated with acetone (300 ml) at 500C, and recrystallised from methyl ethyl ketone giving 4-amino-3-(n-hexadecanamido)-benzoic acid (9.4 g) in the form of a white solid, m.p. 197C199OC.

EXAMPLE 50 Compound QO By proceeding in a similar manner to that hereinbefore described in Example 42 for the preparation of 3,4-bis(n-dodecanamido)benzoic acid but replacing n-dodecanoyl chloride by n-decanoyl chloride, there was prepared 3,4-bis(n-decanamido)-benzoic acid in the form of a white solid, m.p.

1 9401 960C after successive recrystallization from glacial acetic acid and methyl ethyl ketone.

EXAMPLE 51 Compound PP By proceeding in a similar manner to that hereinbefore described in Example 42 for the preparation of 3,4-bis(n-dodecanamido)benzoic acid but replacing n-dodecanoyl chloride by ntridecanoyl chloride, there was prepared 3,4-bis(n-tridecanamido)-benzoic acid in the form of an off white solid, m.p. 1920--1940C after successive recrystallisation from glacial acetic acid and methyl ethyl ketone.

EXAMPLE 52 Compound QO By proceeding in a similar manner to that hereinbefore described in Example 42 for the preparation of 3,4-bis(n-dodecanamido)benzoic acid but replacing n-dodecanoyl chloride by noctadecanoyl chloride there was prepared 3,4-bis(n-octadecanamido)benzoic acid in the form of a white solid, m.p. 1 93 0--1 96 OC after successive recrystallisation from glacial acetic acid and methyl ethyl ketone.

EXAMPLE 53 Compound RR A solution of 2,3-diaminobenzoic acid (40 g) in dimethylformamide (600 ml), containing triethylamine (79.7 g, 109.5 ml), was treated with n-hexadecanoyl chloride (144.5 g). The rate of addition was such as to allow the temperature of the reaction mixture to rise from room temperature to 450--500C. The mixture was then stirred for a further 3 hours and was allowed to stand at room temperature overnight. The resulting mixture was added to water (1200 ml) containing concentrated hydrochloric acid (50 ml, of strength 36.5% w/v), and the resulting solid was collected and washed with water (1200 ml). The solid was stirred with hot water (4000 ml; 650C) for 30 minutes and was collected and dried at 700C in vacuo to give 2,3-bis(n-hexadecanamido)-benzoic acid.

EXAMPLE 54 Compound SS By proceeding in a similar manner to that hereinbefore described in Example 26 for the preparation of methyl 4-amino-3-(n-octanamido)-benzoate but replacing n-octanoyl chloride by nheptanoyl chloride, there was prepared methyl 4-amino-3-(n-heptananido)benzoate in the form of a pale brown solid, m.p. 1 03O1 060C.

The present invention includes within its scope pharmaceutical compositions which comprise at least one of the compounds of general formula I or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable carrier or coating. In clinical practice the compounds of the present invention may be administered parenterally, but are preferably administered rectally or, more preferably, orally.

Solid compositions for oral administration include compressed tablets, pills, powders and granules. In such solid compositions, one or more of the active compounds is, or are, admixed with at least one inert diluent such as starch, sucrose or lactose. The compositions may also comprise, as is normal practice, additional substances other than inert diluents, e.g. lubricating agents, such as magnesium stearate.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art such as water and liquid paraffin. Besides inert diluents such compositions may comprise adjuvants, such as wetting, and suspending agents, and sweetening, flavouring, perfuming and preserving agents. The compositions according to the invention for oral administration also include capsules of absorbable material such as gelatin, containing one or more of the active substances with or without the addition of diluents or exipients.

Preparations according to the invention for parenteral administration include sterile aqueous, aqueous-organic, and organic solutions, suspensions and emulsions. Examples of organic solvents or suspending media are propylene glycol, polyethylene glycol, vegable oils such as olive oil and injectable organic esters such as ethyl oleate. These compositions may also contain adjuvants such as stabilising, preserving, wetting, emulsifying and dispersing agents. They may be sterilized by, for example, filtration through a bacteria-retaining filter, by incorporation in the compositions of sterilizing agents, by irradiation or by heating. They may also be manufactured in the form of sterile solid compositions, which can be dissolved in sterile water or some other sterile injectable medium immediately before use.

Solid compositions for rectal administration include suppositories formulated in accordance with known methods and containing one or more of the compounds of formula I or a pharmaceutically acceptable salt thereof.

The percentage of active ingredient in the compositions of the invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage shall be obtained.

Obviously, several unit dosage forms may be administered at about the same time. The dose employed will be determined by the physician, and depends upon the desired therepeutic effect, the route of administration and the duration of the treatment, and the condition of the patient. In the adult, the doses are generally between 0.1 and 50 mg/kg body weight per day by oral administration, for example as anti-atheroma agents and in associated cardiovascular diseases, between 10 and 50 mg/kg body weight per day by oral administration, and in the treatment of arthritis and associated diseases, between 0.1 and 10 mg/kg body weight per day by oral administration.

The following Example illustrates pharmaceutical compositions according to the present invention.

EXAMPLE 55 No. 2 size gelatin capsules each containing.

methyl 4-amino-3-(n-octanamido)benzoate 20 mg lactose 100 mg starch 60 mg dextrin 40 mg magnegium stearate 1 mg were prepared in accordance with the usual procedure.

Claims (32)

1. Acylaminobenzoic acid derivatives of the general formula.

wherein R' represents a hydrogen atom or a straight- or branched-chain alkyl group containing from 1 to 6 carbon atoms (which may be substituted by one or more than one of the same type of substituents selected from the hydroxy group, alkenyl groups containing from 2 to 5 carbon atoms and alkanoyloxy groups containing from 2 to 7 carbon atoms), R" represents a hydrogen atom or a group of the formula --COR2, and R2 represents a straight- or branched-chain alkyl group, containing from 2 to 20 carbon atoms, and pharmaceutically acceptable salts thereof.

2. Acylaminobenzoic acid derivatives according to claim 1 wherein R' represents a hydrogen atom or a straight-or branched-chain alkyl group containing from 1 to 6 carbon atoms.

3. Acylaminobenzoic acid derivatives according to claim 1 wherein R1 represents a hydrogen atom.

4. Acylaminobenzoic acid derivatives according to claim 1 wherein R' represents a methyl group.

5. Acylaminobenzoic acid derivatives according to claim 1 wherein R' represents a 2,3 dihydroxyprop-1 -yl, allyl or pivaloyloxymethyl group.

6. Acylaminobenzoic acid derivatives according to any one of claims 1 to 5 wherein R2 represents a straight-chain alkyl group containing from 2 to 20 carbon atoms.

7. Acylaminobenzoic acid derivatives according to any one of claims 1 to 6 wherein R2 represents an alkyl group containing from 7 to 1 6 carbon atoms.

8. Methyl 4-amino-3-(n-octanamido)benzoate.

9. Methyl 4-amino-3-(n-hexadecanamido)-benzoate.

1 0. Methyl 4-amino-3-(n-dodecanamido)-benzoate.

11. Methyl 4-amino-3-(n-tetradecanamido)-benzoate.

12. Methyl 4-amino-3-(n-tridecanamido)-benzoate.

1 3. Pharmaceutically acceptable acid addition salts of the compound claimed in each of claims 8 to 12.

14. 3,4-Bis(n-hexadecanamido)benzoic acid, methyl 3,4-bis(n-hexadecanamido)benzoate, methyl 3,4-bis(n-undecanamido)benzoate, methyl 4-amino-3-(n-decanamido)benzoate, methyl 3,4-bis(noctanamido)-benzoate and 3,4-bis(n-pentadecananido)benzoic acid.

1 5. Pharmaceutically acceptable salts of a compound claimed in claim 14.

1 6. Methyl 3,4-bis(n-nonanamido)benzoate, 3,4-bis(n-heptadecanamido)benzoic acid, 3,4-bis(n- heneicosanamido)benzoic acid, 3,4-bis(n-eicosanamido)-benzoic acid, 4-amino-3-(nnonadecanamido)benzoic acid, 3,4-bis(2-methyltetradecanamido)benzoic acid, 4-amino-3-(2hexyloctanamido)benzoic acid, 4-amino-3-(2-ethyldodecanamido)benzoic acid, 4-amino-3-(2butyldecanamido)benzoic acid, 2,3-bis(n-tetradecanamido)benzoic acid, 3-aminoAAn-hexadecanamido) benzoic acid, 4-amino-3-(n-octanamido)benzoic acid, 4-amino-3-(n-dodecanamido)benzoic acid, 4amino-3-(n-octadecanamido)benzoic acid, methyl 3,4-bis(n-dodecanamido)benzoate, methyl 3,4-bis(ntridecanamido)-benzoate, methyl 3,4-bis(n-tetradecanamido)benzoate, methyl 3,4-bis(noctadecanamido)benzoate, methyl 3-amino-4-(n-octanamido)benzoate, 3-amino-4-(n- octanamido)benzoic acid, 3-amino-4-(n-dodecanamido)-benzoic acid, methyl 3,4-bis(ndecanamido)benzoate, 3,4-bis(n-dodecanamido)benzoic acid, 3,4-bis(n-octanamido)benzoic acid, 3,4bis(n-tetradecanamido)benzoic acid, methyl 3-amino-4-(n-dodecanamido)benzoate and methyl 3amino-4-(n-hexadecanamido)benzoate.

1 7. Pharmaceutically acceptable salts of a compound claimed in claim 1 6.

18. Methyl 3-amino-4-(n-decanamido)benzoate, 4-amino-3-(n-hexadecanamido)benzoic acid, 3,4-bis(n-decanamido)benzoic acid, 3,4-bis(n-tridecanamido)benzoic acid, 3 ,4-bis(n- octadecanamido)benzoic acid, 2,3-bis(n-hexadecanamido)benzoic acid and methyl 4-amino-3-(nheptanamido)benzoate.

1 9. Pharmaceitically acceptable salts of each compound claimed in claim 1 8.

20. A process for the preparation of an acylaminobenzoic acid derivative of the general formula depicted in claim 1 wherein RO represents a hydrogen atom which comprises the reduction of a compound of the general formula:

wherein R1 and R2 are as defined in claim 1) by known methods for the reduction of a nitro group to a primary amino group.

21. A process according to claim 20 in which reduction of the nitro group to a primary amino group is effected by catalytic hydrogenation.

22. A process for the preparation of an acylaminobenzoic acid derivative of the general formula depicted in claim 1 wherein RO represents a group of the formula -COB2 (R2 being as defined in claim 1), or the substituent group -NH-COB2 (R2 being as defined in claim 1) is meta to the substitutent.

group --COOR' (R1 being as defined in claim 1) and RO represents a hydrogen atom, which comprises reacting a compound of the general formula.

(wherein R' is as defined in claim 1) with an acylating agent of the general formula.

R2COX' IV wherein RZ is as hereinbefore defined in claim 1, and X1 represents a halogen atom or the hydroxy group.

23. A process for the preparation df an acylaminobenzoic acid derivative of the general formula depicted in claim 1 wherein RO represents a group of the formulaCOR2 (R2 being as defined in claim 1) which comprises reacting a compound of the general formula

(wherein R' and R2 are as defined in claim 1) with an acylating agent of the general formula: R2COX' wherein R2 is as defined in claim 1 and X1 represents a halogen atom or the hydroxy group.;

24.A process for the preparation of an acylaminobenzoic acid derivative as claimed in claim 1, wherein R' represents a straight- or branched-chain alkyl group containing from 1 to 6 carbon atoms (which may be substituted by one or more than one of the same type of substituent selected from the hydroxy group, alkenyl groups containing from 2 to 5 carbon atoms and alkanoyloxy groups containing from 2 to 7 carbon atoms) and RO and R2 are as defined in claim 1, which comprises appropriate esterification of a corresponding carboxylic acid of the general formula depicted in claim 1 wherein R1 represents a hydrogen atom, and RO and R2 are as defined in claim 1.

25. A process for the preparation of an acylaminobenzoic acid as claimed in claim 1 wherein R represents a hydrogen atom which comprises the alkaline hydrolysis of a corresponding ester of the general formula depicted in claim 1 wherein R' represents a straight- or branched-chain alkyl group containing from 1 to 6 carbon atoms, which may be substituted by one or more than one of the same type of substituent selected from the hydroxy group, alkenyl groups containing from 3 to 5 carbon atoms and alkanoyloxy groups containing from 2 to 7 carbon atoms, and RO and R2 are as defined in claim 1.

26. A process according to any one of claims 20 to 25 followed by the step of converting by known methods an acylaminobenzoic acid derivative of the general formula depicted in claim 1 thus obtained into a pharmaceutically acceptable salt.

27. A process for the preparation of an acylaminobenzoic acid derivative of the general formula depicted in claim 1 or a pharmaceutically acceptable salt thereof substantially as hereinbefore described with especial reference to any one of Examples 1 to 10.

28. A process for the preparation of an acylaminobenzoic acid derivative of the general formula depicted in claim 1 or a pharmaceuticaily acceptable salt thereof as hereinbefore described in any one of Examples 11 to 47.

29. A process for the preparation of an acylaminobenzoic acid derivative of the general formula depicted in claim 1 or a pharmaceutically acceptable salt thereof as hereinbefore described in any one of Examples 48 to 54.

30. Pharmaceutical compositions which comprise at least one acyiaminobenzoic acid derivative or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 1 9 in association with a pharmaceutical carrier or coating.

31. Pharmaceutical compositions according to claim 30 substantially as hereinbefore described with especial reference to Example 55.

32. An acylaminobenzoic acid derivative or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 19 for use as a medicament and, more particularly, for the prevention or treatment of atherosclerosis, and of associated conditions such as angina, myocardial infarction, cerebral vascular occlusion, arterial aneurism and peripheral vascular disease; as well as arthritis, immunological disease, cancer and graft rejection.