PT98666A - PREPARATION PROCEDURE OF BENZAMIDE DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM - Google Patents

Description

73019 Ν.62879

The present invention relates to novel therapeutically useful benzamide derivatives, processes for their production and pharmaceutical compositions containing them and processes for their use.

The novel benzamide derivatives of the present invention are compounds of formula I, shown below, in which R 1 represents a straight or branched chain alkyl group containing up to about 20 carbon atoms, optionally containing one or more carbon- carbon atoms and optionally interrupted by one or more heteroatoms, eg oxygen, sulfur or nitrogen atoms, and optionally interrupted by one or more sulfinyl or sulfonyl groups, preferably an alkylthioalkyl, alkylaminoalkyl or dialkylaminoalkyl group or more especially an alkyl, , alkoxyalkyl, alkoxyalkoxyalkyl or alkoxyalkoxyalkoxyalkyl groups, optionally having one or more substituents selected from halogen, eg bromine, iodine, fluorine or preferably chlorine, amino, alkoxy, alkylthio and alkylamino groups, each containing up to about of 3 carbon atoms, and groups of the formula -C0NR6R7 in which R6 is R 2 represents a methyl, trifluoromethyl or trichloromethyl group, R 2, are the same or different and each represents a hydrogen atom, a straight or branched chain alkyl group containing up to 6 atoms carbon or an optionally substituted phenyl group or the two R2 groups together with the carbon atom to which they are attached form a saturated or unsaturated ring containing from 3 to about 8 carbon atoms and optionally containing one or more heteroatoms selected from R 3 represents a hydrogen atom or a straight or branched chain alkyl group containing up to 6 carbon atoms, R 2 represents a straight or branched chain alkylthio or alkoxy group containing up to 6 carbon atoms, Or a 5- to 8-membered heterocycle group containing at least one nitrogen atom and linked through s of that nitrogen atom to the rest of the molecule, eg an imidazol-1-yl or pyrrolidin-1-yl group, and R 5 represents a group of the formula -NR 8 R 9 or -OR 10 in which R 8 and R 9 may be the same or different and each represents a hydrogen atom or a straight or branched chain alkyl group containing up to about 10 carbon atoms optionally containing one or more carbon-carbon double or triple bonds and optionally interrupted by one or more heteroatoms, eg oxygen, sulfur or nitrogen, and optionally interrupted by one or more sulfinyl or sulfonyl groups, and R 10 represents a hydrogen atom or a straight or branched chain alkyl group containing up to about 10 carbon atoms, optionally containing one or more carbon-carbon double or triple bonds, and optionally interrupted by one or more heteroatoms, eg oxygen, sulfur or nitrogen atoms, and optionally interrupted by one or more sulfinyl groups or sulfonyl and pharmaceutically acceptable salts thereof.

As will be apparent to those skilled in the art, some of the compounds of formula I exhibit optical isomerism. All such forms and their mixtures and processes for their preparation and separation are within the scope of the invention.

Particularly important compounds of the present invention include those in which at least one of the symbols has a value selected from the following: (i) R1 represents an alkyl, alkenyl, alkoxyalkyl, alkoxyalkoxyalkyl, alkoxyalkoxyalkoxyalkyl or haloalkyl group, eg chloroalkyl, containing 8 to 20 carbon atoms, preferably an alkyl or alkenyl group containing from 8 to 20, preferably from 10 to 18, carbon atoms; (ii) R 2 is each a hydrogen atom or the two R 2 groups together with the carbon atom to which they are attached form a cycloalkyl ring containing 3 to 8, 730-18%. Preferably 5 or 6, e.g. 5, carbon atoms; (iii) R 3 represents a hydrogen atom; (iv) R4 represents an imidazol-1-yl group or a linear or branched alkyl or alkoxy group containing up to 3, preferably 1 or 2, carbon atoms, preferably methoxy, methylthio or ethylthio; (v) R 8 represents a hydrogen atom or a straight or branched chain alkyl group containing up to 3 carbon atoms, e.g. methyl; (vi) R 9 represents a straight or branched chain alkyl or alkenyl group containing up to 6 carbon atoms, optionally interrupted by one or more oxygen or sulfur atoms or sulfonyl groups, preferably an alkyl, alkoxyalkyl or alkylthioalkyl group containing 3 to 6 carbon atoms. or 4 carbon atoms, or an alkenyl group containing 5 carbon atoms, eg a butyl, methoxyethyl, methylthioethyl, methoxypropyl, methylthiopropyl, methylsulfonylpropyl or metulbut-2-enyl group; (vii) R10 represents a hydrogen atom or a straight or branched chain alkyl group containing up to 6, preferably up to 3, carbon atoms, e.g. methyl; the other symbols being as defined above, and pharmaceutically acceptable salts thereof.

Important compounds according to the invention include: A (Z) -N- (2-methylthio) ethyl-4-methylthio-3- (octadec-9-enamido) benzamide; B (Z) -N- (2-methoxy) ethyl-4-methylthio-3- (octadec-9-enamido) benzamide; Methyl C (Z) -4-methoxy-3- (octadec-9-enamido) benzoate; D N- (2-methylthio) ethyl-3-hexadecanamido-4- (methylthio) benzamide; 73019 Ν.62879

-E-N-butyl-3-hexadecanamido-4- (methylthio) benzamide; F N- (2-methoxy) ethyl-3-hexadecanamido-4- (methylthio) benzamide; G N-butyl-3-dodecanamido-4- (methylthio) benzamide; Η N- (2-methoxy) ethyl-3-dodecanamido-4- (methylthio) benzamide; I N- (2-methylthio) ethyl-3-dodecanamido-4- (methylthio) benzamide; N-butyl-N-methyl-3-hexadecanamido-4-methoxybenzamide; N - (2-methylthio) ethyl-3- (1-decylcyclopentanecarboxamido) -4- (methylthio) benzamide; N - (2-methylthio) ethyl-3- (1-decylcyclopentanecarboxamido) -4-methoxy-3- (octadec-9-enamido) benzamide; Sodium M (Z) -4-methoxy-3- (octadec-9-enamido) benzoate; N (Z) -4-Methoxy-3- (octadec-9-enamido) benzoic acid; N-butyl-3-dodecanamido-4- (ethylthio) benzamide; N-butyl-4-ethylthio-3-hexadecanamidobenzamide; Q N-butyl-4-ethylthio-3-heptadecanamidobenzamide; R-N-butyl-4-ethylthio-3-octadecanamidobenzamide; S-4-ethylthio-3-hexadecanamido-N- (2-methylthioethyl) benzamide; T 4-ethylthio-3-heptadecanamido-N- (2-methylthioethyl) benzamide; U-3-heptadecanamido-4-methylthio-N- (2-methylthioethyl) benzamide; V 3-heptadecanamido-N- (2-methoxyethyl) -4- (methylthio) benzamide; W (Z) -N-butyl-3-octadec-9-enamido-4- (methylthio) benzamide; X 4-ethylthio-N- (3-methylthiopropyl) -3-octadecanamidobenzamide; Y 4-ethylthio-3-heptadecanamido-N- (3-methylthiopropyl) benzamide; Z 4-ethylthio-3-hexadecanamido-N- (3-methylthiopropyl) benzamide; 4-Methylthio-N- (2-methylthioethyl) -3-octadecanamidobenzamide: AB N -butyl-3-dodecanamido-4-methoxybenzamide; -3-hexadecanamido-N- (3-methoxypropyl) benzamide; N-Butyl-3-octadecanamide -4- (methylthio) benzamide; AE 4-methylthio-N- (3-methylthiopropyl) -3-octadecanamidobenzamide; 4-Ethylthio-N- (3-methoxypropyl) -3-octadecanamidobenzamide; N-Butyl-3- (5-chloropentanamido) -4- (ethylthio) benzamide, 3- (4-chlorobutanamido) -4- Methyl 3- (5-chloropentanamido) -4-ethylthio-N- (3-methylthiopropyl) benzamide; 3-Hexadecanamido-4-methoxybenzoate; 4-methoxybenzoic acid 3-hexadecanamido-4-methoxybenzoate AM 3-hexadecanamido-4-methoxy-N- (2-methoxyethyl) benzamide 73019 Ν.62879 ΑΝ 3-hexadecanamido-4-methoxy N-Butyl-4-methylthio-3- (5,9-dioxa-hexadecanamido) benzamide: AP 4-methylthio-N- (3-methylthiopropyl) -3- (3-methylbut-2-enyl) - (5,9-dioxa-hexadecanamido) benzamide; AQ N-butyl-4-ethylthio-3- (5,9,13-trioxahexadecanamido) benzamide; 4-Ethylthio-N- (3-methylthiopropyl) -3- (5,9-dioxa-hexadecanamido) benzamide; AS N-butyl-4-ethylthio-3- (5,9-dioxa-hexadecanamido) benzamide; AT 4-ethylthio-N- (3-methoxypropyl) -3- (5,9-dioxa-hexadecanamido) -benzamide; AU 4-ethylthio-N- (3-methoxypropyl) -3- (5,9,13-trioxahexadecanamide) benzamide; AV 4-ethylthio-N- (3-methoxypropyl) -3- (5-oxahexadecanamido) benzamide; AW 4-methylthio-N- (3-methylthiopropyl) -3- (5-oxahexadecanamido) benzamide; AX N-butyl-4-methylthio-3- (5-oxahexadecanamido) benzamide; AY 4-methoxy-N- (3-methylthiopropyl) -3- (5,9-dioxa-hexadecanamido) benzamide; AZ 4-ethylthio-N- (3-methylthiopropyl) -3- (5,9,13-trioxahexadecanimido) benzamide; Methyl 3-heptadecanamido-4- (imidazol-1-yl) benzoate BA; BB N- (3-methylsulfonylpropyl) -4-methylthio-3- (5,9-dioxa-hexadeca-namido) benzamide; BC 4-ethylthio-N- (3-methylthiopropyl) -3- (5,9-dioxa-octadecanamido) -benzamide; BD N-butyl-4-ethylthio-3- (5,10-dioxa-hexadecanamido) benzamide; BE 4-ethylthio-N- (3-methylthiopropyl) -3- (6,10,14-trioxahexadecanamido) benzamide; BF 4-imidazol-1-yl-N- (3-methylthiopropyl) -3- (5-oxahexadecanamide) benzamide; and BG 3-hexadecanamido-4-imidazol-1-yl-N- (3-methylthiopropyl) -benzamide.

The letters A to BG are assigned to the compounds for ease of reference later in this disclosure.

The compounds according to the invention are acyl 73019 inib inhibitors. 62879 cozyme-A: cholesterol-0-acyltransferase (ACAT; EC 2.3.1.26). They are therefore of value as antiatherosclerotic agents and have utility in the treatment of atherosclerosis, hyperlipidemia, cholesterol ester storage disease and atheroma in vein grafts.

Compounds within the scope of the present invention exhibit positive pharmacological activities as shown by in vitro and in vivo tests. which are believed to correlate with pharmacological activity in humans and other animals.

In in vitro assays microsomes (prepared from rats' livers fed a diet supplemented with 5% w / w cholestrol and 0.25% w / w of cholic acid for 7 days) were incubated with radiolabeled oleoyl-coA in the presence of compounds according to the invention at a concentration of 0.5 μg / ml or 1 μg / ml. The degree of inhibition of ACAT produced was up to 99%.

In the in vivo tests using rats fed a diet similar to that described above and additionally supplemented with 0.01% w / w of the test compound, the compounds according to the invention inhibited increases in plasma cholesterol concentrations, measured after 3 hours. days, relative to control animals fed the cholesterol-supplemented diet without the drug, by up to 100%.

The compounds of formula I may be prepared by the application or adaptation of known processes, which is to say processes used hereinbefore or described in the literature.

According to one aspect of the present invention, the compounds of formula I are prepared by reacting a compound of the general formula II, shown below, in which R 3, R 4 and R 5 are as defined above with a compound of the general formula: (III) in which R 1 and R 2 are as defined above and Z 1 represents a halogen atom, eg chlorine, or an alkoxycarbonyloxy group, for example methoxycarbonyloxy or ethoxycarbonyloxy, or the corresponding anhydride of the general formula: [R1-C (R2) 2 CO] 20 (IV) wherein R1 and R2 are as defined above.

When z 1 represents a halogen atom the reaction may be carried out in the presence of a suitable base, such as a tertiary amine, e.g. triethylamine or pyridine.

In each case the reaction may be carried out in a suitable solvent, e.g. dichloromethane, optionally with heating.

According to a further aspect of the invention, the compounds of formula I, in which R 1 and R 1 are other than hydrogen, are prepared by reacting a compound of the general formula: wherein R 11 represents a straight or branched chain alkyl having up to about 10 carbon atoms optionally containing one or more carbon or carbon double or triple bonds and optionally interrupted by one or more heteroatoms, eg oxygen, sulfur or nitrogen atoms, and optionally interrupted by one or more sulfinyl or sulfonyl groups, or a compound of the general formula: wherein R8 and R9 are as defined above, with a compound of formula VII, shown below, in which R1, R2 , R2 and R4 are as defined above and Z2 represents a hydroxy group, a halogen atom, eg chlorine, or a group -11- " for example methoxycarbonyloxy or ethoxycarbonyloxy, or with the corresponding anhydride.

The reaction conditions are similar to those described above for the reaction between the compounds of formulas II and III.

When Z 2 represents a hydroxy group the reaction is preferably carried out in the presence of a condensing agent, such as dicyclohexylcarbodiimide, or a catalytic amount of an inorganic acid, e.g. hydrochloric acid, optionally prepared in situ.

In each case the reaction may be carried out in a suitable solvent, e.g. dichloromethane, optionally with heating.

According to a further aspect of the invention, the compounds of formula I are prepared by the interconversion of other compounds of formula I. For example, according to one aspect of the invention: (a) compounds of formula I, wherein R3 and or R8 and / or R9 are not a hydrogen atom are prepared from compounds of formula I in which R3 and / or R8 and / or R9 represents a hydrogen atom by the application or adaptation of known alkylation processes; (b) sulfonyl group-containing compounds of formula I are prepared by the oxidation of compounds of formula I which contain a sulfinyl or thio group and compounds of formula I containing a sulfinyl group are prepared by the oxidation of compounds of formula I containing an thio group using a conventional oxidant, such as percarboxylic acid (eg m-chloroperbenzoic acid), in an inert solvent, such as dichloromethane, at or below ambient temperature; according to a further aspect of the invention, (c) compounds of formula I in which R 1 represents a hydrogen atom are prepared from compounds and formula I in which R 10 represents a straight-chain or branched alkyl group containing up to 10 carbon atoms, optionally containing one or more carbon-carbon double or triple bonds, and optionally interrupted by one or more heteroatoms, eg oxygen, sulfur or nitrogen atoms, and optionally interrupted by a or more sulfinyl or sulfonyl groups by hydrolysis of the ester group -COOR 10 by known procedures, for example by reaction with a base, eg aqueous sodium hydroxide solution, followed by neutralization by treatment with an inorganic acid, eg dilute hydrochloric acid; and conversely in accordance with a further aspect of the invention, (d) compounds of formula I in which R 10 represents a straight-chain or branched alkyl group containing up to about 10 carbon atoms, optionally containing one or more double bonds or carbon atoms, and optionally interrupted by one or more heteroatoms, eg oxygen, sulfur or nitrogen atoms, and optionally interrupted by one or more sulfinyl or sulfonyl groups are prepared by esterification of compounds of formula I in which R 10 represents a hydrogen atom by the application by adaptation of known processes.

By the term " pharmaceutically acceptable salts " as used in this specification is meant acid addition salts of which the anions are relatively innocuous to the animal organism when used in therapeutic doses, so that the beneficial pharmaceutical properties of the compounds of formula I are not addicted to side effects attributable to such anions, and salts formed with bases such as alkali metals, eg sodium or potassium, salts and alkaline earth metals, eg calcium or magnesium, salts, the cations of which are relatively innocuous to the animal organism when used in therapeutic doses, so that the beneficial pharmaceutical properties of the compounds of formula I are not vitiated by side effects attributable to such cations.

It is to be understood that where in this disclosure reference is made to the compounds of formula I, it is also intended to refer, where the context permits, to the pharmaceutically acceptable salts thereof.

Acid addition salts suitable for use in the products? -13-

Pharmaceuticals may be selected from salts derived from inorganic acids, for example hydrochlorides, hydrobromides, phosphates, sulfates and nitrates and organic acids, for example oxalates, lactates, tartarates, acetates, salicylates, citrates, propionates, succinates, fumarates, maleates, methylene-bis-8-hydroxynaphthoates, gentisates and di-p-toluate tartrates.

In addition to being useful in themselves as active compounds, the salts of the compounds of formula I are useful for the purification of the parent compounds, for example by exploiting the differences in solubility between the salts and the parent compound, by techniques well known for those skilled in the art.

The salts may be prepared from the parent compounds of formula I by the application or adaptation of known methods and the parent compounds of formula I may be prepared from the salts by the application or adaptation of known methods.

The compounds of formula I may be purified by the usual physical means, for example by crystallization or chromatography.

The compounds of formulas II, III, IV, V, VI and VII may be prepared by the application or adaptation of known processes.

For example the acid halides of formula VII in which Z 1 represents a halogen atom may be prepared from the corresponding carboxylic acids of formula VII in which Z 1 represents a hydroxy group by the application of known processes, eg when Z 1 represents a chlorine atom, by reaction with thionyl chloride or with oxalyl chloride.

Similarly, the acid halides of formula III, wherein Z 1 represents a halogen atom, may be prepared from the corresponding carboxylic acids of the general formula: ## STR1 ## VIII) in which R 1 and R 2 are defined as above by the application or adaptation of known processes, eg, when Z 1 represents a chlorine atom, by reaction with thionyl chloride or oxalyl chloride.

Compounds of the general formula: wherein R 12 represents an alkoxyalkyl group or more particularly an alkoxyalkoxyalkyl or especially an alkoxyalkoxyalkoxyalkyl and R 2 is defined as above are intermediates a process for their preparation and their use in the synthesis of useful pharmaceutical products, eg compounds of formula I, are aspects of the present invention.

According to one aspect of this invention, compounds of formula IX are prepared by oxidation of compounds of the general formula: wherein R 12 and R 2 are as defined above, by the application or adaptation of known processes , for example by reaction with an alkali metal halide, such as sodium bromide, and with a free radical, such as a 2,2,6,6-tetramethyl-1-piperidinyloxy free radical.

This reaction is preferably carried out in the presence of a base such as an aqueous solution of an alkali metal carbonate or bicarbonate and in the presence of a suitable solvent, such as acetonitrile, at or above room temperature. 73019 Ν.62879

-16- 73019 Ν.62879

The following Examples illustrate the preparation of the compounds according to the invention. Examples 1 to 16 illustrate the preparation of compounds of Formula I, Examples 17 and 18 illustrate the preparation of key intermediates of Formula IX and Reference Examples illustrate the preparation of other intermediates. EXAMPLE 1

Compound A

A stirred solution of oleic acid (4.20 g) and triethylamine (1.8 g) in dichloromethane (50 ml) was treated with methyl chloroformate (1.7 g) at -30 ° C. The mixture was stirred for 2 hours, allowing it to warm to room temperature. It was then treated with a solution of N- (2-methylthio) ethyl-4-methylthio-3-aminobenzamide (4.0 g) and triethylamine (2.5 g) in dichloromethane (50 ml). The resulting clear solution was allowed to stand for 17 hours and then diluted with dichloromethane (250 ml), washed sequentially with hydrochloric acid (200 ml; 1N aqueous solution of sodium chloride, saturated aqueous sodium hydrogen carbonate solution ( 100 ml) and finally with aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in diethyl ether (250 ml) and the solution was washed with hydrochloric acid (2 x 150 ml, 2N), dried over magnesium sulfate and concentrated under reduced pressure. the resulting residue was crystallized from a gasoline mixture (mp 40-60 ° C) and diethyl ether to give a waxy solid which was subjected to silica gel column chromatography eluting with ethyl acetate and recrystallized from ether t to give (Z) -N- (2-methylthio) ethyl-4-methylthio-3- (octadec-9-enamido) benzamide (0.7 g) as a colorless solid, mp 84 DEG- 86 ° C. [Elemental analysis: C, 67.4; H, 9.5; N, 5.1; S, 12.2%; calculated: C, 66.88; H, 9.29; N, 5.38; S, 12.31%].

Example 2

Compound B

An ice cold solution of N- (2-methoxy) ethyl-3-amino-4- (methylthio) 7,3019 Ν.62879

(3.99 g) in dry dichloromethane (50 ml) and triethylamine (2.79 ml) was slowly treated with a solution of oleyl chloride (5 g) in dry dichloromethane (30 ml). The mixture was stirred at room temperature for 2.5 hours and was then concentrated under reduced pressure to give a solid. This solid was dissolved in ethyl acetate and the solution was washed sequentially with hydrochloric acid (2N), aqueous sodium hydroxide solution (1N) and with water, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was crystallized from a mixture of amyl acetate (65 ml) and ethyl acetate (5 ml) and then in toluene to give (Z) -N- (2-methoxy) ethyl-4- methylthio-3- (octadec-9-enamido) benzamide (4.81 g) as a white, soft solid, mp 110-112 ° C. [Elemental Analysis: C, 69.1; H, 9.8; N, 5.46; S, 6.5%; calculated: C, 69.00; N, 9.58; N, 5.55; S, 6.35%].

Example 3

Compound C

A solution of methyl 3-amino-4-methoxybenzoate (3.0 g) in dry dichloromethane (50 ml) and dry triethylamine (2.79 ml) was slowly treated with a solution of oleyl chloride (5 g) in dry dichloromethane (30 ml). The mixture was stirred at room temperature for 45 minutes and then concentrated under reduced pressure. The resulting solid was crystallized from aqueous ethanol to give brown crystals (6.63 g), from which a sample (250 mg) was recrystallized from ice-cold petrol (mp 40-60øC) containing a trace of methanol, (195 mg) was obtained as white off-white crystals, mp 46 DEG-47 DEG. [Elemental analysis: C, 72.2; H, 9.65; N, 3.18%; calculated: C, 72.77; H, 9.72; N, 3.14%]. EXAMPLE 4

Compound K

A stirred, chilled solution of (Z) -4-methoxy-3- (octadec-9-enamido) benzoyl chloride (1.5 g) [prepared by the reaction of thionyl chloride with (Z) -4- methoxy-3- (octadec-9-enamido) benzoic acid (itself prepared as described below in dichloromethane (20 ml) was treated with a solution of butylamine (0.5 g) in dry dichloromethane (10 ml). The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The resulting residue was crystallized from cyclohexane and then recrystallized from a mixture of diethyl ether and pentane to give (Z) -N-butyl-4-methoxy-3- (octadec-9-enamido) benzamide ( , 474 g) as a gray solid, mp 81-82 ° C. [Elemental analysis: C, 73.9; H, 10.4; N, 5.7%; calculated: C, 74.03; H, 10.35; N, 5.76%]. EXAMPLE 5

Compounds D. E. F. G. H. J.

A solution of N- (2-methylthio) ethyl-3-amino-4- (methylthio) benzamide (3.0 g) and dry triethylamine (3.0 g) in dry dichloromethane (50 ml) was treated with solution of hexadecanoyl chloride (3.4 g) in dry dichloromethane (20 ml). The solution was stirred at room temperature for 3 hours and then diluted with dichloromethane (250 ml). The solution was washed with hydrochloric acid (100 ml; 1N), dried over magnesium sulfate and concentrated under reduced pressure, and the solid (9: 1 v / v) to give N - (2-methylthio) ethyl-3-hexadecanamido-4- (methylthio) benzamide (5.14 g) as white crystals, mp 104-105 ° C. [Elemental analysis: C, 65.3; H, 9.4; N, 5.6; S, 13.2%; calculated: C, 65.54; H 9.37; N, 5.66; S, 12.96%].

By proceeding in a similar manner, but using the appropriate acid chloride and the appropriate aminobenzamide derivative, there were prepared: N-butyl-3-hexadecanamido-4- (methylthio) benzamide as white crystals, mp 125-126ø W. [Elemental analysis: C, 70.4; H, 10.18; N, 5.88; S, 6.95%; calculated: C, 70.54; H, 10.15; N, 5.88; S, 6.73%]; N- (2-methoxy) ethyl-3-hexadecanamido-4- (methylthio) benzamide as white crystals, m.p. 115-117 ° C. [Elemental analysis: C, 68.1; H, 9.9; N, 5.8; S, 6.88%; calculated: C, 67.74; H 9.69; N, 5.85; 73019 Ν.62879 S, 6.70%]; N-butyl-3-dodecanamido-4- (methylthio) benzamide as white crystals, m.p. 126-128 ° C. [Elemental analysis: C, 68.4; H, 9.6; N, 6.7; S, 7.7%, calculated: C, 68.53; H 9.58; N, 6.66; S, 7.62%]; N- (2-methoxy) ethyl-3-dodecanamido-4- (methylthio) benzamide as white crystals, m.p. 113-115 ° C. [Elemental analysis: C, 65.3; H, 9.2; N, 6.6; S, 7.6%; calculated: C, 65.37; H, 9.06; N, 6.63; S, 7.59%]; N- (2-methylthio) ethyl-3-dodecanamido-4- (methylthio) benzamide as white needles, m.p. 102-104 ° C. [Elemental analysis: C, 63.1; H, 8.8; N, 6.7; S, 14.7%; calculated: C, 62.97; H 8.73; N, 6.39; S, 14.62%]; and N-butyl-N-methyl-3-hexadecanamido-4-methoxybenzamide as an off-white powder (petrol (m.p. 100-120 ° C)], m.p. 66-68 ° C. [Elemental analysis: C, 73.2; H, 10.8; N, 5.61%; calculated: C, 73.37; H 10.62; N, 5.90%]. EXAMPLE 6

Compound L

A solution of 1-decylcyclopentanecarboxylic acid (2.1 g) and thionyl chloride (3 ml) in dry dichloromethane was heated at reflux for 3 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in dichloromethane (30 ml) and added to a solution of dry triethylamine (2.4 g) and N- (2-methylthio) ethyl-3-amino-4- (methylthio) benzamide (2.16 g) in dichloromethane (50 ml). The mixture was stirred at room temperature for 1 hour, then diluted with dichloromethane (100 ml) and washed sequentially with hydrochloric acid (100 ml; 1N), aqueous sodium chloride solution (100 ml), aqueous sodium hydroxide solution (1.5 g in 100 ml), hydrochloric acid (100 ml, 1N) and aqueous sodium chloride (100 ml), dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography, eluting with t-butyl ether, to give N- (2-methylthio) ethyl-3- (1-decylcyclopentanecarboxamido-4- (methylthio) benzamide (3.15 g) as a waxy solid. Elemental analysis: C 66.2, H 9.4, N, 5.24, S 12.3%, calc'd for 1 H-NMR (DMSO-d 6):?

Compounds M and N

A mixture of methyl (Z) -4-methoxy-3- (octadec-9-enamido) benzoate (6.12 g, prepared as described in Example 3), sodium hydroxide (0.6 g), water ( 20 ml) and ethanol (200 ml) was heated at reflux for 1.5 hours. The mixture [containing (Z) -4-methoxy-3- (octadec-9-enamido) benzoate] was cooled to room temperature and then poured into a mixture of crushed ice and hydrochloric acid. The product was collected and recrystallized from methanol to give (Z) -4-methoxy-3- (octadec-9-enamido) benzoic acid (4.14 g) as a white powder, mp 179-183 ° C . [Elemental analysis: C, 72.3; H, 9.5; N, 3.3%; calculated: C, 72.35; H 9.57; N, 3.24%]. EXAMPLE 8

Compounds O to V

Proceeding in a manner similar to that described in Example 5, but employing the appropriate acid chlorides and the appropriate anilines and simply removing the solvent under reduced pressure at the end of the reaction period and crystallizing the residue, were prepared: N-butyl-3- -dodecanamido-4- (ethylthio) benzamide as white plates, mp 102-104øC (in aqueous ethanol). [Elemental analysis: C, 69.0; H, 9.9; N, 6.4; S, 7.4%; calculated: C, 69.08; H 9.74; N, 6.45; S, 7.37%]. N-butyl-4-ethylthio-3-hexadecanamidobenzamide as white crystals, m.p. 89-91 ° C (aqueous ethanol). [Elemental analysis: C, 70.9; H, 10.3; N, 5.4; S, 6.57%; calculated: C, 70.97; H, 10.27; N, 5.71; S, 6.53%]. N-butyl-4-ethylthio-3-heptadecanamidobenzamide as white crystals, m.p. 81-83Â ° C (from aqueous ethanol). [Elemental analysis: C, 71.1; H, 10.7; N, 5.3; S, 6.09%; calculated: C, 71.37; H, 10.38; N, 5.55; S, 6.35%]; N-butyl-4-ethylthio-3-octadecanamidobenzamide as white crystals, m.p. 80-82 ° C (aqueous ethanol). [Elemental analysis: C, 71.6; H, 10.8; N, 5.3; S, 6.02%, calculated: C, 71.76; H, 10.49; N, 5.40; S, 6.18%]; 4-ethylthio-3-hexadecanamido-N- (2-methylthioethyl) benzamide as white crystals, m.p. 92-94 ° C (aqueous ethanol). [Elemental analysis: C, 66.5; H, 9.7; N, 5.5; S, 15.5%; calculated: C, 66.09; H, 9.51; N, 5.51; S, 12.60%]; 4-ethylthio-3-heptadecanamido-N- (2-methylthioethyl) benzamide as white crystals, m.p. 91-93 ° C (aqueous ethanol). [Elemental analysis: C, 66.5; H, 9.7; N, 5.36; S, 12.0%, calculated: C, 66.62; H, 9.64; N, 5.36; S, 12.26%]; 3-heptadecanamido-4-methylthio-N- (2-methylthioethyl) benzamide as white crystals, m.p. 101-102 ° C (aqueous ethanol and then ethyl acetate). [Elemental analysis: C, 66.5; H, 9.8; N, 5.50; S, 12.6%, calculated: C, 66.09; H, 9.51; N, 5.51; S, 12.60%]; and 3-heptadecanamido-N- (2-methoxyethyl) -4- (methylthio) benzamide as white crystals, m.p. 115-116Â ° C (aqueous ethanol and then isopropanol). [Elemental analysis: C, 68.4; H, 10.10; N, 5.65; S, 6.50%; calculated: C, 68.25; H, 9.82; N, 5.69; S, 6.50%]. EXAMPLE 9

Compound W

Proceeding in a similar manner to that described in Example 2, but substituting the appropriate amount of 3-amino-N-butyl-4- (methylthio) -3- (2-methoxy) benzamide and crystallizing the product from toluene, there was prepared (Z) -N-butyl-3- (2-hydroxy-4-methyl-benzthiazole) as a light brown solid pale, mp 118-120 ° C. [Elemental analysis: C, 71.3; H, 10.0; N, 5.59; S, 6.37%, calculated: C, 71.66; H, 10.02; N, 5.57; S, 6.38%]. EXAMPLE 10

Compounds X to AJ

Proceeding in a manner similar to that described in Example 5, but employing the appropriate acid chlorides and the appropriate anilines, there were prepared: 4-Ethylthio-N- (3-methylthiopropyl) -3-octadecanamidobenzamide as colorless crystals, mp 75-76 ° C (from a mixture of t-butyl methyl ether and methanol) [Elemental analysis: C, 67.4; H, 10.0; N, 5.0; S, 11.6%, calculated: C, 67.59; H, 9.88; N, 5.08; S, 11.64%]; 4-ethylthio-3-heptadecanamido-N- (3-methylthiopropyl) benzamide as white crystals, mp 74-77 ° C (from a mixture of t-butyl methyl ether and methanol). ; H, 10.00; N, 5.30; S, 11.70%; calculated: C, 67.11; H, 9.76, N, 5.22; S, 11.95%]; 4-ethylthio-3-hexadecanamido-N- (3-methylthiopropyl) benzamide as white crystals, mp 75-78 ° C (from a mixture of t-butyl methyl ether and methanol). , 5; H, 9.7; N, 5.11; S, 11.9%; calculated: C, 66.62; H, 9.64; N, 5.36; S, 12.26%]? 4-methylthio-N- (2-methylthioethyl) -3-octadecanamidobenzamide as white crystals, mp 104-106 ° C (from a mixture of t-butyl methyl ether and methanol) 6 ' H, 9.9; N, 5.2; S, 12.0%; calculated: C, 66.62; H, 9.64; N, 5.36; S, 12.26%]; N-butyl-3-dodecanamido-4-methoxybenzamide as white crystals, m.p. 107-109 ° C (from a mixture of t-butylmethylether and methanol) [Elemental analysis: C, 70.9; H, 10.10; N, 6.72%; Calc'd: Calc'd: C, 76.19; H, 9.96; N, 6.93%]; 4-ethylthio-3-hexadecanamido-N- (3-methoxypropyl) benzamide as white crystals, m.p. 78-80Â ° C (acetonitrile) [Elemental analysis: C, 68.4; H, 9.93; N, 5.1; S, 6.21%; calculated: C, 68.73; H, 9.94; N, 5.53; S, 6.33%]; N-butyl-3-octadecanamido-4- (methylthio) benzamide as a white powder, mp 115-118 ° C (from a mixture of t-butylmethylether and methanol) [Elemental analysis: C, 71.6 ; H, 10.7; N, 5.13; S, 5.79%; calculated: C, 71.38; H, 10.38; N, 5.55; S, 6.35%]; 4-methylthio-N- (3-methylthiopropyl) -3-octadecanamidobenzamide as a white powder, m.p. 87-94Â ° C (from toluene) [Elemental analysis: C, 66.6; H, 9.85; N, 4.83; S, 11.65%; calculated: C, 67.12; H, 9.76; N, 5.22; S, 11.94%]; 4-ethylthio-N- (3-methoxypropyl) -3-octadecanamidobenzamide as a white powder, m.p. 80-83Â ° C (from toluene): Elemental analysis: C, 69.7; H, 10.3; N, 5.07; S, 5.87%; calculated: C, 69.62; H, 10.18; N, 5.24; S, 5.99%]; N-butyl-3- (5-chloropentanamido) -4- (ethylthio) benzamide as a white powder, m.p. 104-105 ° C (t-butylmethyl ether): Elemental analysis: C, 58.2; H, 7.4; Cl, 9.6; N, 7.5; S, 8.6%; calculated: C, 58.28; H, 7.34; Cl, 9.56; N, 7.55; S, 8.64%]; 3- (4-chlorobutanamido) -4-ethylthio-N- (3-methylthiopropyl) benzamide as a white powder, mp 80-81 ° C (from a mixture of t-butyl methyl ether and methanol). Elemental: C, 52.2; H, 6.87; Cl, 9.5: N, 7.3; S, 15.7%; calculated: C, 52.49; H, 6.48; Cl, 9.11; N, 7.20; S, 16.49%]; 3- (5-chloropentanamido) -4-ethylthio-N- (3-methylthiopropyl) benzamide as a pale yellow powder, mp 95-96 ° C (from a mixture of t-butyl methyl ether and methanol). Elemental: C, 53.7; H, 6.87; Cl, 8.8: N, 6.82; S, 15.6%; calculated: C, 53.65; H, 6.75; Cl, 8.80; N, 6.85; S, 15.91%]; and methyl methyl 3-hexadecanamido-4-methoxybenzoate as colorless needles, m.p. 109-111Â ° C (from ethanol) [Elemental analysis: C, 71.1; H, 9.9; N, 3.26%? calculated: C, 71.56; H, 9.85; N, 3.34%]; EXAMPLE 11

AK and AL Compounds

Proceeding in a similar manner to that described in Example 7 but substituting methyl (3-hexadecanamido-4-methoxybenzoate for methyl (Z) -4-methoxy-3- (Ooctadec-9-enamido) benzoate for the corresponding amount described in Example 10), 3-hexadecanamido-4-methoxybenzoic acid was prepared as colorless needles, mp 198-200 ° C (from ethanol). [Elemental analysis: C, 71.1; H, 9.8; N, 3.40%; calculated: C, 71.07; H, 9.69; N, 3.45%] via sodium 3-hexadecanamido-4-methoxybenzoate. EXAMPLE 12

Compound AM

A mixture of 3-hexadecanamido-4-methoxybenzoic acid (4.04 g, prepared as described in Example 11) and thionyl chloride (1.3 ml) was heated in boiling toluene (100 ml) for 3 hours. The solvent was removed under reduced pressure. The residual acid chloride was dissolved in dry dichloromethane (35 ml) and added to a stirred solution of 2-methoxyethylamine (3 ml) and dry triethylamine (1.6 ml) in dichloromethane (115 ml). After standing at ambient temperature for 2 days, the solution was washed with hydrochloric acid (2 x 200 ml); 2N) and then with water (2 x 200 ml) and then dried over potassium carbonate and concentrated under reduced pressure. The resulting residue was chromatographed on silica gel, eluting with a mixture of diethyl ether and dichloromethane to give 3-hexadecanamido-4-methoxy-N- (2-methoxyethyl) benzamide (2.0 g) as a white solid. a white powder, mp 78-80øC [Elemental analysis: C, 69.8; H, 10.3; N, 5.90%; calculated: C, 70.09; H, 10.02; N, 6.06%]. EXAMPLE 13

Compound AN

A solution of 3-hexadecanamido-4-methoxybenzoyl chloride 73019 Ν.62879 / ί

Jf- * 3Τ ·

[prepared from 3-hexadecanamido-4-methoxybenzoic acid (2.02 g, prepared as described in Example 11) and thionyl chloride] in dichloromethane (50 ml) was added to a stirred solution of 3-methylbut- 2-enylamine (0.98 g) in dichloromethane (100 ml) and triethylamine / 1 ml). The mixture was stirred at room temperature for 1 hour and then washed successively with water (100 ml), aqueous sodium hydroxide solution (100 ml, 2N), dilute hydrochloric acid (100 ml, 2N) and water (100 ml) and then dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was chromatographed on silica gel eluting with a mixture of methanol and dichloromethane to give 3-hexadecanamido-4-methoxy-N- (3-methylbut-2-enyl) benzamide (0.6 g) as a cream solid, mp 109-111 ° C after crystallization from a gasoline mixture (bp 40-60 ° C) and diethyl ether [Elemental analysis; C, 73.2; H, 10.3; N, 5.60%; calculated; Found: C, 73.68; H, 10.24; N, 5.93%]. EXAMPLE 14

Compounds AO to AZ

A solution of 5,9-dioxa-hexadecanoyl chloride in dichloromethane [prepared from 5,9-dioxa-hexahydecanoic acid (2.0 g, prepared as described in Example 17) and oxalyl chloride (2.4 ml) in dichloromethane (25 ml)] was added to a stirred suspension of 3-amino-N-butyl-4- (methylthio) benzamide (1.83 g) in dry dichloromethane (25 ml) and triethylamine 5 g), yielding a clear solution. After standing at room temperature for 65 hours, the solution was concentrated under reduced pressure to about 10 ml. The residue was taken up in t-butyl methyl ether (300 ml) and washed sequentially with dilute hydrochloric acid (100 ml, 0.511), aqueous sodium hydroxide solution (100 ml, 2% w / v) and dilute hydrochloric acid ( 100 ml, 0.5 N) and then dried and concentrated under reduced pressure. The resulting residue was chromatographed on silica gel, eluting with ethyl acetate to give N-butyl-4-methylthio-3- (5,9-dioxa-hexadecanamido) benzamide (2.05 g) as a solid waxy, pale yellow [Elemental analysis; C, 65.4; H, 9.6; N, 5.93; S, 6.42%; Calc'd for C 20 H 30 N 3 O 3: Calc'd: C, 64.96; Δ, 9.23; Δ, 5.83; S, 6.67%].

By proceeding in a similar manner, but using the appropriate acids and suitable anilines, there was prepared: 4-methylthio-N- (3-methylthiopropyl) -3- (5,9-dioxahexadecanamido) benzamide as a a pale yellow waxy solid [Elemental analysis: C, 61.0; H, 8.9; N, 5.36; S, 12.4%; calculated: C, 60.90; H, 8.65; N, 5.46; S, 12.51%]; N-butyl-4-ethylthio-3- (5,9,13-trioxahexadecanamido) benzamide as an amber oil [Elemental analysis: C, 62.5; H, 9.1; N, 5.7; S, 6.43%, calculated: C, 62.87; H, 8.93; N, 5.64; S, 6.46%]; 4-ethylthio-N- (3-methylthiopropyl) -3- (5,9-dioxa-hexadecanamido) benzamide as a waxy, pale yellow solid (eluting with a mixture of dichloromethane and methanol) C, 61.4; H, 8.91; N, 5.34; S, 12.0%; calculated: C, 61.56; H, 8.80; N, 5.32; S, 12.17%]; N-butyl-4-ethylthio-3- (5,9-dioxa-hexadecanamido) benzamide as a pale brown oil (eluting with a mixture of dichloromethane and methanol). Elemental analysis: C, 65.4; H, 9.6; N, 5.5; S, 6.26%, calculated: C, 65.55; H, 9.37; N, 5.66; S, 6.48%]; 4-ethylthio-N- (3-methoxypropyl) -3- (5,9-dioxa-hexadecanamido) benzamide as a pale brown oil (eluting with a mixture of dichloromethane and methanol) 63.2; H, 9.1; N, 5.2; S, 6.12%; calculated: C, 63.50; H, 9.08; N, 5.48; S, 6.28%]; 4-ethylthio-N- (3-methoxypropyl) -3- (5,9,13-trioxahexadecanamido) benzamide as a pale brown oil [Elemental analysis: C, 60.5; H, 8.7; N, 5.16; S, 6.08%; calculated: C, 60.91; H, 8.65; N, 5.46; S, 6.25%]; 4-ethylthio-N- (3-methoxypropyl) -3- (5-oxahexadecanamido) benzamide as a pale brown oil which solidified with the residue 73019 Ν.62879

(Eluting with a mixture of dichloromethane and methanol) [Elemental analysis: C, 66.04; H, 9.8; N, 5.35; S, 6.24%; calculated: C, 66.10; H, 9.51; N, 5.51; S, 6.30%]; 4-methylthio-N- (3-methylthiopropyl) -3- (5-oxahexadecanamido) benzamide as a pale brown oil which solidified on standing (eluting with a mixture of dichloromethane and methanol) : C, 63.6; H, 9.3; N, 5.48; S, 11.9%; calculated: C, 63.49; H, 9.08; N, 5.17; S, 12.55%]; N-butyl-4-methylthio-3- (5-oxahexadecanamido) benzamide as a pale brown oil which solidified on standing (eluting with a mixture of dichloromethane and methanol). Elemental analysis: C, 68.0 ; H, 9.9; N, 5.6; S, 6.24%; calculated: C, 67.74; H, 9.69; N, 5.85; S, 6.70%]; 4-methoxy-N- (3-methylthiopropyl) -3- (5,9-dioxahexadecanamido) benzamide as a pale brown oil (eluting with a mixture of dichloromethane and methanol) 62.5; H, 9.2; N, 5.48; S, 6.19%; calculated: C, 62.87; H, 8.93; N, 5.64; S, 6.46%]; and 4-ethylthio-N- (3-methylthiopropyl) -3- (5,9,13-trioxahexadecanamido) benzamide as a pale brown oil (eluting with a mixture of dichloromethane and methanol) C, 58.2; H, 8.5; N, 4.96; S, 11.3%; calculated: C, 59.06; H, 8.39; N, 5.30; S, 12.13%]; EXAMPLE 15

Compound BA

Heptadecanoyl chloride (2.79 g) was added dropwise over 10 minutes to a stirred solution of methyl 3-amino-4- (imidazol-1-yl) benzoate (2.0 g, prepared as described in Reference Example 1) in dry pyridine (60 ml). When the reaction was complete (judged by a thin layer chromatogram), water (300 ml) was added. The precipitated solid was collected, washed with water and dried, and then dissolved by heating in ethyl acetate (0 ml) containing 28% -28%. Hydrochloric acid (1 ml). The solid which crystallized upon cooling was collected, washed with diethyl ether and dried at 80 ° C to give methyl 3-heptadecanamido-4- (imidazol-1-yl) benzoate as white crystals of the hydrochloride m.p. 106-109Â ° C [Elemental analysis: C, 64.7; H, 8.6; N, 7.9; Cl, 6.83; water 3.8%; Calc'd for C 21 H 43 N 3 O 3 .HCl · H 2 O: C, 64.72; H, 8.99; N, 7.81; Cl, 6.59; water, 3.35%]. EXAMPLE 16

compounds BB to BG

By application or adaptation of the processes described above, more especially in the previous Examples, there was prepared: N- (3-methylsulfonylpropyl) -4-methylthio-3- (5,9-dioxahexadecanamide) benzamide as a pale brown oil that solidified with rest; 4-ethylthio-N- (3-methylthiopropyl) -3- (5,9-dioxaoctadecanamido) benzamide as a pale brown oil (Elemental Analysis: C, 63.1; H, 9.5; N, 4.73%; calculated: C, 62.78; H, 9.08; N, 5.05%]; N-butyl-4-ethylthio-3- (5,10-dioxa-hexadecanamido) benzamide, as a pale yellow solid; 4-ethylthio-N- (3-methylthiopropyl) -3- (6,10,14-trioxahexadecanamido) benzamide as a pale brown oil (Elemental Analysis: C, 58.0; H, 8.5; N, 5.30; S, 11.0%; Calculated: C, 59.06; H, 8.39; N, 4.95; S, 12.13%]; 4-imidazol-1-yl-N- (3-methylthiopropyl) -3- (5-oxahexadecanamido) benzamide as a white powder, mp 77-79øC [Elemental analysis: C, 66.0 ; H, 8.9; N, 10.7% Calculated: C, 65.62; H, 8.74; N, 10.56%]; and 3-hexadecanamido-4-imidazol-1-yl-N- (3-methylthiopropyl) benzamide as a white powder, m.p. 104-105 ° C. Elemental analysis:

Calc'd: C, 68.6; Η, 9.4; Δ, 10.7%, calculated: C, 68.14; Η, 9.15, Ν, 10.60%]; EXAMPLE 17

Compounds ΙΝΤ a. ΙΝΤ b e ΙΝΤ c

Sodium bromide trihydrate (35.0 g) was added to a vigorously stirred cooled mixture of 5,9,13-trioxa-hexadecan-1-ol (11.5 g), 2.2, 6,6-tetramethyl-1-piperidinyloxy, free radical (0.25 g), aqueous sodium hydrogencarbonate solution (450 ml, 5% w / v) and acetonitrile (450 ml) maintaining a temperature of 0 ° C to 10 ° C ;W. The mixture was stirred at room temperature for 4 hours and then quenched by the careful addition of hydrochloric acid and aqueous sodium metabisulfite sufficient to give a pH of 2 to 4 and to consume the excess oxidant. The solution was extracted with t-butyl methyl ether (4 x 200 ml) and the combined organic solution was washed with aqueous sodium chloride solution, dried and concentrated under reduced pressure. The resulting residue was distilled at a furnace temperature of 170 ° C and a pressure of 133.3 Pa (0.1 mm Hg) to give 5,9,13-trioxahexadecanoic acid (10.3 g) in form of a colorless, mobile oil. [Elemental analysis: C, 59.52; H, 9.99%; calculated: C, 59.9; H, 10.9%].

Proceeding in a similar manner but replacing 5,9,13-trioxahexadecan-1-ol with the appropriate amounts of 5,9-dioxa-hexadecan-1-ol and 5-oxa-hexadecan-1-ol, respectively and with the difference that the residue left after concentration under reduced pressure was taken up in t-butyl methyl ether, filtered to remove the solids and concentrated, again under reduced pressure before distillation, there were prepared: 5,9-dioxa -hexadecanoic acid as a colorless, mobile oil [Elemental analysis: C, 64.9; H, 11.3%; calculated: C, 64.58; H, 10.84%]; and 5-oxahexadecanoic acid as a colorless, mobile oil which solidified, m.p. 28-30 ° C. Elemental analysis: C, 68.5; H, 11.6%; calculated: C, 69.72; H, 11.70%].

73019 Ν.62879 -30- ΕΧΕΜΡΙιΟ 18

Compounds ΙΝΤ d. ΙΝΤ e e ΙΝΤ f

Proceeding in a similar manner to that described in Example 17, but using the appropriate alcohols, 6,10,14-trioxahexadecanoic acid was prepared as a colorless, mobile oil [Elemental analysis: C, 57.5; H, 10.0%; Calc'd: C, 59.52; H, 9.99%]; 5,10-dioxahexadecanoic acid, as a colorless, mobile oil, b.p. 97-105 ° C / 133.3 Pa (0.1 mm Hg). Elemental analysis: C, 66.1; H, 11.5%; calculated: C, 64.58; H, 10.84%]; and 5,9-dioxa-hexadecanoic acid, as a colorless, mobile oil [Elemental analysis: C, 66.2; H, 11.4%; calculated: C, 66.63; H, 11.18%]. REFERENCE EXAMPLE 1

Methyl 4- (imidazol-1-yl) -3-nitrobenzoate was reduced by reaction with iron powder (22.0 g) in boiling ethanol (150 ml) containing water (35 ml) and hydrochloric acid (1, 5 ml, 1N). Recrystallization from ethyl acetate gave methyl 3-amino-4- (imidazol-1-yl) benzoate (9.7 g) as pale yellow crystals, m.p. 161-165 ° C. REFERENCE EXAMPLE 2

Methyl 4-fluoro-3-nitrobenzoate (17.0 g) was reacted with imidazole (13.0 g) at room temperature in dry tetrahydrofuran (100 ml) to give 4- (imidazol-1 -yl) -3-nitrobenzoate (14.68 g) as yellow, large needles, mp 71-74 ° C (t-butyl methyl ether). REFERENCE EXAMPLE 3

4-Ethylthio-N- (3-methoxypropyl) -3-nitrobenzamide (47.0 g) was reduced by reaction with iron powder (55.0 g) in boiling ethanol (750 ml) containing hydrochloric acid (95 ml ; 0.5N). Recrystallization from t-butylmethylether gave 3-amino-4-ethylthio-N- (3-methoxypropyl) benzamide (32.4 g) as fine, 73-75 ° W. REFERENCE EXAMPLE 4 Reaction of 3-methoxypropylamine with 4-ethylthio-3-nitrobenzoyl chloride and recrystallization from toluene afforded 4-ethylthio-N- (3-methoxypropyl) -3-nitrobenzamide in 74% yield, a yellow solid, mp 101-103 ° C. REFERENCE EXAMPLE 5

A solution of 3- (3-propoxypropoxy) propan-1-ol (25.39 g) and dry pyridine (11.47 g) in dichloromethane (30 ml) was added over 10 minutes to a stirred solution of trifluoromethanesulfonic anhydride (49 , 1 g) in dichloromethane (90 ml), keeping the temperature below 0 ° C. The mixture was stirred for 3 hours without further cooling and was then washed with ice water (100 ml) and dried. The solution was filtered, diluted with dichloromethane (150 ml) and then stirred with potassium carbonate (27.0 g) and 4-hydroxybutyl acrylate (25.2 g) overnight at room temperature under argon. an atmosphere of argon. The mixture was then heated at reflux for 8 hours. The mixture was filtered, the residue was washed with dichloromethane (300 mL) and the filtrate was then washed with hydrochloric acid (250 mL, 1 N) and with water (2 x 250 mL). The residue which remained after drying and the concentration under reduced pressure was dissolved in ethanol (300 ml) and stirred with a solution of sodium hydroxide (11.4 g) in water (65 ml) for 4 hours. The solution was concentrated under reduced pressure to about 180 ml, diluted with t-butyl methyl ether (1 liter) and washed with water (2.times.400 ml). The residue remaining after drying and concentration under reduced pressure was distilled under reduced pressure giving 5,9,13-trioxahexadecan-1-ol (16.9 g) as a colorless mobile oil, mp 109 DEG-109 DEG. -113øC / 133.3 Pa (0.1 mmHg).

Proceeding in a similar manner, but using the appropriate amount of 3-heptyloxypropan-1-ol instead of 3- (3-propoxypropoxy) propan-1-ol, 5,9-dioxahexadecan-1-ol, as a colorless, mobile oil, bp 123-125 ° C / 133.3 Pa

73019 Ν.62879 (0.1, mmHg) REFERENCE EXAMPLE 6

Lithium hydride-aluminate (3.5 g) was added cautiously to a stirred solution of aluminum chloride (38.98 g) in diethyl ether (200 ml) under a gentle stream of nitrogen, keeping the temperature below 15 ° C. ° C. The mixture was stirred for 2 hours and then 2-decyl-1,3-dioxepane (30.7 g) was added over 30 minutes. The mixture was stirred at reflux for 8 hours and then cooled to room temperature. Water (50 ml) was added dropwise, followed by diethyl ether (300 ml). The aqueous fraction was extracted with diethyl ether (3x200 ml) and the combined organic solution was then dried. The solvent was removed and the residue was distilled, yielding 5-oxahexadecan-1-ol (25.24 g) as an oil, b.p. 126-127 ° C / 133.3 Pa (0.1 mm Hg). The present invention also includes within its scope pharmaceutical compositions which comprise at least one of the compounds of 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, rectally or orally.

Solid compositions for oral administration include pressed tablets, pills, powders and granules. In such solid compositions, one or more active compound (s) is or are mixed with at least one inert diluent such as starch, sucrose or lactose. The compositions also comprise, as is normal practice, additional substances in addition to the 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. In addition to the inert diluents these compositions may comprise adjuvants, such as wetting and suspending agents, and sweetening, flavoring, perfuming and preservative agents. The compositions according to the invention for oral administration also include capsules of absorbable material, such as gelatin, containing one or more active substances with or without the addition of diluents or excipients.

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

Compositions for rectal administration include suppositories formulated according to known methods and containing at least one compound of formula I. The percentage of active ingredient in the compositions of the invention may be varied, it being necessary that it constitutes a ratio such that a dosage. Of course, several unit dosage forms can be administered at about the same time. The dose employed will be determined by the physician and depends on the desired therapeutic effect, the route of administration and the duration of treatment, and the condition of the patient. In the adult, the doses are generally from about 0.5 to about 70, preferably from about 1 to about 10 mg / kg of body weight per day per oral administration. 73019 'Ν. The following examples illustrate the pharmaceutical compositions according to the present invention. EXAMPLE OF COMPOSITION 1

N-Butyl-3-hexadecanamido-4- (methylthio) benzamide 20 mg lactose or the H mg amido 60 mg dextrin 40 mg magnesium stearate 1 was prepared according to the usual procedure, mg

Claims (9)

A process for the preparation of a benzamide derivative of the formula: -C0B5 in which it represents a straight or branched chain alkyl group containing up to 20 carbon atoms optionally containing one or more carbon-carbon double or triple bonds and optionally interrupted by one or more heteroatoms and optionally interrupted by one or more more sulfinyl or sulfonyl groups, optionally with one or more substituents selected from halogen, amino, alkoxy, alkylthio and alkylamino groups each containing up to 3 carbon atoms and groups of the formula -CONR 6 R 7 in which R 6 represents a hydrogen or a methyl group and R 7 represents a methyl, trifluoromethyl or trichloromethyl group, R 2 is the same or different and each represents a hydrogen atom, a straight or branched chain alkyl group containing up to 6 carbon atoms or a optionally substituted phenyl group, or the two R2 groups together with the carbon atom to which they are attached form a saturated or unsaturated ring saturated ring containing 3 to 8 carbon atoms and optionally containing one or more heteroatoms selected from oxygen, sulfur and nitrogen, R 3 represents a hydrogen atom or a straight or branched chain alkyl group containing up to 6 carbon atoms, R 4 represents a straight or branched chain alkoxy or alkylthio group containing up to 6 carbon atoms or a dimethylamino group or a 5- to 8-membered heterocycle group containing at least one nitrogen atom and connected through that nitrogen atom to the rest of the molecule and R 5 represents a group of the formula -NR 8 R 9 or -OR 10 in which R 8 and R 9 may be the same or different and each represents a hydrogen atom or a straight or branched chain alkyl group containing up to 10 carbon atoms optionally containing one or more carbon-carbon double or triple bonds and optionally interrupted by one or more heteroatoms and optionally interrupted by one or more heteroatoms. more sulfinyl or sulfonyl groups, and R 10 represents a hydrogen atom or a straight or branched chain alkyl group containing up to 10 carbon atoms, optionally containing one or more carbon-carbon double or triple bonds and optionally interrupted by one or more heteroatoms and optionally interrupted by one or more sulfinyl or sulfonyl groups, and pharmaceutically acceptable salts thereof, characterized in that it comprises: (A) reacting a compound of the general formula: in which R 3, R 4 and R 5 are as defined above with a compound of the general formula: in which R 2 and R 2 are as previously defined and Z 1 represents a halogen atom or an alkoxycarbonyloxy group or with the corresponding anhydride of the formula: in which R 1 and R 2 are as defined above or (B) when R 5 is not a group OR 3 in which R 3 -0 is hydrogen , reacting a compound of the general formula: wherein R 11 represents a straight-chain or branched alkyl group containing up to 10 carbon atoms, optionally containing one or more carbon-carbon double or triple bonds, and optionally interrupted by one or more heteroatoms and optionally interrupted by one or more sulfinyl or sulfonyl groups or a compound of the general formula: in which R 8 and R 9 are as defined above, with a compound of the general formula: Ν.62879 2 COZ in which R 1, R 2, R 3 and R 4 are as defined above and Z 2 represents a hydroxy group, a halogen atom or an alkoxycarbonyloxy group, or the corresponding anhydride; (C) followed, optionally, by the conversion by known procedures of the compound of formula (I) into another compound of formula (I) (D) followed optionally by conversion to a pharmaceutically acceptable salt. 2. A compound according to claim 1 wherein in the compound prepared R1 is alkylthioalkyl, alkylaminoalkyl or dialkylaminoalkyl. 3. A compound according to claim 1, wherein in the compound prepared R1 is an alkyl, alkenyl, alkoxyalkyl, alkoxyalkoxyalkyl or alkoxyalkoxyalkoxyalkyl group. A process according to any one of the preceding claims characterized in that in the compound prepared the heterocyclic group represented by R 4 is an imidazol-1-yl group or a pyrrolidin-1-yl group. A process according to claim 1, characterized in that in the compound prepared from at least one of the symbols has a value selected from the following; (i) R 1 represents an alkyl, alkenyl, alkoxyalkyl, alkoxyalkoxyalkyl, alkoxyalkoxyalkoxyalkyl or haloalkyl group containing from 8 to 20 carbon atoms; (ii) R 2 is each a hydrogen atom or the two R 2 groups together with the carbon atom to which they are attached form a cycloalkyl ring 73019 Ν 682879 and containing 3 to 8 carbon atoms; (iii) R 3 represents a hydrogen atom; (iv) R4 represents an imidazol-1-yl group or a straight or branched chain alkoxy or alkylthio group containing up to 3 carbon atoms; (v) R 1 represents a hydrogen atom or a straight or branched chain alkyl group containing up to 3 carbon atoms; (vi) R 3 represents a straight or branched chain alkyl or alkenyl group containing up to 6 carbon atoms, optionally interrupted by one or more oxygen or sulfur atoms or sulfonyl groups; (vii) R4 represents a hydrogen atom or a straight or branched chain alkyl group containing up to 6 carbon atoms, the other symbols being defined as in claim 1. 6. A compound as claimed in claim 5, wherein in the compound prepared (i) R 1 represents an alkyl or alkenyl group containing 8 to 20 carbon atoms; (ii) the cycloalkyl ring represented by the two R2 groups together with the carbon atom to which they are attached, contain 5 or 6 carbon atoms; (iii) the alkoxy or alkylthio group represented by R 4 contains 1 or 2 carbon atoms; (iv) R 2 is hydrogen or methyl; (v) R 3 represents an alkyl, alkoxyalkyl or alkylthioalkyl group containing 3 or 4 carbon atoms or an alkenyl group containing 5 carbon atoms; (vi) R4 represents a hydrogen atom or a straight or branched chain alkyl group containing up to 3 carbon atoms. A process according to claim 5 or 6 characterized in that in the compound of formula (I) R1 represents an alkyl or alkenyl group containing 4 to 18 carbon atoms; -39- 73019 Ν.62879 'Ιίϊ-MSiCKgfa (ii) the cycloalkyl ring represented by the two groups R 2 > together with the carbon atom to which they are attached, contain 5 carbon atoms; (iii) the alkoxy or alkylthio group represented by R4 is methoxy methylthio or ethylthio; (iv) R9 is a butyl, methoxyethyl, methylthioethyl, methoxypropyl, methylthiopropyl, methylsulfonyl-propyl or methylbut-2-enyl group; (v) R10 represents a hydrogen atom or a methyl group. A process for the preparation of a benzamide derivative according to claim 1, characterized in that the derivative prepared is a compound selected from the following: (Z) -N- (2-methylthio) ethyl-4-methylthio-3- ( octadec-9-enamido) benzamide; (Z) -N- (2-methoxy) ethyl-4-methylthio-3- (octadec-9-enamido) benzamide; (Z) -4-methoxy) -3- (octadec-9-enamido) benzoate; methyl; N- (2-methylthio) ethyl-3-hexadecanamido-4- (methylthio) benzamide; N-butyl-3-hexadecanamido-4- (methylthio) benzamide; N- (2-methoxy) ethyl-3-hexadecanamido-4- (methylthio) benzamide; N-butyl-3-dodecanamido-4- (methylthio) benzamide; N- (2-methoxy) ethyl-3-dodecanamido-4- (methylthio) benzamide; N-Butyl-N-methyl-3-hexadecanamido-4-methoxybenzamide; (Z) -N-butyl-4-methoxy-3- (2-methylthio) ethyl-3-dodecanamido-4- (methylthiobenzamide; octadec-9-enamido) benzamide; (Z) -4-Methoxy-3- (octadec-9-en-1-yl) enamido) benzoate, N-butyl-3-dodecanamido-4- (ethylthio) benzamide, N-butyl-4-ethylthio-3- (octadec-9-enamido) benzoic acid; 4-ethylthio-3-octadecanamidobenzamide; 4-Ethylthio-3-hexadecanamido-N- (2-methylthioethyl) benzamide; 4-ethylthio-3-heptadecanamido; N-butyl-4-ethylthio-3-heptadecanamidobenzamide; 3-heptadecanamido-N- (2-methylthioethyl) benzamide; 3-heptadecanamido-4-methylthio-N- (2-methylthioethyl) benzamide; (4-methylthio) benzamide; 4-Ethylthio-N- (3-methylthiopropyl) -3-octadecanamidobenzamide; 4-Ethylthio- ethylthio-3-heptadecanamido-N- (3-methylthiopropyl) benzamide; -ethylthio-3-hexadecanamido-N- (3-methylthiopropyl) benzamide; 4-methylthio-N- (2-methylthioethyl) -3-octadecanamidobenzamide; N-butyl-3-dodecanamido-4-methoxybenzamide; 4-ethylthio-3-hexadecanamido-N- (3-methoxypropyl) benzamide; N-butyl-3-octadecanamido-4- (methylthio) benzamide; 4-methylthio-N- (3-methylthiopropyl) -3-octadecanamidobenzamide; 4-ethylthio-N- (3-methoxypropyl) -3-octadecanamidobenzamide; N-butyl-3- (5-chloropentanamido) -4- (ethylthio) benzamide; 3- (4-chlorobutanamido) -4-ethylthio-N- (3-methylthiopropyl) benzamide; 3- (5-chloropentanamido) -4-ethylthio-N- (3-methylthiopropyl) benzamide; Methyl 3-hexadecanamido-4-methoxybenzoate; 3-hexadecanamido-4-methoxybenzoic acid; Sodium 3-hexadecanamido-4-methoxybenzoate; 3-hexadecanamido-4-methoxy-N- (2-methoxyethyl) benzamide; 4-methylthio-N- (3-methylbut-2-enyl) benzamide; N-butyl-4-ethylthio-3- (5,9,13-trioxahexadecanamido) benzamide; 4-Ethylthio-N- (5,9-dioxahexadecanamide) benzamide; N-butyl-4-ethylthio-3- (5,9-dioxa-hexadecanamido) benzamide: 4-Ethylthio-N- (3-methoxypropyl) -3-methylthiopropyl) -3- (5,9-dioxahexadecanamido) benzamide; 4-ethylthio-N- (3-methoxypropyl) -3- (5,9,13-trioxahexadecanamido) benzamide; 4-Ethylthio-N- (3,9-dioxahexadecanamido) benzamide; 4-methylthio-N- (3-methylthiopropyl) -3- (5-oxahexadecanamido) benzamide; 4-methylthiopropyl) -3- (5-oxahexadecanamido) benzamide; Ν.62879 4-methoxy-N- (3-methylthiopropyl) -3- (5,9-dioxa-hexadecanamido) -benzamide 4-methylthio-3- (5-oxahexadecanamido) benzamide; methylthio-N- (3-methylthiopropyl) -3- (5,9,13-trioxahexadecanamide) benzamide Methyl N- (3-methylsulfonyl) -3-heptadecanamido-4- (imidazol-1-yl) benzoate; propyl) -4-methylthio-3- (5,9-dioxa-hexadecanamido) benzamide; 4-ethylthio-N- (3-methylthiopropyl) -3- (5,9-dioxaoctadecanamido) benzamide; N-butyl-4-ethylthio-3- (5,10-dioxa-hexadecanamido) benzamide; 4-ethylthio-N- (3-methylthiopropyl) -3- (6,10,14-trioxahexadecan-amido) benzamide; 4-imidazol-1-yl-N- (3-methylthiopropyl) -3- (5-oxahexadecanamide) benzamide; and 3-hexadecanamido-4-imidazol-1-yl-N- (3-methylthiopropyl) benzamide, or a pharmaceutically acceptable salt thereof. A process for the preparation of a pharmaceutical composition comprising the formulation of a benzamide derivative of the general formula (I) obtained according to claim 1 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable coating or carrier. 10. A process for the preparation of a compound of the general formula: wherein R 12 represents an alkoxyalkyl, alkoxyalkoxy-alkyl or alkoxyalkoxyalkoxyalkyl group and R 2 is as defined in claim 1, characterized in that it comprises the oxidation of a compound wherein: R 2 is defined as in claim 1 and R 12 is as defined above, to convert the -CH 2 OH group to a group -CH 2 OH. 73019 Ν.62879 -42- Lisbon, & '0. 1991 By RHÔNE-POULENC RORER LIMITED = 0 OFFICIAL AGENT =