LU82545A1 - DERIVATIVES OF ACYLAMINOBENZOIC ACIDS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM - Google Patents

Description

915/922 2.4344

-0 2 5—7 JjïRAND-DUCHÉ DE LUXEMBOURG

N® patent ----------------------------------------------- ---. June 24, 1980 / adbft ,,. , „. ., at --------------------------..................... ................ Minister . ôÇïïSu of the National Economy and the Middle Classes

Book title: ______________________________________ _

Industrial Property Service

~ / i / LUXEMBOURG

UW OÀ / ot · ^ Æ ^^^ eman <^ e ßrevet invention I. Application ..U ..... company known as: ...... MAY AND BAKER LIMITED, Dagenham, Essex, _____________ (1 ) Jrander.Dretagne.i ..... represented ..... by Mr. Charles München, .......................

..council ..... in ..... patents ..... in ..... Luxembourg, acting as __________________ (2) .landatai re ............ .................................................. .................................................. .................................................. .................................................

Drop off ........ this ...... twenty-four June 1900 eighty _______________ {3) at ---------- 1§ .. · Μ hours, at the Ministry of National Economy and the Middle Classes, in Luxembourg: 1. this request for obtaining a patent for an invention concerning: .. !!. Derivative s ...... d ..: ... a..c.ld.es ..... acylaminobenzQlques and _______________ (4) pharmaceutical compositions containing ..... ", ___________________________________ declares, assuming responsibility for this declaration, that the inventor (s) is (are): ............................. .................................................. .................................................. .................................................. .................................................. ....................................... (5) ........ .................................................. ...................................... see overleaf____________________________________________________________________________________________ 2. delegation of power, dated__________ (?.?. 9.®..Π.!} Α (!? .---------------- le ----------.... ......._______ 3. description in language ----------- ί.Γ.? .. 5..9.? .. 1.5.® ....... ......................... of the invention in two copies; 4. -------- IT · ____ ______ drawing boards, in two copies; 5. the receipt of the fees paid to the Luxembourg Registration Office, on ___________ 8.4 .... iu.ln ...... 19.8.0 _________________________________________________________________________________________________________________________________________________________________________________________________ claims priority for one or more of the above patent applications application (s) for (6) __________ invention patents filed in (7) _________________________ Great Britain ____________________________ June 25, 1979 under No. 7922011 and April 28, 1980 under (R) ___________________ No. 8013948 ......... .................................................. .................................................. ...................

in the name of _______. l.â ..... ^ .. P..9.?. 4.D.Î-® .................... .................................................. .................................................. .............................................. (9) elects domicile for .lui (elle) and, if designated, for its agent, in Luxembourg ------------------------- lia, boulevard Prmce-Henri ________________________________________________________ (10) requests the grant of a patent for the subject described and represented in the appendices, six this grant has ..................... .......................month.

Π. Deposit Minutes

The above application for a patent for invention has been filed with the Ministry of National Economy and the Middle Classes, Industrial Property Service in Luxembourg, dated: June 24, 1980

Pr- * e Minister at 15.00 days / ^ 3 · / of the National Economy / Medium-sized projects, until \ γ r ^ r § 0¾¾. sv t / r V - £ -Sf v / 7 l T 'V l S Si Μ Λ 3.4 * 44 CASE 915/922

Claim of the priority of (s) la derr: ex · “·; · - (() corresponding (s) deposited) ε.ι 35.0 (,. - H Qtt.gp under lej, n ° i, - ^ gO ^ lBsvg

PATENT

· "

ACYLAMINOBENZOIC ACID DERIVATIVES AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

MAY AND BAKER LIMITED

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The present invention relates to novel therapeutically useful acylaminobenzoic acid derivatives, methods for their preparation and pharmaceutical compositions containing them.

The acylaminobenzoic acid derivatives of the present invention are the compounds of general formula: am-coR2 (i) NHR ° in which R represents a hydrogen atom or a straight or branched aleoyl group containing from 1 to 6 carbon atoms (which may be substituted by one or more substituents of the same type chosen 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, R ° represents a hydrogen atom or a group of formula 2 2 -00R, and R represents a straight or branched aleoyl group, preferably a straight chain group, containing from 2 to 20 (preferably 7 to 16) carbon atoms, and their pharmaceutically acceptable salts. When R is a substituted aleoyl group, it may for example be a 2,3-dihydroxy-propyl-1, allyl or pivaloyloxymethyl group.

It will be understood that in certain cases the substituents 1 2 R and R contribute to an optical isomerism. All of these forms are encompassed by the present invention.

By the term "pharmaceutically acceptable salt" is meant a salt formed, when S ° represents a hydrogen atom, by reaction with an acid or, when R 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 a salt formed by a compound of formula (i) in which R represents 50 an atom of hydrogen) is relatively harmless to the animal body when this salt is used in therapeutic doses, so that the beneficial pharmacological properties of the initial compound / general formula (i) are not adversely affected by side effects attributable to said anion or cation . J y / f

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2

The salts which are suitable among the acid addition salts of the compounds of general formula (i) in which R ° represents a hydrogen atom include salts derived from mineral acids, for example hydrochlorides, 5-bromhy drates , phosphates, sulfates and nitrates, and organic salts, for example methanesulfonates, 2-hydroxyethanesulfonates, oxaiates, lactates, tartrates, acetates, salicylates, citrates, propionates, succinates, fumarates, maleates, methylene-bis-ß-10 hydroxynaphtoates, gentisates and di-p-toluoyltartrates.

Among the salts formed by the compounds of general formula (I) 1 in which R represents a hydrogen atom, those which are suitable include the alkali metal salts (for example of sodium and potassium), the alkaline earth metal salts (e.g. calcium and magnesium), ammonium salts and amine salts known to be pharmaceutically acceptable, for example ethylenediamine, choline, diethanolamine, tri-thanolamine; octadecylamine, diethylamine, trlethylamine, 2-amino-2-hydroxymethyl-propanediol-1, jj and (3,4-dihydroxyphenyl) -l isopropylamino-2 ethanol.

It should be understood that, when in the present text we are talking about the compounds of general formula (I), it is also a question of their pharmaceutically acceptable salts, when the context allows.

The compounds of general formula (i) have useful pharmacological properties. For example, they reduce the proliferation of arterial smooth muscle cells which is a point of major importance for atherosclerotic plaques.

In addition, they inhibit the accumulation of cholesterol esters and the incorporation of cholesterol oleate into total cholesterol esters and other complex lipids characteristic of the fatty acyl enzyme CoA / acyl cholesterol transferase. / <f

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3

The stimulation of this enzyme in the presence of hyperlipemic 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 useful in the prevention or treatment of atherosclerosis and associated conditions such as angina pectoris, myocardial infarction, cerebral vascular occlusion, arterial aneurysm and peripheral vascular diseases; as well as arthritis, immunological diseases, cancer and transplant rejection.

Among the compounds of general formula (i) which are of particular interest, mention may be made of the following compounds and, where appropriate, their optically active forms and their salts: methyl amino-4 n-hexadecanamido-3 benzoate 15 B-4 amino-n-dodecanamido-J methyl benzoate C-4 amino n-tetradecanamido-5 methyl benzoate D-amino 4 n-tridecanamido-3 methyl benzoate E bis (n-hexanamido) acid -3,4 benzoic E bis (n-hexadecanamido) -3.4 methyl benzoate 20 G- bis (n-undecanamido) -3.4 methyl benzoate H 4-amino n-decanamido-3 methyl benzoate I bis (n-octanamido) -3 , 4 methyl benzoate J bis (n-pentadecanamido) acid -3.4 benzoic K bis (n-nonanamido) -3.4 methyl benzoate 25 B bis (n-heptadecanamido) acid -3.4 benzoic acid M bis ( n-heneicosanamido) -3.4 benzoic Έ bis (n-eicosanamido) -3.4 benzoic acid 0 4-amino acid n-nonadecanamido-3 benzoic P bis (methyl-2 tetradecanamido) acid -3.4 benzoic- (RS ) (RS) 30 Q 4-amino acid (2-hexyl octanamido) ~ 3 benzoic acid 1 a mino-4 (2-ethyl dodecanamido) -3 benzoic- (RS) s S amino-4 (2-butyl decanamido) -3 benzoic- (RS) / T bis (n-tetradecanamido) acid -2.3 benzoic / ïï amino-J n-hexadecanamido-4 benzoic acid / y / 7 4 Y amino-4 n-oetanamido-3 benzoic acid W amino-4 n-dodecanamido-3 benzoic acid X amino-4 n-octadecanamido-3 benzoic acid * T amino-4 n-octanamido-3 methyl benzoate 5 Z bis (n-dodeeanamido) -3.4 methyl benzoate = AA bis (n-tridecanamido) -3.4 methyl benzoate BB. bis (n-tetradecanamido) -3.4 methyl benzoate CC bis (n-octadecanamido) -3> 4 methyl benzoate DD amino-3 n-octanamiào-4 methyl benzoate 10 EE 3-amino acid n-octanamido-4 benzoic FF 3-amino acid n-dodecanamido-4 benzoic GG bis (n-decanamido) -3> 4 methyl benzoate HH bis (n-dodecanamido) acid -3} 4 benzoic II bis (n-octanamido) acid, 3 4 benzoic 15 JJ bis (n-tetradecanamido) acid -3.4 benzoic KK amino-3 n-dodecanamido-4 methyl benzoate LL amino-3 n-hexadecanamido-4 methyl benzoate MM amino-3 n-decanamido-4 benzoate methyl UN amino-4 n-hexadecanamido-3 benzoic acid 20 00 bis (n-decanamido) acid -3> 4 benzoic PP bis (n-tridecanamido) acid -3.4 benzoic QQ, bis (n-octadecanamido) acid - 3> 4 benzoic acid ES bis (n-hexadecanamido) -2.3 benzoic and SS amino-4 n-heptanamido-3 methyl benzoate.

The letters A to SS have been assigned to the compounds for easy reference in the remainder of the text, for example in the tables.

The properties of the compounds of formula / general (i) are demonstrated by the following tests: Af f λ 5

Action to inhibit proliferation of aortic smooth muscle cells

Cultured smooth muscle cells are grown from pig thoracic aorta explants using Dulbecco modified Eagles 5 medium (DME) containing 20% fetal calf serum (SFV) and antibiotics. The cells are incubated at yj * C in an atmosphere of 95% of air and 5% of carbon dioxide. When the cells have reached confluence, they are submitted in the usual way to a passage by trypsinization and re-seeded approximately at one third of their density of confluence in a DME medium containing 10% of SFV and antibiotics.

The smooth muscle cells are seeded at densities of 10,000,000 to 200,000 cells per 55 x 10 mm Falcon dish in 2 ml of DME medium, containing 10% SP7 and antibiotics. l5 After 24 hours, when the cells have attached to the dishes, the medium is replaced with 2 ml of DME medium containing 1% SFV and antibiotics. The cultures are incubated for a further three days to allow the cells to rest (i.e. no longer undergoing cell division). The medium is then replaced with 2 ml of control medium or of medium to be tested. The medium to be tested consists of DME medium (containing 10 SFV and antibiotics) and of test compound at a concentration of 5 per ml of medium. The compounds are pre-dissolved in acetone so that the final concentration of the solvent in the medium is 0.2% by volume. The control medium consists of EMI medium (containing 10 $ SFV and antibiotics) and acetone at a concentration of 0.2 / 6 by volume. After three days of incubation in test medium or in control medium, the medium is replaced by test medium or fresh control medium and the cells are incubated for a further three or four days. At the end of the 6 or 7 days of the incubation period, the number of cells is determined by trypsinizing them and counting the cell suspension / in a Coulter counting device, / /

J

6 \

All the results in Table I below represent the average value for four boxes of cells. The percentage of inhibition of proliferation is calculated using the following formula:, 5 Percentage of inhibition of proliferation. * ". (le! "*") where S = average number of cells per dish at the start of the experiment (when adding the control medium or the medium to be tested).

10 T = average number of cells per dish in the cultures tested at the end of the experiment.

C = average number of cells per dish in the control cultures at the end of the experiment.

TABLE I

15 Inhibition compound Y 59,76,84,56,32,40,41,55 B 51,52 D 61,61 C 54,48 20 A 71,76,47,40 KK 24,47

Action to inhibit the accumulation of cholesterol esters in aortic smooth muscle cells

Aortic smooth muscle cells, as described above, at their passage No. 8, are grown to confluence - in Dulbecco modified Eagles medium (DME) containing 10% fetal calf serum (SFV) and antibiotics.

Four dishes of smooth muscle cell replication are incubated for 24 hours in DME medium

30 containing 10% by volume of hyperlipemic rabbit serum, 3 /

H-oleate complexed with defatted bovine serum albumin J

(free fatty acid (FFA) / albumin molar ratio = 0.862; / DD

j *% 7 concentra- tion of oleate in the medium: 0.155 ml), antibiotics (penicillin G 100 IU / ml, streptomycin 100 pg / ml and kanamycin 100 pg / ml) and the test compound at a concentration of 100 pg per ml of medium. 5 control dishes without test compound and control dishes are also incubated with 10% by volume of SFV instead of hyperlipemic rabbit serum.

The sera are inactivated by heating before use; they respectively contain 935 mg / dl or 26 mg / dl of total cholesterol, 10 After the incubation, the cells are washed with Hanks solution, they are subjected to trypsination, they are centrifuged and the pellet is treated with ultrasound centrifugation in 0.27 mM EDTA. Cell concentrations of free and esterified cholesterol and the incorporation of H-labeled cholesterol oleate into the total cholesterol ester and other complex lipids were determined by comparison with the controls.

All the results in Tables II and III below represent the average value of four boxes of cells.

TABLE II

20 1 ° reduction in concentration compared to the controls contained. of hyperlipemic serum! cholesterol free cholesterol ester 25 Y ethanol 16.2 31 A ethanol 32 27

TABLE III

i reduction of AGL incorporation compared to controls containing the same solvent and the same serum

^ Phospholipid compound Total cholesterol triglycerides

I 13 * 1 77.3 55.7 45.2 / A 11.5 73.9 52.5 53.9 / d / 8

Action to inhibit the transformation into lymphocytes of mitogen-stimulated lymph node cells in * guinea pigs

We educate guinea pigs to. Mycobacterium tuberculosum 5 by injections into the soles of the feet of Freund's Complete Adjuvant (FCA) (0.05 ml; 0.5 mg / ml solution at 50 by volume of FCA in sterile physiological saline).

At the end of 14 days, lymph node cells are obtained, which are suspended in minimum l0 Eagles essential medium (EME) containing 10% fetal calf serum (SFV) and buffered with salts of Earle, at a concentration of 2.5 x 10 ^ cells per ml.

0.1 ml of cell suspension is incubated for 24 hours at 37 ° 0 in an atmosphere of 95% air and 5% carbon dioxide in the presence of 0.15 ml of mitogen or mitogen and compound to be tested in EME medium (containing lo # of SFV and buffered with Earle salts).

Eighteen hours before harvest, ¾-thymidine (1 µl of solution at. 100 pCi / ml in a saline solution is added).

20 0.9 # sterile).

We measure, as a DNA index, the rate

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. of incorporation of "t-thymidine by the cells in comparison with the control mitogen.

- The results are shown below in Table IV. / i «9

TABLE IV

Dose in the $ of incorporation inhibition

Com o 'middle. of ^ H-thymidine in the DNA of the cell incubation ÿ relative to the mitogen 5 μg / ml control - (A) ........... (2) 'Q) -

Y 3 5 17 H

10 60 59 61 30 94 97 96 H 3 21 10 10 78 30 90 B 3 27 10 46 30 71 15 3) 3 35 10 51 30 76 C 3 12 10 37 20 30 62 A3 4 10 10 30 15 The usefulness of these compounds are increased by the fact that they have a very low toxicity, as demonstrated by the following test: J Oral toxicity in mice

Groups of mice are treated orally with

It * gradual doses of the test compound (in an aqueous suspension at 0.5% w / v of tragacanth) and are kept under observation for the following three days. The percentages of animals that die during this period for each dose level are used to construct a graph from which / the LL, _0, i.e. the dose, in mg per kg of bodyweight / body is calculated. of the animal, necessary to kill 50% of the mice. / U /

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y ♦ 10

The compounds of formula (i) designated in the above list were tested and the LD, -q of each compound is greater than 1000 mg per kg of body weight of the animal.

The preferred compounds of the invention are those identified above 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 (that is to say methods previously used or described in the chemical literature), for example as indicated below.

(A) According to a characteristic of the present invention, the compounds of general formula (i) in which R ° represents a hydrogen atom are prepared by reduction of a compound of general formula î aKH-COR2 (il) no2 1 2 (in which S and 1 are as defined above) by known methods for the reduction of a nitro group to the primary amino group, for example by catalytic hydrogenation, preferably using palladium on black as catalyst.

(b) According to another characteristic of the present invention, the compounds of general formula (i) in which R ° represents a group of formula -COR (r2 being as defined above), or alternatively the substituent group -RH-COR (R being as defined above) is in the meta position relative to the substituent group -C00R (R being as defined above) and R ° represents a hydrogen atom, are prepared by reaction of a compound of general formula s 1 2 r'ooc — l · - | (III) VAm, 2 / (in which E is as defined above) with an acylating agent of general formula: / \ f 30 r2cqx1 (IY) / s.

11 2 1 in which E is as defined above and X represents a halogen atom (preferably chlorine) or a hydroxy group.

Particularly suitable conditions are as follows: 1) Compounds of general formula (I) in which R ° represents a group of formula -COR (in which R is as defined above) are prepared by reaction of a compound of general formula (ill) (in which R is as defined above) with an acyl halide of general formula (IV) 2 ί 10 (in which R is as defined above and X represents a halogen atom, preferably chlorine) in an inert organic solvent, for example dichloromethane or dimethylformamide, preferably in an anhydrous medium and preferably in the presence of an acid-fixing agent, for example a trialkyl-amine (such as triethylamine), or an alkali metal carbonate or bicarbonate (for example anhydrous sodium or potassium carbonate), at a temperature which may be higher than room temperature, for example between 10 and 50 ° C.

2) The compounds of general formula (i) in which the substituent group -HH-CO (R being as defined above) is in the met position, a with respect to the substituent group -COOR (R being as defined above), and R ° represents a hydrogen atom, are prepared by reaction of a compound of general formula (ill) (especially those in which R represents a straight or branched chain alkyl group containing from 1 to 6 carbon atoms ) with an acyl halide of general formula (iv) (in which R is as defined above • j and X represents a halogen atom, preferably chlorine), under conditions similar to those described above in 1), but using a smaller amount of acyl halide and maintaining the temperature preferably between 0 ° C and room temperature. .Ai s \ 12 (C) According to another characteristic of the present invention, the compounds of general formula (i) in which R ° represents a group of formula -COR (R being as defined above) are prepared from a corresponding compound of general formula (i) (in which R ° represents a hydrogen atom) by reaction with a compound of general formula (IY) - according to known methods.

The compounds of general formula (II) can be prepared - by reaction of a compound of general formula: 10 R100C - (- | (y) \ / ^ ÎI02 • j (in which R is as defined above) with a compound of general formula (IY) in a similar way to that described above in method B 1).

The compounds of general formula (y) can be prepared by known methods.

(D) According to another characteristic of the present invention, the compounds of general formula (i) in which R represents a straight or branched chain alkyl group containing from 1 to 6 carbon atoms (which may be substituted by one or several substituents of the same type chosen from the hydroxy group, the alkenyl groups containing from 2 to 5 carbon atoms and the alkanoyloxy groups containing from 2 to 7 carbon atoms) are prepared by esterification of a corresponding compound of formula • j ^ general (1) in which R represents a hydrogen atom, by 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 another characteristic of the present invention, the compounds of general formula (i) in which /% 15 e R ^ represents a hydrogen atom are prepared by alkaline hydrolysis of a corresponding ester of general formula (i ) in which E represents a straight or branched chain alkyl group containing from 1 to 6 carbon atoms (which may be substituted by one or more substituents of the same type chosen from the hydroxy group, the alkenyl groups containing from 2 to 5 carbon atoms and alkanoyloxy groups containing from 2 to 7 carbon atoms), for example by treatment with an alkali metal hydroxide within a hydroorganic solvent system and at an elevated temperature.

(F) According to another characteristic of the present invention, the compounds of general formula (I) in which E represents a hydrogen atom, and / or R ° represents a hydrogen atom, are transformed into their pharmaceutically acceptable salts. , 15 and vice versa, by application or adaptation of known methods.

This method is useful both in itself and for the purification of the compounds of general formula (i) and their salts by taking advantage of the differences in solubility, in water and in various organic solvents, of these compounds and of Their salts and any impurities present, by known methods such as crystallization.

1) The compounds of general formula (i) in which E

represents a hydrogen atom (E ° and E being as defined above) can be converted into their pharmaceutically acceptable hases salts, for example by reaction with the appropriate base, for example the appropriate amine or a compound of general formula : M ^ R5 (YI)

AT

(in which M represents an alkali metal atom, for example 3 • 50 sodium or potassium, and R represents an alkyl group containing up to 4 carbon atoms, for example methyl or ethyl, or yes hydrogen atom) in a suitable solvent, for example methane or ethanol, or a mixture of water and acetone, followed, if necessary, by the evaporation of all or part of the solvent, and recovery of solid salt. Γ, /> 14

These salts can be retransformed into the original compounds of general formula (i), for example by reaction with a suitable acid, such as glacial acetic acid, in solution in a suitable solvent, for example water or ethanol, 5 followed, if necessary, by all or part of the solvent, and - recovery of the solid compound of general formula (i).

2) The compounds of general formula (i) in which R ° represents a hydrogen atom can be converted into their pharmaceutically acceptable acid addition salts, for example by reaction with the appropriate acid in solution or in suspension in a suitable solvent - for example acetone, methanol or ethanol, followed, if necessary, by evaporation of all or part of the solvent, and recovery of the solid salt.

The acid addition salts can be converted back to the original compounds of general formula (i), for example by reaction with ammonia in the presence of a suitable solvent, for example ethanol, followed by a treatment with a weak acid, for example glacial acetic acid.

The compounds of general formula (i) are also useful as starting materials for the preparation of therapeutically useful benzimidazole derivatives of general formula:

y. IJ

1 / Go 2.

R 00C-- | V, R (VII) \ a /

H

/ 1 2 '(in which R is as defined above and R represents a straight or branched chain alkyl group containing from 25 7 to 20 carbon atoms), the group R 00C being attached to the l position 4 or 5 of the system benzimidazole ring, derivatives into which they can be transformed by application or adaptation of known methods of cyclization.

For example: 30 a) when R ° in the general formula (i) is a group t of formula -COR2 (R2 being as defined above), there is little / f-

J

V

Cyclizing to form a benzimidazole derivative of general formula (YIl) at elevated temperature, for example between 60 and 100 ° C, by reaction with a mineral acid, for example hydrochloric acid, in the presence of water and d an organic solvent, for example an alcohol such as methanol or ethanol, or a ketone such as acetone or methyl ethyl ketone; or b) when E ° in the general formula (l) is a hydrogen atom, the cyclization can be carried out either under conditions similar to those described above in a), or again by reaction with an organic acid ( for example p-toluenesulfonic acid) in water or an organic solvent (for example toluene), preferably at elevated temperature, for example between 60 and 100 ° C., or c) the cyclization can be carried out in absence of solvent and at elevated temperature (for example between 150 and 250 ° C.) or in the presence of water and a mineral acid (for example hydrochloric acid) and in a suitable solvent, for example diglyme.

It will be understood that in carrying out the above methods and those of the present invention, it may be desirable to introduce protecting chemical groups into the reactants in order to prevent side reactions from occurring; for example in the method of preparation of the benzimidazoles described above, the hydroxyl groups of the subset 1 R represented in the general formula (i) were transformed into benzyloxy groups before the reaction as described, with subsequent removal of the group benzyl.

Benzimidazole derivatives of general formula (Vil) are useful for the prevention or treatment of diabetes mellitus,

50 hyperlipoproteinemic states, atherosclerosis and associated states, such as angina pectoris, myocardial infarction, cerebral vascular occlusion, arterial aneurysm, peripheral vascular diseases, recurrent pancreatitis and xanthomas , as well as arthritis, immunological diseases, cancer and transplant rejection. / U

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16 the following examples illustrate the preparation of the compounds of the present invention.

EXAMPLE 1

Compound A

5 Amino-4 n-hexadecanamido-3 benzoate is prepared by one or other of the following methods: a) A stirred solution of 3,4-diamino methyl benzoate (35 G) is treated dropwise ) in 1200 ml of anhydrous dimethylformamide, containing 11.8 c of anhydrous sodium carbonate, with 38 ß of n-hexadecanoyl chloride for one hour. The speed of addition of n-hexadecanoyl chloride is such that it allows the temperature of the reaction mixture to rise from an initial value of 10 ° C. to room temperature. The mixture is then stirred at room temperature for a further 3 hours, then poured into 5 liters of water.

The resulting solid is collected and boiled in 1000 ml of acetone and then the boiling mixture is filtered. The filtrate is cooled to 0 ° C. and the resulting buff-colored solid is filtered off, which gives 48.2 g of methyl amino-4 n-hexadecanamido-3 benzoate, m.p. 112-114 ° C.

B) A stirred solution of methyl diamino-3,4 benzoate (16.6 g) in 270 ml of anhydrous dichloromethane, containing 10.3 g of triethylamine, is treated dropwise with a solution of n-hexadecanoyl chloride. (27.5 &) in 30 ml of anhydrous dichloromethane for 45 minutes. During the addition, the temperature is maintained between 16 25 and 20 ° C. The mixture is stirred for a further 2 hours. The resulting solid is then collected and boiled in a mixture of acetone (10000 ml) and methanol (150 ml) and the insoluble materials are removed by filtration. The filtrate is cooled to 25 ° C. and treated with 800 ml of water, which gives 4-amino-n-hexadecanamido-3/30 methyl benzoate in the form of a buff-colored solid, / J (Mp 112-114 ° C. D // 7

Compound B

EXAMPLE 2 17

A solution of 3-diamino methyl benzoate (25 * 0 g) in 1120 ml of anhydrous dimethylformamide, containing 7 * 7 E 5 of anhydrous sodium carbonate, is treated with 30.5 g of n-dodecanoyl chloride, similarly to that described above in example 1 (to), which gives 4 g of amino- *! n-dodecanamido-3 crude methyl benzoate, in the form of a buff-colored solid.

EXAMPLE 5

10 Compound C

A solution of 3,4-diamino methyl benzoate (25.0 g) in 500 ml of anhydrous dichloromethane, containing 15 * 5 lbs of tricthylamine, is treated dropwise with a solution of n-tetradeoanoyl chloride (57.12 g) in 50 ml of anhydrous dichloromethane 15 in a manner similar to that described above in Example 1 (b), which gives 40 g of crude methyl amino-1-n-tctradecanamido-3 benzoate under form of a buff-colored solid.

EXAMPLE 4

Compound 3) A solution of methyl diamino - ^, benzoate (17 * 8 g) in 350 ml of dichloromethane, containing 10.8 g of triethylamine, is treated with 25 g of n-tridecanoyl chloride, 'a similar way to that described above in Example i (b), which gives 40 g of amino-4 n-trideeanamido-3 benzoate crude methyl.

25 EXAMPLE 5

Compose E

A solution of 3,4-diamino benzoic acid (7.5 g) in 100 ml of dichloromethane, containing 15 g of triethylamine, is treated with 27.5 E of n-hexadecanoyl chloride in a similar manner to that described above. above in example l (b). A solid is collected which is recrystallized from glacial acetic acid and then from methyl ethyl ketone (with filtration of the hot solution), which /

gives 20 g of bis (n-hexadecanamido) -3.4 benzoic acid in the form of iψν / solid, buff color, m.p. 193-202eC. / U

*

Compound F

EXAMPLE 6 18

A solution of 3,4-diamino methyl benzoate (5.0 g) in 50 ml of dichloromethane, containing 6.2 g of 5-triethylamine, is treated with 16.5 g of n-hexadecanoyl chloride in a similar manner. to that described above in Example 1 (b) (the temperature of the reaction mixture is allowed to rise during the addition from 20 to 30 ° C). A solid is collected which is recrystallized from chloroform to give 14.9 E of methyl bis (n-hexadecanamido) -3.4 benzoate as a white solid, m.p. 129-132 ° C.

EXAMPLE 7 v '' T _

Compound G

'A solution of 3,4-diamino methyl benzoate (17.9 g) in 300 ml of dichloromethane, containing 21.8 g of triethyl-15 amine, is treated with 44.3 g of n-undecanoyl chloride so as to treat similar to that described above in Example 6. A solid is collected which is recrystallized twice from ethanol (with filtration of the hot solution), which gives 40.2 g of bis (n-undecanamido ) -3.4 methyl benzoate as a white solid, mp 139-114 ° C.

20 EXAMPLE 8

Compound H

A stirred solution of 3,4-methyl diamino benzoate (166.6 g) in 600 ml of anhydrous dimethylformamide, containing 5.3 g of anhydrous sodium carbonate, is treated dropwise with 19.1 g of sodium chloride. n-decanoyl, in a manner similar to that described above in example l (a), which gives 18.8 g of amino-4 n-decanamido-3 benzoate in the form of a solid buff color, PF 96-98eC.

EXAMPLE 9

• 1 Compound I

50 A solution of 3,4-diamino methyl benzoate (4l, 2 g) in 412 ml of dichloromethane, containing 51.0 g of triethylamine, is treated with a solution of n-oetanoyl chloride (80.6 g ) in 320 ml of dichloromethane, similar to that described above in Example 6, recrystallizing from methanol (with black treatment / 55), which gives 81.6 g of bis (n-octananido ) -3.4 methyl benzoate under the firmness of a white solid, mp 133-140 ° C. fj 1- \ = EXAMPLE 10 19

Compound J

A solution of 3,4-diamino benzoic acid (13 * 85 g) in 180 ml of dimethylformamide, containing 27.6 pounds of triethylamine, is treated with 47.4 g of n-pentadecanoyl chloride, in a similar manner to that described above in Example 1 (a). The resulting solid is collected and recrystallized from methyl ethyl ketone (with black treatment and filtration of the hot solution), which gives 49.3 g of ben (n-pentadecanamido) -3.4 benzoic acid, PP, 10 178-180 ° C.

EXAMPLE 11

Compound E

A stirred solution of 152 g of 3,4-diamino benzoic acid in 1500 ml of dimethylformamide, containing 305 g of triethylamine, is treated dropwise with 549.0 g of n-hexa-decanoyl chloride for 1 hour 1 / 2. The rate of addition of n-hexadecanoyl chloride is such that it allows the temperature of the reaction mixture to rise from room temperature to 35-40 ° C. The mixture is then stirred at room temperature for a further 2 hours, then poured into 10 liters of water maintained at J0 ° G, containing 150 ml of concentrated hydrochloric acid (36.5 i ° w / v ). The resulting solid is collected, which gives 600 g of bis (n-hexadecanamido) -3.4 benzoic acid in the form of a buff-colored solid, m.p. 180-190 ° C.

25 EXAMPLE 12

Compound K

A stirred solution of 20 g of 3,4-methyl diamino benzoate in 250 ml of dichloromethane is treated dropwise.

V

anhydrous, containing 24.2 g of triethylamine, by a solution of 44.12.12 g of nonanoyl chloride in 50 ml of anhydrous dichloromethane, in a similar manner to that described above in Example 1 (b), which gives a pink solid, which is recrystallized from methanol, with black treatment, which gives 30.3 g bis (n ~ nonanamido) -3.4 methyl benzoate in the form of a white solid / 35, PP 142-145 ° C. /// "Compound EXAMPLE 13 20

A stirred solution of 45 ”6 g of 3-diamino 4,4 benzoic acid in 400 ml of dimethyl format, 5 containing 75” 8 g of triethylamine is treated dropwise with 130 g of n-hepta-decanoyl chloride. , similar to that described above in Example 11, which gives 140 g of crude bis (n-heptadecanamido) -3,4 benzoic acid in the form of a pink solid.

EXAMPLE 14

10 Compound M

The stirred solution of 21.9 E of 3,4-diaraino-benzoic acid in 175 king of dimethylformamide, containing 43.6 g of triethylamine, is treated dropwise with 99.2 g of n-heneicosa-nucleus chloride, similarly to that described above in Example 11, which gives 126.5 g of crude bis (n-heneicosanamido) -3.4 benzoic acid as a light brown solid.

EXAMPLE 15

Compound E

A stirred solution of diami-20 no-3,4 benzoic acid (13.3 g) in 290 ml of dimethylformamide, containing 36.5 g of triethylamine, is treated dropwise with 79.4 g of n- chloride. eicosanoylc, similar to that described above in Example 11, which gives 53 g of crude bis (n-eicosanamico) -3.4 benzoic acid in the form of a pale brown solid, PF l6c-170 ° C.

25 EXAMPLE 16

Compound 0

A stirred solution of 38 ° C. of 3-diamino acid, benzoic acid in 500 ml of dimethylformamide, containing p0, j) g this trnethylamine, is treated dropwise with 79 × 1 g of n-nonadecanoyl chloride. Similar to that described above in Example 11, which gives an orange oil which is poured into 300 ml of water containing 100 ml of concentrated hydrochloric acid (36.5% by weight /volume).

The solid is collected, which is washed with water (2 times 190 ml) and then dried, which gives 10? Pound of 4-amino acid n ^ nonadecanamido-3 benzoic acid // 35 crude, m.p. 103-113 ° C. h

Compound P

\ EXAMPLE 17 21

The solution of 17 * 5 G of 3,4-diaroino-benzoic acid in 140 ml of dimethylformamide, containing 5 8 g of triethylamine, is treated dropwise with 59 * 7 Z of pentadecanoyl-2 chloride in a similar manner to that described above in Example 11, which gives 6 £, g of bis (2-methyl-tetradecanamido) -3, benzoic acid (RS) (RS) (RS).

EXAMPLE 18 10 Compound Q.

restless

A solution / of 20.7 E of diamino-3, .l benzoic acid in 165 ml of dimethylformamide * containing 56 * 5 ml of triethylamine is treated dropwise with 67 C of 2-octanoyl chloride, similar to that described in Example 11. The waxy solid is collected and dissolved in 500 ml of diethyl ether; the ethereal solution is dried and evaporated to give a reddish-brown oil.

This oil is extracted with hot methanol, using a continuous extractor, for 5 hours. The methanolic solution is evaporated on a rotary evaporator, which gives a brown solid which is recrystallized from acetone to obtain 15 * 2 g of 4-amino acid (2-hexyloetanamido) -3 benzoic acid, as a white solid, PP

219-221 ° C.

EXAMPLE 19

Compose

A stirred solution of 22.8 g of 5,4-diamino benzoic acid in 200 ml of dimethylformamide, containing 22.7 g of triethylamine, is treated dropwise with 57 g of 2-ethyl dodecanoyl chloride, similar to that described above in - Example 11, After treatment of the reaction product as described above in Example 18, a solid is obtained which is recrystallized from ethyl acetate, with black treatment, which gives 22.2 g of amino-4 (2-ethyl dodecanamido) -5 benzoic acid (RS) in the form of a white solid, P, P. 188-191 ° C, bp EXAMPLE 20

Compound S

22

A stirred solution of 15.8 g of 3,4-diamino benzoic acid in 130 ml of dimethylformamide, 5 containing 43> 4 S of triethylamine, is treated dropwise with 51> 4 S of 2-butyl decanoyl chloride, similarly to that described above in Example 11. After treatment of the reaction product as described above in Example 18, 9 "® S of 4-amino acid (2-butyl deeanamido) are obtained. ~ 3 benzoic acid (RS) in the form of a white solid, 10 PT 178-182 ° C.

EXAMPLE 21

Compound T

A solution of 20 g of 2,3-diamino benzoic acid in 200 ml of dimethylformamide, containing 3S9 G of triethylamine, is treated with 65.0 g of n-tetradecanoyl chloride. The rate of addition of n-tetradecanoyl chloride is such that it allows the temperature of the reaction mixture to rise from room temperature to J | 5-50 ° C. The mixture is then stirred for a further 2 hours and allowed to stand at room temperature for one hour.

20 ml of methanol are added to the mixture, the resulting mixture is stirred for 20 minutes and then treated with concentrated hydrochloric acid (at% by weight / velume) until it is at pH 2. The resulting mixture is poured into 1000 ml of water, the black solid is collected, washed with water (twice 500 ml) and then with 500 ml of warm petroleum ether (PE 60-80 ° C) and finally recrystallized from ethanol, with black treatment, which gives 17.7 E.

bis (n-tetradecanamido) -2.3 benzoic acid as a solid /. buff color, m.p. 150-158 ° C. / d /

Compound ïï 23 EXAMPLE 22

A solution of 22 g of 3-nitro-n-hexadé-canamido-4 benzoic acid is hydrogenated in 500 ml of n-butanol by shaking in the presence of 2.5 g of palladium on black at 5% by weight, 70 ° C and at atmospheric pressure laying 6 hours. The mixture is filtered hot and the filtrate is allowed to cool. The resulting solid is collected and washed with 100 ml of ethanol, which gives 11.6 g of 3-amino-4-hexadecanamido benzoic acid in the form of a cream-colored solid, mp 110 ° -62 ° C. .

The nitro-3 n-hexac3ecanarr, ido-Jl benzoic acid used as "starting material is prepared as follows:

A solution of 18.2 g of 4-amino-3-nitro benzoic acid and 33 "0 g is heated for 90 minutes at 97 ° 0. of decanoyl hcxa-15 chloride in 100 ml of dimethylformamide. The solution is cooled and then glassed on 300 g of pilec ice. The resulting solid is collected, washed with water (3 times ICO ml), dried and recrystallized from a mixture of acetone and water (5 / l) "with treatment with black, which gives 31.7 £ of 3-nitro-n-hexa-20 decanamido- benzoic acid in the form of a yellow solid, PP 153-15 ° C.

EXAMPLE 23

Compound V

By proceeding in a manner similar to that described above.

25 in Example 16 for the preparation of 3-amino-3-benzoic acid, but replacing n-nonadecanoyl chloride with n-octanoyl chloride, 4-amino acid is prepared benzoic n-octanamido-3 in the form of a whitish solid, mp 2Q2-2Q3 ° C after recrystallization from methanol, s "30 EXAMPLE 24

v Compound W

By proceeding in a similar manner to that described above in Example 16 for the preparation of 4-amino-n-nonadecana-mido-3 benzoic acid but by replacing n-nonadecanoyl chloride with chloride of n-dodecanoyl, 4-amino acid n-dodéj eanamido-3 benzoic acid is prepared in the form of a white solid, PF 183-185 0. fu in

V

Compound X

EXAMPLE 25 2k

By proceeding in a similar manner to that described above in Example 16 for the preparation of amino-1l n-nonadecana-5 mido-J benzoic acid but by replacing n-nonadecanoyl chloride by n- chloride octadecanoyl, the arnino- ^ n-octadecana-mido-J benzoic acid is repaired in the form of a light brown solid, mp, 185 ~ 187 ° C after recrystallization from methyl ethyl ketone.

EXAMPLE 26

10 Compound Y

'A solution of diamino-J, 4 methyl benzobate (83.1 g) in 900 ml of anhydrous dimethylformamide, containing 50.8 g of triethylamine, is treated dropwise with 8-1 3 g of n chloride. -octa-core for OJ minutes at a temperature maintained between 5 and 8 ° 0.

The mixture is stirred for a further 2 hours. The solid is removed by filtration and the filtrate is poured into 8000 ml of water. The resulting solid was collected and recrystallized twice from methanol to give 65.5 g of methyl amino-octanamido-benzoate as a white solid, m.p. 120 ° C.

20 EXAMPLE 27

Compound B

By proceeding in a similar manner to that described above in Example 26 but by replacing the n-octa-nucleus chloride with n-dodecanoyl chloride, the amino- · ^ n-dodecanamido- is prepared. J methyl benzoate in the form of a whitish solid, mp 102-1G5 ° C after recrystallization from methanol.

EXAMPLE 28. Compound I)

By proceeding in a similar manner to that described above in Example -26 but by replacing the chloride of n-octa-

embedded in n-tridecanoyl chloride, aminn-4 n-tride-, canamido-J methyl benzoate is prepared in the form of a light brown solid, / mp 101-10 ^ 1 ° C after recrystallization from methanol. /HE

f Λ

Compound G

25 EXAMPLE 29

By proceeding in a similar way to that described in Example 26 ,. but by replacing the n-octanoyl chloride with 5-n-tetradecanoyl chloride, the methyl amino-4 n-tetradecanamido-3 benzoate is prepared in the form of a light brown solid, PF 108-109 C after recrystallization at from methanol.

EXAMPLE 50

Compound A

By proceeding in a similar manner to that described above in Example 26 but by replacing the n-octa-chloride chloride with n-hexadecanoyl chloride, the amino-4 n-hexa-decanamido-3 is prepared. methyl benzoate as a white solid, P, F.

109-110 ° C after recrystallization from methanol.

15 EXAMPLE 31

Compound P

A solution of 5 C> of diamino-3 is treated drop by drop. ”^ Methyl benzoate in 50 ml of dimethylformamide, containing 6.1 G of triethylamine, with a solution of ΐβ, 5 ^ G of hexadeca- chloride 20 embedded in 40 ml of anhydrous dimethylformamide in 5 minutes. The temperature is allowed to rise from 20 to 50 ° C. The mixture is stirred for a further 3 hours. The resulting suspension is poured into 800 ml of water containing 10 ml of concentrated hydrochloric acid (36.5 / 0 by weight / volume). The resulting solid is collected and recrystallized from a mixture (l / l) of chloroform and acetone to give 12.1 g of methyl bis (n-hexadecanamidobenzoate) as a white solid , PP 129 ~ 132 ° C, identical to the product of Example 6.

EXAMPLE 32

Compound I

By proceeding in a similar manner to that described above in Example 31 but by replacing the n-hcxadecanoyl chloride with n-octanoyl chloride, the bis (n-oct & / namido) -3, ^ 1 is prepared. methyl benzoate in the form of a white solid, PF / If j [ij5_ ^ 7cC after recrystallization from acetone. f jf EXAMPLE 53 *

Compound Z

26

By proceeding in a similar manner to that described above in Example 31 but by replacing n-hexadecanoyl chloride 5 with n-dodecanoyl chloride, the bis (n-dodecanamido) - 3,4 methyl benzoate is prepared. in the form of a whitish solid, ”PP 129-131 ° C after recrystallization from acetone.

EXAMPLE 34

Compound AA

By proceeding in a similar manner to that described above in Example 31 but by replacing the n-hexadecanoyl chloride with n-tridecanoyl chloride, the bis (n-tridecana-mido) -3? 4 benzoate is prepared. methyl in the form of a white solid, PP 132-134 ° C after recrystallization from acetone.

15 EXAMPLE 35

BB compound

By proceeding in a similar manner to that described above in Example 31 but by replacing the n-hexadecanoyl chloride with n-tetradecanoyl chloride, the methyl bis (n-tetradeca-20 namido) -3j4 is prepared. in the form of a white solid, PP 132-133 ° C after recrystallization from acetone.

EXAMPLE 36

CC compound

By proceeding in a similar manner to that described above in example 31 but by replacing the n-hexadéoanoyl chloride i by n-ociadecanoyl chloride, the his (n-octadecana-mido) -3j4 benzoate is prepared. methyl in the form of a white solid, /. P.P. 120 ° 0 after recrystallization from a mixture (l / l) / acetone and methanol. j y EXAMPLE 57> ·

DD compound

27

12.1 g of 3-amino-n-octanamidobenzoic acid in 200 ml of methanol are treated with an ethereal solution of diazomethane. 5 Until the reaction is completed, it is observed by thin layer chromatography on silica. using as eluent a mixture (10/90 / 0.5) of methanol, chloroform and glacial acetic acid ^. 0.2 ml of acetic acid is then added and the reaction mixture is concentrated under reduced pressure. The resulting solid 10 is recrystallized from ethyl acetate, which gives 9 * 2 g of 3-amino-n-octanamido-4 benzoate in the form of a cream-colored solid, mp 128-131 °. vs.

EXAMPLE 38

EE compound

15 g of 25 g of 3-nitro-4-octanamido-4-benzoic acid dissolved in 500 ml of ethanol at 50 ° C. are shaken in the presence of 2.5 g of palladium on black at 5% by weight, at 50 ° C and at atmospheric pressure for 3 hours. The mixture is filtered while hot and the filtrate is evaporated under vacuum. The residue is recrystallized from a mixture (l / l) of ethanol and water, which gives 8 g of 3-amino-n-octanamido-4 benzoic acid as a yellow solid, PF 155-156 ° C.

The benzoic-3-n-octanamido-4-nitro acid used as starting material is prepared as follows:

A solution of 18 * 2 g 25 of 4-amino-3-nitro-benzoic acid and 19.4 g of n-octa-nucleus chloride in 100 ml of anhydrous dimethylformamide is treated at 97 ° C. for 90 minutes. The solution is cooled; tion and poured over 300 g of ice. The resulting solid is collected and washed with water (3 times 100 ml), dried and recrystallized from a mixture (8 / l) of methanol and water (with treated with black), which gives 22 g of 3-nitro-n-octanamido-4 ben- / zoic acid in the form of a pale yellow solid, mp 153-15 ^ ° C. /] /,. EXAMPLE 5 9> 28

EF compound

21 g of 3-nitro-n-dodecanamido-4 benzoic acid dissolved in 5 ^ 0 ml of ethyl acetate are hydrogenated, shaking in the presence of 2.5 g of palladium on black at 5% by weight, at 50 ° C and at atmospheric pressure. The resulting mixture is filtered hot, which gives a cream-colored solid upon cooling. This product is recrystallized from methanol, which gives 7.4 g of 3-amino-n-dodé-canamido-4 benzoic acid in the form of a beige solid, m.p. 158-160 ° C.

EXAMPLE 40

10 Compound H

By proceeding in a similar manner to that described above in Example 26 but by replacing the n-octanoyl chloride with n-decanoyl chloride, the amino-4 n-decanami-do-3 benzoate is prepared. as a white solid, PP 9é-100 ° C.

15 EXAMPLE 41

GG compound

By proceeding in a similar manner to that described above in Example 31 but by replacing n-hexadecanoyl chloride with n-decanoyl chloride, methyl bis (n-decanamido) -3.4 is prepared. 20 methyl benzoate as a white solid, P.Ï1. 139—141 ° G after recrystallization from ethanol.

EXAMPLE 42

HH compound

A stirred solution of 10 g of 3-diamino-benzoic acid in 100 ml of anhydrous dimethylformaraide containing 28 g of potassium carbonate is treated dropwise over 5 minutes with a solution of 33.1 E. of n-dodecanoyl chloride in 30 ml of anhydrous dimethylformamide. The temperature is allowed to rise from 20 to 50 ° C. The mixture is stirred for a further 3 hours. The resulting OJ suspension is filtered and the filtrate is poured into 700 ml of water containing 10 ml of hydrochloric acid (36.5% w / v). The resulting solid is collected and recrystallized from glacial acetic acid; the product is washed / then washed with water and recrystallized from methyl · 1 / ethyl ketone, which gives 12.5 g of bis (n-dodecanamido) -3.4 M benzoic acid in the form of a white solid, mp 195_197 ° C. η>

Compound E

29 EXAMPLE 43

Using a procedure similar to that described above in Example 42 but replacing n-dodecanoyl chloride 5 with n-hexadecanoyl chloride and potassium carbonate with sodium carbonate, the bis acid is prepared. (n-hexadeca-mido) -3.4 benzoic in the form of a white solid, mp 198-202 ° C after successive recrystallizations from glacial acetic acid and methyl ethyl ketone.

10 EXAMPLE 44

Compound II

By proceeding in a similar manner to that described above in Example 42 but by replacing the n-dodecanoyl chloride with n-octanoyl chloride, the bis (n-octana-15 mido) -3 acid is prepared ". 4 benzoic in the form of a white solid, mp 195-197 ° C

after successive recrystallizations from glacial acetic acid and methyl ethyl ketone.

EXAMPLE 45

Compound JJ

By proceeding in a similar manner to that described above in Example 42 but by replacing the n-dodecanoyl chloride with n-tetradecanoyl chloride, the bis (n-tetra-decanamido) -3 acid is prepared, 4 benzoic acid in the form of a white solid, mp 20.01-206 ° C. after successive recrystallizations from glacial acetic acid and methyl ethyl ketone.

EXAMPLE 46

KK compound

s 21 g of n-dodecanamido-4 nitro-3 benzoate are hydrogenated. of methyl dissolved in 500 ml of ethyl acetate at 50-55 ° C by shaking it in the presence of 2.0 g of palladium on black at 5 i ° by weight, at 60 ° C and at atmospheric pressure for 2 hours. On / f

V

The mixture is filtered hot and the filtrate is allowed to cool. The solid is collected to obtain 1 * 1.1 c of 3-amino-n-dodecanamido-4 benzoate in the form of a white solid, P. F. 13 ^ -137 "C.

The methyl n-dodecanamido- 3-nitro-benzoate used as starting material is prepared as follows:

19 * 6 g of methyl amino-3-nitro benzoate and 23 g of n-dodecanoyl chloride in 100 ml of dimethylformamide are heated for 2 1/2 hours at 97 ° C, shaking from time to time .

The resulting solution is poured onto 300 ° C. of crushed ice, the solid is collected and rc-10 and recrictallized from a mixture (5/1) of methanol and chloroform, which gives 31% of n-dode- canamido- *! methyl nitro-3 benzoate in the form of a yellow solid, m.p. 78-80 ° C.

The methyl amino-3-nitro-benzoate is prepared as follows:

JO g of 3-amino-3-nitro benzoic acid is added to a solution of anhydrous HCl in methanol (made from 78 g of acetyl chloride and JOC ml of anhydrous methanol). The resulting mixture is heated at reflux for 10 hours, cooled in ice and the solid is collected, which gives 62 g of methyl 4-amino-3-nitro benzoate as a yellow solid, PF 193-195 ° C.

EXAMPLE 47

LL compound

25 By proceeding in a similar manner to that described above in Example 46 for the preparation of 3-amino-n-dodecanamido-4 methyl benzoate but by replacing the n-dodecanamido ~ 4 3-nitro-methyl benzoate by methyl n-hexa-decanamido-3-nitro-3 benzoate, methyl amino-3 n-hexadecanamido-4 benzoate is prepared in the form of a solid / white, mp 135-1 $ 7 ° C. / U / f

Compound MM

31 EXAMPLE 48

By proceeding in a similar manner to that described above in Example 4-6 for the preparation of methyl amino-3 5 n-dodecanamido-4 benzoate but by replacing the 4-n-dodecanamido-3-nitro benzoate methyl with n-decanamido-4 nitro ~ 3 methyl benzoate, anino-3 n-decanamido-4 methyl benzoate is prepared in the form of a white solid, mp 131-133 ° C ·: EXAMPLE 49

10 Compound M

A stirred solution of 8 * 4 £ of 3-diamino benzoic acid in 100 ml of anhydrous dimethylformamide, containing 15.27 ° C. of potassium carbonate, is treated dropwise with a solution of 15 * 17% chloride. n-hexadecanoyl in 30 ml of anhydrous dimethylformamide, in 30 minutes, at 0 ° -5 ° C. The mixture is stirred for a further 2 hours at 0 ° -5 ° C and allowed to warm to room temperature in 30 minutes.

The solution is then poured into 700 ml of water containing 10 ml of hydrochloric acid (36.5% w / v).

The solid is collected, heated with 300 ml of acetone at 50 ° C. and recrystallized from methyl ethyl ketone, which gives 9 * 4 g of 4-amino-n-hexadeanamido-3 benzoic acid in the form of '' a white solid, mp 197-199 ° C.

EXAMPLE 50 25 Compound 00

By proceeding in a similar manner to that described above in Example 42 but by replacing t 'n-dodecanoyl chloride with n-decanoyl chloride, the bis (n-decanamido) -3 * 4 acid is prepared. benzoic in the form of a white solid, m.p. 194-196 ° C. after successive recrystallizations from glacial acetic acid and methyl ethyl ketone. / 7 / EXAMPLE 51 32 *

PP compound

By proceeding in a similar manner to that described above in Example 42 but by replacing the n-dodecanoyl chloride 5 with n-tridecanoyl chloride, the bis (n-tride-. Canamido) acid is prepared ~ 5 > 4 benzoic in the form of a whitish solid, mp 192-194 ° C after successive reoristallizations from glacial acetic acid and methyl ethyl ketone.

EXAMPLE 52 10 Compound Q, Q,

By proceeding in a similar manner to that described above in Example 42 but by replacing the n-dodecanoyl chloride with η-octadecanoyl chloride, the bis (n-octa-decanamido) acid is prepared -5.4 benzoic in the form of a white solid, PE 193-15 196 ° C after successive recrystallizations from glacial acetic acid and methyl ethyl ketone.

EXAMPLE 55

BR compound

A solution of 40 g of 2,3-diamino benzoic acid in 600 ml of dimethylformamide, containing 79 * 7 g (109.5 ml) of triethylamine, is treated with 144.5 g of n-hexadecanoyl chloride. The speed of addition is such that it allows the temperature of the reaction mixture to rise from room temperature to 45-50 ° C. The mixture was then stirred for a further 3 hours and allowed to stand at room temperature overnight. This mixture is added to 1200 ml of water containing 50 ml of concentrated hydrochloric acid (36 * 5 $ 'w / v) and the resulting solid is collected and washed with, v 1200 ml of water. This solid is stirred with 4000 ml of hot water (65 ° C.) • for 50 minutes, it is collected and dried under vacuum at 30 ° C., which gives bis (n-hexadecanamido) acid -2 , 3 benzoic. / / * EXAMPLE 54 35

SS compound

By proceeding in a similar way to that described above! in Example 26 but by replacing the n-octanoyl chloride by 5 of the n-heptanoyl chloride, the amino-4 n-heptanamido-3 benzoate is prepared in the form of a pale brown solid, PP 103- 106 ° C.

The present invention encompasses in its field pharmaceutical compositions which contain at least one of the compounds of general formula (i) or one of their pharmaceutically acceptable salts, in combination with a pharmaceutically acceptable carrier or coating. In clinical practice, the compounds of the present invention may be administered parenterally, but it is preferred to administer them rectally or, better, orally.

Solid compositions for oral administration include tablets, pills, powders and granules. In such compositions, one or more of the active compounds are mixed with at least one inert diluent such as starch, sucrose or lactose. These compositions can also contain, as is common practice, additional substances other than inert diluents, for example lubricants such as magnesium stearate.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and liquids containing the inert diluents commonly used in the art, such as water and paraffin oil. In addition to the inert diluents, these compositions may contain adjuvants, such as wetting agents, suspending agents, sweetening, flavoring agents, perfumes and preservatives. The compositions according to the invention for oral administration include also capsules of ingestible material, such as gelatin, containing one or more active substances with or without the addition of diluents or excipients. / f «- \ 3½

The preparations according to the invention for parenteral administration include aqueous, hydro-organic and organic sterile solutions, suspensions and emulsions. Examples of organic solvents or suspending media include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as oleate 'ethyl. These compositions can also contain adjuvants such as stabilizers, preservatives, wetting agents, emulsifiers and dispersants.

These compositions can be sterilized, for example by filtration through a bacteria-retaining filter, by incorporation of sterilizing agents, by irradiation or by heating. They can also be made on the farm from sterile solid compositions which can be dissolved extemporaneously in sterile water or another sterile injectable medium.

solid compositions for rectal administration include suppositories prepared according to known methods and containing one or more of the compounds of formula (i) or one of their pharmaceutically acceptable salts.

The percentage of active ingredient in the compositions according to the invention can vary, but it is necessary that it constitutes a proportion such that a suitable dosage can be obtained. Of course, several unit dosage forms can be administered at about the same time. The dose to be used will be determined by the doctor, and depends on the desired therapeutic effect, the mode of administration and the duration of treatment, as well as on the condition of the patient. In adults, the doses are general. usually between 0.1 and 50 mg per kg of body weight and per # 55 *. daily, oral administration: for example, as anti-atheroma agents and in associated cardiovascular diseases, between 10 and 50 mg per kg of body weight per day, oral administration, and = in the treatment of arthritis and associated diseases , between 0.1 and 10 mg per kg of body weight per day, by oral administration.

The example which follows illustrates the pharmaceutical compositions according to the present invention.

EXAMPLE 55 10 size 2 gelatin capsules are prepared according to the usual method, containing: 4-amino-n-3-octanamido-benzoate 20 mg lactose 100 mg starch 60 mg

15 dextrin 40 mg ^ D

magnesium stearate 1 mg f y, t *

Claims (9)

1. Acylaminobenzoic acid derivatives, having the general formula: * Iïïï-COR2 R100C-— j | (I) X / ^ NHR0 in which 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 substituents of the same type chosen from hydroxy group, alkenyl groups containing 2 to 5 carbon atoms and alkanoyloxy groups containing 2 to 7 carbon atoms), R ° represents a hydrogen atom or a group of formula -COR, and R represents a straight or branched chain alkyl group containing from 2 to 20 carbon atoms, and the pharmaceutically acceptable salts of these derivatives. 2. 4 amino-n-octanamido-3 methyl benzoate, 4-amino n-hexadecanamido-3 methyl benzoate, 4-amino n-dodeaneanamido-3 benzoate, 4-amino methyl n-tetradecanamido-3 benzoate, amino-4 n-methyl 3-tridecanamido benzoate, bis (n-hexadecanamido) -3.4 benzoic acid, 20 bis (n- hexaded & namido) -3.4 methyl benzoate, bis (n-undecanamido) -3.4 methyl benzoate, 4-amino-n-decanamido-3 methyl benzoate, Λ bis (n-octanamido) - 3s4 methyl benzoate, - x bis (n-pentadeaneanido) -3.4 benzoic acid,. * 25 bis (n-nonanamido) -3j4 methyl benzoate, bis (n-heptadecanamido) -3.4 benzoic acid, bis (n-heneicosanamido) -3.4 benzoic acid, bis ( n ~ eicosanamido) -3.4 benzoic acid / 4-amino acid n ~ nonadecanamido ~ 3 benzoic acid, j \ h 37 bis (2-methyl-tetradecanamido acid) -3.4 "benzoic acid, amino- 4 (2-hexyl octanamido) -3 "benzoic acid, 4-amino (2-ethyl-dodecanamido) -3 benzoic, 4-amino acid (2-butyl decanamido) -3 benzoic, 5 bis acid ( n-tetradeaneanido) -2.3 benzoic acid, 3-amino acid n-hexadecanamido-4 benzoic acid, 4-amino acid n-octanamido-3 benzoic acid, 4-amino acid n-dodecanamido-3 benzoic, l amino-4 n-octadecanamido-3 benzoic acid, 10 bis (n-dodecanamido) -3.4 methyl benzoate, bis (n-tridecanamido) -3.4 methyl benzoate, bis (n-tetradecanamido) -3.4 methyl benzoate, bis (n-octadecanamido) -3.4 methyl benzoate, 3-amino-n-octanamido-4 benzoate, 3-amino-n-4-octanamido benzoic acid , 3-amino acid n-dodecana mido-4 benzoic, bis (n-decanamido) -3.4 methyl benzoate, bis (n-dodecanamido) -3.4 benzoic acid, bis (n-octanamido) -3.4 benzoic acid, 20 bis (n-tetradecanamido) -3,4 benzoic acid, 3-amino-n-dodecanamido-4 methyl benzoate, 3-amino-n-hexadecanamido-4 methyl benzoate, 3-amino -decanamido-4 methyl benzoate, 4-amino acid n-hexadecanamido-3 benzoic, 25 bis (n-decanamido) -3.4 benzoic acid, bis (n-tridecanamido) -3.4 benzoic, bis (n-octadecanamido) -3.4 benzoic acid, bis (n-hexadecanamido) -2.3 benzoic acid, methyl 4-amino-n-heptanamido-3 benzoate, and pharmaceutically acceptable salts of these compounds. 3. Process for the preparation of an acylaminobenzoic acid derivative according to claim 1 in the formula of which R ° represents a / hydrogen atom, characterized in that a dey compound is reduced / · general formula: / if / τ c 58. ΜΗ-COR2 yy R1OOC - j (II) Λ / ^ νο2 "1 2 (in which R and S are as defined in claim 1) by known methods for the reduction of a nitro group into a primary amino group, preferably by catalytic hydrogenation. 4. Process for the preparation of an acylaminobenzoic acid derivative according to claim 1, in the formula in which R ° represents a group of formula -COR (R being as defined in claim 2 2), or else the group substituent -NH-COR (R being as defined in claim 1) is in meta position by 1 1 relative to the substituent group -COOR (R being as defined in claim 1) and R ° represents a hydrogen atom , characterized in that a compound of general formula: r1ooc-- (ni) j 15 (in which R is as defined in claim 1) is reacted with an acylating agent of general formula: r2cox1 (iy) 2 wherein R is as defined in claim 1 and X represents a halogen atom or a hydroxy group. 20 5 · Process for the preparation of an acylaminobenzoic acid derivative - 'according to claim 1 in the formula of which R ° represents a 2/2 group of formula -COR (R being as defined in claim 1), characterized in that a compound of / general formula is reacted: yj / a NE-COR2 /] // 25 R100C — j- | (Jf n / ^ hh2 l 59 £ * 12 (in which R and R are as defined in claim 1) with an acylating agent of general formula: 2 1 * R COX 2 in which R is such as defined in claim 1 and • j 5. represents a halogen atom or a hydroxy group. 6. Process for the preparation of an acylaminohenzoic acid derivative; according to claim 1 in the formula of which R ^ represents a; straight or branched chain alkyl group containing from 1 to 6 carbon atoms (which may be substituted by one or more substituents of the same type chosen from the hydroxy group, alkenyl groups containing from 2 to 5 carbon atoms and the alkanoyloxy groups containing 2 to 7 carbon atoms) and R is as defined in claim 1, characterized in that a corresponding carboxylic acid of the general formula represented in claim 1 is appropriately esterified and in which R represents a hydrogen atom and r ° r2 are as defined in claim ±. 7- Process for the preparation of an acylaminohenzoic acid derivative according to claim 1 in the formula of which R represents an alkaline hydrogen atom, characterized in that hydrolysis / a corresponding ester of the general formula represented in Claim 1 and in which R represents a straight or branched chain alkyl group containing from 1 to 6 carbon atoms, which may be substituted by one or more substituents of the same type chosen from the hydroxy group, the alkenyl groups containing from 2 to 5 carbon atoms and the alkanoyloxy groups containing p from 2 to 7 carbon atoms, and r ° and R are as defined in * f claim 1. ΐ 8. Method according to any one of claims 3 to 7, followed by the step of transformation, by known methods, of an acylaminohenzoic acid derivative thus obtained, of the general formula represented in claim 1, into one of its pharmaceutically acceptable salts. //, f. . e 40 9 · Pharmaceutical compositions which contain, as active ingredient, at least one acylaminobenzoic acid derivative according to claim 1 f or one of its pharmaceutically acceptable salts, in association with a pharmaceutical carrier or packaging. Drawings: ............ U boards ..... tooth pages ........ To ........ page da grrde 35 ...... .ôa description .......... S ....... pages of claims ...... / ........... abridged description Luxembourg le ^ * jüJN 1980 The maprpaiaire: - ^ âoarles München