FR2459794A1 - ACYLAMINOBENZOIC ACID DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME - Google Patents

Abstract

THE INVENTION DEALS WITH NEW ACYLAMINOBENZOIC ACID DERIVATIVES, THEIR PHARMACEUTICALLY ACCEPTABLE SALTS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. THESE DERIVATIVES HAVE THE FORMULA BELOW, IN WHICH RH OR ALCOHYL SUBSTITUTES OR NOT, RH OR COR GROUP, AND RALCOYL. PHARMACOLOGICAL APPLICATIONS IN THE FIELD OF CARDIOVASCULAR AFFECTIONS: (CF DRAWING IN BOPI)

Description

The present invention relates to novel acid derivatives

  therapeutically useful acylaminobenzoics, methods for their preparation and pharmaceutical compositions

containing them.

  The acylaminobenzoic acid derivatives of the present invention are the compounds of the general formula

NH-COR2

R100 (

  I (1) wherein R represents a hydrogen atom or a straight or branched chain alkyl group containing from 1 to 6 carbon atoms (which may be substituted by one or more substituents of the same type selected from the group consisting of hydroxy, alkenyl groups containing from 2 to 5 carbon atoms and alkanoyloxy groups containing from 2 to 7 carbon atoms), preferably a methyl group, RH represents a hydrogen atom or a group of formula -COR2, and R2 represents a group straight or branched chain alkyl, preferably a straight chain group, containing from 2 to 20 (preferably 7 to 16) carbon atoms, and their pharmaceutically acceptable salts. When R 1 is a substituted alkyl group, it may be, for example, a 2,3-dihydroxy group.

  propyl-1, allyl or pivaloyloxymethyl.

  It will be understood that in some cases the R1 and R substituents contribute to optical isomerism. All these forms are

  encompassed by the present invention.

  By the term "pharmaceutically acceptable salt" is meant a salt formed, when R0 represents a hydrogen atom,

  by reaction with an acid or, when R1 represents a hydrogen atom

  gene, by reaction with a base, such 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 R1 represents

  a hydrogen atom) is relatively harmless for the organism

  the therapeutic properties of the parent compound of the general formula (I) are not adversely affected by

  secondary substances attributable to said anion or cation.

  Suitable salts of acid addition salts of compounds of general formula (I) wherein R represents a hydrogen atom include salts thereof

  of mineral acids, for example hydrochlorides, bromhyl-

  drakes, phosphates, sulphates and nitrates, and organic salts. for example, methanesulphonates, 2-hydroxyethanesulphonates, oxalates, lactates, tartrates, acetates, salicylates, citrates, propionates,

  succinates, fumarates; maleates, methylne-bis-1-

  hydroxynaphthoates, gentisates and di-p-toluoyltartrates.

  Among the salts formed by the compounds of general formula (I)

  in which R represents a hydrogen atom, those which are suitable

  These include alkali metal (eg, sodium and potassium) salts, alkaline earth metal (eg, calcium and magnesium) salts, ammonium salts and amine salts known to be pharmaceutically acceptable. , by

  example, ethylbnediamine, choline, diethanolamine, triethylamine,

  ethanolamine; octadecylamine, diethylamine, triethylamine, amino2-hydroxymethyl-2-propanediol-1,3 and 3,4-dihydroxy

  phenyl) -isopropylamino-2-ethanol.

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

  The compounds of the general formula (I) have useful

  pharmacological properties. For example, they reduce the proliferation

  tion of arterial smooth muscle cells which is a point

  of major importance for atheromatous plaques.

  In addition, they inhibit the accumulation of cholesterol esters and the incorporation of cholesterol oleate with total cholesterol esters and other characteristic complex lipids

  fatty acyl enzyme CoA / acyl cholesterol transferase.

  Stimulation of this enzyme in the presence of plasma

  Hyperlipemia occurs in the development of atherosclerotic lesions.

  mateuses. The compounds of general formula (I) also suppress

  lymphocyte transformation as do the anti-drugs

  rheumatic. Thus, they are useful in the prevention or treatment of atherosclerosis and associated conditions such as

  angina pectoris, myocardial infarction, vascular occlusion

  cerebral artery, arterial aneurysm and peripheral vascular disease; as well as arthritis, diseases

  immunological, 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: A 4-amino-3-nhexadecanamido-3-methyl benzoate 4-n-dodecanamido-3-methyl benzoate C-amino-4-n-tetradecanamido-3-methyl benzoate D-amino-3-naphthalamido-3-methyl benzoate E bis (n-hexanamido) -3,4 benzoic acid F bis (n-hexadecanamido) ) -3,4 methyl benzoate G bis (nundecanamido) -3,4 methyl benzoate H amino-4 n-decanamido-3 methyl benzoate I bis (n-octanamido) -3,4 benzoate methyl J acid bis ( npentadecanamido) -3,4 benzo! K bis (n-nonanamido) -3,4 benzoate methyl L bis (n-heptadecanamido) -3,4 benzoic acid M bis (nheneicosanamido) -3,4 benzoic acid N bis acid (N-eicosanamido) -3,4 benzoic acid 0 4-amino-n-3-nonadecanamido benzoic acid P bis (2-methyl-tetradecanamido) -3,4 benzoic acid (RS) (RS) Q-amino acid (hexyl) 2 octanamido) -5 benzo R 4-amino-3- (2-ethyl-3-dodecanamido) -benzoic acid (RS) S 4-amino-3- (2-butyl-decanamido) benzoic acid (RS) T bis (n-tetradecanamido) -2,3-benzoic acid 3-amino-4-N-hexadecanobenzo-benzoic acid 4-amino-3-n-octanamido-3-benzoic acid 4-amino-n-dodecanedio-3-benzoic acid X 4-amino-n-octadecanedio-benzoic acid Y 4-amino-n-octanamido-3-benzoate of methyl Z bis (ndodecanamido) -3,4 benzoate methyl AA bis (n-tridecanamido) -3,4 benzoate methyl BB bis (n-tetradecanamido) -3,4 benzoate methyl CC bis (n-octadecanamido) - 3,4 methyl benzoate DD 3-amino-4-n-octanamido-4-methyl benzoate 3-amino-4-n-octanamido-benzoic acid TFF 3-amino-4-n-dodecanamido benzoic acid GG bis (n-decanamido) -3, 4 methyl benzoate EH acid bis (n-dodecanamido) -3,4 benzoic acid II bis (noctanamido) -3,4 benzoic acid JJ bis (n-tetradecanamido) -3,4 benzoic acid KK amino-3 n-dodecanamido-4 methyl benzoate LL 3-amino-4-nhexadecanamido methyl benzoate 5-amino-N-decanamido-4-methyl benzoate NN 4-amino-n-hexadecanamido-3-benzoic acid 00 bis (ndecanamido) -3,4 benzoic acid PP bis (n-tridecanamido) -3,4 benzoic acid QQ bis acid (n-octadecanamido) -3,4 benzoic acid bis bis (n-hexadecanamido) 2,3 benzoic acid and

  4-amino-4-n-heptanamido-3-methyl benzoate.

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

paintings.

  The properties of the compounds of general formula (I) are demonstrated by the following tests: Inhibition action of the proliferation of aortic smooth muscle cells Smooth muscle cells are grown in culture from thoracic aorta explants. poro, using modified Dulbecco's Eagles Medium (DME) containing 20% serum

  calf fetus (SFV) and antibiotics. The cells are incubated

  at 37 ° C. in an atmosphere of 95% air and 5% carbon dioxide.

  Picnic. When the cells have reached confluence, we submit them

  in the usual way to trypsinization and reseeding.

  approximately one-third of their confluence density in

  DME medium containing 10% SFV and antibiotics.

  The smooth muscle cells are seeded with

  from LOO 000 to 200,000 cells per Falcon bowl of 35 x 10 mm

  in 2 ml of DME medium, containing 10% SWV and antibiotics.

  After 24 hours, when the cells have attached to the boots, the medium is replaced with 2 ml of DME medium containing 1% SFV and antibiotics. The cultures are incubated during

  another three days to allow the cells to

  pos (that is to say, no longer undergoing cell division). The medium is then replaced with 2 ml of control medium or medium to be tested. The medium to be tested consists of DME medium (containing 10%

  of SFV and antibiotics) and test compound at a concentration of

  5 mg 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 DME medium (containing 10% of

  SFV and antibiotics) and acetone at a concentration of

  0.2% by volume. After three days of incubation in medium to be tested or in a control medium, the medium is replaced with test medium or fresh control medium and the cells are incubated for a further three or four days. After 6 or 7 days of the

  incubation period, the number of cells per tryptic

  sination of these and counting of the cell suspension

  in a Coulter counting machine.

  All the results in Table I below represent the average value for four bundles of cells. We caleule the

  percent inhibition of proliferation using the

  next mule: Percentage inhibition of proliferation

(T - S)

  or S average number of cells per boot at the beginning of the ex-

  during the addition of the control medium or

of the medium to be tested).

  10 T = average number of cells per boot in the cul-

  tested at the completion of the experiment.

  C = average number of cells per boot in the cul-

  witnesses at the completion of the experiment.

TABLE I

  Inhibition Action of Cholesterol Ester Accumulation of Aortic Smooth Muscle Cells Aortic smooth muscle cells, as described above, at passage No. 8, are cultured to confluence in Dulbecco's Modified Eagles Medium. (DME) containing 10% serum

  calf fetus (SFV) and antibiotics.

  Four smooth muscle cell replication boots were incubated for 24 hours in DME medium containing 10% by volume of hyperlipemic rabbit serum, 3H-oleate complexed with defatted bovine serum albumin (free fatty acid molar ratio). (AGL) / albunmine = 0.862;% inhibition compound

Y 59.76,84.56,32,40,41.55

B 51.52

D 61.61

C, 54.48

A 71.76.47.40

KK 24.47

[.

  concentration of oleate in the medium: 0.155 mM),

  biotic (penicillin G 100 U.I./ml, streptomycin 100 ug / ml

  and kanamycin 100 μg / ml) and the test compound at a concentration of

  100 μg per ml of medium. Test flocks without test compounds and control boxes are also incubated with

  % by volume of SFV instead of hyperlipemic rabbit serum.

  The sera are inactivated by heating before use; they contain respectively 933 mg / dl or 26 mg / dl of total cholesterol. After the incubation, the cells are washed with

  Hanks' solution, they are subjected to trypsination, they are

  and centrifugally pellet the pellet in 0.27 mM EDTA. Free and esterified cholesterol cell concentrations and incorporation of 3H-cholesterol oleate in the total cholesterol ester are determined.

  other complex lipids compared to controls.

  All the results in Tables II and III below

  represent the average value of four boxes of cells.

TABLE II

% concentration reduction

compared to the witnesses con-

  Solvent compound of hyperlipemic serum Compose SolventI cholesterol ester of free cholesterol Y ethanol 1b6.2 31 A ethanol 32 27

TABLE III

  % reduction in AGL incorporation compared to controls containing the same solvent and serum Compound Phospholipid Triglycerides Lipid Ester Ester of Total Cholesterol Lipids

Y 13.1 77.3 55.7 45.2

At 11.5 73.9 52.5 53.9

  Action of inhibition of the transformation into lymphocytes of eel-

  Mitomycin-stimulated lymph nodes in guinea pigs Mycobacterium tuberculosum guinea pigs were sensitized by infusion of Freund's complete adjuvant (FCA) in the soles of the feet (0.05 ml, 0.5 mg / ml). ml of 50% solution

  FCA volumes in sterile saline).

  After 14 days, lymph node cells are obtained which are suspended in minimal essential Eagles medium (EME) containing 10% fetal calf serum (FCS) and buffered with Earle salts. , at a concentration of 2.5 x 106

cells per ml.

  0.1 ml of cell suspension is incubated for 24 hours at 37.degree. C. 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 10% SFV and

buffered with Earle salts).

  Eighteen hours before harvest, we have H-thymi

  dine (1 μl of 100 μCi / ml solution in brine

0.9% sterile).

  The level of incorporation of 3H-thymidine by the cells in comparison with the DNA synthesis index is measured

with the control mitogen.

  The results are shown below in Table IV.

TABLE IV

  The usefulness of these compounds is increased by the fact that they have a very low toxicity, as demonstrated by the following test. Oral toxicity in mice Groups of mice with

  gradual doses of the test compound (in an aqueous suspension

  0.5% w / v gum tragacanth) and kept under observation for three days thereafter. The percentages of animals that die during this period for each dose level are used to construct a graph from which the LD50, i.e. the dose, is calculated in mg per kg of weight.

  body, necessary to kill 50% of the animals.

  Dose in% Incorporation Inhibition Comps 3% Thymidine Medium in DNA Compose Incubation Cells vs. Mitogen Pg / ml Control (1) | () | (T)

Y 3 5 17 14

60 59 61

94 97 96

H 3 21

78

90

B 3 27

46

71

D 3 35

51

76

C 3 12

37

62

A 3 4

10

15

  The compounds of formula (I) indicated in the list below

  above were tested and the LD50 of each compound is higher than

  than 1000 mg per kg body weight of the animal.

  The compounds of the invention which are preferred are those identified above by the letters Y, A, B, D and C. The compounds of general formula (1) can be

  prepared by applying or adapting known methods (ie

  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 1 represents a hydrogen atom are prepared by reduction of a compound of general formula

NH-COR2

  R Of (II) N2 N2 (in which R and R are as defined above) by known methods for the reduction of a nitro group to a primary amino group, for example by catalytic hydrogenation, of

  preferably using palladium on black as a catalyst.

  (B) According to another characteristic of the present invention

  compounds of the general formula (I) in which RI is

  a group of formula -COR2 (R2 being as defined above).

  or the substituent group -N-COR2 (R2 being as defined above) is in the meta position relative to the substituent group COOR1 (R1 being as defined above) and R0 represents a hydrogen atom, are prepared by reaction of a compound of general formula: NH 2

R DO (III)

  NH 2 (wherein R is as defined above) with an acylating agent of the general formula:

R2 COX1

  (IV) wherein R2 is as defined above and X1 represents

  a halogen atom (preferably chlorine) or a hydroxy group.

  Particularly suitable conditions are the following: 1) The compounds of general formula (I) in which R 0 represents a group of formula -COR 2 (in which R 2 is as defined above) are prepared by reaction of a compound of general formula ( III) (wherein 1 is as defined above) with an acyl halide of general formula (IV) (wherein R is as defined above and X1 represents a halogen atom, preferably chlorine) within a solvent

  inert organic compound, for example dichloromethane or dimethyl-

  formamide, preferably in an anhydrous medium and preferably in

  presence of an acid-fixing agent, for example a trialkyl

  amine (such as triethylamine), or carbonate or bicarbonate

  alkali metal (for example sodium carbonate or potas-

  anhydrous sium) at a temperature which may be greater than

  ambient temperature, for example between 10 and 50C.

  2) Compounds of general formula (I) in which

  the substituent group -NH-COR2 (R2 being as defined previously

  is in the meta position relative to the substituent group -COOR1 (R1 being as defined above), and R0 represents a hydrogen atom, are prepared by reaction of a compound of

  general formula (III) (especially those in which R1 represents

  a straight or branched chain alkyl group containing from 1 to 6 carbon atoms) with an acyl halide of the general formula (IV) (wherein R 2 is as defined above and X 1 represents a halogen atom, preferably chlorine), under conditions similar to those described above but using a lower amount of acyl halide and maintaining the temperature preferably between 00C and

ambient temperature.

  (C) According to another feature of the present invention

  compounds of the general formula (I) in which R0 represents

2 2

  a group of formula -COR (R being as defined above)

  d) are prepared from a corresponding compound of the general formula (I) (wherein R0 represents a hydrogen atom) by reaction with a compound of the general formula (IV)

according to known methods.

  The compounds of the general formula (II) can be prepared by reacting a compound of the general formula NRH2

R 00 ()

  NO 2 (wherein R is as defined above) with a compound of general formula (IV) in a manner similar to that described

above in method B 1).

  The compounds of general formula (V) can be

  prepared by known methods.

  (D) According to another characteristic of the present invention

  compounds of the general formula (I) in which R1 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 selected from hydroxy group, alkenyl groups containing from 2 to 5 carbon atoms and alkanoyloxy containing from 2 to 7 carbon atoms) are prepared by esterification of a corresponding compound of general formula (I) in which R 1 represents a hydrogen atom, by application or adaptation of known methods, for example by reaction with the diazoalkane corresponding in the presence of a

inert organic solvent.

  (E) According to another characteristic of the present invention, the compounds of general formula (I) in which R 1 represents a hydrogen atom are prepared by alkaline hydrolysis of a corresponding ester 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 more substituents of the same type selected from hydroxy group, 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 in a hydroorganic solvent system and with

high temperature

  (F) According to another characteristic of the present invention

  tion, the compounds of general formula (I) in which R 1 represents a hydrogen atom and / or R 1 represents a hydrogen atom, are converted into their pharmaceutically acceptable salts,

  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 impurity present, by known methods

such as crystallization.

  1) The compounds of general formula (I) in which R 1 represents a hydrogen atom (RO and R being as defined above) can be converted into their pharmaceutically acceptable base salts, for example by reaction with the appropriate base, by for example, the appropriate amine or a compound of the general formula:

M1OR3 (VI)

  (wherein m1 represents an alkali metal atom, for example sodium or potassium, and R3 represents an alkyl group containing up to 4 carbon atoms, for example methyl

  or ethyl, or a hydrogen atom) in a suitable solvent.

  such as methanol or ethanol, or a mixture of water and acetone, followed, if necessary, by

  all or part of the solvent, and recovery of the solid salt.

  These salts can be converted back 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, followed, if necessary, all or part of the solvent, and

  recovering the solid compound of general formula (I).

  2) The compounds of general formula (I) in which R 1 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

  all or part of the solvent, and recovery of the solid salt.

  The acid addition salts can be converted back into the original compounds of general formula (I), for example

  by reaction with ammonia in the presence of a suitable solvent

  such as ethanol, followed by treatment with a

  weak acid, for example glacial acetic acid.

  The compounds of general formula (I) are also used

  sands as starting materials for the preparation of therapeutically useful benzimidazole derivatives of general formula N

R100 21 (VII)

H

  (where R1 is as previously defined and R2 is

  a straight or branched chain alkyl group containing from 7 to 20 carbon atoms), the R 100C group being attached to the 4- or 5-position of the benzimidazole ring system, derived from

  which they can be transformed by application or adaptation

  tation of known cyclization methods.

For example:

  a) when R0 in the general formula (I) is a group of the formula -COR2 (R2 being as defined above), the cyclization can be carried out to form a benzimidazole derivative of the general formula (VII) at elevated temperature, for example between 60 and 1000 ° C., by reaction with a mineral acid, for example hydrochloric acid, in the presence of water and 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 R0 in the general formula (I) 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) cyclization can be carried out in the absence of solvent and at elevated temperature (for example between 150 and 2500 ° 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 the execution of the methods

  above and of those of the present invention, it may be desirable

  table to introduce protective chemical groups into the reagents to prevent side reactions from occurring; for example in the method of preparation of benzimidazoles

  described above, the hydroxy groups of the

  R represented in the general formula (I) in benzyloxy groups before the reaction as described, with elimination

subsequent benzyl group.

  The benzimidazole derivatives of general formula (VII) are useful for the prevention or treatment of diabetes mellitus, hyperlipoproteinemic conditions, atherosclerosis and related conditions, such as angina pectoris, myocardial infarction, cerebrovascular occlusion, arterial aneurysm, peripheral vascular disease, recurrent pancreatitis

  and xanthomas, as well as arthritis, immune

  logical, cancer and graft rejection.

  The following examples illustrate the preparation of

  compounds of the present invention.

EXAMPLE 1

  Compound A Methyl 4-amino-3-n-hexadecanamido benzoate is prepared by one or the other of the following methods:

  a) A stirred solution of 3,4-diamino benzene is treated dropwise

  methyl zoate (35 g) in 1200 ml of anhydrous dimethylformamide, containing 11.8 g of anhydrous sodium carbonate, with 58 g of n-hexadecanoyl chloride for one hour. The rate of addition of the N-hexadecanoyl chloride is such as to allow 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

  room for another 3 hours, then poured into 5 liters of water.

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

  b) A stirred solution of 3,4-diamino benzene is treated dropwise

  methyl zoate (16.6 g) in 270 ml of anhydrous dichloromethane, containing 10.3 g of triethylamine, with a solution of nhexadecanoyl chloride (27.5 g) in 30 ml of anhydrous dichloromethane for minutes. During the addition, the temperature is maintained between 16 and 20 ° C. The mixture is stirred for a further 2 hours. The resulting solid is then collected and boiled in a mixture

  acetone (1000 ml) and methanol (150 ml) and filtered off.

  insoluble materials. The filtrate is cooled to 25 ° C. and treated with 800 ml of water to give methyl 4-amino-3-n-hexadecanamido benzoate in the form of a buff-colored solid.

M.p. ii2-11ii40C.

EXAMPLE 2

  Compound B A solution of 3,4-diamino-benzoic acid methyl ester (25.0 g) in 1120 ml of anhydrous dimethylformamide, containing 7.7 g of anhydrous sodium carbonate, is treated with 30.5 g of n-dodecanoyl chloride. in a manner similar to that described above in Example 1 (a) to give 41 g of crude methyl 4-amino-n-dodecanamido-3-benzoate,

  in the form of a buff-colored solid.

EXAMPLE 3

  Compound C A solution of methyl 3,4-diamino benzoate (25.0 g) in 500 ml of anhydrous dichloromethane, containing 15.5 g of triethylaminc, is treated dropwise with one evolution of n-tetradeanoyl chloride (57.0 g). 12 g) in 50 ml of anhydrous dichloromethane in a manner comparable to that described above in Example 1 (b) to give 40 g of methyl-4-tetradecanamido-3-methyl benzoate

  rough in the form of a buff-colored solid.

EXAMPLE 4

  Compound D A solution of 3,4-diamino methyl benzoate is treated

  (17.8 g) in 350 ml of dichloromethane, containing 10.8 g of triethyl

  amine, per 25 g of n-tridecanoyl chloride, in a manner similar to that described above in Example 1 (b), which gives 40 g

  of 4-amino-n-tridecanamido-3-methyl benzoate crude.

EXAMPLE 5

  Compound 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 g of n-hexadecanoyl chloride in a manner similar to that described above. above in Example 1 (b). A solid is collected which is recrystallized from glacial acetic acid and then from methyl ethyl ketone (with filtration of the hot solution), giving 20 g of bis (nhexadecanamido) -3,4 benzoic acid in the form of a

  solid buff color, mp 198-202 ° C.

t8

EXAMPLE 6

  Compound F A solution of 3,4-diamino benzoate of methyl is treated

  (5.0 g) in 50 ml of dichloromethane, containing 6.2 g of triethyl

  amine, by 16.5 g of n-hexadecanoyl chloride in a similar manner

  to that described above in Example 1 (b) (the temperature is

  of the reaction mixture during the addition amounted to 20 to

   C). A solid is collected which is recrystallized from chlorine

  form, giving 14.9 g of bis (n-hexadecanamido) -3,4 benzoate

  methyl as a white solid, m.p. 129-132 ° C.

EXAMPLE 7

  Compound G A solution of 3,4-diamino benzoate of methyl is treated

  (17.9 g) in 300 ml of dichloromethane containing 21.8 g of triethyl

  amine, with 44.3 g of n-undecanoyl chloride in a manner similar to that described above in Example 6. A solid is collected which is recrystallized twice from ethanol (with filtration of the hot solution ), giving 40.2 g of bis (n-undecanamido) -3.4

  methyl benzoate as a white solid, m.p. 139-141C.

EXAMPLE 8

  Compound H A stirred solution of methyl 3,4-diamino benzoate (16.6 g) in 600 ml of anhydrous dimethylformamide, containing 5.3 g of anhydrous sodium carbonate, is treated dropwise with 19.1 g of n-decanoyl chloride, in a manner similar to that described above in Example 1 (a), to give 18.8 g of 4-amono-3-decanamido-3-benzoate

  of methyl as a buff solid, m.p. 96-o98C.

EXAMPLE 9

  Compound I A solution of 3,4-diamino benzoate methyl is treated

  (41.2 g) in 412 ml of dichloromethane, containing 51.0 g of triethyl

  amine, by a solution of n-octanoyl chloride (80.6 g) in 330 ml of dichloromethane, in a manner similar to that described above in Example 6, recrystallizing from methanol (with treatment with black) to give 81.8 g of bis (n-octanamido) -3,4 benzoate

  methyl under a white solid, m.p. 138-140 ° C.

EXAMPLE 10

  A solution of 3,4-diamino benzoic acid (13.85 g) in 180 ml of dimethylformamide, containing 27.6 g of triethylamine, is treated with 47.4 g of n-pentadecanoyl chloride in a similar manner. to that described above in Example i (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 bis (n-pentadecanamido) -3,4 benzoic acid, m.p.

178-180C.

EXAMPLE 11

  Compound E A stirred solution of 152 g of 3,4-diamino benzoic acid is treated dropwise in 1500 ml of dimethylformamide,

  containing 303 g of triethylamine, 549.0 g of n-hexahydrate

  decanoyl for 1 1/2 hours. The rate of addition of nhexadecanoyl 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 and then poured into 10 liters of water maintained at 70 ° C., containing 150 ml of concentrated (36.5% w / v) hydrochloric acid. The resulting solid is collected to give 600 g of bis (nhexadecanamido) -3,4 benzoic acid in the form of a colored solid.

chamois, m.p. 180-190 ° C.

EXAMPLE 12

  Compound K A stirred solution of 20 g of 3,4-diamino benzoate in 250 ml of anhydrous dichloromethane, containing 24.2 g of triethylamine, is treated dropwise with a solution of 44.12 g of nonanoyl chloride. in 50 ml of dichloromethane

  anhydrous, in a manner similar to that described above in the example

  pl (1) (b) to give a pink solid, which is recrystallized from methanol, with a dark treatment to give 30.3 g of methyl bis (nnonamido) -3,4 benzoate in the form of a solid

white, m.p. 142-145C.

EXAMPLE 13

  Compound L A stirred solution of 45.6 g of 3,4-diamino benzoic acid in 400 ml of dimethylformamide, containing 75.8 g of triethylamine, is treated dropwise with 130 g of n-heptadecanoyl chloride, in a manner similar to that described above in Example 11, which gives 140 g of bis (n-heptadecanamido) -3,4 acid

  crude benzoic in the form of a pink solid.

EXAMPLE 14

  Compound M A stirred solution of 21.9 g is treated dropwise

  of 3,4-diamino benzoic acid in 175 ml of dimethylformamide,

  43.6 g of triethylamine, 99.2 g of n-heneicosa-

  embedded in a manner similar to that described above in Example 11, giving 126.5 g of crude bis (n-heneicosanamido) -3,4 benzonac acid

in the form of a light brown solid.

EXAMPLE 15

Compound N

  A soliutocn agitated with dichloride is treated dropwise.

  No. 3, 4 benzoic acid (1i, 3 g) in 200 ml of dimethylformamide, containing 356.5 g of triethylamine, with 79.4 g of n-eicosanoyl chloride, in a manner similar to that described above. in Example 11, which gives 93 g of crude bis (n-cicosanamido) -3,4 benzolc acid in the form of

  of a brown solid, mp 160-1700 C.

EXAMPLE 16

  Compound O A stirred squeeze of 38 g of ace diamin-3 was dropping. benzoic acid, 5 g / ml of methylene-formamide, 5 g of triethylamine, with 79.1 g of n-nonidecyl chloride, in a manner similar to that described in US Pat. Example 11, which gives an orange solution which is poured into 30O ml of water containing

  ml of concentrated hydrochloric acid (r 36.5, w / v).

  The solid is collected, washed with water (2 x 100 ml) and then dried to give 107 mg of 3-amino-nonadecanamido benzoic acid.

crude, m.p. 103-113 C.

EXAMPLE 17

  Compound P A solution of 17.5 g of 3,4-diamino benzoic acid in 140 ml of dimethylformamide, containing 34.8 g of triethylamine, is treated dropwise with 59.7 g of pentadecanoyl chloride similar to that described above in Example 11, this

  which gives 68 g of bis (2-methyl-tetradecanamido) -3,4 benzoic acid

(RS) (RS) gross.

EXAMPLE 18

  Stirred compound A solution of 20.7 g of 3,4-diamino benzoic acid in 65 ml of dimethylformamide containing 56.5 ml of triethylamine was treated dropwise with 67 g of hexyl-2-octanoyl chloride. in a manner similar to that described in Example 11. The waxy solid is collected and dissolved in 500 ml of diethyl ether; we're leaving

  ether solution and evaporated to give a reddish brown oil.

  This oil is extracted with hot methanol using an apparatus

  cenminue extraction, for 5 hours. The methanolic solution is evaporated

  on a rotary evaporator to give a brown solid which is recrystallized from acetone to give 15.2 g of 4-amino-acid

  (2-hexyl octanamido) -) benzoic acid, in the form of a white solid, m.p.

219-221 C.

EXAMPLE 19

  Compound R A stirred solution of 22.8 g of 3,4-diamino benzoic acid in 200 ml of dimethylformamide, containing 22.7 g of triethylamine, is treated dropwise with 37 g of 2-ethyldodecanoyl chloride, in a manner 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 treatment, giving 22.2 g of 4-amino-2- (2-ethyl-dodecanamido) benzoic acid (RS) under

  white solid, m.p. 188-1910C.

EXAMPLE -20

  Compound S A stirred solution of 15.8 g of 3,4-diaminobenzoic acid in 130 ml of dimethylformamide, containing 43.4 g of triethylamine, is treated dropwise with 51.4 g of butyl-2 decanoyl chloride. in a manner similar to that described above in Example 11. After treatment of the reaction product as described above in Example 18, 9.8 g of 4-amino-2-butyl-decanamido acid are obtained. ) -3 benzolque- (RS) as a white solid,

M.p. 178-182 C.

EXAMPLE 21

  Compound T A solution of 20 g of 2,3-diaminozocyclic acid in 200 ml of dimethylformamide, containing 39.9 g of triethylamine, is treated with 65.0 g of n-tetradecanoyl chloride. The speed of addition of the

  n-tetradecanoyl chloride is such as to allow the temperature

  The reaction mixture is allowed to rise from room temperature to 45-50 ° C. The mixture is then stirred for a further 2 hours.

  and allowed to stand at room temperature overnight.

  20 ml of methanol are added to the mixture, the resulting mixture is stirred for 20 minutes and then treated with concentrated hydrochloric acid (36.5% w / v) until it is creased. 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 hot petroleum ether (PE 60-80 ° C). and finally recrystallized from ethanol, with treatment with the black, giving 17.7 g of bis (ntetradecanamido) -2,3 benzoic acid in the form of a solid

buff color, mp 150-158 C.

EXAMPLE 22

ComDose '

  A solution of 22 g of nitro- (n-hexadecene) acid is hydrogenated.

  4-canamido benzoic acid in 500 ml of n-butanol, shaking it in the presence of 2.5 g of palladium on black at 5% by weight, at 70 ° C. and at atmospheric pressure for 6 hours. We filter the mrlarne to

  The mixture is warm and the filtrate is allowed to cool. The solid result is collected

  and washed with 100 ml of ethanol to give 11.6 g of 3-amino-hexadecanamido-4-benzoic acid as a colored solid.

cream, .F .. 16C-162C.

  The n-hexadecanamidoidobenzoic acid used as a starting material is prepared as follows: A solution of 18.2 g is heated for 90 minutes at 97 ° C.

  of 4-aminobenzoic acid and 3.0 g of hexahydrate

  decanoyl; 100 ml of dimethylformamide. The solution was cooled and then C300 glass was poured with crushed glacc. The resulting solid is collected, washed with water (3 x 100 ml), dried and recrystallized from a mixture of ice and water (5: 1).

  with dark trapping, which gives 31.7 g of nitro-3 n-hcxa-

  decanamido-benzoic acid as a solid.

', C.

EXAMPLE 25

  Compound V Proceeding from a similar fagçn to that déerite ei above

  in Example 16 the preparation of amino-1 n-nonadec acid

  namido-) benzoic mals by replacing n-nonadecanoyl chloride

  with n-butanyl chloride, 4-amino-n-octanamido acid is prepared.

  benzoate in the form of a solid blanket, F.F. 202-2030C after

  recrystallization from methanol.

EXAMPLE 24

  Compound W Proceeding in a manner similar to that described above

  in Example 16 for the preparation of 4-amino-n-nonadecanic acid.

  mido-3 benzoic acid but replacing n-nonadecanoyl chloride

  with n-dodecanoyl chloride, the 4-amino-n-dodecanoic acid is prepared.

  canamido-3 benzorque in the form of a white solid, m.p. 183-185 C.

EXAMPLE 25

  Compound X Proceeding in a manner similar to that described above

  in Example 16 for the preparation of 4-amino-n-nonadecanic acid

  mido-3 benzoic acid but replacing n-nonadecanoyl chloride with

  n-octadecanoyl chloride, 4-amino-n-octadecanic acid is prepared.

  3-Benzobenzoic acid as a light brown solid, m.p.

  187 C after recrystallization from methyl ethyl ketone.

EXAMPLE 26

- Y compound

  A solution of 3,4-diamino benzoyl is treated dropwise

  methyl ester (83.1 g) in 900 ml of anhydrous dimethylformamide,

  containing 50 g of triethylamine with 81.3 g of n-octahydrate chloride.

  embedded for 30 minutes at a temperature maintained between 5 and 6 ° C.

  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 is collected and recrystallized twice from methanol to give 65.5 g of methyl 4-amino-3-n-octanamido benzoate under

  form of a white solid, mp 120 C.

EXAMPLE 27

  Compound B Proceeding in a manner similar to that described above

  in Example 26 but replacing the n-octahydrate

  embedded in n-dodecanoyl chloride, 4-amino-n-dodecane is prepared

  canamido-3 methyl benzoate as a whitish solid,

  Mp 10 -250 ° C. after recrystallization from methanol.

EXAMPLE 28

  Compound D Proceeding in a manner similar to that described above

  in Example 26 but replacing the n-octahydrate

  embedded in n-tridecanoyl chloride, the amine, -4 n-tridecanoyl

  3-canamido benzoate as a light brown solid,

  M.p. 101-104 ° C. after recrystallization from methanol.

EXAMPLE 29

  Compound C Proceeding in a manner similar to that described in Example 26 but replacing the n-octanoyl chloride with 4-tetradecanoyl chloride, methyl 4-amino-3-tetradecanamido-benzoate is prepared under light brown solid, PF 108-10 C

  after recrystallization from methanol.

EXAMPLE 30

  Compound A Proceeding in a manner similar to that described above

  in Example 26 but replacing the n-octahydrate

  embedded in n-hexadecanoyl chloride, the 4-amino-n-hexa

  3-decanamido-3-methyl benzoate as a white solid, m.p.

  109-110 ° C. after recrystallization from methanol.

EXAMPLE 31

  Compound F A solution of 5 g of 3,4-diamino-benzoate in 50 ml of dimethylformamide, containing 6.1 g, is added dropwise.

  of triethylamine with a solution of 16.54 g of hexadecamide

  embedded in 40 ml of anhydrous dimethylformamide in 5 minutes. The temperature is allowed to rise from 20 to 500C. 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% w / v)

  lurre). The resulting solid is collected and recrystallized from a mixture (1/1) of chloroform and acetone to give 12.1 g of methyl bis (n-hexadecanamido) -3,4 benzoate in the form of a

  white solid, m.p. 129-132 ° C, identical to the product of Example 6.

EXAMPLE 32

  Compound I proceeding in a manner similar to that described above in Example 31 but replacing the chloride of

  n-hexadecanoyl with n-octanoyl chloride, the bis (n-octahoyl)

  n-methyl) -3,4 benzoic acid methyl ester as a white solid.

  -147C after recrystallization from acetone.

EXAMPLE 33

  Compound Z Proceeding in a manner similar to that described above in Example 31 but replacing the n-hexadecanoyl chloride by n-dodecanoyl chloride, is prepared the bis (n-dodécanamido) -3,4 benzoate methyl in the form of a whitish solid,

  M.p. 129-131 ° C after recrystallization from acetone.

EXAMPLE 34

  AA compound Proceeding in a manner similar to that described above in Example 31 but replacing the n-hexadecanoyl chloride

  with n-tridecanoyl chloride, the bis (n-tridecanoyl)

  mido) -3,4 methyl benzoate as a white solid, m.p.

  132-134 ° C. after recrystallization from acetone.

EXAMPLE 35

  BB compound Proceeding in a manner similar to that described above in Example 31 but replacing the n-hexadecanoyl chloride

  with n-tetradecanoyl chloride, the bis (n-tetradecan)

  namido) -3,4 methyl benzoate as a white solid,

  M.p. 132-133 ° C after recrystallization from acetone.

EXAMPLE 36

  CC compound Proceeding in a manner similar to that described above in Example 31 but replacing the n-hexadecanoyl chloride

  with n-octadecanoyl chloride, the bis (n-octadecane)

  mido) -3,4 methyl benzoate in the form of a white solid, mp 120 ° C. after recrystallization from a mixture (1/1)

acetone and methanol.

EXAMPLE 37

  Compound DD 12.1 g of 3-amino-n-octanamido-benzoic acid in 200 ml of methanol are treated with an ethereal diazomethane solution until the reaction is complete. Lcom-e is observed by layer chromatography. thin 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 was recrystallized from ethyl acetate to give methyl 3-amino-3-n-octanamido-4-benzoate (9.2 g) as a color solid.

cream, m.p. 128-131 ° C.

EXAMPLE 38

  Compound EE 25 g of 3-nitro-n-octanamido-4-benzoic acid dissolved in 500 ml of ethanol at 50 ° C. are hydrogenated by shaking it in the presence of 2.5 g of 5% by weight palladium on black at 500.degree. C and at atmospheric pressure for 3 hours. The mixture is filtered to warmness and the filtrate is evaporated under vacuum. The residue is recrystallized from a mixture (i / i) of ethanol and water to give 8 g of 3-amino acid.

  4-n-octanamido benzoic acid as a yellow solid, m.p. 155-156 C.

  The 3-nitro-n-octanamido benzoic acid used as starting material is prepared as follows: A solution of 1 g, 2 g is treated at 97 ° C. for 90 minutes.

  of 4-amino-3-nitro benzoic acid and 9.4 g of n-octahydrate chloride.

  embedded in 10 ml of anhydrous dimethylformamide. The solution is cooled

  and poured over 300 g of ice. The solid result is collected

  and washed with water (3 x 100 ml), dried and recreated

  from a mixture (S / i) of methanol and water (with

  black), which gives 22 g of nitro-) n-octanamido-4 ben-

  zoic in the form of a pale yellow solid, mp 155-154 ° C.

EXAMPLE 39

  Compound FF 21 g of 3-nitro-4-nododecanobenzobenzoic acid dissolved in 500 ml of ethyl acetate are hydrogenated by shaking in the presence of 2.5 g of 5% by weight palladium on black at 50.degree. C and at atmospheric pressure. The resultant mixture is filtered hot to give a cream-colored solid by cooling. We recrystallize this

  produced from methanol to give 7.4 g of n-dodec

  canamido-4 benzolque in the form of a beige solid, m.p.

EXAMPLE 40

  Compound H proceeding in a manner similar to that described above in Example 26 but replacing the n-octanoyl chloride

  with n-decanoyl chloride, the 4-aminodecanamine is prepared.

  3-methyl benzoate as a white solid, mp 96-1000 ° C.

EXAMPLE 41

  Compound GG Proceeding in a manner similar to that described above in Example 31 but replacing the n-hexadecanoyl chloride by n-decanoyl chloride, is prepared the bis (n-decanamido) -3,4 benzoate methyl as a white solid, mp 139-141 ° C

  after recrystallization from ethanol.

EXAMPLE 42

  Compound HH A stirred solution of 10 g of diamino-3,4-benzoric acid in 100 ml of anhydrous dimethylformamide, containing 28 g of potassium carbonate, is treated dropwise over a period of 5 minutes with a solution of 33 μg 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 suspension is filtered

  and the filtrate is poured into 700 ml of water containing 10 ml of chloroacid.

  Hydrogen (36.5 mc / v). The resulting solid is collected and recrystallized from glacial acetic acid; we wash

  the product with water and recrystallized from methyl-

  ethyl ketone to give 12.5 g of bis (n-dodecanamido) -3,4

  benzene under a white solid, mp 195-197 C.

EXAMPLE 43

  Compound E proceeding in a manner similar to that described above in Example 42 but replacing the n-dodecanoyl chloride by n-hexadecanoyl chloride and potassium carbonate

  with sodium carbonate, the bis (n-hexadecah

  mido) -3,4 benzoic acid as a white solid, m.p. 198-202 C after successive recrystallizations from acetic acid

frost and methyl ethyl ketone.

EXAMPLE 44

  Compound II By proceeding in a manner similar to that described above in Example 42 but replacing the n-dodecanoyl chloride

  with n-octanoyl chloride, the bis (n-octanoyl) acid is prepared.

  mido) -3,4 benzoic acid as a white solid, mp 195-197 ° C after successive recrystallizations from acetic acid

frost and methyl ethyl ketone.

EXAMPLE 45

  JJ Compound Proceeding in a manner similar to that described above in Example 42 but replacing the n-dodecanoyl chloride

  by n-tetradecanoyl chloride, the bis (n-tetradecyl) acid is prepared.

  decanamido) -3,4 benzoic acid as a white solid, mp 201-

  2060C after successive recrystallizations from acid

  glacial acetic acid and methyl ethyl ketone.

EXAMPLE 46

  Compound KK 21 g of 4-n-dodecanamido-3-nitro-3-methyl benzoate dissolved in 500 ml of ethyl acetate at 50-55 ° C. are shaken in the presence of 2.0 g of 5% palladium on black. by weight, at 600C and at atmospheric pressure for 2 hours. The mixture is filtered while hot and the filtrate is allowed to cool. The solid is collected to obtain 14.1 g of 3-amino-n-dodecanamido-4

  Methyl benzoate as a white solid, m.p.

The methyl n-dodecanamido-3-nitro-3-benzoate used as the starting material is prepared as follows: 9.6-aminomethyl-3-methyl-3-benzoate (9.6 g) is heated.

  and 23 g of n-dodecanoyl chloride in 100 ml of dimethylformate

  mide for 2 1/2 hours at 97 C, shaking occasionally.

  The resulting solution is poured onto 3 g of crushed ice,

  picks the solid and recrystallises it from a mixture

  (5/1) of methanol and chloroform, giving 351 g of n-dodecane

  canamido-3-nitro-3-methyl benzoate in the form of a solid yellow,

P. F. 78-80 C.

  Methyl 4-amino-3-nitro benzoate is prepared as follows: 70 g of 4-amino-3-nitro benzoic acid are added to a solution of anhydrous HCl in methanol (made from 78 g of sodium chloride). acetyl and 300 ml of anhydrous methanol). The resulting mixture is refluxed for 10 hours, cooled in ice and the solid is collected to give 62 g of methyl 4-amino-3-nitro benzoate as a yellow solid.

P.F. 193-195 C.

EXAMPLE 47

  Compound LL Proceeding in a manner similar to that described above in Example 46 for the preparation of methyl 3-amino-n-dodecanamido-4-benzoate but replacing the

  methyl 4-n-dodecanamido-3-nitro benzoate by n-hexahydrate

  4-decanamido-3-nitro-benzoate methyl, is prepared 3-amino-4-nhexadecanamido benzoate methyl in the form of a solid

white, mp 135-157 C.

EXAMPLE 48

  MM Compound Proceeding in a similar manner to that described above in Example 46 for the preparation of methyl 3-amino-n-dodecanamido-benzoate but replacing the n-dodecanamido-4-nitro-3-benzoate of methyl with 4-n-decanamido-3-nitro-3-benzo-benzoate, is prepared ami.no-3 n-decanamido-4 benzoate

  of methyl in the form of a white solid, mp 131-133 ° C.

EXAMPLE 49

  Compound NN A stirred solution of 8.4 g of 3,4-diamino benzoic acid in 100 ml of dimethylformamide is treated dropwise.

  anhydrous, containing 15.27 g of potassium carbonate, with a solution

  15.17 g of n-hexadecanoylchloride in 30 ml of anhydrous dimethylformamide were added in 3D minutes at 0.degree.-5.degree. We have it

  mix for a further 2 hours at 0 -5 C and allow it to

  heat to amb-ante 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 C-acetone and recrystallized from methyl ethyl ketone, which

  gives 9 ,; 4-amino-n-hexadecanamido-3-benzoic acid under

  of a white solid, P. F. 197j-199 C.

EXAMPLE 50 Compound 00 Proceeding in a manner similar to that described above in

  Example 42 but substituting n-decanoylchloride for n-dodecanoyl chloride, bis (n-decanamido) -5,4 benzolqua acid is prepared as a white solid,

  M.p. i94-1 6 C after successive recrystallizations from a-

  glacial acetic acid and methyl ethyl ketone.

EXAMPLE 51

  PP compound Proceeding in a manner similar to that described above in Example 42 but replacing the n-dodecanoyl chloride by n-tridecanoyl chloride, the bis (n-tridecanoyl) acid is prepared.

  canamido) -3,4 benzoic acid as a whitish solid, m.p.

  192-1940C after successive recrystallizations from

  glacial acetic acid and methyl ethyl ketone.

EXAMPLE 52

  QQ compound Proceeding in a manner similar to that described above in Example 42 but replacing the n-dodecanoyl chloride

  by n-octadecanoyl chloride, the bis (n-octahydro)

  decanamido) -3,4 benzoic acid as a white solid, m.p.

  196 C after successive recrystallizations from acid

  glacial acetic acid and methyl ethyl ketone.

EXAMPLE 55

  RR 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 was treated with 44.5 g of n-hexadecanoyl chloride. . The rate of addition is such as to allow the temperature of the reaction mixture to rise from room temperature to 45-50 C. The mixture is then stirred for a further 3 hours and allowed to stand at room temperature a night. This mixture is added to 1200 ml of water containing 50 ml of concentrated (36.5% w / v) hydrochloric acid and the resulting solid is collected and washed with 1200 ml of water. This solid is stirred with 4000 ml of hot water (650 ° C.) for 30 minutes, collected and dried under vacuum at room temperature.

  70 C, which gives bis (n-hexadecanamido) -2,5 benzoic acid.

EXAMPLE 54

  Compound SS Proceeding in a manner similar to that described above in Example 26 but replacing the n-octanoyl chloride by n-heptanoyl chloride, is prepared 4-amino-n-heptanamido-3

  methyl benzoate as a pale brown solid, m.p.

1060C.

  The present invention encompasses in its field the

  pharmaceutical positions which contain at least one of the

  ss of general formula (I) or a pharmaceutically acceptable salt thereof

  acceptable, in combination with a carrier or phar-

  Maceutically acceptable. In clinical practice, the compounds of the present invention can be administered parenterally, but it is preferred to administer them rectally or, better, by

Oral route.

  Solid compositions for oral administration

  tablets, pills, powders and granules

  the. 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 customary, additional substances

  other than inert diluents, for

  lubricants such as magnesium stearate.

  Liquid compositions for oral administration

  include emulsions, solutions, suspensions, syrups and

  pharmaceutically acceptable salts containing 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 agents, flavoring agents, perfumes and preservatives. The compositions according to the invention for oral administration also comprise the capsules of

  ingestible material, such as gelatin, containing one or more

  active substances with or without the addition of diluents or

excipients.

  The preparations according to the invention for parenteral administration comprise aqueous, hydro-organic and organic sterile solutions, suspensions and emulsions. As examples

  solvents or organic suspension media, it is possible to

  propylene glycol, polyethylene glycol, vegetable oils and

  such as olive oil, and organic esters injected

  tables such as ethyl oleate. These compositions may also contain adjuvants such as stabilizers,

  preservatives, wetting agents, emulsifiers and dispersants.

  It is possible to sterilize cos compositions, for example by filtration

  through a filter retaining bacteria, by incorporating

  sterilizing agents, by irradiation or by heating. They can also be manufactured as sterile solid compositions which can be dissolved extemporaneously in sterile water or

other 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 may vary, but it is necessary that it

  proportion such that a suitable

  nable. 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 therapeutic effect de-

  the method of administration and the duration of the treatment,

  as well as the patient's condition. In adults, doses are generally

  usually between 0.1 and 50 mg per kg of body weight per day, in oral administration: for example, as antiatheroma 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 related diseases, between 0.1 and 10 mg per kg of body weight per day, in oral administration.

  The following example illustrates the pharmaceutical compositions

  according to the present invention.

EXAMPLE 55

  N-2 gelatin capsules containing: anino-4-n-octanamido-3-methyl benzoate 20 mg lactose 100 mg starch 60 mg dextrin 40 mg magnesium stearate 1 mg are prepared according to the usual method.

R E V E N DI C AT IO N S

  1. Acylaminobenzoic acid derivatives, having the general formula: -COR 2

R100> _ MI

ROO IR

  wherein R 1 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 selected from hydroxy group, alkenyl groups containing 2 to 5 carbon atoms and alkanoyloxy groups containing from 2 to 7 carbon atoms), R represents a hydrogen atom or a group of formula - COR2, and R2 represents a straight or branched chain alkyl group containing from 2 to 20 carbon atoms, and the pharmaceutically acceptable salts of

these derivatives.

  2. Methyl-4-N-octanamido-3-benzoate, 4-amino-3-nhexadecanamido-3-methyl benzoate, methyl-4-amino-3-n-dodecanamido-3-benzoate, 4-amino-n-tetradecanamido 3-methyl benzoate, 4-amino-3-n-tridecanamido-3-methyl benzoate, bis (n-hexadecanamido) -3,4 benzoic acid, methyl bis (n-hexadecanamido) -3,4 benzoate, bis (nundecanamido) -3,4 methyl benzoate, 4-amino-n-decanamido-3-methyl benzoate, methyl bis (n-octanamido) -3,4 benzoate, 1 bis (npentadecanamido) acid; 3,4 benzoic acid, bis (n-nonanamido) -3,4 benzoate methyl, bis (n-heptadecanamido) -3,4 benzoic acid, bis (nheneicosanamido) -3,4 benzoic acid, bis (n-eicosanamido) -3,4 benzoic acid, 4-amino-n-nonadecanamido-3-benzoic acid, bis (2-methyl-tetradecanamido) -3,4 benzoic acid, 4-amino-hexyl acid -2-octanamido) -3-benzoic acid, 4-amino-3- (2-ethyl-3-dodecanamido) benzoic acid, 4-amino-butyl-2-decanamido-3-benzoic acid, bis (nt) acid; 2,3-benzoic acid, 3-amino-n-hexadecanamido-benzoic acid, 4-amino-3-n-octanamido-benzoic acid, 4-amino-3-n-dodecanamido benzoic acid, amino acid -4-n-octadecanamido-3-benzoic acid, bis (ndodecanamido) -3,4 benzoate methyl, bis (n-tridecanamido) -3,4 benzoate methyl, bis (n-tetradecanamido) -3,4 benzoate methyl, methyl bis (n-octadecanamido) -3,4 benzoate, methyl 3-amino-n-octanamido-4-benzoate, 5-amino-n-octanamido-4-benzoic acid, 3-amino-acid n-dodecanamido-4-benzoic acid, methyl bis (n-decanamido) -3,4 benzoate, bis (n-dodecanamido) -3,4 benzoic acid, bis (noctanamido) -3,4 benzoic acid, bis (n-tetradecanamido) -3,4 benzoic acid, 4-amino-4-n-dodecanamido-4-methyl benzoate, 3-amino-4-nhexadecanamido-4-methyl benzoate, 3-amino-n-decanamido 4 methyl benzoate, 4-amino-n-hexadecanamido-3-benzoic acid, bis (ndecanamido) -3,4 benzoic acid, bis (n-tridecanamido) acid Benzoic acid, bis (n-octadecanamido) -3,4 benzoic acid, bis (n-hexadecanamido) -2,3-benzoic acid, 4-amino-n-heptanamido-3-methyl benzoate,

  and the 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 compound of general formula is reduced:

NH-COR2

R100 (II)

a 'NO2

  (wherein R1 and R2 are as defined in the claim

  1) by known methods for reducing a nitro group to 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 of which R represents a

  group of formula -COR2 (R2 being as defined in claim

  cation 1), or the substituent group -NH-COR2 (R2 being as defined in claim 1) is in the meta position relative to the substituent group -COOR1 (R1 being as defined in claim 1) and R represents a hydrogen atom, characterized in that a compound of the general formula NN2 is reacted

R100 (III)

/ EH2

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

R2COX1 (IV)

  wherein R is as defined in claim 1 and

  X1 represents a halogen atom or a hydroxy group.

  A process for the preparation of an acylaminobenzoic acid derivative according to claim 1 in the formula of which R represents a

  group of formula -COR (R being as defined in claim

  cation 1), characterized in that a compound of general formula is reacted:

NE-COR

R100

  (in which R 1 and R 2 are as defined in the claim

  1) with an acylating agent of the general formula

R2COX1

  wherein R2 is as defined in claim 1 and x1 represents a halogen atom or a hydroxy group. A process for preparing an acylaminobenzoic acid derivative according to claim 1 in which R is a straight or branched chain alkyl group containing from 1 to 6 carbon atoms (which may be substituted by one or more substituents of same type selected from hydroxy group, alkenyl groups containing from 2 to 5 carbon atoms and alkanoyloxy groups containing from 2 to 7 carbon atoms) and R2 is as defined in claim 1, characterized in that

  suitably esterified a carboxylic acid corresponding to

  of the general formula represented in claim 1 and wherein R 1 is hydrogen and R 2 and R 2 are

  as defined in claim 1.

  7. Process for the preparation of an acylaminobenzoic acid derivative according to claim 1 in the formula of which R 1 represents a hydrogen atom in m, characterized in that one hydrolysis / one ester

  corresponding to the general formula represented in the

  cation 1 and wherein R 1 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 selected from the group hydroxy, alkenyl groups containing from 2 to 5 carbon atoms and alkanoyloxy groups containing from 2 to 7 carbon atoms, and R 'and R2 are as defined in

claim 1.

  8. Process according to any one of claims 3 to 7

  followed by the step of transformation, by known methods, of an acylaminobenzoic acid derivative thus obtained, of the general formula represented in claim 1, into one of

  pharmaceutically acceptable salts thereof.

  9. Pharmaceutical compositions containing as ingredients

  at least one acylaminobenzoic acid derivative according to claim 1, or a pharmaceutically acceptable salt thereof,

  in association with a pharmaceutical carrier or packaging.