NL8003628A - ACYLAMINOBENZOEIC ACID DERIVATIVES, PHARMACEUTICAL PREPARATIONS AND METHOD FOR PREPARING THEREOF. - Google Patents

Description

* ·.

Ή.Ο. 29,180

The present invention relates to new therapeutically useful acylaminobenzoic acid derivatives, a method of preparation thereof, and to pharmaceutical preparations containing said derivatives.

3rd acylaminobenzoic acid derivatives of the invention '1 are compounds of the general formula 1, wherein H' is a hydrogen atom or a straight or branched alkyl group having 1 to 6 carbon atoms, which may be optionally substituted by one or more of the same type of substituent. tents belonging to the hydroxyl groups, alkenyl groups of 2 to 5 carbon atoms and alkanoyloxy groups of 2 to 7 carbon atoms, and preferably represents a methyl group, R 0 represents a hydrogen atom or a resr of the formula -CGR 4 and O R a straight or branched alkyl group, preferably a straight chain alkyl group, having 2 to 20, preferably 7 to 15, carbon atoms as well as salts, especially η pharmaceutically acceptable salts thereof. If R represents a substituted alkyl group, it may be, for example, a 2,3-dihydroxyprop-1-yl, allyl or pivaloyloxymethyl-20 group.

It will be apparent to those skilled in the art that the substituents R 'and R in certain cases contribute to optical isomerism. All such forms are within the scope of the invention.

The term "pharmaceutically acceptable salt" is understood to mean a salt which, when R ° in formula 1 represents a hydrogen atom, is formed by reaction with an ή acid or, if R represents a hydrogen atom, by reaction with a base, so that it anion (in the case of an acid addition salt) or the cation (in the case of a salt formed by a compound of the general formula 1, wherein R represents a hydrogen atom) is relatively harmless to the animal organism when used in therapeutic doses, so that the beneficial pharmacological properties of the base compound of general formula 1 are not adversely affected by side effects attributable to the anion or cation.

Suitable acid addition salts of the compounds of the general formula I, in which R ° represents a hydrogen atom, are salts derived from inorganic acids, for example hydrochlorides, hydrobromides, phosphates, sulfates and nitrates, and from organic acids, for example methane- sulfonates, 2-hydroxyethanesulfonates, oxalates, lactates, tartrates, acetates, salyllicates, citrates, propionates, succinates, fumarates, maleates, methylene bis-3-hydroxynaphthoates, gentisates and di-p-toluoyl tartrates.

Suitable salts formed by compounds Ί of the general formula 1, in which R represents a hydrogen atom, are the alkali metal (e.g. sodium and potassium), alkaline earth metal (e.g. calcium and magnesium-O and ammonium salts) salts of amines which are known to be pharmaceutically acceptable, for example ethylenediamine, choline, diethanolamine, triethanolamine, octadecylamine, diethylamine, triethylamine, 2-amino-2- (hydroxymethyl) propane-1,3-diol and 1- ( 3,4-dihydroxyphenyl) -20 2-isopropylaminoethanol.

It should be noted that insofar as the description of the invention mentions compounds of the general formula I, it is intended that this also includes the pharmaceutically acceptable salts, insofar as this is possible within the context.

The compounds of the general formula I have useful pharmacological properties. For example, they reduce the proliferation of arterial smooth muscle cells, which is an important aspect of artheromatous disorders. Furthermore, they inhibit the accumulation of cholesterol esters and the incorporation of cholesteryl oleate into the total of the cholesteryl esters and other complex lipids, which are characteristic of the enzyme fatty acid acyl CoA: cholesterol acyl transferase. The stimulation of this enzyme in the presence of hyperlipemic plasma occurs in the development of artheromatous lesions. The compounds of general formula 1 also suppress lymphocyte transformation, as is the case with anti-rheumatic drugs. For example, they are useful in the 4-0 prevention or treatment of artherosclerosis and related disorders, such as angina, myocardial infarction, vascular occlusion in the cerebrum, arterial aneurysm and peripheral vascular disease as well as arthritis, immunological disease , cancer and implant rejection reactions.

The compounds of general formula 1 of particular interest are the following compounds and, where appropriate, their optically active forms and salts thereof.

methyl ester of 4-amino-3- (n-hexadecanamido) benzoic acid A.

10 methyl ester of 4-amino-3- (n-dodecanamido) benzoic acid B.

methyl ester of 4-amino-3- (n-tetradecanamido) benzoic acid C.

methyl ester of 4.amino-3- (n-triacanamido) benzoic acid D

3.4- bis (n-hexadecanamido) benzoic acid E

methyl ester of 3,4-bis (n-hexadecanamido) benzoic acid S

15 methyl ester of 3,4-bis (n-unaecanamido) benzoic acid G

methyl ester of 4-amino-3 * - (n-decanamido) benzoic acid H

methyl ester of 3,4-bis (n-octanamido) benzoic acid I.

3.4- bis (n-pentadecanamido) benzoic acid J

methyl ester of 3,4-bis (n-nonanamido) benzoic acid E

3,4-bis (n-heptadecanamido) henzoic acid 3

3.4- bis (n-heneicosanamido) benzoic acid M

3.4- bis (n-eicosanamido) benzoic acid II

4-amino-3- (n-nonadecanamido) benzoic acid 0

(ES) (ES) -3,4-bis (2-methyltetradecanamido) benzoic acid P

4-aminO 3- (2-hexyloctanamido) benzoic acid Q

(SS) -4-amino ~ 3 "(2-ethyldodecanamido) benzoic acid P

(BS) -4-amino-3- (2-butyldecanamido) benzoic acid S

2,3-bis (n-tetradecanamido) benzoic acid T.

3-amino-4- (n-hexadecanamido) benzoic acid U

4-amino- * 3- (α-octanamido) benzoic acid V

4-amino-3 ~ (n-dodecanamido) benzoic acid W.

4-amino-3- (n-octadecanamido) benzoic acid X

methyl ester of 4-amino-3- (n-octanamido) benzoic acid ï methyl ester of 3j4 - bis (n-dodecanamido) benzoic acid 2

Methyl ester of 3i4-bis (n-tridecanamido) benzoic acid AA

methyl ester of 3 »4-bis (n-tetradecanamido) benzoic acid 33

methyl ester of 3,4-bis (n-octadecanamido) benzoic acid CC

methyl ester of 3-SLmino-4- (n-octanamido) benzoic acid DD

3-amino-4- (n-octanamido) benzoic acid SE

40 3-amino ”4- (n-dodecanamido) benzoic acid SS

0 η n 7 r 9 a 4

methyl ester of 3,4-bis (n-decanamido) benzoic acid GG

3.4- bis (n-dodecanamido) benzoic acid HH

3.4- bis (n-octanamido) benzoic acid II

3.4- bis (n-tetradecanamido) benzoic acid <JJ

5 methyl ester of 3-3mno-4- (n-dodecanamiao) benzoic acid KK

methyl ester of 3 "Siniino-4- (n-hexadecanamido) benzoic acid LL methyl ester of 3-amino-4- (n-decanamido) benzoic acid MM

4-amino-3- (n-hexadec anamido) b and z o z n NN

3.4- bis (n-decanamido) benzoic acid 00

3-3-bis (n-tridecanamido) benzoic acid PP

3.4- bis (n-octadecanamido) benzoic acid QQ

2,3-bis (n-hexadecanamido) benzoic acid and SR

methyl ester of 4-amino-3- (n-heptanamido) benzoic acid SS

The letters A to SS have been assigned to the compounds for easy reference in the further description, for example in the tables.

The properties of the compounds of general formula 1 were demonstrated in the following tests:

Inhibitory activity on the proliferation of aortic smooth muscle cells

Smooth muscle cells were cultured in a pig aortic thoracal explant culture using Dulbecco's Modified Eagles (DME) medium containing 20 ° / o fetal calf serum (POS) and antibiotics.

The cells were incubated at a temperature of 37 ° C in an atmosphere of 95% air and 5% carbon dioxide. At the time of confluence, the cells were subcultured conventionally by trypsinization and streak again on plates at about one third of the density at confluence thereof in DME medium containing 10% FGS and antibiotics.

The smooth muscle cells were streaked at densities of approximately 100,000-200,000 cells per Falcon dish of 35 x 10 mm in 2 ml DME medium containing 10% FCS and antibiotics. After 24 hours, when the cells had adhered to the dishes, the medium was replaced with 2 ml DME medium containing 1% FCS and antibiotics. The cultures were incubated for an additional three days to allow the cells to enter a quiescent state (i.e., no more cell division occurred). The medium was then replaced with 800 3 6 28 5 2 ml control or test medium. The test medium consisted of DME medium (containing 10% FCS and antibiotics) as well as the test compound in a concentration of 5 µg / ml medium. The compounds were previously dissolved in acetone in such a way that the final concentration of the acetone in the medium was 0.2% (v / v). The control medium consisted of DME medium (containing 10% FCS and antibiotics) and acetone at a concentration of 0.2% (v / v). After incubation for three days in the test or control medium, the medium was replaced with fresh test or control medium and the cells were incubated for an additional three or four days. At the end of the incubation period of six or seven days, the cell count was determined by trypsinizing the cells and counting the cell equilibrium in a Coulter counter.

All results listed in Table A below indicate the mean value for four dishes with cells. The percentage of proliferation inhibition was calculated using the following formula: 20 Percentage of proliferation inhibition = 100 - (-..... x 10 x ") V c - sy where S = mean cell count per dish at bet start of the test (at the time of adding the control or test medium).

25 T = Average cell count per dish in test cultures after the end of the test.

C = Average cell count per dish in control cultures at the end of the experiment Table A

50 Compound _% inhibition_ Y 59, 76, 8a, 56, 32, AO, A1, 55 B 51, 52 D 61, 61 C 5A, A8

35 A 71, 76, A7, AO

ZE 2A, A7

Inhibitory activity on the nonsoning of cholesterryl esters in the smooth muscle cell of the aorta

Aortic smooth muscles, as described above, were co-cultured in subculture No. 8 in Dulbecco's modified Eagle's (DME) medium containing 10% fetal calf serum (FCS) and antibiotics. Smooth muscle cell dishes were incubated in quadruplicate for 24 hours in DME medium containing 10% (v / v) rabbit hyperlipemic serum Ή-oleate as a complex with defatted bovine serum albumin (molar ratio of free fatty acid ( FFA): albumin = 0.862; concentration of the oleate in the medium 0.155 mmol), antibiotics (penicil-10 line G 100 IU / ml, streptomycin 100 µg / ml and kanamycin 100 µg / ml) as well as the test compound in a concentration of 100 µg / ml medium. The control dishes without the test compound and control dishes with 10% (v / v) FCS instead of rabbit hyperlipemic serum were also incubated.

The sera were thermally deactivated before use and contained cholesterol to a total of 953 mg / dl and 26 mg / dl, respectively.

After incubation, the cells were washed with Hanks solution 20, tryptinized and centrifuged and the grain obtained in centrifugation in 0.27 mmol EDTA was subjected to sonication.

The cellular concentrations of free and esterified cholesterol and uptake of Ή-labeled cholesteryl oleate in the total of the cholesteryl esters and other complex lipids were determined and compared to the controls.

All results listed in Tables B and C below indicate the mean value for four dishes with cells.

30 Table B

Compound Solvent% Concentration Reduction Compared to Control With Hyperlpemic Serum-Free Cholesteryl-Cholesterol-Esters-Y Ethanol 16.2 31 A Ethanol 32 27 800 3 6 28 7 "

Table C

% reduction in FFA uptake compared to control with the same solution and serum_

Compound Phospholipid Triglycerides Gholesteryl Lipids 5 thing_ester_total T 13.1 77.3 55.7 45.2 A 11.5 73.9 52.5 53.9

Inhibitory activity on lymphocyte transformation in mitogen-stimulated lymph node cells in guinea pigs. 10 Guinea pigs were sensitized to Mycobacterium tuberculosum by injections in the footpad of Freund complete adjuvant (FCA) (0.05 ml; 0.5 mg / ml of 50% (vol , / vol.) FCA solution in sterile physiological saline).

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

After 24 hours, 0.1 ml of cell suspension was incubated at a temperature of 37 ° C in a 95% atmosphere and 5% carbon dioxide in the presence of 0.15 ml of mitogen or mitogen and the test compound in EME medium (which 10% FGS and buffered with Earle's salts). Eighteen hours before collecting the material, 25% thymidine (1 µl of 100 µCi / ml solution in 0.9% sterile saline) was added.

As an index of DNA synthesis, the degree of uptake by the HH-thymidine cells was measured compared to the mitogen control.

30 The results achieved are shown in Table D below. 1 800 3 6 28

Table D

Compound Dose in% inhibition of ^ H-thymidine uptake incubation in cells DNA in comparison, µg / ml king with mitogen control_ 5 (i) (ii) (iii) • I 3 5 17 14 10 60 59 61 30 94 97 96 H 3 21 10 10 78 30 90 B 3 27 10 46 30 71 15 D 3 35 10 51 30 76 C 3 12 10 37 20 30 62 A 3 4 10 10 30 15

The utility of the compounds is favored by the fact that they have only a very low toxicity, as shown by the following test:

Oral toxicity in mice

Groups of mice were administered orally 1 dose of the test compound (in 0.5 percent (w / v) aqueous suspension of tragacanth mucus) and the mice were observed 3 days later. The percentages of the animals that died at each dose during this period were used to draw up a graph showing the LD ^ 0, 6 and the dose in mg / kg body weight of the animal, which was necessary to obtain 50% of to succumb the mice was calculated.

Compounds of the general formula I, mentioned in the above list, were tested, and it was found that LD 1 of each of these compounds was above 800 36 28 9 1000 mg / kg body weight. the animal was.

Preferred compounds according to the invention are the compounds mentioned above, which are indicated by the letters Y, A, B, D and C.

The compounds of the general formula 1 can be prepared in a manner known per se, ie using or adapting known methods (methods hitherto used or methods described in the chemical literature), such as, for example, below. further explained: (A) According to an embodiment of the invention, the compounds of the general formula 1, wherein R ° represents a hydrogen atom, are prepared by reduction of a compound of the general formula 2, wherein R and R are the have the above meanings, according to known methods for the reduction of a nitro group to a primary amino group, for example by catalytic hydrogenation, preferably using palladium on charcoal as a catalyst, (B) According to another embodiment of the invention, the compounds of the general formula 1, wherein o 2 2 R represents a radical of the formula -COR 4, wherein R is the 2 meaning above or the substituent -RH-COR, p where R has the above meaning is in the Ί m position relative to the substituent -C00R, where R has the above meaning, and R represents a hydrogen atom prepared by reacting a compound of the general formula 3 wherein R has the above meaning with an acylating agent of the general formula 4 wherein R has the above meaning

S

30 and X represents a halogen atom, preferably a chlorine atom, or a hydroxyl group.

Particularly suitable conditions are the following: (i) Compounds of the general formula 1, wherein R ° represents a 2 2 35 radical of the formula -COR, wherein R has the above meaning, are prepared by reacting a compound of the general formula 3 »wherein R has the above meaning, with an acyl halide having the formaldehyde

2 1 mule 4, wherein R has the above meaning and X

40 represents a halogen atom, preferably a chlorine atom, 800 3 6 28 ΊΟ in an inert organic solvent, for example dichloromethane or dimethylformamide, preferably under anhydrous conditions and preferably in the presence of an acid binding agent, for example a trialkylamine, at For example triethylamine, or an alkali metal carbonate or bicarbonate, for example anhydrous sodium or potassium carbonate, at a temperature which may be higher than the ambient temperature, for example at a temperature between 10 and 50 ° C.

(Ii) Compounds of the general formula 1, wherein the 2 2 substituent -NH-COR, where R has the above meaning, is in the m position relative to the substituent 1 1 -COCR, where R has the above meaning and R 0 represents a hydrogen atom, are prepared by converting a compound of the general formula 3, especially compounds of the formula 3, wherein R represents a straight or branched alkyl group having 1 to 6 carbon atoms, with an acyl halide of the general formula 4, wherein R has the above meaning and X represents a halo atom, preferably a chlorine atom, under similar conditions as described above under (i), but using a smaller amount of the acyl halide and the temperature is controlled, and preferably a temperature between 0 ° C and room temperature is set.

(C) According to a further embodiment of the invention, the compounds of the general formula 1, wherein R 0 represents a radical of the formula -COR 2, wherein R 2 has the above meaning, are prepared from a corresponding compound having the general formula 1, wherein R 0 represents a hydrogen atom, i.e. a compound of the formula 8, by reaction with a compound of the general formula 4 according to generally known methods.

Compounds of general formula 2 can be prepared by reacting a compound of general formula 5 wherein R has the above meaning with a compound of general formula 4 in the same manner as described above for Embodiment B (i) The compounds of the general formula V can be prepared by well known methods.

800 3 6 28 11 (D) According to a further embodiment of the invention, the compounds of general formula 1, wherein η R represents a straight or branched alkyl group having 1 to 6 carbon atoms, which may be optionally substituted by one or more than one of the same type of substituentan belonging to the hydroxyl groups, alkenyl groups of 2 to 5 carbon atoms and alkanoyloxy groups of 2 to 7 carbon atoms, prepared by esterification of a corresponding η compound of the general formula 1, wherein R represents a hydrogen atom, using or adapting known methods, for example by reaction with the respective diazoalkane in the presence of an inert organic solvent.

(E) According to yet another embodiment of the invention, the compounds of general formula 1, wherein R represents a hydrogen atom, are prepared by alkaline hydrolysis of a corresponding ester of the general formula 1, wherein R represents a straight or branched alkyl group of 1 to 6 carbon atoms, which may be optionally substituted by one or more of the same type of substituents belonging to the hydroxyl groups, alkenyl groups of 2 to 5 carbon atoms and alkanoyloxy groups of 2 to 7 carbon atoms, for example by treatment with an alkali metal hydroxide in an aqueous organic solvent-25 system at an elevated temperature.

(E) According to a further embodiment of the invention, compounds of the general formula 1, in which R represents a hydrogen atom and / or R ° represents a hydrogen atom, are converted into salts, in particular pharmaceutically permissible salts thereof and vice versa. application or adaptation of known methods.

Although useful as such, this method is also useful for the purification of compounds of the general formula 1 and salts thereof, taking advantage of the differences in water solubility and various organic solvents of the compounds and their salts as well as of impurities possibly present according to known methods, such as crystallization.

<Ί (i) Compounds of the general formula 1, in which R represents an o 2 4-0 hydrogen atom and R and R have the above-mentioned meaning τfi 12, can be converted into salts thereof with bases, in particular pharmaceutically admissible bases, for example by reaction with the desired base, for example the desired amine or a compound of the general formula 6, in which M is an alkali metal, for example sodium or potassium, atom and R1 an alkyl group with at most 4 carbon atoms , for example a methyl or ethyl group, or a hydrogen atom, in a suitable solvent, for example methanol or ethanol, or a mixture of water and acetone, if necessary followed by evaporation of the solvent or a part thereof, and collecting the solid salt.

These salts can be converted back into the basic compounds of the general formula 1, for example by reaction with a suitable acid, for example glacial acetic acid, in solution in a suitable solvent, for example water or ethanol, if necessary followed by evaporation of the solvent or part thereof, and collecting the solid compound of the general formula 1.

20. (ii) Compounds of the general formula 1, in which R 0 represents a hydrogen atom, can be converted into acid addition salts thereof, in particular pharmaceutically acceptable acid addition salts, for example, by reaction with the desired acid in solution or suspension in a suitable solution. Release agent, for example acetone, methanol or ethanol, if necessary followed by evaporation of the solvent or part thereof and collection of the solid salt.

The acid addition salts can be converted back into the basic compounds of the general formula 1, for example, by treatment with aqueous ammonia in the presence of a suitable solvent, for example ethanol, followed by treatment with a weak acid, for example glacial acetic acid.

The compounds of the general formula I are also used as starting materials for the preparation of therapeutically useful benzimidazole derivatives of the general formula 7 wherein R has the above meaning 2 'and R a straight or branched alkyl group with 7 to 20 carbon- η represents substance atoms, the radical R 00C- being bonded at position 4 or 5 of the benzimidazole ring system, into which they can be converted using known methods of cyclization.

For example, (i) R ° in the general formula 1 represents a radical of the formula 2 -COR, wherein R has the above meaning, the cyclization to form a benzimidazole derivative of the general formula 7 can be carried out at an increased temperature, for example a temperature between 60 and 100 ° C, by treatment with an inorganic acid, for example hydrochloric acid, in the presence of water and in an organic solvent, for example an alcohol, such as methanol, or ethanol, or a ketone, such as acetone, or methyl ethyl ketone; or (ii) R 0 in the general formula 1 represents a hydrogen atom, the cyclization is carried out either under similar conditions as described above under i) or by treatment with an organic acid (eg p-toluenesulfonic acid) in water or an organic solvent (e.g. toluene) preferably at an elevated temperature, e.g. a temperature between 60 and 100 ° C, or (iii) the cyclization is carried out in the absence of a solvent and at elevated temperatures, e.g. between 150 and 250 ° C, or in the presence of water and an inorganic acid, eg hydrochloric acid, and in a suitable solvent, eg diglyme.

Those skilled in the art will appreciate that in the practice of the above-described embodiments and of the invention, it may be desirable to introduce chemical masking groups into the reactants to prevent the occurrence of secondary reactions, such as, for example, the above-described method for preparing benzimidazoles hydroxyl groups in the η substituent R in the general formula 1 are converted into benzyloxy groups before the described conversion is carried out, while the benzyl group is removed after the conversion.

The aforementioned benzimidazole derivatives of general formula 7 are useful in the prevention or treatment of diabetes mellitus, hyperlipoproteinemic conditions, 4.0 of atherosclerosis and related ailments, such as angina, 800 3 6 28 myocardial infarction, vascular occlusion in the cerebrum, arterial aneurysm and peripheral vascular disease, peripheral vascular disease, chronic pancreatitis and Xanthomonas, as well as arthritis, immunological disease, cancer and implant rejection.

The preparation of the compounds of the invention is further illustrated by the following examples.

Example I 10 Compound A

The methyl ester of 3- (n, hexadecanamido) -4- * aminobenzoic acid was prepared by one of the following methods: (i) In a solution of 35 S methyl ester of 3,4-diamino-benzoic acid in 1200 ml of dry dimethylformamide containing 11.8 g of anhydrous sodium carbonate, 58 g of n-hexadecanoyl chloride were added dropwise with stirring over one hour. The n-hexadecanoyl chloride was added at such a rate that the temperature of the reaction mixture rose from initial 10 ° C to room temperature. The mixture was stirred at room temperature for an additional 5 hours and then poured into 5 liters of water. The solid material obtained was collected and boiled in 1000 ml of acetone, after which the boiling mixture was filtered off. The filtrate was cooled to a temperature of 0 ° C, then the resulting yellow-brown solid was filtered off, yielding 48.2 g of methyl ester of 3- (n-hexadecanamido) -4-amino-benzoic acid, mp 112 to 114 ° C was obtained, ii) In a solution of 16.6 g of methyl ester of 3-4-di-aminobenzoic acid in 270 ml of dry dichloromethane containing 10.3 g of triethylamine, a solution was added dropwise over 45 minutes with stirring. of 27.5 n-hexadecanoyl chloride in 30 ml of dry dichloromethane. The temperature during the addition was kept between 16 and 20 ° C. The mixture was stirred for an additional 2 hours. The resulting solid material was then collected and boiled in a mixture of 1000 ml of acetone and 150 ml of methanol, after which the insoluble material was removed by filtration. The filtrate was cooled to a temperature of 25 ° C and treated with 800 ml of water, the methyl ester of 3- (n.he-40 xadecanamido) -4-aminobenzoic acid in the form of a yellow-800 3 6 28/15 brown solid with a melting point of 112 to 114 ° 0 was obtained *

Example II Compound B

A solution of 25.0 g of methyl ester of 3,4-diaminobenzoic acid in 1120 ml of dry dimethylformamide, containing 7.7 S anhydrous sodium carbonate, was treated with 30.5 S in the same manner as described in Example I (i). n.dodecanoyl chloride, yielding 41 g of crude methyl ester of 10 3- (n.'dodecanamido) -4-aminobenzoic acid in the form of a yellow-brown solid.

Example III Compound 0

To a solution of 25.0 g of methyl ester of 3 »4-di-15-aminobenzoic acid in $ 00 ml of dry dichloromethane containing 15.5 g of triethylamine, a solution of 37 was added dropwise in the same manner as described in Example I (ii). 12 g of n-tetradecanoyl chloride in 50 ml of dry dichloromethane were added to give 40 g of the crude methyl ester of 3- (a-tetradecanamido) -4-aminobenzoic acid as a yellow-brown solid.

Example IV Connection Ί)

A solution of 17.8 g of methyl ester of 3,4-diamino-25 benzoic acid in 350 ml of dichloromethane containing 10.8 g of triethylamine was treated with 25 g of n-tridecanoyl chloride in the same manner as described in Example I (ii), to yield 40 g of the crude methyl ester of 3- (n-tridecanamid-do) -4-aminobenzoic acid.

30 Example V Connection E

A solution of 7.5 g of 3,4-diaminobenzoic acid in 100 ml of dichloromethane containing 15 g of triethylamine was treated in the same manner as described in Example I (ii) with 27.5 g of n-hexadecanoyl chloride. A solid was obtained, which was recrystallized from glacial acetic acid and then recrystallized from methyl ethyl ketone, the hot solution being filtered off, giving 20 g of 3,4-bis (n-hexadecanamido) benzoic acid as a 40-brown solid. was obtained, which melted at a temperature of from 198 to 202 ° C.

Example VI Connection Έ

A solution of 5.0 g of methyl ester of 3 * 4-diamino-5 benzoic acid in 50 ml of dichloromethane containing 6.2 g of triethylamine was described in the same manner as above in Example I (ii) with 16.5 g of n. hexadecanoyl chloride, allowing the temperature of the reaction mixture to rise from 20 ° C to 30 ° C. A solid was obtained, which was recrystallized from chloroform, yielding 14.9 g of methyl ester of 3 * 4-bis (n-hexadecanamido) benzoic acid as a white solid, which was obtained at a temperature from 129 to 132 ° C melted.

Example VII 15 Compound G

A solution of 17.9 g of methyl ester of 3,4-diamino-benzoic acid in 300 ml of dichloromethane containing 21.8 g of triethylamine was treated with 44.3 g of n.undeoanoyl-20 in the same manner as described above in Example VI. chloride. A solid was obtained, which was recrystallized twice from ethanol under filtration of the hot solution, yielding 40.2 g of methyl ester of 3,4-bis (n.un-decanamido) benzoic acid as a white solid with a melting point of 139 to 141 ° C was obtained.

Example VIII Compound H

To a solution of 16.6 g of methyl ester of 3,4-diaminobenzoic acid in 600 ml of dry dimethylformamide containing 5 * 5 g of anhydrous sodium carbonate was added dropwise 19.1 g of n.decanoyl chloride in the same manner as described above in Example I (i), whereby 18.8 g of methyl ester of 3- (n.decanamido) -4-aminobenzoic acid in the form of a yellow-brown solid with a melting point of 96 to 98 ° C were obtained.

Example IX Compound I

A solution of 41.2 g of methyl ester of 3,4-diamino-benzoic acid in 412 ml of dichloromethane containing 51 * 0 g of triethylamine was treated with a solution of 800 3 6 28 in the same manner as described above in Example 6. 17 80.6 g of n-octanoyl chloride in 330 ml of dichloomethane, followed by recrystallization from methanol with charcoal treatment 81.8 g of methyl ester of 3,4-bis (n.octanamido) benzoic acid in the form of a white solid with a melting point 5 from 138 to 140 ° C was obtained.

Example X Connection J

A solution of 13.85 g of 3,4-diaminobenzoic acid in 180 ml of dimethylformamide containing 27.6 g of triethylamine was treated with 47.4 g of pentadecanoyl chloride in the same manner as described in Example I (i). The solid obtained was collected and recrystallized from methyl ethyl ketone under charcoal treatment and hot solution filtration to obtain 49.3 g of 3,4-bis (n.pentadanamido) -15 benzoic acid, m.p. 178 to 180 ° C .

Example ΣΙ Connection E

To a solution of 152 g of 3,4-diaminobenzoic acid in 1500 ml of dimethylformamide containing 303 g of triethylamine, 349.0 g of n-hexadecanoyl chloride was added dropwise with stirring over 1.5 hours. The hexadecanoyl chloride was added at such a rate that the temperature of the reaction mixture rose from room temperature to 35-40 ° C. The mixture was stirred for an additional 2 hours at room temperature and then poured into 10 liters of hot water at a temperature of 70 ° C containing 150 ml of concentrated hydrochloric acid at a concentration of 36.5% (w / v). The resulting solid material was collected to yield 600 g of crude 3,4-bis (n-hexadecanamido) benzoic acid in the form of a yellow-brown solid, which melted at a temperature of 180 to 190 ° C.

Example XII Compound K

To a solution of 20 g of methyl ester of 3,4-diamino benzoic acid in 250 ml of dry dichloromethane containing 24.2 g of triethylamine, a solution of 44.12 g of nonanoyl chloride in 50 ml of dry dichloromethane was added dropwise in the same manner, with stirring. as described in Example 1 (ii), yielding a pink solid 7 98 gene, which was recrystallized from methanol under charcoal treatment, yielding 30.3 g of methyl »3-4-bis (n.honanamido) methyl ester benzoic acid was obtained in the form of a white solid, which melted at a temperature of 14-2 to 14-550.

Example XIII Compound L

To a solution of 4-3.0 g of 3,4-diaminobenzoic acid in 4-00 ml of dimethylformamide containing 75-8 g of triethylamine, 130 g of n-heptadecanoyl chloride were added dropwise with stirring in the same manner as. Described above in Example XI, yielding 14-0 g of crude 3,4-bis (n.heptadecanami-do) benzoic acid in the form of a pink solid.

Example XIV Compound M

A solution of 21.9 g of 3 »4-diaminobenzoic acid in 175 ml of dimethylformamide containing 4-3 * 6 g of triethylamine was treated by stirring and dropwise addition of 99 * 2 g of 20 n-heneicosanoyl chloride in the same manner as described in Example XI. to yield 126.5 g of crude 3 * 4-bis (n-heneicosanamido) benzoic acid in the form of a light brown solid.

Example XV 25 Compound N

A solution of 18.3 g of 3 * 4-diaminobenzoic acid in 200 ml of dimethylformamide containing 36.5 g of triethylamine was treated in the same manner as described in the example by stirring and adding dropwise 79 * 4-g of nicosanoyl chloride. XI, yielding 93 g of crude 3,4-bis (n-eico-sanamido) benzoic acid as a light brown solid, melting at a temperature of 160 to 170 ° C.

Example XVI 35 Compound 0

A solution of 38 g of 3,4-diaminobenzoic acid in 500 ml of dimethylformamide containing 50.5 g of triethylamine was treated with stirring and dropwise addition of 79 µg of nona decanoyl chloride in the same manner as described 4-0 in Example XI, yielding an orange solution, 800 3 6 28 19 which was poured into 3000 ml of water containing 100 ml of concentrated hydrochloric acid at a concentration of 36.5% (w / v). The solid material was collected, washed twice with 100 ml of water each, and then dried, yielding 5 107 S of crude 3- (n.nadeadeamamido) -4-aminobenzoic acid.

that melted at a temperature of from 103 to 113 ° C. Example XVII Compound P

A solution of 17.5 S 3,4-diaminobenzoic acid in 140 ml of dimethylformamide containing 34.8 g of triethylamine was treated in the same manner as described in Example XI by stirring and adding dropwise 59.7 g of pentadecan-2-oyl chloride. yielding 68 g of crude (RS) (HS) -3,4-bis (2-methyltetradecanamido) benzoic acid.

Example XVIII Compound 0.

A solution of 20.7 g of 3,4-diaminobenzoic acid in 165 ml of dimethylformamide containing 56.5 g of triethylamine was treated by stirring and dropwise addition of 67 g of 2-hexyloctanoyl chloride as described in Example XI. A waxy solid was collected, which was dissolved in 500 ml of diethyl ether, the ether solution was dried and evaporated to give a reddish brown oil. This oil was extracted with hot ethanol for 5 hours using a continuously operating extractor. The methanol solution was evaporated on a rotary evaporator to give a brown solid, which was recrystallized from acetone, yielding 15.2 g of 3- (2-hexyl-30 octanamido) -4-aminobenzoic acid in the form of a white solid with a melting point of 219 to 221 ° C was obtained.

Example XIX Connection B

A solution of 22.8 g of 3,4-diaminobenzoic acid in 200 ml of dimethylformamide containing 22.7 g of triethylamine was added by stirring and dropwise adding 37 g of 2-ethyl-dodecanoyl chloride in the same manner as described in Example XI. After working up the conversion product, as described in Example XVIII, a ftO3 3 6 28 solid was obtained, which was recrystallized from ethyl acetate with charcoal treatment to yield 22.2 g of (ES) -3- (2-ethyl dodecanamido). -4-aminobenzoic acid in the form of a white solid was obtained, which melted at a temperature of 188 to 191 ° C.

Example XX Connection S

A solution of 15> 8 g of 3,4-diaminobenzoic acid in 130 ml of dimethylformamide containing 43 µg of triethylamine was treated in the same manner as described in Example XI by stirring and adding 51 µg of 2-butyldecanoyl chloride dropwise. After working up the reaction product, as described in Example XVIII, 9 * 8 g of (RS) -3- (2-butyldecanamido) -4-aminobenzoic acid was obtained in the form of a white solid, which was melted from 178 to 182 ° C.

Example XXI Compound I

To a solution of 20 g of 2,3-diaminobenzoic acid in 200 ml of dimethylformamide containing 39 g of triethylamine, 65 g of n-tetradecanoyl chloride was added. The n-tetra-decanoyl chloride was added at such a rate that the temperature of the reaction mixture rose from initial room temperature to 45 to 50 ° C. The mixture was stirred for an additional 2 hours, then left to stand at room temperature overnight. Then 20 ml of methanol was added to the mixture, the resulting mixture was stirred for 20 minutes and then treated with concentrated hydrochloric acid at a concentration of 36.5% (w / v) until a pH of 2 was reached . The resulting mixture was poured into 1000 ml of water, the black solid was collected, which was washed twice with 500 ml of water and then with 500 ml of hot petroleum ether (boiling range 60 to 80 ° C) and finally under treatment with charcoal from ethanol was recrystallized to give 7 g of 2,3-bis (n-tetradecanamido) benzoic acid as a yellow-brown solid, which melted at a temperature of 150 to 158 ° C.

40 800 3 6 28 21

Example XXII Connection ü

The compound of this example was prepared by adding 22 g of 3-nitro-4- (n.hexadecanamido) benzoic acid as a solution in 500 ml of n-butanol big presence of 2.5 g of 5% (w / w) palladium to hydrogenate on charcoal over 6 hours with shaking at a temperature of 70 ° C under atmospheric pressure. The mixture was filtered while hot and the filtrate was allowed to cool. The resulting solid material was collected and washed with 100 ml of ethanol to give 11.6 g of 3-amino-4- (n, hexadecanamido) benzoic acid as a cream-colored solid, m.p. 160 to 162 ° C .

The 3-nitro-4- (n-hexa-15 decanamido) benzoic acid used as starting material was prepared in the following manner:

A solution of 18.2 g of 3-nitro-4-aminobenzoic acid and 33.0 g of n-hexadecanoyl chloride in 100 ml of dry dimethylformamide was heated to a temperature of 97 ° C for 90 minutes. The solution was cooled and then poured onto 300 g of crushed ice. The resulting solid material was collected, washed three times with 100 ml of water each time, dried and recrystallized from a mixture of acetone and water in a mixing ratio of 5: 1 with charcoal treatment, whereby 31 7 g of 3-aitro- 4- (n.hexadecanamido) -25 benzoic acid in the form of a light yellow solid, mp 153-154 ° C.

Example XXIII Compound V

By following essentially the same procedure as described in Example XVI for the preparation of 3- (n..nonadecanamido) -4-aminobenzoic acid but thereby replacing the n.nonadecanoyl chloride with n.octanoyl chloride, the 3- (n octanamido) -4-aminobenzoic acid in the form of an off-white solid, which, after recrystallization from methanol, had a melting point of 202 to 203 ° C.

Example XXIV Connection W

By following essentially the same procedure as described in Example XVI for the preparation of 3- (n.nonadecanamido) -40 4-aminobenzoic acid, but thereby the n.nonadecanoyl- 800 3 6 28

CLLC

to replace chloride with n.decanoyl chloride

3- (n.dodecanamido) -4-aminobenzoic acid in the form of a white solid, m.p. 183 DEG-185 DEG. Example XXV

5 Connection X

By following essentially the same procedure as described in Example XVI for the preparation of 3- (n.nonadecanamido) -4-aminobenzoic acid, but thereby replacing the n.nonadecanoyl chloride with n.octadecanoyl chloride, the

3- (n-octadecanamido) -4-aminobenzoic acid in the form of a light brown solid, which, after recrystallization from methyl ethyl ketone, had a melting point of 185 to 187 ° C. Example XXVI Connection Y

To a solution of 83.1 g of methyl ester of 3 »4-diminobenzoic acid in 900 ml of dry dimethylformamide, containing 50.8 g of triethylamine, 81.3 g of n-octanoyl chloride were added dropwise over 30 minutes, while the temperature was kept between 5 and 8 ° C. The mixture was stirred for a further 2 hours. The solid material was removed by filtration and the filtrate was poured into 8000 ml of water. The resulting solid material was collected and recrystallized twice from methanol to obtain 65.5 g of methyl ester of 3- (n.octanamido) -4-25 aminobenzoic acid as a white solid, m.p. 120 ° C. .

Example XXVII Compound B

By following essentially the same procedure as described in Example XXVI for the preparation of the methyl ester of 3- (n.octanamido) -4-aminobenzoic acid but replacing the n-octanoyl chloride with n.dodecanoyl chloride, the methyl ester of 3- (n.dodecanamido) -4-amino-benzoic acid in the form of an off-white solid, which melted at a temperature of 102 to 105 ° C after recrystallization from methanol.

Example XXVIII Compound D

By following essentially the same procedure as described in Example XXVI for the preparation of the methyl ester of 800 3 6 28 23 the methyl ester of 3- (E-octanamido) -4-aminobenzoic acid, but replacing n.octanoyl chloride with n.tridecanoyl chloride, the methyl ester of

3- (n.tridecanamido) -4-aminobenzoic acid in the form of a light brown solid, which melted at 101 to 104 ° C after recrystallization from methanol. Example XXIX Compound C

By following essentially the same procedure as described in Example XXVI for the preparation of the methyl ester of 3- (n.octanamido) -4-aminobenzoic acid, but thereby replacing the n.octanoyl chloride with n.tetradecanoyl chloride, the methyl ester of 3- (n-tetradecanamido) -4-aminobenzoic acid in the form of a light brown solid 15 which, after recrystallization from methanol, had a melting point of 108 to 109 ° C.

Example XXX Compound A

By following essentially the same procedure as described in Example XXVI for the preparation of the methyl ester of 3- (n.octanamido) -4-aminobenzoic acid, but thereby replacing the n.octanoyl chloride with n.hexadecanoyl chloride, the methyl ester of 3- (n.hexadecanamido) -4-aminobenzoic acid in the form of a white solid, which, after recrystallization from methanol, had a melting point of 109 bone 110 ° C.

Example XXXI Compound F

To a solution of 5 g of methyl ester of 3> 4-diamino-30 benzoic acid in 50 ml of dry dimethylformamide containing 6.1 g of triethylamine, a solution of 16.54 g of n was added dropwise with stirring over a period of 5 minutes. Hexadecanoyl chloride in 40 ml of dry dimethylformamide.

The temperature of the mixture was allowed to rise from 20 ° C to 35 ° C to 50 ° C. The mixture was stirred for an additional 3 hours. The resulting suspension was poured into 800 ml of water containing 10 ml of hydrochloric acid at a concentration of 36.5% (w / v). The resulting solid material was collected and recrystallized from a 40: 1: 1 mixture of chloroform and acetone to give 12.1 g of methyl ester of 800 3 6 28 3.4-Ms (n-hexadecanamido) benzoic acid in the form of a white solid with a melting range of 129 to 132 ° C was obtained, which was identical to the product of Example VI.

Example XXXII Compound I

By following essentially the same procedure as described in Example XXXI for the preparation of the methyl ester of 3,4-bis (n-hexadecanamido) -benzoic acid, but replacing it with n-hexadecanoyl chloride with n-octanoyl chloride, the methyl ester of 3,4-bis (n.octanamido) -benzoic acid in the form of a white solid, which, after recrystallization from acetone, had a melting point of 145 to 147 ° C.

Example XXXIII Compound Z

By following essentially the same procedure as described in Example XXXI for the preparation of the methyl ester of 3,4-bis (n-hexadecanamido) -benzoic acid, but replacing it with n-hexadecanoyl chloride with n-dodecahoyl chloride, the methyl ester of 3,4-bis (n.dode-canamido) benzoic acid in the form of an off-white solid, which melted at a temperature of 129 to 131 ° C after recrystallization from acetone.

Example XXXIV Compound AA

Following essentially the same procedure as described in Example XXXI for the preparation of the methyl ester of 3,4-bis (n-hexadecanamido) -benzoic acid, but replacing it with n-hexadecanoyl chloride with n-tridecanoyl chloride, the methyl ester was of 3,4-bis (n.tridecanami-do) benzoic acid in the form of a white solid, which, after recrystallization from acetone, had a melting point of 132 to 134 ° C.

35 Example XXXV Connection BB

By following essentially the same procedure as described in Example XXXI for the preparation of the methyl ester of 3,4-bis (n-hexadecanamido) -benzoic acid, but replacing 40 at n-hexadecanoyl chloride with n-tetra- 800 3 6 28 Decanoyl chloride, the methyl ester of 3,4-bis (n.tetra-decanamido) -benzoic acid was prepared in the form of a white solid, which after recrystallization from acetone showed a melting point of 132 to 133 ° C.

5 Example XXXVI Connection CC

By following essentially the same procedure as described in Example XXXI for the preparation of the methyl ester of 3,4-bis (n-hexadecanamido) -benzoic acid, but replacing it at n-hexadecanoyl chloride with n-octadecanoyl chloride, The methyl ester of 3> 4-bis (n.octadecan-amido) -benzoic acid was prepared in the form of a white solid, which after recrystallization from a mixture of acetone and methanol in a mixing ratio of 1: 1, melting point 120 ° 0.

Example XXXVII Connection PD

According to this example, 12.1 g of 3-amino-4- (n.oc-tanamido) -benzoic acid in 200 ml of methanol were treated with diazomethane in ether until conversion was complete (as shown by thin layer chromatography on silicon oxide using methanol: chloroform; glacial acetic acid: 10: 90: 0.5 as eluent). Then 0.2 ml of acetic acid was added and the reaction mixture was concentrated under reduced pressure. The solid obtained was recrystallized from ethyl acetate to obtain 9 2 g of 3-amino-4- (n-octanamido) -benzoic acid methyl ester in the form of a cream-colored solid, which was at a temperature of 128 DEG-130 DEG C. melted.

Example XXXVIII Compound BE

According to this example, 25 g of 3-nitro-4- (n.octan-amido) -benzoic acid, which was dissolved in 500 ml of ethanol at a temperature of 50 ° C, were hydrogenated by the solution in the presence of 2.5 g of 5. Shake percentages (w / w) palladium-on-charcoal at 50 DEG C. under atmospheric pressure for 3 hours. The mixture was filtered while hot, and the filtrate was evaporated in vacuo.

The residue was recrystallized from a mixture of ethanol and water in a 4-0 mixing ratio of 1: 1 to give 8 g of 800 3 6 28 3-amino-4- (n.octanamido) -benzoic acid as a yellow solid with a melting point of 155 to 156 ° C.

The 3-nitro-4- (n.octan-5 amido) -benzoic acid used as starting material was prepared in the following manner:

A solution of 18.2 g of 3-nitro-4-aminobenzoic acid and 19.4 g of n-octanoyl chloride in 100 ml of dry dimethylformamide was heated to a temperature of 97 ° C for 90 minutes. The solution was cooled and then poured onto 300 g of ice. The solid obtained was collected and washed three times with 100 ml of water each time, dried and recrystallized from a mixture of methanol and water in a mixing ratio of 8: 1 with charcoal treatment, whereby 22 g of 3-nitro-4- (n-octanamido benzoic acid in the form of a light yellow solid with a melting point of 153 to 154 ° C was obtained.

Example XXXIX Compound FF

According to this example, 21 g of 3-nitro-4- (n.dodecan-20 amido) -benzoic acid as a solution in 500 ml of ethyl acetate were hydrogenated by palladium in the presence of 2.5 g of 5% (w / w). shake on charcoal at 50 ° C under atmospheric pressure. The resulting mixture was filtered while hot to yield a cream-colored solid after cooling. This product was recrystallized from methanol to give 7.4 g of 3-amino-4- (n.dodecanamido) benzoic acid as a beige solid, mp 158-160 ° C.

Example Xl

30 Connection H

By following essentially the same procedure as described in Example XXVI for the preparation of the methyl ester of 3- (n.octanamido) -4-aminobenzoic acid, but thereby replacing the n.octanoyl chloride with n.decanoyl chloride, the methyl ester of 3 - (n.decanamido) -4-aminobenzoic acid in the form of a white solid, which melted at a temperature of 96 to 100 ° C.

Example XLI Compound G-G

40 By following essentially the same procedure as described in Example 3 800 28 6 for preparing the methyl ester of 3,4-bis (n-hexadecanamido) -benzoic acid, but replacing n-hexadecanoyl chloride with n. decanoyl chloride, the methyl ester of 3,4-bis (n.decanamido) -5 benzoic acid was prepared in the form of a white solid, which melted at 139 DEG-140 DEG C. after recrystallization from ethanol.

Example XLII Compound HH

To a solution of 10 g of 3,4-diaminobenzoic acid in 100 ml of dry dimethylformamide, which contained 28 g of potassium carbonate, was added dropwise, with stirring, a solution of 33 l of n-dodecanoyl chloride in 30 ml of dry dimethylformamide over 5 minutes. . The temperature was allowed to rise from 20 ° C to 50 ° C. The mixture was stirred for a further 3 hours. The resulting suspension was filtered and the filtrate was poured into 700 ml of water containing 10 ml of hydrochloric acid at a concentration of 36.5% (w / v). The solid material obtained was collected and recrystallized from glacial acetic acid, the product was washed with water and recrystallized from methyl ethyl ketone, whereby 12.5 g of 3-4-bis (n.dodecanamido) benzoic acid in the form of a white solid with a melting point of 195 to 197 ° C was obtained.

Example XLIII Compound E

By following essentially the same procedure as described in Example XLII for the preparation of 3,4-bis (n.dode canamido) benzoic acid but replacing the n.dode-30 canoyl chloride with n-hexadecanoyl chloride and the potassium carbonate by sodium carbonate , the 3,4-bis (n-hexadecanamido) -benzoic acid was prepared in the form of a white solid, which melted at a temperature of from 198 to 202 ° C after successive recrystallization from glacial acetic acid and methyl ethyl ketone.

Example XLIV Compound II

By following essentially the same method as described in Example XLII for the preparation of 3,4-bis (n.dodecan-4-0 amido) -benzoic acid, but replacing the n.dodecanoyl and n 3 6 28 chloride with n.octanoyl chloride, the 3,4-bis (n.octanamido) -benzoic acid was prepared in the form of a white solid, which, after successive recrystallization from glacial acetic acid and methyl ethyl ketone, had a melting point of 5 195 to 197 ° C.

Example XLV Connection JJ

By following essentially the same procedure as described in Example XLII for the preparation of 3'-4-bis (n.dodecan-10 amido) -benzoic acid but thereby replacing the n.dodecanoyl chloride with n.tetradecanoyl chloride, the 3.4- bis (n.tetradecanamido) benzoic acid in the form of a white solid, which melted at a temperature of 201 to 206 ° C after successive recrystallization from glacial acetic acid and methyl ethyl ketone.

Example XLVI Connection KK

According to this example, 21 g of methyl ester of 3-nitro-4- (n.dodecanamido) -benzoic acid, which was dissolved in 500 ml of warm ethyl acetate (50-55 ° C), were hydrogenated for 2 hours in the presence of 2, Shake 0 g of 5 percent (w / w) palladium-on-charcoal at atmospheric pressure at 60 ° C. The mixture was filtered while hot and the filtrate was allowed to cool.

The solid material was collected to give 14.1 g of methyl ester of 3 "Saniu-4- (n-dodecanamido) benzoic acid in the form of a white solid, which was at a temperature of from 134 to 137 ° C. melted.

The methyl ester of 3-nitro-4- (n.dodecanamido) -benzoic acid used as starting material was prepared in the following manner:

For hours, 19.6 g of methyl ester of 3-nitro-4-aminobenzoic acid and 23 g of n-dodecanoyl chloride in 100 ml of dimethylformamide were heated to a temperature of 97 ° C and shaken occasionally. The resulting solution was poured onto 300 g of crushed ice, the resulting solid was collected and recrystallized from a mixture of methanol and chloroform in a 5: 1 mixing ratio to give 31 g of methyl ester of 3-nitro-4- ( n.dodecan-40 amido) -benzoic acid in the form of a yellow solid with an 800 3 6 28 t 29 melting point of 78 to 80 ° G was obtained.

The methyl ester of 3-III-4-aminobenzoic acid was prepared in the following manner:

70 g of 3-n-nitro-aminobenzoic acid were added to a solution of anhydrous hydrogen chloride in methanol prepared from 78 S acetyl chloride and 300 ml of dry methanol.

The resulting mixture was refluxed for 10 hours and then cooled in ice, after which the obtained solid material was collected, 62 g of methyl ester of 3 "D.itro-4-aminobenzoic acid in the form of a yellow solid having a melting point of 193 to 195 ° 0 was obtained.

Example XI / VII Compound ItL

By following essentially the same procedure as described in Example XLVI for the preparation of the methyl ester of 3-amino-4 - (n.dodecanamido) -benzoic acid, but with the methyl ester of 3-nitro-4- (dodecanamido) - replacing benzoic acid with the methyl ester of 3-nitro-4- (n.hexa-decanamido) -benzoic acid, the methyl ester of 3-amino-

4- (n.hexadecanamido) -benzoic acid in the form of a white solid with a melting point of 135 to 137 ° C. Example XLVIII

Connection MM

By following essentially the same procedure as described in Example XLVI for the preparation of the methyl ester of 3-amino-4- (n.dodecanamido) -benzoic acid, but thereby the methyl ester of 3-nitro-4 - (n. docbcanamido) -benzoic acid to be replaced by the methyl ester of 3- & itro-4—

(N.decanamido) -benzoic acid, the methyl ester of 3-ami-ηο-4- (η. Decanamido) -benzoic acid was prepared in the form of a white solid, m.p. 131 to 133 °. Example XLIX Connection NN

To a solution of 8.4 g of 3,4-diaminobenzoic acid in 100 ml of dry dimethylformamide containing 15-27 g of potassium carbonate, a solution of 15.17 g of n-hexadecanoyl was added dropwise with stirring over a period of 30 minutes. chloride in 30 ml of dry dimethylformamide added at a 4-0 temperature of 0 to 5 ° 0. The mixture was stirred for a further 2 hours at 800 ° C to 5 ° C, after which the temperature was allowed to rise to room temperature over the course of 30 minutes.

The solution was then poured into 700 ml of water containing 10 ml of hydrochloric acid at a concentration of 36.5% (w / v). The solid was collected, with 300 ml of acetone at a temperature of 50 ° C heated and recrystallized from methyl ethyl ketone to give 9 * 4 g of 3- (n-hexadecanamido) -4-aminobenzoic acid as a white solid, m.p. 197 DEG-199 DEG.

Example L Compound 00

By following essentially the same procedure as described in Example XLII for the preparation of 3 * 4-bis (n.dodecan-amido) -benzoic acid, but thereby replacing the n.dodecanoyl chloride with n.decanoyl chloride, it became 3 4-His (n.decanamido) -benzoic acid in the form of a white solid which, after successive recrystallization from glacial acetic acid and methyl ethyl ketone, had a melting point of 194 to 196 ° C.

Example L!

PP connection

By following essentially the same procedure as described in Example XLII for the preparation of 3 * 4-bis (n.do-decanamido) -benzoic acid, thereby replacing the n-dead canoyl chloride with n-tridecanoyl chloride, 3,4-bis (n-tridecanamido) -benzoic acid in the form of an off-white solid, which, after successive recrystallization from glacial acetic acid and methyl ethyl ketone, had a melting point of 192 to 194 ° C.

Example Lil Connection QQ,

Following essentially the same procedure as described in Example XLII for the preparation of 3-4-bis (n.do-decanamido) -benzoic acid but replacing the n-dead canoyl chloride with n-octadecanoyl chloride, the 3 * 4 - bis (n.octadecanamido) benzoic acid in the form of a white solid, which melted at a temperature of 193 to 196 ° C after successive recrystallization from glacial acetic acid and methyl ethyl ketone.

Example LIII Compound RR

To a solution of 40 g of 2,3-diaminobenzoic acid in 600 ml of dimethylformamide, which contained 79.7 g (109.5 ml) of triethylamine, 144.5 g of n-hexadecanoyl chloride were added. The addition was made at such a rate that the temperature of the reaction mixture could rise from room temperature to 45-50 ° C. The mixture was then stirred for an additional 3 hours, then left overnight at room temperature. The resulting mixture was added to 1200 ml of water containing 50 ml of concentrated hydrochloric acid at a concentration of 36.5% (w / v), the resulting solid material was collected and washed with 1200 ml of water. The solid was stirred with 4000 ml of hot water (65 ° C) for 30 minutes and then collected and dried in vacuo at a temperature of 70 ° C to yield the 2,3-bis (n-hexadecanamido) benzoic acid.

20 Example LIV Connection & S

By following essentially the same procedure as described in Example XXVI for the preparation of the methyl ester of 3- (n.octanamido) -4-aminobenzoic acid, but thereby replacing the n.octanoyl chloride with n.heptanoyl chloride, the methyl ester of 3- (n.heptanamido) -4-amino-benzoic acid in the form of a light brown solid, which melted at a temperature of from 103 to 106 ° C.

Within the scope of the invention are also pharmaceutical preparations containing at least one of the compounds of the general formula 1 or pharmaceutically acceptable salts thereof in combination with a pharmaceutically acceptable carrier or coating. In clinical use, the compounds of the invention can be administered parenterally, although they are preferably administered rectally or especially orally.

Examples of solid preparations for oral administration are compressed tablets, pills, powders and granules. In such solid preparations, one or more of the active compounds are mixed with at least one inert excipient, such as starch, sucrose or lactose. The preparations may also, as is customary in practice, contain further substances other than inert extenders, such as, for example, lubricants, for example magnesium stearate.

Examples of liquid preparations for oral administration are pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs, which contain inert diluents commonly used in this field, such as water and liquid paraffin. In addition to inert diluents, these compositions may contain adjuvants such as wetting and suspending agents, sweetening and flavoring agents, perfumes and preservatives. The compositions of the invention for oral administration also include capsules of absorbable material, such as gelatin, containing one or contain more of the active substances, whether or not in combination with extenders or excipients.

Examples of the compositions of the invention for parenteral administration are sterile aqueous, water-organic and organic solutions, suspensions and emulsions. Examples of organic solvents or suspending agents are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. These formulations may also contain adjuvants such as stabilizing, preserving, wetting, emulsifying and dispersing agents. They can be sterilized by, for example, filtration JO over a bacteria filter, by incorporation into the preparations of sterilizing agents, by irradiation or by heating. They can also be prepared in the form of sterile solid preparations, which can be dissolved in sterile water or any other sterile injectable medium immediately before use.

Solid compositions for rectal administration include suppositories, which are prepared by the methods known in the art, and contain one or more of the compounds of Formula 1 or pharmaceutically acceptable salts thereof.

800 3 6 28 53

The percentage of active ingredient in the compositions according to the invention can vary, however it is necessary that this percentage is such that an appropriate dosage will be obtained.

Of course, several unit dosage forms can be administered at about the same time. The dose used will be determined by the physician and depends on the desired therapeutic effect, the mode of administration and the duration of treatment as well as the patient's condition. For the adult, the doses are generally between 0.1 and 50 mg / kg of body weight per day when administered orally, for example as anti-atheroma agents and in related cardiovascular ailments, between 10 and 50 mg / kg of body weight per day when administered orally. and in the treatment of arthritis and related diseases between 0.1 and 10 mg / kg body weight per day when administered orally.

The following example illustrates the pharmaceutical preparations of the invention.

20 Example LV

No. 2 gelatin capsules, each containing methyl ester of 3- (n-octanamido) -4-aminobenzoic acid 20 mg lactose 100 mg 25 starch 60 mg dextrin 40 mg magnesium stearate 1 mg, were prepared by conventional methods .

800 3 6 28

Claims (29)

Acylaminobenzoic acid derivative characterized by the general formula 1, wherein R represents a hydrogen atom or a straight or branched alkyl group having 1 to 6 carbon atoms, which may be optionally substituted by one or more than one of the same type substituents belonging to the hydroxyl groups, alkenyl groups of 2 to 5 carbon atoms and alkanoyloxy groups of 2 to 7 carbon atoms, and E 0 a hydrogen atom or a radical with 2 2 10 the formula -COR and R represent a straight or branched alkyl group of 2 to 20 carbon atoms, which compound is optionally in the form of a salt, in particular a pharmaceutically acceptable salt. 2. Acylaminobenzoic acid derivative according to claim 1, η 15 characterized by the formula 1, wherein E represents a hydrogen atom or a straight or branched alkyl group having 1 to 6 carbon atoms. Acylaminobenzoic acid derivative according to claim 1, characterized by the formula 1, wherein E represents a hydrogen atom. A cylamino benzoic acid derivative according to claim 1, characterized by the formula 1, wherein R represents a methyl group. Acylaminobenzoic acid derivative according to claim 1, characterized by the formula 1, wherein R represents a 2,3-dihydroxyprop-1-yl, allyl or pivaloyloxymethyl group. 6. Acylaminobenzoic acid derivative according to one or more of claims 1 to 5, characterized by the formula 1, in which R represents a straight alkyl group with 2 to 20 carbon atoms. Acylaminobenzoic acid derivative according to one or more of the preceding claims, characterized by p of the formula 1, wherein R represents an alkyl group with 7 to 16 carbon atoms. 8. Methyl ester of 3- (n-octanamido) -4-aminobenzoic acid. 9. Methyl ester of 3- (n-hexadecanamido) -4-aminobenzoic acid. 10. Methyl ester of 3- (n.dodecanamido) -4-aminobenzoic acid. 800 3 6 28 11. Methyl ester of 3- (n-tetradecanamido) -4-amino-benzoic acid. 12. Methyl ester of 3 ”(--tridecanamido) -4-amino-benzoic acid. 5 Pharmaceutically permissible acid addition salt of a compound according to one or more of claims 2 to 12. 14. 3,4-Bis (n.hexadecanamido) -benzoic acid, methyl ester of 3i4-bis (n.hexadecanamido) -benzoic acid, methyl ester of 3,4-bis (n.undecanamido) -benzoic acid, methyl ester of 10 3- (& Iecanamido) -4-aminobenzoic acid, methyl ester of 3> 4-bis (n.octahamido) -benzoic acid and 3> 4-bis (n-pentadecanamido) -b, etc. acid. Pharmaceutically acceptable salt of any of the compounds defined in claim 14. 16. Methyl ester of 3,4-bis (n.nonanamido) -benzoic acid, 3,4-bis (n.heptadecanamido) -benzoic acid, 3,4-bis (n.heneico-sanamido) -benzoic acid, 3,4-bis (n .eicosanamido) -benzoic acid, 3- (n.nonadecanamido) -4-aminobenzoic acid, 3,4-bis (2-methyl-tetradecanamido) -benzoic acid, 3- (2-hexyloetanamido) -4-amino-benzoic acid, 3- (2-ethyldodecanamido) -4-aminobenzoic acid, 3- (2-butyldecanamido) -4-aminobenzoic acid, 2,3-bis (n.tetra-decanamido) -b etc acid, 3-amino-4- (n. hexadecanamido) -b zozoic acid, 3- (n.octanamido) -4-aminobenzoic acid, 3- (c-cLodecanami-do) -4-aminobenzoic acid, 3- (n.octadecanamido) -4-aminobenzoic acid, methyl ester of 3,4-bis (n.dodecanamido) -benzoic acid, methyl ester of 3,4-bis (n.tridecanamido) benzoic acid, methyl ester of 3,4-bis (n.tetradecanamido) -benzoic acid, methyl ester of 3,4-bis (n.octadecanamido) -benzoic acid, methyl ester of 3-amino-4- (n.octanamido) -benzoic acid, 3-amino-4-30 (n.octanamido) -benzoic acid, 3-amino-4- (n.dodecanamido) -benzoic acid, methyl ester of 3,4-bis (n.decanamido) -benzoin acid, 3,4-bis (n.dodecanamido) -benzoic acid, 3,4-bis (n.octanamido) -benzoic acid, 3,4-bis (n.tetradecanamido) -benzoic acid, methyl ester of 3-amino-4- (n. dodecanamido) -benzoic acid and methyl ester of 3-amino-4- (n-hexadecanamido) -benzoic acid. Pharmaceutically acceptable salt of any of the compounds mentioned in claim 16. 18. Methyl ester of 3-amino-4- (n.decanamido) benzoic acid, 3- (n.hexadecanamido) -4-aminobenzoic acid, 3,4-his 40 (n.decanamido) benzoic acid, 3,4- bis (n.tridecanamido) -benzoic- 800 3 6 28 acid, 3,4-bis (n.octadecanamido) -benzoic acid, 2,3-bis (n.hexadecanamido) -benzoic acid and methyl ester of 3- (n.hep -tanamido) -4-aminobenzoic acid. 19. Pharmaceutically permissible salt of any of the compounds mentioned in claim 18. 20. Process for the preparation of an acylamino-benzoic acid derivative, characterized in that an acylamino-benzoic acid derivative of the general formula 1, wherein r 1, R 1 and R 0, have the meaning specified in claim 1, optionally in the form vifi. & a particularly a pharmaceutically acceptable salt. 21. Process according to claim 20, characterized in that an acylamino benzoic acid derivative of the general formula 1 is prepared, in which R ° represents a hydrogen atom, by reduction of a compound of the general formula 2, wherein R and R are the claims 1, according to known methods for the reduction of a nitro group to a primary amino group. 22. Process according to claim 21, characterized in that the reduction of the nitro group to a primary amino group is carried out by catalytic hydrogenation. 23. Process according to claim 20, characterized in that an acylaminobenzoic acid derivative of the general formula 1 is prepared, wherein R ° represents a radical of the formula 2 -COR, wherein R has the meaning as mentioned in claim 1, or the substituent -NH-COR, wherein p R has the meaning defined in claim 1, is in the η m position relative to the substituent -C00R, η 30 where R has the meaning defined in claim 1 and R ° has a represents hydrogen atom, by reacting a compound of the general formula 3, wherein R has the meaning as defined in claim 1 with an acylating agent O of the general formula 4-, wherein R has the meaning as defined in claim 1 and X represents a halogen atom or a hydroxyl group. 24-. Process according to claim 20, characterized in that an acylamino benzoic acid derivative of the general formula 1 is prepared in which R ° represents a radical having the formula 2 -COR, wherein R has the meaning mentioned in claim 1, 800 3 6 28, by reacting a compound 1 2 of the general formula 8, wherein R and R have the meaning as defined in claim 1, with an acylating agent of the general formula 4, wherein E has the meaning of Ί 5 mentioned in claim 1 and X a halogen atom or represents a hydroxyl group. 25. Process according to claim 20, characterized in that acylaminobenzoic acid derivative of the formula 1 is prepared, in which R represents a straight or branched chain alkyl-group of 1 to 6 carbon atoms, which may be optionally substituted by one or more than one of the same type of substituents belonging to the hydroxyl groups, alkenyl groups of 2 to 5 carbon atoms and alkanoyloxy groups of 2 to 7 carbon atoms, and E ° and R ^ have the meaning defined in claim 1 by esterification of a corresponding carboxylic acid of the general formula 1, o 2 in which E represents a hydrogen atom and R 0 and R have the meaning defined in claim 1. 26. Process according to claim 20, characterized in that an acylaminobenzoic acid of formula 1 is prepared, in which R represents a hydrogen atom by alkaline hydrolysis of a corresponding ester of general formula 1, in which R is straight or branched alkyl group of 1 to 6 carbon atoms, which may optionally be substituted by one or more of the same type of substituents belonging to the hydroxyl groups, alkenyl groups of 2 to 5 carbon atoms and 2 alkanoyloxy groups of 2 to 7 carbon atoms, and E ° and Έτ have the meaning defined in claim 1. 27. Process according to one or more of claims 20 to 26, characterized in that an acylaminobenzoic acid derivative of the general formula 1 obtained is converted into a salt, in particular a pharmaceutically acceptable salt, by a known method. A pharmaceutical composition characterized by at least one acylamino benzoic acid derivative or pharmaceutically acceptable salt thereof according to any of claims 1 to 19 in combination with a pharmaceutical carrier or coating. Ann 3 6 28 29. Pharmaceutical composition according to claim 28, characterized by an acylamino benzoic acid derivative or pharmaceutically acceptable salt thereof, which has been brought in the form of a suitable dosage unit for the treatment or prevention of atherosclerosis and related ailments, such as angina, myocardial infarction vascular occtosis. in the cerebrum, arterial aneurysm and peripheral vascular disease or arthritis, immunological disease, cancer or implant rejection reactions. ******* 800 3 6 28