HU182438B - Process for producing substituted esters of 4-alkylamino-benzoic acids - Google Patents

Abstract

The present invention relates to a process for the preparation of a novel compound of formula I and a pharmaceutically acceptable acid addition salt thereof, wherein R4 is a straight chain alkyl group having from 14 to 19 carbon atoms, Rj is hydrogen, or a C 1-3 hydroxyalkylene group, R 1 is hydrogen or C 1-3 -hydrogen. oxyalkylene, X is hydrogen, hydroxy, lower alkanoyl, C 4 -C 14 -alkylamino benzoyloxy, Y is hydrogen, hydroxy, lower alkanoyl, C 4- (C 14 -C 19) alkylamino benzoyloxy, or X and C Y, together with the alkylene group or the alkylene group, forms an epoxy ring, or forms a cyclic group of the formula -OCRR'-O, where R is hydrogen, or a C1-3 alkyl group, R1 is a C1-3 alkyl group or a phenyl group. The compounds of formula I can be prepared by known methods. New esters reduce serum lipid levels and reduce the deposition of lipids in the aorta. 10 20 25 ϊ ΐ ϊ C-0-CH-C-CH-R3 1 I 3 R, H (0 182438 -1-

Description

This invention relates to novel substituted alkyl esters of 4-alkylaminobenzoic acids of formula I and to pharmaceutical compositions containing the novel compounds as active ingredients.

No. 2,857,417. U.S. Pat. No. 4,123,195 discloses esters of p-aminobenzoic acids with polyalkylene oxide ethers and does not mention the therapeutic effect of these compounds. In particular, esters of alkyl, cycloalkyl or cycloalkylalkylaminobenzoic acids of up to 6 carbon atoms with polyalkylene oxide ethers which are radically different from those described in the present invention have been described.

4-Alkylaminobenzoic acids are described in U.S. Patent 3,868,416. There is no mention in the literature of the hypolipaemic activity of these compounds and they are structurally distinct and superior to known hypolipaemic agents.

The compounds of the present invention reduce acid lipid concentration and reduce lipid deposition in the aorta. Esters, such as glycerol esters, facilitate the intestinal absorption and provide the high and reliable absorption expected from hypolipidemic agents after oral administration. Because these esters are hydrolyzed in the body, they also have the advantage over other esters of obtaining a harmless hydroxylated compound, which is a natural product of mammalian physiological processes. The new esters are more perfectly and uniformly absorbed in the gastrointestinal tract than other carboxylic acids and other esters. They also cause less gastrointestinal irritation than the corresponding carboxylic acids.

In the general formula I

R ₄ is a straight chain alkyl group of 14 to 19 carbon atoms,

R _t is hydrogen or C 1-3 hydroxyalkylene,

R ₃ is hydrogen or C 1-3 hydroxyalkylene,

X is hydrogen, hydroxy, lower alkanoyl, 4- (C 14 -C 19) alkylaminobenzoyloxy,

Y is hydrogen, hydroxy, lower alkanoyl, 4- (C 14 -C 19) alkylaminobenzoyloxy, or

X and Y together form a bond, either together with the alkylene group, to form an epoxy ring, or form a cyclic group of formula -OCRR'-O, wherein R is hydrogen or C 1-3 alkyl,

R 'is C 1-3 alkyl or phenyl.

The present invention also provides pharmaceutically acceptable acid addition salts of the compounds of Formula I.

In preferred compounds of the present invention, R ₄ is a straight-chained C _n H 2 _n +1 alkyl group - where n is 14-19, R 1 is hydrogen, and R 1 is hydrogen, X and Y are the same or different and are hydroxy or lower alkanoyloxy or X and Y together with the alkylene group forms either an epoxy ring (-O-) or a cyclic group (-O- -CRR'-O-) of the alkylene group - wherein R is hydrogen or C 1-3 alkyl and R 'is C 1-3 alkyl or phenyl. . Also pharmaceutically acceptable acid addition salts of the above compounds are preferred.

Administration of the compounds of the present invention may reduce serum lipid levels and reduce lipid deposition in the mammalian aorta.

The novel compounds are generally colorless crystalline materials with characteristic melting points and spectral properties. Organic solvents such as chloroform, benzene, methylene chloride, ^»f acetonitrile, dimethylformamide, dimethylsulfone ^ idban and soluble lower alkanols. They are generally insoluble in water. These compounds are bases and include acids such as sulfuric acid, hydrochloric acid, phosphoric acid, succinic acid, citric acid and the like. to form pharmaceutically acceptable salts.

Suitable ester groups according to the invention may be prepared from the following compounds: glycerol, 2,3-epoxy-1-propanol (glycidol), 1,3- and 1,2-propanediol, O ₂ -acetylglycerol, O ₂ , O ₃ -diacetylglycerol, O _3- (4-alkylaminobenzoyl) glycerol, erythritol, 1,2,3,5-tetrahydroxypentane, pentaerythritol, ribose, glucose, glyceraldehyde, dihydroxyacetone, mannitol, sorbitol, 1,4-butanediol, 2,3-isopropylidene glycerol, 2 , 3-benzylidene glycerol, allyl alcohol, 1,4-butanediol and the like.

Preferred alkyl groups include: η-hexadecyl, n-pentadecyl, η-heptadecyl, 2-tridecyl and the like. -groups. The N-lower alkanoyl derivatives of the compounds of Formula I act in vivo to deacylate to Formula I.

The novel substituted 4-alkylaminobenzoic acid alkyl esters can be prepared by reacting an alkyl halide of formula II wherein R 1 and R ₃ are as defined above and Z is halogen, X and Y are hydroxy or hydrogen and R _p R ₃ , One of X and Y is a non-hydrogen atom, with 4-alkylaminobenzoic acid of formula VI or its sodium or other alkali metal salts, wherein R ₄ is as defined above, in aqueous or anhydrous hexaphosphoramide, dimethylformamide, acetonitrile or other suitable solvent. -you. The salts may be formed in situ from 4-alkylbenzoic acids and the appropriate bases (process (a)).

In another embodiment of the invention, alkyl esters of 4-alkylaminobenzoic acids of formula I can be prepared from alkyl alcohols of formula IV wherein R _p R is hydrogen or hydroxyalkylene having 1 to 3 carbon atoms and X and Y are hydroxy; with benzoic acid, where R ₄ is as defined above, in the presence of an acid catalyst such as toluene sulfonic acid or Lewis acid catalyst (process b) and optionally treated with ether and sodium carbonate.

The substituted alkyl esters (methyl or ethyl ester) may be transesterified with an alkyl alcohol of formula IV wherein R ₁ , R ₃ , X and Y are as defined above, in the presence of an acidic or basic catalyst.

The compound of formula I wherein X and Y are 4- (C 14 -C 19) alkylaminobenzoyloxy, wherein R ₃ is hydrogen and R ₄ is as defined above, is prepared by following procedure (b) preferably in the presence of p-toluenesulfonic acid. and treated with chloroform and sodium carbonate solution (process c).

A chemically similar method for the preparation of compounds of formula I is 4-alkylamines of formula VI

-2182438 nobenzoesavak - wherein R ₄ is as defined above - or certain alkali metal salts of reaction from 20 to 160 ° C, substituted alkylene of the formula III - wherein R _p R _{2, and} R is as defined above and Y is chlorine or hydroxy Process (d) ).

Synthesis of 4-alkylaminobenzoic acid alkyl esters involves the formation of the desired X and Y groups in the final step of the process. For example, when X and / or Y in the formula I is C 1-4 alkanoyloxy or 4- (C 14-19 alkylamino) benzoyloxy, these compounds can be acylated by compounds of the formula I containing X and / or Y as hydroxy or together forming an epoxy group. and can be formed at a temperature of 60 ° C to 120 ° C (process ej), where X and Y together form a cyclic acetal or ketal group of the formula -O-CRR'-O, wherein R is hydrogen, C 1-3 alkyl, and compound I of the formula R 'is C1-3 alkyl or phenyl, X and Y is hydroxy acid ka la lysed reaction with an aldehyde or ketone RR' formula -C-O -. wherein R _p R' above (process ii) In some cases, the reverse reaction is used to form a ketal or acetal derivative. Compounds of formula I wherein X and / or Y are halogen are obtained by treatment of the halogen compounds with silver nitrite followed by mild hydrolysis. The dihydroxy compounds of Formula I may also be prepared by reacting the epoxide ring with a moderate acid catalysis in the 4-alkylaminobenzoic acid epoxy alkyl ester of Formula I wherein R 1, R ₂ , R ₃ and R ₄ are as defined above. in a hydrolytic reaction, resolved in process (iii)). Similar compounds of formula I are also obtained by dihydroxylation of 4-alkylaminobenzoic acid alkenyl ester.

The novel 4-alkylaminobenzoic acid esters can be prepared according to method j by reacting the alkyl 4-aminobenzoates with suitable alkylating agents, such as alkyl halides, in the presence or absence of a solvent at 50-150 ° C. Solvents include lower alkenols, chloroform, Ν, Ν-dimethylformamide, N, N-dimethylacetamide hexamethylphosphoramide, diglyme (diethylene glycol dimethyl ether), dimethylsulfoxide, acetonitrile, toluene, benzene and the like. can come into play. The reaction may be carried out with an excess of one equivalent of 4-aminobenzoic acid ester as a base, or an equivalent of another base, such as an alkali carbonate or bicarbonate, or a catalytic amount of copper powder when the alkylating agent is an alkali halide. In another embodiment of the process of the invention, the desired 4-alkylaminobenzoic acid esters are prepared by reacting the corresponding 4-aminobenzoic acid ester with a C 14 -C 19 alkyl halide in the presence of one equivalent of sodium hydride in an inert solvent such as Ν, Ν-dimethylformamide. , N, N-dimethylacetamide or diglyme (diethylene glycol dimethyl ether) at 50-150 ° C.

We do not require, but we will mention the following methods.

The introduction of the N-alkyl group into the compound of formula I can also be accomplished by subjecting the substituted alkyl esters of 4-aTninobenzoic acid or 4-nitrobenzoic acid to catalytic reductive alkylation by reaction with the appropriate aliphatic aldehyde or ketone. The introduction of the N-alkyl group may be accomplished by reduction of the 4-alkanoylaminobenzoic acid-substituted alkyl esters using copper chromite as the catalyst.

It has been found that certain members of the compound group safely and effectively lower serum sterol and triglyceride levels in warm-blooded animals. These hypolipidemic properties are expected to be useful in the treatment of atherosclerosis. In atherosclerosis, cholesterol and lipoids are deposited in the blood vessels of large and medium-sized arteries in the form of platelets. Atherosclerosis is associated with the degeneration of arterial walls by a mechanism that has not yet been fully elucidated. However, there is a statistical correlation between hypercholesterolaemia and the incidence of cardiovascular disease, particularly bloodless heart disease. For some time, lowering high cholesterol, triglyceride levels and phospholipid levels in mammals has been considered desirable as a possible method of preventing atherosclerosis. In the past, attempts have been made to lower blood cholesterol levels by oral administration of various hypocholesteremic agents. Examples of such materials are lecithin, cottonseed oil and corn oil. In addition, three synthetic lipid lowering agents are known, namely clofibrate, D-thyroxine and nicotinic acid [R. I. Levy and D.S. Frederickson, Postgraduate Medicine 47, 130-136 (1970)]. The compounds of the present invention exhibit better hypocholesteremic activity than the above-mentioned adjuvants and synthetic materials. In addition, these compounds safely stop the development of atheromatous lesions in the warm-blooded aorta and thus offer another way to overcome atherosclerosis. It is not known how the new compounds work in the serum, and no theory has been developed as to why they act in this way. The present application is not limited to either mode of action.

The compounds of the present invention are hypolipidemic agents and the following animal experiments are used to demonstrate their activity:

the test compounds are orally mixed with the diet of a group of 4 male rats (Carworth Farms CFE strain), a control group of 8 rats is fed with food alone, and the test groups are fed with the weight percentage. After 6 days or 4 weeks, the animals are sacrificed and serum sterol concentrations are in mg / 100 ml or (1) according to the Trapp saponification and extraction method, Analyst 77, 321 (1952) and Zlatkis et al. colorimetric method, J. Foot. Clin. 44, 486 (1953) or (2) Η. H. Leffler extraction method. Amer. J. Clin. Path. 31, 310 (1959) and using Zlatkis chlorometric determination, the whole method is modified to an automatic mechanical analyzer.

Whey triglyceride levels were estimated by the automated method of Kesster and Lederer (Automation in Ana-3182438 Analytical Chemistry, Skeggs, L.T.) Ed. (Medad Inc., New York, 1965, 341).

The compound is considered hypolipidemic when tested to control serum sterol and / or triglyceride levels. Table I shows the number of compounds of the present invention and the degree of efficacy with which they reduce serum sterol and 5 triglyceride levels after a 6 day dosing period and a 4 week treatment period.

Table I

Hypolipidemic effect of polysubstituted 4-alkylaminobenzoic acid alkyl esters in rat

The proportion of compound in the feed in ° / ₀ 1 week dosing 4 weeks dosing Compound sterol triglycerides sterol triglycerides level reduction ° / ₀ level reduction% 4- (n-hexadecilamino) -benzoic acid 2,3-dihydroxy- 0.10 42 57 31 57 propyl ester 0.071 28 62 28 45 0.03 . 29 45 23 23 0.01 21 24 0,003 1 19 4- (n-hexadecilamino) -benzoic acid methyl ester 2,3-epoxipropiI 0.1 25 47 0.03 25 40 0.01 8 26 4- (n-hexadeciIamino) benzoic acid 2-acetoxy-3- 0.1 15 52 -hidroxipropilészter 0.03 15 29 4- (n-hexadecilamino) -benzoic acid 2,3-dihydroxypropyl 0.1 31 68 észtcrhidroklorid 4- (n-hexadecilamino) -benzoic acid 2,3- (isopropyliden 0.1 5 32 methylenedioxyphenyl) propyl ester 4- (n-hexadecylamino) benzoate ν-2-phenyl-1,3-dioxolane 0.1 17 50 -4-yl-methyl ester 4- (n-hexadecilamino) benzoic acid 2-hydroxypropyl ester 0.1 17 53 0.03 23 33 0.01 12 26 4- (n-hexadecilamino) benzoic acid 2-propenyl ester 0.1 19 40 0.33 no 40 4- (n-hexadecilamino) -benzoic acid 3-hydroxypropyl ester 0.1 42 62 0.03 26 19 0.01 23 28

CFE mice from Roscoe B. Jackson Memories Laboratories, Bar Harbor, Maine were used to study the mouse. The method used for lipid analysis was the same as that described for the rat test.

II. Table 4 shows the results obtained using 4- (n-hexadecylamino) -benzoic acid 2,3-dihydroxypropyl ester.

II. spreadsheet

Hypolipidemic effect of 4-alkylaminobenzoic acid-substituted alkyl esters in mice

Compound Compound% in food 1 week test, level reduction% sterol triglycerides 4- (n-hexadecilamino) - 0.1 18 19 2,3-dihydroxy-benzoic 0.03 11 30 propyl ester 0.01 9 6

When used as animal models of rabbits, the compounds of the present invention stop the development of atheroma lesions. This ability is effective in combating atherosclerosis, and is also facilitated by a lowering serum lipid concentration. Atheromic injuries were caused by mild mechanical injury to the surface of the rabbit aorta. The diet supplemented with cholesterol is fed and the diet comprises the compounds of the present invention. Aortic tissue was subjected to histological and biochemical analysis and the extent and severity of lesions were measured. The results obtained with 4- (n-hexadecyl mino) benzoic acid 2,3-dihydroxypropyl illustrate the utility of the compounds. The amount of sterol deposited in the aorta of treated rabbits decreased by 40% in the aortic thoracic section and by 36% in the aortic abdominal section compared to the untreated control. The rate of atheroma lesions is expressed as a percentage of lesions in the aorta and decreased by 95% in the thoracic gland and 75% in the lower gonadal compared to untreated controls.

When a monkey is used as an animal model and is radiolabelled for analytical purposes with the propyl ester of 4- (n-hexadecylamino) -benzoic acid 2,3-dihydroxy182438, the compound is more readily absorbed from the corresponding acid disclosed in U.S. Patent 3,868,416. after oral administration. Decreasing serum lipid levels and reducing deposition on the aortic wall increases linearly with the degree of intestinal absorption. The concentration of radiolabelled drug in the bloodstream was four times as high for 3- (n-hexadecylamino) -benzoic acid 2,3-dihydroxypropyl ester than for the corresponding acid.

The clinically used daily dose of Colifibrate is 2 g and the effective dose in rats is 0.3% of the food. The compounds of the present invention exhibit comparable effects on lipid levels in rats at doses ranging from 0.1% to 0.01%. Therefore, dose ranges can vary from 50 mg to 1 g / day, in single or divided doses, and a 50 kg person is used as a model. An effective dose of the compounds is 0.5-40 mg / kg / day.

The lipid-lowering agents of the present invention may be administered orally, for example, with an inert carrier or an assimilable edible carrier, or may be encapsulated in hard or soft gelatin capsules, compressed into tablets or directly incorporated into a food. The active compounds of the present invention may be mixed with excipients and formulated as tablets, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like. can be used. The formulations contain at least 0.1% of the active ingredient. The percentage composition of the compositions may, of course, vary and is preferably in the range of from 5% to 75%. The pharmaceutically acceptable formulations contain an active ingredient such that a suitable dose is obtained. Preferred compositions according to the invention contain from 10 to 500 mg / kg of active ingredient in oral dosage units.

The tablets, lozenges, pills, capsules may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin, an excipient such as dicalcium phosphate, a disintegrant such as corn starch, starch, , a sweetening agent such as sucrose, lactose, saccharin or a flavoring agent such as marjoram, gaulteria oil or cherry flavor. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as fatty oil. Many other substances may be present, such as various coatings, and the physical form of the dosage unit may be modified, e.g., a tablet, pill or capsule may be coated with shellac, with a sugar craving for both. A syrup or elixir may contain, in addition to the active ingredient, a sweetening agent such as sucrose, methyl or propylparaben as a preservative, a dye or a flavoring agent such as cherry or orange. Of course, any material used in a unit dosage form should be pharmaceutically pure and non-toxic in the amounts used.

The active compounds may also be incorporated into sustained release formulations. These types of formulations require higher amounts of active ingredient.

The following examples illustrate the invention.

Example 1

4- (n-Hexadecilamiftö) benzoic acid 2,3-

dihydroxypropyl ester

A solution of 7.34 g of 4-n-hexadecylaminobenzoic acid, 4.80 g of 25% aqueous sodium hydroxide, 12.6 g of 3-iodo-1,2-propanediol in 50 ml of hexamethylphosphoramide is stirred for 24 hours at room temperature. The mixture was treated with water and extracted with ether. The dried extracts were evaporated to give 4- (n-hexadecylamino) -benzoic acid 2,3-dihydroxypropyl ester. Melting point: 112 ° C. Yield: 60%.

Example 2

4- (n-Hexadecilamino) -benzoic acid 2,3-dihydroxypropyl ester

A solution of 7.20 g of 4- (n-hexadecylamino) -benzoic acid in 25 ml of hexamethylphosphoramide is added to a stirred mixture of 0.8 g of sodium hydride in mineral oil 57% and 25 ml of hexamethylphosphoramide. After 1 hour, the solution was reacted with 11 g of 3-chloro-1,2-propanediol and stirred at 60 ° C for 18 hours. Dilute with water and filter to give a white product which, after recrystallization from elanol, gives 4- (n-hexadecylamino) -benzoic acid 2,3-dihydroxypropyl ester, m.p. 112-112 ° C. Yield: 64%.

Example 3

4- (n-Hexadecilamino) -benzoic acid 2,3-dihydroxypropyl ester

A solution of 7.35 g of 4- (n-hexadecylamino) -benzoic acid in 50 ml of hexamethylphosphoramide is treated with 4.8 g of 25% aqueous sodium hydroxide, then 1.0 g of 3-chloro-1,2-propanediol is added, followed by 140 ° C. Heat at C for 6 hours. The mixture was diluted with water and ether, filtered to give a white product. Recrystallization from acetonitrile followed by carbon tetrachloride gave 4- (n-hexadecylamino) -benzoic acid 2,3-dihydroxypropyl ester of analytical purity. Melting point: 112-113 ° C. Yield: 60%.

Example 4

4- (n-Hexadecilamino) -benzoic acid 2,3-dihydroxypropyl ester

A solution of 57.5 g of sodium salt of 4- (n-hexadecylanino) -benzoic acid and 55.0 g of 3-chloro-1,2-propanediol in 350 ml of hexamethylphosphoramide was reacted as in Example 3 to give 4- (n-hexadecylamino). Benzoic acid 2,3-dihydroxypropyl ester is obtained. Mp 112-113 ° C. Yield: 60%.

Example 5

-5182438

4- (n-Hexadecilamino) -benzoic acid 2,3-dihydroxypropyl ester

A mixture of 100 mg of 4- (n-hexadecylamino) -benzoic acid 2,3-epoxypropyl ester, 0.2 ml of 1 N sulfuric acid, 1.0 ml of 1,2-dimethoxyethane was heated at reflux for 1 hour, diluted with water, filtered and 4- (n-hexadecylamino) -benzoic acid 2,3-dihydroxypropyl ester as a white product. Melting point: 112 ° C.

Example 6

4- (n-Hexadecilamino) -benzoic acid 2,3-dihydroxypropyl ester

A mixture of 4- (n-hexadecylamino) -benzoic acid (722 mg), glycerol (736 mg) and p-toluenesulfonic acid (412 mg) was heated at 120 ° C for 4 hours, allowed to cool and treated with ether and 2% aqueous sodium carbonate. Filtration gave a white product which was recrystallized from chloroform to give 4- (n-hexadecylamino) -benzoic acid 2,3-dihydroxypropyl ester. Melting point: 112 'C.

Example 7

4- (n-Hexadecilamino) -benzoic acid 2,3-dihydroxypropyl ester

A solution of 4- (n-hexadecylamino) -benzoic acid (11.8 g), glycerol (1.00 g) and boron trifluoride etherate (5.35 ml) in toluene (200 ml) was stirred at reflux for 48 hours. The solution was treated with boron trifluoride etherate (5.35 mL) and heated at reflux for a further 120 hours. Diluted with water and methylene chloride then filtered to give 4- (n-hexadecylamino) -benzoic acid 2,3-dihydroxypropyl ester.

Example 8

4- (n-HexadeciIamino) -benzoic acid 2,3-dihydroxypropyl ester hydrochloride

A solution of 15.0 g of 4- (n-hexadecylamino) -benzoic acid 2,3-dihydroxypropyl ester in 700 ml of carbon tetrachloride was stirred under reflux and treated with anhydrous hydrogen chloride. The mixture was allowed to cool and filtered to give 4- (n-hexadecylamino) -benzoic acid 2,3-dihydroxypropyl ester hydrochloride as a white product. 126-130 ° C.

Example 9

4- (n-Hexadecilamino) -benzoate

A solution of 4- (n-hexadecylamino) -benzoic acid (50.5 g) in boron trifluoride etherate (34.4 ml) in methanol (200 ml) was stirred at reflux for 44 hours, allowed to cool and treated with ice-cold 5% aqueous sodium chloride (1.20 L). is poured into a carbonate solution. The white product is isolated by filtration, recrystallized from a mixture of benzene and ethanol to give 4- (n

yielding a hexadecylamino-benzoic acid methyl ester. Melting point: 92-93 ° C.

Example 10

4- (n-Hexadecilamino) -benzoic acid 2,3-epixopropilészter

A mixture of 89.0 g of epichlorohydrin, 92.0 g of 4- (n-hexadecylamino) -benzoic acid and 350 ml of hexamethylphosphoramide was stirred at 105 ° C for 5 hours, allowed to cool and poured into 1 liter of water. The white product was removed by filtration and recrystallized from aceto15 nitrile followed by hexane-methyl chloride to give 4- (n-hexadecylamino) -benzoic acid 2,3-epoxypropyl ester. Melting point: 86-89 ° C.

Example 11

4- (n-Hexadecilamino) -benzoic acid 2,3- (izorpopilidéndioxi) propyl ester

A mixture of 4- (n-hexadecylamino) -benzoic acid 2,3-dihydroxypropyl ester (8.70 g) in anhydrous hydrochloric acid (1.10 g), sodium sulfate (3.90 g) and acetone (550 ml) was stirred at reflux for 2 hours. Strain 30 while hot. The filtrate was cooled and the precipitate was collected by filtration. A mixture of the product, 200 ml of chloroform, 8.0 ml of methanol and 14 g of sodium carbonate is stirred for 18 hours and filtered. The filtrate was evaporated and the residual white product was recrystallized from isopropyl alcohol to give 4- (n-hexadecylamino) -benzoic acid 2,3- (isopropylenedioxy) propyl ester. Melting point: 87-88 'C.

Example 12

4- (n-HexíideciIamino) benzoic acid 2-acetoxy-3-hydroxypropyl ester

A mixture of 8.35 g of 4- (n-hexadecylamino) -benzoic acid 2,3-epoxypropyl ester and 7.0 ml of acetic acid was heated at 100 ° C for 4 hours, allowed to cool and diluted with water. Filtration gave 4 (n-hexadecylamino) -benzoic acid 2-acetoxy-350-hydroxypropyl ester. Melting point: 67 ° C, it does not change after recrystallization.

Example 13

4- (n-Hexadecilamino) -benzoic acid 4-hidroxibutilészter

7.66 g of sodium salt of 4- (n-hexadecylamino) -benzoic acid,

A mixture of 7.55 g of 4-chloro-1-butanol and 20.0 ml of hexamethylphosphoramide was stirred at 150 ° C for 2 hours, allowed to cool and then poured into water. The product was isolated by filtration and dissolved in methylene chloride. The solution was washed with water, dried and evaporated. The residue is crystallized from hexane xane to give 4- (n-hexadecylamino)

-6182438 yields 4-hydroxybutyl ester of zoic acid as a white product. M.p. 61-63 ° C. Yield: 35%.

Example 14

4- (n-Hexadecilamino) -benzoic acid 3-hidroxipropílészter

In the same manner as in Example 13, 3-bromopropanol is reacted with the sodium salt of 4- (n-hexadecylamino) -benzoic acid to give 4- (n-hexadecylamino) -benzoic acid 3-hydroxypropyl ester, m.p. 67-69 ° C (28%). .

Example 15 1,2,3-Tris (4-n-hexadecylamino-benzoyloxy) -propane

A mixture of 3.25 g of 4- (n-hexadecylamino) benzoic acid, 0.276 g of glycerol and 2.17 g of p-toluenesulfonic acid is heated at 140 ° C overnight with 20 ml of 10% sodium carbonate solution and 20 ml of chloroform. dilute the mixture. The organic layer was separated and evaporated to give a solid which was chromatographed on silica gel to give a white product. Recrystallization from a mixture of methylene chloride and hexane gave 1,2,3-tris- (4-n-hexadecylaminobenzoyl) -propane as a solid. Melting point: 117-118 ° C.

Example 16 1,2-Bis (4-n-hexadecylamino-benzoyloxy) -propan-3-ol and 1,3-bis (4-n-hexadecylamino-benzoyloxy) -propan-2-ol

4.34 g of 4- (n-hexadecylamino) -benzoic acid and 4.17 g of 2,3-epoxypropyl-4- (n-hexadecylamino) -benzoate were melted in a stream of nitrogen at 95-100 ° C and then at 115 ° C. Heat for 24 hours. The solution was then cooled, diluted with 50 cm ^{3 of} chloroform, and chromatographed on alumina with chloroform and ethanol. The white product obtained by evaporation of the eluates is recrystallized from acetonitrile and then from carbon tetrachloride.

1,2- and 1,3-bis (4-n-hexadecylamino-benzoyloxy) -isomers are obtained and the isomers are separated by thin layer chromatography. Melting point: 101-103 ° C.

Example 17

4- (n-Hexadecilamino) benzoic acid 2-hidroxipropilészter

7.2 g of 4-n-hexadecylaminobenzoic acid, 15.2 g of 1,2-dihydroxypropane, 3.9 ml of boron trifluoride etherate are stirred under nitrogen at 115 ° C for 19 hours. The solution was cooled, diluted with methylene chloride and placed in a refrigerator overnight. The product was isolated, washed with hexane and dried in a drying oven to give a white product. The products were recrystallized from hexane and crude chromatographed on chlorine oxide below with chloroform. This process provides 4- (n-hexadecylamino) -benzoic acid 2-hydroxypropro piles are obtained in the form of a white product. thaw mp 91-93 ° C.

The same product is obtained when 5.16 g of p-toluenesulfonic acid is used as a catalyst instead of boron trifluoride etherate.

Example 18

4- (n-HexadeciIamino) -benzoic acid 2,3-dihidroxipropilészter

3.8 g of sodium salt of 4- (n-hexadecylamino) -benzoic acid,

A solution of 3.7 g of epichlorohydrin and 0.7 ml of water in hexamethylphosphoramide was heated to 90 ° C for 5 hours. An additional 0.7 mL of water was added followed by 1 mL of 1 N sulfuric acid. After 1.5 hours, the reaction mixture was cooled. Dimethoxyethane and benzene are added and the organic layer is separated and washed with water. The solvent was removed in vacuo to give a white product which was recrystallized from acetonitrile (15 mL) to give 4- (n-hexadecylamino) -benzoic acid 2,3-dihydroxypropyl ester. If this material contains all 4- (n-hexadecylammo) -benzoic acid 2,3-epoxypropyl ester intermediates, it can be removed by silica gel chromatography.

Example 19

4- (n-Hexadecilamino) -benzoic acid 2,3-dihidroxipropilészter

A solution of 3.6 g of 4- (n-hexadecylamino) benzoic acid and 1.0 g of 2,3-epoxypropan-1-ol in 100 ml of hexamethylphosphoramide was heated at 90 ° C for 8 hours. Ether and water were added, the ether layer was separated, and the ether extraction was repeated several times. The ethereal extracts were evaporated and the mixture of starting material and 2,3-dihydroxypropyl ester separated by chromatography on silica gel and recrystallization from acetonitrile. M.p. 112 ° C.

Example 20

4- (n-Hexadecilamino) benzoic acid (2,3-dihydroxy-l-hydroxymethyl) propyl ester

A mixture of 4- (n-hexadecylamino) -benzoic acid (3.62 g), mesoerythritol (4.88 g), p-toluenesulfonic acid (7.60 g), toluene (100 mL) was heated under reflux for 3 days and the resulting water was collected in a Dean-Stark condenser. The mixture was partitioned between aqueous sodium carbonate solution and dimethoxyethane. The organic layer was separated, dried over anhydrous magnesium sulfate and evaporated. Recrystallization from chloroform gives 4- (n-hexadecylamino) -benzoic acid (2,3-dihydroxy-1-hydroxymethyl) -propyl ester. Melting point: 123-125 ° C.

Example 21

2-Phenyl-1,3-dioxolan-4-ylmethyl-4- (n-hexadecilamino) benzoate

-7182438

A solution of 8.7 g of 4- (n-hexadecylamino) -benzoic acid 2,3-dihydroxypropyl ester and 21.2 g of benzaldehyde in 100 ml of toluene, containing 1.1 g of hydrochloric acid gas, was heated under reflux for 3.5 hours and then cool to room temperature. Concentrate in vacuo to about 20 mL and dilute with 50 mL hexane, cool the mixture in an ice-ethanol bath and filter. The resulting product was chromatographed on silica gel and recrystallized from dichloromethane-hexane to give the title compound. Melting point: 74.5-76.5 ° C.

Example 22

4- (n-Hexadecilamino) benzoic acid 2-propenilésztre

7.66 g of 4- (n-hexadecylamino) -benzoic acid sodium salt and

A solution of 12.1 g of allyl bromide in 100 ml of dry hexamethylphosphoramide is added to a flask. After 6 hours, the solution was poured into 100 mL of water and the product was collected and recrystallized from 50 mL of acetonitrile. The material was recrystallized from hexanol to give the title compound. Melting point: 81-83 ° C. Yield: 43%.

Example 23

4- (n-Hexadecilamino) -benzoic acid 2,3-diacetoxipropilészter

To a solution of 4.21 g of mineral oil liberated from mineral oil is added 21.7 g of a solution of 4- (n-hexadecylamino) -benzoic acid 2,3-dihydroxypropyl ester in 150 ml of hexamethylphosphoramide. After the evolution of hydrogen ceases, 94 ml of acetic anhydride are added. After stirring for 18 hours, the reaction mixture is treated with water and the product is extracted with ethyl acetate. After chromatography, the product is recrystallized from a mixture of methylene chloride and hexane and melted at 68 ° C.

Claims (2)

Patent claims A process for the preparation of compounds of formula I and pharmaceutically acceptable acid addition salts thereof, wherein R ₄ is a straight chain alkyl of 14 to 19 carbon atoms, R 1 is hydrogen or C 1-3 hydroxyalkylene, R ₃ is hydrogen or C 1-3 hydroxyalkylene, X is hydrogen, hydroxy, lower alkanoyl, 4- (C 14 -C 19) alkylaminobenzoyloxy, Y is hydrogen, hydroxy, lower alkanoyl, 4- (C 14 -C 19) alkylaminobenzoyloxy, or X and Y together form a bond or form an epoxy ring with the alkylene group or -OCRR- wherein R is hydrogen or C 1-3 alkyl, R 1 is C 1-3 alkyl or phenyl and one of R 1, R ₃ , X and Y is other than hydrogen, characterized in that (a) for the preparation of compounds of formula I wherein R 1 and R ₃ are hydrogen, or C 1-3 hydroxyalkylene and R ₄ are as defined above, and X and Y are hydroxy, together form a bond or form an epoxy ring together with the alkylene chain; a compound of formula II wherein: R is halogen, Rj is hydrogen or hydroxyalkylene having from 1 to 3 carbon atoms, Rj is hydrogen or hydroxyalkylene having from 1 to 3 carbon atoms, X and Y are hydroxy or hydrogen and one of R 1, R 1, X and Y is different from hydrogen or X and Y together form a bond or form an epoxy ring with an alkylene chain - VI 4- (hay omos 14-19) -alkilaminobenzoesavval or alkali metal salts thereof - wherein R ₄ is as defined above - is reacted with C in an aqueous or nonaqueous solvent or 20-160 ° b) compounds of formula of I - wherein X and / or Y is hydroxy and R, Rjjelentése C1-3 hydroxyalkylene group or hydrogen and R ₄ is as defined above - for the preparation of a Compound IV of the formula - in which R _t, R ₃ and X and Y is reacted with 4- (C 14 -C 19) -alkylaminobenzoic acid of formula VI where R ₄ is as defined above, in the presence of an acid catalyst, preferably p-toluenesulfonic acid or Lewis acid, and optionally treated with ether and sodium carbonate solution or c) for the preparation of a compound of formula I wherein X and Y are 4- (C 14 -C 19) alkylaminobenzoyloxy and R 1, R ₃ are hydrogen and R ₄ is as defined above, a compound of formula IV where R, , R ₃ , X and Y are reacted with 4- (C 14 -C 19) -alkylaminobenzoic acid of formula VI where R ₄ is as defined above, in the presence of an acid catalyst, preferably p-toluenesulfonic acid, followed by chloroform and sodium. treated with carbonate solution, or d) for the preparation of compounds of formula I wherein X and Y are hydroxy and R 1, R ₃ are hydrogen, and R ₄ is an epoxide of general formula III as above, wherein R _p R ₃ is hydrogen and Y is chlorine; or hydroxy group with 1-alkyl 4-alkylaminobenzoic acid of formula VI where R ₄ is as defined above or an alkali metal salt thereof at 20-160 ° C and optionally i) compounds of the formula I in which X and / or Y is a C 1-4 alkanoyloxy group, a hydroxy group or a 4- (C 14 -C 19 alkylaminobenzoyloxy) group and R _{1 (} R ₃ is a hydrogen atom and R _{4 is} as defined above); preparing something) -X and / or wherein A is or X and Y, Y is hydroxy I containing an epoxy group the compound of formula - wherein R, R ₃ is hydrogen and R ₄ is as defined above - from 60 to 120 ° C is acetylated or ii) the I Compounds of Formula (I) wherein X and Y are cyclic groups -O-CRR'-O- wherein R is hydrogen or (C 1 -C 3) alkyl and R 'is (C 1 -C 3) alkyl or phenyl and R 1, R ₃ is hydrogen and R ₄ is as defined above, for the preparation of any one of -8182438 Reacting a compound of formula I wherein X and Y are hydroxy, wherein R ₍ , R ₃ and R ₄₎ are aldehyde or ketone of formula R R 'C = O, wherein R and R' are as defined above; or iii. ) compounds of formula I wherein X and Y are hydroxy and R 1, R ₃ is hydrogen and R ₄ is as defined above, a compound of formula I wherein X and Y are epoxy, wherein R _p R ₃ is hydrogen and R ₄ is above - hydrolyzed in the presence of an acid catalyst, iv) a compound of formula I R ₁ , R ₃ , R ₄ , X and Y are as above converted to the acid addition salt. 2. A process for the preparation of a medicament for lowering serum lipid levels and lowering lipids in the aorta of warmth, characterized in that a compound of the formula I as claimed in claim 1, wherein R ₄ , X, Y, R _t and R ₃ are as an active ingredient as defined in claim 1, in admixture with conventional pharmaceutically acceptable carriers and / or excipients and converting it to a pharmaceutical composition. 2 sheets with formula