CA1094057A - Polysubstituted esters of 4-alkylaminobenzoic acids - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Polysubstituted-alkyl esters of 4-alkylaminobenzoic acids having hypolipemic activity.

Description

- 10~40~7 BACKGROUND OF THE INVENTIO
The compounds of this invention are new and novel esters of the 4-alkylaminobenzoic acids described in U. S.
Patent No. 3,868,416 and have superior, biological and pharma-cological properties. No hypolipemic activity has been re-ported in the literature for these compounds and they are different in structure and superior in action to other hypo-lipemic agents. The compounds of this invention lower serum-- -lipid concentrations and also decrease the deposition of lipids in the aorta. Esters such as these of glycerol and the like are designated to facilitate the intestinal absorp-tive process and to provide a reliable and high degree of ab-sorption following the oral administration required of hypo-lipidemic agents. To the extent that these esters are hydro-lyzed in the body they have the added advantage, relative to other esters, of producing a hydroxylated compound which is innocuous and is in fact a natural component of mammalian physiological processes. The novel esters of this invention are more completely and more uniformly absorbed from the gas-trointestinal tract than the carboxylic acids and other esters.
Also they cause less gastrointestinal irritation than the cor-responding carboxylic acids.
DESCRIPTION OF THE INVENTION
This invention relates to new organic compounds and more particularly it is concerned with novel polysubstituted--alkyl esters of 4-alkylaminobenzoic acids which may be repre-sented by the following formula:

H O X Y
I ~ 11 1 1 R4-N ~ C-O-C~-C-CH-R3 Rl R2 `` 1~940~7 wherein R4 is an unbranched or branched alkyl group C H2n~l wherein n is 8 to 19; Rl, R2 and R3 are selected from the group consisting of hydrogen, Cl-C3 alkyl, Cl-C3 hydroxyalkylene, and Cl-C3 hydroxyalkylenecarboxaldehyde in which case a tetrahydrofuran or pyran ring is formed when X is OH, and R2 or R3 combined with the appropriate X or Y may constitute a double-bonded oxygen atom; X and Y, which may be the same or different, are selected from the group consisting of hydrogen, hydroxy, loweralkanoyloxy, 4-alkylaminobenzoyloxy, hydroxymethyl, and, when taken together X and Y can comprise a carbon-carbon bond, a cyclic ether linkage (-0-), or a cyclic acetal or ketal (-0-CRR'-0-with R and R' being selected from the group consisting of hydrogen, loweralkyl and phenyl); wherein the alkylaminobenzoyloxy moiety and X may be inter-changed; with the proviso that when Rl, R2 and R3 are all hydrogen or C1-C3 alkyl, then X and Y may not both be hydrogen; and the pharmaceutically acceptable salts thereof.
A preferred embodiment of this invention consists of those compounds wherein R4 is an unbranched or branched alkyl group, C H2n+l wherein n is 8 to 19; Rl is hydrogen; R2 and R3 are both hydrogen, or one of them combined with the appropriate X or Y constitutes a double-bonded oxygen atom; X and Y, which may be the same or different, are selected from the group consisting of hydroxy or lower alkanoyloxy, and, when taken together X and Y can comprise a carbon-carbon bond, a cyclic ether linkage (-0-), or a cyclic acetal or ketal (-0-CRR'-0- with R and R' selected from the group consisting of hydrogen, Cl-C3 alkyl and phenyl); wherein the 4-alkylaminobenzoyloxy moiety and X may be interchanged; and the pharmaceutically acceptable salts thereof.
The invention contemplates a method for lowering serum lipids and for decreasing aortic deposition of lipids in mammals by the administration of said esters.
The novel compounds of this invention are, in general, colorless crystalline solids having characteristic melt-C

-2-10940.~7 ing points and spectral properties. They are soluble in or-ganic solvents such as chloroform, benzene, dichloromethane, acetonitrile, dimethylformamide, dimethylsulfoxide and lower alkanols. They are generally insoluble in water. These com-pounds are bases which form pharmaceutically acceptable salts with acids such as sulfuric, hydrochloric, phosphoric, suc-cinic, citric and the like.
Suitable ester moieties contemplated by the present invention are glycerol, 2,3-epoxy-1-propanol (glycidol), 1,3-and 1,2-propanediol, 02-acetylglycerol, 02,03-diacetylglycerol, 03-(4-alkylaminobenzoyl)~lycerol, erythritol, 1,2,3,5-tetra-hydroxypentane, pentaerythritol, ribose, glucose, glyceraldehyde dihydroxyacetone, mannitol, sorbitol, 1,4-butanediol, 2,3-iso-propylideneglycerol, 2,3-benzylideneglycerol, allyl alcohol, 1,4-butenediol and the like.
Suitable alkyl groups contemplated by the present invention are n-hexadecyl, n-pentadecyl, n-heptadecyl, 2-tri-decyl and the like. The N-loweralkanoyl derivatives of I are active to the extent that they are deacylated in vivo to com-pounds of structure I.
These novel polysubstituted-alkyl 4-alkylaminoben-zoates are prepared by reaction of sodium or other salts of the 4-alkylaminobenzoic acids with the appropriate polysub-stituted-alkyl halides, sulfates, tosylates, trifluoromethyl sulfonates, or the like (II) in aqueous or anhydrous hexa-methylphosphoramide, dimethylformamide, acetonitrile or other suitable solvents at 20-160C. The salts may ~e formed ln situ from the 4-alkylaminobenzoic acids and the appropriate bases.
X Y
Z-C~-C-C~-R3 Rl R2 where Z = the leaving groups II mentioned above 10!34057 o Y
/\ I

Rl R2 III

A similar and chemically related method of preparation is the reaction of the 4-alkylaminobenzoic acids or certain of their salts with substituted-alkylene oxides (III) at 20-160C.
The polysubstituted-alkyl 4-alkylaminobenzoates of the present invention are also synthesized by reaction of the polysubstituted-alkyl alcohols (IV) X Y
Ho-cH-c-cH-R3 Rl R2 IV
with the 4-alkylaminobenzoyl chloride hydrochlorides in the presence of bases, or alternatively, with the 4-alkylamino-benzoic acids using acid catalysis with toluenesulfonic acid and the like or with Lewis acid catalysts. The polysubstituted--alkyl esters are also prepared by transesterification of methyl or ethyl 4-alkylaminobenzoates with polysubstituted-alkyl alcohols (IV) using acidic or basic catalysis.
Certain syntheses of these polysubstituted-alkyl 4-alkylaminobenzoates may also involve the formation of the de-sired X and Y groups as the final step in the process. For ex-- ample, when X and/or Y are alkanoyloxy or 4-alkylaminobenzoyloxy in the desired structure (I), these moieties are produced by acylation of the corresponding compounds in which X and/or Y are hydroxy groups or taken together represent an epoxy group.

Similarly, when X and Y taken together form a cyclic acetal or ketal moiety in the desired structure (I), such a moiety is produced by acid-catalyzed reaction of structure (I) (where X
and Y are both hydroxy) with an aldehyde or ketone. The reverse lQ94057 reaction in certain cases is also used to form the dihydroxy compounds of structure (I) from acetal or ketal derivatives.
When X and/or Y are halogen groups in structure (I) the corre-sponding hydroxy compounds are obtained by treatment with silver nitrite followed by mild hydrolysis. Dihydroxy compounds of structure (I) are also obtained by gentle acid-catalyzed hydro-lytic opening of the epoxide ring in epoxyalkyl 4-alkylaminoben-zoates. Similar dihydroxy compounds of structure (I) result from dihydroxylation of alkenyl 4-alkylaminobenzoates.
The novel 4-alkylaminobenzoate esters of the ~resent invention are prepared by reaction of polysubstituted-alkyl 4--aminobenzoates with suitable alkylating agents such as alkyl halides, sulfates, tosylates, or trifluoromethylsulfonates with or without solvent at 50 to 150C. Suitable solvents are lower alkanols, chloroform, N,N-dimethylformamide, N,N-dimeth-ylacetamide hexamethylphosphoramide, diglyme, dimethyl sulfoxide, acetonitrile, toluene benzene and the like. The reaction may be carried out with an equivalent of the 4-aminobenzoate ester in excess, using it as the base, or with an equivalent of an-other base such as an alkali carbonate or bicarbonate, or witha catalytic amount of copper powder when alkali halides are used as the alkylating agent. Alternatively, the desired 4--alkylaminobenzoate esters are prepared by reaction of the corresponding 4-aminobenzoate ester with an alkyl halide of 8 to 19 carbon atoms in the presence of an equivalent of sodium hydride in an inert solvent such as N,N-dimethylformamide, N,N--dimethylacetamide and diglyme at 50-150C. The introduction of the N--alkyl group in structure (I) is also accomplished by catalytic reductive alkylation of polysubstituted-alkyl esters of 4-aminobenzoic acid or of 4-nitrobenzoic acid with the appro-priate aliphatic aldehyde or ketone. It may also be introduced by copper chromite-catalyzed reduction of polysubstituted--alkyl 4-alkanoylaminobenzoates.

10~4057 We have now found that certain members of this class can safely and effectively lower serum sterols, and triglycer-ides in warm-blooded animals. These hypolipidemic properties would be expected to be useful in the treatment of atherosclero-sis. Atherosclerosis is a form of arteriosclerosis where chol-esterol and lipoid materials are deposited as plaques in the intima of large and medium-sized arteries. Arteriosclerosis is associated with the degeneration of arterial walls by mechanisms not clearly defined. However, there is a statistical correla-tion between hypercholesteremia and the incidence of cardio-vascular disease, particularly ischemic heart disease. For some time it has been considered desirable to lower high cholesterol, triglyceride, and phospholipid levels in mammals as a possible preventive measure against atherosclerosis. In the past, attempts have been made to lower the levels of cholesterol in the blood by the oral feeding of various substances which have been generally referred to in the art as hypocholesteremic ad-juvants. Typical of such substances are lecithin, cottonseed oil and corn oil. In addition, three synthetic lipid-lowering agents are available, namely, clofibrate, D-thyroxine, and nico-tinic acid [R. I. Levy and D. S. Frederickson, Postgraduate Medicine Vol. 47, pages 130-136 (1970)]. The compounds of the present invention exert a more powerful hypocholesteremic action than the aforementioned adjuvants and synthetic drugs. In addi-tion, these compounds have the ability to arrest safely andeffectively the development of atheromatous lesions in the aorta of warm-blooded animals, thereby possessing an important addi-tional way of combatin~ atherosclerosis. It is not known how the novel compounds or method of treatment of the present in-vention operate in blood serum and no theory of why these com-pounds so operate is advanced. It is not intended that the pre-sent invention should be limited to any particular mechanism of their action.

1~940S7 The compounds of the present invention are hypolipi-demic agents and were shown to possess hypolipidemic activity as determined by animal experiments as follows: the compounds studied were administered orally admixed with the diet to groups of 4 male rats, CFE strain from Carworth Farms. A con-trol group of 8 rats was maintained on the diet alone; test groups were maintained on the diet plus the indicated percent-age of compound by weight. After 6 days or 4 weeks the animals were sacrificed and serum-sterol concentrations in milligrams per 100 milliliters were determined either (1) according to the saponification and extraction method of P. Trinder, Anal-yst 77, 321 (1952) and the colorimetric determination of Zlat-kis, et al., J. Lab. Clin. Med. 44, 486 (1953) or (2) by the extraction method of H. H. Leffler, Amer. J. Clin. Path. 31, 310 (1959), and the colorimetric determination of Zlatkis (vide supra), the overall method appropriately modified for use with an automatic mechanical analyzer. Serum triglycerides were estimated by the automated procedure of Kessler and Lederer ("Automation in Analytical Chemistry" Skeggs, L. T.
(Ed.), Mediad Inc., New York, 1965, p 341).
In these tests, a compound is considered to have hypolipidemic activity if it depresses the serum-sterol concen-tration below that of the controls, and/or depresses triglycer-ide concentration below that of the controls. Table I shows several of the compounds of the present invention and the de-gree to which they depress serum sterols and triglycerides after a 6-day dosing period and after a 4-week dosing period.

-- 10~4057 h ~ ~ I`U~
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t: ,.C r~t-l 11) p~,_ ~ ~;5 d> C~ ~ O ~ ~O O
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_ 9 _ . .i For the mouse study, CFE mice from the Roscoe B.
Jackson Memorial Laboratories, Bar Harbor, Maine were used.
The methods used for lipid analysis were the same as those used for the rat study. The results obtained on using 2,3-dihydroxypropyl 4-(n-hexadecylamino)benzoate are shown in Table II.

N I ~
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Compounds of this invention demonstrated the ability to arrest the development of atheromatous lesions using rab-bits as an animal model. Thus they combat atherosclerosis by means of this ability as well as by means of their ability to lower serum-lipid concentrations. The atheromatous lesions were induced by mild mechanical injury of the surface of the aorta of rabbits. After feeding a cholesterol-supplemented diet followed by diet containing these compounds, histologi-cal and biochemical analyses of the aortic tissue and measure-ment of the extent and severity of the lesions were carried out. The results with 2,3-dihydro-xypropyl 4-(n-hexadecylamino)-benzoate illustrate the beneficial effect of these compounds.
The amount of sterol deposited in the aorta of treated rabbits was reduced by 40% in the thoracic segment and by 36% in the abdominal segment of the aorta compared to the untreated con-trols. The extent of formation of atheromatous lesions, mea-sured by the percentage of the aorta having such lesions, was reduced by 95% in the thoracic segment and by 75% in the ab-- dominal segment, compared to the untreated controls.
By using the monkey as an animal model and radio-labeling for analytical purposes, the 2,3-dihydroxypropyl 4--(n-hexadecylamino)benzoate was shown to be much better ab-sorbed than the corresponding acid of U.S. Patent 3,868,416 after the oral dosing required of a hypolipidemic agent. The ability to lower serum lipids and to decrease deposition of lipids on the aortic walls is directly increased in proportion to the degree of absorption from the intestine. The concen-- tration of radiolabeled drug in the bloodstream was found to be 4 times as high with 2,3-dihydroxypropyl 3~ hexadecyl-amino)ben~oate a~ with the corresponding acid.

~0940S7 The clinically used dose of clofibrate is 2 g/day and its effective dose in rats is 0.3% of diet. The compounds of this invention show a comparable effect on serum lipids in rats at doses of only 0.1% to 0.01%. Therefore, the range of doses should be between about 50 mg to 1 g/day in single or divided doses using a 50 kg human as a model. The effective range of the compounds described in this invention would be between about 0.5 and 40 mg/kg/day.
The lipid-lowering agents of the present invention may be orally administered, for example, with an inert dilu-ent or-with an assimilable edible carrier, or they may be enclosed in hard or soft gelatin capsules, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet. For oral therapeutic administra-tion, the active compounds of this invention may be incorpor-ated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gum, and the like. Such compositions an~ preparations should con-tain at least 0.1% of active compound. The percentage in the compositions and preparations may, of course, be varied and may conveniently be between about 5% to about 75~ or more of the weight of the unit. The amount of active compound in such therapeutically useful compositions or preparations is such that a suitable dosage will be obtained. Preferred com-positions or preparations according to the present inventionare prepared so that an oral dosage unit form contains between about 10 and 500 milligrams of active compound.
The tablets, troches, pills, capsules and the like may also contain the following: a binder such as gum traga-canth, acacia, corn starch or gelatin; an excipient such asdicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring. When the dosage unit form is a capsule, it may contain in addition to materials of the above type a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit, for instance, tablets, pills or capsules may be coated with shellac, sugar, or both. A syrup or elixir may contain the active compounds, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such - as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non toxic in the amounts employed.
In addition, the active ingredients may be incorpo-rated into sustained release preparations. Preparations of this type would contain greater quantities of the active in-gredients.
Example 1 2,3-Dihydroxypropyl 4-(n-hexadecylamino)benzoate A solution of 7.34 g of 4-(n-hexadecylamino)benzoic acid, 4.80 g of 25~ aqueous sodium hydroxide, and 12.6 g of

3-iodo-1,2-propanediol in 50 ml of hexamethylphosphoramide is stirred for 24 hours at ambient temperature, diluted with - 100 ml of ether and stirred for 5 days at ambient temperature.
The mixture is treated with water and extracted with ether.
The dried extracts are evaporated to yield 2,3-dihydroxypropyl

4-(n-hexadecylamino)benzoate, m.p. 112C.
Example 2 2,3-Dihydroxypropyl 4-(n-hexadecylamino)benzoate A solution of 7.20 g of 4-(_-hexadecylamino)benzoic acid in 25 ml of hexamethylphosphoramide is added to a stir-red mixture of 0.800 g of sodium hydride (57~ in mineral oil) and 25 ml of hexame~hylphosphoramide. The solution which 109~057 forms after one hour is treated with 11.0 g of 1-chloro-2,3-propanediol and is then stirred at 60C for 18 hours. Dilu-tion with water followed by filtration affords a white solid which is crystallized from ethanol to yield 2,3-dihydroxy-propyl 4-(n-hexadecylamino)benzoate melting at 112-113C.
Example 3 2,3-Dihydroxypropyl 4-(n-hexadecylamino)benzoate A solution of 7.35 g of 4-(n-hexadecylamino)benzoic acid in 50 ml of hexamethylphosphoramide is treated with 4.80 g of 25% aqueous sodium hydroxide followed by 11.0 g of 3-chloro-1,2-propanediol and then is heated at 140C for 6 hours. The mixture is diluted with water and ether and fil-tered to yield a white solid. Recrystallization from aceto-nitrile and then from carbon tetrachloride affords analytically pure 2,3-dihydroxypropyl 4-(n-hexadecylamino)benzoate, mp 112-113C.
Example 4 2,3-Dihydroxypropyl 4-(_-hexadecylamino)benzoate A solution of 57.5 g of sodium 4-(n-hexadecylamino)-benzoate and 55.0 g of 3-chloro-1,2-propanediol in 350 ml of hexamethylphosphoramide is treated in the manner described in Example 3 to yield 2,3-dihydroxypropyl 4-(n-hexadecylamino)-benzoate melting at 112-113C.
Example 5 2,3-Dihydroxypropyl 4-(n-hexadecylamlno)benzoate A mixture of 100 mg of 2,3-epoxypropyl 4-(n-hexa-decylamino)benzoate, 0.2 ml of lN sulfuric acid, and 1.0 ml of 1,2-dimethoxyethane is heated under reflux for one hour, diluted with water, and filtered to yield 2,3-dihydroxypropyl 4-(n-hexadecylamino)benzoate as a white solid, mp 112C.

Example 6 2,3-Dihydroxypropyl 4-(n-hexadec_ mino)benzoate A mixture of 2.25 g of methyl 4-(_-hexadecylamino)-benzoate, 280 mg of glycerol, and 1.37 g of p-toluenesulfonic acid is heated at 180C for 18 hours and then is partitioned between ether and 3~ aqueous sodium carbonate solution. The ether layer is separated, dried, and evaporated to yield 2,3--dihydroxypropyl 4-(n-hexadecylamino)benzoate.
Example 7 2,3-Dihydroxypropyl 4-(n-hexadecylamino)benzoate A mixture of 722 mg of 4-(n-hexadecylamino)benzoic acid, 736 mg of glycerol, and 412 mg of p-toluene sulfonic acid is heated for 4 hours at 120C, allowed to cool, and then is treated with ether and 2% aqueous sodium carbonate solu-1~ tion. Filtration affords a white solid which is recrystal-lized from chloroform to yield 2,3-dihydroxypro~yl 4-(n-hexadecylamino)benzoate, mp 112C.
Example 8 2,3-Dihydroxypropyl 4-(_-hexadecylamino)benzoate A solution of 11.8 g of 4-(n-hexadecylamino)benzoic acid, 1.00 g of glycerol, and 5.35 ml of boron trifluoride etherate in 200 ml of toluene is stirred under reflux for 48 hours. The solution is treated with an additional 5.35 ml of boron trifluoride etherate and refluxing is continued for 120 hours. Dilution with water and methylene chloride followed by filtration affords 2,3-dihydroxypropyl 4-~n-hexadecylamino)-benzoate as a white solid.
Example 9 2,3-Dihydroxypropyl 4-(n-hexadecylamino)benzoate ~drochloride ~ solution of 15.0 C3 of 2,3-dihydroxypropyl 4-(n-hexadecylamino)bellzoate in 700 ml of carbon tetrachloride is stirred under reflux and is treated with anhydrous hydrogen - ~6 -1t)940S7 chloride. The mixture is allowed to cool and is filtered to yield 2,3-dihydroxypropyl 4-(n-hexadecylamino)benzoate hydrochloride as a white solid, mp 126-130C.
Example 10 2,3-Epoxypropyl 4-(n-hexadecylamino)benzoate A mixture of 89.0 g of epichlorohydrin, 9~.0 g of sodium 4-(n-hexadecylamino)benzoate, and 350 ml of hexamethylphosphoramide is stirred at 105 C for 5 hours, allowed to cool, and poured into 1.0 liter of water. The white solid is collected by filtration, recrystallized from acetonitrile and then from hexane-methylene chloride to yield 2,3-epoxypropyl 4-(n-hexa-decylamino)benzoate, mp 86-89C.
Example 11 2,3-(Isopropylidenedioxy)propyl 4-(n-hexadecylamino)benzoate A mixture of 8.70 g of 2,3-dihydroxypropyl 4-(_-hexadecylamino) benzoate, 1.10 g of anhydrous hydrogen chloride, 3.90 g of sodium sulfate, and 550 ml of acetone is stirred under reflux for 2 hours and then filtered while hot. The filtrate is cooled and the precipitate collected by filtration.
A mixture of the solid, 200 ml of chloroform, 8.0 ml of methanol, and 14 g of sodium carbonate is stirred for 18 hours and filtered. The filtrate is evaporated and the residual white solid recrystallized from isopropyl alcohol to yield 2,3-~isopropylidenedioxy)propyl 4-(n-hexadecylamino)-benzoate, mp 87-88C.
Example 12 2-Acetoxy-3-hydroxypropyl 4-(n-hexadecylamino~benzoate A mixture of 8.35 g of 2,3-epoxypropyl 4-(n-hexa-decylamino)benzoate and 7.0 ml of acetic acid is heated at 100C for four hours, allowed to cool, and diluted with water.
Filtration affords 2-acetoxy-3-hydroxypropyl 4-(n-hexadecyl-amino)benzoate, mp 67C unchanged by recrystallization.
Example 13 2,3-Diacetoxypropyl N-acetyl-4-(_-hexadecylamino)benzoate A solution of 6.53 g of 2,3-dihydroxypropyl 4-(n-hexadecylamino)benzoate in 100 ml of chloroform is stirred under reflux while 9.0 ml of acetic anhdyride is added and for 6 hours thereafter. The solution is extracted with 2% aqueous lS sodium carbonate solution and water, dried, and evaporated to yield 2,3-diacetoxypropyl N-acetyl-4-(n-hexadecylamino)benzo-ate as a yellow oil.
Example 14 4-(n-Hexadecylamino)benzoic acid hydrochloride A solution of 2.00 g of 4-(n-hexadecylamino)benzoic acid in 8~ ml of methylene chloride is stirred at 35C and treated with anhydrous hydrogen chloride. The resulting mix-ture is chilled and filtered to yield 4-(n-hexadecylamino)-benzoic acid hydrochloride as a white solid.
Example lS
4-(~ exadecylamino)benzoyl chloride hydrochloride A mixture of 1.00 g of 4-(n-hexadecylamino)benzoic ,acid hydrochloride and S.00 ml of thionyl chloride is allowed to stand at ambient temperature for 20 hours and then is con-centrated ln v~cuo to yield 4-(n-hexadecylamino)benzoyl chloride hydrochloride as an orange solid.

0940s7 _ f Example 16 2-Phenyl-1,3-dioxan-5-yl 4-(n-hexadecylamino)benzoate A solution of 450 mg of 1,3-benzylideneglycerol and 1.22 g. of 4-dimethylaminopyridine in 10 ml. of methylene chloride is treated with 1.16 g. of 4-(n-hexadecylamino)benzoyl chloride hydrochloride and after 15 minutes the solution is washed with water, dried over anhydrous magnesium sulfate, and evaporated. The 2-phenyl-1,3-dioxan-S-yl 4-(n-hexadecylamino)-benzoate, mp 115-117C., is separated from the residue by chromatography using silica gel as the adsorbant.
Example 17 ; 1,3-Dihydroxy-2-propyl 4-(n-hexadecylamino)benzoate A mixture of 2-phenyl-1,3-dioxan-5-yl 4-(n-hexa--; decylamino)benzoate, palladium black, and acetic acid is shaken :
under one atmosphere of hydrogen until hydrogen uptake ceases.
The catalyst is separated by filtration and the solvent is - evaporated. Crystallization from acetonitrile affords 1,3--dihydroxy-2-propyl 4-(n-hexadecylamino)benzoate as a white solid.
Example 18 4-Hydroxybutyl 4-(n-hexadecylamino)benzoate ` A mixture of 7.66 g of sodium 4-(n-hexadecylamino)-benzoate, 7.55 g of 4-chloro-1-butanol, and 20.0 ml of hexa-methylphosphoramide is stirred at 150C for two hours, allowed to cool, and poured into water. The solid is collected by filtration and then is dissolved in methylene chloride. The solution is washed with water, dried, and evaporated. The residual solid is crystallized from hexane to yield 4-hydroxy-- butyl 4-(n-hexadecylamino)benzoate as a white solid, mp 61-63C.
Example 19 3-l3ydroxypropyl 4-(n-hexadecylamino)benzoate In the manner described in Example 15, treatment ,~,..

10!~4057 of 3-bromopropanol with sodium 4-(n-hexadecylamino)benzoate affords 3-hydroxypropyl 4-(n-hexadecylamino)benzoate, mp 67-Example ~-0 1,2,3-Tris(4-_-hexadecylaminobenzoyloxy)propane A mixture of 3.25 g. of 4-(n-hexadecylamino)benzoic acid, 0.276 g. of glycerine, and 2.17 g. of p-toluenesulfonic acid is heated to 140C. overnight and then diluted with 20 ml. of 10~ sodium carbonate solution and 20 ml. of chloroform.
Separation of the organic layer and concentration yields a solid which is chromatographed on silica gel, which in turn yields a white solid. Crystallization from a mixture of methylene chloride and hexane yields l,2,3-tris(4-n-hexadecyl-aminobenzoyloxy)propane as a solid, m.p. 117-118C.
Example 21 1,2-Bis(4-n-hexadecylaminobenzoyloxy)propan-3-ol and 1,3-bis-(4-n-hexadecylaminobenzoyloxy)propan-2-ol A mixture of 4.34 g. of 4-(n-hexadecylamino)benzoic acid and 4.17 g. of 2,3-epoxypropyl-4-(n-hexadecylamino)benzo-ate is melted, under nitrogen, at 95-100C. and then heated at 115C. for 24 hours. The solution is then cooled, diluted with 50 cc. of chloroform, and chromatographed on alumina with chloroform and ethanol. The white solid from the evaporation of the eluates is recrystallized from acetonitrile and then from carbon tetrachloride. The 1,2- and 1,3-bis(4-n-hexadecyl-aminobenzoyloxy)isomers are separated by preparative thin-layer chromatography, m.p. 101-103C.
Example 22 2-~lydroxypropyl 4-(n-hexadecylamino)benzoate A solution of 7.2 g. of 4-n-hexadecylaminobenzoic acid, 15.2 g. of 1,2-dihydxoxypropane, and 3.9 ml. of boron trifluoride etherate are stirred together, under nitrogen, at 115C. for 19 hours. The solution is cooled, diluted with . ~

(- - 10~4~7 methylene chloride, and placed in a freezer overnight. Thc solid is collected, washed with hexane, and oven-dried to yield a white solid. The solid is recrystallized from hexane and chromatographed on alumina with chloroform. This process yields 2-hydroxypropyl 4-(n-hexadecylamino)benzoate as a white solid, m.p. 91-93C.
The same product is obtained when 5.16 g of p-toluene - sulfonic acid is used as catalyst instead of the boron trifluoride etherate.
Example 23 2,3-Dihydroxypropyl 4-(N-acetyl-_-hexadecylamino)benzoate A solution of 3.26 g. of 2,3-dihydroxypropyl-4-(n--hexadecylamino)benzoate and 0.85 ml. of acetic anhydride in 50 ml. of chloroform is heated to reflux for 1 hour and then cooled. The mixture is washed with 90 ml. of water and the solid at the interface filtered. The chloroform layer on concentration in vacuo gives a residue which on trituration with methylene chloride yields a white solid (starting mater-ial) after filtration. The filtrate on concentration in vacuo yields a pale yellow oil. The oil is stirred overnight with water, extracted with chloroform and azeotroped free of acetic acid with benzene. The pale yellow oil obtained by evaporation in high vacuum is then chromatographed to remove a trace of N,0-diacetylated material. The liquid product is characterized by elemental analyses, infrared spectrum and nuclear magnetic resonance.
Example 24 2,3-Diacetoxypropyl 4-(N-acetyl-n-hexad~cylamino)benzoate and 3-Acetoxy-2-hydroxypropyl 4-(N-acetyl-n-hexadecylamino)benzoate A solution of 6.525 g. of 2,3-~ihydroxypropyl-4-(n--hexadecylamino)benzoate and 21 ml. of acetic anhydride in loo ml. of chloroform is hcated to reflux for 3 1/2 hours, cooled to room temperature and concentrated in vacuo to yield r~ - 21 -~094057 a pale yellow liquid. After adding 50 ml. of water and 50 ml.
of chloroform to the liquid, the chloroform layer is separated and washed with water, dried over magnesium sulfate and fil-tered. Concentration of the filtrate in vacuo yields a pale yellow liquid. The liquid is chromato~raphed on silica gel using a 1:2 hexane-ethyl acetate mixture as the eluting sol-vent. The first fraction is shown by elemental analysis, in-frared spectrum and nuclear magnetic resonance to be 2,3-di-acetoxypropyl 4-(N-acetyl-n-hexadecylamino)benzoate. The sec-ond fraction is similarly shown to be 3-acetoxy-2-hydroxypropyl 4-(N-acetyl-n-hexadecylamino)benzoate.
Example 25 2,3-Dihydroxypropyl 4-(n-hexadecylamino3benzoate A solution of 3.8 g. sodium 4-(_-hexadecylamino)ben-zoate, 3.7 g. of epichlorohydrin, and 0.7 ml. of water in hexa-methylphosphoramide is heated to 90C. for five hours. An additional 0.7 ml. of water is added, followed by 1 ml. of lN
suifuric acid. The reaction mixture is cooled after 1 1/2 hours. After adding dimethoxyethane and benzene, the organic layer is separated and washed with water. The solvent is re-moved in vacuo to give a white solid which is recrystallized from 15 ml. of acetonitrile to yield 2,3-dihydroxypropyl 4--(_-hexadecylamino)benzoate. I~ this material contains any of the intermediate 2,3-epoxypropyl 4-(n-hexadecylamino)benzoate, it is removed by chromatography on silica gel.
xample 26 2,3-Dihydroxypropyl 4-(n-hexadecylamino)benzoate A solution of 3.~ g. of 4-(_-hexadecylamino)benzoic acid and 1.0 g. oF 2,3-cpoxypropan-1-ol in 100 ml. of hexa-methylphosphoramidc is heated at 90C. for ~ hours. ~fter ad-dition of ether and water, the ether layer is separated and the ether cxtraction repeated several times. Followin~ eva-poration of the ether extracts, the mixture of starting mater-. - 22 -10~ 57 ial and desired 2,3-dihydroxypropyl ester is separated by chromatography on silica gel and recrystallization from aceto-nitrile.
Example 27 [2,2-Di-(hydroxymethyl)-3-hydroxy]propyl 4-(n-hexadecylamino)-benzoate A mixture of 3.62 g. of 4-(n-hexyldecylamino)benzoic acid, S.44 g. of pentaerythritol, 7.60 g. of ~-toluene sul-fonic acid, and 100 ml. of toluene is stirred under reflux for 3 days and the water which is formed is collected in a Dean-Stark trap. The mixture is extracted with aqueous sodium carbonate and the organic layer is separated, dried over anhydrous mangesium sulfate, and evaporated. Crystallization from chloroform affords (2,2-dihydroxymethyl-3-hydroxy)propyl 4-(n-hexadecylamino)benzoate~
Example 28 (2,3-Dihydroxy-l-hydroxymethyl)propyl 4-(n-hexadecylamino)--benzoate A mixture of 3.62 g. of 4-(n-hexadecylamino)benzoic acid, 4.88 g. of meso-erythritol, 7.60 g. of p-toluene sul-fonic acid, and 100 ml. of toluene is stirred under reflux for 3 days and the water formed is collected in a Dean-Stark trap. The mixture is partitioned between aqueous sodium car-bonate solution and dimethoxyethane. The organic layer is separated, dried over anh~drous magnesium sulfate, and evap-orated. Crystallization from chloroform affords ~2,3-di-hydroxy-1-hydroxymethyl)propyl 4-(n-hexadecylamino)benzoate as a white solid, m.p. 123-125C.
Example 2~
2,3,4,5,6-Pentahydroxyhexyl 4-(n-hexadecylamino)benzoate . _ _ In the manner described in Example 7, 3.62 g. of 4-(n-hexadecylamino)benzoic acid, 1~82 g. of mannitol, and 2.06 g. of ~-toluene sulfonic acid are reacted to yield a C - 23 _ 109~0~7 ._ ~

mixture of mono- and bis-acylated products. Pure 2,~,4,5,6--pentahydroxyhexyl 4-(n-hexadecylamino)~enzoate is separated from the mixture by adsorption chromatography using silica gel as the adsorbant.
Example 30 2,3-Dihydroxypropyl 4-(n-nonadecylamino)benzoate A solution of 8.05 g. of 4-(n-nonadecylamino)benzoic acid in 25 ml. of hexamethylphosphoramide is treated with sodium hydride and then l-chloro-2,3-propanediol in the man-ner described in Example 2 to yield 2,3-dihydroxypropyl 4--(n-nonadecylamino)benzoate as a white solid.
Example 31 2,3-Dihydroxypropyl 4-(n-octylamino)benzoate A solution of 4-(n-octylamino)benozic acid (4.97 g.) in 25 ml. of hexamethylphosphoramide is treated with sodium hydride and then l-chloro-2,3-propanediol in the manner des-cribed in Example 2 to produce white crystals of 2,3-dihy-droxypropyl 4-(n-octylamino)benzoate.
Example 32 2,3-Dihydroxypropyl 4-(n-tridecylamino)benzoate A solution of 6.36 g. of 4-(n-tridecylamino)benzoic acid in 25 ml. of hexamethylphosphoramide is treated with sodium hydride and the l-chloro-2,3-propanediol in the manner described in Example 2 to yield 2,3-dihydroxypropyl 4-(n-tri-decylamino)benzoate as a white solid.
Example 33 2-Phenyl-1,3-dioxolan-4-ylmethyl-4-(n-hexadecylamino)henzoate A solution of 8.7 ~. of 2,3-dihydroxypropyl 4-(n--hexadecylamino)benzoate and 21.2 g. of benzaldehyde in 100 ml. of toluene containing 1.1 g. of gaseous hydrochloric acid is heated to reflux for 3.5 hours cooled to room tempera-- ture. After concentration in vacuo to about 20 ml. and dilution with sn ml. of hexane, the mixture is chilled in an 1~194057 - ~

ice-ethanol bath and filtered. The resulting solid is chroma-tographed on silica gel and then recrystallized from dichloro-methane-hexane to yield the title compound, m.p. 74.5-76.5C.
Example 34 2-Propenyl 4-tn-hexadecylamino)benzoate A solution of 7.66 g. of sodium 4-(n-hexadecylamino)-benzoate and 12.1 g. of allyl bromide in 100 ml. of dry hexa-methylphosphoramide is added to a reaction flask. After 6 hours the solution is poured into 100 ml. of water and the solid collected and recrystallized from 50 ml. of acetonitrile.
This material is recrystallized from hexanol to yield the title compound, m.p. 81-83C.
Example 35 2,3-Diacetoxypropyl 4-(_-hexadecylamino)benzoate To 4.21 g. of sodium hydride (washed free of mineral oil) is added a solution of 21.7 g. of 2,3-dihydroxypropyl 4-(n-hexadecylamino)benzoate in 150 ml. of hexamethylphosphor-amide. After the evolution of hydrogen ceases, 9.4 ml. of acetic anhydride is added. After stirring 18 hours, the reaction mixture is treated with water and the product extract-ed into ethyl acetate. After chromatography, the product is recrystallized from methylene chloride-hexane mixture and melted at 68C.
Example 36 6~14-(n-hexadecylamino)benzoyl~glucopyranose A solution of 2.70 g. of 1,2,5,6-bisisopropylidene glucofuranose and 2.84 g. of 4-dimethylaminopyridine in 100 ml. of chloroform is treated with 4.16 g. of 4-tn-hexa-decylamino)benzoyl chloride hydrochloride. After 16 hours at room temperature, the mixture is washed with water, dried over magnesium sulfate and evaporated. The residue of 3-E4--(n-hexadecylamino)benzoyl]-1,2,5,6-bisisopropylidene gluco-furanose is dissolved in 80~ trifluoroacetic acid at room temp-- 10~40S7 _ ~

eraturc~ and th~ complction of th-~ k~tal clcava~ followcd ~y thin-layer chromatography. The solution is then vacuum evapor-ated at low temperature and the residual solid washed with sodium bicarbonate solution. After recrystallization from acetonitrile, the 6-[4-(n-hexadecylamino)benzoyl]glucopyranose is obtained as a white solid.
Example 37 4-llydroxy-2-buten-1-yl 4-(n-hexadecylamino)benzoate To a mixture of 8.8 g. of 1,4-dihydroxy-2-butene and 2.84 g. of 4-dimethylaminopyridine is added 4.16 g. of 4-(n-hexadecylamino)benzoyl chloride hydrochloride. The heat evolution is moderated with ice and stirring is continued for 4 hours. Chloroform and water are added and the chloro-form extract chromatographed to remove any diacylated by-pro-duct. Evaporation to crystallization yields the 4-hydroxy-2--buten-l-yl 4-(n-hexadecylamino)benzoate as a white solid.
Example 38 3-Hydroxyacetonyl 4-(n-hexadecylamino)benzoate The compound 4-(n-hexadecylamino)benzoyl chloride hydrochloride (4.16 g.) is added to a mixture of 3.6 g. of dihydroxyacetone and 2.44 g. of 4-dimethylaminopyridine in an ice bath. After 4 hours at room temperature, the mixture is treated with chloroform and water. The chloroform extract is chromatographed rapidly and evaporated in vacuo to yield 3--hydroxyacetonyl 4-(n-hexadecylamino)benzoate.
Example 39 4-~n-1~exadecylamino)benzoyl glyceraldehyde To a mixture of 3.6 g. of glyceraldehyde and 2.44 g.
of 4-dimethylaminopyridine in an ice-bath is added 4.16 q. of 4-(n-hexadecylamino)benzoyl chloride hydrochloride. After 4 hours at room temperature, chloroform and water are added.

The chloroform extract is chromatographed quickly and evapora-ted _ vacuo to yield 4-~n-hexadecylamino)~enzoyl glyceraldehyde.

. ~

'- 10!~4(~.S7 `- ~-Examplc 40 4-Hydroxy-3-hydroxymethyl-2-pentyl 4-(n-hexadecylamino)benzoate A 13.4 g. of 2,4-dihydroxy-3-hydroxymethylpentane solution in dimethoxyethane is added to 2.4 g. of sodium hy-dride (washed free of mineral oil). After hydrogen evolution ceased, 12.65 g. of benzyl chloride is added and the mixture refluxed for 4 hours. After cooling to 10C., 24.4 q. of 4--dimethylaminopyridine and 41.6 q. of 4-(n-hexadecylamino)ben-zoyl chloride hydrochloride are added. Chloroform and water are added after 16 hours and the chloroform extract is dried and evaporated to dryness. The residue is dissolved in acetic acid and hydrogenated at 30 psi hydroqen pressure over palla-dium block. After filtration and dilution-with water, the 4--hydroxy-3-hydroxymethyl-2-pentyl 4-(n-hexadecylamino)benzoate is obtained as a white solid.

Claims (6)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROP-ERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A method for the preparation of a compound of the formula:
wherein R4 is an unbranched or branched alkyl group, CnH2n+1 wherein n is 8 to 19; R1, R2 and R3 are selected from the group consisting of hydrogen, C1-C3 alkyl, C1-C3 hydroxyalk-ylene, and C1-C3 hydroxyalkylenecarboxaldehyde in which case a tetrahydrofuran or pyran ring is formed when X is OH, and R2 and R3 combined with the appropriate X or Y may constitute a double-bonded oxygen atom; X and Y, which may be the same or different, are selected from the group consisting of hy-drogen, hydroxy, lower alkanoyloxy, 4-alkylaminobenzoyloxy, hydroxymethyl, and when taken together X and Y can comprise a carbon-carbon bond, a cyclic ether linkage (-O-), or a cyclic acetal or ketal (-o-CRR'-O- with R and R' being selec-ted from the group cimprising hydrogen, C1-C3 alkyl and phenyl); wherein the 4-alkylaminobenzoyloxy moiety and X may be interchanged; with the proviso that when R1, R2 and R3 are all hydrogen or C1-C3 alkyl, then X and Y may not both be hydrogen; which comprises either - (a) reacting a polysub-stituted-alkyl 4-aminobenzoate with suitabl alkylating agents, with or without solvent at 50° to 150°C; or (b) reacting a salt of the 4-alkylaminobenzoic acids with suitable poly-substituted-alkylating agents, in aqueous or anhydrous sol-vents, at 20° to 160°C; or (c) reacting a polysubstituted -2,3-epoxypropyl 4-alkylaminobenzoate with water in dilute acidic aqueous solvent at 60° to 120°C; or (d) reacting a 4-alkylaminobenzoic acid with a polysubstituted-alkyl alcohol in the presence of a mineral acid or Lewis acid catalyst, with or without solvent, at 60° to 140°C.

2. A compound of the formula:
wherein R4 is an unbranched or branched alkyl group, CnH2n+1 wherein n is 8 to 19; R1, R2 and R3 are selected from the group consisting of hydrogen, C1-C3 alkyl, C1-C3 hydroxyalkylene, and C1-C3 hydroxyalkylenecarboxaldehyde in which case a tetrahydro-furan or pyran ring is formed when X is OH, and R2 and R3 com-bined with the appropriate X or Y may constitute a double bonded oxygen atoms; X and Y, which may be the same or different, are selected from the group consisting of hydrogen, hydroxy, lower alkanoyloxy, 4-alkylaminobenzoyloxy, hydroxymethyl, and when taken together X and Y can comprise a carbon-carbon bond, a cyclic ether linkage (-O-), or a cyclic acetal or ketal (-O-CRR'-O- with R and R' being selected from the group consisting of hydrogen, C1-C3 alkyl and phenyl); wherein the 4-alkylamino-benzoyloxy moiety and X may be interchanged; and the pharma-ceutically acceptable salts thereof; with the proviso that when R1, R2 and R3 are all hydrogen or C1-C3 alkyl then X and Y may not both be hydrogen; whenever prepared according to the process of claim 1 or by a chemical equivalent thereof.

3. A method for the preparation of 2,3-dihydroxypropyl 4-(n-hexadecylamino)benzoate, which comprises reacting 4-(n-hexa-decylamino)benzoic acid with aqueous sodium hydroxide and 3-iodo-1,2-propanediol in hexamethylphosphoramide.

4. A method for the preparation of 2,3-dihydroxypropyl 4-(n-hexadecylamino)benzoate hydrochloride, which comprises reacting 2,3-dihydroxypropyl 4-(n-hexadecylamino)benzoate with anhydrous hydrogen chloride in carbon tetrachloride.

5. 2,3-Dihydroxypropyl 4-(n-hexadecylamino)benzoate, whenever prepared by the method of claim 3, or by an obvious chemical equivalent thereof.

6. 2,3-Dihydroxypropyl 4-(n-hexadecylamino)benzoate hydro-chloride, whenever prepared by the method of claim 4, or by an obvious chemical equivalent thereof.