DE2654646A1 - ARYLOXYALKYLAMINOBENZOIC ACIDS AND ACID ESTERS, THE PROCESS FOR THEIR MANUFACTURE AND THEIR USE - Google Patents

Description

Aryloxyalkylaminobenzoic acids and esters, process for their preparation and their use

The invention relates to new aryloxyalkylaminobenzoic acids and acid esters and their preparation. The new compounds represent synthetic hypolipidemic compounds for represent the treatment of arteriosclerosis, as they are able to lower cholesterol, triglycerides and phospholipids in the serum. They can be used to lower serum lipids without being at a late stage in the biosynthesis of cholesterol disturb. These are new substances in chemical terms as well as in terms of their mode of action.

The invention relates to compounds of the general formula

v / orin mean:

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y is a straight or branched alkyl chain with

2 to 12 carbon atoms,

R-j is hydrogen, a lower alkyl radical, a

Phenyl radical, a p-chlorophenyl radical, a benzyl radical, a dialkylaminoethyl radical with lower alkyl groups, an alkoxyethyl radical with a lower alkyl group, an alkylaminoethyl radical with a lower alkyl group, a dialkylaminopropyl radical with lower alkyl groups, a 3-alkoxy-2-hydroxypropyl radical with a lower alkyl group, a 2,3 -Dihydroxypropylrest, a 3-alkylamino-2-hydroxypropyl radical with a lower alkyl group, a 3-dialkylamino-2-hydroxypropyl radical with lower alkyl groups, a 3-amino-2-hydroxypropyl _{radical f} a 2-alkanoylaminoethyl radical with a lower alkyl group, a 3-alkanoylaminopropyl radical with a lower one Alkyl group, a 3-alkanoyloxy-2-hydroxypropyl radical with a lower alkyl group, a 3-alkanoyloxy-2-alkanoyloxypropyl radical with lower alkyl groups, a 3-alkanoylamino-2-hydroxypropyl radical with a lower alkyl group, a 3-alkanoylamino-2-alkanoyloxypropyl radical with lower alkyl groups, a 1-methyl-4-piperidyl radical, a 2-pyridylmethyl radical, a 3-pyridylmethyl rest or a 4-pyridylmethyl radical and

X is a substituted phenyl radical, a napthyl

radical, a thienyl radical, a furyl radical, a 1,2,3,4-tetrahydronaphthyl radical or a 4-chloro-1-napthyl radical, where the substituents of the phenyl radical are halogen, hydroxyl, lower alkoxy, lower Alkyl, cyano, trihalomethyl, amino, lower alkanoylamino, lower alkylamino, dialkyl loweramino, phenoxy, p-chlorophenoxy, benzoyloxy, p-chlorobenzyloxy and cycloalkyl groups come into consideration, or, if Y contains 3 to 12 carbon atoms, a phenyl radical,

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and the salts of the compounds, in the formula of which R _{1 is} hydrogen, with alkalis and organic bases.

The lower alkyl groups are those with 1 to 6 carbon atoms into consideration, for example methyl, ethyl, isopropyl, propyl, tert-amyl, n-hexyl and tert-butyl. Y can, as mentioned, be a straight-chain or branched alkyl group, the branch chain is preferably an alkyl group having 1 to 6 carbon atoms.

The invention also relates to the use of compounds the formula

wherein X, Y and R. have the meanings given above and X can in all cases also be an unsubstituted phenyl radical, as well as their pharmaceutically acceptable acid addition salts, and when R _{1 is} hydrogen, their salts with alkalis or organic bases as active ingredients of drugs for lowering the sterol and triglyceride content of serum from warm-blooded animals.

The compounds according to the invention are colorless or brownish crystalline solids or colorless or brownish oils. in the they are generally in organic solvents such as benzene, chloroform, dichloromethane, Ν, Ν-dimethylformamide, dimethyl sulfoxide and lower alkanols soluble.

The compounds according to the invention are bases and can be converted into their non-toxic acid addition salts with acids such as sulfuric acid, hydrochloric acid, phosphoric acid, succinic acid or citric acid. The compounds in the formula R _{1 is} hydrogen can be mixed with inorganic bases such as sodium hydroxide, potassium hydroxide and ammonium hydroxide or with organic bases such as pyridine and mono-, di- or trialky amines with lower alkyl groups

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Example methylamine, diethylamine, trimethylamine and dibutylamine, are converted to the corresponding carboxylic acid salts.

The compounds according to the invention are prepared by reacting p-aminobenzoic acid or an ester of this acid, for example a lower alkyl ester, with an alkylating agent. Examples of suitable alkylating agents are aryloxyalkyl halides, aryloxyalkanol-O-sulfates, -O-tosylates, -O-trifluoromethanesulfonates or -O-methanesulfonates. The reaction is carried out in the presence or absence of a solvent at 5 (
carried out.

means at 50 to 150 ⁰ C in a time of 1 to 25 hours

Suitable solvents for the alkylation include hexamethylphosphoramide, Ν, Ν-dimethylformamide, N, N-dimethylacetamide, lower Alkanols, chloroform, dimethyl sulfoxide, benzene, xylene and Acetonitrile.

The alkylation reactions can be carried out with one equivalent of a base, for example alkali carbonate or bicarbonate. Instead, the p- (aryloxyalkyl) -aminobenzoate can also be obtained by reacting a lower alkyl ester of p-aminobenzoic acid with an aryloxyalkyl halide in the presence of one equivalent of sodium hydride in an inert solvent such as hexamethylphosphoramide, Ν, Ν-dimethylformamide, N, N-dimethyl acetamide or xylene at 50 to
25 hours can be made.

acetamide or xylene at 50 to 170 ° C for a time of 1 to

In the case of the aryloxyalkyl chlorides, the alkylation of lower Alkyl esters of p-aminobenzoic acid in the presence of one equivalent of sodium or potassium iodide in an inert Solvents such as hexamethylphosphoramide, Ν, Ν-dimethylformiamide or N, N-dimethyl acetamide can be carried out.

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The ρ- (aryloxyalkyl) -aminobenzoic acids according to the invention are by hydrolysis of the corresponding esters with alkali hydroxides, such as sodium hydroxide or potassium hydroxide, in a lower Alkanol, water or aqueous lower alkanol produced at 25 to 100 C. Instead, these acids can also get through Hydrolysis of their esters with mineral acids such as hydrochloric acid, hydrobromic acid or sulfuric acid in water or aqueous Alkanols are obtained.

Esters of p-aryloxyalkylaminobenzoic acids can be converted by the corresponding acids into their acid chlorides with reagents such as thionyl chloride and oxalyl chloride and reaction the acid chlorides with lower alkanols, lower dialkylaminoethanols or lower alkoxyethanols. Instead, a metal salt of carboxylic acid can be used Example the sodium, potassium or zinc salt, with a lower alkyl halide or a substituted propyl halide, for example 3-halo-1,2-propanediol, in a solvent, such as hexamethylphosphoramide or Ν, Ν-dimethylformamide, to one Ester of a p-aryloxyalkylaminobenzoic acid of the formula I implemented will.

The p-aryloxyalkylaminobenzoic acid esters according to the invention can also by reductive alkylation of p-aminobenzoic acid or its lower alkyl esters with an aryloxyalkylaldehyde or -ketone produced in the presence of a noble metal, nickel or cobalt as a catalyst or a suitable metal hydride will. For example, Raney nickel, hydrogen and an aryloxyalkylaldehyde for the reductive alkylation of ethyl p-aminobenzoate can be used. With the reductive Alkylation can use auxiliary catalysts, such as aluminum chloride, Piperidine acetate or acids can be used.

Another possible manufacturing process is the reduction of a 4- (acylamino) benzoic acid or an ester of this acid

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with a metal hydride. The reduction of 4-hexadecanoylaminobenzoic acid or its ethyl ester with diborane at room temperature or above in 1 to 6 hours leads to 4-hexadecylaminobenzoic acid or to your fithylester.

The aryloxyalkylaminobenzoic acids according to the invention and their esters can also be prepared by reacting lower alkyl esters p-aziridinobenzoic acid, from p-haloalkyleneamino benzoic acids or p-alkyl (or aryl) sulfonyloxyalkyleneamino benzoic acids with hydroxyary! compounds under alkaline and acidic conditions getting produced.

Some of the alkylating agents for the preparation of the inventive Connections can be made as follows;

R ₁ R

I ¹ I ¹

XOH + WC (CHJ CO R >> XO-C (CH,) CO ₀ R

^R 2 ^R 2

f 1 V

XO-C (CH ₂ ) CH ₂ Z <~ XO-C (CH ₀ ) CH OH

J ^Δ " ^Δ ι 2 η 2

^R 2 ^R 2

In these formulas, W denotes halogen and Z denotes halogen or a radical such as the O-methanesulfonate radical; η has the value 0 or 1 to 11. R ₁ and R _{2 are} hydrogen or lower alkyl radicals.

The reduction of the aryloxyalkyl derivatives 3 leads to the corresponding Alcohols 4, which are converted into the desired alkylating agents 5.

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The invention also relates to a process for the preparation of a compound of the formula

where mean:

Y is a straight or branched chain alkyl group with 2 to 12 carbon atoms,

R _{1 is} hydrogen or a lower alkyl or 2,3-dihydroxypropyl group,

X is a phenyl, naphthyl, thienyl, furyl, 1,2,3,4-tetrahydronaphthyl, 4-chloro-1-naphthyl group or a substituted phenyl radical whose substituents are halogen or hydroxyl, lower alkoxy, lower alkyl; Cyano, trihalomethyl, amino, lower alkanoylamino, lower alkylamino, lower dialkylamino, Phenoxy, p-chlorophenoxy, benzyloxy, p-chlorobenzyloxy or cycloalkyl groups,

and their pharmaceutically acceptable salts, characterized in that a compound of the formula

X-O-Y-A ..II,

Y is a straight or branched chain alkylene group (C _n H _2n ) with 0 to 11 carbon atoms (η = 0 to 1T),

A is hydrogen when η = 0, or CH ₀ Z, C ^ or C

² \ z

and Z denotes halogen, hydroxy, alkoxy, alkylsulfonate or arylsulfonate esters or trialkylammonium,

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265A6A6

with a compound of the formula

... III

worm

B a haloalkylenamino, alkyl or arylsulfonyloxyalkylenamino, Aziridino, acylamino or amino group or a group which can be converted into this group and

D is a carboxylic acid or ester group or a nitrile or amide group which can be converted into it,

where in formula II A is hydrogen and η has the value 0, if B is a haloalkylamino, alkyl or arylsulfonyloxyalkyleneamino or aziridino group,

is implemented.

The compounds according to the invention show a hypolipidemic effect. The mechanism of action of these compounds is not known, but their effectiveness has been determined by those described below Animal experiments proven. The compounds were orally mixed with in the diet in groups of four to six male rats of the strain CFE (Carworth Farms) administered. A control group of six to eight rats received the feed alone. After 6 days of treatment, the serum sterol concentrations were determined using the extraction method of H. H. Leffler, Amer. J. Clin. Path. Vol. 31, p. 310 (1959) and the dolorimetric Methods by Zlatkis, et. al., J. Lab. Clin. Med. Vol. 44, p. 486 (1953). The serum triglycerides were according to the automated working method of Kessler and Lederer

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// 'Automation in Analytical Chemistry' / Skeggs, LT, (Ed.), Mediad, Inc., New York, 1965, p. 34V. In these tests, a compound is considered to be hypolipidamically active if it has the serum sterol Values to a value below that of the controls and / or the triglyceride values to a value below that of the controls
lowers. Table I shows for several compounds according to the invention the extent to which they lower the serum sterol and triglyceride values after one week of treatment.

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Tabel link

p- (2-Phenoxyethyl) -aminobenzoic acid ethyl p- (2-phenoxyethyl) -aminobenzoate p- (3-phenoxypropyl) -aminobenzoic acid ethyl-p- (3-phenoxypropyl) -aminobenzoate p_ (4-phenoxybutyl) -aminobenzoic acid ethyl- p- (6-phenoxyhexyl) -aminobenzoate p- / 2- (p-bromophenoxy) ethyl / aminobenzoic acid p- (11-phenoxyundecyl) aminobenzoic acid p- / 2- (2-naphthyloxy) -ethyl ./- aminobenzoic acid ethyl-p- / 2- (2- (2-naphthyloxy) -ethylZ-aminobenzoate p- (2-phenoxypropyl) aminobenzoic acid p- / 2- (1-naphthyloxy) -athyiy-aminobenzoic acid percent compound in the feed

0.1 0.1 0.1 0.1 0.1 0.05 0.1 0.1 0.1 0.1 0.05 0.1

Decrease in serum values in percent

Sterol Triglycerides 22nd 41 21 41 16 31 IO 27 4th 53 19th 15th 10 47 7th
13th 41
47 10 43 24 52 17th 42

■ ** "26S4646 - Λ * '

The compounds of the invention are valuable hypolipidemic Mammalian and human agents when administered in amounts of about 0/5 to 40 mg / kg body weight / day. A preferred dosage for best results is in the range of about 2 to 29 mg / kg body weight / day. The daily dose for a living being of about 70 kg is thus between about 35 mg and 2.8 g, preferably between about 140 mg and 2.0 g.

The active ingredients according to the invention can be administered orally, for example with an inert diluent or with an assimilable edible carrier, or they can be in hard or soft gelatin capsules are introduced or compressed into tablets, or they can also be added directly to the nutrients to be introduced. For oral therapeutic administration, the compounds according to the invention can be used with auxiliaries and carriers introduced and in the form of tablets, dragees and capsules, elixirs, suspensions, syrups, wafers or chewing gum be used. Such agents and preparations should contain at least 0.1% active ingredient. Of course you can the percentage in the agents and preparations fluctuate and expediently between about 5 and 75% or more of the Weight of the unit. The amount of active ingredient in such therapeutically useful agents or preparations is dimensioned so that a suitable dosage is achieved. Preferred agents or preparations are produced in such a way that that a dosage unit form for oral administration contains between about 10 and 500 mg of active ingredient.

The tablets, coated tablets, pills, capsules and the like can also contain the following substances: A binding agent, such as gum tragacanth, acacia, corn starch or gelatin, one Carriers such as dicalcium phosphate, a disintegrating agent such as corn starch, potato starch or alginic acid, a lubricant such as magnesium stearate and a sweetening agent such as sucrose, lactose or saccharin, and a flavoring agent Material. If the dosage unit form is a capsule, can

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in addition to the types of substances indicated above, they contain a liquid carrier, for example a fatty oil. Different other materials may be present as coatings or to make other modifications to the physical form of the dosage unit be. For example, tablets, pills, or capsules can be coated with shellac, sugar, or both. A syrup or Elixir can contain the active ingredient, sucrose as a sweetener, methyl and propyl parabens as preservatives, a color and a flavoring agent such as cherry or orange flavor. All for the manufacture of a wide variety of dosage unit forms The substances used should be pharmaceutically pure and practically non-toxic in the quantities used be.

In addition, the active ingredients can be delayed in preparations Release to be processed.

The invention is further illustrated by the following examples.

Example 1 6 "(2-naphthyloxy) -1-hexanol

In a cooled round bottom flask are 4.2 g of a mixture containing 57 percent sodium hydride in oil, 50 ml of hexamethylphosphoramide and 15.8 g of 2-naphthol were introduced. After half an hour, the mixture is allowed to warm to room temperature and adds 13.6 g of 6-chlorohexan-i-ol. The mix will heated to 110 C and kept at this temperature overnight. After cooling, it is diluted with water and extracted with ether. The star extract is made with sodium hydroxide solution and then washed with water, dried over magnesium sulfate and freed from the solvent in vacuo. The solid is in fither is dissolved, and the solution is made with sodium hydroxide solution

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washed. The ether layer is dried over magnesium sulfate, and after removing the solvent in vacuo, 15.9 g of product are obtained as crystals with a melting point of 53 to 56 ^° C.

Example 2
6- (2-naphthyloxy) -1-hexanol-O-methanesulfonate

A mixture of 10.4 g of 6- (2-naphthyloxy) -1-hexanol and 8.1 g of triethylamine in 250 ml of dichloromethane is cooled to -8 ° C. and 5.1 g of methanesulfonyl chloride are added dropwise under nitrogen. After one hour at 0 to -8 ⁰ C the mixture with cold water, 10 percent hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride solution and dried over magnesium sulfate. After removing the solvent in vacuo, the product is obtained as a white solid.

Example 3
Ethyl p- / 6- (2-naphthyloxy) hexyl / aminobenzoate

A solution of 10.0 g of 6- (2-naphthyloxy) -1-hexanol O-methanesulfonate and 9.7 g of ethyl 4-aminobenzoate in 50 ml of hexamethylphosphoramide is 16 hours 110 ⁰ C heated. The solution is cooled, diluted with water, filtered, and the solids are washed with ethanol and water. 7.7 g of product are obtained. By recrystallizing from ethanol and once from acetone / hexane, crystals with a melting point of 109 to 110 ° C. are obtained.

Example4
p- / 6- (2-Naphthyloxy) -hexylV-aminobenzoic acid

A solution of 4.8 g of ethyl p- / 6- (2-naphthyloxy) -hexy1 / -aminobenzoate and 4.8 g, potassium hydroxide in 100 ml of 95 percent ethanol

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is refluxed for 3 hours. The solution is cooled, diluted with water and treated with concentrated hydrochloric acid acidified. After filtering the mixture, the solids are washed with ethanol and water and made up of ether / methylene chloride and acetone recrystallized. Crystals with a melting point of 157 to 159 ° C. are obtained.

Example 5 2- (2-Naphthyloxy) ethanol

A solution of 14.4 g of 2-naphthol, 12.1 g of 2-bromoethanol and 5.9 g of sodium methoxide in 100 ml of ethanol is left to stand for 2 days at room temperature. The solvent is removed in vacuo and the residue is extracted with ether. The ether extract is washed with water and dried over magnesium sulfate. After removing the solvent in vacuo, crystals with a melting point of 65 to 70 ^° C. are obtained.

Example 6 2- (2-Naphthyloxy) ethanol-O-methanesulfonate

13.5 g of 2- (2-naphthyloxy) ethanol in 400 ml of dichloromethane reacted as described in Example 2 with 9.5 g of methanesulfonyl chloride in the presence of 11.4 g of triethylamine. The product is obtained in the form of brownish crystals.

Example 7 Ethyl p- / 2- (2-naphthyloxy) ethyl / aminobenzoate

A mixture of 18.7 g of 2- (2-naphthyloxy) ethanol O-methanesulfonate and 23.6 g of ethyl p-aminobenzoate in 300 ml of hexamethylphosphoramide is heated for 16 hours 110 ⁰ C. The mixture is cooled, diluted with water and described as in Example 3

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worked up, whereby the crystalline product is obtained, which melts ^{at 158 to 162 0 C after recrystallization from ethanol.}

Example 8 2- (2-Thienyl) ethanol O-methanesulfonate

A mixture of 12.8 g of 2- (2-thienyl) ethanol and 20.2 g of triethylamine in 500 ml of dichloromethane is reacted as described in Example 2 with 12.6 g of methanesulfonyl chloride. The product is obtained as an oil.

Example 9 ethyl p- / 2- (2-thienyl) ethyl / aminobenzoate

A mixture of 33.0 g of ethyl p-aminobenzoate and 2- (2-thienyl) ethanol-O-methanesulfonate in 100 ml of hexamethylphosphoramide is heated to 125 ° C. for 16 hours. The solution is cooled, diluted with water and extracted with ether. The ether extracts are dried over magnesium sulfate and freed from the solvent in vacuo. The remaining oil is chromatographed on silica gel (chloroform). The solvent is removed from the fractions containing the product, whereby crystals are obtained which melt ^{at 93 to 96 ° C. after recrystallization from hexane.}

Example 10 p- / 2- (2-Thienyl) -ethylZ-aminobenzoic acid

A mixture of 29.7 g of ethyl p- ^ 2- (2-thienyl) -äthyI / -aminobenzoate and 29 g of potassium hydroxide in 200 ml of 95 percent ethanol is refluxed for 3 hours. The mixture is worked up as described in Example 4, and the product with a melting point of 161 to 163 ^° C. is obtained.

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Example 11 2- (1-Naphthyloxy) ethanol Q-methanesulfonate

A solution of 18.8 g of 2- (1-naphthyloxy) ethanol and 15.1 g of triethylamine in 425 ml of dichloromethane, as described in Example 1, with 12.6 g of methanesulfonyl chloride to give the stated product implemented.

Example 12 Ethyl p- / 2- (1-naphthyloxy) -ethy] ./-aminobenzoate

A solution of 29.1 g of 2- (1-naphthyloxy) ethanol-O-methanesulfonate and 33 g of ethyl p-aminobenzoate in 100 ml of hexamethylphosphoramide is Heated to 100 ° C for 16 hours. The solution is worked up as described in Example 3, and after recrystallization of the product Crystals with a melting point of 124 to 127 ° C are obtained.

Example 13 p- / 2- (1-Naphthyloxy) -ethy1 / aminobenzoic acid

A solution of 12 g of ethyl p- / 2- (1-napthyloxy) ethyl / aminobenzoate and 15.8 g of potassium hydroxide in 100 ml of 95 percent ethanol is refluxed for 3 hours. The solution is diluted with 75 ml of water and acidified with concentrated hydrochloric acid. The solid is filtered off and washed with 50 percent ethanol and then with water. Recrystallization from ethanol gives the product as crystals of F. = 193 to 194 ^° C.

Example 14 ethyl p / 2- (2,4-dichlorophenoxy) ethyl / aminobenzoate

A solution of 22.8 g of .beta.-bromo-2,4-dichlorphenetol and 29.8 g of ethyl 4-aminobenzoate in 100 ml of hexamethylphosphoramide is 16 hours 125 ⁰ C heated. The solution is cooled, diluted with 80 ml of water and filtered. The solid is washed with 50 percent ethanol and recrystallized from ethanol. The product is obtained in the form of crystals with a melting point of 111 to 113 ^° C.

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Example 15 p- / 2- (2,4-dichlorophenoxy) -ethy_l / -aminobenzoic acid

A solution of 15 g of ethyl p- / 2- (2,4-dichlorophenoxy) ethyl / aminobenzoate and 15g potassium hydroxide in 200 ml 95 percent Ethanol is refluxed for three hours. The solution is cooled, diluted with water, concentrated with Acidified hydrochloric acid and filtered. The solid obtained is recrystallized from ethanol, whereby crystals of F. = 203 to 205 ° C can be obtained.

Example 16 6- (phenoxy) -1-hexanol

A solution of 10.3 g of phenol in 25 ml of hexamethylphosphoramide is mixed with 4.2 g of 57 percent sodium hydride in oil. After the evolution of hydrogen has ceased, 13.6 g of 6-chlorohexan-1-ol in 25 ml of hexamethylphosphoramide are added, and the mixture is ^{heated to 110 °} C. for 16 hours. The solution is cooled, diluted with water and extracted with ether. The ether extracts are washed with sodium hydroxide solution and dried over magnesium sulfate. After removing the solvent in vacuo, white crystals with a melting point of 69 to 74 ° C. are obtained.

Example 17 6- (Phenoxy) -I -hexanol-0-methanesulfonate

6.95 g of methanesulfonyl chloride are added to a mixture, cooled to -2 ^° C., of 9.7 g of 6- (phenoxy) -1-hexanol in 250 ml of dichloromethane, which contains 11.1 g of triethylamine. The product is isolated as described in Example 2 to give an oil.

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Example 18 Ethyl p- (6-phenoxyhexyl) aminobenzoate

A solution of 13.6 g of 6- (phenoxy) -i-hexanol O-methanesulfonate and 16.5 g of ethyl p-aminobenzoate in 75 ml of hexamethylphosphoramide wid 16 hours 110 ⁰ C heated. The product is isolated as described in Example 3 and recrystallized from ethanol, whereby crystals with a melting point of 105 to 108 ° C. are obtained.

Example 19 p- (6-Phenoxyhexyl) aminobenzoic acid

A mixture of 5 g of ethyl p- (6-phenoxyhexyl) aminobenzoate and 5 g of potassium hydroxide in 100 ml of 95 percent ethanol is refluxed for 3 hours. The mixture is cooled, acidified with concentrated hydrochloric acid, diluted with water and filtered. By washing the solid with water and 50 percent ethanol, crystals with a melting point of 168 to 170 ^° C. are obtained.

Example 20 11-Phenoxyundecanoic acid

A mixture of 9.4 g of phenol, 26.5 g of 11-bromundecanoic acid and 250 ml of hexamethylphosphoramide is cooled in an ice bath and mixed with 10.5 g of sodium methoxide. A viscous mass forms which is ^{heated to 100 °} C. for 20 hours while stirring. The mixture is diluted with cold water, acidified with concentrated hydrochloric acid, filtered, and the solid is washed with water to give gray crystals. Recrystallization from acetone gives pale gray crystals with a melting point of 76 to 78 ° C. A second crop of crystalline substance with a melting point of 75 to 77 ° C. is obtained from the mother liquor.

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Example 21 11-Phenoxy-i-undecanol

100 ml of 1m diborane in tetrahydrofuran are cooled under nitrogen in an ice bath and 13.92 g of 11-phenoxyundecanoic acid in 50 ml of tetrahydrofuran are added dropwise, which takes 30 minutes. The solution is left to stand at room temperature for 19 hours and poured onto ice. After allowing to stand for a while, the mixture is filtered and the solid is washed with water, whereby white crystals with a melting point of 56 to 58 ^° C. are obtained. A sample is recrystallized from ethanol, gives white crystals, mp = 56.5 to 57.5 ⁰ C.

Example 22 11-Phenoxy-1-undecanol-O-methanesulfonate

A solution of 10.6 g of 11-phenoxy-1-undecanol, 200 ml of dichloromethane and 8.4 ml of triethylamine is cooled in an ice-salt bath to -8 ⁰ C and added dropwise within 10 minutes with a solution of 3, 38 ml of methanesulfonyl chloride in 10 ml of dichloromethane are added. The solution is stirred for 30 minutes at -8 ⁰ C, washed with 150 ml of ice-cold water, 75 ml of cold 10 percent Salsäure, 75 ml of cold saturated sodium bicarbonate solution and 75 ml cold saturated sodium chloride solution and dried over magnesium sulfate. After the solvent has been removed in vacuo, whitish crystals with a melting point of 54 to 58 ^° C. are obtained.

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Example 23 Ethyl p-d1-phenoxyundecyl) aminobenzoate

A mixture of 16.5 g of ethyl-p-aminobenzoate, 10.3 g of phenoxy-1-undecanol-O-methanesulfonate and 50 ml of hexamethylphosphoramide is heated for 20 hours at 100 to 110 ⁰ C, cooled and diluted with 30 ml ethanol and 10 ml Water diluted. Cooling and filtering give a solid which is washed with ethanol / water (1: 1) and water. In this way, yellow crystals with a melting point of 83 to 87 ^° C. are obtained, which are present as yellow needles with a melting point of 89 to 90 ^{° C. after recrystallization from ethanol.}

Example 24 p- (4-Phenoxybutyl) aminobenzoic acid

A mixture of 15 ml of hexamethylphosphoramide, 0.86 g of sodium hydride (56 percent in oil) and 4.32 g 1,4-dibromobutane is cooled in an ice bath and poured within 3/4 hours with 1.88 g of phenol in 15 ml of hexamethylphosphoramide. The mixture is stirred for one hour at 0 ° C, and after adding 3.30 g of ethyl p-aminobenzoate for 16 hours heated in a steam bath. Then the mixture is cooled, diluted with 15 ml of water, cooled again and filtered, and the solid residue is washed with ethanol / water (1: 1). Brownish crystals are obtained.

A mixture of 4.7 g of the crude product, 5 g of potassium hydroxide and 80 ml of ethanol / water (9: 1) is heated to boiling under reflux for 3 hours. The mixture is still concentrated in the heat with Hydrochloric acid acidified and diluted with water. Brownish crystals are obtained by cooling and filtering.

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This crude product is dissolved in chloroform and the solution is filtered through silica gel. After washing the
Silica gel with chloroform, the product is eluted with benzene / acetic acid (3: 1) and chloroform / acetic acid (3: 1).
After removing the solvent, the product is recrystallized from ethanol, whereby brownish crystals from
F. = 153 to 155 ° C.

Example 25 Ethyl p- / 2- (p-bromophenoxy) ethyl / aminobenzoate

A mixture of 26.4 g of ethyl-p-aminobenzoate, 22.4 g of 2-bromoethyl-p-bromphenyläther and 80 ml of hexamethylphosphoramide is heated for 20 hours at 100 to 110 ⁰ C. Then it is cooled, diluted with 25 ml of water, cooled again and filtered. The solid is washed with 100 ml of ethanol / water (1: 1), 25 ml of ethanol and then with water, whereby brownish crystals with a melting point of 128 to 133 ° C. are obtained. By recrystallizing from ethanol, yellow crystals with a melting point of 135.5 to 137 ^° C. are obtained.

Example 26 p- / 2- (p-Bromophenoxy) -ethyl ./- aminobenzoic acid

A mixture of 10.0 g of ethyl p- / 2- (p-bromophenoxy) ethyl / aminobenzoate, 10 g of potassium hydroxide and 100 ml of ethanol / water (9: 1) is refluxed for 3.5 hours.
It is then acidified with concentrated hydrochloric acid while still warm, diluted with water, cooled and filtered. The solid

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it is washed with water, and crystals of F. = 190 to 192 ^° C. are obtained. By recrystallization from 500 ml of ethanol, white crystals of, F. are obtained. = 194 to 196 ⁰ C.

Example 27 p- (11-Phenoxyundecyl) aminobenzoic acid

A mixture of 7.0 g of ethyl p- (11-phenoxyundecyl) aminobenzoate, 7.0 g of potassium hydroxide and 150 ml of ethanol / water (9: 1) is refluxed for 3.5 hours. It is then acidified with concentrated hydrochloric acid while still warm, diluted with water, cooled and filtered. There are obtained white crystals, mp = 117 to 119 ⁰ C, melting after recrystallization from ethanol at 118 to 119.5 ⁰ C.

Example 28 Ethyl p- (2-phenoxyethyl) aminobenzoate

A mixture of 33 g of ethyl p-aminobenzoate, 80 ml of hexamethylphosphoramide and 20.1 g of β-bromophenetol are heated to 110 ° C. for 20 hours. Then it is cooled with 25 ml of water diluted, cooled again and filtered off. After washing the solid with ethanol and then with water, crystals become obtained from m.p. = 126 to 129 ° C, which after recrystallization from ethanol as pale yellow crystals from m.p. = 129 to 131 C.

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Example 29 ρ- (2-Phenoxyethy1) -aminobenzoic acid

A mixture of 12 g of ethyl p- (2-phenoxyethyl) aminobenzoate, 12 g of potassium hydroxide and 200 ml of ethanol / water (9: 1) is refluxed for 3.5 hours. The solution is acidified with concentrated hydrochloric acid while it is still warm, diluted with water, cooled and filtered. By washing the solid with water, crystals with a melting point of 172 to 175 ° C. are obtained. Recrystallization from ethanol yields whitish crystals with a F. = 174 to 176 ^° C.

Example 30 Ethyl p- (3-phenoxypropyl) aminobenzoate

A mixture of 33 g of ethyl p-aminobenzoate, 21.5 g of 3-bromopropylphenyl ether and 100 ml of hexamethylphosphoramide is heated ^{to 100 to 110 ° C. in an oil bath for 20 hours.} Then it is cooled, diluted with 50 ml of water, cooled again and filtered. After washing the solid with ethanol / water (1: 1) and then with water, yellow crystals with a melting point of 73 to 74 ^° C. are obtained.

Example 31 p- (3-Phenoxypropyl) aminobenzoic acid

A mixture of 15 g of ethyl p- (3-phenoxypropyl) aminobenzoate, 15 g of potassium hydroxide and 150 ml of ethanol / water (9: 1) becomes 3.5 Heated to reflux for hours. She is still warm

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acidified with concentrated hydrochloric acid, diluted with water,

cooled and filtered. There are yellow crystals from

F. = 159 to 162 ⁰ C obtained, which after recrystallization from ethanol as pale yellow crystals of M. = 161 to 163 C.

are present.

Example 32 2- phenoxy-1-propanol

200 ml of 1 M boron hydride in tetrahydrofuran is cooled in an ice bath and treated dropwise under nitrogen with stirring with 214.9 g of 2-phenoxypropionic acid in 100 ml of dry tetrahydrofuran, which takes 25 minutes to complete. The mixture is left to stand at room temperature for 23 hours and then poured onto ice. After standing for a while, the mixture is extracted with dichloromethane and the extract is dried over magnesium sulfate and evaporated in vacuo. The product is obtained as a yellow oil.

Example. 33 2-phenoxy-1-propanol-O-methanesulfonate

A solution of 15.2 g of 2-phenoxy-1-propanol, 20.8 ml of triethylamine and 300 ml of dichloromethane is cooled to -10 ° C. in an ice-salt bath and 7.78 ml of methanesulfonyl chloride are added dropwise over a period of 10 minutes . It is stirred for 30 minutes at -10 ⁰ C, with 100 ml of ice water, 100 ml of cold 10 percent hydrochloric acid, 100 ml of cold saturated

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- 2-5 -

Nafcrium bicarbonate solution and 100 ml of cold saturated sodium chloride solution washed and dried over magnesium sulfate. After removing the solvent in vacuo the product is obtained as an oil.

Example 34 p- (2-Phenoxypropyl) aminobenzoic acid

A mixture of 33 g of ethyl p-aminobenzoate, 0.10 mol of 2-phenoxy-1-propanol-0-methanesulfonate and 80 ml of hexamethylphosphoramide is ^{heated to 125 °} C. for 18 hours. Then it is cooled, poured into water and extracted with ether. The ether extract is washed with water, dried over magnesium sulfate and evaporated in vacuo to an oil. After adding 250 ml of ethanol / water (9: 1) and 20 g of potassium hydroxide to the oil, the mixture is refluxed for 3.5 hours. After acidification with concentrated hydrochloric acid and dilution with water, extraction is carried out with chloroform. The chloroform extracts are washed with water, dried over magnesium sulfate and evaporated in vacuo to an oil. After adding ethanol, the mixture is cooled and filtered, whereby the product with a mp = 140 to 144 ° C is obtained. After recrystallization the product is in the form of crystals, mp = 145 to 147 ⁰ C.

Example 35 2- (p-Benzyloxyphenoxy) -2-methy! -Propionic acid

A solution of 10.0 g of hydroquinone monobenzyl ether in 40 ml Hexamethylphosphoramide is mixed with 2.7 g of sodium methoxide. The mixture is stirred for 10 minutes and then become

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10.3 g of ethyl 2-bromoisobutyrate were added. The mixture is then heated to 120 ° C. for 22 hours. After standing for a while, the mixture is filtered off. The solid is dissolved in 150 ml of ethanol / water (9: 1) and, after adding 10 g of potassium hydroxide, the mixture is refluxed for 6 hours, acidified with concentrated hydrochloric acid, diluted with water and filtered. Washing the solid with water gives crystals which are dissolved in aqueous sodium hydroxide. This solution is extracted once with chloroform and once with ether. The aqueous layer is acidified with ether and concentrated hydrochloric acid and then filtered. By recrystallizing the solid from glacial acetic acid, white crystals with a melting point of 134 to 137 ^° C. are obtained.

Reduction with borohydride / tetrahydrofuran gives 2- (p-benzyloxyphenoxy) propan-i-ol, which is converted into O-methanesulfonate is converted and used as such as an alkylating agent.

Example 36 Ethyl 2- (p-benzyloxyphenoxy) propionate

20.0 g of p-benzyloxyphenol in 80 ml of dry hexamethyl phosphoramide are mixed with 5.4 g of sodium methoxide. The mixture is stirred for 10 minutes and then 18.1 g of ethyl 2-bromopropionate are added, an exothermic reaction taking place. After 15 minutes, the mixture is heated on a steam bath for 16 hours, poured onto ice and extracted with ether. The ether extracts are washed with water, dried over magnesium sulfate and evaporated in vacuo, whitish crystals with a melting point of 36 to 44 ^° C. remaining.

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Recrystallization twice from ethanol turns whitish Crystals with a melting point of 46 to 49 ° C were obtained.

Example 37 p- / 2- (2-Naphthyloxy) ethyV-aminobenzoic acid

A mixture of 3.0 g of ethyl p- / 2- (2-naphthyloxy) ethyl / aminobenzoate and 3.0 g of potassium hydroxide in 200 ml of ethanol / water (95: 5) is refluxed for 3 hours. Then it is diluted with 100 ml of water and the pH is adjusted to 6.0 with concentrated hydrochloric acid. The mixture is then filtered and the solid is washed with 50 ml of water and 20 ml of cold ethanol / water (4: 1). In this way, the product with a melting point of 208 to 211 ^° C. is obtained.

Example 38 Ethyl 4- / 2- (4-chlorophenoxy) propylene aminobenzoate

A mixture of 15.1 g of ethyl p-aminobenzoate and 11.3 g of 2- (4-chlorophenoxy) -1-propanol-0-methanesulfonate in 100 ml of hexamethylphosphoramide is heated to 115 to 120 ° C for 4.8 hours. The solution is cooled and distributed between ether and water. The ether layer is separated and the aqueous layer is extracted with ether. The combined ether extracts are dried over magnesium sulfate and the solvent was removed under reduced pressure to give 23 g of a semi-solid. A sample this residue of 8 g is on silica gel with

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-M-

Chromatographed chloroform as the eluent. The first fraction contains 3.8 g of solid, which is chromatographed on silica gel with hexane / ethyl acetate as the eluent. The first fraction yields 1.72 g of a light brownish solid. 0.45 g of this solid is recrystallized from cyclohexane, whereby 0.3 g of white needles with a melting point of 96 to 9 8 ^° C. are obtained.

Example 39 Ethyl 1-4 / 3- (4-chlorophenoxy) propylZ-aminobenzoate

A mixture of 17.1 g of ethyl-p-aminobenzoate, 14.6 g of 3- (4-chlorophenoxy) -1-propanol-0-methanesulfonate and 1OO ml hexamethylphosphoramide is heated for 16 hours 110 to 115 ⁰ C. The solution is diluted with 100 ml of water, allowed to cool and filtered to give 12.5 g of solid, which recrystallization from cyclohexane gives 7.8 g of yellow needles. Chromatography on silica gel gives 6.8 g of product as white crystals with a melting point of 87 to 88 ^° C.

Example 40 4- / 3- (4-Chlorophenoxy) propylZ-aminobenzoic acid

A mixture of 4.5 g of ethyl 1-4- / 3- (4-chlorophenoxy) propyl./ aminobenzoate , 4.5 g of potassium hydroxide and 100 ml of 95 percent ethanol is refluxed for 3 hours. The solution is acidified with hydrochloric acid and the mixture is diluted with 100 ml of water. 3.7 g of solid are obtained, whose recrystallization by dissolving in a mixture of chloroform and ethyl acetate and diluting with hexane gives 3.3 g of product as whitish crystals with a melting point of 180 to 181 ° C.

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Example 41 2- (4-Chlorophenoxy) -1-propanol-O-methanesulfonate

A solution of 8.5 g of 2- (4-chlorophenoxy) -1-propanol, and 9.2 g Triethylamine in 250 ml of dichloromethane is cooled to -5 ° C and 5.7 g of methanesulfonyl chloride were added dropwise. The solution is left to stand for 1 hour at room temperature and with 100 ml each of water, 10 percent hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution washed. The organic layer is dried over magnesium sulfate and the solvent is taken under Vacuum removed. 11.3 g of the product are thus obtained as an oil.

Example 42 3- (4-Chlorophenoxy) -1-propanol-O-methanesulfonate

A solution of 9.7 g of 3- (4-chlorophenoxy) -1-propanol and 10.5 g of triethylamine in 250 ml dichloromethane is cooled to -5 ⁰ C and treated dropwise with 6.7 g methanesulfonyl chloride. After cooling and stirring for one hour, the mixture is washed with cold, 100 ml portions of water, 10 percent hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic layer is dried over magnesium sulfate and the solvent is removed in vacuo. In this way the product is obtained as an oil which crystallizes on standing.

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Example 43 4- / 2- (4-Chlorophenoxy) -propyiy-ainobenzoic acid

A mixture of 15 g of crude Ethy1-4- / 2- (4-chlorophenoxy) propyl / aminobenzoate, 15 g of potassium hydroxide and 100 ml of 95 percent ethanol is refluxed for 3 hours. The solution is cooled / diluted with 100 ml of water and mixed with 14 ml of concentrated hydrochloric acid. Cooling and filtering give 1.8 g of solid which is recrystallized from hexane / chloroform. 1.7 g of the product are thus obtained as brownish crystals with a melting point of 160 to 163 ^° C.

Example 44 2,3-Dihydroxypropyl 4- (3-phenoxypropyl) aminobenzoate

A solution of 5.5 g of 4- (3-phenoxypropyl) aminobenzoic acid, 4.80 g of 25 percent aqueous sodium hydroxide and 12.6 g of 3-iodo-1,2-propanediol in 50 ml of hexamethylphosphoramide Stirred for 24 hours at room temperature, diluted with "JOO ml of ether and then stirred for 5 days at room temperature. The mixture is diluted with water and extracted with ether. Evaporation of the dried extracts gives 2,3-dihydroxypropyl-4- (3-phenoxypropyl) aminobenzoate as a white solid.

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-M-

Example 45 2,3-Dihydroxypropyl 1-4- (3-phenoxypropyl) aminobenzoate

A solution of 5.5 g of 4- (3-phenoxypropyl) aminobenzoic acid in 50 ml of hexamethylphosphoramide is mixed with 4.80 g of 25 percent aqueous sodium hydroxide and then with 11.0 g of 3-chloro-1,2-propanediol added and then heated to 140 ° C for 6 hours. The mixture is diluted with water and ether and filtered to give a white solid substance. Recrystallization from acetonitrile gives pure 2,3-dihydroxypropyl 4- (3-phenoxypropyl) aminobenzoate as a white crystalline substance.

Example 46 2-p-fluorophenoxypropionic acid

A solution of 15.3 g of 2-bromopropionic acid in 50 ml of dimethoxyethane and 10.5 g of 4-fluorophenol in 50 ml of dimethoxyethane is added to 83 g of sodium hydride in 100 ml of dry dimethoxyethane at 5 ° C. The slurry is refluxed for 6 hours, cooled and filtered. The crude solid is distributed between methylene chloride and 1 η hydrochloric acid, and this process is repeated once more. The organic layer is dried and evaporated to 50 ml. The crystals are filtered off, washed with hexane and dried. F. = 113 to 115 ⁰ C.

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- 3 i P -

Example 47 2- (p-Fluorophenoxy) propanol

95 ml of diborane in 95 ml of tetrahydrofuran are mixed with 10.2 g 2- (4-fluorophenoxy) propionic acid in 100 ml of tetrahydrofuran offset. The reaction mixture is stirred for 20 hours at room temperature. The solution is gradually added to 600 g of ice poured and extracted three times with 250 ml of chloroform each time. The combined organic extracts are three times with each 50 ml of water extracted. The solvent is removed in vacuo to give a clear liquid.

Example 48 2- (4-fluorophenoxy) propyl O-methanesulfonate

A solution of 7.7 g of 2- (4-fluorophenoxy) propanol and 12.5 ml Triethylamine in 400 ml of methylene chloride at -5 ° C. is mixed with 8.8 ml of methanesulfonyl chloride. After 1 hour at 0 down to -8 C the mixture is 10 percent more with cold water Hydrochloric acid, saturated sodium bicarbonate solution and saturated saline solution and dried. It will be a light yellow Get liquid.

Example 49 & thyl p-2- (4-fluorophenoxy) propylaminobenzoate

A solution of 11.98 g of 2- {4-fluorophenoxy) propyl-O-methanesulfonic onate and 15.2 g of ethyl 4-aminobenzoate in 200 ml of dry hexamethylphosphoramide 46 hours at 120 to 130 ⁰ C stirred. The solution is diluted with 200 ml of water and extracted three times with 250 ml of ether each time. The United

709 824/1069

Ether extracts are extracted three times with 100 ml of water each time, dried, concentrated and applied to silica gel using chromatographed with chloroform as the eluent. The solution is evaporated and the residue is recrystallized from acetone / water and then from ether. It will be a White solid substance obtained from F. = 96 to 98 C.

Example 50 p-2- (4-Fluorophenoxy) propylaminobenzoic acid

A solution of 2.6 g of ethyl p- / 2- (4-fluorophenoxy) propyl / aminobenzoate in 100 ml of 95 percent ethanol containing 2.7 g of potassium hydroxide is refluxed for 2 hours. After cooling, the reaction mixture is diluted with 100 ml of water and neutralized with 37 percent hydrochloric acid. The solid is filtered off and dried, the white solid substance is dissolved in 25 ml of chloroform and the solution is diluted with 1 ml of hexane. As a result, a solid with a melting point of 171 to 172 ^° C. is obtained.

Example 51 2- (4-fluorophenoxy) ethanol

17.0 g of 4-fluorophenoxyacetic acid in 100 ml of tetrahydrofuran are added dropwise ^{at 5 to 10 °} C. to 200 ml of 1m diborane in tetrahydrofuran. The reaction device is stirred overnight at room temperature and poured into a mixture of 100 ml of ice with 750 ml of chloroform. The aqueous phase is extracted twice with 250 ml of chloroform each time, and the combined organic phases are dried. This solution is concentrated to a light yellow oil. Vacuum distillation of this oil provides 14.8 g of the product.

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- 34 -

Example 52 2- (4-fluorophenoxy) ethyl O-methanesulfonate

A solution of 125 g of 2- (4-fluorophenoxy) ethanol and 23 ml triethylamine in 100 ml methylene chloride at -5 ⁰ C is stirred under N ₂ and treated with 7 ml of methanesulfonyl chloride in 50 ml of methylene chloride. The solution is stirred for 2 hours at room temperature and then extracted with water, 10 percent hydrochloric acid, saturated sodium bicarbonate solution and brine. The organic layer is dried and evaporated to give a clear liquid which is used for the alkylation described in the following example.

Example 53 Ethyl p-2- (4-fluorophenoxy) ethylaminobenzoate

A solution of 18 g of 2- (4-fluorophenoxy) ethyl O-methanesulfonate and 27 g Xthyl 4-aminobenzoate in 150 ml of hexamethylphosphoramide is heated 2 days at 120 ⁰ C. The reaction mixture is then cooled and diluted with 100 ml of water. The solid formed is recovered and recrystallized first from methylene chloride / benzene and then from acetonitrile. In this way a white solid substance with a F. = 122 to 123 ^° C. is obtained.

Example 54 p-2- (4-fluorophenoxy) ethylaminobenzoic acid

6 g of KOH in 100 ml of 95 percent ethanol are added to the ethyl p-2- (4-fluorophenoxy) ethylaminobenzoate. The solution is refluxed for 3 hours and, after cooling, acidified with 9 ml of 37 percent hydrochloric acid. the

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Solution is diluted with 50 ml of water. The solid 'formed is obtained and initially from a mixture of Acetonitrile and ethyl acetate and then recrystallized from terahydrofuran / hexane. In this way a white powder is dated M.p. = 209 to 210 ° C.

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Claims (1)

Claims R _{1 is} hydrogen, a lower alkyl radical, a dialkylaminoethyl radical with lower alkyl groups, a 2,3-dihydroxypropyl radical, a 2-alkanoylaminoethyl radical with a lower alkanoyl group or a 1-methyl-4-piperidyl radical and X is a substituted phenyl radical, a naphthyl radical, a thienyl radical, a furyl radical, a 1,2,3,4-tetrahydronaphthyl radical or a 4-chloro-1-naphthyl radical, with halogen, hydroxyl, lower alkoxy, lower alkyl, cyano, trihalomethyl, amino, lower alkanoylamino, lower Alkylamino, lower dialkylamino, phenoxy, halophenoxy, benzyloxy, halobenzyloxy and cycloalkyl groups come into consideration, or if Y is 3 to 12 carbon contains atoms, a phenyl radical, and the salts of the compounds, in the formula of which R _{1 is} hydrogen, with alkalis and organic bases. 709824/1069 BRD - 2. Compounds according to claim 1, in their more general Formula mean: Y is a straight or branched alkyl chain with 2 to 6 carbon atoms, R. hydrogen or a lower alkyl or 2,3-dihydroxypropy! Group, X is a substituted phenyl radical, a naphthyl radical or a substituted naphthyl radical or, if Y contains 3 to 6 carbon atoms, a phenyl radical and the salts of the compounds, in the formula of which R _{1 is} hydrogen, with alkalis and organic bases. Process for the preparation of a compound of the formula XOY-NH- * 'X) -CO ₂ R ₁ ... I where mean: Y is a straight or branched chain alkylene group with 2 to 12 carbon atoms, R _{1 is} hydrogen or a lower alkyl or 2,3-dihydroxypropyl group, X is a phenyl, naphthyl, thienyl, furyl, 1,2,3,4-tetrahydronaphthyl, 4-chloro-1-naphthyl group or a substituted phenyl radical, the substituents of which are halogen or hydroxyl, lower alkoxy, lower alkyl, Cyano, trihalomethyl, amino, lower alkanoylamino, lower alkylamino, lower dialkylamino, Phenoxy, p-chlorophenoxy, benzyloxy, p-chlorine 709824/10 69 FRG -ν can be benzyloxy or cycloalkyl groups, and their pharmaceutically acceptable salts with alkalis or organic bases, characterized that p-aminobenzoic acid or a lower alkyl or other ester of this acid with an alkylating agent is reacted in the presence or absence of a solvent at 50 to 170 C for 1 to 25 hours. 4. The method according to claim 3, characterized in that an aryloxyalkylhaloxd, aryloxyalkanol-O-sulfate, -0-tosylate, -O-trifluoromethanesulfonate or -O-methanesulfonate is used as the alkylating agent. 5. As a compound according to claim 1, p-2- (4-chlorophenoxy) propylaminobenzoic acid. 6. As a compound according to claim 1, p-2- (4-fluorophenoxy) ethylaminobenzoic acid. 7. As a compound according to claim 1, ethyl p-2- (4-fluorophenoxy) propylaminobenzoate. 8. Process for the preparation of a compound of the formula • · · J. ψ -0-Y-NH- / '^ VcO ₂ R ₁ 709824/10 69 where mean: Y is a straight or branched chain alkylene group with 2 to 12 carbon atoms, R _{1 is} hydrogen, a lower alkyl group, a dialkylaminoethyl group with lower alkyl radicals, a 2,3-dihydroxypropyl group, a 2-alkanoylaminoethyl group with a lower alkanoyl group or a 1-methyl-4-piperidyl group, X is a phenyl, naphthyl, thienyl, furyl, 1, 2,3,4-tetrahydronaphthyl, 4-chloro-1-naphthyl or substituted phenyl group, the substituents of which are halogen, hydroxyl, lower alkoxy, lower alkyl, cyano, trihalomethyl, amino, lower alkanoylamino, lower Alkylamino or dialkylamino, phenoxy, p-chlorophenoxy, Can be benzyloxy, p-chlorobenzyloxy or cyclalkyl and their pharmaceutically acceptable salts, thereby characterized in that a compound of the formula X-O-Y-A ..II, a straight or branched chain alkylene group (C _n H _2n ) with 0 to 11 carbon atoms (n = 0 to 11), Hydrogen when η = 0, or CH ₀ Z, CT or 2 - \ _z and Z halogen, hydroxy, alkoxy, alkylsulfonate or Arylsulfonate ester or trialkylammonium means with a compound of the formula D 709824/1069 BRD - wherein B a haloalkylenamino, alkyl or arylsulfonyloxyalkylenamino , aziridino, acylamino or amino group or a group which can be converted into this and D is a carboxylic acid or ester group or one which can be converted into it. Mean nitrile or amide group, where in formula II A is hydrogen, and η has the value if B is a haloalkylenamino, alkyl or arylsulfonyloxyalkylenamino or aziridino group, is implemented. 9. Process for the preparation of ethyl-p-2- (4-chlorophenoxy) Propylaminobenzoate according to Claim 8, characterized that 2- (4-chlorophenoxy) propyl mesylate is reacted with ethyl 4-aminobenzoate. 10. Process for the preparation of p-2- (4-fluorophenoxy) ethylaminobenzoic acid according to claim 8, characterized ge indicates that 4-fluorophenoxyethyl bromide reacted with 4-aminobenzonitrile and then the formed p- (4-fluorophenoxyethyl) aminobenzonitrile is hydrolyzed. 11. Process for the preparation of ethyl p-2- (4-fluorophenoxy) ethylaminobenzoate according to claim 8, characterized in that sodium 4-fluorophenoxide with ethyl p-2-bromoethylaminobenzoate in the presence of a base, such as potassium carbonate, reacted. 70982A / 1069 BRD - 44 - 12. Process for the preparation of p-2 ~ (4-chlorophenoxy) propylaminobenzoic acid according to claim 8, characterized in that 2- (4-chlorophenoxy) propyl mesylate reacted with N-sodio-ethyl-4-acetylaminobenzoate and then the ethyl N-acetyl-p - / _ 2- (4-chlorophenoxy) propyl / aminobenzoate formed is hydrolyzed. 13. Process for the preparation of p-2- (4-fluorophenoxy) ethylaminobenzoic acid according to claim 8, characterized in that 4-fluorophenoxyacetaldehyde with 4-nitrobenzoic acid is reacted by means of chemical reduction or catalytic hydrogenation. 14. Process for the preparation of ethyl p-2- (4-fluorophenoxy) propylaminobenzoate according to claim 8, characterized in that 2- (4-fluorophenoxy) propionyl chloride reacted with ethyl 4-aminobenzoate and then the ethyl p- / 2- (4-fluorophenoxy) propionyl _ / - aminobenzoate catalytic hydrogenated or reacted with a reducing agent such as diborane. 15. Use of compounds of the formula ζ-0-Y-NHy ^ -CO ₂ R ₁ wherein X, Y and R _{1 have} the meanings given in claim 1 and X can in all cases also be an unsubstituted phenyl radical, as well as their pharmaceutically acceptable acid addition salts, and when R ^ is hydrogen, their salts with alkalis or organic bases as active ingredients of drugs to reduce the sterol and triglyceride content of the serum of warm-blooded animals. 709824/1069