HU185854B - Process for preparing new sulphonamide derivatives - Google Patents

Abstract

FIELD OF THE INVENTION The present invention relates to novel sulfonamides of formula (I) having lipid-lowering and platelet aggregation inhibitory activity, wherein R is hydrogen, C1-C18 alkyl, phenyl or naphthyl optionally substituted with hydroxy, halogen with trifluoromethyl, 1-4. substituted with C 1 -C 4 alkyl or alkyl having 1 to 4 carbon atoms, or C 2-5 alkanoyl, carboxy or alkyl having 1 to 4 carbon atoms, or substituted phenyl with halogen; or R 1 is phenylalkyl or phenylalkenyl containing from 2 to 5 carbon atoms of the alkyl or alkenyl moiety, and the phenyl portion of which may be substituted by halogen, n is 2 or 3; a bond or a straight or branched alkylene chain which is saturated and has an alkyl moiety of 1 to 6 carbon atoms or a double bond and contains 2 to 6 carbon atoms in the alkenyl moiety, and physiologically tolerable salts thereof, C 1 -C 4 alkyl esters and 4-methylpiperazides. R, -SO1-N-1CH2-, VW-C10H1-WY (I) (I) R, -SO3H, R, -SO1-NH1-SO2 -N- (CH2) n- / VW- 2: ni) ÍV) -1-

Description

The present invention relates to novel sulfonamidophenylcarboxylic acids and their derivatives and to pharmaceutical compositions containing them.

Nos. 2604560 and 2532420. Disclosures in the Federal Republic of Germany describe phenylcarboxylic acids substituted with a carboxylic acid group which are blood glucose lowering and lipid lowering agents. Surprisingly, it has been found that analogous phenylcarboxylic acids substituted with one sulfonamide group have excellent lipid-lowering and antiplatelet activity.

Accordingly, the present invention relates to a process for the preparation of sulfonamides of the formula I wherein R is hydrogen,

R 1 is C 1 -C 18 alkyl, phenyl or naphthyl optionally substituted with hydroxy, halogen, trifluoromethyl, C 1 -C 4 alkyl, or alkyl of 1 to 4 carbon atoms in the alkyl group, or C 2 -C 5 alkanoyl, carboxy or alkyl. in each case they may be substituted by an alkoxycarbonyloxy group containing from 1 to 4 carbon atoms or the phenyl group may be substituted twice by halogen, or

R 1 is phenylalkyl or phenylalkenyl having from 2 to 5 carbon atoms in the alkyl and alkenyl moieties which may be optionally substituted by halogen, n being 2 or 3,

W is a bond or a straight or branched alkylene chain which is saturated and is in the alkyl moiety

Containing from 1 to 6 carbon atoms or a double bond and from 2 to 6 carbon atoms in the alkenyl moiety, and their physiologically tolerable salts, C 1 to C 4 alkyl esters and 4-methylpiperazide.

Among the alkyl groups of the R 1 substituent, methyl, ethyl, octyl and hexadecyl are preferred as straight or branched alkyl groups.

In each case, the alkyl groups and the alkoxy groups may be straight or branched. Methyl for straight chain alkyl, tert-butyl for branched chain and methoxy for alkoxy are preferred. A preferred alkanoyl group is acetyl.

Among the phenylalkyl groups, phenethyl and a

4-chloro-phenethyl.

Of the phenylalkenyl groups, such groups having from 2 to 3 carbon atoms alkenyl groups are suitable, preferably the styryl group and the 4-chloro-styryl group.

Halogen is preferably fluorine, chlorine or bromine.

Examples of straight-chain alkylene W include saturated -CH ₂ -, - (CH ₂ ) ₂ and - (CH ₂ ) ₃ - and unsaturated -CH = CH-.

For example, branched chain W alkylene groups are saturated

-CH- ch ₃ —CH ₂ —CH— 1 | ch ₃ , 1 —C— and ích ₃ 1 CH ₃ groups,

and unsaturated —C = CH— —CH = C—

I I

They may be CH ₃ and CH ₃ .

The esters derived from the carboxylic acids of the formula I contain as monohydric alcohols containing from 1 to 4 carbon atoms, preferably methanol, ethanol or n-butanol.

The above definition of compounds of the present invention includes all possible stereoisomers as well as mixtures thereof.

The process of the invention is characterized in that ai) an amine of formula II, wherein R, n and W are as defined above and

Y is a group of the formula - COOR _{2 in} which -OR _{2 is} hydroxy or C 1-4 alkoxy or

Represents a 4-methylpiperazin-1-yl group, or represents a group which, upon condensation, is converted to said COOR ₂ group, or a salt thereof with a sulfonic acid of formula III, wherein R 1 is as defined above - or a derivative thereof, or ₂ ) a free sulfonic acid of the general formula (III)

R1 is as defined above for a compound of formula IV

R, η, Y and W are as defined above and

Ac is an easily replaceable acyl group - reacted in a suitable solvent, or

b) a sulfonamide of formula V in the formula

R and R 1 are as defined above for a compound of formula VI: wherein n and W are as defined above,

Y is a group of the formula -COOR _2, wherein -OR ₂ is hydroxy or C1-4 alkoxy radical, or 4-methyl-piperazin-l-yl or is a group which _two of the said after condensation -COOR is converted to a group of the formula and

X is a reactive group - react.

Some of the compounds of the invention may also be prepared by:

c) reacting a compound of formula IX wherein m is 0, 1 or 2 under optionally modified Willgerodt-Kindler reaction conditions.

Reactive derivatives of the sulfonic acids of the formula III include in particular halides and esters. The reaction of the sulfonic acid halides with the compounds of the formula II is conveniently carried out in the presence of an acid scavenger such as alkali metal acetate, sodium bicarbonate, sodium carbonate, sodium phosphate, calcium oxide, calcium carbonate or magnesium carbonate.

185,854 finally. However, this function may also be performed by organic bases such as pyridine or triethylamine, where inert solvents include ether, benzene, methylene chloride, dioxane or excess tertiary amine.

When using an inorganic acid scavenger, the reaction medium is, for example, water, aqueous ethanol or aqueous dioxane.

The transacylation reaction between the free sulfonic acid (III) and the acylamine (IV) is preferably carried out with an equimolar amount of the two reaction partners in a polar solvent. Suitable polar solvents are, for example, alcohols, in particular ethanol and methanol. The reaction is preferably carried out at the reflux temperature of this solvent. Examples of easy-to-replace acyl groups include acetyl.

The alkylation of the sulfonamides of the formula V is preferably carried out using a compound of the formula VI in which X is an arylsulfonyloxy group, preferably a toluenesulfonyloxy group. Also useful as alkylating agents are alkyl arylsulfonic acid esters. For the application of the latter to sulfonic acid amides, see, for example, Klamann et al., Monatshefte für Chemie, 83, 871. (1952). The reaction is carried out in an alkaline medium, preferably in hot concentrated soda solution as the reaction medium.

The ketones of formula IX used in process c) are readily prepared by Friedel-Crafts acylation. They are reacted with sulfur and a secondary amine, preferably morpholine. The thiomorpholide formed in this Willgerodt-Kindler reaction is saponified to a carboxylic acid in a manner known per se using a strong alkaline base or a strong hydrochloric acid or a mixture of sulfuric acid, acetic acid and water.

Exemplary Y substituents for converting the compounds of formula (IV) to -COOR ₂ include nitrile, carbaldehyde, hydroxymethyl, aminomethyl, and formyl.

Fixed group containing R ₂ substituents optionally converting subsequent condensation with the corresponding carboxylic acid _(R2 = H) by saponification polar such as carboxylic acid ester (R ₂ = alkyl) with a mineral acid or an alkali metal hydroxide in a solvent (such as water, methanol, ethanol, dioxane or acetone) It happens. The saponification is preferably carried out with a strong base (such as sodium or potassium hydroxide), methanol-water, at room temperature, or at a moderately elevated temperature. Conversely, the carboxylic acid can also be esterified in the usual manner or one ester having a particular R ₂ group may be esterified to another ester having a R ₂ group. The esterification of the carboxylic acids is conveniently carried out in the presence of a catalyst such as hydrochloric acid, sulfuric acid, p-toluenesulfonic acid or a strongly acidic ion exchange resin. In contrast, transesterification requires the addition of a small amount of a basic material, such as an alkali metal or alkaline earth metal hydroxide or an alkali metal alcoholate. In principle, any of the aforementioned C 1 -C 4 monovalent alcohols such as methanol, ethanol or propanol are suitable for esterification or transesterification of the carboxyl group.

The 4-methylpiperazide of the carboxylic acids of formula I according to the invention is preferably prepared by methods known per se, from carboxylic acids or their reactive derivatives (e.g. carboxylic acid halides, esters, azides, anhydrides or mixed anhydrides). -piperazine.

With physiologically tolerable organic or inorganic bases such as. to produce salts with sodium hydroxide, potassium hydroxide, calcium hydroxide, methylglucamine, morpholine or ethanolamine, the carboxylic acids are reacted with the appropriate bases. A mixture of the carboxylic acid with a suitable alkali metal carbonate or bicarbonate is also contemplated.

The compounds of formula (I), their physiologically tolerable salts and the said esters and 4-methylpiperazides of the present invention exhibit both excellent lipid lowering activity and a particular antiplatelet effect.

For the preparation of pharmaceutical compositions, the compounds of the formula I are admixed in a manner known per se with suitable pharmaceutical carriers, flavoring, flavoring and coloring agents and, for example, formulated into tablets or dragees or with the addition of suitable excipients in water or oil. suspended or dissolved in olive oil.

The compounds of formula (I) may be administered in liquid or solid form orally or parenterally. Preferably, the injection medium is water, which contains stabilizing agents, solubilizers and / or buffers customary in the preparation of the injection solution. Such additives are e.g. tartrate or borate buffers, ethanol, dimethyl sulfoxide, complexing agents (such as ethylenediaminetetraacetic acid), high molecular weight polymers (such as liquid polyethylene oxide) for viscosity control or polyethylene derivatives of sorbitan anhydrides.

Solid carriers, e.g. starch, lactose, mannitol, methylcellulose, talc, highly dispersed silica, higher molecular weight fatty acids (such as stearic acid), gelatin, agar, calcium phosphate, magnesium stearate, animal and vegetable fats or solid high molecular weight polymers (such as polyols). Formulations suitable for oral administration may, if desired, contain flavoring and sweetening agents.

The dosage administered will depend on the age, health and weight of the individual, the progress of the disease, the concomitant treatment, if any, the frequency of treatment and the effect desired. The daily dose will generally be from 0.1 to 50 mg / kg of active compound. Under normal conditions, 0.5 to 40 and preferably 1.0 to 20 mg / kg / day are administered in a single or multiple daily dose to achieve the desired effect.

The effect of the compounds of the present invention on the commercial acetylsalicylic acid composition is demonstrated by the following experimental results:

Testing methods

1. Lipid reduction

10 to 10 male metabolically healthy rats tested for 7 days 50

It is administered orally at a dose of -3185854 mg / kg in methylcellulose suspension. At the end of the experiment, 3 hours after the final probing, the animals' serum cholesterol and triglyceride values were determined. Change was determined by comparison with a control group of animals.

2. Inhibition of aggregation

The effect on platelet aggregation was investigated by the Born test.

(a) Method

Venous blood from experimental healthy animals is mixed with sodium citrate (9: 1 ratio). Centrifugation at 150 g accelerates the erythrocytes to settle. In the material above the settled material, the platelets are enriched. This supernatant is called Plate-rich Plasma (LDP).

An aliquot of the LDP is filled into the cuvette of an aggregometer (manufactured by the "Braun Melsungen" Universal Aggregometer ") and mixed there with a small magnetic stirrer. The test substance is added as an aqueous solution (about pH 7) to the LDP. Changes in the light transmission of the suspension are continuously recorded by a writing device. After spontaneous aggregation occurs, aggregation occurs with the addition of 5 x 10 ^-1 adrenaline. Larger platelet aggregates are formed and as a result the light transmission of the suspension is increased.

(b) Evaluation

Acid adrenaline-induced aggregation occurs in 2 phases. Light transmission first increases, stagnates briefly, and then increases again. Only phase 2 of aggregation can be influenced by the anti-aggregation agent.

To quantify the results, the angle of aggregation phase 2 with horizontal adrenaline-induced aggregation is determined and is called the 0% inhibitory effect (control experiment).

After addition of the test substance with the same LDP, aggregation is induced with adrenaline and the course of aggregation is recorded with the writing device. The horizontal angle of Phase 2 is again determined and the ratio of the two angles gives the% inhibition of Phase 2 platelet aggregation.

Comparable acetylsalicylic acid inhibits 100% at ΙΟ ^-4 M and 0% at 5 × 10 ^-5 M.

All substances were tested at 5 × 10 ^-5 concentrations.

In addition to those listed in the Examples, the use of the following compounds, which may be obtained by the process of the invention, is particularly advantageous:

4- (2-benzolszulfonamidoetil) phenylacetamide

3- {4- [2- (4-phenylsulfonamidocarbonyl) -ethyl] -phenyl} -propionic acid

3- {4- [2- (4-phenylsulfonamidocarbonyl) -ethyl] -phenyl} -propionamide

3- {4- [2- (4-phenylsulfonamidocarbonyl) ethyl] phenyl] propionate

The following examples illustrate the process of the invention without limiting it.

s. The material of Example lipid lowering Inhibitory effect of adrenaline-induced aggregation triglycerides cholesterol 1 24 7 0 la 9 13 100 lb 0 10 0 juice 38 7 100 cf. 10 10 0 3 34 8 100 3a 0 20 0 3b 10 3 0 3c 30 7 50 3f 24 5 100 3g 20 10 30 4 10 10 100 4a 31 11 100 4b, 10 39 16 20 4c 0 12 0 4d, 9 42 19 100 4e 20 6 100 4f 14 0 100 4g 10 0 100 4h 22 0 50 4i 27 0 100 4j 10 0 10 4k 50 25 50 41 20 0 100 4m 22 12 100 5 20 SHE 6 10 0 0 7 10 0 0

Example 1

4- [2- (2-Feniletánszulfonarnido) ethyl} benzoate

14.3 g (70 mmol) of 4- (2-Aminoethyl) benzoic acid ethyl ester hydrochloride in 150 mL of abs. ice-cooled pyridine solution with stirring for one hour

2-Phenylethanesulfochloride (16.1 g, 70 mmol) was added dropwise. The cooling bath was then removed and the reaction mixture was stirred for 2 hours at room temperature. The mixture was then poured into ice water and acidified with concentrated hydrochloric acid. An oil precipitates out and is dissolved in ether. The aqueous phase is extracted once more with ether, the combined ethereal phases are dried over sodium sulfate and finally evaporated. The residue was crystallized from a mixture of ethyl acetate and ligroin. 18.4 g (73% of theory) of 4- (2- (2-phenylethanesulfonamido) ethyl) benzoic acid ethyl ester are obtained, m.p. 83-86 ° C.

A mixture of 12.5 g (35 mmol) of 4- [2- (2-phenylethanesulfonamido) ethyl] benzoic acid ethyl ester, 70 mL of 1N potassium hydroxide and 200 mL of methanol was heated at 35 ° C for 2 hours. It is then acidified with 2N hydrochloric acid. The methanol was evaporated and the remaining aqueous layer was extracted several times with methylene chloride. The combined methylene chloride layers were washed with water, dried over sodium sulfate and evaporated. The residue was dissolved in sodium bicarbonate solution and precipitated with 5N hydrochloric acid. The crystals are filtered off with suction and dried.

9.3 g (88% of theory) of 4- [22- (2-phenylethanesulfonamido) ethyl] -benzoic acid are obtained, m.p. 183-186 ° C.

185,854

In an analogous way:

a) 4- [2- (4-Chlorobenzenesulfonamido) ethyl] -benzoic acid ethyl ester 4- (2-aminoethyl) benzoic acid hydrochloride and 4-chlorobenzenesulfonate chloride, m.p. 87-89 ° C, were obtained in a yield of 84%, m.p. hydrolysis gives 4- [2- (4-chlorobenzenesulfonamido) ethylbenzoic acid, m.p. 199-201 ° C, in 91% yield,

b) 4- (2-aminoethyl) phenylacetic acid ethyl ester hydrochloride. and 2- (4-chlorophenyl) -ethanesulfochloride, m.p. 69-70 ° C (from aqueous ethanol), 4- {2- [2- (4-chloro-phenyl) -ethanesulfonamido] -ethyl} -phenylacetyl ester is obtained in 76% yield. and hydrolysis to give 4- (2- [2- (4-chlorophenyl) ethanesulfonamido] ethyl) phenylacetic acid, m.p. 155-156 ° C, in 67% yield, m.p.

c) 4- (2-Aminoethyl) -phenylacetic acid ethyl ester hydrochloride and 2- (4-chlorophenyl) -ethanesulfochloride, m.p. 101-102 ° C (from 66% ethanol) 4- [2- (4-chlorophenyl) ethanesulfonamido] - Ethyl} -phenylacetic acid ethyl ester is obtained in a yield of 70% of theory, and hydrolysis gives 4-N- [2- (4-chlorophenyl) ethanesulfonamido] ethyl} phenylacetate, m.p. 175-176 ° C (aqueous). yield,

d) 4- [2- (4-Chloro-benzenesulfonamido) -ethyl] -phenylacetate is obtained from 4- (2-amino-ethyl) -phenyl-acetic acid ethyl ester hydrochloride and 4-chlorobenzenesulfonate by melting at 88-90 ° C (from ethyl acetate-ligroin). yields 4- [2- (4-chlorobenzenesulfonamido) -ethyl] -phenylacetic acid, m.p. 138-140 ° C (from acetic ester + ligroin) in 93% yield, m.p.

e) 4- [2- (4-Carboxybenzenesulfonamido) ethyl] phenylacetate from 4- (2-aminoethyl) phenylacetic acid ethyl ester hydrochloride and 4-carboxybenzene sulfochloride, m.p. > 360 DEG C., m.p. and hydrolysis to give 4- (2- (4-carboxybenzenesulfonamido) ethyl) phenylacetic acid, m.p. 340 DEG C., in 85% yield, m.p.

Example 2

4- (2-Metánszulfonamidoetil) benzoic acid

150 ml Abs. Pyridine, 12.8 g (92 mmol) of powdered anhydrous potassium carbonate and 21.25 g (92 mmol) of ethyl 4- (2-aminoethyl) -benzoic acid hydrochloride are added dropwise at 10-15 ° C to 10.6 g (92 mmol) of methanesulfochloride. . The reaction mixture was then stirred for 30 minutes at 20 ° C, then for 5 minutes at 80 ° C, then cooled and poured into ice water. It is acidified with concentrated hydrochloric acid and the precipitated material is extracted with methylene chloride. After drying over sodium sulfate, the methylene chloride phase is evaporated in this way

24.8 g (98% of theory) of 4- (2-methanesulfonamidoethyl) -benzoic acid ethyl ester, m.p. 96-99 ° C, are obtained.

By analogy to Example 1, hydrolysis of the diethyl ester gave 4- (2-methanesulfonamidoethyl) benzoic acid, m.p. 173-174 ° C, in 93% yield. In an analogous way:

b) 4- (2-Aminoethyl) -phenylacetic acid ethyl ester hydrochloride and methanesulfochloride are obtained in the form of a colorless oil, 4- (2-methanesulfonamidoethyl) -phenylacetic acid ethyl ester in 81% yield, m.p. 170-172 ° C.

4- (2-methanesulfonamidoethyl) phenylacetic acid was obtained in 79% yield, m.p.

b) 2- [4- (2- (2-Aminoethyl) phenyl] propionic acid ethyl ester hydrochloride and 2-phenylethanesulfochloride are obtained in the form of a colorless oil, 2- {4-] 2- (2-phenylethanesulfonamido) ethyl] phenyl-propionic acid ethyl ester. Yield 77% and hydrolysis yields 2- [4- (2- (2-phenylethanesulfonamido) ethyl) phenyl] propionic acid, m.p. 94-97 ° C (69%).

c) 2- [4- (2-Aminoethyl) phenyl] -2-methylpropionic acid ethyl ester hydrochloride and 2-phenylethanesulfochloride as a colorless oil 2- {4- [2- (2-phenylethanesulfonamido) ethyl] phenyl} -2 Methyl propionic acid ethyl ester is obtained in a yield of 52% of theory, by hydrolysis, m.p. 109-110 ° C (from ethanol + water) 2- {4- [2- (2-phenylethanesulfonamido) ethyl] phenyl} -2- methyl propionic acid was obtained in 62% yield.

d) 3- [4- (2-Aminoethyl) phenyl] propionic acid ethyl ester anhydride and 2- (4-chlorophenyl) ethanesulfochloride, m.p. 70-71 ° C (ethanol) 3- (4- {2- [2- (4) -chlorophenyl) -ethanesulfonamido] -ethyl} -phenyl) -propionic acid ethyl ester was obtained in 66% of theory with hydrolysis from 157-158 ° C (ethanol + water) 3- (4- {2- [2- (4) -chlorophenyl) -ethanesulfonamido] -ethyl} -phenyl) -propionic acid was obtained in 76% yield.

e) 3- [4- [2- (4-Chloro-benzenesulfonamido) -ethyl] -phenyl} -3- [4- (2-amino-ethyl) -phenyl] -propionic acid ethyl ester hydrochloride and 4-chlorobenzenesulfonyl chloride m.p. 61-62 ° C. Propionic acid ethyl ester is obtained in a yield of 65% (from ethanol + water) in 65% yield and hydrolysis with 3- {4- [2- (4-chlorobenzenesulfonamido) ethyl] phenyl} propionic acid (87%). yield,

f) 4- [2- (n-Hexadecane sulfonamido) ethyl] cinnamic acid ester from 4- (2-aminoethyl) cinnamic acid hydrochloride and n-hexadecane sulfochloride (m.p. 104 ° C) was obtained in a yield of 71% of theory. from which, by hydrolysis, 4- [2- (n-hexadecylsulfonamido) ethyl] cinnamic acid, m.p. 164-165 ° C (from ethanol + water), is obtained in 76% yield,

g) 4- (2-aminoethyl) cinnamic acid ethyl ester hydrochloride and 2-phenylethanesulfochloride, m.p. 98-99 ° C.

4- [2- (2-Phenylethanesulfonamido) ethyl] cinnamic acid ethyl ester and hydrolyzed to give 4- [2- (2-phenylethanesulfonamido) ethyl] cinnamic acid, m.p. 187-1888, in 76% yield.

k) 4- (2-aminoethyl) cinnamic acid ethyl ester hydrochloride and? - (4-chlorophenyl) ethanesulfochloride. 91-92 ° C (from ethanol + water) 4- {2- [2- (4-chlorophenyl) -ethanesulfonamido] -ethyl} -cinnamic acid ethyl ester is obtained in a yield of 63% with a yield of 212-213 ° C. Melting point C (from ethanol + water) gave 4- {2- [2- (4-chlorophenyl) ethanesulfonamido] ethyl (cinnamic acid) in 94% yield from 4- (2-aminoethyl) cinnamic acid ethyl ester hydrochloride and 97-98 ° C (from ethanol) 4- [2- (4-chlorobenzenesulfonamido) ethyl] cinnamic acid ethyl ester is obtained in 92% yield from theory, m.p. 173-175 ° C. (4-Chlorobenzenesulfonamido) ethyl] cinnamic acid was obtained in 93% yield.

j) 4- [2- (1-Naphthylsulfonamido) ethyl] cinnamic acid ethyl ester 4- (2-aminoethyl) cinnamic acid hydrochloride and 1-naphthyl sulfochloride (m.p. 85-86 ° C) were obtained in 88% yield. and hydrolysis to give 4- [2- (1-naphthylsulfonamido) ethyl] cinnamic acid (m.p. 175 ° C) in 93% yield, m.p.

k) 4- (2- (2-Phenylethylsulfonamido) ethyl) cinnamic acid 4- (2-aminoethyl) cinnamic acid hydrochloride and 2-phenylethylsulfochloride, m.p. 102-104 ° C, are obtained in a yield of 63% of theory. hydrolysis gives 4- [2- (2-phenylethylsulphonamido) ethyl] cinnamic acid, m.p. 190-191 ° C, in 94% yield,

l) 4- (2- [2- (4-Chlorophenyl) ethenesulfonamido) ethyl) 4- (2-aminoethyl) cinnamic acid ethyl ester hydrochloride and 2- (4-chlorophenyl) ethylene sulfochloride, m.p. 131-132 ° C. ) - cinnamic acid ethyl ester (83% of theory) and hydrolysis yields 4- {2- [2- (4-chlorophenyl) -ethenesulfonamido] -ethyl} -cinnamic acid, m.p. 211-212 ° C (from ethanol + water). os.

Example 3

4- [2- (4-toluolszuifonamido) ethyl] -feniIecetsav

14.6 g (60 mmol) of 4- (2-aminoethyl) phenylacetic acid ethyl ester hydrochloride in 120 ml of abs. A solution of 12.0 g (63 mmol) of 4-toluenesulfochloride in 50 ml of pyridine was added dropwise to a solution of pyridine at 0 to 10 ° C over 5 minutes, allowed to warm to room temperature and heated at 60 ° C for 45 minutes. The reaction mixture was then concentrated in vacuo to half volume, poured into ice water and acidified with hydrochloric acid. The viscous mass which precipitated was dissolved in ethyl acetate and dried over sodium sulfate. Concentrate in vacuo and recrystallize the residue from ethyl acetate / ligroin. This gave 4- [2- (4-toluenesulfonamido) ethyl] phenylacetic acid ethyl ester, m.p. 113-115 ° C (18%) (82% of theory).

To a solution of 4- [2- (4-toluenesulfonamido) ethyl] phenylacetic acid ethyl ester (13.3 g, 37 mmol) in ethanol (220 mL) was added dropwise 1 N potassium hydroxide (110 mL) and the reaction mixture was heated at 35-40 ° C for 2 hours. The ethanol is then distilled off in vacuo and the aqueous phase is extracted with ether. Addition of 55 ml of 2N hydrochloric acid gives a colorless precipitate which is filtered off with suction and recrystallized from ethyl acetate-lignin. 10.8 g (88% of theory) of m.p. 141-143 ° C

4- [2- (4-Toluenesulfonamido) ethyl] phenylacetic acid is obtained.

In the same way as above

a) 4- (2- (2-Phenylethylsulfonamido) ethyl) benzoic acid ethyl ester 4- (2-aminoethyl (benzoic acid ethyl ester hydrochloride) and 2-phenylethylsulfochloride, m.p. 59-61 ° C. and hydrolysis

Mp 169.5-170 ° C (from ethyl acetate), yielding 4- [2- (2-phenylethylsulfonamido) ethyl] benzoic acid in 81% yield, m.p.

b) 4- [2- (2-Phenylethanesulfonamido) -ethyl] -phenylacetic acid ethyl ester from 4- (2-aminoethyl) -phenylacetic acid hydrochloride and 2-phenylethylsulfochloride is obtained as a colorless oil in 61% yield with 150% hydrolysis; (Ethyl acetate) 4- [2- (2-phenylethanesulfonamido) ethyl] phenylacetic acid, m.p.

c) 4- [2- (2-Phenylethylsulfonamido) ethyl] phenylacetic acid ethyl ester from 4- (2-aminoethyl) phenylacetic acid ethyl ester hydrochloride and 2-phenylethylsulfochloride is obtained in a yield of 78% from the theoretical amount, ° C (ethyl acetate + Ugride) 4- [2- (2-phenylethylsulfonamido) ethyl] phenylacetic acid was obtained in 81% yield, m.p.

d) 3- {4- [2- (2-Chloro-benzenesulfonamido) -ethyl] -phenyl} -propionic acid ethyl ester from 3- [4- (2-amino-ethyl) -phenyl] -propionic acid hydrochloride and 2-chloro-benzenesulfonamide, m.p. 57-60 ° C. Yield: 94% of theory, and hydrolysis yields 3- {4- [2- (2-chlorobenzenesulfonamido) -ethyl] -phenyl] -propionic acid, m.p. 136-139 ° C (from ethyl acetate).

e) 3- {4- [2- (3-Methoxy-benzenesulfonamido) -ethyl] -phenyl} -propionic acid ethyl ester from 3- (4- (2-aminoethyl) -phenyl] -propionic acid hydrochloride and 3-methoxybenzenesulfonyl chloride as a colorless oil 92 100% to 103 ° C (triturated with ether) to give 3- {4- [2- (3-methoxybenzenesulfonamido) -ethyl] -phenyl {-propionic acid in 65% yield, m.p.

f) 3- [4- (2- (3-Trifluoromethyl-benzenesulfonamido) -ethyl] -phenyl} -propionic acid ethyl ester is obtained from 3- [4- (2-amino-ethyl) -phenyl] -propionic acid hydrochloride and 3-trifluoromethyl-benzenesulfonamide as a colorless oil. (hydrolysis) yields 3- (4- [2- (3-trifluoromethylbenzenesulfonamido) ethyl] phenoxy} propionic acid, m.p. 119-121 ° C, in 74% yield, m.p.

g) 3-] 4- (2-Aminoethyl) phenyl] -propionic acid ethyl ester hydrochloride and 2- (4-chlorophenyl) -ethenesulfonyl chloride, m.p. 94-96 ° C (ethyl acetate + from Hgrom)

3- (4- {2- [2- (4-Chloro-phenyl) -ethenesulfonamido] -ethyl} -phenyl} -propionic acid ethyl ester was obtained in 86% yield with a hydrolysis melting at 165 ° C (from ethyl acetate + ligroin) 3- ( 4-12- [2- (4-Chlorophenyl) -ethenesulfonamido] -ethyl} -phenyl) -propionic acid is obtained in 73% yield.

Example 4

4- [2- (4-Fluorbenzolszulfonamido) ethyl] phenylacetic acid

A mixture of 11.0 g (51 mmol) of 4- (2-Minoethyl) phenylacetic acid hydrochloride, 8.3 g (60 mmol) of potassium carbonate and 200 mL of water is heated to 80 ° C and at this temperature

4-Fluorobenzene sulfochloride (9.5 g, 49 mmol) was added. The reaction mixture was heated at 80 ° C for a further 2 hours, then cooled and adjusted to pH 2 with 2N hydrochloric acid. The precipitate was filtered off with suction, dried and recrystallized from 66% ethanol.

10.2 g (62% of theory) of 4- [2- (4-fluorobenzenesulfonamido) ethyl] phenylacetic acid, m.p. 121-122 ° C.

185,854

In an analogous way

a) 3- [4- (2-Benzenesulfonamidoethyl) phenyl] propionic acid is obtained from 3- [4- (2-aminoethyl) phenyl] propionic acid hydrochloride and benzene sulfochloride, m.p. 102.5-103 ° C (from ethyl acetate + ligroin). with a yield of 63%,

b) 4- (2-Benzenesulfonamidoethyl) -benzoic acid is obtained from 4- (2-aminoethyl) -benzoic acid hydrochloride and benzene sulfochloride, m.p. 144.5-145 ° C (aqueous ethanol), m.p.

c) 4- (2- (4-methoxybenzenesulfonamido) ethyl) -benzoic acid is obtained from 4- (2- (4-methoxybenzenesulfonamido) ethyl) benzoic acid, m.p. 177-178 ° C from 4- (2-aminoethyl) benzoic acid hydrochloride and 4-methoxybenzenesulfonate chloride.

d) 4- (2-Benzenesulfonamidoethyl) phenylacetic acid is obtained from 4- (2-aminoethyl) phenylacetic acid hydrochloride and benzene sulfochloride (m.p. 127-128 ° C) in a yield of 92%, m.p.

e) 4- (2- (4-methoxybenzenesulfonamido) ethyl) phenylacetic acid, m.p. 160-162 ° C (4- (2-aminoethyl) phenylacetic acid hydrochloride, m.p. 160-162 ° C) is obtained in a yield of 72% of theory.

f) 4- [2- (4-Acetylbenzenesulfonamido) -ethyl] -phenylacetic acid is obtained from 4- (2-aminoethyl) -phenylacetic acid hydrochloride and 4-acetylbenzene-sulfochloride, m.p. 193-194 ° C.

g) 4- (2- (2-naphthalenesulfonamido) ethyl) phenylacetic acid is obtained from 4- (2-aminoethyl) phenylacetic acid hydrochloride and 2-naphthalenesulfochloride (m.p. 135-136 ° C) in 68% yield, m.p.

h) 4- (2-aminoethyl) cinnamic acid hydrochloride and benzene sulfochloride, m.p. 164-166 ° C (aqueous ethanol) yields 4- (2-benzenesulfonamidoethyl) cinnamic acid in 73% yield, m.p.

i) 4- (3-Benzenesulfonamidopropyl) -benzoic acid is obtained from 4- (3-aminopropyl) -benzoic acid hydrochloride and benzene sulfochloride, m.p. 207.5-209 ° C (aetone + water), m.p.

(j) 4- (benzenesulfonamidomethyl) phenylacetic acid is obtained from 4-aminomethylphenylacetic acid hydrochloride and benzene sulfochloride (m.p. 144.5-145.5 ° C) in a yield of 76% of theory;

k) 4- (3-Benzenesulfonamidopropyl) phenylacetic acid is obtained from 4- (3-aminopropyl) phenylacetic acid hydrochloride and benzene sulfochloride, m.p. 128-129 ° C (from ethyl acetate + ligroin), m.p.

l) 2- [4- (2-Amino-ethyl) -phenyl] -2-methyl-propionic acid hydrochloride and benzene sulfochloride m.p. 86-88 ° C (from ethyl acetate) 2- [4- (2-benzenesulfonamidoethyl) phenyl] -2- methyl propionic acid is obtained in 80% yield,

m) 4- (2-aminoethyl) phenylacetic acid hydrochloride and

4- (2- (2,5-Dichlorobenzenesulfonamido) ethyl) phenylacetic acid is obtained from 2,5-dichlorobenzenesulfochloride (m.p. 163-164 ° C) in 65% yield, m.p.

n) 4- [4- (2-Benzenesulfonamidoethyl) phenyl] butyric acid is obtained from 4- [4- (2-aminoethyl) -phenyl] -butyric acid hydrochloride and benzene sulfochloride, m.p. 70-71 ° C (from aqueous ethanol). % yield,

o) 2- [4- (2-Aminoethyl) -phenyl] -propionic acid hydrochloride and benzenesulfochloride (m.p. 236-239 ° C) were obtained from 2- (4- (2-benzenesulfonamidoethyl) phenyl] propionic acid, m.p. % yield,

p) 3- [4- (2-Amino-ethyl) -phenyl] -2-methyl-propionic acid hydrochloride and benzenesulfochloride, m.p. 113-115 ° C (ethyl acetate + ligroin) 3- [4- (2-benzenesulfonamidoethyl) phenyl] - 2-methylpropionic acid is obtained in a yield of 85% of theory.

q) 4- (2-aminoethyl) -α-methyl cinnamic acid from hydrochloride and benzene sulfochloride, m.p. 147-148 ° C.

4- (2-benzenesulfonamidoethyl) -? - methyl cinnamic acid is obtained in a yield of 62% of theory.

r) 4- (2- (2-Naphthalenesulfonamido) ethyl) cinnamic acid is obtained in 96% yield from 4- (2-aminoethyl) cinnamic acid hydrochloride and 2-naphthalene sulfochloride (m.p. 192-193 ° C). yield.

Example 5

4- [2- (n-HexadekánszuIfonamido) -ethyl-benzoic acid

To a mixture of 11.5 g (50 mmol) of 4- (2-aminoethyl) -benzoic acid ethyl ester hydrochloride in 150 ml of benzene and 20 g (200 mmol) of triethylamine at 0 ° C with vigorous stirring

N-hexadecanesulfonyl chloride (16.3 g, 50 mmol) was added dropwise, the reaction mixture was stirred for an additional 2 hours in an ice bath and allowed to stand at 20 ° C overnight. It is then poured onto ice, acidified with hydrochloric acid and extracted with ether. The ether layer was washed with water, dried over sodium sulfate and evaporated. The residue was recrystallized from aqueous ethanol. 17.0 g (69% of theory) of 4- [2- (n-hexadecanesulfonamido) -ethyl] -phenylacetic acid ethyl ester, m.p.

Hydrolysis of the ester was carried out in an analogous manner to Example 1 with aqueous potassium hydroxide in methanol. 168-169 ° C (from aqueous ethanol), 4- [2- (nhexadecanesulfonamido) ethyl] benzoic acid is obtained in a yield of 86% of theory.

Example 6

4- [2- (n-Octanesulfonaryl) -ethyl] -phenylacetic acid 9.9 g (43 mmol) of 4- (2-aminoethyl) phenylacetic acid ethyl ester hydrochloride and 9.2 g (43 mmol) of n-oxanesulfonyl chloride are suspended in 175 ml of benzene, with vigorous stirring, a solution of potassium carbonate (11.9 g, 86 mmol) in water (400 mL) was added dropwise, stirred for 10 minutes, and the layers were separated. The benzene layer was washed with water, dried over sodium sulfate and concentrated in vacuo. Recrystallization from aqueous ethanol gave 12.6 g (79% of theory) of 4- (2- (n-octanesulfonamido) ethyl) phenylacetic acid ethyl ester (m.p. 59-60 ° C).

-7185854

A mixture of ethyl ester (10.7g, 29mmol), 2N potassium hydroxide (29ml) and ethanol (29ml) was heated at 40 ° C for 3 hours. The ethanol is then distilled off in vacuo, acidified with hydrochloric acid, filtered off with suction and recrystallized from aqueous ethanol. 9.0 g (91% of theory) of 4- [2- (n-octanesulfonamido) ethyl] phenylacetic acid, m.p. 156-157 ° C.

Similarly, 3- [4- (2-n-octanesulfonamidoethyl) phenyl] 3- [4- (2-n-octanesulfonamidoethyl) hydrochloride and n-octanesulfonyl chloride and n-octanesulfonyl chloride m.p. The ethyl ester of propionic acid is obtained in a yield of 68% of theory and is hydrolyzed to give 3- [4- (2-n-octanesulfonamidoethyl) phenyl] -propionic acid (m.p. 146-148 ° C) in 83% yield.

Example 7

4- (N-Methyl benzenesulphonamido) methyl cinnamate

A mixture of 5.1 g (30 mmol) of N-methylbenzenesulfonamide, 8.8 g (33 mmol) of 4-bromomethyl-cinnamic acid ethyl ester (m.p. 47 ° C, 4.1 g (30 mmol) of potassium carbonate and 50 mL of dimethylformamide was stirred for 4 days. After heating to 60 ° C, the reaction mixture is allowed to cool, stirred in cold water and the organic components are dissolved in ether, the ethereal solution is washed with 0.5 N sodium hydroxide solution, dried over sodium sulfate and evaporated to give a residue. 73%) of 4- (N-methylbenzenesulfonamidomethyl) cinnamic acid, m.p. 112-112.5 ° C are obtained.

Aliquots hydrolysis with 1N methanolic potassium hydroxide solution having a melting point 212-214 ⁰ C. (isopropanol + water) of 4- (N-methyl-benzenesulfonamido) cinnamic acid was obtained, 89% of the theoretical yield.

Example 8

4- [2- (N-Me ~! Benzenesulfonamido-yl) ethyl] phenylacetic acid

10.4 g (30 mmol) of 4- (2-benzenesulfonamidoethyl) -phenylacetic acid ethyl ester (prepared as in Example 4d) by esterification of the acid with ethanol having a melting point of 58-60 ° C, 60 ml of hexamethylphosphoric triamide and 60 ml of abs. Sodium hydride (0.72 g, 30 mmol) (as a suspension in mineral oil) was added to the toluene mixture and stirred at 80 ° C for 2 hours. After cooling, a mixture of 12.8 g (90 mmol) of methyl iodide and 12 ml of hexamethylphosphoric triamide was added, the mixture was stirred for 15 minutes at 20 ° C and then held at 80 ° C for 3 hours. After cooling, it is poured onto ice, adjusted to pH 3 with hydrochloric acid and extracted several times with toluene. The toluene phase is evaporated and the residue is chromatographed on silica gel with toluene. 5.1 g (yield 47%) of 4- [2 N-methyl-benzenesulfonamido) ethyl] -fenilecetsavetilésztert colorless oil, having a refractive index ng ¹ -1.5590.

From this, hydrolysis with 1 N ethanolic potassium hydroxide gave (4- [2- (N-methylbenzenesulfonamido) ethyl) phenyl] acetic acid, m.p. 159-160 ° C, in 63% yield.

Example 9

4- (2-Benzolszulfonamidoetil) phenylacetate

To an ice-cooled mixture of 52.3 g (0.2 mol) of N- (2-phenylethyl) benzenesulfonamide, 80 ml of 1,2,2,2-tetrachloroethane and 40.8 g (0.52 mol) of acetyl chloride was added 88 g (0.664). moles) of aluminum trichloride in portions. The addition

It is completed in 1.5 hours. The reaction mixture was left at 0 ° C for a further 45 minutes and then gradually warmed to 80 ° C. After 1.5 hours, it is poured onto ice and the organic phase is separated. The aqueous layer was extracted with methylene chloride, and the combined organic layers were dried over sodium sulfate and evaporated. The residue is refluxed with 11 2 N sodium hydroxide solution for 2 hours. After cooling, it is extracted with methylene chloride, the organic phase is dried over sodium sulfate and evaporated. The residue is triturated with ether and the crystals are filtered off with suction. 31.3 g (52% of theory) of 4- (2-benzenesulfonamidoethyl) acetophenone, m.p. 133-135 ° C.

A mixture of 9.4 g (31 mmol) of 4- (2-benzenesulfonamidoethyl) acetophenone, 1.6 g (50 mmol) of sulfur and 20 mL of morpholine was heated at 135 ° C for 19 hours. After cooling, the reaction mixture is poured into water and the aqueous phase is extracted with methylene chloride. The methylene chloride phase was washed with 1N hydrochloric acid, dried over sodium sulfate and evaporated. The residue was dissolved in 100 ml of 1 N sodium hydroxide solution and the solution was heated to reflux. The cooled reaction mixture is extracted with ethyl acetate and 4- (2-benzenesulfonamidoethyl) phenylacetic acid, which has the same physical properties as in Example 4d, is precipitated from the aqueous phase by the addition of hydrochloric acid; yield 56% of theory.

Example 10

4- (N-Benzenesulfonamidoethyl) -benzoic acid Dissolve 11.0 g (0.28 mol) of caustic soda in 90 ml of water, add 4 ml of dioxane and add 16 g (0.1 mol) of bromine with stirring. After cooling in an ice bath with further stirring, 4- (2-benzenesulfonamidoethyl) acetophenone (10 g, 0.033 mol) was added. After 2 hours, the carboxylic acid is precipitated by the addition of hydrochloric acid. Crystallization from aqueous ethanol afforded 8.2 g (81% of theory) of 4- (2-benzenesulfonamidoethyl) -benzoic acid, all having the same physical properties as in Example 4b.

Example 77

4- (Benzolszulfonamidometil) phenylacetate n butiIészter

A mixture of 6.11 g (20 mmol) of 4- (Benzenesulfonamidomethyl) phenylacetic acid (Example 4j), 2.83 g (20 mmol) of boron trifluoride ether and 40 ml of n-butanol is heated at reflux for 3 hours, Most of the n-butanol was evaporated in vacuo and the residue diluted with ice-water (100 mL). The reaction mixture was extracted with ether, and the combined extracts were washed successively with 2N hydrochloric acid, water, and sodium bicarbonate solution, dried over sodium 81 sulfate, and evaporated. The residue was recrystallized from ether / ligroin. 6.1 g (84% of theory) of 4- (benzenesulphonamidomethyl) -phenylacetic acid butyl ester are obtained, m.p.

60.5-61 ° C.

Example 12

4- (2-Benzolszulfonamidoetil) -fenilecelsav- [4metilpiperazid]

A mixture of 16.0 g (0.05 mol) of 4- (2-benzenesulfonamidoethyl) phenylacetic acid, 100 ml of benzene and 17.9 g (0.15 mol) of thionyl chloride is heated at reflux for 5 hours. The benzene and excess thionyl chloride are then distilled off in vacuo. The yield of the crude product is quantitative. After recrystallization from toluene

14.9 g (88% of theory) of 4- (2-benzenesulfonamidoethyl) phenylacetyl chloride having a melting point of 82 ° C (with decomposition) are obtained.

3.0 g (30 mmol) of N-methylpiperazine in 100 ml of abs. To a solution of pyridine in ice-cooled solution, 4- (2-benzenesulfonamidoethyl) phenylacetyl chloride (10.1 g, 30 mmol) was added in portions over an hour. The mixture was allowed to warm to 20 ° C, heated at 90 ° C for 5 hours, cooled and cooled to ca. Pour into 500 ml of ice water. The mixture was extracted with methylene chloride and the methylene chloride phase was evaporated after drying over sodium sulfate. The residue was dissolved in ether and the hydrochloride was precipitated with ethereal hydrochloric acid. Recrystallization from ethanol gave 4- (2-benzenesulfonamidoethyl) phenylacetic acid [4-methylpiperazide] hydrochloride, m.p. 168 ° C.

Example 13

4- [2- (4-Hidroxifenilszulfonamido) ethyl] phenylacetic acid

To a mixture of 4- (2-aminoethyl) phenylacetic acid ethyl ester hydrochloride (8.75 g, 36 mmol) in methylene chloride (90 mL) was added triethylamine (7.3 g, 72 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was cooled in an ice bath and a solution of 9.5 g (36 mmol) of 4-ethoxycarbonyloxybenzene sulfochloride in 10 mL of methylene chloride was added slowly dropwise. The reaction mixture was kept at 0 ° C for 1 hour and at room temperature for 3 hours. The organic phase is then washed with dilute hydrochloric acid and water, dried and evaporated.

15.0 g (96% of theory) of 4- [2- (4-ethoxycarbonyloxyphenylsulfonamido) ethyl] phenylacetic acid ethyl ester are obtained in the form of a colorless oil (WS 1184).

The crude ester (14.8 g, 34 mmol) was refluxed with 100 mL of 2 N sodium hydroxide solution for 2 hours. After cooling, the resulting solution was clarified with activated charcoal and precipitated with hydrochloric acid to give 4- [2- (4-hydroxyphenylsulfonamido) ethyl] phenylacetic acid, m.p. 157-159 ° C (67% of theory).

Example 14

Tablets are prepared: each tablet is 10 mg

Contains 3- (4- (2-benzenesulfonamidoethyl) phenyl) propionic acid. The tablets are prepared according to the following formula:

(4- (2-Benzenesulfonamidoethyl) phenyl) propionic acid 10 g lactose 80 g starch 29 g ragragnesium stearate 1 g

The active compound is finely dotted and mixed with lactose and starch. The mixture is granulated in the usual manner. Magnesium stearate is added to the granulate and the mixture is compressed into 1000 tablets weighing 0.12 g each.

Claims (5)

A process for preparing the sulfonamides of formula (I) - 20 R is hydrogen, R 1 is C 1 -C 18 alkyl, phenyl or naphthyl optionally substituted by hydroxy, halogen, trifluoromethyl, C 1 -C 4 alkyl or C 1 -C 4 alkoxy, or They may be substituted by C2-C5 alkanoyl, carboxy, or by an alkoxycarbonyloxy group containing from 1 to 4 carbon atoms in the alkyl moiety, or the phenyl group may be substituted twice by halogen, or R 1 is phenylalkyl or phenylalkenyl, the alkyl or alkenyl 35 of which contains from 2 to 5 carbon atoms and the phenyl of which may be optionally substituted with halogen, n is 2 or 3 W is a bond or a straight or 40 branched alkylene chains, saturated and containing 1 to 6 carbon atoms in the alkyl moiety or a double bond containing 2 to 6 carbon atoms in the alkenyl moiety, and their physiologically tolerable salts, C 1 -C 4 alkyl esters and 4-methylpiperazides, characterized in that a) an amine of formula II in the formula R, n and 50 W is as defined above, and Does Y mean —COOR? a group of the general formula wherein -OR 2 is hydroxy or C 1-4 alkoxy or Represents 4-methyl-piperain-1-yl, 55 or represents a group which, after condensation, is converted to said -COOR2 group, or a salt thereof with a sulfonic acid of formula (III) R 'is as defined above, or a derivative thereof, or (b) a free sulfonic acid of formula (III): wherein: 65 Rí means above - -9185 854 with a compound of formula IV: wherein R, η, Y and W are as defined above and Ac is an easily replaceable acyl group in a suitable solvent, or c) a sulfonamide of the formula V in the formula R and R < 1 > is as defined above with a compound of Formula VI: wherein n and W are as defined above, Y is a group of the formula - COOR 2 wherein -OR 2 is hydroxy or C 1-4 alkoxy or 4-methylpiperazin-1-yl or 5 groups which, after condensation, are converted to said group -COOR2, and X is a reactive group.