AU635367B2 - New phenoxyalkylcarboxylic acid amides, processes for the preparation thereof and pharmaceutical compositions containing them - Google Patents

Description

635367 COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952 COMPLETE SPECIFICATION NAME ADDRESS OF APPLICANT: Boehringer Mannheim GmbH 6800 Mannheim 31 Germany NAME(S) OF INVENTOR(S): Ernst-Christian WITTE Karlheinz STEGMEIER Liesel DOERGE 0 0 ADDRESS FOR SERVICE: DAVIES COLLISON Patent Attorneys 1 Little Collins Street, Melbourne, 3000.

55e

S

COMPLETE SPECIFICATION FOR THE INVENTION ENTITLED: New phenoxyalkylcarboxylic acid amides, processes for the preparation thereof and pharmaceutical compositions containing them

C

The following statement is a full description of this invention, including the best method of performing it known to me/us:-

A

.7 -2- The present invention is concerned with phenoxyalkylcarboxylic acid amides substituted on the phenyl moiety, with processes forthe preparation thereof and with pharmaceutical compositions which contain these compounds.

Published Federal Republic of Germany Patent Specification No. 2809377 describes phenoxyalkylcarboxylic acids and some amides with lipid-sinking and thrombocyte aggregation-inhibiting action which are 10 substituted in the 4-position.

50 Published Federal Republic of Germany Patent Specification No. 36 10 643 describes phenoxyalkylcarboxylic acids and some amides with lipid-sinking and thrombocyte aggregation-inhibiting action which are substituted in the 2- and 3-position.

*Surprisingly, we have now found that substituted phenoxyalkylcarboxylic acid amides in which the amine *3 S component represents an amino acid display an excellent lipid-sinking and thromboxane-A2-antagonistic action.

Therefore, according to the present invention, there are provided new phenoxyalkylcarboxylic acid amides of the general formula:-

SR

3 0--C-CO-N-CH-COOH S

R

4

R

6 R -SO -N-(CH2) n R2 in which the sulphonylaminoalkyl radical is in the Mef6a -position to the phenoxyalkylcarbonamide radical and in which R1 is an aryl, aralkyl or aralkenyl radical, the aryl moiety of which can, in each case, be substituted one or more times by halogen, cyano, alkyl, trifluoromethyl or alkoxy, R 2 is a hydrogen atom or an alkyl or acyl radical, R 3 and R which can be the same or different, are hydrogen atoms or iower alkyl radicals, n is 1, 2 or 3, R is a 6 S" 10 hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms which is optionally terminally substituted

S

by carboxyl, aminocarbonyl or alkoxycarbonyl, by alkylthio, hydroxyl, phenyl or by imidazol-4-yl and

R

5 is a hydrogen atom or, together with R 6 forms an alkylene chain containing 3 or 4 carbon atoms.

Thus, the phenoxycarboxylic acid amides according to the present invention are compounds with amino acids S. as amine components. Apart from the amide-acids, the 6: present invention also includes the physiologically acceptable salts, esters and amides thereof. Since the amine components of the phenoxycarboxylic acid amides contain asymmetrical carbon atoms, the present invention also includes the pure optical isomers (enantiomers) and mixtures (racemates) thereof.

The new compounds of general formula I show an excellent antagonistic action towards thromboxane A 2 as well as towards prostaglandin endoperoxides. They -4inhibit the activation of blood platelets and of other blood cells and prevent the constriction of the smooth musculature of bronchi and blood vessels, as well as the contraction of mesangium cells and similar cells with contractile properties.

This action makes them valuable therapeutic agents for the treatment of cardiovascular diseases, such as acute heart and brain infarct, cerebral and coronary ischaemia, migraine and peripheral arterial 0 10 occlusion diseases, as well as venous and arterial thromboses. Furthermore, an early use thereof can favourably influence the appearance of organ damages in shock patients. In addition, they can be used for the prevention of thrombocyte and leukocyte decrease in the case of interventions with extracorporeal circulation and in the case of haemodialysis. An addition thereof to thrombocyte concentrates.stabilises the blood platelets and thus increases the storability

S.

of the preserved materials.

20 Since thromboxane, in the case of asthma bronchiale, is a mediator of the inflammatory reaction,

S

by means of the use of these thromboxane receptor blockprs, the hyperreactivity characteristic for chronic asthma can be weakened or even overcome.

Furthermore, the new thromboxane receptor blockers are protectively active in the case of gastritis and a tendency to ulcers and can thus be used for the recidivity prophylaxis thereof. In a model of experimental acute pancreatitis, the course thereof can be improved by the use of a thromboxane antagonist. It is thus to be expected that at least certain forms of acute pancreatitis in humans can be improved in their prognosis by the use of these new thromboxane antagonists.

In the case of pathological pregnancy, a disturbance of the equilibrium of the prostaglandins 4 10 is regarded as being the cause. Therefore, by means of a blockade of the thromboxane and PGF2 alpha receptors, especially the premature labour pain activity can be interrupted and, in the case of Seea pregnancy gestosis and eclampsia, a more favourable course can be achieved. In addition, the prostaglandin-caused symptoms of dysmenorrhoea and of the *sew premenstrual syndrome can be therapeutically treated.

S As aryl radical, alone or in combination with A e S* an alkyl or alkenyl chain, is to be understood, in all 20 cases, to be an aromatic hydrocarbon radical containing S" 6 to 14 carbon atoms, especially a phenyl, biphenylyl, naphthyl or fluorenyl radical. These aryl radicals can be substituted one, two or three times in all possible positions, the substituents being, for example, halogen, C 1

-C

6 -alkyl, C1-C 6 -alkoxy, trifluoromethyl or cyano. The phenyl radical is preferred which can be substituted by halogen, preferably chlorine and -6bromine, methoxy, methyl or trifluoromethyl.

Of the alkyl and alkoxy substituents in the aryl, aralkyl and aralkenyl radicals, those are preferred which contain 1 to 4 carbon atoms, especially the methyl, ethyl, isobutyl and tert.-butyl radicals, as well as the methoxy radical.

As aralkyl radicals R 1 those are preferred in which the straight-chained or branched alkylene moiety contains 1 to 5 carbon atoms. Preferred aralkyl S 10 radicals R include the phenethyl and 4-chlorophenethyl radical.

u By aralkenyl radicals R I are to be understood *9 those in which the alkenylene moiety contains 2 or 3 carbon atoms, the styryl and 4-chlorostyryl radical here being preferred.

By halogen is to be understood, in all cases, fluorine, chlorine or bromine.

*S 0 The alkyl groups R 2 are straight-chained or branched and contain 1 to 16 carbon atoms, methyl and octyl radicals being preferred.

Tl 2 The acyl radicals R are derived from aliphatic carboxylic acids containing 2 to 16 carbon atoms, from araliphatic acids and from aromatic carboxylic acids.

Preferred acyl radicals include acetyl, isobutyroyl, cinnamoyl, benzoyl, 4-chlorobenzoyl and 4-aminobenzoyl radicals, as well as n-octanoyl and n-hexadecanoyl radicals.

-7- '3 4 The lower alkyl radicals R 3 and R can be straight-chained or branched and contain 1 to 6, preferably 1 to 4 carbon atoms, the methyl and ethyl radicals being preferred.

n is preferably the number 2.

R

5 is preferably a hydrogen atom or, together with R 6 forms an alkylene chain containing 3 or 4 carbon atoms, a 5- or 6-membered ring is present which contains a nitrogen atom, compounds with 10 membered ring here being preferred.

6 R is preferably a hydrogen atom or is an alkyl chain containing 1 to 4 carbon atoms which is optionally terminally substituted. Preferred substituents include carboxyl, aminocarbonyl, di-C 1

-C

6 -alkylamino- *15 carbonyl, 4-substituted piperazin-l-ylcarbonyl (the 4-positioned substituent being benzyl or 4-chlorobenzyl), C 1

-C

6 -alkoxycarbonyl, C 1

-C

6 -alkylthio,

C

1

-C

14 -aryl-C 1

-C

4 -alkylthio, phenylthio, hydroxyl, phenyl and 4-imidazolyl. The phenyl nuclei possibly 0* 20 contained in these substituents can also contain 1 or 2 halogen atoms and preferably chlorine atoms.

Especially preferred substituents include carboxyl, aminocarbonyl, diethylaminocarbonyl, 4-benzyland 4-(4-chlorobenzyl)-piperazin-l-ylcarbonyl, methoxyand ethoxycarbonyl, methylthio, benzyl- and 4-chlorobenzylthio, phenyl- and 4-chlorophenylthio, hydroxyl, phenyl, 4-chlorophenyl -and 4-imidazolyl.

-8- In the group -N CH-COOH, those radicals R 5 and 5 '6

R

5 R6 R are especially preferred, the meaning of which gives the structure of an essential amino acid. These also include all possible isomers and the mixtures thereof.

The amino acids include, in particular, alanine, arginine, asparagine, aspartic ac-id, cysteine, cystine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, *serine, threonine, tryptophane, tyrosine, valine, 10 homocysteine, homoserine, hydroxylysine, hydroxyproline, ornithine, -arcosine, norvaline and 2-aminobutyric acid.

The esters of the carboxylic acids of the general formula I can be those with lower monohydroxy alcohols, 15 for example methanol and ethanol, and those with polyhydroxy alcohols, for example glycerol, as well as those with alcohols which contain other functional groups, for example ethanolamine.

2* The amides of the carboxylic acids of general 5* 20 formula I are those in which the amine component is, for example, ammonia, a lower dialkylamine, such as diethylamine, or a hydroxyalkylamine, such as ethanolamine or diethanolamine. Other possible amine components include alkyl-, aralkyl- and arylpiperazines.

The present invention also includes the pure optical isomers (enantiomers) of the compounds of general formula I, as well as mixtures (racemates) thereof.

Especially preferred compounds of the formula I are those in which R1 is a phenyl radical Jr a phenyl radical substituted once or twice by halogen, methyl, methoxy or trifluoromethyl, R 2

R

3 and R are hydrogen atoms, n is 2 and the group -N CH-COOH is the residue A6

R

5

R

6 of an essential amino acid or an optical isomer or mixture thereof, the sulphonylaminoalkyl radical there- 10 by preferably being in the meta-position to the phenoxyalkylcarbonylamide radical.

The phenoxycarboxylic acid amides of general formula I can be prepared a) by reacting an amine of the general formula:- 9 *a 9 9. 0 0 9*99 *9*R 9. 9

I'.

0£r 9 9 o HN (CH2) n

R

2 2-n

(II)

in which R 2 and n have the above-given meanings, optionally with intermediate protection of the amino or hydroxyl group, in per se known manner in any desired sequence with a sulphonic acid of the general formula:- R -SO 2 0H (III) in which R has the above-given meaning, or with a derivative thereof and with an optionally opticallyactive compound of the general formula:- X-C-CON CH-Y (IV) 4 5 6 R R R or with a derivative thereof. In general formula IV, 3 4 R and R have the above-given meanings, X is a reactive group and under Y is a radical -COOR 7 (wherein R7 is a hydrogen atom or an equivalent of a metal ion or a lower alkyl, aralkyl or silyl radical)

S

or an acid amide radical. However, Y can also be a 0 radical which, after condensation has taken place, is converted into an acid amide group or into a -COOR radical, whereafter a particular R7 is optionally converted in per se known manner into another substituent R 7 and the compounds obtained are optionally converted into pharmacologically acceptable salts.

The process according to the present invention is preferably carried out in two steps. The condensation of the compounds of general formula II with sulphonic acids of general formula III or

S

20 derivatives thereof, on the one hand, and with compounds of general formula IV, on the other hand, is preferably so carried out by first blocking one of the two reactive groups of the compound of general formula II with a protective group which can easily be split off, reacting the compound obtained with a sulphonic acid of general formula III or with a derivative thereof or with a compound of the general -11formula IV, again splitting off the protective group and subsequently reacting this reactive intermediate product with the not yet used compound of general formula IV or III. A process route is preferred in which the compound protected on the amino group (i.e.

the compound V) is first reacted with a compound of general formula IV. After splitting off the protective group, there then takes place the reaction with a sulphonic acid of general formula III or with 10 a derivative thereof:

S.

0 0000 0 9 0099 Z-N-(CHn- R2 St 0* S #0 *0 00

S.

4* 4 *.0009t

(V)

SZ-N-(CH

2 n-

R

X C CON CH Y 4 5. 6 R R5 R

(IV)

R

3 0 C CON CH Y 4

R

5

R

6 R R R

(VI)

S HN-(CH 2 )n

R

2

R

3 0 C CON CH Y R R 5

R

6

(VII)

-12- R-SO-OH R 1

-SO

2 N-(CH2n) R 3 2 R 22 R (III) R 2 0-C CON CH Y j4 5 6 R R R

(VIII)

2 3 4 5 6 The symbols R 2 n, X, R 3

R

4

R

5 R and Y used in the above general formulae have the above-given meanings and Z is a group suitable for the protection of amino groups. The preparation of the intermediate compound of general formula VI can also be carried out in several partial steps: a compound of general formula V is first reacted with a carboxylic acid of general formula IX, the carboxyl function of which is preferably protected by derivative formation:

R

3 Z-N-(CH X-C-COOH 2 4 R OH R 4 so a V

(IX)

Z-N-(CH

2 )n R3 2 n R 0-C-COOH

R

4

(X)

The phenoxyalkylcarboxylic acid of general formula X is now condensed (possibly after previous splitting off of the carboxyl protective group) with an optionally optically-active amine of the general formula -13- HN CH Y(XI)

(XI)

R

6 or with a salt of the amine. Instead of the free carboxylic acids, reactive derivatives ar- preferably reacted. The resultant compound of general formula VI is then,-as described, freed from the amine protective group and reacted with a sulphonic acid of general formula III.

3 4 When R and R are lower alkyl radicals, the 13 phenoxyalkylcarboxylic acids of general formula X can 10 also be prepared by reacting a phenol of general formula V with a mixture of an aliphatic ketone, chloroform and an alkali metal hydroxide. This variant is preferably used for the preparation of phenoxyisobutyric acid derivatives:

R

3 nC Z-N-(CH2) n C=0 CHC M+OH 2 n

R

2 OH R

(V)

Z-N-(CH2) n R 3

R

2 0-C-COOH

R

(X)

This process can also be used when Z has already been replaced by an R -SO 2 radical' -14b) A further possibility for the preparation of compounds of general formula I, of the salts thereof, as well as of the esters and amides thereof, consists in reacting a sulphonamide of the general formula:-

R

1 -SO NH 2. (XII) 2

R

with an optionally optically-active compound of the general formula:-

X-(CH

2 n/ R3 i (XIII) 0 C CON CH Y 0 -4 5 6 R R R and possibly converting the group Y of the resultant compound of general formula VIII into a carboxyl function or another desired function.

2 When R is to be.an acyl radical, the subsequent .acylation of a compound of general formula I is *2 pr- Jerably carried out in which R is a hydrogen atom 15 and the carboxyl function of which is esterified. The acylation agents used are reactive derivatives of carboxylic acids and preferably acid chlorides.

The reactive derivatives of sulphonic acids of general formula III are preferably the halides, as well as esters. The reaction of the sulphonic acid halides with compounds of the general formulae II or VII preferably takes place with'the addition of an acid-binding agent, for example an alkali metal acetate, sodium hydrogen carbonate, sodium carbonate, sodium phosphate, calcium oxide, calcium carbonate or magnesium carbonate. However, this function can also be undertaken by an organic base, for example pyridine or triethylamine, in which case, as inert solvent, there can be used, for example, diethyl ether, benzene, methylene chloride, dioxan or an excess of the tertiary amine. When using an inorganic acid binder, as 10 reaction medium there can be used, for example, water, aqueous ethanol or aqueous dioxan.

For the reaction of the compound of general formula II with a compound of general formula IV, it has proved to be advantageous first to convert the amino group of the compound of general formula II into a protected amino group. Especially preferred are radicals, such as the benzyloxycarbonyl radical, known from peptide chemistry which are easy to remove, for example by hydrogenation. There can also be used 20 protective radicals such as the phthalimido radical which, after condensation has taken place between IV and V, can easily be split off again in known manner by the use of hydroxylamine. Sometimes, the splitting off again can be completely omitted by initially introducing an R 1

-SO

2 radical. As reactive compounds of general formula IV, IX or XIII, those are especially preferred in which X is the anion of a strong acid, -16for example of a hydrogen halide or sulphonic acid.

The reactions of these reactive compounds can be very favoured when using the reaction components in question in the form of their salts (thus: V in the form of the sodium or potassium phenolate; XII in the form of the sodium or potassium salt of the sulphonamide). The reaction of the reactive compounds of general formula IV, IX or XIII with the sodium or *a S' potassium salts of the compounds of general formulae 10 V and XII takes place in a solvent, for example toluene, S*methyl ethyl ketone, dimethylformamide or dimethyl Ssulphoxide, preferably with warming.

For the reaction of carboxylic acids of general formula X with the amines of general formula XI, it is 15 preferable to use the carboxylic acids in the form of reactive derivatives. As such, there can be used acid halides, anhydrides, imidazolides, mixed anhydrides of the carboxylic acid and a chloroformic acid ester, active esters, for example nitrophenyl esters or 20 hydroxyphthalimide or hydroxysuccinimide esters. Also favourable is the condensation between a free carboxylic acid of general formula X and an amine component of general formula XI in the presence of an agent splitting off water, such as dicyclohexylcarbodiimide. In many cases, the acid function of the amino component can be present in salt form but often it is more preferable to start from the esterified amino- -17carboxylic acid of general formula XI, the use of trialkylsilyl esters thereby having proved to be quite especially preferable. In the case of the preparation of trialkylsilyl esters, the amino group is possibly simultaneously silylated so' that N-trialkylsilylamino acid-trialkylsilyl esters are obtained.

These can be condensed with the activated carboxylic acids of general formula X in the same way as amino acids not silylated on the nitrogen. The amino group of the amino acids or of their esters can possibly also be reacted in the salt form. As solvents, there can be a.

Sused water-alcohol mixtures for the reaction of hydroxysuccinimide esters of the carboxylic acids of general formula X with the sodium salts of the amino S 15 acids of general formula XI (Y -COONa)); methylene chloride, and, in the case of low solubility, dimethyl sulphoxide.

c) Compounds of general formula I can also be obtained by reacting compounds of general formula XIV or their 20 reactive derivatives R-SO -N-(CH 2 3 2 R (XIV) 0-C-COOH

R

4 in which R, R 2

R

3 R and n have the above-given meanings, with an amino acid of general formula XI.

-18- Some of the compounds of general formula XIV are described in published Federal Republic of Germany Patent Specifications Nos. 36 10 643 and 28 09 377 or can be prepared according to the processes described therein.

Reactive derivatives of the compounds of general formula XIV are preferably acid halides, imidazolides or mixed anhydrides. Acid chlorides are obtained in the usual way from the free acids by reaction with, 0* 10 for example, thionyl chloride.

SFor the preparation of compounds of general formula VIII by alkylation of a sulphonamide of general formula XII with a compound of general formula XIII, those compounds of general formula XIII are preferably 15 usecd in which X represents a halogen atom, i.e. a chlorine or bromine atom. A reaction process is preferred in which two moles of a sulphonamide of general formula XI are evaporated to dryness with one mole of a sodium alcoholate solution. The mixture 20 obtained is then reacted with one mole of the alkyl halide of general formula XIII. In this way, the formation of dialkylated sulphonamides is substantially avoided.

The possible subsequent N-alkylation of a compound of general formula VIII, in which R 2 is a hydrogen atom, can be carried out according to known methods, preferably by reacting it with an alkyl -19halide or a dialkyl sulphate in the presence of an acid-binding agent, for example potassium carbonate.

The introduction of an acyl radical R 2 into a sulphonamide of general formula VIII (R 2 H) takes place under conditions such as are usual for the acylation of amines: reaction with an active carboxylic acid derivative, for example an acid halide, a mixed anhydride or an active'ester, in'an inert solvent in the presence of a base. As inert solvent, there can 10 be used, for example, methylene chloride, benzene, dimethylformamide and the like.

S* As substituents Y in compounds of general *7 formula VIII which can be converted into a -COOR 7 radical, there can be used, for example, a nitrile, carbaldehyde, hydroxymethyl, aminomethyl or formyl *6 radical.

The conversion of the substituent R 7 possibly to be carried out subsequent to the condensation, takes place, for example, by saponification of a .97 20 carboxylic acid ester (R alkyl) to the correspondc 7 ing carboxylic acid (R hydrogen) with a mineral acid or an alkali metal/alkaline earth metal hydroxide in a polar solvent, for example water, aqueous methanol, aqueous ethanol or aqueous dioxan, at icebath temperature or at a temperature of up to 40 0

C.

The particular conditions used depend upon the saponifiability of the amide bond present in the molecule.

I>

On the other hand, however, the carboxylic acids

(R

7 HI can also be esterified in the usual way or esters with a particular radical R 7 can be converted by transesterification into an ester with a different radical R 7 The esterifi-ation of the carboxylic acids is preferably carried out in the presence of an acidic catalyst, for example hydrogen chloride, sulphuric acid, p-toluenesulphonic acid or a strongly acidic ion exchanger resin. On the other hand, transesterific- 10 ations require the addition of a small amount of a Goof* 0 basic substance, for example of an alkali metal or C. alkaline earth metal hydroxide or of an alkali metal alcoholate. For the esterification of the carboxyl group or for a transesterification, in principle all 15 alcohols can be used. Preferred are the lower monoseo hydroxy alcohols, for example methanol, ethanol or propanol, as well as polyhydroxy alcohols, for example glycerol, as well as alcohols with other functional groups, for example ethanolamine and glycerol ethers.

20 The amides according to the present invention derived from carboxylic acids of general formula I are preferably pre'ared according to known methods from the carboxylic acids or reactive derivatives thereof, for example carboxylic acid halides, esters, azides, anhydrides or mixed anhydrides, by reaction with amines.

As amino components, there can be used, for example, ammonia, alkylamines and dialkylamines but also amino- -21alcohols, for example ethanolamine and 2-aminopropanol. Other valuable amine components include alkyl-, aralkyl- and arylpiperazines for example benzylpiperazine.

For the preparation of salts with pharmacologically acceptable organic or inorganic bases, for example sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, methylglucamine, morpholine or ethanolamine, the carboxylic acids can be reacted with the corresponding bases. Mixtures of 10 the carboxylic acids with an appropriate alkali metal carbonate or hydrogen carbonate can also be considered.

The pure enantiomers of compounds of general formula I can be obtained by racemate resolution (via salt formation with optically-active bases) or by 15 using optically pure amino acids in the syntheses *6 S* according to processes a) to c).

For the preparation of pharmaceutical compos- So***I itions, compounds of general formula I are mixed in known manner with appropriate pharmaceutical carrier substances, aroma, flavouring and colouring materials and formed, for example, into tablets or dragees or, with the addition of appropriate adjuvants, suspended or dissolved in water or an oil, for example olive oil.

The compounds of general formula I can be administered orally or parenterally in liquid or solid form. As injection medium, water is preferably used which contains the stabilising agents, solubilising -22agents and/or buffers usual in the case of injection solutions. Such additives include, for example, tartrate and borate buffers, ethanol, dimethyl sulphoxide, complex formers (such as ethylenediaminetetraacetic acid), high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation and polyethylene derivatives of sorbit anhydrides.

Solid carrier materials include, for exau.ple, 10 starch, lactose, mannitol, methyl cellulose, talc, hgihly dispersed silicic acid, high molecular weight fatty acids (such as stearic acid), gelatine, agaragar, calcium phosphate, magnesium stearate, animal and vegetable fats and solid high molecular weight polymers (such as polyethylene glycols). Compositions suitable for oral administration can, if desired, contain flavouring and sweetening materials.

The administered dosage depends upon the age, the state of health and the weight of the recipient, the extent of the disease, the nature of further treatments possibly tried out simultaneously, the frequency of the treatme, :s and the nature of the desired action. Usually, the daily dosage of the active compound amounts to 0.1 to 50 mg./kg. of body weight. Normally, 0.5 to 40 and preferably 1.0 to mg./kg,/day in one or more administrations per day are effective in order to obtain the desired results.

-23- Preferred in the meaning of the present invention are, apart from the compounds of general formula I mentioned in the following Examples, as well as the esters, amides and salts thereof, also the following compounds: 1. N-t3-[2-(phenylsulphonylanino)-ethylll-phenoxyacetyl ]-glycine 2. N-[2-12-(4-chlorophenylsulphonylamino)-ethyllphenoxyacetyl ]-alanine Ouse. 10 3. N-[3-[2-(4-methylphenylsulphonylamino)-ethyil- *:doe phenoxyacetyl ]-alanine or 4-trifluoromethylphenylsulphonylamino)-ethyl i,-phenoxyacetyl ]-2-aminobutyric acid N-[3-[2-(4-chlorophenylsulphonylamino)-ethyl]phenylacetyl]-alanine 4-benzylpiperazide 6. N-13-[2-(4-methoxyphenylsulphonylamino)-ethyl]- *0 phenoxyacetyl]-alanine ethyl ester 7. or ethyl ]-phenoxyacetyl I-alanine 8. N-14-[2-(3,5-dichlorophenylsulphonylamino)-ethyllphenoxyacetyl ]-L-alanine 9. N-[4-12-(4-trifluoromethylphenylsulphonylamino)ethyl I-phenoxyacetyl ]-L-alanine N-[4-[2-(4-chlorophenylsulphonylamino)-ethylphenoxyacetyl]-L-serine 11. N-I[4-I2-(4-trifluoromethylphenylsulphonylamino)ethyl I-phenoxyacetyl]I-L-se- ine -24- 12. N-[4-[2-(4-methylphenylsulphonylamiho)-ethyl]phenoxyacetyl]-glycine.

The following Examples show some of the numerous process variants which can be used for the synthesis of the new compounds according to the present invention.

However, they are not to represent a limitation of the subject matter of the present invention.

Example 1.

P

N-[3-[2-(4-Chlorophenylsulphonylamino)-ethyl]phenoxyacetyl]-glycine.

a) 3-[2-(4-Chlorophenylsulphonylamino)-ethyljphenoxyacetyl chloride.

A mixture of 30 g. (81 mmole) 3-[2-(4-chlorophenylsulphonylamino)-ethyl]-phenoxyacetic acid, 15 23.5 ml. (0.32 mole) thionyl chloride and 3 drops of dimethylformamide is stirred for 2 hours at 60 0

C.,

whereafter excess thionyl chloride is distilled off in a vacuum. The residue obtained is dissolved in 4 a anhydrous diethyl ether and clarified with activated 20 carbon. After evaporation, an oil is obtained which slowly crystallises through. It is stirred with isohexane, filtered off with suction and dried. Yield 26.9 g. (94% of theory); m.p. 75 77 0

C.

b) Title compound.

To an ice-cold solution of 0.8 g. (10 mmole) glycine and 15 ml. 2N aqueous sodium hydroxide solution is slowly added dropwise a solution of 3.52 g. of the acid chloride obtained according to a) in 40 ml.

methylene chloride and subsequently allowed to postreact for 2 hours at 0°C. The reaction mixture is then acidified with dilute hydrochloric acid and the weakly acidic phase extracted with ethyl acetate. The organic phase is extracted twice with lN hydrochloric acid, washed with water and dried with anhydrous sodium sulphate. The crude product obtained after evaporation S* e is recrystallised from nitromethane. Yield 2.7 g.

Ok 10 (63% o- theory); m.p. 134 135 0

C.

Example 2.

C N-[3-[2-(4-Bromophenylsulphonylamino)-ethyl]phenoxyacetyl]-L-alanine.

a) N-Trimethylsilyl-L-alanine trimethylsilyl ester.

15 To a suspension of 7.12 g. (80 mmole) L-alanine in 120 ml. anhydrous methylene chloride is added dropwise, with stirring, 20.8 ml. trimethylchlorosilane, followed by briefly heating to reflux temperature, a clear solution thereby being obtained. Then, with 20 gentle cooling, 22.4 ml. triethylamine are added dropwise thereto, with stirring, in such a manner that the reaction mixture does not boil too vigorously. Subsequently, the reaction mixture, a thick suspension, is heated for 5 minutes to reflux temperature, cooled, filtered through a pressure filter and subsequently washed with dry methylene chloride. The product obtained is dried in a current of nitrogen and further -26worked up in crude form.

b) Title compound.

To a solution of 9.28 g. (20 mmole) bromophenylsulphonylamino)-ethyl]-phenoxyacetylimidazole in 75 ml. anhydrous tetrahydrofuran is added at -5 0 with the exclusion of moisture, 5.14 g.

(22 mmole) of the trimethylsilyl compound obtained according to The reaction mixture is allowed to come to ambient temperature in the course of 3 hours 10 and subsequently the tetrahydrofuran is distilled off in a vacuum. The residue is stirred with 2N hydrochloric acid at ambient temperature and then extracted several times with methylene chloride. The combined organic phases are extracted with an amount of 2N aqueous sodium hydrogen carbonate solution sufficient s for salt formation and the extract is acidified. The r precipitated product is filtered off with suction, dried and recrystallised from nitromethane. Yield 6.2 g. (60% of theory); i.p. 191 1920C.

20 Example 3.

N-[3-[2-(4-Chlorophenylsulphonylamino)-ethyl]phenoxyacetyl]-L-alanine.

a) N-[3-[2-(Benzyloxycarbonylamino)-ethyl]phenoxyacetyl]-L-alanine.

To a 40°C. warm solution of 5.0 g. (15.8 mmole) 3-[2-(benzyloxycarbonylamino)-ethyl]-phenoxyacetic acid in 25 ml. anhydrous dimethyl sulphoxide are added -27- 2.56 g. (15.8 mmole) carbonyl-bis-imidazole, followed by stirring for a further 30 minutes at 40 0 C. Subsequently, 1.74 g. (15.8 mmole) L-alanine sodium salt is added thereto, the reaction mixture is kept for 3 hours at 60 0 cooled, stirred into a mixture of ice and so much hydrochloric acid that the mixture reaches a pH value of about 2. The precipitated oil is extracted with methylene chloride. After washing the methylene chloride phase with an aqueous solution of sodium hydrogen carbonate and water, it is dried with anhydrous magnesium sulphate and evaporated.

There are obtained 5.21 g. (82% of theory) of product in the form of a colourless oil.

Alternative synthesis for this compound: *iS 15 A mixture of 22.0 g. (81 mmole) 3-[2-(benzyloxycarbonylamino)-ethyl]-phenol, 200 ml. butanone and 33.5 g. very finely pulverised dry potassium carbonate is maintained for 1 hour at reflux temperature, 300 mg.

potassium iodide and 17.3 g. (89.3 mmole) N-(2-chloroacetyl)-L-alanine ethyl ester are then added thereto 9 and the reaction mixture is maintained at reflux temperature for 16 hours. Subsequently, the reaction mixture is filtered off with suction and the filter cake is then washed with hot butanone. The combined butanone phases are evaporated, the oily residue is taken up in methylene chloride, the methylene chloride phase is washed with water, dried over anhydrous -28magnesium sulphate and evaporated in a vacuum. Yield: practically quantitative.

b) Title compound.

A mixture of 8.0 g. (20 mmole) of the benzyloxycarbonyl compound obtained according to 75 ml.

methanol, 11.0 ml. 2N hydrochloric acid and about 2 g.

palladium-carbon is hydrogenated for 12 hours at ambient temperature and 6 bar pressure until the necessary amount of hydrogen has been taken up. The catalyst is then filtered off with suction and the methanol is distilled off in a vacuum. To the residue, which consists of the crude hydrochloride of aminoethyl)-phenoxyacetyl]-L-alanine, are added 75 ml.

he of water and so much 2N aqueous sodium hydroxide 15 solution that a pH of 10 is reached. With stirring at there are now added thereto 3.16 g. 4-chlorobenzenesulphochloride in small portions and, by the dropwise addition of further dilute aqueous sodium hydroxide solution, care is taken that a pH of 10 is 20 maintained. Subsequently, the reaction mixture is further stirred for 2 hours at 35 0 acidified, filtered off with suction and the produc- is dried and 0g5 recrystallised from nitromethane. Yield 4.7 g. (71% of theory); m.p. 175 177 0

C.

Example 4.

N-[3-[2-(4-Chlorophenylsulphonylamino)-ethyl]phenoxyacetyl]-L-alanine.

-29a) N-[3-[2-(4-chlorophenylsulphonylamino)-ethyl]phenoxyacetyl]-L-alanine ethyl ester.

To an ice-cold mixture of 2.2 g. (14 mmole) Lalanine ethyl ester hydrochloride, 4.3 g. triethylamine and 100 ml. methylene chloride is slowly added dropwise, with stirring, a solution of 5.0 g. (14 mmole) 3-12- (4-chlorophenylsulphonylamino)-ethyl]-phenoxyacetyl chloride in 25 ml. methylene chloride. Subsequently, the reaction mixture is stirred for 1 hour at 0°C. and then for 1 hour at 25 0 shaken out with dilute hydrochloric acid and water, dried over anhydrous sodium S" sulphate and finally evaporated. Yield 5.1 g. (77% of

CC

theory) of a colourless oil.

b) Title compound.

15 A mixture of 2.8 g. (6 mmole) of the ester obtained according to 25 ml. ethanol and 15 ml. 2N aqueous sodium hydroxide solution is stirred for minutes at ice-bath temperature, thereafter diluted with 25 ml. ice water and acidified with dilute hydro- 20 chloric aci-. After filtering off with suction, drying and recrystallising from nitromethane, the yield is 1.9 g. (72% of theory); m.p. 175 177 0 C. The product is identical with that obtained according to Example 3.

Example N-[3-[2-(4-Chlorophenylsulphonylamino)-ethyl]phenoxyacetyl]-L-methionine.

To a solution of 8.0 g. (20 mmole) chlorophenylsulphonylamino)-ethyl]-phenoxyacetic acid in 35 ml. dimethyl sulphoxide is added at 40 0 with stirring, 3.5 g. (20 mmole) carbonyl-bis-imidazole, foam formation thereby taking place. After stirring for 1 hour at 40°C., 4.07 g. (24 mmole) L-methionine sodium salt are added thereto and the reaction mixture then maintained for 18 hours at 60 0 C. It is then cooled, poured on to an ice-hydrochloric acid mixture and the greasy product obtained taken up in ethyl acetate. The ethyl acetate phase is extracted with an aqueous solution of sodium carbonate and the latter again washed with ethyl acetate. The aqueous phase is acidified, filtered off with suction and the product *s t S 15 is washed with water, dried and recrystallised from nitromethane. Yield 8.3 g. (77%'of theory); m.p.

138 139 0

C.

In analogous way, from 3-[2-(4-chlorophenylsulphonylamino)-ethyl]-phenoxyacetic acid, there are obtained the following compounds: 2. with L-histidino sodium salt: N-[3-[2-(4-chlorophenylsulphonylamino)-ethyl]-phenoxyacetyl]-L-histidine hydrochloride.

yield 34%; m.p. 100 103 0

C.

The oily product separating out after pouring into an ice-hydrochloric acid mixture is here triturated with an acetone-ether mixture (1:12 v/v) until it -31crystallises. It is then quickly filtera~d off with suction (hygroscopic) and dried over phosphorus pentoxide.

3. with L-2-aminobutyric acid sodium salt: N-[3-[2-(4-chlorophienylsulphonylamino)-ethyl-phenoxyacetyl]-L-2-aminobutyric acid.

Yield 61% of theory; mn.p. 147 150'C. (recrystallised from nitromethane) 2 4. with L-asparagine sodium salt: N-[3-12-(4-chlorophenylsulphonylamino)-ethyl]-phenoxyacetyl ]-L-a~paragine.

Yield 62%~ of theory; m.p. 133 135'C. (recrystallised from nitromethane).

5. with L-phenylalanine sqdium salt: N-[3-[2-(4-chlorophenylsulphonylamino)-ethyl-phenox.yacetyl I-L--phelnleni.

Yield 63% of theory; m.p. 158 116'C. (recrystallised from aeousl aethano).

6. with L-prine sodium salt: N-[13-[2-(4-clorophenylsulphonylamino)-ethyl]-phenoxyacetyl I-L-rine.

Yield 9%7 of theory; m.p. 1146 148'C. (recrystallised from etylaetate).

-32- 8. with L-norvaline sodium salt: N-[3-[2-(4-chlorophenylsulphonylamino)-ethyl]-phenoxyacetyl]-L-norvaline.

Yield 72% of theory; m.p. 126 128 0 C. (recrystallised from nitromethane).

Example 6.

N-[3-[2-(4-Chlorophenylsulphonylamino)-ethyllphenoxyacetyl]-D-alanine.

Into a 40 0 C. warm solution of 10.0 g. (27 mmole) 3-[2-(4-chlorophenylsulphonylamino)-ethyl]-phenoxyacetic acid in 30 ml. dimethyl sulphoxide are introduced 4.38 g. (27 mmole) carbonyl-bis-imidazole. The mixture is allowed to react for 10 minutes, 3176 g.

a S* (27 mmole) 4-nitrophenol are added thereto, followed 15 by stirring for 10 minutes, 3.0 g. (27 mmole) Dalanine sodium salt are then introduced, followed by stirring for 3 hours at 60°C. After cooling, the reaction mixture is stirred into an ice-hydrochloric acid mixture. The precipitated oil is taken up in ethyl acetate, the organic phase is washed with water, dried over anhydrous sodium sulphate and evaporated.

The oily residue obtained crystallises after the addition of isohexane.' Yield 8.0 g. (67% of theory); m.p. 163 166°C.

Example 7.

In a process method analogous to Example 6, there were prepared from 4-[2-(phenylsulphonylamino)- -33ethyl]-phenoxyacetic acid a) and L-alariine: N- (phenylsuiphonylamino )-ethyl] -phenoxyacetyl L-alanine Yield 62% of theory; m.p. 164 165'C.

b) and D-alanine: N- (phenylsulphonylatnino) -ethyl] -phenoxyacetyl D-alanine Yield 54% of theory; rn.p. 152 -153'C.

0

Claims (9)

1. Compounds of ;.he general formula: R 3 1 0-C-CO-N CH-COOH 4 1 16 1 R1-SO-N-(CH2) R R R 2 1 2n

2 R in which the sulphonylaminoalkyl radical is in the meta- position to the phenoxyalkyl- carbonamide radical and in which R is an aryl, aralkyl c aralkenyl radical, the aryl moiety of which can, in each case, be substituted one or more times SoC.: by halogen, cyano, alkyl, trifluoromethyl or alkoxy, R is a hydrogen atom or an alkyl or acyl radical, 3 4 R and R which can be the same or different, are hydrogen atoms or lower alkyl radicals, n is 1, 2 or

3, R is a hydrogen atom or an alkyl radical contain- ing 1 to 4 carbon atoms which is optionally terminally substituted by carboxyl, aminocarbonyl or alkoxy- carbonyl, by alkylthio, hydroxyl, phenyl or by imidazol-

4-yl and R 5 is a hydrogen atom or, together with R 6 forms an alkylene chain containing 3 or 4 carbon atoms, as well as the physiologically acceptable salts, esters, amides and optical isomers thereof. 2. ,Compounds of general formula I according to claim 1, wherein R is a phenyl radical or a phenyl radical substituted once or twice by halogen, methyl, 920218,ejhdaL075,68163.let,34 methoxy or trifluoromethyl, R 2 R 3 R 4 are hydrogen atoms, n is 2 and the radical -N CH-COOH is the

!5 I6 R R residue of an essential amino acid or of an optical isomer or mixture thereof. 3. Compounds according to claim 1 or 2 wherein the group -N CH COOH i I R 5 R 6 represents the residue of an amino acid selected of the group consisting of glycine, alanine, 2-amino butyric acid, serine, methionine, asparagine, phenylamine, proline or norvaline. 4. Process for the preparation of compounds of the general formula:- R 3 0-C-CO-N CH-COOH 1 4 5 '6 R -SO -N-CH R R R 2 2n R in which the sulphonylaminoalkyl radical is in the meta-position to the phenoxyalkyl- carbonamide radical and in which R is an aryl, aralkyl or aralkenyl radical, the aryl moiety of which can, in each case, be substituted one or more times by halogen, cyano, alkyl, trifluoromethyl or alkoxy, R is a 3 4 hydrogen atom or an alkyl or acyl radical, R and R, which can be the same or different, are hydrogen atoms or lower alky radicals, is 1, 2 or 3, R is a or lower alkyl radicals, n is i, 2 or 3, R is a 920218,cjhdaO75,68163.Ict,35 36 hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms which is optionally terminally substituted by carboxyl, aminocarbonyl or alkoxycarbonyl, by alkylthio, hydroxyl, phenyl or by imidazol-4-yl and R is a hydrogen atom or, together with R 6 forms an alkylene chain containing 3 or 4 carbon atoms, as well as of the physiologically acceptable salts, esters, amides and optical isomers thereof, wherein a) an amine of the general formula:- HN-(CH 2 n (II) R OH in which R 2 and n have the above-given meanings, optionally with intermediate protection of the amino or hydroxyl group, is reacted in known manner in any desired sequence with a sulphonic acid of the general formula R -SO2OH (III) in which R1 has the above-given meaning, or with a 0* 0 derivative thereof and with an optionally optically- active compound of the general formula:- R3 X C CON CH Y (IV) R 4 15 6 R R R in which R R, R 5 and R 6 have the above-given meaninas and X represents a reactive group and Y the group COOH, or with a derivative thereof, or- 37 b) a su.lphonamide of the general formula:- R 1 SO 2 NH (XI) 12 R in which R 1 and R 2 have the above-given meanings, is reacted with a compound of the general formula:- X-(CH2) n R3 0-C-CON CH Y (XIII) 14 15 I 6 R R R in which R 3 R 4 R 5 R 6 X, n and Y have the above- given meanings, or c) a compound of the general formula:- R 1 -SO2-N-(CH2) n R3 R 2 (XIV) 0-C-COOH R in which R, R 2 R 3 R 4 and n have the above-given Smeanings, is reacted with an optionally optically-active S: amine of the general formula:- HN CH Y R 5 R 6 :R R in which R R and Y have the above-given meanings, whereafter, if desired, the acid obtained is converted into a physiologically acceptable salt, ester or amide or, if desired, an ester or amide obtained is converted int .the free acid and, if desired, a racemate obtained is resolved into the enantiomers. Process according to claim 4 for the preparation of compounds according to claim 1, substantially as 38 hereinbefore described and exemplified.

6. Compounds according to claim 1, whenever prepared by the process according to claim 4 or

7. Pharmaceutical compositions containing at least one compound according to any of claims 1 to 3 and 6, as well as conventional carrier and adjuvant materials.

8. The use of compounds according to any of claims 1 to 3 and 6 for the treatment of heart and circulacory diseases. b b 0 9 W S S 11 A -39-

9. A compound of claim 1, a process for the preparation or use thereof, or a pharmaceutical composition comprising a said compound, substantially as hereinbefore described with reference to the Examples. Th-e-steps, features, eempesibiens and eempeunds -0 4 0 DAE hsSVNENHdyo EEBR19 *ohi e Manhi.Gb byDVE &.LIO Paen Atonesfo heaplcnts