CA2032570A1 - Phenoxyalkylcarboxylic acid amides, processes for the prepa ration thereof and pharmaceutical compositions containing them - Google Patents

Abstract

ABSTRACT

The present invention provides compounds of the general formula :- (I) in which the sulphonylaminoalkyl radical is in the ortho-, meta- or para-position to the phenoxyalkyl-carbonamide 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, R2 is a hydrogen atom or an alkyl or acyl radical, R3 and R4, which can be the same or different, are hydrogen atoms or lower alkyl radicals, n is 1, 2 or 3, R6 is a 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 R5 is a hydrogen atom or, together with R6, forms an alkylene chain containing 3-or 4 carbon atoms, as well as the physiologically acceptable salts, esters, amides and optical isomers thereof;
the compounds may be used in the treatment of heart and circulatory diseases.

Description

~32~7~
The present invention is concerned with phenoxy-alkylcarboxylic acid amides substituted on the phenyl moiety, with processes for the preparation thereof and with pharmaceutical compositions which conO~ain these compounds.
Published Federal Republic of Germany Patent Specification No. 2809377 describes phenoxyalkyl-carboxylic acids and some amides with lipid-sinking and thrombocyte aggregation-inhibiting action which are substituted in the 4-position.
Published Federal Republic of Germany Patent Specification No. 36 10 643 describes phenoxyalkyl-carboxylic acids and some amides with lipid-sinking and thrombocyte aggregation-inhibiting action which are substituted in the 2- and 3-position.
Surprisingly, it has now been found that sub~-titutqd phenoxyalkylcarboxylic acid amides in which the amine 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:-Rl-SO2-N-(CH2)n ~ R4 R5R6 -2- 2, ~ ~ 2 3 7 3 in which the sulphonylaminoalkyl radical is in the ortho-, meta- or para-position to the phenoxyalkyl-carbonamide radical and in which Rl is an aryl, aralkyl or aralkenyl radical, the aryl moiety o~ which can, in each case, be substituted one or more times by halogen, cyano, alkyl, trifluoromethyl or alkoxy, R2 is a hydrogen atom or an alkyl or acyl radicalg R3 and R4, which can be the same or different, are hydrogen atoms or lower alkyl radic~ s, _ is 1, 2 or 3, R6 is a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms which is optionally terminally substi~uted by carboxyl, aminocarbonyl or alkoxycarbonyl, by alkylthio, hydroxyl, phenyl or by imidazol-4-yl and R5 is a hydrogen atom or, together with R6, forms an alkylene chain containing 3 or 4 carbon a~oms.
Thus, the phenoxycarboxylic acid amides according to the present invention are compounds with amino acids as amine components. Apart fr.om the amide-acids, the present invention also includes physiologically compatible, pharmaceutically acceptable sales, 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 A2, as well as towards prostaglandin endoperoxides. They.

_3_ ~32;~73 inhibit the activation of blood pla~elets and of other blood cells and prevent the constriction of the smooth musculature of bronchi and blood vessels 9 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, migrain~ and peripheral arterial 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 ~hereof to thrombocyte concentrates stabilises the blood platelets and thus increases the storability of the preserved materials.
Since thromboxane, in the case of asthma bronchiale, is a mediator of the inflammatory reaction, by means of the use of these thromboxane receptor blockers, 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 -4~ 32~7~
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 equilib~ium of the prostaglandins 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 pregnancy gestosis and eclampsia, a more favourable course can be achieved. In addition, the prosta-glandin-caused symptoms of dysmenorrlloea and of the premenstrual syndrome can be therapeutically treated.
As aryl radical, alone or in combination with an alkyl or alkenyl chain, is to be understood, in all cases, to be an aromatic hydrocarbon radical containing 6 to 14 carbon atoms, especia:Lly 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, Cl-C6-alkyl, Cl-C6-alkoxy, trifluoro-methyl or cyano. The phenyl radical is preferred which can be substituted by halogen, preferably chlorine and ~032'~7~
bromine, methoxy, methyl or trifluoromet~yl.
Of the alkyl and alkoxy substituents in the aryl, aralkyl and aralkenyl radicals, those are pre~erred which contain 1 to 4 carbon atoms, espec-ially the methyl, ethyl, isobutyl and tert.-butyl radicals, as well as the methoxy radical.
As aralkyl radicals Rl, those are preferred in which the straight-chained or branched alkylene moiety contains 1 to 5 carbon ato~,s. Preferred aralkyl radicals Rl include the phenethyl and 4-chlorophenethyl radical.
By aralkenyl radicals Rl are to be understood those in which the alkenylene moiety contains 2 or 3 carbon atoms, ~he styryl and 4-chlorostyryl radical here being preferred.
By halogen is ~o be understood, in all cases, fl~lorine, clllorine or bromine.
The alkyl groups R2 are straight-chained or branched and contain 1 to 16 carbon atoms, methyl and octyl radicals being preferred.
The acyl radicals R2 are derived from aliphatic carboxylic acids containing 2 to 16 carbon atoms, from araliphatic acids and from aromatic carboxylic acids.
Preferred acyl radlcals include acetyl, isobutyroyl, cinnamoyl, benzoyl, 4-chlorobenzoyl and 4-aminobenzoyl radicals, as well as n-octanoyl and n-hexadecanoyl radicals.
__ -6- 2~32~7~

The lower alkyl radicals R3 and R4 can be 9 traigh~-chained or branched and contain 1 to 6, pre~erably 1 to 4 carbon atoms, the methyl and e-thyl radicals bein~ preferred.
n`is preferably the number 2.
R5 is preferably a hydrogen atom or, together with R6, forms an alkylene chain containing 3 or 4 carbon atoms, i.e. a 5- or 6-membered ring is present which contains a nitrogen a~tom, compounds with a 5;
membered ring here being preferred.
R6 is pre~erably 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-Cl-C6-alkylamino-carbonyl, 4-substituted piperazin-l-ylcarbonyl (the 4-positioned substituent being benzyl or 4-chloro-benzyl), Cl-C6-allcoxycarbonyl, Cl-C6-alkylthio, Cl-C14-aryl-Cl-C4-alkylthio, phenylthio, hydroxyl, phenyl and 4-imidazolyl. The phenyl nuclei possibly contained in these substituent:s can also contain 1 or 2 halo~en atoms and preferably chlorine atoms.
Especially preEerred substituents include carboxyl, aminocarbonyl, diethylaminocarbonyl, 4-benzyl-and 4-(4-chlorobenzyl)-piperazin-1-ylcarbonyl, methoxy-and ethoxycarbonyl, methylthio, benzyl- and 4-chloro-benzylthio, phenyl- and 4-chlorophenylthio, hydroxyl, phenyl, 4-chlorophenyl and 4-imidazolyl.

_7~ 2 ~ 7 3 In the gro~lp -N - C~l-COOH, those radicals R5 and R6 are especially preferred, the meaning of which gives the structure of an essential amino acid. These also include all possible isomers and the mixtures ~hereof.
The amino acids include, in particular, alanine, arginine, asparagine, aspartic acid, cysteine, cystine 7 glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine~ phenylalanine, proline, serine, threonine, tryptophane, tyrosine, valine, homocysteine, homoserine, hydroxylysine, hydroxy-proline, ornithine, sarcosine, norvaline and 2-amino-butyric acid.
The esters of the carboxylic acids of the general formula I can be those with lower monohydroxy alcohols, for example methanol and ethanol, and those with poly-hydroxy alcohols, for example glycerol, as well as those with alcohols which contain other functional groups, for example ethanolamine.
The amides of the carboxylic acids of general formula I are those in which the amine component is, for example, ammonia, a lower dialkylamine, such as diethylamine, or a hydroxyalkylamine, such as ethanol-amine or diethanolamine. Other possible amine components include aikyl-, aralkyl- and aryl-piperazines.
The present invention also includes the pureoptical isomers (enantiomers) of the compounds of 231~`2~7~

general formula I, as well as mixtures (racemates) thereof.
Especially preferred compounds of the formula I
are those in which Rl is a phenyl radical or a phenyl radical substituted once or twice by halogen, methyl, methoxy or trifluoromethyl, R2, R3 and R4 are hydrogen atoms 3 n is 2 and the group -N - CH-COOH is the residue of an essential ami.no acid er an optical isomer or mixture thereof, the sulphonylaminoalkyl radical there-by preferably being in the meta-position to the phenoxy-alkylcarbonylamide radical.
The phenoxycarboxylic acid amides of general formula I can be prepared a) by reacting an amine of the general formula:-HN - (CH2)n ~ (II) 0~1 .
in whîch R2 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:-Rl-SO2OH (III) in which Rl has the above-given meaning, or with a derivative thereof and with an optionally optically-active co~pound of the gèneral formula:-_ ~t~2~ 7~;~

X-C-CON - CH-Y (IV) or.-with a derivative thereof. In general formula IV, R3 and R4 have the above-given meanings, X is a reactive group and under Y is a radical -CooR7 (wherein R7 is a hydrogen atom or an equivalent of a metal ion or a lower alkyl, aralkyl or silyl radical) or an acid amide radical. ~owever, Y can also be a radical which, after condensation has taken place, is converted into an acid amide group or into a -CooR7 radical, whereafter a particular R7 is optionally converted in per se known manner into ano~her substit-uent R7 and the compounds obtained are opti.onally converted into pharmacologically compatible, pharmaceutically acceptable s~lts.
The process according ~o the present invention is preferably carried out in t.wo steps. The condensation oE the compounds of general formula II
with sulphonic acids of general formula III or 20 derivatives thereof, on the one hand, and with com- -pounds 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 fo-rmula 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 ~hereof or with a compound of the general 2 ~ 2 ~i 7 ~3 formula IV, again splitting off the protective group and subsequently reacting this reactive intermediate product with the not yet used compound of general fo~mula 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 ge~eral formula III or with a derivative thereof:

Z-N-(CH2)n- ~ ~ , , !

(V) (IV) Z-W-(CH2)n ~ R3 (VI) .
~(CH2)n~ ~ ~\ R3 R
O - C - CON - CH - Y
i4 R5 R6 (VII) 7 a Rl-SO20H R -S02N-(CH2)n ~ R3 (III) R 0- C - CON - CH - Y
R4 R5 ~6 (VIII) The symbols R2 n X R3 R4 R5 R6 a d Y d 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 formul~ 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:

Z~N~(cH2)n ~/ ~ + X-C-COOH

(V) (IX) Z-N-(cH2) - ~ \\ 3 (X) The phenoxyalkylcarboxylic acid of general formula X is now condensed (possibly after previous splitting off o~ the carboxyl protective group) with an optionally optically-active amine of the general formula :-~:'` ' ' '' ' .

' oc~2~7a HN - CH - Y (XI) or with a salt o~ the amine. Instead of the free caxboxylic acids, reactive derivatives are preferably reacted. The resultan~ 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.
When R3 and R4 are l~wer alkyl radicals, the phenoxyalkylcarboxylic acids of general formula X can al~so 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 derival:ives:

Z-N-(CH2)n ~ ~ + C;0 ~ CHC13 + M~OH

(V) _ , Z-~-(cH2)n ~ \\ K,3 (X) This process can also be used when Z has already been replaced by an Rl-SO2- radical.

3 ~ 3 b) 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:-Rl-SO2NH (XII) with an optionally optically-active compound of the general formula:- ~
X~(CH2)n ~ `~ R3 I (XIII) and possibly converting the group Y of the resultant compound of general formula VIII into a carboxyl function or another desired function.
When R~ is to be an acyl radical, the subsequent acylation of a compound of general formula I is preferably carried out in which R2 is a hydrogen atom 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 ~ ?~j 7 .

acid-binding agent, for example an alkali metal acetate, sodium hydro~en 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 9 diethyl ether 9 benzene, methylene chloride, dioxan or an excess of the tertiary amine. When using an inorg~nic acid binder, as 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 lS amino group of the compound of general ormula II into a protected amino group. Especially preferred are radicals, such as the benzyloxycarbonyl radical, known from peptide chemis~ry whlch are easy ~o remove, for example by hydrogenation. There can also be used 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 bv the use of hydroxylamine. Sometimes, the splitting off again can be completely omitted by initially introducing an Rl-502- radical. ~s reactive compounds of general formula IV, IX or XIII, those are especially preferred in which X is the anion of a strong acid, -15- ~ 3 ~ 5 7 ~
for example of a hydrogen halide or sulphonic acld.
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 sulphon-amide). The reaction of the reactive compounds of general formula IV, IX or XIII with the sodium or potassium salts of the comp~ounds of general formulae V and XII takes place in a solvent, for example toluene, methyl ethyl ketone, dimethylformamide or dimethyl sulphoxide, preferably with warming.
For the reaction oE carboxylic acids of general formula X with the amines of general formula XI, it is 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 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 water9 such as dicyclohexylcarbo-diimide. In many cases, the acid function of the aminocomponent can be present in salt form but often it is more preferable to start from the esterified amino--16- 2~32~
carboxylic acid of general formula XI, the use of trialkylsilyl esters thereby having proved to be quite especially preferable. In the case of the prepar-ation of trialkylsilyl esters, the amino group is possibly simultaneously silylated so that N-trialkyl-silylamino 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 ~itrogen. 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 used water-alcohol mixtures (e.g. for the reaction of hydroxysuccinimide esters of the carboxylic acids of general formula X with the sodium salts of the amino acids of general formula XI (Y - -COONa)); methylene chloride, and, in the case of low solubility, dimethyl sulpho~ide.
c) Compounds of general formula I can also be obtained by reacting compounds of general formula XIV or their reactive derivatives R -SO2-N-(CH2)n ~ \ R3 R2 ~ (XIV) in which Rl, R2, R3, R4 and n have the above-given meaningsj with an amino acid of general formula XI. --17~ ~c-~2~7~3 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, imida~olides or mixed anhydrides. Acid chlorides are obtained in the usual way from the free~acids by reaction with, for example, thionyl chloride.
, For 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 used 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 obtained is then reacted with one mole of the alkyl halide of general formula XIII. In this way9 the formation of dialkylated sulphonamides-i,s substantially avoided.
The possible subsequent N-alkylation of a compound of general formula VIII, in which R2 is a hydrogen atom, can be carried out according to known _ methods, preferably by reacting it with an alkyl 7 ~
halide or a dialkyl sulphate in the presence of an acid-binding agent, for example potassium carbonate.
The introduction of an acyl radical R2 into a sulphonamide of general formula VIII (R2 = H) takes place under conditlons.such as are usual for the acyl-ation 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 be used, ~or example, methylene chloride3 benzene, di,methylformamide and the like.
As substituents Y in compounds of general ~ormula VIII which can be converted into a -CooR7 radical, there can be used, ~or example, a nitrile, carbaldehyde, hydroxymethyl, aminomethyl or ~ormyl radical.
The conversion o~ the substituent R7 possibly to be carried out subsequent to the condensation, takes place, for example, b~ saponification or hydrolysis of a carboxylic acid ester (R7 = alkyl) to the correspond-ing carboxylic acid (R7 = hydrogen) with a Mineral acid or an alkali metal/alkaline earth metal hydroxide in a polar solvenc, ~or example water, aqueous methanol, aqueous ethanol or aqueous dioxan~ at ice-bath temperature or at a temperature o~ up to 40C.The particular conditions used depend upon the saponifiability or hydrolyzability of the amide bond present in the molecule.

-'9- 2~2~7~
On the other hand, however, the carboxylic acids (R7 = H) can also be esterified in the usual way or es~ers with a particular radical R7 can be converted by transesterification into an ester with a different radical R7. The esterification of the carboxylic acids is preferably carried out in the presence of an acidic catalyst, for example hydrogen chloride, sulphuric acid, ~-toluenesulphonic acid or a strongly acidic ion exchanger resin. On the other hand, transesterific-ations require the addition of a small amount of abasic substance, for example o an alkali metal or alkaline earth metal hydroxide or of an alkali metal alcoholate. For the esterification of the carboxyl group or for a transesterification, in principle all alcohols can be used. Preferred are the lower mono-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.
The amides according to the present in~ention derived from carboxylic acids of general for~ula I are preferably prepared 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--20- ~ 2~
alcohols, for example, eLhanolamine and 2-amino-pro-panol. Other valuable amine components include alkyl , aralkyl- and arylpiperazines, for example, benzylpiper-azine.
For the preparation of salts with pharmacologically or physiologically compatible, pharmaceutically accept-able organic or inorganic bases, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, methyl~ucamine, morpholine or ethanolamine, the carboxylic acids can be reacted with the corresponding bases. Mixtures of the carboxylic acids with an appropriate alkali metal carbonate or hydrogen carbonate can also be considered.
In the specification it will be understood that the qualification that the salts be "pharmaceu-tically accept-able" means that the salts have the necessary physical characteristics, for example, stability, to render them suitable for formulation into pharmaceutical compositions.
The qualiEication that the sa].ts be "physiologically com-patible" is to be understood, as extending to salts ofnon-toxic inorganic or organic cations or base components which have no adverse effects to the extent that such salts would be unsuitable for administration to living bodies.
Salts of compounds of formula (I) which are not pharmaceutically acceptable and physiologically compat-ible form a useful aspect of the invention of the novel derivatlves, inasmuch as they can be readily con-verted, by conventional means, to different salts having ~3257~

the required physical and chemical charac-teristics to make them suitable for administration in pharmaceutical compositions to living bodies.
The pure enantiomers of compounds of general formula (I) can be obtained by racemate resolution (via salt formation with optically-active bases) or by using optically pure amino acids in the syntheses according to processes a) to c).
For the preparation of~pharmaceutical compositions, 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 table-ts 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 ~orm. As .injection med.ium, water is preferably used which contains the stabilising agents, solubilising agents and/or bufEers usual in the case of in2ectl~on solutions. Such additives include, for example, tartrate and borate buffers, ethanol, dimethyl sulphoxide, comple~ formers (such as ethylenediamine-tetraacetic acid), high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation and polyethylene derivatives of sorbit anhydrides.
Solid carrier materia~s include, for example, starch, lactose, mannitol, methyl cellulose, talc, hgihly dispersed silicic acid, high molecular weight fatty acids (such as stearic acid), gelatine, agar-agar, 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 carried out simultaneously, the frequency of the treatments 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 25 weight. Normally, 0.5 to 40 and preferably l.0 to - 20 mg./kg./day in one or more administrations per day are effec-tive in order to obtain the desired results.
-~2~

The physiological activity of the substituted phenoxyalkylcarboxylic acid amides (I) is demonstrated and illustrated as follows.
1. TX ~ntagonis-tic Effect of Human Erythrocytes . _ _ _ ... . _ .
Method The thrombocyte aggregation is investigated by the method of Born and Cross (J. Physiol. 168, 178 (1963) in platelet-rich plasma of healthy blood donors. To inhibit clotting, the blood is mixe~ with 3.2~ citrate in a ra-tio by volume 1:9.
, To induce thrombocyte aggregation, U 46619 (Upjohn ~ Co., Kalamazoo, U.S.A.), which is a stable analog of the prostaglandin endoperoxide PHG2, is used. U 6619 was characterized as a selec-tive thromboxane mimetic (Coleman et al, Brit. J. Pharmacol. 68, 127 P., 1980).
The aggregation tes-t is carried out in a 4-channel aggregometer (Profiler( ), of t:he Bio/Data Co., U.S.A.).
The course of the aggregation is followed over a period of S minutes. At the end of the test, the degree of aggregation attained is printed ou-t. These values, which are obtained in the presence of different con-centrations of the substance to be tested, are used for the determination of the IC50 for the TX
antagonistic effect. The effectiveness varies inversely with the IC50 value.

~,;?.:373 -2~-2. Prevel1tin~ tt~e U 'l6619-Induced Pulmonary Embolism ethod Male NMRI mice, with a body weight of 25g, are used. The test substance is suspended in 1~ methyl-cellulose and administered to the experimental animals with the help of a stomach tube. The provocation test consists of injecting the lethal dose (800-1000 ~ug/kg) of the thromboxane mimetic (U 46619 of the Upjohn Co.) rapidly into the tail vein.~l The duration of the specific antagonistic effect is tested by pretreating the animals with 25 or 1 mg/kg of the different test substances and injecting U 46619 after 4 hours. The survival rate indicates how many of the animals used have survived the injection of the thromboxane mimetic. The results are given in the Table below.

-25- ~2~7 ~o - 'O ~ ~ o o ~r o o a) In ~ er ~
O h O ~1 ~ ~1 E-~ I¢ H

.C
P;
a) ~
r~ tn ~ o o o o o ~ ~ ~ o~ ~ ~0 ~ 00 ~D
~

o o o o o O O O O O
~rl O ~ ~1 ~I r~l ~I r-l o~O
O ~ ,,~

~ Lr CO ~
R (~ ,_1 ") ~ u~ Lo ::~ X

~ 5~2.

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-[3-[2-(phenylsulphonylamino)-ethyl]~phenoxy-acetyl]-glycine 2. N-[2-[2-(4-chlorophenylsulphonylamino) ethyl]-phenoxyacetyl]-alanine ~
3. N-[3~[2-(4-methylphenylsulphonylamino)-ethyl]-~ phenoxyacetyl]-alanine 4. N-[3-[2-(3- or 4-trifluoromethylphenylsulphonyl-arnino)-ethyl]-phenoxyacetyl]-2-aminobutyric acid 5. N-[3-[2-(4-chlorophenylsulphonylamino)-ethyl]-phenylacetyl]-alanine 4-be.nzylpiperazide 6. N-[3-[2-(4-methoxyphenylsulphonylamino)-ethyl]-phenoxyacetyl]-alanine ethyl ester 7. N-[3-[2-(2,4- or 2,5-dichlorophenylsulphonylamino)-ethyl]-phenoxyacetyl]-alanine 8. N-[4-~2-(3,5-dichlorophenylsulphonylamino)-ethyl]-phenoxyacetyl]-L-alanine 9. N-[4-[2-(4-trifluoromethylphenylsulphonylamino)-ethyl]-phenoxyacetyl]-L-alanine 10, N-[4-[2-(4-chlorophenylsulphonylamino)-ethyl]-phenoxyacetyl]-L-serine 11. N-~4-[2-(4-trifluoromethylphenylsulphonylamino)-ethyl]-phenoxyacetyl]-L-serine , ~ . . . .
' ;' -~7- 2 ~32 ~ 7 ?

12. N-~4-[2-(4-methylphenylsulphonylamino)-ethyl]-phenoxyacetyl]-glycine.
The following Examples show some of the numerous prQcess variants which can be used for the synthesis S of the new compounds according to the presen~ invention.
However, they are not to represent a limitation of the subject matter of the present inven~ion.
Example l.
N-[3-[2-(4-Chlorophenylsulphonylamino)-eth~l]-ph~noxYacetyl]-~lycine.
a)'3-[2-(4-Chlorophenylsulphonylamino)-ethyl]-phenoxyacetyl chloride.
A mixture of 30 g. (81 mmole) 3-~2-(4-~hloro-phenylsulphonylamino)-ethyl]-phenoxyacetic acid, 23.5 ml. (0.32 mole) thionyl chloride and 3 drops of dimethylformamide is stirred for 2 hours at 6GC.~
whereafter excess thionyl chloride is distilled off in a vacuum. The residue obtained is dissolved in anhydrous diethyl ether and clarified with activated carbon. After evaporation, an oil is obtained which slowly crystallises through. It is stirred with iso-hexane, filtered off with suction and dried. Yield 26.9 g. (94% of theory); m.p. 75 - 77C.
b) Title compound.
To an ice-cold solution of 0.8 g. (lO mmole) glycine and 15 ml. 2N aqueous sodium hydroxide solution - is slowly added dropwise a solution of 3.52 g. of the -28- ' 2 ~2'?~
acid chloride obtained according to a) in 40 ml.
methylene chloride and subseq~lently allowed to post-react ~or 2 hours a-t 0C. The reaction mix~ure is then acidif~,ed 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 is recrystallised from nitromethane. Yield 2.7 g.
(63% o~ theory); m.p. 134 - 135C.
Example 2.
N-[3-[2~(4-Bromophenylsulphonylamino)-ethyl]-phenoxyacetyl]-L-alanine.
a) N-Tritnethylsilyl-L-alanine trimethYlsilyl ester.
To a suspension o~ 7.12 g. (80 mmole) L-alanine in 120 ml. anhydrous tnethylene chloride is added drop-wise, with stirring, 20.8 ml. trirnethylchlorosilane, followed by brie~ly heating to reflux temperature, a, clear solution thereby being obtained. Then, with gentle cooling, 22.4 ml. triethylamine are added drop-wise thereto, with stirring, in such a man~ler that the reaction mixture does not boil too vigorously. Subse-quently, the reaction mixture, a thick suspension, is heated for 5 minutes to re~lux 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 -29- ~ 7 ~
worked up,in crude form.
b) Title compound.
To a solution of 9.28 g. (20 mmole) 3-[2-(4-bromophenylsulphonylamino)-ethyl]-phenoxyacetyl-imidazole in 75 ml. anhydrous tetrahydrofuran is addedat -5C., with the'exclus~on of moisture, 5.14 g.
(22 mmole) of the trimethylsilyl compound obtained according to a). The reaction mixture is allowed to come to ambient temperatur~ in the course of 3 hours and subsequently the tetrahydrofuran is distilled off in a vacuum. The residue is stirred with 2N hydro-chloric acid at ambient temperature and then extracted several times with methylene chloride. The combined or~anic phases are extracted with an amount of 2N
aqueous sodium hydrogen carbonate solution suf~icient for salt formation and the ext:ract is acidified. The precipitated product is filte~ed oEE with suction, dried and recrystallised from nitromethane. Yield 6.2 g. (60% of theory); m.p. 191 - 192C.
Example 3.
N-[3-[2-(4-Chlorophenylsulphonylamino)-ethyl]-phenoxyacet~l]-L-alanine.
a) N-[3-[2-(Benzyloxycarbonylamino)-ethyl]-phenoxyacet~l]-L-alanine.
To a 40C. warm solution of 5.0 g. (15.8 mmole) 3-[2-(benzyloxycarbonylamino)-ethyl]-phenoxyacetic ,acid in 25 ml. anhydrous dimethyl sulphoxide are added -3~- 2 g~ ~3~'3 7 ~
2.56 g. (15.8 mrnole) carbonyl-bis-imidazole, followed by stirring for a further 30 minutes at 40C. Subse-quently, 1.7~ gA (15.8 mmole) L-alanine sodium salt is added thereto, the reaction mixture is kept for 3 hours at 60C., 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 phas~e 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 o~ a colourless oil.
Alternative synthesis for this compound:
~ mixture of 22.0 g. (81 mmole) 3-[2-(benzyloxy-carbonylamino)-ethyl]-phenol, 200 ml. butanone and 33.5 g. very finely pulverised dry potassium carbonate is maintained ~or 1 hour at reElux temperature, 300 mg.
potassium iodide and 17.3 g. ~89.3 mmole) N-(2-chloro-acetyl)-L-alanine ethyl ester are then added thereto 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 anhydro~s -31- ~3~70 magnesium sulphate and evaporated in a vacuum. Yield:
practically quantitative.
b) Title compound.
~mixture of 8.0 g. (20 mmole) o~ the benzyloxy-carbonyl compound obtained according to a), 75 ml.
methanol, 11.0 ml. 2N hydrochloric acid an~ about 2 g.
10% palladium-carbon is hydrogenated for 12 hours at ambient temperature and 6 ~ar 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 N-[3-(2-aminoethyl)-phenoxyacetyl]-L-alanine, are added 75 ml.
of water and so much 2N aqueous sodium hydroxide solution that a pH of 10 i.s reached. With stirring at 0C., there are now added thereto 3.16 g. 4-chloro-benzenesulphochloride in small portions and, by the dropwise addition of further dilute aqueous sodium hydroxide solution, care is taken that a pH of 10 is maintained. Subsequently, thc reaction mixture is further stirred for 2 hours a-t 35C., acidified, filtered off with suction and the product is dried and recrystallised from nitromethane. Yield 4.7 g. (71%
of theory); m.p. 175 - 177C.
Exam~le 4.
_-[3-[2-(4-Chlorophenylsulphonylam~no)-ethyl]-~ phenoxyacetyl]-L-al nlne.

~257~
a) N-[3-[2-(~-chlorophenylsulphonylamino)-ethyl]-phenoxyacetyl]-L-alanine ethyl ester~
To an ice-cold mixture of 2.2 g. (14 mmole) L-alanine ethyl ester hydrochloride, 4.3 g. triethylamine and 100 ml. methylene chloride is slowly added dxopwise, with stirring, a solution of 5.0 g. (14 mmole) 3-[2-(4-chlorophenylsulphonylamino)-ethyl]-phenoxyacetyl chloride in 25 ml. methylene chloride. Subsequently, the reaction mixture is sti~red for 1 hour at 0C. and then for 1 hour at 25C., shaken out with dilute hydro-chloric acid and water, dried over anhydrous sodium sulphate and finally evaporate.d. Yield 5.1 g. (77% of theory) of a colourless oil.
b) Title compound.
A mixture of 2.8 g. t6 mmole) of the ester obtained according to a), 25 ml. ethanol and 15 ml. 2N
aqueous sodium hydroxide solution i8 S tirred for 5 minutes at ice-bath temperature, thereafter diluted with 25 ml. ice water and acidified with dilute hydro-chloric acid. After filtering off with suction, drying and recrystallising from ni~romethane, the yield is 1.9 g. (72% oE theory); m.p. 175 - 177C. The product is identical with that obtained according to Example 3.
Example 5.
N-[3-[2-(~-Chlorophenylsulphonylamino)-ethyl]
phe oxyacetyll-L-methionine.

2 ~ 7 ~
To a solution of 8.0 g. (20 mmole) 3-[2-(4-chlorophenylsulphonylamino)-ethyl]-phenoxyacetic acid in 35 ml. dimethyl sulphoxide is added at 40C., with stirring, 3.5 g. (20 mmole) car~onyl-bis-imidazole, foam formation thereby taking place. After stirring for 1 hour at 40C., 4.07 g. (24 mmole) L-methionine sodium salt are added thereto and the reaction mixture then maintained for 18 hours at 60C. It is then cooled, poured on to an ice~hydrochloric acid mix~ure and the greasy product obtained taken up in ethyl ac,etate. 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 acidi~ied, ~iltered o~f with suction and the product is washed with water, dried and recrystallised from nitromethane. Yield 8.3 g. (77% of theory); m.p.
138 - 139C.
In analogous way, from 3-[2-~4-chlorophenyl-sulphonylamino)-ethyl]-phenoxyacetic acid, there are obtained the.following compounds:
2. with L-histidine sodium salt:
N-[3-[2-(~-chlorophenylsulphonylamino)-ethyl]-phenoxy-acetyl]-L-histidine hydrochloride.
yield 34%; m.p. 100 - 103C.
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 -3~- 2~ 2~7~

crystallises. ~t is tl~en quickly filtered off with suction (hygroscopic) and dried over phosphorus pentoxide.
3. with L-2-aminobutyric acid sodium salt:
S N-~3-[2-(4-chlorophPnylsulphonylamino)-ethyl]-phenoxy-acetyl]-L-2-aminobutyric acid.
Yield 61% of theory; m.p. 147 - 150C. (recrystallised from nitromethane).
4. with L-asparagine sodiu~ salt:
N-[3-[2-(4-chlorophenylsulphonylamino)-ethyl]-phenoxy-acetyl]-L-asparagine.
- Yield 62% of theory, m.p. 133 - 135C. (recrystallised ~rom nitromethane).
5. with L-phenylalanine sodium salt:
N-[3-[2-(4 chlorophenylsulphol~ylamino)-ethyl]-phenoxy-acetyl]-L-phenylalanine.
Yield 63% of theory; m.p. 158 - 159C. (recrystallised from aqueous ethanol).
6. with L-proline sodium salt:
N-[3-[2-(4-chlorophenylsulphonylamino)-ethyl]-pheno~y-acetyl]-L-proline.
Yield 93% of theory; m.p. 114 - 116C. (recrystallised from ethyl acetate).
7. with L-serine sodium salt:
N-[3-[2-(4-chlorophenylsulphonylamino)-ethyl]-phenoxy-acetyl]-L-serlne~
Yield 49% of theory; m.p. 146 - 148C. (recrystallised from nitromethane).

-35- 2~3~7 ~

8. with L-nGrvaline sodium salt:
N-[3-~2-(4-chlorophenylsulphonylamino)-ethyl]-phenoxy-acetyl]-L-norvaline~
Yield 72% of theory; m.p. 126 - 128C. (recrystallised from nitromethane).
Example 6.
N-[3-[2-(4-Chlorophenylsulphon~lamino~-ethyl]-pheno~yacetyl]-D-alanine.
Into a 4QC. warm sol)~tion of 10.0 g. (27 mmole) 3-[2-(4-chlorophenylsulphonylamino)-ethyl]-phenoxy-ac,etic acid in 30 ml. dimethyl sulphoxide are intro-duced 4.3~ g. (27 mmole) carbonyl-bis-imidazole. The mixture is allowed to react for 10 minutes, 3176 g.
(27 mmole) 4-nitrophenol are added thereto, ~ollowed by stirring for 10 minutes. 3.0 g. (27 mmole) D-alanine sodium salt are then introduced, ~ollowed by st irr ing for 3 hours at 60C. Afte r c o o 1 ing, 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 - 166C.
Example 7.
In a process method analogous to Example 6, there were prepared ~rom 4-[2-(phenylsulphonylamino)--36- ~332~7~

ethyl]-phenoxyacetic acid a) and L-alanine:
N-[4-[2-(phenylsulphonylamino)-ethyl]-phenoxyacetyl]-L-alanine Yield '62~ of theory; m.p. 164 - 165C.
b) and D-alanine:
N-[4-[2-(phenylsulphonylamino)-ethyl]-phenoxyacetyl]-D-ala~ine Yield S4% oE theory; m.p. 152 - 153C.
The Patent Specifications referred to herein are more fully identified below:
Federal Republic of Germany Offenlegungsschrift tLaid Open Patent Specification) 36 10 643~ E.-C.
Witte et al, published (Laid Open) October 1, 1987, assigned to Boehringer Mannheim GmbH.
Federal Republic of Germany Offenlegungsschrift (Laid Open Patent Specification) 28 09 377, published (Laid Open) Setpember 13, 1989, E.-C. Witte et al~
assigned to soehringer Mannheim GmbH.

O

Claims (19)

1. A compound of the general formula (I):
(I) in which the sulphonylaminoalkyl radical is in the ortho-, meta- or para-position to the phenoxyalkylcar-bonamide radical and in which:
R1 is an aryl, aralkyl or aralkenyl radical, the aryl moiety of which is, in each case, unsub-stituted or substituted one or more times by halogen, cyano, alkyl, trifluoromethyl or alkoxy;
R2 is a hydrogen atom or an alkyl or acyl radical;
R3 and R4, which can be the same or dif-ferent, are hydrogen atoms or lower alkyl radicals;
n is 1, 2 or 3;
R6 is a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms which is unsubstituted or terminally substituted by carboxyl, aminocarbonyl or alkoxycarbonyl, by alkylthio, hydroxyl, phenyl or by imidazol-4-yl; and R5 is a hydrogen atom or, together with R6, forms an alkylene chain containing 3 or 4 carbon atoms, and physiologically compatible, pharma-ceutically acceptable salts, esters, amides and optical isomers thereof.

2. A compound of general formula (I), according to claim 1, wherein R1 is a phenyl radical or a phenyl radical substituted once or twice by halogen, methyl, methoxy or trifluoromethyl, R2, R3, R4 are hydrogen atoms, n is 2 and the radical is the residue of an essential amino acid or of an optical isomer or mixture thereof, the sulphonylaminoalkyl radical being in the meta-position to the phenoxy-alkylcarbonamide radical.

3. A compound according to claim 1 or 2, wherein the group represents the residue of an amino acid selected from the group consisting of glycine, alanine, 2-amino butyric acid, serine, methionine, asparagine, phenyl-amine, proline and norvaline.

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

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

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

7. N-[3-[2-(4-Chlorophenylsulphonylamino)-ethyl]
phenoxyacctyl]-L-norvaline.

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

9. A pharmaceutically acceptable, physio-logically compatible salt, ester or amide of an acid of claim 4, 5, 6, 7 or 8.

10. A pharmaceutical formulation for the treat-ment of heart and circulatory diseases comprising an effective, acceptable amount of a compound of formula (I) or a physiologically compatible, pharmaceutically acceptable salt, ester, amide or optical isomer thereof, as defined in claim 1, 2 or 3, in association with a pharmaceutically acceptable carrier.

11. A pharmaceutical formulation for the treat-ment of heart and circulatory diseases comprising an effective, acceptable amount of a compound of claim 4, 5, 6, 7 or 8, in association with a pharmaceutically acceptable carrier.

12. A pharMaceutical forrnulation for the treat-ment of heart and circulatory diseases comprising an effective, acceptable amount of a salt, amide or ester of claim 9, in association with a pharmaceutically acceptable carrier.

13. Use of a compound of formula (I), or a physiologically compatible, pharmaceutically accept-able salt, ester, amide or optical isomer thereof, as defined in claim l, 2 or 3, for the treatment of heart and circulatory diseases.

14. Use of a compound of claim 4, 5, 6, 7 or 8, for the treatment of heart and circulatory diseases.

15. Use of a salt, ester or amide of claim 9, for the treatment of heart and circulatory diseases.

16. Use of a compound of formula (I), or a physiologically compatible, pharmaceutically accept-able salt, ester, amide or optical isomer thereof, as defined in claim 1, 2 or 3, for the manufacture of a medicament for the treatment of heart and circulatory diseases.

17. Use of a compound of claim 4, 5, 6, 7 or 8, for the manufacture of a medicament for the treatment of heart and circulatory diseases.

18. Use of a salt, ester or amide of claim 9, for the manufacture of a medicament for the treatment of heart and circulatory diseases.

19. A process for the preparation of a compound of the general formula:
(I) in which the sulphonylaminoalkyl radical is in the ortho-, meta- or para-position to the phenoxyalkyl-carbonamide radical and in which R1 is an aryl, aralkyl or aralkenyl radical, the aryl moiety of which is, in each case, unsubstituted or substituted one or more times by halogen, cyano, alkyl, trifluoromethyl or alkoxy, R2 is a hydrogen atom or an alkyl or acyl radical, R3 and R4, which can be the same or dif-ferent, are hydrogen atoms or lower alkyl radicals, n is 1, 2 or 3, R6 is a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms which is unsubstituted or terminally, substituted by carboxyl, aminocarbonyl or alkoxycarbonyl, by alkylthio, hydroxyl, phenyl or by imidazol-4-yl and R5 is a hydrogen atom or, together with R6, forms an alkylene chain containing 3 or 4 carbon atoms, as well as of the physiologically compatible, pharmaceutically acceptable salts, esters, amides and optical isomers thereof, wherein a) an amine of the general formula:
(II) in which R2 and n have the above-given meanings, optionally with intermediate protection of the amino or hydroxyl group, is reacted in any desired sequence with a sulphonic acid of the general formula:

R1-SO2-OH (III) in which R1 has the above-given meaning, or with a derivative thereof and with an optionally optically-active compound of the general formula:

(IV) in which R3, R4, R5 and R6 have the above-given meanings and X represents a reactive group and Y the group COOH, or with a derivative thereof, or b) a sulphonamide of the general formula:

(XI) in which R1 and R2 have the above-given meanings, is reacted with a compound of the general formula:

(XIII) in which R3, R4, R5, R5, X, n and Y have the above-given meanings, or c) a compound of the general formula:

(XIV) in which R1, R2, R3, R4 and n have the above-given meanings, is reacted with an optionally optically-active amine of the general formula:

in which R5, R6 and Y have the above-given meanings, whereafter, if desired, the acid obtained is converted into a physiologically compatible, pharmacuetically acceptable salt, ester or amide or, if desired, an ester or amide obtained is converted into the free acid and, if desired, a racemate obtained is resolved into the enantiomers.

#1-12/12/1990