CA1175430A - Sulphimines, the salts thereof and preparation thereof and pharmaceutical compositions containing these compounds - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Compounds of general formula I

(I) wherein n represents the number 0 or 1, A represents a methylene, vinylene or ethylene group optionally substituted by lower alkyl groups, B represents an alkylene group, R1 represents an optionally substituted alkyl, phenyl or naphthyl group, or a cycloalkyl or pyridyl group, and R2 represents a hydrogen atom or an acyl group, and acid addition salts thereof. The new compounds show valuable pharmacological properties, particularly on antithrombotic activity.
Processes for the preparation of the new compounds, as well as pharmaceutical compositions containing them, are also objects of this invention,

Description

1 17~430 , Chemical ComPounds This invention relates to new sulphimines, to processes for their preparation and to pharmaceutical compositions containing them, and to their use as antithrombotic agents.
According to one feature of the present invention, there are provided compounds of general formula I

0 N ~ ~ (I) H ~2 [wherein n is 0 or 1;
represents a methylene, vinylene or ethylene group (optionally substituted by one or two alkyl groups each containing 1 to 3 carbon atoms);
B represents a straight-chain or branched alkylene group containing 2 to 6 carbon atoms;
Rl represents an alkyl group containing 1 to 3 carbon atoms (optionally substituted by a phenyl group); a phenyl group (wherein the aforementioned phenyl nuclei may optionally be substituted by an alkyl group containing 1 to 4 carbon atoms, by a halogen atom, by an alkoxy group containing 1 to 3 carbon atoms, or by a cyclohexyl, phenyl or halophenyl group); an alkyl group containing 4 to 7 carbon atoms; a cycloalkyl group containing 3 to 7 carbon atoms; a phenyl group di- or tri-substituted by alkyl groups containing 1 to 4 carbon atoms or by alkoxy ., ~;

.` 11~5~L30

- 2 -groups containing 1 to 3 carbon atoms and/or by halogen atoms or a hydroxy- or amino phenyl group disubstituted by alkyl groups containing 1 to 4 carbon atoms or by alkoxy groups containing 1 to 3 carbon atoms and/or by halogen atoms, wherein the substituents of the abovementioned phenyl, hydroxyphenyl or aminophenyl nuclei may be identical or different; a naphthyl group (optionally substituted by an alkoxy group containing 1 to 3 carbon atoms); or a pyridyl group; and R2 represents a hydrogen atom or an acyl group of an organic carboxylic acid, an organic or inorganic sulphonic acid or a carbonic acid derivative].
and salt thereof formed with strong acids.
For pharmaceutical use, the strong-acid addition salts referred to above will, of course, be physiologically compatible acid addition salts, but other acid addition salts may find use in the preparation of the compounds of formula I and their pysiologically compatible strong-acid addition salts. The term "acid addition salts"
includes salts formed with organic and inorganic acids.
Where R2 is an acyl group, it may for example, be an acyl group of an optionally sùbstituted aliphatic alkanoic or alkenoic acid (wherein the substituent(s) may, for example, comprise one or more lower alkoxy groups), of an optionally substituted aromatic carboxylic acid (wherein the substituent(s) may, for example, comprise halogen atoms or cyano, lower alkyl or lower alkanoyloxy groups and a -CH=CH- group or one or two =CH- groups may optionally be replaced by an oxygen, sulphur or nitrogen atom), of a carbonic acid ester, of optionally substituted carbamic acid (wherein the substituent(s) may, for example, comprise lower alkyl, phenyl or halophenyl groups) or of an aliphatic or aromatic sulphonic acid, or be a hydroxy-sulphonyl group.

The term "halogen atom" in the above de~inition of Rl includes, for example, a fluorine, chlorine or bromine atom.
A may represent, for example, a methylene, methyl-methylene, dimethylmethylene, diethylmethylene, dipropylmethylene, vinylene, methylvinylene or ethylene group, B may represent, for example, an ethylene, n-propylene, n-butylene, n-pentylene, n-hexylene, l-methyl-ethylene, 2-methyl-ethylene, l-methyl-n-propylene, 2-methyl-n-propylene, 3-methyl-n-propylene, l-methyl-n-butylene, 2-methyl-n-butylene, 3-methyl-n-butylene, 4-methyl-n-butylene, l-methyl-n-pentylene, 2-methyl-n-pentylene t 3-methyl-n-pentylene, 4-methyl-n-pentylene, 5-methyl-n-pentylene, l,l-dimethyl-ethylene, 1,2-dimethyl-ethylene, 2,2-dimethyl-ethylene, l,l-dimethyl-n-propylene, 2,2-dimethyl-n-propylene, 3,3-dimethyl-n-propylene, 1,2-dimethyl-n-propylene, 1,3-dimethyl-n-propylene, l,l-dimethyl-n-butylene, 2,2-dimethyl-n-butylene,

3,3-dimethyl-n-butylene, 4,4-dimethyl-n-butylene, 1,2-dimethyl-n-butylene, 1,3-dimethyl-n-butylene, 1,4-dimethyl-n-butylene, 2,3-dimethyl-n-butylene, l-ethyl-ethylene, 2-ethyl-ethylene, l-ethyl-n-propylene, 2-ethyl-n-propylene, 3-ethyl-n-propylene, l-ethyl-n-butylene, 2-ethyl-n-butylene, 3-ethyl-n-butylene, 4-ethyl-n-butylene, l-methyl-2-ethyl-ethylene, 1-methyl-2-ethyl-n-propylene, 1-methyl-3-ethyl-n-propylene, 1-methyl-2-propyl-ethylene, l-propyl-ethylene, l-butyl-ethylene or l-propyl-n-propylene group, Rl may represent, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl, pentyl, neopentyl, tert.pentyl, hexyl, heptyl, benzyl, l-phenylethyl, 2-phenylethyl, l-phenylpropyl, 3-phenylpropyl, fluorobenzyl, chlorobenzyl, bromobenzyl, methylbenzyl, isopropylbenzyl, 1 ~75430 methoxybenzyl, ethoxybenzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, fluorophenyl, chlorophenyl r bromophenyl, methylphenyl, dimethylphenyl, isopropylphenyl, tert.butylphenyl, methoxyphenyl, ethoxyphenyl, propoxyphenyl, cyclohexylphenyl, biphenylyl, fluorophenyl-phenyl, chlorophenyl-phenyl, difluorophenyl, dichlorophenyl, dibromophenyl, dimethoxyphenyl, methoxychlorophenyl, methoxy-bromophenyl, methyl-tert.butyl-phenyl, methyl-chlorophenyl, methyl-bromophenyl, tert.-butyl-bromophenyl, dichloroamino-phenyl, dibromo-aminophenyl, dimethyl-aminophenyl, dichloro-hydroxyphenyl, dibromo-hydroxyphenyl, dimethyl-hydroxyphenyl, di-tert.butyl-hydroxyphenyl, trimethoxy-phenyl, naphthyl, methoxynaphthyl or pyridyl group and R2 may represent, for example, a hydrogen atom, or a formyl, acetyl, propionyl, pivaloyl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, methoxyacetyl, methoxypropionyl, pinanoyl, benzoyl, fluorobenzoyl, chlorobenzoyl, bromobenzoyl, cyanobenzoyl, methylbenzoyl, ethylbenzoyl, isopropylbenzoyl, tert.butylbenzoyl, difluorobenzoyl, dichlorobenzoyl, dimethylbenzoyl, trimethylbenzoyl, naphthoyl, pyridinoyl, thenoyl, acetoxy-benzoyl, hydroxysulphonyl, methylsulphonyl, ethylsulphonyl, camphorsulphonyl, phenylsulphonyl, methylphenylsulphonyl, fluorophenyl-sulphonyl, chlorophenylsulphonyl, bromophenylsulphonyl, pentamethylphenylsulphonyl, naphthylsulphonyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, benzyloxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, phenylaminocarbonyl or chlorophenylaminocarbonyl group.
Preferred compounds of general formula I are those wherein n is 0 or 1, A represents a dimethylmethylenq, vinylene or ethylene group, B represents a straight-chained alkylene group containing 3 to 5 carbon atoms, Rl represents an alkyl group containing 1 to 6 carbon atoms, a benzyl, phenylethyl, cyclohexyl, naphthyl, methoxy-naphthyl or pyridyl group, a phenyl group (optionally substituted by an alkyl group containing 1 to 4 carbon atoms, by a methoxy, cyclohexyl, phenyl or fluorophenyl group or by a fluorine, chlorine or bromine atom), a phenyl group (disubstituted by alkyl groups containing 1 to 4 carbon atoms, methoxy groups, or chlorine and/or bromine atoms, wherein the substituents of the phenyl nucleus may be the same or different), or an aminophenyl, hydroxyphenyl or methoxyphenyl group substituted by two chlorine or bromine atoms, two methoxy groups or two alkyl groups each containing 1 to 4 carbon atoms, and R2 represents a hydrogen atom, an alkanoyl group containing 1 to 8 carbon atoms (optionally substituted by a methoxy group), a benzoyl or phenylsulphonyl group (optionally substituted by a halogen atom or by a cyano group or by an alkyl group containing 1 to 4 carbon atoms), an alkoxycarbonyl group containing a total of 2 to 4 carbon atoms, an aminocarbonyl group (optionally substituted by a chlorophenyl group or by 1 or 2 methyl groups), or a naphthoyl, pinanoyl, camphorsulphonyl, pentamethylphenylsulphonyl, pyridinoyl group or thenoyl group.
Particularly preferred compounds of general formula I above are, however, those wherein n is 1, A represents a dimethylmethylene, vinylene or ethylene group, B represents an n-butylene group, Rl represents a methyl or methoxynaphthyl group, a phenyl group (optionally substituted by a methoxy group or a fluorine or chlorine atom), a phenyl group substituted by 2 chlorine or bromine atoms, or a methylbromophenyl, 4-amino-3,5-dibromophenyl or di-- 6 - 1~7S43 tert.butyl-hydroxy-phenyl group, and R2 represents a hydrogen atom, an alkanoyl group containing 1 to 3 carbon atoms or a benzoyl or phenyl-sulphonyl group (optionally substituted by an alkyl group containing 1 to 4 carbon atoms).
Also preferred are those compounds of formula Ia O

A ~ o - B - S - R1 O ~ ~ R (Ia) H

wherein A represents an ethylene or vinylene group, B represents an n-butylene group, Rl represents a methyl, phenyl, 4-fluorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl or 3-methyl-4-bromophenyl group, and R2 represents a hydrogen atom, or an acetyl or p-toluenesulphonyl group.
The compounds of general formula I may, for example, be prepared by the following processes, which processes constitute further features of the present invention:
a) For the preparation of compounds of general formula I wherein n is 1 and R2 represents a hydrogen atom:
Reaction of a compound of general formula II

~ ~ O - B - SO - P1 (II) 3~
(wherein A, B and Rl are as hereinbefore defined), with hydrazoic acid optionally formed in the reaction mixture.

1 ~75~30 The reaction is conveniently carried out in a solvent or mixture of solvents such as, for example, methylene chloride, dimethylformamide or tetrahydrofuran at temperatures of between 0 and 40C, preferably at temperatures of between 10 and 35C. It is particularly advantageous to carry out the reaction with an alkali metal azide, e.g. sodium azide, and in the presence of polyphosphoric acid as solvent.
b) For the preparation of compounds of general formula I wherein R2 represents a hydrogen atom:
~eaction of a compound of general formula IIa A - ~ - ~ - StO)n~R1 0 ~ (IIa) wherein A, B, n and Rl are as hereinbefore defined) with a compound of general formula III

H N - 0 - X - R3 tIII) wherein X represents a carbonyl or sulphonyl group 25 and R3 represents an aryl group substituted at least at both o-positions, (such as, for example, a 2,4,6-trimethylphenyl or 2,4,6-tri-isopropylphenyl group) or (if X represents a sulphonyl group~
3D a hydroxy group.
The reaction is conveniently carried out in a solvent or a mixture of solvents such as, for example, methylene chloride, chloroform, dimethylformamide, tetrahydrofuran or dioxan at temperatures of between 0 and 50C, but preferably at temperatures of between 5 and 40C. However, in a particularly advantageous embodiment of the reaction, a compound of general formula III may be used without being isolated beforehand or may be prepared in the reaction mixture.
c) For the preparation of compounds of general formula I wherein n is 1:
Oxidation of a compound of general formula IV

A ~
~ N ~t - B - S - R (IV) H R

wherein A, B, R1 and R2 are as hereinbefore defined.
The oxidation is conveniently effected in a solvent or mixture of solvents, such as, for example, water, water/pyridine, methanol, ethanol, acetone, formic acid, glacial acetic acid, trifluoroacetic acid or dilute sulphuric acid, at temperatures of between -80 and 100C, depending on the oxidising agent used. It is particularly advantageous to carry out the reaction with one equivalent of the oxidising agent used, e.g. with hydrogen peroxide in glacial acetic acid or formic acid at temperatures of from 0 to 20C or in acetone at 0 to 60C, or with a peracid such as for example, performic acid in glacial acetic acid or trifluoroacetic acid at 0 to 50C or with sodium metaperiodate in aqueous methanol or ethanol at 15 to 25C.
d) For the preparation of compounds of general formula I wherein R2 does not represent a hydrogen atom:
Acylation of a compound of general formula V
()n A -1 I ~ - O - B - S -O~N ~
N (V) H ~

1 17543~
g wherein n, A, B and Rl are as hereinbefore defined.
The reaction is conveniently carried out in a solvent or mixture of solvents such as, for example, water, methylene chloride, chloroform, ether, tetrahydro-furan, dioxan or dimethylformamide with a correspondingacylating agent, e.g. with an acid (in the presence of an acid-activating or dehydrating agent such as, for example, thionyl chloride), with an anhydride such as, for example, acetic anhydride, with an ester such as, for example, ethyl p-toluenesulphonate or diethyl carbonate, with a halide such as, for example, acetyl chloride, ethyl chloroformate or p-toluenesulphonic acid chloride or with an isocyana~e, whilst these may optionally also be used as solvents, optionally in the presence of an inorganic or tertiary organic base such as, for example, sodium hydroxide, potassium carbonate, triethylamine or pyridine, whilst the latter may simultaneously also serve as solvents, at temperatures of between -25 and 100C, but preferably at temperatures of between -10 and 80C.
e) Reaction of a compound of general formula VI

~ (VI) (wherein A is as hereinbefore defined~, or an inorganic or tertiary organic base salt thereof, with a compound .

of general formula VII
()n ~ (VII) N

wherein n, Rl, R2 and B are as hereinbefore defined and Z represents a nucleophilically exchangeable group such as, for example, a halogen atom or a sulphonic acid ester group, e.g. a chlorine, bromine or iodine atom or a p-toluenesulphonyloxy or methanesulphonyloxy group.
The reaction is conveniently effected in a solvent or mixture of solvents such as, for example, dioxan, tetrahydrofuran, chloroform or toluene, but preferably in an anhydrous aprotic solvent such as, for example, acetone, dimethylformamide or dimethyl-sulphoxide, optionally in the presence of an alkali base such as, for example, sodium carbonate, potassium carbonate or sodium hydroxide at temperatures of between 0C and the boiling temperature of the solvent - 25 used, e.g. at temperatures of between 0 and 100C, but preferably at temperatures of between 10 and 50C. The reaction may also, however, be carried out without a solvent.
f) For the preparation of compounds of general formula I wherein n is 0:
Reaction of a compound of gèneral formula VIII

C i ~ O - B - S - R1 (wherein A, B and Rl are as hereinbefore defined), with a compound of general form~la I~

Hal R ' - N (IX) ~wherein ~al represents a chlorine or bromine atom and R2' has the meanings given hereinbefore for R2, with the exception of a hydrogen atom) or with an alkali metal salt thereof, with optional subsequent hydrolysis.
The reaction is preferably effected with an alkali metal salt of a compound of general formula IX, e.g. the sodium salt, optionally in the presence of an inorganic base such as, for example, an alkali base, in a solvent or mixture of solvents, such as, for example, methanol, methanol/water or ethanol, conveniently at temperatures of between 0 and 80C, but preferably at temperatures of between 5 and 50C.
The optional subsequent hydrolysis may, for example, be effected in the presence of an acid or base, but preferably in the presence of a base such as, for example, sodium hydroxide solution, in a solvent or mixture of solvents such as, for example, water, methanol, water/methanol or tetrahydrofuran/water at temperatures up to the boiling temperature of the ~olvent u~ed.
The compounds of general formula I initially obtained can, if desired, subseguently be converted into the$r salts with strong acids. Suitable acids include, for example, hydrochloric, sulphuric or mesitylenesulphonic ~cid.
The compounds of general formulae II to IX
u~ed as ~tarting materials are known from the literature, in some cases, or can be obtained using conventional methods.

- 12 - ~ 17543~

Thus, for example, the compounds of general formula II or IIa used as starting materials are the subject of EP-Al-0,003,771 and German Patent Application P 30 42 632.5 of 12th November 1980 or can be prepared using the process described in EP-Al-0,003,771.
The compounds of general formula III used as starting materials can preferably be obtained by reacting a corresponding o-carbonyl- or o-sulphonyl-acethydroxamic acid ester with sulphuric acid andsubsequent extraction, after the addition of a base.
The mercapto compounds of general formula IV
used as starting materials can be obtained, for example, by reacting a corresponding thioether with a chloroamine or with o-mesitylenesulphonyl-hydroxylamine.
A compound of general formula V used as starting material can be obtained, for example, by oxidation of a corresponding mercapto compound which is obtained by reacting a corresponding thioether with a chloroamine and subsequent hydrolysis, or by reacting a corresponding mercapto or sulphinyl compound with o-mesitylenesulphonyl-hydroxylamine.
A compound of general formula VII used as starting material can be obtained, for example, by reacting a corresponding sulphinyl compound, obtained by oxidation of a corresponding thioether, with a corresponding o-mesitylenesulphonyl-hydroxylamine and optional subsequent a~ylation.
A compound of general formula VIII used as starting material can be obtained, for example, by reacting a corresponding hydroxy or mercapto compound with a corresponding halide in the presence of a base.
A compound of general formula IX used as starting material can be obtained, for example, by reacting a corresponding amide with a hypohalite.
The compounds of general formula I possess valuable pharmacological properties, more particularly ~ 175430 \

antithrombotic effects. They give rise to an increase in the synthesis of the aggregation-inhibiting prostaglandin I2 (prostacyclin). Moreover, the compounds of general formula I wherein n is 0 are valuable intermediates for the preparation of the new compounds of general formula I wherein n is 1.
Moreover, the compounds of general formula I show an inhibiting effect on tumour metastasis, which is based on the following properties:
1. They are platelet phosphodiesterase inhibitors, which are known to be inhibitors of tumour metastasis tH. Gastpar, Thrombosis Research 5, 277-289 (1974) and K.V. Honn, Science 212, 1270-1272 tl981)).
2. The compounds give rise to a significant increase in the bleeding time, i.e. they inhibit primary haemostasis, the first aggregation of thrombocytes at the injured blood vessel, to form a clump of platelets, even when administered in very low doses. With the compounds of formula I this cannot be explained by a limita~ion of platelet function alone but must be due to an increased release of prostacyclin from the endothelial cells of the blood vessel. This is confirmed by the fact that the prolongation of bleeding time does not occur if the synthesis of prostacyclin in the endothelial cells is prevented by the administration of cyclooxygenase inhibitors beforehand. Thus, the compounds constitute a hitherto unknown optimum combination of two basic effects, namely an increased cAMP level by stimulating production (prostacyclin) and simultaneous inhibition of degradation (PDE inhibition). According to HONN ( X.V. Honn, Science 212, 1270-1272 (1981)) the increase in prostacyclin activity or prostacyclin synthesis in the wall of the blood vessel thus observed is also a cause of the inhibition of tumour metastasis.
For example, the following compounds have been tested with regard to their biological properties:
A = 6-(4-methylsulphoximino-butoxy)-3,4-dihydrocarbo-styril-mesitylenesulphonate, - 14 - ~175430 B = 6-(4-phenylsulphoximino-butoxy)-3,4-dihydrocarbostyril, C = 6-[4-(4-fluorophenylsulphoximino)~butoxy]-3,4-dihydrocarbostyril, D = 6-[4-(4-chlorophenylsulphoximino)-butoxy]-3,4-dihydrocarbostyril, E = 6-14-(N-acetyl-3,4-dichlorophenylsulphoximino)-butoxy]-3,4-dihydrocarbostyril, F = 6-[4-(N-p-toluenesulphonyl-3,4-dichlorophenyl-sulphoximino)-butoxy]3,4-dihydrocarbostyril, G = 6-[4-(4-fluorophenylsulphoximino)-butoxy]-carbostyril, H = 6-[4-(4 chlorophenylsulphoximino)-butoxyl-carboystyril, I = 6-[4-(3-methyl-4-bromophenylsulphoximino)-butoxy]-carbost~ril, K = 6-14-(4-tert.butylphenyl-sulphoximino)-butoxy]-3,4-dihydro-carbostyril, L = 6-[4-(4-cyclohexylphenyl-sulphoximino)-butoxy]-3,4-dihydro-carbostyril, M = 6-[4-(4-tert.butylphenyl-sulphoximino)-butoxy~-carbostyril, N = 6-(4-cyclohexyl-sulphoximino-butoxy)-carbostyril, O = 6-[4-(N-butyryl-3,4-dichlorophenyl-sulphoximino)-butoxy~-3,4-dihydrocarbostyril, P = 5-[4-(N-acetyl-4-chlorophenyl-sulphoximino)-butoxy]-3,3-dimethyl-indolin-2-one, 5 Q = 6-[4-(N-4-tert.benzoyl-3,4-dimethoxyphenyl-sulphoximino)-butoxy]-3,4-dihydrocarbostyril and R = 6-[4-(3,4-dimethoxyphenyl-sulphoximino)-butoxy]-3,4-dihydrocarbostyril:
1. PDE Inhibition PrinciPle cAMP is hydrolysed to AMP by phosphodiesterase (PDE) from various sources, including blood platelets.
PDE-inhibitors inhibit this hydrolysis, the PDE-inhibition being dependent on the concentration.
Method:
The phosphodiesterase used is prepared by centrifugal extraction at 10,000 g from human blood platelets ~L 17543~

which are frozen in water then thawed.
0.3 ml of a mixture containing 0.1 mol/litre trihydroxy-aminomethane (pH 7.4), 3 mmol/litre magnesium chloride, 1 mmol/litre AMP, 1 ~mol/litre 3H-cAMP
(specific activity about 10 MBq/,umol), PDE and the inhibitor under examination (water in the case of the control) were incubated for 15 minutes at 37C.
The incubation was stopped by the addition of 0.5 ml zinc sulphate (0.266 mol/litre) and 0.5 ml barium hydroxide (0.226 mol/litre), the precipitate was centrifuged and the activity remaining in the unreacted 3H-cAMP in the supernatant determined. From a comparison of the results for inhibitor and control cases, the concentration of the respective inhibitor necessary for a 50% inhibiting effect (IC50) was calculated:

~ 17~430 Substance IC50 (ymol/l) B 2.0 C 1.2 D 0.84 E 0.84 F o.go G 0.40 H 0.17 0.039 K 0.24 L 0.052 M 0.21 N 0.68 O 0.53 p 1.8 Q 3.1 R 1.6 -The inhibiting effect on tumour metastasis can also be demonstrated, according to Gastpar et 25 al (see Thrombosis Research 5, 227-289 (1974)), as an effect which prevents tumour cell embolism. The test substance is administered before the transplanting of the tumour cells and the survival rate of the test animals, for example rats, is determined by 30 comparison with controls.
2. Determination of the prolongation of bleeding time Preliminary remarks:
Humans, as well as other warm-blooded animals have an ingenious mechanism which protects them from 35 blood loss through injury. This system consists of blood platelets (thrombocytes), which quickly seal up injured vessels due to their adhesive properties, thus bringing about E~rimary haemostasis. Besides 1 ~75430 this purely cellular haemostatic mechanism, the body has a blood coagulation system. In this sytem plasma factors (proteins) are activated and finally convert liquid plasma fibrinogen to a fibrin coagulum. The system of primary haemostasis, which is regulated mainly by the thrombocytes but also by the prostacyclin activity of the blood vessel walls, and coagulation complement each other in their common aim of protecting the body effectively from blood loss.
With some diseases it is found that coagulation and thrombocyte aggregation also take place in intact blood vessels. The influence on the coagulation system of coumarin and heparin is known and can easily be measured using known coagulation tests wherein the coagulation time is prolonged under the influence of these substances. (Plasma recalcification time, Quick's test, thrombin time, etc.).
Since, in the event of injury, the first rapid cessation of bleeding is effected by the adhesion and aggregation of the thrombocytes at the vessel wall, the functioning of the thrombocytes or the prostacyclin activity of the vessel wall can easily be determined by measuring the bleeding time with a standardised injury. The normal bleeding time in human beings is between 1 and 3 minutes, assuming that there are sufficient intact, effective thrombocytes.
If the number of thrombocytes is normal and the bleeding time is prolonged this signifies an abnormality in the thrombocytes and/or an increased prostacyclin activity in the vessel wall. This is found in some inborn errors of thrombocyte function. If, on the other hand it is desired to prevent spontaneous aggregation of the thrombocytes and occlusion in the arterial system by drugs, successful therapy affecting the thrombocytes or vessel wall should prolong the bleeding time. Therefore, using an antithrombotic substance, a prolongation of the bleeding time is expected, and a normal coagulation time, since the plasma coagulation - ~175430 system is not affected.
Literature: W.D. Keidel: Kurzgefasstes Lehrbuch der Physiologie, Georg Thieme Verlag Stuttgart 1967, page 31: The process of haemostasis.
To measure the bleeding time, 2.5 mg/kg of the test compounds were administered orally to conscious mice. After 1 hour, 0.5 mm of the tip of the tail of each mouse was cut off and the droplets of blood were gently removed with filter paper every 30 seconds.
The number of drops of blood thus obtained give a measure of the bleeding time (5 animals per experiment).
The results in the following table represent the prolongation in % as compared to a control group:
SubstanceProlongation of bleeding time in % after 1 hour B > 161 E > 194 F ~ 212 I > 275 K > 180 L ? 191 M > 191 N > 184 O ~ 233 p > 169 Q ~ 158 R ~ 218 3. Acute toxicitY
The acute toxicity of the test substances was determined, as a guide, in groups of 10 mice, after oral administration of a single dose (observation period: 14 days):

Substance Approximate acute toxicity A >250 mg (0 out of 10 animals died) B ~250 mg (0 out of 10 animals died) C ~250 mg (0 out of 10 animals died) D ~250 mg (0 out of 10 animals died) E ~1,000 mg (0 out of 10 animals died) F >250 mg (0 out of 10 animals died) G ~250 mg (0 out of 10 animals died) H ~250 mg (0 out of 10 animals died) I ?250 mg (0 out of 10 animals died) In view of their pharmacological properties mentioned above, the new compounds prepared according to the invention are suitable for the prophylaxis of thromboembolic diseases such as e.g. coronary infarct, cerebral infarct, so-called transient ischaemic attacks and amaurosis fuqax and for the prophylaxis of arteriosclerosis and for prophylaxis of metastasis.
According to a yet further feature of the present invention, there are provided pharmaceutical compositions comprising, as active ingredient, at least one compound of general formula I as hereinbefore defined or a physiologically compatible strong-acid salt thereof, in association with one or more pharmaceutical carriers or excipients.
For pharmaceutical administration the compounds of general formula I or their physiologically compatible acid salts with strong-acids may be incorporated into conventional preparations in either solid or liquid form, optionally in combination with other active ingredients. The compositions may, for example, be presented in a form suitable for oral, rectal or parenteral administration. Preferred forms include, for example, plain tablets, coated tablets, capsules, powders, suppositories, suspensions, drops, syrups or ampoules.

The active ingredient may be incorporated in excipients customarily employed in pharmaceutical compositions such as, for example, corn starch, lactose, sucrose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerine, water/sorbitol, non-ionic surfactants (such as e.g. polyoxyethylene fatty acid esters), water/polyethyleneglycol, propyleneglycol, cetyl stearyl alcohol, carboxymethylcellulose, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents and/or preservatives.
Suitable single dosages for adults contain from 0.1 to 4 mg/kg of body weight, preferably 0.2 to 3 mg/kg, of active ingredient according to the invention. Such dosages may, for example, be administered 2 to 4 times daily. The total daily dosage may, however, be varied according to the compound used, the subject treated and the complaint concerned.
Advantageously, however, the compositions may be formulated as dosage units, each dosage unit being adapted to supply a fixed dose of active ingredient.
According to a still further feature of the present invention there is provided a method of treating a patient suffering from or susceptible to thromboembolic diseases, arteriosclerosis or tumour metastasis which comprises administering to the said patient an effective amount of a compound of formula I, as hereinbefore defined, or a physiologically compatible strong-acid addition salt thereof.
The following non-limiting Examples serve to illustrate the invention more fully:
Example 1 6-(4-PhenYlsulPhoximino-butoxy)-3,4-dihydrocarbostyril 3.4 g (0.01 mol) of 6-(4-phenylsulphinyl-butoxy)-3,4-dihydrocarbostyril are stirred into 50 ml of polyphosphoric acid at 45C. After it has virtually all dissolved, 0.98 g (0.015 mol) of sodium azide ~ - 21 - ~175430 are added in small batches within 30 minutes. A slight development of nitrogen gas is observed. The beige-coloured creamy-foamy mass is stirred for 3 hours at 45-50C and then 150 g of ice are added. The cloudy solution formed is ad-justed to pH 8 with concentrated ammonia and the resinous product precipitated is extracted with chloroform. The oily evaporation residue is recrystallized from ethyl acetate. White crystals are obtained.
Melting point: 127-129C, Yield: 1.6 g (44.6% of theory).
Example 2 6-[4-~3,4-dichlorophenylsulphoximino)-butoxy]-3,4-dihydrocarbostyril 24.0 g (0.84 mol) of ethyl o-mesitylenesulphonylacethydroxamate are dissolved in 35 ml of dioxan and 17 ml of 90% sulphuric acid are added dropwise, with stirring, at 20-23C within 20 minutes. The mixture is stirred for a further 10 minutes at the same temperature, then poured into 300 ml of ice-cold water and the o-mesitylenesulphonyl-hydroxylamine formed is extracted with 100 ml of methylene chloride, washed twice more with ice-cold water and dried over magnesium sulphate. 12.4 g (0.03 mol) of 6-[4-(3,4-dichlorophenyl-sulphinyl)-butoxy]-3,4-dihydrocarbostyril are added to the solution obtained and stirred for 18 hours at ambient temperature. The crystal slurry, which is only just stirrable, is diluted with 120 ml of ethyl acetate and then the crystalline 6-[4-(3,4-dichlorophenyl-sulphoximino)-butoxy]-3,4-dihydrocarbo-styril-mesitylenesulphonate is suction filtered. To obtain the free base, it is suspended in 60 ml of methanol and stirred with 17 ml of 2N sodium hydro-xide solution, whereupon all of it goes into solution. After a short time, a white precipitate is obtained, consisting of the 6-[4-~3,4-dichlorophenyl-sulphoximino)-butoxy]-3,4-dihydrocarbostyril.
Melting point: 160-161C, ~ ~75430 Yield: 10.4 g (81.1% of theory).
Example 3 6-[4-(4-tert.butylPhenylsulphoximino)-butoxy]-3~4 dihydrocarbostyril Prepared analogously to Example 2 from 6-[4-(4-tert.butylphenyl-sulphinyl)-butoxy]-3,4-dihydrocarbo-styril and o-mesitylenesulphonylhydroxylamine.
Melting point: 201-203C
Yield: 44% of theory.
Example 4 6-~4-(3,5-Di-tert.butyl-4-hydroxy-phenvlsulphoximino)-butoxy]-3,4-dihydrocarbostyril Prepared analogously to Example 2 from 6-[4-(3,5-di-tert.butyl-4-hydroxyphenylsulphinyl)-butoxy]-3,4-dihydrocarbostyril and o-mesitylenesulphonylhydroxyl-amine.
Melting point: 110-112C, Yield: 52% of theory.
Example 5 6-[4-(4-CyclohexylPhenYlsulphoximino)-butoxy]-3,4-dihYdrocarbostyril Prepared analogously to Example 2 from 6-[4-(4-cyclohexylphenyl-sulphinyl)-butoxy]-3,4-dihydrocarbo-styril and o-mesitylenesulphonyl-hydroxylamine.
Melting point: 174-176C, Yield: 65% of theory.
Example 6 6-[4-(4-Biphenylylsulphoximino)-butoxY]-3,4-dihydro-carbostyril Prepared analogously to Example 2 from 6-[4-(4-biphenylylsulphinyl)-butoxy]-3,4-dihydrocarbostyril and o-mesitylenesulphonylhydroxylamine.
Melting point: 184-186C, Yield: 64% of theory.
Example 7 6-[4-(Naphthyl-(2)-sulphoximino)-butoxy]-3,4-dihydro-carbostyril Prepared analogously to Example 2 from 6-[4-1 17543~

(naphthyl-2-sulphinyl)-butoxy]-3,4-dihydrocarbostyril and o-mesitylenesulphonylhydroxyl-amine.
Melting point:l51-152C, Yield: 71~ of theory.
Example 8 6-[4-(4-fluorophenylsulphoximino)-butoxy]-3,4-dihydro-carbostyril Prepared analogously to Example 1 from 6-[4-(4-fluorophenylsulphinyl)-butoxy]-3,4-dihydrocarbostyril and sodium azide in polyphosphoric acid.
Melting point: 170-173C, Yield: 78% of theory.
ExamPle 9 6-[4-(4-chlorophenylsulphoximino)-butoxy]-3,4-dihydro-carbostyril Prepared analogously to Example 2 from 6-[4-(4-chlorophenylsulphinyl)-butoxy]-3,4-dihydrocarbostyril and o-mesitylenesulphonylhydroxylamine.
Melting point:150-151C, Yield: 60% of theory.
Example 10 6-[4-(3-methyl-4-bromophenylsulphoximino)-butoxy]-3,4-dihydro-carbostyril Prepared analogously to Example 2 from 6-[4-(3-methyl-4-bromophenyl-sulphinyl)-butoxy]-3,4-dihydro-carbostyril and o-mesitylenesulphonylhydroxylamine.
Melting point: 150-152C, Yield: 60% of theory.
Example 11 6-[4-(3,5-dibromo-4-aminophenylsulPhoximino)-butoxy]-3,4-dihydro-carbostYril Prepared analogously to Example 2 from 6-[4-(3,4-dibromo-4-aminophenylsulphinyl)-butoxy]-3,4-dihydro-carbostyril and o-mesitylenesulphonylhydroxylamine.
3S Melting point: 110-113C, Yield: 55% of theory.

~ 175430 Example 12 6-(q-phenylsulphoximino-butoxy)-carbostyril Prepared analogously to Example 2 from 6-(4-phenylsulphinyl-butoxy)-carbostyril and o-mesitylene-sulphonylhydroxylamine.
Melting point: 161-162C, Yield: 60% of theory.
Example 13 6-[4-(4-tert.butylphenylsulphoximino)-butoxy]-carbostyril Prepared analogously to Example 1 from 6-[4-(4-tert.butylphenylsulphinyl)-butoxy]-carbostyril and sodium azide in polyphosphoric acid.
Melting point: 208-210C, Yield: 45% of theory.
~ E~
6-[4-(3,5-Di-tert.butyl-4-hydroxy-phenylsulphoximino)-butoxy]-carbostyril Prepared analogously to Example 2 from 6-[4-(3,4-di-tert.butyl-4-hydroxy-phenylsulphinyl)-butoxy]-carbostyril and o-mesitylene-sulphonylhydroxylamine.
Melting point: 205-207C, Yield: 59% of theory.
Example 15 6-[4-Cyclohexylphenylsulphoximino)-butoxy]-carbostyril Prepared analogously to Example 1 from 6-[4-(4-cyclohexylphenylsulphinyl)-butoxy]-carbostyril and sodium azide in polyphosphoric acid.
Melting point: 195-197C, Yield: 52 % of theory.
ExamPle 16 6-[4-(4-Biphenylylsulphoximino)-butoxy]-carbostyril Prepared analogously to Example 2 from 6-[4-(4-biphenylysulphinyl)-butoxy]-carbostyril and o-mesitylenesulphonylhydroxylamine.
Melting point: 236-238C, Yield: 76 % of theory.

Example 17 6-(4-Cyclohexylsulphoximino-butoxy)-carbostyril Prepared analogously to Example 1 from 6-(4-cyclohexylsulphinyl-butoxy-carbostyril and sodium azide in polyphosphoric acid.
Melting point: 145-147C, Yield: 47 % of theory Example 18 6-[4-(4-Fluorophenylsulphoximino)-butoxY]-carbostyril Prepared analogously to Example 2 from 6-[4-~4-fluorophenylsulphinyl)-butoxy]-carbostyril and o-mesitylenesulphonylhydroxylamine.
Melting point: 177-179C, Yield: 70 % of theory.
Example 19 6-[4-(4-chlorophenYlsulphoximino)-butoxY]-carbostyril Prepared analogously to Example 2 from 6-[4-t4-chlorophenylsulphinyl)-butoxy]-carbostyril and o-mesitylenesulphonylhydroxylamine.
Melting point: 201-203C, Yield: 79 % of theory.
Example 20 6-[4-(4-Bromophenylsulphoximino)-butoxy]-carbostyril Prepared analogously to Example 2 from 6-[4-(4-bromophenylsulphinyl)-butoxy]-carbostyril and o-mesitylenesulphonylhydroxylamine.
Melting point: 211-213C, Yield: 63 % of theory.
Example 21 6-[4-(3,4-Dichlorophenylsulphoximino)-butoxy]-carbostyril Prepared analogously to Example 2 and 6-[4-(3,4-dichlorophenyl-sulphinyl)-butoxy]-carbostyril and o-mesitylenesulphonylhydroxylamine.
Melting point: 214-216C, Yield: 73 % of theory.

~17~30 Example 22 6-[4-(3-Methvl-4-bromophenylsulphoximino)-butoxy]-carbostyril Prepared analogously to Example 1 from 6-[4-(3-methyl-4-bromophenyl-sulphinyl)-butoxy]-carbostyril and sodium azide in polyphosphoric acid.
Melting point: 193-194C, Yield: 54 ~6 of theory.
Example 23 6-[4-(2'-Fluoro-4-biphenylylsulphoximino)-butoxy]-carbostyril Prepared analogously to Example 2 from 6-[4-(2'-fluoro-4-biphenylylsulphinyl)-butoxy]-carbostyril and o-mesitylenesulphonylhydroxylamine.
Melting point: 191-193C, Yield: 74 % of theory.
Example 24 6-[4-(3,5-Dibromo-4-aminophenylsulphoximino)-butoxy]-carbostyril Prepared analogously to Example 2 from 6-[4-(3,5-dibromo-4-aminophenylsulphinyl)-butoxy]-carbostyril and o-mesitylenesulphonylhydroxylamine.
Melting point: 130-135C, Yield: Sl % of theory.
Example 25 3,3-Dimethyl-5-[4-(4-methvlphenylsulphoximino)-butoxy]-indolinone-2 Prepared analogously to Example 2 and 3,3-dimethyl-5-[4-(4-methyl-phenylsulphinyl)-butoxy]-indolinone-2 and o-mesitylenesulphonyl-hydroxylamine.
Melting point: 146-147C, Yield: ô4 96 of theory.
Example 26 3,3-Dimethv1-5-[4-(4-tert.butylphenylsulphoximino)-butoxY]-indolinone-2 Prepared analogously to Example 2 from 3,3-dimethyl-5-[4-(4-tert.butylphenylsulphinyl)-butoxy]-indolinone-2 and o-mesitylenesulphonylhydroxylamine.

Melting point: 195-197C, Yield: 85 ~ of theory.
Example 27 3,3-Dimethyl-5-[4-(2-methyl-4-tert.butylphenylsulphoximino)-butoxy-indolinone-2 Prepared analogously to Example 2 from 3,3-dimethyl-5-[4-(2-methyl-4-tert.butylphenylsulphinyl)-butoxy]-indolinone-2 and o-mesitylene-sulphonyl-hydroxyl-amine.
Melting point: 149-150C, Yield: 26 % of theory.
Example 28 3,3-Dimethyl-5-[4-(3,5-di-tert.butYl-4-hydroxyphenyl-sulphoximino)-butoxy]-indolinone-2 Prepared analogously to Example 2 from 3,3-dimethyl-5-[4-(3,5-di-tert.-butyl-4-hydroxyphenylsulphoximino)-butoxy]-indolinone-2 and o-mesitylenesulphonylhydroxylamine.
Glassy substance. Rf value: 0.25 (silica gel plate, Eluant: ethyl acetate/methylene chloride 1:1).
Yield: 42% of theory.
Example 29 3,3-Dimethyl-5-(4-cYclohexylphenylsulphoximino-butoxy-indolinone-2 Prepared analogously to Example 1 from 3,3-dimethyl-5-(4-cyclohexyl-phenylsulphinyl-butoxy)-indolinone-2 and sodium azide in polyphosphoric acid.
Melting point: 162-163C, Yield: 39 % of theory ExamPle 30 3,3-Dimethyl-5-~4-(2-naphthylsulphoximino-butoxy]-indolinone-2 Prepared analogously to Example 2 from 3,3-dimethyl-5-[4-(2-naphthyl-sulphinyl)-butoxy]-indolinone-2 and o-mesitylenesulphonylhydroxylamine.
Melting point: 120-121C, Yield: 64 % of theory.

~ :~75430 Example 31 3,3-Dimethyl-5-(4-cyclohexYlsulphoximino-butoxy)-indolinone-2 Prepared analogously to Example 2 from 3,3-dimethyl-5-(4-cyclohexylsulphinyl-butoxy)-indolinone-2 and o-mesitylenesulphonylhydroxylamine.
Melting point: 108-109C, Yield: 77 % of theory.
Example 32 3,3-Dimethyl-5-(4-benzvlsulphoximino-butoxy)-indolinone-2 Prepared analogously to Example 2 from 3,3-dimethyl-5-(4-benzylsulphinyl-butoxy)-indolinone-2 and o-mesitylenesulphonylhydroxylamine.
Melting point: 98-99C, Yield: 82 % of theory.
Example 33 3,3-Dimethyl-5-[4-(4-fluorophenYlsulphoximino)-butoxy]-indolinone-2 Prepared analogously to Example 2 from 3,3-dimethyl-5-[4-(4-fluorophenylsulphinyl)-butoxy]-indolinone-2 and o-mesitylenesulphonylhydroxylamine.
Melting point: 101-102C, Yield: 90 % of theory.
Example 34 25 3,3-Dimethyl-5-[4-(4-chlorophenylsulphoximino)-butoxy]-indolinone-2 Prepared analogously to Example 2 from 3,3-dimethyl-5-[4-(4-chlorophenylsulphinyl)-butoxy]-indolinone-2 and o-mesitylenesulphonylhydroxylamine.
30 Melting point: 136-137C, Yield: 76 % of theory.
Example 35 3~3-Dimethyl-5-[4-(4-bromophenylsulphoximino)-butoxy]-indolinone-2 Prepared analogously to Example 2 from 3,3-dimethyl-5-[4-(4-bromophenylsulphinyl)-butoxy]-indolinone-2 and o-mesitylenesulphonylhydroxylamine.
Melting point: 160-161C, Yield: 88 % of theory.
Example 36 3,3-Dimethyl-5-[4-(3,4-dichlorophenvlsulphoximino)-butoxy]-indolinone-2 Prepared analogously to Example 2 from 3,3-dimethyl-5-[4-(3,4-dichlorophenylsulphinyl)-butoxy]-indolinone-2 and o-mesitylenesulphonylhydroxylamine.
Melting point: 147-148C, Yield: 68 % of theory.
Example 37 3,3-Dimethyl-5-[4-(2,5-dichlorophenylsulphoximino)-butoxy]-indolinone-2 Prepared analogously to Example 2 from 3,3-dimethyl-5-[4-~2,5-dichlorophenylsulphinyl)-butoxy]-indolinone-2 and o-mesitylenesulphonylhydroxylamine.
Rf value: 0.3 (silica gel plate, eluant: ethyl acetate/
methylene chloride 1:1), Yield: 18% of theory.
Example 38 3,3-Dimethyl-5-[4-(3-methyl-4-bromophenylsulphoximino)-butoxy]-indolinone-2 Prepared analogously to Example 2 from 3,3-dimethyl-5-[4-(3-methyl-4-bromophenylsulphinyl)-butoxy]-indolinone-2 and o-mesitylenesulphonyl-hydroxylamine.
Melting point: 131-132C, Yield: 84 % of theory.
Example 39 3,3-Dimethyl-5-[4-(2'-fluoro-4-biphenylylsulPhoximino) butoxy]-indolinone-2 Prepared analogously to Example 2 from 3,3-dimethyl-5-[4-(2'-fluoro-4-biphenylylsulphinyl)-butoxy]-indolinone-2 and o-mesitylenesulphonylhydroxylamine.
Melting point: 177-178C, Yield: 90 % of theory.
ExamPle 40 3,3-Dimethyl-5-[4-(3,5-dibromo-4-aminophenylsulphoximino)-butoxy]-indolinone-2 Prepared analogously to Example 2 from 3,3-1 17~43~

dimethyl-5-[4-(3,5-dibromo-4-aminophenylsulphinyl)-butoxy]-indolinone-2 and o-mesitylenesulphonylhydroxylamine.
Melting point: 202-204C, Yield: 76 % of theory.
Example 41 3,3-Dimethyl-5-[4-(4-methoxyphenylsulphoximino)-butoxy]-indolinone-2 Prepared analogously to Example 2 from 3,3-dimethyl-5-[4-(4-methoxy-phenylsulphinyl)-butoxy]-indolinone and o-mesitylenesulphonylhydroxylamine.
Melting point: 140-141C, Yield: 71% of theory.
Example 42 3,3-Dimethyl-5-[4-(2-methoxYphenylsulphoximino)-butoxy]-indolinone-2 Prepared analogously to Example 2 from 3,3-dimethyl-5-[4-(2-methoxyphenylsulphinyl)-butoxy]-indolinone-2 and o-mesitylenesulphonylhydroxylamine.
Colourless resinous substance. Rf vaiue: 0.35 (silica gel, eluant: ethylene chloride/ethanol = 9:1), Yield: 52% of theory.
ExamPle 43 3,3-Dimethyl-5-[4-(3,4-dimethoxYphenylsulphoximino)-butoxY]-indolinone-2 Prepared analogously to Example 2 from 3,3-dimethyl-5-[4-(3,4-dimethoxy-phenylsulphinyl)-butoxy]-indolinone-2 and o-mesitylenesulphonyl-hydroxyamine.
Melting point: 108-109C, Yield: 79% of theory.
Example 44 3,3-DimethY1-5-[4-(6-methoxy-naphth-2-Y1-sulphoximino)-butoxy]-indolinone-2 Prepared analogously to Example 2 from 3,3-dimethyl-5-[4-(6-methoxy-naphth-2-yl-sulphinyl)-butoxy]-indolinone-2 and o-mesitylenesulphonyl-hydroxylamine.
Melting point: 174-175C, Yield: 8896 of theory.

~ 175430 Example 45 6-(4-Methylsulphoximino-butoxy)-3,4-dihydrocarbostyril-mesitylene-sulphonate Prepared analogously to Example 2 from 6-(4-S methylsulphinyl-butoxy)-3~4-dihydrocarbostyril and o-mesitylenesulphonylhydroxylamine.
Melting point: 130-133C, Yield: 8796 of theory.
ExamPle 46 10 3,3-Dimethyl-5-(4-phenylsulphoximino-butoxY)-indolinone-2 Prepared analogously to Example 2 from 3,3-dimethyl-5-(4-phenylsulphinyl-butoxy)-indolinone-2 and O-mesitylenesulphonylhydroxylamine.
Melting point: 111-112C
15 Yield: 86% of theory.
Example 47 6-[4-(N-Acetyl-3,4-dichlorophenylsulphoximino)-butoxy]-3,4-dihydrocarbostyril.
1.40 9 of 6-[4-(3,4-dichlorophenylsulphoximino)-20 butoxy]-3,4-dihydrocarbostyril are suspended in a mixture of 70 ml of glacial acetic acid and 70 ml of acetic anhydride and stirred for 21 hours. The solution formed is mixed with 300 ml of ice-cold water, whilst thorough stirring is continued. After 25 10 minutes, white crystals begin to precipitate.
After 1 hour, the solution is suction filtered, the product is washed with water and crystallised from 140 ml of ethanol, with the addition of a little active charcoal. A white crystalline substance is 30 obtained which is dried in the circulating air drier at 80C.
Melting point: 150-152C, Yield: 12.9 9 (84% of theory).
Example 48 35 6-[4-(N-Carbamoyl-3,4-dichlorophenylsulphoximino)-butoxy]-3,4-dihydrocarbostyril 1.49 g (0.0035 mol) of 6-[4-(3,4-dichloro-phenyl-sulphoximino)-butoxy]-3,4-dihydrocarbostyril are 1 17543~

dissolved in 70 ml of glacial acetic acid, then 2.8 g (0.035 mol) of potassium cyanate are added and the mixture is stirred for 3 hours at ambient temperature.
Then 40 ml of water are added, with stirring, and the oil initially precipitated crystallises out.
It is suction filtered, recrystallised from 65 ml of ethanol and the white crystalline substance is dried at 50C in a circulating air drier.
Melting point: 148-150C, Yield: 1.2 g (70% of theory).
Example 49 6-[4-(N-Butyryl-3,4-dichlorophenylsulphoximino)-butoxy]-3,4-dihydrocarbostyril 3.0 g (0.007 mol) of 6-[4-(3,4-dichlorophenyl-sulphoximino)-butoxy]-3,4-dihydrocarbostyril are suspended in 15 ml of pyridine and 0.9 g (1.2 x 0.007 mol) of n-butyric acid chloride are added. A light yellow solution is formed as the mixture is heated to 40C.
After standing for a further 90 minutes, the mixture is evaporated to dryness, in a water jet vacuum, using a rotary evaporator, the residue is taken up in methylene chloride and extracted by shaking twice with 0.5 N hydrochloric acid and once with water.
After drying over magnesium sulphate, the solvent is distilled off using a rotary evaporator and the residue is recrystallized from 15 ml of ethanol.
Colourless crystals are obtained.
Melting point: 133-135C, Yield: 2.4 g (69% of theory).
Example 50 6-[4-(N-PivoloYl-3,4-dichloroPhenvlsulphoximino)-butoxy]-3,4-dihydrocarbostyril Prepared analogously to Example 49 from 6-[4-(3,4-dichlorophenyl-sulphoximino)-butoxy]-3,4-dihydro-carbostyril and pivalic acid chloride.Melting point: 158-160C, Yield: 81% of theory.

Example 51 6-[4-(N-(2-Methoxyacety~l-3,4-dichlorophenylsulphoximino)-butoxy]-3,4-dihydrocarbostyril Prepared analogously to Example 49 from 6-[4-(3,4-dichlorophenylsulphoximino)-butoxy]-3,4-dihydrocarbo-styril and 2-methoxyacetylchloride.
Melting point: 103-105C, Yield: 50% of theory.
Example 52 6-[4-(N-benzoyl-3,4-dichlorophenylsulPhoximino)-butoxy]-3,4-dihydro-carbostyril Prepared analogously to Example 49 from 6-[4-(3,4-dichlorophenyl-sulphoximino)-butoxy]-3,4-dihydrocarbo-styril and benzoylchloride.
15 Melting point: 110-111C, Yield: 68% of theory.
Example 53 6-[4-(N-4-MethoxYbenzoyl)-3,4-dichlorophenylsulphoximino)-butoxy]-3,4-dihydrocarbostyril Prepared analogously to Example 49 from 6-[4-(3,4-dichlorophenylsulphoximino)-butoxy]-3,4-dihydrocarbo-styril and 4-methoxybenzoylchloride.
Melting point: 186-188C, Yield: 70% of theory.
Example 54 6-[4-(N-Nicotinoyl-3,4-dichloroPhenylsulphoximino)-butoxy]-3,4-dihYdrocarbostyril Prepared analogously to Example 49 from 6-[4-(3,4-dichlorophenyl-sulphoximino)-butoxy]-3,4-dihydrocarbo-styril and nicotinic acid chloride hydrochloride.
Melting point: 101-103C, Yield: 94% of theory.
ExamPle 55 6-[4-(N-(4-methYlPhenylsulphonyl)-3,4-dichlorophenyl-sulphoximino)-butoxy]-3,4-dihydrocarbostyril Prepared analogously to Example 49 from 6-[4-(3,4-dichlorophenylsulphoximino)-butoxy]-3,4-dihydrocarbo-styril and p-toluenesulphochloride.

~ 175430 Melting point: 154-156C, Yield: 84~ of theory.
Example 56 6-[4-(N-~2-acetoxy-phenylacetyl)-3,4-dichlorophenyl-sulphoximino~-butoxY]-3,4-dihYdrocarbostyril Prepared from 6-[4-(3,4-dichlorophenylsulphoximino)-butoxy]-3,4-dihydrocarbostyril and o-acetyl-D,L-mandelic acid chloride analogously to Example 49.
. After purification over a silica gel column with ethylene chloride, the substance is obtained as a non-crystallising glass resin.
Rf value: 0.2 (silica gel plate, ethylene chloride), Yield: 50% of theory.
Example 57 5-[4-(N-acetyl-3,4-dichlorophenylsulphoximino)-butoxy]-3,3-dimethyl-indolinone-2 Prepared analogously to Example 47 from 5-[4-(3,4-dichlorophenylsulphoximino)-butoxy]-3,4-dimethyl-indolinone-2 and acetic anhydride.
20 Melting point 145-146C, Yield: 64~ of theory.
Example 58 5-[4-(N-butyryl-3,4-dichlorophenylsulphoximino)-butoxy]-3,3-dimethyl-indolinone-2 Prepared analogously to Example 49 from 5-[4-(3,4-dichlorophenylsulphoximino)-butoxy]-3,3-dimethyl-indolinone-2 and butyric acid chloride.
Melting Point 120-122C, Yield: 81% of theory.
Example 59 5-[4-(N-(2-Methoxv-acetYl)-3,4-dichlorophenylsulphoximino)-butoxy]-indolinone-2 Prepared analogously to Example 49 from 3,3-dimethyl-5-[4-(3,4-dichlorophenylsulphoximino)-butoxy]-indolinone-2 and 2-methoxyacetyl chloride.
Melting Point: 126-128C, Yield: 72 % of theory.

1 ~75430 ,, Example 60 5-[4-(N-Ethoxycarbonyl-3,4-dichlorophenylsulphoximino)-butoxy]-3,3-dimethyl-indolinone-2 Prepared analogously to Example 49 from 5-[4-(4-chlorophenylsulphoximino)-butoxy]-3,3-dimethyl-indolinone-2 and ethyl chlorocarbonate.
Melting Point: 102-104C, Yield: 79 % of theory.
Example 61 5-[4-(N-Acetyl-4-chlorophenylslllphoximino)-butoxy]
3,3-dimethyl indolinone-2 Prepared analogously to Example 47 from 5-[4-(4-chlorophenylsulphoximino)-butoxy~-3,3-dimethyl-indolinone-2 and acetic anhydride.
15 Melting point: 138-140C, Yield: 75 % of theory.
Example 62 5-[4-(N-Butyryl-4-chlorophenylsulphoximino)-butoxy]-3,3-dimethyl-indolinone-2 Prepared analogously to Example 49 from 5-[4-(4-chlorophenylsulphoximino)-butoxy]-3,3-dimethyl-indolinone-2 and butyric acid chloride.
Melting point: 166-168C, Yield: 38 % of theory.
Example 63 5-[4-(N-Pivaloyl-4-chloroPhenylsulphoximino?-butoxy]-3,3-dimethyl-indolinone-2 Prepared analogously to Example 49 from 5-[4-(4-chlorophenylsulphoximino)-butoxy]-3,3-dimethyl-indolinone-2 and pivalic acid chloride.
Melting point: 95-97C, Yield: 76 % of theory.
Example 64 5-[4-(N-capryl-4-chlorophenYlsulphoximino)-butoxy]-3,3-dimethyl-indolinone-2 Prepared analogously to Example 49 from 5-[4 chlorophenylsulphoximino)-butoxy]-3,3-dimethyl-indolinone-2 and caprylic acid chloride.

Resin.
Rf value: 0.5 (silica gel plate, ethyl acetate/methylene chloride = 1:1), Yield: 95% of theory.
ExamPle 65 5-[4-(N-carbamoyl-4-chlorophenylsulphoximino)-butoxy]-3,3-dimethyl-indolinone-2 Prepared analogously to Example 48 from 5-[4-(4-chlorophenylsulphoximino)-butoxy]-3,3-dimethyl-indolinone-2 and potassium cyanate.
Colourless resin.
Rf value: 0.4 (silica gel plate, ethylene chloride/ethanol = 9~
Yield: 75% of theory.
ExamPle 66 5-[4-(N-Dimethylaminocarbonvl-4-chlorophenylsulphoximino)-butoxy]-3,3-dimethYl-indolinone-2 Prepared analogously to Example 49 from s-L 4-(4-chlorophenylsulphoximino)-butoxy]-3,3-dimethyl-indolinone-2 and dimethylcarbamyl chloride.
Melting point: 170-172C, Yield: 64% of theory.
Example 67 6-[4-(N-AcetYl-3,4-dimethoxy~henylsulphoximino)-butoxy]-3,4-dihydrocarbostyril Prepared analogously to Example 47 from 6-[4-(3,4-dimethoxyphenyl-sulphoximino)-butoxy]-3,4-dihydro-carbostyril and acetic anhydride.
Melting point: 89-92C, Yield: 60% of theory.
Example 68 6-[4-(N-Butyryl-3,4-dimethoxvphenylsulphoximino)-butoxyJ-3,4-dihydrocarbostyril Prepared analogously to Example 49 from 6-[4-(3,4-dimethoxyphenylsulphoximino)-butoxy]-3,4-dihydro-carbostyril and butyric acid chloride. Glassy colourless resin. Rf value: 0.35 (silica gel plate, ethylene chloride/ethanol = 9:1), Yield: 41% of theory.
Example 69 6-[4-(N-Benzoyl-3,4-dimethoxyphenylsulphoximino)-butoxy]-3,4-dihydrocarbostyril S Prepared analogously to Example 49 from 6-[4-(3,4-dimethoxyphenyl-sulphoximino)-butoxy]-3,4-dihydro-carbostyril and benzoyl chloride.
Melting point: 78-80C, Yield: 50 % of theory.
Example 70 6-[4-(N-(4-Chlorobenzoyl)-3,4-dimethoxyphenylsulphox-imino)-butoxy]-3,4-dihydrocarbostyril Prepared analogously to Example 49 from 6-[4-(3,4-dimethoxyphenyl-sulphoximino)-butoxy]-3,4-dihydro-carbost-yril and 4-chlorobenzoyl chloride.
Melting point: 134-137C, Yield: 61 ~ of theory.
Example 71 6-[4-(N-(4-tert.Butylbenzoyl)-3,4-dimethoxyphenylsulphox-imino)-butoxy]-3,4-dihydrocarbostyril Prepared analogously to Example 49 from 6-[4-(3,4-dimethoxyphenyl-sulphoximino)-butoxy]-3,4-dihydro-carbostyril and 4-tert.-butyl-benzoyl chloride.
Melting point: 98-101C, Yield: 87 % of theory.
Example 72 6-[4-(N-Nicotinoyl-3,4-dimethoxYphenylsulPhoximino)-butoxY]-3,4-dihYdrocarbostvril Prepared analogously to Example 49 from 6-[4-(3,4-dimethoxyphenyl-sulphoximino)-butoxy]-3,4-dihydro-carbostyril and nicotinic acid chloride hydrochloride.
Melting point: 90-93C, Yield: 75 % of theory.
Example 73 6-[4-(N-Pentamethylphenylsulphonyl-3,4-dimethoxyphenyl-sulphoximino)-butoxy]-3,4-dihYdrocarbostyril Prepared analogously to Example 49 from 6-[4-(3,4-dimethoxyphenyl-sulphoximino)-butoxy]-3,4-dihydro-carbostyril and pentamethyl-benzene-sulphonic acid chloride.
Melting point: 186-188C, Yield: 75 % of theory.
5 Example 74 5-~4-(N-acetyl-3,4-dimethoxYphenylsulphoximino)-butoxy]-3,3-dimethylindolin-2-one Prepared analogously to Example 47 from 5-[4-(3,4-dimethoxyphenyl-sulphoximino)-bu~oxy]-3,3-dimethyl-10 indolin-2-one and acetic anhydride.
Glass resin.
Rf value: 0.3 (silica gel plate, ethylene chloride/ethanol = 9:1), Yield: 99% of theory.
15 Example 75 5-[4-(N-butyryl-3,4-dimethoxyphenylsulphoximino)-butoxy]-3,3-dimethYl-indolin-2-one Prepared analogously to Example 49 from 5-[4-(3,4-dimethoxyphenyl-sulphoximino)-butoxy]-3,3-dimethyl-20 indolin-2-one and butyric acid chloride. Resin.
Rf value: 0.35 (silica gel plate, ethyl acetate/methylene chloride = 1:1), Yield: 92% of theory Example 76 25 5-[4-(N-pivaloyl-3,4-dimethoxyphenylsulphoximino)-butoxY]-3~3-dimethyl-indolinone-2 Prepared analogously to Example 49 from 5-[4-(3,4-dimethoxyphenylsulphoximino)-butoxy]-3,3-dimethyl-indolinone-2 and pivalic acid chloride. Resin.
30 Rf value: 0.45 (silica gel plate, ethyl acetate/methylene chloride = 1:1) Yield: 88% of theory.
Example 77 5-[4-(N-Carbamoyl-3,4-dimethoxyphenylsulphoximino)-35 butoxy]-3,3-dimethyl-indolinone-2 Prepared analogously to Example 48 from 5-[4-(3,4-dimethoxyphenyl-sulphoximino)-butoxy]-3,3-dimethyl-indolinone-2 and potassium cyanate. Resin.

.
/

Rf value: 0,25 (silica gel plate, ethylene chloride/
ethanol = 9:1), Yield: 75 ~ o~ theory.
Example 78 5-[4-(N-Dimethylaminocarbonvl-3,4-dimethoxyphenvlsulPhox-imino)-butoxy]-3,3-dimethylindolinone-2 Prepared analogously to Example 49 from 5-[4-(3,4-dimethoxyphenyl-sulphoximino)-butoxy]-3,3-dimethyl-indolinone-2 and dimethylcarbamyl chloride. Resin.
Rf value: 0,3 (silica gel plate, ethylene chloride/ethanol = 9:1), Yield: 98 ~ of theory.
Example 79 5-[4-(N-4-Chlorobenzoyl)-3,4-dimethoxyphenYlsulphoximino)-butoxy]-3,3-dimethyl-indolinone-2 Prepared analogously to Example 49 from 5-[4-(3,4-dimethoxyphenyl-sulphoximino)-butoxy]-3,3-dimethyl-indolinone-2 and 4-chlorobenzoyl chloride.
Melting point: 174-177C, Yield: 74 % of theory.
Example 80 5-[4-(N-Nicotinoyl-3~4-dimethoxyphenylsulphoximino) butoxy]-3,3-dimethyl-indolinone-2 Prepared analogously to Example 49 from 5-[4-3,4-dimethoxyphenyl-sulphoximino)-butoxy]-3,3-dimethyl-indolinone-2 and nicotinic acid chloride hydrochloride.
Resin.
Rf value: 0,25 (silica gel plate, ethylene chloride/ethanol = 9 : 1 ) ~
Yield: 76 % of theory.
Example 81 6-[4-(2-N-tNaPhthoyl)-3~4-dimethoxyphenylsulphoximino) butoxY]-3,4-dihydrocarbostyril Prepared analogously to Example 49 from 6-[4-(3~4-dimethoxyphenyl-sulphoximino)-butoxy~-3~4-dihydrocarbo-styril and 2-naphthoic acid chloride. Resin.
Rf value: 0.45 (silica gel plate, ethyl acetate/methylene chloride = 1:1), ~ 17543~

Yield: 93 % of theory.
Example 82 6-[4-(N-(l-Naphthoyl)-3,4-dimethoxyphenylsulphoximino)-butoxy]-3,4-dihydrocarbosty Prepared analogously to Example 49 from 6-[4-(3,4-dimethoxyphenyl-sulphoximino)-butoxy]-3,4-dihydrocarbo-styril and l-naphthoic acid chloride. Resin.
Rf value: 0.3 ~silica gel plate, ethyl acetate/methylene chloride = 1:1), Yield: 83 % of theory.
Example 83 6-[4-(N-(2-Thienoyl)-3~4-dimethoxyphenylsulphoximino)-butoxv]-3,4-dihydrocarbostyril Prepared analogously to Example 49 from 6-[4-(3,4-dimethoxyphenyl-sulphoximino)-butoxy]-3,4-dihydrocarbo-styril and thiophene-2-carboxylic acid chloride.
Resin.
Rf value: 0.3 (silica gel plate, ethyl acetate/methylene chloride = 1:1), Yield: 88 % of theory.
Example 84 6-[4-(3,4-Dimethoxyphenylsulphoximino)-butoxy]-3,4-dihydrocarbostyril Prepared analogously to Example 2 from 6-[4-(3,4-dimethoxyphenylsulphinyl)-butoxy]-3,4-dihydrocarbostyril and o-mesitylenesulphonyl-hydroxylamine.
Melting point: 154-156C, Yield: 64 % of theory.
ExamPle 85 6-[4-(N-Benzoyl-4-fluorophenylsulphoximino)-butoxy]-3,4-dihYdrocarbostYril Prepared analogously to Example 49 from 6-[4-(4-fluorophenylsulphoximino)-butoxy]-3,4-dihydrocarbostyril and benzoylchloride.
Melting point: 64-68C, Yield: 87 96 of theory.

~ ~75430 Example 86 6-[4-(N-(4-chlorobenzoyl)-4-fluorophenylsulphoximino)-butoxy]-3,4-dihydrocarbostyril Prepared analogously to Example 49 from 6-L4-fluorophenylsulphoximino)-butoxy]-3,4-dihydrocarbostyril and 4-chlorobenzoyl chloride.
Melting point: 134-138C, Yield: 78% of theory.
Example 87 6-[4-(3,4-DichloroPhenylsulphoximino)-butoxY]-3,4-dihYdrocarbostyril 145.5 9 of p-toluenesulphonic acid are dissolved in 350 ml of dimethylformamide with stirring, and 70.1 g of 6-[4-t3,4-dichlorophenylsulphinyl)-butoxy]-3,4-dihydrocarbostyril are stirred in. Then 106.7 9 of ethyl o-mesitylenesulphonyl hydroxamate are added.
The reaction is slightly exothermic, and the reaction mixture is occasionally cooled to ensure that the temperature does not exceed 20C. After 46 hours, 350 ml of water are introduced, with thorough stirring, until the first slight turbidity appears. After the addition of a suspension of seed crystals, crystallis-ation of a large proportion of the product begins, over a period of 30 minutes, whilst stirring is continued.
To complete crystallisation, a further 300 ml of water are stirred in. The mixture is stirred for a further 30 minutes, then the crystals of the salt of o-mesitylenesulphonic acid thus formed are suction filtered and washed with water. The filter cake, still wet with water, is suspended in 500 ml of methanol and 100 ml of 2N sodium hydroxide solution are stirred in in one batch. The substance briefly goes into solution, but then crystallisation of the free sulphoximine occurs. The mixture is stirred for a further half hour at ambient temperature, suction filtered and washed with ice-cold methanol. The product is dried at 80C in a circulating air drier.
Melting point: 160-162C, Yield: 61.7 g (84.9% of theory).
ExamPle 88 6-[4-(3,4-dichlorophenYl-N-(4-toluenesulphonyl)-sulphox-imino)-butoxY]-3,4-dihYdrocarbostyril 200 mg of 6-[4-(3,4-dichlorophenyl-N-(4-toluene-sulphonyl)-sulphimino)-butoxy]-3,4-dihydrocarbostyril [prepared from 6-[4-(3,4-dichlorophenylmercapto)-butoxy]-3,4-dihydr QC arbostyril and N-chloro-4-toluene-sulphonamide sodium (Chloramine T)~ are suspended in methanol, then 0.35 ml of 2N sodium hydroxide solution and 0.06 ml of hydrogen peroxide solution (397.4 mg/ml) are added and the resulting mixture is refluxed for 4 hours. As it begins to boil, a clear solution is formed and after 1 hour crystals are precipitated. After further heating, the crystals are suction filtered while still hot and dried in air.
Melting point: 155-157C, Yield: 59% of theory.
ExamPle 89 6-[3-(3,4-Dichlorophenylsulphoximino)-propoxy]-3,4-dihYdrocarbostyril Prepared analogously to Example 2 from 6-[3-(3,4-dichlorophenylsulphinyl)-propoxy]-3,4-dihydrocarbo-styril and o-mesitylenesulphonyl-hydroxylamine.
Melting point: 144-146C, Yield: 67% of theory.
Example 90 6-[5-(3,4-Dichlorophenylsulphoximino)-pentoxy]-3,4-dihydrocarbostyril Prepared analogously to Example 2 from 6-[5-(3,4-dichlorophenylsulphinyl)-pentoxy]-3,4-dihydrocarbo-styril and o-mesitylenesulphonyl-hydroxylamine.
Melting point: 154-155C, Yield: 29 % of theory.
ExamPle 91 6-(3-Ethylsulphoximino-propoxy)-3,4-dihydrocarbostyril Prepared analogously to Example 2 from 6-(3-~ 175430 ethylsulphinyl~propoxy)-3,4-dihydrocarbostyril and o-mesitylenesulphonylhydroxylamine.
Melting point: 107-109C, Yield: 61 % of theory.
5 Example 92 6-[4-tN-4-Cyanobenzovl-3,4-dichlorophenylsulphoximino)-butoxy]-3~4-dihydrocarbostyril Prepared analogously to Example 49 from 6-[4-(3,4-dichlorophenylsulphoximino)-butoxy]-3,4-dihydrocarbo-10 styril and 4-cyanobenæoyl chloride.
Melting point: 200-202C, Yield: 79 % of theory.
Example 93 6-[4-(N-2-Thienoyl-3,4-dichlorophenylsulphoximino)-15 butoxy]-3,4-dihydrocarbostyril Prepared analogously to Example 49 from 6-[4-(3,4-dichlorophenylsulphoximino)-butoxy]-3,4-dihydrocarbo styril and 2-thiophenecarboxylic acid chloride.
Melting point: 100-102C, 20 Yield: 61 % of theory.
Example 94 6-[4-N-(+)-Pinanoyl-3,4-dichlorophenylsulphoximino)-butoxy]-3,4-dihydrocarbostyril Prepared analogously to Example 49 from 6-[4-25 (3,4-dichlorophenylsulphoximino)-butoxy]-3,4-dihydrocarbo-styril and (~)-pinanic acid chloride.
Melting point: 69-74C, Yield: 94 % of theory.

30 6-[4-(N-(-)-Pinanoyl-3,4-dichlorophenylsulphoximino)-butoxy]-3,4-dihydrocarbostyril Prepared analogously to Example 49 from 6-[9-(3,4-dichlorophenylsulphoximino)-butoxy]-3,4-dihydrocarbo-styril and (-)-pinanic acid chloride.
35 Melting point: 69-74C, Yield: 91 % of theory.

11 ~75~30 Example 96 6-[N-Pentamethylphenylsulphonyl-3,4-dichlorophenylsulphox-imino)-butoxY]-3,4-dihYdrocarbostyril Prepared analogously to Example 49 from 6-[4-(3,4-dichlorophenylsulphoximino)-butoxy]-3,9-dihydrocarbo-styril and pentamethylphenyl sulphochloride.
Melting point: 149-151C, Yield: 83 % of theory.
Example 97 6-[4-(N-Methanesulphonyl-3,4-dichlorophenYlsulphoximino)-butoxy]-3~4-dihydrocarbostyril Prepared analogously to Example 49 from 6-[4-(3,4-dichlorophenylsulphoximino)-butoxy]-3,4-dihydrocarbo-styril and methanesulphonyl chloride.
Melting point: 172-174C, Yield: 37 % of theory.
Example 98 6-[4-(N-Acetyl-4-cyclohexylphenyl-sulphoximino)-butoxy]-3,4-dihydrocarbostyril Prepared analogously to Example 47 from 6-[4-(4-cyclohexylphenyl-sulphoximino)-butoxy]-3,4-dihydro-carbostyril and acetic anhydride.
Melting point: 135-136C, Yield: 92 % of theory.
Example 99 6-[4-(N-Pivaloyl-4-cyclohexylphenylsulphoximino)-butoxy]-3,4-dihYdrocarbostyril Prepared analogously to Example 49 from 6-[4-(4-cyclohexylphenyl-sulphoximino)-butoxy]-3,4-dihydro-carbostyril and pivaloyl chloride.
Melting point: 170-172C, Yield: 95 % of theory.
Example 100 6-[4-(N-Benzoyl-4-cYclohexylphenylsulphoximino)-butoxy]-3,4-dihydrocarbostyril Prepared analogously to Example 49 from 6-[4-(4-cyclohexylphenyl-sulphoximino)-butoxy]-3,4-dihydro-carbostyril and benzoyl chloride.

~ ~7S43~

Melting point: 187-189C, Yield: 92 % of theory.
Example 101 6-[4-(N-Acetyl-4-fluorophenylsul~hoximino)-butoxy]-3,4-dihydrocarbostyril Prepared analogously to Example 47 from 6-[4-(4-fluorophenylsulphoximino~-butoxy]-3,4-dihydrocarbo-styril (Rf value: 0.60) and acetic anhydride.
Rf value: 0.65 (silica gel, eluant: ethylene chloride/
ethanol = 85:15~
Yield: 54 % of theory.
Example 102 6-[4-(N-Butyroyl-4-fluorophenylsulphoximino)-butoxy]-3,4-dihydrocarbostyril Prepared analogously to Example 49 from 6-[4-(4-fluorophenylsulphoximino)-butoxy]-3,4-dihydrocarbo-styril (Rf value: 0.60) and butyric acid chloride.
Rf value: 0.70 (silica gel, eluant: ethylene chloride/-ethanol = 85:15) Yield: 78 % of theory.
Example 103 6-[4-(N-2-Methoxyacetvl-4-fluorophenylsulphoximino)-butoxy]-3,4-dihydrocarbostyril Prepared analogously to Example 49 from 6-[4-(4-fluorophenylsulphoximino)-butoxy]-3,4-dihydrocarbo-styril (Rf value: 0.60) and 2-methoxyacetyl chloride.
Rf value: 0.66 (silica gel, eluant: ethylene chloride/-ethanol = 85/15).
Yield: 67 % of theory.
ExamPle 104 6-[4-(N-(+)-Pinanoyl-4-fluorophenylsulphoximino)-butoxY]-3,4-dihYdrocarbostyril Prepared from 6-[4-(4-fluorophenylsulphoximino)-butoxy]-3,4-dihydrocarbostyril and (+)-pinanic acid chloride analogously to Example 49.
Melting point: 116-120C, Yield: 61 % of theory.

~ 175430 Example 105 6-[4-(N-(-)-Pinanoyl-4-fluorophenylsulphoximino)-butoxy]-3,4-dihydrocarbostyril Prepared analogously to Example 49 from 6-[4-(4-fluorophenylsulphoximino)-butoxy]-3,4-dihydrocarbo-styril and (-)-pinanic acid chloride.
Melting point: 122-123C, Yield: 45 % of theory.
Example 106 6-[4-(N-4-Toluenesulphonyl-9-fluorophenylsulphoximino)-butoxy]-3,4-dihydrocarbostyril Prepared analogously to Example 49 from 6-[4-(9-fluorophenylsulphoximino)-butoxy]-3,4-dihydrocarbo-styril and 4-toluenesulphochloride.
Melting point: 67-70C, Yield: 57 % of theory.
Example 107 6-[4-(N-(+)-10-Camphorsulphonyl-4-fluoroPhenvlsulphox-imino)-butoxy]-3,4-dihydrocarbostyril Prepared analogously to Example 49 from 6-[4-(9-fluorophenylsulphoximino)-butoxy]-3,4-dihydrocarbo-styril and (+)-10-camphorsulphochloride.
Melting point: 81-100C, Yield: 61% of theory.
Example 108 6-[4-(N-Chlorobenzovl-4-methylsulphoximino)-butoxy]-3,4-dihydrocarbostvril Prepared analogously to Example 49 from 6-(4-methylsulphoximino)-butoxy)-3,4-dihydrocarbostyril and 4-chlorobenzoyl chloride.
Melting point: 176-178C, Yield: 87 % of theory.
Example 109 6-(4-n-HexYlsulphoximino-butoxy)-3,4-dihydrocarbostyril Prepared analogously to Example 2 and 6-(4-n-hexylsulphinyl-butoxy)-3,4-dihydrocarbostyril and o-mesitylenesulphonylhydroxylamine.
Melting point: 111-113C, ~ 17~430 Yield: 59 % of theory.
Example 110 6-(N-AcetYl-4-n-hexylsulphoximino-butoxy)-3,4-dihYdrocarbo-styril Prepared analogously to Example 47 from 6-(4-n-hexylsulphoximino-butoxy)-3,4-dihydrocarbostyril and acetic anhydride.
Melting point: 119-121C, Yield: 90 % of theory.
Example 111 6-(N-Benzoyl-4-n-hexylsulPhoximino-butoxy)-3,4-dihydrocarbo-styril Prepared analogously to Example 49 from 6-(4-n-hexylsulphoximino-butoxy)-3,4-dihydrocarbostyril and benzoyl chloride.
Melting point: 112-114C, Yield: 75 % of theory.
ExamPle 112 6-[4-(2-PhenylethYlsulPhoximino)-butoxv]-3,4-dihydrocarbo-stYril Prepared analogously to Example 2 from 6-[4-(2-phenylethylsulphinyl)-butoxy]-3,4-dihydrocarbostyril and o-mesitylenehydroxylamine.
Melting point: 158-159C, Yield: 69 % of theory.
ExamPle 113 5-(4-PhenYlsulphoximino-butoxY~-3,4-dihydrocarbostyril Prepared analogously to Example 2 from 5-(4-phenylsulphinyl-butoxy)-3,4-dihydrocarbostyril and o-mesitylenesulphonylhydroxylamine.
Melting point: 159-160C, Yield: 76 % of theory.
ExamPle 114 5-(N-Acetvl-4-Phenylsulphoximino-butoxy)-3~4-dihydrocarb styril Prepared analogously to Example 47 from 5-(4-phenylsulphoximino-butoxy)-3,4-dihyd~ocarbostyril and acetic anhydride.

~ 175430 Melting point: 134-137C, Yield: 61 % of theory.
Example 115 7-(4-Phenylsulphoximino-butoxy)-3,4-dihydrocarbostyril Prepared analogously to Example 87 from 7-(4-phenylsulphinyl-butoxy)-3,4-dihydrocarbostyril, ethyl o-mesitylenesulphonyl hydroxamate and p-toluenesulphonic acid.
Melting point: 137-139C, Yield: 81% of theory.
Example 116 7-(N-Acetyl-q-phenylsulphoximino-butoxy)-3,4-dihydrocarbo-styril Prepared analogously to Example 47 from 7-(4-phenylsulphoximino-butoxy)-3,4-dihydrocarbostyril and acetic anhydride.
Melting point:lll-113C, Yield: 78% of theory.
Example 117 8-(4-Phenylsulphoximino-butoxy)-3,4-dihydrocarbostyril Prepared analogously to Example 2 from 8-(4-phenylsulphinyl-butoxy)-3,4-dihydrocarbostyril and mesitylenesulphonylhydroxylamine.
Melting point:78-80C, Yield: 96% of theory.
Example 118 8-(N-Acetyl-4-PhenYlsulphoximino-butoxy)-3,4-dihydrocarbo-styril Prepared analogously to Example 47 from 8-(4-phenylsulphoximino-butoxy)-3,4-dihydrocarbostyril and acetic anhydride.
Melting point:116-118C, Yield: 82% of theory.
Example 119 6-(3-Ethylsulphoximino-propoxy)-carbostyril Prepared analogously to Example 2 from 6-(3-ethylsulphinyl-propoxy)-carbostyril and o-mesitylene-sulphonylhydroxylamine.

~ 175430 Melting point:ll6-167C, Yield: 80% of theory.
Example 120 6-[4-(N-Benzoyl-4-fluorophenylsulphoximino)-butoxY]-carbostyril Prepared analogously to Example 49 from 6-[4-(4-fluorophenylsulphoximino)-butoxy]-carbostyril and benzoyl chloride.
Melting point: 137-141C, Yield: 34% of theory.
Example 121 3,3-Dimethyl-S-[4-(3,4-dimethylphenylsulphoximino)-butoxy]-indolinone-2 Prepared analogously to Example 87 from 3,3-dimethyl-5-[4-(3,4-dimethylphenylsulphinyl)-butoxy]-indolinone-2, ethyl o-mesitylenesulphonyl hydroxamate and p-toluenesulphonic acid.
Melting point: 153-154C, Yield: 77% of theory.
Example 122 3,3-Dimethyl-5-[4-(N-acetyl-3,4-dimethylphenylsulphox-imino)-butoxY]-indolinone-2 Prepared analogously to Example 47 from 3,3-dimethyl-5-[4-(3,4-dimethylphenylsulphoximino)-butoxy]-indolinone-2 and acetic anhydride.
Melting point: 150-152C, Yield: 78% of theory.
Example 123 3,3-Dimet~yl-5-(4-methylsulphoximino-butoxy)-indolinone-2 Prepared analogously to Example 2 from 3,3-dimethyl-5-(4-methylsulphinyl-butoxy)-indolinone-2 and O-mesitylenesulphonylhydroxyamine.
Melting point: 123-124C, Yield: 98% of theory.
Example 124 3,3-Dimethyl-5-[4-(N-4-chlorophenYlaminocarbonyl-methyl-sulphoximino)-butoxy]-indolinone-2 Prepared from 3,3-dimethyl-5-(4-methylsulphoximino-butoxy)-indolinone-2 and 4-chlorophenylisocyanate in absolute dioxan at ambient temperature for 30 minutes.
Melting point: 175-177C, Yield: 89% of theory.
Example 125 3,3-Dimethyl-5-[4-(N-4-toluenesulphonyl-4-methylsulphox-imino)-butoxy]-indolinone-2 Prepared analogously to Example 49 from 3,3-dimethyl-5-(4-methylsulphoximino-butoxy)-indolinone-2 (Rf value: 0.45) and 4-toluenesulphochloride.
Rf value: 0.70 (silica gel, eluant: ethyl acetate/methylene chloride = 1:1), Yield: 63% of theory.
Example 126 3,3-Dimethyl-5-[4-(N-4-chlorobenzoYl-4-methylsulphoximino)-butoxy]-indolinone-2 Prepared analogously to Example 49 from 3,3-dimethyl-5-(4-methylsulphoximino-butoxy)-indolinone-2 and 4-chlorobenzoyl chloride.
Melting point: 176-178C, Yield: 73% of theory.
Example 127 6-[4-(N-acetyl-3,4-dichlorophenylsulphoximino)-butoxY]-3,4-dihydrocarbostyril 3,4-Dichlorophenylsulphinyl-4-bromobutane is reacted with o-mesitylenesulphonylhydroxylamine analogously to Example 2 to obtain 3,4-dichlorophenylsulphoximino-

4-bromobutane which is then converted into 3,4-dichloro-phenyl-(N-acetyl sulphoximino)-4-bromobutane using acetic anhydride analogously to Example 47.
Melting point: 170-173C
Yield: 98% of theory.
163.2 mg (0.001 mol) of 6-hydroxycarbostyril, dissolved in 2 ml of dimethylsulphoxide, are mixed with 448 mg (0.0013 mol) of 3,4-dichlorophenyl-(N-acetyl-sulphoximino~-4-bromobutane and 276.4 mg (0.002 mol) of anhydrous potassium carbonate and the mixture ~ 1~5~30 is stirred for 17 hours at ambient temperature.
It is then mi~ed with water in small portions, whereupon the reaction product crystallises out in the form of white needles.
Melting point: 149-151C, Yield: 267.1 mg (62.5% of theory).
Example 128 6-(4-Methvlsulphimino-butoxy)-3,4-dihydrocarbostyril-hYdrogen sulphate 0.12 9 of sodium are dissolved in 25 ml of methanol, 1.3 9 of 6-~4-methylmercapto-butoxy)-3,4-dihydrocarbostyril are added with stirring and, within 40 minutes, 0.57 9 of hydroxylamine-o-sulphonic acid are added at a temperature of 17C. The temperature rises to 22C. The mixture is stirred overnight, then the sodium sulphate precipitated is removed by suction filtering and, by the gradual addition of ether, a resinous substance is precipitated, which, when triturated with ether, crystallises to form a somewhat hygroscopic substance. This is suction filtered and dried in a vacuum desiccator over calcium chloride.
Melting point: 75-80C, Yield: 0.656 9 (20% of theory).
Example 129 6-[4-(3,4-DichloroPhenylsulphimino)-butoxy]-3,4-dihydro-carbostyril-mesitYlenesulphonate Prepared analogously to Example 2 from 6-[4-(3,4-dichlorophenylmercapto)-butoxy]-3,4-dihydrocarbostyril and o-mesitylenesulphonylhydroxylamine.
Melting point: 82-83C, Yield: 49% of theory.
Example 130 6-[4-(3,4-Dimethoxyphenylsulphimino)-butoxY]-3,4-dihvdro-carbostYril-mesitYlenesulphonate Prepared analogously to Example 2 from 6-[4-(3,4-dimethoxyphenylmercapto)-butoxy]-3,4-dihydrocarbostyril and o-mesitylenesulphonylhydroxylamine.

Melting point: 140-145C, Yield: 83% of theory.
Example 131 6-[4-(2'-Fluoro-4-biphenylYlsulphimino)-butoxy~-carbo-stYril-mesitylenesulphonate Prepared analogously to Example 2 from 6-[4-(2'-fluoro-4-biphenylyl-mercapto)-butoxy]-carbostyril and o-mesitylenesulphonylhydroxylamine.
Melting point: 125-128C, 10 Yield: 63% of theory.
Example 132 6-[4-(4-tert.butYlphenylsulphimino)-butoxy]-carbostyri Prepared analogously to Example 2 from 6-[4-(4-tert.butylphenylmercapto)-butoxy]-carbostyril 15 and o-mesitylenesulphonylhydroxylamine.
Melting point: lg5-150C, Yield: 55% of theory.
Example 133 6-[4-tN-4-toluenesulphonyl-4-fluorophenylsulphimino)-20 butoxy]-3,4-dihydrocarbostyril 0.70 g of 6-[4-(4-fluorophenylmercapto)-butoxy]-3,4-dihydrocarbostyril are suspended in 20 ml of methanol and a clear solution of 1.16 9 of N-chloro-4-toluenesulphonamide sodium is added. After stirring 25 overnight at ambient temperature, the ethanol is distilled off. The residue obtained is chromatographed on a silica gel column using methylene chloride/ethyl acetate (1:1).
Melting point: 122-124C, 30 Yield: 0.59 g (57% of theory).
Example 134 6-[4-(N-4-ToluenesulPhonYl-3,4-dichlorophenYlsulphimino3-butoxy]-3,4-dihvdrocarbostYril Prepared analogously to Example 133 from 6-35 [4-(3,4-dichlorophenylmercapto)-butoxy]-3,4-dihydrocarbo-styril and N-chloro-4-toluenesulphonamide sodium.
Melting point: 150-152C, Yield: 6296 of theory.

~ 53 ~ 1175430 Example 135

5-[4-(N-4-Toluenesulphonyl-4-bromophenYlsulphimino~-butoxyl-3,3-dimethYl-indolinone-2 Prepared analogously to Example 133 from 5-[4-(4-bromophenylmercapto)-butoxy]-3,3-dimethyl-indolinone-2 and N-chloro-4-toluenesulphonamide sodium.
Melting point: 163-164C, Yield: 33% of theory ExamPle 136

6-[4-(N-4-Toluenesulphonyl-methoxYPhenYlsulPhimin butoxy]-3,4-dihYdrocarbostyril Prepared analogously to Example 133 from 6-[4-(3-methoxyphenylmercapto)-butoxy]-3,4-dihydrocarbo-styril and N-chloro-4-toluenesulphonamide sodium.
15 Melting point: 110-114C, Yield: 38% of theory.
Example 137 6-[4-(N-4-toluenesulPhonYl-PhenYlsulphimino)-but 3,4-dihydro-carbostyril Prepared analogously to Example 133 from 6-(4-phenylmercapto-butoxy)-3,4-dihydrocarbostyril (Rf value = 0.45) and N-chloro-4-toluenesulphonamide sodium.
Melting point: 58~C (sintering) Rf value: 0.37 (silica gel, ethylene chloride/ethanol = g:1), Yield: 62% of theory.
Example 138 6-[4-(N-4-ToluenesulPhonyl-cvclohexylsulphimino-butoxy]
3,4-dihvdrocarbostYril Prepared analogously to Example 133 from 6-(4-cyclohexylmercapto-butoxy)-3,4-dihydrocarbostyril and N-chloro-4-toluenesulphonamide sodium.
Melting point: 162-163~C, Yield: 53~ of theory.

Example 139 6-[4-(N-4-Toluenesulphonyl-3,4-dichlorophenylsulphimino)-butoxy]-carbostYril Prepared analogously to Example 133 from 6-[4-(3,4-dichlorophenylmercapto)-butoxy]-carbostyril (Rf value: 0.34) and N-chloro-4-toluenesulphonamide sodium.
Rf value: 0.32 (silica gel plate, ethylene chloride/ethanol = 9:1), Yield: 39% of theory Example A
Coated tablets containinq 4 mg of 6-[4-(N-acetyl-3,4-dichlorophenylsulphoximino)-butoxy]-3,4-dihydro-carbostyril Composition:
1 Coated tablet core contains:
Active substance(1) 4 0 mg Lactose (2) 27.0 mg Corn starch(3) 14.5 mg Polyvinylpyrrolidone (4) 4.0 mg Magnesium stearate(5) 0.5 mg 50.0 mg Preparation:
- Substances 1-3 are homogeneously moistened with an aqueous solution of 4, then screened through a 1 mm mesh screen, dried and again screened through a 1 mm mesh. After the addition of 5, the mixture is compressed to form tablet cores.
Tablet cores: 5 mm ~, biconvex, round Coatinq:
Usual sugar coating to give a finished weight of 70 mg.
Example B
Tablets containinq 8 mq of 6-[4-(N-acetYl-3,4-dichloro ~henylsulphoximino)-butoxY]-3,4-dihydrocarbostYril 1 Tablet contains:
Active substance8.0 mg Lactose 23.0 mg Corn starch 14.5 mg Polyvinylpyrrolidone 4.0 mg Magnesium stearate0.5 mg 50.0 mg Preparation:
Analogously to the tablet cores.
Description of tablets:
Weight: 50.0 mg Diameter: 5 mm, biplanar, faceted on both sides 1 17$430 Example C
Suppositories containinq 25 mg of 6-[4-(N-acetyl-3,4-dichlorophenylsulphoximino)-butoxy]-3,4-dihvdro-carbostyril 5 1 Suppository contains:
Active substance 0.025 9 Hard fat (e.g. Witepsol H 19 1.695 9 and Witepsol W 45 1.700 9 10 Preparation:
The hard fat is melted. At 38C the ground active substance is homogeneously dispersed in the melt. It is cooled to 35C and poured into slightly pre-cooled suppository moulds.
Weight of suppository: 1.7 g Example D
Suspension containing 8 mg of 6-[4-(N-acetyl-3,4-dichlorophenylsulphoximino)-butoxy]-3,4-dihydrocarbostyril 100 ml of suspension contains:
Active substance0.16 9 Carboxymethylcellulose 0.1 9 Methyl p-hydroxybenzoate 0.05 g Propyl p-hydroxybenzoate 0.01 9 Sucrose 10.0 9 Glycerol 5.0 9 70% sorbitol solution 20.0 9 Flavouring 0.3 9 Distilled waterad 100.0 ml Preparation:
Distilled water is heated to 70C. The methyl and propyl p-hydroxybenzoates and the glycerol and carboxymethyl cellulose are dissolved therein with stirring. The mixture is cooled to ambient temperature and the active substance is added and homogeneously dispersed therein with stirring. After the sugar, sorbitol solution and flavouring have been added and dissolved therein, the suspension is evacuated, with stirring, to remove any air.

Example E
Tablets containing 100 mg of 6-[4-(N-acetY1-3,4-dichloro-phenylsulphoximino)-butoxy]-3,4-dihydrocarbostyril Composition:
S 1 Tablet contains:
Active substance 100.0 mg Lactose 80.0 mg Corn starch 34.0 mg Polyvinylpyrrolidone 4.0 mg Magnesium stearate 2.0 mg 220.0 mg Method of Preparation:
Active substance, lactose and starch are mixed together and homogeneously moistened with an aqueous lS solution of the polyvinylpyrrolidone. After the moist mass has been screened (2.0 mm mesh size) and dried in a rack drier at 50C, it is screened again (1.5 mm mesh size) and the lubricant is added. The finished mixture is made into tablets.
Weight of tablet: 220 mg Diameter:10 mm, biplanar, faceted on both sides and notched on one side.
Example F
Hard ~,elatine ca~sules containing 150 mg of 6-[4-_ _ (N-acetyl-3,4-dichloroPhenylsulphoximino)-butoxy]-3,4-dihydrocarbostyril 1 Capsule contains:
Active substance 150.0 mg Dried corn starch approx. 180.0 mg Powdered lactose approx. 87.0 mg Magnesium stearate 3.0 mq approx.320.0 mg Preparatlon:
The active substance is mixed with the excipients, passed through a screen with a mesh size of 0.75 mm and homogeneously mixed in a suitable apparatus.

The final mixture is transferred into size 1 hard gelatine capsules.
Capsule contents: about 320 mg Capsule shell: Hard gelatine capsule size 1.
Example G
SuPpositOries containinq 150 mg of 6-[4-(N-acetyl-3,4-dichloro-phenylsulphoximino)-butoxy]-3,~-dihydro-carbostyril 1 Suppository contains:
Active substance 150.0 mg Polyethyleneglycol 1500 550.0 mg Polyethyleneglycol 6000 460.0 mg Polyoxyethylene sorbitan monostearate 840.0 mq 2000.0 mg Preparation:
After the suppository mass has been melted, the active substance is homogeneously distributed therein and the melt is poured into pre-cooled moulds.
Example H
Suspension containing 50 mg of 6-[4-(N-acetyl-3,4-dichloro-phenYlsulphoximino)-butoxy]-3,4-dihYdrocarbo-styril per 5 ml 100 ml of suspension contains:
Active substance 1.0 9 Sodium salt of carboxymethyl-cellulose 0.1 9 Methyl p-hydroxybenzoate 0.05 g Propyl p-hydroxybenzoate0.01 g Sucrose 10.0 9 Glycerol 5.0 9 70% sorbitol solution 20.0 9 Flavouring 0.3 9 Distilled water ad 100 ml 35 Preparation:
Distilled water is heated to 70C. The methyl and propyl p-hydroxybenzoates are dissolved therein, with stirring, together with the glycerol and sodium salt of carboxymethylcellulose. The mixture is cooled to ambient temperature and the active substance is added and homogeneously dispersed therein with stirring.
After the sugar, sorbitol solution and flavouring have been added and dissolved, the suspension is evacuated, with stirring, to remove any air.
5 ml of suspension contains 50 mg of active substance.
Example I
Tablets containinq 150 mq of 6-[4-(N-p-toluenesulphonyl-3,4-dichloro-phenyl-sulphoximino)-butoxy]-3,4-dihydro-carbostyril Composition:
1 Tablet contains:
Active subtance150.0 mg Powdered lactose89.0 mg Corn starch 40.0 mg Colloidal silicic acid 10.0 mg Polyvinylpyrrolidone10.0 mg Magnesium stearate1.0 mg 300.0 mg Preparation:
The active substance mixed with the lactose, corn starch and silicic acid is moistened with a 20% aqueous polyvinylpyrrolidone solution and passed through a screen with a mesh size of 1.5 mm.
The granulate, dried at 45C, is again passed through this screen and mixed with the specified quantity of magnesium stearate. Tablets are compressed from the mixture.
Weight of tablets: 300 mg Punch: 10 mm, flat Example K
Coated tablets containing 75 mg of 6-[4-(N-p-toluene-sulphonyl-3,4-dichloro-Phenyl-sulphoximino)-butoxy]-3,4-dihydrocarbostyril 1 Coated tablet core contains:

Active substance 75.0 mg Calcium phosphate 93.0 mg Corn starch 35.5 mg Polyvinylpyrrolidone 10.0 mg Hydroxypropylmethylcellulose 15.0 mg Magnesium stearate 1.5 mg 230.0 mg Preparation:
The active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxy-propylmethyl cellulose and half the specified quantity of magnesium stearate. Using a tablet-making machine, compressed tablets with a diameter of about 13 mm are produced, which are then rubbed through a screen with a mesh size of 1.5 mm and mixed with the remaining quantity of magnesium stearate. This granulate is compressed into tablets of the desired shape in a tablet-making machine.
Weight of core: 230 mg Punch: 9 mm, convex The tablet cores thus produced are coated with a film consisting essentially of hydroxypropylmethyl-cellulose. The finished film-coated tablets are polished with beeswax.
Weight of coated tablet: 245 mg Obviously, all the other compounds of general formula I may be used as active substances in the galenic preparations described hereinbefore.

Claims (59)

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

1. A process for preparing a compound of general formula I
(I) [wherein n is 0 or 1;
A represents a methylene, vinylene or ethylene group (optionally substituted by one or two alkyl groups each containing 1 to 3 carbon atoms);
B represents a straight-chain or branched alkylene group containing 2 to 6 carbon atoms;
R1 represents an alkyl group containing 1 to 3 carbon atoms (option-ally substituted by a phenyl group); a phenyl group (wherein the aforementioned phenyl nuclei may optionally be substituted by an alkyl group containing 1 to 4 carbon atoms, by a halogen atom, by an alkoxy group containing 1 to 3 carbon atoms, or by a cyclohexyl, phenyl or halophenyl group); an alkyl group contain-ing 4 to 7 carbon atoms; a cycloalkyl group containing 3 to 7 carbon atoms;
a phenyl group di- or tri-substituted by alkyl groups containing 1 to 4 carbon atoms or by alkoxy groups containing 1 to 3 carbon atoms and/or by halogen atoms or a hydroxy- or amino-phenyl group disubstituted by alkyl groups con-taining 1 to 4 carbon atoms or by alkoxy groups containing 1 to 3 carbon atoms and/or by halogen atoms, wherein the substituents of the abovementioned phenyl, hydroxyphenyl or aminophenyl nuclei may be identical or different; a naphthyl group (optionally substituted by an alkoxy group containing 1 to 3 carbon atoms);
or a pyridyl group; and R2 represents a hydrogen atom or an acyl group of an organic carboxylic acid, an organic or inorganic sulphonic acid or a carbonic acid derivative]
or a salt thereof formed with a strong acid, which process comprises (a) for the preparation of a compound of formula I wherein n is 1 and R2 represents a hydrogen atom, reacting a compound of general formula II

O - B - SO - R1 (II) (wherein A, B and R1 are as defined above) with hydrazoic acid;
(b) for the preparation of a compound of formula I wherein R2 re-presents a hydrogen atom, reacting a compound of general formula IIa O - B - S(O)n - R1 (IIa) (wherein A, B, n and R1 are as defined above) with a compound of general formula III
H2N-O-X-R3 (III) wherein X represents a carbonyl or sulphonyl group and R3 represents an aryl group at least disubstituted in the o-positions, or (if X represents a sulphonyl group) a hydroxy group;
(c) for the preparation of a compound of formula I wherein n is 1, oxidizing a compound of general formula IV

(IV) wherein A, B, R1 and R2 are as defined above;
(d) for the preparation of a compound of general formula I wherein R2 is other than a hydrogen atom, acylating a compound of general formula V

(V) wherein n, A, B and R1 are as defined above;
(e) reacting a compound of general formula VI
OH (VI) (wherein A is as defined above), or an inorganic or tertiary organic base salt thereof, with a compound of general formula VII

(VII) wherein n, R1, R2 and B are as defined above and Z represents a nucleophili-cally exchangeable group; or (f) for the preparation of a compound of general formula I wherein n is 0, reacting a compound of general formula VIII

- O - B - S - R1 (VIII) (wherein A, B and R1 are as defined above) with a compound of general formula IX

R? (IX) (wherein Hal represents a chlorine or bromine atom and R2 represents R2 as defined above with the exception of a hydrogen atom) or with an alkali metal salt thereof, with optional subsequent hydrolysis;
and if necessary, converting a compound of formula I, initially obtained, into an acid addition salt thereof or converting an acid addition salt of a compound of formula I, initially obtained, into a compound of formula I.

2. A process for the preparation of a compound of formula I as claimed in claim 1, wherein n is 1 and R2 represents a hydrogen atom, which comprises reaction of a compound of general formula II

0 - B - SO - R1 (II) (wherein A, B and R1 are as defined in claim 1) with hydrazoic acid.

3. A process as claimed in claim 2 wherein the hydrazoic acid is formed in the reaction mixture.

4. A process as claimed in claim 2, wherein the reaction is carried out in a solvent.

5. A process as claimed in claim 2, 3 or 4, wherein the reaction is effected at a temperature between 0 and 40°C.

6. A process as claimed in claim l(a), 2 or 3, wherein the reaction is effected at a temperature between 10 and 35°C.

7. A process for the preparation of a compound of formula I as claimed in claim 1 wherein R2 represents a hydrogen atom, which comprises reaction of a compound of general formula IIa O - B - S(O)n-R1 (IIa) wherein A, B, n and R1 are as defined in claim 1) with a compound of general formula III
H2N-0-X-R3 (III) wherein X represents a carbonyl or sulphonyl group and R3 represents an aryl group at least disubstituted in the o-positions, or (if X represents a sulphonyl group) a hydroxy group.

8. A process as claimed in claim 7, wherein R3 represents a 2,4,6-trimethylphenyl or a 2,4,6-triisopropylphenyl group.

9. A process as claimed in claim 7, wherein the compound of general formula III is prepared in the reaction mixture.

10. A process as claimed in claim 7, 8 or 9, wherein the reaction is carried out in a solvent.

11. A process as claimed in claim 7, 8 or 9, wherein the reaction is effected at a temperature of between 0 and 50°C.

12. A process as claimed in claim 7, 8 or 9 wherein the reaction is effected at a temperature between 5 and 40°C.

13. A process for the preparation of a compound as claimed in claim 1 wherein n is 1, which comprises oxidation of a compound of general formula IV

(IV) wherein A, B, R1 and R2 are as defined in claim 1.

14. A process as claimed in claim 13, wherein the reaction is carried out in a solvent.

15. A process as claimed in claim 13 or 14, wherein one equivalent of oxidising agent is used.

16. A process as claimed in claim 13 or 14, wherein the reaction is effected at a temperature between -80 and 100°C.

17. A process as claimed in claim 13 or 14, wherein the reaction is effected at a temperature between 0 and 60°C.

18. A process for the preparation of a compound of general formula I as claimed in claim 1 wherein R2 does not represent a hydrogen atom, which com-prises acylation of a compound of general formula V

(V) wherein n, A, B and Rl are as defined in claim 1.

19. A process as claimed in claim 18, wherein the reaction is carried out in a solvent.

20. A process as claimed in claim 18, wherein the acylating agent used is an acid, an acid anhydride, an ester, an acid halide or an isocyanate.

21. A process as claimed in claim 20, wherein the acylating agent used is an acid and an acid-activating or dehydrating agent is also present.

22. A process as claimed in claim 18, 19 or 20, wherein the reaction is carried out in the presence of an inorganic or tertiary organic base.

23. A process as claimed in claim 18, 19 or 20, wherein the reaction is effected at a temperature of between -25 and 100°C.

24. A process as claimed in claim 18, 19 or 20, wherein the reaction is effected at a temperature between -10 and 80°C.

25. A process for the preparation of compounds of formula I as defined in claim 1, which comprises reaction of a compound of general formula VI

(VI) (wherein A is as defined in claim 1), or an inorganic or tertiary organic base salt thereof, with a compound of general formula VII

Z - B (VII) wherein n, R1, R2 and B are as defined in claim 1 and Z represents a nucleophilically exchangeable group.

26. A process as claimed in claim 25, wherein Z represents a halogen atom or a sulphonic acid ester group.

27. A process as claimed in claim 25, wherein the reaction is carried out in a solvent.

28. A process as claimed in claim 25, wherein the reaction is carried out in the presence of an alkali base.

29. A process as claimed in claim 28, wherein the alkali base is sodium carbonate, potassium carbonate or sodium hydroxide.

30. A process as claimed in claim 25, 26 or 27, wherein the reaction is effected at a temperature between 0°C and the boiling temperature of the solvent used.

31. A process as claimed in claim 25, 26 or 27, wherein the reaction is effected at a temperature between 0 and 100°C.

32. A process as claimed in claim 25, 26 or 27 wherein the reaction is effected at a temperature between 10 and 50°C.

33. A process for the preparation of a compound of general formula I as claimed in claim 1 wherein n is 0, which comprises reaction of a compound of general formula VIII
- B - S - R1 (VIII) (wherein A, B and R1 are as defined in claim 1) with a compound of general formula IX
R2 (IX) (wherein Hal represents a chlorine or bromine atom and R2 represents R2 as defined in claim 1 with the exception of a hydrogen atom) or with an alkali metal salt thereof, with optional subsequent hydrolysis.

34. A process as claimed in claim 33, wherein the reaction is carried out in a solvent.

35. A process as claimed in claim 33, wherein the reaction is carried out in the presence of an alkali base.

36. A process as claimed in claim 33, 34 or 35, wherein the reaction is effected at a temperature between 0 and 80°C.

37. A process as claimed in claim 33, 34 or 35, wherein the reaction is effected at a temperature between 5 and 50°C.

38. A process as claimed in claim 33, wherein the subsequent hydrolysis, if desired, is effected in the presence of an acid or a base in a solvent.

39. A process as claimed in claim 38, wherein the subsequent hydrolysis is effected in the presence of a base.

40. A process as claimed in claim 1, wherein a compound of formula I, initially obtained, is subsequently converted into a physiologically acceptable acid addition salt thereof.

41. A process as claimed in claim 40, wherein the salt is formed with hydrochloric, sulphuric or mesitylenesulphonic acid.

42. A process as claimed in claim 1, wherein starting compounds are chosen in which R2 represents a hydrogen atom or an acyl group of an optionally sub-stituted aliphatic alkanoic or alkenoic acid, or an optionally substituted aromatic carboxylic acid (wherein a -CH=CH- group or one or two =CH- groups may optionally be replaced by an oxygen, sulphur or nitrogen atom), of a carbonic acid ester, of optionally substituted carbamic acid or of an aliphatic or aro-matic sulphonic acid, or represents a hydroxysulphonyl group.

43. A process as claimed in claim 1, wherein starting compounds are chosen in which n is O or l;
A represents a dimethylmethylene, vinylene or ethylene group;
B represents a straight-chain alkylene group containing 3 to 5 carbon atoms;
R1 represents an alkyl group containing 1 to 6 carbon atoms; a benzyl, phenylethyl, cyclohexyl, naphthyl, methoxynaphthyl or pyridyl group; a phenyl group (optionally substituted by an alkyl group containing 1 to 4 carbon atoms, by a methoxy, cyclohexyl, phenyl or fluorophenyl group or by a fluorine, chlorine or bromine atom) or a phenyl group (disubstituted by alkyl groups containing 1 to 4 carbon atoms, methoxy groups, or chlorine and/or bromine atoms, wherein the substituents of the phenyl nucleus may be the same or different);
or an aminophenyl, hydroxyphenyl or methoxyphenyl group substituted by two chlorine or bromine atoms, two methoxy groups or two alkyl groups each contain-ing 1 to 4 carbon atoms; and R2 represents a hydrogen atom; an alkanoyl group containing 1 to 8 carbon atoms (optionally substituted by a methoxy group); a benzoyl or phenyl-sulphonyl group (optionally substituted by a halogen atom or by a cyano group or by an alkyl group containing 1 to 4 carbon atoms); an alkoxycarbonyl group containing a total of 2 to 4 carbon atoms; an aminocarbonyl group (optionally substituted by a chlorophenyl group or by 1 or 2 methyl groups); or a naphthoyl, pinanoyl, camphorsulphonyl, pentamethylphenylsulphonyl, pyridinoyl group or thenoyl group.

44. A process as claimed in claim 1, wherein starting compounds are chosen in which n is 1, A represents a dimethylmethylene, vinylene or ethylene group, B represents an n-butylene group, R1 represents a methyl or methoxy-naphthyl group, a phenyl group (optionally substituted by a methoxy group or a fluorine or chlorine atom), a phenyl group substituted by 2 chlorine or bro-mine atoms, or a methylbromophenyl, 4-amino-3,5-dibromophenyl or di-tert.
butyl-hydroxy-phenyl group, and R2 represents a hydrogen atom, an alkanoyl group containing 1 to 3 carbon atoms or a benzoyl or phenyl-sulphonyl group (optionally substituted by an alkyl group containing 1 to 4 carbon atoms).

45. A process for preparing a compound of general formula Ia (Ia) wherein A represents an ethylene or vinylene group, B represents an n-butylene group, R1 represents a methyl, phenyl, 4-fluorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl or 3-methyl-4-bromophenyl group, and R2 represents a hydrogen atom, or an acetyl or p-toluenesulphonyl group, which process comprises carrying out a process as defined in claim 1 using appropriately substituted starting compounds.

46. A process for preparing 6-[4-N-acetyl-3,4-dichlorophenylsulphoximino)-butoxy]-3,4-dihydrocarbostyril,, which comprises acetylating 6-[4-(3,4-dichloro-phenylsulphoximino)-butoxy]-3,4-dihydrocarbostyril.

47. A process according to claim 46, wherein the 6-[4-(3,4-dichlorophenyl-sulphoximino)-butoxy]-3,4-dihydrocarbostyril is prepared by reacting 6-[4-(3,4-dichlorophenylsulphinyl)-butoxy]-3,4-dihydrocarbostyril with o-mesitylene-sulphonylhydroxylamine and thereafter removing the mesitylenesulphonate group from the resulting 6-[4-(3,4-dichlorophenylsulphoximino)-butoxy]-3,4-dihydro-carbostyril mesitylene sulphonate.

48. A process for preparing 6-[4-N-acetyl-3,4-dichlorophenylsulphoximino)-butoxy]-3,4-dihydrocarbostyril, which comprises reacting 6-hydroxycarbostyril with 3,4-dichlorophenyl-(N-acetyl-sulphoximino)-4-bromobutane in the presence of potassium carbonate.

49. A process for preparing 6-[4-(3-methyl-4-bromophenylsulphoximino)-butoxy]-carbostyril, which comprises reacting 6-[4-(3-methyl-4-bromophenyl-sulphinyl)-butoxy]-carbostyril with sodium azide.

50. A process according to claim 49, wherein the reaction is carried out in polyphosphoric acid.

51. A compound of general formula I
(I) [wherein n is 0 or 1;
A represents a methylene, vinylene or ethylene group (optionally substituted by one or two alkyl groups each containing 1 to 3 carbon atoms);
B represents a straight-chain or branched alkylene group containing 2 to 6 carbon atoms;

R1 represents an alkyl group containing 1 to 3 carbon atoms (option-ally substituted by a phenyl group); a phenyl group (wherein the aforementioned phenyl nuclei may optionally be substituted by an alkyl group containing 1 to 4 carbon atoms, by a halogen atom, by an alkoxy group containing 1 to 3 carbon atoms, or by a cyclohexyl, phenyl or halophenyl group); an alkyl group containing 4 to 7 carbon atoms; a cycloalkyl group containing 3 to 7 carbon atoms; a phenyl group di- or tri-substituted by alkyl groups containing 1 to 4 carbon atoms or by alkoxy groups containing 1 to 3 carbon atoms and/or by halogen atoms or a hydroxy- or amino-phenyl group disubstituted by alkyl groups containing 1 to 4 carbon atoms or by alkoxy groups containing 1 to 3 carbon atoms and/or by halogen atoms, wherein the substituents of the abovementioned phenyl, hydroxy-phenyl or aminophenyl nuclei may be identical or different; a naphthyl group (optionally substituted by an alkoxy group containing 1 to 3 carbon atoms); or a pyridyl group; and R2 represents a hydrogen atom or an acyl group of an organic carboxy-lic acid, an organic or inorganic sulphonic acid or a carbonic acid derivative]
or a salt thereof formed with a strong acid, whenever prepared by the process claimed in claim 1, or by an obvious chemical equivalent thereof.

52. A physiologically compatible strong-acid addition salt of a com-pound of formula I as defined in claim 51, whenever prepared by the process claimed in claim 40, or by an obvious chemical equivalent thereof.

53. The salt formed with hydrochloric, sulphuric or mesitylenesulphonic acid of a compound of formula I as defined in claim 51, whenever prepared by the process claimed in claim 41, or by an obvious chemical equivalent thereof.

54. A compound of formula I as claimed in claim 51, wherein R2 represents a hydrogen atom or an acyl group of an optionally substituted aliphatic alkanoic or alkenoic acid, or an optionally substituted aromatic carboxylic acid (wherein a -CH=CH- group or one or two =CH- groups may optionally be replaced by an oxygen, sulphur or nitrogen atom), of a carbonic acid ester, of option-ally substituted carbamic acid or of an aliphatic or aromatic sulphonic acid, or represents a hydroxysulphonyl group, whenever prepared by the process claimed in claim 42, or by an obvious chemical equivalent thereof.

55. A compound of formula I as defined in claim 51, where n is O or l;
A represents a dimethylmethylene, vinylene or ethylene group;
B represents a straight-chain alkylene group containing 3 to 5 carbon atoms;
R1 represents an alkyl group containing 1 to 6 carbon atoms; a benzyl, phenylethyl, cyclohexyl, naphthyl, methoxynaphthyl or pyridyl group; a phenyl group (optionally substituted by an alkyl group containing 1 to 4 carbon atoms, by a methoxy, cyclohexyl, phenyl or fluorophenyl group or by a fluorine, chlo-rine or bromine atom) or a phenyl group (disubstituted by alkyl groups contain-ing 1 to 4 carbon atoms, methoxy groups, or chlorine and/or bromine atoms, wherein the substituents of the phenyl nucleus may be the same or different);
or an aminophenyl, hydroxyphenyl or methoxyphenyl group substituted by two chlorine or bromine atoms, to methoxy groups or two alkyl groups each containing 1 to 4 carbon atoms; and R2 represents a hydrogen atom; an alkanoyl group containing 1 to 8 carbon atoms (optionally substituted by a methoxy group); a benzoyl or phenyl-sulphonyl group (optionally substituted by a halogen atom or by a cyano group or by an alkyl group containing 1 to 4 carbon atoms); an alkoxycarbonyl group containing a total of 2 to 4 carbon atoms; an aminocarbonyl group (optionally substituted by a chlorophenyl group or by 1 or 2 methyl groups); or a naphthoyl, pinanoyl, camphorsulphonyl, pentamethylphenylsulphonyl, pyridinoyl group or thenoyl group, whenever prepared by the process claimed in claim 43 , or by an obvious chemical equivalent thereof.

56. A compound of formula I as claimed in claim 51, wherein n is l, A
represents a dimethylmethylene, vinylene or ethylene group, B represents an n-butylene group, R1 represents a methyl or methoxynaphthyl group, a phenyl group (optionally substituted by a methoxy group or a fluorine or chlorine atom), a phenyl group substituted by 2 chlorine or bromine atoms, or a methylbromo-phenyl, 4-amino-3,5-dibromophenyl or di-tert.butyl-hydroxy-phenyl group, and R2 represents a hydrogen atom, an alkanoyl group containing 1 to 3 carbon atoms or a benzoyl or phenyl-sulphonyl group (optionally substituted by an alkyl group containing 1 to 4 carbon atoms), whenever prepared by the process claimed in claim 44, or by an obvious chemical equivalent thereof.

57. A compound of general formula Ia (Ia) wherein A represents an ethylene or vinylene group, B represents an n-butylene group, R1 represents a methyl, phenyl, 4-fluorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl or 3-methyl-4-bromophenyl group, and R2 represents a hydrogen atom or an acetyl or p-toluenesulphonyl group, whenever prepared by the process claimed in claim 45, or by an obvious chemical equivalent thereof.

58. 6-[4-N-Acetyl-3,4-dichlorophenylsulphoximino)-butoxy]-3,4-dihydro-carbostyril, whenever prepared by the process claimed in claim 46, 47 or 48, or by an obvious chemical equivalent thereof.

59. 6-[4-(3-Methyl-4-bromophenyl(sulphoximino)-butoxy]-carbostyril, when-ever prepared by the process claimed in claim 49 or 50, or by an obvious chemical equivalent thereof.