NZ189685A - Carbostyril and oxindole derivatives - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number 1 89685 1 8 9*&§ Priosftv OwfpJai- ii-S • 78 J ■|£TT2"" jj & I K»v ILjf t I I I « I I i I r I I I I g I ) ^ Complete Spocif.'cairin Ft':3d: (£'$.'73 CAazB:Co??2°fCQl?2^^ 0 6 JUI 1Qft4 _ CoiJ>lf-05' COU>i^rf^Ccr&^i3°ff\friK3i]y-OM'4-5■ v IW» ^i^bEi-c^aD Eats;,. ...... 06 JUL SS4 H'tsl i<0 _ fey?.jlMtr& fcSsf. ji.ipljl Patents Form No. 5 NEW ZEALAND PATENTS ACT 195 3 COMPLETE SPECIFICATION I CHEMICAL COMPOUNDS I/WE DR KARL THOMAE GESELLSCHAFT MIT BESCHRANKTER HAFTUNG, a Body Corporate organised under the laws of the Federal Republic of Germany, of Biberach an der Riss, Federal Republic of Germany hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement 189685 2" This invention re]a tes to new carbostyril and oxindole derivatives, to process for their preparation and to pharmaceutical compositions containing them.

According to one feature of the present invention there are provided compounds of general formula I, W represents a vinylene group (optionally substituted by a methyl group) or a methylene or ethylene group; R (X) wherein 1 18968' .hi is 0,1 or 2; D represents a straight-chained or branched alkylehe group containing from 2 to 6 carbon atoms, a straight-chained or branched hydroxyalkylene group containing from 5 3 to 6 carbon atoms or a xylylene group; represents a hydrogen atom or an alkyl group containing from 1 to 3 carbon atoms; R^ represents a cycloalkyl group containing from 3 to 6 carbon atoms; an aryl group containing from 6 to 10 10 carbon atoms, an aralkyl group containing from 7 to 11 carbon atoms, a heteroaryl group containing from 4 to 9 carbon atoms or a heteroaralkyl group containing from 5 to 10 carbon atoms, said heteroaryl or heteroaralkyl group containing either a nitrogen atom and/or an 15 oxygen or sulfur atom or two nitrogen atoms (said aryl, aralkyl, heteroaryl or heteroaralkyl group being optionally substituted in the aromatic moiety by an alkyl group containing from 1 to 4 carbon atoms, a hydroxy, methoxy, amino, acetylamino, nitro, carboxyl^ ^ 20 or phenyl group or by a halogen atom and, in the case that the aryl, aralkyl, heteroaryl or heteroaralkyl group being substituted is a phenyl group, said monosubstituted phenyl group optionally being further substituted by 1 or 2 substituents selected from alkyl and alkoxy groups 25 each containing from 1 to 4 carbon atoms and halogen atoms); a 1,2,4-triazolyl, triphenylmethyl, 4,5-bis-(p-chlorophenyl)- ox' azole-2-yl, N-methyl-cyclohexylarnino-carbonylmethyl or amino-iminomethy1 group; or, when either m is 1 or D represents a straight-chained or * \980 189685 branched hydroxyalkylene group containing from 3 to 6 carbon, atoms or a xylylene group, alternatively an alkyl group containing from 1 to 6 carbon atoms; and and R^, which may be the same.or different, each represents a hydrogen or halogen atom, an alkyl group containing from 1 to 4 carbon atoms or an amino, acetylamino or nitro group.

The compounds of general formula I possess interesting pharmacological properties and in particular, in general, a positive inotropic activity as well as an antithrombotic activity.

In formula I, when R£, R^ and /or R^ represent a halogen atom, this may, be a fluorine, chlorine, bromine or iodine atom.

D may, for example, represent an ethylene, n-propylene, n-butylene, n-pentylene, n-hexylene, 1-methylethylene, 2-methylethylene, 1-methyl-n-propylene, 2-methyl-n-propylene, 3-methyl-n-propylene, 1-methyl-n-butylene, 2-methyl-n-butylene, 3-methyl-n-butylene, 4-methyl-n-butylene, 1-methyl-n-pentylene, 2-methyl-n-pentylene, 3-methyl-n-pentylene, 4-methyl-n-pentylene, -methyl-n-pentylene, 1,1-dimethylethylene, 1,2-dimethylethylene, 2,2-dimethylethylene, 1,1-dimethyl-n-propylene, 2,2-dimethyl-n-propylene, 3,3-dimethyl-n-propylene, 1,2-dimethyl-n-propylene, 1,3-dimethyl-n-propylene, 1,1-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, 1-ethylethylene, 2-ethylethylene, 1-ethyl-n- 1 896 propylene, 2-ethyl-n-propylene, 3-ethyl-n-propylene, 1-ethyl-n-butylene, 2-ethyl-n-butylene, 3-ethyl-n-butylene, 4-ethyl-n-butylene, 1-methyl-2-ethyl-ethylene, 1-methyl-2-ethyl-n-propylene, 1-methyl-3-ethyl-n-pro-pylene, 1-methyl-2-propyl-ethylene, 1-propylethylene, 1-butylethylene, 1-propyl-n-propylene, 2-hydroxy-n-propylene, 2-hydroxy-n-butylene, 3-hydroxy-n-butylene, 2-hydroxy-n-pentylene, 3-hydroxy-n-pentylene, 4-hydroxy-n-pentylene, 2-hydroxy-n-hexylene, 3-hydroxy-n-hexylene, l-methyl-2-hydroxy-n-propylene, 2-hydroxy-2-methyl-n-propylene, £-xylylene, o-xylylene or m- xylylene group.

R^ may represent a hydrogen atom or a methyl, ethyl, propyl or isopropyl group.

R2 may, for example, represent a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenylethyl, naphthyl, naphthylmethyl, cyclohexylphenyl, biphenyl, triphenylmethyl, N-methylcyclohexylamino-carbonylmethy1, amino-aminomethy1, pyridyl, pyridylmethyl, furfuryl, benzimidazolyl, benzthiazolyl, pyrimidyl, 1,2,4-triazolyl, quinolyl, quinazoline-4-one-yl, 4-,5-bi s-(£-chlorophenyl)-oxazole-2-yl, pyridyl-oxide, methylphenyl, dimethylphenyl, tert.-butylphenyl, methyl-tert.-butylphenyl, methylpyridyl, methoxyphenyl, dimethoxyphenyl, methoxypyridyl, hydroxypheny1, fluorophenyl, difluorophenyl, trifluorophenyl, fluoro-pyridyl, chlorophenyl, dichlorophenyl, trichlorophenyl, chloropyridyl, bromophenyl, dibromophenyl, aminophenyl, acetylaminophenyl, aminopyridyl, acetylaminopyridyl, nitrophenyl, carboxyphenyl ,hydroxy-dic.hlorophenyl, hydroxy-dibromophenyl, amino-dichlorophenyl, amino-dibromophenyl, 189685 hydroxy-di-tert.-butylphenyl, methoxy-fluorophenyl, methoxy-chlorophenyl, methoxy-bromophenyl, fluoro-methylphenyl, chloromethylphenyl or bromomethylphenyl group. and R^, which may be the same or different, may, for example, represent a hydrogen, fluorine, chlorine, bromine or iodine atom or a methyl, ethyl, propyl, iso-propyl, butyl, tert.-butyl, nitro, amino or acetylamino group.

Preferred compounds 'according to the invention are those wherein R£ represents a cyclohexyl, benzyl, naphthyl, pyridyl, pyrimidyl, 1,2,4-triazolyl, pyridyl-oxide, furfuryl, triphenylmethyl, quinolyl, benzimidazolyl, benzthiazolyl, quinazoline-4-one-yl, 4,5-bis-(]D-chlorophenyl)-oxazole-2-yl, N-methylcyclohexylamino-carbonylmethyl or amino-iminomethy1 group; a phenyl group optionally substituted by a carboxyl, hydroxy, methoxy, amino, acetylamino, nitro, cyclohexyl or phenyl group; a phenyl group substituted by one or two substituents selected from halogen atoms and alkyl groups escch containing from 1 to 4 carbon atoms; or a hydroxyphenyl, halophenyl or aminophenyl group substituted by two halogen atoms or by two alkyl groups each containing from 1 to 4 carbon atoms: R^ represents a hydrogen, chlorine or bromine atom or a methyl, amino, acetylamino or nitro group: and R^ represents a hydrogen atom.

Of these preferred compounds, more preferred are those wherein W represents a vinylene group (optionally substituted by a methyl group) or an ethylene group; 189685 D represents an alkylene group containing from 2 to 5 carbon atoms or a hydroxyalkylene group containing from 3 to 5 carbon atoms; represents a hydrogen atom; R2 represents a cyclohexyl, phenyl, benzyl, naphthyl, biphenyl, cyclohexylphenyl, pyridyl, methylphenyl, methoxyphenyl, fluorophenyl, chlorophenyl, dichlorophenyl, trichlorophenyl, bromophenyl, dibromophenyl, bromomethyl-phenyl, amino-dibromophenyl or hydroxy-di-tert.-butylphenyl group; and R^ represents a hydrogen atom.

Of these more preferred compounds, especially-preferred are those wherein W represents an ethylene, vinylene or 2-methylvinylene group; D represents an ethylene, n-propylene, n-butylene or 2-hydroxy-n-propylene group;and represents a cyclohexyl, phenyl, benzyl, naphth-2-yl,2-methoxyphenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2,5-dichlorophenyl, 4-hydroxy-3,5-di-tert.-butylphenyl, 4-amino-3,5-dibromophenyl or pyrid-2-yl group.

Particularly preferred compounds according to the invention are the following: 6-(4-phenylsulfinylbutoxy)-3,4-dihydrocarbo styri1, 6-[4-(3,4-dichlorophenylsulfinyl)-butoxy]-3,4-dihydrocarbostyril, and 6-[4-(pyrid-2-ylsulfonyl)-butoxy]carbostyril. 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) Reaction of a compound of formula II, 18 96 8 5 w (id -f—OH n 4 (wherein , R^, R^ and W are as hereinbefore defined), or a salt thereof with an inorganic or tertiary organic base, with a compound of formula III, Z - D -SO - R m (III) (wherein D, R^ and m are as hereinbefore defined) and Z represents a nucleophilically exchangeable atom or group, for example a halogen atom or a sulfonic acid ester group, e.g. a chlorine, bromine or iodine atom or a £- The reaction is conveniently carried out in a suitable solvent such as e.g. dioxan, tetrahydrofuran, chloroform or toluene, but preferably, however, in an anhydrous aprotic solvent such as, for example, acetone, 15 dimethylformamide or dimethylsulfoxide. The reaction may optionally be effected in the presence of an alkali metal base, e.g. sodium carbonate, potassium carbonate or sodium hydroxide. Suitable temperatures for the reaction are generally from 0°C to the boiling temperature 20 of the reaction mixture, for example at temperatures of from 0 to 100°C, preferred temperatures being however, from 10 to 50°C. The reaction may, if desired, by carried out in the absence of a solvent. toluenesulfonyloxy or methanesulfonyloxy group). 18 9 6 8 5 B) for the preparation of compounds of general formula I wherein m is 1 or 2: Oxidation of a compound of formula I as hereinbefore defined wherein m is 0 whereby the desired 5 compound of formula I is obtained.

The oxidation is preferably carrie d out in the presence of a solvent, e.g. water, aqueous pyridine, ethanol, methanol, acetone, formic acid, glacial acetic acid, dilute sulfuric acid or trifluoroacetic 10 acid. Suitable temperatures are "generally from -80 to +100pC depending on the oxidising agent used.

The oxidation is most conveniently effected with about one equivalent of an oxidising agent. Oxidation may, for example be effected with hydrogen peroxide in 15 glacial acetic acid or formic acid at 0 to 20°C or in acetone at 0 to 60°C; with a peracid such as e.g. performic acid in glacial acetic acid or trifluoroacetic acid at 0 to 50°C; with sodium metaperiodate in aqueous methanol or ethanol at 15 to 25 °C; with N-bromo-succinimide in 20 ethanol; with tert.-butyl hypochlorite in methanol at -80 to -30°C; with iodobenzene dichloride in aqueous pyridine at 0 to 50°C; with nitric acid in glacial acetic acid at 0 to 20°C; with chromic acid in glacial acetic acid or in acetone at 0 to 20°C; or with sulfuryl 25 chloride in methylene chloride at -70°C, the thioether chlorine complex thus formed being appropriately hydrolysed with aqueous ethanol.

C) for the preparation of compounds of general formula I wherein m is 2: Oxidation of a compound of formula I as herein before defined wherein m is 0 or 1 whereby the 18 96 8 5 desired compound of formula I is obtained.

The oxidation is again preferably carried out in the presence of a solvent such as exemplified in process (B) above. Suitable temperatures are also generally from -80 to +100°C depending on the oxidising agent used. Where it is desired to oxidise a compound of formula I wherein m is 0 at least two or more equivalents of an oxidising agent are preferably used. Where, however, it is desired to oxidise a compound of formula I wherein m is 1, one or more equivalents of an oxidising agent are preferably used.

Oxidation may, for example be carried out with hydrogen peroxide in glacial acetic acid or formic acid at 20 to 100°C or in acetone at 0 to 60°C; with a peracid such as e.g. performic acid or m-chloro-perbenzoic acid in glacial acetic acid, trifluoroacetic acid or chloroform at temperatures of from 0 to 50°C; with nitric acid in glacial acetic acid at 0 to 20°C; or with chromic acid or potassium permanganate in glacial acetic acid, aqueous sulfuric acid or in acetone at 0 to 20°C.

D) for the preparation of compounds of general formula I wherein m is 0: Reaction of a compound of formula IV, 18 96 with a compound of formula V, Y - R2 (V) (wherein, in the above formulae IV and V,'R^, R^, D and W are as hereinbefore defined and either one of 5 X and Y represents a mercapto group whilst the other of X and Y represents a nucleophilically exchangeable atom or group such as, for example, a halogen atom or a sulfonic acid ester group, e.g. a chlorine, bromine or iodine atom or a £-toluenesulfonyloxy or 10 methanesulfonyloxy group, or alternatively, when D represents a hydroxyalkylene group containing from 3 to 6 carbon atoms, X may, together with the hydroxy group in D,. represent an epoxide group, Y then representing a mercapto group).

The reaction is conveniently carried out in a suitable solvent such as e.g. dioxan*, tetrahydrofuran, chloroform or toluene, but preferably, however, in an anhydrous aprotic solvent such as e.g. acetone, dimethylformamide or dimethylsulfoxide. The reaction 20 may, if desired, be effected in the presence of an alkali metal base such as 'e.g. sodium carbonate, potassium carbonate or sodium hydroxide. Suitable reaction temperatures are generally from 0°C to the boiling temperature of the reaction mixture e.g. at 25 temperatures of from Q to 100°C. Preferred temperatures are, however, from 10 to 50°G. The reaction may, if desired, be carried out in the absence of a solvent. 18 9 6 8 5 E) for the preparation of compounds of general formula I wherein R^ represents an alkyl group containing from 1 to 3 carbon atoms: Reaction of a compound of formula I as herein-5 before defined wherein R^ represents a hydrogen atom, or an alkali metal salt thereof, with a compound of formula VI, Z' - Rx (VI) (wherein R^ is as hereinbefore defined and Z'represents 10 a nucleophilically exchangeable atom or group such as, for example, a halogen atom or a sulfonic acid ester group, e.g. a chlorine, bromine or iodine atom or a £-toluenesulfonyloxy or methanesulfonyloxy group).

The reaction is conveniently carried out in the presence of an aprotic solvent, such as e.g. acetone, dimethylformamide or dimethylsulfoxide and conveniently in the presence of an inorganic base such as e.g. potassium carbonate, sodium hydroxide, 20 sodium hydride or potassium hydroxide or of an alcoholate such as e.g. sodium methoxide. Suitable temperatures for the reaction are generally 0 to 50°C, preferred temperatures being from 10 to 25°C. Particular compounds of general formula VI which may 25 be considered are the alkyl halides such as e.g. methyl iodide or isopropyl bromide and the dialkyl sulfates such as e.g. dimethyl or diethyl sulfate. 189685 F) for the preparation of compounds of general formula I wherein W represents a vinylene group; Dehydrogenation of a compound of formula I as hereinbefore defined wherein W represents an ethylene 5 group.

Dehydrogenation may, for example be carried out in the presence of e.g. an oxidising agent such as 2,3-dichloro-5,6-dicyano-benzoquinone, chloranil or of a noble metal catalyst such as e.g. palladium/ charcoal. The dehydrogenation is preferably at elevated temperatures, e.g. at temperatures of from 100 to 200°C, most preferably at the boiling temperature of the reaction mixture.

G) for the preparation of compounds of general formula I wherein W represents an ethylene group and m is 0 or 2: Hydrogenation of a compound of formula I as hereinbefore defined wherein W represents a vinylene group and mis 0 or 2.

The hydrogenation is preferably carried out in the presence of a solvent such as ethanol, ethyl acetate, glacial acetic acid or dioxan. Hydrogenation may, for example, be effected e.g. with hydrogen in the presence of a catalyst such as e.g. palladium/ charcoal, platinum, Raney nickel, Raney cobalt or dirhenium heptasulfide, preferable at a hydrogen pressure of from 1 to 5 bar. Suitable temperatures for the hydrogenation are generally from 0 to 50°C, preferred temperatures being ambient temperatures. 189685 The compounds of general formulae II to VI, useful as starting materials are either known from the literature or they can be obtained according to known processes. For example a 6-, 7- or 8-hydroxy-3,4-dihydro-carbostyril 5 of formula II can be obtained by acylation of a corresponding aniline derivative with an appropriate p-halo-carboxylic acid derivative and subsequent cyclisation according to the method described by Friedel-Crafts (see J. chem. Soc. 1955, 743-744; Chem. Pharm. Bull. 1961, 10 970 - 975 and Ber. dtsch. Chem. Ges. 60, 858 (1927)). A 5-hydroxy-3,4-dihydrocarbostyril of formula II can be obtained by cyclisation of a corresponding 2-(p-cyanoethyl)-cyclohexane-1,3-dione derivative and subsequent aroma-tisation for example with N-bromo-succinimide (see Chem. 15 and Ind. 1970, 1435).

The preparation of the corresponding hydroxy-carbostyrils of general formula II is known from the literature (see for example J. Amer. chem. Soc. 7_2, 346 (1950) and ibid 2402 (1954) or J. Org. Chem. 33, 20 1089 (1968) and ibid _36, 3493 (1971)). Furthermore, the preparation of 5-hydroxyoxindole is described in J. chem. Soc. 1961, 2723.

The compounds of general formula IV useful as starting materials can be obtained by alkylation of a 25 corresponding hydroxy derivative.

As already mentioned above, the compounds of general fb rmula I possess interesting pharmacological activities. Those compounds which we have tested show not only a positive inotropic activity but also 30 antithrombotic activity. Such compounds are thus of use 189685 in the treatment of thrombo-embolic diseases such as e.g. coronary infarct, cerebral infarct, so-called transient ischaemic attacks and amaurosis fugax as well as for the treatment of arteriosclerosis. For example the following compounds were tested with regard to their biological properties: A = 6-(4-Phenylmercapto-butoxy)-3,4-dihydro- carbostyril, B = 6-(4-Phenylsulfinylbutoxy)-3,4-dihydro- carbostyril, C = 6-(4-Phenylsulfonylbutoxy)-3,4-dihydro- carbostyril, D = 6-[4-(2-Pyridylmercapto)-butoxy]-3,4- dihydrocarbostyril , E = 6-[4-(2-Pyridylsulfinyl)-butoxy]-3,4- dihydrocarbostyril, F = 6-[4-(2-Pyridylsulfonyl)-butoxy]-3,4- dihydrocarbostyril , G = 6-(2-Phenylsulfinyl-ethoxy)-3,4-dihydro- carbostyril, H = 6-(4-Benzylsulfinyl-butoxy)-3,4-dihydrocarbostyril, I = 6-[4-(4-Chlorophenylsulfinyl)-butoxy]-3,4- dihydrocarbostyril, K = 6-(4-Cyclohexylsulfinyl~butoxy)-3,4- dihydrocarbostyril , L = 6-[4-(2-Naphthylsulfinyl)-butoxy]-3,4- dihydrocarbostyril, M = 6-[4-(2-Methoxyphenylsulfinyl)-butoxy]-3,4- dihydrocarbostyril, N = 6-(4-Phenylsulfinyl-butoxy)-carbostyril, 1 8968 0 = 6-[4-(4-Hydroxy-3,5-di-tert.-butyl-phenyl- sulfinyl)-butoxy]carbostyril, P = 6-[4-(3,4-Dichlorophenylsulfinyl)-butoxy]-carbostyril, Q = 4-Methyl-6-(4-phenylsulfinyl-butoxy)- carbostyril, R = 6-[4-(3,4-Dichlorophenylsulfonyl)-butoxy]- 3,4-dihydrocarbostyril, S = 6-[4-(2,5-Dichlorophenylsulfinyl)-butoxy]-10 3,4-dihydrocarbostyril, T = 6-[4-(Pyrid-2-yl-sulfonyl)-butoxy]carbostyril and U = 6-[4-(3,4-Dichlorophenylsulfinyl)-butoxy]- 3,4-dihydrocarbostyril. 1. Determination of the thrombocyte aggregation 15 according to the method of Born and Cross (J. Physiol. 170, 397 (1964)): ' The thrombocyte aggregation was measured in the platelet-rich plasma of healthy human donors. The decrease in optical density was measured and recorded 20 photometrically after the addition of adenosine diphosphate or collagen. From the angle of inclination of the density curve, the velocity of aggregation was estimated (Vmax). The optical density was taken as the point on the curve where the most light was 25 transmitted (O.D.).

Small doses of collagen were chosen, but sufficient to give irreversible aggregation. To provoke maximum aggregation, about 0.01 ml of the collagen solution was added to 1 ml of platelet-rich plasma. (Commercial 30 collagen of Messrs. Hormonchemic, Munich). The adenosine 189685 diphosphate (ADP) doses were chosen to give only the first phase of the BORN curve. The necessary amount of ADP was about 1.10 mol/1. Commercial ADP of Messrs. Boehringer Mannheim was used.

The dosage of the test compounds which provoked a 50% inhibition of the thrombocyte aggregation was determined graphically (ED^) -6 Compound ED^Q 10 mol/1 Collagen ADP A 50 > 100 B 4 20 C 5 15 D 45 >100 E 6.5 25 F 20 20 G 3.5 17 H 2.5 14 I 4 10 K 4.5 12 L 1 10 M 4 22 N 0.6 3 0 0.2 0.5 P 0.2 1.8 Q 3.6 40 R 1.5 25 S 1.0 10 T 0.1 6 U 4 15 18 9 685 2. Determination of the prolongation of bleeding time; Preliminary remark: The human organism as well as other warmblooded animals have an ingenious mechanism, which 5 protects them from blood loss in case of injury.

This system consists of blood platelets (thrombocytes), which quickly seal the injured vessels by means of their adhesiveness (primary hemistasis). Beside this cellular hemostatic mechanism, the body has a blood 10 coagulation system. In this system plasma factors (proteins) are activated whereby plasma fibrinogen is converted to a fibrin coagulum. The system of primary hemostasis, mainly due to thrombocytes, and the coagulation system complement each other, both 15 having the aim of protecting the body effectively from blood loss.

With some diseases it is found that coagulation and thrombocyte aggregation take place also in intact blood vessels. The influence on the coagulation 20 system of cumarine and heparine is known and can easily be measured by coagulation loss, the coagulation time being prolonged under the influence of these substances. (Plasma-rrecalcif. time, Quick-Test -Thrombin time, etc.).

The normality of the thrombocytes can be determined by measuring the bleeding time. The normal bleeding time in human beings is in the range of 1 to 3 minutes and requires intact thrombocytes in a sufficient number. If the number of thrombocytes is normal and the 30 bleeding time is prolonged this signifies an abnormality 189685 in the thrombocytes. This is found in some inborn errors of thrombocyte-function (v. Willebrand-disease for example). If, on the other hand it is desired to prevent spontaneous aggregation of the thrombocytes 5 and occlusion in the arterial system by antiplateled drugs, the bleeding time should be prolonged as a consequence. Therefore, using antiplateled substances, a prolongation of the bleeding time is expected. If the plasma coagulation system is not influenced by 10 such a substance, coagulation tests will give a normal result.

Literature: W.D. Keidel: KurzgefasstesLehrbuch der Physiologie, Georg Thieme Verlag Stuttgart 1967, page 31: the proceeding of hemostasis. 15 To measure the bleeding time 10 mg/kg of the test compound is administered orally to conscious mice. After 1 hour 0.5 mm of the tip of the tail of the mouse is cut off and the droplets of blood are gently removed with filter paper every 30 seconds. 29 The number of drops of blood give a measure of the bleeding time (5 animals/experiment).

The values in the following table represent the prolongation in % as compared to a control group: - 20 " 18 96 8 5 Compound Prolongation of the Heeding time in 7o after one hour A 145 B 102 C 26 D 76 E 152 F 91 G H 29 I > 300 K 12 L M 27 0 73 P 12 Q 39 R T U 33 3. Determination of the positive inotropic activity Rats were narcotized with ether and subsequently killed by a blow behind the neck. After opening the thorax the heart was removed and both auricles were isolated. The auricles were placed into an organ bath of 100 ml. The bath had been filled with a tyrode solution at a temperature of 30°C. The tyrode solution 189685 was infused with carbogen (95% of 0^ and 5% of CO^). The spontaneous contractions of the auricles were registered isometrically. The auricles were charged with 1 g. The test compounds were tested on 4 auricles 5 each in a concentration of 1 x 10 g/ml. The variation in the contraction force was registered in % from the starting values.

The following table give the results obtained.

Compound Increase in contraction force in % B 30 C 35 E 16 F 18 I 52 L 63 M 65 Q 58 S 83 T 82 4. Acute toxicity: The acute toxicity of the test compounds was determined in groups of 10 mice each after oral administration of a single dose of 1 000 mg/kg (observation time: 14 days). 18 96 Compound acute toxicity per os A >1 000 mg/kg (0 out of animals died) B >1 000 mg/kg (0 out of animals died) C >1 000 mg/kg (0 out of animals died) D >1 000 mg/kg (0 out of animals died) E >1 000 mg/kg (0 out of animals died) F 000 mg/kg (0 out of animals died) G >1 000 mg/kg (0 out of an ".maIs died) H >1 000 mg/kg (0 out of animals died) I ^1 000 mg/kg (0 out of animals died) K >1 000 mg/kg (0 out of animals died) L 000 mg/kg (0 out of animals died) M 7l 000 mg/kg (0 out of animals died) P 71 000 mg/kg (0 out of animals died) Q >1 000 mg/kg (0 out of animals died) R >1 000 mg/kg (0 out of animals died) S >1 000 mg/kg (0 out of animals died) U >1 000 mg/kg (0 out of animals died) According to a yet further feature of the present invention there are provided pharmaceutical compositions comprising, as active ingredient, at least one compound of formula I as hereinbefore defined in association with a pharmaceutical carrier or excipient.

For pharmaceutical administration the compounds of general formula I may be incorporated into the conventional pharmaceutical preparations in either solid or liquid form, optionally in combination with other active ingredients. The compositions may, for 1 example, be presented in a form suitable for oral, rectal or parenteral administration. Preferred forms include, for example, plain tablets, coated tablets, capsules, suppositories, suspensions and solutions e.g. for injection.

The active ingredient may be incorporated in excipients customarily employed in pharmaceutical compositions such as, for example, talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, 10 aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents and/or preservatives.

Advantageously the compositions may be formulated 15 as dosage units, each unit being adapted to supply a fixed dose of active ingredient. Suitable dosage units for adults contain preferably from 50 to 100 mg of active ingredient. The oral daily dosage, which may be varied according to the compound used, the subject 20 treated and the complaint concerned, may, for example, be from 100 to 300 mg per day in adults.

■ According to a still further feature of the invention there is provided a method of treating animaj^-^iticluding humans, suffering from or susceptjJ>ie^£o thromboembolic 25 diseases and/or arterij^&eierosis which comprises administering-^othe said animal an effective amount of ar-^ompoimd of formula I as hereinbefore defined* The following non-limiting Examples serve to illustrate the present invention. 1 8 9 6 8 Example 1 6-/5-(2-Pvridvlmercapto)-butoxv7-3.4-dlhydrocarbostvril 14.4 g (0.13 mol) of 2-mercaptopyridine and 17.9 g (0.13 mol) of potassium carbonate were stirred in 360 ml of dimethyl-sulfoxide, dried over a molecular sieve, and 36 g (0.12 mol) of 6-(4-bromobutoxy)-3,4-dihydrocarbostyril (m.p.: 142 - 147°C, prepared from 6-hydroxy-carbostyril and 1,4-dibromobutane) were added to this mixture. After stirring for 15 hours at approx. 25°C, the reaction mixture was poured into 3.6 1 of water and again stirred for 30 minutes. The precipitated product was suction filtered, well washed with water, dried and recrystalli-zed from xylene by addition of charcoal. Yellow crystals of m.p. 123 - 124.5°C were obtained.

Yield: 32 g (81.2 % of theory).

Example 2 6- P\-(2-Pvridylsulflnyl)-butoxv7-3.4-dihvdrocarbostvrll 32.8 g (0.1 mol) of (2-pyridylmercapto)-butox^;7-3,4-di- hydrocarbostyril were dissolved in 330 ml of glacial acetic acid and 10.2 g (0.105 mol) of 35 % hydrogen peroxide were added. The solution was stirred for 15 hours at approx. 20°C. The glacial acetic acid was distilled off at 60°C in vacuo, the residue was washed with ether and the thus obtained crude product was recrystallized twice from xylene by addition of charcoal. Colourless crystals of m.p. 144.5 - 146°C were obtained.

Yield: 27.5 g (79.8 % of theory). 189685 Example 3 6-/5-(2-Pyrldylsulfonvl)-butoxv7-3#4-dlhydrocarbostyrll g (0.015 mol) of 6-/2+-(2-pyridylmercapto)-butoxj7-3,4-di-hydrocarbostyril were dissolved in 50 ml of glacial acetic acid and 4.5 g (0.045 mol) of 35 % hydrogen peroxide were added. After stirring for 40 hours at approx. 25°C, the glacial acetic acid was distilled off at 60°C in vacuo. The solid residue was washed with ether and recrystallized from xylene by addition of charcoal. Colourless crystals of m.p. 123.8 - 125°C were obtained.

Yield: 3.8 g (70.3 % of theory).

Example 4 6-(4-Phenylsulfinylbutoxv)-3.4-dlhvdrocarbostyrll 32.6 g (0.2 mol) of 6-hydroxy-3,4-dihydrocarbostyril (see F. F. Mayer et al. in Ber. dtsch. chem. Ges. 60, 858 (1927)) and 27.6 g (0.2 mol) of potassium carbonate were stirred for 5 minutes in 600 ml of dimethylsulfoxide, dried over a molecular sieve,and subsequently 52.2 g 9f 4-phenylsulfinylbutyiy , « - iophenoi • bromide (0.2 mol) (prepared from /bhiophenolft and 1,4-dibromo-butane and subsequent oxidation with hydrogen peroxide in glacial acetic acid analogously to example 2; oily substance, solidified whilst standing in the refrigerator) were added. After stirring for 15 hours at 25°C the reaction mixture was poured into 6 1 of water. After stirring for further 30 minutes the precipitated product was suction filtered and well washed with water. After drying the residue was recrystallized from 600 ml (approx.) of xylene by addition of charcoal. White crystals of m.p. 144.5 - 145.5°C were obtained.

Yield: 49 g (71.3 # of theory). 19 NQV1980 189685 Example 5 6- (4-Phenylmercapto-butoxv)-3. 4-dihydro-carbostvril Prepared analogously to Example 4 from 6-hydroxy-3,4-di- . bu.tul f btwYn cle, hydro-carbostyril and 4- (phenylmercapto)-piityJbromido (b.p. q Q2 ; 96 - 103°C, prepared from thiophenol and 1.4-dibromobutane).

M.p.: 121.5 - 123°C Yield: 75.6 % of theory.

Example 6 6-(4-Phenylsulfonyl-butoxv)-3.4-dihydrocarbostyril Prepared analogously to Example 4 from 6-hydroxy-3^4-di-hydro-carbo#tyril and 4-phenyl-sulfonyl-b^ylbrom^do (prepared from 4-(phenylmercapto)-butylbromide by oxidation analogously to Example 3).

M.p.: 157.5 - 158°C Yield: 65.1 % of theory.

Example 7 6-/?-(4-Fluorophenylmercapto)-butoxv7-5,4-dihydrocarbostyril Prepared analogously to Example 1 from 6-(4-bromobutoxy)-3,4-dihydrocarbostyril (m.p.: 142 - 147°C) and 4-fluoro-thiophenol .

M.p.: 139 - 140°C Yield: 93.1 % of theory. | 19 NOV 1980 f 89685 Example 8 6-/5- (4-Fluorophenvlsulflnyl)-butoxv7-3.4-dlhvdrocarbostyril Prepared analogously to Example 2 from 6-/5-(4-fluorophenyl-mercapto)-butoxj^-3,4-dihydrocarbostyril.

M.p.; 184.5 - 186°C Yield: 88 % of theory.

Example 9 6-/5-(4-Methylphenyl-mercapto)-butoxy7-3,4-dlhydrocarbostyrll Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-3,4-dihydrocarbostyril (m.p. 147 - 148°C) and 4-methylthio-phenol .

M.p.: 120 - 121°C Yield: 91 % of theory.

Example 10 6-/5-(4-Methylphenyl-sulfinvl)-butoxy7-3.4-dihydrocarbo styri1 Prepared analogously to Example 2 from 6-/5-(4-methylphenyl-mercapto)-but0x^7-3,4-dihydrocarbostyril and hydrogen peroxide.

M.p.: 149.5 - 150°C Yield: 97 % of theory.

Example 11 6-/5-(3-Methvlphenvlmercapto)-butoxv7-3.4-dihydrocarbostvrll Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-3,4-dihydrocarbostyril (m.p. 147 - 148°C) and 3-methylthiophenol . 1 8968 M.p.: 95 - 96°C Yield: 91 # of theory.

Example 12 6- /5- (3-Methvlphenvlsulfinvl)-butoxv7-3.4-dlhvdrocarbostvril Prepared analogously to Example 2 from 6-/5-(3-methylphenyl-mercapto)-butox2;7-3,4-dihydrocarbostyril and hydrogen peroxide. Wax-like resin.

Yield: 95 % of theory.

R^-value: 0.48 (thin-layer chromatogram on silica gel -eluent: benzene/ethanol/conc. ammonia = 75/25/1).

Example 13 6-/5-(4-Chlorophenvlmercapto)-butoxv7-3.4-dihvdrocarbostvrll Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-3,4-di hydrocarbostyril (m.p. 147 - 148°C) and 4-chlorothiophenol . M.p.: 144 - 146°C Yield: 88 % of theory.

Example 14 6-/5-(4-Chlorophenvlsulfinvl)-butoxv7-3.4-dihvdrocarbostvril Prepared analogously to Example 2 from 6-/5-(4-chlorophenyl-mercapto)-butox^7-3,4-dihydrocarbostyril and hydrogen peroxide.

M.p.: 148 - 149.5°C Yield: 70 % of theory. 189685 Example 15 6-/5-(3.4-Dlchlorophenvlmercapto)-butoxv7-3.4-dihvdrocarbostvrll Prepared analogously to Example 1 from 6-(4-chlorobutoxy)- 3,4-dihydrocarbostyril (m.p. 147 - 148°C) and 3,4-dichloro- thiophenol .

M.p.: 116.5 - 118°C Yields 87 % of theory.

Example 16 6-/5-(3.4-Dlchlorophenvlsulfinvl)-butoxv7-3.4-dihvdrocarbostvrll Prepared analogously to Example 2 from 6-/5-(3,4-dichlorophenyl-mercapto)-butoxx7-3,4-dihydrocarbostyril and hydrogen peroxide. M.p.: 106.5 - 108°C Yield: 74 % of theory.

Example 17 6-/5-(2-Methoxvphenvlmercapto)-butoxv7-3.4-dihvdrocarbostyril Prepared analogously to Example 1 from 6-(4-bromobutoxy)-3,4-dihydrocarbostyril (m.p. 142 - 147°C) and 2-methoxythio-phenol .

M.p.: 130.5 - 133°C Yield: 74 96 of theory.

Example 18 6-/5-(2-Methoxyphenylsulfinvl)-butoxv7-3.4-dlhvdrocarbostvril Prepared analogously to Example 2 from 6-/5-(2-methoxyphenyl-mercapto)-butox2,7-3,4-dihydrocarbostyril and hydrogen peroxide. 189685 M.p.: 162 - 163°C Yield: 62 % of theory.

Example 19 6-/5-(3-MethoxYphenvlmercapto)-butoxy7-3.4-dlhvdrocarbostyril Prepared analogously to Example 1 from 6-(4-bromobutoxy)- 3,4-dihydrocarbostyril (m.p. 142 - 147°C) and 3-methoxy- thiophenol.

M.p.: 93.5 - 97°C Yield: 61 % of theory.

Example 20 6-/5-(3-Methoxyphenylsulflnyl)-butoxv7-3.4-dihydrocarbostyril Prepared analogously to Example 2 from 6-/5-(3-methoxyphenyl-mercapto)-but03^7-3,4-dihydrocarbostyril and hydrogen peroxide. M.p.: 147 - 148°C , Yield: 49 % of theory. ; Example 21 | 6-/5-(4-Methoxyphenvlmercapto)-butoxv7-3.4-dihydrocarbo styril Prepared analogously to Example 1 from 6-(4-bromobutoxy)- 3,4-dihydrocarbostyril (m.p. 142 - 147°C) and 4-methoxy- thiophenol.

M.p.: 130.5 - 133°C Yield: 82 % of theory. 18 9 6 8 5 Example 22 i 6-/5- (4-MethoxyphenvlsulfInvl)-butoxv7-3.4-dlhydrocarbostvrll Prepared analogously to Example 2 from 6-/5-(4-methoxyphenyl-mercapto)-buto3Cj7-3,4-dihydrocarbostyril and hydrogen peroxide.

M.p.: 132 - 133°C Yields 71 % of theory.

Example 23 6-/5- (3.4-Dlmethoxyphenvlmercapto)-butoxv7-3.4-dlhvdrocarbostvril Prepared analogously to Example 1 from 3,4-dimethoxythiophenol and 6-(4-chlorobutoxy)-3,4-dihydrocarbostyril /prepared from 6-hydroxy-carbostyril (see F. Mayer et al. in Ber. dtsch. chem. Ges. 60, 858 (1927) and 4-chlorobutyl benzenesulfonate7.

M.p.: 117 - 119°C Yields 73 % of theory.

Example 24 6-/5-(3,4-Dimethoxyphenylsulfinyl)-butox^7-3,4-dihydrocarbo-stvrll ___ Prepared analogously to Example 2 from 6-/5-(3,4-dimethoxy- phenylmercapto)-butox2;7-3»4-dihydrocarbostyril and hydrogen peroxide.

M.p.: 145 - 147°C Yield: 79 % of theory. 1 8968 Example 25 6-/5-(3,4-Dimethoxyphenylsulfonyl)-butoxj/ -3,4-dihydro-carbostvrll Prepared analogously to Example 3 from 6-/5-(3,4-dimethoxy- phenylmercapto)-butox£7-3,4-dihydrocarbostyril and hydrogen peroxide.

M.p.: 158 - 160°C Yield: 62 % of theory.

Example 26 6-/5-(4-Blphenylvlmercapto)-butoxy7-3.4-dihydrocarbostyril Prepared analogously to Example 1 from 4-phenylthiophenol and 6-(4-bromobutoxy)-3,4-dihydrocarbostyril.

M.p.: 179.5 - 181°C Yield: 74 % of theory.

Example 27 6-/5-(4-Biphenylvlsulflnvl)-butoxy7-3,4-dihydrocarbostyril Prepared analogously to Example 2 from 6-/5-(4-biphenylylmercap to)-butox2,7-3,4-dihydrocarbostyril and hydrogen peroxide. M.p.: 192 - 192.5°C.

Yield: 86 % of theory.

Example 28 6-/5-(2-Naphthvlmercapto)-butoxv7-3.4-dlhydrocarbostyril Prepared analogously to Example 1 from 2-naphthylmercaptane and 6-(4-bromobutoxy)-3,4-dihydrocarbostyril.

M.p.: 108.5 - 109.5°C Yield: 48 % of theory.

J~ 189685 Example 29 6-/5-(2-NaphthylsulfInvl)-butoxv7-3.4-dlhydrocarbostyrll Prepared analogously to Example 2 from 6-/5-(2-naphthylmer-capto)-butox£7-3,4-dihydrocarbostyril and hydrogen peroxide. M.p.: 147.5 - 148.5°C Yield: 57 % of theory.

Example 30 6-/5-(2-Pyridylsulfinyl)-pentoxv7-3,4-dihydrocarbostyril Prepared analogously to Example 2 from 6-/5-(2-pyridylmercap-to)-pentoxx7-3,4-dihydrocarbostyril and hydrogen peroxide. M.p.: 116 - 118°C Yield: 69 # of theory.

Example 31 6-(2-Methylsulfinylethoxy)-3»4-dihydrocarbostyril 1.42 g (0.006 mol) of 6-(2-methylmercaptoethoxy)-3,4-dihydro-carbostyril were suspended in 12 ml of methanol and a solution of 1.71 g (0.008 mol) of sodium metaperiodate in 8 ml of water was added. The reaction mixture was stirred for »-5" hours, whereby at the beginning a clear heating of the reaction mixture could be observed. Subsequently the mixture was diluted with little water and exhaustively extracted with chloroform. The evaporation residue was recrystallized from ethyl acetate by addition of little ethanol. M.p.: 129 - 131.5°C Yield: 70 % of theory. | ,19 NOV 1980 -3- 1 8 9685 Example 32 6-/5-(2-Pvrldylsulfonvl)-pentoxv7-3.4-dihvdrocarbostyril Prepared analogously to Example 3 from 6-/5-(2-pyrldylmercapto)-pentoxx7-3.4-dihydrocarbostyril and hydrogen peroxide.

M.p.: 113.5 - 115.0°C Yield: 71 96 of theory.

Example 33 6-(4-Methylsulflnylbutoxy)-3t4-dihydrocarbostvril Prepared analogously to Example 2 from 6-(4-methylmercapto-butoxy)-3,4-dihydrocarbostyril and hydrogen peroxide. M.p.: 128.5 - 130.5°C Yield: 58 % of theory, Example 34 7-(4-Phenylsulfonyl-butoxy)-carbostyril Prepared analogously to Example 3 from 7-(4-phenylmercapto-butoxy)-carbostyril and hydrogen peroxide.

M.p.: 199 - 201°C Yield: 85 % of theory.

Example 35 6-(4-Cvclohexvlmercaptobutoxv)-3.4-dihydrocarbostyril Prepared analogously to Example 1 from cyclohexylmercaptane and 6-(4-chlorobutoxy)-3,4-dihydrocarbostyril (m.p.: 147 -148°C).

M.p.: 114 - 115°C Yield: 80 % of theory. 189685 Example 36 6-(4-Cvclohexvlsulflnvl-butoxv)-3.4-dlhydrocarbostyrll Prepared analogously to Example 2 from 6-(4-cyclohexylmercap to-butoxy)-3,4-dihydrocarbostyril and hydrogen peroxide. M.p.: 153 - 155.5°C Yield: 63 96 of theory.

Example 37 6-(4-Benzylmercapto-butoxv)-3.4-dihydrocarbostyril Prepared analogously to Example 1 from benzylmercaptane and 6-(4-chlorobutoxy)-3»4-dihydrocarbostyril.

M.p.: 77.5 - 78.5°C Yield: 90 96 of theory.

Example 38 6-(4-Benzylsulfinyl-butoxy)-314-dihydrocarbostyril Prepared analogously to Example 2 from 6-(4-benzylmercapto-butoxy )-3, 4-dihydrocarbostyril and hydrogen peroxide. M.p.: 141.5 - 142°C Yield: 95 96 of theory.

Example 39 6-/?-(2-Furylmethylmercapto)-butoxy7-3.4-dihydrocarbostyrll Prepared analogously to Example 1 from 2-furfurylmercaptane and 6-(4-bromobutoxy)-3»4-dihydrocarbostyril (m.p.: 142 - 147°C). M.p.: 79 - 80°C Yield: 64 96 of theory. 189685 Example 40 6- fi\-C2-FurvlmethvlsulfInvl)-butoxv7-3.4-dihvdrocarbostvril Prepared analogously to Example 2 from 6-/5-(2-furylmethyl-mercapto)-butoxj7-3,4-dihydrocarbostyril and hydrogen peroxide.

M.p.: 135 - 136°C Yield: 60 % of theory.

Example 41 6-/5-(N-0xldo-2-pvrldvlmercapto)-butoxv7-3.4-dihvdrocarbostvril Prepared analogously to Example 1 from 6-(4-bromobutoxy)-3,4-di hydrocarbostyril and 2-mercaptopyridine-N-oxide.

M.p.: 179.5 - 181°C Yield: 65 % of theory.

Example 42 6-/5-(2-Pvrimidvl-mercapto)-butoxv7-3.4-dlhvdrocarbostvril Prepared analogously to Example 1 from 6-(4-chlorobutoxy)- 3,4-dihydrocarbostyril (m.p.: 147 - 148°C) and 2-mercapto- pyrimidine.

M.p.: 154 - 156°C Yield: 79 % of theory. 189685 Example 43 6-/5- (2-PyrlmidvlsulfInvl)-butoxv7-3.4-dlhydrocarbostyrll Prepared analogously to Example 2 from 6-/5-(2-pyrimidyl- mercapto)-butox27-3,4-dihydrocarbostyril and hydrogen peroxide.

M.p.: 154 - 156°C Yield: 36 % of theory.

Example 44 6-/5- (4-Pyrldvlmercapto)-butoxv7-3.4-dlhvdrocarbostyril To a solution of 1.3 g of 4-mercaptopyridine, 2.3 g of 30 sodium methoxide solution and of 15 ml of methanol, 3.0 g of 6-(4-bromobutoxy)-3,4-dihydrocarbostyril were added and stirred for 14 hours at room temperature. Subsequently the solution was diluted with 20 ml of water and the obtained precipitate was recrystallized from ethanol.

M.p. : 128 - 129°C Yield: 1.6 g (49 96 of theory).

Example 45 6-/5-(2-Benzimidazolylmercapto)-butoxv7-3i4-dihydrocarbostvril Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-3,4-dihydrocarbostyril (m.p.: 147 - 148°C) and 2-mercapto-benzimidazole.

M.p.: 100 - 103°C Yield: 45 % of theory. 18 96 8 5 Example 46 6-/7- (2-Benzlmidazolvlsulfinyl)-butoxv7-3.4-dlhydrocarbostyrll Prepared analogously to Example 2 from 6-/7-(2-benzimidazolyl-mercapto)-butox2;7-3,4-dihydrocarbostyril and hydrogen peroxide. M.p.: 180 - 182°C Yield: 36 % of theory.

Example 47 6-/7-(2-Benzthlazolvl-mercapto)-butoxv7-3.4-dihydrocarbostyril Prepared analogously to Example 1 from 6-(4-chlorobutoxy)- 3,4-dihydrocarbostyril (m.p.: 147 - 148°C) and 2-mercapto- benzthiazole.

M.p. : 157 - 158°C Yield: 70 % of theory.

Example 48 6-/7-(2-Benzthiazolvlsulfinvl)-butoxv7-3,4-dihydrocarbostvr11 Prepared analogously to Example 2 from 6-/7-(2-benzthiazolyl-mercapto)-butoxj;7-3,4-dihydrocarbostyril and hydrogen peroxide. M.p.: 183 -•184°C Yield: 69 % of theory.

Example 49 6-(2-Phenvlmercapto-ethoxv)-3«4-dlhvdrocarbostyril Prepared analogously to Example 1 from thiophenol and 6-(2-chloroethoxy)-3,4-dihydrocarbostyril (m.p.: 152.5 to 153.5°C).

M.p.: 132 - 133.5°C Yield: 91 % of theory. 189685 Example 50 6-(2-Phenvlsulflnvl-ethoxv)-3.4-dihydrocarbostyril Prepared analogously to Example 2 from 6-(2-phenylmercapto-ethoxy)-3,4-dihydrocarbostyril and hydrogen peroxide. M.p.: 171 - 172°C Yield: 84 % of theory.

Example 51 6-(2-Phenylsulfonyl-ethoxy)-3.4-dihydrocarbostyril Prepared analogously to Example 3 from 6-(2-phenylmercapto-ethoxy)-3,4-dihydrocarbostyril and hydrogen peroxide. M.p.: 185 - 186°C Yield: 94 % of theory.

Example 52 6-(3-Phenylmercapto-propoxy)-3.4-dihydrocarbostyril Prepared analogously to Example 1 from 6-(3-bromopropoxy)-3,4-dihydrocarbostyril (m.p.: 111 - 118°C) and thiophenol . M.p.: 111 - 112°C Yield: 77 % of /fe 1^19 NOV 1980 - -4 0 ~ 189685 Example 55 6-(3-Phenvlsulfinvl-propoxv)-5.4-dihvdrocarbostvrll Prepared analogously to Example 2 from 6-/5-(phenylmercapto)- propox£7-3»4-dihydrocarbostyril and hydrogen peroxide. M.p.: 131.5 - 133.5°C Yield: 67 % of theory.

Example 54 1-Methvl-6-(4-phenvlmercapto-butoxv)-3.4-dlhvdrocarbostvril 16.2 g of 6-(4-phenylmercapto-butoxy)-3,4-dihydrocarbostyril were dissolved in 100 ml of dimethylformamide and 4.8 g of a 50 % sodium hydride suspension in paraffin oil were added to this solution. After addition of 12.5 ml of methyl iodide the mixture was stirred for 3 hours at room temperature, diluted with water and extracted with chloroform. The evaporation residue was recrystallized from methanol under addition of activated charcoal.

M.p.: 79.5 - 80.5°C Yield: 71 % of theory.

Example 55 1-Methyl-6-(4-phenvlsulfinyl-butoxv)-3,4-dihydrocarbostyril Prepared analogously to Example 2 from 1-methyl-6-^-phenyl-mercapto-butoxy)^ >4-dihydrocarbostyril and hydrogen peroxide.

M.p.: 82 - 82.5°C Yield: 60 % of theory. 1 8968 41 Example 56 1-Methvl-6-(4-phenvlsulfonvl-butoxy)-3«4-dihvdrocarbostyrll Prepared analogously to Example 3 from 1-methyl-6-(4-phenyl-mercapto-butoxy)-3,4-dihydrocarbostyril and hydrogen peroxide.

M.p. : 108 - 109°C Yield: 49 % of theory.

Example 57 6-(6-Fhenylmercapto-hexoxv)-3.4-dlhydrocarbostvrll Prepared analogously to Example 1 from 6-(6-bromohexoxy)-3,4-dihydrocarbostyril (m.p.: 107.5 - 108°C) and thiophenol. M.p. : 112.5 - 113°C Yield: 34 % of theory.

Example 58 6-(6-Phenylsulfinyl-hexoxv)-3.4-dihydrocarbostyril Prepared analogously to Example 2 from 6-(6-phenylmercapto-hexoxy)-3,4-dihydrocarbostyril and hydrogen peroxide. M.p. : 119.5 - 121.5°C Yield: 35 % of theory. 189685 Example 5Q 6-(2-Hvdroxv-3-phenvlmercapto-propoxy)-3«4-dlhvdrocarbostyril 4.11 g (0.04 mol) of thiophenol were added to a suspension of 2.10 g (0.03 mol) of potassium methoxide in 40 ml of methanol, whereby a clear solution was obtained. Then 4.38 g of 6-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril (m.p. 125 - 128°C) were added whilst stirring, whereby a clear solution was obtained under self-heating. After 5 minutes the separation of a white crystal slurry started. After standing over night the crystals were suction filtered and recrystallized from little methanol. White crystals of m.p. 148 - 149°C were obtained.

Yield: 73 % of theory.

Example 60 6-(2-Hvdroxy-3-phenylsulfinylpropoxy)-3.4-dihydrocarbostyril Prepared analogously to Example 2 from 6-(2-hydroxy-3-phenyl-mercaptopropoxy)-3,4-dihydrocarbostyril and hydrogen peroxide. M.p. : 185 - 187°C Yield: 51 % of theory.

Example 61 6-(2-Hydroxy-3-phenylsulfonyl-propoxy)-3.4-dihydrocarbostyril Prepared analogously to Example 3 from 6-(2-hydroxy-3-phenyl-mercaptopropoxy)-3,4-dihydrocarbostyril and hydrogen peroxide. M.p.: 170 - 172°C.

Yield: 54 % of theory. 189685 Example 62 7-(4-Phenylmercaptobutoxy)-3.4-dihydrocarbostyril Prepared analogously to Example 4 from 7-hydroxy-3,4-dihydrocarbostyril (N. Shigematsu et al. in Chem..Pharm. Bull. 1961, biM-u I broiYI , , 970 - 975) and 4-phenylmercapto-|butylbrom±da (bp.Q ©2 : 96 to 103°C).

M.p.: 121 - 123°C Yield: 72 % of theory.

Example 63 7- (4-Phenyl sulf inyl-butoxy)-3.4-dlhydrocarbostyrll Prepared analogously to Example 4 from 7-hydroxy-3,4-dihydrocarbostyril (N. Shigematsu et al. in Chem. Pharm. Bull. 1961, . , 4-~ L . , bromide 970 - 975) and ft phenylculxinylbputyljbromid^.

M.p.: 134 - 136°C Yield: 80 % of theory.

Example 64 7-(4-Phenylsulfonyl-butoxy)-3,4-dihydrocarbostyril Prepared analogously to Example 4 from 7-hydroxy-3,4-dihydroc; bostyril (N. Shigematsu et al. in Chem. Pharm. Bull. 1961 , 970 - 975) and 4-phenylsulfonylbutylbromide.

M.p.: 178.5 - 179.5°C Yield: 74 % of theory. f 19 NOV 1980 1 1 8968 Example 65 8-(4-Phenylmercaptobutoxy)-3,4-dlhydrocarbostyrll Prepared analogously to Example 4 from 8-hydroxy-3,4-dihydrocarbostyril (J. D. Loudon et al. in J. Chem.. Soc. bu-twt br&m tele. 1955. 743 - 744) and 4-phenylmercapto-/mtyrbromida (hp.Q 02: 96 - 103°C).

M.p.: 101 - 102°C Yield: 75 % of theory.

Example 66 8-(4-Phenylsulfinyl-butoxy)-3.4-dihydrocarbostyril Prepared analogously to Example 4 from 8-hydroxy-3,4-dihydrocarbostyril (J. D. Loudon et al. in J. Chem. Soc. 1955» , , . phenuls,isUJtsivtl bectui br&vni'cls. 743 - 744) and iphciiy 11> ulf iiiy lbutylbiumidtf.

Colourless resin was obtained.

Yield: 60 % of theqry. -tftLn la.tjQ.f* Rf-value: 0.60 (thinlayor chromatogram on silica gel -eluent: benzene/ethanol/conc. ammonia « 75/25/1).

Example 67 8-(4-Phenylsulfonyl-butoxv)-3.4-dihydrocarbostyril Prepared analogously to Example 3 from 8-(4-phenylmercapto-butoxy)-3,4-dihydrocarbostyril and hydrogen peroxide. M.p.: 114.5 - 115°C Yield: 60 % of theory. 19 NOV 1980 P5CSVED 189685 Example 68 6-/5-(2-Benzthiazolvl-sulfonvl)-butoxv7-3.4-dihvdrocarbostyrll Prepared analogously to Example 2 from 6- Z5- (2-benzthiazolyl-mercapto)-butoxx7-3»4-dihydrocarbostyril and hydrogen peroxide. M.p.: 146 - 149°C Yield: 61 % of theory.

Example 69 6-/5-(2-Quinolylmercapto)-butoxv7-3.4-dlhvdrocarbostyrll Prepared analogously to Example 1 from 6-(4-bromobutoxy)- 3,4-dihydrocarbostyril (m.p. 142 - 147°C) and 2-mercapto- quinoline.

M.p.: 115°C Yield: 64 % of theory.

Example 70 6-/5- (2-Quinazoline-4-one-yl-mercapto)-butox^7~3,4-dihydrocar-bostyril Prepared analogously to Example 1 from 6-(4-bromobutoxy)-3,4-di-hydrocarbostyril (m.p.: 142 - 147°C) and 2-mercaptoquinazoline-4-one.

M.p.: 184.5 - 188°C Yieldj 63 % of theory. 189685 Example 71 6-(4-Trlphenylmethylmercapto-butoxy)-3.4-dihydrocarbostyril Prepared analogously to Example 1 from 6-(4-bromobutoxy)-3,4-dihydrocarbostyril (m.p.: 142 - 147°C) and triphenyl-methylmercaptane.

M.p.: 169 i 170°C Yield: 89 % of theory.

Example 72 6-/?-(2-Naphthylmercapto)-ethoxv7-5.4-dlhvdrocarbostvril chloroe.t^nocc-ci Prepared analogously to Example 1 from 6-(4-fthlorobutoxy)-3,4-dihydrocarbostyril (m.p.: 147 - 148°C) and 2-naphthylmercaptane.

M.p.: 147.5 - 147.8°C Yield: 77 % of theory.

Example 73 6-/2-(2-Naphthylsulfinvl)-ethoxv7-3.4-dlhydrocarbostyril Prepared analogously to Example 2 from 6-/2-(2-naphthylmercapto) ethox^7-3,4-dihydrocarbostyril and hydrogen peroxide.

M.p.: 186.5 - 187.5°C Yield: 88 % of theory.

Example 74 V ^9 1980 6-/2- (4-Biphenvlylmercapto)-ethoxv7-3.4-dihvdrocarb6styri»3p Prepared analogously to Example 1 from 6-(2-chloroethoxy)-3,4-dihydrocarbostyril (m.p.: 152.5 - 153.5°C) and 4-mer- 189685 captobiphenyl. M.p.: 192 - 194°C Yield: 92 % of theory.

Example 75 6-/?-(4-Biphenylyl-sulfinyl)-ethoxv7-3.4-dlhydrocarbostyril Prepared analogously to Example 2 from 6-/2-(4-biphenylylmercap-to)-ethox^7-3,4-dihydrocarbostyril and hydrogen peroxide. M.p.: 195 - 196°C Yield: 66 % of theory.

Example 76 6- H>-(2-Pyridylmercapto)-propoxy7-3.4-dlhydrocarbostyrll Prepared analogously to Example 1 from 6-(3-bromopropoxy)-3,4-dihydrocarbostyril and 2-mercaptopyridine.

M.p.: 108 - 108.5°C Yield: 42 % of theory.

Example 77 6-(4-Phenylsulfinvl-butoxv)-3.4-dihydrocarbostyril 1.6 g of 6-(4-phenylmercapto-butoxy)-3,4-dihydrocarbostyril were dissolved in 50 ml of methanol and 0.9 g of N-bromo-succininimide were added. After stirring for 15 hours at room temperature, the mixture was diluted with 500 ml of water (80°C) and decanted from the firstly oily residue, whereby after a while crystals were formed. After re-crystallization from xylene white crystals of m.p. 144 to 145°C were obtained.

Yield: 1.2 g (66 % of theory). 189685 Example 78 6-(4-Phenylsulfinyl-butoxy)-3.4-dihydrocarbostyril 3.3 g of 6-(4-phenylmercapto-butoxy)-3,4-dihydrocarbostyril were dissolved in 50 ml of methylene chloride, cooled to -70°C and a solution of 1.5 g of sulfuryl chloride in 5 ml dro puoi SQ_ of methylene chloride was added /iropwlooly. After 15 hours 20 ml of 95 % ethanol were added and the mixture was heated to room temperature by removing of the cooling bath, neutralized with aqueous sodium carbonate solution, the methylene chloride phase was dried with sodium sulfate and the solvent was removed. The residue was recrystallized from toluene. M.p.: 143 - 145°C Yield: 2.8 g (81 % of theory).

Example 79 -(4-Phenylmercapto-butoxy)-3,4-dlhydrocarbostyrll Prepared analogously to Example 4 from 5-hydroxy-3,4-dihydro-carbostyril and 4-phenylmercaptobutylbromide.

M.p.: 155 - 157°C Yield: 64 % of theory.

Example 80 - (4-Phenylsulfinyl-butoxy)-3.4-dihydro carbostyril Prepared analogously to Example 4 from 5-hydroxy-3,4-dihydro- l. - phenyls hr&m'tde. carbostyril and fr-phenylculiin^n.'butylbromido.

M.p.: 136 - 138°C Yield: 64 % of theory.

IxPATwromee iimmiWi'M T .119 NOV 1980 189685 Example 81 -(4-Phenylsulfonyl-butoxy)-3.4-dihydrocarbostyril Prepared analogously to Example 4 from 5-hydroxy-3»4-dihy- phen/s- (bustii I br&yYi /cL drocarbostyril and f*t phenylsulxonylbutylbromide.

M.p.: 187 - 189°C Yield: 73 % of theory.

Example 82 6-/7-(2-Naphthylsulfonyl)-butoxy7-3t 4-dlhydrocarbostyril Prepared analogously to Example 3 from 6-/7-(2-naphthylmer-capto)-butoxx7-3»4-dihydrocarbostyril and hydrogen peroxide. M.p.: 173 - 175°C Yield: 95 96 of theory.

Example 83 6-/7- (4-Blphenylylsulf onyl )-butoxy7-3t4-dlhydrocarbostyrll Prepared analogously to Example 3 from 6-/7-(4-biphenylyl-mercapto)-butox£7-3,4-dihydrocarbostyril and hydrogen peroxide.

M.p.: 232 - 234.5°C Yield: 83 96 of theory.

Example 84 6-(4-Phenylsulfonyl-butoxy)-3»4-dihydrocarbostyril Prepared analogously to Example 3 from 6-(4-phenylsulfinyl-butoxy )-3,4-dihydrocarbostyril and hydrogen peroxide.^ ^.JHWIIHIWIII ■" ' ■ - .I*—.-— J OVftOV1980 *• , 189685 M.p.: 157 - 158°C Yield: 88 % of theory.

Example 85 6-/7-(2-Pyridylsulfonyl)-butoxy7-3.4-dihydrocarbostyril Prepared analogously to Example 3 from 6-/7-(2-pyridylsulfi-nyl)-but0X^7-3,4-dihydrocarbostyril and hydrogen peroxide. M.p.: 123.8 - 125°C Yield: 76 % of theory.

Example 86 -(4-Phenylsulfonyl-butoxy)-carbostyril 1.87 g of 2,3-dichloro-5,6-dicyano/benzoquinone were added to 1.8 g of 5-(4-phenylsulfonyl-butoxy)-3,4-dihydrocarbo- dioi< styril, dissolved in 45 ml of Jflioxang . The solution was heated for 2.5 hours in an oil bath. The reaction mixture was hot filtered and the unsoluable residue, which was formed d to* a/i during the reaction, was washed out with hot ft-ioxane. The combined filtrates were diluted with 100 ml of chloroform and several times extracted with altogether 150 ml of 2N-sodium hydroxide. After drying the chloroform extracts with sodium sulfate and filtrating in the presence of activated charcoal the residue was evaporated and ethyl acetate was added until white crystals were precipitated.

M.p.: 182 - 183°C Yield: 850 mg (47 % of theory). immo _ 51 _ 189685 Example 87 -(4-Phenvlmercapto-butoxv)-carbostyril Prepared analogously to Example 86 from 5-(4-phenylmercapto- butoxy)-3,4-dihydrocarbostyril and 2,3-dichloro-5,6-dicyano- benzoquinone.

M.p.: 185 - 187°C Yield: 40 % of theory.

Example 88 -(4-Phenylsulfinyl-butoxy)-carbostyril 0.165 ml of 30 % hydrogen peroxide, dissolved in 8 ml of glacial acetic acid, were added to 0.56 g of 5-(4-phenyl-mercapto-butoxy)-carbostyril . The mixture was diluted with water and extracted with chloroform twice. The chloroform extract was washed with diluted sodium carbonate solution , with water, dried over magnesium sulfate and evaporated. The residue was mixed with ethyl acetate and colourless crystals of m.p. 155 - 157°C were obtained.

Yield: 389 mg (65 % of theory).

Example 89 6-(4-Phenylmercapto-butoxv)-carbostyril Prepared analogously to Example 86 from 6-(4-phenylmercapto- butoxy)-3,4-dihydrocarbostyril and 2,3-dichloro-4,5-dicyano- benzoquinone.

M.p.: 162 - 164°C Yield: 35 % of theory. 189685 Example 90 6-(4-Phenylsulfinyl-butoxy)-carbostyril Prepared analogously to Example 86 from 6-(4-phenylsulfinyl-butoxy)-3»4-dihydrocarbostyril and 2,3-dichloro-5»6-dicyano-benzoquinone. For purification the mixture was chromatographed at a silica gel column with a mixture of benzene/ethanol/ conc. ammonia « 75/25/3.

M.p.: 181 - 182.5°C Yield: 48 % of theory.

From the first fractions of the column chromatography 6-(4-phenylmercapto-butoxy)-carbostyril of m.p. 162 - 164°C were isolated in a yield of 15 % of theory.

Example 91 6-(4-Phenylsulfonyl-butoxy)-carbostyril Prepared analogously to Example 86 from 6-(4-phenylsulfonyl-butoxy)-3,4-dihydrocarbostyril and 2,3-dichloro-5,6-dicyano-benzoquinone. Purification .was carried out by column chroma- gcat/l . tography on silica gel (fc&m size: 0.2 - 0.5 mm; with chloro-form/methanol/ethyl acetate = 4/1/1.

M.p.: 212 - 213°C Yield: 54 % of theory.

— Example 92 f j/?N0Vl%0 - (4-Phenylmercapto-butoxy) -carbostyril ~ br&ynicte 49 g of /i ■phonylnercaptobut3rlbronil4^ were added to a mixture of 32.3 g of 5-hydroxycarbostyril, 30 g of potassium carbonate and 650 ml of dimethylsulfoxi.de, dried over a molecular sieve. The mixture was stirred for 20 hours at 25°C, diluted with 3 1 of water and the crystallized reaction product was suction filtered. - 53 18968 M.p-.: 185 - 187°C (from toluene) Yield: 45.0 g (70 % of theory).

Example 95 -(4-Phenylsulfonyl-butoxv)-carbostyril Prepared analogously to Example 88 from 5-(4-phenylmercapto-butoxy)-carbostyril and 4 moles of hydrogen peroxide at a temperature of 60°C and a reaction time of 14 hours. M.p.: 182 - 183°C Yield: 73 % of theory.

Example 94 6-(4-Phenylmercapto-butoxy)-carbostyril Prepared analogously to Example 92 from 6-hydroxycarbostyril L-- phenu\rA<trca-pbobi4J^jl brcvntde. and h phcriylmorbaptooutylbromid£.

M.p.: 161 - 163°C Yield: 78 % of theory.

Example 95 6- (4-Phenylsulfinvl-butoxy)-c arbo s tyr i1 Prepared analogously to Example 88 from 6-(4-phenylmercapto-butoxy)-carbostyril and hydrogen peroxide.

M.p.: 181 - 182°C Yield: 68 % of theory. • • 189685 " 54" Example 96 6-(4-PhenylsulfInyl-butoxv)-carbostyril Prepared analogously to Example 92 from 6-hydroxycarbootyrll 4 - bu-tyt br&yn tC and A-phcnyloulfinylbutylbromide.

M.p.: 181 - 182°C Yield: 71 % of theory.

Example 97 7-(4-Phenylsulfinyl-butoxy)-carbostyril Prepared analogously to Example 86 from 7-(4-phenylsulfinyl-butoxy )-3f4-dihydrocarbostyril.

M.p.: 193 - 194°C Yield: 51 % of theory.

Example 98 8-(4-Phenylmercapto-butoxy)-carbo styril Prepared analogously to Example 86 from 8-(4-phenylmercapto- butoxy)-3,4-dihydrocarbostyril and 2,3-dichloro-5,6-dicyano- benzoquinone.

M.p.: 119 - 120°C Yield: 40 % of theory.

TaiWisn'OFffgfe Example 99 ° ^ NOV 1980 1 8-(4-Phenylsulfinyl-butoxy)-carbostyril Prepared analogously to Example 88 from 8-(4-phenylmercapto-butoxy)-carbostyril by oxidation with hydrogen peroxide. - 55 189685 M.p.: 125.5 - 126.5°C Yield: 60 % of theory.

Example 100 -(4-Phenvlsulfonyl-butoxv)-carbostyril 100 mg of 5-(4-phenylsulfonyl-butoxy)-3,4-dihydrocarbostyril were refluxed with 30 mg of palladium/charcoal and 1 ml of mesitylene. After 3.5 hours further 30 mg of palladium/charcoal were added and the mixture was heated for further 9 hours.

Subsequently the reaction mixture was hot filtered, the fil- on. trate was evaporated and the residue was chromatographed ,-stf a silica gel column with a mixture of benzene/ethanol/conc. ammonia = 75/25/3. Besides the starting material, which did not change during the reaction, 9 mg of 5-(4-phenylsulfonyl-butoxy)-carbostyril were obtained.

M.p.: 182 - 183°C Example 101 6-(4-Amino-lmlnomethylmercapto-butoxy)-3.4-dihydrocarbostyrll 18 g of 6-(4-bromobutoxy)-3,4-dihydrocarbostyril, 5 g of thiourea and 250 ml of water were heated up to boiling until a solution was obtained (approx. 4 hours). After cooling the impurities were extracted with chloroform and the residue was made alkaline by means of ammonia. The precipitated crystals were suction filtered and dried. M.p.: 140 -.141.8°C M.p. of the hydrochloride: 208 - 211°C Yield: 90 % of theory.

NOV I960 - 56 _ i oyot Example 102 6-(4-Phenylsulfonyl)-butoxy-3.4-dihydrocarbostyril 107 mg of 6-(4-phenylsulfonyl)-butoxy-carbostyril were suspended in 15 ml of methanol, mixed with 40 mg of palladium/charcoal and hydrogenated at 50°C and at a hydrogen pressure of 2.5 bar for 14 hours. After filtering off the catalyst and evaporating the clear solution, the as residue was obtained ;Lnr colourless crystals.

M.p.: 153 - 154°C Yield: 89 mg (83 % of theory).

Example 103 6-(4-Benzylmercapto-butoxy)-3.4-dlhvdrocarbostyril 2.5 g of 6-(4-mercaptobutoxy)-3»4-dihydrocarbostyril, dissolved in 25 ml of dimethylsulfoxide, were mixed whilst stirring with 1.4 g of potassium carbonate and subsequently ixfiTWi cfilcnrtcle with 1.3 ml of /bonzylehloridti. After stirring for 15 hours at room temperature the reaction mixture was diluted with 200 ml of water, the precipitated oily substance was separated and recrystallized from ethyl acetate. M.p.: 76 - 78°C Yield: 2.8 g (82 % of theory).

Example 104 6-(5-Phenylmercaptopentoxy)-3.4-dlhydrocarbostyrll Prepared analogously to Example 1 from 6-(5-bromopentoxy)-3,4-dihydro-carbostyril and thiophenol .

M.p.: 117 - 119°C Yield: 71 % of theory. » ,—- N2 PAT5NT OP-^CB | 19 NOV 1980 - 57 _ 189685 Example 105 6-(5-Phenylsulflnyl-pentoxy)-3.4-dihydrocarbostyril Prepared analogously to Example 2 from 6-(5-phenylmercapto-pentoxy)-3,4-dihydrocarbostyril and hydrogen peroxide. M.p.: 104 - 109.5°C Yield: 66 % of theory.

Example 106 6-(5-Phenylsulfinyl-pentoxy)-3.4-dihydrocarbostyril Prepared analogously to Example 3 from 6-(5-phenylmercapto-pentoxy)-3,4-dihydrocarbostyril and hydrogen peroxide. M.p.: 136.5 - 137.8°C Yield: 62 % of theory.

Example 107 6- /5-(2-Pyridyl-mercapto)-pentoxv7-3.4-dihvdrocarbo styril Prepared analogously to Example 1 from 6-(5-bromopentoxy)-3»4-dihydrocarbostyril and 2-mercaptopyridine.

M.p.: 113 - 114.8°C Yield: 76 % of theory.

Example 108 -(2-Hydroxy-3-phenylmercapto-propoxy)-3.4-dihydrocarbostyril Prepared analogously to Example 59 from 5-(2,3-epoxy-propoxy)-3,4-dihydrocarbostyril and thiophenol . 189685 M.p. : 135 - 137°C Yield: 64 % of theory.

Example 109 -(2-Hvdroxv-3-phenylsulflnvl-propoxy)-3.4-dlhvdrocarbostvril Prepared analogously to Example 2 from 5-(2-hydroxy-3-phenyl-mercapto-propoxy)-3,4-dihydrocarbostyril and hydrogen peroxide.

M.p.: 186 - 188°C Yield: 60 % of theory.

Example 110 -(2-Hvdroxv-3-phenvlsulfonvl-propoxv)-3.4-dlhvdrocarbostvril Prepared analogously to Example 3 from 5-(2-hydroxy-3-phenyl-mercapto-propoxy)-3,4-dihydrocarbostyril and hydrogen peroxide. M.p.: 168 - 170°C Yield: 53 % of theory.

Example 111 6-/7-(4-Hvdroxyphenvlmercapto)-butoxv7-3.4-dihydrocarbostvrll Prepared analogously to Example 1 from 6-(4-bromobutoxy)-3,4-dihydrocarbostyril and 4-hydroxythiophenol.

M.p.: 191.5 - 193.0°C Yield: 83 % of theory. 189685 Example 112 6-/7- (4-Hydroxyphenylsulfinyl)-butoxv7-3.4-dlhydrocarbostyrll Prepared analogously to Example 2 from 6-/7-(4-hydroxyphenyl-mercapto)-butoxx7-3,4-dihydrocarbostyril and hydrogen peroxide.

M.p.: 206 - 207.8°C Yield: 84 % of theory.

Example 113 6-/7- (4-Hydroxyphenvlsulfonvl)-butoxv7-3,4-dihvdrocarbostyril Prepared analogously to Example 3 from 6-/7-(4-hydroxyphenyl-mercapto)-butox£7-3,4-dihydrocarbostyril and hydrogen peroxide. M.p.: 219 - 219.5°C Yield: 78 % of theory.

Example 114 6-»/7-(4-Acetaminophenvl me rcapto)-butoxv7-3.4-dihydrocarbostyril Prepared analogously to Example 1 from 6-(4-bromobutoxy)-3,4-dihydrocarbostyril and 4-acetaminothiophenol.

M.p.: 162.5 - 163.0°C Yield: 65 % of theory.

Example 115 6-/7-(4-Acetaminophenylsulfinyl)-butoxv7-3,4-dihydrocarbostyril Prepared analogously to Example 2 from 6-/7-(4-acetaminophenyl-mercapto)-butox£7-3,4-dihydrocarbostyril and hydrogen peroxide. - so - 189685 M.p.: 202.0 - 203.8°C Yield: 55 % of theory.

Example 116 6-/7- (4-Acetamlnophenvlsulfonvl)-butoxy7-3.4-dlhydrocarbostyril Prepared analogously to Example 3 from 6-/7-(4-acetaminophenyl-mercapto)-butox2;7-3,4-dihydrocarbostyril and hydrogen peroxide. M.p.: 143.5 - 147.0°C Yield: 88 96 of theory.

Example 117 6-/7- (4,5-Di~p-chlorophenyl-oxazole-2-yl-mercapto)-butox£7- 3.4-dihydrocarbostyril Prepared analogously to Example 1 from 6-(4-bromobutoxy)-3,4-di-hydrocarbostyril and 2-mercapto-4,5-di-p-chlorophenyl-oxazole. M.p.: 110 - 115°C Yield: 70 % of theory.

Example 118 6-/7-(2-Pyridylsulflnyl)-butoxy7-carbostyril Prepared analogously to Example 86 from 6-/7-(2-pyridylsulfinyl)- butoxx7-3,4-dihydrocarbostyril and 2,3-dichloro-5,6-dicyano- benzoquinone.

M.p.: 152 - 154°C Yield: 48 % of theory. 18 96 8 5 Example 119 6-(4-Phenylmercapto-butoxv)-3.4-dihydrocarbostyril Prepared analogously to Example 102 from 6-(4-phenylmercap to-butoxy)-carbostyril by catalytic hydrogenation with rhenium-VII-sulfide as catalyst.

M.p.: 121 - 122°C Yield: 67 % of theory.

Example 120 8-(4-Phenylsulfonyl-butoxv)-carbostyril Prepared analogously to Example 86 from 8-(4-phenylsulfonyl-butoxy)-3,4-dihydrocarbostyril and 2,3-dichloro-5,6-dicyano-benzoquinone.

M.p.: 146 - 147°C Yield: 41 % of theory.

Example 121 7-(4-Phenylmercapto-butoxy)-carbostyril Prepared analogously to Example 86 from 7-(4-phenylmercapto- butoxy)-3,4-dihydrocarbostyril and 2,3-dichloro-5,6-dicyano- benzoquinone.

M.p.: 157.5 - 158.5°C Yield: 54 % of theory. -62 - . 189685 Example 122 6-/7-fe,5-DichlorophenyImercapto)-butoxv7-3 > 4-dlhydrocarbostyrll 8.94 g (0.03 mol) of 6-(bromobutoxy)-3,4-dihydrocarbostyril (m.p.: 142 - 147°C) were added to a mixture of 2.21 g (0.0315 mol) of potassium methoxide, 5.76 g (0.0315 mol) of 98 % 2,5-dichlorothiophenol and of 54 ml of methanol.

The reaction mixture was refluxed whereby at first su-SSiakn-t a clear solution was obtained. After 5 minutes ^o much crystalline reaction product was precipitat ed, so that the reaction mixture was hardly stirrable. After one hour the mixture was cooled to room temperature, suction filtered and recrystallized from ethanol. Colourless crystals of m.p. 133 - 134°C were obtained. Yield: 10.60 g (89.1 % of theory).

Example 123 6-/5-(2.5-Dichlorophenylsulfinyl)-butoxv7-3.4-dihydrocarbostyril .55 g (0.014 mol) of 6-/5-(2,5-dichlorophenylmercapto)-butoxx7-3,4-dihydrocarbostyril, suspended in 40 ml of glacial acetic acid, were mixed with 1.19 ml of a 40.06 % aqueous solution of hydrogen peroxide (0.014 mol), dissolved in 1.5 ml of glacial acetic acid, and stirred at room temperature. The suspension to gu/e . was feeing cleared farm an almost clear solution fwaa obtaincji.

After 70 hours white crystals were precipitated which were suction filtered and recrystallized from ethanol.

M.p.: 185 - 186°C Yield: 5.43 g (94.1 % of theory).

I 19 NOV 1980 V RECEIVED 11 89685 Example 124 6-/5- (2.5-Dlchlorophenvlsulfonvl)-butoxv7-3.4-dihvdrocarbostyrll 2.97 g (0.0075 mol) of 6-/5-(2,5-dichlorophenylmercapto)-butox^;7- 3,4-dihydrocarbostyril were added to 15 ml of ice-cooled formic acid and mixed with 1.49 ml of 40.08 % hydrogen peroxide (0.0175 mol). After stirring for 2.5 hours the mixture was diluted with three times the amount of water. The precipitated crystals were recrystallized from ethanol.

M.p.: 174.5 - 175.5°C Yield: 1.99 g (61.9 % of theory).

Example 125 6-/5-(3.4-Dichlorophenvlsulfonyl)-butoxv7-3.4-dihydrocarbostyril Prepared analogously to Example 124 from 6-/5-(3,4-dichlorophenyl-mercapto)-butoxx7-3,4-dihydrocarbostyril (m.p.: 116.5 - 118°C) and hydrogen peroxide.

M.p.: 172 - 173°C Yield: 96 % of theory.

Example 126 6-/5- (4-Hydroxy-3,5-di-tert.-butyl-phenylmercapto)-butox^7-3.4-dihydrocarbostyril Prepared analogously to Example 122 from 6-(4-bromobutoxy)- 3.4-dihydrocarbostyril (m.p.: 142 - 147°C) and 4-hydroxy- 3.5-di-tert.-butylthiophenol.

M.p.: 146 - 147°C Yield: 68.8 % of theory. 169685 Example 127 6-/5-(4-Hydroxy-3,5-di-tert.-butyl-phenylsulfinyl)-butox£7-3»4-dlhvdrocarbostvril Prepared analogously to Example 123 from 6-/5-(4-hydroxy-3,5-di-tert.-butyl-phenylmercapto)-butox^7-3»4-dihydrocarbostyril and hydrogen peroxide.

M.p. : 170 - 171°C Yield : 80.7 % of theory.

Example 128 6-/5-(4-Hydroxy-3,5-di-tert.-butyl-phenylsulfonyl)-butox^7-3.4-dihydrocarbostyril Prepared analogously to Example 124 from 6-/5-(4-hydroxy-3,5-di-tert .-butyl-phenylmercapto)-butoxy7-3,4-dihydrocarbostyril and hydrogen peroxide.

M.p. : 165 - 167°C Yield: 97.6 % of theory.

Example 129 6-/5-(2-Carboxyphenvlmercapto)-butoxv7-3.4-dihydrocarbostyril Prepared analogously to Example 122 from 6-(4-bromobutoxy)-3,4-dihydrocarbostyril and 2-thiobenzoic acid.

M.p. : 176 - 179°C Yield: 57.5 % of theory. 189685 Example 130 6-/5- (2-Carboxv-phenylsulfinyl)-butoxv7-3.4-dihvdrocarbostyrll Prepared analogously to Example 123 from 6-/5-(2-carboxy-phenyl-mercapto)-butox2;7-3,4-dihydrocarbostyril and hydrogen peroxide. M.p.: 194 - 196°C Yield: 77.2 % of theory.

Example 131 6-/5-(4-Pyridylsulfinvl)-butoxv7-3.4-dihydrocarbostyril Prepared analogously to Example 122 from 6-(4-bromobutoxy)- 3,4-dihydrocarbostyril and 4-mercaptopyridine and subsequent oxidation of the obtained 6-/5-(4-pyridylmercapto)-butox^7- 3,4-dihydrocarbostyril (m.p.: 128 - 133°C) with hydrogen per oxide analogously to Example 123.

M.p.: 154°C Yield: 57 % of theory.

Example 132 6-/5-(4-Pyridylsulfonyl)-butoxv7-3.4-dihydrocarbostyril Prepared analogously to Example 124 from 6-/5-(4-pyridylmer-capto)-butoxx7-3,4-dihydrocarbostyril and hydrogen peroxide. M.p.: 179 - 183°C Yield: 35.9 % of theory. 189685 Example 155 6-/3-(3,4-Dichlorophenylsulfinyl)-2-hydroxy-propox^7-3,4-di-hydrocarbostyrll 3.51 g (0.016 mol) of 6-(2,3-epoxy-propoxy)-3,4-dihydrocarbostyril (m.p.: 125 - 128°C), dissolved in 35 ml of methanol, were mixed with 4.29 g of 3,4-dichlorothiophenol . The mixture was heated to boiling for 5 hours. After cooling, crystals were obtained, which were suction filtered and recrystallized from ethanol.

M.p.: 175 - 176°C Yield: 2.48 g (38.9 % of theory).

The 6-/5-(3,4-dichlorophenylmercapto)-2-hydroxy-propox^7-3,4-dihydrocarbostyril thus obtained, was oxidized analogously to Example 123 with hydrogen peroxide.

M.p.: 108 - 110°C Yield: 75 % of theory.

Example 134 6-(5-Benzylmercapto-propoxy)-5.4-dihydrocarbostyril Prepared analogously to Example 122 from 6-(3-bromopropoxy)-3,4-dihydrocarbostyril (m.p.: 142 - 147'°C) and benzylmercaptane. M.p.: 97.5 - 99.0°C Yield: 58 % of theory.

Example 135 6-(3-Benzylsulfinyl-propoxy)-3.4-dihydrocarbostyril Prepared analogously to Example 123 from 6-(3-benzylmercapto)-3,4-dihydrocarbostyril and hydrogen peroxide.

M.p.: 144.5 - 147.0°C Yield: 51 % of theory. 189685 Example 136 -(3-tert.-Butylmercapto-2-hydroxy-propoxy)-3,4-dihydrocarbostyril __ • Prepared analogously to Example 133 from 5-(2,3-epoxy-propoxyj- 3,4-dihydrocarbostyril (m.p.: 171 - 173°C) and tert.-butyl- mercaptane.

M.p. : 105 - 109°C Yield: 77.1 % of theory.

Example 137 -(3-tert.-Butylsulfinyl-2-hydroxy-propoxy)-3,4-dihydrocarbo-styril Prepared analogously to Example 123 from 6-(3-tert.-butylmer- capto-2-hydroxy-propoxy)-3,4-dihydrocarbostyril and hydrogen peroxide.

M.p.: 175 - 177°C Yield: 52.1 % of theory.

Example 138 -(3-tert.-Butylsulfonyl-2-hydroxy-propoxy)-3,4-dihydrocarbostyril Prepared analogously to Example 124 from 6-(3-tert.-butylmer- capto-2-hydroxypropoxy)-3,4-dihydrocarbostyril and hydrogen peroxide.

M.p. : 210 - 212°C Yield: 37.1 % of theory. -68 " 189685 Example 139 6-/5-6-Pyrldyl-sulf onyl)-butoxv7-carbostyrll Prepared analogously to Example 124 from 6-/5-(2-pyridyl-sulfinyl)-butoxy7-carbostyril and hydrogen peroxide. M.p. : 179 - 1Q0°C Yield: 65.8 % of theory.

Example 140 4-Methyl-6-(4-phenylmercapto-butoxy)-carbostyril ^cLro^c^tccxyloo&i^jft L .25 g (0.03 mol) of 4-methyl-6-$ydrocarbostyriX (m.p.: 326 -330°C, see R. R. Holmes et al. in J. Amer. Chem. Soc. 76, 2404 (1954)), 8.09 g (0.033 mol) of 4-phenylmercaptobutyiy bromide and 6.22 g (0.045 mol) of potassium carbonate were stirred at room temperature for 16 hours in 70 ml dimethylsul-foxide. Subsequently the mixture was diluted with water and the precipitated crystals were recrystallized from toluene after drying.

M.p.: 148 - 150°C Yield: 6.2 g (61.2 % of theory).

Example 141 4-Methyl-6- (4-phenylsulflnyl-butoxy)-carbostyril Prepared analogously to Example 140 from 4-methyl-6-hydroxy-carbostyril (m.p.: 326 - 330°C) and 4-phenylsulfinylbutyl^-bromide.

M.p.: 167 - 168°C Yield: 47.3 % of theory. im, , f 19nqvi980 - 69 - 18968 Example 142 4-Methyl-6-(4-phenylsulfonyl-butoxy)-carbostyril Prepared analogously to Example 140 from 4-methyl-6-hydroxy-carbostyril (m.p.: 326 - 330°C) and 4-phenylsulfonylbutyl^ bromide.

M.p.: 217 - 219°C Yield: 66.6 % of theory.

Example 143 4-Methyl-6-/?~(2-pyridylmercapto)-butoxv7-carbostyril Prepared analogously to Example 122 from 4-methyl-6-(4-bromo-butoxy)-carbostyril (m.p.: 217 - 219°C) and 2-mercaptopyridine. M.p.: 149 - 151°C Yield: 85.7 % of theory.

Example 144 4-Methyl-6-/?-(2-pyridylsulfinyl)-butoxv7-carbostyril Prepared analogously to Example 123 from 4-methyl-6-/Zf-(2-py-ridylmercapto)-butoxy7carbostyril and hydrogen peroxide. M.p.: 167 - 169°C Yield: 61.8 % of theory.

Example 145 4-Methyl-6-/7-(2-pyrldylsulfonyl)-butoxy7-carbostyril Prepared analogously to Example 124 from 4-methyl-6-/5-(2-pyri-dylmercapto)-butoxy7carbostyril and hydrogen peroxide. « ! 9 NOV 1980 4 189685 M.p.: 195 - 197°C Yield: 29.5 % of theory.

Example 146 4-Methvl-6-/5-(2-quinolylmercapto)-butoxv7-carbostyril Prepared analogously to Example 122 from 4-methyl-6-(4-bromo-butoxy)-carbostyril and 2-mercaptoquinoline.

M.p.: 162 - 163°C Yield: 81.9 % of theory.

Example 147 4-Methy1-6-/5-(2-quinolvlsulfinyl)-butoxy7-carbostyril Prepared analogously to Example 1225 from 4-methyl-6-/5-(2-quinolylmercapto) -butoxy7carbostyril and hydrogen peroxide. M.p.: 189 - 190°C Yield: 47.5 % of theory.

Example 148 4-Methyl-6-/5-(2-quinolylsulfonyl)-butoxv7carbostyril Prepared analogously to Example 124 from 4-methyl-6-/5-(2-quinolylmercapto)-butoxy7carbostyril and hydrogen peroxide. M.p.: 199 - 203°C Yield: 31.5 % of theory. 189685 Example 149 4-Methyl-6-/5-(4-biphenvlvlsulfInvl)-butoxv7carbostyril Prepared analogously to Example 123 from 4-methyl-6-/5-(4-biphenylylmercapto)-butoxy7carbostyrll (m.p.: 174 - 176 C) and hydrogen peroxide.

M.p.: 161 - 162°C Yield: 59 % of theory.

Example 150 6-/5-(4-Chlorophenvlmercapto)-butoxv7carbostyril Prepared analogously to Example 122 from 6-(4-chlorobutoxy) carbostyril (m.p.: 206 - 208°C) and 4-chlorothiophenol » M.p.: 168 - 170°C Yield: 85 % of theory.

Example 151 6-/5-(4-Chlorophenvlsulfinyl)-butoxv7carbostyril Prepared analogously to Example 123 from 6-/5-(4-chloro-phenylmercapto)-butoxy7carb°s"kyril and hydrogen peroxide. M.p.: 157 - 158°C Yield: 81 % of theory.

Example 152 6-/5-(4-Chlorophenvlsulfonyl)-butoxv7carbostyril Prepared analogously to Example 124 from 6-/5-^-chlorophenyl-mercapto^butox^carbostyril and hydrogen peroxide. 189685 M.p.: 197 - 199°C Yield: 99 % of theory.

Example 153 6-/5-(3«4-Dichlorophenylmercapto)-butoxy7carbostvril Prepared analogously to Example 122 from 6-(4-bromobutoxy)-carbostyril (m.p.: 198 - 199°C) and 3,4-dichlorothiophenol . M.p.: 149 - 152°C Yield: 60 % of theory.

Example 154 6-/5-(5.4-Dichlorophenylsulfinyl)-butoxy7carbostyril Prepared analogously to Example 123 from 6-/5-(3,4-dichloro-phenylmercapto)-butoxy7carbostyril and hydrogen peroxide. M.p.: 191 - 196°C Yield: 87 % of theory.

Example 155 6-/5-(314-Di chlorophenylsulfonyl)-butoxy7carbo styril Prepared analogously to Example 124 from 6- (3,4-dichloro-phenylmercapto)-butoxy7carbostyril and hydrogen peroxide. M.p. : 188 - 190°C Yield: 83 % of theory. " 73 " 189685 Example 156 6-/7-(2.5-Dlchlorophenylmercapto)-butoxy7carbostyril Prepared analogously to Example 122 from 6-(4-bromobutoxy)-carbostyril and 2,5-dichlorothiophenol .

M.p. : 175 - 176°C Yield: 85 % of theory.

Example 157 6-/5-(2.5-Dichlorophenvlsulfinyl)-butoxy7carbostvril Prepared analogously to Example 123 from 6-/5-(2,5-dichloro-phenylmercapto)-butoxy7carbostyril and hydrogen peroxide. M.p.: 200 - 202°C Yield: 75 % of theory.

Example 158 6-/5-(2,5-Dichlorophenylsulfonyl)-butoxv7carbostyril Prepared analogously to Example 124 from 6-/5-(2,5-dichloro-phenylmercapto)-butoxy7carbostyril and hydrogen peroxide in formic acid.

M.p.: 203 - 205°C Yield: 79 % of theory.

Example 159 6-/5-(4-Fluorophenylmercapto)-butoxy7carbostyril Prepared analogously to Example 122 from 6-(4-bromobutoxy)-carbostyril and 4-fluorothiophenol • M.p.: 149 - 150°C Yield: 85 % of theory. !89685 Example 160 6-/7-(4-Fluorophenvlsulfinyl)-butoxv7carbostyrll Prepared analogously to Example 123 from 6-/7-(4-fluoro-phenylmercapto)-butoxy7carbostyril and hydrogen peroxide. M.p. : 164 - 165°C Yield: 50 % of theory.

Example 161 6-/7-(4-Fluorophenylsulfonyl)-butoxv7carbostvril Prepared analogously to Example 124 from 6-/7-(4-fluoro-phenylmercapto)-butoxy7carbostyril and hydrogen peroxide in formic acid.

M.p.: 209 - 211°C Yield: 59 % of theory.

Example 162 6-/7-(4-Hydroxy-3,5-di-tert.-butyl-phenylmercapto)-butoxy7-carbostyril Prepared analogously to Example 122 from 6-(4-bromobutoxy)-carbostyril (m.p.: 198 - 199°C) and 4-hydroxy-3,5-di-tert.-butyl-thiophenol (m.p.: 84.5 - 86.0°C).

M.p. : 172 - 173°C Yield: 77 % of theory. 189685 Example 165 6-/5-(4-Hydroxy-3»5-di-tert.-butylphenylsulfinyl)-butoxy7-carbostvril Prepared analogously to Example 123 from 6-/5-(4-hydroxy-3,5-di-tert.-butylphenylmercapto)-butoxy7carbostyril and hydrogen peroxide.

M.p.: 192 - 194°C Yield: 83 % of theory.

Example 164 6-/5-(4-Hydroxy-3,5-di-tert.-butylphenylsulfonyl)-butoxy7-carbostyril Prepared analogously to Example 124 from 6-/5-(4-hydroxy-3,5-di-tert.-butylphenylmercapto)-butoxy7carbostyril and hydrogen peroxide in formic acid.

M.p. : 242 - 244°C Yield: 92 % of theory.

Example 165 6-/5-(4-Biphenylylmercapto)-butoxv7carbostyril Prepared analogously to Example 122 from 6-(4-bromobutoxy)-carbostyril (m.p.: 198 - 199°C) and 4-biphenylmercaptane. M.p.: 191 - 192°C Yield: 82 % of theory.

T 8 96 8 5 Example 166 6-/7-(4-Biphenvlvlsulfinvl)-butoxv7carbostyril Prepared analogously to Example 123 from 6-/7-(4-biphenylyl-raercapto)-butoxy7carbostyril and hydrogen peroxide. M.p.: 196 - 197°C Yield: 80 % of theory.

Example 167 6-/7-(4-Biphenylylsulfonyl)-butoxv7carbostyril Prepared analogously to Example 124 from 6-/7-(4-biphenylyl-mercapto)-butoxy7carbostyril and hydrogen peroxide. M.p.: 213 - 215°C Yield: 73 % of theory.

Example 168 6-/7-(4-Nitro-phenylmercapto)-butoxy7cHrbostyril Prepared analogously to Example 122 from 6-(4-bromobutoxy)-carbostyril (m.p.: 198 - 199°C) and 4-nitrothiophenol . M.p.: 184 - 185°C Yield: 96 % of theory.

Example 169 6-/7-(4-Nitro-phenylsulfinyl)-butoxv7carbostyril Prepared analogously to Example 123 from 6-/7-(4-nitro-phenylmercapto)-butoxy7carbostyril and hydrogen peroxide. 189685 M.p.: 183 - 184°C Yield: 77 % of theory.

Example 170 6-/5-(4-Nitro-phenvlsulfonyl)-butoxv7carbostyril Prepared analogously to Example 124 from 6- Br (4-nitro-phenylsulfinyl)-butoxy7carbostyril and hydrogen peroxide in formic acid.

M.p.: 230 - 232°C Yield: 70 % of theory.

Example 171 6-/5-(2-Quinolylmercapto)-butoxv7carbostyril Prepared analogously to Example 122 from 6-(4-bromobutoxy)- carbostyril (m.p.: 132°C) and 2-mercaptoquinoline.

M.p.: 132°C Yield: 99 % of theory.

Example 172 6-/5-(2-Quinolylsulfinyl)-butoxv7carbostyrll Prepared analogously to Example 123 from 6-/5-(2-quinolyl-mercapto)-butoxy7carbostyril and hydrogen peroxide. M.p.: 161 - 162°C Yield: 66 % of theory. -78 - 1 8 9 685 Example 175 6-/5-(2-Qulnolylsulfonyl)-butoxy7carbostyrll t Prepared analogously to Example 124 from 6-/5-(2-quinolyl-sulfinyl)-butoxy7carbostyril and hydrogen peroxide in formic acid.

M.p.: 197 - 198°C Yield: 58 % of theory.

Example 174 -(4-Phenylmercapto-butoxy)-oxindole Prepared analogously to Example 140 from 5-hydroxyoxindole (J. Chem. Soc. 1961, 2723) and 4-phenylmercaptobutylbromide. M.p.: 131 - 132°C Yield: 13 % of theory.

Example 175 -(4-Phenylsulfinyl-butoxy)-oxindole Prepared analogously to Example 123 from 5-(4-phenylmercapto-butoxy)-oxindole and hydrogen peroxide.

M.p.: 114 - 116°C Yield: 61 % of theory.

Example 176 6-/?-(Phenvlsulfinylmethyl)-benzyloxv7-3.4-dlhydro-carbostyril A mixture of 67.1 g of phthalide, 51.3 ml of thiophenol , .1 g of potassium methoxide and 250 ml of methanol was refluxed. Subsequently the obtained 2-phenylmercaptomethyl-benzoic acid (yield: 78 % of theory, m.p.: 108 - 110°C) was t 18 9 6 8c: - 19 - i 0 7 0 0 j ihionijl chlc^ride. esterified with methanol/ihionylchloride whilst standing at -40°C. After standing over night at room temperature methyl 2-phenylmercaptomethyl-benzoate (yield: 89 % of theory, b.p.Q Qy: 145°C) was obtained, which was converted to the 2-phenylmercaptomethyl-phenylcarbinole (yield: 97 % of theory, m.p.: 64 - 65°C) by means of reduction litbiu^n cCLdmiu-rrl with /Lithiumalumlniunt hydride in diethyl ether. cofWH.fcxz.cl This compound was aiL^d to 2-phenylmercaptomethyl-phenyl-methyl-p-toluenesulfonate by addition of p-toluenesulfo- nyl chloride. (Thin-layer chromatogram: silica gel; lolucrrfc: chloroform/ethyl acetate = 1 : 1; Rf-value = 0.8.

Yield: 55 % of theory). This ester was /reactea-to 6-/2-(phenylmercaptomethyl)-benzyloxy7-3,4-dihydrocarbostyril analogously to Example 140 with 6-hydroxy-3,4-dihydrocarbostyril (thin^layer chromatogram: silica gel; cJLuaurt I Iclucnt: chloroform/ethyl acetate =1 : 1; R^-value = 0.35$ Yield: 64 % of theory).

This substance was analogously to Example 123 oxidized to 6-/2-£>henylsulfinylmethyl)-benzyloxy7-3,4-dihydrocarbostyril by means of hydrogen peroxide.

M.p.: 133 - 135°C Yield: 64 % of theory.

Example 177 6-/~4- (Phenvlmercaptomethvl)-benzyloxv7-3.4-dihydrocarbostyril p-Xtjlylene clic-hlcmde.

Ip "Xylylonodiohlorida was reacted with thiophenol in mol radio xaiir&n 1:1 in the presence of excess potassium carbonate in dimethylsulfoxide. The obtained 4-phenylmercaptomethyl-benzyl-chloride (control: thin^layer chromatogram) was further reacted with 6-hydroxy-3f4-dihydrocarbostyril analogously to Example 140 without isolation.

M.p.: 139 - 141°C Yield: 52 % of theory. lix mmrr omc? — j 19 NOV 1980 escsvtd 18968 Example 178 6-/~4- Cfrhcnvlbt^lflavi )-ben2vloxv7-3t4-dlhydrocarbostyril Prepared analogously to Example 123 from 6-/""4-( phenyl-mercaptomethyl)-benzyloxy7-3,4-dihydrocarbostyril and hydrogen peroxide.

M.p.: 179 - 181°C Yield: 61 % of theory.

Example 179 6-(4-Cyclohexylmercapto-butoxv)-carbostyril Prepared analogously to Example 122 from 6-(4-bromobutoxy)-carbostyril (m.p.: 198 - 199°C) and cyclohexylmercaptane. M.p.: 153 - 159°C Yield: 89 % of theory.

Example 180 6- (4-Cyclohexylsulf inyl-butoxy)-carbostyril Prepared analogously to Example 123 from 6-(4-cyclohexyl-mercapto-butoxy)-carbostyril and hydrogen peroxide. M.p.: 169 - 170°C Yield: 57 % of theory.

Example 181 6-/5- (4-Bromophenylmercapto )-butoxv7carbostyril Prepared analogously to Example 122 from 6-(4-bromobutoxy)-carbostyril (m.p„: 198 - 199°C) and 4-bromothiophenol . 19 NOV 1980 189685 M.p. : 156 - 158°C Yield: 53 % of theory.

Example 182 6-/7- (4-Bromophenylsulfinvl)-butoxv7carbostyril Prepared analogously to Example 123 from 6-/5-(4-bromophenyl-mercapto)-butoxy7carbostyril and hydrogen peroxide.

M.p. : 168 - 170°C Yield: 65 % of theory.

Example 183 6-/5-(3-Methyl-4-bromo-phenylmercapto)-butoxv7carbo styril Prepared analogously to Example 122 from 6-(4-bromobutoxy)-carbostyril (m.p.: 189 - 199°C) and 3-methyl-4-bromo-thio-phenol .

M.p. : 167 - 169°C Yield: 76 % of theory.

Example 184 6-/5-(3-Methyl-4-bromo-phenyl sulf invl)-butoxy7-carbostyril Prepared analogously to Example 123 from 6-/5-(3-methyl- 4-bromo-phenylmercapto)-butoxy7carbostyril and hydrogen peroxide.

M.p. : 169 - 172°C Yield: 79 % of theory. 189685 Example 185 6-/5-(3-Methyl-4-bromo-phenylsulfonyl)-butoxv7carbostvril Prepared analogously to Example 124 from 6-/5-(3-methyl- 4-bromo-phenylmercapto)-butoxy7carbostyril and hydrogen peroxide.

M.p.: 163 - 167°C Yield: 57 % of theory.

Example 186 6-/5-(1.2.4-Trlazole-3-yl-mercapto)-butoxy7carbostyril Prepared analogously to Example 122 from 6-(4-bromobutoxy)-carbostyril and 3-mercapto-1,2,4-triazole.

M.p. : 203 - 20^C Yield: 82 % of theory.

Example 187 6-/5-(2.4.5-Trichlorophenylmercapto)-butoxv7carbostyril Prepared analogously to Example 122 from 6-(4-bromobutoxy)-carbostyril (m.p.: 198 - 199°C) and 2,4,5-trichlorothiophenol . M.p.: 177 - 178°C Yield: 83 % of theory.

Example 188 6-/5-(2.4.5-Trichlorophenylsulfinyl)-butoxv7carbostyril Prepared analogously to Example 123 from 6 -/5-(2,4-5-tri-chlorophenylmercapto)-butoxy7^arbostyril and hydrogen peroxide. 3 - .t 8 9685 M.p.: 206 - 208°C Yield: 98 % of theory.

Example 189 6-/5-(3,5-Dibromo-4-amino-phenylmercapto)-butoxy7-3,4-dihydro-carbostyrll Prepared analogously to Example 122 from 6-(4-bromobutoxy)-3,4-dihydrocarbostyril (m.p.: 142 - 147°C) and 3,5-dibromo-4-amino-thiophenol.

M.p.: 90 - 92°C Yield: 89 % of theory.

Example 190 6-/5-(3,5-Dibromo-4-amino-phenyl-sulfinyl)-butoxy7-3,4-di-hydrocarbostyrll Prepared analogously to Example 123 from 6-/5-(3»5-dibromo-4-amino-phenylmercapto)-butoxy7-3,4-dihydrocarbostyril and hydrogen peroxide.

M.p.: 144 - 146°C Yield: 76 % of theory.

Example 191 6-/5- (3,5-Dibromo-4-amino-phenylsulfonyl)-butoxy7-3»4-dihydro-carbostyrll Prepared analogously to Example 124 from 6-/5-(3>5-dibromo-4-aminophenylsulfinyl)-butoxy7-3,4-dihydrocarbostyril and hydrogen peroxide.

M.p.: 157 - 159°C Yield: 87 % of theory. 1 8 96 8 Example 192 6-/7- (3 *5-Dlbromo-4-amlno-phenvlmercapto)-butoxv7carboatvrll Prepared analogously to Example 122 from 6-(4-bromobutoxy)- carbostyril (m.p.: 198 - 199°C) and 3,5-dibromo-4-amino- thiophenol.

M.p.: 153 - 155°C Yield: 86 % of theory.

Example 195 6-/7-(3»5-Dlbromo-4-amlno-phenylsulfinvl)-butoxv7carbostyrll Prepared analogously to Example 123 from 6-/7-(3,5-dibromo-4-amino-phenylmercapto)-butox2;7carbostyril and hydrogen peroxide.

M.p.: 205 - 207°C Yield: 79 % of theory.

Example 194 6-/7- (3 > 5-Dlbromo-4-amino-phenvlsulfonyl)-butoxv7carbostyrll Prepared analogously to Example 124 from 6-/7-(3,5-dibromo-4-amino-phenylmercapto)-butoxy7carbostyril and hydrogen peroxide in formic acid.

M.p. : 238 - 241°C Yield: 87 % of theory. .1 8 96 8 5 Example 195 6-/5-(4-Bromo-3-methyl-phenylmercapto)-butoxy7-3»4-dihydro-carbostvrll Prepared analogously to Example 122 from 6-(4-bromobutoxy)-3,4-dihydrocarbostyril (m.p.: 142 - 147°C) and 4-bromo-3-methyl-thiophenol.

M.p.: 104 - 109°C Yield: 81 % of theory.

Example 196 6-/5-(4-Bromo-3-methyl-phenylsulfinyl)-butoxy7-3»4-dihydrocarbostyril Prepared analogously to Example 123 from 6-/5-(4-bromo-3-me-thyl-phenylmercapto)-butoxy7-3,4-dihydrocarbostyril and hydrogen peroxide.

M.p.: 129 - 130°C Yield: 75 % of theory.

Example 197 6-/5-(2.5-Dlbromo-phenvlmercapto)-butoxv7-3.4-dlhydrocarbostyrll Prepared analogously to Example 122 from 6-(4-bromobutoxy)- 3,4-dihydrocarbostyril (m.p.: 142 - 147°C) and 2,5-dibromo- thiophenol.

M.p.: 127 - 129°C Yield: 75 % of theory. _ 86 - 189685 Example 198 6-/7-(2.5-Dibromo-phenvlsulfInvl)-butoxv7-3.4-dihvdrocarbostyrll Prepared analogously to Example 123 from 6-/7-(2,5-dibromo- phenylmercapto)-butoxy7-3»4-dihydrocarbostyril and hydrogen peroxide.

M.p.: 182 - 184°C Yield: 84 % of theory.

Example 199 6-/7-(2.5-Dlbromo-phenvlmercapto)-butoxv7carbostyril Prepared analogously to Example 122 from 6-(4-bromobutoxy)-carbostyril (m.p.: 198 - 199°C) and 2,5-dibromo-thiophenol. M.p.: 178 - 185°C Yield: 67 % of theory.

Example 200 6-/7-(2.5-Dlbromo-phenylsulfinvl)-butoxv7carbo styr11 Prepared analogously to Example 123 from 6-/7-(2,5-dibromo-phenylmercapto)-butoxy7carbostyril and hydrogen peroxide. M.p : 187 - 189°C Yield: 45 % of theory.

Example 201 6- /5- (3.4-Dlchloro-phenylmercapto)-propoxv7-3.4-dihydrocarbostyrlI Prepared analogously to Example 122 from 6-(3-bromopropoxy)-3,4-dihydrocarbostyril (m.p.: 111 - 118°C) and 3»4-dichloro-thiophenol. 189685 M.p.: 106 - 107°C Yield: 76 % of theory.

Example 202 6-/?-(3.4-Dichloro-phenylsulfInvl)-propoxv7-3«4-dlhvdrocarbostvril Prepared analogously to Example 123 from 6-/5-(3,4-dichloro- phenylmercapto)-propoxy7-3,4-dihydrocarbostyril and hydrogen peroxide.

M.p.: 170 - 172°C Yield: 84 # of theory.

Example 203 6-/7-(4-Cvclohexyl-phenvlmercapto)-butoxv7-3.4-dlhydrocarbostyrll Prepared analogously to Example 122 from 6-(4-bromobutoxy)- 3,4-dihydrocarbostyril (m.p.: 142 - 147°C) and 4-cyclohexyl- thiophenol.

M.p.: 118 - 120°C Yield: 68 % of theory.

Example 204 6-/7-(4-Cyclohexyl-phenylsulfinyl)-butoxy7-3.4-dihydrocarbostyril Prepared analogously to Example 123 from 6-/7-(4-cyclohexyl- phenylmercapto)-butoxy7-3»4-dihydrocarbostyril and hydrogen peroxide.

M.p.: 155 - 157°C Yield: 65 % of theory. 189685 Example 205 6-/5- (4-Cyclohexvl-phenylsulfonyl)-butoxv7-3.4-dihvdrocarbostyr.il Prepared analogously to Example 124 from 6-/5-(4-cyclohexyl- phenylmercapto)-butoxy7-3,4-dihydrocarbostyril and hydrogen peroxide.

M.p.: 172 - 174°C Yield: 52 % of theory.

Example 206 6-/5-(4-Cvclohexyl-phenylmercapto)-butoxy7carbostyril Prepared analogously to Example 122 from 6-(4-bromobutoxy)-carbostyril (m.p.: 188 - 189°C) and 4-cyclohexylthiophenol. M.p.: 165 - 167°C Yield: 64 % of theory.

Example 207 6-/5-(4-Cyclohexyl-phenylsulfinyl)-butoxy7carbostyrll Prepared analogously to Example 123 from 6-/5-(4-cyclohexyl-phenylmercapto)-butoxy7carbostyril and hydrogen peroxide. M.p.: 188 - 190°C Yield: 64 % of theory.

Example 208 6-/5-(4-Cyclohexyl-phenylsulfonyl)-butoxy7carbostvril Prepared analogously to Example 124 from 6-/5-(4-cyclohexyl-phenylmercapto)-butoxy7carbostyril and hydrogen peroxide. 189685 M.p.: 185 - 186°C Yield: 87 % of theory.

Example 209 6-/7-(4-tert.-Butvl-phenvlmercapto)-butoxy7-5.4-dlhydrocarboBtvrll Prepared analogously to Example 122 from 6-(4-bromobutoxy)- 3,4-dihydrocarbostyril (m.p.: 142 - 147°C) and 4-tert.-butyl- thiophenol.

M.p.: 126 - 127°C Yield: 86 % of theory.

Example 210 6-/7-(4-tert.-Butyl-phenylsulfinyl)-butoxv7-3.4-dihvdrocarbostyrll Prepared analogously to Example 123 from 6-/7-(4-tert.-butyl- phenylmercapto )-butoxy7-3>4-dihydrocarbostyril and hydrogen peroxide.

M.p.: 121 - 123°C Yield: 67 % of theory.

Example 211 6-/7-(4-tert.-Butyl-phenylsulfonyl)-butoxv7-3,4-dlhydrocarbostyriI Prepared analogously to Example 124 from 6- -(4-tert.-butyl- phenylmercapto )-butoxy7-3,4-dihydrocarbostyril and hydrogen peroxide.

M.p.: 198 - 200°C Yield: 83 % of theory. 189685 Example 212 6-/7-(4-tert.-Butvl-phenvlmercapto)-butoxv7carbostyril Prepared analogously to Example 122 from 6-(4-bromobutoxy)-carbostyril (m.p.: 198 - 199 °C) and 4-tert.-butylthiophenol. M.p.: 156 - 158°C Yield: 63 96 of theory.

Example 213 6-/7-(4-tert.- Butyl-phenylsulfinyl)-butoxy7carbostyr11 Prepared analogously to Example 123 from 6-/7-(4-tert.-butyl-phenylmercapto )-butoxy7carbostyril and hydrogen peroxide. M.p.: 164 - 166°C Yield: 74 96 of theory.

Example 214 6-/7-(4-tert.-Butyl-phenylsulfonvl)-butoxy7carbostyril Prepared analogously to Example 124 from 6-/7-(4-tert.-butyl- . phenylmercapto)-butoxy7carbostyril and hydrogen peroxide. M.p.: 203 - 205°C Yield: 56 % of theory.

Example 215 6-/7- (2-Quinolylsulfinyl)-butoxv7-3.4-dlhydrocarbostyril Prepared analogously to Example 123 from 6-/7-(2-quinolyly-mercapto)-butoxy7-3,4-dihydrocarbostyril and hydrogen peroxide. ... 189685 M.p.: 154 - 157°C Yield: 79 % of theory.

Example 216 6-/7-(2-Qulnolylsulfonyl)-butoxv7-3.4-dihydrocarbostyrll Prepared analogously to Example 124 from 6-/7-(2-quinolyl-mercapto)-butoxy7-3,4-dihydrocarbostyril and hydrogen peroxide. . . e.LucLsrfr R^-value: 0.50 (silica gel fluorescent plate; Jbluemt: benzene/ethanol/conc. ammonia = 75/25/2).

Yield: 72 % of theory.

Example 217 6-/2- (N-Methyl-N-cyclohexyl-carbamidomethylmercapto)-ethoxy7-3 >4-dihydrocarbostyril Prepared analogously to Example 122 from 6-(2-chloroethoxy)-3,4-dihydrocarbostyril (m.p.: 152.5 - 153.5°C) and N-methyl-N-cyclohexyl-thioglycolic acid amide. ecucL/rt R^.-value: 0.46 (silica gel fluorescent plate; fcluont: fttwerje chloride . . b thyl on 0 ohl or i d4/methanol = 95/5).

Yield: 63 % of theory.

Example 218 6-/2-(N-Methyl-N-cyclohexyl-carbamidomethylsulfinyl)-ethoxy7-3,4-dihydrocarbostyril Prepared analogously to Example 123 from 6-/2-(N-methyl-N-cyclohexylcarbamidomethylmercapto)-ethoxy7-3,4-dihydrocarbosty ril and hydrogen peroxide. ■ ■ ■ ■ - - . , 11 19 NOV 1980 rscsved 189685 cLuasTt" R^-value: 0.34 (silica gel fluorescent plate; jklucrrl: ethylene chloride/methanol = 93/5).

M.p.: 143 - 146°C Yield: 48 % of theory.

Example 219 6-/5-(N-Methyl-N-cyclohexyl-carbamidomethylsulfonyl)-ethox}r7- 3.4-dlhydrocarbostyrll Prepared analogously to Example 124 from 6-/2-(N-methyl- N-cyclohexylcarbamidomethylmercapto)-ethoxy7-3,4-dihydro- carbostyril and hydrogen peroxide in formic acid.

Rf-value: 0.48 (silica gel fluorescent plate; eluent: ethylene chloride/methanol = 95/5) M.p.: 110 - 111°C Yield: 45 % of theory.

Example 220 6-/?-(N-Methyl-N-cyclohexyl-carbamidomethylmercapto)-ethoxy7- carbostyril Prepared analogously to Example 122 from 6-(2-chloroethoxy)-carbostyril /Rx.-value: 0.30 (silica gel fluorescent plate; cluasrt 1 feluerrt: ethylene chloride/methanol = 95/5)7 and N-methyl- thtoglHtoli c N-cyclohexyl-jbhioglykolig acid amide. eiua-n-t R^-value: 0.41 (silica gel fluorescent plate; fluent: ethylene chloride/methanol = 95/5).

Yield: 62 % of theory. 19 NOV 1980 RECEIVED - 93. - 189685 Example 221 6-/?- (N-Methyl-N-cyclohexyl-carbamidomethylsulf inyl )-ethoxy7-carbostyrll Prepared analogously to Example 123 from 6-/5-(N-methyl-N-cyclohexyl-carbamidomercapto)-ethoxy7carbostyril and hydrogen peroxide.

R^-value: 0.027 (silica gel fluorescent plate; /tluenii: ethylene chloride/methanol = 95/5).

M.p.: 128 - 130°C Yield: 65 % of theory.

Example 222 6-/5-(N-Methyl-N-cyclohexyl-carbamidomethylsulfonyl)-ethoxy7-carbostyrll Prepared analogously to Example 124 from 6-/5-(N-methyl-N-cyclohexyl-carbamidomercapto)-ethoxy7carbostyril and hydrogen peroxide. &Lll<zx+0~C Rf-value: 0.39 (silica gel fluorescent plate; /fcluent: ethylene chloride/methanol = 95/5).

Yield: 67 % of theory.

Example 223 6-/3- (3,4-Dichlorophenylsulfonyl)-propoxy7-3,4-dihydrocarbostyril Prepared analogously to Example 124 from 6-/3-(3,4-dichloro- phenylmercapto)-propoxy7-3,4-dihydrocarbostyril and hydrogen peroxide.

M.p.: 187 - 188°C Yield: 87 % of theory. ISSJEFSSS" f' '19 NOV 1930 ^ 6 9 £> 8 5 Example 224 6-/5-(3,4-Dichlorophenylmercapto)-pentoxy7~3,4-dihydrocarbostyril Prepared analogously to Example 122 from 6-(5-bromopentoxy)-3,4-dihydrocarbostyril (m.p.: 97 - 98°C) and 3,4-dichloro-thiophenol.

M.p.: 101 - 104°C Yield: 69 % of theory.

Example 225 6-/5-(3»4-Dichlorophenylsulfinyl)-pentoxy7-3,4-dihydrocarbostyril Prepared analogously to Example 123 from 6-/5-(3,4-dichloro- phenylmercapto)-pentoxy7-3,4-dihydrocarbostyril and hydrogen peroxide.

M.p.: 165 - 166°C Yield: 74 % of theory.

Example 226 6-/5-(3 »4-Dlchlorophenylsulfonyl)-pentoxy7-3.4-dihydrocarbostyril Prepared analogously to Example 124 from 6-/5-(3,4-dichloro- phenylmercapto)-pentoxy7-3»4-dihydrocarbostyril and hydrogen peroxide.

M.p.: 176 - 178°C Yield: 65 % of theory. . 95 _ 189685 Example 227 6-/7-(2-Methyl-4-tert.-butyl-phenylmercapto)-butoxy7-3.4-dihydrocarbostyril Prepared analogously to Example 122 from 6- (4-bromobutoxy)-3,4-dihydrocarbostyril (m.p.: 142 - 147°C) and 2-methyl-4-tert.-butylthiophenol.

M.p.: 81 - 85°C Yield: 91 % of theory.

Example 228 6-/7-(2-Methyl-4-tert.-butyl-phenylsulfinyl)-butoxy7-3,4-dlhydrocarbostyril Prepared analogously to Example 123 from 6- (2-methyl-4-tert.-butyl-phenylmercapto)-butoxy7-3,4-dihydrocarbostyril and hydrogen peroxide. Resinous substance. eLuasrt R^-value: 0.54 (silica gel fluorescent plate; yklucn^: ethylene chloride/methanol = 95/5).

Example 229 6-/7-(3,5-Dichloro-4-hydroxy-phenylmercapto)-butoxy7-3,4-di-hydrocarbostyril Prepared analogously to Example 122 from 6-(4-bromobutoxy)-3,4-dihydrocarbostyril (m.p.: 142 - l47°C).and 3,4-dichloro- uiert 4-hydroxy-thiophenol under nitrogen as protectigas. M.p.: 110 - 114°C Yield: 94 % of theory. mx patent 03=55® .( 19 NOV 1980 - 9i> - 189685 Example 230 -Bromo-6-(4-phenylmercaptobutoxy)-carbostyril Prepared analogously to Example 122 from 5-bromo-6-(4-bromo-butoxy)-carbostyril (prepared by bromination of 6-(4-bromobutoxy )-carbostyril) and thiophenol.

M.p.: 209 - 213°C Yield: 41 % of theory.

Example 231 -Nitro-6-(4-phenyl-mercaptobutoxy)-carbostyril Prepared analogously to Example 122 from 5-nitro-6-(4-bromobutoxy) -carbostyril (m.p.: 250°C, prepared by nitration of 6-(4-bromobutoxy)-3,4-dihydrocarbostyril) and thiophenol. M.p.: 228 - 230°C Yield: 71 % of theory.

Example 232 -Nltro-6-(4-phenylsulfinylbutoxy)-carbostyril Prepared analogously to Example 123 from 5-nitro-6-(4-phenylmercaptobutoxy) -carbostyril and hydrogen peroxide.

M.p.: 192 - 194°C Yield: 91 % of theory.

Example 233 -Acetamino-6-(4-phenylmercaptobutoxy)-carbostyril Prepared analogously to Example 122 from 5-acetamino-6-(4-bromo-butoxy)-carbostyril (prepared by reduction with zinc in acetic acid of 5-nitro-6-(4-bromobutoxy)-carbostyril under addition of acetic anhydride) and thiophenol. - 9 7 - 18968 M.p.: 238 - 240°C Yield: 80 % of theory.

Example 234 -Acetamino-6-(4-phenylsulfinylbutoxy)-carbostyril Prepared analogously to Example 123 from 5-acetamino-6-(4-phenylmercapto)-butoxy)-carbostyril and hydrogen peroxide. M.p.: 213 - 217°C Yield: 47 % of theory.

Example 235 -Bromo-6-(4-phenylsulfinylbutoxy)-carbostyril Prepared analogously to Example 123 from 5-bromo-6-(4-phenylmercaptobutoxy )-carbostyril and hydrogen peroxide.

M.p.: 190 - 191°C Yield: 82 % of theory.

Example 236 4-Methyl-6-/?-(2-pyridylsulfinyl)-butoxv7carbostyril 0.170 g (0.0005 mol) of 4-methyl-6-/7-(2-pyridylmercapto)-butoxy/carbostyril, dissolved in 5 ml of glacial acetic acid, and 0.107 g (0.0005 mol) of sodium metaperiodate, dissolved in 6 ml of water, were mixed and left stand at room temperature for 22 hours. Subsequently the solution was diluted with 20 ml of water and the reaction product was extracted with chloroform. The extract was shaken once with sodium O-n I^ACXJ-O ULS) bicarbonate solution and dried over jwatdv frojfr magnesium sulfate. After evaporating the organic phase the obtained residue was recrystallized from toluene.

M.p.: 166 - 168 C ... ^ Yield: 0.04 g (22,5 % of theory). I. ^9 WOt/1980 n 98 ~ 189685 Example 257 6-(4-tert.-Butylsulflnyl-butoxv)-3.4-dihvdrocarbostyril Prepared analogously to Example 123 from 6-(4-tert.-butyl-mercapto-butoxy)-3,4-dihydrocarbostyrl (m.p.: 117 - 118°C) and hydrogen peroxide.

M.p.: 126 - 128°C Yield: 62 % of theory.

Example 238 6-/5- (3-Hvdroxv-^jyi,ide-2-t-v^)-butoxy7-3.4-dlhydrocarbostyril Prepared analogously to Example 122 from 6-(4-bromobutoxy)-3,4-dihydrocarbostyril (m.p.: 142 - 147°C) and 3-hydroxy-2-mercapto-pyridine.

M.p.: 211 - 216°C Yield: 58 % of theory.

Example 239 6-/5-(1 ,2.4-Tria2ole-3-yl-sulfinyl)-butoxv7carbostyril Prepared analogously to Example 123 from 6-/5-(1,2,4-t^i-azole-3-yl-^lercapto)-butoxy7carbostyril and hydrogen peroxide. z.Lucxsrtr FU-value: 0.12 (silica gel fluorescent plate, ft-luont: *-<£thuienz chief I'cle. jbthylcnochloridfe/methanol = 95/5). frXftAlWOTFCi r*—1—r--« -- - i | _ 19 NOV 1980 »- or 1896, '0 J Example 240 6-/5-(1,2,4-Triazole-3-yl-mercapto)-butoxy7-3,4-dihydro-carbostyrll Prepared analogously to Example 122 from 6-(4-bromobutoxy)-3»4-dihydrocarbostyril (m.p. : 142 - 147°C) and 3-mercapto-1,2,4-triazole.

M.p.: 152 - 154°C Yield: 82 % of theory.

Example 241 6-/5-(1,2,4-Triazol e-3-yl- sulf inyl) -butoxy7-3,4-dihydrocarbostyril Prepared analogously to Example 123 from 6-/5-(1,2,4-triazole-3-yl-mercapto)-butox^7-3»4-dihydrocarbostyril and hydrogen peroxide. iLuasrt R^-value: 0.18 (silica gel fluorescent plate, /?lubnjfc: cJjt&niUe ^thylonoohloride/methanol = 95/5).

Example 242 6-/5-(1,2,4-Triazole-3-yl-sulfonyl)-butoxy7~3»4-dihydrocarbostyril Prepared analogously to Example 124 from 6-/5-(1,2,4-tri-azole-3-yl-mercapto )-butoxy7-3,4-dihydrocarbostyril and hydrogen peroxide. cLucurt R^-value: 0.22 (silica gel fluorescent plate, fluent: frthy^ cmorffil'nri ri ^/methanol = 95/5).

M.p.: 217 - 224°C. rsn 119 NOV 1930 'T:!VED n S96 Example 245 6-/5-(2,4,5-Trichlorophenylmercapto)-butoxy7-3,4-dihydrocarbostyril Prepared analogously to Example 122 from 6-(4-bromobutoxy) 3,4-dihydrocarbostyril (m.p.: 142 - 147°C) and 2,4,5-tri-chloro-thiophenol.

M.p.: 144 - 145°C Yield: 87 % of theory.

Example A Tablets containing 100 mg of 6-/5-(2-Pyridylsulfinyl)-butoxy7-3 > 4-dihydrocarbostvrll Composition: 1 tablet contains: Active ingredient 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: The active ingredient, mixed with lactose and corn starch, was homogeneously moistened with an aqueous solution of polyvinylpyrrolidone. The mixture was passed through a screen of 2.0 mm mesh-size, dried at 50 C (in aJnurdlq, again passed through a screen of mesh-size 1.5 mm and the lubricant was added* Then the mixture was pressed into tablets.

Weight of tablet: 220 mg ^ /flurla/.

Diameter: 10 mm, Ibiplari with a facet on both sides and a notch on one side.

Example B Coated tablets containing 50 mg of 6-(4-Phenylsulfinylbutoxy)-3.4-dihydrocarbostyrll 1 coated tablet contains: Active ingredient Lactose Corn starch 50.0 mg 40.0 mg 17.0 mg tiz iRA-'VNTOPPggfr 19 NOV J930 \ 89b8 Polyvinylpyrrolidone 2.0 mg Magnesium stearate 1.0 mg 110.0 mg Method of preparation: The granulate was prepared analogously to Example A. The mixture was pressed into coated tablets.

Weight of core: 110 mg Diameter: 8 mm, biconvex.

The cores were isolated and subsequently covered in a coating vessel according to known processes with pyrrolidone and with a coating consisting essentially of sugar up to 200 mg and subsequently coated with pure sugar syrup to 210 mg.

Example C Hard gelatine capsules containing 100 mg of 6-/5-(2-Pyridyl-sulfinvl)-butoxv7-3.4-dihydrocarbo styril 1 capsule contains: Active ingredient 100.0 mg Corn starch (dried) approx. 130.0 mg Lactose (pulverized) approx. 87.0 mg Magnesium stearate 3.0 mg 320.0 mg Method of preparation: The active ingredient and the auxiliary products were mixed, passed through a screen of 0.75 mm mesh-size and mixed homogeneously with a suitable device. The mixture was filled into hard gelatine capsules of size 1.

Content of capsule: approx. 320 mg Capsule: hard gelatine size 1 189685 Example D Suppositories containing 150 mg of 6-(4-Phenylsulfinylbutoxy)-3»4-dlhydrocarbostyrll 1 suppository contains: Active ingredient 150.0 mg Polyethylene glycol 1500 550.0 mg Polyethylene glycol 6000 460.0 mg Sorb'i-frtui Polyoxyethylene ft orb-it an tf monostearate 840.0 mg 2 000.0 mg Method of preparation: After melting the suppository mass^ the active ingredient was homogenously dispersed therein and the melt was poured into pre-cooled moulds.

Example E Suspension containing 50 mg of 6-/5- (2-Pyridyl sulf inyl-butoxy/-3.4-dihydrocarbostyrll per 5 ml 100 ml of suspension contain: Active ingredient 1.0 g Carboxymethyl cellulose^Na^salt 0.1 g 0.05 g 0.01 g 10.0 g 5.0 g 20.0 g 0.3 g 100 ml Methyl/p-hydroxybenzoate Propyl^p-hydroxybenzoate Cane sugar Glycerine Sorbit solution 70 % Aroma Water dist. ad 19 NOV 1980

Claims (68)

- 104 - 189685 Method of preparation; Distilled water was heated to 70°C. Whilst stirring methyl-.p-hydroxybenzoate and propyl^p-hydroxybenzoate as well as glycerine and carboxymethyl cellulose sodium salt were dissolved therein. The mixture was cooled to room temperature and whilst stirring the active ingredient was added and the cits per bC'-cA whole was homogenously (kibperged. After adding and dissolving the sugar, the sorbit solution and the aroma, the suspension was evacuated whilst stirring for deaeration. 5 ml of suspension contain 50 mg of active ingredient. 1 > NOV 1980 HKT.-Vj; - 105 - [WHAT fyWE CLAIM ttt-

1. Compounds of general formula I, /^<"3 ■O-D-SO -R„ m l (i) 0^ R1 4 wherein W represents a vinylene group (optionally substituted by a methyl group) or a methylene or ethylene group; m is 0,1 or 2; D represents a straight-chained or branched alkylene group containing from 2 to 6 carbon atoms, a straight-chained or branched hydroxyalkylene group containing from 3 to 6 carbon atoms or a xylylene group; R^ represents a hydrogen atom or an alkyl group containing from 1 to 3 carbon atoms; R^ represents a cycloalkyl group containing from 3 to 6 carbon atoms; an aryl group containing from 6 to 10 carbon atoms, an aralkyl group containing from 7 to 11 carbon atoms, a heteroaryl group containing from 4 to 9 carbon atoms or a heteroaralkyl group containing from 5 to 10 carbon atoms, said heteroaryl or heteroaralkyl group containing either a nitrogen atom and/or an oxygen or sulfur atom or two nitrogen 189685 ■ 106 " atoms (said aryl, aralkyl, heteroaryl or heteroaralkyl group being optionally substituted in the aromatic moiety by an alkyl group containing from 1 to 4 carbon atoms, a hydroxy, methoxy, amino, acetylamino, nitro, Ctjdohzx i^L carboxy]^or phenyl group or by a halogen atom and,in the case that the aryl, aralkyl, heteroaryl or heteroaralkyl group being substituted is a phenyl group, said monosubstituted phenyl group optionally being further substituted by 1 or 2 substituents selected from alkyl and alkoxy groups each containing from 1 to 4 carbon atoms and halogen atoms); a 1,2,4-triazolyl, triphenylmethyl, 4,5-bis-(j)-chlorophenyl)-oxazole-2-yl, N-methyl-cyclohexylamino-carbonylmethyl or amino-iminomethyl group; or, when either m is 1 or D represents a straight-chained or branched hydroxyalkylene group containing from 3 to 6 carbon atoms or a xylylene group, alternatively an alkyl group containing from 1 to 6 carbon atoms; and and R^, which may be the same or different, each represents a hydrogen or halogen atom, an alkyl group containing from 1 to 4 carbon atoms or an amino, acetylamino or nitro group.

2. Compounds as claimed in claim 1 wherein R2 represents a cyclohexyl, benzyl, naphthyl ,pyridyl, pyrimidyl, 1,2,4-triazolyl, pyridyl-oxide, furfuryl, triphenylmethyl, quinolyl, benzimidazolyl, benzthiazolyl, quinazolin-4-one-yl, 4,5-bis-(£-chlorophenyl)-oxazole-2-yl, N-methyl-cyclohexylamino-carbonylmethyl or amino-iminomethyl group; a phenyl group optionally substituted by a carboxyl, hydroxy , methoxy, amino, acetylamino, fSfk - 107 - nitro, cyclohexyl or phsiyl group; a phenyl group substituted by one or two substituents selected from alkyl groups containing from 1 to 4 carbon atoms and halogen atoms; or a hydroxyphenyl, halophenyl or aminophenyl group substituted by two halogen atoms or by two alkyl groups each containing from 1 to 4 carbon atoms: represents a hydrogen, chlorine or bromine atom or a methyl, amino, acetylamino or nitro group: and represents a hydrogen atom.

3. Compounds as claimed in claim 2 wherein W represents a vinylene group (optionally substituted by a methyl group) or an ethylene group; D represents an alkylene group containing from 2 to 5 carbon atoms or a hydroxyalkylene group containing from 3 to 5 carbon atoms; R^ represents a hydrogen atom; R2 represents a cyclohexyl, phenyl, benzyl, naphthyl, biphenylyl, cyclohexylphenyl, pyridyl, methylphenyl, methoxyphenyl, fluorophenyl, chlorophenyl, dichlorophenyl , trichlorophenyl, bromophenyl, dibromophenyl, bromomethylphenyl, amino-dibromophenyl or hydroxy-di-tert.-butylphenyl group; and R^ represents a hydrogen atom.

4. Compounds as claimed in claim 3 wherein W represents an ethylene, vinylene or 2-methylvinylene group; D represents an ethylene, n-propylene, n-butylene or 2-hydroxy-n-propylene group; and R2 represents a cyclohexyl, phenyl, benzyl, naphth *-2-yl 2-methoxyphenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2,5-dichlorophenyl, 4-amino-3,5-dibromophenyl, 4-;- 108 ";hydroxy-3,5-di-tert.-butylphenyl or pyrid-2-yl group.;

5. 6-(4-Phenylsulf inylbuto xy)-3,4-dihydrocarbos tyri1,;

6. 6-[4-(3,4-Dichlorophenylsulfinyl)-butoxy]-3,4-dihydrocarbostyril.;

7. 6-[4-(Pyrid-2-ylsulfonyl)-butoxy]carbostyril.;

8. Compounds as claimed in claim 1 wherein W represents a vinylene or ethylene group: D represents a straight-chained or branched alkylene group containing from 2;to 6 carbon atoms or a straight-chained or branched hydroxyalkylene group containing from 3 to 6 carbon atoms: represents a cycloalkyl group containing from 3 to 6 carbon atoms; an aryl group containing from 6 to 10 carbon atoms, an aralkyl group containing from 7 to 11 carbon atoms, a heteroaryl group containing from 4 to 9 carbon atoms or a heteroaralkyl group containing from 5 to 10 carbon atoms, said heteroaryl or heteroaralkyl containing a nitrogen atom and/or an oxygen or sulfur atom or two nitrogen atoms (said aryl, aralkyl, heteroaryl or heteroaralkyl group being optionally substituted in the aromatic moiety by a methyl, hydroxy, methoxy, acetylamino or phenyl group or by a halogen atom and, in the case that the aryl, aralkyl, heteroaryl or heteroaralkyl group being substituted is a phenyl group, said monosubstituted phenyl group optionally being further substituted by a methyl or methoxy group or a halogen atom); a triphenylmethyl, 4,5-bis-(£-chlorophenyl)-oxazole-2-yl or amino-iminomethy1 group; or, when either m is 1 or D represents a straight-chained or branched;- 109 -;hydroxyalkylene group containing from 3 to 6 carbon atoms, alternatively an alkyl group containing from 1 to 6 carbon atoms; and and R^ each represents a hydrogen atom.;

9. Compounds as claimed in claim 1 wherein D represents a straight-chained or branched alkylene or hydroxyalkylene group containing from 3 to 6 carbon atoms or a xylylene group: R^ represents a hydrogen atom: R^ represents a phenyl group (optionally substituted by a carboxyl, nitro, amino, phenyl or cyclohexyl group); a phenyl group substituted by one or two substituents selected from halogen atoms and alkyl groups each containing from 1 to 4 carbon atoms; a hydroxyphenyl, halophenyl or aminophenyl group substituted by two alkyl groups each containing from 1 to 4 carbon atoms or by two halogen atoms; a cyclohexyl, benzyl, pyridyl, naphthyl, quinolyl, 1,2,4-triazolyl or N-methyl-cyclohexylamino-carbonylmethyl group; or, when either m is 1 or D represents a straight-chained or branched hydroxyalkylene group containing from 3 to 6 carbon atoms, alternatively a tert.-butyl group.;

10. Compounds as claimed in claim 1, other than those claimed in any one of claims 5 to 7, as herein specifically disclosed in any one of Examples 1 to 243.;

11. Compounds as claimed in claim 8, other than those claimed in any one of claims 5 to 7, as herein specifically disclosed in any one of Examples 1 to 121.;

12. Compounds as claimed in claim 9, other than those claimed in any one of claims 5 to 7, as herein;- 110 -;\\ 896;specifically disclosed in any one of Examples 122 to 235.;

13. A process for the preparation of compounds of general formula I as claimed in claim 1 which comprises reacting a compound of formula II,;(II);(wherein R^, R^, R^ and W are as defined in claim 1), or a salt thereof with an inorganic or tertiary organic base, with a compound of formula III,;Z - D - SO - R0 (III);m z;(wherein D, R£ and m are as defined in claim 1 and Z represents a nucleophilically exchangeable atom or group).;

14. A process as claimed in claim 13 wherein, in the compound of formula III, Z represents a halogen atom or a sulfonic acid ester group.;

15. A process as claimed in claim 13 wherein the reaction is effected in the presence of an anhydrous aprotic solvent.;- Ill -;1 @96©;

16. A process as claimed in any one of claims 13;to 15 wherein the reaction is effected in the presence of an alkali metal base.;

17. A process as claimed in any one of claims 13;to 16 wherein the reaction is effected at temperatures of from 10 to 50°C.;

18. A process for the preparation of compounds of general formula I as claimed in claim 1 wherein m is 1 which comprises oxidising a compound of frmula I as defined in claim 1 wherein m is 0 whereby the desired compound of formula I is obtained.;

19. A process as claimed in claim 18 wherein the oxidation is effected in the presence of a solvent.;

20. A process as claimed in claim 18 or claim 19 wherein oxidation is effected with about one equivalent of an oxidising agent.;

21. A process as claimed in any one of claims 18 to 20 wherein oxidation is effected with hydrogen peroxide in glacial acetic acid at 0 to 20°C or in acetone at 0 to 60°C; with a peracid in glacial acetic or trifluoroacetic acid at 0 to 50°C; with sodium metaperiodate in aqueous methanol or ethanol at 15 to 25°C; with N-bromo-succinimide in ethanol; with tert.-butyl hypochlorite in methanol at -80 to -30°C;;with iodobenzene dichloride in aqueous pyridine at 0 to 50°C; with nitric acid in glacial acetic acid at 0 to 20°C; with chromic acid in glacial acetic acid or in acetone at 0 to 20°G; or with sulfuryl chloride in methylene chloride at.about -70°C,;\\ 896;the thioether chlorine complex thus formed being hydrolysed in aqueous ethanol.;

22. A process as claimed in any one of claims 18 to 20 wherein oxidation is effected with hydrogen peroxide in formic acid at 0 to 20°C.;

23. A process for the preparation of compounds of general formula I as claimed in claim 1 wherein m is 2 which comprises oxidising a compound of formula I as defined in claim 1 wherein m is 0 or 1 whereby the desired compound of formula I is obtained.;

24. A process as claimed in claim 23 wherein the oxidation is effected in the presence of a solvent.;

25. A process as claimed in claim 23 or claim 24 for the oxidation of a compound of formula I wherein m is 0 in which oxidation is effected using two or more equivalents of an oxidising agent.;

26. A process as claimed in claim 23 or claim 24 for the oxidation of a compound of formula I wherein m is 1 in which oxidation is effected using one or more equivalents of an oxidising agent.;

27. A process as claimed in any one of claims 23 to 26 wherein oxidation is effected with hydrogen peroxide in glacial acetic acid at 20 to 100°C or in acetone at 0 to 60°C; with a peracid in glacial acetic acid, trifluoroacetic acid or chloroform at 0 to 50°C; with nitric acid in glacial acetic acid at 0 to 20°C; or with chromic acid or potassium permanganate in glacial acetic acid, aqueous sulfuric acid or acetone at 0 to 20°C.;-113 -;

28. A process as claimed in any one of claims 23 to 26 wherein oxidation is effected with hydrogen peroxide in formic acid at 20 to 100°C.;

29. A process for the preparation of compounds of general formula I as defined in claim 1 wherein m is 0 which comprises reacting a compound of formula IV,;0-d-x with a compound of formula V,;(IV);Y - R2 (V);(wherein, in the above formulae IV and V, R^, R2, R^,;R., D and W are as defined in claim 1 and either 4;one of X and Y represents a mercapto group whilst the other of X and Y represents a nucleophilically exchangeable atom or group or alternatively, when D represents a hydroxyalkylene group containing from 3 to 6 carbon atoms, X may, together with the hydroxy group in D, represent an epoxide group, Y then representing a mercapto group).;

30. A process as claimed in claim 29 wherein the reaction is effected in the presence of an anhydrous aprotic solvent.;- 114 -;1 8968;

31. A process as claimed in claim 29 or claim 30 wherein the reaction is effected in the presence of an alkali metal base.;

32. A process as claimed in any one of claims 29;to 31 wherein the reaction is effected at temperatures of from 10 to 50°C.;

33. A process as claimed in any one of claims 29 to 32 wherein, in formulae IV and V, one of X and Y represents a mercapto group and the other of X and;Y represents a nucleophilically exchangeable atom or group.;

34. A process as claimed in claim 33 wherein the nucleophilically exchangeable atom or group is a halogen atom or a sulfonic acid ester group.;

35. A process for the preparation of compounds of general formula I as defined in claim 1 wherein R^ represents an alkyl group containing from 1 to 3 carbon atoms which comprises reacting a compound of formula I as defined in claim 1 wherein R^ represents a hydrogen atom, or an alkali metal salt thereof,;with a compound of formula VI,;Z' - Rx (VI);(wherein R^ is as defined in claim 1 and Z' represents a nucleophilically exchangeable atom or group).;

36. A process as claimed in claim 35 wherein, in the compound of formula VI, Z' represents a halogen atom or a sulfonic acid ester group.;115- n 896;

37. A process as claimed in claim 35 or claim 36 wherein the reaction is effected in the presence of an aprotic solvent.;

38. A process as claimed in any onecf claims 35;to 37 wherein the reaction is effected in the presence of an inorganic base or of an alcoholate.;

39. A process as claimed in any one of claims 35;to 38 wherein the reaction is effected at temperatures of from 10 to 25°C.;

40. A process for the preparation of compounds of general formula I as defined in claim 1 wherein W represents a vinylene group which comprises dehydro-genating a compound of formula I as defined in claim 1 wherein W represents an ethylene group.;

41. A process as claimed in claim 40 wherein dehydrogenation is effected in the presence of 2,3-dichloro-5,6-dicyano-benzoquinone9 chloranil or a noble metal catalyst.;

42. A process as claimed in claim 40 or claim 41 wherein the dehydrogenation is effected in the presence of an inert solvent.;

43. A process as claimed in any one of claims 40;to 42 wherein the dehydrogenation is effected at the boiling temperature of the reaction mixture.;

44. A process for the preparation of compounds of general formula I as defined in claim 1 wherein W represents an ethylene group and m is 0 or 2 which comprises hydrogenating a compound of formula I as defined in claim 1 wherein W represents a vinylene group and m is 0 or 2.;- 116 ";

45. A process as claimed in claim 44 wherein the hydrogenation is effected in the presence of ethanol, ethyl acetate, glacial acetic acid or dioxan as solvent.;

46. A process as claimed in claim 44 or claim 45 wherein hydrogenation is effected with hydrogen in the presence of a catalyst.;

47. A process as claimed in claim 46 wherern the catalyst is palladium/charcoal, platinum, Raney nickel, Raney cobalt or dirhenium heptasulfide.;

48. A process as claimed in claim 46 or claim 47 wherein the hydrogenation is effected at a hydrogen pressure of from 1 to 5 bar.;

49. A process as claimed in any one of claims 44;to 48 wherein the hydrogenation is effected at ambient temperatures.;

50. A process as claimed in any one of claims 13 to 21, 23 to 27 and 33 to 49 for the preparation of compounds as claimed in claim 8.;

51. A process as claimed in any one of claims 13 to 21, 23 to 27, 29 to 34 and 40 to 49 for the preparation of compounds as claimed in claim 9.;

52. A process for the preparation of compounds as claimed in claim 1 substantially as herein described.;

53. A process for the preparation of compounds as claimed in claim 1 substantially as herein described in any one of Examples 1 to 243.;

54. Compounds as claimed in claim 1 whenever prepared by a process as claimed in any one of claims 13;to 49, 52 and 53.;- 117 _;& 96;

55. A process for the preparation of compounds as claimed in claim 8 substantially as herein described in any one of Examples 1 to 121.;

56. Compounds as claimed in claim 8 whenever prepared by a process as claimed in claim 50 or claim 55.;

57. A process for the preparation of compounds as claimed in claim 9 substantially as herein described in any one of Examples 122 to 235.;

58. Compounds as claimed in claim 9 whenever prepared by a process as claimed in claim 51 or claim 57.;

59. Pharmaceutical compositions comprising, as active ingredient, at least one compound as claimed in claim 1 in association with pharmaceutical carrier or excipient.;

60. Compositions as claimed in claim 59 in a form suitable for oral, rectal or parenteral administration.;

61. Compositions as claimed in claim 59 or claim 60;in the form of plain tablets, coated tablets, capsules, suppositories, solutions or suspensions.;

62. Compositions as claimed in any one of claims 59 to 61 in the form of dosage units.;

63. Compositions as claimed in claim 62 wherein each dosage unit contains from 50 to 100 mg of active ingredient.;

64. Compositions as claimed in any one of claims 59 to 63 wherein the active ingredient comprises a compound as claimed in any one of claims 5 to 7.;

65. Compositions as claimed in claim 59 wherein the active ingredient comprises a compound as claimed in claim 8.;- 118;

66. Compositions as claimed in claim 59 wherein the active ingredient comprises a compound as claimed in claim 9.;

67. Pharmaceutical compositions as claimed in claim 59 substantially as herein described.;

68. Pharmaceutical compositions substantially as herein described in any one of Examples A to E.;£>-9- A method of treating animals suffering from ox-;susceptible to thromboembolic diseases^-andTor arteriosclerosis whichcomprlses administering to the said animal^aR-~e'ffective amount of a compound as s^trlmod in claim 1. * BALDWIN, SON & CAREY