CA1116600A

CA1116600A - Carbostyril and oxindole derivatives, their preparation and their use as pharmaceuticals

Info

Publication number: CA1116600A
Application number: CA000321738A
Authority: CA
Inventors: Erich Muller; Josef Nickl; Josef Roch; Berthold Narr; Walter Haarmann; Johannes M. Weisenberger
Original assignee: Individual
Current assignee: Boehringer Ingelheim Pharma GmbH and Co KG
Priority date: 1978-02-17
Filing date: 1979-02-19
Publication date: 1982-01-19
Also published as: YU41146B; RO82013B; DK157017C; PH16698A; FI790507A7; EP0003771B1; NO152839C; NO790521L; GR66565B; DK69679A; SU852170A3; CS227005B2; NO152839B; IE48179B1; PL213471A1; ES484633A1; NZ189685A; JPS54132581A; YU36679A; RO82013A

Abstract

ABSTRACT
This invention relates to new carbostyril and oxindole derivatives which possess interesting pharmacological properties and in particular, in general, a positive inotropic activity as well as an antithrombotic activity. Processes for the preparation of these compounds are described and exemplified. Examples of pharmaceutical compositions containing the new compounds are also given.

Description

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. .
.

This invention re]ates 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 5 there are provided compounds of general formula I, 3 (I) o~ N~O - D - Sm - R2 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-chain 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;
Rl represents a hydrogen atom or an alkyl group contain-ing from 1 to 3 carbon atoms;
R2 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 hetero-aryl 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 atoms (said aryl, aralkyl, heteroaryl or heteroaralkyl group being optionally substituted in the aromatic moiety by an alkyl group containing from 1 to 4 car-bon atoms, a hydroxy, methoxy, amino, acetylamino, nitro, carboxyl, cyclohexyl 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 select-ed 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-(p-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 L ~ 3 ;6~1D

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 R3 and R4, 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 R2, R3 and /or R4 represent a halogen atom, this may, be a fluorine, chlorine, bromine or iodine atom.
15D may, for example, represent an ethylene, n-propylene, n-butylene, n-pentylene, n-hexylene, 1-méthylethylene, 2-methylethylene, l-methyl-n-propylene,

2-methyl-n-propylene, 3-methyl-n-propylene, l-methyl-n-butylene, 2-methyl-n-butylene, 3-methyl-n-butylene, 4-methyl-n-butylene, l-methyl-n-pentylene, 2-methyl-n-pentylene, 3-methyl-n-pentylene, 4-methyl-n-pentylene, 5-methyl-n-pentylene, l,l-dimethylethylene, 1,2-dimethylethylene, 2,2-dimethylethylene, l,l-dimethyl-n-propylene, 2,2-dimethyl-n-propylene, 3,3-dimethyl-n-propylene, 1,2-dimethyl-n-propylene, 1,3-dimethyl-n-propylene, l,l-dime~hyl-n-butylene, 2,2-dimethyl-n-butylene, 3,3-dimethyl-n-butylene, 4,4-dimethyl-n-butylene, 1,2-dimethyl-n-butylene, 1,3-dimethyl-n-butylene, 1,4-dimethyl-n-butylene, 2,3-dimethyl-n-butylene, l-ethylethylene, 2-ethylethylene, l-ethyl-n-- .- ,. -~ 6~

propylene, 2-ethyl-n-propylene, 3-ethyl-n-propylene, l-ethyl-n-butylene, 2-ethyl-n-butylene, 3-ethyl-n-butylene, 4-ethyl-n-butylene, l-methyl-k-ethyl-ethylene, l-methyl-2-ethyl-n-propylene, l-methyl-3-ethyl-n-pro-pylene, l-methyl-2-propyl-ethylene, l-propylethylene, l-butylethylene, l-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-10 n-hexylene, 1-methyl-2-hydroxy-n-propylene, 2-hydroxy-2-methyl-n-propylene~ p-xylylene, o-xylylene or m-xylylene group.
Rl 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, n.aphthylmethyl, cyclohexylphenyl, biphenyl, triphenylmethyl, N-methylcyclohexylamino-carbonylmethyl,amino-iminomethyl, pyridyl, pyridylmethyl, furfuryl, benzimidazolyl, benzthiazolyl, pyrimidyl, 1,2,4-triazolyl, quinolyl, quinazoline-4-one-yl, 4,5-bis-(~-chlorophenyl)-oxazole-2-yl, pyridyl-oxide, methylphenyl, dimethylphenyl, tert.-butylphenyl, methyl-tert.-butylphenyl, methylpyridyl, methoxyphenyl, dimethoxyphenyl, methoxypyridyl, hydroxyphenyl, - fluorophenyl, difluorophenyl, trifluorophenyl, fluoro-pyridyl~ chlorophenyl, dichlorophenyl~ trichlorophenyl~
chloropyridyl, bromophenyl, dibromophenyl, aminophenyl, acetylaminophenyl, aminopyridyl, acetylaminopyridyl, nitrophenyl, carboxyphenyl,hydroxy dichlorophenyl, hydroxy-dibromophenyl, amino-dichlorophenyl, amino-dibromophenyl, I
' ' 6~?~
, hydroxy-di-tert.-butylphenyl, methoxy-fluorophenyl, methoxy-chlorophenyl, methoxy-bromophenyl, fluoro-methylphenyl, chloromethylphenyl or bromomethylphenyl group.
R3 and R4, 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.
10 - Preferred compounds according to the invention are those wherein R2 represents a cyclohexyl, benzyl,naphthyl, pyridyl, pyrimidyl~ l,2~4-triazolyl, pyridyl-oxide, furfuryl, triphenylmethyl, quinolyl, benzimidazolyl, benzthiazolyl, quinazoline-4-one-yl, 4,5-bis-(~-chlorophenyl)-oxazole-2-yl, N-methylcyclohexylamino-carbonylmethyl or amino-iminomethyl 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 ea~ 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: R3 represents a hydrogen, chlorine or bromine _ 25 atom or a methyl, amino, acetylamino or nitro group: and R4 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;

,, ~ " ,~"" , ,,"~

~ 6~
_ 7 -D represents an alkylene group containing from 2 to 5 carbon atoms or a hydroxyalkylene group containing from

3 to 5 carbon atoms; Rl 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 R3 represents a hydrogen atom.
10 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 R2 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-dihydrocarbostyril, 6-[4-(3,4-dichlorophenylsulfinyl)-butoxy]-3,4-dihydrocarbostyril, and 6-[4-(pyrid-2-ylsulfonyl)-butoxy]carbostyril.
The compounds of general formula I
are prepared by the following processes, which processes constitute further features of the present invention: :
A) Reaction of a compound of formula II, - . . . .. , -6~) // ~ ~ RLOH (II~

(wherein Rl, R3, R4 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 - S0 - R (III) m 2 (wherein D, R2 and m are as hereinbefore defined) and Z represents a nucleophilically exchangeable atom or group,for example ~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 asuitable solvent such as e.g. dioxan, tetrahydrofuran, chloroform or toluene, but preferably, however, in an anhydrous aprotic solvent such as, for example, acetone, 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 generaliy from 0C to the boiling temperature of the reaction mixture, for example at temperatures of from 0 to 100C, preferred temperatures being however, from 10 to 50C. The reaction may, if desired, by carried out in the absence of a solvent.

~`l `
t .~

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_ 9 _ B) for the preparation of compounds of general formula I
wherein m is 1 or 2:
Oxidation of a compound of formula I as herein-before defined wherein m is O whereby the desired compound of formula I lS obtained.
The oxidation is preferably carried 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 +10CC 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 glacial acetic acid or formic acid at 0 to 20C or in acetone at 0 to 60C; with a peracid such as e.g. performic acid in glacial acetic acid or trifluoroacetic acid at 0 to 50C; with sodium metaperiodate in aqueous methanol or ethanol at 15 to 25C; with N-bromo-succinimide in 2Q ethanol; with tert.-butyl hypochlorite in methanol at -80 to -30C; with iodobenzene dichloride in aqueous pyridine at O to 50C; with nitric acid in glacial acetic acid at 0 to 20C; with chromic acid in glacia~
acetic acid or in acetone at 0 to 20C; or with sulfuryl chloride in methylene chloride at -70C, the thioether chlorine complex thus formed being appropriately hydrolysed with aqueous ethanol.
C) for ~he 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 O or 1 whereby the _-- ~

~ - ".:

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 +100C depending on the oxidising agent used. Where it is desired to oxidise a compound of formula I wherein m is O 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 l, 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 100C or in acetone at O to 60C; with a peracid such as e.g. performic acid or _-chloro-perbenzoic acid in glacial acetic acid, trifluoroacetic acid or chloroform at temperatures of from O to 50C;
with nitric acid in glacial acetic acid at O to 20C;
or with chromic acid or potassium permanganate in glacial acetic acid, aqueous sulfuric acid or in acetone at O to 20C.
D) for the preparation of compounds of general formula I wherein m is 0:
Reaction of a compound of formula IV, ,~N~ O - D - X

1 ," " ~ ' __ "
1.

n~

with a compound of formula V, Y - R2 (V) (wherein, in the above formulae IV and V, Rl, R3, R4, D and W are as hereinbefore defined and either one of 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 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 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 0C to the - boiling temperature of the reaction mixture e.g. at temperatures of from Q to ]00C. Preferred temperatures are, however, from lO to 50C. The reaction may, if desired, be carried out in the absence of a solvent.

. ~.
~ . ~ . . . .. .... .
~ , .. . ....
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E) for the preparation of compounds of general formula I wherein Rl represents an alkyl group containing from 1 to 3 carbon atoms:
Reaction of a compound of formula I as herein-before defined wherein Rl represents a hydrogen atom, or an alkali metal salt thereof, with a compound of formula VI, (VI) (wherein Rl is as hereinbefore defined and Z'represents a nucleophilically exchapgeable 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, sodium hydride or potassium hydroxide or of an alcoholate such as e.g. sodium methoxide. Suitable temperatures for the ;reaction are generally 0 to 50C, preferred temperatures being from 10 to 25C.
Particular compounds of general formula VI which may 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.

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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 ~ represents an ethylene 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 200C, most preferably at the boiling temper-ature 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 herein-before defined wherein W represents a vinylene group and m is 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 50C, preferred temperatures being ambient temperatures.

, ~ ~", .. ,. .- , ~
1 " ' ^ ' '-' ' . . ' '', . .
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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 of formula II can be obtained by acylation of a corres-ponding aniline derivative with an appropriate ~-halo-carboxylic acid derivative and subsequent cyclisation according to the method described by Friedel-Crafts (see J. chem. Soc. 1955, 743-744; Chem. Pharm. Bu11~1961, 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-(~-cyanoethyl)-cyclohexane-1,3-dione derivative and subsequent aroma-tisation for example with N-bromo-succinimide (see Chem.
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. 72, 346 (1950) and ibid 76, 2402 (1954) or J. Org. Chem. 33, 1089 (1968) and ibid 3$, 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 corresponding hydroxy derivative.
As already mentioned above, the compounds of general formula I possess interesting pharmacological activities. Those compounds which we have tested show not only a positive inotropic activity but also antithrombotic activity. Such compounds are thus of use 1~16~

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 foll-owing compounds were tested with regard to their bio-logical 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-dihydro-carbostyril, 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, . ~
. ., 6~

'1~

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]-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 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 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 collagen of Messrs. Hormonchemic, Munich). The adenosine ,~

: , .

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/l. Commercial ADP of Messrs.
Boehringer Mannheim was used.
S The dosage of the test compounds which provoked a 50% inhibition of th~ thrombocyte aggregation was determined graphically (ED50) Compound ED50 10 mol/l Collagen ADP

10 A 50 ~ 100 D 45 > 100 E 6.5 25 G 3.5 17-H 2~5 14 K 4,5 12 N 0.6 3 O 0.2 0.5 P 0.2 1.8 25 ~ 3.6 40 R 1.5 25 S 1.0 10 T 0.1 6 ... . . _ ~ r- ,,~
.

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2. Determination of the prolon~ation of bleedin~ time:
Preliminar~ rk:
The human organism as well as other warm-blooded animals have an ingenious mechanism, which 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 coagulation system. In this sys~2m 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 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 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-recalcif. time, Quick-Test Thrombin time~ etc.).
The normality of the thrombocytes can be determined by measuring the bleeding timeO The normal bleeding time in human beings is in the range of l to 3 minutes and requires intact thrombocytes in a sufficient number.
If the number of thrombocytes is normal and the bleeding time is prolonged this signifies an ab~ormality _ ~

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1~16~
.

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 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 such a substance, coagulation tests will give a normal ! result-Literature: W.D. Keidel: KurzgefasstesLehrbuchder Physiologie, Georg Thieme Verlag Stuttgart 1967, page 31: the proceeding of hemostasis.
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.
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:

-. .
' ' ' ' : ~ . . ., _, .
,~' 6~

. .
CompoundProlongation of the ~eeding time in % after one hour .. .. ~
. A 145 !"~ G - 5 I >300 -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 30C. The tyrode solution ~.
r ~ ,~
,., , was infused with carbogen (95% of 2 and 5% of C02).
The spontaneous contractions of the auricles were registered isometrically. The auricles were charged with 1 g. The test compounds w~re tested on 4 auricles 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.
i ~Compound Increase in contraction force in %
.

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).

l ~
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Compoundacute toxicity per os _. _ A~1 000 mg/kg (0 out of 10 animals died) B>1 000 mg/kg (0 out of 10 animals died) C~1 000 mg/kg (0 out of 10 animals died) D~1 000 mglkg (0 out of lQ animaIs died) E~1 000 mg/kg (0 out of 10 animals died) F~l 000 mg/kg (0 out of 10 animals died) G>1 000 mg/kg (0 out of 10 an~mals died) H~1 000 mg/kg (0 out of 10 animals died) 10 ~ 1 000 mg/kg (0 out of 10 animals died) K~1 000 mg/kg (0 out of 10 animals died) L~1 000 mg/kg (0 out of 10 animals died) M~1 000 mg/kg (0 out of 10 animals died) P71 000 mg/kg (0 out of 10 animals died) Q~1 000 mg/kg (0 out of 10 animals died) R~1 000 mg/kg (0 out of 10 animals died) S~1 000 mg/kg (0 out of 10 animals died) U>1 000 mg/kg (0 out of 10 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 .

-~,, ' ; . '' '. '' ~ ., ' - 23 - . -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, lO ! 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 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 lO0 mg of active ingredient. The oral daily dosage, which may be varied according to the compound used, the subject treated and the complaint concerned, may, for example, be from lO0 to 300 mg per day in adults.
The following non-limiting Examples serve to illustrate the present invention.

_ :
,.' ,~ .

~ 6 Example 1 6-/~_(2-PYridYlmerca~to)-butoxy7- ~ -dlpydrocarbostyril 14,4 g (0,13 mol) Or 2-mercaptopyridine and 17.9 g (0.13 mol) of potas~ium carbonate ~ere ~tirred in 360 ml of dimethyl-sulfoxlde, dried over a molecular sieve, and 36 g (0.12 mol) o~ 6-(4-bromobutoxy)-3,4-dihydrocarbostyril (~.p.s 142 - 147C, prepared ~ro~ 6-hydroxy-carbostyril and 1,4-dibromobutane) were added to this mixture~ After ~tirring for 15 hours at approx.
25C, the reaction mixture was poured into 3.6 1 of water and again stirred for 30 minutes. The precipitated product was suction ~iltered, well washed with water, dried and recrystalli-zed ~rom xylene by addition of charcoal. Yellow crystals o~
.p. 123 - 124.5C were obtained.
Yleld: 32 g (81.2 % of theory).

ExamPle 2 6-t~-(2-PyridYlsulfin~l)-butoxY7-3,4-dihYdrocarbostvril 32.8 g (0.1 mol) of 6- ~-(2-pyridylmercapto)-butoxy7-~,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. 20C. The gla-cial acetic acid was di~tilled off at 60C in ~acuo, the resi-due was wa~hed with ether and the thus obtained crude product was recrystallized twice ~rom xylene by addition of charcoal.
Colourless crystals of m.p. 144.5 - 146C were obtained.
Yield: 27.5 g (79.8 % of theory).

_ .. ~
~ ,. . . . .
~i, ~ , . . . . - ~

~66Q~
. .
Example 6- ~ -(2-~yridYlsul~on~ butoxy7-~4-dihydrocarbo~tyrll

5 g (0.015 mol) of 6- ~-(2-pyridylmercapto)-butox~7-3,4-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 ~tirring ior 40 hours at approx. 25C, the glacial acetic acid was di6tilled off at 60C in vacuo.
The solid residue was washed with ether and recrystallized from xylene by addition o~ charcoal. Colourless crystals of m.p. 12308 - 1 25C were obtained.
Yield: 3.8 g (70.3 X of theory).

' Example 4

6-(4-Phenylsulfin~lbutoxv3-3,4-dih~drocarbostyril 32. 6 g (0. 2 mol) of 6-hydroxy-3,4-dihydrocarbostyrll (~ee 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 dimethyl~ulfox~de, dried over a mole-cular ~ieve,and subsequently 52.2 g of 4-phenylsulfinylbutyl-bromide (0.2 mol) (prepared from thiophenole and 1,4-dibromo-butane and subsequent oxidation with hydrogen peroxide in glacial acetic acid analogously to example 2; oily substance, solidiried whilst standing in the refrigerator) were added.
After stirring ~or 15 hours at 25C the reaction mixture was poured into 6 1 of water. After stirring ior further 30 minu-tes the precipitated product was suction filtered and well washed with water. After drying the residue was recry~tallized from 600 ml (approx.) of xylene by addition of charcoal. White crystals oi m.p. 144.5 - 145.5C were obtained.
Yield: 49 g (71.3 % of theory).

....

..

3~ 6~
~ Exam~le 5 6-(4-Phen~lmercapto-butoxy)-3,4-dihydro-carbostyril ., Prepared analogously to Example 4 from 6-hydroxy-3,4-di-hydro-carbo~tyril and 4-(phenylmercapto)-butylbromide (b.p. o 02 : 96 - 103C, prepared irom thiophenol and 1.4-dlbromobutane).
M.p.: 121.5 - 123C
Yield: 75.6 % of theory.

Example 6 6-Ç4-Phenylsulfonyl-butoxy)-3.4-dihydrocarboRtyril Prepared analogously to Example 4 from 6-hydroxy-3,4-di-hydro-carbo~tyril and 4-phenyl-sulfonyl-butylbromide (pre-pared from 4-(phenylmercapto)-butylbromide by oxidation ana-logously to Example 3).
M.p.: 157.5 - 158C
Yield: 65.1 % of theory.

Example 7 6-/Z-(4-Fluoro~hen~lmercapto)-butoxy7-3,4-dihYdrocarbostYril Prepared analogou~ly to Example 1 from 6-(4-bromobutoxy~-3,4-dihydrocarbostyril (m.p.: 142 - 147C) and 4-fluoro-thiophenol .
M.p.: 139 - 140C
Yield: 93.1 % of theory.

. _ ,,,"t". ,,7,~ ,,"_,'' ,, ,', " _, , _, , '' ' ,' . ' _, ' ' . ' ' . I

Exam~le 8 6~ (4-Fluorophenylsulfin~ butoxy7-~,4-dihydrocarbo~tYril Prepared analogously to Example 2 from 6- ~ -(4-fluorophenyl-mercapto)-butox~7-3,4-dihydrocarbostyril.
M.p.: 184.5 - 186C
Yleld: 88 ~ of theory.

Exam~le 9 -(4-Methylphenyl-merca~to)-butoxY7-3~4-dihydrocarbostyril Prepared analogou~ly to Example 1 from 6-(4-chlorobutoxy)-3,4-dihydrocarbostyril (m.p. 147 - 148C) and 4-methylthio-phenol .
M.p.: 120 - 121C
Yield: 91 % of theory.

Example 10 6-/Z~-(4-MethvlPhenvl-sulfinYl~-butoxv7~3,4-dihYdrocarbostyri Prepared analogously to Example 2 from 6- ~-(4-methylphenyl-mercapto)-butoxy7-3,4-dihydrocarbostyril and hydrogen per-oxide.
M.p.: 149.5 - 150C
Yield: 97 % of theory.

Example 11 6-/~-(3-MethylphenYlmerca~to~-butoxr7-3 t 4-dihydrocarbostYri Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-3,4-dihydrocarbostyrll (m.p. 147 - 148C) and 3-methylthiophenol .

. , , - . .

. i ' .. --- 28 -- `
6~i~

M p 95 - 96C
Yield: 91 % oi theory.

Example 12 6~ (3-MethYlphenylsul~invl)-butoxy7-3~4-dihydrocarbostyri Prepared analogously to Example 2 from 6- ~-(3-methylphenyl-mercapto)-butoxy7-3,4-dihydrocarbofltyril and hydrogen peroxide.
Wax-llke resin.
Yield: 95 % o~ theory.
Ri-value: 0.48 (thin-layer chromatogram on silica gel -eluent. benzene/ethanol/conc. ammonla ~ 75/25/1).
!

ExamPle 13 6-/~-(4-Chlorophenvlmercapto)-butoxY7-~t4-dihydrocarbostYril Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-3,4-di-hydrocarbostyril (m.p. 147 - 148C) and 4-chlorothiophenol .
M.p.: 144 - 146C
Yield: 88 % of theory.

Example 14 6-/~-(4-ChloroPhenvlsulfinvl)-butoxy7-3.4-dihydrocarbostYril Prepared analogously to Example 2 from 6-/~-(4-chlorophenyl-mercapto)-butox~7-3,4-dihydrocarbostyril and hydrogen per-oxide.
M.p.: 148 - 149.5C
Yield: 70 % of theory.

. _ _ =
?~
~-; - ..... . - . .,-Example 15 6-/Z;-(3,4-Dichlorophenylmercapto~ butoxv7-3~.4-dihYdrocarbostvril Prepared analogou~ly to Example 1 from 6-(4-chlorobutoxy)-3,4-dihydrocarbostyril (m.p. 147 - 148C) and 3,4-dichloro-thiophenol .
M.p.: 116.5 - 118C
Yield: 87 X of theory.

Exam~le 16 6-/zi-(3.4-Dichlorophenylsulfinyl)-butoxy7-~,4-dihYdrocarbostvri , .
Prepared analogously to Example 2 from 6- ~-(3,4-dichlorophenyl-mercapto)-butoxy7-3,4-dihydrocarbostyril and hydrogen peroxide.
M.p.: 106.5 - 108C
Yield: 74 % of theory.

Exam~le 17 6-/~-(2-Metho~YPhenylmercapto)-butoxv7-3.4-dihydrocarbostyri Prepared analogously to Example 1 from 6-(4-bromobutoxy)-3,4-dihydrocarbostyril (m.p. 142 - 147C) and 2-methoxythio-phenol .
M.p.: 130.5 - 133C
Yield: 74 % oi theory.

Exam~le 18 6-/~-(2-MethoxvphenYlsulfinvl)-butoxv7-3,4-dihYdrocarbostyril Prepared analogou~ly to Example 2 from 6~-(2-methoxyphenyl-mercapto)-butoxy7-3,4-dihydrocarbostyril and hydrogen peroxide.

~r' ~. '`,; .

_ 30 _ M.p.: 162 - 163C
Yield: 62 % of theory.

Ex~m~ 19 6~ (3-Methoxy~henylmercapto ?-butoxY7-3 ! 4-dihYdrocarbo8tvril Prepared analogou~ly to E~ample 1 from 6-(4-bro~obutoxy)-3,4-dihydrocarbostyril (m.p. 142 - 147C) and 3-methoxy-thiophenol.
M.p.: 93.5 - 97C
Yleld: 61 % of theory.
!' .
Example 20 6-¦~-(3-Metho~phenylsulfinyl?-butox~7-3,4-dihydrocarbostyril Prepared analogously to Example 2 from 6- ~-(3-methoxyphenyl-mercapto)-butoxy7-3,4-dihydrocarbostyril and hydrogen peroxide.
M.p.: 147 - 148C
Yield: 49 % o* theory.

Example 21 6-/~-(4-Met ~ -butoxy7-3,4-dihydrocarbostvril Prepared analogously to Example 1 from 6-(4-bromobutoxy)-~,4-dihydrocarbostyril (m.p. 142 - 147C) and 4-methoxy-thiophenol.
M.p.: 130.5 - 133C
Yield: 82 % Or theory.

",,,.~, .
i 1~ 6~
Example 22 6-/~-(4-MethoxyphenylRul~inyl)_butoxv7-3,4-dih~drocarbostYri Prepared analogously to Example 2 ~rom 6- ~-(4-methoxyphenyl-mercapto)-buto~7-3,4_dihydrocarbo3tyril and hydrogen per-oxide.
M.p.: 132 - 133C
Yleld: 71 % Or theory.

Exam~le 23 6- ~ 4-DimethoxYphenylmercapto)-butoxy7-3~4-dihydrocarbost~-ri Prepared analogou~ly to Example 1 from 3,4-dimethoxythiophenol and 6-(4-chlorobutoxy)-3,4-dihydrocarbostyril ~repared from 6-hydroxy-carbo~tyril (see F. Mayer et al. in Ber. dt~ch.
chem. Ge 60, 858 (1927) and 4-chlorobutyl benzenesulfonate7.

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

Example _ 6- ~-(3,4-Dimethoxyphenylsulfinyl)-buto~7-3,4-dihydrocarbo-stvril _ __ Prepared analogously to Example 2 from 6- ~-(3,4-dimethoxy-phenylmercapto)-butoxy7-3,4-dihydrocarbostyril and hydrogen peroxide.
M.p.: 145 - 147C
Yield: 79 % of theory.

~ -,- . , .
~ . . . - . , . . ..

_ 32 - ~166~`~

Example 2 6- ~-(3,4-DimethoXyphenyl~ulronyl)-bUtox~7-3,4-dihYdrO
carbost~ril Prepared analogously to Example 3 from 6- ~-(3,4-dimethoxy-phenylmercapto)-butoxY7-3~4-dlhydrocarbostyril and hydrogen peroxide.
M.p.: 158 - 160C
Yicld: 62 % of theory.

Example 26 6-/Z;-(4-BiphenYlvlmercato)-butoxy7-3,4-dihYdrocarbostvril Prepared analo~ously to Example 1 from 4-phenylthiophenol and 6-(4-bromobutoxy)-3,4-dihydrocarbostyril.
M.p.: 179.5 - 181C
Yield: 74 % of theory.

Example 27 6-/~-(4-Bi~henylylsulfinyl~-butoxv7-~4-dihYdrocarbostYril Prepared analogously to Example 2 from 6- ~-(4-biphenylylmercap-to)-butoxx7-3,4-dihydrocarbostyril and hydrogen peroxide.
M.p.: 192 - 192.5C.
Yield: 86 % of theory.

Example 28 6-/~-~2-Naphthylmerca~to~-butoxy7-3,4-dihydrocarbostyril Prepared analogously to Example 1 from 2-naphthylmercaptane and 6-(4-bromobutoxy)-3,4-dihydrocarbo~tyril.
M.p.: 108.5 - 109.5C
Yield: 48 % of theory.

' ' -- ~ :

- ~3 ~ 1~16 6 Exam~le 29 6-/~_(2-Na~hth~l~ulfinyl)-butoxy7-~,4-dihydrocarbost~ril Prepared analogously to Example 2 from 6- ~-(2-naphthylmer-capto)-butoxy7-3~4-dlhydrocarbo~t~ril and hydrogen perosid~.
M.p.: 147.5 - 148.5C
Yield: 57 % of theory.

Exam~le 30 6-/~-(2-Pyridy~3ulfinvl)-~entoxy7-~4-dihydrocarbo~tvril Prepared analogously to Example 2 from 6- r-(2-pyridylmercap-to)-pentoxy7-3,4-dihydrocarbo~tyril and hydrogen peroxlde.
M.p.: 116 - 118C
Yield: 69 % of theory.

Examp~e_~

6-(2-Methylsulfin~lethoxy~-~.4-dihYdrocarbostyr~l 1.42 g (0.006 mol) of 6-(2-methylmercaptoethoxy~-3,4-dihydro-carbostyril were suspended in 12 ml of methanol and a solu-tion of 1.71 g (0.008 mol) of sodium metaperiodate in 8 ml of water wa~ added. The reaction mixture was stirred for 1,5 hours, whereby at the beginning a clear heating of the reaction mixture could be ob~erved. Subsequently the mix-ture wa!~ diluted with little watrr and exhaustively extrac-ted with chloroform. The evaporation residue was recrystalli-zed from ethyl acetate by addition of little ethanol.
M.p.: 129 - 131.5C
Yield: 70 % o~ theory.

k. . ~ "i, ~ ~, Example ~2 6~ (2-PyridYlsulfonyl~-pentoxy7-3,4-dihydrocarbo~tyril Prepared analogously to Exa~ple 3 from 6- r-(2 pyridylmercapto)-pentox~7-3,4-dihydrocarbostyril and hydrogen peroxide.
M.p.: 113.5 - 115.0C
Yield: 71 % o~ theory.

ExamPle 33 6-(4-Meth~lsulfinylbutoxv)-3.4-dihYdrocarbostYril Prepared analogously to Example 2 from 6-(4-methylmercapto-butoxy)-3,4-dihydrocarbostyril and hydrogen peroxide.
M.p.: 128.5 - 130.5C
Yield: 58 % of theory.

Exam~le 34

7-(4-PhenYlsulfonyl-butoxv)-carbo~tYril Prepared analogously to Example 3 from 7-(4-phenylmercapto-butoxy)-carbostyril and hydrogen peroxide.
M.p.: 199 - 201C
Yield: 85 % of theory.

Exam~le 35 6-(4-CYclohexvlmerca~tobutoxY)-3,4-dihYdrocarbostyril Prepared analogously to Example 1 from cyclohexylmercaptane and 6-(4-chlorobutoxy)-3,4-dihydrocarbo~tyril (m.p.: 147 -148C) M.p.: 114 - 115C
Yield: 80 % of theory.

-., .,~ , , q:r ~

~ - ,5 -1~ 0 Example ~6 6-(4-Cyclohexyl~ulfinyl_butoxy)_3!4-dihvdrocarbostvril Prepared analogously to Example 2 from 6-(4-cyclohexylmercap-to-butoxy)-3,4-dlhydrocarbostyril and hydrogen peroxlde.
M.p.: 153 - 155.5C
Yield: 63 % of theory.

Example 37 6-(4-Benz~lmerca~to-butoxv)-3~4-dihvdrocarbostyrll Prepared analogously to Example 1 ~rom benzylmercaptane and 6-(4-chlorobutoxy)-3,4-dlhydrocarbo~tyrll.
M.p.: 77.5 - 78.5C
Yield: 90 % of theory.

Example 38 6-(4-Benzvlsulflnyl-butoxy)-3,4-dihYdrocarbostyril Prepared analogously to Example 2 from 6-(4-benzylmercapto-butoxy)-3,4-dlhydrocarbostyril and hydrogen peroxide.
M.p.: 141.5 - 142C
Yleld: 95 ~ of theory.

Example 39 6-/z;-(2-Furylmethylmercapto)-butoxv7-3~4-dihydrocarbo~tyril Prepared analogou~ly to Example 1 from 2-furfurylmercaptane and 6-(4-bromobutoxy)-3,4-dihydrocarbostyril (m.p.: 142 - 147C).
M.p.: 79 - 80C
Yleld: 64 % of theory.

, ....
.,~,V',r',. .

_ 36 _ Example 40 6-~ (2-FurYlmethYl~ul~in~l ~buto~ 7-3 ! 4-dihydrocarbostyril Prepared analogou~ly to Example-2 from 6- ~-(2-furylmethyl-mercapto)-butoxy7-3,4-dihydrocarbostyril and hydrogen per-o~lde.
M.p,: 135 - 136C
Yield: 60 % of theory.

Example 41 6- ~-(N-Oxido-2-Ry~ridylmerca~to)~butoxy7-3~4-dihydrocarbostrril Prepared analogously to Example 1 from 6-(4-bro~obutoxy)-3,4-di-hydrocarbo~tyril and 2-mercaptopyridlne-N-oxide.
M.p.: 179.5 - 181C
Yield: 65 % of theory.

Example 42 6-/~-(2-PYrimidyl-merc~pto)-buto~Y7-3~4-dih~drocarbo~tyril Prepared analogou~ly to Example 1 irom 6-(4-chlorobutoxy)-3,4-dihydrocarbo~tyril (m.p.: 147 - 148C) and 2-mercapto-pyrimidine.
M.p.: 154 - 156C
Yield: 79 % of theory.

; .

.~. .

6~
Example 43 6- E~(2-pyrimidyl~ulfinyl)-butoxy7-~4-dihydrocarbo~t~ri Prepared analogously to Example 2 from 6- ~ -(2-pyrimidyl-mercapto)-butoxy7-3,4-dihydrocarbo~tyril and hydrogen peroxide.
M.p.: 154 - 156C
Yield: 36 % of theory.

Example 44 6-/~-(4-Pvridylmerca~to)-butoxy7-3,4-dihYdrocarbostYril To a solution of 1.3 g of 4-mercaptopyridine, 2.3 g of 3~ ~ ~o-dium methoxide ~olution and of 15 ml of methanol, 3.0 g of 6-(4-bromobutoxy)-3,4-dihydrocarbo~tyril were added and stirred for 14 hours at room temperature. Subsequently the qolution was diluted with 20 ml of water and the obtained precipitate was recrystallized from ethanol.
M. p.: 128 - 129C
Yield: 1.6 g (49 % of theory).

ExamPle 45 6- ~-(2-BenzimidazolYlmerca~to~-butox~7-3.4-dihYdrocarbostvril Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-3,4-dihydrocarbo~tyril (m.p.: 147 - 148C) and 2-mercapto-benzimidazole.
M.p.: 100 - 103C
--- Yield: 45 % of theory.

._ . ~
~ - . . . ..
~ 7' '' '. . _ . . ' . ' --- , :, .' .' . - - 38 - -~ ~ ~ 6'~

Example 46 6-~!Z;-(2-senzimidazolYlsulfinyl~-butoxy7-3~4-dihYdrocarbostYril Prepared analogou~ly to Example 2 from 6-/~-(2-benzimidazolyl-mercapto)-butox~7-3,4-dihydrocarbostyril and hydrogen peroxide, M.p,: 180 - 182C
Yield: 36 % of theory.

Example 47 6~ (2-Benzthiazolvl-mercapto)-butoxY7-3,4-dihydrocarbostyril :
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-3,4-dihydrocarbostyril (m.p.: 147 - 148C) and 2-mercapto-benzthiazole, M.p.: 157 - 158C
Yield: 70 % of theory.

Example 48 6-/~-(2-Benzthiazolylsulfinyl ? -butoxY7- 3 . 4-dihYdrocarbo8tyril Prepared analogously to Example 2 froD 6- ~-(2-benzthiazolyl-m~rcapto)-butoxy7-3,4-dihydrocarbostyril and hydrogen peroxide.
M.p.: 183 - 184C
Yield: 69 % of theory.

Exam~le 49 6-(2-PhenYlmercapto-ethox~)-3, 4-dihvdrocarbo8tYril Prepared analogously to Example 1 from thiophenol and 6-(2-chloroethoxy)-3,4-dihydrocarbostyril (m.p.: 152.5 to 153.5C).

. ',.

-- 3 ~ -1~6 M.p.: 132 - 133.5C
Yield: 91 % oi theory.

Example 50 6-(2-Phenylsulfinyl-ethoxy)-3,4_dihydroca~ y~

Prepared analogously to Example 2 from 6-(2-phenylmercapto-etho~y)-3,4-dihydrocarbostyril and hydrogen pero~ide.
M.p.: 171 - 172C
Yield: 84 % Or theory.

Example 51 6-(2-Phen~lsulfonyl-ethoxy)-3,4-dih~d __ arbostYril Prepared analogously to Example 3 from 6-(2-phenylmercapto-ethoxy)-3,4-dihydrocarbostyril and hydrogen peroxide.
M.p.: 185 - 186C
Yield: 94 % Or theory.

Example 52 3-Phenylmercapto-propoxv)-~,4-dihydrocarbo6tyril Prepared analogously to Example 1 from 6-(3-bromopropoxy)-~,4-dihydrocarbostyril (m.p.: 111 - 118C) and thiophenol .
M.p.: 111 - 112C
Yield: 77 % of thoery.

',' ~ ~6 Example 53 6-~ Phenyl~ulfln~l ~ 4-dihYdrocarbostyril Prepared analogously to Example 2 from 6-~ -(phenylmercapto)-propoxy7-3,4-dihydrocarbostyril and hydrogen peroxlde.
M.p.: 131.5 - 133.5C
Yields 67 % of theory.

Example 54 1-Methvl-6-(4-Phenylmercapto-butoxY)-3,4-dihydrocarbostyril 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 thi~ solution. After addition of 12.5 ml of methyl iodide the mixture was stirred for 3 hours at room temperature, dilu-ted with water and extracted with chloroform. The evaporation residue was recrystallized from methanol under addition of activated charcoal.
M.p.: 79.5 - 80.5C
Yield: 71 % of theory.

Example 55 1-Methvl-6-(4-phenylsulfinyl-butoxv)-3.4-dihvdrocarbostYril Prepared analogously to Example 2 from 1-methyl-6-(4-phenyl-mercapto-butoxy)-3,4-dihydrocarbostyril and hydrogen per-oxide.
M.p.: 82 - 82.5C
Yield: 60 % of theory.

F~

Exampl~_~6 1-Methyl-6- ~4-~henyl~ulfonyl-butoxy,)-3,4-dihydrocarbo~tyril Prepared analogou~ly to Example 3 from 1-methyl-6-(4-phenyl-mercapto-butox~)-3,4-dihydrocarbostyril and hydrogen per-oxide.
M.p.: 108 - 109C
Yleld: 49 % of theory, Example 57 6-(6-Phenylmercapto-hexoxY~-3,4-dihYdrocarbostyril Prepared analogously to Example 1 from 6-(6-bromohexoxy)-3,4-dihydrocarbostyril (m.p.: 107.5 - 108C) and thiophenol.
M.p.: 112.5 - 113C
Yield: 34 % of theory.

Example 58 6-(6-Phen~rlsulfinyl-hexoxy?-3~4-dihydrocarbostyril Prepared analogously to Example 2 from 6-(6-phenylmercapto-hexoxy)-3,4-dihydrocarbo~tyril and hydrogen peroxide.
M.p,: 119.5 - 121.5C
Yield: 35 % of theory.

~, i ~ . "
', ., 42 ~

E:cample 59 6-(2-Hydroxy-3-phenylmerca~o proPoxY~-3 4-dihYdrocarbostvril 4.11 g (0.04 mol) of thiophenol were added to a su~pension 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-epo~propo~y)-3,4-dihydrocarbo~tyril (m.p. 125 - 128C) were added whil~t stirring, whereby a clear solution wa~ ob-tain~d u~der self-heating. After 5 minutes the sep~ration o~ a white crystal slurry started. After standing over night the crystal~ were suction filtered and recrystalli-zed from little methanol. White crystals of m.p. 148 - 149C
were obtained.
Yield: 73 % of theory.

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

ExamPle 61 6-(2-HYdrox~-3-phenylsulfonyl-propoxy)-~,4-dihydrocarbostYril Prepared analogously to Example 3 from 6-(2-hydroxy-3-phenyl-mercaptopropoxy)-3,4-dihydrocarbostyril and hydrogen peroxide.
M.p.: 170 - 172C.
Yield: 54 % of theory.

.. , . . . . , ' ' -.. ,,. ' .

Example 62 7-t4-PhenYlmercaPtobutoxy~-3~4-dihydrocarbost~ril Prepared analogously to Example 4 from 7-hydroxy-3,4-dihydro-carbostyril (N. Shigematsu et al. in Chem. Pharm. Bull. 1961, 970 - 975) and 4-phenylmercapto-butylbromide (bp.o 02 : 96 to 103C) M.p.: 121 - 123C
Yield: 72 % of theory.

Example 6 7-(4-PhenYlsulfinvl-butoxy)-3~4-dihydrocRrbostyril Prepared analogously to Example 4 from 7-hydroxy-3,4-dihydro-carbostyril (N. Shigematsu et al. in Chem. Pharm. Bull. 1961, 970 - 975) and 4-phenylsulfinylbutylbromide.
M.p.: 134 - 136C
Yield: 80 % of theory.

Example 64 7-(4-Phenylsulfonyl-butoxy)-3,4-dihYdrocarbostYril Prepared analogously to Example 4 from 7-hydroxy-3,4-dihydrocar-bostyril (N. Shigematsu et al. in Chem. Pharm. Bull. 1961, 970 - 975) and 4-phenylsulfonylbutylbromide.
M.p.: 178.5 - 179.5C
Yield: 74 % of theory.

_ .

1116Gf!'~
Example 65

8-~4-P_enylme captobutoxY)-3.4-dihydrocarbo3tvril Prepared analogou~ly to Example 4 ~rom 8-hydroxy-3,4-di-hydrocarbostyril (J. D. Loudon et al. in J. Chem. Soc.
1955, 743 - 744) and 4-phenylmercapto-butylbromide (bp.o 02:
96 - 103C).
M.p.: 101 - 102C
Yield: 75 % of theory.

Example 66 8-(4-PhenYlsulfinyl-butoxY)-3,4-dihydrocarbostYril Prepared analogously to Example 4 from 8-hydroxy-3,4-di-hydrocarbo~tyril (J. D. Loudon et al. in J. Chem. Soc. 1955, 743 - 744) and phenylsulfinylbutylbromide.
Colourless resin wa~ obtained.
Yield: 60 % of theory.
Rf-~alue: 0.60 (thinlayer chromatogram on silica gel -eluent: benzene/ethanol/conc. ammonia = 75/25/1).

Examplé 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 - 115C
Yield: 60 % of theory.

., ._~ . , -. .
~, , ,, ,, ,~. - ' .... ~ I ' ..
, . ~ .

- 45 _ Example 68 6~ (2-Benzthiazolyl-sulfonvl)-butoxy7-3~4-dihydrocarbo~tyri Prepared analogously to Example 2 from 6- ~ (2-benzthiazolyl-mercapto)-butoxy7~3~4-dihydrocarbo~tyril and hydrogen peroxid~.
M.p.: 146 - 149C
Yield: 61 % of theory.

.
Example 69 6-/~-(2-QuinolylmercaPto)-but_xY7-~,4-dihYdrocarbosty~il Prepared analogou~iy to Example 1 from 6-(4-bromobutoxy)-3,4-dihydrocarbostyril (m.p. 142 - 147C) and 2-mercapto-quinoline.
M.p.: 115C
Yield: 64 % of theory.

Example 70 6- ~-(2-Quinazoline-4-one-yl-mercapto)-butoxY7-3,4-dihydrocar-bost ril v , ~

Prepared analogously to Example 1 from 6-(4-bromobutoxy)-3,4-di-hydrocarbo~tyril (m.p.: 142 - 147C) and 2-mercaptoquinazoline-4-one.
M.p.: 184.5 - 188C
Yield: 63 % of theory.

., ; ~ .

Example 71 6-(4-Tr-ehenylmethylmercapto-butoxy)-3~4-dihydrocarbo3tvri Prepared analogougly to Example 1 from 6-(4-bromobutoxy), 3,4-dihydrocarbostyril (m.p.: 142 - 147C) and triphenyl-methylmercaptane.
M.p.: 169 . 170C
Yleld: 89 ~ of theory.

Example 72 6-!~-(2-NaPhthylmercapto)-ethoxy7-3,4-dihydrocarbostvril Prepared analogou~ly to Example 1 from 6-(4-chlorobutoxy)-3,4-dihydrocarbostyril (m.p,: 147 - 148C) and 2-naphthyl-mercaptane.
M.p.: 147.5 - 147.8C
Yield: 77 % of theory.

ExamPle 73 6-/~-(2-NaphthYlsulfinvl)-ethoxy7-3,4-dihYdrocarbostyril Prepared analogously to Example 2 from 6- ~ -(2-naphthylmercapto)-ethoxY7-3,4-dihydrocarbostyril and hydrogen peroxide.
M.p.: 186.5 - 187.5C
Yield: 88 ~ of theory.

Example 74 6-/2-(4-BiPhenylYlmercapto)-ethoxy7-3.4-dihydrocarbostYril Prepared analogously to Example 1 from 6-(2-chloroethoxy)-3,4-dihydrocarbostyril (m.p.: 152.5 - 153.5C) and 4-mer-captobiphenyl. 13 M.p.: 192 - 194C
Yield: 92 % of theory.

Example 75 6~ (4-BiPhenylyl-sulfinyl)-ethoxy7-~4-dihydrocarbostyril Prepared analogously to Example 2 from 6- ~-(4~biphenylylmercap-to)-ethoxY7-3,4-dihydrocarbostyril and hydrogen peroxide.
M.p.: 195 - 196C
; Yield: 66 % of theory.

Exam~le 76 6-~-(2-PvridvlmercaPto)-~ropoxy7-3,4-dihvdrocarbostYril Prepared analogously to Example 1 from 6-(3-bromopropoxy)-3,4-dihydrocarbostyril and 2-mercaptopyridine.
M.p.: 108 - 108.5C
Yield: 42 % of theory.

Example 77 6-(4-PhenvlsulfinYl-butoxY)-3,4-dihydrocarbostyril 1.6 g of 6-(4-phenylmercapto-butoxyj-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 (80C) and decanted from the firstly oily residue, whereby after a while crystal~ were formed. After re-crystallization from xylene white crystals of m.p. 144 to 145C were obtained.
Yield: 1.2 g (66 % of theory).

~''~1'~ "" .^ ... ..
.

6'~

6-~4-Phenyl~ulfinyl_butox )-3?4-dihydrocarbostYril 3.3 g of 6-(4-phenylmercapto-butoxy)-3,4-dihydrocarbostyril were dissolved ln 50 ml o~ methyle~e chloride, cooled to -70C and a ~olution of 1.5 g of sulfuryl chloride ln 5 ml of methylene chloride wa~ added dropwisely. After 15 hours 20 ml of 95 % ethanol were added and the mixture was heated to room temperature by removing of the cooling bath, neutra-lized with aqueous sodium carbonate solution, the methrlene chloride phase was dried with ~odium sulfate and the solvent was removed. The reRidue was recry~tallized from toluene.
M.p.: 143 - 145C
Yield: 2.8 g (81 % of theory).

ExamPle 79 5-(4-PhenYlmercapto-butoxy)-3,4-dihYdrocarbostyril Prepared analogously to Example 4 from 5-hydroxy-3,4-dlhydro-carbostyril and 4-phenylmercaptobutylbromide~
M.p.: 155 - 157C
Yield: 64 % of theory.

Exam~le 80 5-(4-Phenylsulfinyl-butoxy)-~,4-dihydr~carbostYril Prepared analogously to Example 4 from 5-hydroxy-3,4-dihydro-carbostyril and 4-phenylsulfinylbutylbromide.
M.p.: 136 - 138C
Yield: 64 % of theory.

, ..
. .r ~.~ ' ' r , , ;i~6~ni~
Example 81 5-(4-PhenYl~ulionyl-butoxy~-3~4-dihvdrocarb-ostyril Prepared analogously to Example 4 from 5-hydroxy-3,4-dihy-drocarbostyrll and 4-phenylsulfonylbutylbromide.
M.p.: 187 - 189C
Yield: 73 % of theory.

Example 82 6-/~-(2-Naphth lsulfonvl~-butox ~ ,4-dihYdrocarbo~tyril Prepared analogou~ly to Example 3 from 6- ~-(2-naphthylmer-capto)-butoxx7-3,4-dihydrocarbostyril and hydrogen peroxide.
M.p.: 173 - 175C
Yield: 95 % of theory.

Exam~le 83 6-/~-(4-BiphenYlYlsulfonyl)-butoxY7-3~4-dihydrocarbo~tYril Prepared analogously to Example 3 from 6- ~-(4-biphenylyl-mercapto)-butoxy7-3,4-dihydrocarbostyril and hydrogen per-oxide.
M.p.: 232 - 234.5C
Yield: 83 % of th~ory.

Example 84 6-(4-PhenYlsulfonyl-butoxY)-3 4-dihydrocarbostyr_l Prepared analogously to Example 3 from 6-(4-phenylsulfinyl-butoxy)-3,4-dihydrocarboctyril and hydrogen peroxide.

. ,~

~ -.,r . ..
.

M.p.: 157 - 158C
Yield: 88 % of theory.

Example 85 6-/zi-(2-PyridYlsulfonyl)-butoxy7-7~4-dihydrocarbostyril Prepared analogously to Example 3 from 6- ~-(2-pyridylsulfi-nyl)-butoxy7-3,4-dihydrocarboityril and hydrogen peroxide.
M.p.: 123.8 - 125C
Yield: 76 % of theory.

Exam~le 86 5-(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-styril, dissolved in 45 ml of dioxane . The solution was heated for 2.5 hours in an oil bath. The reaction mixture wa~ hot filtered and the unsoluable residue, which was formed during the reaction, was washed out with hot dioxane. The com-bined 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 re~idue was evaporated and ethyl acetate was added until white crystals were precipitated.
M.p.: 182 - 183C
Yield: 850 mg (47 % of theory).

.

! i ~ ~ ~

Example 87 5-(4-PhenylmercaPto-butoxy)-carbostyril Prepared analogously to Example 86 from 5-(4-phenylmercapto-butoxy)-3,4-dihydrocarbostyril and 2 9 3-dichloro-5,6-dicyano-benzoquinone.
M,p.: 185 - 187C
Yield: 40 % of theory.

Example 88 5-(4-Phenylsulfin~l-butoxv)-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 chloro-form extract was washed with diluted sodium carbonate 801u-tion , with water, dried over magnesium sulfate and evapo-rated. The residue was mixed with ethyl acetate ~nd colour-less crystals of m.p. 155 - 157C were obtained.
Yield: 389 mg (65 % of theory).

Exam~le 89 6-(4-Phenylmercapto-butoxv)-carbostvril Prepared analogously to Example 86 from 6-(4-phenylmercapto-butoxy?-3,4-dihydrocarbostyril and 2,3-dichloro-4,5-dicyano-benzoquinone.
M.p.: 162 - 164C
Yield: 35 % of theory.

~- , ' ~.~_.
,:' t~j} . ; . ~ f^.~ . . . _ . .

'. ''.' ~ 52-Example 9 6-(4-Phenyl ulrinyl-butoxr)-carbo~tyril Prepar~d analogously to Example 86 i'rom 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 nixture of benzene/ethanol/
conc. ammonia ~ 75/25/3.
M. p.: 181 - 182.5C
Yield: 48 % of theory.
From the first fractions of the column chromatography 6-(4-phenylmercapto-butoxy)-carbostyril of m.p. 162 - 164C
were isolated in a yield of 15 % of theory.

Example 91 6-(4-Phenvlsulfonvl-butoxy)-carbostvril 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-tography on ~ilica gel (corn size: 0.2 - 0.5 mm) with chloro-form/methanol/ethyl acetate = 4/1/1.
M.p.: 212 - 217C
Yield: 54 % of theory.

Example 92 5-(4-PhenYlmercapto-butoxY2-carbostyril 49 g of 4-phenylmercaptobutylbromide were added to a mixture of 32.3 g of 5-hydroxycarbostyril, 30 g of potas~ium carbonate and 650 ml of dimethylsulfoxide, dried over a molecular sieve.
The mixture wais stirred for 20 hours at 25C, diluted with 3 l of water and the crystallized reaction product was suction fil-tered.

~ , f, ~ -- . ._ . . _ , _ _.__ _ ._ _._ . .. _ . .. __ _ _ . . ., , ,~
I
. i, , ',' - M.p.: 185 - 187C (from toluene) Yield: 45.0 g (70 % of theory).

Example 9~

5-(4-Phen~lsulfonvl-butoxy)-carbostyril Prepared analogou~ly to Example 88 from 5-(4-phenylmercapto-butoxy)-carbostyril and 4 moles of hydrogen peroxide at a temperature of 60C and a reaction time of 14 hour~.
M.p.: 182 - 183C
Yield: 73 % of theory.

Example 94 6-(4-Phenylmerca~to-butoxY)-carbostyril Prepared analogou~ly to Example 92 from 6-hydroxycarbostyril and 4-phenylmercaptobutylbromide.
M.p.: 161 - 163C
Yield: 78 % of theory.

Example 95 6-~4-PhenYlsulfinvl-butoxY3-carbostyril Prepared analogously to Example 88 from 6-(4-phenylmercapto-butoxy)-carbostyril and hydrogen peroxide.
M.p.: 181 - 182C
Yield: 68 % of theory.

t, . . .

Exam~le ~6 6-~4-Phsnylsulfinyl-butoxy)_carbostyril Prepared analogou~ly to Example 92 from 6-hydroxycarbo~tyrll and 4-phenylsul~inylbutylbromide.
M.p.: 181 - 182C
Yield: 71 % of theory.

ExamPle 97 7-(4-Phenvlsulfinyl-butoxy)-carbo~tyril Prèpared analogou~ly to Example 86 from 7-(4-phenylsulfinyl-butoxy)-3,4-dihydrocarbostyril.
M.p.: 193 - 194C
Yield: 51 % of theory.

Example_~8 8-(4-PhenvlmercaPto-butoxy)-carbostyril Prepared analogously to Example 86 from 8-(4-phenylmercapto-butoxy)-3,4-dihydrocarbostyril and 2,3-dichloro-5,6-dicyano-benzoquinone.
M.p.: 119 - 120C
Yield: 40 % of theory.

Example 99 8-(4-Phenylsulfinyl-butoxy)-carbostyril Prepared analogously to Example 88 from 8-(4-phenylmercapto-butoxy)-carbostyril by oxidation with hydrogen peroxide.

.
.~,~ "

- i~16~
M.p.t 125.5 - 126.5C
Yield: 60 % of theory.

Example 100 5-(4-PhenYlsulfonYl-butoxy)-carbostyril 100 mg of 5-(4-phenyl~ulfonyl-butoxy)-3,4-dihydrocarbostyril were refluxed with 30 mg of palladium/charcoal and 1 ml cf me~itylene. A~ter 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-trate was evaporated and the residue was chromatographed at a silica gel column with a mixture of benzene/ethanol/conc.
ammonia = 75/25/3. Besides the ~tarting material, which did not change during the reaction, 9 mg of 5-(4-phenylsulfonyl-butoxy)-carbo~tyril were obtained.
M.p.: 182 - 183C

Example 101 6-(4-Amino-iminomethylmercapto-butox~)-3,4-d~ydrocarbostvril 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 ~olution wa~ obtained (approx. 4 rhours).
After cooling the impurities were extracted with chloroform and the residue wa~ made alkaline by means of ammonia. The precipitated crystal~ were suction filtered and dried.
M.p.: 140 - 141.8C
M.p. of the hydrochloride: 208 - 211C
Yield: 90 % of theory.

...... .
~,b . -_ 56 _ , 6C~
Example 102 6-(4-PhenylsulfonYl)-buto~-~4-dihydrocarbost ~ il 107 mg o~ 6-(4-phenyl~ulfonyl)-butoxy-carbostyril were suspended in 15 ml of methanol, mixed with 40 mg o~
palladium/charcoal and hydrogenated at 50C and at a hydrogen pressure of 2.5 bar for 14 hours. After f~lt~rlng of~
the cataly~t and evaporating the clear solution, the re~idue was obtained in colourle~s crystal~.
M, p,: 153 - 154C
Yield: 89 mg (83 % o~ theory), . i Example 103 6-(4-BenzYlmercapto-bu_oxy)-3,4-dihydrocarbostyril 2.5 g oi 6-(4-mercaptobutoxy)-3,4-dihydrocarbostyril, dissolved in 25 ml o~ dimethylsulfoxlde, were mixed ~hilst tirring with 1.4 g of potassium carbonate and subsequently with 1.3 ml of benzylchloride. After Atirring for 15 hours at room temperature the reaction mixture wa~ diluted with 200 ml of water, the precipitated oily substance was sepa-rated and recrystallized from ethyl acetate.
M.p.: 76 - 78C
Yield: 2.8 g (82 % of theory).

Example 104 6-(5-PhenylmercaptoPentoxv)-~L4-dihYdrocarbo~tYril Prepared analogously to Example 1 from 6-(5-bromopentoxy)-3,4-dihydro-carbostyril and thiophenol .
M.p.: 117 - 119C
Yield: 71 % of theory.

__ _ , .. ; _ ~

_ 57 _ Example 105 6-(5-PhenylsulfinYl-pentox ~ -dihYdrocarbostyril Prepared analogously to Example 2 from 6-(5-phenylmercapto-pentoxy)-3,4-dihydrocarbo~tyril and hydrogen peroxide.
M.p.: 104 - 109.5C
Yield: 66 % of theory.

ExamPle 106 6-(5-PhenYlsulfinYl-pentoxv~-3,4-dihydrocarbo~tYr1l Prepared analogously to Example 3 from 6-(5-phenylmercapto-pentoxy)-3,4-dihydrocarbo~tyril and hydrogen peroxide.
M.p.: 136.5 - 137.8C
Yield: 62 % of theory.

ExamPle 107 6-/~-(2-PYridYl-mercapto)-Pentox ~-3,4-dihydrocarbostYril Prepared analogously to Example 1 from 6-(5-bromopentoxy)-3,4-dihydrocarbostyril and 2-mercaptopyridine.
M.p.: 113 - 114.8C
Yield: 76 % of theory.

Example 108 5-(2-HvdroxY-3-Phenylmercapto-PropoxY)-3~4-dihydrocarbostyril Prepared analogouQly to Example 5 from 5-(2,3-epoxy-propoxy)-3,4-dihydrocarbostyril and thiophenol .

r~
.,- - . ' ' .. --- - , .

.. .

5~ -M.p.: 135 - 137C
Yield: 64 % of theory.

Example 109 5-(2-HydroxY-3-phenylsulfinyl-propoxy)-3~4-dihydrocarbost~ri Prepared analogously to Example 2 from 5-(2-hydroxy-3-phenyl-mercapto-propoxy)-3,4-dihydrocarbostyril and hydrogen per-o~ide.
M.p.: 186 - 188C
Yield: 60 % of theory.

Example 110 5-(2-HYdroxv-3-phenvlsulfonyl-propoxy)-3,4-dihvdrocarbostYril Prepared analogously to Example 3 from 5-(2-hydroxy-3-phenyl-mercapto-propoxy)-3,4-dihydrocarbostyril and hydrogen peroxide.
M.p.: 168 - 170C
Yield: 53 % of theory.

Example 111 6-/~-(4-HYdroxyphenYlmercapto)-butox~7-3 ! 4-dihvdroca,rbostYri Prepared analogously to Example 1 from 6-(4-bromobutoxy)-3,4-dihydrocarbostyril and 4-hydroxythiophenol.
M.p.: 191.5 - 193.0C
Yield: 83 % of theory.

~-~ , .

. - 59 -6~
Example 112 6-/~-(4-Hydroxyphen~lsulfinyl~-butoxy7-3,4-dihydrocarbo~ty~il Prepared analogouqly-to Example 2 ~'rom 6- ~-(4-hyd~oxyphenyl-mercapto)-butoxy7-3~4-dihydrocarbostyril and hydrogen per-oxide.
M.p.: 206 - 207.8C
Yield: 84 % of theory.

Example 113 6-/~-(4-HYdroxYphenvlsulfonyl)-butoxy7-~4-dihydrocarbostvri Prepared analogously to Example 3 from 6- ~-(4-hydroxyphenyl-mercapto)-butox~7-3,4-dihydrocarbostyril and hydrogen perox~de.
M,p.: 219 - 219.5C
Yield: 78 % of theory.

Example 114 6-f~-(4-AcetaminoPhenylmercapto)-butoxy7-3,4-dihvdrocarbostyril Prepared analogously to Example 1 from 6-(4-bromobutoxy)-3,4-di-hydrocarbostyril and 4-acetaminothiophenol.
M.p.: 162.5 - 163.0C
Yield: 65 % of theory.

ExamPle 115 6-/~-(4-Acetaminophenylsulfinyl)-butoxY7-3.4-dihYdrocarbostYril Prepared analogously to Example 2 from 6- ~-(4-ac~taminophenyl-mercapto)-butox~7-3,4-dihydrocarbostyril and hydrogen peroxide.

. ~- s ~ . - . . . -- , . "

_ 60 _ "
i6~
M.p.: 202.0 - 203.8C
Yleld: 55 X of theory.

Example 116 6- ~ etamino~henylsulfonyl)-butox~7-3 ! 4-dihydrocarbostYrll Prepared analogously to Example 3 from 6-/~-(4-acetaminophenyl-mercapto)-butox~7-3,4-dihydrocarbostyril and hydrogen peroxide.
M.p.: 143.5 - 147.0C
Yleld: 88 % oi~ theory.

6~ ( 4,5-Di-p-chlorophenyl-oxazole-2-yl-mercapto)-butoxy7-3.4-dihydrocarbostYril Prepared analogously to Example 1 from 6-(4-bromobutoxy)-3,4-dl-hydrocarbostyril and 2-mercapto-4,5-di-p-chlorophenyl-oxazole.
M.p.: 110 - 115C
Yield: 70 % of theory.

Example 118 6-/~-(2-PYridYl~ulfin~l)-butoxY7-carbostvril Prepared analogously to Example 86 from 6-/~-(2-pyridylsulfinyl)-butoxy7-3,4-dihydrocarbostyril and 2,3-dichloro-5,6-dicyano-benzoquinone.
M. p.: 152 - 154C
Yield: 48 % of theory.

. ~
,~... .

_61` _ i6~
Example 119 6-(4-PhenvlmercaPto-butoxv)-3,4-dihydrocarbo~tyril Prepared analogou~ly to Example 102 from 6-(4-phenylmercap-to-butoxy)-carbostyril by catalytic hydrogenation with rhenlum-~ sulflde as cataly~t.
M.p.: 121 - 122C
Yield: 67 % of theory.

Example 12Q

8-(4-PhenYlsulfonyl-butoxv)-carbostyril Prepared analogously to Example 86 from 8-(4-phenylsulfonyl-butoxy)-3,4-dihydrocarbostyril and 2,3-dlchloro-5,6-dlcyano-benzoquinone.
M.p.: 146 - 147C
Yield: 41 % Or theory.

Example 121 7-(4-Phenvlmercapto-butoxy)-carbostvril 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 - 158.5C
Yield: 54 % of theory.

Example 122 6-/~* ,5-Dichlorophenylmercapto)-butox ~-3,4-dihydrocarbostyril 8.94 g (0.03 mol) of 6-(bromobutoxy)-3,4-dihydrocarbostyril (m,p.: 142 - 147C) were sdded to a mixture of 2.21 g (0.0315 mol) oi potassium methoxide, 5.76 g (0.0315 mol) o~ 98 %
2,5-dichlorothiophenol and of 54 ml of methanol.
The reaction mixture was refluxed whereby at first a clear solution waq obtained. After 5 minutes so much crystalli-ne reaction product was precipitat ed, 50 that the reaction mix-ture was hardly stirrable. After one hour the mixture was cooled to room temperature, suction filtered and recrystallized from ethanol. Colourless crystal~ of m.p. 133 - 134C were obtained.
Yield: 10.60 g (89.1 % of theory).

Example 123 6-/~-(2,5-Dichloro~henylsulfinvl)-butoxy7-3,4-dihvdrocarbostyril 5.55 g (0.014 mol) of 6- ~ -(2,5-dichlorophenylmercapto)-butox~7-3,4-dihydrocarbostyril, su~pended 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 was being cleared and an almost clear solution was obtained.
After 70 hours white crystals were precipitated which were suction filtered and recrystallized from ethanol.
M.p.: 185 - 186C
Yield: 5.43 g (94.1 % of theory).

~........ - ,, .. -........ ~ ., '\
.,' ,,, Example 124 6-f~-(2,~-Dichlorophenyl~ulfonyl)-butoxy7-3,4-dihydrocarbostyril 2.97 g (O.0075 mol) of 6- ~-(2,5-dichlorophenylmercapto)-butoxy7-3,4-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 wa~
diluted with three times the amount of water. The precipitated crystals were recrystallized from ethanol.
M.p.: 174.5 - 175.5C
Yield: 1.99 g (61.9 % of theory).

Example 125 6-/~;-(3,4-Dichlorophenvlsulfonvl)-butoxY7-3,4-dihydrocarbostyrii Prepared analogously to Example 124 from 6- ~-(3,4-dichlorophenyl-mercapto)-butoxy7-3,4-dihydrocarbostyril (m.p.: 116.5 - 118C) and hydrogen peroxide.
M.p.: 172 - 173C
Yield: 96 % of theory.

Example 126 6- ~-(4-Hydroxy-3,5-di-tert.-butyl-phenylmercapto)-butoxY7-3 ! 4-dihYdrocarbost~ril _ _ Prepared analogously to Example 122 from 6-(4-bromobutoxy)-3,4-dihydrocarbostyril (m.p.: 142 - 147C) and 4-hydroxy-3,5-di~tert.-butylthiophenol.
M.p.: 146 - 147C
Yield: 68.8 % of theory.

, . ',, '.

n~
Example 127 6- ~-(4-Hydroxy-3,5-di-tert.-butyl-phenylsulfinyl)-butoxY7-~,4-dihydrocarbost~ril _ Prepared analogously to Example 123 from 6- ~-(4-hydroxy-3,5-di-tert.-butyl-phenylmercapto)-butoxx7-3,4-dihydrocarbo-styril and hydrogen peroxide.
M.p.: 170 - 171C
Yield: 80.7 % of theory.

Example 128 6- ~-(4-Hydroxy-3,5-di-tert.-butyl-phenylsulfonyl)-butoxy7-~.4-dih~drocarbostYril Prepared analogously to Example 124 from 6~ ~-(4-hydroxy-3,5-di-tert.-butyl-phenylmercapto)-butoxv7-3,4-dihydrocarbostyril and hydrogen peroxide.
M.p.: 165 - 167C
Yield: 97.6 % of theory.

Exam~le 129 6-/z~-(2-Carboxy~henYlmercapto)-butoxy7-3~4-dihydrocarbostyri Prepared analogously to Example 122 from 6-(4-bromobutoxy)-3,4-dihydrocarbostyril and 2-thiobenzoic acid.
M.p.: 176 - 179C
Yield: 57.5 % of theory.

.

~' f~

- Example 130 6-~ -(2-CarboxY-phenylsulfinyl)-butoxy~ 4-dihydrocarbostyril Prepared analogously to Example 123 from 6- ~-(2-carboxy-phenyl-mercapto)-butoxy7-3,4-dlhydrocarbostyril and hydrogen peroxide.
M.p.: 194 - 196C
Yield: 77.2 % of theory.

Example 131 -(4-Pyridylsulfinyl)-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- ~-(4-pyridylmercapto)-butoxy7-3,4-dihydrocarbostyril (m.p.: 128 - 133C) with hydrogen per-oxide analogously to Example 123.
M.p.: 154C
Yield: 57 % of theory.

Example 132 6~ (4-PyridYlsulfonYl~-butoxy7-3,4-dihYdrocarbostyril Prepared analogously to Example 124 from 6- ~ -(4-pyridylmer-capto)-butoxy7-3,4-dihydrocarbostyril and hydrogen peroxide.
M.p.: 179 - 183C
Yield: 35.9 % of theory.

,, . . .. _ r ~ 66-- Example 133 6- ~-(3,4-Dichlorophenylqulfinyl)-2-hydroxy-propox~7-3,4-di-hydrocarbostYril 3.51 g (0.016 mol) of 6-(2,3-epoxy-propoxy)-3,4-dihydrocarbo-styril (m.p.: i25 - 128C), dissolved in 35 ml of methanol, were mixed with 4.29 g of 3,4-dichlorothiophenol . The mix-ture was heated to boiling for 5 hours. After cooling, crystals were obtained, which were suction filtered and recrystallized from ethanol.
M.p.: 175 - 176C
; Yield: 2.48 g (38.9 % of theory).
The 6-~ -(3,4-dichlorophenylmercapto)-2-hydroxy-propoxy7-3,4-dihydrocarbostyril thus obtained, was oxidlzed analogously to Example 123 with hydrogen peroxide.
M.p.: 108 - 110C
Yield: 75 % of theory.

Example 134 6-(3-Benzvlmercapto-propoxy)-3,4-dihydrocarbostYril Prepared analogously to Example 122 from 6-(3-bromopropoxy)-3,4-dihydrocarbostyril (m.p.: 142 - 147C) and benzylmercaptane.
M.p.: 97.5 - 99.0C
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 - 147.0C
Yield: 51 % of theory.

.
r ~ - ~
~ y ! ', . ~

_67 -Example 136 5-(3-tert.-Butylmercapto-2-hydroxy-propoxy)-3,4-dihydrocarbo-st ril Y ~

Prepared analogously to Example 133 from 5-(2,3-epoxy-propoxy~
3,4-dihydrocarbostyril (m.p.: 171 - 173C) and tert.-butyl-mercaptane.
M.p.: 105 - 109C
Yield: 77.1 % of theory.

Example 137 5-(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 - 177C
Yield: 52.1 % of theory.

Example 138 5-(3-tert.-Butylsulfonyl-2-hydroxy-propoxy)-3,4-dihydrocarbo-styril Prepared analogously to Example 124 from 6-(3-tert.-butylmer-capto-2-hydroxypropoxy)-3,4-dihydrocarbostyril and hydrogen peroxide.
M.p.: 210 - 212C
Yield: 37.1 % of theory.

Example 139 6~ Pyrldvl~sulfonyl)-butoxyZ-carbOstYril Prepared analogously to Example 124 from 6- ~-(2-pyridyl-sulfinyl)-butoxy7-carbostyril and hydrogen peroxide.
M.p.: 179 - 180C
Yield: 65.8 % of theory.

ExamPle 140 4-Methyl-6-(4-phenylmercapto-butoxy)-carbostyril 5.25 g (0.0~ mol) of 4-methyl-6-hydrocarbostyril (m.p.: 326 -330C, see R. R. Holmes et al. in J. Amer. Chem. Soc. 76, 2404 (1954)), 8.09 g (0.033 mol) of 4-phenylmercaptobutyl-bromide and 6.22 g (0.045 mol) o~ 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 - 150C
Yield: 6.2 g (61.2 % of theory).

Example 141 4-Methvl-6-(4-phenylsulflnYl-butoxy)-carbostYril Prepared analogously to Example 140 from 4-methyl-6-hydroxy-carbostyril (m.p.: 326 - 330C) and 4-phenylsulfinylbutyl-bromide.
M.p.: 167 - 168C
Yield: 47.3 % of theory.

_ _.
r ~
~`'"'' '' ".

Example 142 4-MethYl-6- (4--phenylsulfonyl-butoxy)-carbostyril Prepared analogously to Example 140 from 4-methyl-6-hydroxy-carbostyril (m.p.: 326 - 330C) and 4-phenylsulfonylbutyl-bromide.
M.p,: 217 - 219C
Yield: 66.6 ~ of theory.

Example 143 4-Methyl-6-/~-(2-PvridYlmercaPto)-butoxy7-carbostyril Prepared analogously to Example 122 from 4-methyl-6-(4-bromo-butoxy)-carbostyril (m.p.: 217 - 219C) and 2-mercaptopyridine.
M.p.: 149 - 151C
Yield: 85.7 % of theory.

Example 144 4-Me~hvl-6-/~-(2-pyridylsulfinyl)-butoxy7-carbostyril Prepared analogously to Example 12~ from 4-methyl-6- ~-(2-py-ridylmercapto)-butox~7carbostyril and hydrogen peroxide.
M.p.: 167 - 169C
Yield: 61.8 % of theory.

Example 145 4-Methyl-6-/~-(2-pyridYlsulfonyl)-butoxy7-carbostyril Prepared analogously to Example 124 from 4-methyl-6- ~-(2-pyri-dylmercapto)-butoxy7carbostyril and hydrogen peroxide.

`.' ' A
66~) M.p.: 195 - 197C
Yield: 29.5 % of theory.

Exam~le 146 4-Me~y1-6-/~-(2-quinolylmercapto)-butoxy7-carbostyril Prepared analogously to Example 122 from 4-methyl-6-(4-bromo-butox~y)-carbostyril and 2-mercaptoquinoline.
M.p,: 162 - 163C
Yield: 81.9 % of theory.
i Example 147 4-Methyl-6-/~-(2-quinolylsulfinvl)-butoxy7-carbostyril Prepared analogously to Example 123 from 4-methyl-6- ~-(2-qui-nolylmercapto)-butoxv7carbostyril and hydrogen peroxide.
M.p.: 189 - 190C
Yield: 47.5 % of theory.

Example 148 4-Methyl-6-/~-(2-qui~no~ylsulfonyl~-butox,y7carbostyril Prepared analogously to Example 124 from 4-methyl-6-~(2-quinolylmercapto)-butoxy7carbostyril and hydrogen peroxide.
M.p.: 199 - 203C
Yield: 31.5 % of theory.

\~
. ....

~6~

Exam~le 149 4-Methvl-6~ (4-biphenYl~lsul~inyl)-butoxv7carbostYril Prepared analogously to Example 123 from 4-methyl-6- ~ -(4-biphenylylmercapto)-butoxY7carbostyril (m.p.: 174 - 176 C) and hydrogen peroxide.
M.p.: 161 - 162C
Yield: 59 % of theory.

Example 150 6-~-(4-ChlorophenYlmercapto)-butoxy7carbostyril Prepared analogously to Example 122 from 6-(4-chlorobutoxy) carbostyril (m.p.: 206 - 208C) and 4-chlorothiophenol , M.p.: 168 - 170C
Yield: 85 % of theory.

Example 151 6-/~-(4-ChlorophenYlsulfinyl)-butoxY7carbostYril Prepared analogously to Example 123 from 6- ~ -(4-chloro-phenylmercapto)-butoxy7carbostyril and hydrogen peroxide.
M.p.: 157 - 158C
Yield: 81 % of theory.

Example 152 6-/~-(4-Chlorophenvlsulfonvl)-butoxy7carbost~ril Prepared analogously to Example 124 from 6- ~ -(4-chlorophenyl-mercapto)-butoxy7carbostyril and hydrogen peroxide.

..

M.p.: 197 - 199C
Yield: 99 % of theory.

Example 153 6~ ~4-Dichlorophenylmercapto)-butoxy7carbostYril Prepared analogously to Example 122 from 6-(4-bromobutoxy)-carbostyril (m.p.: 198 - 199C) and 3,4-dichlorothiophenol .
M.p.: 149 - 152C
Yield: 60 % of theory.

Example 154 6-/~-(3,4-Dichlorophenylsulfinyl)-butoxy7carbostyril Prepared analogously to Example 123 from 6- ~-(3,4-dichloro-phenylmercapto)-butoxY7carbostyril and hydrogen peroxide.
M.p.: 191 - 196C
Yield: 87 % of theory.

Example 155 6-/~-(3,4-Dichlorophenylsulfonyl)-butoxy7carbostyril Prepared analogously to Example 124 from 6- ~ -(3,4-dichloro-phenylmercapto)-butoxy7carbostyril and hydrogen peroxide.
M.p.: 188 - 190C
Yield: 83 % of theory.

_ . . .

: ' I
~ ....
. '' .

Example 156 6 ~ butoxy ~ rbost,y~

Prepared analogously to Example 122 from 6-(4-bromobutoxy)-carbostyril and 2,5-dichlorothiophenol .
M.p.: 175 - 176C
Yield: 85 ~ of theory.

Example 157 6-/~-~2,5-Dichlorophenylsulfinvl)-butoxy7carbostyril Prepared analogously to Example 123 from 6-~-(2,5-dichloro-phenylmercapto)-butoxv7carbostyril and hydrogen peroxide.
M.p.: 200 - 202C
Yield: 75 % of theory.

Example 158 6-~ 2,5-DichlorophenYl~ulfonyl)-butoxY7carbostyril Prepared analogously to Example 124 from 6- ~-(2,5-dichloro-phenylmercapto)-butoxY7carbostyril and hydrogen peroxide in formic acid.
M.p.: 203 - 205C
Yield: 79 % of theory.

Example 159 6-/~-(4-Fluorophenylmercapto)-butoxY7carbostyril Prepared analogously to Example 122 from 6-(4-bromobutoxy)-carbostyril and 4-fluorothiophenol .
M.p.: 149 - 150C
Yield: 85 ~ of theory.

_ 74_ Example 160 6-/~-(4-Fluorophenylsulfinyl~-butoxy7carbostyril Prepared analogously to Example 123 from 6- ~-(4-fluoro-phenylmercapto)-butoxy7carbostyril and hydrogen peroxide, M.p.: 164 - 165C
Yield: 50 % of theory.

Example 161 6-/~-(4-Fluorophenylsulfon~l)-butoxy7carbostyril Prepared analogously to Example 124 from 6- ~-(4-fluoro-phenylmercapto)-butox ~carbostyril and hydrogen peroxide in formic acid.
M.p.: 209 - 211C
Yield: 59 % of theory.

Example 162 6- ~-(4-Hydroxy-3,5-di-tert.-butyl-phenylmercapto)-butoxy7-carbostyril Prepared analogously to Example 122 from 6-(4-bromobutoxy)-carbostyril (m.p.: 198 - 199C) and 4-hydroxy-3,5-di-tert.-butyl-thiophenol (m.p.: 84.5 - 86.0C).
M.p.: 172 - 173C
Yield: 77 % of theory.

i~, . ,:

Example 163 6- ~-(4-Hydroxy-3,5-di-tert,-butylphenylsulfinyl)-butoxy7-carbo tyril Prepared analogously to Example 123 from 6- ~-(4-hydroxy-3,5-di-tert.-butylphenylmercapto)-butoxy7carbostyril and hydrogen peroxide.
M.p.: 192 - 194C
Yield: 83 % of theory.

Example 164 6- ~-(4-Hydroxy-3,5-di-tert.-butylphenylsulfonyl)-butox~7-carbostyril Prepared analogously to Example 124 from 6- ~-(4-hydroxy-3,5-di-tert.-butylphenylmercapto)-butoxy7carbostyril and hydrogen peroxide in formic acid.
M.p.: 242 - 244C
Yield: 92 % of theory.

Example 165 6-/~-(4-Biphenylylmercapto)-butoxy7carbostvril Prepared analogously to Example 122 from 6-(4-bromobutoxy)-carbostyril (m.p.: 198 - 199C) and 4-biphenylmercaptane.
M.p.: 191 - 192C
Yield: 82 % of theory.

, .. ... " . , . . ~ .
. ',.

6f~
Example 166 6- ~-(4-Biphenylylsulfinyl)-butoxY ~arbost~vril Prepared analogously to Example 123 from 6- ~-(4-biphenylyl-mercapto)-butox ~carbostyril and hydrogen peroxide.
M.p.: 196 - 197C
Yield: 80 ~ of theory.
.

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

Example 168 6-/~-(4-Nitro-phenylmercapto)-butoxy7carbostyril Prepared analogously to Example 122 from 6-(4-bromobutoxy)-carbostyril (m.p.: 198 - 199C) and 4-nitrothiophenol .
M.p.: 184 - 185C
Yield: 96 % of theory.

Example 169 6-/~-(4-Nitro-phenyl~ulfinvl)-bùtoxv7carbostyril Prepared analogously to Example 123 from 6- ~ -(4-nitro-phenylmercapto)-butoxy7carbostyril and hydrogen peroxide.

~, , j f . l .. . ____ _, , . , . , . :

_ 77 _ 6n~
M.p.: 183 - 184C
Yield: 77 % of theory.

Example 170 6-/Zi-(4-Nitro-~henvlsulfonyl)-butoxv7carbostyril Prepared analogou~ly to E~cample 124 from 6-/~-(4-nitro-phenylsulfinyl)-butoxy7carbostyril and hydrogen peroxide in *ormic acid.
M.p.: 230 - 232C
Yleld: 70 % of theory.

Example 171 6-/~;-(2-QuinolYlmercapto)-butoxy7carbostYril Prepared analogously to Example 122 from 6-(4-bromobutoxy)-carbostyril (m.p.: 132C) and 2-mercaptoquinollne.
M.p.: 132C
Yield: 99 % of theory.

Example 172 6-/Zi-(2-Quinolylsulfinvl)-butoxv7carbostyril Prepared analogously to Example 123 from 6-~ (2-quinolyl-mercapto)-butoxy7carbostyril and hydrogen peroxide.
M.p.: 161 - 162C
Yield: 66 % of theory.

l ~ , . ~
..
,~, , `D
Example 173 6- ~-(2-Quinolvlsulfonyl)-butoxv7carbostYril Prepared analogously to Example 124 from 6- ~-(2-quinolyl-sulflnyl)-butoxy7carbostyril and hydrogen peroxide in formic acid.
M.p.: 197 - 198C
Yield: 58 % of theory.

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

Example 175 5-(4-PhenylsulfinYl-butoxY)-oxindole Prepared analogously to Example 123 from 5-(4-phenylmercapto-butoxy)-oxindole and hydrogen peroxide.
M.p.: 114 - 116C
Yield: 61 % of theory.

Example 176 6-/~-~PhenylsulfinylmethYl)-benzyloxY7-3.4-dihydro-carbostyril A mixture of 67.1 g of phthalide, 51.3 ml of thiophenol , 35.1 g of potassium methoxlde and 250 ml of methanol was refluxed. Subsequently the obtained 2-phenylmercaptomethyl-benzoic acid (yield: 78 % of theory, m.p.: 108 - 110C) was . ~
~.
~ ,", ,~.~! ~, . - - . .
.
.'"' ' .

_ 79 _ esterified with methanol/thionylchloride whilst standing at -40C. After ~tanding over night at room temperature methyl 2-phenylmercaptomethyl-benzoate (yield: 89 % of theory, b.p.o 07: 145C) was obtained, which was conver-ted to the 2-phenylmercaptomethyl-phenylcarbinole (yield:
97 % of theory, m.p : 64 - 65C) by means of reduction with lithiumaluminium hydride in diethyl ether.
This compound was reacted to 2-phenylmercaptomethyl-phenyl-methyl-p-toluenesulfonate by addition of p-toluene sulfo-~yl chloride. tThin-layer chromatogram: silica gel;
eluent: chloroform/ethyl acetate = 1 : 1; Rf-value = 0.8.
Yield: 55 ~6 of theory). This ester was reacted to 6-~-(phenylmercaptomethyl)-benzyloxy7-3,4-dihydrocarbo-styril analogously to Example 140 with 6-hydroxy-3,4-di-hydrocarbostyril (thin-layer chromatogram: silica gel;
eluent: chloroform/ethyl acetate = 1 : 1; Rf-value = 0.35;
Yield: 64 % of theory).
This substance wa~ analogously to Example 123 oxidized to 6-L~-~henylsulfinylmethyl)-benzyloxv7-3,4-dihydrocarbo-styril by means of hydrogen peroxide.
M.p.: 133 - 135C
Yield: 64 % of theory Example 177 6-r4- (PhenYlmercaptomethyl)-benzyloxv7-3.4-dihydrocarbostyril p-Xylylenedichloride was reacted with thiophenol in the mol ration 1:1 in the presence of excess potassium carbonate in dimethylsulfoxlde. The obtained 4-phenylmercaptomethyl-benzyl-chlorlde (control: thin-layer chromatogram) was further reac-ted with 6-hydroxy-3,4-dihydrocarbostyril analogously to Examp-le 140 without isolation, M.p.: 139 - 141C
Yield: 52 % of theory.

r~
.". . . ..
., ~ 8~
6~
Example 178 6- r4- ~PhenYlsulfinyl)-benzyloxv7-3~4-dihYdrocarbostyri Prepared analogously to Example 123 from 6- r4-( phenyl-mercaptomethyl)-benzyloxy7-3,4-dihydrocarbostyril and hydrogen peroxide.
M.p.: 179 - 181C
Yield: 61 % o~ theory.

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

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

Example 181 6-/~-(4-Bromophenylmercapto)-butoxY7carbostyril Prepared analogously to Example 122 from 6-(4-bromobutoxy)-carbostyril (m.p.: 198 - 199C) and 4-bromothiophenol .

~ . . . .
,..

M.p.: 156 - 158C
Yield: 53 % of theory.

Example 182 6-/~-(4-BromoPhenylsulfinyl)-butoxY7carbostvril Prepared analogously to Example 123 from 6- ~ -(4-bromophenyl-mercapto)-butoxY7carbostyril and hydrogen peroxide.
M.p.: 168 - 170C
Yield: 65 % of theory.

Example 183 6-/~-(3-Methyl-4-bromo-phenYlmercapto)-butoxv7carbostYril Prepared analogously to Example 122 from 6-(4-bromobutoxy~-carbostyril (m.p.: 189 - 199C) and 3-methyl-4-bromo-thio-phenol .
M.p.: 167 - 169C
Yield: 76 % of theory.

Example 184 6-/~-(3-Methy~ ~4-bromo-phenylsulfinyl)-butoxY7-carbostyril Prepared analogously to Example 123 from 6- ~-(3-methyl-4-bromo-phenylmercapto)-butoxy7carbostyril and hydrogen peroxide.
M.p.: 169 - 172C
Yield: 79 b of theory.

~ r r~.

_ 82 -6~
Example 185 6-/~-(3-Methyl-4-bromo-phenvlsulfonyl~-butoxy7carbosty~_l Prepared analogously to Example 124 from 6- ~-(3-methyl-4-bromo-phenylmercapto)-butoxy7carbostyril and hydrogen peroxide.
M. p.: 163 - 167C
Yield: 57 % of theory.

Example 186 6,/~-(1,2,4-Triazole-3-yl-mercapto)-butox~ carbostyril Prepared analogously to Example 122 from 6-(4-bromobutoxy)-carbostyril and 3-mercapto-1,2,4-triazole.
M! p.: 203 - 206C
Yield: 82 % of theory.

Example 187 6-/Z~-(2,4,5-Trichlorophenylmercapto)-butoxy7carbostyril .
Prepared analogously to Example 122 from 6-(4-bromobutoxy)-carbostyril (m.p.: 198 - 199C) and 2,4,5-trichlorothiophenol .
M.p.: 177 - 178C
Yield: 83 % of theory.

~ , .
6-/~-(2,4,5-Trichlorophenylsulfinrl)-butoxy7carbostyril Prepared analogously to Example 123 from 6- ~-(2,4-5-tri-chlorophenylmercapto)-butoxy7carbostyril and hydrogen peroxide.

. .... ,i ~_ . ,.

M.p.: 206 - 208C
Yield: 98 % of theory.

Example 189 6- ~ -(3,5-Dibromo-4-amino-phenylmercapto)-butoxy7-3,4-dihydro-carbostyril Prepared analogously to Example 122 from 6-(4-bromobutoxy)-3,4-dihydrocarbostyril (m.p.: 142 - 147C) and 3,5-dibromo-4-amino-thiophenol.
M.p.: 90 - 92C
Yield: 89 % of theory.

Example 190 6-~ -(3,5-Dibromo-4-amino-phenyl-sulfinyl)-butoxy7-3,4-di-hydrocarbost~vril Prepared analogously to Example 123 from 6- ~-(3,5-dibromo-4-amino-phenylmercapto)-butoxx7-3,4-dihydrocarbostyril and hydrogen peroxide.
M.p.: 144 - 146C
Yield: 76 % of theory.

Example 191 6- ~-(3,5-Dibromo-4-amino-phenylsulfonyl~-butoxY7-3,4-dihydro-carbostYril Prepared analogously to Example 124 from 6-~-(3,5 dibromo-4-aminophenylsulfinyl)-butoxy7-3,4-dihydrocarbostyril and hydrogen peroxide.
M.p.: 157 - 159C
Yield: 87 % of theory.

~ - . , ' . . - . .
~ `
.

ExamPle 192 6-/~-(3 ! 5-Dibromo-4-amino-Phenylmerca~to)-butoxv7carbostyri Prepared analogously to Example 122 from 6-(4-bromobutoxy)-carbostyril (m.p.: 198 - 199C) and 3,5-dibromo-4-amino-thiophenol.
M.p.: 153 - 155C
Yleld: 86 % of theory.

ExamPle 193 6-/~-(3~5-Dibromo-4-amino-phenylsulfinyl)-butoxv7carbostyril Prepared analogously to Example 123 from 6- ~-(3,5-dibromo-4-amino-phenylmercapto)-butox~7carbostyril and hydrogen per-oxide.
M.p.: 205 - 207C
Yield: 79 % of theory.

ExamPle 194 6-/~-(3.5-Dibromo-4-amino-phenylsulfonYl)-butoxy7carbost~ril Prepared analogously to Example 124 from 6- ~-~3,5-dibromo-4-amlno-phenylmercapto)-butoxy7carbostyril and hydrogen per-oxide in formic acid.
M.p.: 238 - 241C
Yield: 87 % of theory.

Example 195 6- ~-(4-Bromo-3-methyl-phenylmercapto)-butoxy7-3,4-dihydro-carbost~ril -Prepared analogously to Example 122 from 6-(4-bromobutoxy)-3,4-dihydrocarbostyril (m.p.: 142 - 147C) and 4-bromo-3-methyl-thiophenol.
M.p.: 104 - 109C
Yield: 81 % of theory.

Example 196 6- ~-(4-Bromo-3-methyl-phenyl~ulfinyl)-butox~7-3,4-dihydro-carbostyril Prepared analogously to Example 123 from 6- ~-(4-bromo-3-me-thyl-phenylmercapto)~butoxY7-~,4-dihydrocarbostyril and hydrogen peroxide.
M.p.: 129 - 1~0C
Yield: 75 % of theory.

Example 197 6~l~-(2.5-Dibromo-Phe xlmercaPto)-butoxY7-3.4-dihYdrocarbostYril Prepared analogously to Example 122 from 6-(4-bromobutoxy)-3,4-dihydrocarbostyril (m.p.: 142 - 147C) and 2,5-dibromo-thiophenol.
M.p.: 127 - 129C
Yield: 75 % of theory.

- 86 _ Example 198 6~ (2 ! 5-Dibromo-~henylsul~inyl)..butoxv7-~ 4-dihYdrocarbostYril Prepared analogously to Example 123 from 6- ~-(2,5-dibromo-phenylmercapto)-butoxv7-3,4-dihydrocarbo tyril and hydrogen peroxide.
M.p.: 182 - 184C
Yield: 84 % of theory.

Exam~le 199 6-/~-(2,5-Dibromo-pheny~mercaPto)-butoxv7carbostyril Prepared analogously to Example 122 from 6-(4-bromobutoxy)-carbostyril (m.p.: 198 - 199C) and 2,5-dibromo-thiophenol.
M.p.: 178 - 185C
Yield: 67 % of theory.

Example 200 6-[~-(2,5-Dibromo-PhenylsulfinYl)-butoxv7carbostYril Prepared analogously to Example 123 from 6- ~-(2,5-dibromo-phenylmercapto)-butoxv7carbostyril and hydrogen peroxide.
M.p : 187 - 189C
Yield: 45 % of theory.

Example 201 6-/~-(3.4-Dichloro-phenylmercapto)-ProPoxy7-3.4-dihydrocarbostyril Prepared analogously to Example 122 from 6-(3-bromopropoxy)-3,4-dihydrocarbostyril (m.p.: 111 - 118C) and 3,4-dichloro-thiophenol.

' ' ~ ' ' _ ' ! ' - . ' ' _--M.p.: 106 - 107C
Yield: 76 % of theory.

Example 202 6-/3-~,4-Dichloro-phenylsulfinyl)-propoxy7-3~4-dihydr _arbostyri Prepared analogously to Example 123 ~rom 6- ~ -(3,4-dichloro-phenylmercapto)-propoxy7-3,4-dihydrocarbostyril and hydroge~
peroxide.
M.p.: 170 - 172C
Yield: 84 % of theory.
.

Example 203 6-/~-(4-Cvclohexyl-phenylmercapto)-butoxyZ-3,4-dihYdrocarbostyri]

Prepared analogously to Example 122 from 6-(4-bromobutoxy)-3,4-dihydrocarbostyril (m.p.: 142 - 147C) and 4-cyclohexyl-thiophenol.
M.p.: 118 - 120C
Yield: 68 % of theory.

Example 204 6-/~-(4-Cvclohexvl-phenYlsulfinyl~-butoxv7-3,4-dihydrocarbostvri~

Prepared analogously to Example 123 from 6-L~- (4-cyclohexyl-phenylmercapto)-butox~7-3,4-dihydrocarbostyril and hydrogen peroxide.
M.p.: 155 - 157C
Yield: 65 % of theory.

1~166~J
Example 205 6-/~-(4-CyclohexYl-phenylsulfonyl)-butoxy7-3!4-dihydrocarbostyrl]

Prepared analogously to Example 124 from 6- ~ -(4-cyclohexyl-phenylmercapto)-butoxy7-3,4-dihydrocarbostyril and hydrogen peroxide.
M.p.: 172 - 174C
Yield: 52 ~ of theory.

Example 206 6- /~- (4-CYC lohexvl-PhenYlmercapto)-butoxv7carbostvril Prepared analogously to Example 122 from 6-(4-bromobutoxy)-carbostyril ~m.p.: 188 - 189C~ and 4-cyclohexylthiophenol.
M.p.: 165 - 167C
Yield: 64 % of theory.

Example 207 6-/~-(4-Cyclohexyl-phenylsulfinvl)-butoxY7carbostYril Prepared analogously to Example 123 from 6- ~ -(4-cyclohexyl-phenylmercapto)-butoxy7carbostyril and hydrogen peroxide.
M.p.: 188 - 190C
Yield: 64 % of theory.

Example 208 6-f~-(4-CvclohexYl-phenylsulfonyl)-butoxy7carbostyril Prepared analogously to Example 124 from 6- ~-(4-cyclohexyl-phenylmercapto)-butoxy7carbostyril and hydrogen peroxide.

i. L . `~

M.p.: 185 - 186C
Yield: 87 % of theory.

Example 209 6-/~-(4-tert.-Butyl-phenylmercapto)-butoxv7-3~4-dih~drocarbostyr~

Prepared analogously to Example 122 from 6-(4-bromobutoxy)-3,4-dihydrocarbostyril (m.p.: 142 - 147C) and 4-tert.-butyl-thiophenol.
M.p.: 126 - 127C
Yield: 86 % of theory.
i Example 210 6-/~-(4-tert.-ButYl-~henylsulfinyl)-butoxy7-3,4-dihydrocarbostvri Prepared analogously to Example 123 from 6- ~-(4-tert.-butyl-phenylmercapto)-butoxy7-3,4-dihydrocarbostyril and hydrogen peroxide.
M.p.: 121 - 123C
Yield: 67 % of theory.

ExamPle 211 6-/~-(4-tert.-Butyl-phenylsulfonyl)-butoxy7-3~4-dihydrocarbostyri Prepared analogously to Example 124 from 6- ~ -(4-tert.-butyl-phenylmercapto)-butox~7-3,4-dihydrocarbostyril and hydrogen peroxide.
M.p.: 198 - 200C
Yield: 83 % of theory.

. _ '~' '~

_90~ -Example 212 6-/Z;-54-tert.-Butyl-phenylmercapto)-butoxy7carbostyril Prepared analogously to Example 122 from 6-(4-bromobutoxy)-carbo~tyrll (m.p.: 198 -199 C) and 4-tert.-butylthiophenol.
M.p.: 156 - 158C
Yield: 63 % of theory.

Example 213 6-l~-(4-tert.-2~tyl-phenYlsulfinYl)-butoxv7carbostYril Prepared analogously to Example 123 from 6- ~-(4-tert.-butyl-phenylmercapto)-butoxy7carbo~tyril and hydrogen peroxide.
M.p.: 164 - 166C
Yield: 74 % of theory.

ExampIe 214 6-/~-(4-tert.-Butyl-phenylsulfonyl)-butoxv7carbostyril Prepared analogously to Example 124 from 6-/~-(4-tert.-butyl-phenylmercapto)-butoxy7carbostyril and hydrogen peroxide.
M.p.: 203 - 205C
Yield: 56 % of theory.

Example 215 6-/~-(2-Quinolylsulfinyl)-butoxy7-3,4-dihYdrocarbostvril Prepared analogously to Example 123 from 6- ~ -(2-quinolyly-mercapto)-butoxy7-3,4-dihydrocarbo~tyril and hydrogen peroxide.

, _ 9] _ -- ~L~
M.p.: 154 - 157C
Yield: 79 % of theory.

Example 216 6-tZ-(2-QuinolYlsulfonyl)-butoxy7-3~4-dihydrocarbostvril Prepared analogously to Example 124 from 6- ~-(2-quinolyl-mercapto)-butoxy7-3,4-dihydrocarbostyril and hydrogen peroxide.
Rf-value: 0.50 (silica gel fluorescent plate; eluent:
benzene/ethanol/conc. ammonia = 75/25/2).
~Yield: 72 % of theory.

Example 217 6- r-(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 - 153.5C) and N-methyl-N-cyclohexyl-thioglycolic acid amide.
Rf-value: 0.46 (silica gel fluorescent plate; eluent:
ethylenechloride/methanol = 95/5).
Yield: 63 % of theory.

.
Example 218 6- r-(N-Methyl-N-cyclohexyl-carbamidomethylsulfinyl)-ethoxy7-3,4-dihydrocarbostyril _ _ Prepared analogously to Example 123 from 6- ~-(N-methyl-N-cyclohexylcarbamidomethylmercapto)-ethox~7-3,4-dihydrocarbosty-ril and hydrogen peroxide.

~ , ~ =c . , , _ 92~

Rf-value: 0.34 (silica gel fluorescent plate; eluent:
ethylene chloride/methanol = 95/5).
M.p.: 143 - 146C
Yleld: 48 % of theory.

Example 219 6-L~-(N-Methyl-N-cyclohe~yl-carbamidomethylsulfonyl)-ethoxy7-3~4-dihvdrocarbostyril Prepared analogously to Example 124 from 6-/2-(N-methyl-N-cyclohexylcarbamidomethylmercapto)-ethox~7-3,4-dihydro-carbo~tyril and hydrogen peroxlde in formic acid.
Rf-value: 0.48 (silica gel fluorescent plate; eluent:
ethylene chloride/methanol = 95/5) M.p.: 110 - 111C
Yield: 45 % of theory.

ExamPle 220 6-~-(N-Methyl-N-cyclohexyl-carbamidomethylmercapto)-athoxv7-carbostyril Prepared analogously to Example 122 from 6-(2-chloroethoxy)-carbo~tyril /Rf-value: 0.30 (silica gel fluorescent plate;
eluent: ethylene chloride/methanol = 95/5 )7 and N-methyl-N-cyclohexyl-thioglykolic acid amide.
Rf-value: 0.41 (silica gel fluorescent plate; eluent: ethylene chloride/methanol = 95/5), Yield: 62 % of theory.

,. ,, ,~

.
A

_ 93 Exam2~e 221 6- ~-(N-Methyl-N-cyclohexyl-carbamidomethylsulfinyl)-ethoxY7-carbostyril Prepared analogously to Example 123 from 6~ (N-methyl-N-cyclohexyl-carbamidomercapto)-ethoxy7carbostyril and hydrogen peroxide.
Rf-value: 0.027 (silica gel fluorescent plate; eluent:
ethylene chloride/methanol = 95/5).
M.p.: 128 - 130C
Yield: 65 % of theory.

Exam~le 222 6- ~-(N-Methyl-N-cyclohexyl-carbamidomethylsulfonyl)-ethox~7-carbostYril , Prepared analogously to Example 124 from 6- ~-(N-methyl-N-cyclohexyl-carbamidomercapto)-ethox~7carbostyril and hydro-gen peroxide.
Rf-value: 0.39 (silica gel fluore~cent plate; eluent:
ethylene chloride/methanol = 95/5).
Yield: 67 % of theory.

Example 223 6-/3-(3,4-Dichlorophenylsulfonyl)-propox~7-3,4-dihydrocarbo-stvril _ _ Prepared analogously to Example 124 from 6- ~-(3,4-dichloro-phenylmercapto)-propoxY7-3,4-dihydrocarbostyril and hydrogen peroxide.
M.p.: 187 - 188C
Yield: 87 % of theory.

. .
r ~ -,,~,i j . . ................................. -_ 94 -.
Example 224 6-L~-(3,4-Dichlorophenylmercapto)-pentoxv7-3,4-dihydrocarbo-stvril ., .
Prepared analogously to Example 122 from 6-(5-bromopentoxy)-3,4-dihydrocarbostyril (m.p.: 97 - 98C) and 3,4-dichloro-thiophenol.
M.p.: 101 - 104C
Yield: 69 % of theory.

Example 225 6- ~ -(3,4-Dichlorophenyl~ulfinyl)-pentoxy7-3,4-dihydrocarbo-styril Prepared analogously to Example 123 from 6- ~ -(3,4-dichloro phenylmercapto)-pentoxy7-3,4-dihydrocarbostyril and hydrogen peroxide.
M.p.: 165 - 166C
Yield: 74 % of theory.

Example 226 6-/5-(3.4-DichlorophenYlsulfonyl)-pentoxy7-3,4-dihydrocarbostyril .
Prepared analogously to Example 124 from 6- ~-(3,4-dichloro-phenylmèrcapto)-pentoxy7-3,4-dihydrocarbostyril and hydrogen peroxide.
M.p.: 176 - 178C
Yield: 65 % of theory.

r I

-- 9:s --Example 227 6- ~-(2-Methyl-4-tert.-butyl-phenylmercapto)-butox~7-3,4-dihYdrocarbostyril Prepared analogously to Example 122 from 6-(4-bromobutoxy)-3,4-dihydrocarbo~tyril (m.p.: 142 - 147C) and 2-methyl-4-tert.-butylthiophenol.
M.p.: 81 - 85C
Yield: 91 % of theory.

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

Example 229 6-~- (3,5-Dichloro-4-hydroxy-phenylmercapto)-butoxv7-3,4-di-hYdrocarbostyril Prepared analogously to Example 122 from 6- (4-bromobutoxy)-3,4-dihydrocarbostyril (m.p.: 142 - 147C) and 3,4-dichloro-4-hydroxy-thiophenol under nitrogen as protective gas.
M.p.: 110 - 114C
Yield: 94 % of theory.

.`

Example 230 5-Bromo-6-(4 phenvl~ercaPtobutoxy)-csrbostvril Prepared analogously to Example 122 from 5-bromo-6-(4-bromo-butoxy)-carbostyril (prepared by bromination of 6-(4-bromo~
butoxy)-carbostyril) and thiophenol.
M.p.: 209 - 213C
Yield: 41 % of theory.

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

Example 232 5-Nitro-6-(4-phenylsulfinvlbutoxv)-carbostYril Prepared analogously to Example 123 from 5-nitro-6-(4-phenyl-mercaptobutoxy)-carbostyril and hydrogen peroxide.
M.p.: 192 - 194C
Yield: 91 % of theory.

Example 233 5-Acetamino-6-(4-PhenylmercaPtobutoxv)-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.

--~- -~ - -r . _ M.p.: 238 - 240C
Yield: 80 % of theory.

Example 234 5-Acetamino-6-(4-phensrlsulfinylbutoxy)-carbostyril Prepared analogously to ;Example 12~ from 5-acetamino-6-(4-phenylmercapto)-butoxy)-carbostyril and hydrogen peroxide.
M.p.: 213 - 217C
Yield: 47 % of theory.
;

.
Example 235 5-Bromo-6-(4-phenylsulfinvlbutoxy)-carbostyril Prepared analogously to Example 12~ from 5-bromo-6-(4-phenyl-mercaptobutoxy)-carbostyril and hydrogen peroxide.
M.p.: 190 - 191C
Yield: 82 % of theory.

Example 2~6 4-Methyl-6-/~- ~-p~ridylsulfinyl)-butoxY7carbostyril 0.170 g (0.0005 mol) of 4-methyl-6-~-(2-pyridylmercapto)-butoxy7carbostyril, 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 tempera-ture 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 bicarbonate solution and dried over water-free magnesium sulfate. After evaporating the organic phase the obtained residue was recrystallized from toluene.
M,p.: 166 - 168C
Yield: 0.04 g (22,5 % of theory).

b~,~,.~ . ` ` ~ . . , ' . .

- . ~ 98 -~ Example 237 6-(4-tert,-Butyl~ulfinyl-butoxY~-3 t 4-dihydrocarbostyril Prepared analogously to Example 123 from 6-(4-tert.-butyl-mercapto-butoxy)-3,4-dihydrocarbostyrl (m~p.: 117 - 118C) and hydrogen peroxide.
M.p.: 126 - 128C
Yield: 62 % of theor~.

Example 238 6-/~-(3-Hydroxy-pyride-2-yl)-butoxy7-3,4-dihydrocarbostyril Prepared analogously to Example 122 from 6-(4-bromobutoxy)-3,4-dihydrocarbostyril (m.p.: 142 - 147C) and 3-hydroxy-2-mercapto-pyridine.
M.p.: 211 - 216C
Yield: 58 % of theory.

ExamPle 239 6-/~-(1,2,4-Triazole-3-Yl-sulfinyl)-butoxy7carbostyril Prepared analogously to Example 123 from 6- ~-(1,2,4-tri-azole-3-yl-mercapto)-butox~7carbostyril and hydrogen per-oxide.
Rf-value: 0.12 (silica gel fluorescent plate, eluent:
ethylenechloride/methanol = 95/5).

.
t-., ~, . . . .

` 99 ExamPle 240 6- ~-(1,2,4--Triazole-3-yl-mercapto)-butox~7-3,4-dihydro-carbostlvril Prepared analogously to Example 122 from 6-(4-bromobutoxy)-3,4-dihydrocarbostyril (m.p.: 142 - 147C) and 3-mercapto-1,2,4-triazole.
M.p.: 152 - 154C
Yield: 82 % of theory.

ExamPle 241 6- ~-(1,2,4-Triazole-3-yl-sulfinyl)-butoxy7-3,4-dihydro-carbostyril Prepared analogously to Example 123 from 6- ~ -(1,2,4-triazole-3-yl-mercapto)-butoxy7-3,4-dihydrocarbostyril and hydrogen peroxide.
Rf-value: 0.18 (silica gel fluorescent plate, eluent:
ethylenechloride/methanol = 95/5).

Example 242 6- ~-(1,2,4-Triazole-3-yl-sulfonyl)-butoxy7-3,4-dihydro-carbostvril Prepared analogously to Example 124 from 6- ~-(1,2,4-tri-azole-3-yl-mercapto)-butoxy7-3,4-dihydrocarbostyril and hydrogen peroxide.
Rf-value: 0.22 (silica gel fluorescent plate, eluent:
ethylenechloride/methanol = 95/5).
M.p.: 217 - 224C.

. ~

]-oo Example 243 6- ~ -(2,4,5-Trichlorophenylmercapto)-butoxy7-3,4-dihydro-carbostvril Prepared analogou~ly to Example 122 from 6-(4-bromobutoxy)-3,4-dihydrocarbostyril (m.p.: 142 - 147C) and 2,4,5-tri-chloro-thiophenol.
M.p.: 144 - 145C
Yield: 87 % oi theory.

, . . . . , . . _ _ Exam~le A

Tablets containing 100 mg of 6- ~ -(2-Pyridyl~ulfinyl)-butoxx7-3.4-dihYdrocarbostYril 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 poly-vinylpyrrolidone. The mixture was passed through a screen of 2.0 mm mesh-size, dried at 50C ~n a hurdl~, 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 Diameter: 10 mm, biplan 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-dihydrocarbostvril 1 coated tablet contains:
Active ingredient 50.0 mg Lactose 40.0 mg Corn starch 17.0 mg . _ ~", . - .
~......................... .. -. , . - .

. ~ , . .

- 1~2~
;

Polyvinylpyrrolidone 2.0 mg Magnesium stearate 1.O mg 110.0 mg Method of PreParation.

The granulate was prepared analogously to Example A.
The mixture wa~ pressed fnto coated tablets.
Weight of core: 110 mg Diameter: 8 mm, biconvex.
The cores were isolated and subsequently covered in a coa-ting vessel according to known procesces with pyrr~lidone and with a coating consisting es3entially 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-/~-(2-Pyridyl-sulfin~ but xy7-3, 4-dihydrocarbostyril 1 cap~ule 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 a~d the auxiliary products were mixed, pa~sed through a screen of 0.75 mm mesh-size and mixed homo-geneously with a suitable device. The mixture was filled into hard gelatine capsules o~ size 1.
Content of capsule: approx. 320 mg Capsule: hard gelatine s~ze 1 ,~ . ... . .. ..
, . ...

Example D

Suppoæitories containing 150 mg of 6-(4-Phenylsulfinylbutoxy)-3,4-dihydrocarbostyril 1 suppository contains:
Active ingredient 150.0 mg Polyethylene glycol 1500 550.0 mg Polyethylene glycol 6000 460.0 mg Polyoxyethylene sorbltane monostearate 840.0 mg 2 000.0 mg ~h~eParation -After melting the suppository mass~the active ingredient was homogenously dispersed therein and the melt was poured in-to pre-cooled moulds.

Example E

Suspension containing 50 mg of 6-L~-(2-Pyridylsulfinyl-butoxY7-3.4-dihYdrocarbostyrii pe~_~ ml _ _ 100 ml of suspension contain:
Active ingredient 1.0 g Carboxymethyl cellulose-Na-salt 0.1 g Methyl-p-hydroxybenzoate 0.05 g Propyl-p-hydroxybenzoate 0.01 g Cane sugar 10.0 g Glycerine ~ 5.0 g Sorbit solution 70 % 20.0 g Aroma 0 3 g Water dist. a~ 100 ml r~. ~ , Method of Preparation:

Distilled water was heated to 70C. Whil~t stirring methyl-p-hydroxybenzoate and propyl-p-hydroxybenzoate as well as glycerine and carboxymethyl cellulose sodium salt were di~-solved therein. The mlxture was cooled to room temperature and whilst stirring the active ingredient was added and the whoIe was homogenously disperged. After adding and dissol-ving the sugar, the sorbit solution and the aroma, the sus-pension was evacuated whilst stirring for deaeration.

5 ml of su~pension contain 50 mg of active ingredient.
i ,. ,.1 , , . , ,~ .
.: i r . . . . , 1 ,, j . . , ,

Claims

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

1. A process for the preparation of compounds of general formula I, (I) 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;
R1 represents a hydrogen atom or an alkyl group contain-ing from 1 to 3 carbon atoms;
R2 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 hetero-aryl 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 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, carb-oxyl, cyclohexyl 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(p-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 hydroxyal-kylene group containing from 3 to 6 carbon atoms or a xylylene group, al-ternatively in alkyl group containing from 1 to 6 carbon atoms; and R3 and R4, 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, selected from the following:
A. Reaction of a compound of formula II, (II) (wherein R1, R3, R4 and W are as defined above) or a salt thereof with an inorganic or tertiary organic base, with a compound of formula III, Z - D - SOm - R2 (III) (wherein D, R2 and m are as defined above and Z represents a nucleophilically exchangeable atom or group), B. for the preparation of compounds of general formula I wherein m is 1:
oxidation of a compound of formula I wherein m is O whereby the desired compound of formula I is obtained, C. for the preparation of compounds of general formula I wherein m is 2:
oxidation of a compound of formula I wherein m is O or 1 whereby the desired compound of formula I is obtained, D. for the preparation of compounds of general formula I wherein m is 0:
reaction of a compound of formula IV, (IV) with a compound of formula V, Y - R2 (V) (wherein, in the above formulae IV and V, R1, R2, R3, R4, D and W are as defined above and either 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), E. for the preparation of compounds of general formula I wherein R1 represents an alkyl group containing from 1 to 3 carbon atoms:
reaction of a compound of formula I wherein R1 represents a hydrogen atom, or an alkali metal salt thereof, with a compound of formula VI, Z' - R (VI) (wherein R1 is as defined above and Z' represents a nucleophilically ex-changeable atom or group), F. for the preparation of compounds of general formula I wherein W
represents a vinylene group:
dehydrogenation of a compound of formula I wherein W represents an ethylene group, G. for the preparation of compounds of general formula I wherein W
represents an ethylene group and m is O or 2:
hydrogenation of a compound of formula I wherein W represents a vinylene group and m is 0 or 2. 0

2. Compounds of general formula I, (I) 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;
R1 represents a hydrogen atom or an alkyl group contain-ing from 1 to 3 carbon atoms;
R2 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 hetero-aryl 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 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, cyclohexyl or phenyl group or by a halogen atom and, in the ease 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 sub-stituents 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-(p-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 hydroxy-alkylene group containing from 3 to 6 carbon atoms or a xylylene group, alternatively an alkyl group containing from 1 to 6 carbon atoms; and R3 and R4, 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, whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.

3. A process as claimed in claim 1 wherein R2 represents a cyclohexyl, benzyl, naphthyl, pyridyl, pyrimidyl, 1,2,4-triazolyl, pyridyl-oxide, fur-furyl, triphenylmethyl, quinolyl, benzimidazolyl, benzthiazolyl, quinozolin-4-one-yl; 4,5-bis-(p-chlorophenyl)-oxazole-2-yl, N-methyl-cyclohexylamino-carbonylmethyl or amino-iminomethyl group; a phenyl group optionally substi-tuted by a carboxyl, hydroxy, methoxy, amino, acetylamino, nitro, cyclohexyl or phenyl group; a phenyl group substituted by one or two substituents select-ed 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: R3 represents a hydrogen, chlorine or bromine atom or a methyl, amino, acetyl-amino or nitro group: and R4 represents a hydrogen atom.

4. A process as claimed in claim 3 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 hydroxy-alkylene group containing from 3 to 5 carbon atoms; R1 represents a hydrogen atom; R2 represents a cyclohexyl, phenyl, benzyl, naphthyl, biphenylyl, cyclo-hexylphenyl, pyridyl, methylphenyl, methoxyphenyl, fluorophenyl, chlorophenyl, dichlorophenyl, trichlorophenyl, bromophenyl, dibromophenyl, bromomethyl-phenyl, amino-dibromophenyl or hydroxy-di-tert.-butylphenyl group; and R3 represents a hydrogen atom.

5. A process as claimed in claim 4 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-dichloro-phenyl, 2,5-dichlorophenyl, 4-amino-3,5-dibromophenyl, 4-hydroxy-3,5-di-tert.-butylphenyl or pyrid-2-yl group.

6. A process according to claim 1 in which W represents an ethylene group, m is one, D is a straight butylene chain, R1, R3 and R4 represents hydrogen atoms, R2 represent a phenyl group and the phenylsulfinylbutoxy group is attached in the 6-position of the carbostyryl nucleus.

7. A process according to claim 1 in which W represents an ethylene group, m is one, D is a straight butylene chain, R1, R3 and R4 represent hydrogen atoms, R2 represents a 3,4-dichlorophenyl group and the 3,4-di-chlorophenylsulfinylbutoxy group is attached on the 6-position of the carbostyryl nucleus.

8. A process according to claim 1 in which W represents an ethylene group, m is two, D is a straight butylene group, R1, R3 and R4 represent hydrogen atoms, R2 represents a 2-pyridyl group and the pyridylsulfonylbutoxy group is attached in the 6-position of the carbostyryl nucleus.

9. A process for the preparation of 6-[4-(2-pyridylsulfonyl)butoxy]-3, 4-dihydrocarbostyryl which comprises oxidising 6-[4-(2-pyridylmercapto)butoxy]-3,4-dihydrocarbostyryl, or 6-[4-(2-pyridylsulfinyl)butoxy]-3,4-dihydrocarbos-tyryl.

10. A process for the preparation of 6-(4-phenylsulfinylbutoxy)-3,4-dihydrocarbostyryl which comprises reacting 6-hydroxy-3,4-dihydrocarbostryl with 4-phenylsulfinylbutyl bromide.

11. A process for the preparation of 6-[4-(3,4-dichlorophenylsulfinyl)-butoxy]-3,4-dihydrocarbostyryl which comprises oxidising 6-[4-(3,4-dichloro-phenylmercapto)-butoxy]-3,4-dihydrocarbostyryl.

12. A process for the preparation of 6-(4-phenylsulfinyl-butoxy)-3,4-dihydrocarbostyryl which comprises oxidising 6-(4-phenylmercapto-butoxy)-3,4-dihydrocarbostyryl.