DD141829A5 - PROCESS FOR THE PREPARATION OF NEW CARBOSTYRIL AND OXINDOL DERIVATIVES - Google Patents

Description

Process for the preparation of new carbostyril and oxindole derivatives

Applicability of the invention

The invention relates to a process for the preparation of novel carbostyril and oxindole derivatives.

These compounds having antithrombotic properties and a positive inotropic effect are used as medicaments. They are also used, for example, for the prophylaxis of thromboembolic disorders such as coronary infarction, cerebral infarction, so-called transient ischemic attacks, amaurosis fugax and for the prevention of arteriosclerosis.

Characteristic of the known technical solutions

Japanese Laid-Open Patent Publication No. 2073-876 discloses 3- i- 4-dihydro-carbostyril and garbostyril derivatives of the general formula

AP O 07 D / 211 077 912 18

1100

in the

Let E- _{1 be} first off atom or an alkyl group with 1 to 3 carbon atoms,

Rp is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms,

R ~ is an alkyl group having 1 to 4 carbon atoms, the allyl group, an aralkyl or aryl group substituted by an alkyl group having 1 to 3 carbon atoms,

Y. an oxygen atom or the carbonyl group and

η is the number 1, 2, 3, 4 or 5, which antiinflammatory and antithrombotic properties on iron _e

Aim of the invention;

The aim of the invention is to provide a simple and economical method for producing new V

AP O 07 D / 211 007 912 18

, _s _ 21.1007

compounds with improved antithrombotic properties, in addition positive inotropic effect and lack of toxic side effects ·

Explanation of the essence of the invention

The invention is based on the object _s suitable easily accessible starting compounds and suitable headers ». Identify conditions for the preparation of such compounds * ·.

According to the invention, new carbostyril and oxindole derivatives of the general formula

0 - D - S0 _m - E ₂ , (I)

manufactured.

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The novel compounds of the above general formula I have valuable pharmacological properties, in addition to a positive inotropic effect, in particular antithrombotic properties.

In the above general formula I means

W is a vinyl group which is optionally substituted by a methyl group, the methylene or ethylene group,

m is the number.O, 1 or 2,

D is a straight-chain or branched alkylene group having 2 to 6 carbon atoms, a straight-chain or branched hydroxyalkylene group having 3 to 6 carbon atoms or a xylylene group,

R _{1 represents} a hydrogen atom or an alkyl group having 1 to 3 carbon atoms,

R is a cycloalkyl group having 3 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 11 carbon atoms, a heteroaryl group having 4 to 9 carbon atoms or heteroaralkyl group containing a nitrogen atom and / or an oxygen or sulfur atom or two nitrogen atoms 5 to 10 carbon atoms, wherein the above-mentioned aromatic nuclei are monosubstituted by an alkyl group having 1 to 4 carbon atoms, by a hydroxy, methoxy, amino, acetyl, nitro, carboxyl, cyclohexyl, phenyl group or a halogen atom and additionally, the above-mentioned monosubstituted phenyl groups may be mono- or disubstituted by alkyl groups having 1 to 4 carbon atoms and / or halogen atoms (wherein the substituents of the phenyl nucleus may be the same or different), 1,2,4-triazolyl, triphenylmethyl -, 4,5-bis (p-chlorophenyl) -oxazol-2-yl, N-methyl-cyclohexylaminocarbonylmethyl or · amino-iminomet hylgruppe or an alkyl group having 1 to 6 carbon atoms, if either m is the number 1 or

D represents a straight-chain or branched hydroxyalkylene group having 3 to 6 carbon atoms or a xylylene group,

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R and R, which may be the same or different, are hydrogen or halogen atoms, alkyl groups having 1 to 4 carbon atoms, amino, acetylamino or nitro groups.

By the term "a halogen atom ¹¹ mentioned in the definition of the radicals R ₁ , R ₃ and R ₄ " is meant, in particular, a fluorine, chlorine, bromine or iodine atom, for which in the definition of the radicals D, R. , R, R and R ₄ meanings mentioned above thus comes for -

D is the meaning of ethylene, n-propylene, n-butylene, n-pentylene, n-hexylene, 1-methyl-ethyl, 2r-methyl-ethyl, 1-methyl-n-propylene, 2 Methyl-n-propylene, 3-methyl-n-propylene, 1-methyl-n-butylene, 2-methyl-n-butylene, 3-methyl-n-butylene, 4-methyl-n -butylene, 1-methyl-n-pentylene, 2-methyl-n-pentylene- _f 3-methyl-n-pentylene, 4-methyl-n-pentylene, 5-methyl-n-pentylene, 1,1 Dimethyl-ethylene, 1,2-dimethyl-ethylene, 2,2-dimethyl-ethylene, 1,1-dimethyl-n-propylene, 2,2-dimethyl-n-propylene, 3,3-dimethyl-n-propylene, 1,2-dimethyl-n-propylene, 1,3-dimethyl-n-propylene, 1,1-dimethyl-n-butylene, 2,2-dimethyl-n-butylene, 3,3-dimethyl-n butylene, 4,4-dimethyl-n-butylene, 1,2-dimethyl-n-butylene, 1,3-dimethyl-n-butylene, 1,4-dimethyl-n-butylene, 2, 3-dimethyl-n-butylene, t-Äthyläthylen-, 2 ~ Äthyläthylen-, 1-ethyl-n-propylene, 2-ethyl-n-propylene, 3-Xthyl-n-propylene, 1-ethyl- n-butylene, 2-ethyl-n-butylene, 3-ethyl-n-rbutylene, 4-ethyl-n-butylene, 1-methyl-2-ethyl-ethylene i-Me thyl-2-ethyl-n-propylene, i-methyl-3-ethyl-n-propylene, 1-methyl-2-propyl-ethylene, 1-propyl-ethylene, 1-butyl-ethylene, 1 Propyl-n-propylene, 2-hydroxy-n-propylene, 2-hydroxy-n-butyl, 3-hydroxy-n-butylene, 2-hydroxy-n-pentylene, 3-hydroxyn -pentylene, 4-hydroxy-n-pentylene, 2-hydroxy-n-hexylene, 3-hydroxy-n-hexylene, 1-methyl-2-hydroxy-n-propylene, 2-hydroxy-2- methyl-n-propylene, p-xylylene, o-xylylene or m-xylylene group, for

R _{1 is} that of the hydrogen atom, the methyl, ethyl, propyl or isopropyl group, for

; - · - 21 1007

R ^ which is the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenylethyl, naphthyl, naphthylmethyl, cyclohexylphenyl, biphenyl, triphenylmethyl, N-methylcyclohexylaminocarbony! Methyl, amino-iminomethyl , Pyridyl, pyridylmethyl, furfuryl, benzimidazolyl, benzthiazolyl, pyrimidyl, quinolyl, quinazolin-4-one-yl, 4,5-bis (p-chlorophenyl) -oxazol-2-yl , Pyridyl-oxide, methylphenyl, dimethylphenyl, tert. Butylphenyl, methyl-tert-butylphenyl, methylpyridyl, methoxyphenyl, dimethoxyphenyl, methoxypyridyl, hydroxyphenyl, dihydroxyphenyl , fluorophenyl, difluorophenyl, trifluorophenyl, 1,2,4-triazolyl, fluoro pyridyl, chlorophenyl, dichlorophenyl, trichlorophenyl, chloropyridyl, bromophenyl, dibromophenyl, aminophenyl, acetylaminophenyl, arninopyridyl, acetylaminopyridyl, nitrophenyl, carboxyphenyl, hydroxy-dichlorophenyl, hydroxy-dibromophenyl, Amino-dichlorophenyl, amino-dibromophenyl, hydroxydi-tert-butylphenyl, methoxy-fluorophenyl, methoxy-chlorophenyl, methoxy-bromophenyl, fluoro-methyl-phenyl, chloro-methyl-phenyl or bromo-methyl-phenyl group

R ₃ and R, which may be the same or different, those of the hydrogen, fluorine, chlorine, bromine or iodine atom, the methyl, ethyl, propyl, isopropyl, butyl, tert. Butyl, nitro, amino or acetylamino group into consideration.

The present application thus relates in particular to those compounds of the general formula I in which W, D and m are as defined above,

Rp represents a cyclohexyl, benzyl, naphthyl, pyridyl, pyrimidyl, 1,2,4-triazolyl, pyridyl-oxide, furfuryl, triphenylmethyl, quinolyl, benzimidazolyl, benzthiazolyl, quinazoline-4 onyl, 4,5-bis (p-chlorophenyl) -oxazol-2-yl, N-methylcyclohexylamino-carbonylmethyl or aminoiminomethyl group, optionally with a carboxyl, hydroxy, methoxy, amino, acetylamino -, nitro, cyclohexyl or phenyl substituted phenyl group, one by halogen atoms and / or alkyl groups having 1 to 4 carbon mono- or disubstituted

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substituted phenyl, a substituted by two halogen atoms or by two alkyl groups having 1 to 4 carbon atoms hydroxyphenyl, halophenyl or aminophenyl, R _{3 is} a hydrogen, chlorine or bromine, the methyl, amino, acetylamino or nitro group and

R. represents a hydrogen atom

 4

However, preferred compounds of the above general formula I are those in which

W is a vinyl group which is optionally substituted by a methyl group or the ethylene group,

m is the number O, 1 or 2,

D is an alkylene group having 2 to 5 carbon atoms or a hydroxyalkylene group having 3 to 5 carbon atoms,

R _{1 is} a hydrogen atom,

R_ is a cyclohexyl, phenyl, benzyl, naphthyl, biphenylyl, cyclohexylphenyl, pyridyl, methylphenyl, methoxyphenyl, fluorophenyl, chlorophenyl, dichlorophenyl, trichlorophenyl, bromophenyl, dibromophenyl, Bronlmethylphenyl-, Amino-dibromophenyl or hydroxy-di-tert-butylphenyl group,

R and R each represent a hydrogen atom.!.

However, most preferred compounds of the above general formula I are those in which

V7 is the ethylene, vinylene or 2-methylvinylene group, m is the number 0, 1 or 2,

R ₁ , R ur.d R. each one hydrogen atom,.

R is the cyclohexyl, phenyl, benzyl, naphthyl (2), 2-methoxyphenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2,5-dichlorophenyl, 4-amino-3,5- dibroinphenyl, 4-hydroxy-3,5-di-tert.butyl

phenyl or pyridyl (2) group and D is the ethylene, n-propylene, n-butylene or 2-hydroxy-n-propylene group.

According to the invention, the novel compounds of general formula I are obtained by the following processes:

- »- 21 100 7

a) reaction of a hydroxy compound of the general formula

  "" I

(II)

in the

R, R, R and W are as defined above, or their salts with inorganic or tertiary organic bases with a compound of general formula

ZD-SO _1n -R ₂ , (III)

in the

D / R ₂ and m are as defined above and Z is a nucleophilically exchangeable group such as a halogen atom or a Sulfonsäureesterrest, for example a chlorine, bromine, iodine atom, a p-toluenesulfonyloxy or methanesulfonyloxy group represents. ,

The reaction is conveniently carried out in a suitable solvent such as dioxane, tetrahydrofuran, chloroform or toluene, but preferably in an anhydrous aprotic solvent such as acetone, dimethylformamide or Djmethylsulfoxid, optionally in the presence of an alkali metal base such as sodium carbonate, potassium carbonate or sodium hydroxide at temperatures between 0 C and the boiling point of the solvent used, eg at temperatures between 0 and 100 C, but preferably, at temperatures between 10 and 50 C carried out. However, the reaction can also be carried out without a solvent.

21 100.7

b) For the preparation of compounds of general formula I in which m represents the number 1 or 2:

Oxidation of a compound of the general formula

W->> ^ oD.-SO-R ₀ »(IV)

η c.

in the

^R 1 ~ ^R 4 ' ^{D and ww:} "- ^ee i ⁿ 9 are defined ^{at <} 3 ^s and η is the number O or 1.

The oxidation is preferably carried out in a solvent, e.g. in water, water / pyridine, ethanol, methanol, acetone, glacial acetic acid, formic acid, dilute sulfuric acid or trifluoroacetic acid, depending on the oxidant used expediently: leads.

moderately carried out at temperatures between -80 and 100 ° C.

For the preparation of compounds of the general formula I in which m is the number 1, the oxidation is conveniently carried out with one equivalent of the oxidizing agent used, e.g. with hydrogen peroxide in glacial acetic or formic acid at 0 to 20 C or in acetone at 0 to 60 C, with a peracid such as performic acid in glacial acetic acid or trifluoroacetic acid at 0 to 50 C, with sodium metaperiodate in aqueous methanol or ethanol at 15 to 25 C, with N -Bromsuccinimid in ethanol, with tert.Butyl hypochlorite in Methanoi at -80 to -30 C, with iodobenzene dichloride in aqueous pyridine at 0 to 50 C, with nitric acid in glacial acetic acid at 0 to

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20 ° C, with chromic acid in glacial acetic acid or acetone at 0 to 20 ° C and with sulfuryl chloride in methylene chloride at -70 ° C, the resulting thioether-chloro complex is suitably hydrolyzed with aqueous ethanol.

For the preparation of compounds of the general formula I in which m is the number 2, the oxidation is conveniently carried out with one or two or more equivalents of the oxidizing agent used, e.g. with hydrogen peroxide in glacial acetic acid or in formic acid at 20 to 100 ° C or in acetone at 0 to 60 C, with a peracid such as performic acid or m-chloroperbenzoic acid in glacial acetic acid, trifluoroacetic acid or chloroform at temperatures between 0 and 50 ° C, with nitric acid in glacial acetic acid at 0 to 20 ° C, with chromic acid or potassium permanganate in glacial acetic acid, water / sulfuric acid or in acetone at 0 to 20 C. Thus, in a compound of the above general formula IV η is the number 0, the reaction is preferably with two or more equivalents of the respective oxidizing agent and quite suitably carried out with at least one equivalent, if η is 1.

c) For the preparation of a compound of general formula I in which m represents the number 0:

Reaction of a compound of the general formula

0 - D - X, (V)

^R ₁

I 4 R

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in the

R- / R- / R ,, D and W are as defined above, with a compound of the ₌ general formula

YR _2. , (VI)

in the

R _{2 is} as defined above and

one of the radicals X or Y in the compounds of the general formulas V and VI is the mercapto group and the other of the radicals X or Y is a nucleophilically exchangeable group such as a halogen atom or a sulphonic acid ester radical, for example a chlorine, bromine or iodine atom, a p-toluenesulphonyloxy radical or methanesulfonyloxy group, or X together with the adjacent hydroxy group of the radical D represents an epoxide group and Y represents a mercapto group.

The reaction is conveniently carried out in a suitable solvent such as dioxane, tetrahydrofuran, chloroform or toluene. but preferably in an anhydrous aprotic solvent such as acetone, dimethylformamide or dimethyl sulfoxide, optionally in the presence of an alkali metal base such as sodium carbonate, potassium carbonate or sodium hydroxide at temperatures between 0 C and the boiling point of the used

  ο

Solvent, e.g. at temperatures between 0 and 100 C, but preferably at temperatures between 10 and 50 C carried out. However, the reaction can also be carried out without a solvent.

d) For the preparation of a carbostyril of the general formula I in which R .. is not hydrogen atom:

Reaction of a compound of the general formula

 - «- 21 100 7

O - D - SO _n , - Rp

^{m 2} , (VII)

.in the

R_ to R, D, W and m are as defined above, or its alkali metal salt with a compound of the general formula

Z - R ₁ , (VIII)

in the

R ₁ as defined above and

Z is a nucleophile-exchangeable group such as a halogen atom or a sulfonic ester residue, e.g. represents a chlorine, bromine or iodine atom, a p-toluenesulfonyloxy or methanesulfonyloxy group.

The alkylation is conveniently carried out in an aprotic solvent such as acetone, dimethylformamide or dimethyl sulfoxide in the presence of an inorganic base such as potassium carbonate, sodium hydroxide, sodium hydride or potassium hydroxide or in the presence of an alcoholate such as sodium methylate at temperatures between 0 and 50 C, but preferably at temperatures between 10 and 25 C, performed. Suitable alkylating agents are in particular alkyl halides such as methyl iodide or isopropylbroiride or dialkyl sulfates such as dimethyl or diethyl sulfate.

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e) For the preparation of a carbostyril of the general formula I, in which W denotes the vinylene group:

Dehydrogenation of a 3,4-dihydro-carbostyril of the general

formula

0 - D - S0 _m - R ₂

, (IX)

in the

R to R, D and m are as defined above.

The dehydration is carried out in the presence of a dehydrating agent, e.g. an oxidizing agent such as 2,3-dichloro-5,6-dicyano-benzoquinone, chloranil or a noble metal catalyst such as palladium / carbon, preferably in an inert solvent such as dioxane or mesitylene at elevated temperatures, e.g. at temperatures between 100 and 200 C, but preferably at the boiling temperature of the solvent used, carried out.

f) For the preparation of a carbostyril of the general formula I in which W represents the ethylene group and ir represents the number 0 or 2:

Hydrogenation of a carbostyril of the general formula

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in the R. to

O - D - SO _m - R ₂

D and m are as defined above.

The hydrogenation is carried out in a suitable solvent such as ethanol, ethyl acetate, glacial acetic acid or dioxane with catalytically-promoted hydrogen, e.g. with hydrogen in the presence of a hydrogenation catalyst such as palladium / carbon, platinum, Raney nickel, Raney cobalt or dirhenium heptasulfid, carried out at temperatures between 0 and 5O ° C, but preferably at room temperature, and at a hydrogen pressure of 1 to 5 bar.

The compounds of the general formulas II to X used as starting materials are known in the literature in some cases or are obtained by methods known per se. For example, one obtains a 6-, 7- or e-hydroxy-S ^ -dihydro-carbostyril of the general formula II by acylation of a corresponding aniline derivative with a corresponding ß-halo-carboxylic acid derivative and subsequent cyclization according to Friedel-Crafts (see J. ehem. Soc., 1955, 743-744, Chem. Pharm. Bull 1961, 970-975 and Ber. Dtsch. Chem. Ges. 60, 858 (1927)) and a 5-hydroxy- · 3,4-dihydrocarbostyril of the general formula II by cyclization of a corresponding 2- (β-CyanoäthylJ-cyclohexanedione-i.3 derivative and subsequent aromatization, for example, with N-bromo-succinimide (see Chem., Ind., 1970, 1435.) The preparation of the corresponding hydroxy-carbostyriles of the general Formula II is known from the literature (see, for example, J. Amer.

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former Soc. Jl ^'34β (1950) and ibid 76, 2402 (1954) or J.'Org. Chem. 32 » ¹⁰⁸⁹ Π968) and ibid 3j6, 3493 (1971)). Further, the preparation of 5-hydroxyoxindole in J. Chem. 1961 , 2723 described.

The compounds of the general formulas IV, V, VII, IX and X used as starting materials are obtained by alkylation of a corresponding hydroxy derivative and optionally subsequent oxidation.

As already mentioned, the novel compounds of the general formula I. prepared according to the invention have valuable pharmacological properties, in addition to a positive inotropic effect, they have antithrombotic properties.

For example, the following compounds were tested for their biological properties:

A - 6- (4-phenylmercapto-butoxy) -3,4-dihydrocarbostyril, B = 6- (4-phenylsulfinylbutoxy) -3,4-dihydrocarbostyril, C = 6- (4-phenylsulfonylbutoxy) -3,4-dihydrocarbostyril, 6-6- (2-pyridylmercapto) -butoxv / -3,4-dihydrocarbostyril, E = 6- / 1- (2-pyridylsulfinyl) -butoxy / -3,4-dihydrocarbostyril, F = 6 "/ _ A - (2-pyridylsulfonyl) -butoxy / -3,4-dihydrocarbostyril, G = 6 ~ (2-phenylsulfinyl-ethoxy) -3,4-dihydrocarbostyril, H = 6- (4-benzylsulfinyl-butoxy) -3,4- dihydrocarbostyril, I = 6- (4- (4-chlorophenylsulfinyl) -butoxy-7,3,4-dihydrocarbostyril, K = 6- (4-i-cyclohexylsulfinyl-butoxy) -3,4-dihydrocarbostyril,

- * - 2 1 100 7

L = 6- / 4- (2-naphthylsulfinyl) -butoxy-7,3,4-dihydrocarbostyril,

M = 6- / 4- (2-methoxyphenylsulfinyl) -butoxy-Si-dihydrocarbostyril, N = 6- (4-phenylsulfinyl-butoxy) -carbostyril,

0 = 6- / 4 - »(4-hydroxy-3,5-di-tert-butylphenylsulfinyl) -butoxy / -carbostyril,.

P - 6- / 4- (3,4-dichlorophenylsulfinyl) -butoxy-1-carbostyril, Q = 4-methyl-6- (4-phenylsulfinyl-butoxy) -carbostyril,

Rβ 6-4- (3,4-dichlorophenylsulfonyl) -butoxy-3,4-dihydrocarbostyril,

S * 6- / 4- (2,5-dichlorophenylsulfinyl) -butoxy_ /-3,4-dihydrocarbostyril,

T = 6- / 4- (2-pyridylsulfonyl) -butoxy-7-carbostyril; and

U = 6- / 4- O -dlchlorophenylsulfinyl-D-butoxy-S, -dihydrocarbo-

1. Determination of Born and Cross Platelet Aggregation (J. Physiol V70, 397 (1964)):

Platelet aggregation was measured in platelet-rich plasma of healthy volunteers. Here, the course of the decrease in optical density after the addition of adenosine diphosphate (ADP) or collagen was photometrically measured and registered. From the inclination angle of the density curve was closed on the aggregation speed (Vmax). The point of the curve with the highest light transmission was used to calculate the optical density (OD). The EC _{5Q figures} in the tables refer to the optical density.

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The collagen doses were chosen as low as possible, but in such a way that an irreversible aggregation resulted. To initiate aggregation, about 0.01 ml of the collagen solution is added to 1 ml of platelet-rich plasma. (Commercially available collagen from Hormonchemie, Münschen). The ADP doses were chosen to give only the first phase of the BORN curve. The amount of ADP required was about 1.1O "mol / l. Commercially available ADP from Boehringer-Mannheim was used.

Substance dose was determined graphically, effecting 50% inhibition of platelet aggregation (EC_ _Q):

Compound EC ₅₀ 10 ~ ⁶ mol / l

Collages * ADP

A B C D E F G H

K L M N 0 P Q R

ε τ υ

50 > 1OO 4 20 5 15 45 > 100 6.5 25 20 20 3.5 17 2.5 14 4 10 4.5 12 1 10 4 22 0.6 3.0 0.2 0.5 0.2 1.8 3.6 40 1.5 25 1.0 10 0.1 6 4 15

 - «-. 2 1.1-00 7

2. Determination of the extension of the bleeding time: Preliminary remark;

The human organism as well as the warm-blooded animal has a sensible mechanism to protect it from blood loss in case of injury. This system consists of blood platelets (thrombocytes), which are to "clog" a vascular defect quickly by means of its adhesive properties and so the pr imäre Haemos t cause ase. In addition to this pure cellular hemostatic mechanism, the body has a blood clotting system. In this system, plasma factors (protein bodies) are brought into an effective form, which eventually make the liquid plasma fibrinogen a fibrin clot. The system of primary hemostasis, which is essentially provided by the platelets, and the coagulation system complement each other in the common goal of effectively protecting the body from blood loss.

In some diseases, an intact vascular system can lead to coagulation processes as well as clumping of platelets. The weakening of the coagulation system by coumarins or heparin is known and can easily be measured by means of known coagulation tests which indicate an extension on administration of the drug (plasma decay time, quick determination, thrombin time, etc.).

Since the first rapid hemostasis by platelets occurs in the case of injury, the function of the platelets can be well determined by the measurement of bleeding time when setting a standardized injury. The normal bleeding time in humans is about 1 to 3 min., But requires efficient and in sufficient numbers available platelets. With a normal platelet count, therefore, a prolonged bleeding time indicates an impaired function of the platelets. We find this, e.g. for some.

211007

boron platelet dysfunction. If, on the other hand, one wishes to prevent the tendency to spontaneous aggregation of the platelets with the consequence of vascular occlusions in the arterial system by means of medicaments, then the bleeding time under the influence of substance must be prolonged in the case of a successful platelet-effective therapy. We therefore expect an extension of the bleeding time for a platelet-active substance and - since the plasmatic coagulation system is not affected - a normal blood clotting time.

Literature: W. D. Keidel: Kurzgefaßtes textbook of the physiology, Georg Thieme publishing house Stuttgart 1967, page 31: the Blutstillungsvorgang.

To determine the bleeding time, the substances to be examined were kept awake in a dose of 10 mg / kg ρ.ο. applied. After one hour, about 0.5 mm of the tail tip of each animal was cut off and the escaping blood was gently blotted with a filter paper at intervals of 30 seconds. The number of blood drops thus obtained gave a measure of the bleeding time (5 animals per experiment). The following figures indicate percent extension over controls:

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Prolongation of bleeding time connection in% after 1 hour A 145 B 102 C 26 D 76 152 F 9-1 G 5 H 29 I > 300 K 12 L 15 M 27 O 73 · P 12 Q , 39 R 30 T 5 U 33

3. Determination of the positive inotropic effect:

Rats were anesthetized with ether and then killed by the throat. After opening the thorax, the heart was removed and both atria separated. The atria were transferred to an organ bath of 100 ml containing Tyrode at 30 ° C, oxygenated with 95% 0% and 5% CO 2. The forecourts beat spontaneously. The force of contraction was measured isometrically with a load of the atria of 1 g.

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The substances to be tested were tested at 1 × 10 g / ml in 4 atria each. The changes of the contraction force were determined in% of the initial values. The following table contains the results found:

substance Increase in contraction force 30 in % 35 B 16 C 18 e 52 F 63 I 65 L 58 M 83 Q 32 S T

4. Acute toxicity:

The acute toxicity of the substances to be tested was determined on the basis of groups of 10 mice after oral administration of a dose of 1 000 mg / kg (observation time: 14 days):

AP C 07 D / 211 007 912 18

substance > 1 000 Acute 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) O > 1 000 ng / kg (0 out of 10 animals died) D > 1 OGO mg / kg (from 10 animals died) D > 1 000 rag / kg (.0 of 10 animals died ' • E > 1 000 mg / kg (0 out of 10 animals died) ^F > 1 000 mg / kg (0 out of 10 animals died) G > 1 000 mg / kg (0 out of 10 animals died) H > 1 000 mg / kg (0 out of 10 animals died) I > 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 (O of 10 animals died) M > 1 000 mg / kg (0 out of 10 animals died) O > 1 000 mg / kg (0 out of 10 animals died) P > 1 000 mg / kg (0 out of 10 animals died) Q > 1 000 mg / kg (0 out of 10 animals died) e > 1 OCO mg / kg (0 out of 10 animals died) S > 1 000 mg / kg (0 out of 10 animals died) T > 1 000 mg / kg (0 out of 10 animals died) U mg / kg (0 out of 10 animals died)

Due to their pharmacological properties, the new compounds of the general formula I are suitable. for the prophylaxis of thromboembolic disorders, me coronary infarction, cerebral infarction, transient ischemic attacks so-called _e, Aiaaurosis fugax so-as for the prevention of atherosclerosis, and-can this possibly in grain 'bination with other active substances in the usual pharma- ··: , , '. - 26a -

AP C 07 P / 211 007 54 · 912 18

- «- 21 100 7

prepare nutritious preparations such as dragees, tablets, capsules, suppositories or suspensions. The single dose is 50 to 100 mg 2 - 3 χ daily and the daily dose thus 100 to 300 mg. ·

Execution (see above).

The following examples are intended to explain the invention in more detail:

example 1

6 / 1- (2-Pyridy! Mercapto) -butoxY7-3,4-dihydrocarbostyril

14.4 g (0.13 mol) of 2-mercaptopyridine and 17.9 g (0.13 mol) of potassium carbonate are stirred in 360 ml of dimethyl sulfoxide dried over molecular sieves and treated with 36 g (0.12 mol) of 6- (4-bromobutoxy ) -3,4-dihydrocarbostyril (melting point: 142-147 C, prepared from 6-hydroxy-carbostyril and 1,4-dibromobutane). Then it is stirred for 15 hours, at about 25 C, then poured the reaction mixture in 3.6 1 of water and stirred again for 30 minutes. The precipitated product is filtered off, washed well with water, dried and recrystallized from xylene under carbon treatment. This gives pale yellow crystals of melting point 123 - 124.5 ° C.

 Yield: 32 g (81.2% of theory).

Example 2

6/4 * * "(2-pyridylsulfinyl) -butoxY7-3 _y 4-dihydrocarbostyril

32.8 g (0.1 mol) of 6 ~ 3 ~ (2-pyridylmercapto) -butoxy_ / -3,4-dihydrocarbostyril are dissolved in 330 ml of glacial acetic acid and admixed with 10.2 g (0.105 mol) of 35% hydrogen peroxide. The mixture is stirred for 15 hours at about 20 C, then distilled off at 60 C in vacuo from the glacial acetic acid, the residue washed with ether and the resulting crude product crystallized twice from xylene under carbon treatment. This gives colorless crystals of melting point 144.5 146 ° C.

 Yield: 27.5 g (79.8.% Of theory)

- »- 21 1007

Example 3 _i 6 ~ / 4 ~ (2 ^ pyridylsulfonyl) -butoxy-7-3 _/ 4-dihydrocarbostyril

5 g (0.015 mol) of 6- / 4- (2-pyridylmercapto) -butoxy-7,3,4-dihydrocarbostyril are dissolved in 50 ml of glacial acetic acid and treated with 4.5 g (0.045 mol) of 35% hydrogen peroxide. The mixture is stirred for 40 hours at about 25 ° C, the glacial acetic acid distilled off at 60 ° C in vacuo, the solid residue is washed with ether and crystallized from xylene under carbon treatment. This gives colorless crystals of melting point 123.8 - 125 ° C. ' Yield: 3.8 g (70.3% of theory)

Example 4 -

6- (4-Phenylsulfinylbutoxy) -3,4-dihydrocarbostyril

32.6 g (0.2 mol) of 6-hydroxy-3,4-dihydrocarbostyril.-see F. Mayer et al., Bersch., Former Ges. §0_, 858 (1927) J and 27, Cg (0.2 mol) of potassium carbonate are stirred in 600 ml of molecular sieve dried dimethyl sulfoxide for 5 minutes and then with 52.2 g of 4-Phenylsulfinylbutylbromid (0.2 mol) (prepared from thiophenol and 1,4-dibromobutane and subsequent oxidation with hydrogen peroxide in Glacial acetic acid analogously to Example 2; oily substance, solidified on standing in a refrigerator) is stirred for 15 hours at 25 ° C., then the reaction mixture is poured into 6 liters of water, followed by stirring for another 30 minutes, the precipitated product is filtered off with suction and washed well After drying, about 600 ml of xylene are recrystallised with charcoal treatment to give white crystals of melting point 144.5 145.5 ° C.

 Yield: 49 g (71.3% of theory)

- afc -

21 1007

Example 5

6- (4-phenylmercapto-butoxy) ~ 3,4-dihydro-carbostyril

Prepared analogously to Example 4 from e-hydroxy-S ^ -dihydro-carbostyril and 4- (phenylmercapto) -butyl bromide (Kp _{Q 0} ~: 96 - 103 C, prepared from thiophenol and 1,4-dibromobutane). Melting point: 121.5 - 123 ° C, yield: 75.6% of theory.

6- (4-phenylsulfonyl -butoxy) -3,4-dihydro- rocarbostyril

Prepared analogously to Example 4 from 6-hydroxy-3,4-dihydro-carbostyril and 4-phenyl-sulfonyl-butyl bromide (prepared from 4- (phenylmercapto) -butylbromid by oxidation analogously to Example

Melting point: 157.5-158 ° C, yield: 65.1% of theory.

Example 7

6- / 3 - ^ 4-fluorophenylmercapto) -butoxy-3,4-dihydro- hydrocarbyl

Prepared analogously to Example 1 from 6- (4-bromobutoxy) -3,4-dihydrocarbostyril (melting point: 142-147 ° C) and 4-fluorothiophenol. Melting point; 139-140 ° C, yield: 93.1% of theory.

21 1007

Example 8

6-Ζ3- (4-fluorophenylsulfinyl) butoxy / -3,4-dihydrocarbostyril

Prepared analogously to Example 2 from 6- / 3 "(4-fluorophenylmercapto) butoxy_7-3,4-dihydrocarbostyril

Melting point: 184.5-186 ⁰ C, yield: 88% of theory.

Example 9

6-Z4 (4-methylphenyl-mercapto) -butoxy7-3,4-dihydrocarbostyril

Prepared analogously to Example 1 from 6- (4-chlorobutoxy) -3,4-dihydrocarbostyril (melting point: 147-148 C) and 4-methylthiophenol. Melting point: 120-121 ° C. Yield: 91% of theory.

Example 10

6- / A- (4-methylphenyl-sulfinyl) -butoxy7-3,4-dihydrocarbostyril

Prepared analogously to Example 2 from 6- / 3- (4-methylphenylmercapto) -butoxx7-3,4-dihydrocarbostyril and hydrogen peroxide. Melting point: 149.5-150 ° C, yield: 97% of theory.

Example 11

6- / 4- (3-Methylphenylmercapto) -butoxy7-3,4-dihydrocarbostyril

Prepared analogously to 6- (4-chlorobutoxy) -3,4-dihydrocarbostyril (melting point: 147-148 ° C.) and 3-methylthiophenols

21 1007

Melting point: 95-96 ° C, yield: 91% of theory.

Example 12

6-Z% ~ (3-methylphenylsulfinyl) -butoxy.7-3,4-dihydrocarbostyril

Prepared analogously to Example 2 from 6- / 4- (3-methylphenylmercapto) · butoxy_ / -3,4-dihydrocarbostyril and hydrogen peroxide. Waxy resin, yield: 95% of theory. Rf value: 0.48 (thin layer chromatogram on silica gel - mobile phase: benzene / ethanol / concentrated ammonia = 75/25/1).

Example 13

6- / 4- (4-chloropheny! Mercapto) -butoxy-3,3,4-dihydrocarbostyril

Prepared analogously to Example 1 from 6- (4-chlorobutoxy) -3,4-dihydrocarbostyril (melting point: 147-148 ° C.) and 4-chlorothiophenol. Melting point: 144 - 146 C, yield: 88% of theory.

Example 14

6 " f \ - (4-chlorophenylsulfinyl) -butoxY7-3,4-dihydrocarbostyril

Prepared analogously to Example 2 from 6- ^ 4- (4-chlorophenylmercapto) butoxyJ7-3, 4-dihydrocarbostyril and hydrogen peroxide. Melting point: 148-149.5 ° C, yield: 70% of theory.

21 100 7

Example 15

6- / 4- (3,4-dichlorophenyl mercapto) -butoxy_7-3,4-dihydrocarbostyril

Prepared analogously to Example 1 from 6- (4-chlorobutoxy) -3,4-dihydro-

Yield: 87% of theory.

carbostyril (melting point: 147-148 ° C) and 3,4-dichlorothiophene melting point: 116.5-118 ° C,

Example 16

6- / 4- (3,4-Dichlorphenylsulfinyl) -butox ^ 7 to 3.4-dihydrocarbostyril

Prepared analogously to Example 2 from 6- / 4- (3,4-dichlorophenyl mercapto) -butoxy_7-3, 4-dihydrocarbostyril and hydrogen peroxide. Melting point: 106.5-108 ⁰ C, yield: 74% of theory.

Example 17

6- / 3- (2-methoxyphenyl mercapto) -butoxY7-3,4-dihydrocarbostyril

Prepared analogously to Example 1 from 6- (4-bromobutoxy) -3,4-dihydrocarbostyril (melting point: 142-147 C) and 2-methoxythiophenol. Melting point: 130.5 - 133 ° C, yield: 74% of theory. ,

Example 18

6- / 4- (2-methoxyphenylsulfinyl) -butoxyy-3,4-dihydrocarbostyril

Prepared analogously to Example 2 from 6- / 4- (2-Methoxyphenylmercapto) hut.QyLyJ-3, 4-dihydrocärbostyril and hydrogen peroxide.

-so- 21 100 7

Melting point: 162-163 ° C, yield: 62% of theory.

Example 19 6-Z 4 - (3-Methoxyphenylmercapto) butoxy-7,3,4-dihydrocarbostyril

Prepared analogously to Example 1 from 6- (4-bromobutoxy) -3,4-dihydrocarbostyril (melting point: 142-147 ° C) and 3-methoxythiophenol. Melting point: 93.5 -V97 ° C, yield: 61% of theory.

Example 20,.

6- / 4 "(3-methoxy- phenylsulfinyl) -butoxy_7-3 _> 4-dihydrocarbostyril

Prepared analogously to Example 2. from 6- ^ 4- (3-Methoxyphenylmercapto) butoxY7-3,4-dihydrocarbostyril and hydrogen peroxide. Melting point: 147-148 ° C, yield: 49% of theory.

Example 21

6- / 3 "(4-methoxyphenyl mercapto!) Butoxy _ / - 3,4-dihydrocarbostyril

Prepared analogously to example 1 from 6- (4-Bromo-butoxy) -3, 4-dihydrocarbostyril (melting point: 142-147 ° C) and 4-methoxythiophenol. Melting point: 130.5 - 133 ° C, yield: 82% of theory.

21 1007

Example 22

6 - /% - (4-methoxyphenylsulfinyl) -butoxy.7-3,4-dihydrocarbostyril

Prepared analogously to Example 2 from 6- / 3- (4-methoxyphenylmercapto) butoxy_ / ~ 3,4-dihydrocarbostyril and hydrogen peroxide. Melting point: 132-133 ° C, yield: 71% of theory.

Example 23

6- ^ 5- {3,4-dimethoxyphenylmercapto) -butoxy_7-3,4-dihydrocarbostyril

Prepared analogously to Example 1 from 3,4-dimethoxythiophenol and 6- (4-chlorobutoxy) -3,4-dihydrocarbostyril (prepared from 6-hydroxy-carbostyril (see F. Mayer et al., Ber et al., Ges. (> O, 858 (1927) and 4-chlorobutanol-benzenesulfonic acid ester) Melting point: 117-119 ° C, yield: 73% of theory.

Example 24

6- (4- (3,4-Dimethoxyphenylsulfinyl) -butoxy-Y7-3 / 4-dihydrocarboxylic styryl _:

Prepared analogously to Example 2 from 6- / 4- (3,4-dimethoxyphenylmercapto) butoxy-1,3-dihydrocarbostyril and hydrogen peroxide. Melting point: 145-147 ° C, yield: 79% of theory.

" ^M " 21 1007

Example 25

6- / 3- (3,4-dimethoxyphenylsulfonyl) -butoxy_7-3,4-dihydrocarbo- styril

Prepared analogously to Example 3 from 6- / 3- (3,4-dimethoxyphenylmercapto) butoxy_J - 3,4-dihydrocarbostyril and hydrogen peroxide. Melting point: 158-160 ° C, yield: 62% of theory.

Example 26

6- / 4- (4-biphenylylmercapto) -butoxv7-3,4-dihydrocarbostyril

Prepared analogously to Example 1 from 4-phenylthiophenol and 6- (4-bromobutoxy) -3,4-dihydrocarbostyril

 Melting point: 179.5 - 181 ° C, yield: 74% of theory.

Example 27

6- / 4 -'- (4rBiphenylylsulf ynyl) -butox ^ _y 7-3 4-dihydrocarbostyril

Prepared analogously to Example 2 from 6- / 4- (4-Eiphenylylmercapto) -butoxy_7 ~ 3, 4-dihydrocarbostyril and hydrogen peroxide. Melting point: 192-192.5 ⁰ C ₇ Yield: 86% of theory.

Example 28

6- / 4- (2-naphthylmercapto) -butox> i 7 ~ 3/4-dihydrocarbostyril

Prepared analogously to Example 1 from 2-naphthyl mercaptan and 6- (4-bromobutoxy) -3,4-dihydrocarbostyril.

I 100 7

Melting point: 108.5 - 109.5 ° C, yield: 48% of theory.

Example 29

6- / 3- (2-naphthylsulfinyl) -butoxyJ-3,4-dihydrocarbostyril

Prepared analogously to Example 2 from 6- / 4- (2-Naphthylinercapto) -butoxy_7 ~ 3,4-dihydrocarbostyril and hydrogen peroxide. Melting point: 147.5-148.5 ° C, yield: 57% of theory.

Example 30

6- / B- (2-pyridylsulfinyl) ~ pentoxY7-3,4-dihydrocarbostyril

Prepared analogously to Example 2 from 6- / 5- (2-pyridylmercapto) -pentoxy_7-3,4-dihydrocarbostyril and hydrogen peroxide. Melting point: 116-118 ° C, yield: 69% of theory.

Example 31

6- (2-methylsulfinylethoxy) -3,4-dihydrocarbostyril

1.42 g (0.006 Mbl) of 6- (2-methylmercaptoethoxy) -3,4-dihydrocarbostyril are suspended in 12 ml of methanol, and a solution of 1.71 g (0.008 mol) of sodium metaperiodate in 8 ml of water is added. The mixture is stirred for 1.5 hours, with a noticeable warming of the reaction mixture being noted at the beginning. "It is then diluted with a little water and exhaustively extracted with chloroform.

- ** - 21 1007

Melting point: 129 - 131.5 ° C, yield: 70% of theory.

Example 32

6- / 5- (2-Pyridy! Sulfonyl) -v> entoxyJ-3, 4-dihydrocarbostyril

Prepared analogously to Example 3 from 6- ^ B- (2-pyridylmercapto) -pentoxyJT'-S ^ -dihydrocarbostyril and hydrogen peroxide. Melting point: 113.5 to 115.0 ⁰ C / Yield: 71% of theory.

Example 33

6- (4-Methylsulfinylbutoxy) -3,4-dihydrocarbostyril

Prepared analogously to Example 2 from 6- (4-methylmercaptobutoxy) -3,4-dihydrocarbostyril and hydrogen peroxide. Melting point: 128.5-130.5 ° C, yield: 58% of theory.

Example 34

7- (4-Phenylsulfonyl-butoxy) carbostyril

Prepared analogously to Example 3 from 7- (4-phenylmercapto-butoxy) -carbostyril and hydrogen peroxide. Melting point: 19 9 - 201 ° C, yield: 85% of theory.

-is 211007

Example 35 ·

6- (4-Cyclohexylmercaptobutoxy) -3,4-dihydrocarbostyril

Prepared analogously to Example 1 from cyclohexylmercaptan and 6- (4-chlorobutoxy) -3,4-dihydrocarbostyril (melting point: 147-148 ° C.), melting point: 114-115 ° C., yield: 80% of theory.

Example 36

\ III I "Hi-I

6- (4-Cyclohexylsulfinylbutoxy) -3,4-dihydrocarbostyril

Prepared analogously to Example 2 from 6- (4-cyclohexylmercapto-butoxy) -3,4-dihydrocarbostyril and hydrogen peroxide. Melting point: 153-155.5 ° C, yield: 63% of theory.

Example 37

6- (4-Benzylmercapto-butoxy) -3,4-dihydrocarbostyril

Prepared analogously to Example 1 from benzylmercaptan and 6- (4-

Chlorobutoxy) _-3-f 4-dihydrocarbostyril. Melting point: 77.5-78.5 ° C, yield: 90% of theory.

Example 38

6- (4-benzylsulphinyl-butoxy) _-3-f 4-dihydrocarbostyril

Prepared analogously to Example 2 from 6- (4-benzylmercapto-butoxy) 3,4-dihydrocarbostyril and hydrogen peroxide.

2 1 1007

Melting point: 141.5 - 142 C, yield: 95% of theory.

Example 39

6-Z4- (2- Fyromethylmercapto) -butoxy J-3,4-dihydrocarbostyril

Prepared analogously to Example 1 from 2-furfurylmercaptan and 6- (4-bromobutoxy) -3,4-dihydrocarbostyrir (melting point: 142-147 C). Melting point: 79 - 8O ° C, yield: 64% of theory.

Example 40

6- / 4- (2- fluoromethylsulfinyl) -butoxy-7,3,4-dihydrocarbostyril

Prepared analogously to Example 2 from 6- / 3- (2-FuryImethylmercapto) -butoxy_7~3,4-dihydrocarbostyril and hydrogen peroxide. Melting point: 135-136 ° C, yield: 60% of theory.

Example 41 6-J ~% - (N-oxido-2-pyridyl mercapto) -butoxy Y7-3,4-dihydrocarbostyril

Prepared analogously to Example 1 from 6- (4-bromobutoxy) -3,4-dihydrocarbostyril and 2-mercaptopyridine N-oxide. Melting point: 179.5-181 ° C, yield: 65% of theory.

21 100 7

Example 42

6-Z3- (2-pyrimidyl-mercapto) -butoxv7-3,4-dihydrocarbostyril

Prepared analogously to Example 1 from 6- (4-chlorobutoxy) -3,4-dihydrocarbostyril (melting point: 147-148 C) and 2-mercaptopyrimidine, melting point: 154-156 ° C., yield: 79% of theory.

Example 43

6- / 3- (2-pyrimidi-sulfinyl) -butoxy-Y7-3,4-dihydrocarbostyril

Prepared analogously to Example 2 from 6- ^ 4- (2-pyrimidylmercapto) -. butoxy - / - 3,4-dihydrocarbostyril and hydrogen peroxide. Melting point: 154-156 C, yield: 36% of theory.

Example 44

6-Z3 "(4-pyridylmercapto) butoxy-7-3,4-dihydrocarbostyril

3 g of 6- (4-bromobutoxy) -3,4-dihydrocarbostyril are added to a solution of 1.3 g of 4-mercaptopyridine with 2.3 g of 30% sodium methylate in 15 ml of methanol and stirred at room temperature for 14 hours. Then diluted with 20 ml of water and the precipitate precipitated out of ethanol.

Melting point: 128-129 ° C, yield: 1.6 g (49% of theory).

1 1007

- Zg -

Example 45 .

6- / 1- (2-Benzimidazolylmercapto) -butoxy7-3,4-dihydrocarbostyril

Prepared analogously to Example 1 from 6- (4-chlorobutoxy) -3,4-dihydrocarbostyril (melting point: 147-148 ° C.) and 2-mercaptobenzimide

Melting point: 100 - 1O3 ° C, yield: 45% of theory.

Example 46

6- / 3- (2-Benzimidazolylsulfinyl) -butoxy7-3,4-dihydrocarbostyril

Prepared analogously to Example 2 from 6- / 3- (2-Eenzimidazolylniercapto) -butoxY7-3,4-dihydrocarbostyril and hydrogen peroxide. Melting point: 180-182 ° C, yield: 36% of theory.

Example 47

6- / 4- (2-mercapto benzothiazolyl ~) -butoxY7-3,4-dihydrocarbostyril

Prepared analogously to Example 1 from 6- (4-chlorobutoxy) -3,4-dihydrocarbosty:

thiazole.

Schmelzpi

Yield: 70% of theory.

carbostyril (melting point: 147-148 c) and 2-mercaptobenz melting point: 157-158 ° C _f .

21 1007

Example 48

6- / 4- (2-Benzthiazolylsulfinyl) -butoxy7-3,4-dihydrocarbostyril

Prepared analogously to Example 2 from 6- / Ji- (2-Eenzthiazolylmercapto) -butdxy _ / - 3,4-dihydrocarbostyril and hydrogen peroxide. Melting point: 183-184 ° C, yield: 69% of theory.

Example 49

6- (2-phenyl-acetyl-ethoxy) -3,4-dihydrocarbostyril

Prepared analogously to Example 1 from thiophenol and 6- (2-chloroethoxy) -3,4-dihydrocarbostyril (melting point: 152.5-153.5 C). Melting point: 132 - 133.5 ° C, yield: 91% of theory.

Example 50

6- (2-phenylsulfinyl-ethoxy) -3,4-dihydrocarbostyril

Prepared analogously to Example 2 from 6- (2-phenylmercapto-ethoxy) -3,4-dihydrocarbostyril and hydrogen peroxide. Melting point: 171-172 ° C, yield: 84% of theory.

Example 51

6- (2- phenylsulfonyl-ethoxy) -3- _> 4-dihydrocarbostyrene

Prepared analogously to Example 3 from 6- (2-phenylmercapto-ethoxy) -3,4-dihydrocarbostyril and hydrogen peroxide.

- HO -

11007

Melting point: 185-186 ° C, yield: 94% of theory.

Example 52

6- (3-phenylmercapto-propoxy) -3,4-dihydrocarbostyril

Prepared analogously to Example 1 from 6- (3-eromopropoxy) -3,4-dihydrocarbostyril (melting point: 111-118 ° C.) and thiophenol. Melting point: 111-112 ° C, yield: 77% of theory.

Example 53

6- (3-phenylsulfinyl-propoxy) -3,4-dihydrocarbostyril .

Prepared analogously to Example 2 from 6- / 3- (phenylmercapto) -propoxyy-3,4-dihydrocarbostyril and hydrogen peroxide. Melting point: 131.5 - 133.5 ° C, yield: 67% of theory.

Example 54

1-methyl-6- (4-phenylmercapto-butoxy) -3,4-dihydrocarbostyril

16.2 g of 6- (4-phenylmercapto-butoxy) -3,4-dihydrocarbostyril are dissolved in 100 ml of dimethylformamide and admixed with 4.8 g of a 50% sodium hydride suspension in paraffin oil. After addition of 12.5 ml of methyl iodide is stirred for 3 hours at room temperature, diluted with water and extracted with chloroform. The evaporation residue is recrystallized with methanol with addition of some activated carbon. Melting point: 79.5-8O, 5 ° C, yield: 71% of theory.

- Hi ~

1 100 7

Example 55

i-Methyl-6- (4-phenylsulfinyl-butoxy) _-3-f 4-dihydrocarbostyril.

Prepared analogously to Example 2 from 1-methyl-6- (4-phenylmercaptobutoxy) -3,4-dihydrocarbostyril and hydrogen peroxide. Melting point: 82-82.5 ° C, yield: 60% of theory.

Example 56

1-Methy1-6- (4-phenylsulfonyl-butoxy) -3,4-dihydrocarbostyril

Prepared analogously to Example 3 from 1-methyl-6- (4-phenylmercaptobutoxy) -3,4-dihydrocarbostyril und.Wasserstoffperoxid. Melting point: 108-109 ° C, yield: 49% of theory.

Example 57

6- (6-phenylmercapto-hexoxy) -3,4-dihydrocarbostyril

Prepared analogously to Example 1 from 6- (6-bromohexoxy) -3,4-dihydrocarbostyril (melting point: 107.5-108 ° C.) and thiophenol. Melting point: 112.5-113 ° C, yield: 34% of theory.

Example 58 .

6- (6-phenylsulfinyl-hexoxy) -3,4-dihydrocarbos "Tyril®

Prepared analogously to Example 2 from 6- (6-phenylmercapto-hexoxy) -3,4-dihydrocarbostyril and hydrogen peroxide.

21 1007

Melting point: 119.5 - 121.5 ⁰ C, yield: 35% of theory.

Example 59

6- (2 ~ hydroxy-3 'phenylmercapto-propoxy) ~ 3,4-dihydrocarbostyril

2.10 g (0.03 mol) of potassium methoxide are suspended in 40 ml of methanol and 4.41 g (0.04 mol) of thiophenol are added, giving a clear solution. 4.38 g of 6- (2,3-epoxypropoxy) -3,4-dihydrocarbostyril (melting point: 125 ° C.) are added while stirring, which also dissolves with slight self-heating. After about 5 minutes, the deposition of a white crystal pulp begins. After standing overnight, it is filtered off with suction and recrystallized from a little methanol. White crystals of melting point 148-149 ° C are obtained

 Yield: 73% of theory.

Example 60

6 _-_ (2-hydroxy-3-phenylsulfinylpropoxy) -3,4-dihydrocarbostyril

Prepared analogously to Example 2 from 6- (2-hydroxy-3-phenylmercaptopropoxy) -3,4-dihydrocarbostyril and hydrogen peroxide. Melting point: 185-187 ° C, yield: 51% of theory.

Example 61

6- (2-hydroxy -3-phenylsulfonyl-propoxy) -3,4-dihydrocarbostyril

Prepared analogously to Example 3 from 6 - ^ - hydroxy-S-phenylmercaptopropoxy) -3,4-dihydrocarbostyril and hydrogen peroxide,

- "-. 21 100 7

Melting point: 170-172 ° C, yield: 54% of theory,

Example 62 7- (4-phenylmercaptobutoxy) -3,4-dihydrocarbostyril

Prepared analogously to Example 4 from 7-hydroxy-3,4-dihydrocarbostyril (Shigematsu, N., et al., Chem., "Pharm. Bull. 1961, 970-975) and 4-phenylmercaptobutyl bromide (bp: 96-103 ° C Melting point: 121 - 123 ° C, yield: 72% of theory.

Example 63

7- (4-phenylsulfinyl-butoxy) _-3-f 4-dihydrocarbostyril

Prepared analogously to Example 4 from 7-hydroxy-3,4-dihydrocarbostyril (Shigematsu, N., et al., Chem. Pharm., Bull., 1961 , 970-975) and 4-phenylsulfinylbutyl bromide

Melting point: 134-136 ⁰ C, yield: 80% of theory.

Example 64

7- (4-phenylsulfonyl-butoxy) -3, 4-dihydroca.rbostyril

Prepared analogously to Example 4 from 7-hydroxy-3,4-dihydrocarboxylate (Shigematsu, N., et al., Chem. Pharm. Bull., 1961, 970-975) and 4-phenylsulfonylbutyl bromide

 Melting point: 178.5 - 179.5 ° C, yield: 74% of theory.

-HH -

21 1007

Example 65

8- (4-phenylmercaptobutoxy) -3,4-dihydrocarbostyril

Prepared analogously to Example 4 from 8-hydroxy-3,4-dihydrocarbostyril (JD Loudon et al., J. Chem. Soc., 19, 55 , 743-744) and 4-phenylirercaptobutyl bromide (bp _no : 96-1O3 ° C.). , Melting point: 101-102 C, yield: 75% of theory.

Example 66 ·

8- (4-phenylsulfinyl-butoxy) -3 . 4-dihydrocarbostyril

Prepared analogously to Example 4 from 8rhydroxy-3,4-dihydrocarbostyril (JD Loudon et al., J. Chem. Soc., 19, 55 , 743-744) and phenylsulfinylbutyl bromide

 Colorless resin, yield: 60% of theory.

R value: 0.60 (thin-layer chromatogram on silica gel - eluent: benzene / ethanol / concentrated ammonia = 75/25/1).

Example 67

8- (4-Phenylsulfonyl-butoxy) -3 . 4-dihydrocarbostyril

Prepared analogously to Example 3 from 8- (4-phenylmercapto-butoxy) -3,4-dihydrocarbostyril and hydrogen peroxide. Melting point: 114.5-115C, yield: 60% of theory.

-n-- 21 1007

Example 68

6- / 4- (2-Benzothiazolyl-sulfonyl) -butoxy-J7-3-dihydrocarbostyril

Prepared analogously to Example 2 from 6- ^ 4 * - (2-benzthiazolyl-mercapto) - "- butoxY7-3,4-dihydrocarbostyril and hydrogen peroxide Melting point: 146-149 ° C, yield: 61% of theory.

Example 69

6- / 4 * - (2-quinolylmercapto) -butoxY7-3,4-dihydrocarbostyril

Prepared analogously to Example 1 from 6- (4-bromobutoxy) -3,4-dihydrocarbostyril (melting point: 142-147 ° C) and 2-mercaptoquinoline. Melting point: 115 C, yield: 64% of theory.

Example 70

6- £ i- (2-quinazolin-4-on-yl ~ mercapto) -butoxy_7-3,4-dihydrocarbostyril

Prepared analogously to Example 1 from 6- (4-erombutoxy) -3,4-dihydrocarbostyr,

lin-4-one.

Schmelzpu:

Yield: 63% of theory.

carbostyril (melting point: 142-147 ° C) and 2-mercaptoquinazo melting point: 184.5-188 ° C;

σ 07 D / 211 007 54 912 18

Example 71

6 ^ (4-O-riphenyl-ethyl-mercapto-butoxy) -J , 4-dih. ydrocarbostyril

Prepared analogous for example 1 from 6- (4-bromobutoxy) -3 $ 4Hlihydro-

carbostyril (melting point: 142-147 ⁰ C) and Triphenylmethyliaercaptan "

Melting point: 169-170 ⁰ O,. '. \

Yield: 89 % of the theory «

Hergeäiellt analog B _e ispiol 1 of 6 "(4-0hlorätIioxy)" 3i4-dihjrdrocarbostyril (SchmelKpunkti 147-148 ⁰ O) and 2-napthyl mercaptan "

Melting point: 147.5 - 147.8 ⁰ O, yield % 77% of theory.

6 ^ / ^ 2 ~ (2-ITaphthylsulfinyl) »- ethoxy-7" -3> 4- »d, ihydrocarbostyril

Prepared analogously to Example 2 from 6 »/ 2 ~ (2-naphthylmercapto) ethoxy-7,3,4-dihydrocarbostyril and hydrogen peroxide, melting point 186.5-187.5 ⁰ G, yield? 88 % of theory. ^

_-__ ^ l ^ ° ± yZ-3 f ^ ajjaydr ο ^{car b} ° ^s ^? - ³ ^ -!

Prepared analogously to Example 1 from (6- (2- chloroform) -3i4-αi hydrocarbostyrlKSchmelsp ^ 152.5 - 153.5 ⁰ C and 4-mercaptobi>

21 1007

phenyl.

Melting point: 192-194 ° C, yield: 92% of _o theory.

Example 75 · '

6-Z £ - (4-biphenylyl-sulfinyl) -ethoxy-Y-3,4-dihydrocarbostyril Prepared analogously to Example 2 from 6- / 2-M-biphenylylmercaptoI

^ -S, 4-dihydrocarbostyril and hydrogen peroxide. Melting point: 195 - 19 6 ⁰ C, yield: 6 6% of theory.

Example 76

6- / 3 ~ (2-Pyridylmercapto) -propoxyJ7-3,4-dihydrocarb o styril

Prepared analogously to 6- (3-bromopropoxy) -3,4-dihydrocarbostyril and 2-mercaptopyridine

 Melting point: 108-1O8.5 ° C, yield: 42% of theory.

Example 77

6- (4-phenylsulfinyl-butoxy) -3,4-dihydrocarbostyril

1.6 g of 6- (4-phenylmercapto-butoxy) -3,4-dihydrocarbostyril are dissolved in 50 ml of methanol and admixed with 0.9 g of N-bromosuccinimide. The mixture is stirred at room temperature for 15 hours, diluted with 500 ml of 80 ° C hot water and decanted from the initially oily residue, which gradually crystallized. After recrystallization from xylene, white crystals of melting point 144-145 ° C. are obtained

 Yield; 1.2g (66% of theory).

- ^Ht - 21 1007

Example 78

6- (4-phenylsulfinyl-butoxy) -3,4-dihydrocarbostyrlI

3.3 g of 6- (4-phenylmercapto-butoxy) -3,4-dihydrocarbostyril are dissolved in 50 ml of methylene chloride, cooled to -70 ° C and then treated dropwise with a solution of 1.5 g of sulfuryl chloride in 5 ml of methylene chloride. After 15 hours with 20 ml of 95% igerr. Ethanol and heated by removing the cooling bath to room temperature. It is neutralized with aqueous sodium carbonate solution, the methylene chloride phase is dried with sodium sulfate, the solvent is evaporated off and the residue is recrystallized from toluene

 Melting point: 143-145 ° C, 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-dihydrocarbostyril and 4-phenylmercaptobutyl bromide. Melting point: 155-157 ° C, yield: 64% of theory.

Example 80 ·

5- (4-phenylsulfinyl-butoxy) -3,4-dihydrocarbostyril

Prepared analogously to Example 4 from 5-hydroxy-3,4-dihydrocarbostyril and 4-Phenylsulfinylbutylbromid. Melting point: 136-138 ° C., yield: 64% of theory.

1 100

Example 81

5- (4-Phenylsulfonyl-butoxy) -3,4-dihydrocarbostyril

Prepared analogously to Example 4 from 5-hydroxy-3,4-dihydrocarbostyril and 4-Phenylsulfonylbutylbromid. Melting point: 187-189 ° C, yield: 73% of theory.

Example 82

6- / ~ ffi (2-naphthylsulfonyl) -butoxY7-3,4-dihydrocarbostyril

Prepared analogously to Example 6 of 6- / 4- (2-naphthylmercapto) butoxy-7-3,4-dihydrocarbostyril and hydrogen peroxide. Melting point: 173-175 ⁰ C, yield: 95% of theory.

Example 83

6-Z * 4 ~ (4-Biphenylylsulfonyl) -butoxy7-3 _y 4-dihydrocarbostyril

Prepared analogously to Example 3 from 6- (4- (4-Eiphenylylmercapto) -butoxy_7-3,4-dihydrocarbostyril and hydrogen peroxide. Melting point: 232-234.5 ° C, yield: 83% of theory.

Example 84

6- (4-phenylsulfonyl-butoxy) -3,4- dihydrocarbostyril

Prepared analogously to Example 3 from 6- (4-phenylsulfinyl-butoxy) -3,4-dihydrocarbostyril and hydrogen peroxide.

-. »- 21 100

Melting point: 157-158 ° C, yield: 88% of theory

Example 85 6-4 "H2-pyridylsulfonyl) -butoxy, 7-3.4 ° dlhydrocarbostyril

Prepared analogously to Example 3 from 6- / 4- (2-pyridylsulfinyl) -butoxy ^ -3,4-dihydrocarbostyril and hydrogen peroxide. Melting point: 123.8-125 ° C, yield: 76% of theory.

Ex iel 86

5- (4-phenylsulfonylbutoxy ) -carbostyril

1.8 g of 5- (4-phenylsulfonyl-butoxy) -3,4-dihydrocarbostyril be dissolved in 45 ml of dioxane, treated with 1.87 g of 2, S-dichloro-Sje-dicyanobenzoquinone and in an oil bath for 2.5 hours to Boil boiling. It is filtered hot and the insoluble residue formed during the reaction is washed with hot dioxane. The combined filtrates are diluted with 100 ml of chloroform and extracted several times with a total of 150 ml of 2N sodium hydroxide solution. After drying the chloroform extracts with sodium sulfate and filtering in the presence of activated carbon is concentrated and treated with ethyl acetate until white crystals precipitate. Melting point: 182-183 ° C, yield: 850 mg (47% of theory).

1 100 7

Example 87

5- (4-phenylmercafo-butoxy) -carbostyril

Prepared analogously to Example 86 from 5- (4-phenylmercapto-butoxy) -3,4-dihydrocarbostyril and 2,3-DiChIOr-S, 6-dicyano-benzoquinone. Melting point: 185-187 ⁰ C, yield: 40% of theory.

Example 88

5- (4-phenylsulfinyl-butoxy) carbostyril

0.56 g of 5- (4-phenylmercapto-butoxy) -carbostyril are mixed with 0.165 ml of 30% hydrogen peroxide dissolved in 8 ml of glacial acetic acid, diluted with water and extracted twice with chloroform. The chloroform extract is washed with dilute sodium carbonate solution, with water, dried over magnesium sulfate and concentrated. After addition of ethyl acetate, colorless crystals of melting point 155.degree.-157.degree. C. are obtained

 Yield: 389 mg (65% of theory)

Example 89

6- (4-phenylmercapto-butoxy) carbostyril

Prepared analogously to Example 86 from 6- (4-phenylmercapto-butoxy) -3,4-dihydrocarbostyril and 2,3-dichloro-4, S-dicyano-benzoquinone. Melting point: 162-164 ° C, yield: 35% of theory.

. :: ** ' 2 t 10ο

Example 90

6- (4-phenylsulfinyl-butoxy) carbostyril

Prepared analogously to Example 6-6 of 6- (4-phenylsulfinylbutoxy) -3,4-dihydrocarbostyril and 2,3-dichloro-5,6-dicyano-benzoquinone. For purification is on a silica gel column with a mixture of benzene / ethanol / conc. Ammonia = 75/25/3 chromatographed. Melting point: 181-182.5 ° C, yield: 48% of theory.

From the first fractions of the column chromatography is isolated in a yield of 15% of theory 6- (4-phenylmercaptobutoxy) carbostyril of melting point 162-164 C.

Example 91

6- (4-ph enylsulfonyl-butoxy) -carbostyril

Prepared analogously to Example 86 from 6- (4-phenylsulfonyl-butoxy) -3,4-dihydrocarbostyril and 2,3-dichloro-5, e-dicyano-benzoquinone. The purification is carried out by column chromatography on silica gel (particle size: 0.2-0.5 mm) with chloroform / methanol / ethyl acetate = 4/1/1

 Melting point: 212-213 ° C, yield: 54% of theory.

Example 92 .

5- (4-phenylmercapto-butoxy) carbostyril

A mixture of 32.3 g of 5-hydroxycarbostyril, 30 g of potassium carbonate and 650 ml of molecular sieve dried Diinethylsulfoxid is mixed with 49 g of 4-phenylmercaptobutyl bromide. It is stirred for 20 hours at 25 C, diluted with 3 liters of water and sucks

-. 2 1 100

crystallized from reaction product. Melting point: 185-187 ° C (from toluene), yield: 45.0 g (70% of theory).

Example 93

5- (4-Phenylsulfonyl-butoxy) carbostyril

Prepared analogously to Example 88 from 5- (4-phenylmercapto-butoxy) -carbostyril and 4 moles of hydrogen peroxide at a temperature of 60 C and a reaction time of 14 hours. Melting point: 182-183 ° C, yield: 73% of theory.

Example 94

6- (4-phenylmercapto-butoxy) carbostyril

Prepared analogously to Example 92 from 6-hydroxycarbostyril and 4-phenylmercaptobutyl bromide. Melting point: 161-163 C, yield: 78% of theory.

Example 95

6- (4-phenylsulfinyl-butoxy) carbostyril

Prepared analogously to Example 88 from 6- (4-phenylmercapto-butoxy) -carbostyril and hydrogen peroxide. Melting point: 181-182 ° C, yield: 68% of theory.

21 100

Example 96

6- (4-phenylsulfinyl-butoxy) carbostyril

Prepared analogously to Example 92 from 6- * hydroxycarbostyril and diphenyl sulfinylbutylbromid. Melting point: 181-182 ° C, yield: 71% of theory.

Example 97

7 ~ (4-phenylsulfinyl -butoxy) -carbostyril

Prepared analogously to Example 86 from 7- (4-phenylsulfinyl-butoxy) -3 / 4-dihydrocarbostyril. Melting point: 193-194 ° C, yield: 51% of theory.

Example 98

8- (4- phenylmercapto-butoxy) -carbostyril

Prepared analogously to Example 86 from 8- (4-phenylmercapto-butoxy) -3,4-dihydrocarbostyril and 2,3-dichloro-5,6-dicyano-benzoquinone. Melting point: 119-12O ° C, 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.

- 5S

- 21 100 7

Ό.

Melting point: 125.5 - 126.5 C, yield: 60% of theory.

Example 100

5- (4-Phenylsulfonyl-butoxy) carbostyril

100 mg of 5- (4-phenylsulfonyl-butoxy) -3,4-dihydrocarbostyril are heated to reflux with 30 mg of palladium / carbon and 1 ml of mesitylene. After 3.5 hours, another 30 mg of palladium / carbon are added and heated for a further 9 hours. It is then filtered hot, the filtrate evaporated and the residue on a silica gel column with a mixture of benzene / ethanol / conc. Ammonia = 75/25/3 chromatographed. 9 mg of 5- (4-phenylsulfonyl-butoxy) -carbostyril of melting point 182 ° -183 ° C. are obtained in addition to unreacted starting material.

Example 101 C- (4-amino-iminomethylmercapto-butoxy) -3,4-dihydrocarbostyril

18 g of 6- (4-bromobutoxy) -3,4-dihydrocarbostyril are boiled together with 5 g of thiourea in 250 ml of water until everything has dissolved (about 4 hours). After cooling, the impurities are extracted with chloroform and rendered alkaline with ammonia. The precipitated crystals are filtered off with suction and dried

Melting point: 140-141.8 ° C, melting point of the hydrochloride: 208 - 211 ⁰ C, yield: 90% of theory.

-. ** - 21 100

Example 102

6 -_ (4-phenylsulfonyl) -butoxy-3,4-dihydrocarbostyril

107 mg of 6- (4-phenylsulfonyU-butoxy-carbostyril are suspended in 15 ml of methanol, combined with 40 mg of palladium / carbon and hydrogenated at 50 ° C. under a hydrogen pressure of 2.5 bar for 14 hours Colorless crystals are obtained from the clear solution, melting point: 153-154 ° C., yield: 89 mg (83% of theory).

Example 103

6- (4-Benzyl mercapto-butoxy) -3,4'-dihydrocarbostyril

2.5 g of 6- (4-mercaptobutoxy) -3,4-dihydrocarbostyril, dissolved in 25 ml of dimethyl sulfoxide, are added with stirring 1.4 g of potassium carbonate and then with 1.3 ml of benzyl chloride. After 15 hours stirring at room temperature, diluted with 200 ml of water, the separated oily substance separates and crystallized from ethyl acetate to. Melting point: 76-78 ° C, yield: 2.8 g (82% of theory).

Example 104

6- (5- phenylmercaptopentoxy) -3,4-dihydrocarbostyril

Prepared analogously to Example 1 from 6- (5-Broir.pentoxy) -3,4-dihydrocarbostyril and thiophenol. Melting point: 117-119 ° C, yield: 71% of theory.

- * »- 2 ί100

Example 105 6- (5-phenylsulfinyl-pentoxy) -3,4-dihydrocarbostyril

Prepared analogously to Example 2 from 6- (5-phenylmercapto-pentoxy) -3,4-dihydrocarbostyril and hydrogen peroxide. Melting point: 104 to 109.5 ⁰ C, yield: 66% of theory.

Example 106

6- (5-phenylsulfinyl-pentoxy) -3,4-dihydrocarbostyril

Prepared analogously to Example 3 from 6- (5-Phenylir.ercapto-pentoxy) 3,4-dihydrocarbostyril and hydrogen peroxide. Melting point: 136.5-137.8 ° C, yield: 62% of theory.

Example 107

6- / 5- (2-pyridylmercapto) -pentoxy-7-3,4-dihydrocarbostyril

Prepared analogously to Example 1 from 6- (5-Ercmpentoxy) -3,4-dihydrocarbostyril and 2-mercaptopyridine. Melting point: 113-114.8 ° C, yield: 76% of theory.

Beis pie l 108

5- (2-hydroxy-3-phenylmercapto-propoxy) -3,4-dihydrocarbostyril

Prepared analogously to Example 59 from 5- (2,3-epoxy-propoxy) -3,4-dihydrocarbostyril and thiophenol.

-'s * - 21 100

 Melting point: 135-137 ° C, yield: 64% of theory.

Example 109

5- (2-hydroxy -3 -phenylsulfinylpropoxy) -3,4-dihydrocarbostyril

Prepared analogously to Example 2 from 5- (2-hydroxy-3-phenylmercaptopropoxy) -3,4-qihydrocarbostyril and hydrogen peroxide. Melting point: 186-188 ° C, yield: 60% of theory.

Example 110

5 - (2 'hydroxy-3-phenylsulfonyl-pro poxy) ~ 3 _f 4-di hydrocarbostyril

Prepared analogously to Example 3 from 5- (2-hydroxy-3-phenylmercapo-propoxy) -3,4-dihydrocarbostyril and hydrogen peroxide. Melting point: 168-170 ° C, yield: 53% of theory.

Example 111

6 ~ Z3- (4-hydroxypheny! Mercapto) -butoxy y7-3,4-dihydrocarbostyril

Prepared analogously to Example 1 from 6- (4-bromobutoxy) -3,4-dihydrocarbostyril and 4-kydroxythiophenol. Melting point 191.5 - 193, O ⁰ C, yield: 83% of theory.

1 1007

Example 112

6-Z3- (4-Hydroxyphenylsulfinyl) -butoxY7-3,4-dihydrocarbostyril

Prepared analogously to Example 2 from 6- ^ 4- (4-hydroxyphenylmercapto) -butoxy_7-3,4-dihydrocarbostyril and hydrogen peroxide. Melting point: 206 to 207.8 ⁰ C, yield: 84% of theory.

Example 113

6- / 4 "- (4-hydroxyphenylsulfonyl) -butoxy_7-3,4-dihydrocarbostyrene

Prepared analogously to Example 3 from 6- ^ 4- (4-hydroxyphenylmercapo) -butoxy_7-3, 4-dihydrocarbostyril and hydrogen peroxide. Melting point: 219-219.5 ° C, yield: 78% of theory.

Example 114

, 6- ^ 4- (4-Acetaminophenylirercapto) butoxy Y7-3 _r 4-dihydrocarbostyril

Prepared analogously to example 6- (4-bromobutoxy) -3,4-dihydrocarbostyril and 4-acetarainothiophenol. Melting point: 162.5-163.0 ° C, yield: 65% of theory.

Example 115

6-Z3- (4 - / (cetaminophenylsulfinyl) -butoxy-7,3,4-dihydrocarbostyril

Prepared analogously to Example 2 from 6- ^ 4- (4-acetaminophenylmercapto) -butoxy_7-4,4-dihydrocarbostyril and hydrogen peroxide. ,

.to.

21 100 7

Melting point: 202.0 - 203.8 C, yield: 55% of theory.

Example 116

6-Z3- (4-Acetaminophenylsulfonyl) -butoxy7-3,4-dihydrocarbostyril

Prepared analogously to Example 3 from 6- (4- (4-acetaminophenylmercapto) butoxy) -7-dihydrocarbostyril and hydrogen peroxide. Melting point: 143.5 - 147.0 ° C,. ·. Yield: 88% of theory.

Example 117 -

6- ^ 2- (4, S-di-p-chlorophenyl-oxazol-1-yl-mercapto) -butoxy-3-3,4- dihydrocarbostyril ; -

Prepared analogously to Example 1 from 6- (4-bromobutoxy) -3,4-dihydrocaibostyril and 2-mercapto-4,5-di-p-chlorophenyl-oxazole. Melting point: 110-115 ° C, yield: 70% of theory.

Example 118

6- ^ 4- (2-pyridylsulfinyl) butoxy ^ carbostyril

Prepared analogously to Example 86 from 6- (4- (2-pyridylsulfinyl) -but-oxy-7,3,4-dihydrocarbostyril and 2,3-dichloro-5,6-dicyano-benzoquinone.

Melting point: 152-154 ° C, yield: 48% of theory.

21 1007

Example 119

6- (4-phenylmeribi-butoxy) -3,4-dihydrocarbostyril

Prepared analogously to Example 102 from 6- (4-phenyl-niaccapto-butoxy) -carbostyril by catalytic hydrogenation with rhenium-VTI-sulphide as catalyst Melting point: 121-122 ° C., yield 67% of theory.

Example 120

8- (4-Phenylsulfonyl-butoxy) carbostyril

Prepared analogously to Example 86 from 8-H-phenylsulfonyl-butoxyJ-S ^ -dihydrocarbostyril and 2,3-dichloro-5, o-dicyano-benzoquinone. Melting point: 146-147 ° C, yield: 41% of theory.

Example 121

7- (4-phenyl- ercapto-butoxv) -carbostyril

Prepared analogously to Example 86 from 7- (4-phenylmercaptobutoxy) -3,4-dihydrocarbostyril and 2,3-dichloro-5,6-dicyano-benzoquinone. Melting point: 157.5-158.5 ° C, yield: 54% of theory.

- "21 iOO7

Ϋ '·. .: ·; , : '·. "

Example 122

6- / 4- (2,5-dichlorophenyl mercapto) -butoxy.7-3,4-dihydrocarbostyril

In 54 ml of methanol, 2.21 g (0.0315 mol) of potassium methylate are dissolved together with 5.76 g (0.0315 mol) of 98% strength 2,5-dichlorothiophenol, to which 8.94 g (0.03 mol) are added. 6- (4-Brorabutoxy) -3,4-dihydrocarbostyril (m.p .: 142-147 ° C). The mixture is heated to boiling at. Reflow, initially clear solution takes place. After about 5 minutes, so much crystalline reaction product separates out that the reaction mixture solidifies to a barely stirrable crystal pulp. After one hour, the mixture is cooled to room temperature, filtered off with suction and recrystallized from ethanol. This gives colorless crystals of melting point 133-134 ° C.

 Yield: 10.60 g (89.1% of theory). *

6 - ^ _"(? 2 5-Dichlorphe nylsulfinyl) -butoxyy-3,4" dihydrocarbostyril

It is suspended in 40 ml of glacial acetic acid 5.55 g (0.014 mol) of 6- ^ 4- (2,5-dichlorophenylmercapto) -butoxy7-3,4-dihydrocarbostyril and treated 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 lightens and a nearly clear solution is formed. After 70 hours, white crystals have separated. It is filtered off and recrystallized from ethanol.

Melting point: 185-186 ° C, yield: 5.43 g (94.1% of theory).

- "- 21 100 7

Example 124

6-Z3- (2,5-dichlorophenylsulfonyl) -butoxy ^ 7-3 . 4-dihydrocarbostyril

2.97 g (0.0075 mol) of 6 - ^ - ^ 2,5-dichlorophenylmercapto) -butoxY7-3,4 <dihydrocarbostyril are introduced into 15 ml of ice-cold formic acid and mixed with 1.49 ml of 40.08% hydrogen peroxide (0 , 0175 mol). It is stirred for 2.5 hours and then diluted with three times the amount of water. The precipitated crystals are recrystallized from ethanol

 Melting point: 174.5-175.5 ° C, yield: 1.99 g (61.9% of theory).

Example 125

6-Z 4 - (3 1 4- dichlorophenylsulfonyl) -butoxy-Y 7 -3,4-dihydrocarbostyril

Prepared analogously to Example 124 from 6- / 4- (3,4-dichlorophenylmercapto) -butoxy_7-3,4-dihydrocarbostyril (melting point: 116.5 118 C) and hydrogen peroxide

 Melting point: 172-173 ° C, yield: 96% of theory.

Example 126

6- [A- (4-Hydroxy-3,5-di-tert-butyl-phenylmercapto) -butoxy_7-3,4-dihydrocarbostyril '

Prepared analogously to Example 122 from 6- (4-bromobutoxy) -3,4-dihydrocarbostyril (Schmelzpi tert.butylthiophenol

 Melting point: 146-147 * Yield: 6 3.8% of theory.

carbostyril (melting point: 142-147 ° C) and 4-hydroxy-3,5-di-

Melting point: 146-147 ° C,

- IH

21 100 7

Example 127

6-_4- (4-hydroxy-3,5-di-tert.-butyl-phenylsulfinyl) -butoxy_7-3,4- dihydrocarbonyne i1

Prepared analogously to Example 123 from 6- / 4- (4-hydroxy-3,5-di-tert, butylphenylmercapto) -butoxy_7-3,4-dihydrocarbostyril and hydrogen peroxide

 Melting point: 17O-171 ° C, yield: 80.7% of theory.

Example 128 '

6- ^ 3 ~ _{(4-hydroxy-3/5} di-tert.butyl-phenylsulfonyl) -butoxy_7-3 _f 4-

dl h ydroc arbosty ril .

Prepared analogously to Example 124 from 6- £ 4- (4-hydroxy-3 _r 5-di-tert, butyl-phenylmercapto) -butoxy_7 ~ 3,4-dihydrocarbostyril and hydrogen peroxide

 Melting point: 165-167 ° C, yield: 9 7.6% of theory.

Example 129

6- (i-2- carboxypheny! Mercapto ) -butoxy-7-3,4-dihydrocarbostyril

Prepared analogously to Example 122 from 6- (4-bromobutoxy) -3,4-dihydrocarbostyril and 2-thiobenzoic acid

 Melting point: 176-179 ° C, yield: 57.5% of theory.

21 100

Example 130

6- (2-carboxy-phenylsulfinyl) -butoxy-7,3,4-dihydrocarbostyril

Prepared analogously to Example 123 from 6- / 4- (2-carboxyphenylmercapto) -butoxy_7-3,4-dihydrocarbostyril and hydrogen peroxide. Melting point: 194-196 ° C, yield: 77.2% of theory.

Example 131

6-Z3- (4-pyridylsulfinyl) -butoxy_ /-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- (4-pyridylmercapto) -butoxy_7-3,4-dihydrocarbostyril (melting point: 128-133 ° C.) analogously to Example 123 with hydrogen peroxide. Melting point: 154 ° C, yield: 57% of theory.

^ Example 132

6- / 4- (4-pyridylsulfonyl) -butoxy-Y7-3,4-dlhydrocarbostyril Prepared as described in Example 124 from 6- (4- (4-pyridylmercapto) -butoxy-7-3,4 -dihydrocarbostyril and hydrogen peroxide. Melting point: 1 × 9-183 ° C., yield: 35.9% of theory.

21 1007

Example 133

6- ^ 5- _(3-f 4 Dichlorphenylsulfinyl) -2-hydroxy-propox ^ -3,4-dihydro carbostyrll '. .

3.51 g (0.016 mol) of 6- (2,3-epoxypropoxy) -3,4-dihydrocarbostyril (melting point: 125-128 ° C.) are dissolved in 35 ml of methanol and treated with 4.29 g of 3,4- Dichlorothiophenol added. The mixture is heated for 5 hours to boiling, then cooled and gives crystals, which are filtered off with suction and recrystallized from ethanol.

Melting point: 175-176 ° C,

Yield: 2.48 g (38.9% of theory).

The thus obtained 6- / 3- (3,4-dichlorophenylmercapto) -2-hydroxy-.

propoxy_7-3,4-dihydrocarbostyril is oxidized analogously to Example 123 with hydrogen peroxide.

Melting point: 108-110 C,.

Yield: 75% of theory.

Example 134

6- (3-B enylmercapto-propoxy) -3,4-dihydrocarbostyril

Prepared analogously to Example 122 from 6- (3-bromopropoxy) -3,4-dihydrocarbostyril (mp 142-147 C) and benzylmercaptan. Melting point: 97.5-99.0 ° C, yield: 58% of theory.

Example 135

6- (3-BBnZyISuIf JnVl- PrOpOXy) -S, 4-dihydrocarbostyril

Prepared analogously to Example 123 from 6- (3-benzylmercapto) -3,4-dihydrocarbostyril and hydrogen peroxide. Melting point: 144 -5 - 147.0 ⁰ C, yield: 51% of theory.

- <- 21 100 7

Example 136

5- (3-tert.Butylmercapto-2-hydroxy-propoxy) -3,4-dihydrocarbostyril

Prepared analogously to Example 133 from 5- (2,3-epoxy-propoxy) -3,4-dihydric acid

captan.

Schmels

Yield: 77.1% of theory.

dihydrocarbostyril (melting point: 171-173 ° C) and tert-butylmer melting point: 1O5-1O9 ° C,

Example 137

5- (3 ~ tert.Butylsulfinyl-2-hydroxy-propoxy) -3,4-dihydrocarbo3ty-

ril , '·

Prepared analogously to Example 123 from 5- (3-tert-butylmercapto-2-hydroxypropoxy) -3,4-dihydrocarbostyril and hydrogen peroxide. Melting point: 175-177 ° C, yield: 52.1% of theory.

Example 138

5- (3-tert.Butylsulfonyl-2-hydroxy-propoxy) -3,4-dihydrocarbosty-

ril,

Prepared analogously to Example 124 from 5- (3-tert-butylmercapto-2-hydroxypropoxy) -3,4-dihydrocarbostyril and hydrogen peroxide. Melting point: 210-212 ⁰ C, yield: 37.1% of theory.

AP C 07 3D / 211 007 5 * 912 18

I 1007

e., "/ _r" ^ ~ (2-Pyr Idyl -sul fonyl) -butoxy7-carbo styril *.

Hexyl analogous to Example 124 from 6 - ^ - (2-pyridylsulfinyl) buto: xy7-carbostyril and hydrogen peroxide. Melting point 179 - 180 ⁰ C,

Yield: 65 ₁ 8% of theory. ,.

Example 140 ·

4 "M ethyl ^ e - ^^ - phenyJ-mer capt o ~ b ut oxy) -carbo styril

5t25 S (O. "P3 mol) of 4-M _e thyl-6-hydrpxyoarbostyril (Schmelzpunktί 326 -330 ⁰ C, sieheJR, E. Holmes et al., J. Amer, Soc. 2§, 2404 (195 *)) t 8 »09 g (0.033 mol) of 4-phenylmercaptobutyl bromide and 6.22 g (0.045 mol) of potassium carbonate are stirred in 70 ml of dimethyl sulfoxide at room temperature for 16 hours, then diluted with water and the crystals precipitated out after drying Toluene umkrist ^ allisiert, melting point: 148 - 150 ⁰ O, yield: 6.2 g (61.2 % of theory).

Example 141 _v - -; :

ft ^ methyl-e - ^^ ^^ p

Prepared analogously to Example 140 from 4-methyl-6-hydroxycarbostyril (melting point: 326-330 ⁰ ) and 4-phenylsulfinylbutyl bromide. '

Melting point: 167 - 168 'C ^0, yield: 4-7 * 3% of theory.

"-β - 21 100

Example 142

4-methyl-6- (4-phenyl- suifonyl-butoxy) -carbostyril

Prepared analogously to Example 140 from 4-methyl-6-hydroxycarbostyril (mp: 325 ~ 33O ° C) and 4-phenylsulfonylbutyl bromide. Melting point: 217-219 ° C, yield: 66.6% of theory.

Example 143

4-methyl -6- / 3 "· (2-pyridylmercapto) -butoxy-carbostyril

Prepared analogously to Example 122 from 4-methyl-6- (4-bromobutoxy) -carbostyril (m.p .: 217-219 C) and 2-mercaptopyridine. Melting point: 149-151 ° C, yield: 85.7% of theory.

Example 144

4-methyl-6- / 4- (2- pyrrolidylsulfinyl) -butoxy-Y-7-carbostyril

Prepared analogously to Example 123 from 4-methyl-6- / 4- (2-pyridylmer ™ capto) -butoxy-7-carbostyril and hydrogen peroxide. Melting point: 167-169 ° C, yield: 61.8% of theory.

Beis piel 145

Prepared analogously to Example 124 from 4-methyl-6- (2- (2-pyridylmercapto) butoxy-7-carbostyril and hydrogen peroxide.

1Ί007

Melting point: 195-197 ° C, yield: 29.5% of theory.

Example 146

4-methyl-6- / 3- (2-quinolylmercapto) -but oxy / carbostyril

Prepared analogously to Example 122 from 4-methyl-6- (4-bromobutoxy) -carbostyril and 2-mercaptoquinoline. ^ Melting point: 162-163 C, yield: 81.9% of theory.

Example 147

4-Methy1-6- / 4- {2-chinolylsulfinyl) -butoxyj-carbostyril

Prepared analogously to Example 123 from 4-methyl-6- ^ 4- (2-quinolylmercapto) butoxy-7-carbostyril and hydrogen peroxide. Melting point: 189-19O ⁰ C, yield: 47.5% of theory.

) Example 148

4-Methyl-6- / J (2-quinolylsulfonyl) butoxy ^ carbostyril

Prepared analogously to Example 124 from 4-methyl-4- / 4- (2-quinolyl-mercapto) -butoxy-carbostyril and hydrogen peroxide. Melting point: 199-2O3 ° C, yield: 31.5% of theory.

- »* -. 21 1007

Example 149

4 ~ methyl-6- / 4- (4-biphenylylsulfinyl) -butoxy7-carbostyril

Prepared analogously to Example 123 from 4-methyl-6 - /. "4- (4-biphenylyl-Riercapto) -butoxy-7-c <hydrogen peroxide Melting point: 161-11 Yield: 59% of theory.

mercapto) -butoxy_7-carbostyril (melting point: 174-176 C) and melting point: 161-162 ° C,

Example 150 6_RZ ^ " _v (4" Chl prpheny! Mercapto) -

Prepared analogously to Example 122 from 6- (4-chlorobutoxy) -carbostyril (melting point: 2O6-2O8 ° C) and 4-chlorothiophenol. Melting point: 168-170 ° C, yield: 85% of theory.

Example 151

6- / j- (4-chlorophenylsulfinyl) -butoxyj-carbostyri1

Prepared analogously to Example 123 from 6- ^ 4- (4-Chlorphenyliriercapto) -butoxy_7 ~ carbostyril and hydrogen peroxide. Melting point: 157-158 ° C, yield: 81% of theory.

  ο

Example 152

6- (Silyl) - (4-chlorophenyl-sulfonyl) -

Prepared analogously to Example 124 from 6r- / 4- (4 ~ Ch1-chloro-mercapto) -butoxy_7-carbostyril and hydrogen peroxide.

-. «- 2 1 100 7

Melting point: 197-199 ⁰ C, yield: 99% of theory.

Example 153

6- / 3- (3,4-Dichlorpheny! Mercapto) -butoxy ~ 7-carbostyril

Prepared analogously to Example 122 from 6- (4-bromobutoxy) -carbostyril (melting point: 1.98-199 ° C) and 3,4-dichlorothiophenol. Melting point: 149-152 ° C, yield: 60% of theory.

Example 154 6-jffi- (3 _> 4-dichlorophenylsulfinyl) -butoxy-Y7-carbostyril

Prepared from 6- / J- (3,4-bichlorophenylmercaptojbutoxy) -carbostyrene and hydrogen peroxide analogously to Example 123. Melting point: 191-196 ° C.> Yield: 87% of theory.

^> Example 155 '

6- / 3- (3,4-dichlorophenylsulfonyl) -butoxy -carbostyril Prepared as in Example 124 from 6- / 3- (3,4-dichlorophenyl mercapto) -butoxy-carbostyril and hydrogen peroxide.

Melting point: 188-190 ° C, yield: 83% of theory.

- «- 21 100

Example 156

.6- / 4- (2 _f 5-chloro-1-chloro- 1-mercapto) -butoxy-7-carbostyril

Prepared analogously to Example 122 from 6- (4-bromobutoxy) -carbostyril and 2,5-dichlorothiophenol. Melting point: 175-176 ° C, yield: 85% of theory.

Example 157

(2/5-Dichlorophenylsulf Ιηγΐ} ^

Prepared analogously to Example 123 from 6- / 3-12,5-dichlorophenylmercapto) butoxy-7-carbostyril and hydrogen peroxide. Melting point: 200-202 ⁰ C, yielder 75% of theory.

Example 158 6- / 1- (2- _> 5- chlorophenylsulfonyl) -butoxy-7-carbostyril

Prepared analogously to Example 124 from 6- ^ 4- (2,5-Dichlorphenylmereapto) -butoxyj? -Carbostyril and hydrogen peroxide in formic acid.

Melting point: 2O3-2O5 ° C, yield: 79% of theory.

Example 159

6 ~ / j- (4-fluorophenylmerca pto) -butoxy y ^ -carbostyril

Prepared analogously to Example 122 from 6- (4-bromobutoxy) -carbostyril and 4-fluorothiophenol.

-. «- 211007

Melting point: 149-15O ° C, yield: 85% of theory.

Example 160

6- ^ 4- (4- fluorophenylsulfinyl) -butoxy-carbostyril

Prepared analogously to Example 123 from 6- / 3- (4-fluorophenylmercapto) -butoxy_7-carbostyril and hydrogen peroxide. Melting point: 164-165 ° C, yield: 50% of theory.

Example 1 € 1

6-Z4- (4-fluoro- phenylsulfonyl) -butoxy-7-carbostyril

Prepared analogously to Example 124 from 6-10 % - (4-fluorophenylmercapto) butoxy_7-carbostyril and hydrogen peroxide in formic acid. Melting point: 2O9-211 ° C, yield: 59% of theory.

Example 162

6- / 4- (4-hydroxy · = 3,5-di-tert-butyl-1-phenyl-mercapto) -butoxy_7-carbo-

styril _§ . , , -

Prepared analogously to Example 122 from 6- (4-bromobutoxy) -carbostyril (melting point 198-199 ° C) and 4-hydroxy-3,5-di-tert-butyl-thiophenol (melting point: 84.5-86, O ° C). Melting point: 172-173 ⁰ C, yield: 77% of theory.

211QO7

Example 163

6- ^ 4- (4-hydroxy-3,5-di-tert.butylphenylsulfinyl) -butoxy7-c ^a l rbostyri

Prepared analogously to Example 123 from 6- / 1- (4-hydroxy-3,5-di-tert-butylphenylmercapto) -butoxy-7-carbostyril and hydrogen peroxide.

Melting point: 192-194 ° C,.

Yield: 83% of theory.

Example 164

6-_4 ~. (4-Hydroxy = 3, S-di-tert.butylphenylsulfonyl) butoxy ^ "-carbostyri l. _..

Prepared analogously to Example 124 from 6- / 3- (4-hydroxy-3,5-di-tert, butylphenylmercapto) -butox_7 · ' ^car t ^| ostyril and hydrogen peroxide in formic acid

 Melting point: 242-244 C, yield: 92% of theory.

· Example 165

6- / 4- (4 ° biphenyl-lyl inercapto) -butoxY7 ~ ^ ^a ^ bostyril

Prepared analogously to Example 122 from 6- (4-bromobutoxy) -carbostyril (mp 198-199 ° C) and 4-bipheny! Mercaptan. Melting point: 191 ~ 192 ° C, yield: 82% of theory.

f 100

Example 166

6 ° Z? "(4-Biphenylylsulfinyl) butoxy ^ -carböstyril

Prepared analogously to Example 123 from 6- / 3- (4-biphenylylmercapto) butoxy-7-carbostyril and hydrogen peroxide. Melting point: 196-197 ° C, yield: 80% of theory.

Example 167

6-Z3- (4-biphenylyl, 1-sulfonyl) -butoxy-7-carbostyril

Prepared analogously to Example 124 from 6- / 4- (4-biphenylyl-mercapto) butoxy-7-carbostyril and hydrogen peroxide. Melting point: 213-215 ° C, yield: 73% of theory.

Example 168

6- / 4- (4-nitro-phenyl-mercapto) -butoxv7-carbostyril

Prepared analogously to Example 122 from 6- (4-bromobutoxy) -carbostyril (melting point 198-199 ° C) and 4-nitrothiophenol. Melting point: 184-185 ⁰ C, yield: 96% of theory.

Example 169

, 6-ZJi- ( 4-nitrophenylsulfinyl) -butoxy-Y-carbostyril

Prepared analogously to Example 123 from 6- ^ 4- (4-Nitrophenylmercapto) -butoxy / -carbostyril and hydrogen peroxide.

- "- 21 1007

Melting point: 183-184 ° C, yield: 77% of theory,

Example 170

.6- / 4 * - (4-Nitrophenylsulphonyl ) - butoxyj-carbostyril

Prepared analogously to Example 124 from 6- / 4- (4-Nitrophenylsulfinyl) -butoxy ^ J-carbostyril and hydrogen peroxide in formic acid. Melting point: 23O-232 ° C, yield: 70% of theory.

Example 171

6- / 4- (2-chloro-mercapto) -butoxy-carbostyrene

Prepared analogously to Example 122 from 6- (4-bromobutoxy) -carbostyril (mp 198-199 ° C) and 2-mercaptoquinoline. Melting point: 132 ° C, yield: 99% of theory.

Example 172

6- / 3- (2-Chinyl isuifinyl) -butoxy- 7-carbostyril

Prepared analogously to Example 123 from 6- / J- (2-quinolylmercapto) -butoxy-Y-carbostyril and hydrogen peroxide. Melting point: 161-162 ° C, yield: 66% of theory.

21

Example 173

6- / 4- (2-quinolylsulfonyl) -butoxy-Y-7-carbostyril

Prepared analogously to Example 124 from 6- / 1- (2-quinolylsulfinyl) -butoxy_7-carbostyril and hydrogen peroxide in formic acid. Melting point: 197-198 ° C, Yield :. 58% of theory.

Example 174

5- (4-phenylmercapto-butoxy) -oxindol

Prepared analogously to Example 140 from 5-hydroxyoxindole (J., soc., 19, 61, 2723) and 4-phenylmercaptobutyl bromide. Melting point: 131-132 ° C,

Yield: 13% of theory.

Example 175

5- (4-phenylsulfinyl-butoxy) -oxindol

Prepared analogously to Example 123 from 5- (4-phenylmercapto-butoxy) -oxindole and hydrogen peroxide. Melting point: 114-116 ° C. Yield: 61% of theory.

Example 176

6-Z% - (phenylsulfinylmethyl) -benzyloxv7 ~ 3 . 4-dihydro-carbostyril

A mixture of 67.1 g of phthalide, 51.3 ml of thiophenol, 35.1 g of potassium methylate and 250 ml of methanol is heated to reflux. Subsequently, the resulting 2-Phenylinercaptomethylbenzoe-

- »'- 2 1 100 7

acid (yield: 78% of theory, melting point: 108-11O ° C) with methanol / thionyl chloride by standing at -40 ° C esterified. After subsequent standing overnight at room temperature gives 2 ~ Phenylmercaptomethyl-benzoate (yield: 89% of theory, Kp._ _r - .; 145 ° C.), · Which by reduction with Lithiuinaluminiumhydrid in Diäthylather in since <s 2-Phenylmercaptomethyl -phenyl-carbinol (yield: 97% of theory, melting point 64-65 ° C) is converted.

This compound is reacted with p-toluenesulfonyl chloride to give 2-phenylmercaptomethyl-phenylcarbinol-p-toluenesulfonic acid ester. (Thin-layer chromatography: silica gel, eluent: chloroform / ethyl acetate = 1: 1, R _f = 0.8, yield: 55% of theory). This ester is reacted with 6-hydroxy-3,4-dihydrocarbostiyl in the same way as in Example 140 to give 6- (2- phenylmercaptomethyl) -benzyloxy-3,4-dihydrocarbostyril (thin-layer chromatogram: silica gel; mobile phase: chloroform / ethyl acetate = 1: 1, R _f = 0.35, yield: 64% of theory).

, This substance is oxidized analogously to Example 123 with hydrogen peroxide to give 6- / 2- (phenylsulfinylmethyl) -benzyloxy / 3,4-dihydrocarbostyril

Melting point: 133-135 ° C, yield: 64% of theory.

Example 177

6- / 4- (phenylmercaptomethyl ) -benzylox yJ-S , 4-dihydrocarbostyril

In dimethyl sulfoxide in the presence of excess potassium carbonate p-xylylene dichloride and thiophenol in a molar ratio of 1: 1 at room temperature to 4-phenylmercaptomethyl-benzyl chloride (control: Dunnschichtchromatogramm) reacted which without isolation in the reaction solution with 6-hydroxy-3,4-dihydrocarbostyril is implemented analogously to Example 140. Melting point: 139-141 ⁰ C, yield: 52% of theory.

AP C 07 D / 211 007 54 912 18

Example 178

Prepared analogously to Example 123 from 6 - ^ - (plienyl-n-aminocaptomethyl-benzyloxy-1-piperidylcarboxyrate and hydrogen peroxide.

Melting point: 179 - 181 ⁰ G, / - r

Yield: 61 % of theory. .:

Example 179

^

6- (4-C cyclohexylmercapto-butoxy) -carbostyril

Prepared analogously to Example 122 from 6- (4-Bromo-butoxy) carbostyril (melting point: 198-199 ⁰ C and cyclohexylmercaptan Sclanelzpurikt. 153-159 ⁰ g, yield: 89% of theory · ^.

-but o: xy) -carbostyril

Prepared analogously to Example 123 from 6- (4-cyclohexylmercapto butoxy) -carbostyril and hydrogen peroxide. _o melting point: 169-170 ⁰ C,

Yield: 57% of theory. ,

, ·. ^

Example 181

4- (4-bromo - plienylmercapto) -but osyj-carbo- styril

Prepared analogously to Example 122 from 6- (4-bromobutoxy) -carbo styril (melting point: 198 - 199 ⁰ C) and 4-bromothiophenol.

1007

Melting point: 156-158 ° C, yield: 53% of theory.

Example 182

67 / I- (4-bromophenylsulfinyl) -butoxy-7'-carbostyril

Prepared analogously to Example 123 from 6- / 3- (4-bromophenylmercapto) butoxy ^ J-carbostyril and hydrogen peroxide. Melting point: 168-170 ° C. _F. Yield: 65% of theory.

Ex iel 183

6- / _T 4- ( 3-methyl-4-bromo-phenylmercapto) -butoxy-carbostyril

Prepared analogously to Example 122 from 6- (4-bromobutoxy) -carbostyril (melting point: 189-199 ° C) and 3-methyl-4-bromothiophenols Melting point: 167-169 ° C, yield: 76% of theory.

Example 184

6- / yy [- (3-methyl-4-bromo- phenylsulfinyl) -butoxy Y.7 ~ carbostyrene

Prepared analogously to Example 123 from 6- ^ 4-i3-methyl-4-bromo-phenylmercapto) -butoxY7 "carbostyril and hydrogen peroxide Melting point: 169-172 ° C, yield: 79% of theory.

- »* -21 1007

Example 185

6- / 3- (3-methyl-4-bromo-phenylsulfonyl) -butox ^ carbostyril

Prepared analogously to Example 124 from 6- / 3- (3-methyl-4-brora-phenylmercapto) -butoxyj'-carbostyril and hydrogen peroxide. Melting point: 163-167 ° C, yield: 57% of theory.

Example 186

6- / 3- (T. 1 2 1 4-triazol-3-yl-mercapto) -butoxy_7-carbostyril

Prepared analogously to Example 122 from 6- (4-bromobutoxy) -carbostyril and 3-mercapto-1,2,4-triazole. Melting point: 2O3-2O6 ° C. Yield: 82% of theories

Example 187 '

6- / 4- (2,4,5-TrichlorphenyImercapto) -butoxYj-carbostyril

Prepared analogously to Example 122 from 6- (4-bromobutoxy) -carbostyril (mp 198-199 ° C) and 2,4,5-trichlorothiophenol. Melting point: 177-178 ° C, yield: 83% of theory.

Example 188 .

6- / 4- (2,4, S-Trichlorphenylsulfinyl) -butoxyZ-carbostyril

Prepared analogously to Example 123 from 6- / ß- (2,4,5-Trichlorpheny1-mercapto) -butoxy7-carbostyril and hydrogen peroxide.

• - * »- 21 100

Melting point: 2O6-2O8 ° C, yield: 98% of theory.

Example 189

6- £ 4- (3 : 5-dibromo-4-amino-phenylmercapto) -butoxy-3,4-dihydrocarbostyril .

Prepared analogously to Example 122 from 6- (4 "bromobutoxy) -3,4-dihydrocarbostyril (melting point: 142-147 ° C) and 3,5-dibromo-4-aininothiophenol.

Melting point: 9O-92 ° C, yield: 89% of theory.

Example 190

6- £ 4- (3,5-dibromo-4-amino-phenyl-sulf inyl) -butoxyJ? -3, 4-dihydro carbostyril '

Prepared analogously to Example 123 from 6- ^ 4- (3,5-dibromo-4-aminophenyl-mercapto) -butoxy_7-3, 4-dihydrocarbostyril and hydrogen peroxide.

Melting point: 144-146 ° C, yield: 76% of theory.

Beis piel 191st

6- "Z" - (3,5-dibromo-4-amino-phenylsulfonyl) -butoxy_ /-3 _/ 4-dihydro-

carbostyril .

Prepared analogously to Example 124 from 6-_4- (3,5-dibromo-4-aminophenyl-sulfinyl) -butoxy-3,4-dihydrocarbostyril and hydrogen peroxide.

-. «-. 21 1

Melting point: 157-159 ° C, yield: 87% of theory.

Example 192

6- / 3- (3,5-dibromo-4-amino-phenyl-mercapto) -butoxY7-carbostyril

Prepared analogously to Example 122 from 6- (4-bromobutoxy) -carbostyril (mp 198-199 ° C) and 3, S-dibromo-amino-thiophenol. Melting point: 153-155 ° C, yield: 86% of theory.

Example 193

6-ZJ - (3,5-dibromo-4-amino-phenylsulfinyl) -butoxy-Z-carbostyril

Prepared analogously to Example 123 from 6- / 3- (3,5-dibromo-4-aminophenyl-mercapto) -butoxY7-carbostyril and hydrogen peroxide. Melting point: 2O5-2O7 ° C, yield: 79% of theory.

- Example 194

6-Z4 (3,5-dibromo-4-amino-phenylsulfonyl) -butoxy7-carbostyril

Prepared analogously to Example 124 from 6- / Λ- (3,5-dibromo-4-aminophenyl-mercapto) -butoxy_7-carbostyril and hydrogen peroxide in formic acid

Melting point: 238-241 ° C. _F. Yield: 87% of theory.

- 21 1007

Example 195

6- / 4- (4-erom-3-methyl-phenylmercapto) -butoxy-7,3,4-dihydro-carbostyril., _____;

Prepared analogously to Example 122 from 6- (4-bromobutoxy) -3,4-dihydrocarbostere;

phenol.

melting]

Yield: 81% of theory.

carbostyril (melting point: 142-147 ° C) and ^ -bromo-S-methyl-thio-melting point: 104-109 ⁰ C,

Beispiel196

6-_4 ~ (4-bromo-3-methyl-phenylsulfinyl) -butoxy_7-3 _f 4-dihydrocarbo styril. ^^^^^^^^^^^^^^.

Prepared analogously to Example 123 from 6-_4- (4-mercapto) -butoxy_7-3,4-dihydrocarbostyril and hydrogen peroxide. Melting point: 129-130 ° C, yield: 75% of theory.

Example 197

S-3 " ( _2f 5-dibromo-phenyl-mercapto) -butoxy-7,3,4-dihydrocarboxylate

Prepared analogously to Example 122 from 6 - (4-bromobutoxy) -3,4-dihydrocarbostyril (mp 142-147 ° C) and 2,5-dibromothiophenol. Melting point: 127-129 ° C, yield: 75% of theory.

-W-

21 IOD 7

Example 198

6 ~ Z% ~ (2,5-dibromo-phenylsulfinyl) -butox ^ 7-3f4-dihydrocarbostyrll

Prepared analogously to Example 123 from S- [ 1- (2,5-dibromo-phenylmercapto) -butoxy-7,3,4-dihydrocarbostyril and hydrogen peroxide. Melting point: 182-184 ° C, yield: 84% of theory

Example 199

6-ZJi- (2,5-Dibromo-phenyl-mercapto) -butoxy-7-carbostyrene 11

Prepared analogously to Example 122 from 6- (4-bromobutoxy) -carbostyril (mp 198-199 ° C) and 2,5-dibromo-thiophenol. Melting point: 178-185 ° C,.

Yield: 67% of theory.

Example 200

6-yl- (2,5-dibromo-phenylsulfinyl) -butoxy-T-carbostyril

Prepared analogously to Example 123 from 6- / 4- (2,5-dibromo-phenylmercapto) -butoxy_7-carbostyril and hydrogen peroxide. Melting point: 187-189 ° C, yield: 45% of theory.

Example 201

6- / 3- (3 . 4-dichloro-phenylmercapto) -propoxY7-3,4-dihydrocarbostyril

Prepared analogously to Example 122 from 6- (3-bromopropoxy) -3,4-dihydro-carbostyril (melting point: 111-118 ° C.) and 3,4-dichloro-thiophenol. ,

1 1 00 7

Melting point: 106-1O7 ° C, yield: 76% of theory.

Example 202

6- ^ 3- (3,4-dichloro-phenylsulfiny1) propoxy ^ -3,4-dihydrocarbosty-

ril '

Prepared analogously to Example 123 from 6- (3- (3,4-dichlorophenylmercapto) = propoxy) -3,4-dihydrocarbostyril and hydrogen peroxide Melting point: 17O-17 2 ° C., yield: 84% of theory.

Example 203

6- (3- (4-Cyclohexylphenylmercapto) -butoxy_7-3,4-dihydrocarbostyril

Prepared analogously to Example 122 from 6- (4-bromobutoxy) -3,4-dihydrocarbosti]

phenol.

melting]

Yield: 68% of theory.

carbostyril (melting point: 142-147 ° C) and 4-cyclohexyl-thio melting point: 118-12O ° C,

Example 204

6- / 1- (4-Cyclohexyl-phenylsulfinyl) -butoxy_7-3 _f 4-dihydrocarbostyrjLl _

Prepared analogously to Example 123 from 6- / 1- (4-cyclohexyl-phenylmercapto) -butoxy-7,4,4-dihydrocarbostyril and hydrogen peroxide. Melting point: 155-157 ° C, yield: 65% of theory.

\ Q07

Example 205

6- / 3- (4-cyclohexyl-phenylsulfony1) -butoxyj? -3,4-dihydrocarbostyri 1

Prepared analogously to Example 124 from 6- / 3- (4-cyclohexyl-phenylmercapto) -butoxy_7-3,4-dihydrocarbostyril and hydrogen peroxide. Melting point: 172-174 ° C, yield: 52% of theory.

Example 206

6-Z4 (4-cyclohexyl-phenyl-mercapto) -butoxy ^ carbostyril

Prepared analogously to Example 122 from 6- (4-bromobutoxy) -carbostyril {melting point; 188-189 ° C) and 4-cyclohexylthiophenol. Melting point: 165-167 ° C,.

Yield: 64% of theory.

Example 207

6- / 3- (4-Cyclohexyl-phenylsulfinyl) -butoxy7-carbostyril

Prepared from 6- / 4- (4-cyclohexyl-phenylmercaptojbutoxy) -carbostyrene and hydrogen peroxide analogously to Example 123. Melting point: 188-190 ° C., yield: 64% of theory.

Example 208

6- / 4- (4-cyclohexyl-phenylsulfonyl) -butoxY7-carbostyril

Prepared analogously to Example -124 from 6- / Ί- (4-cyclohexyl-phenylmercapto) -butoxy_7-carbostyril and hydrogen peroxide.

1 1007

Melting point: 185-186 ⁰ C, yield: 87% of theory.

Example 209

6-_4- (4-tert-butyl-phenyl-mercapto) -butoxy-Y7-3,4-dihydrocarboxylic

ril

Prepared analogously to Example 122 from 6- (4-bromobutoxy) -3,4-dihydrocarbostyril (mp 142-147 ° C) and 4-tert-butylthiophenol. Melting point: 126-127 ° C, yield: 86% of theory.

Example 210

6- / 1- (4-tert-butyl-phenyIsulfinyl) -butoxy7 ~ 3 _f 4-dihydrocarbosty-

ril _ _;

Prepared analogously to Example 123 from S- [A- (4-tert-butylphenylmercaptp) -butoxy_7-3, 4-dihydrocarbostyril and hydrogen peroxide. Melting point: 121-123 ° C. _F. Yield: 67% of theory.

At 211

6-_4- (4-tert-butyl-phenyl-sulfonyl) -butoxy-3,4-dihydrocarboxylic

ril ,

Prepared analogously to Example 124 from 6 - /% - (4-tert-butyl-pheny1-mercapto) -butoxy_7-3, 4-dihydrocarbostyril and hydrogen peroxide, melting point: 198-200 ° C, yield: 83% of theory.

1 1007

Example 212

ß "/ 3" (4-tert-butyl-phenylmercapto) -butoxy-carbostyril

Prepared analogously to Example 122 from 6- (4-bromobutoxy) -carbostyril (mp 198-199 ° C) and 4-tert-butylthiophenol. Melting point: 156-158 ° C, yield: 63% of theory.

Example 213

6-Z3 ~ (4-tert-butyl-phenylsulfinyl) -butoxy7 ~ carbostyril

Prepared analogously to Example 123 from 6- / 4- (4-tert-butyl-phenyl-mercapto) -butoxy_7-carbostyril and hydrogen peroxide. Melting point: 164-166 ° C, yield: 74% of theory.

Example 214

6- / 4- (4-tert-butyl-1-phenylsulfonyl) -butoxy -carbostyril ) Prepared as in Example 124 from 6- / 4- (4-tert-butylphenyl ™ mercapto) -butoxy-7-carbostyril and hydrogen peroxide. Melting point: 2O3-2O5 ° C, yield: 56% of theory.

Example 215

6- / 3 ~ (2-Chinolylsulfinyl) -butoxY7-3,4-dihydrocafbostyril

Prepared analogously to Example 123 from 6- / 1- (2-quinolylmercapto) butoxy / -3,4-dihydrocarbostyril and hydrogen peroxide.

-SA-

1 1

Melting point: 154-157 ° C, yield: 79% of theory.

Example 216

6- / 4- (2- Quinolylsulfonyl) "butoxy-Y ¹ " 3,4 "dihydrocarbostyril

Prepared analogously to Example 124 from 6- / 4- (2-quinolylmercapto) -butoxy_7-3,4-dihydrocarbostyril and hydrogen peroxide

 R_ value: 0.50 (silica gel plate, eluent: benzene / ethanol / concentrated ammonia = 75: 25: 2), yield: 72% of theory,

Example 217

6- / 2- (N-methyl-N-cyclohexylcarbamidomethylmercapto) ethoxy-7,4-dihydrocarbostyril

Prepared analogously to Example 122 from 6- (2-chloroethoxy) -3,4-dihydrocarbostyril (melting point: 152.5-153.5 ° C) and N-methyl-N-cyclohexyl-thioglycolic acid amide.

R_ value: 0.46 (silica gel plate, eluent: ethylene chloride / methanol = 95: 5).

Yield: 63% of theory.

Example 218 .

6- / 2- (N-methyl-N-cyclohexyl-carbamidomethylsulfinyD-ethoxy ^ -

3,4- dihydricarbostyril _:

Prepared analogously to Example 123 from 6- / 2- (N-methyl-N-cyclohexylcarbamidomethyl mercapto) ethoxy_7-3, 4-dihydrocarbostyril and hydrogen peroxide.

211007

R _f value: 0.34 (silica gel plate, mobile phase: ethylene chloride / methanol = 95: 5)

 Melting point: 143-146 ° C, yield: 48% of theory.

Example 219

6- ^ 2- (N -methyl-N-cyclohexylcarbamidomethylsulfonyl) ethoxyj? 3,4-dihydrocarbostyril '

Prepared analogously to Example 124 from 6- (2-N-methyl-N-cyclohexylcarbamidomethylmercapto) ethoxy-7-3,4-dihydrocarbostyril and hydrogen peroxide in formic acid.

R _f value: 0.48 (silica gel plate; 'medium: ethylene chloride / methanol = 95: 5).

 Melting point: 110-111 ° C, yield: 45% of theory.

Example 220

6- ^ 2- (N-methyl-N-cyclohexylcarbamidomethylmercapto) ethoxy- carbostyril _ ^

Prepared analogously to Example 122 from 6- (2-chloroethoxy) -carbostyrilR _f value: 0.30 (silica gel plate; -leaving agent: ethylene chloride / methanol = 95: 5) J7 "and N-methyl-N-cyclohexylthio glycolic acid amide.

P. _f value: 0.41 (Kieselgelleuchtstoffplatte; eluent: ethylene chloride / methanol = 95: 5)

 Yield: 62% of theory.

- ^S3 - 21 100 7

Example 221

6- / 2- (N-methyl-N-cyclohexylcarbamidomethylsulfinyl) -ethoxyj? -Carbostyril _; ,

Prepared analogously to Example 123 from 6- / 2- (N-methyl-N-cyclohexylcarbamidomercapto) -thoxyj ^ -carbostyril and hydrogen peroxide. R value: 0.027 (silica gel plate, eluent: ethylene chloride / methanol = 95: 5

 Melting point: 128-130 ° C, yield: 65% of theory.

Example 222

6- / 5- (N-methyl-N-cyclohexyl-carbamidomethylsulfonyl) -ethoxy_7-c- arbostyril .

Prepared analogously to Example 124 from 6- / 2- (N-methyl-N-cyclohexylcarbamidomercapto) ethoxy_7-carbostyril and hydrogen peroxide. R, - value: 0.39 (silica gel plate; mobile phase: ethylene chloride / methanol = 95: 5

 Yield: 67% of theory.

Bei Piel 223 6 ° / ^ - (3 _ir 4-dichlorophen ylsulfonyl) -propox \ L7-3,4-dihydrocarbostyril

Prepared analogously to Example 124 from 6- / 3- (3,4-dichlorophenylmercapto) propoxyJ7-3,4-dihydrocarbostyril and hydrogen peroxide. Melting point: 187-18S ° C, yield: 87% of theory.

1100 7

Example 224 ^;

6- / 3 " (3, 4-dichloropheny! Mercapto) -pentoxy.7-3, 4-dihydrocarbostyril

Prepared analogously to Example 122 from 6- (5-bromopentoxy) -3,4-dihydrocarbostyril (melting point: 97-98 C) and 3,4-dichlorothiophenol, melting point: 1O1-1O4 ° C, yield: 69% of theory.

Example 225

6- / 5- (3,4-Dichlorphenylsulfinyl) -pentoxY7 ~ 3,4-dihydrocarbostyril

Prepared analogously to Example 123 from 6- / 5- (3,4-dichlorophenylmercapto) -pentoxy_7-3,4-dihydrocarbostyril and hydrogen peroxide. Melting point: 165-166 ° C.

Yield: 74% of theory.

Example 226

6-Z5 (3,4-Dichlorophenylsulphonyl) -pentoxy7-3 . 4-dihydrocarbostyril

Prepared analogously to Example 124 from 6- / 5- (3,4-dichlorophenyl mercapto) pentoxy-7,3,4-dihydrocarbostyril and hydrogen peroxide, melting point: 176-178 ° C,

 Yield: 65% of theory.

-35 · -

1 1007

Example 227

6- / 4- (2-methyl-4-tert-butyl-phenylmercapto) -butoxY7-3 _f 4-dihydrocarbostyril

Prepared analogously to Example 122 from 6- (4-bromobutoxy) -3,4-dihydrocarbostyril (melting point: 142-147 ° C.) and 2-methyl-4-tert-butylthiophenol.

Melting point: 81-85 ° C, yield: .91% of theory.

Example 228

6- / 4- (2-methyl-4-tert-butylphenylsulfinyl) -butoxy_7-3,4- dihydrocarbostyril

Prepared analogously to Example 123 from 6- ^ 4- (2-methyl-4-tert-butylphenylmercapto) butoxy / 3,3-dihydrocarbostyril and hydrogen peroxide. Resinous substance.

R _f value: 0.54 (silica gel plate, eluent: ethylene chloride / methanol = 95: 5).

Example 229

6- / 4- (3,5-dichloro-4-hydroxy-phenylmercapto) carbostyril

Prepared analogously to Example 122 from 6- (4-erombutoxy) -3,4-dihydrocarbostyril (melting point: 142-147 ° C) and: thiophenol under nitrogen as inert gas. Melting point: 110-114 ° C, yield: 94% of theory.

1 1007

Example 230

5-BrOm-S- (4-phenyl-1-mercapto-butoxy) -carbostyril

Prepared analogously to Example 122 from 5-bromo-6- (4-bromobutoxy) -carbostyril (prepared by bromination of 6- (4-bromobutoxy)

carbostyril) and thiophenol melting point: 209-213 ° C, yield: 41% of theory.

^Λ ) Example 231

5-Nitro-6- (4-phenylmercaptobutoxy) carbostyril

Prepared analogously to Example 122 from .S-nitro-6- (4-bromobutoxy) -carbostyril (m.p .: 25O ° C, prepared by nitration of 6- (4-bromobutoxy) -3,4-dihydrocarbostyril) and thiophenol. Melting point: 228-23O ° C, yield: 71% of theory.

Example 232

J 5-Nitro-6- (4-phenylsulfinylbutoxy) carbostyril

Prepared analogously to Example 123 from 5-nitro-6- (4-phenylmercaptobutoxy) -carbostyril and hydrogen peroxide. Melting point: 192-194 ° C, yield: 91% of theory.

Example 233

5 ~ acetamido-6- (4-phenylirtercaptobutoxy) carbostyril

Prepared analogously to Example 122 from S-acetoinino-e- (4-bromobutoxy) carbostyril (prepared by reduction with zinc in acetic acid of 5-nitro-6- (4-bromobutoxy) -carbostyril with the addition of acetic anhydride) and thiophenol

 Melting point: 238-24O ° C, yield: 80% of theory.

Example 234

5-Acetamino-6- (4- phenylsulfinylbutoxy ) -carbostyril

Prepared analogously to Example 123 from 5-acetamino-6- (4-phenylmercapto) butoxy) -carbostyril and hydrogen peroxide. Melting point: 213-217 ° C. _F. Yield: 47% of theory.

Example 235

5-Broin-6- (4-phenylsulfinylbutoxy) -carbostyril

Prepared analogously to Example 123 from 5-Eroin-6- (4-phenylmercaptobutoxy) -carbostyril and hydrogen peroxide. Melting point: 190-191 ⁰ C, yield: 82% of theory.

AP c 07 D / 211 007 54 912 18

1 100 7

Example 236 4-Methyl-6,5'-2'-pyridylsulfinyl-butoxy-7-carbostyril

0.17.0 S (0.0005 mole) of 4-methyl-6-^- (2-pyridylmercapto-butoxy-7-carbostyril dissolved in 5 ml of glacial acetic acid and 0.107 g (0.0005 mole) of sodium metaperiodate dissolved in 6 Then the light brown solution is diluted with 20 ml of water and the reaction product is extracted with chloroform. The extract is shaken once with sodium bicarbonate solution and dried over anhydrous magnesium sulfate. After evaporation is recrystallized from toluene

Melting point: 166-168 ⁰ C, yield: 0.04 g (22.5% of theory!.

Example 237

6- (4-tert-butyl sulfinyl-butoxy) -3,4-dihydrocarbostyril

Prepared analogously to Example 123 from 6- (4-tert "butylmercapto" butoxy) -3,4-dihydrocarbostyril (mp 117-118 ⁰ C and hydrogen peroxide '.

Melting point: 126 ×, 128 ^° C., yield: 62 % of theory.

Example 238 ;

6 - /% <~ (3-hydroxy-pyrr id-2-ylme rcap t o) -but oxy7 ~ 3> 4-dihydropotassium b ο y - · styril

Prepared analogously to Example 122 from 6- (4-bromobutoxy) -3,4-dihydrocarbostyril (Schmelzpunict: 142-147 ⁰ C and 3-Eydroxy-2-mercaptopyridine

Melting point: 211-216 ⁰ g, yield: 58% of theory.

 - * - 21 1007

• Example 239

6- / 4 "Π * ² * 4-triazol-3-yl-sulfinyl) -butoχ VJ carbostyril

Prepared analogously to Example 123 from -6- / f4- (1, 2,4-triazol-3-ylmercapto) butoxyJ7-carbostyril and hydrogen peroxide. Rf value: 0.1.2 (silica gel plate, mobile phase: ethylene chloride / methanol = 95: 5).

Example 240

6- / 4- (1,2,4 ~ triazol-3-yl-mercapto) -butoxy7 ~ 3,4-dihydrocarbostyril

Prepared analogously to Example 122 from 6- (4-bromobutoxy) -3,4-dihydro-

Yield: · 82% of theory.

carbostyril (melting point: 142-147 ° C) and 3-mercapto-1,2,4-tria-melting point: 152-154 ° C,

Example 241

S- / J- (1,2,4-triazol-3-yl-sulfin-1-yl) -butoxy_7-3, 4-dihydrocarboxylic

Prepared analogously to Example 123 from 6- / 4- (1,2,4-triazol-3-ylmercapto) butoxy-7,3,4-dihydrocarbostyril and hydrogen peroxide, R f value: 0.1.8 (silica gel plate, eluent: ethylene chloride / methanol 95: 5).

- -tec -.

21 100 7

Example 242

6-_4- (1,2,4-triazol-3-yl-sulfonyl) -butoxyJ'-3,4-dihydrocarboxylic

ril; _____

Prepared analogously to Example 124 from 6-_4- (1,2,4-triazol-3-ylmercapto) -butoxy-α-3,4-dihydrocarbostyril and hydrogen peroxide, R f value: 0.22 (silica gel plate, mobile phase: ethylene chloride / methanol = 95: 5), m.p .: 217-224 ° C.

Example 243

6- (4- (2,4,5-trichlorophenylmercapto) -butoxy) -3,4-dihydrocarbostyril

Prepared analogously to Example 122 from 6- (4-bromobutoxy) -3,4-dihydrocarbost

phenol.

enamel

Yield: 87% of theory.

carbostyril (melting point: 142-147 ° C) and 2,4,5-trichloro-thio melting point: 144-145C,

Claims (3)

He is entitled to claim 1. A process for the preparation of new carbostyril and Oxinv dolderivaten the general formula R- O - D - S0 _m - R ₂ (1) in the W is optionally substituted by a methyl group Vinylene groupj is the methylene or ethylene group, m is the number 0, 1 or 2, D is a straight-chain or branched alkylene group having 2 to 6 carbon atoms, a straight-chain or branched hydroxyalkylene group having 3 to 6 carbon atoms or a xylylene group,
Rj is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, Ep is a cycloalkyl group having 3 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 11 carbon atoms, a heteroaryl group having 4 to 9 carbon atoms containing a nitrogen atom and / or an oxygen or sulfur atom or two nitrogen atoms Heteroaralkylgruppe having 5 to 10 carbon atoms, wherein the above-mentioned aromatic nuclei by an alkyl group having 1 to 4 carbon atoms, by a hydroxy, methoxy, amino, acetylamino, nitro, carboxyl, cyclohexyl, Ph.enylgru.ppe or a halogen atom and in addition - 21 TOO7 the above-mentioned monosubstituted phenyl group may be mono- or disubstituted by alkyl groups having 1 to 4 carbon atoms and / or halogen atoms (where the substituents of the phenyl nucleus may be the same or different), 1,2,4-triazolyl, triphenylmethyl, 4 ' 5-bis- (P'-chlorophenyl) -oxazol-2-yl, IT-methyl-cyclohexylamino-carbonylmethyl or aminoiminomethyl group or also an alkyl group having 1 to 6 carbon atoms, if either m is the number 1 or D is a straight-chain or represents branched hydroxyalkylene group having 3 to 6 carbon atoms or a xylylene group, o and R, which may be identical or different, denote hydrogen or halogen atoms, alkyl groups having 1 to 4 carbon atoms, amino, acetylamino or nitro groups, characterized in that a) a hydroxy compound of the general formula in the . , R-j, R, R and W are as defined above, or their salts with inorganic or tertiary organic bases with a compound of the general formula Z - D - SO _m - R ₂ , (III) - Ί03 - 1 1 in the- D, Rp and m are as defined above and Z represents a nucleophilically exchangeable group such as a halogen atom or a Sulfonsäureesterrest is reacted or b) for the preparation of compounds of general formula I, in which m is the number 1 or 2, a compound of the general formula 0 ~ D - SO _n - R ₂ , (IV) in the R.J to R., D and ff are as defined above and m is the number O or 1, is oxidized or. c) for the preparation of a compound of the general formula If in which m is the number 0, a compound of the general formula R-W in the ' R ^, R-3J R ^ * D ^and W are as defined above, with a - AOH - 1 100: 7 Compound of the general formula Y ~ R, , (VI) in the . R _{2 is} as defined above and one of the radicals X or Y in the compounds of the general formulas V and VI is the mercapto group and the other of the radicals X or Y is a nucleophilically exchangeable group such as a halogen atom or a sulphonic acid ester radical or X together with the adjacent hydroxyl group of the best D is an epoxide group and Y is one Represents mercapto group, is implemented or - d) for the preparation of a compound of the general formula I in which R ^ is not a hydrogen atom, a compound of the general formula - D - S0 _m - R ₂ , (VII) in the · R ₂ , Ro »R ^ t JDj W and m are as defined above, or its alkali as with a compound of the general formula Z-R- , (VIII) in the -10 & - R-j is as defined above and Z is a nucleophilically exchangeable group such as a halogen atom or a SuIfonsä'ureesterrest, is reacted or e) for the preparation of a Garbostyrils of the general formula I _s in which W represents the vinylene group, a 3,4-dihydro-carbostyril of the general formula O «D - S0 _m ~ , (IX) in the R-J to R, D and m are as defined above, dehydrogenated or f) for the preparation of a 3 »4-dihydro-oarbostyrils of the general formula I in which V / the ethylene group and m represent the number 0 or 2, a carbostyril of the general formula 0 - D - - S0 _m - R _{2 t} (X) in the R ^ ₁ to R, D and m are as defined above, is hydrogenated. 2. A method according to PUu 1a, characterized in that the reaction in a solvent and at temperatures between O ⁰ G and the boiling temperature of the solvent used, for example at temperatures between 0 and 100 ⁰ C, but preferably at temperatures between 10 and 50 ⁰ C, is carried out· 3 · Process according to points 1a and 2, characterized in that the reaction is carried out in the presence of an alkali metal base j · 4 · Method according to item 1b, characterized in that the reaction is carried out in a solvent urfd at temperatures between -80 ° and 100 ⁰ C. 5. The method according to the points 1b and 4 »characterized in that for preparing a compound of the general formula I, _in: m represents the number 1, the oxidation with one equivalent of the respective oxidant and preferably at temperatures from -80 to 60 ⁰ C is performed · The process according to points 1b and 4 is characterized in that, for the preparation of a compound of general formula I in which m. the number 2 represents the oxidation with one, two or more equivalents of the respective oxidizing agent and preferably at temperatures between.-80 and 100 ⁰ C is performed. 7th method according to item 1c, characterized in that the reaction in a solvent and at temperatures between ^{0 0} C and the boiling temperature of the solvent used, for example at temperatures between 0 and TOO ⁰ C, However, preferably at temperatures between 10 and 50 ⁰ C, is performed. Process according to items 1c and 7, characterized in that the reaction is carried out in the presence of an alkali metal base. The method of item 1 d, characterized in that, however, the reaction in a solvent and at temperatures between 0 and 5O ⁰ Gj preferably at temperatures between 10 and 25 ⁰ C C _f is performed " 10 * Process according to items 1d and 9, characterized in that the alkylation is carried out with an alkyl halide or dialkyl sulfate in the presence of an alkali metal base, alkali metal hydride or alkali metal alkoxide. 11, method according to item 1e, characterized in that the dehydrogenation in a solvent at elevated temperatures, z, B * at temperatures between 100 and 200 ⁰ C ,, but preferably at the boiling temperature of the solvent used, carried out 12 _e Method according to items 1e and 11, characterized in that the dehydrogenation is carried out in the presence of an oxidizing agent or a noble metal catalyst « 13o method according to item 1f, characterized in that the hydrogenation is carried out in a solvent in the presence of a hydrogenation catalyst at temperatures between 0 and 5O ⁰ C ₅ but preferably at .Raumtemperatur, and at a hydrogen pressure of 1 to 5 bar «