CS227005B2 - Method of preparing carbostyrile and oxindol derivatives - Google Patents

Abstract

1. New carbostyril derivatives of general formula see diagramm : EP0003771,P26,F1 wherein W represents a vinylene group (optionally substituted by a methyl group) or the ethylene group, m represents the number 0, 1 or 2, D represents a straight-chained or branched alkylene group with 2 to 6 carbon atoms, whilst there must be at least 2 carbon atoms between the oxygen atom and the SOm group, or a xylylene group, R1 represents a cycloalkyl group with 3 to 6 carbon atoms ; an aryl group with 6 to 10 carbon atoms or an aralkyl group with 7 to 11 carbon atoms, whilst the above-mentioned aromatic nuclei may be monosubstituted by an alkyl group with 1 to 4 carbon atoms, by a hydroxy, methoxy, amino, acetylamino, nitro, carboxyl, cyclohexyl or phenyl group or by a halogen atom and, additionally, the above-mentioned monosubstituted phenyl groups may be mono- or disubstituted by alkyl groups with 1 to 4 carbon atoms and/or by halogen atoms (whilst the substituents of the phenyl nucleus may be identical or different) ; an N-methyl-cyclohexylamino-carbonylmethyl, amino-iminomethylene, pyridyl, pyridylmethyl, furfuryl, benzimidazolyl, benzothiazolyl, pyrimidyl, quinolyl, quinazolin-4-on-yl, 4,5-bis-(p-chlorophenyl)-oxazol-2-yl, pyridyloxide, triazolyl, methyl-pyridyl, methoxy-pyridyl, fluoropyridyl, chloropyridyl, aminopyridyl, acetylaminopyridyl or triphenyl-methyl group, or also a tert. butyl group, if m represents the number 1, and R2 and R3 , which may be identical or different, represent hydrogen or halogen atoms, alkyl groups with 1 to 4 carbon atoms, amino, acetylamino or nitro groups.

Description

The present invention relates to novel carbostyril and oxindole derivatives of the formula I _having Jox ^ ° ~ ^D ~ ° ^{with NRZ} (I) possess valuable pharmacological properties.

Thus, in addition to having a positive inotropic effect, the novel compounds of the general formula (I) defined above and below have in particular antithrombotic properties.

The general symbols in formula I above have the following meanings:

W represents an optionally methyl-substituted vinylene, methylene or ethylene group; m is 0, 1 or 2,

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

R1 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms,

R2 represents 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 or a C 5 -C 10 heteroaralkyl group containing a nitrogen atom and / or an oxygen atom or a sulfur atom or two nitrogen atoms, wherein the above aromatic nuclei are optionally monosubstituted with a C 1 -C 4 alkyl group, a hydroxy group, a methoxy group , amino, acetylamino, nitro, carboxyl, cyclohexyl, phenyl or halogen, and in addition optionally the aforementioned monosubstituted phenyl group is mono- or di-substituted with C1-4 alkyl and / or halogen atoms, the substituents being of the phenyl core are the same or different from each other, hereinafter e represents 1,2,4-triazolyl, triphenylmethyl, 4,5-bis- (p-chlorophenyl) oxazol-2-yl, N-methylcyclohexylaminocarbonylmethyl or aminoimino-methyl or also C1-C6 alkyl when either m is 1, or

D is straight or branched. a (C 3 -C 6) hydroxyalkenyl or xylylene group; R 6, which are the same or different from each other, are hydrogen or halogen, C 1 -C 4 alkyl, amino, acetylamino or nitro.

The term "halogen atom" in the meaning of R2, R3 and R4 means, in particular, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; therefore, for the meanings mentioned in the definition of residues D, R1, R2, R3 and Rd above:

D is ethylene, n-propylene, n-butylene, n-pentylene, n-hexylene,

1-methylethylene,

2-methylethylene,

1-methoxyphenyl group,

2-methyl-n-propylene group,

A 3-methyl-n-propylene group,

A 1-methyl-n-butylene group,

2-methyl-n-butylene, 3-methyl-n-butylene,

A 4-methyl-n-butylene group,

A 1-methyl-n-pentylene group,

A 2-methyl-n-pentylene group,

A 3-methyl-n-pentylene group,

A 4-methyl-n-pentylene group,

A 5-methyl-n-pentylene group,

1.1-dimethylethylene,

1,2-dimethylethylene,

2.2-dimethylethylene,

1,1-dimethyl-n-propylene group,

2.2-dimethyl-n-propylene,

3.3-dimethyl-n-propylene,

1,2-dimethylmethyl- [1- (2-methyl-1,2,3-dihydro-1,2,3-dimethyl) -ethoxy] -ethoxy group;

1,3-dimethyl-n-propylene group,

1,1-dimethyl-n-butylene group,

2,2-dimethyl-n-butyrin,

3.3-dimethyl-n-butylene group,

4,4-dimethyl-n-butenyl,

1,2-dimethyl-n-butylene,

1,3-dimethyl-n-butylene,

1,4-dimethyl-n-butylene,

2,3-dimethyl-n-butolene,

1- D -ylethyldne,

A 2-detylethyldne group,

A 1-diethyl-n-p-propylene group,

A 2-ethyl-4'-n'-piperazin-4-yl group,

3-ethyl-n-propyl group, 1-ethyl-n-butylene group, 2-ethyl-n-butylene group,

A 3-dimethyl-n-butyldne group,

A 4-ethyl-n-butylene group,

3-methyl-2-diethyldthdle,

3-methyl-2-diethyl-n-propelene,

A 3-methyl-3-ethyl-n-propyl group;

A 3-methyl-2-propylethelne group,

1-propdethetetone,

1-buldtd-hdndn group,

1-Proipyl-n-propylene group

2-hydroxy-n-propylene, 2-hydroxy-n-butylene, 3-hydroxy-n-butylene, 2-hydroxy-n-butylene, 3-hydroxy-n-butylene,

A 4-hydroxy-n-pentylene group,

2-hydroxy-n-hdxylene, 3-hydroxy-n-hdxylene,

A 1-methyl-2-hydroxy-n-propyl group;

A 2-hydroxyxy-2-methyl-n-piperidinyl group, a p-xylylene group, an o-xylyldine group, or a. m-xylynene group,

Rt represents a hydrogen atom, a methyl, ethyl, propyl or isopropyl group,

R2 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenylethyl, naphthyl, naphthylmethyl, cyclohexylphenyl, biphenyl, triphenymutyl, N-methylcyclohexylaminocarbonylmethyl, pyridylmethyl, furfuryl, benzimidazolyl, benzthiazolyl, pyrimidyl, quinolyl, quinolinyl-4-onyl, b, 5-bis- (p-chlorophenyl) oxazol-2-yl, pyridyloxide, m -bylphenyl methyl, tert-butylphenyl, methyl-tert-butylphenyl, methylpyridyl, methoxyphenyl, dimuthoxyphenyl, methoxypyridyl, hydroxyphenyl, dihydroxyphenyl, fluorophenyl, difluorophenyl; alkyl, 1,2,4-triazolyl, fluoropyridyl, chlorophenyl, dichlorophenyl, tricholinyl, chloropyridyl, chloropyridyl, chloropyridyl, chloropyridyl, chloropyridyl, chloropyridyl, chloropyridyl, chloropyridyl, chloropyridyl, chloropyridyl, chloropyridyl, chloropyridyl, chloropyridyl, chloropyridyl, chloropyridyl, chloropyridyl. bromophenyl, dibromophenyl, aminophdinyl, acutylaminophenyl, aminopyridyl, acdtylaminopyridyl, nitrophenyl, carboxyphenyl, hydroxydichlorophenyl, hydroxydifluorophenyl. a group of amino. a group, an aminodibromophenyl group, a hydroxydi-di-tert-butylphenyl group, a methoxyfluorophenyl group, a methoxychlorophenyl group,. methoxybromphdnyl. a fluoromethylphenyl group,. 'chlorme227005

Compound

EC 50 10 - ⁶ mol / liter collagen adenosine diphosphate

M N O P Q R T T

0.6

0.2

0.2

3.6

1.5

1.0

0.1

3.0

0.5

1.8 40 25

2. Determination of prolonged bleeding time

Preliminary remark:

The human organism as well as the warm-blooded organism has a sophisticated mechanism to protect it from blood loss in the event of injury. This system consists of platelets (platelets) which, due to their sticky properties, are intended to rapidly close a blood vessel defect and thus cause primary hemiostasis. In addition to this purely cellular mechanism for haemostasis, the body has a blood clotting system. In this system, the properties of plasma (protein) are brought into an effective form that converts liquid plasma fibrinogen into fibrin fibers. The primary hemostasis system, which is essentially dependent on platelets, and the blood clotting system are complementary in a joint effort to protect the body ingeniously from blood loss.

In many diseases, even with intact vascular system, bleeding and platelet aggregation may be reduced. The attenuation of the blood clotting system by coumarineim or heparinine is known and can be easily measured by known blood clotting tests which, under the influence of the preparation, show this prolongation (plasma recalcification time, Quick test, determination of thrombin exposure time, etc.).

Since in the case of swallowing, the first rapid bleeding stop is achieved by platelets, using standardized injury, platelet function can be well determined by measuring bleeding time. Normal bleeding time in humans is about 1 to 3 minutes, but assumes functionally capable and sufficient numbers of thromibocytes. Thus, with normal platelet counts, prolonged bleeding time indicates impaired platelet function. This is the case, for example, in some congenital disorders of platelet function. If platelets tend to self-agglutinate due to the occlusion of arteries in the arterial system by medication, the bleeding time for platelet-acting substances must be prolonged under the influence of this substance. Thus, platelet-acting substances are expected to prolong bleeding time and, due to the clotting of the plasma system not being affected, the normal blood clotting time (cf. WD Keidel: GefaBtes Lehrbuch der Physiologie, Georg Thieme Verlag Stuttgart 1967, p. 31). : Blutstilungsvorgang).

To determine the bleeding time, the test substances are orally administered to awake mice at a dose of 10 mg / kg. After one hour, each animal is cut off the tip of a tail of about 0.5 mm and the blood leaking out is carefully aspirated at 30 second intervals using filter paper. The number of blood drops thus obtained is a measure of bleeding time (5 animals per experiment). The following figures indicate the percentage elongation compared to the control.

Compound Increased bleeding time in% after 1 hour

AND 145 В 102 C 26 D 76 E 152 F 91 G 5 H 29 AND > 300 К 12 L 15 Dec M 27 Mar: O 73 P 12 Q 39 R 30 T 5 AT 33

3. Determination of positive · inotropic effect:

The rats are anesthetized with ether and then sacrificed in the back of the nape. After opening the chest, the heart is removed and the two anterooms are separated. These vestibules are transferred to a 100 ml bath containing 100 ml of Tyrode's solution at 30 ° C, which has been oxidized with 95% O 2 and 5% CO 2. Hallways spontaneously beat. The contraction force is measured isometrically at an atrial load of 1 g. Test substances at 1 x 10 ^-5 g / ml are tested on four atria. Changes in contraction force are determined as a percentage of the initial value. The results are as follows:

Substance Increase in Contraction Strength in%

B C F I L M Q S T

4. Acute toxicity

The acute toxicity of the test substances was determined orally in groups of 10 mice after oral administration of 1000 mg / kg (observation period: 14 days):

Substance. Oral toxicity

AND > 1000 mg / kg (none of 10 of animals did not die) (B) > 1000 mg / kg (none of 10 of animals yeuhynulo- C > 1000 mg / kg (none of 10 of animals did not die) D > 1000 mg / kg (none of 10 of animals did not die) E > 1000 mg / kg (none of 10 of animals did not die) F > 1000 mg / kg (none of 10 of animals did not die) G > 1000 mg / kg (none of 10 of animals did not die) H > 1000 mg / kg (none of 10 of animals not died ·) AND > 1000 mg / kg (none of 10 of animals did not die) TO > 1000 mg / kg (none of 10 of animals did not die) L > 1000 mg / kg (none of 10 of animals did not die) M > 1000 mg / kg (none of 10 Animal did not die) O > 1000 mg / kg (none of 10 of animals neuhynulo- P > 1000 mg / kg (none of 10 of animals nnuhynulo) Q > 1000 mg / kg (none of 10 of animals did not die) R > 1000 mg / kg (none of 10 of animals did not die) WITH > 1000 mg / kg (none of 10 of animals did not die) T > 1000 mg / kg (none of 10 of animals did not die) at > 1000 mg / kg (none of 10 of animals did not die)

Owing to their pharmacological properties, the novel compounds of the formula I are suitable for the prophylaxis of thromboembolic diseases such as heart attack, stroke, transient ischemia, Amaurosis fugax as well as for the prophylaxis of arteriosclerosis and can be treated for this purpose optionally in combination with other active substances for conventional pharmaceutical preparations such as dragees, tablets, capsules, suppositories or suspensions. A single dose is 50 to 100 mg 2 to 3 times a day and a daily dose of 100 to 300 mg.

The following examples illustrate the invention but do not limit it in any way.

Ex

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

32.6 g (0.2 mol) of 6-hydroxy-3,4-dihydro-calr] uxstyryl [see F. Mayer et al., Ber. dtsch. Chem. Ges. ' 60, 858 (1927)] and 27.6 g (0.2 mole) of potassium carbonate are stirred in 600 ml of dimethylsulfoxide which has been dried by molecular sieving for 5 minutes and then 52.2 g of potassium carbonate are added. 0.21 mol of thylophenol (made from thiophenol and 1,4-dibromo-butane followed by oxidation with peroxide · hydrogen in glacial acetic acid; · oily substance · solidifies · standing in the refrigerator). Mixture. is allowed to stir. 15 hours at 25 ° C and then pour the reaction mixture into 6 liters of water. After stirring for a further 30 minutes, the precipitated product is filtered off and washed well with water. . After drying, this product crystallizes from about 600 ml of xylene under the action of activated carbon. White crystals having a melting point of 144.5 to 145.5 ° C are obtained. Yield: 49 g (71.3% of theory).

Example 2

6- (4-Phenyl-mercapto-butoxy--3,4-dihydrocarbostyril)

It is produced in analogy to Example 1 from 6-hydroxyoxy-3,4-dihydrocarbostyril and 4- (phenylmercapto) uutyl bromide (boiling point 96 to 103 ° C / 2.7 Pa, made from thiophenol and 1,4-dibromobutane) .

Melting point: 121.5-123 ^° C.

Yield: 75.6% of theory.

Example 3

6- (4-ennylt · · Ulf onylUutoxy) ^{-3,4-dihydro,} rιokarbostyril

This compound is prepared analogously to Example 1 from 6-hydroxy-3,4-dihydrocarbostyril and 4-phenylsulfonylbutyrylbromide [made from 4- (phenylmercapto) butylbromide by oxidation].

Mp 157.5-158 ° C.

Yield: 65.1% of theory.

Example 4

7- (1,4-phenylmercaptobutoxy) -3,4-dihydrocarbostyril

It is produced analogously to Example 1 from 7-hydroxy-3,4-dihydrocarbostyril (N. Shigematsu et al., Chem. Pharim. Bull. 1901, 970-975) and 4-phenylmercaptobutyl bromide (boiling point 96-7). 103 ° C / 2.7 Pa).

Melting point: 121-123 ° C.

Yield: 72%.

Example 5

7- (4-phenylsulfinylbutoxy) -3,4-dihydroicarbostyril

It is prepared analogously to Example 1 from 7-hydroxy-3,4-dihydrocarbostyril (N. Shigematsu et al., Chem. Pharm. Bull. 1961, 970-954) and 4-phenylsulfinylbutyl bromide.

Melting point: 134-136 ° C.

Yield: 80%.

Example 6

7- (4-phenylsulfomybutoxy) -3,4-dihydrocarbostyril

It is produced analogously to Example 1 of

7-hydroxy-3,4-dihydrocarbostyril (N. Shigematsu et al., Chem. Pharm. Bull. 1961, 970-975) and 5-phenylsulfonylbutalbromide.

Melting point: 178.5-179.5 ° C.

Yield: 74%.

Example 7

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

It is produced analogously to Example 1 from 8-hydroxy-3,4-dihydrocarbostyril (JD Loudo et al., J. Chem. Soc. 1955, 743-744) and 4-phenylmercaptobutylbromide (boiling point: 96-7). 103 ° C / 2.7 Pa).

Melting point: 101-102 ° C.

Yield: 75%.

Example 8

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

This compound is prepared analogously to Example 1 from 8-hydrtoxy-3 _R-4 dihydr.okarbostyrilu (JD Loudon et al, J. Chem. Soc. 1955, 743-744) and fenylsulfinylbutylbromidu.

Colorless resin.

Yield: 60%.

_Rf value: 0.60 (thin layer chromatogram on silica gel, solvent system:

a mixture of benzene, ethanol and conc. ammonia: 25: 1).

Example 9

5- (4-phenylmertobutoxy) -3,4-dihydrocarbostyril

This compound is prepared analogously to Example 1 from 5-hydroxy-3,4-dihydrocarbostyrite and 4-phenylmercaptobutyl bromide.

M.p .: 155-157 ^° C.

Yield: 64%.

Example 10

5- (4-phenylsulfinylbutoxy) -3,4-dihydrocarbostyril

This compound was prepared analogously to Example 1 from 5-hydroxy-3,4-dihydrostyril and 4-phenylsulfinylbutylbromide.

M.p .: 136-138 ° C.

Yield: 64%.

Example 11

5- (4-Phenylsulfonylbutoxy) -3,4-dihydrocarbostyril

This compound was prepared analogously to Example 1 from 5-hydroxy-3,4-dihydrocarbostyril and 4-phenylsulfonylbutyl bromide.

Melting point: 187 to 189 ^Q C

Yield: 73%.

Example 12

5- (4-phenylmercaptobutoxy) carbostyril

To a mixture of 32.3 g of 5-hydroxycarbostyril, 30 g of potassium carbonate and 650 ml of dimethylsulfoxide, which is dried by molecular sieving, 40 g of 4-phenylmercaptobutyl bromide are added. The mixture was stirred at 25 ° C for 20 hours, diluted with 3 L of water and the crystallized reaction product was filtered off.

Melting point: 185-187 ° C (from toluene).

Yield: 45.0 g (70% of theory).

Example 13

6- (4-phenylmercaptobutoxy) carbostyril

This compound was prepared analogously to Example 12 from 6-hydroxycarbostyril and 4-phenylmercaptobutyl bromide.

Melting point: 161-163 ° C.

Yield: 78%.

Example 14

6- (4-Phenylsulfinylbutoxy) carbostyril

This compound was prepared in analogy to Example 12 from 6-methyl-4-phenylsulfinylbutyl bromide.

Melting point: 181-182 ° C.

Yield: 71%.

Example 15

4-ether-6- (4-phenylmercaptobutoxy) carbostyril

5.25 g (0.03 mol) of 4-methyl-6-hydroxycarbostyril [melting point: 326 DEG-330 DEG C., see R. R. Holrnes et al. J. Amer. Chem. Soc. 76, 2404 (1954)], 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 dimethalsulfoxide at room temperature for 16 hours, then diluted with water and precipitated. after drying, the crystals are recrystallized from toluene.

M.p .: 148-150 ° C.

Yield: 6.2 g (61.2% of theory).

Example 16

4-π) Αιγ 6-6- (4-Phenylsulfinylbutoxy) carbossyril

This compound was prepared in analogy to Example 15 from 4-phenyl-6-methyl-6-hydroxy-pyrimidine (m.p. 326 DEG-330 DEG C.) and 4-phenylsulfinylbutylbutyl.

Melting point: 167-168 ° C.

Yield: 47.3% of theory.

Example 17

4-Methyl-6- (4-phenylsulfonylbutoxy) carbonyl

This compound was prepared in an analogous manner to that described in Example 15 from 4-methyl-6-hydroxycarbostyril (melting point: 326-330 ° C) and 4-phenylsulfonylbutyl bromide.

Melting point: 217-219 ° C.

Yield: 66.6%.

Example 18

5- (4-Phenylmercaptobutoxy) oxinool

This compound is prepared in an analogous manner to that described in Example 15 from 5-hydroxyoxindole (J. Chem. Soc. 1961, 2723) and 4-phenylmercaptobutyl bromide.

Melting point: 131-132 ° C.

Yield: 13%.

Example 19

6- [2- (Phenylmercaptomethyl) benzyloxy] -3,4-dihydrocarbostyril

Mixture · 67.1 g phthalide, 51.3 ml thiophenol,

35.1 g of potassium methoxide and 250 ml of methanol are heated to reflux. Thereafter, the 2-phenylmercaptomethylbenzoic acid obtained (yield: 78% of theory, melting point: 108-110 ° C) was stirred at a temperature of -40 ° C. After standing overnight at room temperature, 2-phenylmercaptomethyl-benzoic acid methyl ester (yield: 89% of theory, boiling point 145 ° C / 9.3 Pa) was obtained, which was converted to the lithium aluminum hydride in dieleyl ether to give

2-Phenylmercaptomethylene-phenycarbinol (yield: 97% of theory, melting point: 64-65 ° C).

This compound was reacted with p-toluenesulfonyl chloride to give 2-phenylmercaptomethylphenylcarbinol ester with p-toluenesulfonic acid (thin layer chromatograph: silica gel, solvent system: 1: 1 chloroform / ethyl acetate, Rf = 0.8). 55% of theory). This ester was reacted in analogy to Example 15 with 6-eyroxy-3,4-dihydrocarbostyril to give 6- [2- (phenylmethyl) methyl] benzyloxy] -3,4-dihy (Τ (0 <8? (TLC: silica gel, solvent system: CHCl3 / EtOAc 1: 1, Rf = 0.35, Yield: 64%).

Example 20

6- (4- (phenylmercaptomethyl) benzyloxy) -3,4 ^ 11 ^ гокагЬ <^ угП

In dimethylsulfoxide, in the presence of an excess of potassium carbonate, p-xylylene-chlorochloride and thiophenol are reacted in a molar ratio of 1: 1 at room temperature to form

Of 4-phenylpropylmethylbenzylcyclo [alpha] (control: thin layer chromatogram), which is reacted further without isolation in the reaction solution with 6-hydroxy-3,4-dihydrocarbostyril in analogy to Example 15.

Melting point: 139-141 ° C.

Yield: 52%.

In an analogous manner to that described in the above examples, the following compounds are obtained:

644- (2-methylmercapto-) butoxy] -3,4-tetrahydro-4 &lt; -1 &gt;

123 to 124.5% thylphenyl or bromomethylphenyl,

R 3 and R a, which. they may be the same or different from each other and are hydrogen, fluorine, chlorine, bromine. or iodo, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, nitro, amino. Or acetylamino.

In particular, the invention relates to a process for the preparation of compounds of the formula I in which:

W, D and m are as defined above,

R 2 represents cyclohexyl, benzyl, naphthyl, pyridyl, pyrimidyl, 1,2,4-triazolyl, pyridyloxy, furfuryl, triphenylmethyl, quinolyl, benzimidazolyl, benzthiazolyl, chazazolin A 4-yl group, a 6-bis-p-chlorophenyl-oxazol-4-yl group, an N-methylcyclohexylaminocarbonylmethyl group or an aminoiminomethyl group, respectively. carboxyl. a hydroxy group, a methoxy group, an amino group, an acetylamino group, a nitro group, a cyclohexyl group, or a phenyl substituted phenyl group. a halogen atom, and / or a (C 1 -C 4) alkyl group, a mono- or di-substituted phenyl group, two. halogen atoms or two alkyl groups having 1 to 4 carbon atoms substituted with hydroxyphenyl, halophenyl or. . an aminophenyl group,

R3 ·. represents a hydrogen atom,. chlorine or bromine, methyl, amino, acetylamino or ni-troscopene, and

R a represents a hydrogen atom.

Preferred compounds of formula (I) above are those in which:

W stands for. optionally methyl substituted vinyl or ethylene. a group, 'm' is 0, 1 or 2,

D represents an alkylene group having 2 to 5 atoms. or a hydroxyalkylene group having 3. up to 5 carbon atoms,

R 1 represents a hydrogen atom,

R 6 represents cyclohexyl, phenyl, benzyl, naphthyl, biphenylyl, cyclohexylphenyl, pyridyl, methylphenyl, methoxyphenyl, fluorophenyl, chlorophenyl, dichlorophenyl, trichlorophenyl, bromophenyl, dibromophenyl, dibromophenyl, dibromophenyl , aminodibromophenyl or hydroxy-di-tert-butylphenyl,

R 3 and R 6 are hydrogen.

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

W represents an ethylene, vinylene or 2-methylvinylene group, m · represents 0, 1 or 2,

R 1, R 3 and R 6 are hydrogen,

R @ 2 is cyclohexyl, phenyl, benzyl, 2-naphthoyl, 2-methoxyphenyl, 4-chlorophenyl. a 3,4-01-chlorophenyl group. 2,5-dichlorophenyl. group, 4-aminу _3-J 5-dibromfenylуvуu group ... 4-hydroxy-3,5-di-tert-butylphenyl or 2-pyridyl; and

D represents an ethylene group, an n-propylene group, an n-butylene group or a 2-hydroxy-n-propylene group.

According to the invention, the novel compounds of general formula (I) are used. . of formula (I) are prepared by reacting a hydroxy derivative of formula (II)

R1, R3,. Rá. and W are as defined above, or its. salts with inorganic or tertiary organic bases; of formula III

Z-D_SO _m -R ₂ [III] wherein

D, Rz and m are as defined above,

Z is nucleophilic. a replaceable group, such as an atom. halogen ^or: sulfonic acid ester, for example a chlorine, bromine, iodine. p-toluenesulfonynyl or methanesulfonynyloxy.

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 compound such as sodium carbonate, potassium carbonate or sodium hydroxide at temperatures between 0 ° C and the boiling point of the solvent used, for example at temperatures between 0 and 100 ° C, but preferably at temperatures between 10 and 50 ° C. However, the reaction can also be carried out without solvent.

The compounds of the formulas II and III used as starting materials are partly known from the literature or are obtained by methods known per se. Thus, for example, 6-, 7- or 8-hydroxy-3,4-dihydrocarbortyril of formula II is obtained by acylating the corresponding aniline derivative with the corresponding [beta] -halocarboxylic acid derivative followed by Friedel-Craft cyclization [see J. Chem. Soc. 1955, 743-744, Chem. Pharm. Bull. 1961, 970-975 and Ber. dtsch. Chem. Ges. 60, 858 (1927)] or 5-hydroxy-3,4-dihydrocarbostyril of formula II by cyclization of the corresponding 2 - (3-cyanoethyl) cyclohexane-1,3-dione derivative followed by aromatization with, for example, N-bromosuccinimide (see Chem. 1970, 1435).

The preparation of the corresponding hydroxycarbostyrils of formula II is known from the literature [see, for example, J. Amer. Chem. Soc. 72, 346 (1950) and ibid. 76, 2402 (1954) and J. Org. Chem. 33, 1089 (1968) and ibid. 36, 3493 (1971)]. Further, the preparation of 5-hydroxyindole is described in J. Chem. 1961, 2723.

As mentioned above, the novel compounds of formula (I) produced according to the invention have valuable pharmacological properties, i.e., in addition to having a positive inotropic effect, they have antithrombotic properties.

For example, the following compounds have been investigated for their biological properties:

A = 6- (4-phenylmercaptobutoxy) -3,4-dihydrocarbostyril,

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

C = 6- (4-Phenylsulfonyl-3-yl) -3- ₍ 4-dihydroxocarbostyril),

D = 6- [4- (2-pyridylmercapto) butoxy] -3,4-dihydrocarbostyril,

E = 6- [4- (2-pyridylsulfinyl) butoxy] -3,4-dihydrocarbostyril,

F = 6- [4- (2-pyridylsulfonyl) butoxy] -3,4-dihydrocarbostyril,

G · = 6- (2-phenylsulfinylethoxy) -3 ', 4-dihydrocarbostyril,

H = 6- (4-benzylsulphinylbutoxy) = 3,4-dihydrocarbostyril,

I = 6- [4- (4-chlorophenylsulphinyl) butoxy] = -3,4-dihydrocarbyryril,

K = 6- (4-cyclohexylsulphinylbutoxy) -3,4-dihydrocarbostyril,

L = 6- [4- (2-naphthylsulfanyl) butoxy] -3 ‘- ^ ii d d d d d d, ^,,

M = 6- [4- (2-Methoxylenylsulfinyl) butoxy] 3,4-dihydrocarbostyril,

N = 6- (4-phenylsulfonylbutoxy) drrbostyol,

O - 6- [4- (4 = 4-hydroxy = 3,5 = di-tert-butylphenylsulfinyl) butoxy] tastastil,

P = - - - - (- - - - - - - - - - - - - - - - - -

Q = 4-methyl-6- (4- = enylsulinylbutoxy) carbo-styrile,

R = 6 - [(4-3,4-dichlorophenylthietynyl) kutoxy] -3,4-dihydrycarbystyril,

S = 6- [4- (2,5-dichloro-phenylsulfinyl) -butyl] = 3,4- = ii-hydrocarbostyril,

T = 6- [4- (2-pyridylsulfynyl) butyloxy] = caukystyril and

U = 6- [4- (3,4-Dichloyferiylsulfinyl) butoxy] -3,4-dihydrocarbostyril.

1. Determination of Oyombocyte aggregation according to Born and Cross (J. Physiol. 170,

397 [1964]):

Aggregation of · thymocytes was measured in platelet rich plasma of healthy test subjects. The course of the optical density decrease after addition of rdenosine diphosphate (ADP) or collagen is measured photometrically and recorded. From the angle of inclination of this optical density curve, the aggregation rate (V _maii ) is _deduced . The point of the curve at which the highest light transmittance has been reached is used to calculate the optical density of the "optics densities" (ODJ) The EC 50 data in the table refer to the optical density. To induce aggregation, about 0.01 ml of collagen solution is added to one ml of platelet-rich plasma. The required amount of rdenosine diosate is about 1. 10 -6 mol / liter, and is used on the market for the usual rdenosine (ysindiphysiate, a product of Bönger-Mannheim).

The dose of a substance that causes 50% suppression of ππ ^γ aggregation (EC 50) was graphically determined:

Compound

EC50 10 ^-6 mol / liter collagen adenosine diphosphate

AND 50 > 100 (B) 4 20 May C 5 15 Dec D 45 > 100 E 6.5 25 F 20 May 20 May G 3.5 17 H 2.5 14 AND 4 10 TO 4,5 12 L 1 10

6- [4- (4-bromo-3-methylphenylsulfinyl) butoxy] -3,4-dihydrocarbostyril, m.p. 129 ^DEG- 130 ^DEG C.,

6- (4- (2,5-dibromophenylsulfinyl) butoxy] -3,4-dihydrocarbostyril, m.p. 182-184 ° C,

6- [4- (2,5-dibromophenylsulfinyl) butoxy] carbostyril, m.p. 187-189 ° C,

6- (3- (3,4-dichlorophenylsulfinyl) propoxy] -3,4-dihydrocarbostyril, m.p. 170-172 ° C,

6- (4- (4-cyclohexylphenylsulfinyl) butoxy] -3,4-dihydrocarbostyril, m.p. 155-157 ° C,

6- (4- (4-cyclohexylphenylsulfinyl) butoxy] carbostyril, m.p. 188-190 ° C,

6- (4- (4-tert-butylphenylsulfinyl) butoxy] -3,4-dihydrocarbostyril, m.p. 121-123 ° C,

6- [4- (4-tert-Butylphenylsulfinyl) butoxy] carbostyril, m.p. 164-166 ° C,

6- [4- (2-quinolysulfinyl) butoxy] -3,4-dihydrocarbostyril, m.p. 154-157 ^{° C} ,

6- (2- (N-methyl-N-cyclohexylcarbamidomethylsulfinyl) ethoxy] -3,4-dihydrocarbostyril, m.p. 143-146 ° C,

6- (2- (N-Imethyl-N-cyclohexylcarbamidomethylsulfinyl) ethoxy] carbostyril, m.p. 128-130 ° C,

6- (5- (3,4-dichlorophenylsulfinyl) pentoxy] -3,4-dihydrocarbostyril, m.p. 165-166 ° C,

6- [4- (2-methyl-4-terc.butylfenylsulfinyl) butoxy] -3,4-dihydrocarbostyril, R _f: 0.54 (silica gel plates with luminous indicator; solvent system: a mixture of ethylene chloride and methanol, 95: 5)

5-nitro-6- (4-phenylsulfinylbutoxy) carbostyril, m.p. 192-194 ° C;

5-acetamido-6- (4-phenylsulfinylbutoxy) carbostyril, m.p. 213-217 ° C,

5-bromo-6- (4-phenylsulfinylbutoxy) carbostyril, m.p. 190-191 ° C;

4-methyl-6- [4-pyridylsulfinyl) butoxy] carbostyril, m.p. 166-168 ° C,

6- (4-tert-butylsulfinylbutoxy) -3,4-dihydrocarbostyril, m.p. 126 ^DEG- 128 ^DEG C.,

6- (4- (l, 2,4-triazol-3-ylsulfanyl ynyl) butoxy] carbostyril, R _f value: 0.12 (silica gel plate with luminous indicator ,; solvent system: a mixture of ethylene chloride and methanol, 95: 5)

6- (4- (l, 2,4-triazol-3-ylsulfanyl ynyl) butoxy] -3,4-dihydrokarbostyrll, R _f value: 0.18 (silica gel plate with luminous indicator; solvent system: a mixture of ethylene chloride and methanol, 95 : 5),

6- (4- (2-pyridylsulfonyl) butoxy] -3,4-dihydrocarbostyril, m.p. 123.8-125 ° C,

6- (4- (3,4-dimethoxyphenylsulfonyl) butoxy] -3,4-dihydrocarbostyril, m.p. 158-160 ° C,

6- (5- (2-pyridylsulfonyl) pentoxy] -3,4-dihydrocarbostyril, m.p.

113.5 to 115.0 ° C,

7- (4-phenylsulfonylbutoxy) carbostyril, mp 199-201 ° C,

6- (2-phenylsulfonylethoxy) -3,4-dihydrocarbostyril, m.p. 185-186 ° C; 1-methyl-6- (4-phenylsulfonylbutoxy) -3,4-dihydrocarbostyril, m.p. 108-109 ° C;

6- (2-hydroxy-3-phenylsulfonylpropoxy) -3,4-dihydrocarbostyril, m.p. 170-172 ° C,

8- (4-phenylsulfonylbutoxy) -3,4-dihydrocarbostyril, mp 114.5-115 ° C,

6- (4- (2-benzthiazolylsulfonyl) butoxy] -3,4-dihydrocarbostyril, m.p. 146-149 ° C,

6- (4- (2-naphthylsulfonyl) butoxy] -3,4-dihydrocarboistyril, m.p. 173-175 ° C,

6- (4- (4-Biphenylylsulfonyl) butoxy] -3,4-dihydrocarbostyril, m.p. 232-234.5 ° C,

5- (4-phenylsulfonylbutoxy) carbostyril, m.p. 182-183 ° C,

6- (4-phenylsulfonylbutoxy) carbostyril, m.p. 212-213 ° C,

5- (4-phenylsulfonylbutoxy) carbostyril, m.p. 182-183 ° C,

5- (2-hydroxy-3-phenylsulfonylpropoxy) -3,4-dihydrocarbostyril, m.p.

168-170 ^C. C.

6- (4- (4-Hydroxyphenylsulfonyl) butoxy] -3,4-dihydrocarbostyril, m.p. 219-219.5 ° C,

6- (4- (4-Acotaminophenylsulfionyl) butoxy] -3,4-dihydrocarbostyril, m.p.

143.5 to 147.0 ° C,

8- (4-Phenylsulfonylbloxylcarbonyl), m.p. 146-147 ° C;

6- (4- (2,5-dichlorOenylsulfonyl) butoxy] -3,4-dlhydroaabbiostyril, m.p.

174.5 to 175.5 ° C,

6- (4- (3,4-Dichloro-phenylsulfonyl-butoxy)] m.p. 172-173 ° C,

6- [4- (4-Hydroxy-3,5-di-tert-butylphenyl) butoxy] butoxy] -3,4-dihydnababooutyrile, m.p. 165-167 ° C,

6- (4- (4-Pyridylsulphonyl) butoxy] -3,4-dihydrochloride, m.p. 179-183 ° C, m.p.

5- (3-tert-Butylsulphonyl-2-hydroxypropoxy) -3,4-dihydrocarbostyril, m.p. 210-212 ° C,

6- (4- (2-pyridylsulphonyl) butoxy] aarboutyrile, m.p. 179-180 ° C,

4-Chloro-6- [4- (2-pyridylsulfonyl) butoxy] aarbostyril, m.p. 195-197 ° C;

4-methyl-6- [4- (2-quinolyltulonyl) butoxy] aarboutyril, m.p. 199-203 ° C,

6- (4- (4-chloro-phenylsulfonyl) butoxy] aarboutyrile, m.p. 197-199 ° C,

6- (4- (3,4-dichlorennyluuleonyl) butoxy] cardyl-thrile, m.p. 188-190 ° C,

6- (4- (2,5-Dichlorophenylsulfonyl) butoxy] carbostyril, m.p. 203-205 ° C,

6- (4- (4-O-4-fluorophenylsulfonyl) butoxy] arbutyl-ril, m.p. 209-211 ° C,

6- (4- (4-Hydroxy-3,5-di-tert-butyl-phenylsulphonyl) butoxy] fireplace or butyl), m.p. 242 DEG-244 DEG C.,

6- (4- (4-Biphenylsulfonyl) butoxy] carbotyrile, m.p. 213 DEG-215 DEG C.,

6- (4- (4-Chloro-butoxy) -butoxy] -carbutyril, m.p. 230-232 ° C,

6- (4- (2-quinolylsulfonyl) butoxy] aarboutyrile, m.p. 197-198 ° C,

6- (4- (3-Methyl-4-bromophenylsulfonyl) -butoxy) -benzybil, m.p. 163-167 ° C,

6- (4- (3,5-dibromo-4-aminophenyl-butyloxy) butoxy] -3,4-dihydro-carbonylbutyl, m.p. 157-159%

6- (4- (3,5-dibromo-4-aminophenylsulfonyl) butoxy] arboul), m.p.

238-241 ° C,

6- (4- (4-cyano-hexylphenyl) butoxy] -3,4-dihydrocarbostyril, m.p. 172-174 ° C,

6- (4- (4-cyclohexylphenylsulfonyl) butoxy] aroostygil, m.p. 185-186 ° C,

6- (4- (- (- (- (- Sulfonyl) -butyl) butoxy) -3- (3-carboxylic acid) carbo), m.p. 198-200 ° C),

6- (4- (4-tert-butylphenoxybutyl) butoxy] carbonyl-tetrilil, m.p. 203-205 ° C,

6- (4- (2-Cyclohexylethoxy) butoxy] -3,4-dihydrocyclo-octyl, Rf value: 0.50 (uHicagel deciduous); solvent washed: benzene, ethanol and concentrated. ammonia 75: 25: 2),

6- (2- (N-methyl-N-cyclohexylcarbamidomethylsulphonyl) ethoxy] -3,4-dihydrocarbonyl octyl, m.p. 110-111 ° C,

6- [2- (N-methyl-N-cyalkoxy-oxycarbamido-methyl) 10-yl] ethoxy] -carbonyl-silane, Rf value: 0.39. )

6- (3- (3,4-dihydro-benzo) -propoxy) -3,4-dihydro-bicycloethyl, m.p. 187-188 ° C,

6- (5- (3,4-ynyl-LO dichlObf Jpentoxy sulfonyl] -3,4-di- ^| hydblokabb (αstfyΠ, mp 176-178 ° C,

6- (4- (1H-triazol-4-yl-ylphenyl) butoxy] -3,4-dihydbocarbobutylbile, m.p. 217-224 ° C,

M.p. 136.5-137.8 ° C; 6- (5-phthalulfonylpiperoxy) -3,4-dihydraphthabbautyril.

II

6- (4- (4-fluorophenylmercapto) butoxy] -3,4-dihydrocarbostyril, m.p. 139-140 ° C,

6- [4- (4-methylphenylmercapto) butoxy] -3,4-dihydrocarbostyril, m.p. 120-121 ° C,

6- [4- (3-Methylphenylmercapto) butoxy] -3,4-dihydrocarbostyril, m.p. 95-96 ° C

6- [4- (4-chlorophenylmercapto] butoxy] -3,4-dihydrocarbostyril, m.p. 144-146 ° C,

6- (4- (3,4-dichlorophenylmercapto] butoxy) -3,4-dihydrocarbostyril, m.p.

116.5-118 ° C,

6- (4- (2-methoxyphenylmercapto) butoxy] -3,4-dihydrocarbostyril, m.p.

130.5 to 133 ° C,

6- (4- (3-methoxyphenylmercapto) butoxy] -3,4-dihydrocarbostyril, m.p.

93.5 to 97 ° C,

6- (4- (4-methoxyphenylmercapto) butoxy] -3,4-dihydrocarbostyril, m.p.

130.5 to 133 ° C,

6- (4- (3,4-dimethoxyphenylmercapto) butoxy] -3,4-dihydrocarbostyril, m.p. 117-119 ° C,

6- [4- (4-Biphenylmercapto) butoxy] -3,4-dihydrocarbostyril, m.p.

179.5-181 ° C,

6- (6-phenylmercaptohexoxy) -3,4-dihydrocarbostyril, mp 112.5-113 ^° C,

6- (2-hydroxy-3-phenylmercaptopropoxy) -3,4-dihydrocarbostyril, m.p. 148-149 ° C,

6- (4- (2-quinolylmercapto) butoxy] -3,4-dihydrocarbostyril, m.p. 115 ° C,

6- (4- (2-quinazolin-4-onyl-mercapto) butoxy) -3,4-dihydrocarbostyril, m.p. 184.5-188 ° C,

169 DEG-170 DEG C. 6- (4-triphenylmethylmercaptobutoxy) -3,4-dihydrocarbostyril,

6- (2- (2-naphthylmercapto) ethoxy) -3,4-dihydrocarbostyril, m.p.

147.5 to 147.8 ° C,

6- (2- (4-biphenylylimercapto) ethoxy] -3,4-dihydrocarbostyril, m.p. 192-194 ° C,

6- (3- (2-pyridylmercapto) propoxy) -3,4-dihydrocarbostyril, m.p. 108-108.5 ° C,

6- [4- (2-naphthylmercapto) butoxy] -3,4-dihydrocarbostyril, m.p.

108.5 to 109.5 ^C C

6- (4-cyclohexyl-mercaptobutoxy) -3,4-dihydrocarbostyril, m.p. 114-115 ° C;

6- (4-benzylmercaptobutoxy) -3,4-dihydrocarbostyril, m.p. 77.5-78.5 ° C;

6- (4- (2-furylmethylmercapto) butoxy] -3,4-dihydrocarbostyril, m.p. 79-80 ° C,

6- (4- (N-oxido-2-pyridylmercaptO) butoxy] -3,4-dihydrocarbostyril, m.p. 179.5-181 ° C,

6- (4- (2-pyrimidylmercapto) butoxy] -3,4-dihydrocarbostyril, m.p. 154-156 ° C,

6- [4- (4-pyridylmercapto) butoxy] -3,4-dihydrocarbostyril, m.p. 128-129 ° C,

6- (4- (2-benzimidazolylmercapto] butoxy) -3,4-dihydrocarbostyril, m.p. 100-103 ° C,

6- (4- (2-benzothiazoles lmerkapto) butoxy] -3,4-dihydrocarbostyril, m.p. 157-158 ^c C

6- (2-phenylmercaptoethoxy) -3,4-dihydrocarbostyril, m.p. 132-133.5 ° C,

6- (3-phenylmercaptopropoxy) -3,4-dihydrocarbostyril, m.p. 111-112 ° C; 1-methyl-6- (4-phenylmercaptobutoxy) -3,4-dihydrocarbostyril; up to 80,5 = C,

6- (4-phenylmercaptobutoxy) carbostyril, m.p. 162-164 ° C;

5- (4-phenylmercaptobutoxy) carbostyril, m.p. 185-187 ° C (from toluene),

8- (4-phenylmercaptobutoxy) carbostyril, m.p. 119-120 ° C,

6- (4-aminoiminomethylmercaptobutoxy) -3,4-dihydrocarbostyril, m.p. 140-141.8 ° C,

6- (4-benzymercaptobutoxy) -3,4-dihydrocarbostyril, m.p. 76-78 ° C;

6- (5-phenylmercaptopentoxy) -3,4-dihydrocarbostyril, m.p. 117-119 ° C;

6- (5- (2-pyridylmercapto) penthoxy) -3,4-dihydrocarbostyril, m.p. 113-114.8 ° C,

5- (2-hydroxy-3-phenylmercaptopropoxy) -3,4-dihydrocarbostyril, m.p. 135-137 ° C;

6- {4- (4-hydroxyphenylmercapto) butoxy} -3,4-dihydrocarbostyril, m.p.

191.5 to 193.0 ° C,

6- (4- (4-acetaminophenylmercapto) butoxy] -3,4-dihydrocarbostyril, m.p.

162.5 to 163.0 ° C,

6- [4- (4,5-di-p-chlorophenyloxazol-2-ylmercapto) butoxy] -3,4-dihydrocarbostyril, m.p. 110-115 ° C,

7- (4-phenylmercaptobutoxy jicarbostyril), m.p. 157.5-158.5 ° C,

6- [4- (2,5-dichlorophenylmercapto) butoxy] -3,4-dihydrocarbostyril, m.p. 133-134 ° C,

6- [4- (4-hydroxy-3,5-di-tert-butylphenylmercapto) butoxy] -3,4-dihydrocarbostyril, m.p. 146-147 ° C,

6- (4- (2-carboxyphenylmercaptojibutoxy) -3,4-dihydrocarbostyril, m.p. 176-179 ° C,

6- (3-benzyl-tetracyclopropoxy) -3,4-dihydrocarbostyril, m.p. 97.5-99.0 ° C,

5- (3-tert-butylimapto-2-hydroxypropoxy) -3,4-dihydrocarbostyril, m.p. 105-109 ° C,

4-methyl-β- [4- (2-pyridylmercapto) butoxy] carbostyril, m.p. 149-151 ° C;

4-methyl-6- (4- (2-cyano-mercapto) butoxy] carbostyril, m.p. 162-163 ° C;

6- (4- (4-chlorophenylmercapto) butoxy) carbostyril, m.p. 168-170 ° C,

6- (4- (3,4-dichlorophenylmercapto) butoxy] carbostyril, m.p. 149-152 ° C,

6- (4- (2,5-dichlorophenylmercapto} butoxy) carbocyril, m.p. 175-176 ° C,

6- (4- (4-fluorophenylmercapto) butoxy] carbostyril, m.p. 149-150 ° C.

6- (4- (4-hydroxy-3,5-di-tert-butylphenylmercapto) butoxy] carbostyril, m.p. 172-173 ° C,

6- (4- (4-Biphenylylmercapto] butoxy) carbostyril, m.p. 191-192 ° C _;

6- (4- (4-nitro-phenylmercapto) -butoxy] carbostyril, m.p. 18-4 DEG-185 DEG C.,

6- (4- (2-quinolylmercapto) butoxy] carbostyril, m.p. 132 DEG C .;

6- (4-cyclohexylmercaptan-butoxy) carbostyril, m.p. 153-159 ° C,

6- (4- (4-bromophenylmercapto) butoxy) carbostyril, m.p. 156-158 ° C,

6- [4- (3-methyl-4-bromophenylmercapto) butoxy] carbostyril, m.p. 167-169 ° C,

6- [4- (1,2,4-triazol-3-ylmercapto) butoxy] carbostyril, mp 203-206 ° C,

6- (4- (2,4,5-trichlorophenylmercapto) butoxy] carbostyril, m.p. 177-178 ° C,

6- (4- (3,5-dibromo-4-aminophenylmercapto) butoxy] -3,4-dihydrocarbostyril, m.p. 90-92 ° C,

6- (4- (3,5-Dibromo-4-aminophenylmercapto) butoxy] carbostyril, m.p.

153-155 ° C,

6- (4- (4-bromo-3-methylphenylmercapto) butoxy) -3,4-dihydrocarbostyril, m.p. 104-109 ° C.

6- (4- (2,5-dibromophenylmercapto) butoxy] -3,4-dihydrocarbostyril, m.p. 127-1291 ° C,

6- (4- (2,5-dibromophenylmercapto) butoxy]; carbostyril, m.p. 178-185 ° C,

6- [3- (3,4-dichlorophenylmercapto) propoxy] -3,4-dihydrocarbostyril, m.p. 106) -1.7 ° C,

6- [4- (4-cyclohexylphenylmercapto) butoxy] -3,4-dihydrocarbostyril, m.p. 118-12 ° C,

6- (4- (4-cyclohexylphenylmercapto) butoxy] carbostyril, m.p. 165-167 ° C,

6- (4- (4-tert-butylphenylmercapto) butoxy) -3,4-dihydrocarbostyril, m.p. 126-127 ° C,

6- [4- (4-tert-butylphenylmercapto) butoxy] icarbostyril, m.p. 156-158 ° C,

6- (2- (N-methyl-N-cyclohexylcarbamidomethylmercapto) ethoxy) carbostyiril, Rf value: 0.41 (silica gel plate with luminous indicator; solvent system: ethylene chloride / methanol 95: 5),

6- [5- (3,4-chlorophenylmercapto) pentoxy] -3,4-dihydrocarbostyril, m.p. 101-104 ° C,

6- [4- (2-methyl-4-tert-butylphenylmercapto) butoxy] -3,4-di-tertiocarbostyril, m.p. 81-85 ° C,

6- [4- (3,5-dichloro-4-hydroxyphenylmercapto] butoxy] -3,4-dihydrocarbostyril, m.p. 110-114 ° C,

5-bromo-6- (4-phenylmercaptobutoxy) carbostyril, m.p. 209-213 ° C;

5-piperazo-6- (4-enylnaphthalocyloxy) carbostyril, m.p. 228-230 ° C;

5-acetamino-6- (4-phenylmercaptobutoxy) carbostyril, m.p. 238-240 ° C;

6- [4- (1,2,4-triazol-3-yl lmerkapto) butoxy] -3 ,, ^ - ^ - ^ ii ^ j ^ di ^ <^ l ^ <arbostyril, mp 152-154 C ^Q ,

6- [4- (5S-trichloophenylmercapto) biitoxy]] -3,4-dihydrocarbostyril, m.p. 144-145 ° C,

6- [3- (3,4-dichlorophenylinercapto) -2-hydroxypropoxy] -3,4-dihydrocarbostyril, m.p. 175-176 ^° C,

6- (4- (3-hydroxy-2-oxo-2-fluorocapto) butoxy) -3,4-dihydrocarbostyril, m.p. 211-216 ° C,

6- [2- (N-methyl-N-cyklohexylkarbamidomethylm.nfk · apttntht) xy] carbostyril, hoinota R _(: 0.46 (silica gel · ieska a luminous iydikátorem; · 'rozpouštědový system: a mixture. Ethylenéhloriáu · methanol 95: 5),

6- [4- (2-pyridylsulfinyl) butoxy] -3,4-. -diethylcaphtstyfil, melting point

144.5 to 146 ° C,

6- [4- (4-Fluorophenylsulfinyl) butoxy] -3,4-dihydro-alpha-4-biphenyl, m.p.

184.5-186 ° C,

6- [4- (4-Methylphenylsulfinyl) butoxy] -3,4-dihydrocarbstyril, m.p.

149.5 to 150 ° C,

6- [4- (3-methylphenylsulfinyl) butoxy] -3,4-dihydrocarbostyril, Rf value: 0.48 (thin layer silica gel; solvent system: benzene / ethanol / concentrated ammonia 75: 25: 1) ,

6- [4- [4-chlorophenylsulfinyl) butoxy] -3,4-dihydrocarbostyril, m.p. 148-149.5 ° C,

6- (4- (3,4-dichlorophenyl lsulfinyl) butoxy] ^-3,4-di! Hydrtaarbtstyril, m.p.

106.5 to 108 ° C,

6- [4- (2-methoxyphenylsulfinyl) butoxy] -3,4-dihydrocarbostyril, m.p. 162-163 ° C,

6-) 4- (Э-methoxyphenylsulfinyl) butoxy] -3,4-dihydrocarbostyril, m.p. 147-148 ° C,

6- (4- (4-methoxyphenylsulfinyl) butoxy] -3,4-dihydrocarbststyfil, m.p. 132-133 ° C,

6- (4- (3,4-dimethoxyphenylsulfinyl) butoxy] d-dihydrocarbostyril, m.p. 145-147 ° C,

6- (4- (4-biphenylylsulfinyl) butoxy] -3,4-dihydrocarbonylstyril, m.p. 192-192.5 ° C,

6- [4- (2-naphthylsulfinyl) butoxy] -3,4-trifluoromethylstyril, m.p. 147.5-148.5 ° C,

6- [5- (2-pyridylsulphinyl) pentoxy] -3,4-di-chlorocarbostyril, m.p. 116-118 ° C,

6- ^ -meehylsulf шylnthoxy) ^-3,4-di-l hydrokarbostyril, mp 129 ° -131.5 ° C

6- (4-methylsulfinylbutoxy) -3,4-dicyclo-carbostyril, mp 128.5-130.5 ° C,

6- (4-cyalohexylsulfinylbthoxy) -3,4-dihydrogocarbostyfil, m.p. 153-155.5 ° C,

6- (4-Benzylsulfinylbutoxy) -3,4-dihydro-. carbostyril, mp 141.5-142 ° C,

6- (4- (2-furylmethylsulfinyl) butoxy] -3,4-dihydroxycarbostyril, m.p. 135-136 ° C,

6- (4- (2-pyridylsulfinyl) butoxy] -3,4-dihydrocarbstyril, m.p. 154-156 ° C,

6- (4- (2-benzimidazolylsulfiyyl) butoxy] -3,4-dihydrocarbostyril, m.p. 180-182 ° C,

6- (4- (2-benzthiazolylsulfinyl) butoxy] d-dihydrocarbostyril, m.p. 183-184 ° C,

6- (2-Phenylsulfinylethoxy) -3,4- [beta] -carbostyril, m.p. 171-172 ° C,

6- (3-phenylsulfinylpropoxy) -3,4-dihydro-arbostyril, m.p. 131.5-133.5 ° C,

1-Methyl-6- (4-phenylsulfinylbutoxy) -3,4227005 23

-dihydriocarbonyl, m.p. 82-82.5 ° C,

6- (6-Phenylsulfinylhuxoxy) -3 ', 4-dihydrocarbostyril, mp 119.5-121.5 ° C,

6- (2-hydroxy-3-phenylethylpropoxy) -3,4-dihydrocarbostyril, m.p.

185-187 ° C,

6- [2- (2-naphthylsulfinyl) ethoxy] -34-dihydrocarbostyril, mp 186.5-187.5 ° C,

6- [2- (4-Biphenyl-4'-llylsi-4'-10-ylethoxy) -3,4-dihydiocartolitrile, m.p. 195-196 ° C,

5- (4-Isomeric-butyloxybutoxy), m.p. 155-157 ° C;

7- (4-fluoro-sulfonylbutoxy), m.p. 193-194 ° C;

8- (4-Fluoro-butyloxy-butoxy) -carbosulfonyl-tert-butyl, temperature. mp 125.5-126.5 ° C,

6- (5-phenylsulfinylpuntoxy) -3,4-dihydrocarbostyril, m.p. 104-109.5 ° C,

5- (2-Hydroxy-3-phenylsulfinylpropoxy) -3,4-dihydrocarbosyl, m.p.

186-188 ° C,

6- [4- (4-Hydroxyphenylsulfinylbutoxy) -3,4-dihydrocarbonyl] mp, m.p. 206-207.8 ° C,

6- [4- (4-acetaminophenylstinyl) buloxy} -S-dihydrotoarbasyril, mp 202.0-203.8 ° C,

6- (4- (2-chloro-butadiene) butoxy) carbonyl, m.p. 152-154 ° C,

6- (4- (2,5-dichloro-entsulinyl) butoxy} m.p. 185-186 ° C;

6- [4- (4-hydroxy) -xy-3,5-di-tert-butylphenylsulfinyl) butoxy} -3,4-dihydrocarbostyrrole, m.p. 170-171 ° C,

6- (4- (2-carboxylenytoulphinyl) butoxy} -3,4-dihydrocarbonyl), m.p. 194-196 ° C,

6- [4- (4-pyridylsulfinyl) butoxy] -3,4-dihydrocarbostyril, m.p. 154 [deg.] C,

6- [3- ^{(3,4-dimethyl-ichtorfeny} suШny i) -2yhydr.oxypropoxy} -3,4-dihydrokarbostyгil, mp 108- 110 ° C,

6- (3-benzylsulfinylpropoxy) -3,4-dihydrocarbostyril, m.p. 144.5-147.0 ° C;

5- (3-tert-butyl-tert-2-Ilydroyypyropoxy) J 24

-3,4-dihydroltabostyril, m.p. 175-177 ° C,

4-Imeth-6-6- [4- (2-pyrrolidinyl) butoxy) carbostyril, m.p. 167-169 ° C,

4-Methyl-6- [4- (2-quinolysulfinyl) -buloxy} -carbostyril, m.p. 189-190 ° C;

4-Methyl-6- [4- (4-biphenylsulfonyl) butoxy} carbostyril, m.p. 161-162 ° C;

6- (4- (4-chlorofluorosulfonyl) 1-butoxycarbostyril), m.p. 157-158 ° C,

6- [4- (3,4-Dichlorophenylsulfinyl) butoxy} carbostyril, m.p. 191-196 ° C,

6- [4- (2-methoxybutyl) butoxy} -carbostyril, m.p. 200-202 ° C,

6- (4- (4-fluorophenyl) -benzyl) butoxy} carbostyril, m.p. 164-165 ° C,

6- [4- (4-Hydroxy-3,5-di-tert-butynyl-phenyl) -butoxy} -carbostyril, mp 192-194 ° C,

6- [4- (4-Biphenylethylin-1) butoxy} cartostyl, m.p. 196-197 ° C,

6- [4- (4- [4- (4-isophenyl) (2-isopropyl) -2-butoxy] carbostyril, m.p. 183-184 ° C, m.p.

6- [4- (2-carboxylic acid) butoxy} carbostyril, m.p. 161-182 ° C,

5- (4-methyl-oxo-butoxy) oxindole, m.p. 114-110 ° C;

6- (2- (phenylsulfinylmethyl) benzyloxy) -1,4,4-dihydrocarbonyl-m.p.

133 to 135CC,

6- (4- (funyl-4-yl) -benzyloxy} -3,4-dihydrocarbostyril, m.p. 179-181 ° C,

6- (4-cyclohexylsulphinylbutoxy) carbostyril, m.p. 169-170 ° C;

6- (4- (4-bromobutylsulfinyl) butoxy) carbostyril, m.p. 168-170 ° C,

6- (4- (3-methyl-4-bromophenylsulfinyl) ^1- butoxy) carbostyril, m.p. 169-172 ° C,

6- (4- (2,4,5-Trifluorophenylsulfinyl) butoxy} carbostyril, m.p. 206 DEG-208 DEG C.,

6- [4- (3R, 5-Dibromo-4-aminophenyltulphinyl) 1'-butoxy} -3,4'-thiazol-5-one, mp 144-146 ° C,

6- (4- ^(3,5-dΐ: iюm and ^-----! Зí-to0eliy sullfnyl J-butoxy] carbostyril, m.p. 205-207 ° C,

Claims (3)

OBJECT OF THE INVENTION 1. production of carbostyril and (rondel derivatives of the general formula I) AND JT1 * 3 -O-D-SO4 -. · * 1 (AND) in which W represents an optionally substituted methyl group, a methylene group, a methylene group or an ethylene group; m represents a number of · 0, 1 or · 2, D represents a straight or branched alkylene group having 2 to 6 carbon atoms, a straight or branched hydroxyalkylene group having 3 to 6 carbon atoms, or a xylylene group, R1 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, R 2 represents a C 3 -C 6 -cyclostyl group, a C 6 -C 10 aryl group, a C 7 -C 11 aralkyl group, a C 4 -C 9 helene group containing a nitrogen atom and / or an oxygen atom or atom sulfur or two nitrogen atoms or a 5 to 10 carbon heteroaryl group containing a nitrogen atom and / or an oxygen or sulfur atom or two nitrogen atoms, the aromatic nuclei mentioned above being optionally monosubstituted with a C1-4 alkyl group, a hydroxy group Is methoxy, amino, acetylamino, nitro, carboxyl, cyclohexyl, phenyl or halogen, and in addition optionally the abovementioned monesubstituted phenyl is mono- or disubstituted with (C1-C4) -alkyl or / and halogen atoms, wherein the phenyl core tubstituent is the same or different from each other; 1,2,4-triazolyl, triphenylmethyl, 4,5-bis - (- p-chlorophenyl) -oxazol-2-yl, N-methylcyclohexylaminocarbonylmethyl or aminoiminomethyl or also C 1 -C 6 style if either means the number 1, or D is a straight or branched (C 3 -C 6) hydroxyalkyl or xylylene group, R 3 and R 6 are the same or different from each other and are hydrogen or halogen, C 1 -C 4 -tyl, amino, rctramino or nitro, characterized in that the hydroxyl derivative of the general formula II in which: R 1, R 5, R 1 and W are as defined above or are treated with a compound of formula III to form salts thereof with inorganic or tertiary organic bases ZD-SO _m -R 2 (III) wherein D, R 2 and m are as defined above and Z represents a nucleophilic exchangeable group, such as a halogen atom. or the remainder of the sulfonic acid ester, optionally in the presence of a solvent and at temperatures between 0 ° C and the boiling point of the solvent used, and in the presence of an alkali metal compound as a base to form a compound of formula I. 2. The process of item 1 for the preparation of compounds of formula I wherein: W and m have the meanings given in point 1, D is a (C 3 -C 6) alkyl, xylylene or (C 3 -C 6) alkylene group; R 1 represents a hydrogen atom, R 2 represents a phenyl group which is. optionally substituted by carboxyl, nitro, amino, phenyl or cyclohexyl, furthermore, phenyl is mono- or disubstituted by halogen atoms and / or by C1-C4-style groups, furthermore by two C1-C4 asylum groups or a halogen-substituted hydroxyphenyl, halophenyl or aminophenyl group, furthermore a cyclohexyl group, a benzyl group, a pyridyl group, a naphthyl group, a quinolyl group, a 1,2,4-aisopropyl group, a 1,2,4-aisopropyl group, or an N-methylcyclohexylaminocarbonylmethyl group or also a tert-butyl group when either m is 1, or D represents a hydroxyalkylene group having 3 to 6 carbon atoms, R 3 and R 4 are the same or different from each other and are hydrogen, halogen, C 1 -C 4 alkyl, nitro, amino or acetylamino, characterized in that the hydroxy derivative of the general formula (II) in which R 1 is R 3, R 4 and W are as defined above, or their salts with inorganic or tertiary organic bases are treated with a compound of formula III wherein D, R 2 and m are as defined above and Z is as defined in 1, optionally in the presence of a solvent and at temperatures between 0 ° C and the boiling point of the solvent used, and in the presence of an alkali metal compound as a base. 3. The process of item 1 for producing compounds of formula I wherein: W is a vinylene group or an ethylene group, m is as defined in point 1, D represents a straight or branched alkylene group having 2 to 6 carbon atoms, a straight or branched hydroxyalkylene group having 3 to 6 carbon atoms, Ri is as defined in point 1, R2 represents 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, a C 5 -C 10 heteroaralkyl group containing a nitrogen and / or oxygen or sulfur atom, or two nitrogen atoms, wherein the above aromatic nuclei are optionally monosubstituted with methyl, methoxy, hydroxy, acetylamino, phenyl a halogen atom or a triphenylmethyl group, a 4,5-bis-p-chlorophenyl] -1-oxazol-2-yl group or an aminoimino-methyl group or an alkyl group having 1 to 6 carbon atoms, if either * m stands for 1, or D is a straight or branched C 3 -C 6 hydroxyalkylene group, R 3 and R 1 are hydrogen atoms, characterized in that the hydroxy derivative of the general formula (II) in which R 1, R 3, R 1 and W have the meanings given above, or salts thereof, or a salt thereof. mL or tertiary organic bases act with a compound of formula III wherein D, R 2 and m are as defined above and Z is as defined in 1, optionally in the presence of a solvent and at temperatures between 0 ° C and the boiling point of the solvent used; presence of an alkali metal compound as a base.