DE2806721A1 - Substd. alkoxy-carbostyril derivs. - useful as antithrombotic and cardioactive agents, used for treating thromboembolic disorders and arteriosclerosis - Google Patents

Abstract

Carbostyril derivs. of formula (I) are new: (where A and B are H or together form a bond; D is 2-6C alkylene opt. substd. by OH; R1 is H or 1-3C alkyl; R2 is H, 1-6C alkyl, 3-6C cycloalkyl, a 6-10C aryl or 7-11C aralkyl gp. opt. ring-substd. by 1 or 2 Me, MeO, OH, acetylamino, phenyl and/or halogen gps.; a 4-9C heteroaryl or 5-10C heteroaralkyl gp. (opt. in N-xode form), triphenylmethyl, 4,5-bis(p-chlorophenyl)-2-oxazolyl or C(NH)NH2; m = 0,1 or 2). (I) inhibit thrombocyte aggregation and have a positive inotropic effect; they are useful for prophylaxis of thrombo-embolic disorders and arteriosclerosis. Specifically claimed cpds. are 6-(4-X-butoxy)-3,4-dihydrocarbostyril (where X = phenylsulphinyl, 2-pyridylsulphinyl or 4-chlorophenylsulphinyl) and 6-(4-phenylsulphinyl-butoxy)-carbostyril.

Description

New Carbostyril Derivatives

The present invention relates to new carbostyril derivatives of the general formula medicaments containing them and processes for their preparation.

The new carbostyril derivatives have valuable pharmacological properties on, in addition to a positive inotropic effect, in particular antithrombotic properties.

In the above general formula I, A and B each represent a hydrogen atom or together a further bond, D one optionally through a hydroxyl group substituted straight-chain or branched alkylene group with 2 to 6 carbon atoms, R1 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, R2 Hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group with 3 to 6 carbon atoms, an aryl group with 6-10 carbon atoms, one Aralkyl group with 7-11 carbon atoms, a heteroaryl group with 4-9 carbon atoms or a heteroaralkyl group having 5-10 carbon atoms, those listed above aromatic nuclei through methyl, methoxy, hydroxy, acetylamino, phenyl groups and / or halogen atoms mono- or disubstituted and / or N atoms of those listed above heteroaromatic nuclei can be converted into their N-oxides, the triphenylmethyl, 4,5-bis (p-chlorophenyl) -oxazol-2-yl or amino-iminomethyl group and m the number 0, 1 or 2.

For those mentioned at the beginning in the definition of the radicals D, R1 and R2 Meanings are therefore for D in particular the meaning of the ethylene, n-propylene, n-butylene, n-pentylene, n-hexylene, 1-methyl-ethylene, 1-methyl-propylene, 1-ethyl-ethylene, 2-methyl-ethylene, 2-ethyl-ethylene, 2-hydroxypropylene, 2-hydroxy-butylene, 3-hydroxy-butylene, 2-hydroxypentylene, 3-hydroxypentylene, 4-hydroxypentylene or 1-methyl-2-hydroxypropylene group, for R1 that of the hydrogen atom, the methyl, ethyl, propyl or isopropyl group and for R2 that of the hydrogen atom, the methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, n-hexyl, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenylethyl, Naphthyl, naphthylmethyl, biphenylyl, triphenylmethyl, amino-iminomethyl, pyridyl, Pyridylmethyl, furfuryl, benzimidazolyl, benzthiazolyl, methylphenyl, dimethylphenyl, Methoxyphenyl, Dimethoxyphenyl, hydroxyphenyl, dihydroxyphenyl, fluorophenyl, difluorophenyl, Chlorophenyl, dichlorophenyl, bromophenyl, dibromophenyl, acetylaminophenyl, methoxyfluorophenyl, Methoxy-chlorophenyl-, methoxy-bromophenyl-, fluoromethylphenyl-, pyrimidyl-, quinolyl-, Quinazolin-4-on-yl, 4,5-bis (p-chlorophenyl) oxazol-2-yl or pyridyl oxide group into consideration.

The present application therefore particularly relates to those Compounds of the general formula I in which A, B, D, R1 and m are as defined at the outset and R2 is a hydrogen atom, an alkyl group with 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a phenyl group represented by a halogen atom, a hydroxy, acetylamino, methyl and / or methoxy group mono- or disubstituted, a benzyl, naphthyl, biphenyl, triphenylmethyl, Pyridyl, N-oxido-pyridyl, pyrimidyl, furfuryl, benzimidazolyl, benzthiazolyl, Quinolyl, quinazolin-4-on-yl, 4,5-bis (p-chlorophenyl) -oxazol-2-yl or amino-imino-methyl group means.

Preferred compounds of the general formula I, however, are those in which A and B each have a hydrogen atom or together a further bond, D one straight-chain alkylene group optionally substituted by a hydroxyl group with 2 to 6 carbon atoms, R1 is a hydrogen atom or the methyl group, R2 a methyl, cyclohexyl, phenyl, fluorophenyl, chlorophenyl, methylphenyl, hydroxyphenyl, Methoxyphenyl, acetylaminophenyl, dichlorophenyl, dimethoxyphenyl, benzyl, Biphenylyl, triphenylmethyl, naphthyl, pyridyl, pyridyl 1-oxide, furfuryl, Pyrimidyl, benzimidazolyl, quinolyl, quinazolin-4-onyl or benzthiazolyl group and m is the number 0, 1 or 2.

According to the invention, the new compounds of the general formula I are obtained by the following processes: a) Reaction of a hydroxycarbostyril of the general formula in which A, B and R1 are as defined at the beginning, or their salts with inorganic or tertiary organic bases with a compound of the general formula Z - D - SO - R2 (fII) in which D, R2 and m are as defined and Z represents a nucleophilically exchangeable group such as a halogen atom or a sulfonic acid ester residue, for example a chlorine, bromine, iodine atom, a p-toluenesulfonyloxy or methanesulfonyloxy group.

The reaction is expediently carried out in a suitable solvent such as dioxane, tetrahydrofuran, chloroform or toluene, but preferably in one anhydrous aprotic solvents such as acetone, dimethylformamide or dimethyl sulfoxide, optionally in the presence of an alkali base such as sodium carbonate or potassium carbonate or sodium hydroxide at temperatures between 0 0C and the boiling point of the solvent used, e.g. at temperatures between 0 and 100 C, preferably but performed at temperatures between 10 and 50 each. However, the implementation can can also be carried out without a solvent.

b) For the preparation of compounds of the general formula I in which m represents the number 1 or 2: Oxidation of a carbostyril of the general formula in which A, B, D, R1 and R2 are as defined at the outset and n represents the number 0 or 1.

The oxidation is preferably carried out in a solvent, e.g. in water, Water / pyridine, ethanol, methanol, acetone, glacial acetic acid, dilute sulfuric acid or Trifluoroacetic acid, depending on the oxidizing agent used, expediently at Temperatures between -80 and 1000C carried out.

For the preparation of compounds of general formula I in the m represents the number 1, the oxidation is expediently with one equivalent of the oxidizing agent used, e.g. with hydrogen peroxide in glacial acetic acid at 0 to 200C or in acetone at 0 to 600C, with a peracid such as performic acid in glacial acetic acid or trifluoroacetic acid at 0 to 500C, with sodium metaperiodate in aqueous Methanol or ethanol at 15 to 250C, with N-bromosuccinimide in ethanol, with tert-butyl hypochlorite in methanol at -80 to -300C, with iodobenzene dichloride in aqueous pyridine at 0 up to 500C, with nitric acid in glacial acetic acid at 0 to 200C, with chromic acid in glacial acetic acid or in acetone at 0 to 20 0C and with sulfuryl chloride in methylene chloride at -70 0C, the resulting thioether-chlorine complex is expediently mixed with aqueous Ethanol hydrolyzed.

For the preparation of compounds of general formula I in the m represents the number 2, the oxidation is expediently carried out with or with two or more equivalents of the oxidizing agent used, e.g. with hydrogen peroxide in glacial acetic acid at 20 to 1000C or in acetone at 0 to 600C, with a peracid such as performic acid or m-chloroperbenzoic acid in glacial acetic acid, Trifluoroacetic acid or chloroform at temperatures between 0 and 500C, with nitric acid in glacial acetic acid at 0 to 200C, with chromic acid or potassium permanganate in glacial acetic acid, water / Sulfuric acid or in acetone at 0 to 200C. So means in a connection of the above general formula IV n is the number 0, the reaction is preferred with two or more equivalents of the oxidizing agent in question and quite accordingly carried out with at least one equivalent if n is the number 1.

c) For the preparation of a carbostyril of the general formula I, in which m represents the number 0: Implementation of a carbostyril of the general formula in which A, B, D and R1 are as defined at the outset, with a compound of the general formula Y - R2, (VI) in which R2 is as defined at the outset and one of the radicals X or Y in the compounds of the general formulas V and VI the mercapto group and the other of the radicals X or Y represents a nucleophilically exchangeable group such as a halogen atom or a sulfonic acid ester radical, for example a chlorine, bromine or iodine atom, a p-toluenesulfonyloxy or methanesulfonyloxy group.

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

at temperatures between 0 and 100 ° C, but preferably at temperatures between 10 and 500C. However, the reaction can also be carried out without a solvent be performed.

d) For the preparation of a carbostyril of the general formula I in which R1 does not represent a hydrogen atom: Implementation of a carbostyril of the general formula in which A, B, D, R2 and m are as defined at the beginning, or its alkali salt with a compound of the general formula Z - R1, (VIII) in which R1 is as defined and Z is a nucleophilically exchangeable group such as a halogen atom or a Sulfonic acid ester radical, for example a chlorine, bromine or iodine atom, a p-toluenesulfonyloxy or methanesulfonyloxy group represents.

The alkylation is expediently carried out in an aprotic solvent such as acetone, dimethylformamide or dimethyl sulfoxide in the presence of an inorganic one 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.degree. C., but preferably at temperatures between 10 and 250.degree. as Alkylating agents are in particular alkyl halides such as methyl iodide or Isopropyl bromide or dialkyl sulfates such as dimethyl or diethyl sulfate are suitable.

e) For the preparation of a carbostyril of the general formula I in which A and B together denote a further bond: Dehydrogenation of a 3,4-dihydrocarbostyril of the general formula in which D, R1, R2 and m are as defined at the outset.

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 one Noble metal catalyst such as palladium / Coal, preferably in one inert solvents such as dioxane or mesitylene at elevated temperatures, e.g. at temperatures between 100 and 2000C, but preferably at the boiling point of the solvent used.

f) For the preparation of a carbostyril of the general formula I, in which A and B each represent a hydrogen atom and m represents the number 0 or 2: hydrogenation of a carbostyril of the general formula in which R1> R2, D and m are as defined at the beginning.

The hydrogenation is carried out in a suitable solvent such as ethanol, Ethyl acetate, glacial acetic acid or dioxane with catalytically activated hydrogen, e.g. with hydrogen in the presence of a hydrogenation catalyst such as palladium / carbon, Platinum, Raney nickel, Raney cobalt or dirhenium heptasulfide, at temperatures between 0 and 50 ° C, but preferably at room temperature, and at a hydrogen pressure carried out from 1 to 5 bar.

According to the invention, a compound of the general formula is obtained I, in which R2 represents the amino-iminomethyl group and m represents the number O, so can this by means of hydrolysis, preferably in the presence of a base such as sodium hydroxide, touch in a corresponding compound of the general formula I, in which R2 a Represents hydrogen atom.

The compounds of the general formulas used as starting materials II to X are in part known from the literature or are obtained by what are known per se Procedure. For example, a 6-, 7- or 8-hydroxy-3,4-dihydro-carbostyril is obtained of the general formula II by acylation of a corresponding aniline derivative with a corresponding ß-halocarboxylic acid derivative and subsequent cyclization according to Friedel-Crafts (see J. chem.

Soc. 1955, 743-744, Chem. Pharm. Bull 1961, 970-975 and Ber.

dtsch. Chem. Ges. 60, 858 (1927)) or a 5-hydroxy-3,4-dihydrocarbostyril of the general formula by cyclization of a corresponding 2- (ß-cyanoethyl) -cyclohexanedione-1,3 derivative and subsequent aromatization, for example with N-bromosuccinimide (see Chem. and Ind. 1970, 1435). The preparation of the corresponding hydroxy-carbostyrile the general 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)).

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

As already mentioned at the outset, those produced according to the invention have new carbostyril derivatives of general formula I have valuable pharmacological properties on, in addition to a positive inotropic effect, they have antithrombotic properties.

For example, the following compounds have been tested for their biological Properties investigated: A = 6- (4-phenylmercapto-butoxy) -3,4-dihydrocarbostyril, B = 6- (4-phenylsulfinylbutoxy) -3,4-dihydrocarbostyril, C = 6- (4-phenylsulfonylbutoxy) -3,4-dihydrocarbostyril, D = 6- [4- (2-pyridylmercapto) -butoxy] -3,4-dihydrocarbostyril, E = 6- / 4- (2-pyridylsulfinyl) -butoxy / -3,4-dihydrocarbostyril, F = 6- / 4- (2-pyridylsulfonyl) -butoxy? -3,4-dihydrocarbostyril, G - 6- (2-phenylsulfinyl-ethoxy ) -3,4-dihydrocarbostyril, H = 6- (4-benzylsulfinyl-butoxy) -3,4-dihydrocarbostyril, I = 6- / 4- (4-chlorophenylsulfinyl) -butoxy / -3,4-dihydrocarbostyril, K = 6- (4-cyclohexylsulfinyl-butoxy) -3,4-dihydrocarbostyril, L = 6- / 4- (2-naphthylsulfinyl) butoxy? -3,4-dihydrocarbostyril, M = 6- / 4- (2-methoxyphenylsulfinyl) butoxy / -3,4-dihydrocarbostyril and N = 6- (4-phenylsulfinyl-butoxy) -carbostyril 1. Determination of platelet aggregation according to Born and Cross (J. Physiol. 170, 397 (1964)): The thrombocyte aggregation was measured in the platelet-rich plasma of healthy test subjects. Here was the Course of the decrease in optical density after adding adenosine diphosphate (ADP) or collagen measured and registered photometrically. From the angle of inclination of the The density curve was inferred from the aggregation rate (Vmax). The point the curve with the greatest light transmission was used for the calculation the "optimal density" (O.D.). The EC50 data in the tables relate to the optical density.

The collagen doses were chosen as small as possible, but still so, that there was an irreversible aggregation. To trigger the aggregation, approx. Add 0.01 ml of the collagen solution to 1 ml of platelet rich plasma. (Commercial syllables Collages from Hormonchemie, Münschen). The ADP doses were chosen so that only showed the first phase of the BORN curve. The amount of ADP required was around 1.10 6 mol / l. Commercially available ADP from Boehringer-Mannheim was used.

The substance dose that produced a 50% inhibition was determined graphically of platelet aggregation (EC50) caused: Compound EC50 10 6 mol / l collagen ADP A 50> 100 B 4 20 C 5 15 D 45> 100 E 6.5 25 F 20 20 G 3.5 17 H 2.5 14 I 4 10 K 4.5 12 L 1 10 M 4 22 N 0.6 2. Determination of the extension the bleeding time: Preliminary remark: The human organism as well as warm-blooded animals possesses a useful mechanism that keeps him from losing blood in the event of injury should protect. This system consists of the blood platelets (thrombocytes), which should quickly "clog" a vascular defect by means of their adhesive properties and thus bring about primary hemostasis. In addition to this pure cellular hemostasis mechanism the body has a blood clotting system. In this system, plasma factors (Protein bodies) brought into an effective form, which ultimately is the liquid plasma fibrinogen turn into a fibrin clot. The system of primary hemostasis, which is essentially made up of the platelets and complement the coagulation system in the common goal of effectively protecting the body from blood loss.

In some diseases it can also be with an intact vascular system coagulation processes and clumping of platelets occur. The weakening of the blood clotting system by coumarins or heparin is known and can easily be measured with the aid of known blood coagulation tests, which show an extension under the influence of the preparation (plasma decalcification time, quick determination, Thrombin time, etc.).

Because in the event of an injury, the first rapid hemostasis through Platelets happening can be set in a standardized violation determine the function of the platelets well by measuring the bleeding time. The normal bleeding time in humans is around 1 to 3 min., But continues powerful and platelets in sufficient numbers. With a normal platelet count So a prolonged bleeding time indicates a disturbed function of the platelets there. We find this, for example, in some innate ones Platelet dysfunction. On the other hand, if one wants the tendency to spontaneous agglomeration of the platelets with the consequence of vascular occlusions in the arterial system through medication, consequently, in a successful platelet-effective therapy, the bleeding time must be be extended under the influence of substances. So we expect a thrombocyte-active one Substance an extension of the bleeding time and - because the plasmatic coagulation system yes is not touched - a normal clotting time.

Literature: W. D. Keidel: Kurzgefaßtes Lehrbuch der Physiologie, Georg Thieme Verlag Stuttgart 1967, page 31: The hemostasis process.

The substances to be examined were used to determine the bleeding time awake mice at a dose of 10 mg / kg p.o. applied. After an hour it was cut off approx. 0.5 mm from the tip of the tail of each animal and the emerging Gently blot blood with a filter paper every 30 seconds. the The number of blood drops obtained in this way gave a measure of the bleeding time (5 animals per Attempt). The following figures represent a percentage increase compared to controls: renewal the bleeding time connection in Z after 1 hour A 145 B 102 C 26 D 76 E 152 F 91 G -5 H 29 I> 300 K 12 L 15 M 27 3. Determination of the positive inotropic effect: Rats were anesthetized with ether and then sacrificed by striking the neck. After opening the thorax, the heart was removed and both atria separated. The atria were transferred to a 100 ml organ bath, the Tyrode's 300C contains, which was oxygenated with 95% 02 and 5 Z C02. The atria struck spontaneously. The contraction force was measured isometrically with a load on the atria from 1 g.

The substances to be tested were in each case with 1 × 10 6 g / ml on 4 Checked atria. The changes in the force of contraction were in% of the initial values determined. The following table contains the results found: substance Increase in the force of contraction in B 30 35 E 16 F 18 I 52 L 63 M 65 4. Acute toxicity: The acute toxicity of the substances to be examined was based on groups of 10 mice each after oral administration of a dose of 1,000 mg / kg (observation time: 14 days): substance acute toxicity per os A> 1 000 mg / kg (0 of 10 animals died) B> 1,000 mg / kg (0 out of 10 animals died) C> 1,000 mg / kg (0 out of 10 animals died) D) 1,000 mg / kg (of 10 animals died) E> 1,000 mg / kg (0 of 10 animals) Animals died) F) 1,000 mg / kg (0 out of 10 animals died) G> 1,000 mg / kg (0 of 10 animals died) H> 1,000 mg / kg (0 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 (0 of 10 animals died) M) 1 000 mg / kg (0 of 10 animals died) on Because of their pharmacological properties, the new compounds are suitable for general formula I for the prophylaxis of thromboembolic diseases such as coronary infarction, Cerebral infarction, so-called transient ischaemic attacks, amaurosis fugax and for prophylaxis arteriosclerosis, and can be used in combination with others Active substances in the usual pharmaceutical preparation forms such as dragees, Incorporate tablets, capsules, suppositories or suspensions. The single dose here is 50 to 100 mg 2 - 3 times a day and the daily dose is 100 - 300 mg.

The following examples are intended to explain the invention in more detail: example 1 6- [4- (2-pyridylmercapto) butoxy] -3,4-dihydrocarbostyril, 14.4 g (0.13 mol) 2-mercaptopyridine and 17.9 g (0.13 mol) of potassium carbonate are dried in 360 ml over molecular sieves Stirred dimethyl sulfoxide and added 36 g (0.12 mol) 6- (4-bromobutoxy) -3,4-dihydrocarbostyril (Melting point: 142 - 147 ° C, made from 6-hydroxy-carbostyril and 1,4-dibromobutane) offset. The mixture is then stirred for 15 hours at approx. 250 ° C., then the reaction mixture is poured in 3.6 l of water and stir for another 30 minutes. The precipitated product is suctioned off, washed well with water, dried and recrystallized from xylene with carbon treatment. Light yellow crystals with a melting point of 123-124.50C are obtained.

Yield: 32 g (81.2% of theory).

Example 2 6- / 4- (2-pyridylsulfinyl) -butox L7-3,4-dihydrocarbostyril 32.8 g (0.1 mol) of 6- [4- (2-pyridylmercapto) butoxy] -3,4-dihydro carbostyril become dissolved in 330 ml of glacial vinegar and with 10.2 g (0.105 mol) of 35% hydrogen peroxide offset. The mixture is stirred for 15 hours at approx. 200 ° C., then distilled at 600 ° C. in vacuo the glacial acetic acid, washes the residue with ether and crystallizes the resultant Crude product 2 times from xylene with charcoal treatment. Colorless crystals are obtained of melting point: 144.5 -1460C.

Yield: 27.5 g (79.8% of theory) Example 3 6-E4- (2-pyridylsulfonyl) -butoxy7-3 4-dihydrocarbostyril 5 g (0.015 mol) 6 - /) - (2-pyridylmercapto) -butox L7-3,4-dihydrocarbostyril are dissolved in 50 ml of glacial acetic acid and mixed with 4.5 g (0.045 mol) of 35% strength hydrogen peroxide offset. The mixture is stirred for 40 hours at approx.

25 ° C, distilled off the glacial acetic acid at 60 ° C in vacuo, washes the solid Residue with ether and recrystallized from xylene with treatment of charcoal. You get colorless crystals with a melting point of 123.8-1250C.

Yield: 3.8 g (70.3% of theory). Example 4 6- (4-Phenylsulfinylbutoxy) -3,4-dihydrocarbostyril 32.6 g (0.2 mole) 6-hydroxy-3,4-dihydrocarbostyril / see F. Mayer et al. in Ber. German chem. Ges. 60, 858 (1927) 7 and 27.6 g (0.2 mol) of potassium carbonate are in 600 ml of dimethyl sulfoxide dried over molecular sieve was stirred for 5 minutes and then with 52.2 g of 4-phenylsulfinylbutyl bromide (0.2 mol) (prepared from thiophenol and 1,4-Dibromobutane and subsequent oxidation with hydrogen peroxide in glacial acetic acid are analogous Example 2; oily substance, solidified when standing in the refrigerator). One lets Stir for 15 hours at 25 ° C. and then pour the reaction mixture into 6 l of water. Afterward The mixture is stirred for a further 30 minutes, the product which has precipitated is filtered off with suction and washed thoroughly with it Water. After drying, it is crystallized from approx. 600 ml while treating with charcoal Xylene around. White crystals with a melting point of 144.5-145.50C are obtained.

Yield: 49 g (71.3% of theory) Example 5 6- (4-Phenylmercapto-butoxy) -3 4-dihydro-carbostyril Prepared analogously to the example 4 from 6-hydroxy-3,4-dihydro-carbostyril and 4- (phenylmercapto) -butyl bromide (bp 0.02 : 96 - 1030C, made from thiophenol and 1,4-dibromobutane).

Melting point: 121.5-123 ° C., yield: 75.6% of theory.

Example 6 6- [4- (2-pyridylmercapto) butoxy] -3,4-dihydrocarbostyril Prepared analogously to Example 4 from 6-hydroxy-3,4-dihydro-carbostyril and 4-phenyl-sulfonyl-butyl bromide (produced from 4- (phenylmercapto) -butyl bromide by oxidation as in the example 3).

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

Example 7 6-j4 (4-fluorophenylmercapto) -butox7-3 4-dihydrocarbostyril Prepared analogously to Example 1 from 6- (4-bromobutoxy) -3,4-dihydrocarbostyril (melting point: 142-147 ° C) and 4-fluorothiophenol.

Melting point: 139-1400 ° C., yield: 93.1% of theory.

Example 8 6- [4- (4-fluorophenylsulfinyl) butoxy] -3,4-dihydrocarbostyril Prepared analogously to Example 2 from 6- / 4- (4-fluorophenylmercapto) butoxy] -3,4-dihydrocarbostyril.

Melting point: 184.5-1860C, yield: 88% of theory.

Example 9 6- / 4- (4-methylphenyl-mercapto) -butoxy7-3.4-dihydrocarbostyril Prepared analogously to Example 1 from 6- (4-chlorobutoxy) -3,4-dihydrocarbostyril (melting point: 174-148 ° C) and 4-methylthiophenol.

Melting point: 120-1210C, yield: 91% of theory.

Example 10 6- [4- (4-methylphenyl-sulfinyl) -butoxy] -3,4-dihydrocarbostyril Prepared analogously to Example 2 from 6-E4- (4-methylphenylmercapto) -butoxy7-3,4-dihydrocarbostyril and hydrogen peroxide.

Melting point: 149.5-150 ° C., yield: 97% of theory.

Example 11 6- [4- (3-methylphenylmercapto) butoxy / -3,4-dihydrocarbostyril Prepared analogously to Example 1 from 6- (4-chlorobutoxy) -3,4-dihydrocarbostyril (melting point: 147 - 1480C) and 3-methylthiophenol.

Melting point: 95-960 ° C., yield: 91% of theory.

Example 12 6- [4- (3-methylphenylsulfinyl) butoxy] -3,4-dihydrocarbostyril Prepared analogously to Example 2 from 6- / 4- (3-methylphenylmercapto) -butoxy7-3,4-dihydrocarbostyril and hydrogen peroxide.

Waxy resin, yield: 95% of theory.

Rf value: 0.48 (thin-layer chromatogram on silica gel - mobile phase: Benzene / ethanol / conc. Ammonia = 75/25/1).

Example 13 6- / 4- (4-chlorophenylmercapto) -butoxy7-3,4-dihydrocarbostyril Prepared analogously to Example 1 from 6- (4-chlorobutoxy) -3,4-dihydro carbostyril (melting point: 147-1480C) and 4-chlorothiophenol.

Melting point: 144-146 ° C., yield: 88% of theory.

Example 14 6- [4- (4-chlorophenylsulfinyl) butoxy] -3,4-dihydrocarbostyril Prepared analogously to Example 2 from 6- [4- (4-chlorophenylmercapto) -butoxy / -3,4-dihydrocarbostyril and hydrogen peroxide.

Melting point: 148-149.5 ° C., yield: 70% of theory.

Example 15 6- [4- (3,4-Dichlorophenylmercapto) -butoxy] -3,4-dihydrocarbostyril Prepared analogously to Example 1 from 6- (4-chlorobutoxy) -3,4-dihydrocarbostyril (melting point: 147-1480C) and 3,4-dichlorothiophenol.

Melting point: 116.5 ° -1180 ° C., yield: 87% of theory.

Example 16 6- [4- (3,4-Dichlorophenylsulfinyl) -butoxy] -3,4-dihydrocarbostyril Prepared analogously to Example 2 from 6- / 4- (3,4-dichlorophenylmercapto) -butoxy7-3,4-dihydrocarbostyril and hydrogen peroxide.

Melting point: 106.5-108 ° C., yield: 74% of theory.

Example 17 6- [4- (2-Methoxyphenylmercapto) butoxy] -3,4-dihydrocarbostyril Prepared analogously to Example 1 from 6- (4-bromobutoxy) -3,4-dihydrocarbostyril (melting point: 142-1470C) and 2-methoxythiophenol.

Melting point: 130.5-1330 ° C., yield: 74% of theory.

Example 18 6- [4- (2-Methoxyphenylsulfinyl) butoxy] -3,4-dihydrocarbostyril Prepared analogously to Example 2 from 6- / 4- (2-methoxyphenylmercapto) -butoxy / -3,4-dihydrocarbostyril and hydrogen peroxide.

Melting point: 162-1630C, yield: 62% of theory.

Example 19 6- [4- (3-Methoxyphenylmercapto) butoxy] -3,4-dihydrocarbostyril Prepared analogously to Example 1 from 6- (4-bromobutoxy) -, 4-dihydrocarbostyril (melting point: 142 - 147 0C) and 3-methoxythiophenol.

Melting point: 93.5-970 ° C., yield: 61% of theory.

Example 20 6- [4- (3-Methoxyphenylsulfinyl) butoxy] -3,4-dihydrocarbostyril Prepared analogously to Example 2 from 6-t4- (3-methoxyphenylmercapto) -butoxy] -3,4-dihydrocarbostyril and hydrogen peroxide.

Melting point: 147-1480C, yield: 49% of theory.

Example 21 6- / 4- (4-methoxyphenylmercapto) -butoxy7-3 t 4-dihydrocarbostyril Prepared analogously to Example 1 from 6- (4-bromobutoxy) -3,4-dihydrocarbostyril (melting point: 142-1470C) and 4-methoxythiophenol.

Melting point: 130.5-133 ° C., yield: 82% of theory.

Example 22 6- [4- (4-Methoxyphenylsulfinyl) butoxy] -3,4-dihydrocarbostyril Prepared analogously to Example 2 from 6-F4- (4-methoxyphenylmercapto) butoxy / -3,4-dihydrocarbostyril and hydrogen peroxide.

Melting point: 132-133 ° C., yield: 71% of theory.

Example 23 6- [4- (3,4-Dimethoxyphenylmercapto) butoxy] -3,4-dihydrocarbostyril Prepared analogously to Example 1 from 3,4-dimethoxythiophenol and 6- (4-chlorobutoxy) -3,4-dihydrocarbostyril (made from 6-hydroxy-carbostyril (see F. Mayer et al. in Ber. dtsch. chem. Ges, 60, 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] -3,4-dihydrocarbostyril Prepared analogously to Example 2 from 6- / 4- (3,4-Dimethoxyphenylmercapto) -butoxy / -3,4-dihydrocarbostyril and hydrogen peroxide.

Melting point: 145-1470C, yield: 79% of theory.

Example 25 6- [4- (3,4-Dimethoxyphenylsulfonyl) butoxy] -3,4-dihydrocarbostyril Prepared analogously to Example 3 from 6- / 4- (3,4-Dimethoxyphenylmercapto) butoxy] -3,4-dihydrocarbostyril and hydrogen peroxide.

Melting point: 158-1600 ° C., yield: 62% of theory.

Example 26 6-t4- (4-biphenylylmercapto) -butoxy2-3,4-dihydrocarbostyril Prepared analogously to Example 1 from 4-phenylthiophenol and 6- (4-bromobutoxy) -3,4-dihydrocarbostyril.

Melting point: 179.5-1810C, yield: 74% of theory.

Example 27 6- / 4- (4-biphenylylsulfinyl) -butoxy / -3,4-dihydrocarbostyril Prepared analogously to Example 2 from 6- / 4- (4-biphenylylmercapto) -butoxy / -3,4-dihydrocarbostyril and hydrogen peroxide.

Melting point: 192-192.50 ° C., yield: 86% of theory.

Example 28 6- / 4- (2-Naphthylmercapto) -butoxy / -3,4-dihydrocarbostyril Prepared analogously to Example 1 from 2-naphthyl mercaptan and 6- (4-bromobutoxy) -3,4-dihydrocarbostyril.

Melting point: 108.5-109.50 ° C., yield: 48% of theory.

Example 29 6-t4- (2-Naphthylsulfinyl) -butoxv7-3 4-dihydrocarbostyril Prepared analogously to Example 2 from 6- / 4- (2-naphthylmercapto) -butoxy / -3,4-dihydrocarbostyril and hydrogen peroxide.

Melting point: 147.5-148.50 ° C., yield: 57% of theory.

Example 30 6- (2-methylmercapto-ethoxy) -3,4-dihydrocarbostyril Prepared analogous to Example 1 in boiling methanol from chloroethoxy) -3,4-dihydrocarbostyril (Melting point: 152.5-1530C) and methyl mercaptan in the presence of potassium methylate.

Melting point: 117.5-118.50C, Yield: So s of theory.

Example 31 6- (2-methylsulfinylethoxy) -3,4-dihydrocarbostyril 1.42 g (0.006 mol) 6- (2-methylmercaptoethoxy) -3,4-dihydrocarbostyril are in 12 ml Suspended methanol and a solution of 1.71 g (0.008 mol) of sodium metaperiodate in 8 ml of water. The mixture is stirred for 1.5 hours, with one at the beginning significant heating of the reaction mixture noticed. Then you dilute with a little Water and extracted exhaustively with chloroform.

The evaporation residue is made from ethyl acetate with the addition of a little ethanol recrystallized.

Melting point: 129-131,500, yield: 70% of theory.

Example 32 6- (4-methylmercaptobutoxy) -3,4-dihydrocarbostyril Prepared analogously to Example 1 from 6- (4-bromobutoxy) -3,4-dihydrocarbostyril and methyl mercaptan.

Melting point: 87-87,500> Yield: 78% 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 6- (4-methylsulfonylbutoxy) -3 4-dihydrocarbostyril Prepared analogously to Example 3 from 6- (4-methylmercaptobutoxy) -3,4-dihydrocarbostyril and hydrogen peroxide.

Melting point: 172.5-17300, yield: 77% of theory.

Example 35 6- (4-Cyclohexylmercaptobutoxy) -3,4-dihydrocarbostyril Prepared analogously to Example 1 from cyclohexyl mercaptan and 6- (4-chlorobutoxy) -3,4-dihydrocarbostyril (Melting point: 147-1480c).

Melting point: 114-1150C, yield: 80% of theory.

Example 36 6- (4-Cyclohexylsulfinyl-butoxy) -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 benzyl mercaptan and 6- (4-chlorobutoxy) -3,4-dihydrocarbostyril.

Melting point: 77.5-78> 50 ° C., yield: 90% of theory.

Example 38 6- (4-Benzylsulfinyl-butoxy) -3,4-dihydrocarbostyril Prepared analogously to Example 2 from 6- (4-benzylmercapto-butoxy) -3,4-dihydrocarbostyril and hydrogen peroxide. Melting point: 141.5-1420C, yield: 95% of theory.

Example 39 6- [4- (2-Furylmethylmercapto) butoxy] -3,4-dihydrocarbostyril Prepared analogously to Example 1 from 2-furfuryl mercaptan and 6- (4-bromobutoxy) -3,4-dihydrocarbostyril (Melting point: 142-147 ° C).

Melting point: 79-80 ° C., yield: 64% of theory.

Example 40 6- [4- (2-Furylmethylsulfinyl) butoxy] -3,4-dihydrocarbostyril Prepared analogously to Example 2 from 6-L4- (2-furylmethylmercapto) -butoxy / -3,4-dihydrocarbostyril and hydrogen peroxide.

Melting point: 135-1360 ° C., yield: 60% of theory.

Example 41 6-t4- (N-oxido-2-pyridylmercapto) -butoxyi-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.

Example 42 6- [4- (2-pyrimidyl-mercapto) -butoxy] -3,4-dihydrocarbostyril Prepared analogously to Example 1 from 6- (4-chlorobutoxy) -3,4-dihydrocarbostyril (melting point: 147-1480C) and 2-mercaptopyrimidine.

Melting point: 154-156 ° C., yield: 79% of theory.

Example 43 6-L4- (2-pyrimidylsulfinyl) -butoxx7-3.4-dihydrocarbostyril Prepared analogously to Example 2 from 6- / 4- (2-pyrimidylmercapto) -butoxy7-3,4-dihydrocarbostyril and hydrogen peroxide.

Melting point: 154-1560C, yield: 36% of theory.

Example 44 6-54- (4-pyridylmercapto) -butoxyffl / -3, 4-dihydrocarbostyril 3.0 g of 6- (4-bromobutoxy) -3,4-dihydrocarbostyril become a solution of 1.3 g of 4-mercaptopyridine added with 2.3 g of 30% sodium methylate solution in 15 ml of methanol and at room temperature Stirred for 14 hours. It is then diluted with 20 ml of water and the precipitated product is crystallized Precipitate from ethanol.

Melting point: 128-1290C, yield: 1.6 g (49 s of theory) example 45 6- [4- (2-Benzimidazolylmercapto) butoxy] -3,4-dihydrocarbostyril Prepared analogously Example 1 from 6- (4-chlorobutoxy) -3,4-dihydrocarbostyril (melting point: 147-1480C) and 2-mercaptobenzimidazole melting point: 100-1030 ° C., yield: 45% of theory.

Example 46 6- [4- (2-Benzimidazolylsulfinyl) butoxy] -3,4-dihydrocarbostyril Prepared analogously to Example 2 from 6- / 4- (2-benzimidazolylmercapto) butoxy] -3,4-dihydrocarbostyril and hydrogen peroxide.

Melting point: 180-1820C, yield: 36% of theory.

Example 47 6- [4- (2-Benzthiazolyl-mercapto) -butoxy] -3,4-dihydrocarbostyril Prepared analogously to Example 1 from 6- (4-chlorobutoxy) -3,4-dihydrocarbostyril (melting point: 147 - 1480C) and 2-mercaptobenzothiazole.

Melting point: 157-1580C, yield: 70% of theory.

Example 48 6- [4- (2-Benzthiazolylsulfinyl) butoxy] -3,4-dihydrocarbostyril Prepared analogously to Example 2 from 6- / 4- (2-benzthiazolylmercapto) -butox-3,4-dihydrocarbostyril and hydrogen peroxide.

Melting point: 183-1840c, yield: 69% of theory.

Example 49 6- (2-Phenylmercapto-ethoxy) -3,4-dihydrocarbonyl Prepared analogous 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: 171-1720C, yield: 84% of theory.

Example 51 6- (2-Phenylsulfonyl-ethoxy) -3,4-dihydrocarbostyril Prepared analogously to Example 3 from 6- (2-phenylmercapto-ethoxy) -3,4-dihydrocarbostyril and hydrogen peroxide.

Melting point: 185-1860C, yield: 94 a of theory.

Example 52 6- (3-Phenylmercapto-propoxy) -5,4-dihydrocarbostyril Prepared analogously to Example 1 from 6- (3-bromopropoxy) -3,4-dihydrocarbostyril (melting point: 111 - 1180C) 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-L3- (phenylmercapto) -propoxt7-3,4-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 dissolved and treated with 4.8 g of a 50% sodium hydride suspension in paraffin oil. After adding 12.5 ml of methyl iodide, the mixture is stirred for 3 hours at room temperature, diluted with water and extracted with chloroform. The evaporation residue is with Recrystallized methanol with the addition of a little activated charcoal.

Melting point: 79.5-80.50 ° C. Yield: 71 fi of theory.

Example 55 1-Methyl-6- (4-phenylsulfinyl-butoxy) -3 4-dihydrocarbostyril Prepared analogously to Example 2 from 1-methyl-6- (4-phenylmercaptobutoxy) -3,4-dihydrocarbostyril and hydrogen peroxide.

Melting point: 82-82.50C, yield: 60% of theory.

Example 56 1-Methyl-6- (4-phenylsulfonyl-butoxy) -3,4-dihydrocarbostyril Prepared analogously to Example 3 from 1-methyl-6- (4-phenylmercaptobutoxy) -3,4-dihydrocarbostyril and hydrogen peroxide.

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 - 10800) and thiophenol.

Melting point: 112.5-1130C, yield: 34% of theory.

Example 58 6- (6-Phenylsulfinyl-hexoxy) -3,4-dihydrocarbostyril Prepared analogously to Example 2 from 6- (6-phenylmercapto-hexoxy) -3,4-dihydrocarbostyriln and hydrogen peroxide.

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

Example 59 6- (2-Hydroxy-3-heny1mercapto-propoxy) -3.4-dihydrocarbostyril 2.10 g (0.03 mol) of potassium methylate are suspended in 40 ml of methanol and 4.11 is added g (0.04 mol) of thiophenol are added, a clear solution being formed. While stirring adds 4.38 g of 6- (2,3-epoxypropoxy) -3,4-dihydrocarbostyril (melting point: 125 - 1280C), which also dissolves with slight self-heating. After about A white crystal pulp begins to separate out in 5 minutes.

After standing overnight, it is filtered off with suction and recrystallized from a little methanol. White crystals with a melting point of 148 ° -1490 ° 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- (2-hydroxy-3-phenylmercaptopropoxy) -3,4-dihydrocarbostyril and hydrogen peroxide.

Melting point: 170-1720C, yield: 54% of theory.

Example 62 7- (4-Phenylmercaptobutox) -3,4-dihydrocarbostyril Prepared analogously to example 4 from 7-hydroxy-3,4-dihydrocarbostyril (N, Shigematsu et al. in Chem. Pharm. Bull. 1961, 970-975) and 4-phenylmercapto-butyl bromide (bp 0.02: 96 - 1030C).

Melting point: 121-1230C, yield: 72% of theory.

Example 63 7- (4-Phenylsulfinyl-butoxy) -3,4-dihydrocarbostyril Prepared analogously to example 4 from 7-hydroxy-3,4-dihydrocarbostyril (N. Shigematsu et al. in Chem. Pharm. Bull. 1961, 970-975) and 4-phenylsulfinylbutyl bromide.

Melting point: 134-1360 ° C., yield: 80% of theory.

Example 64 7- (4-Phenylsulfonyl-butoxy) -3,4-dihydrocarbostyril Prepared analogously to example 4 from 7-hydroxy-3, 4-dihydrocarbostyril (N. Shigematsu et al. in Chem. Pharm. Bull. 1961, 970-975) and 4-phenylsulfonylbutyl bromide Melting point: 178> 5-179.5 ° C., yield: 74% of theory.

Example 65 8- (4-Phenylmercaptobutoxy) -3,4-dihydrocarbostyril Prepared analogously to Example 4 from 8-hydroxy-3,4-dihydrocarbostyril (J. D. Loudon et al. in J. Chem. Soc. 1955, 743-744) and 4-phenylmercapto-butyl bromide (boiling point 0.02: 96-103 ° C).

Melting point: 101-1O20C, yield: 75% of theory.

Example 66 8- (4-Phenylsulfinyl-butoxy) -3,4-dihydrocarbostyril Prepared analogously to Example 4 from 8-hydroxy-3,4-dihydrocarbostyril (J. D. Loudon et al. in J. Chem. Soc. 1955, 743-744) and phenylsulfinylbutyl bromide.

Colorless resin, yield: 60% of theory.

Rf value: 0.60 (thin-layer chromatogram on silica gel - mobile phase: Benzene / ethanol / conc. 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: 114.5-1150 cm Yield: 60% of theory.

Example 68 6- [4- (2-Benzthiazolyl-sulfonyl) -butoxy] -3,4-dihydrocarbostyril Prepared analogously to Example 2 from 6- [4- (2-benzthiazolyl-mercapto) -butoxy] -3,4-dihydrocarbostyril and hydrogen peroxide.

Melting point: 146-1490C, yield: 61% of theory.

Example 69 6- [4- (2-quinolylmercapto) butoxy] -3,4-dihydriccarbostyril Prepared analogously to Example 1 from 6- (4-bromobutoxy) -3,4-dihydrocarbostyril (melting point: 142 - 147 0C) and 2-mercaptoquinoline.

Melting point: 1150 ° C., yield: 64% of theory.

Example 70 6- [4- (2-quinazolin-4-on-yl-mercapto) -butoxy] -3,4-dihydrocarbostyril Prepared analogously to Example 1 from 6- (4-bromobutoxy) -3,4-dihydrocarbostyril (melting point: 142 - 147 ° C) and 2-mercaptoquinazolin-4-one.

Melting point: 185.4-188 ° C., yield: 63% of theory.

Example 71 6- (4-triphenylmethylmercapto-butoxy) -3,4-dihydrocarbostyril Prepared analogously to Example 1 from 6- (4-bromobutoxy) -3,4-dihydro carbostyril (melting point: 142 - 147 ° C) and triphenylmethyl mercaptan.

Melting point: 169-170 ° C., yield: 89% of theory.

Example 72 6- [2- (2-Naphthylmercapto) ethoxy] -3,4-dihydrocarbostyril Prepared analogously to Example 1 from 6- (4-chlorobutoxy) -3,4-dihydrocarbostyril (melting point: 147 - 14R ° C) and 2-naphthyl mercaptan.

Melting point: 147.5-147.8 ° C., yield: 77% of theory.

Example 73 6- [2- (2-Naphthylsulfinyl) ethoxy] -3,4-dihydrocarbonstyril Prepared analogously to Example 2 from 6- / 2- (2-tiaphthylmercapto) ethoxy] -3,4-dihydrocarbostyril and hydrogen peroxide.

Melting point: 186.5-187.5 ° C., yield: 88% of theory.

Example 74 6- [2- (4-Biphenylylmercapto) ethoxy] -3,4-dihydrocarbostyril Provided analogously to Example 1 from 6- (2-chloroethoxy) -3,4-dihydrocarbostyril (melting point: 152.5-153.5 ° C) and 4-mercaptobiphenyl.

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

Example 75 6- [2- (4-Biphenylyl-sulfinyl) -ethoxy] -3,4-dihydrocarbostyril Prepared analogously to Example 2 from 6- [2- (4-biphenylylmercapto) ethoxy] -3,4-dihydrocarbostyril and hydrogen peroxide.

Melting point: 195-196 ° C, yield: 66% of theory.

Example 76 6- [3- (2-Pyridylmercapto) propoxy] -3,4-dihydrocarbostyril Prepared analogously to Example 1 from 6- (3-bromopropoxy) -3,4-dihydrocarbostyril and 2-mercaptopyridine.

Melting point: 108-108 ° C., yield: 42% of theory, example 77 6- (4-phenylsulfinyl-butoxy) -3,4-dihydrocarbostyril 1.6 g of 6- (3-phenylmercapto-butoxy) -3,4-dihydrocarbostyril are dissolved in 50 ml of methanol and treated with 0.9 g of N-bromosuccinimide.

The mixture is stirred at room temperature for 15 hours, diluted with 500 ml of hot water at 800C and decanted from the oily residue which gradually grows crystallized through. After recrystallization from xylene, white crystals are obtained from melting point 144 - 1450C.

Yield: 1.2 g (66% of theory).

Example 78 6- (4-Phenylsulfinyl-butoxy) -3,4-dihydrocarbostyril 3.3 g of 6- (4-phenylmercapto-butoxy) -3,4-dihydrocarbostyril are dissolved in 50 ml of methylene chloride dissolved, cooled to -70 ° C and then with a solution of 1.5 g of sulfuryl chloride added dropwise in 5 ml of methylene chloride. After 15 hours, 20 ml of 95% ethanol and warmed to room temperature by removing the cooling bath. It is neutralized with aqueous soda solution, and the methylene chloride phase is dried with it Sodium sulfate, the solvent evaporates and the residue crystallizes out Toluene around.

Melting point: 143-145 ° C.

Yield: 2.8 g (81% of theory).

Example 79 t ;- (4-Phenylmercapto-butoxy) -3, 4-dihydrocarbost, rril 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-di-lydrocarbostyril prepared analogous to example 4 from 5-hydroxy-3,4-dihydrocarbostyril and 4-phenylsulfi.nylbutyl bromide.

Melting point: 136-138 ° C., yield: 64% of theory example 81 5- (4-Phenylsulfonyl-butoxy) -3.4-dihydrocarbostyril Prepared analogously to the example 4 from 5-hydroxy-3,4-dihydrocarbostyril and 4-phenylsulfonylbutyl bromide.

Melting point: 187-1890C, yield: 73% of theory.

Example 82 6- [4- (2-Naphthylsulfonyl) butoxy] -3,4-dihydrocarbostyril Prepared analogously to Example 3 from 6- / 4- (2-naphthylmercapto) butoxy] -3,4-dihydrocarbostyril and hydrogen peroxide.

Melting point: 173-1750C, yield: 95% of theory.

Example 83 6- L4- (4-biphenylylsulfonyl) -butox / -3,4-dihydrocarbostyril Prepared analogously to Example 3 from 6- / 4- (4-biphenylylmercapto) -butoxy / -3,4-dihydrocarbostyril and hydrogen peroxide.

Melting point: 232-234.50 ° 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. Melting point: 157-1580C, yield: 88% of theory. Example 85 6- [4- (2-Pyridylsulfonyl) -butoxy] -3,4-dihydrocarbostyril Prepared analogously to Example 3 from 6-F4- (2-pyridylsulfinyl) butoxy] -3,4-dihydrocarbostyril and hydrogen peroxide.

Melting point: 123.8-125 ° C.

Yield: 76% of theory.

Example 86 5- (4-phenylsulfonyl-butoxy) -carbostyril 1.8 g of 5- (4-phenylsulfonyl-butoxy) -3,4-dihydrocarbostyril are dissolved in 45 ml of dioxane, and 1.87 g of 2,3-dichloro-5,6-dicyanobenzoquinone are added and heated to boiling in an oil bath for 2.5 hours. It is filtered hot and washed the insoluble residue formed during the reaction with hot Dioxane.

The combined filtrates are diluted with 100 ml of chloroform and shaken out 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 charcoal is concentrated and mixed with ethyl acetate until deposit white crystals.

Melting point: 182-1830C, yield: 850 mg (47% of theory) example 87 5- (4-Phenylmercapto-butoxy) -carbostyril Prepared analogously to Example 86 from 5- (4-phenylmercapto-butoxy) -3,4-dihydrocarbostyril and 2,3-dichloro-5,6-dicyano-benzoquinone.

Melting point: 185-187 ° C., yield: 40% of theory.

Example 88 5- (4-phenylsulfinyl-butoxy) -carbostyril 0.56 g of 5- (4-phenylmercapto-butoxy) -carbostyril 0.165 ml of 30% hydrogen peroxide, dissolved in 8 ml of glacial acetic acid, are added, diluted with water and extracted twice with chloroform. The chloroform extract is washed with dilute soda solution, with water, dried over magnesium sulfate and narrowed. After addition of ethyl acetate, colorless crystals with a melting point are obtained 155-1570C.

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-4,5-dicyano-benzoquinone.

Melting point: 162-1640C, yield: 35% of theory.

Example 90 6- (4-Phenylsulfinyl-butoxy) -carbostyril Prepared analogously Example 86 from 6- (4-phenylsulfinyl-butoxy) -3,4-dihydrocarbostyril and 2,3-dichloro-5,6-dicyano-benzoquinone.

For cleaning, a silica gel column with a mixture of benzene / ethanol / conc. Ammonia = 75/25/3 chromatographed.

Melting point: 181-182.50 ° C., yield: 48% of theory.

From the first fractions of the column chromatography is isolated in a yield of 15% of theory 6- (4-phenylmercapto-butoxy) -carbostyril vom Melting point 162-1640C.

Example 91 5- (4-Phenylsulfonyl-butoxy) -carbostyril Prepared analogously Example 86 from 6- (4-phenylsulfonyl-butoxy) -3,4-dihydrocarbostyril and 2,3-dichloro-5,6-dicyano-benzoquinone.

The purification is carried out by column chromatography on silica gel (grain size: 0.2-0.5 mm) with chloroform / methanol / ethyl acetate = 4 / i / 1.

Melting point: 212-2130C, yield: 54% of theory.

Example 92 5- (4-Phenylmercapto-butoxy) -carbostyril A mixture from 32.3 g of 5-hydroxycarbostyril, 30 g of potassium carbonate and 650 ml over molecular sieve 49 g of 4-phenyl mercaptobutyl bromide are added to dried dimethyl sulfoxide. The mixture is stirred for 20 hours at 250C, diluted with 3 liters of water and sucked the crystallized Reaction product from.

Melting point: 185-1870C (from toluene), yield: 45.0 g (70% of Theory).

Example 93 5- (4-Phenylsulfonyl-butoxy) -carbostyril Prepared analogously Example 88 from 5- (4-phenylmercapto-butoxy) -carbostyril and 4 moles of hydrogen peroxide at a temperature of 600C and a reaction time of 14 hours.

Melting point: 182-1830C, yield: 73% of theory.

Example 94 6- (4-Phenylmercapto-butoxy) -carbostyril Prepared analogously Example 92 from 6-hydroxycarbostyril and 4-phenyl mercaptobutylbromid.

Melting point: 161-1630C, 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: 181-1820 ° C., yield: 68% of theory.

Example 96 6- (4-Phenylsulfinyl-butoxy) -carbostyril Prepared analogously Example 92 from 6-hydroxycarbostyril and 4-phenylsulfinylbutyl bromide Melting point: 181-1820C, yield: 71% of theory 0 Example 97 7- (4-Phenylsulfinyl-butoxy) -carbostyril Prepared analogously to Example 86 from 7- (4-phenylsulfinyl-butoxy) -3,4-dihydrocarbostyril.

Melting point: 193-1940C, yield: 51% of theory.

Example 98 8- (4-Phenylsulfinyl-butoxy) -carbostyril Prepared analogously Example 86 from 8- (4-phenylmercapto-butoxy) = 3,4-dihydrocarbostyril and 2,3-dichloro-5,6-dicyano-benzoquinone.

Melting point: 119-120 ° C., yield: 40% of theory.

Example 99 8- (4-Phenylsulfinyl-butoxy) -carbostyril Prepared analogously Example 88 from 8- (4-phenylmercaptobutoxy) -carbostyril by oxidation with hydrogen peroxide Melting point: 125.5-126.50C, yield: 60% of theory.

Example 100 5- (4-Phenylsulfonyl-butoxy) -carbostyril 100 mg 5- (4-Phenylsulfonyl-butoxy) -3,4-dihydrocarbostyril are refluxed with 30 mg palladium / charcoal and 1 ml mesitylene. After 3.5 hours further 30 mg palladium / carbon are added and a further 9 hours heated. 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. In addition to unreacted starting material, 9 mg of 5- (4-phenylsulfonyl-butoxy) -carbostyril are obtained from melting point 182-1830C.

Example 101 6- (4-Amino-iminomethylmercapto-butoxy) -3,4-dihydrocarbostyril 18 g of 6- (4-bromobutoxy) -3,4-dihydrocarbostyril are added together with 5 g of thiourea in 250 ml of water heated to the boil until everything has dissolved (approx. 4 hours). After cooling, the impurities are extracted with chloroform and makes it alkaline with ammonia. The precipitated crystals are filtered off with suction and dried.

Melting point: 140 - 141.80C, melting point of the hydrochloride: 208 - 2110C, yield: 90% of theory.

Example 102 6-t4-mercaptobutoxy) -3,4-dihydrocarbostyril 9 g of 6- (4-amino-iminomethylmercapto-butoxy) -3,4-dihydrocarbostyril are boiled in 200 ml of 2N sodium hydroxide solution under nitrogen for 2 hours Heated to reflux. After cooling, it is diluted with 600 ml of water and acidified with concentrated hydrochloric acid. The crystallized substance is washed with water, vacuumed and dried.

Melting point: 130.5-134 ° C., yield: 50% of theory.

Example 103 6- (4-Benzylmercapto-butoxy) -3,4-dihydrocarbostyril 2.5 g 6- (4-mercaptobutoxy) -3,4-dihydrocarbostyril> dissolved in 25 ml dimethyl sulfoxide, are stirred with 1.4 g of potassium carbonate and then with 1.3 ml of benzyl chloride offset. After 15 hours of stirring at room temperature, it is diluted with 200 ml of water, separates the oily substance which has separated off and recrystallizes from ethyl acetate.

Melting point: 76-780 ° C., yield: 2.8 g (82% of theory).

Example 104 6- (5-PhenylmercaPtopentoxy) -3.4-dihydrocarbostyril Prepared analogously to Example 1 from 6- (5-bromopentoxy) -3,4-dihydrocarbostyril and thiophenol.

Melting point: 117-119 ° C., yield: 71 s of theory.

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: 104-109.50 ° C., yield: 66% of theory.

Example 106 6- (5-Phenylsulfinyl-pentoxy) -3,4-dihydrocarbostyril Prepared analogously to Example 3 from 6- (5-phenylmercapto-pentoxy) -3,4-dihydrocarbostyril and hydrogen peroxide.

Melting point: 136.5-137.80C, yield: 62% of theory.

Example 107 6- / 5- (2-pyridyl-mercapto) -pentoxyj-3 .4-dihydrocarbostyril Prepared analogously to Example 1 from 6- (5-bromopentoxy) -3,4-dihydrocarbostyril and 2-mercaptopyridine.

Melting point: 113-114.8 ° C., yield: 76% of theory.

Example 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 Thiophenpol.

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

Example 109 5- (2-Hydroxy-3-phenylsulfinyl-propoxy) -3,4-dihydrocarbostyril Prepared analogously to Example 2 from 5- (2-hydroxy 30phenyl mercaptopropoxy) -3,4-dihydrocarbostyril and hydrogen peroxide.

Melting point: 186-1880C, yield: 60% of theory.

Example 110 5- (2-Hydroxy-3-phenylsulfinyl-propoxy) -3,4-dihydrocarbostyril Prepared analogously to Example 3 from 5- (2-hydroxy-3-phenylmercaptopropoxy) -3,4-dihydrocarbostyril and hydrogen peroxide, melting point: 168-1700C, yield: 53% of theory.

Example 111 6- [4- (4-Hydroxyphenylmercapto) butoxy] -3,4-dihydrocarbostyril Prepared analogously to Example 1 from 6- (4-bromobutoxy) -3,4-dihydrocarbostyril and 4-hydroxythiophenol.

Melting point: 191.5-193.0 ° C., yield: 83% of theory.

Example 112 6- [4- (4-Hydroxyphenylsulfinyl) butoxy] -3,4-dihydrocarbostyril Manufactured analogously to Example 2 from 6- [4- (4-hydroxyphenylmercapto) butoxy / -3,4-dihydrocarbostyril and hydrogen peroxide.

Melting point: 206-207.80C, yield: 84% of theory.

Example 113 6- [4- (4-Hydroxyphenylsulfonyl) butoxy] -3,4-dihydrocarbostyril Prepared analogously to Example 3 from 6- / 4- (4-hydroxyphenylmercapto) -buto7-3,4-dihydrocarbostyril and hydrogen peroxide.

Melting point: 219-219.5 ° C., yield: 78% of theory.

Example 114 6- [4- (4-Acetaminophenylmercapto) butoxy] -3,4-dihydrocarbostyril Prepared analogously to Example 1 from 6- (4-bromobutoxy) -3,4-dihydrocarbostyril and 4-acetaminothiophenol.

Melting point: 162.5-163.00C, yield: 65% of theory.

Example 115 5- [4- (4-Acetaminophenylsulfinyl) butoxy] -3,4-dihydrocarbostyril Prepared analogously to Example 2 from 6- [4- (4-acetaminophenylmercapto) butoxy] -3,4-dihydrocarbostyril and hydrogen peroxide.

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

Example 116 6- [4- (4-Acetaminophenylsulfonyl) butoxy] -3,4-dihydrocarbostyril Prepared analogously to Example 3 from 6- [4- (4-acetaminophenylmercapto) -butoxy7-3,4-dihydrocarbostyril and hydrogen peroxide.

Melting point: 143.5-147.00C, yield: 88% of theory.

Example 117 6- [4- (4,5-Di-p-chlorophenyl-oxazol-2-yl-mercapto) -butoxy] -3,4-dihydrocarbostyril Prepared analogously to Example 1 from 6- (4-bromobutoxy) -3,4-dihydrocarbostyril and 2-mercapto-4,5-di-p-chlorophenyl oxazole.

Melting point: 110-1150C, yield: 70% of theory.

Example 118 6- [4- (2-pyridylsulfinyl) butoxy] carbostyril Prepared analogously to Example 86 from 6-fl4- (2-pyridylsulfinyl) -butoxy / -3,4-dihydrocarbostyril and 2,3-dichloro-5,6-dicyano-benzoquinone.

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

Example 119 6- (4-Phenylsulfonyl) -butoxy-3,4-dihydrocarbostyril 107 mg 6- (4-phenylsulfonyl) -butoxy-carbostyril are suspended in 15 ml methanol, mixed with 40 mg palladium / carbon and at 500C and a hydrogen pressure hydrogenated at 2.5 bar for 14 hours. After filtering off the catalyst and concentrating the clear solution gives colorless crystals.

Melting point: 153-154 ° C., yield: 89 mg (83% of theory).

Example 120 6- (4-Phenylmercapto-butoxy) -3,4-dihydrocarbostyril Prepared analogously to Example 119 from 6- (4-phenylmercapto-butoxy) -carbostyril by catalytic Hydrogenation with rhenium VII sulfide as a catalyst.

Melting point: 121-122 ° C., yield: 67% of theory.

Example 121 6- [5- (2-Pyridylsulfinyl) pentoxy] -3,4-dihydrocarbostyril Prepared analogously to Example 2 from 6- [5- (2-pyridylmercapto) pentox-3,4-dihydrocarbostyril and hydrogen peroxide.

Melting point: 116-1180C, yield: 69% of theory.

Example 122 6- [5- (2-Pyridylsulfonyl) pentoxy] -3,4-dihydrocarbostyril Prepared analogously to Example 3 from 6- [5- (2-pyridylmercapto) -pentox-3,4-dihydrocarbostyril and hydrogen peroxide.

Melting point: 113.5-115.0 ° C., yield: 71% of theory.

Example 123 8- (4-Phenylsulfonyl-butoxy) -carbostyril Prepared analogously Example 86 from 8- (4-phenylsulfonyl-butoxy) -3,4-dihydrocarbostyril and 2,3-dichloro-5,6-dicyano-benzoquinone.

Melting point: 146-1470C, yield: 41% of theory.

Example 124 7- (4-Phenylmercapto-butoxy) -carbostyril Prepared analogously Example 86 from 7- (4-phenylmercaptobueoxy) -3,4-dihydrocarbostyril and 2,3-dichloro-5,6-dicyano-benzoquinone.

Melting point: 157.5-158.5 ° C., yield: 54% of theory.

Example 125 7- (4-Phenylsulfonyl-butoxy) -carbostyril Prepared analogously Example 3 from 7 (4 = phenylmercaptobutoxy) carbostyril and hydrogen peroxide.

Melting point: 199-2010C, yield: 85% of theory.

Example A Tablets containing 100 mg of 6- [4- (2-pyridylsulfinyl) butoxy] -3,4-dihydrocarbostyril Composition: 1 tablet contains: active ingredient 100.0 mg lactose 80.0 mg corn starch 34.0 mg polyvinylpyrrolidone 4.0 mg magnesium stearate 2.0 mg 220.0 mg Manufacturing process: Active ingredient, milk sugar and starch are mixed and mixed with an aqueous solution of the polyvinylpyrrolidone evenly moistened.

After sieving the moist mass (2.0 mm mesh size) and drying in the rack drying cabinet at 500C it is sieved again (1.5 mm mesh size) and that Added lubricant.

The ready-to-press mixture is processed into tablets.

Tablet weight: 220 mg Diameter: 10 mm, biplane with bilateral Facet and one-sided dividing notch.

Example B Coated tablets with 50 mg of 6- (4-phenylsulfinylbutoxy) -3 4-dihydrocarbostyril 1 tablet core contains: active ingredient 50.0 mg lactose 40.0 mg corn starch 17.0 mg polyvinylpyrrolidone 2.0 mg magnesium stearate 4 s0 mg 110.0 mg Production: the granulate was prepared analogously to Example A.

The ready-to-press mixture is processed into tablet cores.

Core weight: 110 mg. Diameter: 8 mm, biconvex.

The cores are in the coating pan after isolation with a polyvinylpyrrolidone layer and a common sugar coating suspension up to 200 mg and then coated coated with pure sugar syrup to 210 mg.

Example C Hard gelatin capsules with 100 mg 6- / 4- (2-pyridylsulfinyl) -butox L7-3 , 4-dihydrocarbostyril 1 capsule contains: Active ingredient 100.0 mg corn starch sep. approx. 130.0 mg powdered milk sugar approx. 87.0 mg magnesium stearate 3.0 mg approx. 320.0 mg Production: The active ingredient is mixed with the excipients through a sieve of 0.75 mm mesh size given and mixed homogeneously in a suitable device.

The final mixture is filled into size 1 hard gelatine capsules.

Capsule filling: approx. 320 mg Capsule shell: hard gelatin capsule size 1.

Example D Suppositories containing 150 mg of 6- (4-phenylsulfinylbutoxy) -3,4-dihydro carbostyril 1 suppository contains: active ingredient 150.0 mg polyethylene glycol 1500 550.0 mg polyethylene glycol 6000 460.0 mg polyoxyethylene sorbitan monostearate 840.0 mg 2 000.0 mg Production: After the suppository mass has melted, the active ingredient is homogeneously distributed in it and the melt poured into pre-cooled molds.

Example E Suspension with 50 mg of 6- [4- (2-pyridylsulfinyl) butoxy] -3,4-dihydrocarbostyril per 5 ml 100 ml suspension contain: Active ingredient 1.0 g carboxymethyl cellulose sodium salt 0.1 g methyl p-hydroxybenzoate 0.05 g propyl p-hydroxybenzoate 0.01 g cane sugar 10.0 g glycerine 5> 0 g sorbitol solution 70% 20.0 g flavor 0.3 g water least. ad 100 ml Production: Distilled water is heated to 700C. Here, p-hydroxybenzoic acid methyl ester and propyl ester as well as Glycerine and carboxymethyl cellulose sodium salt dissolved. It gets to room temperature cooled and the active ingredient added with stirring and homogeneously dispersed. To Adding and dissolving the sugar, the sorbitol solution and the flavor becomes the suspension evacuated with stirring for venting.

5 ml of suspension contain 50 mg of active ingredient.

Claims (22)

P atent claims 1. New carbostyril derivatives of the general formula in which A and B each have a hydrogen atom or together a further bond, D a straight-chain or branched alkylene group with 2 to 6 carbon atoms, optionally substituted by a hydroxyl group, R1 a hydrogen atom or an alkyl group with 1 to 3 carbon atoms, R2 a hydrogen atom, an alkyl group with 1 to 6 carbon atoms, a cycloalkyl group with 3 to 6 carbon atoms, an aryl group with 6-10 carbon atoms, an aralkyl group with 7-11 carbon atoms, a heteroarylo group with 4-9 carbon atoms or a heteroaralkylo group with 5-10 carbon atoms, the above The aromatic nuclei listed above can be mono- or disubstituted by methyl, methoxy, hydroxy, acetylamino, phenyl groups and / or halogen atoms and / or N atoms of the heteroaromatic nuclei listed above can be converted into their N ° oxides, the triphenylmethyl, 4.5 -Bis- (p-chlorophenyl) -oxazol-2-yl or amino-iminomethyl group and m is the number O, 1 or 2. 2. New carbostyril derivatives of the general formula I according to claim 1, in which A, B, D, R1 and m are as defined in claim 1 and R2 is a hydrogen atom, an alkyl group with 1 to 6 carbon atoms, a cycloalkyl group with 3-6 carbon atoms, a phenyl group, which is replaced by a halogen atom, a methyl, hydroxy, acetylamino and / or methoxy group can be mono- or disubstituted, a benzyl, naphthyl, Biphenyl, triphenylmethyl, pyridyl, N-oxido-pyridyl, pyrimidyl, furfuryl, Benzimidazolyl-, benzthiazolyl-, quinolyl-, quinazolin-4-on-yl-, 4,5-bis- (p-chlorophenyl) -oxazol-2-yl- or is an amino-iminomethyl group. 3. New carbostyril derivatives of the general formula I according to claim 1, in which A and B each have a hydrogen atom or together a further bond, D a straight-chain alkylene group optionally substituted by a hydroxyl group with 2 to 6 carbon atoms, R1 is a hydrogen atom or the methyl group, R2 a methyl, cyclohexyl, phenyl, fluorophenyl, chlorophenyl, methylphenyl, hydroxyphenyl, Methoxyphenyl, acetylaminophenyl, dichlorophenyl, dimethoxyphenyl, benzyl, biphenylyl, Triphenylmethyl, naphthyl, pyridyl,, pyridyl-1-oxide, furfuryl, pyrimidyl, benzimidazolyl, Quinolyl, quinazolin-4-on-yl or benzthiazolyl group and m is the number 0, 1 or 2 mean. 4. 6- (4-Phenylsulfinylbutoxy) -3,4-dihydro-carbostyril. 5. 6- / 4- (2-Pyridy 18ulfinyl) -butoxy / -3,4-dihydro-carbostyril. 6. 6- / 4- (4-chlorophenylsulfinyl) -butoxS 3,4-dihydro-carbostyril. 7. 6- (4-Phenylsulfinyl-butoxy) -carbostyril 8. Medicinal products containing a compound of the general formula I according to claim 1 in addition to one or more inert carriers or diluents. 9. Use of a compound of the general formula I according to claim 1 for the manufacture of a remedy for thrombo-embolic diseases on a non-chemical basis Path. 10. Process for the preparation of new carbostyril derivatives of the general formula in which A and B each have a hydrogen atom or together a further bond, D a straight-chain or branched alkylene group with 2 to 6 carbon atoms, optionally substituted by a hydroxyl group, R1 a hydrogen atom or an alkyl group with 1 to 3 carbon atoms, R2 a hydrogen atom, an alkyl group with 1 to 6 carbon atoms, a cycloalkyl group with 3 to 6 carbon atoms, an aryl group with 6 to 10 carbon atoms, an aralkyl group with 7 to 11 carbon atoms, a heteroaryl group with 4 to 9 carbon atoms or a heteroaralkyl group with 5 to 10 carbon atoms, the above-mentioned aromatic Nuclei mono- or disubstituted by methyl, methoxy, hydroxy, acetylamino, phenyl groups and / or halogen atoms and / or N atoms of the heteroaromatic nuclei listed above can be converted into their N-oxides, the triphenyl, 4,5 -Bis- (chlorophenyl) -oxazol-2-yl or amino-iminomethyl group and m means the number 0, 1 or 2 th, characterized in that a) a hydroxycarbostyril of the general formula in which A, B and R1 are as defined at the beginning, or their salts with inorganic or tertiary organic bases with a compound of the general formula Z - D - SOm - R2 (III) in which D, R2 and m are as defined and Z represents a nucleophilically exchangeable group such as a halogen atom or a sulfonic acid ester radical, or b) for the preparation of compounds of the general formula I in which m represents the number 1 or 2, a carbostyril of the general formula in which A, B, D, R1 and R2 are as defined at the outset and n represents the number 0 or 1, is oxidized or c) for the preparation of a carbostyril of the general formula I, in which n represents the number 0, a carbostyril of the general formula in which A, B, D and R1 are as defined at the outset, with a compound of the general formula Y - R2, (VI) in which R2 is as defined at the outset and one of the radicals X or Y in the compounds of the general formulas V and VI the mercapto group and the other of the radicals X or Y represents a nucleophilically exchangeable group such as a halogen atom or a sulfonic acid ester radical, or d) for the preparation of a carbostyril of the general formula I, in which R1 is not a hydrogen atom, a carbostyril of the general formula in which A, B, D, R2 and m are as defined at the beginning or its alkali salt with a compound of the general formula Z - R1, (VIII) in which R1 is as defined and Z is a nucleophilically exchangeable group such as a halogen atom or a sulfonic acid ester residue represents, is reacted or e) for the preparation of a carbostyril of the general formula I, in which A and B together represent a further bond, a 3,4-dihydrocarbostyril of the general formula in which D, R1, R2 and m are as defined at the outset, is dehydrogenated or f) for the preparation of a 3,4-dihydrocarbostyril of the general formula I, in which A and B each represent a hydrogen atom and m represents the number 0 or 2 , a carbostyril of the general formula in which R1 'R2, D and m are as defined at the outset, is hydrogenated and the desired £ all a compound of the general formula I obtained according to the invention, in which R2 is the aminoiminomethyl group and m is the number 0, then by hydrolysis into a corresponding compound of the general Formula I, in which R2 represents a hydrogen atom, is carried over. 11. The method according to claim 10a, characterized in that the Reaction in a solvent and at temperatures between OOC and the boiling point the solvent used, for example at temperatures between 0 and 100 ° C, however, it is preferably carried out at temperatures between 10 and 50 ° C. 12. The method according to responses 10a and 11, characterized in that that the reaction is carried out in the presence of an alkali base. 13. The method according to claim lOb, characterized in that the Reaction carried out in a solvent and at temperatures between -800 and 1000C will. 14. The method according to claims lOb and 13, characterized in that that for the preparation of a compound of the general formula I in which m is the number 1 represents the oxidation with one equivalent of the oxidizing agent in question and is preferably carried out at temperatures between -80 and 60 ° C. 15. The method according to claims lOb and 13, characterized in that that for the preparation of a compound of the general formula I in which m is the number 2 represents the oxidation with one or two equivalents of the oxidizing agent in question and is preferably carried out at temperatures between -80 and 1000C. 16. The method according to claim 10c, characterized in that the Reaction in a solvent and at temperatures between OOC and the boiling point of the solvent used, e.g. at temperatures between 0 and 1000C, preferably but at temperatures between 10 and 500C. 17. The method according to claims 10c and 16, characterized in that that the reaction is carried out in the presence of an alkali base. 18. The method according to claim 10d, characterized in that the Reaction in a solvent and at temperatures between 0 and 50 ° C., preferably but at temperatures between 10 and 250C. 19. The method according to claims 10d and 18, characterized in that that the alkylation with an alkyl halide or dialkyl sulfate in the presence of a Alkali base, alkali hydride or alkali alcoholate is carried out. 20. The method according to claim 10e, characterized in that the Dehydration in a solvent at elevated temperatures, e.g. at temperatures between 100 and 2000C, but preferably at the boiling point of the one used Solvent. 21. The method according to claims 10e and 20, characterized in that that the dehydrogenation in the presence of an oxidizing agent or a noble metal catalyst is carried out. 22. The method according to claim lOf, characterized in that the Hydrogenation in a solvent in the presence of a hydrogenation catalyst Temperatures between 0 and 50 ° C., but preferably at room temperature, and at a hydrogen pressure of 1 to 5 bar is carried out.