FI70408C - FRAMEWORK FOR THERAPEUTIC ACTIVATION OF ACTIVE THERAPEUTIC CARBOSTYRILDERIVAT - Google Patents

Description

[7 ^ 7] rBl ANNOUNCEMENT 70408

™ (11) UTLÄGGNINGSSKRIFT 'U

C (45) Patent roOanetty

Patent .reJdel ^ t 13 CO 1C2C

/ 51 \ κν 1) (4i | ntci · C 07 D 227/087, 401/12

Kv.lk./Int.CI. // C 07 0 215/22, 209/34 (21) Patent application - Patentansökning 792426 (22) Filing date - Ansökningsdag 03.08.79 (F ») (23) Starting date - Giltighetsdag 03.08.79 (41) Published public - Blivic offentlig Q1 gj

National Board of Patents and Registration ^ Date of visitation and publication. - 27 03 86

Patent- oeh registerstyrelsen '' Ansökan utlagd och utl.skriften publicerad '-3 * (86) Kv. application Int. ansökan (32) (33) (31) Claim claimed privilege - Begärd priority 1 4.07.79 German Federal Republic of Germany and Germany (DE) P 2928583.4 (71) Dr. Karl Thomae Gesellschaft mit beschränkter Haftung, Biberach an der Riss, Germany 1 (F)) (72) Erich Muller, Biberach, Germany (74) Lei tz Inger Oy (54) of therapeutic active carbostyrates (61) Addition to patent 69064 - Tillägg till patent 69064

Patent 69064 already describes e.g. processes for the preparation of carbostyril derivatives of general formula I 3 1x7 ° - · "

R1 R4 wherein W is a vinylene group or an ethylene group optionally substituted by a methyl group, D is a straight-chain or branched alkylene group having 2 to 6 carbon atoms, a straight-chain or branched hydroxyalkylene group having 3 to 6 carbon atoms, or a xylylene group, m is 0, 1 or 2,

R 1 is a hydrogen atom or an α1 alkyl group having 1 to 3 carbon atoms, 2 70408 1 * 2 is a cycloalkyl group having 3 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 11 carbon atoms, one nitrogen atom and / or one oxygen or sulfur atom or a heteroaryl group containing 4 to 9 carbon atoms having 4 to 9 carbon atoms, or a heteroaralkyl group having 5 to 10 carbon atoms, wherein the above-mentioned aromatic rings may be mono- or disubstituted by an alkyl group having 1 to 4 carbon atoms, hydroxy, methoxy, amino -, acetylamino, nitro, carboxyl, cyclohexyl, phenyl group or halogen atom and in addition the above-mentioned monosubstituted phenyl group having 1 to 4 carbon atoms alkyl group and / or halogen atom (where the substituents of the phenyl core may be the same or different), 1.2 , A 4-triazolyl, triphenylmethyl, 4,5-bis- (p-chlorophenyl) oxazol-2-yl, N-methylcyclohexylaminocarbonylmethyl or aminoiminomethyl group or also an alkyl group having 1 to 6 carbon atoms when j oko m is the number 1 or D is a straight-chain or branched hydroxyalkylene group having 3 to 6 carbon atoms or a xylylene group,

R and R., which may be the same or different, mean 3 4 J

hydrogen or halogen atoms, alkyl groups having 1 to 4 carbon atoms, amino, acetylamino or nitro groups.

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

It has now been found that carbostyril of the general formula I can also be prepared by the following methods: a) Cyclization of any compound of the general formula II formed in the reaction mixture 3 ° r3 70408

z - C - HyV

Air0- '··· ™

H - N

* R 4 in R 1 and D, W, R 11 to R 4 and m have the same meaning as above and 14 Z is a nucleophilic leaving group such as a hydroxy group, a halogen atom. alkoxy. aryloxy or aralkoxy group.

The cyclization is best carried out in the presence of a condensing agent such as sulfuric acid, concentrated hydrochloric acid, phosphoric acid or thionyl chloride, conveniently in a solvent such as glacial acetic acid. tetrahydrofuran. in dioxane, chloroform, toluene, ethanol or an excess of the condensing agent used, at elevated temperatures, for example at temperatures between 50 and 200 ° C, but preferably at temperatures between 80 and 150 ° C. However, the reaction can also be carried out without a solvent and / or a condensing agent.

The compound of general formula II used as starting material does not need to be isolated. This can often be prepared from the corresponding nitro compound in situ, for example by reducing the nitro group with hydrogen in the presence of a hydrogenation catalyst such as palladium / carbon, palladium / calcium carbonate or palladium / calcium carbonate + lead acetate (Lindlar's catalyst), reduction with metals such as iron or iron. , by treatment with salts such as ferrous sulfate, stannous chloride, chromium (II) chloride or sodium dithionite, or by reduction with hydrazine in the presence of Raney nickel.

If m in the corresponding nitro compound m is 1, the reduction of the nitro group is conveniently carried out with an equivalent amount of the required reducing agent, for example a metal salt such as ferric sulphate, stannous chloride, chromium (II) chloride 11a or sodium dithionite or hydrogen deactivated in the presence of a hydrogenation catalyst, for example palladium / calcium carbonate + lead acetate 4 70408. If the reduction is carried out, for example, in the presence of palladium / carbon, then the sulfoxide group is also partially reduced.

If in the corresponding nitro compound W represents a vinylene group, this group can be hydrogenated to the corresponding ethylene group, especially when the reduction is carried out with catalytically activated hydrogen, for example hydrogen in the presence of palladium / carbon.

(b) For the preparation of compounds of general formula I in which m is the number 2:

Carbostyril of general formula III R3 H-. , 1 - O - D - Y (III) in D, W, R 1, and R 2 are as defined above and Y is a nucleophilically exchangeable group such as a halogen atom or a sulfonic acid ester group, for example chlorine, bromine, an iodine atom, a p-toluenesulfonyloxy or methanesulfonyloxy group, is reacted with a metal salt of general formula IV

Me ^ ^ SO2 - R2 (IV) wherein R2 is as defined above and

Me is an alkali or alkaline earth / 2 metal atom such as sodium, potassium or calcium / 2 atom.

The reaction is conveniently carried out in a suitable solvent such as dioxane, tetrahydrofuran, chloroform or toluene, but most preferably in an anhydrous aprotic solvent such as acetone, dimethylformamide or dimethyl sulfoxide, optionally in the presence of an alkali base such as sodium carbonate, sodium carbonate, 70 ° C or potassium carbonate. 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 a solvent.

c) For the preparation of compounds of general formula I in which W is a vinylene group and m is the number O or 2:

The compound of general formula V formed in the reaction mixture, optionally formed in the reaction mixture, is cyclized, R 4, D and m have the same meaning as above, or their acetal.

The cyclization is conveniently carried out in glacial acetic acid or acetic anhydride in the presence of an alkali acetate such as sodium or potassium acetate at temperatures between 80 and 160 ° C, but preferably at the boiling point of the reaction mixture, for example between 118 and 140 ° C. The compound of general formula V is then conveniently prepared by reduction of the corresponding nitro compound in the presence of acetyl chloride or acetic anhydride; it does not need to be isolated.

The compounds of the general formulas II to V used as starting materials are known in part from the literature or are obtained by methods known per se.

The compound of general formula II is thus obtained by reduction of the corresponding nitro compound, which in turn is obtained by alkylation of the corresponding 2-nitro-5-hydroxy compound with the corresponding α, ω-dihaloalkane, followed by reaction with the corresponding mercapto compound and possibly subsequent coupling with hydrogen peroxide.

6 70408

The starting compound of general formula III is obtained by reacting the corresponding hydroxycarbostyril with a corresponding alkane substituted in the α, ω-position. The corresponding 6-, 7- or 8-hydroxy-3,4-dihydrocarbostyril required for this is obtained by acylation of the corresponding aniline derivative with the corresponding β-halocarboxylic acid derivative and subsequent cyclization by the method of Friedel-Crafts (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 is obtained by cyclization of the corresponding 2- (β-cyanoethyl) -cyclohexanedione-1,3-derivative and subsequent aromatization with, for example, N-bromo-succinimide (see Chem. And Ind. 1970, 1435). The preparation of the required corresponding hydroxycarbostyril is known from the literature (see e.g. J. Amer. Chem. Soc. 7, 236 (1950) and ibid. 76, 2402 (1954) or J. Org. Chem. 33, 1089 (1968) and ibid. 36/3493 (1971)).

The compound of the general formula V used as starting material is obtained, for example, by alkylation of the corresponding hydroxy-nitrobenzaldehyde or its acetal or ester with the corresponding halide, followed by reduction of the nitro group in the presence of acetic anhydride.

The following examples further illustrate the invention:

Example 1 6- [4- (2-Pyridylsulfonyl) -butoxy] -3,4-dihydrocarbostyril a) 2-Nitro-5-hydroxy-cinnamic acid methyl ester 21.0 g of 2-nitro-5-hydroxy-cinnamic acid (SN Chakravarti and PLN

Rao, Chem. Soc. 1938, 172) is dissolved in 200 ml of methanol and 86 ml of thionyl chloride are added dropwise to the solution with stirring over 45 minutes, bringing the temperature to 36 ° C. Stir for a further 25 minutes. After cooling in an ice bath, 18.6 g of 2-nitro-5-hydroxy-cinnamic acid methyl ester are obtained, m.p. 201-203 ° C.

(b) 2-Nitro-5-bromobutoxy-cinnamic acid methyl ester 22.3 g of 2-nitro-5-hydroxy-cinnamic acid methyl ester, 59.7 ml of 1,4-dibromobutane and 13.8 g of potassium carbonate in 200 ml of dimethyl the sulfoxide is stirred for 15 hours at room temperature, after which 800 ml of water are added. Extract with chloroform and, after evaporation of the solvent, 31.7 g of 2-nitro-5-bromobutoxy-cinnamic acid methyl ester, m.p. 60.5-63 ° C, are isolated.

c) 2-Nitro-5- [4- (2-pyridylmercapto) -butoxy] -cinnamic acid methyl ester _______ 10.75 g of 2-nitro-5-bromobutoxy-cinnamic acid methyl ester are added over 60 minutes to a premixed mixture of 5 g of potassium carbonate and 4.0 g of 2-mercaptopyridine in 100 ml of dimethyl sulfoxide, followed by stirring for 18 hours at room temperature. 400 ml of water are added and the oily reaction product is isolated by extraction with ether.

Yield: 11.0 g (94.2% of theory).

d) 2-Nitro-5- [4- (2-pyridylsulfonyl) -butoxy] -cinnamic acid methyl ester__ 7.0 g of 2-nitro-5- [4- (2-pyridylmercapto) -butoxy] -cinnamic acid methyl ester are dissolved in 70 ml, 5.0 ml of 35% hydrogen peroxide are added to the solution and allowed to stand for 3 days at room temperature. After distilling off the glacial acetic acid, it is recrystallized from chloroform / methanol.

Yield: 3.5 g (46.2% of theory), melting point: 118-121 ° C.

e) 6- / 4- (2-Pyridylsulfonyl) -butoxy / 3,4-dihydrocarbostyril 2.1 g of 2-nitro-5- [4- (2-pyridylsulfonyl) -butoxy] -cinnamic acid methyl ester dissolved in 20 ml: glacial acetic acid, hydrogenate with 0.5 g of 10% palladium on carbon under 3 bar of hydrogen and at room temperature. The glacial acetic acid is then distilled off and the residue is heated together with 20 ml of concentrated hydrochloric acid at reflux for 4 hours. Neutralize with 2N sodium hydroxide, then extract with chloroform. The evaporation residue is recrystallized from xylene.

Yield: 1.06 g (55.6% of theory), melting point: J21-123 ° C.

70408 8

Example 2 6- [4- (2-Pyridylsulfonyl) -butoxy] -carbostyril 2.0 g of 2-nitro-5- [4- (2-pyridylsulfonyl) -butoxy] -cinnamic acid methyl ester and 3.0 g of sodium dithionite are heated 4 hours at reflux in a mixture of 20 ml of water and 10 ml of ethanol. This produces a clear solution. The reaction mixture is evaporated and heated at reflux for 3 hours together with 20 ml of concentrated hydrochloric acid. Neutralize with 2N sodium hydroxide, then extract the reaction product with ether and recrystallize from xylene by adding a small amount of dimethylformamide.

Yield: 0.5 g (29% of theory), melting point: 176-179 ° C.

In a similar manner, this compound can be prepared by using hydrogen instead of sodium dithionite as a reducing agent in the presence of a Lindlar catalyst (palladium, partially inactivated with lead). In this case, only the nitro group is reduced, which, after treatment with concentrated hydrochloric acid, gives 6- [4- (2-pyridylsulfonyl) -butoxy] -carbostyril.

Example 3 6- [4- (3,4-Dichloro-phenylmercapto) -butoxy] -carbostyril 4.5 g of 2-nitro-5- [4- (3,4-dichloro-phenylmercapto) -butoxy] -cinnamic acid methyl ester (melting point : 91-92 ° C, prepared from 2-nitro-5-hydroxy-cinnamic acid methyl ester and 4- (3,4-dichlorophenylmercapto) -butyl bromide) and 13.9 g of sodium dithionite are heated at reflux for 4 hours in a mixture of 50 ml of ethanol and 50 ml of of water. The solvent is then distilled off and the residue is refluxed for 4 hours with 100 ml of concentrated hydrochloric acid. The resulting crystalline material is separated by suction and recrystallized from xylene.

Yield: 1.2 g (31% of theory), melting point: 144 ° C.

Example 4 70408 9 6- [4- (3,4-Dichlorophenylsulfonyl) -butoxy] -3,4-dihydrocarbostyril _____________________ In 50 ml of absolute dimethyl sulfoxide, 5.96 g of 6- (4-bromobutoxy) are stirred for 24 hours at room temperature. ) - 3,4-dihydrocarbostyril, 5.53 g of potassium carbonate and 18.75 g of sodium 3,4-dichlorophenylsulphinic acid. It is then taken up in 500 ml of ethyl acetate, washed with water and dried over magnesium sulphate. The crystalline reaction product is obtained by evaporating the solvent. Yield: 4.65 g (54% of theory), melting point: 170-171 ° C.

Example 5 6- [4- (3,4-Dichloro-phenylsulfinyl) -butoxy] -carbostyril a) 2-Nitro-5- [4- (3,4-dichloro-phenylsulfinyl) -butoxy] -cinnamic acid methyl ester____________ 11.2 g 2- the nitro-5-hydroxy-cinnamic acid methyl ester is dissolved in 150 ml of dimethyl sulfoxide and then stirred for 15 minutes together with 9.2 g of anhydrous potassium carbonate.

16.5 g of 4- (3,4-dichlorophenylsulfinyl) -butyl bromide are then added and the mixture is stirred for 40 hours at room temperature. Dilute with 1000 ml of water and extract with a mixture of 200 ml of chloroform and 100 ml of methanol. After evaporation of the organic solvent, an oily residue is obtained which crystallizes thoroughly on treatment with ether.

Yield: 13 g (57% of theory), melting point: 78-81 ° C.

b) 2-Amino-5- [4- (3,4-dichloro-phenylsulfinyl) -butoxy] -cinnamic acid methyl ester____ 4.2 g of 2-nitro-5- [4- (3,4-dichloro-phenylsulfinyl) -butoxy] -cinnamic acid methyl ester In 100 ml of methanol, 0.5 g of Lindlar's catalyst (palladium calcium carbonate, partially inactivated with lead acetate) are hydrogenated at a pressure of 3 bar at room temperature for 10 hours. After filtration of the catalyst, the solvent is evaporated and the resinous dark residue is used immediately in the next reaction.

c) 6- [4- (3,4-Dichlorophenylsulfinyl) -butoxy] -carbostyril

The 2-amino-5- [4- (3,4-dichlorophenylsulfinyl) -butoxy] -cinnamic acid methyl ester described in the previous experiment and 80 ml of 5N hydrochloric acid are heated to reflux for 3 hours and filtered hot. On cooling, colorless crystals separate from the filtrate.

Yield: 2.1 g (56% of theory), melting point: 191-192 ° C.

If iron powder and 80% acetic acid are used as agents in the reduction of 2-nitro-5- / 4- (3,4-dichlorophenylsulfinyl) -butoxy / cinnamic acid methyl ester in the above-mentioned reaction step, then 6- / 4- (3.4 -dichlorophenylsulfinyl) -butoxy / carbocitrile.

Example 6 2.3 g of 2-nitro-5- (3,4-dichlorophenylsulfinyl) -butoxy-cinnamic acid methyl ester in 20 ml of glacial acetic acid are hydrogenated according to Example 5b with 0.3 g of palladium / carbon at 3 bar of hydrogen pressure and at room temperature 7 within an hour. The catalyst is filtered off, after which the glacial acetic acid is distilled off and the residue and 40 ml of 5N hydrochloric acid are heated at reflux for 1 hour. After cooling, a small amount of chloroform is extracted and chromatographed on chut layers (Merck Kieselgel 60 with ethylene chloride / methanol = 9: 1). The compounds formed were identified by UV light and sprayed with iodine spray.

Rf value: 0.30: 6- [4- (3,4-dichlorophenylsulfinyl) -butoxy] -carbostyril, iodine spray blue-violet.

Rf value: 0.42: 6- / 4- (3,4-dichlorophenylmercapto) -butoxy / carbostyril, first orange-yellow with iodine spray, then gradually gray-purple.

70408 11

Rf value: 0.45: 6- [4- (3,4-dichlorophenylsulfinyl) -butoxy] -3,4-dihydrocarbostyril, strong orange-yellow with iodine spray.

Rf value: 0.57: 6- [4- (3,4-dichlorophenylmercapto) -butoxy] -3,4-dihydrocarbostyril, pale egg yolk with iodine spray.

Example 7 6- [4- (2-Pyridylsulfonyl) -butoxy] -carbostyril a) 2-Nitro-5- (4-bromobutoxy) -benzaldehyde 14.4 g of 2-nitro-5-hydroxybenzaldehyde carbonate /F.A. Mason, J. Chem. Soc. 127, 1197 (1925) /, 40 ml of dibromobutane and 24 g of anhydrous potassium carbonate are stirred for 4 hours in 140 ml of dimethyl sulfoxide at room temperature. It is then diluted with 800 ml of water and the reaction product is extracted with chloroform, the oily evaporation residue is triturated several times with petroleum ether to remove excess dibromobutane. The residual oily 2-nitro-5- (4-bromobutoxy) -benzaldehyde (21 g) is used without further purification.

Rf value: 0.75 (thin layer plate (Merck Kieselgel 60 F 254), eluent: ethylene chloride / methanol = 9: 1).

b) 2-Nitro-5- [4- (2-pyridylmercapto) -butoxy] -benzaldehyde 21 g of crude 2-nitro-5- (4-bromobutoxy) -benzaldehyde, 11.6 g of 2-mercaptopyridine and 20 g of anhydrous potassium carbonate are mixed 6 hours at room temperature in 100 ml of dimethyl sulfoxide. It is then diluted with 500 ml of water, extracted with chloroform and the organic solvent is removed in vacuo.

c) 2-Acetamino-5- [4- (2-pyridylsulfonyl) -butoxy] -benzaldehyde diacetate___ 6.6 g of crude 2-nitro-5- [4- (2-pyridylmercapto) -butoxy] -benzaldehyde, 3 ml of acetic anhydride and 0.01 g of anhydrous zinc-1 70408 12 chloride is heated at reflux for 30 minutes, cooled and the mixture, 60 ml of glacial acetic acid and 2.5 g of 35% hydrogen peroxide are stirred for 15 hours at room temperature. The reaction mixture is then hydrogenated in a Parr apparatus with 0.1 g of palladium / carbon under 3 bar of hydrogen at room temperature for 11 hours. To acetylate the amino compound formed, the reaction mixture is evaporated to dryness in vacuo, reheated to boiling for 30 minutes with 20 ml of acetic anhydride and the excess mixture of acetic anhydride and glacial acetic acid is distilled off.

d) 6- [4- (2-pyridylsulfonyl) -butoxy] -carbostyril

The distillation residue obtained in Example c), 20 ml of acetic anhydride and 5 g of anhydrous potassium acetate are heated at reflux for 14 hours. After cooling, add 20 ml of water and allow to stand overnight. This gives colorless crystals.

Yield: 2.9 g (41% of theory), melting point: 178-179 ° C.

In analogy to the previous examples, the following compounds were prepared:

6- (4-phenylmercapto-butoxy) -3,4-dihydrocarbostyril melting point: 121.5-123 ° C

6- (4-phenylsulfinylbutoxy) -3,4-dihydrocarbostyril melting point: 144.5-145.5 ° C

6- (4-Phenylsulfonylbutoxy) -3,4-dihydrocarbostyril Melting point: 157.5-158 ° C

6- [4- (2-Pyridylmercapto) -butoxy] -3,4-dihydrocarbostyril melting point: 123-124.5 ° C

6- [4- (2-Pyridylsulfinyl) -butoxy] -3,4-dihydrocarbostyril melting point: 144.5-146 ° C.

70408 13

6- [4- (2-Pyridylsulfonyl) -butoxy] -3,4-dihydrocarbostyril melting point: 123.8-125 ° C

6- (2-Phenylsulfinyl-ethoxy) -3,4-dihydrocarbostrifil Melting point: 171-172 ° C

6- (4-Benzylsulfinyl-butoxy) -3,4-dihydrocarbostyril Melting point: 141.5-142 ° C

6- [4- (4-chlorophenylsulfinyl) -butoxy] -3,4-dihydrocarbostyril melting point: 148-149.5 ° C

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

melting point: 153-155.5 ° C

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

melting point: 147.5 - 148.5 ° C

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

melting point: 130.5-133 ° C

6- (4-Phenylsulfinyl-butoxy) -carbostyril melting point: 181-182.5 ° C

6- [4- (4-Hydroxy-3,5-di-tert-butyl-phenylsulfinyl) -butoxy] -carbostyril

melting point: 192-194 ° C

6- [4- (3,4-Dichlorophenylsulfinyl) -butoxy] -carbostitrile

melting point: 191-196 ° C

4-methyl-6- (4-phenylsulfinyl-butoxy) -carbostyril melting point: 167-168 ° C

6- / 4- (3,4-dikloorifenyy1isulfonyyli) -butoxy / -3,4-dihydrocarbostyril

melting point: 172-173 ° C

6- [4- (2,5-Dichlorophenylsulfinyl) -butoxy] -3,4-dihydrocarbostyril

melting point: 185-186 ° C

70408 14

6- [4- (2-Pyridyl) sulfonyl-butoxy] -carbostyril melting point: 179-180 ° C

6- [4- (2-Naphthylsulfinyl) -butoxy] -3,4-dihydrocarbostyril melting point: 147.5-148.5 ° C

6- [4- (4-Biphenylylsulfinyl) -butoxy] -carbostyril Melting point: 196-197 ° C

6- [4- (2-Quinolylsulfinyl) -butoxy] -carbostyril melting point: 197-198 ° C

6- (4-Cyclohexylsulfinyl) -butoxy / carbostyril Melting point: 169-170 ° C

5-Bromo-6- (4-phenylsulfinyl-butoxy) -carbostyril Melting point: 190-191 ° C

6- [2- (N-Methyl-N-cyclohexyl-carbamidomethylsulfinyl) -ethoxy] -carbostyril

melting point: 128-130 ° C

6- [4- (3,5-Dibromo-4-aminophenylsulfinyl) -butoxy] -3,4-dihydrocarbostyril

melting point: 144-146 ° C

6- [4- (3,5-Dibromo-4-aminophenylsulfinyl) -butoxy] -carbostyril melting point: 205-207 ° C

6- / 4- (4-Cyclohexylphenylsulfinyl) -butoxy / 3,4-dihydrocarbostyril

melting point: 155-157 ° C

6- [4- (4-Cyclohexylphenylsulfinyl) -butoxy] -carbostyril Melting point: 188-190 ° C

6- [4- (4-tert-Butylphenylsulfinyl) -butoxy] -carbostyril Melting point: 164-166 ° C

70408 15 6- [4- (3,4-Dichlorophenylsulfinyl) -butoxy] -3,4-dihydrocarbostyril

melting point: 106.5-108 ° C

Melting point: 148-149 ° C (1x from toluene and 1x from ethanol). Example 8 6- [4- (2-Pyridylsulfonyl) -butoxy] -carbostyril a) 2-Nitro-5- [4- (2-pyridylsulfonyl) -butoxy] -benzaldehyde 1.0 g of the 2-nitro-obtained obtained according to Example 7b) -5- [4- (2-pyridyl-mercapto) -butoxy] -benzaldehyde is dissolved in 100 ml of glacial acetic acid, 1.0 ml of 35% hydrogen peroxide is added to the solution and boiled for 60 hours at room temperature. Dilute with 200 ml of water, extract with chloroform / methanol 11a to 2: 1 to give an oil after evaporation.

Yield: 1 g (91% of theory),

Rj value: 0.17 (silica gel light plate Merck 60 ^ 54 ‘

Drive solution: Cyclohexane / ethyl acetate = 1: 2).

b) 2-Amino-5- [4- (2-pyridylsulfonyl) -butoxy] -benzaldehyde

The oil obtained in a) is reduced with ferrous sulphate heptahydrate / concentrated aqueous ammonia at 90 ° C.

c) 6- [4- (2-pyridylsulfonyl) -butoxy] -carbostyril

The 2-amino-5- (4-) 2-pyridylsulfonyl) -butoxy) -benzladehyde obtained in b) is acetylated with acetic anhydride / pyridine, the volatiles are distilled off, taken up in acetic anhydride and refluxed for 5 hours with anhydrous potassium acetate. After cooling, dilute with water and extract with chloroform / methanol11a = 2: 1. The evaporation residue crystallizes out after some time. Recrystallize from xylene by adding a little dimethylformaldehyde.

Melting point: 179-181 ° C.

Claims (9)

16. , 70408 R 4 R 1 wherein W is an optionally substituted vinylene group or an ethylene group, D is a straight-chain or branched alkylene group having 2 to 6 carbon atoms, a straight-chain or branched hydroxyalkylene group having 3 to 6 carbon atoms, or a xylylene group, m is O, 1, or 2 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, R 2 is a cycloalkyl group having 3 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 11 carbon atoms, one nitrogen atom and / or one oxygen or sulfur atom or two nitrogen atoms heteroaryl group having 4 to 9 carbon atoms, or a heteroaralkyl group having 5 to 10 carbon atoms, wherein the above-mentioned aromatic nuclei may be mono- or di-substituted with an alkyl group having 1 to 4 carbon atoms, hydroxy, methoxy, amino, acetylamino, nitro , a carboxyl, cyclohexyl, phenyl group or a halogen atom and in addition the above-mentioned monosubstituted phenyl group having an alkyl group having 1 to 4 carbon atoms and / or a halogen atom (where the phenyl ring substituents may be the same or different), 1,2,4-triazolyl, triphenylmethyl, 4,5-bis- (p-chlorophenyl) oxazol-2-yl, N-methylcyclohexylaminocarbonylmethyl - or an aminoiminomethyl group or also an alkyl group having 1 to 6 carbon atoms, when either m is a number 1 or D is a straight-chain or branched hydroxyalkylene group having 3 to 6 carbon atoms or a xylylene group, 70408 17 R3 3a, which may be the same or different , denoting hydrogen or halogen atoms, alkyl groups having 1 to 4 carbon atoms, amino, acetylamino or nitro groups, characterized in that a) the compound of general formula (II) optionally formed in the reaction mixture is cyclized. c - H - ·? R 4 R 1 wherein D, W, R 1 - R 2 and m are as defined above and Z is a nucleophilic leaving group such as a hydroxy group, a halogen atom, an alkoxy, aryloxy or aralkyloxy group, or b) a compound of general formula (I) wherein m is a number 2, a carbostyril of the general formula (III) R 3 W -O - D - Y (III) Λ> R 1 wherein D, W, R 1, and R 4 are as defined above and Y is nucleophilically exchangeable a group such as a halogen atom or a sulfonic acid ester group is reacted with a metal salt of the general formula IV Me © Ogo 2 - R (IV) wherein R 2 is as defined above and Me is an alkali or alkaline earth / 2 metal atom, or 18 70408 c ) to prepare a compound of general formula (I) wherein W is a vinylene group and m is O or 2, optionally cyclizing the compound of general formula (V) 0HC X ^ 3-O - D - SOm - R2 (V) ch3co n formed from the reaction mixture, R4 R1 wherein r - R1, D and m have the same meaning as n above, or its acetal. Processes for the preparation of therapeutically active carbostyric derivatives of general formula (I) R3 W ^ 7-1- "° - D - SO - R (I) ON R 2. A compound according to the invention, which comprises reacting under the condensation medium, isomorphic acid, concentrate salt, phosphorus or thionyl chloride. Process according to Claim 1a, characterized in that the reaction is carried out in the presence of a condensing agent such as sulfuric acid, concentrated hydrochloric acid, phosphoric acid or thionyl chloride. 3. A patent according to claim 2 and 2, which comprises reacting at a temperature of from 50 to 200 ° C, preferably at a temperature of from 80 to 150 ° C. Process according to Claims 1a and 2, characterized in that the reaction is carried out at temperatures between 50 and 200 ° C, but preferably at temperatures between 80 and 150 ° C. 4. A patent according to claims 1a, 2 and 3, which can be used as a reaction solution. Process according to Claims 1a, 2 and 3, characterized in that the reaction is carried out in a solvent. 5. A patent according to the invention, which can be used as a reaction solution. Process according to Claim Ib, characterized in that the reaction is carried out in a solvent. 6. A patent according to claim 5, which is adapted to use a water treatment device. Process according to Claim 5, characterized in that an anhydrous aprotic solvent is used as the solvent. 7. A patent according to claims 1, 5 and 6, which can be used to react with a nervous system. Process according to Claims Ib, 5 and 6, characterized in that the reaction is carried out in the presence of an alkali base. 8. A method according to claims Ib and 5-7, which can be used to react with the nervous system. Process according to Claims Ib and 5 to 7, characterized in that the reaction is carried out at temperatures between 0 ° C and the boiling point of the solvent used, for example at temperatures between 0 and 100 ° C. 19 70408 Process according to Claim 8, characterized in that the reaction is carried out at temperatures between 10 and 50 ° C. Process according to Claim 1e, characterized in that the reaction is carried out using glacial acetic acid or acetic anhydride as solvent. Process according to Claims 1e and 10, characterized in that the reaction is carried out in the presence of alkali acetate. Process according to Claims 1e, 10 and 11, characterized in that the reaction is carried out at temperatures between 80 and 160 ° C, but preferably at the boiling point of the reaction mixture. 20 70408 1 «For the preparation of a therapeutically active carboxyl-styrene derivative with all the compounds of formula (I) *. R. w- I I H— O - D - som - r2 (I) 0. NK R4 is optionally substituted with methyl groups substituted with a vinyl group or an ethyl group, D is used with an alkyl group having 2-6 cholaters, and is preferably substituted with a hydroxyalkyl group having 3-6 chelates or a xyl group, 0 , 1 or 2, R 1 is a hydrogen atom or an alkyl group of 1-3 cholaters, R 2 is a cycloalkyl group of 3-6 cholatomers, an aryl group of 6-10 cholatomers, an aralkyl group of 7-11 cholatomers, and a quaternary atom of och / eller in which the heteroaryl group in which the heteroaryl group is represented by 4-9 cholatomers or in the heteroaralkyl group of 5 to 10 cholatomers, the aromatic radicals may be mono- or disubstituted by an alkyl group of 1 to 4 cholatomers, enoxy, methoxy, amino- , acetylamino, nitro, carboxyl, cyclohexyl, phenyl or halogen atoms to give monosubstituted phenyl groups with alkyl groups having 1-4 cholaters and / or halogen atoms (color phenyl substituents) likadana eller olika), 1,2,4-triazolyl-, triphenylmethyl-, 4,5-bis- (p-chlorophenyl) -oxazol-2-yl-, M-methyl-cyclohexylaminocarbonylmethyl-1-elleraminoimino- methyl group or alkyl group with 1 to 6 carbon atoms, colors of one or more groups of 1 to 20 carbon atoms or alkyl groups having 3 to 6 carbon atoms, or xylyl groups, R 3 and R 4, vilka kan vara likadana eller olika, avser väte - with 2 or 70408 halogen atoms, alkyl groups with 1-4 cholaters, amino-, acetyl-amino- or nitro groups, some of which can be used in the reaction process with the compounds of formula (II) z "£ 'w - 0 - D - SOm - R2 (II) H - NK R4 is D, W, R4 - R4 and R4 are selected from the group consisting of Z and the nucleophilic group, including hydroxyl, halogen, alkoxy, aryloxy or aralkyloxy group, cyclized or b) for the production of a compound of the same formula (I), having the same formula 2, carbostyril of the lower formula (T) II) / 3 w- I II —— o - d - y (ui) «r D, W, Rj, R3 and R4 are decammed with ovan and Y avers in a nucleophilic group, a halogen atom or a sulfonylate- ester group, which is a metal and metal salt with the lower form (IV) Me © © go2 - R2 (tV) to R2 is a solution in which there is an alkali or alkali metal / 2-metal atom, or c) a framställning av en sädan förening in which all the compounds of formula (I) are used, and in the case of a vinyl group and in which they are 0 or 2, the cyclists are optionally reacted in the reaction form with all the compounds of formula (V) 2 ?. 7040 8 0HC * 3 - O - D - SOm - R2 (V) CH3C ° ^ N "1 to R1 - R4, D and the same as in acetal or acetal. 9. A method according to claim 8, which is reacted at a temperature of from 10 to 50 ° C.