NO154131B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE CARBOSTYRIC DERIVATIVES. - Google Patents

Description

In patent 152839 (application 79.0521) procedures for the production of, among other things, are described. carbostyryl derivatives of the general formula

where

W means a vinylene optionally substituted with a methyl group-

group or an ethylene group,

m means the number 0, 1 or 2,

D means a linear alkylene group of 2 to 6 carbon atoms, a 2-hydroxy-n-propylene group or a xylylene group,

R 2 means a cyclohexy1-, benzyl-, naphthyl-, pyridyl-, pyrimidyl-, 1,2,4-triazolyl-, pyridyl-oxide-, furfuryl-, triphenylmethyl-,

quinolyl-, benzimidazolyl-, benzthiazolyl-, quinazolin-4-on-yl-, 4,5-bis-(p-chlorophenyl)-oxazol-2-yl-, N-methyl-N-cyclohexylamino-carbonylmethyl- or aminoiminomethyl group, a phenyl group optionally substituted with a carboxyl, hydroxy, methoxy, amino, acetylamino, nitro, cyclohexyl or phenyl group,

one with halogen atoms and/or alkyl groups with 1-4 carbon atoms mono- or disubstituted phenyl group, one with two halogen atoms or with two alkyl groups with 1-4 carbon atoms substituted

hydroxyphenyl, halophenyl or aminophenyl group,

R^ means a hydrogen or bromine atom or an acetylamino or nitro group, and

the remainder R„-S0 -D-0- is in the 6- or 7-position.

/ m J

The compounds with the above general formula

In addition to a positive inotropic effect, it exhibits valuable therapeutic properties, particularly anti-thrombotic properties, as shown in the main patent.

It has now been found that the carbostyryl derivatives with the general formula I can also be prepared according to the following procedures: a) Ring closure of a possibly in the reaction mixture formed connection with the general formula

where

D, W, R2, R3 and m are as indicated above, and

Z means a nucleophilic leaving group such as a hydroxy group, a halogen atom, an alkoxy, aryloxy or aralkyl group.

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

It is not necessary here to isolate a compound of the general formula II used as starting material.

This can rather be prepared in situ from the corresponding nitro compound, e.g. by reduction of the nitro group with hydrogen in the presence of a hydrogenation catalyst such as palladium/charcoal, palladium/calcium carbonate or palladium/calcium carbonate + lead acetate (Lindlar catalyst), by reduction with metals such

such as iron, tin or zinc in the presence of an acid, by reduction with salts such as iron(II) sulphate, tin(II) chloride, chromium(II) chloride or sodium dithionite or by reduction with hydrazine in the presence of Raney nickel.

If m in a corresponding nitro compound means the number 1, the reduction of the nitro group is suitably carried out with the equivalent amount of the reducing agent used, e.g.

with a metal salt such as iron (II) sulfate, stannous (II) chloride, chromium (II) chloride or sodium dithionite, or with hydrogen in the presence of a deactivated hydrogenation catalyst, e.g. in the presence of palladium/calcium carbonate + lead acetate. If you e.g. if the reduction is carried out in the presence of palladium/charcoal, the sulfoxide group will be partially co-reduced.

Moreover, if W in the corresponding nitro compound

means a vinylene group, this group can, especially when the reduction is carried out with catalytically activated hydrogen, e.g. with hydrogen in the presence of palladium/charcoal, is hydrogenated to the corresponding ethylene group. b) For the preparation of compounds of the general formula I where m means the number 2:

Reaction of a carbostyril with the general formula

where D, W and R 3 are as above indicated, and

Y means a nucleophilic, cleavable group such as a halogen atom or a sulphonic acid residue, e.g. a chlorine, bromine or iodine atom, a p-toluenesulfonyloxy or methanesulfonyloxy group, with a metal salt of the general formula

where R_ is as above indicated, and

Me means an alkali metal atom, and Me^ means an alkaline earth metal atom such as a sodium or potassium atom or a calcium atom, respectively.

The reaction is conveniently carried out in a suitable solvent such as dioxane, tetrahydrofuran, chloroform or toluene, preferably in an aqueous aprotic solvent such as acetone, dimethylformamide or dimethylsulfoxide, optionally in the presence of an alkali base such as sodium carbonate, potassium carbonate or sodium hydroxide at temperatures between 0 °C and the boiling temperature of the solvent used, e.g. at temperatures between 0 and 100°C, preferably at temperatures between 10 and 50°C. The reaction can also be carried out without a solvent. c) For the preparation of compounds with the general formula I where W means a vinylene group and m means the number 0 or 2: Ring closure of an optionally in the reaction mixture formed connection with the general formula

where & 2' R 3' D and m are as indicated above, or an acetal thereof.

The cyclization is suitably 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, preferably at the boiling temperature of the reaction mixture, e.g. at temperatures between 118 and 140°C. A compound of the general formula V is conveniently prepared by reduction of a corresponding nitro compound in the presence of acetyl chloride or acetic anhydride, and it is not necessary to isolate it.

Those used as starting materials compounds with

the general formulas II to Vier are partially known from the literature or can be prepared by methods known per se.

Thus one gets a connection with the general

formula II by reduction of the corresponding nitro compound,

which in turn is obtained by alkylation of a corresponding 2-nitro-5-hydroxy compound with a corresponding a,w-dihaloalkane, subsequent reaction with a corresponding mercapto compound and possibly subsequent oxidation with hydrogen peroxide.

A starting compound of the general formula III

is obtained by reacting a corresponding hydroxycarbostyryl with a corresponding alkane that is substituted in the a,oo position. The necessary corresponding 6-, 7- or 8-hydroxy-3,4-dihydrocarbostyryl is obtained by acylation of a corresponding aniline derivative with a corresponding 3-halocarboxylic acid derivative and subsequent ring closure 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)) resp. a 5-hydroxy-3,4-dihydrocarbostyril by cyclization of a corresponding 2-(3-cyanoethyl)-cyclohexanedione-1,3-derivative and subsequent aromatization, e.g. with N-bromosuccinimide (see Chem. and Ind. 1970, 1435). The production of the necessary hydroxycarbostyrils is known from the literature

(see, e.g., J. Amer. Chem. Soc. 12, 346 (1950) and ibid 16, 2402

(1954) or J. Org. Chem. 3^3, 1089 (1968) and ibid 36 , 3493

(1971) ).

A compound with the general formula V used as starting compound gives, for example, by alkylation of a corresponding hydroxy-nitro-benzaldehyde resp. its acetal or ester with a corresponding halide and subsequent reduction of the nitro group in the presence of acetic anhydride.

The following examples shall serve to 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-hydroxycinnamic acid (S. N. Chakravarti and

P.L.N. Rao, Chem. Soc. 1938, 172) is dissolved in 200 ml of methanol and 86 ml of thionyl chloride is added dropwise with stirring over the course of 45 minutes, whereby the temperature rises to 36°C. You continue to stir for a further 25 minutes. After cooling in an ice bath, 18.6 g of 2-nitro-5-hydroxycinnamic acid methyl ester with a melting point of 201-203°C is obtained.

b) 2-nitro-5-bromobutoxy-cinnamic acid methyl ester

22.3 g of 2-nitro-5-hydroxycinnamic acid methyl ester are stirred

with 59.7 ml of 1,4-dibromobutane and 13.8 g of potassium carbonate in 200 ml of dimethylsulfoxide for 15 hours at room temperature, after which 800 ml of water is added. It is extracted with chloroform, and after evaporation of the solvent, 31.7 g of 2-nitro-5-bromobutoxycinnamic acid methyl ester with a melting point of 60.5-63°C is isolated.

c) 2-nitro-5-[4-(2-pyridylmercapto)-butoxy]-cinnamic acid methyl ester 10.75 g 2-nitro-5-bromobutoxy-cinnamic acid methyl ester

is added to a mixture of 5 g of potassium carbonate and 4.0 g of 2-mercaptopyridine in 100 ml of dimethylsulfoxide which has been stirred for 60 minutes in advance, and is stirred for 18 hours at room temperature. 400 ml of water is added and the oily reaction product is isolated by ether extraction.

Yield: 11.0 g (94.2% of theoretical).

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

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

The above points a)-d) relate to the production of starting material.

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 of glacial acetic acid, is hydrogenated with 0.5 g of 10% palladium charcoal at 3 bar hydrogen pressure and room temperature. The glacial acetic acid is then distilled off, and the residue is heated with 20 ml of concentrated hydrochloric acid for 4 hours to boiling under reflux cooling. After neutralization with 2N caustic soda, extraction is carried out with chloroform. The evaporation residue is recrystallized from xylene. Yield: 1.06 g (55.6% of theory), melting point: 121-123°C.

Example 2

6- [ 4- ( 2- pyridylsulfonyl)- butoxy]- carbostyryl

2.0 g of 2-nitro-5-[4-(2-pyridylsulfonyl)-butoxy]-cinnamic acid methyl ester is heated together with 3.0 g of sodium dithionite in a mixture of 20 ml of water and 10 ml of ethanol for 4 hours to boiling under reflux cooling, whereby a clear solution is formed. The reaction mixture is evaporated and heated with 20 ml of concentrated hydrochloric acid for 3 hours to boiling under reflux. After neutralization with 2N caustic soda, the reaction product is extracted with ether and recrystallized from xylene while adding a little dimethylformamide.

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

In the same way, this compound can be prepared when, instead of sodium dithionite as reducing agent, hydrogen is used in the presence of a Lindlar catalyst (palladium, partially inactivated with lead). Thereby, only the nitro group is reduced, so that after the subsequent treatment with concentrated hydrochloric acid, 6-[4-(2-pyridylsulfonyl)-butoxy]-carbostyril is obtained.

Example 3

6-[ 4-( 3, 4- dichlorophenylmercapto)- butoxy]- carbostyryl

4.5 g of 2-nitro-5-[4-(3,4-dichlorophenylmercapto)-butoxy]-cinnamic acid methyl ester (melting point: 91-92°C; prepared from 2-nitro-5-hydroxy-cinnamic acid methyl ester and 4-(3,4-dichlorophenyl-mercapto)-butyl bromide) is heated to boiling under reflux with 13.9 g of sodium dithionite in a mixture of 50 ml of ethanol and 50 ml of water for 4 hours. The solvent is then distilled off and the residue is boiled under reflux in

4 hours with 100 ml of concentrated hydrochloric acid. It formed crystalline

substance is suctioned off and recrystallized with xylene.

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

Example 4

6-[ 4-( 3, 4- dichlorophenylsulfonyl)- butoxy]- 3, 4- dihydro- carbostyryl

In 50 ml of absolute dimethylsulfoxide, 5.96 g of 6-(4-bromobutoxy)-3,4-dihydrocarbostyril are stirred together with 5.53 g of potassium carbonate and 18.75 g of 3,4-dichlorophenylsulfinic acid sodium for 24 hours at room temperature. The reaction mixture is then taken up in 500 ml ethyl acetate, washed with water and dried over magnesium sulphate. When the solution is evaporated, the crystalline reaction product is obtained.

Yield: 4.65 g (54% of the theoretical), melting point: 170-171°C.

Example 5

6-[ 4-( 3, 4- dichlorophenyl- sulfinyl)- butoxy]- carbostyryl

a) 2-nitro-5-[4-(3,4-dichlorophenylsulfinyl)-butoxy]-cinnamic acid methyl ester

11.2 g of 2-nitro-5-hydroxycinnamic acid methyl ester are dissolved

in 150 ml of dimethyl sulfoxide and stirred with 9.2 g of anhydrous potassium carbonate for 15 minutes, after which 16.5 g of 4-(3,4-dichlorophenyl-sulfinyl)-butyl bromide is 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 remains which, after treatment with ether, crystallizes through.

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

b) 2-amino-5-[4-(3,4-dichlorophenylsulfinyl)-butoxy]-cinnamic acid methyl ester

4.2 g of 2-nitro-5-[4-(3,4-dichlorophenylsulfinyl)-butoxy]-cinnamic acid methyl ester is hydrogenated in 100 ml of methanol with 0.5 g of Lindlar catalyst (palladium on calcium carbonate, partially inactivated with lead acetate) at 3 bar and room temperature for 12 hours. After filtering off the catalyst, the solvent is evaporated and the resinous, dark residue is used immediately for the subsequent reaction.

c) 6-[ 4-( 3, 4- dichlorophenylsulfinyl)-butoxy]- carbostyryl

The 2-amino-5-[4-(3,4-dichlorophenylsulfinyl)-butoxy]-cinnamic acid methyl ester described in the previous step is heated with 80 ml of 5N hydrochloric acid for 3 hours until boiling and filtered while hot. Colorless crystals separate from the filtrate on cooling.

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

If one knows the reaction sequence described above

for the reduction of 2-nitro-5-[4-(3,4-dichlorophenylsulfinyl)-butoxy]-cinnamic acid methyl ester using iron powder and 80% acetic acid as a reducing agent, 6-[4-(3,4-dichlorophenylsulfinyl) is likewise obtained )-butoxy]-carbostyryl as reaction product.

Example 6

2.3 g of 2-nitro-5-(3,4-dichlorophenylsulfinyl)-butoxy-cinnamic acid methyl ester is hydrogenated in 20 ml of glacial acetic acid and 0.3 g of palladium/charcoal at 3 bar hydrogen pressure and room temperature for 7 hours analogously to example 5b. Then f raf The catalyst is removed, the glacial acetic acid is distilled off, and the residue is heated in

1 hour for boiling with 40 ml of 5N hydrochloric acid. After cooling, extract with a little chloroform and separate by chromatography on a thin-layer plate (Merck silica gel 60 F254^

with ethylene chloride/methanol = 9:1. The identification of the compounds formed was carried out in UV light and by spraying with an iodine shower.

Rf value: 0.30: 6-[4-(3,4-dichlorophenylsulfinyl)-butoxy]-carbostyryl, with iodine shower blue violet.

Rf value: 0.42: 6-[4-(3,4-dichlorophenylmercapto)-butoxy]-carbostyril, with iodine shower first orange-yellow, then gradually grey-violet.

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

Rf value: 0.57: 6-[4-(3,4-dichlorophenylmercapto)-butoxy]-3,4-dihydro-carbostyril, with iodine shower light egg-yellow.

Example 7

6- [ 4-( 2- pyridylsulfonyl)- butoxy]- carbostyryl

a) 2-nitro-5-(4-bromobutoxy)-benzaldehyde

14.4 g of 2-nitro-5-hydroxybenzaldehyde carbonate [F.A. Mason,

J. Chem. Soc. 127, 119 7 (19 25)] is stirred together with 40 ml of dibromobutane and 24 g of anhydrous potassium carbonate in 140 ml of dimethyl sulphoxide at room temperature for 4 hours. It is then diluted with 800 ml of water and the reaction product is extracted with chloroform. The oily evaporation residue is washed several times with petroleum ether to remove excess dibromobutane. The remaining oily 2-nitro-5-(4-bromobutoxy)-benzaldehyde (21 g) is further used in the crude state.

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

b) 2-nitro-5-[4-(2-pyridylmercapto)-butoxy]-benzaldehyde

21 g of the crude 2-nitro-5-(4-bromobutoxy)-benzaldehyde

is stirred together with 11.6 g of 2-mercaptopyridine and 20 g of anhydrous potassium carbonate for 6 hours at room temperature in 100 ml of dimethyl sulfoxide. Dilute with 500 ml of water, extract with chloroform and remove the organic solvent in vacuo.

c) 2-acetamino-5-[4-(2-pyridylsulfonyl)-butoxy]-benzaldehyde diacetate

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

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

The distillation residue obtained according to example c).

heated with 20 ml of acetic anhydride and 5 g of anhydrous potassium acetate for 14 hours until boiling. After cooling, add 20 ml of water and let the mixture stand overnight. Colorless crystals are excreted.

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

Example 8

6- [ 4- ( 2- pyridylsulfonyl)- butoxy]- carbostyryl

a) 2-nitro-5-[4-(2-pyridylsulfonyl)-butoxy]-benzaldehyde

1.0 g of the 2-nitro-5-[4-(2-pyridylmercapto)-butoxy]-benzaldehyde obtained according to example 7b) is dissolved in 100 ml of glacial acetic acid, 1.0 ml of 35% hydrogen peroxide is added and stirred for 60 hours at room temperature. It is diluted with 200 ml of water, extracted with chloroform/methanol = 2:1 and, after evaporation, an oil is obtained. Yield: 1 g (91% of theoretical),

R^ value: 0.17 (silica gel fluorescent plate Merck 60 F254' developer: cyclohexane/ethyl acetate = 1:2).

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

The oil obtained under a) is reduced with iron (II) sulfate heptahydrate/conc. aqueous ammonia at 90°C.

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

The 2-amino-5-[4-(2-pyridylsulfonyl)-butoxy]-benzaldehyde obtained under b) is acetylated with acetic anhydride/pyridine, taken up again in acetic anhydride and heated with anhydrous potassium acetate for 5 hours by boiling under reflux. Dilute with water after cooling and extract with chloroform/methanol = 2:1. The evaporation residue crystallizes after some time. Recrystallization is carried out from xylene with the addition of a little dimethylformaldehyde.

Melting point: 179-181°C.

Analogous to the above examples, the following compounds were prepared: 6-(4-phenylmercapto-butoxy)-3,4-dihydrocarbostyril, melting point: 121.5-12 3°C 6-(4-phenylsulfinylbutoxy)-3,4-dihydrocarbostyryl, melting point: 144.5-145.5°C,

6-(4-phenylsulfonylbutoxy)-3,4-dihydrocarbostyryl, melting point: 157.5-158°C,

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

6-[4-(2-pyridylsulfinyl)-butoxy]-3,4-dihydrocarbostyryl, melting point: 144.5-146°C,

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

6-(2-phenylsulfinyl-ethoxy)-3,4-dihydrocarbostyril, melting point: 171-172°C,

6-(4-benzylsulfinyl-butoxy)-3,4-dihydrocarbostyryl, melting point: 141.5-142°C,

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

6-(4-cyclohexylsulfinyl-1-butoxy)-3,4-dihydrocarbostyryl, melting point: 153-155.5°C,

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

6-[4-(2-Methoxyphenylsulfinyl)-butoxy]-3,4-dihydrocarbostyril, melting point: 130.5-133°C,

6-(4-phenylsulfinyl-1-butoxy)-carbostyryl,

melting point: 181-182.5°C,

6-[4-(4-hydroxy-3,5-di-tert.butyl-phenylsulfinyl)-butoxy]carbostyryl

melting point: 19 2-19 4°C,

6-[4-(3,4-dichlorophenylsulfinyl)-butoxy]-carbostyryl, melting point: 191-196°C,

4-methyl-6-(4-phenylsulfinyl-butoxy)-carbostyril,

melting point: 167-168°C,

6-[4-(3,4-dichlorophenylsulfonyl)-butoxy]-3,4-dihydrocarbostyryl, melting point: 172-173°C,

6-[4-(2,5-dichlorophenylsulfinyl)-butoxy]-3,4-dihydrocarbostyryl, melting point: 185-186°C,

6-[4-(2-pyridyl)-sulfony-1-butoxy]-carbostyryl,

melting point: 179-180°C,

6-[4-(2-naphthyl-sulfinyl)-butoxy]-3,4-dihydro-carbostyryl, melting point: 147.5-148.5°C,

6-[4-(4-biphenylylsulfinyl)-butoxy]-carbostyryl,

melting point: 196-197°C,

6-[4-(2-quinolylsulfinyl)-butoxy]-carbostyril,

melting point: 19 7-19 8°C,

6-[4-cyclohexylsulfinyl)-butoxy]-carbostyryl,

melting point: 169-170°C,

5-bromo-6-(4-phenylsulfinyl-butoxy)-carbostyryl,

melting point: 190-191°C,

6-[2-(N-methyl-N-cyclohexyl-carbamidomethyl-sulfinyl)-ethoxy]-carbostyryl,

melting point: 123-130°C,

6-[4-(3,5-dibromo-4-aminophenylsulfinyl)-butoxy]-3,4-dihydrocarbostyryl,

melting point: 144-146°C,

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

6-[4-(3,4-cyclohexylphenylsulfinyl)-butoxy]-3,4-dihydrocarbostyryl,

melting point: 155-157°C,

6-[4-(4-cyclohexylphenylsulfinyl)-butoxy]-carbostyryl, melting point: 188-190°C,

6-[4-(4-tert.butylphenylsulfinyl)-butoxy]-carbostyryl,• melting point: 16 4-16 6°C,

6-[4-(3,4-dichlorophenylsulfinyl)-butoxy]-3,4-dihydrocarbostyryl, melting point: 106.5-108°C,

melting point: 148-149°C (1 x from toluene and 1 x from ethanol).

Claims (1)

Analogous process for the preparation of therapeutically active carbostyryl derivatives as set forth in patent 152839 with the general formula where W means a optionally substituted vinylene with a methyl group group or an ethylene group, m means the number 0, 1 or 2, D means a linear alkylene group of 2 to 6 carbon atoms, a 2-hydroxy-n-propylene group or a xylylene group, 1*2 means a cyclohexyl, benzyl, naphthyl, pyridyl, pyrimidyl, 1,2,4-triazolyl, pyridyloxide, furfuryl, triphenylmethyl , quinolyl, benzimidazolyl, benzthiazolyl, quinazolin-4-on-yl, 4,5-bis-(p-chlorophenyl)oxazol-2-yl, N-methyl-N-cyclohexylaminocarbonylmethyl or aminoiminomethyl group, a phenyl group optionally substituted with a carboxyl, hydroxy, methoxy, amino, acetylamino, nitro, cyclohexyl or phenyl group, one with halogen atoms and/or alkyl groups with 1-4 carbon atoms mono- or disubstituted phenyl group, one with two halogen atoms or with two alkyl groups with 1-4 carbon atoms substituted hydroxyphenyl, halophenyl or aminophenyl group, R^ means a hydrogen or bromine atom or a acetylamino- or nitro group, and the remainder Ro-S0 -D-0- is in the 6- or 7-position, characterized by a) a compound possibly formed in the reaction mixture with the general formula where D, w, , R. and m are as indicated above, and Z means a nucleophilic, leaving group such as a hydroxy group, a halogen atom, an alkoxy, aryloxy or aralkyloxy group, is ring-closed, or" b) for the preparation of a connection with the general formula I where m means the number 2, a carbostyril with the general formula is reacted where D, W and R are as above, and Y means a nucleophilic leaving group such as a halogen atom or a sulphonic acid ester residue, with a metal salt of the general formula where R2 is as indicated above, and Me means an alkali metal atom, and Me^ means an alkaline earth metal atom, or c) for the preparation of a compound of the general formula I where W is a vinylene group and m the number 0 or 2, ring closure an optionally formed compound of the general formula in the reaction mixture where , R^, D and m are as indicated above, or an acetal thereof.