WO1984002908A1 - Carbostyriloximinopropanolamines useful as medicaments and preparation method thereof - Google Patents

Abstract

Carbostyriloximinopropanolamines having the general formula (A),wherein R1 is a hydrogen atom, or an alkyl radical containing from 1 to 3 atoms of carbon, R2 is a hydrogen atom or an alkyloxy, aryloxy radical, containing from 1 to 10 aliphatic or aromatic atoms of carbon, R3 is an optionally substituted alkyl or arylalkyl radical containing from 2 to 30 straight or branched, aliphatic or aromatic atoms of carbon.

Description

 CARBOSTYRILOXIMINOPROPANOLAMINES USEFUL AS MEDICAMENTS AND PROCESS FOR THEIR PREPARATION.

The present invention relates to new beta-blocking compounds with a carbostyril nucleus, to their methods of preparation and to their applications in the therapeutic field, in particular as medicaments useful in the cardiovascular and ophthalmic fields.

The beta-blocking substances currently marketed belong to:

- either to the family of phenyletanolamines of general formula

- or that of aryloxypropanolamines of general formula

- soit à celle des carbostyriloxypropanolamines de formule générale

- or that of carbostyriloxypropanolamines of general formula

Ces derniers composés ont fait l'objet par exemple des brevets US 4.322.425, 4.223.137, 4.072.683, 4.068.076,

The latter compounds have been the subject, for example, of US patents 4,322,425, 4,223,137, 4,072,683, 4,068,076,

4,026,897, 4,022,784, 4,022,776, describing derivatives of

Ateolol, of formula:

This product is used in the form of eye drops in the treatment of glaucoma and marketed in the form of tablets in the treatment of high blood pressure.

Other carbostyril ring derivatives have already been proposed, and there is a very rich literature on this subject. However, the compounds synthesized remain limited in their possibilities of use, either because their activity is not sufficiently intense, or because it does not prolong sufficiently over time.

The Applicant has discovered that certain carbostyriloximino-propanolamines, the structure of which has a fundamental difference with the derivatives cited above, resulting from the presence of an oximino function C = N - O-between the carbostyril nucleus and the propanolamine side chain surprisingly exert a beta-blocking activity useful firstly in the treatment of vascular disorders, but also an activity ocular in the treatment of glaucoma. The subject of the invention is, as a new product, carbostyriloximinopropanolamines of general formula (A)

dans laquelle :

in which :

- R ₁ is a hydrogen atom, or an alkyl radical containing from 1 to 3 carbon atoms,

- R ₂ is a hydrogen atom, or an alkyloxy, aryloxy radical, containing from 1 to 10 carbon atoms, aliphatic or aromatic,

- R ₃ is an optionally substituted alkyl or arylalkyl radical containing from 2 to 30 carbon atoms, linear or branched, aliphatic or aromatic.

The term “arylalkyl radical” denotes above radicals preferably comprising from 1 to 6 carbon atoms in the aliphatic part, the aryl part preferably being the phenyl radical, for example benzyl radical, optionally substituted.

Compounds A can be saturated at 3,4 or have a double bond at this level.

A subject of the invention is also the therapeutically acceptable acid salts of these compounds. These are salts of mineral acids such as phosphoric acid or organic acids, in particular monocarboxylic or dicarboxylic, maleic and fumaric, for example.

In the case of polyacids, the salts may be the salts corresponding to the neutralization of one or more of the acid functions.

The compounds of the invention have beta-blocking properties. They find a particularly interesting application in the treatment of cardiovascular disorders and in the field of ophthalmology.

They can be synthesized according to various methods, depending on the nature of the substituents.

In general, the compounds of the invention are obtained from the corresponding substituted acetyl-5, R ₁ , R ₂ (B) of formula

qui est transformé en la méthylcetone oxime (C) correspondante par réaction avec du chlorhydrate d'hydroxylamine selon le schéma

which is transformed into the corresponding methyl ketone oxime (C) by reaction with hydroxylamine hydrochloride according to the scheme

ladite methylcetone oxime (C) étant transformée en le (carbostyril-5 methylcetone oxime) - 3 epoxypropane- 1,2 de formule (D) correspondant par réaction avec de l'épibromhydrine selon le schéma

said methylcetone oxime (C) being transformed into the (carbostyril-5 methylcetone oxime) - 3 epoxypropane- 1,2 of formula (D) corresponding by reaction with epibromhydrin according to the scheme

ledit composé (D) étant enfin soumis à réaction avec une aminé R₃NH₂ pour conduire aux composés de formule (A) .

said compound (D) being finally subjected to reaction with an amine R ₃ NH ₂ to yield the compounds of formula (A).

Depending on the nature of the substituents R ₁ and R ₂ , three global synthesis schemes can be envisaged, which however all include the above process.

Ce schéma est utilisé en particulier lorsque R₂ est un radical alcoyloxy.

This scheme is used in particular when R ₂ is an alkyloxy radical.

In particular, it made it possible to synthesize the following compounds:

Diagram Nº 2:

Ce schéma est utilisé en particulier lorsque R₂ est hydroxy ou aryloxy.

This scheme is used in particular when R ₂ is hydroxy or aryloxy.

In particular, it made it possible to synthesize the following compounds:

Diagram Nº 3

II est utilisé lorsque R₁ et R₂ sont tous les deux un atome d'hydrogène.

It is used when R ₁ and R ₂ are both a hydrogen atom.

The following examples describe the manufacture of some initial compounds mentioned in the synthetic schemes 1,2 and 3.

A) ACETYL-5 METHOXY-8 CARBOSTYRILE (III)

In a three-necked flask of 21, equipped with a refrigerant and a pneumatic stirring, introduce 500 ml of carbon disulfide. 27 g (0.15 mole) of 8-methoxy-carbostyril are added, then 32 ml (0.45 mole) of acetyl chloride. Cool the mixture using an ice bath, then add in small portions 60 g (0.45 mole) of aluminum chloride. After addition, remove the ice bath and heat at 80 ° C for 10h with stirring. After this time, let cool. Decant carbon disulfide. Hydrolyze gently while cooling and stirring. Filter, wash with water. Take up the solid with chloroform. The aqueous phase is extracted 3 times with chloroform. Gather the chloroform phases. Dry in S0 ₄ Mg, evaporate the chloroform. Obtain 26 g (yield 79%).

B) ACETYL-5 HYDROXY-8 CARBOSTYRILE (VII)

Place 38.5 g (0.177 M) of 5-acetyl-8-methoxy-carbostyril (III) in a one-liter flask. Place the balloon under an argon atmosphere.

Quickly add 61.37 g (0.531 M) of pyridinium hydrochloride under argon.

Put the whole assembly under argon, then immerse the ball in an oil bath heated to 190 ° C. Maintain at 190 ° C for 2 h 30 with magnetic stirring.

Add 500 ml of water, filter, wash with water, then with cyclohexane. To dry. Obtain 33.6 g (93% yield). M => 260 ° C.

C) ACETYL-5 BENZYLOXY-8 CARBOSTYRILE (VIII) In a 500 ml flask, introduce 1.4 g of Nal, 18 g (0.088 M) of 5-acetyl-8-hydroxy carbostyril (VII) and 5.13 g (0.0434 M) of dry Na ₂ CO ₃ (+ 20% in excess).

Solubilize this mixture with an Acetone-Water solution (200 ml). Leave to stir for 1 hour at 60 ° C so that the Na salt forms well. Add 10 ml (0.088 M) of benzyl chloride. Let reflux overnight with magnetic stirring. Evaporate to dryness. The benzyl product crystallizes in water. Filter, dry. Obtain 26 g (approximately 100% yield). Mp 170 ° C. D) BENZYLOXY-8 CARBOSTYRIL-5 METHYL CETONE OXIME (IX)

Introduce 25.8 g (0.088 M) of 5-acetyl-benzyloxy-8 carbostyril (VIII) and 12.23 g (0.276 M) of hydroxylamine hydrochloride into a 250 ml flask. Solubilize everything in about 70 ml of pyridine.

Heat at reflux for 2 hours with magnetic stirring. Cool. Then pour the reaction mixture into about 2 liters of ice water. Shake for half an hour, the product precipitates.

Filter, wash with water. Recrystallize from a MeOH-AcOEt mixture.

Obtain 18.5 g (68% yield). E) [(BENZYLOXY-8 CARBOSTYRIL) -5 METHYLCETONE OXIME] -3 EPOXYPROPANE -1.2 (X)

Mix in a 250 ml flask of 30.8 g (0.1 mole) of benzyloxy-8 carbos tyril-5 methyl ketone oxime (IX) and 50 ml of DMF.

Place the balloon under argon. Slowly add in small portions, under a stream of argon, 5.28 g (0.22 M) of NaH.

Leave to stir for 2 hours. After this time, add the sodium salt dissolved in DMF to 13.7 g (0.1 mole) of epibromhydrin. Leave to stir for another 2 hours at room temperature. Then pour the mixture into approximately 4 1 of cold water. Shake for 15 min.

Extract with chloroform, dry over MgSO ₄ . Evaporate. Chromatograph the product on silica using chloroform as the eluent.

Obtain 16.5 g (45% yield).

F) METHOXY-8 DIHYDRO-3,4 CARBOSTYRILE (II)

In an autoclave bomb with rocking agitation, place 17.5 g (0.1 mole) of 8-methoxy-carbostyril (I) dissolved in 200 ml of absolute alcohol.

Add 30 drops of perchloric acid and 1.5 g of rhodium on 5% alumina; place a pressure of 20 Kg / cm ² for 24 Hours.

Filter the catalyst, evaporate the alcohol. Purify the product by chromatography on silica, using AcOEt 80 CHCl ₃ 20 as eluent.

Obtain 13.5 g (76% yield).

F = 98 ° (± 1) ° C.

G) ACETYL-5 MESYLOXY-8 CARBOSTYRILE (XI) In a 2 1 flask, place 24.7 g (0.12 mole) of 5-acetyl-8-hydroxy-carbostyril (VII) in a solution of 16 g of potassium hydroxide (0.28 mole) in 900 ml of water. Cool in an ice bath, then add dropwise 13.75 g (0.12 mole) of mesyl chloride. Leave to stir for 1 hour. Filter the solid that has formed. Recrystallize from methanol. Filter the insoluble material which is the right product. Obtain 22.4 g (yield 66%). H) ACETYL-5 CARBOSTYRILE (XII) In a 2 liter flask, introduce 26.1 g (0.093 mole) of 5-acetyl-8-mesyloxy-carbostyril (XI). Add 16.7 g (0.3 mole) of potash to 1 1 of water. Shake. Add 3 g of 10% palladium on charcoal and stir under a hydrogen atmosphere for 20 h. Acidify the reaction medium with concentrated HCl juice at pH = 5 and filter the solid which forms.

Obtain 12.1 g of 2 products. According to thin layer chromatography, the most polar product is 5-acetyl-8-hydroxy-carbostyril (VII). To separate the two, dissolve the 12.1 g in 200 ml of potassium hydroxide (N), dilute with 500 ml of water and extract continuously with ethyl acetate. Obtain 6.4 g (37% yield). Mp 252-254 ° C. I) ACETYL-5 METHOXY-8 DIHYDRO-3,4 CARBOSTYRILE (III)

Made from 8-methoxy-3,4-dihydro-carbostyril (II) and acetyl chloride in accordance with Example A. Yield 93%. J) ACETYL-5 HYDROXY-8 DIHYDRO-3,4 CARBOSTYRILE (VII) Made from acetyl-5 methoxy-8 dihydro-3,4 carbostyril (III) and pyridinium hydrochloride in accordance with Example B. Yield 89%. K) ACETYL-5 BENZULOXY-8 DIHYDRO-3,4 CARBOSTYRILE (VIII) Made from 5-acetyl-8-hydroxy-3,4-dihydro-carbostyril (VII) and benzyl chloride, in accordance with Example C Yield 90%. L) (BENZYLOXY-8 DIHYDRO-3,4 CARBOSTYRIL) -5 METHYLCETONE OXIME (IX)

Made from 5-acetyl-8-benzyloxy-3,4-dihydro-carbostyril (VII) and hydroxylamine hydrochloride, in accordance with Example D. Yield 93%. M) [(BENZYLOXY-8 DIHYDRO-3,4 CARBOSTYRIL) -5 METHYLCETONE OXIME] -3 EPOXYPROPANE -1.2 (X)

Made from (8-benzyloxy-3,4-dihydro-carbostyril) methyl ketone oxime (IX) and epibromhydrin, in accordance with Example E. Yield 45%. N) [(METHOXY-8 DIHYDRO-3,4 CARBOSTYRIL) -5 METHYLCETONE OXIME] (IV).

Made from 5-acetyl-8-methoxy-3,4-dihydro-carbostyril (III) and hydroxylamine hydrochloride according to Example D.

Yield 72%. O) (METHOXY-8 DIHYDRO-3,4 CARBOSTYRIL) -5 METHYLCETONE OXIME -3 EPOXYPROPANE -1,2 (V) Made from (methoxy-8 dihydro-3,4 carbostyril) -5 methyl ketone oxime (IV) and epibromhydrin, in accordance with Example E. Yield 59%. P) ACETYL-5 METHOXY-9 METHYL-1 CARBOSTYRILE (III)

Made from 8-methoxy-1-methyl carbostyril and acetyl chloride, in accordance with Example A. Yield 80%. Q) (METHOXY-8 METHYL-1 CARBOSTYRIL) -5 METHYLCETONE OXIME (IV) Made from 5-acetyl-8-methoxy-1-methyl-carbostyril (III) and hydroxylamine hydrochloride, in accordance with Example D Yield 75% R) [(METHOXY-8 METHYL-1 CARBOSTYRIL) -5 METHYLCETONE OXIME] -3 EPOXYPROPANE -1,2 (V) Made from (methoxy-8 methyl-1 carbostyril) -5 methyl ketone oxime (IV ) and epibromhydrin, in accordance with Example E. Yield 65%. S) CARBOSTYRIL-5 METHYLCETONE OXIME (XIII)

Made from 5-acetyl carbostyril (XII) and hydroxylamine hydrochloride, in accordance with Example D. Yield 90%. T) [(CARBOSTYRIL) -5 METHYLCETONE OXIME] -3 EPOXYPROPANE -1.2 (XIV) Made from carbostyril-5 methyl ketone oxime (XIII) and epibromhydrin, in accordance with Example E. Yield 45%.

The following examples illustrate the manufacture of the new compounds according to the invention, which are given in the table below: (see following page).

Exemple 1 : O-(tertbutylamino-& ol-2 propyl) (benzyloxy-8 carbostyrile)-5 méthylcetone oxime. Dans un ballon de 250 ml, intorduire 3,6 g (0,01 mole de [ (benzyloxy-8 corbostyrile)-5 méthylcetone oxime]-3 epoxypropane -1,2 (X),

Example 1: O- (tertbutylamino- & ol-2 propyl) (8-benzyloxy-carbostyril) -5 methyl ketone oxime. Into a 250 ml flask, add 3.6 g (0.01 mole of [(8-benzyloxy-corbostyril) -5 methyl ketone oxime] -3 epoxypropane -1.2 (X),

3.2 ml (0.03 mole) of terbtubylamine and 50 ml of absolute alcohol. Heat at reflux for 12 hours with magnetic stirring. Evaporate to dryness under vacuum. Pass the product on a silica column using AcOEt 95 as eluent

MeOH 5 EST ₂ 5. Yield 2.9 g (70%). Example 2: O- (tert-butylamino-1 ol-2 propyl) phosphate (8-hydroxy carbostyril) -5 methyl ketone oxime (compound No. 3).

In a 250 ml flask, dissolve 2.8 g (0.0066 mole) of O- (tert-butylamino-1 ol-2 propyl) (8-benzyloxy-carbostyril) -5 methyl ketone oxime in 100 ml of methanol. Add 400 mg of 10% palladium on activated carbon suspended in a little methanol. Shake for 10 min under a hydrogen atmosphere. Then filter the catalyst on filter paper. Evaporate the methanol in vacuo.

Yield 2.1 g (91%)

The base is converted into phosphate by dissolving it in water, adding phosphoric acid. Add acetonitrile, allow to crystallize.

Mp = 256 - 257 ° C

C ₁₈ H ₂₅ N ₃ O ₄ H ₃ PO ₄ (445.39)

Calculated: C 48.54; H 6.34; N 9.43

Found: 48.7 6, 35 9.57. Example 3: O- (isopropylamino-1 ol-2 propyl) (benzyloxy-8 carbostyril) -5 methyl ketone oxime. Made from [(8-benzyloxy-carbostyril) -5 methyl ketone oxime] -3 epoxypropane -1,2 (X) and isopropylamine, in accordance with Example 1. Yield 60%.

Example 4: O- phosphate (1-isopropylamino-2-ol propyl) (8-hydroxy carbostyril) -5 methyl ketone oxime (compound No. 4).

Made from O- (isopropylamino-1 ol-2 propyl) benzyloxy-8 carbos tyrile) -5 methyl ketone oxime and 10% palladium on activated carbon, in accordance with Example 2. Yield 95%. PF = 230 - 231 ° CC ₁₇ H ₂₃ N ₃ O ₄ · H ₃ PO ₄ (431.37) Calculated: C 47.33; H 6.07; N 9.74 Found: 47.46 6.02 9.89.

Example 5: O- [(α-methyl β-phenylethylamino-1) ol-2 propyl] (benzyloxy-8 carbos tyril) -5 methyl ketone oxime.

Manufactured from (benzyloxy-8 carbostyril) -5 methyl ketone oxime -3 epoxypropane -1,2 (X) and α-methyl β-phenylethylamine, in accordance with Example 1. Yield 57%.

Example 6: Oxalate of O- [(α-methyl p-phenylethylamino-1) ol-2 propyl] (8-hydroxycarbostyril) -5 methyl ketone oxime (compound No. 5).

Made from O- [(α -methyl β -phenylethyl lamino-1) ol-2 propyl] (benzyloxy-8 carbostyril) -5 methyl ketone oxime and 10% palladium on activated carbon, in accordance with Example 2.

Yield 93%. Mp = 213 - 214 ° C C ₂₃ H ₂₇ N ₃ O ₄ G ₂ H ₂ O ₄ (499.5)

Calculated: C 60.11; H 5.85; N 8.41

Found: 60.22 5.92 8.39. Example 7: O- (3,4-dymethoxyphenyleth4lamino-1) ol-2 propyl (benzyloxy-8 carbostyril) -5 methyl ketone oxime.

Made from (8-benzyloxy-carbostyril) -5 methyl ketone oxime -3 epoxypropane -1, 2 (X) and 3,4-dimethoxy phenylethylamine, in accordance with Example I. Yield 60%. Example 8: O- [(3,4-dimethoxyphenylethylamino -1) ol-2 propyl] oxalate (8-hydroxy carbostyril) -5 methyl ketone oxime (compound No. 6). Manufactured from O- [(3,4-dimethoxyphenylethylamino-1) ol-2 propyl] (8-benzyloxy-carbostyril) -5 methyl ketone oxime and 10% palladium on activated carbon, in accordance with Example 2. Yield 93%.

M.P. = 240 - 241 ° C

C ₂₄ H ₂₉ N ₃ O ₆ C ₂ H ₂ O ₄ (545.53)

Calculated: C 57.24; H 5.73; N 7.70

Found: 57.22 5.80 7.74.

Example 9: O- [(3,4-dimethoxyphenylethylamino) -1 ol-2 propyl] (8-benzyloxy-3,4-dihydro-carbostyril) -5 methyl ketone oxime.

Made from [(3,4-benzyloxy-3,4-dihydro-carbostyril) -5 methyl ketone oxime] -3 epoxypropane -1,2 (X) and -3,4 dimethoxy phenylethylamine, in accordance with Example 1. Yield 45% .

Example 10: Oxalate of O- [(3,4-dimethoxyphenylethylamino) -1 ol-2 propyl] (8-hydroxy-3,4-dihydro-carbostyril) -5 methyl ketone oxime (compound No. 7). Made from O - [(3,4-dimethoxyphenylethylamino) ol -2 propyl] (8-benzyloxy-3,4-dihydro-carbostyril) -5 methyl ketone oxime and 10% palladium on activated carbon, in accordance with the example 2. Yield 93%. Mp = 214 -215 ° C

C ₂₄ H ₃₁ N ₃ O ₆ C ₂ H ₂ O ₄ (547.54)

Calculated: C 57.02; H 6.07; N 7.67

Found: 56.95 6.04 7.77.

Example 11: O - [(α-methyl β-phenylethylamino) -1 ol-2 propyl] (benzyloxy-8 dihydro -3.4 carbos tyril) -5 methyl cetone oxime.

Made from [(3,4-benzyloxy-3,4-dihydro-carbostyril) -5 methyl ketone oxime] -3 epoxypropane -1,2 (X) and α-methyl β-phenylethylamine, in accordance with Example 1. Yield 59%.

Example 12: Oxalate of O- [(α-methyl β-phenylethylamino) -1 ol-2 propyl] (8-hydroxy-3,4-dihydro-carbostyril) -5 methyl ketone oxime (compound No. 8). Made from o - [(α-methyl β -phenylethyl lamino) -1 ol-2 propyl] (8-benzyloxy-3,4-dihydro-carbostyril) -5 methyl ketone oxime and 10% palladium on activated carbon, in accordance with Example 2. Yield 94%. Mp = 140-142 ° C.

C ₂₃ H ₂₉ N ₃ O ₄ C ₂ H ₂ O ₄ (501, 52)

Calculated: C 59.86; H 6.23; N 8.37

Found: 60.01 6.33 8.29.

EXAMPLE 13 Oxalate of o - [(3,4-dimethoxyphenylethylamino) -1 ol-2 propyl] (8-benzyloxy-3,4-dihydro carbosytril. Made from (3,4-benzyloxy-3,4-dihydro) carbostyril) -5 methyl ketone oxime -3 epoxypropane -1,2 (X) and 3,4-dimethoxy phenylethylamine, in accordance with Example 1. Yield 46% PF = 122-123 ° C

C ₃₁ H ₃₇ N ₃ O ₆ · C ₂ H ₂ O ₄ (637.66) Calculated: C 62.15; H 6.16; N 6.59 Found: 62.08 6.19 6.47. Example 14: O- (1-tertubylamino-2-ol-propyl) oxalate (8-methoxy-3,4-dihydro-carbos tyril) -5 methyl ketone oxime (compound No. 10). Made from (8-methoxy-3,4-dihydro-carbostyril) -5 methyl ketone oxime -3 epoxypropane -1,2 (V) and tertbutylamine, in accordance with Example 1.

Yield 87% m.p. = 216 - 217 ° C

C ₁₉ H ₂₉ N ₃ O ₄ · 0.5 C ₂ H ₂ O ₄ (408.46) Calculated: C 58.80; H 7.40; N 10.28 Found: 58.83 6.82 10.27.

Example 15: Oxalate of O- [(3,4-dimethoxyphenylethylamino) -1 ol-2 propyl] (8-methoxy-3,4-dihydro-carbostyril) -5 methyl ketone oxime (compound No. 11) Made from [ (8-methoxy-3,4-dihydro-carbostyril) -5 methyl ketone oxime] -3 epoxypropane -1,2 (V) and 3,4-dimethoxy phenylethylamine, in accordance with Example 1. Yield 50% PF = 153 - 155 ° CC ₂₅ H ₃₃ N ₃ O ₆ C ₂ H ₂ O ₄ (561.57)

Calculated: C 57.74; H 6.28; N 7.48 Found: 57.56 6.33 7.62. Example 16: Oxalate of O- (tert-butylamino-1 ol-2 propyl) (8-methoxy-1-methyl-carbostyril) -5 methyl ketone oxime (compound No. 1). Made from [(8-methoxy-1-methyl-carbostyril) -5 methyl ketone oxime] -3 epoxypropane -1,2 (V) and tert-butylamine, in accordance with Example 1. Yield 95% PF = 1180 - 181 ° C

C ₂₀ H ₂₉ N ₃ O ₄ C ₂ H ₂ O ₄ (465.49)

Calculated: C 56.76; H 6.71; N 9.03 Found: 56.86 6.67 9.16.

Example 17: O- (1-isopropylamino-2-ol-propyl) oxalate (8-methoxy-1-methyl-carbostyril) -5 methyl ketone oxime (compound No. 2).

Made from [(8-methoxy-1-methyl-carbostyril) -5 methyl ketone oxime] -3 epoxypropane -1,2 (V) and isopropylamine, in accordance with Example 1. Yield 85% PF = 197 - 198 ° CC ₁₉ H ₂₇ N ₃ O ₄ · C ₂ H ₂ O ₄ (451.46) Calculated: C 55.87; H 6.47; N 9.31 Found: 56.04 6.40 9.30. Example 18: O- (tert-butylamino-1 ol-2 propyl) fumarate (carbos tyril) -5 methyl ketone oxime (compound No. 12).

Manufactured from [(carbostyril) -5 methyl ketone oxime] -3 epoxypropane-1,2 (XIV) and tertbutylamine, in accordance with Example 1. Yield 87% PF = 136 - 138 ° CC ₁₈ H ₂₅ N ₃ O ₃ · C ₄ H ₄ O ₄ · H ₂ O (465.5) Calculated: C 56.76; H 6.71; N 9.03 Found: 57.13 6.76 9.67. Pharmacological results:

The present invention also relates to the use of the compounds of formula A as a medicament, as well than pharmaceutical compositions containing these drugs.

The pharmaceutical compositions according to the present invention can comprise one or more compounds of formula A optionally in combination with other active ingredients.

Medicines based on the abovementioned products and intended for local administration, in the form of aqueous solutions, eye drops, aqueous suspensions and ophthalmic ointments, have proved to be very effective as antihypertensives and antiglaucomatous, in particular during the treatment of glaucoma when intraocular pressure is greater than 22 mm of mercury. A series of experiments and observations made on collures prepared according to the invention with 0.1 to 1% by weight of active agent, in the fields of toxicology, pharmacology and therapeutics have given very interesting results.

In terms of toxicity, the experiments of oral and intraperitoneal administration to mice and to rats showed a total absence of acute toxicity and a lethal dose LD 50 clearly superior to the maximum doses of administration. The cytogenetic mutagenesis test (or micronucleus test) was negative in rats. In addition, the eye irritation index is practically zero in rabbits and it has been concluded that there is very good tolerance in the human eye.

In the pharmacological field, the results of experiments on rabbits have been highly significant. Tests for measuring the degree of allergenicity (Magnusson test), carried out on guinea pigs, showed that no allergic accident could occur.

Furthermore, experiments on mutagenic activity on various bacteria have made it possible to conclude that the substances according to the invention are not mutagenic.

Finally, the series of numerous clinical studies on patients, undertaken in various hospitals by Clinical experts in ophthalmology, have highlighted the great effectiveness of the drug.

In practice, the compositions according to the invention are particularly suitable for use as eye drops. In addition to the active constituent (or mixture) chosen from the aforementioned class of formula (A), the eye drops can contain various other constituents with various functions and playing in particular the roles: of isotonic agents, such as for example sodium chloride or chloride potassium; buffering agents, such as for example sodium or potassium phosphates, sodium borate; optionally preservatives such as non-toxic mercury salts, quaternary ammoniums, chlorhexidine salts. Of course, as in the case of the other eye drops, the compositions are diluted with distilled water.

The usual dose, which varies according to the subject to be treated and the condition in question, will be of the order of 1 to 4 applications per day of an eye drop containing 0.1% to 1% of active principle in humans. . The efficacy of the compounds according to the invention is demonstrated by comparative tests which are described in more detail below. The reference compound chosen is Timolol, that is to say the compound of basic formula:

utilise sous forme de son maléate.

uses in the form of its maleate.

The compound according to the invention subjected to these comparative tests is that referenced No. 3 in the general table above, that is to say the one whose preparation is reported in Example 2, and which has the basic formula:

utilisé sous forme de son phosphate. Les deux composés A et B ci-dessus sont solubilisés dans l'excipient suivant :

used in the form of its phosphate. The two compounds A and B above are dissolved in the following excipient:

. PO ₄ H ₂ K 0.113 g

. PO ₄ HK ₂ 0.25 g

. NaCl 0.63 g. Benzalkonium CHl 0.01 g

. H ₂ O qs. 100 ml.

The doses of the two compounds are equivalent to 0.5 g% of base. The trials are carried out on series of New Zealand albino rabbits weighing 3.5 to 4.5 kg, operating in double-blind mode, with therapeutic rests between treatments. Measures without treatment were also made, by local anesthesia of the eye of rabbits with posicain, in order to be able to follow the evolution of the intraocular pressure (IOP) in animals. Glaucoma was caused in the right eyes of rabbits by intraocular injection of: alpha-chymo tryps ine according to the SEARS method (Am. J. Ophtalmo 1974, 71p. 378) modified by VAREILLES & Al (Am. J / ophtalmo 1979, 210, P.561). The presence of glaucoma is characterized by the determination of the flow coefficient, from tonographic measurements, the eye being considered to be glaucomatous when this coefficient is less than 0.12 (ZANEN, J .FR. Ophtalmol 1980, 3,9 , pp. 209-218). The IOPs were measured every half hour during the first three hours and then every hour until the 7th hour. At the same time, the effect of local thesis donkeys was measured, each measurement being made on both eyes at the same time, the results of the left untreated eye being used as control tests.

The results are as follows: 1. Hypotensive ocular activity.

The test gave the results gathered in the table below and illustrated by the curves of FIG. 1 appended.

BILATERAL "t" TEST: comparison of the ocular hypotensive activity of compounds A and B at 0.5 g% base (N = 5).

F tabulated at 2.5% point: 9.60 for p = 0.05 (La = 4, Lb = 4) t tabulated for p = 0.05: 2.306 (dof = 8) + Change in IOP expressed in%.

These results show an effectiveness of compound B according to the invention greater than that of Compound A with bare. We see in particular that with compound B, the IOP falls very quickly to its minimum value, reached much later with the compound A, and remains there much longer, since after 7 hours, the IOP is still very low with compound B, while it has almost recovered its initial value with compound A.

The superiority of the compound according to the invention in its main use is therefore demonstrated. 2. Thesy donkey effect.

The local anesthetic effect of each compound is demonstrated after instillation on the cornea of non-glaucomatous rabbits by the number of pulses on the cornea before obtaining the palpebral reflex, after 30 minutes, 60 minutes, 90 minutes. .., until 6 am. The results are collated in the table below:

STATISTICAL ANALYSIS: determination of the mean and standard deviation of the local anesthetic effect (expressed in number of pulses on the cornea) obtained after instillation of the two compounds A and B in the healthy eye of 8 rabbits.

These tests prove that the anesthetic effect of Compound B according to the invention is zero, and that its tolerance is good.

This side effect is of great importance, since a notable anesthetic effect of this kind drug represents a drawback in their implementation. On the contrary, it is known that Timolol has this drawback.

Finally, clinical trials on humans have confirmed these results, in that:

- For practically all the eye drops compositions according to the invention, an effectiveness is obtained which is greater than that of the Timolol derivatives, at equal concentrations, in the antiglaucomatous activity, and this is combined with a high speed of action. On average, for all the active agents according to the invention, the P.I.O. went through a minimum of three hours after instillation and did not return to its initial value after seven hours.

- The anesthetic effect produced by the compositions according to the invention on the cornea is generally zero or very weak for the compounds of the invention unlike the case of timolol.

- the hypotensive action does not vary significantly with the concentration for all the products tested.

- The effectiveness of the active products according to the invention went through a maximum for the various concentrations used, the optimum dose being 0.1%, 0.25% or 0.50% depending on the case (% relative to the weight total eye drops). - The activity study on normal intraocular pressure in humans has shown that the drugs tested rapidly drop the intraocular pressure after instillation of a single drop of eye drops. In patients with chronic open-angle glaucoma, the average blood pressure drop was 13 to 16 mm Hg for an instillation of eye drops dosed at 0.25% in active ingredient.

- finally, clinical trials on humans have not made it possible to highlight any annoying side effects such as, for example, bronchial or cardiovascular disorders observed following the use of ethers-oxides or ethers oximes, having a chemical structure close to that of the products of the invention.

The new eye drops according to the invention have therefore been found to be, in general, excellent therapeutic agents for the treatment of glaucoma.

The compositions of two eye drops according to the invention are given below, having given excellent results when they have been administered to patients with glaucoma, at the rate of two drops per 24 hours.

Column 1:

Compound B 0.5 g

PO ₄ H ₂ K 0.113 g

PO ₄ HK ₂ 0.25 g

Sodium chloride 0.63 g

Benzalkonium HCl 0.01 g

H ₂ O qs 100 ml

Eye drops 2:

Compound B 1.0 g

PO ₄ H ₃ K 0.113 g

PO ₄ HK ₂ 0.25 g

Sodium chloride 0.63 g

Potassium sorbate ... 0.33 g

H ₂ O qs 100 ml

Claims

1. Carbos tyriloximinopropano lamines of general formula (A):

in which: R ₁ is a hydrogen atom, or an alkyl radical containing from 1 to 3 carbon atoms, R ₂ is a hydrogen atom or an alkyl, aryloxy radical, containing from 1 to 10 carbon atoms, aliphatic or aromatic, R ₃ is an optionally substituted alkyl or arylalkyl radical containing from 2 to 30 carbon atoms, linear or branched, aliphatic or aromatic. 2. Compounds according to claim 1, chosen from the following compounds: - O- (tert-butylamino-1 ol-2 propyl) (8-methoxy-1 methyl-carbostyril) -5 methyl ketone oxime, - O- (isopropylamino-1 ol-2 propyl) 8-methoxy-1 methyl carbos tyril) - 5 methyl ketone oxime, - O- (tert-butylamino-1 ol-2 propyl) (8-hydroxy carbostyril) -5 methyl ketone oxime, - O- (isopropylamino-1 ol-2 propyl) (8-hydroxy carbostyril) -5 methyl ketone oxime, - O- 1 [(α-methyl β-phenylethylamino-1) ol-2 propyl] (8-hydroxy carbos tyril) -5 methyl ketone oxime, - O - [(3,4-dimethoxyphenylethylamino-1) ol-2 pro pyl (8-hydroxy carbostyril) -5 methyl ketone oxime, - O- (3,4-dimethoxyphenylethylamino) -1 ol-2 propyl (8-hydroxy-3,4-dihydro-carbostyril -5 methyl ketone oxime, - O- (-methyl -phenylethylamino) -1 ol-2 propyl (8-hydroxy-3,4-dihydro-carbostyril) -5 methyl ketone oxime, - O- (3,4-dimethoxyphenylethylamino) -1 ol-2 propyl (8-benzyloxy-3,4-dihydro-carbostyril-5 methyl ketone oxime, - O- (tert-butylamino-1 oI-2 propyl) (8-methoxy-3,4-dihydro-carbostyril) -5 methyl ketone oxime, - O- (3,4-dimethoxyphenylethylamino) -1 ol-2 propyl (8-methoxy-3,4-dihydro-carbostyril) -5 methyl ketone oxime, - O- (tert-butylamino-1 ol-2 propyl) (carbostyril) -5 methyl ketone oxime. 3. Method for preparing a compound (A) according to any one of claims 1 and 2, characterized in that one starts from the acetyl-5 derivative, R ₁ , R ₂ substituted corresponding (B) of formula

which is transformed into the corresponding methyl ketone oxime (C) by reaction with hydroxylamine hydrochloride according to the scheme

said methyl ketone oxime (C) being transformed into the (carbostyril-5 methyl ketone oxime) -3 epoxypropane -1,2 of formula (D) corresponding by reaction with epibromhydrin according to the scheme

said compound (D) being finally subjected to reaction with an amine R ₃ NH to yield the compounds of formula (A). 4. As new drugs which can be used in the cardiovascular and ophthalmic fields, the compounds of formula (A) according to any one of claims 1 and 2, as well as their pharmaceutically acceptable acid salts.