CH635328A5 - Derivatives of N-(5-tetrazolyl)benzamide and pharmaceutical composition containing them - Google Patents

Description

The present invention includes the pharmaceutically acceptable salts of the compounds of formula (I) with pharmaceutically acceptable bases. The term “pharmaceutically acceptable salts” means salts whose cations are relatively harmless to the animal organism when they are used in therapeutic doses, so that the beneficial pharmacological properties of the original compounds of general formula (I) are not adversely affected by side effects attributable to cations. Among the salts which are suitable, there may be mentioned the alkali metal salts, for example sodium and potassium, the ammonium salts and the amine salts known in the art to be pharmaceutically acceptable, for example ethylenediamine, choline, diethanolamine, triethanolamine, octadecyamine, diethylamine, triethylamine, 2-amino-2-hydroxymethyl-1,3-propanediol and (3,4-dihydroxyphenyl) -1 isopropylamino-2 ethanol.

The pharmaceutically acceptable salts can be prepared by reacting together a compound of formula (I) and the appropriate base, for example hot, with an appropriate solvent or without solvent, followed by recrystallization from an appropriate solvent, by example a hydroxylic solvent, such as water, of the salt thus formed.

In the present text, when we speak of compounds of formula (I), we also mean their pharmaceutically acceptable salts, when the context so requires.

The benzamide derivatives according to the present invention have interesting pharmacological properties, in particular valuable properties for the treatment of respiratory disorders which are manifested by the interaction of antibodies fixed to the tissues with specific antigens, such as asthma. allergic bronchial.

The compounds encompassed by formula (I) as defined above and in which (R ′) n represents an alkyl group, preferably methyl or ethyl, R2 represents a hydrogen atom or an alkyl group, preferably methyl, and R3 represents a hydrogen atom or an alkyl group, preferably containing from 1 to 3 carbon atoms, for example a methyl or isopropyl group, or represents a phenyl or benzyl group, as well as their pharmaceutically acceptable salts, are particularly important.

The compounds encompassed by formula (I) as defined above and in which (R1) ,, represents a substituent in position 5 on the ring, while the group - CR2 = NOR3 is in position 3 on the ring, are especially important.

Among the individual compounds of formula (I) which are of particular importance, the following may be mentioned:

A. 5-Ethyl-2-hydroxy (1-hydroxyimino-ethyl) -3 N- (5-tetrazolyl) -benzamide

B. Ethyl-5 hydroxy-2 (methoxyimino-1 ethyl) -3N- (tetrazolyl-5) - • benzamide

C. 5-Ethyl-2-hydroxy (1-isopropoxyimino-ethyl) -3 N- (5-tetrazolyl) -benzamide

D. (Benzyloxyimino-1 ethyl) -3 ethyl-5 hydroxy-2 N- (tetrazolyl-5) -benzamide

E. Hydroxy-2 (1-hydroxyimino-ethyl) -3 methyl-5 N- (tetrazolyl-5) -benzamide

F. Hydroxy-2 (1-methoxyimino-ethyl) -3 methyl-5 N- (tetrazolyl-5) -benzamide

G. Hydroxy-2 (isopropoxyimino-1 ethyl) -3 methyl-5 N- (tetra-zolyl-5) -benzamide

H. 5-Ethyl-2-hydroxy (1-phenoxyimino-ethyl) -3 N- (5-tetrazolyl) -benzamide

I. 2-Hydroxy-3-methyloxyiminomethyl-5-methyl-N- (5-tetrazolyl) -benzamide and their pharmaceutically acceptable salts.

The letters A to I are assigned to the compounds for easy reference in the rest of this text, for example in the tables.

In pharmacological tests, the compounds of formula (I) suppress the passive anaphylactic skin reaction (CAP) resulting from the combination of reagin antibodies attached to tissues with the appropriate antigenic substance (called reagin /

allergen), these tests being performed in a manner similar in essence to that described by Ogilvie ["Nature" (Lond.) (1964), 204, 91-92; "Immunology" (1967), 12,112-131]. In the method used to test these compounds, sera are obtained from rats which have been infected with larvae of the parasitic nematode Nippostrongylus brasiliensis \ as a result of the parasitic infection, reactin antibodies are formed in the host mammal and are found in sera removed from these animals. Other rats, not infected, receive intradermal injections of appropriate dilutions of these sera and they are given the allergenic substances accompanied by Evans blue dye, intravenously, 48 h later.

The allergenic substances consist of the supernatant fluid after centrifugation of homogenates of adult worms Nippostrongylus brasiliensis which have macerated in Tyrode's solution. The CAP reaction sites are made visible by the diffusion of Evans blue dye from the circulatory network in these areas due to the increase in capillary permeability caused by the release of biologically active substances by the cells in which the binding reacts. / allergen has occurred. The compounds of formula (I), when administered to rats intravenously just before the injection of allergen, or orally 30 min before the intravenous injection of allergen, are capable of preventing the development of the CAP reaction, as shown in Tables I, II and III.

Table I shows the intravenous dose, expressed in milligrams per kilo of body weight of the animal, which produces a 100% inhibition of the CAP reaction (ED100).

Table II shows the percentage inhibition of the CAP reaction produced by an oral dose of 100 mg / kg of body weight of the animal.

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Table III shows the oral dose, expressed in milligrams per kilogram of body weight of the animal, which produces a 50% inhibition of the CAP reaction (ED50).

Table I

Compound

AT

B

VS

D

E

F

G

H

I

DEioo

0.005

0.01

0.2

0.05

0.05

0.02

0.05

0.02

1

Table II

Table V

Compound

AT

B

VS

D

E

F

G

5

Concentration

1

1

of the solution to be tested or or

1

1

2

2

2

(% by weight / vol.)

2 *

2 *

10

DLS0

300

240

140

140

410

320

168

* For lower doses, use the 1% solution and, for higher doses, the 2% solution.

Compound

AT

B

VS

D

E

F

G

% inhibition

43

29

36

30

78

87

48

Table III

Compound

AT

B

VS

D

e

F

G

H

I

de50

100

0.3

0.48

0.59

1.0

3.2

0.77

0.83

6.3

The usefulness of the compounds of formula (I) is reinforced by the fact that they have only a very low toxicity with regard to mammals, which the following tests demonstrate:

Acute oral toxicity in mice

Each mouse is treated, orally, with one of the compounds of formula (I), and the mice are placed under daily observation until there have been at least 3 consecutive d without any death. The LD 50 figures obtained (lethal dose for 50% of the mice tested) appear in Table IV, expressed in milligrams per kilo of body weight of the animal.

Table IV

Compound

AT

B

c d

F

G

dl50

> 1000

> 1000

> 1000

> 1000

> 1000

> 1000

Thus, according to a characteristic of the present invention, the compounds of formula (I) are prepared from compounds of general formula:

conh-

NOT

NOT

s

(II) .nh i

NOT

When the LD50 is indicated as> 1000, a more precise estimate of the LDS0 was not possible due to the too small number of deaths, even at the highest dose used, 1000 mg / kg .

Acute intravenous toxicity in mice

Each mouse is treated, intravenously, with an aqueous solution of the triethanolamine salt of one of the compounds of formula (I), and the mice are observed until there have been at least 3 consecutive d without any death. The LD50 figures obtained are shown in Table V, expressed in milligrams per kilogram of the animal's body weight.

The aqueous solutions are prepared as follows:

A mixture of the test compound and water is gradually treated with triethanolamine until complete dissolution. The solution is then diluted with water to a content of the test compound of 1%, or 2%, w / v.

Various volumes of these solutions are then administered to the mice.

(Table at the top of the next column)

The compounds of formula (I) can be prepared by application or adaptation of known methods.

By known methods is meant, in the present text, methods previously used or described in the literature.

in which R1, R2 and n are as defined above, by application or adaptation of known methods for the preparation of oximes from aldehydes and ketones, for example by reaction with compounds of general formula:

H2NOR3 (III)

wherein R3 is as defined above, in the form of one of their salts, for example a hydrochloride.

Generally, the reaction is carried out in the presence of a base, for example the hydroxide, carbonate or bicarbonate of an alkali metal, for example sodium hydroxide, sodium carbonate or sodium bicarbonate, in a polar medium such as N-40 methylpyrrolidone, and at a temperature close to or above ambient temperature, for example at 15-100 ° C.

The compounds of general formula (II) are described and claimed in British patent application No. 46174/76, and in French patent application No. 77.33193, of the proprietor.

"According to another characteristic of the present invention, the compounds of formula (I), except those in which R1 represents an alkylamino, amino or carboxy group, are prepared by reaction of 5-amino-tetrazole with carboxylic acids of general formula :

coch

(IV)

2 "3 cr = ncft in which R4 represents a halogen atom (ie fluorine, chlorine, bromine or iodine) or an alkyl, alkoxy, alkylthio, alkylsulfonyl or alkylsulfamoyl group, straight or branched , containing from 1 to 6 carbon atoms, a dialkoylsulfamoyl, dialkoylamino or dialkoylcarbamoyl group, in which the two alkyl groups can be identical or different and each contain 1 to 4 carbon atoms, an alkoxycarbonylamino, alkylcarbamoyl group or alkanoylamino, straight or branched chain, containing from 2 to 6 carbon atoms, or a hydroxy, nitro, tri-fluoromethyl, aryl (for example phenyl), benzyloxycarbonyl- group

5

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amino, sulfamoyl, tetrazolyl-5 or carbamoyl, and n represents 0.1 or 2, the substituents R4 being identical or different when n represents 2, and R2 and R3 are as defined above.

The reaction between the 5-amino tetrazole and the carboxylic acids of formula (IV) can be carried out in the presence of a condensing agent such as dicyclohexylcarbodiimide in the presence of a solvent such as pyridine.

The aldehydes and ketones of formula (II) can be prepared by application or adaptation of known methods.

For example, the compounds of formula (II), except those in which R1 represents an alkylamino, amino or carboxy group, can be prepared by reaction of 5-amino-tetrazole with carboxylic acids of general formula:

oh coch h

(R

in which R4, n and R2 are as defined above, or, except when R1 represents an alkylamino, amino or carboxy group, with esters of these acids, of general formula:

oh cocr

= 0

in which R5 represents a halogen atom (that is to say fluorine, chlorine, bromine or iodine) or an alkyl, alkoxy, alkylthio, alkylsulfonyl or alkylsulfamoyl group, containing a straight or branched chain, containing from 1 to 6 atoms carbon, a dialkoylsulfamoyl, dialkoylamino or dialkoylcarbamoyl group, in which the two alkyl groups may be identical or different and each contain from 1 to 4 carbon atoms, an alkoxycarbonylamino, alkylcarbamoyl or alkanoylamino group, containing a straight or branched chain from 2 to 6 carbon atoms, or a hydroxy, nitro, tri-fluoromethyl, aryl (for example phenyl), benzyloxycarbonylamino, sulfamoyl, tetrazolyl-5 or carbamoyl group, and n represents 0.1 or 2, the substituents R5 being identical or different when n represents 2, R6 represents a straight or branched chain alkyl group containing from 1 to 4 carbon atoms and R2 is as defined above, or alternatively, except when R1 represents an alkyl group o, alkoxycarbonylamino, alkanoylamino, hydroxy, benzyloxycarbonylamino, amino, carboxy or carbamoyl, with the acyl halides of the above acids, of general formula:

oh cox cr = 0

wherein R7 represents a halogen atom (i.e. fluorine, chlorine, bromine or iodine) or an alkyl, alkoxy, alkylthio, alkylsulfonyl or alkylsulfamoyl group, containing 1 to 6 atoms carbon, a dialkoylsulfamoyl, dialkoylamino or dialkoylcarbamoyl group, in which the two alkyl groups may be identical or different and each contain from 1 to 4 carbon atoms, a straight or branched chain alkylcarbamoyl group containing from 2 to 6 carbon atoms, or a nitro, trifluoromethyl, aryl (for example phenyl), sulfamoyl or tetrazolyl-5 group, and n represents 0.1 or 2, the substituents R7 being identical or different when n represents 2, X1 represents a chlorine or bromine atom and R2 is as defined above.

The reaction between 5-amino tetrazole and the carboxylic acids of formula (V) can be carried out in the presence of a condensing agent, for example in the presence of dicyclohexylcarbodiimide in the presence of a solvent such as pyridine, or, except when R4 represents an alkanoylamino, alkoxycarbonylamino, hydroxy, benzyloxycarbonylamino or carbamoyl group, in the presence of phosphorus trichloride, preferably in the presence of an inert solvent such as benzene, toluene or xylene, preferably in an anhydrous medium, at temperatures, for example, between 10 and 100 ° C.

The reaction between 5-amino tetrazole and the esters of formula (VI) can be carried out with or without a solvent such as a lower alkanol (for example methanol), an aromatic solvent (for example xylene) or dimethylformamide , preferably hot and optionally in the presence of an alkali metal alkoxide containing from 1 to 4 carbon atoms.

The esters of formula (VI) can be prepared from the corresponding carboxylic acids of formula (V) by application or adaptation of known methods for the esterification of 2-carboxyphenols such as salicylic acid.

The reaction between the acid halides of formula (VII), which can be prepared from the corresponding carboxylic acids encompassed by formula (V), by application or adaptation of known methods, for example by reaction with thionyl chloride, phosphorus trichloride or oxalyl chloride, optionally in situ, and the 5-amino tetrazole may preferably be carried out in an inert solvent, for example benzene, toluene, xylene or pyridine and preferably hot, for example at the reflux temperature of the reaction mixture.

The compounds of formula (II), except those in which R1 represents an alkylthio, nitro or benzyloxycarbonylamino group, can also be prepared by reduction of compounds of general formula:

conh cr = 0

wherein R8 represents a halogen atom (i.e. fluorine, chlorine, bromine or iodine) or an alkyl, alkoxy, alkylsulfonyl, alkylamino or alkylsulfamoyl group, containing from 1 to 6 atoms carbon, a dialkoylsulfamoyl, dialkoylamino or dialkoylcarbamoyl group, in which the two alkyl groups may be identical or different and each contain from 1 to 4 carbon atoms, an alkoxycarbonylamino, alkylcarbamoyl or alkanoylamino group, containing a straight or branched chain, containing 2 with 6 carbon atoms, or a hydroxy, trifluoromethyl, aryl (for example phenyl), amino, sulfamoyl, tetrazolyl-5 carboxy or carbamoyl group, and n represents 0.1 or 2, the substituents R8 being identical or different when n represents 2, and R2 is as defined above. In general, this reduction is carried out

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by hydrogenation in the presence of a catalyst such as palladium on black in an organic solvent, for example N-methyl-pyrrolidone-2 or ethanol.

The compounds of formula (II), except those in which R1 represents an alkyllamino, alkoxycarbonylamino, alkanoylamino, hydroxy, benzyloxycarbonylamino, amino, carboxy or carbamoyl group, can also be prepared by reaction of compounds of general formula:

m11)

conhcn conh

ï

(XI) ■ nh

N N

(r10s),

(IX)

10 in which R2, R10, R11, m and p are as defined above. The reaction can be carried out by the action of a peracid, for example m-chloroperbenzoic acid, in an inert solvent, for example solfolane, or by the action of hydrogen peroxide, preferably in the presence of a carboxylic acid (such as acetic acid) and optionally hot.

One can also prepare compounds of general formula:

in which R9 represents a halogen atom (i.e. fluorine, chlorine, bromine or iodine) or an alkyl, alkoxy, alkylthio, alkylsulfonyl or alkylsulfamoyl group, containing 1 to 6 atoms carbon, a dialkoylsulfamoyl, dialkoylamino or dialkoylcarbamoyl group, in which the two alkyl groups may be identical or different and each contain from 1 to 4 carbon atoms, a straight or branched chain alkylcarbamoyl group containing from 2 to 6 carbon atoms, or a nitro, trifluoromethyl, aryl (for example phenyl), sulfamoyl or tetrazolyl-5 group, and n represents 0.1 or 2, the substituents R9 possibly being identical or different when n represents 2, and R2 is as defined above, with hydrazoic acid or a salt thereof, for example sodium azide, potassium azide or ammonium azide.

In general, this reaction is carried out in an organic solvent, for example N-methylpyrrolidone-2 and, preferably, at a temperature between 0 and 120 ° C.

The compounds of formula (IX) can be prepared by reacting the compounds of formula (VII) with cyanamide. Preferably, this reaction is carried out in an inert solvent, in the presence of an acid-fixing agent, for example pyridine, which can also serve as a reaction medium.

One can also prepare compounds of general formula:

OH

20

O14),

conh

(R ^ Ri ^ NSC ^),

(XII)

nh

N M

\ r '

wherein R12 and R13 may be the same or different and each represents a hydrogen atom or a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, R14 represents a halogen atom (i.e. (say fluorine, chlorine, bromine or iodine) or an alkyl, alkoxy, alkylthio or alkylsulphonyl group, straight or branched chain, containing from 1 to 6 carbon atoms, a dialkoylamino group, in which the two alkyl groups may be identical or different and each contains 1 to 4 carbon atoms, or a hydroxy, nitro, trifluoromethyl, aryl (e.g. phenyl), tetrazolyl-5 or carboxy group, m represents 1 or 2, p represents 0 or 1, and the sum of m and p is 1 or 2, and R2 is as defined above, compounds encompassed by the general formula (II), by action of amines of general formula:

40

HNR12R13

(XIII)

in which R12 and R13 are as defined above, on compounds of general formula:

OH

(r11)

conh

(XIV) —nh

NOT

NOT

wherein R10 represents a straight or branched chain alkyl group containing from 1 to 6 carbon atoms, m represents 1 or 2, R11 represents a halogen atom (i.e. fluorine, chlorine, bromine or iodine) or an alkyl, alkoxy, alkylsulfonyl or alkylsulfamoyl group, straight or branched chain, containing from 1 to 6 carbon atoms, a dialcoylsulfamoyl group or dialcoylcarbamoyl group, in which the two alkyl groups may be identical or different and each contain from 1 to 4 carbon atoms, an alkoxycarbonylamino, alkylcarbamoyl or alkanoylamino group, straight or branched chain, containing from 2 to 6 carbon atoms, or a nitro, trifluoromethyl, aryl (e.g. phenyl), benzyloxycarbonylamino, sulfamoyl, tetrazolyl-5, carboxy group or carbamoyl, and p represents 0 or 1, or else R11 represents a hydroxy group in the para position relative to the tetrazolylcarbamoyl group, and the sum of m and p is 1 or 2, and R2 is as defined above, compounds encompassed by the general formula (II), by oxidation of compounds of the general formula:

in which R2, R14, m and p are as defined above. This reaction can be carried out in an organic solvent (eg ethanol), at room temperature or at a higher temperature.

The compounds of formula (XIV) can be prepared by the action of chlorosulfonic acid on compounds of general formula:

Oh

(XV)

(r1 ^)

■ conh-

"> / VT

b cr = 0

in which R2, R14, m and p are as defined above.

• nh I

NOT

7

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As can be seen, the position (s) of the group (s) - (S02R12R13) m which can be introduced in this way depend on the nature and the position of the group (s) - (R14) p and the reaction conditions employed to transform the compounds of formula (XV) into compounds of formula (XIV); they can be determined by a minimum of experimentation.

One can also prepare compounds of general formula:

OH

(XVI)

conh

NOT

(OgN)

(RÌ51

conh-

T ~

M M

OH

m16),

-conh-

H

cr2 = o each hold from 1 to 4 carbon atoms, an alkylcarbamoyl or alkanoylamino group, with a straight or branched chain, containing from 2 to 6 carbon atoms, or a hydroxy, nitro, trifluoromethyl, aryl group (for example phenyl), sulfamoyl, tetrazolyl-5, carb-5 oxy or carbamoyl, p represents 0 or 1, m represents 1 or 2, and the sum of m and p is 1 or 2, and R2 is as defined above, compounds encompassed by the formula general (II), by reaction of compounds of general formula:

-nh

(XVII)

nh:

40

(XVIII)

nh

N N

(r16).

(XIX)

conh wherein R15 represents a halogen atom (i.e. fluorine, chlorine, bromine or iodine) or an alkyl, alkoxy, alkylsulfonyl, alkylamino or alkylsulfamoyl group, containing from 1 to 6 carbon atoms, a dialkoylsulfamoyl, dialkoylamino or dialkoylcarbamoyl group, in which the two alkyl groups can be the same or different and each contains

1 to 4 carbon atoms, an alkoxycarbonylamino, alkylcarbamoyl or alkanoylamino group, straight or branched chain, containing

2 to 6 carbon atoms, or a hydroxy, nitro, trifluoromethyl, amino, sulfamoyl, tetrazolyl-5, carboxy or carbamoyl group, and p represents 0 or 1, m represents 1 or 2, and the sum of m and p is 1

or 2, and R2 is as defined above, compounds encompassed by the general formula (II), by nitration of compounds of the general formula:

/ VH

nh

NOT

NOT/

in which R2, R15, m and p are as defined above, by application or adaptation of known methods for the nitration of phenyl residues, for example by the action of a mixture of concentrated nitric acid and concentrated sulfuric acid. 45

As can be seen, the position (s) of the nitro group (s) which can be introduced in this way depend on the nature and the position of the group (s) - (Rls) p and on the reaction conditions employed for nitration; they can be determined by a minimum of experimentation. so We can also prepare compounds of general formula:

in which R16 represents a halogen atom (i.e. fluorine, chlorine, bromine or iodine) or an alkyl, alkoxy, alkylthio, alkylsulfonyl, alkylamino or alkylsulfamoyl group, containing a branched or 65 chain, containing 1 with 6 carbon atoms, a dialkoylsulfamoyl, dialkoylamino or dialkoylcarbamoyl group, in which the two alkyl groups may be the same or different and con-

in which R2, R16, m and p are as defined above, encompassed by the general formula (II), with acetic acid and hydrogen bromide.

The compounds of formula (IV) can be prepared, for example, from the compounds of formula (V) by application or adaptation of the methods described above for the preparation of the compounds of formula (I) from the compounds of formula (II) ; for example, especially when R3 represents an alkyl group of 1 to 3 carbon atoms, the polar medium mentioned above can be an aqueous alkanol, for example the corresponding alkanol of general formula:

R17OH (XX)

in which R17 represents an alkyl group of 1 to 3 carbon atoms.

The examples which follow illustrate the preparation of the new compounds of the present invention.

The reference examples which follow illustrate the preparation of starting materials used in the examples.

Example 1:

Compounds A, B, C, D, E, F and G

Hydroxylamine hydrochloride (2.8 g) and anhydrous sodium carbonate (1.6 g) are suspended together in N-methylpyrrolidone (40 ml) and the mixture is heated to 80 ° C for 10 minutes. Then added to the mixture 3-acetyl-5-ethyl-2-hydroxy- (tetrazolyl-5) -benzamide (5.5 g) and the mixture was stirred at 80 ° C for 15 h. This mixture is poured into water (300 ml) and the resulting mixture is acidified by treatment with concentrated hydrochloric acid. The solid precipitate is separated by filtration and recrystallized from aqueous dimethylformamide, which gives 5-ethyl-2-hydroxy (1-hydroxyimino-ethyl) -3 N- (5-tetrazolyl) -benzamide (3.9 g), mp 249-250 ° C (with decomposition).

By proceeding in a similar manner, but replacing the hydroxylamine hydrochloride used as starting material with the appropriate amounts of:

O-methylhydroxylamine hydrochloride,

O-isopropylhydroxylamine hydrochloride, and O-benzylhydroxylamine hydrochloride,

we prepare respectively:

5-ethyl-2-hydroxy (1-methoxyimino-ethyl) -3 N- (5-tetrazolyl) -benzamide, m.p. 272-275 ° C (with decomposition),

5-ethyl-2-hydroxy (1-isopropoxyimino-ethyl) -3 N- (5-tetrazolyl) -benzamide, mp 239-240 ° C (with decomposition) (recrystallized from 2-ethoxyethanol), and (1-benzyloxyimino-ethyl) -3 ethyl-5-hydroxy-2 N- (tetrazolyl-5) -benzamide, mp 233-235 ° C (recrystallized from ethanol).

Using the same procedure again, but replacing the 3-acetyl-5-ethyl-2-hydroxy-N- (5-tetrazolyl) -benzamide used

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as starting material, by the appropriate amount of 3-acetyl-2-hydroxy-5-methyl-N- (5-tetrazolyl) -benzamide, hydroxy-2 (1-hydroxyimino-ethyl) -3 methyl-5 N- is prepared ( tetrazolyl-5) -benzamide, mp 253-254 ° C (with decomposition) (recrystallized from a mixture of dimethylformamide and acetic acid).

Still proceeding in a similar manner, but using 3-acetyl-2-hydroxy-5-methyl-5-N (tetrazolyl) -benzamide as starting material and replacing the hydroxylamine hydrochloride used as other starting material with appropriate amounts of O-methylhydroxylamine hydrochloride and O-isopropylhydroxylamine hydrochloride, respectively:

hydroxy-2 (1-methoxyimino-ethyl) -3 methyl-5 N- (tetrazolyl-5) -benzamide, mp 283-285 ° C (with decomposition), and hydroxy-2 (isopropoxyimino-1 ethyl) - 3 methyl-5 N- (tetrazolyl-5) -benzamide, mp 244-245 ° C (with decomposition) (recrystallized from 2-ethoxyethanol).

Example 2:

Compound H

Using a procedure similar to that described in Example 1, but replacing the hydroxylamine hydrochloride used as starting material with the appropriate quantity of O-phenylhydroxylamine hydrochloride, 5-ethyl-2-hydroxy-2 is prepared ( phenoxy-imino-1 ethyl) -3 N- (tetrazolyl-5) -benzamide, mp 265-270 ° C (with decomposition) (recrystallized from 90% by weight formic acid).

Example 3:

Compound I

An agitated solution of 3-methoxyiminomethyl-5-methyl-salicylic acid (2.09 g) in anhydrous pyridine (25 ml) is treated with anhydrous 5-amino-tetrazole (0.24 g), then with dicyclohexylcarbodiimide. (2.27 g), and the resulting suspension is stirred at room temperature overnight.

The dry mixture is then evaporated and the residue is stirred with a mixture of concentrated ammonia (density 0.880; 25 ml) and dilute ammonia (2N; 25 ml) for 1 h. Then the mixture is filtered and the filtrate is acidified to pH 1 by treatment with concentrated hydrochloric acid. The resulting yellow solid is filtered off (1.8 g) and recrystallized from aqueous dimethylformamide, which gives 2-hydroxy-3-methoxyiminomethyl-5-methyl-5-tetrazolyl-benzamide (0 , 6 g), mp 275-276 ° C (with decomposition).

Reference example 1

Purified thionyl chloride (3 ml) is added to a suspension of dried acetyl-3-methyl-5 salicylic acid (1.94 g) in anhydrous benzene (30 ml), and the mixture is stirred while heating at reflux. for 90 min. The resulting clear solution is evaporated, under vacuum and below 40 ° C.

The residual oil is treated with anhydrous benzene and evaporated again under vacuum, and this process is repeated several times to remove the remaining thionyl chloride.

The 3-acetyl-5-methyl-salicyloyl chloride thus obtained is dissolved in benzene (30 ml), the solution is treated with anhydrous 5-amino-tetrazole (1.7 g) and the mixture is stirred while heating at reflux for 15 h. The mixture is then allowed to cool and is treated with petroleum ether (m.p. 40-60 ° C; 30 ml). The resulting solid is filtered off, washed with petroleum ether (m.p. 40-60 ° C) and stirred with hydrochloric acid (2N; 30 ml). The undissolved solid is filtered off, washed with hydrochloric acid (2N) and with water, then dried and recrystallized twice from a mixture of dimethylformamide and acetic acid. , which gives 3-acetyl-2-hydroxy-5-methyl-N- (5-tetrazolyl) -benzamide, mp 280-282 ° C (with decomposition).

Reference example 2

A mixture of 3-acetyl-5-ethyl-salicylic acid (55.0 g) and dicyclohexylcarbodiimide (60.1 g) in anhydrous pyridine (550 ml) is stirred for 1 h at 25 ° C. Anhydrous 5-amino-tetrazole (24.7 g) is then added to the mixture and stirring is continued at 60 ° C for 24 h. The pyridine is removed in vacuo and the residue is treated with ammonia (2N; 500 ml). The resulting slurry is stirred at 90-100 ° C for 15 min. The insoluble dicyclohexylurea is filtered off and the filtrate is acidified by treatment with concentrated hydrochloric acid. The resulting green precipitate is filtered off and recrystallized twice from aqueous dimethylformamide to give 3-acetyl-5-ethyl-2-hydroxy-N- (tetrazolyl) -benzamide (35.4 g) as a pale yellow solid, mp 257-258 ° C (with decomposition).

Reference example 3

By application or adaptation of the methods described by Amin et al., "J. Indian Chem. Soc. ”, 1964, 41, 833, with 2-acetoxy-5-methyl benzoic acid, 3-acetyl-5-methyl-salicylic acid is prepared, m.p. 132-134 ° C.

Reference example 4

By applying the method of Bumgardner and Lilly, "Chemis-try and Industry" (1962), 559, with hydroxylamine-O-sulfonic acid (42.5 g), O-phenylhydroxylamine is prepared, which dissolved in methylcyclohexane and treated with a saturated solution of hydrogen chloride in ethanol, which gives O-phenylhydroxylamine hydrochloride (4.3 g), mp I31 ° C (with decomposition) .

Reference example 5

Methoxylamine hydrochloride (10.02 g) is treated with a solution of sodium hydroxide (3.6 g) in water (50 ml), then with a solution of sodium hydroxide (3.6 g ) in water (50 ml), then with a solution of 3-formyl-5-methyl-salicylic acid (5.4 g) in methanol (70 ml), at room temperature and with stirring. The mixture is heated at 50 ° C for 20 h, then concentrated in vacuo to about half of its original volume, and acidified to pH 1 by treatment with concentrated hydrochloric acid. The resulting white solid is filtered off, washed with water and recrystallized from aqueous methanol to give 3-methoxyiminomethyl-5-methyl-salicylic acid (4.45 g), PF 161- 164 ° C, sufficiently pure to be used in Example 3 above.

Reference example 6

5-methyl salicylic acid (30 g) is treated according to the general method described in US Patent No. 3,833,660, which gives 3-formyl-5-methyl salicylic acid (19.0 g), PF 190 -194 ° C (recrystallized from aqueous ethanol).

The present invention encompasses in its field pharmaceutical compositions which comprise one or more compounds of formula (I) with a pharmaceutical carrier or coating. In clinical practice, the compounds of the present invention will normally be administered orally, sublingually, nasally, rectally or parenterally.

Solid compositions for oral administration include tablets, pills, dispersible powders and granules. In such solid compositions, the active compound (s) are mixed with at least one inert diluent, such as calcium carbonate, potato starch, alginic acid or lactose. These compositions can also contain, as is common practice, additional substances other than inert diluents, for example lubricants, such as magnesium stearate. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions and elixirs which contain inert diluents commonly used in pharmacy, such as water and paraffin oil. Outraged

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inert diluents, such compositions can also contain adjuvants, such as wetting agents, suspending agents, sweeteners, flavorings, perfumes and preservatives. The compositions according to the invention, for oral administration, also include capsules of absorbable material, such as gelatin, containing the active compound (s) with or without the addition of diluents or excipients.

The compound (s) can also be administered sublingually, by administration of relatively slow dissolving tablets, which, in addition to inert diluents such as are commonly used in pharmacies, may contain sweeteners, flavorings, perfumes and agents conservation.

Solid compositions for rectal administration include suppositories prepared in a manner known per se and containing the active compound (s).

The preparations according to the invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions. As solvents or non-aqueous suspension media, there may be mentioned propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. These compositions can also contain adjuvants, such as preservatives, wetting agents, emulsifiers and dispersants. These compositions can be sterilized, for example by filtration through a bacteria-retaining filter, by incorporation of sterilizing agents, by irradiation or by heating. They can also be manufactured in the form of sterile solid compositions, which can be dissolved extemporaneously in sterile water or in another sterile injectable medium.

The percentage of active ingredient in the compositions according to the invention can vary, while having to constitute a proportion such that a dosage suitable for the therapeutic effect sought can be obtained. Of course, several forms of unit dosages can be administered at about the same time. In general, the compositions should contain 0.1 to 50% by weight of the benzamide derivative, especially when they are in tablet form. When in aerosol form, as described below, these compositions must contain 0.2 to 5%, preferably 2 to 5%, by weight of benzamide derivative.

The active compound (s) can also be administered by known methods for the inhalation of medicaments which are not themselves gaseous under normal conditions of administration. Thus, a solution of the compound (s) in a suitable pharmaceutically acceptable solvent, for example water, can be nebulized using a mechanical nebulizer, for example a Wright nebulizer, to give an aerosol of particles. finely divided liquids suitable for administration by inhalation orally or nasally. Such solutions may contain stabilizers and buffer substances to give them an isotonic character, for example sodium chloride, sodium citrate and citric acid.

The means for producing self-propelling compositions giving rise to aerosols for the administration of medicaments are described in detail, for example, in US Pat.

635,328

The compound (s) can also be administered orally by inhalation in the form of a dry micronized powder which can be diluted with one or more suitable inert solid diluents, pharmaceutically acceptable, chosen, for example, from lyco-pode powder, boric acid , starch, bismuth subcarbonate and heavy magnesium carbonate.

The pharmaceutical compositions according to the present invention may contain, in addition to the compound or compounds of formula (I), one or more substances known per se to have a bronchodilator action in humans, for example isoprenaline, salbutamol and prostaglandin and (PGEj).

It is highly desirable that aerosols or micro-powders have particle sizes of less than about 10 µt, and preferably less than 5 µl, for example between 0.5 and 3 n, to ensure effective distribution to the bronchioles narrower. Preferably, the administration is carried out by means of devices making it possible to administer determined quantities of the active ingredients, for example by means of metering valves.

The dose to be used of the compounds of general formula (I) depends on the desired therapeutic effect, the mode of administration and the duration of the treatment. In adults, the doses are generally from 0.002 to 4 and preferably from 0.002 to 0.4 mg / kg of body weight per day when administered by inhalation in separate doses, and generally from 0.4 to 2000 and preferably from 0.4 to 40 mg / kg of body weight per day by oral administration.

The examples of compositions which follow illustrate pharmaceutical compositions according to the invention.

Composition example 1

5-ethyl-2-hydroxy (1-methoxyimino-ethyl) -3 N- (tetrazolyl-5) -benzamide micronized (600 mg) and the emulsifier YN (150 mg; mixture of ammonium compounds d 'phosphatid acids derived from rapeseed oil) in an aluminum flask (capacity 20 ml). Then added trichloromonofluoromethane (2.7 g), dichlorodifluoromethane (9.4 g) and dichlorotetrafluoroethane (4.4 g), so as to have a total volume of 12.5 ml. The vial is sealed with a metering valve releasing doses of 0.05 ml. Each aerosol dose (generated from 0.05 ml of suspension) released by the pressurized packaging thus obtained contains 2.4 mg of the benzamide derivative.

Composition example 2

Capsules for oral administration are prepared, in the usual manner, by filling gelatin capsules of size No. 2 with, for each, 255 mg of the following composition:

5-ethyl-2-hydroxy (1-methoxyimino-ethyl) -3 N-

(5-tetrazolyl) -benzamide

150 mg lactose

50 mg starch

50 mg magnesium stearate

2.5 mg aerosil (microfine silica)

2.5 mg

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Claims (7)

635,328 2 1. Therapeutically active benzamide derivatives corresponding to the general formula: OH (RM conh 2 3 CR = NÖR N N in which R1 represents a halogen atom or an alkyl group, alkoxy, alkylthio, alkylsulfonyl, alkylamino or alkyl-famoyl, straight or branched chain, each of these groups containing from 1 to 6 carbon atoms, a dialkoylsulfamoyl group , dialkoylamino or dialkoylcarbamoyl, in which the two alkyl groups may be identical or different and each contain from 1 to 4 carbon atoms, an alkoxycarbonylamino, alkyl-carbamoyl or alkanoylamino group, containing a straight or branched chain, containing 2 to 6 atoms carbon, or a hydroxy, nitro, tri-fluoromethyl, aryl, benzyloxycarbonylamino, amino, sulfamoyl, tetrazolyl-5, carboxy or carbamoyl group, and n represents 0.1 or 2, the substituents R1 being identical or different when n represents 2, R2 represents a hydrogen atom or a straight or branched chain alkyl group containing 1 to 5 carbon atoms, or an aryl group, and R3 represents a hydrogen atom or a ch alkyl group straight or branched elder containing 1 to 6 carbon atoms, optionally substituted by one or more substituents chosen from halogen atoms, straight or branched chain alkyl and alkoxy groups containing from 1 to 6 carbon atoms, and groups hydroxy, trifluoromethyls and nitro and their pharmaceutically acceptable salts. 2. Benzamide derivatives according to claim 1, in which (Rl) n represents a substituent in position 5 on the phenyl ring and the group - CR2 = NOR3 is in position 3 on the phenyl ring, and their pharmaceutically acceptable salts. 3. Benzamide derivatives according to claim 1, chosen from: 5-ethyl-2-hydroxy (1-hydroxyimino-ethyl) -3 N- (5-tetrazolyl) - benzamide, 5-ethyl-2-hydroxy (1-methoxyimino-ethyl) -3 N- (5-tetrazolyl) -benzamide, 5-ethyl-2-hydroxy (1-isopropoxyimino-ethyl) -3 N- (5-tetrazolyl) -benzamide, (benzyloxyimino-1 ethyl) -3 ethyl-5 hydroxy-2 N- (tetrazolyl-5) -benzamide, hydroxy-2 (1-hydroxyimino-ethyl) -3 methyl-5 N- (tetrazolyl-5) -benzamide, hydroxy-2 (1-methoxyimino-ethyl) -3 methyl-5 N- (tetrazolyl-5) -benzamide, hydroxy-2 (isopropoxyimino-1 ethyl) -3 methyl-5 N- (tetrazolyl-5) -benzamide, 5-ethyl-2-hydroxy (1-phenoxyimino ethyl) -3 N- (5-tetrazolyl) -benzamide, hydroxy-2 methoxyiminomethyl-3 methyl-5 N- (tetrazolyl-5) -benzamide. 4. Process for the preparation of a benzamide derivative according to claim 1, characterized in that a compound of general formula is reacted: conh in which R1, R2 and n are as defined in claim 1, with a compound of general formula: (I) -nh H, NOR3 (III) s in which R3 is as defined in claim 1 in the form of one of its salts, then, if desired, the product obtained is transformed into one of its pharmaceutically acceptable salts. 5. Method according to claim 4, characterized in that the reaction is carried out in the presence of a base, within a polar medium, preferably N-methylpyrrolidone, and at a temperature of 15 to 100 ° C. 6. Process for the preparation of a benzamide derivative corresponding to the general formula specified in claim 1, with the exception of these derivatives in the formula of which R1 represents an alkyl group. 15 mino, amino or carboxy, characterized in that 5-amino tetrazole is reacted with a carboxylic acid of general formula: Oh (r2 *) not COCH (IV) : NCTK in which R4 represents a halogen atom or an alkyl, alkoxy, alkylthio, alkylsulfonyl or alkylsulfamoyl group, straight or branched chain, each of these groups containing from 1 to 6 carbon atoms, a dialkoylsulfamoyl, dialcoylamino or dialkoylcarbamoyl group, in which the two alkyl groups may be identical or different and each contain from 1 to 4 carbon atoms, an alkoxycarbonylamino, alkyl-carbamoyl or alkanoylamino group, with straight or branched chain, containing from 2 to 6 carbon atoms, or a group hydroxy, nitro, tri-fluoromethyl, aryl, benzyloxycarbonylamino, sulfamoyl, tetra-zolyl-5 or carbamoyl, and n represents 0.1 or 2, the substituents R4 being identical or different when n represents 2, and R2 and R3 are such as defined in claim 1, then, if desired, the product obtained is transformed into one of its pharmaceutically acceptable salts. 7. Method according to claim 6, characterized in that the reaction is carried out in the presence of a condensing agent, preferably dicyclohexylcarbodiimide, in the presence of a solvent, preferably pyridine. 8. Pharmaceutical compositions which comprise, as active ingredient, at least one benzamide derivative according to one of claims 1, 2 or 3, or one of its pharmaceutically acceptable salts, in association with a pharmaceutical carrier or coating . The present invention relates to new therapeutically useful benzamide derivatives, to processes for their preparation and to pharmaceutical compositions containing them. It has been found that the new benzamide derivatives of general formula: (I) TT NOT NOT —NH i NOT 3 635,328 wherein R1 represents a halogen atom (i.e. fluorine, chlorine, bromine or iodine) or an alkyl, alkoxy, alkylthio, alkylsulfonyl, alkylamino or alkylsulfamoyl group, each of these groups containing from 1 to 6 carbon atoms, a dialkoylsulfamoyl, dialkoylamino or dialkoylcarbamoyl group, in which the two alkyl groups may be identical or different and each contain from 1 to 4 carbon atoms, a straight chain alkoxycarbonylamino, alkylcarbamoyl or alkanoylamino group or branched, containing from 2 to 6 carbon atoms, or a hydroxy, nitro, trifluoromethyl, aryl (for example phenyl), benzyloxycarbonylamino, amino, sulfamoyl, tetrazolyl-5, carboxy or carbamoyl group, and n represents 0.1 or 2 , the substituents R1 being identical or different when n represents 2, R2 represents a hydrogen atom or an alkyl group with a straight or branched chain containing from 1 to 5 carbon atoms, or an aryl group (p ar phenyl example), and R3 represents a hydrogen atom or a straight or branched alkyl group containing from 1 to 6 carbon atoms, optionally substituted by a phenyl group, or alternatively represents an aryl group (for example phenyl) optionally substituted with one or more substituents chosen from halogen atoms (that is to say fluorine, chlorine, bromine or iodine), straight or branched chain alkyl and alkoxy groups containing from 1 to 6 carbon atoms, and hydroxy, trifluoromethyl and nitro groups, as well as their pharmaceutically acceptable salts, have interesting pharmacological properties. It will be understood that each of the hydrogen atoms represented in the general formula (I) in the groups CH, CONH and NH can give rise to a tautomerism and that all the resulting tautomeric forms can be present in a greater or lesser proportion. and are in a state of dynamic equilibrium with each other. In addition, the substituents R1, R2 and R3 can contain chiral centers, and thus give rise to optical isomerism, and the group - CR2 = NOR3 can be in syn or anti configuration. The present invention encompasses all the optical and geometric isomers of general formula (I) and all the tautomers of the compounds of general formula (I), as well as their mixtures.