CH630619A5 - New derivatives of N-(5-tetrazolyl)benzamide - Google Patents

Abstract

The new derivatives of N-(5-tetrazolyl)benzamide have the formula below in which R<1> = F, Cl, Br, alkyl, alkoxy, alkylthio, alkylsulphonyl, alkanoylamino, alkylamino, alkylsulphamoyl, dialkylsulphamoyl, dialkylamino, dialkylcarbamoyl, alkanoyl, alkoxycarbonyl, alkoxycarbonylamino, alkylcarbamoyl, hydroxyl, formyl, nitro, trifluoromethyl, aryl, benzyloxycarbonylamino, amino, sulphamoyl, cyano, 5-tetrazolyl, carboxyl, carbamoyl or aroyl, and n = 1, 2 or 3. They can be used for the treatment of respiratory disorders, especially allergic bronchial asthma. <IMAGE>

Description

       

  
 

** ATTENTION ** start of the DESC field may contain end of CLMS **.

 in which Rs represents a fluorine, chlorine or bromine atom, or an alkyl, alkoxy, alkylthio, alkylsulfonyl or alkylsulfamoyl group, straight or branched chain, each of these groups containing from I to 6 carbon atoms, a dialcoylsulfamoyl group , dialkoylamino or dialkoylcarbamoyl (in which the two alkyl groups may be the same or different and each contain from I to 4 carbon atoms), an alkanoyl, alkoxycarbonyl or alkylcarbamoyl group, with straight or branched chain, containing from 2 to 6 carbon atoms , or a formyl, nitro, trifluoromethyl, aryl, sulfamoyl, cyano, tetrazolyl-5 or aroyl group, and n represents I, 2 or 3, the substituents R5 being identical or different when n represents 2 or 3,

   and X represents a chlorine or bromine atom, and in that, if necessary, the derivative obtained is transformed into a salt by reaction with a base.



   6. Process for the preparation of the benzamide derivatives according to claim I, which correspond to the general formula:
EMI2.1
 in which R1 and Roll, which are identical or different, each represent a hydrogen atom or an alkyl group with a straight or branched chain containing from 1 to 4 carbon atoms, r represents 1,2 or 3, R12 represents an atom of fluorine, chlorine or bromine, or an alkyl, alkoxy, alkylthio or alkylsulphonyl group, straight or branched chain, each of these groups containing from 1 to 6 carbon atoms, or a dialkoylamino group, in which the two alkyl groups can be identical or different and each contain from I to 4 carbon atoms, an alkanoyl or alkoxycarbonyl group, with a straight or branched chain,

   containing from 2 to 6 carbon atoms, or a hydroxy, formyl, nitro, trifluoromethyl, aryl, cyano, tetrazolyl-5, carboxy or aroyl group, and p represents zero, 1 or 2, the substituents R12 being identical or different when p represents 2, and the sum of r and p is 1, 2 or 3, and their salts, characterized in that an amine of general formula is reacted:
HNRI R11 (X) in which Rl and Rl l are as defined above, with a compound of general formula:
EMI2.2
 in which R12, r and p are as defined above, and in that, where appropriate, the derivative obtained is converted into a salt by reaction with a base.



   7. Pharmaceutical compositions comprising, as active substance, at least one benzamide derivative according to claim 1 or 2, or one of its pharmaceutically acceptable salts, in association with a pharmaceutical support or coating.



   The present invention relates to new benzamide derivatives useful in therapy, to processes for their preparation and to pharmaceutical compositions containing them.



   It has been found that the new benzamide derivatives represented by the general formula:
EMI2.3
 [in which R1 represents a fluorine, chlorine or bromine atom, or an alkyl, alkoxy, alkylthio, alkylsulfonyl, alkanoylamino, alkyllamino or alkylsulphoyl group, each of these groups containing from 1 to 6 atoms of 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 alkanoyl, alkoxycarbonyl, alkoxycarbonylamino or alkoylcarbamoyl group, containing a straight or branched chain, from 2 to 6 carbon atoms, or a hydroxy, formyl, nitro, trifluoromethyl, aryl (for example phenyl), benzyloxycarbonylamino, arhino, sulfamoyl group,

   cyano, tetrazolyl-5, carboxy, carbamoyl or aroyl (for example benzoyl), and n represents 1, 2 or 3, preferably 1 or 2, the substituents R being identical or different when n represents 2 or 3], 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 OH residues,
CONH and NH can give rise to a tautomerism and that all the resulting tautomeric forms can be present to a greater or lesser degree and are in a state of dynamic equilibrium with each other. In addition, the R1 substituents can contain chiral centers and thus give rise to optical isomerism. The present invention encompasses all optical isomers of general formula (I) and all tautomers of compounds of general formula (I) and mixtures thereof.



   The present invention includes the pharmaceutically acceptable salts of the compounds of formula (I) with pharmaceutically acceptable bases. By the term pharmaceutically acceptable salts is meant 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 compounds of general formula (I) from which they are derived are not upset by side effects attributable to these cations. Among the suitable salts, there may be mentioned the alkali metal salts, such as sodium and potassium, the ammonium salts and the amine salts known to be pharmaceutically acceptable, for example ethylenediamine, choline, diethanolamine, triethanolamine, octadecylamine, diethyla



  mine, triethylamine, amino-2 (hydroxymethyl) -2 propanediol-1,3 and (dihydroxy-3,4 phenyl) -l isopropylamino-2 ethanol.



   These pharmaceutically acceptable salts can be prepared by reaction of a compound of formula (I) and of the appropriate base, that is to say a base as described above, for example hot, with or without a solvent. , such as a hydroxylic solvent, such as water.



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



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



   Among the individual compounds of formula (I) which are of particular importance, the following may be mentioned:
AA 2-hydroxy-4-nitro N- (tetrazolyl-5) -benzamide;
AB 2-hydroxy (N, N-dimethylsulfamoyl) -5 -N- (tetrazolyl-5) -benzamide;
AC hydroxy-2 (N-methyl.N-isopropylsulfamoyl) -5
N- (tetrazolyl-5) -benzamide;
AD 5-hydroxy-2 N- (tetrazolyl-5) -benzamide;
AE 2-hydroxy dinitro-3,5 N- (tetrazolyl-S) -benzamide;
AF 2,5-dihydroxy N- (tetrazolyl-5) -benzamide;
AG 2-hydroxy-5-methyl N- (tetrazolyl-5) -benzamide;
AH 2-hydroxy-3-methyl-N (5-tetrazolyl) -benzamide;
AI 2-hydroxy-3-nitro N- (tetrazolyl.5) -benzamide;
AI 2,4-dihydroxy N- (tetrazolyl-5) -benzamide;
AK 2-hydroxy-4-methyl-N (5-tetrazolyl) -benzamide;
AL 3-bromo-2-hydroxy-N- (tetrazolyl-5) -benzamide;

  ;
AM 3-chloro-2-hydroxy (5-tetrazolyl) -benzamide;
AN 2-hydroxypropoxy-3 N- (tetrazolyl-5) -benzamide;
AO 2-hydroxy-5-nitro N- (tetrazolyl-5) -benzamide;
AP 2-hydroxy-5-methoxy N- (tetrazolyl-5) -benzamide;
AQ la (N, N-dibutylsulfamoyl) -5 hydroxy-2 N- (tetrazolyl-5) -benzamide;
AR 3-acetyl-2-hydroxy-5-methyl-N- (tetrazolyl-5) -benzamide;
AS 3-ethoxy-2-hydroxy (5-tetrazolyl) -benzamide;
AT 2-hydroxy-4-methoxy N- (tetrazolyl-5) -benzamide;
AU-3-chloro-5-hydroxy-2 N- (tetrazolyl-5) -benzamide;
AV acetyl-5 hydroxy-2 N- (tetrazolyl-5) -benzamide;
AW 3,5-diacetyl-2,4-dihydroxy (5-tetrazolyl) -benzamide;
AX 4-chloro-2-hydroxy-N- (tetrazolyl-5) -benzamide;
AY 3,5-dibromo-2-hydroxy-N- (tetrazolyl-5) -benzamide;
AZ 5-acetylamino-2-hydroxy N- (tetrazolyl-5) -benzamide;

  ;
BA tert.-butyl-4 hydroxy-2 N- (tetrazolyl-5) -benzamide;
BB acetylamino-4 hydroxy-2 N- (tetrazolyl-5) -benzamide;
BC trifluoromethyl-4 hydroxy-2 N- (tetrazolyl-5) -benzamide:
BD 4-fluoro-2-hydroxy (5-tetrazolyl) -benzamide;
BE 2-hydroxy-3-methoxy N- (5-tetrazolyl) -benzamide;
BF 2-hydroxy-5-methylthio N- (tetrazolyl-5) -benzamide; BG hydroxy-2phenyl-5N- (tetrazolyl-5) -benzamide;
BH 5-hydroxy-2 N- (tetrazolyl-5) -benzamide;
 BI 2-hydroxy-3-methylthio N- (tetrazolyl-3) -benzamide;
BJ 2-hydroxy-methylsulfonyl-3 N- (tetrazolyl-S) -benzimide;
BK hydroxy-2 bis (methylsulfonyl) -3.5 N- (tetrazolyl-5) -benzamide;
BL 5-formyl-2-hydroxy-N- (tetrazolyl-5) -benzamide;
 BM 5-bromo-2-hydroxy N- (tetrazolyl-5) -benzamide;

  ;
BN 2-hydroxy-methylthio-4 N- (tetrazolyl-5) -benzamide;
BO 2-hydroxy-methyl-5-sulfonyl N- (tetrazolyl-5) -benzamide;
BP 2-hydroxy-methyl-sulfonyl-4 N- (tetrazolyl-5) -benzamide;
BQ 5-benzyloxycarbonylamino-2-hydroxy-N- (tetra zolyl-S) -benzamide;
BR 4-benzyloxycarbonylamino-2-hydroxy-N- (tetrazolyl-5) -benzamide;
BS 5-amino-2-hydroxyN- (tetrazolyl-5) -benzamide;
BT la (N-tert.-butylsulfamoyl) -3 2-hydroxy-5-methyl
N- (tetrazolyl-5) -benzamide;
BU 3-acetyl-2-hydroxy-5-sulfamoyl N- (tetrazolyl-5) -benzamide;
BV 5-trifluoromethyl-2-hydroxy N- (tetrazolyl-5) -benzamide;
BW 3-acetyl-5-ethyl-2-hydroxy- (tetrazolyl-5) -benzamide;
BX 3-acetyl-2-hydroxy-4,5-dimethyl N- (tetrazolyl-5) -benzamide;
BY acetyl-3 sec.-butyl-5 hydroxy-2 N- (tetrazolyl-5) -benzamide;
BZ 3-acetyl-tert.-butyl-5-hydroxy-2 N- (tetrazolyl-5) -benzamide;

  ;
CA 3-hydroxy-2 N- (tetrazolyl-5) -benzamide;
CB 3-acetyl-5-bromo-2-hydroxy N- (tetrazolyl-5) -benzamide;
CC 3-acetyl-5-fluoro-2-hydroxy-N- (tetrazolyl-5) -benzamide;
CD 3-acetyl-2-hydroxy-5-propyl N- (tetrazolyl-5) -benzamide;
CE 2-hydroxy-5-methyl-3-propionyl N- (tetrazolyl-5) -benzamide;
CF 5-ethyl-2-hydroxy-3-propionyl N- (tetrazolyl-5) -benzamide;
CG butyryl-3 ethyl-5 hydroxy-2 N- (tetrazolyl-5) -benzamide;
CH 3-formyl-2-hydroxy-N- (tetrazolyl-5) -benzamide;
CI 3-formyl-2-hydroxy-5-methyl N- (tetrazolyl-5) -benzamide;
CJ 3-cyano-2-hydroxy-N- (tetrazolyl-5) -benzamide;
CK 3-cyano-2-hydroxy N- (tetrazolyl-5) -benzamide;
CL 3-cyano-2-hydroxy-5-methyl N- (tetrazolyl-5) -benzamide;
CM 2-hydroxy-5-methyl (5-tetrazolyl) -3 N- (5-tetrazolyl) -benzamide;
CN [N- (tetrazolyl-5) -carbamoyl] -3salicylic acid;

  ;
CO tert.-butylcarbamoyl-3 hydroxy-2 N- (tetrazolyl-5) -benzamide;
CP 3-hydroxy-3-dimethylamino N- (tetrazolyl-5) -benzamide;
CQ 5-acetyl-2-hydroxy-3-nitro N- (tetrazolyl-5) -benzamide;
CR 3-benzoyl-2-hydroxy-5-methyl-N- (tetrazolyl-5) -benzamide; and
CS 3-acetyl-2-hydroxy-5-nitro N- (tetrazolyl-5) -benzamide; as well as their pharmaceutically acceptable salts.

 

   The groups of letters from AA to CS are used to designate the compounds so that they can be easily referred to later in the course of the description, for example in the tables which follow.



   The preferred compounds of general formula (I) are those in which R1 represents a fluorine, chlorine or bromine atom, or an alkyl, alkoxy, alkylthio, alkylsulfonyl, alkanoylamino or alkylsulfamoyl group, each of these chains groups containing from 1 to 6 carbon atoms, a dialkoylsulfamoyl or dialkoylamino group (in which the two alkyl groups may be identical or different and each contain from 1 to 4 carbon atoms), an alkanoyl or alkylcarbamoyl group, with straight or branched chain , containing from 2 to 6 carbon atoms, or a hydroxy, formyl, nitro, trifluoromethyl, phenyl, benzyloxycarbonylamino, amino, sulfamoyl, cyano, tetrazolyl-5, carboxy or benzoyl group, and n is as defined above, and more particularly those of these compounds in which n represents 1 or 2,

   as well as their pharmaceutically acceptable salts.



   The compounds encompassed by the general formula (I) and in which one of the substituents R1 on the phenyl ring is a nitro, cyano, alkanoyl group (for example acetyl, propionyl or butyryl), formyl or tetrazolyl-5, the others R1 substituents possibly present (preferably not more than one) being as defined above, as well as their pharmaceutically acceptable salts, are of particular importance. In this class, the compounds AE, AI,
AO, BL, BU, BY, BZ, CC, CG, CH, CJ, CK, CQ and especially the compounds AR, BW, CA, DC, CE, CF, CM and CS, are of prime importance. The compounds AN, AP,
BB, BF, BR and, especially, BE, which do not belong to this class, are also of prime importance.



   In pharmacological tests, the benzamide derivatives of general formula (I) suppress the passive anaphylactic skin reaction (CAP) resulting from the combination of reagin antibodies attached to the tissues with the appropriate antigenic substance (called reactin-go gene binding), these tests being performed in a similar manner 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
Parasitic infection, reactin antibodies are developed in the host mammal and are found in the 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 hours 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. -allergene has occurred. The new compounds, when administered to rats intravenously just before the injection of allergen, or orally 30 minutes before the intravenous injection of allergen, are capable of preventing the development of the CAP reaction, as shown in Tables I, II and III below.



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



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



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



   Table I
Compound AA AB AC AD AE AF AG AH AI DEloo 10 2 5 1 0.05 1 1 0.5 0.5
 Compound AJ AK AL AM AN AO AP AR AS DEloo 10 10 10 5 0.5 0.2 0.5 0.1 1
 Compound AT AU AV AW AY AZ BA BB BD DEloo 5 2 10 5 5 10 10 1 10
 Compound BE BF BG BH BI BJ BK BL BM DEIoo 0.2 0.5 10 1 20 20 10 0.5 5
 Compound BN BO BQ BR BS BU BV BW BX
   DEloo 10 5 5 0.5 5 0.5 2 0.1 20
Composed BY BZ CA CB CC CD CE CF CG
DEioo 0.5 0.5 0.1 2 0.2 0.1 0.05 0.05 0.1
Compound CH Ct CJ CK CL CM CN CO CP
DEioo 0.5 2 0.5 0.2 2 0.05 1 5 2
Compound CQ CR CS
DEioo 0.2 1 0.1
 Table II
Compound AA AC AD AE AH At <RTI

    ID = 5. 4> At AK% inhibition 18 20 94 80 82 68 38 32
Compound AL AM AN AO AP AR AS AT% inhibition 69 82 87 48 75 42 76 8
Compound AU AV AW AY BA BB BD BE% inhibition 71 16 84 65 37 26 75 62
Compound BH BJ BK BL BM BN BO BS% inhibition 94 64 29 25 46 8 63 35
Compound BU BV BW BY BZ CA CB CC% inhibition 86 90 51 43 59 64 66 62
Compound CD CE CF CG CH Cl CJ CK% inhibition 64 99 41 55 75 70 50 89
Compound CL CM CN CO CP CQ CR CS% inhibition 26 64 43 26 68 56 22 54
 Table III
Compound AD AE AH AI AL AM AN AO
DEso 13 0.1-0.45 10 5-30 55 85 40 100
Compound AP AR AS AU BE BH BM BV BW
DEso 100 0.75 10 1.8 18 16 65 37 0.1
Compound BY BZ CB CC CE CF CG CH Cl
DEso 1.8 2.6 64 1.9 0.4 0.27 2.2 5.3 5.4
Compound CJ CK CN CP
DEso 37 50 20 26
 The utility of the benzamide derivatives of general formula (I) is enhanced by the

   fact that they have only a very low toxicity towards mammals, as demonstrated by the following tests:
 Acute oral toxicity in mice
 Each mouse is treated, orally, with one of the compounds of formula (I), and they are placed under daily observation until there have been at least 3 consecutive days without any death.     The LD 50 figures obtained (lethal dose for 50% of the mice tested) appear in Table IV below, expressed in mg per kg of body weight of the animal. 



   Table IV
Compound AD AE AG AH AI AL
DLso> 1000> 1000> 1000> 1000> 1000 794
Compound AN AO AP AQ AR AS
 DLso> 1000> 1000> 1000> 1000> 1000> 1000
Compound AU AV AW AX BA BB
DLso> 1000> 1000> 1000> 1000> 1000> 1000
Compound BE BG BH BT BW BX
DLso> 1000> 1000> 1000> 1000> 1000> 1000
Composed BY BZ CA CD CE CF
DLso> 1000> 1000> 1000> 1000> 1000> 1000
Compound CG Cl CQ CR CS
DLso> 1000> 1000> 1000> 1000> 1000
 When the LD 50 is indicated to be> 1000, it is that a more precise estimate of the LD 50 was not possible because of 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 or the sodium salt of one of the compounds of formula (I), and they are observed until there has been at least 3 consecutive days without any death.  The LD 50 figures obtained are shown in Table V below, expressed in mg per kg of body weight of the animal.  In Table V, Na means that the sodium salt was used, and T means the triethanolamine salt. 



   The aqueous solutions are prepared as follows:
 Triethanolamine salts
 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. 



   Sodium salts
 The test compound is dissolved in an aqueous sodium hydroxide solution (1 N) and the solution is brought to pH 8 by treatment with hydrochloric acid.  This solution is then diluted with water to a content of test compound of 2% w / v. 



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



   Table V
 Compound AD AE AG AH AI AL AN AO AP AQ AR AS AU
 Set Na T Na T T T T T Na Na T T T
 Content of the solution
 of test compound 2 2 2 2 2 2 2 2 2 2 2 2 2 by weight / vol. )
 DLso 480 490 670 770> 1000 540 480 870 950 280 430 560 245
 Compound AV AW AX BA BB BE BG BH BI BT BW BX BY
 set T T T T T T T T T Na Na T T
 Content of the solution *
 in test compound 2 2 2 2 2 2 1 lor 2 2 2 2 2
 (% by weight / vol. ) 2
 DLso 645 710 260 230 645 580 200 500 580 500 320 870 180
Compound BZ CA CD CE CF CG CJ CQ CR CS sel T T T T T T T T T T
Content of the solution * in test compound 2 2 2 2 2 lor 2 2 2 2 (n /, by weight / vol. ) 2
DLso 240 500 250 270 280 270> 1000 890 350 780 * for the lower doses, the 1% solution is used, and for the higher doses,

   the 2% solution is used.      



  boxy or carbamoyl) with halides of these acids, of general formula:
EMI8. 1
 [in which R5 represents a fluorine, chlorine or bromine 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 group dialkoylsulfamoyl, dialkoylamino or dialkoylcarbamoyl (in which the two alkyl groups may be the same or different and each contain from 1 to 4 carbon atoms), an alkanoyl, alkoxycarbonyl or alkylcarbamoyl group, with straight or branched chain, containing from 2 to 6 atoms of carbon, or a formyl, nitro, trifluoromethyl, aryl (for example phenyl), sulfamoyl, cyano, tetrazolyl-5 or aroyl (for example benzoyl) group, and n represents I, 2 or 3, preferably 1 or 2,

   the substituents R5 being identical or different when n represents 2 or 3, and X 'represents a chlorine or bromine atom]. 



   The reaction between the 5-amino-tetrazole and the carboxylic acids of formula (II) can be carried out in the presence of a condensing agent, such as N, N-dicyclohexylcarbodiimide, preferably in the presence of a solvent such as pyridine, or (except when R2 represents an alkanoylamino, alkoxycarbonylamino, hydroxy, benzyloxycarbonylamino, carboxy or carbamoyl group) phosphorus trichloride, preferably in the presence of an inert solvent such as benzene, toluene or xylene, preferably in anhydrous medium, at temperatures of, for example, between 10 and 100 "C.    



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



   The esters of formula (III) can be prepared from the carboxylic acids of formula (II) 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 (IV) (which can be prepared from the corresponding carboxylic acids of formula (II) by application or adaptation of known methods, for example by reaction with thionyl chloride, trichloride of phosphorus or oxalyl chloride, optionally in situ) and the 5-amino-tetrazole is preferably carried out in an inert organic solvent, for example benzene, toluene or xylene and, preferably, hot, for example at the reflux temperature of the reaction mixture. 



   The compounds of formula (I) can also be prepared (except those in which R1 represents an alkylthio, formyl, nitro or benzyloxycarbonylamino group) by reduction of compounds of general formula:
 The benzamide derivatives of general formula (I) can be prepared by application or adaptation of known methods.  By the term known methods, as used in the present text, is meant methods which have been previously used or described in the literature. 



   Thus, according to the present invention, the compounds of formula (I) are prepared (except those in which R1 represents an alkylamino or amino group) by reaction of 5-amino-tetrazole with carboxylic acids of general formula:
EMI8. 2
 [in which R2 represents a fluorine, chlorine or bromine atom, or an alkyl, alkoxy, alkylthio, alkylthio, alkylsulfonyl, alkanoylamino or alkylsulfamoyl group, straight or branched chain, each of these groups containing from I 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 alkanoyl, alkoxycarbonyl, alkoxycarbonylamino or alkoylcarbamoyl group, straight or branched,

   containing 2 to 6 carbon atoms or a hydroxy, formyl, nitro, trifluoromethyl, aryl, (for example phenyl), benzyloxycarbonylamino, sulfamoyl, cyano, tetrazolyl-5, carboxy, carbamoyl or aroyl (for example benzoyl) group, and n represents 1,2 or 3, preferably 1 or 2, the substituents R2 being identical or different when n represents 2 or 3],
 or (except those in which R1 in formula (I) represents an alkylamino, hydroxy, amino or carboxy group) with esters of these acids, of general formula:

  :
EMI8. 3
 [in which R3 represents a fluorine, chlorine or bromine atom, or an alkyl, alkoxy, alkylthio, alkylsulfonyl, alkanoylamino or alkylsulfamoyl group, straight or branched chain, 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 I to 4 carbon atoms), an alkanoyl, alkoxycarbonyl, alkoxycarbonylamino or alkoylcarbamoyl group, containing 2 or 3 with 6 carbon atoms, or a formyl, nitro, trifluoromethyl, aryl (for example phenyl), benzyloxycarbonylamino, sulfamoyl, cyano, tetrazolyl-5, carbamoyl or aroyl (for example benzoyl) group, and n represents I, 2 or 3, preferably 1 or 2,

   the substituents R3 being identical or different when n represents 2 or 3, and R4 represents a straight or branched chain alkyl group containing from 1 to 4 carbon atoms],
 or (except those in which R1 in formula (I) represents an alkanoylamino, alkoylamino, alkoxycarbonylamino, hydroxy, benzyloxycarbonylamino, amino, car group.
EMI9. 1
 in which R6 represents a fluorine, chlorine or bromine atom, or an alkyl, alkoxy, alkylsulfonyl, alkanoylamino, alkyllamino or alkylsulfamoyl group, straight or branched chain, each of these groups 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 from 1 to 4 carbon atoms), an alkanoyl group, alkoxycarbonyl,

   alkoxycarbonylamino or alkylcarbamoyl, straight or branched chain, containing from 2 to 6 carbon atoms, or a hydroxy, trifluoromethyl, aryl (for example phenyl), amino, sulfamoyl, cyano, tetrazolyl-5, carboxy, carbamoyl or aroyl group (by example benzoyl), and q represents zero, 1,2 or 3, preferably 1 or 2, the substituents R6 being identical or different when q represents 2 or 3, m represents zero or 1, and the sum of met q is 1, 2 or 3.  In general, the reduction is carried out by hydrogenation in the presence of a catalyst such as palladium on black, in an organic solvent, for example N-methylpyrrolidone-2 or ethanol. 



   The compounds of formula (I) (except those in which R represents an alkanoylamino, alkylamino, alkoxycarbonylamino, hydroxy, benzyloxycarbonylamino, amino, carboxy or carbamoyl group) can also be prepared by reaction of compounds of general formula:
EMI9. 2
 [in which R7 represents a fluorine, chlorine or bromine 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 group dialkoylsulfamoyl, dialkoylamino or dialkoylcarbamoyl (in which the two alkyl groups may be the same or different and each contain from 1 to 4 carbon atoms), an alkanoyl, alkoxycarbonyl or alkylcarbamoyl group, with straight or branched chain, containing from 2 to 6 atoms of carbon, or a formyl group, nitro,

   trifluoromethyl, aryl (e.g. phenyl), sulfamoyl, cyano, tetrazolyl-5 or aroyl (e.g. benzoyl), and n represents 1, 2 or 3, preferably 1 or 2, the substituents R7 being the same or different when n represents 2 or 3] with hydrazoic acid or a salt thereof, for example sodium azide, potassium azide or ammonium avid. 



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



   The compounds of general formula:
EMI9. 3
 [in which R8 represents a straight or branched chain alkyl group containing from 1 to 6 carbon atoms, r represents 1,2 or 3, R9 represents a fluorine, chlorine or bromine atom, or an alkyl or alkoxy group, straight or branched chain alkyl, alkanoylamino or alkyl sulfamoyl, each of these groups containing from 1 to 6 carbon atoms, a dialkoylsulfamoyl or dialkoylcarbamoyl group (in which the two alkyl groups may be the same or different and each contain from 1 to 4 atoms carbon), an alkanoyl, alkoxycarbonyl, alkoxycarbonylamino or alkylcarbamoyl group, straight or branched chain, containing from 2 to 6 carbon atoms, or a nitro, trifluoromethyl, aryl group (for example phenyl), benzyloxycarbonylamino, sulfamoyl, cyano,

   tetrazolyl-5, carboxy, carbamoyl or aroyl (for example benzoyl), and p represents zero, 1 or 2, the substituents R9 being identical or different when p represents 2, or else R9 represents a hydroxy group in the para position relative to the group tetrazolylcarbamoyl, and the sum of r and p is 1, 2 or 3], compounds encompassed by the general formula (I), can be prepared by oxidation of compounds of the general formula:
EMI9. 4
 (in which R8, R9, r and p are as defined above) to transform the acoylthio group or groups of formula -SR8 into alkyl sulfonyl group (s). 

  This oxidation can be carried out by the action of a peracid, for example m-chloroperbenzoic acid, in an inert solvent, for example sulfolane, or alternatively by the action of hydrogen peroxide, preferably in the presence of a carboxylic acid (for example acetic acid) and optionally hot. 



   According to the invention, the compounds of general formula:
EMI9. 5
   [in which R1 and R ", which are identical or different, each represents a hydrogen atom or a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, r represents I, 2 or 3, R'2 represents a fluorine, chlorine or bromine atom, or an alkyl, alkoxy, alkylthio or alkylsulphonyl group, straight or branched chain, each of these groups containing from I to 6 carbon atoms, or a dialkoylamino group (in which the two alkyl groups may be the same or different and each contain from 1 to 4 carbon atoms), an alkanoyl or alkoxycarbonyl group, with a straight or branched chain, containing from 2 to 6 carbon atoms, or a hydroxy or formyl group,

   nitro, trifluoromethyl, aryl (e.g. phenyl), cyano, tetrazolyl-5, carboxy or aroyl (e.g. benzoyl), and p represents zero, I or 2, the substituents Rl2 being the same or different when p represents 2, and the sum of r and p is 1, 2 or 3], compounds encompassed by the general formula (I), are prepared by reaction of an amine of the general formula:
HNR'OR "(X) (in which R'O and Rl l are as defined above) with a compound of general formula:
EMI10. 1
 in which R12, r and p are as defined above. 



  The reaction can be carried out in an organic solvent, for example ethanol, at room temperature or hot. 



   The compounds of formula (XI) can be prepared by the action of chlorosulfonic acid on compounds of general formula:
EMI10. 2
 in which R'2, r and p are as defined above. 



   As can be seen, the position (s) of the group (s) - (SO2R'0R '1) r which can be introduced in this way may depend on the nature and the position of the substituent (s) - (R'2) p (if they exist) and reaction conditions used to transform the compounds of formula (XII) into compounds of formula (XI), and these positions can be determined by a minimum of experimentation. 



   The compounds of general formula:
EMI10. 3
 [in which R'3 represents a fluorine, chlorine or bromine atom, or an alkyl, alkoxy, alkylsulfonyl, alkanoylamino, alkyllamino or alkylsulfamoyl group, straight or branched chain, containing from I to 6 carbon atoms, a group dialkoylsulfamoyl, dialkoylamino or dialkoylcarbamoyl (in which the two alkyl groups may be the same or different and each contain from I to 4 carbon atoms), an alkanoyl, alkoxycarbonyl, alkoxycarbonylamino or alkoylcarbamoyl group, containing from 2 to 6 carbon atoms, or a hydroxy, formyl, nitro, trifluoromethyl, amino, sulfamoyl, cyano, tetrazolyl-5, carboxy or carbamoyl group, and p represents zero, l or 2, the substituents R'3 being identical or different when p represents 2, r represents 1, 2 or 3,

   and the sum of r and p is 1, 2 or 3], these compounds being included by the general formula (I), can be prepared by nitration of compounds of general formula:
EMI10. 4
 (in which Rl3, r 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. 

 

   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 substituent (s) - (R'3) p (if they exist) and the conditions reactions used for nitration, and these positions can be determined by a minimum of experimentation. 



   The compounds of general formula:
EMI10. 5
 [in which Rl4 represents a fluorine, chlorine or bromine atom, or an alkyl, alkoxy, alkylthio, alkylsulfonyl, alkanoylamino, alkyllamino or alkylsulfamoyl group, straight or branched chain, each of these groups containing from 1 to 6 atoms carbon, a dialkoylsulfarnoyl, dialkoylamino or dialkoylcarbamoyl group (in which the two alkyl groups may be the same or different and each contain from 1 to 4 carbon atoms), an alkanoyl or alkylcarbamoyl group, with straight or branched chain, containing from 2 to 6 carbon atoms, or a hydroxy, formyl, nitro, trifluoromethyl, aryl (for example phenyl), sulfamoyl, cyano, tetrazolyl-5, carboxy, carbamoyl or aroyl (for example benzoyl) group, p represents zero, 1 or 2,

   the substituents R'4 being identical or different when p represents 2, r represents 1, 2 or 3, and the sum of r and p is
I, 2 or 3], compounds encompassed by the general formula (I), can be prepared by reaction of compounds of general formula:
EMI11. 1
 (in which Rl4, r and p are as defined above), compounds encompassed by the general formula (I), with acetic acid and hydrogen bromide. 



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



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



   Example I
 Compounds BE, AM, AU, BI, BJ, BK, BB, AZ, AX, BC,
BD, BH, BN, BF, BA, AA, BG, BM, AV, AY and BL
 A stirred mixture of 3-methoxy-salicylic acid (16.8 g), anhydrous 5-amino-tetrazole (16.8 g) and dicyclohexylcarbodiimide (24.7 g) in anhydrous pyridine (400 ml).  A solid (1) is filtered off, and the pyridine is removed from the filtrate under reduced pressure, which leaves a tawny solid (2).  The solids (I) and (2) are combined, added to ammonia (2N) and stirred for 30 minutes.  The mixture is filtered, the filtrate is treated with bleaching black and filtered again, then it is acidified to pH I with concentrated hydrochloric acid. 



  The resulting solid is filtered off and recrystallized from a mixture of dimethylformamide and acetic acid, to give 2-hydroxy-3-methoxy-N- (5-tetrazolyl) -benzamide (14.7 g), P. F.    265-267 "C (with decomposition). 



   By following a similar procedure, but replacing the 3-methoxy-salicylic acid used as starting material with the appropriate amounts of the following acids: 3-chloro-salicylic acid 3-acetyl-5-chloro-salicylic acid 3-methylthio-salicylic acid methylsulfonyl- 3 salicylic acid and bis (methylsulfonyl) -3.5 salicylic acid, and by recrystallizing the compounds obtained from the solvents indicated below after their melting points, instead of the mixture of dimethylformamide and acetic acid, we prepared, respectively, the following compounds: chloro-3 hydroxy-2 N- (tetrazolyl-5) -benzamide, P. F. 



     249-252 "C (with decomposition) (from ethanol); 3-acetyl-5-chloro-2-hydroxyN- (tetrazolyl-5) -benzamide, P. F. 



     268-270 "C (with decomposition) (from acetic acid); 2-hydroxy-3-methylthio N- (5-tetrazolyl) -benzamide, P. F. 



     256-257 "C (with decomposition) (from a mixture of dimethylformamide and acetic acid); 2-hydroxy-3-methylsulfonyl N- (5-tetrazolyl) -benzamide, P. F.    



     245-248 "C (with decomposition) (from a mixture of dimethylformamide and water); and 2-hydroxy bis (methylsulfonyl) -3.5 N- (tetrazolyl-5) -benzamide, P. F.    252-253 "C (with decomposition) (from a mixture of ethanol and water). 



   Still proceeding in a similar way, but stirring the reagents together at 25 "C for 20 to 24 hours instead of doing it at 90" C for 2 hours, and replacing the 3-methoxy salicylic acid used as starting material by the appropriate amounts of the following acids: 4-acetamido salicylic acid 5-acetamido salicylic acid 4-chloro salicylic acid 4-trifluoromethyl-4 salicylic acid 4-fluoro salicylic acid 5-fluoro salicylic acid 4-methylthio salicylic acid 5-methylthio salicylic acid tertiobutyl acid -4 salicylic acid 4-nitro salicylic acid 5-phenyl salicylic acid 5-bromo salicylic acid 5-acetyl salicylic acid 3,5-dibromo salicylic acid and 5-formyl salicylic acid, respectively:
Acetamido-4 hydroxy-2 N- (tetrazolyl-5) -benzamide, P. F. 



     310-312 "C (with decomposition) (from a mixture of
N-methylpyrrolidone-2 and water);
Acetamido-5-hydroxy-2 N- (tetrazolyl-5) -benzamide, P. F. 



     291 -2930C (with decomposition) (from a mixture of dimethylformamide and water); 4-chloro-2-hydroxy-N-tetrazolyl-5) -benzamide, P. F. 



     259-260.5 "C (with decomposition) (from dimethylformamide); 4-trifluoromethyl-2-hydroxy-N- (5-tetrazolyl) -benzamide,
P. F.    263-265 "C (from acetic acid); 4-fluoro-2-hydroxyN- (tetrazolyl-5) -benzamide, P. F. 



     248-250 "C (from acetic acid); 5-fluoro-2-hydroxy-N- (5-tetrazolyl) -benzamide, P. F.    274 "C (with decomposition) (from a mixture of dimethylformamide and acetic acid);
2-hydroxy-methylthio-4 N- (tetrazolyl-5) -benzamide, P. F. 



     282-284 "C (with decomposition) (from a mixture of dimethylformamide and water);
2-hydroxy-methylthio-5 N- (tetrazolyl-5) -benzamide, P. F. 

 

     261-262 "C (with decomposition) from a mixture of dimethylformamide and acetic acid); tert. -butyl-4 hydroxy-2 N- (tetrazolyl-5) -benzamide, P. F. 



     272-274 "C (with decomposition) (not recrystallized, but, instead, boiled in ethanol);
2-hydroxy-nitro-4 N- (tetrazolyl-5) -benzamide, P. F. 



     242-245 "C (from a mixture of dimethylformamide and acetic acid);
2-hydroxy-phenyl-5 N- (tetrazolyl-5) -benzamide, P. F. 



     277-278 C (with decomposition) (from a mixture of dimethylformamide and acetic acid); 5-bromo-2-hydroxy-N- (tetrazolyl-5) -benzamide, P. F.   



     272-274 "C (with decomposition) (from acetic acid); 5-acetyl-2-hydroxy-N- (5-tetrazolyl) -benzamide, P. F. 



     267-269 "C (with decomposition) (from dimethylformamide and water); 3,5-dibromo-2-hydroxy-N- (5-tetrazolyl) -benzamide, P. F. 



     252-253 "C (with decomposition) (from acetic acid); and 5-formyl-2-hydroxy-N- (5-tetrazolyl) -benzamide, P. F. 



     268 "C (with decomposition) (this compound is recrystallized from a mixture of dimethylformamide and acetic acid, then it is dissolved in an aqueous solution of sodium carbonate; the solution is treated with hydrochloric acid and the resulting solid is filtered off and triturated with concentrated hydrochloric acid). 



   Example 2
 Compounds AD, AJ, AF, AG and AT
 Hydrogen a solution of 2-benzyloxy-5-chloro
N- (tetrazolyl-5) -benzamine (2.7 g) in N-methylpyrrolidone-2 (50 ml), at 25 "C and under a pressure of 4.9 kg / cm2 using a 5% catalyst by weight of palladium on black. 



  The reaction mixture is filtered then evaporated in vacuo and the resulting solid is triturated with water, then dried. 



  This solid is boiled in methanol (50 ml) for 10 minutes, the undissolved materials are filtered off and washed with methanol and diethyl ether to give 5-chloro hydroxy -2 N- (tetrazolyl-5) -benzamide (1.5 g), P. F.  266-269C (with decomposition). 



   By proceeding in a similar manner, but replacing the 2-benzyloxy-5-chloro-5- (tetrazolyl-5) -benzamide used as starting material by the appropriate amounts of: 2,4-dibenzyloxy-5- (tetrazolyl-5) -benzamide dibenzyloxy-2,5 N- (tetrazolyl-5) -benzamide-benzyloxy-2 methyl-5 N- (tetrazolyl-5) -benzamide and benzyloxy-2 methoxy-4 N- (tetrazolyl-5) -benzamide, and replacing the purification process described above by the processes indicated below, respectively:

   dihydroxy-2,4 N- (tetrazolyl-5) -benzamide, P. F.    281 -2830C (with decomposition) (dissolved in an aqueous solution of sodium bicarbonate and reprecipitated by treatment with hydrochloric acid); dihydroxy-2,5 N- (tetrazolyl-5) -benzamide, P. F.  299-300 "C (with decomposition) (this compound is recrystallized from a mixture of dimethylformamide and water, then it is dissolved in a saturated aqueous solution of sodium bicarbonate; this solution is treated with acid hydrochloric acid and the resulting solid is filtered off);
2-hydroxy-5-methyl-N (5-tetrazolyl) -benzamide, P. F. 



     289-291 0C (with decomposition) recrystallized from a mixture of dimethylformamide and water); and 2-hydroxy-4-methoxy N- (5-tetrazolyl) -benzamide, P. F. 



     280-281 C (with decomposition) recrystallized from a mixture of dimethylformamide and water). 



   Example 3
 Compounds AI, AH, AK, AG, AP, AL, AM, BE, AS and AN
 Anhydrous 5-amino tetrazole (15 g) and phosphorus trichloride (6 ml) are added to a suspension of 3-nitro salicylic acid (16 g) in anhydrous benzene (250 ml). 



  The mixture is stirred and heated to reflux for 20 hours.  This mixture is then cooled and diluted with petroleum ether (P. E.  60-80 "C; 250 ml) and the resulting solid is separated by filtration.  This solid is treated with dilute hydrochloric acid (200 ml; 2 N) and the mixture is stirred for 30 minutes; the solid is then separated by filtration, washed with ethanol and dissolved in ammonia (2 N).  This solution is treated with bleaching black and filtered; the filtrate is acidified with concentrated hydrochloric acid, which gives 2-hydroxy-3-nitro (5-tetrazolyl) -benzamide (5.0 g), P. F.  236-238 "C (with decomposition). 



   By following a similar procedure, but replacing the 3-nitro-salicylic acid used as starting material with the appropriate quantities of the following acids: 3-methyl salicylic acid 4-methyl salicylic acid 5-methyl salicylic acid 5-methoxy salicylic acid 3-bromo-salicylic acid 3-chloro salicylic acid 3-methoxy salicylic acid 3-ethoxy salicylic acid and 3-propoxy salicylic acid, and by replacing the purification product described above with the processes indicated below, the following are respectively prepared:
Hydroxy-2-methyl-3 N- (tetrazolyl-5) -benzamide, P. F. 



     264-265 "C (recrystallized from a mixture of dimethylformamide and water);
4-hydroxy-methyl-4 N- (tetrazolyl-5) -benzamide, P. F. 



     288-289 "C (with decomposition) recrystallized from a mixture of dimethylformamide and water);
2-hydroxy-5-methyl-N (5-tetrazolyl) -benzamide, P. F. 



     287-289 "C (with decomposition) (recrystallized from a mixture of dimethylformamide and water);
2-hydroxy-5-methoxy N- (tetrazolyl-5) -benzamide, P. F. 



     272-274 "C (with decomposition) (recrystallized from a mixture of dimethylformamide and water); 3-bromo-2-hydroxy-N- (tetrazolyl-5) -benzamide, P. F. 



     248-250 "C (recrystallized from a mixture of dimethylformamide and water); 3-chloro-2-hydroxy-N- (5-tetrazolyl) -benzamide, P. F. 



     250-2510C (with decomposition) recrystallized from ethanol);
2-hydroxy-3-methoxy N- (tetrazolyl-5) -benzamide, P. F. 



     265-267 "C (with decomposition) recrystallized from acetic acid); 3-ethoxy-2-hydroxy (5-tetrazolyl) -benzamide, P. F. 



     257-258 "C (with decomposition) (recrystallized from acetic acid); and 2-hydroxypropoxy-3 N- (tetrazolyl-5) -benzamide, P. F. 



     230-232 "C (with decomposition) dissolved in 2 N ammonia and reprecipitated by treatment with hydrochloric acid). 

 

   Example 4
 Compounds AO, AR and AW
 Purified thionyl chloride (6 ml) is added to a suspension of dried 5-nitro-salicylic acid (3.6 g) in anhydrous toluene (40 ml), the mixture is stirred and heated to reflux for 90 minutes .  The resulting solution, of a light orange-brown color, is evaporated under vacuum below 40 ° C. 



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



   The 5-nitro-salicyloyl chloride thus obtained is dissolved in anhydrous toluene (40 ml), it is treated with anhydrous 5-amino-tetrazole (3.4 g), the mixture is stirred and heated to reflux for 12 hours.  This mixture is then allowed to cool and is treated with petroleum ether (P. E.  40-60 "C; 40 ml).  The resulting solid is filtered off, washed with petroleum ether (P. E.    40-60 "C) and stirred with hydrochloric acid (2N; 100 ml).     The undissolved solid is filtered off, washed with hydrochloric acid (2N) and with water, then dried and dissolved in glacial acetic acid (750 ml). 

  The solution is filtered hot, then concentrated to a volume of 150 ml and then cooled and filtered, which gives 2-hydroxy-5-nitro
N- (tetrazolyl-5) -benzamide (2.2 g), P. F.       271-272 "C (with decomposition). 



   By following a similar procedure, but replacing the 5-nitro-salicylic acid used as starting material with the appropriate amounts of the following acids: 3-acetyl-5-methyl-salicylic acid and 3,5-diacetyl-2,4-dihydro-benzoic acid , respectively: 3-acetyl-2-hydroxy-5-methyl-N- (tetrazolyl-5) -benzamide,
P. F.    280-282 "C (with decomposition) (recrystallized from a mixture of dimethylformamide and acetic acid); and 3,5-diacetyl-2,4-dihydroxy-N- (5-tetrazolyl) -benzamide,
P. F.  above 270 "C (with decomposition) (recrystallized from a mixture of dimethylformamide and acetic acid). 



   Example 5
 Compounds AB, AC and AQ
 2-Hydroxy-N (5-tetrazolyl) -benzamide (2.05 g) is added to chlorosulfonic acid (15 ml) over 15 minutes and the mixture is allowed to stand at 25 "C for 19 hours.  The dark solution is then carefully poured onto a mixture of ice and water (100 ml), keeping the temperature below 3 C. The precipitated white solid is filtered off and washed thoroughly with water .  The wet solid is added to a solution of dimethylamine in methanol (33% w / v; 60 mil), the resulting solution is filtered and allowed to stand at 25 "C overnight. 



  The mixture is then diluted with water (100 ml), acidified with concentrated hydrochloric acid, and cooled in ice.  The resulting white solid is filtered off, washed with water and recrystallized from ethanol to give hydroxy-2 (N, N-dimethylsulfamoyl) -5 N- (tetrazolyl-5 ) -benzamide (2.0 g), P. F.    276-278 "C (with decomposition). 



   By proceeding in a similar manner, but replacing the dimethylamine used as starting material with the appropriate amounts of N-methylisopropylamine and dibutylamine, the following are prepared respectively:
Hydroxy-2 (N-methyl-N-isopropylsulfamoyl) -5 N- (tetrazolyl-5) -benzamide,
P. F.    263-265 "C (with decomposition) (recrystallized from ethanol); and (N, N-dibutylsulfamoyl) -5 2-hydroxy-N- (5-tetrazolyl) -benzamide, P.  F.       240-242 "C (recrystallized from a mixture of dimethylformamide and water). 



   Example 6
 Compound AE
 2-Hydroxy N- (tetrazolyl-5) -benzamide (5.12 g) is dissolved in concentrated sulfuric acid (50 ml), the mixture is treated with concentrated nitric acid (d = 1, 42; 6.7 ml) and kept at 0 ° C. for 3 days.  The dark solution is poured onto a mixture of ice and water (600 ml) and the resulting solid is separated by centrifugation, washed thoroughly with
Water and it is dried, which gives 2-hydroxy-dinitro-3,5
N- (tetrazolyl-5) -benzamide (5.0 g), P. F.  234-236 "C (with decomposition). 



   Example 7
 BP and BO compounds
 2-hydroxy-methylthio-4 N- (tetrazolyl-5) -benzamide (0.5 g; prepared as described in Example 1) is stirred with acetic acid (5 ml) and hydrogen peroxide (2.5 ml at 30% by weight).  The mixture is heated at 100 ° C for 20 hours, then cooled.  The solid is separated by filtration, washed with water and recrystallized from a mixture of dimethylformamide and water, which gives 2-hydroxy-4-methylsulfonyl (5-tetrazolyl) -benzamide, (0.4 g), P. F.    260-273 "C (with decomposition). 



   By proceeding in a similar manner, but by replacing 2-hydroxy-methyl-4-N- (tetrazolyl-5) -benzamide used as starting material by the appropriate amount of 2-hydroxy-methyl-3-methylthio (5-tetrazolyl) -benzamide (prepared as described in Example 1), 2-hydroxy-5-methylsulfonyl N- (tetrazolyl-5) -benzamide is prepared,
P. F.  291-292 "C (with decomposition) (recrystallized from acetic acid). 



   Example 8
 BQ and BR compounds
 By proceeding in a similar manner to that described above in Example 1, but by replacing the 3-methoxy salicylic acid used as starting material with the appropriate amounts of the following acids: salicylic acid benzyloxycarbonylamino-5 salicylic and benzyloxycarbonylamino- 4 salicylic acid, and by stirring the reagents together at 25 "C for 20 to 24 hours, respectively: benzyloxycarbonylamino-5-hydroxy-2 N- (tetrazolyl-5) -benzamide, P. F.    281-282 C (with decomposition) (recrystallized from ethanol); and benzyloxycarbonylamino-4 hydroxy-2 N- (tetrazolyl-5) beuzamide, PF.  above 3600C (recrystallized from acetic acid). 



   Example 9
 BS compound
 Acetic acid (100 ml) is saturated with hydrogen bromide at 10 ° C. and the mixture is treated with benzyloxycarbony-5-amino-2-hydroxy-N- (tetrazolyl-5) -benzamide (1, 77 g).  The mixture is stirred at 250 ° C. for 20 hours, then most of the hydrogen bromide is removed by passing a stream of air through the mixture for 6 hours.  All the finely divided solids in suspension are then removed by centrifugation and the supernatant is separated by decantation.  By vacuum removal of acetic acid, a solid is obtained which is triturated with diethyl ether and dried, which gives 5-amino-2-hydroxy-hydrobromide N- (tetrazolyl-5) -benzamide (1.0 g), P. F. 

 

  above 330 "C.    



   Example 10
 LV and BU compounds
 By proceeding in a manner similar to that described below
 above in Example 5, but replacing the hydroxy-2
 N- (tetrazolyl-5) -benzamide and dimethylamine used
 as starting materials by the appropriate amounts of
 following compounds: 2-hydroxy-5-methyl-N (5-tetrazolyl) -benzamide and tert-butylamine: and 3-hydroxy-2-hydroxy-N- (tetrazolyl-5) -benzamide and ammonia, respectively:

   (N-tertiobutylsulfamoyl) -3 2-hydroxy-5-methyl-N- (5-tetrazolyl) -benzamide, P. F.    249-251 "C (with decomposition) (recrystallized from aqueous dimethylformamide), and 1-acetyl-2-hydroxy-5-sulfamoyl-5- (tetrazolyl-5) -benzamide,
P. F.  above 3100C (the dark color at 270 "C) (recrystallized from aqueous dimethylformamide). 



   Example it
 BV compound
 2-Benzyloxy-5-trifluoromethyl-N- (tetrazolyl-5) -benzamide (2.7 g) is dissolved in ethanol (500 ml) and the solution is hydrogenated at 25 "C, under 5 kg / cm2 of pressure , using a 5% palladium on black catalyst.  The reaction mixture is then filtered and evaporated in vacuo.  The resulting solid is recrystallized from isopropanol, with the aid of bleaching black, which gives 5-trifluoromethyl-2-hydroxy-N- (5-tetrazolyl) -benzamide (0.85 g), P. F. 



     245-246 "C (with decomposition). 



   Example 12
 Compounds BW, BX, BY, BZ, CA, CB, CC, CD, CE, CF, CG, CH, CI, CJ, CK, CL, CM, CN, CO, CP, CQ and CR
 A mixture of 3-acetyl-5-ethyl-salicylic acid (55.0 g) and dicyclohexylcarbodiimide (60.1 g) in anhydrous pyridine (550 ml) is stirred at 25 ° C. for one hour.  Anhydrous 5-amino-tetrazole (24.7 g) was then added to the mixture, and continued to stir at 60 ° C for 24 hours.  We
 remove the pyridine under vacuum, and the residue is treated with
 ammonia (2N; 500 ml).     The resulting slurry is stirred between 90 and 1000C for 15 minutes.  The insoluble dicyclohexylurea is filtered off and the filtrate is acidified with concentrated hydrochloric acid. 

  Separate by filtration
 the resulting green precipitate and it is recrystallized twice at
 from aqueous dimethylformamide, which gives
 3-acetyl-5-ethyl-2-hydroxy (5-tetrazolyl) -benzamide (35.4
 g), in the form of a pale yellow solid, P. F.    257-258 "C.    



   By proceeding in a similar manner, but replacing the 3-acetyl-5-ethyl salicylic acid used as starting material with the appropriate quantities of the following acids: 3-acetyl-4,5-dimethyl salicylic acid 3-acetyl dry acid. -butyl salicylic acid 3-acetyl tert. -butyl-5 salicylic acid 3-acetyl salicylic acid 3-acetyl bromo-5 salicylic acid 3-acetyl fluoro-5 salicylic acid 3-acetyl propyl-5 salicylic acid 5-methyl-propionyl-3 salicylic acid 3-ethyl propionyl salicylic acid butyryl-3 ethyl-5 salicylic acid 3-formyl salicylic acid 3-formyl-5-methyl-salicylic acid 3-cyano salicylic acid 5-cyano salicylic acid 3-cyano-5 methyl-5 salicylic acid 5-tetrazolyl-3) salicylic acid 2-hydroxy isophthalic acid tert. -butylcarbamoyl-3 salicylic acid 3-dimethylamino salicylic acid

   5-acetyl-3-nitro salicylic acid and 3-benzoyl-5-methyl-salicylic acid, respectively: 3-acetyl-2-hydroxy-dimethyl-4,5 N- (tetrazolyl-5) -benzamide, P. F.  245-2470C (with decomposition);
Acetyl-3 sec.  -butyî-5 hydroxy-2 N- (tétrazolyl-5) -benza- mide, P. F.    228-230 "C (with decomposition) (recrystallized from 90% by weight formic); 3-acetyl tert. -butyl-5 hydroxy-2 N- (tetrazolyl-5) -benzamide, P. F.  258-260 "C (with decomposition) (recrystallized from 90% by weight formic acid); 3-acetyl-2-hydroxy-N- (tetrazolyl-5) -benzamide, P. F. 



     291-292 "C (with decomposition); 3-acetyl-5-bromo-2-hydroxy-N- (5-tetrazolyl) -benzamide,
P. F.    253-254 "C (with decomposition:
3-acetyl-5-fluoro-2-hydroxy- (tetrazolyl-5) -benzamide, P. F.  268-2700C (with decomposition) (recrystallized from a mixture of dimethylformamide and acetic acid); Acetyl-3-hydroxy-2-propyl-5 N- (tetrazolyl-5) -benzamide, P. F.  257-258 "C (with decomposition);
2-hydroxy-5-methyl-3-propionyl- (tetrazolyl-5) -benzamide, P. F. 280-281 (with decomposition);
5-ethyl-2-hydroxy-3-propionyl N- (tetrazolyl-5) -benzamide, P. F.  257-258 "C (with decomposition); 3-butyryl-5-ethyl-2-hydroxyN- (5-tetrazolyl) -benzamide, P. 

  F.       253-254 "C (with decomposition); 3-formyl-2-hydroxy-N- (5-tetrazolyl) -benzamide, P. F. 



     251-254 "C (with decomposition) (recrystallized from formic acid); 3-formyl-2-hydroxy-5-methyl-N- (5-tetrazolyl) -benzamide,
P. F.    238-242 "C (with decomposition) (recrystallized from formic acid) 3-cyano-2-hydroxy-N- (tetrazolyl-5) -benzamide, P. F. 



     259-260 "C (with decomposition); 5-cyano-2-hydroxy-N- (5-tetrazolyl) -benzamide, P. F. 



     310-312 "C (with decomposition) (recrystallized from acetic acid); 3-cyano-2-hydroxy-5-methyl-N- (5-tetrazolyl) -benzamide, P. F.  243-245 "C (with decomposition) (recrystallized from a mixture of dimethylformamide and acetic acid);
Hydroxy-2 methyl-5 (tetrazolyl-5) -3 N- (tetrazolyl-5) -benzamide hydrate, P. F.  above 360 "C;
Salicylic [N- (tetrazolyl-5) -carbamoyl] -3 acid, P. F. 



     257-259 "C (with decomposition); tert. -butylcarbamoyl-3 hydroxy-2 N- (tetrazolyl-5) -benzamide, P. F.    285-287 "C (with decomposition) (recrystallized from a mixture of dimethylformamide and acetic acid);
2-hydroxy-3-dimethylamino N- (tetrazolyl-5) -benzamide, P. F.  262-263 "C (with decomposition) (recrystallized from acetic acid);
5-acetyl-2-hydroxy-3-nitro N- (tetrazolyl-5) -benzamide, P. F. 



     248-249 "C (with decomposition) (recrystallized from dimethyl sulfoxide); and benzoyl-3-hydroxy-2-methyl-5 N- (tetrazolyl-5) -benzamide,
P. F.    274-275 "C (with decomposition). 

 

   Example 13
 Compound CS
 3-acetyl-2-N-hydroxy (5-tetrazolyl) -benzamide (6.0 g) is dissolved in concentrated sulfuric acid (30 ml).  The solution is then cooled to 0 ° C., while stirring, it is treated with concentrated nitric acid (density 1.42; 1.62 ml), at a rate such that the temperature does not exceed 10 "C.     The mixture is left to stand between 0 and 5 "C for 20 hours, then it is poured into a mixture of ice and water (300 ml).  The precipitated solid is collected, washed with water and recrystallized from 98% by weight formic acid, which gives 3-acetyl-2-hydroxy-5-nitro-5 (tetrazolyl-5 ) -benzamide, P. F. 



     255 "C (with decomposition). 



   Reference example I
 By applying or adapting the methods described by
Baine et al. , J.  Org.  Chem. , 1954, 19, 510, with the appropriate starting materials, we prepare:
3-methylthio salicylic acid, P. F.    168-170 "C;
Tert.acid -4-salylylic acid, P. F.  138-141 "C;
3-methyl salicylic acid, P. F.    169-170 "C;
4-methyl salicylic acid, P. F. 176-178 C;
5-methyl salicylic acid, P. F.  150-1 520C;
Bromo-3 salicylic acid, P. F.    183-184 "C; and 3-chloro salicylic acid, P. F.  171-174 "C.    



   Reference example 2
 Heated at 95-1000C for 18 hours a mixture of 3-methylthio salicylic acid (2.0 g), glacial acetic acid (18 ml) and hydrogen peroxide (6 ml at 30% by weight).  The solvents are then removed under vacuum and the residue is recrystallized from water with the aid of bleaching black, which gives 3-methylsulfonyl salicylic acid (1.5 g) P. F. 



     179.5-180.5 "C.    



   Reference example 3
 a) An intimate mixture of bis (chlorosulfonyl acid (3.5 salicylic acid (3.5.1 g) and sodium bicarbonate (75.5 g)) is added in portions over 30 minutes to a stirred solution. anhydrous sodium sulfite (81 g) and sodium bicarbonate (5.4 g) in water (550 ml), at 60-70 "C, and the mixture was stirred for another 30 minutes.  Methanol (550 ml) is then added, followed by methyl iodide (108 ml).     The mixture is stirred and heated to reflux for 24 hours.  An excess of an aqueous solution of sodium hydroxide (50% by weight) is added and the methanol is removed by distillation over one hour. 

  The mixture is then acidified with aqueous sulfuric acid (50% w / v) while cooling, which gives a crystalline solid which is separated by filtration and which is recrystallized from water to obtain the acid. bis (methylsulfonyl) -3.5 salicylic (24.4 g), P. F.  267-271 0C (with decomposition). 



   b) Bis (chlorosulfonyl) -3.5 salicylic acid used as starting material and obtained as follows:
 Salicylic acid (10 g) is added to chlorosulfonic acid (60 ml) over 5 minutes.  The mixture is then heated to 130-140 "C for 90 minutes.  The mixture is cooled, then added dropwise to an excess of a mixture of ice and water, keeping the temperature below 0 C.     The precipitated solid is extracted with dichloromethane, and the organic extract is dried over sodium sulfate, concentrated in vacuo to a low
 volume and treated with petroleum ether (P. E.    40-60 "C).    



  The precipitate is separated by filtration and recrystallized from a large volume of toluene to give bis (chlorosulfonyl) -3.5 salicylic acid (9.95 g), P. F.    185-187 "C.    



   Reference example 4
 To prepare 5-bromo-salicylic acid, the method described for its preparation by Hewitt et al. , J. 



  Chem.  Soc. , 1904, 85, 1228. 



   The insoluble solid remaining from crystallization from water in this preparation is recrystallized from aqueous ethanol, which gives 3,5-dibromo-salicylic acid, P. F 220 C.    



   Reference example 5
 a) Anhydrous 2-benzyloxy-5-chloro-benzoic acid (1.15 g) is treated, with stirring, with anhydrous pyridine (20 ml) and anhydrous 5-amino tetrazole (3.72 g) .  The mixture is stirred at 25 "C and treated dropwise with silicon tetrachloride (0.45 g), then the resulting mixture is stirred at 25" C for 20 hours.  The resulting light yellow solution is carefully poured into a mixture of ice and water (50 ml) and the mixture is acidified to pH 1 with concentrated hydrochloric acid. 

  The precipitated white solid is filtered off, washed with water, with ethanol and with diethyl ether and recrystallized from a mixture of dimethylformamide and water, which gives 2-benzyloxy-chloro-5 N- (tetrazolyl-5) -benzamide (0.29 g) P. F.  256-257 "C (with decomposition). 



   By following a similar procedure, but replacing the 2-benzyloxy-5-chloro-benzoic acid used as starting material by the appropriate amounts of the following acids: 2,4-dibenzyloxy-benzoic acid 2,5-dibenzyloxy benzoic acid 2-benzyloxy acid 5-methyl benzoic and 2-benzyloxy-4-methoxy benzoic acid, respectively: 2,4-dibenzyloxy-N- (5-tetrazolyl) -benzamide, P. F. 



     247-250 "C (with decomposition) (recrystallized from dimethylformamide); dibenzyloxy-2,5 N- (tetrazolyl-5) -benzamide, P. F. 



     252-253 "C (with decomposition) (recrystallized from aqueous dimethylformamide); 2-benzyloxy-5-methyl-N- (5-tetrazolyl) -benzamide, P. F.    



     258.5-259.5 "C (with decomposition) (recrystallized from aqueous dimethylformamide); and 2-benzyloxy-4-methoxy-N (5-tetrazolyl) -benzamide, P. F. 



     254-256 "C (with decomposition) (recrystallized from dimethylformamide). 



   b) (1) The 2-benzyloxy-5-chloro-benzolic acid used as starting material is prepared as follows:
Stirred and heated in an oil bath at 120 ° C. for 20 hours a mixture of 5-chloro-salicylic acid (7.7 g), benzyl chloride (10.35 ml), anhydrous potassium carbonate ( 6.2 g) and anhydrous sulfolane (100 ml).  The resulting yellow solution is cooled, poured into a mixture of ice and water (300 ml) and the resulting mixture is acidified to pH 1 with hydrochloric acid.  The brown oil which has separated is extracted with diethyl ether (400 ml), the ethereal extract is washed with an aqueous sodium carbonate solution (2N; 150 ml), dried over sodium sulfate. magnesium and evaporated, which gives a white solid (16 g), P. F. 



     45-50 "C, consisting mainly of benzyloxy-2-chloro-5 benzyl benzoate.  This body is heated to reflux with an aqueous solution of sodium hydroxide (2N; 100 ml) for 3 hours.  The mixture is then treated with methanol (40 ml) and heated to reflux for 6 hours.  The resulting solution is neutralized to pH 7 with hydrochloric acid (2N), then concentrated under reduced pressure, acidified to pH 5 with hydrochloric acid (2N) and cooled to 10 C.    

 

  The solid which has separated is filtered and washed with a mixture of ice and water, then it is recrystallized from acetic acid (100 ml) (by removing some insoluble matter by filtration), which gives 2-benzyloxy-5-chloro benzoic acid (5.23 g), P. F.    113-115 "C.    



   b) (2) The 2,5-dibenzyloxy-benzoic acid used as starting material is prepared as follows:
A mixture of methyl gentisate (16.8 g) and anhydrous potassium carbonate (7.0 g) in anhydrous sulfolane (150 ml) is treated, with stirring, with benzyl chloride (12.7 g), and the resulting mixture was stirred by heating at 1000C for 4 hours. 

  This mixture is then poured into water (800 ml) and the solid which has separated is filtered and then recrystallized from ethanol (with the aid of bleaching black), which gives 5-benzyloxy. methyl salicylate (10.7 g), P. F.  108-I 12 "C.     This ester (9.2 g) is heated at 150 "C for 3 hours with a mixture of anhydrous potassium carbonate (2.5 g) and benzyl chloride (4.52 g) in anhydrous sulfolane (100 ml) , then the resulting mixture is cooled and poured into a mixture of ice and water (700 ml), and the resulting mixture is extracted with diethyl ether (2 times 300 ml). 

  The ethereal extracts are combined and evaporated, the residual oil is triturated with water (100 ml), the oil is separated and the aqueous layer is extracted with diethyl ether (25 ml).  The oil and extracts are combined and washed with brine, dried over magnesium sulfate and evaporated, resulting in crude methyl 2,5-dibenzyloxy benzoate (12.7 g).  This ester is heated to reflux with an aqueous sodium hydroxide solution (2N; 400 ml) for 2 hours, then allowed to cool.  The sodium salt which has separated is filtered and ground with hydrochloric acid (6N; 100 ml); the mixture is heated to reflux for 5 minutes, then cooled. 

  The solid which has separated is filtered, washed with water and dried, to give 2,5-dibenzyloxy-benzoic acid (8.2 g), P. F.    107-108.5 "C.    



   b) (3) The 2,4-dibenzyloxy-benzoic acid used as starting material is prepared as follows:
2,4 dihydroxy benzoic acid (48.0 g), anhydrous potassium carbonate (21.5 g), benzyl duchloride (39.4 g) and anhydrous sulfolane (400 ml) are heated together ), with stirring, at 1000C for 20 hours.  The mixture is then poured into water (2 liters), the resulting oil is separated and the aqueous layer is extracted with diethyl ether (300 ml). 

  The ether extract is evaporated and the residue is combined with the above-mentioned oily layer and washed with water (500 ml) to remove the sulfolane, then washed with brine, the aqueous washing liquids are extracted with diethyl ether (400 ml), these extracts are combined with the oil and dried and evaporated to give crude benzyl 2,4-dihydroxy-benzoate (64 g), P. F.    83-88 "C.     This ester (20 g) is treated with anhydrous potassium carbonate (17.0 g) and benzyl chloride (22.8 g) in anhydrous sulfolane (300 ml) and the mixture is stirred while heating to
   140 "C for 3 hours.  It is allowed to cool, then it is poured into water (1500 ml) and the resulting mixture is neutralized to pH 7 with hydrochloric acid. 

  The crude precipitate of 2,4-dibenzyloxy-benzyl benzoate is heated to reflux with a mixture of aqueous sodium hydroxide solution (2N; 400 ml) and ethanol (50 ml) for 10 hours. 



  The solution is allowed to cool, then it is diluted with a large volume of water and acidified to pH 1 with hydrochloric acid (2N), which gives a white solid which is separated by filtration and which is recrystallized from ethanol to obtain 2,4-dibenzyloxy-benzoic acid (16.8 g), P. F. 



      126-128 "C.    



   b) (4) The 2-benzyloxy-5-methyl benzoic acid used as starting material is prepared as follows:
5-methyl salicylic acid is reacted with methanol and sulfuric acid by the general method of Brunner (Monatsh.  1913, 34, 916), which gives methyl 5-methyl salicylate, P. E.  115-116 "C at 10 mmHg.  This ester (12.0 g) is heated with benzyl chloride (9.1 g) and anhydrous potassium carbonate (5.0 g) in anhydrous sulfolane (90 ml) at 100 ° C for 22 hours.  The mixture is then poured into a mixture of ice and water (1200 ml), which gives crude methyl 2-benzyloxy-5-methyl benzoate (17.6 g). 

  This ester (4.3 g) is heated under reflux with an aqueous sodium hydroxide solution (2N; 100 ml) for 2 hours, then the mixture is cooled, diluted with water and acidified up to pH 2 with concentrated hydrochloric acid, which gives 2-benzyloxy-5-methyl benzoic acid (3.65 g), P. F.    98-100 "C.    



   b) (5) The 2-benzyloxy-4-methoxy-benzoic acid used as starting material is prepared as follows:
2,4-dihydroxy methyl benzoate [12 g; prepared from 2,4-dihydroxy benzoic acid by the general Brunner method (Monatsh.  1913, 34, 916)] with methyl iodide (12.2 g) and anhydrous potassium carbonate (4.95 g) in anhydrous sulfolane (140 ml), at 60-70 "C.     After 8 hours, a new quantity of methyl iodide (12.2 g) is added and the heating is continued for 14 hours. 



  The excess methyl iodide is evaporated, the mixture is poured into a mixture of ice and water (I liter) and the resulting mixture is acidified with aqueous acetic acid (2N).  The solid which has separated is filtered and washed with water to give 2-hydroxy-4-methoxy-benzoate (10.8 g), P. F.    47-50 "C [including a sample, purified by chromatography on silica gel (elution with chloroform), has a melting point of 49-51" C].     This crude methyl 2-hydroxy-4-methoxy-benzoate (2.0 g) is heated with benzyl chloride (1.88 g) and anhydrous potassium carbonate (0.76 g) in anhydrous sulfolane (15 ml) , at 100 "C for 16 hours,

   then pour the mixture into a mixture of ice and water (300 ml).     The resulting mixture is extracted with diethyl ether and the extract is washed with several portions of an aqueous solution of sodium hydroxide (0.5N) at 0 C, then dried and evaporated, giving crude methyl 2-benzyloxy-4 methoxy benzoate (2.5 g) as an oil.  This substance is heated to reflux with a mixture of an aqueous solution of sodium hydroxide (2N; 100 ml) and ethanol (20 ml) for 3 hours.  The resulting mixture is then treated with water (100 ml), then cooled and extracted with diethyl ether (2 times 50 ml). 

  The aqueous layer is cooled to 10 ° C. and acidified to pH 2 with concentrated hydrochloric acid, which gives 2-benzyloxy-4-methoxy-benzoic acid (1.6 g), P. F. 



     99-101 "C.    



   Reference example 6
 2,3-dihydroxy benzoic acid (6.16 g) and propyl iodide (6.8 g) are added to a mixture of aqueous potassium hydroxide solution (20 ml; 25% by weight ), water (50 ml) and ethanol (50 ml) and the resulting mixture is stirred by heating at reflux for 5 hours.  A further quantity of propyl iodide (17 g) is then added and the mixture is further heated at reflux for 4 hours, while adding small quantities of solid potassium hydroxide to maintain the pH at around 10.  Bleaching black is then carefully added, the mixture is filtered while hot and the filtrate is acidified to pH 1 with concentrated hydrochloric acid.  

  The resulting solid is filtered off, dissolved in ammonia (2N), and the solution is treated with bleaching black, filtered and the filtrate is acidified to pH 1 with hydrochloric acid, which gives 3-propoxy-salicylic acid (5.1 g) P. F.    114-1 180C.    



   By proceeding in the same way, but replacing the propyl iodide used as starting material with the
 appropriate amount of ethyl iodide, acid is prepared
   Salicylic 3-ethoxy, P. F.    157 C (recrystallized from
 aqueous ethanol). 



   Reference example 7
 By applying or adapting 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, P. F.       132-134 "C.    



   Reference example 8
 By proceeding in a similar manner to that described above in reference example 1, one prepares:
Tert.acid -5-salylylic acid, P. F.    150 -1520C;
Dry acid. -5-salylylic acid, P. F.    65-68 "C;
5-fluoric salicylic acid, P. F.  179-1800C; and 5-chloro salicylic acid, P. F.    171-172 "C.    



   Reference example 9
 By proceeding in a similar manner to that described above in reference example 7, but by replacing 2-acetoxy-5-methyl-benzoic acid used as starting material with the appropriate amounts of the following acids: 2-acetoxy-chloro acid -5 benzoic acid-2-acetoxy-5-bromo-benzoic acid-2-acetoxy-5-fluoro benzoic acid 5-ethyl-2-propionyloxy benzoic acid 2-benzoyloxy-5-methyl benzo-2-acetoxy-4,5-dimethyl benzoic acid- 2-acetyl-5-propyl-benzoic and 5-methyl-propionyloxy-2-benzoic acid, respectively:

  :
3-acetyl-5 chloro-salicylic acid, P. F.  139-140 "C;
3-acetyl-5 bromo-salicylic acid, P. F.    145-146 "C;
3-acetyl-5-fluoro salicylic acid, P. F.       157-590C;
5-ethyl-propionyl-3-salicylic acid, P. F. 135-136 C;
Benzoyl-3 methyl-5 salicylic acid, P. F.  152-154 "C;
3-acetyl-4,5-dimethyl salicylic acid, P. F.    168-171 "C;
3-acetyl-5-propyl salicylic acid, P. F.  95-96 "C; and 5-methyl-propionyl-salicylic acid, P. F.    110 "C.    



   Reference example 10
 A vigorously stirred solution of tert-acid is treated. -5-butyl salicylic acid (3.88 g) in carbon sulphide (80 ml), in portions, with anhydrous aluminum chloride (8.8 g).  The mixture is carefully brought to reflux temperature and treated with acetyl chloride (3.45 g) dropwise over 15 minutes.  The mixture was heated to reflux with vigorous stirring for 20 hours, then added to a mixture of chloroform (80 ml), ice (100 g) and concentrated hydrochloric acid (20 ml), and stirred for hour again.  The organic layer is then separated, washed with water (3 times 20 ml), dried over anhydrous magnesium sulfate and the solvent is removed in vacuo. 

  The resulting solid is recrystallized from ethyl acetate, which gives 3-acetyl tert acid. -5-butyl salicylic acid (2.3 g), P. F.    159-161 "C.    



   By proceeding in a similar manner, but by replacing the tert acid. -butyl-5 salicylic used as a starting material by the appropriate amount of dry acid. -5-butyl salicylic, 3-acetyl acid is prepared dry. -5-salylylic acid, P. F. 



     131-133 C (recrystallized from ethyl acetate, at low temperature). 



   Reference example II
 The preparation of 5-formyl salicylic acid is carried out
 by applying the method described for this preparation bywayneetcolî. , J.  Chem.  Soc. , 121.1022 (1922).     3-Formyl salicylic acid is obtained from the mother liquors by means of its insoluble barium salt. 



   Reference example 12
 Prepared 3-formyl-5-methyl salicylic acid, P. F. 



     190-194 "C (recrystallized from aqueous methanol) from 5-methyl salicylic acid by applying the methods described in American patent 3 833660.    



   Reference example 13
 3-Formyl-2-hydroxy-acetophenone (15.0 g) is added to a stirred suspension of freshly prepared silver oxide (I) (23.15 g) in an aqueous solution of sodium hydroxide (0, 9N; 300 ml), between 5 and 10 "C, within one hour.  The mixture is then stirred for another hour. 



  After filtration to remove the silver, the resulting orange solution is treated with bleaching black and filtered, then acidified with concentrated hydrochloric acid.  The resulting precipitate is collected and recrystallized from water, with the aid of bleaching black, to give 3-acetyl salicylic acid (9.4 g), P. F.    135-136 "C.    



   The 3-formyl-2-hydroxy acetophenone used as starting material is prepared as follows:
Cooled between -65 and -700C a solution of 2-hydroxy-3-propenyl acetophenone (40.9 g) in anhydrous ethyl acetate (600 ml).     There is then passed through a stream of oxygen, containing about 2% ozone, until the yellow color of the solution has disappeared and a white precipitate has formed, and until no There is more absorption of ozone (as indicated by the sudden release of iodine from a test solution of potassium iodide by the outgoing gas).  Dimethyl sulfide (60 ml) is then added, the mixture is allowed to warm to room temperature over 2 hours and allowed to stand at this temperature for 15 hours.  The solvents are removed in vacuo and water (200 ml) is added to the residue. 

  The resulting solid is extracted with diethyl ether (250 ml).     The ethereal layer is washed with water (3 times 20 ml), dried over anhydrous sodium sulfate, then the solvent is removed in vacuo.  The residue is recrystallized from a mixture of petroleum ether (P. E.    60-80 "C) and carbon tetrachloride, which gives 3-formyl-2-hydroxy-acetophenone (20.0 g), P. F.    67-69 "C.    



   The 2-hydroxy-3-propenyl acetophenone used as starting material is prepared as follows:
A solution of allyl-3 hydroxy-2 acetophenone (100 g) in toluene (300 ml) is treated with bis (benzonitrile) -palladium (II) chloride (5 g).  The mixture is heated at reflux for 20 hours.  It is then filtered and the solvent is removed in vacuo from the filtrate.  By fractional distillation of the resulting oil, 2-hydroxy-3-propenyl acetophenone (90 g), P. E.    153 -1550C at 18 mmHg. 

 

     The allyl hydroxy-2 acetophenone used as starting material is prepared according to the methods described by Takuhashi et al. , J.  Pharm.  Soc.  Japan, 74,48-51 (1954).    



   Reference example 14
 Dicyclohexylcarbodiimide (1.03 g) is added to a solution of 2-benzyloxy-5-trifluoromethyl benzoic acid (1.48 g) and 5-amino tetrazole (0.425 g) in anhydrous pyridine (25 ml) , and the resulting mixture is stirred at room temperature for 20 hours.  The pyridine is removed in vacuo, the residue is treated with ammonia (4N; 75 ml) and stirred for one hour.  The insoluble dicyclohexylurea is filtered off, and the filtrate is acidified with concentrated hydrochloric acid.  The precipitated solid is recrystallized from ethanol, which gives 2-benzyloxy-trifluoromethyl-5 N- (tetrazolyl-5) -benzamide (1.25 g), P. F.  248-2490C (with decomposition). 



   The 2-benzyloxy-5-trifluoromethyl benzoic acid used as starting material is prepared as follows:
Powdered sodium hydride (0.08 g) is added to anhydrous benzyl alcohol (15 ml) and the mixture is heated to complete the resulting reaction.  The mixture is then treated with 2-chloro-5-trifluoromethyl benzonitrile (0.62 g) and heated, with stirring, to 90-95 "C for 20 hours.  Then the mixture is diluted with benzyl alcohol (10 ml), the resulting mixture is filtered and the filtrate is evaporated in vacuo.  The resulting oil is then treated with a solution of sodium hydroxide (6 g) in aqueous ethanol (95%; 30 ml) and heated to reflux. 

  The solvent is removed in vacuo, water (25 ml) and diethyl ether (25 ml) are added to the residue, the mixture is stirred and the layers are separated. 



   The aqueous layer is then acidified with concentrated hydrochloric acid.  The precipitate is separated by filtration and recrystallized from water to give 2-benzyloxy-5-trifluoromethyl benzoic acid (0.35 g), P. F.  94-95 "C.    



   2-chloro-5-trifluoromethyl benzonitrile, used as starting material, is prepared by adapting the methods of
Garder et al. , Arzneimittel Forschung, 13, 802 (1963). 



   Reference example 15
 Trifluoroacetic acid (0.8 ml) was added to anhydrous lutidine-2,6 (10 ml) and the mixture was then treated with 3-cyano-5-methyl salicylic acid (0.885 g), sodium azide (0.65 g) and lithium chloride (20 mg) and heated to reflux for 20 hours.  The mixture is then diluted with water (20 ml) and acidified with concentrated hydrochloric acid.  The resulting precipitate is collected and recrystallized from a large amount of acetic acid to give 5-methyl (5-tetrazolyl) -3 salicylic acid (0.65 g), P. F.    290-292 "C) with decomposition). 



   Reference example 16
 3-Formyl-5-methyl salicylic acid (3.6 g) is dissolved in dimethylformamide (20 ml) and the solution is treated with hydroxylamine hydrochloride (1.53 g).  The mixture is heated to reflux for 10 minutes, then the solvent is removed in vacuo.  The residue is treated with water (20 ml) and hydrochloric acid (2N; 10 ml).    



   The precipitated solid is filtered and recrystallized from aqueous ethanol to give 3-cyano-5-methyl salicylic acid (2.7 g), P. F.  193-194 "C.    



   Proceeding in a similar manner, but replacing the 3-formyl-5-methyl-salicylic acid used as starting material with the appropriate amounts of 3-formyl salicylic acid and 5-formyl salicylic acid, the acid is prepared respectively salicylic cyano-3, P. F.    213-214 "C, and 5-cyano salicylic acid, P. F.  217-220 "C.    



   Reference example 17
 A suspension of 3-amino salicylic acid (5.0 g) in acetic acid (75 ml) is treated with hydrochloric acid (2N), slowly and shaking until complete dissolution is achieved.  The solution is then treated with an aqueous formaldehyde solution (40% w / v; 20 ml), a catalyst containing 5% palladium on black (2.0 g) is added thereto, and the mixture is hydrogenated at 25 " C and under atmospheric pressure for 18 hours.  The catalyst is removed by filtration, the filtrate is evaporated in vacuo and the resulting residue is dissolved in hydrochloric acid (2N; 100 ml), then the pH of the solution is adjusted to 5 with concentrated ammonia.  The mixture is left to stand for 24 hours in the refrigerator. 

  The precipitate is then reviewed, giving 3-dimethylamino salicylic acid (3.0 g), P. F. 



     273-277 "C (with decomposition). 



   Reference example 18
 Benzyl chloroformate (5.5 g) is added to a suspension of 5-amino salicylic acid (4.6 g) in anhydrous pyridine (25 ml), at 0 C, over 5 minutes.  The mixture is allowed to warm to 25 "C and is stirred for 20 hours, then poured into a mixture of ice (100 g) and concentrated hydrochloric acid (50 ml).     The solid which precipitated is then filtered off, dissolved in ethanol (50 ml) and treated with a little bleaching black.  The mixture is filtered and the filtrate is evaporated to dryness, which gives 5-benzyloxycarbonylamino-salicylic acid (2.5 g), P. F.  222-224 "C.    



   By proceeding in a similar manner, but replacing the 5-amino salicylic acid used as starting material by the appropriate amount of 4-amino salicylic acid, the benzyloxycarbonylamino-4 salicylic acid, P. F. 



     184-186 "C.    



   Reference example 19
 2-Hydroxy isophthalic acid (1.82 g) and dicyclohexylcarbodiimide (2.17 g) are dissolved together in anhydrous pyridine (30 ml) and the mixture is stirred for 2 hours at room temperature.  This mixture is then treated with ahydrous tert-butylamine (5 ml), and the resulting mixture is stirred at 60 ° C for 20 hours.  The solvents are removed in vacuo, and the residue is treated with a saturated aqueous solution of sodium bicarbonate (50 ml).  The mixture is stirred for 15 minutes.  The insoluble dicyclohexylurea is then removed by filtration, the resulting filtrate is treated with bleaching black and filtered again. 

  The filtrate is then acidified with concentrated hydrochloric acid, which gives a white solid which is filtered and recrystallized from a mixture of petroleum ether (P. E.  60-80 "C) and benzene, which gives tert acid. -butylcarbamoyl-3 salicylic (1.2 g), P. F.  191-195 "C.    



   Reference example 20
 5-Acetyl salicylic acid (9.0 g) is dissolved in concentrated sulfuric acid (20 ml).  The solution is cooled to 0 C and treated, with stirring, with a mixture of concentrated nitric acid (density 1.42; 3.8 ml) and concentrated sulfuric acid (3.8 ml), drop dropwise, at a rate such that the temperature does not exceed 5 "C.     The mixture is left to stand at 0 ° C. for 5 hours, then it is poured onto a mixture of ice and water (100 ml).  The precipitated solid is filtered off and recrystallized from water to give 5-acetyl-3-nitro-salicylic acid (8.6 g), P. F.  192-193 "C.    

 

   Reference example 21
 Diacetyl-3,5-dihydroxy-2,4-benzoic acid is prepared according to the methods described by Amin et al. , J.  Ind.  Chem. 



     Soc. , 29.351 (1952).     


    

Claims (7)

 CLAIMS 1. Benzamide derivatives having the general formula: EMI1.1  in which R1 represents a fluorine, chlorine or bromine atom, or an alkyl, alkoxy, alkylthio, alkylsulfonyl, alkanoylamino, alkyllamino or alkylsulfamoyl group, straight or branched chain, 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, an alkanoyl, alkoxycarbonyl, alkoxycarbonylamino or alkoylcarbamoyl group, containing 2 or more with 6 carbon atoms, or a hydroxy, formyl, nitro, trifluoromethyl, aryl, benzyloxycarbonylamino, amino, sulfamoyl, cyano, tetrazolyl-5, carboxy, carbamoyl or aroyl group, and n represents 1,2 or 3,  the substituents R1 being identical or different when n represents 2 or 3, and their salts.  2. A derivative according to claim 1, corresponding to the following designation: Acetyl-3-hydroxy-2-methyl-5 N- (tetrazolyl-5) -benzamide, 2-hydroxy-3-methoxy N- (tetrazolyl-5) -benzamide, 3-acetyl-5-ethyl-2-hydroxy-N- (tetrazolyl-5) -benzamide, 3-acetyl-2-hydroxy-N- ( tetrazolyl-5) -benzamide, acetyl-3-hydroxy-2-propyl-5 N- (tetrazolyl-5) -benzamide, Hydroxy-2-methyl-5-propionyl-3 N- (tetrazolyl-5) -benzamide, ethyl-5-hydroxy-2-propionyl-3 N- (tetrazolyl-5) -benzamide, Hydroxy-2 methyl-5 (tetrazolyl-5) -3 N- (tetrazolyl-5) -benzamide, acetyl-3 hydroxy-2 nitro-5 N- (tetrazolyl-5) -benzamide, 2-hydroxy-dinitro-3,5 N- (tetrazolyl-5) -benzamide, Hydroxy-2 nitro-3 N- (tetrazolyl-5) -benzamide, hydroxy-2 propoxy-3  N- (tetrazolyl-5) -benzamide, Hydroxy-2 nitro-5 N- (tetrazolyl-5) -benzamide, 2-hydroxy-5-methoxy N- (tetrazolyl-5) -benzamide, 4-acetylamino-2-hydroxy-N- (tetrazolyl-5) -benzamide, 2-hydroxy-methylthio-5 N- (tetrazolyl-5) -benzamide, 5-formyl-hydroxy-2 N- (tetrazolyl-5) -benzamide, benzyloxycarbonylamino-4 hydroxy-2 N- (tetrazolyl-5) - benzamide, acetyl-3 hydroxy-2 sulfamoyl-5 N- (tetrazolyl-5) -benzamide, acetyl-3 sec.-butyl-5 hydroxy-2 N- (tetrazolyl-5) -benzamide, Acetyl-3 tert.-butyl-5 hydroxy-2 N- (tetrazolyl-5) -benzamide, acetyl-3 fluoro-5 hydroxy-2 N- (tetrazolyl-5) -benzamide, butyryl-3 ethyl -5 hydroxy-2 N- (tetrazolyl-5) -benzamide, formyl-3 hydroxy-2 N- (tetrazolyl-5) -benzamide, cyano-3 hydroxy-2 N- (tetrazolyl-5) -benzamide,  cyano-5 hydroxy-2 N- (tetrazolyl-5) -benzamide, acetyl-5 hydroxy-2 nitro-3 N- (tetrazolyl-5) -benzamide.  3. Process for the preparation of the benzamide derivatives corresponding to the general formula specified in claim 1 and of their salts, except the derivatives in the formula of which R1 represents an alkylamino or amino group, characterized in that one reacts with l 5-amino tetrazole with a carboxylic acid of general formula: : EMI1.2  in which R2 represents a fluorine, chlorine or bromine atom, or an alkyl, alkoxy, alkylthio, alkylsulfonyl, alkanoylamino or alkylsulfamoyl group, straight or branched chain, 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 the same or different and each contain from I to 4 carbon atoms, an alkanoyl, alkoxycarbonyl, alkoxycarbonylamino or alkoylcarbamoyl group, containing from 2 to 6 carbon atoms, or a hydroxy, formyl, nitro, trifluoromethyl, aryl, benzyloxycarbonylamino, sulfamoyl, cyano, tetrazolyl-5, carboxy, carbamoyl or aroyl group, and n represents 1,2 or 3,  the substituents R2 being identical or different when n represents 2 or 3, and in that, where appropriate, the derivative obtained is converted into a salt by reaction with a base.  4. Process for the preparation of the benzamide derivatives corresponding to the general formula specified in claim 1, and of their salts, except the derivatives in the formula of which R1 represents an alkylamino, hydroxy, amino or carboxy group, characterized in that 5-amino tetrazole is reacted with an ester of general formula: : EMI1.3  in which R3 represents a fluorine, chlorine or bromine atom, or an alkyl, alkoxy, alkylthio, alkylsulfonyl, alkanoylamino or alkylsulfamoyl group, straight or branched chain, each of these groups 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 from 1 to 4 carbon atoms), an alkanoyl, alkoxycarbonyl, alkoxycarbonylamino or alkoylcarbamoyl group, containing from 2 to 6 carbon atoms, or a formyl, nitro, trifluoromethyl, aryl, benzyloxycarbonylamino, sulfamoyl, cyano, tetrazolyl-5, carbamoyl or aroyl group, and n represents 1,2 or 3, the substituents R3 being identical or different when n represents 2 or 3,  and R4 represents a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, and in that, where appropriate, the derivative obtained is converted into a salt by reaction with a base.  5. Process for the preparation of the benzamide derivatives corresponding to the general formula specified in claim 1 and of their salts, except the derivatives in the formula of which R1 represents an alkanoylamino, alkoylamino, alkoxycarbonylamino, hydroxy, benzyloxycarbonylamino, amino, carboxy or carbamoyl, characterized in that 5-amino tetrazole is reacted with an acid halide of general formula: : EMI1.4   in which Rs represents a fluorine, chlorine or bromine atom, or an alkyl, alkoxy, alkylthio, alkylsulfonyl or alkylsulfamoyl group, straight or branched chain, each of these groups containing from I to 6 carbon atoms, a dialcoylsulfamoyl group , dialkoylamino or dialkoylcarbamoyl (in which the two alkyl groups may be the same or different and each contain from I to 4 carbon atoms), an alkanoyl, alkoxycarbonyl or alkylcarbamoyl group, with straight or branched chain, containing from 2 to 6 carbon atoms , or a formyl, nitro, trifluoromethyl, aryl, sulfamoyl, cyano, tetrazolyl-5 or aroyl group, and n represents I, 2 or 3, the substituents R5 being identical or different when n represents 2 or 3,  and X represents a chlorine or bromine atom, and in that, if necessary, the derivative obtained is transformed into a salt by reaction with a base.  6. Process for the preparation of the benzamide derivatives according to claim I, which correspond to the general formula: EMI2.1  in which R1 and Roll, which are identical or different, each represent a hydrogen atom or an alkyl group with a straight or branched chain containing from 1 to 4 carbon atoms, r represents 1,2 or 3, R12 represents an atom of fluorine, chlorine or bromine, or an alkyl, alkoxy, alkylthio or alkylsulphonyl group, straight or branched chain, each of these groups containing from 1 to 6 carbon atoms, or a dialkoylamino group, in which the two alkyl groups can be identical or different and each contain from I to 4 carbon atoms, an alkanoyl or alkoxycarbonyl group, with a straight or branched chain,  containing from 2 to 6 carbon atoms, or a hydroxy, formyl, nitro, trifluoromethyl, aryl, cyano, tetrazolyl-5, carboxy or aroyl group, and p represents zero, 1 or 2, the substituents R12 being identical or different when p represents 2, and the sum of r and p is 1, 2 or 3, and their salts, characterized in that an amine of general formula is reacted: HNRI R11 (X) in which Rl and Rl l are as defined above, with a compound of general formula: EMI2.2  in which R12, r and p are as defined above, and in that, where appropriate, the derivative obtained is converted into a salt by reaction with a base.  7. Pharmaceutical compositions comprising, as active substance, at least one benzamide derivative according to claim 1 or 2, or one of its pharmaceutically acceptable salts, in association with a pharmaceutical support or coating.  The present invention relates to new benzamide derivatives useful in therapy, to processes for their preparation and to pharmaceutical compositions containing them.  It has been found that the new benzamide derivatives represented by the general formula: EMI2.3  [in which R1 represents a fluorine, chlorine or bromine atom, or an alkyl, alkoxy, alkylthio, alkylsulfonyl, alkanoylamino, alkyllamino or alkylsulphoyl group, each of these groups containing from 1 to 6 atoms of 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 alkanoyl, alkoxycarbonyl, alkoxycarbonylamino or alkoylcarbamoyl group, containing a straight or branched chain, from 2 to 6 carbon atoms, or a hydroxy, formyl, nitro, trifluoromethyl, aryl (for example phenyl), benzyloxycarbonylamino, arhino, sulfamoyl group,  cyano, tetrazolyl-5, carboxy, carbamoyl or aroyl (for example benzoyl), and n represents 1, 2 or 3, preferably 1 or 2, the substituents R being identical or different when n represents 2 or 3], 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 OH residues, CONH and NH can give rise to a tautomerism and that all the resulting tautomeric forms can be present to a greater or lesser degree and are in a state of dynamic equilibrium with each other. In addition, the R1 substituents can contain chiral centers and thus give rise to optical isomerism. The present invention encompasses all optical isomers of general formula (I) and all tautomers of compounds of general formula (I) and mixtures thereof.  The present invention includes the pharmaceutically acceptable salts of the compounds of formula (I) with pharmaceutically acceptable bases. By the term pharmaceutically acceptable salts is meant 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 compounds of general formula (I) from which they are derived are not upset by side effects attributable to these cations. Among the suitable salts, there may be mentioned the alkali metal salts, such as sodium and potassium, the ammonium salts and the amine salts known to be pharmaceutically acceptable, for example ethylenediamine, choline, diethanolamine, triethanolamine, octadecylamine, diethyla ** ATTENTION ** end of the CLMS field may contain start of DESC **.