NO770914L - PROCEDURES FOR THE PREPARATION OF CHROMONE DERIVATIVES - Google Patents

Description

Method of manufacture of

chromone derivatives.

The present invention relates to a method for the production of chromone derivatives, more particularly a new and industrially feasible method for the production of chromone derivatives of formula (I) or pharmaceutically acceptable salts thereof,

and which can be used as medicines to prevent and/or treat allergic disorders, especially bronchial asthma and rhinitis for both humans and animals;

where m is 0, 1 or 2, and R is a halogen atom, nitro, an amino group which may be unsubstituted or substituted with alkyl, aryl, aralkyl or acyl groups, alkyl, alkoxy, acyloxy, hydroxy, -C00R' where R' is hydrogen, alkyl or alalkyl, carboxamide which may be unsubstituted or substituted with at least one alkyl or aralkyl group, butadienylene (-CH=CH-CH=CH-) which forms a benzene ring with the two adjacent carbon atoms in the 5' positions 6, 7 and 8, or pharmaceutically acceptable salts of these compounds.

The present method involves reacting a compound with the following formula (II): where m and R are as defined above; R is hydrogen, alkyl, aralkyl or aryl, with formic acid or a derivative thereof and, if necessary, a removal of the group R . Furthermore, the invention relates to new acetophenone derivatives with formula (III):

at 1

where R, R and m are as defined above, and R is hydrogen,

alkyl or aralkyl.

The new acetophenone derivatives can be used as intermediates for the production of said chromone derivatives (I) which have an effective anti-allergic effect. Also has connections with

etc. 2

formula (III), where both R and R are hydrogen and salts thereof, an anti-allergic activity-, and can consequently be used as medicines.

A method has so far been indicated for the preparation of compounds of formula (I) (ie US patent no. 3,896.II4) where salts of hydrogen azide, e.g. sodium azide, is used in the synthesis of the tetrazole ring. These compounds tend to evolve hydrogen azide which is a highly explosive and harmful gas, or give an explosive metal salt, and are consequently a compound which is commercially difficult to process. The present process does not include the use of hydrogen azide or its salts, and consequently it has been possible to develop a commercially very advantageous method.

With respect to the substituent indicated by the symbol R

in formulas I and II, the alkyl group may be a straight chain, branched or cyclic alkyl group having from 1 to 6 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl, pentyl, cyclopentyl, hexyl and cyclohexyl. Especially desirable for commercial purposes are lower alkyl groups with from 1 to 3 carbon atoms. The halogen atom can be chlorine, bromine, iodine or fluorine. The substituted amino group can e.g. be amino groups which

is mono- or di-substituted such as alkylamino, arylamino, aralkylamino or an acylamino group. Examples of said alkyl-amino groups can be mentioned amino substituted with one or two lower

alkyl groups with from 1 to 3 carbon atoms, e.g. methylamino, ethylamino, propylamino, dimethylamino, diethylamino and dipropylamino. The arylamino group can e.g. be phenylamino or di-phenylamino, while said aralkylamino group can e.g. be benzylamino or phenethylamino. As examples of said acylamino group, mention may be made of amino groups substituted with lower alkylcarbyl or arylcarbonyl groups, e.g. acetyl, propionyl, butyryl, benzoyl. The alkoxy group can be a group whose alkyl part contains from 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy or butoxy. The acyloxy group can e.g. be a lower alkylcarbonyloxy or arylcarbonyloxy group,

such as acetoxy, propionyloxy, butyryloxy and benzoyloxy.

The formula -COOR' represents carboxy and its derivative group, where R' is hydrogen, alkyl or aryl alkyl. The alkyl group represented by R' can have from 1 to 3 carbon atoms and can be represented by medtyl, ethyl, propyl and isopropyl, and typical examples of the aralkyl group are indicated by the symbol R' can be benzyl or phenethyl. The alkyl-substituted carboxamide group represented by R includes mono- or dialkyl-substituted groups, the alkyl part of which is a lower alkyl group having from 1 to 3 carbon atoms and mono- or diaralkyl (eg benzyl) substituted groups. Typical examples in this group are N-methylcarboxamide, N,N-dimethylcarboxamide, N-ethylcarboxamide, N,N-diethylcarboxamide, N-propylcarboxamide, N-benzylcarboxamide and N,N-dibenzylcarboxamide.

With regard to the substituent R', the alkyl group can be methyl, ethyl, propyl or butyl and the aralkyl group can e.g. be benzyl or phenethyl.

As the substituent R p , the alkyl, aralkyl and aryl group can optionally be substituted with a group containing heteroatoms. More particularly, said alkyl group can be a group with from 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl-tert.butyl, 2-methoxyethyl, 2-cyanoethyl, etc. The aralkyl group can e.g. be benzyl or 4-methoxybenzyl, while the aryl group can be a phenyl group.

The present invention includes reacting

a compound of formula II with formic acid or its derivative, and then subjecting the reaction product to a reaction to remove the protecting group R<2>.

As an example of formic acid derivatives that can be used

for the cyclization reaction for compound II, mention can be made of esters such as methyl formate, ethyl formate, propyl formate, butyl formate, methyl ortho formate, ethyl ortho formate, etc, amide derivatives such as formamide, dimethylformamide, diethylformamide, N-phenyl-N-methylformamide, etc.

and mixed anhydride of formic acid and other organic acids, e.g. acetic acid. The reaction between compound II and a formic acid derivative is preferably carried out in the presence of a base, e.g. sodium methoxide, sodium ethoxide, potassium t-butoxide, sodium hydride, potassium hydride or calcium hydride. The reaction is usually advantageously carried out in an organic solvent. Examples of such solvents include alcohols such as methanol, ethanol, propanol, butanol, etc.; hydrocarbons such as benzene, toluene, xylene,

and petroleum petrol etc, as well as ethers such as tetrahydrofuran, • dioxane, ethyl ether, ethylene glycol dimethyl ether etc. The amount of formic acid derivatives used in the cyclization reaction is normally from 1 to 40 molar equivalents per xmol of the starting compound for practical purposes. Temperature, time and other conditions in the reaction are not particularly critical. The reaction is usually carried out at temperatures from room temperature to 150°G for a period of time from 30 minutes to 2 days. When using a formic acid amide derivative, the amount of said amide derivative is not particularly critical, although it is generally advantageous to use from 1 to 40 molar equivalents in relation to compound II. Although the formic acid amide derivative as such can be used,

it is advantageous to use the amide derivative together with from 1 to 40 molar equivalents relative to the compound II, of an inorganic halide, such as phosphorus oxychloride, tetrachloropyrophosphoric acid, thionyl chloride, phosphorus pentachloride or phosgene. Usual-

however, the amine derivative as such can be used as a solvent. Alternatively, aromatic hydrocarbons can be used. such as benzene^, toluene and xylene as well as semi-generic hydrocarbons such as chloroform, dichloromethane and tetracotethane as solvents.

In the above reaction, the compound of formula III where R"*" is alkyl or aralkyl instead of compound II can be reacted with formic acid, whereby the compound of formula I is obtained. The reaction between the compound of formula III, where

R"<*>"is alkyl or aralkyl with formic acid is preferably carried out in the presence of an acid, e.g. hydrochloric acid, bromic acid, iodic acid or phosphoric acid. The amount of formic acid is not particularly critical, as it can be used as a solvent, although it is advantageous to use from 1 to 100 mole equivalents relative to the starting compound. Temperature and reaction time are not particularly critical. The reaction is usually carried out at temperatures from room temperature to 160°C from 30 minutes to 3 days.

For example can compounds of formula II, where R"<*>"is

2 12'

methyl and R is tert.butyl, R is methyl and R is hydrogen, or R I- is hydrogen and R 2 is tert.butyl respectively, are heated with a mixture of hydrobromic acid and formic acid directly so that the corresponding compounds with formula are obtained IN.

The ratio between bromic acid and formic acid and the respective volumes of these are not particularly critical, although it is advantageous that the starting compound is homogeneously dissolved during heating.

It is theoretically assumed that the removal of the protective group R"*" which occurs during the reaction results in a cyclization of the compound III to the compound of formula I. The occurrence of such a reaction should thus be included in the interpretation of the present reaction.

p If necessary, the protecting group R can be removed from the compound obtained by cyclization of compound II. A compound of formula I is then obtained. The reaction used to remove the protective group R 2 is usually carried out in the presence of a mineral acid or a Lewis acid. Examples of mineral acids that can be used include hydrochloric acid, bromic acid, hydrogen bromide, hydrogen chloride or a solution of hydrogen chloride or hydrogen bromide in an organic

acid such as acetic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid, while as mentioned Lewis acid, aluminum chloride, aluminum bromide, zinc chloride or boron fluoride can be used. When the Lewis acid is solid, the reaction will usually be carried out in an organic solvent. As an example of solvents that can be used, mention may be made of aromatic hydrocarbons such as benzene, toluene and xylene, as well as halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane and tetrachloroethane.

The amount of mineral or Lewis acid used

in the reaction to remove the protecting group R , is usually

from 1 to 100 mol equivalents per moles of the compound obtained by cyclization of the compound of formula II. The reaction is usually carried out at temperatures from 4-0°C to 160°C for from 30 min. to 3 days.

The compound of formula II can be prepared by reacting a compound of formula IV with a compound of formula VI, and if necessary removing the protecting group R 1 .

(In the above formulas, R, R 1 , R 2 and m are as defined above, R^ is alkyl, aralkyl or aryl; X is hydroxy or halogen, provided that the substituent(s) R in connection with formula IV is substituted in any position other than 2-

• the position).

The above reaction is carried out in the presence of a Lewis acid of the type usually used in Friedel-Craft reactions, such as aluminum chloride, stannous chloride, titanium tetrachloride, zinc chloride, boron fluoride, polyphosphoric acid, etc. whereby a compound of formula III is obtained.

When the Lewis acid is liquid, it can be used as a solvent. The amount of such a Lewis acid is not particularly critical, although for practical purposes it is usual to use from 1 to 20 mol equivalents per mol, of the starting boron bond. Although the solvent can be any type that does not affect the reaction, examples can be mentioned of aromatic hydrocarbons such as benzene, xylene, nitrobenzene etc, halogenated hydrocarbons such as carbon tetrachloride, 1,2-dichloroethane, tetrachloroethane etc, carbon disulphide and hydrocarbons such as n-hexane, petroleum petrol etc. The compound of formula IV can be used in an excess, so that

it also acts as a solvent. Although the reaction is usually carried out at temperatures close to the boiling point of the solvent, no harmful results are obtained if a lower temperature is used. In practical terms, it is preferred to use temperatures from 40 to 160°C. There are also cases where the reaction proceeds more satisfactorily in the presence of a catalyst such as iodine.

The crude and impure oily residue containing the compound of formula III can be used in the next reaction as such.

The type and ratio of compounds of formula III obtained in the above reaction will vary with the type of Lewis acid or substituent R"'" or the reaction conditions used. E.g. when using a compound of formula VI, where R-^ is tert-butyl and X is chlorine and reacts this with a compound of formula IV, where R"<*>" is methyl in dichloroethane as solvent in the presence of anhydrous stannous chloride , one obtains a mixture of compounds of formula III, where R"<*>"is methyl and R<2>is tert.butyl, R is methyl-L °S R is hydrogen and R<1>is hydrogen and R 2 is tert.butyl, or when a compound of formula VI, where R-^ is ethyl and X is chlorine is reacted with a compound of formula

IV, where R"<*>" is methyl in dichloroethane in the presence of anhydrous aluminum chloride, one obtains one compound of formula III, where R"'" is methyl and R is ethyl.

Each of the above mixtures can be separated into

their respective connections, e.g. by extraction and chromatography, although it is preferred to let the reaction mixture as such enter into the next reaction.

The compound of formula III obtained in the above reaction, where R 2 is alkyl, aralkyl or aryl and R 1 is alkyl or aralkyl, can be converted into a compound (II-1), (II-2) or (II-3) by heating together with hydrobromic acid, hydroiodic acid, sulfuric acid, pyridine hydrochloride or the like in the absence or presence of an organic acid such as e.g. formic or acetic acid.

Compounds III and II-2 can be converted into compounds (II-3) and (II-1) by removing the protecting group R 2 in a manner similar to that described for removing the protecting group R from the compound obtained by cyclization the compound of formula II, respectively.

The type of compound obtained by said reaction 12

by removing the protective groups R and R will vary according to the reaction conditions, reagents and solvents used.

When e.g. a compound of formula III, when R"*" is methyl and R is tert.butyl, is reacted with 50-60% sulfuric acid in acetic or formic acid, a compound (II-3) will be obtained where

12

R is methyl and R is hydrogen, and when using a compound

1 2

with formula III where R is methyl and R is tert.butyl and this reacts with 47% hydrobromic acid in acetic acid, a compound is obtained

12

with formula II-1, where R and R are hydrogen, while when a compound of formula III, where R 1 is methyl and R 2 is ethyl is heated with 47% hydrobromic acid, a compound of formula II-2 is obtained, where

1 2

R is hydrogen and R is ethyl.

The compound of formula (II-3) can be converted to the compound of formula (II-1) by heating, e.g. with hydrobromic acid in the absence or presence of acetic acid.

The compound of formula (II-1) can be converted into the compound of formula (II-2) by subjecting it to alkylation, aralkylation or arylation. The resulting compound (II-2) is normally a mixture of the compound with 1-substitution on the tetrazole ring and the compound with 2-substitution on the same ring, and this mixture can be resolved into its respective isomers, e.g. by fractional crystallization or chromatography, although it is preferred to use the reaction mixture as such in the next reaction. The aforementioned alkylationaralkylation or arylation can be carried out by reacting the compound in the presence of an acid, e.g. sulfuric acid, e.g. with tert.butanol or benzyl alcohol which can act as a solvent, or by using trifluoroacetic acid as a solvent. Alternatively, the compound may be reacted with an alkyl halide (eg ethyl bromide, methyl iodide, propyl bromide, isopropyl bromide, butyl bromide or tert-butyl bromide), benzyl chloride, benzyl bromide or phenyl chloride, e.g. in the presence of a base, e.g. an alkali metal compound (potassium carbonate?sodium carbonate, sodium hydride, sodium hydroxide, potassium hydroxide, etc.) or an organic amine (triethylamine, etc.).

By the above-mentioned methods, one obtains the compounds (II-1), (II-2) and (II-3), that is, the compound of general formula II.

The compounds of formula I and II-1 can each be converted into the corresponding organic amine salt, alkali metal salt or ammonium salt by methods known per se, e.g. by heating a compound of formula I or II-1 together with an organic amine (e.g. ethanolamine, dj£-methylephidrine, l-(3>5-di-hydroxyphenyl)-L-isopropylaminoethanol, isoproterenol, dexgrome- .torphan, hetrazan (diethylcarbamazine), diethylamine, triethylamine, etc.), an alkali metal hydroxide (sodium hydroxide, potassium hydroxide, etc.) or ammonia in a suitable solvent.

The resulting compound of formula I and II-1, as well as salts thereof, have anti-allergic properties and are thus valuable as prophylactic or therapeutic agents for the treatment of allergic disorders such as allergic asthma, allergic skin disorders and hay fever.

As said alkali metal or organic amine salts are well soluble in water and give stable aqueous solutions, they can be suitably used for the preparation of injections, aqueous solutions or other dosage forms. When a compound according to the present invention is used as a prophylactic or therapeutic agent for the aforementioned allergic disorders, a normal dose for an adult patient will be from 1 to 500 mg daily when using a compound of formula I or a salt thereof, and from 10 to 1000 mg daily when using a compound of formula II-2 or a salt thereof.The dosage forms may include tablets, capsules, powders and aqueous solutions for oral administration and injectable solutions, inhalations, ointments, etc.

One of the starting compounds used in the present invention, that is to say the compound of formula IV, can be prepared by a method corresponding to that described by W.T. Olson et al. in "The Journal of American Chemical Society" 69, 2451 (1947)* This means that one reacts a compound of formula V:

where R and m are as defined previously, under the condition that the substituent R is placed in any position other than the 2-position, e.g. with an alkyl halide (eg methyl iodide, ethyl bromide, propyl bromide, butyl bromide, tert-butyl bromide) or an aralkyl halide (eg benzyl chloride, benzyl bromide, phenethyl chloride).

The second compound used in the present invention, i.e. compound of formula VI, can be prepared by the following reaction step, starting from the compound of formula VIII, seam then again can be obtained by the method described by I. Va, Postovskii, Dohl. Acad.Nauk.SSSR 170, 604

(1966).

where R-^ is as defined previously, and X' is halogen.

The alkylation, aralkylation or arylation of the compound of formula VIII usually gives a compound of formula VII which is in reality a mixture of the compound with 1-substitution on the tetrazole ring and the compound with 2-substitution on the same ring. Although these isomers can be easily isolated, it is more advantageous to subject the mixture as such to the next reaction. The aforementioned alkylation, aralkylation or arylation reaction can be carried out in the presence of an acid, such as e.g. sulfuric acid, using tert.butanol or benzyl alcohol as solvent, or in the presence of trifluoroacetic acid as solvent.

Alternatively, an alkyl halide (e.g. ethyl bromide, methyl iodide, propyl bromide, isopropyl bromide, butyl bromide, tert-butyl bromide), benzyl chloride or benzyl bromide or phenyl chloride, e.g. is reacted with the compound in the presence of a base such as an alkali metal compound (potassium carbonate, sodium carbonate, sodium hydride, sodium hydroxide, potassium hydroxide) or an organic amine (e.g. triethylamine.) The compound of formula VII will not normally be purified, but hydrolyzed in a aqueous solution of alkali, e.g. sodium hydroxide, to the compound of formula VI-2.

This compound (VI-2) can be reacted with a halogenating agent, e.g. phosphorus pentachloride, phosphorus trichloride, or thionyl chloride, in the absence or presence of any type of solvent that does not harm the reaction (e.g. dichloroethane), whereby one obtains the acid halide of the formula VI-1.

The reaction mixture obtained by the above reaction can be subjected to the next reaction as such, i.e.

a Friedel-Craft reaction.

The compound of formula II-1 can also be synthesized by the following method. Thus, the compound of formula I which can be obtained by the method described in US Patent No. 3,896,114 will be reacted with an aqueous solution of alkali. As the aforementioned alkali, one can e.g. use sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate or aqueous ammonia. The amount of said alkali will normally be from 1 to 20 molar equivalents, for practical purposes based on the amount of the compound of formula I. Although the reaction temperature, time and other conditions are not particularly critical, it is usual to carry out the reaction from ^ 0°G to the boiling point of said solvent, and a period of time from 10 minutes to 5 hours. After the hydrolysis reaction, the product can be treated with a suitable acid, e.g. with a mineral acid such as hydrochloric or sulfuric acid, whereby the compound of formula II-1 with a free tetrazole ring is obtained.

This compound can then be subjected to the aforementioned alkylation, aralkylation or arylation reaction, whereby a compound with the formula II-2 is obtained.

Reference example 1

A solution consisting of ethyl (1H-tetrazol-5-yl)-acetate (1.64 g), tert-butanol (1.2 ml), trifluoroacetic acid (40 ml) and concentrated sulfuric acid (0.3 ml) was stirred at room temperature for 24 hours and then concentrated under reduced pressure. To the residue was added a 1N aqueous solution of sodium hydroxide (20 ml), together with 5 ml of concentrated aqueous solution of sodium hydroxide, and the whole mixture was stirred at room temperature for 2 hours. The mixture was then shaken with ethyl acetate and the aqueous layer was taken off, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was recrystallized from ethyl acetate-petroleum ether, and by this method (2-tert-butyl-2H-tetrazol-5-yl)-acetic acid was obtained as colorless crystals. Yield: 1.01 g, m.p. 125-127°C.

Infrared absorption spectrum (KBr) : 1725 cm-"1" (CO) Nuclear magnetic resonance spectrum (CDC1^)6 : 10.78 (1H,s,0H),

4.02 (2H,s,CH2),

1.72 (9H,s,t-Bu) Elemental analysis for CyH-^N^Og

Reference example 2

A mixture of 3.1 g of ethyl (1H-tetrazol-5-yl)-acetate, 20 ml of dimethylformamide, 2.8 g of ethyl bromide and 8.9 g of triethylamine was stirred at room temperature for 5 hours. The solvent was distilled off and after adding 70 ml of water, the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with 20% aqueous ammonia and water, after which the ethyl acetate was distilled off and 3>0 g of a pale yellow oil was obtained. Based on its NMR spectrum (in deuteriochloroform) it was assumed that the product was a mixture of ethyl (2-ethyl-2H-tetrazol-5~yl)acetate and ethyl (1-ethyl-1H-tetrazol-5~yl)acetate (approx. 3;1)-

A 2.8 g portion of the above mixture was refluxed with 50 ml of a 5% alcoholic potassium hydroxide solution for one and a half hours. The solvent was distilled off, and the residue was shaken with ethyl acetate. The aqueous layer was removed and acidified with hydrochloric acid. After addition of sodium chloride, an oily precipitate was obtained which was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, and the ethyl acetate was distilled off, whereby 1.6 g of crystals were obtained. This residue was recrystallized twice from ethyl acetate. By the above method, (2-ethyl-2H-tetrazol-5~yl)acetic acid was obtained as colorless needles, m.p. 88-92°C.

Elemental analysis for C^HgN^Og

Reference example 3

A mixture of 1.56 g of ethyl (1H-tetrazol-5-yl)acetate,

2 ml of t-butanol, 10 ml of trifluoroacetic acid and 5 drops of concentrated sulfuric acid were stirred at room temperature for one hour. The solvent was distilled off under reduced pressure, and water was added to the residue. The resulting oily precipitate was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dilute aqueous ammonia and water in the order mentioned herein, and the ethyl acetate was then distilled off.

By the above procedure, 1.8 g of ethyl-(2-t-butyl-2H-tetrazol-5-yl)acetate was obtained as an oily residue.

The above oil was refluxed with 10 ml of a 10% alcoholic potassium hydroxide solution for 2 hours, after which the solvent was distilled off. Water was added to the residue and the mixture was acidified with hydrochloric acid, after which crystals were precipitated. 1.2 g of crystals were obtained by filtration. These crystals were further recrystallized from ethyl acetate, and (2-t-butyl-2H-tetrazol~5-yl)acetic acid was obtained as colorless prisms, m.p. 124-125°C.

Elemental analysis for CyH-^N^Og

. Reference example

On. the same way as stated in Ref.ex. 2 and 3 the following compounds were synthesized.

(1-n-butyl-1H-tetrazol-5-yl)acetic acid m.p. 114-115°C

Elemental analysis for CyH-^N^Og

(2-benzyl-2H-tetrazol~5-yl)acetic acid m.p. 87-88°C Elemental analysis for C]_oHl0^4<~>2

(1-benzyl-1H-tetrazol-5-yl)acetic acid

m.p. 150-151°C '

Elementary analysis for ^iq^ iq^^2

Reference example 5

A mixture of 5.0 g of (2-ethyl-2H-tetrazol~5-yl)-acetic acid, •4j9g of phosphorus pentachloride and 20 ml of benzene was stirred at 70-75°C for one and a half hours. The solvent and the by-product phosphorus oxychloride were distilled off under reduced pressure. By the above-mentioned method, 5.5 g of (2-ethyl~2H-tetrazol-5-yl)acetyl chloride was obtained as an oily product.

Infrared absorption spectrum (liquid film) : 1795 cm Nuclear magnetic resonance spectrum (CDCl^) ppm: 1.6l (3H,t-J=7Hz)

4.45 (2H,s)

4.66 (2H,q,J<=>7Hz)

Reference example 6

A mixture of 18.4 g of (2-t-butyl-2H-tetrazol-5-yl)-acetic acid and 150 ml of benzene was stirred and after adding 21.8 g of phosphorus pentachloride in small amounts, the mixture was stirred at 70-75 °C for an hour and a half. The solvent and the by-product phosphorus oxychloride were distilled off under reduced pressure. By the above procedure, 20.0 g of 3-(2-t-butyl-2H-tetrazol~5-yl)-acetyl chloride was obtained as an oil.

Infrared absorb ion spectrum (liquid film): 1800 crn""^ Nuclear magnetic resonance spectrum (CDCl^) ppm: 1.73(9H,s).

4.48(2H,s)

Example 1

A 2.1 g portion of an oil, the preparation of which is described in reference example 5>, was added to a mixture of 1.4 g p-ethylanisole and 20 ml 1,2-dichloroethane, after which 2.8 g anhydrous aluminum chloride was added. The mixture was refluxed for 2 hours. The mixture was then poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, a dilute solution of sodium hydroxide and water, and then dried over anhydrous magnesium sulfate. The ethyl acetate was distilled off, and the oily residue was purified by silica gel chromatography (elution with benzene). By the aforementioned method, 1.2 g of 2-(2-ethyl-2H-tetrazol-5-yl)-5'-ethyl-2'-methoxy-

acetophenone as an oily product.

A mixture of 0.7 g of the above oil and 7 ml of 47% hydrobromic acid was refluxed for one hour, after which water was added. The resulting oily precipitate was . extracted with benzene and the benzene layer was washed with dilute aqueous solution of ammonia and water, then dried over anhydrous magnesium sulfate. BenzeneBn was distilled off and n-hexane added to the solid residue. By filtration, 400 mg of crystals were obtained. Recrystallization from a mixture of benzene and n-hexane gave 2-(2-ethyl-2H-tetrazol-5-yl)-5'-ethyl-2'-hydroxyacetophenone as colorless flakes.

Temp. 68-69°C.

Elementary analysis for ^X3%6^4^2

Example 2

A mixture of 6.1 g of p-ethylphenol, 80 ml of 1,2-dichloroethane and 10 g of anhydrous aluminum chloride was stirred at room temperature, and a mixture of 10.1 g of the acid chloride. whose preparation is described in reference example 6 and 40 nil dichloroethane are added dropwise, added over the course of 20 minutes. The mixture was then refluxed for 3 hours. 300 ml of water was then added and the dichloroethane layer was separated and the water layer extracted with ethyl acetate. The solvent layer was combined and washed with a 5% solution of sodium hydroxide and then with water. The solvents were distilled off and 11.5 g of a brown oil was obtained. To remove the by-product p-(2-t-butyl-2H-tetrazol-5-yl)acetoxyethylbenzene, the above oil and 40 ml of a 10% alcoholic potassium hydroxide solution were refluxed for 1 hour. The solvent was distilled off and water was added, after which the oily precipitate was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The ethyl acetate was distilled off, and the oily residue was purified by silica gel chromatography (elution with benzene-ethyl acetate). The crystalline product was recrystallized from a mixture of n-hexane and ethyl acetate. By the above-mentioned method, 2-(2-t-butyl-2H-tetrazol-5-yl)-5'-ethyl-2'-hydroxyl-acetophenone was obtained as f heirless flakes, m.p. rJ^ >- rj6°G. Elementary analysis for ^ i^ ZQ^^ Pz

By a method similar to the methods described in Examples 1 and 2, the following compounds were synthesized: 2-(1-ethyl-1H-tetrazol-5-yl)-5'-ethyl-2'-hydroxyacetophenone, m.p. 107-109°C Elemental analysis for ^ i^ l6^'/\ P2 2-(1-H-tetrazol-5-yl)~5'-ethyl-2'-hydroxyacetophenone, m.p. 172-173°C Elemental analysis for 2^ 4^ 2 2-(2-b,enzyl-2H-tetrazol-5-yl)-5T-ethyl-2T-hydroxy acetophenone, m.p. §2-83°C Elementary analysis for C]_8^i8^4^2

2-(1-benzyl-1H-tetrazol-5-yl)-5'-ethyl-2'-hydroxy-• acetophenone, m.p. 97>5~98.5°c .

Elementary analysis for G]_8<%>8<N>4°2

2-(2-n-butyl-2H-tetrazol-5-yl)~5'-ethyl-2'-hydroxyacetophenone Infrared absorption ion spectrum (liquid film) : 1643 cm Nuclear magnetic resonance spectrum (CDCl^) ppm: 4.51 11.58 (1H,singlet,OH) 2-(2-t-butyl-2H-tetrazol-5-yl)-4'-methoxy-2'-hydroxyacetophenone, . m.p. 72-73°^ 2-(2-t-butyl-2H-tetrazol-5-yl)-5!-chloro-2'-hydroxy-acetof enone, m.p. 133-135°C 1-hydroxy-2-[2,-('2-t-butyl-2H-tetrazol-5-yl)acetyl-7-naphthalene, m.p. 129-130°C.

Example 3

A mixture of 1.99 g of (2-t-butyl-2H-tetrazol-5-yl)-acetic acid, 2.3 g of phosphorus pentachloride and 4 ml of dichloroethane was stirred at 50-60°C for two and a half hours, and after cooling, 3.0 g of p-ethylanisole was added. A mixture of 2.9 g of anhydrous stannous chloride and 3 ml of dichloroethane was then added dropwise to the mixture. The whole was then stirred at 80-85°G for two hours, after which 10 ml of water and 2 ml of concentrated hydrochloric acid were added under ice-cooling.

The resulting dichloroethane layer was separated and the aqueous layer extracted with fresh new chloroethane. The dichloroethane plants were combined and washed with a dilute hydrochloric acid and water, and then with a dilute aqueous ammonia and water. The dichloroethane was distilled off and 4jl5.g of an oil was obtained. The dilute aqueous ammonia layer was acidified with hydrochloric acid. The resulting crystalline precipitate was extracted with ethyl acetate to give 0.44 g of crystals. Recrystallization from ethyl acetate gave 2-(1H-tetrazol-5-yl)-5'-ethyl-2'-methoxyacetophenone as colorless needles, m.p. 159"160°C.

Elemental analysis for C-^H-^OgN

4>15 g of the above oil was purified by chromatography on silica gel (elution with a mixture of n-hexane and ethyl acetate). By the above procedure, 0.2 g of 2-(2-t-butyl-2H-tetrazol-5~yl)-5T<->ethyl-2'-hydroxy-acetopheone and 1.45 g of 2-(2- t-butyl-2H-tetrazol~5-yl)-5'-ethyl-2'-methoxyacetofenone. The former compound was consistent with an authentic sample by thin layer chromatography. The latter compound crystallized on standing. Recrystallization from a mixture of n-hexane and ethyl acetate gave colorless prisms, m.p.' 44--4-6°C.

Elemental analysis for C]_5H22°2N4

Example 4.

A mixture of 4.0 g of 2-(2-t-butyl-2H-tetrazol~5-yl)-5'-ethyl-2'-methoxyacetophenone, 30 ml of 99% acetic acid and 10 ml

50% sulfuric acid was refluxed for 16 hours and after cooling, 100 ml of water was added. The resulting crystalline precipitate was extracted with ethyl acetate. The ethyl acetate layer was shaken with a dilute aqueous ammonia, and the aqueous ammonia layer was then taken out and acidified with hydrochloric acid, and the crystalline precipitate was extracted with ethyl acetate. The ethyl acetate layer was washed with water and distilled off, after which 2.8 g of crystals were obtained. Recrystallization from ethyl acetate gave 2-(1H-tetrazol-5~yl)-5f-ethyl-2'-methoxyacetophenone as colorless needles,

m.p. 159-160°C.

Example 5

A mixture of 1.5 g of 2-(1H-tetrazol-5-yl)-5,_ethyl-2'-methoxyacetophenone and 8 ml of 48% hydrobromic acid was stirred at 120-130°C for three hours, and after cooling added man 100 ml of water. The resulting crystalline precipitate was extracted

with ethyl acetate. The ethyl acetate layer was washed with water and the ethyl acetate was distilled off, whereby 1.42 g of crystals were obtained which were recrystallized from ethyl acetate. By this method 2-(1H-tetrazol-5-yl)~5'-ethyl-2T<->hydroxyacetophenone was obtained as colorless needles, m.p. 172-173°C

Example 6

A mixture of 0.59 g of 2-(2-t-butyl-2H-tetrazol-5~yl)-5T<->ethyl-2'-methoxyacetophenone, 1 ml of 99% acetic acid and 5 ml of 47% hydrobromic acid was stirred at 110-120°C for 6 hours, and after cooling water was added. The resulting crystalline precipitate was extracted with ethyl acetate. The ethyl acetate layer was shaken with aqueous dilute ammonia. The dilute aqueous ammonia layer was taken out, acidified with hydrochloric acid and extracted with ethyl acetate. The ethyl acetate was washed with water and distilled off to give

0.31 g of crystals. By infrared absorption spectrum, these crystals proved to be 2-(1H-tetrazol-5-yl)~5'-ethyl-2'-hydroxyacetophenone.

Example 7

A mixture of 107 g of £-(1H-tetrazol-5-yl)chromone and 20 ml of 1N sodium hydroxide was heated to 100°C with stirring for one hour. The mixture was then acidified with 1N hydrochloric acid, and the resulting precipitate was recovered by filtration and then recrystallized from ethanol. This method gave 690 mg of 2-(1H-tetrazol-5-yl)-2'-hydroxyacetophenone as colorless needles, m.p. 200-201°G.

Infrared absorption ion spectrum (KBr) : 1655 (C0)cm~^ Nuclear magnetic resonance spectrum (dg-DMS0)£:

approx. 11.37 (1H, wide) 7.95 (1H,dd,J=8&2H2)

approx. 7.57 (lH,m) approx. 7.00(2H,m) 4.93(2H,s)

Elemental analysis for GgHgN^Og

In the same manner as mentioned above, the following compounds were prepared:

Example 8

A mixture of 232 mg of 2-(1H-tetrazol-5-yl)-5-ethyl-2'-hydroxyacetophenone, 0.2 ml of t-butanol, 1 ml of trifluoroacetic acid and 2 drops of sulfuric acid was stirred at room temperature for one hour and . then concentrated under reduced pressure. To the residue was added water together with ethyl acetate, and the ethyl acetate layer was separated, washed with a saturated aqueous solution of sodium hydrogen carbonate and then with 1N hydrochloric acid and finally dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. By the above procedure, 300 mg of 2-(2-t-butyl-2H-tetrazol-5-yl)-5'-ethyl-2'-hydroxyacetophenone was obtained as an oily residue.

Nuclear magnetic resonance spectrum (CDC1^)£ : 4j62(2H,s,CH2). l,-73(9H,s5CH3x3)

In the same manner as mentioned above, the following compounds were prepared:

Example 9

600 mg of sodium metal was dissolved in 19 ml of ethanol

and after cooling, 14 ml of ethyl formate were added. Then became

.1.27 g of 2-(2-ethyl-2H-tetrazol-5-yl)-5'-ethyl-2'-hydroxyacetophenone added and the mixture refluxed for six and a half hours. The solvent was distilled off, and after adding water, the residue was acidified with hydrochloric acid. The oily precipitate was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and dried over anhydrous magnesium sulfate. The ethyl acetate was distilled off and. the residue was crystallized by adding n-hexane and ethyl acetate. By filtration, 1.16 g of crystals were obtained. Recrystallization from ethylaceti-n-hexane gave 6-ethyl--3-(2-ethyl-'2H-tetrazol-5~yl)chromone as f heirless needles, mp 98-100°C. Elemental analysis for Ct/H-, .N«Op

Example 10

In 12 ml of ethanol, 4-00 mg of sodium metal was dissolved, and after cooling, 9 ml of ethyl formate was added. Then 900 mg of 2-(2-t-butyl-2H-tetrazol-5-yl)-5,-ethyl-2'-hydroxyacetophenone was added and the mixture was refluxed for six hours. The solvent was distilled off and the residue diluted with ethyl acetate and water. The mixture was acidified with hydrochloric acid, and the ethyl acetate layer was separated, washed with water and dried over anhydrous magnesium sulfate. The ethyl acetate was then distilled off and the resulting oily residue was purified by chromatography on silica gel (elution with benzene-ethyl acetate). By the above procedure, 0.85 g of 6-ethyl-3-(2-t-butyl-2H-tetrazol-5-yl)chromone was obtained. This compound crystallized on standing, and the melting point was 54--5<6>°C.

Elemental analysis for C^gH-^gN^Og

In the same manner as above, the following compounds were synthesized: 6-ethyl-3-(2-benfcyl-2H-tetrazol-5-yl)chromone

m.p. 95-96°C

Elemental analysis for C-^cjH-^gN^Og

6-Ethyl-3~(2-n-butyl-2H-tetrazol-5-yl)-chromone

m.p. 96-97°C

Elemental analysis for G-^gH^gN^Og

Example 11

A 2 ml dimethylformamide solution of 10 mg of 1-hydroxy-2-[2'-(2-t-butyl-2H-tetrazol-5-yl)acetyl-7-naphthalene was, under ice-cooling, dropwise added over the course of five minutes to 0.4 ml phosphoryl trichloride. The mixture was then stirred under ice-cooling for half an hour and then at room temperature for five hours. The reaction mixture was poured into ice water, and the precipitate was recovered by filtration and washed with water. Recrystallization from ethanol gave 100 mg of 3~(2-t-butyl-2H-tetrazol-5-yl)-benzo(h)-chromone as pale yellow needles, m.p. I76-I78 C.

Example 12.

To a 5 ml benzene solution of 310 mg of 1-hydroxy-2-(2'-(2-t-butyl-2H-tetrazol-5-yl)acetyl/naphthalene) was added 0.6 ml of triethylamine. Then 1 ml (approx. 5 mmol) was added

at 5-7°C' of an ether solution of a mixed formic and acetic anhydride during 10 minutes. The mixture was stirred at room temperature for 1 hour and, while cooling, 0.3 ml (dropwise) of triethylamine and 0.5 ml (approx. 5 mmol) of the aforementioned ether solution of the mixed formic acid-acetic anhydride were added, after which the mixture was stirred at room temperature for one hour. The reaction mixture was poured into ice water, adjusted to pH 2 with 10% HCl and extracted with benzene. The benzene layer was washed with water and dried over sodium sulfate. After distilling off the solvent, the residue was crystallized from ethanol. - By the above-mentioned method, 270 mg of 3-(2-t-butyl-2H-tetrazol-5-yl)-benzo(h)-chromone were obtained as colorless needles, m.p. 176-177°C.

Example 13

A mixture of 370 mg of 6-ethyl~3-(2-t-butyl-2H-tetrazoan-5-yl)chromone, 2 ml of acetic acid and 4 g of 60% sulfuric acid was refluxed for two and a half hours.

Water was added to the reaction mixture and the resulting crystals were recovered by filtration and recrystallized from ethanol. By the above procedure, 6-ethyl-3~ was obtained

(1H-tetrazol-5-yl)chromone as colorless needles, m.p. 219-221°C. An infrared absorption spectrum could confirm that this product was in accordance with an authentic sample.

Example 14.

A mixture of 540 mg of 6-ethyl-3~(2-ethyl-2H-tetrazol-5-yl)chromone, 5»4 ml of 57% hydroiodic acid and 1 ml of acetic acid. was refluxed for 27 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was shaken with dilute aqueous ammonia and the aqueous layer was taken out, acidified with hydrochloric acid and extracted with ethyl acetate. The ethyl acetate was distilled off and the crystalline residue was recrystallized from ethanol. Using the above-mentioned method, 6-ethyl-3_(1H-tetrazol-5-yl)chromone was produced as colorless needles,

m.p. 219-221°C.

Example 15

A mixture of 200 mg of 6-ethyl-3-(2-benzyl-2H-tetrazol-5-yl)chromone and 2 ml of 47% hydrobromic acid was refluxed for half an hour. Water was added to the reaction mixture, and the resulting precipitate was recovered by filtration and recrystallized from dimethylformamide and water. Using the above procedure, 6-ethyl-3-(1H-tetrazol-5-yl)chromone was obtained as colorless needles, m.p. •219-221°C..

Example 16

Impure crystals of (2-ethyl-2H-tetrazol-5-yl)acetic acid (containing about 25% (1-ethyl-1H-tetrazol-5-yl)acetic acid) were reacted in the same manner as indicated in Reference Example 5°g Example 1, whereby a mixture of 2-(2-ethyl-2H-tetrazol-5-yl)-5'-ethyl-2'-hydroxyacetophenone and 2-(1-ethyl-1H-tetrazol-5-yl) was obtained -5f<->ethyl-2'-hydroxyacetophenone. The above-mentioned mixture was directly treated as described in Example 9°g 14» whereby 6-ethyl-3-(1H-tetrazol-5-yl)chromone was obtained.

Example 17

1.4 g of sodium metal were dissolved in 30 ml of ethanol, and then 1.5 g of 2-(1H-tetrazol-5-yl)-5'-ethyl-2'-hydroxyacetophenone and 20 g of ethyl formate were added. The mixture was refluxed for 2 hours, after which the ethanol was distilled off. The residue was then added to 120 ml of 1N hydrochloric acid, and the crystalline precipitate was recovered by filtration and recrystallized from ethanol. By the above procedure, 6-ethyl~3-(1H-tetrazol-5-yl)-chromone was obtained as colorless needles, m.p. '219-221°C.

Elementary analysis for ^ i2^ 10^/\^ 2

Example 1§

35 mg of sodium metal was dissolved in 2 ml of ethanol,

and then added 116 mg of 2-(1H-tetrazol-5-yl)-γ,5'-dimethyl-2'-hydroxyacetophenone and 0.5 ml of ethyl formate. The mixture was refluxed and stirred for 2 hours. To the reaction mixture was then added a solution of 35 mg of sodium metal in 2 ml of ethanol, together with 0.5 ml of ethyl formate and the whole mixture was refluxed for one and a half hours. The solvent was distilled off and the residue acidified with dilute hydrochloric acid. The slightly soluble fraction was recovered by filtration and recrystallized from dimethylformamide. By the above-mentioned method, 62 mg of 6,8-dimethyl-3-(1H-tetrazol-5-yl)chromone were obtained as colorless crystals, m.p. 273-274°C (decomposition)..

Example 19

A mixture of 3.5 g of 2-(1H-tetrazole)-5'-ethyl-2'-hydroxyacetophenone, 35 ml of 95% formic acid and 3.5 ml of concentrated sulfuric acid was stirred at 120°C for 13 hours, and after after cooling, 100 ml of water was added and crystals were precipitated. These were recovered by filtration and recrystallized from ethanol. 3.15 g of 6-ethyl-3-(1H-tetrazol-5-yl)chromone were obtained in this way as colorless needles, m.p. 219-221°C.

Example 20

. A mixture of 1.19 g of 2-(2-t-butyl-2H-tetrazol-5-yl)-5'-ethyl-2'-methoxyacetophenone, 6 ml of 85% formic acid and 6 ml of 47% hydrobromic acid was stirred at 110 -120°C for 7 hours, and after cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was shaken with dilute aqueous ammonia, this layer was separated and concentrated to 0.16 g of an oily residue. This was purified by chromatography on silica gel (elution with a mixture of n-hexane and ethyl acetate). By the above procedure, 6-ethyl-3~(2-t-butyl-2H-tetrazol-5-yl)chromone was obtained. An infrared absorption spectrum showed that this product was in accordance with an authentic sample.

The above dilute ammonia solution was acidified with hydrochloric acid and the resulting crystals were extracted with ethyl acetate to give 0.87 g of a crystalline residue. Recrystallization from ethanol gave 6-ethyl~3-(1H-tetrazol-5~yl)chromone as needles, m.p. 219-221°C.

It was confirmed by thin-layer chromatography that the mother liquor contained 6-ethyl-3~(1H-tetrazol-5-yl)-5T<->ethyl-2'-hydroxyacetophenone.

Example 21

A mixture of 0.83 g of 2-(1H-tetrazol-5-yl)-5T<->ethyl-2'-methoxyacetophenone, 455ml of 85% formic acid and 4j5ml of 47% hydrobromic acid was stirred at 110-120°C in 7 hours, and after cooling, the reaction mixture was diluted with water and extracted with ethyl acetate, after which 0.8 g of crystals were obtained. Based on thin layer chromatography, it could be confirmed that these crystals were a mixture of '6-ethyl-3~(lH- tetrazol-5-yl)chromone and 2-(1H-tetrazol-5-yl)-5'-ethyl-2'-hydroxyacetophenone. This mixture was then stirred together with 9 ml of 95% formic acid and 0.7 ml of conc. sulfuric acid at 110-120°G for 9 hours, and after cooling, water was added. The resulting crystalline precipitate was recovered by filtration. The precipitate was recrystallized from ethanol. By the above procedure, 0.46 g of 6-ethyl-3~( 1H-tetrazol-5-yl)chromone as needles, mp 219-221°C.

Claims (48)

1. Process for the production of chromone derivatives with the following formula: where m is 0, 1 or 2, and R is halogen, nitro, or an amino group which may be unsubstituted or substituted with alkyl, aryl, aralkyl ..or acyl group, alkyl, alkoxy, acyloxy, hydroxy, -COOR 'where R' is hydrogen,' alkyl or aralkyl, carboxamide which may be unsubstituted or substituted with at least one alkyl or aralkyl group, or the butadienylene (-CH=CH-CH=CH-) which forms a benzene ring with any of the two adjacent carbon atoms in positions 5 > 6, 7 and 8," or pharmaceutically acceptable salts of these compounds, characterized by reacting a compound with the following formula: where m and R are as defined above; R p is hydrogen, alkyl, aralkyl or aryl, with formic acid or a derivative thereof, and optionally the chromone derivative thus produced undergoes a reaction to remove the protective group R . 2. Method according to claim 1, characterized in that the formic acid derivative is a formic acid ester. 3- Method according to claim 1, characterized in that the formic acid derivative is a formic acid amide derivative. 4- Method according to claim 1, characterized in that the formic acid derivative is a mixed anhydride of formic acid and - another organic acid. 5- Method according to claim 2, characterized in that the formic acid ester is ethyl formate. 6. Process according to claim 3> characterized in that the formic acid amide derivative is dimethylformamide. 7. Method according to claim 4, characterized in that the mixed anhydride of formic acid and another organic acid is a mixed anhydride of formic acid and acetic acid. 8. Chemical compound, characterized by the following general formula: where are you. 0, 1 or 2, R is a halogen atom, a nitro or an amino group which may be unsubstituted or substituted by alkyl, aryl, aralkyl or an acyl group, alkyl, alkoxy, acyloxy, hydroxy, -C00R < T> where R' is hydrogen, alkyl or aralkyl", carboxamide which may be unsubstituted or substituted with at least one alkyl or aralkyl group, or the butadienylene (^ CH=CH-CH=CH-) which forms a benzene ring with any of the two adjacent carbon atoms in positions 5, 6, 7 and 8, R^" is hydrogen, alkyl or aralkyl, or R per hydrogen, alkyl, aralkyl or aryl, or their salts which can be obtained when R 1 and R ? is hydrogen. 9. Compound according to claim 8, characterized in that m is 0. 10. Compound according to claim 8, characterized in that m is 1. 11. Compound according to claim 8, characterized in that m is 2. 12. Compound according to claim 8, characterized in that R is a halogen atom. 13. Compound according to claim 8, characterized in that R is alkyl. 14. Compound according to claim 8, characterized in that R is amino. 15. Compound according to claim 8, characterized in that R is amino substituted with alkyl. 16. Compound according to claim 8, characterized in that R is amino substituted with acyl. 17. Compound according to claim 8, characterized in that R is alkoxy. 18.. Compound according to claim 8, characterized in that R is the butadienyl which forms a benzene ring with the adjacent carbon atoms in positions 5 > 6 > 7 and 8. 19. Compound according to claim 8, characterized in that R is -C00R', where R' is hydrogen. 20. Compound according to claim 8, characterized in that R is -C00R', where R' is alkyl. 21. Compound according to claim 8, characterized in that R is carboxamide. 22. Compound according to claim 8, characterized in that R is carboxamide substituted with alkyl. 23. Compound according to claim 8, characterized in that R"*" is hydrogen. 24- Connection according to claim 8, . characterized in that R"1" is alkyl. 25. Compound according to claim 8, characterized 2 in that R is hydrogen. 26. Compound according to claim 8, characterized 0 in that R is alkyl. 27. Compound according to claim 8, characterized by being 2-(1H-tetrazol-5-yl)-2'-hydroxyacetophenone. 28. Compound according to claim 8, characterized by being 2-(1H-tetrazol-5-yl)-5'-ethyl-2T <-> hydroxyacetophenone. 29. Compound according to claim 8, characterized by being 2-(1H-tetrazol-5-yl)~3T>5T-dimethyl-2'-hydroxy-acetophenone. 30. Compound according to claim 8, characterized by being 1-hydroxy-2-[2'-(1H-tetrazol-5-yl)acetyl/naphthalene. 31. Compound according to claim 8, characterized by being 2-(1H-tetrazol-5-yl)-5'-nitro-2'-hydroxyacetophenone. 32. Compound according to claim 8, characterized by being 2-(.1H-tetrazol-5-yl)-5'-n-propyl-2'-hydroxyacetophenone. 33* Compound according to claim 8, characterized by being 2-(1H-tetrazol-5-yl)-4'-methoxy-2'-hydroxyacetophenone. 34* Compound according to claim 8, characterized by being 2-(1H-tetrazol-5-yl)-5'-chloro-2'-hydroxyacetophenone. 35- Compound according to claim 8, characterized by being 2-(2-ethyl-2H-tetrazol-5-yl).-5'-ethyl-2'-hydroxy acetophenone. 36. Compound according to claim 8, characterized by being 2-(2-t-butyl-2H-tetrazol-5-yl)-5'-ethyl-2'-hydroxy-. acetophenone. 37« Compound according to claim 8, characterized by being 2-(1-ethyl-1H-tetrazol-5-yl)-5'-ethyl-2T <-> hydroxy-acetof enone. 38. Compound according to claim 8, characterized by being 2-(2-benzyl-2H-tetrazol-5-yl)-5'-ethyl-2'-hydroxyacetophenone. 39- Compound according to claim 8, characterized by being 2-(1-benzyl-1H-tatrazol-5-yl)-5'-ethyl-2T <-> hydroxy-acet <o> f enone. 40. Compound according to claim 8, characterized by being 2-(2-n-butyl-2H-tetrazol-5-yl)-5'-ethyl-2T <-> hydroxyacetophenone. 41. Compound according to claim 8, characterized by being 2-(2-t-butyl-2H-tetrazol-5-yl)-4'-methoxy-2α-hydroxyacetophenone. 42. Compound according to claim 8, characterized by being 2-(2-t-butyl-2H-tetrazol-5-yl)-5'-chloro-2'-hydroxy-. cyacetophenone. 43* Compound according to claim 8, characterized by being 1-hydroxy-2-[2'-(2-t-butyl-2H-tetrazol-5-yl)acetyl/-naphthalene. 44» Compound according to claim 8, characterized by being 2-(2-t-butyl-2H-tetrazol-5-yl)~3',5<T-> dimethyl-2'-hydroxyacetophenone. 45. Compound according to claim 8, characterized by being 2-(1H-tetrazol-5-yl)-5'-ethyl-2'-methoxyacetophenone. 46. Compound according to claim 8, characterized by being 2-(2-ethyl-2H-tetrazol-5-yl)-5'-ethyl-2'-methoxy-acetophenone. 47- Compound according to claim 8, characterized by being 2-(2-t-butyl-2H-tetrazol-5-yl)-5'-ethyl-2'-methoxy-acetophenone. 48. Process for the preparation of a 2-(1H-tetrazol-^-yl)-acetof enone derivative with the following formula: where m is 0, 1 or 2, R is a halogen atom, a nitro group or an amino group which may be unsubstituted or substituted with alkyl, aryl, aralkyl or acyl group; alkyl, alkoxy, acyloxy, hydroxy, -C00R' where -RT is hydrogen, alkyl or aralkyl, carboxamide which may be unsubstituted or substituted with at least one alkyl or aralkyl group, or butadienylene (-CH=CH-CH=CH-) , which can form a benzene ring with any of the two adjacent carbon atoms in positions 5 > 6, 7° and 8, R"*" is hydrogen, alkyl or aralkyl, or R <2> is hydrogen, alkyl, aralkyl or aryl , or their salts which can be prepared when R"*" and R 2 are hydrogen, characterized by reacting a compound with the following formula: where m, R and R''" are as defined above, provided that the substituent!e) R is substituted in one or more positions other than the 2-position, with a compound of the following general formula: where R 1 is alkyl, aralkyl or aryl, and X is hydroxy or halogen.