NO793504L - PROCEDURE FOR THE PREPARATION OF 5,6,7,8-TETRAHYDRO-4 (3H) -KINAZOLINON DERIVATIVES - Google Patents

Description

Procedure for the preparation of 5,6,7,8-tetrahydro-4(3H)-quinazolinone derivatives

The present invention relates to a method for the production of new therapeutically active 5,6,7,8-tetrahydro-4(3H)-quinazolinone derivatives.

The process compounds according to the present invention have the general formula:

where

R is hydrogen or alkyl with 1-5 carbon atoms,

R 2 is alkyl with 1-5 carbon atoms, aryl or aryl substituted with alkyl with 1-5 carbon atoms, and/or halogen,

and salts thereof.

The term "alkyl" is used to denote straight chain or branched alkyl groups with 1 to 5, preferably 1 to 4, carbon atoms.

The term aryl is used here to denote phenyl or naphthyl, preferably phenyl.

The term halogen includes chlorine, bromine, fluorine and iodine, chlorine and bromine being the preferred halogens.

The salts of the compounds of formula (I) can be formed with inorganic or organic acids, such as hydrochloric acid, hydrogen bromide, sulfuric acid, maleic acid, tartaric acid and fumaric acid.

The present invention relates to a method for the preparation of the compounds of formula (I) and salts thereof, which are characterized in that

a) .an amine with the formula:

where R 2 is as indicated above, or a salt thereof, is reacted with cyclohexenecarboxylic acid derivatives of the formula: or benzoxazinone derivatives of the formula:

where

R"*" is as above indicated, and

R 3 is hydrogen or alkyl with 1-5 carbon atoms, or

b) an alkyl-2-oxo-cyclohexane carboxylate of the formula:

where

R 5 is alkyl with 1-5 carbon atoms, is reacted with an amidine derivative with the formula:

12

wherein R and R are as above, or with a salt thereof, and, if desired, the compounds of formula (I) are converted into their inorganic or organic salts.

The compounds of formula (I) are not particularly described in the literature, but some of them are covered by the general formula stated in Belgian patent 620 379.

According to a method stated in Belgian patent 620 379, 3-amino-crotonic acid derivatives are reacted with carboxylic acids or with iminoether derivatives thereof, and 2,3,6-trisubstituted-4-pyrimidone derivatives are obtained.

Analogously, by reacting l-carboxy-2-amino-cyclohexene derivatives with iminoether derivatives of carboxylic acids, compounds of formula (I) are obtained.

The known 5,6,7,8-tetrahydro-4(3H)-quinazolinone derivatives are prepared by reacting carbethoxycyclohexanone with amidine, with a yield of 38 to 54% [J. Am. Chem. Soc. 80, 6609 (1958)]. New quinazoline derivatives according to the present invention can also be prepared by following this method, as described in variant b) of the claimed method.

According to a preferred embodiment of method variant a), the compounds of formula (I) are prepared by reacting 2-acylamino-cyclohexenecarboxylic acids or carboxylic acid derivatives of formula (III) with amines of formula (II). The main advantage of this method lies in the fact that it can be carried out with a high (approx. 80%) yield, and the substituents in the 2- and 3-positions can be chosen as desired.

The compounds of formula (III) are also new and can be prepared by acylating 2-amino-cyclohexene-carboxylic acid esters

[Liebig's Ann. 317, 100 (190.1);. Am. Chem. Soc. 78, 2873 (1956)]

and subjecting the obtained acylamino-cyclohexene-carboxylic acid esters to selective hydrolysis, as shown by the equation:

According to a more preferred embodiment of method variant a), the compounds of formula (III) are reacted with compounds of formula (II) in the presence of an acidic dehydrating agent, such as thionyl chloride, and the reaction is preferably completed by heating.

The reaction can be carried out in a solvent or in the absence of a solvent, by mixing the reactants. Water-immiscible solvents such as benzene, toluene, xylene, petrol or chloroform are preferably used as solvents, but the reaction can also be carried out in water-miscible solvents such as acetic acid or alcohol.

In yet another preferred embodiment of method variant a), compounds of the formula (III) are reacted with amines of the formula (II) in the presence of organic or mineral acids, or salts of the amines are used in this reaction. The reaction may be carried out in the absence of solvent or in any of the above solvents.

In another embodiment of method variant a), 5,6,7,8-tetrahydro-4H-3,1-benzoxazin-4-one derivatives of the formula (IV) are reacted with amines of the formula (II) or with their salts. The reaction can optionally be carried out in the presence of a condensing agent in a suitable solvent, or without a solvent by melting the reactants. The 5,6,7,8-tetrahydro-4H-3,1-benzoxazin-4-one derivatives used as starting materials are new and can e.g. are prepared from 2-acylamino-cyclohexene-carboxylic acids with dehydrating agents, such as phosphorus oxychloride, acetic anhydride, dicyclohexy1-carbodiimide.

In variant b) of the method according to the invention, alkyl-2-oxo-cyclohexane carboxylates of the formula (V) are reacted with amidines of the formula (VI). The reaction can be carried out in a solvent such as alcohol, benzene, toluene, tetrahydrofuran, dioxane, or without a solvent by mixing the reactants. The reaction can be brought to completion by heating. Amidines of formula (VI) can be used in the form of bases or salts. If the salts of the amidines are used, bases may also be present to eliminate the acids that have been used in making the salts. Preferred bases are alkali alcoholates.

The reaction mixture obtained by following any of the process variants according to the invention is made alkaline with alkali or alkaline earth hydroxides or carbonates, and the solvent is eliminated by distillation or the mixture is subjected to steam distillation. Steam distillation is particularly advantageous if water-insoluble unreacted amines are to be removed. When the steam distillation is finished, the products, if obtained in a non-crystalline form, are separated by extraction with a solvent and subsequent evaporation.

The products can optionally be purified by crystallization.

The compounds of formula (I) can be converted to their inorganic or organic salts by methods known per se. Certain acids which can be used or form salts are mentioned above as examples.

The compounds of formula (I) have useful therapeutic properties and exhibit spasmolytic action.

The method compounds can be processed into pharmaceutical preparations which comprise as active ingredient a compound of formula (I) or a pharmacologically acceptable, non-toxic salt thereof, in admixture with suitable solid or liquid carriers or diluents. The preparations can be prepared in solid form, such as e.g. tablets, suppositories, powder mixtures, or in liquid form as solutions or suspensions.

As carriers, conventional carriers can be used.

The preparations may possibly contain common additives such as lubricants and fillers.

The administration can take place orally, parenterally or enterally.

The spasmolytic effect of the compounds of formula (I) is not accompanied by a sedative or narcotic effect. 2-methyl-3-o-tolyl-5, 6, 7, 8-tetrahydro-4 (3H)-quinazolinone inhibits e.g.

in a dose of 100 mg/kg, convulsions induced by Tetracor without exerting a narcotic effect. On the other hand, e.g. phenyl-ethyl-barbituric acid ("Sevenal") and diphenyl-hydantoin ("biphedan") which are well-known commercial spasmolytic preparations, a strong narcotic effect in the same dose.

Another application of the compounds of formula (I) is that they can be transferred to 4(4H)-quinazolinone derivatives by dehydrogenation, and among those. the latter compounds are several known therapeutically active compounds (eg 2-methyl-3-o-tolyl-4(3H)-quinazolinone which is marketed as "Mathaqualone" for narcotic purposes). . Further details of the present invention will be found in the examples without limiting the scope of the invention to the examples.

Example 1

9.3 g of 2-acetamido-cyclohexene-carboxylic acid are suspended in

90 ml of toluene, and after adding 12.5 ml of aniline, 3.43 g of phosphorus trichloride in 20 ml of toluene is added dropwise to the mixture while stirring. The reaction mixture is refluxed for a further 3 hours with stirring. After cooling, 100 ml of 20% aqueous sodium carbonate solution is added, and the mixture is subjected to steam distillation. Steam distillation is continued until oil droplets are observed in the distillate. An alkaline, aqueous solution of a crystallizable resinous product is obtained as a distillation residue. After cooling, the product is filtered, washed neutrally with water and treated with petrol to remove resin residues. It is then dried to constant weight, whereby 9.71 g of a crude product is obtained which melts at 138 - 142°C.

Crystallization from a 1:1 (by volume) mixture of benzene and gasoline gives 2-methyl-3-phenyl-5,6,7,8-tetrahydro-4(3H)-quinazolinone which melts at 154 - 155°C.

Example 2

9.3 g of 2-acetamido-cyclohexenecarboxylic acid are dissolved in 25 ml of acetic acid, and 5.5 ml of p-toluidine and 1 ml of phosphorus trichloride are added to the resulting solution. The reaction mixture is refluxed with stirring for 3 hours. Acetic acid is distilled off in a vacuum, and the residue is made alkaline with a 20% aqueous sodium carbonate solution. The separated resin is extracted with benzene, the benzene solution is dried over sodium sulphate and evaporated. You get 8.42 g of a residue. Recrystallization from a 1:1 mixture of benzene and gasoline and decolorization with aluminum oxide gives 2-methyl-3-o-.tolyl-4 (3H)-quinazolinone which melts at 150 - 153°C.

Example 3

By following the procedure in example 2, but starting from 8 g of 2-acetamido-cyclohexenecarboxylic acid, 5.1 ml of p-amino-ethylbenzene, .21.5 ml of acetic acid and 0.86 ml of phosphorus trichloride, 9.9 g are obtained 2-methyl-3-p-ethylphenyl-5,6,7,8-tetrahydro-4(3H)-quinazolinone which melts at 128 - 131°C (after recrystallization from petrol).

Example 4

By following the procedure in example 1, but by reacting 9.3 g of 2-acetamido-cyclohexenecarboxylic acid and 16 g of o-chloroaniline in 90 ml of toluene with a mixture of 2.18 g of phosphorus trichloride with 20 ml of toluene, 10.86 g are obtained 2-methyl-3-o-chlorophenyl-5,6,7,8-tetrahydro-4(3H)-quinazolinone melting at 123 - 128°C. After recrystallization from a 1:1 mixture of benzene and petrol, the melting point is 130 - 132°C.

Example 5

By following the procedure in example 1, but by reacting 18.3 g of 2-acetamido-cyclohexenecarboxylic acid and. 35.4 g of 5-chloro-2-methylaniline in 180 ml of toluene with a mixture of 4.36 ml of phosphorus oxychloride with 40 ml of toluene, 22.42 g of 2-methyl-3-(2-methyl-5-chlorophenyl)- 5,6,7,8-tetrahydro-4(3H)-quinazolinone melting at 126 - 128°C (after recrystallization from a 1:1 mixture of benzene and gasoline).

Example 6

By following the procedure in Example 1, but by reacting 18.3 g of 2-acetamido-cyclohexenecarboxylic acid and 35.4 g of 4-chloro-2-methylaniline in 180 ml of toluene with a mixture of 4.36 ml of phosphorus trichloride and 40 ml of toluene , 16.48 g of 2-methyl-3-(4-chloro-2-methylphenyl)-5,6,7,8-tetrahydro-4(3H)-quinazolinone are obtained which melts at 151 - 153°C (after recrystallization from a 1:1 mixture of benzene and gasoline).

Example 7

To a mixture of 2-acetamido-cyclohexene-carboxylic acid and 3.65 g of isobutylamine in 90 ml of toluene, a mixture of 2.18 ml of phosphorus trichloride and 20 ml of toluene is added dropwise while stirring. The reaction mixture is refluxed for a further 3 hours with stirring and then subjected to steam distillation. The separated oil is then extracted with 3 x 50 ml of benzene, the benzene solution obtained is dried over potassium carbonate and evaporated.

Residue: 6.8 g of a resinous product.

The resinous product is dissolved in 40 ml of acetone, and the solution is acidified with a 40% aqueous hydrogen bromide solution. Ether is added to the mixture until pale. The precipitated crystals are filtered off, washed with ether and dried to constant weight. 4.5 g of 2-methyl-3-isobutyl-5,6,7,8-tetrahydro-4(3H)-quinazolinone is obtained which melts at 218 - 221°C.

Example 8

4.98 g of 2-methyl-5,6,7,8-tetrahydro-benzoxazin-4-one (prepared from 2-acetamido-cyclohexenecarboxylic acid by boiling with acetic anhydride and purification by distillation in vacuum) and 3.3 ml o -toluidine is boiled at 150 - 160°C for 5 hours. After crystallization from a 1:1 mixture of benzene and gasoline, 4.1 g of 2-methyl-3-o-tolyl-5,6,7,8-tetrahydro is obtained -4(3H)-quinazolinone, which has the same physical and chemical properties as the product from example 2. Melting point: 150 - 153°C.

Example 9

A solution of 17 g of ethyl-2-oxo-cyclohexanecarboxylate and 13.4 g of N-phenylacetamidine in 75 ml of absolute alcohol is allowed to stand for 15 hours. It is then evaporated, and the residue is crystallized from a mixture of benzene and petrol. 17.1 g of 2-methyl-3-phenyl-5,6,7,8-tetrahydro-4(3H)-quinazolinone are obtained, which melts at

138 - 142°C.

The physical and chemical properties of the above product are identical to those of the product from example 1.

The method according to the invention produces: 2-methyl-3-phenyl-5,6,7,8-tetrahydro-4(3H)-quinazolinone and salts thereof,

2-methyl-3-o-tolyl-5,6,7,8-tetrahydro-4(3H)-quinazolinone and salts thereof,

2-methyl-3-p-ethylphenyl-5,6,7,8-tetrahydro-4(3H)-quinazolinone and salts thereof,■

2-methyl-3-o-chlorophenyl-5,6,7,8-tetrahydro-4(3H)-quinazolinone and salts thereof,

2-methyl-3-(2-methyl-5-chlorophenyl)-5,6,7,8-tetrahydro-4(3H)-quina-. zolinone and salts thereof,

2-methyl-3-(4-chloro-2-methylphenyl)-5,6,7,8-tetrahydro-4(3H)-quinazolinone and salts thereof,.

2-methyl-3-(isobutyl)-5,6,7,8-tetrahydro-4(3H)-quinazolinone and salts thereof,

2-ethyl-3-o-tolyl-5,6,7,8-tetrahydro-4(3H)-quinazolinone and salts thereof,

2-ethyl-3-p-ethylphenyl-5,6,7,8-tetrahydro-4(3H)-quinazolinone.and salts thereof, and

2-propyl-3-o-chlorophenyl-5, 6,7,8-trihydro-4 (3H)-quinazolinone and salts thereof.

Claims (4)

1. Procedure for the preparation of 5,6,7,8-tetrahydro-4(3H)-quinazolinone derivatives with the general formula: where R is hydrogen or alkyl with 1-5 carbon atoms, R 2 is alkyl with 1-5 carbon atoms, aryl which is optionally substituted with alkyl with 1-5 carbon atoms and/or halogen, and salts thereof, characterized by ata) an amine with the formula: where R 2 is as stated above, or a salt thereof, is reacted with a cyclohexenecarboxylic acid derivative with the formula: or a benzoxazinone derivative of the formula: where R^" is as stated above, and R <3> is hydrogen or alkyl with 1-5 carbon atoms, or b) an alkyl-2-oxo-cyclohexanecarboxylate of the formula: where R is alkyl with 1-5 carbon atoms, reacts with an amidine derivative with the formula: where R 1 and R <2> are as indicated above, or with a salt thereof, and optionally a compound of formula (I) obtained is transferred to its salt with an inorganic or organic acid. 2. Procedure according to claim 1, characterized in that in process variant a) amines of formula (II), where R 2 is as indicated above, or a salt thereof, are reacted with carboxylic acid derivatives of formula (III) in the presence of an acidic dehydrating agent and toluene or acetic acid. 3. Method according to claim 1, characterized by the fact that in method variant a) 2 react an amine with the formula (II), where R is as stated above, or a salt thereof, with a benzoxazinone derivative of formula (IV), where R" <*> " is as stated above, in a melt.. 4. Method according to claim 1, characterized in that in method variant b) the reaction is carried out in an alcoholic solution.