DD146950A1 - PROCESS FOR PREPARING 5,6,7,8-TETRAHYDRO-4 (3H) -CHINAZOLINE DERIVATIVES - Google Patents

Abstract

Process for the preparation of novel 5,6,7,8-tetrahydro-4 (3H) -quinazolinone derivatives of the general formula (I) in which R & exp1! Hydrogen or a C & ind1-5! Alkyl group and R & exp2! a C & ind1-5! Alkyl group, an unsubstituted or by C & ind1-5! Alkyl groups and / or halogen atoms substituted aryl group, by reacting amines of the formula R & exp2! -NH & ind2! with 2-Atylamino-cyclohexene-carboxylic acids or derivatives thereof or 5,6,7,8-tetrahydro-4H-3,1-benzoxazin-4-one derivatives. Another variant of the process is the reaction of 2-oxo-cyclohexanecarboxylic acid alkyl esters with amidines of the formula & formula! The new 5,6,7,8-tetrahydro-4 (3H) -quinazolinone derivatives have a spasmolytic effect.

Description

Process for the preparation of 5,6,7,8-tetrahydro-4 (.3H)

quinazolinone derivatives

Field of use. _{r ί} the invention: _r

The invention relates to a process for the preparation of novel 5,6,7,8-tetrahydro-4- (3K) -quinazolinone derivatives of general formula (I), wherein

R is hydrogen or an alkyl group having 1 to 5 carbon atoms and 2 R is an alkyl group having 1 to 5 carbon atoms, a

Aryl group or an aryl group substituted by alkyl groups having 1 to 5 carbon atoms and / or halogen atoms means «

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Characteristic of the known technical solutions:

The compounds of the general formula (I) which can be prepared according to the invention are not described in the previous literature. Although some of the compounds fall into the domain of definition in the BE-PS Ur. However, in this patent no compounds defined by the above general formula (I) are mentioned in concrete form or described in any way. , '

According to the cited BE-PS, β-amino-crotonic acid derivatives are reacted with garboxylic acids or with imino-ether derivatives thereof to give 2,3,6-trisubstituted 4-pyrimidone derivatives.

This process can also be used for the preparation of the compounds of the general formula (I) according to the invention, analogously reacting 1-carboxy-2-aminocyclohexene derivatives with imino-ether derivatives of carboxylic acids.

After J. Am. Chem. Soc. 80, 6609 (1958) become known 5,6,7,8-tetrahydro-4 (3H) -quinazolinone derivatives not covered by the above general formula (I) by reacting ethoxycarbonyl-cyclohexanone with amidines in yields of 38 to 54 %. manufactured. This process can also be used for the preparation of the novel quinazolinone derivatives of the above general formula (I), as indicated in process claim b).

Object of the invention:

The invention is intended to provide improved pharmaceutically active compounds.

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Pari egiin ^^. De s ^ _We seng, the, invention; _t

The object of the invention is to specify a process for preparing spasmolytically active compounds of the general formula (I).

The new compounds of general formula (I) and their salts are prepared according to the invention by

a) Amines of the general formula (II) in which R has the above meaning, or their salts with cyclohexenecarboxylic acid

derivatives of the general formula (III) in which R has the meaning and R represents hydrogen or an alkyl group having 1 to 5 carbon atoms, or with benzoxazinone derivatives of the general formula (IV) in which R has the above meaning, or

b) alkyl S-oxo-cyclohexane-carboxylates of the general formula V, wherein R is an alkyl group having 1 to 5 carbon atoms, with amidine derivatives of the general formula

1 ρ

(VI) in which R and R have the above meanings, or salts thereof, and, if desired, converting the resulting compounds of general formula (I) into the corresponding salts by reaction with inorganic or organic acids.

For the preparation of orally, rectally or parenterally administrable, spasmolytic drug preparations containing the inventively prepared novel compounds of the above-defined general formula (I) or salts thereof, can be prepared by methods known per se in the pharmaceutical industry.

According to a particularly advantageous embodiment of variant a) of the process according to the invention, the compounds of the general formula (I) are obtained by reacting S-acylamino-cyclohexene-carboxylic acids or derivatives thereof of the general formula (III) with amines of the general formula

2165

Formula (II) prepared. This procedure entails the significant advantages over the processes described in the publications cited above, that on the one hand obtain the desired products in high, about 80 % yields and on the other hand, the substituents on the carbon atom in the 2-position and on the nitrogen atom in the 3-position of the product to be produced can be chosen arbitrarily.

The starting compounds of general formula (III) are also novel products obtained by acylating 2-amino-cyclohexene-carboxylic acid esters (see Liebig's Ann. 317 (1901); Am. Chem. Soc., 8, 2873 (1956). ) and subsequent selective hydrolysis of the obtained 2-acylamino-cyclohexene-carboxylic acid esters; This method of preparation is illustrated by Reaction Scheme A.

The advantageous variant of the process according to the invention described above can be carried out in practice by reacting the compounds of the general formula (III) in the presence of acidic water binders, e.g. of thionyl chloride, phosphorus (III) chloride or a carboxylic acid chloride with the amines of the general formula (II), and the reaction is conveniently completed by heating the reaction mixture.

This reaction can be carried out in a suitable solvent or simply by mixing the reactants without the use of solvents. As the solvent, there are advantageously used water-immiscible organic solvents, e.g. Benzene, toluene, xylene, benzine, chloroform, etc., but this reaction can also be used in water-miscible solvents, e.g. in acetic acid or alcohol.

The same process variant can also be carried out so that the compound of the general formula

(III) in the presence of an organic or mineral acid reacts with the amine of general formula (II) or the amine is used in the form of a salt. Also in this case, the reaction can be carried out in one of said solvents or even without a solvent.

In another embodiment of process variant a), 5,6,7,8-tetrahydro-4H-3,1-benzoxaziri-4-one derivatives of the general formula (IV) with amines of the general formula (II) or with salts thereof implemented. This reaction can be carried out in the presence of a condensing agent or even without condensing agent, or in a solvent or in the melt of the reactants, without solvent.

The 5,6,7,8-tetrahydro-4H-3si-benzoxazin-4-one derivatives of the general formula to be used as starting compounds

(IV) are also new products, e.g. from 2-acylaminocyclohexene-carboxylic acids with the aid of Y / extractants, e.g. of phosphorus oxychloride, acetic anhydride or dicyclohexylcarbodiimide.

According to variant b) of the process according to the invention, 2-oxo-cyclohexanecarboxylic acid alkyl esters of the general formula (V) are reacted with amidines of the general formula (VI). The reaction can be carried out in the presence of solvents, for example of alcohol, benzene, toluene, tetrahydrofuran or dioxane, or else without solvent, by simply mixing the reactants. The reaction can be completed by heating the reaction mixture. The amidines of general formula (VI) are used as free bases or in the form of a salt, in the latter case any base can be used to bind the acid free in the reaction. Alkali alcoholates are particularly well suited for this purpose. ,

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The working up of the reaction mixtures obtained by the various variants of the process according to the invention can be carried out by making the reaction mixture alkaline with alkali or alkaline earth metal hydroxides or alkali metal carbonates and removing the solvent by distillation or subjecting the reaction mixture to steam distillation. The steam distillation is very suitable for removing the water-immiscible unreacted amines. After distillation, the product, if it is not a crystalline substance, can be isolated by extraction with a solvent and subsequent evaporation of the solvent. , ,

The product obtained in the above manner may be further purified by recrystallization if necessary. If desired, the products obtained as bases can be converted into their salts. For salt formation, organic acids such as maleic acid, fumaric acid, tartaric acid or inorganic acids, e.g. Hydrochloric acid, hydrobromic acid or sulfuric acid can be used.

The compounds of the general formula (I) according to the invention can be used in therapy in the form of customary pharmaceutical preparations suitable for oral, rectal or parenteral administration. Such pharmaceutical preparations can be prepared by known pharmaceutical methods, using carrier materials, fillers, lubricants and other customary excipients, expediently in the form of tablets, suppositories, powder mixtures, aqueous solutions or suspensions.

The 5> 6> 7,8-tetrahydro-4 (3H) -quinazolinones according to the invention have a very advantageous spasmolytic effect, without these being accompanied by sedative or narcotic effects. Thus, e.g. the 2-methyl-3-o-tolyl-5,6,7,8-tetrahydro

4 (3H) -ohinazolinon-l _{1 Iethyl-3-o-tolyl-5Y6>} 7,8-tetrahydro-4 (3H) -quinazolinone in doses of 100 mg / kg induced by pentamethylenetetrazole cramps, without causing a narcotic effect occurs. The Phenyläthylbarbitürsäure and the Diphenylhydantoin 'in such doses already significant narcotic effects.

Another important use of the compounds of the invention is their further processing to other therapeutically active products. Thus, these tetrahydro-4 (3H) quinazolinone derivatives can be converted by dehydration into the corresponding 4 (3H) -quinazolinone derivatives, among which are numerous valuable drugs. As an example of such drugs, mention may be made of the well-known hypnotic 2-methyl-3-o-tolyl-4 (3H) -quinazolinone (methaqualone).

The preparation of the new compounds of the invention is further illustrated by the following examples, but the invention is in no way limited to the content of these examples.

9.3 g of 2-acetamidocyclohexenecarboxylic acid are suspended in 90 ml of toluene, 12.5 ml of aniline are added and the solution of 3.43 g of phosphorus trichloride in 20 ml of toluene is added dropwise to this mixture while stirring. The mixture is then refluxed with stirring for three hours, then cooled and treated with 100 ml of 20% sodium carbonate solution. Subsequently, the mixture is subjected to a steam distillation, which is continued until the oil drops appear in the distillate with the water. As distillation residue remains in the alkaline

21 65

aqueous solution of a crystallizable heart-like product. After cooling, the product obtained is separated by filtration, washed with water until neutral reaction, then with petrol until complete removal of the resin residues and dried to constant weight. There are obtained in this way 9.71 g of 2-methyl-3-phenyl-5,6,7,8-tetrahydro-4 (3H) -quinazolinone; F. 138 to 142 ⁰ C. After recrystallization from a 1: 1 (vol./vol.) Mixture of benzene and gasoline will melt the product at 154-155 C. Analysis:

Calculated: C 75.0 % H 6.67 % H 11.7 % Found: C 74.8 % H 6.60 % N 11.7 %.

Example 2

To 9.3 g of 2-acetamido-cyclohexencarboxylic acid, dissolved in 25 ml of acetic acid, 5.5 ml of o-toluidine and 1 ml of phosphorus trichloride are added. The mixture is refluxed with stirring for 3 hours, then the acetic acid is distilled off in vacuo and the residue made alkaline with 20% sodium carbonate solution. The precipitating resinous product is extracted with benzene, the benzene solution dried over anhydrous sodium sulfate and evaporated. The residue obtained was 8, 42 g of 2-methyl-3-o-tolyl-5,6,7,8-tetrahydro-4 (3H) -quinazolinone. This crude product is dissolved hot in a 1: 4 mixture of benzene and gasoline, the solution clarified with aluminum oxide and cooled. The purified product obtained in this way melts at 150 to 153 ^° C. Analysis:

calculated: C 75.7 % H 7.09 % N 11.0 % found: C 75.87% H 7,14 % N 10,7 %.

Example 3

From 8 g of 2-acetamidocyclohexenecarboxylic acid and 5.1 ml of p-aminoethyl-benzene in 21.5 ml of acetic acid, with

0.86 ml of phosphorus trichloride, according to the method described in Example 2, 9.9 g of 2 ~ methyl ~ 3-p-ethylphenyl-5,6,7,8-tetrahydro ~ 4 (3H) -quinazolinone. The recrystallized from gasoline product melts at 128-131 ⁰ C. _Analysis:;

Calculated: C 76.30 % H 7.46 % Έ 10.42 % Found: C 76.44 % H 7.70 % M "10.64 %.

From 9> 3 g of 2-acetamido-cyclohexencarboxylic acid and 16 g of o-chloroaniline are dissolved in 90 ml of toluene, with a mixture of 2.18 ml of phosphorus trichloride and 20 ml of toluene, according to the method described in Example 1, 2.86 g of 2 ~ methyl 3-o-chloro-phenyl-5,6,7,8-tetrahydro-4 (3H) -quinazolinone; P ₀ : 123 to 128 ⁰ G. The product recrystallized from a 1: 1 mixture of benzene and gasoline melts at 130 to 132 ^° C. Analysis:

Calculated: C 65.70 % H 5.46 % N 9.82 % Cl 12.95 % Found: C 65.71 % H 5.20 # UIO, 10 % Cl 12.77 %.

From 18.3 g of 2-Acetainido-cyclohexencarbonsäure and 35.4 g of 5-chloro-2-methyl ~ aniline are in 180 ml of toluene, with a mixture of 4.36 ml of phosphorus trichloride and 40 ml of toluene, after that described in Example 1 Method 22.42 g of 2-methyl-3- (2-methyl-5-chlorophenyl) -5,6,7,8-tetrahydro-4- (3H) -quinazolinone. The recrystallized from the 1: 1 mixture of Ben zol and gasoline product melts at 126 to 128 ⁰ C.

 Analysis:

Calculated: C 67.00 % H 5.96 % Ή 9.76 % Cl 12.4 % Found: C 67.20 % H 6.45% U 9.97 % Cl 12.4%.

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Example 6

From 18.3 g of 2-acetamido-cyclohexencarboxylic acid and 35.4 g of 4-chloro-2-methyl-aniline v / earth in 180 ml of toluene, with a mixture of 4.36 ml Phosphortrichlorid and 40 ml of toluene, after the Example 16.48 g of 2-methyl-3- (4-chloro-2-methylphenyl) -5,6,7,8-tetrahydro-4- (3H) -quinazolinone obtained in Example 1. The recrystallized from the 1: 1 mixture of benzene and benzene product melts at 151 to 153 ⁰ C _c

Analysis:

Calculated: C 67.00 % H 5.96 % N 9.76 % Cl 12.4 %

found: C 66.53 % H 6.03 % Έ 9.99 % Cl 11.99%.

Example 7

A mixture of 9.3 g of ^ -Acetamido-cyclohexencarbonsäure and 3.65 g of isobutylamine is added dropwise in 90 ml of toluene with stirring, the solution of 2.18 ml of phosphorus trichloride in 20 ml of toluene. The mixture is then refluxed with further stirring for 3 hours and then subjected to steam distillation. The oil which separates out of the steam distillate is extracted three times with 50 ml of benzene each time, and the resulting benzene solution is dried over anhydrous potassium carbonate and evaporated. The residue obtained is 5.8 g of a resinous product which is dissolved in 40 ml of acetone, whereupon the solution is acidified with 40% aqueous hydrobromic acid solution. This mixture is mixed with ether until cloudy, whereupon the product precipitates in crystalline form. The resulting crystals are filtered off, washed with ether and dried to constant weight. There are obtained in this way 4.5 g of 2-methyl-3-isobutyl-5,6,7,8-tetrahydro-4 (3H) -quinazolinone; P. 218 to 221 ⁰ C.

Example 8

A mixture of 2-methyl-5,6,7,8-tetrahydro-benzoxazin-4-one (prepared from 2-acetamido-cyclohexenecarboxylic acid by boiling with acetic anhydride and subsequent purification by vacuum distillation) and 3.3 ml of o-toluidine becomes 5 Heated at 150 to 16O ⁰ C hours. The crude product obtained as a reaction mixture is recrystallized from a 1: 1 mixture of benzene and benzene; there are obtained in this way 4.1 g of 2 ^ methyl-3-o-tolyl-5,6,7,8-tetrahydro-4 (3H) -quinazolinone; F. 150 to 153 ^° C. The other physical and chemical properties of the product are identical to those of the compound obtained according to the example.

example ^

A solution of 17 g of 2-0xo ~ cyclohexancarbonsäureäthylester and 13.4 g of H-phenyl-acetamidine in 75 ml of abs ₀ ethanol is allowed to stand for 15 hours, then evaporated and the residue from a mixture of benzene and gasoline unicrystallized. There are obtained in this way 17.1 g of 2-Hethy1-3-phenyl-5,6,7,8-tetrahydro ~ 4 (3H) -quinazolinone; F. 138 to 142 ^° C.

The physical and chemical properties of this product are identical to those of the compound obtained in Example 1.

4 · Method according to item 1, variant b), characterized in that one carries out the reaction in alcoholic solution.

HziLJLSeiten Formulas

Ss.

H ₂ NR ²

JZ

2ΖΓ

R ¹ -C-NH-R ²

NH

12.ΜΛΪ19Bö * Sii £> IO

~ 'f K

-ς

to o

Ö Q

Claims (3)

-12-. 2165 86 Inventor's pruch: · 1. A process for the preparation of 5,6,7,8 ~ tetrahydro-4 (3H) -quinazolinone derivatives of the general formula (I) wherein R V / erstoff or an alkyl group having 1 to 5 hydrocarbon atoms and R is an alkyl group having 1 "to 5 carbon atoms, an aryl group, in particular a phenyl group or an aryl group substituted by alkyl groups having 1 to 5 carbon atoms and / or halogen atoms, preferably phenyl group and salts of these compounds, characterized in that a) amines of general formula (II), wherein R is the above Meaning, or their salts with cyclohexenecarboxylic acid derivatives of the general formula (IJI), wherein 1 3 R has the above meaning and R ^ V acid or an alkyl group having 1 to 5 carbon atoms, or with Benzoxazinonderivaten the general formula (IV), wherein R has the above meaning, or b) Alkyl 2-oxo-cyclohexanecarboxylic acid esters of the general formula (V), wherein R ^{3 represents} an alkyl group having 1 to 5 carbon atoms, with amidine derivatives 1 2 of the general formula (IV) in which R and R have the above meanings or their salts, and, if desired, the resulting compounds of the general formula (I) are converted by reaction with inorganic or organic acids into the corresponding salts. 2. Method according to item 1, variant a), characterized in that the amines of the general formula (II), wherein R has the meaning given in point 1, or their salts in the presence of acidic water binders and of toluene or acetic acid with carboxylic acid derivatives of general formula (III), wherein R and R ^ have the meanings given in point 1, have reacted.   , - 13 - 3. Method according to item 1, variant a), characterized in that the / mine of the general formula (II), wherein R has the meaning given in point 1, in the melt with the Benzoxazinonderivaten of the general formula (IV),
has, implements. •1 Formula (IV), wherein H is the meaning given in point 1