GB2035316A

GB2035316A - 5,6,7,8-Tetrahydro-4(3H)- quinazolinone derivatives useful as spasmolytics

Info

Publication number: GB2035316A
Application number: GB7937857A
Authority: GB
Original assignee: Chinoin Gyogyszer es Vegyeszeti Termekek Gyara Zrt
Current assignee: Chinoin Private Co Ltd
Priority date: 1978-11-01
Filing date: 1979-11-01
Publication date: 1980-06-18
Also published as: HU179687B; PL219363A1; FR2440361A1; DD146950A1; BE879763A; ES485333A1; DK460379A; SE7908991L; NO793504L; FI793403A; DE2943568A1; NL7907915A

Abstract

Compounds of the formula (I> <IMAGE> (wherein R<1> represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms; and R<2> represents an alkyl group having 1 to 5 carbon atoms, or an aryl group optionally substituted by at least one atom or group selected from halogen atoms and alkyl groups having 1 to 5 carbon atoms) and salts thereof have been found to possess spasmolytic activity without accompanying sedative and narcotic side- effects. Processes for the preparation of the compounds of formula I and the salts thereof are described and exemplified and pharmaceutical compositions containing the compounds of formula I or a physiologically compatible salt thereof are disclosed.

Description

SPECIFICATION 5,6,7,8-Tetrahydro-4(3H)-quinazolinone derivatives, processes for their preparation, pharmaceutical compositions containing them and their use as spasmolytics The present invention relates to 5,6,7,8-tetrahydro-4(3H)-quinazolinone derivatives, processes for their preparation, pharmaceutical compositions containing them and their use as spasmolytics.

The present invention is based on the discovery that the compounds of formula I as hereinafter defined possess spasmolytic activity without undesired accompanying sedative or narcotic effects.

According to one feature of the present invention,there is thus provided a compound of the formula (I)

(wherein R' represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms; and R2 represents an alkyl group having 1 to 5 carbon atoms, or an aryl group optionally substituted by at least one atom or group selected from halogen atoms and alkyl groups having 1 to 5 carbon atoms) and salts thereof The term "alkyl", as used throughout the specification, refers preferably to straight or branched chain alkyl groups having 1 to 5, especially 1 to 4, carbon atoms.

The term "aryl", as used throughout the specification, preferably refers to phenyl or naphthyl groups, especially the phenyl group.

The term "halogen", relates to chlorine, bromine, fluorine and iodine atoms; chlorine and bromine being the preferred halogen atoms.

Preferred compounds of formula I by virtue of their especially favourable spasmolytic activity thus include such components wherein R2 represents a C1 5 alkyl group or a naphthyl group selected from halogen atoms and alkyl groups having 1 to 5 carbon atoms and especially compounds of formula I wherein R2 represents a phenyl group optionally substituted by at least one atom or group selected from halogen atoms and alkyl groups having 1 to 5 carbon atoms and/or halogen.

Especially preferred compounds of formula I by virtue of their particularly favourable spasmolytic activity include the following compounds 2-methyl-3-phenyl-5,6,7,8-tetrahydro-4(3H)-quinazolinone and salts thereof, 2-methyl-3-o-tolyl-5,6,7,8-tetrahydro4(3H)-quinazolinone and sa Its 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-tetrahydrn-4(3H)-quinazolinone and salts thereof, 2-methyl-3-(2-methyl-5-ch lorophenyl )-5,6,7,8-tetrahydro-4(3H)-quinazolinone and salts thereof, 2-Methyl-3-(4-chloro-2-methylphenyl )-5,6,7,8-tetrahydro-4(3H)-quinazoline and salts thereof, 2-methyl-3-(isobul)-5,6,7,8-tetrahydro-4(3H)-quinaolinone and salts thereof, 2ethyl-3-o-tolyl-5,6,7,S-tetrahydro-4(3H)-quinazol inone and salts thereof, 2-ethyl-3-p-ethyl phenyl-5,6,7,8-tetrahydro-4(3H )-qu inazolinone and salts thereof, 2-prnpyl-3-o-chlornphenyl-5,6,7,84etrahydrn-4-(3H)-quinazolinone and salts thereof.

The salts of the compounds of formula (I) may be formed with inorganic or organic acids, such as for example hydrochloric acid, hydrobromic acid, sulphuric acid, maleic acid, tartaric acid and fumaric acid.

The salts of the compounds offormula I suitable for incorporation in pharmaceutical compositions are the physiologically compatible salts thereof, but other salts may be of use in the preparation of compounds of formula I and the physiologically compatible salts thereof.

Certain 5,6,7,8-tetrahydro-4(3H)-quinazolinone derivatives falling within the scope of the compounds of the present invention are disclosed in a general way in Belgian Patent Specification No. 620,379. The derivatives disclosed in the aforementioned specification are stated to possess sedative and analgesic activity as well as anticonvulsive activity. The presence of sedative activity in a spasmolytic is clearly a disadvantage and the present invention is based on the discovery that the compounds of formula I and the physiologically compatible salts thereof do not possess such sedative activity whilst possessing good spasmolytic activity. Thus, for example, 2-methyl-3-o-tolyl-5,6,7,8-tetrahydro-4(3H)-quinazolinone inhibits spasms induced by Tetracor without exerting a narcotic effect in a dose of 100 mg/kg.On the other hand, phenyl-ethyl-barbituric acid (Sevenal) and diphenyl-hidantoin (Diphedan), for example, which are wellknown commercial spasmolyic preparates, have a strong narcotic effect when administered in the same dose.

The compounds of formula (I) and the salts thereof are also of interest as intermediates in the preparation of 4(4H)-quinazolinone derivatives by dehydrogenation. Among these derivatives are known therapeutically active compounds (e.g. 2-methyl-3-o-tolyl-4(3H)-quinazolinone which is marketed as "Mathaqualone" for narcotic purposes).

The compounds of the present invention may for example be prepared by any convenient method, but the following processes, which constitute further features of the present invention, have been found to be of interest: a) reacting an amine of the formula (II) H2N - R2 (II) (wherein R2 is as hereinbefore defined), or a salt thereof with a cyclohexenecarboxylic acid derivative of the formula (III)

(wherein R1 is as hereinbefore defined and R3 represents a leaving atom or group) and where a compound of formula I is obtained, if desired, converting the said compound of formula I into a salt thereof.

A compound of formula Ill is preferably used in which R3 represents a hydroxy group or an alkoxy group e.g. with 1 to 5, especially 1 to 4, carbon atoms.

b) reacting an amine of formula II as hereinbefore defined or a salt thereof with a benzoxazinone derivative of the formula (IV)

(wherein R1 is as defined in claim 1 ) and where a compound of formula I is obtained, if desired, converting the said compound of formula I into a salt thereof; and c) reacting a 2-oxo-cyclohexane-carboxylate of the formula (V)

(wherein R5 represents a leaving atom or group) with anamidine derivative of the formula (VI)

(wherein R1 and R2 are as hereinbefore defined, or a salt thereof, and where a compound of formula I is obtained if desired converting the said compound of formula (I) into a salt thereof.

A compound of formula V is preferably used in which R5 represents an alkoxy group e.g. with 1 to 5, especially 1 to 4, carbon atoms.

According to a process disclosed in the Belgian Patent Specification No. 620,379 ss-amino-crotonic acid derivatives are reacted with carboxylic acids or with iminoether derivatives thereof, to form 2,3,6-trisu bstituted-4-pyrimidone derivatives.

Compounds of formula I may for example be obtained in a similar manner by reaction of 1-carboxy2amino-cyclohexene derivatives with iminoether derivatives of carboxylic acids.

Known 5,6,7,8-tetrahydro-4(3H)-quinazolinone derivatives are prepared by reacting carbethoxy-cyclohexanone with amidine, giving a yield of 38 to 54% [J. Am. Chem. Soc. 80,6609(1958)]. The quinazoline derivatives of the present invention may also be prepared by a similar method, as described in process (c).

According to a preferred embodiment of process a), compounds of formula (I) are preferably prepared by reacting 2-acylamino-cyclohexene-carboxylic acids or carboxylic acid derivatives of formula (III) with amines of the formula (II). The main advantage of this process is that it results in a high (about 80%) yield, and the substituents in the 2- and 3-positions can be specifically selected.

The compounds of formula (III) are also new, and may be prepared by acylating 2-amino-cyclohexene carboxylic acid esters [Liebig's Ann. 317, 100(1901); Am. Chem. Soc. 78,2873 (1956)] and subjecting the acylamino-cyclohexene-carboxylic acid esters obtained to selective hydrolysis, as shown below:

According to an especially preferred embodiment of process a), 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 at an elevated temperature.

The reaction of process a) is conveniently effected in the presence of a solvent or, in the absence of a solvent by mixing the reactants. As a solvent water-immiscible solvents, such as benzene, toluene, xylene, petrol, chloroform are preferably employed, but the reaction can also be effected in water-miscible solvents such as acetic acid and alcohol.

According to another preferred embodiment of process a) compounds of formula (III) are reacted with amines of formula (II) in the presence of an organic or mineral acid, or salts of the amines may be used in the reaction. The reaction can be performed in the absence of any solvent or in the presence of any one of the solvents listed above.

According to process b) 5,6,7,8-tetrahydro-4H-3,1-benzoxazin-4-one derivatives of formula (IV) are reacted with amines of formula (II) or with the salts thereof. The reaction may, for example, be effected in the presence of a condensing agent conveniently in the presence of an appropriate solvent or in the absence of a solvent preferably in a melt of the reactants. 5,6,7,8-tetrahydro-4H-3,1-benzoxazin-4-one derivatives derivatives used as starting compounds, are new and may for example be prepared by dehydrating a 2-acylaminocyclohexenecarboxylic acid using a dehydrating agent, such as phosphorus oxychloride, acetic anhydride, dicyclo-hexyl carbodiimide.

According to process c) a 2-oxo-cyclohexane-carboxylate of formula (V) is reacted with an amidine of formula (VI). The reaction may for example be effected in the presence of a solvent, such as an alcohol, benzene, toluene, tetrahydrofuran, dioxan, or in the absence of a solvent merely by mixing the reactants. The reaction can be completed by heating. Amidines of formula (Vi) may for example be used in the form of a base or in salt form. If the amidine is used in salt form, bases can also be present to eliminate the acids which have been used to prepare salts. Preferred bases include, for example, alkali metal alcoholates.

The reaction mixture obtained according to any of the processes of the invention may, for example, be made alkaline using an alkali metal or alkaline earth metal hydroxide or carbonate and the solvent may be eliminated by distillation or the mixture subjected to stream distillation. Steam distillation is especially advantageous if water-immiscible unreacted amines are to be eliminated. When steam distillation is complete, the products if obtained in non-crystalline form may for example be separated by solvent extraction and subsequent evaporation.

The products if desired, may be purified by crystallisation.

The compounds of formula (I) may, for example, be converted into their inorganic or organic salts by methods known per se. Certai n acids wh ich may be em ployed or form salts a re listed a bove by way of example.

According to a further aspect of the present invention, there are provided pharmaceutical compositions comprising as active ingredient at least one compound of formula (I) or a physiologically compatible salt thereof in association with a pharmaceutical carrier or excipient. Inert solid or liquid carriers or excipients may be used. The compositions may be formulated as solid (e.g. tablets, suppositories, powder mixtures) or liquid (e.g. solutions, suspensions) compositions.

As carriers the conventional carriers can be used.

The compositions may optionally contain conventional additives, such as lubricating, filling agents.

Administration may, for example, be effected orally, parenterally or enterally.

According to a still further feature of the present invention there is provided a compound of formula las hereinbefore defined (wherein R2 represents a C1 5 alkyl group or a naphthyl group optionally substituted by at least one atom or group selected from halogen atoms or Con 5 alkyl groups) when used as a spasmolytic.

As stated above the compounds of formulae Ill and IV are novel and these compounds constitute a further feature of the present invention.

The following Examples illustrate the present invention.

Example I 9.3 g of 2-acetamido-cyclohexane-carboxylic acid are suspended in 90 ml of toluene, and following the addition of 12.5 ml of aniline, 3.43 g of phosphorus trichloride in 20 ml of toluene are added to the mixture obtained dropwise, with stirring. The reaction mixture is refluxed for additional 3 hours with stirring. After cooling 100 ml of a 20 % aqueous sodium carbonate solution are added and the mixture is subjected to steam distillation. Steam distillation is continued until oil drops are observed in the distillate. As a distillation residue an alkaline aqueous solution of a crystallizable resinous product is obtained. After cooling the product is filtered off, washed to neutral with water and is treated with petrol to eliminate the traces of resin.

It is then dried until constant weight to give 9.71 g of a crude product which melts at 138 to 142 "C.

Crystallization from a 1:1 (v/v) mixture of benzene and petrol 2-methyl-3-phenyl-5,6,7,8-tetrahydro-4(3H)- quinazolinone is obtained, melting at 154to 155 "C.

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

Example 2 9.3 g of 2-acetamido-cyclohexenecarboxylic acid are dissolved in 25 ml of acetic acid and to the solution obtained 5.5 ml of o-toluidine and 1 ml of phosphorus trichloride are added. The reaction mixture is refluxed with stirring for 3 hours. Acetic acid is distilled coffin vacuo and the residue is alkalized with a 20 % aqueous sodium carbonate solution. The separated resin is extracted with benzene, the benzene solution is dried over sodium sulphate and is evaporated. 8.42 g of a residue are obtained. Recrystallization from a 1:1 mixture of benzene and petrol and decolouring with alumina yields 2-methyl-3-o-tolyl-4(3H)-quinazolinone, melting at 150to 153 C.

Analysis: Calculated: C 75.7 % H 7.09 % N 11 % Found: C 75.87 % H 7.14 % N 10.7 %.

Example 3 Following the procedure of Example 2, but starting from 8 g of 2-acetamido-cyclohexenecarboxylic acid, 5.1 ml ofp-amino-ethylbenzene, 21.5 ml of acetic acid and 0.86 ml of phosphorus trichloride 9.9 g of 2-methyl-3-p-ethyphenyl-5,6,7,8-tetrahydro-4(3H)-quinazolinone are obtained, melting at 128 to 131 C (after recrystallization from petrol).

Analysis: Calculated: C76.3% H7.46% N 10,42% Found: C 76.44 % H 7.70 % N 10.64 %.

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

Analysis: Calculated: C 65.7 % H 5.46 % N 9.82 % Cl 12.95 % Found: C 65.71% H 5.20% N 10.10% Cl 12.77%.

Example 5 Following the procedure of Example 1, but reacting 18.3 g of 2-acetamido-cyclohexenecarboxylic acid and 35.4g of 5-chloro-2-methyl-aniline in 180 ml ml oftoluenewith 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 are obtained, melting at 126 to 128 C (after recrystallization from a 1:1 mixture of benzene and petrol).

Analysis: Calculated: C 67.0 % H 5.96 % N 9.76 % Cl 12.4 % Found: C 67.20 % H 6.45 % N 9.97 % CI 12.4 % Example 6 Following the procedure of Example 1, but reacting 18.3 g. of 2-acetamido-cyclohexene-carboxylic acid and 35.4 g of 4-chloro-2-methylaniline in 180 ml of toluene with a mixture of 4.36 ml of phosphorus tri-chloride and 40 ml of toluene, 16.48 g of 2-methyl-3-(4-chloro-2-methyl-phenyl)-5,6,7,8-tetrahydro-4(3H)- quinazolinone are obtained, melting at 151 to 153 C (after recrystallization from a 1:1 mixture benzene and petrol).

Analysis: Calculated: C 67.0 % H 5.96 % N 9.76 % CI 12.4 % Found: C 66.53 % H 6.03 % N 9.99 % Cl 11.99% Example 7 To a mixture of 2-acetamido-cyclohexenecarboxylic acid and 3.65 g of isobutylamine in 90 ml of toluene a mixture of 2.18 ml of phosphorus trichloride and 20 ml oftoluene is added dropwise, with stirring. The reaction mixture is refluxed for further 3 hours with stirring, then is subjected to steam distillation. The separated oil is thereafter extracted with three 50-ml. portions 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 hydro-bromic acid solution. To the mixture ether is added until turbidity. The precipitated crystals are filtered off, washed with ether and dried till constant weight. 4.5 g of 2-methyl-3-isobutyl-5,6,7,8qetrahydro-4-(3H) quinazolinone are obtained, melting at 218 to 221 "C.

Example 8 4.98 g of 2-methyl-5,6,7,8-tetrahydro-benzoxazine-4-one (which has been prepared from 2-acetamidocyclohexenecarboxylic acid by boiling with acetic anhydride and purified by distillation in vacuo) and 3.3 ml.

of o-toluidine are boiled at 150 to 160 C for 5 hours. After crystallization from a 1:1 mixture of benzene and petrol 4.1 g of 2-methyl-3-o-tolyl-5,6,7,8-tetrahydro-4(3H)-quinazolinone are obtained, which has the same physical and chemical properties as the product of Example 2. Melting point: 150 - 153"C.

Example 9 A solution of 17 g of ethyl 2-oxo-cyclohexane-carboxylate 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, melting at 138 to 142"C.

The physical and chemical properties of the above product are identical with those of the product of Example 1.

Claims

1. Acompound oftheformula (I)

(wherein R1 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms; and R2 represents an alkyl group having 1 to 5 atoms, or an aryl group optionally substituted by at least one atom or group selected from halogen atoms and alkyl groups having 1 to 5 carbon atoms) and salts thereof.

2. A compound as claimed in claim 1 wherein R2 represents a Con 5 alkyl group or naphthyl group optionally substituted by at least one atom or group selected from halogen atoms and alkyl groups having 1 to 5 carbon atoms.

3. A compound as claimed in claim 2 wherein R2 represents a phenyl group optionally substituted by at least one atom or group selected from halogen atoms and alkyl groups having 1 to 5 carbon atoms.

4. A compound as claimed in any one of the preceding claims wherein R2 represents an aryl group substituted by at least one chlorine or bromine atom.

5. 2-Methyl-3-phenyl-5,6,7,84etrahydroA(3H1-quinazolinone-and salts thereof.

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

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

8. 2-Methyl-3-ochlorophenyl-5,6,7,8-tetrahydro-4(3H)-quinazolinone and salts thereof.

9. 2-Methyl-3-(2-methyl-5-chlorophenyl )-5,6,7,8-tetrahydro-4(3H)-quinazolinone and salts thereof.

10. 2-Methyl-3-(4-chloro-2-methylphenyl)-5,6,7,8-tetra hydro-4(3H)-quinazolinone and salts thereof.

11. 2-Methyl-3-(isobutyl)-5,6,7,8-tetrahydro-4(3H)-quinazolinone and salts thereof.

12. 2-Ethyl-3-o-tolyl-5,6,7,8-tetrahydrn4(3H1-quinazolinone and salts thereof.

13. 2-Ethyl-3-p-ethylphenyl-5,6,7,8-tetrahydro-4(3H(-QUINAZOlinone and salts thereof.

14. 2-Propyl-3-o-chlorophenyl-5,6,7,8-tetrahydro-4(3H)-quinazolinone and salts thereof.

15. A compound as claimed in any one of the preceding claims in the form of a physiologically compatible salt thereof.

16. A process for the preparation of a compound as defined in claim 1 which comprises reacting an amine of the formula (Il) H2N - R2 (II) (wherein R2 is as defined in claim 1 ) or a salt thereof with a cyclohexenecarboxylic acid derivative of the formula (III)

(wherein R' is as defined in claim 1 and R3 represents a leaving atom or group) and where a compound of formula I is obtained, if desired, converting the said compound of formula I into a salt thereof.

17. A process as claimed in claim 16 wherein a compound of formula Ill is used in which R3 represents a hydroxy group or an alkoxy group with 1 to 5 carbon atoms.

18. A process as claimed in claim 16 or claim 17 wherein a compound of formula Ill is used in which R represents an alkyl group with 1 to 5 carbon atoms.

19. A process as claimed in any one of claims 16 to 18 wherein the reaction is effected in the presence of an acidic dehydrating agent.

20. A process as claimed in claim 19 wherein the reaction is effected in the presence of toluene or acetic acid as solvent.

21. A process for the preparation of a compound as defined in claim 1 which comprises reacting an amine of formula II (as defined in claim 16) or a salt thereof with a benzoxazinone derivative of the formula (IV)

(wherein R1 is as defined in claim 1) and where a compound of formula I is obtained, if desired, converting the said compound of formula I into a salt thereof.

22. A process as claimed in claim 21 wherein the reaction is effected in a melt.

23. A process for the preparation of a compound as defined in claim 1 which comprises reacting a 2-oxo-cyclohexane-carboxylate of the formula (V)

(wherein R5 represents a leaving atom or group with an amidine derivative of the formula (VI)

(wherein R and R2 are as defined in claim 1), or a salt thereof, and where a compound of formula I is obtained if desired converting the said compound offormula (I) into a salt thereof.

24. A process is claimed in claim 23 wherein a compound of formula (V) is used in which R5 represents a alkoxy group with 1 to 5 carbon atoms.

25. A process as claimed in claim 23 or claim 24 wherein the reaction is effected in the presence of an alcohol as solvent.

26. A process as claimed in any one of claims 16, 20 and 23 substantially as herein described.

27. A process for the preparation of a compound as defined in claim 1 substantially as herein described in any one of the Examples.

28. A compound as defined in claim 1 when prepared by a process as claimed in any one of claims 16 to 27.

29. A pharmaceutical composition comprising as active ingredient at least one compound of formula I or a physiologically compatible salt thereof in association with a pharmaceutical carrier or excipient.

30. A compound of formula I as defined in claim 1 (wherein R2 represents a C1 5 alkyl group or a naphthyl group optionally substituted by at least one atom or group selected from halogen atoms or C15 alkyl groups) when used as a spasmolytic.

31. A compou nd of the formula: -

wherein R1 is as defined in claim 1 and R3 represents an alkoxy group.

32. Compounds oftheformula:

(wherein R1 is as defined in claim 1) and salts thereof.