CH520145A - Anti-inflammatory quinazolinones - Google Patents

Abstract

ANTI-INFLAMMATORY QUINAZOLINE DERIVS. N3A- Of formula (I):- (where R degree = NO2, NH2, NH (1-4C) alkyl, N (1-4C)alkyl 2, or N-morpholino; R=H, F, Cl, Br, (1-5C) alkyl, or (1-4C) o-alkyl, with the proviso that R is not equal H if R degree =NO2 or NH2; R'=(1-5C) alkyl, allyl or propargyl with the proviso that R'=alkyl if R degree=NH alkyl; and R2=Ph or C6H3(Y)n, where Y=H, F, Cl, Br, (1-4C) alkyl, CF3, or (1-4C) o-alkyl, and n=1 or 2 with the proviso that not more than one CF3 group is present) and salts of I, are useful anti-inflammatories at 20-2000 mg/day. - They are prepared by a variety of standard routes.

Description

  

  Process for the preparation of 2 (1H) -quinazolinones The invention relates to a process for the preparation of 2 (1H) -quinazolinones of the general formula I
EMI0001.0001
    in which R1 stands for a nitro group, an N-dialkylamino group, in which each alkyl denotes an alkyl group having 1-4 carbon atoms; or an N-morpholino group, R denotes hydrogen, fluorine, chlorine or bromine, an alkyl group with 1-5 carbon atoms or an alkoxy group with 1-4 carbon atoms, with the proviso that R does not represent hydrogen if R1 is a nitro group means R1 'for an alkyl group with 1-5 carbon atoms, with the exception that there is no tert.

   May be alkyl group whose tert. Carbon atom is bonded directly to the ring nitrogen atom, an allyl or propargyl group and R ″ stands for phenyl or a group of the general formula II
EMI0001.0006
    wherein Y is fluorine, chlorine, bromine, an alkyl group with 1-4 carbon atoms, an alkoxy group with 1-4 carbon atoms or a trifluoromethyl group and Y 'is hydrogen, fluorine, chlorine, bromine, an alkyl group with 1-4 carbon atoms or an alkoxy group with Mean 1-4 carbon atoms. The inventive method is characterized in that compounds of the general. For mel III
EMI0001.0008
    wherein R1, R, R1 'and R "have the above meaning with an alkyl carbamate, wherein the alkyl group has 1-5 carbon atoms, in the presence of a catalytic amount of Lewis acid reacted.



  The reaction is conveniently carried out at temperatures between 160 and 200 ° C. for one to 4 hours in an inert organic solvent, for example o-dichlorobenzene, in the presence of a catalytic amount of a Lewis acid, for example zinc chloride. The inert organic solvent can be replaced by an excess of the carbamate.



  The compounds of the general formula I obtained according to the invention are isolated after the reaction from the corresponding reaction mixtures in a manner known per se, for example by filtering, extraction, evaporation of the corresponding solutions, salt formation of the basic substituted compounds of the general formula I etc. and then optionally cleaned in a manner known per se, for example by recrystallization.



  The basic-substituted compounds of the general formula I can be released from the salts obtained by treatment with aqueous alkali metal hydroxide solutions. The basic substituted compounds of the general formula I obtained according to the invention can, if appropriate, subsequently be converted into their acid addition salts by reaction with suitable acids.



  The connections used as starting compounds of the all. Formula III can be prepared in a manner known per se. If connections of the all-. Formula III, i.e. o-Alkylaminobenzophenones are to be prepared in which the alkyl group is a branched alkyl group and the branching takes place on the carbon atom that is bonded directly to the stick material atom -Aminobenzophenone directly to alkylate with corresponding alkyl iodides or bromides in a manner known per se. The reaction is preferably carried out in the presence of a base, e.g.

    an alkali carbonate, and in an organic solvent such as dioxane, benzene or toluene. The process is expediently carried out at temperatures between 70 and 140 ° C., preferably 80-100 ° C. Compounds of the general formula III which have a 5-nitro substituent can preferably be prepared by reacting the corresponding 5-nitro-2-chlorobenzophenone with a suitable amine (R1'-NH2) in the presence of a suitable catalyst, for example a mixture of copper and copper chloride.



  Those compounds of the general formula I in which R1 is an N-dialkylamino or N-morpholino group can likewise be obtained in the form of their acid addition salts. Hydrochloric acid, fumaric acid, maleic acid, formic acid, acetic acid, sulfonic acid and malonic acid have proven to be suitable for the formation of the acid addition salts.



  The compounds of general formula I obtained according to the invention have extraordinarily favorable pharmacodynamic properties. In particular, as can be seen from the results of the Carraghen-induced edema test in rats, these compounds have an extremely favorable anti-inflammatory effect. The amount to be administered daily should be between 20 and 2000 g, which are preferably administered in several (2-4) daily doses of 5-1000 mg or in retarded form.



  The compounds prepared according to the invention can be used as medicaments alone or in corresponding medicament forms for oral or parenteral administration. In order to produce suitable medicament forms, these are processed with inorganic or organic, pharmacologically indifferent auxiliaries.



  Those compounds of the general formula I in which R1 is an N-dialkylamino or N-morpholino group can also be used in the form of their acid addition salts, the salts having the same activity as the free bases.



  Those compounds of the general formula I are preferred in which R1 'is an isopropyl group. If in the all-. Formula I R, R1 or Y represent an alkyl or alkoxy group, the alkyl or the alkoxy groups each have 1-3 or 1 or 2 carbon atoms.



  Starting compounds, the preparation of which is not described, are either known or can be prepared in a manner known per se. Processes for the preparation of these starting compounds are described in Belgian Patent Nos. 714 568; 723 041, 728 869 and 735 344.



  In the following examples, which explain the execution of the process but are not intended to restrict the invention in any way, all temperatures are given in degrees Celsius and have been corrected.



  <I> Example 1 </I> 1-Isopropyl-7-methyl-6-nitro-4-phenyl- -2 (1H) -quinazolinone a) 2-Isopropylamino-4-methyl-5-nitro-benzophenone A mixture of 15 g of 2-chloro-4-methyl-5-nitrobenzophenone, 700 mg of copper powder, 700 mg of copper chloride, 15 ml of ethanol and 15 ml of liquid isopropylamine are refluxed for 20 hours. Then 200 ml of methylene chloride are added, the inorganic material is filtered off and the filtrate is washed with 100 ml of water.

   The organic phase is dried over sodium sulfate, filtered and evaporated to dryness in vacuo, the 2-isopropylamino--4-methyl-5-nitro-benzophenone being obtained as a residue.



  b) 1-Isopropyl-7-methyl-6-nitro-4-phenyl-2 (IH) - -quinazolinone A mixture of 37g 2-isopropylamino-4-methyl-5--nitro-benzophenone, 45 g urethane and 1, 7 g of zinc chloride is heated to 180-200 C in an oil bath for 4 hours. It is then cooled to room temperature and mixed with 220 ml of methylene chloride. The mixture obtained is filtered and the filtrate is washed twice with 110 ml of water each time. The organic phase is then dried over sodium sulfate, filtered and evaporated to dryness in vacuo.

   The residue is recrystallized from ethyl acetate, 1-isopropyl-7-methyl-6-nitro-4-phenyl-2 (1H) -quinazolinone with a melting point of 192-194 ° C. being obtained.



  <I> Example 2 </I> In a manner analogous to Example 1, using appropriate starting materials, the following compounds are obtained: 2 a) 7-dimethylamino-1-isopropyl-4-phenyl-2 (1H) - -quinazolinone; 181-183 C.



  2 b) 6-dimethylamino-1-isopropyl-7-methyl-4-phenyl--2 (1H) -quinazolinone; 184-186 C.



  2 c) 6-dimethylamino-1-isopropyl-4-phenyl-2 (1H) - -quinazolinone; M.p. 167-168 C.



  2 d) 6-diisopropylamino-1-isopropyl-4-phenyl-2 (1H) - -quinazolinone; M.p. 225 C (dec.).



  2 e) 6- (N-ethyl-N-isopropyl) -amino-1-isopropyl-4-phenyl-2 (1H) -quinazolinone; M.p. 165 C.



  2 f) 1-isopropyl-6-morpholino-4-phenyl-2 (1H) -quinazolinone; 172-175 C.



  2 g) 1-isopropyl-7-methyl-6-morpholino-4-phenyl--2 (1H) -quinazolinone; M.p. 218-221 C.



  2 h) 7-chloro-6-dimethylamino-1-isopropyl-4-phenyl--2 (1H) -quinazolinone; 160-163 C.



  2 i) 1-isopropyl-7-morpholino-4-phenyl-2 (1H) -quinazolinone; 175-176 C.

 

Claims (1)

PATENT CLAIM Process for the preparation of 2 (1H) -quinazolinones of the general formula I. EMI0003.0000 where R1 is a nitro group, an N-dialkylamino group, in which each alkyl denotes an alkyl group having 1-4 carbon atoms; or an N-morpholino group, R denotes hydrogen, fluorine, chlorine or bromine, an alkyl group with 1-5 carbon atoms or an alkoxy group with 1-4 carbon atoms, with the proviso that R does not represent hydrogen if R1 is a nitro group means, R1 'for an alkyl group with 1-5 carbon atoms, with the exception that there is no tert. May be alkyl group whose tert. Carbon atom is bonded directly to the ring nitrogen atom, an allyl or propargyl group and R ″ stands for phenyl or a group of the general. Formula II EMI0003.0007 wherein Y is fluorine, chlorine, bromine, an alkyl group with 1-4 carbon atoms, an alkoxy group with 1-4 carbon atoms or a trifluoromethyl group and Y 'is hydrogen, fluorine, chlorine, bromine, an alkyl group with 1-4 carbon atoms or an alkoxy group with 1-4 carbon atoms, characterized in that compounds of the general formula III EMI0003.0008 wherein R1, R, R1 'and R "have the above meaning, with an alkyl carbamate, in which the alkyl group has 1-5 carbon atoms, in the presence of a catalytic amount of Lewis acid. SUBSTANTIAL CLAIM Process according to claim, characterized in that compounds the general Formula III is reacted with an alkyl carbamate at temperatures between 160 and 200 ° C. in the presence of zinc chloride as the Lewis acid.