IL32504A - Quinazoline-2(1h)-thione derivatives,their preparation and pharmaceutical preparations containing them - Google Patents

Description

iniK a»^»3an mnpn "wni QUI ZOLI B-2(1H)-THIGNE DERIVATIVES, THEIR PREPARATION AND PHARMACEUTICAL PREPARATIONS CONTAINING- THEM SAND02 A.G Case 600-62X8 IMPROVEMENTS IN OR RELATING TO ORGANIC COMPOUNDS The present invention relates to quinazoline-2(lH)-thione derivatives and their preparation.

The present invention provides novel compounds of formula I, in which R signifies a hydrogen, fluorine, chlorine or bromine atom, an alkyl radical of 1 to 5 carbon atoms, an alkoxy or alkylthio radical of 1 to h carbon atoms, or a nitro ,trifluoromethyl or di- (C-j_^)alkylamino group, n represents 1 or 2, with the proviso that when n is 2, the R substituentp which may be the same or different signify a hydrogen, fluorine, chlorine or bromine atom, an alkyl radical of 1 to 5 carbon atoms or an alkoxy radical of 1 to 4 carbon atoms, R^ signifies an alkyl radical of 1 to 5 carbon atoms, or an allyl or propargyl radical, R^ signifies a phenyl radical or a substituted phenyl radical of formula II, 132504/2 in which Y signifies torn, alkyl iadica of 1 to 4 carbon atoms, or an aLkoxy radical of 1 to 4 carbon atoms, or a trif luoromethyl group, and Y1 represents a hydrogen, fluorine, chlorine or bromine atom, an alkyl radical of 1 to 4 carbon atoms, or an alkoxy radical of 1 to 4 carbon atoms.

Quinozoline-2(lH)-one compounds having an oxo group instead of ,a thiono group in the 2-position are known from French Patents 1,520,745 and B3M 6001.

The invention also provides processes for t e production ! of compounds of formula I, characterised by j · a) producing a compound of formula Ia> in which R, R , R≥ and n have the significance stated above, (i) by reacting at elevated temperature a compound of formula III, in which R, R^ R2 and n have the significance stated above, with phosphorus pentasulphide, in the presence of an organic solvent which is inert under the reaction conditions, or - 3 - 60O-6218 by eyclisin a compound of formula IV, R R2 in which R, R^, R and n have the significance stated above, by subjecting it to the action of an acid chloride or bromide and an isothiocyanate of formula V, MN=C=S V in which M signifies an alkali or alkaline earth metal cation or the ammonium cation, or to the action of the reaction product of an. acid ohloride or. brpmide and an isothiocyanate of formula V stated above^or (iii) by reacting a compound of formula IV stated above with isothio-cyanic acid, or b) producing a compound of formula lb, in which R, R , R and n have the significance stated above, 1 by reacting a compound of formula VI, - ¾. - 600-62X8 c) producing a compound of formula lb', R, in which R' signifies a hydrogen, fluorine, chlorine or bromine atom, an alkyl radical of 1 to 5 carbon atoms, or an alkoxy radical of 1 to h carbon atoms, signifies an alkyl radical of 1 to 5 Qarbon atoms, and n' signifies 1 or 2, provided that when n' is 2, no more than one R' radioal may signify a halogen atom or a branched chain substituent, and provided that R1 is other than a branched chain substituent when in the 5- or 8- position of the ring, and y signifies a hydrogen, fluorine , chlorine or bromine atom, an alkyl radical of 1 to 3 carbon atoms or an alkoxy radical of 1 to 2 carbon atoms, reacting a compound of formula IX, R .v C=S IX NH, in which R', R^ and n'have the significance stated above, with a compound of formula X, CHO - 5 - 600-6218 in which Y has the significance stated above, at an elevated temperature.

Process a)(i) is preferably effected at a temperature of from about 70°C to about l80°C, more preferably from 100°C to 130°C, and conveniently at the reflux temperature of the reaction medium, in an organic solvent which is inert under the reaction conditions.

Suitable organic solvents include pyridine, toluene and xylene, of which pyridine is preferred since it appears to have a beneficial effect on the rate of reaction. Reaction time may vary for example from 1 to 50 hours, more typically from 10 to 30 hours.

Process a)(ii) is conveniently effected in an organic solvent which is inert under the reaction conditions, at a temperature of from 10°C to 80°C, preferably 30°C to 70°C. As indicated, the process may be effected by reacting a compound of formula IV with the reaction product of an acid chloride or bromide and an isothlocyanate of formula V, and it is generally preferred to first react the acid halide and compound of formula V and then add the compound of formula IV to the resulting reaction mixture. The reaction of the acid halide and compound V is exothermic and is preferably initiated at a temperature of from 10°C to 30°C. It will be understood that the acid halides employed should not carry substituents or functional groups which would interfere with the process. Suitable acid halides include acetyl chloride and benzoyl chloride, preferably benzoyl chloride. ΝαίμΓ ^Ιν, the most suitable compounds of formula V are those most readily react-ing with the acid halide to eliminate as a by-product a halide of the cation M. Suitably, the compound of formula V is an alkali metal isothiocyanate such as sodium isothiocyanate or ammonium 6 - 600-6218 isothiocyanate, and preferably ammonium isothiocyanate . Suitable solvents include lower alcohols, ketones and cyclic ethers, acetone being preferred. When the compound of formula IV bears certain sub-stituentSj for example when R signifies an alkyl radical;e.g. -me h l-2-isopropylamino-benzophenone, the reaction may lead to a mixture of products including the desired compound of formula la and a non-cyclized by-product, and the latter may even represent the major product of the reaction. In such situations, the resulting mixture may be treated with a strong base at elevated temperatures to cyclize the previously non-cyclized by-product to the desired compound of formula la in high yield. Such treatment is suitably effected at a temperature of from 60°C to 100°C in the presence of an alkali metal hydroxide guch as sodium hydroxide or potassium hydroxide and in an aqueous solvent medium comprising water and an inert organic solvent such as a cyclic ether, e.g. dioxane. Process a)(ii) is particularly suitable for the preparation of compounds of formula la in which Y and/or is other than an ortho-substituent .

Process a) (iii) is suitably effected at a temperature of from 50°C to 150°C, preferably 100°C to l 0°C. Isothiocyanic acid is well known to be unstable and is therefore desirably prepared _in situ. Thus the process may be effected in acidic medium employing a salt of isothiocyanic acid of formula V stated above. - 7 - 600-6218 The compound of formula V is preferably an alkali metal, e.g. sodium or potassium salt or most preferably the ammonium salt. The acid employed to produce in situ the desired isothiocyanic acid from the compound of formula V. is preferably a lower carboxylic acid, desirably acetic acid, which may also be conveniently employed as a solvent for the reaction.

Process b) is preferably carried out in an acid aqueous medium, nt elevated temperature, for example at from 50°C to 1 0°C, preferably from 70° to 110°C. In analogous manner to that described above in connection with process a)(iii), the process may be effected in an acidic medium employing a compound of formula V stated above. The cation M is preferably a cation of an alkali metal, e.g. sodium, an alkaline earth metal, e.g. calciunijOr most preferably the cation of ammonia, i.e. the ammonium salt. The acid employed to produce in situ the desired isothiocyanic acid from compound V is preferably a strong inorganic acid, for example sulfuric acid, nitric acid, and hydrochloric acid, most preferably hydrochloric acid. If desired or required, an organic co-solvent may be employed to insure optimum solubility of compound VI in an aqueous reaction medium.

Suitable co-solvents for this purpose are well known and include methanol, ethanol and dioxane. The reaction time of process b) is typically from 10 minutes to 5 hours, and more usually 15 to 60 minutes.

Process c) is effected at elevated temperatures suitably from 50°C to 120°C, preferably from 50°C to 100°C. The reaction is suitably carried out in the presence of an acid as catalyst and under anhydrous conditions adapted to effect condensation of compounds IX and X. The acid employed is desirably a strong acid which is also a - 8 - 600-6218 with compounds IX and X. An acid suitably employed is anhydrous hydrochloric acid (hydrogen chloride in an aromatic solvent) although one may employ other strong acids which are dehydrating agents including organic acids such as arylsulfonic acids or alkylsulfonic acids, such as benzenesulfonic acid, p-toluenesulfonic acid and methanesulfonic acid, preferably p-toluenesulfonic acid. The amount of acid employed may vary depending upon the particular acid used and, in the case of hydrochloric acid, may be suitably a substantial excess. The reaction is conveniently carried out in an organic solvent which is inert under the reaction conditions, preferably an aromatic solvent such as benzene. The reaction time may, for example, range from 1 to 50 hours.

It was thought that the production of compounds of formula lb' in accordance with process c) proceeded via an intermediate of formula A, R' in which R', n', R^ and have the significance stated above. From experimentation conducted in accordance with the preferred embodiments of the process, however, it is evident that an intermediate of formula A is merely formed on a transient basis, and that process c) may directly form compounds of formula lb' in essentially a single stage operation when conducted under the preferred conditions.

It will be unders ood that in formulae IX and A, the R' - 9 - 600-6218 It should be mentioned that processes a)(ii) and a)(iii) are considered to be distinct reactions inter alia because different mechanisms ahd/or intermediary compounds are involved.

The compounds of formula III employed as starting materials in process a)(i) may be produced by tl) cyclising a compound of formula VII, R2 in which R, R , R and n have the significance stated above, with phosgene, or ) reacting a compound of formula IVa, (R)n C=0 R2 wherein Rj' has the same significance as R^ stated above, except that it may not signify a tertiary alkyl group in which the tertiary carbon atom is directly attached to the nitrogen atom, and R^, R^ and n have the significance stated above, with a lower alkyl (C -C ) carbamate in the presence of a catalytic amou "4 -10 - 600-6218 of a Lewis acid, to obtain a compound of formula Ilia, R" .' 1 in which R, n, " and R^ have the significance stated above, or β) reacting a compound of formula VIII, R2 in which R, R^ and n have the significance stated above, and signifies an alkali metal atom, with a compound of formula XV, R ' ' X XV wherein R^' has the significance stated above, and X signifies a chlorine, bromine or iodine atom, to obtain a compound of formula Ilia stated above.

Process ίΐ) is suitably carried out at a temperature of 0° to 50°C, preferably 10° to 30°C. Desirably an inert organic solvent is used, e.g. an aromatic hydrocarbon such as benzene, toluene or xylene, benzene being preferred. The mole ratio of phosgene to compound VII is not critical and a substantial excess of phosgene is employed in preferred embodiments of the process to - 11- 600-6218 Process σ) should be carried out at a temperature above l40°C, preferably, from l60° to 200°C, the preferred Lewis acid being zinc chloride and the preferred carbamate being ethyl carbamate. If desired, the reaction may be carried out in an organic solvent which is inert under the reaction conditions, e.g. o-dichlorobenzene, but this is not necessary since an excess of the carbamate can be used for this purpose. Depending on the particular conditions _employed, a suitable reaction time is from about 20 minutes to about 2 hours.

Process 0) is conveniently carried out at room temperature (approximately 20°C) or at elevated temperatures up to about 100°C. Suitable organic solvents which are inert under the reaction conditions include dimethylacetamide, diethylacetamide, dimethylformamide, dimethylsulfoxide and dibxane. Preferably the compound of formula VEI is a sodium or potassium salt, and the compound of formula XV is preferably an iodide.

The compounds of formula Ilia, wherein the nitrogen atom of the quinazolinone ring carries a branched alkyl substituent and the branching occurs at the carbon atom- directly attached to the ring nitrogen atom, e.g. isopropyl and sec-butyl, are advantageously prepared by process a) rather than ø) since better yields of the desired product are then obtained.

The resulting compound of formula III may be isolated and purified by conventional techniques. - 12 - 600-6218 The compounds of formula IV employed as starting materials in processes a)(ii), a)(iii) and a) are either known or can be prepared in manner known per se . Where the benzene ring of compounds IV carries a 5-nitro or 5-trifluoromethyl substituent, the compounds are preferably prepared by reaction of the corresponding 5- (nitro or tri-fluoromethyl )-2-chloro-benzophenone with an appropriate amine (R^NH^) in the presence of a suitable catalyst, e.g. a mixture of copper and cuprous chloride. Where the compound of formula IV is an o-alkylamino-benzophenone in which the alkyl moiety is a branched chain and the branching occurs on the carbon atom directly attached to the nitrogen atom, particularly when it is an o-isopropylaminobenzophenone, it may desirably be prepared by a method analogous to that described in Belgian Patent No. 723·θΊΐ , using an appropriate o-amino-benzophenone and a secondary alkyl bromide or iodide.

The compounds of formula VI employed as starting materials in process b) are either known or can be prepared in manner known per se . One preferred method for preparation of compounds of formula VI involves reduction of a 2-aminobenzophenone (compound IV) with sodium borohydride in a suitable inert, organic solvent, as illustrated hereinafter in Example 5, and described in the literature by G.N. Walker, J. Org. Chem. 27, 1929 (X962) .

The compounds of formula IX used as starting materials in process c) may be suitably prepared by subjecting a compound of formula XI, - 600-6218 in which R', R and n' have the significance stated above and A signifies the acid residue of an acid halide, to alkaline hydrolysis at elevated temperatures.

The process may suitably be carried out at temperatures of from 50°C to l 0°C, preferably 80°C to 120°C. The hydrolysis is suitably effected employing an alkali metal hydroxide, preferably sodium or potassium hydroxide. The reaction is suitably carried out in a solvent medium preferably comprising water and a water-miscible organic solvent which is inert under the reaction conditions, such as an acyclic or cyclic ether, preferably dioxane. The compound of formula IX may be isolated and purified by conventional techniques.

The compounds of formula XI may be prepared by reacting a compound of the formula XII, wherein R', R1 and ' have the significance stated above, with an isothiocyanate of formula V stated above and an acid halide of the formula XIII, A Z XIII wherein A has the significance stated above and Z signifies a chlorine or bromine atom, referabl a - 11 - ^00-6218 The process may be carried out in manner analogous to that described for process a)(ii) above. The compound of formula XI may be isolated from the resulting mixture and purified using conventional techniques. However', complete isolation and/or purification of the compound of formula XI may not be necessary in so far as the resulting reaction mixture which may contain varying amounts of the compound of formula XI may be employed directly for the production of the compounds of formula IX.:.

The compounds of formula XII are either known or may be prepared in manner known per se . A preferred method involves tosylation, alkylation and detosylation of a compound of formula XIV, in which R' and n' have the significance stated above, in manner known per se .

Those compounds of formula XII in which Rj is a branched alkyl radical in which the branching occurs at the carbon atom attached to the amino nitrogen atoms, e.g. an isopropyl group, may be most conveniently prepared by direct reaction of a compound of formula XIV with the appropriate alkyl halide.

The compounds of formula VII used as starting materials in process Τί) are either known or can be prepared from available materials by one or more of a number of well-established procedures, as will be evident to those skilled in the art. In general, they may be produced by reaction of a corresponding o- aminobenzophenone of formula IV with ammonia, desirably in a sealed reactor under anhydrous conditions, and at elevated temper¬ atures and pressures. Reaction temperatures are suitably in the with a suitable co-solvent, e.g. dioxane\ and is followed by recovery using conventional techniques. Another well-known procedure involves tosylation, alkylation and detesylation of an appropriately substituted anthranilonitrile to obtain the corresponding 2-ainino-benaonitrile which is then reacted with a phenyl Grignard compound or phenyllithium compound, followed by working up using conventional techniques to obtain the compound of formula VII. However, this latter method should desirably not be used for compounds wherein R is nitro.

The compounds of formula VIII used as starting materials in process β) may readily be obtained by treating the corresponding l-unsubsti u ed quinasolinone in manner known per se for the preparation of such alkali metal salts, e.g. with sodium hydride or an alkali metal alkoxide such as sodium methoxide, sodium ethoxide, potassium methoxide or potassium ethoxide. The reaction is suitably carried out at room temperature in an organic solvent which is inert under the reaction conditions, e.g. dimethylacetamide, diethyl-acetamide, dlmethylformamide, dimethylsulfoxide or dioxane.

Suitably the same solvent is used for the subsequent preparation of compounds of general formula Ilia.

The l-unsubstituted quinazolinonea themselves are either known or can be prepared in a manner analogous to that described in the literature (e.g. Japanese Patent Ho. 20865/65» published September 16th, 1963) for known compounds. Such quinazolinones can also be prepared from the appropriately substituted 2-aDiino-ben2i0phenones by the reaction of process a). fhe compounds of formula I in which R signifies a dialkylamino radical m y be produced and isolated in he form of acid addition salts. Examples of such salts include the hydrochlorides, fumarateB, maleates, formates,, acetates, sulphortates and malonates. The acid addition salt forms may be produced from the corresponding free base forms in manner known per se. Conversely* the free base forms may be obtained from the salt forms in manner known per se.

She compounds of foraaila I possess pharmacological activity. In particular, the compounds possess anti-inflammatory activity as indicated by the Garrageena^lndtteed edema test 6n rats, and are therefore indicated for use as antiinflammatory agents.

Suitable indicated daily dosages range from about f mg to about 1Θ00 mg preferably administered in divided dosages of from about mg to about 500 mg two to four times a day or in retard form, he compounds may be used mixed with a pharmaceutically acceptable carrier and any Other conventional adjuvants as may be desired, and administered orally in such forms as tablets, capsules, elixirs and suspension^, or paren ©rally in the form of injectable solutions o suspensions.

She compounds of formula I in which R signifies a dialkylamino radical may be used in the form of physiologically acceptable, non-toxic acid addition salts, which salts have a similar order of activity to the free base forms. *■ 16a ' .

A representative formulation is a tablet prepared by conventional tabletting techniques and having the following composition by weights Ingredient Parts by Weight Compound of formula I, e.g. l~i8opropyl- *-phenyl-¾uinaa©line- 2(lH)-thione 50 tragacanth. 2 lactose 39.5 com stach 5 talcum 3 magnesium stearate 0.5 Preferred compounds of formula I are those in ttfhich is ethyl or isopropyl, particularly high activity being demonstrated by l~isopropyl-7-methyl-i4-phenyl^quina-zoline- ( H)-thione.

The compounds of formula la are also useful as intermediates for the preparation of compounds of formula III stated above, the latter themselves being pharmaceutically active.

The term "in manner known per se" as used herein signifies methods in use or described in the literature on the subject.

The following Examples further illustrate the invention. - 17 - 600-6218 EXAMPLE 1: l-isopropyl- -phenylquinazoline-2(lH)-thione [Process a) a) Preparation of l-isopropyl-^-phenyl-2(lH)~auina201inone A mixture of 21 g. of crude o-isopropyla inobenzophenoae, 1*0 g. of urethane and 1.5 g. of zinc chloride is heated for k hours at loO~20Q°C. (oil hath). The resulting mixture is cooled to room temperature and then there is added thereto 200 ml. of methylene chloride, The resulting mixture is filtered and the filtrate extracted twice with 100 ml. (each) t of water. The organic phase is dried over anhydrous sodium sulfate and evaporated in vacuo. The residue is crystallized from ethyl acetate to obtain l-isopropyl-4-phenyl-2(lK)-quinazolinone, m.p. 140°C. b) Preparation of l-isopropyl-^-phenylQuinazoline-2(lH) -thioae A mixture of 9.0 g. of l-isopropyl-U~phenyl-2(lK) ~¾uinazolinone , 30 g. of phosphorus pentasulfide and 100 ml. of pyridine is refluxed for 20 hours. The resulting mixture is poured onto 500 ml. of ice water and the resulting mixture extracted twice each with 200 ml. of methylene chloride. The organic layers are combined, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to obtain a yellow crystalline residue which is filtered with methylene chloride through a 3 cm.layer of aluminum oxide. The filtrate is concentrated in vacuo to a volume of about 20 ml. and the said concentrate is then treated by addition of diethyl ether (about 100 ml.) to crystallize orange needles of 1-isopropyl-¾-phenylquinazoline-2(lH)-thione, m.p. 2l6-217°C. _ 18 - 600-6218 EXAMPLE 2 : l-ethyl- -phenylquinazollne-2(lH)-thlone [Process a)(i)] a) Preparation of l-ethyl-^-phenyl-2( 1H ) -quinazolinone- To a solution of 2.2 g. of ¼-phenyl-2(lH)-quinazoli.ncne in 50 ml. of dimethylacetamide is added, at room temperature , 0.75 g. of sodium hydride (50j2 in mineral oil). The resulting mixture is stirred for 15 minutes at room temperature and then k ml. of ethyl iodide is added. The mixture is stirred for an additional 30 minutes at room temperature and then heated at 60°C. for 30 minutes to complete the reaction. The mixture is then evaporated i vacuo to remove most of the solvent, and the residue poured over 100 g. of ice. The resulting solid material is filtered off, dissolved in 50 ml. of methylene chloride and the resulting solution dried over sodium sulfate and the solvent then evaporated in_ vacuo . The resulting oily residue is crystallized from ethyl acetate to obtain l-ethyl-^-phenyl^lHj-^uinazolincne, n.p . 183-185°C b) Preparation of l-etl\yl- -phenylquina2oline-2(li)-thionc.

Following the procedure of Example lb), and employing proportional solvent amounts, unless otherwise indicated, g. of 1-ethyl-li~phenyl-2(lH)-quinazolinone is reacted vith 20 g. of phosphorus pentasulfide in 100 ml.cf pyridine to obtain on crystallisation from methylene chloride/diethyl ether (1:5) pale orange needles of 1-ethyl- l»-phenylquinazoline-2(lH)-thioae, .p, 232-235°C. - 19 - 600-6218 1 EXAMPLE 3: l-lsopropyl-7-methyl- -phenylqulnazollne-2(lH)-thione (Process a) (l) ] a) Preparation of -methyl-2-isopropylaninobenzophenone A mixture of 7 g of l*-methyl-2-aminoben2ophenone , 6.35 g of sodium carbonate and 18.8 ml of 2-iodopropane is stirred and refluxed for 3 days . The cooled reaction mixture is then diluted vith 200 nil of benzene and vashed twice with water and twice with brine. The organic phase is separated, dried over anhydrous sodium sulfate and concentrated in vacuo to remove substantially all of the benzene. The resulting yellow oil is dissolved in about 10 ml of methylene chloride and subjected to column chromatography employing alumina (about 1*00 g) and methylene chloride as eluant to give a first fraction which on concentration in vacuo to remove methylene chloride produced a yellow oil of ¾-methyl-2-isopropylaminobenzophenone. b) Preparation of l~isopropyl-7-methyl- -phenyl-2(lH)-quina7.olinone A mixture of 5.9 g of lt-methyl-2-isopropylaminobenzophenone prepared in a) above , 13.9 g of urethane and 500 milligrams of zinc ^chloride is heated at a temperature of 190° C for 1 1/2 hours . There is then additionally added 7 g of urethane and 250 milligrams of zinc chloride , and the heating continued at a temperature of 190° C for an additional 2-1/2 hours . The resulting mixture is cooled to about 100° C and diluted with chloroform. The resulting mixture is then filtered and the filtrate washed first with water and then with brine. The organic phase is separated dried over anhydrous sodium sulfate and concentrated ijn vacuo to remove substantially all of the chloroform and obtain an oily residue which is - 20 - 600-6218 dissolved in a small amount of about 20 ml of methylene chloride. The resulting solution is then diluted vith about kO ml of ethyl acetate and concentrated in vacuo to crystallize l-isopropyl~7-methyl-U-phenyl-2(lH)~ quinazolinone ; mp 137° to 138° C. c) Preparation of l-isopropyl-7-methyl- -phenylQuina2olir.e-2(lH)-thione Following the procedure of Example lb), and. employing proportional solvent volumes, 2 g of 1- sop op l-7~methyl-U-phenyl-2(IK)-quinazolinone is reacted vith k g of phosphorus penta-sulfide in 20 ml of pyridine (2 1/2 hours reflux) to obtain on crystallization from methylene chloride/di thyl ether (1 : 5 ) orange needles of l-isopropyl-7-methyl-^-phenylquinazoline^ilHj-thione; mp 19¼? to 198° C.

EXAMPLE : ]-allyl- -phenylquinazol.ine-2(lH)-thione [Process a)(i)] a) Preparation of l-allyl-^-phenyl-2(lH)-quinazollnone Following the procedure of Example 2a) , and employing equivalent amoun s, -phenyl-2(lH)~quinazolinone is reacted vith sodium hydride and allyl iodide to obtain on crystallization from ethyl acetate crystals of l-allyl- -phenyl-2(lH)-quinazolinone mp 159° to 160° C. b) Preparation of l-allyl-^-phenylquinazoline-2(lH)-thione Following the procedure of Example lb) and employing equivalent amounts, l-allyl- -phenyl-2(lK)-quinazolinone is reacted vith phosphorus pentasulfide in 30 ml of pyridine (2 hours - 21 - 600-6218 EXAMPLE 5: , -dihydro-l-lsopropyl- -phenyl-quina2ollne-2(lH)-thlone [Process b) ] a) Preparation o 2-isopropylaTr.inobenzohydrol To a solution of 2k g. of 2-isopropyiaminobenzophenone in 200 ml. of 5# ethanol is added total of 8 g, of sodium borohydride attemperature of 60°C. over a period of 30 minutes. This mixture is stirred for 3 hours a " ■ at temperature of 60°C. and acetic acid is then added dropvise until gas evolution ceases. The resulting mixture is then concentrated i vacuo to a volume of about 80 ml. There is then added 300 ml. of vater and ml. of 2N sodium hydroxide and the resulting mixture extracted three times each vith 100 ml. of methylene chloride. The extracts are combined, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a crude pale yellow oil of 2-isopropylaminobenzohydrol. b) Preparation of 3^-dihydro-l-isopropyl-U-phenyl-quiaazoline- 2(lK)-thione The crude 2-isopropylaninobenzohydrol obtained from a), above, is combined vith 100 ml. of vater, 10 ml. of dioxane and 7.7 ml. of cone, hydrochloric acid and to th s mixture is added 7 g. of ammonium isothiocyaaate. The resulting mixture is stirred at temperature of 100°C. for 30 minutes to obtain vhite crystals of 3> -dihydro-l-isopropyl-l*-phenyl-a^a&zoline-2(lH)-thione, m.p. 185°C. _ 22 _ 600-6218 EXAMPLE 6 ; 3 , -dihydro-l-methyl- -phenyl-quinazoline-2(lH)-thione (Process b)) To a solution of 15.6 g. of 2-methylsjainobenzohydrol dissolved in 80 ml. of Hi hydrochloric acid is added 6 .1 g. of ammonium isothio-cyanate. The resulting mixture is refluxed for 15 minutes, then diluted vith 100 EI. of water and filtered to obtain a crystalline solid of 3,^" dihydro~l- ethyl-4-phenyl-auinaz^ .p. l88-190°C.

EXAMPLE 7 : 6-chloro- 3 , -dihydro-l-methyl- -phenyl-quina2oline-2(lH)-thione (Process b) ) To a solution of 36 g. of 5-chloro~2-methylaminobenzohydrol dissolved in 20 ral. of dioxane and l60 ml. of Hi hydrochloric acid is added 12.U g. of ammonium isothiocyanate. The resulting mixture is stirred at a temperature of 100°C. for 20 minutes, then made alkaline by addition of 21i sodium hydroxide, and filtered to obtain crystals of 6-chloro~3 , ¾-dihydro-l-methyl- -phenyl^uinazoline-2(lH)->thione, m.p. l68-170°C.

EXAMPLE 8 : 5 , -dihydro- 1-isopropyl-7-methyl- -phenyl-quinazoline-2(1H)-thione (Process b)) a) Preparation of -methyl-2-isopropylaminobenzohydrol To a solution of 7.5 g. of 4-methyl-2-isopropylaminobenzophenone in 0 ml. of 90 ethanol is added a total of 2.5 g. of sodium borohydride in divided portions at about room temperature over a period of about 10 minutes. The resulting mixture is heated at a temperature of 85-90°C., cooled to about room temperature, treated by dropwise addition of acetic acid to decompose residual sodium borohydride, made acidic by addition of 2Ii hydrochloric acid and then allowed to stand at room temperature for about 1/2 hour to decompose the boron complex formed during reaction. The resulting mixture is then made alkaline with 2ii sodium hydroxide and extracted three times each with 100 ml. of methylene chloride to obtain after - 25 - 600-62 8 ' b) Prcpa.rr.tion of 3 ,^- ihydro-l-isopropyl-7-niethyl-^-phenyl-q.uina2ollne 2(lK)-thione To a solution of 7.5 g. of -methyl-2-isopropylaminober.zohydrol obtained from a) . above , dissolved in 5 ml. of dioxane and 33 ml. of IN hydrochloric acid is added 2.5 g. of amaonium/thiocyanate . The re-suiting mixture is heated at temperature of 80-90°C. for 30 minutes resulting in the formation of .a heavy brown oil. The reaction mixture i3 then made slightly alkaline by addition of 2N sodium hydroxide and extracted three tines each with 100 ml . of methylene chloride. The organic phases are combined, dried over anhydrous sodium sulfate , filtered and evaporated in vacuo to solid residue which is crystallized from diethyl ether/petroleum ether (1:1) to obtain crystals of 3,¾-dihydro-l~isopropyl-7-niethyl-¾-phenyl-quinazoline-2( lK)-thione , n.p. 125-127°C.

EXAMPLE 9: 3 , -dihydro-l-isopropyl-7-methoxy- -phenyl-quinazoline-2(lH)-thione (Pror!flf»R b) ) a) Preparation of U-methoxy-2-isopropylamlnobenzoh.ydrol Following the procedure of Example 8a) , and employing equivalent amounts , 3.0 g. of U- ethoxy-2-isopropylaminobenzophenoae is reacted with sodium borohydride to obtain a crude oil of U-methoxy-2-isopropylaminobenzohydrol. b) Preparation of S^-dihydro-l-isopropyl^-methoxy-U-phenyl- ¾uinazoline-2( IE) -thione Following the procedure of Example 8b) , and employing equivalent amounts , li-methoxy-2-isopropyla inobenzohydrol obtained from Ho a) above, is reacted with ammonium/ thiocyanate (100°C. for 30 minutes) - 24 - 600-6218 EXAMPLE 10: [process a)(i)] Following the procedure of Example 1 and employing appropriate starting materials in appropriate proportions, the following compounds may be obtained: l-ethyl-6-nitro-4-phenyl-quinazolin<i 2(lH)-thione, m.p. 256-257°C (Crystallization from methylene chloride/diethyl ether) . l-isopropyl-7-methylthio-4-phenyl- quinazolin 2(lH)-thione, m.p. 168-170°C.

(Crystallization from ethanol/pentane) . 4, 6-chloro-l-methyl-4-phenyl-quinazolini-2(lH)- thione, m.p. 228-2)0°C. (Crystallization from methylene chloride/diethyl ether). l-isopropyl-6-methoxy-4-phenyl-quinazolin£- 2(lH)-thione, m.p. l47-150°C. (Crystallization from acetone/pentane) .

EXAMPLE 11: l-isopropyl-4-phenyl-2(lH)-quinazolin^2(lH)-thione [process a)(ii) a) Preparation of o-isopropylaminobenzophenone A mixture of 20 g of o-aminobenzophenone, lOg of sodium carbonate and 50 ml of isopropyl iodide is refluxed with stirring for 5 days. The excess isopropyl iodide is then evaporated off in vacuo, and the resulting residue extracted with 200 ml of benzene. The benzene extract is then filtered, washed twice with 100 ml (each) of water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness in vacuo to obtain o-isopropylaminobenzophenone as an oil. - 25 - 600-6218 b) Preparation of l-isopropyl-4-phenyl-quinazolln&2(lH)-thione To a solution of 11.3 S of ammonium isothiocyanate in 100 ml of acetone at room temperature is added dropwise 18.8 g of benzoyl chloride. The resulting suspension is refluxed for minutes, cooled and there is then added 30 g of o-isopropylaminobenzophenone. The resulting mixture is refluxed for 3 hours, cooled, evaporated _in vacuo , suspended in methylene chloride, insoluble material filtered off, and the filtrate evaporated followed by crystallization from ethyl acetate/ diethyl ether to obtain l-isopropyl-4-phenyl-quinazolin£-2(lH)-thione, m.p. 212-214°C.

EXAMPLE 12 : l-lsopropyl-7-methyl-4-phenyl-quinazolin--2(lH) -thione [Process a) (ii) ] To a solution of 3 ·5 g of ammonium isothiocyanate in 100 ml of acetone at room temperature is added dropwise 6.2 g of benzoyl-chloride. The resulting suspension is refluxed for minutes, cooled and there is thenadded 10 g of 4-methyl-2-isopropylaminobenzophenone (prepared as in Example 3a) ) . The resulting mixture is refluxed for 3 hours, cooled; evaporated _in vacuo , and the residue dissolved in 500 ml of tetrahydrofuran. To the resulting solution is added 50 ml of 2 NaOH followed by refluxing on a steam bath for 1 hour. The resulting mixture is evaporated to remove solvent and the mixture extracted with methylene chloride, the organic phase dried and evapor- recrystallised from ethanol/diethyl ether to obtain l-isopropyl-7-methyl-4-phenyl-quinazolin 2(lH)-thione, m.p. 18 -190°C. - 26 - 600-6218' EXAMPLE I?: [process a)(ii)] Following the procedure of Examples 11 or 12 and employing appropriate starting materials in appropriate proportions, the following compounds may> be obtained: l-ethyl-4-phenyl-quinazoline-2(lH)- thione, m.p. 232-235°C. 6-chloro-l-methyl-4-phenyl-quinazo- lin&2(lH)-thione, m.p. 228-230°C. l-isopropyl-6-methoxy- -phenyl- quinazolin£2(lH)-thione, m.p. l44-l 5°C. and l-allyl-4-phenyl-quinazolina.2(lH)- thione, m.p. l80°C.

EXAMPLE lb: l-isopropyl-7-methyl- - henyl-?, -dihydro-quinazoling- 2(lH)-thione [process c)] a) Preparation of K-isopropyl-3-methylaniline To a solution of 3· ^- gras. of isopropyl iodide and 2 gns. of triethylamine in 50 mis. n-propanol is added 1 gn. of m-toluidine in one portion. The reaction mixture is then refluxed for 18 hours. The reaction is cooled and any precipitate which separates is removed by filtration. The clear brown filtrate is evaporated at reduced pressure and the resultant oil is triturated with 50 "Is. of diethyl ether. Any solid which thus forms is removed by filtration and the filtrate is evaporated at reduced pressure. The treatment with diethyl ether is repeated as long as any solid separates. The oil obtained is subjected to column chromatograph and the fraction eluted with 75 mis. of E^Cl^ is collected and evaporated at reduced - 27 - . 600-6218 "\ b) Preparation of N-isopropyl-N- (ni-tolyl)-N' -benzoylthiourea To a solution of 10 gms. of ammonium thiocyanate in 100 mis. of acetone is added a solution of 9· 5 nis. of benzoyl chloride in 75 ials. of acetone. The mixture is stirred during this addition and for 3° minutes subsequently. Then a solution of 10 gras. of N-isopropyl- 3-methylaniline in 75 rols» of acetone is added dropwise, also with stirring. At the end of this addition the reaction mixture is refluxed for 3 hours, cooled, 200 mis. of methylene chloride are added, and the mixture filtered. The filter cake is washed with a further 100 mis. of and methylene chloride and the filtrates combined / evaporated under reduced pressure. The residue is recrystallized from isopropanol to obtain N-isopropyl-N-(m-tolyl)-N' -benzoylthiourea, m. . 112-113°C.

°) Preparation of N- sopropyl-^- (m-tolyl)thiourea To a solution of Κ$ mis. of dioxane in 200 mis. of water is added 27 gms. of sodium hydroxide and the mixture stirred until dissolution is complete. Then 15. ms. of N-isopropyl-N-(m-tolyl)-Ν·-benzoylthiourea is added and the resulting reaction mixture refluxed for h hours. The resulting mixture is cooled, acidified with concentrated hydrochloric acid, and made slightly basic with concentrated ammonium hydroxide. The resulting basic aqueous solution is filtered free of any solids and the solids are washed with 100 mis. of chloroform. The clear filtrate is extracted three times each with 200 mis. of chloroform and to these filtrates is added the chloroform used to wash the solids. The combined solution is dried, evaporated at reduced pressure, and the residue recrystallized from cyclohexane to obtain>N-isopropyl-N-(m-tolyl)thiourea, m.p. 126-127CC - 28 - 600-62lS^ d) Preparation of 1-isopropyl -7-methyl - -phenyl-3,U- dihydro-quinazoliuA2(lH)-thione To 25 mis. of a saturated solution of anhydrous hydrogen chloride gas in anhydrous benzene is added 1 gra. of N-isopropyl-N-(m-tolyl)thiourea. The resulting mixture is stirred and a solution of 2 gms. of benzaldehyde in 10 mis. of anhydrous benzene is added drop ise. The reaction mixture is then refluxed for 15 hours, cooled, ' and evaporated at reduced pressure to obtain a semi-solid which is triturated with 50 wis. of diethyl ether. The thus-formed solid is removed by filtration and the filtrate washed several times with 10$ aqueous solution of sodium bisulphite. The ethereal solution is then evaporated at reduced pressure to obtain l-isopropyl-7-methyl- -phenyl-3^-dihydro-quinazolii^2(lH)-thione as an aTiorphous powder which can be crystallized from diethyl ether/petroleum ether to again obtain the l-isopropyl-7-methyl- -phei^l-3,^-dihydro-q.uina-zolii^2(lH)-thionei n.p. 125-12 °C EXAMPLE 15: l-methyl-U-phenyl-quinazoline-2( 1H) -thione [Process a)iii)] 2.11 g of o-methylaminobenzophenone is dissolved in 2 mis ho of glacial acetic acid, and l« 5g of ammonium/thiocyanate are added to the resulting solution. The mixture is then warmed at 55° to 6o°c for 20 hours. Ice is added and the mixture is made neutral with 2N sodium hydroxide solution. The mixture is extracted with methylene chloride and the organic phase dried and evaporated in vacuo. The residue is crystallised from diethyl ether to obtain the heading compound m.p. 182° to l8k°C. - 29 - 600-6218 EXAMPLE ID: l-isopropyl-^-phenyl-7-methyl-quinazoline-2(lH)-thione [Process a)lii) ] .1 g of -methyl-2-isopropylaminobenzophenone [prepared as in Example 3 a) ] is dissolved in 50 mis of glacial acetic acid, and 3.0 g of ammonium /thiocyanate are added. The resulting mixture is warmed at 70° to 90°C for 2k hours. A further 3.0 g of ammonium •i¾.o thiocyanate is then added and the mixture is heated at 90° to 110°C for a further 2h hours. The mixture is poured on ice-water, and extracted with methylene chloride. The organic phase is evaporated to obtain a dark red oil which is then crystallised from methylene chloride/diethyl ether to obtain the heading compound m.p. 190° to 192°C .

EXAMPLE 17: l-methyl- -phenyl-6-chloro-quinazoline-2(IH) -thione [Process a) ii) ] g of l-methylamino-5-chlorobenzophenone are dissolved in 150 mis of glacial acetic acid, and l 2 of ammonium/ thiocyanate are added . The resulting mixture is stirred and refluxed for half an r o o hour and then heated at 60 to 70 C, with stirring, for a further 20 hours. The mixture is poured on ice and extracted with methylene chloride. The organic phase is evaporated and the resulting solid residue is crystallised from methylene chloride/diethyl ether to obtain orange crystals of the heading compound. The crystals are dissolved in methylene chloride and charcoal is added. The resulting mixture is filtered through a short column of silica gel employing ^00 mis of methylene chloride/2^ methanol (in 200 mis fractions) as eluent.

The resulting solid is crystallised from methylene chloride/diethyl ether ( 1 : 2) to obtain the heading compound m.p. 228° to 230°C. 29a - EXAMPLE 18; Following the procedure of Example 11 or 12, but using appropriate starting materials in approximately equivalent amounts, there is obtained 1-ethy1-6-trifluoro-methyl-4-phenyl-quinazoline-2 (IH) -thione which, when recrystallised from ethyl acetate/pentane, has a melting point of 158-168°C.

EXAMPLE 19; Following the procedure of Example 12, but using appropriate starting materials in approximately equivalent amounts and replacing the methylene chloride, used therein with a) ether on a steam bath, b) methanol, c) ether, or d) methanol there is obtained a) 1. isopropyl-7-methyl-4- (3 ' , 41 -dichlorophenyl) quinazolin-2 (1H) -thione, m.p. 201-206°C, b) l-isopropyl-7-methyl-4- ( 1 -fluorophenyl) -quinazolin-2 (1H) -thione, m.p. 229-.232°C c) l-isopropyl-7-methyl-4T (4 '-methylphenyl) - i! quinazolin-2 (1H) -thione, m.p. 228-232°C, or d) l-isopropyl-7-methyl-4-i(4 ' -methoxyphenyl) -quinazolin-2 (1H) -thione, m.p. 165-167°C, respectively.

Claims (1)

1. What we claim is:- 1. A process for the production of a compound of formula I, in which R signifies a hydrogen, fluorine, chlorine or bromine atom, an alkyl radical of 1 to 5 carbon atoms, an alkoxy or alkylthio radical of 1 to carbon atoms, or a nitro,trifluorcmethyl or di- (C3_ ) lk lamino group, n represents 1 or 2, with the proviso that when n is 2, the R substituents which may be the same or different signify a hydrogen, fluorine, chlorine or bromine atom, an alkyl radical of 1 to 5 carbon atoms or an alkoxy radical of 1 to carbon atoms, R^ signifies an alkyl radical of 1 to 5 carbon atoms, or an allyl or propargyl radical, R signifies a phenyl radical or a substituted phenyl radical of formula II, - 31 - 600-6218 in which Y signifies a fluorine, chlorine or bromine atom, an alkyl radical of 1 to 4 carbon atoms, or an alkoxy radical of 1 to carbon atoms, or a tri- fluorometh l group, and represents a hydrogen, fluorine, chlorine or bromine atom, an alkyl radical of 1 to 4 carbon atoms, or an alkoxy radical of 1 to 4 carbon atoms, characterised by a) producing a compound of formula la, in which R, Rg and n have the significance stated above, by reacting a.t elevated temperature a compound of formula III* in which R, R , R2 and n have the significance stated above, with phosphorous pentasulphide, in the presence of an organic solvent which is inert under the reaction conditions, or 32 - 600-6218 by cyclisin a compound of formula IV, in which R, ^, and n have the significance stated above, by subjecting it to the action of an acid chloride or bromide and an isothiocyanate of formula V, MN=C=5 V in which M signifies an alkali or alkaline earth metal cation or the ammonium cation, or to the action of the reaction product of an, acid chloride or bromide and an isothiocyanate of formula V stated above,or (iii) by reacting a compound of formula TV stated above with isothio-cyanic acid, or producing a compound of formula lb, in which R, R^, R2 and n have the significance stated above, by reacting a compound of formula VI, - - 600-6218:^ c) producing a compound of formula lb', In which R' signifies a hydrogen, fluorine, chlorine or bromine atom, an alkyl radical of 1 to 5 carbon atoms, or an alkoxy radical of 1 to k carbon atoms, R^ signifies an alkyl radical of 1 to 5 carbon atoms, an n' signifies 1 or 2, provided that when n' is 2, no more than one R' radical may signify a halogen atom or a branched chain substituent, and provided that R' is other than a branched chain substituent when in the 5- or 8"- position of the ring, and signifies a hydrogen, fluorine, chlorine or bromine atom, an alkyl radical of 1 to 3 carbon atoms . or an alkoxy radical of 1 to 2 carbon atoms, by reacting a compound of formula IX, R: C=S DC (R') n in which R', R' and n1 have the significance stated above. with a compound of formula X, 3fc - 600-6218 2. A process according to Claim 1, in which the reaction with phosphorous pentasulphide is effected at a temperature of from about 70° to I80°C employing pyridine as organic solvent. j5. A process according to Claim l,in which the acid chloride or bromide is benzoyl chloride. . A process according to Claim 1 or 3, in which the compound of formula IV is cyclised with the acid chloride or bromide and the compound of formula V or the reaction product thereof, at a temperature of from 10° to 8o°C in an organic solvent which is inert under the reaction conditions. 5. A process according to Claim l,in which the reaction of a compound of formula IV or formula VI with isothiocyanic acid is effected at a temperature of from 50°to 150°C. b. A process according to Claim 1 or 5 , in which the isothio-cyanic acid is formed in situ by effecting the reaction in acidic medium and employing a compound of formula V, stated in Claim l,in place of the isothiocyanic acid. 7. A process according to Claim 1 , or 6, in which the compound of formula V is ammonium isothiocyanate. 8. A process according to Claim l,in which the reaction of the compound of formula IX with the compound of formula X is effected at a temperature of from 0°to 120°C, under anhydrous conditions and in the presence of an acid catalyst. 9- A process according to Claim 8 , In which the acid catalyst is anhydrous hydrochloric acid. 10. A process for the production of a compound of formula I, stated in Claim 1, substantially as- herein described with reference' to any one of the Examples. - 35 11. A compound of formula I, stated in Claim 1» whenever produced by a process as claimed in any one preceding Claims, 12. A compound of formula I, stated in Claim 1. 13. l-isopropyl-4-phenyl-quinazoline-2(1H)-thione· 14. l-ethyl-4-phenyl*quina30line-2(1H)-thione. 15. l-isopropyl-7-methyl-4-phenyl-¾uinazollne-2(1H)-thione. 16. l-ailyl-4-phenyl—quinazoline-2(lH)-thione. 17. 1-ethyl-6-nitro-4-phenyl-quinazoiine-2(1H)-thione, 18. l-isopropyl-7-methylthio-4-phenyl^uinazoline-2(IB)-thione. 19. 6-chloro-l-methyl-4-phenyl-quinazoline«-2(IE)-thione. 20. l-isopropyl-6-methoxy-4-phenyl-quinaaoline- (1H)-thione. 21. l-methyl-4-phenyl-quinazoline-2(1H)-thione, 22. 3, -dihydro-l-iaopropyl-4^phenyl-quinazollne-2(1H)-thione. 23. 3,4-dihydro-l-methyl-4-phenyl-l*-quina2oline-2(1H)-thione. 24. 6-chloro-3t «dil^dro-l-methyl-4-phenyl-q ina2oline-2(OJtt)-thione. 2 . 3,4-dihydro-l-isopropyl-7-methyl-4-p enyl-qt^nazoline-2(1H)-thione. 26. 3,4-dihydro-l-isopropyl-7-methoxy-4-phenyl-quinazoline-2(1H)-thione. 27. pharmaceutical composition comprising a compound of formula I» stated in Claim 1, including, when appropriate, free base forms and physiologically acceptable acid addition salt forms, in association with a physiologically acceptable - 36 - 28; A pharmaceutical composition according to Claim 27 in unit d sage form in which the amount of the compound of foramla If stated in Claim 1, is from about 5 to 500 milligrams. 29. A pharmaceutical composition according to Claim 27* substantially as hereinbefore described. PCiSS