IE47977B1 - 6,7-di(loweralkoxy)-4-amino-2-(substituted piperidino)quinazolines - Google Patents

Description

The invention relates to therapeutic agents which are novel derivatives of 4-amino-2-piperidinoquinazoline. Such compounds are useful as regulators of the cardiovascular systsn and, in particular, in the treatment of hypertension.

The novel compounds according to the invention are those having the general formula: and X, which is attached to the 3- or 4- position of the piperidino group, is a group of the formula: Phenyl 12 I 1 2 -(CH_) CONR R , -O(CH.) CONR R or -OCHCONR R , n in — wherein n is 0, 1 or 2; and either R^ is hydrogen or lower alkyl, and R is lower alkyl·, ' phenyl (as hereinafter defined); C^-C^ cycloalkyl; or lower alkyl substituted by phenyl (as hereinafter defined), cycloalkyl, halogen, trifluoromethyl, hydroxy, lower alkoxy, lower alkenyl, lower alkynyl, lower alkoxycarbonyl, phenoxy (as hereinafter defined) or a group of the formula· 4 3 4 -NR R wherein R and R each independently represent hydrogen, lower alkyl, lower alkanoyl or lower alkylsulfonyl; - 3 2 with the proviso that any 0, N or halogen atom in R is separated by at least 2 carton atoms from the nitrogen 2 atom to which R is attached; 2 or R and R taken together with the nitrogen atom to which they are attached form a morpholino group optionally substituted by one or two lower alkyl groups, or a 1,2,3,4-tetrahydroisoquinolyl group optionally substituted on the benzene ring portion by one or two lower alkoxy groups; and the pharmaceutically acceptable acid addition salts thereof.

Xn this specification, halogen means fluorine, chlorine, bromine or iodine. The term lower applied to an alkyl, alkoxy, alkanoyl, alkenyl or alkynyl group indicates that such a group contains up to 6 carbon atoms, preferably up to 4 carbon atoms, and, where appropriate, such a group may be straight or branched chain.

By phenyl and phenoxy as used herein /including in-OCH (phenyDCONR^R2/ is meant a phenyl or phenoxy group optionally substituted by one or two substituents selected from lower alkyl, lower alkoxy and halogen.

Pharmaceutically acceptable acid addition salts are those formed from acids which form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as the hydrochloride, hydrobromide, sulphate or bisulphate, phosphate or acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, saccharate or jn-toluenesulfonate salts. 4797^ - 4 ίο The compounds of the invention containing one or more asymmetric centres will exist as one or more pairs of enantiomers, and such pairs or individual isomers may be separable by physical methods, e.g. by fractional crystallisation of suitable salts. The invention includes the separated pairs as well as mixtures thereof, as racemic mixtures or as separated d- and 1- optically active isomeric forms. , Phenyl I 12 '2 In one aspect X is other than -OCHCONR R , and R is other than lower alkyl substituted by lower alkenyl, lower alkynyl or lower alkoxycarbonyl.

Preferred compounds of the invention have the formula (I) wherein: R is methyl; X is attached to the 4- position of the piperidino group and is a group of the formula! 1 2 15 (a) -CONR R in which R is hydrogen, methyl or ethyl; and R is C -C, alkyl; phenyl (as hereinbefore defined); C-C, cycloalkyl; o J o or Cj to alkyl substituted by phenyl (as hereinbefore defined), C-C, cycloalkyl, hydroxy, C or C„ alkoxy, -CH=CH , -C=CH„, b 12 2(3 CH -C^CH, (C^ or C^ alkoxy)carbonyl, phenoxy (as 3 hereinbefore defined), -N(CH ) , -NHCOCH ,-NHSO CH or halogen; 2 3 2 3 with the proviso that any 0, N or halogen atom in R is separated 2 by at least 2 carbon atoms from the nitrogen atom to which R 1 2 is attached; or R and R taken together with the nitrogen atom to which they are attached form a morpholino group or a 1,2,3,4tetrahydro-isoquinolyl group optionally substituted on the benzene ring portion by one or two methoxy groups; - 5 2 2 (b) -CH.CONHR wherein R is C.-C, alkyl, benzyl, cyclopropylmethvl io or -CH CH=CH 2 2 2 (c) “CH2CH2CONHR wherein R is Cj-C& alkyl or benzyl; (d) -O(CH2) CONIKCj-Cg alkyl) wherein n is 0 or 1; or 2 (e) -OCHCONHR wherein R is C.-Cr alkyl, benzyl or cyclopropylraethyl. ό The «ost preferred compounds have the formula (I) in which each R is methyl and X is in the 4- position and represents a group of the formula: -CONHC.H, io -conh(ch2)3ch3 -CONHCH2. cyclopropyl -CONH.benzyl -conh.ch2ch=ch2 -CHjCONH(CHj)2CH3 or -CH2CONHCH2·cyclopropyl. - 6 The compounds of the invention may be prepared by a number of routes, including the following:20 (1) The compounds may be prepared by reacting a quinazoline of the formula: (II) - 7 wherein R is as defined for formula (I), 2 represents a facile leaving group such as chloro, bromo, iodo, lower alkoxy, (lower alkyl) thio or (lower alkyl)sulphonyl, with a piperidine of the formula: HN (III) wherein X is as defined for formula (I). is preferably chloro or bromo.

Typically the reaction is carried out in the presence of a tertiary organic amine base such as triethylamine or excess reagent of the formula (III), but this is not essential.

In a typical procedure, the reactants are heated together, e.g. under reflux, in an inert organic solvent, e.g. n-butanol, for periods of up to about 48 hours. The product can be isolated and purified by conventional procedures. Typically, the reaction mixture can be cooled, the solvent evaporated in vacuo, and the resulting solid shaken with e.g. chloroform and water. After filtration, the solid (or a salt thereof) can be recrystallised from a suitable solvent, e.g. ethanol, or may be purified by chromatography.

The intermediates of the formula (II) are in general known compounds or may be prepared by methods analogous to those of the prior art. - 8 The intermediates of the formula (III) are either known compounds or may be prepared by conventional methods; the following routes are for example possible:(CH,) COCI (a) '2'n hydrogenation.

CH,) CONR1!?2 ί η An acid bromide, activated ester or mixed anhydride could be used instead of the acid chloride; The starting 1-benzyloxycarbonylpiperidine-3- or 4-carboxylic acid chloride may be prepared similarly to the procedure of J. Org.

Chem., 31, 2957 (1966). (c) OH OCNHR Pd/H2 II OCNHR (d) CH2C6H5 CH2C6H5 1„2 C£> /Z = Cl, OCH, or OC2H5-/ O(CH2)nCONR R /n = 1 or 2/ - 10 ρΐ (f) The acid chlorides and esters may be prepared by conventional procedures from the corresponding free acids. The pyridine acids in which n is 1 are either known compounds or may be prepared by procedures analogous to those of the prior art; those in which n is 2 may also be prepared by conventional procedures, e.g. from the corresponding alcohols: CH2Ph 2 (2) The compounds of the formula (I) in which X is -(CHj) CONR R 2 wherein n is 0, 1 or 2, -O(CH-) CONR R wherein n is 1 or 2, or 2 n 1 2 -OCH(phenyl)CONR R , R and R in all cases being as defined for formula (I), may be prepared by reacting an amine of the formula: 2 R R NH with a compound of the formula: nh2 wherein n is as defined above in this method and R is as defined for formula (I), or with its functional equivalent as an acylating agent, e.g. an acid chloride or bromide, activated ester, mixed. anhydride or imidazolide of the compound of the formula' (IV). - 11 If the free acid form (IV) is used, the reaction should generally be carried out in the presence of a dehydrating agent such as dicyclohexyl carbodiimide.

The acid chlorides and bromides may be prepared by conven5 tional procedures, e.g. by reacting the free acid with, respectively, thionyl chloride or bromide.

The preferred activated esters are the succinimido and phthalimido esters, which again may be prepared by conventional procedures, e.g. by reacting the free acid with N-hydroxysuccinimide or N-hydroxyphthalimide in the presence of a dehydrating agent, e.g. dicyclohexylcarbodiimide.

Suitable mixed anhydrides have the formula: (CH ) CO.O.COiC,-Cr alkyl) z n lb O(CH_) CO.O.COiC.-t’ alkyl) or 2 n 16 — OCH(Phenyl)CO.0.CO(C-C- alkyl) • 1 6 — (V) NH2 wherein R and n are as defined above in this method. These may be prepared by conventional procedures, e.g. by reacting the free acid with the appropriate alkanoyl chloride (e.g. pivaloyl chloride) in the presence of a base such as triethylamine. - 12 The imidazol j'.les of the formula: Z=rN (VI) wherein R and n are as defined above in this method may be prepared by the conventional technique of reacting the free acid (IV) in a suitable solvent, e.g. dimethylformamide, with N,N‘-carbonyldiimidazole.

Xn a typical procedure, Ν, N'-carbonyldiimidazole can be added to a solution of the free acid (IV) in a suitable solvent, e.g. optionally dimethylformamide, in the presence of molecular sieves, at a temperature of 50 - 100°C. After stirring the solution for 2-4 hours at this 1 2 temperature, the amine of the formula R R NH is added and the solution maintained in this tsnperature range for up to about 10 hours. After cooling, the molecular sieves can be removed by filtration, and washed well with chloroform. The chloroform washings and the filtrate can then be combined, washed with water, dried, and evaporated in vacuo to leave the crude product, which can be purified by conventional procedures. (3) A compound in which R is hydroxy-substituted lower alkyl can also ba prepared by hydration of the corresponding compound in which R2 is lower alkenyl-substituted lower alkyl, using conventional methods for such hydration. 7977 “ 13 Λη acid addition salt may be prepared by taking the crude product up in the minimum quantity of a suitable solvent, e.g. chloroform, and treating this solution with a solution of the appropriate acid in a suitable solvent, e.g. ethereal hydrogen chloride. The resulting 5 precipitate of the acid addition salt may be filtered off, and if necessary, recrystallised from a suitable solvent, e.g. isopropanol/ methanol.

The free acids of the formula (IV) may be prepared by conventional procedures, e.g. by reacting the appropriate 4-amino~6,710 di-(lower alkoxy)-2-chloroquinazoline with the appropriate substituted piperidine by a procedure similar to that of route (1) above.

The antihypertensive activity of the compounds of the invention is shown by their ability to lower the blood pressure of conscious spontaneously hypertensive rats and conscious renally hyper15 tensive dogs, when administered orally at doses of up to 5 mg/kg.

The compounds of. the invention can be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavouring or colouring agents. They may be injected parenterally, for example, intramuscularly, intravenously or subcutaneously. 7977 ~ 14 For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other solutes, for example, enough salt or glucose to make the solution isotonic.

Thus the invention also provides a pharmaceutical composition 5 comprising a compound of the formula (I) or a pharmaceutically acceptable acid addition salt thereof, together with a pharmaceutically acceptable diluent or carrier.

The compounds of the invention can be administered to humans for the treatment of hypertension by either the oral or parenteral routes, typically in unit dosage form, and may be administered orally at dosage levels approximately within the range 0.5 to 50 mg/day for an average adult patient (70 kg), given in a single dose or up to 3 divided doses. Intravenous dosage levels would be expected to he about |th to Ιθ th of the daily oral dose. Thus for an average adult patient, individual oral doses in tablet or capsule form will be approximately in the range from 0. 25 to 25 mg of ths active compound. Variations will necessarily occur depending on the weight and condition of the subject being treated and the particular route of administration chosen as will be known to those skilled in the art. - 15 The following Examples, in which all temperatures are in c, illustrate the invention:47977 EXAMPLE 1 Preparation of 4-Amino-6,7-dimethoxy-2-/?- (N-n-butylcarbaraoyl) piper id ino/quinazoline hydrochlorid e 4-Amino-2-chloro-6,7-dimethoxyquinazoline (1.2 g), 4-(N-nbutylcarbamoyl) piperidine (1.01 g) and triethylamine (2.52 g) in nbutanol (105 ml, were heated under reflux for 24 hours. The mixture was then cooled, the solvent evaporated in vacuo, and the resultant solid shaken with chloroform and water. The solid product was collected by filtration, and recrystallised twice from ethanol to give 4-amino6, 7-dimethoxy-2-/4- (N-n-hutylcarbamnyUpiperidino/quinazoline hydrochloride (0.57 g), m.p. 263 - 264°.

Analysis t:Found: C, 56.8; H, 7.4; N, 16.5 Calculated for C20H29N5°3'Htl' C, 56.7; H, 7.1; N, 16.5. “ 17 “ EXAMPLES 2-18 The following quinazolines were prepared similarly to Example 1, starting from 4-amino-2-chloro-6,7-dimethoxyquinazoline and the appropriately substituted pijieridine, and were isolated in the form indicated. In Examples 9 and 16, the crude product was purified by chromatography. ’ ~ 7 9 7 7 ~ 22 7 9 7 7 479 7 7 - 24 EXAMPLE 19 Preparation of 4-Araino-6,7-diraethoxy-2-/4-(N-phenethylcarbamoyl) piperidino/quinazoline hydrochloride Ν,Ν-carbonyldiimidazole (2.0 g) was added to 4-amino-2(4-carboxypiperidino)-6,7-dimethoxy quinazoline (2.0 g) in dimethylformamide (100 ml) in the presence of 3A molecular sieves at 70°.

The solution was stirred at 70° for 2 hours, then 2-phenylethylamine (1.0 g) was added and the reaction maintained at 70° for a further 5 hours. The mixture was then allowed to stand at room temperature overnight, then stirred at 70° for 3 hours. After cooling, the molecular sieves were removed by filtration, and washed well with chloroform. The filtrate and the chloroform washings were combined and the resulting solution was washed with water, dried (NajSO^) and 15 evaporated in vacuo. The resulting residue was taken up in the minimum volume of chloroform, treated with ethereal hydrogen chloride, the solid product collected, washed with ether, and crystallised from isopropanol/methanol to give 4-amino-6,7-diroethoxy-2-/4-(N-phenethylcarbamoyl)piperidino/quinazoline hydrochloride (0.81 g), m.p. 284 285°. “ 25 ~ Analysis i: Found: C, 61.0; H, 6.5j N, 14.5 Calculated for ¢.,H-nN_O,.HCl: C, 61.1; H, 6.4; N, 14.8. b J EXAMPLES 20- 43 The following compounds were prepared similarly to Example 19, starting from the appropriate carboxy-containing quinazoline, Ν,Ν'-carbonyl-di-imidazole, and the appropriate amine of the formula 1 2 R R NH. In Examples 20 to 22, 25, 27 to 30: 3^. and 40-43. the crude product was purified by chromatography on silica eluting with a mixture of chloroform and methanol.

“ Analysis * (Theoretical in brackets) C Κ M 54.6 6.3 1 6.0 (54.9 6.4 16.0) L 47.5 6.4 16.5 (48.0 6.7 16.8) σ\ in J Φ Oi —< o- o- ο οκό ιΟ m in Form IsoLated and m.p. (°C) fl? Ό •rl M 00 O A O Ο n 2/\ 0 3 S Λη r-l 0 rT X JJ Oi u n( 0 Μ 1 Μ Ό Ό >iT >1 A Q A OI 2 T3 fl? Ό •HO Μ O) 0 V r-l Oi .G U ί 0 H oj Ό >4 oi Λ X 0 o u I O} ΠΊ EC υ a Oi 22 32 (J 32 Z o o 1 0 11 -CHCH CNHCH CH Example No. m oi OI in OI 97 7 σι ζ 4J c» χ u «0 'Q a Λ •Ρ X W rM S fi «-Μ D d ή C 4J < o s Λ H U CD 10 •e <3* w-t .-4 m in ID ID iD «π cn σ> in in 56.6 7.0 15.6 (56.7 7.0 15.7) 53.3 6.6 18.0 (53.0 6.8 17.7) § ϋ P o « r-l 0 V) Λ Π C k '0 0 c £u ιΰ o Ό O •η o in m 4J in 0 rt in r4 M χ: Ό ι U >i o £ <1 u τΐ in •ό s ™ >t c £5 Λ GJ '0 O •~i Q] Ch M U rr 0 -U ΓΜ H k Λ u J 0 >1 0 Λ Is Μ ·Η Λ Λ GJ 15 *0 ή s> r* Η -p m 0 f? CM rH M x rc> ι U >1 0 x: ID n -m ΙΛ Ό β N r*1 GJ X5 Λ X Q JN 1 2 O=«U CM X U 1 V CM 35 V X 2 0=0 CM 35 U t m 33 (J o=^ 2 m *~TM X U a 2 0-0 1 Φ r—( £o <3 Z & cr. CM O m M 7 9 7 7 7 9 7 7 CM O' eJ* f*> t£> a> *-T '7 W Ή •h/ >« as r-ι U <0 ·Μ C 4J < ω kl ο n vo vo co cn *M «—1 in in tn ej· Φ Φ Έϋ v 0 <3 O'-HO V · U Φ •H 4JO U flj TM 0 M rl Ό N Λ > ϋ rC f Ο H & £ o Ό ,£ CM Λ Φ «. Τ3 Φ •H 4JO H <0 CO Ο M tn r4 Ό CM Λ >1 ϋ fC / O H S /> Ό u in >,£ cm Λ 0) Ό Q> Ή 4J 0 H co 0 kt r-t T3 CM & >1 ϋ Λ I Ο ·Η MEN T3 Q> E* >ιΛ CM Λ 8« · isg 0=0 co M uc S5Z CM X 4s X ϋ X z o -u I ~ 33 - - 34 EXAMPLE 44 Preparation of 4-Amino-2-/4-(N-allylcarbamoyl)piperidino/-6, V-diniethoxyguinazoline hydrochloride 4-Amino- 2-/T-carboxypiperidino7-6,7-dimethoxy-quinazoline (2.3 g), dicyclohexylcarbodiimide (DCCD)(1.4 g) and N-hydroxysuccinimide (NHS) (0.8 g) were stirred together in dry dimethyl^formamide (DMF) for 2 hours at 60°. Allylamine (0.4 g) was then added to the resultant suspension and heating at 60° was continued for a further 6 hours. 5N Hydrochloric acid (00 ml) was then added to the cooled mixture, followed by the addition of chloroform (50 ml). The mixture was shaken and separated. The aqueous phase was basified to pH 12 with 5N sodium hydroxide solution and extracted with chloroform (2 x 50 ml). The chloroform extract was dried (MgSO^) and evaporated in vacuo to give a yellow gum (1.4 g) which was taken up in the minimum quantity of isopropanol and treated with dry hydrogen chloride gas to slight excess. Recrystallisation of the product from a mixture of ethyl acetate-methanol gave pure 4-amino-2-/4-(N-allylcarbamoyl)piperidino/ -6, 7-dimethoxy'quinazoline hydrochloride hemihydrate (0.6 g), m.p. 277°. - 35 Analysis %: Found: C, 54.9; H, 6.5; N, 16.9 C, „H_ ..N O,. HCl.511,0 requires: C, 54.6; H, 6.6; N, 16.6. ly 25 □ J Z EXAMPLES 45 TO 55 The following compounds were prepared similarly to the previous Example, starting from the appropriate carboxy-containing piper idinoquinaxol ine, N-hydroxysuccinimide, dicyclohexylcarbodiimide 1 2 and the appropriate amine of the formula R R NH.

Analysis *3 (Theoretical in brackets) C Η H m m io io \O © Ό Φ m r— m in in in sr cn ”3· -3· ( ·-< co m in io in tn m f*\ in m > -rH sr tn m cn m in m «β» «S’ «S' i m in* SG XJ 0 n> — = o · « cl £ yj Ό 0 c Lu nJ O Ό *· •H flfo k -P cn 0 nJ > H N x v υ >< ι 0 ~ Jj -Η ο Ό ε r> GJ CN C JZ (U jj eo 0) M •U ΌΟ (ti >1 CN »-L £ «□* (ti 0 CN X c 0 0 ε (D °o 4J - in (ti O cn H CN rti E 1 o*Ht-ro «S' Oi X Y CM E υ re 2 U^O 1 Ol <*) E re u. u X/ u CM a y g=O az in °N E U E 2 U=O 1 o r—( cu c 0 (0 2 a m •d· VO 0- -d· 7 9 7 7 47θ77 7 9 7 7 7 9 7 7 - 40 EXAMPLE 56 Preparation of 4-Anuno-6,7-dlmothoxy-'2-/4-(N~^? -mcthyl-2hyhoxypropyi^carbamoyl)piperidino7quinazoline hydrochloride monohydrate 4-Amino-6,7-dLncthoxy-i-24-(!'-^-aethyl2allylJearba.'Soyl) piperidino/quinazoline (2.0g) was dissolved in 5056 aqueous sulphuric acid (100ml) and the solution was allowed to stand at ambient temperature for 24 hours. The mixture was then cooled by ice-water and basified to pH 8.0 by the addition of concentrated (0.880 density) ammonia, after which it was evaporated to dryness. The residue was suspended in hot ethanol (200ml), filtered to remove inorganic salts and the filtrate concentrated in vacuo to give a white solid (l.6g). The solid was dissolved in methanol (10ml) and treated with a slight excess of ethereal hydrochloric acid. Becrystallisation of the resultant solid from ethylacetate/methanol gave 4-™ino-6,7 dimethoxy-2-24-(N^2 -methyl-2-hydroxypropyl ~ carbaaoyl)piperidino7quinazoline hydrochloride monohydrate (0.6g), m.p. 252 - 4°.

Analysis, Found: C,52.4;H,6.8;N,15.1 Calculated for C^H N5O4.HC1.H2O:C,52.5;H,7.O;N,15.5 EXAMPLE 57 Preparation of 4-Amino-2-/4- (N-n~butyl-carbamoylmethyl)piperidino/-6, 7-dimethoxyquinazoline hydrochloride 4-Amino-2-/4-carboxymethylpiperidino/-0, 7-dimethoxyquinazoline 5 (3.0 g), Ν, Ν' -dicyclohexylcarbodiimide (183 g) and N-hydroxj/succinimide (1.04 g) in dry DMF (50 ml) were stirred at 70° for 2 hours, llButylaraine (10 ml) was then added and the solution stirred at 50° for 4 hours. The cooled solution was filtered, the filtrate treated with hydrochloric acid solution (5N, 50 ml) and extracted with chloroform 10 (3 x 50 ml). The chloroform extract was dried (Na2SO^) and the solvent evaporated in vacuo to give an oil which was taken up in hydrochloric acid (10 ml, 2N) and shaken with ethyl acetate. The aqueous phase was separated, adjusted to pH 11 with sodium hydroxide solution and extracted with chloroform (3 x 20 ml). The chloroform extract was dried and the solvent evaporated in vacuo. The residue was treated with dioxan, filtered and the filtrate evaporated in vacuo. The product was chromatographed on silica (100 g) eluting with chloroform followed by chloroform/methanol (30:1). Fractions containing the product were combined, concentrated and the residue in chloroform converted to the hydrochloride salt by treatment with ethereal hydrogen chloride. Recrystallisation from methanol/dioxan gave 4-amino-2/4- (Ν-ιι-bu tylcarbamoylmethyl) piper id ino/-6,7-dimethoxyquinazoline hydrochloride hemihydrate, (0.25 g), m.p. 238 - 239°. 9 7 7 - 42 Ana 1 ysis %: Found: C, 56.5; H, 7.3; N, 15.4 Calculated for Cj Η^Ν^.ΗΟΙΛ^Ο: C, 56.4; H, 7.4; N, 15.7. .· _ u\ >.—y-a7 EXAMPLE 58 Preparation of 4-Amino-6,7-dimethoxy-2-/4-(N-/2,2-dimethylpropyl/ car baraoylmethyl) piper id ino/qu inazo1ine hydrochlor id e 4-Araino-2-/4-(cartoxymethylJpiperidino/-6,7-dimethoxyquinazoline (3.0 g), Ν,Ν'-dicyclohexylcarbodiimide (1.83 g) and N-hydroxysuccinimide (1.04 g) in dry DMF were stirred at 70° for 2¾ hours. Then 2,2-diroethylpropylamine (0.78 g) was added and the mixture stirred for 4 hours at 50°. The cooled solution was filtered and the filtrate concentrated in vacuo. The residue was taken up in chloroform (50 ml), extracted with sodium bicarbonate solution, the organic layer dried (Na2S04) and the solvent evaporated in vacuo.

The residue was chromatographed on silica (120 g) eluting with chloroform followed by chloroform/methanol 20:1. Fractions containing the product were combined, concentrated and the residue in chloroform converted to the hydrochloride salt by treatment with ethereal hydrogen chloride. Recrystallisation of the solid from methanol/ dioxan followed by metbanol/acetonitrile gave 4-aroino-6,7-dimethoxy -2-/4-(U-/2,2-dimethylpropyl^carbamoylmethylJpiperidino/quinazoline, hydrochloride hemihydrate (O.45g), m.p. 228 - 231°. - 43 Analysis 4;Found: C, 57.3; H, 7.8; N, 15.3 Calculated for Ο^Η,^Ν^.ΗΟίΛΗ^: C, 57.3; H, 7.7; N, 15.2.

EXAMPLE 59 Preparation of 4-Amino-6,7-dimethoxy-2-/4-(N-n-propylcarbamoyl) piperidino/quinazoline hydrochloride This was prepared similarly to the previous Example from 4-amino~2- (4-carboxypiperidino) -6,7-dimethoxyquinazoline and ny propylamine but without chromatographic purification. The hydrochloride hemihydrate was recrystallised from methanol/isopropanol followed by ethanol and had an m.p. of 263..- 264°.

Analysis 4:Found: C, 54.4; H, 6.6; N, 16.8 Calculated for CjgH^N^ .HCl.’sH.jO: C, 54.5; H, 7.0; N, 16.7. - 44 The following Preparations, in which all temperatures are given in °C, illustrate the preparation of certain of the starting materials used in the previous Examples:Preparation A Preparation of 4-(N-phenylcarbaaoyl)piperidine 4-(N-phenylcartamoyl)pyridine /75.0 g, prepared as in Chem.

Abs., 2013h (1958)/ was hydrogenated in acetic acid (800 ml) using a platinum oxide catalyst at 50 p.s.i./30°. The catalyst was then removed by filtration, the solution evaporated, the residue basified to about pH 12 with sodium hydroxide, extracted with chloroform, and the organic extract discarded. The aqueous phase was evaporated to dryness, the residue boiled with chloroform, filtered and evaporated to leave 4-(N-pbenylcarbamoyl)piperidine (17.0 g), m.p. 121 - 127°. The hydrochloride salt, m.p. 231 - 233°, was prepared in isopropanol from the free base and hydrogen chloride, and was-reerystallised from isopropanol/ethyl acetate.

Analysis %: Found: C, 60.1; H, 7.2; N, 11.7 Calculated for C,,Η.,N,O.HCl: 1Z lo 4 C, 59.9; H, 7.1; N, ll.S. - 45 Preparation Β Preparation of 4-(N-n-butylcarbarooyl) piperidine Isonicotinoyl chloride (100.0 g) was added over 1 hour to a solution of n-butylamine (52.6 g) in toluene (600 ml) at 0°. The mixture was allowed to stand overnight, heated on a steam bath for h hour, then water was added. The aqueous layer was separated, basified to about pH 12 (NaOH), and extracted with ethyl acetate (2 times). The combined organic extracts were dried (HgSO^), evaporated and the resulting residue (36.0 g) dissolved in acetic acid (400 ml) and hydrogenated at 50 p.s.i./30° in the presence of platinum oxide. The catalyst was removed by filtration, the solution evaporated to dryness, the residue basified to about pH 12 (Na^COj), and extracted with chloroform. The chloroform extracts were dried (NajSO^) ard evaporated to give 4-(N-ri-butylcarbamoyl)piperidine, (18.7 g), m.p. 75 - 79°. The oxalate salt was prepared in isopropanol from the free base and oxalic acid and was recrystallised from isopropanol/ ethyl acetate, m.p. 143 - 144°.

Analysis Found: C, 52.9? H, 8.0f N, 10.3 Calculated for ciqH20N2°'C2K2°4: C, 52.5? H, 8.1? N, 10.2. 97 7 _ 46 _ Preparation C Preparation of 4-(N-2,4-dichlorobenzylcarbamoyl)piperidine —> A solution of 1-benzyloxycarbonylj3iperidine-4-carboxylic acid chloride /4.6 g, prepared as in J. Org. Chem. 31, 2957 (1966)./ in chloroform (25 ml) was added dropwise to a cooled (ice/water) solution of 2,4-dichlorobenzylamine (3.87 g) and triethylamine (2.2 g) in chloroform (100 ml). After the addition was complete, the solution was left at room temperature for 1 hour, washed with water, dried (NajSO^) and evaporated. The resulting solid residue was crystallised from toluene/methanol to give 1-benzyloxycarbonyl4-(n-2,4-dichlorobenzylcarbamoyl)piperidine (7.04 g), m.p. 144 - 145°. Analysis %: Found: C, 60.0; H, 5.2; N, 6.8 Calculated for C21H22N2O3C12: C, 59.9; H, 5.3; N, 6.7.

A cooled (ice/water) and stirred solution of the above product (6.5 g) in acetic acid (25 ml) was slowly treated with a saturated solution of hydrogen bromide in acetic acid (25 ml). The reaction mixture was stirred at 20° for 1 hour when a precipitate formed. Dry ether (100 ml) was then added, the solid product collected, and washed with ether to give 4- (N-2,4-dichlorobenzylcarbamoyl)piperidine hydrobromide (3.4 g), m.p. 171 - 173°, with i.r. and n.m.r. spectra consistent with this structure.

The product was used in Example 5 without further purification. -47Preparation D Preparation of 4- W-2-methoxybenzylcarbamoyl)piperidine The above compound was prepared similarly to Preparation C starting from l-bcnz.yloxycarbonylpiperidine-4-carboxylic acid chloride and 2-methoxybenzylamine and had an m.p. of 139 - 140°.

Analysis Pound: C, 67.3; H, 8.1; N, 11.0 Calculated for c14H20N2°2: C, 67.7; H, 8.1; N, 11.3.

Preparation E Preparation of 4-(N-methyl-N-benzylcarbamoyllpiperidine This compound was prepared similarly to Preparation C starting from l-benzyloxycarbonylpiperidine-4-carbpxylic acid chloride and N-methylbenzylnmine, and was used directly in Example 10. This intermediate was characterised as the hydrochloride salt, m.p. 175 15 176°.

Analysis Found; C, 62.4; H, 7.7; N, 10.1 Calculated for Ο^Η^θΝ^Ο.ΗΟΙ: C, 62.6; H, 7.9; N, 10.4. -48Pr epar at ion F Preparation of 4- (1,2,3,4-Tetrahydroisoquinol-2-ylcarbonyl)piperidine This compound was prepared similarly to Preparation C, starting from l-benzyloxycarbonylpiperidine-4-carboxylic acid chloride and 1,2,3,4-tetrahydroisoquinoline, and was used directly in Example 13. This intermediate was characterised as the hydrochloride salt, m.p. 24 5 - 247°. Analysis Found: C, 63*6; H, 7.6; N, 9.9 10 Calculated fcr ci4H20N2°'**C1: c, 64.2; H, 7.6; N, 10.0. Preparation G Preparation of 4-/N-(2-methoxyethyl)carbamoyl/piperidine -Benzyloxycarbonyl -4 -/N- (2-methoxy”' ethyl) carbamoyl/ piperidine /5.76 g, m.p. 85 - 86°, Analysis Ϊ: C, 63.9; H, 7.5; N, 8.4; Calculated; C, 63.7; H, 7.6; N, 8.8; prepared similarly to Preparation C but using toluene in place of chloroform and starting from 1-benzyloxycarbonylpiperidine-4-carboxylic acid chloride and 2-methoxyethylamine/ in ethanol (75 ml) was hydrogenated over 5% palladium on charcoal at 50 p.s.i./50°. The catalyst was removed by filtration, and the filtrate evaporated to give 4-/5-(2methoxyethyl)carbamoyl/piperidine as an oil which solidified on standing. I.r. and n.m.r. spectra were consistent with this structure and the product was used in Example 7 without further purification. - 49 Preparation Η Preparation of 4-/N-(2-hydroxyethyl)carbamoyl/piperidine 1-Benzyloxycarbonyl-4-/N-(2-hydroxyethyl)carbamoyl/piperidine /6.24 g, m.p. 107 - 108°, Found: C, 62.8; H, 7.2; N, 9.0,- Calculated: C, 62.7; H, 7.2; N, 9.1; prepared similarly to Preparation C but starting from 1-benzyloxycarbonylpiperidine-4-carboxylic acid chloride and 2-hydroxycthylamine/ was hydrogenated as in Preparation G to give 4-/N-(2-hydroxyethyl)carbarooyl7piperidine. The i.r. and n.m.r. spectra were consistent with this structure and the product was used in Example 6 without further purification.

Preparation I Preparation of 4-/N-( -methylbenzyl)carbamoyl/piperidine 1- Benzyloxycarbonyl -4-/N-(o'. -methylbenzyl)carbamoyl/ piperidine [5.5 g, m.p. 136°, prepared as in Preparation C starting IS from l-benzyloxycarbonylpiperidine-4-carboxylic acid chloride and ci. -methylbenzylamine; Analysis %: Found: C, 72-2; H, 7.1; N, 7.5; Calculated for Co.H_.N,0,: C, 72.1; H, 7.2; N, 7.7? was hydroZZ Zo Z 3 genated as in Preparation G and the crude product was used in Example without further purification. , 4797J - 50 Preparation J Preparation of 4--Aroino-2- (4-carboxypiperidino)-6, 7-diroethoxyguinazoline roonohydrate The ahpve was prepared similarly to Example 1, starting from 4-amino-2-chloroT6, 7-dimethoxyquinazoline and 4-carboxypiperidine and had an m.p. of 2g5°.

Analysis %:Found: C, 54.9; H, 6.0; N, 16.1 Calculated for C, ,H,„N.O..H,O: C, 54.8,- H, 6.4; N, 16.0.

ZU 4 4 2 I (: Preparation K Preparation of 4-(N-Ethylcarbamoyloxy)piperidine 1-Benzyl-4-piperidinol (293.4 g), ethyl isocyanate (120 g) o and 1,2-dichlojjethane (1467 ml', were heated and stirred together under reflux for 7 hoijps. A further 10.9 g of ethyl isocyanate was then added and reflux was continued for another 6 hours. After cooling and standing fox 36 hours at room temperature, the reaction had not proceeded to completion and so a further 33 g of ethyl isocyanate was added and heatijjg under reflux continued for a further 6 hours. The mixture was coojpd, poured into water (2000 ml) and stirred for 1¾ hours, after w'hieh the organic layer was separated, washed with saturated sodium bicarbonate solution (2000 ml) and water (2000 ml). - 51 The combined aqueous phases were further extracted with o dicblo^ethane (150 ml) and the bulked organic phases were dried (MgSO^) and evaporated in vacuo to give a crude product which was stirred with boiling hexane, cooled, and filtered to give 1-benzyl5 4-(N-ethylcarbaraoyloxy)piperidine (354.4 g), m.p. 96 - 98°C.

This product (118 g) in industrial methylated spirit (826 ml) was hydrogenated at 50°/50 p.s.i. over 5% palladium on charcoal catalyst (12 g) until uptake of hydrogen ceased. The catalyst was then removed by filtration, the filtrate evaporated in vacuo, and the resulting residue was recrystallised from a mixture of hexane (450 ml) and ethyl acetate (112 ml) to give 4-(N-ethyljcarbamoyloxy)piperidine (208.1 g), m.p. 85 - 87°, used directly in Example 12.

Preparation L .

A. Preparation of 2-(l-benzylpiperidin-4-oxy)acetic acid, hydrochloride l-Benzyl-4-hydroxypiperidine (10 g) in dry DMF (50 ml) was added dropwise to a stirred suspension of sodium hydride (5 g, 50% dispersion in mineral oil) in dry DMF (50 ml) at 20° under an atmosphere of nitrogen. The suspension was stirred at 20° for 4 hours, then 2chloroacetic acid (4.95 g) in DMF (50 ml) was added slowly in two equal portions with a 2 hour interval between each. The resulting thick slurry was stirred at 20° for 24 hours. Isopropanol (75 ml) was added and the slurry was acidified to pH 6 with 2N hydrochloric acid then concentrated in vacuo. - 52 The aqueous residue was adjusted to pH 10 with sodium hydroxide solution and extracted with chloroform (3 x 100 ml) . The aqueous layer was separated, acidified to pH 3 with 2n hydrochloric acic and extracted with chloroform (3 x 100 ml). The organic extracts were again discarded and the aqueous phase was concentrated to half volume, filtered and the filtrate evaporated in vacuo to give 2-(1-benzylpiperidin-4-oxy)acetic acid, hydrochloride (3 g), characterised by n.m.r.

B. Preparation of N-n-butyl-2-(piperidin-4-oxy) acetamide, hydrochloride 2-(l-Benzylpiperidin-4-oxy)acetic acid, hydrochloride, (7.0 g) and thionyl chloride (5 ml) in dry chloroform (100 ml) were heated under reflux for 2½ hours. The solvent was evaporated in vacuo and the resulting acid chloride taken up in chloroform (50 ml) and added dropwise to a solution of n-butylamine (5 ml) in chloroform (50 ml) with 15 stirring at 0°. The solution was stirred at 0° for 4 hours then left at room temperature overnight. The chloroform solution was washed with water (3 x 50 ml), sodium hydroxide solution (3 x 50 ml, 2N) and hydrochloric acid solution (3 x 50 ml, 2n) . The aqueous acid solution was basified to pH 12 and extracted with chloroform (3 x 100 ml).

The chloroform extract was dried and the solvent evaporated in vacuo.

The residue in ether was treated with ethereal hydrogen chloride, the resulting solid collected, washed with ether and dried to give N-n-butyl -2-(l-benzylpiperidin-4-oxy)acetamide, hydrochloride (3.5 g) identified by n.m.r. spectroscopy. - 53 This product (3 g) in ethanol (100 ml) was hydrogenated over 5% palladium on charcoal (Engelhardt special debenzylation catalyst) at 50°/50 p.s.i. The catalyst was removed by filtration and the solvent evaporated in vacuo. The residue was triturated with ether and the white solid filtered off to give N-n-butyl-2-(piperidin-4-oxy) acetamide, hydrochloride, (1.7 g). A sample was recrystallised from isopropanol/diethyl ether then ethyl acetate and had an m.p. of 145 - 145°.

Analysis 4:10 Found: C, 52.3; H, 9.2; N, 10.9 Calculated for Cj H^N^.HCl: C, 52.7; H, 9.3; N, 11.2.

Preparation H preparation of N~ethyl-2-(piperidln-4-oxy)acetamide 2-(l-Benzylpiperidin-4-oxy)acetic acid, hydrochloride, prepared similarly to Preparation L Part A'Was converted to its methyl ester by refluxing in methanol plus concentrated hydrochloric acid. Methyl 2-(l-benzylpiperidin-4-oxy)acetate (10 g) and ethylamine (50 ml) with 3A molecular sieves were heated in a bomb at 120° for 6 hours.

The solvent was then evaporated in vacuo, the residue triturated with ether, filtered and the filtrate evaporated to give N-ethyl-2(l-benzylpiperidin-4-oxy)acetamide (7.7 g) as an oil. This product (7.0 g) in ethanol (150 ml) was hydrogenated over 5% palladium on charcoal (Engelhardt special debenzylation catalyst) at 50° and 50 p.s.i. - 54 The catalyst was removed by filtration, the filtrate evajjorated and the residue taken up in toluene and evaporated in vacuo to give N-etliyl-2- (piperidin-4-oxy)acetamide (4.8 g) as an oil. A sample in ether was converted to the hydrochloride salt by treatment with 5 ethereal hydrogen chloride followed by recrystallisation from methanol/ ether then isopropanol, m.p, 172 - 173°.

Analysis %:Found: C, 48.8; H, 8.8.; N, 12.4 Calculated for C.H, .N.0..HC1: C, 48.5; H, 8.6; N, 12.6. y 18 2 2 Preparation N Preparation of 3-(N-n-butylcarbamoyl)piperidine N-n-Butylnicotinamide (7.0 g) in acetic acid (100 ml) was hydrogenated over platinum oxide at 50° and 50 p.s.i. The catalyst was removed by filtration, the filtrate evaporated and the residue treated with toluene and evaporated in vacuo. The residue in chloroform (50 ml) was washed with sodium bicarbonate solution (3 x 50 ml) the organic layer separated, dried (Na^SO^) and the solvent evaporated in vacuo to give as an oil 3-(N-n-butylcarbamoyl)piperidine (3.8 g), A sample in chloroform was converted to the oxalate salt by treatment with oxalic acid in ether, the resulting semi—solid triturated with ether and ethyl acetate then reerystallised from isopropanol, m.p. 145 - 146°.

Analysis %:Found: C, 52.9; H, 8.4; N, 10.0 Calculated for ε10,ί2ϋΝ2Ο· C2H2°4: C' 52-5' H' 8’lf N' 10-2 - 55 Preparation Ο Preparation of 4-/N-(2,4-dimethoxybenzyl)carbamoyVpiperidine 1-Benzyloxycarbonyl-4-/N-2,4-dimethoxybenzylcarbamoyl7 piperidine was prepared similarly to Preparation C starting from 1e benzyloxycarbonylpiperidin^-4-carboxylic acid chloride and 2,4dimethoxybenzylamine. The product was identified by n.m.r. spectroscopy. This product (7.6 g) in ethanol (150 ml) was hydrogenated over 5% palladium on charcoal at 50°/50 p.s.i. The catalyst was removed by filtration and the filtrate evaporated in vacuo to give 4-/N-(2,4-dimethoxybenzyl)carbamoyl/piperidine (5.0 g) as a solid.

A sample in chloroform was·converted to the hydrochloride salt by treatment with ethereal hydrogen chloride and reerystallised frora isopropanol, m.p. 222 - 224°. Analysis Found: C, 57.4; H, 7.5; N, 8.9 Calculated forC15H22N2°3'HC1: C, 57.2j H, 7.4; N, 8.9 Preparation P Preparation of 4-amino-2-(4-carb0xymethylplperidino)-6,7-dimethoxyquinazoline hydrochloride 4-Aroino-2-chloro-6,7-dimethoxyquinazoline (17.3 g), piperidine -4-acetic acid hydrochloride (12.0 g) and triethylamine (20 ml) in ny butanol (500 ml) were stirred under reflux for 20 hours. - 56 The mixture was then cooled to 0 - 4° and the separated product collected. The solid was slurried with acetone (100 ml), filtered, slurried with chloroform (100 ml), filtered and washed with ether to give 4-amino-2- (4-carboxyraethylpiperidino) -6, 7-dimethoxyquinazoline hydrochloride (19.0 g). A sample was recrystallised from acetic acid and had an m.p . of 250 - 252°. Analysis Found: C, 53.1,- H, 6.4; N, 14.2 Calculated forC17H22N4 O4.HC1: C, 53.3-, H, 6.1; N, 14.6.

Preparation Q Preparation of 4-Amino-2-/4-(2-carboxyethyl) piperidino/-6,7-dimethoxy15 quinazoline hydrochloride 4-Amino-2-chloro-6,7-dimethoxyquinazoline (24.9 g) and 3-(4-piperidinyl)propionic acid, hydrochloride (20 g) in ii-butanol (1000 ml) were stirred under reflux for 20 hours. The hot suspension was filtered and the insoluble material discarded. The filtrate was cooled in ice/water, the precipitated solid collected and the filtrate evaporated in vacuo. The resulting solid and the precipitated solid were combined and crystallised from isopropanol to give 4-amino-2/4-(2-^n-butoxycarbonyl^ethyl)piperidino/-6,7-dimethoxyquinazoline, hydrochloride (27.0 g) with m.p. 250 - 252°.

Analysis Found: C, 58.0; H, 7.3; M, 12.5 Calculated for CHNO.HC1: 32 4 4 C, 58.3; H, 7.3; N, 12.4. - 57 This n-butyl ester (20 g) in methanol (50 ml) «nd sodium hydroxide solution (50 ml, 5N) was hasted under reflux for 4 hours.

The organic solvent was evaporated and the aqueous residue acidified with 2N hydrochloric acid, and cooled. The precipitated solid was collected, dried, slurried with ether and filtered to give 4-amlno2-/4-(2-carboxyethyl)piperidino/-6,7-dimethoxyquinazoline, hydrochloride (17.9 g), A sample was recrystallised from water followed by DMF ~ud had an m.p. of 238 - 241°.

AnaxysiS Found: C, 54.2; H, 6.3; N, 14.3 Calculated for θΗ^Ν^. HCl: C, 54.5; H, 6.4,- N, 14.1 Preparation R A. Preparation of ethyl 2.-(l-Acetyl-piperidin-4-oxy)phenylacetate N-Acetyl-4-hydroxypiperidine (27.5 g) in dry DMF (100 ml) was added slowly to a stirred suspension of sodium hydride (25 g, 50% dispersion in mineral oil) in DMF (150 ml) and dimethoxyethane (10 ml). The suspension was stirred at room temperature for 3 hours. 2,-Bromophenylacetic acid (45 g) in DMF (250 ml) was then added slowly with ice/water cooling. The mixture was stirred at room 20 temperature for 20 hours, then isopropanol added and the solvent evaporated in vacuo. The residue was taken up in water, acidified to pH 1 with 2N hydrochloric acid and extracted four times with chloroform (300 ml!. 977 - 58 The combined chloroform extracts were washed with water and brine, dried (MgSO^) and the solvent evaporated in vacuo. The residue in anhydrous ethanol (450 ml) with concentrated sulphuric acid (9 ml) was heated under reflux for 8 hours. The cooled solution was cautiously neutralised with aqueous sodium carbonate solution and the organic solvent evaporated in vacuo. The aqueous residue was adjusted to pH 10 with sodium carbonate solution and extracted twice with chloroform. The combined chloroform extracts were dried (MgSO^), and evaporates in vacuo. Distillation of the residue gave ethyl 2- (1 -acetyl-piperidin-4-oxy)phenylacetate (37.2 g), b.p. 190 - 194° /0.18 mra.

Analysis %:Found: C, 65.4; H, 7.8; N, 4.5 Calculated for C^H Ν(γ C, 66.9; H, 7.6; N, 4.6.

B. Preparation of 2. -/piperidin-4-oxy7phenylacetic acid, hydrochlorid Ethyl 2.-/1-acetylpiperidin-4-oxy/phenylacetate (10.0 g) in methanol (50 ml) and sodium hydroxide solution (30 ml, 5N) was heated under reflux for 5 hours. The organic solvent was evaporated in vacuo and the aqueous residue was acidified to pH 2 with hydrochloric acid solution and filtered. The filtrate was evaporated in vacuo, treated with toluene and evaporated in vacuo. The residue was treated with isopropanol (50 ml), filtered and the solid washed with isopropanol. The filtrate and washings were combined and the solvent evaporated in vacuo. - 59 The residue was triturated with acetone, the white solid collected and crystallised from isopropanol to give 3,r- (piperidin-4-oxy) plienylacetjc acid, hydrochloride, m.p. 180 - 182° (5.05 g).

Analysis %:5 Found: C, 57.4} H, 6.8; N, 5.5 Calculated for Cj3Hj7N0^.HC1: C, 57.5; H, 6.7; N, 5.2.

C. Preparation of 4-amino-2-/4- (1-carboxy-l-phenyl-methoxy) piperidino/-6,7 -d im ethoxyguinazoline 4-Amino-2-chloro-6,7-dimethoxyquinazoline (4.8 g), 2phenylacetie acid hydrochloride (4.9s) (piperidin-4-oxy7 and triethylamine (5 ml) in in-butanol (100 ml) were heated under reflux for 20 hours. The mixture was cooled, and the precipitated solid was collected and washed with ether. A sample of this solid (0.7 g) was recrystallised from acetic acid, and the resulting solid washed with ether to give 4-amino-2-/4-(1-carboxy15 1-phenyl-methoxy)piperidino/-6,7-dimethoxyquinazoline, acetate (0.56 g) m.p. 271 - 274°.

Analysis Found: c, 60.0; H, 6.0; N, 11.3 Calculated for C, 60.2; H, 6.1; N, 11.2 20 The remaining product was slurried . with hot isopropanol, filtered and the solid washed with isopropanol and ether to give 4amino-2-/4-(l-carboxy-l-phenyl-methoxy)piperidino/-6,7-dimethoxy quinazoline (6.46 g). - 60 Preparation Ξ Preparation of Mono-N-(methanesulphonyl)ethylene diamine Methanesulphonyl chloride (16.8 g) in dry chloroform (25 ml) was added dropwise to a stirred solution of mono-N-acetyl5 ethylene diamine (15 g) and triethylamine (15 ml) in dry chloroform (25 ml) at 0°. The solution was stirred at ambient temperature for 60 hours. The reaction mixture was then extracted with water (3 x ml) and the combined aqueous fractions were shaken with chloroform and separated. The aqueous fraction was evaporated in vacuo and the residue in methanol (100 ml) and concentrated hydrochloric acid (50 ml) was heated under reflux for 12 hours. The solvent was then evaporated in vacuo and the residue treated with methanol at reflux.

The insoluble solid was filtered off and discarded. The filtrate was evaporated in vacuo and the residue treated with chloroform at reflux. The solvent was decanted leaving N-monomethanesulphonylethylene diamine, hydrochloride as a semi-solid also containing triethylamine hydrochloride. The product was used in the preparation of the product of Example 36 without further purification. - 61 /It should be noted that 4-amino-2-chloro-6,7-dimethoxyquinazoline and the substituted piperidine intermediates used in Examples 3, 8 and 9 are known compounds; also, the preparation of the piperidine intermediate used in Example 14 is described in Preparation 21 of our co-pending British Patent Application No. 26202/78. Similarly the amines used in Example 19 onwards (apart from the amine used in Example 36, whose preparation is described above) are known compounds/.

Claims (6)

CLAIMS:

1. Compounds having the general formula: nh 2 wherein R is lower alkyl; Xj which is attached to the 3- or 4- position of the piperidino group, is a group of the formula: Phenyl -(CH.) CONrY 2 , ~O(CH ) CONr’r 2 or -OCHCONR^R 2 , 2. n 2 n wherein n is Ο, 1 or 2; and either R^ is hydrogen or lower alkyl, and 2 R is lower alkyl; phenyl (as hereinbeforedefined); C^-C^ cycloalkyl; or lower alkyl substituted by phenyl (as hereinbeforedefined), C^-C^ cycloalkyl, halogen, trifluoromethyl, hydroxy, lower alkoxy, lower alkenyl, lower alkynyl, lower alkoxycarbonyl, phenoxy (as hereinbefore 3 4 3 defined) or a group of the formula -NR R wherein R and 4 R each independently represent hydrogen, lower alkyl, lower alkanoyl or lower aikylsulfonyl; with the proviso that 2 any 0, N or halogen atom in R is separated by at least 2 2 carbon atoms from the nitrogen atom to which R is attached; - 63 1 2 or, R and R taken together with the nitrogen atom to which a they are attached formymorpholino group optionally substituted by one or two lower alkyl groups, or a l,2,3i4-tetrahydroisoquinolyl group optionally substituted on the benzene ring portion by one or two lower alkoxy groups; and the pharmaceutically acceptable acid addition salts thereof.

2. A compound as claimed in claim 1 wherein each R is methyl; X is attached to the 4- position of the piperidino group and is a group of the formula; 12 1 2 (a) -CONR R in which R is hydrogen, methyl or ethyl; and R is C -C, alkyl; phenyl (as hereinbefore defined); C.-C, cycloalkyl; lb 3 o or to alkyl substituted by phenyl (as hereinbefore defined), Cj-Cg cycloalkyl, hydroxy, or alkoxy, -CH=CHg, -^=CHg, -C5CH, (C or C 2 alkoxy)carbonyl, phenoxy (as hereinbefore defined), -N(CH ) , -NHCOCH , -NHSO CH or halogen; with the proviso that any 3 2 3 2 3 0, N or halogen atom in R is separated by at least 2 carbon atoms from 2 12 the nitrogen atom to which R is attached; or R and R taken together with the nitrogen atom to which they are attached form a morpholino group or a 1,2,3,4-tetrahydroisoquinolyl group optionally substituted on the benzene ring portion by one or two methoxy groups; 2 2 (b) -CHgCONHR wherein R is C^-Cg alkyl, benzyl, cyclopropylmethyl or -CH CH=CH ; 2 2 (c) (d) (e) -CHgCHgCONHR 2 wherein R 2 is C^-Cg alkyl or benzyl; -O(CH ) CONlKC -C, alkyl) wherein n is 0 or 1; or 2 n lb — 2 2 -OCHCONHR wherein R is C^-Cg alkyl, benzyl or cyclopropylmethyl. (PCL. 275) 47S77

3. A compound as claimed in claim 2 wherein X is: -CONHC 2 H 5 -CONH(CH 2 > 3 CH 3 -CONHCH 2 . cyclopropyl -CONH.benzyl -conhch 2 ch=ch 2 -ch 2 conh(ch 2 ) 2 ch 3 or -CH 2 CONHCH 2 .cyclopropyl.

4. A compound as claimed in claim 1 wherein X is other than Phenyl J 1 2 ? -OCHCONR R , and R is other than lower alkyl substituted by lower alkenyl, lower alkynyl or lower alkoxycarbonyl. S' A process for preparing a compound of the formula (I) as 15 defined in claim 1 which comprises reacting a quinazoline of the formula: wherein R is as defined in claim 1 and 2 is a facile leaving group, with a piperidine of the formula: wherein X is as defined in claim 1. (PLC. 275) 6. A process for preparing a compound of t.he formula (I) ac· defined in claim 1 in which X is -(CH^nCON'R^l’/ wherein n is 0, 12 12 1 or 2, -0(CH2) n C0NR R wherein n is 1 or 2 or -OCH(phenyl)CONR S , 1 2 R and R in all cases being as defined in claim 1, which comprises 1 2

5. Reacting an amine of the formula: R R NH with a compound of the formula: (CH.) COOH χ n 0 (CH) COOH or 2 n — OCH(phenyl)COOH (IV) wherein n is as defined above in this method, and R is as defined in claim 1, or with its functional equivalent as an acylating agent. 10 7. A process as claimed in claim θ wherein said functional equivalent as an acylating agent is an acid chloride or bromide, activated ester, mixed anhydride or imidazolide of the compound of the formula (IV). g. A process as claimed in claim 5 or 6 substantially as 15 hereinbefore described in any one of the Examples. g. A compound of the formula (I) as claimed in claim 1 or a pharmaceutically acceptable acid addition salt thereof which lias been prepared by a process as claimed in any one of the claims 5 to 8.

6. 10. A pharmaceutical composition comprising a compound of the 20 formula (I) as claimed in any one of claims 1 to 4 and 9 , or a pharmaceutically acceptable acid addition salt thereof, together with a pharmaceutically acceptable diluent or carrier.