AP248A - Azole derivatives. - Google Patents

Abstract

The invention concerns novel, pharmaceutically useful compounds of formula i in which q is a 5 membered heteroaryl optionally bearing 1 or 2 substituents independently selected from (1-4c)alkyl and halogeno.

Description

AZOLE DERIVATIVES

This invention concerns novel azole derivatives and, more particularly, certain 2-heteroaryl-triazolo(1,5-a]{1,3,5]triazines and pyrazolo(2,3-a](1,3,5-1 triazines which have useful pharmacological properties (and in particular antagonise the actions of adenosine such as vasodilation). The invention also includes pharmaceutical compositions containing the novel azole derivatives for use in treating certain diseases and disorders affecting mammalian cardiac, peripheral and/or cerebral vascular systems. Also included are processes for the manufacture and formulation of the novel azole derivatives.

The compound theophylline (1,3-dimethylxanthine) has been used clinically (usually as its ethylene diamine salt, which is also . known as aminophylline) as a respiratory stimulant, a centrally acting stimulant, a bronchodilator, a cardiac stimulant and as a diuretic. This diversity of clinical uses is an indication of the range of pharmacological actions which have been attributed to theophylline. These include phosphodiesterase inhibition, adenosine receptor antagonism, mobilisation of intracellular calcium and the release of catecholamines. Recently theophylline has also been reported to be useful in treating myocardial ischaemia (Maseri et al., The Lancet, 1989, 683-686), skeletal muscle ischaemia ( Picano et al., Angiology, 1989, in press) and cerebral ischaemia (Skinhoj et al., Acta. Neurol. Scand., 1970, 46, 129-140). The beneficial effects of theophylline in these ischaemic disorders are believed to be due to a reduction or prevention of the phenomenon known as vascular steal by virtue of the compound's ability to antagonise the actions of adenosine by blocking the adenosine receptors which mediate metabolism-linked vasodilatation.

The vascular steal phenomenon can occur when the major artery supplying a particular vascular bed is partially or totally occluded resulting in ischaemia. In this situation, the compromised vascular bed dilates and blood flov is maintained by either an increase in flow across the narrowed vessel or by an increase in flow through the collateral vessels. However, increased metabolic activity

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- 2 in adjacent vascular beds results in release of mediators such as adenosine, causing them to dilate, resulting in the limited blood flow to the compromised vascular bed being stolen by these adjacent areas. The loss of blood from compromised to normally perfused vascular beds by the phenomenon of vascular steal further diminishes the blood flow in the compromised vascular bed.

The diversity of pharmacological properties possessed by theophylline make it difficult to use in the regular treatment or prevention of occlusive diseases and conditions of the vasculature. Thus, its associated action as a phosphodiesterase inhibitor results in cardiac stimulation which is deleterious for patients with myocardial ischaemia. Furthermore, the relatively low potency of theophylline means that dose-levels which are therapeutically useful are close to those which can cause serious central side-effects.

Certain 2-heteroaryl-pyrazolo[2,3-a][1,3,5]triazines are known from V. Ried and S. Aboul-Fetouh, Tetrahedron, 44(23),

7155-7162, 1988. In addition, European patent application publication no. EP A2 383589, published on 22nd August, 1990, names certain other 2-heteroaryl-pyrazolol2,3-a|(l,3,5]triazines, although no details of their preparation are given. No therapeutic use is ascribed to any of these compounds.

Several triazolo(l,5-a][l,3,5]triazines and pyrazolo[2,3-a][1,3,5]triazines, which do not have a 2-heteroaryl substituent, have been ascribed therapeutic uses. Thus, certain triazolo[l,5-a][l,3,5]triazines have been disclosed as bronchodilators (see United States patent no. 4734413). Certain pyrazolo[2,3-a][l,3,5]triazines have been variously disclosed as inhibitors of gastric acid secretion (see British patent application publication no. 2134107 and European patent application publication no. EP A2 0172608); as antiinflammatory agents (see European patent applications publication nos. EP A2 0172608 and EP A2 207651); as bronchodilators (see British patent application publication no. GB 2016002, Belgian patent no. 815405 and United States patent no. 3995039), and as phosphodiesterase inhibitors (see United States patent no. 3846423).

Ve have now discovered (and this is a basis for our invention) that a group of novel 2-heteroaryl-triazolo[l,5-a][l,3,5JBAD ORIGINAL $

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- 3 triazines and pyrazoloj2,3-aJ11,3,5Jtriazines of formula I defined belov are effective antagonists of the actions of adenosine and in particular of its vasodilatory actions.

According to the invention there is provided a compound of the formula I set out hereinafter (together with the other formulae appearing in Roman numerals)vherein:

Q is a 5-membered heteroaryl optionally bearing 1 or 2 substituents independently selected from (l-4C)alkyl and halogeno;

is hydrogen, (l-6C)alkyl, or (l-4C)alkanoyl;

r2 is hydrogen, (3-12C)cycloalkyl, (3-6C)alkenyl, phenyl(3-6C)alkenyl, tetrafluorophenyl, pentafluorophenyl, 5- or 6-membered heteroaryl, optionally substituted (l-6C)alkyl or optionally substituted phenyl, said optionally substituted alkyl being unsubstituted or substituted by one of (3-6C)cycloalkyl, optionally substituted 5- or 6-membered heteroaryl, optionally substituted phenyl and a group of formula R¹⁰(C0)_nXb(C0)_nj in which R¹⁰ is (l-6C)alkyl, (3-6C)cydoalkyl, optionally substituted phenyl or optionally substituted phenyl(l-4C)alkyl, n+m is 0 or 1, provided that when m is 0, X and Xb are separated by at least two carbon atoms, Xb is oxy, thio, sulphinyl, sulphonyl or an imino group of formula -NRb in which Rb is hydrogen, (l-6C)alkyl or together with R^ and the adjacent nitrogen atom forms a 4 to 6-membered saturated heterocyclic ring, said optionally substituted 5- or 6-membered heteroaryl being unsubstituted or substituted by 1 or 2 of (l-4C)alkyl, (l-4C)alkoxy and halogeno, and any of said optionally substituted phenyl being unsubstituted or substituted by (l-4C)alkylenedioxy or by 1,2 or 3 of halogeno, cyano, trifluoromethyl, (l-4C)alkoxycarbonyl, hydroxy, (l-4C)alkanoyloxy, benzyloxy, halogenobenzyloxy, nitro, and (l-4C)alkyl or alkoxy optionally bearing a group of formula R^CO in which is

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- 4 (1-4C)alkoxy, (3-6C)alkylamino, (3-6C)cycloalkylamino or

JN-(l-4C)alkylJ |N-(l-4C)dialkylamino(l-4C)alkyl]amino, and sulphamoyl ~3 4 3 4 of formula -SO».NR R in which R and R are independently hydrogen or A (l-4C)alkyl, or R^J is hydrogen and K is [(2-5C)alkoxycarbony1Jmethyl, carbamoylmethyl or (N-(l-4C)alkylcarbamoylJmethyl; and *

X is oxy, thio, sulphinyl, sulphonyl or an imino group of formula -NRa- in which Ra is hydrogen, (l-6C)alkyl or together with Rj and the adjacent nitrogen atom forms a 4 to 6-membered saturated heterocyclic ring; and

A is N or CT in which T is hydrogen or (l-4C)alkyl;

or a pharmaceutically acceptable salt thereof.

One group of compounds of general formula I consists of those wherein Q is a 5-membered heteroaryl (e.g. furyl or thienyl) optionally bearing 1 or 2 substituents independently selected from (l-4C)alkyl and halogeno; X is oxy, thio or an imino group of the formula -NRa- in which Ra is hydrogen or (l-6C)alkyl; R^ is hydrogen, (l-6C)alkyl or (l-4C)alkanoyl; and is:

(a) phenyl, pyridyl, isoxazolyl, thiadiazolyl, tetrafluorophenyl, pentafluorophenyl, or phenyl bearing 1, 2 or 3 substituents independently selected from (l-4C)alkyl, (l-4C)alkoxy, halogeno, cyano, trifluoromethyl, nitro, benzyloxy, halogenobenzyloxy, hydroxy, and a sulphamoyl group of the formula -SO.. nr³r⁴ in which R^ and R* ^Z 3 4 are independently hydrogen or (l-4C)alkyl, or R is hydrogen and R is ((2-5C)alkoxycarbonyllmethyl, carbamoylmethyl or JN-(l-4C)alkylcarbamoylJmethyl;

(b) (l-6C)alkyl, (3-12C)cycloalkyl, (3-6C)cycloalkyl(l-4C)alkyl, furyl, thienyl, phenyl(l-4C)alkyl, furyl(l-4C)alkyl, thienyl(l-4C)alkyl, a furyl, thienyl or phenyl moiety of which may itself optionally bear 1 or 2 substituents independently selected from (l-4C)alkyl, (l-4C)alkoxy and halogeno; or (c) a group of the formula R^.Xa.CH^.CHj- in which R$ is (l-6C)alkyl or phenyl which latter may optionally bear 1 or 2 substituents independently selected from (l-4C)alkyl, (l-4C)alkoxy and halogeno, and Xa is oxy, thio, sulphinyl, sulphonyl, imino or N-(l-6C)alkylBAD ORIGINAL

AP 000248

- 5 imino, or in which the group R^.Za- is morpholino, thiomorpholino, pyrrolidino, piperidino or azetidino; and A is N or CT in which T is hydrogen or (l-AC)alkyl; or a pharmaceutically acceptable salt thereof.

It will be appreciated that depending on the nature of the substituents, in containing one or more chiral centres, the formula I compounds may exist in and be isolated in one or more different enantiomeric or racemic forms (or a mixture thereof). It is to be understood that the invention includes any of such forms vhich possesses the property of antagonising the actions of adenosine, it being well known how to prepare individual enantiomeric forms, for example, by synthesis from appropriate chiral starting materials or by resolution of a racemic form. Similarly, the adenosine antagonist properties of a particular form may be readily evaluated, for example by use of one or more of the standard in vitro or in vivo screening tests detailed hereinbelow.

A particular value for Q when it is a 5-membered heteroaryl is, for example, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl or isothiazolyl, which heteroaryl moieties may optionally bear 1 or 2 substituents independently selected from methyl, ethyl, fluoro, chloro and bromo. An example of a particularly preferred value for Q is furyl, optionally substituted as defined above. The 2-furyl group is preferred.

A particular value for R^ when it is alkyl is, for example, methyl, ethyl, propyl or butyl, and when it is alkanoyl is, for example, formyl, acetyl or propionyl, of which formyl is preferred. Another preferred value for alkanoyl is acetyl. An example of a particularly preferred value for R^ is hydrogen.

A particular value for T when it is alkyl is, for example, methyl, ethyl or propyl.

An example of a particularly preferred value for T is hydrogen.

A particular value for R when it is alkyl is, for example, methyl, ethyl, isopropyl, propyl, butyl or sec-butyl. Another particular value is n-pentyl.

A particular value for Ra vhen it is alkyl is, for example,

ο ο ι) q a

- 6 methyl or ethyl.

Particular values for optional substituents vhich may be 2 5 present when R or R is phenyl (or on a phenyl, furyl or thienyl moiety attached to alkyl) include, for example:

for alkyl: methyl or ethyl; * for alkoxy: methoxy or ethoxy; and for halogeno: fluoro, chloro or bromo.

A particular value for a halogenobenzyloxy substituent vhich 2 may be present on R when it is phenyl is, for example,

4-fluorobenzyloxy or 4-chlorobenzyloxy.

A particular value for R vhen it is alkenyl is allyl.

A particular value for R vhen it is phenylalkenyl is

3-phenyl-2-trans-propenyl.

Particular values for R vhen it is 5- or 6-membered heteroaryl include, for example, pyridyl, isoxazolyl or thiadiazolyl.

4

A particular value for R or R vhen it is alkyl is, for example, methyl or ethyl.

A particular value for R vhen it is (alkoxycarbonyl)methyl is, for example, (methoxycarbonyl)methyl or (ethoxycarbonyl)methyl, and vhen it is (N-alkylcarbamoyl)methyl is, for example, (N-methyl- or N-e thylcarbamoyl)me thy1.

A particular value for R vhen it is cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or norbornyl, and vhen it is cycloalkylalkyl is, for example, one of the latter cycloalkyl moieties attached to methyl, ethyl (at position 1 or thereof) or propyl (at position 1, 2 or 3 thereof).

A particular value for R vhen it is phenylalkyl, furylalkyl or thienylalkyl is, for example, benzyl, 1-phenylethyl, 2-phenylethyT, 2-furylmethyl, 3-furylmethyl, 2-thienylmethyl, 3-thienylmethyl or 2-(2-thienyl)ethyl.

Particular values for optional substituents on alkyl vhen R is optionally substituted alkyl (such as methyl or ethyl) include, for example:

for cycloalkyl: cyclopropyl;

for optionally substituted 5- or 6-membered heteroaryl: furyl, pyridyl or thienyl;

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- 7 for a group of formula R^(CO) Xb(CO) :

n m for R : methyl, ethyl, n-propyl, cyclohexyl, phenyl or

4-hydroxybenzyl, for Xb: oxy, thio, sulphinyl, imino, methylimino or, together with R^, piperidino.

Particular values for optional substituents on phenyl when

R is optionally substituted phenyl or optionally substituted phenylalkyl (such as 2-phenylethyl) include, for example: for alkylenedioxy: methylenedioxy;

for halogeno: fluoro, chloro or bromo;

cyano;

trifluoromethyl;

for alkoxycarbonyl: methoxycarbonyl;

hydroxy;

for alkanoyloxy: pivaloyloxy;

benzyloxy;

for halogenobenzyloxy: 4-fluorobenzyloxy or 4-chlorobenzyloxy; nitro;

for alkyl or alkoxy optionally substituted by a group of formula R^CO: methyl, methoxy, ethyl, ethoxy, 2-(t-butoxycarbonyl)ethyl, methoxycarbonylmethyl, methoxycarbonylmethoxy, 2-(methoxycarbonyl)ethyl, n-propylaminocarbonylmethyl, n-propylaminocarbonylmethoxy, cyclopentylaminocarbonylethyl, cyclohexylaminocarbonylmethyl, (N-methyl, N,N-dimethylaminoethylJaminocarbonylmethyl or (N-methyl, N,N-dimethylaminoethylJaminocarbonylmethoxy; and for sulphamoyl: -SC^Ni^ or -SC^NiCH^^·

A particular value for when it is alkyl is, for example, methyl, ethyl, isopropyl, propyl or butyl.

Particular values for X include, for example, oxy, thio, imino, methylimino or, together vith R , morpholino, thiomorpholino, pyrrolidino, piperidino or azetidino.

A particular value for Xa vhen it is N-alkylimino is, for example, methylimino, ethylimino or propylimino.

A group of compounds which is of particular interest comprises those compounds of the formula II set out hereinafter

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- 8 wherein X is oxy, thio or an imino group of the formula -NRa- in which Ra is hydrogen or (l-6C)alkyl; Y is hydrogen, halogeno or (l-4C)alkyl; and R° is:

(a) phenyl, pentafluorophenyl, pyridyl, thiadiazolyl, or phenyl bearing 1 or 2 substituents independently selected from (l-4C)alkyl, .(l-4C)alkoxy, halogeno, cyano, trifluoromethyl, benzyloxy, ’ halogenobenzyloxy and hydroxy; ·*( (b) (l-6C)alkyl, (3-6C)cycloalkyl, norbornyl, (3-6C)cycloalkyl(l-4C)alkyl, furyl, thienyl, phenyl(l-4C)alkyl, furyl(l-4C)alkyl, thienyl(l-4C)alkyl, a furyl, thienyl or phenyl moiety of which may itself optionally bear 1 or 2 substituents independently selected from (l-4C)alkyl, (l-4C)alkoxy and halogeno; or (c) a group of the formula R^.Xa.CBj.CH^- in which R^ is (l-6C)alkyl or phenyl which latter may optionally bear 1 or 2 substituents independently selected from (l-4C)alkyl, (l-4C)alkoxy and halogeno, and Xa is oxy, thio, sulphinyl, sulphonyl, imino or N-(l-6C)alkylimino, or in which the group R^.Xa- is morpholino, pyrrolidino or piperidino; and is N or CT^ in which is hydrogen or methyl; together with the pharmaceutically acceptable salts and

N-(1-6C)alkanoyl derivative thereof.

Specific values for the generic radicals embodied within R^ include, for example, the appropriate values for R defined above.

6

Specific values for the group R .X- or R .X- include, for example, the following:phenoxy, ethoxy, 4-chlorophenoxy, benzyloxy, 4-benzyloxyphenoxy,

4-(4-chlorobenzyloxy)phenoxy, 4-hydroxyphenoxy, 4-methoxyphenoxy,

3- fluorophenoxy, 2-phenylethoxy, 2-phenoxyethoxy, 2-methoxyethoxy,

4- cyanophenoxy, butoxy, 3-methoxyphenoxy, 2-methoxyphenoxy,

2-fluorophenoxy, allyloxy, 2-(phenylthio)ethoxy, 4-fluorophenoxy, 2-cyanophenoxy, [l,2]isoxazol-3-yloxy, pyrid-3-yloxy, [1,2,5]thiadiazol-3-yloxy, thiophenoxy, cyclopentylthio, (2-furylmethyl)thio, methylthio, 2-methoxyphenylthio, benzylthio, cyclohexylamino, propylamino, anilino, allylamino, pyrrolidino, morpholino, benzylamino, methylamino, ethylamino, isopropylamino, butylamino, (2-phenylethyl)amino, [S]-(l-phenylethyl)amino and (2-dimethylaminoethyl)amino.

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- 9 A particularly preferred group of compounds of general formula I consists of those compounds wherein:

Q is furyl;

is hydrogen or acetyl;

R is cyclopentyl, cyclohexyl, tetrafluorophenyl, pentafluorophenyl, pyridyl, thiadiazolyl, (4-6C)alkyl, optionally substituted phenyl(l-2C)alk.yl, optionally substituted phenyl, furylmethyl or pyridyImethyl, any of said optionally substituted phenyl being unsubstituted or substituted by methylenedioxy, or by one of fluoro, chloro, cyano, trifluoromethyl, methoxycarbonyl, hydroxy, pivaloyloxy, nitro, methyl, methoxy, t-butoxycarbonylethyl and sulphaooyl;

X is oxy or imino; A is N or CT in which T is hydrogen; and pharmaceutically acceptable salts thereof.

Of this particularly preferred group of compounds, those wherein R is cyclohexyl, tetrafluorophenyl, 2-methylpropyl, phenyl, 2-fluorophenyl, 3-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 2-cyanophenyl, 3-cyanophenyl, 2-nitrophenyl, 2-methoxycarbonylphenyl,

2- methoxyphenyl, 3-methoxyphenyl, 2-methylphenyl, 3-methylphenyl,

3- trifluoromethylphenyl, benzyl, 2-fluorobenzyl, 3-methoxybenzyl, 2-furyImethyl, 2-phenylethyl, 2-(4-chlorophenyl)ethyl,

2-(2-methylphenyl)ethyl, 2-(4-t-butoxycarbonylphenyl)ethyl,

2-(4-hydroxyphenyl)ethyl, 2-(4-sulphamoylphenyl)ethyl and

2-(4-pivaloyloxyphenyl)ethyl are especially preferred.

Particular pharmaceutically acceptable salts include, for example, salts with acids affording physiologically acceptable anions, for example, salts with strong acids, such as hydrochloric, hydrobromic, sulphuric, phosphoric, methanesulphonic and trifluoracetic acids. In addition, for those compounds of formula I which are sufficiently basic, suitable salts include, for example, salts with organic acids affording a physiologically acceptable anion such as salts with oxalic, citric or maleic acid. Certain compounds 2 of formula I, for example those in which R comprises a phenol group, may form base salts with bases affording physiologically acceptable cations, such as alkali metal and alkaline earth metal salts.

Specific compounds of the formula I which are of interest

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- 10 are described hereinafter in the accompanying examples. Of these, compounds of particular interest include, for example, the compounds described in Examples 1, 3, 4, 12, 17, 18, 19, 24, 27, 32, 38, 44, 72, 75, 81, 82, 83, 84, 102, 118, 129, 136 and 142 or the pharmaceutically acceptable acid-addition salts thereof, and these are provided as a further feature of the invention. i

The compounds of formula I may be manufactured using , procedures analogous to those veil known in the arts of heterocyclic and organic chemistry for the production of structurally analogous compounds. Such procedures are included as a further feature of the invention and include the following preferred procedures for the 1 2 manufacture of a compound of the formula I in which R , R , X, A and Q have any of the meanings defined above:

(a) The reaction of a compound of the formula III in which Z is a suitable leaving group, for example hydrocarbylsulphonyl such as (l-6C)alkylsulphonyl (such as methylsulphonyl or ethyIsulphonyl), ary loxy such as phenoxy or halogeno (such as chloro or bromo), with a 2 compound of the formula R .XH .

The process is generally carried out under basic conditions.

These may be conveniently provided by the inherent basicity of the 2 compound of formula R .XH itself, for example when X is imino or when R contains an amino group. Alternatively, the basic conditions may be provided by adding a suitable base to the reaction mixture.

Suitable bases include, for example, tertiary amines such as trimethylamine, triethylamine, pyridine, 2,6-dimethylpyridine and 1,8-diazabicyclo(5.4.0Jundec-7-ene. It will be appreciated that the basic conditions may also be provided by using the compound of the formula R .XH in the form of a salt such as an alkali metal salt, for example, a lithium, sodium or potassium salt. Such a salt may be prepared separately, or formed in situ immediately prior to the above process (a), by any conventional method, for example by reacting the compound of the formula R .XH with an alkali metal (l-4C)alkoxide, hydroxide or hydride in a suitable solvent or diluent such as acetonitrile, 1,2,-dimethoxyethane, £-butyl methyl ether, tetrahydrofuran, ethanol or Ν,Ν-dimethylformamide.

The process (a) will generally be performed at a temperature ^SA° original $

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- 11 in the range, for example, 10 to 120°C and conveniently in the range 30 to 80°C and in a suitable solvent or diluent such as acetonitrile, ethanol, tetrahydrofuran, 1,2-dimethoxyethane, £-butyl methyl ether or N,N-dimethylformamide.

The starting materials of formula III (certain of which are also compounds of the invention) may be obtained by standard procedures veil knovn in the art. Thus, for example, those compounds of formula III in which Z is alkylsulphonyl may be made by oxidation of the corresponding alkyl thio derivative of formula IV in which R⁷ is (l-6C)alkylthio, using a conventional oxidant such as a peracid, for example, peracetic, perbenzoic or chloroperbenzoic acid, conveniently at a temperature in the range, for example, 0 to 40 °C, and in a suitable solvent or diluent such as dichloromethane or chloroform. Similarly, those compounds of the formula III in which Z is chloro or bromo may be obtained, for example, by reacting an alkylthio derivative of formula IV (especially in which R? is methyithio or ethylthio) with chlorine or bromine in the presence of hydrogen chloride or hydrogen bromide, respectively, at a temperature in the general range, for example, -20 to 15 ^eC and in a generally inert polar solvent such as ethanol or 2-propanol. The compounds of formula III in which Z is phenoxy may conveniently be prepared by one of processes (b) to (e) described hereinafter.

The starting alkylthio starting materials of formula IV (certain of vhich are also compounds of the invention) may themselves be obtained, for example, by reaction of a compound of the formula V vith the appropriate dialkyl N-cyanodithioiminocarbonate of formula VI, in vhich R? has any of the meanings defined above, at elevated temperature in the range, for example, 60 to 200 “C, conveniently as a melt in the absence of solvent or diluent, to give the compound of formula IV in vhich R^ is hydrogen. Vhen a compound of formula I in vhich r! is alkyl is required, the compound of formula IV in vhich R^ is hydrogen may be alkylated or acylated in conventional manner.

It vill be understood that in some circumstances, vhen A is N, some of the isomeric 7-alkylthio-5-amino compound of formula IVa may also be obtained during the reaction of the formula V and VI compounds and that this material may be separated by conventional

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- 12 procedures, for example by chromatography.

The starting compounds of formula V wherein A is N may themselves be obtained, for example by reacting the appropriate iminoether of the formula Q.C(OR)=NH in which R is (l-4C)alkyl such as methyl or ethyl (formed from the corresponding nitrile of the formula

Q.CN and alcohol of the formula R.OH in the presence of an anhydrous^: acid such as hydrogen chloride) with an aminoguanidine salt 4 (especially the nitrate) in the presence of a suitable base, such as pyridine or 2,6-lutidine, which may also be used as the reaction solvent, at a temperature in the range, for example, 60-120 ^eC.

The starting compounds of formula V wherein A is CT may themselves be obtained, for example by reacting the appropriate ester of the formula (in which R is lower alkyl such as methyl or ethyl) under basic conditions with an alkali metal salt of the formula T.CBM.CN (in which M is an alkali metal such as sodium or lithium), conveniently produced in situ by adding a nitrile of the formula T.CH^.CN to a solution of the alkali metal in liquid ammonia, to give the corresponding cyanoalkylketone of the formula (J.CO.CB(T).CN. The latter compound is then cyclised with hydrazine, for example by heating in a suitable solvent or diluent such as ethanol or propanol to give the required pyrazole of formula V.

(b) Por those compounds of formula I in which X is thio or oxy, a compound of the formula V is reacted at elevated temperature with a compound of formula VII in which X is thio or oxy.

The process is generally performed at a temperature in the general range, for example, 60 to 200 °C and may be performed in the:

absence of any solvent or diluent especially when R is alkyl or phenyl. Otherwise any conventional solvent or diluent may r conveniently be used which is generally inert and of adequate boiling point. It will be appreciated that, under certain circumstances for example when the reaction is performed at temperatures only slightly above room temperature, it is possible to produce significant quantities of the thermodynamically less stable, isomeric (l,2,4Jtriazolo(4,3-a}(l,3,5Jtriazine derivative of the formula VIII, and this isomeric material may be separated by conventional procedures such as chromatography.

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- 13 (c) The invention accordingly provides a further process for preparing a compound of formula I in which A is H, in which a [1,2,4]triazolo[4,3-a][1,3,5]triazine derivative of the formula VIII is rearranged.

The rearrangement is generally carried out by heating the compound of formula VIII in a suitable solvent or diluent, for example, a (1-6C)alkanol, such as ethanol, 2-propanol or butanol, at a temperature in the general range, for example, 60 to 140 “C. The rearrangement may optionally be carried out in the presence of an acid or base catalyst, for example an alkali metal alkoxide or hydroxide such as sodium hydroxide.

The starting materials of formula VIII may be obtained, for example, as described in connection with (b) above as illustrated in Example 4 hereinafter or by conventional techniques of heterocyclic chemistry.

(d) For those compounds of formula I in which R is hydroxyphenyl, a corresponding derivative of formula I in which the hydroxy group is protected, for example with a benzyl group, is deprotected.

The protecting group and deprotection conditions are those veil knovn in the art for use with hydroxy groups and which are compatible vith the presence of other reactive groups in the formula I compound. Thus, for example, a benzyl group may be removed by hydrogenation in the presence of a suitable catalyst such as palladium-on-carbon at or about atmospheric pressure of hydrogen in a suitable inert diluent or solvent such as methanol, ethanol or £-butyl methyl ether and at or about ambient temperature.

The protected derivatives of formula I may in general be made using analogous procedures to processes (a)-(c) above but starting from the appropriately protected starting materials.

(e) For those compounds of formula I in which A is N and R^ is hydrogen or (l-6C)alkyl, a compound of formula 1 in which Za is a suitable leaving group, for example aryloxy (such as phenoxy), alkylthio (such as methylthio) or halogeno (such as chloro or bromo) is reacted with a compound of formula R^NH?·

The process is conveniently effected at a temperature in

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- Μ the range of, for example, from 0 to 100°C. Suitable solvents for the process include alcohols such as ethanol and ethers such as tetrahydrofuran. When R^ is hydrogen, it is particularly convenient to employ a solution of ammonia in an alcohol, such as ethanol, at ambient temperature. *

The starting materials of formula X may be obtained by dehydrating a compound of formula XI. Suitable dehydration agents & include, for example, phosphorus pentoxide or a sulphonyl chloride such as p-toluenesulphonylchloride. The dehydration is conveniently effected at a temperature in the range of from 60-180’C. Vhen phosphorus pentoxide is used, convenient solvents include the aromatic hydrocarbons such as xylene or toluene. Vhen a sulphonyl chloride is used, convenient solvents include tertiary amines such as pyridine.

It will be appreciated that the compounds of formula X in which Za represents alkylthio correspond with the compounds of formula IVa whose preparation is described hereinbefore.

The compounds of formula XI may be obtained by reacting a compound of formula XII with a compound of formula QCOHal in which Hal is a halogen atom such as a chlorine atom. The reaction is conveniently effected at a temperature in the range of from -10 to 40°C. Suitable solvents for the reaction include halogenated hydrocarbons such as dichloromethane.

The compounds of formula XII may be obtained by reacting a compound of formula XIII in which Zb is a leaving group as defined for Za with hydrazine.

Alternatively, the compounds of formula XI may be obtained' by reacting a compound of formula XIII with a compound of formula qconhnh₂.

Process (e) is particularly suitable for preparing compounds 2 of formula I in which R X is phenoxy, starting from the compound of 2 formula XIII in vhich R X and Za are phenoxy.

It will be appreciated that those compounds in which R^ is other than hydrogen may also be obtained by carrying out a conventional alkylation or acylation of the corresponding formula I compound in vhich R^ is hydrogen obtained by one of processes (a)-(d) above.

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- 15 It will also be appreciated that those coapounds of foraula

2 I in which R contains an acyloxy group, for exaaple where R is (l-4C)alkanoyloxyphenyl or (l-4C)alkanoyloxyphenyl(l-6C)alkyl, aay be prepared by acylating the corresponding compounds of foraula I in

2 which R comprises a hydroxy group, as for example where R is hydroxyphenyl or hydroxyphenyl(l-4C)alkyl. The acylation aay be conducted by reaction with any conventional acylating agent, for example a (l-4C)alkanoyl halide or (l-4C)alkanoic acid anhydride.

Compounds of formula I wherein X, Xa or Xb is sulphinyl or sulphonyl may conveniently be prepared by oxidising the corresponding compounds of formula I wherein X, Xa or Xb is thio or sulphinyl. Suitable oxidising agents include for example, peracids such as peracetic, perbenzoic or chloroperbenzoic acid. The oxidation is conveniently effected at a temperature in the range of fro· 0 to 40’C. Suitable solvents include halogenated hydrocarbons such as dichloromethane or chloroform.

Whereafter, when a pharmaceutically acceptable salt is required, it may be obtained, for example, by reacting a compound of formula I with the appropriate acid or base affording a physiologically acceptable ion or another conventional procedure.

Similarly, when an optically active form of a chiral compound of formula I is required, either one of processes (a)-(e) above may be carried out using the appropriate optically active starting material or else a racemic form may be resolved by a conventional procedure, for example, using an optically active form of a suitable acid.

Certain of the starting materials used in the processes according to the invention are novel, and these are provided as further aspects of the invention. For example, the invention provides compounds of formula V in which A is N and Q is as defined hereinabove, and acid addition salts thereof (e.g., hydrochloride salts). The invention also provides compounds of formula VIII in

2 which Q, R , R and X are as defined hereinabove. The invention also 2 provides compounds of formula X in which Q, R , X and Za are as defined hereinabove.

As stated above, the compounds of the invention possess the

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- 16 property of antagonising one or aore of the physiological actions of adenosine and are valuable in the treatment of diseases and medical conditions affecting the mammalian cardiac, peripheral and/or cerebral vascular systems, such as ischaemic heart disease, peripheral vascular disease (claudication) and cerebral ischaemia. The compounds may alsfe be useful in the treatment of migraine. *

The effects of compounds of formula 1 as adenosine receptor^ antagonists may be demonstrated in one or more of the following standard in vitro and/or in vivo tests.

(a) Adenosine receptor affinity test

This test involves the ability of a test adenosine antagonist to displace the known adenosine mimetic agent pH]-N-ethylcarboxamidoadenosine (NECA) from binding sites on membrane preparations derived from the rat phaeochromocytoma cell line PC 12 (available from the Beatson Institute, Glasgow). The basic procedure has been described by Williams et al. (J. Neurochemistry, 1987, 48(2), 498-502).

The membrane preparation is obtained as follows:

Frozen pellets of PC12 cells are washed twice with ice cold, buffered, physiological saline and the cells recovered by centrifugation (1500G) at 3^eC. The separated cells are then suspended in hypotonic solution (distilled water), allowed to stand on ice for 30 minutes and are then carefully homogenized using a standard high-speed homogeniser vith periodic ice-cooling to obtain a fine suspension. The homogenate is centrifuged (48000G) and the pellet is resuspended in 50 mM tris-HCl buffer, pH 7.4 containing adenosine deaminase (5 units/ml, Type VII from calf intestinal mucosa, available from Sigma Chemical

Corporation, under reference no. A128O). The mixture is then incubated at 37°C. After 20 minutes, the reaction is terminated by dilution vith ice-cold buffer and transfer onto ice. The material obtained containing the cell membranes is recovered by centrifugation and washed by resuspension in buffer and recentrifugation. The pellet produced is then resuspended in ice-cold buffer using a hand-driven homogenizer. The resultant membrane suspension is frozen and stored under liquid nitrogen until required.

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AP ο Ο Ο 2 4 8

- 17 Binding studies are carried out in microtitre plates, the assay mixtures being buffered in 50 mM tris-HCl, pH 7.4 at room temperature. The test compound is dissolved in dimethyl sulphoxide (DMSO) and then diluted with assay buffer to give the test solutions. (The final concentration of DMSO is not allowed to exceed 12 by volume, at which level it does not affect radioligand binding to the membrane receptor.] Incubations are performed at 30’C for 90 minutes in a total volume of 150 ul comprising the test solution or buffer (50 ul), tritiated NECA (50 ul) and membrane suspension (50 ul). After incubation, the samples are rapidly filtered over glass-fibre mats and the filter mats are washed to remove non-receptor-bound radioligand. Receptor-bound radioligand entrapped on the filter mats is then determined by liquid scintillation counting. Filtration and washing are carried out using a conventional vacuum filtration cell harvester. The specific binding (defined as the difference between the total binding and the non-specific binding) in the presence of the particular test compound is determined and compared with the control value. Results are conveniently expressed as the negative logarithm of the concentration required to cause a 502 displacement of control specific binding (ρΙΟ^θ).

In general, compounds of the formula I showing antagonist activity in this assay typically show a ρΙΟ^θ 1° the above test (a) of 6 or more. Thus for example, the compound of Example 1 herein shows a ρΙΟ^θ of about 8, and the compound of Example 119 herein shows a ρΐϋ^θ of about 8.5. Using the same test procedure, the known compound

1,3-dimethylxanthine typically shows a ρΐϋ^θ of about 5.

(b) Guinea-pig Aortic Constriction Test

This test has been described by Collis et al. (British J. Pharmacology, 1989, 97, 1274-1278) and involves the assessment of the ability of a test compound to antagonise the attenuatory effect of adenosine on phenylephrine induced constriction of a guinea-pig aortic ring preparation, an effect mediated via the adenosine receptor known as A^.

The aortic ring preparation is obtained as follows:Sections (3-5 mm) of guinea pig thoracic aorta (from Dunkin Hartley

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- 18 strain, 250-400g males) are mounted in organ baths containing oxygenated Krebs solution (95Z 0₂: 5Z C0₂) at 37*C. (The nucleoside transport inhibitor, dipyridamole (10 uM) is present in the Krebs solution]. The isometric tension development is recorded and the tissue placed under a resting tension of lg and allowed to equilibrate -5 * for 1 hour. The aortic ring preparation is then sensitised to 10 M phenylephrine. Erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) (10 yM) is added to the preparation and after 10 minutes the tissue is constricted to approximately 50Z maximum by adding 3 x 10~°M

-7 -3 phenylephrine. Adenosine is next added cumulatively (10 M to 10 M) and the evoked relaxation is measured. After washout for 20 minutes, a 10^-^M solution of the test compound in DMSO (maximum 1Z by volume) diluted with Krebs solution is added and left to equilibrate for 30 minutes. Twenty minutes into the equilibration period further EHNA (10 yM) is added to the preparation and 10 minutes later phenylephrine (3 x 10^M) is introduced to produce constrictive tone again. A repeat dose response curve to adenosine is then carried out followed by washout.

Test compounds are assessed by plotting the percentage relaxation observed against the logarithm of the adenosine concentration, competitive adenosine antagonism producing a parallel shift in the standard adenosine concentration/relaxation (dose response) curve. The dose ratio (DR) is calculated from the ratio of the concentration of adenosine to produce a 50Z relaxation (Εϋ^θ) in the presence of the test antagonist divided by the Εϋ^θ concentration of adenosine in the absence of the test antagonist for each aortic ring. Significant antagonist activity in this assay is indicated by a DR of >2. The pA2 value, vhich is an estimate'of the concentration of antagonist to give a dose ratio of 2, may also be calculated using a standard computation technique. In general, compounds of formula I showing antagonist activity in this assay have a pA2 of 6 or more.

Thus, the compound of Example 1 herein has a pA2 of 7.4; and the compound of Example 119 herein has a pAj of 7.3. Using the same test procedure the known compound, 1,3-dimethylxanthine, has a pA2 of about

5.

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AP000248

- 19 (c) Guinea-pig Atrial Bradycardic Test

This test has also been described by Collis et al. (British Pharmacology, 1989, 97, 1274-1278) and involves the ability of a test compound to antagonise the bradycardic effect of the adenosine mimetic, 2-chloroadenosine, in a beating guinea-pig atrial preparation, an effect mediated via the adenosine receptor known as ^Al'

The atrial pair preparation may be obtained as follovs:Atrial pairs are obtained fro· guinea-pigs (Dunkin Hartley strain,

250-400g males) and mounted in organ baths containing oxygenated Krebs buffer solution (952 C^; 52 Ct^) at 37’C. The spontaneously beating atria are then placed under a resting tension of 1 g and allowed to equilibrate for 50 minutes with continuous overflow. Overflow is then stopped and adenosine deaminase (1 (Jnit\ml) added to prevent the accumulation of endogenously produced adenosine. After equilibration for 15 minutes, a cumulative dose response curve to the adenosine -8 -4 mimetic, 2-chloroadenosine (10 H to 10 H) is administered to produce a maximal slowing of atrial rate. After washout during 30 minutes, adenosine deaminase is readministered to the bath which is allowed to equilibrate for 15 minutes. A 10^-JM solution of the test compound in DMSO is then added to the bath which is left to incubate for 30 minutes. Any effect on the beating rate due to the test compound is noted before the dose response curve to 2-chloroadenosine is repeated. Compounds which are adenosine antagonists attenuate the

2-chloroadenosine response.

Test compounds are assessed by comparing dose response curves to 2-chloroadenosine alone with those obtained in the presence of the compound. Competitive adenosine antagonists produce a parallel shift in the 2-chloroadenosine dose response curve. The dose ratio (DR) is calculated from the ratio of the concentration of

2-chloroadenosine to produce a 502 reduction in atrial rate (Εϋ^θ) in the presence of the test compound divided by the ED^q concentration of 2-chloroadenosine in the absence of the test compound for each atrial pair. The pA2 is then obtained in an analogous manner to that referred to in (b) above. In general, compounds of formula I showing antagonist activity in this assay have a pA2 of about 6. Thus the

BAD ORIGINAL ft s ο ο ο<?α

- 20 compound of Example 1 herein has a pA2 of 6.2 and the compound of Example 119 herein has a pA2 of 6.0. Similarly, the known compound,

1,3-dimethylxanthine, typically shows a pA2 of about 5.

(d) Anaesthetised cat blood pressure Test

This test assesses the ability of a test compound to antagonise the fall in diastolic blood pressure produced by administration of the adenosine mimetic, 2-chloroadenosine.

Hale cats (2-3 kg) are anaesthetised with sodium pentobarbitone (45 mg/kg, ip). The following blood vessels are catheterised: right jugular vein (for infusion of the anaesthetic at approximately 7 mg/kg per hour as a 3 mg/ml solution in isotonic saline), the left jugular vein (for administration of test agents) and the right common carotid artery (for monitoring blood pressure and pulse rate). The blood gas status and pH are determined, and are maintained within physiological limits, before administration of 2-chloroadenosine. A control dose response curve (DRC) to 2-chloroadenosine (0.3 to 30 Ug/kg) against the fall in diastolic blood pressure is determined. A solution of the test compound in a mixture of 50Z v/v polyethylene glycol (PEG) 400 and 0.1M sodium hydroxide is then administered i.v. and after 15 minutes the DRC to 2-chloroadenosine is determined. This procedure is repeated twice with blood gases and pH being monitored and maintained within physiological limits between each DRC. The concentration of 2-chloroadenosine required to cause a 30 mm Hg fall in diastolic blood pressure is then calculated for each dose of test compound and a Schild plot constructed for those which produce a dose ratio (DR) of _? >2. From this plot a K_ value is determined. In general compounds* of formula I shoving activity in this test possess a Kg of 1 mg/kg (or much less). For example the compound of Example 1 has a Kg of 30 Ug/kg and the compound of Example 119 has a Kg of 0.7 mg/kg.

The above Test (d) may conveniently be modified to allow evaluation of orally administered test compounds by administering the test compound to conscious cats with indwelling arterial and venous catheters and measuring the effect in preventing an adenosine induced decrease in blood pressure. Those compounds of formula I which show

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- 21 oral activity, for example the compound of Example 1, show significant adenosine antagonist activity at a dose of 1 - 3 mg/kg or less vithout any sign of overt toxicity at several times the minimum effective dose.

(e) Anaesthetised dog Test

This test involves the assessment of the effects of a test compound on antagonising the actions of adenosine in lowering heart rate and increasing vasodilation (as measured by a fall in hind-limb perfusion pressure).

Beagles (12 - 18 kg) are anaesthetised with sodium pentobarbitone (50 mg/kg, iv). The following blood vessels are catheterised: right jugular vein (for infusion of the anaesthetic at approximately 112 mg per hour as a 3 mg/ml solution in isotonic saline), right brachial vein (for administration of drugs and test agents), right brachial artery (for measurement of systemic blood pressure and pulse rate) and the left carotid artery (for administration of adenosine into the left ventricle). Both vagi, the right femoral and sciatic nerves are ligated and severed. A bolus injection of 1250 U heparin is administered before perfusing the right hindlimb at constant blood flow with blood from the iliac artery. The right leg is tied just below the ankle. Xamoterol (1 mg/kg) is then administered to the animal to stabilise heart rate at a high level and nitrobenzylthioinosine (NBTI, 0.5 mg/kg) to inhibit the uptake of adenosine. The animal is sensitised to adenosine during the equilibration time following NBTI by carrying out a dose response curve (DRC). During this time any blood gas or pH imbalance is corrected. A control DRC is performed followed by up to three DRC's after cumulative administration of the test compound (as described in (d) above). Each DRC is carried out 15 minutes after administration of test compound and after the measured parameters of heart rate and hindlimb perfusion pressure have returned to a stable state.

Similarly, blood gases and pH are maintained within physiological limits throughout the evaluation.

The amount of adenosine required to cause a 50Z fall in measured parameter (Εϋ^θ) i.e. heart rate and hindlimb perfusion

BAD ORIGINAL ? t' i 0 0 Q a A

- 22 pressure is calculated for each does of test compound and a Schild plot constructed. From this plot a Kg value is determined for antagonism of heart rate response and vasodilator response to adenosine. In general, compounds of formula I shoving activity in this test possess a K. of 1 mg/kg (or much less) for antagonism of o * vasodilator response to adenosine with no indication of toxic or othe^ ·%.

untoward properties at doses several times greater than the minimum effective dose. For example the compound of Example 1 has a Kg of 30. pg/kg and the compound of Example 119 has a Kg of 1.1 mg/kg.

f) Anaesthetised cat exercise hyperaemia test

This test involves assessment of the effect of a test compound to antagonise the vasodilatation response vhich occurs during twitch contraction of skeletal muscle. The vasodilation is mediated partly by the release of endogenous adenosine from the contracting skeletal muscle.

Cats (2.4-3.6 kg) are anaesthetised with sodium pentobarbitone (50 mg.kg^ ip). The following blood vessels are catheterized: left jugular vein (for infusion of anaesthetic, at approximately 0.12 mg^min^ as a 6 mg.ml solution in isotonic saline), right external jugular vein (for administration of drugs and test compounds), right common carotid artery (for measurement of systemic arterial blood pressure and pulse rate) and right brachial artery (for withdrawal of blood).

Blood flow to the left hind limb is measured with an electromagnetic flow probe around the left external iliac artery. The whole of the left hind limb is made to contract at 3Hz for 20 minutes duration by stimulating the sciatic and femoral nerves. Active tension produced by the extensor digitorum longus and peroneous longus muscles is measured isometrically vith a force transducer. Exercise is repeated twice within the same animal, in either the absence or presence of the test compound. Test compounds are assessed for their ability to reduce the vasodilatation during skeletal muscle

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AP000248

- 23 contraction.

In general, compounds of formula I, for example the compound of Example 1, produce significant inhibition of vasodilatation during exercise over the range, 0.1-1 mg.kg . The known compound,

1,3-dimethylxanthine, produces significant inhibition at 10 mg.kg*^.

In general, the majority of compounds of formula I show activity as adenosine antagonists which is predominantly selective for adenosine receptors.

The compounds of the invention are generally best administered to varm-blooded animals for therapeutic or prophylactic purposes in the treatment or prevention of cardiovascular diseases and adverse conditions in the form of a pharmaceutical composition comprising said compound of formula I or a pharmaceutically acceptable salt thereof, in admixture or together vith a pharmaceutically acceptable diluent or carrier. Such compositions are provided as a further feature of the invention.

In general, it is envisaged that a compound of formula I vill be administered orally, intravenously or by some other medically acceptable route (such as by inhalation, insufflation, sub-lingual or transdermal means) so that a dose in the general range, for example, 0.001 mg to 10 (and more particularly in the range, for example, 0.05 to 5 mg/kg) mg/kg body veight is received. However, it vill be understood that the precise dose administered vill necessarily vary according to the nature and severity of the disease or condition being treated and on the age and sex of the patient.

A composition according to the invention may be in a variety of dosage forms. For example, it may be in the form of tablets, capsules, solutions or suspensions for oral administration; in the form of a suppository for rectal administration; in the form of a sterile solution or suspension for administration by intravenous or intramuscular injection; in the form of an aerosol or a nebuliser solution or suspension, for administration by inhalation; in the form of a powder, together with pharmaceutically acceptable inert solid diluents such as lactose, for administration by insufflation; or in the form of a skin patch for transdermal administration. The compositions may conveniently be in unit dose from containing, for

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- 24 example, 5 - 200 mg of the compound of formula I or an equivalent amount of a pharmaceutically acceptable salt thereof.

The compositions may be obtained by conventional procedures using pharmaceutically acceptable diluents and carriers veil known in the art. Tablets and capsules for oral administration may

X conveniently be formed with an enteric coating (such as one based on _m cellulose acetate phthalate) to minimise the contact of the active * ingredient of formula I with stomach acids.

The compositions of the invention may also contain one or more agents known to be of value in the diseases or conditions of the cardiovasculature intended to be treated. Thus, they may contain, in addition to the compound of formula I, for example: a known platelet aggregation inhibitor, prostanoid constrictor antagonist or synthase inhibitor (thromboxane A£ antagonist or synthase inhibitor), cyclooxygenase inhibitor, hypolipidemic agent, anti-hypertensive agent, inotropic agent, beta-adrenergic blocker, thrombolytic agent or a vasodilator.

In addition to their use in therapeutic medicine, the compounds of formula I are also useful as pharmacological tools in the development and standardisation of test systems for the evaluation of new cardiovascular agents in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice.

The invention will now be illustrated by the following non-limiting Examples in which, unless otherwise stated:(i) evaporations were carried out by rotary evaporation in vacuo;

(ii) operations were carried out at room temperature, that is in the range 18-26*C;

(iii) flash column chromatography or medium pressure liquid chromatography (MPLC) was performed on silica gel [either Fluka Kieselgel 60 (catalogue no. 60738) obtained from Fluka AG, Buchs, Switzerland, or Merck Kieselgel Art. 9385, obtained from E Merck, Darmstadt, Germany|;

(iv) yields are given for illustration only and are not necessarily the maximum attainable by diligent process development;

(v) proton NMR spectra were normally determined at 200 MHz in

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AP Ο 00 2 48

- 25 deuterated dimethyl sulphoxide as solvent, using tetramethylsilane (TMS) as an internal standard, and are expressed as chemical shifts (delta values) in parts per million relative to TMS using conventional abbreviations for designation of major peaks: s, singlet; m, multiplet; t, triplet; br, broad; d,doublet; q,quartet; and (vi) all end-products were characterised by microanalysis, NMR and/or mass spectroscopy.

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- 26 Exaaple 1

Phenol (6.4 g) and l,3-diaaabicyclo(5.4.0|undec-7-ene (DBU, 3.8 ml) were added to a suspension of 7-amino-2-(2-furyl)-5-methylsulphonyl-[ 1,2,4 ] t r iazolo{ 1,5-a] [ 1,3,5 J triazine (6.4 g) in di methoxy ethane (150 al) and the resulting aixture was heated under $ reflux for 1 hour, after which tiae thin layer chromatographic (TLC) analysis on silica plates (elnant: 5-10Z v/v ethyl acetate in 1 dichloromethane) indicated that no aethylsulphonyl starting material remained. The solvent was evaporated and the residue was purified by column chromatography on silica (250 g) eluting with an increasing amount of ethyl acetate in didtloroaethane (5-10Z v/v). The colourless amorphous solid (5-4 g) thereby obtained vas crystallised from ethanol to give 7-amino-2-<2-furyl)-5-phenoxy-ll,2,4]triazolo(1,5-aJ(1,3,5]triazine (3.A g) as colourless fluffy crystals, a.p. 250-252®C; microanalysis, found: C,56.7; H,4.1; N,26.2Z; ^14^19^5^2’ O.5C₂H₅OH requires: C,56.8; 5,4.1; N.26.5Z; NHR: 1.05 (t, 1.5H, CH₃CH₂OH), 3.45(q, 1H, CH^-Cg), 4.3(br s, 0.5B, CH^HjOH), 6.7 (dd, 1H, furyl-4H), 7.l(d, 1H, furyI-3H), 7.3(m, 3H, phenoxy), 7.4(a, 2H, phenoxy), 7.9(d, 1H, furyl-Ξδ). 8.8-9.l(d, 2H, NH₂); m/e 294 (H⁺).

The necessary starting aaterial vas prepared as follows:(1) Hydrogen chloride gas (20.Og) vas bubbled into an ice-cooled mixture of 2-furonitrile (46.5 g) and absolute ethanol (23.0 g).

After addition of the gas, solid crystallised from the mixture. The crystalline solid vas collected by filtration and heated in pyridine (300 ml) with aminoguanidine citrate (56.0 g) under reflux for 4 »· hours. The mixture vas cooled, solid saterial removed by filtration ,and the filtrate evaporated tc give crude 3-amino-5-(2-furyl)-l,2,4-.fc. triazole. This material vas ccrified by treatment vith nitric acid (400 ml of 50Z v/v). The crystalline salt vhich formed vas collected by filtration, washed sequentially with vater (100 ml) and ethanol (50 ml) and air dried to give 3-aaico-5-(2-furyl)-l,2,4-triazole nitrate (45.0 g), m.p. 130-133^aC (decoc.). Several batches (184.Og) of this salt (184 g) vere suspended ic hot vater (400 ml) and sodium carbonate (46.0 g) vas added in portions. The basic solution obtained was allowed to cool to give 3-aainc-5-(2-furyl)-l,2,4-triazole (82.0 g) as

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AP Ο Ο Ο 2 4 8

- 27 colourless prisms, m.p. 204-206’C; NMR 6.05(s, 2H, N^)* 6.6(s, 1H, furyl-4H), 6.7(s, 1H, furyl-3H), 7.7(s,lH, furyl-5H), 12.05(br S,1H NH).

(2) An intimate mixture of 3-amino-5-(2-furyl)-l,2,4-triazole (33.0 g) and dimethyl N-cyanodithioiminocarbonate (33.0 g) was heated at 170°C for 1 hour, under a slow stream of argon. After cooling, the resulting solid was purified by column chromatography on silica (600 g) eluting with an increasing amount of ethyl acetate in dichloromethane (5-102 v/v) to give 7-amino-2-(2-furyl)5-methylthio-l1,2,4Jtriazolofl,5-a)(l,3,5Jtriazine as a colourless solid (11.1 g), essentially pure by TLC, which was used without further purification. (A small amount of the above solid was recrystallised from ethanol to give, crystals, m.p. 238-240’C; microanalysis, found: C,44.0; H,3.3; N.33.7; CgHgN^SO. Ο.Οδί^Η^ΟΗ requires C,43.6; H,3.3; N,33.6; NMR 1.05 and 3.4 (t+q, ethanol of crystallisation), 2.5 (s, 3H, CH^S-), 6.7(dd, 1H, furyl-4H), 7.2(d,

1H, furyl-3H), 7.7(d, 1H, furyl-5H) 8.7-9.0(br d, 2H, NHj); a/e 248 (M*).

(3) A solution of 3-chloroperoxybenzoic acid (502 strength,

45.Og) in dichloromethane (300 ml) was added to a stirred,ice-cooled suspension of 7-amino-2-(2-furyl)-5-methylthio-(l,2,4Jtriazoloil,5-aJ{l,3,5Jtriazine (8.0 g) in dichloromethane (300 ml). The residual aqueous layer was discarded. The resulting suspension was allowed to warm to ambient temperature and stirred for 16 hours. The solvent was evaporated and ethanol (150 ml) was added to the residue. The suspension obtained was left to stand for 30 minutes with occasional swirling. The solid was then collected by fitration, washed with ethanol and dried to give 7-aaino-2-(2-furyl)5-aethylsulphonyl-[l,2,4Itriazolo(l,5-a|(l,3,5]triazine (6.6 g) as colourless solid, NMR: 3.3(s, 3H), CHyS0₂), 6.7(q, 1H, furyl-4H), 7.3(q, 1H, furyl-3H), 7.9(q, 1H, furyl-5H), 9.4-9.8(d, 2H, NH₂), vhich was used without further purification.

Example 2

Thiophenol (0.4 ml) and DBU (0.7ml) were added to a suspension of 7-amino-2-(2-furyl)-5-methylsulphonyl-[l,2,4JtriazoloBAD ORIGINAL

Ci.

0 0 SA

- 28 [l,5-a)[l,3,5)triazine (1.0 g) in acetonitrile (50 al) and the resulting suspension was heated under reflux for 16 hours. The solvent was evaporated and the residue was purified by column chromatography on silica (75 g) eluting sequentially with dichloromethane and then ethyl acetate in dichloromethane (1:9 v/v) to give the product as an amorphous solid (0.4g). This was crystallised' from ethanol to give 7-amino-2-(2-furyl)-5-thiophenoxy-[1,2,4J- j triazolof1,5-aJ[1,3,5) triazine as colourless prisms (O.25g), m.p. 301-302’C; microanalysis, found: C,54.4; H,3.1; N.27.3Z; Cj^Bj^NgSO requires: C,54.2; H,3.2; N,27.1Z; NMR: 6.7(dd, IR, furyl-4H), 7.1(d, 1H, furyl-3H), 7.5(m, 3H, thiophenoxy), 7.65(m, 2H, thiophenoxy), 7.9(d, 1H, furyl-5H), 8.8-9.0(d, 2H, NH₂); m/e 310 (M*).

Example 3

Propylamine (6.0ml) was added to a stirred suspension of

7-amino-2-(2-furyl)-5-methylsulphonyl-[ 1,2,4 J triazolof1,5-aJ(1,3,5)triazine (2.0 g) in acetonitrile (30 ml) and stirring was continued for 4 hours. The solvent was evaporated and the residue was purified by chromatography on silica (100 g) eluting with dichloromethane containing methanol (2.5Z v/v). The solid (0.85 g) obtained was crystallised from £-butyl acetate to give 7-amino-2-(2-furyl)5-(propylamino)-{1,2,4) triazolof1,5-a][1,3,5)triazine as a crystalline solid (0.5g), m.p. 197-198^eC; microanalysis, found: C,53.2; H,6.1;

N, 31.1Z; C_nH_l3N₇O. O.5C_&H₁₂O₂ requires: C,53.O; H,6.0; N,30.9Z; NMR:

O. 9(t,3H, CH₃CH₂CH₂), 1.4(_s, 4.5B, t-butyl acetate), 1.5-1.7(m, 2H, CH₃CH₂-), 1.9(s, 1.5H, t-butyl acetate), 3.25(t, 2H, CH₃CH₂CH₂-), 6.7(dd, 1H, furyl-4H), 7.0(d, 1H, furyl-3H), 7.4(br t, 1H, -NH-),

7.8(q, 1H, furyl-5H), 7.9-8.3(br d, 2H, NH₂); m/e 260 (M+H)⁺.

Example 4

A solution of 4-amino-3-(2-furyl)-6-phenoxy-fl,2,4)triazolo[4,3-a)[l,3,51triazine (0.65 g) in absolute ethanol (40 ml) was heated under reflux for 1 hour. The resulting solution was concentrated to half-volume ijn vacuo and allowed to crystallise to give

7-amino-2-(2-furyl)-5-phenoxy-) 1,2,4) triazolof 1,5-a) )1,3,5] triazine (0.35 g) as fluffy crystals, m.p. 253-255’C; microanalysis, found:

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AP Ο Ο Ο 2 4 8

- 29 C.56-7; Η,4.3; Ν,25.62; ^c14^Hio^N6°2' 0-75C₂H₅OH requires: C,56.6;

Η,4.4; N.25.62; NMR: l.O(t, ca. 2H, CH₃CH₂OH); 3.4(q, ca. 1.5H, CH₃CH₂OH), 4.3(br s, ca. O.75H, CH₃CH₂0H), 6.7(dd, IH, furyl-4H),

7.l(d, IH, 3-furyl H), 7.2-7.4(m, 3H, ArH), 7.5(m, 2H, ArH), 7.9(d,

IH, furyl-5H), 8.8-9.l(br d, 2H, NH₂); m/e 294 (M⁺).

The starting material was prepared as follows:Diphenyl cyanocarbonimidate (13.6 g) was added to a stirred suspension of 3-amino-5-(2-furyl)-l,2,4-tria2ole (75.0 g) in acetonitrile (250 ml). The resulting suspension was stirred for 72 hours and then heated under reflux for 1 hour. The solvent was evaporated and the residue was purified by chromatography on silica (600 g), eluting first with ethyl acetate in dichloromethane (1:9 v/v) and then with methanol in dichloromethane (1:19 v/v) to give

4-amino-3-(2-furyl)-6-phenoxy-( 1,2,4]triazolo[4,3-a][1,3,5]triazine as a colourless solid. This solid was recrystallised from acetonitrile to give material with m.p. 195-197’C, (followed by resolidification and remelting at 250-255’C); microanalysis, found: C,57.3; H,3.0; N,28.32; C^H^N^ requires: C,57.1; H,3.4; N.28.62; NMR: 6.7(dd, IB, furyl-4H), 7.1(d, IH, furyl-3H), 7.2-7.4(m, 3H, ArH), 7.4-7.6(m, 2H, ArH), 8.0 (d, IH, furyl-5H), 6.8-9.7 (br, NH₂); m/e 294 (M⁺).

Example 5

Using an analgous procedure to that described in Example 2, but starting from

7-amino-2-(5-methyl-2-furyl)-5-methylsulphonyl-[1,2,4]triazolo[1,5-a][1,3,5]triazine obatined from the corresponding 5-methylthio compound described in Example 47 below, there was obtained 7-amino-2-[2-(5-me thylfury1)]-5-pheny1thio-[1,2,4]triazolo(l,5-a](1,3,5]triazine, as a solid, m.p. 311-313°C, microanalysis, found: C, 55.6; H, 3.6; N, 26.32; ^ci₅h ₃₂N^OS requires: C, 55.5; H, 3.7; N, 25.92; NMR: 2.37(s, 3H, CHj), 6.30(d, IH, furyl-4H), 7.0(d, IH, furyl-3H), 7.5(m, 3H, phenyl o+p-H), 7.63(m, 2H, phenyl m-H) and 8.88(br s, 2H, NH₂); m/e 325 (M+H)⁺.

bad original d

- 30 Example 6

A solution of 7-amino-2-(2-furyl)-5-methylsulphonyl(l,2,4Jtriazolo[l,5-aJ[l,3,5Jtriazine (1.6 g) in ethanol (40 el) containing DBU (1.0 ml) vas heated under reflux until no starting material remained by TLC analysis. The solvent was removed by 3» evaporation and the residue purified by chromatography on silica using

5-10Z v/v ethyl acetate in dichloromethane as eluant, followed by . crystallisation from ethanol to give 7-amino-5-ethoxy-2-(2-furyl)[1.2.4] triazolo[1,5-aJ[1,3,5]triazine as hygroscopic crystals, m.p. 211-213’C; microanalysis, found: C, 48.7; H, 4.5; N, 31.4; HjO, 1.2Z; ^C10^H10^N6°2· °-^33C2^H5°^h· 0-^165h2° requires: C, 48.4; B, 4.7; N, 31.8; H₂0, 1.1Z; NMR: 1.05(t, 1H, CH-jCf^OH), 1.35(t, 3B, CH-jCHp, 3.4(q, CH₃CH₂OH), 4.3(q, 2H, CH₃CH₂O-), 6.7(dd, IB, furyl-4H), 7.1(d, IB, furyl-3H), 7.9(d, 1H, furyl-5H), 8.5-9.0(d, 2H, NI^); m/e 246 (M₊).

Examples 7-9

Using a similar procedure to that described in Example 1, but using the appropriate substituted phenol or benzyl alcohol instead of phenol, the following compounds were prepared:

[Example 7]: 7-amino-5-(4-chlorophenoxy)-2-(2-furyl)-[l,2,4[triazolo]l,5-a][l,3,5]triazine, as colourless prisms (crystallised from 2-propanol), m.p.294-295’C; microanalysis, found: C, 52.0;

H, 3.8; N, 22.2; Cl, 9.7Z; ^c14^H9^N6^cl02· 0.66C₃H_?OH requires: C, 52.1;

B, 3.9; N, 22.8; Cl, 9.6Z; NMR: 1.05(d, 4H, CH^, 3.8(m, 2/3H, CHOH), 4.3(d, 2/3H, OH), 6.7(dd, 1H, furyl-4H), 7.1(d, 1H, furyl-3H), 7.3(m, 2H, phenoxy), 7.5(m, 2H, phenoxy), 7.9(d, 1H, furyl-5fl),

8.8-9.2(d, 2H, NH^; m/e 328, 330 (M+);

[Example 8]: 7-amino-5-benzyloxy-2-(2-furyl)-( 1,2,4] triazolo[l,5-a[- ·;.

[1.3.5] triazine as colourless prisms (crystallised from ethanol), m.p. 256-258’C; microanalysis, found: C, 58.1; H, 4.0; N, 27.2Z; ^C15^H12^N6°2 requires: C, 58.4; H, 3-9; N, 27.3Z; NMR: 5.4 (s, 2H, CH₂),

6.7(dd, 1H, furyl-4H), 7.1(d, 1H, furyl-3H), 7.3-7.5(m, 5H, phenyl), 7.9(d, 1H, furyl-5H), 8.6-9.0(d, 2H, NH₂); m/e 308 (M⁺); and [Example 9]: 7-amino-5-(4-benzyloxyphenoxy)-2-(2-furyl)-[l,2,4[triazolo[l,5-a[[l,3,5[triazine as colourless crystals (crystallised from ethanol), m.p. 260-262’C; microanalysis, found: C, 62.1; H, 4.7;

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- 31 N, 19.72; ^C2i^Hi6^N6°3' °-^66C2^H5^{OH re}9^uires: C, 62.5; H, 4.2; N, 19.62; NMR: 1.05(t, 2B, CHp, 3.4(q, CH-jCHp, 4.3(t, CH-jCl^OH), 5.1(s, 2H, phenyl.CHj), 6.7(dd, 1H, furyl-4H), 7.0-7.2(m, 5H, phenyl), 7.3-7.5(m, 5H, phenyl), 7.9(d, 1H, furyl-5H), 8.7-9.1(d, 2H, Ni^); m/e 400 (M⁺).

Example 10

A solution of 7-amino-5-(4-benzyloxyphenoxy)-2-(2-furyl)[l,2,4]triazolo[l,5-a]fl,3,5]triazine (1.0 g) in methanol (400 ml) containing palladium-on-carbon catalyst (102 v/v, 200 mg) and acetic acid (20 ml) vas treated vith hydrogen gas at atmospheric pressure.

The reaction vas monitored by tic analysis (system as Example 1) and once no further starting material vas detected, the catalyst vas removed by filtration. Solvent vas evaporated from the filtrate. The solid residue obtained vas crystallised from ethanol to give 7-amino2-(2-furyl)-5-(4-hydroxyphenoxy)-[l,2,4] triazolo[l,5-a)[1,3,5]triazine as colourless hygroscopic crystals, m.p. 292-294’C; microanalysis, found: C, 53.5; H, 3.6; N, 26.4; H₂0, 2.12; O.33H₂O requires: C, 53.2; H, 3.4; N, 26.6; H, 3.6; N, 26.4; H₂0, 2.12; NMR: 6.7(dd, 1H, furyl-4H), 6.8(d, 2H, phenyl), 7.0(d, 2H, phenyl), 7.1(d, 1H, furyl-3H), 7.9(d, 1H, furyl-5H), 8.7-9.1(d, 2H, NHp, 9.4(br s,

1H, 0H_;m/e 310 (M*).

Example 11-17

Using a procedure similar to that described in Example 1, but using the appropriate substituted phenol or alcohol instaed of phenol, the following compounds were obtained:

[Example 11]: 7-amino-2-(2-furyl)-5-(4-methoxyphenoxy)-(l,2,4]triazolo]1,5-a][1,3,5]triazine as colourless fluffy crystals (crystallised from ethanol), m.p. 264-265’C; microanalysis, found: C, 55.7; H, 3.6; N, 25.62; ^ΐ5^ΐ2^6θ3 ^re9^u^^{res: c}» 55.5; H, 3.7; N,

25.92; NMR: 3.8(s, 3H, -OCHp, 6.7(dd, 1H, furyl-4H), 7.0(m, 2H, phenyl), 7.2(m, 3H, phenyl + furyl-3H), 7.9(d, 1H, furyl-5H),

8.8-9.l(d, 2H, NH₂): m/e 324 (M⁺);

[Example 12]: 7-amino-5-(3-fluorophenoxy)-2-(2-furyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine as colourless crystals (crystallised from ethanol), m.p. 271-273’C; microanalysis, found: C, 54.1; H, 2.8; N,

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- 32 26.6; C₁₄H_gN₆FO₂ requires: C, 53.8; B, 2.9; N, 26.9Z; NMR 6.7(dd, IB, furyl-4H), 7.1-7.3(m, 4B, phenoxy > furyl-3B), 7.4-7.6(m, 1H, phenoxy), 7.9(d, 1H, furyl-5B), 8.8-9.2(d, 2H, NH^; m/e 312 (MJ; [Example 13): 7-amino-2-(2-fury 1)-5-(2-phenylethoxy)-[ 1,2,4Jtriazolo[1,5-a][1,3,5]triazine as colourless crystals (crystallised from ethanol), m.p. 198-200°C; microanalysis, found: C, 59.5; H, 4.2;

N, 26.OZ; C₁₆H₁₄N_&0₂ requires: C, 59.6; H, 4.3; N, 26.1Z; NMR: 3.1 ,, (t, 2B, phenyl.CH₂), 4.5(t, 2H, CH₂O), 6.7(dd, 1H, £uryl-4H),

7.1(d, 1H, furyl-3H), 7.2-7.4(·, 5H, phenyl), 7.9(d, 1H, furyl-5H),

8.6-9.0(d, 2H, NH₂); m/e 323 (M+H)*;

[Example 14]: 7-amino-2-(2-furyl)-5-(2-phenoxyethoxy)-[l,2,4Jtriazolo[1,5-aJ[1,3,5]triazine as colourless crystals (crystallised from ethanol), m.p. 255-257°C; microanalysis, found: C, 57.1; H, 4.3,

N, 24.4Z; C₁₆B_1z,N₆O₃ requires: C, 56.8; H, 4.1; N, 24.8Z; NMR:

4.3(m, 2H, phenoxy .CB^BJ , 4.6(m, 2H, phenoxy.OCH₂), 6.7(dd, 1H, furyl-4H), 7.0(m, 3H, phenoxy), 7.1(d, 1H, furyl-3H), 7.3(m, 2H, phenoxy), 7.9(d, 1H, furyl-5H), 8.7-9.0(d, 2H, NBJ; m/e 339 (M+B)⁺; [Example 15]: 7-amino-2-(2-furyl)-5-(2-methoxyethoxy)-[l,2,4]triazolo(1,5-a][1,3,5]triazine as colourless crystals, m.p. 232-234°C; microanalysis, found: C, 48.2; H, 4.5; N, 30.4Z; ^C11^B12^N6°3 requires:

C.47.8; B, 4.3; N, 30.5Z; NMR: 3.7(m, 2B, CB-jOCBJ, 4.4(m,

2B, CH₃OCB₂CH₂), 6.7(dd, 1H, furyl-4B), 7.1(d, 1H, furyl-3H), 7.9(d,

IB, furyl-5H), 8.6-9.0(d, 2H, NHJ; m/e 277 (M+H)*;

[Example 16[: 7-amino-5-(4-cyanophenoxy)-2-(2-furyl)-[l,2,4]triazolo[ 1,5-a][1,3,5]triazine, as colourless crystals (crystallised from ethanol), m.p. >285°C; microanalysis, found: C, 56.6; B, 2.8; _s.

N, 30.9Z; C₁₅H_gN₇O₂ requires: C, 56.4; H, 2.8; N, 30.7Z; NMR: _#

6.7(dd, IB, furyl-4B), 7.1(d, 1H, furyl-3H), 7.5(d, 2H, phenoxy-H),

7.8-8.0(q+d, 3H, phenoxy + furyl-5H), 8.8-9.2(d, 2H, NHJ; m/e 319 (M⁺); and [Example 17]: 7-amino-5-butoxy-2-(2-furyl)-[l ,2,4] triazolo[l,5-a]11,3,5] triazine as colourless crystals (crystallised from ethanol), m.p. 177-178’C; microanalysis, found: C, 52.6; B, 4.8; N, 30.4Z;

^C12^H14^N6°2 ^re9^{uires: c}' ⁵²·⁵’ ^H’ ⁵*^{1; N}’ 30.6Z; NMR: 1.0(t, 3H, CHJ, 1.4(m, 2H, CB₃CH₂), 1.7(m, 2B, CH₂CB₂O), 4.3(t, 2B, CB₂0), 6.7(dd, 1H, furyl-4H), 7.1(d, IB, furyl-3H), 7.9(d, IB, furyl-5B), 8.5-8.9(d, 2B,

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- 33 NH₂); m/e 274 <M⁺).

Examples 18-19

Using a similar procedure to that described in Example 6, but using 3-methoxyphenol or allyl alcohol instead of ethanol, there were obtained:

(Example 18|: 7-amino-2-(2-furyl)-5-(3-methoxyphenoxy)-(l,2,4(triazolo(l,5-a](l,3,5Jtriazine vas obtained as colourless crystals (crystallised from ethanol), m.p. 226-227^eC; microanalysis, found: C, 55.6; H, 3.6; N, 25.52; requires: C, 55.5; H, 3.7; N,

25.92; NMR: 3.8(s, 3H, CHp, 6.7(dd, 1H, furyl-4H), 6.8(m, 3B, phenoxy), 7.1(d, 1H, furyl-3H), 7.35(m, 1H, phenoxy), 7.9(d, IB, furyl-5H) 8.8-9.l(d, 2H, NH^); m/e 324 (M*); and (Example 19(: 5-allyloxy-7-amino-2-(2-furyl)-(l,2,4Jtriazolo(1,5-a](1,3,5 J triazine as colourless crystals (crystallised from ethanol), m.p. 169-171°C, microanalysis, found: C, 51.5; H, 3.8; N, 32.52; C_HH_1ON₆O₂ requires: C, 51.4; H, 3.5; N, 32.72; NMR 4.8 (m, 2H, CH₂O), 5.2-5.5(m, 2H, CH2=CH.CHjO), 6.0-6.2(m, IB, CH₂=CB.CH₂O), 6.7(dd, 1H, furyl-4H), 7.1(d, IB, furyl-3H), 7.9(d, IB, furyl-5B),

8.6-9.O(d, 2H, NH₂); m/e 258 (M⁺).

Examples 20-25

Using a similar procedure to that described in Example 1, but starting from the appropriate hydroxy compound instead of phenol, there were obtained the following compounds:

(Example 20(: 7-amino-2-(2-furyl)-5-(2-aethoxyphenoxy)-(l,2,4]triazolo( 1,5-a][1,3,5]triazine as colourless crystals (crystallised from ethanol), m.p. 221-222°C, microanalysis, found: C, 55.2; H, 3.7; N, 25.0; H₂0, 0.72; O.IC^OH. 0.1251^0 requires: C, 55.2;

H, 3.7; N, 25.0; H₂0, 0.72; NMR: 3.8(s, 3H, CHp, 6.7(dd, IB, furyl-4H), 6.9-7.4(m, 5H, phenoxy + furyl-3H), 7.9(d, 1H, furyl-5H),

8.7-9.2(d, 2H, NH₂); NMR spectrum also contains C^H^OH (0.1 mole); m/e 324 (M⁺);

(Example 21]: 7-amino-5-(2-fluorophenoxy)-2-(2-furyl)-(l,2,4]triazolo(l,5-a](l,3,5]triazine as colourless crystals (crystallised from ethanol), m.p. 252-253°C; microanalysis, found: C, 53.4; H, 3.3; N,

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- 34 25.8; Η₂Ο, 1.22; C₁₄H₉N₆F0_r O.125C₂H₅OH. O.2H₂O requires: C, 53.2; H, 3.2; N, 26.1; H₂O, 1.12; NMR: 6.7(dd, IB, furyl-4H), 7.1(d, IB, furyl-3H), 7.2-7.5(a>, 4H, phenoxy), 7.9(d, IH, furyl-5fl), 8.8-9.3(d,

2H, NH2); m/e 312 (H⁺);

(Example 22]: 7-amino-2-(2-furyl)-5-(2-phenylthioethoxy)-(l,2,4(triazolo(l,5-aj(l,3,5]triazine as colourless crystals (crystallised from ethanol), m.p. 216-218°C; microanalysis, found: C, 54.4; B, 3.8;·» N, 23.32; C₁₆ ^H14^N6SO₂ requires: C, 54.2; H, 4.0; N, 23.72; NMR: 3.4(t, 2H, SCH₂), 4.4(t, 3H, OCHp, 6.7(dd, IH, furyl-4H), 7.1(d, IH, furyl-3H), 7.2-7.5(m, 5H, phenyl), 7.9(d, IH, furyl-5B),

8.6-9.0(d, 2H, NH₂); m/e 355 (M+H⁺);

(Example 23]: 7-amino-5-(4-fluorophenoxy)-2-(2-furyl)-(l,2,4(triazolo(1,5-a|[1,3,5 J triazine as colourless crystals (crystallised from ethanol) m.p. 277-278°C; microanalysis, found: C, 53.2; B, 3.2; N,

24.7; H₂0, 1.22; C₁₄ ^H9^N6^F02· O.4C₂H₅OH. 0.25 HjO requires: C, 53.0; H, 3.6; N, 25.1; H₂0, 1.32; NMR: 1.05(t, Cf^CHjOH), 3.45(q+d, CH-jCHjOH), 4.3(t, CH₃CH₂OH), 6.7(dd, IH, furyl-4H), 7.1(d, IB, furyl-3H), 7.3(d, 4H, phenoxy), 7.7(d, IH, furyl-5H), 9.0(br s, IB, NH^; m/e 313, (M>H)₊;

(Example 24(: 7-amino-5-(2-cyanophenoxy)-2-(2-furyl)-(l,2,4(triazolo[1,5-aJ (1,3,5]triazine as colourless crystals (crystallised fora methanol), m.p. >290’C; microanalysis, found: C, 56.7; H, 2.5;

N, 30.92; C₁₅H₉N_?O₂ requires: C, 56.4; H, 2.8; N, 30.72; NMR:

6.7(dd, IB, furyl-4H), 7.1(d, IH, furyl-3H), 7.5(m, 2H, phenoxy),

7.8-8.l(m, 3H, furyl-5H + phenoxy), 9.2(br s, 2H, NH₂); m/e 320 (M*H)*; and x (Example 25(: 7-amino-2-(2-furyl)-5-(3-isoxazolyloxy)-( 1,2,4Jtriazolo[1,5-a](1,3,5(triazine as colourless crystals (crystallised from 2-propanol), m.p. 274-275’C; microanalysis, found: C, 46.4;

H, 2.4; N, 34.12; C^f^N-^ requires: C, 46.3; H, 2.5; N, 34.42; NMR 6.7(dd, IH, £uryl-4H), 6.75(d, IH, isoxazole-4H), 7.2(d, IH, furyl-3H), 7.9(d, IH, furyl-5H), 8.9(d, 1H, isoxazole-5H),

9.0-9.4(br s, 2H, NH₂); m/e 286 <M₊H)\

Examples 26-40

Using a procedure similar to that described in Example 3, but

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- 35 using the appropriate amine instead of propylamine, the following compounds of formula I were obtained:(Example 26): 7-amino-5-cyclohexylamino-2-(2-£uryl)-( 1,2,4] triazolo(1,5-aJ(1,3,5]triazine as pale cream prisms, (crystallised from 2-propanol), m.p. 278-28O^eC (decomposition); microanalysis, found: C, 56.5; H, 5.7; Ν, 31.8Z; C^Hp^O. O.125C₃H_?OB requires: C, 56.3;

H, 5.9; N, 32.OX; NMR: 1.05(d, CHp, 3.8(m, CHOH), 4.3(d, CHOH),

I. l-1.4(complex, 5H, CH₂), 1.5-1.9(complex, 5B, CHj), 3.75(a, IH, NHCH), 6.68(q, IH, furyl-4H), 7.05(q, IH, furyl-5H), 7.25(1H, d, NH), 7.88(d, 10, furyl-3H), 7.95-8.3(complex, 20, NH₂>; m/e 299 (M*>; (Example 27(: 7-amino-2-(2-furyl)-5-phenylamino-(l,2,4]triazolo(1,5-aJ(1,3,5]triazine as pale yellow plates (crystallised from ethanol), m.p. 280°C; microanalysis, found: C, 57.3; H, 3.5; N, 33.IX;

^C14^H11^N7° ^re9^{uires: C}’ ⁵⁷-^{3; H}’ ³*^{8; N}’ ³³'⁴*; NMR: 6.7(q, IH, furyl-4H), 7.0(t, 10, g-phenyl-0), 7.1(q, 10, furyl-30), 7.3(t, 20, m-phenyl-H), 7.8(d, 20, o-phenyl-0), 7.88(d, IH, furyl-5H), 8.4(br,

20, N0₂) and 9.63(s, 10, NH); m/e 294 (M+H)*;

(Example 28(: 5-allylamino-7-amino-2-(2-furyl)-( 1,2,4(triazolo(l,5-aj(1,3,5 J triazine as pale yellow crystals (crystallised from ethyl acetate), m.p. 182-184’C; microanalysis, found: C, 51.5; H, 4.3;

N, 37.9Z; requires: C, 51.4; H, 4.3; N, 38.1Z; NMR:

3.95(complex, 20, C0₂N), 5.07(dd, 10, =CH), 5.17(dd, 10, =CH),

5.91(m, 10, =C0.C0₂), 6.68(dd, IE, furyl-40), 7.05(d, 10, furyl-3H), 7.56(br, IH, NH), 7.86(d, IH, furyl-5H) and 8.0-8.4(complex, 2H, NH₂); m/e 242, 257 <M⁺);

(Example 29]: 7-amino-2-(2-furyl)-5-pyrrolidino-(l,2,4] triazolo[l,5-a](l,3,5] triazine as a solid (crystallised from ethanol), m.p. > 300°C (decomposition); microanalysis found: Cf 53.4; H, 4.8; N, 35.9Z; ^C12^H13^N7° ^recl^ui^{res: c}» 53.1; 0, 4.8; N, 36.2Z; NMR: 1.91(complex, 4H, CH₂CH₂), 3.5O(br, 4H, CHjNCHp, 6.65(dd, IH, furyl-4H), 7.03(d, IB, furyl-3H), 7.83(m, IH, furyl-5H) and 8.19(br, 20, NH₂); m/e 271 (M⁺);

(Example 30 J: 7-amino-2-( 2- furyl)-5-morpholino- [1,2,4] triazolo (1,5-a ][ 1,3,5]triazine as a solid (crystallised from ethanol), m.p. > 300*C; microanalysis, found: C, 50.6; H, 4.3; N, 34.4Z; requires:

C, 50.2; H, 4.6; N, 34.1Z; NMR: 3.64-3.75(complex, 4H, CHp, 6.67(dd, IH, furyl-4H), 7.05(d, IH, furyl-3H), 7.86(m, IH, furyl-50) and

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- 36 8.32(br s. 2H, NH^; m/e 288 (M+H)*;

(Example 31J: 7-amino-5-benzylami no-2-( 2 - furyl) -11,2,4 J t riazo loll, 5-al(1,3,5]triazine as pale yellow plates (crystallised from ethanol), m.p. 222-224°C; microanalysis, found: C, 58.8; H, 4.1; N,

CH₂N), 6.65(dd, IH, furyl-4H), 7.04(d, IH, furyl-38),

7.15-7.4(complex, 58, phenyl), 7.85(d, IH, furyl-58), 7.93(t, 18, NH) j and 8.16(br, 28, NH^); m/e 307 (M*);

(Example 32j: 7-aaino-5-butylamino-2-(2-furyl)-(l,2,4]triazolo(l,5-aj(1,3,5(triazine as a solid (crystallised from 2-propanol), m.p. 220-221’C; microanalysis, found: C, 52.9; 8, 5.6; N, 35.5X; requires: C, 52.7; 8, 5.5; N, 35.9X; NMR: 0.90<t, 3H, CHj),

1.32(q, 2H, CHjCHp, 1.50(m, 2H, C8₂CH₂CB₃), 3.32(m, CB^), 6.66(d,

IH, furyl-4H), 7.04(s, IH, furyl-3H), 7.38(br s, IB, NH), 7.84(s, 18, furyl-5H) and 8.05(br s, 2H, NHp; m/e 274(M+H)*;

(Example 33(: 7-amino-5-ethylamino-2-(2-furyl)-(l,2,4Jtriazolo(1,5-a)[1,3,5]triazine as colourless prisms (crystallised from ethanol), m.p. 230-232’C; microanalysis, found: C, 49.4; H, 4.2; N, 40.OX; CjqH^jN^O requires: C, 49.0; B, 4.5; N, 40.OX; NMR 1.12(t, 38, CHp, 3.32(m,

CH₂), 6.67(dd, IH, furyl-4H), 7.03(d, 18, furyl-38), 7.38(t, IB, NH), 7.86(d, 18, furyl-58) and 8.07(br, 28, NH₂); m/e 245 (M*);

(Example 34): 7-amino-2-(2-furyl)-5-isopropylamino-(l,2,4] triazolo(1,5-aJ (1,3,5J triazine as colourless prisms (crystallised from ethanol), m.p. 226-8^eC; microanalysis, found: C, 51.4; H, 5.0;

N, 37.5X; ^Hj^O requires: C, 51.0; H, 5.1; N, 37.8X; NMR 1.15(d, 6H, CH₃), 4.08(m, 18, CH.N), 6.66(dd, IH, furyl-48), 7.03(d_r> IH, furyl-3H), 7.26(br, IH, NH), 7.84(d, IH, furyl-5H) and 8.03(br, IH, NH₂); m/e 259(M*); ' ₃ (Example 35(: 7-amino-2-(2-furyl)-5-(2-phenylethyl)amino-(l,2,4(triazolo[l,5-a)(l,3,5(triazine as pale cream crystals (crystallised from ethanol), m.p. 258-260’C; microanalysis, found: C, 60.1; H, 4.8;

N, 30.5X; C₁₆H₁₅N_?O requires: C, 59.8; H, 4.7; N, 30.5X; NMR: 2.86(t, 2H, CH₂Ph), 3.5O(q, 2H, CH₂NH), 6.68(dd, IH, furyl-4H), 7.66(d, IH, furyl-3H), 7.l-7.4(complex, 5H, ArH), 7.45(br t, IH, NH), 7.87(d, IH, furyl-5H) and 8.12(br, 2H, N^); m/e 321 (M*);

(Bxample 36): 7-amino-2-(2-furyl)-5-(2-furyl)methylamino-) 1,2,4(BAD ORIGINAL

AP Ο Ο Ο 2 4 8

- 37 triazolo]1,5-a ][1,3,5]triazine as pale cream crystals (crystallised from ethanol), m.p. 196-198’C; microanalysis, found: C, 52.8, B, 4.6, N, 30.3Z; ^c13^H11^N7°2- 0-66C₂H₅0H requires: C, 52.5; H, 4.6; N, 29.9Z; NMR: 1.06(t, (¾). 3.45(m, CHj), 4.31(t, 08), 4.49(d, 28, CHjN,

6.28(s, IH, furylmethyl-3H), 6.37(dd, IH, furylmethyl-4H), 6.66(dd,

IH, furyl-4H), 7.05(d, IB, furyl-3H), 7.54(s, IH, furylmethyl-5H), 7.85(br s, 28, furyl-5H ♦ NB) and 8.18(br, 2H, NH^; m/e 297 (M+); (Example 37]: (S)-7-amino-5-(e-methylbenzylamino]-2-(2-furyl)-(l,2,4Jtriazolof1,5-aJ(1,3,5(triazine as a solid (crystallised from toluene), m.p. 136-140°C; microanalysis, found: C, 62.1; H, 5.1; N, 28.3Z;

^C16^H15^N7°· °-^3C7^B8 ^re9^{uires: c}» 62.3; ^Η» 5.0; 28.IX; NMR

l. 44(d, 3H, CH₃), 2.29(s, Ph.CH₃), 5.18(t, IH, CHN), 6.65(dd,

IH, furyl-4H), 7.03(d, IH, furyl-3H), 7.l-7.5(complex, 58, phenyl), 7.83(s, IH, furyl-58), 7.94(d, IH, NH) and 8.09(s, 2H, NI^); m/e 322 (M+H)⁺;

(Example 38(: 7-amino-5-isobutylamino-2-(2-furyl)-[l,2,4J triazolo[1,5-aJ(1,3,5(triazine as a solid (crystallised from ethyl acetate),

m. p. 244-245 °C; microanalysis, found: C, 52.9; H, 5.5; N, 36.1Z; ^C12^H15^N7° ^re<l^{uires: c}’ 52.7; ^H’ ⁵·^{5ί N}’ 35.9X; NMR: 0.89(d, 68, CH₃), 1.88(m, IH, CH(CH₃)₂J, 3.09(t, 28, CHjN), 6.65(dd, IH, furyl-4H), 7.03(d, IH, furyl-3H), 7.43(t, IH, NH), 7.84(d, IH, furyl-5H) and 8.03(br s, 2H, NHj); m/e 274 (M+H)⁺;

(Example 39]: 7-aaino-5-dimethylamino-2-(2-furyl)-(l,2,4] triazolo[1,5-a](1,3,5J triazine as a solid (crystallised from 2-propanol), m.p. > 298°C; microanalysis, found: C, 49.4; H, 4.1; N, 39.9Z; C^qH^N^O requires: C, 49.0; H, 4.5; N, 40.0Z; NMR: 3.13(s, 68, CH₃),

6.65(dd, IH, furyl-4H), 7.03(d, IH, furyl-3H), 7.8(s, IH, furyl-5H) and 8.22(br s, 28, NHj); m/e 246(M+H)⁺; and (Example 40]: 7-amino-5-(2-dimethylaminoethyl)amino-2-(2-furyl)(1,2,4]triazolo(1,5-a]]1,3,5]triazine as colourless prisms, m.p. 233-235 °C; microanalysis, found: C, 50.3; H, 5.8; N, 38.7Z; ^εΐ2^Ηΐ6^Ν8θ requires: C, 50.0; H, 5.6; N, 38.9Z; NMR: 2.2O(s, 6H, N(CH₃)₂J,

3.48(m, CH₂CH₂NH); 6.66(dd, IH, furyl-4H), 7.04(d, IH, furyl-3H), 7.20(br, 18, NH), 7.85(s, IH, furyl-5H) and 8.09(br, 2H, NHp.

BAD ORIGINAL A

- 38 Examples 41-44

Using a procedure similar to that described in Example 2, the following compounds of formula I were obtained starting with the appropriate thiol:IExample 411: 7-amino-5-cyclopenty1thio-2-(2-fury1)-(1,2,4(1riazolo(1,5-a][1,3,5Jtriazine as a solid (crystallised from methanol), m.p. ’4 213-214’C; microanalysis, found: C, 51.9; H, 4.4; N, 28.1.Z; fc ^C13^H14^N6^{SO re}9^{uires: c}> 51.7; ^Η» ⁴·⁶ί ^Ν» 27.8Z; NMR: 1.63(a, 6H, CH.CH₂CH₂.CH), 2.21(m, 2H, CH), 3.98(m, IH, CH-S), 6.7O(dd, IH, furyl-4H), 7.16(dd, IH, furyl-3H), 7.9O(m, IH, furyl-5H) and 8.80(br d, 2H, NH₂); m/e 302 (M*);

(Example 42(: methyl 5-(7-amino-2-(2-furyl)-(l,2,4Jtriazolo(l,5-a|(1,3,5(triazine)thioacetate as a solid (crystallised from methanol), m.p. 265-267’C (decomposition); microanalysis, found: C, 43.2; H, 3.3; N, 27.5Z; C₁₁H_1ON_&SO₃ requires: C, 43.1; H, 3.3; N, 27.4X; NMR:

3.69(s, 3H, CH₃), 4.06(s, 2H, CH₂S), 6.71(dd, IH, furyl-4H), 7.18(d, IH, furyl-3H), 7.92(m, IH, furyl-5H) and 8.92(br s, 2H, Ng₂); m/e 302 (M*);

(Example 43(: 7-amino-2-(2-furyl)-5-(2-furyl)methylthio-(l,2,4Jtriazolo]1,5-aJ]1,3,5]triazine ^{as a} solid (crystallised from methanol), m.p. 246-247’C; microanalysis, found: C, 49.9; H, 3.1;

N, 26.3X; requires: C, 49.7; H, 3.2; N, 26.7Z; NMR:

4.46(s, 2H, CH₂.S), 6.39(m, 2H, furylmethyl 3H+4H), 6.70(dd, IH, furyl-4H), 7.17(d, IH, furyl-3H), 7.56(s, IH, furylmethyl 5-H),

7.9O(s, IH, furyl-5H) and 8.90(br d, 2H, NHp; m/e 314 (M*); and (Example 44(: 7-amino-5-benzylthio-2-(2-fury1)-]1,2,4(triazolo(1,5-a(?(1,3,5]triazine as a solid, (crystallised from ethanol), m.p. ~

273-275’C; microanalysis, found: C, 55.8; H, 3.6; N, 25.9Z; Ο^Η^ΝθΟδ requires: C, 55.5; H, 3.7; N, 25.9Z; NMR: 4.41(s, 2H, CH₂S), 6.7O(dd, IH, furyl-4H), 7.18(d, IH, furyl-3H), 7.2-7.6(complex, 5H, phenyl-H), 7.91(m, IH, furyl-5H) and 8.81(br d, 2H, NHp, m/e 291, 324 (M*);

Examples 45-47

Using a similar procedure to that described in part 2 of Example 1 the following compounds were obtained:[Example 45]: 7-amino-2-(3-furyl)-5-methylthio-(l,2,4]triazolo(l,5-a(rBAD ORIGINAL

AP000248

- 39 (1,3,5]triazine as a solid (crystallised from methanol), m.p. 279-281 °C; microanalysis, found: C, 43.1; H, 3.3; N, 33.72; CgHgN^OS requires: C, 43.5; H, 3.2; N, 33.92; NMR: 2.5O(s, SCH-j), 6.93(d, IH, furyl-4H), 7.83(t, IB, furyl-5H), 8.30(d, IH, 2-furyl H) and 8.74(br d, 2H, NH₂);

(Example 46(: 7-amino-2-(5-chloro-2-furyl)-5-methylthio-(l,2,4Jtriazolo(l,5-a)(l,3,5]triazine as a solid (crystallised from ethanol), m.p. 273-275’C; NMR: 2.50,(s, 3H,SCH.j), 6.73(d, IB, furyl-4B), 7.23(d, IH, furyl-30), 8.86 (br d, 2H, NH₂); and (Example 47(: 7-amino-2-(5-methyl-2-furyl)-5-methylthio-(l,2,4]triazolo(1,5-aJ(1,3,5]triazine as a solid (crystallised from ethanol), m.p. 266-268’C; microanalysis, found: C, 46.2; H, 3.6; N, 32.IX;

^C10^H10^N6^{0S re<}1^{uires: c}’ ⁴⁵·^θ; ^Η» ³·^θί ^N’ 32.IX; NMR 2.38(s, 3H, CHg), 2.5O(s, SCHp, 6.31(d, IH, furyl-4H), 7.04(d, IH, furyl-3H) and 8.80(d, 2H, NH₂); m/e 263 (M+H)*.

Examples 48-51

Using a similar procedure to that described in Example 1 but starting from the appropriate methyithio derivative and phenol, there were obtained the following compounds of formula I:(Example 48(: 7-amino-2-(3-furyl)-5-phenoxy-(1,2,4(triazolo(l,5-a((1,3,5(triazine as a solid (crystallised from methanol), m.p.

286-287*C (decomposition); microanalysis, found: C, 57.5; B, 3.3; N, 28.62; C₁₄H₁₀N₆0₂ requires: C, 57.1; H, 3.4; N, 28.62; NMR: 6.91(m,

IB, furyl-4H), 7.25(m, 3H, phenyl o- + £-0), 7.83(t, IH, furyl-5H), 8.27(s, IH, furyl-2H) and 8.86(d, 2H, NH₂); m/e 294 (M)₊;

(Example 49(: 7-amino-2-(5-chloro-2-fury1)-5-(2-fluorophenoxy)-(1,2,4] triazolo(1,5-aJ(1,3,5(triazine as a solid (crystallised from ethanol), m.p. 286-288’C; microanalysis, found: C, 48.5; H, 2.2; N, 24.1Z; C₁₄HgClFN₆0₂ requires: C, 48.5; H, 2.3; N, 24.2Z; NMR: 6.72(d,

IH, furyl-4H), 7.18(d, IH, furyl-3H), 7.2-7.5(complex, 4H, phenyl) and 9.08(br s, 2H, Nl^); m/e 346, (M)+;

(Example 50(: 7-aaino-2-(5-aethyl-2-furyl)-5-phenoxy-(l,2,4Jtriazolo[ 1,5-aJ(1,3,5(triazine as a solid (crystallised from ethanol), m.p. 227-228’C; microanalysis, found: C, 57.8; H, 4.3; N, 25.3Z; ^ci5^Hi2^N6°2 0.5 C₂H₅OH requires: C, 58.0; H, 4.5; N, 25.42; NMR 2.38(s, 3H, CHg),

BAD ORIGINAL ft θ ί S' Ο Ο 0 ^C»A

- 40 6.31(d, 1Η, furyl-4H), 7.00(d, 1H, furyl-3H), 7.25(complex, 38, phenyl o— + £-H), 7.45(t, 28, phenyl m-H) and 8.94(br d,2H, NHj);

[Example 511: 7-amino-5-(2-methoxyethoxy)-2-(5-methyl-2-furyl)[l,2,41triazololl,5-a|[l,3,5|triazine as a solid (crystallised form ethanol), m.p. 220-222’C; microanalysis, found: C, 50.0; 8, 4.6; N,

29.OX; C.,H..N,0, requires C, 49.6; H, 4.8; N, 29.OX; NMR 2.37(s, 3H, u 1* b J

CH-j), 3.30(s, CH₃), 3-65( t, 2H, Cl^OCHp, 4.41(t, 2H, CHjCH^),

6.30(m, 1H, £uryl-4H), 7.01(d. 18, £uryl-3H) and 8.75(br d, 2H, NH^); m/e 291 — -/.

Examples 52-54

Using a similar procedure to that described in Example 3 but starting from the appropriate methylthio derivative and amine, there were obtained the following compounds of formula I:[ Example 52 J: 7-aaino-5-cyclohexylamino-2-(3-furyl)-(1,2,4]triazoio[1,5-a ][1,3,5]triazine as a solid (crystallised from methanol), m.p. 254-256’C (decomposition); microanalysis, found: C, 56.4; H, 5.7;

N, 32.82; requires C, 56.2; H, 5.7; N, 32.8X; NMR:

l. 0-1.4(complex, 5H, CH2), 1.5-2.0(complex, 5H, CH₂), 3.74(br s, 1H, CHN), 6.88(m, 1H, furyl-4H), 7.2-7.4(complex t and d rotamers, 1H, CHNH), 7-81(t, 1H, furyl-5H), 7.95(br s, 2H, NH₂) and 8.22(s, 1H, £uryl-2H); m/e 299 (M)*;

[Example 531: 7-amino-2-(5-chloro-2-£uryl)-5-cyclohexylamino-[1,2,4Jtriazolo[l,5-a][1,3,5]triazine as a solid (crystallised from ethanol),

m. p. >300°C; microanalysis, found: C, 50.8; H, 4.6; N, 28.4X; C_uH₁₆C1N₇0. 0.2C_oH₅OH requires: C, 50.5; H, 4.9; N, 28.6X; NMR:

l. l-1.9(complex, 10H, CHp, J.74(br s, 1H, CHN), 6.68(d, 1H, furyl-4H), 7.09(d, 1H, furyl-3H), 7.32(complex,' 1H, NH) and

8.06(s, 2H, NH₂); m/e 333, (M)⁺; and [Example 54]: 7-amino-2-(5-methyl-2-furyl)-5-propylamino-[ 1,2,4]triazolo[l,5-a][l,3,5]triazine as a solid (crystallised from ethanol),

m. p. 23O-231°C; microanalysis, found: C, 53.1; H, 5.5; N, 35.8X; ^C12^H15^N7° ^re(l^u^^{res: C}’ 52.7; H, 5.5; N, 35.9; NMR: 0.89(t, 3H, CH^), 1.52(m, 2H, CHp, 2.36(s, 3H, CHp, 3.20(m, 2H, CH₂N), 6.26(m,

1H, furyl-4H), 6.91(d, 1H, £uryl-3H), 7.35(br s, 1H, NH) and 8.01(br s, 2H, NH₂).

BAD ORIGINAL

AP000248

- 41 Examples 55-58

Using a similar procedure to that described in Example 2 but starting vith the appropriate methylthio derivative and thiophenol, the following compounds of formula I were obtained:[Example 55 [: 7-amino-2-(3-furyl)-5-phenylthio-l1,2,4[triazolo[ 1,5-aJ[1,3,5]triazine as a solid (crystallised fro· methanol), m.p. 297-298’C (decomposition); microanalysis, found: C, 54.2; H, 3.1;

N, 26.62; C^H^OS, 0.05CH₃0H requires: C, 54.1; H, 3.3; N, 26.952; NMR: 6.91(d, IH, furyl-4H), 7.47-7.66(complex, 5H, phenyl), 7.83(t,

IH, furyl-5fl), 8.27(s, IH, furyl-2H) and 8.83(br d, 2H, NHj); m/e 311 (M+H)+;

[Example 561: 7-amino-5-(4-fluorophenylthio)-2-(3-furyl)-[1,2,4Jtr iazolo(1,5-aJ[1,3,5 J triazine as a solid (crystallised from ethanol), m.p. 314-315°C (decomposition); microanalysis, found: C, 51.5; H, 2.8; N, 25.42; C₁₄H₁₉FN_&0S requires: C, 51.2; H, 2.7; N, 25.62; NMR:

6.90(d, IH, furyl-4H), 7.32(t, 2H, phenyl), 6.67(m, 2H, phenyl),

7.81(t, IH, furyl-5H), 8.26(s, 1H, furyl-2H) and 8.83(br d, 2H, NHj); m/e 328 (M)*;

[Example 57j: 7-amino-5-cyclopentylthio-2-(3-furyl)-[1,2,4[triazolo[ 1,5-aJ[1,3,5}triazine as a solid (crystallised from methanol), m.p. 260-261’C; microanalysis, found: C, 52.0; H, 4.8; N, 28.22; C^H^N^OS requires C, 51.7; H, 4.6; N, 27.82; NMR: 1.5-1.80(complex, 6H, CHj), 2.21(m, 2H, CH₂SCH₂), 3.98(m, IH, CHS), 6.96(d, IH, furyl-4H),

7.35(t, IH, furyl-5H), 8.32(s, IH, furyl-2H) and 8.72(br d, 2H, NHj); m/e 303 (M+H)*; and [Example 58 [: 7-amino-2-(5-chloro-2-furyl)-5-phenylthio-|l,2,4Jtriazoloj1,5-a][1,3,5 J triazine as a solid (crystallised from ethanol), m.p. >300’C; microanalysis, found: C, 48.6; H, 2.4; N, 24.22; C^HgClNgOS requires: C, 48.7; H, 2.6; N, 24.42; NMR 6.72(d,

IH, furyl-4H), 7.18(d, IH, furyl-3H), 7.51(complex, 3H, phenyl o+g-H),

7.64(complex, 2H, phenyl m-H) a/id 9.04(br d, 2H, NH₂); m/e 345 (M+H) ⁺ .

Example 59

Using a similar procedure to that described in part 2 of Example 1, 7-amino-5-methylthio-2-(2-thienyl)-!1,2,4Jtriazolo(1,5-aJ[ 1,3,5 J triazine was obtained as a solid (crystallised from methanol),

BAD ORIGINAL ft

- 42 m.p. 263-265’C (decomposition); microanalysis, found: C, 40.7; H, 3.7; N, 29.5X; C^gN^S?. O.6CH.jOH requires: C, 40.8; H, 3.7; N, 29.82; NMR: 2.51(s, SCH₃), 3.18(s, CH-jOH), 7.23(dd, IH, thienyl-4H), 7.77(complex, 2H, thieny1-3H+5H) and 8.77(br d, 28, NH₂); m/e 264<H⁺).

Examples 60-61

Using a similar procedure to that described in Example 1, but using the appropriate methylthio derivative and phenol, there were obtained the following compounds of formula I:(Example 60]: 7-a>ino-5-phenoxy-2-(2-thienyl)-(1,2,4]triazolo[l,5-a](1,3,5 J triazine as a solid, m.p. 285-287’C, after recrystallisation from ethanol; microanalysis, found: C, 54.4; H, 3.2; N, 26.52; ^C14^H10^N6^0S requires: ^c’ 54.2; ^H’ ³·²’ ^Ν· ²6·8Ζ; NMR: 7.25(complex, 4H, phenyl + thienyl-4H), 7.45{t, 2H, phenyl), 7.77(complex, 2H, thienyl-3H+5H) and 8.9(br d, 2H, NH₂); m/e 310 (M*); and (Example 611: 7-amino-5-(2-methoxyphenoxy)-2-(2-thienyl)-(l,2,4]triazolo[l,5-aJ(l,3,5Jtriazine as a solid, m.p. 257-259’C, after recrystallisation from ethanol; microanalysis, found: C, 52.9;

N, 24.6X; C₁₅ ^H12^N6°2^S requires: C, 53.0; H, 3.5; N, 24.7X; NMR j,

3H, CH-jO), 6.99(m, IH, thienyl-4H), 7.1-7.3<coaplex, 4H, phenyl 7.74(m, 2H, thienyI-3H+5H) and 8.81(br d, 2H, NH₂); m/e 341 (M-H)\

Example 62-63

Using a similar procedure to that described in Example 3, but using the appropriate methylthio derivative and amino compound, there vere obtained the following compounds of formula I:(Example 62]: 7-amino-5-cyclohexylamino-2-(2-thienyl)-[1,2,4]triazolo(1,5-a]11,3,5]triazine as a solid, m.p. 2892-91’C; microanalysis, found: C, 52.5; H, 5.3; N, 30.4X; C^HpNyS 0.25 H₂0 requires:

C, 52.5; H, 5.5; N, 30.6X; NMR 1.0-2.0(complex, 10H, CHp, 3.73(br s, IH, CHN), 7.21(dd, IH, thienyl-4H), 7.26(m, IH, NH), 7.72(m, 2H, thienyl-3H,5H) and 7.99(br s, 2H, NHj); m/e 316 (M+H*); and (Example 63}: 7-amino-5-propylamino-2-(2-thienyl)-[1,2,4]triazolo[ 1,5-a][1,3,5]triazine as a solid, m.p. 225-6’C, after recrystallisation from ethanol; microanalysis, found: C, 48.5; H, 4.7; N, 35.52; (0.1 C^OH) requires: C, 48.1; H, 4.9; N, 35.IX;

^SAD ORIGINAL $

AP000248

- 43 NMR 0-89(t, 3H, Cf^), 1.54(m, 2H, CHj), 3.24(m, 2H, CH₂N), 7.18(dd,

1H, thienyl-4H), 7.40<t, 1H, NH), 7.7O(m, 2H, thienyl-3H,5H) and 7.99(br s, 2H, Nl^); m/e 276 (M+H)⁺.

Example 64

Using a similar procedure to that described in Example 2 but starting from 7-amino-5-methylthio-2-(2-thienyl)-(l,2,4)triazolo[l,5-a[[l,3,5Jtriazine and using thiophenol, there was obtained 7-amino-5-phenylthio-2-(2-thienyl)-[1,2,4 Jtriazolo|l,5-a1(1,3,51triazine as a solid, m.p. >300^eC (decomposition); microanalysis, found: C, 51.9; H, 3.1; N, 25.62; requires: C, 51.5; H,

3.1; N, 25.82; NMR 7.2O(dd, 1Η, thienyl-4H), 7.4-7.8(complex, 1H, phenyl-H, thienyl-3H,5H) and 8.83(d, 2H, NH₂).

Examples 65-80

Using a procedure similar to that described in Example 3, but using the appropriate amine instead of propylamine, the following compounds of formula I were obtained:[Example 65): 7-amino-2-(2-furyl)-5-(3-pyridylmethyl)aeino[l,2,4Jtriazolo[l,5-aJ[l,3,5-Jtriazine as colourless prisms (crystallised from methanol), m.p. 261-262°C; microanalysis, found: C,54.7; H,3.8; N,36.32; Ο^Η^ΝθΟ requires: C,54.5; H,3.9; N,36.42; NMR: 4.5(d,2H, CHp, 6.5(q,lH, furyl-4H), 7.0(s,lH, furyl-3H), 7.3(complex, 1H, pyridyl-5H), 7.75(d,lH, pyridyl-4H), 7.85(s,lH, furyl-5H), 8.0(broad s,lH), NH), 8.2(broad d,2H, NH₂), 8.45(d,lH, pyridyl-6H), 8.55(s,lH, pyridyl-2H) m/e 309 (M+H)*.

[Example 66): 7-amino-2-(2-furyl)-5-n-pentylamino-[1,2,4Jtriazolof1,5-aJ[1,3,5 J triazine as colourless prisms (crystallised from ethanol), m.p. 219-220’C; microanalysis, found: C,54.6; H,6.1;

N,33.92; C^Hp^O requires: C.54.3; H, 6.0; N,34.12; NMR: O.9(t,3H,

CH-j), 1.2-1.4(complex, 4H, Cl^CHp, 1.55(complex, 2H CH₂CH₂N),

3.2(t,2H, CH₂N), 6.65(q,lH, furyl-4H), 7.05(d,lH, furyl-3H),

7.3-7.5(complex, 1H, NH), 7.85(q,1H, furyl-5H), 7.9-8.4(broad d, 2H,

BAD ORIGINAL &

- 44 NH₂); m/e 287 (M+).

(Example 67]: 7-amino-5-cyclopropylmethylamino-2-(2-furyl)-(1,2,4]triazolo]1,5-a] (1,3,5]triazine as colourless prisms (crystallised from toluene/ethyl acetate mixture), m.p. 188-191’C; microanalysis, found: C.53.5; B,5.0; N,36.52; ^cj2^H13^7° ^re9^ui^res: C,53.1; H,4.8; N,36.2Z; NMR: 0.1-0.5 (complex, 4H, cyclopropyl-CHj), l.l(complex, IB, CH), 3.15(t,3B, CB₂N), 6.65(q,lH, furyl-4B), 7.05(d,lB, furyl-3H),

7.4-7.6(complex, IB, NH), 7.85(d,lH, furyl-5H), 8.0-8.5(broad d,2H, NH₂); m/e 272 (M+H)\ (Example 68]: (R)-7-amino-2-(2-furyl-7-j o-aethylbenzylaminoj(1,2,4]triazolo{l,3,5]triazine as a colourless microcrystalline povder (crystallised from toluene) m.p. range; microanalysis, found: C,62.5; H,5.3; N,28.3Z; C₁₆H₁₅N_?O + 0.33 C_?H_g requires: C,62.5; B,5.1;

N,27.9Z; NMR: 1.5(d,3H, CH^), 2.3(s,lH equivalent, toluene CH^), 5.0-5.3 (complex, IB, CH), 6.65(q,lH, furyl-4H), 7.05(d,lH, furyl-3B), 7.1-7.5 (complex, 5H, phenyl-H + toluene), 7.85(d,lH, furyl-5H), 7.9-8.4 (complex, 3H, NH + NH₂); m/e 322 (M+H)⁺.

(Example 69]: 7-amino-5-(2-(4-chlorophenyl)ethylamino]-2-(2furyl)-(l,2,4Jtriazolo]1,5-a] (1,3,51 triazine as pale yellov prisms (crystallised from ethanol), m.p.'259-261’C; microanalysis, found: C,54.3; H,3.8; N,27.5Z; C₁₆H₁₄N_?ClO requires: C.54.0; H,3.9; N.27.6Z; NMR: 2.85(t,2H, Cl^Ar), 3.5(m,2H, CH-jN), 6.65(q,lH, furyl-4H), 7.05(q,lB, furyl-3H), 7.2-7.4 (complex, 4H, phenyl-H), 7.4-7.6 (complex, 1H, NH), 7.35(d,lH, furyl-5H), 8.0-8.5(broad d,2H, NH₂);

356 (M+H)\ (Example 70]: 7-amino-2-(2-furyl)-5-(exo-2-norbornyl)amino-(1,2,4]triazolof1,5-a] (l,3,5]triazine as colourless prisms (crystallised from 2-propanol) m.p. 290-293’C; microanalysis, found: C,58.5; H,6.9; N.26.6Z; C^HpN-jO.C^OH requires: C,58.3; H,6.7; N,26.4Z; NMR: l,05(d,6H, (CH₃)₂), 1.1-1.7 (complex, 8H, norbornyl-CHp, 2.2 (broad s,lH, norbornyl-CH), 3.6-4.4(broad d, 1H, NH), 3.8(m,lH, CHOH), 6.65(q,lH, furyl-4H), 7.05(d,lH, furyl-3H), 7.2-7.5 (complex, 1H, NH), bad original

AP000248

- 45 7.85(d,lH, furyl-5H), 7.9-8.4(broad d,2H, NHj); m/e 312 (M+H)+.

[Example 71]: 7-amino-2-(2-furyl)-5-[2-(2-methoxyphenyl)ethylamino]-[1,2,4]triazolo[ 1,5-a] [1,3,5]triazine as colourless prisms (crystallised from ethanol), m.p. 189-190°C; microanalysis, found: C.58.3; H,5.0; N,28.32; C₁₇H₁₇N_?O₂ requires: C,58.1; N,4.9; N.27.9Z; NMR: 2.8(t,2H, ArCH₂), 3.45(t,2H, CH₂N), 3.8(s,3H, CHjO), 6.7(q,lH, furyl-4H), 6.8-7.0 (complex, 2H, ArH), 7.05(q,lH, furyl-3H), 7.1-7.3 (complex, 2H, ArH), 7.3-7.5 (broad t,lH, NH), 7.85(d,lH, furyl-5H), 8.0-8.4(broad d,2H, NHj); m/e 352 (M+H>⁺.

[Example 72[: 7-amino-5-(2-fluorobenzyl)amino-2-(2-furyl)[1,2,4-Jtriazolof1,5-a] 11,3,5)triazine as pale yellow prisms (crystallised from ethanol), m.p.244-246°C; microanalysis, found: C.55.5; H,3.6; N.30.12; C₁₅H₁₂FN_?O requires: C.55.4; H,3.7; N,30.12; NMR: 4.5(d,2H, CHp. 6.65(q,lH, furyl-4H), 7.0-7.5 (complex, 5H, ArH + furyl-3H), 7.85(d,lH, furyl-5H), 7.9(broad t,lH, NH), 8.0-8.4(broad s,lH, NH₂); m/e 326 (M+H)⁺.

[Example 73[: 7-amino-2-(2-furyl)-5-(3-methoxybenzyl)amino[1.2.4J- triazolo[1,5-aJ [1,3,5]triazine as a pale yellow prisms (crystallised from ethyl acetate), m.p. 194-196^OC; microanalysis, found: C,57.3; H,4.3; N,29.22; requires: C,57.O; H,4.4;

N,29.12; NMR: 3.75(s,3H, CHp, 4.5(d,2H, CHp, 6.65(q,lH, furyl-4H), 6.8 (complex, 1H, phenyl-4H), 6.9 (complex, 2H, phenyl-2H and 6H), 7.05(d,lH, furyl-3H), 7.2(t,lH, phenyl-5H), 7.85(d,lH, furyl-5H), 7.35-8.05 (complex, ΙΗ,ΝΗ), 8.0-8.5(broad d,2H, NH₂); m/e 338 (M+H)\ [Example 74]: 7-amino-2-(2-furyl)-5-(3,4-methylenedioxybenzyl)amino-[1,2,4J-triazolo[ 1,5-a[ [1,3,5]triazine, pale yellow prisms (crystallised from ethanol), m.p. 217-219’C (decomposed); microanalysis, found: C,55.0; H,3.5; N,28.0; requires:

C,54.7; H,3.7; N,27.92. NMR: 4.4(d,2H, CHp, 5.95(s,2H, OCH₂O), 6.65(q,lH, furyl-4H), 6.7-6.9 (complex, 3H, phenyl-H), 7.05(d,lH, furyl-3H), 7.85(d,lH, furyl-5H), 7.85-8.05 (complex, 1H, NH),

8.05-8.5(broad d,2H, NHp; m/e 352 (M+H)*.

BAD ORIGINAL ft

- 46 (Example 75J: 7-amino-5-(2-(4-(2-t-butoxycarbonylethyl)phenylJethylaeino(-2-(2-furyl)-{1,2,4(triazolo-[1,5-aJ(1,3,5(triazine, as colourless prisms (crystallised from 2-propanol), m.p.: 197-199’C; microanalysis, found: C,61.4; H,6.2; N,21.8Z; ^re<J^ui^res; $

C.61.5; H,6.1; N,21.8X; NMR: 1.35(s,9H, (CHpp, 2.5(t,2H, CH₂C0), ,

2.7-2.9 (complex, 4H, CH₂-Ar-CH₂), 3.5(q,2H, CH₂N), 6.65(q,lH, furyl-4H), 7.05(q,lH, furyl-3H), 7.15(q,4H, phenyl-H), 7.4-7.6 (complex, IH, NH), 7.85(d,lH, furyl-5H), 8.0-8.4(broad d,2H, NHj); m/e 450 (M+H)*.

The required 2-(4-(2-t-butoxycarbonylethyl)phenyl]ethylamine was prepared as described in Journal of Medicinal Chemistry, 1990, 33, 1919-1924.

(Example 76(: 7-amino-2-(2-furyl)-5-(2-(4-hydroxyphenylacetamido)ethylJamino(l,2,4]-triazolo[1,5-aJ (1,3,5(triazine as colourless prisms (crystallised from ethanol), m.p. 242-245^eC (decomposed); microanalysis, found: C,54.7; H,4.9; N,28.82; ^ιθΗ^θΝθΟ^ requires: C,54.8; H.4.6; N.28.42; NMR: 3.1-3.5 (complex, 6H, 3CH₂>, 6.65 (complex, 3H, phenyl-H + furyl-4H), 7.05 (complex, 3H, phenyl H + furyl-3H), 7.3-7.5(broad t,lH, NH), 7.85(q,lH, furyl-5H), 7.95(broad t,lH, NH), 8.0-8.5(broad d,2H, NHp, 9.15(broad s,lH, OH); m/e 395 (M+H)*.

The starting amine was prepared as follows: A solution of ethyl 4-hydroxyphenylacetate (18 g) in 1,2-diaminoethane (50 ml) was heated under reflux overnight. The solvent was removed in vacuo and the residue triturated with acetonitrile to yield a solid (12.4 g). This was crystallised from an acetonitrile/ethanol mixture (1:1 v/v) to give

2-aminoethyl-(4-hydroxyphenyl)acetamide as colourless crystals, m.p. 168-170’C, which was essentially pure by TLC and was used without further characterisation.

BAD ORIGINAL

AP000248

- 47 [Example 77): 7-amino-2-(2-furyl)-5-(3-phenyl-2-trans-propenyl)amino-[l,2,4]triazolo[l,5-a] [1,3,5]triazine as pale yellow prisms, (crystallised from 2-propanol), m.p. 184-187°C, resolidified, then m.p. 218-220°C; microanalysis, found: C,61.2; 61.1; H,4.2; 4.3;

N,29.3, 29.3; C₁₇H₁₅N_?O requires: C,61.2; H,4.5; N.29.4Z; NMR: 4.3(broad s,2H, CH₂), 6.2-6.4(d of t,lH, CHCHp, 6.5(d,lH, CH Ar), 6.65(q,lH, furyl-4H), 7.05(d,lH, furyl-3H), 7.2-7.5 (complex, 5H, phenyl H), 7.6-7.8 (complex, 1H, NH), 7.85(q,lH, furyl-5H), 8.0-8.6(broad d,2H, NH₂); m/e 334 (M+H)⁺.

[Example 78]: 7-amino-2-(2-furyl)-5-(2-methoxyethyl)amino-[l,2,4]trlazolo-(1,5-a] [1,3,5]triazine as pale yellow prisms (crystallised from ethanol), m.p.: 198-200°C; microanalysis, found: C,48.4; H,4.9; N,35.2Z; C^^N^ requires: C48.0; H,4.8; N.35.6Z; NMR: 3.25(s,3H, CH₃O), 3.45(s, 4H, CH₂CH₂), 6.65(q,lH, furyl-4H), 7.05(d,lH, furyl-3H), 7.3-7.5(broad d,lH, NH), 7.8(q,lH, furyl-5H), 8.0-8.4(broad d,2H, NH₂); m/e 276 (M+H)⁺.

[Example 79]: 7-amino-5-cyclopentylamino-2-(2-furyl)-(1,2,4]triazolo-(1,5-a][1,3,5]triazine as colourless prisms (crystallised from ethanol), m.p.: 151-154^eC; microanalysis, found: C, 55.1; H, 5.4; N, 34.1Z; C₁₃H₁₅N_?O requires: C, 54.7; H, 5.3; N, 34.4Z; NMR: 1.4-2.0 (complex, 8H, cyclopentyl-CHp, 4.l-4.3(complex, 1H, CHN), 6.65(q, 1H, furyl-4H), 7.05(d, 1H, furyl-3H), 7.3-7.5(complex, 1H, NH), 7.85(d,

1H, furyl-5H), 7.9-8.4(broad d, 2H, NH₂); m/e 286 (M-H)\ [Example 801^: 7-amino-5-[2-(4-t-butoxycarbonylmethoxy)phenylethyl] amino-2-(2-furyl-[1,2,4|-triazolo(1,5-a](1,3,5]triazine as colourless fluffy crystals (crystallised from ethanol), m.p.: 199-200“C; microanalysis, found: C, 58.4; H, 5.5; N, 21.72; ^C22^H25^N7°4 ^re9^uires C, 58.5; H, 5.6; N, 21.7Z; NMR: 1.4(s, 9H, t-butyl-H), 2.8(t, 2H, ArCH₂), 3.45(complex, 2H, CHjN), 4.6(s, 2H, CHjO) 6.65(q, 1H, furyl-4H), 6.8(d, 2H, phenyl-H), 7.05(d, 1H, furyl-3H), 7.15(d, 2H, phenyl-H), 7.3-7.5(complex, 1H, NH), 7.85(d, 1H, furyl-5H),

8.0-8.4(broad d, 2H, NH^; m/e 452 (M+H)⁺.

The required 2-[4-(2-t-butoxycarbonylmethoxy)phenyl]BAD ORIGINAL ft t * 5' 0 0 0 S A

- 48 ethylamine may be prepared as described in Journal of Medicinal Chemistry, 1990, 33, 1919-1924.

Example 81

4-(2-Aminoethyl)phenol (2.74 g) vas added to a stirred suspension of 7-amino-2-(2-furyl)-5-methylsulphonyl-(l,2,4]triazolo- > [l,5-a[[l,3,5[triazine (1.4 g) in acetonitrile (150 ml) and stirringsvas continued overnight. The solvent vas evaporated and the residue4vas purified by chromatography on silica (100 g) eluting with dichloromethane containing methanol (502 v/v). The solid (1.23 g) obtained vas crystallised from ethyl acetate to give 7-amino-2-(2furyl)-5-[2-(4-hydroxyphenyl)ethyl]amino-I1,2,4]-triazolof1,5a][1,3,5]triazine, m.p. 225-227°C; microanalysis, found: C, 56.7; H, 4.6; N, 29.42; ^C16^H15^N7°₂ requires C, 57.0; H, 4.5; N, 29.12, NMR: 2.73(t, 2H, CH₂Ar), 3.41(t, 2H, NHCH₂), 6.66(complex, 3H, 2phenyl-H and furyl-4H), 7.02(complex, 3H, 2phenyl-H and furyl-3H), 7.40(br t, ΙΗ, -NH-), 7.82(q, 1H, furyl-5H), 8.0-8.4(br d, 2H, NH₂) and 9.1(s,

IH, OH); m/e 333 (M+H)⁺.

Example 82

7-Amino-2-(2-fury1)-5-[2-(4-hydroxyphenyl)ethy1]aminoli,2,4J-triazolo(l,5-aJ[l,3,5J triazine (1 g, prepared as described in Example 81) vas suspended in dichloromethane (20 ml) and trifluoroacetic acid (20 ml) vas added vith stirring. Pivaloyl chloride (0.4 ml) vas added dropwise at ambient temperature. The mixture vas stirred for 2 hours and then the dichloromethane and trifluoroacetic acid vas removed in vacuo. The residue vas purified** by chromatography on silica (100 g) eluting vith dichloromethane ί containing methanol (5.02 v/v). The solid obtained (1.2 g) vas crystallised from toluene and finally from isopropanol (25 ml) to give 7-amino-2-(2-fury1)-5-[2-(4-pivaloyloxyphenyl)ethyl]aminoII, 2,4]-triazolo[l,5-a][1,3,5Jtriazine as a solid; m.p. 208-210’C; microanalysis, found: C, 59.6; H, 6.1; N, 21.72; ^₂1^24^7θ3 C^H^OH requires C, 59.9; H, 6.0; N, 21.72; NMR 1.06(d, ca 3H, (CH^CHOH), 1.3(s, 9H, CHjC), 2.9(t, 2H, CH₂ Ar), 3.55 (t, 2H, CH₂N), 3.80(heptet, ca 0.5 H, (CH₃)₂CHOH), 6.68(dd, 1H, furyl-4H), 7.01 and 7.30 (A^

BADORJG/NAL $

AP0 00 24 8

- 4» pattern, 4H, phenyl-B). 7.08 (d. 13. furyI-3H) and 7.82(d, 1H, furyl-5H); m/e 422 (H-8)*.

Examples 83-109

Using a procedure similar to that described in Example 1, but using the appropriate alcohol instead of phenol, the following compounds of foraula I were obtained:

[Example 83 [: 7-aaino-2-(2-furyl)-5-<3-aethylphenoxy)[ 1,2,4]triazoloj1,5-aJ(1,3,5[triazine ^{i5 a} white solid froa isopropanol, a.p. 221-223*C; xicroanalysis. found: C, 58.5; H, 3.9; N, 27.4Z; C₁₅H₁₂N₆O₂ requires; C, 58.4; 2. 3.9; S, 27.3Z; NMR 2.35(s, 3H, ArCH^), 6.68(dd, 13. furyl-48). 7.C-~.*(ccaplex, 5H, 4phenyl-H and furyl-3H), 7.89(s, 1=. furyl-58) and 3.94(d, 23, NH₂); m/e 309 (M+H)⁺.

[Example 84[: 7-aaino-2-(2-furyl)-5_(2-aethylpropyloxy)[ 1,2,4Jtriazolof1,5-aJ[1,3,5[triazine as a white solid from toluene, m.p. 184-185’C aicroanalysis, found: 2. 52.9; H, 5.2; N, 30.3; ^C12^H14^N6°2 ^re9^{uires: c}· 52.5; 8, 5.1: N, 10.6X; NMR 0.99(d, 6H, CH-j), 2.05(m, 1H, CH(CH₃)₂). 4.10(d, 28, 0¾). 6.63(dd, 1H, furyl-48), 7.11(d, 1H, furyl-38). 7.89(d, 18, frryl-55) and 8.75(brs, 28, NHj); m/e 275 (M+H)*.

[Example 85[: 7-aaino-2-(2-furyl)-5-(3-pyridyloxy)-[l,2,4[ triazolo[ 1,5-aJ[1,3,5 J triazine as colourless crystals (crystallised from ethanol), m.p. 287-291’C {decomposed ; microanalysis, found C, 53.2;

6.70 (dd, 13, furylpyridyl-5H), 7.75 (d (complex, 2H, pyridy

296 (M-Hf (Example 86[: 7-aaino-2-(2-furyl)-5-(l-[l,2,5-thiadiazolyloxyJ[l,2,4]triazolo[l,5-a[[l,3,5Jtriazine as a white solid from ethanol,

6 8 2

BAD ORIGINAL ft

AS 0 C Ο

- 50 furyl-4H), 7.16 (d, 1H, furyl-3H), 7.91 (d, IB, furyl-5H), 8.85 (s,

IB, thiadiazolyl-4H) and 9.21 (br s, 2H, NB₂); m/e 303 (M+B)*.

The starting material may be prepared as described in Journal of Organic Chemistry, 32, 2828 (1967).

i [Example 87); 7-amino-2-(2-furyl)-5-(3-trifluoro«ethylphenoxy)[1,2,41triazolof1,5-aJ[1,3,5]triazine as a crystalline solid from isopropanol, m.p. 236-238’C; microanalysis, found C, 49.6; H, 2.3; N, 22.92; C₁₅H₉F₃N₆O₂ requires: C, 49.7; H, 2.5; N, 23.22; NMR 6.70 (dd, 1H, furyl-4H), 7.13 (d, IB, furyl-3H), 7.55-7.75 (complex, 4B, phenyl-H), 7.91 (s, 1H, furyl-5H) and 9.03 (br s, 2B, NH₂); m/e 362 M*.

[Example 887-a«ino-5-(3-chlorophenoxy)-2-(2-furyl)-[l,2,4]triazolo[l,5-a][l,3,5]triazine as colourless needles from ethyl acetate, m.p. 224-226’C; microanalysis, found C, 50.9; B, 2.6; N, 25.62; C₁₄H₉C1N₆O₂ requires: C, 51.1; H, 2.7; N, 25.62; NMR 6.57 (dd, IB, furyl-4H), 7.1-7.4 (complex, 5H, phenyl-H and furyl-3H), 7.70 (s, 1H, furyl-5H) and 8.25 (d, 2B, Nf^); m/e 328 M*.

[Example 891: 7-amino-5-(2-ethylsulphinylethoxy)-2-(2-furyl)-(l,2,4Jtriazolo[1,5-aJ[1,3,5Jtriazine as a vhite solid from ethanol, m.p. 253-5’C; microanalysis; found C, 45.0; H, 4.3; N, 26.42; C^B^N^O^S requires: C. 44.7: B, 4.3: N, 26.12: NMR 1.22 (t, 3H, CHp, 2.7-3.3 (m, 4H, CH₂S(0)CH₂), 4.66 (m, 2H, OCHp, 6.70 (dd, IB, furyl-4H), 7-14 (d, 1H, furyl-38), 7.90 (s, 1H, furyl-5H) and 8.84 (br d, 2H, NH₂); m/e 323 (M+H)*.

The starting alcohol vas prepared as follovs:To a solution of 2-ethylthioethanol (10.6g) in a methanol/vater mixture (2:1 v/v) vas added sodium metaperiodate (21.4

g), and the mixture vas heated under reflux for 2 hours. The suspension vas then cooled and filtered, and the filtrate evaporated in vacuo. The residue vas distilled to give 2-ethylsulphinyl ethanol bad °k/g/nal $

AP000248

- 51 as a colourless oil, b.p. 125-126’C (0.5 mm Hg), NMR: 1.35 (t, 3H, CH₃), 2.7-3.0 (m, 4H, CH₂S(O)CH₂), 4.05 (m,2H, CH₂O), 4.45 (s, IH,

OH); m/e 123(M+H)\ (Example 90(: 7-amino-5-(2-chlorophenoxy)-2-(2-furyl)-( 1,2,4(triazolo(1,5-a](1,3,51triazine as a white solid from ethanol, m.p. 271-273’C; microanalysis, found: C, 51.2, H, 2.7; N, 25.42; C^H^CIN^^ requires: C, 51.1: H, 2.7; N, 25.62; NMR 6.68 (dd, IH, furyl-4H), 7.11 (d, IH, furyl-3H), 7.3-7.7 (complex, 4H, phenyl-H), 7.89 (s, IH, furyl-5H) and 9.05 (br s, 2H, NH^; m/e 329 (M+H)*.

[Example 91(: 7-amino-2-(2-furyl)-5-(2,3,4,5,6-pentafluorophenoxy)[ 1,2,4Jtriazolof1,5-aJ(1,3,5Jtriazine as white crystals from ethanol, m.p. 312-314 (decomposed); microanalysis, found: C, 43.9;, H, 1.4; N, 21.92; C₁₄H₅F₅N₆O₂ requires: C, 43.7; H, 1.3: N, 21.92; NMR 6.70(dd,

IH, furyl-4H), 7.14 (d, IH, furyl-3H), 7.92 (s, IH, furyl-5H) and 9.27 (br s, 2H, NH₂); m/e 385 (M*H)⁺.

I Example 92 J: 7-amino-5-( 3-cyanophenoxy )-2-( 2-f uryl)- (1,2,4] triazolo(1,5-aJ(1,3,5]triazine as a white solid from ethanol, m.p.>300’C; microanalysis, found: C, 56.6; H, 2.9; N, 30.62; requires:

C, 56.4; H, 2.8; N, 30.72; NMR 6.70 (dd, IH, furyl-4H), 7.13 (d, IH, furyl-3H), 7.4-7.85 (complex, 4H, phenyl-H), 7.91 (s, IH, furyl-5H) and 9.06 (d, 2H, NHj); m/e 320 (M+H)⁺.

(Example 93(: 7-amino-5-(4-N-dimethylaminosulphonylphenoxy)-2(2-furyl)-(1,2,4Jtriazoloj1,5-aJ[1,3,5(triazine as colourless crystals, m.p. 272-274’C (decomposed); microanalysis, found: C, 47.6;

H, 3.8: N, 23.3; H₂0 1.32; C^H^N^S 0.33 C^OH, O.33H₂O requires:

C, 47.4; H, 4.1; N, 23.2; H₂0, 1.42; NMR 2.67 (s, 6H, N(CH₃)₂), 6.70 (dd, IH, furyl-4H), 7.13 (d, IH, furyl-3H), centre 7.5 (A₂B₂ pattern, 4H, phenyl-H), 7.91 (s, IH, furyl-5H) and 9.04 (d, 2H, NH₂); m/e 402 (M+H)⁺.

The phenol starting material was prepared as follows:

BAD ORIGINAL

Λ υ i) ('

- 52 Sodium 4-hydroxybenzenesulphonate (20 g) was heated under reflux in thionyl chloride (200 ml) for 2½ hours. The solvent was then removed in vacuo, and the residue was azeotroped with toluene and then treated with a solution of dimethylamine in industrial methylated spirits (200 ml). Purification by chromatography on silica (eluting with dichloromethane/methane (99:1 v/v) gave *

N,N-dimethyl-4-hydroxybenzenesulphonamide as colourless needles (crystallised from water), m.p. 82-84’C; NMR: 2.55 (s, 6H, 2CH₃), 6.95 (d, 2H, phenyl-H), 7.55 (d, 2H, phenyl-H), 10.5 (s, 1H, OH); m/e 202 (M+H).

(Example 94 J: 7-amino-2-(2-fury1)-5-(2-ni trophenoxy)-[1,2,4)triazolo)1,5-a)[1,3,5]triazine as a pale yellow solid, m.p. 303-305°C (decomposed); microanalysis, found: C, 49.7, H, 2.6; N, 28.52; C₁₄H₉N_?0₄ requires: C, 49.6, H, 2.6; N, 28.92; NMR 6.70 (dd, 1H, furyl-4H), 7.21 (d, 1H, furyl-3H), 7.59 (complex, 2H, phenyl-5H and 6H), 7.85 (dd, 1H, phenyl-4H), 7.91 (s, 1H, furyl-5H), 8.20 (dd, 1H, phenyl-3H) and 9.15 (d, 2H, NH^; m/e 340 (M+H)*.

[Example 95): 7-amino-5-(2-methoxycarbonylphenoxy)-2-(2-furyl)[ 1,2,4Jtriazolo)1,5-a][1,3,5)triazine as a solid from methanol, m.p. 287-288°C; microanalysis, found; C, 54.4; H, 3.2; N, 23.62; ^ΐβ^ΐ2^6θ4 requires: C, 54.5; H, 3.4; N, 23.92; NMR 3.67 (s, 3H, CO^), 6.69 (dd, 1H, furyl-4H), 7.12 (d, 1H, furyl-3H), 7.3-7.8 (complex, 3H, phenyl-H), 7.90 (s, 1H, furyl-5H) and 9.00 (d, 2H, NH₂).

[Example 96): 7-amino-5-(4-methoxycarbonylphenoxy)-2-(2-furyl)- >

[ 1,2,4]triazolo[l,5-a)(1,3,5)triazine as a white solid from ethanol,¹ m.p. 293-5°C (decomposition); microanalysis, found: C, 54.6; H, 3.6;

N, 23.52; C^H^N^ requires: C, 54.5; H, 3.4; N, 23.92; NMR 3.88 (s, 3H, CO₂CH₃), 6.70 (dd, 1H, furyl-4H), 7.13 (d, 1H, furyl-3H), 7.41 and 8.05 (A₂B₂ pattern, 4H, phenyl-H), 7.90 (s, 1H, furyl-5H) and 9.04 (d, 2H, NH₂); m/e 353 (M+H)*.

[Example 97): 7-amino-5-(3-methoxycarbonylphenoxy)-2-(2-furyl)[l,2,4)triazolo(l,5-a][l,3,5)triazine as a white solid from ethanol, ^BAD original $

AP Ο 00 2 4 8

- 53 m.p. 226-228’C; microanalysis, found: C, 52.7; H, 3.6; N, 22.5; 1^0, 3.72; ^ci6^Hi2^N6°4 ^{0,1 C}2^H5^OH (O-JSBjO) requires: C, 52.5; H, 3.8, N, 22.7; H₂0, 3.62; NMR 3.86 (s, 3H, CO₂CH₃), 6.68 (dd, IH, furyl-4H), 7.12 (d, IH, furyl-3H), 7.5-7.9 (complex, 5H, 4 phenyl-H) and furyl-5H) and 9.00 (d, 2H, NH₂); m/e 353 (M₊H)⁺.

[Example 98]: 7-amino-5-(4-methoxycarbony Imethy lphenoxy)-2-(2-furyl)[1,2,4Jtriazolo]1,5-aJ[1,3,5[triazine as a white solid from ethanol, m.p. 234-236’C; microanalysis, found: C, 55.7; H, 4.0; N, 22.72;

^C17^H14^N6°4 ^re9^{uires: c}’ ⁵⁵·⁷; ^H’ ³·⁸’ ^N’ 23.02; NMR 3.65 (s, 3H, CO₂CH₃), 3.71 (s, 2H, Cl^COCHp, 6.68(dd, IH, furyl-4H), 7.10 (d, IH, furyl-3H), 7.13 and 7.33 (A₂B₂ pattern, 4H, phenyl-H), 7.88 (d, IH, furyl-5H) and 8.96 (d, 2H, NHj); m/e 367 (M+H)⁺.

The phenol starting material was prepared as follows:

A solution of 4-hydroxyphenoxyacetic acid (33.6 g) in methanol was treated vith hydrogen chloride gas and left to stand at ambient temperature overnight. The solvent was removed in vacuo and the residue taken up in ethyl acetate. This solution was vashed sequentially vith saturated sodium hydrogen carbonate solution (2 x 100 ml) and brine (100 ml), then dried (MgSO^) and the solvent evaporated to give methyl 4-hydroxyphenoxyacetate as a colourless crystalline mass, m.p. 112-114’C; NMR: 3.8 (s, 3H, CH₃), 4.55 (s, 2H, CH₂>, 6.75 (s, 4H, phenyl-H) 6.8-7.8 (broad s, IH, OH); m/e 200 (M₊NH₄)⁺.

[Example 99]: 7-amino-5-(4-methoxycarbonylmethoxyphenoxy)-2-(2-furyl)[1,2,4]triazolo[1,5-a][1,3,5|triazine as a white solid from ethanol, m.p. 265-267’C; microanalysis, found: C, 53.8; H, 3.7; N, 21.62;

^C17^H14^N6°5 ^re9^{uires: c}’ 53.4; ^H’ ³·⁷? ^N’ 22.02; NMR 3.72 (s, 3H, C0₂CH₃), 4.81 (s, 2H, 0CH₂), 6.69 and 7.15 (A^ pattern, 4H, phenyl-H), 7.10 (d, IH, furyl-3H), 7.89 (s,lH, furyl-5H) and 8.94 (d, 2H, NH₂); m/e 383 (M₊H)⁺.

BAD ORIGINAL ft * £ \ ο ο η

- 54 (Example 1001; 7-amino-2-(2-furyl)-5-(4-[(l-propyl)aminocarbonylmethoxy]phenoxy)-[l,2,4|triazolofl,5-a]|l,3,51 triazine as a solid from ethanol, m.p. 203-205’C; microanalysis, found: C, 55.8; H, 4.8; N,

23.82; C₁₉H₁₉N_?O₄ requires: C, 55.7; H, 4.7; N, 24.02; NMR 0.85 (t,

3H, CH₂CH₃), 1.47 (m, 2H, Cf^CHp, 3.11 (q, 2H, Cf^N), 4.47 (s,2H,

0CH₂), 6.67 (dd, IH, furyl-4H), 6.98 and 7.14 (A₂B₂ pattern, 4H, phenyl-H), 7.10 (d, IH, furyl-3H), 7.87 (s, IH, furyl-5H), 8.03 (t,

IH, NH) and 8.82 (d, 2H, NH,); m/e 410 (M₊H)⁺. - -i *

The requisite phenol starting material vas prepared as follows:

A solution of 1-propylamine (4.1 ml) and methyl

4-hydroxyphenoxyacetate (3.64 g) in methanol (50 ml) vas left to stand for 72 hours at ambient temperature. The solvent vas evaporated in vacuo and the residue taken up in ethyl acetate. The solution vas washed sequentially vith 1M HC1 (2 x 25 ml) and brine (30 ml), then dried (MgSOp and the solvent evaporated to give

N-(l-propyl)-4-hydroxyphenoxyacetamide as a red oil, NMR: 0.95 (t, 3H, CH₃), 1.55 (m, 2H, CHp, 3.3 (q, 2H, CH₂N), 4.4 (s, 2H, CH₂0), 6.5-6.7 (broad s, IH, OH), 6.8 (s, 4H, phenyl-H); m/e 227 (M+NH^)*, 210 (M+H)*.

[Example 101(:

7-ami no-5-[4-( [N-d ime thy laminoe thy 1-N-methylJaminocarbony Ime thoxy )phen

-oxy|-2-(2-furyl)-[l,2,4Jtriazolo[l,5-aHl>3,5Jtriazine as a solid from ethanol, m.p. 192-4’C; microanalysis, found: C, 55.9; H, 5.7; N,

24.82; C,,H,.N_o0, requires: C, 55.7; H, 5.3: N, 24.82; NMR 2.2 (d, 6H, Cl cb O *+ jjN(CH₃)₂), 2.47 (m, 2H, CH₂N(CH₃)₂), 2.36 and 3.02 (s, 3H, NCH₃ rotamers), 3.41 (m, 2H, CONCH,), 4.33 (d, 2H, OCHp, 6.68 (dd, IH, furyl-4H), 6.95 and 7.13 (A₂B₂ pattern, 4H, phenyl-H), 7.12 (s, IH, furyl-3H), 7.88 (m, IH, furyl-5H) and 8.95 (d, 2H, NH₂); m/e 453 (M+H)*.

The requisite phenol starting material was prepared as follows:

bad

ORIGINAL A

AP000248

- 55 A solution of methyl 4-hydroxyphenoxyacetate (3.64 g) and Ν,Ν,Ν'-trimethylethylenediamine (5.1 g) in methanol (50 ml) was heated under reflux for 24 hours. The solvent was then evaporated in vacuo and the residue purified by chromatography on silica (eluting with dichloromethane/methanol 9:1 v/v) to give N-(4-hydroxyphenoxyacetyl)Ν,Ν'Ν’-trimethylethylenediamine as a pale brovn oil, NMR: 2.3 (s, 6H, 2CH₃), 2.5 (t, 2H, CH₂NMe₂), 3.0 (d, 3H, CH-j), 3.5 (m, 2B, CHp,

4.5-4.7 (d, 2H, CH₂0), 6.6-6.8 (m, 4H, phenyl-H); m/e 253 (M+H)*.

Example 102

A solution of 7-amino-2-(2-furyl)-5-phenoxy-(l,2,4Jtriazolo(1,5-a](1,3,51triazine (950mg) in acetic anhydride vas heated under reflux for 1.5 hours. The solvent vas then evaporated in vacuo and the residue vas purified by chromatography on silica eluting vith dichloromethane containing ethyl acetate (52 v/v). The amorphous solid thereby obtained vas crystallised from toluene to give 7-acetylamino-2-(2-furyl)-5-phenoxy-11,2,4(-triazoloj1,5-aJ(1,3,5( triazine as colourless prisms, m.p. 168-170°C; microanalysis, found; C, 60.9; H, 4.2; N, 22.62; C₁₆H₁₂N₆0₃ 0.45 C_?H₈ requires: C, 60.9; H,

4.1; N, 22.32; NMR 2.3 (s, 3H equivalent, toluene CH₃), 2.35 (s, 3B, CH₃C0), 6.7 (q, IH, furyl-4H), 7.1-7.6 (complex, 6H, furyl-3H ♦ phenyl-H + toluene), 7.95(d, IH, furyl-5H), 11.5 (broad s, IH, NH); m/e 336 (M⁺).

EXAMPLES 103-109

Using a procedure similar to that described in Example 1, but using the appropriate alcohol instead of phenol, the following compounds of formula I were obtained:(EXAMPLE 103 J: 7-amino-5-(4-N-cyclohexylaminocarbonylmethylJphenoxy)-2-(2-furyl)-(l,2,4(triazolo(l,5-aJ(l,3,5(triazine as a vhite solid from ethanol, m.p. 294-297°C; microanalysis, found: C,60.5; H,5.4; N,22.4; H₂0, 0.82; ^C22^H23^N7°3⁽⁰·^2)H2° requires 0,60.5; H,5.4; N,22.4;

H₂0, 0.82; NMR: 1.0-1.8 (complex, 10H, -CHj-), 3.40 (s,2H, CH₂CO), 3.52(m,lH, CHN), 6.69(dd,lH, furyl-4H), 7.11(d,lH, furyl-3H), 7.15 and

BAD ORIGINAL ft

- 56 7.3O(A₂B₂ pattern, 4H, phenyl-H), 7.9O(m,lH, furyl-5H), 7.95(d,lH, NH) and 8.97(d,2H, NH₂); m/e 434 (M+H)⁺.

The phenol starting material vas prepared by a procedure essentially similar to that described in Example 102, using _; cyclohexylamine instead of 1-propylamine giving

N-cyclohexyl-4-hydroxyphenylacetamide as a colourless crystalline solid, m.p. 87-89’C, NMR: 1.0-1.5 (complex 5H, cyclohexyl-CB₂),

l. 5-1.8 (complex, 5H, cyclohexyl-CH₂), 3.25(s,2H, ArCH₂), 3.5(·,1Η, CHN), 6.65(d,2H, phenyl-H), 7.0(d,2H, phenyl-H), 7.75(t,lH, NH), 9.15(s,lH, -OH); m/e 234 (M+H)⁺.

[EXAMPLE 104]: 7-a«ino-5-[4-([N-dieiethylaminoethyl-N-methylaminocarbonylmethy1)phenoxyJ-2-(2-furyl-(1,2,4 Jtriazolo(1,5-aJ[1,3,5Jtriazine as a hydrochloride salt from isopropanol. The chromatographed free base prepared by a procedure similar to that described in Example 1, vas dissolved in methanol and treated with ethereal hydrogen chloride, the solvent evaporated and the residue crystallised from isopropanol); microanalysis, found: C,52.4; H,5.9; N,22.0; Cl,6.9; HjO, 1.62; C₂1^H24^N8°3 ^HC1 °'^{3 C}3^H7^OH °-^5H2° requires:

C,52.6; H,5.6; N.22.4; Cl,7.1; HjO 1.82; NMR 2.77(s,6H, N(CH₃)₂), 3.3(s,3H, N-CH₃), 3.23(t,2H, CHjN*), 3.75 (complex, 4H, CH₂N and CH₂CO), 6.69(dd,lH, furyl-4H), 7.12(d,lH, furyl-3H), 7.15 and 7.31 (A₂B₂ pattern, 4H, phenyl-H), 7.9O(m,lH, furyl-5H), 9.00(d,2H, NHp and 10.5(br s, IH, N+H) m/e 437(M*H)⁺.

The phenol starting material was prepared by a procedure essentially similar to that described in Example 102, using _x

Ν,Ν,N'-trimethylethylenediamine instead of 1-propylamine, to give the product as a pale yellow oil, essentially pure by TLC, which was used directly.

[EXAMPLE 1051: 7-amino-2-(2-furyl-5-(4-[methoxycarbonylethylJphenoxy[1,2,4]triazolo[l,5-a](1,3,5]triazine as white crystals from ethanol,

m. p. 245-247’C; microanalysis, found: C,56.9; H,4.4; N,22.32; ^C18^H16^N6°4 ^re<1^uires: C.56.8; H,4.2; N.22.12; NMR: 2.67( t,2H, CH₂

BAD ORIGINAL

AP Ο Ο Ο 2 4 8

- 57 phenyl), 2.90(t,2H CHjCO), 3.61(s,3H, CO₂CH₃), 6.70(dd,lH, furyl-4H), 7.11(d,lH, furyl-3H), 7.15 and 7.29 pattern, 4H, phenyl-H),

7.9O(d,lH, £uryl-5H) and 8.95(d,2H, NH/ m/e 381 (M₊H)⁺.

[EXAMPLE 1061? 7-amino-5[4-(3-[N-cyclopentylcarbamoyl]ethyl)phenoxy]-2-(2-furyl)-l,2,4-triazolo(l,5-a][l,3,5]triazine as a solid from ethanol m.p. 257-259°C; microanalysis, found: C,60.8; H,5.3; N.22.3X. C₂₂H₂₃N_?O₃ requires: C,61.0; H,5.3; N,22.6X; NMR: 1.2-1.9 (complex, 8H, -CHj-) 2.37(t,2H, CHjCO), 2.84(t,2B, CH₂ phenyl), 3.99(m,lB, CHN), 6.69(dd,lH, furyl-4H), 7.10(d,lH, furyl-3H) , 7.15 and 7.28 (A^ pattern, 4H, phenyl-H), 7.74(d,lH, NH), 7.89(d,lH, furyl-5H) and 8.95(d,2H, NH₂); m/e 434 (M+H)\

The requisite phenol starting material was prepared as follows:

A mixture of 3-(4-hydroxyphenyl)propionate (3.6 g) and cyclopentylamine (15 ml) was refluxed for 18 hours. The reaction mixture was then taken up in ethyl acetate (150 el) and the solution washed sequentially with 2M HC1 (4 x 75 ml), water (50 ml) and brine (50 ml), then dried (MgSO^.) and evaporated to give N-cyclopentyl-3(4-hydroxyphenyl)propionate as a brown oil, NMR: 1.2-1.9 (complex, 8H, cyclopentyl-H), 2.25(t,2H, CHp, 2.7(t,2H, CHp, 4.0(m,lH cyclopentyl-H), 6.65(d,2H, phenyl-H), 7.0(d,2H, phenyl-H), 7.65(d,lH, NH), 9.1(s,lH, OH); m/e 251 (M₊NH₄)⁺, 234 (M+H)⁺.

[EXAMPLE 107]:

7-amino-2-(2-fury1)-5-(2-methylphenoxy )-[ 1,2,4]triazole[1,5-a][1,3,5]triazine as a powder from isopropanol, m.p. 239-241’C; microanalysis, found: C,58,3; H.4.9; N,24.5X; C₃₃H₃₂N^0₂(0.SjCjH^OH requires: C.58.5; H.4.7; N.24.8X; NMR: 2.16(s.3H, phenyl CH₃>, 6.69(dd,lH, furyl-4H), 7.1-7.4 (complex, 5H, phenyl-H and furyl-3H); 7.89(s,lH, furyl-5H) and 8.96(d,2H, NH₂); m/e 309 (M+H)⁺.

[EXAMPLE 108]: 7-amino-2-(2-furyl)-5-(4-methylphenoxy)-[ 1,2,4-]triazolo(l,5-a][1,3,5]triazine as fluffy crystals from isopropanol, bad ORIGINAL

- 58 m.p. 248-250°C; microanalysis, found: C,58.3; H,5.5; N.23.5X;

^C15^H12^N6°2^(O,8)C3^H7^{OH re}9^uires: C.58.6; H,5.2; N.23.6Z; NMR: 2.32(s,3H, phenyl CHJ, 6.68(dd,lH, £uryl-4H), 7.11(d,lH, furyl-3H), 7.0 and 7.24 (A^Bj pattern, 4H, phenyl-H), 7.9O(s,lH, furyl-5H) and 8.91(s,2H, NH₂) m/e 3O9(M₊H)⁺.

EXAMPLE 109

A stirred suspension of 7-amino-2-(2-£uryl)-5methylsulphonyl-[l,2,4]triazolo[l,5-aHl,3,5]triazine (1.4 g) in 1,2-dimethoxyethane (25 ml) vas treated vith an aqueous solution of 1M sodium hydroxide (25 ml). After 3 hours at room temperature the reaction mixture vas acidified vith 1M hydrochloric acid (pH 2-3) and stirred for 2 hours. The precipitated yellov solid vas collected by filtration and vashed vith vater. Crystallisation from boiling distilled vater gave 7-amino-2-(2-furyl)-5-hydroxy-l,2,4-triazolo(l,5-aJ(l,3,5Jtriazine (0.47 g) as a pale yellov solid m.p. >300’C; microanalysis, found: C.44.3; H,2.5; N.38.7Z, CgH^N^0₂ requires: C.44.0; H,2.8; N.38.5Z; NMR: 6.69(dd,lH, furyl-4H), 7.10(d,lH, furyl-3H), 7.90(d,lH, £uryl-5H), 8.36(br s, 2H, NHJ and 12.1(br s, 1H,OH); m/e 219 (M+H)⁺.

EXAMPLES 110-112

Using a procedure similar to that described in Example 2, the folloving compounds of formula I vere obtained starting vith the appropriate thiol:[EXAMPLE 110]: 7-amino-5-(lcyclohexylaminocarbonyl]methylthio)-2(2-furyl)-ll,2,4]triazolo(l,5-a][l,3,5]triazine as a vhite solid from isopropanol, m.p. 249-252°C; microanalysis, found: C, 51.3; H,5.3; N,26.1Z; C₁₆H₁₉N_?O₂S requires: C,51.5; H,5.1; N.26.3Z; NMR: 1.0-1.8 (complex, 10H, -CH₂~) 3.51(m,lH, NCH), 3.85(s,2H, CH₂S), 6.69(dd, 1H, furyl-4H), 7.14(d,lH, furyl-3H), 7.89(m,lH, furyl-5H), 7.95(d,lH, NH) and 8.88(d,2H, NHJ; m/e 374' (M+H) ⁺.

The thiol starting material vas prepared as follovs:SAD ORiqi_Nal

AP Ο 00 2 4 8

- 59 A solution of ethyl 2-mercaptoacetate (12 g) and cyclohexylamine (29.7 g) in ethanol (50 ml) was allowed to stand at ambient temperature for 72 hours, and was then refluxed for 6 hours. The solvent was evaporated and the residue dissolved in ethyl acetate (200 ml). The solution was washed sequentially with 2M HC1 (3 x 50 ml), water (2 x 50 ml) and brine (50 ml), and the solvent removed in vacuo. The crude product vas purified by chromatography on silica (eluting with dichloromethane/methanol 99:1 v/v) to give

N-cyclohexyl-2-mercaptoacetamide as low-melting tan crystals, NMR: 1.0-2.0 (complex, 11H, cyclohexyl-C^ and SH), 3.2(d,2H, CH₂),

3.6-3.9(m,IH, cyclohexyl -CH), 6.4-6.9 (broad d,lH, NH); m/e 174 (M+H)⁺.

(EXAMPLE 111]: 7-amino-2-(2-furyl)-5-(N-piperidinocarbonyl)methylthio-[l,2,4]triazolo(l,5-a|(1,3,5Jtriazine as a white solid from isopropanol m.p. 218-220’C; microanalysis, found: C,49.9; H,4.8; N,27.3X; requires: C,50.2; H,4.7; N.27.3Z; NMR: 1.4-1.7 (complex, 6H, -CH₂->, 3.48(m,4H, CH₂NCH₂), 4.19(s,2H, SCHj),

6.7O(dd,lH, furyl-4H), 7.15(d,lH, furyl-3H), 7.90(m,lH, furyl-5H) 8.88(d,2H, NH₂); m/e 360 (M+H)*.

The thiol starting material was prepared by a procedure similar to that described in Example 110, but using piperidine instead of cyclohexylamine. The product was distilled to give a viscous yellow oil which was used directly.

[EXAMPLE 112}: 7-amino-5-([(1-propyl)aminocarbonylJmethylthio)-2(2-furyl-(l,2,4Jtriazolo(l,5-aJ[l,3,5]triazine as a white solid from isopropanol, m.p. 2O3-2O5°C; microanalysis, found: C, 46.6; H,4.8;

N, 28.5Z C₁₃H₁₅N_?O₂S (O.15)C₃H_?OH requires C.46.9; H.4.7; N.28.5Z; NMR:

O. 84(t,3H CH₃), 1.43(m,2H, CHjCHp, 3.04(q,2H, CH₂N), 3.87(s,2H,

CH₂S), 6.69(dd,lH, furyl-4H), 7.15(d,lH, furyl-3H), 7.91(d,lH, furyl-5H), 8.07(t,lH, NH) and 8.90(d,2H, NH₂); m/e 334 (M+H)*.

The thiol starting material was prepared in a manner

BAD ORIGINAL $

0 G Α Λ

- 60 similar to that described in Example 110, but using 1-propylamine instead of cyclohexylamine. The product was distilled to give a pale yellow viscous oil which was used directly.

EXAMPLE 113 i

Sodium hydride (150 mg of a 50Z dispersion in oil) was added to a stirred solution of 7-amino-2-(2-furyl)-5-phenoxyll,2,4J- _Λ triazolo-l1,5-a](1,3,5]triazine (800 mg) in dimethylformamide (10 ml). The mixture was stirred until the effervescence had ceased and a clear solution had been obtained. Iodoethane (0.22 ml) was then added and the reaction mixture was stirred overnight at ambient temperature. Water (150 ml) and glacial acetic acid (1.0 ml) were then added and the resulting aqueous suspension was extracted with ethyl acetate (3 x 40 ml). The organic extracts were combined and washed with water (2 x 40 ml) and brine (40 ml), dried (MgSOp and evaporated to yield a pale brown gum (800 mg). This was purified by chromatography on silica eluting with dichloromethane containing ethyl acetate (4Z v/v). The colourless foam thereby obtained was crystallised from tetrachloromethane to give 7-ethylamino-2-(2-furyl)-5-phenoxy-(l,2,4]~ triazolo]1,5-a]|1,3,5]triazine as colourless crystals, m.p. 127-129’C; microanalysis, found: C.54.2, 54.1; H,4.0, 3.8; N.23.1, 23.1; C1.10.2Z; C₁₆H₁₄N₆0₂-0.25CC1₄ requires: C,54.1; H,3.9; N.23.3;

C1.9.8Z; NMR: 1.2(t,3H, C!^), 3.54(m,2H, CH₂), 6.7(q,lH, furyl-4H), 7.1(dd,lH, furyl 3H), 7.2-7.5 (complex, 5H, phenyl-H), 7.9(q,lH, furyl-5H), 9.35(t,lH, NH); m/e 322 (M*). _rEXAMPLE 114 ’ χ

Using a procedure similar to that described in Example 113, but using iodomethane instead of iodoethane, 7-aethylamino-2(2-furyl)-5-phenoxy-(1,2,4]-1riazolo(1,5-a](l,3,5]triazine was prepared as colourless fluffy crystals (crystallised from ethanol), m.p. 220-222’C; microanalysis, found: C,58.6; H,3.7; N.27.4X; ^C15^H12^N6°2 ^re9^uires: C.58.4; H,3.9; N.27.3Z; NMR: 3.0(s,3H, CH-j), 6.7(q,lH, furyl-4H), 7.1(d,lH, furyl-3H), 7.2-7.5 (complex, 5H,

AP Ο Ο Ο 2 4 8

- 61 phenyl-H), 7.9(d,lH, furyl-5H), 9.25(s,lH, NH); m/e 308 (M⁺).

EXAMPLE 115

Using a procedure similar to that described in Example 1, but using the appropriate alcohol instead of phenol, 7-aaino-2(2-furyl)-5-(4-(N-(l-propyl)aminocarbonylmethyl|phenoxy)-ll,2,4Jtriazolo[l,5-a](l,3,5Jtriazine was prepared as a white solid from ethanol, m.p. 240-242^eC, microanalysis, found: C,57.7; H,4.7; N.24.8X; ^C19^H19^N7°3 ^re9^uires: C.58.0; H,4.8; N.25.0X; NMR: O.87(t,3H,

CH₂CH₃), 1.45(m,2H, CH₂CH₃), 3.04(q,2H, NCHp, 3.42(s,2H CH₂C0), 6.68(dd,lH, furyl-4H) 7.1-7.4(A₂B₂ pattern, 4H, phenyl-H), 7.88(m,lH, furyl-5H), 8.03(t,lH, NH); 8.96(d,2H, NH^; m/e 394(M+H)*.

The phenol starting material was prepared as follows:To a solution of N-(l-propyl)-4-acetoxyphenylacetaraide (11.4 g) in methanol (25 ml) was added a solution of sodium carbonate (2.65 g) in water (50 ml), and the mixture stirred overnight at ambient temperature. The methanol was removed in vacuo and the aqueous residue acidified to pH2. The product was extracted with ethyl acetate (3 x 50 ml), and the organic extracts combined and washed with brine (50 ml), dried (MgSO^). The solvent was evaporated to give N-(l-propyl)-4-hydroxyphenylacetamide as a yellow oil, essentially pure by TLC, NMR: O.85(t,3H, CH-j), 1.3-1.6(m,2H, CH₂CH₃), 3.15(t,2H, CH₂N), 3.5(s,2H, CHjAr), 5.75 (broad t,lH, NH), 6.85(d,2H, phenyl-H), 7.Q5(d,2H, phenyl-H) (the spectrum also contained peaks due to ethyl acetate); m/e 194 (M+H)*.

The requisite N-(l-propyl)-4-acetoxyphenylacetamide was prepared as follows:To an ice-cold solution of 1-propylamine (9 g) in water (50 ml) was added solution of 4-acetoxyphenylacetyl chloride (10.6 g) in diethyl ether (100 ml), keeping the temperature of the mixture between 15 and 25°C with external cooling. The ether layer was separated,

BAD ORIGINAL <

AP000248

- 62 washed with brine and evaporated to give N-(l-propyl)-4-acetoxyphenylacetamide as a pale yellow oil, essentially pure by TLC, which was used without further purification or characterisation.

EXAMPLE 116

Using a similar procedure to that described in Example 3 but starting from 7-amino-2-(5-methyl-2-furyl)-5-methylsulphonyl-[l,2,4Jtriazolo[l,5-a[[l,3,5]triazine obtained from the corresponding

5-methylthio compound described in Example 47, and the appropriate amine, there was preprared 7-amino-5-[2-(4-hydroxyphenylethyl)[amino2-(5-methyl-2-furyl)-[l,2,4J-triazolo[l,5-a[[l,3,5Jtriazine as a crystalline solid from ethanol, m.p. 29O-292^eC; microanalysis, found: C,57.4; H,5.8; N,24.72; C^H^N^.C^fLOH requires C.57.4; H,5.8; N,24.7; NMR 2.36(s,3H, CHp, 2.72( t,2H, NCHp, 3.44(m,2H, CHj-phenyl), 6.28(d,lH, furyl-4H), 6.68 and 7.03 (A^B^ pattern, 4H, phenyl-H), 6.93(d,lH, furyl-3H), 7.88(t,lH, NH), 8.08(br s, 2H, NHj) and 9.12(s,lH, OH); m/e 352 (M+H)*.

EXAMPLE 117

A solution of 5,7-diphenoxy-2-(5-isoxazolyl)-[l,2,4-Jtriazolo[1,5-aJ[1,3,5)triazine (3.5 g) in ethanolic ammonia (200 ml) was allowed to stand at ambient temperature for 1 hour. The solvent was then evaporated and the residue was purified by chromatography on silica-gel eluting sequentially with dichloromethane-ethyl acetate mixtures 9:1 v/v to give a pale yellow solid (1.61 g). This was crystallised from ethanol to give 7-amino-2-(5-isoxazolyl)-5-phenoxy[1,2,4]triazolo[l,5-a][l,3,5]triazine as colourless crystals, m.p. 255-257’C (decomposetion); microanalysis, found: C,53.O; H,4.2; N.29.32; C^H^O^O.75)C₂H₅OH requires C,52.8; H,4.1; N,29.72; NMR: 7.12(d,lH, isoxazolyl-3H), 7.2-7.6 (complex 5H, phenyl-H), 8.79(d,lH; isoxazolyl-4H) and 9.13 (s,2H, NH₂); m/e 296 (M+H)*.

The starting material was prepared as follows:BAD ORIGINAL £

AP Ο 00 2 4 8

- 63 (a) A solution of 5-isoxazolycarbonyl chloride (6.6 g) in dichloromethane vas added to a stirred solution of 2,4-diphenoxy6-hydrazino-]l,3,5]triazine (15 g) in dichloromethane at O’C. After stirring for 2 hours at ambient temperature, the organic solution was washed with water (x2), brine (xl), dried and evaporated to yield a yellow foam (18.0 g). The residue was crystallised from toluene to give pale yellow crystals (11.0 g) which were used directly.

(b) A suspension of phosphorus pentoxide (20 g) and the product of step (a) (8.0 g) in toluene (250 ml) was heated under reflux for 18 hours. The solvent vas evaporated and the residue partitioned between water and dichloromethane. The organic solution was washed with water, saturated sodium bicarbonate solution, water and brine, dried and evaporated to give as a brown solid 5,7-diphenoxy-2-(5-isoxazoly)[ 1,2,4-]triazolo]1,5-a](1,3,5-, triazine (3.6 g).

EXAMPLE 118

A solution of 7-amino-2-(2-furyl)-5-phenoxy-[l,2,4]triazolo(1,5-a](1,3,5 J triazine (1.01 g) and tyramine (1.43 g) in dimethylformamide (40 ml) was stirred at 100’C until tic analysis indicated that most of the phenoxy starting material had disappeared (2-3 hours). The solvent was removed in vacuo and the residue purified by chromatogrphy on silica (100 g) eluting with ethyl acetate. The solid (1.3 g) obtained vas crystallised from ethyl acetate to give 7-amino-2-(2-furyl)-5-(2-(4-hydroxyphenylethyl]-amino[ 1,2,4]triazolo]1,5-a][1,3,5]triazine as colourless prisms m.p. 222-225’C; microanalysis, found: C,56.6; H,5.1; N,26.42;

^C16^H15^N7°2·^{0,33 C}4^H8°2 ^re9^uires: C,56.8; H,4.8; N,26.72; NMR: 2.75(t,2H, CH₂ Ar), 3.4(t,2H, CH₂N), 6.7 (complex 3H, furyl-4H + phenyl-H), 7.05 (complex, 3H, furyl-3H + phenyl-H), 7.4-7.6(dt,IH,

NH), 7.85(d,lH, furyl-5H), 8.0-8.5(broad d,2H, NHp, 9.15(s,lH, OH), the spectrum also contained signals due to ethyl acetate (0.33 mole); m/e 338 (M+H)*.

The requisite 5-phenoxy starting material vas prepared in a manner similar to that described in Example 117, but starting with

RW O9!GINAL O ΐ/Λ

-645,7-diphenoxy-2-(2-furyl)-(1,2,4|-triazolo(1,5-a((1,3,5 J triazine, m.p. 246-248’C (crystallised from ethyl acetate); microanalysis, found: C.64.8; H,3.3; N.19.22; ε_2Ο ^Η13^Ν5^θ3 requires: C,64.7; H,3.5; N,18.92; NMR: 6.7(dd,lH, 3-furyl H); 7.2-7.7 (complex, 11H, 4-furyl H and phenyl H), 8.0(d,lH, 5-furyl H); a/e 372 (M+H)⁺.

t

The requisite 5,7-diphenoxy starting material vas prepared in a manner similar to that described in Example 117(b) but starting^-1 vith N-2-(4,6-diphenoxy)-(1,3,5(-triazinyl-N'-(2-furoyl)-hydrazine,, m.p. 182-184°C (crystallised from 2-propanol, microanalysis, found: C,61.4; 8,3.8; N,17.72; requires: C.61.7; H,3.9; N, 18.02;

NMR: 6.65(dd,lH, 3-furyl H); 7.0-7.6 (complex, UH, 4-furyl-H, phenyl-H); 7.9(d,lH, 5-furyl-H); 9.95(broad s,lH, NH); 10.35(broad S,1H, NH); m/e 390 (M+H)⁺.

The requisite hydrazine starting material vas prepared in a manner similar to that described in Example 117(a) using 2-furoyl chloride instead of isoxazole-5-carbonyl chloride.

Example 119

Phenol (4.7g) vas added to a suspension of 7-amino-2(2-furyl)-5-methylsulphonyl-pyrazolo(2,3-a((1,3,5(triazine (4.6 g) in 1,2-dimethoxyethane (120 ml) and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 2.8 ml). The mixture vas heated under reflux for 1 hour. The solvent vas removed in vacuo and the residue vas purified by chromatography on silica (250 g) eluting vith dichloromethane w

containing ethyl acetate (42 v/v) to give a colourless amorphous solid (1.25 g). This vas crystallised from ethanol'to give 7-amino-2(2-furyl)-5-phenoxy-pyrazolo(2,3-a((1,3,5]triazine (0.9 g) as colourless needles, m.p. 275-277C; microanalysis, found: C,61.8;

H,3.7; N,24.12; requires: C,61.4; H,3.8; N,23.92; NMR: 6.4 (s,lH, =CH-), 6.65(q,lH, furyl-4H), 7.0(q,lH, furyl-3H), 7.2(m,3H, phenyl-H), 7.4(m,2H, phenyl-H), 7.8(q,lH, furyl-5H), 8.4-8.8(d,2H, NH2); m/e 294 (M+H⁺).

The necessary methylsulphonyl starting material vas prepared as follows :BAD ORIGINAL

AP000248

- 65 To a cooled suspension of 7-amino-2-(2-furyl)-5-methylthiopyrazolo[2,3-a]-l,3,5-triazine (4.3 g) in dichioromethane (50 ml) was added a solution of 3-chloroperoxybenzoic acid (15 g, 502 w/v) in dichioromethane (100 ml), discarding the aqueous layer. The reaction mixture was allowed to warm to ambient temperature and stirred for 16 hours. The solvent was removed in vacuo and the residue was triturated vith ethanol. The solid formed was collected by filtration, vashed vith ethanol and dried to give an off-white solid (19.4 g). This material was crystallised from ethanol to give

7-amino-2-(2-furyl)-5-methylsulphonyl-pyrazolo(2,3-a](l,3,5J triazine as a crystalline solid, m.p. 215-219’C; microanalysis, found: C,42.9; H,3.4; N.24.72; C^N^S requires: C,43.0; H,3.2; N,25.02; NMR, 3.3(s,3H, CH₃SO₂-), 6.6 (d,lH, furyl-4H), 6.8(s,lH, pyrazole-3H), 7.1(d,lH, furyl-3H), 7.7(d,lH, furyl-5H); m/e 280 (M+H⁺).

The starting methylthio compound was itself prepared as follows:An intimate mixture of 3-amino-5-(2-furyl)pyrazole (3.0 g; obtainable from the Maybridge Chemical Company Ltd., Tintagel, Cornwall) and dimethyl N-cyanodithioiminocarbonate (3.2 g) was heated at 180°C for 5 minutes. The reaction mixture vas cooled and the solid vhich formed vas crystallised from ethanol to give 7-amino-2-(2-fury 1)-5-methylthio-pyrazolo(2,3-a 1(1,3,5] triazine as a colourless crystalline solid, m.p. 234-236°C; microanalysis, found: C,48.9; H,3.7; N,28.02; C^H^OS requires: C.48.6; H,3.6; N.28.32; NMR: 2.5(s,3H, CH₃S), 6.5(s,lH, pyrazole-CH), 6.7(q, IH, furyl-4H), 7.0(q,lH, furyl-3H), 7.8(q,lH, furyl-5H), 8.2-8.7(br d, 2H, NH^; m/e 247 (M⁺).

Example 120

Propylamine (6.0 ml) was added to a suspension of 7-amino-2-(2-furyl)-5-(methylsulphonyl)pyrazolo[l ,5-a]] 1,3,5] triazine (2.0 g) in 1,2-dimethoxyethane (50 ml) (6.0 ml) and the mixture was heated under reflux for 2 hours. The solvent was removed in vacuo and the residue vas purified by chromatography on silica (100 g) eluting vith an increasing concentration of ethyl acetate in dichioromethane to give a white solid (0.76 g). This vas crystallised from ethanol to give 7-amino-2-(2-furyl)-5-(propylamino)pyrazolo[2,3-a )(1,3,5)^8adorig,_Nal $ ·'* t> S 9 Ο () 9,4

- 66 triazine, as a solid, m.p. 221-223^eC; microanalysis, found: C, 55.6; H, 5.3; N, 32.52; C12^H14^N6° requires C, 55.8; H, 5.5; N, 32.52; NMR: 0.89(t, 3H, CH3), 1.53(m, 2H, CHp, 3.20(m, 2H, CH₂N), 6.05(s, 1H, pyrazole-3H)» 6.62(dd, 1H, furyl-4H), 6.90(d, IB, furyl-3H), 6.95(br s, IB, NH), 7.78(d 1H, furyl-5H) and 7.8(br, 2H, NH₂); m/e 258 (M⁺)._lV Examples 121-133

Using a similar procedure to that described in Example 119¾ but using the appropriate phenol or hydroxy compound, the following «'· compounds of formula I were obtained:

[Example 121]:

7-amino-5-(4-chlorophenoxy)-2-(2-furyl)pyrazolo[2,3-a][1,3,5]triazine as a solid, m.p. >300°C (from ethanol); microanalysis, found: C, 54.4; H, 3.2; N, 20.9; H₂0, 0.1X; C^H^N^IC^. O.O5H₂O requires: C, 54.8;

H, 3.1; N, 21.3; H₂0, 0.32; NMR: 6.4(s, 1H, pyrazole-3H), 6.6(dd, 1H, furyl-4H), 7.0(d, 1H, furyl-3H), 7.2-7.3(m, 2H, phenyl-H), 7.4-7.5(m, 2H, phenyl-H), 7.8(d, 1H, furyl-5H), 8.3-8.9(d, 2H, NH₂); m/e 327 (M⁺);

[Example 122]:

7-amino-5-ethoxy-2-(2-furyl)pyrazolo[2,3-a][1,3,5]triazine, as a colourless solid, (using ethanol as reaction solvent), m.p. 206-208*C recrystallised from ethanol); microanalysis, found: C, 54.1; H, 4.5;

N, 28.32; requires: C, 53.9; H, 4.5; N, 28.62; NMR: 1.3(t,

3H, CH₃CH₂O), 4.3(q, 2H, CHjCHjO), 6.4(s, 1H, pyrazole-3H), 6.65(dd, 1H, furyl-4H), 7.0(d, 1H, furyl-3H), 7.0(d, 1H, furyl-5H), 8.0-8.6(br d, 2H, -NH₂); m/e 245 (M*>;

[Example 123]: r

7-amino-5-(3-chlorophenoxy)-2-(2-furyl)pyrazolo[2,3-aJ[1,3,5]triazole, as a solid, m.p. 252-254’C, (recystallised from toluene);

microanalysis, found: C, 55.4; H, 3.0; N, 21.22;

requires: C, 55.0; H, 3.1; N, 21.42; NMR: 6.45(s, 1H, pyrazole-3H), 6.65(dd, 1H, furyl-4H), 7.0(d, 1H, furyl-3H), 7.1-7.5(m, 4H, phenyl-H), 7.8(d, 1H, furyl-5H), 8.3-9.0(br d, 2H, -NHj); m/e 328 (M+H)⁺;

[Example 124]:

7-aaino-2-(2-fury1)-5-(3-methoxyphenoxyJpyrazolo]2,3-a](1,3,5]triazine, as a solid, m.p. 227-229’C (recrystallised from

AP000248

- 67 toluene); microanalysis, found: C, 59.8; H, 3.9; N, 21.62; ^35^33^5^3 requires: C, 59.4; H, 4.1; N, 21.72; NMR: 3.8(s, 3H, CH-jO), 6.4(s, IB, pyrazole-3H), 6.65(dd, IH, furyl-4H), 6.8(m, 3H, phenyl-H), 7.0(d, IH, furyl-3H), 7.3(m, IH, phenyl-H), 7.8(d, IH, furyl-5H), 8.3-8.9(br d, 2H, -NH₂); m/e 324 (M+H)*;

(Example 125]:

7-amino-5-(1-butoxy)-2-(2-furyl)pyrazolo(2,3-a|(1,3,5J triazine, (using butanol as reaction solvent), as a solid, m.p. 171-173’C (recrystallised from toluene); microanalysis, found: C, 57.4; H, 5.4; N, 25.32; C^H^N^ requires: C, 57.1; H, 5.5; N, 25.62; NMR: 1.0(t, 3H, CH-j), 1.3-1.5(m, 2H, CH-jCt^), 1.6-1.8(m, 2H, CH-jCHjCHp, 4.2(t,

2H, CH₂O-), 6.4(s, IH, pyrazole-3H), 6.65(dd, IH, furyl-4H), 7.0(d,

IH, furyl-3H), 7.8(d, IH, furyl-5H), 8.1-8.7(br d, 2H, 1¾); m/e 274 (M*H)⁺;

[Example 126(:

7-amino-5-(4-cyanophenoxy)-2-(2-furyl)pyrazolo[2,3-a([1,3,5( triazine, as a solid, m.p. 3O7-3O9°C, (recrystallised from ethanol); microanalysis, found: C, 60.2; H, 3.0; N, 26.22; ^35^3θ^5θ2 ^re9^u^^res: C, 60.4; H, 3.2; N, 26.42; NMR: 6.45(s, IH, pyrazole-3H), 6.65(dd, IH, furyl-4H), 7.0(d, IH, 3-furyl H), 7.4-7.5(d, 2H, phenyl-H), 7.85(d,

IH, furyl-5H), 7.9-8.0(d, 2H, phenyl-H), 8.4-9.0(br d, 2H, NH₂); a/e 319 (M+H)*;

[Example 127(:

7-amino-2-(2-fury1)-5-(2-furylmethoxy)pyrazolo(2,3-aJ[1,3,5]triazine, as a solid, m.p. 205-207°C (recrystallised from ethyl acetate); microanalysis, found: C, 56.7; H, 3.8; N, 23.32; requires:

C, 56.6; H, 3.7; N, 23.62; NMR: 5.3(s, 2H, CHjO-), 6.45(s,

IH, pyrazole-3H), 6-5(dd, IH, furyl-4H), 6.6(d, IH, furyl-3H),

6.65(dd, IH, furyl-4H), 7.0(d, IH, furyl-3H), 7.7(d, IH, furyl-5H), 7.85(d, IH, 5-furyl H), 8.1-8.8(br d, 2H. NH^; m/e 298 (M+H)*; [Example 128(:

7-amino-5-(3-cyanophenoxy)-2-(2-furyl)pyrazolo[2,3-a1[1,3,5( triazine, as a solid, m.p. 261-263^eC, (recrystallised from ethanol); microanalysis, found: C, 60.0; H, 3.2; N, 26.22; requires:

C, 60.4; H, 3.2; N, 26.42; NMR: 6.45(s, IH, pyrazole-3H), 6.65(dd, IH, furyl-4H), 7.0(d, IH, furyl-3H), 7.5-7.9(m, 5H, phenyl-H + furyl-5H),

BAD ORIGINAL

- 68 8.4-9.0(br d, 2H, NH^); m/e 319 (M+B)*;

(Example 1291:

7-amino-5-(2-[e thy lsulphinyl [ethoxy )-2-( 2-f uryl)pyrazolo[ 2,3-a J[1,3,5]triazine, as a solid, m.p. 182-184’C, (recrystallised from ethanol); microanalysis, found: C, 48.9; H, 4.8; N, 21.92; requires: C, 48.6; B, 4.7; N, 21.82; NMR: 1.2(t, 3H, CH₃), 2.6-3.3(m, 4H, CH2.SO.CH₂), 4.5-4.8(m, 2H, CH₂O), 6.45(s, IB, pyrazole-3H), *

6.65(dd, 1H, furyl-4B), 7.0(d, 1H, furyl-3H), 7.85(d, IB, furyl-5H), 8.1-8.8(br d, 2H, NHp; m/e 322 (M+H)⁺;

[Example 130]:

7-amino-5-(2-f luorophenoxy )-2-( 2-f uryl)pyrazolo[ 2,3-a J [1,3,5] triazine, as a solid, m.p. 253-255’C, (recrystallised from ethanol); microanalysis, found: C, 57.6; H, 3.1; N, 22.52; ^Ι5^ιο^5^θ2 ^re9^u^^res: C, 57.8; H, 3.2; N, 22.52; NMR: 6.45(s, 1H, pyrazole-3H), 6.65(dd, IB, furyl-4H), 7.0(d, 1H, furyl-3H), 7.3-7.5(m, 4H, phenyl-B), 7.8(d, 1H, furyl-5H), 8.4-9.0(br d, 2H, NHp; m/e 312 (M+H)⁺;

[Example 131]:

7-amino-2-(2-furyl)-5-( 3-isoxazolyloxy )pyrazolo[ 2,3-a J [1,3,5] triazine, as a solid, m.p. 235-237’C (recrystallised from 2-propanol); microanalysis, found: C, 50.8; H, 2.9; N, 28.92; C^HgNgOy O.li^H^OH requires: C, 50.8; H, 3.1; N, 28.92; NMR: 6.45(s, IB, pyrazole-3H), 6.65(dd, 1H, furyl-4H), 6.75(d, 1H, isoxazole-4H), 7.05(d, 1H, £uryl-3H), 7.85(d, 1H, furyl-5H), 8.9(d, 1H, isoxazole-5B), 8.5-9.2(br d, 2H, NHp(spectrum also contains signals for 2-propanol (0.1 mole)]; m/e 284 (M⁺);

(Example 132]: 7-amino-2-(2-furyl)-5-[3-(l,2,5-thiadiazolyl)oxy]- -. pyrazolo(2,3-a][1,3,5|triazine, as a solid, m.p. 246-248°C (recrystallised from ethanol); microanalysis, found: C, 43.9; H, 2.0j N, 32.72; C_nH₇N₇SO₂ requires: C, 43.8; H, 2.3; N, 32.62; NMR: 6.55(s, 1H, pyrazole-3H), 6.65(dd, 1H, furyl-4H), 7.05(d, 1H, furyl-3H),

7.85(d, 1H, furyl-5H), 8.9(s, 1H, 4-thiadiazole H), 8.6-9.2(br d, 2H, NH„); m/e 301 (M⁺); and —z.

[Example 133]:

7-amino-2-(2-furyl)-5-(3-pyridyloxy)pyrazolo[2,3-a][1,3,5]triazine, as a solid, m.p. 278-28O°C (recrystallised from ethanol); microanalysis, found: C, 57.2; H, 3.1; N, 28.22; C₁₄ ^H10^N6°₂ requires: C, 57.1; H,

BAD ORIGINAL ft

- 69 3.4; N, 28.6X; NMR: 6.45(s, 1H, pyrazole-3H), 6.65(dd, 1H, furyl-4H), 7.0(d, 1H, furyl-3H), 7.5(dd, 1H, pyridyl-5H), 7.7(m, 1H, pyridyl-4H), 7.8(d, 1H, furyl-5H), 8.45(dd, 1H, pyridyl-6H), 8.55(d, 1H, pyridyl-2H), 8.4-9.O(br d, 2H, NH₂); m/e 294 (M⁺).

Example 134-141

Using a similar procedure to that described in Example 120, but using the appropriate amino compound, the following compounds of formula I were prepared:

[Example 134];

7-amino-2-(2-furyl)-5-(piperidino)pyrazolo(2,3-a|[1,3,5]triazine, as a solid, m.p. 274-276°C, (recrystallised from ethanol); microanalysis, found: C, 58.8; H, 5.7; N, 29.32; C₁₄H₁₍₎N₆O requires: C, 59.1; H, 5.7; N, 29.62; NMR: 1.68(m, 6H, CH₂), 3.88(t, 4H, CH₂ N CHp, 6.22(s, 18, pyrazole-3H), 6.78(dd, 1H, furyl-4H), 7.08(d, 1H, furyl-3H), 7.96(s, 1H, furyl-5H) and 8.05(br s,2H, NH₂); m/e 284 (M⁺);

[Example 135[:

7-amino-2-(2-furyl)-5-(exo-norbornylamino)pyrazolo[2,3-aJ[l,3,5Jtriazine, as a solid, m.p. 247-249°C, (recrystallised from ethanol); microanalysis, found: C, 61.7; H, 5.8; N, 26.92; requires:

C, 61.9; H, 5.8; N, 27.12; NMR: 1.0-1.7(complex, 8H, CHj), 2.19(s, 2H, CHCH₂), 3.67(br, 1H, CHNH), 6.03(s, 1H, pyrazole-3H), 6.60(dd, 18, furyl-4H), 6.74(d, 1H, NHCH), 6.67(d, 1H, furyl-3H), 7.67(br s, 2H, NH₂) and 7.75(d, 1H, furyl-5H); m/e 310 (M⁺);

[Example 136]:

7-amino-5-cyclohexylamino-2-(2-furyl)pyrazolo[2,3-a](1,3,5]triazine, as a solid, m.p. 218-220°C, (recrystallised from ethanol); microanalysis, found: C, 60.4; H, 5.9; N, 28.0Z; ^reQ^uires:

C, 60.4; H, 6.0; N, 28.2Z; NMR: 1.0-2.0(complex', 10H, CHj), 3.69(br s, 1H, NH), 6.02(s, 1H, pyrazole-3H), 6.61(dd, 1H, furyl-4H), 6.70(d, 1H, NH), 6.88(d, 1H, furyl-3H), 7.71(br, 2H, NHp and 7.76(dd, 1H, furyl-5H); m/e 298 (M⁺);

[Example 137]:

7-amino-2-(2-furyl)-5-anilinopyrazolo|2,3-a][l,3,5]triazine, as a solid, m.p. 284-286’C, (recrystallised from ethanol); microanalysis, found: C, 61.7; H, 4.1; N, 28.1Z; C^Hj^O O.OSC^OH requires: C, 61.6; H, 4.2; N, 28.52; NMR: 6.25(s, 1H, pyrazole-3H); 6.66(dd, 1H, bad original

- 70 furyl-4H), 6.98(complex, 2H, furyl-3H + p-phenyl-H), 7.28(t, 2H, m-phenyl-H), 7.81(complex, 3H, furyl-5H + o-phenyl-H), 8.08(br s, 2H, NH₂) and 9.27(br s, 1H, NH); m/e 292 (M*);

(Example 138]:

7-amino-5-(2-dimethylaminoethyl)amino-2-(2-furyl)pyrazolo(2,3-a}[l,3,5]triazine, as a solid, m.p. 169-171^eC (recrystallised from ethanol); microanalysis, found: C, 54.5; H, 6.0; N, 34.4.2;

.τ ^C13^H17^N7° ^re<1^{uires: c}’ ⁵⁴’^{4; H}’ ^{5>9; N}’ ³⁴·²*; NMR: 2.73(s, 6H, NCHp, 3.16(t, 2H CH₂N), 3.56(t, 2H, C^N), 6.08(s, 1H, pyrazole-3H),

6.59(dd, 1H, furyl-4H), 6.89(d, 1H, furyl-3H) and 7.72(s, 1H, £uryl-5H); m/e 288;

(Example 1391:

7-ami no-2-( 2-fury 1)-5-( 2-f ury Imethy lamino)pyrazolo-(2,3-a] (1,3,5 (triazine, as a solid, m.p. 213-215°C, (recrystallised from ethanol); microanalysis, found: C, 57.0; H, 3.9; N, 28.22; ^^Η^₂Ν^0₂ requires: C, 56.7; H, 4.05; N, 28.42; NMR: 4.45(d, 2H, CHjNH), 6.07(s, 1H, pyrazole-3H), 6.23(d, 1H, furylmethylamino-3H), 6.35(dd, 1H, furylmethylamino-4H), 6.60(dd, 1H, furyl-4H), 6.90(d, 1H, furyl-3H), 7.27(t, 1H, NH), 7.52(d, 1H, £urylmethylamino-5H), 7.76(d, 1H, furyl-5H) and 7,85(br s, 2H, NH₂); m/e 296 (M)⁺;

(Example 140]:

(S)-7-amino-2-(2-furyl)-5-( α-methyl benzy lamino]pyrazolo( 2,3-aJ(1,3,5]triazine, as a solid, m.p. 115-118^eC (with decomposition), (recrystallised from methanol); microanalysis, found: C, 63.0; H, 5.4; N, 25.62; ^C17^H16^N6O 0.25 CH₃0H requires: C, 63.1; H, 5.2; N, 25.62; NMR: 1.42(d, 3H, CH-j), 5.15(m, 1H, CHN), 6.00(s, 1H, pyrazole-3H), 6.60(dd, 1H, £uryl-4H), 6.88(d, 1H, furyl-3H), 7.1-7.5(complex, 6H..NH + phenyl H) and 7.75(br d, 3H, NH_? + £uryl-5HT; m/e 320 (M)⁺; and (Example 141]:

7-amino-2-(2-fury1)-5-(3-pyridylmethylamino)pyrazolo(2,3-a](1,3,5(triazine, as a solid, m.p. 215-217’C, (recrystallised from ethanol); microanalysis, found: C, 59.0; H, 4.1; N, 32.02; requires:

C, 58.7; H, 4.2; N, 31.92; NMR: 4.5(d, 2H, NCHp, 6.07(s, 1H, pyrazole-3H), 6.62(dd, 1H, furyl-4H), 6.8(d, 1H, furyl-3H), 7.32(dd,

1H, pyridyl-5H), 7.48(t, 1H, NH), 7.75(complex, 2H, furyl-5H + pyridyl-4H), 7.85(br, 2H, NHp, 8.42(dd, 1H, pyridyl-6H) and 8.55(d,

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- 71 IH, pyridyl-2H); m/e 307 (M)*.

Example 142

Using a similar procedure to that described in Example 119, but using thiophenol instead of phenol, there vas obtained 7-amino-2(2-furyl)-5-(phenylthio)pyrazolo(2,3-a( [ 1,3,5( triazine, ^{as a} solid, m.p. >300^eC (vith decomposition, (recrystallised from ethanol); microanalysis, found: C, 58.2; H, 3.5; N, 22.32; C^^H^jN^OS requires: C, 58.2; H, 3.6; N, 22.62; NMR: 6.44(s, IH, pyrazole-3H), 6.62(dd, IH, furyl-4H), 6.99(d, IH, furyl-3H), 7.49(complex, 3H, phenyl-·- + β-Η), 7.61(complex, 2H, phenyl-o-H), 7.81(d, IH, furyl-5H) and 8.51(br d,

2H, NH₂); m/e 310 (M+H)⁺.

Example 143

4-(2-aminoethyl)phenol (1.37 g) vas added to a stirred suspension of 7-amino-2-(2-furyl)-5-(methylsulphonyl)pyrazolo(2,3-al[1,3,5 J triazine (1.4 g) in acetonitrile (150 ml) and the mixture vas heated under reflux for 6 hours. The solvent vas removed in vacuo and the residue vas purified by chromatography on silica (100 g) eluting vith dichloromethane containing methanol (5.02 v/v). The solid obtained vas crystallised from ethanol to give 7-aaino-2( 2-furyl )-5-( 2-(4-hydroxyphenyle thy 1) Jaminopyrazolo( 2,3-a J (1,3,5J triazine as a crystalline solid (0.36 g), m.p. 213-215’C; microanalysis, found: C,60.0; H,5.3; N,24.0X; C|yHjgNgO₂ O.3C₂H^OH requires C,60.2; H,5.2; N,24.02; NMR: 1.05(t, CH-jCHjOH), 2.70(t, 2H, CH₂Ar), 3.4 (complex, NC§₂ and CH^f^OH), 4.31( t, CH-jCH^H), 6.08(s, IH, pyrazole-3H), 6.62(dd, IH, furyl-4H), 6.7 and 7.05 (AjBj pattern, 4H, phenyl-H), 6.86(t,IH, NH), 6.92(dd, IH, furyl-3fl), 7.8(br s, 2H, NH₂) and 9.12 (s, IH, OH); m/e 337 (M+H)\

EXAMPLES 144-148

Using a procedure similar to that described in Example 1, but using the appropriate phenol or hydroxy compound, the following compounds of formula I vere obtained:

(EXAMPLE 144(: 7-amino-5-(2-cyanophenoxy)-2-(2-furyl)pyrazolo[2,3a] [ 1,3,5 J triazine as colourless prisms from ethanol, m.p. 296-298’C (decomposed); microanalysis, found: C, 60.0; H, 3.0; N, 26.12;

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- 72 θ16^Β10^6θ2 ^re9^ui^res’ C, 60.4; Η, 3.1; Ν, 26.42; NMR: 6.5(s, 1Η, pyrazole-3H), 6.65(q, 1Η, furyl-4H), 7.0(q, 1H, £uryl-3H), 7.4-7.6(m, 2H, phenyl-H), 7.7-8.0(m, 3H, phenyl-H and furyl-5H), 8.5-9.l(broad d, 2H, NH₂); m/e 319 (M+H)*.

[EXAMPLE 145): 7-amino-2-(2-fury1)-5-(2,3,4,5,6-pentafluorophenoxy )_r pyrazolo[2,3-a][1,3,5]triazine as colourless crystals from ethanol,

m.p. 285-288°C; microanalysis, found: C, 47.2; H, 1.7; N, 18.42;

^C15^B6^F5^N5°2 ^re9^{uires: c}’ ^{47,0; a}’ ^{1,6; N}’ ¹⁸·³*; NMR: 6.5O(s, 1H, pyrazole-3H), 6.65(dd, 1H, furyl-4H), 7.02(d, 1H, furyl-3H), 7.85(d, 1H, furyl-5H), 8.75-9.10(br d, 2H, NHp,· m/e 384 (M+H)*.

[EXAMPLE 146]: 7-amino-2-(2-fury 1)-5-(2-aethoxycarbonylphenoxy) pyrazolo[2,3-a|[1,3,5]triazine as colourless prisms from methanol, m.p. 249-251’C; microanalysis, found: C, 57.7; H, 3.6; N, 19.82;

^C17^H13^N5°4 ^re9^{uires: c}> ^38,1» ³·⁷? ^N’ 19.92; NMR: 3.65(s, 3H, CHj),

6.4(s, 1H, pyrazole-3H), 6.65(q, 1H, furyl-4H), 6.95(q, 1H, £uryl-3H), 7.3-7.5(complex, 2H, phenyl-H), 7.7(t of d, 1H, phenyl-5H), 7.8(d, 1H, furyl-5H), 7.9(dd, 1H, phenyl-3H), 8.3-8.9(broad d, 2H, NH^; m/e 325 (M+H)*.

[EXAMPLE 147]: 7-amino-2-(2-furyl)-5-(4-N-(l-propyl)aminocarbonyl ethoxy)phenoxypyrazolo[2,3-a][l,3,5]triazine as colourless crystals from ethanol, m.p. 224-226°C; microanalysis, found: C, 58.6; H, 4.7;

N, 20.22; ε_2θΗ_2θΝ₆Ο₄ requires: C, 58.8; H, 4.9; N, 20.62; NMR: 0.86(t, 3H, CH₃), 1.48(m, 2H, -CHj-), 3.12(q, 2H, -CHjN), 4.5O(s, 2H, OCH^O) , 6.40(s, 1H, pyrazole-3H), 6.65(dd, 1H, £uryl-4H), 6.95-7.05 (complex, 3H, phenyl-H and furyl-3H), 7.10-7.20 (complex, 2H, phenyl-H), 7.83(d, 1H, furyl-5H), 8.10( t, 1H, CONH), 8.4-8.8(br d, 2H, NH^; m/e 409 (M+H)*.

The phenol starting material was prepared as follovs:A solution of 1-propylamine (4.1 ml) and methyl

4-hydroxyphenoxyacetate (3.64 g) in methanol (50 ml) was left to stand for 72 hours at ambient temperature. The solvent was evaporated in vacuo and the residue taken up in ethyl acetate. The solution was

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- 73 washed sequentially vith 1M HCl (2 x 25 ml) and brine (30 ml), dried (MgSOp and the solvent evaporated to give N-(l-propyl)-4hydroxyphenoxyacetamide as a red oil, NMR: O.95(t, 3H, CH^), 1.55(m, 2H, CH₂), 3.3(q, 2H, CHjN), 4.4(s, 2H, CH₂O), 6.5-6.7(broad s, IH,

OH), 6.8(s, 4H, phenyl-H); m/e 227 210(M+H)⁺.

[EXAMPLE 1481: 7 -ami no-5- ( 3-me thoxy car bony 1 phenoxy )-2-(2-furyl)pyrazoloj2,3-a][1,3,5]triazine as a solid from ethanol, m.p.

244-247’C; microanalysis, found: C, 57.7; H, 3.8; N, 19.82; C^H^N^O^ requires: C, 58.1; H, 3.7; N, 19.92; NMR: 3.89(s, 3H, (X^CHj), 6.42(s, IH, pyrazole-3H), 6.65(dd, IH, furyl-4H), 6.99(dd, IH, furyl-3H),

7.5-7.9(complex, 5H, furyl-5H and phenyl-H) and 8.64(d, 2H, NH₂); m/e 352 (M+H)⁺.

EXAMPLES 149-152

Using a procedure similar to that described in Example 120, but using the appropriate amino compound, the following compounds of formula I was obtained:[EXAMPLE 149[:

7-amino-2-(2-furyl)-5-(2-phenylethylamino)pyrazolo[2,3-aJ [1,3,5 [triazine as off-white crystals from ethanol, m.p. 225-227^eC; microanalysis, found: C, 63.3; H, 4.9; N, 26.12; ^^Η^-Ν^Ο requires: C, 63.7; H, 5.0; N, 26.22; NMR: 2.74(t, 2H, CHp, 3.97(q, 2H, CH₂N), 6.05(s, IH, pyrazole-3H), 6.62(dd, IH, furyl-4H), 6.90(complex, 2H, furyl-3H and NH), 7.14-7.36(complex, 5H, phenyl-H), 7.78(d, IH, furyl-5H), 7.8O(br, 2H, NH₂); m/e 321 (M+H)*.

[EXAMPLE 150); 7-amino-5-cyclopropylmethylamino-2-(2furyl)pyrazolo[2,3-a[[l,3,5[-triazine as off-white crystals from toluene, m.p. 200-202°; microanalysis, found: C, 58.0; H, 5.4; N, 30.82; C_nH₁₄N₆O requires: C, 57.8; H, 5.2; N, 31.12; NMR:

0.17-O.29(complex, 2H, cyclopropyl-CHp, 0.31-0.45(complex 2H, cyclopropyl CH₂), 0.95-1.18(complex, IH, cyclopropyl CH), 3.13(t, 2H, CH₂N), 6.03(s, IH, pyrazole-3H), 6.62(dd, IH, furyl-4H), 6.88(d, IH, furyl-3H), 6.93(br s, IH, NH), 7.76(d, IH, furyl-5H) and 7.77(br, 2H,

BAD ORIGINAL ft <' S' Ο Ο Ο <?Α

- 74 ΝΗ₂>; m/e 270 (Μ⁺).

(EXAMPLE 151(: 7-aa i no-5-(2-(4-ami nosulphony1phenyl) e thy 1 ] ami no2-(2-furyl)pyrazolo(2,3-al(l,3,5(triazine as off-white crystals from ethanol, m.p. 245-248’C; microanalysis, found: C, 50.6; H, 4.7; N, 23.2; H₂0, 2.22; C^H^N^S. 0.3C₂H₅0H. O.5H₂O requires: C, 50.3; H, 4.7; N, 23.2; HjO, 2.22; NMR: 2.93(t, 2H, CHj), 3.43-3.55(complex, 2H, CH₂N), 6.08(s, IH, pyrazole-3H), 6.62(dd, IH, furyl-4H), 6.90(d, IH,* furyl-3H), 6.96(br t, IH, NH), 7.25(s, 2H, SO₂NH₂), 7.41-7.46(d, 2H,' phenyl-H), 7.73-7.77(brd, 5H, furyl-5H, phenyl-H and NHj); m/e 399 (M*).

(EXAMPLE 152(: 7-amino-2-(2-furyl)-5-(2-(4-pivaloyloxyphenyl)ethyl(aminopyrazolo (2,3-aJ(l,3,5(triazine as pale yellow prisms from 2-propanol, m.p. 211-213’C; microanalysis, found: C, 62.4; H, 6.1; N, 19.82; C₂₂ ^h24^N6O₃ requires: C, 62.8; H, 5.8; N, 20.02; NMR: 1.3(s, 9H, (CH₃)₃), 2.85(t, 3H, CH₂ Ar), 3.5(m, 2H, CH₂N), 6.05(s, IH, pyrazole-3H), 6.6(q, IH, furyl-4H), 6.9(q, IH, furyl-3H), 7.0(d, 2H, phenyl-H), 7.75(d, 2H, phenyl-H), 7.5-8.0(complex, 4H, NH₂, NH and furyl-5H); m/e 421 (M+H)⁺.

The requisite amine starting material vas prepared as follows:

A solution of pivaloyl chloride (10.0 ml) vas added dropwise to a stirred solution of tyramine (10.2 g) in a dichloromethane/ trifluoroacetic acid mixture (1:1 v/v). The reaction mixture vas stirred for 4 hours and the solvents then removed in vacuo. The syrupy residue vas triturated with an ethyl acetate/diethyl ether mixture (3:1 v/v) to give 2-(4-pivaIoyloxyphenyl)ethylamine as a colourless trifluoroacetate salt, m.p. 255-257°C; NMR: 1.3(s, 9H, pivaloyl-H), 2.85(m, 2H, CH₂Ph), 3.05(m, 2H, C^N), 7.05(d, 2H, phenyl-H), 7.3(d, 2H, phenyl-H), 8.0(broad s, 3H, NH₃); m/e 222 (M+H)*.

EXAMPLES 153-157

Using a procedure similar to that described in Example 119, but using an appropriate thiol compound instead of phenol, the

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AP000248

- 75 following compounds of formula I were obtained:

(EXAMPLE 1531: 7-amino-2-(2-furyl)-5-(2-furylmethylthio)pyrazolo[2,3-a][l,3,5]triazine as colourless crystals from ethanol, m.p. 207-209’C; microanalysis, found: C, 53.8; H, 3.4; N, 22.3Z; ^C14^H11^N5°2^{S re}9^{uires: c}’ 53.7; H, 3.5; N. 22.4Z; NMR: 4.45(s, 2H, CH₂S), 6.40(complex, 2H, furyl 3'H and 4'H), 6.55(s, IH, pyrazole-3H), 6.67(dd, IH, furyl-4H), 7.03(d, IH, furyl-3H), 7.58(s, IH, furyl-5H), 7.84(d, IH, furyl-5H), 8.40-8.70(br d, 2H, NHj); m/e 314 (M+H)*.

(EXAMPLE 154]: 7-a«ino-5-cyclopenty1thio-2-(2-fury1)pyrazolo]2,3a](1,3,5]triazine as colourless plates from ethanol, m.p. 226-228’C; microanalysis, found: C, 56.2; H, 5.4; N, 23.2Z; C^H^N^SO requires: C, 55.8; H, 5.0; N, 23.2X; NMR: 1.4-1.8(complex, 6H, cyclopentyl-H),

2.1-2.3(complex, 2H, cyclopentyl-H), 3.8-4.0(complex, IH, cyclopentyl-ΙΗ), 6.5(s, IH, pyrazole-3H, 6.65(q, IH, furyl-4H), 7.0(d, IH, furyl-3H), 7.8(d, IH, furyl-5H), 8.1-8.7(broad d, 2H, NHj); m/e 301 (M)*.

[EXAMPLE 155]: 7-aeino-2-(2-furyl)-(N-(l-propyl)aainocarbonyl methylthio)pyrazolo[2,3-a](1,3,5]triazine as yellow crystals from ethanol; m.p. 25O-253°C; microanalysis, found: C, 50.5; H, 4.7; N,

25.0Z; ^c14^h16ⁿ6°2^S requires: C, 50.6; H, 4.8; N, 25.3Z; NMR: 0.75(t, 3H, CH₃), 1.42(m, 2H, CHj), 3.05(q, 2H, CH₂N), 3.82(s, 2H, SCH₂C0), 6.48(s, IH, pyrazole-3H), 6.68(dd, IH, furyl-4H), 7.05(d, IH, furyl-3H), 7.85(d, IH, furyl-5H), 8.05(t, IH, NH); 8.40-8.70(br d, 2H, NH₂); m/e 333 (M+H)*.

The starting material was prepared in a manner essentially similar to that described in Example 156, but using 1-propylamine instead of cyclohexylamine. The product was distilled to give a pale yellow viscous oil vhich was used directly.

(EXAMPLE 156]: 7-ajnino-5-(cyclohexylaminocarbonylniethylthio)-2-(2furyl pyrazolo (2,3-a](l,3,5]triazine as yellow crystals from isopropanol; m.p. 253-256’C; microanalysis, found: C, 55.1; H, 5.5; N, 22.7Z; C₁₇ ^h2Oⁿ6O₂ ^S squires: C, 54.8; H, 5.4; N, 22.6Z; NMR:

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- 76 1.00-1.40(complex, 5H, cyclohexyl-H), 1.45-1.85(complex, 5H, cyclohexyl-H), 3.51(br, 1H, CH-N), 3.79(s, 2H, CH₂S), 6.46(s, 1H, pyrazole-3H), 6.66(dd, 1H, furyl-4H), 7.02(d, 1H, furyl-3H), 7.83(d, 1H, furyl-5H), 7.94(d, 1H, CONH), 8.2-8.8(br d, 2H, NHj); m/e 373

The thiol starting material vas prepared as follows:A solution of ethyl 2-mercaptoacetate (12 g) and cyclohexylamine (29.7 g) in ethanol (50 ml) vas alloved to stand at ambient temperature for 72 hours, and vas then refluxed for 6 hours. The solvent vas evaporated and the residue dissolved in ethyl acetate (200 ml). The solution vas washed sequentially vith 2M HC1 (3 x 50 ml), vater (2 x 50 ml) and brine (50 ml) and the solvent removed in vacuo. The crude product was purified by chromatography on silica (eluting with dichloromethane/methanol 99:1 v/v) to give

N-cyclohexyl-2-mercaptoacetamide as low-melting tan crystals; NMR:

1.0-2.0(complex, 11H, cyclohexyl-CH₂ and SH), 3.2(d, 2H, CHj),

3.6-3.9(m, 1H, cyclohexyl-CH), 6.4-6.9(broad d, 1H, NH); m/e 174 (M+H)*.

[EXAMPLE 157}: 7-amino-2-(2-furyl)-5-(piperidinocarbonylmethylthio) pyrazolo[2,3-a][l,3,5[triazine as colourless crystals from isopropanol; m.p. 198-200’C; microanalysis, found; C, 53.8; H, 5.3; N, 23.5X; ^C16^H18^N6^O2^S requires: C, 53.6; H, 5.0; N, 23.5X; NMR: 1.45-1.59(complex 6H, piperidine CH), 3.44-3.52(complex, 4H, NCH₂), 4.12(s, 2H, CH₂S), 6.48(s, 10,pyrazole-3H), 6.64(dd, 1H, furyl-4H), 7.02(dd, 1H, furyl-3H), 7.82(d, 1H, furyl-5H), 8.2-8.8(br d, 2H, Nf^); m/e 359 (M+H*).

The starting material was prepared by a procedure essentially similar to that described in Example 156, but using piperidine instead of cyclohexylamine. The product was distilled to give a viscous yellow oil which was used directly.

Exaaple 158

Using a procedure similar to that described in Example 118 there was prepared 2-(2-furyl)-5-[2-(4-hydroxyphenyl)ethylJaaino-7methylamino-[1,2,4-[-triazolol1,5-a|[1,3,5[triazine, m.p. 248-250°C;

It

BAD ORIGINAL &

AP Ο Ο Ο 2 4 8

- 77 microanalysis, found: C,58.0; Η,4.9; N,28.0Z; CiyHjjNyOj requires: C,58.1; H,4.8; N,27.9Z, NMR: 2.74(t,2H, CH₂Ar), 2.92 and 2.99 (d,3H, NHCH^ rotamers), 3.45(m,2H, NHCHJ, 6.69 (complex, 3H, 2 phenyl-H and furyl-4H), 7.04 (complex, 3H, 2 phenyl-H and furyl-3H), 7.63(t,lH, -NH-CH₂), 7.86(d,lH, furyl-5H), 8.48 and 8.63 (q,lH, NHCH^ rotamers) 9.17(s,lH, OH); m/e 352 (M+H)*.

Example 159

Using a procedure similar to that described in Example 117 but starting from 5,7-diphenoxy-2-[5-(3-methylisoxazolyl)J-(1,2,4]triazolo]1,5-a][1,3,5]triazine, there vas prepared 7-amino-2-(5-(3methylisoxazolyl) J-5-phenoxy-[1,2,41-1riazolo[1,5-a|(1,3,5]triazine as colourless needles from ethanol m.p. 279-281°C; microanalysis, found: C,54.2; H,4.5; N.29.0Z; (0.6) C^HJH requires: C,54.2;

H,4.3; N,29.1X; NMR: 2.33(s,3H, CHJ, 7.0(s,lH, isoxazolyl-4H) 7.2-7.6 (complex, 5H, phenyl-H) and 9.12(s,2H, NHJ; m/e 310 (M+H)*.

The starting material vas prepared as follovs:(a) A solution of 5-(3-methylisoxazolyl)carbonyl chloride (4.36 g) in dichloromethane vas added to a stirred solution of

2,4-diphenoxy-6-hydrazino-[1,3,5]triazine (8.9 g) and triethylamine (3.03 g) in dichloromethane at 0°C. After stirring for 4 hours at ambient temperature, the organic solution vas vashed vith vater (x 2), brine (x 1), dried and evaporated to yield a foam (13.5 g). Chromatography on silica-gel and elution vith dichloromethane methanol (IX v/v) gave the desired product (6.7 g). Crystallisation of an aliquot from ethanol gave a solid m.p. 195-8°C; NMR: 2.32(s,3H, CHJ, 6.93(s,lH, isoxazolyl-4H), 7.1-7.4 (complex, 10H, phenyl-H), 10.18 (s,lH, NH) and 10.87 (s,lH CONH); m/e 405 (M+H)\ (b) A solution of the acylated hydrazine (2.02 g) and p-toluene sulphonyl chloride (1.90 g) in pyridine (50 ml) vas heated at 100°C for 2 hours. The pyridine vas removed on a rotary evaporator, the residue dissolved in dichloromethane and solution vashed vith 2N HCl (2 x 50 ml), vater (50 ml) and brine (50 ml). The organic solution

BAD ORIGINAL ft

- 78 was dried (MgSOp, filtered, evaporated and used directly.

Example 160

Using a procedure similar to that described in Example 118 but starting from 7-amino-2-I5-(3-methylisoxazolyl)l-5-phenoxy[l,2,4]-triazolo]l,5-ajtriazine, there was obtained 7-amino-5-|2-(4hydroxyphenyl)ethyl]amino-2-[5(3-methylisoxazolyl)J-[1,2,4J-triazolo[1,5-a]triazine, m.p. 233-235’C; microanalysis, found: C,54.7; H,4.8; N,31.1X; C₁₆H₁₆NgO₂ (0.1) C^OH requires: C,54.6; H,4.8; N,31.4X;

NMR: 2.32(s,3H, CHp, 2.71(t,2H, NCHp; 3.42(m,2H, CHj-phenyl), 6.68 and 7.03 (A₂B₂ patterns, 4H, phenyl-H), 6.90(s,lH, isoxazolyl-4H),

7.56 and 7.66 (t,lH, CH₂NH), 8.27(brs, 2H, NHp and 9.15(s,lH, OH); m/e 353 (M+H)*.

Example 161

Using a procedure similar to that described in Example 3 there was obtained 7-amino-2-(2-furyl)-5-|2-(4-methoxyphenyl)ethylamino-(l,2,4|-triazolo(l,5-a](l,3,5]triazine, m.p. 211-213’C microanalysis, found: C,58.2; H,4.7; N.27.82; requires:

C,58.1; H,4.9; N,27.92; NMR: 2.80(t,2H, CHj-phenyl); 3.44(m,2H, CH₂N); 3.72(s,3H, CH-jO), 6.66(d of d, IH, furyl-4H), 6.65 and 7.14 (A^ pattern, 4.11, 4-phenyl-H); 7.05(d,lH, furyl-3H), 7.45(t,lH, NH); 7.86(d,lH, furyl-5H) and 8.04(brs, 2H, NH₂); m/e 352 (M+H)⁺.

Example 162

Using a procedure similar to that described in Example 3 there vas obtained 7-amino-5-]2-(2-benzyloxyphenyl)ethyl]amino-2(2-furyl)-]l,2,41-triazolo]l,5-a|]l,3,5|triazine; m.p. 151-153’C microanalysis, found: C,64.4; H,4.8; N,23.O2; C^H^N^Oj requires: C.64.6; H,4.95; N.22.92; NMR: 2.9O(t,2H, phenyl CH₂); 3.53(m,2H,

CHjN); 5.13(s,2H, CH^O); 6.68(d of d. IH, furyl-4H), 7.04(d,lH, furyl-3H), 6.8-7.6 (complex, 9H, phenyl-H); 7.88(s,lH, furyl-5H) and 8.11 (brs, 2H, NH^; m/e 428 (M+H)\

Example 163

Using a procedure similar to that described in Example 3

BAD ORIGINAL ft

AP Ο 00 2 4 8

- 79 there was obtained 7-amino-5-((3-benzyloxy-4-methoxyphenyl)methylJamino-2-(2-furyl)-)1,2,4|-triazololl,5a|11,3,5)triazine, m.p.

173-175’C microanalysis, found: C.62.3; H.4.6; N.22.12; θ23^21^7θ3 requires: C.62.3; H,4.8; N,22.12; NMR 3.76(s,3H, CH-jO), 4.44(d,2H, CH₂N); 5.04(s,2H, CH₂O) 6.66(d of d, 1H. furyl-4H), 6.75-7.75 (complex, 8H, phenyl-H), 7.03(d,lH, furyl 3H), 7.5(s,lH, furyl-5H), 7.66(m,lH, NH) and 8.18(brs, 2H, NHj); m/e 444 (M+H)\

Example 164

Using a procedure similar to that described in Example 3 there was obtained 7-amino-2-(2-furyl)-5-J2-(3-methoxyphenyl)ethyl]amino-[l,2,4]-triazolo[l,5-a]{l,3,5]triazine, m.p. 172-174’C microanalysis, found: C,57.6; H,4.7; N.28.0; HjO, 0.42;

C₁₇H₁₇N₇O₂(O.1)H₂O requires: C.57.7; H,4.9; N.27.8; HjO, 0.52; NMR: 2.83(t,2H, phenyl-CH₂); 3.5O(m,2H, CH₂N); 3.74(s,3H, CHjO); 6.65(d of d, 1H, furyl-4H); 6.7-7.3 (complex, 4H, phenyl-H); 7.04(d,lH, £uryl-3H), 7.40(t,lH, NH), 7.83(m,lH, furyl-5H), 8.07(brs, 2H, NI^); m/e 352 (M+H)*.

Example 165

Using a procedure similar to that described in Example 3 there was obtained 7-amino-2-(2-furyl)-5-((2-methoxphenyl)methylJamino-)1,2,4]-triazolo(1,5-aJ)1,3,5)triazine, m.p. 249-251’C microanalysis, found: C,56.9; H,4.4; N.29.22; ^ΐ6^|5^7θ2 ^re£I^uires: C.57.0; H.4.5; N.29.12; NMR: 3.83(s,3H, CH₃O), 4.49(d,2H, CH₂N), 6.65(d of d, 1H, furyl-4H), 6.3-7.3 (complex, 4H, phenyl-H); 7.03(s,lH, furyl-3H), 7.69(t,lH, NH), 7.34(d,lH, £uryl-5H) and 8.15(brs, 2H, NH₂); m/e 338 (M*H)\

Example 166

Using a procedure similar to that described in Example 3 there was obtained 7-amino-2-(2-furyl)-5-[(4-methoxyphenyl)methylJamino-(l,2,41-triazolo(l,5-al(l,3,5)triazine, m.p. 237.5-239’C microanalysis, found: C,56.7; H.4.5; N.28.82; ^ci6^Hi5^N7°2 requires: C.57.0; H.4.5; N.29.12; NMR: 3.72(s,3H, CH-jO), 4.42(d,2H, CHjN); 6.66(d of d, 1H, furyl-4H), 6.86 and 7.28 (A₂B₂ pattern, 4H,

BAD ORIGINAL

SOnnqA

- 80 9 phenyl-H), 7.04(d,lH, furyl-3H), 7.86(m,lH, furyl-5H), 7.91 (complex, IH, NH) and 8.16(brs, 2H, NHj); m/e 338 (M+H)*.

Example 167

A solution of the product of Example 161 (0.9 g) in methanol (150 ml) vas hydrogenated at room-temperature and pressure using 10Z palladium on carbon (0.9 g) catalyst. After the uptake of .

hydrogen vas complete, the catalyst was filtered off and the solvent evaporated. The residue vas crystallised from ethanol, and gave 7-amino-2-(2-furyl)-5-[2-(hydroxyphenyl)ethyl]amino-]l,2,4]triazolo(1,5-a][1,3,5]triazine, m.p. 260-263°C microanalysis, found: C,57.2; H,4.8; N.28.6Z; C₁₆H₁₅N_?O₂ (0.15) C^OH requires: C,57.O; H,4.7; N,28.5Z; NMR: 2.81(t,2H, phenyl-H), 3.49(m,2H, CH₂N); 6.71(d of d, IH, furyl-4H), 7.03(d,lH, furyl-3H), 6.7-7.15 (complex, 4H, phenyl-H); 7.85(m,lH NH); 7.84(s,lH, furyl-5H); 8.09(brs, 2H, NHp and 9.31(s,lH, OH); m/e 338 (M+H)*.

Example 168

Using a procedure similar to that described in Example 2 there was obtained 7-amino-2-(2-furyl)-5-(2-phenylethylthlo)(l,2,4Jtriazolo]1,5-a](l,3,5]triazine, as white needles from ethanol m.p. 219-221°C, microanalysis, found: C,57.2; H,4.1; N,24.6Z; C^H^N^OS requires: C,56.8; H,4.2; N.24.8Z; NMR: 3.01(m,2H, phenyl-CHj), 3.36(m,2H, CH₂S), 6.71(d of d, IH, furyl-4H), 7.18(d,lH, furyl-4H), 7.2-7.4 (complex, 5H, phenyl-H); 7.91(m,lH, furyl-5H) and 8.88 (dbr, 2H, NH₂), m/e 339 (M+H)*. >

Example 169

Using a procedure similar to that described in Example 119 but using 2-phenylethanethiol instead of phenol, there was obtained 7-amino-2-(2-furyl)-5-(2-phenylethylthio)-pyrazolo(2,3-a](1,3,5]triazine as a white solid from ethanol m.p. 233-235°C microanalysis, found: C,60.9; H,4.4; N,20.8Z; C^H^N^OS requires: C.60.5; H,4.5; N.20.8Z; NMR: 3.00(t,2H, phenyl-CHj), 3.31(t,2H, CH₂S), 6.54(s,lH, pyrazole-3H), 6.66(d of d, IH, furyl-4H), 7.03(d of d, IH, furyl-3H), 7.2-7.4 (complex, 4H, phenyl-H), 7.63(m,lH, furyl-5H) and 8.5(brd, 2H,

BAD ORIGINAL ft

AP Ο Ο Ο 2 4 8

- 81 NH₂); m/e 338 (M+H)*.

Example 170

Using a procedure similar to that described in Example 3 there was obtained 7-aaino-5-(3,4-dimethoxyphenyl)-2-(2-furyl)[1,2,4J-triazolo(1,5-aH1,3,5|triazine as a crystalline solid from ethanol, m.p. 205-208°C; microanalysis, found: C,56.5; H,5.0; N,25.7X; ^C18^H19^N7°3 ^re9^uires: C,56.7; H,5.0; N.25.7X; NMR: 2.79(t,2H, phenyl-CH₂), 3.45(m,2H, CH₂N), 3.71(s,3H, CH-jO), 3.75(s,3H, Cg₃O); 6.66(d of d, IH, furyl-4H); 6.7-6.9 (complex, 3H, phenyl-H), 7.04(d, IH, furyl-3H), 7.40(t,lH, NH), 7.84(m,lH, furyl-5H) and 8.09(brs, 2H, NH₂); m/e 382 (M+H)*.

Example 171

Using a procedure similar to that described in Example 3 there was obtained 7-amino-(2-furyl)-5-[[2-(4-hydroxyphenoxy)ethyl]amino]-[ 1,2,4J-triazolo)1,5-aJ(1,3,5Jtriazine, m.p. 266-268^eC; microanalysis, found: C,54.0, H,4.O, N.27.5X; requires:

C.54.4; H.4.3; N.27.7X; NMR: 3.6O(brd, 2H, CH₂N), 4.0(m,2H, OCHp,

6.66 (complex, IH, furyl-4H), 6.66 and 6.76 (A₂B₂ pattern, 4H, phenyl-H), 7.04(d, IH, furyl-3H), 7.48 (complex, IH, NH), 7.83(d, IH, furyl-5H), 8.13(brs, 2H, NHp and 8.83(s,lH, OH): m/e 354 (M+H)*.

Example 172

Using a procedure similar to that described in Example 16 there was obtained 7-amino-2-(2-furyl)-5-[2-(3-hydroxyphenyl)ethyl]amino-[l,2,41-triazolo(l,5-alll,3,5Jtriazine, m.p. 190-193°C; microanalysis, found C,57.3; H,4.4; N.29.2Z; ^re9^ui^res:

C.57.0; H,4.4; N,29.1X; NMR: 2.76(t,2H, phenyl-CH₂); 3.46(m,2H, CH₂N), 6.65(m,lH, furyl-4H), 6.5-7.2 (complex, 4H, phenyl-H), 7.04(d,lH, furyl-3H), 7.43(t,lH, NH), 7.85(d,lH, furyl-5H), 8.1(brs,2H, NHp and 9.24(s,lH, OH); m/e 338 (M+H)*.

Example 173

Using a procedure similar to that described in Example 1 there was obtained 7-amino-5-(3,5-dimethylphenoxy)-2-(2-furyl)ⁿ D ORIGINAL ft ί’. i ζ 0 C C Ri\

- 82 [1,2,4-]triazoloj1,5-a[[l,3,5Jtriazine as a crystalline solid from ethanol m.p. 234-236’C; microanalysis, found: C.59.2; H,4.1; N,25.8X; ^C16^H14^N6°2 ^re9^{uires: c}<⁵⁹·⁶; H,4.4; N.26.LZ; NMR: 2.28(s,6H, CH^), 6.67(d of d, 1H, furyl-4H), 6.82(s.2H, phenyl-23 and phenyl-68), 6.88(s,lH, phenyl-4H), 7-10(d of d, 18, furyl-38). ?.90(s,lH, furyl-5H) and 8.95(brs, 2H, NHj); m/e 323 (M-H)*.

Example 174

Using a procedure similar to that described in Example 3 there was obtained 7-amino-2-(2-furyl)-5-[(3,4,5-trimethoxyphenyl)ethyl]amino-[1,2,4 J-triazolo[1,5-a|[1,3,511riaziae. m.p. 221-224°C; microanalysis, found: C.54.5; H.4.?; N.2+.3X: C,.2,^N^O^ requires: C.54.4; H.4.8; N.24.7X; NMR: 3.63(s,3H. CS.O), 2.75(s,6H, 2 x C^O-), 4.45(d,2H, CHjN), 6.66(m,3H, furyI--»H and 2 phenyl-3), 7.03(1,1H, furyl-3H), 7.84(d of d, 1H, furyl-5H). 7.3?(brt. 13. NH) and 3.15(brs, 2H, NH₂), m/e 398 (M+H)⁺.

Example 175

Using a procedure similar to that described in Example 3 there was obtained 7-aaino-2-(2-furyl)-5-[(2~ethaxyphenyl)methyl]amino-[1,2,4J-triazoloj1,5-aJ[1,3,5Jtriazine. m.p. 243-246’C: microanalysis, found: C,58.3; H,4.?; N.28.0X: C.-3.,N₂0₂ requires: C,58.1; H.4.8; N.27.9X. NMR: 1.37(:.38. CH_?), 4.2’(q,2H, CS.O), 4.49(d,2H, CH₂N), 6.65(d of d, 1H. furyi--*5). 6. SI-' .01(m, 3H. furyl-3H and 2 phenyl-H), 7.15-7.22(m,2H, 2-phenyI-13). 7.d~(brt, 18, NH), 7.84(d,lH, furyl~5H), 8.15(brs,2H. N3.); u s 312 --3)\

Example 176

Using a procedure similar :o rha: described in Example 1 there was obtained 7-amino-2-(2-furyl)-5-[(3,5-diaethoxy)phenoxy][ 1,2,4J-triazolo[1,5-aJ[1,3,5 J triazine. m.p. 2-3-lfl’C; microanalysis, found: C,54.4; H,4.0; N.24.0X; C. .3. N.O requires: C.54.2; 3.4.0;

1*3 L-* 0 ->

N.23.7X, NMR: 3.74(s,6H, CH₃O), 6. +2(11.23.. 1 ?heryl-H); 6.6c(d of d, 1H, furyl-4H), 7. ll(d of d, 1H, furyl-3H). '.39(d of d, 1H. furyl-5H), 8.82-9.09(brd, 2H, NHj); m/e 355 <M-H)\ bad ORIGINAL $

AP Ο Ο Ο 2 4 8

- 83 Example 177

Using a procedure similar to that described in Example 1 there vas obtained 7-amino-2-(2-furyl)-5-((3,5-difluoro)phenoxy((1,2,4|triazolo[l,5-aJ(1,3,5]triazine, m.p. >3OO°C; microanalysis, found: C, 50.6; H, 2.5; N, 25.32; ^ci4^Hg^2^N6°2 ^re9^uires: C» 50.9; H 2.4; N, 25.42; NMR: 6.69 (d of d, IH, furyl-4H); 7.11-7.16 (m, 4H, furyl-3H and 3 phenyl-H); 7.90 (d of d, IH, furyl-5H); 8.80-9.30 (br d, 2H, NH₂); m/e 331 (M₊H)\

Example 178

Using a procedure similar to that described in Example 1 there vas obtained 7-amino-2-(2-furyl)-5-((2,6-dichloro)phenoxy([1,2,4(triazolof1,5-aJ[1,3,5(triazine, m.p. 27O-272°C; microanalysis, found: C, 46.7; H 2.9; N, 21.72; C^HgCl^Oj. (0.4)C₂H₅0H requires: C, 46.6; H, 2.7; N, 22.02; NMR: 6.69-6.72 (d of d, IH, furyl-4H); 7.13-7.16 (d of d, IH, furyl-3H); 7.35-7.44 (d of d, IH, phenyl-H); 7.62-7.67 (d, 2H, 2 phenyl-H); 7.92-7.93 (d of d, IH, furyl-5H); 9.11-9.32, (br.d, 2H, NH^; m/e 362 (M)*.

Example 179

Using a procedure similar to that described in Example 3 there vas obtained 7-amino-2-(2-furyl)-5-((3-fluorophenyl)methyl(amino[1,2,4]triazolo]1,5-a][1,3,5]triazine, m.p. 216-218’C; microanalysis, found: C, 55.7; H, 3.8; N, 30.4; F, 5.52; C^Hj^FN^O requires: C, 55.4; H, 3.7; N, 30.1; F, 5.82; NMR 4.50, (d, 2H, CH2N); 6.66 (d of d, IH, furyl-4H); 7.03 (d, IH, furyl-3H); 7.1-7.5 (complex, 5H, phenyl-H), 7.84 (d, IH, furyl-5H); 7.97 (t, IH, NH) and 8.19 (br s, 2H. NH₂); m/e 326 (M+H)+.

EXAMPLE 180

The folloving illustrate representative pharmaceutical dosage forms containing a compound of formula I, for example as illustrated in any of the previous Examples, (hereafter referred to as compound X), for therapeutic or prophylactic use in humans:BAD ORIGINAL (a) Tablet mg/tablet

Compound X................................... 50

Lactose Ph.Eur............................... 223.75

Croscarmellose sodium........................ 6.0

Maize starch................................. 15.0 *

Polyvinylpyrrolidone (52 v/v paste).......... 2.25

Magnesium stearate........................... 3.0 ‘ (b) Capsule mg/capsule

Compound X.. .............................. 10

Lactose Ph.Eur ............................ 488.5

Magnesium stearate ........................ 1.5

The above formulations may be obtained by conventional procedures veil known in the pharmaceutical art. The tablets may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.

BAD ORIGINAL

AP000248

	- 85 -
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τπ.	XV

1 Sfc Ν Ν .V	ΗΝ-“ λ Λ0 ηχμ *
IVa	V
«Λ. C=: MCN &'	Λ*Χ χ C= HChJ Λ1* '
νχ	νΕ

BAD ORIGINAL

CHEMICAL FORMULAE (continued)

HHfl.

(4HA

Λ

Μ M , A Av » V N

VUL

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XX ^{M 14} V-Q

F

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Claims (13)

1. Uhat is claimed is:1.

   A compound of the formula I wherein:

   Q is a 5-membered heteroaryl optionally bearing 1 or 2 substituents independently selected from (l-4C)alkyl and halogeno;

   is hydrogen, (l-6C)alkyl, or (l-4C)alkanoyl;

   R (vhen not as hereinbelow defined together with X) is hydrogen, (3-12C)cycloalkyl, (3-6C)alkenyl, phenyl(3-6C)alkenyl, tetrafluorophenyl, pentafluorophenyl, 5- or 6-membered heteroaryl, optionally substituted (l-6C)alkyl or optionally substituted phenyl, said optionally substituted alkyl being unsubstituted or substituted by one of (3-6C)cycloalkyl, optionally substituted 5- or 6-meabered heteroaryl, optionally substituted phenyl and a group of foraula RlO(CO)_nXb(CO)_a in which R^ (vhen not as hereinbelow defined together vith Xb) is (l-6C)alkyl, (3-6C)cycloalkyl, optionally substituted phenyl or optionally substituted phenyl(l-4C)alkyl, n>a is 0 or 1, provided that vhen a is 0, X and Xb are separated by at least tvo carbon atons, Xb is oxy, thio, sulphinyl, sulphonyl or an iaino group of foraula -NRb in vhich Rb is hydrogen, (l-6C)alkyl or together with rIO and the adjacent nitrogen atom forms a 4 to 6-membered saturated heterocyclic ring, said optionally substituted 5- or 6-membered heteroaryl being unsubstituted or substituted by 1 or 2 of (l-4C)alkyl, (l-4C)alkoxy and halogeno, and any of said optionally substituted phenyl being unsubstituted or substituted by (l-4C)alkylenedioxy or by 1,2 or 3 of halogeno, cyano, trifluoromethyl, (l-4C)alkoxycarbonyl, hydroxy, (l-4C)alkanoyloxy, benzyloxy, halogenobenzyloxy, nitro, and (l-4C)alkyl or alkoxy optionally bearing a group of formula R^CO in vhich R^ is (l-4C)alkoxy, (3-6C)alkylamino, (3-6C)cycloalkylamino or (N-(l-4C)alkyl) [N-(l-4C)dialkylamino(l-4C)alkylJamino, and sulphamoyl bad ORIGINAL f·· .·· C ? 5 RA

   - 88 3 4 3 4 of formula -SO-.NR R in vhich R and R are independently hydrogen or ^3 4 (l-4C)alkyl, or R is hydrogen and R is ((2-5C)alkoxycarbonyl(methyl, carbamoylmethyl or (N-(l-4C)alkylcarbamoyl(methyl; and X is oxy, thio, sulphinyl, sulphonyl or an imino group of formula -NRa- in vhich Ra is hydrogen, (l-6C)alkyl or together vith R2 and the adjacent nitrogen atom forms a 4 to 6-membered saturated heterocyclic ring; and

   A is N or CT in vhich T is hydrogen or (l-4C)alkyl;

   or a pharmaceutically acceptable salt thereof.
2. 2. A compound as claimed in claim 1 wherein Q is a 5-membered heteroaryl optionally bearing 1 or 2 substituents independently selected from (l-4C)alkyl and halogeno; X is oxy, thio or an imino group of the formula -NRa- in vhich Ra is hydrogen or (l-6C)alkyl;

   is hydrogen, (l-6C)alkyl or (l-4C)alkanoyl; and R is:

   (a) phenyl, pyridyl, isoxazolyl, thiadiazolyl, tetrafluorophenyl, pentafluorophenyl, or phenyl bearing 1, 2 or 3 substituents independently selected from (l-4C)alkyl, (l-4C)alkoxy, halogeno, cyano, trifluoromethyl, nitro, benzyloxy, halogenobenzyloxy, hydroxy,
3. 3 4 3 4 and a sulphamoyl group of the formula -SO».NR R in vhich R and R ^z 3 4 are independently hydrogen or (l-4C)alkyl, or R is hydrogen and R is ((2-5C)alkoxycarbonyl(methyl, carbamoylmethyl or (N-(l-4C)alkylcarbamoylJme thyl;

   (b) (l-6C)alkyl, (3-12C)cycloalkyl, (3-6C)cycloalkyl(l-4C)alkyl, furyl, thienyl, phenyl(1-4C)alky1, furyl(l-4C)alkyl, thienyl(l-4C)alkyl, a furyl, thienyl or phenyl moiety of vhich may itself optionally bear 1 or 2 substituents independently selected from (l-4C)alkyl, (l-4C)alkoxy and halogeno: or (c) a group of the formula R^.Xa.Ci^-C^- in vhich is (l-6C)alkyl or phenyl vhich latter may optionally bear 1 or 2 substituents independently selected from (l-4C)alkyl, (l-4C)alkoxy and halogeno, and Xa is oxy, thio, sulphinyl, sulphonyl, imino or N-(l-6C)alkylimino, or in vhich the group R^.Xa- is morpholino, thiomorpholino, pyrrolidino, piperidino or azetidino; and

   A is N or CT in vhich T is hydrogen or (l-4C)alkyl;

   or a pharmaceutically acceptable salt thereof.

   BAD ORIGINAL ft

   AP000248

   - 89 2

   3. A compound as claimed in claim 1 wherein R is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, allyl,

   3- pheny1-2-trans-propenyl, tetrafluorophenyl, pentafluorophenyl, pyridyl, isoxazolyl, thiadiazolyl, optionally substituted (l-6C)alkyl or optionally substituted phenyl, said optionally substituted alkyl being methyl, ethyl, isopropyl, propyl, butyl, sec-butyl or n-pentyl unsubstituted or substituted by one of cyclopropyl, furyl, pyridyl, thienyl, optionally substituted phenyl and a group of formula in which R^ is methyl, ethyl, n-propyl, cyclohexyl, phenyl or 4-hydroxybenzyl, Xb is oxy, thio, sulphinyl, imino, methylimino or, together with R^, piperidino, and n and m are as defined in claim 1, and any of said optionally substituted phenyl being unsubstituted or substituted by methylenedioxy or by 1,2 or 3 of fluoro, chloro or bromo, cyano, trifluoromethyl, methoxycarbonyl, hydroxy, pivaloyloxy, benzyloxy, 4-fluorobenzyloxy, 4-chlorobenzyloxy, nitro, methyl, methoxy, ethyl, ethoxy, 2-(t-butoxycarbonyl)ethyl, methoxycarbonylmethyl, methoxycarbonylmethoxy, 2-(methoxycarbonyl)ethyl, n-propylaminocarbonylmethyl, n-propylaminocarbonylmethoxy, cyclopentylaminocarbonylethyl, cyclohexylaminocarbonylmethyl, [N-methyl, N,N-dimethylaminoethylJaminocarbonylmethyl or (N-methyl, Ν,Ν-dimethylaminoethylJaminocarbonylmethoxy, -SO^NHj or -SOjNiCH^)^, or R together with X forms morpholino, thiomorpholino, pyrrolidino, piperidino or azetidino.

   ₂
4. 4. A compound as claimed in any one of claims 1 to 3 wherein R X is phenoxy, ethoxy, 4-chlorophenoxy, benzyloxy, 4-benzyloxyphenoxy,

   4- (4-chlorobenzyloxy)phenoxy, 4-hydroxyphenoxy, 4-methoxyphenoxy,

   3- fluorophenoxy, 2-phenylethoxy, 2-phenoxyethoxy, 2-methoxyethoxy,

   4- cyanophenoxy, butoxy, 3-methoxyphenoxy, 2-methoxyphenoxy,

   2-fluorophenoxy, allyloxy, 2-(phenylthio)ethoxy, 4-fluorophenoxy, 2-cyanophenoxy, [1,2Jisoxazol-3-yloxy, pyrid-3-yloxy,

   BAD ORIGINAL &

   ' ⁿ Ο Ο 9A ί

   - 90 [l,2,5)thiadiazol-3-yloxy, thiophenoxy, cyclopentylthio, (2-furylmethyl)thio, methylthio, 2-methoxyphenylthio, benzylthio, cyclohexylamino, propylamino, anilino, allylamino, benzylaaino, methylamino, ethylamino, isopropylamino, butylamino, (2-phenylethyl)amino, [S]-(l-phenylethyl)amino and — .*i (2-dimethylaminoethyl)amino, or together vith X, pyrrolidino or morpholino.
5. 5. A compound as claimed in any one of claims 1 to 4, vherein Q is furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl or isothiazolyl, vhich may optionally bear 1 or 2 substituents independently selected from methyl, ethyl, fluoro, chloro and bromo.
6. 6. A compound as claimed in claim 5, vherein Q is 2-furyl.
7. 7. A compound as claimed in any one of claims 1 to 6, vherein is hydrogen, methyl, ethyl, propyl or butyl, formyl, acetyl or propionyl.
8. 8. A compound as claimed in any one of claims 1 to 7, vherein A is nitrogen or CH.
9. 9. A compound as claimed in any one of claims 1 to 8, vherein X is oxy, thio, imino, methylimino or, together vith R morpholino, thiomorpholino, pyrrolidino, piperidino or azetidino.
10. 10. A compound as claimed in claim 1, vherein:

    Q is furyl;

    r1 is hydrogen or acetyl;

    R is cyclopentyl, cyclohexyl, tetrafluorophenyl, pentafluorophenyl, pyridyl, thiadiazolyl, (4-6C)alkyl, optionally substituted phenyl(l-2C)alkyl, optionally substituted phenyl, furylmethyl or pyridylmethyl, any of said optionally substituted phenyl being unsubstituted or substituted by methylenedioxy, or by one of fluoro, chloro, cyano, trifluoromethyl, methoxycarbonyl, hydroxy, pivaloyloxy, nitro, methyl, bad original

    AP000248

    - 91 methoxy, t-butoxycarbonylethyl and sulphamoyl;

    X is oxy or imino; A is N or CT in which T is hydrogen; or a pharmaceutically acceptable salt thereof.
11. 11. A compound selected from:

    7-amino-2-(2-furyl)-5-phenoxy-[l,2,41triazolof1,5-aJ[1,3,5 J triazine; 7-amino-2-(2-furyl)-5-(propylamino)-[1,2,4]triazolof1,5-a]f1,3,5]triazine;

    7-amino-2-(2-furyl)-5-phenoxy-11,2,4]triazolof1,5-a] (1,3,5] triazine;

    7-amino-5-(3-fluorophenoxy)-2-(2-furyl)-11,2,4]triazolof1,5-a] [1,3,5]triazine;

    7-amino-5-butoxy-2-(2-furyl)-(1,2,4]triazolof1,5-a][1,3,5]triazine;

    7-amino-2-(2-fury1)-5-(3-methoxyphenoxy)-f1,2,4]triazolof1,5-aJ(1.3.5] triazine;

    5-allyloxy-7-amino-2-(2-turyl)-(1,2,4]triazolof1,5-a][1,3,5]triazine; 7-amino-5-(2-cyanophenoxy)-2-(2-furyl)- (1,2,4]t riazolo-f1,5-a](1.3.5] triazine;

    7-amino-2-(2-fury1)-5-phenylamino-(1,2,4]triazolof1,5-a](1,3,5]triazine;

    7-amino-5-butylamino-2-(2-fury1)-( 1,2,4]triazolof1,5-aJ-[1,3,5]triazine;

    7-amino-5-isobutylamino-2-(2-furyl)-(1,2,4]triazolof1,5-a]f1,3,5]triazine;

    7-amino-5-benzylthio-2-(2-furyl)-(1,2,4]triazolof1,5-a] — [1,3,5]triazine;

    7-amino-5-(2-fluorobenzyl)amino-2-(2-furyl)-(1,2,4-] triazolofl,5-a]fl,3,5]triazine;

    7-amino-5-[2-f4-(2-t-butoxycarbonylethyl)phenyl]ethylamino] -2-(2- furyl)- {1,2, 4] triazolo-[1,5-a][1,3,5]triazine;

    7-amino-2-(2-fury1)-5-[2-(4-hydroxyphenyl)ethyl]amino-(1,2,4]-triazolo [1,5-a](1,3,5]triazine;

    7-amino-2-(2-furyl)-5-]2-(4-pivaloyloxyphenyl)ethyl]amino-[1,2,4]triazolo[1,5-a][1,3,5]triazine;

    7-amino-2-(2-fury1)-5-(3-methylphenoxy)-]1,2,4]triazolof1,5-a]{1,3,5]triazine;

    7-amino-2-(2-fury1)-5-(2-methylpropyloxy)-[1,2,4] triazolo{1,5-a]BAD ORIGINAL $

    - 92 (1,3,5 J triazine;

    7-acetylamino-2-(2-furyl)-5-phenoxy-11,2,41-triazolo(l,5-al(1,3,5]triazine;

    7-amino-2-(2-fury1)-5-(2-(4-hydroxyphenylethyl1-amino]1,2,4] triazolo[1,5-a]{1,3,5} triazine;

    7-amino-5-(2-]ethylsulphinyl]ethoxy )-2-(2 - furyl)pyrazolo(2,3-a]]1,3,5]triazine;

    7-amino-5-cyclohexylamino-2-(2-furyl)pyrazolo(2,3-a](1,3,5]triazine; * 7-amino-2-(2-furyl)-5-(phenylthio)pyrazolo{2,3-a](1,3,5]triazine; and pharmaceutically acceptable salts thereof.
12. 12. A process for the manufacture of a compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 1, which is characterised in that:

    (a) a compound of the formula III in which Z is a suitable leaving group is reacted with a compound of the formula R .XH;

    (b) for a compound of formula I in which X is thio or oxy, a compound of the formula V is reacted at elevated temperature with a compound of formula VII in which X is thio or oxy;

    (c) for a compound of formula I in which A is N, a [1,2,4]triazolo{4,3-a1]1,3,5]triazine derivative of the formula VIII is rearranged;

    (d) for a compound of formula I in which R is hydroxyphenyl, a corresponding derivative of formula I in which the hydroxy group is protected, is deprotected;

    (e) for a compound of formula I in which A is N and R is hydrogen or (l-6C)alkyl. a compound of formula X in which Za is a suitable leaving group is reacted vith a compound of formula R^NH₂;

    whereafter, when a pharmaceutically acceptable salt is required, a compound of formula I is reacted with the appropriate acid or base affording a physiologically acceptable ion, or by any other conventional salt formation procedure;

    when a compound of formula I in which any of X, Xa and Xb is sulphinyl or sulphonyl is required, oxidising a corresponding compound of formula I in which X, Xa or Xb is thio or sulphinyl respectively;

    when a compound of formula I in which R^ is (l-6C)alkyl or

    BAD ORIGINAL

    AP Ο Ο Ο 2 4 8

    - 93 (l-4C)alkanoyl is required, the corresponding compound of formula I in which is hydrogen is alkylated or acylated;

    when a compound of formula I in which R is an (l-4C)alkanoyloxyphenyi or (1-4C)alkanoyloxypheny1(l-6C)alkyl, acylating a corresponding compound of formula I in which R is an hydroxyphenyl or hydroxypheny1(l-4C)alkyl; and when an optically active form of a chiral compound of formula I is required, either one of processes (a)-(e) above may be carried out using the appropriate optically active starting material or else a racemic form may be resolved; and 1 2 wherein A, R , R , X and Q have any of the meanings given in claim 1; and wherein the chemical formulae referred to by Roman numerals are set out as the final part of these claims.
13. 13. A pharmaceutical composition, which comprises a compound of formula I, or a pharmaceutically acceptable salt thereof, as claimed in claim 1 in admixture or together vith a pharmaceutically acceptable diluent or carrier.