WO1994000450A1 - Chromanderivatives as angiotensin ii antagonists - Google Patents

Abstract

The invention concerns pharmaceutically useful compounds of formula (I), wherein Q is selected from (IIa), (IIb), (IIc), (IId), (IIe), (IIf), Z is carboxy or non-toxic metabolically labile ester thereof, 1H^_-tetrazol-5-yl, -CO.NH.(1H^_-tetrazol-5-yl) or a group of the formula -CO.NH.SO2.G1 in which G1 is alkyl, cycloalkyl or phenyl. The novel compounds are of value in treating such conditions such as hypertension and congestive heart failure. The invention further concerns processes for the manufacture of the novel compounds and the use of the compounds in medical treatment.

Description

Chromander1vat1ves as angiotensin II antagonlstes

This invention concerns novel nitrogen derivatives and, more particularly, novel nitrogen derivatives which possess pharmacologically useful properties in antagonising at least in part one or more of the actions of the substances known as angiotensins, and in particular of that known as angiotensin II (hereinafter referred to as "All"). The invention also concerns pharmaceutical compositions of the novel compounds for use in treating diseases or medical conditions such as hypertension, congestive heart failure and/or hyperaldosteronism in warm-blooded animals (including man), as well as in other diseases or medical conditions in which the renin-angiotensin-aldosterone system plays a significant causative role. The invention also includes processes for the manufacture of the novel compounds and their use in treating one of the afore-mentioned diseases or medical conditions and for the production of novel pharmaceuticals for use in such medical treatments.

The angiotensins are key mediators of the renin-angiotensin- aldosterone system, which is involved in the control of homeostasis and fluid/electrolyte balance in many warm-blooded animals, including man. The angiotensin known as All is produced by the action of angiotensin converting enzyme (ACE) on angiotensin I, itself produced by the action of the enzyme renin on the blood plasma protein angiotensinogen. All is a potent spasmogen especially in the vasculature and is known to increase vascular resistance and blood pressure. In addition, the angiotensins are known to stimulate the release of aldosterone and hence result in vascular congestion and hypertension via sodium and fluid retention mechanisms. Hitherto there have been a number of different approaches to pharmacological intervention in the renin-angiotensin-aldosterone system for therapeutic control of blood pressure and/or fluid/electrolyte balance, including, for example, inhibiting the actions of renin or ACE. However, there remains a continuing need for an alternative approach because of the side-effects and/or idiosyncratic reactions associated with any particular therapeutic approach.

In our published co-pending European Patent Applications, Publication Nos. 399731, 412848, 454831, 453210, 511791 and 516392 there are respectively disclosed certain imidazopyridine, quinoline, naphthyridine, pyridine, pyrrolopyridine and naphthyridone derivatives which have All antagonist activity. In European Patent Application, publication nos. 475206 and 459136 certain pyrimidine and benzimidazole derivatives are also described as having All antagonist activity.

We have now discovered that the compounds of the invention (set out below) surprisingly antagonise one or more of the actions of the substances known as angiotensins (and in particular of All) and thus minimise the physiological effects associated with their presence in warm-blooded animals (including man) and this is the basis of the invention.

According to the invention there is provided a nitrogen derivative of the formula I (set out hereinafter, together with the other chemical formulae identified by Roman numerals) wherein Q is selected from a group of the partial structural formula Ha, lib, He, lid, He or Ilf in which ring B of formula Ha completes a benzene or pyridine ring; R , T and F are independently selected from (1-8C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-4C)alkyl, phenyl, phenyl(1-4C)alkyl or substituted (l-4C)alkyl, the latter containing one or more fluoro substituents or bearing an (l-4C)alkoxy substituent;

2 2 2

R , T and F are independently selected from hydrogen, (l-8C)alkyl,

(3-8C)cycloalkyl, (3-8C)cycloalkyl-(l-4C)alkyl, carboxy, (l-4C)alkoxycarbonyl, (3-6C)alkenyloxycarbonyl, cyano, nitro, phenyl or phenyl(1-4C)alkyl;

3 4

R and R are optional substituents on ring B independently selected from (l-4C)alkyl, (l-4C)alkoxy, halogeno, trifluoromethyl, cyano, nitro, fluoro(l-4C)alkoxy, hydroxy or hydroxy(l-4C)alkyl;

3 T is selected from halogeno, (l-4C)alkoxy, amino, alkylamino and dialkylamino of up to 6 carbon atoms and any of the values defined for

I¹.

T and F are independently selected from hydrogen, (l-4C)alkyl,

(l-4C)alkoxy, (1-4C)alkyl containing one or more fluoro substituents, carboxy, (l-4C)alkoxycarbonyl, (3-6C)alkenyloxycarbonyl, halogeno, cyano, nitro, carbamoyl, (l-4C)alkanoyl, N-alkylcarbamoyl and di-(N-alkyl)carbamoyl of up to 7 carbon atoms, amino, alkylamino and dialkylamino of up to 6 carbon atoms, and a group of the formula

-A .B wherein A is (l-6C)alkylene, a carbonyl group or a direct bond and B is

(1) an unsubstituted phenyl or phenyl bearing one or two substituents independently selected from (l-4C)alkyl, (l-4C)alkoxy, halogeno, cyano, trifluoromethyl, nitro, hydroxy, carboxy, (l-4C)alkanoylamino, (l-4C)alkanoyl, fluoro(l-4C)alkoxy, hydroxy(1-4C)alkyl, (l-4C)alkoxy(l-4C)alkyl, carbamoyl, N-alkyl or di-(N-alkyl)carbamoyl of up to 7 carbon atoms, sulphamoyl, N-alkyl or di-(N-alkyl)sulphamoyl of up to 6 carbon atoms, (l-4C)alkoxycarbonyl,

(l-4C)alkanesulphonamido, (l-4C)alkyl.S(0) - [in which n is zero, 1 or

1 ⁿ 2] and lH-tetrazol-5-yl; or B is

(2) a 5 or 6-membered saturated or unsaturated heterocyclic ring optionally bearing a (l-4C)alkyl group and containing a single heteroatom selected from oxygen, sulphur and nitrogen or containing two heteroatoms one of which is nitrogen and the other is oxygen, sulphur or nitrogen; or T 3 and T4 together form an (3-6C)alkenylene group, an

(3-6C)alkylene group or an (3-6C)alkylene group in which a methylene

3 4 is replaced by carbonyl, provided that when T and T together form

2 one of said latter three groups then T is additionally selected from any of the previous values defined for T ;

Y is oxygen or a group of the formula -NRb- wherein Rb is hydrogen,

(l-4C)alkyl, (l-4C)alkanoyl or benzoyl; linking group A of formula He is selected from -CH=CH-, -CH=CH-C0-,

-C0-CH=CH-, -CO-CH₂-CH₂-, -CH.--CH₂-C0, -CH₂-C0 and -C0-CH₂-;

E is hydrogen, (l-8C)alkyl or trifluoromethyl;

2 E is hydrogen, (l-δC)alkyl, halogeno, (l-4C)alkoxy, trifluoromethyl, carboxy, (l-4C)alkoxycarbonyl, (3-6C)alkenyloxycarbonyl, cyano, nitro, ( (ll--44CC))aallkkaannooyyll,, (l-4C)alkyl.S(0)_m- [in which m is zero, 1 or 2] or pheennyyllssuullpphhoonnyyll;;

33 EE iiss hhyyddrrooggeenn,, (l-δC)alkyl, (l-4C)alkoxy, halogeno or t :rriifflluuoorroomethyl; E E 4 aanndd EE5 aarree ooppitional substituents on linking group A independently selected from (l-4C)alkyl, substituted (l-4C)alkyl containing one or more fluoro substituents, phenyl, pyridyl, alkoxy, halogeno, cyano, nitro, carboxy, (l-4C)alkoxycarbonyl, (3-6C)alkenyloxycarbonyl, carbamoyl, N-alkylcarbamoyl and di-(N-alkyl)carbamoyl of up to 7 carbon atoms, (l-4C)alkylthio, (l-4C)alkylsulphinyl,

(l-4C)alkylsulphonyl, phenylthio, phenylsulphinyl, phenylsulphonyl and

(l-4C)alkanoyl;

X is CH or a nitrogen atom;

L¹ is (l-8C)alkyl or (l-δC)alkoxy;

2 3 L and L are independently selected from hydrogen, (l-4C)alkyl and carboxy or a non-toxic metabolically labile ester thereof;

4 F is hydrogen or (1-4C)alkyl;

2 3 or F and F together complete a benzene ring, said benzene ring optionally bearing one or two substituents independently selected from

3 any of the previous values defined for F ;

2 3 or F and F together form an (3-6C)alkenylene group, an

(3-6C)alkylene group or an (3-6C)alkylene group in which a methylene is replaced by carbonyl; or F 3 and F4 together form a linking group A2 which is selected from

-CH₂-CH₂-, -CH₂-CH₂-CH₂-, -C0-CH₂-, -CH₂-C0-, -CO-CH₂-CH₂-, -CH₂-CH₂-C0-, -C0-CH=CH- and -CH=CH-C0-, and wherein said linking group A optionally bears one or two substituents independently

4 5 selected from any of the values defined for E or E ;

1 0 / 1

M , M , M and M have any of the values defined above for E , E , E and , E4 respectively;

Rm and Rn are independently selected from hydrogen, (l-4C)alkyl,

(1-4C)alkoxy, halogeno, trifluoromethyl, cyano and nitro;

Z is carboxy or non-toxic metabolically labile ester thereof, lH-tetrazol-5-yl, -CO.NH. (lH-tetrazol-5-yl) or a group of the formula

-CO.NH.SO-.G¹ in which G¹ is (l-6C)alkyl, (3-δC)cycloalkyl or phenyl;

1 0 1 0 ^*3 0 / and wherein any of said phenyl moieties of R , R , T , T , T , E , E ,

"^ 1 0 0 / 1

E , F , F , M , M or G may be unsubstituted or bear one or two substituents independently selected from (l-4C)alkyl, (l-4C)alkoxy, halogeno, cyano and trifluoromethyl; or a non-toxic salt thereof.

It will appreciated that, depending on the nature of the substituents, certain of the formula I compounds may possess one or more chiral centres and may be isolated in one or more racemic or optically active forms. It is to be understood that this invention concerns any form of such a compound of formula I which possesses the afore-mentioned useful pharmacological properties, it being well known how to make optically active forms, for example by synthesis from suitable chiral intermediates, and how to determine their pharmacological properties, for example by use of the standard tests described hereinafter.

It is to be understood that generic terms such as "alkyl" include both straight and branched chain variants when the carbon numbers permit. However, when a particular radical such as "propyl" is given, it is specific to the straight chain variant, branched chain variants such as "isopropyl" being specifically named where intended.

The same convention applies to other radicals.

2 3 It is to be further understood that when X is CH, L or L can be attached at X.

1 2 1 2 1 2 A particular value for R , R , T , T , F or F where appropriate, include, by way of example, for alkyl: methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, pentyl and hexyl; for cycloalkyl: cyclopropyl, cyclopentyl and cyclohexyl; for alkyl containing one or more fluoro substituents: fluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl and pentafluoroethyl; for alkyl bearing an (l-4C)alkoxy substituent: 2-methoxyethyl and

2-ethoxyethyl; for cycloalkyl-alkyl: cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and 2-cyclopentyl-ethyl; for phenylalkyl: benzyl, 1-phenylethyl and 2-phenylethyl; for alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; and for alkenyloxycarbonyl: allyloxycarbonyl,

2-methyl-2-propenyloxycarbonyl and 3-methyl-3-butenyloxycarbonyl. A particular value for T 3, T4, F3 or for T2 when it is

4 selected from a value for T , where appropriate, includes, by way of example, for alkyl: methyl, ethyl and propyl; for alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; for alkenyloxycarbonyl: allyloxycarbonyl, 2-methyl-2-propenyloxycarbonyl and 3-methyl-3-butenyloxycarbonyl; for halogeno: fluoro, chloro, bromo and iodo; for alkoxy: methoxy, ethσxy-and propoxy; for alkyl containing one or more fluoro substituents: fluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl and pentafluoroethyl; for alkanoyl: formyl, acetyl and butyryl; for N-alkylcarbamoyl: N-methyl and N-ethylcarbamoyl; for di(N-alkyl)carbamoyl: N,N-dimethylcarbamoyl and N,N-diethylcarbamoyl; for alkylamino: methylamino, ethylamino and butylamino; and for dialkylamino: dimethylamino, diethylamino and dipropylamino.

A particular value for A when it is alkylene is, for example, methylene, ethylene or propylene.

3 4 Particular values for R , R or an optional substituent on

B when it is phenyl bearing one or two substituents, where appropriate, include, by way of example, for alkyl: methyl and ethyl; for alkoxy: methoxy and ethoxy; for halogeno: chloro, bromo and iodo; for alkanoylamino: formamido, acetamido and propanamido; for alkanoyl: formyl, acetyl and butyryl; for fluoroalkoxy: trifluoromethoxy, 2-fluoroethoxy,

2,2,2-trifluoroethoxy and 3,3,3-trifluoropropoxy; for hydroxyalkyl: hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl; for alkoxyalkyl:

2-methoxyethyl and 2-ethoxyethyl; for N-alkylcarbamoyl: N-methyl and

N-ethylcarbamoyl; for di(N-alkyl)carbamoyl: N,N-dimethylcarbamoyl and

N,N-diethylcarbamoyl; for N-alkylsulphamoyl: N-methyl and

N-ethylsulphamoyl; for di(N-alkylsulphamoyl: N,N-dimethylsulphamoyl and N,N-diethylsulphamoyl; for alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; for alkanesulphonamido: methanesulphonamido and ethanesulphonamido; for alkylthio: methylthio and ethylthio; for alkylsulphinyl; methylsulphinyl and ethylsulphinyl; and for alkylsulphonyl: methylsulphonyl and ethylsulphonyl.

A particular value for B when it is a 5 or 6-membered saturated or unsaturated heterocyclic ring containing a single hetero atom selected from oxygen, sulphur or nitrogen includes, for example, a thienyl, furyl, pyrrolyl, pyrrolidinyl, pyridyl and piperidyl ring.

A particular value for B when it is a 5 or 6-membered saturated or unsaturated heterocyclic ring containing two heteroatoms one of which is nitrogen and the other is oxygen, sulphur or nitrogen includes, for example, an imidazolyl, imidazolidinyl, pyrazolyl, pyrazolinyl, thiazolyl, thiazolinyl, oxazolyl, oxazolidinyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, morpholinyl and thiomorpholinyl ring.

A particular value for an alkyl group which may be present on B when it is a saturated or unsaturated heterocyclic ring is, for example, methyl or ethyl. A particular value for T 3 and T4, or for F2 and F3, when together they form (3-6C)alkylene is, for example, trimethylene, tetramethylene or pentamethylene; when together they form

(3-6C)alkenylene is, for example, 1-propenylene, 2-propenylene,

1-butenylene, 2-butenylene or 3-butenylene; and when together they form (3-6C)alkylene wherein one of the methylene groups is replaced by a carbonyl group is, for example, 1-oxopropylidene, 3-oxopropylidene,

1-oxobutylidene or 4-oxobutylidene.

A particular value for Rb when it is alkyl is, for example, methyl or ethyl; and when it is alkanoyl is, for example, formyl, acetyl or propanoyl.

1 2 3 1 2 3 1 A particular value for E , E , E , M , r_ , M or L when it is alkyl is, for example, methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, pentyl or hexyl.

A particular value for L when it is alkoxy is, for example,

(1-4C)alkoxy such as methoxy, ethoxy or propoxy.

2 3 2 3 A particular value for E , E , M or M when it is halogeno is, for example, fluoro, chloro, bromo or iodo; and when it is alkoxy is, for example, methoxy, ethoxy or propoxy.

2 A particular value for E2 or M when it is alkoxycarbonyl is, for example, methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl; when it is alkenyloxycarbonyl is, for example, allyloxycarbonyl,

2-methyl-2-propenyloxycarbonyl or 3~methyl-3-butenyloxycarbonyl; when it is alkanoyl is, for example, formyl, acetyl or butyryl; when it is alkylthio is, for example, methylthio or ethylthio; when it is alkylsulphinyl is, for example, methylsulphinyl or ethylsulphinyl; and when it is alkylsulphonyl is, for example, methylsulphonyl or ethylsulphonyl.

4 5 4 Particular values for E , E or M or for an optional

2 substituent on linking group A include, by way of example, for alkyl: methyl and ethyl; for alkyl containing one or more fluoro substituents: fluoromethy , trifluoromethyl, 2,2,2-trifluoroethyl and pentafluoroethyl; for alkoxy: methoxy and ethoxy; for halogeno: chloro, bromo and iodo; for alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; for alkenyloxycarbonyl: allyloxycarbonyl, 2-methyl-2-propenyloxycarbonyl and 3-methyl-3-butenyloxycarbonyl; and for alkanoyl: formyl, acetyl or butyryl; for N-alkylcarbamoyl: N-methylcarbamoyl and N-ethylcarbamoyl; for di(N-alkyl)carbamoyl: N,N-dimethylcarbamoyl and N,N-diethylcarbamoyl; for alkylthio: methylthio and ethylthio; for alkylsulphinyl: methylsulphinyl and ethylsulphinyl; and for alkylsulphonyl: ethylsulphonyl and ethylsulphonyl. A particular value for L 2, L3 or F4 when it is alkyl is, for example, methyl or ethyl.

A particular value for Rm, Rn or for an optional substituent

1 0 1 0 0 0 / which may be present on a phenyl moiety of R , R , T , T , T , E , E , 1 o o /

E , F , F , M or M include, by way of example, for alkyl: methyl and ethyl; for alkoxy: methoxy and ethoxy; and for halogeno: chloro, bromo and iodo.

A particular value for G when it is alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl or pentyl; and when it is cycloalkyl is, for example, cyclobutyl, cyclopentyl or cyclohexyl.

A metabolically labile ester of a carboxy group of Z, L or

2 L includes, for example, an (l-6C)alkyl (such as methyl or ethyl), alkenyl (such as vinyl), alkynyl (such as ethynyl), alkoxyalkyl (such as methoxymethyl) , alkanoyloxyalkyl (such as pivaloyloxymethyl) , alkoxycarbonyloxyalkyl (such as 1-(ethoxycarbonyloxy)ethyl) , cycloalkyloxycarbonyloxyalkyl (such as l-(cyclohexyloxycarbonyloxy)- ethyl), phenyl or benzyl ester.

1 1 11 3 1 2 AA vvaalluuee ffoorr RR ,, TT ,, TT , F or F of particular interest is, for example, methyl, ethyl or propyl.

2 A value for R of particular interest is, for example, hydrogen

2 A value for T of particular interest is, for example, hydrogen or alkoxycarbonyl or, when T 3 and T4 form alkylene is, for example, halogeno.

4

AA vvaalluuee for T of particular interest is, for example, alkoxycarbonyl or halogeno

3 4 2 3

AA vvaalluuee ooff ppaarrttiicular interest for T and T , or F and F . when together they form alkylene is, for example, trimethylene or tetramethylene.

A value for Y of particular interest is, for example, oxygen or a group of the formula -NRb- in which Rb is hydrogen.

A value for linking group A of formula He of particular interest is, for example, an optionally substituted group of the formula -CH=CH-, -CH=CH-C0- or -CH--CH_?-C0-.

1 A value of particular interest for E is, for example,

2 3 methyl, ethyl or propyl; for E is, for example, hydrogen; for E is,

4 5 for example, methyl, ethyl or halogeno; for E or E is, for example, hydrogen, alkyl, halogeno, phenyl, pyridyl, alkoxycarbonyl, carbamoyl,

N-N-dialkylcarbamoyl, cyano, hydroxy, phenylthio or phenylsulphinyl.

1 3 A value of particular interest for M or H is, for example,

2 4 methyl, ethyl or propyl; for H is, for example, hydrogen; for M is, for example, substituted or unsubstituted phenyl.

3 AA vvaalluuee ooff particular interest for F is, for example, hydrogen or halogeno.

3 4 A value of particular interest for F and F when together

2 they form linking group A is, for example, -CH=CH-C0-, -CH„-CH„-CH„- or -CH₂-CH₂-C0-.

A value of particular interest for L is, for example,

2 3 (1-4C)alkyl such as ethyl, propyl or butyl; and for L and L is, for example, methyl.

A value of particular interest for Z is carboxy or lH-tetrazol-5-yl, the latter being preferred.

A preferred value for Rm or Rn is, for example, hydrogen.

A combination of values of special interest is, for example,

1 3 1 3 1 when R and R are both alkyl; when T and T are both alkyl; when T is alkyl and T 3 together with T4 form alkylene; or when E4 and E5 are both hydrogen.

A particular group of compounds of the invention which is of interest comprises those compounds of the formula I in which Q is a group of the formula Ha, lib, He or He having any of the values defined above or Q is a group of the formula Hd in which X is a

1 2 3 nitrogen atom; L is (1-δC)alkyl; and L and L are independently selected from hydrogen and (l-4C)alkyl; or a non-toxic salt thereof.

Particular groups of compounds of the invention comprise those compounds of the formula I in which Q constitutes:- (1) a group of the partial structural formula Ha in which ring

1 2 3 4 B, R , R , R and R have any of the values defined hereinbefore;

(2) a group of the partial structural formula lib in which T ,

2 3 4 T , T , T and Y have any of the values defined hereinbefore;

(3) a group of the partial structural formula He in which E ,

2 3 4 5 E , E , E , E and linking group A have any of the values defined hereinbefore;

(4) a group of the partial structural formula Hd in which L ,

2 3 L and L have any of the values defined hereinbefore;

1

(5) a group of the partial structural formula He in which F ,

2 3 F and F have any of the values defined hereinbefore; and

(6) a group of the partial structural formula Hf in which M ,

2 3 4 M , M and M have any of the values defined hereinbefore; and wherein in each of said groups the variables Z, Rm or Rn have any of the values defined hereinbefore; together with the non-toxic salts thereof.

Sub-groups of compounds of the invention of special interest from within the groups of compounds of particular interest (1) to (4) above comprise those compounds of the formula I in which Q constitutes:-

(a) a group of the partial structural formula Ha wherein ring B together with the pyridine ring to which it is attached constitutes a quinoline ring;

(b) a group of the partial structural formula Ha wherein ring B together with the pyridine ring to which it is attached constitutes a pyrido-pyridine ring (that is a naphthyridine);

(c) a group of the partial structural formula Hb wherein Y is an oxygen atom;

(d) a group of the partial structural formula lib wherein Y is a group of the formula -NH-;

(e) a group of the partial structural formula He wherein linking group A together with the nitrogen atom and pyridine ring to which it is attached constitutes a l,6-naphthyridin-2(lH)-one ring or a l,2,3,4-tetrahydronaphthyridin-2-one ring;

(f) a group of the partial structural formula He wherein linking group A together with the nitrogen atom and pyridine ring to which it is attached constitutes a lH-pyrrolo[3,2-cJpyridine ring; and 2 (g) a group of the partial structural formula Hd wherein L and 3 L are respectively attached at the 5 and 7 positions of the . imidazof4,5-b]pyridine ring;

1 0 0 / 1 0 0 / 1 and wherein in each of said groups R , R , R , R , T , T , T , T , E ,

2 3 4 5 E , E , E and E , where present have any of the values defined above and the variables Z, Rm or Rn have any of the values defined hereinbefore; together with the non-toxic salts thereof.

Of groups (a) to (g), group (g) is of particular interest.

It will be appreciated that the formula I compounds ^'can form salts with suitable acids or bases. Particularly suitable non-toxic salts for such compounds include, for example, salts with bases affording physiologically acceptable cations, for example, alkali metal (such as sodium and potassium), alkaline earth metal (such as magnesium and calcium), aluminium and ammonium salts, as well as salts with suitable organic bases, such as with ethanolamine, methylamine, diethylamine or triethylamine, as well as salts with acids forming physiologically acceptable anions, such as salts with mineral acids, for example with hydrogen halides (such as hydrogen chloride and hydrogen bromide), sulphuric and phosphoric acid, and with strong organic acids, for example with p_-toluenesulphonic and methanesulphonic acids.

The compounds of formula I may be obtained by standard procedures of organic chemistry well known in the art for the production of structurally analogous compounds. Such procedures are provided as a further feature of the invention and include, by way of example, the following procedures in which the generic radicals have any of the values given above, unless stated otherwise:

a) For those compounds in which Z is carboxy, a carboxylic acid derivative of the formula HI, in which V is a protected carboxy group selected from (1-6C)alkoxycarbonyl (especially methoxy-, ethoxy-, propoxy- or t-butoxy-carbonyl), phenoxycarbonyl, benzyloxyearbonyl and carbamoyl, is converted to carboxy.

The conversion may be carried out, for example by hydrolysis, conveniently in the presence of a suitable base such as an alkali metal hydroxide, for example, lithium, sodium or potassium hydroxide. The hydrolysis is generally carried out in the presence of a suitable aqueous solvent or diluent, for example in an aqueous (l-4C)alkanol, such as aqueous methanol or ethanol. However, it may also be performed in a mixture of an aqueous and non-aqueous solvent such as water and toluene using a conventional quaternary ammonium phase transfer catalyst. Alternatively, the hydrolysis may be carried out under acidic conditions, for example, using a suitable mineral acid, such as hydrochloric acid, and conveniently in the presence of a suitable solvent or diluent, such as dioxan. The hydrolysis is generally performed at a temperature in the range, for example, 0 - 120°C, depending on the reactivity of the group W. In general, when W is carbamoyl, temperatures in the range, for example, 40 - 120°C are required to effect the hydrolysis.

Alternatively, when W is benzyloxyearbonyl the conversion may also be performed by hydrogenolysis, for example using hydrogen at 1-3 bar in the presence of a suitable catalyst, such as palladium on charcoal or on calcium sulphate, in a suitable solvent or diluent such as a (l-4C)alkanol (typically ethanol or 2-propanol) and at a temperature in the range, for example, 0 - 40°C.

Further, when W is t-butoxycarbonyl, the conversion may also be carried out by hydrolysis at a temperature in the range, for example, 0 - 100°C, in the presence of a strong acid catalyst, such as trifluoroacetic acid. The hydrolysis may either be performed in an excess of the acid or in the presence of a suitable diluent such as tetrahydrofuran, t-butyl methyl ether or 1,2-dimethoxyethane.

b) For those compounds of formula I wherein Z is tetrazolyl, a compound of the formula IV in which P is a suitable protecting group, such as trityl, benzhydryl, trialkyltin (for example trimethyltin or tributyltin) or triphenyltin, affixed to a nitrogen of the tetrazolyl moiety, is deprotected.

The reaction conditions used to carry out the deprotection necessarily depend on the nature of*the group P . As an illustration, when it is trityl, benzhydryl, trialkyltin or triphenyltin, the decomposition conditions include, for example, acid catalysed hydrolysis in a mineral acid (such as-aqueous hydrochloric acid), conveniently in an aqueous solvent (such as aqueous dioxan or 2-propanol). Alternatively, a trityl or benzhydryl group may be removed by hydrogenolysis, for example as described in (a) above for conversion of a benzyloxyearbonyl to a carboxy.

Compounds of the formula IV wherein P is trialkyltin or triphenyltin may be obtained, for example, by reaction of a nitrile of the formula VII with a trialkyltin azide, such as tributyltin azide, or triphenyltin azide respectively. The reaction is conveniently carried out in a suitable solvent or diluent, such as toluene or xylene, and at a temperature in the range, for example, 50-150°C. In a modified procedure, a formula I compound wherein Z is tetrazolyl may be obtained directly by in situ removal of the trialkyltin or triphenyltin group without prior isolation of the formula IV compound, for example by the addition of aqueous mineral acid or gaseous hydrogen chloride to the reaction mixture. The nitriles of the formula VII may be obtained, for example, by alkylation of a compound of the formula Q.H with a nitrile of the formula VIII wherein Hal. stands for a suitable leaving group such as chloro, bromo, iodo, methanesulphonyloxy or p_-toluenesulphonyloxy, using similar conditions to those used in process (c) described hereinafter. The necessary compounds of formula VIII may be made by standard procedures such as that illustrated in Scheme 12, using methods of organic chemistry well known in the art. Alternatively, the nitriles of the formula VII may be obtained from stepwise conversion of a compound of formula I wherein Z is carboxy or an ester thereof under standard conditions. Trialkyltin azides and triphenyltin azides are either commercially available or may be prepared by standard procedures well known in the art, such as by reaction of a trialkyltin halide with an alkali metal azide.

c) A compound of the formula Q.H is alkylated with a compound of the formula V wherein Hal. stands for a suitable leaving group such as chloro, bromo, iodo, methanesulphonyloxy or p_-toluenesulphonyloxy. The reaction is generally carried out in the presence of a suitable base, for example, an alkali metal alkoxide such as sodium methoxide or sodium ethoxide or an alkali metal hydride such as sodium hydride or an alkali metal carbonate such as sodium or potassium carbonate, or an organic base such as diisopropylethylamine and in a suitable solvent or diluent, for example, a (l-4C)alkanol such- as methanol or ethanol when an alkali metal alkoxide is used, or in a polar solvent such as N,N-dimethylformamide or N-methylpyrrolidone and at a temperature in the range, for example, 10 - 100°C. Alternatively, a quaternary ammonium hydroxide may be used in a mixture of an aqueous and non-aqueous solvent such as water and dichloromethane. In carrying out process (c), when in the starting material Z is an acidic group, about two molecular equivalents of a suitable base is generally required, whereas when Z is a non-acidic group the presence of one molecular equivalent of a suitable base is generally sufficient.

Procedure (c) is particularly suitable for the production of those compounds of the formula I in which Z is a metabolically labile ester group, for example wherein Z is an (l-6C)alkyl, benzyl or phenyl ester, which compounds are also starting materials of formula HI for the reaction described in (a) above. Similarly, using an analogous procedure, but starting with the appropriate halomethyl tetrazolyl derivative of the formula VI, the starting materials of the formula IV may be obtained for procedure (b). The compounds of formula V and VI may be obtained, for example, as illustrated in Scheme 13, or by analogy therewith.

Many of the compounds of formula Q.H (or the tautomers thereof) are already known and the remainder can be made by analogy therewith using standard procedures of organic chemistry well known in the art, for example as described in standard works of heterocyclic chemistry such as that edited by Elderfield. Certain 4-quinolones are described in EPA, Publication No. 412δ4δ and certain 4-naphthyridones are described in International Patent Application No. PCT/GB90/01776. Certain 4-pyridones are described in Monatshefte fur Chemie, 1969, 100, 132; J. Chem. Soc. (B), 1968, 866; Liebigs Ann. Chem. , 1982, 1656; Heterocycles, 1982, 13_, 239; and J. Am. Chem. Soc, 1974, 96(4), 1152. Certain 4-aminopyridines may be obtained as described in Tet. Lett. , 1990, 3485 from intermediates obtainable as described in J. Het. Chem. , 1989, 26, 1575 or European Patent No. 129408. Certain imidazo[4,5-b]pyridines are described in EPA 399731 and EPA 400974. Certain benzimidazoles are described in EPA 459136. Other compounds of the formula Q.H may be obtained as illustrated in Schemes 1 to 12, or by analogy therewith.

Whereafter, those compounds of formula I wherein Z is lH-tetrazol-5-yl may be obtained by stepwise conversion of a compound of the formula I wherein Z is carboxy, or a metabolically labile ester thereof, into the corresponding nitrile under standard conditions, followed by reaction of the nitrile with an azide such as an alkali metal azide, preferably in the presence of an ammonium halide, and preferably in the presence of a suitable polar solvent such as N,N-dimethylformamide and at a temperature in the range, for example, 50 to 160°C.

Whereafter, those compounds of the formula I wherein Z is -CO.NH. (lH-tetrazol-5-yl), a group of the formula -CO.NH.SO.,.G or a metabolically labile ester group, may be obtained, for example, by reacting a carboxylic acid of the formula I in which Z is carboxy (or a reactive derivative of said acid) with 5-aminotetrazole, a sulphonamide of the formula NH_?.SO_?.G or a salt thereof (for example, an alkali metal salt), or an appropriate alcohol or phenol or a salt thereof (for example an alkali metal salt). Suitable reactive derivatives include, for example the chloride, bromide, azide, anhydride and mixed anhydride with formic or acetic acid of the carboxylic acid of formula I as defined above. When the free acid form is used, the reaction is generally carried out in the presence of a suitable dehydrating agent such as dicyclohexycarbodiimide or 3-(3-dimethylaminopropyl)-l-ethylcarbodiimide in the presence of a base such as triethylamine, pyridine or 4-dimethylaminopyridine. When a reactive derivative is used, either the reaction is carried out in the presence of a base such as mentioned above, or, for the preparation of a compound of the formula I wherein Z is a group of the formula -C0.NH.S0„.G or a metabolically labile ester group, the sulphonamide or alcohol or phenol is used in the form of a salt, such as its alkali metal salt (in particular the lithium, sodium or potassium salt thereof). The reaction is generally performed in the presence of a suitable diluent or solvent such as dioxan, t-butyl methyl ether or tetrahydrofuran and at a temperature in the range, for example, 0 - 60°C.

Whereafter, when a non-toxic salt of a compound of formula I is required, it may be obtained, for example, by reaction with the appropriate base affording a physiologically acceptable cation, or with the appropriate acid affording a physiologically acceptable anion, or by any other conventional salt formation procedure.

Further, when an optically active form of a compound of formula I is required, one of the aforesaid processes may be carried out using an optically active starting material. Alternatively, the racemic form of a compound of formula I may be resolved, for example by reaction with an optically active form of a suitable organic base, for example, ephedrine, N,N,N-trimethyl(l-phenylethyl)ammonium__ hydroxide or 1-phenylethylamine, followed by conventional separation of the diastereoisomeric mixture of salts thus obtained, for example by fractional crystallisation from a suitable solvent, for example a (l-4C)alkanol, whereafter the optically active form of said compound of formula I may be liberated by treatment with acid using a conventional procedure, for example using an aqueous mineral acid such as dilute hydrochloric acid.

Certain of the intermediates defined herein are novel, for example the compounds of the formula III, IV, VI, VII and VIII, and are provided as further separate features of the invention.

As stated above, the compounds of formula I will have beneficial pharmacological effects in warm-blooded animals (including man) in diseases and medical conditions where amelioration of the vasoconstrictor and fluid retaining properties of the renin- angiotensin-aldosterone system is desirable, at least in part by antagonism of one or more of the physiological actions of AH. The compounds of the invention will thus be useful in the treatment of diseases or medical conditions such as hypertension, congestive heart failure and/or hyperaldosteronis in warm-blooded animals (including man) , as well as in other diseases or medical conditions in which the renin-angiotensin-aldosterone system plays a significant causative role. The compounds of the invention may also be useful for the treatment of ocular hypertension, glaucoma, cognitive disorders (such as Alzheimer's disease, amnesia, senile dementia and learning disorders), as well as other diseases such as renal failure, cardiac insufficiency, post-myocardial infarction, cerebrovascular disorders, anxiety, depression and certain mental illnesses such as schizophrenia.

The antagonism of one or more of the physiological actions of AH and, in particular, the antagonism of the interaction of AH with the receptors which mediate its effects on a target tissue, may be assessed using one or more of the following, routine laboratory procedures:

Test A: This In vitro procedure involves the incubation of the test compound initially at a concentration of 100 micromolar (or less) in a buffered mixture containing fixed concentrations of radiolabelled AH and a cell surface membrane fraction prepared from a suitable angiotensin target tissue. In this test, the source of cell surface membranes is the guinea pig adrenal gland which is well known to respond to AH. Interaction of the radiolabelled AH with its receptors (assessed as radiolabel bound to the particulate membrane fraction following removal of unbound radiolabel by a rapid filtration procedure such as is standard in such studies) is antagonized by compounds which also bind to the membrane receptor sites and the degree of antagonism (observed in the test as displacement of membrane-bound radioactivity) is determined readily by comparing the receptor-bound radioactivity in the presence of the test compound at the specified test concentration with a control value determined in the absence of the test compound. Using this procedure compounds showing at least 50% displacement of radiolabelled AH binding at a

-4 concentration of 10 M are retested at lower concentrations to determine their potency. For determination of the IC (concentration for 50% displacement of radiolabelled AH binding), concentrations of the test compound are ordinarily chosen to allow testing over at least four orders of magnitude centred about the predicted approximate IC_cn, which latter is subsequently determined from a plot of percentage displacement against concentration of the test compound.

In general, the compounds of formula I as defined above show significant inhibition in Test A at a concentration of about 50 micromolar or much less. For example, the compound of Example 1 gave an IC₅₀ of 7xl0^"9M.

Test B: This in vitro test involves the measurement of the antagonistic effects of the test compound against All-induced contractions of isolated rabbit aorta, maintained in a physiological salt solution at 37°C In order to ensure that the effect of the compound is specific to antagonism of AH, the effect of the test compound on noradrenaline-induced contractions may also be determined in the same preparation.

In general, the compounds of formula I as defined above show significant inhibition in Test B at a final concentration of about 50 micromolar or much less.

Test C: This in vivo test involves using terminally-anaesthetised or conscious rats in which an arterial catheter has been implanted under anaesthesia for the measurement of changes in blood pressure. The AH antagonistic effects of the test compound following oral or parenteral administration, are assessed against angiotensin H-induced pressor responses. To ensure that the effect is specific, the effect of the test compound on vasopressin-induced pressor responses may also be determined in the same preparation.

The compounds of formula I generally show specific All-antagonist properties in Test C at a dose of about 50 mg/kg body weight or much less, without any overt toxicological or other untoward pharmacological effect.

Test D: This in vivo test involves the stimulation of endogenous AH biosynthesis in a variety of species including rat, marmoset and dog by introducing a diet of low sodium content and giving appropriate daily doses of a saluretic known as frusemide. The test compound is then administered orally or parenterally to the animal in which an arterial catheter has been implanted under anaesthesia for the measurement of changes in blood pressure.

In general compounds of formula I will show All-antagonist properties in Test D as demonstrated by a significant reduction in blood pressure at a dose of about 50 mg/kg body weight or much less, without any overt toxicological or other untoward pharmacological effect.

The compounds of formula I will generally be administered for therapeutic or prophylactic purposes to warm-blooded animals (including man) requiring such treatment in the form of a pharmaceutical composition, as is well known in the pharmaceutical art. According to a further feature of the invention there is provided a pharmaceutical composition comprising a compound of formula I, or a salt thereof, as defined above, together with a pharmaceutically acceptable diluent or carrier. Such compositions will conveniently be in a form suitable for oral administration (e.g. as a tablet, capsule, solution, suspension or emulsion) or parenteral administration (e.g. as an injectable aqueous or oily solution, or injectable emulsion).

The compounds of formula I may also be advantageously administered for therapeutic or prophylactic purposes together with another pharmacological agent known in the general art to be of value in treating one or more of the diseases or medical conditions referred to hereinabove, such as a beta-adrenergic blocker (for example atenolol), a calcium channel blocker (for example nifedipine), an angiotensin converting enzyme (ACE) inhibitor (for example lisinopril) or a diuretic (for example furosemide or hydrochlorothiazide) . It is to be understood that such combination therapy constitutes a further aspect of the invention.

In general a compound of formula I (or a pharmaceutically acceptable salt thereof as appropriate) will generally be administered to man so that, for example, a daily oral dose of up to 50 mg/kg body weight (and preferably of up to 10 mg/kg) or a daily parenteral dose of up to 5 mg/kg body weight (and preferably of up to 1 mg/kg) is received, given in divided doses as necessary, the precise amount of compound (or salt) administered and the route and form of administration depending on size, age and sex of the person being treated and on the particular disease or medical condition being treated according to principles well known in the medical arts.

In addition to their aforesaid use in therapeutic medicine in humans, the compounds of formula I are also useful in the veterinary treatment of similar conditions affecting commercially valuable warm-blooded animals, such as dogs, cats, horses and cattle.. In general for such treatment, the compounds of the formula I will generally be administered in an analogous amount and manner to those described above for administration to humans. The compounds of formula I are also of value as pharmacological tools in the development and standardisation of test systems for the evaluation of the effects of AH in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the continuing search for new and improved therapeutic agents.

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

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

(iii) flash column chromatography was performed on Merck Kieselgel 60 (Art. no. 9385) obtained from E Merck, Darmstadt, Germany; (iv) yields, where given, are intended for the assistance of the reader only and are not necessarily the maximum attainable by diligent process development;

(v) H NMR spectra were normally determined at 200 MHz in CDCl, or 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; , multiplet; t, triplet; br, broad; d, doublet; and (vi) all end-products had satisfactory microanalyses.

EXAMPLE 1

6-[(5,7-Dimethyl-2-propyl-3H-imidazo[4,5-b pyridin-3-yl)]- methyl]-2-phenylchroman-2-carbonitrile (A) (203 mg) and tributyltin azide (1.0 g) was dissolved in toluene (2 ml). The mixture was heated at reflux under an atmosphere of argon for 16 hours, then cooled and the solvent was removed by evaporation. The residue was purified by reverse phase high pressure liquid chromatography (using a 21 x 250 mm 60A C18 silica column with dynamic axial compression) eluting with 80% aqueous acetonitrile. The product was dissolved in ethanol and hydrogen chloride gas was passed into the solution for 30 seconds. Ether was then added and the solid precipitate was collected by filtration to give 5,7-dimethyl-3-[(2-phenyl-2-(lH-tetrazol-5-yl)- chroman-6-yl)methyl]-2-propyl-3H-imidazo[ ,5-b]-pyridine dihydrochloride (23 mg) as a white solid, m.p. 149-151°C (decomp.); NMR (d₆-DMS0)/CD₃0D): 0.89(t, 3H) , 1.69(m, 2H), 2.58(s, 6H), 2.6-2.9(m, 4H), 2.98(t, 2H), 5.50(s, 2H), 7.0-7.15(m, 3H), 7.17(s, 1H), 7.7-7.9(m, 3H), 7.9-8.0(m, 2H); mass spectrum (positive fast atom bombardment (+ve FAB), DMSO/nitrobenzyl alcohol(NBA)) : 480 (M+H)⁺; microanalysis, found: C, 58.4; H, 5.9; N, 17.2%; C_2gH₂₉N₂0.2.0HC1.1.5H₂0 requires: C, 5δ.l; H, 5.9; N, 17.0%.

The starting material A was obtained as follows:- (i) A solution of 6-methylcoumarin (64.δ g) in ethanol (800 ml) was hydrogenated at 40 psi and 60°C over 6 g of 10% palladium on carbon catalyst until hydrogen uptake ceased. The catalyst was removed by filtration and the filtrate was concentrated by evaporation. Toluene (1 litre) and p_-toluenesulphonic acid monohydrate (0.5 g) were added, and half the solvent volume was removed from the mixture by distillation. The remaining mixture was cooled and ether (500 ml) was added. The mixture was then washed with saturated sodium bicarbonate solution (100 ml) and water (100 ml). The organic phase was dried (MgSO,) and concentrated by evaporation to give 6-methyl-dihydrocoumarin (B) (70 g) as a white solid; NMR (CDC1₃): 2.32(s, 3H) , 2.75(t, 2H), 2.96(t, 2H), 6.9-7.l(m, 3H); mass spectrum (positive chemical ionisation (+ve CI)): 162 (M+H) ; microanalysis, found: C, 73.9; H, 6.3%; C.^H._^O- requires: C, 74.1; H, 6.2%. (ii) A I M solution of diisobutylaluminiu hydride in hexane (75 ml) was added over 45 minutes to a stirred solution of compound B (8 g) in dichloromethane (80 ml) at -75°C and under an atmosphere of argon. The resulting mixture was stirred for 1.5 hours at -75°C, then methanol (10 ml) was added dropwise. The mixture was stirred for a further 20 minutes, then poured into 0.5M sulphuric acid (300 ml). The mixture was extracted with ether (2 x 150 ml), the combined extracts were dried (MgSO,) and volatile material was removed by evaporation. The residue was purified by column chromatography on silica, eluting with hexane/ethyl acetate (1:0 v/v, increasing to 4:1 v/v), to give 6-methylchroman-2-ol (C) (7.0 g) as an oil; NMR (CDC1.,): 1.85-2.05(m, 2H), 2.25(s, 3H) , 2.65(dt, 1H), 2.95(m, 1H) , 5.58(s, 1H) , 6.71(d, 1H), 6.85-6.95(m, 2H); mass spectrum (+ve CI): 160 (M+NH₄)⁺; microanalysis, found: C, 72.7; H, 7.5%; C.^H.-O^ requires C, 73.1; H, 7.4%.

(iii) A solution of compound C (3.2δ g) in ether (20 ml) was added over 30 minutes to a stirred 3M solution of phenylmagnesium bromide in ether (20 ml) at 5°C under an atmosphere of argon. The mixture was stirred at ambient temperature for 16 hours, then diluted with ether (40 ml) and poured into saturated aqueous ammonium chloride solution (50 ml). The organic phase was separated and the aqueous layer was extracted with ether (3 x 50 ml). The combined organic phases were dried (MgSO,) and the solvent was removed by evaporation to give 4-methyl-2-(3-hydroxy-3-phenylpropyl)phenol (D) (5.0 g) as a white solid; NMR (CDCL_j): l.δ5-2.2(m, 2H), 2.26(s, 3H), 2.6-2.75(m, 1H), 2.9(m, 1H), 4.63(dd, 1H), 6.75(m, 1H), 6.90(s, 2H), 7.2-7.65(m, 5H); mass spectrum (+ve CI): 224 (M-H-O) ; microanalysis, found: C, 79.7; H, 7.3; C₁₆H₁₈0₂ requires: C, 79.3; H, 7.5%.

(iv) Jones reagent (4.5 ml), obtained from a mixture of chromium (VI) oxide (1.34 g) and concentrated sulphuric acid (1.16 ml) made up to 4.5 ml with water, was added dropwise to a stirred solution of compound D (5.2 g) in acetone (140 ml) at 5°C. The mixture was stirred for 5 minutes at 0°C, then 10% sodium metabisulphite solution (2 ml) was added, followed by ether^{^}(100 ml). The organic phase was separated, dried (MgSO,) and volatile material was removed by evaporation. The residue was dissolved in methanol (40 ml) and trimethyl orthoformate (20 ml) and p-toluenesulphonic acid monohydrate (300 mg) were added. The mixture was stirred at ambient temperature for 16 hours, then poured into saturated sodium bicarbonate solution (15 ml) and extracted with ether (3 x 50 ml). The combined extracts were dried (MgSO,) and the solvent was removed by evaporation. The residue was purified by column chromatography, eluting with hexane/ethyl acetate (1:0 v/v, increasing to 3:1 v/v) to give 2-methoxy-6-methyl-2-phenylchroman (E) (2.7 g) as an oil; NMR (CDC1-): 1.8-2.2(m, 2H), 2.29(s, 3H), 2.5-3.0(m, 2H), 3.09(s, 3H), 6.75-7.05(m, 2H), 7.15-7.65(m, 6H) ; mass spectrum (+ve CI): 254 M⁺.

(v) Trimethylsilyl cyanide (3.3 ml) was added to a stirred solution of compound E (2.25 g) in acetonitrile (100 ml) under an atmosphere of argon. Titanium tetrachloride (0.1 ml) was added dropwise and the mixture was stirred for 65 hours. A further amount of titanium tetrachloride (0.1 ml) was added and the mixture stirred a further lδ hours. Methanol (10 ml) was added dropwise, followed by water (500 ml) and the mixture was extracted with ethyl acetate (3 x 200 ml). The combined extracts were dried (MgSO,) and concentrated by evaporation to give 6-methyl-2-phenylchroman-2-carbonitrile (F) (1.6 g) as an oil; NMR (CDC1₃): 2.3(m, 1H), 2.30(s, 3H) , 2.47(m, 1H) , 2.δ4(m, 1H), 3.2(m, 1H) , 6.δ5-7.05(m, 3H), 7.25-7.7(m, 5H) ; mass spectrum (+ve CI): 267 (M+NH₄)⁺, 223.

(vi) N-Bromosuccinimide (1.25 g) and azobisisobutyronitrile (125 mg) were added to a stirred, degassed solution of compound F (1.6 g) in carbon tetrachloride (30 ml) under an atmosphere of argon. The mixture was refluxed for 4 hours, then cooled to 40°C and filtered. The filtered solid was washed with carbon tetrachloride (30 ml). The filtrate was concentrated by evaporation to give crude 6-bromomethyl-2-phenylchroman-2-carbonitrile (1.9 g). The crude bromomethyl compound (1.3 g) was dissolved in DMF (5 ml) and 5,7-dimethyl-2-propyl-3H-imidazo[4,5-b]pyridine (obtained as described in European Patent Application, Publication No. 400974) (0.76 g) and potassium carbonate (2.76 g) was added. The mixture was stirred for lδ hours under argon and then poured into water (50 ml). The mixture was extracted with ethyl acetate (2 x 50 ml), the combined extracts dried (MgSO,) and the solvent was removed by evaporation. The residue was purified by column chromatography, eluting with dichloromethane/ ethyl acetate (1:0 v/v, increasing to 9:1 v/v) to give 6-[(5,7-dimethyl-2-propyl-3H-imidazo[4,5-b]pyridin-3-yl)]methyl]-2- phenylchroman-2-carbonitrile (A) (203 mg) as an oil; NMR (d,-DMS0): 0.85-1.0(m, 3H), 1.6-1.75(m, 2H), 1.8(m, 1H), 2.3(m, 1H) , 2.6(m, 1H), 2.73(s, 3H), 2.79(t, 2H), 2.9(s, 3H), 3.1(m, 1H) , 5.4(s, 2H), 6.9-8.0(m, 9H); mass spectrum (+ve FAB, DMS0/NBA): 437 (M+H)⁺..

EXAMPLE 2

(Note: all parts by weight)

The compounds of the invention may be administered for therapeutic or prophylactic use to warm-blooded animals such as man in the form of conventional pharmaceutical compositions, typical examples of which include the following:-

a) Capsule (for oral administration)

Active ingredient * 20

Lactose powder 57δ.5

Magnesium stearate 1.5

b) Tablet (for oral administration)

Active ingredient * 50

Microcrystalline cellulose 400

Starch (pregelatinised) 47.5

Magnesium stearate 2.5

c) Injectable Solution (for intravenous administration)

Active ingredient * 0.05 - 1.0

Propylene glycol 5.0

Polyethylene glycol (300) 3.0 - 5.0

Purified water to 100% d) Injectable Suspension (for intramuscular administration)

Active ingredient * 0.05 - 1.0

Methylcellulose 0.5

Tween 80 0.05

Benzyl alcohol 0.9

Benzalkonium chloride 0.1

Purified water to 100%

Note: the active ingredient * may typically be an Example described hereinbefore and will conveniently be present as a pharmaceutically acceptable acid-addition salt, such as the hydrochloride salt. Tablets and capsules formulations may be coated in conventional manner in order to modify or sustain dissolution of the active ingredient. Thus, for example, they may be coated with a conventional enterically digestible coating.

Scheme 1

Note: T = Tr = methyl or ethyl; Rx and Ry are optional substituents;

Ph = phenyl; R' = lower alkyl Reagents: a) NaOH, methanol, water, reflux b) Sublimation at 250°C c) Iodine, NaOH, water d) C₆H₅CH₂C1, NaH, DMF, 50°C e) Proauct from (d) added to (Rx)(Ry)PhCH₂ZnBr in THF (from activated zinc, (Rx)(Ry)PhCH-Br in THF), then (Ph₃P) Pd f) hydrogenation over palladium on carbon, methanol g) (Ph_P) Pd, methanol, aq. NaHCO,, toluene, reflux h) ammonium formate, 10% palladium on carbon, methanol i) tert-ButylLi/pentane; trimethyl borate/THF/-78°C; aq. HCl Scheme 2

Note: R' = lower alkyl

Reagents: a) R'0CH=C(C0₂R^/)₂, 110°C b) hydrogen, Pd on C or PtO- c) Ph-Ph/Ph-O-Ph mixture, reflux d) (i) NaOH; (ii) as for step (c) Scheme 3

Note: R' = lower alkyl; R" = lower alkyl Reagents: a) SnCl,, toluene, reflux b) aqu. NaOH, methanol, reflux; then HCl c) heat, 220°C d) I~, [bis(trifluoroacetoxy)iodo]benzene, CH-Cl.., methano! e) Pd(II)acetate, tri(2-methylphenyl)phosphine, Et-N, DMF, 130°C, CH₂=CHC0₂Rⁿ f) NaOCH , methanol, reflux h) hydrogen, palladium on carbon, acetic acid/ethanol, 20 atmospheres, 70°C Scheme 4

Note: Et = ethyl; Ph = phenyl; R' = lower alkyl

Reagents: a) diethyl malonate, NaOEt, EtOH, 150°C, autoclave b) Ph_P=C(Rb)C0₂Et, xylene or toluene, reflux c) RbCH₂C0₂Et (e.g. Rb = C0₂Et, Ph, Pyridyl, CN, SPh), EtOH, piperidxne, reflux d) aqu.HCl, dioxan, reflux Scheme 5

Note: R' = lower alkyl Reagents: a) hydrogen, Pd on C or PtO„ b) heat

Reagents: a) l-(tert-butyl.CO)imidazole, toluene, heat b) (i) tert-butyllithium (2 equivalents), -78°C, THF; (ii) iodomethane c) as (b)(i); then carbon dioxide d) aqueous HCl, heat Scheme 7

Note: R' and R" = lower alkyl; Reagents: (a) NaOHe, heat

(b) (i) NaOH (ii) HCl (iii) heat

(c) hydrazine hydrate, 2-ethoxyethanol, reflux; then acetone, reflux

(d) Ph-Ph/Ph-O-Ph mixture, reflux

(e) P0C1,, PCI,., heat

(f) P0CL₃ (freshly distilled), reflux

(g) (CH- ,0BF,, dichloromethane

3'3 Scheme 8

Note: Ph = phenyl Reagents: (a) P0C1-/DMF

(b) Catalytic hydrogenation over palladium on carbon

(c) N-Chlorosuccinimide, dichloromethane

(d) (i) n-BuLi, THF/hexane, -78 to 0°C (ii) PhS0₂Cl, THF, -78 to ambient

(e) Nal, aqueous HI, methyl ethyl ketone, reflux

(f) Cul, KF, triethyl(trifluoromethyl)silane, DMF/NMP, 80°C

(g) NaOH, aqu. methanol, reflux Scheme 9

Note: R" = lower alkyl; Tos = p_-toluenesulphonyl (tosyl) Reagents: (a) Heat, 120°C

(b) £-Toluenesulphonyl isocyanate, acetonitrile, reflux

(c) Lithium aluminium hydride, THF, reflux

(d) Activated MnO-, toluene, reflux

(e) NaH, DMF, Brc cO-CH-, 0°C

(f) (i) NaN(SiMe 7₀, THF, 0°C; (ii) Pyridine, S0C -, 0°C

(g) NaN(SiMe₃)₂, THF

(h) NaH, DHF? BrCH CN, 0°( Scheme 10

Note: Rw and Rx are optional substituents Reagents: (a) polyphosphoric acid, acetic acid

(b) (i) boron trifluoride, acetic anhydride (ii) NaH or (isopropyl)„NLi, ethyl acetate

(iii) benzene, PTSA, heat or cone. H„S0,, ambient temp.

(c) acetic acid, 0-50°C

(d) heat, 120°C

(e) ethanolic ammonia, 120°C, sealed tube

(f) heat

(g) ethanolic ammonia - 36 -

Scheme 11

Note: R' = lower alkyl; Rx and Ry are optional substituents Reagents: a) sodium ethoxide, ethanol, ambient temperature b) jj-Toluenesulphonic acid, benzene, reflux with azeotropic removal of water; heat c) P0C1₃, reflux d) NH_O. EtOH, ambient to 180°C e) bxs( rifluoroacetox )iodobenzene, I_, CH„Cl₂/MeOH f) tetrakis(triphenylphosphine)palladium, triethylamine, dimethoxyethane g) ethyl acrylate, Pd(II)acette, EtgN, 120°C, DMF h) sodium ethoxide, ethanol, reflux i) hydrogenation, palladium on carbon - 37 -

Scheme 12

Note: R' = lower alkyl; Ph = phenyl; Py = pyridyl Reagents: (a) P0CL-, reflux

(b) hydrazine hydrate, ethanol, reflux Scheme 13

Note: R = lower alkyl; Tr = triphenylmethyl (trityl) Reagents: a) hydrogenation over palladium on carbon, ethanol b) [(CH )₂CHCH ] A1H, hexane/CH Cl₂, -75°C c) (Rn)PhHgBr, ether, 0°C to amδient d) (i) Jones reagent (chromic acid and sulphuric acid in water), acetone, 0-5°C (ii) trimethyl orthoformate, p_-toluenesulphonic acid e) trimethylsilyl cyanide, acetonitrile, TiCl, f) tributyltin azide, toluene; HCl, toluene g) Tr.Cl, triethylamine, CH₂Cl₂ h) N-bromosuccinimide, bisisobutyronitrile, CC1, i) ROH, aqu.HCl

Claims

CLAIMSVhat we claim is :

1. A nitrogen derivative of the formula I

wherein

Q is selected from a group of the partial structural formula Ila, lib,

He, lid, He of Hf

in which ring B of formula Ha completes a benzene or pyridine ring; R , T and F are independently selected from (l-8C)alkyl, (3-δC)cycloalkyl, (3-δC)cycloalkyl-(1-4C)alkyl, phenyl, phenyl(1-4C)alkyl or substituted (l-4C)alkyl, the latter containing one or more fluoro substituents or bearing an (l-4C)alkoxy substituent;

2 2 2

R , T and F are independently selected from hydrogen, (l-δC)alkyl,

(3-8C)cycloalkyl, (3-8C)cycloalkyl-(l-4C)alkyl, carboxy,

(1-4C)alkoxycarbonyl, (3-6C)alkenyloxycarbonyl, cyano, nitro, phenyl or phenyl(l-4C)alkyl;

3 4

R and R are optional substituents on ring B independently selected from (l-4C)alkyl, (l-4C)alkoxy, halogeno, trifluoromethyl, cyano, nitro, fluoro(1-4C)alkoxy, hydroxy or hydroxy(l-4C)alkyl;

3 T is selected from halogeno, (1-4C)alkoxy, amino, alkylamino and dialkylamino of up to 6 carbon atoms and any of the values defined for

T¹;

4 3

T and F are independently selected from hydrogen, (l-4C)alkyl,

(l-4C)alkoxy, (l-4C)alkyl containing one or more fluoro substituents, carboxy, (l-4C)alkoxycarbonyl, (3-6C)alkenyloxycarbonyl, halogeno, cyano, nitro, carbamoyl, (1-4C)alkanoyl, N-alkylcarbamoyl and di-(N-alkyl)carbamoyl of up to 7 carbon atoms, amino, alkylamino and dialkylamino of up to 6 carbon atoms, and a group of the formula

-A .B wherein A is (l-6C)alkylene, a carbonyl group or a direct bond and B is

(1) an unsubstituted phenyl or phenyl bearing one or two substituents independently selected from (l-4C)alkyl, (l-4C)alkoxy, halogeno, cyano, trifluoromethyl, nitro, hydroxy, carboxy, (l-4C)alkanoylamino, (1-4C)alkanoyl, fluoro(1-4C)alkoxy, hydroxy(1-4C)alkyl, (l-4C)alkoxy(l-4C)alkyl, carbamoyl, N-alkyl or di-(N-alkyl)carbamoyl of up to 7 carbon atoms, sulphamoyl N-alkyl or di-(N-alkyl)sulphamoyl of up to 6 carbon atoms, (1-4C)alkoxycarbonyl,

(l-4C)alkanesulphonamido, (l-4C)alkyl.S(0) - [in which n is zero, 1 or

1 ⁿ 2] and lH-tetrazol-5-yl; or B is

(2) a 5 or 6-membered saturated or unsaturated heterocyclic ring optionally bearing a (l-4C)alkyl group and containing a single heteroatom selected from oxygen, sulphur and nitrogen or containing two heteroatoms one of which is nitrogen and the other is oxygen, sulphur or nitrogen; — or T3 and T4 together form an (3-6C)alkenylene group, an

(3-6C)alkylene group or an (3-6C)alkylene group in which a methylene

3 4 is replaced by carbonyl, provided that when T and T together form

2 one of said latter three groups then T is additionally selected from any of the previous values defined for T ;

Y is oxygen or a group of the formula -NRb- wherein Rb is hydrogen,

(l-4C)alkyl, (1-4C)alkanoyl or benzoyl; linking group A of formula He is selected from -CH=CH-, -CH=CH-C0-,

-C0-CH=CH-, -C0-CH₂-CH₂-, -CH₂-CH₂-C0, -CH₂-C0 and -C0-CH₂-;

E is hydrogen, (1-δC)alkyl or trifluoromethyl;

2 E is hydrogen, (l-δC)alkyl, halogeno, (l-4C)alkoxy, trifluoromethyl, carboxy, (l-4C)alkoxycarbonyl, (3-6C)alkenyloxycarbonyl, cyano, nitro,

(1-4C)alkanoyl, (l-4C)alkyl.S(0) - [in which m is zero, 1 or 2] or phenylsulphonyl;

3 E is hydrogen, (l-δC)alkyl, (l-4C)alkoxy, halogeno or trifluoromethyl;

4 5 E and E are optional substituents on linking group A independently selected from (l-4C)alkyl, substituted (l-4C)alkyl containing one or more fluoro substituents, phenyl, pyridyl, alkoxy, halogeno, cyano, nitro, carboxy, (1-4C)alkoxycarbonyl, (3-6C)alkenyloxycarbonyl, carbamoyl, N-alkylcarbamoyl and di-(N-alkyl)carbamoyl of up to 7 carbon atoms, (1-4C)alkylthio, (1-4C)alkylsulphinyl,

(l-4C)alkylsulphonyl, phenylthio, phenylsulphinyl, phenylsulphonyl and

(1-4C)alkanoyl;

X is CH or a nitrogen atom;

L¹ is (1-δC)alkyl or (1-8C)alkoxy;

2 3 L and L are independently selected from hydrogen, (l-4C)alkyl and carboxy or a non-toxic metabolically labile ester thereof; F is hydrogen or (l-4C)alkyl;

2 3 or F and F together complete a benzene ring, said benzene ring optionally bearing one or two substituents independently selected from

3 any of the previous values defined for F ;

2 3 or F and F together form an (3-6C)alkenylene group, an

(3-6C)alkylene group or an (3-6C)alkylene group in which a methylene is replaced by carbonyl;

3 4 2 o)rr FF 3 aanndd FF4 ttooggeetthheerr ffoo:rm a linking group A which is selected from

-CH₂-CH₂-, -CH₂-CH₂-CH₂-, -CO-CH^, -CH₂-C0-, -C0-CH₂-CH₂- -CH₂-CH₂-CO-, -C0-CH=CH- and -CH=CH-C0-, and wherein said linking group A optionally bears one or two substituents independently selected from any of the values defined for E 4 or E5;

1 - ^*} / 1

M , M , M , and M have any of the values defined above for E , E ,

3 4 E and E respectively;

Rm and Rn are independently selected from hydrogen, (l-4C)alkyl,

(1-4C)alkoxy, halogeno, trifluoromethyl, cyano and nitro;

Z is carboxy or non-toxic metabolically labile ester thereof, lH-tetrazol-5-yl, -CO.NH. (lH-tetrazol-5-yl) or a group of the formula

-C0.NH.S02.G¹ in which G¹ is (l-6C)alkyl, (3-8C)cycloalkyl or phenyl;

1 0 1 0 Q • 0 / and wherein any of said phenyl moieties of R , R , T , T , T , E , E , 1 / 1

E , F , F , M , M or G may be unsubstituted or bear one or two substituents independently selected from (l-4C)alkyl, (l-4C)alkoxy, halogeno, cyano and trifluoromethyl; or a non-toxic salt thereof.

2. A compound as claimed in claim 1 wherein R , T and F are independently selected from methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, pentyl, hexyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopentyl-ethyl, phenyl, benzyl, 1-phenylethyl, 2-phenylethyl, fluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl,

2-methox eth l and 2-ethoxyethyl;

2 2 2

R , T and F are independently selected from hydrogen, methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, pentyl, hexyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopentyl-ethyl, carboxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, allyloxycarbonyl, 2-methyl-2-propenyloxycarbonyl, 3-methyl-3-butenyloxycarbonyl, cyano, nitro, phenyl, benzyl, 1-phenylethyl and 2-phenylethyl;

3 4

R and R are optional substituents on ring B independently selected from methyl, ethyl, methoxy, ethoxy, chloro, bromo, iodo, trifluoromethyl, cyano, nitro, trifluoromethoxy, 2-fluoroethoxy,

2,2,2-trifluoroethoxy, 3,3,3-trifluoropropoxy, hydroxy, hydroxymethyl,

1-hydroxyethyl and 2-hydroxyethyl; 3 T is selected from methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, pentyl, hexyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopentyl-ethyl, phenyl, benzyl, 1-phenylethyl, 2-phenylethyl, fluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 2-methoxyethyl, 2-ethoxyethyl, fluoro, chloro, bromo, iodo, methoxy, ethoxy, propoxy, amino, methylamino, ethylamino, butylamino, dimethylamino, diethylamino and dipropylamino;

4 3 T and F are independently selected from hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, fluoromethyl, trifluoromethyl,

2,2,2-trifluoroethyl, pentafluoroethyl, carboxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, allyloxycarbonyl,

2-methyl-2-propenyloxycarbonyl, 3-methyl-3-butenyloxycarbonyl, .fluoro, chloro, bromo, iodo, cyano, nitro, carbamoyl, formyl, acetyl, butyryl,

N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,

N,N-diethylcarbamoyl, amino, methylamino, ethylamino, butylamino, dimethylamino, diethylamino, dipropylamino, and a group of the formula

-A .B wherein A is methylene, ethylene, propylene, a carbonyl group or a direct bond and B is

(1) an unsubstituted phenyl or phenyl bearing one or two substituents independently selected from methyl, ethyl, methoxy, ethoxy, chloro, bromo, iodo, cyano, trifluoromethyl, nitro, hydroxy, carboxy, formamido, acetamido, propanamido, formyl, acetyl, butyryl, trifluoromethoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, 3,3,3-trifluoropropoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-methoxyethyl, 2-ethoxyethyl, carbamoyl, N-methylcarbamoyl and N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, sulphamoyl, N-methylsulphamoyl, N-ethylsulphamoyl, N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, methanesulphonamido, ethanesulphonamido, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, methylsulphonyl, ethylsulphonyl and lH-tetrazol-5-yl; or B is

(2) a heterocyclic ring selected from thienyl, furyl, pyrrolyl, pyrrolidinyl, pyridyl, piperidyl, imidazolyl, imidazolidinyl, pyrazolyl, pyrazolinyl, thiazolyl, thiazolinyl, oxazolyl, oxazolidinyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, morpholinyl and thiomorpholinyl, said ring optionally bearing a methyl or ethyl group; or T and T together form a trimethylene, tetramethylene, pentamethylene, 1-propenylene, 2-propenylene, 1-butenylene, 2-butenylene, 3-butenylene, 1-oxopropylidene, 3-oxopropylidene,

1-oxobutylidene or 4-oxobutylidene group, provided that when T and T

2 together form one of said latter twelve groups then T is additionally

4 selected from any of the previous values defined for T ;

Y is oxygen or a group of the formula -NRb- wherein Rb is hydrogen, methyl, ethyl, formyl, acetyl, propanoyl or benzoyl;

E and M are independently selected from hydrogen, methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, pentyl, hexyl and trifluoromethyl;

2 2

E and M are independently selected from hydrogen, methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, pentyl, hexyl, fluoro, chloro, bromo, iodo, methoxy, ethoxy, propoxy, trifluoromethyl, carboxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, allyloxycarbonyl, 2-methyl-2-propenyloxycarbonyl, 3-methyl-3-butenyloxycarbonyl, cyano, nitro, formyl, acetyl, butyryl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, methylsulphonyl, ethylsulphonyl and phenylsulphonyl;

3 3

E and M are independently selected from hydrogen, methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, pentyl, hexyl, fluoro, chloro, bromo, iodo, methoxy, ethoxy, propoxy and trifluoromethyl;

4 5 4 E , E and M are independently selected from methyl, ethyl, fluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, phenyl, pyridyl, methoxy, ethoxy, chloro, bromo, iodo, cyano, nitro, carboxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, allyloxycarbonyl, 2-methyl-2-propenyloxycarbonyl,

3-methyl-3-butenyloxycarbonyl, carbamoyl, N-methylcarbamoyl,

N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, methylsulphonyl, ethylsulphonyl, phenylthio, phenylsulphinyl, phenylsulphonyl, formyl, acetyl and butyryl;

L is methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, pentyl, hexyl, methoxy or ethoxy; L 2 and L3 are independently selected from hydrogen, methyl, ethyl, carboxy, vinyloxycarbonyl, ethynyloxycarbonyl, methoxymethyloxycarbonyl, pivaloyloxymethyloxycarbonyl, l-(ethoxycarbonyloxy)ethyloxycarbonyl, l-(cyclohexyloxycarbonyloxy)ethyloxycarbonyl, phenoxycarbonyl and benzyloxyearbonyl;

4 F is hydrogen, methyl or ethyl;

2 3 or F and F together complete a benzene ring, said benzene ring optionally bearing one or two substituents independently selected from

3 any of the values defined above for F ;

2 3 or F and F together form trimethylene, tetramethylene, pentamethylene, 1-propenylene, 2-propenylene, 1-butenylene, 2-butenylene, 3-butenylene, 1-oxopropylidene, 3-oxopropylidene,

1-oxobutylidene or 4-oxobutylidene;

3 4 2 or F and F together form a linking group A which is selected from

-CH₂-CH₂-, -CH₂-CH₂-CH₂-, -C0-CH₂~, -CH₂~C0-, -C0-CH₂-CH₂-, -CH₂-CH₂-C0-, -C0-CH=CH- and -CH=CH-C0-, and wherein said linking group A optionally bears one or two substituents independently

4 5 selected from any of the values defined above for E or E ;

Rm and Rn are independently selected from hydrogen, methyl, ethyl, methoxy, ethoxy, chloro, bromo, iodo, trifluoromethyl, cyano and nitro;

Z is carboxy, (1-6C)alkoxycarbonyl, phenoxycarbonyl, benzyloxyearbonyl, lH-tetrazol-5-yl, -CO.NH. (lH-tetrazol-5-yl) or a group of the formula -C0.NH.S0„.G in which G is methyl, ethyl, propyl, isopropyl, butyl, pentyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl;

1 0 1 0 0 0 / and wherein any of said phenyl moieties of R , R , T , T , T , E , E , c o 0 / 1

E , F , F , M , M or G may be unsubstituted or bear one or two substituents independently selected from methyl, ethyl, methoxy, ethoxy, chloro, bromo, iodo, cyano and trifluoromethyl; or a non-toxic salt thereof; or a metabolically labile ester thereof.

3. A compound as claimed in claim 1 or 2 wherein Q is a group of the partial structural formula Ha, lib, He or He as defined therein, or Q is a group of the partial structural formula Hd in

1 2 3 which X is a nitrogen atom; L is (1-δC)alkyl; and L and L are independently selected from hydrogen and (l-4C)alkyl; or a non-toxic salt thereof.

4. A compound as claimed in claim 1, 2 or 3 wherein Q is a group of partial structural formula He in which linking group A together with the nitrogen atom and pyridine ring to which it is attached constitutes a l,6-naphthyridin-2(lH)-one ring or a l,2,3,4-tetrahydro-l,6-naphthyridin-2-one ring; or a non-toxic salt thereof.

5. A compound as claimed in claim 1, 2 or 3 wherein Q is a group of partial structural formula Hd; or a non-toxic salt thereof.

6. The compound 5,7-dimethyl-3-[ (2-phenyl-2-(lH-tetrazol-5-yl)- chroman-6-yl)methyl]-2-propyl-3H-imidazo[4,5-b]-pyridine; or^' a non-toxic salt thereof.

7. A salt as claimed in any one preceding claim which is selected from salts with acids forming physiologically acceptable anions and salts with bases forming physiologically acceptable cations.

8. A process for the manufacture of a compound of the formula I, or a non-toxic salt thereof, as claimed in claim 1, which is characterised in that:-

(a) For those compounds in which Z is carboxy, a carboxylic acid derivative of the formula III

in which W is a protected carboxylic acid group selected from (1-6C)alkoxycarbonyl, phenoxycarbonyl, benzyloxyearbonyl and carbamoyl, is converted to carboxy; or

(b) For those compounds of formula I wherein Z is tetrazolyl, a compound of the formula IV

in which P is a suitable protecting group affixed to a nitrogen of the tetrazolyl moiety, is deprotected; or

(c) A compound of the formula Q.H (or a tautomer thereof) is alkylated with a compound of the formula V

wherein Hal. stands for a suitable leaving group;

whereafter: when a compound of the formula I is required wherein Z is lH-tetrazol-5-yl, a compound of the formula I wherein Z is carboxy or a metabolically labile ester thereof is converted into the corresponding nitrile under standard conditions, followed by reaction of the nitrile with an azide; when a compound of the formula I is required wherein Z is -CO.NH. (lH-tetrazol-5-yl), a group of the formula -CO.NH.S0₂.G or a metabolically labile ester group, a carboxylic acid of the formula I in which Z is carboxy (or a reactive derivative of said acid) is reacted with 5-aminotetrazole, a sulphonamide of the formula NH₂.S0„.G or an appropriate alcohol or phenol, or with a salt thereof; when a non-toxic salt of a compound of formula I is required it is obtained by reaction with the appropriate acid or base affording a physiologically acceptable ion, or by any other conventional salt formation procedure; and when an optically active form of a compound of the formula I is required, one of the aforesaid processes (a), (b) or (c) is carried out with an optically active starting material, or the racemic form of a compound of formula I is resolved by reaction with an optically active form of a suitable organic base followed by conventional separation of the diastereoisomeric mixture of salts thus obtained, and liberation of the required optically active form of said compound of formula I by conventional treatment with acid; and wherein Q, Z, Rm and Rn have any of the meanings defined in any of claims 1 to 5 unless otherwise stated.

9. A pharmaceutical composition which comprises a compound of the formula I, or a non-toxic salt thereof, as claimed in any of claims 1 to 7, together with a pharmaceutically acceptable diluent or carrier.

10. A compound of the formula VI

wherein Hal. is a suitable leaving group, P is a suitable protecting group and Rm and Rn have any of the meanings defined in claim 1 or 2.

11. A compound of the formula VIII

wherein Hal. is a suitable leaving group and Rm and Rn have any of the meanings defined in claim 1 or 2.