WO1991009031A1 - Trifluoromethyl substituted compounds and a pharmaceutical composition - Google Patents

Abstract

A compound of formula (I) or, where appropriate, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, wherein A1, A2, A3, A4, R1, R2, R3, R4 and Y are as defined herein; a process for preparing such a compound, a pharmaceutical composition containing such a compound and the use of such a compound and composition in medicine.

Description

Trifluoromethyl substituted compounds and a. pharmaceutical composition.

This invention relates to novel compounds having smooth muscle relaxant activity, to processes for their preparation and to their use as pharmaceuticals.

EP-A-76075, 93535, 95316, 107423, 120426, 126311, 126350, 126367 and 138134 describe certain benzopyran derivatives having inter alia antihypertensive activity. EP-A-176689 also discloses that certain benzopyran derivatives are useful for the treatment of inter alia disorders of the respiratory system.

Within the general class of benzopyrans described in the abovementioned European Patent Publications a particular class of benzopyrans has now been identified which surprisingly show good selectivity for airways smooth muscle relative to the vascular smooth muscle. These compounds may therefore be considered to be especially useful as bronchodilators in the treatment of disorders of the respiratory tract, such as reversible airways obstruction and asthma. Such compounds will also be of use in the treatment of hypertension and in the treatment of disorders associated with smooth muscle contraction of the gastro-intestinal tract, uterus or urinary tract. Such disorders include irritable bowel syndrome and diverticular disease; premature labour; and incontinence. Such compounds are also indicated as of potential use in the treatment of cardiovascular disorders other than hypertension, such as congestive heart failure, angina, peripheral vascular disease and cerebral vascular disease.

Accordingly, the present invention provides a compound of formula (I) :

SUBSTITUTE SHEET

(I)

or, where appropriate, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof

wherein:

one of A-_j^, A2 and A3 represents -CF3 and the remaining two variables of A^, A₂ and A each represent a hydrogen atom;

Y-L represents -0-, -CH2- or NR° wherein R° is hydrogen, alkyl or alkylcarbonyl;R₁ and R₂ independently represent hydrogen or alkyl; or R-^ and R₂ together represent a C2- polymethylene moiety;

R represents hydrogen, hydroxy, alkoxy, acyloxy or O. O2 and R₄ is hydrogen or R3 and R₄ together represent a bond;

A₄ represents either a moiety of formula (a) :

R₆-N-A-R₅

(a)

UBSTITUTE SHEET wherein A represents >C=X wherein X is 0, S or NR-y wherein R₇ represents CN, N0₂, CORg wherein Rg is alkyl, amino, monoalkylamino, fluoroalkyl, phenyl or substituted phenyl or R₇ is S0₂Rg wherein Rg is as defined above, or A represents a bond; when A represents >C=X wherein X is 0 or S, then R^ is hydrogen; alkyl optionally substituted by one or more groups or atoms selected from halogen, hydroxy, alkoxy, alkoxycarbonyl, carboxy or an ester or amide thereof, amino, monoalkylamino or dialkylamino; alkenyl; amino optionally substituted by an alkyl or alkenyl group or by an alkanoyl group optionally substituted by up to three halo atoms, by a phenyl group optionally substituted by alkyl, alkoxy or halogen; substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; and Rg represents hydrogen or alkyl; or R5 and Rg together represent a linking chain of formula -A₅~Ag-, Ag being attached to the nitrogen atom of the moiety -N-A- and A being attached to the group A on the said moiety, and wherein A^ represents a substituted or unsubstituted methylene group, Ag represents 2 or 3 linking members, one of the linking members optionally representing 0, S or NR and the other linking members each independently representing a substituted or unsubstituted methylene group; R represents hydrogen, alkyl, alkanoyl, phenyl Cι- _ alkyl, arylcarbonyl wherein the aryl group may be substituted or unsubstituted; or R is mono- or bi-cyclic- heteroarylcarbonyl;

when A represents >C=X wherein X represents NR₇, then R5 represents -NH.Rg wherein Rg is hydrogen, alkyl,

^3~6 cycloalkyl alkenyl or alkynyl and R is hydrogen or alkyl; or R and Rg together represent C₂~₄ polymethylene;

when A represents a bond, then R5 and Rg together with the nitrogen atom to which they are attached, form an

SUBSTITUTE SHEET unsaturated heterocyclic ring having 5 to 7 ring atoms, which ring atoms comprise up to 2 further nitrogen atoms and a carbon atom, the carbon atom being substituted with either an oxo group or a thioxo group, the remaining ring atoms being substituted or unsubstituted;

or A_* represents a moiety of formula (b) :

T

(b)

wherein T^ represents >C-0H or N(0)_n wherein n is zero or 1 and ₂ together with C-T-^, when T-^ is >C-OH, represents an optionally substituted aryl group or ₂ together with C -^, when T-L is N(0)_n, represents an optionally substituted, N- heteroaryl group;

or A₄ represents a moiety of formula (c)

wherein L^ represents 0 or NR-_jn wherein R-,_n represents hydrogen, alkyl, formyl, acetyl or hydroxymethyl, L₂

SUBSTITUTE SHEET represents N or CL₄ wherein L₄ is hydrogen, halogen, formyl or hydroxymethyl, L3 represents CH₂, 0, S, >CHLc wherein L5 is halogen or NLg wherein Lg is hydrogen or alkyl and R^ and R-L2 each independently represent hydrogen or alkyl or R- together with R₁₂ represents oxo or thioxo; and p represents 1,2 or 3.

Suitably, A₂ or A3 represent CF3.

Preferably, A₂ represents CF3.

Suitably, ^ represents a moiety of formula (a) .

Suitably, A represents >C=X

Suitably, X represents 0.

When R5 together with R represents a linking chain of formula -A^-Ag-, one particular linking chain is that chain having the formula -CH -(CH₂)_n~Z- (CH₂)_m- wherein m and n are 0 to 2 such that m + n is 1 or 2 and Z is CH₂, 0, S or NR wherein R is hydrogen, alkyl, alkanoyl, aralkyl, arylcarbonyl or aralkylcarbonyl, the said aryl moieties being substituted or unsubstituted, or R is mono- or bi- cyclic heteroarylcarbonyl.

When R₅ represents substituted or unsubstituted aryl, suitably phenyl, particular optional substituents include alkyl, alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, acyl, amino or amino carbonyl the latter two groups being optionally substituted with one or two alkyl groups.

When R₅ is alkyl it is suitably C-^ alkyl, such as methyl or ethyl, an example being ethyl.

SUBSTITUTE SHEET In one aspect Rg is hydrogen.

In one particular aspect, the present invention provides a compound of formula (I) or, when the compound of formula (I) contains a salifiable group, a pharmaceutically acceptable salt thereof, wherein:

one of R-_j^ and R2 is hydrogen or C- -^ alkyl and the other is C-1-4 alkyl or R-^ and R2 together are 2-5 polymethylene;

either R3 is hydrogen, hydroxy, C-^- alkoxy or ^-η acyloxy and R4 is hydrogen or R3 and R4 together are a bond;

R5 is hydrogen, C-^-g alkyl optionally substituted by halogen, hydroxy C-^-g alkoxy, C-^-g alkoxycarbonyl, carboxy or amino optionally substituted by one or two independent C-L~g alkyl groups, or C2~g alkenyl, amino optionally substituted by a C-^-g alkyl or C2~g alkenyl group or by a C-^-g alkanoyl group optionally substituted by up to three halo atoms, by a phenyl group optionally substituted by Ci-g alkyl, C-^-g alkoxy or halogen; or aryl or heteroaryl, either being optionally substituted by one or more groups or atoms selected from the class of C^-g alkyl, -^-g alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, I-T carboxylic acyl, or amino or aminocarbonyl optionally substituted by one or two C-^-g alkyl groups and Rg is hydrogen or C-i-g alkyl, or R5 and Rg together are

-CH2-(CH2)_n-Z-(CH₂)_m-wherein m and n are 0 to 2 such that m + n is 1 or 2 and Z is CH₂, 0, S or NR wherein Ris hydrogen, Cτ_-g alkyl, C₂ ^_ ₇ alkanoyl, phenyl C^-₄~ alkyl, naphthylcarbonyl, phenylcarbonyl or benzyl- carbonyl optionally substituted in the phenyl or naphthyl ring by one or two of C-^- alkyl, C-^-g alkoxy or halogen; or R is mono- or bi-cyclic- heteroarylcarbonyl;

SUBSTITUTE SHEET X is oxygen or sulphur; and one of A-^, A₂ and A represents CF3, the remaining two variables of A-^, A₂ and A each representing hydrogen.

Suitably, the nitrogen-containing group in the 4-position is disposed trans to the R3 group when R3 is hydroxy, C-^- alkoxy, suitably alkoxy, or C-L-₇ acyloxy.

Preferably, R^ and R₂ are both ^-^ alkyl, in particular both represent methyl.

When R3 is alkoxy, suitably C-^- alkoxy, and R4 is hydrogen, preferred examples of R include methoxy and ethoxy, of which methoxy is more preferred. When R is acyloxy, suitably C^-η acyloxy, and R₄ is hydrogen, a preferred class of R3 is unsubstituted carboxylic acyloxy, such as unsubstituted aliphatic acyloxy. However, it is more preferred that R3 and R4 together are a bond, or that R3 and R4 are both hydrogen, or in particular, that R is hydroxy and R4 is hydrogen.

Examples of R when Re_, is alkyl, suitably C-^-g alkyl, include methyl, ethyl and n- and iso-propyl. Preferably such R^ is methyl. Preferaby such Rg is ethyl.

A sub-group of Rg when Rg is alkyl substituted by halogen, is C-^-g alkyl substituted by chloro or bromo. Examples thereof include methyl or ethyl terminally substituted by chloro or bromo.

Examples of Rg when Rg is alkyl, suitably C-^- alkyl, substituted by hydroxy, include methyl or ethyl terminally substituted by hydroxy.

A sub-group of Rg when Rg is alkyl substituted by alkoxy, is ^cl~6 ^alky¹ substituted by methoxy or ethoxy. Examples

SUBSTITUTE SHEET thereof include methyl or ethyl terminally substituted by methoxy or ethoxy.

A sub-group of Rg when Rg is alkyl substituted by alkoxycarbonyl, suitably C-^-g alkoxycarbonyl, is C^-g alkyl substituted by methoxycarbonyl or ethoxycarbonyl. Examples thereof include methyl or ethyl terminally substituted by methoxycarbonyl or ethoxycarbonyl.

Examples of Rg when alkyl, suitably C-^-g alkyl, substituted by carboxy include methyl or ethyl terminally substituted by carboxy.

An example of Rg when alkyl, suitably C-^g alkyl, substituted by amino optionally substituted by one or two independent alkyl, suitably C-^-g alkyl groups, includes a group (CH₂)_nNR_sR_t where n is 1 to 6 and R_s and R_t are each independently hydrogen or C-^-g alkyl. Examples of n include 1 and 2. Preferably R_g and R^. are each independently selected from hydrogen and methyl.

Examples of Rg when alkenyl, suitably C2~g alkenyl, include vinyl, prop-1-enyl, prop-2-enyl, 1-methylvinyl, but-1-enyl, but-2-enyl, but-3-enyl, 1-methylenepropyl, or l-methylprop-2-enyl, in both their E and Z forms where stereoisomerism exists.

Examples of Rg when amino optionally substituted as hereinbefore defined, include an amino optionally substituted by a methyl, ethyl, propyl, butyl, allyl or trichloroacetyl group or by a phenyl group optionally substituted by one methyl, methoxy or chloro group or atom, in particular amino, methylamino, and phenylamino optionally substituted in the phenyl ring by one methyl, methoxy or chloro group or atom.

BSTITUTE SHEET Examples or Rg when aryl as defined, includes phenyl and naphthyl, of which phenyl is preferred. The phenyl group may be substituted or unsubstituted. When substituted a preferred substituent is a halogen atom especially a fluorine atom. One example of such an Rg group is a 4- fluorophenyl group.

A sub-group of Rg when heteroaryl is 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heteroaryl of which 5- or 6-membered monocyclic heteroaryl is preferred. In addition, 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heteroaryl preferably contains one, two or three heteroato s which are selected form the class of oxygen, nitrogen and sulphur and which, in the case of there being more than one heteroatom, are the same or different.

Examples of 5- or 6-membered monocyclic heteroaryl containing one, two or three heteroatoms which are selected from the class of oxygen, nitrogen and sulphur include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl and thiadiazolyl, and pyridyl, pyridazyl, pyrimidyl, pyrazyl and triazyl. Preferred examples of such groups include furyl, thienyl, pyrrolyl and pyridyl, in particular 2- and 3-furyl, 2- and 3-pyrrolyl 2- and 3-thienyl, and 2-, 3- and 4-pyridyl.

Examples of 9- or 10-membered bicyclic heteroaryl containing one, two or three heteroatoms which are selected from the class of oxygen, nitrogen and sulphur include benzofuryl, benzothienyl, indolyl and indazolyl, quinolinyl and isoquinσlinyl, and quinazolinyl. Preferred examples of such groups include 2- and 3-benzofuryl, 2- and 3-benzothienyl, and 2- and 3-indolyl, and 2- and 3-quinolinyl.

Preferably, the number of groups or atoms for optional substitution of aryl or heteroaryl is one, two, three or four.

SUBSTITUTE SHEET Preferred examples of the groups or atoms for optional substitution of aryl or heteroaryl include methyl, methoxy, hydroxy, chloro, nitro or cyano.

A sub-group of Rg is phenyl or naphthyl or a 5- or 6-membered monocyclic or a 9- or 10-membered bicyclic heteroaryl, the phenyl, naphthyl or heteroaryl group being optionally substituted by one, two, three or four groups or atoms selected from the class of C-^- alkyl, C-^-g alkoxy, halogen, trifluoromethyl, nitro or cyano.

A preferred sub-group of phenyl optionally substituted as hereinbefore defined is phenyl, 4-substituted phenyl, 3-substituted phenyl, 3,4-disubstituted phenyl and 3, 4, 5-trisubstituted phenyl.

A preferred sub-group of 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heteroaryl optionally substituted as hereinbefore defined is unsubstituted or mono-substituted 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heteroaryl, in particular unsubstituted 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heteroaryl.

When R and Rg together represent a linking chain -Ag-Ag-, suitably the abovedefined moiety -Cf_?-(CH₂)_n-Z- (CH2,_m-, the resulting radical substituting the benzopyran in the 4-position is preferably either pyrrolidinyl or piperidinyl.

When Z is other than Cf-2, m is often 0 or 1 and n is often 0 or 1. Suitable examples of R when Z is NR include hydrogen, methyl, ethyl, n- and iso-propyl, n-, sec- and text- butyl, benzyl, phenylcarbonyl or benzylcarbonyl optionally substituted in the phenyl ring by methyl, methoxy, chloro or bromo; furylcarbonyl, thienylcarbonyl, pyrrolylcarbonyl or

TITUTE SHEET indolylcarbonyl. Preferably R is hydrogen, methyl, n-butyl, acetyl, benzyl, benzylcarbonyl, phenylcarbonyl or furylcarbonyl. Most preferably R is methyl.

Preferably Rg and Rg together are C3 or C4 polymethylene.

Preferably, X is oxygen.

When used herein the term ''halogen'' refers to fluorine, chlorine, bromine and iodine; preferably chlorine.

Suitably alkyl groups, or alkyl groups forming part of other groups such as in the alkoxy group, are ^--^ alkyl groups especially C-^-g alkyl groups e.g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl or tert-butyl groups.

Suitably alkenyl groups are

groups especially C2~ alkenyl groups.

Suitable alkynyl groups are C₂~₁₂ alkynyl groups especially ^C2^~6 ^alkYⁿY¹ groups.

Suitable acyloxy groups include alkylcarbonyloxy groups wherein the alkyl group is as defined above.

When used herein the term ''fluoroalkyl'' includes alkyl groups as defined above when substituted by one or more fluorine atoms, particular examples being trifluoromethyl and pentafluoroethyl.

When used herein the term 'aryl' includes phenyl and naphthyl optionally substituted with up to five, preferably up to three, groups selected from halogen, alkyl, phenyl,

SUBSTITUTE SHEET alkoxy, haloalkyl, hydroxy, amino, nitro, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl alkylcarbonyloxy, or alkylcarbonyl groups.

Suitable pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts and salts of carboxy groups.

Examples of pharmaceutically acceptable acid addition salts of the compounds of formula (I) includes acid addition salts of optionally substituted amino groups, such as the hydrochloride and hydrobromide salts. Such a salifiable group may form part of an Rg group.

Examples of pharmaceutically acceptable salts of carboxy groups include metal salts, such as alkali metal salts, or optionally substituted ammonium salts.

The compounds of formula (I) may also exist as hydrates and the invention extends to these.

The compounds of formula (I) , wherein 3 is hydrogen, hydroxy, alkoxy, suitably C-^-g alkoxy, acyloxy, suitably C- -η acyloxy or O.N0₂, and R4 is hydrogen, are asymmetric, and, therefore, can exist in the form of optical isomers. The present invention extends to all such isomers individually and as mixtures, such as racemates.

Examples of compounds of formula (I) include the compounds prepared in the Examples hereinafter.

The present invention also provides a process for the preparation of a compound of formula (I) or, where appropriate a pharmaceutically acceptable salt thereof,

SUBSTITUTE SHEET which comprises;

i) for compounds of formula (I) wherein A4 represents a moiety (a) and wherein A represents >C=X wherein X is 0 or S, acylating a compound of formula (II) :

wherein, R_{l f} R₂ and Y-^ are as defined hereinbefore, A-_j , A₂' and A3' each respectively represent A-_j_, A₂ or A3 as defined in relation to formula (I) or protected forms thereof, R3¹ is hydrogen, hydroxy, alkoxy or acyloxy, and R ¹ is hydrogen or alkyl,

a) with an acylating agent of formula (III) :

R₁₃-CO-L₇ (III)

wherein L₇ is a leaving group, and R-,3 is hydrogen, alkyl optionally substituted by halogen, hydroxy, alkoxy, alkoxycarbonyl, carboxy or amino optionally substituted as hereinbefore defined for Rg, alkenyl or optionally substituted aryl or heteroaryl as hereinbefore defined for Rg, or a group convertible to R as hereinbefore defined, and thereafter, when R g is hydrogen and R-^ is Y2(CH2)₂, wherein z is 3 or 4 and Y2 is a leaving group, cyclising the resultant compound;

SUBSTITUTE SHEET b) with a compound of formula (IV)

X=C=N.R₁₄ (IV)

wherein R₁₄ is hydrogen, alkyl, alkenyl, alkanoyl optionally substituted by up to three halo atoms, or phenyl optionally substituted by alkyl, alkoxy or halogen; and X is oxygen or sulphur, and thereafter when R₁₄ is hydrogen, optionally converting R14; or

ii) for compounds of formula (I) wherein A4 represents a moiety (a) and wherein A represents >C=X wherein X is 0 or S, and Rg and Rg together represent a linking chain -Ag-Ag- as defined above in relation to formula (I) , reacting a compound of formula (V) :

(V)

wherein A-^', A₂', A3', R-^, R2 and Y-_j_ are as hereinbefore defined, with an activated form of a compound of formula (VI) :

R₁₆NHCOR₁₅ (VI)

wherein R^g and R-^ together represent a linking chain of formula -Ag-Ag-;

SUBSTITUTE SHEET iii) for compounds of formula (I) wherein A represents a moiety (a) and wherein A represents a bond and Rg and Rg together with the nitrogen to which they are attached form an unsaturated heterocyclic ring having 5 to 7 ring atoms, which ring atoms comprise up to 2 further nitrogen atoms and a carbon atom, the carbon atom being substituted with either an oxo group or a thioxo group, the remaining ring atoms being substituted or unsubstituted, by reacting a compound of the abovedefined formula (V) with an activated form of a compound of formula (VIA) :

Rg²NHR₅ ¹ (VIA)

wherein R ^x and R together with the nitrogen to which they are attached form the said heterocyclic ring;

(iv) for compounds of formula (I) wherein R4 represents a moiety of formula (a) in which A is >C=X and X is NR₇, either:

a) for compounds wherein Rg is other than hydrogen and R₇ is CN or SO2NH2, by reacting a compound of formula (VII) :

wherein R-^, R₂, R4, Rg and Y^ are as defined in relation to formula (I) and A-^, A₂', A3' and R3¹ are as defined in relation to formula (II) , with phosgene (COCI2) and either cyanamide (for compounds wherein R₇ is CN) or sulphamide (for compounds wherein R₇ is S0₂NH₂); or

SUBSTITUTE SHEET b) for compounds wherein Rg and Rg together are C2- polymethylene and R₇ is CN, by reacting dimethyl

N-cyanodithioiminocarbonate with a compound of formula

(VIII) :

wherein q is 2, 3 or 4 and the remaining variables are as hereinbefore defined; or

v) for compounds of formula (I) wherein A₄ represents a moiety of formula (b) , either:

a) for compounds wherein .T^ in moiety (b) represents >C-OH, by deprotecting a compound of formula (IX) :

wherein R_l R₂, R₄ and Y are as defined in relation to formula (I), A_j', A₂', A3' and R3¹ are as defined in relation to formula (II) , T-^ represents >C-0Ϊ4 wherein T₄ is a hydroxyl protecting group and T_? together with CT ^ represents an optionally substituted aryl group; or

SUBSTITUTE SHEET b) for compounds wherein T-^ in moiety (b) represents N(0)_n, by oxidising a compound of formula (X):

wherein R-^, R₂, R3 , , A-^', A₂', A3' and Y-^ are as defined above and T₂ together with C-N represents an optionally substituted or N-heteroaryl group; or

vi) for compounds of formula (I) wherein A4 represents a moiety of formula (c) , by reacting a compound of the abovedefined formula (V) , with a compound of formula (XI) :

^Eιι

L,H (XI)

wherein L^, L₂, 3, R^, R-^₂ and p are as defined in relation to moiety (c) of formula (I) ;and thereafter if required, carrying out one or more of the following optional steps:

SUBSTITUTE SHEET (a) converting A-^' to A-^ and/or converting A₂' to A₂ and/or converting A ' to 3;

(b) converting a compound of formula (I) into a further compound of formula (I) ; (c) forming a pharmaceutically acceptable salt of the compound of formula (I) ;

(d) forming a pharmaceutically acceptable solvate of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

In the process variant i) a) acylation of a compound of formula (II) with an acylating agent of formula (III) , the leaving group L₇ is a group that is displaceable by a primary or secondary amino nucleophile. Examples of such a group include

alkanoyloxy, and halogen, such as chloro and bromo. When the leaving group L-^ is either of these examples, the acylating agent of formula (III) is either an acid anhydride or an acid halide. When it is an acid anhydride, it may be a mixed or simple anhydride. If it is a mixed anhydride, it may be prepared in situ from a carboxyliic acid and an acid halide, although this is less preferred than using the halide itself.

In process variant i) a) , when Rg in the desired compound of formula (I) is an Rg optionally substituted amino-substituted alkyl group as hereinbefore defined, it is preferred that

is a group convertible to the Rg substituted alkyl group as hereinbefore defined, in particular that it is alkyl substituted by halo, especially bromo. The R^ halo substituent in the resultant compound of process variant i) a) may be converted to an Rg substituent which is amino optionally substituted as hereinbefore defined by a conventional amination reaction with ammonia or a corresponding alkyl- or dialkylamine.

SUBSTITUTE SHEET Less favourably R13 may be alkyl substituted by protected amino, protected alkylamino or amino substituted by two independent alkyl groups, it being necessary to protect the Rg amino function in process variant i) a) .

When the acylating agent of formula (III) is an acid anhydride, the acylation of the compound of formula (II) may be carried out in the presence of an acid acceptor, such as sodium acetate, optionally using the anhydride as the solvent.

When the acylating agent of formula (III) is an acid halide, the acylation of the compound of formula (II) is, preferably, carried out in a non-aqueous medium, such as dichloromethane, in the presence of an acid acceptor, such as triethylamine, trimethylamine, pyridine, picoline or calcium, potassium or sodium carbonate.

When the compound of formula (II) comprises a hydroxy group, for example when R3 is hydroxy, there is a risk of a side-reaction between the hydroxy group and the acylating agent of formula (III) . However, the reaction may be carried out under controlled conditions such that only the amine, Rg NH-is acylated, for example, by using a ₂~ acyloxy group as the leaving group L₇, in the acylating agent of formula (III) in the manner as previously described for an acid anhydride, and/or effecting the reaction at relatively low temperature, e.g. at below 10°C.

Alternatively R3 may be C±-η acyloxy in a compound of formula (II) , although less preferably if R3 in the resultant compound of formula (I) is to be hydroxy, and, after reaction with the acylating agent of formula (III) , be converted into hydroxy, as described hereinafter.

SUBSTITUTE SHEET When R-_j is Y2(CH₂)_Z where the variables are as hereinbefore defined, the leaving group Y is a group that is displaceable by a secondary amino nucleophile adjacent to a carbonyl function. A preferred example is chloro.

The cyclisation reaction when

is Y (CH₂)₂ where the variables are as hereinbefore defined is preferably carried out in an inert solvent such as dimethylformamide.

In process variant i) b) , when R^₄ in a compound of formula (IV) is alkyl, alkenyl, alkanoyl optionally substituted as hereinbefore defined, or phenyl optionally substituted as hereinbefore defined, the reaction between the compounds of formulae (II) and (IV) is, preferably, carried out in a solvent, such as dichloromethane, at below room temperature, in particular below 10°C.

When is hydrogen, the reaction between the compounds of formulae (II) and (IV) is, preferably, carried out using a corresponding alkali metal cyanate or thiocyanate, for example that of sodium or potassium, in an optionally methanolic aqueous medium acidified with a mineral acid, such as dilute hydrochloride acid. A slightly elevated temperature such as 50 to 90°C is apt.

In process variant ii) , a suitable activated form of a compound of formula (VI) is an ionic form. Thus in the reaction between a compound of formula (V) and a compound of formula (VI) , it is preferred that the reaction is carried out under basic conditions so as to facilitate the formation of the anion of the compound of formula (VI) , for example, in the presence of an alkali metal base such as potassium t-butoxide or sodium hydride.

SUBSTITUTE SHEET The reaction between the compounds of formula (V) and (VI) may be carried out in any suitable aprotic solvent at a temperature that provides a convenient rate of formation of the compound of formula (I) , such as at ambient temperature or at an elevated temperature,for example 40°C.

Conveniently, the compound of formula (VI) may itself be used as the solvent for the reaction between compounds of formulae (V) and (VI) .

In process variant iii) , a suitable activated form of a compound of formula (VIA) is an ionic form. Thus in the reaction between a compound of formula (V) and a compound of formula (VIA) , it is preferred that the reaction is carried out under basic conditions so as to facilitate the formation of the anion of the compound of formula (VIA) , for example, in the presence of an alkali metal base such as potassium t-butoxide or sodium hydride.

The reaction between the compounds of formulae (V) and (VIA) may be carried out in any suitable aprotic solvent, for example dimethylsulphoxide, at a temperature that provides a convenient rate of formation of the compound of formula (I) , such as at ambient temperature or at an elevated temperature, but conveniently at ambient temperature.

In process variant iva) , the reaction is preferably carried out in an inert solvent, such as tetrahydrofuran, at -10 to +25°C, preferably around 0°C to ambient, in an inert atmosphere, for example, under nitrogen, preferably in the presence of a base, such as diisopropylethylamine.

Alternative methods of forming compounds of formula (I) wherein R represents a moiety of formula (a) in which A is

SUBSTITUTE SHEET >C=X and X is NRg are as described in J.Med.Chem. 1978 Vol 21 p773-781.

Intermediates of formula (VII) may be prepared according to 5 analogous procedures disclosed in EP-A-107423, EP-A-168619, EP-A-126367, EP-A-205292 and EP-A-321175 or in European Patent Application Number 89309272.6.

In process variant ivb) , the reaction suitably takes place 10 at elevated temperatures, preferably at reflux temperatures, in an inert solvent, such as toluene.

The reaction conditions for proces variant v) are generally equivalent to those described in European Application, 15 Publication Number 298452.

The intermediate compounds of formula (IX) and (X) may conveniently be prepared using analogous procedures to those described in EP 298452. 20

In process variant vi) , the reaction is suitably effected by using an anionic form of compound (XI) formed in situ by using a strong base, for example sodium hydride.

25 In process variant vi) the reaction conveniently takes place in an inert solvent, for example in dimethylformamide, dimethyl sulphoxide, tetrahydrofuran, dimethylpropylene-urea or mixtures thereof, at low, medium or high temperatures, preferably at room temperature, for example at about 20 to

3025°C. It is often convenient to catalyse the reaction, for example using catalytic or stoichiometric quantities of copper(I)bromide, magnesium bromide or titanium alkoxides, or to catalyse the epoxide opening with catalytic or stochiometric quantities of a Lewis acid such as BF3.0Et₂.

35

SUBSTITUTE SHEET The compounds of formula (XI) may suitably be prepared using analogous procedures to those described in European

Application, Publication Number 107423 or United Kingdom

Application, Publication Number 2204868.

Suitable conversions of a compound of formula (I) to a further compound of formula (I) include:

(i) converting R in the resulting compound of formula (I) into another R3; (ii) converting a compound of formula (I) wherein R3 and R represent hydroxy and hydrogen respectively to give another compound of formula (I) , wherein R3 and R4 together represent a bond;

(iii) reducing any compound of formula (I) wherein R3 and R4 together represent a bond; to give another compound of formula (I) , wherein R3 and R each represent hydrogen; (iv) thiating a compound of formula (I) to convert any -CO- group in the moiety of formula Rg.N.A.Rg into a -CS- group; or (v) when R is other than hydrogen, interconverting the cis and trans mutual configuration of the variables R and R .

The reaction of the compounds of formulae (II) with (III) or (IV) results in a compound of formula (I) wherein R3 is hydroxy, alkoxy or acyloxy, whereas the reaction of the compounds of formulae (V) and (VI) and (V) with (VIA) results in a compound of formula (I) wherein R3 is hydroxy. Examples of an optional conversion of R3 in a compound of formula (I) into another R are generally known in the art. For example, when R3 is hydroxy, it may be alkylated using an alkyl iodide in an inert solvent, such as toluene, in the presence of a base, such as sodium hydride or potassium hydroxide, or it may be acylated using a carboxylic acid chloride or an appropriate anhydride in a non-hydroxylic solvent, such as toluene or dichloromethane, in the presence of an acid acceptor such as triethylamine. When R is

SUBSTITUTE SHEET alkoxy it may be converted into a hydroxy group by any conventional dealkylation method for example by treatment with trimethylsilyliodide in an aprotic solvent. In addition, when R3 is acyloxy it may be converted into hydroxy by conventional hydrolysis using, for example, dilute mineral acid.

The optional conversion of a compound of formula (I) , wherein R3 and R4 are hydroxy and hydrogen respectively, into another compound of formula (I) , wherein R3 and R4 together are a bond, may be carried out by dehydration under conventional dehydration conditions, for example, by using a dehydrating agent, such as sodium hydride, in inert solvent, such as dry tetrahydrofuran, at reflux temperature; alternatively the hydroxy group represented by R may be converted into a leaving group such as a mesyloxy or tosyloxy group and the resulting compound treated with a base such as sodium hydride to provide the compound of formula (I) wherein R3 and R together represent a bond.

The reduction of a compound of formula (I) , wherein R3 and R4 together are a bond, into another compound of formula (I) , wherein R3 and R₄ are each hydrogen, may be carried out by hydrogenation using a catalyst of palladium on charcoal.

The thiation of the Rg.N.A.Rg moiety in a compound of formula (I) to give another compound of formula (I) , is, preferably, carried out with conventional thiation agents, such as hydrogen sulphide, phosphorus pentasulphide and Lawesson's reagent (p-methoxyphenylthiophosphine sulphide dimer) . The use of hydrogen sulphide and phosphorus pentasulphide may lead to side-reactions and, therefore, the use of Lawesson's reagent is preferred. The thiation reaction conditions are conventional for the thiation agent employed. For example, the use of hydrogen sulphide is,

SUBSTITUTE SHEET preferably, acid catalysed by, for example, hydrogen chloride in a polar solvent, such as acetic acid or ethanol. The preferred use of Lawesson's reagent is, preferably, carried out under reflux in a dry solvent, such as toluene or methylene chloride.

The interconversion of the cis and trans configuration of the variables R₃ and R₄ is generally carried out by changing the configuration of variable R3, especially when R3 represents hydroxyl, by means of any convenient conventional procedure.

The optional formation of a pharmaceutically acceptable salt, when the resulting compound of formula (I) contains a salifiable group, may be carried out conventionally.

Similarly, pharmaceutically acceptable solvates, for example hydrates, may be prepared using any convenient conventional procedure.

A compound of formula (II) may be prepared by reacting a compound of formula (V) , as defined hereinbefore, with a compound of formula (XII) :

Rg¹NH₂ (XII)

wherein Rg¹ is as defined hereinbefore; and optionally converting R3 hydroxyl in the resulting compound of formula (II) into another R3 -

The reaction is normally carried out in a solvent, such as a C-L- alcohol, in particular methanol, ethanol or propanol at an ambient or an elevated temperature, for example 12 to 100°C. The reaction proceeds particularly smoothly if carried out in ethanol under reflux.

The resulting compound of formula (II) may be isolated from the reaction mixture by removal of the solvent, for example,

SUBSTITUTE SHEET by evaporation under reduced pressure. Any epoxide impurity may be removed conventionally, for example for chromatography.

Alternatively, for compounds of formula (II) wherein Rg is hydrogen, a compound of formula (V) may be treated with a source of azide ions, such as sodium azide, and thereafter the resulting azide reduced to the required product using conventional reduction methods.

The optional conversion of the hydroxy group for R3 in the resulting compound of formula (II) into a alkoxy or acyloxy group may be carried out as described hereinbefore in relation to the corresponding conversion of R3 in a compound of formula (I) .

A compound of formula (V) may be prepared by reacting a compound of formula (XIII) :

(XIII)

wherein A-_j , A₂', A3', R_{l r} R₂ and Y- are as hereinbefore defined, the bromine atom being trans to the hydroxy group, with a base, suitably an alkali metal base such as a potassium alkoxide, for example potassium t-butoxide, or potassium hydroxide, in a solvent, such as ether aqueous dioxan or dimethylsulphoxide.

In one preferred form of the process for preparing a compound of formula (I) , a compound of formula (V) may be

SUBSTITUTE SHEET prepared jLn situ, preferably in anhydrous conditions, by reaction of a compound of formula (XIII) with a strong base, preferably an alkali metal alkoxide, for example potassium t-butoxide, andthereafter the said compound of formula (V) may be reacted in the abovedefined process ii) , iii) or vi) to provide a compound of formula (I) .

A compound of formula (XIII) may be prepared by reaction of a compound of formula (XIV) :

wherein A-^', A₂' , A ', R-^, R₂ and Y^_ are as defined hereinbefore, with N-bromosuccinimide in a solvent, such as aqueous dimethyl sulphoxide.

A compound of formula (V) may also be prepared from a compound of formula (IX) by reaction with a peracid, preferably m-chloroperbenzoic acid, in an inert solvent such as dichloromethane at ambient temperature.

A compound of a formula (XIV) may be prepared in accordance with analogous processes to those described in the aforementioned European Patent publications, i.e. by the process depicted below:

SUBSTITUTE SHEET (Process)

)

wherein one of A-^, A or A3 represents CF3 and the remaining two variables of A-^, A₂ and A3 represent hydrogen, and process steps (a), (b) , (c) are:

(a) Reflux; acetone; K2CO3/KI;

(b) Heat in ortho-dichlorobenzene or N,N-diethyl aniline;

SUBSTITUTESHEET (c N-bromosuccinimide/dimethylsulphoxide/water;

As will be appreciated when -^ or A3 is CF3 the cyclisation process to give (XIV) produces C-5 and C-7 CF3 substituted chromenes. These may be separated by conventional techniques such as chromatography. Alternatively, and in fact preferably, they may be separated more easily after conversion to the corresponding epoxides of formula (V) as defined above.

As mentioned previously, some of the compounds of formula (I) may exist in optically active forms, and the processes of the present invention produce mixtures of such forms. The individual enantiomers may be resolved by conventional methods. For example, a mixture of enantiomers of a compound of formula (I) may be derivatised with an optically active derivatising agent to provide a mixture of diastereoisomeric derivatives, which may then be separated using any convenient procedure, for example chromatography. A suitable derivatising agent is an optically active isocyanate, such as (-)-α-methylbenzylisocyanate, which provides the corresponding carbamate.

It is preferred that the compounds of formula (I) are isolated in substantially pure form.

The intermediates of formulae (II), (V), (VII), (VIII), (IX), (X), (XIII) or (XIV) are believed to be novel and accordingly form part of the present invention.

The intermediates of formulae (III) , (IV) , (VI) , (VIA) or (XII) are known or may be prepared using conventional procedures, for example those disclosed in Advanced Organic Chemistry, 3rd Edition, (1985) , Published by John Wiley and Sons.

SUBSTITUTE SHEET The compounds of formula (I) have been found to have particularly advantageous bronchodilator activity. They also have blood-pressure lowering activity. These compounds are therefore useful in the treatment of respiratory tract disorders, such as reversible airways obstruction, diverticular disease and asthma and also hypertension. They may also be of potential use in the treatment of other disorders hereinbefore described.

The present invention accordingly provides a pharmaceutical composition which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The compositions are preferably adapted for oral administration. However, they may be adapted for other modes of administration, for example in the form of a spray, aerosol or other conventional method for inhalation, for treating respiratory tract disorders; or parenteral administration for patients suffering from heart 'failure. Other alternative modes of administration include sublingual or transdermal administration.

The compositions may be in the form of tablets, capsules, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations, such as oral or sterile parenteral solutions or suspensions.

In order to obtain consistency of administration it is preferred that a composition of the invention is in the form of a unit dose.

Unit dose presentation forms for oral administration may be tablets and capsules and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin,

SUBSTITUTE SHEET sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline [Bcellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulphate.

The solid oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are of course conventional in the art. The tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.

Oral liquid preparations may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils) , for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.

For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, and,

SUBSTITUTE SHEET depending on the concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, a preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

Compositions of this invention may also suitably be presented for administration to the respiratory tract as a snuff or an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case the particles of active compound suitably have diameters of less than 50 microns, preferably less than 10 microns. Where appropriate, small amounts of other anti-asthmatics and bronchodilators, for example sympathomimetic amines such as isoprenaline, isoetharine, salbutamol, phenylephrine and ephedrine; xanthine derivatives such as theophylline and aminophylline and corticosteroids such as prednisolone and adrenal stimulants such as ACTH may be included.

The compositions may contain from 0.1% to 99% by weight, preferably from 10-60% by weight, of the active material,

SUBSTITUTE SHEET depending on the method of administration.

The present invention further provides a method of treatment of respiratory tract disorders or hypertension in mammals including man, which comprises administering to the suffering mammal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

An effective amount will depend on the relative efficacy of the compounds of the present invention, the severity of the respiratory tract disorder or hypertension being treated and the weight of the sufferer. However, a unit dose form of a composition of the invention may contain from 0.01 to lOOmg of a compound of the invention (0.01 to lOmg via inhalation) and more usually from 0.1 to 50mg, for example 0.5 to 25mg such as 1, 2, 5, 10, 15 or 20mg. Such compositions may be administered from 1 to 6 times a day, more usually from 2 to 4 times a day, in a manner such that the daily dose is from 0.02 to 200mg for a 70 kg human adult and more particularly from 0.05to lOOmg.

No toxicological effects are indicated at the aforementioned dosage ranges.

The present invention further provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of respiratory tract disorders or hypertension.

The following descriptions relate to the preparation of intermediates and the following examples relate to the preparation of compounds of formula (I) .

SUBSTITUTE SHEET Description 1

3-Methyl-3- (3-trifluoromethylphenoxy)but-1-yne

3-Trifluoromethylphenol (16.2g, O.lmol) was combined with 3-chloro-3-methylbut-l-yne (12.Og, 0.12mol), potassium carbonate (16.8g, 0.12mol), potassium iodide (1.5g, 9mmol) and dry acetone (100ml) . The mixture was stirred and refluxed for 18 hours, cooled and filtered. The acetone was evaporated and the resulting oil purified by chromatography on silica gel eluting with dichloromethane/hexane (1:9) to give the title compound as a yellow oil 2.4g (10.5%), which was used without further purification.

IR (film) cm-¹: 3300, 1610, 1590, 695.

¹H NMR (CDC1₃) δ: 1.63 (s,6H), 2.60 (s,lH), 7.4 (m,4H) .

SUBSTITUTE SHEET Description 2

2,2-Dimethyl-5- and 7-trifluoromethyl-2H-l-benzopyran

10

3-Methyl-3- (3-trifluoromethylphenoxy)but-1-yne (2.4g, 10.5mmol) was heated in N,N-diethylaniline (12.5ml) at 160° under nitrogen for 18 hours. The mixture was cooled and treated with hydrochloric acid (5M, 1 litre) and extracted

15 with ether (3 x 250ml) . The combined extracts were washed with 2M hydrochloric acid

(1 x 200ml) and brine (1 x 200ml) . Evaporation of the ether gave 2.1g (87.5%) of an oil consisting of a mixture of 2,2-dimethyl-5-and 7-trifluoromethyl-2H-l-benzopyran

20

IR (film) cm-¹; 2975, 985, 765.

¹H NMR (CDC1₃) δ: 1.50 (s,6H), 5.71 (dd,J₁=10Hz,J₂=lHz) , 5.75(d,J=10Hz) , 6.37(d,J=10Hz) , 6.67(dd,J₁=10 and J₂=2.5Hz) , 257.17 (m,3H) .

SUBSTITUTE SHEET Description 3

2,2-Dimethyl-3,4-dihydro-3,4-epoxy-5-and 7-trifluoro- methyl-2H-l-benzopyran

A mixture of 2,2-dimethyl-5- and 7-trifluoromethyl-2H-l- benzopyran (2.1g, 9.2mmol) was combined with m-chloroperbenzoic acid (2.0g, 80%, 9mmol) and dichloromethane (30ml) . The mixture was stirred for 2 days before being filtered and the solvent removed. The resulting oil was purified by chromatography on silica gel eluting with chloroform/hexane (3:7). This gave the 5-isomer of the title compound, 870mg (38%) followed by the 7-isomer 172mg (7.6%).

5-ISOMER: white solid m.p. 41°C (hexane)

IR (film) cm- : 2900, 1610, 1590, 1460, 810, 790, 745, 713.

^-H NMR (CDC1₃) δ: 1.33(s,3H), 1.63(s,3H),

3.50(d,IH,J=4.5Hz) , 4.27(m,lH), 7.03 and 7.33 (m's,3H)

ANALYSIS Found C:58.80, H:4.56

^C12^H11^F3°2 requires C:59.20, H:4.54%

SUBSTITUTE SHEET 7-ISOMER: white solid m.p. 75-6°C (EtOAc/hexane)

IR (Nuiol) cm-¹: 1590, 1510, 1460, 970, 920, 910, 880, 850, 830, 800, 760, 750, 720, 670. NMR (CDC1₃) δ: 1.30(s,3H), 1.67(s,3H), 3.53(d,IH,J=5Hz) 3.93 (d,lH,J=5Hz), 7.13(s,lH), 7.23 and 7.53 (d's,lH each,J=7.5Hz)

ANALYSIS Found C:58.93, H:4.52

^C12^H11^F3°2 requires C.59.20, H:4.54%.

Description 4

Trans-3-bromo-3,4-dihydro-2,2-dimethyl-7-trifluoro- methyl-2H-l-benzopyran-4-ol

OH

N-Bromosuccinimide (8.81g, 49.56mmol) was added to a cold (4°C) solution of 2,2-dimethyl-7-trifluoromethyl- 2H-1-benzopyran (5.65g, 24.76mmol) in dimethyl sulphoxide (50ml) and water (0.89ml). After the exothermic reaction, the solution was stirred at room temperature for 16 hours then poured into water and extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulphate, filtered and evaporated leaving the crude bromohydriii, 8g (100%)

SUBSTITUTE SHEET ¹H NMR (CDC1₃) δ: 1.45 (s, 3H) , 1 . 68 (s, 3H) , 3.33 (d, IH, J=5Hz) , 4 . 12 (d, IH, J=8Hz) , 4 . 9 (dd, IH, J₁=5Hz, J₂=8Hz) , 7 . 12 (bs, IH) , 7.23 (bd, IH, J=8z) , 7. 62 (d, IH, J=8Hz) .

Description 5

Trans-4-azido-3,4-dihydro-2,2-dimethyl-7-trifluoro- methyl-2H-l-benzopyran-3-ol

3,4-Dihydro-2,2-dimethyl-3,4-epoxy-7-trifluoromethyl-2H-l- benzopyran (790 mg, 3.2 mmol) was treated with sodium azide (250 mg, 3.85 mmol) in dioxan (8 ml/water (1 ml) at 50°C for 24 hours. Aqueous workup gave a mixture which was purified by chromatography to give the title compound as an oil (590 mg, 64%)

^XH NMR (CDCl₃)δ: 1.30 (s,3H), 1.53 (s,3H), 2.53 (d, IH,J=4.5Hz) , 3.80 (dd,IH,J_χ=9,J₂=4.5Hz) , 4.45 (d, IH,J=9Hz) ,7.13 (S,1H),7.25 (d,IH,J=9Hz) ,7.53 (d,IH,J=9Hz) .

SUBSTITUTE SHEET Description 6

Trans-4-amino-3 , 4-dihvdro-2 , 2-dimethyl-7-trifluoromethyl- 2H-l-benzopyran-3-ol

4-Azido-3,4-dihydro-2,2-dimethyl-7-trifluoromethyl-2H-l- benzopyran-3-ol (500 mg,1.75 mmol) was hydrogenated over Pd/C in ethanol. Workup yielded the title compound (450 mg, 15100%) .

¹H NMR (CDCl₃)δ: 1.25 (s,3H), 1.50 (s,3H), 2.17 (s,3H) 3.38 (d,IH,J=10Hz) , 3.70 (d,IH,J=10Hz) , 7.10 (s,lH,8H), 7.23 (d,IH,J=9Hz) , 7.57 (d, IH,J=9Hz) . 20

ANALYSIS

Found C: 55.21, H: 5.37, N: 5.39;

^C12^H14^F3^N02 requires C: 55.17, H: 5.40, N: 5.36.

25 Description 7

3-Methyl-3- (4-trifluoromethylphenoxy)-but-1-yne

SUBSTITUTE SHEET A mixture of 4-(trifluoromethyl)-phenol (5.1g), potassium carbonate (5g) , potassium iodide (0.2g) and

3-chloro-3-methyl-but-l-yne (4.8g) in dry acetone (50ml) was heated and stirred, under reflux, for 4 days. The mixture was cooled, filtered and solvent removed in vacuo to give the propargyl ether as a yellow oil (6.3g, 88%), having:-

¹H n.m.r. (CDCI3) 1.54 (s, 6H) , 2.40 (s,lH), 7.25 (dd,J=9,9Hz,4H) .

Description 8

2,2-Dimethyl-6-trifluoromethyl-2H-l-benzopyran

A solution of

3-methyl-3-(4-trifluoromethylphenoxy)-but-1-yne (6.3g) in ortho-dichlorobenzene (30ml) was heated under reflux, under nitrogen, for 2 hours. Solvent was removed in vacuo, and the residue chromatographed on silica gel eluted with ethyl acetate:pentane (1:9) to give the desired chromene as a yellow oil (3.0g, 48%) having:

^!H n.m.r. (CDCI3) 1.40 (s,6H), 5.50 (d,J=9Hz,IH) , 6.15 (d,J=9Hz,lH) , 6.65 (d,J=8Hz,IH) , 7.10 (m,2H) .

(Found: M⁺ 228.0757; C₁₂ ^Hll^OF3 requires M⁺ 228.0762).

SUBSTITUTE SHEET Description 9

Trans-6- (trifluoromethyl) -3 , 4-dihydro-2 , 2-dimethyl-3- bromo-4-hvdroxy-2H-l-benzopyran

(D9)

A solution of 2,2-dimethyl-6-trifluoromethyl-2H-l- benzopyran (3.0g) in dimethylsulphoxide (30ml) and water (3ml) was treated with N-bromosuccinimide (4.8g) and the mixture stirred vigorously for 2 hours. Water was added, and the mixture extracted into ethyl acetate. The combined organic extracts were washed with water, then brine, and dried over magnesium sulphate. Removal of drying agent and solvent gave the required bromohydrin (4.0g, 93%) having:

¹H n.m.r. (CDC1₃) 1.40 (s,3H), 1.60 (s,3H), 2.75 (br s,OH), 4.10 (d,J=9Hz,lH) , 4.85 (d,J=9Hz,IH) , 6.75 (d,J=9Hz, IH) , 7.35 (dd,J=9Hz,2Hz,lH) , 7.70 (d,J=2Hz, IH) .

SUBSTITUTE SHEET Description 10

6-Trifluoromethyl-3,4-epoxy-3, -dihydro-2,2-dimethyl-2H- 1-benzopyran

(D10)

A mixture of trans-6-trifluoromethyl-3,4-dihydro-2,2- dimethyl-3-bromo-4-hydroxy-2H-l-benzoρyran (4.0g) and potassium hydroxide pellets (4.0g) in dry ether (500ml) was stirred vigorously for 48 hours. Filtration and evaporation of solvent under reduced pressure gave the epoxide (2.5g, 83%) having:

¹H n.m.r. (CDCI3) 1.30 (s,3H), 1.60 (s,3H),

3.45 (d,J=4Hz,lH) , 3.85 (d,J=4Hz,IH) , 6.80 (d,J=8Hz,IH) , 7.50 (m,2H) .

SUBSTITUTE SHEET Example 1

Trans-3 , 4-dihydro-2 , 2-dimethyl-4- (2-oxopjperidin-l-yl) -7- trifluoromethyl-2H-l-benzopyran-3-ol

2-Piperidone (108mg, l.lmmol) and potassium t-butoxide (130mg, 1.15mmol) were stirred in dimethyl sulphoxide (3ml) under nitrogen for 30 minutes.

3, -Dihydro-2,2-dimethyl-3,4-epoxy-7-trifluoro- methylbenzopyran (120mg, 0.49mmol) was added and the mixture stirred overnight. Aqueous work up yielded a gum (203rαg) which was purified by chromatography (Si0 eluting with 1:1 hexane/dichloromethane) and crystalization from ethyl acetate yielded the title compound, 125mg (74%) m.p. 163-4°C.

IR (Nuiol) cm-¹: 3250, 2920, 1620, 1600, 880.

¹H NMR (CDC1₃) δ: 1.28 (s,3H), 1.52(s,3H), 1.75 (m,4H) , 2.60 (t,2H,J=7Hz) , 2. 4 (m,IH) , 3.06(m,lH), 3.3 (d,IH,J=5Hz) , 3.81(dd,IH,J₁=10Hz, J₂=5Hz) , 5.95(d,IH,J=10Hz) , 7.1(m,3H) .

ANALYSIS

Found C:60.11, H:5.87, N:4.09%.

^C17^H20^F3^NO3 requires C:59.47, H.-5.87, N:4.08%.

SUBSTITUTE SHEET Examples 2 and 3

Trans-3,4-dihvdro-2,2-dimethyl-4-(2-oxopiperidin-l-yl)-7- trifluoromethyl-2H-l-benzopyran-3-ol and 2,2-dimethyl- 4-(2-oxopiperidin-l-yl)-7-trifluoromethyl-2H-l-benzopyran

a) 2-Piperidinone (500mg, 5mmol) and potassium t-butoxide (520mg, 4.64mmol) were stirred in dimethyl sulphoxide (10ml) under nitrogen for 30 minutes.

2,2-Dimethyl-3,4-dihydro-3,4-epoxy-7-trifluoromethyl-2H-l- benzopyran (1.10g, 4.5mmol) was added and the mixture stirred overnight. Aqueous work up yielded a gum which was purified by chromatography (Si0₂ eluting with chloroform/ ether 1:1) to give 2,2-dimethyl-4- (2-oxopiperidin-l-yl) - 7-trifluoromethyl-2H-l- benzopyran (210mg, 14%) followed by trans-3,4-dihydro-2,2-dimethyl-4- (2-oxopiperidin-l- yl)-7-trifluoromethyl- 2H-l-benzopyran-3-ol (730mg, 47%).

Example 2

m.pt. 163.5-164°C (EtOAC)

IR (Nuiol) cm-¹: 3250, 2920, 1620, 1600, 880.

SUBSTITUTE SHEET ^-HMR (CDCI3) δ: 1.28 (s,3H), 1.52 (s,3H), 1.75 (m,4H), 2.60(t,2H, J=7Hz), 2. 4 (m, IH) , 3.06 (m, IH) , 3.3 (d, IH, J=5Hz) , 3.81 (dd, IH, J₁=10Hz, J₂=5Hz) , 5.95 (d,lH, J=10Hz) , 7.1 (m, 3H) .

ANALYSIS Found C: 59.58, H: 5.87, N: 4.09% ^C17^H20^F3^NO3 requires C:59.47, H: 5.87, N: 4.08%

Example 3

m.pt. 106° (sublimation)

IR(Nuiol) cm-¹: 1660, 1645, 870, 825

¹H NMR (CDCI3) δ: 1.53 (s,6H), 1.93 (m,4H) , 2.55 (m,2H), 3.47(m,2H), 5.70(s,lH), 6.9-7.2 (m,3H) .

ANALYSIS

Found C: 62.86, H: 5.59, N: 4.32% C₁₇H₁₈F₃N0₂ requires C: 62.76, H: 5.58, N: 4.31%

b) Trans-3-bromo-3,4-dihydro-2,2-dimethyl-7-trifluoro= methyl-2H-l- benzoρyran-4-ol (8g, 24.7mmol) was stirred with potassium t-butoxide (5.56g, 49.52mmol) in dimethyl sulphoxide (120ml) at room temperature for one hour. Piperidone (12.27g, 124mmol) and potassium t-butoxide (13.9g, 124mmol) were added, the mixture stirred for four hours then poured into HC1 (2N) and extracted with ethyl acetate. The organic phase was washed with brine and dried over magnesium sulphate. Evaporation of the solvent and chromatography (Siθ2 eluting with ethyl acetate) gave trans-3,4-dihydro-2,2-dimethyl-4-(2-oxopiperidin-l-

SUBSTITUTE SHEET yl)-7-trifluoromethyl-2H-l-benzopyran-3-ol, 3.3g (39%) m.p. 162-3°C and 2,2-dimethyl-4-(2-oxoρiperidin-l-yl)-7- trifluoromethyl-2H-l-benzopyran, 370mg (5%)

Examples 4 and 5

(-) and (+) Trans-3,4-dihydro-2,2-dimethyl-4- (2-oxo¬ piperidin-l-yl)-7-trifluoromethyl-2H-l-benzopyran-3-ol

A solution of (±)-trans-3,4-dihydro-2,2-dimethyl-4-(2- oxopiperidin-1-yl)-7- trifluoromethyl-2H-l-benzopyran-3-ol (730mg, 2.13mmol) and (-)-α-methylbenzylisocyanate (0.35ml, 2.47mmol) in dry toluene (20ml) was refluxed for 39 hours. The solvent was evaporated and the residue was purified by chromatography (Si0₂ eluting with 9:1 chloroform/hexane) yielding the carbamate of the (-)-enantiomer of the title compound (270mg, 26%), the carbamate of the (+)- enantiomer of the title compound (255mg, 24%) and a mixture of (+)- and (-)- carbamates (360mg, 35%).

The pure carbamates were hydrolyzed to the parent alcohols by treatment with triethyla ine (2 equivalents) and trichlorosilane (2 equivalents) at 35°-40°C for 18 hours. After aqueous work-up the crude products were purified by chromatography on silica gel. Elution with ethyl acetate gave the pure (-)-enantiomer (132mg, 70%); and similarly the pure (+)- enantiomer of the title compound (125mg, 70%).

BSTITUTE SHEET Example 4

(-)-enantiomer

m.p. : 170-171°C

[CC]_D ²⁵ (CHC1₃, C=0.17), - 11.9°

ANALYSIS

Found C: 59.43, H: 6.04, N: 3.98% ^c17^H20^NO3^F3 requires C: 59.47, H: 5.87, N: 4.08%

IR and HNMR: were identical to the spectra of the racemic mixture.

Example 5

(+)- enantiomer

m.p. : 172-173°C

[α]_D ²⁵ (CHCI3, C=0.16), + 12.1°

ANALYSIS:

Found C: 59.60, H: 5.90, N: 4.32%

^C17^H20^NO3^F3 requires C: 59.47, H: 5.87, N: 4.08%

^•1 IR and ^XH NMR: identical to the spectra of the racemic mixture.

SUBSTITUTE SHEET Example 6

Trans-3, 4-dihvdro-2 , 2-dimethyl-4- (2-oxopiperidin-l- yl) -5-trifluoromethylbenzo-2H-l-pyran-3-ol

Piperidin-2-one (220 mg, 2.2mol) in dimethyl sulphoxide (5 ml) under nitrogen was treated with potassium t-butoxide (250 mg, 2.2 mmol) and stirred for 30 minutes.

2,2-Dimethyl-3,4-dihydro-3,4-epoxy-5-trifluoromethyl-2H- 1-benzopyran (488 mg, 2 mmol) was added and the mixture stirred for 5 hours. The mixture was poured into water and extracted with ethyl acetate, the extracts washed with water and evaporated. The crude product was purified by chromatography (chloroform on Si0₂) to yield the title compound as white crystals (572 mg, 83%) , mp 137-8°C (EtOAc) .

¹H NMR (CDC1₃) δ: 1.20 (s, 3H) , 1.50 (s, 3H) , 1.6-1.85 (m, 4H) , 2.54 (m, 2H) , 2.6 (m, IH) , 2.9 (m, IH) , 3.90 (d, IH, J=8Hz), 4.40 (s, IH) , 6.00 (d, IH, J=8Hz) , 7.1-7.3 (m, 3H) .

ANALYSIS

Found C: 59.40, H: 5.92, N: 4.07

^C17^H20^F3^NO3 requires C: 59.47, H: 5.87, N: 4.08%.

SUBSTITUTE SHEET Example 7

2 , 2-Dimethyl-4- (2-oxopiperidin-l-yl) -5-trif luoro- methylbenzo-2H-l-pyran

Trans-3,4-dihydro-2,2-dimethyl-4-(2-oxoρiρeridin-l-yl)-5- trifluoromethylbenzo-2H-l-pyran-3-ol (173 mg, 0.5 mmol) was combined with sodium hydride (16mg, 80%, 0.57 mmol) in dry tetrahydrofuran and heated under reflux overnight. The solvent was removed and the residue partitioned between ethyl acetate and water. The organic layer was washed with water, dried and evaporated to give the title compound as a white powder mp 125-6°C after sublimation under vacuum.

^XH NMR (CDC1₃) δ: 1.55 (s, 6H) , 1.77 (m, 4H) , 2.53 ( , 2H) , 3.53 (m, 2H) , 5.80 (s, IH) , 7.05-7.50 (m, 3H) .

ANALYSIS:

Found C: 63.14, H: 6.28, N: 3.98

C₁₇H₁₈F₃N0₂ requires C: 62.76, H: 5.58, N: 4.13%.

SUBSTITUTE SHEET Example 8

Trans-3,4-dihydro-2,2-dimethyl-4-(2-oxopyrrolidin-l- yl)-7-trifluoromethyl-2H-l-benzopyran-3-ol

The title compound was prepared in 87% yield by the method used for Example 1 but replacing 2-piperidone by 2-pyrrolidinone. M.p. 166°C (ethyl acetate) .

IR (Nuiol) cm-¹: 3300,1650,1590,1000,975,960,885.

^XH NMR (CDC1₃) : 1.28 (s,3H), 1.53 (s,3H), 2.1 (m,2H) 2.57 (t,2H), 3.08 (m,lH), 3.31 (m, IH) , 3.57 (d,IH) , 3.78 (dd,IH,J=10.5Hz) , 5.30 (d,IH,J=10.5Hz) , 7.1 (m,3H) .

ANALYSIS

Found C-57.91, H:5.46, N:4.39;

^C16^H18^F3^N03 requires C:58.35,H:5.51,N:4.26%.

SUBSTITUTE SHEET Example 9

2,2-Dimethyl-4- (2-oxopyrrolidin-l-yl)-7-trifluoromethyl- 2H-l-benzopyran

The title compound (m.p. 80°C) was prepared in 93% yield from trans-3,4-dihydro-2,2-dimethyl-4-(2-oxxoρyrrolidin-l -yl)-7-trifluoromethyl-2H-l-benzopyran-3-ol (190 mg, 0.61 mmol) and sodium hydride (18.5 mg, 80%, 0.61 mmol) in tetrahydrofuran (10 ml) according to the method of Example 7.

IR (Nuiol) cm-¹: 1660,1645,870,825 cm-¹

¹H NMR (CDC1₃) δ: 1.50 (s,6H) , 2.20 (t,2H,J=7.5hz) , 2.57 (t,2H,J=7.5Hz) , 3.62 (t,2H,J=7.5Hz) , 5.72 (s, IH) , 7.0-7.1 (m,3H) .

ANALYSIS

Found C: 61.47, H: 5.18, N: 4.50;

C₁gH₁₆F₃N0₂ requires C: 61.73, H: 5.18, N: 4.50.

SUBSTITUTE SHEET Example 10

Trans-3,4-dihvdro-2,2-dimethyl-4-(N-propionylamino)-7- trifluoromethyl-2H-l-benzopyran-3-ol

Trans 4-amino-3,4-dihydro-2,2-dimethyl-7-trifluoromethyl- 2H-l-benzopyran-3-ol (100 mg, 0.38 mmol) was combined with triethylamine (40 mg, 0,40 mmol), propionyl chloride (44 mg, 0.39 mmol), in dichloromethane (2ml) and the mixture stirred for one hour. Work up gave the title compound (81 mg, 67%), m.p. 148°C (hexane/ethyl acetate) .

¹H NMR (CDC1₃) δ: 1.23 (t,3H,J=8Hz) , 1.26 (s,3H), 1.49 (s,3H), 2.37 (q,2H,J=8Hz) , 3.65 (dd, IH,J_χ=9,J₂=2.8Hz) , 4.33 (bs,lH), 5.08 (t,lH,J=8Hz) , 5.85 (bs,lH), 7.11 (s,lH), 7.17 (d,IH,J=9), 7.31 (d,1H,J=8).

ANALYSIS

Found C:56.44, H:5.70, N:4.42;

^C15^H18^F3^N03 requires C:56.78, H:5.72, N:4.41.

SUBSTITUTE SHEET Example 11

Trans-3,4-dihydro-2,2-dimethyl-4- (4-fluorobenzoylamino) -7-trifluoromethyl-2H-l-benzopyran-3-ol

The title compound (m.p. 165°C) was prepared by an analogous method to that used in Example 10, but replacing propionyl chloride with 4-fluorobenzoyl chloride.

¹H NMR (CDC1₃) δ: 1.2 (s,3H), 1.44 (s,3H, 1.44 (s,3H), 3.30 (bs,lH), 3.80 (m,IH) , 5.08 (t,21H), 5.72 (d,IH) , 7.25 (m,4H), 8.01 (dd,2H), 8.82 (d,IH) .

SUBSTITUTE SHEET Example 12

Trans-3,4-dihvdro-2,2-dimethyl-4-(2-oxopyrrolidinyl) -6-(trifluoromethyl-2H-l-benzopyran-3-ol 5

15

Pyrrolidinone (0.21g) was added to a stirred suspension of sodium hydride (68mg) in dry dimethylsulphoxide (15ml) and

20 the mixture stirred for 1 hour, under nitrogen. Then a solution of 6-trifluoromethyl-3,4-epoxy-3, -dihydro- 2,2-dimethyl-2H-l-benzopyran (0.5g) in dimethylsulphoxide (5ml) was added and the mixture stirred for 16 hours. Water was added, and the mixture extracted into ethyl acetate.

25 The combined organic extracts were washed with water, then brine, and dried over magnesium sulphate. Removal of solvent in vacuo and recrystallisation of the residue from ethyl acetate: 60-80° petroleum-ether (1:1) gave the title compound as off-white needles (300mg, 44%) having m.pt.

30181-2°C;

^XH NMR (CDC1₃) : 1.30 (s,3H), 1.50 (s,3H, ) 2.15 (m,2H) , 2.50 (m,2H), 3.20 (m,2H) , 3.75 (d,J=10Hz,IH) ,

SUBSTITUTE SHEET 4.60 (br s,OH), 5.25 (d,J=10Hz,IH) , 6.80 (d,J=8Hz,IH) , 7.10 (d,J=2Hz,lH) , 7.30 (dd,J=8Hz,IH) . Found: M⁺ 329.1238; C₁gH₁₈N0₃F₃ requires M⁺ 329.1238.

Examples 13 and 14

The following compounds were prepared according to procedures described hereinbefore, with particular reference to the Examples and Procedures sections:

*When R3 is OH, then R3 and Rg.N.CX.Rg are configurated in the trans configuration with respect to each other.

SUBSTITUTE SHEET Pharmacolocrical Data

1. Bronchodilator Activity

(a) Bronchodilation in vitro; guinea pig tracheal spiral preparations.

Male guinea pigs (300-600g) were stunned by a blow to the head and bled from the carotid artery. The trachea was exposed, dissected free of connective tissue, and transferred to oxygenated krebs solution at 37°C. Next, spirals (2 per trachea) were prepared by cutting the whole trachea spirally along its longitudinal axis and then dividing this spiral lengthwise. Each preparation was mounted, using silk thread, in a 10ml organ bath filled with krebs solution at 37°C and bubbled with 5% CO2 with 0₂. The resting tension of the preparations was set at 2g and changes in muscle tension were monitored isometrically by means of a UFI (2oz) force and displacement transducer (Ormed Ltd) connected to a Linseis pen recorder. All preparations were allowed to equilibrate for 60 minutes. Duringthis equilibration period the preparations were washed by upward displacement at 15 minute intervals and, if necessary, the resting tension was readjusted to 2g using a mechanical micromanipulator system.

Once a steady resting tension had been obtained, the preparations were dosed cumulatively with the test compound (10-⁸-2xlO-⁵M) , and finally a maximum relaxation achieved by addition of 10-³M isoprenaline. The fall in tension evoked by the test compound was expressed as a percentage of the total relaxation evoked in the presence of 10-^M isoprenaline. Appropriate concentration-relaxation curves were then constructed and values for potency (ICg₀) and intrinsic activity (I.A.) were obtained.

SUBSTITUTE SHEET The composition of Krebs solution is: sodium chloride 118.07mM, sodium hydrogen carbonate 26.19mM, potassium chloride 4.68mM, potassium orthophosphate l.lδmM, magnesium sulphate septahydrate 1.8mM and calcium chloride 2.52mM;pH ca. 7.45.

Animals were prepared according to the methodology described by Konzett and Rossler (1) . Guinea pigs were anaesthetized by an intraperitoneal injection of Urethane (1500mg/kg) and then prepared with tracheal, arterial and venous cannulae. The animals were connected to a respiratory pump which was adjusted to deliver a volume of 1ml per lOOg body weight to the guinea pig. The back pressure of the Ugo Basile 7020 overflow sensor was then adjusted to give a constant, resting overflow volume. The animals were then allowed to equilibrate for 10 minutes before experimentation began.

Arterial blood pressure was recorded with a pressure transducer (Bell and Howell 4-422-0001) connected via a Devices 3552 pressure pre-amplifier to a Devices pen recorder. Changes in overflow volume - an index of total pulmonary resistance - were expressed as a percentage of the maximum bronchoconstriction obtained by total occlusion of the tracheal cannula. In all determinations of

SUBSTITUTE SHEET bronchoconstrictor activity, peak overflow volumes were used.

Bronchoconstriction was produced by a bolus injection of a submaximal dose of 5-hydroxytryptamine (5-HT) into the jugular vein. The bronchodilator activity of the test compound was assessed by its ability to inhibit a subsequent 5-HT-induced bronchoconstriction, 5-HT being given at a dose that caused approximately 60% bronchoconstriction.

1. H. Konzett and R. Rossler (1940) Arch. Exp. Path. Pharmak (Naunyn Schmiedeberg) 195, 71-74.

Results: In test (b) jLn vivo, a dose of 460μg/kg i.v., of the compound of Example 1 inhibited by 50% the bronchoconstriction effect of 5-HT.

2. Antihvpertensive Activity

Blood Pressure Lowering Activity

Systolic blood pressures were recorded by a modification of the tail cuff method described by I.M. Claxton, M.G. Palfreyman, R.H. Poyser, R.L. Whiting, European Journal of Pharmacology, 37_., 179 (1976) . A W+W BP recorder, model 8005 was used to display pulses.Prior to all measurements rats were placed in a heated environment (33.5 ± 0.5°C) before transfer to a restraining cage. Each determination of blood pressure was the mean of at least 6 readings. Spontaneously hypertensive rats (ages 12-18 weeks) with systolic blood pressures >180 mmHg were considered hypertensive.

SUBSTITUTE SHEET Compound of Example 1

Dose l.Omg/kg, p.o.

SUBSTITUTE SHEET

Claims

Clai s

1. A compound of formula (I) :

(I)

or, where appropriate, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof

wherein:

one of A-_j_, A₂ and A3 represents -CF3 and the remaining two variables of A-^, ₂ and A3 each represent a hydrogen atom;

Y- represents -0-, -CH₂~ or NR° wherein R° is hydrogen, alkyl or alkylcarbonyl;R2 and R₂ independently represent hydrogen or alkyl; or R-^ and R₂ together represent a C ~₇ polymethylene moiety; R3 represents hydrogen, hydroxy, alkoxy, acyloxy or O.N0₂ and R4 is hydrogen or R3 and R4 together represent a bond;

A₄ represents either a moiety of formula (a) :

BSTITUTE SHEET

Rg-N-A-Rg

(a)

wherein A represents >C=X wherein X is 0, S or NR₇ wherein R₇ represents CN, N0₂, CORg wherein Rg is alkyl, amino, monoalkylamino, fluoroalkyl, phenyl or substituted phenyl or R₇ is S0₂Rg wherein Rg is as defined above, or A represents a bond; when A represents >C=X wherein X is 0 or S, then Rg is hydrogen; alkyl optionally substituted by one or more groups or atoms selected from halogen, hydroxy, alkoxy, alkoxycarbonyl, carboxy or an ester or amide thereof, amino, monoalkylamino or dialkylamino; alkenyl; amino optionally substituted by an alkyl or alkenyl group or by an alkanoyl group optionally substituted by up to three halo atoms, by a phenyl group optionally substituted by alkyl, alkoxy or halogen; substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; and Rg represents hydrogen or alkyl; or Rg and Rg together represent a linking chain of formula -Ag-Ag-, Ag being attached to the nitrogen atom of the moiety -N-A- and Ag being attached to the group A on the said moiety, and wherein A represents a substituted or unsubstituted methylene group, Ag represents 2 or 3 linking members, one of the linking members optionally representing

SUBSTITUTE SHEET O, S or NR and the other linking members each independently representing a substituted or unsubstituted methylene group; R represents hydrogen, alkyl, alkanoyl, phenyl C-^-^_ alkyl, arylcarbonyl wherein the aryl group may be substituted or unsubstituted; or R is mono- or bi-cyclic- heteroarylcarbony1;

when A represents >C=X wherein X represents NR₇, then Rg represents -NH.Rg wherein Rg is hydrogen, alkyl, C3~g cycloalkyl, alkenyl or alkynyl and Rg is hydrogen or alkyl; or R and R together represent C₂~4 polymethylene;

when A represents a bond, then Rg and Rg together with the nitrogen atom to which they are attached, form an unsaturated heterocyclic ring having 5 to 7 ring atoms, which ring atoms comprise up to 2 further nitrogen atoms and a carbon atom, the carbon atom being substituted with either an oxo group or a thioxo group, the remaining ring atoms being substituted or unsubstituted;

or A4 represents a moiety of formula (b) :

T

2 T. \_^- 1

(b)

wherein T-^ represents >C-OH or N(0)_n wherein n is zero or 1 and T₂ together with C-T-^, when T^ is >C-OH, represents an optionally substituted aryl group or T together with CT-,, when T-L is N(0)_n, represents an optionally substituted, N- heteroaryl group;

or A4 represents a moiety of formula (c) :

SUBSTITUTE SHEET ^R12

^Ll

I (c)

wherein L-^ represents 0 or NR-^_Q wherein R-^_Q represents hydrogen, alkyl, formyl, acetyl or hydroxymethyl, L₂ represents N or CL wherein L4 is hydrogen, halogen, formyl or hydroxymethyl, L3 represents CH2, 0, S, >CHLg wherein Lg is halogen or NLg wherein L is hydrogen or alkyl and R-, ■, and R₁₂ each independently represent hydrogen or alkyl or

represents oxo or thioxo; and p represents 1,2 or 3.

2. A compound according to claim 1, wherein A2 or A3 represent CF3.

3. A compound according to claim 1, wherein A represents a moiety of formula (a) .

4. A compound according to claim 1, wherein R together with Rg represents C3 or C polymethylene.

5. A compound according to claim 1, wherein A represents >C=X

6. A compound according to claim 1, wherein X represents 0.

7. A compound according to claim 1, being selected from:

trans-3,4-dihydro-2,2-dimethyl-4- (2-oxopiperidin-l-yl)-7-

SUBSTITUTE SHEET trifluoromethyl-2H-l-benzopyran-3-ol;

trans-3,4-dihydro-2,2-dimethyl-4- (2-oxopiperidin-l-yl)-7- trifluoromethyl-2H-l-benzopyran-3-ol;

2,2-dimethyl-4-(2-oxopiperidin-l-yl)-7-trifluoromethyl- 2H-l-benzopyran;

(-) trans-3,4-dihydro-2,2-dimethyl-4-(2-oxo- piperidin-1-yl)-7-trifluoromethyl-2H-l-benzopyran-3-ol;

(+) trans-3, -dihydro-2,2-dimethyl-4-(2-oxo¬ piperidin-l-yl)-7-trifluoromethyl-2H-l-benzopyran-3-ol;

trans-3,4-dihydro-2,2-dimethyl-4-(2-oxopiperidin-l- yl)-5-trifluoromethylbenzo-2H-l-pyran-3-ol;

2,2-dimethyl-4-(2-oxopiperidin-l-yl)-5-trifluoro- methylbenzo-2H-l-ρyran;

trans-3,4-dihydro-2,2-dimethyl-4-(2-oxopyrrolidin-l- yl)-7-trifluoromethyl-2H-l-benzoρyran-3-ol;

2,2-dimethyl-4-(2-oxopyrrolidin-l-yl)-7-trifluoromethyl- 2H-1-benzopyran;

trans-3,4-dihydro-2,2-dimethyl-4- (N-propionylamino)-7- trifluoromethyl-2H-l-benzoρyran-3-ol; and

trans-3,4-dihydro-2,2-dimethyl-4-(4-fluorobenzoylamino) -7-trifluoromethyl-2H-l-benzopyran-3-ol; or, where appropriate, a pharmaceutically acceptable salt thereof.

SUBSTITUTE SHEET 8. A process for preparing a compound of formula (I) or, where appropriate a pharmaceutically acceptable salt thereof, which process comprises;

i) for compounds of formula (I) wherein ₄ represents a moiety (a) and wherein A represents >C=X wherein X is 0 or S, acylating a compound of formula (II) :

wherein, R-^, R2 and Y-^ are as defined hereinbefore, A-^', A₂' and A3' each respectively represent Ai , A₂ or A as defined in relation to formula (I) or protected forms thereof, R is hydrogen, hydroxy, alkoxy or acyloxy, and Rg¹ is hydrogen or alkyl,

a) with an acylating agent of formula (III) :

R₁₃-C0-L₇ (III)

wherein L₇ is a leaving group, and R-^ is hydrogen, alkyl optionally substituted by halogen, hydroxy, alkoxy, alkoxycarbonyl, carboxy or amino optionally substituted as hereinbefore defined for Rg, alkenyl or optionally substituted aryl or heteroaryl as hereinbefore defined for Rg, or a group convertible to Rg as hereinbefore defined, and thereafter, when R g is hydrogen and R-^ is Y₂ (CH₂) , wherein z is 3 or 4 and Y is a leaving group, cyclising the resultant compound;

SUBSTITUTE SHEET b) with a compound of formula (IV)

wherein R₁₄ is hydrogen, alkyl, alkenyl, alkanoyl optionally substituted by up to three halo atoms, or phenyl optionally substituted by alkyl, alkoxy or halogen; and X is oxygen or sulphur, and thereafter when R-^ is hydrogen, optionally converting 14; or

ii) for compounds of formula (I) wherein 4 represents a moiety (a) and wherein A represents >C=X wherein X is 0 or S, and Rg and Rg together represent a linking chain -Ag-Ag- as defined above in relatin to formula (I) , reacting a compound of formula (V) :

wherein -^, A₂', A3', R-^, R₂ and -^ are as hereinbefore defined, with an activated form of a compound of formula (VI) :

R₁₆NHCOR₁₅ (VI)

wherein R-^g and R-^g together represent a linking chain of formula -Ag-Ag-;

SUBSTITUTE SHEET iii) for compounds of formula (I) wherein A₄ represents a moiety (a) and wherein A represents a bond and Rg and Rg together with the nitrogen to which they are attached form an unsaturated heterocyclic ring having 5 to 7 ring atoms, which ring atoms comprise up to 2 further nitrogen atoms and a carbon atom, the carbon atom being substituted with either an oxo group or a thioxo group, the remaining ring atoms being substituted or unsubstituted, by reacting a compound of the abovedefined formula (V) with an activated form of a compound of formula (VIA) :

Rg^HRg¹ (VIA)

wherein Rg 1 and Rg 7 together with the nitrogen to which they are attached form the said heterocyclic ring;

(iv) for compounds of formula (I) wherein R4 represents a moiety of formula (a) in which A is >C=X and X is NR₇, either:

a) for compounds wherein Rg is other than hydrogen and R₇ is CN or SO2NH2, by reacting a compound of formula (VII)

wherein R-^, R₂, R4, Rg and Y-^ are as defined in relation to

-1 formula (I) and A-^', A₂', A3' and R3 are as defined in relation to formula (II) , with phosgene (COCI2) and either cyanamide (for compounds wherein R₇ is CN) or sulphamide (for compounds wherein R₇ is S0₂NH₂); or

SUBSTITUTE SHEET b) for compounds wherein Rg and Rg together are C2-4 polymethylene and R₇ is CN, by reacting dimethyl N-cyanodithioiminocarbonate with a compound of formula (VIII) :

wherein q is 2, 3 or 4 and the remaining variables are as hereinbefore defined; or

v) for compounds of formula (I) wherein A4 represents a moiety of formula (b) , either:

a) for compounds wherein T-^ in moiety (b) represents >C-OH, by deprotecting a compound of formula (IX) :

wherein R-^, R2, R4 and Y-^ are as defined in relation to formula (I), A-^', A2', A3' and R3¹ are as defined in relation to formula (II) , T-^¹ represents >C-0T₄ wherein T₄ is a hydroxyl protecting group and T2 together with CT-,¹ represents an optionally substituted aryl group; or

SUBSTITUTE SHEET b) for compounds wherein T-^ in moiety (b) represents N(0)_n, by oxidising a compound of formula (X):

wherein R-_j_, R , R3 , R4, A-^, A₂', A3' and Y-_j_ are as defined above and T₂ together with C-N represents an optionally substituted or N-heteroaryl group; or

vi) for compounds of formula (I) wherein A₄ represents a moiety of formula (c) , by reacting a compound of the abovedefined formula (V) , with a compound of formula (XI) :

wherein L-^, L2, L3, , Rχ2 ^anci P ^{are as} defined in relation to moiety (c) of formula (I) ;and thereafter if required, carrying out one or more of the following optional steps:

SUBSTITUTE SHEET (a) converting A-^' to A-^ and/or converting A2' to A2 and/or converting A3' to A3;

(b) converting a compound of formula (I) into a further compound of formula (I) ;

5 (c) forming a pharmaceutically acceptable salt of the compound of formula (I) ;

(d) forming a pharmaceutically acceptable solvate of the compound of formula (I) or a pharmaceutically acceptable salt thereof. 10

9. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

1510. A method of treatment of respiratory tract disorders or hypertension in mammals including man, which comprises administering to the suffering mammal an effective, non-toxic amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

20

11. A compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of respiratory tract disorders or hypertension.

2512. The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of respiratory tract disorders or hypertension in mannals.

SUBSTITUTE SHEET