PHARMACOLOGICALLY ACTIVE BENZOPYRANES

Abstract: Compounds of formula (I) and pharmaceutically accetable salts thereof: wherein: Y is N or (when R₃ is hydroxy, C₁₋₆ alkoxy or C₁₋₇ acyloxy) CH; one of R₁ and R₂ is hydrogen or C₁₋₄ alkyl and the other is C₁₋₄ alkyl or R₁ and R₂ together are C₂₋₅-polymethylene; R₃ is hydrogen, hydroxy, C₁₋₆ alkoxy or C₁₋₇ acyloxy; R₄ is a C₃₋₈ cycloalkyl group or a C₁₋₆ alkyl group optional­ ly substituted by a group R₇ which is hydroxy, C₁₋₆ alkoxy, amino optionally substituted by one or two C₁₋₆ alkyl groups; C₁₋₇ alkanoylamino, C₃₋₈ cycloalkyloxy, C₃₋₈ cycloalkylamino, or 1,3-dioxo-2-isoindoline; when Y is N, R₅ is hydrogen, C₁₋₆ alkyl optionally substi­ tuted by halogen, hydroxy, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, carboxy or amino optionally substituted by one or two indepen­ dent C₁₋₆ alkyl groups, or C₂₋₆ alkenyl, amino optionally sub­ stituted by a C₁₋₆ alkyl, C₃₋₈ cycloalkyl or C₁₋₆ alkenyl group or by a C₁₋₆ alkanoyl group optionally substituted by up to three halo atoms, by a phenyl group optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy or halogen, or aryl or heteroaryl, either being optionally substituted by one or more groups or atoms selected from the class of C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxy, halogen tri-­ fluoromethyl, nitro, cyano, C₁₋₁₂ carboxylic acyl, or amino or aminocarbonyl optionally substituted by one or two C₁₋₆ alkyl groups and R₆ is hydrogen or C₁₋₆ alkyl, or R₅ and R₆ 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, O, S or NR wherein R is hydrogen, C₁₋₉ alkyl, C₂₋₇ alkanoyl, phenyl C₁₋₄-alkyl, naph­ thylcarbonyl, phenylcarbonyl or benzyl-carbonyl optionally substituted in the phenyl or naphthyl ring by one or two of C₁₋₆ alkyl, C₁₋₆ alkoxy or halogen; mono- or bi-cyclic- heteroaryl­ carbonyl; when Y is CH, R₅ is NR₈R₉ wherein R₈ and R₉ are indepen­ dently C₁₋₆ alkyl, R₈ is hydrogen and R₉ is C₁₋₆ alkyl or R₈ and R₉ together are C₄₋₅ polymethylene; or R₆ and R₈ together are -(CH₂) p - wherein p is 2 or 3, and R₉ is hydrogen or C₁₋₆ alkyl; or R₅ is CH₂R₁₀ wherein R₁₀ is hydrogen or C₁₋₅ alkyl; or R₆ and R₁₀ are -(CH₂) q - wherein q is 2 or 3;

Description: The present invention relates to novel benzopyrans having pharmacological activity, to a process and intermediates for preparing them, to pharmaceutical compositions containing them, and to their use in the treatment of mammals. European Patent Publications 76075, 93535, 95316, 107423, 120427, 126311, 126350, 126367 and 138134 disclose classes of compounds that are described as having blood pressure lowering activity or anti-hypertensive activity. A class of compounds has now been discovered which are 4-substituted benzopyrans substituted in the 6-position by an alkyl group. In addition, such benzopyrans have been found to have blood pressure lowering activity, useful in the treatment of hypertension. In addition, these compounds are believed to be K⁺ channel activators which indicates that they are of potential use in the treatment of disorders associated with smooth muscle contraction of the gastro-intestinal tract, respiratory system, uterus or urinary tract. Such disorders include irritable bowel syndrome and diverticular disease, reversible airways obstruction and asthma; premature labour; and incontinence. They are alos 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) or, when the compound of formula (I) contains a salifiable group, a pharmaceutically acceptable salt thereof: wherein: Y is N or (when R₃ is hydroxy, C₁₋₆ alkoxy or C₁₋₇ acyloxy) CH; One of R₁ and R₂ is hydrogen or C₁₋₄ alkyl and the other is C₁₋₄ alkyl or R₁ and R₂ together are C₂₋₅-polymethyene; R₃ is hydrogen, hydroxy, C₁₋₆ alkoxy or C₁₋₇ acyloxy; R₄ is a C₃₋₈ cycloalkyl group or a C₁₋₆ alkyl group optionally susbtituted by a group R₇ which is amino; When Y is N, R₅ is hydrogen, C₁₋₆ alkyl optionally substituted by halogen, hydroxy, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, carboxy or amino optionally substituted by one or two independent C₁₋₆ alkyl groups, or C₂₋₆ alkenyl, amino optionally substituted by a C₁₋₆ alkyl, C₃₋₈ cycloalkyl or C₁₋₆ alkenyl group or by a C₁₋₆ alkanoyl group optionally substituted by up to three halo atoms, by a phenyl group optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy or halogen, or aryl or heteroaryl, either being optionally substituted by one or more groups or atoms selected from the class of C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, C₁₋₁₂ carboxylic acyl, or amino or aminocarbonyl optionally substituted by one or two C₁₋₆ alkyl groups and R₆ is hydrogen or C₁₋₆ aklyl, or R₅ and R₆ 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, O, S or NR wherein R is hydrogen, C₁₋₉ alkyl, C₂₋₇ alkanoyl, phenyl C₁₋₄-alkyl, naphthylcarbonyl, phenylcarbonyl or benzyl-carbonyl optionally substituted in the phenyl or naphthyl ring by one or two of C₁₋₆ alkyl, C₁₋₆ alkoxy or halogen; mono- or bi-cyclic- heteroarylcarbonyl; When Y is CH, R₅ is NR₈R₉ wherein R₈ and R₉ are independently C₁₋₆ alkyl, R₈ is hydrogen and R₉ is C₁₋₆ alkyl or R₈ and R₉ together are C₄₋₅ polymethylene; or R₆ and R₈ together are -(CH₂) p - wherein p is 2 or 3, and R₉ is hydrogen or C₁₋₆ alkyl; or R₅ is CH₂R₁₀ wherein R₁₀ is hydrogen or C₁₋₅ alkyl; or R₆ and R₁₀ are -(CH₂) q - wherein q is 2 or 3; X is oxygen or sulphur; or R₅, R₆, X and Y (when N) together are tetrahydroisoquinolinone or tetrahydroisoquinolinthione, optionally substituted in the phenyl ring as defined for R above; the nitrogen-containing group in the 4-position being trans to the R₃ group when R₃ is hydroxy, C₁₋₆ alkoxy or C₁₋₇ acyloxy. Y is preferably N. Preferably, R₁ and R₂ are both C₁₋₄ alkyl, in particular both methyl. When R₃ is C₁₋₆ alkoxy, preferred examples of R₃ include methoxy and ethoxy, of which methoxy is more preferred. When R₃ is C₁₋₇ acyloxy a preferred class of R₃ is unsubstituted carboxylic acyloxy, such as unsubstituted aliphatic acyloxy. However, it is more preferred that R₃ is hydroxy. Examples of R₄ include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methyl, ethyl, n - and iso -propyl, n -, iso -, sec - and tert -butyl, optionally substituted by R₄ is preferably C₅₋₇ cycloalkyl or C₁₋₄ alkyl. When Y is N: Examples of R₅, when C₁₋₆ alkyl, include methyl, ethyl and n - and iso -propyl. Preferably such R₅ is methyl. A sub-grop of R₅, when C₁₋₆ alkyl substituted by halogen is C₁₋₆ alkyl substituted by chloro or bromo. Examples thereof include methyl or ethyl terminally substituted by chloro or bromo. Examples of R₅, when C₁₋₆ alkyl substituted by hydroxy, include methyl or ethyl terminally substituted by hydroxy. A sub-group of R₅, when C₁₋₆ alkyl substituted by alkoxy is C₁₋₆ alkyl substituted by methoxy or ethoxy. Examples thereof include methyl or ethyl terminally substituted by methoxy or ethoxy. A sub-group of R₅, when C₁₋₆ alkyl substituted by C₁₋₆ alkoxycarbonyl is C₁₋₆ alkyl substituted by methoxycarbonyl or ethoxycarbonyl. Examples thereof include methyl or ethyl terminally substituted by methoxycarbonyl or ethoxycarbonyl. Examples of R₅, when C₁₋₆ alkyl substituted by carboxy include methyl or ethyl terminally substituted by carboxy. Examples of R₅ when alkyl substituted by amino optionally substituted by one or two independent C₁₋₆ alkyl groups include a group (Ch₂) r NR a R b where r is 1 to 6, and R a and R b are each independently hydrogen or C₁₋₆ alkyl. Examples of r include 1 and 2, in particular 1. Preferably R a and R b are each independently selected from hydrogen and methyl. Examples of R₅, when C₂₋₆ alkenyl include vinyl, prop-1-enyl, prop-2-enyl, 1-methylvinyl, but-1-enyl, but-2-enyl, but-3-enyl, 1-methylenepropyl, or 1-methylprop-2-enyl, in both their E and Z forms where stereoisomerism exists. Examples of R₅ when amino optionally substituted as hereinbefore defined include amino optionally substituted by a C₁₋₄ alkyl group as described for R₇¹, an allyl or thrichloroacetyl group or by 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. R₅ when aryl is phenyl or naphthyl, of which phenyl is preferred. R₅ heteroaryl or heteroaryl in a Z moiety when NR, 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 contains one, two or three heteroatoms which are selected from 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, pyrryl, oxazolyl, thiazolyl, imidazolyl and thiadiazolyl, and pyridyl, pyridazyl, pyrimidyl, pyrazyl and triazyl. Preferred examples of such groups include furanyl, thienyl, pyrryl and pyridyl, in particular 2- and 3-furyl, 2- and 3-pyrryl, 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 benzofuranyl, benzothienyl, indolyl and indazolyl, quinolyl and isoquinolyl, and quinazonyl. Preferred examples of such groups include 2- and 3-benzofuryl, 2- and 3-benzothienyl, and 2- and 3-indolyl, and 2- and 3-quinolyl. Preferably, the number of groups or atoms for optional substitution of aryl or heteroaryl is one, two, three or four. Preferred examples of the groups or atoms for optional substitution of aryl or heteroaryl include methyl, methoxy, hydroxy, bromo, chloro, fluoro, nitro or cyano. A sub-group of R₅ 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 C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen, (such as chloro, bromo or, in particular, fluoro), trifluoromethyl, nitro or cyano. A preferred subgroup 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. R₅ and R₆, when together are -CH₂-(CH₂) n -Z-(CH₂) m - as defined the resulting radical substituting the benzopyran in the 4-position is preferably either pyrrolidonyl or piperidonyl. when Z is other than CH₂, 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 -, iso -, sec - and tert - butyl, benzyl, phenylcarbonyl or benzylcarbonyl optionally substituted in the phenyl ring by methyl, methoxy, chloro or bromo; furylcarbonyl, thienylcarbonyl, pyrrolylcarbonyl or indolylcarbonyl. Preferably R is hydrogen, methyl, n -butyl, acetyl, benzyl, benzylcarbonyl, phenylcarbonyl or furylcarbonyl. Most preferably R is methyl. Preferred examples of R₅ and R₆ are R₅ methyl and R₆ hydrogen and R₅ and R₆ together are C₃ or C₄ polymethylene. When Y is CH, R₆ is preferably hydrogen and R₅ is NR₈R₉. Examples of R₈ and R₉, include hydrogen (for R₈), methyl, ethyl, n - and iso -propyl, and n -, iso -, sec - and t -butyl, C₄ or C₅ polymethylene or R₈ together with R₆ is -(CH₂)₂- or -(CH₂)₃-, and R₉ is hydrogen or an alkyl group as described above. Preferably R₈ and R₉ are each methyl or R₆CHCXNR₈R₉ forms a pyrrolidone or piperidone ring and R₉ is methyl. Preferably, X is oxygen. Examples of a pharmaceutically acceptable salt of a compound of formula (I), when the compound contains a salifiable group which is an optionally substituted amino group, include acid addition salts such as the hydrochloride and hydrobromide salts. Such a salifiable group may be within an R₄ or R₅ group. A carboxy group within R₅ may also be salified to form metal salts, such as alkali metal salts, or optionally substituted ammonium salts. The compounds of formula (I) may also exist as hydrates and these are included wherever a compound of formula (I) or a salt thereof is herein referred to. The compounds of formula (I), 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, when the compound of formula (I) contains a salifiable group, a pharmaceutically acceptable salt thereof, which comprises; i) (When Y is N) acylating a compound of formula (II): wherein R₄′ is R₄ or a group convertible thereto; R₁ R₂ and R₃ are as hereinbefore defined, and R₆¹ is hydrogen or C₁₋₆ alkyl, the R₆¹NH group being trans to the R₃ group, a) with an acylating agent of formula (III): R₁₁-CO-L₁ (III) wherein L₁ is a leaving group, and R₁₁ is hydrogen, C₁₋₆ alkyl optionally substituted by halogen, hydroxy, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, carboxy or amino optionally substituted as hereinbefore defined for R₅, C₂₋₆ alkenyl or optionally substituted aryl or heteroaryl as hereinbefore defined for R₅, or a group convertible to R₅ as hereinbefore defined, and thereafter, when R₆ is hydrogen and R₁₁ is Q(CH₂) z -, where z is 3 or 4; and Q is a leaving group, cyclising the resultant compound; b) with a compound of formula (IV) X=C=N.R₁₂ (IV) wherein R₁₂ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆ alkanoyl optionally substituted by up to three halo atoms, or phenyl optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy or halogen; and X is oxygen or sulphur, and thereafter when R₁₂ is hydrogen, optionally converting R₁₂; or ii) where, in the resultant compound of formula (I), Y is N and R₅ and R₆ are joined together, or Y is CH, reacting a compound of formula (V): wherein R₄′, R₁ and R₂ are as hereinbefore defined, with a compound of formula (VI): R₁₄YHCOR₁₃ (VI) or an anion thereof (when Y is CH); wherein (when Y is N), R₁₃ and R₁₄ together are -CH₂-(CH₂) n -Z-(CH₂ m - or R₁₄YHCOR₁₃ is tetrahydroisoquinolinone; or (when Y is CH) R₁₃ is NR₈′R₉ or CHR₁₀CO₂R₁₅ wherein R₁₅ is C₁₋₆ alkyl or benzyl, R₈′ is R₈ or an amino protecting group and the remaining variables are as hereinbefore defined; and thereafter, if necessary, converting R₁₃ to R₇, converting R₈′ to R₈; optionally converting R₃ in the resulting compound into another R₃; converting R₄′ to R₄ and optionally thiating the R₆-Y-CO-R₅ group in the resulting compound to give a compound wherein X is sulphur; and when the resulting compound of formula (I) contains a salifiable group, optionally forming 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 L₁ is a group that is displaceable by a primary or secondary amino nucleophile. Examples of such a group include C₁₋₄ alkanoyloxy, and halogen, such as chloro and bromo. When the leaving group L₁ 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 carboxylic acid and an acid halide, although this is less preferred than using the halide itself. In process variant i) a), when R₅ in the desired compound of formula (I) is an R₅ optionally substituted amino-substituted alkyl group as hereinbefore defined, it is preferred that R₁₁ is a group convertible to the R₅ substituted alkyl group as hereinbefore defined, in particular that it is C₁₋₆ alkyl substituted by halo, especially bromo. The R₁₁ halo substituent in the resultant compound of process variant i) a) may be converted to an R₅ substituent which is amino optionally substituted as hereinbefore defined by a conventional amination reaction with ammonia or a corresponding alkyl- or dialkylamine. Less favourably R₁₁ may be C₁₋₆ alkyl substituted by protected amino, protected C₁₋₆ alkylamino or amino substituted by two independant C₁₋₆ alkyl groups, it being necessary to protect the R₁₁ 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 R₃ in a compound of formula (II) 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 R₆¹YH- is acylated, for example, by using a C₂₋₉ acyloxy group as the leaving group L₁, 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 C₁₋₇ 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. When R₉ is Q (CH₂) z where the variables are as hereinbefore defined, the leaving group Q 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 R₁₁ is Q (CH₂) z where the variables are as hereinbefore defined is preferably carried out in an inert solvent such as dimethylformamide. In process variant i) b), when R₁₂ in a compound of formula (IV) is C₁₋₆ alkyl, C₁₋₆ 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 methylene chloride, at below room temperature, in particular below 10°C. When R₁₂ is hydrogen, the reaction between the compounds of formula (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 hydrochloric acid. A slightly elevated temperature such as 50 to 90°C is apt. In the process variant ii) when Y is N, reaction of a compound of formula (V) with a compound of formula (VI), it is particularly 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 sodium hydride. In the process variant ii) when Y is CH, the reaction is preferably carried out in a solvent such as terahydrofuran at a temperature of -70°C to reflux, depending on the anion of the compound of formula (VI). The anion is generated by use of a base, such as lithium diisopropylamide. An intermediate compound wherein R₁₃ is CHR₁₀CO₂R₁₅ may be converted to a compound of formula (I) wherein R₇ is CH₂R₁₀, by deesterification followed by decarboxylation. Deesterification may be effected conventionally, the most appropriate method depending to some extent on the nature of the group R₁₄. However, basic reaction conditions will generally be applicable. The process conditions described hereinafter for the decarboxylation in the presence of base are in general suitable for this deesterification. When R₁₄ is, for example, a tert -butyl group, deesterification may alos be affected conventionally in the presence of acid such as trifluoroacetic acid or aqueous hydrochloric acid. Reaction may be effected at ambient temperature or a slightly higher temperature. When R₁₄ is for example a benzyl group, deesterification may also be effected conventionally by hydrogenolysis, for example by transition-metal catalysed hydrogenation, such as that using palladium/charcoal. The decarboxylation is conveniently effected by treatment with a moderately strong base optionally in an aqueous reaction medium. Examples of bases for the reaction include inorganic bases such as sodium hydroxide. Examples of reaction media include water, usually in admixture with a water-miscible solvent such that the compound is soluble therein. Examples include aqueous alcohols such as aqueous ethanol and aqueous polyethers such as aqueous dioxan. Reaction is conveniently effected at a moderately elevated temperature, such as 50 to 150°C, conveniently at the boiling point of the reaction medium. Alternatively the decarboxylation may be effected by heating to a non-extreme temperature, for example 60 to 150°C in an inert solvent, such as benzene, toluene or xylene, for example at solvent boiling point. Spontaneous decarboxylation may occur under the reaction conditions for the deesterification. Even where this is not the case, it is convenient to decarboxylate the CHR₁₀CO₂H compound in situ without isolation. It is especially convenient to carry out the conversion CHR₁₀CO₂R₁₂ to CH₂R₁₀ as a single-step one-pot process, by treatment with a moderately strong base optionally in an aqueous reaction medium. Suitable conditions are as hereinbefore described for decarboxylation. The reaction of the compounds of formulae (II) with (III) or (IV) results in a compound of formula (I) wherein R₃ is hydroxy, C₁₋₆ alkoxy or C₁₋₇ acyloxy, whereas the reaction of the compounds of formulae (V) and (VI) 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 R₃ 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 potassium hydroxide, or it may be acylated using a carboxylic acid chloride or anhydride in a non-hydroxylic solvent in the presence of antacid acceptor. Alternatively, when R₃ is C₁₋₇ acyloxy or C₁₋₆ alkoxy, it may be converted into hydroxy by conventional hydrolysis with, for example, dilute mineral acid. Suitable conversions of R₄′/R₄ are conventional. It is usually preferred, however, that such conversions are carried out at an earlier stage. R₄′ may be cyano which may be converted to R₄ when a substituted methyl group, by conventional methods as described in the Examples hereinafter, for example, reduction to give an aminomethyl group. The optional thiation of the R₆-Y-CO-R₅ group in a compound of formula (I) to give another compound of formula I, wherein X is sulphur, is, preferably, carried out with conventional thiation agents, such as hydrogen sulphide, phosporous pentasulphide and Lawesson's reagent (p-methoxyphenylthiophosphine sulphide dimer). The use of hydrogen sulphide and phosphorous pentalsulphide 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, preferably, acid catalysed by, for example, hydrogen chloride in a polar solvent, such as acetic acid for 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 optional formation of a pharmaceutically acceptable salt, when the resulting compound of formula (I) contains a salifiable group, may be carried out conventionally. A compound of formula (II) wherein R₃ is hydroxy, C₁₋₆ alkoxy or C₁₋₇ acyloxy may be prepared by reacting a compound of formula (V), as hereinbefore defined, with a compound of formula (VII): R₆¹NH₂ (VIII) wherein R₆¹ is as defined hereinbefore; and optionally converting R₃ hydroxyl in the resulting compound of formula (II) into R₃₀ when C₁₋₆ alkoxy or C₁₋₇ acyloxy. The reaction is normally carried out in a solvent, such as a C₁₋₄ 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 removed from the reaction mixture by removal of the solvent, for example, by evaporation under reduced pressure. Any epoxide impurity may be removed conventionally, for example by chromatography. The optional conversion of the hydroxy group for R₃ in the resulting compound of formula (II) into a C₁₋₆ alkoxy or C₁₋₇ 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 (II) wherein R₃ is hydrogen may be prepared by known methods, for example as described in Khim. Geterot. Soed 5(3), 434, 1969. A compound of formula (V) may be prepared by reacting a compound of formula (VIII): wherein R₁ and R₂ are as hereinbefore defined, the bromine atom being trans to the hydroxy group, with a base, such as potassium hydroxide, in a solvent, such as ether or aqueous dioxan. A compound of formula (VIII) may be prepared by reacting a compound of formula (IX): wherein R₁ and R₂ are as hereinbefore defined, with N-bromosuccinimide in a solvent, such as aqueous dimethyl sulphoxide. A compound of formula (IX) may be prepared in accordance with analogous processes to those described in the aforementioned European Patent publications, i.e. by the process depicted below: (a) Reflux; acetone; K₂CO₃/KI; or phase transfer catalytic method with optional sonification; (b) Heat in o-dichlorobenzene or N,N-diethylaniline; (c) N-bromosuccinimide/dimethylsulphoxide/water; 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. It is preferred that the compounds of formula (I) are isolated in pharmaceutically acceptable form. The intermediates of formulae (II) represent part of the present invention. The intermediates of formulae (III), (IV), (V), (VI), (VII), (VIII) and (IX) are known or may be prepared in accordance with an appropriate known process. As mentioned previously, the compounds of formula (I) have been found to have blood-pressure lowering activity. They are therefore useful in the treatment of hypertension. They are also believed to be of potential use in the treatment of other disorders hereinbefore referred to. 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. In particular, the present invention provides an anti-hypertensive pharmaceutical composition which comprises an anti-hypertensive effective amount of 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 parenteral administration for patients suffering from heart failure. Other alternative modes of administration include sublingual or transdermal administration. A composition may be in the form of spray, aerosol or other conventional method of inhalation, for treating respiratory tract disorders. The compositions may be in the form of tablets, capsules, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations, such as oral or sterile parental 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, 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 cellulose; 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 ther 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, gelating, 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, 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. The compositions may contain from 0.1% to 99% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration. The present invention further provides a method of prophylaxis or treatment of hypertension in mammals including man, which comprises administering to the suffering mammal an anti-hypertensive 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 hypertension being treated and the weight of teh sufferer. However, a unit dose form of a composition of the invention may contain from 1 to 100 mg of a compound of the invention and more usually from 1 to 50 mg, for example 1 to 25 mg such as 1, 2, 5, 10, 15 or 20mg. Such compositions may be administered from 1 to 6 times a day, more usually from 1 to 4 times a day, in a manner such that the daily dose is from 1 to 200 mg for a 70 kg human adult and more particularly from 1 to 100 mg. 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 or prophylaxis of hypertension. The following descriptions relate to the preparation of intermediates and the following example relates to the preparation of a compound of formula (I). All temperatures therein are in °C. Description 1 2,2-Dimethyl-6-t-butyl-2H-1-benzopyran (D1) 4-t-Butylphenol (10g) and sodium hydroxide (3.99g) were added to a stirred mixture of water (60ml) and dichloromethane (60ml) followed by benzyltrimethyl-ammonium hydroxide (40% solution in methanol, 150ml) and 3-chloro-3-methyl-butyne (13.65g). After stirring at ambient temperature for 11 days, the layers were separated and the aqueous layer extracted with chloroform. The combined organic extracts were concentrated in vacuo and the residue dissolved in diethyl ether. The solution was washed with water, 10% sodium hydroxide solution, then brine, and dried over magnesium sulphate. Removal of drying agent and solvent gave 3-methyl-3-(4-t-butylphenoxy)-but-l-yne as a yellow oil (13.35g). A solution of this product in ortho-dichlorobenzene (27ml) was heated under reflux, under nitrogen, for 12 hours. Solvent was removed in vacuo , and the residue chromatographed on silica gel eluted with ethyl acetate: 60-80 petroleum ether (1:19) to give the desired chromene as a brown oil (3.4g) having: ¹H nmr (CDCl₃) 1.27 (s, 9H) 1.40 (s, 6H) 5.50 (d, J=9Hz, 1H) 6.25 (d, J=9Hz, 1H) 6.60 (d, J=8Hz, 1H) 7.10 (m, 2H) Description 2 Trans-6-(t-butyl)-3,4-dihydro-2,2-dimethyl-3-bromo-4-hydroxy-2H-1-benzopyran (D2) A solution of 2,2-dimethyl-6-t-butyl-2H-1-benzopyran (3.4g) in dimethyl sulphoxide (35ml) and water (3ml) was treated with N-bromosuccinimide (3.1g) and the mixture stirred vigorously for 1 hour. 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 (0.88g) having M.pt. 122-3°C ¹H nmr (CDCl₃) 1.30 (s, 9H) 1.40 (s, 3H) 1.58 (s, 3H) 2.44 (d, J=6Hz, 1H) 4.14 (d, J=10Hz, 1H) 4.90 (dd, J=10,6Hz, 1H) 6.73 (d, J=9Hz, 1H) 7.25 (dd, J=9,3Hz, 1H) 7.48 (d, J=3Hz, 1H) Mass spectrum: Found M⁺ 312.0723; C₁₅H₂₁O₂Br requires M⁺ 312.0725 Description 3 6-t-Butyl-3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (D3) A mixture of trans -6-t-butyl-3,4-dihydro-2,2-dimehtyl-3-bromo-4-hydroxy-2H-1-benzopyran (0.88g) and potassium hydroxide pellets (0.88g) in dry diethyl ether (88ml) was stirred vigorously for 4 days. Filtration and removal of solvent in vacuo gave the desired epoxide as a brown oil (0.52g) having ¹H nmr (CDCl₃) 1.20 (s, 3H) 1.30 (s, 9H) 1.55 (s, 3H) 3.40 (d, J=4Hz, 1H) 3.80 (d, J=4Hz, 1H) 6.60 (d, J=9Hz, 1H) 7.13 (dd, J=9,3Hz, 1H) 7.20 (d, J=3Hz, 1H) Mass spectrum: Found M⁺ 232.1463; C₁₅H₂₀O₂ requires M⁺ 232.1465. Description 4 2,2-Dimethyl-6-i-propyl-2H-1-benzopyran (D4) The title compound (2.2g) was prepared from 4-i-propyl phenol (9.07g) as in Description 1. ¹H nmr (CDCl₃) 1.20 (d, J=7Hz; 6H) 1.40 (s, 6H) 2.80 (septet, 1H) 5.45 (d, J=10Hz, 1H) 6.20 (d, J=10Hz, 1H) 6.70-7.30 (m, 3H) Description 5 Trans-6-(i-propyl)-3,4-dihydro-2,2-dimethyl-3-bromo-4-hydroxy-2H-1-benzopyran (D5) 2,2-Dimethyl-6-i-propyl-2H-1-benzopyran (2.2g) was reacted as in Description 2 to give the title compound (2.7g) as an oil having ¹H nmr (CDCl₃) 1.20 (d, J=7Hz, 6H) 1.37 (s, 3H) 1.55 (s, 3H) 2.80 (septet, J=7Hz, 1H) 4.03 (d, J=9Hz, 1H) 4.80 (m, 1H) 6.55 (d, J=8Hz, 1H) 6.80-7.20 (m, 2H) Mass spectrum: Found M⁺ 298.0563, 300.0553; C₁₄H₁₉O₂Br requires 298.0568, 300.0548 Description 6 Trans-6-(i-propyl)-3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (D6) Trans -6-(i-propyl)-3,4-dihydro-2,2-dimethyl-3-bromo-4-hydroxy-2H-1-benzopyran (2.7g) was reacted as in Description 3 to give the tittle compound (1.89g) as a pale brown oil having ¹H nmr (CDCl₃) 1.20 (d, J=7Hz, 6H) 1.20 (s, 3H) 1.50 (s, 3H) 2.80 (septet, J=7Hz, 1H) 3.40 (d, J=4Hz, 1H) 3.80 (d, J=4Hz, 1H) 6.60 (d; J=8Hz, 1H) 6.80-7.30 (m, 2H) Mass spectrum: Found M⁺ 218.1325; C₁₄H₁₈O₂ requires 218.1307 Description 7 trans-4-Amino-3,4-dihydro-2,2,6-trimethyl-2H-1-benzopyran-3-ol (D7) A solution of 3,4-epoxy-3,4-dihydro-2,2,6-trimethyl-2H-1-benzopyran (7g, see J.Med.Chem. 26 , 1582, 1983) in concentrated ammonia solution (90 ml) and ethanol (160 ml) was stirred at room temperature for 5 days. Evaporation of solvent gave the title compound (7g) as a crude solid which was used directly, without purification. NMR (CDCl₃) δ 1.15 (s, 3H) 1.38 (s, 3H) 2.25 (s, 3H) 3.23 (d, J=9Hz, 1H) 3.57 (d, J=9Hz, 1H) 6.68 (d, J=8Hz, 1H) 6.87 (q, J=8,2Hz, 1H) 7.02 (narrow m, 1H) Description 8 trans-4-Amino-3,4-dihydro-2,2-dimethyl-6-isopropyl-2H-1-benzopyran-3-ol (D8) The epoxide of description 6 (2.5g) was stirred in ethanol (125 ml) and 0.88 ammonia solution (120 ml) at room temperature for 20 h. The solution was evaporated and partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over anhydrous magnesium sulphate, filtered and evaporated to gibe the title compound (1.49g) which was used directly. NMR (CDCl₃) δ 1.17 (s, 3H) 1.20 (d, J=6Hz, 6H) 2.43 (m, 3H, exchangeable with D₂O) overlapped with 2.80 (m, J=6Hz, 5 lines visible, 1H) 3.28 (d, J=9Hz, 1H) 3.61 (d, J=9Hz, 1H) 6.59 (d, J=8Hz, 1H) 6.92 (q, J=8Hz, 1H) 7.05 (narrow m, 1H) Description 9 6-Ethyl-2,2-dimethyl-2H-1-benzopyran (D9) To 4-ethylphenol (8.15g) and sodium hydroxide pellets (3.99g) stirred in dichloromethane (60 ml) and water (60 ml) was added benzyltrimethylammonium hydroxide (40% solution in methanol, 150 ml) and 3-chloro-3-methyl-butyne (13.65g). The reaction mixture was stirred at room temperature for 2 weeks. The layers were separated, and the aqueous layer extracted with chloroform. The combined organic extracts were evaporated, and the residue taken up in ether and washed with 5N hydrochloric acid, 10% aqueous sodium hydroxide, water, and brine and dried over anhydrous magnesium sulphate. Removal of drying agent and solvent gave en oil (9.9g) which was refluxed in NN-diethylaniline (50 ml) under nitrogen for 2.75 h. The mixture was cooled, and poured into cooled 5N hydrochloric acid (100 ml) and the solution extracted with ether. The organic phase was washed with 5N hydrochloric acid and brine and dried over anhydrous magnesium sulphate. Removal of drying agent and solvent left a brown oil (9.0g) which was chromatographed on silica gel and eluted with 5% ethyl acetate-pentane to give the title benzopyran (2.36g) as an oil. Mass spectrum (Ei) M⁺ at m/z 188.1192. C₁₃H₁₆O requires 188.1201. Description 10 trans-3-Bromo-6-ethyl-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-ol (D10) To a solution of 6-ethyl-2,2-dimethyl-2H-1-benzopyran (2.36g) in dimethyl sulphoxide (20 ml) and water (2 ml) was added N-bromosuccimimide (2.46g) and the mixture stirred for 1.5 h. Water was added and the mixture extracted with ethyl acetate. The organic extract was washed with water, brine and dried over anhydrous magnesium sulphate. Removal of drying agent and solvent left the title promohydrin as a brown oil (3.0g). NMR (CDCl₃+D₂O) 1.22 (t, J=7Hz, 3H) 1.40 (s, 3H) 1.60 (s, 3H) 2.58 (q, J=7Hz, 2H) 4.14 (d, J=9Hz, 1H) 4.91 (d, J=9Hz, 1H) 6.72 (d, J=8Hz, 1H) 6.95-7.40 (m, 2H) Description 11 3,4-Epoxy-6-ethyl-3,4-dihydro-2H-1-benzopyran (D11) The bromohydrin of description 10 (3.0g) and potassium hydroxide pellets (3.1g) were stirred vigoroulsy in diethyl ether (500 ml) for 6 days at room temperature. Filtration and evaporation gave the title epoxide (1.91g) as a brown oil, which was used directly in example 13. Description 12 2,2-Dimethyl-6-cyclopentyl-2H-1-benzopyran (D12) 4-Cyclpentylphenol (10.0g), and sodium hydroxide pellets (3.7g) were stirred in water (60 ml) and dichloromethane (60 ml). Benzyltrimethylammonium hydroxide (75 ml, 40% solution in methanol) was added to the solution, followed by 3-chloro-3-methylbutyne (12.63g) and the reaction mixture stirred under reflux condenser, with sonication. The layers were separated, and the aqueous phase extracted with chloroform. The combined organic layers were evaporated, and the residue taken up in ether. The ether solution was washed with 10% sodium hydroxide solution, and brine and dried over anhydrous magnesium sulphate. Filtration and evaporation gave a pale brown oil (10.89g) which was refluxed in o-dichlorobenzene (22 ml) under nitrogen for 2h. Evaporation and chromatography of the resulting brown oil (9.3g) gave the title benzopyran (4.18g). NMR (CDCl₃) δ 1.42 (s, 6H) 1.47-1.86 (m, 6H) 2.03 (m, 2H) 2.90 (m, 1H) 5.57 (d, J=10Hz, 1H) 6.28 (d, J=10Hz, 1H) 6.68 (d, J=8Hz, 1H) 6.83 (d, J=2Hz, 1H) 6.97 (q, J=8,2Hz, 1H) Description 13 trans-3-Bromo-3,4-dihydro-2,2-dimethyl-6-cyclopentyl-2H-1-benzopyran-4-ol (D13) To the benzopyran of description 12 (4.08g) in dimethyl sulphoxide (40 ml) and water (4 ml) was added N-bromosuccinimide (3.49g) and the reaction mixture stirred at room temperature for 2 h. before the addition of further N-bromosuccinimide (0.35g), and an additional 0.5 h of stirring. Extraction via ethyl acetate yielded a yellow solid (5.36 g) which was usd directly to form the epoxide of description 14. Mass spectrum (EI) M⁺ at m/z 324.0727. C₁₆H₂₁O₂Br requires 324.0726. Description 14 3,4-Epoxy-3,4-dihydro-2,2-dimethyl-6-cyclopentyl-2H-1-benzopyran (D14) The bromohydrin of description 13 (5.0g) and potassium hydroxide pellets (5.0g) were vigorously stirred in ether (500 ml) at room temperature for 6 days. Filtration and evaporation gave the epoxide of this description as a pale brown oil (3.12g). NMR (CDCl₃) δ 1.24 (s, 3H) 1.56 (s, 3H) 1.52-1.86 (series of m, 6H) 2.04 (m, 2H) 2.93 (symmetrical m, 1H) 3.47 (d, J=4Hz, 1H) 3.87 (d, J=4Hz, 1H) 6.72 (d, J=8Hz, 1H) 7.09 (q, J=8,2Hz, 1H) 7.18 (d, J=2Hz, 1H) Example 1 trans-6-Methyl-2,2-dimethyl-4-(2-oxopiperidinyl)-2H-1-benzopyran-3-ol (E1) 2-Piperidone (1.0g) was added to a stirred suspension of sodium hydride (300 mg) in dry dimethylsulphoxide (20 ml) and the mixture stirred for 1 hour, under nitrogen. Then a solution of 6-methyl-3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (1.9g) in dimethylsulphoxide (10 ml) was added and the mixture stirred for 16 hours, at room temperature. 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 solvent in vacuo , and recrystallisation of the residue from ethyl acetate: 60-80° petroleum-ether (1:9) gave the title compound as colourless prisms (400 mg, 15%) having m.p. 162-4°C; ¹H n.m.r. (CDCl₃) 1.25 (s, 3H) 1.50 (s, 3H) 1.80 (m, 1H) 2.25 (s, 3H) 2.60 (t, J=8Hz, 2H) 3.00 (m, 2H) 3.60 (br s,O H ) 3.75 (d, J=10Hz, 1H) 5.85 (d, J=10Hz, 1H) 6.80 (m, 3H) Anal . Found: C 70.53%, H 8.13%, N 4.88%; C₁₇H₂₃NO₃ requires: C 70.56%, H 8.01%, N 4.84%. Example 2 trans-6-t-Butyl-2,2-dimethyl-4-(2-oxo-pyrrolidinyl)-2H-1-benzopyran-3-ol (E2) An 80% dispersion of sodium hydride in oil (0.067g) was added to a stirred solution of trans -6-t-butyl-3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (0.52g) and 2-pyrrolidinone (0.19g) in dry dimethyl sulphoxide (25ml), and the mixture stirred for 20 hours under nitrogen. 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 solvent in vacuo and recrystallisation of the residue from ethyl acetate/ 60-80 petroleum ether gave the title compound as fine white needles (0.11g) having M.pt. 227-8°C ¹H nmr (CDCl₃) 1.25 (s, 9H) 1.27 (s, 3H) 1.49 (s, 3H) 1.95-2.20 (m, 2H) 2.57 (m, 2H) 3.00-3.15 (m, 2H) 3.20-3.30 (m, 1H) 3.73 (dd, J=11,6Hz, 1H) 5.30 (d, J=11Hz, 1H) 6.75 (d, J=9Hz, 1H) 6.90 (d, J=3Hz, 1H) 7.20 (dd, J=9,3Hz, 1H) Mass spectrum: Found M⁺ 317.1992; C₁₉H₂₇NO₃ requires 317.1991 Analysis: Found C, 71.46; H, 8.43; N, 4.17; C₁₉H₂₇NO₃ requires C, 71.89; H, 8.57; N, 4.41 Example 3 trans-6-(i-Propyl)-2,2-dimethyl-4-(2-oxo-pyrrolidinyl)-2H-1-benzopyran-3-ol (E3) Trans -6-(i-propyl)-3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (1.89g) reacted as in Example 2 to give the title compound (0.31g) as fine white needles having M.pt. 167-173°C ¹H nmr (CDCl₃) 1.19 (d, J=7Hz, 6H) 1.26 (s, 3H) 1.49 (s, 3H) 2.10 (m, 2H) 2.58 (m, 2H) 2.80 (septet, J=7Hz, 1H) 2.95 (d, J=6Hz, 1H) 3.10 (m, 1H) 3.25 (m, 1H) 3.75 (dd, J=10,6Hz, 1H) 5.28 (d, J=10Hz, 1H) 6.75 (m, 2H) 7.04 (dd, J=9,3Hz, 1H) Mass spectrum: Found M⁺ 303.1843; C₁₈H₂₅NO₃ requires 303.1835 Analysis: Found C, 71.43, 71.12; H, 8.54, 8.43; N, 4.59, 4.58; C₁₈H₂₅NO₃ requires C, 71.26; H, 8.31; N, 4.62 Example 4 trans-3,4-Dihydro-2,2,6-trimethyl-4-(2-oxopyrrolidinyl)-2H-1-benzopyran-3-ol (E4) 2-Pyrrolidone (1.02g) was added to a suspension of sodium hydride (0.3g, 80% dispersion in oil) in dry dimethyl sylphoxide (20 ml) under nitrogen at room temperature, and the mixture stirred for 1 h. A solution of 3,4-epoxy-3,4-dihydro-2,2,6-trimethyl-2H-1-benzopyran in dry dimethyl sulphoxide (10 ml) was then added, and the reaction mixture stirred for an additional 16 h. Cautions addition of water and extraction via ethyl acetate gave a crude product (1.84g) which was chromatograped on silica gel and eluted with 60-80°C petroleum ether-ethyl acetate mixtures to give a foam (0.7g) which was recrystallised from 60-80°C petroleum ether-ethyl acetate (0.53g). Two further recrystallisations from ethyl acetate-pentane gave the analytical sample of the title compound mp 187-188°C. Analysis: Found C, 70.01; H, 8.10; N, 4.83. C₁₆H₂₁NO₃ requires C, 69.79; H, 7.69; N, 5.09. Example 5 trans-3,4-Dihydro-2,2,6-trimethyl-4-[N,N-dimethyl-2-acetamido]-2H-1-benzopyran (E5) A solution of lithium diisopropylamine in tetrahydrofuran (20 ml) was prepared at -20° from n-butyl lithium (6.7 ml, 1.5 M soln. in hexane) and diisopropylamine (1.4 ml) under N₂. A solution of N,N-dimethylacetamide (0.87g) in tetrahydrofuran (15 ml) was then added dropwise at -20°C and the solution stirred for 0.5 h. A solution of 3,4-epoxy-3,4-dihydro-2,2,6-trimethyl-2H-1-benzopyran (1.9g) in tetrahydrofuran (20 ml) was then added at 0°C and the mixture allowed to attain room temperature and then refluxed for 2 h. After cooling, the reaction mixture was partitioned between ethyl acetate and dil. HCl, and the organic layer washed with water, brine and then dried over anhydrous MgSO₄, filtered and evaporated, to give a white solid which was recrystallised from ethyl acetate - 60-80°C petroleum ether (0.26g) as an off-white solid m.p. 151-153°C. NMR (CDCl₃) δ 1.15 (s, 3H) 1.47 (s, 3H) 2.27 (s, 3H) 2.63 (q, J=17,10Hz, 1H) 3.04 (s, 3H) 3.08 (s, 3H) 3.15 (q, J=17,2Hz, 1H) 3.27 (t, J=10,9Hz, 1H) 3.53 (q, J=9,3Hz, 1H, collapsing to J=9Hz on addition of D₂O) 5.33 (d, J=3Hz, 1H exchangeable with D₂O) 6.73 (d, J=8Hz, 1H) 6.93 (m, 2H) Example 6 trans-4-Acetylamino-3,4-dihydro-2,2,6-trimethyl-2H-1-benzopyran-3-ol (E6) To the crude aminoalcohol of description 7 (1.0g) in dichloromethane (60 ml) and triethylamine (0.47 ml) was added acetyl chloride (0.34 ml) dropwise, with stirring at room temperature. After the reaction mixture had been stirred for an additional 3 h the organic phase was washed with water and brine before drying over anhydrous MgSO₄. Filtration and evaporation and chromatography (chromatotron 30% pentane-EtOAc-EtOAc) and recrystallisation from EtOAc gave the title compound m.p. 188-190°C. Example 7 trans-3,4-Dihydro-2,2,6-trimethyl-2-(N-methylureido)-2H-1-benzopyran-3-ol (E7) To the crude aminoalcohol of description 7 (lg) dissolved in dichloromethane (40 ml) was added methyl isocyanate (0.46 ml) during 5 min with stirring at 0°C. After an additional 2 h at 0°C, the solution was washed with water and brine and dried over anhydrous MgSO₄. Filtration and evaporation and chromatography (chromatotron CHCl₃ ― 10% MeOH - CHCl₃) gave a solid which was recrystallised from ethyl acetate - 60-80°C petroleum ether (450 mg). A further recrystallistion of a small amount gave the title compound as the 0.25 hydrate, m.p. 170-171°C. NMR (CDCl₃) δ 1.22 (s, 3H) 1.43 (s, 3H) 2.25 (s, 3H) 2.79 (s, 3H) 3.51 (d, J=9Hz, 1H) 4.74 (d, J=9Hz, 1H) 6.63 (d, J=8Hz, 1H) 6.93 (q, J=8,2Hz, 1H) 7.03 (narrow m, 1H) Example 8 trans-4-(4-Fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-6-isopropyl-2H-1-benzopyran-3-ol (E8) To the aminoalcohol of description 8 (1.45g), and triethylamine (0.94 ml) in dichloromethane (50 ml) cooled to 0°C under nitrogen, was added p-fluorobenzoyl chloride (0.8 ml). The mixture was stirred for a further 10 min at 0°C and for 16 h at room temperature, and then washed with water containing a little sodium hydroxide solution, and brine. The organic layer was dried over anhydrous magnesium sulphate, filtered and evaporated and the crude solid recrystallised from ethyl acetate - 60-80°C petroleum ether to give the compound of this example as a white solid (0.66g) of mp 235-236°C. Mass spectrum M⁺ at m/z 357.1740. C₂₁H₂₄NO₃F requires 357.1750. Example 9 trans-6-Aminomethyl-3,4-dihydro-2,2-dimethyl-4-(2-oxopyrrolidinyl)-2H-1-benzopyran-3-ol (E9) trans-6-Cyano-3,4-dihydro-2,2-dimethyl-4-(2-oxopyrrolidinyl)-2H-1-benzopyran-3-ol (5g, prepared as described in J.Med.Chem. 29 , 2194 (1986)), in ethanol (375 ml) and glacial acetic acid (75 ml) containing concentrated HCl (5 ml) was shaken in the presence of 10% Pd/C (lg) in an atmosphere of hydrogen for 4 h. The catalyst was filtered off and the solution neutralised with 10% aqueous NaOH solution, and the solution evaporated to dryness. Acid-base extraction, and drying of a dichloromethane solution of the residue, furnished, after recrystallisation from ethyl acetate-pentane, 2.03g of the required aminomethyl compound of mp 191-193°C as the hemihydrate. NMR (CD₃)₂SO δ 1.14 (s, 3H) 1.41 (s, 3H) 1.95 (m, 2H) 2.39 (m, 2H) 2.88 (m, 1H) 3.28 (m, 3H including 2H exchangeable with D₂O) 3.58 (s, 2H) 3.64 (d, J=10Hz, 1H) 4.97 (d, J=10Hz, 1H) 5.53 (m, 1H exchangeable with D₂O) 6.70 (d, J=8Hz, 1H) 6.81 (narrow m, 1H) 7.09 (q, J=8,2Hz, 1H) Example 10 trans-6-Ethyl-3,4-dihydro-2,2-dimethyl-4-(2-oxopyrrolidinyl)-2H-1-benzopyran-3-ol (E10) To a mixture of pyrrolidone (0.416g) and sodium hydride (0.146g, 80% dispersion in oil) in dimethyl sulphoxide (50 ml) was added the epoxide of description 11 (1.0g). The mixture was stirred at room temperature under nitrogen for 4 h. Cautious addition of water and extraction via ethyl acetate gave an oil which was purified on the chromatotron (20% ethyl acetate - 60-80°C petroleum ether - ethyl acetate) to give the compound of example 13 after recrystallisation from ethyl acetate - 60-80°C petroleum ether as crystals of mp 154-163°C. Mass spectrum (EI) M⁺ at m/z 289.1683. C₁₇H₂₃NO₃ requires 289.1678. Example 11 trans-3,4-Dihydro-2,2-dimethyl-4-(2-oxopyrrolidinyl)-6-cyclopentyl-2H-1-benzopyran-3-ol (E11) To the epoxide of description 14 (1.5g) dissolved in dimethyl sulphoxide (15 ml) was added pyrrolidone (0.404g) with stirring under nitrogen. Sodium hydride (0.142g, 80% dispersion in oil) was added to the mixture which was stirred for 18 h. Cautious addition of water and extraction via ethyl acetate gave the title compound (0.55g) after recrystallisation from ethyl acetate-pentane m.p. 179-184°C. Mass spectrum (EI) M⁺ at m/z 329.1993. C₂₀H₂₇NO₃ requires 329.1991. Example 12 4-Chloroacetamido-3,4-dihydro-2,2,6-trimethyl-2H-1-benzopyran (E12) To a solution of 4-amino-3,4-dihydro-2,2,6-dimethyl-2H-1-benzopyran (1.63g, described in Khim. Geterot. Soed. 5(3) , 434, 1969) in 40 ml dichloromethane at 0°C was added triethylamine (1.2 ml) followed by chloroacetyl chloride (0.96 g). The solution was stirred for 16 h then washed with saturated brine solution, separated, dried (MgSO₄) and concentrated to a cream solid. Chromatography (silica, CH₂Cl₂ eluent) provided 4-chloroacetamido-3,4-dihydro-2,2,6-trimethyl-2H-1-benzopyran (1.78 g, 78%) as a white solid. m.p. 147-148°C. NMR (CDCl₃) δ 1.3 (s, 3H) 1.4 (s, 3H) 1.75 (d.d., J=13.2, 10.7Hz, 1H) 2.25 (d.d., J=13.2, 6.6Hz, 1H) 2.3 (s, 3H) 4.15 (ABq, J=15.6Hz, 2H) 5.25 (d.d., J=10.7, 6.6Hz, 1H) 6.8 (br d, J=8Hz, 1H) 7.0 (m, 2H). PHARMACOLOGICAL DATA Antihypertensive 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. The compound of Example 1 gave a maximum fall in blood pressure of 33 ± 2% at a dose of 1.0mg/kg po. The compound of Example 10 gave a maximum fall in blood pressure of 54 ± 2% at a dose of 1.0 mg/kg po. Other compounds of the Examples, such as E2, E3 and E11 showed significant falls in blood pressure at a dose of 1.0 mg/kg po.

Claims: Claims for the following Contracting States: BE, CH, DE, FR, GB, IT, LI, LU, NL, SE 1. A compound of formula (I) or, when the compound of formula (I) contains a salifiable group, a pharmaceutically acceptable salt thereof: wherein: Y is N or (when R₃ is hydroxy, C₁₋₆ alkoxy or C₁₋₇ acyloxy) CH; one of R₁ and R₂ is hydrogen or C₁₋₄ alkyl and the other is C₁₋₄ alkyl or R₁ and R₂ together are C₂₋₅-polymethylene; R₃ is hydrogen, hydroxy, C₁₋₆ alkoxy or C₁₋₇ acyloxy; R₄ is a C₃₋₈ cycloalkyl group or C₁₋₆ alkyl group optionally substituted by a group R₇ which is, amino; when Y is N, R₅ is hydrogen, C₁₋₆ alkyl optionally substituted by halogen, hydroxy, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, carboxy or amino optionally substituted by one or two independent C₁₋₆ alkyl groups, or C₂₋₆ alkenyl, amino optionally substituted by a C₁₋₆ alkyl, C₃₋₈ cycloalkyl or C₁₋₆ alkenyl group or by a C₁₋₆ alkanoyl group optionally substituted by up to three halo atoms, by a phenyl group optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy or halogen, or R₅ is aryl or heteroaryl, either being optionally substituted by one or more groups or atoms selected from the class of C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, C₁₋₁₂ carboxylic acyl, or amino or aminocarbonyl optionally substituted by one or two C₁₋₆ alkyl groups and wherein aryl is phenyl or naphthyl and heteroaryl is monocyclic 5- or 6-membered or bicycli 9- or 10-membered, containing one, two or three heteroatoms selected from oxygen, nitrogen and sulphur; and R₆ is hydrogen or C₁₋₆ alkyl, or R₅ and R₆ 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, O, S or NR wherein R is hydrogen, C₁₋₉ alkyl, C₂₋₇ alkanoyl, phenyl C₁₋₄-alkyl, naphthylcarbonyl, phenylcarbonyl or benzyl-carbonyl optionally substituted in the phenyl or naphthyl ring by one or two of C₁₋₆ alkyl, C₁₋₆ alkoxy or halogen; mono- or bi-cyclic- heteroarylcarbonyl; When Y is CH, R₅ is NR₈R₉ wherein R₈ and R₉ are independently C₁₋₆ alkyl, R₈ is hydrogen and R₉ is C₁₋₆ alkyl or R₈ and R₉ together are C₄₋₅ polymethylene; or R₆ and R₈ together are -(CH₂) p - wherein p is 2 or 3, and R₉ is hydrogen or C₁₋₆ alkyl; or R₅ is CH₂R₁₀ wherein R₁₀ is hydrogen or C₁₋₅ alkyl; or R₆ and R₁₀ are -(CH₂) q - wherein q is 2 or 3; X is oxygen or sulphur; or R₅, R₆, X and Y (when N) together are tetrahydroisoquinolinone or tetrahydroisoquinolinthione, optionally substituted in the phenyl ring as defined for R above; the nitrogen-containing group in the 4-position being trans to the R₃ group when R₃ is hydroxy, C₁₋₆ alkoxy or C₁₋₇ acyloxy. 2. A compound according to claim 1 wherein Y is N. 3. A compound according to claim 1 or 2 wherein R₁ and R₂ are both methyl. 4. A compound according to any one of claims 1 to 3 wherein R₃ is hydroxy. 5. A compound according to any one of claims 1 to 4 wherein R₄ is C₅₋₇ cycloalkyl or C₁₋₄ alkyl. 6. A compound according to any one of claims 1 to 5 wherein X is oxygen and R₅ and R₆ together form C₃ or C₄ polymethylene. 7. trans -6-Methyl-2,2-dimethyl-4-(2-oxopiperidinyl)-2H-1-benzopyran-3-ol, trans -6-butyl-2,2-dimethyl-4-(2-oxopyrrolidinyl)-2H-1-benzopyran-3-ol, trans -6-(i-propyl)-2,2-dimethyl-4-(2-oxopyrrolidinyl)-2H-1-benzopyran-3-ol, trans -3,4-dihydro-2,2,6-trimethyl-4-(2-oxopyrrolidinyl)-2H-1-benzopyran-3-ol, trans -3,4-dihydro-2,2,6-trimethyl-4-[N,N-dimethyl-2-acetamido]-2H-1-benzopyran, trans -4-acetylamino-3,4-dihydro-2,2,6-trimethyl-2H-1-benzopyran-3-ol, trans -3,4-dihydro-2,2,6-trimethyl-2-(N-methylureido)-2H-1-benzopyran-3-ol, trans -4-(4-fluorobenzoylamin)-3,4-dihydro-2,2-dimethyl-6-isopropyl-2H-1-benzopyran-3-ol, trans -6-aminomethyl-3,4-dihydro-2,2-dimethyl-4-(2-oxopyrrolidinyl)-2H-1-benzopyran-3-ol, trans -6-ethyl-3,4-dihydro-2,2-dimethyl-4-(2-oxopyrrolidinyl)-2H-1-benzopyran-3-ol, trans -3,4-dihydro-2,2-dimethyl-4-(2-oxopyrrolidinyl)-6-cyclopentyl-2H-1-benzopyran-3-ol, or 4-chloroacetamido-3,4-dihydro-2,2,6-trimethyl-2H-1-benzopyran. 8. A process for the preparation of a compound according to claim 1, which process comprises; i) (When Y is N) acylating a compound of formula (II): wherein R₄′ is R₄ or a group convertible thereto; R₁ R₂ and R₃ are as defined in claim 1, and R₆¹ is hydrogen or C₁₋₆ alkyl, the R₆¹NH group being trans to the R₃ group, a) with an acylating agent of formula (III): R₁₁-CO-L₁ (III) wherein L₁ is a leaving group, and R₁₁ is hydrogen, C₁₋₆ alkyl optionally substituted by halogen, hydroxy, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, carboxy or amino optionally substituted as defined in claim 1 for R₅, C₂₋₆ alkenyl or optionally substituted aryl or heteroaryl as defined in claim 1 for R₅, or a group convertible to R₅ as defined in claim 1, and thereafter, when R₆ is hydrogen anti R₁₁ is Q(CH₂) z -, where z is 3 or 4; and Q is a leaving group, cyclising the resultant compound; b) with a compound of formula (IV) X=C=N.R₁₂ (IV) wherein R₁₂ is hydroyen, C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆ alkanoyl optionally substituted by up to three halo atoms, or phenyl optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy or halogen; and X is oxygen or sulphur, and thereafter when R₁₂ is hydrogen, optionally converting R₁₂; or ii) where, in the resultant compound of formula (I), Y is N and R₅ and R₆ are joined together, or Y is CH, reacting a compound of formula (V): wherein R₁ and R₂ are as defined in claim 1, with a compound of formula (VI): R₁₄YHCOR₁₃ (VI) or an anion thereof (when Y is CH); wherein (when Y is N), R₁₃ and R₁₄ together are -CH₂-(CH₂) n -Z-(CH₂) m - or R₁₄YHCOR₁₃ is tetrahydroisoquinolinone; or (when Y is CH) R₁₃ is NR₈′R₉ or CHR₁₀CO₂R₁₅ wherein R₁₅ is C₁₋₆ alkyl or benzyl, R₈′ is R₈ or an amino protecting group and the remaining variables are as defined in claim 1; and thereafter, if necessary, converting R₁₃ to R₇, converting R₈′ to R₈; optionally converting R₃ in the resulting compound into another R₃; converting R₄′ to R₄ and optionally thiating the R₆-Y-CO-R₅ group in the resulting compound to give a compound wherein X is sulphur; and when the resulting compound of formula (I) contains a salifiable group, optionally forming a pharmaceutically acceptable salt thereof. 9. An intermediate of formula (II): wherein R₁, R₂ and R₃ are as defined in claim 1, and R₆¹ is hydrogen or C₁₋₆ alkyl, the R₆¹NH group being trans to the R₃ group, wherein R₄′ is R₄, other than the compound wherein R₁ and R₂ are both methyl, R₃ is hydrogen, R₄′ is methyl and R₆¹ is hydrogen. 10. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier. 11. A compound according to any one of claims 1 to 7 for use as an active therapeutic substance. 12. A compound according to any one of claims 1 to 7 for use in the treatment of hypertension. 13. Use of a compound according to any one of claims 1 to 7 in the manufacture of a medicament for the treatment of hypertension. 14. Use of a compound according to any one of claims 1 to 7, in the manufacture of a medicament for the treatment of disorders associated with smooth muscle contraction of the gastro-intestinal tract, respiratory system, uterus or urinary tract. Claims for the following Contracting State: ES 1. A process for the preparation of compound of formula (I) or, when the compound of formula (I) contains a salifiable group, a pharmaceutically acceptable salt thereof: wherein: Y is N or (when R₃ is hydroxy, C₁₋₆ alkoxy or C₁₋₇ acyloxy) CH; one of R₁ and R₂ is hydrogen or C₁₋₄ alkyl and the other is C₁₋₄ alkyl or R₁ and R₂ together are C₂₋₅-polymethylene; R₃ is hydrogen, hydroxy, C₁₋₆ alkoxy or C₁₋₇ acyloxy; R₄ is a C₃₋₈ cycloalkyl group or C₁₋₆ alkyl group optionally substituted by a group R₇ which is amino; when Y is N, R₅ is hydrogen, C₁₋₆ alkyl optionally substituted by halogen, hydroxy, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, carboxy or amino optionally substituted by one or two independent C₁₋₆ alkyl groups, or C₂₋₆ alkenyl, amino optionally substituted by a C₁₋₆ alkyl, C₃₋₈ cycloalkyl or C₁₋₆ alkenyl group or by a C₁₋₆ alkanoyl group optionally substituted by up to three halo atoms, by a phenyl group optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy or halogen, or R₅ is aryl or heteroaryl, either bein optionally substituted by one or more groups or atoms selected from the class of C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, C₁₋₁₂ carboxylic acyl, or amino or aminocarbonyl optionally substituted by one or two C₁₋₆ alkyl groups and wherein aryl is phenyl or naphtyl and heteroaryl is monocyclic 5- or 6-membered or bicyclic 9- or 10-membered, containing one, two or three heteroatoms selected from oxygen, nitrogen and sulphur; and R₆ is hydrogen or C₁₋₆ alkyl, or R₅ and R₆ 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, O, S or NR wherein R is hydrogen, C₁₋₉ alkyl, C₂₋₇ alkanoyl, phenyl C₁₋₄-alkyl, naphthylcarbonyl, phenylcarbonyl or benzyl-carbonyl optionally substituted in the phenyl or naphtyl ring by one or two of C₁₋₆ alkyl, C₁₋₆ alkoxy or halogen; mono- or bi-cyclic- heteroarylcarbonyl; When Y is CH, R₅ is NR₈R₉ wherein R₈ and R₉ are independently C₁₋₆ alkyl, R₈ is hydrogen and R₉ is C₁₋₆ alkyl or R₈ and R₉ together are C₄₋₅ polymethylene; or R₆ and R₈ together are -(CH₂) p - wherein p is 2 or 3, and R₉ is hydrogen or C₁₋₆ alkyl; or R₅ is CH₂R₁₀ wherein R₁₀ is hydrogen or C₁₋₅ alkyl; or R₆ and R₁₀ are -(CH₂) q - wherein q is 2 or 3; X is oxygen or sulphur; or R₅, R₆, X and Y (when N) together are tetrahydroisoquinolinone or tetrahydroisoquinolinthione, optionally substituted in the phenyl ring as defined for R above; the nitrogen-containing group in the 4-position being trans to the R₃ group when R₃ is hydroxy, C₁₋₆ alkoxy or C₁₋₇ acyloxy; which process comprises; i) (When Y is N) acylating a compound of formula (II): wherein R₄′ is R₄ or a group convertible thereto; R₁ R₂ and R₃ are as defined, and R₆¹ is hydrogen or C₁₋₆ alkyl, the R₆¹NH group being trans to the R₃ group, a) with an acylating agent of formula (III): R₁₁-CO-L₁ (III) wherein L₁ is a leaving group, anti R₁₁ is hydrogen, C₁₋₆ alkyl optionally substituted by halogen, hydroxy, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, carboxy or amino optionally substituted as defined for R₅, C₂₋₆ alkenyl or optionally substituted aryl or heteroaryl as defined for R₅, or a group convertible to R₅ as defined, and thereafter, when R₆ is hydrogen and R₁₁ is Q(CH₂) z -, where z is 3 or 4; and Q is a leaving group, cyclising the resultant compound; b) with a compound of formula (IV) X=C=N.R₁₂ (IV) wherein R₁₂ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆ alkanoyl optionally substituted by up to three halo atoms, or phenyl optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy or halogen; and X is oxygen or sulphur, and thereafter when R₁₂ is hydrogen, optionally converting R₁₂; or ii) where, in the resultant compound of formula (I), Y is N and R₅ and R₆ are joined together, or Y is CH, reacting a compound of formula (V): wherein R₁ and R₂ are as defined, with a compound of formula (VI): R₁₄YHCOR₁₃ (VI) or an anion thereof (when Y is CH); wherein (when Y is N), R₁₃and R₁₄ together are -CH₂-(CH₂) n -Z-(CH₂) m - or R₁₄YHCOR₁₃ is tetrahydroisoquinolinone; or (when Y is CH) R₁₃ is NR₈′ R₉ or CHR₁₀CO₂R₁₅ wherein R₁₅ is C₁₋₆ alkyl or benzyl R₈′ is R₈ or an amino protecting group and the remaining variables are as defined; and thereafter, if necessary, converting R₁₃ to R₇, converting R₈′ to R₈; optionally converting R₃ in the resulting compound into another R₃; converting R₄′ to R₄ and optionally thiating the R₆-Y-CO-R₅ group in the resulting compound to give a compound wherein X is sulphur; and when the resulting compound of formula (I) contains a salifiable group, optionally forming a pharmaceutically acceptable salt thereof. 2. A process according to claim 1 wherein Y is N. 3. A process according to claim 1 or 2 wherein R₁ and R₂ are both methyl. 4. A process according to any one of claims 1 to 3 wherein R₃ is hydroxy. 5. A process according to any one of claims 1 to 4 wherein R₄ is C₅₋₇ cycloalkyl or C₁₋₄ alkyl. 6. A process according to any one of claims 1 to 5 wherein X is oxygen and R₅ and R₆ together form C₃ or C₄ polymethylene. 7. A process according to claim 1 for the preparation of trans -6-methyl-2,2-dimethyl-4-(2-oxopiperidinyl)-2H-1-benzopyran-3-ol, trans -6-t-butyl-2,2-dimethyl-4-(2-oxopyrrolidinyl)-2H-1-benzopyran-3-ol, trans -6-(i-propyl)-2,2-trimethyl-4-(2-oxopyrrolidinyl)-2H-1-benzopyran-3-ol, trans -3,4-dihydro-2,2,6-trimethyl-4-(2-oxopyrrolidinyl)-2H-1-benzopyran-3-ol, trans -3,4-dihydro-2,2,6-trimethyl-4-[N,N-trimethyl-2-acetamido]-2H-1-benzopyran, trans -4-acetylamino-3,4-dihydro-2,2,6-trimethyl-2H-1-benzopyran-3-ol, trans -3,4-dihydro-2,2,6-trimethyl-2-(N-methylureido)-2H-1-benzopyran-3-ol, trans -4-(4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-6-isopropyl-2H-1-benzopyran-3-ol, trans -6-aminomethyl-3,4-dihydro-2,2-dimethyl-4-(2-oxopyrrolidinyl)-2H-1-benzopyran-3-ol, trans -6-ethyl-3,4-dihydro-2,2-dimethyl-4-(2-oxopyrrolidinyl)-2H-1-benzopyran-3-ol, trans -3,4-dihydro-2,2-dimethyl-4-(2-oxopyrrolidinyl)-6-cyclopentyl-2H-1-benzopyran-3-ol, or 4-chloroacetamido-3,4-dihydro-2,2,6-trimethyl-2H-1-benzopyran. 8. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1, in the manufacture of a medicament for the treatment of hypertension. 9. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in claim 1, in the manufacture of a medicament for the treatment of disorders associated with smooth muscle contraction of the gastro-intestinal tract, respiratory system uterus or urinary tract. Claims for the following Contracting State: GR 1. A compound of formula (I) or, when the compound of formula (I) contains a salifiable group, a pharmaceutically acceptable salt thereof: wherein: Y is N or (when R₃ is hydroxy, C₁₋₆ alkoxy or C₁₋₇ acyloxy) CH; one of R₁ and R₂ is hydrogen or C₁₋₄ alkyl and the other is C₁₋₄ alkyl or R₁ and R₂ together are C₂₋₅-polymethylene; R₃ is hydrogen, hydroxy, C₁₋₆ alkoxy or C₁₋₇ acyloxy; R₄ is a C₃₋₈ cycloalkyl group or a C₁₋₆ alkyl group optionally substituted by a group R₇ which is amino; when Y is N, R₅ is hydrogen, C₁₋₆ alkyl optionally substituted by halogen, hydroxy, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, carboxy or amino optionally substituted by one or two independent C₁₋₆ alkyl groups, or C₂₋₆ alkenyl, amino optionally substituted by a C₁₋₆ alkyl, C₃₋₈ cycloalkyl or C₁₋₆ alkenyl group or by a C₁₋₆ alkanoyl group optionally substituted by up to three halo atoms, by a phenyl group optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy or halogen, or R₅ is aryl or heteroaryl, either being optionally substituted by one or more groups or atoms selected from the class of C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, C₁₋₁₂ carboxylic acyl, or amino or aminocarbonyl optionally substituted by one or two C₁₋₆ alkyl groups and wherein aryl is phenyl or naphthyl and heteroaryl is monocyclic 5- or 6-membered or bicyclic 9- or 10-membered, containing one, two or three heteroatoms selected from oxygen, nitrogen and sulphur; and R₆ is hydrogen or C₁₋₆ alkyl, or R₅ and R₆ 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, O, S or NR wherein R is hydrogen, C₁₋₉ alkyl, C₂₋₇ alkanoyl, phenyl C₁₋₄-alkyl, naphthylcarbonyl, phenylcarbonyl or benzyl-carbonyl optionally substituted in the phenyl or naphthyl ring by one or two of C₁₋₆ alkyl, C₁₋₆ alkoxy or halogen; mono- or bi-cyclic- heteroarylcarbonyl; When Y is CH, R₅ is NR₈R₉ wherein R₈ and R₉ are independently C₁₋₆ alkyl, R₈ is hydrogen and R₉ is C₁₋₆ alkyl or R₈ and R₉ together are C₄₋₅ polymethylene; or R₆ and R₈ together are -(CH₂) p - wherein p is 2 or 3, and R₉ is hydrogen or C₁₋₆ alkyl; or R₅ is CH₂R₁₀ wherein R₁₀ is hydrogen or C₁₋₅ alkyl; or R₆ and R₁₀ are -(CH₂) q - wherein q is 2 or 3; X is oxygen or sulphur; or R₅, R₆, X and Y (when N) together are tetrahydroisoquinolinone or tetrahydroisoquinolinthione, optionally substituted in the phenyl ring as defined for R above; the nitrogen-containing group in the 4-position being trans to the R₃ group when R₃ is hydroxy, C₁₋₆ alkoxy or C₁₋₇ acyloxy. 2. A compound according to claim 1 wherein Y is N. 3. A compound according to claim 1 or 2 wherein R₁ and R₂ are both methyl. 4. A compound according to any one of claims 1 to 3 wherein R₃ is hydroxy. 5. A compound according to any one of claims 1-4 wherein R₄ is C₅₋₇ cycloalkyl or C₁₋₄ alkyl. 6. A compound according to any one of claims 1 to 5 wherein X is oxygen and R₅ and R₆ together form C₃ or C₄ polymethylene. 7. trans -6-Methyl-2,2-dimethyl-4-(2-oxopiperidinyl)-2H-1-benzopyran-3-ol, trans -6-t-butyl-2,2-dimethyl-4-(2-oxopyrrolidinyl)-2H-1-benzopyran-3-ol, trans -6-(i-propyl)-2,2dimethyl-4-(2-oxopyrrolidinyl)-2H-1-benzopyran-3-ol, trans -3,4-dihydro-2,2,6-trimethyl-4-(2-oxopyrrolidinyl)-2H-1-benzopyran-3-ol, trans -3,4-dihydro-2,2,6-trimethyl-4-[N,N-dimethyl-2-acetamido]-2H-1-benzopyran, trans -4-acetylamino-3,4-dihydro-2,2,6-trimethyl-2H-1-benzopyran-3-ol, trans -3,4-dihydro-2,2,6-trimethyl-2-(N-methylureido)-2H-1-benzopyran-3-ol, trans -4-(4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-6-isopropyl-2H-1-benzopyran-3-ol, trans -6-aminomethyl-3,4-dihydro-2,2-dimethyl-4-(2-oxopyrrolidinyl)-2H-1-benzopyran-3-ol, trans -6-ethyl-3,4-dihydro-2,2-dimethyl-4-(2-oxopyrrolidinyl)-2H-1-benzopyran-3-ol, trans -3,4-dihydro-2,2-dimethyl-4-(2-oxopyrrolidinyl)-6-cyclopentyl-2H-1-benzopyran-3-ol, or 4-chloroacetamido-3,4-dihydro-2,2,6-trimethyl-2H-1-benzopyran. 8. A process for the preparation of a compound according to claim 1, which process comprises; i) (Wen Y is N) acylating a compound of formula (II): wherein R₄′ is R₄ or a group convertible thereto; R₁ R₂ and R₃ are as defined in claim 1, and R₆¹ is hydrogen or C₁₋₆ alkyl, the R₆¹NH group being trans to the R₃ group, a) with an acylating agent of formula (III): R₁₁-CO-L₁ (III) wherein L₁ is a leaving group, and R₁₁ is hydrogen, C₁₋₆ alkyl optionally substituted by halogen, hydroxy, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, carboxy or amino optionally subsituted as defined in claim 1 for R₅, C₂₋₆ alkenyl or optionally substituted aryl or heteroaryl as defined in claim 1 for R₅, or a group convertible to R₅ as defined in claim 1, and thereafter, when R₆ is hydrogen and R₁₁ is Q(CH₂) z -, where z is 3 or 4; and Q is a leaving group, cyclising the resultant compound; b) with a compound of formula (IV) X=C=N.R₁₂ (IV) wherein R₁₂ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆ alkanoyl optionally substituted by up to three halo atoms, or phenyl optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy or halogen; and X is oxygen or sulphur, and thereafter when R₁₂ is hydrogen, optionally converting R₁₂; or ii) where, in the resultant compound of formula (I), Y is N and R₅ and R₆ are joined together, or Y is CH, reacting a compound of formula (V); wherein R₁ and R₂ are as defined in claim 1, with a compound of formula (VI): R₁₄YHCOR₁₃ (VI) or an anion thereof (when Y is CH); wherein (when Y is N), R₁₃ and R₁₄ together are -CH₂-(CH₂) n -Z-(CH₂) m - or R₁₄YHCOR₁₃ is tetrahydroisoquinolinone; or (when Y is CH) R₁₃ is NR₈′ R₉ or CHR₁₀CO₂R₁₅ wherein R₁₅ is C₁₋₆ alkyl or benzyl, R₈′ is R₈ or an amino protecting group and the remaining variables are as defined in claim 1; and thereafter, if necessary, converting R₁₃ to R₇, converting R₈′ to R₈; optionally converting R₃ in the resulting compound into another R₃; converting R₄′ to R₄ and optionally thiating the R₆-Y-CO-R₅ group in the resulting compound to give a compound wherein X is sulphur; and when the resulting compound of formula (I) contains a salifiable group, optionally forming a pharmaceutically acceptable salt thereof. 9. An intermdediate of formula (II): wherein R₁, R₂ and R₃ are as defined in claim 1, and R₆¹ is hydrogen or C₁₋₆ alkyl, the R₆¹NH group being trans to the R₃ group, wherein R₄′ is R₄, other than the compound wherein R₁ and R₂ are both methyl, R₃ is hydrogen, R₄′ is methyl and R₆¹ is hydrogen. 10. A compound according to any one of claims 1 to 7 for use as an active therapeutic substance. 11. A compound according to any one of claims 1 to 7 for use in the treatment of hypertension. 12. Use of a compound according to any one of claims 1 to 7 in the manufacture of a medicament for the treatment of hypertension. 13. Use of a compound according to any one of claims 1 to 7, in the manufacture of a medicament for the treatment of disorders associated with smooth muscle contraction of the gastro-intestinal tract, respiratory system, uterus or urinary tract.

Inventors: BURRELL, GORDON C/O BEECHAM PHARMACEUTICALS,, CASSIDY, FREDERICK C/O BEECHAM PHARMACEUTICALS,, EVANS, JOHN MORRIS C/O BEECHAM PHARMACEUTICALS,, STEMP, GEOFFREY C/O BEECHAM PHARMACEUTICALS,
Applicants: BEECHAM GROUP PLC
Application year: 1987
Main classification: C07D405
IPC codes: C07D405, C07D311