EP0516658A1 - Benzopyrans having pharmacological activity - Google Patents

Abstract

The invention relates to new benzopyranes having pharmacological activity, to a process and to intermediates allowing the preparation of these compounds, as well as to their use as pharmaceutical products.

Description

Benzopyrans having pharmacological activity

The present invention relates to novel benzopyrans having pharmacological activity, to a process and intermediates for preparing them and to their use as pharmaceuticals.

EP-A-250077 (Beecham Group p.I.e.) and EP-A-298452

(Hofmann-La Roche) describe classes of benzopyran-3-ol derivatives which are K⁺ channel activators.

EP-A-412760 (Beecham Group p.I.e.) discloses

3,4-dihydro-2,2-dimethyl-6-ethenyl-4R-(2-oxopiperidin-1-yl)- 2H-1-benzopyran-3S-ol (E5) as an intermediate for preparing the corresponding 6-ethyl derivative.

A class of pharmaceutically active compounds has now been discovered which are 4-substituted benzopyran derivatives substituted in the 6-position by an alkenyl or alkynyl group.

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. Such disorders include hypertension, including pulmonary hypertension, and cardiovascular disorders other than hypertension, such as congestive heart failure, angina, peripheral vascular disease and cerebral vascular disease. Other disorders include those of the gastro-intestinal tract, respiratory system, uterus and urinary tract. Such disorders include irritable bowel syndrome and diverticular disease; reversible airways obstruction such as asthma;

premature labour; and incontinence and kidney stones. The compounds may also be of potential use as anticonvulsants in the treatment of epilepsy.

These compounds are of formula (I) or, when the compound of formula (I) contains a salifiable group, a pharmaceutically acceptable salt thereof:

wherein

one of R₁ and R₂ is hydrogen or C_1-4 alkyl and the other is C_{1- 4} alkyl or R₁ and R₂ together are C_2-5

polymethylene;

R₃ is hydrogen, hydroxy, C_1-6 alkoxy or C_1-7 acyloxy;

R₄ is a C_2-6 alkenyl or C_2-6 alkynyl group;

E is a moiety of structure E ¹:

wherein

Y is N or (when R₃ is hydroxy, C_1-6 alkoxy or C_1-7

acyloxy) CH;

when Y is N:

either R₅ is hydrogen, C_1-6 alkyl optionally substituted by hydroxy, C_1-6 alkoxy, C_1-6 alkoxycarbonyl or carboxy, C_1-6 alkyl substituted by halogen, or C2-6 alkenyl; aryl or heteroaryl either being optionally substituted by one or more groups or atoms selected from the class of C_1-6 alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, C_1-12 carboxylic acyl, or amino or aminocarbonyl optionally substituted by one or two C_1-6 alkyl groups; and

R₆ is hydrogen or C_1-6 alkyl; or

R₅ and R₆ are joined together to form C_3-4 polymethylene optionally substituted by one or two C_1-6 alkyl groups or -CH₂-(CH₂)_n-Z-(CH₂)_m- wherein m and n are integers 0 to 2 such that m+n is 1 or 2 and Z is oxygen, sulphur or NR₉ wherein R₉ is hydrogen, C_{1- 9} alkyl, C_2-7 alkanoyl, phenyl C_1-4 alkyl, naphthylcarbonyl, phenylcarbonyl or benzylcarbonyl optionally

substituted in the phenyl or naphthyl ring by one or two C_1-6 alkyl, C_1-6 alkoxy or halogen; mono- or bi-cyclic heteroarylcarbonyl; or R₅ and R₆ are joined to form -B¹=B²-B³=B⁴- wherein one of B¹ to B⁴ is CR_r or N and the other three are CR_r wherein R_r is

hydrogen or C_1-6 alkyl;

when Y is CH:

either R₅ is NR₇R₈ wherein R₇ and R₈ are independently C_1-6 alkyl, R₇ is hydrogen and R₈ is C_1-6 alkyl or R₇ and

R₈ together are C_4-5 polymethylene; and

R₆ is hydrogen or C_1-6 alkyl; or

R₆ and R₇ together are -(CH₂)_p- wherein p is 2 or 3, and R₈ is hydrogen or C_1-6 alkyl; or

R₅ is CH₂R₁₀ wherein R₁₀ is hydrogen or C_1-5 alkyl or R₆ and

R₁₀ together are -(CH₂)_q- wherein q is 2 or 3; and X is oxygen or sulphur; or

R₅, R₆, X and Y (wnen N) together are

tetrahydroisoquinolinone or

tetrahydroisoquinolinthione, optionally substituted in the phenyl ring as defined for R₉ above; or

E is 2-pyridine-N-oxide, 2-pyrazinyl-1-oxide, or 2- or

6-pyrimidinyl-1-oxide;

the nitrogen-containing group in the 4-position being trans to the R₃ group when R₃ is hydroxy, C_1-6 alkoxy or C_1-7 acyloxy.

Y is preferably N. Preferably, R₁ and R₂ are both C_1-4 alkyl, in particular both methyl.

When R₃ is C_1-6 alkoxy, preferred examples of R₃ include methoxy and ethoxy, of which methoxy is more preferred.

When R₃ is C_1-7 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 vinyl, prop-2-enyl, 1-methylvinyl, but-1-enyl, but-2-enyl, but-3-enyl, 1-methylenepropyl,

1-methylprop-1-enyl and 1-methylprop-2-yl in their E and Z forms where stereoisomerism exists; and the corresponding alkynyl anologues (where appropriate) of the above.

When Y is N:

Examples of R₅, when C_1-6 alkyl, include methyl, ethyl and n- and iso-propyl. Preferably such R₅ is methyl.

A sub-group of R₅, when C_1-6 alkyl substituted by halogen is C_1-6 alkyl substituted by chloro or bromo. Examples thereof include methyl or ethyl terminally substituted by chloro or bromo.

Examples of R₅, when C_1-6 alkyl substituted by hydroxy, include methyl or ethyl terminally substituted by hydroxy. A sub-group of R₅, when C_1-6 alkyl substituted by alkoxy is C_1-6 alkyl substituted by methoxy or ethoxy. Examples thereof include methyl or ethyl terminally substituted by methoxy or ethoxy. A sub-group of R₅, when C_1-6 alkyl substituted by C_1-6 alkoxycarbonyl is C_1-6 alkyl substituted by methoxycarbonyl or ethoxycarbonyl. Examples thereof include methyl or ethyl terminally substituted by methoxycarbonyl or ethoxycarbonyl.

Examples of R₅, when C_1-6 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 C_1-6 alkyl groups include a group (CH₂)_rNR_aR_b where r is 1 to 6, and R_a and R_b are each independently hydrogen or C_1-6 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 C_2-6 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 C_1-4 alkyl group as described for R₇ ¹, an 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.

Examples of R₅ when aryl include phenyl and naphthyl, of which phenyl is preferred. A sub-group of R₅ heteroaryl or heteroaryl in a Z moiety when it is NR₉ which 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 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-guinolyl.

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 C_1-6 alkyl, C_1-6 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 thebenzopyran in the 4-position is preferably either pyrrolidonyl or

piperidonyl. R₅ and R₆, when together are -B¹=B²-B³=B⁴-, the resulting radical substituting the benzopyran in the 4-position is preferably pyridonyl.

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 NR₉ 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; fiarylcarbonyl, thienylcarbonyl, pyrrolylcarbonyl or indolylcarbonyl . Preferably R₉ is hydrogen, methyl, n-butyl, acetyl, benzyl, benzylcarbonyl, phenylcarbonyl or furylcarbonyl. Most preferably R₉ 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 NR₇R₈. Examples of R₇ and R₈, include hydrogen (for R₇), methyl, ethyl, n- and iso-propyl, and n-, iso-, sec- and t-butyl, C₄ or C₅ polymethylene or R₇ together with R₆ is -(CH₂)₂- or -(CH₂)₃-, and R₈ is hydrogen or an alkyl group as described above. Preferably R₇ and R₈ are each methyl or R₆CHCXNR₇R₈ forms a pyrrolidone or piperidone ring and R₈ 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 invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, other than the compound E5 hereinbefore defined.

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 1-4 hereinafter. A process for the preparation of a compound of formula (I) wherein E is a moiety of structure E¹ as defined, or, when the compound of formula (I) contains a salifiable group, a pharmaceutically acceptable salt thereof, 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 R₆ ¹ is hydrogen or C_1-6 alkyl, the R₆ ¹NH group being trans to the R₃ group, a) with an acylating agent of formula (III)

R_{1 1} -CO-L₁ (III)

wherein L₁ is a leaving group, and R₁₁ is hydrogen, C_1-6 alkyl optionally substituted by halogen, hydroxy, C_1-6 alkoxy, C_1-6 alkoxycarbonyl, carboxy or amino optionally. substituted as hereinbefore defined for R₅, C_2-6 alkenyl or optionally substituted aryl or heteroaryl a 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, C_1-6 alkyl, C_1-6 alkenyl, C_1-6 alkanoyl optionally substituted by up to three halo atoms, or phenyl optionally substituted by C_1-6 alkyl, C_1-6 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-,

-B¹=B²-B³=B⁴- or R₁₄YHCOR₁₃ is tetrahydroisoquinolinone; or (when Y is CH) R₁₃ is NR₇'R₈ or CHR₁₀CO₂R₁₅ wherein R₁₅ is C_1-6 alkyl or benzyl, R₇' is R₇ or an amino protecting group and the remaining variables are as hereinbefore defined; and thereafter, if necessary, converting R₁₃ to R₅, converting R₇' to R₇; 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 C_1-4 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 C_1-6 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 animation reaction with ammonia or a corresponding alkyl- or dialkylamine.

Less favourably R₁₁ may be C_1-6 alkyl substituted by protected amino, protected C_1-6 alkylamino or amino

substituted by two independent C_1-6 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 R₆ ¹YH- is acylated, for example, by using a C_2-9 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 C_1-7 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 dimethyIformamide. In process variant i) b), when R₁₂ in a compound of formula (IV) is C_1-6 alkyl, C_1-6 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 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 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 tetrahydrofuran 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 R₅ 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 also be effected 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, C_1-6 alkoxy or C_1-7 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 C_1-7 acyloxy or C_1-6 alkoxy, it may be converted into hydroxy by conventional hydrolysis with, for example, dilute mineral acid.

R₄' may be formyl which may be converted to R₄ by

conventional methods as described in the Examples

hereinafter, for example, reduction to give ethenyl, which may in turn be reacted with butyl lithium to form

prop-1-enyl as a mixture of E and Z isomers. 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 phosporous 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, 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 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, C_1-6 alkoxy or C_1-7 acyloxy may be prepared by reacting a

compound of formula (V), as hereinbefore defined, with a compound of formula (VII) :

R₆ ¹NH₂ (VII) wherein R₆ ¹ is as defined hereinbefore; and optionally converting R₃ hydroxyl in the resulting compound of formula (II) into R₃ when C_1-6 alkoxy or C_1-7 acyloxy.

The reaction is normally carried out in a solvent, such as a C_1-4 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 C_1-6 alkoxy or C_1-7 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 in accordance with the methods described in the patent publications herein referred to in the name of Beecham Group p. I.e.

When E in formula (I) is other than E¹ as defined, the compounds of formula (I) may be prepared in accordance with the processes described in EP-A-298452.

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 invention provides the foregoing process for preparing compounds in formula (I) and pharmaceutically acceptable salts thereof, other than compound E5. 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 of potential use 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.

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 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 .

Suitable conventional formulations are described in

EP-A-412760.

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 the 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 invention also provides the use of a benzopyran

derivative potassium channel activator having an alkenyl or alkynyl group in the 6-position, in the manufacture of a medicament for use in the treatment of disorders associated with smooth muscle contraction, or as an anticonvulsant. Such benzopyran derivatives may be prepared in a similar manner to the known benzopyran derivatives having other 6-substituents and according to the methods described hereinbefore. Such compounds are described in EP-A-372998 (Beecham Group p.l.c).

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

All temperatures therein are in °C.

Description 1 trans-6-(2-Chloroethenyl)-2,2-dimethyl-4-(2-oxoρyrrolid- inyl)-2H-1-benzopyran-3-ol (D1) n-Butyllithium (12 ml, 1.45 M) was added dropwise to a stirred solution of piperidirie (1.51 g) in dry diethyl ether (20 ml) at -40°C under a nitrogen atmosphere. The solution was allowed to slowly warm to -10° then

chloromethyltriphenylphosphonium chloride (5.6 g) was added portionwise with stirring. After warming to room

temperature the mixture was stirred for 3 h. Dry

dimethylformamide (100 ml) was added to the mixture and the resulting solution stirred for a further 2 h.

Trans-2,2-dimethyl-6-formyl-4-(2-oxopyrrolidinyl)-2H- 1-benzopyran-3-ol (2.33 g) was added portionwise and the solution was then allowed to stand at room temperature, under nitrogen atmosphere, for 16 h. The solution was concentrated by evaporation of the solvent in vacuo to give a brown gum. Water was added and the mixture was extracted with chloroform. The organic extracts were thoroughly washed with water, then brine and dried over anhydrous magnesium sulphate. Evaporation of the solvent in vacuo and column chromatography (Kieselgel 60, eluting with

chloroform-methanol) gave a mixed fraction containing the required product and starting material. This mixture was dissolved in ethyl acetate and thoroughly washed with saturated sodium metabisulphate solution. The chloroform solution was washed with water then brine and dried over anhydrous magnesium sulphate. Evaporation of the solvent in vacuo gave the title compound as a mixture of E and Z.

isomers as a white solid (2.07 g).

60 MHz ¹H nmr (CDCI₃) δ 1.17 (s, 3H); 1.54 (s, 3H);

1.83-2.33 (m, 2H); 2.33-2.8 (m, 2H); 2.9-3.5 (m, 2H); 3.73 (dd, J=5Hz, 6Hz, 1H); 4.25 (d, J=6Hz, 1H); 5.23 (d, J=10Hz, 1H); 5.93-7.2 (m, 3H); 7.2-7.56 (m, 2H).

Example 1 trans-2,2-Dimethyl-6-ethenyl-4-(2-oxopyrrolidinyl)-2H- 1-benzopyran-3-ol (E1)

Sodium hydride (80%, 0.104g) was added to dry dimethyl sulphoxide (4 ml) under a nitrogen atmosphere. The mixture was warmed to 65°C and stirred for 1.5 h. After cooling to room temperature methyltriphenylphosphonium iodide (1.4g) was added portionwise over several minutes, and the solution was stirred for a further 30 min at room temperature.

trans-2,2-Dimethyl-6-formyl-4-(2-oxopyrrolidinyl)-2H-1- benzopyran-3-ol (Ig described in J.Med.Chem. 29, 2194

(1986)) was added portionwise and the solution was then allowed to stand at room temperature, under nitrogen

atmosphere, for 16 h. The solution was concentration in vacuo and water was added and the mixture was extracted with chloroform. The organic extracts were thoroughly washed with water, then brine and dried over anhydrous sodium sulphate. Evaporation of the solvent in vacuo and column chromatography (Neutral alumina, Brockmann grade 1, eluting with dichloromethane-chloroform) gave a mixed fraction containing the required product and starting material.

Recrystallisation from ethyl acetate gave the required product obtained from the mother liqueurs. This solid was further recrystallised from ethyl acetate to give the title compound as a white crystalline solid (0.11g) having m.p. 162-4°C.

1H nmr (CDCI₃) δ 1.27 (s, 3H)

1.51 (s, 3H)

1.96-2.17 (m, 2H)

2.58 (t, J=8Hz, 2H)

3.08-3.16 (m, 1H)

3.24-3.38 (m, 2H)

3.76 (dd, J=10,6Hz, 1H)

5.12 (d, J=11Hz, 1H)

5.27 (d, J=10Hz, 1H)

5.57 (d, J=18Hz, 1H)

6.61 (dd, J=18,11Hz, 1H)

6.79 (d, J=8Hz, 1H)

6.92 (d, J=2Hz, 1H)

7.27 (dd, J=8,2Hz, 1H)

Mass spectrum: found M⁺ 287.1522.

C₁₇H₂₁NO₃ requires 287.1521.

Analysis: Found C,71.02; H, 7.65; N,4.84.

C₁₇H₂₁NO₃ requires C,71.06; H,7.37; N, 4.87.

Example 2 trans-2,2-Dimethyl-3,4-dihydro-6-prop-1-en-1-yl-4-(2- oxopyrrolidinyl)-2H-1-benzopyran-3-ol (E2)

1 lithium (1.55M, 5 ml) was added dropwise to a stirred suspension of ethyltriphenylphosphonium iodide (3.18g) in dry tetrahydrofuran (80 ml) at room temperature under an atmosphere of dry nitrogen. The mixture was then heated under reflux for 1 h. After cooling. trans-2,2-dimethyl-6-formyl-4-(2-oxopyrrolid-inyl)-2H-1- benzopyran-3-ol (D1) (2g) was added and stirred for 0.5 h at room temperature then heated under. reflux for 16 h. The solvent was evaporated in vacuo, water was added and the mixture extracted with chloroform. The organic phase was washed with water, then brine and dried over anhydrous sodium sulphate. Evaporation of the solvent in vacuo gave a brown oil. Column chromatography (Kieselgel 60, eluting with chloroform-methanol) gave the title compound as a mixture of E and Z isomers as a white crystalline solid

(0.31g) of m.p. 176-182°C after recrystallisation from ethyl acetate.

Mass spectrum: Found 301.1677.

C₁₈H₂₃NO₃ retires 301.1678.

Analysis: Found C, 71.73; H,7.69; N,4.65.

C₁₈H₂₃NO₃ requires C, 71.77; H, 7.63; N,4.60.

Example 3 trans-2,2-Dimethyl-6-ethynyl-4-(2-oxopyrrolidinyl)-2H- 1-benzopyran-3-ol (E3)

A solution of trans-6-(2-chloroethenyl)-2,2-dimethyl-4- (2-oxopyrrolidinyl)-2H-1-benzopyran-3-ol (2 g) in dry tetrahydrofuran (30 ml) was added to a previously prepared solution of sodium amide (from sodium metal (0.43 g)) in liquid ammonia (30 ml) at -30°C. The mixture was stirred for a further 6.5 h, then ammonium chloride (1 g) was added and the mixture allowed to warm to room temperature and stand for 16 h. The resulting mixture was filtered and the residue washed with chloroform. Evaporation of the solvent in vacuo and column chromatography (Kieselgel 60, eluting with ethyl acetate-methanol) gave the title compound as a white crystalline solid (0.1 g) having m.p. 199-205°C, after recrystallisation from ethyl acetate, three times and then acetonitrile.

¹H nmr (CDCI₃) δ 1.27 (s, 3H); 1.52 (s, 3H); 2.01-2.18 (m, 2H); 2.58 (t, J=8Hz, 2H); 2.98 (s, 1H); 3.04-3.22 (m, 2H); 3.22-3.36 (m, 1H); 3.75 (dd, J=10Hz, 5Hz, 1H); 5.26 (d,

J=10Hz, 1H); 6.78 (d, J=8Hz, 1H); 7.08 (d, J=2Hz, 1H); 7.31 dd, J=8Hz, 2Hz, 1H).

Analysis: found C, 71.25; H, 6.95; N, 5.21.

C₁₇H₁₉NO₃ requires C, 71.56; H, 6.71; N, 4.91%.

Example 4 trans-2,2-Dimethyl-6-prop-1-yn-1-yl-4-(2-oxopyrrolidinyl)- 2H-1-benzopyran-3-ol (E4)

Bromine (1.06 g) was added dropwise to a stirred solution of 2,2-dimethyl-3,4-dihydro-6-prop-1-en-1-yl- trans-4-(2-oxopyrrolidinvl)-2H-benzopyran-3-ol (2 g) in chloroform (4 ml) at room temperature. After 2 h the solvent was evaporated in vacuo and the residual brown foam dissolved in dry dimethylsulphoxide (10 ml).

1,8-Diazabicyclo[5,4,0]-undec-7-ene (10 g) was added and the solution heated in an oil-bath at 140°C under a nitrogen atmosphere for 12 h. After cooling ethyl acetate (120 ml), and water (100 ml) were added, the mixture then made acidic (pH 4) with dilute sulphuric acid. The two phases were separated, and the aqueous phase was further extracted with ethyl acetate (100 ml). The combined organic phase was thoroughly washed with water, then brine and dried over anhydrous magnesium sulphate. Evaporation of the solvent in vacuo and column chromatography (Kieselgel 60, eluting with chloroform-methanol) gave a white crystalline solid.

Recrystallisation from ethyl acetate, three times, gave the title compound (0.62 g) having m.p. 205-207°C. ¹H nmr (CDCI₃) δ 1.34 (s, 3B); 1.59 (s, 3H); 2.05-2.26 (m, 5H; includes singlet at δ 2.11); 2.66 (t, J=8Hz, 2H);

3.14-3.27 (m, 1H); 3.30-3.75 (m, 2H; includes broad singlet at δ 3.54); 3.83 (d, J=10Hz, 1H); 5.32 (d, J=10Hz, 1H); 6.82 (d, J=8Hz, 1H); 7.06 (d, J=2Hz, 1H); 7.28 (dd, J=8Hz, 2Hz, 1H). trans-6-Etheny1-3,4-dihydro-2,2-dimethyl-4R-(2-oxo- piperidinyl)-2H-1-benzopyran-3S-ol (E5) m.p. 205-208°C was prepared in accordance with the method described in

EP-A-412760.

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 >170 mmHg were considered hypertensive.

The compounds of the Examples and compound E5 were shown to have blood pressure lowering activity in the above test, at a dose of 10 mg/kg or less.

Claims

Claims

1. A pharmaceutical composition comprising a compound of formula (I) as defined herein, or a pharmaceutically

acceptable salt thereof and a pharmaceutically acceptable carrier.

2. A compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of hypertension.

3. A composition or compound according to claim 1 or 2 wherein E is E¹ and Y is N. 4. A composition or compound according to claim 2 or 3 wherein R₁ and R₂ are both methyl.

5. A composition or compound according to any of claims 1 to 4 wherein R₃ is hydroxy.

8. A compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, other than

3,4-dihydro-2,2-dimethyl-6-ethenyl-4R-(2-oxopiperidin-1-yl)- 2H-benzopyran-3S-ol.

9. trans-2,2-Dimethyl-6-ethenyl-4-(2-oxopyrrolidinyl)- 2H-1-benzopyran-3-ol, trans-2,2-dimethyl-3,4-dihydro-6-prop-1-en-1-yl-4-(2- oxopyrrolidinyl)-2H-1-benzopyran-3-ol, trans-2,2-dimethyl-6-ethynyl-4-(2-oxopyrrolidinyl)-2H- 1-benzopyran-3-ol or trans-2,2-dimethyl-6-prop-1-yn-4-(2-oxopyrrolidinyl)-2H- 1-benzopyran-3-ol.

10. The use of a benzonyran derivative potassium channel activator having an alkenyl or alkynyl group in the

6-position, in the manufacture of a medicament for use in the treatment of disorders associated with smooth muscle contraction, or as an anticonvulsant.