BENZOPYRANS HAVING PHARMACOLOGICAL ACTIVITY

Abstract: Novel benzopyrans having pharmacological activity, a process and intermediates for preparing them and their use as pharmaceuticals.

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— 12760 (Beecham Group p.I.e.) discloses 3,4-dihydro-2,2-dimethyl-6-ethenyl-4R-(2-oxopiperidin-l-yl)- 2H-l-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: (I) wherein one of R- j^ and R2 is hydrogen or C 1-4 alkyl and the other is Cι__4 alkyl or R-^ and R2 together are C _5 polymethylene; R3 is hydrogen, hydroxy, C-^. alkoxy or 1 _- j acyloxy; R4 is a 2_g alkenyl or C2_g alkynyl group; E is a moiety of structure E 1: C=X Y 1 wherein Y is N or (when R3 is hydroxy, C-^g alkoxy or C-,_ 7 acyloxy) CH; when Y is N: either R5 is hydrogen, C^g alkyl optionally substituted by hydroxy, C-^. alkoxy, C^g alkoxycarbonyl or carboxy, ^1-6 a l^yl substituted by halogen, or 2-6 a lkenyl; aryl or heteroaryl either being optionally substituted by one or more groups or atoms selected from the class of C-^.g alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, carboxylic acyl, or amino or aminocarbonyl optionally substituted by one or two C- ! _g alkyl groups; and Rg is hydrogen or C-^_ alkyl; or Rc j and Rg are joined together to form C^.^ polymethylene optionally substituted by one or two C-^g 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 NRg wherein Rg is hydrogen, C- _g alkyl, c 2-7 alkanoyl, phenyl alkyl, naphthylcarbonyl, phenylcarbonyl or benzylcarbonyl optionally substituted in the phenyl or naphthyl ring by one or two C-^_ alkyl, C^_g alkoxy or halogen; mono- or bi-cyclic heteroarylcarbonyl; or R5 and Rg are joined to form wherein one of B 1 to B is CRr, or N and the' other three are CR r wherein R r is hydrogen or C^_g alkyl; when Y is CH: either R5 is NR 7 Rg wherein R and Rg are independently C-^_ alkyl, R 7 is hydrogen and Rg is C^_g alkyl or R 7 and Rg together are C^..^ polymethylene; and R is hydrogen or C- j ^g alkyl; or Rg and R 7 together are -(CI^J p - wherein p is 2 or 3, and R is hydrogen or C-^_g alkyl; or R5 is CH2R10 wherein R-^ is hydrogen or C-^.^ alkyl or Rg and R lfj together are -(CH 2 ) - wherein q is 2 or 3; and X is oxygen or sulphur; or R 5' R 6' X an( ~- ~- (wnen N ) together are tetrahydroisoquinolinσne or — tetrahydroisoquinolinthione, optionally substituted in the phenyl ring as defined for Rg above; or E is 2-pyridine-N-oxide, 2—pyrazinyl-l-oxide, or 2- or 6-pyrimidinyl-l-oxide; the nitrogen-containing group in the 4-position being trans to the R group when R3 is hydroxy, C-^.g alkoxy or C-,_ acyloxy. Y is preferably N. Preferably, Rη ^ and R2 are both C-,_ 4 alkyl, in particular both methyl. When R3 is C^_ alkoxy, preferred examples of R include methoxy and ethoxy, of which methoxy is more preferred. When R3 is C^_ 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-l-enyl and l-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^_g alkyl, include methyl, ethyl and n- and iso-propyl. Preferably such R5 is methyl. A sub-group of R5, when C- j ^ alkyl substituted by halogen is C " l-6 alkyl substituted by chloro or bromo. Examples thereof include methyl or ethyl terminally substituted by chloro or bromo.' Examples of R5, when C-^_g alkyl substituted by hydroxy, include methyl or ethyl terminally substituted by hydroxy. A sub-group of R 5 , when C-ι_ alkyl substituted by alkoxy is C- _ 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^_g alkyl substituted by C^_g alkoxycarbonyl is C^_g alkyl substituted by methoxycarbonyl or ethoxycarbonyl. Examples thereof include methyl or ethyl terminally substituted by methoxycarbonyl or ethoxycarbonyl. Examples of R , when C^_g 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-^.g alkyl groups include a group (C^J j - R^^ where r is 1 to 6, and R a and R^ are each independently hydrogen or C-j_g alkyl. Examples of r include 1 and 2, in particular 1. Preferably R a and R j .. are each independently selected from hydrogen and methyl. Examples of R5, when C2_g alkenyl include vinyl, prop-1-enyl, prop-2-enyl, 1-methylvinyl, but-1-enyl, but-2-enyl, but-3-enyl, 1-methylenepropyl, or l-methylprop-2-enyl, in both their E and Z forms where stereoisomerism exists. Examples of R5 when amino optionally substituted as hereinbefore defined include amino optionally substituted by a C^.^ alkyl group as described for R 7 , 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 R 5 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 NRg 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 Rg is phenyl or naphthyl or a 5- or 6-membered monocyclic or a 9- or 10-membered bicyclic heteroaryl, the phenyl, naphthyl or heteroaryl group being optionally substituted by one, two, three or four groups or atoms selected from the class of C^_g alkyl, C 1 _g 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 Rg, when together are -CH 2 ~(CH2) n ~Z- (CH2) m - as defined the resulting radical substituting thebenzopyran in the 4-position is preferably either pyrrolidonyl or piperidonyl. R5 and Rg, when together are -B =B -B -B 4 -, the resulting radical substituting the benzopyran in the 4-position is preferably pyridonyl. When Z is other than CH 2 , m is often 0 or 1 and n is often 0 or 1. Suitable examples of R when Z is NRg 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 Rg is hydrogen, methyl, n-butyl, acetyl, benzyl, benzylcarbonyl, phenylcarbonyl or furylcarbonyl. Most preferably Rg is methyl. Preferred examples of R5 and R are R5 methyl and Rg hydrogen and R5 and Rg together are C3 or C 4 polymethylene. When Y is CH, Rg is preferably hydrogen and R 5 is NR 7 Rg. Examples of R 7 and Rg, include hydrogen (for R 7 ) , methyl, ethyl, n- and iso-propyl, and n-, iso-, sec- and t-butyl, C4 or C5 polymethylene or R 7 together with Rg is -(CH2>2 - or -(CH2>3-, and Rg is hydrogen or an alkyl group as described above. Preferably R 7 and Rg are each methyl or RgCHCXNR 7 Rg forms a pyrrolidone or piperidone ring and Rg 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 Re group. A carboxy group within Re 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 E 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 R or a group convertible thereto; R-^ R2 and R3 are as hereinbefore defined, and Rg is hydrogen or C^_g alkyl, the Rg 1NH group bei.ng trans to * the R group, a) with an acylating agent of formula (III) Rη -1 CO L (III) wherein L-^ is a leaving group, and R- is hydrogen, C^_g alkyl optionally substituted by halogen, hydroxy, C- j ^g alkoxy, C^_g alkoxycarbonyl, carboxy or amino optionally. substituted as hereinbefore defined for R5, C2_g alkenyl or optionally substituted aryl or heteroaryl a hereinbefore defined for R5, or a group convertible to R 5 as hereinbefore defined, and thereafter, when Rg is hydrogen and R-^ 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) wherein R-^ is hydrogen, C-^g alkyl, C-^.g alkenyl, C- j __g alkanoyl optionally substituted by up to three halo atoms, or phenyl optionally substituted by C-,_g alkyl, C^_g alkoxy or halogen; and X is oxygen or sulphur, and thereafter when or ii) where, in the resultant compound of formula (I) , Y is N and Re and Rg are joined together, or Y is CH, reacting a compound of formula (V) : wherein 4', R^ and R2 are as hereinbefore defined, with a compound of formula (VI) : R 14 YHCOR 13 (VI) or an anion thereof (when Y is CH) ; wherein (when Y is N) , R 13 and R 14 together are -CH 2 ~(CH 2 ) n -Z-(CH 2 ) m -, -B 1= B -B -B - or R 14 YHCOR 1 3 is tetrahydroisoquinolinone; or (when Y is CH) R 13 is NR 7 'Rg or CHR-, Q CC^R^ wherein R 15 is C^_ alkyl or benzyl, R 7 ' is R or an amino protecting group and the remaining variables are as hereinbefore defined; and thereafter, if necessary, converting to R5, converting R ' to R 7 ; optionally converting R3 in the resulting compound into another R ; converting R 4 ' to R4 and optionally thiating the Rg-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 1^ 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 L-^ is either of these examples, the acylating agent of formula (III) is either an acid anhydride or an acid halide. When it is an acid anhydride, it may be a mixed or simple anhydride. If it is a mixed anhydride, it may be prepared iji 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 R 5 in the desired compound of formula (I) is an R5 optionally substituted amino-substituted alkyl group as hereinbefore defined,it is preferred that R-i^ is a group convertible to the Re substituted alkyl group as hereinbefore defined, in particular that it is C-^. alkyl substituted by halo, especially bromo. The R^ 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 R^-, may be C-^g alkyl substituted by protected amino, protected C-^.g alkylamino or amino substituted by two independent C^_g al'kyl groups, it being necessary to protect the R-^ 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-acueous 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 Rg-'-YH- is acylated, for example, by using a C2_g acyloxy group as the leaving group L-^, 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^_ 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 Rg 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 R-^ is Q(CH2) Z where the variables are as hereinbefore defined is preferably carried out in an inert solvent such as dimeth Iformamide. In process variant i) b) , when R-,2 in a compound of formula (IV) is C-L_g alkyl, C-^g 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 R-^ 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 diisopropyla ide. An intermediate compound wherein R-^ is CHR^ Q CC^ T^ may be converted to a compound of formula (I) wherein Re is 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 R 14 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 R"L4 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 CHR-tøCC^H compound .in situ without isolation. It is especially convenient to carry out the conversion CHR^ Q CC^R ] ^ to CH 2 R 10 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^_ alkoxy or C- _η acyloxy, whereas the reaction of the compounds of formulae (V) and (VI) results in a compound of formula (I) wherein R 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 R 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, wtiϋen R is C- j __ 7 acyloxy or C 1 _ 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. r. The optional thiation of the. Rg-Y-CO-R^ 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-i alkoxy or C^_ 7 acyloxy may be prepared by reacting a compound of formula (V) , as hereinbefore defined, with a compound of formula (VII) : R 6 1NH 2 ( VII ) wherein Rg is as defined hereinbefore; and optionally converting R3 hydroxyl in the resulting compound of formula (II) into R3 when C-ι_g alkoxy or C 1-7 acyloxy. The reaction is normally carried out in a solvent, such as a 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-^g alkoxy or C-L_ 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 R 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 E 1 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 . t 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-l-benzopyran-3-ol (Dl) 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- l-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 ^H nmr (CDCI3) δ 1.17 (s, 3H) ; 1.54 (s, 3H) ; 1.83-2.33 ( , 2H) ; 2.33-2.;8 ( , 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- l-benzopyran-3-ol (El) 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 (O.llg) having m.p. 162-4°C. H 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=llHz, 1H) 5.27 (d, J=10Hz, 1H) 5.57 (d, J=18Hz, 1H) 6.61 (dd, J=18,llHz, 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. C 17 H 21 N0 3 requires 287.1521. Analysis: Found C,71.02; H, 7.65; N,4.84. C 17 H 21 N0 3 requires C,71.06; H,7.37; N,4.87. Example 2 trans-2,2-Dimethyl-3,4-dihydro-6-prop-l-en-l-yl-4- (2- oxopyrrolidinyl) -2H-l-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. -23- trans-2,2-dimethyl-6-formyl-4-(2-oxopyrrolid-inyl)-2H-1- benzopyran-3-ol (Dl) (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. C 18 H 23 N0 3 retires 301.1678. Analysis: Found C,71.73; H,7.69; N,4.65. C 18 H 23 N0 3 requires C,71.77; H,7.63; N,4.60. Example 3 trans-2,2-Dimethyl-6-ethynyl-4-(2-oxopyrrolidinyl)-2H- l-benzopyran-3-ol (E3) A solution of trans-6-(2-chloroethenyl)-2,2-dimethyl-4- (2-oxopyrrolidinyl)-2H-l-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. ^H 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) ; 53.22-3.36 (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. C 17 H 19 0 3 requires C, 71.56; H, 6.71; N, 4.91%. 0 Example 4 trans-2,2-Dimethyl-6-prop-l-vn-l-yl-4-(2-oxopyrrolidinyl)- 2H-l-benzopyran-3-ol (E4) 5 Bromine (1.06 g) was added dropwise to a stirred solution of 2,2-dimethyl-3,4-dihydro-6-prop-l-en-l-yl- trans-4- (2-oxopyrrolidinvl)-2H-benzopyran-3-ol (2 g) in chloroform (4 ml) at room temperature. After 2 h the 0 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), 5 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 0 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. 5 ^H 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, IH) ; 3.30-3.75 (m, 2H; < includes broad singlet at δ 3.54); 3.83 (d, J=10Hz, IH) ; 5.32 (d, J=10Hz, IH) ; 6.82 (d, J=8Hz, IH) ; 7.06 (d, J=2Hz, IH) ; 7.28 (dd, J=8Hz, 2Hz, IH) . trans-6-Etheny1-3,4-dihydro-2,2-dimethyl-4R-(2-oxo- piperidinyl)-2H-l-benzopyran-3S-ol (E5-V m.p. 205-208°C was prepared in accordance with the method described in EP-A-412760. Antihvpertensive 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, 3_2, 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 5 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 10 treatment of hypertension. 3. A composition or compound according to claim 1 or 2 wherein E is E 1 and Y is N. 154. A composition or compound according to claim 2 or 3 wherein R^ and R2 are both methyl. 5. A composition or compound according to any of claims 1 to 4 wherein R3 is hydroxy. 20 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-l-yl)- 2H-benzopyran-3S-ol. 25 9. trans-2,2-Dimethyl-6-ethenyl-4- (2-oxopyrrolidinyl)- 2H-l-benzopyran-3-ol, trans-2,2-dimethy1-3,4-dihydro-6-prop-l-en-l-yl-4- (2- 30 oxopyrrolidinyl)-2H-l-benzopyran-3-ol, trans.-2,2-dimethyl-6-ethyny1-4-(2-oxopyrrolidinyl)-2H- l-benzopyran-3-ol or -27- trans-2,2-dimethyl-6-prop-l-yn-4-(2-oxopyrrolidinyl)-2H- l-benzopyran-3-ol. 10. 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.

Inventors: BURRELL GORDON, CASSIDY FREDERICK, EVANS JOHN MORRIS, STEMP GEOFFREY, BURRELL, GORDON, CASSIDY, FREDERICK, EVANS, JOHN, MORRIS, STEMP, GEOFFREY
Applicants: BEECHAM GROUP PLC
Application year: 1991
Main classification: A61K31
IPC codes: A61K31, A61P9, C07D311, C07D405, C07D409, C07D413, C07D417