WO1987007607A1 - PYRANO (3,2-c) PYRIDINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM - Google Patents

Abstract

Compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein, R1 is hydrogen or alkyl; R2 is alkyl or R1 and R2 are polymethylene; R3 is hydrogen, hydroxy, alkoxy, acyloxy; R4 is hydrogen or R3 and R4 are a bond; R5 is hydrogen, optionally substituted alkyl, alkenyl, optionally substituted amino, optionally substituted aryl or heteroaryl, carboxy, alkoxycarbonyl or aminocarbonyl; R6 is hydrogen or alkyl or R5 and R6 together are -CH2-(CH2)n-Z-(CH2)m-, wherein m and n are 0 to 2, m + n is 1 or 2, Z is CH2, O, S, NR; R is hydrogen, alkyl, alkanoyl, phenyl-alkyl, naphthycarbonyl, phenylcarbonyl, benzylcarbonyl, or heteroarylcarbonyl; X is O, S or R5, R6, X and N together are tetrahydroisoquinolinone or tetrahydroisoquinolinthione. These compounds show anti-hyper tensive activity.

Description

Pyrano (3,2-c) pyridine derivatives, process for their preparation and pharmaceutical compositions containing them.

The present invention relates to novel pyranopy i ines 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, 91748, 93535, 95316, 107423, 120426, 120427, 126311 and 126367 disclose classes of compounds that are described as having blooα pressure lowering activity or anti-hypertensive activity.

A structurally distinct class of compounds has now been discovered which are [2,3-c]pyranopyridines substituted in the 4-position by a cyclic or acyclic amide, the nitrogen atom of the amide moiety being bonded directly to the carbon atom in the 4-ρosition. Such pyranopyridines have oeen found to have blood pressure lowering activity, useful in the treatment of hypertension. In addition, these compounds are oelieved 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 peptic ulcers, irritable bowel syndrome and diverticular disease, reversible airways obstruction and asthma; premature labour; and incontinence. They are also indicated as of potential use in the treatment of cardiovascular disorders other than hypertension, such as congestive heart failure, angina, peripheral vascular disease and cerebral vascular disease. Accordingly, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:

^R6\_N/^C=X

(I)

wherein:

one of R_j_ and R2 is hydrogen or C-_j__^ alkyl and tne other is C_j__4 alkyl or R-^ and R₂ together are C₂_5 polymethylerie;

either R3 is hydrogen, hydroxy, Cτ__₆ alkoxy or

C_]__7 acyloxy and R is hydrogen or R3 and R together are a oond;

R5 is hydrogen; C_j__ alkyl optionally substituted by up to three halo atoms, by hydroxy, C_]__g alkoxy, Cτ__g alkoxycarbonyl, carboxy, or ami o optionally substituted by one or two independent Cτ__g alkyl groups or disubstituted by 04.5 polymethylene; C2-6 alkenyl; amino optionally substituted oy a Cτ__g alkyl or C_j__g alkenyl group or by a Cτ__5 alkanoyl group optionally substituted by up to three halo atoms, by a phenyl group optionally substituted by C_j__g alkyl, C_j__₆ alkoxy or halogen; or aryl or heteroaryl, either being optionally substituted by one or more groups or atoms selected from the class of Cτ__g alkyl, C_j__g alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, C]__;L2 carboxylic acyl, or amino or aminocarbonyl optionally substituted by one or two Cτ__g alkyl groups; or (when X is 0), R5 is selected from the class of carboxy, C __Q alkoxycarbonyl, or aminocarbonyl optionally substituted by one or two CJ__Q alkyl groups; and

Rg is hydrogen or Cι_g alkyl; or

R₅ and Rg together are -CH2-(CH2)n"^z""( ^H2)m- wherein m and n are 0 to 2 such that m + n is 1 or 2 and Z is CH2, 0, S or NR wherein R is hydrogen, C_]__g alkyl, C2-.7 alkanoyl, phenyl C_]__4-alkyl, naphthylcarbonyl, phenylcarbonyl or benzyl-carbonyl optionally substituted in the phenyl or naphthyl ring by one or two of C_1-6 alkyl, C_1-6 alkoxy or halogen; or R is heteroarylcarbonyl;

X is oxygen or sulphur; or

R5, Rg, X and N together are tetrahydroisoquinolinone or tetrahydrσisoquinolin-thione 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, C^.g alkoxy or Cι_7 acyloxy.

Preferably, R_]_ and R are both Cτ__4 alkyl, in particular both methyl.

When R3 is C-_j__₆ alkoxy and R₄ is hydrogen, preferred examples of R3 include methoxy and ethoxy, of which methoxy is more preferred. When R3 is C__7 acyloxy and R4 is hydrogen, a preferred class of R3 is unsubstituted carboxylic acyloxy, such as unsubstituted aliphatic acyloxy. However, it is more preferred that R3 and R4 together are a bond, or that R3 and R are both hydrogen, or, in particular, that R3 is hydroxy and R is hydrogen.

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 Cι_g alkyl substituted by halogen is C_j__g alkyl substituted by fluoro, chloro or bro^'mo. Examples thereof include methyl or ethyl terminally substituted by one, two or three fluoro, chloro or bromo.

Examples of R5, when Cτ__₆ alkyl substituted by hydroxy, include methyl or ethyl terminally substituted by hydroxy.

A sub-group of R5, when C_]__g alkyl substituted by C_j__g alkoxy is C_j__g alkyl substituted by methoxy or ethoxy. Examples thereof include methyl or ethyl terminally substituted by methoxy or ethoxy.

A sub-group of R5, when CJ___Q alkyl substituted by CJ___Q alkoxycarbonyl is Cτ__g alkyl substituted by methoxycarbonyl or ethoxycarbonyl. Examples thereof include methyl or ethyl terminally suostituted by methoxycarbonyl or ethoxycarbonyl.

Examples of R5, when C^_ 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)_n RgR_1Q where n is 1 to 6, and Rg and R]_g are each independently hydrogen or Cτ__5 alkyl or together are C or C5 polymeth lene. Examples of n include 1 and 2, in particular 1.

Preferably Rg and R_]_ 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, put-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 an amino optionally substituted by a methyl, ethyl, propyl, butyl, allyl or trichloroacetyl group or by a phenyl group optionally substituted by one methyl, methoxy or chloro group or atom, in particular amino, me-chylamino, 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 for an R moiety in Z, 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. 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-ρyridyl.

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, chloro, fluoro, nitro or cyano, most preferably fluoro.

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_j__g alkyl, C]__5 alkoxy, halogen, trifluoromethyl, nitro or cyano. A preferred subgroup of phenyl optionally substituted as hereinoefore defined is phenyl, 4-substituteα phenyl, 3-substituted phenyl, 2-substituted phenyl, 2,4, 2,6 and 3,4-disubstituted phenyl and 3,4,5-trisubstituted phenyl.

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

When X is 0, examples of R5 also include carboxyl, methoxycarbonyl, ethoxycarbonyl,' aminocarbonyl, methylamino-carbonyl and dimethylaminocarbonyl.

R5 and Rg, when together are -CH2-(CH2)_n-Z-(CH2)_m- as defined the resulting radical substituting the pyranopyridine in the 4-position is preferably either pyrrolidonyl or piperidonyl. Other examples of 4-substituents when R5 and R_§ are joined together include those described in EP-A-107423.

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-, sec- and tert- butyl, benzyl, phenylcarbonyl or benzylcarbonyl optionally substituted in the phenyl ring by methyl, methoxy, chloro or brorao; furylcarbonyl, thienylcarbonyl, pyrrolylcarbonyl or indolylcarbonyl. Preferably R is hydrogen, methyl, n-butyl, acetyi, benzyl, benzylcarbonyl, phenylcarbonyl or furylcarbonyl. Most preferably R is hydrogen. Preferred examples of R5 and Rg are R5 is methyl or halophenyl, such as 2- or 4-fluorophenyl and g hydrogen and R5 and R₆ together are C3 or C polymethylene.

Preferably, X is oxygen.

Examples of a pharmaceutically acceptable salt of a compound of formula (I), when the compound contains a salifiable substituent 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 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.

It will also be appreciated that the pyridine in the compound of formula (I) is also salifiable, to give pyridine salts with acids, such as those with HC1 and HBr. Alternatively, internal salts such as the N-Oxide may be formed by per-acid oxidation of the corresponding compound of formula (I).

The compounds of formula (I) may also exist as solvates such as hydrates and the invention extends to these; such solvates are included wherever a compound of formula (I) is herein referred to.

The compounds of formula (I), wherein R3 is hydrogen, hydroxy, C^.g alkoxy or C_j__7 acyloxy and R is hydrogen, are asymmetric, and, therefore, can exist in the form of optical isomers.

The present invention extends to all such isomers individually and as mixtures, such as racemates. Examples of compounds of formula (I) include the compounds prepared in tne Examples hereinafter.

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

i ) acylating a compound of formula ( II ) or an N-oxide thereof :

(II)

wherein, R-. and R₂ are as hereinbefore defined, R is hydroxy, C_]__g alkoxy or G₁_₇ acyloxy, and Rg¹ is hydrogen or C_1-6 alkyl, the R^ H group being trans to the R3¹ group,

a) with an acylating agent of formula (III)

R3-CO- 1 (III)

wherein L]_ is a leaving group, and R3 is hydrogen, C]__5 alkoxycarbonyl, Cι_g alkyl optionally substituted by halogen, hydroxy, C__g alkoxy, Cτ__g alkoxycarbonyl, carboxy or amino optionally substituted as hereinbefore defined for R5 ^2-6 alkenyl or optionally substituted aryl or heteroaryl as hereinbefore defined for R5, or a group convertible to R5 as hereinbefore defined, and thereafter, when Rg is hydrogen and R_Q is Y(CH2)_Z' where z is 3 or 4 and Y is a leaving group, cyclising tne resultant compound;

b) with a compound of formula (IV)

wherein R_j_^ is hydrogen, C_]__ alkyl, _g alkenyl, ^Gl-6 alkanoyl optionally substituted by up to three nalo atoms, or phenyl optionally substituted by Cτ__g alkyl, C_]__g alkoxy or halogen; and X is oxygen or sulphur, and thereafter when R_]__j_ is hydrogen, optionally converting R_]_τ_; or

ii) where, in the resultant compound of formula (I), R5 and Rg are joined together or R5 is aminocarbonyl, reacting a compound of formula (V) or an N-oxide thereof:

wherein Rη_ and R2 are as hereinbefore defined, with a compound of formula (VI):

R₁₃NHCOR₁₂ (VI)

w_herein Rio is R5 as defined and R]_₂ is aminocarbonyl; R]_2 and R₁₃ together are -CH₂-(CH2)_n-Z-(CH₂)_m- or R13 HCOR12 ^is tetrahydroisoquinolinone; optionally converting R3 in the resulting compound into another R3 ; in the case where R3 and R in the resulting compound are hydroxy and hydrogen respectively, optionally dehydrating the compound to give another compound wherein R3 and R4 together are a bond, and optionally reducing the resulting compound wherein R3 and R4 together are a bond, to give another compound, wherein R3 and R are each hydrogen; and optionally thiating the Rg-N-CO-Rs group in the resulting compound to give a compound wherein X is sulphur; and 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 _]_ is a group that is displaceable by a primary or secondary amino nucleophile. Examples of such a grbup include C_j__₄ alkanoyloxy, _,and halogen, such as chloro and bro o or hydroxy. When the leaving group -_j_ 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 annydride, it may be prepared in situ from a carboxylic acid and an acid halide, although this is less preferred than using the halide itself. When Lτ_ is hydroxy, conventional coupling methods using dicyclohexylcarbodiimide are suitable.

In process variant i) a) , wnen R5 in the desired compound of formula (I) is an R5 optionally substituted amino-substituted alkyl group as hereinbefore defined, it is preferred that R3 is a group convertible to the R5 substituted alkyl group as hereinbefore defined, in particular that it is C]__6 alkyl substituted by halo, especially bromo. The Rs ^hai° 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. When R3 is C_j__galkoxycarbonyl, this may be converted to R5 is carboxy by conventional hydrolysis.

Less favourably R_g may be C_]__^ alkyl substituted by protected amino, protected C^-g alkylamino or amino substituted by two independent CI__Q alkyl groups, it being necessary to protect the R3 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, or calcium, potassium or sodium caroonate.

When the acylating agent of formula (III) is an acid the acylation of a compound of formula (II) is conveniently performed in the presence of a dehydrating agent, such as dicyclohexyldicarbodiimide in an inert solvent, such as dimethylformamide at a temperature of 0°C to ambient.

When R3I 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 amine, Rg^ H- is acylated, for example, by using a C2-.9 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 R3I 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 Y(CH2)_Z where the variables are as hereinbefore defined, the leaving group Y is a group that is displaceable by a secondary amino nucleophile adjacent to a carbonyl function. A preferred example is chloro.

The cyclisation reaction when R is Y(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 R^τ_ in a compound of formula (IV) is C_j__5 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 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) 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.

The reaction of the compounds of formulae (II) with (III) or (IV) results in a compound of formula (I) wherein R3 is hydroxy, C_j__₆ alkoxy or C_j__ 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 R are generally known in the art. For example, when R3 is hydroxy, it may be alkylated using an alkyl iodide in an inert solvent, such as toluene, in the presence of a base, such as potassium hydroxide, or it may be acylated using a carooxylic acid chloride or annydride in a non-hydroxylic solvent in the presence of an acid acceptor. Alternatively, when R is C±_{^ j} acyloxy or C_]__5 alkoxy, it may be converted into hydroxy by conventional hydrolysis or dealkylation respectively.

The optional dehydration of the resulting compound of formula (I), wherein R₃ and R₄ are hydroxy and hydrogen respectively, into another compound of formula (I), wherein R3 and R4 together are a bond, may be carried out under conventional dehydration conditions, for example, by using a dehydrating agent, such as sodium hydride, in an inert solvent, such as dry tetrahydrofuran, at reflux temperature.

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

The optional thiation of the R5-N-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, phosphorus pentasulphide and Lawesson's reagent ("p-methoxyphenylthiophosphine sulphide dimer) . The use of hydrogen sulphide and phosphorus pentasulphide may lead to side-reactions and, therefore, the use of Lawesson's reagent is preferred.

The thiation reaction conditions are conventional for the thiation agent employed. For example, the use of hydrogen sulphide is, preferably, acid catalysed by, for example, hydrogen chloride in a polar solvent, such as acetic acid or etnanol. 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 may oe carried out conventionally. It should be appreciated that formation of an N-Oxide by oxidation may affect other substituents and appropriate modification of reaction conditions and/or protection will be taken where necessary.

A compound of formula (II) may be prepared by reacting a compound of formula (V) , or an N-oxide thereof, as hereinbefore defined, with a compound of formula (VII):

R₆ ¹NH₂ (VII)

wherein Rg is as hereinbefore defined; and optionally converting R3¹ hydroxyl in the resulting compound of formula (II) into another R3¹.

The reaction is normally carried out in a solvent, such as a C_]__ 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 chromatograph .

The optional conversion of the hydroxy group for R3I in the resulting compound of formula (II) into a C_]___Q alkoxy or Cτ__7 acyloxy group may be carried out as hereinbefore described in relation to the corresponding conversion of R3 in a compound of formula (I).

A compound of formula (V) may be prepared by reacting a compound of formula (VIII) or an N-oxide therof:

wherein R-_j_ 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 aqueous dioxan. It is preferred that the compound of formula (V) is used directly in the reaction with (VI) .

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

- IS - (a) Room temperature; NaOH/40% benzyltrimethyl-ammonium hydroxide in methanol;

(b) Heat in o-dichlorobenzene;

(c) BuLi; anhydrous ether; -78°C, quench with water;

(d) N-bromosuccinimide/dimethylsulphoxide/water;

It is necessary to introduce a blocking moiety such as bromo, in order to direct the cyclisation (b) to produce the required product. The bromo moiety may be removed at a convenient later stage, using butyl lithium. The intermediates in the above scheme are preferably in the form of the N-oxide. The N-oxide formation is favourably carried out between stages (c) and (d) and subsequent reduction to form the unoxidised form may be carried out at a convenient later stage, by reduction, using hydrogenation or, in particular, a reducing agent such as that described in J. Am Chem. Soc. 91 , 2788, 1969.

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 substantially pure, pharmaceutically acceptable form.

The intermediates of formulae (II), (V), (VIII), (IX) and (X) are believed to be novel and represent part of the present invention. The intermediates of formulae (III), (IV), (VI) and (VII) are known or may be prepared in accordance with an appropriate known process for preparing structurally similar known compounds.

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 may also be of potential use in the treatment of other disorders hereinbefore described.

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

The form and preparation of compositions are as described for the compounds of EP-A-205292.

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 2 to 50 mg, for example 5 to 25 mg such as 6, 10, 15 or 20mg. Such compositions may be administered from 1 to 6 times a day, more usually from 2 to 4 times a day, in a manner such that the daily dose is from 5 to 200 mg for a 70 kg human adult and more particularly from 10 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 examples relate to the preparation of compounds of formula (I); the following descriptions relate to the preparation of intermediates thereto.

All temperatures therein are in °C. Descriptions

1. 8-Bromo-2,2-dimethyl-2H-pyrano[2,3-c]pyridine (DI)

2-Bromo-3-hydroxypyridine (25 g) , 40% benzyltrimethyl- ammonium hydroxide in methanol (50 ml) and 3-chloro-3- methylbut-1-yne (22 g) were dissolved in dichloromethane (150 ml). To this stirred solution was added sodium hydroxide pellets (10 g) dissolved in water (150 ml), and the resulting mixture stirred at room temperature for 6 days. The layers were separated and the aqueous layer further extracted with chloroform. The combined organic layers were evaporated and the resulting oil taken up in ether and washed successively with 10% sodium hydroxide solution, water, brine, then dried over anhydrous magnesium sulphate. Evaporation of solvents, after filtration, gave the crude propargyl ether which was heated under reflux in o-dichlorobenzene for 1 hour. Solvent was evaporated in vacuo and the residue distilled to give the title pyranopyridine (12.2 g) of b.p. 60-62°C/0.1 mmHg. NMR (CDC1₃) ό 1.47 (s, 6H) 5.78 (d, J=llHz, 1H)

6.23 (d, J=llHz, 1H) 6.79 (d, J=4Hz, 1H) 7.73 (d, J=4Hz, 1H)

2. 2,2-Dimethyl-2H-pyrano[2,3-c]pyridine (D2)

To a solution of 8-bromo-2,2-dimethyl-2H-pyrano[2,3-c] pyridine (12.2 g) dissolved in dry ether (50 ml) at -78°C was added n-butyl lithium (41 ml, 1.6 M in nexane) dropwise with stirring under nitrogen during 15 min. After an additional 45 min under these conditions, water was added cautiously and the mixture allowed to attain room temperature. The layers were separated, and the aqueous layer further extracted with ether. The combined organic extracts were washed with water, then brine, and dried over anhydrous magnesium sulphate. Filtration and evaporation gave the crude title compound as an oil (8.64 g) . A portion was distilled to give the purified sample of b.p. 70°C/0.1 mmHg.

NMR (CDC1₃) δ 1.42 (s, 6H)

5.67 (d, J=10Hz, 1H) 6.18 (d, J=10Hz, 1H)

6.68 (d, J=5Hz, 1H) 7.93 (d, J=5Hz, 1H)

7.97 (m, 1H)

3. 2,2-Dimethyl-2H-pyranoC2,3-c]pyridine oxide (D3)

m-Chloroperbenzoic acid (9.15 g) was added to a stirred chloroform (150 ml) solution of 2,2-dimethyl-2H-pyrano [2,3-c]pyridine (8.64 g) during 15 min. The solution was then heated under reflux for 1 h. The solution was cooled and evaporated and the residue chromatographed on silica gel (500 g) . Elution with 5% methanol- chloroform gave the title oxide (5.96 g) as a chromatographically homogeneous colourless gum. NMR (CDCI3) δ 1.45 (s, 6H)

5.73 (d, J=10Hz, 1H) 6.27 (d, J=10Hz, 1H)

6.87 (d, J=6Hz, 1H) 7.75 (irregular m, 2H) 4. trans-3-Bromo-3,4-dihydro-2,2-dimethyl~2H- pyrano[2, 3-c]pyridin-4-ol oxide (D4)

To the pyranopyridine N-oxide of description 3 (5.35 g) in dimethyl sulphoxide (25 ml) and water (0.54 ml) was added N-bromosuccinimide (5.25 g) with stirring at room temperature. The reaction mixture was stirred for 20 min when a precipitate formed. The solution was diluted with water and extracted with chloroform. The organic phase was washed with water, brine, and dried over anhydrous magnesium sulphate. The solution was filtered and evaporated to give the bromohydrin as a brown solid (5.87 g) . A small portion was triturated with ethyl acetate, and recrystallised from ethyl acetate-methanol to give crystals of m.p. 185-187°c.

5. 3,4-Epoxy-3,4-dihydro-2, 2-dimethyl-2H- pyrano[2, 3-c]pyridin-4-ol oxide (D5)

The bromohydrin of description 4 (1.56 g) and powdered potassium hydroxide pellets (2.0 g) were heated under reflux and stirred during 4 h. The solution was cooled, filtered and evaporated to give a gum which crystallised (1.01 g) on standing. NMR (CDC1₃) δ 1.31 (s, 3H) 1.58 (s, 3H) 3.51 (d, J=4Hz, 1H) 3.88 (d, J=4Hz, 1H) 7.20 (d, J=7Hz, 1H)

7.75 (irregular m, 2H) 6. trans-4-Amino-3,4-dihydro-2,2-dimethyl-2H- pyrano[2, 3-c]pyridin-3-ol oxide (D6)

The epoxide of description 5 (1.01 g) was dissolved in dry ethanolic ammonia (30 ml)- and the mixture stirred at room temperature for 7 days. Evaporation and trituration with ethyl acetate gave the aminoalcohol (0.62 g) as a pale yellow solid. A portion recrystallised from ethyl acetate-ethanol had m.p. 206-208°C (witn decomposition).

7. trans-4-Chlorovaleroylamino-3,4-dihydro-2,2- dimethyl-2H-pyrano[2,3-c]pyridin-3-ol oxide (D7)

The aminoalcohol of description 6 (0.55 g) and triethylamine (0.40 ml) were stirred in dichloromethane (600 ml) with ultrasonication. 4-Chlorovaleryl chloride (0.37 ml) was added dropwise to the solution during 1 h, and the stirring and sonication continued for 10 min. The solution was evaporated and chromatographed on silica gel and eluted with chloroform containing up to 10% methanol in a gradient elution. The title compound of description 7 was obtained as a crude solid (0.44 g) . Mass spectrum E.I. ⁺-H2θ at m/z 310.

8. trans-4-(4-chlorobutyroylamino)-3,4-dihydro-2,2- dimethyl-2H-pyrano[2,3-c]pyridin-3-ol oxide (D8)

To an ultrasonicated, stirred solution of the aminoalcohol of description 6 (1.54 g) dissolved in dichloromethane (600 ml) and triethylamine (0.64 ml) was added chlorobutyryl chloride (0.91 ml). The conditions were maintained for a further 1 h. The solution was evaporated and the residue chromatographed on silica gel (200 g) and eluted with chloroform 10% methanol-chloroform in a gradient elution, to give the title compound (1.0 g) . NMR (CDC1₃ + CD3OD) δ 1.38 (s, 3H)

? 1.53 (s, 3H)

2.15 ( , 2H)

2.43 (m, 2H)

3.62 (m, 3H) 4.92 (d, J=10Hz, 1H)

7.10 (d, J=6Hz, 1H)

7.73 (m, 2H)

Example 1

trans-3,4-Dihydro-2, 2-dimethyl-4-(2-oxypiperidinyl)-2H- pyrano[2,3-c]pyridin-3-ol oxide (El)

The valeroylamino compound of description 7 (0.44 g) was dissolved in dry tetrahydrofuran (10 ml) and sodium hydride (45 mg ; 80% dispersion in oil) was added to the stirred solution under nitrogen. The reaction mixture was stirred for 16 h. Water was cautiously added and the solution reduced in volume and extracted with chloroform (-4x) . The material from the first two extractions was chromatographed on the chromatotron (chlorofor —methanol gradient, silica gel) and the desired material (140 mgm) combined with the product of the last two extractions (110 mgm). Recrystallisation from ethyl acetate-methanol gave the piperidone compound of example 2 as crystals (120 mgm) of m.p. 258-259°C.

NMR ( (CD₃)SO) δ 1.23 s, 3H) 1.47 s, 3H) 1.83 m, 4H) 2.46 m, 2H) 2.78 m, 1H) 3.22 m, 1H) 3.73 q, J.=10,6Hz, 1H) 5.67 m, 2H) 6.90 d, J=6Hz, 1H) 7.75 d, J=6Hz, 1H) 7.79 s, 1H) Example 2

trans-3,4-Dihydro-2,2-dimethyl-4-(2-oxopiperidinyl)-2H -pyrano[2,3-c]pyridin-3-ol (E2)

To the N-oxide of example 2 (66 mgm) in dry chloroform (20 ml) was added hexachlorodisilane (0.4 ml) dropwise with stirring under nitrogen. The mixture was stirred for 1 h at room temperature then cooled to 0°c. Aqueous sodium nydroxide solution (5 ml; 10%) was added cautiously to the chloroform solution and the layers separated. The aqueous layer was further extracted with chloroform, and the combined organic layers were dried over anhydrous magnesium sulphate. Filtration and evaporation and trituration with diethyl ether gave the compound of example 3 as an off-white powder (11 mgm) . Mass spectrum E.I. M⁺ at m/z 276.1467. ^G15^H20^N2°3 requires 276.1474.

NMR (CDC1₃) δ 1.27 (s, 3H) 1.55 (s, 3H) 1.84 (irreg m, 4H) ^' 2.60 (t, J=6Hz, 2H)

2.93 (irreg m, 1H) 3.10 (irreg m, 1H) 3.82 (d, J=10Hz, 1H) 5.93 (d, J=10Hz, 1H) 6.90 (d, J=4Hz, 1H)

8.16 (m, 1H) 8.23 (m, 1H) Example 3

trans-^"3,4-Dihydro-2,2-dimethyl-4-(2-oxopyrrolidinyl)-2H 5 -pyran[2, 3-c]pyridin-3-ol oxide (E3)

The chlorobutyroylamino compound of description 8 (487 mgm) was dissolved in dry dimethyl sulphoxide

15 (10 ml) and dry tetrahydrofuran (10 ml), and to this solution, under nitrogen, was added sodium hydride (50 mgm, 80% dispersion in oil) , and the reaction was stirred for 16 hours. Water was added cautiously to the reaction mixture, and the resulting solution

20 extracted with chloroform. The chloroform extracts were dried over anhydrous magnesium sulphate filtered and evaporated to give a residue (390 mg) which was recrystallised from ethyl acetate-methanol to give the compound of example 3 as needles (135 mg) of .p.

25 268-271°C.

Mass spectrum El M⁺ at m/z 278.1259. ^C14^H18^N2°4 requires 278.1267.

30

35 Example 4

trans-3, -Dihydro-2,2-dimethyl-4-(2-oxopyrrσlidinyl)-2H 5 -pyrano[2, 3-c]pyridin-3-ol (E4)

To the N-oxide of example 1 (240 mgm) in dichloromethane (200 ml) was added hexachlorodisilane

15 (0.4 ml) in dichloromethane (20 ml) dropwise with stirring under nitrogen. The mixture was stirred for 1 h and 10% aqueous sodium hydroxide solution (0.5 ml) was added to it. The solution was stirred for 10 min and evaporated to dryness. Extraction with chloroform,

20 and with methanol and combination of the solutions 'and evaporation gave a gummy solid which was purified (chromatotron : gradient elution chloroform — 6% methanol - chloroform) to give the title compound (110 mgm) as a crystalline solid m.p. 221-225°C.

25 Mass spectrum (El) M⁺ at m/z 262.1316. ^G14^H18^N2°3 requires 262.1318.

NMR (CD₃OD) δ 1.29 (s, 3H) 1.55 (s, 3H) 2.13 ( , 2H)

30 2.58 (m, 2H) 3.07 (m, 1H) 3.38 (m, 1H) 3.76 (d, J=10Hz, 1H) 5.22 (d, J=10Hz, 1H)

35 6.93 (d, J=5Hz, 1H) 8.07 (d, J=5Hz, 1H) 8.13 (s, 1H) PHARMACOLOGICAL DATA

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, 21_, 1 9 (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 compound of example 1 lowered systolic blood pressure by 40 ± 14 at 4 post dose, on administration of a dose of 10 mg/kg p.o. to a group of 6 rats.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

R, „C=X

^■N

wherein:

one of Ri and R2 is hydrogen or C]__4 alkyl and the other is C]__ alkyl or R_]_ and R₂ together are C _5 polymethylene;

either R3 is hydrogen, hyαroxy, ^" Cι_<- alkoxy or

C__7 acyloxy and R4 is hydrogen or R3 and R4 together are a bond;

R5 is hydrogen; C1-6 alkyl optionally substituted by up to three halo atoms, by hydroxy, Cχ-6 alkoxy, C]__g alkoxycarbonyl, carboxy, or amino optionally substituted by one or two independent C_]__g alkyl groups or disubstituted by 04_^5 polymethylene; C2-6 alkenyl; amino optionally substituted by a C]__6 alkyl or C_]__g alkenyl group or by a C]__g alkanoyl group optionally suostituted by up to three halo atoms, by a phenyl group optionally substituted by C^-o alkyl, Cj._«5 alkoxy or halogen; or aryl or heteroaryl, either being optionally substituted by one or. more groups or atoms selected from the class of C__g alkyl, C_]__g alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, Cχ_i2 carboxylic acyl, or amino or aminocarbonyl optionally substituted by one or two Cj__ alkyl groups; or (when X is 0), R5 is selected from the class of carboxy, Cι_g alkoxycarbonyl, or aminocarbonyl optionally substituted by one or two C^-^ alkyl groups; and

R6 is hydrogen or C]__6 alkyl; or

R5 and Re- together are -CH2-(CH2)n~^z~( ^H2)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 Cχ_4-alkyl, naphthylcarbonyl, phenylcarbonyl or benzyl-carbonyl optionally substituted in the phenyl or naphthyl ring by one or two of C₁__b alkyl, C^_ alkoxy or halogen; or R is heteroarylcarbonyl;

X is oxygen or sulphur; or

R₅, R5, X and N together are tetrahydroisoquinolinone or tetrahydroisoquinolin-thione 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, C_]__g alkoxy or C]__7 acyloxy.

2. A compound according to claim 1 wherein R and R2 are both methyl.

3. A compound according to claim 1 or 2 wherein R5 is hydroxy and R5 is hydrogen, or R5 and R_$ together are a bond.

4. A compound according to any one of claims 1 to 3 wherein R5 and Rg are joined to form

-CH2- CH2) ~^z"(^CH2)m~ ^s defined in claim 1.

5. A compound according to any one of claims 1 to 4 wherein R5 is methyl or R5 is phenyl or amino either being optionally substituted as defined in claim 1 ; and Rό is methyl, ethyl or hydrogen.

6. trans-3, -Dihydr0-2,2-dimethyl-4-(2- oxypiperidinyl)-2H-pyranoL2, 3-c]pyridin-3-ol oxide,

trans-3,4-dihydro-2, 2-dimethyl-4-(2-oxopiperidinyl)- 2H-pyrano[2,3-cjpyridin-3-ol,

trans-3,4-dihydro-2,2-dimethyl-4-(2-oxopyrrolidinyl)- 2H-pyranL2, 3-c]pyridin-3-ol oxide or

trans-3, -dihydro-2, 2-dimethyl-4-(2-oxopyrrolidinyl)- 2H-pyranoL2, -cjpyridin-3-ol.

7. A process for the preparation of a compound according to claim 1 or a pharmaceutically acceptable salt thereof, which comprises;

i) acylating a compound of formula (II) or an N-oxide thereof:

wherein, R]_ and R2 are as defined in claim 1, R3¹ is hydroxy, Cχ-6 alkoxy or C -7 acyloxy, and Rg¹ is hydrogen or C]__g alkyl, the Rg-'-NH group being trans to the R3¹ group,

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

R8-CO-L! (Ill)

wherein Li is a leaving group, and R3 is hydrogen, C__ alkoxycarbonyl, Cι_6 alkyl optionally substituted by halogen, hydroxy, Ci-g alkoxy, C]__6 alkoxycarbonyl, carboxy or amino optionally substituted as hereinbefore defined for R5, C₂_g 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 R^ is hydrogen and R3 is Y(CH₂)_Z, where z is 3 or 4 and Y is a leaving group, cyclising the resultant compound;

b) with a compound of formula (IV)

X=C=N.R_X1 (IV)

wherein Ru is hydrogen, Cχ-6 alkyl, Cι_g alkenyl, C]__6 alkanoyl optionally substituted by up to three halo atoms, or phenyl optionally substituted by Ci-g alkyl, Cj__6 alkoxy or halogen; and X is oxygen or sulphur, and thereafter when R_]__j_ is hydrogen, optionally converting Rχι; or

ii) where, in the resultant compound of formula (I), R5 and R5 are joined together or R5 is aminocarbonyl, reacting a compound of formula (V) or an N-oxide thereof:

wherein R]_ and R2 are as defined in claim 1, with a compound of formula (VI ) :

R13NHCOR12 (VI)

wherein R13 is Rg as defined and R]_2 is aminocarbonyl; Rl₂ and R13 together are -CH2-(CH2)_n-Z-(CH2)_m" ^or R]_3NHCOR_2 is tetrahydroisoquinolinone;

optionally converting R3 in the resulting compound into another R3; in the case where R3 and R4 in the resulting compound are hydroxy and hydrogen respectively, optionally dehydrating the compound to give another compound wherein R3 and R4 together are a bond, and optionally reducing the resulting compound wherein R3 and R4 together are a bond, to give another compound, wherein R3 and R₄ are each hydrogen; and optionally thiating the R6-N-CO-R5 group in the resulting compound to give a compound wherein X is sulphur; and optionally forming a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

9. A compound according to any one of claims 1 to 6 for use as an active therapeutic substance.

10. Use of a compound according to any one of claims 1 to 6 in the manufacture of a medicament for use in the treatment of hypertension.