CHROME DERIVATIVES

Abstract: A compound of formula (I): wherein: either one of R, and R₂ is hydrogen and the other is selected from the class of C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonyloxy, C₁₋₆ alkylhydroxymethyl, nitro, cyano, chloro trifluoromethyl, C₁₋₆ alkylsulphinyl, C₁₋₆ alkylsul­ phonyl, C₁₋₆ alkoxysulphinyl, C₁₋₆ alkoxysulphonyl, C₁₋₆ alkyl­ carbonylamino, C₁₋₆ alkoxycarbonylamino, C₁₋₆ alkyl­ thiocarbonyl, C₁₋₆ alkoxy-thiocarbonyl, C₁₋₆ alkyl­ thicarbonyloxy, 1-mercapto C₂₋₇ alkyl, formyl, or aminosul­ phinyl, aminosulphonyl or aminocarbonyl, the amino moiety being optionally substituted by one or two C₁₋₆ alkyl groups, or C₁₋₆ alkylsulphinylamino, C₁₋₆ alkylsulphonylamino, C₁₋₆ alkoxysulphinylamino or C₁₋₆ alkoxysulphonylamino, or ethylenyl terminally substituted by C₁₋₆ alkylcarbonyl, nitro or cyano, or -C(C₁₋₆) alkyl)NOH or -C(C₁₋₆ alkyl)NNH₂, or one of R₁and R₂ is nitro, cyano or C₁₋₃ alkylcarbonyl and the other is methoxy or amino optionally substituted by one or two C₁₋₆ alkyl or by C₂₋₇ alkanoyl; one of R₃ and R₅ is hydrogen or C₁₋₄ alkyl and the other is C₁₋₄ alkyl or R₃ and R₄ together are C₂₋₅ polymethylene; either R₅ is hydrogen, hydroxy, C₁₋₆ alkoxy or C₁₋₇ acyloxy and R₆ is hydrogen or R₅ and R₆ together are a bond; R₇ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, C₁₋₁₂ carboxylic acyl, or amino or aminocarbonyl optionally substituted by one or two C₁₋₆ alkyl; X is oxygen or sulphur; n is 1 or 2; the nitrogen-containing group in the 4-position being trans to the R₅ group when R₅ is hydroxy, C₁₋₆ alkoxy or C₁₋₇ acyloxy; or a pharmaceutically acceptable salt or solvate thereof, a process for its preparation, and its use as a pharmaceutical.

Description: The present invention relates to novel chromans and chromenes having pharmacological activity, to a process for preparing them, to pharmaceutical compositions containing them, and to their use in the treatment of animals. U.S. Patents 4 110 347, 4 119 643 and 4 251 537 and European Patent Publications 28 064 and 28 449 disclose classes of compounds that are described as having blood pressure lowering activity or anti-hypertensive activity. European Patent Publications 76 075, 91 748, 93 534 and 95 310 disclose classes of chromans that are described as having blood pressure lowering activity. In addition, European Patent Publication 93 535 discloses a class of chromans and chromenes that are also described as having blood pressure lowering activity. A further class of chromans and chromenes has now been discovered which have a tetrahydroisoquinolin-1-on-2-yl, tetrahydroisoquinolin-1-thion-2-yl, 1-oxo-1,3-dihydroisoindol-2-yl or 1-thioxo-1,3-dihydroisoindol-2-yl moiety that substitutes the chroman or chromene in the 4-position. In addition, such chromans and chromenes have been found to have blood pressure lowering activity. Accordingly, the present invention provides a compound of formula (I): wherein: either one of R₁ and R₂ is hydrogen and the other is selected from the class of C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonyloxy, C₁₋₆ alkylhydroxymethyl, nitro, cyano, chloro, trifluoromethyl, C₁₋₆ alkylsulphinyl, C₁₋₆ alkylsulphonyl, C₁₋₆ alkoxysulphinyl,C₁₋₆ alkoxysulphonyl, C₁₋₆ alkylcarbonylamino, C₁₋₆ alkoxycarbonylamino, C₁₋₆ alkyl-thiocarbonyl, C₁₋₆ alkoxy-thiocarbonyl, C₁₋₆ alkyl-thiocarbonyloxy, 1-mercapto C₂₋₇ alkyl, formyl, or aminosulphinyl, aminosulphonyl or aminocarbonyl, the amino moiety being optionally substituted by one or two C₁₋₆ alkyl groups, or C₁₋₆ alkylsulphinylamino, C₁₋₆ alkylsulphonylamino, C₁₋₆ alkoxysulphinylamino or C₁₋₆ alkoxysulphonylamino, or ethylenyl terminally substituted by C₁₋₆ alkylcarbonyl, nitro or cyano, or -C(C₁₋₆ alkyl)NOH or -C(C₁₋₆ alkyl)NNH₂, or one of R₁ and R₂ is nitro, cyano or C₁₋₃ alkylcarbonyl and the other is methoxy or amino optionally substituted by one or two C₁₋₆ alkyl or by C₂₋₇ alkanoyl; one of R₃ and R₄ is hydrogen or C₁₋₄ alkyl and the other is C₁₋₄ alkyl or R₃ and R₄ together are C₂₋₅ polymethylene; either R₅ is hydrogen, hydroxy, C₁₋₆ alkoxy or C₁₋₇ acyloxy and R₆ is hydrogen or R₅ and R₆ together are a bond; R₇ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, C₁₋₁₂ carboxylic acyl, or amino or aminocarbonyl optionally substituted by one or two C₁₋₆ alkyl; X is oxygen or sulphur; n is 1 or 2; the nitrogen-containing group in the 4-position being trans to the R₅ group when R₅ is hydroxy, C₁₋₆ alkoxy or C₁₋₇ acyloxy; or a pharmaceutically acceptable salt or solvate thereof. When one or R₁ and R₂ is hydrogen, the other is preferably selected from the class of C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, nitro and cyano. In particular, when one of R₁ and R₂ is hydrogen, the other is preferably acetyl, nitro or cyano, especially nitro or cyano. When one or R₁ and R₂ is hydrogen, it is preferred that R₂ is hydrogen. When one of R₁ and R₂ is nitro, cyano or C₁₋₃ alkylcarbonyl, the other is preferably amino optionally substituted by one or two C₁₋₆ alkyl or by C₂₋₇ alkanoyl. In particular, when one of R₁ and R₂ is nitro, cyano or C₁₋₃ alkylcarbonyl, the other is amino, methylamino, dimethylamino or acetylamino. Most preferably, one of R₁ and R₂ is nitro or cyano, especially cyano and the other is amino. When one of R₁ and R₂ is nitro, cyano or C₁₋₃ alkylcarbonyl, it is preferred that R₁ is nitro, cyano or C₁₋₃ alkycarbonyl. The alkyl groups or alkyl moieties of alkyl-containing group for R₁ and R₂ are, preferably, methyl or ethyl. Preferably, R₃ and R₄ are both C₁₋₄alkyl. In particular, they are both methyl or ethyl, preferably both methyl. When R₅ is C₁₋₆ alkoxy and R₆ is hydrogen, preferred examples of R₅ include methoxy and ethoxy, of which methoxy is more preferred. When R₅ is C₁₋₇ acyloxy and R₆ is hydrogen, a preferred class of R₅ is unsubstituted carboxylic acyloxy, such as unsubstituted aliphatic acyloxy or benzoyloxy. However, it is more preferred that R₅ and R₆ together are a bond or that R₅ and R₆ are both hydrogen, or, in particular, that R₅ is hydroxy and R₆ is hydrogen. When R₇ is C₁₋₁₂ carboxylic acyl, preferred examples thereof include C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl and carboxy. When R₇ is C₁₋₆ alkyl or is a C₁₋₆ alkyl-containing group, the alkyl moiety is, preferably, methyl or ethyl. Preferably, R₇ is hydrogen. Preferably, X is oxygen. Examples of a pharmaceutically acceptable salt of a compound formula (I) include the acid addition salts of a compound of formula (I), wherein one or the other of R₁ or R₂ is an amino or an amino-containing group, or wherein R₇ is amino, for example the hydrochloride and hydrobromide salts. Examples of a pharmaceutically acceptable solvate of a compound of formula (I) include the hydrate. Preferably, a compound of formula (I) is in substantially pure form. The compounds of formula (I), wherein R₅ is hydrogen, hydroxy, C₁₋₆ alkoxy or C₁₋₇ acyloxy and R₆ 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 racemic modifications. Examples of compounds of formula (I) include the compound prepared in the Example hereinafter. The present invention also provides a process for the preparation of a compound of formula (I), which comprises the reaction of a compound of formula (II): wherein R₁¹ is R₁ as defined hereinbefore or a group or atom convertible thereto, R₂¹ is R₂ as defined hereinbefore or a group or atom convertible thereto, and R₃ and R₄ are as defined hereinbefore, and a compound of formula (III): wherein R₇¹ is R₇ as defined hereinbefore or a group or atom convertible thereto, and X and n are as defined hereinbefore; in the case where R₁¹ is a group or atom convertible into R₁, converting the group or atom into R₁; in the case where R₂¹ is a group or atom convertible into R₂, converting the group or atom into R₂; in the case where R₇¹ is a group or atom convertible into R₇, converting the group or atom into R₇; optionally converting R₁ and/or R₂ and/or R₇ in the resulting compound of formula (I) into another R₁,R₂ or R₇ respectively; optionally converting the resulting compound of formula (I), wherein R₅ is hydroxy and R₆ is hydrogen, into another compound of formula (I). wherein R₅ is C₁₋₆ alkoxy or C₁₋₇ acyloxy and R₆ is hydrogen; optionally dehydrating the resulting compound of formula (I), wherein R₅ is hydroxy and R₆ is hydrogen, so as to obtain the corresponding compound of formula (I), wherein R₅ and R₆ together are a bond; optionally reducing the resulting compound of formula (I), wherein R₅ and R₆ together are a bond, so as to obtain the corresponding compound of formula (I), wherein R₅ and R₆ are both hydrogen; in the case where in the resulting compound of formula (I), X is oxygen, optionally thiating the compound so as to obtain the corresponding compound of formula (I), wherein X is sulphur; and optionally forming a pharmaceutically acceptable salt or solvate. It is particularly preferred that the reaction between the compounds of formulae (II) and (III) is carried out under basic conditions so as to facilitate the formation of the anion of the compound of formula (III), for example, in the presence of sodium hydride. Examples of conversions of a group or atom for R₁¹ or R₂¹ into R₁ or R₂ are generally known in the art of aromatic chemistry. For example, if it is desired to obtain a compound of formula (I), wherein one of R₁ and R₂ is hydrogen and the other is nitro, it is possible to carry out the reaction between the compounds of formulae (II) and (III) with one of R₁¹ and R₂¹ being hydrogen and the other being acetamido and then to nitrate the resulting compound in conventional manner and subsequently to convert the acetamido group into a hydrogen atom by hydrolysis, diazotisation and decomposition in conventional manner. Examples of conversions of a group or atom for R₇¹ into R₇ are generally known in the art of aromatic chemistry as for R₁¹ and R₂¹ above. If the optional conversion of the resulting compound of formula (I), wherein R₅ is hydroxy and R₆ is hydrogen, into another compound of formula (I), wherein R₅ is C₁₋₇ acyloxy and R₆ is hydrogen, is to be carried out, then it is preferred first to protect any unsubstituted terminal amine that may be present for R₁, R₂ or R₇ and after the acylation reaction to convert the protected amino moiety into the required terminal amine.Examples of protecting agents and their addition and removal are generally known in the art. If, in the case where, in the resulting compound of formula (I), X is oxygen, the optional thiation of the compound is to be carried out so as to obtain the corresponding compound of formula (I), wherein X is sulphur, then it is preferred first to protect any carbonyl function that may be present as part of the group for R₁, R₂ or R₇ and, after the thiation, to convert the protected carbonyl-containing group into the required group for R₁ , R₂ or R₇. Examples of preferred carbonyl protecting group include ketalising agents, which may be added and removed in conventional manner. Examples of an optional conversion of R₁ or R₂ in the resulting compound of formula (I) into another R₁ or R₂, as defined hereinbefore, include the optional conversion of an α-hydroxyethyl group into acetyl by oxidation, the optional conversion of an amino group into a chloro atom by diazotisation and reaction with a chloride salt, the optional conversion of an amino group into an amino group substituted by one or two C₁₋₆ alkyl or by C₂₋₇ alkanoyl, or the optional conversion of a hydrogen atom into a nitro group by nitration. The optional conversion of R₇ in the resulting compound of formula (I) into another R₇, as defined hereinbefore may be carried out by conventional procedures, such as by the appropriate examples given for the optional conversion of R₁ or R₂ above. The optional conversion of the resulting compound of formula (I), wherein R₅ is hydroxy and R₆ is hydrogen, into another compound of formula (I), wherein R₅ is C₁₋₆ alkoxy or C₁₋₇ acyloxy and R₆ is hydrogen, may be carried out respectively by alkylation using an alkyl iodide in an inert solvent, such as toluene, in the presence of a base, such as potassium hydroxide, or by acylation using a carboxylic acid chloride or anhydride in a non-hydroxylic solvent in the presence of a base such as trimethylamine, triethylamine or piperidine. The optional dehydration of the resulting compound of formula (I), wherein R₅ is hydroxy and R₆ is hydrogen, so as to obtain the corresponding compound of formula (I), wherein R₅ and R₆ together are a bond, may be carried 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 R₅ and R₆ together are a bond, so as to obtain the corresponding compound of formula (I), wherein R₅ and R₆ are both hydrogen, may be carried out in conventional manner by catalytic hydrogenation using palladium on charcoal. In the case where, in the resulting compound of formula (I), X is oxygen, the optional thiation of the compound may be carried out so as to obtain the corresponding compound of formula (I), wherein X is sulphur, 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 any of R₁, R₂ and R₇ in the resulting compound of formula (I) is amino or an amino-containing group, may be carried out conventionally. The compounds of formula (II) are known compounds and can be prepared in accordance with the processes described in the aforementioned U.S. patents and European Patent Publications, the contents of which are incorporated herein by reference. The compounds of formula (III) are also known compounds or can be prepared by conventional procedures from 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. The present invention accordingly provides a pharmaceutical composition which comprises a compound of this invention 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 this invention 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. 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 unit dose forms include tablets, capsules and powders in sachets or vials. Such unit dose forms 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 20 mg. 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 1 to 200 mg for a 70 kg human adult and more particularly from 1 to 10 mg. No toxicological effects are indicated for the compounds of the invention at the above dosage range. The compositions of the invention may be formulated with conventional excipients, such as a filler, a disintegrating agent, a binder, a lubricant, a flavouring agent and the like. They are formulated in conventional manner, for example in a manner similar to that used for known anti-hypertensive agents, diuretics and β-blocking agents. The present invention further provides a compound of the invention for use as an active therapeutic substance. Compounds of formula (I) are of particular use in the treatment of hypertension. The present invention yet further provides a method of treating hypertension in mammals including man, which comprises adminstering to the suffering mammal an anti-hypertensive effective amount of a compound or a pharmaceutical composition of the invention. The following example relates to the preparation of a compound of formula (I). Example 1 6-Cyano-3,4-dihydro-2,2-dimethyl-trans-4-(N-tetrahydroisoquinolin-1-one)-2H-benzo[b]-pyran-3-ol (E1) To a mixture of 6-cyano-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-benzo[b]pyran (1.27g) and 1,2,3,4-tetrahydroisoquinolin-1-one (0.93g) stirred in dry dimethyl sulphoxide (30 ml) was added sodium hydride (0.19g, 80% dispersion in oil). After stirring at room temperature for 4 hours, water (60 ml) was added and the reaction stirred for 1 hour. The solid precipitate was filtered off, chromatographed and recrystallised from ethyl acetate-pentane, to give the title compound (0.45g) as crystals of m.p. 218-219°C. NMR (CDCl₃) δ 1.35 (3H, s) 1.57 (3H, s) 2.80-3.05 (2H, m) 3.10-3.40 (3H, m) including 1H exchangeable with D₂O 3.65-3.93 (1H, m) collapsing to d, J=10Hz on addition of D₂O 6.04 (1H, d, J=10Hz) 6.92 (1H, d, J=10Hz) 7.10-7.55 (5H, m) 7.98-8.15 (1H, m) 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, 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 o 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.

Claims: A compound of formula (I): wherein: either one of R₁ and R₂ is hydrogen and the other is selected from the class of C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonyloxy, C₁₋₆ alkylhydroxymethyl, nitro, cyano, chloro, trifluoromethyl, C₁₋₆ alkylsulphinyl, C₁₋₆ alkylsulphonyl, C₁₋₆ alkoxysulphinyl,C₁₋₆ alkoxysulphonyl, C₁₋₆ alkylcarbonylamino, C₁₋₆ alkoxycarbonylamino, C₁₋₆ alkyl-thiocarbonyl, C₁₋₆ alkoxy-thiocarbonyl, C₁₋₆ alkyl-thiocarbonyloxy, 1-mercapto C₂₋₇ alkyl, formyl, or aminosulphinyl, aminosulphonyl or aminocarbonyl, the amino moiety being optionally substituted by one or two C₁₋₆ alkyl groups, or C₁₋₆ alkylsulphinylamino, C₁₋₆ alkylsulphonylamino, C₁₋₆ alkoxysulphinylamino or C₁₋₆ alkoxysulphonylamino, or ethylenyl terminally substituted by C₁₋₆ alkylcarbonyl, nitro or cyano, or -C(C₁₋₆ alkyl)NOH or -C(C₁₋₆ alkyl)NNH₂, or one of R₁ and R₂ is nitro, cyano or C₁₋₃ alkylcarbonyl and the other is methoxy or amino optionally substituted by one or two C₁₋₆ alkyl or by C₂₋₇ alkanoyl; one of R₃ and R₄ is hydrogen or C₁₋₄ alkyl and the other is C₁₋₄ alkyl or R₃ and R₄ together are C₂₋₅ polymethylene; either R₅ is hydrogen, hydroxy, C₁₋₆ alkoxy or C₁₋₇ acyloxy and R₆ is hydrogen or R₅ and R₆ together are a bond; R₇ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, C₁₋₁₂ carboxylic acyl, or amino or aminocarbonyl optionally substituted by one or two C₁₋₆ alkyl; X is oxygen or sulphur; n is 1 or 2; the nitrogen-containing group in the 4-position being trans to the R₅ group when R₅ is hydroxy, C₁₋₆ alkoxy or C₁₋₇ acyloxy; or a pharmaceutically acceptable salt or solvate thereof. A compound according to claim 1, wherein one of R₁ and R₂ is hydrogen and the other is selected from the class of C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, nitro and cyano. A compound according to claim 2, wherein R₂ is hydrogen and R₁ is nitro or cyano. A compound according to any preceding claim, wherein R₃ and R₄ are both methyl. A compound according to any preceding claim, wherein R₅ is hydroxy, C₁₋₆ alkoxy or C₁₋₇ acyloxy and R₆ is hydrogen. A compound according to any preceding claim, wherein n is 2. 6-cyano-3,4-dihydro-2,2-dimethyl- trans -4-(N-tetrahydroisoquinolin-1-one)-2H-benzo[b]-pyran-3-ol. A process for the preparation of a compound of formula (I) as defined in claim 1, which comprises the reaction of a compound of formula (II): wherein R₁¹ is R₁ as defined in claim 1 or a group or atom convertible thereto, R₂¹ is R₂ as defined in claim 1 or a group or atom convertible thereto, and R₃ and R₄ are as defined in claim 1, and a compound of formula (III): wherein R₇¹ is R₇ as defined in claim 1 or a group or atom convertible thereto, and X and n are as defined in claim 1; in the case where R₁¹ is a group or atom convertible into R₁, converting the group or atom into R₁; in the case where R₂¹ is a group or atom convertible into R₂, converting the group or atom into R₂; in the case where R₇¹ is a group or atom convertible into R₇, converting the group or atom into R₇; optionally converting R₁ and/or R₂ and/or R₇ in the resulting compound of formula (I) into another R₁,R₂ or R₇ respectively; optionally converting the resulting compound of formula (I), wherein R₅ is hydroxy and R₆ is hydrogen, into another compound of formula (I), wherein R₅ is C₁₋₆ alkoxy or C₁₋₇ acyloxy and R₆ is hydrogen; optionally dehydrating the resulting compound of formula (I), wherein R₅ is hydroxy and R₆ is hydrogen, so as to obtain the corresponding compound of formula (I), wherein R₅ and R₆ together are a bond; optionally reducing the resulting compound of formula (I), wherein R₅ and R₆ together are a bond, so as to obtain the corresponding compound of formula (I), wherein R₅ and R₆ are both hydrogen; in the case where in the resulting compound of formula (I), X is oxygen, optionally thiating the compound so as to obtain the corresponding compound of formula (I), wherein X is sulphur; and optionally forming a pharmaceutically acceptable salt or solvate. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier. A compound according to any one of claims 1 to 7 or a pharamceutically acceptable salt or solvate thereof, for use in the treatment of hypertension.

Inventors: ASHWOOD, VALERIE ANNE, EVANS, JOHN MORRIS
Applicants: BEECHAM GROUP PLC
Application year: 1985
Main classification: C07D405
IPC codes: C07D405, A61P9, A61K31