WO1985001290A1

WO1985001290A1 - Antihypertensive pyrrylchromanes

Info

Publication number: WO1985001290A1
Application number: PCT/GB1984/000312
Authority: WO
Inventors: Valerie Anne Ashwood
Original assignee: Beecham Group PLC
Current assignee: Beecham Group PLC
Priority date: 1983-09-14
Filing date: 1984-09-13
Publication date: 1985-03-28
Anticipated expiration: 1986-03-14
Also published as: GB8324547D0; EP0157843A1

Abstract

Compounds 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, C1-6 alkyl-thiolmethyl, 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 C1-7 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 hydroxy, C1-6 alkoxy or C1-7 acyloxy and R6 is hydrogen or R5 and R6 together are a bond and R7 is hydrogen, halogen, CF3, C1-6 alkyl or C1-6 alkoxy; the pyrryl group being trans to the R5 group when R5 and R6 together are not a bond; or, when one or the other of R1 and R2 is an amino or an amino-containing group, a pharmaceutically acceptable salt thereof a process for their preparation and their use in the treatment of hypertension.

Description

Antihypertensive pyrrylchromanes

The present invention relates to novel compounds having pharmacological activity, to a process for preparing them, to pharmaceutical compositions containing them, and to their use in the treatment of mammals.

U.S. Patent 4 110 347, U.S. Patent 4 251 532, U.S. Patent 4366163, European Patent Publication 9912, European Patent Publication 28064 and European Patent Publication 76075 describe classes of chromans that have blood pressure lowering activity.

A class of chroman derivatives has now been discovered having a 4-pyrryl substituent. In addition such derivatives have been found to have blood pressure lowering activity.

Accordingly, the present invention provides a compound of formula (I):

( I )

wherein:

either one of R₁ and R₂ is hydrogen and the other is selected from the class of C_1-6 alkylcarbonyl, C₁_₆ alkoxycarbonyl, C₁_₆ alkylcarbonyloxy, C_{1- 6} alkylhydroxymethyl, nitro, cyano, chloro, trifluoromethyl, C_1-6 alkylsulphinyl, C_1-6 alkylsulphonyl, C_1-6 alkoxysulρhinyl,C_1-6 C_1-6 alkoxysulphonyl, C_1-6 alkylcarbonylamino, C_1-6 alkoxycarbonylamino, C_1-6 alkyl-thiocarbonyl, C_1-6 alkoxy-thiocarbbnyl, C_1-6 alkyl-thiocarbonyloxy, C_1-6 alkyl-thiolmethyl, formyl or aminosulphinyl, aminosulphonyl or aminocarbonyl, the amino moiety being optionally substituted by one or two C_1-6 alkyl groups or C_1-6 alkylsulphinylamino, C_1-6 alkylsulphonylamino, C_1-6 alkoxysulphinylamino or C_1-6 alkoxysulphonylamino or ethylenyl terminally substituted by C_1-6 alkylcarbonyl, nitro or cyano, or -C(C_1-6 alkyl)NOH or -C(C_1-6 alkyl)NNH₂, or one of R₁ and R₂ is nitro, cyano or C_1-3 alkylcarbonyl and the other is methoxy or amino optionally substituted by one or two C_1-6 alkyl or by C_{1- 7} alkanoyl;

one of R₃ and R₄ is hydrogen or C_1-4 alkyl and the other is C_1-4 alkyl or R₃ and R₄ together are C_2-5 polymethylene;

either R₅ is hydroxy, C_1-6 alkoxy or C_1-7 acyloxy and

R₆ is hydrogen or R₅ and R₆ together are a bond and

R₇ is hydrogen, halogen, CF₃, C_1-6 alkyl or C_1-6 alkoxy;

the pyrryl group being trans to the R₅ group when R₅ and R₆ together are not a bond; or, when one or the other of R₁ and R₂ is an amino or an amino-containing group, a pharmaceutically acceptable salt thereof. When one of R₁ and R₂ is hydrogen, the other is preferably selected from the class of C_1-6 alkylcarbonyl, C_1-6 alkoxycarbonyl, C_1-6 alkylcarbonyloxy, C_1-6 alkylhydroxymethyl, nitro or cyano. In particular, when one of R₁ and R₂ is hydrogen, the other is preferably nitro, cyano or C_1-3 alkylcarbonyl, such as acetyl.

When one of R₁ and R₂ is hydrogen, it is preferred that R₂ is hydrogen.

When one of R₁ and R₂ is nitro, cyano or C_1-3 alkylcarbonyl the other is preferably amino optionally substituted by one or two C_1-6 alkyl or by C_2-7 alkanoyl. In particular, when one of R₁ and R₂ is nitro, cyano or C_{1- 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 C_1-3 alkylcarbonyl, it is preferred that R₁ is nitro, cyano or C_1-3 alkylcarbonyl.

The alkyl groups or alkyl moieties of alkyl-containing groups for R₁ or R₂ are, preferably, methyl or ethyl.

Preferably, R₃ and R₄ are both C_1-4 alkyl. In particular, they are both methyl or ethyl, preferably both methyl.

When R₅ is C_1-6 alkoxy and R₆ is hydrogen, preferred examples of R₅ include methoxy and ethoxy, of which methoxy is more preferred. When R₅ is C_1-7 acyloxy and R₆ is hydrogen, a preferred class of R₅ is unsubstituted carboxylic acyloxy, such as unsubstituted aliphatic acyloxy or bensoyloxy. However, it is preferred that R₅ and R₆ together are a bond, or, more preferably, that R₅ is hydroxy and R₆ is hydrogen.

Suitable values for R₇ include chloro, bromo, CF₃, methyl, ethyl, n- and iso-propyl, methoxy, ethoxy, n- and iso-propoxy. Preferably R₇ is hydrogen.

There is a group of compounds within formula (I) of formula (II):

wherein the variables are as defined in formula (I).

Suitable and preferred values for the variables are as described for the corresponding variables under formula (I).

It will be appreciated that there is a favourable sub-group of compounds within formula (II) of formula (III):

(III)

wherein one of R₁ ¹ and R₂ ¹ is hydrogen and the other is cyano or nitro, R₅ ¹ is R₅ when other than together with R₆ forms a bond and the remaining variables are as defined in formula (I).

Suitable and preferred values for the variables are as described under formula (I).

From the aforesaid it will be appreciated that there is a preferred compound within formula (III) of formula (IV):

(IV)

There is a further sub-group of compounds within formula (II) of formula (V):

(V)

wherein:

one of R₁ ² and R₂2 is cyano or nitro and the other is amino optionally substituted as defined and the remaining variables are as defined in formula (I). Favourably R₁ ² is cyano or nitro and R₂ ² is amino. Suitable and preferred values for the remaining variables are as described under formula (I).

The compounds of the formula (I) are disymmetric and, therefore, can exist as stereoisomers. The present invention extends to all such stereoisomers individually and as mixtures, such as racemic modifications.

The present invention also provides a process for the preparation of a compound of formula (I), which process comprises the reaction of a compound of formula (VI):

(VI)

with an anion of formula (VII):

(VII)

wherein R₁'and R₂'are R₁ and R₂ as defined in formula (I), or a group or atom convertible thereto and the remaining variables are as defined in formula (I); and thereafter in the case where R₁'or R₂'is a group or atom convertible into R₁ or R₂, converting the group or atom into R₁ or R₂; optionally converting R₁ , R₂ or R₅ in the resulting compound of formula (I) into another R₁, R₂ or R₅; in the case where R₅ and R₆ in the resulting compound of formula (I) are hydroxy and hydrogen respectively, optionally dehydrating the compound to give another compound of formula (I), wherein R₅ and R₆ together are a bond; and, when one or the other of R₁ and R₂ in the resulting compound of formula ( I ) is amino or an amino-containing group , optionally forming a pharmaceutically acceptable salt.

The reaction is preferably carried out in an inert solvent such as dimethylsulphoxide in the presence of a base, such as sodium hydride.

Conversions of an aromatic group or atom into one of the class of substituents as defined hereinbefore are generally known. For example, it is preferred, when carrying out the reaction, to protect any unsubstituted terminal amino moieties, such as when the R₁/R₂ is amino, aminosulphinyl, aminosulphonyl or aminocarbonyl, with a protecting agent. Examples of protecting agents include acyl groups, such as acetyl. Removal of the acyl protecting agent is carried out by base hydrolysis.

If it is desired to protect an amino group in the presence of a cyano group then a more suitable method is to use a trifluoroacetyl protecting group which may be removed by mild hydrolysis. A further suitable method of deprotection of a protected amino group in the presence of a cyano group is to utilise a benzyloxycarbonyl or p-nitrobenzyloxycarbonyl protecting group which groups may be removed by mild catalytic hydrogenolysis. Benzyloxycarbonyl amino and p-nitrobenzyloxycarbonylamino groups may be formed by reaction of the appropriate chloride with the free amine function. In addition a hydrogen atom may be replaced by a nitro group by nitrating in a known manner a compound,wherein one of R₁' and R₂' is hydrogen and the other is acetamido, followed by hydrolysing the compound, converting the resulting amine into a diazonium salt, and finally decomposing it, leaving a compound of formula (I), wherein one of R₁ and R₂ is hydrogen and the other is nitro.

It is preferred that any of these conversions are carried out at an earlier stage as mentioned hereafter. For example, it is preferred that the replacement of a hydrogen atom by a nitro group is carried out on the chromene before Stage (c) or (d) in the Scheme hereinafter.

Examples of an optional conversion of R₅ in a compound of formula (I) into another R₅ are generally known in the art. For example, when R5 is hydroxy, it may be alkylated using an alkyl ioide 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 a condensation promoting agent, such as dicyσlohexylcarbodiimide. Alternatively, when R₅ is C_1-7 acyloxy or C_1-6 alkoxy it may be converted into hydroxy by conventional hydrolysis with for example, dilute mineral acid.

The optional dehydration of a resulting compound of formula (I), wherein R₅ and R₆ are hydroxy and hydrogen respectively, into another compound of formula (I), wherein R₅ and R₆ together are a bond, may be carried out in accordance with conventional dehydration procedures. Compounds of formula (VI) may be prepared, preferably in situ, by reacting a compound of formula (VIII):

(VIII)

wherein R₁', R₂', R₃ and R₄ are as hereinbefore defined a base, such as potassium hydroxide, in a solvent, such as ether or aqueous dioxan.

Compounds of formula (VIII) are known and may be prepared in accordance with any appropriate known process, for example, by the process described in the aforementioned U.S. patents and European patent publications. Schematically, such process can be depicted thus.

Scheme

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

(b) Keat in o-dichlorobenzene;

( c) N-bromosuccinimide/dimethylsulphoxide/water;

(d) Bromine in carbon tetrachloride; and

(e) Acetone/water.

The above process may produce mixtures of compounds during reaction (b) owing to the two sites available for ring formation. It is therefore advisable to remove any of the undesired compound by, for example, chromatography, before reaction (c) or (d).

As mentioned previously, the compounds of formula (I) exist in optically active forms, and the processes of the present invention produce mixtures of such forms. The individual isomers may be separated one from the other by, for example, chromatography using a chiral phase.

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 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 this invention and a pharmaceutically acceptable carrier.

The compositions are preferably adapted for oral administration. However, they may be adapted for other 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 5 to 200 mg for a 70 kg human adult and more particularly from 10 to 100 mg.

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 formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of hypertension.

The present invention yet further provides a method of treating 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 or a pharmaceutical composition of the invention.

The following example relates to the preparation of a compound of formula (I). Example

6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-(N-pyrrole-2H-1benzoPyran-3-ol

(E1)

To a mixture of 6-cyano-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-1-benzopyran (0.75g) and pyrrole (0.26g) stirred in dry dimethyl sulphoxide (25mls) under nitrogen was added sodium hydride (0.12g, 80% dispersion in oil). After stirring at room temperature for ½ hr. water (50 mis) was added and the aqueous phase extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulphate, filtered, and evaporated to give an orange oil. Chromatography (chromatotron, pentane-ethyl acetate gradient elution, 2mm silica gel) gave a fraction (0.19g) which was recrystallised to give the title compound (0.12g) as crystals of mpt 124-125°C. Mass spectrum M⁺ at m/z

268.1207. Cald. for C₁₆H₁₆N₂O₂ 268.1212.

NMR (CDC1₃) δ 1.32 (3H, s)

1.55 (3H,

s)

2.29 (1H, s) exchangeable

3.39 (1H, d, J=10Hz)

4.88 (1H, d, J=10Hz)

6.26 (2H, t, J=2Hz)

6.70 (2H, t, J=2Hz)

6.92 (1H, d, J=9Hz)

7.03 (1H, narrow m)

7.48 (1H, m) Systolic blood pressures were recorded by a inodification 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±0.5ºC) 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.

oi c 1 Dose ystl Rat

* at 2 and 6 hours only 2 rats had measurable pulses ** Only 3 rats had measurable pulses

Toxicity

No toxic effects were observed in the above test.

Claims

A compound of formula ( I ) :

2

wherein:

either one of R₁ and R₂ is hydrogen and the other is selected from the class of C_1-6 alkylcarbonyl, C_1-6 alkoxycarbonyl, C_1-6 alkylcarbonyloxy, C_1-6 alkylhydroxymethyl, nitro, cyano, chloro, trifluoromethyl, C_1-6 alkylsulphinyl, C_1-6 alkylsulphonyl, C_1-6 alkoxysulphinyl, C_1-6 C_1-6 alkoxysulphonyl, C_1-6 alkylcarbonylamino, C_1-6 alkoxycarbonylamino, C_1-6 alkyl-thiocarbonyl, C_1-6 alkoxy-thiocarbonyl, C_1-6 alkyl-thiocarbonyloxy, C_1-6 alkyl-thiolmethyl, formyl or aminosulphinyl, aminosulphonyl or aminocarbonyl, the amino moiety being optionally substituted by one or two C_1-6 alkyl groups or C_1-6 alkylsulphinylamino, C_1-6 alkylsulphonylamino, C_1-6 alkoxysulphinylamino or C_1-6 alkoxysulphonylamino or ethylenyl terminally substituted by C_1-6 alkylcarbonyl, nitro or cyano, or -C(C_1-6 alkyl)NOH or -C(C_1-6 alkyl)NNH2, or one of R₁ and R₂ is nitro, cyano or C_1-3 alkylcarbonyl and the other is methoxy or amino optionally substituted by one or two C_1-6 alkyl or by C_1-7 alkanoyl;

one of R₃ and R₄ is hydrogen or C_1-4 alkyl and the other is C_1-4 alkyl or R₃ and R₄ together are C_1-5 polymethylene;

either R₅ is hydroxy, C_1-6 alkoxy or C_1-6 acyloxy and Rg is hydrogen or R₅ and R₆ together are a bond and

R₇ is hydrogenf halogen , CF₃, C_1-6 alkyl or C_1-6 alkoxy;

the pyrryl group being trans to the R₅ group when R₅ and Rg together are not a bond; or, when one or the other of R₁ and R₂ is an amino or an amino-containing group, a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 of formula (II):

wherein the variable groups are as defined in claim 1

3. A compound according to claim 2 of formula III:

wherein one of R₁ ¹ and R₂ ¹ is hydrogen and the other is cyano or nitro, R₅ ¹ is R₃ when other than together with

R₆ forms a bon and the recurring variables are as defined in claim 1.

4. 6-Cyano-3,4-dihydro-2, 2-dimethyl-trans-4-(N-pyrrole)-2H-l-benzopyran-3-ol.

5. A compound according to claim 1 of formula (V):

wherein one of R₁ ² and R₂ ² is cyano or nitro and the other is amino optionally substituted as defined and the remaining variables are as defined in claim 1.

6. A process for the preparation of a compound of formula (I), which process comprises the reaction of a compound of formula (VI):

(VI)

with an anion of formula (VII):

(VII)

wherein R₁'and R₂'are R₁ and R₂ as defined in formula (I), or a group or atom convertible thereto and the remaining variables are as defined in formula (I); and thereafter in the case where R₁'or R₂'is a group or atom convertible into R₁ or R₂, converting the group or atom into R₁ or R₂; optionally converting R₁, R₂ or R₅ in the resulting compound of formula (I) into another R₁, R₂ or R₅; in the case where R₅ and R₆ in the resulting compound of formula (I) are hydroxy and hydrogen respectively, optionally dehydrating the compound to give another compound of formula (I), wherein R₅ and R₆ together are a bond; and, when one or the other of R₁ and R₂ in the resulting compound of formula (I) is amino or an amino-containing group, optionally forming a pharmaceutically acceptable salt.

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

8. A compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance.

9. A compound according to any one of claims 1 to 5 for use in the treatment of hypertension in mammals.