GB2175585A

GB2175585A - Benzodioxino-pyrrole derivatives

Info

Publication number: GB2175585A
Application number: GB08609766A
Authority: GB
Inventors: John Kitchin; Peter Clive Cherry; Alan David Borthwick; Adrian John Pipe; Andrew James Crame
Original assignee: Glaxo Group Ltd
Current assignee: Glaxo Group Ltd
Priority date: 1985-04-23
Filing date: 1986-04-22
Publication date: 1986-12-03
Also published as: GB8609766D0; GB8510293D0

Abstract

Compounds of general formula (I): <IMAGE> wherein R is hydrogen, C1-6 alkyl or C1-6 alkanoyl; R<1> is hydrogen, fluorine, chlorine, methyl, triflouromethyl, methoxy or hydroxyl; and R<2> is hydrogen, fluorine or chlorine and physiologically acceptable salts thereof, have selective alpha 2-adrenoreceptor antagonist action and are potential antidepressants. Conventional pharmaceutical formulations of these compounds may optionally contain other active ingredients such as an established antidepressant. These compounds may be prepared by pyrolysis of a N-oxide of formula (II): <IMAGE> where R<3> is a readily eliminated group.

Description

SPECIFICATION Heterocyclic amino compounds This invention relates to novel benzodioxino-pyrrole derivatives, to processes for the preparation thereof, to pharmaceutical preparations containing them, and to their use in medicine.

The alpha (a)-adrenoreceptors of the sympathetic nervous system are classified pharmacologically into two sub-groups, namely a1 and t2 The lX2- type are situated predominantly on the presynaptic terminals of noradrenergic neurones and are activated by the released neurotransmitter. Such activation results in a diminished release of noradrenaline on subsequent stimulation of the neurones, the R2- adrenoreceptors thus forming part of an autoinhibitory feedback mechanism for regulating the synaptic concentration of the neurotransmitter.A selective ar adrenoreceptor antagonist would be expected to produce and increase in the synaptic concentrations of noradrenaline by blocking the autoinhibitory feedback mechanism and would thus be of potential value in human medicine for the treatment of disorders such as depression which are associated with a deficiency of noradrenaline at postsynaptic adrenoreceptors.

a2-Adrenoreceptors also occur at non-neuronal sites such as on blood-platelets, in pancreatic islet cells, on adipocytes and in the proximal tubules of the kidney. Activation of a2-adrenoreceptors at these sites leads to platelet aggregation, inhibition of insulin release, inhibition of lipolysis and retention of sodium respectively.

A selective aTadrenoreceptor antagonist thus has a potential therepeutic use as an antidepressant either alone or in a complimentary combination with an established antidepressant, and in either treating or preventing conditions such as migraine, thrombosis, diabetes, obesity, hypertension, constipation, paralytic ileus and senile dementia.

We have now found that the compounds of formula (I) below and their physiologically acceptable salts have a selective aradrenoreceptor antagonist action.

The invention thus provides compounds of general formula (I)

wherein R is a hydrogen atom or a straight or branched C1-6 6 alkyl or C1 6 alkanoyl group; R1 is a hydrogen atom or a fluorine or chlorine atom or a group selected from methyl, trifluoromethyl, methoxy and hydroxyl; and R2 is a hydrogen atom or a fluorine or a chlorine atom: and physiologically acceptable salts thereof.

When R is an alkyl group it may be for example a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl, pentyl or hexyl group.

When R is an alkanoyl group it may be for example a formyl, acetyl or propionyl group.

Suitable physiologically acceptable salts are the acid addition salts formed with inorganic acids, for example hydrochlorides, hydrobromides, phosphates and sulphates, and with organic acids for example citrates, tartrates, acetates, maleates and succinates. The hydrochlorides are particularly useful.

It will be appreciated that each compound of general formula (I) is a trans isomer and exists as two enantiomers. The structural formulae herein are to be understood to depict either or both enantiomers of each of the compounds concerned as well as mixtures of the enantiomers, including racemates, even though the precise structure as set out only relates to one enantiomer.

The compounds of the invention have selective a2.adrenornceptor antagonist action. The test for determining the a2-adrenoreceptor antagonist action is based on the ability to prevent the action of a selective a2-adrenoreceptor agonist such as clonidine or 5-brnmo-N-(4,5-dihydrn-1 H-imidazol-2-yl)-6- quinoxalinamine, [R-(R*R*)]-2,3-dihydroxybutanedioate (UK 14304-18) on the rat field stimulated vas deferens preparation.

Clonidine and UK 14304-18 inhibit the twitch response of the rat isolated vas deferensto low frequency motor nerve stimulation. This inhibition is a consequence of activation of presynaptic adrenoreceptors of the 2- type. Antagonism of the effect of clonidine or UK 14304-18 is quantified by measuring the parallel shift,to the right of the inhibitory ol2-adrenoreceptor agonist log10 (concentration)/response curve in the presence of increasing concentrations of the antagonist. Potency and competitivenes of antagonism are determined by the method of Arunlakshana & Schild (Br. J.Pha rmac. 1959, 1448-58).

The a-adrenoreceptor-type selectivity of the compounds of general formula (I) is similarly assessed by measuring the ability to produce a parallel shift to the right of the log10 (concentration)/response curve for the a1-adrenoreceptor agonist phenylephrine. The a1- adrenoreceptor-mediated responses of phenylephrine measured were contractions of the rat isolated anococcygeus muscle (Leighton, Butz & Parameter, Eur.

J.Pharmac., 1979,5827-38).

The compounds ofthe invention are thus of interest in the treatment or prevention of migraine, thrombosis, diabetes, obesity, hypertension, constipation, paralytic ileus and senile dementia, and in particular for the treatment of depression.

According to a further aspect, the invention provides compounds of general formula (I) and their physiologically acceptable salts for use in the therapy or prophylaxis of migraine, thrombosis, diabetes, obesity, hypertension, constipation, paralytic ileus and senile dementia and in particular depression. The compounds of the invention may be used either alone or with an additional active ingredient. Thus, for example, in the treatment of depression, the compound of the invention may be used alone, or may be co-administered with an established antidepressant (e.g. desmethylimipramine, imipramine or amitriptyline) either in a single formulation or in separate formulations. The established antidepressant can be used in accordance with conventional practice.

The compounds according to the invention may be formulated in a conventional manner, optionally together with one or more other active ingredients, for administration by any convenient route for example for oral, rectal, intravenous or intramuscular administration. Oral administration is preferred.

Thus according to another aspect, the invention provides a pharmaceutical composition comprising a compound of general formula (I) and/or a physiologically acceptable salt thereof together with a physiologically acceptable carrier or excipient. The composition may optionally contain an additional active ingredient, for example an antidepressant such as desmethylimipramine, imipramine or amitriptyline.

For oral administration, the pharmaceutical composition may take the form of, for example, tablets, capsules, powders, solutions, syrups or suspensions prepared by conventional means with physiologically acceptable excipients.

Compositions for rectal administration may be in the form of suppositories using a conventional suppository excipient.

The compounds may be formulated for intravenous or intramuscular administration in dry form for reconstitution before use, or as a sterile solution or suspension.

A proposed daily dose for administration to man is 0.01 to 1 Omglkg, for example 0.05 to 3mg/kg, which may be conveniently administered in 1 to 3 doses per day. The precise dose administered will of course depend on the age and condition of the patient. The daily dosage may conveniently be administered in the form of dosage units, each unit containing for example 0.01 to 3 mg/kg of active ingredient.

The compounds according to the invention may be prepared as follows: Thus, a compound of formula (I) in which R is a hydrogen atom may be prepared by pyrolysis of a N-oxide of formula (II)

(wherein R3 is a readily eliminated group, e.g. an aralkyl group such as phenethyl).

The reaction may be effected, for example, by heating a N-oxide of formula (II) to its melt temperature.

The N-oxides of formula (II) are novel compounds and form a further aspect of the invention.

N-oxides of formula (11) may be prepared by oxidation ofatertiaryamine of formula (III)

(wherein R3 is as defined previously).

using for example a peracid such as m-chloroperbenzoic acid in an inert solvent such as dichloromethane.

The amines of formula (III) may be prepared by the following sequence of reactions:

(wherein Bz represents benzyl, Ts represents

and X represents a hydrocarbylsulphonyloxy group e.g. methylsulphonyloxy).

Reaction of the known dibenzyl threitol (VIII) with 4-toluenesulphonyl chloride in pyridine yields the bistosylate (VII) which may be converted to the compound of formula (VI) by heating with the appropriate catechol in acetonitrile containing cesium fluoride or cesium carbonate. The compound (VI) is then reduced to the diol (V) using hydrogen and palladium on charcoal with a solvent such as ethanol. Reaction of the diol (V) with a halide X1A (where Xa is a hydrocarbylsulphonyl group such as methylsulphonyl, and A is a halogen atom, such as a chlorine atom) in the presence of a base such as triethylamine, in a solvent, e.g.

dichloromethane, yields an intermediate of formula (IV) which may then be converted to the desired compound of formula (lil) by reaction with an amine R3NH2 at an elevated temperature, e.g. reflux or sealed tube at e.g. 1 100C, preferably in the presence of a suitable base or in the presence of an excess of the amine R3NH2, optionally in the presence of a solvent such as an ether, e.g. dioxan.

Another process for the preparation of a compound of formula (I) comprises interconverting another compound of general formula (I).

For example, a compound of formula (I) in which R is an alkyl group may be prepared by alkylation of a compound of formula (I) in which R is a hydrogen atom. The alkylation may be performed with an alkylating agent RX2 (where R is an alkyl group, and X2 is a leaving group such as a halogen atom e.g. a chlorine, bromine or iodine atom, or a hydrocarbylsulphonyloxy group such as methylsulphonyloxy orptoluenesulphonyloxy) in the presence of a base e.g. sodium, sodium hydride or a strong base such as sodium hydroxide, optionally in a solvent such as dichloromethane.

According to another example, a compound offormula (I) in which R is an alkanoyl group may be prepared by acylation of a compound of formula (I) in which R is a hydrogen atom. Conventional acylation procedures may be used, for example reaction with an appropriate acid RCOOH (where R is a hydrogen atom or a C1 5 alkyl group) or an activated derivative thereof e.g. an acid chloride, acid anhydride or chloroformate in the presence of a base such as triethylamine or pyridine.

A specific enantiomer of general formula (I) may be prepared by resolution of a mixture of enantiomers of formula (I) by conventional methods, e.g. by salt formation with an optically active acid followed by separation of the resulting diastereoisomeric salts, e.g. by fractional crystallisation. Alternatively, resolution may be effected at any suitable intermediate stage.

Physiologically acceptable salts of the compounds of general formula (I) may be prepared by reacting the free base of formula (I) or a salt thereof with an appropriate acid, such as hydrogen chloride in the presence of a suitable solvent e.g. ethyl aetate, ether or CH2CI2 or hydrochloric acid in a solvent such as methanol, to obtain the desired physiologically acceptable salt.

The following examples illustrate the invention. All temperatures are in "C.

Intermediate 1 f+)trans 2,3,3a,9a-Tetrahydro-2-(2-phenylethyl)- lH-f?,4]benzo dioxin o-f2,3-cip vrrnie Intermediate 2 (+)trans-2,3,3a,9a-Tetrabydro-2-62-phenylethyl)- lH-[1,41benzodioxino-[2,3-cApyrrole, 2-oxide 80% Meta chloroperbenzoic acid (0.78g) was added, over 0.25h, to a solution of Intermediate 1 (100g) in dichloromethane (30ml) and the resulting mixture was stirred at ambient temperature for 1.5h. An hydrous potassium carbonate was added to the resulting solution and the mixture was stirred for a further 1 h. The mixture was filtered through a pad of potassium carbonate and the solid was washed well with dichloromethane. The filtrate was evaporated and the residue triturated under ether. The solid was collected, washed with ether and dried in vacuo to yield the title compound (0.97g) as white plates m.p. 135-136".

Example 1 {~)trans 1, 3,3a, 9a- Te trah ydro -2 H-[ 1, 4/b enzo dioxin o[2,3-clp yrrole-2-oI Intermediate 2 (0.70g) was heated at 140-150" for 0.25h, causing the solid to melt and then resolidify. After cooling, the solid was triturated under ether, collected, washed with ether and dried in vacuo to give the title compound (0.429) as white prisims m.p. 194-196", NMR (TFA)T2.96 (4Hj,arnmatic), 5.0-6.4 (6H,multiplets N-OK, 1-H2, 3-H2, 3a-H and 9a-H).

Claims

1. Compounds of general formula (I):

wherein R is a hydrogen atom or a C1.6 alkyl or Cur 6 alkanoyl group; R1 is a hydrogen atom or a fluorine or chlorine atom ora group selected from methyl, trifluoromethyl, methoxy and hydroxyl; and R2 is a hydrogen atom or a fluorine or a chlorine atom; and physiologically acceptable salts thereof.

2. Compounds according to claim 1, wherein the physiologically acceptable salts are selected from the hydrochlorides, hydrobomides, phosphates, sulphates, citrates, tartrates, acetates, maleates and succinates.

3. Compounds according to claim 2, wherein the physiologically acceptable salts are the hydrochlorides.

4. A pharmaceutical composition comprising an effective amount of at least one compound selected from compounds of general formual (I) as defined in claim 1 and physiologically acceptable salts thereof together with one or more physiologically acceptable carriers or excipients.

5. A pharmaceutical composition according to claim 4which comprises an additional active ingredient which is an antidepressant.

6. A process for preparing a compound of general formula (I) as defined in claim 1 or a physiologically acceptable salt thereof which comprises: (A) in order to prepare a compound of general formula (I) wherein R is a hydrogen atom subjecting to pyrolysisa N-oxide of formula (ill):

wherein R1 and R2 are as defined in claim 1 and R3 is a readily eliminated group; or (B) converting a compound of general formula (I) our a salt thereof into another compound of general formula (I); and if necessary or desired subjecting the resulting compound of general formula (i) to a further reaction comprising: (C) converting a compound of general formula (I) or a salt thereof into a physiologically acceptable salt thereof.

7. Compounds of general formula (ill):

wherein R1 is a hydrogen atom or a fluorine or chlorine atom or a group selected from methyl, trifluoromethyl, methoxy and hydroxyl; R2 is a hydrogen atom or a fluorine or a chlorine atom; and R3 is a readily eliminated group; and physiologically acceptable salts thereof;