WO1992010494A1

WO1992010494A1 - Pharmaceuticals

Info

Publication number: WO1992010494A1
Application number: PCT/GB1991/002173
Authority: WO
Inventors: Francis David King
Original assignee: Beecham Group P.L.C.
Priority date: 1990-12-13
Filing date: 1991-12-06
Publication date: 1992-06-25
Also published as: IE914315A1; ZA919756B; PT99771A; AU9078391A; GB9027098D0; MX9102499A; CA2098309A1; JPH06503331A; AU651645B2; EP0561910A1; KR930703307A; NZ240938A

Abstract

Compounds of formula (I) and pharmaceutically acceptable salts thereof wherein the variable groups are as defined in the specification.

Description

PHARMACEUTICALS

This invention relates to novel compounds having

pharmacological activity, to a process for their preparation and their use as pharmaceuticals.

UK Patent No. 1571447 (Societe D'Etudes Scientifiques et Industrielles de L'Ile-de-France) describes a group of benzamide derivatives having dopamine antagonist activity.

A group of novel compounds have now been discovered, which compounds are 5-HT3 receptor antagonists.

Accordingly, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof:

wherein

R₁ is hydrogen, halo, nitro, amino, C_1-6 alkyl or C_1-6

alkoxy;

R₂ is halo, C_1-6 alkyl or C_1-6 alkoxy;

A is (poly)methylene of 1-3 carbon atoms, optionally

substituted by one or two C_1-6 alkyl group (s);

L is O or NH; and

Z is a di-azacyclic or azabicyclic side chain;

having 5-HT₃ receptor antagonist activity. Suitable examples of alkyl moieties in R₁ and R₂ and A include methyl, ethyl, n- and iso-propyl, n-, iso-, sec- an tert-butyl. Suitable examples of halo moieties include fluoro, chloro and bromo, preferably chloro or bromo.

Often R₁ is hydrogen and R₂ is chloro or bromo. A is preferably unsubstituted polymethylene of 1 or 2 carbo atoms (i.e. O-A-O is methylenedioxy or ethylenedioxy).

Suitable examples of Z are described in the art relating to 5-HT₃ receptor antagonists, ie. as follows: i) GB 2125398A (Sandoz Limited)

ii) GB 2152049A (Sandoz Limited)

iii) EP-A-215545 (Beecham Group p.l.c.)

iv) EP-A-214772 (Beecham Group p.I.c.)

v) EP-A-377967 (Beecham Group p.I.c.)

vi) PCT/GB91/01629 (Beecham Group p.I.c.)

vii) EP-A-358903 (Dianippon)

Particular side chains of interest are depicted thus:

Tropane

Granatane

Oxa/thia/aza-qranatane

Quinuclidine

Isoquinuclidine

Isogranatane

Oxa/thia-isoqranatane

Isotropane

or

wherein

R is hydrogen or methyl; and X is oxygen, sulphur or

nitrogen optionally substituted by C_1-6 alkyl, C_3-8

cycloalkyl, C_3-8 cycloalkyl C_1-4 alkyl, phenyl, naphthyl, phenyl C_1-4 alkyl or naphthyl C_1-4 alkyl wherein a phenyl or naphthyl moiety is optionally substituted by one or more of halo, C_1-6 alkoxy or C_1-6 alkyl.

Side chains Z of particular interest include tropane, oxagranatane and azagranatane, where R is methyl. Suitable values for N-substituents when X is N are as described in PCT/GB91/01629, for example, iso-propyl or ethyl.

L is preferably NH.

Alternatively, COL in formula (I) may be replaced by a bioisostere therefor, for example, 1,2,4-oxadiazole and the other groups of structure h) described in EP-A-377967

(Beecham Group p.l.c.).

The pharmaceutically acceptable salts of the compounds of the formula (I) include acid addition salts with

conventional acids such as hydrochloric, hydrobromic, boric, phosphoric, sulphuric acids and pharmaceutically acceptable organic acids such as acetic, tartaric, maleic, citric, succinic, benzoic, ascorbic, methanesulphonic, α-keto

glutaric, α-glycerophosphoric, and glucose-1-phosphoric acids. The pharmaceutically acceptable salts of the compounds of the formula (I) are usually acid addition salts with acids such as hydrochloric, hydrobromic, phosphoric, sulphuric, citric, tartaric, lactic and acetic acid.

Preferably the acid addition salt is the hydrochloride salt.

Examples of pharmaceutically acceptable salts include quaternary derivatives of the compounds of formula (I) such as the compounds quaternised by compounds R_x-T wherein R_x is C_1-6 alkyl, phenyl-C_1-6 alkyl or C₅_₇ cycloalkyl, and T is a radical corresponding to an anion of an acid. Suitable examples of R_x include methyl, ethyl and n- and iso-propyl; and benzyl and phenethyl. Suitable examples of T include halide such as chloride, bromide and iodide.

Examples of pharmaceutically acceptable salts also include internal salts such as N-oxides. The compounds of the formula (I), their pharmaceutically acceptable salts, (including quaternary derivatives and N-oxides) may also form pharmaceutically acceptable

solvates, such as hydrates, which are included wherever a compound of formula (I) or a salt thereof is herein referred to.

It will of course be realised that some of the compounds of the formula (I) have chiral or prochiral centres and thus are capable of existing in a number of stereoisomeric forms including enantiomers. The invention extends to each of these stereoisomeric forms (including enantiomers), and to mixtures thereof (including racemates). The different stereoisomeric forms may be separated one from the other by the usual methods. The invention also provides a process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, which process comprises reacting a compound of formula (II):

with a compound of formula (III) :

HLZ' (III) or a reactive derivative thereof, when L is 0; wherein R₁', R₂' and/or Z' are R₁, R₂ and/or Z respectively or groups or atoms convertible thereto; Q₁ is a leaving group; and the remaining variables are as hereinbefore defined; and thereafter optionally converting R₁', R₂' and/or Z' to another group or atom R₁, R₂, R₃ or Z; and optionally forming a pharmaceutically acceptable salt of the resultant compound of formula (I).

Examples of leaving groups Q₁, displaceable by a

nucleophile, include halogen such as chloro and bromo, C_1-4 alkoxy, such as CH₃O and C₂H₅O-, PhO-, activated

hydrocarbyloxy, such as Cl₅C₆O- or Cl₃CO-, or a nitrogen- linked heterocycle, such as imidazole.

If a group Q₁ is a halide, then the reaction is preferably carried out at non-extreme temperatures in an inert

non-hydroxylic solvent, such as benzene, dichloromethane, toluene, diethyl ether, tetrahydrofuran (THF) or dimethylformamide (DMF). It is also preferably carried out in the presence of an acid acceptor, such as an organic base, in particular a tertiary amine, such as triethylamine, trimethylamine, pyridine or picoline, some of which can also function as the solvent. Alternatively, the acid acceptor can be inorganic, such as calcium carbonate, sodium

carbonate or potassium carbonate. Temperatures of 0°-100°C, in particular 10-80°C are suitable. If a group Q₁ is C_1-4 alkoxy, phenoxy or activated

hydrocarbyloxy then the reaction is preferably carried out in an inert polar solvent, such as toluene

ordimethylformamide. It is also preferred that the group Q₁ is CI₃CO- and that the reaction is carried out in toluene at reflux temperature.

When L is O the compound of formula (III) may be in the form of a reactive derivative thereof, which is often a salt, such as the lithium, sodium or potassium salt.

It will be apparent that compounds of the formula (I) containing an R₁ or R₂ group which is convertible to another such group are useful novel intermediates, i.e. a hydrogen substituent is convertible to a halogen substituent by halogenation using conventional halogenating agents.

Z' when other than Z may be wherein R is replaced by R' which is a hydrogenolysable protecting group which is benzyl optionally substituted by one or two groups selected from halo, C_1-4 alkoxy and C_1-4 alkyl. Such benzyl groups may, for example, be removed, when R₁/R₂ is not halogen, by conventional transition metal catalysed hydrogenolysis to give compounds of the formula (I) wherein R is hydrogen. This invention also provides a further process for the preparation of a compound of the formula (I) wherein R is methyl or a pharmaceutically acceptable salt thereof, which comprises N-methylating a compound of formula (I) wherein R is hydrogen, and optionally forming a pharmaceutically acceptable salt of the resulting compound of the formula (I). In this further process of the invention

'N-methylation' may be achieved by reaction with a compound CH₃Q₃ wherein Q₃ is a leaving group.

Suitable values for Q₃ include groups displaced by

nucleophiles such as Cl, Br, I, OSO₂CH₃ or OSO₂C₆H₄pCH₃, preferably Cl, Br or I.

The reaction may be carried out under conventional

alkylation conditions for example in an inert solvent such as dimethylformamide in the presence of an acid acceptor such as potassium carbonate. Generally the reaction is carried out at non-extreme temperature such as at ambient slightly above. Alternatively, 'N-methylation' may be effected under

conventional reductive alkylation conditions.

Interconverting R in the compound of the formula (III) before coupling with the compound of the formula (II) is also possible. Such interconversions are effected

conveniently under the above conditions. It is desirable to protect any amine function with a group readily removable by acidolysis such as a C_2-7 alkanoyl group, before R/Z

interconversion.

It is often convenient in the preparation of such a compound of formula (III) to prepare the corresponding compound wherein the methyl group is replaced by alkoxycarbonyl.

Such compounds may then be reduced using a strong reductant such as lithium aluminium hydride to the corresponding compound of formula (II).

The compounds of formula (II) are known or are preparable analogously to, or routinely from, known compounds, such as described in UK 1571278.

Compounds of the formula (III) are generally prepared from the corresponding exocyclic keto derivative of the

azabicyclic side chain, prepared by condensation methods, often using a substituted piperidine.

They may be prepared by processes described in the

aforementioned Patent Publications relating to values of the side chain Z.

It will be realised that in the compounds of the formula (I) having a tropane, granatane or oxa/thia/aza-granatane side chain, the -COL- linkage has an endo orientation with respect to the ring of the bicyclic moiety to which it is attached. A mixture of endo and exo isomers of the compound of the formula (I) may be synthesised non-stereospecifically and the desired isomer separated conventionally therefrom e.g. by chromatography; or alternatively the endo isomer may if desired by synthesised from the corresponding endo form of the compound of the formula (II). Corresponding

geometric isomeric pairs are possible for the

isoquinuclidine, isogranatane, oxa/thia-isogranatane and isotropane side chains. Pharmaceutically acceptable salts of the compounds of this invention may be formed conventionally.

The salts may be formed for example by reaction of the base compound of formula (I) with a pharmaceutically acceptable organic or inorganic acid. The compounds of the present invention are 5-HT3 receptor antagonists and it is thus believed may generally be used in the treatment or prophylaxis of pain, emesis, CNS disorders and gastrointestinal disorders. Pain includes migraine, cluster headache, trigeminal neuralgia and visceral pain; emesis, includes, in particular, that of preventing vomiting and nausea associated with cancer therapy, post-operative emesis, and nausea associated with migraine. Examples of such cancer therapy include that using cytotoxic agents, such as platinum complexes including cisplatin, and also doxorubicin and cyclophosphamide, particularly cisplatin; and also radiation treatment. CNS disorders include

anxiety, psychosis, cognitive disorders such as senile dementia and age associated memory impairment (AAMI), and drug dependence. Gastrointestinal disorders include

irritable bowel syndrome and diarrohea.

5-HT₃ receptor antagonists may also be of potential use in the treatment of obesity, arrhythmia, and/or disorders associated with myocardial instability.

The invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Such compositions are prepared by admixture and are usually adapted for oral or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid

preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions or suppositories. Orally administrable compositions are preferred, since they are more convenient for general use. Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents. The tablets may be coated according to well known methods in the art, for example with an enteric coating.

Suitable fillers for use include cellulose, mannitol, lactose and other similar agents. Suitable disintegrants include starch, polyvinylpolypyrrolidone and starch

derivatives such as sodium starch glycollate. Suitable lubricants include, for example, magnesium stearate.

Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be

presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats,

emulsifying agents, for example lecithin, sorbitan

moπooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.

Oral liquid preparations are usually in the form of aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs or are presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, a flavouring or colouring agents. The oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.

For parenteral administration, fluid unit dose forms are prepared containing a compound of the present invention an a sterile vehicle. The compound, depending on the vehicle and the concentration, can be either suspended or dissolve Parenteral solutions are normally prepared by dissolving th compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing.

Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in th vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure of ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform

distribution of the compound of the invention.

The invention further provides a method of treatment or prophylaxis of pain, emesis, CNS disorders and/or

gastrointestinal disorders in mammals, such as humans, which comprises the administration of an effective amount of a compound of the formula (I) or a pharmaceutically acceptabl salt thereof.

An amount effective to treat the disorders herein- before described depends on the relative efficacies of the

compounds of the invention, the nature and severity of the disorder being treated and the weight of the mammal.

However, a unit dose for a 70kg adult will normally contain 0.05 to 1000mg for example 0.5 to 500mg, of the compound of the invention. Unit doses may be administered once or more than once a day, for example, 2, 3 or 4 times a day, more usually 1 to 3 times a day, that is in the range of

approximately 0.0001 to 50mg/kg/day, more usually 0.0002 to 25 mg/kg/day.

No adverse toxicological effects are indicated within the aforementioned dosage ranges.

The invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance, in particular for use in the treatment of pain, emesis, CNS disorders and/or

gastrointestinal disorders. The following Examples illustrate the preparation of compounds of formula (I).

Example 1 endo-N-(9-Methyl-9-azabicyclo[3.3.1]nonan-3-yl)-7-chloro- 1,4-benzodioxan-5-carboxamide (El)

A solution of 7-chloro-1,4-benzodioxan-5-carboxylic acid (UK patent 1,571,278, Societe D' Etudes Scientifiques et

Industrielles de L'Ile-de-France) (0.25g) in SOCl₂ (5 mL) was stirred at room temperature for 2h. The reaction mixture was evaporated to dryness and re-evaporated with xylene (2 x 20 mL). The residue was dissolved in CH₂Cl₂ (20 mL) and treated with a solution of endo-9-methyl-9-azabicyclo[3.3.1]nonan-3-amine (0.2g) in CH₂Cl₂ (10 mL).

After standing at room temperature overnight, the reaction mixture was washed with sat. NaHCO₃ (50 mL), dried (K₂CO₃) and evaporated to dryness. The residue was purified by column chromatography (AI₂O₃, eluting with CH₂Cl₂) to give the title compound, converted to its HCl salt with ethanolic HCl, precipitation with Et₂O. (0.31 g).

¹H NMR (d⁶-DMSO)δ8.40, 8.20 (2-d, 1H)

7.10 (s, 2H)

4.65-4.15 (m, 5H including 4.30, brs, 4H) 3.65-3.45 (m, 2H)

2.81, 2.79 (2-s, 3H)

2.55-2.30 (m, 4H)

2.20-1.95 (m, 2H)

1.82-1.53 (m, 2H)

1.55-1.35 (m, 2H) Prepared similarly was;

Example 2 endo-N-(9-Methyl-9-azabicyclo[3.3.1]nonan-3-yl)-6-chloro-1,3-benzodioxole-4-carboxamide (E2)

¹H NMR (CDCl₃)δ7.51 (d, 1H)

6.88 (d, 1H)

6.72 (brd, 1H)

6.13 (s, 2H)

4.58-4.38 (m, 1H)

3.09 (brd, 2H)

2.60-2.40 (m, 5H including 2.50 s, 3H) 1.98 (brd 3H)

1.59-1.42 (m, 1H)

1.31 (dt, 2H)

1.03 (brd, 2H)

5-HT₃ Receptor Antagonist Activity

Compounds are evaluated for antagonism of the von

Bezold-Jarisch reflex evoked by 5-HT in the anaesthetised rat according to the following method:

Male rats 250-350g, are anaesthetised with urethane

(1.25g/kg intraperitoneally) and blood pressure and heart rate are recorded as described by Fozard J.R. et al., J. Cardiovasc. Pharmacol. 2, 229-245 (1980). A submaximal dos of 5-HT (usually 6μg/kg) is given repeatedly by the

intravenous route and changes in heart rate quantified. Compounds are given intravenously and the concentration required to reduce the 5-HT-evoked response to 50% of the control response (ED₅₀) is then determined.

The compounds of the Examples are both active at a dose of 10μg/kg i.v.

Claims

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

wherein

R₁ is hydrogen, halo, nitro, amino, C_1-6 alkyl or C_1-6

alkoxy;

R₂ is halo, C_1-6 alkyl or C_1-6 alkoxy;

A is (poly)methylene of 1-3 carbon atoms, optionally

substituted by one or two C_1-6 alkyl group (s);

L is O or NH; and

Z is a di-azacyclic or azabicyclic side chain;

having 5-HT₃ receptor antagonist activity.

2. A compound according to claim 1 wherein R₁ is hydrogen and R₂ is chloro or bromo.

3. A compound according to claim 1 or 2 wherein O-A-O is methylenedioxy or ethylenedioxy.

4. A compound according to any one of claims 1 to 3 wherein the side chain Z is tropane, granatane,

oxa/thia/aza-granatane, quinuclidine, isoquinuclidine, isogranatane, oxa/thia-isogranatane or isotropane.

5. A compound according to claim 4 wherein Z is tropane, oxagranatane or azagranatane.

6. A compound according to any one of claims 1 to 5

5 wherein L is NH.

7. endo-N-(9-Methyl-9-azabicyclo[3.3.1]nonan-3-yl)-7- chloro-1,4-benzodioxan-5-carboxamide.

8. endo-N-(9-Methyl-9-azabicyclo[3.3.1]nonan-3-yl)-6- chloro-1,3-benzodioxole-4-carboxamide.

9. A pharmaceutically acceptable salt of a compound according to claim 7 or 8.

10. A compound according to claim 1 substantially as defined herein with reference to the Examples.

11. A process for the preparation of a comound according to0 claim 1, or a pharmaceutically acceptable salt thereof, which process comprises reacting a compound of formula (II):

with a compound of formula (III) :

HLZ' (III) or a reactive derivative thereof, when L is O; wherein R₁', R₂' and/or Z' are R₁, R₂ and/or Z respectively or groups or atoms convertible thereto; Q₁ is a leaving group; and the remaining variables are as hereinbefore defined; and thereafter optionally converting R₁', R₂' and/or Z' to another group or atom R₁, R₂, R₃ or Z; and optionally forming a pharmaceutically acceptable salt of the resultant compound of formula (I).

12. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

13. A method of treatment or prophylaxis of pain, emesis, CNS disorders and/or gastrointestinal disorders in mammals, such as humans, which comprises the administration of an effective amount of a compound according to claim 1.

14. A compound according to any one of claims 1 to 11 for use as an active therapeutic substance .

15. A compound according to any one of claims 1 to 11 for use in the treatment of pain, emesis, CNS disorders and/or gastrointestinal disorders.

16. The use of a compound according to any one of claims 1 to 11 in the manufacture of a medicament for the treatment and/or prophylaxis of pain, emesis, CNS disorders and/or gastrointestinal disorders.