WO1992014733A1

WO1992014733A1 - Pharmaceuticals

Info

Publication number: WO1992014733A1
Application number: PCT/GB1992/000310
Authority: WO
Inventors: Francis David King; Laramie Mary Gaster
Original assignee: Smithkline Beecham P.L.C.
Priority date: 1991-02-23
Filing date: 1992-02-20
Publication date: 1992-09-03
Also published as: AU1209592A; GB9103839D0

Abstract

Compounds of formula (I) and pharmaceutically acceptable salt thereof, wherein X is a phenyl group or a monocyclic 5 or 6 membered heteroaryl group, either of which group is optionally fused to a saturated or unsaturated 5-7 membered carbocyclic or heterocyclic ring; Y is NCN, NRx or CRx wherein Rx is NO2, CORy or SO2Ry, wherein Ry is C1-3 alkyl, NH2, NH(C1-3 alkyl), CF3 or phenyl optionally substituted by one, two or three groups selected from C1-4 alkyl, C1-4 alkoxy, nitro, halo, CF3 and cyano; and Z is a di-azacyclic or azabicyclic side chain, such as a saturated azabicyclic moiety; are 5-HT3 receptor antagonists.

Description

PHARMACEUTICALS

This invention relates to novel compounds having useful pharmacological properties, to a process for their

preparation, and to their use as pharmaceuticals.

EP-A-158265, EP-A-200444, EP-A-247266, EP-A-235878,

EP-A-254584, EP-A-255297, EP-A-289170, EP-A-315390,

WO 91/17161, PCT GB 91/02173, PCT GB 91/02210 and PCT GB 92/00050 (Beecham Group p. I.e.), EP-A-158532 (A.H. Robins Company, Inc.), GB 2125398A and GB 2145416A (Sandoz

Limited), EP-A-322016 (Duphar international Research B.V.), EP-A-307172 (Eli Lilly and Company), EP-A-323077,

EP-A-306148 and GB 2208385A (John Wyeth and Brother

Limited), EP-A-234872 (Adria Laboratories Inc.), EP-A-294292 (Adir et Compagnie), EP-A-339950 (Rorer International

(overseas), Inc.), EP-A-309423 (Instituto de Angeli S.p.A.), EP-A-313393 (Yoshitomi Pharmaceutical industries Limited), EP-A-329932 (Merrell Dow Pharmaceuticals Inc.), WO 90/06039 (Rorer International (Overseas), Inc.), EP-A-378111 (Zambon Group S.p.A.) and USA Patents 4920219 and 4920227 (Rorer Pharmaceutical Corp.) disclose classes of compounds which have a saturated azabicyclic moiety, such as tropanyl, granatyl or quinuclidinyl, having a -CO-NH- linkage, and are 5-HT₃ receptor antagonists.

A class of novel, structurally distinct compounds has now been discovered in which the carbonyl function in the

-CO-NH- moiety is replaced by, for example, guanidino or amidino. These compounds have 5-HT₃ receptor antagonist activity.

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

wherein

X is a phenyl group or a monocyclic 5 or 6 membered

heteroaryl group, either of which group is optionally fused to a saturated or unsaturated 5-7 membered carbocyclic or heterocyclic ring;

Y is NCN, NR_x or CR_x wherein R_x is NO₂, COR_y or SO₂R_y

wherein R is C_1-3 alkyl, NH₂, NH (C₁_₃ alkyl), CF₃ or phenyl optionally substituted by one, two or three groups selected from C_1-4 alkyl, C_1-4 alkoxy, nitro, halo, CF₃ and cyano; and

Z is a di-azacyclic or azabicyclic side chain, such as a saturated azabicyclic moiety;

having 5-HT₃ receptor antagonist activity. X may be unsubstituted or substituted, usually by one or more substituents selected from halogen, C_1-6 alkoxy, C_1-6 alkylthio, C_1-6 alkyl, hydroxy, amino, C_1-6 alkylamino, C_1-7 alkanoylamino, or two substituents on X (when fused), may be linked to form a saturated or unsaturated optionally

substituted carbocyclic ring.

Heteroatoms for heteroaryl and heterocyclic groups are selected from oxygen, nitrogen and sulphur. Halo includes bromo, chloro and fluoro.

X may be joined to C=Y by an aromatic carbon atom, or (when

X is fused), by a carbocyclic ring carbon atom, or by a heterocyclic ring carbon or nitrogen atom. When X is fused, and C=Y is attached at an aromatic carbon atom, it is preferably attached at the aromatic carbon adjacent a

'fused' carbon atom, which is attached to the heteroatom of a heterocyclic ring in formula (I). X may also be further joined to the N depicted in formula (I), as defined in formula (IA) hereinafter, when N-R₁₀ is N-B=N.

Suitable examples of X are as described in the

aforementioned patent publications relating to 5-HT₃

receptor antagonists and references quoted therein, the subject matter of which is incorporated herein by

reference. For the avoidance of doubt, the suitable X values in formula (I) which are described in the referenced patent

publications, are that part of the structure remaining when the saturated azabicyclic moiety and the -CONH- linkage are disregarded.

Z may be any of the values desclosed in the aforementioned Patent references, in particular, the following:- 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/GB91/01029 (Beecham Group p.I.c.)

vii) EP-A-358903 (Dianippon)

In a particular aspect, the present invention provides a compound of formula (IA), or a pharmaceutically acceptable salt thereof:

wherein

X₁ is a group of formula (a), (b), (c), (d), (e), (f), (g) or (h):

wherein

R_a to R_e and R_g to R_h are selected from hydrogen, halogen or hydroxy;

R₁ is hydrogen and R₂ is hydrogen or C_1-4 alkyl; or

R₁ and R₂ together are a bond;

R₃ to R₇ are independently hydrogen or C_1-6 alkyl; and

R₄ together with R₂ may be C_2-7 polymethylene or C_2-6

polymethylene interrupted by an -O- linkage when R₁ is hydrogen;

R₈ and R₉ are independently selected from hydrogen or

C_1-6 alkyl or R₈ and R₉ together are C_2-9

polymethylene or C_2-5 polymethylene interrupted by an -O- linkage;

either R₁₀ is hydrogen, C_1-6 alkoxy, C_3-8 cyeloalkyloxy or C_3-8 cycloalkyl C_1-4 alkyloxy; or R₁₀ is joined to Y so that Y-R-io ^{is N_B=N} where B is N or CH; and

R₁₁ is hydrogen, halo, C_1-6 alkoxy or C_1-6 alkyl; or

R₁₀ and R₁₁ are joined to form -OCH (R₁₅R₁₆)-E- wherein E is

(CH₂)_n, (CH₂)_pO NR₁₇CO(CH₂)m wherein n is 1 or 2, p is 0 or 1 and m is 0 or 1 and R₁₅, R₁₆ and R₁₇ are independently selected from hydrogen or C_1-6 alkyl; R₁₂ is hydrogen, C_1-6 alkoxy or; amino optionally

substituted by a C_1-6 alkyl group, or R₁₂ is

alkanoylamino; and

R₁₃ is halo, C_1-6 alkyl, C_1-6 alkoxy or C_1-6 alkylthio;

R₁₄ is hydrogen or C_1-6 alkyl;

in formula (h):

CY-NH- is in the 1-position and either R₁₅ is in the

3-position and is hydrogen, C_1-6 alkyl or C_1-6 alkoxy, or R₁₅ is in the 4-position and is hydrogen, halogen, CF₃, C_1-6 alkyl, C_1-7 acyl, C_1-7 acylamino, phenyl optionally substituted by one or two C_1-6 alkyl, C_1-6 alkoxy or halogen groups, or amino, aminocarbonyl or aminosulphonyl, optionally substituted by one or two C_1-6 alkyl or C_3-8 cYcloalkyl groups or by C_4-5

polymethylene or by phenyl, C_1-6 alkylsulphonyl, C_1-6 alkylsulphinyl, C_1-6 alkoxy, C_1-6 alkylthio, hydroxy or nitro; or

CY-NH- is in the 3-position and either R₁₅ is in the

1-position and is hydrogen, C_1-6 alkyl or C_1-6 alkoxy, or R₁₅ is in the 4-position and is hydrogen or C_1-6 alkoxy;

L is CH or N;

Z is tropane, granatane, oxa/thia/aza-granatane,

quinuclidine, isoquinuclidine, isogranatane,

oxa/thia-isogranatane or isotropane; and

Y is as defined in formula (I).

Examples of moieties in alkyl or alkyl containing groups in Z or in R₁ to R₁₅ include methyl, ethyl, n- and iso-propyl, n-, iso-, sec- and tert-butyl, preferably methyl.

Cycloalkyl moieties include C₃, C₄, C₅, C₆, C₇ and C₈ cycloalkyl. Halo moieties include fluoro, chloro, bromo and iodo.

Suitable examples of R₂ and R₄ or R₈ and R₉ when joined include C₂, C₃, C₄, C₅ or C₆ polymethylene, preferably C₂, C₃, C₄ or C₅ polymethylene.

R_a to R_e and R_g to R_h are preferably selected from hydrogen, fluoro, chloro and hydroxy, most preferably hydrogen. R_b may be 5-, 6- or 7-chloro or fluoro.

When X is of sub-formula (a), one of R₁ and R₃ is preferably hydrogen and one or both of R₂ and R₄ (most preferably both) are alkyl groups, such as methyl, or are joined to form C_2-7 polymethylene; or when one of R₂ and R₄ is hydrogen, the other is preferably ethyl or n- or iso- propyl.

When X is of sub-formula (b), R₅ is preferably hydrogen or a methyl or ethyl group. When X is of sub-formula (c), one of CY-NM- and R₆ is attached at the 1-position and the other is attached at the 3-position as depicted in sub-formula (c), and R₆ is preferably methyl or ethyl. When X is of sub-formula (d), R₇ is preferably methyl.

When X is of sub-formula (e), R₈ and R₈ are preferably both methyl groups.

When X is of sub-formula (f), and R₁₀ is C_1-6 alkoxy or is joined to Y, R₁₂ is preferably amino and R₁₃ is preferably chloro or bromo, most preferably chloro. R₁₀ is preferably methoxy when C_1-6 alkoxy.

When X is of sub-formula (f), and R₁₀ is hydrogen, R₁₁ and R₁₃ are preferably chloro or methyl and R₁₀ is preferably hydrogen. Other values of X within sub-formula (f) of interest are those described in EP-A-307172 (Eli Lilly and Company), EP-A-313393 (Yoshitomi Pharmaceutical Industries Limited), PCT/GB91/02173 and 02210 (Beecham Group p. I.e.). When X is of sub-formula (g), R₁₄ is preferably hydrogen or methyl.

When X is of sub-formula (h), and CY-NH- is in the

1-position suitable examples of R₁₅ when in the 4-position, include the following: hydrogen, chloro, bromo, methyl, ethyl, amino, methylamino, dimethylamino, phenyl, C_1-4 alkanoylamino such as formylamino, acetylamino,

propionylamino, n- and iso-butyrylamino, aminosulphonyl, and amino and aminosulphonyl optionally substituted by one or two methyl, ethyl, n- or iso-propyl, n-, sec-, iso- or

tert-butyl or phenyl groups; nitro, n- and iso-propoxy, methylthio, ethylthio, n- and iso-propylthio, hydroxy, methylsulphonyl and ethylsulphonyl or when R-_jc is in the 3-position suitable examples, include the following groups, hydrogen, methyl, ethyl, n- or iso-propyl, methoxy, and ethoxy. When X is at sub-formula (h), and CY-NH- is in the

3-position, suitable examples of R₁₅ when in the 1-position, include hydrogen, methyl, ethyl, n- or iso- propyl, or when R₁₅ is in the 4-position, suitable examples include the following: hydrogen, methoxy and ethoxy.

Preferred R₁₅ groups, in any of the positions specified above, include hydrogen, methyl and methoxy. CY-NH- is preferably in the 1-position.

Suitable values for R_y in Y are as described for R₁ to R₁₅ when C_1-3 alkyl. When R is substituted phenyl, suitable substituents are selected from methyl, methoxy, hydroxy, chloro, nitro or cyano.

Y is preferably N-CN.

Values of Z₁ are depicted thus: Tropane

Granatane

Oxa/thia/aza-qranatane

Quinuclidine

Isoquinuclidine

Isogranatane

Qxa/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.

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. Examples of pharmaceutically acceptable salts include quaternary derivatives of the compounds of formula (I) such as the compounds quaternised by compounds R_z-T wherein R_z is C_1-6 alkyl, phenyl-C_1-6 alkyl or C_5-7 cycloalkyl, and T is a radical corresponding to an anion of an acid. Suitable examples of R_z 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 also be realised that X-CY-NH- in compounds of formula (I) may adopt an α or β or configuration with respect to Z.

It will also be appreciated that the Y substituent may be in the E or Z (trans or cis) configuration with respect to the X or NHZ substituent.

When X₁ is of formula (a) or (d), the compounds of formula (I) may be prepared according to the following method; by reacting a compound of formula (II):

X₁ ^aH

(II) with a compound of formula (III)

wherein X₁ ^a is X₁ when of formula (a) or (d) and Q is a leaving group.

Suitable values for Q include SCH₃, chloro, C_1-6 alkoxy or phenoxy, preferably SCH₃.

The reaction preferably takes place in an inert solvent, such as acetonitrile, preferably at elevated temperatures. Subsequent substituent interconversions within X₁ ^a, Y and Z may be carried out, as well as salt formation.

The compounds of formula (III) are prepared from the compounds of formula H₂NZ by reaction with the compound of formula (IV):

were E is a leaving group. Suitable values of E are as described for Q, preferably SCH₃. Compounds of formula H₂NZ are prepared according to the methods described in the patent references i) to vii) listed hereinbefore.

Compounds of formula (I) wherein X is other than of formula (a) or (d) may be prepared from the corresponding compounds of formula (IV):

by reaction with a chlorinating agent to form a compound of formula (VI):

or by reaction with P₂S₅ or Lawesson's reagent to form a compound of formula (VII):

and thereafter reacting the compound of formula (VI) or (VII) or an activated form thereof, with an appropriate nucleophile reactant.

Suitable activated forms include wherein the compound of formula (VII) is reacted with an alkylating agent to form or S-alkyl leaving group, for example S-methyl, by reaction with dimethylsulphate.

When R_x is CN, the reactant is cyanamide, and when R_x is SO₂NH₂ the reactant is sulfamide. When Y is CH-NO₂, the reactant is nitromethane in the presence of a base.

When R_x is other than CN, the reaction preferably takes place in an inert solvent, such as tetrahydrofuran, at -10 to +25°C, preferably around 0°C to ambient, in an inert atmosphere, for example under nitrogen, preferably in the presence of a base, such as diisopropylethylamine. When R_x is CN, the reaction preferably takes place in actonitrile or dimethylformamide, at reflux temperatures.

Alternative methods of forming compounds of formula (I) are as described in J. Med. Chem. 1978 Vol 21 pp 773-781 and UK 1565966 (Allen and Hanburys Limited).

Pharmaceutically acceptable salts may be formed

conventionally, by reaction with the appropriate 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

monooleate, 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, and 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 and a sterile vehicle. The compound, depending on the vehicle and the concentration, can be either suspended or dissolyed-Parenteral solutions are normally prepared by dissolving the 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 the 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 acceptable salt thereof.

An amount effective to treat the disorders hereinbefore 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); the following description relates to the preparation of an intermediate. Description

S-Methyl-N-cyano-3,3-dimethyl-1-indolinylthiocarboxamide

(D1)

A solution of 3,3-dimethylindoline (1.46g) and dimethyl-N- cyanodithioiminocarbonate (1.46g) in CH₃CN (10mL) was heated under reflux under a stream of nitrogen overnight. The reaction mixture was cooled and the residue concentrated and triturated with Et₂O to give the title compound (0.45g) as a yellow solid. A further quantity (1.0g) was obtained from the mother liquors by column chromatography (SiO₂, 1:1

Et₂O:petrol). m.p. 100-102°C. ¹H NMR (CDCI₃, 250 MHz) δ 8.20 (d, 1H)

7.1-7.3 (m, 3H)

4.0 (s, 2H)

2.94 (s, 3H)

1.38 (s, 6H)

Example No. X₁ Y Z₁

E1 a¹ NCN tropane

E2 a¹ CHNO₂ tropane

E3 a¹ NCN oxagranatane

(a¹ = 3,3-dimethyl-1-mdolinyl) Example 1 endo-N-Cyano-N -(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)- 3,3-dimethyl-1-indolinyliminocarboxamide (E1) A mixture of 3, 3-dimethylindoline (1.46g, 0.0099 mole) and dimethyl-N-cyanodithioiminocarbonate (1.46g, 0.01 mole) in acetonitrile (30 ml) was heated in an oil bath at 90°C under a stream of nitrogen for 2 days. The reaction mixture was allowed to cool and a solution of 8-methyl-8-azabicyclo(3.2.1)octan-3-amine (1.40g, 0.01 mole) in

acetonitrile (15 ml) was added. After heating at 90°C under a stream of nitrogen for a further 24 hours, the solvent was removed in vacuo and the residue was purified by column chromatography on silica gel using chloroform (80%) methanol (20%) as eluent.

The product was isolated as a pale brown foam which

solidified on standing.

Recrystallisation from ether/ethyl acetate gave a beige solid 540 mg, m.p. 178-80°C. ¹H NMR (D6-DMSO 250 MHz)

δ 7.22 (m, 3H)

6.98 (t, 1H)

4.00-4.15 (b, 1H)

3.82 (s, 2H)

3.35-3.6 (b, 1H)

3.0-3.12 (b, 2H)

2.23 (s, 3H)

1.70-2.12 (m, 8H)

1.28 (s, 6H) Example 2 endo-1-(3,3-Dimethylindolin-l-yl)-1-(8-methyl-8-azabicyclo- [3.2.1]octan-5-yl)amino-2-nitroethene (E2)

A mixture of 3, 3-dimethylindoline (1.46g, 0.0099 mole) and 1,1-bis(methylthio)2-nitroethene (1.98g, 0.01 mole) in toluene (50 ml) was heated under reflux under a stream of nitrogen for 2 hours.

The reaction mixture was allowed to cool and a solution of 8-methyl-8-azabicyclo (3.2.1) octan-3-amine (1.40g, 0.01 mole) in toluene (10 ml) was added. After heating under reflux under a stream of nitrogen for a further 3 hours, the solvent was removed in vacuo and the residue was purified by column chromatography on alumina using chloroform (99.75%) methanol (0.25%) to give a pale yellow solid, 300mg. m.p. 55-7°C.

¹H NMR (CDCl₃, 250MHz) δ 10.5 (d, 1H)

7.18 (m, 2H)

7.02 (t, 1H)

6.90 (d, 1H)

6.72 (s, 1H)

3.75-3. .88 (b, 1H)

3.55 (s, 2H)

3.15 (b, 2H)

2.27 (s, 3H)

1.65-2..26 (m, 8H)

1.28 (s, 6H) Example 3 endo-N-Cyano-N'-(9-methyl-9-aza-3-oxabicyclo[3.3.1]nonan-7- yl)-3,3-dimethyl-1-indolinyliminocarboxamide (E3) A solution of endo-9-methyl-9-aza-3-oxabicyclo[3.3.1]nonan-7-amine (0.3g) and S-methyl-N-cyano-3, 3-dimethyl-1-indolinylthiocarboxamide (D1, 0.4g) in CH₃CN (5mL) was heated under reflux for 24h. The reaction mixture was cooled and the product isolated by flash column

chromatography on TLC grade SiO₂ eluting with CHCI₃, containing increasing quantities of MeOH, to give (E3, 0.18g). m.p. 142-143°C. ¹H NMR (CDCI₃, 250 MHz) δ 8.15 (brd, 1H)

7.46 (d, 1H)

7.23-7.12 (m, 2H)

7.09-6.99 (m, 1H)

4.79-4.65 (m, 1H)

3.97 (brd, 2H)

3.86 (s, 2H)

3.70 (d, 2H)

2.74-2.68 (m, 2H)

2.62-2.49 (m, 5H including 2.52, s, 3H)

1.56 (d, 2H)

1.33 (s, 6H) 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 dose 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.

Claims

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

wherein X, Y and Z are as defined in the specification, are 5-HT₃ receptor antagonists.

2. A compound according to claim 1, of formula (IA), or a pharmaceutically acceptable salt thereof, wherein formula (1A) is defined herein with reference to the specification.

3. A compound according to claim 1 or 2 wherein Y is NCN.

4. A compound according to claim 2 or 3 wherein X is of sub-formula (a), one of R₁ and R₃ is hydrogen and R₂ and R₄ are both C_1-6 alkyl groups or are joined to form C_2-7 polymethylene.

5. A compound according to claim 2 or 3 wherein X is of sub-formula (b), and R₅ is hydrogen or a methyl or ethyl group.

6. A compound according to claim 2 or 3 wherein X is of sub-formula (d) and R₇ is methyl.

7. A compound according to claim 2 or 3 wherein X is of sub-formula (f) wherein R₁₀ is methoxy, R₁₂ is amino and R₁₃ is chloro or bromo.

8. A compound according to claim 2 or 3 wherein X is of sub-formula (g) wherein R₁₄ is hydrogen or methyl.

9. endo-N-Cyano-N -(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-3,3-dimethyl-1-indolinyliminocarboxamide.

10. endo-1-(3,3-Dimethylindolin-l-yl)-1-(8-methyl-8-azabicyclo[3.2.1]octan-5-yl)amino-2-nitroethene.

11. endo-N-Cyano-N'-(9-methyl-9-aza-3-oxabicyclo[3.3.1]nonan-7-yl)-3,3-dimethyl-1-indolinyliminocarboxamide.

12. A pharmaceutically acceptable salt of a compound according to any one of claims 9 to 11 .

13. A compound according to claim 1, substantially as described herein with reference to any one of the Examples.

14. A process for the preparation of a compound according to claim 1 as described herein with reference to the

specification.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, and a

pharmaceutically acceptable carrier.

16. A pharmaceutical composition for use in the treatment of pain, emesis, CNS disorders or gastrointestinal disorders comprising an effective amount of a compound according to claim 1, and a pharmaceutically acceptable carrier.

17. A compound according to any one of claims 1 to 13, for use as an active therapeutic substance.

18. A compound according to any one of claims 1 to 13, for use in the treatment of pain, emesis, CNS disorders or gastrointestinal disorders.

19. Use of a compound according to any one of claims 1 to 13, in the manufacture of a medicament for the treatment of pain, emesis, CNS disorders or gastrointestinal disorders.

20. A method of treatment of pain, emesis, CNS disorders or gastrointestinal disorders in mammals, which comprises the administration of an effective amount of a compound according to claim 1.