,9-diazabicyclo(3.3.1)nonane derivatives with 5-HT3 receptor antagonist activi

This invention relates to novel compounds having pharmacological 5 activity, to a process and intermediates 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, WO 92/10494

10 (Beecham Group p.l.c), EP-A- 158532 (A.H. Robins Company, Inc.), EP-A-67770 (Merrell Toraude et Compagnie), GB 2125398A and GB 2145416A (Sandoz Limited), EP-A-322016 and EP-A-436245 (Duphar international Research B.V.), EP-A-307172 (EU Lilly and Company), EP-A-323077, EP-A-306148, GB 2208385A and WO91/05738 (John Wyeth

15 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 and EP-A-407137 (Yoshitomi Pharmaceutical industries Limited), EP-A-328200 and EP-A-337547 (Merck Sharp and Dohme Limited),

20 EP-A-329932 (MerreU Dow Pharmaceuticals Inc.), WO 90/06039 and WO 91/04738 (Rorer International (Overseas), Inc.), EP-A-378111 (Zambon Group S.p.A.), EP-A-430190 (Syntex (U.S.A.) Inc.) and USA Patents 4920219 and 4920227 (Rorer Pharmaceutical Corp.) disclose classes of compounds which have a saturated azabicyclic moiety, such as tropanyl,

25 granatyl or quinuclidinyl, and are 5-HT3 receptor antagonists.

WO 92/05174 (Beecham Group p.l.c) and EP-A-469449 Nisshin Flour Milling Co., Ltd) describe 5-HT3 receptor antagonists where the saturated azabicyclic moiety is endo-3,9-diazabicyclo[3.3.1]nonan-7-yl.

30

A class of novel compounds has now been discovered in which the saturated azabicyclic moiety is endo-3,9-diazabicyclo[3.3.1]nonan-7-yl substituted by an acyl group. These compounds have 5-HT3 receptor antagonist activity.

35

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

(I)

wherein

Xis a phenyl group or a monocy ic 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; A is a linking moiety; Z is a carboxylic acyl group; and R is hydrogen or methyl; having 5-HT3 receptor antagonist activity.

X may be unsubstituted or substituted, usually by one or more substituents selected from halogen, Ci.g alkoxy, C]_6 alkylthio, Cχ_g alkyl, hydroxy, amino, CI_Q alkyla ino, C1.7 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 within X are selected from oxygen, nitrogen and sulphur.

Halo includes bromo, chloro and fluoro.

X may be joined to A 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 A 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). The azagranatane side chain may be attached to A in a 'spiro' configuration.

X may also be further joined to A as defined in formula (IA) hereinafter, when Y-R10 s N-B=N.

Suitable examples of X are as described in the aforementioned patent

publications relating to 5-HT3 receptor antagonists, the subject matter of which is incorporated herein by reference.

Suitable examples of A include CONH (amide), COO (ester), NHCONH 5 (ureide), CONHCONH (extended ureide), or a group of structure (_):

10 wherein the dotted circle represents two double bonds in any position in the 5 membered ring; two of G, H and I are selected from oxygen, sulphur, nitrogen and carbon and the other is oxygen, sulphur or nitrogen; and E is a bond or C1-.5 alkylene optionally substituted by phenyl or hydroxy; or E 15 is absent and the heterocycle in structure (j) is joined to the azagranatane, in a 'spiro' configuration, when G is nitrogen, H is methylene and I is oxygen or sulphur.

For the avoidance of doubt, the suitable X values in formula (I) which are 20 described in the referenced patent publications, are that part of the structure remaining when the saturated azabicyclic moiety and A (where A is one of the suitable examples listed above), are disregarded.

Z is often C1.7 alkanoyl or benzyl optionally substituted in the phenyl 25 ring by one or more of halo, Cj.g alkoxy or Cj.g alkyl. Z is often acetyl.

R is preferably methyl.

There is a group of compounds within formula (I) wherein Z is Cj.g alkyl, 30 phenyl or phenyl C1.4 alkyl optionally substituted as defined in formula (I).

( In a particular aspect, the present invention provides a compound of

-* formula (LA), or a pharmaceutically acceptable salt thereof:

(IA)

wherein

Y is NH or O (or is joined to Rio as defined below);

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

(a)

(b)

(0

(d)

10 (e)

15 (f)

20 (g)

(h) wherein

R _a to R _e and Rg to Rfr are selected from hydrogen, halogen or hydroxy; Rl is hydrogen and R2 is hydrogen or Cχ_4 alkyl; or R and R together are a bond;

R3 to R7 are independently hydrogen or Cι_g alkyl; and R4 together with R2 may be C2-.7 polymethylene or C2-.6 polymethylene interrupted by an -0- linkage when R is hydrogen; and Rg are independently selected from hydrogen or

Cι_6 alkyl or Rg and Rg together are C2-6 polymethylene or C2-5 polymethylene interrupted by an -O- linkage; either Rio is hydrogen, Cι_g alkoxy, C3.8 cycloalkyloxy or C3.8 cycloalkyl Cι_4 alkyloxy; or RIQ is joined to Y so that Y-R10 is N-B=N where B is N or CH; and R i is hydrogen, halo, Cι_g alkoxy or Cι_g alkyl; or RlO and R ι are joined to form -OCH(R 5Rιg)-E- wherein E is (CH2) _n or NRi7CO(CH2)m wherein n is 1 or 2 and m is 0 or 1 and R15, Ri and 17 are independently selected from hydrogen or Cι_g alkyl; l2 is hydrogen, Ci.g alkoxy or; a ino optionally substituted by a Cι_g alkyl group, or R 2 is alkanoylamino; and Rl3 is halo, Cι_g alkyl, C _ alkoxy or Cι_g alkylthio; R14 is hydrogen or Cι_ alkyl; in formula (h): CO-Y- is in the 1-position and either R15 is in the 3-position and is hydrogen, Cι_g alkyl or Cι_g alkoxy, or R15 is in the 4-position and is hydrogen, halogen, CF3, Cι_g alkyl, C1.7 acyl, C1.7 ac-ylamino, phenyl optionally substituted by one or two Cι_g alkyl, Cι_g alkoxy or halogen groups, or amino, aminocarbonyl or aminosulphonyl, optionally substituted by one or two Cι_g alkyl or C3_g cycloalkyl groups or by C4_5 polymethylene or by phenyl, Ci.g alkylsulphonyl, Cι_g alkylsulphinyl, C _ alkoxy, Cι_g alkylthio, hydroxy or nitro; or

CO-Y- is in the 3-position and either R15 is in the 1-position and is hydrogen, Cι_g alkyl or Cι_g alkoxy, or R15 is in the 4-position and is hydrogen or Cι_g alkoxy;

L is CH or N; and Z and R are as defined in formula (I).

Examples of moieties in alkyl or alkyl containing groups in Z or in Ri to Rl5 include methyl, ethyl, n- and iso-propyl, n-, iso-, sec- and tert -butyl, preferably methyl. Cycloalkyl moieties include C3, C4, C5, Cg, C7 and Cg cycloalkyl. Halo moieties include fluoro, chloro, bromo and iodo.

Suitable examples of R2 and R4 or Rg and Rg when joined include C2, C3, C4, C5 or Cg polymethylene, preferably C2, C3, C4 or C5 polymethylene.

R _a to R _e and Rg to ^~ R\_ are preferably selected from hydrogen, fluoro, chloro and hydroxy, most preferably hydrogen. Rtø may be 5-, 6- or 7-chloro or fluoro.

When X is of sub-formula (a), one of i 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 C2.7 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 CO-Y and Rg is attached at the 1-position and the other is attached at the 3-position as depicted in sub-formula (c), and Rg is preferably methyl or ethyl.

When X is of sub-formula (d), R7 is preferably methyl.

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

When X is of sub-formula (f), and R Q is Cι_g alkoxy or is joined to Y, R12 is preferably amino and 3 is preferably chloro or bromo, most preferably chloro. Rio is preferably methoxy when Cι_g alkoxy.

When X is of sub-formula (f), and Rio is hydrogen, Rg and Rn are preferably chloro or methyl and Rio is preferably hydrogen.

Other values of X within sub-formula (f) of interest are those described in EP-A-307172 (Eh Lilly and Company) and EP-A-313393 (Yoshitomi Pharmaceutical Industries limited).

When X is of sub-formula (g), 1 is preferably hydrogen or methyl.

When X is of sub-formula (h), and CO-Y- 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, C1-.4 alkanoylamino such as formylamino, acetylamino, propionylamino, n- and wo-butyrylamino, aminosulphonyl, and amino and aminosulphonyl optionally substituted by one or two methyl, ethyl, n- or iso-propyl, n-, sec-, iso- or ferf-butyl or phenyl groups; nitro, n- and iso-propory, methylthio, ethylthio, n- and iso-propylthio, hydroxy, methylsulphonyl and ethylsulphonyl or when R15 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 the CO-Y- is in the 3-position, suitable examples of R15 when in the 1-position, include hydrogen, methyl, ethyl, n- or iso- propyl, or when 5 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. CO-Y- is preferably in the 1-position.

Y is preferably NH.

In an alternative aspect, the carbonyl group in CO-Y may be replaced by a carbonyl bioisostere, when Y is NH, as described in WO 92/14733 (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 quatemised by compounds Rχ-T wherein Rx is Cι_ alkyl, phenyl-Cι_g alkyl or C5.7 cycloalkyl, and T is a radical corresponding to an anion of an acid. Suitable examples of Rx 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.

It will be appreciated that mono- or di- salts may be formed owing to the presence of two salifiable nitrogens in the azagranatane side chain.

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) which process comprises reacting a compound X'-Ai with a compound of formula (II):

(π)

wherein Ai and A2 are moieties which react together, usually by an amide or ester coupling, or by condensation to form a heterocycle (j) as hereinbefore defined, to form A as defined; X is X or a group convertible thereto and R' and Z' are R and Z as defined or a hydrogenolysable protecting group; and thereafter as desired or necessary, converting X' to X, converting R'/Z', when other than R Z, to R Z, and optionally forming a pharmaceutically acceptable salt of the compound of formula (I).

Suitable values of Ai and A2 are as described in the aforementioned patent publications.

Intermediates of the formula X'-Ai are generally known from the aforementioned patent publications/references, or are prepared by analogous methods to those used for structurally related known compounds.

Intermediates of the formula (II) are generally prepared from the compound of formula (HI):

(III)

which is prepared by the condensation/cyclisation of as appropriate 2,6-disubstituted piperazine derivative, as described in the descriptions hereinafter.

In a particular aspect, the invention also provides a process for the preparation of a compound of formula (IA), or a pharmaceutically acceptable salt thereof, which process comprises reacting a compound of formula (IV):

Xl'-COQi

(IV)

with a compound of formula (V):

(V)

or a reactive derivative thereof, when Y is O;

wherein Xi' is Xi or a group convertible thereto; Qi is a leaving group; R' is R as defined, or a hydrogenolysable protecting group; and the remaining variables are as hereinbefore defined; and thereafter optionally converting Xi' to Xi, including any R _a , Rfo, R _c , Rj, R _e , Rg, Rj _j or RIQ, Rll, R12, R13, R14 or R15 group to another such group, converting R'/Z', when other than R/Z, to R/Z; and optionally forming a pharmaceutically acceptable salt of the resultant compound of formula (IA).

Examples of leaving groups Qi, displaceable by a nucleophile, include halogen such as chloro and bromo, C .4 alkoxy, such as CH3O and C2H5O-, PhO-, or activated hydrocarbyloxy, such as CLjCgO- or CI3CO-

If a group Qi 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 Qi is Cι_4 alkoxy, phenoxy or activated hydrocarbyloxy then the reaction is preferably carried out in an inert polar solvent, such as toluene ordimetiiylformamide. It is also preferred that the group Qi is CI3CO- and that the reaction is carried out in toluene at reflux temperature.

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

Usually, Xi' will be Xi, but when IQ is joined to Y, in formula (IA), Xi' is of sub-formula (f) wherein RIQ is nitro or amino, which may be subsequently be linked to Y as described in EP-A-315390.

It will be apparent that compounds of the formula (IA) containing an R _a to R _e , Rg, Rfc or Rio to R15 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; or a C1.7 alkanoylamino substituent is convertible to amino by conventional hydrolysis.

R' Z' when other than R Z may be a hydrogenolysable protecting group which is benzyl optionally substituted by one or two groups selected from halo, Cι_4 alkoxy and C1-4 alkyl. Such benzyl groups may, for example, be removed, when Ra to R _e , Rg, Rfc, Rn to R15 is not halogen, by conventional transition metal catalysed hydrogenolysis to give the corresponding compound wherein R'/Z' is hydrogen.

A further process for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, therefore comprises N-acylating a compound of formula (I), wherein Z 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-acylation' comprises the substitution of the azabicyclic N-atoms by a group Z as hereinbefore defined. This maybe achieved by reaction with a compound ZQ3 wherein

Z is as hereinbefore defined and Q3 is a leaving group. Suitable values for

Q3 include groups displaced by nucleophiles such as halo or ZQ3 may be an acid anhydride, e.g. acetic anhydride. The reaction may be carried out under conventional acylation conditions for example in an inert solvent such as dichloromethane in the presence of an acid acceptor such as triethylamine. Generally the reaction is carried out at non-extreme temperature such as at ambient or slightly above.

Interconverting R or Z in the compotmd of the formula (V) before coupling with the compound of the formula (IV) is also possible. Such interconversions are effected conveniently under conventional conditions, using appropriate protection of amine function(s).

The compounds of formula (IV) are known or are preparable analogously to, or routinely from, known compounds.

Compounds of the formula (I) may also be prepared by the processes analogous to those described in the aforementioned European Patent Publications.

It will be realised that in the compotmd of the formula (I) the -A- 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).

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 and/or arrhythmia.

Some of the compounds of the invention may also have gastric prokinetic activity, useful in the treatment of gastrointestinal disorders, for example when R14 is Ci. alkyl.

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 hquid 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, polyvinylpolypyrroHdone 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 compotmd, depending on the vehicle and the concentration, can be either suspended or dissolved. Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter steriHsing 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 steriHsed by exposure of ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to faciHtate uniform distribution of the compound of the invention.

The invention fiirther 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 pharmaceuticaHy 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 lOOOmg for example 0.5 to 500mg, of the compotmd 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 usuaHy 1 to 3 times a day, that is in the range of approximately 0.0001 to 50mg/kg/day, more usuaHy 0.0002 to 25 mg/kg day.

No adverse toxicological effects are indicated at any of the aforementioned dosage ranges.

The invention also provides a pharmaceutical composition for use in the treatment and or prophylaxis of pain, emesis, CNS disorders and/or gastrointestinal disorders which composition comprises an effect non-toxic amount of a compound of formula (D or a pharmaceutically acceptable salt thereof and pharmaceuticaHy acceptable carrier.

The invention also provides a compound of formula (I) or a pharmaceuticaHy 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 foUowing descriptions iHustrate the preparation of intermediates.

Description

a) To methyl-4-bromocrotonate (50g) in diethyl ether (500ml) was added, dropwise benzylamine (22ml) in diethyl ether (20ml) at 0°C. The reaction mixture was stirred at room temperature for 72h. The precipitate was removed by filtration and the filtrate washed with water (75 ml). The organic phase was dried (MgS04), the solvent evaporated under reduced pressure and the residue purified using flash chromatography on silica eluting with Hght petrol and diethyl ether to afford dimethyl-4,4'- benzyliminodi--.rαns-2-butenoate (17.1g).

b) To dimethyl-4,4'-be----zyliminodi-ini/is-2-butenoate (17.1g) in methanol (250 ml) was added dropwise methylamine (7.5 ml, 33% w/w in IMS) at 0°C. The reaction mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure and the residue chromatographed on siHca using Hght petrol and diethyl ether as the eluant to afford dimethyl- l-benzyl-4-methyl piperazinyl-3,5-diacetate as a mixture of cis and trans isomers (9.29g).

c) To potassium tert-butoxide (9.67g) in toluene (350 ml) was added dimethyl-4-benzyl-l-methyl piperazinyl-2,6-diacetate (9.26g) in toluene (150 ml) at room temperature under a nitrogen atmosphere. The reaction mixture was heated to reflux for 3h. The reaction mixture was cooled and washed with 5N HC1 (4x75ml). The combined aqueous extracts were heated to reflux for 13h. The reaction mixture was cooled, the solvent concentrated under reduced pressure and the residue saturated with solid potassium carbonate. The product was extracted into chloroform (4x75ml), the organic phase dried (MgSθ4) and the solvent evaporated under reduced pressure. Flash chromatography on silica using chloroform with increasing volumes of ethanol (up to 10%) eluant gave 3-benzyl-9- methyl-3,9-diazabicyclo[3.3.1]nonan-7-one (1.8g).

d) To a stirred solution of the above ketone (1.80g) in ethanol (50ml) was added hydroxylamine hydrochloride (0.54g). The reaction mixture was then heated to reflux for 2h. The reaction mixture was cooled and the solvent evaporated under reduced pressure. The residue was triturated with diethyl ether to give 3-benzyl-9-methyl-3,9-diazabicydo[3.3.1]nonan- 7-one oxime hydrochloride (1.87g).

e) To a stirred solution of alane [generated by the action of cone. H2SO4 (0.93ml) on Hthiu aluminium hydride (0.88g) in dry THF (30ml)] was added 3-benzyl-9-methyl-3,9-diazabicyclo[3.3.1]nonan-7-one oxime [generated by the treatment of 3-benzyl-9-methyl-3,9- diazabicyclo[3.3.1]nonan-7-one oxime hydrochloride with potassium carbonate). The reaction mixture was then heated to reflux overnight under a nitrogen atmosphere. The reaction mixture was cooled and 40% aqueous NaOH solution (2ml) and water (1ml) were added dropwise. Diethyl ether (5ml) was added and the mixture stirred for lh. The resultant precipitate was removed by filtration through keiselguhr and the filtrate concentrated under reduced pressure to afford crude βΛio-3- be--ι--yl-9-ιnethyl-3,9-diazabi(yclo[3.3.1]nonan-7-amine (0.90g).

Example 1

endo-N-3,3-Dimethylindolin-l-yl(3-acetyl-9-methyl-3,9- diazabicyclo[3.3.1]nonan-7-yl)carboxamide (El)

a) A solution of 3,3-dimethylindoHne (1.5g) and triethylamine (1.42ml) in CH2CI2 (15ml) was added dropwise to a cooled stirred solution of phosgene (9ml, 12.5% w/w in toluene) in CH2CI2 (15ml). The reaction mixture was stirred for lh at 0°C and then poured into pentane (100ml), washed with 5N sulphuric acid (5ml) and brine (5ml). The organic phase was dried (MgSθ4) and the solvent evaporated under reduced pressure to give crude l-(2,3-dihydro-3,3-dimethyl)indolylcarbonyl chloride (1.7g).

b) To a stirred solution of l-(2,3-dihydro-3,3-dimethyl)indolylcarbonyl chloride (771mg) in CH2CI2 (15ml) at ambient temperature was added endo-3-be--ι-^l-9-methyl-3,9-diazabicyclo[3.3.1]nonan-7-ami ne (902mg) and triethylamine (512μl) in CH2CI2 (15ml). The reaction mixture was

stirred at room temperature overnight. The resulting solution was washed with aqueous NaHC03 solution, dried (MgS04) and the solvent removed by rotary evaporation. Flash chromatography on silica using chloroform and ethanol as the eluant gave endo-N-3,3-dimethylindoHn-l- yl(3-benzyl-9-methyl-3,9-diazabicyclo[3.3. l]nonan-7-yl)carboxamide

(360mg) mp 188-191°C.

iH NMR (CDC1 ₃ ) 250MHz;

δ: 1.29 (s, 6H), 1.48 (d, 2H), 2.40-2.57 (m, 5H), 2.62-2.78 (m, 4H), 2.83-2.90 (m, 2H), 3.53 (s, 2H), 3.70 (s, 2H), 4.39-4.42 (m, IH), 6.90 (t, IH), 7.05-7.46 (m, 8H), 7.81 (d, IH), 8.78 (d, IH).

c) e/ido-N-3,3-Dimethylindolin-l-yl(3-benzyl-9-methyl-3,9- diazabicyclo[3.3.1]nonan-7-yl)carboxamide (E13) (350 mg) was hydrogenated at atmospheric pressure in methanol (50ml) over 5% Pd/C catalyst for 4h. The catalyst was removed by filtration and the filtrate evaporated to give endo-N-3,3-dimethyHndolin-l-yl-(9-methyl-3,9- diazabicyclo[3.3. l]nonan-7-yl)carboxamide (149mg).

mp 248-251°C

*H NMR (CDCI3) 250 MHz;

δ: 1.35 (s, 6H), 1.68 (d, 2H), 2.50-2.67 (m, 3H), 2.75 (s, 3H), 2.99 (d, 2H), 3.17-3.26 (m, 2H), 3.58 (s, 2H), 3.61-3.71 (m, 2H), 4.37-4.49 (m, IH), 6.89- 6.97 (m, IH), 7.06-7.20 (m, 2H), 7.88 (m, IH).

M+ 329

d) To a solution of endo-N-3,3-dimethyHndolin-l-yl(9-methyl-3,9- diazabicyclo[3.3.1]nonan-7-yl)carboxamide (50mg) in CH2CI2 (6ml) was added triethylamine (23 μl) and acetic anhydride (16μl). The reaction mixture was stirred at ambient temperature for 2h. The solvent was evaporated under reduced pressure and the residue partitioned between water (5 ml) and chloroform (10ml). The organic phase was dried (MgS04) and the solvent removed by rotary evaporation to yield crude title compound. This was subjected to flash chromatography on silica

eluting with chloroform and ethanol. The resulting product was triturated with Hght petrol (bp 60-80°) to give the title compound (29mg).

mp 165-168°

iH NMR (CDC1 ₃ ) 250MHz;

δ: 1.36 (s, 6H), 1.58-1.71 (m, IH), 2.10 (s, 3H), 2.44-2.61 (m, 5H), 2.95-3.10 (m, 2H), 3.14-3.28 (m, IH), 3.37-3.68 (m, 4H), 4.14-4.25 (m, 2H), 4.79-4.88 (m, IH), 6.93 (t, IH), 7.05-7.21 (m, 2H), 7.93 (d, IH).

MH+ 371

Example 2

eiMfo-N-3,3-Dimethy-Lindol--n-l-yl(3-be--ι---oyl-9-methy l-3,9- diazabicyclo[3.3.1]nonan-7-yl)carboxamide (E2)

FoHowing the procedure outlined in Example 1(d), reaction of endo-N-3,3- dimethylindoHn-I-yl(9-methyl-3,9-diaza _^ ,bicyclo[3.3.1]nonan-7- yl)carboxamide (40mg) with benzoyl chloride (15 μl) and triethylamine (18 μl) afforded the title compotmd (E2) (35mg).

mp 182-185°

^X H NMR (CDCI3) 250MHz;

δ: 1.31 (s, 6H), 1.43-1.60 (m, IH), 2.44-2.70 (m, 5H), 2.88-2.98 (m, IH), 3.09-3.13 (m, IH), 3.35-3.80 (m, 5H), 4.20-4.35 (m, IH), 4.38-4.52 (m, IH), 4.81-4.93 (m, IH), 6.94 (t, IH), 7.06 (d, IH), 7.17 (t, IH), 7.28-7.48 (m, 5H), 7.92 (d, IH).

MH+ 433

5-HT3 RECEPTOR ANTAGONIST ACITVTTΎ

Compotmds 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.