CA2098729A1 - Azabicyclic amides or esters of halogenated benzoic acids - Google Patents

Abstract

Compounds of formula (I) wherein Z is a di-azacyclic or azabicyclic side chain having 5-HT3 receptor antagonist activity.

Description

2~9 2 ~ ~ Q 7 ~ 1 PCTIG~91/OZ210 AZABICYCLIC AMII~ES OR ESTERS OF HALOGE~ATED BENZOIC ~C`IDS

This invention relates to novel compounds having pharmacological activity, ~o a process ror ~helr preparat~
5 and their use as pharmaceu~icals.

E~-A-2200l1 (Beecham Group p.l.c.) desc ibes the use of 2 benzamide derlvative, as a 5~ 3 receptor antagonist.

~o A group of novel com~ounds has now Deen alscove~ed, whi_~.
compounds are 5-HT~ recepto- antagonlsts.

.~ccorcingly, the ~reser.. inven~ion ?~ovides a c~m~ounci c 'ormuia (~), c- c p~2rm2ce~ âl ly aooe~abie ~ e-^^ :
_ ~O-L-Z

20~/ ~ ~ R2 NH2 ~I) wherein R~ ls hydrogen or ~1-6 alkox~i .5 R2 is halo;
R3 is halo;
L ls O or NH; and - ;Z is a di-azacyclic or azabicyclic side chain;
ha-~ing 5-HT3 receptor antagonist acti~ity.
: ;O
Suitable~examples of alkyl moieties ln Rl include methy1, et-yl, ~- and 1~ -propy1, ~ s~_, sec- anc t~ ut~

' '~

W09~ 259 ~ a ~ -2- PCT/GB91/02210 Suitable examples of halo moieties il~clude f1uoro, chloro and bromo.

c In particular, ~1 is hydrogen, R2 is chloro and R3 is chloro; or R1 is methoxy, R2 is fluoro or chloro and R3 s chloro.

Suitable examples of Z are described in the ar~ relating to o 5-HT3 rece?to- ar~aaonists, ie. as follows:

i) GR 2l25398~. (Sandoz Limited) ~i) G3 ~1520~9`. (Sandoz Li~ ed) ' ii) ~P-,~-21 ~54~ (Peecha~ G.oup p.l.c.) ~ -i-2'47,. (Beecnam Group p.i.c.) v) EP-~-377967 (Beecham Group p.l.c.) vi) PCT~GB9l/0l629 (Beecham Grcup p.l.c.) vii) EP A-358903 (Dianippon) 20 Parlicula; side chains of interest are depicted thus:

Tro~ane : ' ~l . ,.
... ......
Granatane ~ NR
'5 I ~ 1 ' '.

WU 9i!fll259 a n ~ r~ PCI'~G391/0~210 Oxa/thia-~rranatane Ouinucl idine s oau _ nuc ' i ~ ~ ne 2 0 ~ NR

, :

: :.

Oxa/thia-lsoaranatane : ~

Isotropane ~9 ~ or wherein R is hydrogen or methyl; and X is oxygen, sulphur or 10 nitrogen option211t~ substituted by C1_~ alkyl, C3 8 _~cloal;~yl, C3_8 cycloalkyl C1_4 al~yl, phenyl, naphthyl, ph2nyl C~_~ al.~,~l o_ naphthyl C1_~ Glkyl wherein a phenyl c-na3h~hyl moi~_y s sptiGn211y substi-~ute~ b~ one or mor? o h~lo, C~_~ c~Xsxy c- C~-6 alkyl.

Side chains ~ of par~icular interest include ~.ropane, oxagranatane and azagranatane, where R ls methyl. Sui~able values for N-subs~ituents when X is N are as described in ~:
PCT/GB91/01629, for example, 1so-propyl or ethyl.
~0 .,,,~. ~
T iS preferably N~.

Alternatively, COL in rormula (I) may be ;eplaced by a bioisostere therefor, for example, 1,~,4-oxadiazole an~ the 5 othe- groups of s~ru-ture h) descri~ed in EP-A-377967 ~Beecham Group p.l.c.).

The pharmaceutically acceptable sal~s of the compounds o' ~he formula ~I) include acid addition salts with

3~0 conventional acids such as hydrochloric, hydxobromic, boric, phosphoric, sulphuric acids and pharmaceu~ically acceptable organic~acids such as acetic, tartaric, maleic, citric, succinic,~benzoic, ascorbic, methanesulphonic, ~-kcto gl;utaric, ~-glyceroph~osphoric, and glucose-1-phospho-ic 3s acids. ~
~ . :

. . .

:

WO9~/11259 PC~/GB91/02210 2Q9~7729 -~-~xamples of pharmaceutically acceptable salts include quaternaxy derivatives of the compounds of formula ~I) suc~
as the compounds quaternised by compounds RX-T wherein Rx ,s C1_6 alkyl, phenyl-Cl_6 alkyl o~ C5_7 cycloalkyl, and T is a 5 radical cor~esponding to an anlon of an acid. Sultabie examples of Rx include methyl, ethyl and n- and iso-propyl;
and benzyl and phenethyl. Suitable exam~les o~ T incluà~
halide such as chloride, bromide and iod de.

0 Examples of pharmaceutlcally acceptabl2 salts also ir.cIuae internal salts such as N-oxides.

The compounds G - .he formula (I), ~he~r ~.2-maceut~c2'I~
acce?table s21ts, (lncIuding c~a~ 2~ i2.~2s a-.
~5 N-oxides) may also form phar~aceu~ca_iv acce~.able solvates, such as hydrates, which are incluàeà wherever 2 compound of formula (I) or a salt the~eo-^ is herein refer-e~
to.
. . .
20 I' will.of course be realised that some of the compounds c the formula (I) have chiral or prochiràl cen~res and thus are capable Oc existing in a number of stereoisomeric forms including enan~iomers. The invention extends to each cf ~hese stereoisomeric rorms (includina enantiomers), and .
~5 mixtures thereof (including racemates). ~he àifferen.
stereoisomeric forms may be separated one from the other by the usual methods.
.
The invention also provides a process for the preparation of ~0 a compound o~ formula ~I), or a pharmaceutically acceptable salt thereof, whiCh process comprises reaC~ing a compound o.
formula ':
3 5 ~ R
~ I ' .
R~3~--R~z ( I I 7 NHR'4 ` WO 92J11259 ~, r~ 6- PCT/G~91/02210 with a compound of formula (III):

HL~' (I~I) 5 cr a reactive de_ vatlve thereof, wh~n L is O;

wherein R1', R2', R3~ andJor Z' are R1~ R2, R3 a~d~o- ~
respectively or g!cups o~ atoms convertible theretc; R~ s hydrogen or an N-protecting g~oup; Q1 is a leaving croup;
lo and the remaining varia~les are as hereinbefore define~; arc thereaf~ex optlonally conver.ing R1', R2', R3' and~or Z' ta another group or atom R~, R2! R3 or Z; and oo~ion211 orming a pha-mace_~ic~ ac_20table salt o the -esu co~pound cr ^-mu'a ( ~

Examples of R4, when other than hydrogen, include C _1Q acy`
such as Cl_7 alkanoyl, whereia the alkyl may be as lls~ed Cor R1, preferably acetyl R4 is usually hydrogen qo Examples of leaving groups Q1~ displaceable by a nucleophile, include halogen such as chloro and bromo, hydroxy, C1_4 alkoxy, such as r~30 and C2H50-, ~hO-, ac~ivated hydrocarbyloxy, such as C15C60- or C'3CO~; o~
q, COQ~, forms a mixed anhydride, so tha~ Ql is carboxyl~c acyloxy; or a nit ogen-linked heterQcycle, such âs imidâ201e.

a group Ql is a halide, or COC1, forms a mixed anhydride, 30 then the reaction is preferably car~ied cut at non-extreme ;temperatures in an inert non-hydroxylic solvent, such as - ;
-~ benzene, dichloromethane, toluene, die~hyl ether, tetrahydrofuran ~TXF) or dimethylformamide (DMF) It is al~so preferably carried out in the presence of an acià
.
~5 acceptor, such as an organic base, in particular a ter~iarv amine, such as triethylamine, -~ methylamine, py-ldlne c~
:

WO92/11259 2 0 9 ~ ~ 2 i~ PCT/GB91~02210 picoline, some of which can also function as the solvent.
Alternatively, the acid accep~or can be lnorganic, such as calcium carbonate, sodium carbonate or potasslum carbonate.
Temperatures of 0-100C, in particular 10-80C are 5 suitable.

If a group Ql is Cl_4 alkoxy, phenoxy o~ activated hydrocarbyloxy then the reaction ls pref~ably ca--iPd c-__ in an inert polar solvent, such as toluene or lO dimethylformamide. It is also preferre~ tha~ the g~3u~ ~^
is C13CO- and that the reaction is carrieà out in t~iuene z reflux temperature.

If a group Ql is hydroxy, ~her. the reac~icn s cenera`'~, ' 5 carried OUt ln an inert non-hydr~xylic s~lvent, suc;~ cs dichloromethane, THF or DMF optionally in the presence cf 2 dehydrating agent such as a carbodiimide, for example dicyclohexylcarbodiimide. The reaction may be carried out at any non-extreme temperature, such as -lO to 100C, fo-20 example, 0 to 80C. Generally, higher reaction ~emperaturesare employed with less active compounds whereas lower temperatu~es are employed with the more active compounds.

I a group Q1 is carboxylic acyioxy, then ,he reac ii~n ~s 25 preferably carried in substantially the same manner as thQ
reaction when Ql is halide. Sui.able examples of acyloxy leavin~ groups include Cl_4 alkanoyloxy and Cl_4 alkoxycarbonyloxy, in which case the reaction is preferably carried out in an inert solvent, such as dichloromethane, a-30 a non-extreme temperature for example ambient temperatures in the presence of an acid accep~or, such as triethylamine.
Cl_4 alkoxycarbonyloxy leaving c-oups may be genera~ed situ by treatment of the corresponding comDound wherein Q
is hydroxy with a Cl_4 alkyl chl~roformate.

W092/11259 ~0 9 ~ 9 . -a- PCT/GB91/0'210 If a group Ql is ac~ivated hydrocarbyloxy then the reaction is preferably car-ied ou~ in an iner~ polar solvent, such as dimethylformamide. It is also preferred that the activatec hydrocarbyloxy croup is a pentachlorophenyl ester and that the reaction is carried 0l1t at ambient temperature.

When Y is O the compound of fcrmula (IIT) may be in the .or~
of a reactive de~l~atlve thereo., which s of~e~ a salt, such as the lith um, sodium or ?0~2ssiul~ salt.

An R2' or R3' g-oup wnich is convertible ~2 or R3 lncluce _ hydroqen substituen~ w;-lch ls convertibl~ to a halogen substituent ~v halo~enation usi-~ conven- onal halocena~~n~
agents.
s z' when other than Z may be wherein R is replaced by R' which is a hydro~enolysable protecting group which is benzyl optionally substituted by one or two groups selected from halo, Cl_4 alkoxy and Cl_~ alkyl. Such benzyl groups may, for example, be removed, when Rl/R2 is not halogen, by conventional transition metal catalysed hydrogenolysis to give compounds of the formula (I) wherein R is hydrogen.

Thls inven~ion also provides c ~ the~ process for the ~5 preparation or a compound of ~he formula (T) whexein R is methyl or a pharmaceutically accep~able salt thereof, wh ch - comprises N-methylating a compound of formula (I) wherein P~
is hydrogen, and op~ionally formlng a pharmaceutically acceptable salt of the resultin~ compound of the formula ~O (I). In this further process of the invention 'N-methylation' may be achieved ~y reaction with a compound ~ CH3Q2 wherein Q2 is a leaving grvup.
:: : .
~Suitable values for Q2 include cr3ups displaced by 3s nuc1eoph'1s such as C1, Br, -, C~02Cn3 or OSO2C6H~pCH3, O 92/11;!59 2 0 9 ~3 7 2 9 Pl ~/GB91/02210 _a_ ~referably C1, sr or I.

The reaction may be carried out under conventi~nal alkylation conditions for example in an inert solvent suc.
s as dime~hylformamide in the presence of an acid accep~o~
such as po~assium carbonate. Generally the reaction is carried out at non-extreme temperature suc~ as a~ am~ent -~slightly above.

~o Alternatively, 'N-methylation' may be errected unde~
conventional reductive alkylatlon condi~ions.

Interconve-~ing R in ~he comDound c~ the ormulz (II-~before coupling with the compoun~ of the fo-mulc i--) __ s also possi~le. Such interconversions are efIec~ed conveniently under the above conditions. It is desiraD e ~~
protect any amine func~ion with a group readily removable oy acidolysis such as a C2_7 alkanoyl group, before R/Z
interconversion.
,.0 I~ ls often convenient in the preparation of such a compound cf formula (ILI) to prepare the corresponding compound wherein the methyl group is replaced by alkoxycarbony:.
Cuch compounds may then be reàuced using a s~rong re~uc_ar..
~5 such as 'ithium aluminium hvdride to the correspondin~
compound of formula (II).

The benzoic acid derivative in~ermediates of formula (TI) are known or are preparable analogously to, or routinely 30 ,rom, known compounds. When R2 is fluoro, the intermedia~
may be prepared by fluorination of the corresponding ~2 ~5 hydrogen compound, using a suitale fluorinating catalys_, such as trifluoromethyl hypofluorlte, as described in Description 1 hereinafter.
Compounds of the formula (II.) are generally prepareG -^ o~
~he corresponding exocyclic keto derivative of the ''.,'.

.

WO92~11259 ~ PCT/GB91/02210 ~10--azabicyclic side chaln, prepared by condensation methods, often using a substi~uted piperidine. They may be prepared Dy processes described in the aforementioned Patent Publlcatlons rela~ing to values of the side chain Z.
, It will be realiseà th2t in ~he compounds of the formula (I
having a tropane, granatane or oxa/thia/aza-granatane side chain, the -COL- lin~ag~ has an ~ndo orientation with respect to the -ing cf the bicyclic moiety to ~hic~ it is O attached. A mixture o~ o ar,d ~iCO isomers of the compound of the formula (I) may be synthesised non-stereospeclficall~
and rhe desired isome- sepaLa~ed conventionally theref-om e.g. by chroma~ogra~hy; or alternati~ely the ~ndo isome- m~v if desired bv syn~hes sed Lro." the c^r~espondin~ ~ndo o~m of the compound o~ ~he formula (II). Correspondin~
geometric isomeric pairs are ~ossible for the isoquinuclidine, isogranatane, oxa/thia-isograna~ane an-isotropane side chains.

20 Pharmaceu~ically acceptable salts of ~he ccm~ounds of this invention may be formed conventionally.

~he salts may be formed for e.Yam?le by reacticn OL the base com?ound of formula ( ) with a pharmaceu~ically accep~able _^ organic or inorganic acid.

-- The compounds or the present nvention are 5-~T3 receptor an~agonists and it is thus believed may generally be used in the treatment or prophylaxis of pain, emesis, CNS disorders 30 and gastrointestinal disorders. Pain includes migraine, cluster headache, trigeminal neuralgia and visce~al pain;
emes~is, includes, in particula~, that of preventing vomitin~
and nausea associa~ed with cancer therapy, post-operative emesis, and nausea associated with migraine. ~xamples o~
3s such cancer ~herapy include that using cytotoxic agents, such as pla~inum complexes including cisplatin, and also WO92/11259 2 0 ~ 3 7 2 9 ~ PCT/GB91/02210 doxorubicin and cyclophosphamide, par~icularly cisplatini and also radiation treatment. CNS disorders include anxiety, psychosis, cognitive disorders such as senile dementia and age associated memory lmpairment (AAMI), and 5 drug dependence. Gastroin~estinal disorders include irritable bowel syndrome and diarrohea.

5-HT3 recep~or antagonists may also be of potential use i~.
the treatment of obesity, arrhythmia, and/or disorders 0 associated with myocardial instability.

The inven.tion also provides ~ pharmaceutical composi lon comp-isins 2 compound o~ formula ( ), or a pharmaceu~
accep~able salt the~eof, an~ a pha.maceutically acc~?.a~
s carrie~.
-. :
Such compositions are prepared by admixture and are usuall~
adapted for oral or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid 20 prepara~ions, powders, granules, loæenges, reconstitutable powders, injectable and infusable solu~ions or suspen5ions or~suppositoriesO Orally administrable compositions are preferred, since they are more convenient for general use.

2s Tablets and capsules for oral adm'nistration are usuall~
presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, ;
tabletting agents, lubricants, disintegrants, colouran~s, flavourings, and we~ting agen~s. The tablets may be coatec ccording to well known methods in the ar~, for example wi-h.
an enteric coating.

Suitable fillers for use include cellulose, mannitol, lactose and other similar agents. Suitable disin~egran~s , 3s 1nclude starch, polyvinylpolypyrrolidone and s~arch ' : ':

:

O9?/'11~9 ~f~ r~l ~9 PCT/GB9~/022 derivatives such as sodium starch glycollate. Suitable iubricants include, for example, mag~esium s~earate.

Suitable pharmaceutically acceptable wettina agents inclua~
5 sodium lauryl sulphate. Oral liquid preparations may be ~.
the form of, for example, aqueous o_ oily suspenslons, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconsti~u~ion ~th. wate~ c-other suitable vehicle before use. Such liquid preparatio~.s 10 may contain conventional additives such as sus?encirc agents, fo- example sorbitol, syrup, me~hyl c~ilulose, gelatir., hydroxyethylcellulose, car~ox~methylceliulose, aluminium stearate gel or hydrogena~ed edible fats, emulslfying agen~s, ror example lec ~hin, sorbitan ~onoolea~e, o~ acacia; non~aoueous veh el~s (~ic~ ,~ay include edible oils), for example, almond oil, fractionates coconut oil, oily esters such as esters of slycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, 20 and if desired conventional flavouring or coiouring agents.

Oral liquid preparations are usually in the form of aqueous o- oily suspensions, solutions, emulsicns, syrups, or elixirs or are presented as a ~ry p-oduct for reco~stitu~io..
with wa~er or other sui~able vehicle berore use. Such liquid preparations may contain conventional additives suc:~.
as suspending agents, emulsifying agents, non~aqueous vehic~es (which may include edible oils), preservatives, and flavouring or colouring agen~s.
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 employlng large 35 quan~ities of fillers. Such o?era~ions are, of course, ~ .

wo g2~ll259 2 ~ 9 ~ 7 2 .9 pcT/Gs91/o22lo conventional in the art.
.

For paxenteral administration, fluid unit dose forms are prepared containina a compound of the present invention and 5 a sterile vehicle. ~'he compound, depending on ~he vehicle and the concentration, can be either suspended or dissoived.
Parenteral solutions are normally prepared ~y dissolving the compound in a vehicle and filter sterilisina before filling into a suitable vial or ampoule rand sealing.
~o Advantageously, adjuvants such as a local anaesthetic, preserva~ives and buffering agents are also dissol~ed in he vehicle. To enhance ~he stability, the composition can ~e ~rozen afte- ri llina ~r.~o the vial anc the wa~er remove~
un~er vacuum.

Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in he vehicle instead of being dissolved and sterilised by exposure of ethylene oxide before suspending in the sterile 20 vehicle. Ad~antageously, a surfactant or wet~ing agent is included in the comDosi~ion to facilitate uniform distribution of the compound of the invention.
' `
.e invention 'urthe= provides a methoà of t~ea~ment or ~-ophylaxis 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 accepLable salt thereof.
3~
An amoun~ effective to treat the disorders herein- before described depends on the relative efficacies of the compounds of the invention, the nature and severity or ~he disorder being treated and the weight of the mammal.
However, a unit dose ror a 70kg adult will normally contain O.C5 to lOOOms for example 0.~ to 500mg, of the compound OI
the invention. Unit doses may be administered once o~ mo~e WO9~/112~9 ~ S ~d 9 l4 PCT/C~91/U221n than once a day, for example, 2, 3 or 4 times a day, more usually l to 3 times a day, that is in the range of approximately 0.000l to 50mg/kg/day, more us~ally 0.0002 to 25 mg/kg/day.
s No adverse toxicological effects are indicated ~: hin the aforementioned dosage ranges.

The invention also provides a comDound of formula (I) o~ a l0 pharmaceutically acceptable salt the_eof for US2 as an active therapeutic substance, in particula- fo use in .he treatment of pain, emesis, CNS di~or-~s and/cr gast-ointestinal àisoraers.

:S The following ~xample~s illus.rate t;ne Dre~aratiO. c-^
compounds of formula (I).

Exa~les Ex. No. Rl R2 R3 L Z

H C 1 C 1 Nn NmT
2 H Cl Cl NH Q
25 3 OCH3 Cl Cl NH NmT
q OCH3 Cl Cl NH NmO
OCH3 F Cl NH NmT

; 30 NmT = N-methyltropane Q = Quinuclidin-3-yl NmO = N-methyloxagranatane ~ ' :~ : '::

~ ' .

wo 9~ i ~sg 2 ~ 9 ~ 7 2 ~ 5 PCT/GB9l/02210 D

a) Methyl-4-acetamido-5-chloro-3-fluoro-Z-methoxybenzoate s Methyl-4-acetamido-5-chloro-2-methoxy ben~oate (10.9g) ~as dissolved in chloroform (40 ml), cooled to -10C under nit~ogen. A three molar excess of trifluoromethyl hypofluorite was slowly bubbled through the stirred, cooleG
solution for 6 hours. A slow positive nitrogen stream was o maintained throughout the reaction. After warming to -oom temperature ~nd thoroughly purging with nitrogen, the chloroform ~'2S removed in vacuo.

The resiàue was chromatographed or. silica using chloro~o~,, lS with increasing amounts of methanol as eluant. The proa~c~
was isolated as an off white solid.

lH NMR (CDC13) 250MHz 20 ~: 7.64 (d, lH), 7.37 (bs, lH), 3.98 (bs, 3H), 3.9 (s, 3 2.2 (s, 3H) b) 4-Amino-~-chloro-3-fluoro-2-methoxvbenzoic acid 2s Methyl-4-acetamido-~-chloro-3-fluoro-2-methoxybenzoate (1.89g) in 25 ml ethanol was treated with a solution of sodium hydroxide ( 1.15g) in 15 ml water . The mixture was heated under reflux for 16 hours then cooled. The solvent was removed in vacuo and the residue acidified. The 30 precipitated solid was collec~ed by filtration to give 1.48c product.

~1H NMR (DMSO) 250MHz ::
' 35 ~: 7.49 (d, lH), 6.19 (bs, lH), 3.80 (s, 3H) ;~
.
`" ,:

~' : ,...... .

WO92/1l2~9 ~ ~ 9~ 9 -16- PCT/GB9l/072l0 Exam~le 1 ~ndo-N-~ -Methyl-8-azabicyclo~3~2~1loctall-3-yl~-4-arnino-3~r di~chlorobenzamide (E1) .
t1e O~NH
iO
l 1~ .
Cl ~/ Cl ~12 ~5 ~o a stirred solution of 4-amino-3,5~cichlorobenzo~c ac d (l.lg) in CH2Cl2 (50 ml) and Et3N (0.8 ml) at 0C was added EtC2CCl (0.48 ml~. After stirring to room temperatu~e fo-lh, a solution of the e~do-8-methyl-8-azabicyclo[3.2.1]oc~an-3-amine (0.7 g) in CH2C12 (lO ml) was 20 added and the whole stirred overnight. The reaction mixture was washed wi~h sat. NaHCO3 solution, dried and evaporated.
Recrystallisation of the residue ~EtoAc/petrol) gave tAe ~itle compound (0.35 g) mp 192-193~C.

c lH NMR (CDCl3) ~ 7.55 ~s, 2H) 6.25 (brd lH)

4.76 (brs, 2H) 4.~2 (q, 1~) 3.21 ~brs, 2H) 30~ 2.33 ~s, 3H) 2.35-2.10 ~m, 4H) 1.88-1.68 (m, 4H) ' : ~ ,~.. :. .

W~92/112~9 2 0 ~ g 7 2 9 PCT/G~9l/02210 Prepared similarly was:

~xamPle 2

5 N-(1-Azabicvclo~2.2.21Oc~an-3-yl)-9-amino-~ 5-dichlorobenzam.l..de (E2L

mp 233-235C.

Exam~le 3 cndo-~l-(8-Methvl-8-azabicvclo[3.2.11octan-3~ 4-amino-J!

aichloro-2-merhoxYbenzamide (E3?
:` :
A solution of e~do-N-(8-methyl-8-azabicyclo[3.2.13Oc~an-3-yl)-4-amino-5-chloro-2-methoxybenzamide (0.8g) in CH3COOH
(25 mL) was treated with a solution of C12 (0.18 g) in CH3COOH (5 mL). After standing at room temperature ,0 overnight, the solvent was removed by rotary evaporation and the residue partitioned between EtOAc and aqueous NaHCO3 h: -solution. The organic extrac~ was separated, dried (~2CO3) evaporated and the residue purified by flash chroma~ogra?h~
(S O2, 5-10% MeOH~CHC13) to give the title compound (0.065 g) mp 148-151C.
~:.

Prepared similarly was:

Example 4 :.
~:
endo-N~(9-Methvl-9-aza-3-azabicvclo[3.3.11nonan-7-yl~-4- ` :
amino-3,5-dichloro-2-methoxYbenzamide (E4) , mp 170-172~C.
:

"'' ,.

: ~ :
,.

, ..:
. . .

W092/~1259 PCI/GEI9l/0721n ~ ~ c~ 9 - 1 8 -Ex~

endo~4-Amino-5-chloro-3-fluoro-2-methoxy-N-(8-methvl-~=
azabicvclo~3 2.11Octan-3-vlLbenzamide (E5)_ s The tltle compound was prepared from 4-amino-S-c`nl~rc-~-fluoro-2-methoxybenzoic acid via an analagous procedure tC
that described for Example 1.

~o The product was isolated as the hydrochloride s21~ ?
203C.

-:. NM~ (free base), (CDC13), 250 ~:z ~: 8.6~ d, lH), 7.81 (d, lH), ~.34 (bs, 2H), ~.2~
lH), 3.98 (d, 3H), 3.10 (b, 2H), 1.53-2.21 (m, 11~ nc.s, 2.21, 3H).

5-HT3 RecePtor-Antaaonist Activity Compounds are evaluated for antagonism of the von Bezold-Jarisch reflex e~Joked by 5-HT in the anaes.he~ls~_ ~s rat according to the following me~hod: -Male rats 250-350g, are anaesthetised with urethane (1.25~/kg intraperitoneally) and blood pressure and hear~
rate are recorded as described by Fozard J.R. et al., J.
30 Cardiovasc. Pharmacol. 2, 229-245 (1980). A submaximal dose of 5-HT ~usually 6~g/kg) is given repeatedly by the intravenous route and changes in heart rate quantified.
Compounds are given intravenouslv and the concentration required to reduce the 5-HT-evoked response ~o 50-~ of tre ,. . .
35 control response (ED50) is then delermined.

'

Claims (19)

Claims

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

(I) wherein R1 is hydrogen or C1-6 alkoxy;
R2 is halo;
R3 is halo;
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, R2 is chloro and R3 is chloro.

3. A compound according to claim 1 wherein R, is methoxy, R2 is fluoro or chloro and R3 is chloro.

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 wherein L is NH.

7. endo-N-(8-Methyl-8-azabicyclo[3.2.1]octan-3-yl)-4-amino-3,5-dichlorobenzamide.

8. N-(1-Azabicyclo[2.2.2]octan-3-yl)-4-amino-3,5-dichlorobenzamide.

9. endo-N-(8-Methyl-8-azabicyclo[3.2.1]octan-3-yl)-4-amino-3,5-dichloro-2-methoxybenzamide.

10. endo-N-(9-Methyl-9-aza-3-azabicyclo[3.3.1]nonan-7-yl-4-amino-3,5-dichloro-2-methoxybenzamide.

11. endo-4-Amino-5-chloro-3-fluoro-2-methoxy-N-(8-methyl-?-azabicyclo[3.2.1.]octan-3-yl)benzamide.

12. A pharmaceutically acceptable salt of a compound according to any one of claims 7 to 11.

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

14. A process for the preparation of a compound according to claim 1, which process comprises reacting a compound of formula (II):

(II) with a compound of formula (III):

HLZ' (III) or a reactive derivative thereof, when L is O;

wherein R1', R2', R3' and/or Z' are R1, R2, R3 and/or Z
respectively or groups or atoms convertible thereto; R4 is hydrogen or an N-protecting group; Q1 is a leaving group;
and the remaining variables are as defined in claim 1; and thereafter optionally converting R1', R2', R3' and/or another group or atom R1, R2, R3 or Z; and optionally forming a pharmaceutically acceptable salt of the resultant compound of formula (I).

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

16. 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.

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 and/or gastrointestinal disorders.

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