CA2081350A1

CA2081350A1 - Isoquinoline amides and esters as 5 ht3 receptor antagonists

Info

Publication number: CA2081350A1
Application number: CA002081350A
Authority: CA
Inventors: Francis D. King
Original assignee: Individual
Current assignee: Beecham Group PLC
Priority date: 1990-04-27
Filing date: 1991-04-22
Publication date: 1991-10-28
Also published as: NZ237957A; AU7753991A; TW199157B; GB9009542D0; JPH05507071A; WO1991017161A1; PT97490A; EP0526545A1; ZA913123B; IE911399A1

Abstract

Isoquinoline derivatives (I) having 5-HT3 receptor antagonist activity, a process for their preparation and their use as pharmaceuticals. In formula (I) E is NH or O, R1 is hydrogen, halogen, alkyl, alkoxy, hydroxy or nitro; Z is an azacyclic or azabicyclic side chain, such as a group of formula (a), (b) or (c) wherein;
p is 1 or 2; q is 1 to 3; r is 1 to 3; R3 or R4 is hydrogen or alkyl, and Y is a group -CH2-X-CH2- wherein X is -CH2-, oxygen, sulphur or X is a bond; and (I) when the group CO-E-Z is in the 1-position and either R2 is in the 3-position and is hydrogen, alkyl, or alkoxy, or R2 is in the 4-position and is hydrogen CF3, alkyl, acyl, acylamino (substituted) phenyl or (substituted) amino, (substituted) aminocarbonyl or (substituted) aminosulphonyl; (II) the group CO-E-Z- is in the 3-position and either R2 is in the 1-position and is hydrogen, alkyl or alkoxy or R2 is in the 4-position and is hydrogen or alkoxy.

Description

WO 91/171~1 PCr/C~B91/00636 -1~ 2~3a~

RECEPTOR ANTAGONISTS.
This invention rela~es to novel com~ounds having useful pharmacological proper~ies, to pharmac~uti.cal compositions 5 containing them, tO a process an~ intermediates for their preparation, and to the'r use as .~narmaceu~lcals.

GB 2145416A (Sandoz Ltd) describes a group of naphthylene, --chromene and quinolin~ de-i~a~ e-^ with satura.ed o azabicyclic side chains, and hav_z.g ~-HT3 receptor antagonis 2ctivi'y.

A c72ss of ~truct-ra''~ ~ sl ?.C_ -^m?O'~ S ~a',~' ~q a.
isoquinoline moie~, ..as now Dee-. aisi-overe~. Thes~
5 compounds have 5-HT3 receptor an~agonist actiYvrity.

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

CO-E-Z

~ (I) Rl R2 ~ wherein i-s NH or O, R1 is hydrogen, halogen, C1_4 al'~:yl, C1_4 alkoxy, hydroxy or nltro;
Z is an;azacycli.c or azabicyclic side chain, such as a group of formula (a), (b) or (c):

WO 91/1716] PCr/GB91/006~6 3'~

1`1 ~ N ~
(CH ) q I

2 p~/ ~b) .'" .
~:~

~ ~NR~
. ( C ) : whe re in p is 1 or 2; q is 1 to 3; r is 1 to 3;
30 R3:: or R4 is hydrogen or C1_4 ~lkyl, and Y is a group CH2-X~-CH2- wherein X is -CH2-, c:~y erl, sulphur or X is a ond; and: ~

~: ~

:
: .

WO ~1/17161 13 ~- ~3 PCr/C~91/00636 i) the group CO-E-Z ls in the 1-posltion and either R2 is in the 3-position and is hydrogen, C1_6 alkyl Dr C1_6 alkoxy, or R2 ls in the 4-position and is hydrogen, halogen, CF3, C1_6 alkyl, C1_7 acyl, C1_7 acylamino, phenyl optionally substituted by one or two C1_6 alkyl, C1_6 alkoxy or halogen grou~s, o- amino, aminocarbonyl or aminosulphonyl, optionally substituted by one or two C~-6 alkyl or C3_8 cycloalkyl groups or by C~_~ polyme~hylene or by phenyl, C1_6 alkylsulphony', C'_~ alkvlsulphinyl, C1_~ :
alkoxy, C1_6 alkylthio, hyG~oxy c- nit-o; or ii) the group CO-E-Z is in the 3 posi~on and either R2 is 1~ in the 1-position and is hydrogen, C1_6 alkyl or C1_6 alkoxy, or R2 is in ~he 4-posi~ion and is hydrogen or Cl_6 alkoxy;

: having 5 HT3 receptor antagonist activity.
~20 Suitable examples of the group R1 include hydrogen, bromo, chloro, methyl, ethyl, n- and iso-propyl, n-, lso_, sec- and tert-butyl, methoxy, ethoxy, n- and iso-propoxy, and n-, lso , sec- and tert-butoxy.
: 25 Suitab:le examples of Z are descri~ed in the art relating to 5-:HT3 receptor antagonists, ie. as follows:

i) GB 2125398A (Sandoz Limited) 30 li) GB 2152049A (Sandoz Limlted) P-A-2~15545 (Beecham Grcup ~. .c.) iv?: EP-A-214772 (Beecham Group ?.1.c.) v):~ ~ EP-A-377967 (Eieecham Group p.l.c.) Vl j~ ~ EP-A-3~58903 (Dianippon Pharmaceutical Co. Ltd.) 3 5 : : ~
Particular side chains or intereC~ are depicted thus:

~ , ~,VO 91~ ~ 7161 PCr/GB91/00636 ~rop,an~

~ MR

Granatane / MR
~ .

15 O.~:a/thia- ranatane NR

Qulnuc idine . ' ' .

~; 25: ~ ~
~J
~: N : :

Isoqulnuclidlne i: ~:..

WG91~1716~ PCT/GB91/nO636 : ~5~ 2 0~ ~ 3 ~ a so~ranatane ~ .
s V

Oxa/thla-isoqranatane ~/
~,J
S Isotropane or wherein R is hydrogen or methyl; and X is oxvgen or sulphur.
.
; : 25 Side chains Z of particular interest include tropane and oxasranatane,~where~ R ls methyl.

Ejls preferably NH.

O~When~the group~CO~E-Z is in the l-position sultable examples of~the group R2 when in t~he 4-positlon, include the following~groups;:hydrogen, chloro, bromo, methyl, ethyl, amino, me:thylarnino,~dimet~hylamino, phenyl, Cl_4 ~ : j ::alkanoylamino such:as formylamino, ace~ylamino, :~ : 35~propionylam:ino, n- and~lso-butyrylam no, aminosulphonyl, and ~: ami:no and aminosulphony~l op~ionally substituted by one or wo gl/17161 ~ 3 PCI/GB')1/()0636 two methyl, ethyi, n- or iso-propyl, n-, seC-, iso or tert-butyl or phenyl groups; nltro, methoxy, ethoxy, n- and iso-propoxy, methylthio, ethylthio, n- and iso-propylthio, hydroxy, methylsulphonyl and ethylsulphonyl or when R2 is in 5 the 3-position suitable e:.amples, include the following groups, hydrogen, methyl, e~nyl, n- or iso-propyl, methoxy, and ethoxy.

When the grou~ CO-E-~ is in the 3-position, suitable o examples o ~he c_ou? ~2 when in the 1-position, include the groups hyGrogen, methyl, et~y', n- or ~so- ~ropvl, methoxy and ethoxy, or when ~ ~s in the ~-pos~tion, suitable examples inc'ude the _ol'o"ing crou?s; ~ydrocen, me~ho~y and etho~y.

~referred R2 groups, in any of the positions specified above, include hydrogen, methyl and metho~y. R2 is prefexably in the 1-position.

20 For the avoidance of doubt, all alkyl and alkyl containing moie~ies are straight chained or branched. -Examples of R3/R4 when alkyl are methyl, ethyl, n- and iso-propyl, n , iso-, sec- and tert-butyl, prefe~ably 25 methyl.

Preferab1y p, q and r are 1 or 2.

The pharmaceutically acceptable salts of the compounds of 30 the formula (I) include acid addition salts wlth conventional acids such as hydrochlo~lc, hyd~obromic, boric, phosphoric, sulphuric acids and pha-maceutically acceptable organic acids such as acetic, tartaric, lactic, maleic, citric, succinic, ben~oic, ascorbic, methanesulphonic, 35 ~-~eto glutaric, a-glycerophosphoric, and glucose-1-phosphoric acids.

.:
,::

WO~1/17161 PCr/CB~1/0063 _7_ ~ ~ 8~ 3^~ n The pharmaceutically accep~able salts of the compounds of the formula (I) are usually acld addition salts Wlth aclds such as hydrochloric, hydrobromlc, phosphoric, sulphuric, citric, tartaric, lactic and acetic acid.
s Examples of pharmaceutically acce?table salts include quaternary derivatives of the comDourlds of fo-~ula (I) SUC~I
as the compounds quaternised by compounds Ra-T wherein Ra is Cl_6 alkyl, phenyl-Cl_6 alkyl or r5_7 cycloal.kyl, and T ~s a lO radical corresponding to an anio.-, o~ an acid. Suitable examples of Ra include methyl, e~~yl and r.- and iso-DrCDyi;
and benzyl and phenethyl, prefer_~l,y methyl. Suitable examples of T include halide su :~. as c!.lorid_, bro~ide anc iodide.

Examples of pharmaceu~ically accep~able salts of compounds of formula (I) also include internal salts such as pharmaceutically acceptable N-oxides.

20 The compounds of the formula (I), their pharmaceutically acceptable salts, (inclu~ing 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 sal~ thereof is herein referred 25 to.

It will of course be realised that some of the compounds of the formula (Ij have chiral or prochiral centres and thus are capable of existing in a number of stereoisomeric forms 30 including enantiomers. The invention extends to each of these stereoisomeric forms (incl~ding enantiomers), and to :: :
mixtures thexeof (including racema~es). The different stereoisomeric forms may be separated one from the other by the usual methods.
, ,:
: ;. :: :

W09~/17~ a- rCI/GI191/0061~1 It will also be realised that the isoquinoline nucleus in compounds of rormula (I) may adopr an endo or exo configuration with respect to Z. The endo confi~uration is preferred.

A group of compo~n~s within formu a (I) is of formula (II): ;

~CO-E ~ N~3 10 ~.
11 ' 1' (r-~

lS
wherein the variables are as def ned in formula (I).

Examples of the variables and preferred variables are as so described for corresponding variables in relation to formula 20 (I).

A further group of compounds within formula (I) is of , .
formula (III):
.: ,' ' ::. ' 2s ~N P~

30 ~ :
2 :.

:
wherein ql is l or 2 and the reTna n:.ng vzriables are as 5 defined in formulae (I) and (II).

: ~ :

:~ :' WO91/17161 pcT/Gssl/oo636 ~ ~ 8 ~

Examples of the variables and preferred vari.ables are as so described ~or the corresponding variables ln formula (I).

There is a further group of compounds wlthin formula (T) of S formula ~IV):

~ j/ CO- E ----~NR4 ;IV) wherein rl is l or 2 and the remalnlng varlables are as defined in formulae (I) and (II).

Examples of the variables and preferred variables are so described as the corresponding variables .in formula (I).
The invention also provides a process for the preparation of a compound of formula (I) which pxocess comprises reacting a compound of formula (V):

A ~ :

l 2 ~V) with a compound Of formula A2-Z' wAerein Z' is Z as defined : ~ in formula (I) wherein R3 and R4 are replaced by R3' and , , .-; `- ~, .' '., ;. . '' . , . , :

W091~l7~ PC~/G~91/00636 R4', A1 and A2 are moieties which react together to form an amide or este.r linkage and R3' and R4' are R3 and R4 respectively, as defined in formula (I) or a hydrogenolysable protectin~ group; and thereaf~er as desired s or necessary, conve-tina R3', or R~' when other than R3 or R4 respectively, to R3 and R4 respectlvely, and optionally forming a pharmaceutically ac^~?table salt of the compound of formula (I).

o Suitable values of ~1 anà ~ are, for eY.ample, as descrlbed in the aforemen_ioned pa~ent ~u~lica~io~s. For e.Yam~le, A1 may be an ac~ived ca-~onyI fun ~ on suc:- 2S an acid chloride or N-hyd-o~.t~succlnm~e es~er a..~ ~, ma~ b~ an a.m,Lno g_~u?, when E in rorl~ula (I) is `~In .
Intermediates of the formula (V) are generally known or are prepared by analogous methods to those used for structurally related known compounds.

20 Intermediates of formula A2-Z' may be prepared from the corresponding exocyclic keto derivative of the azabicyclic side chain, prepared by condensation methods, often using a substituted piperidine, as described in the aforementioned patent references.
- In a particular aspecl, 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 (VI): - .
.
;~ 30 :

: 35 ~ '~;J ~:~
2 (VI) :
:

WO91~17161 PCT/CB91/00636 2~813a~
with a compound of fo~mula HJ-Z', or when J ls oxygen, an active derlvatlve thereof, wherein J ls oxygen or NH, Q is a leaving group; R3~ and R9' respectively is R3 and R4 respectlvely, as deflned, or a hydrogenolysable protectlng 5 group; and the remaining variables are as hereinbefore defined; and thereafter optionally converting R3' or R~', when other than R3 or R4, to R3, or R~ respectively, and optionally forming a pharmaceutically acceptable salt of the resultant compound of formula (I).

~xamples of leaving groups Q, dis?laceable b~ a nucleop~.~le, include halogen such as chloro and bromo, C1_4 alko~y, such as CH30 and C2H~O-, PhO-, or ac~ ~ated hyd-oca~bylox~ uch as Cl5C6O- or COQ forms a mixed anhydriàe, so .hac Q is carboxylic acyloxy.

If a group Q is a halide or COQ forms a mixed anhydride, then the reaction is preferably carried out at non-extreme temperatures in an inert ncn-hydroxylic solvent, such as 20 benzene, dichloromethane, tolucne, 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, tximethylamine, pyridine or 25 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 0-100C, in par~icular 10~80C are suitable.
If a group Q is Cl_4 alkoxy, phenoxy or activated hydrocarbyloxy, or activated es~er, such as N-hydroxysuccinimide, then the reaction is preferably carried out in an inert polar solvent, such as toluene or 35 dimethylformamide. It is also p~eferred that the ~roup Q is Cl3CO- and that the reaction is car-ied out in toluene at ., .
:' WO91/17161 ~3~ -12- PCT/~91/00636 reflux temperature.

If a group Q is hydro~y, then t~.e reacl on is generally carried out in an lnert non-hydro~ylic solve~t, such as s dichloromethane, THF or DM~ o~ti~nally ~n the presence of a dehydrating agent such as a carbodiimlae, for e.~ample dicyclohexylcarbodlimide, optlor.ally l~ ~he presence of ~-hydroxysuccinimiàe. ~he reaction may be car-ied out at any non-extreme temperature, such as -lO to 100C, for example, lO 0 to 80C. Generall~r~, higner reaction ,emperatures are employed with less aC' ive c~m~ounds ~h~reas lower temperatu~es are emsloye~ wi~h ,'e more ac,ive com~ounds.

If a group Q is caroo.YyIic acyic::y, tnen the reac ion is preferably carried in substantia`ly the same manner as the reaction when Ql is halide. Sui,able e.~amples of acyloxy leaving groups include Cl_4 alkanoyloxy and Cl_4 alkoxycarbonyloxy, in which case the reaction is preferably carried out in an inert solven~, such as dichloromethane, at 20 a non-ex~reme temperature for example ambient temperatures in the presence of an acid acceptor, such as triethylamine.
Cl_4 alkoxycarbonyloxy leaving g-oups may be generated ln situ by treatment or the corresponding compound wherein Q is hydroxy with a Cl_4 alkyl chloro^ormate.
If a group Q is activated hydrocarbyloxy then the reaction is preferably carried ou~ in an nert polar solvent, such as dimethylformamide. It is also p-eferreà that the activated hydrocarbyloxy group is a pentachlorophenyl ester and that 30 the reaction is carried out at ambien~ temperature.

When J is 0 the compound of formula HJ-Z', may be in the form of a reactive derivative thereof, which is often a salt,~ such as the lithium, sodium o- po~asslum salt.

: .
':

W~91/17161 T'~/~B9!/0063~
2~g ~ ~'0 R3' and Rql when other than R3 and R4 respectlvely, may be a hydrogenolysable protectlng group which is benzyl optionall~
substituted by one or two groups selected from halo, Cl_~
alkoxy and Cl_4 alkyl. Such benzyl groups may, for example, 5 be removed, by conventional transitlon metal catalysed hydrogenolysls to give compounds of the formula (VII) or (VIII) respectlvely:

CO-J ~ ~N-r.

~ ~
Rl R2 (VII) ~
CO-J ~ (c~)lH
I ~1 2S Rl ~ R2 (VIII) : wherein the variables are as hereinbefore defined.

30 This invention also pro~ides a further process for the preparation of a compound of the formula (I) wherein Z is a) or c) or a pharmaceutically acceptable salt thereof, which : compr1ses N-alkylating a compound of formula (VII) or (VIII) ;
.

.... , . . , . , , , .. ,. ~ " ~, , ,. .. , ,, .. . .. .. . ., . . . . ~ .

WO 9]/1'7161 PC~/CB~1/00636 3~
respectively, and optionally forming a pharmaceutically acceptable salt of the resultln~ compound of the formula tI).

s In this further process of the ~nvention 'N-alkylation' comprises the substitutlon of -the N-atom aepicted in forrnula (VII) or (VIII) respectively, bv a grou? R3 or R4 respectively as hereinbefore der led. Thls mav be achleved by reaction with a compo~nd ~3Q3 or R9Q^; as .~ecessary o wherein R3 and R4 are as he-ein'v~-~ore àe__ned ~nd Q3 is a leavlng group.

Suitable values for Q3 include c-ou~s à~s?~ 2ced b~
nucleophiles such as C', 3r, , _SO2C.ï3 _- Cv~2~6.14pCH3.

Favoured values for Q3 include C:, B- anc I.

The reaction may be carried out under conventional alkylation conditions, for example in an inert solvent such 20 as dimethylformamide in the presence of an acid acceptor such as potassi~m carbonate. Generally the reaction is carried out at non-extreme temperature such as a~ ambient or slightly above.
~ ..
25 Alternatively, 'N-alkylation' may be effected under conventional reductive alkylation condi~ions.

Intercon-verting R3 and R4 respec-ively in the compound of the formula (VII~, or (VIII) respectively, before coupling 30 with the compound of the formul2 (VI) is also posslble.
Such interconversions are effected conveniently under the above conditions. It is desirabie ~o pro~ec~ any amine function with a group readily removable by acidolysis such as a C2_7 alkanoyl group, before R3 or R~ interconversions.
3s It is~often convenient in the preparatlon of such a compound of formula ~VII) or (VIII) to pre~are the corresponding : ' WO9t/17161 PCT/GBs)1/0~63~
3 :~ ~
compound wherein the methylene group is replaced by -Co-, or for R3 or R4 is methyl, where the methyl group is replaced by alkoxycarbonyl. Such compounds may then be reduced using a strong reductant such as llthium aluminium hydride to the 5 corresponding compound of formula (VII) or (VIII) respectively.

The compounds of formula (VI) are known or are preparable analogously to, or routinely from, known isoq~inoline 0 compounds.

It will be realised that in the compounds of _he formula (T) having a ~ropane, granatane or o~a/thia-grana-ane side chain, the -COE- linkage has an e~do orien~ation wit;n lS respect to the rlng 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 syntheslsed non-stereospecifically and the desired isomer separated conventionally therefrom e.g. by chromatographyi or alternati~ely the endo isomer may 20 if desired by synthesised from ~he corresponding endo form of thé compound of the formula (II). Corresponding - geometric isomeric pairs are possible for the isoquinuclidine, isogranatane, oxa/thia-isogranatane and isotropane side chains.
~harmaceutically acceptable salts of the compounds of this invention may be formed conventionally. The acid addition salts may be formed for example by reaction of the base compound of formula (I) with a pharmaceutically acceptable 30 organic or inoryanic acid.

The compounds of the present invention are 5-HT3 recep~or antagonists and it is thus believed may generally be used in the treatment or prophylaxis of ~ain, emesis, CNS disorders 3s and gastrointestinaI disorders. ~ain includes migraine, 1uster headache, trigemlnal neuralgia and visceral pain;

:~: ::

~,VO '~1/17161 ", ~ P'CT/GB~1,'00636 ~ -16-emesis, includes in particular that of preventing vomiting and nausea associated wlth cancer thera?y, and motion sic~ness. Examples of such cancer the-apy include that using cytotoxic agents, such as clsplatln, doxorubicln and 5 cyclophosphamide, particularly cisplati.~i and also radlatlon treatment. CNS disorders include an~ y, psychosis, senlle dementia and drug dependence. Gastrointestinal disorde~s include irritable bowel syndrome and àiarrohea.

0 S-HT3 receptor antagonis~s may also be c~ ?o~ential ~s_ in the treatmen~ of obesity and/or ~--hyt:n~ia.

The invention also provides a pharmaceu ical co~pcsi^_ioo comprlsing a compound c for~ul~ (~ 2h~_,~ace~
5 acceptable salt thereof, and a pharmaceu~ieally acceptable carrier.
.
Such compositions are prepared by admixture and are sui~ably adapted for oral or paren~eral administration, and as such 20 may be in the form of tablets, capsules, oral liquid preparationS, powders, granules, lo~enges, reconstitutable powders, injectable and infusable solutions or suspensions or s~uppositories. Orally administrable compositions are preferred, since they are more convenient for general use.
TabIets and capsules fo~ oral adminis~.ration are usuall~
presented in a unit dose, and contain conventional excipients such-as binding agents, fillers, diluents, : tabletting agents, lubricants, disin~egrants, colourants, 30 flavourings, and wetting agents. The tablets may be coated according to well known methods ln the art, ror example wi~h an enteric coating.
.: ~:
: : SultabIe ~illers for use include cellulQse, mannitol, 3s lactose and other similar agen~s. Sui~able disintegrants :.
.
::

WO 91/171~1 PCT/~ 1/0063f~
2~135~
~17-include starch, polyvinylpolypyrrolidone and starch deri~atives such as sodi~m starch glycollate. Sultable lubricants include, for example, magnesium stearate.

5 Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate. Oral liquid preparations may be in the form of, ~or example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or o other suitable vehicle before use. Such liquid preparations may contain conven~ional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel o- hydrogenated edible îa~s, 15 emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractlonated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservativesl for 20 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 2s elixirs or are presented as a dry produc~ for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional addltives such ; as suspending agents, emulsifying agen~s, non-aqueous vehicles (which may include edible oils), preservatives, and 30 flavouring or colouring agents.

The oral compositions may be prepared by conventlonal methods of blending, filling or tabletting. Repeated blending operations may be used to àistribute the actlve s agent throughout those compositions employing large WO91/17161 P~T/GBs)1/0~636 " ~
~ 18-quanti~ es of fillers. Such operatlons are, of course, conventional in the art.

For parenteral a~ninistratlon, fluid unit dose forms are 5 prepared containing a compound of the present invention and a sterile vehicle. The compound, depending on the vehicle and the concentration, can be either susoend~d or dissolved.
Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before f lling lO into a suitable vial or ampoule and sealinc.
Advantageously, adjuvants such as â local anaes~het.c, preservatives and buffering agents are also àissolvec in the vehicle. To enhance the stabil1 y, the o^mp^s.tion can ~e frozen after filling in~o the v al ana ~he wa~er removed 15 under vacuum.

~arenteral suspensions are prepared in subs~antially the same manner excep~ that the compound is suspended in the vehicle instead of being dissolved and sterilised by 20 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.

25 The invention further provides a method of treatment or prophylaxis of pain, emesis, CN5 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 30 salt thereof.
~ . , .
:
An amount effective to treat the disorders nereinbefore described depends on the relative efficacies of the compounds of the invention, the nature and severity of the 35 disorder being treated and the weignt of the mammal.
Howeverj a unit dose~for a 70kg adult will normally con~ain ' WO 91/17161 P(~/G E~9 1~006~6 3 ~ ~
0.05 to lOOOmg for example 0.1 to 500mg, of the compound of the inven~ion. Unlt doses may be administered once or more than once a day, ~or example, 2, 3 or 4 times a day, more usually 1 to 3 times a day, that ls in the range of 5 approximately 0.0001 to 50mg/kg/day, more usually 0.0002 to 25 mg/kg/day~

No adverse toxicological effects are indicated at any of ~he aforeme~tioned dosage ranges.

The inventlon also provides a pharmaceutical composition for use in the treatment and/or prophyla~ls of pain, emesis, CNS
disorders and/or gastrointestinal disorders whi~h composition comprises an effect non-toxic amount of â
compound of formula (I) or a pharmaceu~ically acceptable salt thereof and pharmaceutically acceptable carrier.

The invention also provides â compound of formula (I) or a pharmaceutically acceptable salt thexeof for use as an 20 acti~e therapeutic substance, in particular for use in the treatment of pain, emesis, CNS disorders and/or gastrointestinal disorders.

The invention further provides the use of ~ compound of 25 formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment and/or prophylaxis of pain, emesis, CNS disorders and~or gastrointestinal disorders.

30 The following ~xamples illustrate the preparation of compounds of ~ormula (I~, the following descriptions illustrate the preparation of intermedia~es.
.
' ~

WO9l/17161 PCT/GB~ 063O
'~s9 ~ 20-Desc~iption 1 4-Methy,l-l-isoquinoline carbo:~aldeh~d~ ~ ~

s To a solution of 1,4-dimethyl isoc~inoline (C'.465) (- -.
Agrawal, P.D. Mooney and A. C. Sar~orelll, v Med. C~e~., 1976, 19, 970) in 1,4-dioxane (250 ml) was added selenium dioxide (6.65g) and the mixture heated under _eflux, unaer an atmosphere of nitrogen, ror 4h. Af~er al_owing rhe o reaction mixture to cool to room temDerature, the precipitated selenium was removeà oY~ r ' o~ Q
filtrate concentrated to dryness. Tne res-d~e wa~ pur ~e~ -hy flash chromatograDhv on sil-c~ ~ s .~ _o'eum ether (bp 60-80C) ana dle~hyl e~;.er (up 5 ~% V/vj as 5 eluent, to afford the aldehyde (~1) (3.78g) as a ~an solld.
Mp. 61-63.

M.S. M+ 171 n.m.r. (CDC13, 250 MHz~
20 S 2.74 (s, 3H) 7.71-7.87 (m, 2H) 8.05 ~d, lH) 8.63 ~s, lH) 9.38 (d, lH) 10.35 ~s, lH) DescriD~ion 2 4-Methyl-1-isoquinoline carboxylic acid (D2) 30~ ~
To an aqueous solution of silver o.~ide (prepar5~d by the addition of silver nitra~e (5g) in water (10 ml) to a stirred solution of sodium hydroxide (2.40g) in water (lO
ml)) was added, at 0C, 4-methyl-1-~ soquinoline .
:

. ' ~ ', . '.' ' . ' ' , . - ' . ., ' ' . ' I ~ ' ' ' ' ' . .

YO91.~17161 PCT/~391/5)063~
2~$ ~3~

carboxaldehyde (D.l) (2.50g), in portions. The reaction mixture was stir~ed at ambient temperatures overnight. The silver suspension was removed by filtration and washed with hot water (3x5 ml). The combined filtrate and washlngs were 5 acidified with conc. HCl and extracted with chloroform (3x50 ml). The organlc phase was dried (MgSO4) and concentrated ln vacuo to afford the title compound (D2) (980 mg) as a beige solid mp. 155-57.

10 M.S. MH+ 188 n.m.r. (CDC13, 250 MHz) 2.75 (s, 3H) 7.79-7.92 (m, 2U.) 8.07 (d, lr.) 8.43 (s, lH) 9.67 (d, lH) 10.58 (bs, lH) ExamPle-l ,.
endo-N- ~9-Methyl-9-azabicYcloL~3.1 ~nonan-3-yl)isoquinolin-l-carboxamide (E1) :

I ~ ~-Me - ~ CO-NH J ~

~ (El) ::

:

: ~ :
.
:

WO ~1/17161 ,~ PCr/GB91/00636 Q ~J
~ -22- -A solution of ~soquinolin-l-carboxylic acid (2g), N-hydroxysuccinimide (1.5g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimicle (2.6g) was stlrred in dry DMF (SOml) at room temperature for 4 hours.
5 The reaction mixture was cooled at 0C, endo-N-(9-me~hyl-9-azablcyclo[3.3.1]nonan-3-am1ne (~g) ln CH2Cl2 (30ml) was added and the mi~ture s~irred at 30m temperature overnight. The solvent was remo~ed and ~he residue dissolved in CH2C12, washed with saturated aqueous o NaHC03 solution, dried and concent~ateà. The residue was recrystallised from Ethyl acetate and ~etrol (~p~. -ange 60-80C), to glve the title compound (2.4g).

m.p. 155-157C.
:
ExamDles 2 to 6 .
, . . .
The following compounds arP prepared analogously to example 1 or as hereinbefore descri~edO
. :

_ ._ .............. _ . . ._ Example Point of R2l Zl 2s attachment of CO-NH Zl :.
_ ~ ~ _ E2 1 H N-methyltropane :
~3 H N-methyltropane 1 H quinuclidin-3-yl : ~ E5 : 1 4-CH3 N-methyltropane : :
. ~6 : 1 H N-methyloxagranatane ~ ~ , ,' , ':

:
. ,.

, .
:

WO 9 l / l 7 1 6 l ~Cl /Gns 1/00636 ~23- 2~
F.xample 2 endo-N-(8-Methvl-8-azabicyclo[3 2.11octan-3-vl~isoqulnolin-1-carboxamide (E2) mp 87-88 H-NMR (CDC13) 3.67 (d, lH) o 8 . 75 (d, lH) 8 . 48 (d, lH) 7 . 9-7.6 (m, 4H) 4.42-4 .28 (m~ lH) 3.25 (brs, 2H) 2.42-1.70 (m, ~IH including 2.35, s, 3H) ~= _~_ 20 1soquinolin-3-carboxamide (E3) mp 133-136 1H-NMR (CDC13) 25 ~ 9.19 (s, lH) 8.85 (brd, lH) 8.60 (s, lH) 8.10-7.95 (m, 2H) - 7 . 80-7 . 65 (m, 2H) 4.36 (dt, lH) 3.25 (brs, 2H) 2 . 44-1.95 (m, 9H including 2 . 36, s, 3H) 1.85 (brd, 2H) WO91tl7161 ~ ~ ~ PCr/Cn91/00636 Example 4 N~ouinuclidin-3-yl)isoquinolin-l-carboxamide(E4) s mp 115-117 H-NMR (CDCl3) 9.62 (d, lh) 8.51-8.40 (m, 2h) 7 . 9-7. 62 (m, 4h) :
4. 35-4 .15 (m, lh) 3.58-3.41 (m, lh) 3.10-2.82 (m, 4h) . .
:
2. 75 (dd, lh) ~.
2.41-l.S (m, 5h) _ ~=~_ 20 ~ in-l-car}:oxamide (E5L
; .
mp 148 150 ~ .

lH-NMR (CDCl3) 2s ~ 10 . 03 (brd, lH) 9.42 (d, lH) 8.50 (d, lH) - 7.9-7.62 -(m, 4H) 4 . 88-4 . 72 ~m, lH) ~ 4.10 (d, 2H) 3.68: ~ (d, 2H) 2 . 75 (brs, 2H) .
: 2 . 67-2 .50 (m, SH including 2.60, s, 3H) 1. 60 (d, 2H) 3s ~ ~

.:
~:~ :: ~ .', ~: :

WO91/17161 PCT/GB91/0~63~
2 ~ o 1 3 S 13 Example 6 endo-N-(8-Methvl-8-azabicyclo[3.2.11octan-3-yl)-4-methyl-l-isoquinolin-l~carboxamide hydrochloride (~L

A solution of 4-rnethyl-1-isoquinoline carboxyllc acid (500 mg) (D2) and N-hydroxy succinimide (368 mg) in dry DMF (15 ml) was stirred under an atmosphere of nitrogen at amblent temperatures for 30 min. 1-Ethyl-3-(3-dime~hylamlnopropyl)-o carbodiimide (768 mg) was added in one portion and stirrlngcontinued for lh. The reaction mix~ure was cooled to 0~C
and a solution of endo-8-met~yi-8-azabicyclo[3.2.1]octan-3-amine (374 mg) in DMF (5 ml) was added dropwise and stirrina continued fo- 20h at ambient tempe-atures. The solvent W2S
15 removed in vacuo and the residue partitioned between chloroform (50 ml) and 10% aq. NaOH (5 ml). The organlc phase was dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chroma~ography on silica gel, using chloroform and ethanol (up to 10% v/~) 20 as the eluent to afford an oil~ Treatment with ethanolic HCl gave the title compound ~200 mg) as a pale yellow solid.
m.p. 140~43.

M.S. M+ 309 (Free base) 25 1E~-NMR (d4-MeOH, 250 MHz) 2.33-2.52 (m, 5H) 2.59-2.65 (m, 2H) 2.84 (s, 3H) - 2.92 (s, 3H) 30 ~ 3.02 . (d, lH) : 3.89-4.06 (m, 2H) 4O40-4.53 (m, lH) 8.10 (t, lH) 8.30 (t, lH) 8.44-8.60 (m, 3E~) WO 91/17161 ,~,3~`J PCrt(;B~ )0636 q,9~

5-HT3 ~eceptor ~ntaqonlSt Activity Compounds are evaluated for antagonism of the von Bezold-Jarisch reflex evoked by 5-HT in ~he anaesthetised 5 rat according to the following method:

Male rats 250-350g, are anaesthetised ~ith urethane (1.25g/kg intraperitoneally) and blood pressure and heart rate are recorded as described by Fozard J.R. et al,, J.
lO Cardiovasc. Pharmacol. 2, 229-245 (1980). A subma~imal dose of 5-HT (usually 6~cj/kg) is given repea~edlv by the lntravenous route and changes in heart rate quantified.
Compounds are given intravenously and the concentration required to reduce the 5-HT-evoked res?onse to 5~% 3- ~:.e 15 control response (ED50) is then determined.

'.
, , '':

;

,~
` ' ::

:
. . :

Claims

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

(I) wherein E is NH or C, R1 is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy or nitro;
Z is an azacyclic or azabicyclic side chain; and i) the group CO-E-Z is in the 1-position and either R2 is in the 3-position and is hydrogen, C1-6 alkyl or C1-6 alkoxy, or R2 is in the 4-position and is hydrogen, halogen, CF3, C1-6 alkyl, C1-7 acyl, C1-7 acylamino, phenyl optionally substituted by one or two C1-6 alkyl, C1-6 alkoxy or halogen groups, or amino, aminocarbonyl or aminosulphonyl, optionally substituted by one or two C1-6 alkyl or C3-8 cycloalkyl groups or by C4-5 polymethylene or by phenyl, C1-6 alkylsulphonyl, C1-6 alkylsulphinyl, C1-6 alkoxy, C1-6 alkylthio, hydroxy or nitro; or ii) the group CO-E-Z is in the 3-position and either R2 is in the 1-position and is hydrogen, C1-6 alkyl or C1-6 alkoxy, or R2 is in the 4-position and is hydrogen or C1-6 alkoxy;

having 5-HT3 receptor antagonist activity.

2. A compound according to claim 1 wherein E is NH.

3. A compound according to claim 1 or 2 wherein CO-E-Z is in the 1-position.

4. A compound according to any one of claims 1 to 3 wherein R1 is hydrogen.

5. A compound according to any one of claims 1 to 4 wherein Z is tropane, granatane, oxa/thia-granatane, quinuclidine, isoquinuclidine, isogranatane, oxa/thia-isogranatane or isotropane.

6. endo-N-(9-Methyl-9-azabicyclo[3.3.1]nonan-3-yl)iso-quinolin-1-carboxamide.

7. endo-N-(8-Methyl-8-azabicyclo[3.2.1]octan-3-yl)-isoquinolin-1-carboxamide.

8. endo-N-(8-Methyl-8-azabicyclo[3.2.1]octan-3-yl)-isoquinolin-3-carboxamide.

9. N-(Quinuclidin-3-yl)isoquinolin-1-carboxamide.

10. endo-N-(9-Methyl-9-aza-3-oxabicyclo[3.3.1]nonan-7-yl)-isoquinolin-1-carboxamide.

11. endo-N-(8-Methyl-8-azabicyclo[3.2.1]octan-3-yl)-4-methyl-1-isoquinolin-1-carboxamide.

12. A pharmaceutically acceptable salt of a compound according to any one of claims 6 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 (V):

(V) with a compound of formula A2-Z' wherein Z' is Z as defined in claim 1 wherein R3 and R4 are replaced by R3' and R4', A1 and A2 are moieties which react together to form an amide or ester linkage and R3' and R4' are R3 and R4 respectively, as defined in claim 1, or a hydrogenolysable protecting group;
and thereafter as desired or necessary, converting R3', or R4' when other than R3 or R4 respectively, to R3 and R4 respectively, and optionally forming a pharmaceutically acceptable salt of the 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.