CA2116024A1 - 5-ht4 receptor antagonists - Google Patents

Abstract

Compounds of formula (I): X-CO-Y-Z wherein the variable groups are as defined in the specification, of use in the treatment of gastrointestinal disorders, cardiovascular disorders and CNS
disorders.

Description

WO 93/03725 211 6 ~ 2 4 PCI/CB92/01519 This invention relates to the u~e of compounds as 5-HT4 receptor antagoDists in the treatment of gastrointestinal disorders, CNS disorders and/or cardiovascular disorders, and to certain novel compounds having 5-H14 receptor antagonist activity.

European Journal of Pharmacology 146 (1988), 187-188, and Naunyn-Schmiedeberg's Arch. Pharmacol. (1989) 340:403-410, describe a non classical 5-hydroxytryptamine receptor, now designated the 5-m4 receptor, and that ICS 205-930, which i8 also a 5-HT3 receptor antagonist, acts as an antagonist at this receptor.

PCT/GB9V00650 (SmithKline and French Laboratories I~mited) describes the u~e of cardiac 5-HT4 receptor antagonists in the treatment of atrial arrhyt~mias and fitroke.

Some 5-HT3 receptor antagonists have been disclosed as of potential use in the treatment of certain aspects of irritable bowel syndrome t&ee EP-A-189002 (Sandoz Limited) and EP-A-200444 ~Beecham Group p.l.c)].

5-HT3 receptor interaction~ wbich are of potential use in the treatment of IBS are those associated eitber with the visceral pain and abnormal perception of sensation aspects of tbis disease, or they are related to tbe ability of some 5-HT3 receptor antagonists to cause consl ipation in volunteer~.

Some 5-H'r3 receptor antagonists ha~e been disclosed as of potential use in the treatment of gastrointestinal disorders associated with upper gut motili1y [see EP-A-226266 (Glaxo Group Ltd.) and EP-A-189002 (Sandoz -Limited)3. 6-HT3 receptor antagonists are also well known antiemetics, such as ondarsetron, granisetron and tropisetron (see Drugs of the Future 1989, 1~ (9) p.875 - E.D. King and G.J. Sanger).

35 EP-A-189002 (Sandoz L~mited) and EP-A-429984 (Nisshin Flour MillingCo., Ltd.) di~lose compounds whi~ are described as 5-HT3 receptor antagonists usefi~l in the treatment of gastrointestinal disorders.

WO 93/03725 PCI'/GB92/01519 2116G2~ -2- ~
We have now di~covered that certain of t;hese compounds and related compound~ act as antagoni~t~ at 5-H14 receptors and are of potential use in the treatment of IBS or atrial arrh~ias and stroke.

5 The compounds of the present invention also have a potential use in the treatment of CNS disorder~ such as anxiety and/or migraine, in 1 he treatment of upper gut motility disorders and as antieInetics.

VVhen u~ed herein~ 'treatment' includes prophylaxis as appropnate.
The invention therefore provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof:

X~CO-Y-Z (1~
wherein X i8 a group of formula (a), (b) or (c):

R~L (a) R6J~R2 ,~ J, o Rs ~ F~3 -R~

~ (C) c wo93/0372s 2 11 6 () ~ ~ PCr/GB92/01519 wherein L iB N or CRB wherein R6 iB hydrogen, Cl 6 alkoxy, halogen, Cl~ alkyl or cyano;
Q is NR1, CH2, 0 or S;
5 WisCHorN;
Ra is hydrogen, halo, Cl 6 alkyl, amino, nitro or Cl 6 alkoxy;
Rb is hydrogen, halo, Cl 6 alkyl or Cl 6 alkoxy;
Rl is hydrogen, Cl lo alkyl, Cw alkenyl, aralkyl, C2 6 alkanoyl or C2 6 alkanoyl Cl 3 alkyl;
10 R2 is Cl 6 alkoxy; and R3 i8 hydrogen, chloro or fluoro; ~:
R4 is hydrogen,Cl 6 alkyl, amino optionally subs~tuted by a Cl 6 alkyl group, halo, hydroxy or C1 6 alkoy;
Rs i6 hydrogen, halo, Cl 6 alkyl, Cl 6 alkoxy, nitro, amino or Cl 6 alkylthio; and R6 is hydrogen, halo, Cl 6 alkyl, Cl 6 alkoxy or amino; ~ ;
Rc is hydrogen, Cl 6 alkoxy, halo or Cl 6 alkyl;
Y is O or NH;
Z is of su~formula (d) or (e):

H2)n~ (d) ` Rd .

)n2 N~ (e) R~ - :
.:
wherem nlisO, 1,2,30r4;n2is2,3,40r5; ::
25 q is 0, 1, 2 or 3;
Rd i8 hydrogen, C1 12 alkyl or aralkyl;
R7 and R8 are hydrogen or C1 6 alkyl; and Rg is hydrogen or C1 1o alkyl; :
in the manufacture of a medicament for use as a 5-HT4 receptor 30 antagonist.

WO 93/03725 PCr/Gs92/01519 .. q E~ample~ of alkyl or alkyl containing groups include Cl, C2, C3, C4, Cs, C6, C7, Cg, Cg, Clo, Cll or C12 branched, straight chained or cyclic alkyl, a~ appropriate. Cl 4 alkyl groups include methyl, ethyl n- and iso-propyl, n-, iso-, sec- and tert-butyl. Cyclic alkyl includes cyclopropyl, cycJobutyl, 5 cyclopentyl, cyclohe~grl, cycloheptyl and cyclooctyl. Alkenyl include~ all suitable ~ralues including E and Z fo~ns.

Aryl includes phenyl and naphthyl optionally ~ub~tituted by one or more gub~tituents selected from halo, Cl 6 alkyl and Cl 6 alko~
'' Halo inc3udes fluoro, chloro, bromo and iodo.

When Z i5 of su~formula (d), nl i8 preferably 2, 3 or 4 when the azacycle is attached at the nitrogen atom and nl is preferably 1 when the azacycle 15 i8 attached at a carbon atom, such as the 4-position wheTl q i8 2.

VVhen Z is of sub-~ormula (e), n2 i8 preferably 2, 3 or 4.

R8 and Rg are preferably both alkyl, espec ally one of R8 and Rg is C4 or 20 larger alkyl.

Specific values of Z of particular interest are as follows:

~--~N Bu ~) --~N ^O ~li) --N3 aii) ~NMenBu ~Iv) Tbe invention also provides novel compounds within formula (I) with side chains (i), (ii), (iii) or (iv).

wO 93~03725 2116 0 2 4 pcrlGB92/o15l9 The invention also provides novel compounds within fiormula (I) wherein X iB of formula (a) wherein L is C-OCH3, C-CH3 or C- Cl, in particular those wherein the side chain Z i6 of sub-formula (i), (ii), (iii) or (iv).

5 Other values of Z of interest are described with re~erence to the Esamples, such as those in Example~ 19 onwards. In particular, the side chain of formula (i) or (ii) i8 replaced by a corresponding side chain wi~h an alkyl or optionally substituted benzyl N-substituent and/or wherein the 4- -piperidinyl gro~p is replaced by 3-azetidinyl or 3-pyrrolidinyl.
~:'~
L in formula (a) is favourably C-H, C-CH3, C-Cl or C-OCH3. ;

Q in formula (a) i~ favourably NRl, usually NH or N-methyl.

Rl i8 preferably hydrogen or a methyl or ethyl group.

R2 is preferably methoxy.

R4 iB preferably amino.

R5 i8 preferably halo.

R6 iB preferably hydrogen.

A substituent when halo is selected from fluoro, chloro, bromo and iodo, preferably chloro. Rb when halo is preferably iodo.
:
Y iB preferably 0.

Particularly suitable esamples of compounds of formula (I) include those described in the Examples hereinafter and in Example 2 of EP-A-429984.
.
The pharmaceutically acceptable salts of the compounds of the formula (I) include acid addition salts with conventional acids such as hydrochloric, 35 hydrobromic, boric, phosphoric, sulphuric acids and pha~maceutically acceptable organic acids such as acetic, tartaric, maleic, citric, succu~ic, benzoic, ascorbic, methanesulpho~ic, a-keto glutaric, -glycerophosphoric, and glucose-l-phosphoric acids.
:

WO 93/03725 pcr/GB92/ol~l9 2 1 1 ~ ~3 2 1 - 6 -Examples of pharmaceutically acceptable salts include quaternary derivative6 of the compounds of formula (I) BUCh as the compounds quaternised by compounds RX-T where;n R~ is Cl 6 alkyl, phenyl-Cl 6 5 alkyl or Cs 7 cycloalkyl, and T is a radical corresponding to an anion of an acid. Suitable e~amples of R,~ include methyl, ethyl and n- and iso-propyl;
a~d benzyl and phenethyl. Suitable examples of T include halide 8uch a6 chloride, bromide and iodide.

10 E~amples of phar~naceutically acceptable salts also include internal salts such as N-02ides.

The compounds of the formula (I), their pharmaceutically acceptable salts, (including quaterna~ derivatives and N-o~ides) may also form 15 pharmaceutically acceptable solvates, such as hydrates, which are included wherever a compound of formula (I) or a salt tbereof i8 herein referred to.

5-HT4 receptor antagonist activity may be iden~fied accordi~g to 20 standard methods, such as those described hereinafter.

Esampl~s of 5-HT4 receptor antagonists include ICS 20~930 (tropisetron), which is described in the above mentioned patent reference~
and GB 2125398A, R 50 595 (Janssen), whic~ is described in FR76530 and 25 Eur.J. Pharmacol., 1~1 119^125 (1990), and SDZ 205-557, wbich is described by KH. Buchheit and R. Gamse in Naunyn-S;chmiedeberg's Ar~h. Pha~macol., ~ (Suppl.), R101 (1991).

In one aspect, the compound of formula (I) is a more potent antagonist at 30 5-HT4 receptors than at 5-H'r3 receptors.

PreferaUy, the 5-HT4 receptor antagonist of formula ;a) is in substantially pure pharmaceutically acceptable form.

35 The compounds of formula a) may be prepared as descnbed in the aforeme~tioned patent references, or by analogous methods thereto.

The compounds of the present invention are 5-HT4 receptor antago~ists wo 93/03725 2 116 0 2 4 PCI/GB92/01519 and it is thus believed may generally be used in the ~eatment or prophylaxis of gastrointsstinal disorders, cardiovascular disorders and CNS disorders.

5 They are of potential interest in the treatment of irritable bowel syndrome (IBS), in particular the diarrhoea aspects of IBS, i.e., these compounds block the ability of 5-HT to stimulate gut motility via activation of enteric neurones. In animal models of IBS, this can be conveniently measured as a reduction of the rate of defaecation. They are also of potential use in the 10 treatment of unnary incontinence which is often associated with IBS.

They may also be of potential use in other gastrointestinal disorders, such as those associated wîth upper gut motility, and as antiemetics. In particular, they are of potential use in the treatment of the nausea and 15 gastric symptoms of gastro oesophageal reflu~c disease and dyspepsia.
An~emetic activity îs determined in known animal models of ~-cytotosic-agent/radiation induced emesis. -~

Specific cardiac 5-HT4 receptor antagonists wbich prevent atrial ~-20 fibrillation and other atrial arrhythmias associated with 5-HT, would also be e~cpected to reduce occurrence of stroke (see A.J. Kaumann 1990, Naumyn-Scbmiedeberg's Arch. Pharmacol. 342, 619-622, for appropriate ~ -a~ test method). -25 It is believed that platelet-de~ived 5-HT induces atrial arrhythmias which encourage atrial fibrillation and atrial disorders are associabed with 6ymptomatic cerebral and sytemic embolism. Cerebral embolism is the most common cause of ischaemic stroke and the heart the most common ~ -source of embolic material. Of particular concern i8 the frequency of 30 embolism associated with atrial fibrillation.

An~iolytic activity is likely to be effected via the hippocampus (Dumuis et al 1988, Mol Pharmacol., 34, 880-887). Activity may be demonstrated in Etandard animal models, the social interaction test and the X-maze test.
M~graine suf~erers ofte~ undergo situations of an~ciety and emotional -~
stress that precede the appearaDce of headache (Sachs, 1985, Migraine, Pan Books, London). It has also been observed that during and within 48 WO 93/03725 PCI/GB92/01~519 211602 1 -8- ~
hours of a migraine attack, cyclic AMP levels are considerably increased in the cerebrospinal ~uid (Welch et al., 1976, Headache 16, 160-167). It i8 believed that a migraine, including tbe prodomal pha~e and the asso~ated increased levels of cyclic AMP are related to ~timulation of 5-HT4 5 receptor6, and hence that administration of a 5-HT4 antagonist iB of potential benefit in relieving a migraine attack.

The invention also provides a 5-HT4 antagonist pharmaceutical composition compri~ing a compound of formula (I), or a pharmaceutically 10 acceptable salt thereof, and a pharmaceutically acceptable carrier.

Such compositions are prepared by admi~cture and are u~ually adspted for enteral such ss oral, nasal or rectal, or parenteral administrstion, and as such may be in the form of tablets, capsules, oral liquid preparations, 15 powders, granules, lozenges, reconstitutable powders, nasal sprays, suppositries, injectable and infi~sable solutions or suspensions.
Sublingual or transdermal administration is also envisaged. Orally admiDistrable compositions are preferred, since they are more convenient for general use.
Tablets snd capsule~ for oral administration are usually presented in aunit dose, and contain conventional excipients such as binding age~ts, filler~, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents. The tablets may be coated according to 25 well known methods in the art, for example ~vith an enteric coating Suitable fillers for use include cellulose, maImitol, lactose and other similar agents. Suitable disintegrants include starch, polyvinylpolypyrrolidone and starch denvatives such as sodium starch 30 glycollate. Suitable lubncants include, for example, magnesium stearate.

Suitable pharmaceutically acceptable wetting agents in~:lude sodium lauryl sulphate. Oral liquid preparations may be in the form of, for esample, aqueous or oily suspensions, solutions, emulsion~, syrups, or 35 elisirs, or may be presented as a dry product for reconstitution ~nth water or other suitable vehicle before use. Su~ liquid preparations may contain conventio~al additives such as suspending agents, for esample sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, WO 93/03725 2 11 5 a ~ '1 P~/GB92/OlSl9 9 . -.~
carbo~yl.lethylcellulose, aluminium ~tearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for esample, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, 5 propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydrosybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
~ .
Oral liquid preparations are usually in the form of aqueou6 or oily 10 suspensions, solutions, emulsions, 6yrups, or eli~irs or are presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives ~uch as suspending agents, emulsifying agents, non-aqueous vehicles ~which may include edible oils), preservatives, and flavouring or colounng agents.
The oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated Uending operations may be used to distribute the active agent throughout those compositions employing ;~
large quantities of fillers. Such operations are, of course, conventional in 20 the art.
. .
For parenteral admiI~istration, ~uid unit dose forms are prepared containing a compound of the present invention and a sterile vehicle. The compound, depending on the vehicle and the concentration, can be either 25 suspended or dissolved. Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling i~to a suitable vial or ampoule and sealing Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are also di6solved in the vehicle. To enhance the stability, the composition can be 30 frozen af~er filling into the vial and the water removed uIlder vacuum.

Parenteral suspensis are prepared in substantially the 6ame manner except t}~at the compound is suspended in the vehicle instead of being dissolved and sterilised by esposure of ethylene oside before suspending 35 in the sterile vehicle. Advantageously, a 6u~ctant or wetting agent i8 in~luded in the composition to facilitate uniform distribution of the compound of the invention.

wO 93/0372s PCr/GB92/01519 2 1 1 6 0 ~ 4 - 1 o -The invention further provides a method of treatment or prophyla~is of i~itable bowel syndrome, gastro-oesophagal reflu~ disease, dyspepsia, atrial arrhythmias and stroke, anxiety and/or migraille in mammfllB, BUCh a~ humans, which compri~es the administration of an e~ective amount of 5 a compound of the formula (I) or a pharmaceutically acceptable salt thereof.

An amount effective to treat the disorders hereinbefore described depends on the relative efficacies of the compound~ to be administered, the nature 10 and severity of the di~order being treated and the weight of the mammal.
However, a unit dose for a 70 kg adult will normally contain 0.05 to 1000 mg for example 0.5 to 500 mg, of the compound. Unit doses may be administered once or more than once a day, for esample~ 2, 3 or 4 times a day, more usually 1 to 3 times a day, that is in the range of approgimately 15 0.0001 to 50 mgA~g/day, more usually 0.0002 to 25 mg/'kglday.

No adverse to~cological effects are indicated within the aforementioned dosage ranges.

20 The invention also provides a compound of formula (I) or a pba~maceutically acceptable ~alt thereof for u~e as an active therapeutic substance, in particular for use in the treatment of irritable bowel syndrome, gastro oesophagal reflus disease, dyspepsia, atrial arrhythmias and stroke, an~ciety and/or migraine.
The following Examples illustrate the preparation of compounds of -formula (I); the following descriptions relate to the preparation of side chain (Z containing) intermediates.

:.-WO 93/03725 2 1 1 ~ 0 2 4 PCI/GB92/01519 .

~ Y Z :.
:
El (a~, O CH2-(1-ethyl-4-piperidyl) :
L~CH, RalRb = H, Q = NH.
E2 (b~, R6=H O (CH2)2-(1-piperidyl) R2 = OMe, R3-H, R4=NH2 Rs = Cl.

E3 (b), R6=H NH CH2-(1-ethyl~-piperidyl) R2 = OMe, R3 = F, ~:
. 20 R4=NH2 Rs = Cl.

E4 (b), R6=H O SH2-(1-butyl-4-piperidyl) R2 = OMe, R3 = H, R4 = NH2~
Rs = Cl. ~-':
E5 (as E3) O CH2-(1-butyl-~pipendyl) . --E6 (-~El) ~O CH2~ butyl4-piperidyl) ~ ..

`,:

W6) 93/03725 PCI~/GB92/01~;19 211602~ 12-~am~ (contd.) ~ Y z E7 (c),* O CH2~ butyl-4-pipelidyl) W=CH, Rc=3-OMe E8 (c),* O CH2-(1-butyl-4-piperidyl~
W=N

E9 (c),** O CH2-(1-butyl~-pipendyl3 W=N :~

ElO (a), O CH2-(l-butyl-4-piperidyl) L~N, ;
Ra~b = H, Q = NMe Ell (as El) O (CH2)2-(1-homopiperidyl) El2 (as El) O (CH2)3-(1-piperidyl) E13 (as El) O (CH2)4-(1-piperidyl) El4 (a), O (CH2)2-(1-pipendyl) L=CH, R~ = 5-Br, Rb-H
Q ~ NH

* l-~ubstituted ~: ~ 35 **3-substituted .

W0 93/~3725 2 116 0 2 4 PCr/GB92/01519 - 1 3 - ~-Eacam~le~ (contd.) ~. Y Z ~

5 E16 (b), O (CH2)2-(1-piperidyl) R2 = OMe, R3 = H, R4 = Me, R5 =
E16 (a), O (CH2)2-(1-pipendyl) L = COCH3, Ra~Rb = H~ :
Q = NH
E17 (a), O (CH2-(1-butyl~-pipendyl) L=CH, R~/Rb - H, Q-CH2 .,:, E18 ~a), O (CH2)2-(1-piperidyl) L = CH, - Ra~Rb = H, Q=S
~ -El9 (as E2) O CH2-(1-butyl-3-pyrrolidinyl~
:~ `
E20 (as E1) O CH2-(1-butyl-3-pyrrolidinyl) ~:

30E21 (as E2) O (CH2)2-(1-pentyl-3-pyrrolidinyl) E22 (asE1) i O ~ (CH2)2-(1-pentyl-3-pyrrolidinyl) E23 (asE2) O CH2-(hexahydr~1-bul;yl-3-azepinyl) WO Q3/0372~ pcr/GB92~olsl9 211~1~2~ -14-~lml21~ (contd.) ~ Y Z

E24 (a~ E1) O CH~-(hexahydro-1-butyl-3-azepinyl) -E26 (as E2) O (CH2)2-(1-butyl-3-piperidyl) ;
E26 (as E1) O (CH2~2-(l-butyl-3-piperidyl) E27 (as E2) O (CH2)2-(1-butyl~2-pipendyl) E28 (as E2) O CH2-(l~butyl-3-piperidyl) :~
E29 (as E1) O CH2-(1-butyl-3-piperidyl) E30 (as E2) O l-butyl~-piperidyl ~.

E~l (as E2) O CH2-(1-butyl-1,2,5,~
tetrahydropyridyl) - ~

E32 (a), Q (i) L=CH, ~a~b = H~
Q - NEt E33 (a), O (i) L=CH, RaJRb = H, Q - NCH

E34 (as E33) O (ii) E36 ~a~ E2) O C~I2-(1-butyl-3-azetidinyl) ~:

WO 93/03725 211 ~ ~ 2 ~ pcr/GB92/olsl9 Q5 (contd.) ~ Y Z ~:
~:
E36 (a), O CH2-(1-butyl-4-piperidyl) L = C-CH3 Ra~Rb = H, ~:~
Q=NH
E37 (a), O CH2~ butyl-4-piperidyl) L=C-Cl :
Ra~Rb = H, Q = NCH3 :
E38 (a), O CH2-(1-butyl-4-pipendyl) L = C-OCH3 ::
Ra/Rb = H, Q = NH
E39 (a), NH CH2-(1-butyl~-piperidyl) L = C-H
Ra/~b = H, Q=NH
E40 (a), ~H CH2-(1-butyl~-piperidyl) Ra~b = H
Q=NH

E41 (as E36) O (CH2~(1-piperidyl) ~- E42 (b), R6-H O (i) R2=OMe, ` R3=Cl, ~-R4=NH2 '.

:~:

WO 93/03725 PCr/GB92/01~19 211~024 -16-De~cr~ption 1 (intermediates for Examples 19 and 20) a) l-Butyl-3-carbomethosypyrrolid-5-one 5 To a cooled solution of butylamine (9.4 ml) in methanol (10 ml) was added, dropwise, dimethyl itaconate (15g). The reaction mi~ture wa~ stirred at room temperature overnight. The solvent wa~ evaporated under reduced pressure to af~ord crude 1-bu~ 3-carbomethoxy-pyrrolidi~-5-one (17.9g).

10 b) 1-Butyl 3-hydroxymethylpyrrolidine To a stirred slurry of lithium aluminium hydride (4.29g) in diethyl ether (70 ml) was added 1-butyl-3-carbometho~ypyrrolid-5-one (lOg) in diéthyl ether (20 ml). The reaction mixture has maintained at reflus for 3h under 15 a nitrogen atmosphere, and stirnng continued overnight at room temperature. The mixture was cooled and water (4 ml), 10% aqueous NaOH (6 ml) and water (8 ml) were added seque~tially. Diethyl ether was added and the misture stirred for lh. The resultant precipitate was removed by filtration through keiselguhr and the filtrate concentrated 20 u~der reduced pre~sure. Distillation at reduced pressure gave pure 1-butyl-3-hydrosymethylpyrrolidine (Dl) (5.13g).
., lH NMR (CDC13) 250 MHz ~: 3.69 (dd, lH), 3.51 (dd, lH), 2.80 (dt, lH), 2.64 (dd, lH), 2.24-2.53 (m, 5H), 1.92-2.07 (m, lH), 1.60-1.73 (m, lH), 1.2~1.55 (m, 4H), 0.92 (t, 3H). -~

Desc~iption 2 (intermediate for Examples 21 and 22) 30 a) Following the procedures outlined in Description 1, the follo~ving compound was obtained:

1-pentyl-3-hydro~ymethylpyrrolidine 35 b) 3-Chloromethyl-l-pentylpyrrolidine (6.54g) in ~hloroform (lO ml) wa~ saturated with hydrogen chlonde and the misture heated to reflus. A
solution of thionyl chloride (5.6 ml) in chloroform (10 ~1) was added dropwise and stirring continued for lh The reaction mixture was cooled ``' WO 93/03725 ~ O ~ ~ PCI/GB~2/01519 to room temperature and ~tirIing continued overnight. The reaction mi~ture was concentrated to half-volume and azeotroped with ethanol (2 10 ml). Tbe residue was diluted with water and extracted with diethyl ether. I~e aqueous phase was basified with 50% aqueous sodium hydro2~ide and extracted with diethyl ether. The organic phase was washed with water, dried (Na2S04) and concentrated in vacuo to afford a~ oil. Distillation under reduced pressure gave pure 3-chloromethyl-1- -pentylpyrrolidine (5.79g).

A 6tirred solution of 3-chloromethyl-1-pentyl pyrrolidine (5.415g), tricaprylmethyl smInonium chloride (375 mg), snd sodium cysnide (7.25g) in water (12.5 ml) was heated at 100C for 24h. The reaction mi~ture was cooled to room tempersture and extracted with ethyl acetate. The organic phase was washed with water, dried (Na2S04) and concentrated 15 in vacuo to sfford crude 3-cyanomethyl-1-pentylpyrrolidine (5.04g).

d) A solution of 3-cyanomethyl-1-pentylpyrrolidine (2.982g) in methanolic HCl (60 ml) was allowed to fitand at room temperature for 16h.
The solvent was removed under reduced pressure, the residue diluted 20 with water, basified with aqueous sodium hydro~nde solu~on and e~tracted with diethyl ether. The orgaDic phase was washed with water, dned (Na2S04) filtered and concentrated in vacuo to a~ord crude methyl 3-(1-pentyl pyrrolidino) acetate. Mstillation under reduced pressure (100C at 0.2 mm Hg) gave tille compound (2.13g).
e) To a ~uspension of lithium aluminium hydride (0.7g) in diethyl ether (40 ml) was added methyl 3-(1-pentyl pyrrolidino) acetate (1.967g) under a nit~ogen atmosphere. The mi~ture was heated to reflu~c and stirnng continued for 4h. The reaction mi~ture was cooled to room 30 temperature and stirring continued overnight. Water (5 ml) was added dropwise and the resultant precipitate removed by filtration and washed with dichloromethane. The combined organic filtrate was concentrated in vacuo to af~ord an oil. Dis~llation under reduced pressure (150C l l.0 mm Hg) gave pure 3-hydroxyethyl-1-pentylpyrrolidine (D2) (1.48g).
lH NMR (250 ~OEIz) (CDC13) ~: 4.18-4.41 (8, lH), 3.52-3.73 (m, 2H), 2.7~
2.85 (m, lH), 2.33-2.52 (m, 6H), 1.92-2.08 (m, lH), 1.45-1.80 (m, 5H), 1.22-?-38 (m, 4H), 0.88 (t, 3H).

wo 93/03725 pcl/Gs92/olsls Degcription 3 (inte~nediate for Examples 23 and 24) a) Hexahydro-l-butyl-azepin-2-one 5 To a solution of hexahydro-1H-azepin-2-one (lOg) i~l dry THF (300 ml) was added potassium tert-butoxide (9.86g). The reaction mixture was heated to reflux. 1-Bromobutane (9.45 ml) was added after lh. Stirring was continued for 2h. The reaction misture was cooled to room temperature and water (10 ml) added. The solvent was concentrated under reduced 10 pressure and the residue dissolved in et~yl acetate (250 ml) and washed ~nth brine. The organic phase was dried (Na2S04) filtered and concentrated in vacuo to afford an oil.

Kugelrohr distillation af~orded pure title compound (12.0g).
b) Hesahydr~l-butyl-3-carbosyazepin-2-one To a solution of hexahydro-1-butylazepin-2-one (6.0g) in dry 1~ (30 ml) was added lithium diisopropylamide in cyclohexane (1.5M, 23.3 ml) at 20 0C. Stirring was continued at ambient temperature for 30 min. C02 pellets was added to the reaction misture which were subsequently poured into ice-water (200 ml). The l~IF was concentrated in vacuo and 1 he aqueous phase adjusted to pH2 with 5N HCl. The aqueou~ phase was ext~acted with chloroform (4 s 200 ml) and the combined organic estracts 25 were d~ied (NaaS04), filtered and concentrated in vacuo to afford an oil.
Elash chromatography on silica u~ing chloroform and ethanol as the eluant gave pure title compound (1.9Og).

c) He~ahydro-l-buty1-3-hydrosymethylazepine To a slurrg of lithium aluminium hydride (1.03g) in THF (50 ml) was added a solution of he~cahydro 1-butyl 3-carboxyl azepin-2-one (1.9Og) in 1~ (50 ml) under a nitrogen atmosphere. Stimng was continued at ambient temperature for 70h. The reaction mi~ture was heated to reflux 35 for 5h, cooled and quenched by the sequential addition of water (1 ml), 10~6 aqueous NaOH (1~ nd) and water (2~ ml). Stimng was continued at room temperature for lh. The resultant precipitate was remo ~ed by ;~
filtration and the filtrate concentrated in vacuo to afford an oil. -WO 93/03725 211 6 Q 2 ~1 PCrJGB92/01519 - 19- .
Kughlerohr distillation gave pure ~tle compound ~D3) (0.76g).

H NMR (CDC13) 250 MHz ~: 4.71 (m, lH~, 3.81 (dd, lH), 3.49-3.57 (m, lH), 2.70-2.85 (m, 3H), 2.43 (dt, 2H), 2.07-2.30 (m, lH), 1.41-1.90 (m, 9H), 5 1.22-1.37 ~m, 2H), 0.92 (t, 3H).

De~cription 4 (intermediate for E~ampl~s 25 and 26) 10 a) Ethyl 1-buty1-3-pyridylacetateiodide To a cooled solution of ethyl 3-pyridylacetate (12g) in acetone (50 ml) was added l-iodobutane (12.90 ml). The reaction mixture was ~tirred at room temperature overnight and then heated to reflu~. The reaction mi~cture 15 was cooled to room temperature and diethyl ether waæ added. S~rriIlg waB continued for 15 min. The resultant precipitate was removed by filtration and dried to afford crude title compound (23.76g).

b) Ethyl-1-buty1~3-piperidylacetat~ -A solution of ethyl 1^butyl-3-pyridylacetate iodide (21g) in ethanol wa~ -~
hydrogenated over PtO2 (2g) at atmospheric pressure and room temperature. The catalyst wa~ removed by filtration through keiselguhr and the filtrate concentrated in vacuo. The residue wa~ dissolved in 25 water, basified from K2C03 and e~tracted with chloroform. The organic phase svas dried (Na2S04) filtered and concentrated in vacuo to afford ethyl 1-butyl-3-piperidylacetate (13.6g) as an oiL

c) l-But3~1-3-pipendyletha~ol To a slurry of litbium alumi~ium hydride (3.51g~ in diethyl ether (50 ml) wa8 add~d, dropwise, a 801ution of ethyl 1-but~rl-3-piperidyl acetate ~7.0g) in diethyl ether (50 ml) at 0C under a nitrogen atmosphere. Stir~ing was continued at smbient temperature for ffOh. The reaction misture was 35 cooled to 0C and treated ~equentially with water (3.5 ml), 10% aqueous NaOH (5.2 ml) and water (8.7 ml). Stirring was continued for lh. The precipitate wa~ removed by filtration through Keiselguhr and the filtrate evaporated under reduced pressure to afford crude product. Vacuum WO 93/03725 PCI/GB92/0~519 211~02-1 ~
dis~llation gave pure title compound (D4) (4.0g).

lH NMR (CDCI3) 250 MHz ~: 3.59-3.77 (m, 2H), 2.64-2.69 (m, 2H), 2.23-2.35 (m, 2H), 2.11-1.96 (m, lH), 1.40-1.88 (m, 9H), 1.22-1.38 (m, 2H), 0.98-1.14 (m, lH), 0.92 (t, 3H).
MH+ 186 De~cription 6 (intermediate for Example 27) a) Ethyl l-butyl-2-piperidylacetate To a solution of ethyl lH-piperidyl-2-acetate (8.3g) in ethanol (100 ml) was added potassium carbonate (14.35g) and 1-bromo butane (11.7 ml). The reaction mixture was heated to reflux overnight. The reaction mi~cture was cooled to room temperature and filtered through keiselguhr. The filtrate was evaporated under reduced pressure to afford an oil. Flash cbromatography on silica eluting with chloroform and ethanol gave pure title compound (5.85g). -b) l-Butyl-2-pipe~idylethanol Following the procedure ou~ined in Description 4c), ethyl 1-butyl-2-piperidyl acetate (4.44g) gave the title compound as an oil afl;er kugelrohr dis~llation (2.27g).

lH NMR (CDC13) 250 MHz ~: 5.45 (m, lH), 3.82-3.94 (m, lH), 3.70-3.80 (m, lH), 3.00-3.09 (m, lH), 2.73-2.85 (m, lH), 2.61-2.72 (m, lH), 2.40-2.52 --~m, lH), 2.21-2.34 (m, lH), 1.81-1.96 (m, lH), 1.23-1.75 (m, 11H), 0.90 (t, 3H).
`'..

MH+ 186 :

wo 93/0372s 2116 0 2 4 PCI/Gs92/OlSlg Description 6 (intermediate for E~ample 28) a) E:thyl-l-buty1-3-piperidyl carbo~ylate 5 Following the procedure ou~lined in description 5a), ethyl-lH-piperidyl 3-carbo~ylate (15.7g) gave ~tle compound (17.1g).
b) l~Buty1-3-pipe~dylmethanol `~

10 Following the procedure outlined i~ Description 5b), ethyl l-butyl -3-piperidyl carbox~rlate (17.1g) gave l-butyl 3-pipendinyl methanol (D6) (3.9g).

lH NMR (250 MHz) (CDC13) ~: 3.38-3.53 (m, 2H), 2.82-3.03 (m, 2~I), 15 2.23-2.34 (m, 2H), 1.98-2.02 (m, lH), 1.36-1.97 (m, 8H), 1.22-1.35 (m, 2H), 0.92 (t, 3H).

Description 7 (intermediate for Esample 30) a) Dimethyl-2, 2'-butyliminodiethanoate Methyl acrylate (11.78g) was added dropwise to n-butylamine (6g), at 0C.
The reaction misture wa~ heated to re~u~ for 24h The reaction mi~ture 25 was cooled to room temperature, diluted with ethyl acetate and washed with water (3x). The organic phase was dried (Na2S04), filtered and concent~ated u~der reduced pressure to afford an oil. Purificat~on by kugelrohr distillation gave the title compound (9.95g).
, 30 b) l~Butyl-4piper~done Potassium te~-buto~ndé (6.82g) was added to a solution of dimethyl-2,2 -butyl iminodiethanoate (9.95g) in diethyl ether under a nitrogen atmosphere. The reaction mi~ture was stirred at room temperature 35 overnight. The mixture was estracted into 5N HCl (100 ml) and heated under reflux for 2h The reaction misture was cooled to room temperature and e~raporsted under reduced pressure. The residue was basified with K2C03 and e~tracted unth ethyl acetate. The organic phase was dried wO 93J03725 pcr/Gs92/ol5l9 2 11 ~ 0 2 4 - 22 -(Na2S04) filtered and concentrated in vacuo. Flash chromatography on silica using ethyl acetate as the eluant gave pure 1-butyl-4-pipe~idone (3.68g).
c) 1-Butyl-4-pipe~idol To a slurry of lit~ium al=um hydride (0.96g) in diethyl etber (50 ml) wa~ added 1-butyl~piperidiDone (2.6g) in diethyl ether (50 ml), at 0C -:
under a nitrogen atmosphere. The reaction mi~ture waB stirred ove~ight at ambient temperature, cooled to 0C and treated sequentially with water (1.0 ml), 10~b NaOH (1.4 ml) and water (2.4 ml). The misture wa~ ~
stirred at ambient temperature for lh and the precipitate removed by ::
filtra~on through keiselguhr. Tbe filtrate was concentrated under ~-reduced pres~ure to afford an oil. Purification by vacuum dis~llation gave 1-butyl~-piperidol (D7) (1.98g).

lH NMR (CDC13) 250 MHz ~: 3.61-3.74 (m,l H), 2.71-2.82 (m, 2H), 2.2~
2.34 (m, 2H), 2.0~-2.16 (m, 2H), 1.82-1.95 (m, 3H), 1.38-1.67 (m, 4H), 1.22- -1.37 (m, 2H), 0.9 (t, 3H).
~scription 8 (interInediate for E~ample 31) a) Ethyl l~butyl-4-pyridyl carbo~ylate iodide , :~
Following the procedure ou~lined in Desc iption 4a), ethyl 4-pyridine carbo~ylate (lOg) gave the title compound (22.2g).

b) Ethyl 2-butyl-(1,2,6,0-tetrahydropiperidyl4-carbo~ylate To a suspension of sodium borohydride (4.6g) in ethanol (300 ml~, at 0C, wag added ethyl l-but~yl~pyridyl carboylate iodide (lOg) u~der an atmosphere of nitrogen. The reaction mi~ture was stirred for 2h at ambient temperautre. The mi~cture was poured into water and tbe solve~t :~
concentrated under reduced pressure. The residue was estracted into ~hlo~oform and the organic pha~e dried (Na2S04), filtered and concentrated to afford an oil. Flash chromatography on silica using c~loroform and ethanol a8 eluant gave pure title compound (2.59g).

WO 93/03725 2 11~ ~ 2 '1 PCI/GB92/Ot51g c) l-Buty1-(1,~,5,6)-tetl ahydropiperidyl-4-methanol Following the procedure outlined in Description 4c), ethyl l-butyl-5 (1,2,5,6~ tetrahydropipelidyl-4-carbo~ylate t2g) gave pure ~tle compouDd (D8) (630 mg).

lH NMR (CDCl3) 250 MHz ~: 5.59 (8, lH), 3.92 (8, 2H), 2.95 (8, 2H), 2.59 (t,2H), 2.36 -2.50 (m, 2H), 2.10-2.20 (m, 2H), 1.25-1.60 (m, 6H), 0.92 (t, 10 3H).
M+ 169 15 Description 9 (intermediate for E:Eample 35~
a) l-Benzyl 4-chloro-3-hydro:cybutylamine To a 801u~ion of epichlorohydrin (150ml) in cyclohesane (1l) was added :~
20 benzylamine (240ml). The reaction mixture was stirred at room temperature for 24h The precipitate w88 removed by filtration, washed with petrol (bp 60-80~C) and dried (327.7g) b) l-Benzyl-3-trimethylsilo~yazetidi~e To a solution of imidazole (112g) and triethyl amine (825ml) in acetonitrile (1.51~ was added, dropwise chlorotrimethylsilane (203ml) at -5C uIlder nitrogen. Stirnng was continued at room temperature for 11/2h. 1-benzyl-4-chloro-3-hydroxybutylamine (310g) wa~ added to the 30 reaction and t~e resulting misture heated to re~ux for 72b, with vigorous stirring. The mixture was cooled to room temperature, toluene (21) was added and the mi~ture left to stand overDight. The precipitate was removed by filtration, ~lurned in petrol (bp 60-B0C) (2l) and washed with water (200ml). The filtrate was concentrated in vacuo and the residue 35 partitioned between water and petrol (bp 60-80C) (1l). The organic layer~ were dried (MgSO4), filtered and concentrated in uacuo to af~ord an oil. Purification by vacuum distillation gave l-benzyl-3-trimethylsilo~cy azetidine (130g) as a colourless oil.

WO 93/03725 PCI~GB92/OtS19 211602~ -24-c) l-Be~zyl-3-hydro~yazetidine A solution of l-benzyl-3-trimethylsiloxyazetidine (89g) in cHCI/water (53/350ml) was stirred vigorously at room temperature for lOmin. The misture was basified with K2C03 and extracted ~ntb diethyl ether. The -~
ethereal extracts were dried (MgS04), filtered and concentrated in vacuo to afford l-benzy1-3-hydroxyazetidine (59.6g) as a white solid.

d) l-Benzyl-3-cyanoa~etidine To a stirred solution of 1-benzyl-3-hydroxyazetidine (B3.1g) and triethylamine (71ml) in toluene (610ml) and triethylamine (71ml) was added, dropwise, over 20min methane sulphonyl chloride (39.5ml).
During addition the internal temperature was maintained between O ~nd 5C. On completion of addition stirring was continued for a further 30min. Water (20ml) was added to the reaction misture and the separated toluene layer removed. The aqueous layer was furt~er e~acted with toluene (2~100ml). The organic estracts were combined and washed vri~Lh brine. The organic phase was treated with Adogen 464 -~
(25g) and a solution of sodium cyanide (29.5g) in water (173ml). The reaction misture was heated to re~ux for ll/2h and allowed to cool to room temperature. The mixture was transferred to a separato~y funnel and the aqueous layer removed. The organic phase was washed with water (3x200ml) and brine (200ml), dried (MgS04), filtered, and concentrated in vacuo. Distillation of the residue gave pure 1-benzyl-3-cyanoazetidine (62.9g).
e) Methyl l~benzyl-3-azetidinyl carbo~ylate To a ~olution of 1-benzy1-3-cyanoazetidine (lOg) in methanol (40ml) wa~ -added cH2S04 (35ml), dropwise, 80 as to maintain the reaction at a ma~imum 55C. The reaction mixture was heated to 80C for 2h, cooied to r.t. and poured into ice (240g3. The mixture was basified with aq.
ammonia and extracted into dichloromethane. The orgaDic phase was washed with water, dried (Na2S04), filtered and concentrated in vacuo to a~ord crude title compound (10.18g).

f) Methyl-lH-3-azetidinyl carboxylate acetate A ~olution of methyl 1-benzyl-3-azetidi~yl carbsgylate (5.45g) in et~ol ~lOOml) and acetic a~d (6ml) wa~ hydrogenated over 10% Pd/C at 50pBi 5 alld 50C for 6h. The catalyst was removed by filt~ation tbrough keiselguhr and the filtrate concent~ated in vacuo to af~ord met~yl l-H-3-azetidinyl carbo~ylate acetate (3.65g).

g) Methyl l-but~l-3-azetidinyl carbosylate To a ~olution of methyl l-H-3-aze~dinyl carbo~cylate acetate (2.80g) and triel~hylamiDe ~4.6ml) in dicbloromethane (60ml) wa~ added, drop~e, butyryl chloride (1.6ml). The reaction mixture was ~tirr~d at ambient temperature for 70h. The mixture was washed witb water and t~e ::
15 organic phase dried (Na2SO4), filtered and concentrated under reduced pressure to af~ord crude methyl 1-butyryl-3-azetidinyl carbo~ylate (2.60g).

Buty1-3-hydro~ymethylazetidine 20 To a solution of I,ithium aluminium hydride (2.20g) in dry THF (26ml) wa~ added a ~olution of methyl 1-butyryl-3-azetidinyl carbos~ylate (3.60g) iD dry l'HF, st 0C, under a nitrogen atmosphe;e. The reaction mi~ture was stirred at am~ient temperature o~ren~ight. The reaction was quenched by sequential addition of water (21/2ml), 10% aq. NaOH (4ml) 25 and water (5ml). Diethyl ether (20ml) was added and stirring continued for lh The precipitate ~ras removed by filtration through Keiselguhr and the filtrate concelltrated in vacl~o to afford an oil. Kug~lerobr distillatio~
afforded pure title compound (D9) (1.lg).

1H ~MR 250M~Iz (CDCl3), ~: 3.67 (d,2H3, 3.23-3.47 (m,2H), 2.97-3.08 (m,2H), 2.55-2.68 (m,lH), 2~35-2.7 (m,2H), 1.27-1.38 (m,4H), 0.8~0.98 (m,3H), ~IH+ 144 WO 93/03725 pcr/GB92/ol5l9 21160~

De~c~ption 10 (intermediate for E~ample 4) 1 -Butyl-4-piperidinemethanol 5 A mixture of ethyl isonipecotate (31.4g, 0.2mole), K2CO3 (54g, 0.4mole) and ~BuBr (27.4g, 0.2mole) in EtOH (400ml) was stirred under reflux for 3 hours. The reaction mixture was allowed to cool, filtered through keiselguhr and the filtrate concentrated to give a pale yellow oil. This was dissolved in dry Et20 (200ml) and added dropwise to a suspension of 10 LiA~I4 (20g, 0.26mole) in dry Et2O. The reaction mi~ture was stirred at room temperature overnight then cooled in an ice bath. Water (20ml) was carefully added, followed by 20% aq. NaOH ~20ml), followed by water (60ml). The mi~ture was stirred at room temperature for 30 minute~ then filtered through keiselguhr. The filtrate was concentrated in vacuo to give 15 a colourless oil (25.0g).

NMR 250MHz (CDC13) ~: 3.48(d,2H), 2.93-2.99(bd,2H), 1.18-2.4(m,14H), 0.9(t,3H) -~

WO 93/0372~ 21 1 6 0 2 4 PCI/GB92~01519 Preparation of Intermediate Acid for Example 3 a) Methyl-4-acetamido-5-chloro-2-methoxybenzoate (10.9g) was dissolved in chloroform (40 ml), cooled to -10 C under nitrogen. A three molar excess of trifluoromethyl hypofluorite was slowly bubbled through ~he stirred, cooled 601ution for 6 hours. A slow posi~ve nitrogen stream was maintained throughout the reaction. After warming to room temperature and thoroughly purging with nitrogen, the chloroform was -~-removed in vacuo.
The residue was chromatographed on silica using chloroform with increasing amounts of methanol as eluant. Methyl4-acetamido-5-chloro-3-~uoro-2-metho~ybenzoate was isolated as an off white solid.

1H NMR (CDC13) 250MHz; ~: 7.64 (d, lH), 7.37 (bs, lH), 3.98 (bs, 3H), 3.9 (s, 3H), 2.2 (s, 3H) b) Methyl-4-acetamido-5-chloro-3-fluor~2-methoxybenzoate (1.89g) in 25 ml ethanol was treated with a solution of sodium hydroxide (1.15g) in 15 ml water. The mi~cture was heated under reflux for 16 hours then cooled. 1ne solvent was removed in vacuo and the residue acidified. The precipitated solid was collected by filtration to give 1.48g of 4-amino-5-chloro-3-fluoro-2-methoxybenzoic acid. -lH NMR (DMS0) 250MHz; ~: 7.49 (d, lH), 6.19 (bs, 2H), 3.80 (s, 3H) WO 93/03725 PCr/GB92/01519 2116~24 -28-EYamP1e 1 (1-EthY1-4-PiPeridY1)methYI 1H indO1e-3 CarbO~ (E1) A suspen~ion of indole-3-carboxylic acid (500 mg, 0.003 mole) in dichloromethane (50 ml) was treated with osalyl chloride (0.635, 0.005 mole) and two drop6 of dimethylformamide. The mi~ture was stirred at room temperature for one and a half hours then the solvent wa~ removed in vacuo. The residue was redissolved in dichloromethane (50 ml) and a :~
601ution oftIiethylamine (612 mg, 0.006 mole) and l-ethyl~-hydrosymethylpiperidine (430 mg, 0.003 mole) in dichloromethane (20 ml) wa~ added dropwise. The reaction misture was stirred at room temperature overnight then washed with aqueous potassium carbonate solution and water, dried and concentrated to give a gummy solid which 15 was purified by column chromatography on silica gel using chloroform 95%, methanol 5% as eluant to give a white solid 405 mg, mp 135-6C.

lH NMR (250MHz) CDC13; ~: 10.08 (bs, lH), 8.10 - 8.20 (m, lH), 7.76 (d, :
lH), 7.35 - 7.45 (m, lH), 7.20 - 7.28 (m, 2H), 4.20 (d, 2H), 3.0-3.12 (bd, 20 2H), 2.5 (dd, 2H), 1.4-2.10 (m, 7H), 1.10 (t, 3H).

Esample 2 25 4-Amino-5-chloro-2-methosy-(2-(1-piperidyl)ethyl)benzoate (E2) A solution of 4-amin~3-chlor~2-methosybenzoic acid (2.01g, 0.01 mole) in acetonitrile (30 ml) was treated with bi~-carbonyldiimidazole (1.62g, 0.01 ~ole) and the mi~cture was stirred at room temperature for one and a balf 30 hours. The solvent was removed in vacuo to leave the crude imidazolide.

A ~olution of 1-(2-hydro~yethyl)piperidine (1.29g, 0,01 mole) in dry TE~
(10 ml) under an atmosphere of nitrogen, was cooled in an ice bath n-Butyllitbium (6.25 ml of 1.6M solution in hesane) was added dropwise 35 and the resulting solution stirred at 0C for 15 minutes.

The imidazolide was dissolved in dry 1~' (20 ml) and the resulting solution added dropwise to the solution of the lithium alko~cide at 0C.

WO 93/03725 2116 0 ~ 4 PCI/GB92/01519 ~9 The reaction mixture was allowed to warm to room temperature and was ~tirred for 3 hours. The solvent was removed in vacuo and the residue partitioned between chloroform and water. The cblorofo~m was separated, washed several times with water, dried and concentrated to give a white ~;
5 eolid (recrystallised from ether/petroleum ether) yield 2.6g, mp 135-6C.

lH NMR (250MHz) CDC13; ~: 7.82 (s, lH), 6.30 (8, lH), 4.48 (bs, 2H), 4.38 -~
(t, 2H), 3.82 (8, 3H), 2.72 (t, 2H), 2.45-2.56 (m, 4H), 1.52-1.66 (m, 4H), -1.40-1.50 (m, 2H).
.

E~ample 3 4-Amino-6-chloro-3-fluoro-2-metho~y-(1-ethyl-4-15 piperidyl)methylbenzamide (E3) A solution of 4-amin~5-chloro-3-fluoro-2-metho~cybenzoic acid (210mg, -0.001 mole) in acetonitrile (15ml) was treated with bis-carbonyldiimidazole (162mg, 0.001 mole). The misture was stirred at 20 room temperature for one and a half hours.

A ~olution of 1-ethyl-4-aminomethylpiperidine (142 mg, 0.001 mole) in acetonitrile (10 ml) was added dropwise and the reaction mixture was stirred at room temperature for 3 hours.
The solvent was removed in vacuo and the residue partitioned between ~ -chloroform and water. The chlorofo~n layer was removed, washed several times with water, drièd and concentrated to give a beige solid which was converted to the hydrochloride salt, 110 mg, mp 208-9C.
lH NMR (250 ~Hz) CDC13 (free base); ~: 7.82 (d, lH), 7.65-7.75 (bt, lH), 4.30 ~bs, 2H), 4.40 (B, 3H), 3.25 ~t, 2H), 2.82-2.95 (bd, 2H), 2.28-2.38 (dd, ~ ;
2H), 1.10-1.90 (m, 7H), 1.0 (t, 3H). -:.

211~0~ll 30 Example 4 4-Amino-5-chlor~2-methoxy.(l-butyl4-piperidyl)methyl benzoate (E4) -The title compound was prepared from 4-amino-5-chloro-2-methoxybenzoic acid and 1-butyl4-piperidinemethanol by the method described for Example 2. It was isolated as a white solid, mp 62-53C.

1H N~IR (250 MHz) CDC13; ~: 7.80 (8, lH), 6.28 (8, lH), 4.42 (bs, 2H), 4.10 (d, 2H), 3.85 (s, 3H), 2.92-3.02 (bd, 2H), 2.35 (m, 2H), 1.20-2.02 (m, 11H), 0.92 (t, 3H).

15 Esample 6 4-Amino-5-chloro-3-fluoro-2-methoy-(1-butyl-4-piperidyl)methyl benzoate (E5~

20 The title compound was prepared from 4-amino-5-chloro-3-~uoro-2-methoxybenzoic acid and 1-butyl-4-piperidinemethanol by the method -described for E~ample 2. It was isolated as a colourless gwn and converted to the hydrochloride salt, mp 195-7C.

25 lH NMR (250 MHz) CDC13 (free base); ~: 7.62 (d, lH),4.45 (bs, 2H), 4.12 (d, 2H), 3.90 (s, 3H), 2.92-3.15 (bd, 2H), 2.28-2.38 (m, 2H), 1.2~2.00 (m, l1H), 0.90 (t, 3H).

30 E~ample 6 (1~Bu~ piperidyl)methyl-lH-indole-3-carbosylate (E6) A ~uspension of indole-3-carboxylic acid (500mg, 0.003 mole) in 35 dichloromethane (50 ml) was treated with oxalyl chloride (0.635g, 0.005 mole) and two drops of dimethylformamide. The misture was stirred at room temperature for one and a half hour~ then the solvent was remo~red . ~ in vacuo to leave the acid chloride.

WO 93/0372~; 211 6 0 2 4 PCI/GB92/01519 A solution of 1-butyl-4-piperidinemethanol (513 mg, 0.003 mole) in dry THF (10 ml) under an atmosphere of nitrogen, was cooled ~n an ice bath.
n-Butyllithium (1.88 ml of 1.6m ~olution in hexane) was added dropwise and the resulting solution ~tirred at 0C for 15 minutes.

The acid chlo~de was dissolved in dry THF (20 ml) and the solution added dropwise to the solution of the lithium alko2nde at 0C.

The reaction mixt~e was allowed to warm to room temperature and was stirred for 3 hours. The solvent was removed in v~cuo and the residue partitioned between chloroform and water. The chloroform was separated, washed ~everal times with water, d~ied and concentrated to give a pale brown gum.
lH NMR (250 MHz) CDC13; o: 9.90 (bs, lH), 8.10-8.18 (m, lH), 7.78 (d, lH), 7.37-7.46 (m, lH), 7.1~7.28 (m, 2H), 4.19 (d, 2H), 3.05-3.15 (bd, 2H), 2.40-2.49 (m, 2H), 1.20-2.18 (m, 11H), O.90~t, 3H).

Esample 7 3-Metho~y-2-(1-butyl-4piperidyl)methylnaphthoate (E7) The title compound was prepared from 3-metho~y-2-naphthoic acid and 1-butyl4-piperidinemethanol by the method described for Example 2. It ~ -was isolated as a pink solid MP 65-6C.
.
lH NMR (250 MHz) CDCl3; o: 8.28 (s, lH), 7.84 (d, lH), 7.75 (d, lH), 7.51 ` -(t, lH)f 7.37 (t, lH), 7.19 (8, lH), 4.22 (d, 2H), 3.98 (~, 3H), 3.00 (bd, 2H), - :
2.32-2.40 (m, 2H), 1.24-2.03 (m, 11H), 0.92 (t, 3H).
.::
...
:: :

: "

WO 93/0~725 PCr/GB92/01519 211~02`~ -32- ~
Example 8 (l-Butyl-4-piperidyl)methyl-isoquinoline-1-carbo~ylate ~E8) 5 The title compound was prepared from isoquinoline-1-carbo~ylic acid and 1-butyl-4-piperidine-methanol by the method described for E~ample 2. It was isolated as a colourless gum.

lH NMR (250 MHz) CDC13; ~: 8.70 (dd, lH), 8.65 (d, lH), 7.88 (dd, lH), 10 7.81 (d, lH), 7.60-7.78 (m, 2H), 4.39 (d, 2H), 3.00 (bd, 2H), 2.28-2.39 (m, 2H), 1.20-2.05 (m, llH), 0.90 (t, 3H).

Esample 9 -(l-Butyl-4-piperidyl)methyl-isoquinoline-3-carbosylate (E9) The til~le compound was prepared from isoquinoline-~carbo~cylic acid and l-butyl4-piperidinemethanol by the method described for Esample 2. It 20 was isolated as a white solid, mp 82-3C.

lH~ (250 MHz) CDC13; ~: 9.38 (s, lH), 8.60 (s, lH), 8.10 (dd, lH), 7.98 (dd, lH), 7.70-7.87 (m, 2H), 4.35 (d, 2H~, 3.00 (bd, 2H), 2.26-2.40 (m, 2H), 1.20-2.05 (m, 11H), 0.91 (t, 3H). -Esample lO

(l-Butyl-4-piperidyl)methyl-l-methylindazole-3-carbosylate (E10) The ~tle compound was prepared in a similar man~er to the compound of E~cample 6, from the 1-methylindazole acid (EP-A-323105) m.p. 190C. (hydro~hloride salt).
Reference: lU.K Patent 1571278 (SOG D'Etudes Sci. et. Ind. D'Ille de Fr.) wo 93/03725 211 6 0 2 ~ PCI/GB92/01519 Examples 11 to 14 The following compouIlds were prepared (as hydrochloride salts), in a similar manner to that described in EP-A-429984.
(l-Homopipe~dyl)ethyl-lH-indole ~-carbosylate (Ell) m.p. 123-125C

10 ~1-Piperidyl)propyl-lH-indole-3-carbosylats (E12) m.p. 184-187~C ' (I-Piperidyl)butyl-lH-indole-3-carbosylate (E13) m.p. 170-173C

(l-Piperidyl)ethyl-6-bromo-lH-indole-3 carbo~y1ate(E14) 20 m.p. 186-188C

E~ample 16 5-Chloro-2-methosy-4-methyl-(2-(l-piperidyl)ethyl)benzoate (E15) "

The title compound was prepared in a similar manner to the compound of example 2, from 5-c~llor~2-methoxy~-methylbenzoic a~d (J. Chem. Soc., 1963, p.730), and isolated as the hydrochloride sait, m.p. 185-186C.
:~:

~Esamplé i6 (l-Pipe~idylethyl)-2-methosyindole-3-carbosylate hydrochloride ' 35 (E16) Following the procedure outlined in GB 2125398A, E~cample A-S, (N-piperidylethyl)indole-3-carboxylate (0.21g) was conver,ted to the title WO 93/03725 PCI/GB92~111519 compound (38mg, 16%). -lH NMR (CDC13) 250MHz (free base) o: 9.25(brs,1H), 8.0(d,1H), 7.29(d,1H), 7.25-7.95(m,2H), 4.55(t,2H), -4.12(6,3H), 2.90(t,2H), 2.67(brs,4H), 1.75-1.6(m,4H), 1.55-1.35(m,2H).

EYamP1e 17 (l-Buty1-4-pipe~dyl)methylindene-1-carbosylate hydroc~loride (E17) ~:.
A solution of indene-l-carboxylic acid (187mg) (N.H. Cromwell and D.B.
Capps, J. Amer. Chem. Soc., ~, 44448, 1952) in dichloromethane (1Oml) was treated with oxalyl chloride (lOOmg) and two drops of dimet}lylformamide. The mixture was stirred at room t~mperature for one and a half hours then the solvent was removed in vacuo to leave the acid chloride.
A solution of 1-butyl-4-piperidinemethanol (120mg) in dry THF (5ml) under an atmosphere of nitrogen, was cooled in an ice bath. n-Butyllit~ium (0.5ml of 1.6m solution in hexane) was added dropwise and the resulting solution stirred at 0c for 15 minute~.
The acid chloride was dissolved in dry THF (1Oml) and the solution added dropwise to the solution of the lithium alkoxide at 0C.

The reaction mi~Lure was allowed to warm to room temperature and was stirred for 3 hours. The solvent was removed in vacuo and the residue part;itioned between c~loroform and water. The chloroform was separated, washed several timës with water, dned and concentrated to giYe a pale gum which ~Ya~ converted to the hydrochlo~ide salt 120mg, mp 131-3C.

lH NMR (250MHz) CDC13 ~: 8.02(d,1H), 7.55-7.45(m,2H), 7.38(t,1H), 7.28(t,1H), 4.21(d,2H), 3.55(d,2H), 3.20(brd,2H), 2.65-1.25(m,13H), 0.95(t,3H).
:

W093/03725 2116 0 2 4 pcr/Gs92/ol519 Example 18 2~ Piperidyl)ethyl-3~benzothiophene carbosylate (E18) 5 Benzothiophene-3-carbo~cylic acid (J. Matsuki, J. Chem. Soc. Jpn, 1966, ~Z, 18b) (400mg) was heated under reflux with SOC12 (0.7ml) in dry toluene (15ml) for 30 minutes. The toluene was removed in vacuo and the --residue dried under high vacuum.

10 l-Piperidineethanol (290mg) was dissolved in dry tl'~!' (5ml) and nBuLi (1.4ml of 1.6M Soln in hexane) was added. The mixture was ~tirred at room temperature for 15 minutes then a ~olution of the acid cbloride from a~ove in d~r THF (10ml) was added. The reaction misture was stirred at room temperature for 2hrs then the solvent was removed in ~acuo. The 15 residue vas partitioned bet~veen H20 and EtOAc and the EtOAc layer removed wased several times with H20, dried (MgSO4) and concentrated to give a pale yellow oil. This was purified by column chromatography on SiO2 using EtOAc as eluant. The product was isolated as a pale yellow oil and converted to the hydrochlo~de salt, 30mg mp 192-4C.
~0 , .
H NMR (250MHz) (DMSO) (free base) :9.70(s,1H), 8.5(dd,1H), 8.12(dd,1H), 7.5(dt,2H), 4.4(t,2H), 2.68(t,2H), 3.28-2.49(m,4H), 1.30-1.55(m,6H).

Esample 19 (l-Bu~y1 3-pyrroli&yl)methyl-4-amino-5-chloro-2- ' 30 methosybenzoate hydrochlo~ide (El9) To a slurry of 4-amino-5-chloro-2-methoxy benzoic acid (l.OOg) in - acetonit~ile (25 ml) was added bis carbonyl diimidazole (820 mg). The reac~on mixture was gtirred at ambient temperature for 2h. The solvent 35 was removed in vacuo and the residue dissolved in dichlorometbane and uashed with water. The organic phase was dried and filtered aIld concentrated in vacuo. Crystallisation from he~aneldic~loromethane a~orded the i~termediate imidazolide as a beige solid (9~3 mg).

wo 93/03725 PCr/GB92/OlSlg To a solution of 1-butyl-3-hydroxymethylpyrrolidine (D1) (485 mg) in dry (THF (20 ml) was added nBuli (1.6M in hexane, 1.92 ml) at 0C under a I~itrogen atmosphere. Stirring waS continued at amWent temperature for 5 30 min. The imidazolide (776 mg) in 'l'~' (20 ml) was added to the reaction mi~cture and stirring colltinued for 20h. Water (1ml) was added and the ~olvent concent~ated in vacuo. The residue was partit;ioned between chloroform and water. The organic phase was dried (NaS04) filtered and concentrated in vacl~o to afford crude product. Flash 10 ~hromatography on silica using chloroform and ethanol gave (1-butyl-3-pyrrolidinyl)methyl-4-~5-chlor~2-methoxy benzoate, whic~ wa~
treated with ethereal HCl to a~ord the title compound ~154 mg).

mp 181-184C.
lH ~MR (CD30D) 400 MHz ~: 7.69 (lH, s), 6.47 (lH, ~), 4.15-4.32 (4H, m), 3.81 (s, 3H), 3.50-3.59 (lH, m), 3.34-3.41 (2H, m), 3.11-3.16 (3H, m), 2.74-2.83 (lH, m), 2.23-2.34 (lH, m), 1.88-1.99 (lH, m), 1.66-1.75 (2H, m), 1.38-1.48 (2H, m), 0.98 (3H, t) MH+ 341 (Cl+).

E~ample 20 (l-Butyl-3~pyrrolidinylmethyl)-lH~indole-3-carbosylate hydrochloride (E20) To a ~lu2Ty of indole-3-carboxylic acid (l.OOg) in dicbloromethane (20 ml) 30 was added oxalyl chlonde (1.1 ml) and N,N'dimet~yl fo~mamide (2 drops).
The reaction mixture was stirred at ambient temperature for 2h The solvent was evaporated under reduced pressure to afford crude indole-3 carbonyl chloride (960 mg).

35 To a solution of 1-butyl-3-hydroxymethylpyrrolidine (D1) (SOO mg) in dry THF (20 ml) was added Buli (1.6M in he~canes, 1.99 ml) at 0C under a nitrogen atmosphere. Stirring was continued at ambient temperature for 30 min. Indole-3-carbonylchloride (571 mg) in dry THF (10 ml) was added , WO 93/03725 211 6 0 2 4 PCr/GB92/01519 to the reaction mixture and stiIring con1;inued for 20h. Water (1 ml~ was added to the reaction mixture and the solvent concentrated in vacuo. The residue was partitioned between chlorofolm and water. The organic phase was dried (NaSO4), filtered and concent~ated in vacuo to afford 5 crude product. Flash chromatography on silica using chlorofonn and ethanol gave (l-butyl-3-pyrrolidinylmethyl~lH-indole-3-carbo~ylate which was treated with ethereal HCl to af~ord ~tle compound.

m.p 59-62C
lH NMR (CD3OD) 270 MHz ~: 7.98-8.05 (m, 2H), 7.41-7.48 (m, lH), 7.15-7.26 (m, 2H), 4.28-4.47 (m, 2H), 3.51-3.93 ~m, 2H), 3.42-3.56 (m, lH), -2.81-3.25 (m, 4H), 2.19-2.47 (m, lH), 1.82-2.16 (m, lH), 1.60-1.80 (m, 2H), 1.34-1.50 (m, 2H), 0.94-1.02 (m, 3H).
M+ 300 Esample 21 (l~Penty1-3-pyrrolidinyl)ethyl 4-amino-6-chloro-2- -metho~ybenzoate hydrochloride (E21) -~

Following the procedure outlined in Example 19, 3-hydroxymethyl-1-25 pentyl pyrrolidine (D2) (500 mg) gave the title compound (158 mg).

lH NMR (d6-DMSO) 270 MHz ~: 7.58 (s, lH), 6.47 (s, lH),4.054.22 ~m, -~
2H), 3.74 (s, 3H), 3.58-3.70 (m, lH), 3.36-3.57 (m, lH), 3.21 ~t, 2H), 2.87- ~-3.12 (m, 3H), 2.68-2.84 (q, lH), 2.28-2.45 (m, lH), 2.03-2.27 (m, lH), 1.51-30 1.91 (m, 5H), 1.18-1.37 (m, 4H), 0.87 (t, 3H).

M+ 368;(Freebase) -~ .: . ' ~
WO 93/03725 PCI/GB92/0l519 211602-i -38-E~ample 22 (l-Pen~ 3-pyrrolidinyl)ethyl-lH~ dole-3-carbo~ylate hydrochloride (E22) The ~tle compound wa~ prepared in a similar manner to the compouIld of E~ample 20.

mp 48-51C
lH NMR (d6-DMSO) 270 MHz ~: 12.05 (bs, lH), 8.08 (d, lH~, 7.9~8.03 (m, lH), 7.45-7.52 (m, lH), 7.14-722 (m, 2H), 4.20-4.33 (m, 2H), 3.42-3.72 ~m, 3H), 3.23 (t, lH), 2.90-3.15 (m, 2H), 2.73 (q, lH), 2.35-2.82 (m, lH), 2.06-2.30 (m, lH), 1.49-1.98 (m, 4H), 1.29-1.47 (m, 4H), 0.88 (t, 3H).
M+ 328 (Freebase3 Example 23 (HeYahydro-l-bu~1-3-azepinylmethyl)-4-a~o-5-chloro-2-methov benzoate (E23) Following the procedure out~ined in E~a~ple 19, reac~on of he~ahydro 1-25 butyl-3-hydro~ymet hyl azepine (D3) (500 mg) gave the 1itle compound, as a ~ee base, (318 mg).

mp 72-75C

30 lH NMR (CDCl3) 250 MHz ~: 7.82 (s, lH), 6.29 (s, lH~, 4.50 (bs, 2H), 3.96 4.18 (m, 2H), 3.84 (s, 3H), 2.83 (dd, lH), 2.61-2.75 (m, 2H), 2.43-2.60 (m, 3H), 2.05-2.20 (m, lH), 1.21-1.86 ~m, 10H), 0.89 (t, 3H). ~ `

WO 93/03725 211 6 0 2 I PCr/GB9U01519 E~ample 24 (Hesahydro-l-butyl-3-azepinylmethyl)-lH-indole-3-c~rbosylate hydrochloride (E24) ~:
Follo~ving t~e procedure outlined in Example 20, reaction of he~ahydro-l-butyl 3-hydroxymethyl azepine (D3) (500 mg) gave the ~tle compound ::
(155 mg).

mp 75-78C

H NMR (CDCI3) 250 MHz Free base ~: 9.45 (m, lH), 8.14-8.22 (m, lH), 7.95 (d, lH), 7.40-7.48 (m, lH), 7.22- -7.31 (m, 2H), 4.10-4.28 (m, 2H), 3.00 (dd, lH), 2.51-2.89 (m, 5H), 2.23-2.48 (m, lH), 1.40-1.94 (m, 8H), 1.18-1.33 (m, 2H), 0.82 (t, 3H). -MH+ 329 -:

E~ample 25 4-Ami~o-5-Chloro-2-metho~y-(1-butyl-3-piperidyl)ethyl-benzoate (E25) Follo~nng the procedure outlined in Example 19, reaction of 1-butyl-3-piperidyl ethanol (D4) (lg) gave the title compound as a firee base (1.41g).

mp 102-104C
~:
lH NMR (CDCl3) 250 MHz ~: 7.80 (s, lH), 6.28 (s, lH), 4.45 (s, 2H), 4.27 - -(t, 2Hj, 3.84 (s, 3H), 2.81-2.96 (m, 2H), 2.25-2.33 (m, ZH), 1.40-1.90 (m, ;~ ~ 11H), 1.22-1.48 (m, 2H), 0.92 (t, 3H). ~

M+ 368 :

WO g3/03725 P(~/GB92/01519 211602~ 40 E~ample 26 (l-Buty1-3-piperidylethyl)-lH.indole-3-carbosylate hydrochloride (E26) Following the procedure outLined in Example 21, reaction of 1-butyl-3-piperidyl ethanol (D4) (500 mg~ g~ve the title compound (205 mg).

lH NMR (CDCl3) 250 MHz Free base ~: 10.02 (s, lH), 8.13-8.20 (m, lH), 7.79-7.81 (m, lH), 7.32-7.44 (m, lH), 7.19-7.30 (m, 2H), 4.30-4.47 (m, 2H), 2.92-3.08 (m, 2H), 2.31-2.42 (m, 2H), 1.44-1.98 (m, lOH), 1.21-1.35 (m, 2H), 0.83-1.06 (m, 4H).

15 M+ 328 Esample 27 20 4-Amino-5-chloro-2-metho~y-(1-butyl-2-pipe~idylethyl)-benzoate (E27) Follo~ving t~e procedure outlined in E~ample 19, reaction of 1-butyl 2-piperidyl ethanol (D5) (750 mg) gave the title compound (650 mg).
mp 75-77C

lH NMP~ (CDCl3) 250 MHz o: 7.81 (s, lH), 6.29 (s, lH), 4.48 (s, 2H), 4.19- "
4.35 (m, 2H), 3.82 (s, 3H), 2.77-2.88 (m, lH), 2.22-2.70 (m, 4H), 1.99-2.13 (m, lH), 1.21-1.86 (m, 11H), 0.90 ~t, 3H). -'~
M+ 36B

, .
.

WO 93~03725 211 ~ ~) 2 ~ PCI'/GB92/01519 Esample 28 4-~nin~5-chlor~2-methosy-(1-butyl 3-piperidylmethyl)- benzoate hydrochloride (E28) :
Following the procedure outlined in Example 19, 1-butyl-3-piperidyl methanol (D6) (500 mg) gave title compound (100 mg). ::
mp 218-221C -:' H NMR (CDC13) 250 MHz Free base ~: 7.81 (s, lH), 6.27 (s, lH), 4.46 (8, 2H), 4.00-4.19 (m, 2H~, 3.84 (s, 3H), 2.84-3.06 (m, 2H), 2.29-2.38 (m, 2H), 2.01-2.18 (m, lH), 1.22-1.98 (m, 15 llH), 0.91 (t, 3H).

M+ 354 :

20 E~ample 29 (I-Butyl~3-piperidylmethyl) IH-indole-3-csrbosylate h~rdrochloride (E29) .

25 Following the procedure outlined in Example 20, 1-butyl 3-pipendyl methanol (D6) (500 mg) gave pure title compound (36 mg).

lH NMR (CDCl3) 250 MHz - Free base 30 ~: 9.96 (s, lH), 8.17-8.21 (m, lH), 7.90-7.95 (m, lH), 7.3~7.44 (m, lH~, 7.21-7.29 (m, 2H), 4.19 (d, 2H)? 3.12-3.22 (m, lH), 2.95-3.04 (m, lH), 2.31-2.45 (m, 2H), 2.10-2.30 (m, lH), 1.42-2.06 (m, 6H), 1.03-1.40 (m, 4H~, 0.90 :
(t, 3H).

35 MH+ 315 wo 93/03725 PCr/GB92/015l9 2 1 ~ ~ ~ 2 1 - 42 -E~:ample 30 4-Amino-5-chloro-2-metho~y-(l~butyl-4-piperidyl)benzoate (E30) 5 Following the procedure ou~ined in Example 19, 1-butyl 4-piperidinol (D7) (500 mg) gave the title compound (150 mg). -mp 83-85C

1H NMR (CDC13) 250 MHz ~: 7.80 (s, lH), 6.28 (s, lH), 4.94-5.05 (m, lH), 4.47 (fi, 2H), 3.83 (s, 3H), 2.66-2.81 (m, 2H), 2.29-2.45 (m, 4H), 1.93-2.08 ~m, 2H), 1.76-1.90 (m, 2H), 1.43-1.58 (m, 2H), 1.23-1.41 (m, 2H), 0.93 (t, ::
3H).

M+ 340 -Esample 31 .'~' 20 4-Amino-5-chloro-2-methosy-(1-butyl-1,2,5,~tetrahydro~
py~idylmethyl)benzoate (E31j -`

Foilowing tlle procedure outlined in Example 19, 1-butyl (1,2,5,6) tetrahydropiperidyl-4-methsnol (D7) (300 mg) gave pure title compound 25 (220 mg).
. .
mp 75-77C ~-lH NMR (CDC13) 250 MHz 8: 7.83 (8, lH), 6.28 (8, lH), 5.76 (s, lH), 4.63 30 (8, 2H), 4.48 (s, 2H), 3.81(8, 3H), 3.00 (8, 2H), 2.61 (t, 2H), 2.36-2.56 (m,2H), 2.25 (m, 2H), 1.4~2.09 (m, 2H), 1.28-1.41 (m, 2H), 0.93 (t, 3H).

MH+ 353 WO 93/03725 21 1 6 0 2 4 PCl /GB92/01519 E~ample 32 (l-Butyl-4-piperidyl)methyl-1-ethyl-lH-indole-3-carbosylate (E32) 5 A suspension of 1-ethyl indole-3-carboxylic acid (500 mg) in dichloromethane (50 ml~ was treated with o~calyl chloride (0.635g, 0.005 mole) and two drops of dimethylformamide. The mixture was stirred at room temperature for 1~ hours then the solvent was removed in vacuo to leaYe the acid chloride.
A solution of l-butyl-4-piperidinemethanol (513 mg, 0.003 mole) in dry THF (10 ml) under an atmosphere of nitrogen, was cooled in an ice bath.

n-Butyllithium (1.88 ml of 1.6M solution in hexane) was added dropwise 15 and the resulting solution stirred at 0C for 15 minutes.

The ac d chloride was dissolved in dry THF (20 ml) and the solution added dropwise to the solution of the lithium alko~de at 0C.

20 The reaction mi~cture was allowed to warm to room temperature and was s'drred for 3 hours. I~e solvent was removed in vacuo and the residue partitioned between chloroform and water. The chloroform was separated, was}ied several times with water, driedand concentrated to give a pale brown gum which was converted to the hydrochlo~ide salt, mp 158-9C.
lH ~MR (250 MHz) (CDCl3) (firee ba~e) ~: 8.10-8.19 (m, lH), 7.88 (s, lH), 7.2-7.38 (m, 3H), 4.20 (m, 4H), 2.92-3.03 (bd, 2H), 2.28-2.40 (m, 2H), 1.20-2.0 (m, 14H), 0.90 (t, 3H).

WO 93/03725 PCl'/GB92/01519 211~a24 _44 E~ample~ ~3 and ~4 The follo~g compounds were prepared from the colTe~ponding indole carbo~cylic acid by the method des~ibed for Example 32.
~:~
(l-But3rl-4-piperidyl)methyl-1-methyl-lH-indole-3-carbosylate (E33) :
.--mp 187-8C (hydrochloride salt) ~:~
'"' H NMR (250 MHz) (CDC13) (free base) :

~: 8.10-8.19 (m, lH), 7.88 (8, lH), 7.2-7.38 (m, 3H~, 4.20 (d, 2H), 3.82 (8, ~ .
3H), 2.82-2.98 (bd, 2H), 2.28-2.39 (m, 2H), 1.20-2.18 (m, 11H), 0.90 (t, 3H). ~:"
(l-Cyclohe~ylmethyl 4-piperidyl)methyl-1-methyl-lH-indole 3- ::
carbosylate (E34) mp 164-5C (hydrochloride ~alt) H NMR (250 MHz) (CDCl3) (free base) ~: 8.10-8.19 (m, lH), 7.80 (8, lH), 7.22--7.4 (m, 3H), 4.20 (d, 2H), 3.82 (8, 3H), 2.86-2.96 (bd, 2H), 2.12 (d, 2H), 0.8~1.98 (m, 18H).
:..
Esample 35 .
(l-Butyl-3-azetidinylme1 hyl)-4-a~o-5-chloro-2-methosybenzoate 3n (E35) -Following the procedures outlined above, 1-butyl-3-hydro~cymetbyl azetidine (D9) (500mg) gsve the title compound (240mg). M+ 326 lH NMR 250MHz, CDCl3, o:7.83 (s,1H), 6.28 (s,1H), 4.50 (bs,2H), 4.33 (d,2H), 3.84 (s,3H), 3.38-3.49 (m,2H), 2.81-3.00 (m,3H), 2.38-2A5 (m,2H), 1.2~1.37 (m,4H), 0.85-0.94 (m,3H) -WO 93/03725 211 6 D 2 ~ PCI~GB92~01519 E~ample 36 (N-Butylpiperid-4-ylmethyl)~2~methylindole-3-carbosylate (E36) 5 Following the procedure outlined in E~cample 6 (except that methyllithium used in place of n-butyllithium), 2-methylindol~3-carbosylic acid (D1) (950mg) was converted to the ~tle compound (134mg, 8%) mp 128-130C

1H NMR (CHCl3) 200MHz ;

~: 8.1-8.0 (m, lH), 7.38-6.9 (m, 4H), 4.22 (d, 2H), 3.05 (brd, 2H), 2.75 (~, -3H), 2.5-2.25 (m, 2H), 2.15-1.70 (m, 4H), 1.70-1.16 (m, 7H), 0.92 (t, 3H) -~

Esample 37 (N-Bu1 ylpipefid4-ylme~hyl)-2-chloro-l methylindob 3-carbosylate hydrochloride (E37) FollowiDg the procedure outlined in GB 2125398A, Esample A5, N- -Butylpiperid-4-ylmethyl-1-methyl)indole-3-carbo~ylate (E33) (300mg) was converted to the title compound (65mg, 15%) mp 238~4QC

25 lH NMR (CDCl3) 200MHz (free base) ~: 8.18-8.05 (m, lH), 7.33-7.20 (m, 3H), 4.24 (d, 2H), 3.77 (s, 3H), 3.05 (brd, 2H), 2.4~2.3 (m, 2H), 2.12-1.7 ~m, 5H), 1.65-1.15 (m, 6H), 0.92 (t, 3H) 2 115 ~,? '3 ~1 - 46 -E~ample 38 (N-Butylpiperid-4-ylmethyl) 2-metho~yindole-3-carbosylate hydrochloride (E38) Following the procedure outlined in GB 2125398A E~ample A5, (N-butylpiperid-4-ylmethyl~indole-3-carboxylate (E6) (0.25g) was converted to the 1itle compouIld (108mg, 36%) mp 168-170C. --'':
10 lH NMR (CDCl3) 250MHz (free base) ~: 7.95 (d, lH), 7.3-7.05 (m, 3H), 4.20 (d, 2H), 4.07 (s, 3H), 3.07 (brd, 2H), 2.49-2.36 (m, 2H), 2.09 (br t, 2H), 1.99-1.75 (m, 3H), 1.7-1.2 (m, 6H), 0.91 (t, 3H) E~ample 39 (N-Butylpiperid-4-ylmethyl)indole-3-carbosamide (E39) To a stirring solution of indo~e-3-carboxylic acid (lg) in dichloromethane (20ml) at 0C under nitrogen was added oxalyl chloride (0.81 ml) and dry dimethylformamide (3 drops). After 3 hours, the solvents were evaporated under reduced pressure. A portion of the residual acid 25 chloride (420mg) was dissolved in dichloromethane (12ml) and added dropwise to a solution of N-butylpiperid-4-ylmethylamine (40ûmg) in dicbloromethane 12ml) followed by triethylamine (0.36ml). Af'cer stirnng at ambient temperature overnight, the reaction mixture was washed with saturated NaHC03 and the organic phase was dried (Na2S04). The 30 solvent was evaporated under reduced pressure and the residue recrystallised from ethylacetate to give the title compound (467mg, 64C).

lH NMR (CDCl3) 250MHz 35 ~: 9.29 (br s, lH), 8.05-7.9 (m, lH), 7.81 (d, lH), 7.55-7.4 (m, lH), 7.39 7.2 (m, 2H), 6.28 (br 8, lH), 3.39 (t, 2H), 3.0 (br d, 2H), 2.45-2.25 (m, 2H), 2.1-`

wO 93/03725 2 11 6 0 2 4 PCr/Gs92/015l9 - 47 ^ -1.1 (m, 11H), 0.9 (t, 3H) Esample 40 a~-Butylpipe~d-4-ylmethyl)-2.methoxyindole.3.carboxamide hydrochloride (E40) .
Follovving the procedure outlined in GB 2125398A, Example A5, (N-10 Butylpiperid-4-ylmethyl)indole-3-carboxamide (E39) (220mg) was convered to the ~tle compound (230mg, 86~o). Mp 138-144C ;-lH NMR SCDC13) 250MHz (free base) 15 ~ 9.85 (br s, lH), 8.25 (d, lH), 7.4-7.0 (m, 3H), 6.78 (t, lH), 4.18 (s, 3H),3.35 (t, 2H), 2.98 (br d, 2H), 2.45-2.25 (m, 2H), 1.95 (br t, 2H), 1.82-1.2 (m, 9H), 0.91 (t, 3H) 20 E~ample 41 l-Pipendylethyl-2-methylindole-3-carbo~ylate hydrochloride (E41) 25 Following the procedure outlined in Example 36, 2-methylindole-3-carboxylic acid (490 mg) was converted to the title compound (76mg) mp 147-9(~.

lH NMR (CDC13) 200 MHz ~: 8.65(br s,1H), 8.15-8.00(m,1H), 7.35-7.00(m,3H), 4.49(t,2H), 2.82(t,2H), 2.68(s,3H), 2.6-2.45(m,4H), 1.7-1.35(m,6H).

wo 93~03725 PCI/Gs92/0l5l9 2 1 ~ 4 Esample 42 4-Amino-3,5-dichloro-2-methoxy-(1-butyl-4-piperidyl)methyl benzoate (E42) The title compound wa~ prepared from ~amino-3,5-dichloro-2-methoxybenzoic acid and 1-butyl4-piperidylmetbanol by the methsd described in Example 2, except that MeLi was used in place of nBuL~. The product was isolated as the hydrochloride salt.
mp l90-191C

H NMR (200MHz) CDCl3 (free bsse) ~: 7.72(s,1H), 4.9(bs,2H), 4.12(d,2H), 3.85(s,3H), 2.85-3.0(bd,2H), 2.2-2.34(m,2H), 1.2-2.00(m,11H), O.90(t,3H).

.

: .

~ .

WO 93/03725 211 6 0 ~ ~ PCI/GB92/01519 Further compounds of potential use in the inven~ion which were preparedare as follows:
~, ~CO2Y(CH2) nR
a~
r Ral Rl Y n R m.p.

H Et O 2 l-pipe~idyl 175-177C

H npr O 2 1-piperidyl 198-199C

H nBu O 2 1-pipe~dyl 202-204C

MeO H O 2 1-piperidyl 142-144C

Cl H O 2 1-pipendyl 153.5-154.5C
1 5 ~-H H O 2 NHBz 233-235C

H H O 4 N(CH3)2 153~C

H H O 2 N(CH3)2 108-9C

H H O 3 N(CH3)2 208-210C

H O 2 N(Et~2 15~7C
H H NH 2 N((~H3)2 194-5C

H ~I NH 2 N(Et)2 97-98C

: 30 H Bz O 2 N(CH3)2 165-166C

H Bz O 4 N(CH3)2 138-9C

~: ' :

WO 93/03725 PCr/GB92/01519 211 ~3~1 ~

5-HT4 RECE:PTOR ANT~GONIST ACTIVll Y

1) Guinea pig colon Male guinea-pigs, weighing 250-400g are usea. Longitudinal muscle-myenteric plexus preparations, appro~mately 3cm long, are obtained from the di~tal colon region. These are suspended under a 0.5g load in isolated tissue baths containing Krebs solution bubbled with 5% C02 in 2 and maintained at 37C. In all experiments, the Krebs solution also contains -~
methiothepin 10-7M and granisetron 10-6M to block effects at 5-HT1, 5-HT2 and 5-HT3 receptors.

After constraction of a simple concentration-response curve with 5-HT, using 308 contact tiInes and a 15min dosing cycle, a concentration of 5-HT ~-is selected 80 as to obtain a contraction of the mu~cle approximately 40- ~ -70% maximum(10~9M approx). The tissue is then alternately dosed every 15min with this concentration of 5-HT and then with an approximately equi-effective concentration of the nicotine receptor stimulant, 20 dimethylphenylpiperazinium (DMPP). Af~cer obtaining consistent responses to both ~HT and DMPP, increasing concentrations of a putative 5-HT4 re~eptor antagonist are then added to the bathing solution. The effects of this compound are then determined as a percentage reduction of the contractions evoked by 5-HT or by DMPP. From this data, pIGso 25 values are determined, being defined as the -log concentration of antagonist which reduces the contraction by 50%. A compound which reduces the response to 5-HT but not to DMPP is believed to act as a 5-HT4 receptor antagonist.

30 - Compounds were generally sctive in the range of` concentrations of the order of pICso=6 or more, E4 and E7 showing particularly good activity.
.
2) Piglet Atria 35 Compounds were tested in the piglet spontaneous beating screen (Naunyn-Schmiedeberg's Arch. Pharmacol 342, 619-622). pRg (-log1o Kg) value for the compounds were generally of the order of 6 or more, E6 and E16 showing particularly good activity.

W O 93/03725 211 6 0 2 'I PC~r/G B92/01519 3) Rat oe~ophagu~

Rat oesophageal tunica muscularis mucosae i~ set up according to Baxter 5 et. al. Naunyn-Schmiedeberg's Arch. Pharmacol., 343, 439446 (1991).
The inner smooth muscle tube of the muscularis mucosae is isolated and ~:
mounted fior isometric tension recording in o~zygenated (95% 2/5% C2) Tyrodes solution at 37~C. All e~penments are perfonned in pargyline pre-treated preparations (lOO~lM for 15 min followed by washout) and in the :-10 presence of cocaine (30~1M). Relaxant responses to 5-HT are obtained after pre-contracting the oesophagus tissue ~vith carbachol (3 4) 6-HT-induced motilit~r in dog gastric pouch 15 Compounds are tested for inhibition in the in vivo method described in "Stimulation of canine motility by BRL 24924, a new gastric prokinetic `~:
agent", Ber nudez et al, J. Gastrointestinal Motility, 1990, 2(4), 281-286.

,)

Claims (10)

Claims

1. The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof;

X-CO-Y-Z (I) wherein X, Y and Z are as defined in the specification, in the manufacture of a medicament for use as a 5-HT4 receptor antagonist.

2. The use according to claim 1 for use as a 5-HT4 antagonist in the treatment or prophylaxis of gastrointestinal disorders, cardiovascular disorders and CNS disorders.

3. The use according to claim 2 for use in the treatment of IBS.

4. The use according to claim 2 for use in the treatment of gastro-oesophagal reflux disease and dyspepsia.

5. The use according to claim 2 for use in the treatment of atrial arrhythmias and stroke.

6. The use according to claim 2 for use in the treatment of anxiety.

7. The use according to claim 2 for use in the treatment of migraine.

8. The use of 2-piperidinoethyl 1H-indole-3-carboxylate or any one of the compounds of the Examples, E1 to E42, in the manufacture of a medicament for use as a 5-HT4 receptor antagonist.

9. A compound selected from the compounds of Examples 1 to 42, or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising a compound according to claim 9, and a pharmaceutically acceptable carrier.