AU667874B2 - Benzopyran, benzothiopyran and benzofuran derivatives as 5-HT4 antagonists - Google Patents

Description

OPI DATE 03/09/93 AJP DATE 11/11/93

L

E~

APPLN. ID 34572/93 PCT NUMBER PCT/GB93/00214 I ilII I l IIlI llllllllIL AU 2 l lll AU9334572 (51) International Patent Classification 5 (11) International Publication Number: WO 93/16072 C07D 405/12, 409/12 Al A61K 31/445 (43) International Publication Date: 19 August 1993 (19.08.93) (21) International Application Number: PCT/GB93/00214 (74) Agent: JONES, Pauline; SmithKline Beecham, Corporate Patents, Great Burgh, Yew Tree Bottom Road, Epsom, Surrey (22) International Filing Date: 1 February 1993 (01.02.93) KTI8 5XQ (GB).

Priority data: (81) Designated States: AU, CA, JP, KR, NZ, US, European 9202510.5 6 February 1992 (06.02.92) GB patent (AT, BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, 9215499.6 21 July 1992 (21.07.92) GB LU, MC, NL, PT, SE).

9221446.9 13 October 1992 (13.10.92) GB 9225788.0 10 December 1992 (10.12.92) GB Published With international search report.

(71) Applicant (for all designated States except US): SMITH- KLINE BEECHAM PLC [GB/GB]; New Horizons Court, Brentford, Middelsex TW8 9EP (GB).

(72) Inventors; and Inventors/Applicants (for US only) KING, Francis, David [GB/GB]; SmithKline Beecham Pharmaceuticals, Coldharbour Road, The Pinnacles, Harlovi, Essex CM19 GASTER, Laramie, Mary [GB/GB]; Smith- Kline Beecham Pharmaceuticals, Coldharbour Road, The Pinnacles, Harlow, Esse> CM19 5AD JOIN- ER, Graham, Francis [GB/GB]; SmithKline Beecham Pharmaceuticals, Coldharbour Road, The Pinnacles, Harlow, Essex CMI9 5AD, gb (GB).

(54)Title: BENZOPYRAN, BENZOTHIOPYRAN AND BENZOFURAN DERIVATIVES AS 5-HT4 ANTAGONISTS ,(CH R

N

Ra

CO-Y-Z

F1x

(CH

2 )CH, R

-H)

0 2 C2).

N

.l -(CH2)3 -N--Re "'R9 (c) (57) Abstract Compounds of formula and pharmaceutically acceptable salts thereof, in which Xi-(CH 2 )x-X 2 and the aromatic carbon atoms to which they are attached form a 5-7 membered ring wherein: one of X 1 and X 2 is O, S or CH 2 and the other is

CH

2 x is 1, 2 or 3; R, is hydrogen, amino, halo, Cl.

6 alkyl, hydroxy or Ci.

6 alkoxy; R 2 is hydrogen, halo, Ci.

6 alkyl, Ci.

6 alkoxy, nitro, amino or Ci.6 alkylthio, R 3 is hydrogen, halo, CI.

6 alkyl, Ct.

6 alkoxy or amino; R 4 and R 5 are independently hydrogen or Ci.

6 alkyl; Y is O or NH; Z is of sub-formula or wherein n I is 1, 2, 3 or 4; n 2 is 1 or 2; n 3 is 2, 3, 4 or q is 0, 1, 2 or 3; p is 0, 1 or 2; m is 0, 1 or 2; Ra is hydrogen or a lipophilic group, such as C1.

1 2 alkyl or aralkyl; or Ra is

(CH

2 )rRio wherein r is 2 or 3 and Rio is selected from cyano, hydroxyl, C 1 6 alkoxy, phenoxy, C(O)CI.

6 alkyl, COC 6

H

5 -CRIIRi2, NRI CORI2, SOZNRIIRi 2 or NRIISO 2

RI

2 wherein Rti and RI2 are hydrogen or CI.

6 alkyl; and R 6

R

7 and Rg are independently hydrogen or CI.

6 alkyl; and R 9 is hydrogen or Cl.1o alkyl; or a compound of formula wherein the CO- Y linkage is replaced by a heterocyclic bioisostere; and their use as pharmaceuticals in the treatment of gastrointestinal disorders, cardiovascular disorders and CNS disorders.

r r- 1" 1 WO 93/16072 PCT/GB93/00214 -1- Benzopyran, benzothlopyran and benzofuran derivatives as 5-HT4 antagonists This invention relates to the use of compounds as 5-HT 4 receptor antagonists in the treatment of gastrointestinal disorders, CNS disorders including migraine and/or cardiovascular disorders, and to certain novel compounds having 5-HT 4 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-HT 4 receptor, and that ICS 205-930, which is also a 5-HT 3 receptor antagonist, acts as an antagonist at this receptor.

WO 91/16045 (SmithKline and French Laboratories Limited) describes the use of cardiac 5-HT 4 receptor antagonists in the treatment of atrial arrhythmias and stroke.

EP-A-501322 (Glaxo Group Limited) describes indole derivatives having 5-HT 4 antagonist activity.

Some 5-HT 3 receptor antagonists have been disclosed as of potential use in the treatment of certain aspects of irritable bowel syndrome [EP-A-189002 (Sandoz Limited) and EP-A-201165 (Beecham Group 3 receptor interactions which are of potential use in the treatment of IBS are those associated either with the visceral pain and abnormal perception of sensation aspects of this disease, or they are related to the ability of some

HT

3 receptor antagonists to cause constipation in volunteers.

Some 5-HT 3 receptor antagor'sts have been disclosed as of potential use in the treatment of gastrointestinal disorders associated with upper gut motility [EP-A-226266 (Glaxo Group Ltd.) and EP-A-'189002 (Sandoz Limited)].

3 receptor antagonists are also well known antiemetics, such as ondansetron, granisetron and tropisetron [Drugs of the Future 1989, 14 (9) p.875 F.D. King and G.J. Sanger].

i~ -e -2- EP-A-234872 (Adria), US 4859683 (Rorer) and EP-A-307172 (Lilly) describe 3 receptor antagonists derived from a benzoic acid nucleus, 2,3disubstituted by alkyleneoxy.

It has now been discovered that certain of the compounds embraced by the general formulae disclosed therein, and related compounds, have 5-HT 4 receptor antagonist properties, and are therefore of potential use in the treatment of IBS or atrial arrhythmias and stroke.

The compounds of the present invention also have a potential use in the treatment of CNS disorders such as anxiety and/or migraine, in the treatment of upper gut motility disorders and us antiemetics.

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

CO-Y-Z

R

3 R4 Sone of X1 and X2 is O, S or CH2 and the other is CH2; x is 1, 2 or 3; R1 is hydrogen, amino, halo, C1-6 alkyl, hydroxy or C1-6 alkoxy; o 0 °R2 is hydrogen, halo, alkyl, C1-6 alkoxy, nitro, amino or C1-6 alkylthio; R3 is hydrogen, halo, 1-6 alkyl, 01-6 alkoxy or amino; R4 and R5 are independently hydrogen or C1-6 alkyl; Y is 0 or NH; xis 1, 2° _ihdoe hl *oR shdoehlC 6 akl 1 6 akxnto mn rC6aklho

R

1 AshdoeamnhlC 6 a 4 ,hdoo 1 6 akw Q

:R

2 i ydoehao 1. lyi 1 6 aloy nto aioo C. lk0ho ea V -3- Z is of formula:

NR

Ra

NR

wherein Ra is alkyl or optionally substituted benzyl.

Examples of alkyl or alkyl containing groups include C 1

C

2

C

3

C

4

C

5

C

6

C

7

C

8

C

9

C

10

C

1 1 or C 12 branched, straight chained or cyclic alkyl, as appropriate. C 1 -4 S 15 alkyl groups include methyl, ethyl n- and iso-propyl, iso-, sec- and tert-butyl. Cyclic alkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Aryl includes phenyl and naphthyl optionally substituted by one or more substituents selected from halo, C1-6 alkyl and C1- 6 alkoxy.

Halo includes fluoro, chloro, bromo and iodo.

A suitable bioisostere for the amide or ester linkage containing Y in formula is of Sa 25 formula (d) T 1 0 9 a- 950818,p:\oper\dab,34572.spe,3 -4-

H-J

(d) wherein the dotted circle represents one or two double bonds in any position in the membered ring; H, J and I independently represent oxygen, sulphur, nitrogen or carbon, provided that at least one of H, J and I is other than carbon; U represents nitrogen or carbon.

Suitable examples of are as described for X, Y and Z in EP-A-328200 (Merck Sharp Dohme Ltd.), such as an oxadiazole moiety.

Suitable examples of the X 1 -(CH2)x-X2 include O-(CH 2 2

-CH

2

O-(CH

2 3

CH

2

O-CH

2

-CH

2 or corresponding values wherein X 1 X2 CH 2 wherein any of the methylene linkages are optionally mono- or di-substituted by C 1 -6 alkyl groups, such as methyl. Preferably X 1

-(CH

2 2

-X

2 is O-(CH 2 2

-CH

2 o "0 R 1 is preferably hydrogen or amino.

.0 R 2 is preferably hydrogen or halo.

R

3 is preferably hydrogen or halo.

R

4 and R 5 are often hydrogen. When R 4

/R

5 is C1-6 alkyl, it is often methyl.

In particular R 4 and R 5 are methyl such that the disubstituent containing X 1 25 and X 2 is X 1

-C(CH

3 2

-X

2 Y is preferably O or NH.

A k-: Specific values of Z of particular interest are as follows: nBu The invention also provides novel compounds within formula with side chains Do 03 9 (I DSs

D

a 01 8 006 a

D

oicg ~Oae os oo a a r os oi o n C O oo o~o ~o r o aco 4 oo C 950817,p:\oper\dab,34572.spe,5 t i :n ,1- -6- The invention also provdes novel compounds within formula having

X

1 -(CH2)x-X2 as O-(CH 2 2

-CH

2 The pharmaceutically acceptable salts of the compounds of the formula (I) include acid addition salts with conventional acids such as hydrochloric, hydrobromic, boric, phosphoric, sulphuric acids and pharmaceutically acceptable organic acids such as acetic, tartaric, maleic, citric, succinic, benzoic, ascorbic, methanesulphonic, a-keto glutaric, a-glycerophosphoric, and glucose-1 -phosphoric acids.

Examples of pharmaceutically acceptable salts include quaternary derivatives of the compounds of formula such as the compounds quatemised by compounds Rx-T wherein Rx is C 1 -6 alkyl, phenyl-C 1 -6 alkyl or C5.7 cycloalkyl, and T is a radical corresponding to an anion of an acid. Suitable 0 :20 examples of Rx include methyl, ethyl and n- and iso-propyl; and benzyl and 9 S* phenethyl. Suitable examples of T include halide such as chloride, bromide o .and iodide.

a Exariples of pharmaceutically acceptable salts also include internal salts such 25 as N-oxides.

The compounds of the formula their pharmaceutically acceptable salts, (including quaternary derivatives and N-oxides) may also form .pharmaceutically acceptable solvates, such as hydrates, which are included 30 wherever a compound of formula or a salt thereof is herein referred to.

K

_(LI_

T ii i111 1 1111 ii- ^rr WO 93/16072 PCT/GB93/00214 -7- The compounds of formula wherein CO-Y is an ester or amide linkage are prepared by conventional coupling of the Z moiety with the appropriate acid.

Suitable methods are as described in GB 2125398A (Sandoz Limited), GB 1593146A, EP-A-36269 and EP-A-289170 (Beecham Group When CO-Y is replaced by a heterocyclic bioisostere, suitable methods are described in EP-A-328200 (Merck Sharp Dohme Limited). Reference is also made to EP-A-501322 (Glaxo Group Limited).

Aza(bi)cyclic side chain intermediates are known compounds or may be prepare's L rding to the methods described in PCT/GB92/01519 and /01612 (SmithKline Beecham The compounds of the present invention are 5-HT 4 receptor antagonists and it is thus believed may generally be used in the treatment or prophylaxis of gastrointestinal disorders, cardiovascular disorders and CNS disorders.

They are of potential interest in the treatment of irritable bowel syndrome (IBS), in particular the diarrhoea aspects of IBS, these compounds block the ability of 0-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 treatment of urinary incontinence which is often associated with IBS.

They may also be of potential use in other gastrointestinal disorders, such as those associated with upper gut motility, and as antiemetics. In particular, they are of potential use in the treatment of the nausea and gastric symptoms of gastro-oesophageal reflux disease and dyspepsia. Antiemetic activity is determined in known animal models of cytotoxic agent induced emesis.

Specific cardiac 5-HT 4 receptor antagonists which prevent atrial fibrillation and other atrial arrhythmias associated with 5-HT, would also be expected to reduce occurrence of stroke (see A.J. Kaumann 1990, Naumyn- Schmiedeberg's Arch. Pharmacol. 342, 619-622, for appropriate animal test method).

Anxiolytic activity is likely to be effected via the hippocampus (Dumais et al 1988, Mol Pharmacol., 34, 880-887). Activity can be demonstrated in standard animal models, the social interaction test and the X-maze test.

L WO 93/16072 PCT/GB93/00214 -8- Migraine sufferers often undergo situations of anxiety and emotional stress that precede the appearance of headache (Sachs, 1985, Migraine, Pan Books, London). It has also been observed that during and within 48 hours of a migraine attack, cyclic AMP levels are considerably increased in the cerebrospinal fluid (Welch et al., 1976, Headache 16, 160-167). It is believed that a migraine, including the prodomal phase and the associated increased levels of cyclic AMP are related to stimulation of 5-HT 4 receptors, and hence that administration of a 5-HT 4 antagonist is of potential benefit in relieving a migraine attack.

The invention also provides a pharmaceutical composition comprising a compound of formula or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Such compositions are prepared by admixture and are usually adapted for oral or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutioins or suspensions or suppositories. Orally administrable compositions are proferred, since they are more convenient for general use.

Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents. The tablets may be coated according to well known methods in the art, for example with an enteric coating.

Suitable fillers for use include cellulose, mannitol, lactose and other similar agents. Suitable disintegrants include starch, polyvinylpolypyrrolidone and starch derivatives-such as sodium starch glycollate. Suitable lubricants include, for example, magnesium stearate.

Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl 4 i WO 93/16072 PCT/GB93/00214 -9cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.

Oral liquid preparations are usually in the form of aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs or are presented as a dry product for reconstitution with water or other suitable vehicle before use.

Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and flavouring or colouring agents.

The oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.

For parenteral administration, fluid unit dose forms are prepared containing a compound of the present invention and a sterile vehicle. The compound, depending on the vehicle and the concentration, can be either suspended or dissolved. Parenteral solutions are normally prepared by dissolving the compound in a vehicl' and filter sterilising before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum.

Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure of ethylene oxida before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to Iacilitate uniform distribution of the compound of the invention.

WO 93/16072 PCT/GB93/00214 The invention further provides a method of treatment or prophylaxis of irritable bowel syndrome, dyspepsia, atrial arrhythmias and stroke, anxiety and/or migraine in mammals, such as humans, which comprises the administration of an effective amount of a compound of the formula or a pharmaceutically acceptable salt thereof.

An amount effective to treat the disorders hereinbefore described depends on the relative efficacies of the compounds of the invention, the nature and severity of the disorder being treated and the weight of the mammal.

However, a unit dose for a 70kg adult will normally contain 0.05 to 1000mg example 0.5 to 500mg, of the compound of the invention. Unit doses may be administered once or more than once a day, for example, 2, 3 or 4 times a day, more usually 1 to 3 times a day, that is in the range of approximately 0.0001 to 50mg/kg/day, more usuaily 0.0002 to 25 mg/kg/day.

No adverse toxicological effects are indicated within the aforementioned dosage ranges.

The inventio. also provides a compound of formula or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance, in particular for use in the treatment of irritable bowel syndrome, gastrooesophageal reflux disease, dyspepsia, atrial ariryihmias and stroke, anxiety and/or migraine.

The following Examples illustrate the preparation of compounds of formula the following descriptions relate to intermediates.

A preferred compound corresponds to any example, but wherein there is an amino substituent in the 4-position and a chloro substituent in the 5-position of the benzoic acid nucleus depicted in formula Examples

R

1

R

2

R

3

X

1 1X 2 V Z El H H H O-(CH2) 2

-CH

2 0 E2 H H H O-CH 2

-CH

2 0 E3 H Cl H 0-(CH2) 2

-CH

2 0 (G) E4 H H H 0-C(CH1 3 2

-(CH

2 2 0 (G) H Cl H O-C(CH 3 2

-CH

2 0 (W E6 NH 2 CI H O-(CH2) 2

-CH

2 0 (1) E7 H Cl H O-(CH 2 2

-CH

2 NH (i) E8 H Cl H O-C(CH 3 2 2 2 0 (G) E 9 H H H S-(CH2) 2

-CH

2 0 (G) ElO H Br H S-(CH2) 2

-CH

2 0 (G) Ell NH 2 Cl 0-(CH 2 2

-CH

2

GH()

9508 18,pAoper\dab,34572.speI I /2 J WO 93/16072 PCT/GB93/00214 -12- Example 1 (1-Butyl-4-piperidyl)methyl-[2H]-3,4-dihydro-1-benzopyran-8-carboxylate (El) To a stirred solution of [2H]-3,4-dihydro-1-benzopyran-8-carboxylic acid (0.3g) in dichloromethane (15mi) at OoC under nitrogen, was added oxalyl chloride (0.16 ml) and dry dimethylfcrmamide (3m drops). After 1 hour, the solvents were evaporated under reduced pressure. The residual acid chloride was dissolved in dry THF (20 ml) and added dropwise to a solution of the lithium anion of 1 -butyl-4-piperidinemethanol in dry THF, prepared by treating a solution of 1-butyl-4-piperidinemethanol (0.29g) in dry THF (20ml) with butyllithium (1.1 ml of a 1.6 molar solution in hexane), at 0oC under nitrogen for 15 minutes. After stirring at ambient temperature overnight, the reaction mixture was diluted with water, the volatile solvent was evaporated under reduced pressure, and the product was extracted into dichloromethane. The organic phase was dried (Na 2

SO

4 and the solvent was evaporated under reduced pressure. The residue was chromatographed through a short flash silica column using an increasing proportion of methanol in chloroform The product was isolated as the hydrochloride salt from IPA/Et20 to give the title compound (177mg).

mp 166-80C.

1H NMR 250MHz (CDCI 3 (free base) 8: 7.62(d,1 7.19(d,1 6.85(t,1 4.30(t,2H), 4.15(d,2H), 3.02(d,2H), 2.83(t,2H), 2.45-2.25(m,2H), 2.1-1.9(m,4H), 1.9-1.65(m,3H), 1.6-1.2(m,6H), 0.92(t,3H)

~I_

'i~ WO 93/16072 PCT/GB93/00214 13- Example 2 (1-Butyl-4-piperidyl)methyl-2,3-dihydrobenzofuran-7-carboxylate hydrochloride (E2) To a stirred solution of 2,3-dihydrobenzofuran-7-carboxylic acid (D1) (0.2g) in dichloromethane (15ml) at OoC under nitrogen was added oxalyl chloride (0.12ml) and dry dimethylformamide (3 drops). After 1 hour the solvents were evaporated under reduced pressure. The residual acid chloride was dissolved in dichloromethane (15ml) and treated with a solution of 1-butyl-4piperidine methanol (0.21g) in dichloromethane (10ml) and triethylamine (0.19ml). After stirring at ambient temperature overnight, the reaction mixture was washed with saturated NaHCO 3 and the organic phase was dried (Na 2

SO

4 The solvent was evaporated under reduced pressure and the residue chromatographed through a short flash silica column, eluting with increasing proportions of methanol in chloroform The product was isolated as the hydrochloride salt from IPA/Et 2 0 to give the title compound (84 mg).

mp 187-90C 1H NMR 250MHz (CDCI 3 (free base) 8: 7.72(d,1H), 7.35(d,1H), 6.88(t,1H), 4.72(t,2H), 4.19(d,2H), 3.22(t,2H), 3.1- 2.9(d,2H), 2.5-2.25(m,2H), 2.1-1.2(m, 11H), 0.92(t,3H) WO 93/16072 PCT/GB93/00214 -14- Example 3 (1-Butyl-4-piperidyl)methyl-6-chloro-[2H]-3,4-dihydro-1-benzopyran-8carboxylate (E3) Following the procedure outlined in Example 1 (except that methyllithium was used in a place of n-butyllithium), 6-chloro-[2H]-3,4-dihydro-1 -benzopyran-8carboxylic acid (300 mg) was converted to the title compound (143 mg, 28%).

1 H NMR 250 MHz (CDCI 3 8:7.55 1H), 7.15 1H), 4.29 2H), 4.15 2H), 3.05 (brd, 2H), 2.80 (t, 2H), 2.5-2.25 2H), 2.18-1.10 13H), 0.94 3H) Example 4 2,2-Dlmethyl- q'-3,4-dihydro-1-benzopyran-8-(1-butyl-4piperidyl)methylcarboxylate hydrochloride (E4) To a solution of 2,2-dimethyl-[2H]-3,4-dihydro-1 -benzopyran-8-carboxylic acid (EP-A-307172) (300 mg) in acetonitrile (20 ml) was added N, N'carbonyldiimidazole (236mg). Stirring was continued at ambient temperature for 1 h. The solvent was concentrated in vacuo to afford crude imidazolide.

Methyllithium (1.5M in diethyl ether, 0.97 ml) was added dropwise to a cooled (0OC) solution of 1-butyl-4-piperidinemethanol (250 mg) in dry THF (10 ml) under a nitrogen atmosphere. Stirring was continued at room temperature for min. A solution of the imidazolide in dry THF (10ml) was added and stirring continued overnight. Water was added and the solvent concentrated in vacuo. The residue was partitioned between chloroform and water. The organic phase was dried (Na 2 SO4), filtered and concentrated. The residue was chromatographed on silica using chloroform and ethanol as eluant to afford pure ester (471 mg) as an oil. Treatment with ethereal HCI and trituration of the resultant gum with diethyi ether gave title compound as a solid.

O WO 93/16072 WO 9316072PCF/GB93/00214 1 H NMR 250 MHz (CDCI 3 8: 7.60(d,l 7.19.(d,1 6.82(t,1 3.99(d,2H), 2.93-3.03(m,2H), 2.81 (t,2H), 2.28-2.37(m,2H), 1.61 -2.02(m,7H), 1.23-1 .56(m,1 2H inc s,6H), 0.94(t,3H) Example 7-(1 -Butyl-4-piperidy)methyl-5-chloro-dthydro-2,2-dlmethylbenzofurancarboxylate Following the procedure outlined in Example 4, 5-chloro-2,3-dihydro-2,2dimethylbenzofuran-7-carboxylic acid was converted to the title compound.

mp 225-60C (hydrochloride salt) 1 HNMR 250MHz (CDCI 3 (free base) 8: 7.65(d, 1 7.22 1H), 4.12(d,2H), 2.92-3.11 (m,4H inc. s2H), 2.28-2.38 1.22-2.0 (in, 17H inc s,6H), 0.92 (t,3H) Example 6 (1 -ButyI-4-plperldyl)methyl-5-amino-6-chloro-[2H]-3,4-dihydro-1benzopyran--Arboxylate hydrochloride (E6) Following the procedure outlined in Example 4, 5-amino-6-chloro-[2H]-3,4dihydro-1 -benzopyran-8-carboxylic acid (D4) (200mg) was converted to the title compound (68mg 1 mp 209-2 130C 1 HNMR 250 MHz (CDCI 3 (free base) 8: 7.7(s,1 4.39(brs, 4.22(t,2H), 4.10O(d,2H1), 3.05(brd,2H), 2.6- S 2.25(m,4H), 2.2-1 .93(m,4H), 1.9-1 .68(m,3H), 1.65-1 0.92(t,3H) 16 Example 7 (1 -Butyl-4-piperidyl)methyl-6-ctiIoro-[2H]-3,4-dihydro-1 -benzopyran-8carboxamide hydrochloride (E7) A solution of 6-chloro-[2H]-3,4-dihydro-1 -benzopyran-8-carboxylic acid (200mg) in dry dichloromethane (6ml) was treated with oxalyl chloride 13 ml) and dry dimethylformamide (2 drops) under nitrogen. After stirring for four hours at ambient tempera~wre the solvent was evaporated under reduced pressure. The resulting ai- chloride was dissolved in dry dichloromethane (6ml) and added to a stirring solution of 1 -butylpiperidin-4-ylmethylamine (1 60mg) in dry dichioromethane (5ml) containing triethytamine 14 ml).

After stirring at ambient temperature overnight under nitrogen, the reaction mixture was washed with NaHCO 3 and the organic phase dried over Na 2

SO

4 The solvent was evaporated under reduced pressure to give the V. product which was purified using column chromatography (SiO 2 methanol/chloroform), and converted to the hydrochloride salt (E61) (1 38mg, 37%) .mp 227-90C.

9508 1 8,p:\opec~dab,34572.spe, 16 -17- H NMR 250 MHz (ODC1 3 (free base) 8: 7.98(s,1 7.12(s,1 4.35(t,2H), 3.35(t,2H), 3.08(brd, 2H), 2.85(t,2H), 2.5-2.3(m,2: 2.2-1 .92(m,4H), 1.9-1 O.92(t,3H) Example 8 6-Chlo ro-2,2-dimethyl-3,4-dihyd ro-1I-benzo pyran-8-(1-butyl-4-piperidyl) methyl carboxylate hydrochloride (E8) Following the procedure outlined in Example 4,6-chloro-2,2-dimethyl-[2H]-3,4dihydro-l-benzopyran-8-carboxylic acid (D5) (1g) was converted to the title compound (31 0mg) 1 H NMR 250 MHz (CDC1 3 (free base) 8: 7.55(d,1 7.16(d,1 4.13(d,2H), 2.98(bd, 2H), 2.79(t,2H), 2.32(t,2H), 1.68-2.00(m,7H), 1.24-1.54(m,1 2H inc s,6H), 0.92(t,3H) Example 9 (l-Butyl-4-piperidyl)methylthiochroman-8-carboxylate (E9) 4 4 2 This was prepared according to the general method described in Example 1.

Thus thiochroman-8-carboxylic acid 160g, 0.525 mmol) (D6) was converted to the title compound 145g, 53%) which was subsequently transformed into its hydrochloride salt m.pt 157-1580C.

t1 t 1 H NMR (250 MHz, CDC1 3 (free base), 8: 7.82 1 7.17 1 7.00 1 4.15 2H), 3.00 (in, 4H), 2.87 (t, 2H), 2-.38 2H), 2.20-1.95 (in, 5H), 1.80 (in, 2H), 1.50 (mn, 4H), 1.30 (mn, 2H), 0.90 311).

41; -18- Example (1-B utyl-4-piperididyl)methyl-6-bromothiochroman-8-carboxylate This was prepared according to the general method described in Example 1.

Thus 6-bromothiochroman-8-carboxylic acid (0.318g, 1.17mmol) (D7) was converted to the title compound (0.217g, 44%) which was subsequently transformed into its hydrochloride salt. m.pt. 197-1980.

1 H NMR (200 MHz, CDCI3) (free base) 8: 7.90 1H), 7.30 1H), 4.20 2H), 3.00 4H), 2.88 2H), 2.32 (t, 2H), 2.10 2H), 2.00-1.70 4H), 1.55-1.20 7H), 0.92 3H).

Example 11 Sa 5-Amino-(1-butyl-4-piperidyl)methyl-6-chloro-[2H]-3,4-dihydro-1benzopyran-8-carboxamide (El1) A solution of 5-amino-6-chloro-[2H]-3,4-dihydro-1 -benzopyran-8-carboxylic acid (D4, 200mg in acetonitrile (6ml) was treated with biscarbonyldiimidazole (171mg) and the resulting solution was stirred at room temperature for 2 hours. A solution of (1-butyl-4-piperidyl) methylamine 25 (150mg) in acetonitrile (10ml) was added and the reaction mixture was stirred a a S, at room temperature for 15 hours. The solvent was removed in vacuo and S" the residue partitioned between water and dichloromethane. The dichloromethane layer was removed and the aqueous extracted further with Sdichloromethane. The organic extracts were combined and washed with 30 water, then dried (Na 2

SO

4 and concentrated to give a yellow gum that was purified by column chromatography on silica using CHCl 3 with increasing quantities of MeOH as eluant to give the title compound as an off white solid mp 65-6oC.

1 H NMR (250 MHz CDCI3) 8: 8.0 7.96-7.8 4.45-4.15 3.32 3.02 2.53 2H), 2.39 2.2-1.9 1.86-1.15(m,9H), 0.92 (t,3H) /Tr S-' WO 93/16072 PCr/GB93/00214 -19- Descriptions Description 1 (intermediate for Example 2) [2H]-3,4-Dlhydro-1 -benzopyran48-carboxylic acid Following the procedure outlined in EP-A-3071 72 Example 15, [2H]-3,4dihydro-1 -benzopyran (0.85g) was converted to the title compound (131) (0.77g) 1 HNMVR (200MHz)(CDC1 3 8: 8.0(d,1 7.3(d, 1 7.0(tL,1 4.45(t,2H), 2.89(t,2H), 2.25-2.O(m,2H) Description 2 (intermediate for Example 2) 2,3-Dihydrobenzofuran-7-carboxylic acid Following the procedure outlined in EP-A-3071 72, Example 15, 2,3dihydrobenzofuran (0.59g) was converted to the title compound (D2) (0.41 g) 11-1 NMVR 250MHz (CDC1 3 8: 7.82(d,1 7.44(d,1 6.96(t,1 4.80(t,2H), 3.30(t,2H) WO 93/16072 PCT/GB93/60214 20 Description 3 (intermediate for Example 3) 6-Chloro-[2H]-3,4-dihydro-1-benzopyran-8-carboxylic acid A solution of [2H]-3,4-dihydro-1 -benzopyran-8-carboxylic acid (D1) (150mg) in glacial acetic acid (10ml) was treated with a solution of 1.3 equivalents of chlorine (80mg) in glacial acetic acid (2.8 mis) dropwise with ice-cooling.

After stirring overnight at ambient temperature the solvents were evaporated under reduced pressure, and the residue triturated with diethyl ether to give the title compound (D3) (64mg, 36%).

1H NMR 200 MHz (CDCl 3 8:10.78 (brs, 1H), 7.95 1H), 7.25 1H), 4.45 2H), 2.88 2H), 2.25- 2.0 2H) Description 4 (intermediate for Example 6) a) Methyl(4-acetylamino-2-propargyloxy)benzoate A solution of methyl-4-acetylamino-2-hydroxybenzoate (prepared as described in EP-A-234872) (5 g) in a mixture of dry tetrahydrofuran (100 ml) and dry dimethylformamide (150 ml) was treated with 1 equivalent of sodium hydride (0.72g of an 80% dispersion in oil). After stirring for 1 hour under nitrogen, 2.5 equivalents of propargylbromide (5.33 ml) were added, and the mixture was heated under reflux for three days. The solvents were evaporated under reduced pressure and the residue partitioned between sodium hydroxide and ethyl acetate. The organic phase was dried over Na 2 SO4 and evaporated under reduced pressure to give a red oil which, after trituration with 600-800 petrol-ether gave the title compound as a light tan powder (4.95g, 84%) 1H NMR 200 MHz (CDCI 3 8: 7.91(brs, 1H), 7.81(d,1H), 7.68(s,1H), 7.05(d,1H), 4.78(d,2H), 3.86(s,3H), 2.54(/f,1 2.2(s,3H) WO 93/16072 PCr/GB93/00214 -21b) Methyl (5-acetamldo-[2H 1-1-benzopyran)4-8-carboxylate A solution of methyl(4-acetamido-2-propargyloxy)benzoate (6.38g) in 1,2dichlorobenzene (65m1) wes heated under ref lux under nitrogen for 60 hours.

The solvent was evaporated under reduced pressure and the residue purified on a silica column, eluting with metharolchloroform, to give the title compound as a tan solid (3.47g, 54%) 1 H NMR 200 MHz (ODC1 3 7.79(brs, 1 7.64(d,1 7.3(d,1 6.46(d,1 5.85(m,1 4.75(brs,2H), 3.85(s,3H), 2.20(s,3H) C) Methyl(5-acetamido-[214]-3,4-dihydro-1 -benzopyran)-8carboxylate A solutio 1 of methyl (5-acetamido-[2H]-1 -benzopyran)-8-carboxylate (D23) (770mg) in ethanol, was hydrogenated over 10% palladium on charcoal at atmospheric pressure for 1.25 hours. The reaction mixture was filtered and the filtrate evaporated under reduced pressure to give the title compound as a white powder (670 mg, 86%) 1 H NMR 250 MHz (CDCI 3 5: 7.68(d,1 7.49(brs, 1 7.1 9(brs,1 4.22(t,2H), 3.88(s,3H), 2.62(t,2H), 2.20(s,3H), 2.1-1 .96(m,2H) d) Methyl(5-acetamldo-6-chloro-[2H]-3,4-ihydro-1 -benzopyran-8carboxylate Following the procedure outlined in Description 3, methyl(5-acetamido-[2H]- 3,4-dihydro-1 -benzopyran)-8-carboxylate (660mg) was converted to the title compound which was isolated as a light tan powder (525mg, 1 H NMR 250 MHz (C0013) 8: 7.7(s,1 7.1 5(s,1 4.29(t,2H), 3.89(s,3H), 2.70(t,2H), 2.25(s,3H), 2.05- 1 .9(m,2H) WO 93/16072 Pr1'/GB93/00214 -22e) 5-Amino-6-chloro-[2H]-3,4-dlhydro-1 -benzopyran-8-carboxyllc acid A solution of methyl (5-acetamido-6-ch Iorc-[2H]-3,4-dih, dro-l-benzopyran-8carboxylate (1.01 5g) in ethanol (20 ml) water (10 ml) and 10% sodium hydroxide (30 ml) was heated under ref lux for 24 hours, then cooled and treated with concentrated hydrochloric acid (until pH 2) and the resulting precipitate was filtered off to give the title compound (D4) (427mg, 52%) 1 NMR 250 MHz (CDC1 3 7.85(s,1 4.34(t,2H), 2.54(t,2H), 2.25-2.0(m,2H) Description 5 (intermediate for Example* 6-Chloro-2,2-d methyl.[2H]-3,4-dihydro-l-benzopyran-8-carboxr!j c acid 'Following the procedure outEd in Description 3, 2,2-dimethyl-[2H]-3,4dihydro-l-benzopyran-8-carboxylic acid (EP-A-307172) (2.41g) gave the title compound (D5) (2.68g). M+ 240 (El) 4 i- I WO 93/16072 PCT/GB93/00214 -23- Description 6 (intermediate for Example a) Methylthiochroman-4-one-8-carboxylate |-(2-carbomethoxythiophenoxy) propionic acid (6.00g, 0.025mol) Still and M.J. Thomas J.Org. Chem 1968, 2733) was added slowly to ice cooled cone. sulphuric acid (75ml) with stirring. After 21h, the reaction mixture was poured into ice water and then made alkaline using solid sodium hydrogen carbonate. The resultant suspension was then extracted with CH 2

CI

2 (3X).

The combined organic layers were then dried (Na2SO4), and evaporated under reduced pressure to give an orange oil which was dried in vacuo and crystallised on standing to give (2.40g, 43%).

b) Methylthiochroman-4-ol-8-carboxylate Methylthiochroman-4-one-8-carboxylate (0.500g, 2.25mmol) was dissolved with stirring in ethanol (20 ml). After 1 h, the reaction mixture was evaporated under reduced pressure and the residue partitioned between ethyl acetate and water. The aqueous layer was then extracted with ethyl acetate (1 X) and the combined organic layers were dried (Na 2

SO

4 and evaporated under reduced pressure to give a yellcw oil, which was purified by silica-gel chromatography (1:1 Pentane:EtOAc as eluant) to give the title compound as a colourless oil (0.499g, 99%) 1H NMR (200 MHz, CCCl3) 8: 7.95 (dd, 1H), 7.55 (dd, 1H), 7.12 1 4.87 1H), 3.92 3H) 3.23 1H), 2.88 1H), 2.37 1H), 2.08 H), 1.92 1H).

c) Methyl-2H-thiochromene-8-carboxylate SMethyl thiochroman-4-ol-8-carboxylate (0.337g, 1.50 mmol) was dissolved in toluene (25ml) and was treated with p-toluenesulphonic acid (0.028g, 0.15 mmol). The mixture was then heated to reflux with stirring. After 2h, the reaction mixture was allowed to cool and was washed with sodium hydrogen carbonate solution. The aqueous layer was then extracted with EtOAc (1 X), and the combined organic layers were dried (Na 2 SO4) and evaporated under 1ALz reduced pressure to give a pale yellow oil which was purified by silica-gel chromatography (pentane: Et20 2:1 as eluant) to give the titi, compound WO 93/16072 PCT/GB93/00214 -24- (D2b) as a pale yellow oil (0.270g, 87%) 1 H NMR (200 MHz, CDCI 3 8: 7.80 (dd, 1H), 7.20 (dd, 1H), 7.10 1H), 6.52 1 6.02 1 3.92 3H), 3.48 (dd, 1 H).

d) Methylthiochroman-8-carboxylate Methyl-2H-thiochromene-8-carboxylate (1.83g, 8.88 mmol) was dissolved in ethanol (100ml) and treated with 10% PdC The mixture was then hydrogenated at atmospheric pressure at room temperature. After 19h the reaction mixture was filtered through celite and evaporated under reduced pressure to give a colourless oil which was dried in vacuo to give the title compound (1.25g, 68%) 1 H NMR (200 MHz, CDCI 3 8 7.80 1H), 7.62 1 6.97 1 3.89 (s, 3H), 2.97 2H), 2.87 2H), 2.12 2H).

e) Thiochroman-8-carboxylic acid Methylthiochroman-8-carboxylate (0.220g, 1.05mmol) was dissolved in ethanol (5ml) and treated with 10% sodium hydroxide solution (10ml). The mixture was then heated to reflux with stirring. After 5h, the reaction mixture was allowed to cool. The ethanol present was then removed by evaporation under reduced pressure. The aqueous residue was then washed with

CH

2

CI

2 (2X) before being acidified to pH1 using 5M HCI. The resultant pale yellow precipitate was then filtered off and dried in vacuo to give the title compound (0.156g, 76%) (D6).

1 H NMR (200 MHz, 8: 7.80 1 7.20 1H), 7.00 1H), 2.90 4H), 2.08 2H).

i (I WO 93/16072 PCT/GB93/00214 -o Description 7 (intermediate for Example 1t=) a) Methyl-6-bromothiochroman-8-carboxylate A solution of methylthiochroman-8-carboxylate (0.300g, 1.44 mmol) (D6a) in dichloromethane (20ml) was treated with bromine (0.106 ml, 2.07 mmol) and the reaction mixture left at room temperature. After 4 days the reaction mixture was washed with sodium metabisulphile solution. The organic layer was then dried (Na 2

SO

4 and evaporated under reduced pressure to give the title compound as a colourless oil (0.340g, 82%).

1H NMR (250 MHz, CDCI 3 8: 7.92 1H), 7.30 1H), 3.92 3H), 3.00 (t, 2H), 2.88 2H), 2.10 2H).

b) 6-Bromothiochroman-8-carboxylic acid This was prepared according to the general method described in Description 6e). Thus, methyl-6-bromo-thiochroman (0.325g, 1.13mmol) was converted to the title compound (0.306g, 99%) (D7).

1 H NMR (200MHz, CD 3

SOCD

3 13.25 (brs, 1H), 7.82 1H), 7.50 1H), 2.92 4H), 2.00 2H).

i- ~uk~ WO 93/16072 PCT/GB93/00214 26 4 RECEPTOR ANTAGONIST

ACTIVITY

1) Guinea pig colon Male guinea-pigs, weighing 250-400g are used. Longitudinal musclemyenteric plexus preparations, approximately 3cm long, are obtained from the distal colon region. These are suspended under a 0.5g load in isolated tissue baths containing Krebs solution bubbled with 5% C02 in 0 2 and maintained at 370C. In all experiments, the Krebs solution also contains methiothepin 10-7M and granisetron 10- 6 M to block effects at 5-HT 1 5-HT 2 and 5-HT 3 receptors.

After construction of a simple concentration-response curve with 5-HT, using 30s contact times and a 15min dosing cycle, a concentration of 5-HT is selected so as to obtain a contraction of the muscle approximately 40-70% maximum(10-9M approx). The tissue is then alternately dosed every with this concentration of 5-HT and then with an approximately equi-effective concentration of the nicotine receptor stimulant, dimethylphenylpiperazinium (DMPP). After obtaining consistent responses to both 5-HT and DMPP, increasing concentrations of a putative 5-HT 4 receptor 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, plC50 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-HT 4 receptor antagonist.

Compounds were generally active in the range of concentrations of the order of plC50=7 or more, E3, E8 and E12 showing particularly good activity.

2) Piglet Atria Compounds were tested in the piglet spontaneous beating screen (Naunyn- Schmiedeberg's Arch. Pharmacol 342, 619-622). pKB (-log10 KB) value for the compound of Examples 3 ad7=were 7.7 ropootivly.

,RAU,2 1 k I'

I"

WO 93/16072 PCT/GB93/00214 27 3) Rat oesophagus Rat oesophageal tunica muscularis mucosae is set up according to Baxter et.

al. Naunyn-Schmiedeberg's Arch. Pharmacol., 343, 439-446 (1991). The inner smooth muscle tube of the muscularis mucosae is isolated and mounted for isometric tension recording in oxygenated (95% 02/5% CO 2 Tyrodes solution at 37 0 C. All experiments are performed in pargyline pre-treated preparations (100l.M for 15 min followed by washout) and in the presence of cocaine (30p.M). Relaxant responses to 5-HT are obtained after precontracting the oesophagus tissue with carbachol (3pM).

4) 5-HT-induced motility in dog gastric pouch Compounds are tested in the in vivo method described in "Stimulation of canine motility by BRL 24924, a new gastric prokinetic agent", Bermudez et al, J. Gastrointestinal Motility, 281-286.

The compound E3 showed inhibition at a dose of 1 0pg kg- 1 ~-TI~rsax3EO-praP~ b-a~ r

L"~

27a Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

o*ro o a 0 o *a0 i*1 950817,p:\oper\dab,34572.spe,27

Claims (20)

1. A compound of formula or a pharmaceutically acceptable salt thereof CO-Y-Z R 3 4 (I) (CH 2 )X R 2 R 1 in which Xi-(CH 2 )x-X 2 and the aromatic carbon atoms to which they are attached form a 5-7 membered ring; wherein: one of X 1 and X 2 is O, S or CH 2 and the other is CH 2 x is 1, 2 or 3; 15 R1 is hydrogen, amino, halo, C 1 i 6 alkyl, hydroxy or C 1 -6 alkoxy; o R 2 is hydrogen, halo, C1-6 alkyl, C1-6 alkoxy, nitro, amino or C 1 -6 alkylthio; 0 R 3 is hydrogen, halo, C 1 -6 alkyl, Ci-6 alkoxy or amino; R4 and R 5 are independently hydrogen or C 1 -6 alkyl; SY is O or NH; Z is of formula: N R NR 1 a Na N R, 1 wherein Ra is alkyl or optionally substituted benzyl.

2. A compound according to claim 1 wherein R 1 is hydrogen or amino. 950818,p:\oper\dab,34572.spe,28 -29-

3. A compound according to claim 1 or 2 wherein R 2 is hydrogen or halo.

4. A compound according to claim 1, 2 or 3 wherein R3 is hydrogen or halo.

5. A compound according to claim 1, 2, 3 or 4 wherein XI-(CH 2 )x-X 2 is O- (CH 2 2 -CH 2 O-(CH 2 3 -CH 2 O-CH 2 -CH 2 or corresponding values wherein X 1 =X 2 =CH 2 wherein any of the methylene linkages are optionally mono- or di- substituted by C 1 -6 alkyl groups, such as methyl.

6. A compound according to claim 5 wherein the disubstituent is O-(CH 2 2 -CH 2

7. A compound according to any one of claims 1 to 6 wherein Y is NH. 1 15 8. A compound according to any one of claims 1 to 7 wherein Ra is cyclohexylmethyl. I rt r s; Ir *r r 1 ci rr- re ri r r c 1 rr. i I rrp

9. alkyl. 1 A compound according to any one of claims 1 to 7 wherein Ra is C 3 to C 12 1

10. A compound according to claim 9 wherein Ra is n-butyl. 1

11. A compound according to any one of claims 1 to 7 wherein Ra is optionally substituted benzyl.

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

13. (1-Butyl-4-piperidyl)methyl-[2H]-3,4-dihydro-l-benzopyran-8-carboxylate.

14. (1-Butyl-4-piperidyl)methyl-2,3-dihydrobenzofuran-7-carboxylate. S c 950818,p:\oper\dab,34572.spe,29 (1-uy--ieiy~ehl--hoo 2]34dhdo 1-benzopyrel-8- carboxylate.

16. 2,2-Dimethyl-3 ,4-dihydro-l1-benzopyran-8-(1 -butyl-4-piperidyl)methylcarboxylate.

17. 1 -Butyl-4-piperidyl)methyl-5 -chloro-3 -hydro-2,2-dimethylbenzofuran- carboxylate.

18. (1-Butyl-4-piperidyl)methyl-5-amino-6-chloro-[2H]-3,4-dihydro- 1 -benzopyran-8- carboxylate.

19. (1 -Piperidyl)ethyl-6-chloro- [2H]-3,4-dihydro- 1 -benzopyran-8-carboxylate. (1 -Butyl-4 -pip eridyl)methyl-6-chloro- [2H] -3 ,4-dihydro- 1 -benzopyran-8- carboxamide.

21. 6-Chloro-2,2-dimethyl-3 ,4-dihydro-l1-benzopyran-8-(1 -butyl-4-piperidyl)methyl

44. carboxylate. 22. (1 -Butyl-4-piperidyl)methylthiocbroman-8-carboxylate.

423. (1 -Butyl-4-piperidy)methy-6-bromothiochroman-8-carboxylate. 24. 5-Amino-(l1-butyl-4-piperidyl)methyl-6-chloro-[2H]-3,4-dihydro-1-benzopyran-8- carboxamide. A compound according to any one of claims 13 to 24 in free base or in the form of a pharmaceutically acceptable salt. 26. A process for preparing a compound of formula according to claim 1, which comprises reacting a compound of formula (II) or a reactive derivative thereof: 950818,p\oper\dab,34572.spe,30 Y^a ,1 1i. i^Me *rr=~--Fhti~Sic=pnsn~-~l ~rsr~ 31 n3\ (II) f( CH R, wherein XI-(CH 2 )x-X 2 R 1 R 2 R 3 R 4 and R 5 are as defined in claim 1; with HOZ or H 2 NZ, wherein Z is as defined in claim 1. 27. A pharmaceutical composition comprising a compound according to any one of claims 1 to 25 and a pharmaceutically acceptable carrier. 28. Use of a compound of formula according to any one of claims 1 to 25 as a 15 5-HT 4 receptor antagonist. 4 4 a t 29. A method for the treatment or prophylaxis of gastrointestinal disorders, cardiovascular disorders and CNS disorders which comprises administering an effective *amount of a compound of formula according to any one of claims 1 to 25 to a subject in need thereof. 4t DATED this 24th day of January, 1996 SmithKline Beecham plc By Its Patent Attorneys DAVIES COLLISON CAVE 960124,p:\opecrdab,34572.spe,31 INTERNATIONAL SEARCH REPORT UulsApplicedi No PCT/GB 93/002 14 L CAdBUWCATION OF mmjLcr MATU U-10Med vpN6Ik;deqgly, e Accelbg to ftumbaloo Patoo QC1ffmfin (C Of to both Nsdul OCkldem WWn IPC Int.Cl. 5 C07D405/12; C07D409/12; A61K31/445 EL FIELD)S SEARQ(ED 1&inwo Doonftsm Sached' Chlafaficosin systM. ClauM'.lla Symbols Int.Cl. 5 C07D ;A61K Docon.mtatcm Soachdi othe thea Misim D0000161or to te Emads that soch Doammt bnld la the Fields Seuched UlL DOCUMENTS CONSIDERED TO ME RELEVANT 9 Cesapy 0 Citation of Doammt, 11 with laisiam0, where Wnm.ilaz, of the relvan Pesagat Ralevat to CGain No.U X EP,A,0 234 872 (ADRIA LABORATORIES) 1-6,12 2 September 1987 cited in the application see pages 2-3; table pages 6-12, compounds 16-18, 22-32,36,42,44,48,50,53,54,56-58,63, 66,67,69-75; table VI, compounds 13a,13b, 13e-13k; table VII, compounds 16a-c,16k, 161 X EP,A,O 231 139 (LABORATOIRES DELAGRANGE) 1-6,12 Auguit 1987 see page 1 page 2; examples 10,20,21 *SPNWa atares ofd ud iemmvts :10 Tr lte daCm PudlIbb hotd the iinenmelAl filig date prie dowae a t aflict with the mM. omht Ae demmit ddlala the pumw oate of the an V"hicIs we =twi a the prladpie or 6-Yn =llgthe awdr to be of psfae.,iltmne m wE -ftil. docint but pebliAhe estor oer the immsoWl qr daWMme pmk fd w ,lna~the caimed lavatlm 611mg daue Mooft be amdrduela a be comered to Lf doonot which my thiw dawu am priorty claim(s) ar anolve m isvntve nep which i t"e to whllsh the publiatif date of mother -r decmme a purhmbr raieuaaq the claimed lawm dtiadmaor ethe special rum (as spedrod) aAintboolmdere to aal ma t la epwhathe O0' doownt vdmnla to ma =Wa diodmuers, 66htam orate is emhlaed wit me orte other uth doco- omie am", a, a mbhi beNW i641 ebvim to a peSkilled q' damne poblished prior to the itotrmiml SAft dale bot iteat ater thu the Pionity date claMed "eove amber ad the ame Pat" famil TV. CWTIFICAION Duze of the Actual Complelom ad the lazmmalm San*h Daoe ad Malilag d tugs imtimid Surh Repai M'ARCH 1993 26.0(a93 1AMM fifti" Aot ipame ad Aaterized Officer EUROPEAN PAWTf OFFICE RUSSELL F. ENGLISH ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION NO. 9300211v 69373 T1han ame= fia the patent faily inentla relating to the patent docummats cited in the abovomeoned izurmda inarth report. The members are as contained in the European Patent Office EDP file on The EuropeanZ Patent Office is in no way liable for these partimual.. which are merely given for the purpoe of informationa. 15/03/93 Patent dnaeonit Publication Potnt faily Publication cited in searc report I date Imember(s) Idate EP-A-0234872 02-09-87 US-A- CA-A- DE-A- JP-A- US-A- US-A- US-A- 4888353 1301170 3774727 62234083 5175173 5122528 5126364 19-12-89 19-05-92 09-01-92 14-10-87 29-12-92 16-06-92 30-06-92 EP-A-0231139 05-08-87 FR-A- AU-B- AU-A- BE-A-- CA-A- CH-A- CN-A- DE-A- DE-A- GB-A, B JP-A- LU-A- OA-A- SU-A- SU-A- US-A- 2593504 593605 6785587 1000164 1300161 670827 1062144 3702005 3774888 2187188 62277376 86747 8472 1609451 1607688 5006570 31-07-87 15-02-90 06-08-87 05-07-88 05-05-92 14-07-89 24-06-92 06-08-87 16-01-92 03-09-87 02-12-87 02-06-87 29-07-88 23-11-90 15-11-90 09-04-91 0 0 h. 0 b For mere ~*aik about thin maex Offielal Jmal of the Fm.pema Patent Offio.~ No. 12/32