WO1994029298A1

WO1994029298A1 - 8-amino-7-chloro-1,4-benzodioxan-5-carboxylic acid, -1-butyl-4-piperidinyl ester as a 5-ht4-receptor antagonist

Info

Publication number: WO1994029298A1
Application number: PCT/EP1994/001939
Authority: WO
Inventors: Laramie Mary Gaster
Original assignee: Smithkline Beecham Plc
Priority date: 1993-06-16
Filing date: 1994-06-14
Publication date: 1994-12-22
Also published as: JPH08511259A; GB9312348D0; EP0703914A1

Abstract

The preparation of 8-amino-7-chloro-1, 4-benzodioxan-5-(1-butyl-4-piperidinyl)carboxylate of formula (I) for use as a 5-HT4 receptor antagonist in the treatment or prophylaxis of gastrointestinal disorders, cardiovascular disorders and CNS disorders.

Description

8-AMINO-7-CHLORO-1,4-BENZ0DI0XAN-5-CARB0XYLIC ACID,-1-BUTYL-4-PIPERIDINYL

ESTER AS A 5-HT4-RECEPTOR ANTAGONIST

This invention relates to novel compounds having pharmacological activity, to a process for their preparation and to their use as pharmaceuticals.

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-HT₄ receptor, and that ICS 205-930, which is also a 5-HT₃ receptor antagonist, acts as an antagonist at this receptor.

WO 91/16045 (SmithKline and French Laboratories Limited) describes the use of cardiac 5-HT₄ receptor antagonists in the treatment of atrial arrhythmias and stroke.

EP-A-501322 (Glaxo Group Limited), WO 93/02677, WO 93/03725, WO 93/05038, WO 93/05040 and WO 93/18036 (SmithKUne Beecham pic) describe compounds having 5-HT₄ receptor antagonist activity.

It has now been discovered that certain novel compounds also have 5-HT₄ receptor antagonist properties.

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

X-CO-Y-Z (I) wherein

X is a group of formula (a), (b), (c) or (d):

wherein

X₁-(CH₂)_x-X₂ forms a 5-7 membered ring wherein Xj is O or S; X₂ is O, S, -CH₂-, NR or NRCO wherein R is hydrogen or C_1-6 alkyl; and

x is 1, 2 or 3;

one of X3 and X4 is N and the other is C; and

X5 is N or CR wherein R is hydrogen, C_1-6 alkoxy, halo, C_1-6 alkyl or cyano;

R₁ ^a is hydrogen, amino, halo, C_1-6 alkyl, hydroxy or C_1-6 alkoxy;

R₂ ^a is hydrogen, halo, C_1-6 alkyl, C_1-6 alkoxy, nitro, amino or C_1-6 alkylthio; R₃ ^a is hydrogen, halo, C_1-6 alkyl, C_1-6 alkoxy or amino;

R₄ ^a and R₅ ^a are independently hydrogen or C_1-6 alkyl;

R₁ ^b is hydrogen, halogen, CF₃, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylthio, C_1-6

alkylsulphonyl, C_1-6 alkylsulphinyl, C_1-6 acyl, cyano, C_1-6 alkoxycarbonyl, C_1-7 acylamino, hydroxy, nitro or amino, aminocarbonyl, or aminosulphonyl, optionally N-substituted by one or two groups selected from C_1-6 alkyl, C_3-8 cycloalkyl, and C_3-8 cycloalkyl C_1-4 alkyl or disubstituted by C₄ or C₅ polymethylene; phenyl or phenyl C_1-4 alkyl group optionally substituted in the phenyl ring by one or two of halogen, C_1-6 alkoxy or C_1-6 alkyl groups; R₃ ^b is hydrogen, halo, C_1-6 alkyl, amino, nitro or C_1-6 alkyl;

R₄ ^b is hydrogen, halo, C_1-6 alkyl or C_1-6 alkoxy;

X₆-X₇ is NR_z-CO or CR₁ ^cR₂ ^c-CR₃ ^cR₄ ^c where

R_z and R₁ ^c to R₄ ^C are independently hydrogen or C_1-6 alkyl; and/or

R₁ ^c/R₂ ^c and R₃ ^c/R₄ ^c together are a bond and/or R₁ ^c/R₂ ^c/R₃ ^c/R₄ ^c are joined to form C_3-6 polymethylene;

R_a ^c is hydrogen, halo, C_1-6 alkyl, amino, nitro or C_1-6 alkyl;

R_b ^c is hydrogen, halo, C_1-6 alkyl or C_1-6 alkoxy;

X^d is O, S, SO, SO₂, CH₂, CH, N or NR wherein R is hydrogen or C_1-6 alkyl; A is a saturated or unsaturated polymethylene chain of 2 - 4 carbon atoms;

R₁ ^d and R₂ ^d are hydrogen or C_1-6 alkyl;

R₃ ^d is hydrogen, halo, C_1-6 alkyl, amino, nitro or C_1-6 alkoxy;

R₄ ^d is hydrogen, halo, C_1-6 alkyl or C_1-6 alkoxy;

Y is O or NH;

Z is of sub-formula:

wherein

q is 0, 1, 2 or 3;

R_a is hydrogen, C_1-12 alkyl, aralkyl or R_a is (CH₂)_z-R₇ wherein z is 2 or 3 and R₇ is selected from cyano, hydroxyl, C_1-6 alkoxy, phenoxy, C(O)C_1-6 alkyl,

COC₆H₅, -CONR₈R₉, NR₈COR₉, SO₂NR₈R₉ or NR₈SO₂R₉ wherein R₈ and R₉ are hydrogen or C_1-6 alkyl; and

R₆ is hydrogen or C_1-6 alkyl;

or a compound of formula (I) wherein the CO-Y linkage is replaced by a heterocyclic bioisostere;

in the manufacture of a medicament for use as a 5-HT₄ receptor antagonist.

Examples of alkyl or alkyl containing groups include C₁, C₂, C₃, C₄, C₅, C₆,

C₇, C₈, C₉, C₁₀, C _{1 1} or C₁₂ branched, straight chained or cyclic alkyl, as appropriate. C1.4 alkyl groups include methyl, ethyl, n- and iso-propyl, n-, iso-, sec- and tert-butyl. Cyclic alkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl optionally substituted by one or more alkyl groups of up to 4 carbon atoms.

Aryl includes phenyl and naphthyl optionally substituted by one or more substituents selected from halo, C_1-6 alkyl and C_1-6 alkoxy.

Halo includes fluoro, chloro, bromo and iodo, preferably chloro.

A suitable bioisostere for the amide or ester linkage containing Y in formula (I) is of formula:

wherein

the dotted circle represents one or two double bonds in any position in the

5-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 bioisosteres 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 X₁-(CH₂)_x-X₂ moiety include O-(CH₂)₂-O, O-(CH₂)₃-O, O-CH₂-O, O-(CH₂)₂-NR, O-(CH₂)₂-S or O-CH₂-CONR, wherein any of the methylene linkages are optionally mono- or di- substituted by C_1-6 alkyl groups, such as methyl. Preferably X₁-(CH₂)₂-X₂ is O-(CH₂)₂-O.

Further suitable examples of X₁-(CH₂)_x-X₂ include O-(CH₂)₂-CH₂, O-(CH₂)₃-CH₂, O-CH₂-CH₂, or corresponding values wherein X₁ = X₂ = CH₂, wherein any of the methylene linkages are optionally mono- or di-substituted by C_1-6 alkyl groups, such as methyl. Preferably such X₁-(CH₂)₂-X₂ is O-(CH₂)₂-CH₂- R₁ ^a is preferably hydrogen or amino.

R₂ ^a is preferably hydrogen or halo.

R₃ ^a is preferably hydrogen or halo.

R₄ ^a and R₅ ^a are often hydrogen. When R₄ ^a/R₅ ^a is C_1-6 alkyl, it is often methyl. In particular R₄ ^a and R₅ ^a are methyl such that the disubstituent containing X₁ and X₂ is O-C(CH₃)₂-O.

R₁b is preferably CF₃ or an ethyl group.

X₅ is preferably N, C-H or C-OCH₃;

R₃ ^b is preferably hydrogen.

R₄ ^b is preferably hydrogen or halo, such as iodo.

Suitable examples of X₆-X₇ when CR₁ ^cR₂ ^c-CR₃ ^cR₄ ^c include CH₂-CH₂ and CH=CH. X₆-X₇ is preferably NR_z-CO, however, such as NH-CO or NEt-CO.

R_a ^c is preferably hydrogen.

R_b ^c is preferably hydrogen or halo, such as iodo.

Values for A include -CH₂-(CH₂)_r-CH₂- wherein r is 0, 1 or 2;

-CH₂-CH=CH-; -C(CH₃)=CH- or when X- is CH or N, A may be -(CH₂)₂-CH= or -CH=CH-CH=.

Rjd and R-~ are often hydrogen or R\- and R2^d are gem-dimethyl.

r is often 1.

R~~ is preferably hydrogen.

R4⁽ⁱ is preferably hydrogen or halo, such as fluoro.

Y is preferably O or NH.

The azacycle Z is preferably attached at a 4-position carbon atom, when q is 2. Values of Z of interest include 4-piperidinyl and 4-pyrrolidinyl, N-substituted by R_a.

Values for R_a of interest are as described in the aforementioned patent publications. A particularly preferred value is n-butyl. The pharmaceutically acceptable salts of the compounds of the formula (I) include acid addition salts with conventional acids such as hydrochloric,

hydrobromic, boric, phosphoric, sulphuric acids and pharmaceutically acceptable organic acids such as acetic, tartaric, maleic, citric, succinic, benzoic, ascorbic, methanesulphonic, α-keto glutaric, α-glycerophosphoric, and glucose- 1 -phosphoric acids.

Examples of pharmaceutically acceptable salts include quaternary derivatives of the compounds of formula (I) such as the compounds quaternised by compounds R_x-T wherein R_x is Cj.g alkyl, phenyl-C_1-6 alkyl or C_5-7 cycloalkyl, and T is a radical corresponding to an anion of an acid. Suitable examples of R_x include methyl, ethyl and n- and wø-propyl; and benzyl and phenethyl. Suitable examples of T include halide such as chloride, bromide and iodide.

Examples of pharmaceutically acceptable salts also include internal salts such as N-oxides.

The compounds of the formula (I), their pharmaceutically acceptable salts,

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

The compounds of formula (I) 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, EP-A-289170 and WO 92/05174 (Beecham Group p.l.c). 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).

Suitable examples of conversions in the Z containing moiety include conventional modifications of the N-substituent by substitution and/or deprotection or, in the case of a 2-, 3- or 4- substituted piperidyl desired end compound, reduction of an appropriate pyridyl derivative.

The compounds of the present invention are 5-HT₄ 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, 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 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/radiation induced emesis.

Specific cardiac 5-HT₄ receptor antagonists which prevent atrial fibrillation and other atrial arrhythmias associated with 5-HT, would also be expected to reduce occurrence of stroke (see AJ. 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 (Dumuis 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.

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-HT₄ receptors, and hence that administration of a 5-HT₄ antagonist is of potential benefit in relieving a migraine attack.

Other CNS disorders of interest include schizophrenia, Parkinson's disease and Huntingdon's chorea.

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

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

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

Suitable fillers for use include cellulose, mannitol, lactose and other similar agents. Suitable disintegrants include starch, 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 cellulose, gelatin, hydroxyethylcellulose,

carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.

Oral liquid preparations are usually in the form of aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs or are presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and flavouring or colouring agents.

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

For parenteral administration, fluid unit dose forms are prepared containing a compound of the present invention and a sterile vehicle. The 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 vehicle 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 oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the invention. 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 (I) 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 for 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 usually 0.0002 to 25 mg/kg/day.

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

The invention also provides a compound of formula (I) or a

pharmaceutically acceptable salt thereof for use as an active therapeutic substance, in particular for use in the treatment of irritable bowel syndrome, gastro-oesophageal reflux disease, dyspepsia, atrial arrhythmias and stroke, anxiety and/or migraine.

The following Example illustrates the preparation of compounds of formula

(I), and the following Description relate to the preparation of 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 (I).

Example

8-Amino-7-chloro-1,4-benzodioxan-5-(1-butyl-4-piperidinyl)carboxylate

[X = (a), X₁-(CH₂)_X-X₂ = O-(CH₂)₂-O, R₁ ^a = NH₂, R₂ ^a = Cl, R₃ ^a = H,

R₄ ^a R₅ ^a = H; Y = O, Z = 4-piperidinyl, R_a = n-butyl]

8-Amino-7-chloro-l,4-benzodioxan-5-carboxylic acid (4.0g;17.4mmol) was dissolved in dry DMF (30ml) and treated with biscarbonyldiimidazole

(3.10g;19.2mmol) and stirred overnight. The solution was evaporated in vacuo to a brown gum. 1-Butyl-4-piperidinol (3.01g;19.2mmol) was dissolved in dry THF (40ml) and treated with methyllithium (14.1ml of a 1.5M solution in diethyl ether; 21.09mmol) with stirring under Ar. After 15 minutes, the solution of alkoxide was added to the brown imidazolide residue and the whole stirred ar RT (48 hours). The reaction mixture was evaporated in vacuo, partitioned between H₂O/ethyl acetate, the organic layer separated and dried over Na₂SO₄ then filtered and the filtrate evaporated in vacuo to an orange gum. The gum was purified by flash silica-gel chromatography, with 2% MeOHICHCl₃ as eluant to yield a clear oil (0.22g) which contained 1-butyl-4-piperidinol. The oil was triturated with pet. ether 60°- 80° at - 78°C, the solvent decanted and the residue dried in vacuo to yield the title compound as a clear oil (0.12g), which was converted to the oxalate salt, mp=94-96°C.

¹ H NMR (250MHz,CDCl₃) (Free Base)

δ: 7.45 (s,1H), 5.00-4.90 (m,1H), 4.50-4.20 (m,6H), 2.80-2.60 (m,2H), 2.40-2.25

(m,4H), 2.05-1.85 (m,4H), 1.55-1.20 (m,4H), 0.90 (t,3H)

Description

a) 1-Butyl-4-piperidone

4-Piperidone monohydrate hydrochloride (5.0g;32.6mmol) was dissolved in acetone (50ml) and treated with 1-bromobutane (3.5ml;32.6mmol) and K₂CO₃ (9.0g;65.1mmol). The mixture was heated at reflux (48 hours), cooled and filtered through kieselguhr. The filtrate was evaporated in vacuo to an orange liquid which was purified by flash silica-gel chromatography with CHCI₃ as eluant to yield the title compound as an orange liquid (5.0g;99%).

¹ H NMR (250MHz, CDCI₃)

δ: 2.75 (t,4H), 2.50-2.35 (m,6H), 1.60-1.25 (m,4H), 0.95 (t,3H)

b) 1-Butyl-4-piperidinol

1-Butyl-4-piperidone (5.0g;32.3mmol) was dissolved in dry diethyl ether (50ml) and added to a suspension of LiAlH₄ (1.8g;48.4mmol) in dry diethyl ether (50ml) with stirring. After 2 hours, H₂O (1.8ml) was added carefully, followed by 10% NaOH (aq) (2.7ml) then H₂O (4.5ml). The mixture was stirred for 1 hour, filtered and the filtrate evaporated in vacuo to yield the title compound as an amber oil (4.76g;94%), bpt 105°C/0.05mmHg.

¹ H NMR (250MHz,CDCl₃)

δ: 3.75-3.60 (m,1H), 2.85-2.70 (m,2H), 2.20-2.05 (m,4H), 2.00-1.85 (m,2H), 1.70-1.20 (m,7H), 0.90 (t,3H) 5-HT₄ RECEPTOR ANTAGONIST ACTIVITY

1) Guinea pig colon

Male guinea-pigs, weighing 250-400g are used. Longitudinal muscle- myenteric 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% CO₂ in O₂ and maintained at 37°C. 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 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 15min 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-HT₄ 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, pIC₅₀ 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.

The compound of the Example gave a pIC50 value of 8.6.

Claims

1. A compoundof formula (I) or a pharmaceutically acceptable salt thereof:

X-CO-Y-Z (I) wherein

X is a group of formula (a), (b), (c) or (d):

wherein

X₁-(CH₂)_x-X₂ forms a 5-7 membered ring wherein Xi is O or S; X₂ is O, S, -CH₂-

NR or NRCO wherein R is hydrogen or C _1-6 alkyl; and

x is 1, 2 or 3;

one of X₃ and X₄ is N and the other is C; and

X₅ is N or CR wherein R is hydrogen, C_1-6 alkoxy, halo, C_1-6 alkyl or cyano; R₁ ^a is hydrogen, amino, halo, C_1-6 alkyl, hydroxy or C_1-6 alkoxy;

R₄ ^a and R₅ ^a are independently hydrogen or C_1-6 alkyl;

alkylsulphonyl, C_1-6 alkylsulphinyl, C_1-7 acyl, cyano, C_1-6 alkoxycarbonyl, C_1-7 acylamino, hydroxy, nitro or amino, aminocarbonyl, or aminosulphonyl, optionally N-substituted by one or two groups selected from C_1-6 alkyl, C_3-8 cycloalkyl, and C_3-8 cycloalkyl C_1-4 alkyl or disubstituted by C₄ or C₅ polymethylene; phenyl or phenyl C_1-4 alkyl group optionally substituted in the phenyl ring by one or two of halogen, C_1-6 alkoxy or C_1-6 alkyl groups; R₃ ^b is hydrogen, halo, C_1-6 alkyl, amino, nitro or C_1-6 alkyl;

R₄b is hydrogen, halo, C_1-6 alkyl or C_1-6 alkoxy;

X₆-X₇ is NR_z-CO or CR₁ ^cR₂ ^c-CR₃ ^cR₄ ^c where

R_z and R₁ ^c to R₄ ^c are independently hydrogen or C_1-6 alkyl; and/or

R_a ^c is hydrogen, halo, C_1-6 alkyl, amino, nitro or C_1-6 alkyl;

R_b ^c is hydrogen, halo, C_1-6 alkyl or C_1-6 alkoxy;

X^d is O, S, SO, SO₂, CH₂, CH, N or NR wherein R is hydrogen or C_1-6 alkyl;

A is a saturated or unsaturated polymethylene chain of 2 - 4 carbon atoms;

R₁d and R₂ ^d are hydrogen or C_1-6 alkyl;

R₃ ^d is hydrogen, halo, C_1-6 alkyl, amino, nitro or C_1-6 alkoxy;

R₄ ^d is hydrogen, halo, C_1-6 alkyl or C_1-6 alkoxy;

Y is O orNH;

Z is of sub-formula:

wherein

q is 0, 1, 2 or 3;

R_a is hydrogen, Cι_i2 alkyl, aralkyl or R_a is (CH2VR7 wherein z is 2 or 3 and R7 is selected from cyano, hydroxyl, Cj.g alkoxy, phenoxy, C(O)Cj.6 alkyl, COC6H5, -CONRgRg, NRgCOR9, SO2NRgR9 or NRgSO2R9 wherein Rg and R9 are hydrogen or Cμg alkyl; and

Rβ is hydrogen or C\.β alkyl; or a compound of formula (I) wherein the CO-Y linkage is replaced by a heterocyclic bioisostere.

2. A compound according to claim 1 wherein:

X₁-(CH₂)_x-X₂ moiety is O-(CH₂)₂-O, O-(CH₂)₃-O, O-CH₂-O, O-(CH₂)₂-

NR, O-(CH₂)₂-S or O-CH₂-CONR, wherein any of the methylene linkages are optionally mono- or di- substituted by C_1-6 alkyl groups; O-(CH₂)₂-CH₂,

O-(CH₂)₃-CH₂, O-CH₂-CH₂, or corresponding values wherein X₁ = X₂ = CH₂, wherein any of the methylene linkages are optionally mono- or di-substituted by C_1-6 alkyl groups;

R₁ ^a is hydrogen or amino;

R₂ ^a is hydrogen or halo;

R₃ ^a is hydrogen or halo;

R₄ ^a and R₅ ^a are hydrogen or methyl.

3. A compound according to claim 1 wherein:

R₁ ^b is CF₃ or an ethyl group;

X₅ is N, C-H or C-OCH₃;

R₃ ^b is hydrogen;

R₄ ^b is hydrogen or halo;

4. A compound according to claim 1 wherein:

X₆-X₇ is NH-CO or NEt-CO;

R_a ^c is hydrogen;

R_b ^c is hydrogen or halo;

5. A compound according to claim 1 wherein:

A is-CH2-(CH₂)_rCH₂- wherein r is 0, 1 or 2; -CH₂-CH=CH-; -C(CH₃)=CH- or when X^d is CH or N, A is -(CH₂)2-CH= or -CH=CH-CH=;

R₁ ^d and R₂ ^d are often hydrogen or R₁ ^d and R₂ ^d are gem-dimethyl;

r is 1;

R₃ ^d is hydrogen;

R₄ ^d is hydrogen or halo.

6. A compound according to any one of claims 1 to 5 wherein Z is 4-piperidinyl or 4-pyrτolidinyl, N-substituted by R_a as defined in claim 1.

7. A compound according to claim 6 wherein R_a is n-butyl.

8. 8-Amino-7-chloro-1,4-benzodioxan-5-(1-butyl-4-piperidinyl)carboxylate.

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8, and a pharmaceutically acceptable carrier.

10. A compound according to claim 1 for use as an active therapeutic substance.

11. The use of a compound according to claim 1 in the manufacture of a medicament for use as a 5-HT₄ receptor antagonist.

12. The use according to claim 11 for use as a 5-HT₄ receptor antagonist in the treatment or prophylaxis of gastrointestinal disorders, cardiovascular disorders and CNS disorders.