WO1997035861A1

WO1997035861A1 - Azaspiro derivatives

Info

Publication number: WO1997035861A1
Application number: PCT/EP1997/001403
Authority: WO
Inventors: Paul Adrian Wyman
Original assignee: Smithkline Beecham Plc
Priority date: 1996-03-27
Filing date: 1997-03-19
Publication date: 1997-10-02
Also published as: EP0889892A1; JP2000507253A

Abstract

Compounds of formula (I) where B is oxygen or sulphur, D is nitrogen or CH, E is oxygen, CR20R21 or NR22 with 5HT1B receptor antagonistic activity.

Description

AZASPIRO DERTVATTVES

The present invention relates to novel piperidine derivatives, processes for their preparation, and pharmaceutical compositions containing them.

EPA 0 533 266/7/8 disclose a series of benzanilide derivatives which are said to possess 5HT_1D receptor antagonist activity. PCT/EP/95/04889 discloses further 5HT_{1 D} receptor antagonists having a spiropiperidine structure. These compounds are said to be of use in the treatment of various CNS disorders. The 5HT_{1 D β} receptor has now been reclassified as the 5HT_{1 B} receptor (P.R Hartig et al Trends in Pharmacological Science, 1996, 17, 103 - 105.

A structurally distinct class of compounds have now been discovered and have been found to exhibit 5HT_{1 B} receptor antagonist activity. In a first aspect, the present invention therefore provides a compound of formula (I) or a salt or N-oxide thereof:

in which

R¹ is hydrogen, halogen, C_{1 -6}alkyl, C_3-6cycloalkyl, COC_{1 -6}alkyl, C_{1 -6}alkoxy, hydroxy, hydroxy C_{1 -6}alkyl, hydroxy C_{1 -6}alkoxy, C_{1 -6}alkoxyC_{1 -6}alk oxy, acyl, nitro,

trifluoromethyl, cyano, SR¹¹, SOR^{1 1}, SO₂R¹¹ , SO₂NR¹²R¹³, CO₂R¹², NR¹²SO₂R¹³,

CONR¹²R¹³, CO₂NR¹²R¹³, CONR¹²(CH₂)_pCO₂R¹³, (CH₂)_pNR¹²R¹³,

(CH₂)_pCONR¹²R¹³, (CH₂)_pNR¹²COR¹³, (CH₂)_pCO₂C_1-6alkyl, CO₂(CH₂)_pOR¹², CONHNR¹²R¹³, NR¹²R¹³, N=CNR ¹¹ NR¹²R¹³, NR¹²CO₂R¹³,

NR¹²CO(CH₂)_pNR¹²R¹³, NR¹²CONR¹²R¹³, CR¹²=NOR¹³, CNR¹²=NOR¹³, or NR¹⁴COR¹⁵ where R¹¹, R¹² and R¹³ are independently hydrogen or C _1-6alkyl, p is 1 to 4, R¹⁴ is hydrogen, C _1-6alkyl or is attached to the phenyl ring to form a group (CH₂)k where k is 2, 3 or 4 and R¹⁵ is hydrogen, C_1-6alkyl or optionally substituted aryl; or R¹ is an optionally substituted bicyclic heterocyclic ring or 5 to 7-membered monocyclic heterocyclic ring each containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur;

R² and R³ are independently hydrogen, halogen, C_{1 -6}alkyl, C_3-6cycloalkyl, C_3-6cycloalkenyl, C_{1 -6}alkoxy, hydroxyC_{1 -6}alkyl, C_{1 -6}alkylOC_{1 -6}alkyl, acyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO₂R¹², CONR¹²R¹³, NR¹²R¹³ where R¹² and R¹³ are independently hydrogen or C_{1 -6}alkyl, or R² and R³ together form a group -(CH₂)_r-R¹⁶-(CH₂)_s- where R¹⁶ is O, S, CH₂ or NR¹⁷ where R¹⁷ is hydrogen or C_{1 -6}aIkyl and r and s are independently 0, 1 or 2.

B is oxygen or sulphur;

D is nitrogen or a CH group;

R⁶ is hydrogen or C_{1 -6}alkyl and R⁷ is hydrogen, C_{1 -6}alkyl, C_{1 -6}alkoxy or halogen or R⁶ together with R⁷ forms a group -A- where A is (CR¹⁸R¹⁹)_t where t is 2, 3 or 4 and R¹⁸ and R¹⁹ are independently hydrogen or C_{1 -6}alkyl or A is (CR ¹⁸R ¹⁹)_u-J where u is 0, 1, 2 or 3 and J is oxygen, sulphur, CR¹⁸=CR¹⁹, CR¹⁸=N, =CR¹⁸O, =CR¹⁸S or

=CR¹⁸-NR¹⁹;

R⁸ is hydrogen, C_{1 -6}alkyl, C_3-6cycloalkyl, C_2-6alkenyl or

C_1-6alkylC_3-6cycloalkyl;

R⁹ and R¹⁰ are independently hydrogen or C_1-6alkyl ;

E is oxygen, CR²⁰R²¹ or NR²² where R²⁰, R²¹ and R²² are independently hydrogen or C_{1 -6}alkyl or E is S(O)_v where v is 0, 1 or 2;

G is C=O or CR²³R²⁴ where R²³ and R²⁴ are independently hydrogen or C_1-6alkyl;

X and Y are independently CR⁹R¹⁰ where R⁹ and R¹⁰ are as defined above; and m is 1, 2 or 3.

C_1-6alkyl groups, whether alone or as part of another group, may be straight chain or branched. As used herein the term aryl includes phenyl and naphthyl. Heteroaryl groups include thienyl, furyl, pyridyl, pyrimidyl and pyrazinyl groups. Optional substituents for aryl and heteroaryl groups include those groups listed above for R²/R³.

Suitably R¹ is hydrogen, halogen, C_1-6alkyl, C_3-6cycloalkyl, COC_1-6alkyl,

C_1-6alkoxy, hydroxy, hydroxyC_{1 -6}alkyl, hydroxyC_1-6alkoxy, C_1-6alkoxyC_1-6alkoxy, acyl, nitro, trifluoromethyl, cyano, SR^{1 1}, SOR¹¹, SO₂R¹¹, SO₂NR¹²R¹³, CO₂R¹²,

NR¹²SO₂R¹³, CONR¹²R¹³, CO₂NR¹²R¹³, CONR¹²(CH₂)_pCO₂R¹³,

(CH₂)pNR¹²R¹³, (CH₂)pCONR¹²R¹³, (CH₂)_pNR¹²COR¹³, (CH₂)_pCO₂C_1-6alkyl, CO₂(CH₂)_pOR¹², CONHNR¹²R¹³, NR¹²R¹³, N-CNRHNR ¹²R¹³, NR¹²CO₂R¹³,

NR¹²CO(CH₂)pNR¹²R¹³, NR¹²CONR¹²R¹³, CR¹²=NOR¹³, CNR¹²=NOR¹³, or

NR¹⁴C0R¹⁵ where R^{1 1}, R¹² and R¹³ are independently hydrogen or C_1-6alkyl, p is 1 to

4, R¹⁴ is hydrogen, C_{1 -6}alkyl or is attached to the phenyl ring to form a group (CH₂)k where k is 2, 3 or 4 and R¹⁵ is hydrogen, C_{1 -6}alkyl or optionally substituted aryl; or R¹ is an optionally substituted bicyclic heterocyclic ring or 5 to 7-membered monocyclic heterocyclic ring each containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur. When R¹ is an optionally substituted bicyclic heterocyclic ring or 5 to 7- membered monocyclic heterocyclic ring each containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur said groups can be saturated, partially saturated or aromatic. The R¹ groups can be linked to the remainder of the molecule via a carbon atom or, when present, a nitrogen atom. Suitable aromatic groups include thienyl, furyl, pyrrolyl, triazolyl, diazolyl, imidazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyrimidyl and pyrazinyl. Suitable saturated and partially saturated groups include those having an oxo or thioxo moiety such as lactams and thiolactams. Preferred groups of this type are lactams of formula (a):

where a is 1, 2 or 3. Preferably a is 1 or 2, forming a 5- or 6-membered ring, most preferably a is 1. Other preferred lactam groups include bicyclic rings of formula (b):

where a is 1 or 2, preferably where a is 1.

Preferably R¹ is an optionally substituted oxadiazolyl or 2-oxopyrrolidin-1-yl ring, more preferably R¹ is oxadiazolyl substituted by C_{1 -6}alkyl, most preferably a 5- methyl-1,2,4-oxadiazol-3-yl group.

Suitably R² and R³ are independently hydrogen, halogen, C_{1 -6}alkyl,

C_3-6cycloalkyl, C_3-6cycloalkenyl, C_{1 -6}alkoxy, hydroxy C_{1 -6}alkyl, C_{1 -6}alkylOC_{1 -6}alkyl, acyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO₂R^{1 1}, CONR¹²R¹³,

NR¹²R¹³ where R^{1 1}, R¹² and R¹³ are independently hydrogen or C _1-6alkyl, or R² and R³ together form a group -(CH₂)r-R¹⁴-(CH₂)s- where R¹⁴ is O, S, CH₂ or NR¹⁵ where R¹⁵ is hydrogen or C_1-6alkyl and r and s are independently 0, 1 or 2.

Preferably R² is C_1-6alkyl. Preferably the R² group is ortho with respect to the biphenyl linkage. Most preferably R² is methyl. Preferably R³ is hydrogen.

Suitably B is oxygen or sulphur. Preferably B is oxygen.

Suitably D is nitrogen or a CH group. Preferably D is nitrogen. Suitably R⁶ is hydrogen or C_{1 -6}alkyl and R⁷ is hydrogen, C_{1 -6}alkyl, C_1-6alkoxy or halogen or R⁶ together with R⁷ forms a group -A- where A is (CR¹⁸R¹⁹)_t where t is 2, 3 or 4 and R¹⁸ and R¹⁹ are independently hydrogen or C_{1 -6}alkyl or A is (CR¹⁸R¹⁹)_U-J where u is 0, 1, 2 or 3 and J is oxygen, sulphur, CR¹⁸=CR¹⁹, CR¹⁸=N, =CR¹⁸O, =CR¹⁸S or =CR¹⁸-NR¹⁹. Preferably R⁶ and R⁷ are both hydrogen.

Suitably R⁸ is hydrogen, C_{1 -6}alkyl or C_3-6cycloa.kyl. Preferably R⁸ is C_1- 6alkyl, most preferably R⁸ is methyl. Preferably m is 2 forming a spiro-piperidine ring, Suitably B is oxygen or sulphur, preferably B is oxygen.

Suitably R⁹ and R¹⁰ are independently hydrogen or C_1-6alkyl. Preferably R⁹ and R¹⁰ are both hydrogen.

Suitably E is oxygen, CR²⁰R²¹ or NR²² where R²⁰, R²¹ and R²² are independently hydrogen or C_{1 -6}alkyl or E is S(O)_v where v is 0, 1 or 2. Preferably E is oxygen.

Suitably G is C=O or CR²³R²⁴ where R²³ and R²⁴ are independently hydrogen or C_{1 -6}alkyl. Preferably G is CH₂.

Suitably X and Y are independently CR⁹R¹⁰ where R⁹ and R¹⁰ are as defined above. Preferably X and Y are both CH₂.

Particularly preferred compounds of the invention include:

N-[2'-Methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]-2,3-dihydro-1'- methylspiro[benzofuran-3,4'-piperidine]-5-carboxamide,

N-[2'-Methyl-4'-(2-oxopyrrolidin-1-yl)biphenyl-4-yl]-2,3-dihydro-1'-methylspiro

[benzofuran-3,4'-piperidine]-5-carboxamide,

or pharmaceutically acceptable salts thereof.

Preferred salts of the compounds of formula (I) are pharmaceutically acceptable salts. These include acid addition salts such as hydrochlorides, hydrobromides, phosphates, acetates, fumarates, maleates, tartrates, citrates, oxalates, methanesulphonates and p-toluenesulphonates.

Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and the mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the invention.

In a further aspect the present invention provides a process for the preparation of a compound of formula (I) which comprises.

for compounds of formula (I) where D is nitrogen, B is oxygen and R⁶ is hydrogen or C_{1 -6}alkyl, reaction of a compound of formula (II):

in which R¹, R², R³ are groups as defined in formula (I) or protected derivatives thereof and R⁶ is hydrogen or C_1-6 alkyl with a compound of formula (III):

wherein R⁷, R⁸, R⁹, R¹⁰, E, G, X, Y, m and n are groups as defined in formula (I) or protected derivatives thereof, and optionally thereafter in any order:

• removing any protecting groups,

• converting a compound of formula (I) into another compound of formula (I),

• forming a pharmaceutically acceptable salt.

Suitable activated carboxylic acid derivatives of formula (III) include acyl halides and acid anhydrides. Activated compounds of formula (III) can also be prepared by reaction of the corresponding carboxylic acid with a coupling reagent such as

carbonyldiimidazole, dicyclohexylcarbodiimide or diphenylphosphorylazide.

Compounds of formulae (II) and (III) are typically reacted together in an inert organic solvent such as DMF, THF or dichloromethane at ambient or elevated temperature in the presence of a base such as an alkali metal hydroxide, triethylamine or pyridine.

Alternatively compounds of formula (II) can be reacted with compounds of formula (III) where L is an ester forming group in the presence of an organo-aluminium reagent such as trimethylaluminium. Such a reaction is typically carried out in the presence of an inert solvent such as toluene.

Intermediate compounds of formula (II) and (III) can be prepared using standard procedures known in the art. Certain intermediate compounds of formula (II) and (III) are novel and form a further aspect of the invention.

It will be appreciated to those skilled in the art that it may be necessary to protect certain reactive substituents during some of the above procedures. Standard protection and deprotection techniques can be used such as those described in Greene T.W. 'Protective groups in organic synthesis' New York, Wiley (1981). For example, primary amines can be protected as phthalimide, benzyl, benzyloxycarbonyl or trityl derivatives. These groups can be removed by conventional procedures well known in the art.

Carboxylic acid groups can be protected as esters. Aldehyde or ketone groups can be protected as acetals, ketals, thioacetals or thioketals. Deprotection is achieved using standard conditions.

5HTJB receptor antagonists, and in particular the compounds of the present invention, are expected to be of use in the treatment of CNS disorders such as mood disorders, including depression, seasonal affective disorder and dysthymia; anxiety disorders, including generalised anxiety, panic disorder, agoraphobia, social phobia, obsessive compulsive disorder and post-traumatic stress disorder; memory disorders, including dementia, amnestic disorders and age-associated memory impairment; and disorders of eating behaviours, including anorexia nervosa and bulimia nervosa. Other CNS disorders include motor disorders such as Parkinson's disease, dementia in

Parkinson's disease, neuroleptic-induced Parkinsonism and tardive dyskinesias, as well as other psychiatric disorders.

5HTiβ receptor antagonists, and in particular compounds of the present invention, may also be of use in the treatment of endocrine disorders such as hyperprolactinaemia, in the treatment of vasospasm (particularly in the cerebral vasculature) and hypertension, as well as disorders in the gastrointestinal tract where changes in motility and secretion are involved. They may also be of use in the treatment of sexual dysfunction and

hypothermia.

Therefore, the present invention provides a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in therapy.

The present invention also provides a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in the treatment of the

aforementioned disorders.

In another aspect the invention provides the use of a compound of general formula (I) or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of the aforementioned disorders.

In a further aspect the invention provides a method of treating the aforementioned disorders which comprises administering an effective amount to a patient in need of such treatment of a compound of general formula (I) or a pharmaceutically acceptable salt or solvate thereof.

In particular the invention provides a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in the treatment or prophylaxis of depression. It will be appreciated by those skilled in the art that the compounds according to the invention may advantageously be used in conjunction with one or more other therapeutic agents, for instance, different antidepressant agents.

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

A pharmaceutical composition of the invention, which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusible solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.

Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents. The tablets may be coated according to methods well known in normal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of 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, if desired, conventional flavourings or colorants.

For parenteral administration, fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are 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 sterilisation cannot be

accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

The composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration. The dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. However, as a general guide suitable unit doses may be 0.05 to 1000 mg, more suitably 1.0 to 200 mg, and such unit doses may be administered more than once a day, for example two or three a day. Such therapy may extend for a number of weeks or months.

The following Examples illustrate the preparation of compounds of the invention.

Description 1

Ethyl 3-bromo-4-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)methoxybenzoate

A stirred solution of ethyl 3-bromo-4-hydroxybenzoate (5.0g, 0.020 mole), 1-methyl- 1,2,5,6-tetrahydroρyrid-4-ylmethanol (2.67g, 0.021 mole; J. Med. Chem. 1988, 31, 545) and triphenylphosphine (5.5g, 0.021 mole) in dry THF (150ml) at room temp, under argon was treated dropwise over 10 minutes with a solution of diethyl azodicarboxylate (3.3ml, 0.021 mole) in THF (15ml). The reaction mixture was stirred at room temp, for 2 hours, then concentrated in vacuo. The residue was treated with ethyl acetate (150ml) and 2M HCI (150ml), shaken well, and the acid layer separated, basified by addition of solid K₂CO₃, then extracted with ethyl acetate. The extract was dried (Na₂SO₄), concentrated in vacuo and the residue purified by chromatography on silica gel eluting with 0-20% methanol/ethyl acetate to afford the title compound as a beige solid (3.34g, 47%). ¹H NMR (250MHz, CDCl₃) δ (ppm): 8.22 (d, 1H), 7.95 (dd, 1H), 6.90 (d, 1H), 5.84

(brs, 1H), 4.55 (s, 2H), 4.35 (q, 2H), 3.00 (brs, 2H), 2.59 (t, 2H), 2.37 (s, 3H), 2.40 - 2.25 (m, 2H), 1.38 (t, 3H).

Description 2

Ethyl 2,3-dihydro- 1'-methyIspiro[benzofuran[3,4']piperidine]-5-carboxylate

A stirred solution of ethyl 3-bromo-4-(l-methyl-1,2,5,6-tetrahydropyrid-4- yl)methoxybenzoate (D1, 3.32g, 0.0094 mole) in toluene (180ml) at 80°C under argon was treated dropwise over 40 minutes with a solution of tributyltin hydride (3.76ml, 0.014 mole) and AIBN (250mg) in toluene (60ml). The reaction mixture was heated at 80°C for a further 1.5 hours, then allowed to cool and concentrated in vacuo. The residue was treated with 1M HCI (100ml) and ethyl acetate (100ml), shaken well and the acid layer separated, basified with K ₂CO₃ and extracted with ethyl acetate. The extract was dried (Na₂SO₄) and concentrated under vacuum to afford the title compound as a beige solid (2.08g, 81%). 1H NMR (200MHz, CDCl₃) 5 (ppm): 7.90 (dd, 1H), 7.84 (d, 1H), 6.80 (d, 1H), 4.45

(s, 2H), 4.33 (q, 2H), 2.95 - 2.80 (m, 2H), 2.33 (s, 3H), 2.10 - 1.90 (m, 4H), 1.85 - 1.65 (m, 2H), 1.37 (t, 3H). Description 3

2'-Methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-amine

2'-Methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carboxylic acid (EP

0533268A1) (5.0g, 0.017 mole) was treated with thionyl chloride (60 ml) and

stirred at room temperature for 3 hours, then concentrated in vacuo to give the

acid chloride as a pale yellow solid. This material was dissolved in

dichloromethane (150 ml), cooled to 0°C, then treated with tetrabutylammonium bromide (50mg) and a solution of sodium azide (1.45g, 0.022 mole) in water (25 ml), then stirred vigorously at 0°C for 1.75 hours. The mixture was diluted with water (100 ml) and the dichloromethane layer was separated, dried (Na₂SO₄) and treated with trifluoroacetic acid (2.03 ml, 0.026 mole) and heated under reflux, with stirring, for 20 hours. The reaction mixture was concentrated in vacuo to

leave the trifluoroacetamide as an orange solid. This was treated with 2% NaOH solution (200 ml), methanol (200 ml) and dichloromethane (200 ml) and the

resulting solution was stirred and heated under reflux for 12 hours. The mixture was concentrated in vacuo to remove the organic solvents and the aqueous residue extracted with dichloromethane. The extract was dried (Na₂SO₄), concentrated in vacuo and the residue chromatographed on silica gel eluting with 50-100%

ether/60.80 petrol to afford the title compound as a white solid (2.26, 50%). 1H NMR (200MHz, CDCl₃) δ (ppm): 7.96 (s, 1H), 7.90 (dd, 1H), 7.32 (d,

1H), 7.17 (d, 2H), 6.75 (d, 2H), 3.75 (br s, 2H), 2.67 (s, 3H), 2.37 (s, 3H). Description 4

Propyl 2,3-dihydro-1' -methylspiro[benzofuran-3,4'-piperidine]-5-carboxylate

The title compound was prepared from propyl 3-bromo-4-hydroxybenzoate by similar procedure to the corresponding ethyl ester (D1 and 2). 1H NMR (250 MHz, CDCI₃) δ (ppm): 7.92 (dd, 1H), 7.85 (d, 1H), 6.80 (d, 1H), 4.45 (s, 2H), 4.22 (t, 2H), 2.95-2.85 (m, 2H), 2.34 (s, 3H), 2.10-1.96 (m, 4H), 1.85-1.70 (m, 4H), 1.13 (t, 3H). Description 5

1-(4-Bromo-3-methyIphenyl)pyrrolidin-2-one

A stirred solution of 4-bromo-3-methylaniline (50.3g, 0.27 mole) and triethylamine (41.1 ml, 0.30 mole) in THF (250 ml) at 0°C under argon was treated dropwise with 4- chlorobutyryl chloride (33.4 ml, 0.30 mole). The mixture was stirred for 1 hour at 0-5°C, then potassium t-butoxide (82.5g, 0.74 mole) was added portionwise over 20 minutes, maintaining temperature below 25°C. The reaction mixture was stirred at 25°C for a further 2.5 hrs, then treated with water (100 ml), followed after 0.25 hrs with 10%

Na₂CO₃ solution and then extracted with ethyl acetate. The extract was washed with water, dil. HCI acid, then brine, dried (Na₂SO₄) and concentrated in vacuo to afford the title compound as a pale yellow solid (61.6g, 89%).

¹H NMR (250 MHz, CDCl₃) δ (ppm): 7.54 (d, 1H), 7.48 (d, 1H), 7.30 (dd, 1H), 3.82 (t, 2H), 2.58 (t, 2H), 2.40 (s, 3H), 2.16 (quintet, 2H).

Description 6

2'-Methyl-4'-(2-oxopyrrolidin-1-yl)biphenyl-4-carboxylic acid A stirred mixture of 1-(4-bromo-3-methylphenyl)pyrrolidin-2-one (D5, 50g, 0.20 mole) and 4-boronobenzoic acid (32g, 0.20 mole) in DME (500 ml) was treated with a solution of sodium carbonate (94g, 0.88 mole) in water (500 ml), then de-gassed by bubbling argon through for 0.25 hrs. Tetrakis (triphenylphosphine)palladium (0) (5g) was added and the mixture heated under reflux for 22 hours, then allowed to cool and concentrated in vacuo to approx. 50% volume. The aqueous residue was diluted with water to approx. 1000 ml, washed with ethyl acetate, then acidified with cone. HCI acid. The precipitate was filtered off, washed with water, dried and recrystallised from ethanol to afford the title compound as a cream solid (30.3g, 52%). ¹H NMR (250 MHz, d⁶DMSO) δ (ppm): 8.01 (d, 2H), 7.67-7.58 (m, 2H), 7.49 (d, 2H), 7.25 (d, 1H), 3.86 (t, 2H), 2.52 (t, 2H), 2.25 (s, 3H), 2.09 (quintet, 2H). Description 7

2'-Methyl-4^,-(2-oxopyrrolidin-1-yl)biphenyl-4-amine

The title compound was prepared from 2'-methyl-4'-(2-oxopyrrolidin-1-yl)biphenyl-4- carboxylic acid (D6) using a similar procedure to Description 3, except that sodium carbonate was used in place of sodium hydroxide in the final hydrolysis step.

¹H NMR (250 MHz, CDCl₃) δ (ppm): 7.49 (s, 1H), 7.41 (dd, 1H), 7.22 (d, 1H), 7.10 (d, 2H), 6.73 (d, 2H), 3.89 (t, 2H), 3.7 (br, 2H), 2.62 (t, 2H), 2.30 (s, 3H), 3.7 (br, 2H), 2.26- 2.08 (m, 2H).

Example 1

N-[2'-Methyl-4'-(5-methyl-1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]-2,3-dihydro-

1'-methylspiro[benzofuran-3,4'-piperidine]-5-carboxamide

A stirred solution of 2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4- amine (D3, 390mg, 1.4 mmole) in toluene (30 ml) at room temperature under

argon was treated with 2M trimethylaluminium in toluene (0.87 ml, 1.7 mmole).

After 15 minutes, the solution was treated with a solution of ethyl 2,3-dihydro-l'- methylspiro[benzofuran[3,4']piperidine]-5-carboxylate (D2, 400mg, 1.4 mmole) in toluene (15 ml) and heated under reflux for 1.5 hours. The reaction mixture was allowed to cool, then poured into a stirred slurry of silica gel (15 g) in

dichloromethane (30 ml). When effervescence had ceased, the slurry was packed into a chromatography column and eluted with 10% methanol/chloroform to

afford the title compound as a pale yellow oil (136mg, 20%). This was converted to its hydrochloride salt, which crystallised as a white solid from acetone. 1H NMR (free base) (250MHz, CDCl₃) δ (ppm): 7.98 (s, 1H), 7.93 (d, 1H),

7.85 (s, 1H), 7.75 - 7.65 (m, 4H), 7.40 - 7.30 (m, 3H), 6.88 (d, 1H), 4.48 (s, 2H), 2.95 - 2.80 (m, 2H), 2.68 (s, 3H), 2.35 (s, 3H), 2.33 (s, 3H), 2.15 - 1.95 (m, 4H), 1.85 - 1.70 (m 2H). Example 2

N-[2'-Methyl-4'-(2-oxopyrrolidin-1-yl)biphenyl-4-yl]-2,3-dihydro-1'-methylspiro

[benzofuran-3,4'-piperidinel-5-carboxamide

2'-Methyl-4'-(2-oxopyrrolidin-1-yl)biphenyl-4-amine (D7, 276 mg, 1.05 mmole) was reacted with propyl 2,3-dihydro- 1'-methylspiro[benzofuran-3,4'-piperidine]-5-carboxylate (D4, 300 mg, 1.04 mmol) by a similar procedure to that described in Example 1 to afford the title compound as a dark beige solid (22%). This was converted to the hydrochloride salt which crystallised from acetone as a beige solid.

¹H NMR (free base) (250 MHz, CDCl₃) δ (ppm): 7.90 (s, 1H), 7.74 (s, 1H), 7.70 (d, 1H), 7.66 (d, 2H), 7.53 (d, 1H), 7.45 (dd, 1H), 7.36-7.15 (m, 3H), 6.86 (d, 1H), 4.47 (s, 2H), 3.90 (t, 2H), 2.99-2.80 (m, 2H), 2.63 (t, 2H), 2.36 (s, 3H), 2.31 (s, 3H), 2.27-1.95 (m, 6H), 1.90-1.66 (m, 2H).

Claims

CLAIMS:

1. A compound of formula (I) or a salt or N-oxide thereof:

in which

R¹ is hydrogen, halogen, C_{1 -6}alkyl, C_3-6cycloa.kyl, COC_{1 -6}alkyl, C_{1 -6}alkoxy, hydroxy, hydroxyC_{1 -6}alkyl, hydroxyC_{1 -6}alkoxy, C_{1 -6}alkoxy C_{1 -6}alkoxy, acyl, nitro,

trifluoromethyl, cyano, SR¹¹, SOR¹¹, SO₂R^{1 1}, SO₂NR¹²R¹³, CO₂R¹², NR¹²SO₂R¹³,

(CH₂)_pCONR¹²R¹³, (CH₂)_pNR¹²COR¹³, (CH₂)_pCO₂C_1-6alkyl, CO₂(CH₂)_pOR¹², CONHNR¹²R¹³, NR¹²R¹³, N=C NR ¹¹NR ¹²R¹³, NR¹²CO₂R¹³,

NR¹²CO(CH₂)_pNR¹²R¹³, NR1²C0NR¹²R¹³, CR¹²=NOR¹³, CNR¹²=NOR¹³, or NR¹⁴COR¹⁵ where R¹¹, R¹² and R¹³ are independently hydrogen or C_{1 -6}alkyl, p is 1 to 4, R¹⁴ is hydrogen, C_{1 -6}alkyl or is attached to the phenyl ring to form a group (CH₂)k where k is 2, 3 or 4 and R¹⁵ is hydrogen, C_1-6alkyl or optionally substituted aryl; or R¹ is an optionally substituted bicyclic heterocyclic ring or 5 to 7-membered monocyclic heterocyclic ring each containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur;

R² and R³ are independently hydrogen, halogen, C_1-6alkyl, C_3-6cycloalkyl,

C_3-6cycloalkenyl, C_{1 -6}alkoxy, hydroxyC_1-6al kyl, C_{1 -6}alkylOC_{1- 6}alkyl, acyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO₂R¹², CONR ¹²R¹³, NR¹²R¹³ where R¹² and R¹³ are independently hydrogen or C_1-6 alkyl, or R² and R³ together form a group -(CH₂)_r-R¹⁶-(CH₂)_s- where R¹⁶ is O, S, CH₂ or NR¹⁷ where R¹⁷ is hydrogen or C_1-6alkyl and r and s are independently 0, 1 or 2.

B is oxygen or sulphur;

D is nitrogen or a CH group;

R⁶ is hydrogen or C_{1 -6}alkyl and R⁷ is hydrogen, C_{1 -6}alkyl, C_{1 -6}alkoxy or halogen or R⁶ together with R⁷ forms a group -A- where A is (CR¹⁸R¹⁹)_t where t is 2, 3 or 4 and R¹⁸ and R¹⁹ are independently hydrogen or C_{1 -6}alkyl or A is (CR¹⁸R¹⁹)_U-J where u is 0, 1, 2 or 3 and J is oxygen, sulphur, CR¹⁸=CR¹⁹, CR¹⁸=N, =CR¹⁸O, =CR¹⁸S or =CR¹⁸-NR¹⁹;

R⁸ is hydrogen, C_{1 -6}alkyl, C_3-6cycloal kyl, C_2-6alkenyl or

C_{1 -6}alkylC_3-6cycloalkyl;

R⁹ and R¹⁰ are independently hydrogen or C_{1 -6}alkyl;

G is C=O or CR²³R²⁴ where R²³ and R²⁴ are independently hydrogen or C _1-6alkyl; X and Y are independently CR⁹R¹⁰ where R⁹ and R^{1 0} are as defined above; and m is 1 , 2 or 3.

2. A compound according to claim 1 in which R¹ is optionally substuituted oxadiazolyl or 2-oxopyrrolidin-1-yl.

3. A compound according to claim 1 or 2 in which R² is C_{1 -6}alkyl and R³ is hydrogen.

4. A compound according to any one of claims 1 to 3 in which m is 2.

5. A compound according to any one of claims 1 to 4 in which R⁸ is C_1-6alkyl.

6. A compound according to any one of claims 1 to 5 in which X and Y are both CH₂.

7 A compound according to claim 1 which is:

N-[2'-Methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]-2,3-dihydro-1'- methylspiro[benzofuran-3,4'-piperidinel-5-carboxamide,

N-[2'-Methyl-4'-(2-oxopyrrolidin-1-yl)biphenyl-4-yl]-2,3-dihydro- 1' -methylspiro

[benzofuran-3,4'-piperidine]-5-carboxamide,

or pharmaceutically acceptable salts or N-oxides thereof.

8. A process for the preparation of a compound of formula (I) which comprises:

(a) for compounds of formula (I) where D is nitrogen, B is oxygen and R⁶ is hydrogen or C_{1 -6}alkyl, reaction of a compound of formula (II):

in which R¹, R², R³ are groups as defined in formula (I) or protected derivatives thereof and R⁶ is hydrogen or C_{1 -6}alkyl with a compound of formula (III):

• removing any protecting groups,

• converting a compound of formula (I) into another compound of formula (I),

• forming a pharmaceutically acceptable salt.

9. A compound according to any one of claims 1 to 7 for use in therapy.

10. A pharmaceutical composition which comprises a compound according to any one of claims 1 to 7 in association with a pharmaceutically acceptable carrier or excipient.