EP1104413A2

EP1104413A2 - Piperidine and piperazine derivatives, process for their preparation and pharmaceutical compounds containing them

Info

Publication number: EP1104413A2
Application number: EP99936874A
Authority: EP
Inventors: Stephen Richard Baker; David Bleakman; John Goldsworthy; Patric James Hahn; Gunnar Erik Jagdmann; Shelley Hunnings Turkington
Original assignee: Eli Lilly and Co Ltd; Eli Lilly and Co
Current assignee: Eli Lilly and Co Ltd; Eli Lilly and Co
Priority date: 1998-08-07
Filing date: 1999-08-04
Publication date: 2001-06-06
Also published as: WO2000008006A3; AU5184599A; GB9817197D0; WO2000008006A2; CA2305406A1; JP2003510244A

Abstract

A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically-acceptable salt or ester thereof in which X, R?1, R2, R3, R4, R5 and R6¿ have the meanings given in the specification, is useful in the treatment of diseases of the central nervous system. The invention further relates to a compound of formula (I) or a pharmaceutically-acceptable salt or ester thereof useful in the treatment of diseases of the central nervous system.

Description

PHARMACEUTICAL COMPOUNDS

This invention relates to novel chemical compounds and their use as pharmaceuticals.

It is well known that excitatory neurotransmission in the mammalian central nervous system is primarily mediated by the amino acid, L-glutamate, acting on ionotropic and metabotropic receptors, and compounds that modify neurotransmission by interaction with these receptors are of interest for their potential use in the treatment of disorders of the central nervous system.

This invention relates to a pharmaceutical composition comprising a compound of formula I,

(I)

in which X is N or C, where X is C it can be bonded to its adjacent carbon by either a single or a double bond;

R^x and R2 are each independently H or Cι__g alkyl or ^ -ζ alkenyl or C3_]_Q cycloalkyl, or R1 and R^ together with the nitrogen atom to which they are attached combine to form a saturated heterocyclic ring of 4-10 atoms;

R³ and R⁴ are each independently H or Cι__ alkyl or C3_ι_o cycloalkyl, R^ and R^ together with the carbon atom to which they are attached combine to form a C₄_₁₀ carbocyclic ring;

R5 and R^ are each independently H or Cι_₆ alkyl, Cι-6 alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl , nitro, a ino, Cι_₄ acyla ino and Cι_₆ alkylthio, Cι-₆ alkylsulphone, or halo Cι_₆ alkylsulphone;

or a pharmaceutically-acceptable salt or ester thereof.

The compounds of the invention have been found to be active in tests indicative of their use in the treatment of diseases of the central nervous system such as neurological diseases, for example, neurodegenerative diseases, and as antipsychotic, anticonvulsant, analgesic and anti-emetic agents.

In the above general formula, a Cχ_₆ alkyl group can be straight or branched chain, such as, for example, methyl, ethyl, propyl , isopropyl, butyl and isobutyl, and is preferably methyl. A C₃_₆ alkenyl group includes, for example, vinyl, prop-2-enyl, but-3-enyl, pent-4-enyl and isopropenyl, and an alkenyl group can contain more than one double bond and, in addition, one or more triple bonds. A preferred alkenyl group is of the formula R'-CH=CH- where R' is Cχ-₄ alkyl.

A c₃_ιo cycloalkyl group is preferably, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and these groups may optionally be substituted by one or two Cι-₆ alkyl, for example methyl, substituents , or can be a bicyclo-system as, for example, bicyclooctane .

A saturated heterocyclic ring of 4-10 atoms includes, a ring containing a further heteroatom in addition to the nitrogen to which they are attached, such as nitrogen and oxygen, for example, piperidino or morpholino.

A halo Cι_₆ alkylsulphone includes a Cι_₆ alkylsulphone substituted with halo atoms, for example trifluoromethylsulphone, or perfluoroethylsulphone .

A preferred group of compounds according to formula (I) is one in which R^ and R^ are independently trifluoromethyl or halo, especially bromo, chloro and fluoro, preferably when they are in position 3 and 4 in the phenyl ring. Another preferred group is one which R^ and R^ are methyl Particularly preferred compounds are compounds wherein R^ is H or Cχ_₃ alkyl, R² is H, R³ and R⁴ are methyl, R⁵ and R are Chloro .

Even more particularly preferred compounds are

4- [ (1-n-Propylcarbamoyl-l-Methyl) Ethyl] -1- (3, 4- Dichlorophenyl) Piperazine,

4-[ (1-carbamoyl-l-methyl) Ethyl] -1- (3, 4-

Dichloropheny1 ) Piperazine ,

1- [ ( 1-carbamoyl-l-methyl) Ethyl] -4- (3 , 4-Dichlorophenyl) -

1,2,5,6, -Tetrahydropyridine , especially,

4- [ (1-carbamoyl-l-methyl) Ethyl] -1- (3,4-

Dichlorophenyl) Piperazine and,

1- [ (1-carbamoyl-l-methyl) Ethyl] -4- (3 , 4-Dichlorophenyl) -

1,2,5,6, -Tetrahydropyridine .

US 4,457,931 describes a phenylpiperazine of formula (I) as an intermediate in a process for making anticholinergic agents and/or antihistamines .

A further aspect of the invention relates to a compound of formula (I)

(I) in which

X is N or C, where X is C it can be bonded to its adjacent carbon by either a single or a double bond;

R! and R² are each independently H or Cχ_g alkyl or C3_g alkenyl or C3__]__Q cycloalkyl, or R^ and R² together with the nitrogen atom to which they are attached combine to form a saturated heterocyclic ring of 4-10 atoms;

R³ and R⁴ are each independently H or C]__g alkyl or C3-.10 cycloalkyl, R³ and R⁴ together with the carbon atom to which they are attached combine to form a C carbocyclic ring;

R5 and R^ are each independently H or Cχ-₆ alkyl, Cχ-6 alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl , nitro, amino, Cχ-₆ acylamino and Cι-6 alkylthio, Cι_-6 alkylsulphone, or halo Cι_₆ alkylsulphone;

or a pharmaceutically-acceptable salt or ester thereof, for use as a pharmaceutical .

Some of the compounds of formula (I) are new. Accordingly, in a further aspect of the invention there are provided compounds of formula (I) as defined above, with the exception of those in which, R¹ and R² together with the nitrogen atom to which they are attached form a morpholino group, R³ and R⁴ are methyl, X is N, and R⁵ and R⁵ are H,

or salt thereof .

It will also be understood that salts of the compounds of the invention can be prepared and such salts are included in the invention. They can be any of the well known acid addition salts. Acid addition salts are preferably the pharmaceutically-acceptable, non-toxic addition salts with suitable acids, such as those with inorganic acids, for example hydrochloric, hydrobromic, nitric, sulphuric or phosphoric acids, or with organic acids, such as organic carboxylic acids, for example glycollic, maleic, fumaric, malic, tartaric, citric, salicyclic or o-acetoxybenzoic acids, or organic sulphonic acids, methane sulphonic, 2-hydroxyethane sulphonic, toluene-p-sulphonic or naphthalene-2 -sulphonic acids,

In addition to pharmaceutically-acceptable salts, other salts are included in the invention. They may serve as intermediates in the purification of compounds or in the preparation of other, for example pharmaceutically- acceptable, salts, or are useful for identification, characterisation or purification. It will be appreciated that the compounds of the invention can contain an asymmetric carbon atom as indicated by the asterisk in formula (I), and this gives rise to enantiomers . The compounds can be prepared as racemates or as enantiomers, and individual enantiomers can be isolated from racemates by conventional techniques if so desired. Such racemates and individual enantiomers form part of the present invention.

The invention also includes a process for the production of compounds of the invention, which comprises a Strecker reaction of an arylpiperazine or piperidine ring with the corresponding cyanohydrin to give compound of formula (IV) , where X, R³ , R⁴, R⁵ and R⁶ have the meaning given above, followed by elaboration of the side chain by partial hydrolysis of the corresponding nitrile with for example, hydrogen peroxide and an aqueous sodium hydroxide; or by hydrolysis to the acid of formula (V) followed by dehydrative coupling of the corresponding acid and amine with for example, 1- (3-dimethylaminopropyl) -3- ethylcarbodiimide hydrochloride.

(IV) (V) The present invention also provides novel intermediates of formula IV and V.

According to a further aspect of the invention the compounds described above have pharmaceutical activity. They have been shown to possess affinity for glutamate receptors .

Excitatory amino acid or glutamate receptors are subdivided into two types, ionotropic and metabotropic .

Ionotropic glutamate receptors are intrinsic ligand gated ion channels that are composed of multiple subunit proteins forming multimeric complexes . Ionotropic glutamate receptors are selectively activated by the agonists N-methyl-D-asparate, AMPA, and kainate (Sommer B. And Seeburg P.H., Trends Pharmacol. Sci. 13: 291-296, 1993). Metabotropic glutamate receptors are a family of G-protein coupled receptors with novel molecular structure that are coupled to increases in phosphoinositide hydrolysis and decreases in cAMP formation.

(Schoepp D. D. And Conn J. P., Trends Pharmacol. Sci. 14: 13-20, 1993) .

The compounds of the present invention are active in a screen for activity in ionotropic receptors as described in more detail below. (Example 12) The compounds of the invention are thus indicated for use in the treatment of neurological disorders such as acute neurodegenerative diseases, for example stroke, cerebral ischaemia and head and spinal cord trauma, and chronic neurodegenerative diseases such as, for example,

Alzheimer's disease, Parkinson's disease, Amyotropic lateral sclerosis, AIDS-induced dementia and Huntington's Chorea. The compounds are also indicated for use as antipsychotic, anticonvulsant, analgesic and anti-emetic agents . They are also of potential use as anxiolytic and antidepressant agents .

The invention also includes a pharmaceutical composition comprising a pharmaceutically-acceptable diluent or carrier in association with a compound of formula (I) , or a pharmaceutically-acceptable salt thereof.

The compounds may be administered by various routes, for example, by the oral or rectal route, topically or parenterally, for example by injection, and are usually employed in the form of a pharmaceutical composition. Such compositions form part of the present invention and are prepared in a manner well known in the pharmaceutical art and normally comprise at least one active compound in association with a pharmaceutically-acceptable diluent or carrier. In making the compositions of the present invention, the active ingredient will usually be mixed with a carrier, or diluted by a carrier, and/or enclosed with a carrier which may, for example, be in the form of a capsule, sachet, paper or other container. Where the carrier serves as a diluent, it may be a solid, semi- solid, or liquid material which acts as a vehicle, excipient or medium for the active ingredient. Th s, the composition may be in the form of tablets, lozenges, sachets, cachets, elixirs, suspensions, as a solid or in a liquid medium, ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, injection solutions and suspensions and sterile packaged powders.

Some examples of suitable carriers are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates , tragacanth, gelatin, syrup, methyl cellulose, methyl- and propyl- hydroxybenzoate, talc, magnesium stearate and mineral oil. Compositions in injectable form may, as it is well known in the art, be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient.

When the compositions are formulated in unit dosage form, it is preferred that each unit dosage form contains from 5 mg to 500 mg, for example, from 15 mg to 200 mg. The term ^vunit dosage form' refers to physically discrete units suitable as unit dosages for human subjects and animals. Each unit contains a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier.

The active compounds are effective over a wide dosage range and, for example, dosages per day will normally fall within the range of from 0.5 to 300 mg/kg, more usually in the range of from 5 to 100 mg/kg. However, it will be understood that the amount administered will be determined by the physician in the light of the relevant circumstances, including the condition to be treated, the choice of compound to be administered and the chosen route of administration, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way.

The invention is illustrated by the following Examples.

EXAMPLE 1

4- [ (1-Carbamoyl-l-Methyl) Ethyl] -1- (3,4- Dichlorophenyl) Piperazine

(i)A mixture of 3 , 4-dichlorophenylpiperazine (11.45g, 50mmoi; and acetone cyanohydrin (6.85ml, 75mmol) in absolute ethanol (15ml) was heated under reflux for 24 hours. The reaction mixture was evaporated in vacuo and the solid residue dried in a vacuum oven at 50°C for 2 hours to give 4- [ (1-cyano-l-methyl) ethyl] -1- (3 , 4-dichlorophenyl) - piperazine as a white solid.

(ii)To a solution of 4- [ (1-cyano-l-methyl) ethyl] -1- (3 , 4- dichlorophenyl) -piperazine (13.80g, 46.6mmol) in DMSO (300ml), cooled to 0-5°C, was added, sequentially, 30% hydrogen peroxide (37ml, 326.2mmol) and 15% sodium hydroxide solution (18.8ml, 69.9mmol) . The reaction mixture was stirred at room temperature for 16 hours.

The reaction mixture was diluted with dichloromethane (800ml) and stirred with methanol-washed cation-exchange resin (Dowex 50WX8-100) (180g) for 4 hours. The mixture was filtered over a pad of more ion-exchange resin (180g) on a glass sinter and then washed sequentially with (1) dichloromethane : methanol 1:1 (2) 15% ammoniacal methanol. Evaporation in vacuo of the ammoniacal wash gave a colourless solid (12.80g). Recrystallisation from absolute ethanol yielded the title compound as a white solid (4.56g). MS 318.0.

Example 2

4- [ (1-carbamoyl-l-methyl) Ethyl] -1- (4-Nitrophenyl) -Piperazine

(i)A mixture of 4-fluoronitrobenzene (1.41g, lOmmol), piperazine (17.20g, 200mmol) and potassium carbonate (6.90g, 50mmol) in dry DMF (100ml) was stirred at 100°C for 3 hours. The DMF was evaporated in vacuo and the residual solid partioned between water and ethyl acetate (3X) ; the combined organic extracts were washed with (1) water (3X) (2) saturated sodium chloride solution, dried over magnesium sulphate and evaporated in vacuo to give 1- (4-nitrophenyl ) - piperazine as a yellow solid (1.76g) .

(ii)A mixture of 1- (4-nitrophenyl ) iperazine (1.70g, 8.2mmol), and acetone cyanohydrin (1.13ml, 12.3mmol) in absolute ethanol (2.5ml) was reacted according to the procedure of example 1 (i) , to give 4- [ (2-cyano-2-methyl) ethyl] -1- (4-nitrophenyl) - piperazine as a yellow solid (1.95g) .

(iii) A mixture of 4- [ (2 -cyano-2 -methyl) ethyl] -1- (4- nitrophenyl) -piperazine (1.90g, 7.36mmol), 30% hydrogen peroxide (5.8ml, 51.52mmol) and 15% sodium hydroxide (3ml, 11.04mmol) in DMSO (40ml) was reacted according to the procedure of example 1 (ii) . The crude product (2.04g) was further purified by partial dissolution in ethyl acetate, and filtration of the undissolved solid. The filtered solid was dried in vacuo to yield the title compound as a yellow solid (550mgs) . MS 293.0.

Example 3

4- [ (1-carbamoyl-l-methyl) Ethyl] -1- (4- Methylsulphonylphenyl ) Piperazine

(i)A mixture of 4-fluoromethyl sulphone (1.47g, 8.44mmol), piperazine (14.53g, 168.8mmol) and potassium carbonate (5.83g, 42.2mmol) in dry DMF (lOOmls) was reacted according to the method of example 2 (i) . The reaction mixture was evaporated in vacuo , the residual solid dissolved in water and purified by cation-exchange chromatography (Dowex 50X8-100; column eluted sequentially with water, dichloromethane : methanol 1:1, and water again. The piperazine was finally eluted with 15% methanolic ammonia) . Evaporation of the basic eluant in vacuo gave 1- (4-methanesulphonyl) piperazine as white crystals (2.70g). (ii)A mixture of 1- (4-methanesulphonyl) piperazine (2g, 8.33mmol) , acetone cyanohydrin ( 1.2mls , 12.5mmol) and absolute ethanol (2.5mls) was reacted according to the method of example 1 (i), to give, after drying in vacuo at 70°C for 3 hours, 4- [ ( 2 -cyano-2 -methyl) ethyl] -1- (4- methylsulphonylphenyl) piperazine as a white solid (2.02g).

(iii) A mixture of 4- [ (2-cyano-2 -methyl) ethyl] -1- (4- methylsulphonylphenyl) piperazine (2g, 6.51mmol) , 30% hydrogen peroxide (5.2ml, 45.57mmol) and 15% sodium hydroxide (2.6ml, 9.76mmol) in DMSO (40ml) was reacted according to the method of example 1 (ii). The crude product (654mg) was then partially dissolved in dichloromethane, the suspension filtered, and the filtrates evaporated in vacuo to give an off-white solid (540mg) . This solid was suspended in water (50ml) and stirred vigorously for 15 minutes. Finally, the solid was collected by filtration and dried in vacuo to yield the title compound as a white solid (284mg) . MS 326.1.

Example 4

1- [ (1-carbamoyl-l-methyl) Ethyl] -4- (3 , 4-Dichlorophenyl) - 1,2,5,6, -Tetrahydropyridine

(i)To magnesium turnings (0.92g, 37.6mmol) under dry diethyl ether (50ml) was added, dropwise, a solution of l-bromo-3,4- dichlorobenzene ( 8.52g, 37.6mmol) in dry diethyl ether (100ml).

(The reaction was iniated by addition of 1 , 2-dibromoethane and heating) . The reaction mixture was stirred until all the magnesium had dissolved (30 minutes) . To this solution of Grignard reagent, cooled in an ice- bath, was added, dropwise, a solution of N-(t- butoxycarbonyl) -4-piperidone (5g,25mmol) in dry diethyl ether (50ml) (white precipitation) . When addition was complete, the reaction mixture was refluxed for 30 minutes. The reaction was quenched with saturated ammonium chloride solution, the ether phase separated, and the aqueous phase extracted twice more with diethyl ether. The combined organic extracts were washed with (1) water (2) saturated sodium chloride solution, dried over magnesium sulphate and evaporated in vacuo to give a yellow viscous oil. This oil was dissolved in acetonitrile and washed with petroleum spirit (40-60°) five times; the acetonitrile phase was separated and evaporated in vacuo to give l-(t- butoxycarbonyl ) -4- (3 , 4-dichlorophenyl) -4-hydroxypiperidine as a yellow viscous gum (6.38g) .

(ii)To a solution of 1- (t-butoxycarbonyl) -4- (3 , 4- dichlorophenyl) -4-hydroxypiperidine ( 6g, 17.4mmol) in dry DMF (50ml) at room temperature and under a nitrogen atmosphere was added, dropwise, a solution of (methoxycarbonylsulfamoyl) - triethylammonium hydroxide, inner salt [Burgess reagent] (4.55g, 19.13mmol) in dry DMF (20ml). The reaction mixture was then stirred at 70°C for 4 hours. The reaction mixture was allowed to cool and then poured into excess water. The aqueous phase was extracted three times with diethyl ether, and the combined ethere l extracts washed with (1) water (2) saturated sodium chloride solution; dried over magnesium sulphate, filtered and evaporated in vacuo . The crude product was purified by flash chromatography on silica gel (eluant hexane 50% diethyl ether) to give 1- ( -butoxycarbonyl) -4- (3 , 4-dichlorophenyl) - 1 , 2 , 5 , 6-tetrahydropyridine as a viscous, colourless oil (1.56g) . (iii)To a solution of 1- (t-butoxycarbonyl) -4- (3 , 4- dichlorophenyl) -1, 2 , 5 , 6-tetrahydopyridine (1.18g, 3.6mmol ) in moist diethyl ether (30ml) , cooled in an ice-bath, was added trifluoroacetic acid (10ml) . The reaction mixture was allowed to warm to room temperature and stirred for a further 6 hours. The reaction mixture was evaporated in vacuo, water added to the residue, and the mixture azeotroped in vacuo . The residue was dissolved in water/methanol and the solution basified with saturated sodium carbonate solution. The methanol was evaporated in vacuo and the remaining aqueous phase extracted three times with ethyl acetate. The combined organic extracts were dried over magnesium sulphate, filtered and evaporated in vacuo to give 4- (3, 4- dichlorophenyl) -1, 2 , 5, 6- etrahydropyridine as a semi-solid material (0.71g) .

(iv) A mixture of 4- (3 , 4-dichlorophenyl) -1 , 2 , 5 , 6- tetrahydropyridine (0.71g, 3.12mmol) and acetone cyanohydrin (0.43ml, 4.77mmol) in absolute ethanol (2ml) was reacted according to the method of example 1 (i) to give l-[(2-cyano- 2-methyl) ethyl] -4- (3, 4-dichlorophenyl) -1,2,5,6- tetrahydropyridine as an off-white solid (0.8g) .

(v) A mixture of 1- [ (2-cyano-2-methyl) ethyl] -4- (3 , 4- dichlorophenyl) -1, 2 , 5, 6-tetrahydropyridine (0.6g, 2mmol) , 30% hydrogen peroxide (1.62ml, 14.3mmol) and 15% sodium hydroxide (0.82ml, 3.06mmol) in DMSO (20ml) was reacted according to the method of example 1 (ii) to give a white solid (228mg) . The crude product was purified by flash chromatography on silica gel (eluant ethyl acetate) to give the title compound as a white solid (180mg) . MS 313.0. Example 5

4- [ (1-n-Propylcarbamoyl-l-Methyl) Ethyl] -1- (3, 4- Dichlorophenyl) Piperazine (i)A solution of 4- [( 1-carbamoyl-l-methyl ) ethyl] -1- (3 , 4- dichlorophenyl) piperazine (2.37g, 7.5 mmol) in 4N HCL (15 mL) was heated to 95°C for 18h, then cooled and treated with sodium hydroxide (3.0g, 75 mmol) in water (25 mL) . The suspension was concentrated in vacuo to a sludge, which was cooled (0°C) , filtered, and the solid rinsed with cold brine and set aside. The filtrate was concentrated in vacuo to a sludge, cooled (0°C) , filtered, and the solid rinsed with cold brine and combined with the first batch. This was then taken up in methanol (25 mL) , diluted with 2-propanol (100 mL) , heated (50°C) , and filtered to remove inorganic salts. The filtrate was concentrated in vacuo to afford sodium salt, which was taken up in water (30 mL) and treated with 0. IN HCL (75 mL) . A precipitate soon formed, and this was filtered and rinsed with cold water, then air dried to afford 4- [2-carboxy-2-methyl) ethyl] -1- (3 , 4-dichlorophenyl) piperazine (1.79g, 75%) as a white solid, which could be recrystallized from ethanol (2 crops) or triturated from acetonitrile. MS 317.3.

(ii)A suspension of 1- (3-dimethylaminopropyl) -3- ethylcarbodiimide hydrochloride (115mg, 0.60 mmol) in anhydrous N,N-dimethylformamide (DMF, 0.5 mL) and dichloromethane (1.0 mL) was treated with 4- [ 2 -carboxy-2 - methyl) ethyl] -1- (3 , 4-dichlorophenyl) piperazine (159mg, 0.50 mmol), then with 1-hydroxybenzotriazole hydrate (92mg, 0.60 mmol). After 10 min the suspension had cleared, and after another 10 min N-propylamine (44mg, 0.75 mmol) in dichloromethane (0.2 mL) was added. The mixture was stirred at room temperature for 18h, then exhaustively concentrated in vacuo to remove DMF. The residue was dissolved in dichloromethane and loaded onto a short column of silica gel, then eluted with 0.5%, then 1% methanol/dichloromethane to afford 4-[(2-N- propylcarbamoyl-2-methyl) ethyl] -1- (3 , 4- dichlorophenyl) piperazine (163mg, 91%) as a white solid. MS 358.5.

Example 6

4- [ (1- (Pyrrolidin-1-ylcarbonyl) -1-Methyl) -Ethyl] -1- (3, 4- Dichlorophenyl ) Piperazine

A suspension of 1- (3-dimethylaminopropyl) -3- ethylcarbodiimide hydrochloride (115mg, 0.60 mmol) in anhydrous N,N-dimethylformamide (DMF, 0.5 mL) and dichloromethane (1.0 mL) was treated with 4- [2-carboxy-2- methyl) ethyl] -1- (3 , 4-dichlorophenyl) piperazine (159mg, 0.50 mmol), then with 1-hydroxybenzotriazole hydrate (92mg, 0.60 mmol) . After 10 min the suspension had cleared, and after another 10 min pyrrolidine (54mg, 0.75 mmol) in dichloromethane (0.2 mL) was added. The mixture was stirred at room temperature for 18h, then exhaustively concentrated in vacuo to remove DMF . The residue was dissolved in dichloromethane and loaded onto a short olumn of silica gel, then eluted with 1%, 1.5%, and 2% methanol/dichloromethane to afford 4- [ (1- (pyrrolidin-1- ylcarbonyl) -1-methyl) ethyl] -1- (3 , 4- dichlorophenyl) iperazine (150mg, 81%) as a white solid. MS 370.6.

Example 7 4- [ ( 1-Carbamoyl-1-Methyl ) Ethyl] -1- ( 3 - TrifluoromethyIphenyl) Piperazine

Prepared combinatorially by solution-phase synthesis in a parallel array. Chemistry is conducted in a 96-glass well microtiter plate.

(i) To a 1-mL glass well containing a solution of 3- trifluoromethylphenylpiperazine ( 0.5M solution in methanol, 100 mL, 60 mmol) was added acetone cyanohydrin (7.66 mg, 90 mmol, 1.5 eq) in absolute ethanol (25 mL) . Additional ethanol (375 mL) was added to give a 500 mL total volume for the well. The reaction well was capped and heated to 65-C with agitation for 36 hours. The reaction well was uncapped and the solvent removed by evaporation in vacuo to give 4- [l-cyano-2-methyl) ethyl] -1- (3-trifluoromethyIphenyl) piperazine.

(ii) To a 2-mL glass well containing a solution of 4- [2- cyano-1-methyl) ethyl] -1- (3- trifluoromethyIphenyl) piperazine in dimethylsulfoxide (300 mL) , cooled to 0-5 -C, was added, sequentially, 30% hydrogen peroxide (100 mL, 0.98 mmol) and 15% sodium hydroxide solution (200 mL, 0.74 mmol) . A slight exotherm was observed. The mixture was agitated at room temperature for 16 hours. The reaction mixture was diluted with dichloromethane (600 mL) , treated with methanol-washed cation-exchange resin (Biorad AG50W-X8 sulfonic acid resin) (100 mg) , and agitated for 8 hours. The mixture was filtered through a pad of cation-exchange resin (100 mg) and the resin washed with dichloromethane : methanol 1:1 (400 mL) to remove non-basic impurities. The product was recovered by washing with 15% aqueous ammonia in methanol (3 X 400 mL) and concentrated in vacuo. The product was solubilized in methylene chloride (1 mL) , loaded onto a pad of silica gel, and eluted with ethyl acetate (400 mL) . The filtrate was evaporated in vacuo to yield the title compound (4.10 mg) .

Example 8 - Tablet

A tablet is prepared using the ingredients below:

Quantity

(mg/tablet )

Active Ingredient 250 Cellulose, microcrystalline 400

Silicon dioxide, fumed 10

Stearic acid 5

Total 665 mg

The components are blended and compressed to form tablets each weighing 665 mg.

Example 9 - Tablet

Tablets each containing 60 mg of active ingredient are made as follows: Active Ingredient 60 mg

Starch 45 mg

Microcrystalline cellulose 35 mg

Polyvinylpyrrolidone 4 mg Sodium carboxymethyl starch 4.5 mg

Magnesium stearate 0.5 mg

Talc 1 mg

Total 150 mg

The active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No . 14 mesh U.S. sieve. The granules so produced are dried at 50°C and passed through a No . 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No . 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.

Example 10 - Capsules

Capsules each containing 80 mg medicament are made as follows : Active Ingredient 80 mg

Starch 59 mg

Microcrystalline cellulose 59 mg

Magnesium stearate 2 mg

Total 200 mg

The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No . 45 sieve, and filled into hard gelatin capsules in 200 mg quantities.

Example 11 - Suspensions

Suspensions each containing 50 mg of medicament per 5 ml dose are made as follows :

Active Ingredient 50 mg

Sodium carboxymethyl cellulose 50 mg

Syrup 1.25 ml

Benzoic acid solution 0.10 ml Flavor q.v.

Color q.v.

Purified water to total 5 ml The medicament is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste. The benzoic acid solution, flavor and color are diluted with some of the water and added, with stirring. Sufficient water is then added to produce the required volume.

Example 12 - Assay

HEK iGluR6 cells were obtained as described in Hoo, K.H. ; Nutt, S.; Fletcher, E. J.; Elliot, C . ; Korczak, B . ; Deverill, M. ; Rampersad, Y. ; Fantaske, R. P.; Kambo , R. K. Functional Expression and Pharmacological

Characterization of the Human EAA4 (GluRβ) Glutamate Receptor: A Kainate Selective Channel Subunit. Receptors Channels 1994, 2, 327-337. The cells were plated out onto 96 well plates, previously coated with 50μg/ml of Poly-L- Lysine (Sigma), two to three days prior to the assay. To achieve a confluent layer, cells were plated at 1 x 10⁵/well for two days or at 5 x 10 /well for three days. The Culture Media was Dulbecco ' s Modified Eagle Media without Sodium Pyruvate, with 4500mg/L of Glucose, 1% of Penicillin/Streptomycin, (Gibco) , 10% of heat inactivated Foetal Calf Serum, (Seralab) and 500μg/ml of Geneticin, (Gibco) . Cells are loaded with 50μl of 20μM Fluo-3AM dye [Calbiochem or Molecular Probes) which was reconstituted to 3.54mM by addition of 20% F127 in DMSO (lmg Fluo - 3AM+221.2μl 20% F127)] and 25μl of stock in 5ml of HEPES buffer, (138 mM NaCl, ImM MgCl2 , 5mM CaC12 , lOmM Glucose, lOmM HEPES, 5mM KCl, pH to 7.4 with NaOH adjusted to 315 mOsm with NaCl) .

The wells were 200μl/well unless stated otherwise. Once the dye has been loaded, plates should be kept in the dark.

The 96 well plates were washed three times with HEPES (5CaNa) Solution, and 50μl of Fluo-3AM dye were added to each well and they were incubated at room temperature for one hour. Then the well plates were washed twice with a buffer and they were left to stand in the second wash solution for 30min. Then the well plates were washed with buffer and they were replaced with 45μl buffer. The fluorescence was measured with a 96 well plate fluorescence reader, Labsystems Fluoroskan II, at the Excitation wavelength of 485nM, and the Emission wavelength of 538nM to give basal reading. The wash solution was removed and the well plates were preincubated for lOmin with 45μl of a Buffer solution containing compound and lμM Concanavalin A solution. The fluorescence was read to give the corresponding pre challenge values. The Agonist Glutamate was added in a volume of 15μl, at 400μM to give a final concentration of lOOμM, and the fluorescence measurements were taken at 1, 3 and 5 min post challenge. The results were calculated as a percentage change of fluorescence from control challenged cells.

Claims

1. A pharmaceutical composition comprising a compound of formula I ,

(I)

in which

R! and R^ are each independently H or C╧ç_g alkyl or C3-.10 alkenyl or C3_╬╣_o cycloalkyl, or R! and R^ together with the nitrogen atom to which they are attached combine to form a saturated heterocyclic ring of 4-10 atoms;

R3 and R⁴ are each independently H or C╬╣__g alkyl or C3_╬╣o cycloalkyl, R^ and R⁴ together with the carbon atom to which they are attached combine to form a C carbocyclic ring;

R5 and R^ are each independently H or C_╬╣_₆ alkyl, C╬╣_₆ alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl , nitro, amino, C╬╣_₆ acylamino and C╬╣_₆ alkylthio, C╬╣_₆ alkylsulphone, or halo C╬╣_₆ alkylsulphone; or a pharmaceutically-acceptable salt or ester thereof, together with a pharmaceutically-acceptable diluent or carrier .

2. A compound of formula (I)

(I)

in which

R! and R^ are each independently H or C╧ç_g alkyl or C3_ alkenyl or C3_╧ço cycloalkyl, or R^ and R^ together with the nitrogen atom to which they are attached combine to form a saturated heterocyclic ring of 4-10 atoms;

R3 and R^ are each independently H or C _g alkyl or C3_]_Q cycloalkyl, R^ and R^ together with the carbon atom to which they are attached combine to form a C 4ΓÇ₧-,10 carbocyclic ring;

R5 and R^ are each independently H or C╬╣_₆ alkyl, C╬╣-₆ alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl , nitro, amino, C╬╣-6 acylamino and C╬╣-₆ alkylthio, C╬╣-₆ alkylsulphone, or halo C╬╣-6 alkylsulphone;

or a pharmaceutically-acceptable salt or ester thereof, for use as a pharmaceutical.

3. The use according to claim 2 wherein R^ and R^ are independently trifluoromethyl or halo.

4. The use according to claim 2 wherein R^ and R^ are chloro .

5. The use according to claim 2 wherein R^ and R^ are in position 3 and 4 in the phenyl ring.

6. The use according to claim 2 wherein R^ and R^ are methyl .

7. The use according to claim 2 wherein R^ is H or d-₃ alkyl, R2 is H.

8. The use according to claim 2 wherein the compound is selected from 4- [ (1-n-Propylcarbamoyl-l-Methyl) Ethyl] -1- (3,4- Dichlorophenyl) Piperazine, 4- [ (1-carbamoyl-l-methyl) Ethyl] -1- (3,4- Dichlorophenyl) Piperazine, and

1- [ (1-carbamoyl-l-methyl) Ethyl] -4- (3 , 4-Dichlorophenyl ) -

1,2,5,6, -Tetrahydropyridine .

9. A compound of formula I with the exception of those in which, R¹ and R² together with the nitrogen atom to which they are attached form a morpholino group, R³ and R⁴ are methyl, X is N, and R⁵ and R⁶ are H, or salt thereof.

10. A process for the production of compounds of formula (I) which comprises a Strecker reaction of an arylpiperazine or piperidine ring with the corresponding cyanohydrin to give compound of formula (IV) , where X, R³ , R⁴, R⁵ and R⁶ have the meaning given above, followed by elaboration of the side chain by partial hydrolysis of the corresponding nitrile with for example, hydrogen peroxide; or by hydrolysis to the acid of formula (V) followed by dehydrative coupling of the corresponding acid and amine with for example, l-(3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride .

(IV) (V)

11. Use of a compound as defined in claim 2 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disorder of the CNS.

12. A method of treating an animal, including a human, suffering from or susceptible to a disorder of the central nervous system, which comprises administering a compound according to claim 1, or a pharmaceutically acceptable salt or ester thereof.