WO1995023135A1

WO1995023135A1 - Diphenyl-2-piperidinone and -2-pyrrolidinone derivatives having anti-convulsant and neuroprotective activity

Info

Publication number: WO1995023135A1
Application number: PCT/GB1994/000387
Authority: WO
Inventors: Robert John Murray; Richard Jon Schmiesing
Original assignee: Fisons Corporation; Fisons Plc
Priority date: 1991-03-07
Filing date: 1994-02-28
Publication date: 1995-08-31

Abstract

Compounds of formula (I), wherein two of R?1, R2, R3 and R4¿ independently represent phenyl optionally substituted by one or more groups selected from halogen, hydroxy, nitro, amino, C¿1-6?alkyl and C1-6alkoxy; and the ramainder of R?1, R2, R3 and R4¿ independently represent hydrogen or C¿1-6?alkyl; R?5 and R6¿ independently represent hydrogen, C¿1-6?alkyl or C3-6cycloalkyl, or R?5 and R6¿ together with the nitrogen atom to which they are attached form a C¿4-6?N heterocycle; m is 1 or 2; and n is 1, 2 or 3; and pharmaceutically acceptable acid addition salt thereof; are useful in the treatment of neurodegenerative disorders, particularly epilepsy.

Description

DIPHENYL-2-PIPERIDINONE AND -2-PYRR0LIDIN0NE DERIVATIVES HAVING ANTI-CONVULSANT AND NEUROPROTECTIVE ACTIVITY

This invention relates to diphenyl-l-(aminoalkyl)-2-piperidinone and -2-pyrrolidinone derivatives, their use as pharmaceuticals, processes for their preparation and pharma- 5 ceutical formulations including them.

US Patent N° 4,216,221 discloses l-(aminoalkyl)-2-piperidinones and -2-pyrrolidinones as intermediates in the preparation of l,3-disubstituted-2-thioureas which are indicated as pharmaceuticals. 0

According to the invention there is provided a compound of formula I,

wherein s two of R¹, R², R³ and R⁴ independently represent phenyl optionally substituted by one or more groups selected from halogen, hydroxy, nitro, amino, C_w alkyl and C,^ alkoxy; and the remainder of R¹, R², R³ and R⁴ independently represent hydrogen or C^ all^l;

R⁵ and R⁶ independently represent hydrogen, C,^ alkyl or C₃^ cycloalkyl, or R⁵ and R⁶ together with the nitrogen atom to which they are attached form a C₄^N heterocycle; 0 m is 1 or 2; and n is 1, 2 or 3; or a pharmaceutically acceptable acid addition salt thereof (hereinafter referred to together as "the compounds of the invention").

s Pharmaceutically acceptable acid addition salts include salts of mineral acids, for example hydrochloric or hydrobromic acids; and organic acids, for example formic, acetic or lactic acids. The acid may be polybasic, for example sulphuric, fumaric, maleic or citric acid. Acid addition salts of compounds of formula I may be formed by reacting the free base, or a salt or derivative thereof, with one or more equivalents of the appro¬ priate acid. The reaction may be carried out in a solvent in which the salt is insoluble or in which the salt is soluble or in mixtures of the solvents. Acid addition salts may be converted to the free base by the action of a stronger base. The phrase "pharmaceuti- cally acceptable acid addition salts" includes hydrates of such salts.

The invention provides all stereoisomers of the compounds of the invention.

Preferred groups of compounds of the invention include those in which: n is 1;

R¹ and R² both represent phenyl;

R³ and R⁴ both represent H;

R^s and R⁶ independently represent hydrogen, Cι.₃ alkyl or cyclopropyl, more preferably

R⁵ and R⁶ both represent hydrogen or one of R^s and R⁶ represents hydrogen and the other represents methyl; and m is 2.

According to the invention there is also provided a process for the preparation of the compounds of the invention which comprises: (a) for compounds of formula I in which n is 1, reacting a compound of formula II,

in which R¹, R², R³, R⁴ and m are as first defined above, n is 1 and X is a suitable leaving group, with a compound of formula R⁵R⁶NH in which R⁵ and R⁶ are as first defined above;

(b) for compounds of formula I in which n is 2 or 3, reacting a compound of for¬ mula III, R ¹

R ³

I I

^R I

H

in which R\ R², R³, R⁴ and m are as first defined above, with a compound of formula IV,

R⁵R⁶N-(CH₂)_n-X IV

in which n is 2 or 3, X is a suitable leaving group and R⁵ and R⁶ are as first defined above and in addition NR⁵R⁶ may represent protected amino; or (c) for compounds of formula I containing one or more amino or hydroxy groups, removing a protecting group from a corresponding compound in which one or more of the amino or hydroxy groups is protected; and where desired or necessary converting the resulting compound of formula I into a pharmaceutically acceptable acid addition salt thereof or vice versa.

In the reaction of process (a), suitable leaving groups which X may represent include halogen (preferably chlorine) or an alkane- or arenesulphonate group (for example methanesulphonate or p-toluenesulphonate). The amination reaction may be carried out in an inert aprotic solvent such as toluene or tetrahydrofuran at a temperature of -80-120°C.

In the reaction of process (b), the leaving group X may be the same as in process (a). The alkylation reaction may be carried out in the presence of a base such as potassium hydroxide, in a polar solvent such as dimethyl sulphoxide, ethanol, water or mixtures thereof. Suitable protected amino groups that NR⁵R⁶ may represent include benzyloxy- carbonylamino, t-butyloxycarbonylamino and a phthalimide group.

In process (c), the amine protecting groups may be removed by: for the benzyloxycarb- onyl group, catalytic hydrogenation over palladium or platinum on carbon in an inert solvent such as methanol; for the t-butyloxycarbonyl group, treatment with an acid such as trifluoroacetic or hydrochloric acid; and for the phthalimide group, treatment with hydrazine in a C.^ alkanol such as ethanol.

Compounds of formula II may be prepared by reacting a compound of formula III, as defined above, with formaldehyde to give a compound of formula V,

wherein R¹, R², R³, R⁴ and m are as first defined above, followed by reaction of the compound of formula V with a halogenating agent or an alkane- or arenesulphonyl halide. The reaction with formaldehyde may be carried out in a suitable protic solvent such as aqueous ethanol, in the presence of a base such as sodium hydroxide, and at a temperature of 20-100°C. The resulting hydroxymethyl compound may be reacted with a halogenating reagent such as thionyl chloride, in an inert solvent such as methylene chloride or benzene. The halogenation reaction may be carried at a temperature of 0- 100°C. Alternatively, the hydroxymethyl compound may be reacted with an alkane- or arenesulphonyl halide in the presence of a base such as pyridine or triethylamine in an inert solvent such as toluene or tetrahydrofuran, at a temperature of 20°-120°C.

Compounds of formula III are either known or may be prepared by conventional methods. Methods for preparing phenyl and substituted phenyl 2-pyrrolidinones and 2- piperidinones are described in US Patents N°s 2,742,475, 3,468,893 and 3,718,743; Japan¬ ese Kokai 47-42656; Utjes-Le Gall et al, Bull Soc Chim Fr N° 11-12, 1175-1181 (1977); and Y Yamawaki et al, Y Zasshi, 97 (2), 177 (1977).

Examples of C_w alkyl groups which R¹, R², R³, R⁴, R⁵ and R⁶ may represent or include are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl and s-butyl. Examples of cycloalkyl groups which R^s and R⁶ may represent are cyclopropyl, cyclobutyl, cyclopentyl and cyclo- hexyl. Examples of C,^ alkoxy groups which R¹, R², R³ and R⁴ may include are meth- oxy, ethoxy and propoxy. Examples of halogen groups which R\ R², R³ and R⁴ may include are fluorine, chlorine, bromine or iodine.

The compounds of the invention are indicated as pharmaceuticals, in particular as anticonvulsants and neuroprotective agents in the treatment of neurodegenerative dis¬ orders. Specific neurodegenerative disorders that may be mentioned include stroke, cerebral ischaemia, cerebral palsy, the effects of hypoglycaemia, epilepsy, AIDS-related dementia, Alzheimer's disease, Huntington's chorea, Olivo-ponto-cerebellar atrophy, perinatal asphyxia, Parkinson's disease, anoxia, neuronal damage associated with sub- stance abuse (for example, narcotics or cocaine), retinopathies, schizophrenia, ischaemic states after cardiac arrest or surgical operations, intoxication or injuries of the spinal cord, head injury and amyotrophic lateral sclerosis. Epilepsy is of particular interest.

While not being limited by theory, neurodegeneration is thought to be caused or acceler- ated by neuronal excitation leading to release of glutamate and other excitatory com¬ pounds found naturally in the central nervous system (CNS). Glutamate is an endoge¬ nous amino acid which has been characterized as a fast excitatory transmitter in the mammalian brain. Glutamate is also known as a powerful neurotoxin capable of killing CNS neurons under certain pathologic conditions which accompany stroke and cardiac arrest. It has been shown that the sensitivity of central neurons to hypoxia and ischaemia can be reduced by inhibiting the release of glutamate or by the specific antag¬ onism of post synaptic glutamate receptors. Since voltage-gated sodium channels are important for neuronal excitation and release of glutamate it therefore follows that compounds which decrease voltage-gated sodium currents will be anticonvulsant as well as neuroprotective; such has been found [see C P Taylor, TINS, Vol 16, 455-460 (1993) and references therein].

The pharmacological activity of the compounds of the invention may be measured in the tests set out below.

(a) Antiepileptic activity may be measured by assessing a compound's ability to prevent the hind limb tonic extension component of the seizure in groups of mice or rats induced by maximal electroshock (MES) after oral, intraperitoneal, intravenous or subcutaneous administration, according to the procedures of the Epilepsy Branch, NINCDS as published by R J Porter et al, Cleve Clin Quarterly 1984, , 293, and compared with the standard agents dilantin and phenobarbital.

(b) Limitation of Sustained Repetitive Firing of Sodium Action Potentials is beli- eved to reflect the mechanism of action of drugs effective against generalized tonic- clonic seizures including phenytoin, carbamazepine (R L Macdonald et al, Advances in Neurology, 1986, 44, 713) and lamotrigine (H Cheung et al, Epilepsy Research, 1992, 13, 107). In this test rodent CNS neurons maintained in culture are induced to fire prolonged trains of action potentials. The ability of known concentrations of a drug to limit this hyperactivity is measured as described in Cheung, op cit.

(c) Whole-cell patch clamp recordings are used to investigate a compound's effects on voltage-gated sodium channels, believed to be a site of action for several anticonvulsant compounds (M A Rogawski et al, Pharmacol Reviews, 1990, 42, 223). These studies are carried out using acutely-dissociated neurons from rodent brain (A R Kay et al, J Neurosci Methods, 1986, JL6, 227), and voltge protocols similar to those of Ragsdale et al (Mol Pharm, 1991, 40, 756) to determine the effects of the compounds on channel activation and inactivation, and the voltage-dependence of these effects.

(d) Antihypoxia activity may be measured conveniently in mice. Groups of mice are tested at various times after the intraperitoneal administration of graded doses of the test compound. The animals' survival time in a temperature-controlled hypoxic environment (96% nitrogen and 4% oxygen) is recorded. A statistical comparison is made between coincident vehicle treated animals and the experimental group. The dose-response and minimum active dose (MAD) for compounds are obtained [A A Artu and J D Michenfelder, Anaesthesia and Analgesia, 1981, 60, 867]. Other modes of administration can also be used.

(e) The 4-vessel occlusion (4-VO) model of stroke is used to produce global isc¬ haemia in the rat and is an essential technique to evaluate the effectiveness of com¬ pounds to prevent damage to areas of selective vulnerability in the brain, notably the CA1 pyramidal neurons of the hippocampus. This area is involved in the pathways for short term memory formation in both laboratory animals and humans. The procedure consists of cauterizing the vertebral arteries and isolating the carotid arteries of rats maintained under anaesthesia on day 1. On day 2 the carotids are clamped for varying periods of time, ten minutes is sufficient to destroy the CA1 neurons. The clamps are removed, reflow initiated and drugs administered at various times post reflow. Body temperature is maintained at 37°C throughout the ischaemia and recovery periods. The CA1 neurons die off over a 48-72 hour period and normally the rats are treated for at least 3 days with drug (ip, iv, or po) and at 7 days the brains are removed for histology. Rating of CA1 damage is accomplished using two methods, counting of viable CA1 neurons and scoring of degree of gross pathology [W A Pulsinelli and A Buchan, "The NMDA receptor/ion channel: Its importance to in vivo ischemia injury to selectively vulnerable neurons', Pharmacology of Cerebral Ischemia, edited by J Krieglstein and H Oberpichler, published by Wissenschaftliche Verlagsgeseilschaft, Stuttgart, 1990, pl69]. (f) In the Focal Model of Stroke, spontaneously hypertensive rats (SHR) are used as experimental subjects because of their relatively poor collateral brain circulation. A 2 hour focal ischaemia is achieved in SHR by clamping the middle cerebral artery and the ipsilateral carotid while maintaining anaesthesia. Drugs can be administered (usually ip) either before or various times after clamping the arteries or when reflow commences at 2 hours. The brains are removed 24 hours after the experiment, frozen and sectioned and drug effects toward reducing infarct volume of the cerebral cortex are determined using a custom-built computer quantification system [A M Buchan, D Xue and A Slivka, Stroke, 1992, 23, 273]

Toxicity and side effects of the compounds of the invention may be measured in the following tests.

(i) Dose ranging studies based on those described by N W Spurting and P F Carey, 'A protocol for dose selection in repeat dose toxicity studies', poster presentation 974 at the Society of Toxicology annual meeting, Seattle, USA, 23-27 February 1992. Rats are dosed intravenously daily with progressively increasing doses of test compound until a maximum repeatable dose is found above which the incidence of convulsions and other abnormal clinical signs is unacceptable. (ii) The inverted screen test [L L Cougenour, J R McLean, and R B Parker, Pharm¬ acol Biochem Behav, 1977, 6, 351]. Mice are dosed with te-v- compound and 30 minutes later are placed on a small wire platform which is inverted tnrough an arc of 180°. Mice unable to climb to the upright position within 30 seconds are rated as failures. Using sufficient doses and numbers of animals an appropriate TD₅₀ (dose in which 50% fail) can readily be determined.

(iii) The observation test for 28 behavioral signs according to S Irwin [Psycho- pharmacology 1968, 13, 222]. Groups of 3 mice per dose are administered incremental amounts of test compound in the range 25-400 mg kg and observed for 28 symptoms immediately after dosing, 30 minutes, 3 hours and 24 hours post dose, (iv) Test for Phencyclidine (PCP)-Like Behaviour. PCP-like behaviours are a side effect of potent competitive and non-competitive NMDA receptor antagonists, which as a class show anticonvulsant and neuroprotective activity. In a screen to determine whether a compound possesses this liability, rats are dosed orally with test compound (expressed as multiples of the oral ED₅₀ for protection in the MES test) and placed into individual clear plastic cages and observed over a 4 hour period for any incidence of 5 characteristic behaviours associated with PCP, namely hyperactivity, ataxia, circling, head weaving and retropulsion. Five rats per treatment group are observed and compared to a control group receiving PCP. A total incidence score would be 25, i.e. 5 rats exhibi¬ ting all 5 behaviours. PCP at 10 times the ED₅₀ produces a score of 25 [W Koek, J H Woods, P Ornstein, 1987, Psychopharmacology, 9_1, 297].

(v) Gang Plank Escape Test to measure neural impairment in rats [G E Garske et al, Epilepsy Research, 1991, 9, 161]. Rats are placed on a narrow board (1.25cm wide suspended 40cm above the bench top) in a well lit entry cubicle which enters a progress¬ ively darkened box connected to a dark escape cubicle at the other end (board is 63cm long). A rat is impaired if it fails to negotiate the plank. The task takes into account two known behaviours of rats, i.e. fear of height and seeking a dark environment, (vi) The influence of test compounds on learning acquisition is measured by the following method. Naive, male rats (Long Evans, fasted for 30 hours) are placed in an operant chamber and receive a food reward upon choosing the correct lever. The cumulative number of food pellets received are tabulated hourly for up to 14 hours. In order to facilitate learning a pellet was automatically delivered each hour. For the first 50 food pellets one lever press equals one pellet, for the next 50 pellets two lever presses are required and for each subsequent 50 pellets the response requirement is further increased. The task requires a degree of exploratory activity, attention and problem-solving behaviour. Interference with any of these behavioural processes will result in impaired memory. For the above-mentioned uses the dosage administered will, of course, vary with the compound employed, the mode of administration and the treatment desired. However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about O.lmg to about 20mg per kg of animal body weight, preferably given in divided doses 1 to 4 times a day or in sustained release form. For man, the total daily dose is in the range of from 5mg to l,400mg, more preferably from lOmg to lOOmg, and unit dosage forms suitable for oral administration comprise from 2mg to l,400mg of the compound admixed with a solid or liquid pharma¬ ceutical carrier or diluent.

The compounds of the invention may be used on their own or in the form of appropri¬ ate medicinal preparations for enteral or parenteral administration. According to a further aspect of the invention, there is provided a pharmaceutical formulation including preferably less than 80% and more preferably less than 50% by weight of a compound of the invention in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

Examples of diluents and carriers are: for tablets and dragees: lactose, starch, talc, stearic acid; for capsules: tartaric acid or lactose; for injectable solutions: water, alcohols, glycerin, vegetable oils; for suppositories: natural or hardened oils or waxes.

According to a further aspect of the invention, there is provided the use of a compound of the invention as active ingredient in the manufacture of an anticonvulsant or neuro¬ protective medicament. Use in the manufacture of an anticonvulsant medicament is of particular interest.

The compounds of the invention may have the advantage that they are less toxic, more efficacious, are longer acting, are more potent, produce fewer side effects (for example, they have a less detrimental effect on learning and/or they are not proconvulsant at higher doses), are more easily absorbed or have other more useful pharmacological properties, than the compounds of the prior art. The invention is illustrated by the following examples.

Intermediate IA 5,5-Diphenyl-2-piperidinone

(a) 4-Carbethoxy-2.2-diphenylbutanenitrile

To a stirred suspension of sodium hydride (27g of a 60% oil suspension) in 600ml of diy dimethylformamide (DMF) at room temperature was added over 1 hour a solution of diphenylacetonitrile (130g, 0.67mol) in 400ml of DMF. The mixture was stirred until the evolution of hydrogen ceased, about 1 hour. Ethyl 3-chloropropionate (90ml, lmol) was added dropwise over 1 hour and the resulting mixture was stirred for a further 1 hour, then it was partitioned between water and ether. The organic layer was washed with brine and dried. Concentration of the solvents afforded a residue which was vacuum distilled to give 4-carbethoxy-2,2-diphenylbutanenitrile (HOg).

(b) 5,5-Diphenyl-2-piperidinone

A mixture of the nitrile from step (a) (50g, 0.17mol) and platinum oxide (2g) in acetic acid (250ml) was subjected to 2.7atm (40psi) of hydrogen on a Parr apparatus for 3 days. The catalyst was filtered and the filtrate concentrated to dryness using a toluene azeotrope. The resulting semi-solid residue was triturated with toluene and filtered to give the title product as a white solid (15g), p 177-180°C.

Intermediate IB 4.4-Diphenyl-2-pyrrolidinone

The title compound was prepared using the method used to prepare Intermediate IA, but substituting ethyl 2-bromoacetate for ethyl 3-chloropropionate.

Intermediate 2 cis- and tratts-5,6-Diphenyl-2-piperidinone

(a) Ethyl 4.5-diphenyl-5-oxopentanoate To a solution of 140g (0.71mol) of deoxybenzoin and 170g (1.7mol) of ethyl acrylate in 21 of absolute ethanol at ambient temperature was added in portions 20ml of 50% aque¬ ous sodium hydroxide. An additional I70g (1.7mol) of ethyl acrylate was then added over a 15 minute period. The mixture was stirred vigorously for 2.5 hours, poured into 11 of water and extracted with 3 x 11 of ether. The organic layers were combined, washed with water and brine, and dried over sodium sulphate. The filtrate was concen¬ trated to near dryness, triturated with 1.51 of pentane, filtered and the filtrate allowed to stand at -20°C giving 145g (69%) of ethyl 4,5-diphenyl-5-oxopentanoate as a white solid (mp 45-57°C).

(b) Ethyl 4.5-diphenyl-5-oximidopentanoate

A mixture of 145g (0.49mol) of ethyl 4,5-diphenyl-5-oxopentanoate, 40g (0.58mol) of hydroxylamine hydrochloride, and 142g (1.8mol) of pyridine in 300ml of absolute ethanol was allowed to stand at ambient temperature for 3.5 days. The mixture was poured into 500ml of water and extracted with 3 x 700ml of ether. The organic layers were com¬ bined, washed with 3 x 200ml of IN hydrochloric acid, water, brine and dried over sodium sulphate. Concentration of the filtrate gave 150g (98%) of ethyl 4,5-diphenyl-5- oximidopentanoate as a white solid.

(c) cis- anc t 7t -5.6-diphenyl-2-piperidinone

A mixture of 150g (0.48mol) of ethyl 4,5-diphenyl-5-oximidopentanoate and 20g of 10% palladium on carbon in 11 of glacial acetic acid was subjected to 2.7atm (40psi) of hydro¬ gen on a Parr apparatus for 2 days. The catalyst was filtered and the filtrate concen¬ trated to near dryness by azeotropic removal of the acetic acid with toluene. The result- ing residue was dissolved in 21 of ethyl acetate and washed successively with 3 x 200ml of IN hydrochloric acid, water, brine and dried over sodium sulphate. Repeated recrystallization of the crude solid product from toluene gave 35g (29%) of pure trans- 5,6-diphenyl-2-piperidinone as a white solid (mp 160-164°C). Concentration of the toluene filtrates and repeated recrystallization from toluene gave 35g (29%) of pure cis- 5,6-diphenyl-2-piperidinone as a white solid (mp 183-186°C). Any remaining mixture of cis and trans isomers could be separated by chromatography on silica gel. Work-up of the aqueous acidic washes by standard basification and extraction procedures gave 40g (28%) of ethyl 5-amino-4,5-diphenylpentanoate as a mixture of isomers, which could be warmed at 50-60°C in 150ml of pyridine for 25 hours to give, after an extractive work-up procedure, an additional 30g of a mixture of cis and trans isomers, separable by recrystallization or chromatography.

s Intermediate 3

6.6-Diphenyl-2-piperidinone

(a) 4-bromo-l.l-diphenyl-l-butene

To a vigorously stirred solution of 250g (l.lmol) of cyclopropyl diphenyl carbinol in 2.51 o of toluene at ambient temperature was added rapidly 3.11 of 48% aqueous hydrobromic acid. After stirring for several hours, the layers were separated, the organic phase was washed with 11 of water, 11 of 10% aqueous sodium bicarbonate, and dried over sodium sulphate. The resulting crude oil residue was subjected to high vacuum short path distil¬ lation to give 300g (95%) of 4-bromo-l,l-diphenyl-l-butene as a clear oil. 5

(b) 5.5-diphenyl-4-pentenenitrile

To a stirred solution of 73g (1.5mol) of sodium cyanide in 11 of hexamethylphosphor- amide at ambient temperature was added over a 1 hour period a solution of 290g (lmol) of 4-bromo-l,l-diphenyl-l-butene in 0.51 of hexamethylphosphoramide. The 0 mixture was stirred overnight, poured into 21 of water and extracted with 3 x 11 of ether. The ether extracts were combined, washed with 3 x 0.51 of water, 0.51 of brine, and dried over sodium sulphate. The resulting crude solid was recrystallized from isopropyl ether to give 190g (80%) of 5,5-diphenyl-4-pentenenitrile as a white solid (mp 64-66°C).

5 (c) 6.6-diphenyl-2-piperidinone

A stirred mixture of 24g (0.17mol) of granular phosphorus pentoxide and 240g (2.5mol) of 98% methanesulphonic acid was maintained at 110°C until all the solid dissolved (1 hour). To this solution was added in portions over several minutes 12g (0.05mol) of 5,5- diphenyl-4-pentenenitrile. The resulting dark mixture was heated for 5 minutes longer 0 and then carefully added to an ice-cooled vigorously stirred mixture of 11 of saturated aqueous sodium bicarbonate and 11 of ethyl acetate. The basic aqueous phase was extracted with 3 x 500ml of fresh ethyl acetate, the organic layers were combined, washed with 2 x 500ml of water, 1 x 500ml brine, and dried over sodium sulphate. The resulting crude solid was recrystallized from toluene to give 8.5g (66%) of 6,6-diphenyl-2- piperidinone as a white solid (mp 193-196°C),

Example 1 l-fAminomethylV5,5-diphenyl-2-piperidinone maleate

(a) l-fHydroxymethyO-5.5-diphenv1-2-piperidinone

To a stirred mixture of 37g (0.147mol) of 5,5-diphenyl-2-piperidinone and 2.4g of sodium hydroxide in 170ml of ethanol at ambient temperature was added dropwise 165ml of a 35-40% formaldehyde in water solution during 10 minutes. The mixture was heated at reflux temperature overnight, concentrated to near dryness and partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and dried. Concentration at less than 30°C under vacuum, trituration with hexanes and filtration gave 28g of product, mp 140-150°C (decomp).

(b) l-fChloromethyO-5,5-diphenyl-2-piperidinone

To a stirred suspension of 28g (O.lmol) of the product of step (a) in 150ml of benzene at 10°C was added dropwise a solution of 16ml (1.63mol) of thionyl chloride in 150ml of benzene. The mixture was allowed to warm to ambient temperature, stirred over- night and concentrated to dryness. Fresh benzene was added and the solution reconcentrated several more times to give 27g of crude l-(chloromethyl)-5,5-diphenyl-2- piperidinone as a white solid.

(c) l-fAminomethylV5,5-diphenyl-2-piperidinone maleate l-Chloromethyl-5,5-diphenyl-2-piperidinone (16g) was added portionwise over 15 min¬ utes to a mixture of ammonia (100ml), toluene (100ml) and tetrahydrofuran (THF, 100ml) at -40°C with stirring and the mixture was allowed to warm to room temperature over 3 days. The reaction mixture was partitioned between water and chloroform and the combined organic solvents were washed with water and brine. Concentration of the solvents to dryness gave 15g of crude product which was dissolved in absolute ethanol (150ml) and treated with maleic acid (6g) dissolved in ethanol (15ml). Ether (50ml) was added and the precipitated solid (13g) was filtered off. The solid (13g) was dissolved in 850ml of water having a temperature of 40°C, filtered and the aqueous solution was freeze-dried to give the title product as a maleate salt (mp 136°C).

Example 2 trα/ y-l-Aminomethyl-5.6-diphenyl-2-piperidinone

Using essentially the method described above in Example 1(a) but substituting trans-5,6- diphenyl-2-piperidinone for 5,5-diphenyl-2-piperidinone resulted in the formation of trα/w-l-(hydroxvmethyl)-5,6-diphenyl-2-piperidinone (mp 127-129°C). Using essentially the methods described in Example 1(b) and 1(c) above and substituting trα/w-l-(hydroxy- methyl)-5,6-diphenyl-2-piperidinone for l-(hydroxyrnethyl)-5,5-diphenyl-2-piperidinone, gave tr /w-l-(aminomethyl)-5,6-diphenyl-2-piperidinone hydrochloride (mp 115-117°C dec).

Example 3 l-ffMethylaminolmethylj-S.S-diphenyl-Σ-piperidinone hydrochloride

l-(Chloromethyl)-5,5-diphenyl-2-piperidinone (27g) was added portionwise during 20 minutes to a solution of methylamine (120ml) in a mixture of toluene (100ml) and THF (100ml) at -30°C with stirring and the mixture was allowed to warm to room tempera¬ ture overnight. The reaction mixture was partitioned between ethyl acetate and water and the organic solvent layer was washed with water and brine. The aqueous layers were re-extracted with ethyl acetate and then chloroform. All the organic extracts were combined and concentrated to give the crude title product as a solid which was con- verted to the hydrochloride salt by dissolution in isopropanol/methanol [5:1] and then adding portionwise a solution of hydrogen chloride in isopropanol until the medium was acidic. The solution was cooled overnight at 0-5°C and the hydrochloride salt of the title product was filtered of as a solid, mp 169-171°C.

Example 4 Following essentially the methods of Example 3 but substituting ethylamine, isopropyl- amine, cyclopropylamine, propylamine and dimethylamine for methylamine resulted in the formation of the following compounds:

(a) l-[(ethylamino)methyl]-5,5-diphenyl-2-piperidinone hydrochloride, mp 100- 105°C;

(b) l-[(isopropylamino)methyl]-5,5-diphenyl-2-piperidinone hydrochloride, mp 170- 172°C;

(c) l-[(cyclopropylamino)methyl]-5,5-diphenyl-2-piperidinone hydrochloride, mp 143-145°C; (d) l-[(propylamino)methyl]-5,5-diphenyl-2-piperidinone maleate, mp 161-164°C; and

(e) l-[(dimethylamino)methyl]-5,5-diphenyl-2-piperidinone hydrochloride, mp 100- 110°C dec.

Example 5 l-[3-fDimethylamino propyl]-5.5-diphenyl-2-piperidinone hydrochloride

To a vigorously stirred mixture of 5,5-diphenyl-2-piperidinone (5.0g) and 45% potassium hydroxide (15ml) in dimethyl sulphoxide (50ml) was added in one portion 3-(dimethyl- amino)propyl chloride (5.5g) at room temperature. The reaction was stirred overnight, then it was partitioned between water and ethyl acetate. The organi layer was separ¬ ated, washed with water and dried. Evaporation of the solvents afforded a syrup which was chromatographed over ammonia-washed silica gel and the resultant title product amine was treated with isopropanol/HCl. The precipitated hydrochloride salt was col- lected by filtration, recrystallized from absolute ethanol and dried to give the title prod¬ uct as the hydrochloride salt (3.6g), mp 220-225°C.

Example 6 l-[2- Dimethylamino )ethyl]-5,5-diphenyl-2-piperidinone hydrochloride

Following essentially the method of Example 5 but substituting 2-(dimethylamino)ethyl chloride for 3-(dimethylamino)propyl chloride resulted in the formation of l-[2-(di- methylamino)ethyl]-5,5-diphenyl-2-piperidinone hydrochloride, mp 247-248°C. Example 7 l-fAminomethylV4.4-diphenyl-2-pyrrolidinone maleate

Using essentially the method described above in Example l(a)-(c), but substituting 4,4- s diphenyl-2-pyrrolidinone for 5,5-diphenyl-2-piperidinone, gave l-(aminomethyl)-4,4-di- phenyl-2-pyrrolidinone maleate, mp 141°-143^CC.

Example 8 l-fAminomethylV5.5-diphenyl-2-piperidinone maleate monohydrate 0

Using essentially the methods described in Example 1, the solid maleate obtained by precipitation from ethanol with ether was obtained and found to contain 12% ethanol, wt=24.8g. The solid was dissolved in water (100ml) at 60°C. On cooling to 15°C, a crystalline solid precipitated and was filtered off to give the title compound in the form s of a monohydrate, wt=21.5g, mp 95-105°C.

Example 9 l-(AminomethylV5.5-diphenyl-2-piperidinone hydrochloride

o Using essentially the methods described in Example 1, but substituting dry hydrochloric acid for maleic acid, the solid obtained from ethanol/ether was collected by filtration and dried in vacuo at 56°C to give the title compound as a white solid, mp 168-171°C.

Example 10 5

The compound of Example 1 was tested in test (a) described above, with oral dosing of rats, and found to inhibit seizures by 50% (ED_S0) at a dose of 21mg.kg^'1.

Claims

Claims:

1. A compound of formula I,

wherein two of R\ R², R³ and R⁴ independently represent phenyl optionally substituted by one or more groups selected from halogen, hydroxy, nitro, amino, C_w alkyl and C,^ alkoxy; and the remainder of R¹, R², R³ and R⁴ independently represent hydrogen or C,^ alkyl; o R⁵ and R⁶ independently represent hydrogen, C,^ alkyl or C₃^ cycloalkyl, or R⁵ and R⁶ together with the nitrogen atom to which they are attached form a C₄^N heterocycle; m is 1 or 2; and n is 1,

2 or 3; or a pharmaceutically acceptable acid addition salt thereof, s 2. A compound as claimed in claim 1, wherein n is 1.

3. A compound as claimed in claim 1 or claim 2, wherein R¹ and R² both repre¬ sent phenyl.

4. A compound as claimed in any one of the preceding claims, wherein R^s and R⁶ independently represent hydrogen, C,.₃ alkyl or cyclopropyl. o

5. A compound as claimed in any one of the preceding claims, wherein R^s and R⁶ both represent hydrogen.

6. A compound as claimed in any one of claims 1 to 4, wherein one of R⁵ and R⁶ represents hydrogen and the other represents methyl.

7. A compound as claimed in any one of the preceding claims, wherein m is 2. 5

8. A compound as claimed in claim 1, which is: l-[(methylamino)methyl]-5,5-diphenyl-2-piperidinone; l-(aminomethyl)-5,5-diphenyl-2-piperidinone; tran5-l-(aminomethyl)-5,6-diphenyl-2-piperidinone; l-[(dimethylamino)methyl]-5,5-diphenyl-2-piperidinone; l-[(ethylamino)methyl]-5,5-diphenyl-2-piperidinone; l-[(isopropylamino)methyl]-5,5-diphenyl-2-piperidinone; l-[(cyclopropylamino)methyl]-5,5-diphenyl-2-piperidinone; 5 l-[(propylamino)methyl]-5,5-diphenyl-2-piperidinone; l-[3-(dimethylamino)propyl]-5,5-diphenyl-2-piperidinone; l-[2-(dimethylamino)ethyl]-5,5-diphenyl-2-piperidinone; or l-(aminomethyl)-4,4-diphenyl-2-pyrrolidinone; or a pharmaceutically acceptable acid addition salt thereof. o

9. A pharmaceutical formulation including a compound of formula I, as defined in claim 1, or a pharmaceutically acceptable acid addition salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

10. A compound of formula I, as defined in claim 1, or a pharmaceutically accept¬ able acid addition salt thereof, for use as a pharmaceutical, s

11. The use of a compound of formula I, as defined in claim 1, or a pharmaceuti¬ cally acceptable acid addition salt thereof, in the manufacture of an anticonvulsant or neuroprotective medicament.

12. A process for the production of a compound of formula I, as defined in claim

1, or pharmaceutically acceptable acid addition salt thereof, which comprises: o (a) for compounds of formula I in which n is 1, reacting a compound of formula II,

in which R¹, R², R³, R⁴ and m are as defined in claim 1, n is 1 and X is a suitable leav¬ ing group, with a compound of formula R⁵R⁶NH in which R⁵ and R⁶ are as defined in 5 claim 1;

(b) for compounds of formula I in which n is 2 or 3, reacting a compound of for¬ mula III,

in which R\ R², R³, R⁴ and m are as defined in claim 1, with a compound of formula IV,

R⁵R⁶N-(CH₂)_n-X IV

in which n is 2 or 3, X is a suitable leaving group and R^s and R⁶ are as defined in claim 1 and in addition NR^SR⁶ may represent protected amino; or (c) for compounds of formula I containing one or more amino or hydroxy groups, removing a protecting group from a corresponding compound in which one or more of the amino or hydroxy groups is protected; and where desired or necessary converting the resulting compound of formula I into a pharmaceutically acceptable acid addition salt thereof or vice versa.