GB2231048A - Bicyclic aminohydroxamate neuroprotective agents - Google Patents

Abstract

Compounds of formula I or acid addition salts thereof: <IMAGE> wherein R<1>, R<3> and R<4> independently represent hydrogen or hydrocarbon; R<2> represents hydrogen, hydrocarbon, halogen, OR<a>, -SR<a>, -NR<a>R<b>, -NR<a>COR<b>, -NR<a>CO2R<b>, -NR<a>SO2R<b>, -NR<c>CTNR<a>R<b>, -CO2R<a> or -CONR<a>R<b>; U represents oxygen or sulphur; X, Y and Z independently represent a bond or a group of formula -(CH2)m- or -(CH2)qCH=CH(CH2)r-, provided that X, Y and Z do not simultaneously each represent a bond; R<a>, R<b> and R<c> independently represent hydrogen or hydrocarbon; T represents oxygen. sulphur or a group of formula =N.E; E represents hydrocarbon or an electron-withdrawing group; m is an integer from 1 to 4; and q and r independently represent zero or 1, are specific antagonists of N-methyl-D-aspartate receptors and are useful for treatment and/or prevention of neurodegenerative disorders.

Description

BICYCLIC AXINOHYDROXAMATES AS NEUROPROTECTIVE AGENTS This invention relates to a class of bicyclic aminohydroxamates which are specific antagonists of N-methyl-D-aspartate (NMDA) receptors and are therefore useful in the treatment and/or prevention of neurodegenerative disorders arising as a consequence of such pathological conditions as stroke, hypoglycaemia, cerebral palsy, transient cerebral ischaemic attack, cerebral ischaemia during cardiac pulmonary surgery or cardiac arrest, perinatal asphyxia, epilepsy, Huntington's chorea, Alzheimer's disease, Olivo-pontocerebellar atrophy, anoxia such as from drowning, spinal cord and head injury and poisoning by exogenous NMDA receptor agonists and neurotoxins. The compounds are also useful as anticonvulsant agents and muscle relaxants.

The compound 3 -amino-l-hydroxypyrrol idin-2 -one is disclosed in Collect. Czech. Chem. Commun., 1959, 24, 1672, and its use in the treatment of epilepsy and Parkinson's disease is described in British Patent No.

1,041,861. That compound, known as HA-966, has also been described as being able to antagonise selectively NMDAinduced excitation (Evans et al., Brain Research, 1978, 148, 536-542).

We have now found a class of bicyclic aminohydroxamates that have dramatically improved NMDA receptor antagonist activity compared with HA-966 itself.

Accordingly, the present invention provides a compound of formula I or an acid addition salt thereof:

wherein R1, R3 and R4 independently represent hydrogen or hydrocarbon; R2 represents hydrogen, hydrocarbon, halogen, ORa, SRa, NRaRb, -NRaCORb, -NRaCO2Rb, NRaCO2Rb -NRCCTNRaRb, -CO2Ra or CONRaRb; U represents oxygen or sulphur; X, Y and Z independently represent a bond or a group of formula -(CH2)m- or (CH2)qCH=CH(CH2)r, provided that X, Y and Z do not simultaneously each represent a bond; Ra, Rb and Rc independently represent hydrogen or hydrocarbon; T represents oxygen, sulphur or a group of formula =N.E; E represents hydrocarbon or an electronwithdrawing group;; m is an integer from 1 to 4 and q and r independently represent zero or 1.

For use in medicine, the salts of the compounds of formula I will be non-toxic pharmaceutically acceptable acid addition salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their non-toxic pharmaceutically acceptable salts. Suitable pharmaceutically acceptable acid addition salts of the compounds of this invention include pharmaceutically acceptable inorganic salts such as sulphate, nitrate, phosphate, borate, hydrochloride and hydrobromide, and pharmaceutically acceptable organic acid addition salts such as acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methanesulphonate, a-ketoglutarate, a-glycerophosphate and glucose-lphosphate. Preferably the acid addition salt is a hemisuccinate, hydrochloride, a-ketoglutarate, a-glycerophosphate or glucose-l-phosphate, in particular the hydrochloride salt.

The term "hydrocarbon" as used herein includes straight-chained, branched and cyclic groups, including heterocyclic groups, containing up to 18 carbon atoms, suitably up to 15 carbon atoms, and conveniently up to 12 carbon atoms. Suitable hydrocarbon groups include C16 alkyl, C26 alkenyl, C26 alkynyl, C37 cycloalkyl, C37 cycloalkyl(C1,6)alky1, aryl, aryl(C1,6)alkyl, C37 heterocycloalkyl, C37 heterocycloalkyl(C1-6)alkyl, heteroaryl and heteroaryl(C1,6)alky1.

Suitable alkyl groups include straight-chained and branched alkyl groups containing from 1 to 6 carbon atoms. Typical examples include methyl and ethyl groups, and straight-chained or branched propyl and butyl groups.

Particular alkyl groups are methyl, ethyl and t-butyl.

Suitable alkenyl groups include straightchained and branched alkenyl groups containing from 2 to 6 carbon atoms. Typical examples include vinyl and allyl groups.

Suitable alkynyl groups include straightchained and branched alkynyl groups containing from 2 to 6 carbon atoms. Typical examples include ethynyl and propargyl groups.

Suitable cycloalkyl groups include groups containing from 3 to 7 carbon atoms. Particular cycloalkyl groups are cyclopropyl and cyclohexyl.

Suitable aryl groups include phenyl and naphthyl groups.

A particular aryl(C1,6)alkyl group is benzyl.

Suitable heterocycloalkyl groups include piperidyl, piperazinyl and morpholinyl groups.

Suitable heteroaryl groups include pyridyl, quinolyl, isoquinolyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furyl, benzofuryl, thienyl, benzthienyl, imidazolyl, oxadiazolyl and thiadiazolyl groups. Particular heteroaryl groups are pyridyl and oxadiazolyl.

The hydrocarbon group may in turn be optionally substituted by one or more groups selected from C16 alkyl, adamantyl, phenyl, halogen, C16 haloalkyl, trifluoromethyl, hydroxy, C16 alkoxy, aryloxy, keto, C1-3 alkylenedioxy, nitro, cyano, carboxy, C16 alkoxycarbonyl, C16 alkoxycarbonyl(C1-6)alkyl, C16 alkylcarbonyloxy, optionally substituted arylcarbonyloxy, C16 alkylcarbonyl, optionally substituted arylcarbonyl, C1-6 alkylthio, C16 alkylsulphinyl, C16 alkylsulphonyl, amino, mono- or di(C16)alkylamino, C16 alkylcarbonylamino and C1-6 alkoxycarbonylamino.

When the group E represents an electronwithdrawing group, this group is suitably cyano, nitro, -CORa, -CO2Ra or -SO2Ra, in which Ra is as defined above.

When R1 represents a hydrocarbon group, this group is suitably C16 alkyl, aryl or aryl(C1-6)alkyl.

Preferably, R1 represents hydrogen, methyl, phenyl or benzyl.

The R2, R3 and R4 substituents may be present at any available position within the bicyclic ring system of formula I above, including either bridgehead position and the unsaturated moiety. Suitably, R2 represents hydrogen, hydroxy, amino, C14 alkyl, aryl(C14)alkyl, C14 alkoxy or C24 alkoxycarbonyl, preferably hydrogen, hydroxy, amino, methyl, benzyl, methoxy or methoxycarbonyl, and particularly hydrogen. Suitably, R3 and R4 independently represent hydrogen, C14 alkyl or aryl(C1-4)alkyl.

Suitably, the groups X, Y and Z independently represent a bond or a methylene, ethylene or propylene group, either unsubstituted or substituted by one or more groups R2, R3 and R4 as defined above. In particular, X suitably represents a substituted or unsubstituted methylene or ethylene group; and Z suitably represents a bond or a substituted or unsubstituted methylene group.

The compounds according to the invention generally have at least one asymmetric centre, and can accordingly exist both as enantiomers and as diastereoisomers. In particular, those compounds possessing a substituted bicyclic ring system may exist as exo and endo isomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.

A particular subgroup of compounds within the scope of the present invention is represented by the compounds of formula II and acid addition salts thereof:

wherein R1, R2, R3, R4 and U are as defined with reference to formula I above; and x, y and z independently represent zero, 1, 2, 3 or 4, provided that they are not simultaneously each zero. Suitably, x and y independently represent 1, 2 or 3; and z is zero or 1.

Preferred values of (x,y,z) include (1,2,0), (0,2,1), (2,1,0), (1,3,0) and (1,1,1), giving rise to the 2,6 diazabicyclo(3. 2. l]octane, 2,7-diazabicyclo[3. 3. 0]octane, 2,5-diazabicyclo[2.2.2]octane, 2,7-diazabicyclo (4.2. l]nonane and 3, 6-diazabicyclo(3.2.ljoctane ring systems respectively. A particularly preferred ring system of formula II is that wherein x is 1, y is 2 and z is zero, i.e. the 2,6-diazabicyclo[3.2.1]octane ring system.

Specific compounds within the scope of the present invention include the following, and acid addition salts thereof:

2,6-diaza-6-hydroxy 7-oxobicyclo[3.2.lloctane 2,6-diaza-6-hydroxy-8-endo-methyi- 7-oxobicyclo[3.2.1]octane The invention also provides pharmaceutical compositions comprising one or more compounds of this.

invention in association with a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, or suppositories, for oral, parenteral or rectal administration. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a nontoxic pharmaceutically acceptable salt thereof.When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.

In the treatment of neurodegeneration, a suitable dosage level is about 0.01 to 1000 mg/kg per day, preferably about 0.05 to 500 mg/kg per day, and especially about 1 to 100 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day The compounds according to the invention wherein U is oxygen may be prepared by a process which comprises cyclising a hydroxylamine derivative of formula III:

wherein R2, R3, R4, X, Y and Z are as defined above, R5 represents hydrogen or a hydroxy-protecting group, R11 is as defined for R1 above or represents an amino-protecting group, and Q represents a reactive carboxylate moiety; followed, where appropriate, by removal of the protecting groups.

When the group Q represents a reactive carboxylate moiety, suitable values for this group include esters, for example C14 alkyl esters; acid anhydrides, for example mixed anhydrides with C14 alkanoic acids; acid halides, for example acid chlorides; orthoesters; and primary, secondary and tertiary amides.

Suitably, the group Q represents carboxy, in which case the cyclisation is conveniently carried out in the presence of a condensing agent such as 1,3-dicyclohexylcarbodiimide.

When Q represents a reactive carboxylate moiety as defined above, the cyclisation is conveniently effected in the presence of a base, for example sodium methoxide.

Examples of hydroxy-protecting groups for the substituent R5 suitably include allyl, alkoxyalkyl, acyloxyalkyl, t-butyl and benzyl. Preferably R5 represents benzyl or t-butyl. Removal of hydroxy protecting groups will be dependent upon the nature of the group concerned, but will in general be effected by conventional means. For example, a benzyl protecting group may conveniently be removed by hydrogenation in the presence of a suitable catalyst, e.g. palladium; and a t-butyl protecting group may conveniently be removed by mild mineral acid hydrolysis.

Suitable examples of amino-protecting groups for the substituent R11 include carboxylic acid groups such as chloroacetyl, trifluoroacetyl, formyl, benzoyl, phthaloyl, phenylacetyl or pyridinecarbonyl; acid groups derived from carbonic acid such as ethoxycarbonyl, benzyloxycarbonyl, t-butoxycarbonyl, biphenylisopropoxycarbonyl, p-methylbenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, p-phenylazobenzyloxycarbonyl, p- (p '-methoxyphenyl- azo)benzyloxycarbonyl or t-amyloxycarbonyl; acid groups derived from sulphonic acid, e.g. p-toluenesulphonic acid; and other groups such as o-nitrophenylsulphenyl.

Preferred amino-protecting groups include t-butoxycarbonyl and benzyloxycarbonyl.

The removal of the amino-protecting group present in the resultant compound may be effected by an appropriate procedure depending upon the nature of the protecting group. Typical procedures include hydrogenation in the presence of a palladium catalyst (e.g. palladium carbon or palladium black) for benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, p-phenylazobenzyloxycarbonyl and p-(p'-methoxyphenylazo)benzyloxycarbonyl groups; treatment with hydrogen bromide in glacial acetic acid or trifluoroacetic acid for benzyloxycarbonyl, p-bromobenzyloxycarbonyl, p-phenylazobenzyloxycarbonyl and t-butoxycarbonyl groups; and treatment with hydrochloric acid and/or acetic acid for t-butoxycarbonyl and formyl groups.

Where the product obtained from the abovedescribed process is a compound of formula I above in which R1 is hydrogen, and where the desired final product is a compound of formula I in which R1 is other than hydrogen, the hydrocarbon group R1 may be attached subsequently. This may be effected by conventional methods such as alkylation or arylation, for example by treating the N-H compound with an alkyl halide, or by reductive amination. The latter process comprises acylating the N-H compound in the presence of a reducing agent. Suitable reducing agents include sodium borohydride, sodium cyanoborohydride, and hydrogen in the presence of a catalyst such as palladium on charcoal or platinum oxide.

The compounds of the invention wherein U is sulphur may be prepared from the corresponding compounds of formula I above wherein U represents oxygen by treating the latter compound with Lawesson's reagent or phosphorus pentasulphide in a suitable solvent, e.g.

pyridine, at ambient or elevated temperatures, suitably at reflux temperature.

The intermediates of formula III above may be prepared by reduction of an oximino derivative of formula IV:

wherein R2, R3, R4, R5, Rll, Q, X and Y are as defined above; and Z1 represents a bond direct to the ring, or represents a group of formula -(CH2)m-1CH' or -(CK2)qCH=CHCH=, in which m and q are as defined above.

A preferred reducing agent for effecting this transformation is sodium cyanoborohydride in a suitable solvent, e.g. an alcoholic solvent such as methanol, in the presence of an acid such as hydrochloric acid, suitably at ambient temperature.

The compounds of formula IV may be prepared by reaction of a carbonyl compound of formula V:

wherein R2, R3, R4, R11, Q, X, Y and "1 are as defined above; with a compound of formula H2N-OR5, in which R5 is as defined above.

The reaction is preferably effected in the presence of a base, e.g. triethylamine, or under mildly acidic conditions, suitably at ambient temperature.

The carbonyl compounds of formula V above may conveniently be prepared by the methods described in Tetrahedron Lett., 1981, 22, 4607 and Tetrahedron Lett., 1988, 29, 2231, or by methods analogous thereto.

The above-described processes for the preparation of the compounds according to the invention will generally give rise to mixtures of stereoisomers.

At an appropriate stage, these isomers may be separated by conventional techniques such as preparative chromatography.

The novel compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The novel compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-dtartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base. The novel compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary.

During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective GrouPs in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, 1981. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

The compounds useful in this invention potently and selectively block responses to NMDA in a brain slice from rat cortex, and inhibit glycine binding to the strychnine-insensitive site present on the NMDA receptor.

Cortical Slice Studies The effects of compounds of the invention on responses to NMDA were assessed using the rat cortical slice as described by Wong et al., Proc. Natl.

Acad. Sci. USA, 1986, 83, 7104. The apparent equilibrium constant (Kb) was calculated from the righthand shift in the NMDA concentration-response curve produced by the compound under test. The compounds of the accompanying Examples were tested and each was found to possess a Kb value below 100 ssM.

Inhibition of Glvcine Binding The ability of test compounds to displace 3H-glycine binding to the strychnine-insensitive site present on the NMDA receptor of rat forebrain membranes was determined by the method of Donald et al., Proceedings of The British Pharmacological Society, University of Nottingham, September 1988, Abstract P122.

The concentration of the compounds of the accompanying Examples required to displace 50% of the specific binding (IC50) was found to be below 20 pM in each case.

EXAMPLE 1 2 6-Diaza-6-hvdroxv-7-oxobicvclo[3 .2. ijoctane a) Ethyl N4-butoxycarbonyl-4-ketopiperidine-2-carboxylate.

A solution of ethyl N-t-butoxycarbonylglycinate (7.15g) and Nbromosuccinimide (6.27g) in carbon tetrachloride (50ml) was irradiated with a quartz lamp (lANEBEAM 800) for Ih at 20"C.

The solution was filtered and the solvent removed in vacuo to give a pale yellow oil. To a solution of this oil in dry toluene, (50ml) cooled to OOC, was added diisopropylethylamine (7ml).

After 10 minutes 2-trimethylsilyloxybutadiene (5g) was added and the solution heated for 16h at 80 C under an atmosphere of nitrogen. The solution was filtered, evaporated and methanol (50ml) and Dowex 50W-x 8 (H+form, 20g) were added and the solution heated to boiling for 5 minutes, cooled, filtered and evaporated to dryness. The residue was chromatographed on silica gel (15 x 7cm) in diethylether/hexane 1:1 to give ethyl N-tbutoxycarbonyl-4-ketopiperidine-2-carboxylate 2.63g (27.6%) as an oil, nile CI+ 272 (M+H), CI-270 (M-H). An analytical sample (lOmg) was treated with anhydrous TFA (lOml) for 20 min followed by evaporation to give 1H NMR (250 MHz, CDCl3) 4.5 (1H; dd; NCH-CO), 4.35 (2H; q; OCH2CH3), 3.92(1H; m; NCAHB), 3.6(1H;m;NCHAHB), 3.22-2.72(4H; m; CH2COCH2), 1.30(3H;t; OCH2CH3) b) Ethyl cis-4-0-benzylhydroxylamino-N-t-butoxy- carbonslpiperidine-2-carboxYlate Ethyl N-t-butoxycarbonyl-4-ketopiperidine-2 -carboxylate (EXAMPLE la, 2.2g) and O-benzylhydroxylamine hydrochloride (1.3g) were dissolved in isopropanol (50ml) and triethylamine (1.13ml) for 16h.Methanol (50ml), sodium cyanoborohydride (1.28g) and methyl orange (ca 20mg) were added and the solution cooled to OOC. A solution of conc HCl/MeOH (1:3) was added dropwise until the solution became a red colour and the solution was maintained red in colour over 2h by continued addition of acid as required. Water (200ml) and solid sodium carbonate were added until pH=lO. The product was extracted into ethyl acetate (3x200ml) and the combined organic phases were washed with saturated brine and dried over MgS04.After removal of the solvent in vacuo the residue was chromatographed on silica gel eluting with ethyl acetate/hexane (1:4) to give the cis-isomer (494mg) eluting slightly earlier than the trans isomer (521mg) of ethyl 4-O-benzylhydroxvlamino-N-t- butoxycarbonolpiperidine-2-carboxylate.

c) 6-Benzvloxy-2-butoxvcarbonyl -2,6-diaza-7 - oxobicyclof3 .2. octane The cis-isomer (EXAMPLE lb, 250mg) was dissolved in methanol (0.35ml) and 4N-sodium hydroxide (0.35ml) added.

After 2h methanol (0.18ml) and 4N-sodium hydroxide (0.18ml) were added. After a further Ih methanol (15ml) and Dowex 50W x 8 (H+form, 5ml) were added, the solution filtered and the solvent removed in vacuo. Dichloromethane (15ml) and N,N-dicyclohexylcarbodiimide (0.136g) were added and after 16h 1-hydroxybenzotriazole (0.101g) was added. After a further 1h glacial acetic acid (0.075ml) was added for 20 min followed by ethyl acetate (15ml). The solution was filtered, evaporated and chromatographed on silica gel eluting with ethyl acetate/hexane (1:1) to give 6-benzyloxy-2-butoxycarbonyl-2,6-diaza-7-oxo bicyclo[3.2.1]octane (0.104g, 44%) as an oil.

d) 2,6-diaza-6-hydroxy-7-oxobicyclo[3.2.1]octane The oil (EXAMPLE Ic, 104mg) was dissolved in ethanol (20ml), palladium black (40mg) was added and the suspension hydrogenated at SOpsi for 3h. The solution was filtered and the solvent removed in vacuo. Tosic acid monohydrate (72mg) in ethanol (5ml) was added, the solution evaporated and the residue washed (2x20ml) with diethyl ether. The residue was recrystallized from ethanol/ethyl acetate to give colourless crystals of 2 q6-diaza-6-hvdroxv-7-oxobicvclo(3.2.1]octane 49.7mg, mp= 192-192.5 C, m/e CI+ 143 (M + H), CI 141 (M - H).

1H NMR (360 MHz, D20) 7.70 (2H; d; tosyl 2CH and 6C~), 7.38 (2H; d; tosyl 3CH and 5CH, 4.17 (1H; t; CHNOH), 4.11 (1H; d: CHCO), 3.54(1H; dd; CH2CHAHBN),3.14 (1H; m; CH2CHAHBN), 2.47 (1K; m; CHAHBCHCO), (3H; s, tosyl CH3),2.30(1H;m;CHAHBCH2N), 2.17(1H;d;CHAHBCHCO), 2.11 (1H; m; CHAHBCH2N. Anal. Calcd. for C6H1oN202 C7HgS03: C, 49.67; H,5.77; N,8.91. Found: C, 49.54; H,5.75; N,8.90.

EXAMPLE 2 2,6-Diaza-6-hydroxy-8-endo-methyl-7 - oxobicsclo[3.2. octane a) Ethyl t-butoxYcarbonyl-4-oxo-1.2.3.4- tetrahvdropvridine-2-carboxvlate Ethyl t-butoxycarbonylglycinate (28.6g) was brominated as in method a (above) with N-bromosuccinimide (25g), filtered, evaporated and dissolved in toluene (200ml). To this solution was added diisopropylethylamine (28ml) followed by 1-methoxy3-trimethylsilyloxy-1,3-butadiene (26.0g) and the suspension heated at 80 C for 16h. On cooling to 40 C methanol (40ml) was added and the solution washed with 10% aqueous citric acid, water and saturated brine.After drying over sodium sulfate, the solvent was removed in vacuo and the residual oil crysallised from diethyl ether/hexane to give ethyl N-t butoxycarbonvl-4-oxo-1 .2.3 .4-tetrahvdropvridine-2-carboxylate, 22.8g, mp 95-96 C.

b) Ethyl N-t-butoxycarbonyl-3-trans-methyl-4- oxopiperidine-2-carboxylate To a cooled (-70 C) solution of potassium hexamethyldisilazide (0.75M in toluene, 26ml) in tetrahydrofuran (50ml) was added dropwise a solution of ethyl N-t-butoxycarbonyl-4-oxo-1 ,2 ,3 ,4-tetrahydropyridine-2- carboxylate (Example 2a, 5g) in tetrahydrofuran (50ml) over 20 minutes. After stirring the solution for 30 minutes at -700C methyl iodide (3.3ml) was added and the solution warmed to -30 C over 3h. Water (4ml) was added and the mixture partitioned between diethyl ether (lOOml) and water (2 x 100ml). The combined organic phases were washed with saturated brine and dried over magnesium sulfate.After the solvent had been removed in vacuo the residue was chromatographed on silica gel eluting with ethyl acetate/petrol (bp 60-80"C) (30:70) to give ethyl N-t-butoxycarbonyl-3-methyl 4-oxol ,2 ,3 ,4-tetrahvdropiperidine-2 -e arb oxlvlate, 2g. A solution of the above (2g) in ethanol (lOOml) was hydrogenated in the presence of 10% palladium on charcoal (150mg) at 50 psi for 4h.

The solution was filtered and after removal of the solvent in vacuo the residue was chromatographed on silica gel eluting with ethyl acetate/petrol (bp 60-80"C) (1:2) to give the title compound, 350mg nile CI+ 286 (M+H), CI- 285 (M).

c) cis-4-O -benzvlhydroxvlamine-N-t-butoxycarbonyl-trans- 3-metholpiperidine-2-carboxylic acid To a solution of ethyl N-t-butoxycarbonyl-3-trans-methyl- 4-oxopiperidine-2-carboxylate (Example 2b, 1.lg) in isopropanol (50ml) was added O-benzylhydroxylamine hydrochloride (623mg) and triethylamine (0.54ml). After stirring the mixture at room temperature for 16h the solution was poured into a mixture of water (30ml) and ethyl acetate (50ml). The aqueous phase was separated and washed further with ethyl acetate (2 x 50ml). The combined organic phases were washed with saturated brine, dried over magnesium sulfate and evaporated in vacuo.To a solution of the residue in isopropanol (50ml) (containing methyl orange (ca 50mg)) was added sodium cyanoborohydride (756mg) followed by solid citric acid (added until a red-orange colour was formed). After stirring the solution for 3 days at room temperature it was poured onto water (30ml) and the product extracted with ethyl acetate (4 x 50ml). The combined organic phases were washed with saturated brine and dried over magnesium sulfate. After removal of the solvent in vacuo the residue was chromatographed on silica gel eluting with ethyl acetate/petrol (bp = 60-80"C) (30:70) to yield two isomeric 0 benzvlhvdroxvlamines.

To a solution of the earlier eluting isomer (600mg) in methanol (40ml) was added 4N-sodium hydroxide (4ml) for 4h.

The solvent was removed in vacuo and the residue partitioned between water (30ml) and ethyl acetate (50ml). The aqueous phase was extracted with ethyl acetate (2 x 50ml) and the combined organic phases were dried over magnesium sulfate and evaporated to an oil of cis-4-O-benzvlhydroxylamino-N-t- butoxycarbonyl-trans-3-methvlpiperidine-2-carboxvlic acid. The stereochemical assignment was confirmed by lH-NMR n.O.e.

experiments on a small sample of this material which had been treated with anhydrous trifluoroacetic acid to remove the Nbutoxycarbonyl group.

d) 6-Benzyloxy-2-butexycarbonyl-2,6-diaza-8-endo-methyl- 7-oxobicyclo3 .2. ijoctane To an ice-cold solution of the cis-O-benzvlhydroxvlamino isomer (Example 2c, 110mg) and triethylamine (0.084ml) in dichloromethane (10ml) was added bis(2-oxo-3oxazolidinyl)phosphinic chloride (76.2mg). After 3h the solution was partitioned between water (10ml) and dichloromethane (20ml). The organic phase was washed with saturated brine and dried over magnesium sulfate. After removal of the solvent in vacuo the residue was chromatographed on silica gel eluting with ethyl acetate/petrol (bp 60-800C) (1:2) to give the title compound, 100mg. lH-NMR (250MHz, CDCl3) showed the presence of a mixture of rotamers.A sample was treated with anhydrous trifluoroacetic acid to remove the N-butoxycarbonyl group to give 1H-NMR (250MHz, CDCl3) 7.4 (5H, m, phenyl); 5.0 (2K, dd, benzyl CH2); 4.1 (1H, m, CH-NO); 3.6 (1H, m, CHCO); 3.4 (1H, m, CHAHBN); 3.1 (1H, m, CHAHBN); 2.4 (1H, m, CHCH3); 2.0 m, CH2CH2N), 1.2 (3H, d, CHCH3).

e) 2,6-Diaza-6-hydroxy-8-endo-methyl-7- oxobicyclo[3.2.1]octane tosylate The endo-methyl isomer (Example 2d, 100mg) was dissolved in anhydrous trifluoroacetic acid (4ml) for 30 minutes followed by evaporation in vacuo and repeated evaporation of a methanolic solution. A solution of the residue (70mg) in ethanol (15ml) was hydrogenated in the presence of palladium black (50mg) at 50 psi for 2h. The solution was filtered, evaporated and redissolved in a solution of p-toluene sulfonic acid monohydrate (40mg) in ethanol (5 ml).After repeated evaporation from ethanol the residue was recrystallised from ethanol/diethyl ether to give 2,6-Diaza-6-hydroxy-8-endo- methyl-7-oxobicyclo[3.2.1]octane tosylate, 25mg, mp 226-2280C, m/e CI+ 157 (M+H), CI 155 (M-H). 1H NMR (360MHz, D20) 7.70 (2H, d, tosyl 2C11 and 6CH); 7.38 (2H, d, tosyl 3CH and 5C11); 3.97 (1H, m, CHNOH), 3.92 (1H, d, J = 3.66Hz, CHCO); 3.47 (1H, dd, CH2CHAHBN); 3.10 (1H, m, CH2CHACHBN); 2.74 (1K, m, CHCHJ3); 2.40 (3H, s, tosyl C113); 2.16 (2H, m, CH2CH2NH); 1.24 (3H, d, J = 7.2Hz). Anal.Calcd. for C7H12N202. C7H8SO3: C, 51.21; H, 6.14; N, 8.53. Found: C, 50.94; H, 6.10; N, 8.40.

EXAMPLE 3 Tablet Preparation Tablets containing 1.0, 2.0, 25.0, 26.0, 50.0 and 100.0mg, respectively, of 2,6-Diaza-6-hydroxy-7-oxobicyclo[3.2.1]octan and 2,6-Diaza-6-hydroxy-8-endo-methyl-7-oxobicyclo(3.2.1]octane are prepared as illustrated below.

TABLE FOR DOSES CONTAINING FROM 1-25MG OF THE ACTIVE COMPOUND Amount-mg.

Active Compound 1.0 2.0 25.0 Microcrystalline cellulose 49.25 48.75 37.25 Modified food corn starch 49.25 48.75 37.25 Magnesium stearate 0.50 0.50 0.50 TABLE FOR DOSES CONTAINING FROM 26-100MG OF THE ACTIVE COMPOUND Amount-mg Active Compound 26.0 50.0 100.0 Microcrystalline cellulose 52.0 100.0 200.0 Modified food corn starch 2.21 4.25 8.5 Magnesium stearate 0.39 0.75 1.5 All of the active compound, lactose, and a portion of the corn starch are mixed and granulated to 10% corn starch paste.

The resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate. The resulting granulation is then compressed into tablets containing 1.Omg, 2.0mg, 25.0mg, 26.0mg, 50.0mg, and 100mg of active ingredient per tablet.

Claims (20)

Claims:

1. A compound of formula I or an acid addition salt thereof:

wherein R1, R3 and R4 independently represent hydrogen or hydrocarbon; R2 represents hydrogen, hydrocarbon, halogen, -ORa, -SRa, -NRaCORb, -NRaRb, -NRaCORb, -NRaSO2Rb, -NRCCTNRaRb, CO2Ra or U represents oxygen or sulphur; X, Y and Z independently represent a bond or a group of formula -(CH2)m- or (CH2)qCH=CH(CH2)r, provided that X, Y and Z do not simultaneously each represent a bond; Ra, Rb and RC independently represent hydrogen or hydrocarbon; T represents oxygen, sulphur or a group of formula =N.E; E represents hydrocarbon or an electronwithdrawing group; m is an integer from 1 to 4; and q and r independently represent zero or 1.

2. A compound as claimed in claim 1 wherein R1 represents hydrogen, methyl, phenyl or benzyl.

3. A compound as claimed in claim 1 or claim 2 wherein R2 represents hydrogen, hydroxy, amino, C14 alkyl, aryl(C14)alkyl, C14 alkoxy or C24 alkoxycarbonyl.

4. A compound as claimed in any one of the preceding claims wherein R3 and R4 independently represent hydrogen, C14 alkyl or aryl(C1,4)alkyl.

5. A compound as claimed in any one of the preceding claims wherein X, Y and Z independently represent a bond or a methylene, ethylene or propylene group, either unsubstituted or substituted by one or more groups R2, R3 and R4 as defined in claim 1.

6. A compound as claimed in claim 1 represented by formula II and acid addition salts thereof:

wherein R1, R2, R3, R4 and U are as defined in claim 1; and x, y and z independently represent zero, 1, 2, 3 or 4, provided that they are not simultaneously each zero.

7. A compound as claimed in claim 6 wherein (x,y,z) is (1,2,0), (0,2,1), (2,1,0), (1,3,0) or (1,; 1).

8. A compound as claimed in claim 7 wherein (x,y,z) is (1,2,0).

9. A compound selected from the following: 2, 6-diaza-6-hydroxy-7-oxobicyclo [3.2. l octane; 2,6-diaza-6-hydroxy-8-endo-methyl-7-oxobicyclo[3.2.1]- octane; and acid addition salts thereof.

10. A compound as claimed in claim 1 as herein specifically disclosed

11. A pharmaceutical composition comprising a compound as claimed in any one of the preceding claims in association with a pharmaceutically acceptable carrier.

12. A pharmaceutical composition substantially as herein described.

13. A compound as claimed in any one of claims 1 to 10 for use as a therapeutic agent.

14. The use of a compound as claimed in any one of claims 1 to 10 for the manufacture of a medicament for the treatment and/or prevention of neurodegenerative disorders.

15. The use of a compound as claimed in any one of claims 1 to 10 for the manufacture of a medicament for the treatment and/or prevention of convulsions.

16. The use of a compound as claimed in any one of claims 1 to 10 for the manufacture of a medicament for use as a muscle relaxant.

17. A process for the preparation of a compound as claimed in any one of claims 1 to 10 which comprises cyclising a hydroxylamine derivative of formula III:

wherein R2, R3, R4, X, Y and Z are as defined in claim 1, R5 represents hydrogen or a hydroxy-protecting group, R11 is as defined for R1 in claim 1 or represents an aminoprotecting group, and Q represents a reactive carboxylate moiety; followed, where appropriate, by removal of the protecting groups; with subsequent attachment, if desired, where the product initially obtained is a compound of formula I as defined in claim 1 in which R1 is hydrogen, of the hydrocarbon group R1 by conventional alkylation or arylation methods.

18. A process for the preparation of a compound as claimed in any one of claims 1 to 10 wherein U is sulphur, which process comprises treating the corresponding compound wherein U represents oxygen with Lawesson's reagent or phosphorus pentasulphide.

19. A process for the preparation of a compound as claimed in any one of claims 1 to 10 substantially as herein described.

20. A compound as claimed in any one of claims 1 to 10 whenever prepared by a process as claimed in any one of claims 17 to 19.