This invention relates to novel spirofurane derivatives, processes for their preparation, pharmaceutical compositions containing them, and to their use in the treatment of 5 neurological and mental illnesses.

According to the cholinergic hypothesis of memory impairment in Alzheimer's disease, senile dementia and age-associated memory impairment, a deficiency of cholinergic function plays a major role in the progressive development of the disease. This has led ιo to the belief that enhancement of muscarinic cholinergic transmissions at cerebral cortical sites would be beneficial for treatment of the disease.

International Patent Application No WO 90/15804 discloses a large group of spirofurane derivatives which are indicated in the treatment of various neurological disorders, is Japanese Patent Application No 3-153690 also discloses a group of spirofurane derivatives.

We have now found a small group of spirofurane derivatives which are particularly useful in the treatment of neurological and mental illnesses.

20

According to the invention there are provided compounds of formula I,

wherein

R ¹ represents hydrogen or alkyl C ₃ ,

R ² represents hydrogen or alkyl

R ³ represents OCONR ⁴ R ⁵ or NHCOOR ⁶ ,

R ⁴ , R ⁵ , and R ⁶ represent hydrogen or C^ alkyl, and salts and solvates thereof.

It will be appreciated that salts of the compounds for use in medicine will be non-toxic pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds of formula I or their non-toxic pharmaceuticall acceptable salts. Acid addition salts, for example, may be formed by mixing a solution of the compound of formula I with a solution of a pharmaceutically acceptable non-toxi acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, carbonic acid o phosphoric acid.

Solvates of the compounds of formula I and their salts include in particular, hydrates o s the salts, for example, hemihydrates and monohydrates.

Alkyl groups which R ¹ may represent include methyl, ethyl, n-propyl and iso-propyl.

Alkyl groups which R ² , R ⁴ , R ⁵ and R ⁶ may represent include methyl, ethyl, n-propyl o iso-propyl, n-butyl, iso-butyl, s-butyl and t-butyl.

Alkenyl groups which R ² may represent include 2-propenyl, 2-butenyl an 2-methyl-2-propenyl.

5 Alkynyl groups which R ² may represent include 2-propynyl and 2-butynyl.

We prefer compounds of formula I or pharmaceutically acceptable salts thereof, i which: R ¹ represents hydrogen or methyl, preferably methyl; R ² represents hydrogen o methyl, preferably methyl; R ⁴ represents hydrogen or methyl, preferably methyl; 0 represents hydrogen or methyl, preferably methyl; and R ⁶ represents methyl or ethy preferably ethyl.

Substituents which are not readily inactivated by hydrolysis in vivo are also preferred

Many of the compounds of the present invention have at least one asymmetric centre and can therefore exist as enantiomers, and in some cases as diastereoisomers. Some of the compounds of the present invention contain carbon-carbon double bonds, and all contain a carbon-nitrogen double bond: they can therefore exist as isomers. It is to be understood that the invention covers all such isomers and mixtures thereof.

Compounds in which the carbon-nitrogen double bond has the s^n (equivalent to Z) configuration are preferred.

The compounds of the present invention are useful because they possess pharmacological activity in animals. In particular, the compounds stimulate central muscarinic acetylcholine receptors as can be demonstrated in studies of the affinity constants of the compounds for [ ³ H]-oxotremorine-M binding sites in rat cortical membrane preparations. The compounds may therefore be useful in the treatment of neurological and mental illnesses whose clinical manifestations are due to involvement of specific populations of cholinergic neurones. Such diseases include memory impairment, presenile and senile dementia (also known as Alzheimer's disease and senile dementia of the Alzheimer type respectively), Huntington's chorea, tardive dyskinesia, hyperkinesia, mania and Tourette Syndrome. The compounds are also useful analgesic agents and therefore useful in the treatment of severe painful conditions such as rheumatism, arthritis, and terminal illness.

Biochemical procedures for measuring affinity and estimating efficacy at brai muscarinic receptors are indicative of the potential utilities for these compounds. 5

Based largely on the selectivity of the antagonist, pirenzepine, muscarinic receptors hav been classified as Ml (high affinity for pirenzepine) and M2 (low affinity). Brai receptor subtypes appear pharmacologically similar to those in peripheral ganglia (Ml and heart (M2). Receptor subtypes are coupled preferentially to different secon o messengers and ion channels. Thus in brain as well as other tissues, Ml receptor stimulate phosphatidyl inositol (PI) hydrolysis while M2 receptors inhibit adenylat cyclase. From the results of animal experiments, it is suggested that muscarinic agonist

having Ml receptor selectivity may be advantageous in improving impaired performance, memory retention and other clinical manifestations of senile dementia.

Two binding assays are used to estimate the affinity and predict the efficacy of test compounds at muscarinic receptors in rat cerebral cortex.

The procedure is described in detail by Freedman, SB, Harley, EA, and Iversen LL, in Br J Pharmacol 93: 437-445 (1988). A rat brain crude membrane preparation is incubated with a radiolabeled antagonist [([ ³ H]N-Methyl- scopolamine)(NMS)] or agonist [([ ³ H]Oxotremorine-M)(Oxo-M)] and various concentrations of test compound at 30°C for 40 and 60 minutes, respectively. The membranes are then collected by vacuum filtration on filters and receptor bound radioactivity is determined by liquid scintillation spectroscopy. The affinities (Ki) of the test compound for the agonist high affinity state (radiolabelled agonist) and high and low agonist affinity states together (radiolabelled antagonist) are determined from the competition binding curves using a nonlinear iterative curve fitting computer program. The ratio of measured dissociatio constants (the Ki's) are also used as an index of agonist efficacy. Full agonists such as carbachol exhibit an antagonist/agonist ratio of > 1800. Partial agonists show a rang of ratios extending from 20 to 1500. Antagonists have ratios from 1 to 10.

Compounds of formula I with a high affinity for the Oxo-M binding site with a Ki of les than lμm and preferably less than O.lμm and a NMS-Ki/Oxo-M-Ki ratio of greater tha 100 are preferred.

In a procedure for measuring agonist efficacy at Ml muscarinic receptors in rat brai hippocampus, the muscarinic cholinergic agonist activity of a test compound is measure using an in vitro Ml muscarinic receptor linked enzyme assay which measures th formation of inositol phosphate from phosphatidyl inositol. The assay procedure i described in detail by Fisher SK and Bartus RT, J. Neurochem. 45: 1085-1095(1985) Rat brain hippocampal tissue was cross sliced into 35Qx350μ,m segments which wer equilibrated for one hour at 37°C in oxygenated Krebs-Hensleit buffer. Aliquots o slices were then incubated with [ ³ H]myo-inositol, lithium chloride, and variou concentrations of test compound for 120 minutes in a 95% 0 ₂ /5% C0 ₂ atmosphere a

37°C. The reaction is terminated by addition of chloroform/methanol solution (1:2, v/v) and the [ ³ H]inositol phosphates were extracted into the aqueous phase. [ ³ H]Inositol phosphates were purified by ion exchange chromatography using Dowex AG-lx8 anion exchange resin in the formate form. Inositol phosphates were selectively eluted from the resin with a 1M ammonium formate 0.1M formic acid solution. Tritium was determined by liquid scintillation spectroscopy. The magnitude of stimulation of inositol phosphate formation by high concentrations of full agonists such a carbachol was assigned a value of 100%. Partial agonists produced a maximal rate of inositol phosphate formation which varied, according to the compound, from 10 to 80%. Weak partial agonists and antagonists did not stimulate the formation of inositol phosphates.

Compounds of formula I with a maximal rate of inositol phosphate formation of greater than 15% are preferred.

s Partial agonists identified in the above assays may be tested for any selectivity for Ml versus M2 receptors. A measure of M2-receptor mediated inhibition of adenylate cyclase in rat heart membranes can be obtained according to procedures described by Ehlert, F.J. et al [J Pharmacol. Exp. Ther. 228:23-29(1987)].

o Some of the compounds may possess muscarinic antagonist properties and thus may be useful as antisecretory agents in the management of peptic ulcers and acute rhinitis, or in the treatment of motion sickness and parkinsonism.

A measure of the effects of cholinergic drugs on memory and performance can be 5 obtained in vivo by evaluating the effects of drugs on memory and motor performance of rats according to the procedures described by Ordy, J M, et al; An Animal Model o Human-Type Memory Loss Based on Aging, Lesion, Forebrain Ischemia, and Dru Studies With the Rat; Neurobiology of Aging, Volume 9, pp. 669-683 (1988) Compounds with muscarinic agonist activity such as arecoline, for example, enhance 0 memory in old rats, without effects on performance.

Thus according to another aspect of the invention, there is provided the use of a compound of formula I, as defined above, or a pharmaceutically acceptable salt thereof, as a pharmaceutical.

According to yet another aspect of the invention, there is provided the use of a compound of formula I, as defined above, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of neurological disorders.

The compounds of the invention may be administered by any convenient route, eg orally, parenterally or rectally. The daily dose required will of course vary with the particular compound used, the particular condition being treated and with the severity of that condition. However, in general a total daily dose of from about 0.1 to 10 mg/kg of body weight, preferably about 0.1 to lmg/kg is suitable, administered from 1 to 4 times a day.

The compound of formula I will generally be administered in the form of a suitable pharmaceutical composition. Thus according to another aspect of the invention, there is provided a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable carrier.

The pharmaceutical composition is preferably in unit dose form. Such forms include solid dosage forms, eg tablets, pills, capsules, powders, granules, and suppositories for oral, parenteral or rectal administration, and liquid dosage forms, eg sterile parenteral solutions or suspensions, suitably flavoured syrups, flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil and peanut oil, and elixirs and similar pharmaceutical vehicles.

Solid compositions may be prepared by mixing the active ingredient with pharmaceutical carriers, eg conventional tabletting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, gums and other diluents, eg water, to form a homogeneous preformulation composition in which the active ingredient is uniformly dispersed so that it may be readily subdivided into equally

effective unit dosage forms containing typically from 0.1 to about 500mg of the active ingredient. The solid dosage forms may be coated or otherwise compounded to prolong the action of the composition.

s In order to reduce unwanted peripherally mediated side effects, it may be advantageous to include in the composition a peripherally acting cholinergic antagonist (or anti-muscarinic agent) such as N-methylscopolamine, N-methylatropine, propantheline, methantheline or glycopyrrolate.

o The compounds of the invention have the advantage that they are more potent, have a longer duration of action, have a broader range of activity, have fewer side effects, are more stable, are more selective, or have other more useful properties than prior art compounds previously used to treat neurological and mental illnesses.

s According to the invention, there is also provided a process for the preparation of compounds of formula I or pharmaceutically acceptable salts or solvates thereof, which comprises a) preparing a compound of formula I in which R ³ represents OCONR ⁴ R ⁵ and R ⁴ and R ^s are as defined above, by reacting the corresponding compound of formula I in

20 which R ³ is OH with the corresponding aminocarbonyl halide, or b) preparing a compound of formula I in which R ³ represents NHCOOR ⁶ and R ⁶ is as defined above,by reacting the corresponding compound of formula II,

in which R ¹ and R ² are as defined above, with the corresponding nitrogen nucleophile of the formula H ₂ NNHCOOR ⁶ , or c) removing a protecting group from a compound of formula I in which the amino group is protected, or d) preparing a pharmaceutically acceptable salt of a compound of formula I, by treating a compound of formula I with an appropriate acid, or preparing a free base of a compound of formula I, by treating the acid addition salt with a stronger base.

In the reaction of process (a), conventional acylation techniques for amines may be used, for example, the reactions may be carried out in the absence of a solvent; however, a suitable inert solvent may be used, for example, toluene, methylene chloride or tetrahydrofuran. The reactions may be carried out in the presence of a base, for example, sodium hydride or pyridine. The reactions may be carried out at a temperature of, for example, from 0°-100°C.

The reaction of process (b) may be carried out with the nitrogen nucleophile in a suitable solvent at a temperature of, for example, from 0°-100°C. Protic solvents are preferred, for example, methanol or ethanol. The reaction may be carried out in the presence of an acid, for example, hydrogen chloride.

In the reaction of process (c), removal of the protecting group depends on the nature of the protecting group and includes acidic or basic cleavage or hydrogenolysis. Suitable amine protecting groups are, for example, ethoxycarbonyl, benzyloxycarbonyl, t-butyloxycarbonyl or C^ alkanoyl. Further protecting groups and methods for thei removal are described in T. W. Greene, Protecting Groups in Organic Synthesis, Wile Interscience, 1981.

In process (d), the salts may be formed by reacting the free base, or a salt or derivativ thereof with one or more equivalents of the appropriate acid. The reaction may b carried out in a solvent in which the salt is insoluble or in which the salt is soluble or i mixtures of the solvents.

The starting materials for the reaction of process (a) can be prepared from the corresponding ketones of formula II by reaction with hydroxylamine essentially according to the procedures described for method (b) above.

The starting ketones of formula II can be prepared by a variety of methods, for example: e) Oxidation of the corresponding alcohol compound. Conventional oxidation techniques for secondary alcohols may be used in a suitable solvent. A preferred oxidizing agent is that of a mixture of oxalyl chloride and dimethylsulfoxide in a suitable inert solvent, for example, methylene chloride. The reaction may be carried out at a temperature of, for example, from -80°-30°C. f) Reacting the corresponding compound in which R ^l is a protecting group and the carbonyl group is protected as a ketal with a reducing agent and subsequent deprotection by hydrolysis of the ketal. Ketal protection and deprotection of the ketone is effected by conventional methods, for example, with 1,2-dihydroxy ethane in the presence of an acid, for example, p-toluene sulfonic acid to form the ketal and by aqueous acid hydrolysis for removal of the ketal group. Reduction of the nitrogen protecting group, for example, a C ₃ alkanoyl or alkoxycarbonyl may be carried out with a hydride reducing agent, for example, diborane or sodium bis (2-methoxyethoxy) alumimum hydride in an aprotic solvent, for example, tetrahydrofuran. The reduction may be carried out at a temperature of, for example, from 0°-100°C. g) Compounds of formula II in which R ² represents C^ alkenyl or C ₃ ^ alkynyl may be prepared by reacting the corresponding compound in which R ² represents hydrogen with compounds of the formula

R ⁷ -CH=CH-CH,Z or R ⁷ -C≡C-CH,Z

in which R ⁷ represents Cι. ₃ alkyl and Z represents a halogen. The reaction may b carried out in the presence of a base, for example, sodium hydride, sodium amide o potassium t-butoxide in a suitable solvent, for example, 1,2-dimethoxyethane, ether toluene or t-butylalcohol and at a temperature of from -80°-100°C. h) Preparing a compound of the formula II in which R ² represents H or C^ alkyl and R ¹ is a protecting group, by cyclizing a compound of the formula III,

This reaction may be carried out by metal catalyzed cyclization according to procedures similar to those described by Saimoto, et al [J Amer Chem Soc 103, 4975-4977 (1981)]. A preferred metal is mercury (II) which may be used in the form of a polymer agent, for example, mercury Nafion-H in aqueous alcoholic solvents, for example, aqueous ethanol, at a temperature of, for example, 0-100°C. Nafion-H is a perfluorinated ion-exchange membrane.

Intermediates for the preparation of the ketones may be prepared by a variety of methods, for example: i) Preparing a compound of the formula IV,

in which

R ² represents H or C_^ alkyl, and R ¹ represents a protecting group, by cyclizing a compound of the formula V,

Cyclization may be carried out in the presence of a base in a suitable inert solvent or the base may be used in the absence of a solvent. A suitable base may be an organic amine, for example, pyridine. Cyclization may be facilitated by concomitant derivatization of the alcohol to form a better leaving group, for example, the p-toluene sulfonate ester may be formed by adding p-toluene sulfonyl chloride to the reactants. The reaction may be carried out at a temperature of, for example, 0°-100°C.

The starting materials for the cyclization reactions (h) and (i) can be prepared by a variety of methods which include: j) Preparing a compound of formula II as defined above by reacting a compound of formula VI,

0

I

R

in which R ¹ is a protecting group, with a compound of the formula

R ⁸ -CHOH-C≡CH

in which R ⁸ is H or C^ alkyl. The reaction may be carried out in the presence of a base, for example, butyl lithium in an inert aprotic solvent, for example, hexane or tetrahydrofuran or mixtures thereof. The reaction may be carried out at a temperature of for example, from -80°C-10°C. k) Preparing a compound of formula V as defined above by:

1) reacting a compound of the formula VI with a compound of the formula R ⁹ -CH=CH-CH ₂ MgZ in which R ⁹ represents H or C^ alkyl and Z represents a halogen, for example, chlorine, bromine or iodine to give a compound of formula VII,

2) epoxidation of the compound of formula VII to the epoxide of formula VIII,

3) ring-opening of the compound of formula VIII. The alkylation reaction may be carried out under conventional Grignard reaction conditions, for example, using alkyl magnesium bromide in an inert solvent such as ether or tetrahydrofuran, at a temperature of, for example, from 0°-80°C. The epoxidation reaction may be carried out with an organic peracid or hydrogen peroxide. The organic peracid, for example, m-chloroperbenzoic acid may be used in an inert aprotic solvent, for example, methylene chloride at a temperature of, for example, from 0-50°C. The ring opening of the epoxide may be acid catalyzed, for example, using perchloric acid in a suitable solvent, for example, aqueous tetrahydrofuran, at a temperature of, for example, from 0°-80°C. 1) Reduction of a compound of the formula IV in which R ¹ represents a protecting group, for example ethoxycarbonyl, and R ² is as defined above. Reduction may be carried out with a hydride reducing agent, for example, sodium bis(methoxyethoxy) aluminium hydride in an inert solvent, for example, THF and at a temperature of, for example, from 0°-80°C.

The invention will now be illustrated, but in no way limited, by the following Examples in which all temperatures are in degrees Celsius, THF is tetrahydrofuran, DMSO is dimethyl sulphoxide and ether is diethylether. Solvents which are dried before concentration are dried over magnesium sulfate or sodium sulfate. Stereoisomers are designated by the terms Z and E which are synonymous with the terms ris and trans or s n and anti respectively.

Preparation of Intermediates

Intermediate 1 3-Hydroxy-8-methyl-l-oxa-8-azaspiro[4.5]decane hvdrochloride

a) l-Ethoxycarbonyl-4-hvdroxy-4-f2-propenylVpiperidine

Allyl magnesium bromide was prepared in situ by suspending Mg turnings (21.2g, 0.87mol) in dry ether 700ml) and adding allyl bromide (34.8g, 0.29mol) gradually until the reaction initiated and then at sufficient rate to maintain reflux. The reaction was stirred at room temperature for 1.5 hours.

The reaction was cooled to -15°C with a methanol ice bath and l-ethoxycarbonyl-4-piperidinone (25g, 0.146mol) was added in ether (700ml). The reaction was stirred at room temperature for four hours and then left overnight.

The reaction was cooled with an ice bath while quenching with ammonium chloride (360ml of a saturated solution diluted to 1440ml). The reaction was stirred and the phases separated. The aqueous layer was extracted once more with ether and the combined organic layers were washed with brine, dried and stripped. Purification by flash chromatography on silica and elution with CHCl _j /NHj, then gave the sub-title compound as a yellow oil (17.2g).

b) l-EthoxycarbonvI-4-hvdroxy-4-f2,3-epoxypropylVpiperidine

The product of step a) (17.2g, 0.081mol) was dissolved in dry CH ₂ C1 ₂ (370ml) under nitrogen. m-Chloroperbenzoic acid (80%, 35g, O.lόmol) was added and the reaction was stirred at room temperature overnight. The white precipitate was removed by suction filtration, and washed with CH ₂ C1 ₂ . The CH ₂ C1 ₂ was washed with 10% sodium sulphite and this was extracted once with CH ₂ C1 ₂ . The combined organic layers were washed with 10% sodium hydrogen carbonate and this was extracted with CH ₂ C1 ₂ . The combined organic layers were dried over Na ₂ S0 ₄ and stripped. The yellow oil obtained was stored under nitrogen in the freezer. Purification by silica flash chromatography, eluting with MeOH/CHCl ₃ gave the sub-title compound as a yellow oil (11. lg).

c) l-Ethoxycarbonyl-4-hvdroxy-4-f2.3-dihvdroxypropyπpiperidine

The partially purified product of step b) (78.9g, 0.34mol) was dissolved in 250ml of THF and 500ml of deionized water. Concentrated HC10 ₄ (50ml) was added and the reaction was stirred overnight. The solution was cooled with an ice bath and neutralized with saturated aqueous NaHC0 ₃ . The suspension was then washed with CH ₂ C1 ₂ , and this was back-extracted with H ₂ 0.

The aqueous layers were stripped. The resulting residue was digested with four portions of methanol. These were combined, diluted with CHC1 ₃ and dried over Na ₂ S0 ₄ . The solvents were stripped and the crude was purified by eluting from silica with an ammoniated methanol/CHCl ₃ gradient. This gave 37.3g of brown oil or 13% for the three steps from the ketone.

d) 8-Ethoxycarbonyl-3-hvdroxy-l-oxa-8-azaspiro[4.5]decane

The product of step c) (5.2g, 0.021mol) was dissolved in dry pyridine (60ml), placed under nitrogen and cooled with an ice-bath. Tosyl chloride (4.8g, 0.025mol) was dissolved in pyridine (30ml) and added dropwise. The reaction was heated at 110°C. After 5 hours another 2.2g (0.01 lmol) tosyl chloride was added in 20ml pyridine at room temperature and the heating was continued overnight.

The pyridine was removed as an azeotrope with three portions of toluene and the residue digested seven times with anhydrous ether. The combined organic extracts were filtered and stripped. Purification on silica, flash column using gave the sub-title compound as a colourless oil (l.lg). Further ether digestion of the residue, followed by extraction with ether and purification gave a further 1.3g of product.

e) 3-Hvdroxy-8-methyl- l-oxa-8-azaspiro[4.5]decane hvdrochloride

The product of step d) (1.3g, 5.7mmol) was dissolved in dry THF (60ml), placed under nitrogen and cooled with an ice bath. Vitride (70%, 2.7ml) in THF (30ml) was added dropwise and the reaction stirred at room temperature overnight. Three further

portions of Vitride (5ml each) in THF (15ml each) were added dropwise to the cooled solution and after each portion the solution was stirred for several hours. The reaction was cooled again and treated with 5% NaOH until evolution of hydrogen ceased.

s The addition of NaOH was continued at room temperature until a sticky white paste had precipitated. The THF was decanted, suction filtered, and the paste washed once with THF. The solvent was then dried and stripped, and the paste washed once with THF. Purification by silica flash column using MeOH/CHCl ₃ gave a viscous yellow oil (l.lg) which partially solidified on standing to white needles. The solid was taken up o in isopropyl alcohol and the solution cooled and acidified with HCl/ethanol. This gave a white precipitate which was collected and washed with cold ether to yield the title compound as the hydrochloride salt (0.47g), mp 228-229°C.

Intermediate 2 s 8-Methyl-l-oxa-8-azaspiro[4.5]decan-3-one

Oxalyl chloride (1.9g, 14.3mmol) was dissolved in dry CH ₂ C1 ₂ (150ml), placed under N ₂ and cooled to -60°C with a dry ice/acetone bath. Dry DMSO (2.2g, 29mmol) in dry CH ₂ C1 ₂ (30ml) was added in slow drops. The reaction was stirred for 10 minutes. The 0 free base of Example 1 (1.5g, 8.8mmol) in CH ₂ C1 ₂ (100ml) was added in slow drops, the temperature being maintained below -60°. The reaction was stirred for 20 minutes and then was treated dropwise with diisopropylethylamine (9.0g, 67.5mmol).

The bath was removed and the reaction allowed to warm somewhat. The solution was 25 treated with distilled water (150ml) in rapid drops. The layers were separated and the aqueous layer was extracted three times with CH ₂ C1 ₂ . A little saturated Na ₂ C0 ₃ was added and two more CH ₂ C1 ₂ extractions were done.

The organic layers were dried with Na^O., and stripped. Purification by silica flash 30 chromatography, using MeOH/CHCl ₃ /NH ₃ gave the title product as a yellow oil (1.5g).

Intermediate 2A 8-Methyl-l-oxa-8-azaspiro[4.5]decan-3-one maleate

_ho nr and *en a

The carbamate-ketal from step (a) (lOg, .035mol) in THF (50ml) was added at room temperature during 30 mins. to a solution of Vitride (0.105mol) in THF (150ml). The reaction was stirred for 1 hour then decomposed by the addition of 20ml of 20% aqueous THF then additional water until a clear supernatant layer formed. The solvent layer was separated and evaporated in vacuo. The residue was chromatographed on silica gel and eluted with 20% MeOH/CH ₂ Cl ₂ to give the dimethyl-ethylene ketal as a thick oil (14.4g). A sample of the oil (0.5g) was converted to the maleate salt in ether and crystallized from methylene chloride/ether to give the salt (0.24g), mp 105-108°C.

C H N Theory: 55.96 7.34 4.08

Found: 56.10 7.48 4.10

c) 2.8-Dimethyl- l-oxa-8-azaspiro[4.5]decan-3-one maleate

The ketal base from step (b) (14.4g, 0.0634mol) dissolved in 1.25N HCl (100ml) was heated at 50°C for 4 hours. The reaction was cooled, basified with saturated aqueous Na ₂ C0 ₃ solution and the precipitated base was extracted into chloroform. The chloroform solution was dried and the solvent evaporated in vacuo to give the ketone as an oil (13.35g).

A sample of the oil (4.46g) was converted to the maleate salt in ether. The precipitated salt was recrystallized twice from ethyl acetate to give the title product (3.11g), mp 137.5-139°C.

C H N Theory: 56.18 7.07 4.68

Found: 56.23 7.14 4.70

Intermediate 6 2.8-Dimethyl-l-oxa-8-azaspirof4.5]decan-3-one oxime fumarate

Following essentially the same procedure as described for Intermediate 3 and substituting 2,8-dimethyl-l-oxa-8-azaspiro[4.5]decan-3-one (1.4g, 7.7mmol) for 8-methyl-l-oxa-8-azaspiro[4.5]decan-3-one afforded the free base as an oil (2.1g). The

oil was dissolved in ethyl acetate and diluted with a saturated solution of fumaric acid in ether. The precipitated solid was filtered and dried to give the title product (1.5g).

C H N

Theory: 53.49 7.05 8.91 s Found: 53.48 7.24 9.55

Preparation of Examples

Example 1 0 N-Ethoxycarbonyl-2.8-dimethyl l-oxa-8-azaspiro[4.5]decan-3-one hvdrazone fumarate

2,8-Dimethyl-l-oxa-8-azaspiro[4.5]decan-3-one (3g, 0.017 mol) and ethyl carbazate (1.56g) were dissolved in absolute EtOH (175mL) and acidified with HCl/EtOH to pH4. The reaction was stirred overnight at room temperature and then the ethanol was s evaporated. The residue was dissolved in CHC1 ₃ and partitioned with aqueous Na ₂ C0 ₃ . The chloroform layer was dried (Na^O and concentrated. The residue was purified by chromatography on silica gel and eluting with ammoniated 2-10% MeOH/CHCl ₃ to give 1.4g of an oil. The oil was dissolved in diethyl ether and acidified with a solution of fumaric acid in diethyl ether. The precipitated solid was recrystallized from 0 ethanol/diethyl ether to give a hygroscopic solid which was dried under high vacuum at 50°C to give the title compound as a solid mp 103.5 - 104.5°C.

C H N

Theory: 52.98 7.06 10.90

Found: 52.34 7.32 11.29

25

Example 2

2.8-Dimethyl-l-oxa-8-azaspiro[4.5]decan-3-one Q-|Ydimethylaminotearbonylloxime fumarate

30 A solution of 2,8-Dimethyl-l-oxa-8-azaspiro[4.5]decan-3-one oxime (lg, 5 mmol dissolved in dry THF containing sodium hydride (0.24g of a 60% oil suspension) wa stirred until hydrogen evolution had ceased. (Dimethylamino)carbonyl chlorid (0.66mL) was added and the reaction was stirred at room temperature overnight, the

it was heated at reflux for 5 hours. The reaction was treated with aliquots of (dimethylamino)carbonyl chloride and further heating until the reaction was complete. The solvent was evaporated and the residue was dissolved in chloroform, partitioned with aqueous sodium carbonate and the chloroform layer was concentrated to dryness. s The residue was chromatographed on silica gel and eluted with ammoniated 2-10% MeOH/CHCl ₃ to give an oil (lg). The oil was treated with maleic acid (0.43g) in ethyl acetate and concentrated to dryness. The residue was dissolved in isopropanol/ethylacetate and concentrated under vacuum until turbidity occurred. A small quantity of oil separated and the supernatant solution was decanted and o concentrated. The free base was recovered from the maleate salt by treatment with aqueous sodium carbonate and further purified by chromatography. The recovered base (0.3g) was then treated with fumaric acid in ethylacetate/diethyl ether to give the fumarate salt of the title compound, 0.24g, mp. 165-169°C. C H N is Theory: 52.98 7.06 10.90

Found: 52.89 7.01 10.50 solid was filtered and dried to give the title product (1.5g).

C H N

Theory: 53.49 7.05 8.91

20 Found: 53.48 7.24 9.55