WO1994013678A1

WO1994013678A1 - Spirofuranone derivatives and their use in the treatment of neurodegenerative disorders

Info

Publication number: WO1994013678A1
Application number: PCT/GB1993/002500
Authority: WO
Inventors: Alexander Kover; James Loch, Iii; George Mullen; Edwin Shen-Chou Wu
Original assignee: Fisons Corporation; Fisons Plc
Priority date: 1992-12-05
Filing date: 1993-12-06
Publication date: 1994-06-23
Also published as: EP0672046A1; NO952194D0; AU5655394A; FI952733A; NO952194L; FI952733A0; CA2150947A1; MX9307679A; JPH08503955A; IL107881A0; KR950704322A

Abstract

Compounds of formula (I), wherein ring A is a ring of formula (AI) or (AII) (in which the spiro atom is indicated by *), R1 represents H or alkyl C¿1-6; R?2 represents -(CH¿2)n-OR?3, -(CH¿2?)m-C(O)R?4¿, fluoroalkyl C¿1-6?, cyanoalkyl C1-6 or alkyl C1-6 substituted with a 4-7 membered optionally unsaturated heterocyclic ring; R?3¿ represents H, alkyl C¿1-6? (optionally substituted with alkoxy C1-6), cycloalkyl C4-7, a 4-7 membered optionally unsaturated heterocyclic ring, phenyl (optionally substituted with halogen, hydroxy or alkyl C1-6), or benzyl (optionally substituted with halogen, hydroxy or alkyl C1-6); R?4¿ represents OR?5, NR6R7, N(OR6)R7¿ or alkyl C¿1-6; R?5 represents H, alkenyl C¿2-6?, alkynyl C2-6 or alkyl C1-6) optionally substituted with phenyl); R?6 and R7¿ independently represent H or alkyl C¿1-6; R?8 represents H or alkyl C¿1-6?; n is 2-5; m is 1-5; p is 1 or 2; and pharmaceutically acceptable salts thereof; are useful in the treatment of neurodegenerative disorders.

Description

SPIROFURANONE DERIVATIVES AND THEIR USE IN THE TREATMENT

OF NEURODEGENERATIVE DISORDERS ******************************

This invention relates to furanone derivatives useful in therapy (in particular in the treatment of neurodegenerative disorders), methods for their use, formulations including them and processes for their production.

Japanese Patent Application 3-153690 (to Yamanouchi Pharmaceutical Co), European Patent Application 311313 (and its US equivalents US Patents N°s 4,996,210 and 4,940,795, to Yamanouchi Pharmaceutical Co), International Patent Application WO 90/15804 and European Patent Application 491562 (both to Fisons Corporation) disclose furanone derivatives which are indicated for use in the treatment of neurodegenerative disorders.

Muscarinic agonists are thought to be useful in the treatment of neurodegenerative disorders including Alzheimer's disease. However, at least three subtypes of muscarinic receptor have been identified (M„ M₂ and M₃) and the proportion of each varies between the different tissues of the body. It is believed that compounds which are able to stimulate M, receptors selectively will have a beneficial effect in the treatment of neurodegenerative disorders without causing unwanted side effects [see for example N M J Rupinak, Drug Development Research, 27, 77-88 (1992), in particular page 85].

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

wherein ring A is a ring of formula Al or All (in which the spiro atom is indicated by *),

R¹ represents H or alkyl C,^;

R² represents -(CH₂)_n-OR³, -(CH₂)_m-C(0)R⁴, fluoroalkyl C^, cyanoalkyl C_w or alkyl C 1-6 substituted with a 4-7 membered optionally unsaturated heterocyclic ring; R³ represents H, alkyl C,^ (optionally substituted with alkoxy C^), cycloalkyl C₄.₇, a 4-7 membered optionally unsaturated heterocyclic ring, phenyl (optionally substituted with halogen, hydroxy or alkyl C_w), or benzyl (optionally substituted with halogen, hydroxy or alkyl C_w);

R⁴ represents OR⁵, NR⁶R⁷, N(OR⁶)R⁷ or alkyl C_w; R^s represents H, alkenyl C_2.6, alkynyl C₂.₆ or alkyl C ₆ (optionally substituted with phenyl);

R⁶ and R⁷ independently represent H or alkyl C,^; R⁸ represents H or alkyl C_1-6; n is 2-5; m is 1-5; p is 1 or 2; and pharmaceutically acceptable salts thereof (hereinafter referred to en bloc as "the compounds of the invention").

A number of the compounds of the invention may 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 (in particular they may be able to stimulate the M, receptor more selectively), or have other more useful properties than the compounds of the prior art.

Pharmaceutically acceptable salts of compounds of formula I include acid addition salts, for example maleate. fumarate, hydrochloride and hydrobromide salts. J

The invention includes all optical and geometric isomers of the compounds of formula I. in particular both an - (or E-) and syn- (or Z-) isomers of the carbon-nitrogen double bond, and both (R)- and (S)-stereoisomers at the 2-position of the furanone ring.

Preferred groups of compounds of the invention which may be mentioned are those in which: a) R¹ represents methyl; b) R² represents -(CH₂)_n-OR³ or -(CH₂)_m-C(0)R⁴; c) R³ represents alkyl C^ (optionally substituted with alkoxy C,^) (for example methyl, ethyl or ethoxyethyl) or phenyl; d) R⁴ represents 0-(alkyl C_w) or N(alkyl C ₂ (for example methoxy, ethoxy, propyloxy or dimethylamino); e) R⁸ represents methyl; f) n is 2; g) m is 1; h) p is 1; i) ring A is a ring of formula Al; and j) the carbon-nitrogen double bond is syn (i.e. -OR² is disposed adjacent to R¹).

Heteroatoms in heterocyclic rings which R² may include and R³ may represent include N. S and O. Particular heterocyclic rings which may be mentioned are tetrahydrofuran and 1,3-dioxan.

According to another aspect of the invention, there is provided a process for the produc- tion of a compound of the invention, which comprises reaction of a compound of for¬ mula II,

in which A and R¹ are as defined above, with a compound of formula III. H₂NOR² III

in which R² is as defined above, and where necessary converting the resulting compound into a pharmaceutically acceptable salt.

Compounds of formula II may be prepared by the methods disclosed in the prior art documents mentioned above (see in particular Intermediates 2 and 5 of European Patent Application 491562) or by routine modifications to such methods which will be apparent to those skilled in the art.

Compounds of formula III are either known or may be prepared by reacting a cyclic imido ether of a 1,4- or 1,5-dicarboxylic acid of formula IV,

in which R² is as defined above, with a primary aliphatic amino alcohol as described by Wild et al in US Patent N° 5,120,849.

In an alternative method for the production of compounds of the invention, an oxime of formula V,

wherein A and R¹ are as defined above, is reacted with a compound of formula VI,

R²X VI wherein R² is as defined above and X is a leaving group (for example halogen), in the presence of a base (for example sodium hydride).

Compounds of formula V may be prepared from compounds of formula II by reaction with hydroxylamine.

Compounds of formula I which are optically pure (with regard to the 2-position of the furanone ring) may be prepared from compounds of formula II which are optically pure (with regard to the 2-position of the furanone ring). Compounds of formula II which are optically pure with regard to the 2-position of the furanone ring may be prepared from the corresponding mixture of enantiomers by reaction with a sterically hindered base (for example tri-sec-butylborohydride) to give (RR) and (SS) cis-alcohols, followed by addition of a chiral group [for example (R)- or (S)-C(0)NHCH(CH₃)(l-naphthyl)] to form diastereoisomers, followed by selective precipitation of one diastereoisomer, removal of the chiral group (for example using bis(2-methoxyethoxy)aluminium hydride) and oxidation to the ketone (for example using N-chlorosuccinimide and dimethylsulph- ide).

It will be apparent to those skilled in the art that sensitive functional groups may need to be protected and deprotected during synthesis of a compound of the invention. This may be achieved by conventional techniques, for example as described in 'Protective Groups in Organic Synthesis' by T W Greene and P G M Wuts, John Wiley and Sons Inc, 1991.

The compounds of the invention may also be interconverted, for example compounds in which R² contains a carboxylic acid group may be converted to a corresponding ester or amide by conventional techniques.

The compounds of the invention are useful because they possess pharmacological activ- ity in animals. In particular, the compounds are useful in the treatment of neurodegen¬ erative disorders including 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. Thus, according to another aspect of the invention, there is provided a method of treatment of a neurodeg¬ enerative disorder (including presenile and senile dementia, Huntington's chorea, tardive dyslάnesia, hyperkinesia, mania and Tourette Syndrome) which comprises administering a therapeutically effective amount of a compound of the invention to a patient suffering s from such a disorder. The use of the compounds of the invention as pharmaceuticals, and the use of the compounds of the invention in the manufacture of a medicament for the treatment of neurodegenerative disorders, are also provided.

Biochemical procedures for measuring affinity and estimating efficacy at brain ιo muscarinic receptors are believed to be indicative of the potential utilities for these compounds.

Muscarinic receptor subtypes are coupled preferentially to different secondary messen¬ gers and ion channels. Thus in brain as well as other tissues, M, receptors stimulate is phosphatidyl inositol (PI) hydrolysis while M₂ receptors inhibit adenylate cyclase. From the results of animal experiments it is suggested that muscarinic agonists having M, receptor selectivity may be advantageous in improving impaired performance, memory retention and other clinical manifestations of senile dementia.

0 Assays used to estimate the affinity and predict the efficacy of test compounds at muscarinic receptors in rat cerebral cortex are set out below.

Binding Affinity

Rat brain crude membrane preparation is incubated with a radiolabelled agonist ([³H]- s oxotremorine-M, Oxo-M) and various concentrations of test compound at 30°C for 60 minutes. 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 are determined from the competition binding curves using a non-linear iterative curve-fitting computer program. Compounds of the inven- 0 tion with a high affinity for the Oxo-M binding site with a Ki of less than lμM and preferably less than O.lμM are preferred.

Agonist Efficacy To measure agonist efficacy at M, muscarinic receptors in rat brain hippocampus, rat brain hippocampal tissue is cross sliced into 350x350μm segments which are incubated with ³H-myoinositol, lithium chloride, and various concentrations of test compound for 120 minutes. The ³H-inositol phosphates formed are purified by ion exchange chroma- tography and the tritium content is determined by liquid scintillation spectroscopy. The ability of a compound to stimulate the hydrolysis of phosphatidyl inositol is compared with that of the full agonist carbachol, which is assigned a value of 100%. Partial agonists produce a maximal rate of inositol phosphate formation which varies, according to the compound, from 10 to 80%. Weak partial agonists and antagonists do not stimu- late the formation of inositol phosphates. Compounds of the invention with a maximal rate of inositol phosphate formation of greater than 15% are preferred.

Partial agonists identified in the above assays may be tested for any selectivity for M, 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 F J Ehlert et al, J Pharmacol Exp Ther, 228:23-29 (1987). 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 Parkinson's disease.

The compounds of the invention may be administered by any convenient route, for example 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 sever¬ ity of that condition. However, in general a total daily dose of from about 0.1 to lOmg/kg of body weight, and preferably about 0.1 to lmg/kg, is suitable, administered from 1 to 4 times a day.

The compound of the invention will generally be administered in the form of a suitable pharmaceutical formulation. Thus, according to another aspect of the invention, there is provided a pharmaceutical formulation including preferably less than 50% by weight of a compound of the invention in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. The pharmaceutical formulation is preferably in unit dose form. Such forms include solid dosage forms, for example tablets, pills, capsules, pow- ders, granules, and suppositories for oral, parenteral or rectal administration; and liquid dosage forms, for example 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.

5

Solid formulations may be prepared by mixing the active ingredient with pharmaceutical carriers, for example conventional tabletting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, gums and other diluents, for example water, to form a homogeneous preformulation formulation ιo 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 formulation.

is In order to reduce unwanted peripherally mediated side effects, it may be advantageous to include in the formulation a peripherally acting cholinergic antagonist (or anti-muscar- inic agent) such as N-methylscopolamine, N-methylatropine, propantheline, methanth- eline or glycopyrrolate.

0 The invention is illustrated by the following Examples, in which all chiral HPLCs were run on a 25cm Chiralcel OD column (Chiral Technologies, Inc), and the following abbreviations are used: dp = diastereoisomeric purity; ee = enantiomeric excess; HPLC = high pressure liquid chromatography; EtOAc = ethyl acetate; Et₂0 = diethyl ether; TLC = thin layer chromatography; MeOH = methanol; DMF = dimethylformamide; 5 and EtOH = ethanol.

Example 1

Svn- and anti-2,8-dimethyl-l-oxa-8-azaspiro[4.5]decane-3-one, O-fcarboxymethvπ oxime o A solution of 2,8-dimethyl-l-oxa-8-azaspiro[4.5]decane-3-one (the compound of Inter¬ mediate 5, European Patent Application 491562) (4.5g, 0.025 mole) in 380ml of meth¬ anol was treated with carboxyrnethoxylamine hydrochloride (2.7g, 0.013 mole). The resulting suspension was heated under nitrogen using an oil bath, and the solid dissolved completely. After one hour at reflux the reaction was virtually complete.

The methanol was removed in vacuo and the residue was taken up in deionized water. The pH was adjusted to 6.5 with saturated aqueous Na₂C0₃. The aqueous layer was washed with a small volume of CHC1₃, and this was extracted twice with water. The combined aqueous layers were evaporated in vacuo at 35°C. The residue was then treated with four portions of absolute ethanol, followed by anhydrous CH₂C1₂ (with evaporation in vacuo after each addition) to give 7.5g of crude product.

A 0.84g sample of the crude product was purified by flash chromatography on silica using CHCyCH₃OH/CH₃C0₂H/H₂0 [6:3:1:1]. The solvents were evaporated in vacuo and then anhydrous toluene was added to the residue and subsequently evaporated in vacuo. The residue was taken up in 40ml of deionized water and lyophilized, yielding 0.15g of a mixture of the title compounds as a foamy powder.

No distinct m.p.: gradual transition to foamy glass.

MS (CI): 257 (M+H)⁺; 183 (loss of -OCH₂C0₂ ).

IR (KBr) cm ¹: 1606 (-C0₂ ). NMR (CDC1₃) δ: 4.95-4.30 (3H, overlapping multiplets, -CHCH₃ and -OCH₂); 3.40-2.80

(4+H, two broad multiplets, -CH,N plus exchangeable (H₂0)); 2.75-2.10 (5H, singlet overlapping small multiplets, -NCH₃ and -CH₂C = N); 2.25-1.75 (4H, overlapping multiplets, -CH₂); 1.40 (3H, overlapping doublets, -CHCH₃).

HPLC (Novapak C₁₈, CH₃CN/H₂0, KH₂P0₄ buffer at Ph 2.5): Two major peaks at 4.54 and 6.31 minutes in 4/1 ratio.

Calculated for C^H^N^: C 56.24, H 7.87, N 10.93; adjusted for H₂0 and entrapped

CH₃C0₂H: C 54.95, H 7.85, N 10.35; found: C 52.98, H 7.62, N 10.00 (probably due to the hygroscopic nature of the product)

Example 2

Syn- and anti-2,8-dimethyl-l-oxa-8-azaspiro[4.5]decane-3-one, O-fcarboxymethvπ oxime ethvl ester maleate A solution of the crude title compound of Example 1 (1.3g, assumed 5.0 mmoles) in 325ml of CH₂C1₂ was placed under nitrogen and cooled to 0°C with an ice bath. The solution was treated with hydroxybenzotriazole (1.08g, 5.0 mmoles) and dicyclohexylca- rbodiimide (0.87g, 5.5 mmoles). The ice bath was removed and the reaction was stirred at ambient temperature for 30 minutes. The suspension was cooled to 0°C and vacuum filtered directly into an addition funnel.

The cold solution was added rapidly to absolute ethanol (1.2g, 25.0 mmoles) in 130ml of dry CH₂C1₂ under nitrogen and cooled to 0°C. The reaction was allowed to warm and was stirred overnight at ambient temperature. The suspension was vacuum filtered and evaporated in vacuo.

The crude product was purified by flash chromatography on silica using an ammoniated 5-20% CH₃OH/CHCl₃ gradient. This gave 0.62g of yellow oil (44%) which gradually crystallized. The maleic salt of 0.3g was precipitated from EtOAc Et₂0 giving 0.32g of white solid.

m.p. 83-85°C, with decomposition. MS (CI): 285 (M+H)⁺. IR (Kbr) cm^"1: 2473 (-NH⁺); 1755 (-C0₂Et); 1703 (-C0₂H); 1579 (-C0₂ ^").

NMR (DMSO-d₆) <S: 6.05 (2H, singlet, -C=CH); 4.80-455 (3H, singlet overlapping two quartets at 4.8 (minor) and 4.6 (major,) -CHCH₃ and -OCH₂); 4.15 (2H, quartet, -OCH₂- CH₃); 3.25 (4H, broad multiplet,-CH₂N); 2.90-2.50 (5H, strong singlet overlapping com¬ plex multiplet, -NCH₃ and -CH₂-C=N); 1.90 (4H, complex multiplet, -CH₂); 1.40-1.20 (6H, triplet overlapping two doublets (minor at 1.4) -CH₂CH₃ and -CHCH₃ (3/1 ratio of isomers)).

HPLC (Novapak Phenyl, CH₃CN/H₂0, KH₂P0₄ buffer at Ph 2.5): Two major peaks at 12.06 and 12.91 in 3/1 ratio. Calculated for C^H^NA: C 53.99, H 7.05, N 7.00; found: C 53.82, H 6.97, N 6.96

Example 3

Svn- and anti-2.8-dimethyl-l-oxa-8-azaspiro[4.5]decane-3-one. Q-(2-ethanamidvπ oxime maleate Absolute ethanol (lOOml) was saturated with anhydrous NH₃ and a crude sample of the title compound of Example 2 (0.3g, assumed 1.0 mmole) was added. The flask was stoppered and stirred at ambient temperature. Over the next six days the progress was followed by TLC and more NH₃ was bubbled through the solution from time to time. 5 When no further progress was evident the ethanol was evaporated in vacuo.

The crude product was purified by flash chromatography on silica using an ammoniated 10-20% CH₃OH/CHCl₃ gradient. An NMR of recovered starting material showed that the acid was enriched in syn to a 3/2 ratio. The maleate salt of the amide was obtained ιo from ethyl acetate/Et₂0, giving 0.3 lg (84%) of white solid.

mp 104.5-106.5°C.

MS (CI): 256 (M+H)⁺; 197 (loss of -CH₂CONH₂).

IR (Kbr) cm ¹: 1678 (-CONH₂); 1583 (-C0₂ ). i5 NMR (DMSO-cy δ: 7.50-7.10 (2H, broad multiplet, -CONH₂); 6.10 (2H, singlet, -C=C-

H); 4.85-4.35 (3H, quartets at 4.8 (minor) and 4.5 (major) in 4/1 ratio and singlet with shoulder, -CHCH₃ and -OCH₂); 3.25 (4H, broad multiplet, -NCH₂); 2.95-2.55 (5H, singlet plus multiplet, -NCH₃ and -CH₂-C=N); 1.85 (4H, broad multiplet, -CH₂); 1.35 and 1.25 (3H, two doublets with minor at 1.3, CHCH₃). 0 HPLC (Novapak Phenyl, CH₃CN/H₂0, KH₂P0₄ buffer at Ph 2.5): Two major peaks at

3.07 and 3.84 minutes in 4/1 ratio.

Calculated for C^H^N_jO,: C 51.75, H 6.79, N 11.31; adjusted for residual solvents: C

51.54, H 6.84, N 11.19; found: C 51.03, H 6.63, N 11.00.

5 Example 4

Svn- and anti-2,8-dimethyl-l-oxa-8-azaspiro[4.5]decane-3-one, O-f2-methoxyethy0 oxime a) 2-methoxy-O-ethoxylamine hvdrochloride

The subtitle compound was prepared by a modification of the process disclosed in Ger- 0 man Patent Application N° 3615473 as follows. N-hydroxyphthalimide (17.0g, 0.11 mole) was combined with K₂C0₃ (10.5g, 0.076 mole) and anhydrous N-methylpyrollidinone

(115ml). The mixture was placed under a nitrogen atmosphere and 2-bromoethylmethyl ether (16.0g, 0.105 mole) was added. The reaction was heated with an oil bath at 50°C and stirred magnetically for four hours. The reaction was left at ambient temperature overnight and then heated for another 8 hours the next day. A TLC the next morning indicated complete reaction. The reaction was concentrated to a thick slurry in vacuo. The slurry was poured into 500ml of crushed ice/H₂0 with stirring. The off-white pow- der was collected and washed with a small volume of water, yielding 16.8g.

m.p. 90-92°C

NMR (DMSO-d₆) δ 7.90 (4H, broad multiplet, ArH); 4.30 (2H, multiplet, -NOCH₂);

3.65 (2H, multiplet, -OCH₂); 3.25 (3H, singlet, -OCH₃); plus total of 3 exchangeable Hs

The phthalimide (16.8g, 0.076 mole) was combined with absolute ethanol (150ml) under nitrogen. Hydrazine hydrate (3.8ml, 0.076 mole) was added and the reaction was stirred and heated with an oil bath at 95°C for 30 minutes. The reaction was monitored to completion using TLC, and was cooled in an ice bath while acidifying with concentrated HC1. The reaction was heated at reflux for 15 minutes, and then cooled with an ice bath. The white solid was collected and washed with cold ethanol. The filtrate was evaporated in vacuo and three portions of absolute ethanol were added and evaporated in vacuo to remove water. A portion of ethyl acetate was then added and removed by evaporation in vacuo and the residue was triturated with ethyl acetate. The off-white solid was collected and washed with ethyl acetate. The hygroscopic material was dried over P₂O_s giving 8.05g of the subtitle compound.

m.p. 48-50°C (dec) MS (CI): 92 (M+H)⁺ NMR (DMSO-d₆) δ: 4.15 (2H, multiplet, -NOCH₂); 3.6 (2H, multiplet, -OCH₂); 3.45 (3H, exchangeable); 3.30 (3H, singlet, -OCH₃)

b) Syn- and anti-2.8-Dimethyl-l-oxa-8-azaspiro[4.5]decane-3-one, 0-C2- methoxyethvP oxime 2,8-dimethyl-l-oxa-8-azaspiro[4.5]decane-3-one maleate (1.5g, 5.0 mmole) was combined with CH₃OH (200ml), the subtitle compound of step (a) (0.7g, 5.5 mmole) and pyridine (0.45g, 5.0 mmoles). The reaction was heated at reflux under a nitrogen atmosphere for one hour. The reaction was monitored to completion using TLC and the methanol was evaporated in vacuo. The residue was taken up in chloroform and washed with satu¬ rated aqueous Na₂C0₃. The basic layer was extracted with 3 portions of CHQ₃, and the combined organic layers were dried over MgS0₄ and evaporated in vacuo. The crude product was combined with that of a 1.65 mmoles trial run and purified by two runs 5 through a Delta Prep HPLC using silica columns and ammoniated CH₃0H/CHC1₃ gradi¬ ents. This yielded 0.4g of the lower isomer (syn), 0.9g of the upper (anti), and 0.28g of a mixture of isomers.

Syn isomer: ιo MS (CI): 257 (M+H)⁺.

IR (3M card) cm ¹: 1071 (ether C-O-C).

NMR (CDC1₃) δ: 4.7 (1H, quartet, -CHCH₃); 4.15 (2H, multiplet, =N-OCH₂); 3.60 (2H, multiplet, -OCH₂); 3.40 (3H, singlet, -OCH₃); 2.75-2.30 (9H, complex multiplet with singlet, -NCH₂, -CH₂-C=N, and -NCH₃); 2.05-1.65 (4H, multiplet, -CH₂); 1.40 (3H, is doublet, -CHCH₃).

HPLC (Novapak C_lg, CH₃CN/H₂0, KH₂P0₄ buffer at Ph 2.5): Major peak at 10.12 minutes with no anti isomer detected.

Calculated for C^H^NA: C 60.91, H 9.44, N 10.93; found: C 60.79 H 9.33 N 10.31.

0 Anti isomer:

MS (CI): 257 (M+H)⁺. IR (3M card) cm ¹: 1069 (ether C-O-C).

NMR (CDC1₃) δ: 4.5 (1H, quartet, -CHCH₃); 4.2 (2H, multiplet, =NOCH₂); 3.63 (2H, multiplet, -OCH₂); 3.4 (-OCH₃); 2.80-2.30 (9H, complex multiplet with singlet, -NCH₂, - 5 CH₂-C=N, and -NCH₃); 1.80 (4H, multiplet, -CH₂); 1.37 (3H, doublet, -CHCH₃). HPLC (Novapak C_lg, CH₃CN/H₂0, KH₂P0₄ buffered to Ph 2.5): Major peak at 9.57 minutes, with no syn isomer detected. Calculated for C^H^N : C 60.91, H 9.44, N 10.93; found: C 60.53, H 9.27, N 10.52

o Example 5

Syn- and anti-2,8-dimethyl-l-oxa-8-azaspiro[4.5]decane-3-one. O-fcarboxymethyπ oxime methyl ester The title compounds were prepared from methanol and the title compound of Example 1 using the method of Example 2.

C₁₃H₂₂N₂0₄ requires C 57.76, H 8.20, N 10.36; adjusted for 0.58% Et₂0 C 57.80, H 8.23,

5 N 10.36; found C 57.74, H 8.53, N 9.99.

MS (CI): 253 (M-H₂0)⁺; 197 (M-CH₂C0₂Me)⁺.

HPLC (Novapak Phenyl, CH₃CN/H₂0, buffer KH₂P0₄ at Ph 2.5): Major peaks at 10.31 and 10.89 mins for anti/syn ratio of 4.8/1; peaks at 6.72 and 7.84 mins for anti/syn ratio of acid produced by hydrolysis. ιo IR (3M card) cm^"1: 1765 (shoulder 1744)(-C0₂Me); 1210 (-C-C0₂).

NMR (CDC1₃) δ: 4.80 CHCH₃(syn)) plus 4.63 (with shoulder,-OCH₂-) plus 4.55 (total 3H, q, CHCH₃ (anti)); 3.75 (3H, s with shoulder, -OMe) 2.90-2.40 (9H, s overlapping m, -NCH₃ plus -NCH₂ plus N=C-CH₂) 1.80 (4H, m -CH₃) 1.45 (d, -CH₃ (syn) plus 1.37 (3H, d, -CH₃ (a i)).

15

Example 6

Syn- and anti-2.8-dimethyl-l-oxa-8-azaspiro[4.5]decane-3-one, Q-(2-phenoxyethvπ oxime The title compounds were prepared by reacting 2,8-dimethyl-l-oxa-8-azaspiro[4.5]- decane-3-one with 2-phenoxyethyl hydroxylamine hydrochloride [154 (M+H)⁺, m.p. 153- 20 160°C (dec)] using the methods of Example 4.

Anti isomer:

C_lgH₂₆N₂0₃ requires C 67.90, H 8.23, N 8.80; adjusted for 0.69% H₂0 C 67.43, H 8.25, N 8.74; found C 67.11, H 8.29, N 8.62.

25 MS (CI): 319 (M+H)⁺.

IR (3M card) cm ¹: 3040 (OH); 1246 (C-O-0); 1068 (C-O-C).

NMR (CDC1₃) <S: 7.25 (2H, m) and 6.95 (3H, m, 0H plus CHC1₃); 4.45 (q, CHCH. ₃(anti)) and 4.40(3H, m, -C=NOCH₂); 4.25 (2H, m, -OCH₂); 2.75-2.30 (9H. s overlap¬ ping m, -NCH₃ plus -NCH, plus N=C-CH₂ (a i)); 1.90-1.55 (4H, m, -CH₂) 1.40 (3H, 0 d, CHCH₃).

HPLC (Novapak Phenyl. CH₃CN/H₂0, KH,P0₄ buffer at Ph 2.5) Major peak at 12.55 mins, no svn detectable Syn isomeπ

C,_gH₂₆N₂0₃ requires C 67.90, H 8.23, N 8.80; adjusted 0.11% H,0 and 0.57% Et₂0. C 67.81, H 8.26 N 8.74; found 67.21, H 8.18, N 8.57. MS (CI): 319( M+H)⁺ IR (Kbr) cm ¹: 1250 (C-O-0); 1068 (C-O-C).

NMR (CDC1₃) δ: 7.25 (2H,m) and 6.95 (3H, m, 0H plus CHC1₃); 4.67 (1H, q, -CHCH- ₃(syn)); 4.35 (2H, m, -C=NOCH₂); 4.17 (2H, -OCH₂); 2.65-2.30 (9H, two s overlapping broad m, -NCH₃ plus -NCH₂ plus =N-C-CH₂ (syn)); 2.05-1.60 (4H, m,-CH,); 1.40 (3H, t, CHCH₃). HPLC (Novapak Phenyl, CH₃CN/H₂0, KH₂P₄ buffer at Ph 2.5) major peak at 13.15 mins. No anti detectable.

Example 7

Svn- and anti-2,8-dimethyl-l-oxa-8-azaspiro[4.5]decane-3-one, 0-f2-ethoxyethvP oxime The title compounds were prepared by reacting 2,8-dimethyl-l-oxa-8-azaspiro[4.5]- decane-3-one with 2-ethoxyethyl hydroxylamine hydrochloride [106 (M+H)^*, m.p. 74- 77°C (unc)] using the methods of Example 4.

Anti isomer: C_I4H₂₆N₂0₃ requires C 62.19, H 9.69, N 10.36; adjusted for 0.44% H₂0 C 61.92, H 9.70,

N 10.32; found C 61.67, H 9.66, N 10.10.

MS (CI): 271 (M+H)⁺.

IR (neat, NaCl) cm^"1: 1067 (C-O-C).

HPLC (Novapak Phenyl, CH₃CN/H₂0, KH₂P0₄ buffer at Ph 2.5) major peak at 12.28 mins. No syn detectable.

NMR (CDC1₃) δ: 4.50 (1H, m, CHCH₃)(anti)); 4.20 (2H, m, =NOCH₂); 3.67 (m, CH₂C-

H₂0) plus 3.55 (total 4H, q (4H, q, -OCH₂ CH₃); 2.80-2.30 (9H, s overlapping m, -NCH₃ plus -NCH₂ plus N=C-CH₂); 1.95-1.60 (4H,m, -CH₂); 1.40 (3H, d, CHCH₃); 1.13 (3H, t. -OCH₂CH₃).

Syn isomer:

C_HH_JJN_JO_J requires C 62.19, H 9.69, N 10.36; adjusted for 0.74% H₂0 C 61.73, H 9.70, N 10.28: found C 61.91. H 9.68. N 9.95. MS (CI): 271 (M + H)⁺. IR (neat NaCl) cm ¹: 1069 (C-O-C).

HPLC (Novapak Phenyl, CH₃CN/H₂0, KH₂P0₄ buffer at Ph 2.5) major peak 12.79 mins with no anti detectable. NMR (CDC1₃) δ: 4.73 (1H, q, CHCH₃); 4.17 (2H, m, =NOCH₂); 3.63 (m, -CH₂CH₂-) plus 3.55 (4H, q-OCH₂ CH₃); 2.65-2.30 (9H, s plus m, -NCH₃ plus -NCH₂ plus N=C- CH₂); 1.95-1.5 (4H, m,-CH₂); 1.43 (3H, CHCH₃); 1.23 (3H, d, CHCH₃); 1.23 (3H, t, CH₂ CH₃).

Example 8

Syn- and anti-2,8-dimethyl-l-oxa-8-azaspiro[4.5]decane-3-one, O-fN-methyl-2-ethanam- idvH oxime

A solution of a crude sample of the title compound of Example 1 (l.Og, assumed 3.7m- moles) and dimethylaminopyridine (0.06g, 0.44mmoles) in anhydrous CH₂Q₂ (72ml) was placed under nitrogen and cooled to 0°C with an ice bath. The solution was treated with bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (1.9g, 4.1mmoles) in one portion. The reaction was then treated with gaseous methylamine using a bubbler tube.

The reaction was stirred at room temperature overnight.

The reaction was diluted with CHC1₃ and washed with saturated aqueous sodium car¬ bonate. The aqueous layer was extracted with five portions of CHC1₃. The combined organic layers were dried and stripped. Two passes through silica Prep-paks using an ammoniated toluene/acetonitrile/methanol gradient gave 0.9g, or 70% yield. The white solid which froze out on storing cold appeared to be hygroscopic and gave a broad melting range.

C_UH_JJN_JO_J requires C 57.97, H 8.61 , N 15.60; adjusted for 0.69% H₂0 and 0.16% Eψ C 57.58, H 8.6 N 15.47; found C 56.96, H 8.44, N 15.11. MS (CI): 270 (M+H)⁺. IR (Kbr) cm^'1: 3366 (HN-C=0); 1653 (N-C=0).

NMR (CDCl_j) δ: 6.15 (1H, broad s, HN-C=0); 4.65 (q, CHCH₃ (syn) plus 4.55 (3H, s overlapping q at 4.50, =NOCH₂ plus -CHCH₃ (anti)); 2.90 (3H, d, 0=C-NMe); 2.85- 2.40 (9H, m overlapping s with shoulder, -NCH₃ plus -NCH₂ plus N=C-CH₂); 2.15-1.75 (4H, m, -CH₂); 1.45 (d, -CH₃ (syn)) plus 1.35 (3H, d, -CH₃ (anti)). HPLC (Novapak Phenyl, CH₃ CN/H₂0, KH₂P0₄ buffer at Ph 2.5) Major peaks at 5.75 (anti) and 6.68 mins (syn) in 4.3/1 ratio.

Example 9

Svn- and anti-2.8-dimethyl-l-oxa-8-azaspiro[4.5]decane-3-one, O-fN.N-dimethyl-2-etha- namidyP oxime

The title compounds were prepared from the title compound of Example 1 and dime- thylamine using the method of Example 8.

^N requires C 59.34, H 8.89, N 14.83; adjusted for 0.37% H₂0 and 0.77% E

C 59.16, H 8.94, N 14.66; found C 58.49, H 8.67, N 14.19. MS (CI): 284 (M+H)⁺.

IR (neat, NaCl) cm ¹: 1671 (0=C-Nme₂); 1071 (C-O-C).

NMR (CDC1₃) δ: 4.80 (q, -CHCH₃ (syn)) plus 4.75 (s with shoulder, =NOCH₂) plus 4.55

(3H, q, -CHCHj (anti)); 3.00 (6H, d, -Nme₂); 2.90-2.35 (9H, s, with shoulder overlapping m, -NCH₃ plus NCH₂ plus N=C-CH₂); 2.05-1.60 (4H, m, -CH₂) 1.50 (d, CH₃ (syn) and 1.40 (total 3H, d, -CH₃ (anti)) ratio 3.8/1 anti/syn.

HPLC (Novapak Phenyl, CH₃ CN/H₂0, KH₂P0₄ buffer at Ph 2.5) single major peak at

9.83 mins (isomers unresolved).

Example 10 Svn- and anti-2.8-dimethyl-l-oxa-8-azaspiro[4.5]decane-3-one. O-fcarboxymethvP oxime propargyl ester

A suspension of a crude sample of the title compound of Example 1 (0.55g, assumed 2.05mmoles) and diisopropylethylamine (0.36ml, 2.05 mmoles) in dry THF (100ml) were placed under N₂ and cooled to -10°C with an ice/salt bath. Pivaloyl chloride (0.26ml, 2.05mmoles) was added and the reaction was stirred at -10°C for 20 minutes. The propargyl alcohol (2.5ml in excess, containing another 0.36ml of DIEA) was added dropwise. The reaction was stirred at room temperature overnight. The next morning the reaction was heated at 45°C for one hour. After allowing to cool the reaction was diluted with CHC1₃ and washed with saturated aqueous sodium carbon¬ ate. The aqueous layer was extracted three times with chloroform, and the combined organic layers were dried and evaporated. The crude was purified on a silica flash 5 column, using an ammoniated 4-6% MeOH /CHC1₃ gradient. This yielded 0.30g or 49.7% of hygroscopic solid.

C-sH-^N requires C 61.21, H, 7.53, N 9.52, adjusted for 0.85% H₂0 60.69, H 7.56, N

9.44; found C 60.00, H 7.41, N 9.25. ιo MS (CI): 295 (M+H)⁺.

IR (Kbr) cm ¹: 1767.

NMR (CDC1₃) δ: 4.85-4.45 (total 5H)(q (4.80) CHCH₃ (syn)) overlapped by d, -CH₂

C=H) plus (s with shoulder and q (4.50) -OCH2 C=0 and CH-CH3 (anti)); 2.90-2.30

(10H, complex m, overlapped by t and s, -NCH₃ plus -NCH₂ plus -C=CH plus N=C- i5 CH₂); 1.95-1.60 (4H, m, -CH₂); 1.95-1.60 (4H, m, -CH₂); 1.45 (d, -CH₃ (syn) plus 1.35

(total 3H, d, -CH3 (anti).

HPLC (Novapak Phenyl, CH₃CN/H₂0, KH₂P0₄ buffer at Ph 2.5): Major peaks at 8.68 and 9.47 mins in 5/1 ratio anti/syn.

0 Example 11

Svn- and anti-2,8-dimethyl-l-oxa-8-azaspiro[4.5]decane-3-one, O-fcarboxymethvπ oxime propyl ester

The title compounds were prepared from the title compound of Example 1 and propanol using the method of Example 10. 5

MS (CI): 299 (M+H)\

C^H-^NA requires C 60.38, H, 8.78, N 9.39; found C 59.95, H 8.56, N 8.79. IR (neat, NaCl) cm ¹; 1761 (shoulder 1738) (0=C-0).

HPLC (Novapak Phenyl, CH₃ CN/H₂0, KH₂P0₄ buffer at Ph 2.5) single major peak at o 10.96 mins.

NMR (CDC1₃) <S: 4.85-4.45 (total 3H, q (4.80) CHCH₃ (syn) plus s, with shoulder, N=C- 0-CH₂ plus q(4.60) CHCH₃ (anti)) with 4.15 (2H. two overlapped t, -OCH,CH); 2.90- 2.35 (9H. s, overlapping m, -NCH₃ plus -NCH₂ plus -CH₂-C=N); 2.10-1.50 (6H, appar- ent sextuplet overlapping m, -OCH₂CH;,- plus CH₂); 1.55-1.35 (3H, t, -CH₃) ratio 3.6/1 anti/syn by integration of CHCH₃;

Example 12 5 Svn- and anti-2,8-dimethyl-l-oxa-8-azaspiro[4.5]decane-3-one, O-fcarboxymethvO oxime benzyl ester

The title compounds were prepared from the title compound of Example 1 and benzyl alcohol using the method of Example 10. C₁₉H₂₆N₂0₄ requires C 65.88, H, 7.57, N 8.09; found C 65.41, 7.66, 7.83

10

MS (CI): 347 (M+H)⁺.

IR (neat, NaCl) cm ¹: 1761 (shoulder 1738) (0=C-0).

HPLC (Novapak Phenyl, CH₃CN/Η₂0, KH₂P0₄ buffer at Ph 2.5) single major peak. NMR (CDC1₃) δ: 7.35 (5H, s, 0H); 5.20 (2H, s, OCH₂0); 4.80-4.40 (3H, s, with shoulder is plus two q, -CHCH₃ plus -OCH₂); 2.95-2.35 (8H, s, overlapping m, -NCH₃ plus -NCH₂ plus N=C-CH₂); 2.20-1.70 (3H, m, -CH₂); 1.45-1.35 (3H, two d, CH₃) ratio 4/1 anti to syn by CHCH₃

Example 13 o fS -fl/zt -2,8-Dimethyl-l-oxa-8-azaspiro[4.5]decan-3-one, O-fN.N-dimethylglvcolamide^ oxime

(a) CJ5-2,8-Dimethyl-l-oxa-8-azaspiro[4.5]decan-3-ol

Under a nitrogen atmosphere, a solution of lithium tri-sec-butylborohydride in tetra¬ hydrofuran (6ml of a 1M solution, όmmoles) was added dropwise over 10 minutes to a 5 solution of 2,8-dimethyl-l-oxa-8-azaspiro[4.5]decan-3-one (315mg, 1.72mmoles) in tetrah¬ ydrofuran (25ml) precooled in a dry ice/acetone bath to -78°C. The reaction mixture was allowed to warm gradually over 1 hour to 0°C and quenched by addition of satu¬ rated aqueous sodium chloride solution (1ml). The reaction mixture was diluted with of 10% aqueous sodium carbonate solution (100ml) and extracted with chloroform o (4x75ml). The combined organic extract was dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to a light yellow oil. Flash chromatography through neutral silica gel using ammoniated chloroform/methanol [9:1] gave 177mg (55%) of the subtitle compound as a light yellow oil. MS (CI): 185 [M+H]⁺

(b) r2S.3S. l 'R^v)-2.8-Dimethyl- l -oxa-8-azaspiro[4.5]decan-3-yl N-f l-f 1- naphthyl ethyl]carbamate s Under a nitrogen atmosphere, a solution of the product of step (a) (13.3g, 71mmoles), (R)-l-(l-naphthyl)ethyl isocyanate (16g, δlmmoles), and dibutyltin dilaurate (0.22ml, 1.3mmoles) in anhydrous toluene (350ml) was heated at reflux for 3.5 hours. The reac¬ tion mixture was cooled to ambient temperature and concentrated in vacuo. The resi¬ due was dissolved in dichloromethane (500ml), washed successively with saturated aque- ιo ous sodium bicarbonate solution (100ml) and brine (100ml), dried over anhydrous magnesium sulphate, and evaporated in vacuo. The residue was treated with anhydrous hydrogen chloride in 2-propanol to obtain 11.3g (42%) of the subtitle compound as its hydrochloride salt.

is Chiral HPLC (15% ethanol/hexane, 0.5ml/min): 99.97% dp MS (CI): 383 [M+H]⁺ m.p. 160-162°C (2-propanol)

(c) f2S.3SV2.8-Dimethyl-l-oxa-8-azaspiro[4.5]decan-3-ol 0 Under a nitrogen atmosphere, the compound of step (b) (2.1g, 5mmoles) was added portionwise over 30 minutes to a solution of sodium bis(2-methoxyethoxy)aluminium hydride (22.44mmoles) in anhydrous tetrahydrofuran (50ml). The reaction was heated at reflux for 2 hours, cooled in an ice bath, and treated with water dropwise until the precipitated salts formed a separable mass. The solvent layer was decanted, the salts 5 were extracted with tetrahydrofuran (2x50ml) and the combined organics were concen¬ trated in vacuo. Purification by flash chromatography using ammoniated chloroform/me- thanol/water [78:20:2] gave 900mg (98%) of the subtitle compound.

Chiral HPLC (4% ethanol/hexane, 0.75ml/min) 100% ee o m.p. >250°C (hydrochloride salt, 2-propanol)

(d) rS -2,8-Dimethyl-l-oxa-8-azaspiro[4.5]decan-3-one N-Chlorosuccinimide (12.4g, 92mmoles) was dissolved in anhydrous dichloromethane (380ml), placed under a nitrogen atmosphere, and cooled with an ice bath. A solution of dimethylsulphide (8.7ml, 120mmoles) in dichloromethane (23ml) was added dropwise, producing a white precipitate. The suspension was stirred at 0°C for 90 minutes, then 5 cooled to -28°C with a dry ice/carbon tetrachloride bath. A solution of the subtitle compound of step (c) (11.5g, 62mmoles) in dichloromethane (78ml, adjusted to Ph 6 using trifluoroacetic acid) was added dropwise and the resulting mixture was stirred at -28°C for 90 minutes. Finally, a solution of triethylamine (12.9ml, 92 mmoles) in dichlor¬ omethane (28ml) was added dropwise. The reaction mixture was stirred for an addi- ιo tional 5 minutes, the dry ice/carbon tetrachloride bath was removed and the reaction was allowed to warm to ambient temperature. A freshly prepared saturated solution of aqueous sodium bicarbonate (320ml) was added to the reaction mixture, which was then stirred vigorously for 15 minutes. The layers were separated and the aqueous layer was extracted with chloroform (3x500ml). The combined organic layer was dried over s anhydrous magnesium sulphate and filtered. The filtrate was acidified with 2.2 equival¬ ents of acid (maleic acid or citric acid) dissolved in warm 2-propanol. The precipitated salt was collected and dried under high vacuum.

m.p. 153-155°C (citrate salt, ethyl acetate) o MS (CI): 184 [M+H]⁺

(e) (SVαnri-2.8-Dimethyl-l-oxa-8-azaspiro[4.5]decan-3-one oxime and (^,SVyyn-2,8-Dimethyl-l-oxa-8-azaspiro[4.5]decan-3-one oxime 5 The subtitle compounds were prepared from the subtitle compound of step (d) (42mmoles) by the method of Example 14(d), giving 3.26g of the first subtitle compound {m.p. 153-154.5°C (cyclohexane), MS (CI, M/z): 199 [M+H]⁺}, followed by 1.8g of the second subtitle compound {m.p. 135°C (toluene/petroleum ether), MS (CI): 199 [M+H⁺]}, in 61% yield overall for 2 steps.

(f) ■ S -gnn^'-2,8-Dimethyl-l-oxa-8-azaspiro[4.5]decan-3-one.O-(N.N-dimethylglycol- amide) oxime Under a nitrogen atmosphere, sodium hydride (43mg of a 60% dispersion in mineral oil. 1.07 mmoles) was added to an ice cold solution of the first subtitle compound of step (e) (172mg, 0.87mmoles) in dry dimethylformamide (10ml). After stirring for 40 min¬ utes, a solution of 2-chloro-N,N-dimethylacetamide (130mg, 1.07mmoles) in dimethyl- s foπnamide (5ml) was added dropwise over 2 minutes. The resulting suspension was allowed to warm gradually to ambient temperature over 30 minutes and stirred for an additional 4 hours. The reaction was then poured into 5% aqueous sodium carbonate solution (50ml) and extracted with chloroform (4x40ml). The combined organic extract was dried over anhydrous magnesium sulphate and concentrated to a yellow oil in vacuo. ιo The yellow oil was flash chromatographed through neutral silica gel using ammoniated chloroform and methanol [92:8] as the eluant, giving 167mg (68%) of the title compound as a light yellow oil.

MS (CI): 284 [M+H]⁺. 5

Example 14

(RVflnt -2.8-Dimethyl-l-oxa-8-azaspiro[4.5]decan-3-one. O-fN.N-dimethylglycolamide^ oxime

(a) r2R.3R. l 'SV2.8-Dimethyl- l -oxa-8-azaspiro[4.51decan-3-yl N-[ l-f l- o naphthvHethyljcarbamate

The subtitle compound was prepared from the subtitle compound of Example 13(a) (3.18g, 17mmoles) and (S)-l-(l-naphthyl)ethyl isocyanate (3.75g, 19mmoles) using the method of Example 13(b), providing 2.53g (35%) of the hydrochloride salt.

5 Chiral HPLC (15% ethanol/hexane, 0.5ml/min): 100% dp MS (CI): 383 [M+H]⁺ m.p. 158-16FC (2-propanol)

(b) f2R.3R>2.8-Dimethyl-l-oxa-8-azaspiro[4.5]decan-3-ol The subtitle compound was prepared from the compound of step (a) (27.8g, 66.4mmoles) by the method of Example 13(c), providing 12.4g (100%).

Chiral HPLC (4% ethanol hexane, 0.75ml/min) 100% ee m.p. 265-267°C (hydrochloride salt. 2-propanol)

(c) fRV2,8-Dimethyl-l-oxa-8-azaspiro[4.5]decan-3-one

The subtitle compound was prepared from the compound of step (b) (0.44g, 2.4mmoles) 5 using the method of Example 13(d), giving lOOmg (18%) as the maleate salt.

m.p. 148-149°C (ethyl acetate) MS (CI): 184 [M+H]⁺

ιo (d) fRVqnt/-2,8-Dimethyl-l-oxa-8-azaspiro[4.5]decan-3-one oxime and fRV vn-2.8-Dimethyl-l-oxa-8-azaspiro[4.5]decan-3-one oxime Under a nitrogen atmosphere, the crude product of step (c) (89mmoles) was dissolved in methanol (1.51). Hydroxylamine hydrochloride (7.53 g, 1.2equiv) was added and the is Ph of the solution was adjusted to 4 with triethylamine. The solution was stirred at ambient temperature for 2.5 hours, the methanol was removed in vacuo and the residue taken up in 20% methanol/chloroform (11), which was then washed with saturated aque¬ ous sodium carbonate solution (200ml). The aqueous layer was extracted with 20% methanol/chloroform (5x11) and the combined organic layer was dried over anhydrous o magnesium sulphate, filtered and concentrated in vacuo. The isomers were separated and purified using preparative HPLC. Elution with a 4-10% ammoniated methan¬ ol/chloroform gradient gave 5.5g of the first subtitle compound {m.p. 151-153°C (toluene/petroleum ether), MS (CI): 199 [M + H]⁺}, followed by 2.0g of the second subtitle compound {m.p. 135-136°C (toluene/petroleum ether), MS (CI): 199 [M+H]⁺} 5 in a combined yield of 43% overall for the 2 steps.

(e) R1-gnt -2,8-Dimethyl-l-oxa-8-azaspiro[4.5]decan-3-oneO-rN,N-dimethylglvcol- amide oxime The title compound was prepared from the first subtitle compound of step (d) (301mg, o 1.52mmoles) and 2-chloro-N,N-dimethylacetamide (231mg, 1.90mmoles) by the pro¬ cedure of Example 13(f), providing 389mg (90%) as an oil following flash chromatogra¬ phy using ammoniated chloroform/methanol [92:8]. MS (CI): 284 [M + H] ⁺

Example 15 fS - v -2.8-Dimethyl-l-oxa-8-azaspiro[4.5]decan-3-one, Q-fN,N-dimethylglvcolamide oxime

The title compound was prepared from the second subtitle compound of Example 13(e) (300mg, 1.51mmoles) and 2-chloro-N,N-dimethylacetamide (223mg, 1.83 mmoles) by the procedure of Example 13(f), yield 227mg (53%) following flash chromatography using ammoniated chloroform/methanol [92:8].

m.p. 128-130°C (oxalate salt, ethyl acetate) MS (CI): 284 [M+H]⁺

Example 16 fRV.yyn-2.8-DimethvI-l-oxa-8-azaspiro[4.5]decan-3-one, O-fN.N-dimethylglvcolamide') oxime

The title compound was prepared from the second subtitle compound of Example 14(d) (300mg, 1.51mmoles) and 2-chloro-N,N-dimethylacetamide (226mg, 1.85mmoles) by the procedure of Example 13(f), yield 310mg (73%) following flash chromatography using ammoniated chloroform/methanol [95:5]-[90:10].

MS (CI): 284 [M+H]⁺

Example 17 rSVαnt -2.8-Dimethyl-l-oxa-8-azaspiro[4.5]decan-3-one, O-fmethoxycarbonylmethvπ oxime

The title compound was prepared from the first subtitle compound of Example 13(e) (300mg, 1.51mmoles) and methyl chloroacetate (209mg, 1.92 mmoles) by the procedure of Example 13(f), yield 317mg (77%).

MS (CI): 271 [M+H]⁺

Example 18 ι R)- /tn-2,8-Dimethyl-l-oxa-8-azaspiro[4.5]decan-3-one. O-fmethoxycarbonylmethyπ oxime

The title compound was prepared from the first subtitle compound of Example 14(d) - (200mg, l.OOmmoles) and methyl chloroacetate (130mg, 1.20mmoles) by the procedure 5 of Example 13(f), yield 90mg (25%) as its oxalate salt.

m.p. 139-142°C (ethyl acetate) MS (CI): 271 [M+H]⁺

ιo Example 19 fSVwn-2.8-Dimethyl-l-oxa-8-azaspiro[4.5]decan-3-one. O-fmethoxycarbonylmethvO oxime The title compound was prepared from the second subtitle compound of Example 13(e) (248mg, 1.25mmoles) and methyl chloroacetate (166mg, 1.53mmoles) by the procedure of Example 13(f), yield 159mg (47%) following flash chromatography using ammoniated s chloroform/methanol [92:8].

m.p. 146-149°C (maleate salt, ethyl acetate) MS (CI): 271 [M+H]⁺

o Example 20

(R)- vn-2.8-Dimethyl-l-oxa-8-azaspiro[4.5]decan-3-one, O-dnethoxycarbonylmethvπ oxime

The title compound was prepared from the second subtitle compound of Example 14(d)

(200mg, l.OOmmoles) and methyl chloroacetate (130mg, 1.20mmoles) by the procedure s of Example 13(f), yield 180mg (47%) as maleate salt.

m.p. 144.5-146.5°C (ethyl acetate) MS (CI): 271 [M+H]⁺

0 Example 21

(S -g/ιtz^'-2,8-Dimethyl-l-oxa-8-azaspiro[4.5]decan-3-one, Q-(2-methoxyethvπ oxime The title compound was prepared from the first subtitle compound of Example 13(e) (300mg, 1.51mmoles) and 2-bromoethyl methyl ether (264mg, 1.90mmoles) using the method of Example 13(f), yield 333mg (86%) following flash chromatography using ammoniated chloroform/methanol [96:4].

m.p. 87-89°C (oxalate salt, ethyl acetate) MS (CI): 257 [M+H]⁺

Example 22 fR nri-2.8-Dimethyl-l-oxa-8-azaspiro[4,5]decan-3-one. O-^-methoxyethvO oxime The title compound was prepared from the first subtitle compound of Example 14(d) (301mg, 1.52mmoles) and 2-bromoethyl methyl ether (265mg, 1.91mmoles) using the method of Example 13(f), yield 290mg (75%) following flash chromatography using ammoniated chloroform/methanol [94:6].

m.p. 94-96°C (oxalate salt, ethyl acetate) MS (CI): 257 [M+H]⁺

Example 23 fS -5v -2,8-Dimethyl-l-oxa-8-azaspiro[4,5]decan-3-one, O-f2-methoxyethv0 oxime The title compound was prepared from the second subtitle compound of Example 13(e) (300mg, 1.51mmoles) and 2-bromoethyl methyl ether (268mg, 1.93mmoles) using the method of Example 13(f), yield 225mg (58%) following flash chromatography using ammoniated chloroform/methanol [95:5].

m.p. 89-91°C (oxalate salt, ethyl acetate) MS (CI): 257 [M+H]⁺

Example 24 fRV vn-2.8-Dimethyl-l-oxa-8-azaspiro[4,5]decan-3-one, O-(2-methoxyethy0 oxime The title compound was prepared from the second subtitle compound of Example 14(d) (301mg, 1.52mmoles) and 2-bromoethyl methyl ether (270mg, 1.94mmoles) using the method of Example 13(f), yield 343mg (88%) following flash chromatography using ammoniated chloroform/methanol [95:5]. m.p. 85-88°C (oxalate salt, ethyl acetate) MS (CI): 257 [M+H]⁺

Example 25 s CSV.w.n-2.8-Dimethyl-l-oxa-8-azaspiro[4.5]decan-3-one, 0-f2-ethoxyethyπ oxime

The title compound was prepared from the second subtitle compound of Example 13(e) (300mg, 1.51mmoles) and 2-bromoethyl ethyl ether (330mg, 1.94mmoles) using the method of Example 13(f), yield 230mg (56%) following flash chromatography using ammoniated chloroform/methanol [95:5], followed by ammoniated ethyl acetate/hex- ane/methanol [6:6:1].

MS (CI): 271 [M+H]⁺

Example 26 fR>svn-2.8-Dimethyl-l-oxa-8-azaspiro[4,5]decan-3-one, Q-f2-ethoxyethyπ oxime

The title compound was prepared from the second subtitle compound of Example 14(d) (350mg, 1.76 mmoles) and 2-bromoethyl methyl ether (385mg, 2.26mmoles) using the method of Example 13(f), yield 230mg (48%) following flash chromatography using amm¬ oniated chloroform methanol [95:5], followed by ammoniated ethyl acetate/hexane/methanol [6:6:1].

MS (CI): 271 [M+H]⁺

Example 27 2,8-Dimethyl-l-oxa-8-azaspiro[4.5]decan-3-one O-cyanomethyl oxime

The title compound was prepared from 2,8-dimethyl-l-oxa-8-azaspiro[4.5]decan-3-one hydrochloride ( l.Og, 4.55mmol) and cyanomethoxyamine hydrochloride (0.62g, 4.57mmol) according to the methods of Example 4, providing 850mg (79%) of a 3:1 anti/syn mixture of isomers following purification by HPLC (Delta Prep 4000) eluting with ammoniated chloroform/methanol [98:2] to [95:5].

MS (CI): 238 [M+H]⁺ Example 28

2,8-Dimethyl-l-oxa-8-azaspiro[4.5]decan-3-one O-f2,2,2-trifluoroethy0 oxime The title compound was prepared from 2,8-dimethyl-l-oxa-8-azaspiro[4.5]decan-3-one and 2,2,2-trifluoroethoxyamine hydrochloride using the methods of Example 4. providing 5 0.4g of αnri-isomer {m.p. 168.5-170.5°C (oxalate salt, EtOAc), MS (CI): 281 [M+H]⁺} and 0.2g of sγn-isomeτ {m.p. 131-132°C (oxalate salt, EtOAc), MS (CI): 281 [M+H]⁺} following HPLC separation eluting with ammoniated chloroform/methanol [96:4] to [93:7].

ιo Example 29

2,8-Dimethyl- l-oxa-8-azaspiro[4.5]decan-3-one Q-[2-f 2-ethoxyethoxy)ethyl] oxime The title compound was prepared from 2,8-dimethyl-l-oxa-8-azaspiro[4.5]decan-3-one (2.3g) and 2-(2-ethoxyethoxy)ethoxyamine hydrochloride using the methods of Example 4, providing 2.2 g of απtz^'-isomer {m.p. 125-129°C (citrate salt, EtOAc), MS (CI): 315 s [M+H]⁺} and 1.2g of .yyn-isomer {m.p. 119.5-121.5°C (oxalate salt, EtOAc), MS (CI): 315 [M+H]⁺} following HPLC separation eluting with ammoniated chloroform methanol [96:4] to [93:7].

Example 30 o flnri-2.8-Dimethyl-l-oxa-8-azaspiro[4.5]decan-3-one O-fethoxycarbonylmethvπ oxime The title compound was prepared from a racemic mixture of the first title compound of Example 13(e) and the first title compound of Example 14(d) (500mg, 2.52mmol) and ethyl bromoacetate (530mg, 3.17mmol) using the method of Example 13(f), providing 420mg (58%) following flash chromatography eluting with ammoniated chloroform meth- 5 anol [95:5].

m.p. 123-127°C (Oxalate salt, EtOAc) MS (CI): 285 [M+H]⁺

Example 31

2,8-Dimethyl-l-oxa-8-azaspiro[4.5]decan-3-one O-fN,Q-dimethylglvcolhvdroxamide ) oxime The title compound was prepared from the title compound of Example 1 (500mg) and N,0-dimethylhydroxylamine hydrochloride using the method of Example 2, giving 480mg of a mixture of syn- and αnt/^'-isomers.

5 m.p. 94-104°C (oxalate salt, EtOAc) MS (CI): 300 [M+H]⁺

Example 32 flnπ-8-Methyl-l-oxa-8-azaspiro[4.5]decan-3-one 0-fmethoxycarbonylmethvO oxime ιo αnri-8-Methyl-l-oxa-8-azaspiro[4.5]decan-3-one oxime was first prepared from 8-methyl- l-oxa-8-azaspiro[4.5]decan-3-one oxime (the compound of Example 3, International Patent Application WO 90/15804) using HPLC. The title compound was then prepared from this ann-o me (50mg) and methyl chloroacetate following the method of Example 13(f), giving 70mg of the citrate salt following flash chromatography on silica gel using is 0-10% ammoniated methanol in chloroform as the eluant.

m.p. 147.5- 148.5°C (1:1 EtOAc/isopropanol) MS (CI): 257 [M+H]⁺

0 Example 33 vn-8-Methyl-l-oxa-8-azaspiro[4.5]decan-3-one O-fmethoxycarbonylmethvP oxime yn-8-Methyl-l-oxa-8-azaspiro[4.5]decan-3-one oxime was first prepared from 8-methyl-l- oxa-8-azaspiro[4.5]decan-3-one oxime (the compound of Example 3, International Patent Application WO 90/15804) using HPLC. The title compound was then prepared from 5 this .syti-oxime (280mg) and methyl chloroacetate following the method of Example 13(f), giving 245mg of the citrate salt following flash chromatography on silica gel using 0-10% ammoniated methanol in chloroform as the eluant.

m.p. 167.5-169°C (1:1 EtOAc/isopropanol) o MS (CI): 257 [M+H]⁺

Example 34 αrct.-2,8-Dimethyl-l-oxa-8-azaspiro[4.5]decan-3-one. Q-d.3-dioxoian-2-ylmethyl) oxime The title compound was prepared from a racemic mixture of the first title compound of Example 13(e) and the first title compound of Example 14(d) (400mg) and 2-brom- omethyl-l,3-dioxolane using the method of Example 13(f), providing 270mg (47%) following flash chromatography eluting with ammoniated chloroform/methanol [95:5].

m.p. 140-141.5°C (citrate salt, isopropanol/ether) MS (CI): 285 [M+H]⁺

Example 35 flnt -2.8-Dimethyl-l-oxa-8-azaspiro[4.5]decan-3-one. O-ftetrahvdrofuran-2-ylmethvπ oxime

The title compound was prepared from a racemic mixture of the first title compound of Example 13(e) and the first title compound of Example 14(d) (400mg) and 2-brom- omethyl-tetrahydrofuran using the method of Example 13(f), providing 130mg (24%) following flash chromatography eluting with ammoniated chloroform/methanol [95:5].

m.p. 142-145°C (citrate salt, isopropanol/ethyl acetate) MS (CI): 283 [M+H]⁺

Example 36

[la,3a.4a.4'E]- and [la.3a.4a.4'Z]-5'-Methylspiro[l-azabicvclo[2.2.1]heptane-3.2'r3'HV furan]-4Y5'HVone. Q-f2-methoxyethvπ oxime 2,4.6-trinitrobenzenesulphonate

(a) 3-fCarboethoxymethylene)-l-azabicvclo[2.2.1]heptane

Sodium (2.96g, 129mmol) was dissolved in cold ethanol (0°C, 250ml), triethyl phosph- onoacetate (31g, 137mmol) was added and the solution was stirred at room temperature for 5 hours. l-Azabicyclo[2.2.1]heptan-3-one (9.53g, 85.8mmol) was added and stirring continued for about 2 hours, when the reaction appeared complete by TLC.

The solvent was evaporated, the residue was taken up in water, acidified with dilute HC1 and extracted with 2 portions of ether. The aqueous layer was basified with sodium carbonate and the product was extracted with 3 portions of ether and the combined extracts were dried (MgS0₄). The solvent was evaporated and the residue was flash chromatographed through NH₃-deactivated silica eluting with CHClj/MeOH [40: 1 then 20:1] to give the subtitle compound (13.2g) as a clear liquid.

(b) Ethyl exo-S'-methylspirofl-azabicvclotllljheptane-S^YS'HVfuran ^YS'H^-one- 3'-carboxylate

Sodium hydride (60% dispersion in oil, 8.8g, 221mmol) was washed with hexane, sus¬ pended in DMF (80ml), cooled on ice and ethyl lactate (26. lg, 221mmol) added cau¬ tiously keeping the foaming under control. The mixture was stirred at room tempera- ture for 1 hour and the product of step (a) (8g) was added slowly to the resulting dark solution. The reaction was stirred at room temperature overnight.

The reaction mixture was then diluted with ether (200ml) and acidified with Hcl satu¬ rated ethanol. Hexane (100ml) was added and the top solvent layer was separated. The bottom layer, which contained most of the subtitle compound, was washed with ether and the combined washings were diluted with hexane, precipitating a brown oil which also contained some of the subtitle compound. The original bottom layer was then suspended in CHCLJMeOH [2:1], the resulting white solid was filtered off and the filtrate was combined with the brown oil and flash chromatographed through NH₃- deactivated silica eluting with CHCl_j MeOH [10:1 then 4:1] giving 0.87g of mostly pure high Rf material as a brown solid and a large amount of brown oil.

The impure fractions obtained above were combined and rechromatographed through NH₃-deactivated silica eluting with CHClj/MeOH [10:1] giving the subtitle compound as a high Rf material (1.42g).

(c) Exo-5'-methylspiro[l-azabicvclo[2.2.1]heptane-3.2Y3ΗVfuran]-4Y5ΗVone A solution of the keto ester from step (b) (1.42g) in IN Hcl (20ml) was heated at reflux for 4 hours and left to stand overnight at room temperature.

The reaction mixture was basified with 25% NaOH, extracted with 2 portions of CHC1₃, the extracts were dried (MgS0₄), the solvent was evaporated and the residue was flash chromatographed through NH₃-deactivated silica eluting with CHClj/MeOH [20:1] giving 0.49g of a yellow solid.

A 0.44g sample of the yellow solid was dissolved in propan-2-ol, and 0.28g (1 eq) of fumaric acid was added. The mixture was heated to give a solution and the solid was allowed to precipitate while stirring at room temperature. The white solid was collected and dried under vacuum overnight at 60°C. 0.52g (constant weight) of white solid resulted.

C₁₀H₁₅NO₂.C₄H₄O₄ requires C 56.559%, H 6.442%, N 4.711% Found C 56.42%, H 6.41%, N 4.68% C 56.33%, H 6.44%, N 4.66%

MS (CI): 182 [M+H]⁺ mp: 139-141°C

(d) [la.3a.4a.4^,E]-and [la.3a.4a.4'Z]-5'-Methylspiro[l-azabicvclo[2.2.1]heptane- 3,2Y3Η)-furan]-4Y5ΗVone, O-f 2-methoxyethyD oxime 2.4.6-trinitrobenzenesulphonate A solution of the subtitle compound of step (c) (1.5g, 4.8mmole) and 2-methoxyethoxya- mine hydrochloride (0.61g, 4.8mmole) in methanol (25ml) was stirred at room tempera¬ ture for 3 hours. The reaction was then heated to reflux for 1.5 hours. The reaction mixture was concentrated, and the residue was partitioned between 20ml saturated aqueous Na₂C0₃ solution and 20ml CHC1₃. The layers were separated, and the aqueous layer was extracted with CHC1₃ (3x20ml). The organic layers were then combined, dried (MgS0₄), and concentrated, yielding 1.14g of crude product.

The crude product was purified using HPLC using two high resolution columns, eluting with toluene/ethyl acetate/ammoniated methanol [84:8:8], to give 520mg of the E-isomer, followed by 300mg of mixed fractions. The 2,4,6-trinitrobenzenesulphonic acid salt was made of the E-isomer, and, after recrystallization from isopropanol, yielded 630mg of the pure salt (m.p. 154-157°C). Further purification of the mixed fractions obtained from the HPLC purification gave the Z-isomer as a tan oil (20mg) [m.p. 167-171°C (2,4,6-trinitrobenzenesulphonic acid salt, isopropanol)].

Example 37

[la.3a.4a.4Ε]-5'-Methylspiro[l-azabicvclo[2.2.1]heptane-3.2Y3ΗVfuran]-4Y5ΗVone. O- fN,N-dimethylglycolamide^ oxime

(a) [la,3a.4a.4Ε]-and [la.3a.4a.4^,Z]-5^,-Methylspiro[l-azabicvclof2.2.nheptane- 3.2Y3ΗVfuran]-4Y5ΗVone oxime

Reaction of the subtitle compound of Example 36(c) (4.8g, 15.4mmol) and hydroxyl- amine hydrochloride (1.17g, 16.9mmol) using the method of Example 36(d) yielded the subtitle E-isomer (1.19g) and Z-isomer (307mg).

(b) [la.3a.4a.4Ε]-5^,-MethvIspiro[l-azabicvclo[2.2.11heptane-3,2Y3ΗVfuran1-4Y5ΗV one. O-TN.N-dimethylglycolamide^ oxime

To a suspension of 60% NaH oil suspension (0.065g, 1.63mmol) in dry DMF (6ml) under nitrogen was added the E-isomer of step (a) (0.32g, 1.63mmol) and the mixture was then stirred for 0.5 hour. The resulting solution was cooled to -5°C with an ice- methanol bath and N,N-dimethyl chloroacetamide (0.198g, 1.63mmol) was added in one portion. The reaction mixture was warmed to room temperature, diluted with ether, acidified with Hcl saturated EtOH, and diluted with hexane. The liquid was decanted and the precipitated gum was washed with ether. The residue was partitioned between chloroform and saturated sodium carbonate. The organic layer was separated and the aqueous layer was extracted with chloroform twice. The organic layers were combined and dried (MgS0₄), giving 377 mg of an oil which solidified on standing. The crude product was flash-chromatographed through ammoniated silica gel eluting with CHCl-_j/MeOH [10:1]. The purified product (297mg) was then recrystallized twice from cyclohexane.

m.p. 111-114°C

Example 38 ria.3a.4a.4'Z]-5'-Methylspirofl-azabicvclor2.2.1]heptane-3.2Y3'HVfuranl-4Y5'HVone. O- fN,N-dimethylglycolamide) oxime

Following the method of Example 37(b), the title compound was prepared from the Z- isomer of Example 37(a) (lOOmg, 0.51mmol). The reaction mixture was partitioned between CHC1₃ and water. The aqueous layer was extracted with CHC1₃, the organic extracts were dried (MgS0₄), the solvent was evaporated and residual DMF was removed under high vacuum. Chromatographic purification afforded 37mg of the title compound which was recrystallized from cyclohexane.

m.p. 113-117°C

Example 39

The syn -isomer of the compound of Example 4 was tested for M_ and M₂ efficacy in the tests described above, and found to have an M, efficacy of 23% (in comparison with carbachol), and zero M₂ efficacy.

Claims

Claims:

1. A compound of formula I,

R¹ represents H or alkyl C,^; R² represents -(CH₂)_n-OR³, -(CH₂)_m-C(0)R⁴, fluoroalkyl C_w, cyanoalkyl C,^ or alkyl C_M substituted with a 4-7 membered optionally unsaturated heterocyclic ring;

R³ represents H, alkyl C,^ (optionally substituted with alkoxy C,^), cycloalkyl C₄.₇, a 4-7 membered optionally unsaturated heterocyclic ring, phenyl (optionally substituted with halogen, hydroxy or alkyl C,^), or benzyl (optionally substituted with halogen, hydroxy or alkyl C^);

R⁴ represents OR⁵, NR⁶R⁷, N(OR⁶)R⁷ or alkyl C_w;

R^s represents H, alkenyl C₂.₆, alkynyl C₂.₆ or alkyl C,.₆ (optionally substituted with phenyl);

R° and R⁷ independently represent H or alkyl C,^; R⁸ represents H or alkyl C^; n is 2-5; m is 1-5; p is 1 or 2; and pharmaceutically acceptable salts thereof.

2. A compound as claimed in claim 1, wherein R¹ represents methyl.

3. A compound as claimed in claim 1 or claim 2, wherein R² represents -(CH₂)_n- OR³ or -(CH₂)_m-C(0)R\

4. A compound as claimed in any one of the preceding claims, wherein R³ repre- 5 sents alkyl C^ (optionally substituted with alkoxy C,^) or phenyl.

5. A compound as claimed in any one of the preceding claims, wherein R⁴ repre¬ sents 0-(alkyl C_w) or N(alkyl C,^)₂.

6. A compound as claimed in any one of the preceding claims, wherein R⁸ repre¬ sents methyl. ιo

7. A compound as claimed in any one of the preceding claims, wherein ring A is a ring of formula Al.

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

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

10. A compound of formula I, as defined in claim 1, or a pharmaceutically accept¬ able salt thereof, for use in the manufacture of a medicament for the treatment of a neurodegenerative disorder. o 11. A method of treatment of a neurodegenerative disorder, which comprises administering a therapeutically effective amount of a compound of formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, to a patient suffering from such a disorder. 12. A process for the production of a compound of formula I, as defined in claim 5 1, or a pharmaceutically acceptable salt thereof, which comprises: (a) reaction of a compound of formula II,

in which A and R¹ are as defined in claim 1, with a compound of formula III, H₂NOR² III

in which R² is as defined in claim 1; or

(b) reaction of a compound of formula V,

wherein A and R¹ are as defined in claim 1, with a compound of formula VI,

R²X VI

wherein R² is as defined in claim 1 and X is a leaving group, in the presence of a base; and where necessary converting the resulting compound into a pharmaceuticaUy accept¬ able salt.