CA2150947A1 - Spirofuranone derivatives and their use in the treatment of neurodegenerative disorders - Google Patents

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 C1-6; represents -(CH2)n-OR3, -(CH2)m-C(O)R4, fluoroalkyl C1-6, cyanoalkyl C1-6 or alkyl C1-6 substituted with a 4-7 membered optionally unsaturated heterocycle ring; R3 represents H, alkyl C1-6 (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); R4 represents OR5, NR6R7, N(OR6)R7 or alkyl C1-6; R5 represents H, alkenyl C2-6, alkynyl C2-6 or alkyl C1-6) optionally substituted with phenyl); R6 and R7 independently represent H or alkyl C1-6; R5 represents H, alkenyl alkyl C1-6; 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

~ 094/1367$ 21~ O ~ ~ 7 PCT/GB93/02500 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 s them and processes for their production.

Japanese Patent Application 3-153690 (to Yamanouchi Pharmaceutical Co), EuropeanPatent Application 311313 (and its IJS equivalents US Patents Ns 4,996,210 and 4,940,795, to Yamanouchi Pharmaceutical Co), International Patent Application WO,o 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 lS disorders including Alzheimer's rlice~ce 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 Ml receptors selectively will have a beneficial effect in the treatment of neurodegenerative disorders without causing unwanted side effects [see for example N
7~.0 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, R l N -0 R 2 O

75 wherein ring A is a ring of formula AI or AII (in which the spiro atom is indicated by ~), WO 94/13678 - ~ PCT/GB93/02500 ~
215~7 A I
N ~~ Al I
1 8 ~N

R' represents H or alkyl Clb;
R2 represents -(CH2)n-OR3, -(CH2)m-C(O)R4, fluoroalkyl Cl6, cyanoalkyl Clb or alkyl Cl6 s substituted with a 4-7 membered optionally unsaturated heterocyclic ring;
R3 represents H, alkyl Clb (optionally substituted with alkoxy C,b), cycloalkyl C4 7, a 4-7 membered optionally unsaturated heterocyclic ring, phenyl (optionally substituted with halogen, hydroxy or alkyl Cl4), or benzyl (optionally substituted with halogen, hydroxy or alkyl Clb);
lO R4 represents ORs, NR6R', N(OR6)R' or alkyl C,b;
Rs represents H, alkenyl C26, alkynyl C26 or alkyl Cl 6 (optionally substituted with phenyl);
R6 and R7 independently represent H or alkyl C,b;
R8 represents H or alkyl Clb;
s n is 2-5;
m is 1-5;
p is 1 or 2;
and pharmaceutically acceptable salts thereof (hereinafter referred to ell ~oloc 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 Ml receptor more selectively), or have other more useful properties ~s 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.

215~9~7 WO 94113678 pcTlGs93lo~5oo l~e invention includes all optical and geometric isomers of the compounds of formula I, in particular both ann- (or E-) and ~1- (or Z-) isomers of the carbon-nitrogen double bond, and both (R)- and (S)-stereoisomers at the 2-position of the furanone ring.

s Preferred groups of compounds of the invention which may be mentioned are those in J which:
a) R' represents methyl;
b) R2 represents -(CH2)D-OR3 or -(CH2)m-C(O)R4;
c) R3 represents alkyl C~4 (optionally substituted with alkoxy Cl4) (for example,o methyl, ethyl or ethoxyethyl) or phenyl;
d) R4 represents O-(alkyl C~4) or N(alkyl C,4)2 (for example methoxy, ethoxy, propyloxy or dimethylamino);
e) R8 represents methyl;
f) n is 2;
,s g) m is 1;
h) p is 1;
i) ring A is a ring of formula AI; and j) the carbon-nitrogen double bond is ~yn (i.e. oR2 is disposed adjacent to R').

20 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-25 tion of a compound of the invention, which comprises reaction of a compound of for-mula II, R~o o in which A and R' are as defined above. with a compound of formula III.

WO 94/13678 . PcT/Gss3/02500 ~
21~09~7 H,NOR2 III

in which R2 is as defined above, and where necessary converting the resulting compound into a pharmaceutically acceptable salt.
s Compounds of formula II may be prepared by the methods disclosed in the prior art documents mentioned above (see in particular Intermediates 2 and S 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, O, (~N - O R 2 I V

15 in which R2 is as defined above, with a primary aliphatic amino alcohol as described by Wild e~ 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, R l N - 0 H

0~

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

'5 Wo 94/13678 21 5 n ~ ~ 7 PCTlGs93lo25oo 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 s with l.yd.uAylamine.

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 o 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(O)NHCH(CH3)(1-naphthyl)]
to form diastereoisomers, followed by selective precipitation of one diastereoisomer, lS 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 20 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.

25 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 pharrnacological activ-30 ity in ~nim~l~. 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 dvskinesia. hyperkinesia, mania and Tourette Syndrome. Thus, according to WO 94/13678 pcTlGs93lo25oo 2~9~7 6 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 dvskinesia~ hyperkinesia, mania and Tourette Syndrome) which comprises ~/lminictering a therapeutically effective amount of a compound of the invention to a patient suffering c 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 ~o 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 s phosphatidyl inositol (PI) hydrolysis while M2 receptors inhibit adenylate cyclase. From the results of animal experiments it is sug~ested that muscarinic agonists having M, receptor selectivity may be advantageous in improving impaired performance, memory retention and other clinical manifestations of senile dementia.

20 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 30C 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-30 tion with a high affinity for the Oxo-M binding site with a Ki of less than 1,LM and preferably less than 0.1,lLM are preferred.

Agonist Eff~lcacy -~YO 94/13678 215 0 9 ~ 7 pcTlGs93lo25oo To measure agonist efficacy at M, muscarinic receptors in rat brain hippocampus rat brain hippocampal tissue is cross sliced into 350x350~m 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-s 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 I~ llal 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 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 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.
~o 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 2s 10mgJkg of body weight, and preferably about 0.1 to lmg/kg, is suitable, a~lministered 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 30 is provided a pharmaceutical formulation including preferably less than 50~7c 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-Wo 94/13678 pcTlGs93lo25oo 215û9~7 ~; 8 ders granules, and suppositories for oral. parenteral or rectal ~minictration; and liquiddosage 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.
s 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 o in which the act*e 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.

lS in order to reduce unwanted peripherally me~ ted 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.

2~ 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; iIPLC
= high pressure liquid chromatography; EtOAc = ethyl acetate; Et2O = diethyl ether;
TLC = thin layer chromatography; MeOH = methanol; DMF = dimethylformamide;
2s and EtOH = ethanol.

Example 1 Svn- and anti-2 8-dimethvl-1-oxa-8-azaspiro[4.5]decane-3-one O-(carboxvmethyl) oxime 30 A solution of 2,8-dimethyl-1-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 carboxymethoxylamine hydrochloride (2.7g, 0.013 mole). The :
~WO 94/13678 21~ 0 ~ 17 l~cTlGs93lo25oo 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.
s The pH was adjusted to 6.5 with saturated aqueous Na2CO3. The aqueous layer was washed with a small volume of CHCI3, and this was extracted twice with water. The combined aqueous layers were evaporated in vacuo at 35C. The residue was then treated with ~our portions of absolute ethanol, followed by anhydrous CH2CI2 (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 CHCI3/CH3OH/CH3CO~H/H2O [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 Iyophilized, yielding S 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-OCH2CO2).
I~ (KBr) cm-l: 1606 (-CO2).
20 NMR (CDCI3) ~: 4.95-4.30 (3H, overlapping multiplets, -CHCH3 and -OCH2); 3.40-2.80 (4+H. two broad multiplets, -CH~N plus exchangeable (H2O)); 2.75-2.10 (SH, singlet overlapping small multiplets, -NCH3 and -CH2C=N); 25-1.75 (4H, overlapping multiplets, -CH2); 1.40 (3H, overlapping doublets, -CHCH3).
HPLC (Novapak Clg, CH3CN/H2O, KH2PO4 buffer at Ph 2.5): Two major peaks at 4.54 25 and 6.31 minutes in 4/1 ratio.
Calculated for Cl2H2~,N20,: C 56.24. H 7.87, N 10.93; adjusted for H20 and entrapped CH3CO2H: 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) 30 Example 2 Syn- and anti-2,8-dimethyl-1-oxa-8-azaspiro~4.5]decane-3-one. O-(carboxvmethvl) oxime ethvl ester maleate WO 94/13678 , PCT/GB93/02500 ~
2~50~7 lO
A solution of the crude title compound of Example 1 (1.3g, assumed S.0 mmoles) in 325ml of CH2Cl2 was placed under nitrogen and cooled to 0C with an ice bath. The solution was treated with hydroxybenzotriazole (1.08g, S.0 mmoles) and dicyclohexylca-rbodiimide (0.87g, S.S mmoles). The ice bath was removed and the reaction was stirred at ambient temperature for 30 minutes. The suspension was cooled to 0C and vacuum filtered directly into an addition funnel.

The cold solution was added rapidly to absolute ethanol (1.2g, ~S.0 mmoles) in 130ml of dry CH2CI2 under nitrogen and cooled to 0C. The reaction was allowed to warm and ,0 was stirred overnight at ambient temperature. The suspension was vacuum filtered and evaporated i~l vacuo.

The crude product was purified by flash chromatography on silica using an ammoniated S-20% CH30H/CHCl3 gradient. This gave 0.62g of yellow oil (44%) which gradually ~s crystallized. The maleic salt of 0.3g was precipitated from EtOAc/Et2O giving 0.32g of white solid.

m.p. 83-85C, with decomposition.
MS (CI): 285 (M+H)+.
;o IR (Kbr) cm-': 2473 (-NH+); 1755 (-CO2Et); 1703 (-CO2H); 1579 (-CO2-).
NMR (DMSO-d6) ~: 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 (SH, strong singlet overlapping com-plex multiplet, -NCH3 and -CH2-C=N); 1.90 (4H, complex multiplet, -CH2); 1.40-1.20 2s (6H, triplet overlapping two doublets (minor at 1.4) -CH2CH3 and -CHCH3 (3/1 ratio of isomers)).
HPLC (Novapak Phenyl, CH3CN/H20, KH2PO, buffer at Ph 2.5): Two major peaks at 12.06 and 12.91 in 3/1 ratio.
Calculated for C,8H28N2O8: C 53.99, H 7.05, N 7.00; found: C 53.82, H 6.97, N 6.96 Example 3 Syn- and anti-2.8-dimethvl-1-oxa-8-azaspiro[4.5]decane-3-one. 0-(2-ethanamidvl) oxime maleate 21~09~7 Absolute ethanol (lOOml) was saturated with anhydrous NH3 and a crude sample o~ 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.
When no further progress was evident the ethanol was evaporated in vacuo.

The crude product was purified by flash chromatography on silic~ using an ammoniated 10-20% CH30H/CHCl3 gradient. An NMR of recovered starting material showed that the acid was enriched in syn to a 3/2 ratio. The m~ te salt of the amide was obtained lO from ethyl acetate/Et20, giving 0.31g (84%) of white solid.

mp 104.5-106.5C.
MS (CI): 256 (M+H)+; 197 (loss of -CH CONH2).
IR (Kbr) cm-l: 1678 (-CONH2); 1583 (-CO2).
NMR (DMSO-d6) ~: 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).
20 HPLC (Novapak Phenyl, CH3CN/H20, KH2PO, buffer at Ph 2.5): Two major peaks at 3.07 and 3.84 minutes in 4/1 ratio.
Calculated for C,6H2sN307: 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.

2s Example 4 Svn- and anti-2.8-dimethvl-1-oxa-8-azaspiro[4.5]decane-3-one. 0-(2-methoxvethvl)oxime a) 2-methoxv-0-ethoxylamine hydrochloride The subtitle compound was prepared by a mo-lific~tinn of the process disclosed in Ger-30 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 50C

-and stirred magnetically for four ho~Fs. 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-s der was collected and washed with a small volume of water, yielding 16.8g.

m.p. 9~92C
NMR (DMSO-d6) ~: 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 phth~limide (16.8g, 0.076 mole) was combined with absolute ethanol (lSOml) under nitrogen. Hyd~ e hydrate (3.8ml, 0.076 mole) was added and the reaction was stirred and heated with an oil bath at 95C for 30 minutes. The reaction was monitored to completion using TLC, and was cooled in an ice bath while acidif~ing with concentrated s HCI. 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 u~ 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 i~t vacuo and the residue was triturated with ethyl acetate. The off-white 20 solid was collected and washed with ethyl acetate. The hygroscopic material was dried over P~Os giving 8.05g of the subtitle compound.

m.p. 4~50C (dec) MS (CI): 92 (M+H)+
25 NMR (DMSO-d6) ~: 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-Dimethvl-1-oxa-8-azaspiro[4.5]decane-3-one. 0-(2-methoxvethyl) oxime 30 2,~dimethyl-1-oxa-~azaspiro[4.5]decane-3-one m~ te (1.Sg, S.O mmole) was combined with CH30H (200ml), the subtitle compound of step (a) (0.7g, S.S mmole) and pyridine (0.45g, S.O 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 21509~7 ~!wo 94/13678 PCT/GB93/02500 evaporated in vacuo. The residue was taken up in chloroform and washed with satu-rated aqueous Na2CO3. The basic layer was extracted with 3 portions of CHC13, and the combined organic layers were dried over MgSO4 and evaporated in vaCuo. The crudeproduct was combined with that of a 1.65 mmoles trial run and purified by two runs s through a Delta Prep HPLC using silica columns and ammoniated CH30H/CHCI3 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:
l0 MS (CI): 257 (M+H)+.
IR (3M card) cm-l: 1071 (ether C-O-C).
NMR (CDCl3) ~: 4.7 (lH, 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,l5 doublet,-CHCH3).
HPLC (Novapak C,8, CH3CN/H2O, KH2PO~ buffer at Ph 2.5): Major peak at 10.12 minutes with no anti isomer detected.
Calculated for Cl3H2.,N203: C 60.91, H 9.44, N 10.93; found: C 60.79 H 9.33 N 10.31.

20 Anti isomer:
MS (CI): 257 (M+H)+-IR (3M card) cm ': 1069 (ether C-O-C).
NMR (CDC13) ~: 4.5 (lH, 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, -25 CH2-C=N, and -NCH3); 1.80 (4H, multiplet, -CH2); 1.37 (3H, doublet, -CHCH3).
HPLC (Novapak C18, CH3CN/H20, KH2POJ buffered to Ph 2.5): Major peak at 9.57 minutes, with no syn isomer detected.
Calculated for Cl3H24N2O3: C 60.91, H 9.44, N 10.93; found: C 60.53, H 9.27, N 10.52 30 Example S
Svn--and anti-28-dimethvl-1-oxa-8-azaspiro[4.5]decane-3-one. O-(carboxymethyl) oxime methyl ester wo 94/1 7~ 7 14 PCT/GB93/02500 The title compounds were prepared from methanol and the title compound of Example 1 using the method of Example 2.

Cl3HXN2O4 requires C 57.76, H 8.20, N 10.36; adjusted for 0.58% Et20 C 57.80, H 8.23, s N 10.36; found C 57.74, H 8.53, N 9.99.
MS (CI): 253 (M-H2O)t; 197 (M-CH2CO2Me)+.
HPLC (Novapak Phenyl, CH3CN/H2O, buffer KH2PO~ 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.
o IR (3M card) cm-': 1765 (shoulder 1744)(-CO2Me); 1210 (-C-CO2).
NMR (CDC13) ~: 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 (anti))-Example 6Svn- and anti-2,8-dimethyl- 1-oxa-8-azaspiro[4.5]decane-3-one. 0-(2-phenoxvethyl ) oxime The title compounds were prepared by reacting 2,8-dimethyl-1-oxa-8-azaspiro[4.5]-decane-3-one with 2-phenoxyethyl hydroxylamine hydrochloride [154 (M+H)+, m.p. 153-20 160C (dec)] using the methods of Example 4.

Anti isomer:
Cl8H26N203 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-': 3040 (OH); 1246 (C-O-0); 1068 (C-O-C).
NMR (CDCl3) ~: 7.25 (2H, m) and 6.95 (3H, m, 0H plus CHCl3); 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 (anti)); 1.90-1.55 (4H, m, -CH2) 1.40 (3H,30 d, CHCH3).
HPLC (Novapak PhenyL CH3CN/H.O, KH,PO, buffer at Ph 2.5) Major peak at 1'.55 mins no svn detectable 2~ 509~7 WO 94/13678 PCTIGB93tO2500 Syn isomer C,gH26N203 requires C 67.90, H 8.23, N 8.80; adjusted 0.11% H.0 and 0.57~c Et.O, C
67.81, H 8.26 N 8.74; found 67.21, H 8.18, N 8.57.
MS (CI): 319( M+H)+
s IR (Kbr) cm-': 1250 (C-O-0); 1068 (C-O-C).
NMR (CDCI3) ~: 7.25 (2H,m) and 6.95 (3H, m, 0H plus CHC13); 4.67 (lH, 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,-CH2); 1.40 (3H, t, CHCH3)-lO HPLC (Novapak Phenyl, CH3CN/H2O, ~H2P~ buffer at Ph 2.5) major peak at 13.15mins. No anti detectable.

Example 7 Svn- and anti-2,8-dimethyl-1-oxa-8-azaspiro[4.5]decane-3-one. 0-(2-ethoxvethyl) oxime The title compounds were prepared by reacting 2,8-dimethyl-1-oxa-8-azaspiro[4.5]-decane-3-one with 2-ethoxyethyl hydroxylamine hydrochloride [106 (M+H)~, m.p. 74-77C (unc)] using the methods of Example 4.

Anti isomer:
20 C,sH26N203 requires C 62.19, H 9.69, N 10.36; adjusted for 0.44~c 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~': 1067 (C-O-C).
HPLC (Novapak Phenyl, CH3CN/H2O, KH2PO4 buffer at Ph 2.5) major peak at 12.28 25 mins. No syn detectable.
NMR (CDCl3) ~: 4.50 (lH, m, CHCH3)(anti)); 4.20 (2H, m, =NOCH2); 3.67 (m, CH2C-H2O) 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).

Svn isomer:
C,,H26N203 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.

Wo 94/13678 pcTlGs93lo25oo ~
2~9~47 ~ 16 MS (CI): 271 (M+H)+.
IR (neat NaCl) cm-l: 1069 (C-O-C).
HPLC (Novapak Phenyl, CH3CN/H20, KH2PO4 buffer at Ph 2.5) major peak 12.79 mins with no anti detectable.
s NMR (CDCl3) ~: 4.73 (lH, 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); 1.9S-1.5 (4H, m,-CH2~; 1.43 (3H, CHCH3); 1.23 (3H, d, CHCH3); 1.23 (3H, t, CH2 CH3).

,o Example 8 Svn- and anti-2~8-dimethyl-1-oxa-8-azaspiro[4.5]decane-3-one. 0-(N-methyl-2-ethanam-idyl) oxime A solution of a crude sample of the title compound of Example 1 (1.Og, assumed 3.7m-moles) and dimethylaminopyridine (0.06g, 0.44mmoles) in anhydrous CH2CI2 (72ml) was ,s placed under nitrogen and cooled to 0C with an ice bath. The solution was treated with brom~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.

20 The reaction was diluted with CHCl3 and washed with saturated aqueous sodium car-bonate. The aqueous layer was extracted with five portions of CHCl3. The combined organic layers were dried and stripped. Two passes through silica Prep-paks using an ammoniated toluene/acetonitrile/methanol gradient gave O.9g, or 70% yield. The white solid which froze out on storing cold appeared to be hygroscopic and gave a broad 25 melting range.

Cl3HaN303 requires C 57.97, H 8.61, N 15.60; adjusted for 0.69% HzO and 0.16% Et~O
C 57.58, H 8.6 N 15.47; found C 56.96, H 8.44. N 15.11.
MS (CI): 270 (M+H)+.
30 IR (Kbr) cm-': 3366 (HN-C=O); 1653 (N-C=O).
NMR (CDCl3) ~: 6.15 (lH, broad s, HN-C=O); 4.65 (q, CHCH3 (syn) plus 4.55 (3H, s overlapping q at 4.50, =NOCH2 plus -CHCH3 (anti)); 2.90 (3H, d, O=C-NMe); 2.85-VO 94/13678 215 0 9 4 7 pcTlGs93lo2~oo 2.40 (9H, m overlapping s with shoulder, -NCH3 plus -NCH2 plus N=C-CH~); 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, KH2PO4 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-1-oxa-8-azaspiro[4.5]decane-3-one~ 0-(N.N-dimethyl-2-etha-namidyl) oxime lO The title compounds were prepared from the title compound of Example 1 and dime-thylamine using the method of Example 8.

Cl4H2sN303 requires C 59.34, H 8.89, N 14.83; adjusted for 0.37% H20 and 0.77% Et20 C 59.16, H 8.94, N 14.66; found C 58.49, H 8.67, N 14.19.
l5 MS (CI): 284 (M+H)+.
IR (neat, NaCl) cm-l: 1671 (O=C-Nme2); 1071 (C-O-C).
NMR (CDCI3) ~: 4.~'.0 (q, -CHCH3 (syn)) plus 4.75 (s with shoulder, =NOCH2) plus 4.55 (3H, q, -CHCH3 (anti)); 3.00 (6H, d, -Nme2); 2.9~2.35 (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) and2() 1.40 (total 3H, d, -CH3 (anti)) ratio 3.8/1 anti/syn.
HPLC (Novapak Phenyl, CH3 CN/H20, KH2PO, buffer at Ph 2.5) single major peak at 9.83 mins (isomers unresolved).

Example 10 25 Syrl- and anti-2,8-dimethyl-1-oxa-8-azaspiro[4.5]decane-3-one. O-(carboxymethyl) oxime proparg;yl ester A suspension of a crude sample of the title compound of Example 1 (0.55g, assumed 2.05mmoles) and diisopropylethylamine (0.36ml, 2.05mmoles) in dry THF (lOOml) were placed under N7 and cooled to -10C with an ice/salt bath. Pivaloyl chloride (0.26ml, 30 2.05mmoles) was added and the reaction was stirred at -10C for 20 minutes. The propargyl alcohol (2.5ml in excess, containing another 0.36ml of DIEA) was addeddropwise. The reaction was stirred at room temperature overnight.

Wo 94/13678 pcTlGs93lo25oo 2~947 : 18 The next morning the reaction was heated at 45C for one hour. After allowing to cool the reaction was diluted with CHCI3 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 column, using an ammoniated 4-6% MeOH /CHCl3 gradient. This yielded 0.30g or 49.7% of hygroscopic solid.

ClsH22N2O4 requires C 61.21, H, 7.53, N 9.52, adjusted for 0.85% H2O 60.69, H 7.56, N
9.44; found C 60.00, H 7.41, N 9.25.
l0 MS (CI): 295 (M+H)+-IR (Kbr) cm-': 1767.
NMR (CDCl3) ~: 4.85-4.45 (total SH)(q (4.80) CHCH3 (syn)) overlapped by d, -CH2 C=H) plus (s with shoulder and q (4.50) -OCH2 C=O and CH-CH3 (anti)); 2.90-2.30 (lOH, complex m, overlapped by t and s, -NCH3 plus -NCH2 plus -C=CH plus N=C-s 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, KH2PO4 buffer at Ph 2.5): Major peaks at 8.68 and 9.47 mins in 5/1 ratio anti/syn.

~o Example 11 Svn- and anti-2,8-dimethyl-1-oxa-8-azaspiro[4.5]decane-3-one. O-(carboxvmethvl) oxime propyl ester The title compounds were prepared from the title compound of Example 1 and propanol using the method of Example 10.

MS (CI): 299 (M+H)+.
ClsH26N2O4 requires C 60.38, H, 8.78, N 9.39; found C 59.95, H 8.56. N 8.79.
~R (neat, NaCl) cm l: 1761 (shoulder 1738) (O=C-O).
HPLC (Novapak Phenyl, CH3 CN/H20, KH2PO~ buffer at Ph 2.5) single major peak at 10.96 mins.
NMR (CDCl3) ~: 4.85-4.45 (total 3H, q (4.80) CHCH3 (syn) plus s, with shoulder N=C-O-CH2 plus q(4.60) CHCH3 (anti)) with 4.15 (2H. two overlapped t -OCH,CH); 2.90-'.35 (9H. s, overlapping m, -NCH3 plus -NCH~ plus -CH.-C=N); ~.10-1.50 (6H. appar-~0 94113678 21 S O 9 17 ~ PCT/Gs93/~25Qo ent sextuplet overlapping m, -OCH.CH.- plus CH~); 1.55-1.35 (3H, t, -CH3) ratio 3.6/1 antilsyn by integration of CHCH3;

Example 12 s Svn- and anti-2,8-dimethvl-1-oxa-8-azaspiro[4.5]decane-3-one. O-(carboxymethvl) oxime ben~yl ester The title compounds were prepared from the title compound of Example 1 and benzyl alcohol using the method of Example 10.
C,gH26N204 requires C 65.88, H, 7.57, N 8.09; found C 65.41, 7.66, 7.83 MS (CI): 347 (M+H)+.
IR (neat, NaCl) cm-': 1761 (shoulder 1738) (O=C-O).
HPLC (Novapak Phenyl, CH3CN/H20, KH2PO4 buffer at Ph 2.5) single major peak.
NMR (CDC13) ~i: 7.35 (5H, s, 0H); 5.20 (2H, s, OCH20); 4.80-4.40 (3H, s, with shoulder ,s 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 20 (S)~lti-2.8-Dimethyl-1-oxa-8-azaspiro[4.5]decan-3-one, O-(N.N-dimethvlglycolamide) oxime (a) Cis-2.8-Dimethyl- 1 -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 lM solution, 6mmoles) was added dropwise over 10 minutes to a 2s solution of 2,8-dimethyl-1-oxa-~a~ o[4.5]decan-3-one (315mg, 1.72mmoles) in tetrah-ydrofuran (25ml) precooled in a dry ice/acetone bath to -78C. The reaction mixture was allowed to warm gradually over 1 hour to 0C and quenched by addition of satu-rated aqueous sodium chloride solution (lml). The reaction mixture was diluted with of 10% aqueous sodium carbonate solution (lOOml) and extracted with chloroform - 30 (4x75ml). The combined organic extract was dried over anhydrous magnesium sulphate, filtered and concentrated i~l v~cuo 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 vellow oil.

~ 94n3~7~ PCT/GB93/02500 ~
2 ~ ~ q~ : o MS (CI): 185 [M+H]~

(b) (2S 3S,1 'R)-2.8-Dimethyl- 1 -oxa-8-azaspiro~4.5]decan-3-vl N-[1-(1-naphthvl)ethvl]carbamate s Under a nitrogen atmosphere, a solution of the product of step (a) (13.3g, 71mmoles), (R)-1-(1-naphthyl)ethyl isocyanate (16g, 81mmoles), 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 succe~ively with saturated aque-o ous sodium bicarbonate solution (lOOml) and brine (lOOml), dried over anhydrousm~ sium 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.

s Chiral HPLC (15% ethanol/hexane, O.5ml/min): 99.97% dp MS (CI): 383 [M+H]+
m.p. 160-162C (2-propanol) (c) (2S,3S)-2,8-Dimethvl- 1-oxa-8-azaspiro[4.5]decan-3-ol 20 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 (SOml). 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 2s were extracted with tetrahydrofuran (2xSOml) 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 30 m.p. >250C (hydrochloride salt, 2-propanol) (d) (S)-2.8-Dimethvl- l -oxa-~-azaspiro[4.5]decan-3-one ~0 94/13678 ~15 o 9 ~ 7 pcTlGs93lo25oo 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 0C for 90 minutes, then s cooled to -28C 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 -28C for 90 minutes. Finally, a solution of triethylamine (12.9rnl, 92 mmoles) in dichlor-omethane (28ml) was added dropwise. The reaction mixture was stirred for an addi-lO 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 (320rnl) was added to the reaction mixture, which was then stirred vigorously for 15 minutes. The la~ers were separated and the aqueous layer was extracted with chloroform (3xSOOml). 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. 153-155C (citrate salt, ethyl acetate) 20 MS (CI): 184 [M+H]+

(e) (S)~nti-2.8-Dimethyl-1-oxa-8-azaspiro[4.5]decan-3-one oxime and (S)-svn-2 8-Dimethyl- 1-oxa-8-azaspiro[4.5]decan-3-one oxime 2s 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. 153-154.5C (cyclohexane), MS (CI, M/z): 199 [M+H]+}, followed by 1.8g of the second subtitle compound {m.p. 135C (toluene/petroleum ether), MS (CI): 199 [M+H+]}, in 615~o yield overall for 2 steps.

(f) (S)~nti-2 8-Dimethvl-1-oxa-8-azaspiro[4.5]decan-3-one,O-(N.N-dimethvlglycol-amide) oxime WO 94/13678 ~ PCT/Gs93/02500 ~
215~47 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 (lOml). After stirring for 40 min-utes, a solution of 2-chloro-N.N-dimethylacetamide (130mg, 1.07mmoles) in dimethvl-s formamide (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 (SOml) and extracted with chloroform (4x40ml). The combined organic extract was dried over anhydrous m~ sium sulphate and concentrated to a yellow oil Ul vacuo.
,o The yellow oil was flash chromatographed through neutral silica gel using ammoniated chl~,urullll and methanol ~92:8] as the eluant, giving 167mg (68%) of the title compound as a light yellow oil.

MS (CI): 284 [M+H]+.
,s Example 14 (R)-anti-2,8-Dimethyl- 1 -oxa-8-azaspiro[4.5~decan-3-one. O-(N,N-dimethylglycolamide) oxime (a) (2R,3R.1'S)-2,8-Dimethyl- 1-oxa-8-azaspiro[4.5]decan-3-yl N-[1-(1-naphthyl)ethvl]carbamate The subtitle compound was prepared from the subtitle compound of Example 13(a) (3.18g, 17mmoles) and (S)-1-(1-naphthyl)ethyl isocyanate (3.75g, 19mmoles) using the method of Example 13(b), providing 2.53g (35%) of the hydrochloride salt.

zs Chiral HPLC (15% ethanol/hexane, O.5ml/min): 100% dp MS (CI): 383 [M+H]+
m.p. 158- 161C (2-propanol) (b) (2R,3R)-2 8-Dimethvl-1-oxa-8-azaspiro[4.5]decan-3-ol 30 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 (~o ethanol/hexane, 0.75ml/min) 100% ee WO 94/13678 2 1 5 0 9 1 7 PCT/Gs93/02soo . 3 m.p. 265-267C (hydrochloride salt~ 2-propanol) (c ) (R)-2,8-Dimethyl- 1-oxa-8-azaspiro[4.5]decan-3-one The subtitle compound was prepared from the compound of step (b) (0.44g, 2.4mmoles) s using the method of Example 13(d), giving 100mg (18%) as the maleate salt.

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

(d) (R)-anti-2.8-Dimethyl-1-oxa-8-azaspiro[4.5]decan-3-one oxime and (R)-syn-2 8-Dimethyl- 1-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 s 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% methanoVchlolofollll (11), which was then washed with saturated aque-ous sodium carbonate solution (200ml). The aqueous layer was extracted with 20%
methanol/chlo.oforlll (5x11) and the combined organic layer was dried over anhydrous magnesium sulphate, filtered and concentrated i)l 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. 151-153C
(toluene/petroleum ether), MS (CI): 199 [M+H]+}, followed by 2.0g of the second subtitle compound {m.p. 135-136C (toluene/petroleum ether), MS (CI): 199 [M+H]+}
2s in a combined yield of 43% overall for the 2 steps.

(e) (R)~nti-2~8-Dimethyl- 1-oxa-8-azaspiro~4.5]decan-3-oneO-(N.N-dimethylglycol-amide) oxime The title compound was prepared from the first subtitle compound of step (d) (301mg, 30 1.52mmoles) and 2-chloro-N,N-dimethylacetamide (231mg, 1.90mmoles) by the pro-cedure of Example 13(f), providing 389mg (90~c) as an oil following flash chromatogra-phy using ammoniated chloroform/methanol [92:8].

WO 94/13678 PCT/GB93/02500 ~
2~5~l17 ~4 MS (CI): 284 ~M+H]+

Example 15 (S)-svn-2~8-Dimethyl-1-oxa-8-azaspiro[4.5]decan-3-one~ O-(N~N-dimethvlglvcolamide) s oxlme The title compound was yle~ared from the second subtitle compound of Example 13(e) (300mg, 1.51mmoles) and 2-chloro-N,N-dmethylacetamide (223mg, 1.83 mmoles) by the procedure of E~cample 13(f), yield 227mg (53%) following flash chromatography using ammoniated chloroform/methanol [92:8].

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

Example 16 lS (R)-syn-2~8-Dimethyl-l-oxa-8-azaspiro[4.s]decan-3-one~ O-(N~N-dimethvlglycolamide) oxime The title compound was prepared from the second subtitle compound of Example 14(d) (300mg, 1.51mmoles) and 2-chloro-N7N-dimethyl~cet~mi~le (226mg, 1.85mmoles) by the procedure of Example 13(f), yield 310mg (73~o) following flash chromatography using ammoniated chloroforrn/methanol [95:5]-[90:10].

MS (CI): 284 [M+H]+

Example 17 2s (S)-antL-2 8-Dimethyl-1-oxa-8-azaspiro[4.5]decan-3-one~O-(methoxycarbonvlmethyl) oxime The title compound was prepared from the first subtitle compound of Example 13(e) (300mg, 1.51mmoles) and methyl chloroacetate (209rng, 1.92 mmoles) by the procedure of Example 13(f), yield 317mg (77~o).
.
MS (CI): 271 [M+H]+

Example 18 21~09~7 Wo 94/13678 pcTlGs93lo25oo ~5 (R)-anh-2 8-Dimethvl-l-oxa-8-azaspiro[4.5]decan-3-one. O-(methoxvcarbonvlmethvl)oxime The title compound was prepared from the first subtitle compound of Example 14(d) (200mg, 1.00mmoles) and methyl chloroacetate (130mg, 1.20mmoles) by the procedure s of Example 13(f), yield 90mg (25%) as its oxalate salt.
r m.p. 139-142C (ethyl acetate) MS (CI): 271 [M+H]+

o Example 19 (S)-svn-28-Dimethyl-1-oxa-8-azaspiro[4.5]decan-3-one. O-(methoxvcarbonvlmethvl) 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 lS chloroform/methanol [92:8].

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

20 Example 20 (R)-syn-2 8-Dimethvl-1-oxa-8-azaspiro[4.5]decan-3-one. O-(methoxycarbonvlmethyl) oxime The title compound was prepared from the second subtitle compound of Example 14(d) (200mg, 1.00mmoles) and methyl chloroacetate (130mg, 1.20mmoles) by the procedure 2s of Example 13(f), yield 180mg (47%) as maleate salt.

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

30 Example 21 (S)-anti-2 8-Dimethvl- l -oxa-8-azaspiro[4 5~decan-3-one. 0-(2-methoxyethyl) oxime The title compound was prepared from the first subtitle compound of Example 13(e) (300mg, 1.51mmoles) ~nd 2-bromoethyl methyl ether (264mg, 1.90mmoles) using the Wo 94/13678 PcT/Gsg3/02500 ~
2150947 ~ ~6 method of Example 13(f), yield 333mg (86~c) following flash chromatographv usingammoniated chloroform/methanol [96:4].

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

Example 22 (R)~n~-2~8-Dimethyl-1-oxa-8-azaspiro[4~5]decan-3-one~ 0-~2-methoxyethyl) oxime The title compound was prepared from the first subtitle compound of Example 14(d) o (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. 94-96C (oxalate salt, ethyl acetate) lS MS (CI): 257 [M+H]+

Example 23 (S)-syn-2~8-Dimethyl-1-oxa-8-azaspiro[4~5]decan-3-one~ 0-(2-methoxyethyl) 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. 89-91C (oxalate salt, ethyl acetate) .s MS (CI): 257 [M+H]+

Example 24 (R)-s~n-2~8-Dimethvl-1-oxa-8-azaspiro[4~5]decan-3-one~ 0-~2-methoxvethvl) oxime The title compound was prepared from the second subtitle compound of Example 14(d) 3~ (301mg, 1.52mmoles) and 2-bromoethyl methyl ether (270mg, 1.94mmoles) using the method of Example 13(f), yield 343mg (88~o) following flash chromatography usingammoniated chloroform/methanol [95:5].

WO 94/13678 21~ ~ 9 ~ 7 pcTlGss3lo2soo ~7 m.p. 85-88C (oxalate salt. ethvl acetate) MS (CI): 257 [M+H]+

Example 25 (S)-sYn-2,8-Dimethyl-1-oxa-8-azaspiro[4,5]decan-3-one, 0-(2-ethoxvethyl) 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 acetatelhex-lO anelmethanol [6:6:1].

MS (CI): 271 [M+H]+

Example 26 l5 (R)-svn-2,8-Dimethvl-1-oxa-8-azaspiro[4,5]decan-3-one. 0-(2-ethoxyethvl) 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 themethod of Example 13(f), yield 230mg (48%) following flash chromatography using amm-oniated chlorofo",~,/methanol [95:5], followed by ammoniated ethyl acetate/hexane/methanol [6:6:1]-MS (CI): 271 [M+H]+

Example 27 2s 2,8-Dimethyl-1-oxa-8-azaspiro[4.5]decan-3-one O-cvanomethyl oxime The title compound was prepared from 2,8-dimethyl-1-oxa-8-azaspiro[4.5]decan-3-one hydrochloride (1.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 30 with ammoniated chloroform/methanol [98:2] to [95:5].

~IS (CI): 238 [M+H~+

WO 94/13678 pcTlGs93lo25oo 2 ~ '1 7 ~8 Example 28 2,8-Dimethyl-1-oxa-8-azaspiro[4.5]decan-3-one 0-(2 ~.2-trifluoroethyl) oxime The title compound was prepared from 2,8-dimethyl-1-oxa-8-azaspiro[4.5]decan-3-one and 2,2,2-trifluoroethoxyamine hydrochloride using the methods of Example 4. providing s 0.4g of anti-isomer {m.p. 168.5-170.5C (oxalate salt, EtOAc), MS (CI): 281 [M+H]+}
and 0.2g of syn-isomer {m.p. 131-132C (oxalate salt, EtOAc), MS (CI): 281 [M+H]t}
following HPLC separation eluting with ammoniated chloroform/methanol [96:4] to [93 7].

o Example 29 2 8-Dimethvl- 1-oxa-8-azaspiro[4.5]decan-3-one 0-~2-(2-ethoxyethoxv)ethvl] oximeThe title compound was prepared from 2,8-dimethyl-1-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 anti-isomer {m.p. 125-129C (citrate salt, EtOAc), MS (CI): 315 IS [M+H]+} and 1.2g of ~y l-isomer {m.p. 119.5-121.5C (oxalate salt, EtOAc), MS (CI):
315 [M+H]+} following HPLC separation eluting with ammoniated chloror~ /meth~nol[96:4] to [93:7].

Example 30 20 anti-2~8-l:)imethyl-1-oxa-8-azaspiro[4.5]decan-3-one O-(ethoxycarbonylmethvl) 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) (SOOmg, 2.52mmol) and ethyl bromoacetate (530mg, 3.17mmol) using the method of Example 13(f), providing 420mg (58%) following flash chromatography eluting with ammoniated chlororol,l.Jmeth-~s anol [95:5].

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

30 Example 31 2,8-Dimethvl-1-oxa-8-azaspiro[4.5~decan-3-one O-(N~O-dimethvlglycolhvdroxamide) oxime r Wo 94/13678 215 0 9 4 7 pcTlGs93lo2soo 29 The title compound was prepared ~rom the title compound of Example 1 (500mg) andN,O-dimethylhydroxylamine hydrochloride using the method of Example 2, giving 480mg of a mixture of ~yn- and anti-isomers.

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

Example 32 ann-8-Methyl-1-oxa-8-azaspiro[4.5~decan-3-one O-(methoxycarbonylmethvl) oxime o anti-8-Methyl-1-oxa-8-azaspiro[4.5]decan-3-one oxime was first prepared from 8-methyl-1-oxa-8-azaspiro[4.5]decan-3-one oxime (the compound of Example 3, InternationalPatent Application WO 90/15804) using HPLC. The title compound was then p~e~ar~dfrom this anh-oxime (SOmg) and methyl chloroacetate following the method of Example 13(f), giving 70mg of the citrate salt following flash chromatography on silica gel using l5 0-10% ammoniated methanol in chloroform as the eluant.

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

20 Example 33 svn-8-Methvl-1-oxa-8-azaspiro[4.5]decan-3-one O-(methoxvcarbonylmethyl) oxime ~yn-8-Methyl-1-oxa-8-~ piro[4.5]decan-3-one oxime was first prepared from 8-methyl-1-oxa-~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 ~s this ~yn-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. 167.5-169C (1:1 EtOAc/isopropanol) 30 MS (CI): 257 [M+H]+

Example 34 Wo 94/13678 pcTlGs93lo2soo ~
2~ 47 30 anti-2,8-Dimethyl-1-oxa-8-azaspiro[4.5]decan-3-one, 0-(1,3-dioxolan-2-ylmethvl) 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-1,3-dioxolane using the method of Example 13(f), providing 270mg (47%) following flash chromatography eluting with ammoniated chloroform/methanol [95:5].

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

o Example 35 an~i-2,8-Dimethyl-1-oxa-8-azaspiro[4.5]decan-3-one, O-(tetrahvdrofuran-2-vlmethyl) oxlme 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-,s omethyl-tetrahydrofuran using the method of Example 13(f), providing 130mg (24%) following flash chromatography eluting with ammoniated chloroform/methanol [95:5].

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

Example 36 [la,3a,4a,4'E]- and [1a,3a,~a.4'Z]-5'-Methylspiro[1-azabicyclo~2.2.1]heptane-3.2'(3'H)-furan]-4'(5'H)-one, 0-(2-methoxyethyl~ oxime 2,4,6-trinitrobenzenesulphonate 2s (a) 3-(Carboethoxymethylene )- 1-azabicyclo[2.2.1]heptane Sodium (2.96g, 129mmol) was dissolved in cold ethanol (0C, 250ml), triethyl phosph-onoacetate (31g, 137mmol) was added and the solution was stirred at room temperature for 5 hours. 1-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 HCI
and extracted with 2 portions of ether. The aqueous laver was basified with sodium carbonate and the product was extracted with 3 portions of ether and the combined extracts were dried (MgSO,). The solvent was evaporated and the residue was flash chromatographed through NH3-deactivated silica eluting with CHCI3/MeOH [40:1 then 20:1] to give the subtitle compound (13.2g) as a clear liquid.

s (b) Ethyl exo-S'-methvlspiro[1-azabicyclo[2.2.1]heptane-3.2'(3'H)-furan]~'(5'H)-one-3'-carboxvlate Sodium hydride (60% dispersion in oil, 8.8g, 221mmol) was washed with hexane, sus-pended in DMF (80ml), cooled on ice and ethyl lactate (26.1g, 221mmol) added cau-tiously keeping the fo~ming under control. The mixture was stirred at room tempera-o ture for 1 hour and the product of step (a) (8g) was added slowly to the resulting darksolution. 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 s 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 thensuspended in CHCI3/MeOH [2:1], the resulting white solid was filtered off and the filtrate was combined with the brown oil and flash chromatographed through NH3-~o deactivated silica eluting with CHClJMeOH [10:1 then 4:1] giving 0.87g of mostly purehigh 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 CHClJMeOH [10:1] giving the subtitle compound 2s as a high Rf material (1.42g).

(c) Exo-5'-methylspiro[1-azabicyclo[2.2.1]heptane-3.2'(3'H)-furan]-4'(5'H)-one A solution of the keto ester from step (b) (1.42g) in lN Hcl (20ml) was heated at reflux for 4 hours and left to stand overnight at room temperature.
The reaction ~ Lule was basified with 25% NaOH, extracted with 2 portions of CHCI3, the extracts were dried (MgSO,), the solvent was evaporated and the residue was flash Wo 94/13678 PCT/GB93/02500 ~
2150~7 32 chromatographed through NH3-deactivated silica eluting with CHCI3/MeOH [~0:1] 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 s fumaric acid was added. The mixture was heated to give a solution and the solid was allowed to precipitate while stirring at room te~ t-~re. The white solid was collected and dried under vacuum overnight at 60C. 0.52g (constant weight) of white solidresulted.

l0 CloH,sNO2.C4H,O~ 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]+
s mp: 139-141C

(d) [ la.3a~4a,4'E]- and [ la.3a.4a.4'Z]-5'-Methylspiro[1-azabicyclo[2.2.1]heptane-3 2'(3'H)-furan]-4'(5'H)-one 0-(2-methoxyethvl) oxime 2.4 6-trinitrobenzenesulphonate A solution of the subtitle compound of step (c) (1.5g, 4.8mmole) and 2-methoxyethoxya-20 mine hydrochloride (0.61g, 4.2~mmole) in methanol (25ml) was stirred at room te~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 saturatedaqueous Na2CO3 solution and 20ml CHCI3. The layers were separated, and the aqueous layer was extracted with CHCl3 (3x20ml). The organic layers were then combined, dried 25 (MgSO4), 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 30 made of the E-isomer, and, after recrystallization from isopropanol, yielded 630mg of the pure salt (m.p. 154-157C).

~/0 94/13678 215 0 ~ ~ 7 PCT/GB93/02500 Further purification of the mixed fractions obtained from the HPLC purification gave the Z-isomer as a tan oil (20mg) [m.p. 167-171C (2,4,6-trinitrobenzenesulphonic acid salt, isopropanol)].
.
s Example 37 [la,3a,4a4'E]-5'-Methvlspiro[l-azabicvclo[2.2.1]heptane-3,2'(3'H)-furan]-4'(5'H)-one~ O-(N~N-dimethylglycolamide) oxime (a) [la 3a 4a.4'E]-and~la.3a.4a.4'Z~-5'-Methylspiro[1-azabicyclo[2.2.1~heptane-3.2'(3'H)-furan]-4'(S'H)-one 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,4'E]-5'-Methvlspiro[1-azabicvclo[2.2.1]heptane-3.2'(3'H)-furan]-4'(5'H)-one, O-(N,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 ~ Lule was then stirred for 0.S hour. The resulting solution was cooled to -5C with an ice-20 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 chlolo~o"l, and saturated sodium carbonate. The organic layer was separated and the 2s aqueous layer was extracted with chlo,o~,lll twice. The organic layers were combined and dried (MgSO4), giving 377 mg of an oil which solidified on standing. The crude product was flash-chromatographed through ammoniated silica gel eluting with CHClJMeOH [10:1]. The purified product (297mg) was then recrystallized twice from cyclohexane.

m.p. 111-114C

Example 38 wo 94~116~ 7 34 pcTlGs93/o25oo [ la,3a 4a~4'Z]-5'-Methylspiro[ 1-azabicvclo[2.2. 1 ]heptane-3~2'(3'H)-furan]-4'rS'H)-one, O-(N.N-dimethvlglvcolamide) 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 s between CHCI3 and water. The aqueous layer was extracted with CHCl3, the organic extracts were dried (MgSO~), 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.

o m.p. 113-117C

Example 39 The ~yn-isomer of the compound of Example 4 was tested for Ml and M2 efflcacy in the tests described above, and found to have an M, efficacy of 23% (in comparison with s carbachol), and zero M2 efficacy.

Claims (12)

Claims:

1. A compound of formula I, wherein ring A is a ring of formula AI or AII (in which the spiro atom is indicated by *), AI
AII

R1 represents H or alkyl C1-6;
R2 represents -(CH2)n-OR3, -(CH2)m-C(O)R4, fluoroalkyl C16, cyanoalkyl C1-6 or alkyl C1-6 substituted with a 4-7 membered optionally unsaturated heterocyclic ring;
R3 represents H, alkyl C1-6 (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);
R4 represents OR5, NR6R7, N(OR6)R7 or alkyl C1-6;
R5 represents H, alkenyl C2-6, alkynyl C2-6 or alkyl C1-6 (optionally substituted with phenyl);
R6 and R7 independently represent H or alkyl C1-6;
R8 represents H or alkyl C1-6;
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)m-OR3 or -(CH2)m-C(O)R4.

4. A compound as claimed in any one of the preceding claims, wherein R3 repre-sents alkyl C1-6 (optionally substituted with alkoxy C1-6) or phenyl.

5. A compound as claimed in any one of the preceding claims, wherein R4 repre-sents O-(alkyl C1-6) or N(alkyl C1-6)2.

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

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

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 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.

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 claim1, or a pharmaceutically acceptable salt thereof, which comprises:
(a) reaction of a compound of formula II, II

in which A and R1 are as defined in claim 1, with a compound of formula III, in which R2 is as defined in claim 1; or (b) reaction of a compound of formula V, V

wherein A and R1 are as defined in claim 1, with a compound of formula VI, 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 pharmaceutically accept-able salt.