CA2023267A1 - Compounds - Google Patents

Abstract

B2818/Abs Abstract Novel Compounds A compound of formula (I) or a pharmaceutically acceptable salt thereof:

(I) in which Z is a heterocyclic group in which Q represents a 3-membered divalent residue completing a 5-membered aromatic ring and comprises one or two heteroatoms selected from oxygen, nitrogen and sulphur, or three nitrogen atoms, any amino nitrogen being substituted by a C1-2 alkyl, cyclopropyl or propargyl group, and any ring carbon atom being optionally substituted by a group R1; or a group in which A1, A2 and A3 complete a 5-membered aromatic ring and Al is oxygen or sulphur, one of A2 and A3 is CR2 and the other is nitrogen or CR3, or A2 is oxygen B2818/Abs or sulphur, one of A1 and A3 is CR2 and the other is CR3; and R1, R2 and R3 are independently selected from hydrogen, halogen, CN, OR4, SR4, N(R4)2, NHCOR4, NHCOOCH3, NHCOOC2H5, NHOR4, NHNH2, NO2, COR4, COR5, cyclopropyl, C2-5 straight chain alkenyl, C2-5 straight chain alkynyl or C1-5 straight chain alkyl optionally terminally substituted with OR4, N(R4)2, SR4, CO2R4, CON(R4)2 or one, two or three halogen atoms, in which each R4 is independently hydrogen or C1-3 alkyl and R5 is OR4, NH2 or NHR4;

or in which Z is a group -C(R7)-NR6 in which R6 is a group OR8, where R8 is C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, a group OCOR9 where R9 is hydrogen or R8, or a group NHR10 or NR11R12 where R10, R11 and R12 are independently C1-2 alkyl and R7 is hydrogen or C1-4 alkyl, subject to the proviso that when R6 is a group OCOR9 or NHR10, R7 is C1-4 alkyl.

Description

C~$~ ~

05 This invention relates to compounds having 06 pharmaceutical activity, to a process for their 07 preparation and their use as pharmaceuticals.

09 EP-A-0287356 discloses certain substituted l-azabicyclic compounds whlch enhance acetylchollne 11 function via an action at muscarlnic receptors within 12 the central nervous system.

14 A novel group of compounds has been discovered which also enhance acetylcholine function via an action at 16 muscarinic receptors within the central nervous system 17 and are therefore of potential use in the treatment 18 and/or prophylaxis of dementia in mammals.

Accordlng to the present invention, there is provided a 21 compound of formula (I) or a pharmaceutically 22 acceptable salt thereof:

24 z 29 ~I) 31 ln whlch Z is a heterocycllc group 34 ~ N
~ ) ~ ~7~ t7 01 - 2 - s2818 03 in which Q represents a 3-membered divalent residue 04 completing a s-membered aromatic ring and comprises one 05 or two heteroatoms selected from oxygen, nitrogen and 06 sulphur, or three nitrogen atoms, any amino nitrogen 07 being substituted by a Cl_2 alkyl, cyclopropyl or 08 propargyl group, and any ring carbon atom being 09 optionally substituted by a group Rl; or a group 12 A` ' A

in which Al, A2 and A3 complete a 5-membered aromatic 16 ring and Al is oxygen or sulphur, one of A2 and A3 is 17 CR2 and the other is nitrogen or CR3, or A2 is oxygen 18 or sulphur, one of Al and A3 is CR2 and the other is 19 CR3; and Rl, R2 and R3 are independently selected from hydrogen, halogen, CN, OR4, SR4, N(R4)2, NHCOR4, 21 NHCOOCH3, NHCOOC2H5, NHOR4, NHNH2, N02, COR4, COR5, 22 cyclopropyl, C2_5 straight chain alkenyl, C2_5 straight 23 chain alkynyl or Cl_5 straight chain alkyl optionally 24 terminally substituted with OR4, N(R4)2, SR4, C2R4, CON(R4)2 or one, two or three halogen atoms, in which 26 each R4 is independently hydrogen or Cl_3 alkyl and R5 27 is OR4, NH2 or NHR4;

29 or in which Z is a group -C(R7)~NR6 ln which R6 is a group OR8, where R8 is Cl_4 alkyl, C2_4 alkenyl, C2_4 31 alkynyl, a group OCORg where Rg ls hydrogen or Rg, or a 32 group NHRlo or NRllR12 where Rlo, Rll and R12 are 33 independently C1_2 alkyl and R7 is hydrogen or Cl_4 34 alkyl, sub;ect to the proviso that when R6 is a group OCORg or NHRlo, R7 is Cl_4 alkyl.

37 The term halogen includes bromine, chlorine and 38 fluorine.

-03 Compounds of formula (I) in which Z is -C(R7)=NR6 are 04 capable of existing as geometric isomers. The 05 invention extends to each of these stereoisomeric 06 forms, and to mixtures thereof. The different 07 stereoisomeric forms may be separated one from the 08 other by the usual methods, or any glven isomer may be Os obtained by stereospecific synthesis.
11 The compounds of formula (I) can form acid addition 12 salts with acids, such as the conventional 13 pharmaceutically acceptable acids, for example 14 hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, oxalic 16 and methanesulphonic.

18 5-Membered aromatic heterocycles within the definition 19 of variable Z include oxadiazole such as 1,2,4-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl and 21 1,3,4-oxadiazol-2-yl, oxazole such as 1,3-oxazol-2-yl, 22 1,3-oxazol-4-yl 1,3-oxazol-5-yl, 1,2-oxazol-3-yl and 23 1,2-oxazol-5-yl, thiadiazole such as 24 1,2,4-thiadiazol-5-yl and 1,3,4-thiadiazol-2-yl, thiazole such as 1,3-thiazol-2-yl, 1,3-thiazol-5-yl and 26 1,2-thiazol-5-yl, furan such as furan-2-yl and 27 furan-3-yl, triazole such as 1-alkyl-, 2-alkyl- or 28 3-alkyl- 1,2,3-triazol-4-yl and 1,2,4-triazol-3-yl 29 including 1-alkyl-1,2,4-triazol-3-yl, l-alkyl-totrazol-5-yl and 2-alkyl-tetrazol-5-yl, where 'alkyl' slgnifies 31 a Cl_2 alkyl, cyclopropyl or propargyl group.

33 In a preferred aspect, variables Rl, R2 and R3 are 34 independently selected from hydrogen, halogen, N(R41)2 in which each R41 is independently hydrogen or methyl, 36 straight chain C2_3 alkenyl, straight chain C2_3 37 alkynyl, cyclopropyl or straight chain Cl_s alkyl 38 optionally terminally substituted with oR42 or one, two ~ Q ~ c ~ t~

03 or three fluorine atoms, in which R42 is methyl.

OS Values for Rl, R2 and R3 include hydrogen, methyl, 06 methoxymethyl, ethyl, n-propyl, n-butyl, n-pentyl, 07 cyclopropyl, but-2-enyl, NH2 and CH2F, preferably 08 hydrogen, methyl, ethyl, n-propyl, n-butyl and 09 n-pentyl.
ll It will be appreciated that the range of values for Rl, 12 R2 and R3 will be limited by the preparative 13 constraints and/or stabil~ty of the group Z. For 14 example, an oxazole ring will tolerate a 2-amino substituent whereas 2-amlno-furans are unstable.
16 Conversely, 2-halo-furans are stable whereas 2-halo-17 oxazoles are very labile compounds. Where Z is a tri-18 or tetrazole group, the amino nitrogen must be ls subst$tuted, preferably y to the position of the azabicyclic moiety.

22 Examples of heterocyclic z include 3-amino-1,2,4-23 oxadiazol-5-yl, 3-methyl-1,2,4-oxadiazol-5-yl, 24 1,3-oxazol-5-yl, 1,3-oxazol-2-yl, 3-ethyl-1,2,4-oxadiazol-5-yl, 3-propyl-1,2,4-oxadiazol-5-yl, 26 3-cyclopropyl-1,2,4-oxadiazol-5-yl, 3-butyl-1,2,4-27 oxadiazol-5-yl, 3-methoxymethyl-1,2,4-oxadiazol-5-yl, 28 3-pentyl-1,2,4-oxadiazol-5-yl, 3-but-2-enyl-1,2,4-29 oxadiazol-5-yl, fur-2-yl and 2-methyl-1,3,4-oxadiazol-5-yl.

32 The groups R8 and Rg in R6 are preferably selected from 33 methyl, ethyl, allyl and propargyl. Rlo, Rll and Rl2 34 are preferably methyl. Sultable examples of R6 include methoxy, ethoxy, allyloxy, propargyloxy, acetoxy and 36 dimethylamino.

2~3~o&~7 03 When R6 is a group ORg or NRl1R12, R7 is preferably 04 hydrogen or methyl.

06 When R6 is a group OCORg or NHRlo, R7 is preferably 07 methyl.

09 The invention also provides a process for the preparation of a compound of formula (I), or a 11 pharmaceutically acceptable salt thereof, whlch process 12 comprlses cycllsing a compound of formula (II):

19 ( II ) 21 ln whlch A represents Z or an electron withdrawing 22 group convertible thereto, L is a leaving group and R13 23 represents hydrogen or an N-protecting group, and thereafter, optionally or as necessary, removing 26 any R13 protecting group, converting A to Z, 27 interconverting Z and/or forming a pharmaceutically 28 acceptable salt.

Examples of the N-protecting group R13 lnclude benzyl 31 and substituted benzyl. However, lt ls greatly 32 preferred that R13 ls hydrogen.

34 Examples of the leaving group L lnclude halo such as 3s chIoro.

37 Examples of A lnclude Cl_4 alkoxycarbonyl and cyano, 38 most preferably Cl_4 alkoxycarbonyl.

, ~ n r1 03 The cyclisation is preferably effected in a suitable 04 solvent such as isopropanol under basic conditions at 05 elevated temperature.

07 Conversion of A to a group z, as defined for formula 08 (I), may be carried out using procedures as described 09 in, for example standard text books on heterocyclic chemistry such as 'Comprehensive Heterocyclic 11 Chemistry', A.R. Katritzky and C.W. Rees, Pergamon, 12 1984.

14 The A group is first converted, as necessary, to a suitable starting group Z' for the chosen conversion 16 reaction to give the required group Z.

18 A Z' carboxy group may be obtained by conventional 19 de-esterification of an A alkoxycarbonyl group.
21 A Z' chlorocarbonyl group may be obtained by treatment 22 of a Z' carboxy group by conventional routes under 23 appropriate condltions.

A Z' aminocarbonyl group may be obtained by treatment 26 of a z' chlorocarbonyl or, more preferably, an 27 alkoxycarbonyl group with ammonia.

29 A Z' cyano group may be obtalned by treatment of a Z~
aminocarbonyl group with a dehydratlng agent such as 31 phosphorus pentoxlde ln toluene or trlfluoroacetic acid 32 anhydride ln tetrahydrofuran and pyridine.

34 A Z' alkylcarbonyl group may be obtained from an A
cyano group by treatment with the appropriate alkyl r.~ 7 03 lithium in sther at depressed temperature, or by 04 treatment of a LiOOC group with the appropriate alkyl 05 lithium, the LiOOC group being obtained by hydrolysis 06 of an A alkoxycarbonyl group with lithium hydroxide in 07 water. Alternatively and less preferably, a z' 08 alkylcarbonyl group may be obtained by reaction of a 09 Z' chlorocarbonyl group with N,O-dimethylhydroxylamine and treatment wlth an alkyl lithium or Grlgnard 11 reagent.

13 A Z' bromomethylcarbonyl group may be obtained by 14 treatment of a Z' COCH3 group either with bromine in a suitable solvent such as methanol, the nitrogen of the I6 azabicycle being protected as the hydrochloride or 17 hydrobromide salt, or with lithium diisopropylamide and 18 trimethylsilyl chloride at low temperature followed by 19 N-bromosuccinimide in tetrahydrofuran at low temperature. Alternatively and less preferably, a Z' 21 -COCl group may be converted to a -COCH2Br group by 22 treatment with diazomethane in ether at low temperature 23 followed by hydrogen bromide in acetic acid at ambient 24 temperature.
26 A Z' formyl group may be obtained by conventional 27 reduction of an A alkoxycarbonyl group with a reducing 28 agent such as diisobutylaluminium hydride in an inert ' 29 solvent such as toluene at low temperature, or, alternatively and less preferably, hydrolysis with 31 acid, followed by conversion to the acid chloride and 32 reaction with O-N-methylated dimethyl hydroxylamine 33 hydrochloride in the presence of pyridine in a suitable 34 solvent such as dichloromethane to give the O-N-dimsthyl amide. Reduction with diisobutyl 36 aluminium hydrid~ under similar conditions as above 37 yields the required formyl group.

r~ ~
01 - 8 - s2818 02 ~ _ 03 A Z' CH2N_C group may be obtained from a 04 formamidomethyl group by treatment with phosgene and 05 triethylamlne. The formamidomethyl group may in turn 06 be obtained from the aminomethyl group by reaction with 07 an ester of formic acid such as ethyl formate. The 08 aminomethyl group may be obtained by reduction of the 09 aminocarbonyl group with lithium aluminium hydride.

1I When Z represents a 1,2,3-triazol-4-yl group, a Z' 12 formyl group may be treated with triphenyl phosphine, 13 carbon tetrabromide and zinc in an inert solvent such 14 as dlchloromethane at ambient temperature to provlde a 2,2-dibromoethenyl group whlch may be eliminated with 16 n-butyl lithium in hexane to give an ethynyl group.
17 Treatment of the latter with azidotrimethyl silane in 18 an inert solvent such as tetrahydrofuran at elevated 19 temperature followed by lower alcohol at ambient temperature yields the unsubstituted 1,2,3-triazol-4-yl 21 group which is alkylated as required. A 2-alkyl group 22 may be introduced by treatment with the corresponding 23 dlazoalkane in ether at ambient temperature.

Alternatively a Z' acetyl group may be successively 26 treated with hydrogen chloride, chlorine and 27 triphenylphosphine to yield a triphenylphosphine-28 methylenecarbonyl group which may be treated with 29 m-nitrobenzoyl azide in acetonitrile at elevated temperature to yleld the 1,2,3-trlazol-4-yl group which 31 ls protected at the 1 posltlon by m-nitrobenzoyl. The 32 protecting group may be removed by prolonged heating in 33 a lower alcohol, by treatment with ammonia or by 34 chromatography on basic alumina in a lower alcohol.
3s The resulting unsubstituted 1,2,3-triazol-4-yl group 36 may then be alkylated as described above.

ol g ~ 7 B2818 03 Compounds of formula (I) in which Z represents a 04 l-alkyl or 3-alkyl-1,2,3-triazol-4-yl group may be 05 obtained as minor products in the preparation of the ~6 corresponding 2-alkyl-1,2,3-triazol-4-yl compounds and 07 separated chromatographically.

~9 When Z represents a 2-alkyltetrazol-5-yl group, a Z' cyano group may be treated with azidotrimethyl silane 11 in an inert solvent such as tetrahydrofuran at elevated 12 temperature to yield a 2-trimethylsilyl-2H-tetrazol-S-13 yl group. Treatment of the latter with methanol 14 effects deprotection of the amino nitrogen which may then be alkylated as described above.

17 Compounds of formula (I) in which Z represents a 18 1-alkyltetrazol-5-yl group may be obtained as a minor 19 product in the preparation of the corresponding 2-alkyltetrazol-s-yl compound and separated 21 chromatographically.

23 When Z re~resents a 1,2,4-triazol-3-yl group a Z' cyano 24 group may be treated with dry ethanol saturated with 2s hydrogen chloride gas to give an imidate. This may be 26 treated with an alkyl hydrazine,to form the 27 corresponding amidrazone. Treatment of this with 28 anhydrous formic acid or triethyl orthoformate will 29 give the required 1-alkyl-1,2,4-triazol-3-yl group.
31 When Z represents 3-substituted-1,2,4-oxadlazol-5-yl, 32 an alkoxycarbonyl group may be reacted with an 33 appropriate amide oxime at elevated temperature in the 34 presence of sodium alkoxide in a lower alcohol such as ethanol. The amide oxime is commercially available or 36 may be prepared conventionally. For example, alkyl 03 substituted amide oximes may be obtained by reacting 04 hydroxylamine hydrochloride with the appropriate 05 nitrile.

07 Alternatively, when z represents 3-methyl-1,2,4-08 oxadiazol-5-yl, reaction of a Z' aminocarbonyl group og with an acetal of N,N-dimethylacetamide such as the dimethyl or diethyl acetal at elevated temperature 11 yields an acyl amidine group -CON~C(CH3)N(CH3)2 which 12 may then be reacted with hydroxylamine, in the presence 13 of acid, such as acetic acid, which may also function 14 as the solvent. The reaction may be carried out at ambient temperature, the N-hydroxy acyl amidine 16 intermediate optionally isolated and then cyclised at 17 elevated temperature, or alternatively in a single step 18 at elevated temperature.

Alternatively and less preferably, a Z' chlorocarbonyl 21 group may be reacted with an appropriate amide oxime, 22 at elevated temperature in an inert, polar solvent such 23 as chloroform, and the resulting substitution product 24 cyclised at elevated temperature in a suitable solvent such as toluene or xylene.

27 When Z represents 3-amino-1,2,4-oxadiazol-5-yl, a 28 Z' chlorocarbonyl or, more preferably, a carboxy ester 29 group A may be reacted with a hydroxy guanidine derivative under basic condltlons.

32 When Z represents optlonally 3-substltuted-1,2,4-33 thiadiazol-5-yl, a Z' aminocarbonyl group may be 34 converted into an aminothiocarbonyl group using phosphorus pentasulphide or Lawesson's reagent (S.
36 Scheibye, B.S. Pederson and J.O. Lawesson, Bull. Soc.
37 Chim. Belg., 1978, 87 (3), 229). The aminothiocarbonyl 01 ~ B2818 03 may be converted into a thioacyl amidine group and 04 cyclised as described above for the 1,2,4-oxadiazole 05 group.

07 When ~ represents 5-substituted-1,2,4-oxadiazol-3-yl, a 08 Z' cyano group may be reacted with hydroxylamine, in a og polar solvent such as methanol, to yield the corresponding amide oxime. The amide oxime may be 11 cyclised using a suitable derivative of a carboxylic 12 acid such as the anhydride or a trialkylorthoester 13 such as triethyl orthoacetate, the acid derivative 14 acting as the solvent, at elevated temperature.
16 When Z represents optionally 5-substituted-1,3,4-17 oxadiazol-2-yl, a Z' carboxy or carboxy ester group A
18 may be converted to the acid hydrazide by conventional 19 procedures. For example, the acid may be converted to a Cl_6 alkyl ester e.g. methyl, with the appropriate 21 Cl_6 alkanol e.g. methanol under conventional 22 esterification conditions, and the resulting ester 23 reacted with hydrazine at ambient or elevated 24 temperature to give the acid hydrazide. The acid hydrazide may then be cyclised by condensation with a 26 suitable derivative of the appropriate carboxylic acid 27 RCO2H, e.g. an acyl halide or a trialkyl ortho-ester, 28 such as the triethyl ortho-ester, the acid derivative 29 acting as the solvent, at elevated temperature.
Alternatively and preferably, the Z' carboxy ester 31 group A may be converted to a diacyl hydrazide group 32 -CONHNHCOR by treatment with the appropriate acyl 33 hydrazide at ambient or elevated temperature. The 34 diacyl hydrazide may then be cyclised by treatment with phosphorus pentoxide and methanesulphonic acid.

o~ 7 B2818 03 When z represents optionally 5-substltuted-1,3,4-04 thiadiazol-2-yl a Z' dlacyl hydrazide group, 05 -CONHNHCOR, obtained as described above can be cyclised 06 uslng phosphorus pentasulphide. The cyclisation is 07 preferably carried out in the absence of solvent with 08 the nitrogen of the azabicycle protected as the 09 hydrochloride salt.
11 When Z represents 1,3-oxazol-2-yl, the conversion may 12 be effected by reaction of a Z' aminocarbonyl group 13 with vinylene carbonate at elevated temperature in the 14 presence of a strong acid such as polyphosphoric acid, which may also function as the solvent.

17 When Z represents optionally 5-substituted-1,3-18 oxazol-2-yl, a z' carboxy group may first be converted 19 to the carboxylic acid chloride and then reacted with a compound of formula NH2CH2CR~OR')2, or more preferably 21 the Z' carboxy group may be reacted directly with the 22 compound of formula NH2CH2CR(OR )2 in the presence of a 23 condensing agent such as dicyclohexylcarbodiimide or a 24 chloroformate ester such as ethyl chloroformate, to give a group CONHCH2C(OR')2R; which may be cyclised 26 using a suitable dehydrating agent such as 27 polyphosphoric acid, phosphorus oxychloride, phosphorus 2a pentachloride, sulphuric acid or sulphuryl chloride, 29 preferably polyphosphoric acid.
31 A Z optlonally 5-substituted-1,3-thlazol-2-yl group may 32 be obtained by cycllsatlon of a ~' -CONHCH2C10R')2R
33 group using phosphorus pentasulphlde. The reaction is 34 preferably carried out in the absence of solvent with the nitrogen of the azabicycle protected as the 36 hydrochloride salt.

' 7 03 1,3-Oxazol-2-yl groups 4-methyl-substituted may be 04 provided by the cyclisation of a Z' aminocarbonyl group 05 with propargyl alcohol or acetate ester thereof, in the 06 presence of a dehydrating agent such as polyphosphoric 07 acid,using a catalyst such as HgSO4, at elevated 08 temperature.

Alternative routes to optionally 4-substituted 11 1,3-oxazol-2-yl groups include:

13 i) the condensation of a Z' aminocarbonyl group 14 with the appropriate compound BrCH2COR at elevated temperature; or 17 ii) the reaction of a z' carboxy group under basic 18 conditions with the appropriate compound BrCH2COR to 19 give a group -COOCH2COR which may be cyclised with ammonium chloride.

22 Where R is hydrogen the aldehyde is preferably 23 protected as an acetal.

During the reactio~ (i) above, the nitrogen atom of the 26 azabicyclic moiety may require protection.

28 When Z is optionally 4-substituted-1,3-thiazol-2-yl a 29 z' aminothiocarbonyl group may be reacted with the appropriate a-halo acyl compound such as BrCH2COCH3 as 31 indlcated for the correspondlng 1,3-oxazole.

33 1,3-Oxazol-4-yl groups optlonally 2-substituted may be 34 provided by reacting a bromomethylcarbonyl group with an appropriate amide. Preferably, the reaction with 36 acetamide is carried out at elevated temperature and ' \

f~ t~

03 the reaction with formamide is carried out in sulphuric 04 acid.

06 An unsubstituted 1,3-oxazol-4-yl group may 07 alternatively be obtained by treatment of a Z' -CH2N_C
08 group with a formate ester such as methyl formate after 09 deprotonation wlth a strong base such as n-butyl lithium or potassium t-butoxide.

12 When Z represents optionally 3-substituted-1,2-13 oxazol-5-yl, the reaction of a Z' CH3CO group may be 14 carried out at depressed temperature with the appropriate ethyl ester in a suitable solvent such as 16 toluene, under basic conditions such as sodium hydride 17 and catalytic ethanol, followed by reflux, to yield the 18 sodium salt of the resulting dicarbonyl compound.
19 Cyclisation at ambient temperature with an aminating agent such as hydroxylamine-O-sulphonic acid in a dry 21 solvent such as methanol, ethanol or diglyme, 22 preferably in the presence of an acid such as sulphuric 23 acid, p-toluene sulphonic acid or potassium hydrogen 24 sulphate to minimise amination of the azabicycle, ylelds a compound of formula (I).

27 Alternatively, the dicarbonyl compound sodium salt may 28 be treated prior to the cyclisation step with 29 dimethylamine in ethanol in the presence of glacial acetlc acld at ambient temperature to give the 31 vinylogous amide which may be cycllsed as described 32 above.

34 When Z epresents an optionally 5-substituted 1,2-oxazol-3-yl group, a Z' -C-N+-O- nitrile oxide 36 group may be reacted with an olefin of the structure 01 - 15 - ~ B2818 03 R-C(W)=CH2, where W is halo such as chloro, OCOCH3 or 04 OSi(CH3)3. The highly reactive nltrile oxide may 05 conveniently be generated in situ from an appropriate 06 z' halo oxime -c(sr)8NoH by treatment with a base such 07 / as triethylamine in a solvent such as 08 N,N-dimethylformamide. The halo oxime is prepared by 09 treatment of a Z'-CH=NOH oxime group with N-bromosuccinimide in N,N-dimethylformamide at ambient 11 temperature, the azabicyclic being in the form of the 12 hydrochloride salt. The Z' -CH-NOH oxime group may be 13 prepared from a Z'-CHO group by reaction with 14 hydroxylamine hydrochloride in a solvent such as methanol.

17 When Z represents an optionally 2-substituted-1,3-18 oxazol-5-yl group, a Z -COCH2Br group may be converted 19 to -COCH2NH2 by treatment with NaN3 in acetone or N,N-dimethylformamide followed by hydrogenation over a 21 Pd/C catalyst in ethanolic HCl, or by treatment with 22 hexamethylene tetramine followed by hydrolysis in 23 methanolic HCl.

The -COCH2NH2 group may then be acylated with the 26 appropriate derivative of formic acid such as 27 acetic-formic anhydride or higher carboxylic acid such 28 as the anhydride or chloride to yield an acyl amino 29 ketone which can be cyclised using a suitable dehydrating agent such as polyphosphoric acld, 31 sulphuric acid or phosphorous pentachloride at elevated 32 temperature.

34 Alternatively, a Z' -CHO group may be treated with tosylmethyl isocyanide and anhydrous potassium 36 carbonate in methanol under reflux followed by heating ~w3~7 03 the 4-methoxyoxazoline product with polyphosphoric acid 04 to afford a z 1,3-oxazol-S-yl group.

06 When Z represents 2-furyl, a Z' CHO group may be 07 treated with a reactive derivative of propanal such as 08 the 3-tosyl derivative and ln which the carbonyl group 09 is preferably protected as a cyclic acetal (III):

l3 CH3 ~ S2 16 ~III

18 prepared by reaction of sodium 4-methylphenyl-19 sulphinate with 2-(2-bromoethyl)-1,3-dioxolane in dimethyl formamide at ambient temperature. The 21 reactlon of the compound of formula (III) with the 22 Z' -CHO group in an inert solvent such as 23 tetrahydrofuran in the presence of a base such as 24 n-butyl lithium, lnitially at low temperature, rising 2s to ambient, yields a compound of formula (IIIa):

28 o~ ~O

31 T Az 32 ~ S2 33 CH3 ~
(IIIa) 36 in which Az represents the azabicyclic moiety, which 7~ r.~

03 may be cyclised at elevated temperature in the presence 04 of an acid such as glacial acetic acid which may also 05 function as the solvent.

07 Alkyl-substituted 2-furyl groups may be obtained 08 analogously using the appropriately substituted og analogue of the compound of formula (III) prepared from the corresponding ketone or aldehyde.

12 A Z 1,3-thiazol-5-yl group may be obtained by 13 dehydrating and cycllsing the corresponding acyl amino 14 ketone using phosphorous pentasulphlde at elevated temperature.

17 Optionally 3-substituted 1,2-thiazol-5-yl groups may be 18 prepared from the corresponding 1,2-oxazolyl group by 19 ring opening effected by treatment with a reducing agent such as Raney nickel and hydrogen in a suitable 21 solvent such as methanol or ethanol to yield a 22 vinylogous amide which may be cyclised using 23 phosphorous pentasulphide in the presence of a suitable 24 oxidising agent such as sulphur or chloranil in a solvent such as toluene at elevated temperature.

27 Compounds of formula (I) in which Q contains a sulphur 28 atom in place of oxygen may be prepared analogously. A
29 sulphur-contalning group Z' ls obtained by treatment of a carbonyl-containing group 2' with either phosphorus 31 pentasulphide or wlth Lawesson's reagent (S.Scbeibye, 32 B.S. Pederson and S.O. Lawesson, Bull. Soc. Chim.
33 Belg., 1978, 87t3), 229). The resulting 34 sulphur-containing group Z' may then be converted to the required sulphur-containing group z analogously to 03 the conversion of carbonyl-contalnlng groups. Where the 04 thlolating agent is phosphorus pentasulphide, this may 05 also effect cyclisatlon.

07 In the above descrlptlon, R represents H or alkyl as 08 approprlate and R' represents Cl_6 alkyl such as methyl 09 or ethyl or the R' groups together represent C2_6 polymethylene such as ethylene.

12 Interconverslon of carbon substituents Rl, R2 and R3 13 withln a group Z may be carried out conventlonally.
14 Thus an amino group may be converted to chloro, or -NHNH2, via a diazonium intermediate.

17 Similarly a chloro substituent may be converted by 18 reaction with a nucleophile such as methoxlde; and 19 alkoxycarbonyl groups may be converted, vla carboxy, to an amlno substltuent.

22 When Z represents a -C(R7)=NR6 group, a Z' COR7 group 23 may be reacted wlth a compound of formula (IV).

R6'-NH2 ~IV

27 wherein R6' represents R6 or hydroxy, and thereafter 28 convertlng R6' to R6 when hydroxy.

The inventlon also provides a process for the 31 preparation of a compound of formula (I) in whlch Z is 32 -C(R7)=NR6, or a pharmaceutlcally acceptable salt 33 thereof, whlch process comprises reactlng a compound of 34 formula (v):

ol - 19 ~ 7 B2818 05 ~ ~7 07 (v ogwith a compound of formula (IV):
11 R6'-NH2 (IV

13 wherein R6' represents R6 or hydroxy, converting R6' to 14 R6 when hydroxy, and thereafter formlng a pharmaceutically acceptable salt.

17 The reaction between the compounds of formulae (v) and 18 (IV) is preferably carried out in a hydroxylic solvent 19 such as methanol or ethanol, at ambient temperature, or where appropriate, at elevated temperature.

22 Where R6 in compounds of formula (I) is a group OR8, 23 NHRl0 or NRllR12~ a compound of formula (v) is 24 conveniently reacted with a compound of formula (IV) in 25~ which R6' is R6-27 : : Where R6 in compounds of formula ( T ) iS a group OCORg, :28~ a compound of formula (v) may be reacted with the 29 compound of formula (IV) in whlch R6' ls hydroxy, with subsequent acylation of the resultlng oxime by 31 treatment with a suitable acylatlng agent such as an 32 acyl halide, for example acetyl chloride.

34 Novel intermediates of formula (VI) and salts thereof:

2 ~ 7 04 ~ ' 08 ~VI

wherein Z'' is a group convertible to z, also form part 11 of the invention. A preferred value for Z'' ls an 12 electron withdrawing group, most preferably C1_4 13 alkoxycarbonyl. Compounds of formula tVI) may be 14 prepared by the cyclisation of a compound of formula (II) in which R13 is hydrogen and A is an electron 16 withdrawing group, the conversion of the resulting Z'' 17 electron withdrawing group to other Z'' and optionally 18 forming a salt.

Compounds of formula (II) may be prepared by treatment 21 of a compound of formula (VII):

26 ~ / N
27 Rl3 ;28 (VII) wherein R13 and A are as deflned in formula (II), with 31 a compound Ll(CH2)3L, whereln L ls as deflned ln 32 formula (II) and Ll ls a leaving group.

34 In compounds of formula (VII) it is preferred that R13 is an N-protectlng group and A is cyano. This can be 36 converted to other A groups, such as Cl_4 37 alkoxycarbonyl by acid hydrolysis, before cyclisation 38 of the compound of formula (II).

::

.

t~ a tl~7 03 In the compound Ll(CH2)3L, the leaving group L is 04 preferably halo and preferably other than L, for 05 example iodo.

07 The compound of formula (VII) in which R13 is benzyl 08 and A is cyano is described in EP-0169603.

Pharmaceutically acceptable salts of the compounds of 11 formula (I) may be formed conventlonally by reactlon 12 with the appropriate acid such as described above under 13 formula (I).

The compounds of the present lnvention enhance 16 acetylcholine function vla an action at muscarinic 17 receptors within the central nervous system and are 18 therefore of potential use in the treatment and/or 19 prophylaxis of dementia.
21 The present lnvention also provides a pharmaceutical 22 composition, which comprises a compound of formula (I
23 or pharmaceutically acceptable salt thereof, and a 24 pharmaceutically acceptable carrier.
26 The compositions may be in the form of tablets, 27 capsules, powders, granules, lozenges, suppositories, 28 reconstit'utable powders, or liquid preparations such as 29 oral or sterile parenteral solutions or suspensions.
31 In order to obtain conslstency of admlnlstration it is 32 preferred that a composition of the invention is in the 33 form of a unit dose.

Unit dose presentation forms for oral administration 36 may be tablets and capsules and may contain 37 conventional excipients such as binding agents, for 03 example syrup, acacia, gelatin, sorbitol, tragacanth, 04 or polyvinylpyrrolidone; fillers, for example lactose, 05 sugar, maize-starch, calcium phosphate, sorbitol or 06 glycine; tabletting lubricants, for example magnesium 07 stearate; disintegrants, for example starch, 08 polyvinylpyrrolidone, sodium starch glycollate or 09 microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl 11 sulphate.

13 The solid oral compositions may be prepared by 14 conventional methods of blending, filling, tabletting or ~he like. Repeated blending operations may be used 16~ to distribute the active agent throughout those 17 compositions employing large quantities of fillers.
18 Such operations are of course conventional in the art.
19 The tablets may be coated according to methods well 2~ known in normal pharmaceutical practice, in particular 21 with an enteric coating.

23 Oral liquid preparations may be in the form of, for 24 example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with 26 water or other suitable vehicle before use. Such 27 liquid preparations may contain conventional additives 28 such as suspending agents, for example sorbitol, syrup, 29 methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, 31 hydrogenated edible fats; emulsifying agents, for 32 example lecithin, sorbitan monooleate, or acacia:
33 non-aqueous vehicles (which may include edible oils)~
34 for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, 36 or ethyl alcohol; preservatives, for example methyl or ~ J~ 7 03 propyl p-hydroxybenzoate or sorbic acid; and if desired 04 conventional flavouring or colouring agents.

06 For parenteral administration, fluid unit dosage forms 07 are prepared utilizing the compound and a sterile 08 vehicle, and, depending on the concentration used, can 09 be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dlssolved ln 11 water for in~ection and filter sterllized before 12 filling into a suitable vial or ampoule and sealing.
13 Advantageously, ad~uvants such as a local anaesthetic, 14 a preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition 16 can be frozen after filling into the vial and the water 17 removed under vacuum. Parenteral suspensions are 18 prepared in substantially the same manner, except that 19 the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be 21 accomplished by filtration. The compound can be 22 sterilized by exposure to ethylene oxide before 23 suspending in the sterile vehicle. Advantageously, a 24 surfactant or wetting agent is included ln the composition to facilitate uniform distribution of the 26 compound.

28~ The compositions may contain from 0.1% to 99% by 29 weight, preferably from 10-60% by weight, of the active materlal, depending on the method of administration.

32 The invention also provides a method of treatment 33 - and/or prophylaxis of dementia in mammals including 34 humans, which comprises administering to the sufferer an effectlve amount of a compound of formula ~I) or a 36 pharmaceutically acceptable salt thereof.

03 The dose of the compound used in the treatment of such 04 disorders will vary in the usual way with the 05 seriousness of the disorders, the weight of the 06 sufferer, and the relative efficacy of the compound.
07 However, as a general guide suitable unit doses may be 08 0.05 to lOo mg. for example 0.2 to somg; and such unit og doses may be administered more than once a day, for example two or three times a day, so that the total 11 daily dosage is in the range of about 0.01 to 5 mg/kg;
12 and such therapy may extend for a number of weeks or 13 months.

Within the above indicated dosage ranges no 16 toxicological effects are indicated for the compounds 17 of the invention.

19 In a further aspect the invention provides a compound of formula (I) or a pharmaceutically acceptable salt 21 thereof for use as an active therapeutic substance.

23 The invention further provides a compound of formula 24 (I) or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prophylaxis of dementia.

27 In another aspect the invention provides the use of a 28 compound of formula ~I) or a pharmaceutlcally 29 acceptable salt thereof for the preparation of a medicament for the treatment and/or prophylaxis of 31 dementia.

33 The following examples illustrate the invention and the 34 following descriptions illustrate the preparation of intermediates thereto.

01 - 25 - ~2818 03 Descri~tion 1 05 1-BenzYl-3-(3-chloroPro~Yl)azetidine-3-carbonitrile 06 (-1 CN

~, Cl N_ 11 ~
12 Ph 13 (Dl) A stirred solution of lithium diisopropylamide (24ml of 16 1.5M solution in cyclohexane, 0.036 mole) and 17 N,N,N',N'-tetramethylethylenediamine (5.4ml~ 0.036 18 mole) in dry ether (300ml) at -70C under nitrogen was 19 treated dropwise over 5 minutes with a solution of 1-benzylazetidine-3-carbonitrile* t5.8g, 0.034 mole) 21 and 1-chloro-3-iodopropane ~3.6ml, 0.034 mole) in ether 22 (40ml). The resulting mixture was stirred at -65C for 23 15 minutes, then allowed to warm up to -40C over a 24 further 15 minutes, before pouring into aqueous potassium carbonate solution (200ml). The ether layer 26 was separated and the aqueous further extracted with 27 ethyl acetate (l x lsoml). The two organic solutions 28 were combined, drled (Na2so4) and concentrated in vacuo 29 to leave an orange oll~ Thls was purlfied by column chromatography on slllca gel elutlng lnltlally wlth 10%
31 ether/pentane to remove non-polar lmpurltles and then 32 with 50% ether/pentane to glve the tltle compound (Dl) 33 as a colourless oil (5.35g~ 64%).
34 lH Nmr ~CDC13) ~:
1.86-2.02 (2H, m)~ 2.03-2.16 (2H, m)~ 3.25 (2H, 36 d, J=8Hz), 3.52 (2H, d, J=8Hz), 3.60 (2H, t, 37 J-7HZ), 3.65 (2H, s)~ 7.22-7.38 (5H, m)~

39 ~see EP 0 169 603 Al ~ k ~ t~ ~

03 DescriPtion 2 05 Methvl l-benzvl-3-(3-chloro~roPvl)azetidine-3-carboxv-06 late oxalate salt (D2) 08 COOMe og ~ ~ Cl N

11 Ph (COOH)2 (D2) lS A stirred solution of l-benzyl-3-(3-chloropropyl)-16 azetidine-3-carbonitrile (Dl, 5.35g, 0.022 mole) in 17 methanol (75ml) was treated cautiously with 18 concentrated sulphuric acid (lSml) and then heate~ at 19 80C for 20h. The solution was cooled in an ice bath and a further 12ml of concentrated sulphuric acid 21 added. The solution was heated at 80C for a further 9 22 hours, the~ allowed to cool, before pouring cautiously 23 into ice/water (400ml) with vigorous stirring. The 24 aqueous mixture was basified by the addition of 0.88 ammonia solution, then extracted wlth ethyl acetate (2 26 x 200ml). The combined extracts were dried ~Na2SO4) 27 and concentrated in vacuo to leave an orange oll, which 28 was flltered through a basic alumlna column elutlng 29 wlth ether. The colourless oll obtained was dlssolved in ether (150ml) and treated with a solution of oxallc 31 acld (2.0g, 0.022 mole) ln methanol (loml). The title 32 compound (D2) was flltered off as a whlte crystalllne 33 solid (7.25g, 9~
34 Free base:- lH NMR (CDC13) ~:
1.64-1.80 (2H, m)~ 2.00-2.13 (2H, m), 3.17 (2H, 36 d, J=8Hz), 3.49 (2H, d, J-8Hz), 3.52 (2H, t, 37 J=7HZ), 3.62 (2H, s)~ 3.72 (3H, s~, 7.20-7.35 38 (SH, m).

3~

03 Description 3 05 Methvl 3-(3-chloroPropyl) azetidine-3-carboxYlate (D3) 07 COOMe ~~ Cl 12 ~D3) 14 A solution of methyl l-benzyl-3-(3-chloropropyl)-azetidine-3-carboxylate oxalate salt (D2, 6.73g, 0.018 16 mole) in methanol (8ooml) was hydrogenated over 10%
17 palladium on charcoal catalyst (1.4g) at 40C and 18 atmospheric pressure until the uptake of hydrogen 19 ceased. The reaction mixture was filtered through a pad of kieselguhr and the filtrate concentrated in 21 vacuo to give a white solid. This material was treated 22 wlth excess concentrated potassium carbonate solution 23 ~50ml) and extracted with chloroform ~3 x 70ml). The 24 combined extracts were dried (Na2SO4) and concentrated in vacuo to give the title compound ~D3) as a 26 colourless oil (3.3g~ 96%).
27 lH NMR (CDC13) ~:
28 1.63-1.78 (2H, m)~ 2.05-2.15 (2H, m), 2.25-(lH, 29 br.s, NH), 3.42 (2H, d, J-8Hz), 3.53 (2H, t, J~7HZ), 3.73 (3H, s)~ 3.96 (2H, d, J~8Hz).

03 Descri~tion 4 05 MethYl l-azabicvclor3.1.11hept-5-Ylcarboxvlate oxalate 06 salt (D4) COOMe 08 ~
09 1 1 ~
V

12 (COOH) 2 13 (D4) A solution of methyl 3-~3-chloropropyl~azetidlne-3-16 carboxylate (D3, 3.3g, 0.017 mole) in propan-2-ol 17 (400ml) was treated with anhydrous potassium carbonate 18 (7.5g, 0.054 mole) and heated under reflux for 18h.
19 The mixture was concentrated in vacuo and the residue treated with concentrated potassium carbonate solution 21 (soml) and extracted with ethyl acetate (2 x looml).
22 The combined extracts were dried (Na2SO4) and 23 concentrated in vacuo to leave a yellow oil (2~6g)~
24 which was a 1:1 mixture of methyl and isopropyl esters. This was dissolved in methanol (2ooml)~
26 treated with a solution of sodium methoxide (0.045 27 mole) in methanol (40ml) and stirred at room 28 temperature for 2h. The solutlon was cooled ln ice, 29 ad~usted to pH 4 with methanolic hydrogen chloride and concentrated in vacuo. The residue was treated with 31 excess concentrated potassium carbonate solution and 32 extracted with ethyl acetate. The combined extracts 33 were dried (Na2S04) and concentrated in vacuo to leave 34 a yellow oil, which was distilled in a ~ugelrohr apparatus (b.p. approx. 100C at 0.2mmHg) to give 600mg 36 ~23%) of a colourless oil. A portion of this material 3 ~ ~ ~

03 was converted to its oxalate salt, which was 04 recrystallised from methanol/ether to give the title 05 compound (D4) as a white solid m.p. 114-116C.
06 Oxalate salt:- lH NMR td6 DMSO) 6:
07 2.08-2.20 (2H, m), 2.20-2.30 (2H, m)~ 3.35-3.45 08 (2H, m), 3.47-3.57 ~2H, m), 3.65 ~3H, s), 09 4.27-4.37 ~2H, m).
13C NMR (d6DMSO) 6:
11 13.1, 26.6, 44.6, 48. , 52.6, 57.5, 165.0, 12 170.5.
13 Analysis: CgHl3No2.c2H2o4 14 requlres C: 48.98; H: 6.17; N: 5.71 found C: 49.22; H: 6.15; N: 5.84 17 DescriPtion 5 19 Acetamide oxime (D51 21 A solution of sodium methoxide, prepared from 2.90g 22 (0.126 mole) of sodium, in methanol ~50ml) was added to 23 a stirred solution of hydroxylamine hydrochloride 24 (8.7g~ 0.126 mole) in methanol ~lOOml). The mixture was stirred at room temperature for lh, then filtered 26 and the filtrate treated with acetonitrile (6.8ml~ 0.13 27 mole) and heated under reflux for 6h. A further 6.8ml 28 of acetonitrile was added and reflux continued for a 29 further 16h. The solutlon was concentrated in vacuo to give the tltle compound ~D5) as a white solld (7.7g, 31 83%~ m.p. 123-127C.
32 lH NMR (d6 DMSO) 6:
33 1.60 (3H, s)~ 5.35 (2H, br.s), 8.60 (lH, s) nl ~ ~

03 Description 6 05 1-AzabicYclor3.1.11hePt-5-vlcarboxaldehyde ( D6 ) , 09 ~
\J

12 (D6) 14 A stirred solution of methyl l-azabicyclo[3.1.1]hept-5-ylcarboxylate (D4, 800mg, 0.0052 mole) in dry toluene 16 (15ml) and hexane (15ml) at -65C under nitrogen was 17 treated with a 1.5M solution of diisobutylaluminium 18 hydride in toluene (3.8ml~ 0.0056 mole). The reaction ~19 mixture was stirred at -65C for 0.75h, then poured into excess lM hydrochloric acid, with vigorous 21 stirrlng. The mixture was baslfied with 10% sodium 22 hydroxide solution, washed with ethyl acetate ~1 x 23 60ml) and the aqueous solution then saturated with 24 potassium carbonate and extracted with chloroform (3 x 60ml). The combined extracts were dried (Na2S04) and 26 concentrated in vacuo to give a colourless oil (620mg), 27 containing the title compound (D6). This was used 28 without further purification.

Description 7 32 ProPlonamide oxime ~D7 34 A solution of hydroxylamine hydrochloride (6.90g, o.lo mole) in methanol (lOOml) was added to a stirred 36 solution of sodium methoxide, prepared from 2.30g (O.lO
37 mole) of sodium in methanol (40ml). The mixture was 03 stirred at room temperature for lh, then filtered and 04 the filtrate treated with propionitrile (7.9ml, 0.11 05 mole) and heated under reflux for 12h. The solution 06 was concentrated ln vacuo, the residue shaken with 07 chloroform (200ml) and then filtered through 08 Kieselguhr. The filtrate was dried (Na2SO4) and 09 concentrated in vacuo to give the title compound (D7) as a colourless oil (5.5g~ 62%).
11 lH NMR (CDC13) 6:
12 1.12 (3H, t, J-7Hz), 2.12 (2H, q, J57Hz), 4.60 13 (2H, br.s), 8.60 (lH, br.s).
14 IR (film) ~C~N 1655cm~
16 Descri~tion 8 18 Butvramide oxime ~D8 The title compound (D8) was prepared from butyronitrile 21 using the method given ln Description 7, as a 22 colourless oil (31~).
23 lH NMR (CDC13 + d6DMSO) 6:
24 O.9s (3H, t, J=7Hz), 1.60 (2H, sextet, J=7HZ), 2.12 (2H, t, J-7Hz), 4.75 (2H, br.s), 7.25 (lH, 26 br.s).

28 DescriPtion 9 2g Cvclo~ro~vlcarboxamide oxlme (D9) 32 The title compound (D9) was prepared from 33 cyclopropylcarbonitrile using the method given in 34 Description 7, as a pale green waxy solid (55%).
lH NMR (CDC13 + d6DMSO) 5:
36 0.65-0.80 (4H, m)~ 1.40-1.53 (lH, m), 4.65 (2H, 37 br.s), 8.20 (lH, br.s).

~t ~ r~ ~ 7 03 DescriPtion 10 OS Methoxvacetamide oxime (D10) 07 The title compound ~D10) was prepared from 08 methoxyacetonitrile using the method given in 09 Description 7, as a pale pink solid (100%) m.p.
46-49C.
11 lH NMR (CDC13) 6:
12 3.35 (3H, s)~ 3.94 (2H, s), 4.40 (2H, br.s), 13 5.00 (lH, br.s) DescriPtion 11 17 Valeramide oxime (Dll) 19 The title compound (D11) was prepared from valeronitrile using ths method given in Description 7, 21 as a pale green oil (53~).
22 lH NMR (CDC13 ~ d6DMS0) 6:
23 0.92 (3H, t, J=7Hz), 1.30-1.45 (2H, m)~
24 1.50-1.70 t2H, m)~ 2.20 (2H, t, J=7Hz), 5.40 (2H, br.s)~ 7.15 ~lH, br.s) 27 DescriPtion 12 29 l-AzabicYclo r 3.1.11he~t-5-Ylcarboxamide (D12) 36 ~D12) f.~k3~ ~

03 Methyl 1-azablcyclo[3.1.1]hept-5-ylcarboxylate (D4, 04 1.35g, 0.0087 mole) was treated with 20M aqueous 05 ammonia solution (25ml) and the mixture stirred at room 06 temperature for 2 days. The solution was saturated 07 with potassium carbonate and shaken with chloroform 08 (4oml). The mixture separated into three layers. The 09 chloroform solution contained some product, however the ma~ority was in the middle layer. These two were 11 combined and concentrated in vacuo and the residue then 12 treated with toluene (60ml) and again concentrated in 13 vacuo to azeotrope out the water. The title compound 14 (D12) remained as a white solid (1.07g, 88%) m.p.
188-192C.
16 lH NMR (d6DMSO) 6:
17 1.80-1.93 (2H, m), 2.07-2.20 (2H, m)~ 2.60-2.68 18 (2H, m)~ 2.95 (2H, t, J=7Hz), 3.35-3.45 (2H, m), 19 6.80 (lH, br.s)~ 7.05 tlH, br.s) 21 Descri~tion 13 23 Hexanoamide oxime ~D13) The title compound (D13) was prepared from 26; hexanenltrile using the method given in Description 7, 27 as a beige solid (73~) m.p. 40-42C.
28 1H NMR (CDC13) 6:
29 0.90 (3H, t, J=7Hz), 1.25-1.40 (4H, m)~
1.50-1.65 (2H, m)~ 2.14 ~2H, t, J-7Hz), 4.55 31 ~2H, br.s)~ 8.00 ~lH, br.s).

.

~æ f~ ~ ;2 ~ ~7 03 DescriPtion 14 05 E-Pent-3-enamide oxime ~D14) 07 The title compound (D14) was prepared from 08 E-pent-3-enenitrile using the method given in 09 Description 7, as a yellow oil (55%).
1H NMR (CDC13 + d6 DMSO~ 6:
11 1.60 (3H, d, J=7Hz), 2.77 (2H, d, J=7Hz), 4.80 12 (2H, br.s)~ 5.30-5.45 (lH, m), 5.48-5.65 (lH, 13 m)~ 7.80 (lH, br.s).

DescriPtion 15 17 N'-Acetyl-l-azabicvclor3.l.l.lhept-s-vlhydrazide (D15) 19 CONHNHCOMe 21 N ~ /

24 (D15) 26 A mixture of methyl l-azabicyclo[3.1.1]hept-5-yl-27 carboxylate (D4, 770mg, 0.0050 mole) and acethydrazide 28 (410mg, 0.0055 mole) in water (1.2ml) was stirred at 29 room temperature for 30h, then warmed to 50C for a further 8h. The solutlon was concentrated in vacuo, 31 using toluene to azeotrope out the remaining traces of 32 water. The title compound.(D15) remained as a beige 33 solid (98omg~ 100%).
34 lH NMR (CD30D) ~:
1.95 (s, 3H), 2.25-2.45 (4H, m), 3.45-3.60 (4H, 36 m)~ 4.28-4.37 (2H, m)~ 5.03 (2H, br.s).

J~

03 DescriPtion 16 05 5-Acetvl-l-azabicyclo r 3.1.11heptane ~D 16 07 ~COC~3 /

12 (D 16) ~3 14 A solution of methyl l-azabicyclo[3.1.1]hept-5-ylcarboxylate (D4, 1.12g, 0.0072 mole) in methanol 16 (~ml) was treated with a solution of lithium hydroxide 17 monohydrate (308mg, 0.0073 mole) in water ~20ml) and 18 the resulting solution stirred at room temperature for 19 20h, then concentrated in vacuo to leave a white solid which was dried thoroughly. A stirred suspension of 21 this product ln dry THF (120ml) under nitrogen was 22 treated at room temperature with lM methyllithium in 23 ether (8.oml~ 0.0080 mole) and then heated under reflux 24 for 3.5h. The mixture was allowed to cool, then poured lnto excess well stirred cold lM hydrochloric acid.
26 The resulting solution was basified to saturation point 27 with potassium carbonate and extracted with ethyl 28 acetate (1 x looml)~ followed by chloroform (2 x 29 6oml)~ The combined extracts were dried (Na2so4) and concentrated in vacuo to give the title compound (D 16 31 as a yellow oll (36omg~ 36~). Thls materlal was used 32 wlthout further purification.
33 lH NMR (CDC13) ~:
34 1.95-2.08 (2H, m~, 2.04 (3H, s)~ 2.16-2.30 (2H, m)~ 2.79-2.87 (2H, m)~ 3.17 (2H, t, J=7Hz), 36 3.70-3.80 (2H, m) 03 Example 1 05 5-~3-Amino-1,2,4-oxadiazol-5-Yl)-l-azabicYclor3.1.11 06 he~tane (El) 07 N~2 08 N - - ~
0 9 /¦ N
/~~
11 ~

13 tEl) A stirred solution of sodium ethoxide (O.Ol9 mole) in 16 ethanol (40ml) at room temperature under nitrogen was 17 treated with powdered 3A molecular sieves (4g) and methyl l-azabicyclo~3.1.1]hept-5-ylcarboxylate (D4, 370mg, 0.0024 mole)~ followed by hydroxyguanidine hemi-sulphate hemi-hydrate ~960mg, 0.0072 mole). The mixture was heated under reflux for 1.25h, then cooled in an ice bath and the pH ad~usted to 5 by the addition of glaclal acetic acid, before concentrating in vacuo.
The residue was shaken with concentrated potassium carbonate solution (50ml) and ethyl acetate (50ml) then i filtered through a plug of kieselguhr and the organic 7 layer separated. The aqueous was extracted with 8 chloroform (2 x 50ml) and all three organic solutions 29 combined, dried (Na2so4) and concentrated in vacuo to leave a yellow gum. This was chromatographed on baslc 31 alumina eluting with 20% methanol/ethyl acetate to glve 32 the required material, which was trlturated with ether 33 - to give the title compound (El) as a white solld (32mg, 34 7%) m.p. 167-170C.
lH NMR (CDC13) ~:
36 2.00-2.20 (2H, m)~ 2.48 (2H, t, J-7HZ), 2.98 2 ~

03 (2H, dd, J=7Hz and 2Hz), 3.23 (2H, t, J=7Hz), 04 4.01 (2H, dd, J=7Hz and 2Hz), 4.55 (2H, br.s, 05 NH2) 06 13C NMR (CDC13) ~
07 14.5, 2g.3, 43.4, 52.7, 59.0, 167.9, 178.9 og ExamPle 2 11 5-(3-MethYl-1,2,4-oxadlazol-5-vl)-l-azabicvclor3,1,11-12 hePtane oxalate salt ~E2) 13 C~3 14 N--~/
~ \~
6 ~ o~

18 N ~ .(COOH)2 19 (E2) 21 To a stirred solution of sodium ethoxide, prepared from 22 390mg (0.017 mole) of sodium in ethanol (30ml) under 23 nitrogen, was added powdered 3A molecular sieves (3g), 24 methyl 1-azabicyclo[3.1.1]hept-5-ylcarboxylate (D4, 430mg, 0.0028 mole) and acetamide oxime (D5, 1.03g, 26 0.014 mole). The mixture was heated under reflux for 27 lh, then cooled in an ice bath and adjusted to pH 5 by 28 the addition of glacial acetic acld. The mlxture was 29 concentrated in vacuo and the residue baslfied wlth concentrated potassium carbonate solutlon, then shaken 31 well with ethyl acetate (lOOml) and filtered. The 32 organic layer was separated, dried (Na2SO4) and 33 concentrated in vacuo to leave an orange oil, which was 34 chromatographed on basic alumina eluting initially with ether and then with 1:2 ether/ethyl acetate to give a 36 pale yellow oil ~290mg). This was converted to its -03 oxalate salt and recrystallised from ether~methanol to 04 give the title compound tE2) as a white solid (27omg~
05 36%) m.p. 153-156C.
06 Oxalate salt:- lH NMR ~d6DMSO) ~:
07 2.18-2.32 (2H, m)~ 2.35 (3H, s)~ 2.50 (2H, t, 08 J57Hz), 3.51 ~2H, t, J-7Hz), 3.75 (2H, dd, J-7Hz og and 2HZ), 4.52 (2H, dd, J=7Hz and 2Hz).
13C NMR (d6DMSO) ~:
11 11.04, 11.06, 13.18, 26.60, 47.92, 58.36, 12 164.68, 167.02, 176.43 13 AnalySlS: CgH13N3O-C2H2O4 14 requires C: 49.07; H: 5.62; N: 15.61%
found C: 48.97; H: 5.62; N: 15.55%

17 Exam~le 3 19 5-(1.3-Oxazol-5-vl~-1-azabicvclo r 3.1.11he~tane oxalate salt (E3) N
21 ~ \\
22 ~ O /

26 '(C~)2 27 ~E3) 29 A stirred solution of crude l-azabicyclo~3.1.1]hept-S-ylcarboxaldehyde (D6, 620mg, 0.0050 mole) ln methanol 31 (15ml) was treated wlth anhydrous potassium carbonate 32 (83omg~ 0.0060 mole) and tosylmethyl isocyanlde (1.07g, 33 0.0055 mole). The mixture was heated under reflux for 34 1.5h, then concentrated ln vacuo and the resldue treated with concentrated potassium carbonate solutlon 36 (10ml) and extracted with chloroform (3 x 30ml). The 03 combined extracts were dried (Na2so4) and concentrated 04 in vacuo to leave a yellow oil, which was treated with 05 polyphosphoric acld (20g) and heated at 140C for 06 0.25h. The hot solution was poured cautiously into 07 excess cold potassium carbonate solution, with good 08 stirring. The mlxture was extracted with ethyl acetate 09 (2 x 50ml) and the combined extracts dried (Na2SO4) and concentrated in vacuo to leave an orange oil. This was 11 chromatographed on baslc alumina eluting with ethyl 12 acetate. The colourless oil obtained was converted to 13 its oxalate salt and crystallised from methanol/acetone 14 to give the title compound (E3) as a pale yellow solid (12mg) m.p. 139-143C.
16 Oxalate salt:- lH NMR (CD30D) ~:
17 2.32-2.47 (2H, m)~ 2.47-2.60 (2H, m)~ 3.63 (2H, 18 t, J=7Hz), 3.76 (2H, dd, J=7Hz and 2Hz), 4.58 19 (2H, dd, J=7Hz and 2Hz), 7.15 ~lH, s)~ 8.24 (lH, s).
21 MS:- CgH12N2O requires M+ = 164.0949 22 found M+ = 164.0951 24 Exam~le 4 26 5-(1~3-Oxazol-2-vl)-l-azabicyclor3.~ heptane oxalate 27 salt (E4) N
28 ~t \~
29 ~ ~ o /
31 N ~
32 .( COOH ) 2 34 (E4) 36 A well stirred mixture of l-azabicyclo[3.1.1]hept-5-37 ylcarboxamide (D12, 640mg, 0.0046 mole) and vinylene ~ ~ 'h `~ ?~
01 - 40 - ~2818 03 carbonate (600mg, 0.0069 mole) in polyphosphoric acid 04 (25g) was heated at 120C for lh. The hot solution was 05 then poured cautiously, with good stirring, into excess 06 potassium carbonate solution. The aqueous mixture was 07 saturated with potassium carbonate and extracted with 08 ethyl acetate (1 x lOOml), followed by chloroform (1 x 09 looml). The combined extracts were dried (Na2SO4) and concentrated in vacuo at room temperature. The residue 11 was immediately chromatographed on basic alumina 12 eluting initially with ethyl acetate, increasing to 15%
13 methanol/ethyl acetate to give a colourless oil 14 (60mg). This was converted to its oxalate salt and recrystallised from methanolJether to give the title 16 compound (E4) as a white solid (65mg, 6~) m.p.
17 165-166C.
18 lH NMR (d6DMSO) 6:
19 2.20-2.33 (2H, m)~ 2.45-2.55 (2H, m), 3.52 (2H, t, J-7Hz), 3.75 (2H, dd, Js7Hz and 2Hz), 4.47 21 (2H, dd, J=7Hz and 2Hz), 7.27 (lH, s)~ 8.18 (lH, 22 s).
23 AnalySiS: CgHl2N2o.c2H2o4 24 requires C: 51.97; H: 5.55; N: 11.02%
found C: 51.74; H: 5.55; H: 10.73%

~e~
01 - 41 - ~2818 03 ExamPle 5 05 5-(3-EthY~ 2~4-oxadiazol-5-vl)-l-azabicvclo r 3.1.11-06 heptane oxalate salt (E5) C2H5 07 N ~
08 ~ N
09 ~ O' ~
11 N ~
. (cooa)2 13 ~E5) The title compound (E5) was prepared from methyl 16 1-azabicyclo[3.1.1]hept-5-ylcarboxylate (D4) and 17 propionamide oxime (D7) using the method given in 18 Example 2, as a white solid (39%) m.p. 148-150C.
19 Oxalate salt:- lH NMR (d6DMSO) 6:
1.24 ~3H, t, J=7Hz), 2.17-2.32 (2H, m)~
21 2.45-2.52 (2H, m)~ 2.74 (2H, q, J-7Hz), 3.50 22 (2H, t, J-7HZ), 3.77 (2H, dd, J=7Hz and 2Hz), 23 4.50 (2H, dd, J-7Hz and 2Hz).
24 AnalySiS: CloHlsN3o--c2H2o4 requires C: 50.88; H: 6.05; N: 14.83%
26 - found C: 50.66; H: 6.00; N; 14.80 03 ExamPle 6 05 5-(3-ProPyl-1,2,4-oxadiazol-5-vl)-1-azabicvclo r 3.1.11-06 heptane oxalate salt (E6) nC3H
N /
08 ~ N
09 ~ o~
. 1 11 N ~ COOH )2 13 (E6) The title compound (E6) was prepared from methyl 16 1-azabicyclo[3.1.1]hept-5-ylcarboxylate (D4) and 17 butyramide oxime (D8) using the method given in Example 18 2, as a white solld (33%) m.p. 135-137C.
19 Oxalate salt:- lH NMR (d6DMSO) 6:
0.93 (3H, t, J-7Hz), 1.69 ~2H, sextet, J=7Hz), 21 2.17-2.32 (2H, m)~ 2.45-2.55 (2H, m)~ 2.68 (2H, 22 t, J~7Hz), 3.50 (2H, t, J-7Hz), 3.76 (2H, dd, 23 J=7Hz and 2Hz), 4.50 (2H, dd, J=7Hz and 2HZ).
24 AnalyS iS: Cl lH17N3O-C2H2O4 requires C: 52.52; H: 6.44; N: 14.13%
26 found C:52:35; H: 6.44; N: 14.22%

03 Example 7 05 5-(3-CvcloProPvl-l~2~4-oxadiazol-5-yl)-l-azabi 06 r 3.1.1lheptane oxalate salt (E7) A

08 N ~
/ ~ O ~N
1 ~\
11 ~ ~ .~COOH)2 13 (E7) The title compound (E7) was prepared from methyl 16 1-azabicyclo[3.1.1]hept-5-ylcarboxylate (D4) and 17 cyclopropylcarboxamide oxime (D9) using the method 18 given in Example 2, as a white solid (36%) m.p.
19 149-150C.
Oxalate salt:- lH NMR (d6DMSO) 0.85-0.93 (2H, m)~
21 1.02-1.14 (2H, m), 2.07-2.30 (3H, m)~ 2.40-2.53 22 (2H, m)~ 3.47 (2H, t, Js7Hz), 3.72 (2H, dd, 23 J-7Hz and 2Hz), 4.45 (2H, dd, J=7Hz and 2Hz) 24 Analysis: CllHlsN3O-C2H2O4 requires C: 52.88; H: 5.80; N: 14.23%
26 found C: 52.75; H: 5.80; N: 14.06%

03 Example 8 05 5-(3-Buty~ 2~4-oxadiazol-5-yl)-l-azabicyclo r 3.1.11-06 hePtane oxalate salt (E8) o78 nc4~9 --~~
11 1 ~ (CO0~)2 13 ~ (E8) The title compound (E8) was prepared from methyl 16 1-azabicyclo[3.1.1]hept-5-ylcarboxylate (D4) and 17 valeramide oxime (Dll) using the method given in 18 Example 2, as a white solid (37~) m.p. 128-130C.
19 Oxalate salt:- lH NMR (d6DMSO) ~:
0.88 ~3H, t, J=7Hz), 1.25-1.40 (2H, m), 21 1.55-1.70 ~2H, m), 2.15-2.30 ~2H, m), 2.45-2.55 22 ~2H, m)~ 2.68 ~2H, t, J=7Hz), 3.48 ~2H, t, 23 J=7Hz), 3.74 ~2H, dd, J=7Hz and 2Hz), 4.50 (2H, 24 dd, J57Hz and 2Hz).
Analysis:- Cl2HlgN3o-c2H2o4 26 requires C: 54.01; H: 6.80; N: 13.50%
27 found C: 53.88; H: 6.87; N: 13.28%

01 - 45 - s2818 03 Example g 05 5-~3-Methoxvmethvl-1,2,4-oxadiazol-5-vl)-1-azabicvclo-06 r 3.1.11he~tane oxalate salt (E9) 0 8 N--t/
09 ~ N
~/ o~
11 N ~ . ( COOH ) 2 13 (E9) A stirred solution of sodium methoxide, prepared from 16 290mg (0.012 mole) of sodium in methanol (20ml), under 17 nitrogen was treated with methyl 1-azabicyclo[3.1.1]-18 hept-5-ylcarboxylate (D4, 300mg, 0.0019 mole), 19 methoxyacetamide oxime (D10, 1.0g, 0.0097 mole) and powdered 3A molecular sleves ~2.5g). The mixture was 21 heated under reflux for 3.5h, then cooled in an ice 22 bath and adjusted to pH 6 by the addition of glacial 23 acetic acid. The mixture was concentrated in vacuo and 24 the residue basified with concentrated potassium carbonate solution, then shaken with ethyl acetate 26 ~l00ml). The mixture was filtered and the organic 27 layer separated, dried ~Na2SO4) and concentrated in 28 vacuo to leave a yellow oil. This material was 29 chromatographed twlce on basic alumina, each time eluting initlally with ether then with 20% ethyl 31 acetate/ether to eventually glve a colourless oil 32 ~80mg). This was converted to its oxalate salt and 33 crystallised from acetone to give the title compound 34 ~E9) as a white solid ~12~) m.p. 102-104C.
Oxalate salt:- lH NMR ~d6DMSO) 6:
36 2.15-2.30 ~2H, m)~ 2.47-2.55 ~2H, m)~ 3.33 ~3X, ~2~267 03 s)~ 3.50 (2H, t, J=7HZ), 3.77 ~2H, dd, Js7HZ and 04 2Hz), 4.53 (2H, dd, J=7Hz and 2Hz), 4.55 (2H, 05 s~.

07 Example 10 09 s-~3-pentvl-l~2~4-oxadiazol-5-vl)-l-azabicvclo r 3.1.11-hePtane oxalate salt ~E10) 12 N ~ nCSHll 13 ~ N
14 ~ O~
N~ ~ .(COOH)2 16 ~
17 (E10) 19 The title compound (E10) was prepared from methyl 1-azabicyclo~3.1.1]hept-5-yl-carboxylate (D~) and 21 hexanoamide oxlme (D13) using the method given in 22 Example 2, as a white solid (32%) m.p. 127-129C.
23 Oxalate salt:- lH NMR (d6 DMSO) 6:
24 0.87 (3H, t, J=7Hz), 1.25-1.40 (4H, m), 1.57-1.73 (2H, m)~ 2.15-2.30 (2H, m)~ 2.45-2.55 ;26 (2H, m)~ 2.68 (2H, t, J=7HZ), 3.50 (2H, t, 27 J=7Hz), 3.75 (2H, dd, J=7Hz and 2Hz), 4.50 (2H, 28 dd, J=7Hz and 2HZ).
29 AnaylSiS: C13H21N3O-C2H2O4 requires C: 55.37; H: 7.13; N: 12.92%
31 found C: 55.53; H: 7.16; N: 12.91 03 Example 11 05 E-5-(3-But-2-envl-1,2,4-oxadiazol-5-yl)-1-azabicvclo-06 r3.1.11he~tane oxalate salt ~Ell) 07 N ~ ~ Me 09 ~ /o ~N
lo ! I\

12 \---' (Coo~)2 13 (E11 Methyl 1-azabicyclo[3.1.1]hept-5-ylcarboxylate (D4) was 16 treated with E-pent-3-enamide oxime (D14) using the 17 procedure described for Example 2. The crude product 18 was purified by chromatography on basic alumina eluting 19 initially with 1:1 ether/pentane and then with neat ether to give a colourless oll. This was converted to 21 its oxalate salt and recrystallised from methanol/ether 22 to give a white solid (25%) containing 90% of the title 23 compound (Ell) and 10% of the corresponding l-butene 24 isomer. m.p. 132-135C.
Oxalate salt:-26 lH NMR (d6 DMSO) ~: (ma~or isomer) 27 1.64 (3H, d, J-7Hz), 2.16-2.32 (2H, m), 28 2.43-2.57 (2H, m)~ 3.40-3.57 (4H, m), 3.75 (2H, 29 dd, J~7Hz and 2HZ), 4.48 (2H, dd, J-7Hz and 2Hz), 5.48-5.74 (2H, m).
31 13C NMR (d6 DMSO) ~: (ma~or isomer) 32 13.22, 17.66, 26.66, 28.64, 38.96, 47.96, 58.41, 33 124.30, 128.76, 164.78 (COOH)2, 169.16, 176.65.

03 Example 12 05 5-(Fur-2-yl)-1-azabicvclo r 3.1.1lhe~tane ~E12) 07 ~ ~ 3 N J

12 ~E12) 14 A stirred solution of lithium diisopropylamide ~4.Oml of 1.5M cyclohexane solution; 0.0060 mole) in dry 16 tetrahydrofuran ~lOOml) at -65C under nitrogen was 17 treated with a solution of 2-~2-(4-methylphenyl-18 sulphonyl)ethyl]-l~3-dioxolane ~compound D5 in 19 EP-0322182, 1.54g, 0.0060 mole) in dry tetrahydrofuran (5ml). After stirring the resulting solution at -65CC
21 for 10 minutes, a solution of crude 22 1-azabicyclot3.1.1]hept-5-ylcarboxaldehyde (D6, 550mg, 23 0.0044 mole) in dry THF (8ml) was added. The reaction 24 mlxture was allowed to warm up to -20C over 30 minutes, then treated with glacial acetic acid (5ml) 26 and concentrated in vacuo. The residue was dissolved 27 in glacial acetic acid (lOOml), treated with 28 4-toluenesulphonic acid (20mg) and heated under reflux 29 for 24h. The solution was concentrated in vacuo and the residue basified with concentrated potasslum 31 carbonate solution and extracted with chloroform (2 x 32 80ml). The combined extracts were dried (Na2S04) and 33 concentrated in vacuo to leave a brown oil, which was 34 distilled in a Kugelrohr apparatus. The material boiling at 130-150C at O.lmmHg was collected and then 36 chromatographed on basic alumina eluting initially with 37 ether to remove f ~
01 - 49 - ~2818 03 impurities, then with 10% methanol/ethyl acetate to 04 remove the title compound (E12), which was obtained as OS a colourless oil (4mg).

07 lH NMR (CDC13) ~:
08 1.93-2.08 (2H, m), 2.25-2.35 (2H, m), 2.84-2.94 09 (2H, m), 3.17 (2H, t, J-7HZ), 3.86-3.95 (2H, m)~
5.92-5.95 (lH, m)~ 6.20-6.25 (lH, m), 7.25-7.28 11 (lH, m).

13 ExamPle 13 5-(2-Methvl-1.3.4-oxadiazol-5-vl)-1-azabicvClo r 3.1.11-16 hePtane oxalate salt ~E13) }8 ~ ~ Me 19 1 < o 1 _ ) 21 ~ J (cOOH)2 23 (E13) A mixture of phosphorus pentoxide (2.8g, 0.025 mole) 26 and methanesulphonic acid (28g, 0.25 mole) was stirred 27 at room temperature for lh, then added to 28 N'-acetyl-l-azabicyclo[3.1.1]hept-5-ylhydrazide (D15, 29 980mg, 0.0050 mole) and the mixture heated at 70C for 2h. The solution was allowed to cool, then added 31 carefully to excess cold concentrated potassium 32 carbonate solution, with good stirring. The mixture 33 was extracted with chloroform (2 x 70ml), and the 34 combined extracts dried (Na2SO4) and concentrated in vacuo to leave a yellow oll. This was chromatographed 36 on basic alumina eluting with 10% methanol/ethyl ;~ S` ~ rr~ ~ ~

03 acetate and the colourless oil obtained converted to 04 its oxalate salt. This was recrystallised from 05 methanol/ether to give the title compound (E13) as a 06 white solid (19Omg, 14%) m.p. 149-150C.
07 Oxalate:-08 1H NMR (d6 DMSO) 6:
09 2.18-2.32 (2H, m)~ 2.43-2.57 (2H, m), 2.48 (3H, s), 3.50 (2H, t, J-7HZ), 3.76 (2H, dd, J-7Hz and 11 2Hz), 4.47 (2H, dd~ J-7Hz and 2Hz~.
12 AnalysiS:- CgHl3N3o.c2H2o4 13 requires C: 49.07; H: 5.62; N: 15.61~
14 found C: 48.93; H: 5.63; N: 15.83%
16 Example 14 18 E-l-AzabicYclor3.~ hePt-5-~lcarboxaldehYde-o-meth 19 oxime oxalate salt ~E14) OMe N
21 ll 2 2 ~ H

(C~)2 26 (E1 28 A solution of crude l-azabicyclo[3.1.1]hept-5-ylcarbox-29 aldehyde (D6, 0.0026 mole) ln methanol (l5ml) was treated wlth O-methylhydroxylamlne hydrochlorlde 31 (22omg~ 0.0026 mole) and the resulting solutlon left to 32 stand for 2 days at room temperature. The solutlon was 33 concentrated in vacuo, the residue basified with 34 concentrated potassium carbonate solution and extracted with chloroform (2 x 50ml). The combined extracts were 36 dried (Na2SO4) and concentrated in vacuo to leave a 03 pale yellow oil, which was chromatographed on basic 04 alumina eluting with 10% methanol/ethyl acetate. The 05 colourless oil obtained was converted to its oxalate 06 salt and recrystallised from methanol/ether to give the 07 title compound (E14) as a white solid (8omg~ 13%) m.p.
08 126-129C.
09 Oxalate salt:- lH NMR (d6DMSO) 6:
2.05-2.20 (4H, m)~ 3.38-3.53 (4H, m), 3.75 (3H, 11 s~, 4.15-4.25 (2H, m)~ 7.47 (lH, s).
12 AnalySiS: CgHl4N2o.c2H2o4 13 requires C: 49.18; H: 6.60; N: 11.47%
14 found C: 49.08; H: 6.65; N: 11.36%
16 The hydrochloride salt is obtained analogously from the 17 free base using hydrogen chloride in ether.

19 Example 15 21 E and Z-5-Acetvl-l-azabicvclo~3.1.11hePtane O-methvl-22 oxime oxalate salt (E15~
23 ~JoMe ) 1~
26 Me 27 ~ (C~)2 28 N ~ ~E:Z = 2:3) 29 (E15) 31 A stirred solution of 5-acetyl-l-azabicyclo[3.l.l]-32 heptane (D16, 360mg, 0.0026 molel in methanol (2oml) 33 was treated with O-methylhydroxylamine hydrochloride 34 (250mg, 0.0030 mole) and left at room temperature for 20h. The solutlon was concentrated in vacuo and the 36 residue basified with concentrated potassium carbonate 37 solution and extracted with chloroform (2 x 60ml). The 03 comblned extracts were dried (Na2S04) and concentrated 04 in vacuo to leave a brown oil, which was 05 chromatographed on basic alumlna eluting with 5%
06 methanol/ethyl acetate. The pale yellow oil obtained 07 was converted to its oxalate salt and crystallised from 08 methanol/ether to give the title compound (E15) as a 09 2:3 mixture of E:Z isomers, as a white solid (llOmg, 14%) m.p. 110-116C.
11 Oxalate salt:- lH NMR (2:3 mixture of E/Z lsomers) 12 (d6DMSO) ~:
13 1.70 and 1.71 (together 3H, 2 x s)~ 2.05-2.20 14 (4H, m), 3.35-3.45 (2H, m), 3.47-3.60 (2H, m)~
3.67 (s, CH30, Z-isomer), 3.76 (s~ CH30, 16 E-isomer), 4.13-4.25 (2H, m) s~$~1 03 Bioloaical Actlvitv 05 Radio liaand Bindina 07 Cerebral cortex from Hooded Lister rats (olac~ UK) is 08 homogenised in 2.5 vols ice-cold 50mM tris buffer 09 pH 7.7 ~at 25C). After centrifugation at 25,000 x g at 4C for 15 min the pellet is resuspended in 2.5 vols 11 buffer and the wash repeated 3 times more. The final 12 resuspension ls in 2.5 volumes and the homogenates are 13 stored in lml allquots at -20C.

Incubations (total volume 2ml) are prepared using the 16 above buffer with the addition of 2mM magnesium 17 chloride in the 3H-Oxotremorine-M ~3H-OXO-M) 18 experiments. For 3H-Quinuclidinyl Benzilate (3H-QNB), 19 lml of stored membranes is diluted to 30ml and 0.lml mixed with test compound and 0.27nM (c. 25,000 cpm) 21 3H-QNB (Amersham International). For 3H-OXO-M, lml of 22 membranes is diluted to 6ml and 0.lml mixed with test 23 compound and 2nM tc. 250,004 cpm) 3H-OXO-M ~New England 24 Nuclear).
26 Non-specific binding of 3H-QNB is defined using l~M
27 Atropine sulphate (2~M Atropine) and of 3H-OXO-M using 28 10~M Oxotremorine. Non-specific binding values 29 typlcally are 5% and 25% of total blnding, respectively. Incubations are carried out at 37C for 31 30 min and the samples filtered using Whatman GF/B
32 filters. (In the 3H-OXO-M experiments the filters are 33 presoaked for 30 min in 0.05% polyethylenimine in 34 water). Filters are washed with 3 x 4ml ice-cold buffer. Radioactivity is assessed using a Packard BPLD
36 scintillation counter, 3ml Pico-Fluor 30 (packard) as 37 scintillant.

03 This test provides an indication of the muscarinic 04 binding activity of the test compound. The results are 05 obtained as IC50 values (i.e. the concentration which 06 inhibits binding of the ligand by 50%) for the 07 displacement of the muscarinic agonist 3H-OXO-M and the 08 muscarinic antagonist 3H-QNB. The ratio 09 IC50(3H-QNB)/IC50(3H-OXO-M) gives an indication of the agonist character of the compound. Agonists typically 11 exhibit a large ratio; antagonists typically exhibit a 12 ratlo near to unity.

14 The results are shown in Table 1.
16 Table 1 18 - 3H-oXo-M 3H-QNB

21 ExampleICso (nM) ICso (nM) 2223 El 11 11000 4l E10 141 2400 4423 Ell 165 1850

Claims (11)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

(I) in which z is a heterocyclic group in which Q represents a 3-membered divalent residue completing a 5-membered aromatic ring and comprises one or two heteroatoms selected from oxygen, nitrogen and sulphur, or three nitrogen atoms, any amino nitrogen being substituted by a C1-2 alkyl, cyclopropyl or propargyl group, and any ring carbon atom being optionally substituted by a group R1; or a group in which A1, A2 and A3 complete a 5-membered aromatic ring and A1 is oxygen or sulphur, one of A2 and A3 is CR2 and the other is nitrogen or CR3, or A2 is oxygen or sulphur, one of A1 and A3 is CR2 and the other is CR3; and R1, R2 and R3 are independently selected from hydrogen, halogen, CN, OR4, SR4, N(R4)2, NHCOR4, NHCOOCH3, NHCOOC2H5, NHOR4, NHNH2, NO2, COR4, COR5, cyclopropyl, C2-5 straight chain alkenyl, C2-5 straight chain alkynyl or C1-5 straight chain alkyl optionally terminally substituted with OR4, N(R4)2, SR4, CO2R4, CON(R4)2 or one, two or three halogen atoms, in which each R4 is independently hydrogen or C1-3 alkyl and R5 is OR4, NH2 or NHR4;

or in which Z is a group -C(R7)-NR6 in which R6 is a group OR8, where R8 is C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, a group OCOR9 where R9 is hydrogen or R8, or a group NHR10 or NR11R12 where R10, R11 and R12 are independently C1-2 alkyl and R7 is hydrogen or C1-4 alkyl, subject to the proviso that when R6 is a group OCOR9 or NHR10, R7 is C1-4 alkyl.

2. A compound according to claim 1 in which the 5-membered aromatic ring in Z is an oxadiazole, oxazole, thiadiazole, thiazole, furan, triazole or tetrazole ring.

3. A compound according to claim 1 in which R1, R2 and R3 are independently selected from hydrogen, halogen, N(R41)2 in which each R41 is independently hydrogen or methyl, straight chain C2-3 alkenyl, straight chain C2-3 alkynyl, cyclopropyl or straight chain C1-5 alkyl optionally terminally substituted with OR42 or one, two or three fluorine atoms, in which R42 is methyl.

4. A compound according to claim 1 in which R6 is methoxy, ethoxy, alkyloxy, propargyloxy, acetoxy or dimethylamino.

5. A compound according to claim 4 in which R7 is hydrogen or methyl.

6. 5-(3-Amino-1,2,4-oxadiazol-5-yl)-1-aza-bicyclo[3.1.1] heptane.

5-(3-methyl-1,2,4-oxadiazol-5-yl)-1-azabicyclo-[3.1.1]heptane, 5-(1,3-oxazol-5-yl)-1-azabicyclo[3.1.1]heptane, 5-(1,3-oxazol-2-yl)-1-azabicyclo[3.1.1]heptane, 5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1-azabicyclo-[3-1-1]heptane, 5-(3-propyl-1,2,4-oxadiazol-5-yl)-1-azabicyclo-[3.1.1]heptane, 5-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-1-aza-bicyclo[3.1.1]heptane, 5-(3-butyl-1,2,4-oxadiazol-5-yl)-1-azabicyclo-[3.1.1]heptane, 5-(3-methoxymethyl-1,2,4-oxadiazol-5-yl)-1-aza-bicyclo[3.1.1]heptane, 5-(3-pentyl-1,2,4-oxadiazol-5-yl)-1-azabicyclo-[3.1.1]heptane, E-5-(3-but-2-enyl-1,2,4-oxadlazol-5-yl)-1-aza-bicyclo[3.1.1]heptane, 5-(fur-2-yl)-1-azabicyclo[3.1.1]heptane, 5-(2-methyl-1,3,4-oxadlazol-s-yl)-1-azabicyclo-[3.1.1]heptane, E-1-azabicyclo[3.1.1]hept-5-ylcarboxaldehyde-O-methyloxime or E and Z-5-acetyl-1-azabicyclo[3.1.1]heptane O-methyl-oxime, or a pharmaceutically acceptable salt of any of the foregoing compounds.

7. A process for the preparation of a compound according to claim 1, which process comprises cyclising a compound of formula (II):

(II) in which A represents Z or an electron withdrawing group convertible thereto, L is a leaving group and R13 represents hydrogen or an N-protecting group, and thereafter, optionally or as necessary, removing any R13 protecting group, converting A to Z, interconverting Z and/or forming a pharmaceutically acceptable salt.

8. A compound of formula (VI) or a salt thereof:
(VI) wherein Z'' is a group convertible to Z as defined in claim 1.

9. Methyl 1-azabicyclo[3.1.1]hept-5-ylcarboxylate, 1-azabicyclo[3.1.1]hept-5-ylcarboxaldehyde, 1-azabicyclo[3.1.1]hept-5-ylcarboxamide, N'-acetyl-1-azabicyclo[3.1.1.]hept-5-ylhydrazide or 5-acetyl-1-azabicyclo[3.1.1]heptane.

10. A pharmaceutical composition which comprises a compound according to claim 1 and a pharmaceutically acceptable carrier.

11. A method of treatment and/or prophylaxis of dementia in mammals including humans, which comprises administering to the sufferer an effective amount of a compound according to claim 1.