AU648789B2

AU648789B2 - Bicyclic 1-aza-cycloalkanes

Info

Publication number: AU648789B2
Application number: AU77130/91A
Authority: AU
Inventors: Helmut Ensinger; Ulrike Kufner-Muhl; Franz Josef Kuhn; Enzio Muller; Werner Stransky; Gerhard Walther; Karl-Heinz Weber
Original assignee: Boehringer Ingelheim International GmbH
Current assignee: Boehringer Ingelheim International GmbH
Priority date: 1990-05-19
Filing date: 1991-05-20
Publication date: 1994-05-05
Anticipated expiration: 2011-05-20
Also published as: YU84791A; JPH04226981A; NO911934L; IL98176A0; AU7713091A; NO911934D0; FI912409A7; IE911688A1; CS144891A3; FI912409A0; HUT58091A; EP0458214A1; JP2853837B2; CZ281837B6; CA2042860A1; FI912409L; PT97703A; KR910020009A; HU911663D0; SK279168B6

Description

AUSTRALIA

PATENTS ACT 1952 COMPLETE SPECIFICATICII

(ORIGINAL)

Form FOR OFFICE USE Short Title: 648789 Int. Cl: Application Number: I Lodged: ,'Complete Specification Lodged: Accepted: Lapsed: Published: Priority: Related Art: TO BE COMPLETED BY APPLICANT 11ame of Applicant: Address of Applicant: Adtual hiventors: Address for Service: BOELIRINGER INGELHEIM4 INTERNATIONAL GMBH D-6507 Ingeiheim am Rhein, Germany Gerhard WALTHER Ulrike KU FNER-MUHL Werner STRANSKY Karl-Heinz WEBER Helmut ENSINGER Franz Jose f KUHN' Enzio MfULLER CALLINAN LAWRIE, Patent Attorneys, 278 H-igh Street, Kew, Victoria 3101, Australia.

Complete Specification for the invention entitled: BICYGLIC 1-AZA-CYCLOALKANFS The following statement is a full description of this invention, including the best method of performing it known to me:r I.

e la- 56651.19 Bicyclic 1-aza-cycloalkanes The present invention relates to novel bicyclic 1aza-cycloalkanes of general formula I, to processes for their preparation and to their use as pharmaceutical compositions.

According to the present invention we provide compounds of general formula I sees*:

S

o ooo 0*5 0 0

S

o 7 (CH 2

-X-R

A

_N-C

wherein R represents a C 1 6 -alkyl group, a C 3 -6-alkenyl group or a C 3 _6-alkynyl group, the alkyl, alkenyl or alkynyl group being optionally substituted by a substituted or unsubstituted phenyl group, a substituted or unsubstituted biphenyl group, a substituted or unsubstituted oxetan ring or a substituted or s- or rNunsubstituted 6- or 7-membered\heterocyclic group; or R represents a substituted or unsubstituted phenyl group, a substituted or unsubstituted biphenyl group or a substituted or unsubstituted 6- or o-,.s-or N- 7-membered\heterocyclic group; X represents oxygen or sulphur; A, B and C independently of one another represent CH 2 or a single bo'nd A/s, A/C or C sN AM\oneousy n represents 0, 1 or 2; Sao* a 9 a a 0 a a a 0*0 :0.

0 So 000*0 0 0 0.a.

and all race-mic and tautomeric forms, enantiomers'? diastereomers and mixtures thereof and acid addition salts thereof and additionally the quaternary salts thereof; with the proviso that i) for a compound of formula I wherein the bicyclic ring system is quinuclidine, R imay. ot pepes t an unsubstituted alyalke n y or alyninyl grouk ii) f-,r a compoun d off fonaula I wherein the b icjclic ~ring system is 1- JCkz.CM(C.Y I I] hfw azabicyclo[3,i2, 1] octane/, the grop -(CH2)n-X-R may not -S -XvOX of C I kow- C AL 10 rpresnv_%r~i grcup; and 11i) for a compound of formula I wherein the-bicyclic ring system is Iazabicyclo [2,2,2 )octane, the group -(CH2)-X-R may not represent a 3-2-pyridinyloxy)- group.

15 Examples of alkyl groups for the purposes of this invention are branched or unbranched Cl-6-alkyl groups such as methyl, ethyl, propyl, butyl, pentl and hexyl groups as well as the branched isomers thereof such as isopropyl, isobutyl, tert.-butyl, sec.-butyl etc.; the C3-6-alkenyl groups are branched or unbranched C3-6-alkenyl groups such as propenyl, butenyl, pentenyl and hexenyl groups having a single double bond; c36-alkynyl groups are branched or unbranched C3-6-alkynyl groups such as propynyl, butynyl and pentynyl having a single triple bond. Alkenyl or alkynyl groups in which a double or triple bond respectively is in a terminal position are preferred.

The term "substituted phenyl" indicates, unless otherwise stated, phenyl groups which are mono-, di- or trisubstituted by a halogen atom, or by a hydroxy, a branched or unbranched Ci--alkyl, a substituted or unsubstituted C,-6-cycloalkl, a C,-5-hydroxyalkyl, an amino or a mono- or disubstitted-c1 -4-alkylamino group.

The terms "substituted cycloalkyl" and "substituted biphenyl" indicate cycloalkyl and biphenyl groups-in which the cycloalkyl ring and either of the phenyl rings L; in a bipheny. group may be substituted as specified -3 se@ 0 OOeS 0* *e 0 S

S

eSSOSS 0

S..

S.

S

*55 0 SSS Thes S. SO S 55 0 above for a substituted phenyl group. Examples of substituted phenyl groups include: 2-chiorophenyl, 2, 6-dichiorophenyl, 2-bromophenyl, 3-f luorophenyl, 2, 3-dichiorophenyl, 4-hydroxyphenyl, 2-methyiphenyl, 4-methyiphenyl, 3-ethyiphenyl, 4-propyiphenyl, 4-isopropylphenyl, 4-butyiphenyl, 4-tert. -butyiphenyl, 4-pentyiphenyl, 2, 4-dimethyiphenyl, 2-trifluoromethyiphenyl, 3-trifidoromethyiphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 3-ethoxyphenyl, 2 -propoxyphenyl, 4 -butoxyphenyl, 2,4 -dimethoxyphenyl, 3,4, The term "heterocyclic group" indicates a 5- to 7- 15 membered ring which contains one or more heteroatoms selected from oxygen, sulphur and nitrogen and onto which another aromatic ring, preferably a phenyl group, may optionally be fused.

Examples of saturated heterocyclic 6-membered rings include: 1,4- and 1,3-dioxan, morpholine,thiomorpholine, piperidine, piperazine, 4-Cl- 4 alkylpiperazine, N-hydroxy-C 14 -alkylpiperazine, diketopiperazine and tetrahydropyran. Examples of saturated heterocyclic 5-meinbered rings include: tetrahydropyrrole, tetrahydrofuran, proline, tetrahydropyrazole, imidazolidine, hydroxyproline, pyrrolidine, pyrazolidine, pyrrolidone, thiolan, butyrolactone and 1,2-oxathiolan.

Examples of 6- and 7-membered mono- and 30 polyunsaturated heterocyclic rings incl ude: pyrrole, imidazole, imidazoline, 1,2,4- and 1,2,3triazole, tetrazole, isothiazole, furan, dihydrofuran, thiophene, pyridine, pyrimidine, pyran, dihydropyrrole, thiazole, thiadiazine, azepine, 1,2oxathiepan, pyrazoline, dimethylpyrrole, 2-acylfuran and dihydrothiophene. Examples of other heteroaryl groups include pyrazinyl, quinolyl, isoquinolyl, quinazolyl, 0* 0

S~.S

5 *5 S 0 5 *5 -4

S..

S

55..

S S 0 505005

S

*0

S

5*5

S

005 quinoxalyl, thiazolyl, benzothiazolyl, isothiazolyl, oxazolyl, benzoxazolyl, isoxazolyl, imidazolyl, benzimidazolyl, pyrazolyl, and indolyl. A preferred heterocyclic group is the pyridine group which may be mono- to tetrasubstituted, preferably mono- to disubstituted, with identical or different substituents, selected from hydroxy, C 1 4 -alkyl, C 1 4 -alkoxy, NH 2 monoor di-(C 1 4 -alkylamino, halogen, CF 3 1 CH or nitro.

Examples of 5, 6 or 7-membered heterocyclic rings bound via a nitrogen atom also include: phenanthridin-6-one, quinolin-2-one, isoquinolin-l, 3dione, benz[c,d]indole, l,4-benzoxazin-3-one, indol-2,3dione, indol-2-one, l,2,4-triazolo[4,3-a]pyridin-3-one, 1, 2-benzisothiazol-3-one, lH-indazole, lH-benzimidazole, 15 lH-benztriazole, benzothiazin-3-one, isoindol-l, 3-dione,, benz[d,e] isoquinolin-l,3-dione, 4-quinazolinone, isoindol-l-one, pyrrolo[l,2-c]inmidazol-l,3-dione, 1,3dihydro-2H-indol-2-one, tetrahydro-lH-isoindol-l, 3dione, 3, 7-dihydro-lH-purin-2, 6-dione, indole, indazole, benzimidazole, benzimidazol-2-one-, *l,4-berzothiazin-3one and 1H-isoindol-1,3-dione.

The heterocyclic group may be mono- or polysubstituted by a halogen atom, or a hydroxy, a branched or unbranched C 1 4 -alkyl, a C 1 4 -hydroxyalkyl or a C 1 4 -alkoxy group. The heterocyclic group may additionally contain a keto-function as in e.g.

dihydrotetrafuranone.

Preferred compounds according to the present invention are compounds of general formula I as defined 30 above wherein X represents oxygen; n represents 0 or 1; the substituent -(CH 2 )n-X-R is in the a- or fl-position relative to the carbocyclic bridgehead; and R re resents oX -mn r- Cn" op:tr-' mvon~o- zU\ceI 9IU an cjptlznall-y substituted C 1 3 -alkyl,\ C 3 4 -alkenyl, or C-4 alkynyl group, a substituted or unsubstituted phenyl grou 5 or asubstituted or unsubstituted 5- or 6-membered aromatic heterocyclic group.

Particularly preferred compounds according to the 505505

S

'.59

SS

OS S S0

S

SSSS

S

00 S S S S

S.

1* -1 5 sees.

0 *0 0.

see

C.

C

O g present invention are quinuclidine compounds of general formula I as defined above wherein n represents 0 or 1; X represents oxygen; R represents a substituted or unsubstituted pyridine, thiophene, furan, pyrimidine, imidazole, pyrazole, 1,2,4-triazole, oxetan, tetrahydrofuran, pyrrolidine or oxolan group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted benzyl group; the side chain -(CH 2 )n-X-R being in the 3-position of the quinuclidine system.

Further particularly preferred compounds according to the present invention are l-azabicyclo[2,2,1]heptanes of general formula I as defined above wherein X represents oxygen; n represents 0 or 1; R represents an optionally substituted C 1 3 -alkyl, C 3 4 -alkenyl or C3 4 alkynyl group, a substituted or unsubstituted pyridine, thiophene, furan, pyrimidine, irmidazole, pyrazole, 1,2,4-triazole, oxetan, tetrahydrofuran, pyrrolidine or oxolan group, a substituted or unsubstituted phenyl group or a substituted or unsubstituted benzyl group; the side chain -(CH 2 )n-X-R being in the 3-position of the bicyclic system.

Further particularly preferred compounds according to the present invention are l-aza-bicyclo[3,2,1]octanes of general formuila I as defined above wherein X represents oxygen; n represents 0 or 1; R represents an optionally substituted C..

3 -alkyl, C..

4 -alkenyl group or

C

3 4 -alkynyl group, a substituted or unsubstituted pyridine, thiophene, furan, pyrimidine, imidazole, 30 pyrazole, 1,2,4-triazole, oxetan, tetrahydrofuran, pyrrolidine or oxolan group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzyl group; the side chain -(CH 2 )n-X-R being in the 3- or 6-position of the bicyclic group.

Further particularly preferred compounds according to the present invention are l-a-a-bicyclo[3,3,1]nonanes of general formula I as defined above wherein X

C

SCSC

QOQ

0.00

C

.CC

C. S 5 C CC -6 represents oxygen; n represents 0 or 1; R represents an optionally substituted C 1 3 -alkyl, C 3 4 -alkenyl or C 3 4 alkynyl group, a substituted or unsubstituted pyridine, thiophene, furan, pyrimidine, imidazole, pyrazole, 1,2,4-triazole, oxetan, tetrahydrofuran, pyrrolidine or oxolan group, a substituted or unsubstituted phenyl group or a substituted or unsubstituted benzyl group; the side chain -(CH 2 being in the 3-position of the bicyclic group.

Especially preferred compounds according to the present invention are compounds of general formula (CH 1--R 2' 0 00 .0 0 0 0 0

S.

0 0*@ 0e

S

0 000000 0 .500 0* 00 25

SO

S 0 005 S. 50 0 0U 0 0S *0 wherein n represents 0 or 1; R represents a group of formula

-CH

2

R

-CH

2 I -CH

<R)

2 T R 2 0)z -CH

(R

2

-CH

2 t R 2 -7 p 3 -NH .J' -N

N

3 N

NN

SN

R 3 -CH

(R

0 15 -CH f -i(R _CI (RA 1 0 Voss &s*so

OS

S

S*.

S.

0

S..

0 a 0*e0 S S 25

US

S 6 *0e S

-CH

2

R

2 1

N

RP

3 in which N(D (R2

)A

R

3 (R

A

1

N

R

1 represents a hydrogen atom, a Cl- 4 -alkyl group, preferably methyl, a C 1 4 -alkoxy group, preferably methoxy, an amino, C 1 4 -alkylamino, C 1 4 -dialkylamino, hydroxy, or C 3 6 -cycloalkyl group, a substituted or unsubstituted phenyl group or a keto-function; k represents 1, 2 or 3, whilst if k~ is greater-than 1 the R, groups may be identical Qr different,

R

2 represents a hydrogen or halogen atom, a C,.

4 -alkyl 8 15 go* 0 group, preferably methyl, a C, 4 -alkoxy group, preferably methoxy or a keto-function; 1 represents 1 or 2, preferably 1, whilst when 1 represents 2 the groups R 2 may be identical or different;

R

3 represents a hydrogen atom or a C 1 4 -alkyl group, preferably methyl; and all racemic and tautomeric forms, enantiomers, diastereomers and mixtures thereof and acid addition salts thereof and additionally the quaternary salts thereof.

Further especially preferred compounds according to the present invention are those of general formula -(CH9-O-R (CH2)- 0- R (CH2)n- 0o-R.

2

(CH

2

O-R

Nf ofe 0 eee wherein n represents 0 or 1, preferably zero; R represents a C 3 -alkynyl group, a C 3 -alkenyl group, or a group of formula 9-

-CH

2

-CH

2

R~

-CH2

R)

(2

-CH

2

_K<N

t 1

(R

2 1

(RA)

S

.me.

OS .5 S S

S

C

C C S5 S. C bO 5e 6 005 5 C C 14 S CS 5 CS in which R 1

R

2 k anid 1 are as hereinbefore defined; and 25 all racemic and tautomeric forms, enantiomers, diastereomers and mixtures thereof and acid addition salts thereof and additionally the quaternary salts thereof.

Further especially preferred compounds according to 30 the present invention are those of general formula (CH 2 )r

R

10 wherein n represents 0 or 1; R represents a C 3 -alkynyl group, a C 3 -alkenyl group, or a methyl, ethyl or propyl group, or a group of formula i *5 a. a

S

BS

a0

-CH

2 )k

-CH

2 (R )k -CH

R

SN .N

-CH

2 -o -(Ri)k R2 1

N

S

I

R2 1

S

I R 0 25 fr (R2 )I 2 S :.00.

'.Do wherein R 1

R

2 k and 1 are as hereinbefore defined; and 30 all racemic and tautomeric forms, enantiomers, S* S* diastereomers and mixtures thereof and the acid addition salts thereof and additionally the quaternary salts thereof.

Certain compounds analogous to compounds of general formula I are described in the prior art. Thus, for example, EP 370415 discloses compounds of formula la 11

(CH

2 (Ia)

N

wherein R' represents an unsubstituted C 1 _6-alkyl, C3.

6 alkenyl or C 3 .6-alkynyl group; X' represents an oxygen or sulphur atom; Lnd m represents 0, 1 or 2.

UK Patent No. 2208385 discloses compounds of general formula Ib N (Ib) l* S20wherein R" represents a 3-(2-pyridinyloxy)- group.

However these compounds are described as antagonists. European Patent No. 257741 discloses S* 2 compounds of formula Ic (Ic) *0 wherein represents a propyloxy group.

However certain of the optically active compounds of formulae Ia, Ib and Ic are not specifically mentioned by name in EP 370415, GB 2208385 and EP 257741.

12 @0"9 Sr bb SS

S

Hence according to a further feature of the present invention there are provided compounds of formulae Ia, Ib and Ic as defined above in the form of individual enantiomers and acid addition salts thereof and additionally the quaternary salts thereof, collectively termed the compounds of formula with the proviso that in the compounds of formula Ia when X' represents oxygen and m represents 0, R' cannot represent a C 3 alkynyl group or an ethyl group.

A most especially preferred compound according to the present invention is (+)-(propargyloxymethyl)-lazabicyclo[2,2,2]octane and acid addition salts thereof and additionally the quaternary salts thereof.

When in the compounds of general formula I, R represents an aliphatic group such compounds may be prepared analogously to the methods described by L.

Stotter et al. in Heterocycles, Vol. 25 (1987), page Hence, according to a further feature of the present invention we provide a process for the preparation of a compound of formula I as-defined above wherein R represents an aliphatic group, characterised in that a corresponding optionally N-protected derivative of general formula I (in which R represents H and the nitrogen atom of the bicyclic group is blocked 25 by a protecting group Z, e.g. Bh) is deprotonated, for example with a strong base, and is subsequently reacted with an alkylating reagent of general formula Y-R, wherein R is as defined hereinbefore and Y represents a readily removable aving group such as halogen or p- 30 toluenesulphonate. The reaction is carried cut in polar inert organic solvents such as dimethylformamide, tetrahydrofuran, dioxan.

Whereas the deprotonation and conversion of the hydroxy compound into a metal salt is preferably carried out at ambient or slightly elevated temperature, the subsequent alkylation is carried out whilst cooling with ice. After the reaction has ended the protecting group a t, S. S

S

*h6J S. S 13 is cleaved and the compounds are optionally converted into their acid addition salts or quaternary compounds using known reaction conditions; the preferred quaternary compounds are the methoiodides and methobromides.

Preferred reagents for the deprotonation step are sodium hydride, sodium amide and alkali metal alkoxides such as potassium tert.-butoxide.

Preferred acid addition salts are physiologically acceptable acid addition salts and include, for example salts with hydrochloric, hydrobromic, sulphuric, phosphoric, methanesulphonic, ethanesulphonic, toluenesulphonic, benzenesulphonic, lactic, malonic, succinic, maleic, fumaric, malic, tartaric, citric and benzoic acid.

The starting compounds required for the synthesis, namely the corresponding hydroxyazabicycloalkanes, are known from the prior art, being of formula 0 a

S

ge

S

(CH

2 )OH (CH2)

OH

N C2(CH, OH

HO(CH

2 )n N

(CH

2 nOH II b

IV

fibV 06.6 Ge* 0 25 IIa Thus, for example, for those wherein n represents 0 from JACS 74, 2215 (1952) (IIa), J. Org. Chem. 33, 4376 30 (1968) (IIb), European Patent Application 307 140 (III) and J. Pharm. Science 52, 331 (1954) Starting compounds (R H) wherein n represents 1 or 2 can be obtained by reduction of the corresponding alkylesters (X-R COOalkyl). Starting from the corresponding ketones the thiols of general formulae II and III may be prepared analogously to the method described in J. Chem.

43, 1965.

14 When the group R in the compounds of general formula I is an aromatic or heteroaromatic group, the compounds of general formula I may be obtained using the Mitsunobu reaction Mitsunobu in Synthesis, 1, 1981, Georg Thieme Verlag, Stuttgart; J. C. S. Perkin I, page 462, 1975).

Hence, according to a yet further feature of the present invention is provided a process for the preparation of compounds of formula I as defined above wherein R represents an aromatic or a heterocyclic group, characterised in that a compound of the formula

(CH

2

X-H

"15 o 0 °o 0* 0 0 00 o@ ooo wherein A, B, C, n and X are as hereinbefore defined, is reacted with a compound of formula HOR (in which R represents an aromatic or heterocyclic group as hereinbefore defined) in the presence of triphenylphosphine and alkylazodicarboxylate. The reaction is generally carried out in inert organic solvents at 25 ambient temperature.

The novel individual enantiomers of formula Id may be prepared by a separation process, as is now described for the first time in Example 3, starting from the corresponding racemic compounds using optically active salts e.g. or tartaric acid, by methods known per se. This process comprises a further feature of the present invention. The corresponding racemate may be prepared by a process analogous to that for the preparation of the compounds of formula I as hereinbefore described using appropriate starting materials.

The novel compounds of general formulae I and Id 0 15 according to the present invention have valuable pharmacological properties as do the known compounds of formulae la, Ib and Ic. Thus, in bonding studies, the compounds showed affinities for muscarinic receptors and muscarin-agonistic GTP shifts (GTP guanosine triphosphate). (Birdsall, E.C. Hulme and I.M.

Stockton 1984 in T.I.P.S. Supplement, Proc. Internat.

Symposium on Subtypes of Muscarinic Receptors, Ed.

Hirsshowitz, Hammer, Giacchetti, Klirns, Levine; Elsevier p. 4 8).

The receptor binding studies were carried out in accordance with the following literary reference [A.

Closse, H. Bittiger, D. Langenegger and A. Wahner; Naunyn-Schmiedeberg's Arch. Pharmacol. 335, 372 377 15 (1987)].

O0@ S e O go 0* 66 seat*:

S

0 o 55 Table A: Receptor binding studies Radioliqand: L(+)cis-[2-methyl- 3 H]-N,N,N-trimethyl-l,3dioxolan-4-methanammonium-iodide NET-647,-Messrs. NEN (New England Nuclear DU PONT).

Organ: Cerebral cortex (rat) Table A:

S

9 OS 00 30 Example Ki [nMol/l]

-O-CH

2 -phenyl

-O-C

6

H

5 120 229 89 As muscarinic agonists (cholinomimetics) the compounds of formulae I, Id, Ib and Ic are therefore therapeutically useful for the treatment of diseases caused by the reduced function of the cholinergic system.

In the light of the studies on binding to the 16 0ses 0 so 0

OS

0

S.

muscarine subtypes M, M 2 and M 3 (rat) and the stimulation of the phosphatidyl inositol turnover (CHO cell cultures with human M 1 receptor subtype), the compound (+)-(propargyloxymethyl)-1-azabicyclo[2.2.2]octane was found to be more effective than the racemate and the (-)-enantiomer in vitro and this (+)-enantiomer is thus particularly preferred for use in therapy. The cholinomimetic in-vivo efficacy of (propargyloxymethyl)-l-aza-bicyclo-[2.2.2]octane was demonstrated in the rabbit by EEG (theta wave increase).

Surprisingly the (+)-enantiomer has less than half the toxicity of the racemate.

In the light of the pharmacological findings the compounds of general formulae I, Id, Ib and Ic as defined above are therefore useful for treatment of, for example, the following diseases: Alzheimer's disease, senile dementia and cognitive disorders; the compounds may also be used to improve memory performance.

Quaternary compounds of general formulae I, Id, Ib and Ic are particularly suitable-for peripheral application, e.g. for treating glaucoma.

According to a yet further feature of the present invention there are provided pharmaceutical compositions comprising as active ingredient at least one compound of 25 formula I or Id, as defined above, or a physiologically acceptable acid addition salt thereof in association with one or more pharmaceutically acceptable carriers, diluents or excipients.

The compounds of general formula I or Id may be 30 used on their own or in conjunction with other active substances according to the invention, possibly in conjunction with other pharmacologically active substances, e.g. cerebroactivators and/or a peripheral cholinergic blocker. Suitable preparations include, for example, tablets, capsules, suppositories, solutions, syrups, emulsions or dispersible powders.

Corresponding tablets may be made for example by

S

5050

OS

55 0

OS

*OGG

S 5 0550 0e a S.

17 mixing the active substance or substances with known excipients, e.g. inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for achieving delayed release such as carboxymethylcellulose, cellulose acetate phthalate or polyvinylacetate. The tablets may also consist of several layers.

A yet further feature of the present invention is a method of treatment of diseases or conditions in a subject which arise from the reduced function of the cholinergic system which comprises administering to said subject an effective amount of a compound of formula I, o* 15 Id, Ib or Ic as hereinbefore defined above or a physiologically acceptable acid addition salt thereof or a quaternary salt thereof, in particular wherein the disease or condition is Alzheimers disease, senile dementia, a cognitive disorder, glaucoma or reduced memory performance.

Coated tablets may be produced in the same way by coating cores made analogously to the tablets with Sagents conventionally used in tablet coating, such as collidone or shellac, gum arabic, talc, titanium dioxide or sugar. In order to achieve delayed release or avoid incompatibilities the core may also consist of several layers. Similarly, the tablet coating may be made of several layers in order to achieve delayed release, using the excipients mentioned for the tablets above.

30 Syrups of the active substances or combinations of active substances according to the invention may additionally contain a sweetener such as saccharin, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanillin or orange extract.

They also contain suspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents, e.g. condensation products of fatty alcohols with 18 ethylene oxide or preservatives such as p-hydroxybenzoates.

Injectable solutions are produced in the usual way, e.g. by adding preservatives such as p-hydroxybenzoates or stabilisers such as alkali metal salts of ethylenediaminetetraacetic acid and transferring them into injection vials or ampoules. The capsules containing one or more active substances or combinations thereof may be produced f- exxample by mixing the active substances with inert carriers such as lactose or sorbitol and encapsulating the mixture in gelatine capsules.

*eg Suitable suppositories can be produced for example by mixing with carriers provided for this purpose such 15 as neutral fats or polyethyleneglycol or derivatives thereof.

The therapeutically effective single dose is in the °0 range from 1 to 100 mg.

The following non-limiting Examples serve to illustrate the present invention:

S

19 Examples of Pharmaceutical Formulations A) Tablets per tablet Active substance Lactose Corn starch Polyvinylpyrrolidone Magnesium stearate 80 mg 140 mg 240 mg 15 mg 5 mg 480 mg 15 #sees: 0 @0060 0 0 9 9s

S.

0 The finely ground active substance, lactose and some of the corn starch are mixed together. The mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, moist-granulated and dried. The granules, the remaining corn starch and magnesium stearate are screened and mixed together. The mixture is compressed to form tablets of suitable shape and size.

B) Tablets per tablet 9 0 00 05 25 *000 of* 30 Active substance Corn starch Lactose Microcrystalline cellulose Polyvinylpl trolidone Sodium carboxymethyl starch Magnesium stearate 60 mg 190 mg 55 mg 35 mg 15 mg 23 mg 2 mq 380 mg The finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and processed with the remainder of the corn starch and water to form granules which are dried and screened. The sodium carboxymethyl starch and the 20 magnesium stearate are added thereto and mixed and the mixture is compressed to form tablets of a suitable size.

C) Ampoules Active substance Sodium chloride Twice distilled water q.s. to 20 mg 10 mg 1.0 ml @00g e 0 0r *See 0 Ob

S

Preparation: The active substance and sodium chloride are dissolved in twice distilled water and the solution is transferred under sterile conditions into ampoules.

D) Drops Active substance Methyl p-hydroxybenzoate Propyl p-hydroxybenzoate Demineralised water q.s. to 5.0 g 0.1 g 0.1 g 100.0 ml Preparation: The active substance and preservatives are dissolved in demineralised water and the solution is filtered and transferred into 100 ml vials.

25 se 0 21 Example 1: 3-ProDarqvloxv-l-azabicvclor2,2.llheDtane 5.6 g (0.05 mol) of 1 azabicyclo[2,2,l]heptan-3-ol are dissolved in 150 ml of absolute tetrahydrofuran under a nitrogen atmosphere and at 0°C 50 ml of IM boran-THF-complex are added. After it has all been added the resulting mixture is stirred for one hour at ambient temperature, evaporated to dryness, the residue is taken up in saturated saline solution and extracted with dichloromethane. The combined organic phases are dried and concentrated by evaporation, the residue is dissolved in 120 ml of absolute THF and 2.08 g 15 (0.052 mol) of sodium hydride are added in batches under a nitrogen atmosphere. After one hour the mixture is cooled to 0"C and at this temperature 17.55 g of propargyl bromide are added dropwise as a 50% solution in THF. The mixture is stirred for 12 hours at ambient temperature, then the excess hydride is decomposed with ethanol, the mixture is evaporated down, the residue is taken up in saturated saline solution and extracted with S dichloromethane. After drying and evaporation of the combined organic phases, an oil is obtained which is 25 distilled under a high vacuum (Bpl mbar 45-46*C). The fumarate is prepared with one equivalent of fumaric acid, recrystallised from ethanol/ether and dried in vacuo. 2.1 g of colourless crystals of the title compound are obtained, m.p. 121-123"C.

1 H-NMR(250 MHz, CDSOD, TMS): 6 6.68 (2H, s, fumaric acid); 4.47 (1H, m, 4.21 (2H, m, CH 2 3.73-2.86 (7H, m, CH2-2, 6, 7; 2.95 (1H, t, J=3Hz, H-9); 2.30; 1.96 (2H, m, CH 2 22 Example 2: 3-Phenoxy-l-azabicyclo 22,22]octane 3.82 g (0.03 mol) of 3-hydroxyquinuclidine, 2.82 g (0.03 mol) of phenol and 7.96 g (0.03 mol) of triphenylphosphine and 5.22 g (0.03 mol) of diethylazodicarboxylate are dissolved in 150 ml of absolute THF and stirred for 2 days at ambient temperature. The mixture is evaporated to dryness, the residue is taken up in 20 ml of 6N HC1 and 50 ml of H20 and extracted with ether. The aqueous phase is made alkaline and extracted with ethyl acetate, the combined ethyl acetate phases are dried and concentrated by evaporation. After distillation, 3.6 g of colourless oil are obtained (Bpo.l ,r 104-105"C).

C..

0 4 Bk..

O C 6

H,

i 25

C

COB.

too 0 a of 30 1 H-NMR (250 MHz, fDC1 3 TMS): 6=7.26; 6.87 (5H, m, aryl-H); 4.36 (1H, m, 3.34-2.63 (6H, m, CH 2 6, 2.19-1.27 (5H, m, CH-4); CH 2 5, 8).

The base is converted in an ethanolic solution into the fumarate, which is precipitated with ether and recrystallised from acetonitrile.

4.1 g of colourless crystals are obtained, m.p.

122-124*C.

23 Example 3: and (-)-3-(Proparqyloxymethyl)-1-azabicyclo- [22,2 2octane ±-(3-quinuclidinylmethyl)-acetate Racemic 3-quinuclidinylmethanol is prepared by methods known from the literature, e.g. using cyanohydrin synthesis from quinuclidin-3-one according to Helv. Chim. Acta 37, 1695 (1954) and acylated with acetylchloride and triethylamine in chloroform as solvent at ambient temperature, the racemic (3quinuclidinylmethyl)-acetate being obtained in an 82% 15 yield and with a boiling point of 130 to 134" at 30 mbar.

@000

S

OS

S

@0 0 000

S.

(-)-3-quinuclidinylmethanol *0 055

S

5S Si 20 26.5 g of (3-quinuclidinylmethyl)-±-acetate and 21.7 g of L-(+)-tartaric acid are heated to boiling in 275 ml of 95% ethanol; during the subsequent slow cooling, crystalline tartaric acid salt is obtained which is recrystallised from 95% ethanol about 5 times 25 until the angle of rotation is constant. The 13.5 g of salt thus obtained, with a rotational value 0- -16.93" (c 2, H 2 0) are stirred in 80 ml of 2N sodium hydroxide solution for 2 hours at ambient temperature, then 80 g of potash are added to the solution and the 30 mixture is worked up extractively with chloroform. In this way, with simultaneous ester saponification, 5.6 g of (-)-3-quinuclidinylmethanol are liberated as a light coloured oil with [a] 0 -66° (c 1, 2, in IN HCl).

Analytical checking of the enantiomeric purity was carried out after derivatisation with phenylisocyanate using HPLC on a chiracel-OD column and yielded an enantiomer distribution of 98.6% 1.4% 24 enantiomer.

(+)-3-quinuclidinylmethanol The accumulated mother liquors obtained during the production of (-)-3-quinuclidinylmethanol are evaporated down in vacuo. The residue is taken up in a little water, made alkaline with potash and extracted with chloroform. The resulting 19.5 g of optically enriched 3-quinuclidinyimethyl acetate are converted into the diastereomeric salt with 16.0 g of D-(+)-tartaric acid in 200 ml of 95% ethanol. After 5 recrystallisations from 95% ethanol, 12.7 g of salt are obtained, with a rotary value 16.8 (c 2, H20), from which 4.7 g 15 of (+)-3-quinuclidinylmethanol are liberated as a light coloured oil with +66.5" (c 1, in lN HCl), analogously to the (-)-enantiomer, using 75 ml of 2N sodium hydroxide solution.

After derivatisation with phenylisocyanate, the 20 enantiomeric purity was determined by HPLC on a chiracel-OD column with 97.4% 2.6% unantiomer.

a g 0 0 0 t 0S

S.

*SS

S.

5@5 3a: (+)-3-(Propargyloxymethyl)-l-azabicyclo[2,2,2]octane 5.6 g of (+)-3-quinuclidinylmethanolhydrochloride, 1.32 g of sodium borohydride and 100 ml of tetrahydrofuran are stirred overnight. The solvent is 30 removed from the filtrate, the residue is taken up in ethyl acetate and the resulting solution is washed with saturated saline solution. After drying and removal of the solvent, 3.4 g of (+)-3-quinuclidinylmethanol-boran complex remain in the form of a light coloured oil.

3.4 g of the boran complex are stirred in 100 ml of tetrahydrofuran for 30 minutes with 2.63 g of 60% sodium hydride at ambient temperature, then reacted with 4.89 g of 80% propargyl bromide and stirred for a further 6 25 hours. The reaction mixture is carefully decomposed with alcohol, the solvent is eliminated, the residue is taken up in 150 ml of ethylacetate, the solution is washed with saturated saline solution and the solvent is removed once more. In order to destroy the boran protecting group the residue is taken up in 50 ml of acetone and stirred overnight with 20 ml of 3N HC1.

After the acetone has evaporated off the aqueous phase is washed with ethy3acetate, made alkaline with potash and extracted with ethylacetate. The extraction residue is flash-chromatographed on silica gel using ethylacetate:methanol:NH 3 85:15:1 as eluant and yields 4.3 g of propargylether, which is converted in alcohol, with the calculated quantity of fumaric acid, into the o* 15 fumaric salt which is re-precipitated from alcohol-ether and is obtained in a 3.9 g yield with a melting point of 132-133'C and [a]2 0 28.47' (c 1, methanol).

•g.

S* 25 0.

o 3b: (-)-3-(Propargyloxymethyl)-l-azabicyclo[2,2,2]octane Analogously to 3a, the boran protecting group is introduced into (-)-3-quinuclidinylmethanol, etherification is carried out with propargyl bromide and after the boran protecting group has been split off the free base is converted into the fumarate, m.p. 132-133°C and [a]20= -28.42° (c 1, methanol).

OSSS

S

@505 OS S

S.

26 The following compounds of general formula I may be prepared by analogous methods of synthesis to those described in the Examples above.

TABLE I Compounds of formula Example

S

55.5

SC

S S a a

S

55.55.

S

S.

S

0*S 4.

S.

S..

-0 *2HC( 0 'N -0

N

236 (decomp,) 164 166 Fumarate 160 161 Fumarate

S

SSSS CS

S

55** S S S. S 55 *S S 5*5 5 -0-CH 2 135-136 Fumarate 5005 5 *S.w 55 S a a

S.

4a (+)Enantiomer

-O-CH

2 [aID= 27,5 (c 1, H120) 27 Example 4b (-)Enantiomer -O0-CH 2 a Go of* -0 -CH 2 (c 1, H 2 0) 110 (Decomp.) Fumar ate 110-112 Funarate 112-114 Furarate Go a 0.

-0-CH2

S

108-110 Fuma rate -0-0 122-1 2 4 Fumarate -28 Example 9a (+)-EnantiomerA 9b (-)-EnantiomerA [a1D 22.2 (c 2, 22. 9 (c 2, r

P

C

-0 CH3 147 149 Fumarate r r r -0 -0 CH2 CH(CH3)2 -0 0 0\ 11 -n-QcN CH3 SCH3 126 129 Fumarate A The reaction takes place with inversion.

29 Exampl~e lla ib -0 ~/CH

,H

>CH

3 -0 CH

,CH

3 CH3 -Enaritiomer -Enantiomer

S

5550

OS

S S 9 5

S

.555.5 5

S

S 055

S

*s* -0o

CH

3 Cl -0 125 126 Fumarate 147 149 Fumarate 5.55 0S 55 5

S.

5 55..

S

55 S S 55 14 -0

OCH

3 15 -0o 0 CH 3 16 N lo 128-13 1 Fumarate 30 Example 17 -0 N S

OH

3 18 S0

N

197-198 Fumarate @09 @6 .6 6O 0 0 6

S.*@S

6 *0 6 *0@

S.

6**

N

)CH 3

/-N

-CCHJ

-C -CH 2 N 91

S

*056 S. S S S 60

OH

3

N'

cUH 3 31 Example S SO

S

S. .5 5

S

Sea

-O-C

2 010 H I

CH

3

CH~

-0--CH 2 0 0 -CH0 -0-,CH 2 K 'N

N-N

CH3 so.500 b* 6* Se

-CH

2 -0-O 117 118 Fumarate 189 191 Fumarate 32 Example R*M..o N 158 -160

-CH

2 -O Fumarate 33a

S.

S S

S

SSSSOS

5

S.

S

555

S

555

S

555555

S

0O 0* S 55 S S 555 S S 6 eSee S. S 5~ S 33 TABLE II Compounds of formula Example R* 121-127 Fuma rate -o -CH C Come

S

me..

C. CS 0 0

C

0

S

0 em 0 S SO.

Sm

S.

**O

-O-CH

2

-CH=CH

2

-N

-0 x *see em..0 0 Go -0-0 -0-CH2-0

N-

0

N

114 16 Oxalate _S

N:

-N

34 TABLE III Compounds of formula Example R

P

N-Ja ~C endo -O-CH 2

CH

exo -0-CH 2

-C=ECH

121-124 Oxalate oil Oxalate ~0@

S

SOS.

*O SO 0 0 0 0 050000 0 0 .ee

SO

S..

.00.

-0-CHf C=CH 2

H

-0-OH -0mN

CH

3 93-95 Oxalate 5500 O 0 5505 00 S 05 TABLE IV Compounds of formula Examnpl e endo -0-CH 2

CH

148-149 Fumarate 49a exo -G-CH 2

CH

@0O~ *e %a a. a a 0* a.

0

*.S

exo

-O-CH

2

-CH:CH

2 147 148 Fumnarate 99-101 Fumarate 113-114 Fumarate 147-148 Fumarate 115-117 Fumarate endo CH 2

-CH=CH

2 0 4 goa a .00.* exo

-G-CH

2

-CH

3 51a endo O-CH 2 -CH3

-O-C

6

H

-O-CH

2

C

6

H

36 Example R

ND

540 &sees 37 TABLE V Compounds of formula Exp. R 56

-O-CH

2 -CH -CH 2 57 -O-CHf-CE-:CH ~'s 6. *8F Em eg g ~j

V

0 ewO~S d

'S

a ma.

OE

hEm

-O-C

6

H

N

-O-CH

2

C

6

H

O-CH

2

-CH

3

Claims

56651000.52 Claim L. COMIn 3-7ds of general -form.ula A\r wherein R~ represents a C 1 -alkyl group, a c-. 6 alkanyl group or a C.-alv grout), -the alkyl, alkenvil or alkcynv1 9--tou-p bei, opotionally substituted by a substitr-ixted IS oil, unstibs-.t ~ted zohen-yl group, a. sbstituited or wisubstituted binbhenyl g-rowo, a substituted or 'Unsubstituted oxetan ring or a substi.1tuted or see*. 'Uzsubstituted 6- or 7-membered S- or R raD ,esents a subsLtituted or urnsubst-itLtel phenyl *group, a substituted or unsuhstitutz4d biplenvl group or a substitutad or- unsubstit-uted. 6- or 7-memabered S- or Nbtroci group; x represents :Oxvgezl or sulphur; L B nd C independently of one a-notbher reoresent ca. or a single bond but A/3, A/C or B/C do not sinulta-neouslv re~oesent C. n represents 0, 1 or 2; andi all I acemic and tautorneric forms, enantiom.ers, diastereomers and mixturesj thereoff and acid addition sal-tL~ thereof and' addition-Lally th~e quatkeznarv salts tbhereozt; wi'tti th~e tbrviso that i) for a caouind. off 4 t 1 1 ormula 2: wherein the bicvclic 2rig system is cuinuclidine, R may nc.Q represeat am unsubstitutci.d al-kyl, alJcenyl or alicynyl group and th-'e group(E9-- m-ay not represent a 2-nhenoiy g-rou-p; ii) foL- omo ol formula i wherein the bicyclic ring syst-n is2- azabiacclor .3.2.l]octane or i-azabicyclo[2-2-1haptane, the grroup may not representl-- a C 1 3 -alkoxy- o= C 1 2 ,-alkoxy-cli- group; a-rd iii) ffor a compound of.L- formula Z: wterZein the bicyclic rin-.g system is l-azabicyclo- *C2.2.23octane, he gro7up may not represent". a *3 -(2-pvr idinv2.oxy)-gop 2. -Compounds of general fjormula Z: as claimed in claim 2. wb.rei X remrasents oxygen; n. represents 0 or 1; t-he substiuet Ris ini the or ,8-nosition relativ~e to the carbocyclic bridgehead; and R represeirts a Mori-substituted C 1 3 -alkyl, or an optionallyv mono- subst-itated C -alkenyl or tC- 4 -aFkyny.. group, a substi4tuted or irnxsabstitute&. phenyJ. group or a subs t1ituted or tznsubstit1uted 5- or -membara-d aromatic 3. Compounds or general formula 1 as claimed in claim-, 1 or claim 2 Wherein the ring system S* 4o selected from. a grotto comprising qiuldn,1 azbcca22.1aun.
2-azabicyclo[3.2. !]octane or lose -azabicyclk[3.3-11nona-ne; X rersnsoxygen; n repesets0 or 1; R rpeet oosbtttdC 3 aLtoyl, or an optionally mono-substit-uted C -alknlo -alknl rup sbsitu"ted or unsubs tituted pyridinie, thiphene, f-uran, pyri-midine, imidazole, pyrazole, 1,2, 4-triazole, oxetan, ttayrfuan prrolidine .r oxolan group, a substi--tuted or uriubsitudphneny2. group or a substituted or unstxbstit-uted benzvl group, t1he side chain n-X-P. being in, the 3-pt;ositian of the biaclic cgr-oilp and iz. the case ofj l--azabicyclo[3.2.1octane 40 optionally in the 6-pc sition. 4. Compounds as claimed in any of claims 1 to 3 of general formula CH-O- n wherein n represents 0 or 1; R represents a group of formula Ose a 0 00 0055 s S.0 -CH 2 (Ri -CH 2 (RI -CH 2 2(R FO -CH2fsl 2 1 KN (R 1) k (Rj)k Cur R 2)1 (R 2 )1 0 SeeS S. 0 SO S. S *0 SOS S 0050 S 0005 30 0* NN R p
3 NN C H C 2 1 R 3 41 C H 2 _C,(R 0 -CH 2 0 i"O (RP2 1 1 C 15 C. C S S 0 0 *4' em 0** 6@ 0eS -CH 2 N R 3 -CH 2 fY P) 2 ON (p 2 )A N R 3 -tN in which *000 0S S Ri represents a hydrogen atom, a C 1 4 -alkyl group, a C 14 -alkoxy group, an amino,C C 1 4 -akylamino, C 14 dialkylamino, hydroxy or C 3 6 -cycloalkyl group, a substituted or unsubstituted phenyl group or a keto-funct ion; k represents 1, 2 or 3, whilst if k is greater than 1 the R, groups may be identical or different, R 2 represents a hydrogen or halogen atom, a C 1 4 -alkyl group, a C 1 4 -alkoxy group or a keto-function; 1 represents 1 or whilst when 1 repres;ents 2 the groups R 2 may be identical or different; R 3 represents a hydrogen atom or a C 1 4 -alkyl group; and all racemic and tautomeric forms, enantiomers, diastereomers and mixtures thereof and acid addition salts thereof and additionally the 42 quaternary salts thereof. Compounds as claimed in any one of claims 1 to 3 of general formula (CH,29- 0-PR beef a 00 0*00 *06 (CH9)- 0- R n wherein n~ represents 0 or 1; 20 R represents a C 3 -alkynyl group, a C 3 -alkenyl group, or a group of formula -CH 2 R~ 0.. -CH 2 (R NJ -CH (2) 2~ S _rX(P" 2 '1 43 -C H (~$Z~RA (R 2 )I N,,,N in which R 1 R 2 k and 1 are as defined in claim 4; and all racemic and tautomeric forms, enantiomers, diastereomers and mixtures thereof and acid addition salts thereof and additionally the quaternary salts thereof. 6. Compounds as claimed in any one of claims 1 to 3 of general formula eq 0 &*60 0S .0 a 0 I a 0 a' S *0. 0S 0@ S@* (C H2)n 0 FR where in n represents 0 or 1; too 0 R represents a C 3 -alkynyl group, a C 3 -alkenyl group, or a 25 methyl, ethyl or propyl group, or a group of formula -CH 2 (R)k N MiP~lk KN,, I wherein k 'and L are a~s defined in Claim 4; and all racamic and tailtomeric forms, enan.it-iomers diastareomers and mixtures thereof and thle acid addition salts thereofI and additionally Ithe auaterna--7 salts 7. Compound~s of qeneral -for-mula Th or To, (CHzl2j-:i.P goo 25 wherein Ri rersents ausbtuedC alvC_- *0 alkenyl or C,---al]<YTnYL oU;X'rpantsaoxgo- suilphur atoma; and, M rsprssents 0 I or 2 R" represent-s a 3-(2-Myridlinyloxv) groap or a 2-phenoxy group and pRit rerresen. a C alko or a C 1 ,-alkoxy-Ci-gru; n ~~-lazaicylo~22.lhepane(wherein R Zis as de-fined abova); in the torm of iiifivid-ua enantiomers, and acid addition salts thereo~f and additionally the ruaternary. salts thereolf, collecti-Vely termed the caoounds of formula Td; 1with the i:roviso that in the compounds; of formula, Ta wherein XI reprezaents oxygen and m. repre.zents 0, cannot represent a C-ailkynyl group or an ethyl group. 45 a. -(ropargYlOXYniethVl) -l-aZabicvclOC2, 2, octarne and acid addition salts thereof and additionally the quaternar! salts thersof. 9. Conocunds as claimed in anyv one of the _ozecedina claims as herein speciffically disclosed in. any one of the Examples. o rocess for the vreparati on of comnounds- of :0genera forula T, as claimed, in, any one. of claims I toa 6 and 9 wherein R. rearesearts an alipbtatic grou-p, ch.acteriseo. in that a comtpound 6f general formula (CH) H n 7' *Whereill A, B, C, n. and X are as defined La clam= I and Z represents a protecting g-roup (Whiere X=S the protecti-rg group Z cani be omitteC-d) is deprotonated, and reacted w~ith an alkylating reagent of the formula p wherein R re-oresentS an aliphatic grou.p as indic ed in -clai-m and Y represznt s a raadilv removable leav-,ing S0group, the porotecting gr-oup is then cleaved and, if desired, the compo~und thereby obtained is converted in~to an acid additioin salt or a qatErnaxy salt thereof and/or, if desirad, separ-ated into the Optically active isomers thereof by aiown methods. 11. M roCeSS aSLc~ai.Med in claim 10 wherei the deprotonat.Lon is effected by means of a stCrong base, th~e I' I r -46 reaction being ef-fectMed izi a polar inert organic solvent. 12. process as claimed in claim. 11 wherein the strong base is selected from sodi= h~ydride, sodium amide and alkali maetal alkoxides and th~e solvent is Selected from dimethyJ-fformamide, tetrehydro fuiran and dioxan 12 n rocess for the preparation of compounds Of general fornala I as claimied in any one ofj.- c.aims 1 to 6 and 9, w'herain R represents an aromnatL-ic or a heteaocvclic 9-roup, charzacterised in tha-t a comp~ound of tte formula is (C H;J-X- H A -N wherein A, 13, C, n and X are as defined in claim, 1, is reacted w~.ith a compound of formula HOR (in "aIich R renresents an aromatic or h~eterocyclic group~ as Indicated i claim in the presence of tripbhenyl- 0.."25 phosphine. and alkylazodicarboxylate. 14. A process for the preparation of compounds of ,irz-l 1d, as--6ie nc frmua I as erico.~.nc2.aim 7 wherein the -corresipondingc racemate is resolved using an opICicallv active salt by a knoa-n method. A process as claimed in any of claims 10 to 2.4 subszantia2.ly, as hereLnbefore described wIth reference to the Exampoles. 16. Coinnounds as cLaimed in any one, of claims J_ to 9 whenever prepared'by a process as claimed in any one of 47 Ilaims 1to14. 17. PharmaceUtical compositions comprising as active ingredient atL least one compound of formula T- or Zd, claimed in claim 21 or claim ,j or a physiologically acceltatboe acid addition salt t-hereof in association with one or more pharmaceutically acceptable carriers, diluents or excipients. 18. Comvposilions as claimed in claim 217 zubstantially as hereina defined and with reference to the Examples. 19. Compounds oif general formula, 1 or Id as claimed i-a claim I or claim 7 for use in therapy. A method of treatment of diseases or conditions in Oseo a subj ect whlich arise froim the reduced function of the cholinergic system which comprises admainistering' to said subject an effective amounit of a compound of formula i or Id, as claimed in claim 1; or clai-m 7, or an eff active too* :0 amount of a compound of formula Thb or 1c a.-4 deffined int claimu 7 and all racetaic f'orms, d-iastereomers and m.i-,tures thereof and nhvsiolbgically acceptable acid addition salts thereof and additionally the cgnaternary fe. salts thereof. 21. A method as claimed in claim, 20 wherein the disease -or condition is A-lzbeirners disease, senile dementia, a cognitive disorder, glaucoma or reduce,, memory promne DATED this 13th day of December, 1993 BOEHRINGER INGELHEIM INTERNATIONAL GMBH By their Patent Attorneys: CALLINAN LAWRIE Ile4$ Abstract The invention relates to bicyclic 1-aza- cycloalkanes, processes for preparing them and their use as pharmaceutical compositions with cholinomimetic properties. off