IE57089B1 - Carbo-and hetero-bycyclic carboxylic acid azabicycloalkyl esters or amides - Google Patents

Abstract

Novel cpds. (I) which are di-carbocyclic or heterocyclic carboxylic acid esters of a piperidinol or corresp. amide contg. an alkylene bridge or esters or amides of a substd. benzoic acid and a piperidinol or piperidyl amine contg. an alkylene bridge have the following structural characteristics (a) each benzoic acid ester which possesses an alkylene bridge between 2C atoms of the piperidyl ring is substd. in the Ph ring in at least one of the ortho or meta positions; (b) in each benzoic acid ester which is unsubstd. in both ortho-positions of the Ph ring or which is substd. by halogen or alkyl in at least one of the ortho-positions but possesses only H or halogen in meta- and para-positions and which possesses an alkylene bridge between 2-ring C of the piperidyl ring, this alkylene bridge contains at least 3C; (c) in each benzoic acid ester which contains an oxy gp. and which possesses an alkylene bridge between the N atom of the piperidyl ring and a ring C atom, there is at least one substituent other than oxy or only 2 oxy substituents in the benzoic acid nucleus; (d) in each mono-cyclic or heterocyclic carboxylic acid amide or ester in which the heterocycle is a 6-membered ring, or in each cyclic hetero-cyclic carboxylic acid amide in which the heterocycle contains 2 O atoms, there is an alkylene bridge in the piperidyl ring between a piperidyl N-atom and a piperidyl C atom; (e) in each benzoic acid amide, the alkylene bridge of the piperidyl ring is attached to a ring C and the ring N; (f) in no benzoic acid amide is there an alkyl, OH or halogen substit. in the ortho-position; (g) thienoyl and naphthoyl-8-aza-bicyclo (3,2,1) oct-3-yl esters are excluded. The salts of these cpds., e.g. their acid addn. salts and quat. ammonium salts e.g. of the N atom of the piperidyl ring are also new.

Description

The present invention provides a process for the production of a compound of formula I A-CO-B-D I wherein A is a group of formula II - 2 X is -CH2-f -NR3-, -0-, or -SRi and R2 independently are hydrogen, halogen, (Οχ- )-alkyl, (Cx^Jalkoxy, hydroxy, amino, (Ci_4)alkyl-.imino, di(Cx-4)alkylamino, mercapto or (Cx_«)alkyl-thio, R3 is hydrogen, (Ci_<)alkyl, (C3_5)alkenyl, aryl or ar(Cx_4)alkyl wherein the aryl moiety is unsubstituted phenyl or phenyl mono- or poly-substituted by (C1_4)alkyl, halogenrhydroxy or (Ci.4)alkoxy, or B is -0- or -NH-, and D is a group of formula IV wherein n is 2,3 or 4 Rs is hydrogen, (Cx_7)alkyl, (C3.5)alkenyl, or ar(Cx„«,alkyl. wherein the aryl raoiety 1$ unsubstituted phenyl or phenyl mono- or poly-substituted by (Ci_s)alic.ylP halogen, hydroxy or (Ci.<)alkoxyP or D is a group of formula V which in a) condensing an appropriate compound of formula VI A-C0-0H VI wherein A is as defined above, or a reactive derivative thereof, or a precursor of the acid or derivative, with an appropriate compound of formula VXI - 3 HB-D VII wherein B and D are as defined above, or a precursor of the compound, or b) alkylating a compound of formula I having a secondary amino group to produce a compound of formula I with a tertiary amino group, c) deprotecting any protected form of a compound of formula I to obtain a compound of formula I 2 is hydrogen to obtain the corresponding compound wherein Rj is halogen, and e) alkoxylating a compound of formula I wherein A is a group of formula II and R2 is halogen to obtain the corresponding compound wherein Rj is alkoxy, and recovering the resultant compound of formula I as such or as an acid addition salt or as a quaternary ammonium salt thereof.

Any alkyl moii ty preferably is methyl, ethyl or propyl. Alkoxy is preferably methoxy or ethoxy. Aralkyl is aryl (Cj-4)-alkyl.

Alkenyl is preferably allyl or methallyl.

Any aryl moieiy is unsubstituted phenyl or phenyl mono- or poly-substituied by (Cp^) alkyl, e.g. methyl, halogen, e.g. fluorine, hydioxy, or (Cj-4) alkoxy, e.g. methoxy. Preferably any substituted atyl group is mono-substituted. Aralkyl is conveniently benzyl. Halogen is fluorine, chlorine, bromine or iodine.

In the group of formula II, the carbonyl side chain may be attached to the ring carbon atom in positions 2,3,4,5,6 or 7 of the nucleus, but preferably in position 4 and 5. Most preferably the carbonyl group is attached to the ring containing X especially in position 3. Preferably A is indole.

Rj is attached to the ring carbon atom in position 4,5,6 or 7 of the nucleus, preferably position 5 and Rg attached to the ring carbon atom in position 2 or 3 of the nucleus. Tautomers are also covered by formula I e.g. when R^ 1S hydroxy or mercapto in the 2 position.

• R^ is conveniently hydrogen or alkyl. Conveniently n is 3 or 4, more preferably 3.

The group IV may exist in different conformations. For example the six-membered ring containing the nitrogen atom and the carbon atom to which the 8-moiety is attached-hereinafter referred to as the piperidyl ring - may exist in the chair or boat conformations or in an intermediate conformation.

The moiety B may have two different configurations. These can be appreciated by making group IV have a conformation wherein a reference plane may be drawn through the carbon atoms of the piperidyl ring and the nitrogen atom is above the plane and the alkylene bridge is below the plane. The B moiety has the £< configuration when it is below the plane on the same side as the alkylene bridge. This corresponds to the endo configuration and also to the configuration in tropine etc. The B moiety has the ^-configuration when if is above the plane on the seme side as the nitrogen bridge. This corresponds to the exo configuration and also the configurafion in pseudotropine etc. Used hereinafter is the exo/endo nomenclature. The endo isomers are preferred.

Rg is preferably alkyl and especially methyl.

A group of formula V is also known as quinuclidinyl. Conveniently this is 3or 4- quinuclidinyl and especially 3-quinuclidinyl. - 5 A group of compounds comprises compounds of formula Iqa wherein the free valence is attached to either fused ring, and n* is 2 or 3B and Ri, R2. r3 and r8 are as defined above, as well as acid addition salts and quaternary ammonium salts thereof.

Another group of compounds comprises indole carboxylic acid tropine and isopelletierine (homotropane) esters, particularly of formula iqb wherein the free valence 1s attached to either fused ring* and Rjqb and R^qb are Independently hydrogen* halogen or (Ci.^alkyl* Rgqb is hydrogen or (C^)alkyl 3 Rgqb 1s hydrogen or (0χ_7)alkyl or aralkyl, and n1 Is as defined abovep as well as acid addition salts and quaternary ammonium salts thereof. - 6 A further group of compounds comprises indole carboxylic acid tropine and isopelletierine (homotropane) amides, in particular of formula Iqc 1C wherein the free valence is attached to either fused ring, and R2qc is as R2 defined above other than (Ci-a)alkoxy and hydroxy and, n*D Pj, R3, Re are as defined above, as well as add addition salts and quaternary ammonium salts thereof.

The present invention furthermore provides a process for the production of a compound of a invention which includes the step of condnnsing an appropriate di-carbocyclic or heterocyclic carboxyilic acid or benzoic acid or a reactive acid derivative thereof, or a precursor of the acid or derivative,, with an appropriate alkylene bridged piperidyl amine or piperidinol, or a precursor thereof, and as necessary converting the resultant piperidyl ester or amide, or acid addition salt or quaternary ammonium salt thereof into the required piperidyl ester or amide or acid addition salt or quaternary ammonium salt thereof and recovering the resultant piperidyl ester or amide as such or as an acid addition salt or as a quaternary ammonium salt thereof. - 7 The present invention provides a process for the production for a compound of formula I as well as acid addition salts thereof or quaternary ammonium salts thereof which includes the step of a) condensing an appropriate compound of formula VI A-CO-OH VI wherein A is as deiined above, a reactive derivative thereof, or a precursor of the acid or derivative, with an appropriate compound of formula Vii HB-D Vii wherein B and D are as defined above, or a precursor of the compound, or b) alkylating a compound of formula I having a secondary amino group to produce a compound of formula I with a tertiary amino group, c) deprotecting any protected form of a compound of formula I to obtain a compound of formula I, - 8 f·· d) halogenating a compound of formula I wherein A 1s a group of formula II and R;> Is hydrogen to obtain the corresponding compound wherein Rg 1s halogen, or 15 e) alkoxylating a compound of formula I wherein A is a group of formula II and Rg is halogen to obtain the corresponding compound wherein Rg Is alkoxy, and recovering the resultant compound of formula I as such or as an on acid addition salt or as a quaternary ammonium salt thereof.

The condensation process of the invention to obtain amides and *, 25 10 esters may be effected in conventional manner for analogous compounds.

For example the carboxylic acid group may be activated In the form of a reactive acid derivative, especially for the production of snides.

Suitable reactive acid derivatives may be formed by reaction with SM'-carbonyl-diimidazole producing an intermediate carboxylic acid imidazolide, or with M~hydroxySucc1niraidee Alternatively an acid chloride may be used, e.g. produced by reaction with oxalyl chloride. - 9 For production of esters, the alcohol may be used e.g.in the form of an alkali metal salt, preferably the lithium salt. Such salts may be produced in conventional mannerp e.g. by reaction of a n-butyl lithium with the alcohol in tetrahydrofuran.

If desired a heterocyclic or tertiary amine, e.g. pyridine or triethylamine, may be present, especially for the production of 5 amides.

Suitable reaction temperatures may be from about -10* to about *.In the case of compounds wherein B is HH and 0 is a group of formula V the reaction temperature may be for example up to about 100* Ca e.g. in boiling methanol or ethanol.

Other suitable inert organic solvents include, e.g. tetrahydrofuran or dimethoxyethane.

» In these reactions fhe endo or exo configuration of the substituent B in the group of formula IV is believed to be maintained, fhe compound of formula VII may be reacted if desired as a mixture of endo and exo isomers and the pure endo or exo isomer isolated, e.g. by chromatography or crvstallization.

The compounds of the Invention may be converted into other compounds of fhe invention,, e.g. in conventional manner. Some interconversions are exemplified in processes b)(1 c)p d) and e).

The alkylation reaction of process b) may be effected in conventional manner. Any free amino group may be alkylatedQ especially compounds of formula II wherein X = NH. Appropriate alkylation conditions Include reaction with an alkyl halide in fhe presence of a sodium alcoholate. Suitable temperatures may be from about -50e to about -30*C. - 10 The deprotection reaction of process c) is specifically suitable for the production of compounds with secondary amino groups, e.g- Rg = H in the group of formula IV or primary amino groups, e.g. Rg c NH2.

For example a compound of formula I may be produced In protected form, e.g. Rg being replaced by a secondary amino protecting group such as benzyl.

The benzyl group may be split off in conventional manner, e.g. by hydrogenation to produce the corresponding compound of formula Ϊ wherein Rs is hydrogen.

Suitably the hydrogenation may be effected in the presence of a palladium on active charcoal at room temperature or at a slightly elevated temperature. Suitable solvents include acetic acid, ethyl acetate or ethanol.

A primary amino group as Rg may be protected by e.g.

N-benzyloxycarbonyl. This group may be split off by hydrogenation analogously to that indicated above. In the presence of a benzyl group the M-benzyloxycarbonyl group is generally split off first so that this group may be selectively split off.

Also the amino group may be obtained frsm a nitro group. This can be selectively reduced in conventional manner, e.g. by iron In hydrochloric acid. - 11 Halogenation according to process d) may be effected in conventional manner. For example with ^-chloro-succinimide may lead to chlorination. Such reactions may be effected in a suspension in chloroform. Reaction with N-iodo-succinimide may alternatively lead to iodination.

Replacement of reactive halogen groups according to process e) may be effected in conventional manner e.g. by reaction with a appropriate alcohol at e.g. room temperature from 10 to 20 hours at least.

A precursor of a starting material may be employed if desired, i Such a precursor may be capable of being converted into the starting material in conventional manner but instead the process of the invention is carried out with the precursor and the other starting material or materials or a precursor thereof. The resultant product is converted into the compound of the invention in conventional manner^ e.g. by using the same reaction conditions by which the precursor may be converted into the starting material. Typical precursors include protected forms of a starting material, e.g. wherein amino groups are temporarily protected.

The compounds of the invention may be Isolated and purified in conventional manner. - 12 Insofar as the production of any starting material is not particularly described herein, it is known, or may be produced in analogous manner to known compounds, in analogous manner to that described herein, e.g. the examples, or to known procedures for analogous compounds.

Compounds of formula VII wherein B is -NH-fD is a group of formula IV wherein n is 4 are new.

The compounds are useful intermediates e.g. for the preparation of amides as described herein which have an interesting pharmacological profile and e.g. have never been disclosed as Serotonin 14 antagonists and having other activities disclosed hereinafter.

These compounds of formula VII may for example be produced by reduction of the corresponding oxime, like the other compounds of formula VII wherein B is 41H-. Compounds of formula VII wherein B is -0- may be produced in conventional manner by reduction of the corresponding ketone.

All the above reductions may be effected, e.g. by catalytic hydrogenation, e.g. over platinum (believed to lead primarily to endo isomers), Bouveault-Blanc reaction procedures, e.g. sodium/amyl alcohol or butanol (believed to lead primarily to exo isomers), or aluminium hydride procedures, or sodium borohydride (often leading to mixture of endo/exo isomers).

Any mixture of the exo and endo forms may be separated by chromatography. - 13 Free base forms of compounds of the invention may be converted into salt forms. For example acid addition salts may be produced in conventional manner by reacting with a suitable acid6 and vice versa. Suitable acids for salt formation include hydrochloric acida malonic acids hydrobromic acid, maleic acidp malic acid, fumaric acid* methanesulphonic acid, oxalic acid, and tartaric acid. Quaternary ammonium salts of the compounds of the invention may be produced in conventional manner,, e.g. by reaction with methyl iodide.

In the following examples all temperatures are in degrees Centigrade and are uncorrected. All n.m.r.spectra values are in ppm (tetramethylsilane B 0 ppm).

Nomenclature i IN. ·!!.« .1 .1 « »» 1 Endo-8Hnethyl-8-aza-b1cyclo[3,2el]oct"3-y1 = tropyl or a-tropyl Exo-8-methyl-8-aza-bicyclo[3.2.1]oct~3-yl s pseudo- or β-tropyl Endo-9-methy1-9-aza-bicyclo[3,3el]non~3-yl - isopelletierinyl or cs-homo-tropanyl Exo-9-methyl-9-aza»bicyclo[3.3.1]non-3-yl - β-isopelletierinyl or β-homo-tropanyl or pseudopelletierinyl l-aza-bicyclo[2.2.2]octyl = quinuclidinyl The configurations of the title compounds of Example A-2; A-3; and 8-6 have been confirmed by x-ray analysis. The configuration of the remaining compounds is believed to follow that of the starting materials of formula VII which were used pure6 except where otherwise stated. - 14 In the tables the columns heading "configuration" gives the indicated configuration of the group B-0P i.e. endo or exo. The column heading "Prep" gives the number of the Example in the A series describing the preparation process.

Abbreviations: 1) hydrogen maleate 2) hydrogen malonate decomposition 4) bis [base] fumarite ) obtained by reduction of corresponding 4-nitro compound hydrobromide via Imldazolyl intermediate exo form has C-3 H broad multiplet at ca 5.15 ppm 1n HllLM.R. - endo form has C-3 H double triplet at 5.1 ppm. Exo alcohol is j eluted before endo isomer on silica gel-eluant CH2Cl2^ CH3OH/5» NH4OH 9) hydrogen oxalate ^°)in presence of triethylamine instead of pyridine EXAMPLE A-l: H-(endo-9-methy1-9-aza-b1cyclo[3.3.llnon-3-y1) indol-3-yl carboxylic acid amide also called N-(3oc-homQtropanyI )-1ndoI-3-yl carboxylic acid amide (process a) {compound of formula I wherein A = ϊ I in 3 position; Rj = R* H; X - WH; B K NH; 0 * IV-α configuration; n ~ 3; R$ = CH3) - 15 a) Indol-3-yl carboxylic acid chloride 32.2 g (0,2 M) dry 1ndol-3-yl carboxylic acid are suspended in 150 ml absolute methylene chloride. 26 ml (0.3 M) oxalyl chloridei are added to the stirred mixture at 20*C over 30 minutes. Gas evolution results. The mixture is stirred for 3 1/2 hours at 20C. 150 ml Hexane are added. The mixture is stirred for another 20 minutes and the resultant heading compound filtered offGwashed with methylene chloride/hexane 1:1 dried at 20’ in a vacuum to 1Ό give beige crystals, M.pt. 135-136e (decomp) which are used further without purification. b) 9-methyl-9-aza-b1cyc1o[3.3.l· ]nonan-3-one oxime (also called 15 3-homqtropanone oxime) 176 g (2.15 M) sodium acetate and 150 g (2.15 Mol) hydroxylamine hydrochloride are pounded in a mortar to a thin paste, extracted with 1 litre methanol» the salt filtered off and the solution treated with 99.5 g(0.65 M) endo-9-methyl-9aza-b1cyclo[3.3.l]nonan-3-one (3-homotropane). The oxime begins to crystallize after 10 minutes and the mixture is stirred for another 4 hours at 20*C. To work up the mixture is concentrated under a vacuum, the residue treated with potassium hydrogen carbonate solution and extracted with chloroform containing some isopropanol. The combined organic phases are washed with a I1ttl« water, dried with sodium sulphate and concentrated to give the heading compound. M.pt. 126-127* (from toluene/hexane). . c) Endo-9-methyl-9-aza-b1cyc1o[3.3.l]non-3yl amine (also called jg-amino-homotropane) A solution of 50.5 ml (0.95 M) concentrated sulphuric acid in 200 ail absolute tetrahydrofuran are added to a cooled and stirred mixture of 73 g (1„9 M) lithium aluminium hydride in 900 ml absolute tetrahydrofuran at -10*0 within 2 hours. The mixture is allowed to stand overnight. A solution of 80 g (0.475 M) endo-9-methyl-9-aza-b1cycloC3e3.l]nonan-3-one oxime in 1.4 litres absolute tetrahydrofuran 1s added dropwise over 30 minutes to the stirred mixture at 30" and allowed to react further at 401 for 3 - 16 hours. Io work up the reaction mixture is cooled to 10° and a mixture of 150 ml water in 150 ml tetrahydrofuran is added carefully. The mixture is stirred for an hour at 30°C. The resultant precipitate is filtered off. The residue is washed with methylene chloride and ether. The organic phases are combined and distilled to give the heading compound b.pt. 115-119°. (17-18 Torr) - n20 = 1.5066.

D (As will be appreciated the reduction gives mainly the endo product. Analogous reduction of 8-methyl-8-aza-bicyclo[3.2.1]-octan-3-one oxime gives the exo product. d) ^-(endo-9-methvl-9-aza-bicvc1or3.3.11non-3-y1) indo-3-yl carboxylic acid amide A solution of 15.4 g (0.1 £4) endo-9~methyl-9-aza-bicyclo-[3.3.1]non-3-yl amine in 50 ml absolute pyridine is added dropwise to a stirred suspension of 14.5 g (0.08 M) indol-3-yl carboxylic acid chloride (produced in step a) in 50 ml absolute methylene chloride at -10° C to 0° C.

The resultant yellow suspension is warmed to 20° and stirred overnight. To work up 21^ aqueous sodium carbonate is added. The mixture is extracted several times with methylene chloride and worked up in conventional manner. The title compound is obtained after crystallisation three times, R.pt. 247-249° (decomp.). - 1'/ EXAMPLE A-2: Indol-3~yl carboxylic acid endo-8-niethy1-8-azabicyylo[3._2.l]oct-3~yl ester (process a) (Compound-of formula Ϊ wherein A "II in 3 position; Ri=R2aH; X = NH;B=O;D - IV in a configuration; n - 2; Rg- CH3) 6.35 g (45 mM) endo-8-methyl-8-aza-bicyclot3.2.1]octan-3-ol (Tropine) in 20 ml absolute tetrahydrofuran are treated at Cf to 10m with 17 ml of a 2 molar solution of butyl lithium in hexane. The mixture is stirred for a further 30 minutes. The hexane is removed under a vacuum and replaced by a corresponding amount of lV ZeZrahydrofuran to give the lithium salt. 4.8 g (27 mM) of indol-3-yl carboxylic acid chloride in 20 ml \ tetrahydrofuran are added to the mixture and the beige suspension stirred overnight at 20C. The mixture is worked up in the usual manner partitioning between methylene chloride and sodium carbonate to give the heading compound in crude form which is chromatographed on silicagel (250 g) eluting the heading compound with methylene chloride containing 10£ methanol and 0.5* ammonia. M.pt. 201-202* (methylene chloride/ethyl acetate).

M.pt. 283-285* {decomp.) - hydrochloride salt. Methoiodide 285-287* (decomposition).

Alternatively 1ndol-3-yl carboxylic acid chloride may be reacted * with N,N*-carbonyl di-imidazole to form the imidazolide. This may be reacted with the above lithium salt at 10 to 15*° in tetrahydrofuran. - 18 -/ EXAMPLE A-3: j. methyl-N-(endo-9-inethyl-9-aza-b1c,yclo[ 3,3. llnon3-yl) lndoi-3-yl carboxylic acid amide also called 1-methyl-N-(3a-homotropany1)- indol-3-yl carboxylic acid amide (process b) (compound of formula I wherein A = II in 3 position; Rl « R2=H; X " NCH3;B = NH; D « IV in a configuration^ = 3; Rq s ch3). 0.46 g (20 wM) sodium dissolved in 170 ml dry liquid ammonia at -δΟ" a^e treated dropwise with 1.3 ml (22.5 mM) absolute ethanol diluted with some absolute ether. The resultant colourless suspension of sodium ethanol ate is stirred for 16 minutes at «50*. 4.46 g (15 mM) ^-(endo-9-methyl-9-aza-bicyc1o-[3.3.1]non-.3-yl) lndol-3-yl carboxylic acid amide are added giving a clear solution. The mixture is stirred for 10 minutes at -SO'1’ and 1.25 ml (20 mM) methyl iodide in 4 ml absolute ether is added.

The mixture, is stirred at -50® for a further 4 1/2 hours. To work up the ammonia is removed in a vacuum. The residue is partitioned between methylene chloride and water and worked up in the usual manner to give a colourless foam which Is chromatographed on 120 g silicagel eluting with methylene chloride containing 5£ methanol/3% ammonia the heading compound.from the acid; M.pt. 210-212° (recrystallised from ethyl acetate/methanol). M.pt. 295-297° (decomp.) - hydrochloride salt.

The compound may alternatively be produced in analogous manner to Example 1 starting from l-methyl-indol-3-yl carboxylic acid. - 19 EXAMPLE A-4: 5-fluoro-l-methyl-1ndo1-3-yl carboxylic acidendo-9-azabicyclof3.3.1]non-3-yl ester also called (N-desmethyl -3g-hpmotr_opanyl )-5-f 1 uoro-1methyl-indol-3-yl carboxylic acid ester (process c) (compound of formula I; A-II in 3 position; Rj * 5-F; R2= H; X= NCH3; B = -0-; D - IV in a configuration; n 3; Rfi = H) 4.9 g of 5-fluoro-l-methyl-indol-3-yl carboxylic acid endo-9benzyl-9-aza-bicyclo[3.3.1] non-3-yl ester in 200 ml ethanol are hydrogenated at room temperature and normal pressure in the presence of 1.5 g (10«) palladium on active charcoal catalyst. After 45 minutes the uptake of ca 230 ml hydrogen is finished and the catalyst filtered off. The solvent is removed in a vacuum to, give a crystalline residue of the title compound. M.pt. 130-131’ (recrystallised from ethanol/1ittle hexane).

EXAMPLE A-5: 2-methoxy"1ndol-3-y1 carboxylic acid (endo-8-methyl-8~azabicyclo[3.2.1]oct-3-yl) ester also called 2_"_methoxy-indo1-3*yl carboxylic acid tropyl ester (processes d and e) (Compound of formula I A - II in 3 position; Rj c H; R? = 2-0CH3, X = HH; B = 0; D = IV in a configuration; n = 2; Rg= CH3) • 20 5.68 g (20 mM) ir.dol-3-yl carboxylic acid endo-8-methyl-8-azabicyc1ot3.2.1]oci-3-yl ester is added to a stirred suspension of 4 g (30 mM) N-chloro-succinirnlde in 80 ml absolute chloroform at 20. The mixture is stirred for 3 hours at 20’ to give 2-chloro5 indol-3-yl carboxylic acid (endo-8-methyl-8-aza-bicycloL3.2.1]oct-3-yl) ester in a clear yellow solution.

The clear yellow solution is treated with 10 ml absolute methanol and allowed to stand overnight. Usual working up by partitioning the mixture between IN aqueous sodium carbonate and methylene chloride gave a crude product which is chromatographed on silicagel (30 fold amount) eluting with methylene chloride containing 10% methanol and Oe5% ammonia the title compound, M.pt. 204 to 206" (from ethanol). - 21 EXAMPLE A-6: 3-io_do-1ndolr4-yl carboxylic acid _end_o~>Rfjgthyl-6-aza-bicyc1,o[3.2,l]oct-3-y1 ester (compound of formula 1 wherein A * II in 4 position, R^ = H; Rg c 3-1; X = NH; B = -0-; D = IV in a configuration; n = 2; Rg = CH3) (process d) A solution of 2.84 g (10 mM) indol-4-yl carboxylic acid endo-8methyl-8~aza-bicyclo[3„2.1]oct-3-yl ester is added dropwise at 15° to a stirred suspension of 2W48 g (11 mM) N-iodo-succinimid : in 200 ml absolute chloroform. The mixture is stirred for a further 30 minutes at 20’. Partitioning between IN sodium carbonate solution and methylene chloride and usual working up gives the heading compound 163-165* (decomp) (from ethanol). Although the compound may be produced from 3-iodo-1ndol-4-yl carboxylic acid in analogous manner to that disclosed in Example 2.

EXAMPLE A-7 : Indol-4-yl carboxylic acid endo-8-methyl-8-a?abicyclo[3.2.1]oct-3-yl esteralsocalied Indol20 4-yl carboxylic acid tropylester (Compound of formula I A =11 in 4 position;Ri= Rg* H; R3 - NH; B 0; 0 = IV in a configuration; n-2; Rg = CH3) g (50mM) endo-8-methyl-8-aza-bicyclo[3.2..1]octan-3-ol (tropine in 15 ml absolute tetrahydrofuran is treated at 10 to 15* dropwise with 20 ml (40 mM) of 2 Molar Butyl lithium in hexane.

The mixture is stirred for 30 minutes at 20\ and then concentrated to a volume of about 10 ml to remove the hexane to 30 give the lithium enolate. 10 ml tetrahydrofuran is added. - 22 4.8 g (30 mM) dry indol-4-yl carboxylic acid in 15 ml absolute tetrahydrofuran is treated portionwise with 5.85 g (36 mM) N9N’~carbonil-diimidazole. The mixture is allowed to stand for 90 minutes at 20* and then is added dropwise to the lithium enolate. The resultant suspension is stirred overnight at 20*Ce and partitioned between methylene chloride/a little Isopropanol and 1H sodium carbonate. The organic phases are washed and dried over sodium sulphate to give on evaporation the heading compound.

M.pt. 220-222" (decomp) (from ethanol).

EXAMPLE A-8s Indpl-4-yl carboxylic acid endo-9-methy1-9-azabicyc1o[3.3.1jnon-3-y1 ester also called 3a-homotropanyl indol-4-yl, carboxylic ester (Compound of fonnula I A=II in 4 position; X = NH;.Ri~ R2 c H; R3 = NH; B = 0; 0=IV in a conf iguration; n = 3; P^- CH3) (process a) a) 7.65 g (50 mM) endo-9-methyl-9-aza-bicyclo[3.3.1]nonan-3-ol in 15 ml absolute tetrahydrofuran are treated dropwise at 10 to ’ with 20 ml (40 mM) 2 Molar Butyl lithium hexane solution. The resultant mixture is stirred for 30 minutes at 20*. The hexane is then evaporated and replaced by tetrahydrofuran to give a solution of the lithium salt. b) 4.8 g (30 mM) dry indol-4-yl Carboxylic acid in 15 ml absolute tetrahydrofuran is treated portionwise at room temperature with 5.85 g (36 mM) N.tf-carbonyl-di imidazole. After gas evolution finishes the solution is stood for 99 minutes at 20* and then treated dropwise with the above lithium salt at 10 to 15*. The resultant suspension is stirred for 15 hours at 20’ and partitioned between methylene chloride/1ittle isopropanol and IN sodium carbonate solution. The organic phase is washed with water9 dried with sodium sulphate and evaporated to give the heading compound. M.pt. 189-190" (from ethanol). - 23 B SERIES EXAMPLES The following compounds of formula I wherein 0 is a compound of formula IV are produced:- Example A B n «8 Conf. M.pt. Prep 5 B-l 5-chloro- indol-3-yl 0 2 ch3 endo 235-237*3) 2 B-2 4-methoxy- indol-3-yl 0 2 ch3 endo 193-194 2 B-3 5-methoxy- 10 1ndol-3-yl 0 2 ch3 endo 214-216’ 2 B-4 1-methyl- indol-3*yl 0 2 ch3 endo 143-144- 3 B-5 indol-3-yl 0 2 ch3 exo 239-240-3) 2 B-6 indol-3-yl 0 3 ch3 endo 208-209*3) 2 15 B-7 indol-3-yl 0 2 n-C3H/ endo 158-159’ 2 B-8 indol-3-yl 0 2 benzyl exo 164-165-8) 2 B-9 1ndol-3-yl 0 2 benzyl endo 162-163"8) 2 B-10 indol-3-yl 0 2 H endo 261-263’3) 8f B"ll 5-fluoro- 20 indol-3-yl 0 3 H endo 247-248-3) 4 B-12 1-methyl- indol-3-yl 0 3 H endo 147-148’ 4 B-13 indol-3-yl 0 3 H endo 234-235*3) 4 B-14 5-methyl- 25 indol-3-yl 0 3 ch3 endo 228-230* 2 Example A B n Conf. M.pt. Prep. B-15 2-methyl1ndol-3-yl 0 3 ch3 endo 204-205 2 B-16 5-fluoro-l- metftylindol3-yl 0 3 ch3 endo 107-108* 3 or 2 B-17 5-fluoro-in- dol-3-yl 0 3 ch3 endo 244-245*3) 2 B-18 5-fluoro-l- methyl indol3-yl 0 3 benzyl endo 127-128* 3 B-19 l-methyl-indol-3-yl 0 3 ch3 endo 103-104* 3 Example A Bn B-20 5-meth/Mn- dol-3-yl NH 3 B-21 5-fluoro-in- dol-3-yl NH 2 B-22 l-methyl-in- dol-3-yl NH 2 B-23 2-methyl-indol-3-yl NH 2 B-24 indol-3-yl NH 2 8-25 indol-3-yl NH 2 B-26 5*chloro-in~ dol-3-yl NH 2 B-27 indol-3-yl 0 3 8-28 l-methyl-in- dol-3-yl 0 3 B-29 5-fluoro-1n- dol-3-yl 0 3 R8 Conf. M.pt. Prep. ch3 endo 265-2673) 1 ch3 endo 220-222 1 ch3 endo 169-170 3 or 1 ch3 endo 196-19703) 1 ch3 exo 261-2623) 1 C«3 endo 205-206* 1 ch3 endo 210-212 1 benzyl endo 234-235 1 benzyl endo 147-148* 2 benzyl endo 193-194* 2 Example A B n Conf. E4.pt. Prep, B-3o benzothlen- 3-yl 0 3 ch3 endo 129-130* 2 B-31 5 benzothlen- 3-yl NH 3 ch3 endo 225-226° I7) B-32 benzofuran- 3-yl NH 3 ch3 endo 199-201* 1 B-33 benzfurany- 3-yl 0 3 ch3 endo 77-78* 2 10 8-34 l(H)inden- 3-yl NH 3 ch3 endo 181-183* 1 B-35 indol-3-yl NH 4 ch3 exo 264-266*3) 110) B-36 indol-3-yl 0 4 ch3 exo 264-267"3) 2 C SERIES EXAMPLES The following compounds of formula I wherein I) is a group of formula IV are produced:- Example A B n Ra Conf. M.pt. Prep 5 C-l indol-5-yl 0 2 ch3 endo 191-193* 2 02 indol-5-yl 0 3 ch3 endo 148-149* 10 03 3-iodo-in- dol-5-yl 0 3 ch3 endo 172-174* 6 04 indoI-4-yi NH 2 ch3 exo 267-269**) 1 10 05 indol-4-yl HH 2 ch3 endo 221-223*3) 1 06 indol-5-yl HH 2 ch3 endo 220-221* 1 - 28 F SERIES EXAMPLES The following compounds of formula I wherein A is a group of formula II and 0 is a group of formula V, are produced:Example ABO substituent M.pt. Prep.

E-l indol-3-yl 0 3 219-221°4)3) 7 - 29 REPRESENTATIVE STARTING MATERIALS OF FORMULA VII EXAMPLE n Conf. B Characterisation Trivial name a) 2 ch3 endo 0 m.pt.59-61* Tropine b) 2 ch3 exo 0 m.pt.105-107* Pseudotropine 5 c) 2 ch3 endo NH bpt 82712mm Tropinamine d) 2 ch3 exo NH bpt 7570.05 mm Pseudotropin- amine e) 3 ch3 endo NH bpt 115717 mm f) 3 ch3 endo OH amorphous* 10 g) 3 benzyl endo OH m.pt.69-70*+ h) 2 n-C3H7 endo OH oil ++ + prepared by reduction of ketone by NaBH4 with separation of Isomers ++ prepared by reduction of ketone by NaBHq* Major product. - 30 i) N-methyl -10-aza-b 1 c,yclo[4.3. l]dec-8-yl amine (for Example B-35) g of sodium are reacted in analogous manner to that disclosed below in Example j, with 9.69 g 10-methyl-10-azab i cyc lo[4.3.1]decan-8-one oxime acetate [m.pt. 253-253.5° C prepared in analogous manner to that disclosed in Exainple A-lb] giving an oil bpt 105*70.9, mm after working up in conventional manner.

'H.N.M.R, (200 MHz) 3.27-3.04 (multipletw2HpHC-(l)- and H-C(6); 2.59 (singlet83H,H-C(ll)), 2.01-1.49 (multiplet,13H 6 x 2H-C and H-C(8)); 1,24 (singlet02H; 2.H-N exchangeable with D20); 13c N.M.ft. (25.2 MHz) 56.41 (d) doublet), 42.85 (quartet C-ll)B 41.44 (doublet),, 37.13 (triplet^ C-7 and C-9)β 32.54 (triplet,, C-2 and ΐ C-5) and 24.88 (triplet C-3 and C-4). The configuration is believed to be exo.

J) N-methyl-10-azabicyc1o[4,3.1 ]decan-8-o 1 (for Example B-36) g sodium pieces are added to a hot solution of 3.5 g 8-methyl10-azabicycloL4.3.1]decan-8-one in 100 ml of dry n-butanol. The mixture is refluxed for an hour* cooled and acidified with concentrated hydrochloric acid to pH 2. The mixture is evaporated to dryness to give a residue which is taken up in sodium hydroxide. The mixture is extracted with chloroform, dried and distilled, b.pt. 90-9570.025 - 31 Ή.N.M.R. (200 MHz) 4.07-4.23 (multiplet, 'H-C-(8) half width ca 20Hz); 3.63 - 3.69 (triplet^ 0.33 H? j * 7Hz,HO-C-(8) one isomer exchangable with 020), 2.13 -1.38 (multiple!, 12H, 6 x CH2). 13C.N.M.R. (25.2 MHz) 63.10 (doublet C-8)a 56.80 (doublet, C-l and C-6), 43.13 (quartet, KCHg), 36.30 (triplet-C-7 and C-9)g . 34.80 (triplet, C-2 and C-5), 25.04 (triplet C-3 and C-4).

The configuration is believed to be exo. - 32 The compounds of the invention exhibit pharmacological activity and are therefore useful as pharmaceuticals,e.g. for therapy.

In particular the compounds exhibit serotonin M receptor antagonist activity as indicated in standard tests. For example, in one test the action of the compounds in inhibiting the action of serotonin in reducing the amplitude of the compound action potential from the isolated rabbit vagus nerve was observed according to the principles of Riccioppo Neto, European Journal of Pharmacology (1978) 49 351-3569under conditions permitting 10differentiation between action potentials generated in myelinated nerve fibres (A fibres) and those generated in small non-myelinated fibres (C fibres) as described by 8.Oakley and R.Schater, Experimental Neurobiology, A Laboratory Manual» * University of Michigan Press, 1978p p.85 to 96. Serotonin itself exerts its effect selectively on the C fibres and reduces the amplitude of the action potential in these fibres progressively with dosage. This action of serotonin is not blocked by the known serotonin antagonists, metiteplne, methysergide, BOL -148, which have been said to block 0 receptors for serotonin» but not M receptors (see Gaddam and Picarelli, Brit.J.Pharmacol.(1957), 12, 323-328). It therefore appears that serotonin reduces the amplitude of the action potential carried by the C fibres through an effect mediated by M receptors for serotonin which are located on these nerve fibres. -33 The test may be effected by establishing a dose response curve for serotonin (IO'7 - 5 x IO6 M) after setting up the nerve. The serotonin is washed out and when the C fibre action potential has regained its original amplitude the compound of the invention at a set concentration of from about 10^6 M to about 10'6 M is preincubated with the nerve for 30 to 60 minutes. Varying concentrations of serotonin (IO**7 to 10'^ M) are then applied with the compound of the invention at the concentration as was present during the preincubation period.

The M receptor antagonists of the invention either entirely block the action of serotonin (non-competitive antagonist) or cause a parallel shift of the serotonin/dose response curve to the right (i.e. increased concentrations of serotonin were required for effect) (competitive antagonist). The p0'2 or oA2 value may be obtained in the conventional manner.

The serotonin M receptor antagonist activity is also indicated by inhibiting the effect of serotonin on the isolated rabbit heart according to the method of J.R.fozard and A.T.Moborak Ali, European Journal of Pharmacology, (1978) 49, 109-112 at concentrations of 10’H to 106 M of the compound of the Invention. p0*2 or pA2 values may be calculated in the conventional manner.

The action of the compounds as serotinin M receptor antagonists for the treatment of analgesia is confirmed by action in the hot plate test at a dose of from about 0.1 to 100 mg/kg s.c. or p.o. - 34 The serotonin M receptor antagonist activity is furthermore indicated in the cantharidine blister base test at a concentration of about 10® M. A blister is produced on the skin of the forearm of human volunteers with cantharidine. When serotonin is applied to the base of such blisters it produces pain which can be measured, the intensity being proportional to the concentration of serotonin applied. The procedure has been described by C.A. Keele and D.Armstrong in Substances producing Pain and Itch, Edward Arnold, London, 1964, p.30 to 57. This algesic action of serotonin is not inhibited by the serotonin D receptorantagonists such as lysergic acid diethylamide or its bromo derivai ive and is therefore believed to be mediated by M receptors.

In the procedure followed the area under the curve instead of the peak amplitude is measured by a linear integrator coupled to a pain intensity indicator which is operated by the volunteer. With increasing concentrations of serotonin a cumulative dose-response curve to serotonin may be obtained. When no further reponse on increasing the serotonin concentration is obtained, the serotonin is washed off and the blister incubated with physiological buffer solution for at least 40 minutes before the compound of the invention, e.g. the preferred compounds of Examples A-2 or A-3, is applied. The test substance is preincubated with the blister base for 30 minutes at a concentration of about 10® M before varying concentrations of serotonin are applied. A ρΛ2 value may be obtained in the conventional manner. - 35 The compounds of the Invention are therefore be indicated for use as serotonin M receptor antagonists e.g. for the treatment of pain, especially migraine,, vascular and cluster headaches and trigeminal neuralgia and also for the treatment of heart circulation disorders, e.g. for the treatment of sudden death, and possibly as anti-psychotics.

An indicated daily dose is from about 0.5 to 500 mg conveniently administered in divided doses in unit dosage form 2 to 4 times a day containing from about 0.2 to about 250 mg of the compound or in sustained release form. - 36 The compounds of the invention furthermore exhibit anti-arrhythmic activity as indicated by their serotonin M receptor antagonist activity and in standard tests. For example the compounds inhibit arrhythmias induced by norepinephrine in anaesthetized rats. In this test infusions of ncrepinerphrine (3 to 10 microgram/animal body weight) are given until an arrhythmic phase as indicated by ECG measurements lasts longer than 10 seconds duration. After control of 3 consecutive injections of norephinephrine the compound of the invention is injected at from about 10 to about 500 microgram/kg animal body weight followed by norepinephrine injections. The arrhythmic phase is reduced» or abolished depending on the dose of test compound.

The compounds are therefore indicated for use as anti-arrhythmic agents. An indicated daily dose is from about 0.5 to about 500 mg conveniently administered orally or by Injection in divided doses 2 to 4 times a day or In unit dosage form containing from about 0.2 to about 250 mg, or In sustained release form. - 37 The present Invention accordingly provides a compound of the invention in pharmaceutically acceptable form, e.g. in free base form, or pharmaceutically acceptable acid addition salt form or quaternary ammonium salt form, for use as a pharmaceutical , particularly for use as a serotonin M antagonist for those diseases where blockage of serotonin M recpetors would be expected to have beneficial effects, e.g. as an analgesic agent, especially as an anti-migraine agent and as an anti-arrhythmic agent.

The preferred indication is the analgesic indication. The preferred compounds are the title compounds of Examples A2 and A3.

The compounds of the invention may be administered in free base form» or in pharmaceutically acceptable salt form, e.g. suitable acid addition salts and quaternary ammonium salts. Such salts exhibit the same order of activity as the free bases. The present invention accordingly also provides a pharmaceutical composition comprising a compound of the invention, in particular a compound of fonnula lp an acid addition salt thereof or a quaternary ammonium salt thereof, in association with a pharmaceutical carrier or diluent. Such compositions may be formulated in conventional manner so as to be for example a solution or a tablet. - 38 A group of compounds comprises compounds of formula I wherein A is a group of formula II, wherein R^ and R^ independently are hydrogen, halogen, (C)a 1ky1 , or (C j ) a 1 koxy, R^ is in the 4 or 5 positions, R.^ is hydrogen or (Cj_4)a 1ky1, the free valence is in position 3, 4 or 5; D is a group of formula IV wherein Rg is hydrogen, (Cl4)alky1 or benzyl or a group of formula V wherein the free valence is attached to the 3 position and subject to the,above proviso to formula I.

A group of compounds comprises the compounds of the above formula I excluding any one of the specific examples, e.g. the compound of Examples A2 or A3.

In the following claims, ve make no claim to the compound indol-3-yl ^carboxylic acid endo-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl ester, in free base or in acid addition salt form which forms the subject-matter of our Patent Specification No.5¾¾

Claims (25)

1. A process for the production of a compound of formula 1 A-CO-B-D wherein A is a group of formula 11 R R, II wherein the free valence is attached to either fused ring, X is -CHj-, —^R 3 -, -0—, or —S— Ri and Rj independently are hydrogen, halogen, (Ci-ii)-alkyl, (Ci_«)alkoxy, hydroxy, amino, (Ci-ο)alkyl-amino, di(Ci_ fl -)alkylamino, mercapto or (Ci_4)alkyl-thio, R 3 is hydrogen, (Ci.«)alkyl, (C 3 - 5 )alkenyl, aryl or ar(Ci. 4 )alkyl wherein the aryl moiety is unsubstituted phenyl or phenyl mono- or poly-substituted by (Ci-a)alkyl, halogen p hydroxy or (Ci_4)alkoxy, or B is -0- or and D is a group of formula IV IV - 39 wherein n is 2,3 or 4 Re is hydrogen, (Ci- 7 )alkyl, (Cj_ 5 )alkenyl, or ar(Ci. Gl )alkyl «herein the aryl saoiety is unsubstituted phenyl or phenyl mono- or poly-substituted by (Ci. 4 )alkyl, halogen, hydroxy or (C x _4)alkoxy, or D is a group of formula V which includes the step of a) condensing an appropriate compound of formula VI A-CO-OH VI wherein A is as defined above, or a reactive derivative thereof, or a precursor of the acid or derivative, with an appropriate compound of formula VII HB-D VII wherein B and D are as defined above, or a precursor of the compound, or b) alkylating a compound of formula I having a secondary amino group to produce a compound of formula I with a tertiary amino group, - 40 c) deprotecting any protected form of a compound of formula I to obtain a compound of formula I d) halogenating a compound of formula X wherein A is a group of formula XI and R 2 is hydrogen to obtain the corresponding compound wherein R 2 is halogen, and e) alkoxylating a compound of formula X wherein A is a group of formula II and R 2 is halogen to obtain the corresponding compound wherein R 2 is alkoxy, and recovering the resultant compound of formula I as such or as an acid addition salt or as a quaternary ammonium salt thereof.

2. A process for the production of bicyclic heterocyclic carboxylic acid ester or amide as defined in claim 1, or an acid addition salt or quaternary ammonium salt of the ester or amide substantially as hereinbefore described with reference to any one of the examples·

3. A bicyclic heterocyclic carboxylic acid ester or amide as defined in claim 1 or an acid addition salt or quaternary salt of the ester or amide whenever prepared according to the process of claim 1 or 2«

4. A compound of formula 1 as defined in claim 1, as well as acid addition salts thereof and quaternary ammonium salts thereof.

5. A compound of claim 4 which is a compound of formula Iqa - 41 wherein the free valence is attached to either fused ring, and n' is 2 or 3, and Ri, r 2» r s and R o are as defined in claim 1, as veil as acid addition salts and quaternary ammonium salts thereof. I R 3qb vherein the free valence is attached to either fused ring, and R x qb and R 2 qb are independently hydrogen, halogen, or (C x .<)alkyl, R>qb is hydrogen or (C 1 _ 4 )alkyl R u qb is hydrogen, (Ci_ 7 )alkyl or aralkyl, and n' is 2 or 3, as well as acid addition salts and quaternary ammonium salts thereof.

6. 7. A compound of claim 4 of formula Iqc R - 42 wherein the carbonyl group is attached to either fused ring» and R 2 qc is as R 2 defined in claim 1 other than (Ci- 4 )alkoxy and hydroxy, and 5 n' f Ri, Rj, R 8 are as defined in claim 1 as well as acid addition salts and quaternary ammonium salts thereof. 10

7. 8. A compound of claim 4 wherein R x and R 2 independently are hydrogen, halogen, (Ci-Oalkyl, or (Ci-Oalkoxy, R 2 is in the 4 or 5 positions, Rj is hydrogen or (Ci„ 4 )alkyl, and the free valence is in position 3, 4 or 5, and D is a group of formula IV wherein Rq 15 is hydrogen, (Ci-^)alkyl or benzyl or a group of formula V wherein the free bond is attached to the 3 position, as well as acid addition salt and quaternary ammonium salts thereof.

8. 9. A compound of claim 4 which is N-(endo-9-methyl-9-aza20 bicyclo[3.3.11non-3-yl) indol-3-yl carboxylic acid amide, as well as acid addition salts and quaternary ammonium salts thereof.

9. 10. A compound of claim 4 which is l-methyl-N-(endo-9-methyl-9-aza-bicyclo(3.3.1]non-3-yl) indol-3-yl carboxylic acid amide, as well as acid addition salts and quaternary ammonium salts thereof.

10. 11. A compound of claim 4 which is 5-fluoro-l-methyl-indol-3-yl carboxylic acid endo-9-aza-bicyclo[3.3.1]non-3-yl ester as well as acid addition salts and quaternary ammonium salts thereof. - 43

11. 12. A compound of claim 4 which Is 2-methoxy-indol’3-yl carboxylic acid endo-8-methyl-8-aza-bicyclol3.2.1]oct-3-yl ester, as will as acid addition salts and quaternary ammonium salts thereof.

12. 13. A compound of claim 4 which is 2-chlorc-indol-3-yl carboxylic acid endo-8-methyl-8-aza-blcyclo(3.2.1 Joet-3-yl ester, as well as acid addition salts and quaternary ammonium salts thereof.

13. 14. A compound of claim 4 which is 3-iodo-indol-4-yl carboxylic acid endo-8-raethyl-8-aza bicyclo[3*2.1Joct-3-yl ester, as well as acid addition salts and quaternary ammonium salts thereof.

14. 15^ a compound of claim 4 which is indol-4-yl carboxylic acid endo-8-methyl-8-aza-bicyclo(3.2-l]oct-3-yl ester, as well as acid addition salts and quaternary ammonium salts thereof.

15. 16. A compound of claim 4 which is indol-4-yl carboxylic acid endo-9-methyl-9-aza-bicyclo[3.3.11non-3-yl ester, as well as acid addition salts and quaternary ammonium salts thereof.

16. 17. A compound of claim 4 wherein 0 is a group of formula IV and A, B, n, R d and the configuration of the moiety B - D are 5-chloro-indol-3-yl, 0, 2, CHj and endo, as well as acid addition salts and quaternary ammonium salts thereof.

17. 18. A compound of claim 4 wherein D is a group of formula IV and A, B, n, Rc and the configuration of the moiety B - D are 4-raethoxy-indol-3-yl, 0, 2, CH 3 and endo, as veil as acid addition salts and quaternary ammonium salts thereof. - 44 A compound of claim 4 wherein D is a group of formula IV and A, B, n, Ra and the configuration of the moiety B - D are 5-methoxy-indol-3-yl, 0, 2, CHj and endo, as well as acid addition salts and quaternary ammonium salts thereof. <

18. 20. A compound of claim 4 wherein D is a group of formula IV and V A, B, n, Re and the configuration of the moiety B - D are l-methyl-indol-3-yl, 0, 2, CH 3 and endo, as well as acid < addition salts and quaternary ammonium salts thereof.

19. 21« A compound of claim 4 wherein D is a group of formula IV and A, B, n, Rc, and the configuration of the moiety B - D are indol-3-yl, 0, 2, CH 3 and exo, as well as acid addition salts and quaternary ammonium salts thereof.

20. 22. A compound of claim 4 wherein D is a group of formula IV and A, B, n, R e and the configuration of the moiety B - D are indol-3-yl, 0, 3, CH 3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.

21. 23. A compound of claim 4 wherein D is a group of formula IV and A, B, n, R o and the configuration of the moiety B - D are indol-3-yl, 0, 2, n-C 3 H7 and endo, as well as acid addition salts and quaternary ammonium salts thereof.

22. 24. a compound of claim 4 wherein D is a group of formula IV and A, B, n, R e and the configuration of the moiety B - D are indol-3-yl, 0, 2, benzyl and exo, as well as acid addition salts and quaternary ammonium salts thereof. - 45 25. A compound of claim 4 wherein 0 is a group of formula IV and A, B, n, R e and the configuration of the moiety B - 0 are indol-3-yl, 0, 2, benzyl and endo, as well as acid addition salts and quaternary ammonium salts thereof. 2®· A compound of claim 4 wherein D is a group of formula IV and A, B, n, R e and the configuration of the moiety B - D are indol-3-yl, 0, 2, H and endo, as well as acid addition salts and quaternary ammonium salts thereof. 27 s a compound of claim 4 wherein D is a group of formula IV and A, B, n, R a and the configuration of the moiety B - D are 5-fluoro-indol-3-yl, 0, 3, H and endo, as well as acid addition salts and quaternary ammonium salts thereof. 28. A compound of claim 4 wherein D is a group of formula IV and A, B, n, R e and the configuration of the moiety B - D are l-methyl-indol-3-yl, 0, 3, H and endo, as well as acid addition salts and quaternary ammonium salts thereof. 29. A compound of claim 4 wherein D is a group of formula IV and A, B, n, R e and the configuration of the moiety B - D are indol-3-yl, 0, 3, H and endo, as well as acid addition salts and quaternary ammonium salts thereof. 30. A compound of claim 4 wherein D is a group of formula IV and A, B, n, R e and the configuration of the moiety B - D are 5-raethyl-indol~3-yl, 0, 3, CH 3 and endo, as well as acid addition salts and quaternary ammonium salts thereof. -46 31 · A compound of claim 4 wherein D is a group of formula IV and A, B, n, R 0 and the configuration of the moiety B - D are 2-methyl-ind0l-3-ylf 0, 3, CHj and endo* as well as acid addition salts and quaternary ammonium salts thereof. 32. A compound of claica 4 wherein D is a group of formula IV and A, B| n, R o and the configuration of the moiety B - D are S-fluoro-l-methyl-indol-3-yl, 0, 3, CH 3 and endo, as well as acid addition salts and quaternary ammonium salts thereof. 33. A comp< und of claim 4 wherein D is a group of formula IV and A, Β, ι , Κ ΰ and the configuration of the moiety B - D are 5-fluoj o-indol-3-yl, 0, 3 y CH S and endo, as well as acid additi 34· A compound of claim 4 wherein D is a group of formula IV and A, B, n, Rq and the configuration of the moiety B - D are 5-fluoro~l-methyl-indol-3-yl, 0, 3, benzyl and endo, as well as acid addition salts and quaternary ammonium salts thereof 35- A compound of claim 4 wherein D is a group of formula XV and A, B, n, R q and the configuration of the moiety B - D are l-methyl-lndol-3-yl, 0, 3, CB 3 and endo, as well as acid addition salts and quaternary ammonium salts thereof. 36. A compound of claim 4 wherein D is a group of formula IV and A, B, n, R o and the configuration of the moiety B - D are 5-methyl-indol-3-yl# MH, 3, CH 3 and endo# as well as acid addition salts and quaternary ammonium salts thereof. 37. A compound of claim 4 wherein D is a group of formula IV and A, B, n, Re and the configuration of the moiety B - D are 5-fluoro-indol-3-yl, 2, CH 3 and endo# as well as acid addition salts and quaternary ammonium salts thereof. - 47 38. A compound of claim 4 wherein 0 is a group of formula IV and A, B, n, R o and the configuration of the moiety B - D are 1- methyl indol-3-yl, NH, 2, CH a and endo, as well as acid addition salts and quaternary ammonium salts thereof. 3$ . A compound of claim 4 wherein D is a group of formula IV and A, B, n, R a and the configuration of the moiety B - D are 2- methyl-indol-3-yl, NH, 2, CHj and endo, as veil as acid addition salts and quaternary ammonium salts thereof. 40. A compound of claim 4 wherein D is a group of formula IV and A, B, n f R a and the configuration of the moiety B - D are indol-3-\l, NH, 2, CHa and exo, as well as acid addition salts an< quaternary ammonium salts thereof. 41. A compound of claim 4 wherein D is a group of formula IV and A, B, n, Ro and the configuration of the moiety B - D are indol-3-jl, NH, 2, CHj and endo, as well as acid addition salts an< quaternary ammonium salts thereof. 42. A compound of claim 4 wherein D is a group of formula IV and A, B, n, R g and the configuration of the moiety B - D are 5-chloroindol-3-yl, NH, 2, CB 3 and endo, as well as acid addition salts and quaternary ammonium salts thereof. 43. A compound of claim 4 wherein D is a group of formula IV and A, B, n, R d and the configuration of the moiety B - D are indol-3-yl, 0, 3, benzyl and endo, as well as acid addition salts and quaternary ammonium salts thereof. 44. A compound of claim 4 wherein D is a group of formula IV and A, B, n, K s and the configuration of the moiety B - D are 1-methyl- mdol-3-yl, 0, 3, benzyl and endo, as well as acid addition salts and quaternary ammonium salts thereof. - 48 / 45. A compound of claim 4 wherein D is a group of formula IV and A, B, n, R a and the configuration of the moiety B - D are 5-fluoro-indoI-3-yl, 0, 3, benzyl and endo, as well as acid addition salts and quaternary ammonium salts thereof. 5 46 . A compound of claim 4 wherein D is a group of formula IV and A, B, n. Rg and the configuration of the moiety B - D are benzothien-3-yl, 0, 3, CH 3 and endo, as well as acid addition salts and quaternary ammonium salts thereof. fl ! 0 47 . A compound of claim 4 wherein D is a group of formula IV and A, B, n, R @ and the configuration of the moiety B - D are benzothien-3-yl, NH, 3, CH 3 and endo, as well as acid addition salts and quaternary ammonium salts thereof. 15 48- A compound of claim 4 wherein D is a group of formula IV and A, B, n, R 3 and the configuration of the moiety B - D are benzofuran-3-yl, NH, 3, CH 3 and endo? as well as acid addition salts and quaternary ammonium salts thereof. 20 49 . A compound of claim 4 wherein D is a group of formula XV and A, B, n, R a and the configuration of the moiety B - D are benzofuran-3-yl, 0, 3, CH 3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.

23. 25 §g . A compound of claim 4 wherein D is a group of formula IV and A, B, n, R 8 and the configuration of the moiety B - D are l(H)-inden-3-yl, NH, 3, CH 3 and endo, as well as acid addition salts and quaternary ammonium salts thereof. 3Q 51 . A compound of claim 4 wherein D is a group of formula IV and A, B, n, R e and the configuration of the moiety B - D are indol-3-yl, NH, 4, CH 3 and exo, as well as acid addition salts and quaternary ammonium salts thereof. - 49 / 52 - A compound of claim 4 wherein D is a group of formula XV and A, B, n, R a and the configuration of the moiety B - D are indol-3-yl, 0, 4, CHj and exo, as well as acid addition salts and quaternary ammonium salts thereof. 53. A compound of claim 4 wherein D is a group of formula IV and A ( B, n, R a and the configuration of the moiety B - D are indol-5-yt, 0, 2, CHj and endo, as well as acid addition salts and quaternary ammonium salts thereof. 54. A compound of claim 4 wherein D is a group of formula IV and A, B, n, Ba and the configuration of the moiety B - D are indol-5-yl, 0, 3, CH 3 and endo, as well as acid addition salts and quaternary ammonium salts thereof. 55. A compound of claim 4 wherein D is a group of formula IV and A, B, n, R a and the configuration of the moiety B - D are 3-iodo-indol-5-yl, 0, 3, CH 3 and endo, as well as acid addition salts and quaternary ammonium salts thereof. 56. A compound of claim 4 wherein D is a group of formula IV and A, B, n, R a and the configuration of the moiety B - D are indol-4-yl, NH, 2, CH 3 and exo, as well as acid addition salts and quaternary ammonium salts thereof. 57. A compound of claim 4 wherein D is a group of formula IV and A, B, n, R o and the configuration of the moiety B - 0 are indol-4-yl, NH, 2, CH 3 and endo, as veil as acid addition salts and quaternary ammonium salts thereof. 58 A compound of claim 4 wherein D is a group of formula IV and A, B, n, R e and the configuration of the moiety B - D are indol*5-yl, NH, 2, CH 3 and endo, as well as acid addition salts and quaternary ammonium salts thereof. - 50 59. compound of claim 4 wherein A is indolyl-3-yl, B is -0-, and D is 3-quinuclidlnyl as well as acid addition salts and quaternary ammonium salts thereof· 5 60. A compound of claim 4 wherein 0 is a group of formula IV, and acid addition salts and quaternary ammonium silts thereof. 61. A compound of claim 60 wherein n is 3, and acid addition 10 salts and quaternary ammonium salts thereof. 62. A compound of claim 4 wherein D is a group of formula V, and acid addition salts and quaternary ammonium salts 15 thereof. 63. A compound of claim 4 wherein A is Indolyl and a< id addition salts and quaternary ammonium salts thereof. 64, A compound of claim 4 which is a quaternary ammonium salt of indol-3-yl carboxylic acid endo-8-methyl-8-aza-bicyclo{3.2.1Joct-3-yl ester. 25 65. A compound of any one of claims 3 to 64 or a pharmaceutically acceptable acid addition salt or quaternary ammonium salt for use as a pharmaceutical. 66. A compound of any one of claims 3 to 64 or a pharmaceutically

24. 30 acceptable acid addition salt or quaternary ammonium salt , thereof for use as a serotonin M antagonist, an analgesic agent, an anti-migraine agent or an anti-arrhythmic agent. 67. A pharmaceutical composition comprising a compound of any one

25. 35 of claim*.' 3 to 64 or a pharmaceutically acceptable acid addition salt or quaternary ammonium salt thereof in association with a pharmaceutical carrier of diluent.