CA1293256C - Substituted benzoic acid alkylene bridged pyridil derivatives - Google Patents
Substituted benzoic acid alkylene bridged pyridil derivativesInfo
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- CA1293256C CA1293256C CA000580287A CA580287A CA1293256C CA 1293256 C CA1293256 C CA 1293256C CA 000580287 A CA000580287 A CA 000580287A CA 580287 A CA580287 A CA 580287A CA 1293256 C CA1293256 C CA 1293256C
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Abstract
Abstract:
The invention provides a bicyclic heterocyclic carboxylic acid alkylene bridged piperidyl ester or amide in which the alkylene bridge contains a minimum of 3 carbon atoms and is attached to two of the piperidyl ring carbon atoms with the proviso that the bicyclic heterocycle does not contain two oxygen atoms, as well as acid addition salts and quaternary ammonium salts thereof. Production of the compounds includes the step of condensing an appro-priate bicyclic heterocyclic carboxylic acid or a reactive acid derivative thereof, or a precursor of the acid or derivative, with an appropriate alkylene bridged piperidyl amine or piperindinol, 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, They are useful intermediates in the production of products having seratonin M antagonist activity.
The invention provides a bicyclic heterocyclic carboxylic acid alkylene bridged piperidyl ester or amide in which the alkylene bridge contains a minimum of 3 carbon atoms and is attached to two of the piperidyl ring carbon atoms with the proviso that the bicyclic heterocycle does not contain two oxygen atoms, as well as acid addition salts and quaternary ammonium salts thereof. Production of the compounds includes the step of condensing an appro-priate bicyclic heterocyclic carboxylic acid or a reactive acid derivative thereof, or a precursor of the acid or derivative, with an appropriate alkylene bridged piperidyl amine or piperindinol, 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, They are useful intermediates in the production of products having seratonin M antagonist activity.
Description
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~G~ - 5PtY~
lZ93ZSG
- iA -BENZOIC ACI~ PIPERIDYL ESTER DERIVATIVES
.
Thi invention relates to benæoic acid piperidyl ester derivatives, including analogues of benzoic acid e.g.
polycarboxyclic and heterocyclic carboxylic acids.
The present invention provides a bicyclic heterocyclic carboxylic acid alkylene bridged piperidyl ester or amide, with the provisos that a) in any bicyclic heterocyclic carboxylic acid amide, the bicyclic heterocycle does not contain two oxygen atoms and .
b) any blcyclic heterocyclic carboxylic acid ester hac an : ~ alkylene bridge containing a minimum Q~ 3 carbon atoms, attached to two piperidyl ring carbon atoms as :well as acid addition saIts and quarternary ammonium , salts thereof.
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The compounds may be substituted where desired. In one group of compounds the acid nucleus conveniently contains one ring heteroatom. Conveniently the alkylene bridge has a minimum of 3 carbon atoms. Alternatively the bridge is attached to the piperidyl nitrogen atom. Conveniently, the alkylene bridge of the bicyclic heterocyclic carboxylic acid alkylene bridged amide may be between two piperidyl carbon atoms.
Also the present invention provides a compound of formula I
.A-~0-~-0 wherein A is a group of formula II
~l ~ R2 II
wherein the free valence is attached to either fused ring, X is -CH2-, NR3, -0-, or -S-, R1 and R2 independently are hydrogen , halogen, (C14) alkyl, (C14) alkoxy, hydroxy, amino, (C14) alkylamino, di (C14) alkylamino, mercapto, or (C1~4) alkylthio, and R3 is hydrogen or (Cl4) alkyl.
B is -O- or -NH-, D is a group of formula III
r7\
r~ \ (C~ nN~R 4 ITI
W
wherein n is 2,3 or 4, R4 is hydrogen, (C17) alkyl~, (C35) alkenyl, or aralkyl, or a group of formula IV
r, ~ IV
as well as acid addition salts and q~laternary ammonium salts thereof.
Any alkyl moiety preferably is methyl, ethyl or propyl. Alkoxy is preferably methoxy or athoxy. Aralkyl is conveniently aryl (C~ alkyl. Alkenyl is preferably allyl or methallyl.
Any aryl moiety is preferably unsubstituted phenyl or phenyl mono- or poly-substituted by (C14) alkyl, e.g. methyl, halogen, e.g. fluorine, hydroxy, or ~C14) alkoxy, e.g.
methoxy. Preferably any substituted aryl group in mono-substituted. Aralkyl is conveniently benzyl. Halogen is~luorine, 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 containiny X especially in position 3. Pre~erably A is indole.
Rl is a~tached to the rin~ carbon atom in position 4,5,6 or 7 of the nucleus, preferably position 5, and R2 is attached to the ring carbon atom in position 2 or 3 of the nucleus.
Tautomers are also covered by formula I, e.g. when R2 is hydroxy or mercapto in the 2 position.
R3 is conveniently hydrogen or alkyl. Conveniently n is 3 or 4, more preferably 3.
The group III may exist in different conformations. For example the six-membered ring containing the nitrogen atom and the carbon atom to which the B-moiety is attached-hereinafter referred to as the piperidyl ring -may exist in the chair or boat conformations or in an intermediate conformation.
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The moiety B may have two different configurations. These can be appreciated by making group III 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 it is above the plane on the same side as the nitrogen bridge. This corresponds to the exo configuration and also the configuration in pseudotropine etc. Used hereinafter is the exo/endo nomenclatureO The endo isomers are preferred.
R4 is preferably alkyl and especially methyl.
~ group of formula IV is also known as quinuclidinyl.
Conveniently this is 3- or 4- quinuclidinyl and especially 3-quinuclidinyl.
A group of compounds comprises compounds of formula Iqa C O . o ,~,~ ( CH2 ~ ~ N-P~4 ~N Iqa wherein the free valence is attached to either fused ring, and n' is 2 or 3, and R1, R2, R3 and R4 are as defined above, as well as acid addition salts and quaternary ammonium salts thereof.
1~32S6 Another group of compounds comprises indole carboxylic acid tropine and isopelletierine (homotropane) esters, particularly of formula Iqb - - ~ ~ ~ ~
Rlqb ~ R2q~ R4qb 3q~
wherein the free valence is attached to either fused ring, and R1qb and R2qb are independently hydrogen, halogen or ( C~ 4 ) alkyl, R3qb is hydrogen or (C14) alkyl, R4qb is hydrogen or (C17) alkyl or aralkyl, and n' is as defined above, as well as acid addition salts and quaternary ammonium salts thereof.
A further group of compounds comprises indole carboxylic acid tropine and isopelletierine (homotropane) amides, in particular of formula Iqc CO.~'H ~ N-~
R~ ~ R2qc .
. ;
. ~
6 ~93Z56 -wherein the free valence is attached to either fused ring, and R2qc i9 as R2 defined above other than (C14) alkoxy and hydroxy and, n', R1, R3, R4 are as defined above, 5. as well as acid ~ddition salts and quaternary ammonium salts thereof.
The present invention furthermore provides a process for the production of a compound o~ the invention which includes the : step of condensing an appropriate bicyclic heterocyclic carboxylic 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 ac.id 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.
:
' ~L293256 In particular the present invention provides a process for the production of 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 V
A-CO-GH
wherein A is as defined above, a reactive derivative thereof, or a precursor of the acid or derivative, : wlth an appropriate compound of formula VI
H~-D YI
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, ~i' .
lZ93256 d) halogenating a compound of formula I wherein A is a group of formula II and R2 is a hydrogen to obtain the corresponding compound wherein R2 is halogen, or 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 R2 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.
The condensation process of the invention to obtain amides and 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 amides.
Suitable reactive acid derivatives may be formed by reaction with N,N'-carbonyl-diimidazole producing an intermediate carboxylic acid imidaæolide, or with N-hydroxy-succinimide.
Alternatively an acid chloride may be used, e.g. produced by reaction with oxalyl chloride.
........
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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 manner, 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 amides.
Suitable reaction temperatures may be from about - 10 ~ to I0 about 10C- In the case of compounds wherein B is NH and D is a group of formula IV the reaction temperature may be for example up to about 100 C ,e.g. in boiling methanol or ethanol.
Other suitable inert organic solvents include, e.g tetrahydrofuran or dimethoxyethane.
In these reactions the endo or exo configuration of the substituent B in the group of formula III is believed to be maintained. The compound of formula VI 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 crystallization.
The compounds of the invention may be converted into other compounds of the invention, e.g. in conventional manner. Some interconversions are exemplified in processes b), c), d) and e).
The alkylation reaction of process b) may be effected in conventional manner. ~ny free amino group may be alkylated, especially compounds of formula II wherein X = NH.
Appropriate alkylation con~itions include reaction with an alkyl halide in the presence of a sodium alcoholate. Suitable temperatures may be from about - 50C to about - 30C.
~, ~
~3Z~6 The deprotection reaction of process c) is specifically suitable for the production of compounds with secondary amino groups, e.g. R4 = H in the group of formula III or primary amino groups.
For example a compound of formula I may be produced in protected form, e.g. R4 being replaced by a secondary amino protectiny 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 I wherein R4 is hydrogen.
Suitably the hydrogenation may be effected in the presence of palladium on active charcoal at room temperature or at a slightly elevated temperature. Suitable solvents include acetic acid, ethyl acetate or ethanol.
93~
Halogenation according to process d) may be effected in the conventional manner. For example reaction with N-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 iodina-tion.
Replacement of reactive h~logen groups according to process e) may be effected in conventional manner, e.g. by reaction with an 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.
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 temporaril~ protected.
The compounds of the invention may be isolated and purified in conventional manner.
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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 VI wherein B is -NH-, and D is a group of formula III wherein n is 4 are new. These compounds have never been specifically suggested before although they fall under various generic disclosures.
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 M antagonists and having other activities disclosed hereinafter.
These compounds of formula VI may for example be produced by reduction of the corresponding oxime, like the other compounds of formula VI wherein B is -NH-. Compounds of formula VI
wherein B is -O- 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 aluminum hydride procedures, or sodium borohydride (often leading to a mixture of endo/exo isomers).
Any mixture of the exo and endo forms may be separated by chromatography.
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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 acid, and vice versa. Suitable acids for salt formation include hydrochloric acid, malonic acid, hydrobromic acid, maleic acid, 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 = O ppm).
Nomenclature Endo-8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl = tropyl or ~-tropyl Exo-8-methyl-8-aza-bicyclo [3.2.1] oct~3-yl = pseudo- or ~-tropyl Endo-9-methyl-9-aza-bicyclo C3.3.1] non-3~yl =
isopelletierinyl or ~-homo-tropanyl Exo-9-methyl-9-aza-bicyclo [3.3.1] non-3-yl = ~-isopelletierinyl or ~-homo-tropanyl or pseudopelletierinyl l-aza-bicyclo [2.2.2] octyl = quinuclldinyl The configurations of the title compounds of Examples A 2; A-3; and B-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 VI which were used pure, except where otherwise stated.
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In the tables the column heading "conf." gives the indicated configuration of the group B-D, i.e. endo or exo. The column heading "Prep" gives the number of the Example in the A series describing the preparation process.
The title compounds of Examples A-7, A-8 and A-9 do not fall under the present invention, however the process described therein may be applied in the production of compounds of the present invention.
1) hydrogen maleate 2) decomposition 3) bis [base] fumarate 4) via imidazolyl intermediate 5) exo form has C-3 H broad multiplet at ca 5.15 ppm in HlN.M.R. endo form has C-3 H double triplet at 5.1 ppm. Exo alcohol is eluted before endo isomer on silica gel-eluant CH2C12/5% CH30H/5% NH40H
6) in presence of triethylamine instead of pyridine.
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~3ZS6 EXAMPLE A-1:
acid amide also called N-(3a-homotropan~ indol-3-yl ~Z~9~
S (compound of formula I wherein A = II in 3 position; R1 = R2 = H;
X = NH; B = NH; D a IV-a configuration; n = 3; R8 = CH3) a) Indol-3;~1 carbox~ic acid chloride 32.2 9 (0.2 M) dry indo1-3-yl carboxylic acid are suspended in 150 ml absolute methylene chloride. 26 ml (0.3 M) oxalyl chloride 10 are added to the stirred mixture at 20C over 30 minutes. Gas evolution results. The mixture is stirred for 3 1/2 hours at 20C. lS0 ml Hexane are added. The mixture is stirred for another 20 minutes and the resultant heading compound ~iltered off,washed with methylene chloride/hexane 1:1 dried at 20- in a vacuum to 15 give beige crystals, M.pt. 135~136 (decomp) which are used further without purification.
b) ~ee~L
176 9 (2.15 M~ sodium acetate and 150 9 (2.15 Mol) hydroxyl-amine hydrochloride are pounded in a mortar to a thin paste, extracted with 1 litre methanul, the salt filtered off ~93~5~i and the solution treated with 99.5 9(0.65 ~) endo-9-methyl-9-;i aza-bicyclo~3.3.1]nonan-3-one (3-homotropane). The oxime begins to crystallize after 10 minutes and the mixture is stirred for another 4 hours at 20C. To work up the mixture is concentrated ~` S 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 little water, dried with sodium sulphate and concentrated to give the heading compound. M.pt. 126 127 (from toluene/hexane).
10 c) ~ 2_2~!5,~ bicyclo[3.3.1]non-3-yl amine (also called 3a-amino-homotropane) A solution of 50.5 ml (0.95 M) concentrated sulphuric acid in 200 ml absolute tetrahydrofuran are added to a cooled and stirred mixture of 73 9 (1~9 M) lithium aluminium hydride in 900 15 ml absolute tetrahydrofuran at -10C within 2 hours. The mixture is allowed to stand overnight. A solution of 80 ~ (0.475 M) endo-9-methyl-9-aza-bicycloC3.3.1]nonan-3-one oxime in 1.4 litres absolute tetrahydrofuran is added`dropwtse over 30 minutes to the stirred mixture at 30 and allowed to react further at 40 for 3 20 hours. To work up the reaction mixture is cooled to 10 and a mixture of 150 ml water in 150 ml te~rahydrofuran is added carefully, The mixture is~stirred for an hour at 30~C. The resultant precipitate is ~iltered off. The residue is washed with ~; methylene chloride and ether. The organic phases are combined and 25~distllled to give the heading compound b.pt. 115-119"
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.
' ~L~9i325~i - l7 - 100-5819 (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) N-(endo-9-meth~-9-aza-bicycloC3.3.1]non-3-~ indol-3-yl carboxylic acid amide A solution of 15.4 g (0.1 M) endo-9 methyl-9-aza-bicyclo-L3.3.1]non-3-yl amine in 50 ml absolute pyridine is added dropwise to a stirred suspension of 14.5 9 (0.08 M) indol-3-yl 10 carboxylic acid chloride (produced ~n step a) in 50 ml absolute methylene chloride at -lO~C to 0C.
The resultant yellow suspension is warmed to 20 and stirred overnight. To work up 2N aqueous sodium carbonate is added. The m~xture ls extracted several times with methylene chloride and lS worked up in conventional manner. The ti~le compound is obtained after crystallisation three times. M.pt. 247-249- (decomp.).
~, ~2~3Z56 - l8 - 100-5819 EXAMPLE A-2:
bicyclo~3.2.1]oct-3-yl ester (process a) (Compound of formula I wherein A =II in 3 position; R1=R2=H; X =
~ NH;B=O;D =III in a configuration; n = 2; R4= CH3) ; ~:
6.35 9 (45 mM) endo-8-methyl-8-aza-bicyclo[3.2.1~octan-3-ol (Tropine) in 20 ml absolute tetrahydrofuran are treated at 0 to 10 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 tetrahydrofuran to give the lithium salt.
4,8 9 (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 15 carbonate to give the heading compound in crude form which is chromatographed on silicagel (250 9) eluting the heading compound with methy1ene chloride containing 10X methanol and 0.5X
ammonia. M.pt. 201-202~ (methylene ohloride/ethyl acetate).
M.pt. 283-285 (decomp.) - hydrochlorlde salt. Methoiodide 20 285-287 (decomposition).
Alternatively indol-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.
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~, ,, 5~i - l9 - 100-5819 EXAMPLE A-3: 1-methyl-N-(endo-9-methyl-9-aza-bicycloC3.3.1]non-~ ~ d~
S (process b) (compound of formula I wherein A = II in 3 position;
R1 = R2=H; X = NCH3;B - NH; D = III in a configuration;n = 3; R4=
CH3).
0.46 9 (20 mM) sodium dissolved in 170 ml dry liquid ammonia at -50 are treated dropwise with 1.3 ml ~22.5 mM) absolute ethanol 10 diluted with some abso1ute ether. The resultant colourless suspension of sodium ethanolate is stirred for 15 minutes at -50. 4.46 g (15 mM) N-(endo-9-methyl-9-aza-bicyclo-C3.3.1]-non-3-yl) indol-3-yl carboxylic acid amide are added giving a clear solution. The mixture is stirred for 10 minutes at -50 and 15 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 ~s removed in a vacuum. The resîdue is partitioned between methylene chloride and water and worked up in the usual manner to give a colourless foam which is chromatographed on 120 20 9 silicagel eluting with methylene chloride containing 5~
methan~l/3X 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 alternativçly be produced in analogous manner to 25 Example 1 starting from 1-methyl-indol-3-yl carboxylic acid.
~93;~56 EXAMPLE A-4: ~
.. ~ .
~ (process c) (compound of formula I; A=II in 3 position;
R1 = 5-F; Q2= H; X= NCH3; 8 = -0-; D = III in a configuration; n =
3; R4= H) 4.9 9 of 5-fluoro-1-methyl-indol-3~yl carboxylic acid endo-9-benzyl-9-aza-bicycloL3.3,1] non-3-yl ester in 200 ml ethanol are 10 hydrogenated at room temperature and normal pressure in the presence of 1.5 9 (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 crystall~ne residue of the title compound. M.pt. 130-131 15 (recrys-talllsed from ethanol/little hexane).
EXAMPLE A-5:
.
~20 ~Compound of formula I A - II in 3 position; R1 a H; R2 ' 2-OCH3, X -~NH B O; D a IIIin a configuration; n = 2; R4= CH3) 5.68 g (20 mM) indol-3-yl carboxylic acid endo-8-methyl-8-aza-~ bicyclo[3,2.1~oct-3-yl ester is added to a stirred suspension of ;~ 4 g (30 mM) N-chloro-succinimide in 80 ml absolute chloroform at 20, The mixture is stirred for 3 hours at 20 to give 2-chloro-indol-3-yl carboxylic acid (endo-8-methyl-8-aza-bicyclo[3.2.1]-oct-3-yl) estèr in a clear yellow solution.
~ t The clear yellow solution is treated with 10 ml absolute methanol and allowed to stand overnight, Usual working up by partitioning the mixture between lN aqueous sodium carbonate and methylene 10 chloride gave a crude product which ls chromatographed on silicagel (30 fold amount) eluting with methylene chloride containing 10X methanol and O.S~ ammonia the title compound~
M.pt. 204 to 206 (from ethanol).
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~3 ~2~33Z56 EXAMPLE A-6:
endo-~-methyl-8-aza-bicyclo-[ ~ 3 ~l ~ster (compound of formula I wherein A = II in 4 position, R1 ~ H; R2 = 3-I; X = NH, B = -0-; D =IIIin a configuration; n - 2; R4~ CH3) (process d) A solution of 2.84 9 (10 mM) indol-4-yl carboxylic acid endo-8-- methyl-8-aza-bicyclo[3,2.1]oct-3-yl ester is added dropwise at 15 to a stirred suspension of 2.48 9 (11 mM) N-iodo-succinimide in 200 ml absolute chloroform. The mixture is stirred for a 10 further 30 minutes at 20. Partitioning between lN 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-indol-4-yl carboxylic acid chlorlde in analogous manner to that disclosed 15 in Example A-2.
EXAMPLE A-7: 5-ch,loro-2-methoxy-4-methylamino-benzoic acid called u _~ .L~ C (process a) a) ~
12 9 N,N'-carbonyl~diimidazole are added to a stirred solution of 8 9 5-chloro-4-methylamino-2-methoxy-benzoic acid in 300 ml dry , ~ tetrahydrofuran at 20 to 25. The mlxture is stirred under anhydrous oonditions for 1~hour, and the solvent removed at 35 to 40.The residue is dissolved in methylene chloride.
~ .
, The mixture is washed 2 to 3 times with water, dried over magnesium sulphate, filtered and concentrated. The heading compound crystallises from methylene chloride/hexane.M.pt.
152-I54.
b) ~ ~
27 ml n-butyl lithium (1.6 Molar) in hexane is added dropwise to a stirred solution of 5.56 9 1-aza-bicyclo~2.2.2]octan-3-ol (quinuclidin-3-ol) in 100 ml absolute tetrahydrofuran at 0 to 5 10 under dry nitrogen. The mixture is stirred for a further 10 to 15 minutes at 0 to 5 and then a solution of 5-chloro-4-methyl-amino-2-methoxy-benzoic acid imidazolide in 100 ml absolute tetra-hydrofuran is added. It is stirred for an hour. 5 ml saturated aqueous potassium hydrogen carbonate solution is added 15 and the solution is decanted. The residue is washed twice with tetrahydrofuran. The combined organic phases are dried over magnesium sulphate, filtered and concentrated. The crude product is treated with an equivalent amount of malonic acid to glve the heading compound in hydrogen malonate form.M.pt. 170-172 (from 20 acetone).
~: :
-~?i .,~ . , ~ - 24 - 100-5819 , EXAMPLE A-8: 4-amino-5-chloro-2-methoxy-benzoic acid exo-8-ben-__ 4-amino-5-chloro-2-methoxY-benzoic acid 8-benzYl e ~ ~9L~ J~ L~t.~L (process c) .
a) ester A solution of 42.1 g 4-amino-2-methoxy-benzoic acid methyl ester in 600 ml toluene i5 boiled under reflux for 2 1i2 hours together with 60 ml chloroformic pheny1 ester. The solution is cooled and crystals of the heading compound filtered off.M.pt. 137-138.
b) 18 9 chlorine gas (dried over sulphuric acid) is passed through a ; stirred solution of 61.4 9 4-(N-benzyloxycarbonyl)amino-2-metho-lS xy-benzoic acid methyl ester in 1 litre chloroform at 20 for 20 to 25 minutes. The reaction mixture is concentrated under a vacuum to give the crystals of the heading rompound which is reacted further as such.
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200 ml 2N aqueous sodium hydroxide solution is added dropwise to a stirred solution of 72.1 9 of the benzoic acid methyl ester produced in s~ep b) in 800 ml dioxane. The mix~ure is stirred for 20 hours and the organic solvent removed under a vacuum. The residue is dissolved in water and adjusted to pH S-6 with 3N
hydrochloric acid. The heading compound is filtered off and washed with water. M.pt. 182-183 tfrom methanol).
d) 4-(N-benzyloxycarbonylamino)-5-chloro-2-methoxy-benzoic acid imidazolide The compound is produced in analogous manner to Example A-7a.
e) ~ id The co-pound fs praduced in dnilogous manner to Exdmple A-7b.
~Z~3;~S6 ) 3~l ester 5.4 9 4-(N-benzyloxycarbonylamino)-5-chloro-2-methoxy-benzoic acid exo-8-benzyl-8-aza-bicyclo[3.2.1~oc~-3-y1 ester in 100 ml ethanol are hydrogenated in the presence of 0.7 9 pallad1um (10%) on charcoal for 50 minutes at atmospheric pressure taking up one equivalent of hydrogenO The mixture is filtered through a filtering aid (Hyflo Supercell) and the filtrate concentrated.
The residue is chromatographed on silicagel with methylene 10 chloride containing 5% methanol and the heading compound obtained in free base form. M.pt. 241-242 (hydrobromide produced from HBr, in ethanol).
EXAMPLE A-9: 4-amino-5-chloro-2-methox~-benzoiç acid exo-8-aza-bicYclo~3.2.1]oct-3-yl ester also called 4-amino-5-15ester (process c?
8.4 g 4-(N-benzyloxycarbonylamino)-5-chloro2-methoxy-benzoic acid exo-8-benzyl-8-aza-bicyclo~3.2.1]oet-3-yl ester in 250 ml ethyl acetate or acetic acid are hydrogenated in the presence of ~; 20 1.2 9 lOX palladlum~on charcoal at atmospheric pressure and at 20 to 25 for 2 hours. The mixture is filtered (e.g. through Hyflo), the filtrate is evaporated and the residue dissolved in methylene chloride.
. ~ i lZ~3Z~G
The organic phase is washed with lN sodium hydroxide and then with water, dried over magnesium sulphate and concentrated. The product is chromatographed through si1icagel using methylene chloride ~ 5% methanol and methylene chloride + 20% methanol. The title compound is crystallised as the hydrochloride. M.pt.
258-259 (from ethanol).
EXAMPLE A-10: ~t~ Cb9 .
blc~clo[3.2.1]oc~-3-yl ester also called Indol-10 (Compound of formula I A =II in 4 position;R1- R2~ H; R3 = NH; B=
O; D ~ III in a configurat~on; n-2;R4 ~ CH3) 7 9 (50mM) endo-8-methyl-8-aza-bicycloL3.2.1]octan-3-ol (tropjne) in 15 ml absolute tetrahydrofuran is treated at 10 to 15e dropwise with 20 ml (40 mM) of 2 Molar Butyl lithium in hexane.
15 The mixture is stirred for 30 minutes at 20, and then concentrated to a volume of about 10 ml to remove the hexane to give the lith1um enolate. 10 ml tetrahydrofuran is added.
4.8 9 (3Q mM) dry lndol-4-yl carboxylic acid in 15 ml absolute tetrahydrofuran is treated portionwise with 5~85 9 (36 mM) 20 N,N'-carbonyl-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 20C, and partitioned between methylene chloride/a little isopropanol and lN 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~
__ bicvclo[3.3.1]non-3-Yl ester al50 called 3a-homo-(Compound of formula I A=II in 4 position; X = NH;R1= R2 = H; R3 = NH; B - 0; D=IIIin a configuration; n = 3; R4= CH3) (process a) a) 7.65 9 (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 15 with 20 ml (40 mM~ 2 Molar Butyl lithium hexane solution. The resultant mixture is stirred for 30 minutes at 20. The hexane is 10 then evaporated and replaced by tetrahydrofuran to give a solution of the lithium salt.
b) 4.8 9 (30 mM) dry indol-4-yl carboxylic acid in 15 ml absolute tetrahydrofuran is treated portionwise at room temperature with 5.85 5 (36 mM) N,N'-carbonyl-dilmidazole. After gas 15 evolution finishes the solution is stood for 90 minutes at 20 and then treated dropwise with the above llthium salt at 10 to 15. The resultant suspension is stirred for 15 hours at 20 and part~tioned between methylene chloride/little isopropanol and lN
sodium carbonate solution. The organic phase is washed with 20 water, dried with sodium sulphate and evaporated to give the heading compound. M.pt. 189-190 (from ethanol).
~3;~S~;
B SERIES EXAMPLES
___ The following compounds of formula I wherein D is a compound of formula IV are produced:-Example A B n R4 Conf. M.pt. Prep.
B-1 5-chloro-indol-3-yl 0 2 CH3 endo 235-237 ) 2 B-2 4-methoxy-indol-3-yl 0 2 CH3 endo 193-194 2 B-3 S-methoxy-indol-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 ~ndol-3-yl 0 2 CH3 exo 239-240 ) 2 B-6 indol-3-yl 3 CH3 endo 208-209 ) 2 15 B-7 indol-3-yl 0 2 n-C3H7 endo 158-159 2 B-8 indol-3-yl 0 2 benzyl exo 164-165~ ) 2 B-9 indol-3-yl 0 2 benzyl endo 162-1635) 2 B-10 indol-3-yl 0 2 H endo 261-263 ) 8f B-11 5-fluoro-: 20 indol-3-yl 0 3 H endo 247-248 ) 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 ) 4 B-14 5-methyl-indol-3-yl 0 3 CH3 endo ?28-230 2 , ~
~3;2~6 `
Example A B nR4 Conf. M.pt. Prep.
B-15 2-methyl-indol-3-yl 0 3 CH3 endo 204-205 2 B-16 5-fluoro-1-S m~thylindol-3-yl 0 3 CH3 endo 107-108 3 or 2 B-17 5-fluoro-in- 2 dol-3-yl 0 3 CH3 endo 244-245~ ) 2 B-18 5-fluoro-1-methyl indol-3-yl 0 3 benzyl endo 127-128 3 B-19 1-methyl-in-dol-3-yl 0 3 CH3 endo 103-104 3 '~
~932S6 - 3l - 100-5819 Example A B n R4 Conf. M~pto Prep.
B-20 5-methyl-ln-dol-3-yl NH 3 CH3 endo 265-267 ) 1 B-21 5-fluoro-in-dol-3-yl NH 2 CH3 endo 220-222 B-22 1-methyl-in-dol-3-yl NH 2 CH3 endo 169-170 3 or 1 : B-23 2~methyl-in-dol-3-yl NH 2 CH3 endo 196-197 ) 1 10 B-24 indol-3-yl NH 2 CH3 exo 261-2622) 1 B-25 indol-3-yl NH 2 CH3 endo 205-Z06 B-26 5-chloro-in-dol-3-yl NH 2 CH3 endo 210-212 B-27 indol-3-yl 0 3 benzyl endo 234-235 15 B-28 1-methyl-in-dol-3-yl 0 3 benzyl endo 147-148 2 B-29 5-fluoro-1n-dol-3-yl 0 3 benzyl endo 193-194 2 ~L~93256 Example A 8 nR4 Conf. M.pt. Prep.
:' B-30 benzothien-3-yl 0 3 CH3 endo 129-130 2 B-31 benzothien-3-yl NH 3 CH3 endo 225-226~ 1 ) B-32 benzofuran-3-yl NH 3 CH3 endo 199-201 B-33 benzfurany-3-yl 0 3 CH3 endo 77 78 2 10 B-34 1(H)inden-3-yl NH 3 CH3 endo 181-183 B-35 indol-3-yl NH 4 CH3 exo 264-266 ) 1 B-36 indol-3-yl 0 4 CH3 exo 264-267 ) 2 ~a32~
C SERIES EXAMPLES
The following compounds of formula I wherein D is a group of formula IV are produced:-Example A B n R~ Conf. M.pt. Prep.
C-1 indol-5-yl 0 2 CH3 endo 191-193 2 C-2 indol-5-yl 0 3 CH3 endo 148-14~ 10 C-3 3-iodo-in-dol-5-yl 0 3 CH3 endo 172-174'2 6 C-4 indol-4-yl NH 2 CH3 exo 267-269 ) 1 10 C-5 indol-4-yl NH 2 CH3 endo 221-223 ) 1 C-6 indol-S-yl NH 2 CH3 endo 220-22~- 1 ~t~
3Z~
D SERIES EXAMPLES
. .
The following compound of formula I wherein A is a group of formula II and D is a group of formula IV, is produced:-Example A B D substit- M.pt. Prep.
E-1 indol-3-yl 0 3 219-2213)2) 7 ,~, , . .I
~3~25;6 REPRESENTATIVE STARTING MATERIALS OF FORMULA VI
EXAMPLE n R4 Conf. B Characterisation Trivial name a) 2 CH3 endo O m.pt.59-61 Tropine b) 2 CH3 exo O m.pt.lO5-107 Pseudotropine o) 2 CH3 endo NH bpt 82/12mm Tropinamine d) 2 CH3 exo NH bpt 75/0.05 mm Pseudotropin-amine e) 3 CH3 endo NH bpt 115/17 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 ke~one by Na~H4. M~or product.
.
~2932Sgi i) N-methyl-10-aza-bicyclot4.3.1]dec-8-~lamine ~` (for Example B-35) 15 9 of sodium are reacted in analogous manner to that disclosed below in Examp1e j) with 9.69 9 10-methyl-10-azabicyclo-~4.3.1]decan-8-one oxime acetate CmOpt. 253~253.5 C prepared in analogous manner to that disclosed in Example A-lb] giving an oil bpt 105/0.9, mm after working up in conventional manner 'H.N.M R. (200 MHz) 3.27-3.04 (multiplet~2H,HC-(1) and H-C(6);
2.59 (singlet,3H,H-C(11)), 2.01-1.49 (multiplet,13H 6 x 2H-C and H-C(8)); 1.24 (singlet,2H; 2.H-N exchangeable with D20); 13C
10 N.M.R. (2S.2 MHz) 56.41 (d) doublet), 42.85 (quartet C-ll), 41.44 (doublet), 37.13 (triplet, C-7 and C-9), 32.54 (triplet9 C-2 and C-5) and 24.88 (triplet C-3 and C-4). The configuration is believed to be exo.
i) ~ (for Example B-36) 15 5 9 sodium pieces are added to a hot solution of 3.5 9 8-methyl-10-azabicyclo[4.3.1]decan-8-one in 100 ml of dry n-butanol. The mixture is refluxed for an hour9 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 20 hydroxide. The mixture is extracted with chloroform, dried and distilled, b~pt. 90-95/0.025 mm.
~$3;2~i 'H,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,H0-C-(8) one isomer exchangable with D20), 2.13 -1.38 (multiplet, 12H, 6 x CH2).
3C.N.M.R. (25.2 MHz) 63.10 (doublet C-8~, 56.80 (doublet9 C-l S and C-6)9 43.13 (quartet9 NCH3), 36.30 (triplet-C-7 and C-9), 34.80 (triplet, C-2 and C-5), 25.04 (triplet C-3 and C-4).
The configuration is believed to be exo.
;6 .~
- 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) 49 351-356,under conditions permitting 10 differentation between action potentials generated in myelinated nerve fibres (A fibres) and those generated in small non-myelinated flbres (C fibres) as described by B.Oakley and R.Schater, Experimental Neurobiology, A Laboratory Manual, ! University of Michigan Press, 1978, p.85 to 96. Serotonin itself lS exerts its effect selectively on the C fibres and reduces the amplitude of the action potential ln these fibres progressively w;th dosage. This action of serotonin is not blocked by the known serotonin antagonlsts, metitepine, methysergide, BOL ~148, which have been said to block D receptors for serotonin, but not M
20 receptors (see Gaddam and Picarelli9 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 ~or serotonin which are located on these nerve libres.
~?
3~5~i ~ 39 ~ 100-5819 The test may be effected by establishing a dose response curve for serotonin (10-7 - 5 x 10-6 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 10-16 M to about 10-6 M is preincubatPd with the nerve for 30 to 60 minutes. Varying concentrations of serotonin (10 7 to 10-4 M) are then applied with the compound of the invention at the concentration as was present during the preincubation period.
10 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) (competitlve antagonist). The PD'2 or PA2 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) 499 109-112 at 20 concentrations of 10-11 to 10-5 M of the compound of the invention. PD'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 25 plate test at a dose of from about 0.1 to 100 mg/kg s,c. or p.o.
~ J
~, 1~3256 ~ - 40 - 100-5819 i The serotonin M receptor antagonist activity is furthermore indicated in the cantharidine blister base test at a concentration of about 10-8 M. A blister is produced on the skin of the forearm of human volunteers with cantharidine. When S serotonin is applled 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, London9 1964, p.30 to 57. This 10 algesic action of serotonin is not inhibited by the serotonin D
receptorantagonists such as lysergic acid diethylamide or its bromo derivative and is therefore believed to be mediated by M
receptors.
.
In the procedure followed the area under the curve instead of the 15 peak amplltude is measured by a linear integrater 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 20 is washed off and the blister incubated with physiological buffer solution for at least 40 mlnutes before the compound of the invention, e.g. the preferred compounds of Examples A-2 or A-3, ls~applied. The test substance is preincubated with the blister base for 30 minutes at a concentration of about 10-8 M before ~25 varying concentrations of serotonin~are applied. A Ph2 value may be obtained in the~conventional manner.
~ : ' ~t32S6 ; 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 10 in sustained release form.
.
3Z~6 :
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 norepinerphrine (3 to 10 microgram/animal body weight) are given until an arrhythmic pha~se as indicated by ECG measurements lasts longer than 10 seconds duration. After control of 3 consecutive injections of norephinephriné the compound of the invention is injected at 10 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 lndicated for use as anti-arrhythmic agents, An indicated daily dose is from about O.S to about 500 mg 15 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 2S0 mg, or in sustained release form.
: ~ :
, :~
:
~2~13;~6 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 anmonium salt form, for use as a pharmaceutical, particularly for use dS a serotonin M antagonist for those diseases where blockage of serotonin M receptors 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.
10 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 15 acid add~tion salts and quaternary ammonlum 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 formula I, an acid addition salt thereo~ or a quaternary - 20 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.
~LZ9325~
;
'.
A group of compounds comprises compounds of formula I wherein A
: ~ is a group of formula II, wherein R1 and R2 independently are hydrogen, halogen, (C1 4)alkyl, or (C1 4)alkoxy, Rl is in the 4 or 5 positions, R3 is hydrogen or (C1 4)alkyl, the free valence is in position 3,4 or 5;
D is a group of formulaIIIwherein R4 is hydrogen, (C1 4)alkyl or benzyl or a group of formula I~wherein the free valence is attached to the 3 : position~
~ 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, :
~: : : : : :
~G~ - 5PtY~
lZ93ZSG
- iA -BENZOIC ACI~ PIPERIDYL ESTER DERIVATIVES
.
Thi invention relates to benæoic acid piperidyl ester derivatives, including analogues of benzoic acid e.g.
polycarboxyclic and heterocyclic carboxylic acids.
The present invention provides a bicyclic heterocyclic carboxylic acid alkylene bridged piperidyl ester or amide, with the provisos that a) in any bicyclic heterocyclic carboxylic acid amide, the bicyclic heterocycle does not contain two oxygen atoms and .
b) any blcyclic heterocyclic carboxylic acid ester hac an : ~ alkylene bridge containing a minimum Q~ 3 carbon atoms, attached to two piperidyl ring carbon atoms as :well as acid addition saIts and quarternary ammonium , salts thereof.
.
': ~
~Z~3;~5~;
The compounds may be substituted where desired. In one group of compounds the acid nucleus conveniently contains one ring heteroatom. Conveniently the alkylene bridge has a minimum of 3 carbon atoms. Alternatively the bridge is attached to the piperidyl nitrogen atom. Conveniently, the alkylene bridge of the bicyclic heterocyclic carboxylic acid alkylene bridged amide may be between two piperidyl carbon atoms.
Also the present invention provides a compound of formula I
.A-~0-~-0 wherein A is a group of formula II
~l ~ R2 II
wherein the free valence is attached to either fused ring, X is -CH2-, NR3, -0-, or -S-, R1 and R2 independently are hydrogen , halogen, (C14) alkyl, (C14) alkoxy, hydroxy, amino, (C14) alkylamino, di (C14) alkylamino, mercapto, or (C1~4) alkylthio, and R3 is hydrogen or (Cl4) alkyl.
B is -O- or -NH-, D is a group of formula III
r7\
r~ \ (C~ nN~R 4 ITI
W
wherein n is 2,3 or 4, R4 is hydrogen, (C17) alkyl~, (C35) alkenyl, or aralkyl, or a group of formula IV
r, ~ IV
as well as acid addition salts and q~laternary ammonium salts thereof.
Any alkyl moiety preferably is methyl, ethyl or propyl. Alkoxy is preferably methoxy or athoxy. Aralkyl is conveniently aryl (C~ alkyl. Alkenyl is preferably allyl or methallyl.
Any aryl moiety is preferably unsubstituted phenyl or phenyl mono- or poly-substituted by (C14) alkyl, e.g. methyl, halogen, e.g. fluorine, hydroxy, or ~C14) alkoxy, e.g.
methoxy. Preferably any substituted aryl group in mono-substituted. Aralkyl is conveniently benzyl. Halogen is~luorine, 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 containiny X especially in position 3. Pre~erably A is indole.
Rl is a~tached to the rin~ carbon atom in position 4,5,6 or 7 of the nucleus, preferably position 5, and R2 is attached to the ring carbon atom in position 2 or 3 of the nucleus.
Tautomers are also covered by formula I, e.g. when R2 is hydroxy or mercapto in the 2 position.
R3 is conveniently hydrogen or alkyl. Conveniently n is 3 or 4, more preferably 3.
The group III may exist in different conformations. For example the six-membered ring containing the nitrogen atom and the carbon atom to which the B-moiety is attached-hereinafter referred to as the piperidyl ring -may exist in the chair or boat conformations or in an intermediate conformation.
~;Z~325~
The moiety B may have two different configurations. These can be appreciated by making group III 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 it is above the plane on the same side as the nitrogen bridge. This corresponds to the exo configuration and also the configuration in pseudotropine etc. Used hereinafter is the exo/endo nomenclatureO The endo isomers are preferred.
R4 is preferably alkyl and especially methyl.
~ group of formula IV is also known as quinuclidinyl.
Conveniently this is 3- or 4- quinuclidinyl and especially 3-quinuclidinyl.
A group of compounds comprises compounds of formula Iqa C O . o ,~,~ ( CH2 ~ ~ N-P~4 ~N Iqa wherein the free valence is attached to either fused ring, and n' is 2 or 3, and R1, R2, R3 and R4 are as defined above, as well as acid addition salts and quaternary ammonium salts thereof.
1~32S6 Another group of compounds comprises indole carboxylic acid tropine and isopelletierine (homotropane) esters, particularly of formula Iqb - - ~ ~ ~ ~
Rlqb ~ R2q~ R4qb 3q~
wherein the free valence is attached to either fused ring, and R1qb and R2qb are independently hydrogen, halogen or ( C~ 4 ) alkyl, R3qb is hydrogen or (C14) alkyl, R4qb is hydrogen or (C17) alkyl or aralkyl, and n' is as defined above, as well as acid addition salts and quaternary ammonium salts thereof.
A further group of compounds comprises indole carboxylic acid tropine and isopelletierine (homotropane) amides, in particular of formula Iqc CO.~'H ~ N-~
R~ ~ R2qc .
. ;
. ~
6 ~93Z56 -wherein the free valence is attached to either fused ring, and R2qc i9 as R2 defined above other than (C14) alkoxy and hydroxy and, n', R1, R3, R4 are as defined above, 5. as well as acid ~ddition salts and quaternary ammonium salts thereof.
The present invention furthermore provides a process for the production of a compound o~ the invention which includes the : step of condensing an appropriate bicyclic heterocyclic carboxylic 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 ac.id 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.
:
' ~L293256 In particular the present invention provides a process for the production of 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 V
A-CO-GH
wherein A is as defined above, a reactive derivative thereof, or a precursor of the acid or derivative, : wlth an appropriate compound of formula VI
H~-D YI
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, ~i' .
lZ93256 d) halogenating a compound of formula I wherein A is a group of formula II and R2 is a hydrogen to obtain the corresponding compound wherein R2 is halogen, or 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 R2 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.
The condensation process of the invention to obtain amides and 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 amides.
Suitable reactive acid derivatives may be formed by reaction with N,N'-carbonyl-diimidazole producing an intermediate carboxylic acid imidaæolide, or with N-hydroxy-succinimide.
Alternatively an acid chloride may be used, e.g. produced by reaction with oxalyl chloride.
........
3Z5~
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 manner, 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 amides.
Suitable reaction temperatures may be from about - 10 ~ to I0 about 10C- In the case of compounds wherein B is NH and D is a group of formula IV the reaction temperature may be for example up to about 100 C ,e.g. in boiling methanol or ethanol.
Other suitable inert organic solvents include, e.g tetrahydrofuran or dimethoxyethane.
In these reactions the endo or exo configuration of the substituent B in the group of formula III is believed to be maintained. The compound of formula VI 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 crystallization.
The compounds of the invention may be converted into other compounds of the invention, e.g. in conventional manner. Some interconversions are exemplified in processes b), c), d) and e).
The alkylation reaction of process b) may be effected in conventional manner. ~ny free amino group may be alkylated, especially compounds of formula II wherein X = NH.
Appropriate alkylation con~itions include reaction with an alkyl halide in the presence of a sodium alcoholate. Suitable temperatures may be from about - 50C to about - 30C.
~, ~
~3Z~6 The deprotection reaction of process c) is specifically suitable for the production of compounds with secondary amino groups, e.g. R4 = H in the group of formula III or primary amino groups.
For example a compound of formula I may be produced in protected form, e.g. R4 being replaced by a secondary amino protectiny 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 I wherein R4 is hydrogen.
Suitably the hydrogenation may be effected in the presence of palladium on active charcoal at room temperature or at a slightly elevated temperature. Suitable solvents include acetic acid, ethyl acetate or ethanol.
93~
Halogenation according to process d) may be effected in the conventional manner. For example reaction with N-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 iodina-tion.
Replacement of reactive h~logen groups according to process e) may be effected in conventional manner, e.g. by reaction with an 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.
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 temporaril~ protected.
The compounds of the invention may be isolated and purified in conventional manner.
:
- .
3~5i~
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 VI wherein B is -NH-, and D is a group of formula III wherein n is 4 are new. These compounds have never been specifically suggested before although they fall under various generic disclosures.
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 M antagonists and having other activities disclosed hereinafter.
These compounds of formula VI may for example be produced by reduction of the corresponding oxime, like the other compounds of formula VI wherein B is -NH-. Compounds of formula VI
wherein B is -O- 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 aluminum hydride procedures, or sodium borohydride (often leading to a mixture of endo/exo isomers).
Any mixture of the exo and endo forms may be separated by chromatography.
", 5~
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 acid, and vice versa. Suitable acids for salt formation include hydrochloric acid, malonic acid, hydrobromic acid, maleic acid, 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 = O ppm).
Nomenclature Endo-8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl = tropyl or ~-tropyl Exo-8-methyl-8-aza-bicyclo [3.2.1] oct~3-yl = pseudo- or ~-tropyl Endo-9-methyl-9-aza-bicyclo C3.3.1] non-3~yl =
isopelletierinyl or ~-homo-tropanyl Exo-9-methyl-9-aza-bicyclo [3.3.1] non-3-yl = ~-isopelletierinyl or ~-homo-tropanyl or pseudopelletierinyl l-aza-bicyclo [2.2.2] octyl = quinuclldinyl The configurations of the title compounds of Examples A 2; A-3; and B-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 VI which were used pure, except where otherwise stated.
~`:`` J ' 14 1~3;:5~
In the tables the column heading "conf." gives the indicated configuration of the group B-D, i.e. endo or exo. The column heading "Prep" gives the number of the Example in the A series describing the preparation process.
The title compounds of Examples A-7, A-8 and A-9 do not fall under the present invention, however the process described therein may be applied in the production of compounds of the present invention.
1) hydrogen maleate 2) decomposition 3) bis [base] fumarate 4) via imidazolyl intermediate 5) exo form has C-3 H broad multiplet at ca 5.15 ppm in HlN.M.R. endo form has C-3 H double triplet at 5.1 ppm. Exo alcohol is eluted before endo isomer on silica gel-eluant CH2C12/5% CH30H/5% NH40H
6) in presence of triethylamine instead of pyridine.
7~
~3ZS6 EXAMPLE A-1:
acid amide also called N-(3a-homotropan~ indol-3-yl ~Z~9~
S (compound of formula I wherein A = II in 3 position; R1 = R2 = H;
X = NH; B = NH; D a IV-a configuration; n = 3; R8 = CH3) a) Indol-3;~1 carbox~ic acid chloride 32.2 9 (0.2 M) dry indo1-3-yl carboxylic acid are suspended in 150 ml absolute methylene chloride. 26 ml (0.3 M) oxalyl chloride 10 are added to the stirred mixture at 20C over 30 minutes. Gas evolution results. The mixture is stirred for 3 1/2 hours at 20C. lS0 ml Hexane are added. The mixture is stirred for another 20 minutes and the resultant heading compound ~iltered off,washed with methylene chloride/hexane 1:1 dried at 20- in a vacuum to 15 give beige crystals, M.pt. 135~136 (decomp) which are used further without purification.
b) ~ee~L
176 9 (2.15 M~ sodium acetate and 150 9 (2.15 Mol) hydroxyl-amine hydrochloride are pounded in a mortar to a thin paste, extracted with 1 litre methanul, the salt filtered off ~93~5~i and the solution treated with 99.5 9(0.65 ~) endo-9-methyl-9-;i aza-bicyclo~3.3.1]nonan-3-one (3-homotropane). The oxime begins to crystallize after 10 minutes and the mixture is stirred for another 4 hours at 20C. To work up the mixture is concentrated ~` S 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 little water, dried with sodium sulphate and concentrated to give the heading compound. M.pt. 126 127 (from toluene/hexane).
10 c) ~ 2_2~!5,~ bicyclo[3.3.1]non-3-yl amine (also called 3a-amino-homotropane) A solution of 50.5 ml (0.95 M) concentrated sulphuric acid in 200 ml absolute tetrahydrofuran are added to a cooled and stirred mixture of 73 9 (1~9 M) lithium aluminium hydride in 900 15 ml absolute tetrahydrofuran at -10C within 2 hours. The mixture is allowed to stand overnight. A solution of 80 ~ (0.475 M) endo-9-methyl-9-aza-bicycloC3.3.1]nonan-3-one oxime in 1.4 litres absolute tetrahydrofuran is added`dropwtse over 30 minutes to the stirred mixture at 30 and allowed to react further at 40 for 3 20 hours. To work up the reaction mixture is cooled to 10 and a mixture of 150 ml water in 150 ml te~rahydrofuran is added carefully, The mixture is~stirred for an hour at 30~C. The resultant precipitate is ~iltered off. The residue is washed with ~; methylene chloride and ether. The organic phases are combined and 25~distllled to give the heading compound b.pt. 115-119"
~`
.
' ~L~9i325~i - l7 - 100-5819 (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) N-(endo-9-meth~-9-aza-bicycloC3.3.1]non-3-~ indol-3-yl carboxylic acid amide A solution of 15.4 g (0.1 M) endo-9 methyl-9-aza-bicyclo-L3.3.1]non-3-yl amine in 50 ml absolute pyridine is added dropwise to a stirred suspension of 14.5 9 (0.08 M) indol-3-yl 10 carboxylic acid chloride (produced ~n step a) in 50 ml absolute methylene chloride at -lO~C to 0C.
The resultant yellow suspension is warmed to 20 and stirred overnight. To work up 2N aqueous sodium carbonate is added. The m~xture ls extracted several times with methylene chloride and lS worked up in conventional manner. The ti~le compound is obtained after crystallisation three times. M.pt. 247-249- (decomp.).
~, ~2~3Z56 - l8 - 100-5819 EXAMPLE A-2:
bicyclo~3.2.1]oct-3-yl ester (process a) (Compound of formula I wherein A =II in 3 position; R1=R2=H; X =
~ NH;B=O;D =III in a configuration; n = 2; R4= CH3) ; ~:
6.35 9 (45 mM) endo-8-methyl-8-aza-bicyclo[3.2.1~octan-3-ol (Tropine) in 20 ml absolute tetrahydrofuran are treated at 0 to 10 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 tetrahydrofuran to give the lithium salt.
4,8 9 (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 15 carbonate to give the heading compound in crude form which is chromatographed on silicagel (250 9) eluting the heading compound with methy1ene chloride containing 10X methanol and 0.5X
ammonia. M.pt. 201-202~ (methylene ohloride/ethyl acetate).
M.pt. 283-285 (decomp.) - hydrochlorlde salt. Methoiodide 20 285-287 (decomposition).
Alternatively indol-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.
~ , ~
~, ,, 5~i - l9 - 100-5819 EXAMPLE A-3: 1-methyl-N-(endo-9-methyl-9-aza-bicycloC3.3.1]non-~ ~ d~
S (process b) (compound of formula I wherein A = II in 3 position;
R1 = R2=H; X = NCH3;B - NH; D = III in a configuration;n = 3; R4=
CH3).
0.46 9 (20 mM) sodium dissolved in 170 ml dry liquid ammonia at -50 are treated dropwise with 1.3 ml ~22.5 mM) absolute ethanol 10 diluted with some abso1ute ether. The resultant colourless suspension of sodium ethanolate is stirred for 15 minutes at -50. 4.46 g (15 mM) N-(endo-9-methyl-9-aza-bicyclo-C3.3.1]-non-3-yl) indol-3-yl carboxylic acid amide are added giving a clear solution. The mixture is stirred for 10 minutes at -50 and 15 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 ~s removed in a vacuum. The resîdue is partitioned between methylene chloride and water and worked up in the usual manner to give a colourless foam which is chromatographed on 120 20 9 silicagel eluting with methylene chloride containing 5~
methan~l/3X 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 alternativçly be produced in analogous manner to 25 Example 1 starting from 1-methyl-indol-3-yl carboxylic acid.
~93;~56 EXAMPLE A-4: ~
.. ~ .
~ (process c) (compound of formula I; A=II in 3 position;
R1 = 5-F; Q2= H; X= NCH3; 8 = -0-; D = III in a configuration; n =
3; R4= H) 4.9 9 of 5-fluoro-1-methyl-indol-3~yl carboxylic acid endo-9-benzyl-9-aza-bicycloL3.3,1] non-3-yl ester in 200 ml ethanol are 10 hydrogenated at room temperature and normal pressure in the presence of 1.5 9 (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 crystall~ne residue of the title compound. M.pt. 130-131 15 (recrys-talllsed from ethanol/little hexane).
EXAMPLE A-5:
.
~20 ~Compound of formula I A - II in 3 position; R1 a H; R2 ' 2-OCH3, X -~NH B O; D a IIIin a configuration; n = 2; R4= CH3) 5.68 g (20 mM) indol-3-yl carboxylic acid endo-8-methyl-8-aza-~ bicyclo[3,2.1~oct-3-yl ester is added to a stirred suspension of ;~ 4 g (30 mM) N-chloro-succinimide in 80 ml absolute chloroform at 20, The mixture is stirred for 3 hours at 20 to give 2-chloro-indol-3-yl carboxylic acid (endo-8-methyl-8-aza-bicyclo[3.2.1]-oct-3-yl) estèr in a clear yellow solution.
~ t The clear yellow solution is treated with 10 ml absolute methanol and allowed to stand overnight, Usual working up by partitioning the mixture between lN aqueous sodium carbonate and methylene 10 chloride gave a crude product which ls chromatographed on silicagel (30 fold amount) eluting with methylene chloride containing 10X methanol and O.S~ ammonia the title compound~
M.pt. 204 to 206 (from ethanol).
`~ .
:: :
: ~ :
~3 ~2~33Z56 EXAMPLE A-6:
endo-~-methyl-8-aza-bicyclo-[ ~ 3 ~l ~ster (compound of formula I wherein A = II in 4 position, R1 ~ H; R2 = 3-I; X = NH, B = -0-; D =IIIin a configuration; n - 2; R4~ CH3) (process d) A solution of 2.84 9 (10 mM) indol-4-yl carboxylic acid endo-8-- methyl-8-aza-bicyclo[3,2.1]oct-3-yl ester is added dropwise at 15 to a stirred suspension of 2.48 9 (11 mM) N-iodo-succinimide in 200 ml absolute chloroform. The mixture is stirred for a 10 further 30 minutes at 20. Partitioning between lN 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-indol-4-yl carboxylic acid chlorlde in analogous manner to that disclosed 15 in Example A-2.
EXAMPLE A-7: 5-ch,loro-2-methoxy-4-methylamino-benzoic acid called u _~ .L~ C (process a) a) ~
12 9 N,N'-carbonyl~diimidazole are added to a stirred solution of 8 9 5-chloro-4-methylamino-2-methoxy-benzoic acid in 300 ml dry , ~ tetrahydrofuran at 20 to 25. The mlxture is stirred under anhydrous oonditions for 1~hour, and the solvent removed at 35 to 40.The residue is dissolved in methylene chloride.
~ .
, The mixture is washed 2 to 3 times with water, dried over magnesium sulphate, filtered and concentrated. The heading compound crystallises from methylene chloride/hexane.M.pt.
152-I54.
b) ~ ~
27 ml n-butyl lithium (1.6 Molar) in hexane is added dropwise to a stirred solution of 5.56 9 1-aza-bicyclo~2.2.2]octan-3-ol (quinuclidin-3-ol) in 100 ml absolute tetrahydrofuran at 0 to 5 10 under dry nitrogen. The mixture is stirred for a further 10 to 15 minutes at 0 to 5 and then a solution of 5-chloro-4-methyl-amino-2-methoxy-benzoic acid imidazolide in 100 ml absolute tetra-hydrofuran is added. It is stirred for an hour. 5 ml saturated aqueous potassium hydrogen carbonate solution is added 15 and the solution is decanted. The residue is washed twice with tetrahydrofuran. The combined organic phases are dried over magnesium sulphate, filtered and concentrated. The crude product is treated with an equivalent amount of malonic acid to glve the heading compound in hydrogen malonate form.M.pt. 170-172 (from 20 acetone).
~: :
-~?i .,~ . , ~ - 24 - 100-5819 , EXAMPLE A-8: 4-amino-5-chloro-2-methoxy-benzoic acid exo-8-ben-__ 4-amino-5-chloro-2-methoxY-benzoic acid 8-benzYl e ~ ~9L~ J~ L~t.~L (process c) .
a) ester A solution of 42.1 g 4-amino-2-methoxy-benzoic acid methyl ester in 600 ml toluene i5 boiled under reflux for 2 1i2 hours together with 60 ml chloroformic pheny1 ester. The solution is cooled and crystals of the heading compound filtered off.M.pt. 137-138.
b) 18 9 chlorine gas (dried over sulphuric acid) is passed through a ; stirred solution of 61.4 9 4-(N-benzyloxycarbonyl)amino-2-metho-lS xy-benzoic acid methyl ester in 1 litre chloroform at 20 for 20 to 25 minutes. The reaction mixture is concentrated under a vacuum to give the crystals of the heading rompound which is reacted further as such.
:: ; :
' ~
" , ~93~56 c) ~L ~ ~
200 ml 2N aqueous sodium hydroxide solution is added dropwise to a stirred solution of 72.1 9 of the benzoic acid methyl ester produced in s~ep b) in 800 ml dioxane. The mix~ure is stirred for 20 hours and the organic solvent removed under a vacuum. The residue is dissolved in water and adjusted to pH S-6 with 3N
hydrochloric acid. The heading compound is filtered off and washed with water. M.pt. 182-183 tfrom methanol).
d) 4-(N-benzyloxycarbonylamino)-5-chloro-2-methoxy-benzoic acid imidazolide The compound is produced in analogous manner to Example A-7a.
e) ~ id The co-pound fs praduced in dnilogous manner to Exdmple A-7b.
~Z~3;~S6 ) 3~l ester 5.4 9 4-(N-benzyloxycarbonylamino)-5-chloro-2-methoxy-benzoic acid exo-8-benzyl-8-aza-bicyclo[3.2.1~oc~-3-y1 ester in 100 ml ethanol are hydrogenated in the presence of 0.7 9 pallad1um (10%) on charcoal for 50 minutes at atmospheric pressure taking up one equivalent of hydrogenO The mixture is filtered through a filtering aid (Hyflo Supercell) and the filtrate concentrated.
The residue is chromatographed on silicagel with methylene 10 chloride containing 5% methanol and the heading compound obtained in free base form. M.pt. 241-242 (hydrobromide produced from HBr, in ethanol).
EXAMPLE A-9: 4-amino-5-chloro-2-methox~-benzoiç acid exo-8-aza-bicYclo~3.2.1]oct-3-yl ester also called 4-amino-5-15ester (process c?
8.4 g 4-(N-benzyloxycarbonylamino)-5-chloro2-methoxy-benzoic acid exo-8-benzyl-8-aza-bicyclo~3.2.1]oet-3-yl ester in 250 ml ethyl acetate or acetic acid are hydrogenated in the presence of ~; 20 1.2 9 lOX palladlum~on charcoal at atmospheric pressure and at 20 to 25 for 2 hours. The mixture is filtered (e.g. through Hyflo), the filtrate is evaporated and the residue dissolved in methylene chloride.
. ~ i lZ~3Z~G
The organic phase is washed with lN sodium hydroxide and then with water, dried over magnesium sulphate and concentrated. The product is chromatographed through si1icagel using methylene chloride ~ 5% methanol and methylene chloride + 20% methanol. The title compound is crystallised as the hydrochloride. M.pt.
258-259 (from ethanol).
EXAMPLE A-10: ~t~ Cb9 .
blc~clo[3.2.1]oc~-3-yl ester also called Indol-10 (Compound of formula I A =II in 4 position;R1- R2~ H; R3 = NH; B=
O; D ~ III in a configurat~on; n-2;R4 ~ CH3) 7 9 (50mM) endo-8-methyl-8-aza-bicycloL3.2.1]octan-3-ol (tropjne) in 15 ml absolute tetrahydrofuran is treated at 10 to 15e dropwise with 20 ml (40 mM) of 2 Molar Butyl lithium in hexane.
15 The mixture is stirred for 30 minutes at 20, and then concentrated to a volume of about 10 ml to remove the hexane to give the lith1um enolate. 10 ml tetrahydrofuran is added.
4.8 9 (3Q mM) dry lndol-4-yl carboxylic acid in 15 ml absolute tetrahydrofuran is treated portionwise with 5~85 9 (36 mM) 20 N,N'-carbonyl-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 20C, and partitioned between methylene chloride/a little isopropanol and lN 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~
__ bicvclo[3.3.1]non-3-Yl ester al50 called 3a-homo-(Compound of formula I A=II in 4 position; X = NH;R1= R2 = H; R3 = NH; B - 0; D=IIIin a configuration; n = 3; R4= CH3) (process a) a) 7.65 9 (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 15 with 20 ml (40 mM~ 2 Molar Butyl lithium hexane solution. The resultant mixture is stirred for 30 minutes at 20. The hexane is 10 then evaporated and replaced by tetrahydrofuran to give a solution of the lithium salt.
b) 4.8 9 (30 mM) dry indol-4-yl carboxylic acid in 15 ml absolute tetrahydrofuran is treated portionwise at room temperature with 5.85 5 (36 mM) N,N'-carbonyl-dilmidazole. After gas 15 evolution finishes the solution is stood for 90 minutes at 20 and then treated dropwise with the above llthium salt at 10 to 15. The resultant suspension is stirred for 15 hours at 20 and part~tioned between methylene chloride/little isopropanol and lN
sodium carbonate solution. The organic phase is washed with 20 water, dried with sodium sulphate and evaporated to give the heading compound. M.pt. 189-190 (from ethanol).
~3;~S~;
B SERIES EXAMPLES
___ The following compounds of formula I wherein D is a compound of formula IV are produced:-Example A B n R4 Conf. M.pt. Prep.
B-1 5-chloro-indol-3-yl 0 2 CH3 endo 235-237 ) 2 B-2 4-methoxy-indol-3-yl 0 2 CH3 endo 193-194 2 B-3 S-methoxy-indol-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 ~ndol-3-yl 0 2 CH3 exo 239-240 ) 2 B-6 indol-3-yl 3 CH3 endo 208-209 ) 2 15 B-7 indol-3-yl 0 2 n-C3H7 endo 158-159 2 B-8 indol-3-yl 0 2 benzyl exo 164-165~ ) 2 B-9 indol-3-yl 0 2 benzyl endo 162-1635) 2 B-10 indol-3-yl 0 2 H endo 261-263 ) 8f B-11 5-fluoro-: 20 indol-3-yl 0 3 H endo 247-248 ) 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 ) 4 B-14 5-methyl-indol-3-yl 0 3 CH3 endo ?28-230 2 , ~
~3;2~6 `
Example A B nR4 Conf. M.pt. Prep.
B-15 2-methyl-indol-3-yl 0 3 CH3 endo 204-205 2 B-16 5-fluoro-1-S m~thylindol-3-yl 0 3 CH3 endo 107-108 3 or 2 B-17 5-fluoro-in- 2 dol-3-yl 0 3 CH3 endo 244-245~ ) 2 B-18 5-fluoro-1-methyl indol-3-yl 0 3 benzyl endo 127-128 3 B-19 1-methyl-in-dol-3-yl 0 3 CH3 endo 103-104 3 '~
~932S6 - 3l - 100-5819 Example A B n R4 Conf. M~pto Prep.
B-20 5-methyl-ln-dol-3-yl NH 3 CH3 endo 265-267 ) 1 B-21 5-fluoro-in-dol-3-yl NH 2 CH3 endo 220-222 B-22 1-methyl-in-dol-3-yl NH 2 CH3 endo 169-170 3 or 1 : B-23 2~methyl-in-dol-3-yl NH 2 CH3 endo 196-197 ) 1 10 B-24 indol-3-yl NH 2 CH3 exo 261-2622) 1 B-25 indol-3-yl NH 2 CH3 endo 205-Z06 B-26 5-chloro-in-dol-3-yl NH 2 CH3 endo 210-212 B-27 indol-3-yl 0 3 benzyl endo 234-235 15 B-28 1-methyl-in-dol-3-yl 0 3 benzyl endo 147-148 2 B-29 5-fluoro-1n-dol-3-yl 0 3 benzyl endo 193-194 2 ~L~93256 Example A 8 nR4 Conf. M.pt. Prep.
:' B-30 benzothien-3-yl 0 3 CH3 endo 129-130 2 B-31 benzothien-3-yl NH 3 CH3 endo 225-226~ 1 ) B-32 benzofuran-3-yl NH 3 CH3 endo 199-201 B-33 benzfurany-3-yl 0 3 CH3 endo 77 78 2 10 B-34 1(H)inden-3-yl NH 3 CH3 endo 181-183 B-35 indol-3-yl NH 4 CH3 exo 264-266 ) 1 B-36 indol-3-yl 0 4 CH3 exo 264-267 ) 2 ~a32~
C SERIES EXAMPLES
The following compounds of formula I wherein D is a group of formula IV are produced:-Example A B n R~ Conf. M.pt. Prep.
C-1 indol-5-yl 0 2 CH3 endo 191-193 2 C-2 indol-5-yl 0 3 CH3 endo 148-14~ 10 C-3 3-iodo-in-dol-5-yl 0 3 CH3 endo 172-174'2 6 C-4 indol-4-yl NH 2 CH3 exo 267-269 ) 1 10 C-5 indol-4-yl NH 2 CH3 endo 221-223 ) 1 C-6 indol-S-yl NH 2 CH3 endo 220-22~- 1 ~t~
3Z~
D SERIES EXAMPLES
. .
The following compound of formula I wherein A is a group of formula II and D is a group of formula IV, is produced:-Example A B D substit- M.pt. Prep.
E-1 indol-3-yl 0 3 219-2213)2) 7 ,~, , . .I
~3~25;6 REPRESENTATIVE STARTING MATERIALS OF FORMULA VI
EXAMPLE n R4 Conf. B Characterisation Trivial name a) 2 CH3 endo O m.pt.59-61 Tropine b) 2 CH3 exo O m.pt.lO5-107 Pseudotropine o) 2 CH3 endo NH bpt 82/12mm Tropinamine d) 2 CH3 exo NH bpt 75/0.05 mm Pseudotropin-amine e) 3 CH3 endo NH bpt 115/17 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 ke~one by Na~H4. M~or product.
.
~2932Sgi i) N-methyl-10-aza-bicyclot4.3.1]dec-8-~lamine ~` (for Example B-35) 15 9 of sodium are reacted in analogous manner to that disclosed below in Examp1e j) with 9.69 9 10-methyl-10-azabicyclo-~4.3.1]decan-8-one oxime acetate CmOpt. 253~253.5 C prepared in analogous manner to that disclosed in Example A-lb] giving an oil bpt 105/0.9, mm after working up in conventional manner 'H.N.M R. (200 MHz) 3.27-3.04 (multiplet~2H,HC-(1) and H-C(6);
2.59 (singlet,3H,H-C(11)), 2.01-1.49 (multiplet,13H 6 x 2H-C and H-C(8)); 1.24 (singlet,2H; 2.H-N exchangeable with D20); 13C
10 N.M.R. (2S.2 MHz) 56.41 (d) doublet), 42.85 (quartet C-ll), 41.44 (doublet), 37.13 (triplet, C-7 and C-9), 32.54 (triplet9 C-2 and C-5) and 24.88 (triplet C-3 and C-4). The configuration is believed to be exo.
i) ~ (for Example B-36) 15 5 9 sodium pieces are added to a hot solution of 3.5 9 8-methyl-10-azabicyclo[4.3.1]decan-8-one in 100 ml of dry n-butanol. The mixture is refluxed for an hour9 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 20 hydroxide. The mixture is extracted with chloroform, dried and distilled, b~pt. 90-95/0.025 mm.
~$3;2~i 'H,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,H0-C-(8) one isomer exchangable with D20), 2.13 -1.38 (multiplet, 12H, 6 x CH2).
3C.N.M.R. (25.2 MHz) 63.10 (doublet C-8~, 56.80 (doublet9 C-l S and C-6)9 43.13 (quartet9 NCH3), 36.30 (triplet-C-7 and C-9), 34.80 (triplet, C-2 and C-5), 25.04 (triplet C-3 and C-4).
The configuration is believed to be exo.
;6 .~
- 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) 49 351-356,under conditions permitting 10 differentation between action potentials generated in myelinated nerve fibres (A fibres) and those generated in small non-myelinated flbres (C fibres) as described by B.Oakley and R.Schater, Experimental Neurobiology, A Laboratory Manual, ! University of Michigan Press, 1978, p.85 to 96. Serotonin itself lS exerts its effect selectively on the C fibres and reduces the amplitude of the action potential ln these fibres progressively w;th dosage. This action of serotonin is not blocked by the known serotonin antagonlsts, metitepine, methysergide, BOL ~148, which have been said to block D receptors for serotonin, but not M
20 receptors (see Gaddam and Picarelli9 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 ~or serotonin which are located on these nerve libres.
~?
3~5~i ~ 39 ~ 100-5819 The test may be effected by establishing a dose response curve for serotonin (10-7 - 5 x 10-6 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 10-16 M to about 10-6 M is preincubatPd with the nerve for 30 to 60 minutes. Varying concentrations of serotonin (10 7 to 10-4 M) are then applied with the compound of the invention at the concentration as was present during the preincubation period.
10 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) (competitlve antagonist). The PD'2 or PA2 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) 499 109-112 at 20 concentrations of 10-11 to 10-5 M of the compound of the invention. PD'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 25 plate test at a dose of from about 0.1 to 100 mg/kg s,c. or p.o.
~ J
~, 1~3256 ~ - 40 - 100-5819 i The serotonin M receptor antagonist activity is furthermore indicated in the cantharidine blister base test at a concentration of about 10-8 M. A blister is produced on the skin of the forearm of human volunteers with cantharidine. When S serotonin is applled 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, London9 1964, p.30 to 57. This 10 algesic action of serotonin is not inhibited by the serotonin D
receptorantagonists such as lysergic acid diethylamide or its bromo derivative and is therefore believed to be mediated by M
receptors.
.
In the procedure followed the area under the curve instead of the 15 peak amplltude is measured by a linear integrater 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 20 is washed off and the blister incubated with physiological buffer solution for at least 40 mlnutes before the compound of the invention, e.g. the preferred compounds of Examples A-2 or A-3, ls~applied. The test substance is preincubated with the blister base for 30 minutes at a concentration of about 10-8 M before ~25 varying concentrations of serotonin~are applied. A Ph2 value may be obtained in the~conventional manner.
~ : ' ~t32S6 ; 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 10 in sustained release form.
.
3Z~6 :
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 norepinerphrine (3 to 10 microgram/animal body weight) are given until an arrhythmic pha~se as indicated by ECG measurements lasts longer than 10 seconds duration. After control of 3 consecutive injections of norephinephriné the compound of the invention is injected at 10 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 lndicated for use as anti-arrhythmic agents, An indicated daily dose is from about O.S to about 500 mg 15 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 2S0 mg, or in sustained release form.
: ~ :
, :~
:
~2~13;~6 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 anmonium salt form, for use as a pharmaceutical, particularly for use dS a serotonin M antagonist for those diseases where blockage of serotonin M receptors 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.
10 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 15 acid add~tion salts and quaternary ammonlum 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 formula I, an acid addition salt thereo~ or a quaternary - 20 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.
~LZ9325~
;
'.
A group of compounds comprises compounds of formula I wherein A
: ~ is a group of formula II, wherein R1 and R2 independently are hydrogen, halogen, (C1 4)alkyl, or (C1 4)alkoxy, Rl is in the 4 or 5 positions, R3 is hydrogen or (C1 4)alkyl, the free valence is in position 3,4 or 5;
D is a group of formulaIIIwherein R4 is hydrogen, (C1 4)alkyl or benzyl or a group of formula I~wherein the free valence is attached to the 3 : position~
~ 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, :
~: : : : : :
Claims
CLAIMS:
1. A process for the production of a bicyclic heterocyclic carboxylic acid alkylene bridged piperidyl ester or amide in which the alkylene bridge contains a minimum of 3 carbon atoms and is attached to two of the piperidyl ring carbon atoms with the proviso that the bicyclic heterocycle does not contain two oxygen atoms, as well as acid addition salts and quaternary ammonium salts thereof, which includes the step of condensing an appropriate bicyclic heterocyclic carboxylic acid or a reactive acid derivative thereof, or a precursor of the acid or derivative, with an appropriate alkylene bridged piperidyl amine or piperindinol, 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 an acid addition salt or as a quaternary ammonium salt thereof.
2. A process as claimed in claim 1, wherein the bicyclic heterocyclic carboxylic acid alkylene bridged ester or amide is a compound of formula I
A-CO-B-D I
wherein A is a group of formula II
II
wherein the free valence is attached to either fused ring, X is -CH2-, NR3-, -0-, or -S-, R1 and R2 independently are hydrogen, halogen, (C1-4) alkyl (C1-4) alkoxy, hydroxy, amino, (C1-4) alkylamino, di(C1-4) alkylamino, mercapto, or (C1-4) alkylthio, and R3 is hydrogen or (C1-4) alkyl.
B is -o- or -NH-, D is a group of formula III
III
wherein n is 2,3 or 4, R4 is hydrogen, (C1-7) alkyl, (C3-5) alkenyl, or aralkyl, or a group of formula IV
IV
3. A process for the production of a compound of formula I
A-CO-B-D I
wherein A is a group of formula II
II
wherein the free valence is attached to either fused ring, X is -CH2-, -NR3-, -O-, or -S-R1 and R2 independently are hydrogen, halogen, (C1-4)-alkyl, (C1-4) alkoxy, hydroxy, amino, (C1-4) alkyl-amino, di-(C1-4) alkylamino, mercapto or (C1-4) alkylthio, R3 is a hydrogen or (C1-4) alkyl B is -o- or -NH-D is a group of formula III
III
wherein n is 2,3 or 4 R4 is hydrogen , (C1-7) alkyl, (C3-5) alkenyl, or aralkyl, or a group of formula V
IV
as well as acid addition salts and quaternary ammonium salts thereof, which includes the step of a) condensing an appropriate compound of formula V
A-CO-OH V
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 VI
HB-D VI
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, d) halogenating a compound of formula I wherein A is a group of formula II and R2 is hydrogen to obtain the corresponding compound wherein R2 is halogen, or 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 R2 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.
4. A bicyclic heterocyclic carboxylic acid ester or amide as defined in claim 1, or a compound of formula I as defined in claim 3, or an acid addition salt or quaternary ammonium salt of the ester or amide for use as a pharmaceutical.
5. A bicyclic heterocyclic carboxylic acid ester or amide, or a compound of formula I as defined in claim 3, or an acid addition salt or quaternary salt of the ester or amide whenever prepared according to the process of any one of claims 1 to 3.
6. A bicyclic heterocyclic carboxylic acid alkylene bridged piperidyl ester or amide with the proviso that a) in any bicyclic heterocyclic carboxylic acid amide, the bicyclic heterocycle does not contain two oxygen atoms and b) any bicyclic heterocyclic carboxylic acid ester has an alkylene bridge containing a minimum of 3 carbon atoms, attached to two piperidyl carbon atoms as well as acid addition salts and quaternary ammonium salts thereof.
7. A bicyclic heterocyclic carboxylic acid, alkylene bridged piperidyl amide as claimed in claim 6, in which the alkylene bridge is between two piperidyl carbon atoms, as well as acid addition salts and quaternary ammonium salts.
thereof.
8. A compound of formula I as defined in claim 3, as well as acid addition salts thereof and quaternary ammonium salts thereof 9. A compound of claim 8 wherein aralkyl is (C1-4) alkyl substituted by unsubstituted phenyl of phenyl mono- or poly-substituted by (C1-4) alkyl, halogen, hydroxy or (C1-4) alkoxy, as well as acid addition salts and quaternary ammonium salts thereof .
10. A compound of claim 8 which is a compound of formula Iqa wherein the free valence is attached to either fused ring, and n' is 2 or 3, and R1, R2, R3 and R4 are as defined in claim 3, as well as acid addition salts and quaternary ammonium salts thereof.
11. A compound of claim 8 which is a compound of formula Iqb wherein the free valence is attached to either fused ring, and R1qb and R2qb are independently hydrogen, halogen,or (C1-4) alkyl, R3qb is hydrogen or (C1-4) alkyl R4qb is hydrogen, (C1-7) alkyl or aralkyl, and n' is 2 or 3, as well as acid addition salts and quaternary ammonium salts thereof.
12. A compound of claim 6 of formula Iqc wherein the carbonyl group is attached to either fused ring, and R2qc is as R2 defined in claim 2 other than (C1-4) alkoxy and hydroxy, and n', R1, R3, R7 are as defined in claim 8 or 11 as well as acid addition salts and quaternary ammonium salts thereof.
13. A compound of claim 8 wherein A is a group of Formula II, wherein R1 and R2 independently are hydrogen, halogen, (C1-4) alkyl, or (C1-4) alkoxy, R1 is in the 4 or 5 positions, R3 is hydrogen or (C1-4) alkyl, and the free valence is in position 3, 4 or 5, and D is a group of formula III wherein R4 is hydrogen, (C1-4) alkyl or benzyl or a group of formula IV
wherein the free bond is attached to the 3 position as well as acid addition salts and quaternary ammonium salts thereof.
14. A compound of claim 8 which is N-(endo-9-methyl-aza-bi-cyclo[3.3.1]non-3-yl) indol-3-yl carboxylic acid amide as well as acid addition salts and quaternary ammonium salts thereof.
15. A compound of claim 7 wherein the alkylene bridge contains at least 3 carbon atoms.
16. A compound of claim 8 which is 1-methyl-N-(endo-9 methyl-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.
17. A compound of claim 8 which is 5-fluoro-1-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.
18. A compound of claim 8 which is 2-methoxy-indol-3-yl carboxylic acid endo-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl-ester as well as acid addition salts and quaternary ammonium salts thereof.
19. A compound of claim 8 which is 2-chloro-indol-3-yl carboxylic acid endo-8-methyl-8-aza-bicyclo[3,2.1]oct-3-yl ester as well as acid addition salts and quaternary ammonium salts thereof.
20. A compound of claim 8 which is 3-iodo-indol-4-yl carboxylic acid endo-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl ester as well as acid addition salts and quaternary ammonium salts thereof.
21. A compound of claim 8 which is indol-4-yl carboxylic acid endo-3-methyl-8-aza-bicyclo[3.2.1]oct-3-yl ester as well as acid addition salts and quaternary ammonium salts thereof.
22. A compound of claim 8 which is indol-4-yl carboxylic acid endo-9-methyl-9-aza-bicyclo[3.3.1]non-3-yl ester as well as acid addition salts and quaternary ammonium salts thereof.
23. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are 5-chloro-indolyl-3-yl,0,2,CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
24. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are 4-methoxy-indol-3-yl, 0,2,CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
25. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are 5-methoxy indol-3-yl,0,2,CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
26. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are 1-methyl-indol-3-yl, 0, 2, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
27 A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are indol-3-yl, 0, 2, CH3 and exo, as well as acid addition salts and quaternary ammonium salts thereof.
28. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are indol-3-yl, 0, 3, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
29. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are indol-3-yl, 0, 2, n-C3H7 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
30. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are indol-3-yl, 0, 2, benzyl and exo, as well as acid addition salts and quaternary ammonium salts thereof.
31. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are indol-3-yl, 0, 2, benzyl and endo, as well as acid addition salts and quaternary ammonium salts thereof.
32. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are indol-3-yl, 0, 2, H and endo, as well as acid addition salts and quaternary ammonium salts thereof.
33. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are 5-fluoro-indol-3-yl, 0, 3, H and endo, as well as acid addition salts and quaternary ammonium salts thereof.
34. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are 1-methyl-indol-3-yl, 0, 3, H and endo, as well as acid addition salts and quaternary ammonium salts thereof.
35. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are indol-3-yl, 0, 3, H and endo, as well as acid addition salts and quaternary ammonium salts thereof.
36. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are 5-methyl-indol-3-yl, 0, 3, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
37. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are 2-methyl-indol-3-yl, 0, 3, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
38. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are 5-fluoro-1-methyl-indol-3-yl, 0, 3, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
39. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are 5-fluoro-indol-3-yl 0,3, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
40. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are 5-fluoro-1-methyl-indol-3-yl, 0, 3, benzyl and endo, as well as acid addition salts and quaternary ammonium salts thereof.
41. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are 1-methyl-indol-3-yl, 0,3, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
42. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are 5-methyl-indol-3-yl, NH, 3, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
43. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are 5-fluoro-indol-3-yl, NH, 2, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
44. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are 1-methyl-indol-3-yl, NH, 2, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
45. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are 2-methyl-indol-3-yl, NH, 2, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
46. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are indol-3-yl, NH,2, CH3 and exo, as well as acid addition salts and quaternary ammonium salts thereof.
47. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are indol-3-yl, NH, 2, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
48. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are 5-chloro-indol-3-yl, NH, 2, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
49.A compound of claim 8wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are indol-3-yl, 0, 3, benzyl and endo, as well as acid addition salts and quaternary ammonium salts thereof.
50.A compound of claim 8wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B- D respectively are 1-methyl-indol-3-yl, 0, 3, benzyl and endo, as well as acid addition salts and quaternary ammonium salts thereof, 51.A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are 5-fluoro-indol-3-yl, 0,3, benzyl and endo, as well as acid addition salts and quaternary ammonium salts thereof, 52.A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are benzothien-3-yl, 0, 3, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
53.A compound of claim 8wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are benzothien-3-yl, NH, 3, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
54.A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are benzofuran-3-yl, NH, 3, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
55. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are benzofuran-3-yl, O, 3, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
56. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are 1(H)-inden-3-yl, NH, 3, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
57. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are indol-3-yl, NH, 4, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
58. A compound of claim 8 wherein 1) is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are indol-3-yl, O, 4, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
59. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are indol-5-yl, 0, 2, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
60. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are indol-5-yl, 0,3, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
61. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are 3-iodo-indol-5-yl, 0,3, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
62. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are indol-4-yl, NH, 2, CH3 and exo, as well as acid addition salts and quaternary ammonium salts thereof.
63. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are indol-4-yl, NH, 2, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
64. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are indol-5-yl, NH,2, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
65. A compound of claim 8 wherein A is indolyl-3-yl, B is -O-, and D is 3-quinuclidinyl as well as acid addition salts and quaternary ammonium salts thereof.
66. A compound of claim 8 wherein D is a group of formula III t and acid addition salts and quaternary ammonium salts thereof.
67. A compound of claim 66 wherein n is 3, and acid addition salts and quaternary ammonium salts thereof.
68. A compound of claim 8 wherein D is a group of formula IV, and acid addition salts and quaternary ammonium salts thereof.
69. A compound of claim 8 wherein A is indolyl and acid addition salts and quaternary ammonium salts thereof.
70. A pharmaceutical composition comprising a bicyclic heterocyclic carboxylic acid ester or amide as defined in claim 1, or a compound of formula I as defined in claim 3, or an acid addition salt or quaternary ammonium salt of the ester or amide together with a pharmaceutical carrier or diluent.
1. A process for the production of a bicyclic heterocyclic carboxylic acid alkylene bridged piperidyl ester or amide in which the alkylene bridge contains a minimum of 3 carbon atoms and is attached to two of the piperidyl ring carbon atoms with the proviso that the bicyclic heterocycle does not contain two oxygen atoms, as well as acid addition salts and quaternary ammonium salts thereof, which includes the step of condensing an appropriate bicyclic heterocyclic carboxylic acid or a reactive acid derivative thereof, or a precursor of the acid or derivative, with an appropriate alkylene bridged piperidyl amine or piperindinol, 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 an acid addition salt or as a quaternary ammonium salt thereof.
2. A process as claimed in claim 1, wherein the bicyclic heterocyclic carboxylic acid alkylene bridged ester or amide is a compound of formula I
A-CO-B-D I
wherein A is a group of formula II
II
wherein the free valence is attached to either fused ring, X is -CH2-, NR3-, -0-, or -S-, R1 and R2 independently are hydrogen, halogen, (C1-4) alkyl (C1-4) alkoxy, hydroxy, amino, (C1-4) alkylamino, di(C1-4) alkylamino, mercapto, or (C1-4) alkylthio, and R3 is hydrogen or (C1-4) alkyl.
B is -o- or -NH-, D is a group of formula III
III
wherein n is 2,3 or 4, R4 is hydrogen, (C1-7) alkyl, (C3-5) alkenyl, or aralkyl, or a group of formula IV
IV
3. A process for the production of a compound of formula I
A-CO-B-D I
wherein A is a group of formula II
II
wherein the free valence is attached to either fused ring, X is -CH2-, -NR3-, -O-, or -S-R1 and R2 independently are hydrogen, halogen, (C1-4)-alkyl, (C1-4) alkoxy, hydroxy, amino, (C1-4) alkyl-amino, di-(C1-4) alkylamino, mercapto or (C1-4) alkylthio, R3 is a hydrogen or (C1-4) alkyl B is -o- or -NH-D is a group of formula III
III
wherein n is 2,3 or 4 R4 is hydrogen , (C1-7) alkyl, (C3-5) alkenyl, or aralkyl, or a group of formula V
IV
as well as acid addition salts and quaternary ammonium salts thereof, which includes the step of a) condensing an appropriate compound of formula V
A-CO-OH V
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 VI
HB-D VI
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, d) halogenating a compound of formula I wherein A is a group of formula II and R2 is hydrogen to obtain the corresponding compound wherein R2 is halogen, or 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 R2 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.
4. A bicyclic heterocyclic carboxylic acid ester or amide as defined in claim 1, or a compound of formula I as defined in claim 3, or an acid addition salt or quaternary ammonium salt of the ester or amide for use as a pharmaceutical.
5. A bicyclic heterocyclic carboxylic acid ester or amide, or a compound of formula I as defined in claim 3, or an acid addition salt or quaternary salt of the ester or amide whenever prepared according to the process of any one of claims 1 to 3.
6. A bicyclic heterocyclic carboxylic acid alkylene bridged piperidyl ester or amide with the proviso that a) in any bicyclic heterocyclic carboxylic acid amide, the bicyclic heterocycle does not contain two oxygen atoms and b) any bicyclic heterocyclic carboxylic acid ester has an alkylene bridge containing a minimum of 3 carbon atoms, attached to two piperidyl carbon atoms as well as acid addition salts and quaternary ammonium salts thereof.
7. A bicyclic heterocyclic carboxylic acid, alkylene bridged piperidyl amide as claimed in claim 6, in which the alkylene bridge is between two piperidyl carbon atoms, as well as acid addition salts and quaternary ammonium salts.
thereof.
8. A compound of formula I as defined in claim 3, as well as acid addition salts thereof and quaternary ammonium salts thereof 9. A compound of claim 8 wherein aralkyl is (C1-4) alkyl substituted by unsubstituted phenyl of phenyl mono- or poly-substituted by (C1-4) alkyl, halogen, hydroxy or (C1-4) alkoxy, as well as acid addition salts and quaternary ammonium salts thereof .
10. A compound of claim 8 which is a compound of formula Iqa wherein the free valence is attached to either fused ring, and n' is 2 or 3, and R1, R2, R3 and R4 are as defined in claim 3, as well as acid addition salts and quaternary ammonium salts thereof.
11. A compound of claim 8 which is a compound of formula Iqb wherein the free valence is attached to either fused ring, and R1qb and R2qb are independently hydrogen, halogen,or (C1-4) alkyl, R3qb is hydrogen or (C1-4) alkyl R4qb is hydrogen, (C1-7) alkyl or aralkyl, and n' is 2 or 3, as well as acid addition salts and quaternary ammonium salts thereof.
12. A compound of claim 6 of formula Iqc wherein the carbonyl group is attached to either fused ring, and R2qc is as R2 defined in claim 2 other than (C1-4) alkoxy and hydroxy, and n', R1, R3, R7 are as defined in claim 8 or 11 as well as acid addition salts and quaternary ammonium salts thereof.
13. A compound of claim 8 wherein A is a group of Formula II, wherein R1 and R2 independently are hydrogen, halogen, (C1-4) alkyl, or (C1-4) alkoxy, R1 is in the 4 or 5 positions, R3 is hydrogen or (C1-4) alkyl, and the free valence is in position 3, 4 or 5, and D is a group of formula III wherein R4 is hydrogen, (C1-4) alkyl or benzyl or a group of formula IV
wherein the free bond is attached to the 3 position as well as acid addition salts and quaternary ammonium salts thereof.
14. A compound of claim 8 which is N-(endo-9-methyl-aza-bi-cyclo[3.3.1]non-3-yl) indol-3-yl carboxylic acid amide as well as acid addition salts and quaternary ammonium salts thereof.
15. A compound of claim 7 wherein the alkylene bridge contains at least 3 carbon atoms.
16. A compound of claim 8 which is 1-methyl-N-(endo-9 methyl-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.
17. A compound of claim 8 which is 5-fluoro-1-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.
18. A compound of claim 8 which is 2-methoxy-indol-3-yl carboxylic acid endo-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl-ester as well as acid addition salts and quaternary ammonium salts thereof.
19. A compound of claim 8 which is 2-chloro-indol-3-yl carboxylic acid endo-8-methyl-8-aza-bicyclo[3,2.1]oct-3-yl ester as well as acid addition salts and quaternary ammonium salts thereof.
20. A compound of claim 8 which is 3-iodo-indol-4-yl carboxylic acid endo-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl ester as well as acid addition salts and quaternary ammonium salts thereof.
21. A compound of claim 8 which is indol-4-yl carboxylic acid endo-3-methyl-8-aza-bicyclo[3.2.1]oct-3-yl ester as well as acid addition salts and quaternary ammonium salts thereof.
22. A compound of claim 8 which is indol-4-yl carboxylic acid endo-9-methyl-9-aza-bicyclo[3.3.1]non-3-yl ester as well as acid addition salts and quaternary ammonium salts thereof.
23. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are 5-chloro-indolyl-3-yl,0,2,CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
24. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are 4-methoxy-indol-3-yl, 0,2,CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
25. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are 5-methoxy indol-3-yl,0,2,CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
26. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are 1-methyl-indol-3-yl, 0, 2, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
27 A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are indol-3-yl, 0, 2, CH3 and exo, as well as acid addition salts and quaternary ammonium salts thereof.
28. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are indol-3-yl, 0, 3, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
29. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are indol-3-yl, 0, 2, n-C3H7 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
30. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are indol-3-yl, 0, 2, benzyl and exo, as well as acid addition salts and quaternary ammonium salts thereof.
31. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are indol-3-yl, 0, 2, benzyl and endo, as well as acid addition salts and quaternary ammonium salts thereof.
32. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are indol-3-yl, 0, 2, H and endo, as well as acid addition salts and quaternary ammonium salts thereof.
33. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are 5-fluoro-indol-3-yl, 0, 3, H and endo, as well as acid addition salts and quaternary ammonium salts thereof.
34. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are 1-methyl-indol-3-yl, 0, 3, H and endo, as well as acid addition salts and quaternary ammonium salts thereof.
35. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are indol-3-yl, 0, 3, H and endo, as well as acid addition salts and quaternary ammonium salts thereof.
36. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are 5-methyl-indol-3-yl, 0, 3, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
37. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are 2-methyl-indol-3-yl, 0, 3, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
38. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are 5-fluoro-1-methyl-indol-3-yl, 0, 3, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
39. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are 5-fluoro-indol-3-yl 0,3, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
40. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are 5-fluoro-1-methyl-indol-3-yl, 0, 3, benzyl and endo, as well as acid addition salts and quaternary ammonium salts thereof.
41. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are 1-methyl-indol-3-yl, 0,3, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
42. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are 5-methyl-indol-3-yl, NH, 3, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
43. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are 5-fluoro-indol-3-yl, NH, 2, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
44. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are 1-methyl-indol-3-yl, NH, 2, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
45. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are 2-methyl-indol-3-yl, NH, 2, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
46. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are indol-3-yl, NH,2, CH3 and exo, as well as acid addition salts and quaternary ammonium salts thereof.
47. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are indol-3-yl, NH, 2, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
48. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are 5-chloro-indol-3-yl, NH, 2, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
49.A compound of claim 8wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are indol-3-yl, 0, 3, benzyl and endo, as well as acid addition salts and quaternary ammonium salts thereof.
50.A compound of claim 8wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B- D respectively are 1-methyl-indol-3-yl, 0, 3, benzyl and endo, as well as acid addition salts and quaternary ammonium salts thereof, 51.A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are 5-fluoro-indol-3-yl, 0,3, benzyl and endo, as well as acid addition salts and quaternary ammonium salts thereof, 52.A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are benzothien-3-yl, 0, 3, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
53.A compound of claim 8wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are benzothien-3-yl, NH, 3, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
54.A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are benzofuran-3-yl, NH, 3, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
55. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are benzofuran-3-yl, O, 3, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
56. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are 1(H)-inden-3-yl, NH, 3, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
57. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are indol-3-yl, NH, 4, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
58. A compound of claim 8 wherein 1) is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are indol-3-yl, O, 4, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
59. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are indol-5-yl, 0, 2, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
60. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are indol-5-yl, 0,3, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
61. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are 3-iodo-indol-5-yl, 0,3, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
62. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are indol-4-yl, NH, 2, CH3 and exo, as well as acid addition salts and quaternary ammonium salts thereof.
63. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are indol-4-yl, NH, 2, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
64. A compound of claim 8 wherein D is a group of formula III and A, B, n, R4 and the configuration of the moiety B - D respectively are indol-5-yl, NH,2, CH3 and endo, as well as acid addition salts and quaternary ammonium salts thereof.
65. A compound of claim 8 wherein A is indolyl-3-yl, B is -O-, and D is 3-quinuclidinyl as well as acid addition salts and quaternary ammonium salts thereof.
66. A compound of claim 8 wherein D is a group of formula III t and acid addition salts and quaternary ammonium salts thereof.
67. A compound of claim 66 wherein n is 3, and acid addition salts and quaternary ammonium salts thereof.
68. A compound of claim 8 wherein D is a group of formula IV, and acid addition salts and quaternary ammonium salts thereof.
69. A compound of claim 8 wherein A is indolyl and acid addition salts and quaternary ammonium salts thereof.
70. A pharmaceutical composition comprising a bicyclic heterocyclic carboxylic acid ester or amide as defined in claim 1, or a compound of formula I as defined in claim 3, or an acid addition salt or quaternary ammonium salt of the ester or amide together with a pharmaceutical carrier or diluent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000580287A CA1293256C (en) | 1982-06-29 | 1988-10-14 | Substituted benzoic acid alkylene bridged pyridil derivatives |
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH3979/82 | 1982-06-29 | ||
| CH4267/82 | 1982-07-13 | ||
| CH6950/82 | 1982-11-30 | ||
| CH6951/82 | 1982-11-30 | ||
| CH7494/82 | 1982-12-22 | ||
| CH7495/82 | 1982-12-22 | ||
| CA000580287A CA1293256C (en) | 1982-06-29 | 1988-10-14 | Substituted benzoic acid alkylene bridged pyridil derivatives |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000431385A Division CA1257870A (en) | 1982-06-29 | 1983-06-28 | Benzoic acid piperidyl ester derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1293256C true CA1293256C (en) | 1991-12-17 |
Family
ID=4138923
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000580287A Expired - Lifetime CA1293256C (en) | 1982-06-29 | 1988-10-14 | Substituted benzoic acid alkylene bridged pyridil derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1293256C (en) |
-
1988
- 1988-10-14 CA CA000580287A patent/CA1293256C/en not_active Expired - Lifetime
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