SUBSTITUTED BENZOIC ACID ALKYLENE BRIDGED PYRIDIL DERIVATIVES

DERIVES PYRIDILES A PONT ALKYLENE DE L'ACIDE BENZOIQUE SUBSTITUES

English 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.

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
<IMG> 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.

46
B is -o- or -NH-,
D is a group of formula III
<IMG> 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
<IMG> 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
<IMG> 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

47
B is -o- or -NH-
D is a group of formula III
<IMG> 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
<IMG> 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.

- 48 -
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.

49
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
<IMG>
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
<IMG>
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
<IMG>

51
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.

- 52 -
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.

-53- 100-5819
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.

-54- 100-5819
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.

100-5819
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.

- 56 - 100-5819
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.

- 57 - 100-5819
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.

- 58 - 100-5819
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.

- 59 - 100-5819
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.

- 60 - 100-5819
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.

- 61 - 100-5819
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.

- 62 - 100-5819
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.

- 63 -
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.

Description

. -- ~
~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

3Z56
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
R3
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~
12
Insofar as the production of any starting material is not
particularly described herein, it is known, or may be produced
in analogous manner to known compounds, in analogous manner to
that described herein, e.g. the examples, or to known
procedures for analogous compounds.
Compounds of formula 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~
13
Free base forms of compounds of the invention may be converted
into salt forms. For example acid addition salts may be
produced in conventional manner by reacting with a suitable
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
- 15 - 100-5819
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
- 16 - 100-5819
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
- 20 - 100-5819
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)

3256
- 21 - 100-5819
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
- 22 - 100-5819
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.
~ .
,

- 23 - 100-5819
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
.,~ . ,

1293256
~ - 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
- 25 - 100-5819
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
- 26 - 100-5819
)
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
- 27 - 100-5819
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).

56
- 28 - 100-5819
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~;
- 29 - 100-5819
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
`
- 30 - 100-5819
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
- 32 - 100-5819
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~
- 33 - 100-5819
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~
- 34 - 100-5819
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
100-5819
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
- 36 - 100-5819
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
- 37 - 100-5819
'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
.~
- 38 - 100-5819
- 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
- 41 - 100-5819
; 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
- 42 - 100-5819
:
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
- 43 100-5819
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~
- 44 - 100-5819
;
'.
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,
:
~: : : : : :