U.S. patent application number 10/554558 was filed with the patent office on 2007-03-15 for quinuclidine derivatives binding to mucarinic m3 receptors.
Invention is credited to Gurdip Bhalay, Stephen Paul Collingwood, Brian Cox, Nicholas James Devereux.
Application Number | 20070060563 10/554558 |
Document ID | / |
Family ID | 33420896 |
Filed Date | 2007-03-15 |
United States Patent
Application |
20070060563 |
Kind Code |
A1 |
Collingwood; Stephen Paul ;
et al. |
March 15, 2007 |
Quinuclidine derivatives binding to mucarinic m3 receptors
Abstract
Compounds of formula I ##STR1## in salt or zwitterionic form
wherein, wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 have the
meanings as indicated in the specification, are useful for treating
conditions that are mediated by the muscarinic M3 receptor.
Pharmaceutical compositions that contain the compounds and a
process for preparing the compounds are also described.
Inventors: |
Collingwood; Stephen Paul;
(West Sussex, GB) ; Cox; Brian; (West Sussex,
GB) ; Bhalay; Gurdip; (West Sussex, GB) ;
Devereux; Nicholas James; (West Sussex, GB) |
Correspondence
Address: |
NOVARTIS;CORPORATE INTELLECTUAL PROPERTY
ONE HEALTH PLAZA 104/3
EAST HANOVER
NJ
07936-1080
US
|
Family ID: |
33420896 |
Appl. No.: |
10/554558 |
Filed: |
April 30, 2004 |
PCT Filed: |
April 30, 2004 |
PCT NO: |
PCT/EP04/04605 |
371 Date: |
October 3, 2006 |
Current U.S.
Class: |
514/210.21 ;
514/255.05; 514/256; 514/275; 514/303; 514/305; 544/331; 544/405;
546/117; 546/133; 546/137 |
Current CPC
Class: |
A61P 37/08 20180101;
A61P 11/08 20180101; C07D 453/02 20130101; A61P 11/06 20180101;
A61P 17/06 20180101; A61P 29/00 20180101; A61P 43/00 20180101; A61P
11/00 20180101; A61P 11/02 20180101 |
Class at
Publication: |
514/210.21 ;
514/305; 514/256; 514/255.05; 514/275; 514/303; 544/331; 544/405;
546/117; 546/133; 546/137 |
International
Class: |
C07D 471/02 20060101
C07D471/02; C07D 453/02 20060101 C07D453/02; A61K 31/506 20060101
A61K031/506; A61K 31/497 20060101 A61K031/497; A61K 31/4745
20060101 A61K031/4745 |
Foreign Application Data
Date |
Code |
Application Number |
May 2, 2003 |
GB |
0310232.4 |
Oct 24, 2003 |
GB |
0324887.9 |
Claims
1. A compound of formula I ##STR514## in salt or zwitterionic form
wherein R.sup.1 and R.sup.3 are each independently a
C.sub.3-C.sub.15-carbocyclic group or a 4- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur, or --CR.sup.1R.sup.2R.sup.3
together form a group of formula ##STR515## where R is a bond,
--O--, --S--, --CH.sub.2--, --CH.dbd.CH--, --CH.sub.2--CH.sub.2--,
amino or --N(CH.sub.3)--; R.sup.2 is hydrogen, halo, hydroxy,
C.sub.1-C.sub.8-alkoxy or C.sub.1-C.sub.8-alkyl optionally
substituted by hydroxy; R.sup.4 is C.sub.1-C.sub.8-alkyl
substituted by --NHR.sup.5, --NR.sup.5--CO--R.sup.6,
--NR.sup.5--CO--NH--R.sup.7, --NR.sup.5--SO.sub.2--R.sup.8,
--CO--NR.sup.9R.sup.10, --OR.sup.11, --O--CO--NHR.sup.12,
--O--CO--R.sup.13 or --CO--O--R.sup.14, or R.sup.4 is
C.sub.3-C.sub.10-alkynyl optionally substituted by a
C.sub.3-C.sub.15-carbocyclic group or a 4- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur; R.sup.5 is hydrogen or
C.sub.1-C.sub.8-alkyl; R.sup.6 is C.sub.1-C.sub.8-alkyl,
C.sub.2-C.sub.8-alkenyl, C.sub.2-C.sub.10-alkynyl or
C.sub.1-C.sub.8-alkoxy in each case optionally substituted by a
C.sub.3-C.sub.15-carbocyclic group or a 4- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur, or R.sup.6 is a
C.sub.3-C.sub.15-carbocyclic group or a 4- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur; R.sup.7 is a
C.sub.3-C.sub.15-carbocyclic group; R.sup.8 is a
C.sub.3-C.sub.15-carbocyclic group; R.sup.9 is hydrogen or
C.sub.1-C.sub.8-alkyl; R.sup.10 is hydrogen, C.sub.1-C.sub.8-alkyl
optionally substituted by cyano, amino, nitro, carboxy,
C.sub.1-C.sub.8-alkoxy, a C.sub.3-C.sub.15-carbocyclic group, or by
a 4- to 12-membered heterocyclic group having at least one ring
heteroatom selected from nitrogen, oxygen and sulphur, or R.sup.10
is a C.sub.3-C.sub.15-carbocyclic group or a 4- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur; R.sup.11 is hydrogen,
C.sub.1-C.sub.8-alkyl, C.sub.1-C.sub.8-alkyl-C.sub.1-C.sub.8-alkoxy
or C.sub.1-C.sub.8-alkyl-O--R.sup.15; R.sup.12 is a
C.sub.3-C.sub.15-carbocyclic group; R.sup.13 is
C.sub.1-C.sub.8-alkyl or a C.sub.3-C.sub.15-carbocyclic group;
R.sup.14 is hydrogen, a C.sub.3-C.sub.15-carbocyclic group,
C.sub.1-C.sub.8-alkenyl, or C.sub.1-C.sub.8-alkyl optionally
substituted by a C.sub.3-C.sub.15-carbocyclic group; and R.sup.15
is a C.sub.3-C.sub.15-carbocyclic group.
2. A compound according to claim 1, wherein R.sup.1 and R.sup.3 are
each independently a C.sub.3-C.sub.15-carbocyclic group or a 4- to
12-membered heterocyclic group having at least one ring heteroatom
selected from nitrogen, oxygen and sulphur; R.sup.2 is halo or
hydroxy; R.sup.4 is C.sub.1-C.sub.8-alkyl substituted by
--NHR.sup.5, --NR.sup.5--CO--R.sup.6, --NR.sup.5--CO--NH--R.sup.7,
--NR.sup.5--SO.sub.2--R.sup.8, --CO--NR.sup.9R.sup.10,
--O--CO--NH--R.sup.2, --O--CO--R.sup.13 or --CO--O--R.sup.4, or
R.sup.4 is C.sub.3-C.sub.10-alkynyl optionally substituted by a
C.sub.3-C.sub.15-carbocyclic group or a 4- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur; R.sup.5 is hydrogen or
C.sub.1-C.sub.8-alkyl; R.sup.6 is C.sub.1-C.sub.8-alkyl,
C.sub.2-C.sub.10-alkynyl or C.sub.1-C.sub.8-alkoxy in each case
optionally substituted by a C.sub.3-C.sub.15-carbocyclic group or a
4- to 12-membered heterocyclic group having at least one ring
heteroatom selected from nitrogen, oxygen and sulphur, or R.sup.6
is a C.sub.3-C.sub.15-carbocyclic group or a 4- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur; R.sup.7 is a
C.sub.3-C.sub.15-carbocyclic group; R.sup.8 is a
C.sub.3-C.sub.15-carbocyclic group; R.sup.9 is hydrogen or
C.sub.1-C.sub.8-alkyl; R.sup.10 is C.sub.1-C.sub.8-alkyl optionally
substituted by cyano, C.sub.1-C.sub.8-alkoxy, a
C.sub.3-C.sub.15-carbocyclic group or by a 4- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur, or R.sup.10 is a
C.sub.3-C.sub.15-carbocyclic group or a 4- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur; R.sup.12 is a
C.sub.3-C.sub.15-carbocyclic group; R.sup.13 is
C.sub.1-C.sub.8-alkyl; and R.sup.14 is hydrogen, a
C.sub.3-C.sub.15-carbocyclic group, C.sub.1-C.sub.8-alkenyl, or
C.sub.1-C.sub.8-alkyl optionally substituted by a
C.sub.3-C.sub.15-carbocyclic group.
3. A compound according to claim 2, wherein R.sup.1 and R.sup.3 are
each independently a C.sub.6-C.sub.10-carbocyclic aromatic group or
a 4- to 12-membered heterocyclic group having at least one ring
heteroatom selected from nitrogen, oxygen and sulphur; R.sup.2 is
halo or hydroxy; R.sup.4 is C.sub.1-C.sub.8-alkyl substituted by
--NHR.sup.5, --NR.sup.5--CO--R.sup.6, --NR.sup.5--CO--NH--R.sup.7,
--NR.sup.5--SO.sub.2--R.sup.8, --CO--NR.sup.9R.sup.10,
--O--CO--NH--R.sup.2, --O--CO--R.sup.13 or --CO--O--R.sup.4, or
R.sup.4 is C.sub.3-C.sub.8-alkynyl optionally substituted by a
C.sub.3-C.sub.10-carbocyclic group or a 4- to 10-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur; R.sup.5 is hydrogen or
C.sub.1-C.sub.4-alkyl; R.sup.6 is C.sub.1-C.sub.4-alkyl,
C.sub.2-C.sub.8-alkynyl or C.sub.1-C.sub.4-alkoxy in each case
optionally substituted by a C.sub.3-C.sub.10-carbocyclic group or a
4- to 12-membered heterocyclic group having at least one ring
heteroatom selected from nitrogen, oxygen and sulphur, or R.sup.6
is a C.sub.3-C.sub.10-carbocyclic group or a 4- to 10-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur; R.sup.7 is a
C.sub.3-C.sub.10-carbocyclic group; R.sup.8 is a
C.sub.3-C.sub.10-carbocyclic group; R.sup.9 is hydrogen or
C.sub.1-C.sub.4-alkyl; R.sup.10 is C.sub.1-C.sub.4-alkyl optionally
substituted by cyano, C.sub.1-C.sub.4-alkoxy, a
C.sub.3-C.sub.10-carbocyclic group or by a 4- to 10-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur, or R.sup.10 is a
C.sub.3-C.sub.10-carbocyclic group or a 4- to 10-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur; R.sup.12 is a
C.sub.3-C.sub.10-carbocyclic group; R.sup.13 is
C.sub.1-C.sub.4-alkyl; and R.sup.14 is hydrogen, a
C.sub.3-C.sub.10-carbocyclic group, C.sub.1-C.sub.4-alkenyl, or
C.sub.1-C.sub.4-alkyl optionally substituted by a
C.sub.3-C.sub.10-carbocyclic group.
4. A compound of formula I ##STR516## in salt or zwitterionic form
wherein R.sup.1 and R.sup.3 are each independently a
C.sub.3-C.sub.15-carbocyclic group or a 4- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur, or --CR.sup.1R.sup.2R.sup.3
together form a group of formula ##STR517## where R is a bond,
--O--, --S--, --CH.sub.2--, --CH.dbd.CH--, --CH.sub.2--CH.sub.2--,
amino or --N(CH.sub.3)--; R.sup.2 is hydrogen, halo, hydroxy,
C.sub.1-C.sub.8-alkoxy or C.sub.1-C.sub.8-alkyl optionally
substituted by hydroxy; R.sup.4 is C.sub.1-C.sub.8-alkyl
substituted by --NHR.sup.5, --NR.sup.5--CO--R.sup.6,
--NR.sup.5--CO--NH--R.sup.7, --NR.sup.5--SO.sub.2--R.sup.8,
--CO--NR.sup.9R.sup.10, --OR.sup.11, --O--CO--NHR.sup.12,
--O--CO--R.sup.13 or --CO--O--R.sup.4, or R.sup.4 is
C.sub.3-C.sub.10-alkynyl optionally substituted by a
C.sub.3-C.sub.15-carbocyclic group or a 4- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur; R.sup.5 is hydrogen or
C.sub.1-C.sub.8-alkyl; R.sup.6 is C.sub.1-C.sub.8-alkyl,
C.sub.2-C.sub.8-alkenyl, C.sub.2-C.sub.10-alkynyl or
C.sub.1-C.sub.8-alkoxy in each case optionally substituted by a
C.sub.3-C.sub.15-carbocyclic group or a 4- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur, or R.sup.6 is a
C.sub.3-C.sub.15-carbocyclic group or a 4- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur; R.sup.7 is a
C.sub.3-C.sub.15-carbocyclic group; R.sup.8 is a
C.sub.3-C.sub.15-carbocyclic group; R.sup.9 is hydrogen or
C.sub.1-C.sub.8-alkyl; R.sup.10 is hydrogen, C.sub.1-C.sub.8-alkyl
optionally substituted by cyano, amino, nitro, carboxy,
C.sub.1-C.sub.8-alkoxy, a C.sub.3-C.sub.15-carbocyclic group, or by
a 4- to 12-membered heterocyclic group having at least one ring
heteroatom selected from nitrogen, oxygen and sulphur, or R.sup.10
is a C.sub.3-C.sub.15-carbocyclic group or a 4- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur; R.sup.11 is hydrogen,
C.sub.1-C.sub.8-alkyl, C.sub.1-C.sub.8-alkyl-C.sub.1-C.sub.8-alkoxy
or C.sub.1-C.sub.8-alkyl-O--R.sup.15; R.sup.12 is a
C.sub.3-C.sub.15-carbocyclic group; R.sup.13 is
C.sub.1-C.sub.8-alkyl or a C.sub.3-C.sub.15-carbocyclic group;
R.sup.14 is hydrogen, a C.sub.3-C.sub.15-carbocyclic group, or
C.sub.1-C.sub.8-alkyl optionally substituted by a
C.sub.3-C.sub.15-carbocyclic group; and R.sup.15 is a
C.sub.3-C.sub.15-carbocyclic group.
5. A compound according to claim 4, wherein R.sup.1 and R.sup.3 are
each independently a C.sub.3-C.sub.15-carbocyclic group or a 4- to
12-membered heterocyclic group having at least one ring heteroatom
selected from nitrogen, oxygen and sulphur; R.sup.2 is halo or
hydroxy; R.sup.4 is C.sub.1-C.sub.8-alkyl substituted by
--NHR.sup.5, --NR.sup.5--CO--R.sup.6, --NR.sup.5--CO--NH--R.sup.7,
--NR.sup.5--SO.sub.2--R.sup.8, --CO--NR.sup.9R.sup.10,
--O--CO--NH--R.sup.2, --O--CO--R.sup.13 or --CO--O--R.sup.4, or
R.sup.4 is C.sub.3-C.sub.10-alkynyl optionally substituted by a
C.sub.3-C.sub.15-carbocyclic group or a 4- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur; R.sup.5 is hydrogen or
C.sub.1-C.sub.8-alkyl; R.sup.6 is C.sub.1-C.sub.8-alkyl,
C.sub.2-C.sub.10-alkynyl or C.sub.1-C.sub.8-alkoxy in each case
optionally substituted by a C.sub.3-C.sub.15-carbocyclic group or a
4- to 12-membered heterocyclic group having at least one ring
heteroatom selected from nitrogen, oxygen and sulphur, or R.sup.6
is a C.sub.3-C.sub.15-carbocyclic group or a 4- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur; R.sup.7 is a
C.sub.3-C.sub.15-carbocyclic group; R.sup.8 is a
C.sub.3-C.sub.15-carbocyclic group; R.sup.9 is hydrogen or
C.sub.1-C.sub.8-alkyl; R.sup.10 is C.sub.1-C.sub.8-alkyl optionally
substituted by cyano, C.sub.1-C.sub.8-alkoxy, a
C.sub.3-C.sub.15-carbocyclic group or by a 4- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur, or R.sup.10 is a
C.sub.3-C.sub.15-carbocyclic group or a 4- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur; R.sup.12 is a
C.sub.3-C.sub.15-carbocyclic group; R.sup.13 is
C.sub.1-C.sub.8-alkyl; and R.sup.14 is hydrogen, a
C.sub.3-C.sub.15-carbocyclic group or C.sub.1-C.sub.8-alkyl
optionally substituted by a C.sub.3-C.sub.15-carbocyclic group.
6. A compound according to claim 5, wherein R.sup.1 and R.sup.3 are
each independently a C.sub.6-C.sub.10-carbocyclic aromatic group or
a 4- to 12-membered heterocyclic group having at least one ring
heteroatom selected from nitrogen, oxygen and sulphur; R.sup.2 is
halo or hydroxy; R.sup.4 is C.sub.1-C.sub.8-alkyl substituted by
--NHR.sup.5, --NR.sup.5--CO--R.sup.6, --NR.sup.5--CO--NH--R.sup.7,
--NR.sup.5--SO.sub.2--R.sup.8, --CO--NR.sup.9R.sup.10, --O--CO--N
H--R.sup.12, --O--CO--R.sup.13 or --CO--O--R.sup.14, or R.sup.4 is
C.sub.3-C.sub.8-alkynyl optionally substituted by a
C.sub.3-C.sub.10-carbocyclic group or a 4- to 10-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur; R.sup.5 is hydrogen or
C.sub.1-C.sub.4-alkyl; R.sup.6 is C.sub.1-C.sub.4-alkyl,
C.sub.2-C.sub.8-alkynyl or C.sub.1-C.sub.4-alkoxy in each case
optionally substituted by a C.sub.3-C.sub.10-carbocyclic group or a
4- to 12-membered heterocyclic group having at least one ring
heteroatom selected from nitrogen, oxygen and sulphur, or R.sup.6
is a C.sub.3-C.sub.10-carbocyclic group or a 4- to 10-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur; R.sup.7 is a
C.sub.3-C.sub.10-carbocyclic group; R.sup.8 is a
C.sub.3-C.sub.10-carbocyclic group; R.sup.9 is hydrogen or
C.sub.1-C.sub.4-alkyl; R.sup.10 is C.sub.1-C.sub.4-alkyl optionally
substituted by cyano, C.sub.1-C.sub.4-alkoxy, a
C.sub.3-C.sub.10-carbocyclic group or by a 4- to 10-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur, or R.sup.10 is a
C.sub.3-C.sub.10-carbocyclic group or a 4- to 10-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur; R.sup.12 is a
C.sub.3-C.sub.10-carbocyclic group; R.sup.13 is
C.sub.1-C.sub.4-alkyl; and R.sup.14 is hydrogen, a
C.sub.3-C.sub.10-carbocyclic group or C.sub.1-C.sub.4-alkyl
optionally substituted by a C.sub.3-C.sub.10-carbocyclic group.
7. A compound of formula I ##STR518## in salt or zwitterionic form
wherein R.sup.1 and R.sup.3 are each independently a
C.sub.3-C.sub.15-carbocyclic group or a 5- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur, or --CR.sup.1R.sup.2R.sup.3
together form a group of formula ##STR519## where R is a bond,
--O--, --S--, --CH.sub.2--, --CH.dbd.CH--, --CH.sub.2--CH.sub.2--,
amino or --N(CH.sub.3)--; R.sup.2 is hydrogen, halo, hydroxy,
C.sub.1-C.sub.8-alkoxy or C.sub.1-C.sub.8-alkyl optionally
substituted by hydroxy; R.sup.4 is C.sub.1-C.sub.8-alkyl
substituted by --NHR.sup.5, --NR.sup.5--CO--R.sup.6,
--NR.sup.5--CO--NH--R.sup.7, --NR.sup.5--SO.sub.2--R.sup.8,
--CO--NR.sup.9R.sup.10, --OR.sup.11, --O--CO--NHR.sup.2,
--O--CO--R.sup.13 or --CO--O--R.sup.14, or R.sup.4 is
C.sub.3-C.sub.10-alkynyl optionally substituted by a
C.sub.3-C.sub.15-carbocyclic group or a 5- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur; R.sup.5 is hydrogen or
C.sub.1-C.sub.8-alkyl; R.sup.6 is C.sub.1-C.sub.8-alkyl or
C.sub.1-C.sub.8-alkoxy in either case optionally substituted by a
C.sub.3-C.sub.15-carbocyclic group or a 5- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur, or R.sup.6 is a
C.sub.3-C.sub.15-carbocyclic group or a 5- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur; R.sup.7 is a
C.sub.3-C.sub.15-carbocyclic group; R.sup.8 is a
C.sub.3-C.sub.15-carbocyclic group; R.sup.9 is hydrogen or
C.sub.1-C.sub.8-alkyl; R.sup.10 is hydrogen, C.sub.1-C.sub.8-alkyl
optionally substituted by cyano, amino, nitro, carboxy,
C.sub.1-C.sub.8-alkoxy, a C.sub.3-C.sub.15-carbocyclic group, or by
a 5- to 12-membered heterocyclic group having at least one ring
heteroatom selected from nitrogen, oxygen and sulphur, or R.sup.10
is a C.sub.3-C.sub.15-carbocyclic group or a 5- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur; R.sup.11 is hydrogen,
C.sub.1-C.sub.8-alkyl, C.sub.1-C.sub.8-alkyl-C.sub.1-C.sub.8-alkoxy
or C.sub.1-C.sub.8-alkyl-O--R.sup.15; R.sup.12 is a
C.sub.3-C.sub.15-carbocyclic group; R.sup.13 is
C.sub.1-C.sub.8-alkyl or a C.sub.3-C.sub.15-carbocyclic group;
R.sup.14 is hydrogen, C.sub.1-C.sub.8-alkyl or a
C.sub.3-C.sub.15-carbocyclic group; and R.sup.15 is a
C.sub.3-C.sub.15-carbocyclic group.
8. A compound according to claim 7, wherein R.sup.1 and R.sup.3 are
each independently a C.sub.3-C.sub.15-carbocyclic group or a 5- to
12-membered heterocyclic group having at least one ring heteroatom
selected from nitrogen, oxygen and sulphur; R.sup.2 is halo or
hydroxy; R.sup.4 is C.sub.1-C.sub.8-alkyl substituted by
--NHR.sup.5, --NR.sup.5--CO--R.sup.6, --NR.sup.5--CO--NH--R.sup.7,
--NR.sup.5--SO.sub.2--R.sup.8, --CO--NR.sup.9R.sup.10,
--O--CO--NH--R.sup.2, --O--CO--R.sup.13 or --CO--O--R.sup.14, or
R.sup.4 is C.sub.3-C.sub.10-alkynyl optionally substituted by a
C.sub.3-C.sub.15-carbocyclic group or a 5- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur; R.sup.5 is hydrogen; R.sup.6 is
C.sub.1-C.sub.8-alkyl or C.sub.1-C.sub.8-alkoxy in either case
optionally substituted by a C.sub.3-C.sub.15-carbocyclic group or a
5- to 12-membered heterocyclic group having at least one ring
heteroatom selected from nitrogen, oxygen and sulphur, or R.sup.6
is a C.sub.3-C.sub.15-carbocyclic group or a 5- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur; R.sup.7 is a
C.sub.3-C.sub.15-carbocyclic group; R.sup.8 is a
C.sub.3-C.sub.15-carbocyclic group; R.sup.9 is hydrogen or
C.sub.1-C.sub.8-alkyl; R.sup.10 is C.sub.1-C.sub.8-alkyl optionally
substituted by cyano, C.sub.1-C.sub.8-alkoxy, a
C.sub.3-C.sub.15-carbocyclic group or by a 5- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur, or R.sup.10 is a
C.sub.3-C.sub.15-carbocyclic group or a 5- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur; R.sup.12 is a
C.sub.3-C.sub.15-carbocyclic group; R.sup.13 is
C.sub.1-C.sub.8-alkyl; and R.sup.14 is hydrogen,
C.sub.1-C.sub.8-alkyl or a C.sub.3-C.sub.15-carbocyclic group.
9. A compound according to claim 8, wherein R.sup.1 and R.sup.3 are
each independently a C.sub.6-C.sub.10-carbocyclic aromatic group or
a 5- to 12-membered heterocyclic group having at least one ring
heteroatom selected from nitrogen, oxygen and sulphur; R.sup.2 is
halo or hydroxy; R.sup.4 is C.sub.1-C.sub.8-alkyl substituted by
--NHR.sup.5, --NR.sup.5--CO--R.sup.6, --NR.sup.5--CO--NH--R.sup.7,
--NR.sup.5--SO.sub.2--R.sup.8, --CO--NR.sup.9R.sup.10,
--O--CO--NH--R.sup.2, --O--CO--R.sup.13 or --CO--O--R.sup.4, or
R.sup.4 is C.sub.3-C.sub.8-alkynyl optionally substituted by a
C.sub.3-C.sub.10-carbocyclic group or a 5- to 10-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur; R.sup.5 is hydrogen; R.sup.6 is
C.sub.1-C.sub.4-alkyl or C.sub.1-C.sub.4-alkoxy in either case
optionally substituted by a C.sub.3-C.sub.10-carbocyclic group or a
5- to 12-membered heterocyclic group having at least one ring
heteroatom selected from nitrogen, oxygen and sulphur, or R.sup.5
is a C.sub.3-C.sub.10-carbocyclic group or a 5- to 10-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur; R.sup.7 is a
C.sub.3-C.sub.10-carbocyclic group; R.sup.8 is a
C.sub.3-C.sub.10-carbocyclic group; R.sup.9 is hydrogen or
C.sub.1-C.sub.4-alkyl; R.sup.10 is C.sub.1-C.sub.4-alkyl optionally
substituted by cyano, C.sub.1-C.sub.4-alkoxy, a
C.sub.3-C.sub.10-carbocyclic group or by a 5- to 10-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur, or R.sup.10 is a
C.sub.3-C.sub.10-carbocyclic group or a 5- to 10-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur; R.sup.12 is a
C.sub.3-C.sub.10-carbocyclic group; R.sup.13 is
C.sub.1-C.sub.4-alkyl; and R.sup.14 is hydrogen,
C.sub.1-C.sub.4-alkyl or a C.sub.3-C.sub.10-carbocyclic group.
10. A compound according to claim 1, which is also a compound of
formula XIV ##STR520## where R.sup.1, R.sup.2, R.sup.3, and R.sup.4
are as shown in the following table: TABLE-US-00004 R.sup.1 and
R.sup.3 R.sup.4 R.sup.2 ##STR521## ##STR522## OH ##STR523##
##STR524## OH ##STR525## ##STR526## OH ##STR527## ##STR528## OH
##STR529## ##STR530## OH ##STR531## ##STR532## OH ##STR533##
##STR534## OH ##STR535## ##STR536## OH ##STR537## ##STR538## OH
##STR539## ##STR540## OH ##STR541## ##STR542## OH ##STR543##
##STR544## OH ##STR545## ##STR546## OH ##STR547## ##STR548## OH
##STR549## ##STR550## OH ##STR551## ##STR552## OH ##STR553##
##STR554## OH ##STR555## ##STR556## OH ##STR557## ##STR558## OH
##STR559## ##STR560## OH ##STR561## ##STR562## OH ##STR563##
##STR564## OH ##STR565## ##STR566## OH ##STR567## ##STR568## OH
##STR569## ##STR570## OH ##STR571## ##STR572## OH ##STR573##
##STR574## OH ##STR575## ##STR576## OH ##STR577## ##STR578## OH
##STR579## ##STR580## OH ##STR581## ##STR582## OH ##STR583##
##STR584## OH ##STR585## ##STR586## OH ##STR587## ##STR588## OH
##STR589## ##STR590## OH ##STR591## ##STR592## OH ##STR593##
##STR594## OH ##STR595## ##STR596## OH ##STR597## ##STR598## OH
##STR599## ##STR600## OH ##STR601## ##STR602## OH ##STR603##
##STR604## OH ##STR605## ##STR606## OH ##STR607## ##STR608## OH
##STR609## ##STR610## OH ##STR611## ##STR612## OH ##STR613##
##STR614## OH ##STR615## ##STR616## OH ##STR617## ##STR618## OH
##STR619## ##STR620## OH ##STR621## ##STR622## OH ##STR623##
##STR624## OH ##STR625## ##STR626## OH ##STR627## ##STR628## OH
##STR629## ##STR630## OH ##STR631## ##STR632## OH ##STR633##
##STR634## OH ##STR635## ##STR636## OH ##STR637## ##STR638## OH
##STR639## ##STR640## OH ##STR641## ##STR642## OH ##STR643##
##STR644## OH ##STR645## ##STR646## OH ##STR647## ##STR648## OH
##STR649## ##STR650## OH ##STR651## ##STR652## OH ##STR653##
##STR654## OH ##STR655## ##STR656## OH ##STR657## ##STR658## OH
##STR659## ##STR660## OH ##STR661## ##STR662## OH ##STR663##
##STR664## OH ##STR665## ##STR666## OH ##STR667## ##STR668## OH
##STR669## ##STR670## OH ##STR671## ##STR672## OH ##STR673##
##STR674## OH ##STR675## ##STR676## OH ##STR677## ##STR678## OH
##STR679## ##STR680## OH ##STR681## ##STR682## OH ##STR683##
##STR684## OH ##STR685## ##STR686## OH ##STR687## ##STR688## OH
##STR689## ##STR690## OH ##STR691## ##STR692## OH ##STR693##
##STR694## OH ##STR695## ##STR696## OH ##STR697## ##STR698## OH
##STR699## ##STR700## OH ##STR701## ##STR702## OH ##STR703##
##STR704## OH ##STR705## ##STR706## OH ##STR707## ##STR708## OH
##STR709## ##STR710## OH ##STR711## ##STR712## OH ##STR713##
##STR714## OH ##STR715## ##STR716## OH ##STR717## ##STR718## OH
##STR719## ##STR720## OH ##STR721## ##STR722## OH ##STR723##
##STR724## OH ##STR725## ##STR726## OH ##STR727## ##STR728## OH
##STR729## ##STR730## OH ##STR731## ##STR732## OH ##STR733##
##STR734## OH ##STR735## ##STR736## OH ##STR737## ##STR738## F
##STR739## ##STR740## F ##STR741## ##STR742## F ##STR743##
##STR744## OH ##STR745## ##STR746## OH ##STR747## ##STR748## OH
##STR749## ##STR750## OH ##STR751## ##STR752## OH ##STR753##
##STR754## OH ##STR755## ##STR756## OH ##STR757## ##STR758## OH
##STR759## ##STR760## OH ##STR761## ##STR762## OH ##STR763##
##STR764## OH
##STR765## ##STR766## OH ##STR767## ##STR768## OH ##STR769##
##STR770## OH ##STR771## ##STR772## OH ##STR773## ##STR774## OH
##STR775## ##STR776## OH ##STR777## ##STR778## OH ##STR779##
##STR780## OH ##STR781## ##STR782## OH ##STR783## ##STR784## OH
##STR785## ##STR786## OH ##STR787## ##STR788## OH ##STR789##
##STR790## OH ##STR791## ##STR792## OH ##STR793## ##STR794## OH
##STR795## ##STR796## OH ##STR797## ##STR798## OH ##STR799##
##STR800## OH ##STR801## ##STR802## OH ##STR803## ##STR804## OH
##STR805## ##STR806## OH ##STR807## ##STR808## OH ##STR809##
##STR810## OH ##STR811## ##STR812## OH ##STR813## ##STR814## OH
##STR815## ##STR816## OH ##STR817## ##STR818## OH ##STR819##
##STR820## OH ##STR821## ##STR822## OH ##STR823## ##STR824## OH
##STR825## ##STR826## OH ##STR827## ##STR828## OH ##STR829##
##STR830## OH ##STR831## ##STR832## OH ##STR833## ##STR834## OH
##STR835## ##STR836## OH
11. A compound according to claim 1, which is also a compound of
formula XIV ##STR837## where R.sup.1, R.sup.2, R.sup.3, and R.sup.4
are as shown in the following table: TABLE-US-00005 R.sup.1 and
R.sup.3 R.sup.4 R.sup.2 ##STR838## ##STR839## OH ##STR840##
##STR841## OH ##STR842## ##STR843## OH ##STR844## ##STR845## OH
##STR846## ##STR847## OH ##STR848## ##STR849## OH ##STR850##
##STR851## OH ##STR852## ##STR853## OH ##STR854## ##STR855## OH
##STR856## ##STR857## OH ##STR858## ##STR859## OH ##STR860##
##STR861## OH ##STR862## ##STR863## OH ##STR864## ##STR865## OH
##STR866## ##STR867## OH ##STR868## ##STR869## OH ##STR870##
##STR871## OH ##STR872## ##STR873## OH ##STR874## ##STR875## OH
##STR876## ##STR877## OH ##STR878## ##STR879## OH ##STR880##
##STR881## OH ##STR882## ##STR883## OH ##STR884## ##STR885## OH
##STR886## ##STR887## OH ##STR888## ##STR889## OH ##STR890##
##STR891## OH ##STR892## ##STR893## OH ##STR894## ##STR895## OH
##STR896## ##STR897## OH ##STR898## ##STR899## OH ##STR900##
##STR901## OH ##STR902## ##STR903## OH ##STR904## ##STR905## OH
##STR906## ##STR907## OH ##STR908## ##STR909## OH ##STR910##
##STR911## OH ##STR912## ##STR913## OH ##STR914## ##STR915## OH
##STR916## ##STR917## OH ##STR918## ##STR919## OH ##STR920##
##STR921## OH ##STR922## ##STR923## OH ##STR924## ##STR925## OH
##STR926## ##STR927## OH ##STR928## ##STR929## OH ##STR930##
##STR931## OH ##STR932## ##STR933## OH ##STR934## ##STR935## OH
##STR936## ##STR937## OH ##STR938## ##STR939## OH ##STR940##
##STR941## OH ##STR942## ##STR943## OH ##STR944## ##STR945## OH
##STR946## ##STR947## OH ##STR948## ##STR949## OH ##STR950##
##STR951## OH ##STR952## ##STR953## OH ##STR954## ##STR955## OH
##STR956## ##STR957## OH ##STR958## ##STR959## OH ##STR960##
##STR961## OH ##STR962## ##STR963## OH ##STR964## ##STR965## OH
##STR966## ##STR967## OH ##STR968## ##STR969## OH ##STR970##
##STR971## OH ##STR972## ##STR973## OH ##STR974## ##STR975## OH
##STR976## ##STR977## OH ##STR978## ##STR979## OH ##STR980##
##STR981## OH ##STR982## ##STR983## OH ##STR984## ##STR985## OH
##STR986## ##STR987## OH ##STR988## ##STR989## OH ##STR990##
##STR991## OH ##STR992## ##STR993## OH ##STR994## ##STR995## OH
##STR996## ##STR997## OH ##STR998## ##STR999## OH ##STR1000##
##STR1001## OH ##STR1002## ##STR1003## OH ##STR1004## ##STR1005##
OH ##STR1006## ##STR1007## OH ##STR1008## ##STR1009## OH
##STR1010## ##STR1011## OH
12. A compound according to claim 1, which is also a compound of
formula XIV ##STR1012## where R.sup.1, R.sup.2, R.sup.3, and
R.sup.4 are as shown in the following table: TABLE-US-00006 R.sup.1
and R.sup.3 R.sup.4 R.sup.2 ##STR1013## ##STR1014## OH ##STR1015##
##STR1016## OH
13. A compound according to claim 1 in combination with another
drug substance which is an anti-inflammatory, a bronchodilator, an
antihistamine, a decongestant or an anti-tussive drug
substance.
14. (canceled)
15. A pharmaceutical composition comprising as active ingredient a
compound according to claim 1 in combination with another drug
substance which is an anti-inflammatory, a bronchodilator, an
antihistamine, a decongestant or an anti-tussive drug substance,
optionally together with a pharmaceutically acceptable diluent or
carrier.
16-17. (canceled)
18. A process for the preparation of a compound of formula I as
claimed in claim 1 which comprises (i) (A) reacting a compound of
compound of formula II ##STR1017## or a protected form thereof
where R.sup.1, R.sup.2 and R.sup.3 are as defined in claim 1, with
a compound of formula III R.sup.4--X III where R.sup.4 is as
hereinbefore defined and X is chloro, bromo or iodo; (B) for the
preparation of compounds of formula I where R.sup.4 is
C.sub.1-C.sub.8-alkyl substituted by --NR.sup.5--CO--R.sup.6 where
R.sup.5 and R.sup.6 are as defined in claim 1, reacting a compound
of formula IV ##STR1018## or a protected form thereof where
R.sup.1, R.sup.2, R.sup.3 and R.sup.5 are as defined in claim 1,
optionally in the presence of a coupling agent, and T denotes
C.sub.1-C.sub.8-alkylene, with a compound of formula V ##STR1019##
where R.sup.6 is as defined in claim 1 or an amide-forming
derivative thereof such as an acid halide; (C) for the preparation
of compounds of formula I where R.sup.4 is C.sub.1-C.sub.8-alkyl
substituted by --NR.sup.5--CO--NH--R.sup.7 where R.sup.5 and
R.sup.7 are as defined in claim 1, reacting a compound of formula
IV or a protected form thereof where R.sup.1, R.sup.2, R.sup.3 and
R.sup.5 are as defined in claim 1 and T denotes
C.sub.1-C.sub.8-alkylene, with a compound of formula VI
O.dbd.C.dbd.N--R.sup.7 VI where R.sup.7 is as defined in claim 1;
(D) for the preparation of compounds of formula I where R.sup.4 is
C.sub.1-C.sub.8-alkyl substituted by --NR.sup.5--SO.sub.2--R.sup.8
where R.sup.5 and R.sup.8 are as defined in claim 1, reacting a
compound of formula IV or a protected form thereof where R.sup.1,
R.sup.2, and R.sup.3 are as defined in claim 1 and T denotes
C.sub.1-C.sub.8-alkylene, with a compound of formula VII
##STR1020## where R.sup.8 is as defined in claim 1 and X is halo;
or (E) for the preparation of compounds of formula I where R.sup.4
is C.sub.1-C.sub.8-alkyl substituted by --CO--NR.sup.9R.sup.10
where R.sup.9 and R.sup.10 are as defined in claim 1, reacting a
compound of formula VIII ##STR1021## or a protected form thereof
where R.sup.1, R.sup.2, and R.sup.3 are as defined in claim 1 and T
denotes C.sub.1-C.sub.8-alkylene, optionally in the presence of a
coupling agent, or an amide-forming derivative thereof such as an
acid halide, with a compound of formula IX ##STR1022## where
R.sup.9 and R.sup.10 are as defined in claim 1; and (ii) recovering
the product in salt or zwitterionic form.
19. A pharmaceutical composition comprising as active ingredient a
compound according to claim 1.
20. A method of treating a condition mediated by the muscarinic M3
receptor in a subject in need of such treatment, which comprises
administering to said subject an effective amount of a compound of
formula I as defined in claim 1 in free form or in the form of a
pharmaceutically acceptable salt.
21. A method of treating an inflammatory or obstructive airways
disease in a subject in need of such treatment, which comprises
administering to said subject an effective amount of a compound of
formula I as defined in claim 1 in free form or in the form of a
pharmaceutically acceptable salt.
Description
[0001] This invention relates to organic compounds, their
preparation and use as pharmaceuticals.
[0002] In one aspect the invention provides compounds of formula I
##STR2## in salt or zwitterionic form wherein R.sup.1 and R.sup.3
are each independently a C.sub.3-C.sub.15-carbocyclic group or a 4-
to 12-membered heterocyclic group having at least one ring
heteroatom selected from nitrogen, oxygen and sulphur, or
--CR.sup.1R.sup.2R.sup.3 together form a group of formula ##STR3##
where R is a bond, --O--, --S--, --CH.sub.2--, --CH.dbd.CH--,
--CH.sub.2--CH.sub.2--, amino or --N(CH.sub.3)--; R.sup.2 is
hydrogen, halo, hydroxy, C.sub.1-C.sub.8-alkoxy or
C.sub.1-C.sub.8-alkyl optionally substituted by hydroxy; R.sup.4 is
C.sub.3-C.sub.10-alkyl substituted by --NHR.sup.5,
--NR.sup.5--CO--R.sup.6, --NR.sup.5--CO--NH--R.sup.7,
--NRS--SO.sub.2--R.sup.8, --CO--NR.sup.9R.sup.10, --OR.sup.11,
--O--CO--NHR.sup.12, --O--CO--R.sup.13 or --CO--O--R.sup.14, or
R.sup.4 is C.sub.3-C.sub.10-alkynyl optionally substituted by a
C.sub.3-C.sub.15-carbocyclic group or a 4- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur; R.sup.5 is hydrogen or
C.sub.1-C.sub.8-alkyl; R.sup.6 is C.sub.1-C.sub.8-alkyl,
C.sub.2-C.sub.8-alkenyl, C.sub.2-C.sub.10-alkynyl or
C.sub.1-C.sub.8-alkoxy in each case optionally substituted by a
C.sub.3-C.sub.15-carbocyclic group or a 4- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur, or R.sup.6 is a
C.sub.3-C.sub.15-carbocyclic group or a 4- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur; R.sup.7 is a
C.sub.3-C.sub.15-carbocyclic group; R.sup.8 is a
C.sub.3-C.sub.15-carbocyclic group; R.sup.9 is hydrogen or
C.sub.1-C.sub.8-alkyl; R.sup.10 is hydrogen, C.sub.1-C.sub.8-alkyl
optionally substituted by cyano, amino, nitro, carboxy,
C.sub.1-C.sub.8-alkoxy, a C.sub.3-C.sub.15-carbocyclic group, or by
a 4- to 12-membered heterocyclic group having at least one ring
heteroatom selected from nitrogen, oxygen and sulphur, or R.sup.10
is a C.sub.3-C.sub.15-carbocyclic group or a 4- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur; R.sup.11 is hydrogen,
C.sub.1-C.sub.8-alkyl, C.sub.1-C.sub.8-alkyl-C.sub.1-C.sub.8-alkoxy
or C.sub.1-C.sub.8-alkyl-O--R.sup.15; [0003] R.sup.12 is a
C.sub.3-C.sub.15-carbocyclic group; [0004] R.sup.13 is
C.sub.1-C.sub.8-alkyl or a C.sub.3-C.sub.15-carbocyclic group;
[0005] R.sup.14 is hydrogen, a C.sub.3-C.sub.15-carbocyclic group,
C.sub.1-C.sub.8-alkenyl, or C.sub.1-C.sub.8-alkyl optionally
substituted by a C.sub.3-C.sub.15-carbocyclic group; and R.sup.15
is a C.sub.3-C.sub.15-carbocyclic group.
[0006] Terms used in the specification have the following
meanings:
[0007] "Optionally substituted" means the group referred to can be
substituted at one or more positions, e.g. 1, 2 or 3 positions, by
any one or any combination of the radicals described.
[0008] "C.sub.1-C.sub.8-alkyl" as used herein denotes straight
chain or branched alkyl having 1 to 8 carbon atoms. Preferably,
C.sub.1-C.sub.8-alkyl is C.sub.1-C.sub.4-alkyl.
[0009] "C.sub.1-C.sub.8-alkylene" as used herein denotes straight
chain or branched alkylene that contains 1 to 8 carbon atoms.
Preferably, C.sub.1-C.sub.8-alkylene is
C.sub.1-C.sub.4-alkylene.
[0010] "C.sub.2-C.sub.8-alkenyl" as used herein denotes straight
chain or branched hydrocarbon chains that contain two to eight
carbon atoms and one or more carbon-carbon double bonds. Preferably
"C.sub.2-C.sub.8-alkenyl" is "C.sub.2-C.sub.4-alkenyl".
[0011] "C.sub.2-C.sub.10-alkynyl" as used herein denotes straight
chain or branched hydrocarbon chains that contain two to ten carbon
atoms and one or more carbon-carbon triple bonds. Preferably
"C.sub.2-C.sub.10-alkynyl" is "C.sub.3-C.sub.8-alkynyl".
[0012] "C.sub.3-C.sub.15-carbocyclic group" as used herein denotes
a carbocyclic group having 3 to 15 ring carbon atoms, for example a
monocyclic group, either cycloaliphatic, such as a
C.sub.3-C.sub.8-cycloalkyl, or aromatic such as phenyl, which can
be substituted by one or more, usually one or two,
C.sub.1-C.sub.4-alkyl groups, or a bicyclic group such as
bicyclooctyl, bicyclononyl including indanyl and indenyl, and
bicyclodecyl including naphthyl, again any of which can be
substituted by one or more, usually one or two,
C.sub.1-C.sub.4-alkyl groups. Preferably the
C.sub.3-C.sub.15-carbocyclic group is a
C.sub.3-C.sub.10-carbocyclic group, for example cyclopropyl,
cyclopentyl, cyclohexyl, cyclohepcyl, phenyl, indanyl or naphthyl.
The C.sub.3-C.sub.15-carbocyclic group can be substituted or
unsubstituted. Preferred substituents include halo (e.g. fluoro,
chloro or bromo), cyano, hydroxy, amino, nitro, carboxy,
C.sub.1-C.sub.8-alkyl (e.g. methyl or ethyl),
halo-C.sub.1-C.sub.8-alkyl, C.sub.1-C.sub.8-alkoxy,
C.sub.1-C.sub.8-alkylcarbonyl, C.sub.1-C.sub.8-alkylsulfonyl,
--SO.sub.2NH.sub.2, a C.sub.3-C.sub.15-carbocyclic group and a 5-
to 12-membered heterocyclic group having at least one ring
heteroatom selected from nitrogen, oxygen and sulphur.
[0013] "C.sub.3-C.sub.8-cycloalkyl" as used herein denotes
cycloalkyl having 3 to 8 carbon atoms. Preferably
"C.sub.3-C.sub.8-cycloalkyl" is "C.sub.3-C.sub.6-cycloalkyl".
[0014] "C.sub.1-C.sub.8-haloalkyl" as used herein denotes
C.sub.1-C.sub.8-alkyl as hereinbefore defined substituted by one or
more halogen atoms, preferably one, two or three halogen atoms.
Preferably "C.sub.1-C.sub.8-haloalkyl" is
"C.sub.1-C.sub.4-haloalkyl".
[0015] "C.sub.1-C.sub.8-alkylcarbonyl" as used herein denotes
C.sub.1-C.sub.8-alkyl as hereinbefore defined linked to a carbonyl
group. Preferably "C.sub.1-C.sub.8-alkylcarbonyl" is
"C.sub.1-C.sub.4-alkylcarbonyl".
[0016] "C.sub.1-C.sub.8-alkylthio" as used herein denotes
C.sub.1-C.sub.8-alkyl as hereinbefore defined linked to --S--.
Preferably "C.sub.1-C.sub.8-alkylthio" is
"C.sub.1-C.sub.4-alkylthio".
[0017] "C.sub.1-C.sub.8-alkylsulfonyl" as used herein denotes
C.sub.1-C.sub.8-alkyl as hereinbefore defined linked to
--SO.sub.2--. Preferably "C.sub.1-C.sub.8-alkylsulfonyl" is
"C.sub.1-C.sub.4-alkylsulfonyl".
[0018] "C.sub.1-C.sub.8-alkoxy" as used herein denotes straight
chain or branched alkoxy having 1 to 8 carbon atoms. Preferably,
C.sub.1-C.sub.8-alkoxy is C.sub.1-C.sub.4-alkoxy.
[0019] "C.sub.1-C.sub.8-haloalkoxy" as used herein denotes
C.sub.1-C.sub.8-alkoxy as hereinbefore defined substituted by one
or more halogen atoms, preferably one, two or three halogen atoms.
Preferably "C.sub.1-C.sub.8-haloalkoxy" is
"C.sub.1-C.sub.4-haloalkoxy".
[0020] "di(C.sub.1-C.sub.8-alkyl)sulfamoyl" as used herein denotes
--SO.sub.2--NH.sub.2 where the nitrogen atom is substituted at two
positions by C.sub.1-C.sub.8-alkyl as hereinbefore defined, which
may be the same or different. Preferably
di(C.sub.1-C.sub.8-alkyl)sulfamoyl is
--SO.sub.2--N(CH.sub.3).sub.2.
[0021] "Halo" or "halogen" as used herein denotes a element
belonging to group 17 (formerly group VII) of the Periodic Table of
Elements, which may be, for example, fluorine, chlorine, bromine or
iodine. Preferably halo or halogen is fluorine, chlorine or
bromine.
[0022] "Aminocarbonyl" as used herein denotes amino attached
through the nitrogen atom to a carbonyl group.
[0023] "4- to 12-membered heterocyclic group containing at least
one ring heteroatom selected from nitrogen, oxygen and sulphur" as
used herein denotes a monoheterocyclic, biheterocyclic or
triheterocyclic group, which may be saturated or unsaturated, that
has 4 to 12 ring atoms. Monoheterocyclic groups include azetidinyl,
tetrahydrofuranyl, furyl, pyrrolyl, pyrrolidinyl, pyrazolyl,
imidazolyl, triazolyl, tetrazolyl, thienyl, thiazolyl,
thiadiazolyl, isothiazolyl, oxadiazolyl, pyridinyl, oxazolyl,
isoxazolyl, piperidinyl, pyridinyl, pyrazinyl, pyridazinyl,
pyrimidinyl, piperazinyl, morpholinyl, triazinyl, oxazinyl,
thiazolyl or tetrahydropyranyl. Biheterocyclic groups include
thienothienyl, benzazolyl, benzothienyl, benzimidazolyl,
benzodioxinyl, indazolyl, benzothiazolyl, imidazopyridinyl and
naphthyridinyl. Preferred 4- to 12-membered heterocyclic groups
include azetidinyl, tetrahydrofuranyl, furyl, pyrrolyl, pyrazolyl,
triazolyl, thienyl, thiazolyl, thiadiazolyl, oxazolyl, isoxazolyl,
tetrahydropyranyl, piperidinyl, pyridinyl, pyrazinyl, pyrimidinyl,
thienothienyl, benzazolyl, benzothienyl, benzimidazolyl,
benzodioxinyl, indazolyl and benzothiazolyl, imidazopyridinyl,
naphthyridinyl. The 4- to 12-membered heterocyclic group can be
unsubstituted or substituted at one or more positions, e.g. 1, 2 or
3 positions, by any one or any combination of substituents.
Preferred substituents include halo (e.g. fluoro, chloro or bromo),
cyano, oxo, hydroxy, carboxy, nitro, C.sub.1-C.sub.8-alkyl (e.g.
methyl or ethyl), halo-C.sub.1-C.sub.8-alkyl (e.g.
trifluoromethyl), C.sub.1-C.sub.8-alkylcarbonyl,
di(C.sub.1-C.sub.8-alkyl)sulfamoyl and C.sub.1-C.sub.8-alkoxy
optionally substituted by aminocarbonyl. Especially preferred
substituents include halo, oxo, C.sub.1-C.sub.4-alkyl and
C.sub.1-C.sub.4-alkylcarbonyl.
[0024] Throughout this specification and in the claims that follow,
unless the context requires otherwise, the word "comprise", or
variations such as "comprises" or "comprising", will be understood
to imply the inclusion of a stated integer or step or group of
integers or steps but not the exclusion of any other integer or
step or group of integers or steps.
[0025] In a second aspect the invention provides compounds of
formula I ##STR4## in salt or zwitterionic form wherein R.sup.1 and
R.sup.3 are each independently a C.sub.3-C.sub.15-carbocyclic group
or a 4- to 12-membered heterocyclic group having at least one ring
heteroatom selected from nitrogen, oxygen and sulphur, or
--CR.sup.1R.sup.2R.sup.3 together form a group of formula ##STR5##
where R is a bond, --O--, --S--, --CH.sub.2--, --CH.dbd.CH--,
--CH.sub.2--CH.sub.2--, amino or --N(CH.sub.3)--; R.sup.2 is
hydrogen, halo, hydroxy, C.sub.1-C.sub.8-alkoxy or
C.sub.1-C.sub.8-alkyl optionally substituted by hydroxy; R.sup.4 is
C.sub.1-C.sub.8-alkyl substituted by --NHR.sup.5,
--NR.sup.5--CO--R.sup.6, --NR.sup.5--CO--NH--R.sup.7,
--NR.sup.5--SO.sub.2--R.sup.8, --CO--NR.sup.9R.sup.10, --OR.sup.11,
--O--CO--NHR.sup.12, --O--CO--R.sup.13 or --CO--O--R.sup.14, or
R.sup.4 is C.sub.3-C.sub.10-alkynyl optionally substituted by a
C.sub.3-C.sub.15-carbocyclic group or a 4- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur; R.sup.5 is hydrogen or
C.sub.1-C.sub.8-alkyl; R.sup.6 is C.sub.1-C.sub.8-alkyl,
C.sub.2-C.sub.8-alkenyl, C.sub.2-C.sub.10-alkynyl or
C.sub.1-C.sub.8-alkoxy in each case optionally substituted by a
C.sub.3-C.sub.15-carbocyclic group or a 4- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur, or R.sup.6 is a
C.sub.3-C.sub.15-carbocyclic group or a 4- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur; R.sup.7 is a
C.sub.3-C.sub.15-carbocyclic group; R.sup.8 is a
C.sub.3-C.sub.15-carbocyclic group; R.sup.9 is hydrogen or
C.sub.1-C.sub.8-alkyl; R.sup.10 is hydrogen, C.sub.1-C.sub.8-alkyl
optionally substituted by cyano, amino, nitro, carboxy,
C.sub.1-C.sub.8-alkoxy, a C.sub.3-C.sub.15-carbocyclic group, or by
a 4- to 12-membered heterocyclic group having at least one ring
heteroatom selected from nitrogen, oxygen and sulphur, or R.sup.10
is a C.sub.3-C.sub.15-carbocyclic group or a 4- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur; R.sup.11 is hydrogen,
C.sub.1-C.sub.8-alkyl, C.sub.1-C.sub.8-alkyl-C.sub.1-C.sub.8-alkoxy
or C.sub.1-C.sub.8-alkyl-O--R.sup.13; R.sup.12 is a
C.sub.3-C.sub.15-carbocyclic group; R.sup.13 is
C.sub.1-C.sub.8-alkyl or a C.sub.3-C.sub.15-carbocyclic group;
R.sup.14 is hydrogen, a C.sub.3-C.sub.15-carbocyclic group, or
C.sub.1-C.sub.8-alkyl optionally substituted by a
C.sub.3-C.sub.15-carbocyclic group; and R.sup.15 is a
C.sub.3-C.sub.15-carbocyclic group.
[0026] In a third aspect the invention provides compounds of
formula I ##STR6## in salt or zwitterionic form wherein R.sup.1 and
R.sup.3 are each independently a C.sub.3-C.sub.15-carbocyclic group
or a 5- to 12-membered heterocyclic group having at least one ring
heteroatom selected from nitrogen, oxygen and sulphur, or
--CR.sup.1R.sup.2R.sup.3 together form a group of formula ##STR7##
where R is a bond, --O--, --S--, --CH.sub.2--, --CH.dbd.CH--,
--CH.sub.2--CH.sub.2--, amino or --N(CH.sub.3)--; R.sup.2 is
hydrogen, halo, hydroxy, C.sub.1-C.sub.8-alkoxy or
C.sub.1-C.sub.8-alkyl optionally substituted by hydroxy; R.sup.4 is
C.sub.1-C.sub.8-alkyl substituted by --NHR.sup.5,
--NR.sup.5--CO--R.sup.6, --NR.sup.5--CO--NH--R.sup.7,
--NRS--SO.sub.2--R.sup.8, --CO--NR.sup.9R.sup.10, --OR.sup.11,
--O--CO--NHR.sup.12, --O--CO--R.sup.13 or --CO--O--R.sup.14, or
R.sup.4 is C.sub.3-C.sub.10-alkynyl optionally substituted by a
C.sub.3-C.sub.15-carbocyclic group or a 5- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur; R.sup.5 is hydrogen or
C.sub.1-C.sub.8-alkyl; R.sup.6 is C.sub.1-C.sub.8-alkyl or
C.sub.1-C.sub.8-alkoxy in either case optionally substituted by a
C.sub.3-C.sub.15-carbocyclic group or a 5- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur, or R.sup.6 is a
C.sub.3-C.sub.15-carbocyclic group or a 5- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur; R.sup.7 is a
C.sub.3-C.sub.15-carbocyclic group; R.sup.8 is a
C.sub.3-C.sub.1-5-carbocyclic group; R.sup.9 is hydrogen or
C.sub.1-C.sub.8-alkyl; R.sup.10 is hydrogen, C.sub.1-C.sub.8-alkyl
optionally substituted by cyano, amino, nitro, carboxy,
C.sub.1-C.sub.8-alkoxy, a C.sub.3-C.sub.15-carbocyclic group, or by
a 5- to 12-membered heterocyclic group having at least one ring
heteroatom selected from nitrogen, oxygen and sulphur, or R.sup.10
is a C.sub.3-C.sub.15-carbocyclic group or a 5- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur; R.sup.11 is hydrogen,
C.sub.1-C.sub.8-alkyl, C.sub.1-C.sub.8-alkyl-C.sub.1-C.sub.8-alkoxy
or C.sub.1-C.sub.8-alkyl-O--R.sup.15; [0027] R.sup.12 is a
C.sub.3-C.sub.15-carbocyclic group; R.sup.13 is
C.sub.1-C.sub.8-alkyl or a C.sub.3-C.sub.15-carbocyclic group;
R.sup.14 is hydrogen, C.sub.1-C.sub.8-alkyl or a
C.sub.3-C.sub.15-carbocyclic group; and R.sup.15 is a
C.sub.3-C.sub.15-carbocyclic group.
[0028] Preferred compounds include those of formula I in salt or
zwitterionic form, where R.sup.1 and R.sup.3 are each independently
a C.sub.3-C.sub.15-carbocyclic group or a 4- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur;
R.sup.2 is halo or hydroxy;
R.sup.4 is C.sub.1-C.sub.8-alkyl substituted by --NHR.sup.5,
--NR.sup.5--CO--R.sup.6, --NR.sup.5--CO--NH--R.sup.7,
--NR.sup.5--SO.sub.2--R.sup.8, --CO--NR.sup.9R.sup.10,
--O--CO--NH--R.sup.12, --O--CO--R.sup.13 or --CO--O--R.sup.14,
or R.sup.4 is C.sub.3-C.sub.10-alkynyl optionally substituted by a
C.sub.3-C.sub.15-carbocyclic group or a 4- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur;
R.sup.5 is hydrogen or C.sub.1-C.sub.8-alkyl;
R.sup.6 is C.sub.1-C.sub.8-alkyl, C.sub.2-C.sub.10-alkynyl or
C.sub.1-C.sub.8-alkoxy in each case optionally substituted by a
C.sub.3-C.sub.15-carbocyclic group or a 4- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur,
or R.sup.6 is a C.sub.3-C.sub.15-carbocyclic group or a 4- to
12-membered heterocyclic group having at least one ring heteroatom
selected from nitrogen, oxygen and sulphur;
R.sup.7 is a C.sub.3-C.sub.15-carbocyclic group;
R.sup.8 is a C.sub.3-C.sub.15-carbocyclic group;
R.sup.9 is hydrogen or C.sub.1-C.sub.8-alkyl;
R.sup.10 is C.sub.1-C.sub.8-alkyl optionally substituted by cyano,
C.sub.1-C.sub.8-alkoxy, a C.sub.3-C.sub.15-carbocyclic group or by
a 4- to 12-membered heterocyclic group having at least one ring
heteroatom selected from nitrogen, oxygen and sulphur,
or R.sup.10 is a C.sub.3-C.sub.15-carbocyclic group or a 4- to
12-membered heterocyclic group having at least one ring heteroatom
selected from nitrogen, oxygen and sulphur;
R.sup.12 is a C.sub.3-C.sub.15-carbocyclic group;
R.sup.13 is C.sub.1-C.sub.8-alkyl; and
[0029] R.sup.14 is hydrogen, a C.sub.3-C.sub.15-carbocyclic group,
C.sub.1-C.sub.8-alkenyl, or C.sub.1-C.sub.8-alkyl optionally
substituted by a C.sub.3-C.sub.15-carbocyclic group.
[0030] Preferred compounds include those of formula I in salt or
zwitterionic form, where R.sup.1 and R.sup.3 are each independently
a C.sub.3-C.sub.1-5-carbocyclic group or a 4- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur;
R.sup.2 is halo or hydroxy;
R.sup.4 is C.sub.1-C.sub.8-alkyl substituted by --NHR.sup.5,
--NRS--CO--R.sup.6, --NR.sup.5--CO--NH--R.sup.7,
--NR.sup.5--SO.sub.2--R.sup.8, --CO--NR.sup.9R.sup.10,
--O--CO--NH--R.sup.12, --O--CO--R.sup.13 or --CO--O--R.sup.14,
or R.sup.4 is C.sub.3-C.sub.10-alkynyl optionally substituted by a
C.sub.3-C.sub.15-carbocyclic group or a 4- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur;
R.sup.5 is hydrogen or C.sub.1-C.sub.8-alkyl;
R.sup.6 is C.sub.1-C.sub.8-alkyl, C.sub.2-C.sub.10-alkynyl or
C.sub.1-C.sub.8-alkoxy in each case optionally substituted by a
C.sub.3-C.sub.15-carbocyclic group or a 4- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur,
or R.sup.6 is a C.sub.3-C.sub.15-carbocyclic group or a 4- to
12-membered heterocyclic group having at least one ring heteroatom
selected from nitrogen, oxygen and sulphur;
R.sup.7 is a C.sub.3-C.sub.15-carbocyclic group;
R.sup.8 is a C.sub.3-C.sub.15-carbocyclic group;
R.sup.9 is hydrogen or C.sub.1-C.sub.8-alkyl;
R.sup.10 is C.sub.1-C.sub.8-alkyl optionally substituted by cyano,
C.sub.1-C.sub.8-alkoxy, a C.sub.3-C.sub.15-carbocyclic group or by
a 4- to 12-membered heterocyclic group having at least one ring
heteroatom selected from nitrogen, oxygen and sulphur,
or R.sup.10 is a C.sub.3-C.sub.15-carbocyclic group or a 4- to
12-membered heterocyclic group having at least one ring heteroatom
selected from nitrogen, oxygen and sulphur;
R.sup.12 is a C.sub.3-C.sub.15-carbocyclic group;
R.sup.13 is C.sub.1-C.sub.8-alkyl; and
R.sup.14 is hydrogen, a C.sub.3-C.sub.15-carbocyclic group or
C.sub.1-C.sub.8-alkyl optionally substituted by a
C.sub.3-C.sub.15-carbocyclic group.
[0031] Preferred compounds also include those of formula I in salt
or zwitterionic form, where R.sup.1 and R.sup.3 are each
independently a C.sub.3-C.sub.15-carbocyclic group or a 5- to
12-membered heterocyclic group having at least one ring heteroatom
selected from nitrogen, oxygen and sulphur;
R.sup.2 is halo or hydroxy;
R.sup.4 is C.sub.1-C.sub.8-alkyl substituted by --NHR.sup.5,
--NR.sup.5--CO--R.sup.6, --NR.sup.7--CO--NH--R.sup.7,
--NR.sup.5--SO.sub.2--R.sup.8, --CO--NR.sup.9R.sup.10,
--O--CO--NH--R.sup.12, --O--CO--R.sup.13 or --CO--O--R.sup.14,
or R.sup.4 is C.sub.3-C.sub.10-alkynyl optionally substituted by a
C.sub.3-C.sub.15-carbocyclic group or a 5- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur;
R.sup.5 is hydrogen;
R.sup.6 is C.sub.1-C.sub.8-alkyl or C.sub.1-C.sub.8-alkoxy in
either case optionally substituted by a
C.sub.3-C.sub.15-carbocyclic group or a 5- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur,
or R.sup.6 is a C.sub.3-C.sub.15-carbocyclic group or a 5- to
12-membered heterocyclic group having at least one ring heteroatom
selected from nitrogen, oxygen and sulphur;
R.sup.7 is a C.sub.3-C.sub.15-carbocyclic group;
R.sup.8 is a C.sub.3-C.sub.15-carbocyclic group;
R.sup.9 is hydrogen or C.sub.1-C.sub.8-alkyl;
R.sup.10 is C.sub.1-C.sub.8-alkyl optionally substituted by cyano,
C.sub.1-C.sub.8-alkoxy, a C.sub.3-C.sub.15-carbocyclic group or by
a 5- to 12-membered heterocyclic group having at least one ring
heteroatom selected from nitrogen, oxygen and sulphur,
or R.sup.10 is a C.sub.3-C.sub.15-carbocyclic group or a 5- to
12-membered heterocyclic group having at least one ring heteroatom
selected from nitrogen, oxygen and sulphur;
R.sup.12 is a C.sub.3-C.sub.15-carbocyclic group;
R.sup.13 is C.sub.1-C.sub.8-alkyl; and
R.sup.14 is hydrogen, C.sub.1-C.sub.8-alkyl or a
C.sub.3-C.sub.15-carbocyclic group.
[0032] Especially preferred compounds include those of formula I in
salt or zwitterionic form where R.sup.1 and R.sup.3 are each
independently a C.sub.6-C.sub.10-carbocyclic aromatic group or a 4-
to 12-membered heterocyclic group having at least one ring
heteroatom selected from nitrogen, oxygen and sulphur;
R.sup.2 is halo or hydroxy;
R.sup.4 is C.sub.1-C.sub.8-alkyl substituted by --NHR.sup.5,
--NR.sup.5--CO--R.sup.6, --NR.sup.5--CO--NH--R.sup.7,
--NR.sup.5--SO.sub.2--R.sup.8, --CO--NR.sup.9R.sup.10,
--O--CO--NH--R.sup.12, --O--CO--R.sup.13 or --CO--O--R.sup.14,
or R.sup.4 is C.sub.3-C.sub.8-alkynyl optionally substituted by a
C.sub.3-C.sub.10-carbocyclic group or a 4- to 10-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur;
R.sup.5 is hydrogen or C.sub.1-C.sub.4-alkyl;
R.sup.6 is C.sub.1-C.sub.4-alkyl, C.sub.2-C.sub.8-alkynyl or
C.sub.1-C.sub.4-alkoxy in each case optionally substituted by a
C.sub.3-C.sub.10-carbocyclic group or a 4- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur,
or R.sup.6 is a C.sub.3-C.sub.10-carbocyclic group or a 4- to
10-membered heterocyclic group having at least one ring heteroatom
selected from nitrogen, oxygen and sulphur;
R.sup.7 is a C.sub.3-C.sub.10-carbocyclic group;
R.sup.8 is a C.sub.3-C.sub.10-carbocyclic group;
R.sup.9 is hydrogen or C.sub.1-C.sub.4-alkyl;
R.sup.10 is C.sub.1-C.sub.4-alkyl optionally substituted by cyano,
C.sub.1-C.sub.4-alkoxy, a C.sub.3-C.sub.10-carbocyclic group or by
a 4- to 10-membered heterocyclic group having at least one ring
heteroatom selected from nitrogen, oxygen and sulphur,
or R.sup.10 is a C.sub.3-C.sub.10-carbocyclic group or a 4- to
10-membered heterocyclic group having at least one ring heteroatom
selected from nitrogen, oxygen and sulphur;
R.sup.12 is a C.sub.3-C.sub.10-carbocyclic group;
R.sup.13 is C.sub.1-C.sub.4-alkyl; and
R.sup.14 is hydrogen, a C.sub.3-C.sub.10-carbocyclic group,
C.sub.1-C.sub.4-alkenyl, or C.sub.1-C.sub.4-alkyl optionally
substituted by a C.sub.3-C.sub.10-carbocyclic group.
[0033] Especially preferred compounds include those of formula I in
salt or zwitterionic form where R.sup.1 and R.sup.3 are each
independently a C.sub.6-C.sub.10-carbocyclic aromatic group or a 4-
to 12-membered heterocyclic group having at least one ring
heteroatom selected from nitrogen, oxygen and sulphur;
R.sup.2 is halo or hydroxy;
R.sup.4 is C.sub.1-C.sub.8-alkyl substituted by --NHR.sup.5,
--NR.sup.5--CO--R.sup.6, --NR.sup.5--CO--NH--R.sup.7,
--NR.sup.5--SO.sub.2--R.sup.8, --CO--NR.sup.9R.sup.10,
--O--CO--NH--R.sup.12, --O--CO--R.sup.13 or --CO--O--R.sup.14,
or R.sup.4 is C.sub.3-C.sub.8-alkynyl optionally substituted by a
C.sub.3-C.sub.10-carbocyclic group or a 4- to 10-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur;
[0034] R.sup.5 is hydrogen or C.sub.1-C.sub.4-alkyl; R.sup.6 is
C.sub.1-C.sub.4-alkyl, C.sub.2-C.sub.8-alkynyl or
C.sub.1-C.sub.4-alkoxy in each case optionally substituted by a
C.sub.3-C.sub.10-carbocyclic group or a 4- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur, or R.sup.6 is a
C.sub.3-C.sub.10-carbocyclic group or a 4- to 10-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur; R.sup.7 is a
C.sub.3-C.sub.10-carbocyclic group; R.sup.8 is a
C.sub.3-C.sub.10-carbocyclic group; R.sup.9 is hydrogen or
C.sub.1-C.sub.4-alkyl; R.sup.10 is C.sub.1-C.sub.4-alkyl optionally
substituted by cyano, C.sub.1-C.sub.4-alkoxy, a
C.sub.3-C.sub.10-carbocyclic group or by a 4- to 10-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur, or R.sup.10 is a
C.sub.3-C.sub.10-carbocyclic group or a 4- to 10-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur; R.sup.12 is a
C.sub.3-C.sub.10-carbocyclic group; R.sup.13 is
C.sub.1-C.sub.4-alkyl; and R.sup.14 is hydrogen, a
C.sub.3-C.sub.10-carbocyclic group or C.sub.1-C.sub.4-alkyl
optionally substituted by a C.sub.3-C.sub.10-carbocyclic group.
[0035] Especially preferred compounds also include those of formula
I in salt or zwitterionic form where
R.sup.1 and R.sup.3 are each independently a
C.sub.6-C.sub.10-carbocyclic aromatic group or a 5- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur;
R.sup.2 is halo or hydroxy;
R.sup.4 is C.sub.1-C.sub.8-alkyl substituted by --NHR.sup.5,
--NR.sup.5--CO--R.sup.6, --NR.sup.5--CO--NH--R.sup.7,
--NR.sup.5--SO.sub.2--R.sup.8, --CO--NR.sup.9R.sup.10,
--O--CO--NH--R.sup.12, --O--CO--R.sup.13 or --CO--O--R.sup.14,
or R.sup.4 is C.sub.3-C.sub.8-alkynyl optionally substituted by a
C.sub.3-C.sub.10-carbocyclic group or a 5- to 10-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur;
R.sup.5 is hydrogen;
R.sup.6 is C.sub.1-C.sub.4-alkyl or C.sub.1-C.sub.4-alkoxy in
either case optionally substituted by a
C.sub.3-C.sub.10-carbocyclic group or a 5- to 12-membered
heterocyclic group having at least one ring heteroatom selected
from nitrogen, oxygen and sulphur,
or R.sup.6 is a C.sub.3-C.sub.10-carbocyclic group or a S-- to
10-membered heterocyclic group having at least one ring heteroatom
selected from nitrogen, oxygen and sulphur;
R.sup.7 is a C.sub.3-C.sub.10-carbocyclic group;
R.sup.8 is a C.sub.3-C.sub.10-carbocyclic group;
R.sup.9 is hydrogen or C.sub.1-C.sub.4-alkyl;
R.sup.10 is C.sub.1-C.sub.4-alkyl optionally substituted by cyano,
C.sub.1-C.sub.4-alkoxy, a C.sub.3-C.sub.10-carbocyclic group or by
a 5- to 10-membered heterocyclic group having at least one ring
heteroatom selected from nitrogen, oxygen and sulphur,
or R.sup.10 is a C.sub.3-C.sub.10-carbocyclic group or a 5- to
10-membered heterocyclic group having at least one ring heteroatom
selected from nitrogen, oxygen and sulphur;
R.sup.12 is a C.sub.3-C.sub.10-carbocyclic group;
R.sup.13 is C.sub.1-C.sub.4-alkyl; and
R.sup.14 is hydrogen, C.sub.1-C.sub.4-alkyl or a
C.sub.3-C.sub.10-carbocyclic group.
[0036] The compounds of formula I are quaternary ammonium salts.
Suitable counter ions are pharmaceutically acceptable counter ions
including, for example, fluoride, chloride, bromide, iodide,
nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate,
propionate, butyrate, lactate, citrate, tartrate, malate, maleate,
succinate, benzoate, p-chlorobenzoate, diphenylacetate or
triphenylacetate, o-hydroxybenzoate, p-hydroxybenzoate,
1-hydroxynaphthalene-2-carboxylate,
3-hydroxynaphthalene-2-carboxylate, methanesulfonate and
benzenesulfonate.
[0037] Compounds of formula I that contain a basic centre are
capable of forming acid addition salts, particularly
pharmaceutically acceptable acid addition salts. Pharmaceutically
acceptable acid addition salts of the compound of formula I include
those of inorganic acids, for example, hydrohalic acids such as
hydrofluoric acid, hydrochloric acid, hydrobromic acid or
hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid; and
organic acids, for example aliphatic monocarboxylic acids such as
formic acid, acetic acid, trifluoroacetic acid, propionic acid and
butyric acid, aliphatic hydroxy acids such as lactic acid, citric
acid, tartaric acid or malic acid, dicarboxylic acids such as
maleic acid or succinic acid, aromatic carboxylic acids such as
benzoic acid, p-chlorobenzoic acid, diphenylacetic acid or
triphenylacetic acid, aromatic hydroxy acids such as
o-hydroxybenzoic acid, p-hydroxybenzoic acid,
1-hydroxynaphthalene-2-carboxylic acid or
3-hydroxynaphthalene-2-carboxylic acid, and sulfonic acids such as
methanesulfonic acid or benzenesulfonic acid. These salts may be
prepared from compounds of formula I by known salt-forming
procedures.
[0038] Compounds of formula I which contain acidic, e.g. carboxyl,
groups, are also capable of forming salts with bases, in particular
pharmaceutically acceptable bases such as those well known in the
art; suitable such salts include metal salts, particularly alkali
metal or alkaline earth metal salts such as sodium, potassium,
magnesium or calcium salts, or salts with ammonia or
pharmaceutically acceptable organic amines or heterocyclic bases
such as ethanolamines, benzylamines or pyridine. These salts may be
prepared from compounds of formula I by known salt-forming
procedures. Compounds of formula I that contain acidic, e.g.
carboxyl, groups may also exist as zwitterions with the quaternary
ammonium centre.
[0039] The compounds of the invention contain at least one
asymmetric carbon atom and thus they exist in individual optically
active isomeric forms or as mixtures thereof, e.g. as racemic
mixtures. In cases where additional asymmetric centres exist the
present invention also embraces both individual optically active
isomers as well as mixtures, e.g. diastereomeric mixtures,
thereof.
[0040] Specific especially preferred compounds of the invention are
those described hereinafter in the Examples. These have R
stereochemistry at the 3 position of the quinuclidine.
[0041] The invention also provides a process for the preparation of
compounds of formula I which comprises (i) (A) reacting a compound
of compound of formula II ##STR8## [0042] or a protected form
thereof where R.sup.1, R.sup.2 and R.sup.3 are as hereinbefore
defined, with a compound of formula III R.sup.1--X III [0043] where
R.sup.4 is as hereinbefore defined and X is chloro, bromo or iodo;
[0044] (B) for the preparation of compounds of formula I where
R.sup.4 is C.sub.1-C.sub.8-alkyl substituted by
--NR.sup.5--CO--R.sup.6 where R.sup.5 and R.sup.6 are as
hereinbefore defined, reacting a compound of formula IV ##STR9##
[0045] or a protected form thereof where R.sup.1, R.sup.2, R.sup.3
and R.sup.5 are as hereinbefore defined, optionally in the presence
of a coupling agent, and T denotes C.sub.1-C.sub.8-alkylene, with a
compound of formula V ##STR10## [0046] where R.sup.6 is as
hereinbefore defined or an amide-forming derivative thereof such as
an acid halide; [0047] (C) for the preparation of compounds of
formula I where R.sup.4 is C.sub.1-C.sub.8-alkyl substituted by
--NR.sup.5--CO--NH--R.sup.7 where R.sup.5 and R.sup.7 are as
hereinbefore defined, reacting a compound of formula IV or a
protected form thereof where R.sup.1, R.sup.2, R.sup.3 and R.sup.5
are as hereinbefore defined and T denotes C.sub.1-C.sub.8-alkylene,
with a compound of formula VI O.dbd.C.dbd.N--R.sup.7 VI [0048]
where R.sup.7 is as hereinbefore defined; [0049] (D) for the
preparation of compounds of formula I where R.sup.4 is
C.sub.1-C.sub.8-alkyl substituted by --NR.sup.5--SO.sub.2--R.sup.8
where R.sup.5 and R.sup.8 are as hereinbefore defined, reacting a
compound of formula IV or a protected form thereof where R.sup.1,
R.sup.2, and R.sup.3 are as hereinbefore defined and T denotes
C.sub.1-C.sub.8-alkylene, with a compound of formula VII ##STR11##
[0050] where R.sup.8 is as hereinbefore defined and X is halo; or
[0051] (E) for the preparation of compounds of formula I where
R.sup.4 is C.sub.1-C.sub.8-alkyl substituted by
--CO--NR.sup.9R.sup.10 where R.sup.9 and R.sup.10 are as
hereinbefore defined, reacting a compound of formula VIII ##STR12##
[0052] or a protected form thereof where R.sup.1, R.sup.2, and
R.sup.3 are as hereinbefore defined and T denotes
C.sub.1-C.sub.8-alkylene, optionally in the presence of a coupling
agent, or an amide-forming derivative thereof such as an acid
halide, with a compound of formula IX ##STR13## [0053] where
R.sup.9 and R.sup.10 are as hereinbefore defined; and (ii)
recovering the product in salt or zwitterionic form.
[0054] Process variant (A) may be effected using known procedures
for reacting quinuclidinol esters with halogenides or analogously
as hereinafter described in the Examples. The reaction is
conveniently carried out in water or an organic solvent, for
example acetonitrile, dimethylformamide (DMF), dimethylsulphoxide
(DMSO), ethyl acetate or chloroform. The reaction is carried out at
a temperature between 20.degree. C. to 120.degree. C., conveniently
between room temperature and 80.degree. C.
[0055] Process variant (B) may be effected using known procedures
for reacting amines with carboxylic acids or amide-forming
derivatives thereof such as acid halides to give amides or
analogously as hereinafter described in the Examples. The reaction
between the carboxylic acid and the amine is conveniently carried
out in an organic solvent, for example dimethylformamide (DMF),
optionally in the presence of a coupling agent, for example
O-(7-azabenzotriazol-1-yl)-N,N,--N',N'-tetramethyl-uronium
hexafluorophophate (HATU), and a base, for example
diisopropyl-ethylamine (DIPEA) or triethylamine. Suitable reaction
temperatures are from 0.degree. C. to 50.degree. C., conveniently
room temperature.
[0056] Process variant (C) may be effected using known procedures
for reacting amines with isocyanates to give ureas or analogously
as hereinafter described in the Examples. The reaction is
conveniently carried out in an organic solvent, for example
dimethylformamide (DMF), and preferably in the presence of a base,
for example DIPEA. Suitable reaction temperatures are from
-78.degree. C. to 40.degree. C., conveniently room temperature.
[0057] Process variant (D) may be effected using known procedures
for reacting amines with sulfonylhalides to give sulfonamides or
analogously as hereinafter described in the Examples. The reaction
is conveniently carried out in an organic solvent, for example
dimethylformamide (DMF), and preferably in the presence of a base,
for example DIPEA. Suitable reaction temperatures are from
0.degree. C. to 50.degree. C., conveniently room temperature.
[0058] Process variant (E) may be effected using known procedures
for reacting carboxylic acids or amide-forming derivatives thereof
such as acid halides with amines to give amides or analogously as
hereinafter described in the Examples. The reaction between the
carboxylic acid and the amine is conveniently carried out in an
organic solvent, for example dimethylsulfoxide (DMSO) or
dimethylformamide (DMF), optionally in the presence of a coupling
agent, for example HATU, and preferably in the presence of a base,
for example DIPEA. Suitable reaction temperatures are from
0.degree. C. to 50.degree. C., conveniently room temperature.
[0059] Compounds of formula II are known or may be prepared by
known procedures such as those disclosed in W. J. Rzeszotarski et
al, J. Med. Chem. 1988, 31, 1463, international patent publication
WO 01/04118 and U.S. Pat. No. 3,833,592.
[0060] Compounds of formula III are known or may be prepared by
known procedures.
[0061] Compounds of formula IV may be prepared by deprotecting a
compound of formula X ##STR14## where R.sup.1, R.sup.2, R.sup.3 and
R.sup.5 are as hereinbefore defined, Q is an amine protecting group
and T denotes C.sub.1-C.sub.8-alkylene, e.g. when Q is
t-butyloxycarbonyl by treatment with a strong acid, e.g.
hydrochloric acid or hydrobromic acid, which is conveniently
carried out in an organic solvent, for example dioxan
(1,4-dioxycyclohexane), and suitable reaction temperatures are from
0.degree. C. to 60.degree. C., conveniently room temperature.
[0062] Compounds of formula V, VI and VII are known or may be
prepared by known procedures.
[0063] Compounds of formula VIII may be prepared by cleavage of a
corresponding ester of formula XI ##STR15## where R.sup.1, R.sup.2,
and R.sup.3 are as hereinbefore defined, T denotes
C.sub.1-C.sub.8-alkylene and W denotes a group that is readily
replaceable by hydrogen. For example when W is t-butyl the compound
may be reacted with an anhydrous strong acid, e.g. hydrochloric
acid, hydrobromic acid or trifluoroacetic acid, which is
conveniently carried out in an organic solvent, for example
dioxane, and suitable reaction temperatures are from -20.degree. C.
to 40.degree. C., conveniently room temperature.
[0064] Compounds of formula IX are known or may be prepared by
known procedures.
[0065] Compounds of formula X may be prepared by reacting a
compound of formula II where R.sup.1, R.sup.2 and R.sup.3 are as
hereinbefore defined, with a compound of formula XII ##STR16##
where R.sup.5 is as hereinbefore defined, Q is an amine protecting
group e.g. t-butyloxycarbonyl, X.sup.1 is chloro, bromo or iodo and
T denotes C.sub.1-C.sub.8-alkylene. The reaction is conveniently
carried out in an organic solvent, for example DMF. Suitable
reaction temperatures are from 40.degree. C. to 120.degree. C.,
conveniently between room temperature and 80.degree. C.
[0066] Compounds of formula XI may be prepared by reacting a
compound of formula II where R.sup.1, R.sup.2 and R.sup.3 are as
hereinbefore defined, with a compound of formula XIII ##STR17##
where T denotes C.sub.1-C.sub.8-alkylene, X.sup.2 is chloro, bromo
or iodo and W is a group that is readily replaceable by hydrogen.
For example when W is t-butyl the reaction is conveniently carried
out in an organic solvent, for example DMF. Suitable reaction
temperatures are from 0.degree. C. to 120.degree. C., conveniently
between room temperature and 60.degree. C.
[0067] Compounds of formula XII and XIII are known or may be
prepared by known procedures.
[0068] Where reference is made herein to protected functional
groups or to protecting groups, the protecting groups may be chosen
in accordance with the nature of the functional group, for example
as described in Protective Groups in Organic Synthesis, T. W.
Greene and P. G. M. Wuts, John Wiley & Sons Inc, Third Edition,
1999, which reference also describes procedures suitable for
replacement of the protecting groups by hydrogen.
[0069] Compounds of formula I are quaternary ammonium salts and may
be converted between different salt forms using ion exchange
chromatography. The compounds can be obtained in the form of
hydrates or solvates containing a solvent used for crystallization.
Compounds of formula I can be recovered from reaction mixtures and
purified using known methods. Isomers, such as enantiomers, may be
obtained in a conventional manner, e.g. by fractional
crystallization, chiral phase chromatography or asymmetric
synthesis from correspondingly asymmetrically substituted, e.g.
optically active, starting materials.
[0070] Compounds of formula I in pharmaceutically acceptable salt
or zwitterionic form, hereinafter referred to alternatively as
agents of the invention, are useful as pharmaceuticals. Accordingly
the invention also provides a compound of formula I in
pharmaceutically acceptable salt or zwitterionic form for use as a
pharmaceutical. The agents of the invention act as muscarinic
antagonists, particularly muscarinic M3 receptor antagonists,
thereby inhibiting acetylcholine-induced contraction of smooth
muscle in e.g. respiratory tract, digestive tract and urinary
systems.
[0071] The affinity (Ki) of agents of the invention at the human
muscarinic acetylcholine M3 receptor can be determined in a
competitive filtration binding assay with the radio-labelled
antagonist [.sup.3H] n-methyl scopolamine methyl chloride
(NMS):
[0072] Membranes prepared from CHO cells stably transfected with
human M3 receptor at 10 .mu.g protein/well are incubated with
serial dilutions of the agents of the invention, [.sup.3H]NMS (0.25
nM) and assay buffer (20 mM HEPES, 1 mM MgCl.sub.2 at pH 7.4) for
17 hours at room temperature. The assay is carried out in a 250
.mu.L final volume, in the presence of a final dimethyl sulfoxide
concentration of 1%. Total binding of [.sup.3H]NMS is determined in
the absence of the agents of the invention with a corresponding
substituted volume of assay buffer. Non-specific binding of
[.sup.3H] NMS is determined in the presence of 300 nM ipratropium
bromide. Following the incubation period, the membranes are
harvested onto a Unifilter.TM. GF/B filter plate containing 0.05%
polyethyleneimine, using a Brandel.TM. filtration harvester 9600.
Filter plates are dried for two hours at 35.degree. C. before the
addition of Microscint.TM. `O` cocktail, and read on a Packard
Topcount.TM. scintillator using a .sup.3H-Scintillation protocol.
All IC50s are calculated with the aid of XL-Fit graph package and
K.sub.i values derived using the Cheng-Prusoff correction (Cheng
Y., Prusoff W. H. (1973) Biochem. Pharmacol 22 3099-3109).
[0073] The compounds of the Examples herein below generally have Ki
values below 1 .mu.M in the above assay. For instance, the
compounds of Examples 17, 34, 52, 54, 71, 76, 96, 114, 138, 159,
170, 190, 209, 221, 242 and 244 have M3 K.sub.i values of 0.0144,
0.0023, 0.0019, 0.0001, 0.0005, 0.0011, 0.0046, 0.0002, 0.0022.
0.0007, 0.0007, 0.0007, 0.0010, 0.0013, 0.0003 and 0.0003 .mu.M
respectively.
[0074] Having regard to their inhibition of acetyl choline binding
to M3 muscarinic receptors, agents of the invention are useful in
the treatment of conditions mediated by the muscarinic M3 receptor,
particularly those associated with increased parasympathetic tone
leading to, for example, excessive glandular secretion or smooth
muscle contraction. Treatment in accordance with the invention may
be symptomatic or prophylactic.
[0075] Having regard to their antimuscarinic activity, the agents
of the invention are useful in the relaxation of bronchial smooth
muscle and the relief of bronchoconstriction. Relief of
bronchoconstriction can be measured in models such as the in vivo
plethysmography models of Chong et al, J. Pharmacol. Toxicol.
Methods 1998, 39, 163, Hammelmann et al, Am. J. Respir. Crit. Care
Med., 1997, 156, 766 and analogous models. The agents of the
invention are therefore useful in the treatment of obstructive or
inflammatory airways diseases. In view of their long duration of
action, it is possible to administer the agents of the invention
once-a-day in the treatment of such diseases. In another aspect,
agents of the invention commonly exhibit characteristics indicating
a low incidence of side effects commonly encountered with
.beta..sub.2 agonists such as tachycardia, tremor and restlessness,
such agents accordingly being suitable for use in on demand
(rescue) treatment as well as prophylactic treatment of obstructive
or inflammatory airways diseases.
[0076] Inflammatory or obstructive airways diseases to which the
present invention is applicable include asthma of whatever type or
genesis including both intrinsic (non-allergic) asthma and
extrinsic (allergic) asthma. Treatment of asthma is also to be
understood as embracing treatment of subjects, e.g. of less than 4
or 5 years of age, exhibiting wheezing symptoms and diagnosed or
diagnosable as "wheezy infants", an established patient category of
major medical concern and now often identified as incipient or
early-phase asthmatics. (For convenience this particular asthmatic
condition is referred to as "wheezy-infant syndrome".)
[0077] Prophylactic efficacy in the treatment of asthma will be
evidenced by reduced frequency or severity of symptomatic attack,
e.g. of acute asthmatic or bronchoconstrictor attack, improvement
in lung function or improved airways hyperreactivity. It may
further be evidenced by reduced requirement for other, symptomatic
therapy, i.e. therapy for or intended to restrict or abort
symptomatic attack when it occurs, for example anti-inflammatory
(e.g. corticosteroid) or bronchodilatory. Prophylactic benefit in
asthma may in particular be apparent in subjects prone to "morning
dipping". "Morning dipping" is a recognised asthmatic syndrome,
common to a substantial percentage of asthmatics and characterised
by asthma attack, e.g. between the hours of about 4 to 6 am, i.e.
at a time normally substantially distant from any previously
administered symptomatic asthma therapy.
[0078] Other inflammatory or obstructive airways diseases and
conditions to which the present invention is applicable include
adult/acute respiratory distress syndrome (ARDS), chronic
obstructive pulmonary or airways disease (COPD or COAD), including
chronic bronchitis, or dyspnea associated therewith, emphysema, as
well as exacerbation of airways hyperreactivity consequent to other
drug therapy, in particular other inhaled drug therapy. The
invention is also applicable to the treatment of bronchitis of
whatever type or genesis including, e.g., acute, arachidic,
catarrhal, croupus, chronic or phthinoid bronchitis. Further
inflammatory or obstructive airways diseases to which the present
invention is applicable include pneumoconiosis (an inflammatory,
commonly occupational, disease of the lungs, frequently accompanied
by airways obstruction, whether chronic or acute, and occasioned by
repeated inhalation of dusts) of whatever type or genesis,
including, for example, aluminosis, anthracosis, asbestosis,
chalicosis, ptilosis, siderosis, silicosis, tabacosis and
byssinosis.
[0079] Having regard to their antimuscarinic activity, the agents
of the invention are also useful in the treatment of a condition
requiring relaxation of smooth muscle of the uterus, bladder or
vascular system. They are thus useful for the prevention or
alleviation of premature labour pains in pregnancy. They are also
useful in the treatment of chronic and acute urticaria, psoriasis,
allergic conjunctivitis, actinitis, rhinitis including allergic
rhinitis, mastocytosis, urinary disorders such as urinary
incontinence (particularly that caused by overactive bladder),
pollakiuria, neurogenic or unstable bladder, cytospasm and chronic
cystitis; gastrointestinal disorders such as irritable bowel
syndrome, spastic colitis, diverticulitis and peptic ulceration;
and cardiovascular disorders such as vagally induced sinus
bradycardia, as well as in ophthalmic interventions.
[0080] The agents of the invention are also useful as
co-therapeutic agents for use in combination with other drug
substances such as anti-inflammatory, bronchodilatory,
antihistamine, decongestant or anti-tussive drug substances,
particularly in the treatment of obstructive or inflammatory
airways diseases such as those mentioned hereinbefore, for example
as potentiators of therapeutic activity of such drugs or as a means
of reducing required dosaging or potential side effects of such
drugs. An agent of the invention may be mixed with one or more
other drug substances in a fixed pharmaceutical composition or it
may be administered separately, before, simultaneously with or
after the other drug substance(s). Accordingly the invention
includes a combination of an agent of the invention as hereinbefore
described with an anti-inflammatory, bronchodilatory,
antihistamine, decongestant or anti-tussive drug substance, said
agent of the invention and said drug substance being in the same or
different pharmaceutical composition. Such anti-inflammatory drugs
include steroids, for example glucocorticosteroids such as
budesonide, beclamethasone, fluticasone, ciclesonide or mometasone,
or steroids described in WO 02/88167, WO 02/12266, WO 02/100879 or
WO 02/00679, especially those of Examples 3, 11, 14, 17, 19, 26,
34, 37, 39, 51, 60, 67, 72, 73, 90, 99 and 101, and non-steroidal
steroid agonists such as those described in WO 00/00531, WO
02/10143, WO 03/082280, WO 03/082787, WO 03/104195, WO 04/005229;
LTB4 antagonists such as those described in U.S. Pat. No.
5,451,700; LTD4 antagonists such as montelukast and zafirlukast;
PDE4 inhibitors such as cilomilast (Ariflo.RTM. GlaxoSmithKline),
Roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer),
SCH-351591 (Schering-Plough), Arofylline (Almirall Prodesfarma),
PD189659 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801
(Celgene), SelCID(TM) CC-10004 (Celgene), KW-4490 (Kyowa Hakko
Kogyo), WO 03/104204, WO 03/104205, WO 04/000814, WO 04/000839 and
WO 04005258 (Merck), as well as those described in WO 98/18796 and
WO 03/39544; A2a agonists such as those described in EP 1052264, EP
1241176, EP 409595A2, WO 94/17090, WO 96/02543, WO 96/02553, WO
98/28319, WO 99/24449, WO 99/24450, WO 99/24451, WO 99/38877, WO
99/41267, WO 99/67263, WO 99/67264, WO 99/67265, WO 99/67266, WO
00/23457, WO 00/77018, WO 00/78774, WO 01/23399, WO 01/27130, WO
01/27131, WO 01/60835, WO 01/94368, WO 02/00676, WO 02/22630, WO
02/96462, and WO 03/086408; and A2b antagonists such as those
described in WO 02/42298.
[0081] The agents of the invention are useful in combination
therapy with chemokine receptor antagonists, calcium channel
blockers, alpha-adrenoceptor antagonists, dopamine agonists,
endothelin antagonists, substance-P antagonists, 5-LO inhibitors,
VLA-4 antagonists and theophylline.
[0082] The agents of the invention are also particularly useful as
co-therapeutic agents for use in combination with beta-2
adrenoceptor agonists or corticosteroids. Suitable beta-2
adrenoceptor agonists include salbutamol, terbutaline, salmeterol
and, especially, formoterol and pharmaceutically acceptable salts
thereof, and compounds (in free or salt or solvate form) of formula
I of WO 0075114, which document is incorporated herein by
reference, preferably compounds of the Examples thereof, especially
a compound of formula ##STR18## and pharmaceutically acceptable
salts thereof, as well as compounds (in free or salt or solvate
form) of formula I of WO 04/16601.
[0083] Co-therapeutic antihistamine drug substances include
cetirizine hydrochloride, acetaminophen, clemastine fumarate,
promethazine, loratidine, desloratidine, diphenhydramine and
fexofenadine hydrochloride.
[0084] Combinations of agents of the invention and one or more of
beta-2 adrenoceptor agonists, steroids, PDE4 inhibitors, A2a
agonists, A2b agonists and LTD4 antagonists may be used, for
example, in the treatment of asthma but particularly COPD.
[0085] In accordance with the foregoing, the present invention also
provides a method for the treatment of an obstructive or
inflammatory airways disease which comprises administering to a
subject, particularly a human subject, in need thereof a compound
of formula I, or a pharmaceutically acceptable salt or solvate
thereof, as hereinbefore described. In another aspect, the
invention provides a compound of formula I, or a pharmaceutically
acceptable salt or solvate thereof, as hereinbefore described for
use in the preparation of a medicament for the treatment of an
obstructive or inflammatory airways disease.
[0086] The agents of the invention may be administered by any
appropriate route, e.g. orally, for example in the form of a tablet
or capsule; parenterally, for example intravenously; topically to
the skin, for example in the treatment of psoriasis; intranasally,
for example in the treatment of hay fever; or, preferably, by
inhalation, particularly in the treatment of obstructive or
inflammatory airways diseases. In particular, the agents of the
invention may be delivered as an inhalable formulation for the
treatment of COPD and asthma.
[0087] In a further aspect, the invention also provides a
pharmaceutical composition comprising a compound of formula I in
free form or in the form of a pharmaceutically acceptable salt or
solvate thereof, optionally together with a pharmaceutically
acceptable diluent or carrier thereof. Such compositions may be
prepared using conventional diluents or excipients and techniques
known in the galenic art. Thus oral dosage forms may include
tablets and capsules. Formulations for topical administration may
take the form of creams, ointments, gels or transdermal delivery
systems, e.g. patches. Compositions for inhalation may comprise
aerosol or other atomizable formulations or dry powder
formulations.
[0088] When the composition comprises an aerosol formulation, it
preferably contains, for example, a hydro-fluoro-alkane (HFA)
propellant such as HFA134a or HFA227 or a mixture of these, and may
contain one or more co-solvents known in the art such as ethanol
(up to 20% by weight), and/or one or more surfactants such as oleic
acid or sorbitan trioleate, and/or one or more bulking agents such
as lactose. When the composition comprises a dry powder
formulation, it preferably contains, for example, the compound of
formula I having a particle diameter up to 10 microns, optionally
together with a diluent or carrier, such as lactose, of the desired
particle size distribution and a compound that helps to protect
against product performance deterioration due to moisture. When the
composition comprises a nebulised formulation, it preferably
contains, for example, the compound of formula I either dissolved,
or suspended, in a vehicle containing water, a co-solvent such as
ethanol or propylene glycol and a stabiliser, which may be a
surfactant.
[0089] The invention also includes (A) a compound of formula I as
hereinbefore described in free form, or a pharmaceutically
acceptable salt or solvate thereof, in inhalable form; (B) an
inhalable medicament comprising such a compound in inhalable form
together with a pharmaceutically acceptable carrier in inhalable
form; (C) a pharmaceutical product comprising such a compound in
inhalable form in association with an inhalation device; and (D) an
inhalation device containing such a compound in inhalable form.
[0090] Dosages of agents of the invention employed in practising
the present invention will of course vary depending, for example,
on the particular condition to be treated, the effect desired and
the mode of administration. In general, suitable daily dosages for
administration by inhalation are of the order of 0.0001 to 30
mg/kg, typically 0.01 to 10 mg per patient, while for oral
administration suitable daily doses are of the order of 0.01 to 100
mg/kg.
[0091] The invention is illustrated by the following Examples.
EXAMPLES
[0092] Especially preferred compounds of formula I include
compounds of formula XIV ##STR19##
[0093] where R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are as shown in
Table 1 below, the method of preparation being described
hereinafter. All compounds are quaternary ammonium salts. The table
also shows mass spectrometry data. TABLE-US-00001 TABLE 1 M/s Ex.
R.sup.1 and R.sup.3 R.sup.4 R.sup.2 M+ 1 ##STR20## ##STR21## OH
395.4 2 ##STR22## ##STR23## OH 499.4 3 ##STR24## ##STR25## OH 549.5
4 ##STR26## ##STR27## OH 524.5 5 ##STR28## ##STR29## OH 527.5 6
##STR30## ##STR31## OH 575.5 7 ##STR32## ##STR33## OH 564.5 8
##STR34## ##STR35## OH 577.5 9 ##STR36## ##STR37## OH 500.4 10
##STR38## ##STR39## OH 533.4 11 ##STR40## ##STR41## OH 559.4 12
##STR42## ##STR43## OH 533.4 13 ##STR44## ##STR45## OH 527.4 14
##STR46## ##STR47## OH 567.4 15 ##STR48## ##STR49## OH 567.4 16
##STR50## ##STR51## OH 567.4 17 ##STR52## ##STR53## OH 559.5 18
##STR54## ##STR55## OH 529.4 19 ##STR56## ##STR57## OH 529.4 20
##STR58## ##STR59## OH 557.5 21 ##STR60## ##STR61## OH 559.5 22
##STR62## ##STR63## OH 559.5 23 ##STR64## ##STR65## OH 524.4 24
##STR66## ##STR67## OH 547.4 25 ##STR68## ##STR69## OH 524.4 26
##STR70## ##STR71## OH 529.5 27 ##STR72## ##STR73## OH 500.4 28
##STR74## ##STR75## OH 500.4 29 ##STR76## ##STR77## OH 504.4 30
##STR78## ##STR79## OH 505.7 31 ##STR80## ##STR81## OH 519.7 32
##STR82## ##STR83## OH 491.7 33 ##STR84## ##STR85## OH 493.7 34
##STR86## ##STR87## OH 513.7 35 ##STR88## ##STR89## OH 527.7 36
##STR90## ##STR91## OH 548.7 37 ##STR92## ##STR93## OH 505.7 38
##STR94## ##STR95## OH 501.6 39 ##STR96## ##STR97## OH 539.7 40
##STR98## ##STR99## OH 514.7 41 ##STR100## ##STR101## OH 514.7 42
##STR102## ##STR103## OH 544.6 43 ##STR104## ##STR105## OH 533.2 44
##STR106## ##STR107## OH 577.2 45 ##STR108## ##STR109## OH 527.7 46
##STR110## ##STR111## OH 465.6 47 ##STR112## ##STR113## OH 514.4 48
##STR114## ##STR115## OH 584.3 49 ##STR116## ##STR117## OH 535.4 50
##STR118## ##STR119## OH 485.4 51 ##STR120## ##STR121## OH 546.3 52
##STR122## ##STR123## OH 471.4 53 ##STR124## ##STR125## OH 485.4 54
##STR126## ##STR127## OH 376.3 55 ##STR128## ##STR129## OH 535.0 56
##STR130## ##STR131## OH 390.3 57 ##STR132## ##STR133## OH 418.2 58
##STR134## ##STR135## OH 452.2 59 ##STR136## ##STR137## OH 495.4 60
##STR138## ##STR139## OH 452 61 ##STR140## ##STR141## OH 481 62
##STR142## ##STR143## OH 396 63 ##STR144## ##STR145## OH 567 64
##STR146## ##STR147## OH 404.2 65 ##STR148## ##STR149## OH 535.2 66
##STR150## ##STR151## OH 507.4 67 ##STR152## ##STR153## OH 500.4 68
##STR154## ##STR155## OH 506.5 69 ##STR156## ##STR157## OH 404.3 70
##STR158## ##STR159## OH 507.3 71 ##STR160## ##STR161## OH 416.3 72
##STR162## ##STR163## OH 519.4 73 ##STR164## ##STR165## OH 512.3 74
##STR166## ##STR167## OH 388.2 75 ##STR168## ##STR169## OH 497.1 76
##STR170## ##STR171## OH 483.3 77 ##STR172## ##STR173## OH 518.4 78
##STR174## ##STR175## OH 558.3 79 ##STR176## ##STR177## OH 464.7 80
##STR178## ##STR179## OH 475.2 81 ##STR180## ##STR181## OH 505.2 82
##STR182## ##STR183## OH 539.2 83 ##STR184## ##STR185## OH 501.3 84
##STR186## ##STR187## OH 505.2 85 ##STR188## ##STR189## OH 449.3 86
##STR190## ##STR191## OH 516.3 87 ##STR192## ##STR193## OH 485.3 88
##STR194## ##STR195## OH 519.2 89 ##STR196## ##STR197## OH 499.3 90
##STR198## ##STR199## OH 511.3 91 ##STR200## ##STR201## OH 519.2 92
##STR202## ##STR203## OH 519.2 93 ##STR204## ##STR205## OH 535.3 94
##STR206## ##STR207## OH 520.3 95 ##STR208## ##STR209## OH 553.2 96
##STR210## ##STR211## OH 505.3 97 ##STR212## ##STR213## OH 491.3 98
##STR214## ##STR215## OH 437.3 99 ##STR216## ##STR217## OH 423.2
100 ##STR218## ##STR219## OH 449.2 101 ##STR220## ##STR221## OH
437.3 102 ##STR222## ##STR223## OH 477.3 103 ##STR224## ##STR225##
OH 491.2 104 ##STR226## ##STR227## OH 453.3 105 ##STR228##
##STR229## OH 499.3 106 ##STR230## ##STR231## OH 448.3 107
##STR232## ##STR233## OH 578.3 108 ##STR234## ##STR235## OH 495.3
109 ##STR236## ##STR237## F 474.3 110 ##STR238## ##STR239## F 378.2
111 ##STR240## ##STR241## F 426.3 112 ##STR242## ##STR243## OH
500.4 113 ##STR244## ##STR245## OH 402.3 114 ##STR246## ##STR247##
OH 430 115 ##STR248## ##STR249## OH 535.2 116 ##STR250## ##STR251##
OH 510.2 117 ##STR252## ##STR253## OH 513.3 118 ##STR254##
##STR255## OH 561.3 119 ##STR256## ##STR257## OH 550.2 120
##STR258## ##STR259## OH 563.2
121 ##STR260## ##STR261## OH 486.2 122 ##STR262## ##STR263## OH
519.2 123 ##STR264## ##STR265## OH 545.2 124 ##STR266## ##STR267##
OH 519.2 125 ##STR268## ##STR269## OH 513.2 126 ##STR270##
##STR271## OH 553.2 127 ##STR272## ##STR273## OH 553.2 128
##STR274## ##STR275## OH 553.2 129 ##STR276## ##STR277## OH 545.2
130 ##STR278## ##STR279## OH 515.2 131 ##STR280## ##STR281## OH
515.2 132 ##STR282## ##STR283## OH 543.2 133 ##STR284## ##STR285##
OH 545.2 134 ##STR286## ##STR287## OH 511.2 135 ##STR288##
##STR289## OH 515.3 136 ##STR290## ##STR291## OH 513.2 137
##STR292## ##STR293## OH 491.3 138 ##STR294## ##STR295## OH 487.2
139 ##STR296## ##STR297## OH 525.2 140 ##STR298## ##STR299## OH
475.3 141 ##STR300## ##STR301## OH 520.2 142 ##STR302## ##STR303##
OH 525.3 143 ##STR304## ##STR305## OH 491.3 144 ##STR306##
##STR307## OH 488.3 145 ##STR308## ##STR309## OH 503.3 146
##STR310## ##STR311## OH 566.3 147 ##STR312## ##STR313## OH 507.2
148 ##STR314## ##STR315## OH 490.3 149 ##STR316## ##STR317## OH
489.3 150 ##STR318## ##STR319## OH 521.3 151 ##STR320## ##STR321##
OH 535.3 152 ##STR322## ##STR323## OH 533.2 153 ##STR324##
##STR325## OH 525.2 154 ##STR326## ##STR327## OH 569.2 155
##STR328## ##STR329## OH 503.3 156 ##STR330## ##STR331## OH 555.2
157 ##STR332## ##STR333## OH 503.3 158 ##STR334## ##STR335## OH
485.2
Preparation of Specific Examples
[0094] Abbreviations used are as follows: DAST is
diethylaminosulfur trifluoride, DCE is dichloroethane, DCM is
dichloromethane, DIPEA is diisopropylethylamine, DME is
dimethoxyethane, HATU is O-(7-azabenzotriazol-1-yl)-N,N,
--N',N'-tetramethyl-uronium hexafluorophophate, HPLC is High
Performance Liquid Chromatography, Isolute CBA is propylcarboxylic
acid, NBS is N-bromosuccinimide, PyBOP is
benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate
and THF is tetrahydrofuran. BEMP:
2-tert-Butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphospho-
rine, polymer bound.
[0095] In cases where purification is performed by C18 reverse
phase column chromatography utilising trifluoroacetic acid as a
component of the eluent, the composition of the resulting counter
ion was not confirmed spectroscopically, and may indeed be a
variable mixture of trifluoroacetate and the halide resulting from
the quaternarisation reaction. Where HATU is used as a coupling
agent the counter ion may also be hexa fluorophosphate.
Example 1
(R)-1-(3-Amino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-
[2.2.2]octane
(i) Bromide:
[0096] To a stirred solution of hydroxy-diphenyl-acetic acid
(R)-(1-aza-bicyclo[2.2.2]oct-3-yl) ester (5 g, 14.82 mmol) in DMF
(40 ml) is added 3-aminopropyl bromide (pre-neutralised from
3-aminopropyl bromide hydrobromide using polymer supported diethyl
amine) (6.47 g, 29.54 mmol). The reaction mixture is heated to
40.degree. C. overnight and then concentrated in vacuo. The crude
residue is diluted with acetonitrile and the resulting precipitate
is filtered and redissolved in DMF (20 ml). Merrifield resin is
added to this solution followed by potassium carbonate (20 mg,
catalytic amount) and the reaction is stirred at 40.degree. C. for
24 hours. The reaction mixture is filtered and acetonitrile is
added to the filtrate. The resulting precipitate is filtered and
dried in vacuo to yield the titled compound.
(ii) Chloride:
(a)
(R)-1-(3-tert-Butoxycarbonylamino-propyl)-3-(2-hydroxy-2,2-diphenyl-ac-
etoxy)-1-azonia-bicyclo[2.2.2]octane bromide
[0097] Hydroxy-diphenyl-acetic acid
(R)-(1-aza-bicyclo[2.2.2]oct-3-yl) ester (1 g, 2.97 mmol) and
3-(BOC-amino)propylbromide (1.06 g, 4.73 mmol) are dissolved in DMF
(10 ml) and stirred to 60.degree. C. for 4 hours. The solvent is
removed in vacuo and purification of the crude residue by
chromatography on C18 silica, eluting with water:acetonitrile
affords the title compound as a colourless foam.
(b)
(R)-1-(3-Amino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bic-
yclo[2.2.2]octane chloride hydrochloride
[0098] To a stirred solution of
(R)-1-(3-tert-Butoxycarbonylamino-propyl)-3-(2-hydroxy-2,2-diphenyl-aceto-
xy)-1-azonia-bicyclo[2.2.2]octane bromide [Example 1(ii)(a)] (1 g,
2.02 mmol) in dioxane (10 ml) at room temperature is added
hydrochloric acid (1.5 ml, 4M aqueous solution). The reaction
mixture is stirred for 16 hours and the solvent is removed in vacuo
to yield the titled compound as a white solid.
Example 2
(R)-1-(3-Benzoylamino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia--
bicyclo[2.2.2]-octane trifluoroacetate
[0099] To a stirred solution of benzoic acid (0.012 g, 0.1 mmol)
and HATU (0.038 g, 0.1 mmol) in DMF (0.5 ml) is added DIPEA (0.05
ml). The reaction mixture is left to stand at room temperature for
15 minutes after which time, a solution comprising
(R)-1-(3-amino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicycl-
o[2.2.2]octane chloride hydrochloride [Example 1(ii)] (0.047 g, 0.1
mmol) in DMF (0.5 ml) is added. The reaction mixture is stirred at
room temperature for 30 minutes and the solvent is removed in
vacuo. Purification by mass directed preparative HPLC eluting with
acetonitrile: water: trifluoroacetic acid yields the titled
compound as a colourless oil.
Examples 3 to 46
[0100] These compounds, namely
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{3-[(naphthalene-2-carbonyl)-ami-
no]-propyl}-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-1-[3-(4-Cyano-benzoylamino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy-
)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-1-[3-(2,6-Dimethyl-benzoylamino)-propyl]-3-(2-hydroxy-2,2-diphenyl-ac-
etoxy)-1-azonia-bicyclo-[2.2.2]octane trifluoroacetate,
(R)-1-[3-[(Biphenyl-4-carbonyl)-amino)-propyl)-3-(2-hydroxy-2,2-diphenyl--
acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(4-pyrrol-1-yl-benzoylamino)--
propyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(3-methanesulfonyl-benzoyl-am-
ino)-propyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(3-[(pyridine-3-carbonyl)-amino]-
-propyl)-1-azonia-bicyclo-[2.2.2]octane trifluoro-acetate,
(R)-1-[3-(4-Chloro-benzoylamino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetox-
y)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-1-[3-(3,5-Dimethoxy-benzoylamino)-propyl]-3-(2-hydroxy-2,2-diphenyl-a-
cetoxy)-1-azonia-bicyclo-[2.2.2]octane trifluoroacetate,
(R)-1-[3-(3-Chloro-benzoylamino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetox-
y)-1-azonia-bicyclo[2.2.2]-octane trifluoroacetate,
(R)-1-[3-(4-Ethyl-benzoyl-amino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetox-
y)-1-azonia-bicyclo[2.2.2]octane trifluoro-acetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(3-trifluoromethyl-benzoylami-
no)-propyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(4-trifluoromethyl-benzoyl-am-
ino)-propyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(2-trifluoromethyl-benzoyl-am-
ino)-propyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-1-[3-(3,4-Dimethoxy-benzoylamino)-propyl]-3-(2-hydroxy-2,2-diphenyl-a-
cetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(4-methoxy-benzoylamino)-prop-
yl]-1-azonia-bicyclo-[2.2.2]octane-trifluoro-acetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(2-methoxy-benzoylamino)-prop-
yl]-1-azonia-bicyclo[2.2.2]octane trifluoro-acetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(4-isopropoxy-benzoylamino)-p-
ropyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-1-[3-(2,4-Dimethoxy-benzoylamino)-propyl]-3-(2-hydroxy-2,2-diphenyl-a-
cetoxy)-1-azonia-bicyclo-[2.2.2]octane trifluoroacetate,
(R)-1-[3-(2,3-Dimethoxy-benzoyl-amino)-propyl]-3-(2-hydroxy-2,2-diphenyl--
acetoxy)-1-azonia-bicyclo-[2.2.2]octane trifluoro-acetate,
(R)-1-[3-(2-Cyano-benzoylamino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy-
)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-1-[3-(3-Fluoro-4-methoxy-benzoylamino)-propyl]-3-(2-hydroxy-2,2-diphe-
nyl-acetoxy)-1-azonia-bicyclo[2.2.2]-octane trifluoroacetate,
(R)-1-[3-(3-Cyano-benzoyl-amino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetox-
y)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(3-methoxy-benzoylamino)-prop-
yl]-1-azonia-bicyclo[2.2.2]octane trifluoro-acetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{3-[(pyridine-2-carbonyl)-amino]-
-propyl}-1-azonia-bicyclo[2.2.2]octane-trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(3-[(pyridine-4-carbonyl)-amino]-
-propyl)-1-azonia-bicyclo-[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(3-[(5-methyl-isoxazole-3-carbon-
yl)-amino]-propyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-1-[3-(Cyclohexanecarbonyl-amino)-propyl]-3-(2-hydroxy-2,2-diphenyl-ac-
etoxy)-1-azonia-bicyclo-[2.2.2]octane trifluoroacetate,
(R)-1-[3-(Cycloheptanecarbonyl-amino)-propyl]-3-(2-hydroxy-2,2-diphenyl-a-
cetoxy)-1-azonia-bicyclo-[2.2.2]octane trifluoroacetate,
(R)-1-[3-(Cyclopentane-carbonyl-amino)-propyl]-3-(2-hydroxy-2,2-diphenyl--
acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-1-[3-(3,3-Dimethyl-butyrylamino)-propyl]-3-(2-hydroxy-2,2-diphenyl-ac-
etoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(3-phenylacetylamino-propyl)-1-a-
zonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(3-phenyl-propionylamino)-pro-
pyl]-1-azonia-bicyclo-[2.2.2]octane trifluoroacetate,
(R)-1-(3-[(1-Acetyl-piperidine-4-carbonyl)-amino]-propyl]-3-(2-hydroxy-2,-
2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-1-[3-(2-Cyclopentyl-acetylamino)-propyl]-3-(2-hydroxy-2,2-diphenyl-ac-
etoxy)-1-azonia-bicyclo[2.2.2]-octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-{3-[(pyrazine-2-carbonyl)-amino]-p-
ropyl}-1-azonia-bicyclo-[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(3-[(indane-2-carbonyl)-amino]-p-
ropyl)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(2-pyridin-2-yl-acetylamino)--
propyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(3-[(2-methyl-pyridine-3-carbony-
l) amino]-propyl)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(2-nitro-benzoylamino)-propyl-
]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-1-[3-(2-Chloro-benzoylamino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetox-
y)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(2-methanesulfonyl-benzoylami-
no)-propyl]-1-azonia-bicyclo[2.2.2]-octane trifluoroacetate,
(R)-1-[3-(3,5-Dimethyl-benzoylamino)-propyl]-3-(2-hydroxy-2,2-diphenyl-ac-
etoxy)-1-azonia-bicyclo-[2.2.2]octane trifluoroacetate and
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(3-isobutyryl-amino-propyl)-1-az-
onia-bicyclo[2.2.2]octane trifluoroacetate respectively, are all
prepared by the procedure of Example 2 from
(R)-1-(3-Amino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicycl-
o[2.2.2]octane chloride [Example 1(ii)] and the appropriate
acid.
Example 47
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(3-phenyl-ureido)-propyl]-1-az-
onia-bicyclo-[2.2.2]octane trifluoroacetate
[0101] To a solution comprising
(R)-1-(3-amino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicycl-
o[2.2.2]octane chloride [Example 1(ii)] (0.023 g, 0.05 mmol) and
DIPEA (0.025 ml) in DMF (0.25 ml) is added phenyl isocyanate (0.006
ml). The reaction mixture is left to stand at room temperature
overnight. Purification using mass directed preparative HPLC
eluting with acetonitrile: water: trifluoroacetic acid affords the
titled compound.
Example 48
(R)-1-{3-[3-(4-Butyl-2-methyl-phenyl)-ureido]-propyl}-3-(2-hydroxy-2,2-dip-
henyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate
[0102] This compound is made via an analogous procedure to
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(3-phenyl-ureido)-propyl)-1-a-
zonia-bicyclo[2.2.2]octane trifluoroacetate (Example 47) by
replacing phenyl isocyanate with
4-butyl-1-isocyanato-2-methyl-benzene.
Example 49
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(toluene-4-sulfonylamino)-ethy-
l]-1-azonia-bicyclo[2.2.2.]octane trifluoroacetate
(i)
(R)-1-(2-tert-Butoxycarbonylamino-ethyl)-3-(2-hydroxy-2,2-diphenyl-ace-
toxy)-1-azonia-bicyclo[2.2.2]octane bromide
[0103] To a stirred suspension of hydroxy-diphenyl-acetic acid
(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (2.5 g, 7.42 mmol) in DMF
(50 ml) under an atmosphere of argon is added
(2-Bromo-ethyl)-carbamic acid tert-butyl ester (2.5 g, 11.16 mmol).
The reaction mixture is heated to 60.degree. C. overnight and then
the solvent is removed in vacuo to yield a brown oil which is used
crude in the next step.
(ii)
(R)-1-(2-Amino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bic-
yclo[2.2.2]octane bromide hydrobromide
[0104] To a stirred suspension of
(R)-1-(2-tert-butoxycarbonylamino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetox-
y)-1-azonia-bicyclo[2.2.2]octane bromide (0.5 g, 1.04 mmol) in
dioxane (25 ml) is added hydrogen bromide solution in dioxane (1
ml, prepared by bubbling HBr gas through dry, cooled dioxane). The
reaction mixture is stirred at room temperature overnight. The
solvent is removed in vacuo and purification of the crude residue
by chromatography on C18 silica, eluting with water:acetonitrile
affords the title compound as a brown solid.
(iii)
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(toluene-4-sulfonylamino-
)-ethyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate
[0105] A solution comprising
(R)-1-(2-amino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-
[2.2.2]octane bromide hydrobromide [Example 50(ii)] (0.032 g, 0.059
mmol) p-toluenesulfonyl chloride (0.011 g, 0.059 mmol) and DIPEA
(0.041 ml, 0.236 mmol) in DMF (0.5 ml) is allowed to stir at room
temperature for 66 hours. Purification using mass directed
preparative HPLC eluting with acetonitrile: water: trifluoroacetic
acid affords the titled compound.
Example 50
(R)-1-(2-Benzoylamino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-b-
icyclo[2.2.2]-octane bromide
(i)
(R)-1-(2-tert-Butoxycarbonylamino-ethyl)-3-(2-hydroxy-2,2-diphenyl-ace-
toxy)-1-azonia-bicyclo[2.2.2]octane bromide
[0106] To a stirred suspension of hydroxy-diphenyl-acetic acid
(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (2.5 g, 7.42 mmol) in DMF
(50 ml) under an atmosphere of argon is added
(2-Bromo-ethyl)-carbamic acid tert-butyl ester (2.5 g, 11.16 mmol).
The reaction mixture is heated to 60.degree. C. overnight and then
the solvent is removed in vacuo to yield a brown oil which is used
crude in the next step.
(ii)
(R)-1-(2-Amino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bic-
yclo[2.2.2]octane bromide hydrobromide
[0107] To a stirred suspension of
(R)-1-(2-tert-butoxycarbonylamino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetox-
y)-1-azonia-bicyclo[2.2.2]octane bromide (0.5 g, 1.04 mmol) in
dioxane (25 ml) is added hydrogen bromide solution in dioxane (1
ml, prepared by bubbling HBr gas through dry, cooled dioxane). The
reaction mixture is stirred at room temperature overnight. The
solvent is removed in vacuo and purification of the crude residue
by chromatography on C18 silica, eluting with water:acetonitrile
affords the title compound as a brown solid.
(iii)
(R)-1-(2-Benzoylamino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-az-
onia-bicyclo[2.2.2]-octane bromide
[0108] To a stirred suspension of
(R)-1-(2-Amino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-
[2.2.2]octane bromide hydrobromide [50(ii)] (0.28 g, 0.517 mmol) in
DCM at 0.degree. C. is added triethylamine (0.216 ml, 1.552 mmol)
followed by benzoyl bromide (0.122 ml, 1.03 mmol). The reaction
mixture is stirred at 0.degree. C. for 1.5 hours and the solvent
was removed in vacuo. Purification of the crude residue by
chromatography on C18 silica, eluting with water:acetonitrile
affords the title compound.
Example 51
(R)-1-[(5-Fluoro-benzothiazol-2-ylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diph-
enyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate
[0109] Hydroxy-diphenyl-acetic acid
(R)-(1-aza-bicyclo[2.2.2]oct-3-yl) ester (0.050 g, 0.148 mmol),
2-Bromo-N-(5-fluoro-benzothiazol-2-yl)-acetamide (0.064 g, 0.222
mmol) and potassium carbonate (0.01 g, catalytic quantity) are
added to DMSO (0.5 ml) and stirred together at 40.degree. C.
overnight. Purification using mass directed preparative HPLC
eluting with acetonitrile: water: trifluoroacetic acid affords the
titled compound.
Example 52
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-phenylcarbamoylmethyl-1-azonia-bi-
cyclo[2.2.2]octane
(i) Trifluoroacetate:
[0110] To a sealed vial containing hydroxy-diphenyl-acetic acid
(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (0.020 g, 0.059 mmol in
DMSO) is added 2-chloro-N-phenyl-acetamide (0.030 g, 0.177 mmol in
methylene chloride. The reaction mixture is stirred at room
temperature overnight and purification using mass directed
preparative HPLC eluting with acetonitrile: water: trifluoroacetic
acid affords the titled compound.
(ii) Chloride:
[0111] Hydroxy-diphenyl-acetic acid
(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (0.2 g, 0.593 mmol) and
2-chloro-N-phenyl-acetamide (0.12 g, 0.89 mmol) are added to DMSO
(2 ml) and stirred at 40.degree. C. overnight. The solvent in
removed in vacuo and purification by chromatography on C18 silica
eluting with water:acetonitrile yields the titled compound as a
chloride salt.
Example 53
(R)-1-(Benzylcarbamoyl-methyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-
-bicyclo[2.2.2]-octane trifluoroacetate
[0112] The title compound is made via an analogous procedure to
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-phenylcarbamoylmethyl-1-azonia-b-
icyclo[2.2.2]octane chloride [Example 52 (ii)] by replacing
2-chloro-N-phenyl-acetamide with
3-chloro-N-phenyl-propionamide.
Examples 54 to 58
[0113] These compounds, namely
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-prop-2-ynyl-1-azonia-bicyclo[2.2-
.2]octane trifluoroacetate,
(R)-1-(3-Benzenesulfonylamino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)--
1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-1-But-2-ynyl-3-(2-hydroxy-2,2-dipheny]-acetoxy)-1-azonia-bicyclo[2.2.-
2]octane trifluoroacetate,
(R)-1-Hex-2-ynyl-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.-
2]octane trifluoroacetate, and
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(3-phenyl-prop-2-ynyl)-1-azonia--
bicycio[2.2.2]-octane trifluoroacetate are prepared made via an
analogous procedure to
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-phenylcarbamoylmethyl-1-azonia-b-
icyclo[2.2.2]octane trifluoroacetate [Example 52 (i)] by replacing
2-chloro-N-phenyl-acetamide with the appropriate alkyl halide.
Example 59
(R)-1-(3-tert-Butoxycarbonylamino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetox-
y)-1-azonia-bicyclo[2.2.2]octane bromide
[0114] Preparation of this compound is described in Example
1(ii)(a).
Example 60
(R)-1-tert-Butoxycarbonylmethyl-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azoni-
a-bicyclo[2.2.2]-octane bromide
[0115] To a solution comprising hydroxy-diphenyl-acetic acid
(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (0.2 g, 0.593 mmol) in dry
chloroform (5 ml) is added t-butylbromoacetate (0.438 ml, 2.96
mmol). The reaction mixture is left to stand at room temperature
overnight. The solvent is removed in vacuo and purification of the
crude residue by chromatography on C18 silica, eluting with
water:acetonitrile affords the title compound as a white solid.
Example 61
(R)-1-(2-tert-Butoxycarbonylamino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy-
)-1-azonia-bicyclo[2.2.2]octane bromide
[0116] The title compound is made via an analogous procedure to
(R)-1-tert-butoxycarbonylmethyl-3
(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane
bromide (Example 60) by replacing t-butylbromoacetate with
(2-bromo-ethyl)-carbamic acid tert-butyl ester.
Example 62
(R)-1-Carboxymethyl-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.-
2.2]-octane trifluoroacetate
[0117] To a stirred solution of
(R)-1-tert-Butoxycarbonylmethyl-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azon-
ia-bicyclo[2.2.2]octane bromide (Example 60) (0.14 g, 0.264 mmol)
in chloroform (5 ml) is added trifluoroacetic acid (1 ml). The
reaction mixture is left to stir at room temperature overnight. The
solvent is removed in vacuo and purification of the residue by
chromatography on C18 silica, eluting with water:acetonitrile
affords the titled compound as a white solid.
Example 63
(R)-1-[(5,6-Diethyl-indan-2-ylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-
-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate
[0118] To a stirred suspension of
(R)-1-carboxymethyl-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2-
.2.2]octane trifluoroacetate [Ex. 62] (0.052 g, 0.102 mmol) in dry
DMF (5 ml) is added DIPEA (0.070 ml, 0.408 mmol), HATU (0.097 g,
0.255 mmol) and 5,6-Diethyl-indan-2-ylamine hydrochloride (0.058 g,
0.255 mmol). The mixture is left to stir at room temperature
overnight. The solvent is removed in vacuo and purification by mass
directed preparative HPLC eluting with acetonitrile: water:
trifluoroacetic acid yields the titled compound.
[0119] Alternatively, to a stirred suspension of
(R)-1-carboxymethyl-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2-
.2.2]octane trifluoroacetate [Ex. 62] (0.052 g, 0.102 mmol) in dry
DMF (5 ml) is added DIPEA (0.053 ml, 0.306 mmol), HATU (0.058 g,
0.153 mmol) and 5,6-Diethyl-indan-2-ylamine hydrochloride (0.035 g,
0.153 mmol). The mixture is left to stir at room temperature
overnight. The solvent is removed in vacuo and purification by mass
directed preparative HPLC eluting with acetonitrile: water:
trifluoroacetic acid yields the titled compound.
Example 64
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-pent-4-ynyl-1-azonia-bicyclo[2.2.-
2]octane trifluoroacetate
[0120] Hydroxy-diphenyl-acetic acid
(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (0.02 g, 0.059 mmol),
5-chloro-pent-1-yne (0.0073 g, 0.071 mmol), sodium iodide (0.009 g,
catalytic amount) and potassium carbonate (0.009 g, catalytic
amount) are added to acetonitrile (0.5 ml) and stirred together at
9 hours. Purification is carried out using mass directed
preparative HPLC eluting with acetonitrile: water: trifluoroacetic
acid. Further purification is carried out by heating the resulting
product in Merrifield resin in acetonitrile at 80.degree. C. for 6
hours. The mixture is allowed to cool to room temperature and then
filtered. The filtrate is concentrated in vacuo to yield the titled
product as an oil.
Example 65
(R)-1-[3-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-prop-2-ynyl]-3-(2-hydroxy-2-
,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane
trifluoroacetate
[0121] The title compound is made via an analogous procedure to
(R)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-pent-4-ynyl-1-azonia-bicyclo[2.2-
.2]octane trifluoroacetate (Example 64) by replacing
5-chloro-pent-1-yne with
2-(3-Chloro-prop-1-ynyl)-isoindole-1,3-dione, acetonitrile with
DMSO and not adding poptassium carbonate.
Examples 66 to 69
[0122] These compounds, namely
(R)-1-(2-Cyclohexylcarbamoyloxy-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-
-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(3-phenyl-ureido)-ethyl]-1-az-
onia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-1-[2-(3-Cyclohexyl-ureido)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)--
1-azonia-bicyclo-[2.2.2]octane trifluoroacetate and
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-pent-2-ynyl-1-azonia-bicyclo[2.2-
.2]octane trifluoroacetate, are all prepared made via an analogous
procedure to
(R)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-pent-4-ynyl-1-azonia-bicyclo[2.2-
.2]-octane trifluoroacetate (Example 64) by replacing acetonitrile
with DMSO and 5-chloro-pent-1-yne with the appropriate alkyl
halide.
Example 70
(R)-1-(3-tert-Butoxycarbonylamino-propyl)-3-(2-hydroxy-2,2-di-thiophen-2-y-
l-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide
(i) Hydroxy-di-thiophen-2-yl-acetic acid methyl ester
[0123] Potassium hydroxide (100 ml, 1.25 M solution) is added to
2,2'-thenil (Ubichem) at room temperature and the reaction mixture
is heated to reflux for 4 hours and then cooled to room
temperature. The solution is acidified to pH2 and extracted with
ethyl acetate (3.times.100 ml). The combined organic portions are
washed with water (100 ml), dried over Na.sub.2SO.sub.4 and cooled
to 0.degree. C. TMS-diazomethane (20 ml of a 2M solution in
hexanes) is added dropwise and the mixture is allowed to warm to
room temperature. Acetic acid (4 ml) is added and the reaction
mixture is left at room temperature overnight. The solvent is
removed in vacuo and the crude product is dried and triturated with
hexane to yield the titled compound as a brown amorphous solid.
(ii) Hydroxy-di-thiophen-2-yl-acetic acid
(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester
[0124] To a flask containing sodium metal (0.018 g, 0.786 mmol)
under an atmosphere of argon was added a suspension comprising
hydroxy-di-thiophen-2-yl-acetic acid methyl ester [Example 70
(i)](0.2 g, 0.786 mmol) and (R)-1-Aza-bicyclo[2.2.2]octan-3-ol
(0.149 g, 1.179 mmol) in toluene (3 ml). The reaction mixture was
stirred under the inert atmosphere at 85.degree. C. for 4 hours and
the solvent was removed in vacuo. The resulting crude residue was
dissolved in DCM and washed with saturated sodium bicarbonate
solution. The organic portion was dried over MgSO.sub.4 and
concentrated in vacuo to yield a brown oil. Trituration with
acetonitrile affords the titled compound.
(iii)
(R)-1-(3-tert-Butoxycarbonylamino-propyl)-3-(2-hydroxy-2,2-di-thioph-
en-2-yl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide
[0125] Hydroxy-di-thiophen-2-yl-acetic acid
(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (0.758 g, 2.17 mmol) and
3(BOC-amino)propylbromide (0.775 g, 3.25 mmol) are dissolved in DMF
(7 ml) and heated at 60.degree. C. for 2.5 hours. The solvent is
removed in vacuo and purification of the crude residue by
chromatography on C18 silica, eluting with water:acetonitrile
affords the titled compound as an oil.
Examples 71 to 75
[0126] These compounds, namely
(R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-pent-2-ynyl-1-azonia-bic-
yclo[2.2.2]octane trifluoroacetate,
(R)-1-(2-Cyclohexylcarbamoyloxy-ethyl)-3-(2-hydroxy-2,2-di-thiophen-2-yl--
acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-[2-(3-phenyl-ureido)-eth-
yl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-prop-2-ynyl-1-azonia-bic-
yclo[2.2.2]octane trifluoroacetate and
(R)-1-(Benzylcarbamoyl-methyl)-3-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-
-1-azonia-bicyclo[2.2.2]octane trifluoroacetate are all made via an
analogous procedure to
(R)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-pent-4-ynyl-1-azonia-bicyclo[2.2-
.2]-octane trifluoro-acetate (Example 64) by replacing
hydroxy-diphenyl-acetic acid
(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester with
hydroxy-di-thiophen-2-yl-acetic acid
(R)-(1-aza-bicyclo-[2.2.2]oct-3-yl)ester (Example 70(ii)), by
replacing acetonitrile with DMSO and by replacing
5-chloro-pent-1-yne with the appropriate alkyl halide.
Alternative Preparation of the Compound of Example 71 as a Bromide
Salt:
[0127] A solution of 1-bromo-2-pentyne (0.51 g, 3.44 mmol) in
chloroform (2 ml) is treated with polymer supported TEA resin.
After a few minutes this solution is added to a solution of
hydroxy-di-thiophen-2-yl-acetic acid
(R)-(1-aza-bicyclo-[2.2.2]oct-3-yl)ester (Example 70(ii)) (1.0 g,
2.87 mmol) in chloroform (2 ml). The resulting mixture is heated to
50.degree. C. for 18 h and the mixture allowed to cool to room
temperature. A white solid is isolated by filtration, washed with
chloroform and dried. Recrystallisation from
chloroform-acetonitrile, washing the resultant solid with cold
acetonitrile, and drying under vacuum gives
(R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-pent-2-ynyl-1-azonia-bic-
yclo[2.2.2]octane bromide.
Example 76
(R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-phenylcarbamoylmethyl-1-a-
zonia-bicyclo[2.2.2]octane trifluoroacetate
[0128] Hydroxy-di-thiophen-2-yl-acetic acid
(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 70(ii)) (0.03 g,
0.0857 mmol), 2-chloro-N-phenyl-acetamide (0.0218 g, 0.129 mmol),
sodium iodide (0.0026 g, catalytic amount) and potassium carbonate
(0.0026 g, catalytic amount) are added to DMSO (1 ml) and heated to
40.degree. C. overnight. The solvent is then removed in vacuo and
purification is carried out using mass directed preparative HPLC
eluting with acetonitrile: water: trifluoroacetic acid. Further
purification is required and is carried by chromatography on C18
silica, eluting with water:acetonitrile to afford the titled
compound.
Examples 77 to 79
[0129] These compounds, namely
(R)-1-[2-(3-Cyclohexyl-ureido)-ethyl]-3-(2-hydroxy-2,2-di-thiophen-2-yl-a-
cetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-1-[(5-Fluoro-benzothiazol-2-ylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-di--
thiophen-2-yl-acetoxy)-1-azonia-bicyclo[2.2.2]octane
trifluoroacetate and
(R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-(3-phenyl-prop-2-ynyl)-1-
-azonia-bicyclo[2.2.2]octane trifluoroacetate are all prepared by
an analogous procedure to
(R)-3-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-phenylcarbamoyl-methyl-1-
-azonia-bicyclo[2.2.2]octane trifluoroacetate (Example 76) by
replacing 2-chloro-N-phenyl-acetamide with the appropriate alkyl
halide.
Example 80
(R)-1-{[(Furan-2-ylmethyl)-carbamoyl]-methyl}-3-(2-hydroxy-2,2-diphenyl-ac-
etoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate
[0130] To a solution of
(R)-1-carboxymethyl-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-[-
2.2.2]octane trifluoroacetate [Example 62) (0.04 g, 0.078 mmol) in
DCM (0.5 ml) is added DIPEA (0.056 ml) and C-furan-2-yl-methylamine
(0.056 ml, 0.634 mmol) followed by PyBOP (0.055 g, 0.106 mmol) in
DMF (1 ml). The reaction mixture is left to stir at room
temperature over 48 hours. Initial purification is carried out
using Solid Phase Extraction with a pH 8 pre-conditioned column (pH
adjusted using Isolute CBA). Further purification is carried out
using mass directed preparative HPLC eluting with acetonitrile:
water: trifluoroacetic acid to afford the titled compound.
[0131] Alterbatively, to a solution of
(R)-1-carboxymethyl-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-[-
2.2.2]octane trifluoroacetate [Example 62] (0.04 g, 0.078 mmol) in
DCM (0.5 ml) is added DIPEA (0.056 ml) and C-furan-2-yl-methylamine
(0.021 ml, 0.234 mmol) followed by PyBroP (0.055 g, 0.118 mmol) in
DMF (1 ml). The reaction mixture is left to stir at room
temperature over 48 hours. Initial purification is carried out
using Solid Phase Extraction with a pH 8 pre-conditioned column (pH
adjusted using Isolute CBA). Further purification is carried out
using mass directed preparative HPLC eluting with acetonitrile:
water: trifluoroacetic acid to afford the titled compound.
Examples 81 to 108
[0132] These compounds, namely
(R)-1-[(4-Chloro-phenylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-aceto-
xy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-1-[(3,4-Dichloro-phenyl-carbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl--
acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(4-methoxy-phenylcarbamoyl)-met-
hyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-1-[(3-Chloro-phenylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-aceto-
xy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-1-[(2-Chloro-phenylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-aceto-
xy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(4-nitro-phenylcarbamoyl)-methy-
l]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(o-tolylcarbamoyl-methyl)-1-azon-
ia-bicyclo[2.2.2]octane trifluoro-acetate,
(R)-1-[(4-Chloro-benzylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-aceto-
xy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(phenethylcarbamoyl-methyl)-1-az-
onia-bicyclo[2.2.2]octane trifluoroacerate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(indan-2-ylcarbamoylmethyl)-1-az-
onia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-1-[(3-Chloro-benzylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-aceto-
xy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-1-[(2-Chloro-benzylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-aceto-
xy)-1-azonia-bicyclo[2.2.2]octane
trifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-([(naphthalen-1-
-ylmethyl)-carbamoyl]-methyl)-1-azonia-bicyclo[2.2.2]octane
trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-([3-(2-oxo-pyrrolidin-1-yl)-prop-
ylcarbamoyl]-methyl)-1-azonia-bicyclo[2.2.2]octane
trifluoroacetate,
(R)-1-[(3,4-Dichloro-benzylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-a-
cetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(2-thiophen-2-yl-ethylcarbamoyl-
)-methyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-1-[(Cyclo-hexylmethyl-carbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-ac-
etoxy)-1-azonia-bicyclo[2.2.2]-octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(isopropylcarbamoyl-methyl)-1-az-
onia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-1-Ethylcarbamoylmethyl-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bi-
cyclo[2.2.2]octane trifluoroacetate,
(R)-1-[(Cyclo-propylmethyl-carbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-a-
cetoxy)-1-azonia-bicyclo[2.2.2]-octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-propylcarbamoylmethyl-1-azonia-b-
icyclo[2.2.2]octane trifluoroacetate,
(R)-1-Cyclohexylcarbamoylmethyl-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azon-
ia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{[(thiophen-2-ylmethyl)-carbamoy-
l]-methyl}-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(2-methoxy-ethylcarbamoyl)-meth-
yl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(4-methyl-benzylcarbamoyl)-meth-
yl]-1-azonia-bicyclo[2.2.2]octane trifluoro-acetate,
(R)-1-[(2-Cyano-ethylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy-
)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-([2-(4-sulfamoyl-phenyl)-ethylca-
rbamoyl]-methyl)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate and
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(3-isopropoxy-propylcarbamoyl)--
methyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate are all
prepared by an analogous procedure to
(R)-1-[(furan-2-ylmethyl)-carbamoyl]-methyl]-3-(2-hydroxy-2,2-diphenyl-ac-
etoxy)-1-azonia-bicyclo[2.2.2]-octane trifluoroacetate (Example
80)) by replacing C-furan-2-yl-methylamine with the appropriate
amine.
Example 109
(R)-3-(2-Fluoro-2,2-diphenyl-acetoxy)-1-phenoxycarbonylmethyl-1-azonia-bic-
yclo[2.2.2]-octane bromide
(i) Fluoro-diphenyl-acetic acid
(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester
[0133] To a cooled (0.degree. C.), stirred solution of DAST (0.101
ml, 0.826 mmol) in DCM (0.5 ml) under an atmosphere of argon is
added, dropwise over 10 minutes, a suspension of
hydroxydiphenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester
(0.209 g, 0.62 mmol) in DCM (10 ml). The reaction mixture is
stirred at 0.degree. C. for 1 hour after which time water (5 ml) is
added dropwise followed by sodium hydrogen carbonate solution (3
ml, 10% w/w NaHCO.sub.3) to adjust the pH of the solution to pH8.
The reaction mixture is diluted with DCM (10 ml) and the organic
portion is separated. The aqueous layer is extracted with DCM (10
ml) and the organic portions are combined, dried over MgSO.sub.4
and concentrated in vacuo. Purification of the crude residue is
carried by chromatography on silica, eluting with DCM: methanol to
yield the titled compound as a brown oil.
(ii)
(R)-3-(2-Fluoro-2,2-diphenyl-acetoxy)-1-phenoxycarbonylmethyl-1-azoni-
a-bicyclo[2.2.2]-octane bromide
[0134] To a solution of fluoro-diphenyl-acetic acid
(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester [Example 109(i)] (0.034 g,
0.1 mmol) in DMSO (0.25 ml) is added bromo-acetic acid phenyl ester
(0.071 ml, 0.5 mmol). The reaction mixture is left standing at room
temperature overnight. Purification is carried out by
chromatography on C18 silica, eluting with water:acetonitrile to
yield the titled compound as a colourless oil.
Examples 110 and 111
[0135] These compounds, namely
(R)-3-(2-Fluoro-2,2-diphenyl-acetoxy)-1-prop-2-ynyl-1-azonia-bicyclo[2.2.-
2]octane bromide and
(R)-1-(2-Acetoxy-ethyl)-3-(2-fluoro-2,2-diphenyl-acetoxy)-1-azonia-bicycl-
o[2.2.2]octane bromide are prepared by an analogous method to
(R)-3-(2-fluoro-2,2-diphenyl-acetoxy)-1-phenoxycarbonylmethyl-1-azonia-bi-
cyclo[2.2.2]octane bromide (Example 109) by replacing bromo-acetic
acid phenyl ester with the appropriate alkyl halide.
Example 112
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(3-phenyl-ureido)-ethyl]-1-azo-
nia-bicyclo[2.2.2]-octane trifluoroacetate
[0136] This compound is made analogously to
(R)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-[2-(toluene-4-sulfonylamino)-eth-
yl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate (Example 49) by
replacing p-toluenesulfonyl chloride with phenyl isocyanate.
Example 113
(R)-1-But-2-ynyl-3-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-azonia-bicyc-
lo[2.2.2]octane trifluoroacetate
[0137] This compound is made analogously to
(R)-3-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-phenylcarbamoylmethyl-1--
azonia-bicyclo[2.2.2]octane trifluoroacetate (Example 76) by
replacing 2-chloro-N-phenyl-acetamide with the appropriate alkyl
halide.
Example 114
(R)-1-Hex-2-ynyl-3-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-azonia-bicyc-
lo[2.2.2] octane trifluoroacetate
[0138] A stirred solution comprising
hydroxy-di-thiophen-2-yl-acetic acid
(R)-(1-aza-bicyclo[2.2.2]-oct-3-yl)ester (Example 70(ii)) (0.03 g,
0.086 mmol), 1-bromo-2-hexyne (0.021 g, 0.0129 mmol), potassium
carbonate (0.002 g, catalytic amount) in acetonitrile (0.5 ml) is
heated to 50.degree. C. overnight. The solvent is removed in vacuo
and purification by mass directed preparative HPLC eluting with
acetonitrile: water: trifluoroacetic acid yields the titled
compound.
Example 115
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(naphthalene-2-carbonyl)-amin-
o]-ethyl}-1-azonia-bicyclo[2.2.2]octane trifluoroacetate
[0139] To a solution of naphthalene-2-carboxylic acid (0.019 g,
0.113 mmol) in DMF (0.28 ml) is added diisopropylethylamine (0.02
ml, 0.113 mmol) in DMF (1 ml) followed by HATU (0.043 g, 0.113
mmol) in DMF (0.28 ml). The reaction mixture is allowed to stand
for 20 minutes after which time a solution comprising
(R)-1-(2-amino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-
[2.2.2]octane bromide hydrobromide [Example 49(ii)] (0.051 g, 0.113
mmol) and diisopropylethylamine (0.02 ml, 0.113 mmol) in DMF (0.57
ml) is added. The reaction mixture is allowed to stand at room
temperature over night. Initial purification is carried out using
Solid Phase Extraction with a 1 g Isolute ALB cartridge. Further
purification is carried out using mass directed preparative HPLC
eluting with acetonitrile: water: trifluoroacetic acid to afford
the titled compound.
Examples 116 to 157
[0140] These compounds, namely
(R)-1-[2-(4-Cyano-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-
-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-1-[2-(2,6-Dimethyl-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-ace-
toxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-1-(2-[(Biphenyl-4-carbonyl)-amino]-ethyl)-3-(2-hydroxy-2,2-diphenyl-a-
cetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(4-pyrrol-1-yl-benzoylamino)--
ethyl]-1-azonia-bicyclo[2.2.2]octane trifluoro-acetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(3-methanesulfonyl-benzoylami-
no)-ethyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(pyridine-3-carbonyl)-amino]-
-ethyl}-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-1-(2-(4-Chloro-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy-
)-1-azonia-bicyclo-[2.2.2]octane trifluoroacetate,
(R)-1-[2-(3,5-Dimethoxy-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-ac-
etoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-1-[2-(3-Chloro-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy-
)-1-azonia-bicyclo[2.2.2] octane trifluoroacetate,
(R)-1-[2-(4-Ethyl-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-
-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(3-trifluoromethyl-benzoylami-
no)-ethyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(4-trifluoromethyl-benzoylami-
no)-ethyl]-1-azonia-bicyclo-[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(2-trifluoro-methyl-benzoylam-
ino)-ethyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-1-[2-(3,4-Dimethoxy-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-ac-
etoxy)-1-azonia-bicyclo[2.2.2]-octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(4-methoxy-benzoyl-amino)-eth-
yl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(2-methoxy-benzoylamino)-ethy-
l]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(4-isopropoxy-benzoylamino)-e-
thyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-1-[2-(2,4-Dimethoxy-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-ac-
etoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-1-[2-(2-Cyano-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-
-1-azonia-bicyclo[2.2.2]-octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(3-methoxy-benzoyl-amino)-eth-
yl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(3-phenyl-propionylamino)-eth-
yl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-1-[2-(2-Cyclopentyl-acetylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-ace-
toxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(pyrazine-2-carbonyl)-amino]-
-ethyl}-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(indane-2-carbonyl)-amino]-e-
thyl}-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-1-[2-(2-Carbamoyl-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acet-
oxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate and
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(2-nitro-benzoylamino)-etbyl]-
-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(2-pyridin-3-yl-acetylamino)--
ethyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-1-{2-[(Furan-3-carbonyl)-amino]-ethyl}-3-(2-hydroxy-2,2-diphenyl-acet-
oxy)-1-azoniabicyclo[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(5-nitro-furan-2-carbonyl)-a-
mino]-ethyl}-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(2-[(1H-indazole-3-carbonyl)-ami-
no)-ethyl)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(2-[(thiophene-3-carbonyl)-amino-
]-ethyl)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(2-[(1-methyl-1H-pyrrole-2-carbo-
nyl)-amino]-ethyl)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-1-{2-[(2,5-Dimethyl-2H-pyrazole-3-carbonyl)-amino]-ethyl}-3-(2-hydrox-
y-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane
trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{(2-[(5-methyl-2-phenyl-2H-[1,2,-
3]triazole-4-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octane
trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(4-methyl-[1,2,3]thiadiazole-
-5-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octane
trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(2-[(5-methyl-isoxazole-3-carbon-
yl)-amino]-ethyl)-1-azonia-bicyclo [2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(3-methyl-furan-2-carbonyl)--
amino]-ethyl}-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(4-methoxy-thiophene-3-carbo-
nyl)-amino]-ethyl}-1-azonia-bicyclo [2.2.2]octane trifluoroacetate,
(R)-1-{2-[(3-Ethoxy-thiophene-2-carbonyl)-amino]-ethyl}-3-(2-hydroxy-2,2--
diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-1-{2-[(5-Acetyl-thiophene-2-carbonyl)-amino]-ethyl}-3-(2-hydroxy-2,2--
diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane
(R)-1-(2-[(3-Chloro-thiophene-2-carbonyl)-amino]-ethyl)-3-(2-hydroxy-2,2--
diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-1-{2-[(3-Bromo-thiophene-2-carbonyl)-amino]-ethyl}-3-(2-hydroxy-2,2-d-
iphenyl-acetoxy)-1-azonia-bicyclo [2.2.2]octane trifluoroacetate,
(R)-1-{2-[(2,5-Dimethyl-furan-3-carbonyl)-amino]-ethyl}-3-(2-hydroxy-2,2--
diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-1-{2-[(5-Bromo-furan-2-carbonyl)-amino]-ethyl}-3-(2-hydroxy-2,2-diphe-
nyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-1-(2-[(1,5-Dimethyl-1H-pyrazole-3-carbonyl)-amino]-ethyl)-3-(2-hydrox-
y-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane
trifluoroacetate are all prepared by an analogous procedure to
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(naphthalene-2-carbonyl)-ami-
no]-ethyl}-1-azonia-bicyclo[2.2.2]octane trifluoroacetate (Example
115) by replacing naphthalene-2-carboxylic acid with the
appropriate acid.
Example 158
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(methyl-phenyl-carbamoyl)-methyl-
]-1-azonia-bicyclo[2.2.2]octane
[0141] Hydroxy-diphenyl-acetic acid
(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (0.03 g, 0.09 mmol) and
2-Chloro-N-methyl-N-phenyl-acetamide (0.025 g, 0.136 mmol), are
dissolved in acetonitrile--DMSO (3:2, 5 ml) and stirred together at
18 hours at 50.degree. C. Chloromethyl polystyrene resin
(Merrifield resin) is added and the reaction stirred for an
additional 4 hours at room temperature. Filtration and purification
using mass directed preparative HPLC eluting with
acetonitrile:water:trifluoroacetic acid followed by treatment with
polymer bound Hunig's base then dissolution in ethyl acetate and
washing with water, drying and concentration in vacuo gives the
titled product as a solid.
[0142] Other especially preferred compounds of formula I include
compounds of formula XIV where R.sup.1, R.sup.2, R.sup.3, and
R.sup.4 are as shown in Table 2 below, the method of preparation
being described hereinafter. All compounds are quaternary ammonium
salts. The table also shows mass spectrometry data. TABLE-US-00002
TABLE 2 M/s Ex. R.sup.1 and R.sup.3 R.sup.4 R.sup.2 M+ 159
##STR336## ##STR337## OH 485.1 160 ##STR338## ##STR339## OH 473.1
161 ##STR340## ##STR341## OH 487.2 162 ##STR342## ##STR343## OH
487.3 163 ##STR344## ##STR345## OH 480.25 164 ##STR346## ##STR347##
OH 495.3 165 ##STR348## ##STR349## OH 417.2 166 ##STR350##
##STR351## OH 428.1 167 ##STR352## ##STR353## OH 433.3 168
##STR354## ##STR355## OH 452.2 169 ##STR356## ##STR357## OH 419.9
170 ##STR358## ##STR359## OH 431.9 171 ##STR360## ##STR361## OH
405.2 172 ##STR362## ##STR363## OH 424.2 173 ##STR364## ##STR365##
OH 499.3 174 ##STR366## ##STR367## OH 513.35 175 ##STR368##
##STR369## OH 513.3 176 ##STR370## ##STR371## OH 395.3 177
##STR372## ##STR373## OH 499.3 178 ##STR374## ##STR375## OH 509.3
179 ##STR376## ##STR377## OH 501.3 180 ##STR378## ##STR379## OH
501.3 181 ##STR380## ##STR381## OH 486.2 182 ##STR382## ##STR383##
OH 395.2 183 ##STR384## ##STR385## OH 499.3 184 ##STR386##
##STR387## OH 551.2 185 ##STR388## ##STR389## OH 490.3 186
##STR390## ##STR391## OH 493.3 187 ##STR392## ##STR393## OH 580 188
##STR394## ##STR395## OH 489 189 ##STR396## ##STR397## OH 489.6 190
##STR398## ##STR399## OH 475.3 191 ##STR400## ##STR401## OH 464 192
##STR402## ##STR403## OH 478 193 ##STR404## ##STR405## OH 492 194
##STR406## ##STR407## OH 492 195 ##STR408## ##STR409## OH 464 196
##STR410## ##STR411## OH 472 197 ##STR412## ##STR413## OH 487 198
##STR414## ##STR415## OH 500.4 199 ##STR416## ##STR417## OH 540.6
200 ##STR418## ##STR419## OH 488 201 ##STR420## ##STR421## OH 473
202 ##STR422## ##STR423## OH 476 203 ##STR424## ##STR425## OH 472
204 ##STR426## ##STR427## OH 492 205 ##STR428## ##STR429## OH 492
206 ##STR430## ##STR431## OH 472 207 ##STR432## ##STR433## OH 491.3
208 ##STR434## ##STR435## OH -- 209 ##STR436## ##STR437## OH 539.2
210 ##STR438## ##STR439## OH 589.2 211 ##STR440## ##STR441## OH
516.3 212 ##STR442## ##STR443## OH 547.2 213 ##STR444## ##STR445##
OH 561.3 214 ##STR446## ##STR447## OH 571.2 215 ##STR448##
##STR449## OH 543.3 216 ##STR450## ##STR451## OH 549.3 217
##STR452## ##STR453## OH 486.3 218 ##STR454## ##STR455## OH 549.3
219 ##STR456## ##STR457## OH 566.2 220 ##STR458## ##STR459## OH
504.3 221 ##STR460## ##STR461## OH 465.3 222 ##STR462## ##STR463##
OH 605.3 223 ##STR464## ##STR465## OH -- 224 ##STR466## ##STR467##
OH 449.3 225 ##STR468## ##STR469## OH 598.2 226 ##STR470##
##STR471## OH 545.3 227 ##STR472## ##STR473## OH 553.3 228
##STR474## ##STR475## OH 603.2 229 ##STR476## ##STR477## OH 525.2
230 ##STR478## ##STR479## OH 537.2 231 ##STR480## ##STR481## OH
555.3 232 ##STR482## ##STR483## OH 558.3 233 ##STR484## ##STR485##
OH 447.3 234 ##STR486## ##STR487## OH 516.3 235 ##STR488##
##STR489## OH 596.3 236 ##STR490## ##STR491## OH 509.3 237
##STR492## ##STR493## OH 555.2 238 ##STR494## ##STR495## OH 479.4
239 ##STR496## ##STR497## OH 493.35 240 ##STR498## ##STR499## OH
522 241 ##STR500## ##STR501## OH 551.2 242 ##STR502## ##STR503## OH
462.2 243 ##STR504## ##STR505## OH 474.1 244 ##STR506## ##STR507##
OH 485.1 245 ##STR508## ##STR509## OH 473.2
Preparation of Specific Examples
Example 159
A) Bromide salt of
(R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-(pyrazin-2-ylcarbamoyl-m-
ethyl)-1-azonia-bicyclo[2.2.2]octane
i) 2-Bromo-N-pyrazin-2-yl-acetamide
[0143] To a solution of 2-aminopyrazine (5.0 g, 52.6 mmol) in
chloroform (250 ml) under an argon atmosphere is added
triethylamine (8.79 ml, 63.1 mmol) and the temperature of the
resulting mixture reduced to -40.degree. C. To this solution is
added a solution of bromoacetylbromide (4.57 ml, 52.6 mmol) in
chloroform dropwise over 20 minutes, and stirring continued at
-20.degree. C. to -40.degree. C. for 1 hour. The reaction mixture
is then quenched by addition to saturated aqueous sodium
bicarbonate solution. The chloroform later is separated and washed
sequentially with saturated aqueous sodium bicarbonate solution,
0.5 M citric acid and brine. Concentration followed by purification
by flash silica column chromatography (gradient elution:ethyl
acetate/hexane 4:6 to 4:1) gives the title compound.
ii)
(R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-(pyrazin-2-ylcarbamoy-
lmethyl)-1-azonia-bicyclo[2.2.2]octane bromide
[0144] A solution of 2-bromo-N-pyrazin-2-yl-acetamide (0.77 g, 3.56
mmol) and hydroxy-di-thiophen-2-yl-acetic acid
(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 70(ii)) (1.12 g,
3.23 mmol) in dry chloroform are heated at 50.degree. C. for 2
hours. The mixture is then cooled to room temperature and extracted
with water. The aqueous layer is concentrated under reduced
pressure then redissolved in a small volume of acetonitrile
containing a few drops of water. The mixture is allowed to stand at
room temperature for several hours, the resulting solid is filtered
and dried then redissolved in a small volume of water containing a
few drops of acetonitrile. After several hours a solid is formed
which is filtered and dried to give the title compound as a white
solid.
B) Chloride salt of
(R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-(pyrazin-2-ylcarbamoyl-m-
ethyl)-1-azonia-bicyclo[2.2.2]octane
[0145] Pyrazin-2-yl-amine (400 .mu.l, 0.5 M solution in DMF) and
triethylamine (500 .mu.l, 0.5 M solution in DMF) are combined and
cooled in an ice bath. Chloroacetyl chloride (500 .mu.l, 0.5 M
solution in DMF) is added dropwise and stirred at 0.degree. C. for
1 hour. To the crude 2-Chloro-N-pyrazin-2-yl-acetamide and
hydroxy-di-thiophen-2-yl-acetic acid
(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 70(ii)) (800
.mu.l, 0.25 M solution in DMF) is added triethylamine (30 .mu.l, 1
equivalent) and the mixture stirred at room temperature overnight.
PS-Bromoacetamidomethyl-NovaGel 2.3 mmol/g (0.3 g) and
triethylamine (30 .mu.l, 1 equivalent) are added to the reaction
mixture and shaken at room temperature for 2 hours. The reaction
mixture is filtered and PS-bromoacetic acid 1.2 mmol/g (0.2 g) is
added to the filtrate and shaken at 30.degree. C. for 1 hour. The
reaction mixture is passed through a 1 g Isolute SPE (Al-B)
cartridge. The solvent is removed in vacuo and purification of the
crude residue by mass directed preparative HPLC eluting with
water:acetonitrile:trifluoroacetic acid yield the compound as a
yellow oil.
Examples 160 to 171
[0146] These compounds, namely
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(pyrimidin-4-yl
carbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(3-hydroxy-phenylcarbamoyl)-met-
hyl]-1-azonia-bicyclo[2.2.2]octane bromide,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(4-hydroxy-phenylcarbamoyl)-met-
hyl]-1-azonia-bicyclo[2.2.2]octane bromide,
(R)-1-(3-tert-Butoxycarbonyl-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-
-azonia-bicyclo[2.2.2]octane bromide,
(R)-1-((R/S)-2-tert-Butoxycarbonyl-amino-propyl)-3-(2-hydroxy-2,2-dipheny-
l-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide,
(R)-1-(3-Cyclopropyl-prop-2-ynyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-az-
onia-bicyclo-[2.2.2]octane bromide,
(R)-1-(3-Cyclopropyl-prop-2-ynyl)-3-(2-hydroxy-2,2-di-thiophen-2-yl-aceto-
xy)-1-azonia-bicyclo[2.2.2]octane bromide,
(R)-1-(4,4-Dimethyl-pent-2-ynyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azo-
nia-bicyclo[2.2.2]octane bromide,
(R)-1-(4,4-Dimethyl-pent-2-ynyl)-3-(2-hydroxy-2,2-di-thiophen-2-yl-acetox-
y)-1-azonia-bicyclo[2.2.2]octane bromide,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(4-methyl-pent-2-ynyl)-1-azonia--
bicyclo-[2.2.2]octane bromide,
(R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-(4-methyl-pent-2-ynyl)-1-
-azonia-bicyclo[2.2.2]octane bromide, and
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-pent-3-ynyl-1-azonia-bicyclo[2.2-
.2]octane bromide, are all prepared analogously to
(R)-1-tert-Butoxy-carbonylmethyl-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azo-
nia-bicyclo[2.2.2]-octane bromide (Example 60) by replacing
t-butylbromoacetate with the appropriate organic halide and heating
the mixture at 50.degree. C. for 2 to 21 hours. The compounds are
purified either by trituration with organic solvents, C18
chromatography (as for Example 60) or recrystalisation from
acetonitrile, water or chloroform. The required halides for
quaternarisation are either commercially available or readily
synthesised by methods well known in the art.
Example 172
(R)-1-(3-Carboxy-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia
bicyclo[2.2.2]octane bromide
[0147] To a stirred solution of
(R)-1-(3-tert-Butoxycarbonyl-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-
-azonia-bicyclo[2.2.2]octane bromide [Example 163] (0.2 g, 0.41
mmol) in methylene chloride (1.5 ml) under an argon atmosphere at
room temperature is added hydrobromic acid (33% in acetic acid,
0.36 ml). After stirring at room temperatue for 30 minutes,
concentration is followed by dissolution in water/acetonitile and
stirring for a further 30 minutes. Concentration then gives the
title product.
Examples 173 to 175
[0148] These compounds, namely
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(3-phenylcarbamoyl-propyl)-1-azo-
nia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(methyl-phenylcarbamoyl)-prop-
yl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate and
(R)-1-(3-Benzylcarbamoyl-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azo-
nia bicycle [2.2.2]octane trifluoroacetate are all prepared
analogously to
(R)-1-[(5,6-diethyl-indan-2-ylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-dipheny-
l-acetoxy)-1-azonia-bicyclo [2.2.2]octane trifluoroacetate [Example
63] but by replacing
(R)-1-carboxymethyl-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2-
.2.2]octane trifluoroacetate [Example 62] with
(R)-1-(3-carboxy-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia
bicyclo[2.2.2] octane bromide [Example 172] and by replacing
5,6-Diethyl-indan-2-ylamine hydrochloride with the appropriate
amine.
Example 176
(R)-1-(2-Amino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azoniabicyclo[-
2.2.2]octane chloride hydrochloride
[0149] This compound is prepared analogously to
(R)-1-((R/S)-2-Amino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-b-
icyclo[2.2.2]octane bromide hydrobromide [Example 49ii] but by
replacing
(R)-1-(2-tert-butoxycarbonylamino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetox-
y)-1-azonia-bicyclo[2.2.2]octane bromide [Example 49i] with
(R)-1-((R/S)-2-tert-Butoxycarbonylamino-propyl)-3-(2-hydroxy-2,2-diphenyl-
-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide [Example 164] and
hydrogen bromide solution in dioxane with hydrogen chloride
solution in dioxane. The product is isolated on concentration of
the reaction medium, without further purification.
Example 177
(R)-1-((R/S)-2-Benzoylamino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-a-
zonia-bicyclo[2.2.2] octane trifluoroacetate
[0150] This compound is prepared analogously to
(R)-1-(3-benzoylamino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-
-bicyclo[2.2.2]-octane trifluoroacetate [Example 2] but by
replacing
(R)-1-(3-amino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicycl-
o-[2.2.2]octane chloride hydrochloride [Example 1(ii)] with
(R)-1-((R/S)-2-amino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azoniab-
icyclo[2.2.2]octane chloride hydrochloride.
Example 178
(R)-1-[3-(tert-Butoxycarbonyl-methyl-amino)-propyl]-3-(2-hydroxy-2,2-diphe-
nyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane chloride
[0151] (3-Chloro-propyl)-methyl-carbamic acid tert-butyl ester
(2.00 g 9.629 mmol) is solubilised in DMF (20 ml) and polystyrene
bound DIPEA added, and after a few minutes removed. This solution
is then added to a mixture of hydroxy-diphenyl-acetic acid
(R)-(1-aza-bicyclo [2.2.2]oct-3-yl)ester (2.1634 g 6.419 mmol) and
200 mg of K.sub.2CO.sub.3 followed by the addition of sodium iodide
(10 mg) and heating at 60.degree. C. for 2 days. 2.5 g Merrifield
resin and 100 mg K.sub.2CO.sub.3 is then added to the mixture and
heating resumed at 40.degree. C. for 12 hours. The resin is then
removed, and the mixture purified by gradient C18 column
chromatography to give the title product.
Example 179
(R)-1-[2-(4-Hydroxy-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy-
)-1-azonia-bicyclo[2.2.2]octane bromide
i)
(R)-1-[2-(4-Benzyloxy-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-ac-
etoxy)-1-azonia-bicyclo[2.2.2]octane bromide
[0152] To a solution of 4-benzyloxybenzoic acid (0.126 mg, 0.55
mmol) in DMF (3 ml) is added diisopropylethylamine (0.3 ml)
followed by HATU (0.155 mg, 0.55 mmol). The reaction mixture is
stirred for 30 minutes at room temperature after which time a
solution comprising
(R)-1-(2-amino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-
[2.2.2]octane bromide hydrobromide [Example 49(ii)] (0.200 g, 0.37
mmol) and the resulting mixture is stirred at room temperature over
night. Purification is carried out using preparative C18 column
chromatography eluting with acetonitrile: water to afford the
titled compound.
ii)
(R)-1-[2-(4-Hydroxy-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-ace-
toxy)-1-azonia-bicyclo[2.2.2]octane bromide
[0153] To a solution of
(R)-1-[2-(4-Benzyloxy-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acet-
oxy)-1-azonia-bicyclo[2.2.2]octane bromide (0.075 g, 0.11 mmol) in
DMF (1 ml) under an argon atmosphere is added 10% Pd on carbon (40
mg) and the resulting solution hydrogenated for 3 hours. The
catalyst is then removed by filtration and concentration in vacuo
yields the title compound.
Example 180
(R)-1-[2-(3-Hydroxy-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy-
)-1-azonia-bicyclo[2.2.2]octane chloride
i)
(R)-1-(2-Amino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetyl)-1-azonia-bicycl-
o[2.2.2]octane chloride hydrochloride
[0154] To a solution of
(R)-1-(2-tert-butoxycarbonylamino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetyl-
)-1-azonia-bicyclo[2.2.2]octane bromide [Example 49i] (8.292 g,
14.82 mmol) in dioxane (100 ml) at room temperature is added
hydrochloric acid (18.5 ml, 4 M in dioxane). The reaction mixture
is stirred for 20 hours. The solvent is removed in vacuo and
purification of the crude residue by chromatography on C18 silica,
eluting with water:acetonitrile affords the titled product as a
white solid.
ii)
(R)-1-[2-(3-Hydroxy-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-ace-
toxy)-1-azonia-bicyclo[2.2.2]octane chloride
[0155] This is prepared analogously to
(R)-1-[2-(4-Hydroxy-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetox-
y)-1-azonia-bicyclo[2.2.2]octane bromide [Example 179] but
4-benzyloxy-benzoic acid is replaced by 3-benzyloxybenzoic acid and
(R)-1-(2-amino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-
[2.2.2]octane bromide hydrobromide is substituted by
(R)-1-(2-amino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-
[2.2.2]octane chloride hydrochloride [Example 180 i].
Example 181
(R)-1-Benzyloxycarbonylmethyl-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia--
bicyclo [2.2.2]octane bromide
[0156] A suspension of hydroxy-diphenyl-acetic acid
(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (1 g, 2.96 mmol) and
bromoacetic acid benzyl ester (0.516 ml, 3.26 mmol) in ethylacetate
(20 ml) is heated at 50.degree. C. for 2 hours. The reaction
mixture is cooled to room temperature and the precipitate removed
by filtration. Recrystallisation from acetonitrile (20 ml) gives
the title compound.
Example 182
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(2-methylamino-ethyl)-1-azonia-bi-
cyclo [2.2.2]octane bromide hydrobromide
[0157] (2-Bromo-ethyl)-methyl-carbamic acid tert-butyl ester (0.09
g, 0.38 mmol) is added to a solution of hydroxy-diphenyl-acetic
acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (0.265 g, 0.79 mmol)
in DMF (10 ml). The resulting mixture is heated at 60.degree. C.
for 5 hours and concentrated. This procedure is repeated twice
giving the title compound as a mixture containing unreacted
hydroxy-diphenyl-acetic acid
(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester.
Example 183
(R)-1-[2-(Benzoyl-methyl-amino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)--
1-azonia-bicyclo[2.2.2]octane trifluoroacetate
[0158] The crude product from Example 182 is dissolved in
acetonitrile (10 ml) and filtered then cooled over an ice bath,
under an argon atmosphere. To this cooled solution is added
triethylamine (127 .mu.l) followed by benzoyl bromide (64 .mu.l)
and the reaction stirred for 1 hour. Purification is carried out
using mass directed preparative HPLC eluting with
acetonitrile:water:trifluoroacetic acid to afford the titled
compound.
Example 184
(R)-1-[(2-Bromo-phenylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy-
)]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate
(i) N-(2-Bromo-phenyl)-2-chloro-acetamide
[0159] 2-Bromoaniline (371 .mu.l, 467 mmol) and triethylamine (651
.mu.l, 5.84 mmol) are dissolved in DMF (2 ml) and cooled in an ice
bath. Chloroacetyl chloride (371 .mu.l, 4.67 mmol) is added
dropwise and stirred at 0.degree. C. for 1 hour. The solvent is
removed in vacuo and used crude in the next step.
ii)
(R)-1-[(2-Bromo-phenylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-ace-
toxy)]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate
[0160] N-(2-Bromo-phenyl)-2-chloro-acetamide (155 mg, 0.622 mmol)
and hydroxyl-diphenyl-acetic acid
(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (210 mg, 0.622 mmol) are
dissolved in DMF (4 ml). The reaction mixture is stirred at
0.degree. C. for 2 hours. PS-Bromoacetamidomethyl-NovaGel 2.3
mmol/g (0.5 g) is added to the reaction mixture and shaken at room
temperature for 4 hours. PS-Triphenylphosphine 3 mmol/g (0.5 g) is
added to the reaction mixture and shaken at room temperature
overnight. The reaction mixture is then passed through a 1 g
Isolute SPE (Al-B) cartridge. The solvent is removed in vacuo and
purification of the crude residue by mass directed preparative HPLC
eluting with water:acetonitrile:trifluoroacetic acid yields the
titled compound.
Example 185 to 189
[0161] These compounds, namely
(R)-1-[(3,4-Dimethyl-isoxazol-5-ylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-dip-
henyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(3-methyl-[1,2,4]thiadiazol-5-y-
lcarbamoyl)-methyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-1-[(5-Bromo-3,4-dimethyl-pyridin-2-yl-carbamoyl)-methyl]-3-(2-hydroxy-
-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane
trifluoroacetate,
(R)-1-[(2,S-Dimethyl-2H-pyrazol-3-ylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-d-
iphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
and
(R)-1-[(2-Ethyl-2H-pyrazol-3-ylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphen-
yl-acetoxy)-1-azonia-bicyclo-[2.2.2]octane trifluoroacetate are all
prepared analogously to
(R)-1-[(2-Bromo-phenyl-carbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-aceto-
xy)]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate [Example 184]
by replacing 2-Bromoaniline with the appropriate amine.
Example 190
(R)-1-{2-[(Furan-2-carbonyl)-amino]ethyl}-3-(2-hydroxy-2,2-diphenyl-acetyl-
)-1-azonia-bicyclo[2.2.2]octane hexafluorophosphate
[0162] To a stirred solution of 2-furoic acid (91.5 mg, 8.21 mmol)
and HATU (284 mg, 7.52 mmol) in DMF (7.5 ml) is added polymer bound
morpholine, 2.5 mmol/g (1.36 g, 34.2 mmol). The reaction mixture is
left to stand at room temperature for 15 minutes after which time,
a solution comprising of
(R)-1-(2-amino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetyl)-1-azonia-bicyclo[-
2.2.2]octane chloride hydrochloride [Example 180 i]] (310 mg, 6.84
mmol) in DMF (7.5 ml) is added. The reaction mixture is stirred at
room temperature overnight. The reaction mixture is passed through
a 2 g Isolute SPE (Al-B) cartridge. The filtrate is concentrated in
vacuo and purification of the crude residue by chromatography on
C18 silica, eluting with water:acetonitrile affords the title
compound as a white solid.
Example 191
(R)-1-{2-[(Azetidine-3-carbonyl)-amino]-ethyl}-3-(2-hydroxy-2,2-diphenyl-a-
cetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate
(i)
(R)-1-{2-[1-tert-Butoxycarbonyl-azetidine-3-carbonyl)-amino]ethyl}-3-(-
2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane
hexafluorophosphate
[0163] This compound is prepared analogously to
(R)-1-{2-[(Furan-2-carbonyl)-amino]ethyl}-3-(2-hydroxy-2,2-diphenyl-acety-
l)-1-azonia-bicyclo[2.2.2]octane hexafluorophosphate [Example 190]
by replacing 2-furoic acid with 1-BOC-azetidine-3-carboxylic
acid.
(ii)
(R)-1-{2-[(Azetidine-3-carbonyl)-amino]-ethyl}-3-(2-hydroxy-2,2-diphe-
nyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate
[0164]
(R)-1-2-[(1-tert-butoxycarbonyl-azetidine-3-carbonyl)-amino]ethyl--
3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane
hexafluorophosphate is dissolved in TFA: DCM (1:1) (2 ml) and
stirred at room temperature for 1 hour. TFA:DCM (2 ml) is added to
the reaction mixture to complete the reaction. The solvent is
removed in vacuo and purification of the crude residue by mass
directed preparative HPLC eluting with
water:acetonitrile:trifluoroacetic acid yields the titled
compound.
Example 192 to 195
[0165] These compounds, namely
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[((S)-pyrrolidine-2-carbonyl)-
-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[((R)-piperidine-2-carbonyl)--
amino]-ethyl}-1-azonia-bicyclo[2.2.2] octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[((S)-piperidine-2-carbonyl)--
amino]-ethyl}-1-azonia-bicyclo[2.2.2]octane trifluoroacetate and
(R)-1-{2-[((S)-Azetidine-2-carbonyl)-amino)-ethyl}-3-(2-hydroxy-2,2-diphe-
nyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate are
prepared analogously to
(R)-1-{2-[(Azetidine-3-carbonyl)-amino]-ethyl}-3-(2-hydroxy-2,2-diphenyl--
acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate [Example
191] by replacing 1-BOC-azetidine-3-carboxylic acid with the
corresponding BOC protected amino acid.
Example 196
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(pyridine-2-ylcarbamoyl
methyl)-azonia-bicyclo[2.2.2]octane trifluoroacetate
[0166] This compound is prepared analogously to
(R)-1-[(2-Bromo-phenylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetox-
y)]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate [Example 184].
However instead of using PS-triphenylphosphine, BEMP 2.3 mmol/g
(0.1 g, 1 eqv) is used with the PS-bromoacetamidomethyl-NovaGel 2.3
mmol/g (0.3 g, 1 eqv).
Example 197
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(4-methyl-pyrimidin-2-ylcarbamoy-
l)-methyl]-1-azonia-bicyclo[2.2.2]octane chloride
[0167] This compound is prepared analogously to
(R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-(pyrazin-2-ylcarbamoylme-
thyl)-1-azonia-bicyclo[2.2.2]octane chloride [Example 159B] by
substituting hydroxy-di-thiophen-2-yl-acetic acid
(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester and Pyrazin-2-yl-amine with
hydroxy-diphenyl-acetic acid
(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester and
4-Methyl-pyrimidin-2-ylamine.
Examples 198 to 201
[0168] These compounds, namely
(R)-1-[(6-Ethyl-pyridin-2-ylcarbamoyl)methyl]-3-(2-hydroxy-2,2-diphenyl-a-
cetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(3-trifluoromethyl-pyridin-4-yl-
carbamoyl)-methyl]-1-azonia-bicyclo [2.2.2]octane trifluoroacetate,
R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(3-hydroxy-pyridin-2-ylcarbamoyl-
)-methyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate, and
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(pyrimidin-2-ylcarbamoylmethyl)--
1-azoniabicyclo[2.2.2] octane trifluoroacetate are all prepared
analogously to
(R)-1-[(2-bromo-phenyl-carbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-aceto-
xy)]-1-azonia-bicyclo[2.2.2]octane chloride [Example 184] by
substituting 2-bromoaniline with the corresponding heterocyclic
amines, however in these examples PS-triphenylphosphine is not
used.
Examples 202 to 206
[0169] The title compounds, namely
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(4-methyl-oxazol-2-ylcarbamoyl)-
-methyl]-1-azonia-bicyclo[2.2.2]octane chloride,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(pyridin-4-ylcarbamoylmethyl)-1--
azonia-bicyclo[2.2.2]octane chloride,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(5-methyl-thiazol-2-ylcarbamoyl-
)-methyl]-1-azonia-bicyclo[2.2.2]octane chloride,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(4-methyl-thiazol-2-ylcarbamoyl-
)-methyl]-1-azonia-bicyclo[2.2.2]octane chloride, and
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(pyridin-3-ylcarbamoylmethyl)-1--
azoniabicyclo[2.2.2] octane chloride, are all prepared analogously
to
(R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-(pyrazin-2-ylcarbamoylme-
thyl)-1-azonia-bicyclo[2.2.2]octane chloride [Example 159B] by
substituting hydroxy-di-thiophen-2-yl-acetic acid
(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester with
hydroxyl-diphenyl-acetic acid
(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester and replacing
Pyrazin-2-yl-amine with the corresponding heterocyclic amines.
Example 207
(R)-3-(2-Hydroxy-2,2-diphenyl-acetyl)-1-[2-[thiophene-2-carbonyl)-amino]-e-
thyl]-1-azonia-bicyclo[2.2.2]octane hexafluorophosphate
[0170] To a stirred solution of 2-thiophenecarboxylic acid (15.4
mg, 0.12 mmol) and HATU (42 mg, 0.11 mmol) in DMF (0.6 ml) is added
triethylamine (42 .mu.l, 0.3 mmol). The reaction mixture is left to
stand for 20 minutes after which time, a solution comprising of
(R)-1-(2-amino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetyl)-1-azonia-bicyclo[-
2.2.2]octane bromide [Example 49 ii)] (45 mg, 0.1 mmol) in DMF (0.6
ml) is added. The reaction mixture is stirred at room temperature
overnight. The reaction mixture is passed through a 1 g Isolute SPE
(Al-B) cartridge and the filtrate concentrated in vacuo.
Purification by mass directed preparative HPLC eluting with
water:acetonitrile:trifluoracetic acid yields the titled
compound.
Examples 208 to 241
[0171] These compounds, namely
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(3-methyl-thiophene-2-carbon-
yl)-amino]-ethyl}-1-azonia-bicyclo[2.2.21 octane hexafluoro
phosphate,
(R)-1-{2-[(3-Chloro-4-methyl-thiophene-2-carbonyl)-amino]-ethyl}-3-(2-hyd-
roxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane hexafluoro
phosphate,
(R)-1-{2-[(5-Chloro-3-methyl-benzo-[b]thiophene-2-carbonyl)-amino]-ethyl)-
-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-[2.2.2]octane
hexafluorophosphate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(2-hydroxy-6-methyl-pyridine-
-4-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octane
hexafluoro-phosphate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(thieno[3,2-b]thiophene-2-ca-
rbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2] octane
hexafluoro-phosphate,
(R)-1-{2-[(6-Fluoro-4H-benzo[1,3]dioxine-8-carbonyl)-amino]-ethyl}-3-(2-h-
ydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane
hexafluoro phosphate,
(R)-1-(2-[(5-Bromo-thiophene-2-carbonyl)-amino]-ethyl)-3-(2-hydroxy-2,2-d-
iphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane hexafluorophosphate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(2-propoxy-benzoylamino)-ethy-
l]-1-azonia-bicyclo[2.2.2]octane hexafluorophosphate,
(R)-1-[2-(5-Chloro-2-methoxy-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphen-
yl-acetoxy)-1-azonia-bicyclo[2.2.2]octane hexafluorophosphate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(pyridine-4-carbonyl)-amino]-
-ethyl}-1-azonia-bicyclo[2.2.2]octane hexafluorophosphate,
(R)-1-[2-(2,6-Dimethoxy-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-ac-
etoxy)-1-azonia-bicyclo[2.2.2]octane hexafluorophosphate,
(R)-1-(2-[(5-Bromo-pyridine-3-carbonyl)-amino]-ethyl)-3-(2-hydroxy-2,2-di-
phenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane hexafluorophosphate,
(R)-1-(2-[(3,5-Dimethyl-isoxazole-4-carbonyl)-amino]-ethyl)-3-(2-hydroxy--
2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane hexafluoro
phosphate,
(R)-1-{2-[(1-Hydroxy-cyclo-propanecarbonyl)-amino]-ethyl}-3-(2-hydroxy-2,-
2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]-octane
hexafluorophosphate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(2-trifluoro-methyl-[1,8]nap-
hthyridine-3-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octane
hexa-fluorophosphate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(2-[(6-methyl-pyridine-3-carbony-
l)-amino]-ethyl)-1-azonia-bicyclo-[2.2.2]octane
hexafluorophosphate,
(R)-1-[2-(Cyclopropanecarbonyl-amino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-ac-
etoxy)-1-azonia-bicyclo-[2.2.2]octane hexafluorophosphate,
(R)-1-[2-(4-Chloro-3-sulfamoyl-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diph-
enyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane hexafluorophosphate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(2-[(4,5,6,7-tetrahydro-benzo[c]-
thiophene-1-carbonyl)-amino]-ethyl)-1-azonia-bicyclo[2.2.2]-octane
hexafluorophosphate,
(R)-1-[2-[(2,7-Dimethyl-imidazo[1,2-a]pyridine-3-carbonyl)-amino]-ethyl]--
3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2] octane
hexa-fluorophosphate,
(R)-1-{2-[(3-Chloro-4-methanesulfonyl-thiophene-2-carbonyl)-amino]-ethyl}-
-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-[2.2.2] octane
hexafluorophosphate,
(R)-1-{2-[(5-Chloro-thiophene-2-carbonyl)-amino]-ethyl}-3-(2-hydroxy-2,2--
diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane
hexafluorophosphate,
(R)-1-[2-(3-Chloro-4-fluoro-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-dipheny-
l-acetoxy)-1-azonia-bicyclo[2.2.2]octane hexafluorophosphate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(3-methyl-benzo[b]thiophene--
2-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octane
hexa-fluorophosphate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-[(3-methyl-5-trifluoromethyl--
isoxazole-4-carbonyl)-amino]-ethyl]-1-azonia-bicyclo[2.2.2]octane
hexafluorophosphate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(1-oxo-but-2-ynylamino)-ethyl-
]-1-azonia-bicyclo-[2.2.2]octane hexafluorophosphate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-2-[(2-methoxy-pyridine-3-carbony-
l)-amino]-ethyl)-1-azonia-bicyclo[2.2.2]octane
hexafluoro-phosphate,
(R)-1-(2-[(5-Dimethylsulfamoyl-2-methyl-furan-3-carbonyl)-amino]-ethyl}-3-
-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2] octane
hexafluorophosphate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(3-phenyl-propynoylamino)-eth-
yl]-1-azonia-bicyclo-[2.2.2]octane hexafluorophosphate,
(R)-1-[2-[(5-Chloro-4-methoxy-thiophene-3-carbonyl)-amino]-ethyl)-3-(2-hy-
droxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane
hexa-fluorophosphate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[((R)-tetrahydro-furan-2-carb-
onyl)-amino]-ethyl}-1-azonia-bicyclo [2.2.2]octane
hexafluoro-phosphate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(tetrahydro-pyran-4-carbonyl-
)-amino]-ethyl)-1-azonia-bicyclo[2.2.2]octane hexafluoro phosphate,
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(2-[(3-methoxy-thiophene-2-carbo-
nyl)-amino]-ethyl)-1-azonia-bicyclo-[2.2.2]octane
hexafluoro-phosphate, and
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(5-methoxy-thiophene-2-c-
arbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octane
hexafluoro-phosphate, are all prepared analogously to
(R)-3-(2-Hydroxy-2,2-diphenyl-acetyl)-1-{2-[thiophene-2-carbonyl)-amino]--
ethyl}-1-azonia-bicyclo[2.2.2]octane hexafluorophosphate [Ex. 207]
by substituting 2-thiophenecarboxylic acid with the corresponding
carboxylic acid.
Example 242
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(isoxazol-3-ylcarbamoylmethyl)-1--
azonia-bicyclo[2.2.2]octane bromide
i) 2-Bromo-N-isoxazol-3-yl-acetamide
[0172] To a stirred solution of bromoacetylbromide (5.36 ml, 61.6
mmol) in diethylether (100 ml) at -40.degree. C. is added, dropwise
over 20 minutes, a solution of 3-aminoisoxazol (5.0 ml, 67.0 mmol)
and triethylamine (8.5 ml, 61.4 mmol) in diethylether (20 ml).
Additional diethylether (50 ml) is added and stirring continued for
3 hours. The reaction mixture is filtered and the solution then
washed with 1 M sodium carbonate solution, 1 M hydrochloric acid
and brine. Concentration followed by purification by flash silica
column chromatography (ethyl acetate/iso-hexane 4:7) gives the
title compound as a white solid.
ii)
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(isoxazol-3-ylcarbamoylmethyl-
)-1-azonia-bicyclo[2.2.2]octane bromide
[0173] A solution of 2-Bromo-N-isoxazol-3-yl-acetamide (0.82 g, 4.0
mmol) in chloroform/acetonitrile(1:1) is added to a solution of
hydroxyl-diphenyl-acetic
acid(R)-(1-aza-bicyclo-[2.2.2]oct-3-yl)ester (1.12 g, 3.32 mmol) in
dry chloroform (10 ml) and the resulting mixture heated to
55.degree. C. under an argon atmosphere for 4 hours. The mixture is
then cooled to room temperature and concentrated. The residue is
dissolved in acetonitrile and concentration followed by
redissolution in hot acetone and cooling gives a jelly like
precipitate which is filtered. Recrystallisation of the crude
precipitate from acetonitrile containing a few drops of water
followed by further crystallisation from acetonitrile gives the
title compound as light brown crystals.
[0174] In an alterntaive method for preparing
2-Bromo-N-isoxazol-3-yl-acetamide, to a stirred solution of
bromoacetylbromide (5.36 ml, 61.6 mmol) in diethylether (100 ml) at
-40.degree. C. is added, dropwise over 20 minutes, a solution of
3-aminoisoxazol (5.0 ml, 67.7 mmol) and triethylamine (8.5 ml, 61.4
mmol) in diethylether (20 ml). Additional diethylether (50 ml) is
added and stirring continued for 3 hours. The reaction mixture is
filtered and the solution then washed with 1 M sodium carbonate
solution, 1 M hydrochloric acid and brine. Concentration followed
by purification by flash silica column chromatography (ethyl
acetate/iso-hexane 3:7) gives the title compound as a white
solid.
Example 243
(R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-(isoxazol-3-ylcarbamoylme-
thyl)-1-azonia-bicyclo[2.2.2]octane bromide
[0175] A solution of 2-Bromo-N-isoxazol-3-yl-acetamide [Example 242
i]) (0.70 g, 3.5 mmol) in chloroform (10 ml) is added to a solution
of hydroxy-di-thiophen-2-yl-acetic acid
(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (1.01 g, 2.9 mmol)
acetonitrile (5 ml) and the resulting mixture heated to 55.degree.
C. under an argon atmosphere for 4 hours. The mixture is then
cooled to room temperature and concentrated. The residue is
triturated with ethylacetate and then purification by C-18 reverse
phase column chromatography (eluent: water-acetonitrile) to give
the title compound as a white foam.
Example 244
(R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-(pyrimidin-4-ylcarbamoylm-
ethyl)-1-azonia-bicyclo[2.2.2]octane bromide
i) 2-Bromo-N-pyrimidin-4-yl-acetamide
[0176] To a solution of 4-aminopyrimidine (7.0 g, 73.6 mmol) in
chloroform (300 ml) under an argon atmosphere is added
triethylamine (12.3 ml, 88.3 mmol) and the temperature of the
resulting mixture reduced to -40.degree. C. To this solution is
added a solution of bromoacetylbromide (6.4 ml, 73.6 mmol) in
chloroform (5 ml) dropwise and stirring continued for 1.5 hours.
The reaction mixture is then quenched by addition to saturated
aqueous sodium bicarbonate solution. The chloroform later is
separated and washed with 0.5 M citric acid solution. Concentration
followed by purification by flash silica column chromatography
(gradient elution:ethyl acetate/hexane 1:4 to methanol/ethyl
acetate 1:10) gives the title compound.
ii)
(R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-(pyrimidin-4-ylcarbam-
oylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide
[0177] A solution of 2-Bromo-N-pyrimidin-4-yl-acetamide (0.90 g,
4.17 mmol) and hydroxy-di-thiophen-2-yl-acetic acid
(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 70(ii)) (1.32 g,
3.79 mmol) in dry chloroform-acetonitrile (20 ml+4 ml) are heated
at 50.degree. C. for 3 hours. The mixture is then cooled to room
temperature and concentrated. Purification by reverse phase C18
column chromatography (gradient elution 100% water to 100%
acetonitrile) gives after concentration a light brown solid. The
solid was triturated with hot acetonitrile then dissolved in hot
acetonitrile containing a few drops of water. After standing at
5.degree. C. for several hours crystals are formed which are
filtered and dried to give the title compound.
Example 245
(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(pyrazin-2-ylcarbamoylmethyl)-1-a-
zonia-bicyclo[2.2.2]octane
[0178] A solution of 2-bromo-N-pyrazin-2-yl-acetamide (1.50 g, 6.94
mmol) and hydroxyl-diphenyl-acetic acid
(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (2.13 g, 6.31 mmol) in dry
chloroform (10 ml) are heated at 50.degree. C. for 2 hours. The
mixture is then cooled to room temperature filtered and
concentrated. The resulting foam is dissolved in acetonitrile and
cooled to -20.degree. C., an orange oil is formed from which the
acetonitrile layer is decanted. The orange oil is dissolved in
water and washed with chloroform before concentration.
Redissolution in hot water followed by precipitation by cooling to
room temperature gives the title product as a white solid.
[0179] Further especially preferred compounds of formula I include
compounds of formula XIV where R.sup.1, R.sup.2, R.sup.3, and
R.sup.4 are as shown in Table 3 below, the method of preparation
being described hereinafter. All compounds are quaternary ammonium
salts. The table also shows mass spectrometry data. TABLE-US-00003
TABLE 3 M/s Ex. R.sup.1 and R.sup.3 R.sup.4 R.sup.2 M+ 246
##STR510## ##STR511## OH 448.3 247 ##STR512## ##STR513## OH
408.3
Preparation of Specific Examples
Example 246
1-Allyloxycarbonylmethyl-3-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-azon-
ia-bicyclo-[2.2.2]octane
[0180] A solution of bromo-acetic acid allyl ester (0.8 g, 4.46
mmol) and hydroxy-di-thiophen-2-yl-acetic acid
(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 70(ii)) (1.3 g,
3.7 mmol) in dry chloroform are heated at 50.degree. C. for 2
hours. The contents are then allowed to cool and then concentrated
in vacuo. This residue is then taken up in 1% water in acetone at
reflux and allowed to cool to room temp. After several hours a
solid is formed which is filtered and dried to give the title
compound as a brown solid.
Example 247
1-Carboxymethyl-3-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-azonia-bicycl-
o[2.2.2]octane
[0181] To a stirred solution of
1-allyloxycarbonylmethyl-3-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-azo-
nia-bicyclo[2.2.2]octane (Example 246) (0.79 g, 1.50 mmol) in dry
chloroform, under argon, is added tetrakis-palladium triphenyl
phosphine (0.02 g, 0.017 mmol). The mixture is strirred at room
temp., under argon, for 20 minutes before morpholine (0.196 ml,
2.25 mmol) is added. Stirring is continued for a further 4 hrs at
room temp. The mixture is concentrated in vacuo and purified by
gradient C18 column chromatography to give a pale yellow solid. The
solid is then redissolved in a small volume of acetonitrile
containing a few drops of water. After several hours a solid is
formed which is filtered and dried to give the title compound as a
pale yellow solid.
* * * * *