U.S. patent application number 10/426364 was filed with the patent office on 2004-03-18 for therapeutic ureas.
Invention is credited to Mammen, Mathai, Oare, David.
Application Number | 20040054187 10/426364 |
Document ID | / |
Family ID | 23811737 |
Filed Date | 2004-03-18 |
United States Patent
Application |
20040054187 |
Kind Code |
A1 |
Mammen, Mathai ; et
al. |
March 18, 2004 |
Therapeutic ureas
Abstract
This invention relates to urea compounds that are muscarinic
receptor antagonists and agonists, pharmaceutical compositions
comprising such compounds, and methods of preparing these
compounds.
Inventors: |
Mammen, Mathai; (San Mateo,
CA) ; Oare, David; (Belmont, CA) |
Correspondence
Address: |
THERAVANCE, INC.
901 GATEWAY BOULEVARD
SOUTH SAN FRANCISCO
CA
94080
US
|
Family ID: |
23811737 |
Appl. No.: |
10/426364 |
Filed: |
April 30, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10426364 |
Apr 30, 2003 |
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09732514 |
Dec 7, 2000 |
|
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09732514 |
Dec 7, 2000 |
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09456170 |
Dec 7, 1999 |
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Current U.S.
Class: |
546/277.1 ;
546/316; 548/311.4; 548/338.1; 548/473; 548/537 |
Current CPC
Class: |
A61P 11/00 20180101;
C07D 471/08 20130101; A61P 1/00 20180101; C07D 405/12 20130101;
A61P 25/08 20180101; A61P 11/06 20180101; C07D 495/08 20130101;
A61P 13/10 20180101; A61P 43/00 20180101; C07D 211/48 20130101;
C07D 413/06 20130101; A61P 1/04 20180101; A61P 13/02 20180101; C07D
401/14 20130101; A61P 25/00 20180101; C07D 471/14 20130101; A61P
27/02 20180101; C07D 409/12 20130101; C07D 401/06 20130101; A61P
1/02 20180101; C07D 401/12 20130101; C07D 471/10 20130101; A61P
25/28 20180101; C07D 211/52 20130101 |
Class at
Publication: |
546/277.1 ;
546/316; 548/311.4; 548/338.1; 548/473; 548/537 |
International
Class: |
C07D 43/02; C07D 41/02;
C07D 213/56; C07D 209/48; C07D 233/90 |
Claims
What is claimed is:
1. A compound of Formula (I): L.sub.1--X--L.sub.2 (I) wherein:
L.sub.1 is a group of formula (a): 590wherein: A is an aryl or a
heteroaryl ring; B" is --NR.sup.a-- wherein R.sup.a is hydrogen,
alkyl, aryl, heteroaryl, or substituted alkyl; R.sup.1 is hydrogen
or alkyl; R.sup.2 is Het, or is selected from a group consisting of
formula (i), (ii), and (iii): 591wherein: - - - is an optional
double bond; n.sub.1 is an integer of from 1 to 4; n.sub.2 is an
integer of from 1 to 3; V is --CH--, --O--, --S(O)n.sub.3-- (where
n.sub.3 is an integer of from 0 to 2), or --NR.sup.4-- (wherein
R.sup.4 is hydrogen, alkyl, substituted alkyl, aryl, or
heteroaryl); "Het" is a heteroaryl ring which optionally attaches
(a) to a linker; R.sup.3 is hydrogen, alkyl, halo, amino,
substituted amino, --OR.sup.a (where R.sup.a is hydrogen, alkyl, or
acyl), or a covalent bond attaching (a) to a linker; R.sup.5 is
hydrogen, alkyl, halo, amino, substituted amino, --OR.sup.b (where
R.sup.b is hydrogen or alkyl), aryl, aralkyl, heteroaralkyl, or a
covalent bond attaching (a) to a linker; R.sup.6, R.sup.7, and
R.sup.8 are, independently of each other, hydrogen, halo, hydroxy,
alkoxy, haloalkoxy, carboxy, alkoxycarbonyl, alkyl optionally
substituted with one, two or three substituents selected from halo,
hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino,
substituted amino, or a covalent bond attaching (a) to a linker; K
is a bond or an alkylene group; K" is a bond, --C(O)--,
--S(O).sub.n4-- (where n.sub.4 is an integer of from 0 to 2), or an
alkylene group optionally substituted with a hydroxyl group; and B
is heterocycloamino or heteroarylamino, which optionally attaches
(a) to a linker; provided that at least one of the R.sup.5,
R.sup.6, R.sup.7, R.sup.8, "Het", heterocycloamino or
heteroarylamino groups attaches (a) to a linker; X is a linker; and
L.sub.2 is an organic group comprising at least one primary,
secondary, or tertiary amine; or a pharmaceutically acceptable
salt; or prodrug thereof.
2. The compound of claim 1 wherein L.sub.2 is a group selected from
a group consisting of: (i) a group of formula (b): 592wherein: D"
is alkylene; D is --NR.sup.31R.sup.32,
--N.sup.+(R.sup.33R.sup.34R.sup.35) or --OR.sup.32 where R.sup.31,
R.sup.33, and R.sup.34 are, independently of each other, hydrogen,
alkyl, or aralkyl; and R.sup.32 and R.sup.35 represent a covalent
bond attaching (b) to a linker; R.sup.27 is hydrogen, halo, nitro,
cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio,
alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido,
alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or
dialkylcarbamoyl, amino, mono- or dialkylamino, aryl, aryloxy,
arylthio, heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl,
heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally
substituted with one, two or three substituents selected from halo,
hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino,
or substituted amino; R.sup.28 is hydrogen, halo, nitro, cyano,
hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio,
alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido,
carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or
dialkylamino, or alkyl optionally substituted with one, two, or
three substituents selected from halo, hydroxy, carboxy,
alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted
amino; R.sup.29 and R.sup.30 are, independently of each other,
hydrogen, alkyl, haloalkyl, halo, nitro, cyano, hydroxy, alkoxy,
alkoxycarbonyl, acyl, thio, alkylthio, amino, mono- or
dialkylamino; or one of R.sup.27, R.sup.28, R.sup.29, or R.sup.30
together with the adjacent group forms a methylenedioxy or
ethylenedioxy group; (ii) a group of formula (c): 593wherein:
n.sub.11 is an integer of from 1 to 7; n.sub.12 is 0 to 7; F is
--NR.sup.40--, --O--, --S--, or --CHR.sup.41-- (wherein R.sup.40
and R.sup.41 are, independently of each other, hydrogen, alkyl, or
substituted alkyl); F" is a covalent bond, --OR.sup.43,
--NR.sup.42R.sup.43, or --N.sup.+R.sup.43R.sup.44R.sup.45 wherein
R.sup.42 is hydrogen or alkyl, R.sup.44 and R.sup.45 are alkyl, and
R.sup.43 is hydrogen, alkyl, or a covalent bond attaching (c) to a
linker; R.sup.36 is hydrogen, alkyl, halo, nitro, cyano, hydroxy,
alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio,
alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido,
carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or
dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy,
heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl,
heteroaralkyl, or alkyl optionally substituted with one, two or
three substituents selected from halo, hydroxy, carboxy,
alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted
amino; R.sup.37 is hydrogen, alkyl, halo, nitro, cyano, hydroxy,
alkoxy, alkoxycarbonyl, acyl, thio, alkylthio, amino, mono- or
dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy,
heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl,
heteroaralkyl, or alkyl optionally substituted with one, two or
three substituents selected from halo, hydroxy, carboxy,
alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted
amino; and R.sup.38 is hydrogen, alkyl, halo, hydroxy, alkoxy, or a
covalent bond attaching the ligand to a linker provided that at
least one of R.sup.38 and R.sup.43 attaches (c) to a linker;
R.sup.39 is hydrogen, alkyl, halo, hydroxy, alkoxy, or substituted
alkyl; and (iii) a group of formula (d) or (e): 594wherein:
R.sup.46 is alkyl, substituted alkyl, cycloalkyl, substituted
cycloalkyl, or heterocycle; R.sup.47 is alkyl, substituted alkyl,
aryl, acyl, heterocycle, or --COOR.sup.50 where R.sup.50 is alkyl;
or R.sup.46 and R.sup.47 together with the nitrogen atom to which
they are attached form heterocycle, which heterocycle, in addition
to optionally bearing the optional substituents defined hereinbelow
for a heterocycle, can also optionally be substituted with one or
more alkyl, substituted alkyl, alkenyl, substituted alkenyl,
alkynyl, or substituted alkynyl. R.sup.48 is a covalent bond that
attaches the (d) to a linker; and R.sup.49 is alkyl.
3. The compound of claim 1 or 2 wherein A is phenyl or pyridyl.
4. The compound of claim 1 or 2 wherein B" is --NH--.
5. The compound of claim 1 or 2 wherein R.sup.1 is hydrogen,
methyl, or ethyl.
6. The compound of claim 1 or 2 wherein R.sup.2 is pyrrolyl,
pyridinyl, or imidazolyl.
7. The compound of claim 1 or 2 wherein R.sup.2 is phenyl.
8. The compound of claim 1 or 2 wherein K is a bond or a methylene
group.
9. The compound of claim 1 or 2 wherein K" is a bond.
10. The compound of claim 1 or 2 wherein B is a heterocycloamino
group which attaches (a) to a linker.
11. The compound of claim 1 or 2 wherein B is pyrrolidine,
piperidine, or hexahydroazepine attaching (a) to a linker.
12. The compound of claim 1 or 2 wherein B is piperidine wherein
the nitrogen atom of said piperidine attaches (a) to a linker.
13. The compound of claim 1 or 2 wherein B is piperidin-4-yl,
piperidin-3-yl, or 4-methylpiperidin-4-yl wherein the nitrogen at
the 1 position optionally attaches (a) to a linker.
14. The compound of claim 2 wherein: R.sup.46 is alkyl or
substituted alkyl; R.sup.47 is alkyl, substituted alkyl, or
heterocycle; or R.sup.46 and R.sup.47 together with the nitrogen
atom to which they are attached form heterocycle.
15. The compound of claim 1 or 2 wherein L.sub.2 has any one of the
formula A1-A590 shown hereinabove.
16. The compound of claim 1 or 2 wherein L.sub.2 is A234, A363,
A364, A153, A28, A324, A329, A562, A87, or A239.
17. The compound of claim 1 wherein L.sub.1 is: 595
18. The compound of claim 18 wherein the piperidino nitrogen of
L.sub.1 is bonded to X.
19. The compound of claim 1 or 2 wherein X is alkylene optionally
substituted with one, two, or three hydroxy groups, alkylene
wherein one, two or three carbon atoms have been replaced by an
oxygen atom, -alkylene-phenylene-alkylene- wherein the phenylene
ring is optionally substituted with one or two chloro or fluoro
groups.
20. The compound of claim 1 or 2 wherein X is a group of formula:
--X.sup.a--Z--(Y.sup.a--Z).sub.m--Y.sup.b--Z--X.sup.a--wherein m is
an integer of from 0 to 20; X.sup.a at each separate occurrence is
selected from the group consisting of --O--, --S--, --NR--,
--C(O)--, --C(O)O--, --C(O)NR--, --C(S)--, --C(S)O--, --C(S)NR-- or
a covalent bond where R is as defined below; Z at each separate
occurrence is selected from the group consisting of alkylene,
substituted alkylene, cycloalkylene, substituted cylcoalkylene,
alkenylene, substituted alkenylene, alkynylene, substituted
alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene,
heteroarylene, heterocyclene, or a covalent bond; Y.sup.a and
Y.sup.b at each separate occurrence are selected from the group
consisting of --O--, --C(O)--, --OC(O)--, --C(O)O--, --NR--,
--S(O)n--, --C(O)NR'--, --NR' C(O)--, --NR' C(O)NR'--, --NR'
C(S)NR'--, --C(.dbd.NR')--NR'--, --NR'--C(.dbd.NR')--,
--OC(O)--NR'--, --NR'--C(O)--O--, --N.dbd.C(X.sup.a)--NR'--,
--NR'--C(X.sup.a).dbd.N--,--- P(O)(OR')--O--, --O--P(O)(OR')--,
--S(O).sub.nCR'R"--, --S(O)n--NR'--, --NR'--S(O).sub.n--, --S--S--,
and a covalent bond; where n is 0, 1 or 2; and R, R' and R" at each
separate occurrence are selected from the group consisting of
hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted
cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted
cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and
heterocyclic; provided at least one of X.sup.a, Y.sup.a, Y.sup.b or
Z is not a covalent bond.
21. The compound of claim 1 or 2 wherein X is an alkylene group
having from 3 to 20 carbon atoms; wherein one or more carbon atoms
in the alkylene group is optionally replaced with --O--; and
wherein the chain is optionally substituted on carbon with one or
more hydroxyl.
22. The compound of claim 1 or 2 wherein X is nonane-1,9-diyl,
octane-1,8-diyl, propane-1,3-diyl, 2-hydroxypropane-1,3-diyl, or
5-oxa-nonane-1,9-diyl.
23. The compound of claim 1 or 2 wherein X has the following
formula: 596wherein the phenyl ring is optionally substituted with
1, 2, or 3 fluoro groups.
24. The compound of claim 1 or 2 wherein X has one of the following
the formula: 597
25. The compound of claim 2 which is a compound of Formula (Ia):
598or a pharmaceutically acceptable salt or prodrug thereof.
26. The compound of claim 25 wherein X is alkylene optionally
substituted with one, two, or three hydroxy groups, alkylene
wherein one, two or three carbon atoms have been replaced by an
oxygen atom, -alkylene-phenylene-alkylene- wherein the phenylene
ring is optionally substituted with one or two chloro or fluoro
groups.
27. The compound of claim 25 wherein X is a group of formula:
--X.sup.a--Z--(Y.sup.a--Z).sub.m--Y.sup.b--Z--X.sup.a--wherein m is
an integer of from 0 to 20; X.sup.a at each separate occurrence is
selected from the group consisting of --O--, --S--, --NR--,
--C(O)--, --C(O)O--, --C(O)NR--, --C(S)--, --C(S)O--, --C(S)NR-- or
a covalent bond where R is as defined below; Z at each separate
occurrence is selected from the group consisting of alkylene,
substituted alkylene, cycloalkylene, substituted cylcoalkylene,
alkenylene, substituted alkenylene, alkynylene, substituted
alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene,
heteroarylene, heterocyclene, or a covalent bond; Y.sup.a and
Y.sup.b at each separate occurrence are selected from the group
consisting of --O--, --C(O)--, --OC(O)--, --C(O)O--, --NR--,
--S(O)n--, --C(O)NR'--, --NR' C(O)--, --NR' C(O)NR'--, --NR'
C(S)NR'--, --C(.dbd.NR')--NR'--, --NR'--C(.dbd.NR')--,
--OC(O)--NR'--, --NR'--C(O)--O--, --N.dbd.C(X.sup.a)--NR'--,
--NR'--C(X.sup.a).dbd.N--,--- P(O)(OR')--O--, --O--P(O)(OR')--,
--S(O).sub.nCR'R"--, --S(O).sub.n--NR'--, --NR'--S(O).sub.n--,
--S--S--, and a covalent bond; where n is 0, 1 or 2; and R, R' and
R" at each separate occurrence are selected from the group
consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl,
substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl,
substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl,
heteroaryl and heterocyclic; provided at least one of X.sup.a,
Y.sup.a, Y.sup.b or Z is not a covalent bond.
28. The compound of claim 25 wherein X is an alkylene group having
from 3 to 20 carbon atoms; wherein one or more carbon atoms in the
alkylene group is optionally replaced with --O--; and wherein the
chain is optionally substituted on carbon with one or more
hydroxyl.
29. The compound of claim 25 wherein X is nonane-1,9-diyl,
octane-1,8-diyl, propane-1,3-diyl, 2-hydroxypropane-1,3-diyl, or
5-oxa-nonane-1,9-diyl.
30. The compound of claim 25 wherein X has the following formula:
599wherein the phenyl ring is optionally substituted with 1, 2, or
3 fluoro groups.
31. The compound of claim 25 wherein X has one of the following the
formula: 600
32. The compound of claim 1 which is a compound of formula (IVa):
601wherein X, an L.sub.2 are defined as in claim 1; or a
pharmaceutically acceptable salt or prodrug thereof.
33. The compound of claim 32 wherein X is alkylene optionally
substituted with one, two, or three hydroxy groups, alkylene
wherein one, two or three carbon atoms have been replaced by an
oxygen atom, -alkylene-phenylene-alkylene- wherein the phenylene
ring is optionally substituted with one or two chloro or fluoro
groups.
34. The compound of claim 32 wherein X is a group of formula:
--X.sup.a--Z--(Y.sup.a--Z).sub.m--Y.sup.b--Z--X.sup.a--wherein m is
an integer of from 0 to 20; X.sup.a at each separate occurrence is
selected from the group consisting of --O--, --S--, --NR--,
--C(O)--, --C(O)O--, --C(O)NR--, --C(S)--, --C(S)O--, --C(S)NR--or
a covalent bond where R is as defined below; Z at each separate
occurrence is selected from the group consisting of alkylene,
substituted alkylene, cycloalkylene, substituted cylcoalkylene,
alkenylene, substituted alkenylene, alkynylene, substituted
alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene,
heteroarylene, heterocyclene, or a covalent bond; Y.sup.a and
Y.sup.b at each separate occurrence are selected from the group
consisting of --O--, --C(O)--, --OC(O)--, --C(O)O--, --NR--,
--S(O)n--, --C(O)NR'--, --NR' C(O)--, --NR' C(O)NR'--, --NR'
C(S)NR'--, --C(.dbd.NR')--NR'--, --NR'--C(.dbd.NR')--,
--OC(O)--NR'--, --NR'--C(O)--O--, --N.dbd.C(X.sup.a)--NR'--,
--NR'--C(X.sup.a).dbd.N--,--- P(O)(OR')--O--, --O--P(O)(OR')--,
--S(O).sub.nCR'R"--, --S(O).sub.n--NR'--, --NR'--S(O).sub.n--,
--S--S--, and a covalent bond; where n is 0, 1 or 2; and R, R' and
R" at each separate occurrence are selected from the group
consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl,
substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl,
substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl,
heteroaryl and heterocyclic; provided at least one of X.sup.a,
Y.sup.a, Y.sup.b or Z is not a covalent bond.
35. The compound of claim 32 wherein X is an alkylene group having
from 3 to 20 carbon atoms; wherein one or more carbon atoms in the
alkylene group is optionally replaced with --O--; and wherein the
chain is optionally substituted on carbon with one or more
hydroxyl.
36. The compound of claim 32 wherein X is nonane-1,9-diyl,
octane-1,8-diyl, propane-1,3-diyl, 2-hydroxypropane-1,3-diyl, or
5-oxa-nonane-1,9-diyl.
37. The compound of claim 32 wherein X has the following formula:
602wherein the phenyl ring is optionally substituted with 1, 2, or
3 fluoro groups.
38. The compound of claim 32 wherein X has one of the following the
formula: 603
39. The compound of claim 1 wherein L.sub.2 is a group of formula
(d) wherein R.sup.46 and R.sup.47 together with the nitrogen atom
to which they are attached form heterocycle which is substituted
with 1 to 5 substituents independently selected from the group
consisting of substituted alkyl, alkenyl, substituted alkenyl,
alkynyl, and substituted alkynyl.
40. The compound of claim 1 wherein L.sub.2 is a group of formula
(d) wherein R.sup.46 is a heterocycle, optionally substituted with
1 to 5 substituents independently selected from the group
consisting of alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl, and substituted alkynyl; and R.sup.47 is alkyl,
substituted alkyl, acyl, or --COOR.sup.50.
41. The compound of claim 1 wherein L.sub.2 is a group of formula
(d) wherein R.sup.46 is alkyl that is optionally substituted with
from 1 to 5 substituents independently selected from the group
consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted
cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl,
acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl,
cyano, halogen, hydroxyl, keto, thioketo, carboxylalkyl,
thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol,
thioalkoxy, substituted thioalkoxy, heterocyclic, heterocyclooxy,
hydroxyamino, alkoxyamino, NR.sup.aR.sup.b, wherein R.sup.a and
R.sup.b may be the same or different and and are chosen from
hydrogen, alkyl, substituted alkyl, cycloalkyl, alkenyl,
cycloalkenyl, alkynyl, and heterocyclic.
42. The compound of claim 1 wherein L.sub.2 is a group of formula
(d) wherein R.sup.46 is a heterocycle which is optionally
substituted with 1 to 5 substituents independently selected from
the group consisting of alkoxy, substituted alkoxy, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,
acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl,
aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto,
thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy,
thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy,
aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic,
heterocyclooxy, hydroxyamino, alkoxyamino, nitro, --SO-alkyl,
--SO-substituted alkyl, --SO-aryl, --SO-heteroaryl,
--SO.sub.2-alkyl, --SO.sub.2-substituted alkyl, --SO.sub.2-aryl
--SO.sub.2-heteroaryl, alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, and substituted alkynyl.
43. The compound of claim 1 wherein L.sub.2 is a group of formula
(d) wherein R.sup.46 is 3-piperidinyl, 4-piperidinyl, or
3-pyrrolidinyl, which R.sup.46 is optionally substituted with 1 to
3 substituents independently selected from the group consisting of
alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy,
amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl,
cyano, halogen, hydroxyl, keto, thioketo, carboxylalkyl,
thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol,
thioalkoxy, substituted thioalkoxy, heterocyclic, heterocyclooxy,
hydroxyamino, alkoxyamino, alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, and substituted alkynyl.
44. The compound of claim 1 wherein R.sup.46 and R.sup.47 together
with the nitrogen atom to which they are attached form a piperidine
or pyrrolidine ring which ring is optionally substituted with 1 to
3 substituents independently selected from the group consisting of
alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy,
amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl,
cyano, halogen, hydroxyl, keto, thioketo, carboxylalkyl,
thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol,
thioalkoxy, substituted thioalkoxy, heterocyclic, heterocyclooxy,
hydroxyamino, alkoxyamino, alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, and substituted alkynyl.
45. The compound of claim 1 wherein R.sup.46 and R.sup.47 together
with the nitrogen atom to which they are attached form a
heterocycle that is an aza-crown ether (e.g. 1-aza-12-crown-4,
1-aza-15-crown-5, or 1-aza-18-crown-6).
46. Compound number 1-643 as described in Table A, Table B, Table
C, Table D, Table E, or Table F; or a pharmaceutically acceptable
salt or prodrug thereof.
47. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier and a compound of claim 1 or 2.
48. A method of treating a disease mediated by a muscarinic
receptor in a mammal, comprising administering to said mammal a
therapeutically effective amount of a compound of claim 1 or 2.
49. The method of claim 48 wherein the disease is urinary
incontinence, chronic pulmonary obstructive disease, asthma,
hyper-salivation, a cognitive disorder, blurred vision, or
irritable bowel syndrome.
50. A compound of formula L.sub.1--H wherein L.sub.1 has the values
defined in claim 1; or a salt thereof
51. The compound of claim 50 which is 604or a salt thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS:
[0001] This application is a continuation-in-part of U.S. patent
application Ser. No. 09/456,170, filed Dec. 7, 1999.
BACKGROUND OF THE INVENTION
[0002] A receptor is a biological structure with one or more
binding domains that reversibly complexes with one or more ligands,
where that complexation has biological consequences. Receptors can
exist entirely outside the cell (extracellular receptors), within
the cell membrane (but presenting sections of the receptor to the
extracellular milieu and cytosol), or entirely within the cell
(intracellular receptors). They may also function independently of
a cell (e.g., clot formation). Receptors within the cell membrane
allow a cell to communicate with the space outside of its
boundaries (i.e., signaling) as well as to function in the
transport of molecules and ions into and out of the cell.
[0003] A ligand is a binding partner for a specific receptor or
family of receptors. A ligand may be the endogenous ligand for the
receptor or alternatively may be a synthetic ligand for the
receptor such as a drug, a drug candidate or a pharmacological
tool.
[0004] The super family of seven transmembrane proteins (7-TMs),
also called G-protein coupled receptors (GPCRs), represents one of
the most significant classes of membrane bound receptors that
communicate changes that occur outside of the cell's boundaries to
its interior, triggering a cellular response when appropriate. The
G-proteins, when activated, affect a wide range of downstream
effector systems both positively and negatively (e.g., ion
channels, protein kinase cascades, transcription, transmigration of
adhesion proteins, and the like).
[0005] Muscarinic receptors are members of the G-protein coupled
receptors that are composed of a family of five receptor sub-types
(M.sub.1, M.sub.2, M.sub.3, M.sub.4 and M.sub.5) and are activated
by the neurotransmitter acetylcholine. These receptors are widely
distributed on multiple organs and tissues and are critical to the
maintenance of central and peripheral cholinergic
neurotransmission. The regional distribution of these receptor
subtypes in the brain and other organs has been documented (Bonner,
T. I. et al., Science (Washington D.C.) 1987, 237, 527-532; Goyal,
R. K., J. Med., 1989, 321, 1022; Hulme, E. C., et al., Annu. Rev.
harmacol.Toxicol. 1990, 30, 633; and Eglen, R. M. and Hegde, S. S.,
Drug News Perspect. 1997, 10(8), 462-469). For example, the smooth
muscle is composed largely of M.sub.2 and M.sub.3 receptors,
cardiac muscle is composed largely of M.sub.2 receptors, and
salivary glands are largely composed of M.sub.3 receptors.
[0006] It has been established that the muscarinic receptors are
involved in diseases such as chronic obstructive pulmonary disease,
asthma, irritable bowel syndrome, urinary incontinence, rhinitis,
spasmodic colitis, chronic cystitis, and alzheimer,s disease,
senile dementia, glaucoma, schizophrenia, gastroesophogeal reflux
disease, cardiac arrhythmia, and hyper salvation syndromes (Fisher,
A., Invest. Drugs, 1997, 6(10), 1395-141 1; Martel, A. M., et al.,
Drugs Future, 1997, 22(2), 135-137; Graul, A. and Castaner, J.,
Drugs Future, 1996, 21(11), 1105-1108; and Graul, A., et al., Drugs
Future, 1997, 22(7), 733-737).
[0007] A number of compounds having muscarinic receptor
antagonistic activities are being used to treat these diseases. For
example, oxybutynin is being used for the treatment of urinary urge
incontinence and dicyclomine is being used for the treatment of
irritable bowel syndrome. However, these drugs have limited utility
as they produce side effects such as dry mouth, blurred vision, and
mydriasis.
[0008] There is currently a need for novel muscarinic receptor
antagonists.
SUMMARY OF THE INVENTION
[0009] The invention is directed to urea derivatives that are
muscarinic receptor antagonists and agonists and that are useful in
the treatment and prevention of diseases mediated by muscarinic
receptors (e.g. chronic obstructive pulmonary disease, chronic
bronchitis, irritable bowel syndrome, urinary incontinence, and the
like).
[0010] Accordingly, the invention provides a compound of the
invention which is a compound of Formula (I):
L.sub.1--X--L.sub.2
[0011] wherein:
[0012] L.sub.1 is a group of formula (a): 1
[0013] wherein:
[0014] A is an aryl or a heteroaryl ring;
[0015] B" is --NR.sup.a-- wherein R.sup.a is hydrogen, alkyl, aryl,
heteroaryl, or substituted alkyl;
[0016] R.sup.1 is hydrogen or alkyl;
[0017] R.sup.2 is Het, or is selected from a group consisting of
formula (i), (ii), and (iii): 2
[0018] wherein:
[0019] - - - is an optional double bond;
[0020] n.sub.1 is an integer of from 1 to 4;
[0021] n.sub.2 is an integer of from 1 to 3;
[0022] V is --CH--, --O--, --S(O)n.sub.3-- (where n.sub.3 is an
integer of from 0 to 2), or --NR.sup.4--(wherein R.sup.4 is
hydrogen, alkyl, substituted alkyl, aryl, or heteroaryl);
[0023] "Het" is a heteroaryl ring which optionally attaches (a) to
a linker;
[0024] R.sup.3 is hydrogen, alkyl, amino, substituted amino,
--OR.sup.a (where R.sup.a is hydrogen, alkyl, or acyl), or a
covalent bond attaching (a) to a linker;
[0025] R.sup.5 is hydrogen, alkyl, amino, substituted amino,
--OR.sup.b (where R.sup.b is hydrogen or alkyl), aryl, aralkyl,
heteroaralkyl, or a covalent bond attaching (a) to a linker;
[0026] R.sup.6, R.sup.7, and R.sup.8 are, independently of each
other, hydrogen, halo, hydroxy, alkoxy, haloalkoxy, carboxy,
alkoxycarbonyl, alkyl optionally substituted with one, two or three
substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl,
alkylthio, alkylsulfonyl, amino, substituted amino, or a covalent
bond attaching (a) to a linker;
[0027] K is a bond or an alkylene group;
[0028] K" is a bond, --C(O)--, --S(O).sub.n4--(where n.sub.4 is an
integer of from 0 to 2), or an alkylene group optionally
substituted with a hydroxyl group; and
[0029] B is heterocycloamino or heteroarylamino, which optionally
attaches (a) to a linker;
[0030] provided that at least one of the R.sup.5, R.sup.6, R.sup.7,
R.sup.8, "Het", heterocycloamino or heteroarylamino groups attaches
(a) to a linker;
[0031] X is a linker;
[0032] L.sub.2 is a group selected from a group consisting of:
[0033] (i) a group of formula (b): 3
[0034] wherein:
[0035] D" is alkylene;
[0036] D is --NR.sup.31R.sup.32,
--N.sup.+(R.sup.33R.sup.34R.sup.35) or--OR.sup.32 where R.sup.31,
R.sup.33, and R.sup.34 are, independently of each other, hydrogen,
alkyl, or aralkyl; and R.sup.32 and R.sup.35 represent a covalent
bond attaching (b) to a linker;
[0037] R.sup.27 is hydrogen, halo, nitro, cyano, hydroxy, alkoxy,
carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl,
alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl,
thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or
dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy,
heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl,
heteroaralkyl, or alkyl optionally substituted with one, two or
three substituents selected from halo, hydroxy, carboxy,
alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted
amino;
[0038] R.sup.28 is hydrogen, halo, nitro, cyano, hydroxy, alkoxy,
carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl,
alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl,
thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or
dialkylamino, or alkyl optionally substituted with one, two, or
three substituents selected from halo, hydroxy, carboxy,
alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted
amino;
[0039] R.sup.29 and R.sup.30 are, independently of each other,
hydrogen, alkyl, haloalkyl, halo, nitro, cyano, hydroxy, alkoxy,
alkoxycarbonyl, acyl, thio, alkylthio, amino, mono- or
dialkylamino; or
[0040] one of R.sup.27, R.sup.28, R.sup.29, or R.sup.30 together
with the adjacent group forms a methylenedioxy or ethylenedioxy
group;
[0041] (ii) a group of formula (c): 4
[0042] wherein:
[0043] n.sub.11 is an integer of from 1 to 7;
[0044] n.sub.12 is 0 to 7;
[0045] F is --NR.sup.40--, --O--, --S--, or --CHR.sup.41-- (wherein
R.sup.40 and R.sup.41 are, independently of each other, hydrogen,
alkyl, or substituted alkyl);
[0046] F" is a covalent bond, --OR.sup.43, --NR.sup.42R.sup.43, or
--N.sup.+R.sup.43R.sup.44R.sup.45 wherein R.sup.42 is hydrogen or
alkyl, R.sup.44 and R.sup.45 are alkyl, and R.sup.43 is hydrogen,
alkyl, or a covalent bond attaching (c) to a linker;
[0047] R.sup.36 is hydrogen, alkyl, halo, nitro, cyano, hydroxy,
alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio,
alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido,
carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or
dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy,
heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl,
heteroaralkyl, or alkyl optionally substituted with one, two or
three substituents selected from halo, hydroxy, carboxy,
alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted
amino;
[0048] R.sup.37 is hydrogen, alkyl, halo, nitro, cyano, hydroxy,
alkoxy, alkoxycarbonyl, acyl, thio, alkylthio, amino, mono- or
dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy,
heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl,
heteroaralkyl, or alkyl optionally substituted with one, two or
three substituents selected from halo, hydroxy, carboxy,
alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted
amino; and
[0049] R.sup.38 is hydrogen, alkyl, halo, hydroxy, alkoxy, or a
covalent bond attaching the ligand to a linker provided that at
least one of R.sup.38 and R.sup.43 attaches (c) to a linker;
[0050] R.sup.39 is hydrogen, alkyl, halo, hydroxy, alkoxy, or
substituted alkyl; and
[0051] (iii) a group of formula (d) or (e): 5
[0052] wherein:
[0053] R.sup.46 is alkyl, substituted alkyl, cycloalkyl,
substituted cycloalkyl, or heterocycle;
[0054] R.sup.47 is alkyl, substituted alkyl, aryl, acyl,
heterocycle, or --COOR.sup.50 where R.sup.50 is alkyl; or
[0055] R.sup.46 and R.sup.47 together with the nitrogen atom to
which they are attached form heterocycle, which heterocycle, in
addition to optionally bearing the optional substituents defined
hereinbelow for a heterocycle, can also optionally be substituted
with one or more (e.g. 1, 2, 3, or 4) alkyl, substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl.
[0056] R.sup.48 is a covalent bond that attaches the (d) or the (e)
to a linker; and
[0057] R.sup.49 is alkyl;
[0058] or a pharmaceutically acceptable salt; or prodrug
thereof.
[0059] Preferably X is a group of formula:
--X.sup.a--Z--(Y.sup.a--Z).sub.m--Y.sup.b--Z--X.sup.a--
[0060] wherein
[0061] m is an integer of from 0 to 20;
[0062] X.sup.a at each separate occurrence is selected from the
group consisting of --O--, --S--, --NR--, --C(O)--, --C(O)O--,
--C(O)NR--, --C(S)--, --C(S)O--, --C(S)NR-- or a covalent bond
where R is as defined below;
[0063] Z at each separate occurrence is selected from the group
consisting of alkylene, substituted alkylene, cycloalkylene,
substituted cylcoalkylene, alkenylene, substituted alkenylene,
alkynylene, substituted alkynylene, cycloalkenylene, substituted
cycloalkenylene, arylene, heteroarylene, heterocyclene, or a
covalent bond;
[0064] Y.sup.a and Y.sup.b at each separate occurrence are selected
from the group consisting of --O--, --C(O)--, --OC(O)--, --C(O)O--,
--NR--, --S(O)n--, --C(O)NR'--, --NR'C(O)--, --NR' C(O)NR'--,
--NR'C(S)NR'--, --C(.dbd.NR')--NR'--, --NR'--C(.dbd.NR')--,
--OC(O)--NR'--, --NR'--C(O)--O--, --N.dbd.C(R")--NR'--,
--NR'--C(R").dbd.N--,--P(O)(OR')-- -O--, --O--P(O)(OR')--,
--S(O).sub.nCR'R"--, --S(O).sub.n--NR'--, --NR'--S(O).sub.n--,
--S--S--, and a covalent bond; where n is 0, 1 or 2; and R, R'and
R" at each separate occurrence are selected from the group
consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl,
substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl,
substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl,
heteroaryl and heterocyclic (preferably, at least one of X.sup.a,
Y.sup.a, Y.sup.b or Z is not a covalent bond).
[0065] The invention also provides a compound of the invention
which is a compound of formula (IV): 6
[0066] wherein R.sup.2, K", A, K, R.sup.1, B", B, X, and L.sub.2
have any of the values defined herein; or a pharmaceutically
acceptable salt; or prodrug thereof. A preferred compound of the
invention is a compound of formula (IVa): 7
[0067] wherein X, and L.sub.2 have any of the values defined
herein; or a pharmaceutically acceptable salt; or prodrug
thereof.
[0068] The invention also provides a pharmaceutical composition
comprising a pharmaceutically acceptable carrier and a compound of
the invention or a pharmaceutically acceptable salt or prodrug
thereof.
[0069] The invention also provides synthetic intermediates
disclosed herein, as well as synthetic methods useful for preparing
such intermediates, and synthetic methods useful for preparing
compounds of the invention or salts thereof.
[0070] The invention also provides a method of treating diseases
mediated by a muscarinic receptor in a mammal, comprising
administering to said mammal a therapeutically effective amount of
a compound of the invention or a pharmaceutically acceptable salt
or prodrug thereof.
[0071] The invention also provides a compound of the invention or a
pharmaceutically acceptable salt or prodrug thereof for use in
medical therapy, as well as the use of a compound of Formula (I) or
a pharmaceutically acceptable salt or prodrug thereof in the
preparation of a medicament for the treatment of a disease mediated
by a muscarinic receptor in a mammal.
[0072] Applicant has discovered that urea compounds of the present
invention are metabolically more stable than compounds lacking such
a urea functionality. Accordingly, compounds of the present
invention have longer metabolic half-lives and/or longer duration
of action in vivo, which can reduce the dose required for
administration or can reduce the likelihood of the generation of
unwanted metabolites.
DETAILED DESCRIPTION OF THE INVENTION
[0073] The following terms have the following meanings unless
otherwise indicated. Any undefined terms have their art recognized
meanings.
[0074] The term "alkyl" refers to a monoradical branched or
unbranched saturated hydrocarbon chain preferably having from 1 to
40 carbon atoms, more preferably 1 to 10 carbon atoms, and even
more preferably 1 to 6 carbon atoms. This term is exemplified by
groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl,
iso-butyl, n-hexyl, n-decyl, tetradecyl, and the like.
[0075] The term "substituted alkyl" refers to an alkyl group as
defined above wherein one or more carbon atoms in the alkyl chain
have been optionally replaced with a heteroatom such as --O--,
--S(O)n-- (where n is 0 to 2), --NR-- (where R is hydrogen or
alkyl) and having from 1 to 5 substituents selected from the group
consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted
cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl,
acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl,
azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl,
carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,
thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy,
heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,
hydroxyamino, alkoxyamino, nitro, --SO-alkyl, --SO-aryl,
--SO-heteroaryl, --SO.sub.2-alkyl, --SO.sub.2-aryl,
--SO.sub.2-heteroaryl, and -NR.sup.aR.sup.b, wherein R.sup.a and
R.sup.b may be the same or different and and are chosen from
hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl,
cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic. This term
is exemplified by groups such as hydroxymethyl, hydroxyethyl,
hydroxypropyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl,
3-dimethylaminoprppyl, 2-sulfonamidoethyl, 2-carboxyethyl, and the
like.
[0076] The term "alkylene" refers to a diradical of a branched or
unbranched saturated hydrocarbon chain, preferably having from 1 to
40 carbon atoms, more preferably 1 to 10 carbon atoms and even more
preferably 1 to 6 carbon atoms. This term is exemplified by groups
such as methylene (--CH.sub.2--), ethylene (--CH.sub.2CH.sub.2--),
the propylene isomers (e.g., --CH.sub.2CH.sub.2CH.sub.2-- and
--CH(CH.sub.3)CH.sub.2--) and the like.
[0077] The term "substituted alkylene" refers to an alkylene group,
as defined above, having from 1 to 5 substituents, and preferably 1
to 3 substituents, selected from the group consisting of alkoxy,
substituted alkoxy, cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy,
amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl,
azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl,
carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,
thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy,
heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,
hydroxyamino, alkoxyamino, nitro, --SO-alkyl, --SO-substituted
alkyl, --SO-aryl, --SO-heteroaryl, --SO.sub.2-alkyl,
--SO.sub.2-substituted alkyl, --SO.sub.2-aryl and
--SO.sub.2-heteroaryl. Additionally, such substituted alkylene
groups include those where 2 substituents on the alkylene group are
fused to form one or more cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted cycloalkenyl, aryl, heterocyclic or
heteroaryl groups fused to the alkylene group. Preferably such
fused groups contain from 1 to 3 fused ring structures.
[0078] The term "alkylaminoalkyl", "alkylaminoalkenyl" and
"alkylaminoalkynyl" refers to the groups R.sup.aNHR.sup.b-- where
R.sup.a is alkyl group as defined above and R.sup.b is alkylene,
alkenylene or alkynylene group as defined above. Such groups are
exemplified by 3-methylaminobutyl,
4-ethylamino-1,1-dimethylbutyn-1-yl, 4-ethylaminobutyn-1-yl, and
the like.
[0079] The term "alkaryl" or "aralkyl" refers to the groups
-alkylene-aryl and -substituted alkylene-aryl where alkylene,
substituted alkylene and aryl are defined herein. Such alkaryl
groups are exemplified by benzyl, phenethyl and the like.
[0080] The term "alkoxy" refers to the groups alkyl-O--,
alkenyl-O--, cycloalkyl-O--, cycloalkenyl-O--, and alkynyl-O--,
where alkyl, alkenyl, cycloalkyl, cycloalkenyl, and alkynyl are as
defined herein. Preferred alkoxy groups are alkyl-O-- and include,
by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy,
n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy,
1,2-dimethylbutoxy, and the like.
[0081] The term "substituted alkoxy" refers to the groups
substituted alkyl-O--, substituted alkenyl-O--, substituted
cycloalkyl-O--, substituted cycloalkenyl-O--, and substituted
alkynyl-O-- where substituted alkyl, substituted alkenyl,
substituted cycloalkyl, substituted cycloalkenyl and substituted
alkynyl are as defined herein.
[0082] The term "haloalkoxy" refers to the groups alkyl-O-- wherein
one or more hydrogen atoms on the alkyl group have been substituted
with a halo group and include, by way of examples, groups such as
trifluoromethoxy, and the like.
[0083] The term "alkylalkoxy" refers to the groups
-alkylene-O-alkyl, alkylene-O-substituted alkyl, substituted
alkylene-O-alkyl, and substituted alkylene-O-substituted alkyl
wherein alkyl, substituted alkyl, alkylene and substituted alkylene
are as defined herein. Preferred alkylalkoxy groups are
alkylene-O-alkyl and include, by way of example, methylenemethoxy
(--CH.sub.2OCH.sub.3), ethylenemethoxy
(--CH.sub.2CH.sub.2OCH.sub.3), n-propylene-iso-propoxy
(--CH.sub.2CH.sub.2CH.sub.2OCH(CH.sub.3).sub.2), methylene-t-butoxy
(--CH.sub.2--O--C(CH.sub.3).sub.3), and the like.
[0084] The term "alkylthioalkoxy" refers to the group
-alkylene-S-alkyl, alkylene-S-substituted alkyl, substituted
alkylene-S-alkyl and substituted alkylene-S-substituted alkyl
wherein alkyl, substituted alkyl, alkylene and substituted alkylene
are as defined herein. Preferred alkylthioalkoxy groups are
alkylene-S-alkyl and include, by way of example,
methylenethiomethoxy (--CH.sub.2SCH.sub.3), ethylenethiomethoxy
(--CH.sub.2CH.sub.2SCH.sub.3), n-propylene-iso-thiopropoxy
(--CH.sub.2CH.sub.2CH.sub.2SCH(CH.sub.3).sub.2),
methylene-t-thiobutoxy (--CH.sub.2SC(CH.sub.3).sub.3), and the
like.
[0085] The term "alkenyl" refers to a monoradical of a branched or
unbranched unsaturated hydrocarbon group preferably having from 2
to 40 carbon atoms, more preferably 2 to 10 carbon atoms and even
more preferably 2 to 6 carbon atoms and having at least 1 and
preferably from 1-6 sites of vinyl unsaturation. Preferred alkenyl
groups include ethenyl (--CH.dbd.CH.sub.2), n-propenyl
(--CH.sub.2CH.dbd.CH.sub.2), iso-propenyl
(--C(CH.sub.3).dbd.CH.sub.2), and the like.
[0086] The term "substituted alkenyl" refers to an alkenyl group as
defined above having from 1 to 5 substituents, and preferably 1 to
3 substituents, selected from the group consisting of alkoxy,
substituted alkoxy, cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy,
amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl,
azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl,
carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,
thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy,
heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,
hydroxyamino, alkoxyamino, nitro, --SO-alkyl, --SO-substituted
alkyl, --SO-aryl, --SO-heteroaryl, --SO.sub.2-alkyl,
--SO.sub.2-substituted alkyl, --SO.sub.2-aryl and
--SO.sub.2-heteroaryl.
[0087] The term "alkenylene" refers to a diradical of a branched or
unbranched unsaturated hydrocarbon group preferably having from 2
to 40 carbon atoms, more preferably 2 to 10 carbon atoms and even
more preferably 2 to 6 carbon atoms and having at least 1 and
preferably from 1-6 sites of vinyl unsaturation. This term is
exemplified by groups such as ethenylene (--CH.dbd.CH--), the
propenylene isomers (e.g., --CH.sub.2CH.dbd.CH-- or
--C(CH.sub.3).dbd.CH--), and the like.
[0088] The term "substituted alkenylene" refers to an alkenylene
group as defined above having from 1 to 5 substituents, and
preferably from 1 to 3 substituents, selected from the group
consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted
cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl,
acylamino, acyloxy, amino, substituted amino, aminoacyl,
amninoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto,
thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy,
thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy,
aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic,
heterocyclooxy, hydroxyamino, alkoxyamino, nitro, --SO-alkyl,
--SO-substituted alkyl, --SO-aryl, --SO-heteroaryl,
--SO.sub.2-alkyl, --SO.sub.2-substituted alkyl, --SO.sub.2-aryl and
--SO.sub.2-heteroaryl. Additionally, such substituted alkenylene
groups include those where 2 substituents on the alkenylene group
are fused to form one or more cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted cycloalkenyl, aryl, heterocyclic or
heteroaryl groups fused to the alkenylene group.
[0089] The term "alkynyl" refers to a monoradical of an unsaturated
hydrocarbon preferably having from 2 to 40 carbon atoms, more
preferably 2 to 20 carbon atoms and even more preferably 2 to 6
carbon atoms and having at least 1 and preferably from 1-6 sites of
acetylene (triple bond) unsaturation. Preferred alkynyl groups
include ethynyl (--C.ident.CH), propargyl (--CH.sub.2C.ident.CH),
and the like.
[0090] The term "substituted alkynyl" refers to an alkynyl group as
defined above having from 1 to 5 substituents, and preferably 1 to
3 substituents, selected from the group consisting of alkoxy,
substituted alkoxy, cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy,
amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl,
azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl,
carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,
thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy,
heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,
hydroxyamino, alkoxyamino, nitro, --SO-alkyl, --SO-substituted
alkyl, --SO-aryl, --SO-heteroaryl, --SO.sub.2-alkyl,
--SO.sub.2-substituted alkyl, --SO.sub.2-aryl, and
--SO.sub.2-heteroaryl.
[0091] The term "alkynylene" refers to a diradical of an
unsaturated hydrocarbon preferably having from 2 to 40 carbon
atoms, more preferably 2 to 10 carbon atoms and even more
preferably 2 to 6 carbon atoms and having at least 1 and preferably
from 1-6 sites of acetylene (triple bond) unsaturation. Preferred
alkynylene groups include ethynylene (--CE.ident.C--), propargylene
(--CH.sub.2C.ident.C--), and the like.
[0092] The term "substituted alkynylene" refers to an alkynylene
group as defined above having from 1 to 5 substituents, and
preferably 1 to 3 substituents, selected from the group consisting
of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy,
amino, substituted amino, aminoacyl, arninoacyloxy, oxyaminoacyl,
azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl,
carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,
thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy,
heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,
hydroxyamino, alkoxyamino, nitro, --SO-alkyl, --SO-substituted
alkyl, --SO-aryl, --SO-heteroaryl, --SO.sub.2-alkyl,
--SO.sub.2-substituted alkyl, --SO.sub.2-aryl and
--SO.sub.2-heteroaryl.
[0093] The term "acyl" refers to the groups HC(O)--, alkyl-C(O)--,
substituted alkyl-C(O)--, cycloalkyl-C(O)--, substituted
cycloalkyl-C(O)--, cycloalkenyl-C(O)--, substituted
cycloalkenyl-C(O)--, aryl-C(O)--, heteroaryl-C(O)-- and
heterocyclic-C(O)-- where alkyl, substituted alkyl, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,
aryl, heteroaryl, and heterocyclic are as defined herein.
[0094] The term "acylamino" or "aminocarbonyl" refers to the group
--C(O)NRR where each R is independently hydrogen, alkyl,
substituted alkyl, aryl, heteroaryl, heterocyclic or where both R
groups are joined to form a heterocyclic group (e.g., morpholino)
wherein alkyl, substituted alkyl, aryl, heteroaryl, and
heterocyclic are as defined herein.
[0095] The term "aminoacyl" refers to the group --NRC(O)R where
each R is independently hydrogen, alkyl, substituted alkyl, aryl,
heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl,
heteroaryl, and heterocyclic are as defined herein.
[0096] The term "aminoacyloxy" or "alkoxycarbonylamino" refers to
the group --NRC(O)OR where each R is independently hydrogen, alkyl,
substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl,
substituted alkyl, aryl, heteroaryl, and heterocyclic are as
defined herein.
[0097] The term "acyloxy" refers to the groups alkyl-C(O)O--,
substituted alkyl-C(O)O--, cycloalkyl-C(O)O--, substituted
cycloalkyl-C(O)O--, aryl-C(O)O--, heteroaryl-C(O)O--, and
heterocyclic-C(O)O-- wherein alkyl, substituted alkyl, cycloalkyl,
substituted cycloalkyl, aryl, heteroaryl, and heterocyclic are as
defined herein.
[0098] The term "aryl" refers to an unsaturated aromatic
carbocyclic group of from 6 to 20 carbon atoms having a single ring
(e.g., phenyl) or multiple condensed (fused) rings (e.g., naphthyl
or anthryl). Preferred aryls include phenyl, naphthyl and the like.
Unless otherwise constrained by the definition for the aryl
substituent, such aryl groups can optionally be substituted with
from 1 to 5 substituents, preferably 1 to 3 substituents, selected
from the group consisting of acyloxy, hydroxy, thiol, acyl, alkyl,
alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted
alkyl, substituted alkoxy, substituted alkenyl, substituted
alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino,
substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy,
azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl,
heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy,
oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy,
thioheteroaryloxy, --SO-alkyl, --SO-substituted alkyl, --SO-aryl,
--SO-heteroaryl, --SO.sub.2-alkyl, --SO.sub.2-substituted alkyl,
--SO.sub.2-aryl, --SO.sub.2-heteroaryl and trihalomethyl. Preferred
aryl substituents include alkyl, alkoxy, halo, cyano, nitro,
trihalomethyl, and thioalkoxy.
[0099] The term "aryloxy" refers to the group aryl-O-- wherein the
aryl group is as defined above including optionally substituted
aryl groups as also defined above.
[0100] The term "arylene " refers to the diradical derived from
aryl (including substituted aryl) as defined above and is
exemplified by 1,2-phenylene, 1,3-phenylene, 1,4-phenylene,
1,2-naphthylene and the like.
[0101] The term "amino" refers to the group --NH.sub.2.
[0102] The term "substituted amino" refers to the group --NRR where
each R is independently selected from the group consisting of
hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted
cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted
cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, and
heterocyclic provided that both R's are not hydrogen.
[0103] The term "carboxyalkyl" or "alkoxycarbonyl" refers to the
groups "--C(O)O-alkyl", "--C(O)O-substituted alkyl",
"--C(O)O-cycloalkyl", "--C(O)O-substituted cycloalkyl",
"--C(O)O-alkenyl", "--C(O)O-substituted alkenyl", "--C(O)O-alkynyl"
and "--C(O)O-substituted alkynyl" where alkyl, substituted alkyl,
cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl,
alkynyl and substituted alkynyl alkynyl are as defined herein.
[0104] The term "cycloalkyl" refers to cyclic alkyl groups of from
3 to 20 carbon atoms having a single cyclic ring or multiple
condensed rings. Such cycloalkyl groups include, by way of example,
single ring structures such as cyclopropyl, cyclobutyl,
cyclopentyl, cyclooctyl, and the like, or multiple ring structures
such as adamantanyl, and the like.
[0105] The term "substituted cycloalkyl" refers to cycloalkyl
groups having from 1 to 5 substituents, and preferably 1 to 3
substituents, selected from the group consisting of alkoxy,
substituted alkoxy, cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy,
amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl,
azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl,
carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,
thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy,
heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,
hydroxyamino, alkoxyamino, nitro, --SO-alkyl, --SO-substituted
alkyl, --SO-aryl, --SO-heteroaryl, --SO.sub.2-alkyl,
--SO.sub.2-substituted alkyl, --SO.sub.2-aryl and
--SO.sub.2-heteroaryl.
[0106] The term "cycloalkenyl" refers to cyclic alkenyl groups of
from 4 to 20 carbon atoms having a single cyclic ring and at least
one point of internal unsaturation. Examples of suitable
cycloalkenyl groups include, for instance, cyclobut-2-enyl,
cyclopent-3-enyl, cyclooct-3-enyl, and the like.
[0107] The term "substituted cycloalkenyl" refers to cycloalkenyl
groups having from 1 to 5 substituents, and preferably 1 to 3
substituents, selected from the group consisting of alkoxy,
substituted alkoxy, cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy,
amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl,
azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl,
carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,
thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy,
heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,
hydroxyamino, alkoxyamino, nitro, --SO-alkyl, --SO-substituted
alkyl, --SO-aryl, --SO-heteroaryl, --SO.sub.2-alkyl,
--SO.sub.2-substituted alkyl, --SO.sub.2-aryl and
--SO.sub.2-heteroaryl.
[0108] The term "halo" or "halogen" refers to fluoro, chloro, bromo
and iodo.
[0109] The term "heteroaryl" refers to an aromatic group of from 1
to 15 carbon atoms and 1 to 4 heteroatoms selected from oxygen,
nitrogen and sulfur within at least one ring (if there is more than
one ring). Unless otherwise constrained by the definition for the
heteroaryl substituent, such heteroaryl groups can be optionally
substituted with 1 to 5 substituents, preferably 1 to 3
substituents, selected from the group consisting of acyloxy,
hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, substituted alkyl, substituted alkoxy, substituted
alkenyl, substituted alkynyl, substituted cycloalkyl, substituted
cycloalkenyl, amino, substituted amino, aminoacyl, acylamino,
alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano,
halo, nitro, heteroaryl, heteroaryloxy, heterocyclic,
heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted
thioalkoxy, thioaryloxy, thioheteroaryloxy, --SO-alkyl,
--SO-substituted alkyl, --SO-aryl, --SO-heteroaryl,
--SO.sub.2-alkyl, --SO.sub.2-substituted alkyl, --SO.sub.2-aryl,
--SO.sub.2-heteroaryl and trihalomethyl. Preferred aryl
substituents include alkyl, alkoxy, halo, cyano, nitro,
trihalomethyl, and thioalkoxy. Such heteroaryl groups can have a
single ring (e.g., pyridyl or furyl) or multiple condensed rings
(e.g., indolizinyl or benzothienyl). Preferred heteroaryls include
pyridyl, pyrrolyl and furyl.
[0110] The term "heteroaralkyl" refers to the groups
-alkylene-heteroaryl where alkylene and heteroaryl are defined
herein. Such heteroaralkyl groups are exemplified by pyridylmethyl,
pyridylethyl, indolylmethyl, and the like.
[0111] The term "heteroaryloxy" refers to the group
heteroaryl-O--.
[0112] The term "heteroarylene" refers to the diradical group
derived from heteroaryl (including substituted heteroaryl), as
defined above, and is exemplified by the groups 2,6-pyridylene,
2,4-pyridiylene, 1,2-quinolinylene, 1,8-quinolinylene,
1,4-benzofuranylene, 2,5-pyridnylene, 2,5-indolenyl, and the
like.
[0113] The term "heterocycle" or "heterocyclic" or refers to a
monoradical saturated unsaturated group having a single ring or
multiple condensed rings, from 1 to 40 carbon atoms and from 1 to
10 hetero atoms, preferably 1 to 4 heteroatoms, selected from
nitrogen, sulfur, phosphorus, and/or oxygen within the ring. Unless
otherwise constrained by the definition for the heterocyclic
substituent, such heterocyclic groups can be optionally substituted
with 1 to 5, and preferably 1 to 3 substituents, selected from the
group consisting of alkoxy, substituted alkoxy, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,
acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl,
aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto,
thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy,
thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy,
aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic,
heterocyclooxy, hydroxyamino, alkoxyamino, nitro, --SO-alkyl,
--SO-substituted alkyl, --SO-aryl, --SO-heteroaryl,
--SO.sub.2-alkyl, --SO.sub.2-substituted alkyl, --SO.sub.2-aryl and
--SO.sub.2-heteroaryl. Such heterocyclic groups can have a single
ring or multiple condensed rings. Preferred heterocyclics include
morpholino, piperidinyl, and the like.
[0114] Examples of nitrogen heteroaryls and heterocycles include,
but are not limited to, pyrrole, thiophene, furan, imidazole,
pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine,
isoindole, indole, indazole, purine, quinolizine, isoquinoline,
quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline,
cinnoline, pteridine, carbazole, carboline, phenanthridine,
acridine, phenanthroline, isothiazole, phenazine, isoxazole,
phenoxazine, phenothiazine, imidazolidine, imidazoline,
pyrrolidine, piperidine, piperazine, indoline, morpholine,
tetrahydrofuranyl, tetrahydrothiophene, and the like as well as
N-alkoxy-nitrogen containing heterocycles.
[0115] The term "heterocyclooxy" refers to the group
heterocyclic-O--.
[0116] The term "thioheterocyclooxy" refers to the group
heterocyclic-S--.
[0117] The term "heterocyclene" refers to the diradical group
formed from a heterocycle, as defined herein, and is exemplified by
the groups 2,6-morpholino, 2,5-morpholino and the like.
[0118] "Heteroarylamino" means a 5 membered aromatic ring wherein
one or two ring atoms are N, the remaining ring atoms being C. The
heterocycloamino ring may be fused to a cycloalkyl, aryl or
heteroaryl ring, and it may be optionally substituted with one or
more substituents, preferably one or two substituents, selected
from alkyl, substituted alkyl, cycloalkyl, aryl, aralkyl,
heteroaryl, heteroaralkyl, halo, cyano, acyl, amino, substituted
amino, acylamino, --OR (where R is hydrogen, alkyl, alkenyl,
cycloalkyl, acyl, aryl, heteroaryl, aralkyl, or heteroaralkyl), or
--S(O)nR [where n is an integer from 0 to 2 and R is hydrogen
(provided that n is 0), alkyl, alkenyl, cycloalkyl, amino,
heterocyclo, aryl, heteroaryl, aralkyl, or heteroaralkyl]. More
specifically the term heterocycloamino includes, but is not limited
to, imidazole, pyrazole, benzimidazole and benzpyrazole.
[0119] "Heterocycloamino" means a saturated monovalent cyclic group
of 4 to 8 ring atoms, wherein at least one ring atom is N and
optionally contains one or two additional ring heteroatoms selected
from the group consisting of N, O, or S(O)n (where n is an integer
from 0 to 2), the remaining ring atoms being C, where one or two C
atoms may optionally be replaced by a carbonyl group. The
heterocycloamino ring may be fused to a cycloalkyl, aryl or
heteroaryl ring, and it may be optionally substituted with one or
more substituents, preferably one or two substituents, selected
from alkyl, substituted alkyl, cycloalkyl, aryl, aralkyl,
heteroaryl, heteroaralkyl, halo, cyano, acyl, amino, substituted
amino, acylamino, -OR (where R is hydrogen, alkyl, alkenyl,
cycloalkyl, acyl, aryl, heteroaryl, aralkyl, or heteroaralkyl), or
-S(O)nR [where n is an integer from 0 to 2 and R is hydrogen
(provided that n is 0), alkyl, alkenyl, cycloalkyl, amino,
heterocyclo, aryl, heteroaryl, aralkyl, or heteroaralkyl]. More
specifically the term heterocycloamino includes, but is not limited
to, pyrrolidino, piperidino, morpholino, piperazino, indolino, or
thiomorpholino. The term heterocycloamino also includes,
quinuclidine, 1 -azabicyclo[2.2.1]heptyl, 1-azabicyclo[3.2.1]octyl
and the derivatives thereof.
[0120] The term "oxyacylamino " or "aminocarbonyloxy" refers to the
group --OC(O)NRR where each R is independently hydrogen, alkyl,
substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl,
substituted alkyl, aryl, heteroaryl and heterocyclic are as defined
herein.
[0121] The term "spiro-attached cycloalkyl group " refers to a
cycloalkyl group attached to another ring via one carbon atom
common to both rings.
[0122] The term "thiol" refers to the group --SH.
[0123] The term "thioalkoxy" or "alkylthio" refers to the group
--S-alkyl.
[0124] The term "substituted thioalkoxy" refers to the group
--S-substituted alkyl.
[0125] The term "thioaryloxy" refers to the group aryl-S-- wherein
the aryl group is as defined above including optionally substituted
aryl groups also defined above.
[0126] The term "thioheteroaryloxy" refers to the group
heteroaryl-S-- wherein the heteroaryl group is as defined above
including optionally substituted aryl groups as also defined
above.
[0127] As to any of the above groups which contain one or more
substituents, it is understood, of course, that such groups do not
contain any substitution or substitution patterns which are
sterically impractical and/or synthetically non-feasible. In
addition, the compounds of this invention include all
stereochemical isomers arising from the substitution of these
compounds.
[0128] Unless specified otherwise, all ranges referred to herein
include the stated end-point values.
[0129] The term "pharmaceutically-acceptable salt" refers to salts
which retain biological effectiveness and are not biologically or
otherwise undesirable. In many cases, the compounds of this
invention are capable of forming acid and/or base salts by virtue
of the presence of amino and/or carboxyl groups or groups similar
thereto.
[0130] Pharmaceutically-acceptable base addition salts can be
prepared from inorganic and organic bases. Salts derived from
inorganic bases, include by way of example only, sodium, potassium,
lithium, ammonium, calcium and magnesium salts. Salts derived from
organic bases include, but are not limited to, salts of primary,
secondary and tertiary amines, such as alkyl amines, dialkyl
amines, trialkyl amines, substituted alkyl amines, di(substituted
alkyl) amines, tri(substituted alkyl) amines, alkenyl amines,
dialkenyl amines, trialkenyl amines, substituted alkenyl amines,
di(substituted alkenyl) amines, tri(substituted alkenyl) amines,
cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines,
substituted cycloalkyl amines, disubstituted cycloalkyl amine,
trisubstituted cycloalkyl amines, cycloalkenyl amines,
di(cycloalkenyl) amines, tri(cycloalkenyl) amines, substituted
cycloalkenyl amines, disubstituted cycloalkenyl amine,
trisubstituted cycloalkenyl amines, aryl amines, diaryl amines,
triaryl amines, heteroaryl amines, diheteroaryl amines,
triheteroaryl amines, heterocyclic amines, diheterocyclic amines,
triheterocyclic amines, mixed di- and tri-amines where at least two
of the substituents on the amine are different and are selected
from the group consisting of alkyl, substituted alkyl, alkenyl,
substituted alkenyl, cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl,
heterocyclic, and the like. Also included are amines where the two
or three substituents, together with the amino nitrogen, form a
heterocyclic or heteroaryl group. Examples of suitable amines
include, by way of example only, isopropylamine, trimethyl amine,
diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine,
ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine,
arginine, histidine, caffeine, procaine, hydrabamine, choline,
betaine, ethylenediamine, glucosamine, N-alkylglucamines,
theobromine, purines, piperazine, piperidine, morpholine,
N-ethylpiperidine, and the like. It should also be understood that
other carboxylic acid derivatives would be useful in the practice
of this invention, for example, carboxylic acid amides, including
carboxamides, lower alkyl carboxamides, dialkyl carboxamides, and
the like.
[0131] Pharmaceutically acceptable acid addition salts may be
prepared from inorganic and organic acids. Salts derived from
inorganic acids include hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid, and the like. Salts
derived from organic acids include acetic acid, propionic acid,
glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid,
succinic acid, maleic acid, fumaric acid, tartaric acid, citric
acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic
acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid,
and the like.
[0132] The term "pharmaceutically-acceptable cation " refers to the
cation of a pharmaceutically-acceptable salt.
[0133] The term "protecting group" or "blocking group" refers to
any group which when bound to one or more hydroxyl, thiol, amino or
carboxyl groups of the compounds (including intermediates thereof)
prevents reactions from occurring at these groups and which
protecting group can be removed by conventional chemical or
enzymatic steps to reestablish the hydroxyl, thiol, amino or
carboxyl group. The particular removable blocking group employed is
not critical and preferred removable hydroxyl blocking groups
include conventional substituents such as allyl, benzyl, acetyl,
chloroacetyl, thiobenzyl, benzylidine, phenacyl,
t-butyl-diphenylsilyl and any other group that can be introduced
chemically onto a hydroxyl functionality and later selectively
removed either by chemical or enzymatic methods in mild conditions
compatible with the nature of the product. Preferred removable
thiol blocking groups include disulfide groups, acyl groups, benzyl
groups, and the like. Preferred removable amino blocking groups
include conventional substituents such as t-butyoxycarbonyl
(t-BOC), benzyloxycarbonyl (CBZ), fluorenylmethoxy-carbonyl (FMOC),
allyloxycarbonyl (ALOC), and the like which can be removed by
conventional conditions compatible with the nature of the product.
Preferred carboxyl protecting groups include esters such as methyl,
ethyl, propyl, t-butyl etc. which can be removed by mild conditions
compatible with the nature of the product.
[0134] The term "optional" or "optionally" means that the
subsequently described event, circumstance or substituent may or
may not occur, and that the description includes instances where
said event or circumstance occurs and instances where it does
not.
[0135] The term "inert organic solvent" or "inert organic solvent"
means a solvent which is inert under the conditions of the reaction
being described in conjunction therewith including, by way of
example only, benzene, toluene, acetonitrile, tetrahydrofuran,
dimethylformamide, chloroform, methylene chloride, diethyl ether,
ethyl acetate, acetone, methylethyl ketone, methanol, ethanol,
propanol, isopropanol, t-butanol, dioxane, pyridine, and the like.
Unless specified to the contrary, the solvents used in the
reactions described herein are inert solvents.
[0136] The term "treatment" refers to any treatment of a pathologic
condition in a mammal, particularly a human, and includes:
[0137] (i) preventing the pathologic condition from occurring in a
subject which may be predisposed to the condition but has not yet
been diagnosed with the condition and, accordingly, the treatment
constitutes prophylactic treatment for the disease condition;
[0138] (ii) inhibiting the pathologic condition, i.e., arresting
its development;
[0139] (iii) relieving the pathologic condition, i.e., causing
regression of the pathologic condition; or
[0140] (iv) relieving the conditions mediated by the pathologic
condition.
[0141] The term "pathologic condition which is modulated by
treatment with a ligand" covers all disease states (i.e.,
pathologic conditions) which are generally acknowledged in the art
to be usefully treated with a ligand for the muscarinic receptors
in general, and those disease states which have been found to be
usefully treated by a compound of the invention. Such disease
states include, by way of example only, the treatment of a mammal
afflicted with chronic obstructive pulmonary disease, chronic
bronchitis, irritable bowel syndrome, urinary incontinence, and the
like.
[0142] The term "therapeutically effective amount" refers to that
amount of a compound which is sufficient to effect treatment, as
defined above, when administered to a mammal in need of such
treatment. The therapeutically effective amount will vary depending
upon the subject and disease condition being treated, the weight
and age of the subject, the severity of the disease condition, the
manner of administration and the like, which can readily be
determined by one of ordinary skill in the art.
[0143] The term "linker", identified by the symbol `X` refers to a
group or groups that covalently attaches L.sub.1 and L.sub.2.
Additionally, the linker can be either a chiral or achiral
molecule. The term "linker" does not, however, extend to cover
solid inert supports such as beads, glass particles, fibers, and
the like. But it is understood that the compounds of this invention
can be attached to a solid support if desired. For example, such
attachment to solid supports can be made for use in separation and
purification processes and similar applications.
[0144] "Pro-drugs" means any compound which releases an active
parent drug according to Formula (I) in vivo when such prodrug is
administered to a mammalian subject. Prodrugs of a compound of
Formula (I) are prepared by modifying functional groups present in
the compound of Formula (I) in such a way that the modifications
may be cleaved in vivo to release the parent compound. Prodrugs
include compounds of Formula (D) wherein a hydroxy, amino, or
sulfhydryl group in compound (I) is bonded to any group that may be
cleaved in vivo to regenerate the free hydroxyl, amino, or
sulfhydryl group, respectively. Examples of prodrugs include, but
are not limited to esters (e.g., acetate, formate, and benzoate
derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) of
hydroxy functional groups in compounds of Formula (I), and the
like.
[0145] While the broadest definition of this invention is set forth
in the Summary of the Invention, certain compounds of Formula (I)
may be preferred. Specific and preferred values listed herein for
radicals, substituents, and ranges, are for illustration only; they
do not exclude other defined values or other values within defined
ranges for the radicals and substituents
[0146] A preferred value for A is phenyl or pyridine
[0147] A preferred value for R.sup.1 is hydrogen methyl, or
ethyl.
[0148] Another preferred value for R.sup.1 is hydrogen.
[0149] A preferred value for R.sup.2 is pyrrolyl, pyridinyl, or
imidazolyl.
[0150] Another preferred value for R.sup.2 is phenyl.
[0151] A preferred value for V is --CH-- or --NR.sup.4-- (wherein
R.sup.4 is hydrogen, alkyl, substituted alkyl, aryl, or
heteroaryl).
[0152] A preferred value for R.sup.3 is hydrogen or alkyl
[0153] A preferred value for R.sup.5 is hydrogen, alkyl, aryl,
aralkyl, heteroaralkyl, or a covalent bond attaching (a) to a
linker
[0154] Another preferred value for R.sup.5 is hydrogen, methyl,
phenyl optionally substituted with alkyl, alkoxy, halo, hydroxy,
carboxy, or amino, benzyl optionally substituted with alkyl,
alkoxy, halo, hydroxy, carboxy, or amino.
[0155] A preferred value for R.sup.6, R.sup.7, and R.sup.8
independent of each other is hydrogen, alkyl, nitro, hydroxy, or
amino.
[0156] A preferred value for K is alkylene having from 1 to 10
carbon atoms.
[0157] A preferred value for K is alkylene having from 1 to 5
carbon atoms.
[0158] A preferred value for K is a bond or a methylene group.
[0159] A preferred value for K" is a bond.
[0160] A preferred value for R.sup.a is hydrogen.
[0161] A preferred value for B is a heterocycloamino group which
attaches (a) to a linker.
[0162] Another preferred value for B is a formula selected from a
group consisting of formula (j), formula (k), and formula (l):
8
[0163] wherein:
[0164] n.sub.13 and n.sub.14 are, independently of each other, an
integer of from 0 to 4 provided that n.sub.13+n.sub.14 is an
integer of from 3 to 5;
[0165] n.sub.15 and n.sub.17 are, independently of each other, an
integer of from 0 to 4 provided that n.sub.15+n.sub.17 is an
integer of from 3 to 5;
[0166] n.sub.16 is an integer of from 0 to 3 provided that
n.sub.15+n.sub.16 is an integer of from 3 to 5;
[0167] n.sub.18, n.sub.19 and n.sub.20 are, independently of each
other, an integer of from 0 to 3 provided that
n.sub.18+n.sub.19+n.sub.20 is 2 or 3;
[0168] n.sub.21 is an integer of from 1 to 3;
[0169] W.sup.a and W.sup.c are, independently of each other: 9
[0170] where:
[0171] n.sub.22 is 0 or 1;
[0172] R.sup.53 and R.sup.54 are, independently of each other,
hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkyl, aralkyl, or
heterocyclylalkyl or a covalent bond attaching (a) to a linker;
[0173] R.sup.55 is alkyl, alkenyl or alkynyl; and
[0174] W.sup.b is --N(O)n.sub.23 or --N.sup.+--R.sup.56 where
n.sub.23 is 0 or 1, and R.sup.56 is alkyl, alkenyl, alkynyl, or
aralkyl, or a covalent bond attaching (a) to a linker;
[0175] provided that a carbon other than a bridge head carbon is
bonded to B".
[0176] Another preferred value for B is a ring represented by the
following general formulae: 10
[0177] wherein a carbon atom other than a bridge head carbon is
bound to B"; and W.sup.c is as defined above.
[0178] A more preferred value for B is pyrrolidine, piperidine, or
hexahydroazepine attaching (a) to a linker.
[0179] Another more preferred value for B is piperidine wherein the
nitrogen atom of said piperidine attaches (a) to a linker.
[0180] Another more preferred value for B is piperidin-4-yl wherein
the nitrogen at the 1 position optionally attaches (a) to a
linker.
[0181] Another more preferred value for B is quinuclidine,
1-azabicyclo[2.2.1]-heptyl, or 1-azabicyclo[3.2.1]octyl attaching
(a) to a linker, wherein a carbon other than a bridge head carbon
is bound to B".
[0182] A preferred value for D" is --(CH.sub.2)n.sub.43-- where
n.sub.43 is an integer of from 1-10, preferably 2-8, more
preferably 2-4. Another preferred value for n.sub.43 is an integer
of from 3-10.
[0183] A preferred value for D is --NR.sup.31R.sup.32 or
--N.sup.+(R.sup.33R.sup.34R.sup.35)M.sup.- where R.sup.31,
R.sup.33, and R.sup.34 are, independently of each other, hydrogen
or methyl, and R.sup.32 and R.sup.35 represent a covalent bond
attaching (b) to a linker. More preferably R.sup.31, R.sup.33, and
R.sup.34 methyl, and R.sup.32 and R.sup.35 represent a covalent
bond attaching (b) to a linker.
[0184] A preferred value for R.sup.27 is hydrogen.
[0185] A preferred value for R.sup.28 is hydrogen.
[0186] A preferred value for R.sup.29 and R.sup.30 independently is
hydrogen; or one of R.sup.27, R.sup.28, R.sup.29, or R.sup.30
together with the adjacent group forms a methylenedioxy or
ethylenedioxy group.
[0187] A preferred value for n.sub.11 is 1.
[0188] A preferred value for n.sub.12 is 6.
[0189] A preferred value for F is --O--.
[0190] A preferred value for F" is a covalent bond, --OR.sup.43,
--NR.sup.42R.sup.43 wherein R.sup.42 is hydrogen or alkyl, or
--N.sup.+(R.sup.43R.sup.44R.sup.45) wherein R.sup.44 and R.sup.45
are alkyl, and R.sup.43 is a covalent bond attaching (c) to a
linker.
[0191] A preferred value for F" is --O--, --NH--, N(CH.sub.3)-- or
--N(CH.sub.3).sub.2--
[0192] A more preferred value for F" is --NH--, N(CH.sub.3)-- or
--N(CH.sub.3).sub.2-- wherein the nitrogen atom attaches (c) to a
linker.
[0193] A preferred value for R.sup.36 is hydrogen.
[0194] Preferably R.sup.37 is ortho to the --(CHR.sup.38)-- group
and is hydrogen or alkoxy. More preferably R.sup.37 is ortho to the
--(CHR.sup.38)-- group and is methoxy.
[0195] Preferably is R.sup.38 is hydrogen.
[0196] Preferably R.sup.39 is hydrogen.
[0197] Preferably L.sub.2 is a group of formula (d) wherein:
R.sup.46 is alkyl or substituted alkyl; R.sup.47 is alkyl,
substituted alkyl, or heterocycle; or R.sup.46 and R.sup.47
together with the nitrogen atom to which they are attached form
heterocycle.
[0198] Preferably, L.sub.2 is a group of formula A1-A241 as shown
in the following table. L.sub.2 is preferably linked to X through a
non-aromatic nitrogen atom (e.g. a secondary amino nitrogen) of
L.sub.2.
1 No. L.sub.2 A1 11 A2 12 A3 13 A4 14 A5 15 A6 16 A7 17 A8 18 A9 19
A10 20 A11 21 A12 22 A13 23 A14 24 A15 25 A16 26 A17 27 A18 28 A19
29 A20 30 A21 31 A22 32 A23 33 A24 34 A25 35 A26 36 A27 37 A28 38
A29 39 A30 40 A31 41 A32 42 A33 43 A34 44 A35 45 A36 46 A37 47 A38
48 A39 49 A40 50 A41 51 A42 52 A43 53 A44 54 A45 55 A46 56 A47 57
A48 58 A49 59 A50 60 A51 61 A52 62 A53 63 A54 64 A55 65 A56 66 A57
67 A58 68 A59 69 A60 70 A61 71 A62 72 A63 73 A64 74 A65 75 A66 76
A67 77 A68 78 A69 79 A70 80 A71 81 A72 82 A73 83 A74 84 A75 85 A76
86 A77 87 A78 88 A79 89 A80 90 A81 91 A82 92 A83 93 A84 94 A85 95
A86 96 A87 97 A88 98 A89 99 A90 100 A91 101 A92 102 A93 103 A94 104
A95 105 A96 106 A97 107 A98 108 A99 109 A100 110 A101 111 A102 112
A103 113 A104 114 A105 115 A106 116 A107 117 A108 118 A109 119 A110
120 A111 121 A112 122 A113 123 A114 124 A115 125 A116 126 A117 127
A118 128 A119 129 A120 130 A121 131 A122 132 A123 133 A124 134 A125
135 A126 136 A127 137 A128 138 A129 139 A130 140 A131 141 A132 142
A133 143 A134 144 A135 145 A136 146 A137 147 A138 148 A139 149 A140
150 A141 151 A142 152 A143 153 A144 154 A145 155 A146 156 A147 157
A148 158 A149 159 A150 160 A151 161 A152 162 A153 163 A154 164 A155
165 A156 166 A157 167 A158 168 A159 169 A160 170 A161 171 A162 172
A163 173 A164 174 A165 175 A166 176 A167 177 A168 178 A169 179 A170
180 A171 181 A172 182 A173 183 A174 184 A175 185 A176 186 A177 187
A178 188 A179 189 A180 190 A181 191 A182 192 A183 193 A184 194 A185
195 A186 196 A187 197 A188 198 A189 199 A190 200 A191 201 A192 202
A193 203 A194 204 A195 205 A196 206 A197 207 A198 208 A199 209 A200
210 A201 211 A202 212 A203 213 A204 214 A205 215 A206 216 A207 217
A208 218 A209 219 A210 220 A211 221 A212 222 A213 223 A214 224 A215
225 A216 226 A217 227 A218 228 A219 229 A220 230 A221 231 A222 232
A223 233 A224 234 A225 235 A226 236 A227 237 A228 238 A229 239 A230
240 A231 241 A232 242 A233 243 A234 244 A235 245 A236 246 A237 247
A238 248 A239 249 A240 250 A241 251
[0199] Preferably, L.sub.2 can also be a group of formula A301-A439
as shown in the following table. L.sub.2 is preferably linked to X
through a non-aromatic nitrogen atom (e.g. a secondary amino
nitrogen) of L.sub.2.
2 A301 252 A302 253 A303 254 A304 255 A305 256 A306 257 A307 258
A308 259 A309 260 A310 261 A311 262 A312 263 A313 264 A314 265 A315
266 A316 267 A317 268 A318 269 A319 270 A320 271 A321 272 A322 273
A323 274 A324 275 A325 276 A326 277 A327 278 A328 279 A329 280 A330
281 A331 282 A332 283 A333 284 A334 285 A335 286 A336 287 A337 288
A338 289 A339 290 A340 291 A341 292 A342 293 A343 294 A344 295 A345
296 A346 297 A347 298 A348 299 A349 300 A350 301 A351 302 A352 303
A353 304 A354 305 A355 306 A356 307 A357 308 A358 309 A359 310 A360
311 A361 312 A362 313 A363 314 A364 315 A365 316 A366 317 A367 318
A368 319 A369 320 A370 321 A371 322 A372 323 A373 324 A374 325 A375
326 A376 327 A377 328 A378 329 A379 330 A380 331 A381 332 A382 333
A383 334 A384 335 A385 336 A386 337 A387 338 A388 339 A389 340 A390
341 A391 342 A393 343 A394 344 A395 345 A396 346 A397 347 A398 348
A399 349 A400 350 A401 351 A402 352 A403 353 A404 354 A405 355 A406
356 A407 357 A408 358 A409 359 A410 360 A411 361 A412 362 A413 363
A414 364 A415 365 A416 366 A417 367 A418 368 A419 369 A420 370 A421
371 A422 372 A423 373 A424 374 A425 375 A426 376 A427 377 A428 378
A429 379 A430 380 A431 381 A432 382 A433 383 A434 384 A435 385 A436
386 A437 387 A438 388 A439 389
[0200] Preferably, L.sub.2 can also be a group of formula A501-A523
as shown in the following table. L.sub.2 is preferably linked to X
through a non-aromatic nitrogen atom of L.sub.2.
3 No. L.sub.2 A501 390 A502 391 A503 392 A504 393 A505 394 A506 395
A507 396 A508 397 A509 398 A510 399 A511 400 A512 401 A513 402 A514
403 A515 404 A516 405 A517 406 A518 407 A519 408 A520 409 A521 410
A522 411 A523 412 A524 413 A525 414 A526 415 A527 416 A528 417 A529
418 A530 419 A531 420 A532 421 A533 422 A534 423 A535 424 A536 425
A537 426 A538 427 A539 428 A540 429 A541 430 A542 431 A543 432 A544
433 A545 434 A546 435 A547 436 A548 437 A549 438 A550 439 A551 440
A552 441 A553 442 A554 443 A555 444 A556 445 A557 446 A558 447 A559
448 A560 449 A561 450 A562 451 A563 452 A564 453 A565 454 A566 455
A567 456 A568 457 A569 458 A570 459 A571 460 A572 461 A573 462 A574
463 A575 464 A576 465 A577 466 A578 467 A579 468 A580 469 A581 470
A582 471 A583 472 A584 473 A585 474 A586 475 A587 476 A588 477 A589
478 A590 479
[0201] A more preferred value for L.sub.2 is A234, A363, A364,
A153, A28, A324, A329, A562, A87, or A239.
[0202] A preferred value for X is alkylene optionally substituted
with one, two, or three hydroxy groups, alkylene wherein one, two
or three carbon atoms have been replaced by an oxygen atom,
-alkylene-phenylene-alkylene- wherein the phenylene ring is
optionally substituted with one or two chloro or fluoro groups.
[0203] Another preferred value for X is an alkylene group having
from 3 to 20 carbon atoms; wherein one or more carbon atoms (e.g.
1, 2, 3, or 4) in the alkylene group is optionally replaced with
--O--; and wherein the chain is optionally substituted on carbon
with one or more hydroxyl (e.g. 1, 2, 3, or 4).
[0204] Another preferred value for X is an alkylene group having
from 6 to 15 carbons atoms; wherein one or more carbon atoms (e.g.
1, 2, 3, 4) in the alkylene group is optionally replaced with
--O--; and wherein the chain is optionally substituted on carbon
with one or more hydroxyl (e.g. 1, 2, 3, or 4).
[0205] Another preferred value for X is is nonane-1,9-diyl,
octane-1,8-diyl, propane-1,3-diyl, 2-hydroxypropane-1,3-diyl, or
5-oxa-nonane-1,9-diyl.
[0206] Another preferred value for X is a group of the following
formula: 480
[0207] wherein the phenyl ring is optionally substituted with 1, 2,
or 3 fluoro groups.
[0208] Another preferred value for X is a group of one of the
following formulae: 481
[0209] A preferred group of compounds of formula (I) are compounds
wherein R.sup.2 is selected from formula (i) and (iii); and wherein
K" is a bond or methylene.
[0210] A preferred group of compounds of formula (I) are compounds
wherein R.sup.2 is formula (i); R.sup.3 is hydrogen, methyl, ethyl,
propyl, isopropyl, fluoro, or trifluoromethyl; and K" is a bond or
methylene.
[0211] A preferred group of compounds of formula (I) are compounds
wherein R.sup.2 is formula (iii); R.sup.6, R.sup.7, and R.sup.8 are
each hydrogen, methyl, ethyl, propyl, isopropyl, fluoro, or
trifluoromethyl; and K" is a bond or methylene.
[0212] A preferred group of compounds are compounds of formula (I)
wherein R.sup.46 is alkyl, substituted alkyl, cycloalkyl,
substituted cycloalkyl, or heterocycle; R.sup.47 is alkyl,
substituted alkyl, aryl, acyl, heterocycle, or --COOR.sup.50 where
R.sup.50 is alkyl; or R.sup.46 and R.sup.47 together with the
nitrogen atom to which they are attached form heterocycle.
[0213] A preferred group of compounds are compounds of formula (I)
wherein L.sub.2 is a group of formula (d) wherein R.sup.46 and
R.sup.47 together with the nitrogen atom to which they are attached
form heterocycle which is substituted with 1 to 5 substituents
independently selected from the group consisting of alkoxy,
substituted alkoxy, cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy,
amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl,
azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl,
carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,
thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy,
heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,
hydroxyamino, alkoxyamino, nitro, --SO-alkyl, --SO-substituted
alkyl, --SO-aryl, --SO-heteroaryl, --SO.sub.2-alkyl,
--SO.sub.2-substituted alkyl, --SO.sub.2-aryl
--SO.sub.2-heteroaryl, alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, and substituted alkynyl.
[0214] A more preferred group of compounds are compounds of formula
(I) wherein L.sub.2 is a group of formula (d) wherein R.sup.46 and
R.sup.47 together with the nitrogen atom to which they are attached
form heterocycle which is substituted with 1 to 3 substituents
independently selected from the group consisting of alkoxy,
substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted
amino, aminoacyl, aminoacyloxy, oxyaminoacyl, cyano, halogen,
hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, hydroxyamino,
alkoxyamino, alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl, and substituted alkynyl.
[0215] A preferred group of compounds are compounds of formula (I)
wherein L.sub.2 is a group of formula (d) wherein R.sup.46 and
R.sup.47 together with the nitrogen atom to which they are attached
form heterocycle which is substituted with 1 to 5 substituents
independently selected from the group consisting of substituted
alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted
alkynyl.
[0216] A preferred group of compounds are compounds of formula (I)
wherein L is a group of formula (d) wherein at least one of
R.sup.46 and R.sup.47 individually, or R.sup.46 and R.sup.47 taken
together, is a group that comprises a basic nitrogen atom (e.g. a
nitrogen atom with a pKa of preferably at least about 5, more
preferably al least about 6, or most preferably at least about
7).
[0217] A preferred group of compounds are compounds of formula (I)
wherein L.sub.2 is a group of formula (d) wherein R.sup.46 is a
heterocycle, optionally substituted with 1 to 5 substituents
independently selected from the group consisting of alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and
substituted alkynyl; and R.sup.47 is alkyl, substituted alkyl,
acyl, or --COOR.sup.50.
[0218] A preferred group of compounds are compounds of formula (I)
wherein L.sub.2 is a group of formula (d) wherein R.sup.46 is alkyl
that is substituted by a group that comprises a basic nitrogen atom
(e.g. a nitrogen atom with a pKa of preferably at least about 5,
more preferably al least about 6, or most preferably at least about
7).
[0219] A preferred group of compounds are compounds of formula (I)
wherein L.sub.2 is a group of formula (d) wherein R.sup.46 is alkyl
that is optionally substituted with from 1 to 5 substituents
independently selected from the group consisting of alkoxy,
substituted alkoxy, cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy,
amino, aminoacyl, aminoacyloxy, oxyaminoacyl, cyano, halogen,
hydroxyl, keto, thioketo, carboxylalkyl, thioaryloxy,
thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy,
substituted thioalkoxy, heterocyclic, heterocyclooxy, hydroxyamino,
alkoxyamino, NR.sup.aR.sup.b, wherein R.sup.a and R.sup.b may be
the same or different and and are chosen from hydrogen, alkyl,
substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, and
heterocyclic.
[0220] A preferred group of compounds are compounds of formula (I)
wherein L.sub.2 is a group of formula (d) wherein R.sup.46 is a
heterocycle which is optionally substituted with 1 to 5
substituents independently selected from the group consisting of
alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy,
amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl,
azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl,
carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,
thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy,
heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,
hydroxyamino, alkoxyamino, nitro, --SO-alkyl, --SO-substituted
alkyl, --SO-aryl, --SO-heteroaryl, --SO.sub.2-alkyl,
--SO.sub.2-substituted alkyl, --SO.sub.2-aryl
--SO.sub.2-heteroaryl, alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, and substituted alkynyl.
[0221] A preferred group of compounds are compounds of formula (I)
wherein L.sub.2 is a group of formula (d) wherein R.sup.46 is
3-piperidinyl, 4-piperidinyl, or 3-pyrrolidinyl, which R.sup.46 is
optionally substituted with 1 to 3 substituents independently
selected from the group consisting of alkoxy, substituted alkoxy,
cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted
cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino,
aminoacyl, aminoacyloxy, oxyaminoacyl, cyano, halogen, hydroxyl,
keto, thioketo, carboxylalkyl, thioaryloxy, thioheteroaryloxy,
thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy,
heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and
substituted alkynyl.
[0222] A preferred group of compounds are compounds of formula (I)
wherein R.sup.46 and R.sup.47 together with the nitrogen atom to
which they are attached form a piperidine or pyrrolidine ring which
ring is optionally substituted with 1 to 3 substituents
independently selected from the group consisting of alkoxy,
substituted alkoxy, cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy,
amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl,
cyano, halogen, hydroxyl, keto, thioketo, carboxylalkyl,
thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol,
thioalkoxy, substituted thioalkoxy, heterocyclic, heterocyclooxy,
hydroxyamino, alkoxyamino, alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, and substituted alkynyl.
[0223] A preferred group of compounds are compounds of formula (I)
wherein R.sup.46 and R.sup.47 together with the nitrogen atom to
which they are attached form a heterocycle that is an aza-crown
ether (e.g. 1-aza-12-crown-4, 1-aza-15-crown-5, or
1-aza-18-crown-6).
[0224] A preferred group of compounds of formula (I) are compounds
wherein: A is an aryl or a heteroaryl ring; B" is --NRa-- wherein
Ra is hydrogen, alkyl, or substituted alkyl; R.sup.1 is hydrogen or
alkyl; R.sup.2 is selected from a group consisting of formula (i),
(ii), (iii), or "Het":
[0225] wherein: - - - is an optional double bond; n, is an integer
of from 1 to 4; n.sub.2 is an integer of from 1 to 3; V is --CH--,
--O--, --S(O)n.sub.3-- (where n.sub.3 is an integer of from 0 to
2), or --NR.sup.4-- (wherein R.sup.4 is hydrogen, alkyl,
substituted alkyl, aryl, or heteroaryl); "Het" is a heteroaryl ring
which optionally attaches the ligand to a linker; R.sup.3 is
hydrogen, alkyl, amino, substituted amino, --OR.sup.8 (where
R.sup.a is hydrogen, alkyl, or acyl), or a covalent bond attaching
the ligand to a linker; R.sup.5 is hydrogen, alkyl, amino,
substituted amino, --OR.sup.b (where R.sup.b is hydrogen or alkyl),
aryl, aralkyl, heteroaralkyl, or a covalent bond attaching the
ligand to a linker; R.sup.6, R.sup.7, and R.sup.8 are,
independently of each other, hydrogen, halo, hydroxy, alkoxy,
haloalkoxy, carboxy, alkoxycarbonyl, alkyl optionally substituted
with one, two or three substituents selected from halo, hydroxy,
carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino,
substituted amino, or a covalent bond attaching the ligand to a
linker; K is a bond or an alkylene group; K" is a bond, --C(O)--,
--S(O).sub.n4-- (where n.sub.4 is an integer of from 0 to 2), or an
alkylene group optionally substituted with a hydroxyl group; and B
is a heterocycloamino group which optionally attaches the ligand to
a linker; provided that at least one of the R.sup.5, R.sup.6,
R.sup.7, R.sup.8, "Het", or the heterocycloamino group attaches the
ligand to a linker.
[0226] A preferred compound of formula (I) is a compound of Formula
(Ia): 482
[0227] wherein A, R.sup.1, R.sup.2, K, K", B, X, R.sup.46 and
R.sup.47 are as defined herein.
[0228] For a compound of Formula (Ia) a preferred group of
compounds is that wherein A is phenyl or pyridine; and K and K" are
bond.
[0229] For a compound of Formula (Ia) another preferred group of
compounds is that wherein A is phenyl or pyridine; R.sup.2 is
phenyl; and K and K" are bond.
[0230] For a compound of Formula (Ia) another preferred group of
compounds is that wherein B has any of the preferred values
identified herein.
[0231] The invention also provides a compound of formula (IV):
483
[0232] wherein L.sub.2 is an organic group comprising at least one
(e.g. 1, 2, 3, or 4) primary, secondary, or tertiary amines.
Typically, the amine of L.sub.2 should be basic, having a pH of at
least about 5, and preferably at least about 6, more preferably at
least about 7. The nature of the group L.sub.2 is not critical
provided the compound has suitable properties (e.g. solubility,
stability, and toxicity) for its intended use (e.g. as a drug or as
a pharmacological tool). Typically the group L.sub.2 will have a
molecular weight below 500 and preferably below about 300.
Additionally, the group L.sub.2 preferably comprises 5 or fewer
hydrogen bond donors (e.g. OH, --NHR--, and --C(.dbd.O)NHR--) and
ten or fewer hydrogen bond acceptors (e.g. --O--, --NRR--, and
--S--). Preferably, the nitrogen of B shown in formula (IV) is
separated from an amine of the group L.sub.2 by about 15 angstroms
to about 75 angstroms (based on conventionally acceptable bond
lengths and angles). More preferably, the nitrogen of B is
separated from an amine of the group L.sub.2 by about 25 angstroms
to about 50 angstroms. Preferred compounds of formula (IV) also
have a log D between about -3 and about 5. Using the above
parameters, one skilled in the art can readily determine compounds
of formula (IV) possessing the desired properties for an intended
use.
[0233] General Synthetic Schemes
[0234] Compounds of this invention can be made by the methods
depicted in the reaction schemes shown below.
[0235] The starting materials and reagents used in preparing these
compounds are either available from commercial suppliers such as
Aldrich Chemical Co., (Milwaukee, Wis., U.S.A.), Bachem (Torrance,
Calif., U.S.A.), Emka-Chemie, or Sigma (St. Louis, Mo., U.S.A.) or
are prepared by methods known to those skilled in the art following
procedures set forth in references such as Fieser and Fieser's
Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons,
1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and
Supplementals (Elsevier Science Publishers, 1989), Organic
Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's
Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition), and
Larock's Comprehensive Organic Transformations (VCH Publishers
Inc., 1989).
[0236] The starting materials and the intermediates of the reaction
may be isolated and purified if desired using conventional
techniques, including but not limited to filtration, distillation,
crystallization, chromatography, and the like. Such materials may
be characterized using conventional means, including physical
constants and spectral data.
[0237] Furthermore, it will be appreciated that where typical or
preferred process conditions (i.e., reaction temperatures, times,
mole ratios of reactants, solvents, pressures, etc.) are given,
other process conditions can also be used unless otherwise stated.
Optimum reaction conditions may vary with the particular reactants
or solvent used, but such conditions can be determined by one
skilled in the art by routine optimization procedures.
[0238] Additionally, as will be apparent to those skilled in the
art, conventional protecting groups may be necessary to prevent
certain functional groups from undergoing undesired reactions. The
choice of a suitable protecting group for a particular functional
group as well as suitable conditions for protection and
deprotection are well known in the art. For example, numerous
protecting groups, and their introduction and removal, are
described in T. W. Greene and G. M. Wuts, Protecting Groups in
Organic Synthesis, Second Edition, Wiley, New York, 1991, and
references cited therein.
[0239] These schemes are merely illustrative of some methods by
which the compounds of this invention can be synthesized, and
various modifications to these schemes can be made and will be
suggested to one skilled in the art having referred to this
disclosure.
[0240] Preparation of a Compound of Formula (I)
[0241] In general, compounds of Formula (I) can be prepared as
illustrated and described in Schemes A. 484
[0242] A compound of Formula (I) is prepared by covalently
attaching one equivalent of a compound of formula 1 with a compound
of formula 2 where X is a linker as defined herein, FG.sup.1 is a
functional group, FG.sup.2 is a functional group that is
complimentary to FG.sup.1, PG is a protecting group, and FG.sup.2PG
is a protected functional group, to give an intermediate of formula
(II). Deprotection of the functional group on the linker, followed
by reaction of resulting compound 3 with one equivalent of compound
4, then provides a compound of Formula (I). The reaction conditions
used to link compounds 1 and 4 to compound 2 and 3 depend on the
nature of the functional groups on compounds 1, 2, 3 and 4 which in
turn depend on the type of linkage desired. Examples of the
functional groups and the reaction conditions that can be used to
generate a specific linkage is described below.
4TABLE I Representative Complementary Binding Chemistries First
Reactive Group Second Reactive Group Linkage carboxyl amine amide
sulfonyl halide amine sulfonamide hydroxyl alkyl/aryl halide ether
hydroxyl isocyanate urethane amine epoxide .beta.-hydroxyamine
amine alkyl/aryl halide alkylamine hydroxyl carboxyl ester
[0243] Reaction between a carboxylic acid of either the linker or
the ligand and a primary or secondary amine of the ligand or the
linker in the presence of suitable, well-known activating agents
such as dicyclohexylcarbodiimide, results in formation of an amide
bond covalently linking the ligand to the linker; reaction between
an amine group of either the linker or the ligand and a sulfonyl
halide of the ligand or the linker, in the presence of a base such
as triethylarnine, pyridine, and the like, results in formation of
a sulfonamide bond covalently linking the ligand to the linker; and
reaction between an alcohol or phenol group of either the linker or
the ligand and an alkyl or aryl halide of the ligand or the linker
in the presence of a base such as triethylamine, pyridine, and the
like, results in formation of an ether bond covalently linking the
ligand to the linker.
[0244] Suitable dihydroxyl and dihalo starting materials useful for
incorporating a group X into a compound of the invention are shown
in the following table. Preferably, an alcohol is reacted with a
ligand bearing a leaving group to provide an ether bond, while a
dihalo compound is preferably reacted with an amine of the ligand
to form a subatituted amine.
5 No. X X1 485 X2 486 X3 487 X4 488 X5 489 X6 490 X7 491 X8 492 X9
493 X10 494 X11 495 X12 496 X13 497 X14 498 X15 499 X16 500 X17 501
X18 502 X19 503 X20 504 X21 505 X22 506 X23 507 X24 508 X25 509 X26
510 X27 511 X28 512 X29 513 X30 514 X31 515 X32 516 X33 517 X34 518
X35 519 X36 520 X37 521 X38 522 X39 523 X40 524 X41 525 X42 526 X43
527 X44 528 X45 529 X46 530 X47 531 X48 532 X49 533 X50 534 X51 535
X52 536 X53 537 X54 538 X55 HOCH.sub.2(CF.sub.2).sub.8CH.sub.2OH
X56 539 X57 540 X58 541 X59 542 X60 543 X61 544 X62 545 X63 546 X64
547 X65 548 X66 549 X67 550 X68 551 X69
HOCH.sub.2(CH.sub.2).sub.4CH.sub.2OH X70 552 X71 553 X72 554 X73
555 X74 556 X75 557 X76 558 X77 559 X78 560 X79 561 X80 562 X81 563
X82 564 X83 565 X84 566 X85 567 X86 568 X87 569 X88 570 X89 571 X90
572 X91 573 X92 574 X93 575 X94 576 X95 577 X96 578 X97 579 X98 580
X99 581 X100 HOCH.sub.2(CF.sub.2).sub.3CH.sub.2OH
[0245] Typically, a compound selected for use as a ligand will have
at least one functional group, such as an amino, hydroxyl, thiol or
carboxyl group and the like, which allows the compound to be
readily coupled to the linker. Compounds having such functionality
are either known in the art or can be prepared by routine
modification of known compounds using conventional reagents and
procedures.
[0246] A compound of formula (a) wherein A is phenyl, pyridyl, and
the like can be prepared as described in EP 747 355 and as
described by Naito, R. et al., Chem. Pharm. Bull., 1998, 46(8),
1286.
[0247] Scheme B
L.sub.1--H+ R.sub.a--X--L.sub.2 .fwdarw. (I)
[0248] A compound of formula (I) wherein L.sub.1 comprises a
nitrogen that is bonded to X, can be prepared by alkylating a
corresponding compound of formula L.sub.1--H wherein --H is bound
to the nitrogen, with a corresponding compound of
R.sub.a--X--L.sub.2 wherein X and L.sub.2 have any of the values
defined herein and R.sub.a is a suitable leaving group. Suitable
leaving groups an conditions for the alkylation of an amine are
known in the art (for example, see Advanced Organic Chemistry,
Reaction Mechanisms and Structure, 4 ed., 1992, Jerry March, John
Wiley & Sons, New York. For example, R.sub.a can be halo (e.g.
chloro, bromo, or iodo), methylsulfonyl, 4-tolylsulfonyl, mesyl, or
trifluoromethylsulfonyl.
[0249] Accordingly, the invention provides a method for preparing a
compound of formula (I) wherein L.sub.1 comprises a nitrogen that
is bonded to X, comprising alkylating a corresponding compound of
formula L.sub.1--H with a compound of R.sub.a--X--L.sub.2 wherein X
and L.sub.2 have any of the values defined herein and R.sub.a is a
suitable leaving group.
[0250] The invention also provides a compound of formula L.sub.1--H
wherein L.sub.1 has any of the values defined herein. The following
compounds are preferred compounds of formula L.sub.1--H: 582
[0251] The invention also provides a compound of formula
R.sub.a--X--L.sub.2 wherein X, and L.sub.2 have any of the values
defined herein and R.sub.a is a suitable leaving group. The
compound of formula L.sub.1--H can also be alkylated by treatment
with an aldehyde of formula L.sub.2--V--CHO (wherein
--V--CH.sub.2-- is equivalent to --X--), under reductive alkylation
conditions. Reagents and conditions suitable for carrying out the
reductive alkylation of an amine are known in the art (for example,
see Advanced Organic Chemistry, Reaction Mechanisms and Structure,
4 ed., 1992, Jerry March, John Wiley & Sons, New York).
[0252] Accordingly, the invention provides a method for preparing a
compound of formula (I) wherein L.sub.1 comprises a nitrogen that
is bonded to X, comprising alkylating a corresponding compound of
formula L.sub.1--H with a compound of formula L.sub.2--V--CHO
(wherein --V--CH.sub.2-- has any of the values for --X-- described
herein).
[0253] Scheme C
L.sub.1--X--R.sub.a+H--L.sub.2 .fwdarw. (I)
[0254] A compound of formula (I) wherein L.sub.2 comprises a
nitrogen that is bonded to X, can be prepared by alkylating a
corresponding compound of formula L.sub.2--H wherein --H is bound
to the nitrogen, with a corresponding compound of
L.sub.1--X--R.sub.a wherein X and L.sub.1 have any of the values
defined herein and R.sub.a is a suitable leaving group. Suitable
leaving groups an conditions for the alkylation of an amine are
known in the art (for example, see Advanced Organic Chemistry,
Reaction Mechanisms and Structure, 4 ed., 1992, Jerry March, John
Wiley & Sons, New York. For example, R.sub.a can be halo (e.g.
chloro, bromo, or iodo), methylsulfonyl, 4-tolylsulfonyl, mesyl, or
trifluoromethylsulfonyl.
[0255] Accordingly, the invention provides a method for preparing a
compound of formula (I) wherein L.sub.2 comprises a nitrogen that
is bonded to X, comprising alkylating a corresponding compound of
formula L.sub.2--H with a compound of L.sub.1--X--R.sub.a wherein X
and L.sub.1 have any of the values defined herein and R.sub.a is a
suitable leaving group.
[0256] The compound of formula L.sub.2--H can also be alkylated by
treatment with an aldehyde of formula L.sub.1--V--CHO (wherein
--V--CH.sub.2-- is equivalent to --X--), under reductive alkylation
conditions. Reagents and conditions suitable for carrying out the
reductive alkylation of an amine are known in the art (for example,
see Advanced Organic Chemistry, Reaction Mechanisms and Structure,
4 ed., 1992, Jerry March, John Wiley & Sons, New York).
[0257] Accordingly, the invention provides a method for preparing a
compound of formula (I) wherein L.sub.2 comprises a nitrogen that
is bonded to X, comprising alkylating a corresponding compound of
formula L.sub.2--H with a compound of formula L.sub.1--V--CHO
(wherein --V--CH.sub.2-- has any of the values for --X-- described
herein).
[0258] It will be understood that the alkylation reactions in
Schemes B and C can optionally be carried out using suitably
protected derivatives of L.sub.1--H, L.sub.2--H,
L.sub.1--X--R.sub.a, R.sub.a--X--L.sub.2, L.sub.1V--CHO, and
L.sub.2--V--CHO. Suitable protecting groups as well as conditions
for their incorporation and removal are known in the art (for
example, see Greene, T. W.; Wutz, P. G. M. "Protecting Groups In
Organic Synthesis" second edition, 1991, New York, John Wiley &
sons, Inc.). Thus, a compound of formula (I) can also be prepared
by deprotecting a corresponding compound of formula (I) bearing one
or more protecting groups.
[0259] Accordingly, the invention provides a method for preparing a
compound of formula (I) comprising deprotecting a corresponding
compound of formula (I) that bears one or more protecting groups.
The invention also provides an intermediate compound of formula (I)
that bears one or more protecting groups.
[0260] Combinatorial Synthesis
[0261] Compounds of formula (I) can conveniently be prepared using
combinatorial synthesis methods (e.g. solid phase and solution
phase combinatorial synthesis methods) that are known in the art.
For example, compounds of formula (I) can be prepared using
combinatorial methods like those escribed in International Patent
Application Publication Number WO 99/64043.
[0262] Utility, Testing, and Administration
[0263] Utility
[0264] The compounds of this invention are muscarinic receptor
antagonists or agonists. A preferred sub-groug of compounds of the
invention are M.sub.2 muscarinic receptor antagonists. Accordingly,
the compounds and pharmaceutical compositions of this invention are
useful in the treatment and prevention of diseases mediated by
these receptors such as chronic obstructive pulmonary disease,
asthma, irritable bowel syndrome, urinary incontinence, rhinitis,
spasmodic colitis, chronic cystitis, and Alzheimer's disease,
senile dementia, glaucoma, schizophrenia, gastroesophogeal reflux
disease, cardiac arrhythmia, hyper salvation syndromes, and the
like.
[0265] Testing
[0266] The ability of the compounds of formula (I) to inhibit a
muscarinic receptor (e.g. the M.sub.2 or M.sub.3 subtype) may be
demonstrated using a variety of in vitro assays and in vivo assays
known in the field, or may be demonstrated using an assay described
in biological examples 1-6 below.
[0267] Pharmaceutical Formulations
[0268] When employed as pharmaceuticals, the compounds of this
invention are usually administered in the form of pharmaceutical
compositions. These compounds can be administered by a variety of
routes including oral, rectal, transdermal, subcutaneous,
intravenous, intramuscular, intravesicular, and intranasal. These
compounds are effective as both injectable and oral compositions.
Such compositions are prepared in a manner well known in the
pharmaceutical art and comprise at least one active compound.
[0269] This invention also includes pharmaceutical compositions
which contain, as the active ingredient, one or more of the
compounds described herein associated with pharmaceutically
acceptable carriers. In making the compositions of this invention,
the active ingredient is usually mixed with an excipient, diluted
by an excipient or enclosed within such a carrier which can be in
the form of a capsule, sachet, paper or other container. When the
excipient serves as a diluent, it can be a solid, semi-solid, or
liquid material, which acts as a vehicle, carrier or medium for the
active ingredient. Thus, the compositions can be in the form of
tablets, pills, powders, lozenges, sachets, cachets, elixirs,
suspensions, emulsions, solutions, syrups, aerosols (as a solid or
in a liquid medium), ointments containing, for example, up to 10%
by weight of the active compound, soft and hard gelatin capsules,
suppositories, sterile injectable solutions, and sterile packaged
powders.
[0270] In preparing a formulation, it may be necessary to mill the
active compound to provide the appropriate particle size prior to
combining with the other ingredients. If the active compound is
substantially insoluble, it ordinarily is milled to a particle size
of less than 200 mesh. If the active compound is substantially
water soluble, the particle size is normally adjusted by milling to
provide a substantially uniform distribution in the formulation,
e.g. about 40 mesh.
[0271] Some examples of suitable excipients include lactose,
dextrose, sucrose, sorbitol, mannitol, starches, gum acacia,
calcium phosphate, alginates, tragacanth, gelatin, calcium
silicate, microcrystalline cellulose, polyvinylpyrrolidone,
cellulose, sterile water, syrup, and methyl cellulose. The
formulations can additionally include: lubricating agents such as
talc, magnesium stearate, and mineral oil; wetting agents;
emulsifying and suspending agents; preserving agents such as
methyl- and propylhydroxy-benzoates; sweetening agents; and
flavoring agents. The compositions of the invention can be
formulated so as to provide quick, sustained or delayed release of
the active ingredient after administration to the patient by
employing procedures known in the art.
[0272] The compositions are preferably formulated in a unit dosage
form, each dosage containing from about 0.001 to about 1 g, usually
about 0.1 to about 500 mg, more usually about 1 to about 50 mg, of
the active ingredient. The term "unit dosage forms" refers to
physically discrete units suitable as unitary dosages for human
subjects and other mammals, each unit containing a predetermined
quantity of active material calculated to produce the desired
therapeutic effect, in association with a suitable pharmaceutical
excipient. Preferably, the compound of Formula (I) above is
employed at no more than about 20 weight percent of the
pharmaceutical composition, more preferably no more than about 15
weight percent, with the balance being pharmaceutically inert
carrier(s).
[0273] The active compound is effective over a wide dosage range
and is generally administered in a pharmaceutically effective
amount. It, will be understood, however, that the amount of the
compound actually administered will be determined by a physician,
in the light of the relevant circumstances, including the condition
to be treated, the chosen route of administration, the actual
compound administered and its relative activity, the age, weight,
and response of the individual patient, the severity of the
patient's symptoms, and the like.
[0274] For preparing solid compositions such as tablets, the
principal active ingredient is mixed with a pharmaceutical
excipient to form a solid preformulation composition containing a
homogeneous mixture of a compound of the present invention. When
referring to these preformulation compositions as homogeneous, it
is meant that the active ingredient is dispersed evenly throughout
the composition so that the composition may be readily subdivided
into equally effective unit dosage forms such as tablets, pills and
capsules. This solid preformulation is then subdivided into unit
dosage forms of the type described above containing from, for
example, 0.1 to about 500 mg of the active ingredient of the
present invention.
[0275] The tablets or pills of the present invention may be coated
or otherwise compounded to provide a dosage form affording the
advantage of prolonged action. For example, the tablet or pill can
comprise an inner dosage and an outer dosage component, the latter
being in the form of an envelope over the former. The two
components can be separated by an enteric layer which serves to
resist disintegration in the stomach and permit the inner component
to pass intact into the duodenum or to be delayed in release. A
variety of materials can be used for such enteric layers or
coatings, such materials including a number of polymeric acids and
mixtures of polymeric acids with such materials as shellac, cetyl
alcohol, and cellulose acetate.
[0276] The liquid forms in which the novel compositions of the
present invention may be incorporated for administration orally or
by injection include aqueous solutions, suitably flavored syrups,
aqueous or oil suspensions, and flavored emulsions with edible oils
such as corn oil, cottonseed oil, sesame oil, coconut oil, or
peanut oil, as well as elixirs and similar pharmaceutical
vehicles.
[0277] Compositions for inhalation or insulation include solutions
and suspensions in pharmaceutically acceptable, aqueous or organic
solvents, or mixtures thereof, and powders. The liquid or solid
compositions may contain suitable pharmaceutically acceptable
excipients as described supra. Preferably the compositions are
administered by the oral or nasal respiratory route for local or
systemic effect. Compositions in preferably pharmaceutically
acceptable solvents may be nebulized by use of inert gases.
Nebulized solutions may be inhaled directly from the nebulizing
device or the nebulizing device may be attached to a face mask
tent, or intermittent positive pressure breathing machine.
Solution, suspension, or powder compositions may be administered,
preferably orally or nasally, from devices which deliver the
formulation in an appropriate manner.
EXAMPLES
[0278] The following preparations and examples are given to enable
those skilled in the art to more clearly understand and to practice
the present invention. They should not be considered as limiting
the scope of the invention, but merely as being illustrative and
representative thereof.
[0279] In the examples below, the following abbreviations have the
following meanings. Unless otherwise stated, all temperatures are
in degrees Celsius. If an abbreviation is not defined, it has its
generally accepted meaning.
[0280] g=gram
[0281] mg=milligram
[0282] min=minute
[0283] ml=milliliter
[0284] mmol=millimol
Synthetic Examples
Example 1
[0285] The intermediate compound of formula 1B was prepared as
follows. 583
[0286] Biphenyl-2-isocynate (50 g, 256 mmol) was dissolved in 400
mL anhydrous acetonitrile in a 2L rbf at room temperature. After
cooling to 0 C. using an ice bath, a solution of
4-amino-N-benzylpiperidine (48.8 g, 256 mmol) dissolved in 400 mL
anhydrous acetonitrile was added over 5 minutes. Precipitate was
observed immediately. After 15 minutes, an additional 600 mL
anhydrous acetonitrile was added to permit stirring of the viscous
solution for 12 h at 35 C. The solids were filtered, and washed
with cold acetonitrile then dried under vacuum, yielding a
colorless solid (100 g, 98%). This material was characterized by
.sup.1H-NMR, .sup.13C-NMR and MS.
[0287] Compound 1A (20 g, 52 mmol) was dissolved in 800 mL of a 3:1
mixture of anhydrous methanol to anhydrous DMF. Aqueous HCl was
added (0.75 mL of 37% conc solution, 7.6 mmol) and nitrogen gas
bubbled through the solution vigorously for 20 min. Pd(OH)2
(Pearlman's catalyst, 5 g) was added under a stream of nitrogen. A
large balloon containing H2 gas was placed and the solution allowed
to stir for 4 d. The solution was passed twice through pads of
celite to remove the catalyst, and the solution evaporated to
dryness under vacuum to yield a colorless solid (13 g, 85%). This
material was characterized by .sup.1H-NMR, .sup.13C-NMR and MS.
[0288] Following the procedures described above but substituting
the appropriate starting materials, the compounds of the invention
(formula (VI)) listed in Table A below were prepared. Unless
otherwise noted, for the compounds in Tables A-F, L.sub.2 is
attached to X through the secondary non-aromatic amine of
L.sub.2.
6TABLE A (VI) 584 Compound L2 Mass Spec Found 1 A224 411.6 2 A87
488.6 3 A172 517.7 4 A90 514.7 5 A141 607.8 6 A169 517.7 7 A164
517.78 8 A208 451.6 9 A199 467.6 10 A23 534.6 11 A70 542.7 12 A73
542.7 13 A156 605.8 14 A95 511.7 15 A115 467.6 16 A156 605.8 17
A516 487.7 18 A364 511.7 19 A96 485.6 20 A508 537.7 21 A509 537.7
22 A190 505.7 23 (135) 616.8 24 A51 532.7 25 A524 496.7 26 A410
542.7 27 A368 516.7 28 A84 515.7 29 A65 516.7 30 A193 548.8 31 A142
604.8 32 A177 556.8 33 A68 515.7 34 A501 529.7 35 A525 574.7 36
A168 554.7 37 A437 604.8 38 A61 536.7 39 A117 480.6 40 A166 542.7
41 78 520.7 42 A49 583.7 43 A367 514.7 44 A526 572.7 45 A229 547.7
46 A239 427.6 47 A179 483.7 48 A182 437.6 49 A55 467.6 50 A510
514.7 51 A502 502.7 52 A43 551.7 53 A218 518.7 54 A123 494.6 55
A126 538.7 56 A134 534.6 57 A120 480.6 58 A157 517.7 59 A396 533.7
60 A25 569.7 61 A83 559.7 62 A161 469.6 63 A11* 571.1 64 A420 554.7
65 A135 541.7 66 A411 543.7 67 A88 531.7 68 A386 527.7 69 A404
538.7 70 A72 529.7 71 A26 569.8 72 A75 513.7 73 A419 553.7 74 A375
517.7 75 A20 527.7 76 A427 571.7 77 A527 619.8 78 A9 485.6 79 A520
467.6 80 A19 453.6 81 A513 551.7 82 A10 517.7 83 A110 466.6 84 A4
494.6 85 A19 453.6 86 A103 530.7 87 A60 536.7 88 A131 600.7 89 A114
440.6 90 A197 468.6 91 A151 451.6 92 A195 463.6 93 A528 495.7 94
A347 487.7 95 A328 467.6 96 A22 526.7 97 A336 480.6 98 A77 585.8 99
A145 452.6 100 A211 550.7
[0289] Following the procedures described above but substituting
appropriate starting materials, the compounds of the invention
(formula (VII)) listed in Table B below were prepared.
7TABLE B (VII) 585 Compound L2 Mass Spec Found 101 A224 395.6 102
A87 472.6 103 A529 381.5 104 A530 533.1 105 A172 501.7 106 A141
591.8 107 A164 501.7 108 A199 451.6 109 A70 526.7 110 A73 526.7 111
A156 589.8 112 A230 521.7 113 A391 515.7 114 A95 495.7 115 A156
589.8 116 A516 471.7 117 A97 495.7 118 A96 469.6 119 A508 521.7 120
A509 521.7 121 A190 489.7 122 A435 600.8 123 A410 526.7 124 A84
499.7 125 A193 532.8 126 A142 588.8 127 A177 540.8 128 A68 499.7
129 A433 588.8 130 A166 526.7 131 A31 498.7 132 A526 556.7 133 A436
616.1 134 A50 602.1 135 A132 505.7 136 A231 526.5 137 A229 531.7
138 A401 522.1 139 A373 501.7 140 A90 498.7 141 A502 486.7 142 A43
535.7 143 A43@ 536.7 144 A576 522.7 145 A374 501.7 146 A17 511.7
147 A21 517.7 148 A83 543.7 149 A531 538.7 150 A125 525.7 151 A210
527.7 152 A88 515.7 153 A78 511.7 154 A404 522.7 155 A72 513.7 156
A26 553.8 157 A75 497.7 158 A419 537.7 159 A527 603.8 160 A520
451.6 161 A513 535.7 162 A164 501.7 163 A4 478.7 164 A521 515.7 165
A60 520.7 166 A522 584.7 167 A192 551.7 168 A122 533.7 169 A109
499.7 170 A383 507.7 171 A395 516.7 172 A503 594.8 173 A528 479.7
174 A99 471.7 175 A22 510.7 176 A532 569.8
[0290] Following the procedures described above but substituting
appropriate starting materials, the compounds of the invention
(formula (VIII)) listed in Table C below were prepared.
8TABLE C (VIII) 586 Compound L2 Mass Spec Found 177 A508 607.8 178
A509 607.8 179 A501 599.8 180 A90 584.8 181 A502 572.8 182 A43
621.8 183 A513 621.8 184 A503 681.0 185 A87 558.8 186 A164 587.8
187 A90 584.8 188 A90.sup.@ 585.8 189 A10 587.8 190 A172 587.8 191
A208 521.7 192 A330 537.8 193 A70 612.9 194 A73 612.9 195 A8 601.8
196 A95 581.8 197 A115 537.8 198 A516 557.8 199 A97 581.8 200 A96
555.8 201 A358 575.9 202 A517 687.0 203 A62 612.9 204 A74 586.8 205
A84 585.8 206 A65 586.8 207 A193 618.9 208 A142 674.9 209 A177
626.9 210 A501 585.8 211 A217 644.8 212 A168 624.9 213 A166 612.9
214 A31 584.8 215 A28 642.9 216 A104 702.3 217 A144 608.2 218 A373
587.8 219 A90.sup.@ 585.8 220 A43.sup.@ 622.8 221 A576 608.8 222
A374 587.8 223 A17 597.9 224 A396 603.8 225 A214 625.9 226 A83
629.8 227 A418 622.9 228 A135 611.6 229 A210 613.9 230 A88 601.8
231 A404 608.8 232 A121 624.8 233 A520 537.8 234 A164 587.8 235 A4
564.8 236 A521 601.8 237 A60 606.9 238 A522 670.9 239 A109 585.8
240 A22 596.8 241 A532 655.9 242 A397 604.7 243 A120 550.8 244 A533
509.7 245 A505* 626.9 246 A506 598.8 247 A431 659.9 248 A388 597.9
249 A366 583.8 250 A534 578.8 251 A417 622.9 252 A577 575.8 253
A319 536.7 254 A381 593.8 255 A338 550.8 256 A329 537.8 257 A403
608.8 258 A333 549.8
[0291] Following the procedures described above but substituting
appropriate starting materials, the compounds of the invention
(formula (IX)) listed in Table D below were prepared.
9TABLE D (IX) 587 Compound L2 Mass Spec Found 259 A508 591.8 260
A509 591.8 261 A501 583.8 262 A510 568.8 263 A502 556.8 264 A43
605.8 265 A512 581.8 266 A513 605.8 267 A503 665.0 268 A223 542.8
269 A224 465.7 272 A535 661.9 273 A536 571.8 274 A537 571.8 275
A306 505.7 276 A580 521.8 277 A578 588.7 278 A538 596.9 279 A539
596.9 280 A321 520.8 281 A156 659.9 282 A400 591.9 283 A8 585.8 284
A363 565.8 285 A359 560.8 286 A324 521.8 287 A156 659.9 288 A516
541.8 289 A364 565.8 290 A346 539.8 291 A581 559.9 292 A517 671.0
293 A394 586.8 294 A410 596.9 295 A368 570.8 296 A84 569.8 297 A369
570.8 298 A193 602.9 299 A432 658.9 300 A423 610.9 301 A68 569.8
302 A525 628.8 303 A168 608.9 304 A45 658.9 305 A398 590.8 306 A117
534.8 307 A166 596.9 308 A378 574.9 309 A198 523.8 310 A137 534.8
311 A316 520.7 312 A339 534.8 313 A322 520.8 314 A352 548.8 315
A430 637.9 316 A384 568.8 317 A28 626.9 318 A436 686.3 319 A50
672.2 320 A132 575.8 321 A205 550.8 322 A154 566.8 323 A413 601.8
324 A144 592.2 325 A301 481.7 326 A344 537.8 327 A182 491.7 328
A373 571.18 329 A340 535.8 330 A325 521.8 331 A94 567.8 332 A218
572.8 333 A348 548.8 334 A519 588.9 335 A126 592.8 336 A397 588.7
337 A155 571.18 338 A308 507.7 339 A387 581.9 340 A311 521.8 341
A21 587.8 342 A426 623.9 343 A422 609.9 344 A424 613.8 345 A418
606.9 346 A161 523.7 347 A11 625.9 348 A420 608.8 349 A406 595.8
350 A210 597.9 351 A374 585.8 352 A386 581.9 353 A540 592.8 354 A72
583.8 355 A26 623.9 356 A365 567.8 357 A419 607.9 358 A341 535.8
359 A412 599.8 360 A121 608.8 361 A375 571.8 362 A385 581.8 363
A427 625.9 364 A527 674.0 365 A345 539.8 366 A327 521.8 367 A583
507.7 368 A227 673.0 369 A312 511.7 370 A4115 603.8 371 A376 571.8
372 A98 592.8 373 A317 520.7 374 A4 548.8 375 A165 535.7 376 A380
577.8 377 A541 585.8 378 A584 589.8 379 A311 507.7 380 A521 585.8
381 A390 584.9 382 A399 590.9 383 A131 654.9 384 A27 495.7 385 A204
548.8 386 A122 603.9 387 A350 548.8 388 A425 617.9 389 A109 569.8
390 A542 664.0 391 A114 494.7 392 A331 522.7 393 A235 577.8 394
A543 586.8 395 A151 505.8 396 A313 517.7 397 A528 549.9 398 A99
541.8 399 A328 521.8 400 A384 580.8 401 A314 519.8 402 A335 534.8
403 A360 562.2 404 A77 639.9 405 A145 506.7 406 A71 563.8 407 A124
523.7 408 A377 573.8 409 A416 604.8 410 A329 521.8 411 A43 606.8
412 A307 505.8 413 A397 588.7 414 A337# 534.8 415 A303 493.7 416
A544 610.9 417 A506 582.8 418 A431 643.9 419 A388 581.9 420 A366
567.8 421 A523 562.8 422 A545 606.9 423 A577 559.8 424 A319 520.7
425 A381 577.8 426 A351 548.8 427 A338 534.8 428 A362 563.8 429
A507 477.7 430 A402 592.8 431 A403 592.8 432 A315 519.8 433 A333
533.8
[0292] Following the procedures described above but substituting
appropriate starting materials, the compounds of the invention
(formula (X)) listed in Table E below were prepared.
10TABLE E (X) 588 Compound L2 Mass Spec Found 434 A130 525.7 435
A105 521.8 436 A356 571.8 437 A415 617.8 438 A579 585.8 439 A98
606.8 440 A317 534.8 441 A349 562.8 442 A465 549.8 443 A380 591.8
444 A546 599.8 445 A547 548.8 446 A548 587.8 447 A386 676.9 448
A311 521.8 449 A521 599.9 450 A127 490.7 451 A390 598.9 452 A399
604.9 453 A342 550.8 454 A27 509.7 455 A549 562.9 456 A550 635.9
457 A238 617.9 458 A350 562.8 459 A425 631.9 460 A109 583.9 461
A114 508.7 462 A331 536.8 463 A551 585.8 464 A235 591.9 465 A395
600.8 466 A13 615.8 467 A552 507.8 468 A151 519.8 469 A313 531.8
470 A35 507.8 471 A99 555.8 472 A328 535.8 473 A22 594.9 474 A314
533.8 475 A336 548.8 476 A228 684.0 477 A360 576.2 478 A145 520.7
479 A302 505.8 480 A71 577.8 481 A553 656.9 482 A124 537.8 483 A554
587.8 484 A416 618.9 485 A555 625.9 486 A556 701.0 487 A557 716.0
488 A558 638.9 489 A559 624.8 490 A560 654.0 491 A561 654.0 492
A508 605.8 493 A509 605.8 494 A501 597.9 495 A510 582.8 496 A502
570.8 497 A43 619.9 498 A512 595.8 499 A513 619.9 500 A503 679.0
501 A504 556.8 502 A514 613.9 503 A402 606.9 504 A403 606.9 505
A397 602.8 506 A337 548.8 507 A303 507.7 508 A505 624.9 509 A506
596.9 510 A431 658.0 511 A388 595.9 512 A366 581.9 513 A523 576.8
514 A417 620.9 515 A577 573.8 516 A319 534.8 517 A381 591.8 518
A351 562.8 519 A338 548.8 520 A362 577.8 521 A507 491.7 522 A324
535.8 523 A315 533.8 524 A333 547.8 525 A427 718.8 526 A402 685.8
527 A562 506.7 528 A563 506.7 529 A564 520.8 530 A565 731.0 531
A370 585.8 532 A371 585.8 533 A372 585.8 534 A587 519.7 535 A330
535.8 536 A320 534.8 537 A578 602.8 538 A588 548.8 539 A538 610.9
540 A539 610.9 541 A321 534.8 542 A156 674.0 543 A141 675.9 544
A569 687.0 545 A400 605.9 546 A391 599.9 547 A363 579.8 548 A359
574.9 549 A311 535.8 550 A570 602.9 551 A515 674.0 552 A178 680.0
553 A364 579.8 554 A346 553.8 555 A358 573.9 556 A517 685.0 557
A571 634.0 558 A51 600.8 559 A64 564.8 560 A67 619.9 561 A62 610.9
562 A180 617.9 563 A74 584.8 564 A84 583.8 565 A65 584.8 566 A193
616.9 567 A432 672.9 568 A200 591.9 569 A177 624.9 570 A572 632.0
571 A174 603.9 572 A68 583.8 573 A525 642.9 574 A168 622.9 575 A45
673.0 576 A61 604.8 577 A117 548.8 578 A166 610.9 579 A378 588.9
580 A137 548.8 581 A34 534.8 582 A93 548.8 583 A59 562.9 584 A585
651.9 585 A31 582.8 586 A28 640.9 587 A436 700.3 588 A50 686.3 589
A3 675.0 590 A379 589.8 591 A573 610.7 592 A355 564.8 593 A413
615.9 594 A401 606.3 595 A301 495.7 596 A179 551.8 597 A82 551.8
598 A12 585.8 599 A55 535.8 600 A133 607.9 601 A94 581.8 602 A100
570.8 603 A123 562.8 604 A589 606.9 605 A134 602.8 606 A203 548.8
607 A17 595.9 608 A66 535.8 609 A214 623.9 610 A574 627.9 611 A154
585.8 612 A6 636.9 613 A185 521.8 614 A2 525.7 615 A119 569.8 616
A21 601.8 617 A25 637.9 618 A33 620.9 619 A161 537.8 620 A11* 639.9
621 A420 622.9 622 A135 609.9 623 A210 611.9 624 A88 599.9 625 A72
597.9 626 A69 521.8 627 A26 637.9 628 A365 581.9 629 A171 621.9 630
A81 549.8 631 A412 613.9 632 A121 622.9 633 A18 663.9 634 A232
585.8 635 A575 670.0 636 A20 595.8 637 A153 639.9 638 A590 688.0
639 A91 477.7 640 A9 553.8 641 A194 535.8 642 A310 521.8 643 A227
687.0
[0293] Following the procedures described above but substituting
appropriate starting materials, the compounds of the invention
(formula (XI)) listed in Table F below were prepared.
11TABLE F (XI) 589 Compound L2 Mass Spec Found 270 A224 609.6 271
A87 686.7
[0294] In the above tables *signifies that L.sub.2 is attached to X
through the piperidine nitrogen of L.sub.2; .sup.@ signifies that
L.sub.2 is attached to X through the pyridine nitrogen of L.sub.2;
and #signifies that L.sub.2 is attached to X through the
pyrrolidine nitrogen of L.sub.2.
Formulation Examples
Example 1
[0295] Hard gelatin capsules containing the following ingredients
are prepared:
12 Quantity Ingredient (mg/capsule) Active Ingredient 30.0 Starch
305.0 Magnesium stearate 5.0
[0296] The above ingredients are mixed and filled into hard gelatin
capsules in 340 mg quantities.
Example 2
[0297] A tablet Formula is prepared using the ingredients
below:
13 Quantity Ingredient (mg/tablet) Active Ingredient 25.0
Cellulose, microcrystalline 200.0 Colloidal silicon dioxide 10.0
Stearic acid 5.0
[0298] The components are blended and compressed to form tablets,
each weighing 240 mg.
Example 3
[0299] A dry powder inhaler formulation is prepared containing the
following components:
14 Ingredient Weight % Active Ingredient 5 Lactose 95
[0300] The active ingredient is mixed with the lactose and the
mixture is added to a dry powder inhaling appliance.
Example 4
[0301] Tablets, each containing 30 mg of active ingredient, are
prepared as follows:
15 Quantity Ingredient (mg/tablet) Active Ingredient 30.0 mg Starch
45.0 mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone 4.0
mg (as 10% solution in sterile water) Sodium carboxymethyl starch
4.5 mg Magnesium stearate 0.5 mg Talc 1.0 mg Total 120 mg
[0302] The active ingredient, starch and cellulose are passed
through a No. 20 mesh U.S. sieve and mixed thoroughly. The solution
of polyvinylpyrrolidone is mixed with the resultant powders, which
are then passed through a 16 mesh U.S. sieve. The granules so
produced are dried at 50.degree. to 60.degree. C. and passed
through a 16 mesh U.S. sieve. The sodium carboxymethyl starch,
magnesium stearate, and talc, previously passed through a No. 30
mesh U.S. sieve, are then added to the granules which, after
mixing, are compressed on a tablet machine to yield tablets each
weighing 120 mg.
Example 5
[0303] Capsules, each containing 40 mg of medicament are made as
follows:
16 Quantity Ingredient (mg/capsule) Active Ingredient 40.0 mg
Starch 109.0 mg Magnesium stearate 1.0 mg Total 150.0 mg
[0304] The active ingredient, starch, and magnesium stearate are
blended, passed through a No. 20 mesh U.S. sieve, and filled into
hard gelatin capsules in 150 mg quantities.
Example 6
[0305] Suppositories, each containing 25 mg of active ingredient
are made as follows:
17 Ingredient Amount Active Ingredient 25 mg Saturated fatty acid
glycerides to 2,000 mg
[0306] The active ingredient is passed through a No. 60 mesh U.S.
sieve and suspended in the saturated fatty acid glycerides
previously melted using the minimum heat necessary. The mixture is
then poured into a suppository mold of nominal 2.0 g capacity and
allowed to cool.
Example 7
[0307] Suspensions, each containing 50 mg of medicament per 5.0 mL
dose are made as follows:
18 Ingredient Amount Active Ingredient 50.0 mg Xanthan gum 4.0 mg
Sodium carboxymethyl cellulose (11%) Microcrystalline cellulose
(89%) 50.0 mg Sucrose 1.75 g Sodium benzoate 10.0 mg Flavor and
Color q.v. Purified water to 5.0 mL
[0308] The active ingredient, sucrose and xanthan gum are blended,
passed through a No. 10 mesh U.S. sieve, and then mixed with a
previously made solution of the microcrystalline cellulose and
sodium carboxymethyl cellulose in water. The sodium benzoate,
flavor, and color are diluted with some of the water and added with
stirring. Sufficient water is then added to produce the required
volume.
Example 8
[0309] A formulation may be prepared as follows:
19 Quantity Ingredient (mg/capsule) Active Ingredient 15.0 mg
Starch 407.0 mg Magnesium stearate 3.0 mg Total 425.0 mg
[0310] The active ingredient, starch, and magnesium stearate are
blended, passed through a No. 20 mesh U.S. sieve, and filled into
hard gelatin capsules in 425.0 mg quantities.
Example 9
[0311] A formulation may be prepared as follows:
20 Ingredient Quantity Active Ingredient 5.0 mg Corn Oil 1.0 mL
[0312] Another preferred formulation employed in the methods of the
present invention employs transdermal delivery devices ("patches").
Such transdermal patches may be used to provide continuous or
discontinuous infusion of the compounds of the present invention in
controlled amounts. The construction and use of transdermal patches
for the delivery of pharmaceutical agents is well known in the art.
See, e.g., U.S. Pat. No. 5,023,252, issued Jun. 11, 1991, herein
incorporated by reference in its entirety. Such patches may be
constructed for continuous, pulsatile, or on demand delivery of
pharmaceutical agents.
[0313] Other suitable formulations for use in the present invention
can be found in Remington's Pharmaceutical Sciences, edited by E.
W. Martin (Mack Publishing Company, 18th ed., 1990).
Biological Examples
Example 1
M.sub.2 Muscarinic Receptor In Vitro Binding Assay
[0314] The M.sub.2 muscarininc receptor binding activity of
compounds of the invention was tested as follows.
[0315] SF9 cell membranes containing human M.sub.2 muscarinic
receptor was obtained from NEN (Boston, Mass.). In 96-well
microtiter plates, eight serial five-fold dilutions were prepared
with the compound to be assayed; the highest concentration was
typically 4 .mu.M (4.times. the final concentration). To 100 .mu.l
of compound dilution was added 150 .mu.L M.sub.3 receptor membrane
preparation in PBS/1.0 mM MgCl.sub.2/pH 7.4. 50 .mu.l of 3.2 nM
3H-N-methylscopolamine radioligand was added. The total volume in
each well was then 300 .mu.l. The filter plate was pre-blocked
using 0.3% PEI for at least 15 minutes, and then washed twice with
200 .mu.l PBS. The assay plate was incubated for 1 hour at room
temperature with gentle shaking. The contents of the assay plate
were then transferred to the filter plate, and washed three times
using 200 .mu.l PBS. About 40 .mu.l of scint was added to each well
and then the plate was allowed to sit at room temperature for 2 h,
and then counted using a Packard Topcount NXT. Counting was
typically performed for 1 minute per well using a standard protocol
on a Packard top counter. The raw data was fit to a standard
4-parameter equation given below and a value of IC.sub.50
obtained.
Y=(a-d)/(1+(x/c).sup.b)+d where
[0316] Y=cpm
[0317] a=total binding
[0318] b=slope
[0319] c=IC.sub.50
[0320] x=[compound]
[0321] d=nonspecific binding
[0322] Representative compounds of the invention were found to have
pK.sub.b values of greater than 6, and to have IC.sub.50 values of
less than about 50 .mu.m.
[0323] A similar protocol was used to measure M1, M3, M4 and M5
human muscarinic receptor activity.
Example 2
Rat Heart Muscarinic Receptor In Vitro Binding Assay
[0324] Tissue (rat heart) muscarininc receptor binding activity of
compounds of the invention was tested as follows.
[0325] Muscarinic receptor enriched membranes were isolated from
whole hearts (Pelfreeze Laboratories). Rat heart tissue was
typically prepared as follows. 25 .mu.l of ice cold buffer (20 mM
HEPES, 100 mM NaCl/10 mM MgCl.sub.2 at pH 7.5 with "Complete"
protease inhibitor cocktail purchased from Boehringer Mannheim was
added into an oakridge tube. To the tube was then added 2 g of rat
heart (purchased from Harlan). The contents of the tube were then
transferred to a wheaton glass cylinder and homogenized using a
Polytron homogenizer (setting 22, 15 seconds .times.2), and then
transferred back to the oakridge tube, and centrifuged for 10
minutes at 1500 g. The supernatant was removed and then centrifuged
for 20 minutes at 45000 g. The supernatant was removed and the
pellet resuspended in 5 mL buffer and transferred to a wheaton
glass cylinder. This material was then homogenized using a Potter
type glass teflon homogenizer with 7-8 passes. The material was
then transferred to an oakridge tube and the total volume was
brought up to 25 mL. This material was then centrifuged for 20
minutes at 45000 g, and the pellet re-suspended in 2 mL buffer
using 2 passes of a teflon homogenizer, and stored at -80.degree.
C. until used.
[0326] A protocol similar to that used for cloned receptor binding
was used: Eight serial five-fold dilutions were prepared with the
compound to be assayed; the highest concentration was typically 4
.mu.M (4.times. the final concentration). To 50 .mu.l of compound
dilution in a 96-well assay plate was added an appropriate amount
of rat heart membrane (usually 12.5 .mu.l of membrane prep in 87.5
.mu.l of 20 mM HEPES, 100 mM NaCl/10 mM MgCl.sub.2 at pH 7.5). The
amount of membrane added depends in general on the results of
signal optimization, and ranges from 6.25-12.5 .mu.l. Last, 50
.mu.l of 2.12 nM 3H-N-methylscopolamine radioligand was added. The
total volume in each well was 200 .mu.l. The filter plate was
pre-blocked using 0.3% PEI for at least 15 min., and then washed
twice with 200 .mu.l PBS. The assay plate was incubated for 1 h at
room temperature with gentle shaking. The contents of the assay
plate were then transferred to the filter plate, and washed three
times using 200 .mu.l PBS. About 40 .mu.l of scint was added to
each well and then the plate was allowed to sit at room temperature
for 18 h, and then counted using a Packard Topcount NXT. Counting
was typically performed for 1 min., per well using a standard
protocol on the Packard counter. The data was fit to normal
isotherms and values for inhibition constants were extracted.
Representative compounds of the invention were found to have
pK.sub.b values of greater than 6, and to have IC.sub.50 values of
less than about 50 .mu.m.
[0327] A similar procedure was used to measure muscarinic receptor
binding at rat submaxillary gland, rat bladder, rat submandibular
gland, guinea pig heart, guinea pig submaxillary gland, guinea pig
bladder, and guinea pig submandibular gland, as well as in similar
human tissues..
Example 3
Rat Bladder M.sub.3 In Vitro Binding Assay
[0328] Bladder was comprised of both M.sub.2 and M.sub.3 muscarinic
receptors. The ratio was typically 4:1 M.sub.2:M.sub.3. In order to
measure binding of test compounds to one of M.sub.2 or M.sub.3, the
other was blocked with a reversible ligand that binds selectively
to that receptor. The following example illustrates the procedure
for M.sub.3 bladder binding.
[0329] Membranes from rat bladder were prepared in a similar
fashion to that used to isolate heart membrane above. Eight serial
five-fold dilutions were prepared with the compound to be assayed
in compound dilution buffer (20 mM HEPES/100 mM NaCl/10 mM
MgCl.sub.2/4 .mu.M Methoctramine); the highest concentration was
typically 4 .mu.M (4.times. the final concentration). The
concentration of methoctramine was sufficient to block >99% of
the M2 receptor in bladder, but less than 40% of the M.sub.3
receptor in bladder. To 50 .mu.l of compound dilution in a 96-well
assay plate was added an appropriate amount of rat heart membrane
(usually 25 .mu.l of membrane prep in 75 .mu.l of 20 mM HEPES, 100
mM NaCl/10 mM MgCl.sub.2 at pH 7.5). The amount of membrane added
depended in general on the results of signal optimization, and
ranged from 12.5-25. Last, 50 .mu.l of 2.12 nM
3H-N-methylscopolamine radioligand in compound dilution buffer was
added. The total volume in each well was 200 .mu.l. The final
concentration of methoctramine was 2 .mu.M. The filter plate was
pre-blocked using 0.3% PEI for at least 15 mins., and then washed
twice with 200 .mu.l PBS. The assay plate was incubated for 1 hour
at room temperature with gentle shaking. The contents of the assay
plate was then transferred to the filter plate, and washed three
times using 200 .mu.l PBS. About 40 .mu.l of scint was added to
each well, the plate was allowed to sit at room temperature for 18
h, and then counted using a Packard Topcount NXT. Counting was
typically performed for 1 minute per well using a standard protocol
on the Packard counter. The data was fit to normal isotherms and
values for inhibition constants were extracted. Representative
compounds of the invention were found to have IC.sub.50 values of
less than about 500 .mu.m.
[0330] A similar procedure was used to measure binding at bladder
M.sub.2, but in this case, 2 .mu.M Darifenacin was used to block
>99% of the M.sub.2 receptor, but minimal M.sub.3 receptor.
Example 4
Ex Vivo Rat Bladder Contraction Assay
[0331] The ability of the test compound to inhibit cholinergically
stimulated bladder contraction was tested as follows.
[0332] Male Sprague-Dawley rats weighing 250-300 g are killed by
CO.sub.2 overdose. The bladder was removed and placed in a petri
dish containing Krebs-Henseleit solution at room temperature. The
apex and dome areas of the bladder were discarded and the remaining
tissue cut into longitudinal strips (4 from each rat). The strips
were mounted in an organ bath containing Krebs-Henseleit solution
at 37.degree. C., under a resting tension of 0.5 g. The tissues
were allowed to equilibrate for 60 min., (washes at 0, 30 and 60
min.). Tension was readjusted to 1 g as necessary. A cumulative
concentration response curve to carbachol (10-8 M to 10-5 M (e.g.)
in 3-fold increments) was constructed in each tissue. Tissues were
then washed every 5 min., for 30 min., and tension readjusted to 1
g. After additional 30 min., muscarinic antagonist (typically
1.times.10-7 M) or vehicle was added. Thirty minutes after
antagonist or vehicle addition, a cumulative concentration response
curve to carbachol (10-8M to 10-3M (e.g.)) was constructed. Data
from each concentration response curve was expressed as a
percentage of the maximum contraction to carbachol. The EC.sub.50
values were calculated. The concentration-ratios were calculated
taking into account any spontaneous shift in the control tissue.
For competitive antagonists, the pKb value was calculated using the
following equation: 1 pKb = - log [ antagonist concentration ] CR -
1
[0333] Representative compounds of the invention were found to have
pK.sub.b values of greater than 5.
Example 5
In Vivo Rat Salivation Assay
[0334] Male Sprague-Dawley rats weighing 250-300 g were
anesthetized with pentobarbital (60 mg/kg i.p.). Rats were placed
on a heated blanket under a 20 degree incline. A swab was placed in
the rat's mouth. Muscarinic antagonist or vehicle was administered
i.v. via the tail vein. After 5 min., oxotremorine (0.3 mg/kg) was
administered s.c. The swab was discarded and replaced by a
pre-weighed swab. Saliva was then collected for 15 min. After 15
min., the swab was weighed and the difference in its weight was
used to calculate the antisecretory potency of the antagonists. The
data was fit to normal isotherms and ID.sub.50 values were
extracted.
Example 6
In Vivo Bladder Assay
[0335] Male Sprague-Dawley rats weighing 250-300 g were
anesthetized with urethane (1.3 g/kg, i.p.), inactin (25 mg/kg,
i.p.), and xylazine (4 mg, i.p.). The jugular (or femoral) vein was
isolated and ligated and a small incision was made in the vein
distal to the ligation. A catheter (micro-Renathane tubing (0.014
mm ID.times.0.033 mm OD) filled with saline was inserted into the
vein and secured into place with suture thread. The trachea was
isolated and placed in a small hole between two of the rings.
Tubing (1.57 mm ID.times.2.08 mm OD) was inserted into the trachea
and tied into place with suture thread. The incision was closed
leaving the tubing exposed. The tracheotomy was to prevent the
animal from asphyxiating on his own saliva following oxotremorine
administration. The stomach was shaved and then cleaned with
ethanol. A midline sagital incision was made in the skin and muscle
layers of the lower stomach. The bladder was exposed and the saline
filled cannula (22-gauge needle attached to a pressure transducer
with PE 90 tubing) was inserted into the apex of the bladder to the
most distal part of the bladder. The bladder was placed back into
the peritoneal cavity. The bladder was emptied manually by
disconnecting the cannula and allowing the contents to flow out
until the bladder was approximately 1 cm in diameter. The incision
was closed with suture thread, first the muscle layer, then the
skin in order to keep the bladder moist and warm. The exposed
portion of the cannula to the skin surface was sutured to hold it
in place. After 15 min. oxotremorine (0.3 mg/kg, SC, baseweight)
was injected. After 10 min., (or until baseline stabilized) a test
compound or a reference standard was injected with a dose
equivalent to 0.005-0.01 mg/kg, IV, baseweight of atropine that
produced a 30-70% decrease in intraluminal pressure. After 5 min.,
a high dose of atropine 0.1 mg/kg was injected, i.v., to establish
the true 100% inhibition point.
[0336] For data analysis, the oxotremorine response (zero
inhibition) was determined by measuring the mean pressure 1 minute
prior to the antagonist injection. Then, to assess antagonist
inhibition, mean pressure was mesured beginning at 1 minute and
ending 2 minutes after antagonist administration. If the pressure
had not leveled off after 1 minute, a wait was initiated until it
was stable and then a 1-minute sample of the mean was taken.
Lastly, to determine the true 100% inhibition point, the mean
pressure was measured beginning 1 minutes and ending 2 minutes
after the high dose atropine challenge. The percent inhibition by
the antagonist can be determined by the ratio of the decrease from
the zero to 100% values.
[0337] The formula is: oxotremorine mean-treatment mean*100
oxotremorine mean-atropine mean.
[0338] Additionally, the activity of a compound of the invention on
other tissues can be determined using screening protocols that are
known in the art. For example, an assessment of increased locomotor
activity (assay for CNS penetration) can be carried out as
described by Sipos M L, et al., (1999) Psychopharmacology
147(3):250-256; an assessment of the effects of a compound on
gastrointestinal motility can be carried out as described by Macht
D I, and Barba-Gose J (1931) J Am Pharm Assoc 20:558-564; an
assessment of the effects of a compound on pupil diameter
(mydriasis) can be carried out as described by Parry M, Heathcote B
V (1982) Life Sci 31:1465-1471; and an assessment of a compounds
effects on urinary bladder in dog can be carried out as described
by Newgreen D T, et al. (1996) J Urol 155:600A.
[0339] Preferred compounds of the invention may display selectivity
for one or more tissues over other tissues. For example, compounds
of the invention that are useful for treating urinary incontinence
may show higher activity in the assay of Example 6 than in the
assay of Example 5.
[0340] Preferred compounds useful for treating urinary incontinence
and irritable bowel syndrome have greater antagonist activity at
the M.sub.2 receptor than at the M.sub.3 receptor or the other
muscarinic receptors.
[0341] Preferred compounds useful for treating unwanted salivation
have greater antagonist activity at the M.sub.3 receptor than at
the M.sub.2 receptor or the other muscarinic receptors.
[0342] The foregoing invention has been described in some detail by
way of illustration and example, for purposes of clarity and
understanding. It will be obvious to one of skill in the art that
changes and modifications may be practiced within the scope of the
appended claims. Therefore, it is to be understood that the above
description is intended to be illustrative and not restrictive. The
scope of the invention should, therefore, be determined not with
reference to the above description, but should instead be
determined with reference to the following appended claims, along
with the full scope of equivalents to which such claims are
entitled.
[0343] All patents, patent applications and publications cited in
this application are hereby incorporated by reference in their
entirety for all purposes to the same extent as if each individual
patent, patent application or publication were so individually
denoted.
* * * * *