U.S. patent application number 11/650268 was filed with the patent office on 2007-06-14 for antiinflammation agents.
This patent application is currently assigned to Amgen, Inc.. Invention is credited to Michelle F. Browner, David L. Clark, Timothy D. Cushing, Xiaolin Hao, Ronald C. Hawley, Xiao He, Juan C. Jaen, Sharada S. Labadie, Marc Labelle, Marie-Louise Smith, Francisco X. Talamas, Nigel P.C. Walker.
Application Number | 20070135464 11/650268 |
Document ID | / |
Family ID | 22919310 |
Filed Date | 2007-06-14 |
United States Patent
Application |
20070135464 |
Kind Code |
A1 |
Browner; Michelle F. ; et
al. |
June 14, 2007 |
Antiinflammation agents
Abstract
Compounds, compositions and methods that are useful in the
treatment of inflammatory, immunoregulatory, metabolic and cell
proliferative conditions or diseases are provided herein. In
particular, the invention provides compounds which modulate the
expression and/or function of proteins involved in inflammation,
metabolism and cell proliferation. The subject compounds contain
fused carbocyclic or heterocyclic rings.
Inventors: |
Browner; Michelle F.;
(US) ; Clark; David L.; (US) ; Cushing;
Timothy D.; (US) ; Hao; Xiaolin; (US) ;
Hawley; Ronald C.; (US) ; He; Xiao; (US)
; Jaen; Juan C.; (US) ; Labadie; Sharada S.;
(US) ; Smith; Marie-Louise; (US) ; Talamas;
Francisco X.; (US) ; Walker; Nigel P.C.;
(US) ; Labelle; Marc; (US) |
Correspondence
Address: |
JONES DAY
222 EAST 41ST ST
NEW YORK
NY
10017
US
|
Assignee: |
Amgen, Inc.
|
Family ID: |
22919310 |
Appl. No.: |
11/650268 |
Filed: |
January 5, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10928784 |
Aug 26, 2004 |
7186841 |
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11650268 |
Jan 5, 2007 |
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10004287 |
Oct 23, 2001 |
6846834 |
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10928784 |
Aug 26, 2004 |
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60243581 |
Oct 26, 2000 |
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Current U.S.
Class: |
514/267 ;
514/314; 544/250; 546/167 |
Current CPC
Class: |
A61P 11/02 20180101;
A61P 21/00 20180101; C07D 401/04 20130101; A61P 37/08 20180101;
A61P 17/04 20180101; A61P 17/06 20180101; A61P 1/16 20180101; A61P
37/06 20180101; C07D 405/14 20130101; A61P 11/00 20180101; A61P
19/02 20180101; A61P 17/00 20180101; A61P 11/06 20180101; C07D
471/04 20130101; A61P 35/00 20180101; A61P 25/00 20180101; A61P
43/00 20180101; A61P 19/06 20180101; A61P 9/10 20180101; A61P 27/16
20180101; A61P 31/04 20180101; A61P 3/04 20180101; A61P 25/28
20180101; C07D 417/04 20130101; A61P 1/04 20180101; C07D 401/14
20130101; C07D 403/04 20130101; A61P 3/10 20180101; A61P 19/08
20180101; A61P 19/10 20180101; A61P 27/02 20180101; A61P 29/00
20180101; A61P 13/12 20180101 |
Class at
Publication: |
514/267 ;
544/250; 546/167; 514/314 |
International
Class: |
A61K 31/519 20060101
A61K031/519; A61K 31/4709 20060101 A61K031/4709; C07D 403/04
20060101 C07D403/04 |
Claims
1. A compound having the formula: ##STR134## wherein W and X are
independently selected from the group consisting of N and CH; Y is
selected from the group consisting of O, S and N(R); wherein R is
selected from the group consisting of H, CN, NO.sub.2,
(C.sub.1-C.sub.10)alkyl, (C.sub.3-C.sub.10)cycloalkyl,
(C.sub.4-C.sub.10)cycloalkyl-alkyl, (C.sub.3-C.sub.10)alkenyl and
(C.sub.2-C.sub.10)alkynyl; Z is selected from the group consisting
of H, (C.sub.1-C.sub.10)alkyl, (C.sub.3-C.sub.10)cycloalkyl,
(C.sub.4-C.sub.10)cycloalkyl-alkyl, (C.sub.2-C.sub.10)alkenyl,
(C.sub.2-C.sub.10)alkynyl and NR.sup.2R.sup.3; R.sup.1, R.sup.2 and
R.sup.3 are independently selected from the group consisting of H,
(C.sub.1-C.sub.10)alkyl, (C.sub.3-C.sub.10)alkenyl,
(C.sub.2-C.sub.10)alkynyl, (C.sub.1-C.sub.10)heteroalkyl
(C.sub.3-C.sub.10)cycloalkyl, (C.sub.4-C.sub.10)cycloalkyl-alkyl,
(C.sub.3-C.sub.10)cycloheteroalkyl-alkyl,
(C.sub.3-C.sub.10)cycloheteroalkyl, aryl,
aryl(C.sub.1-C.sub.4)alkyl, aryl(C.sub.1-C.sub.4)heteroalkyl,
heteroaryl(C.sub.1-C.sub.4)alkyl,
heteroaryl(C.sub.1-C.sub.4)heteroalkyl and
perfluoro(C.sub.1-C.sub.6)alkyl; and wherein when Z is
NR.sup.2R.sup.3, R.sup.2 and R.sup.3 can be combined to form a 5-
to 7-membered heterocyclyl ring; R.sup.4 is selected from the group
consisting of H, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.6)cycloalkyl, (C.sub.4-C.sub.7)cycloalkyl-alkyl,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl; A is a
substituted or unsubstituted fused carbocyclic or heterocyclic ring
system, said ring system being mono- or bicyclic wherein said mono-
or bicyclic rings are selected from the group consisting of five-
and six-membered rings that are aromatic or partially or completely
saturated; and B is a substituted or unsubstituted five- or
six-membered ring which is aromatic or partially or completely
saturated, containing at least one nitrogen atom, and from 0 to 3
additional heteroatoms, wherein the B ring substituents are
selected from the group consisting of halogen, CF.sub.3, CF.sub.3O,
(C.sub.1-C.sub.6)alkyl, perfluoro(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)thioalkoxy, amino, (C.sub.1-C.sub.6)alkylamino,
di(C.sub.1-C.sub.6)alkylamino, (C.sub.3-C.sub.10)cycloalkyl,
(C.sub.4-C.sub.10)cycloalkyl-alkyl,
(C.sub.3-C.sub.10)cycloheteroalkyl, cyano, nitro, sulfonamido,
(C.sub.1-C.sub.6)acyl, (C.sub.1-C.sub.6)acylamino,
(C.sub.1-C.sub.6)alkoxycarbonyl,
(C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkyl, carboxamido
and (C.sub.1-C.sub.6)heteroalkoxy.
2. A compound of claim 1, wherein W is N and X is CH.
3. A compound of claim 1, wherein W is N and X is N.
4. A compound of claim 1, wherein W is CH and X is N.
5. A compound of claim 1, wherein W is CH and X is CH.
6. A compound of claim 2, wherein Y is selected from the group
consisting of O and S.
7. A compound of claim 2, wherein Y is O.
8. A compound of claim 2, wherein Y is S.
9. A compound of claim 2, wherein Z is NR.sup.2R.sup.3.
10. A compound of claim 6, wherein R.sup.4 is H.
11. A compound of claim 1, wherein A is selected from the group
consisting of: ##STR135##
12. A compound of claim 1, wherein A is selected from the group
consisting of: ##STR136## wherein R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 are independently selected from the group consisting of H,
halogen, CF.sub.3, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)thioalkoxy, amino, (C.sub.1-C.sub.6)alkylamino,
di(C.sub.1-C.sub.6)alkylamino, (C.sub.3-C.sub.10)cycloalkyl,
(C.sub.4-C.sub.10)cycloalkyl-alkyl,
(C.sub.3-C.sub.10)cycloheteroalkyl,
(C.sub.3-C.sub.10)cycloheteroalkyl-alkyl, cyano, nitro,
(C.sub.1-C.sub.6)acyl, (C.sub.1-C.sub.6)acylamino,
(C.sub.1-C.sub.6)alkoxycarbonyl, (C.sub.1-C.sub.6)alkoxycarbonyl
(C.sub.1-C.sub.6)alkyl, CONH.sub.2, CO--NH--(C.sub.1-C.sub.6)alkyl,
CO--N[(C.sub.1-C.sub.6)alkyl].sub.2, SO.sub.2NH.sub.2,
SO.sub.2NH--(C.sub.1-C.sub.6)alkyl,
SO.sub.2N--[(C.sub.1-C.sub.6)alkyl].sub.2 and
(C.sub.1-C.sub.6)heteroalkoxy; or two adjacent R groups selected
from R.sup.5, R.sup.6, R.sup.7 and R.sup.8, can be linked together
to form a new 5- or 6-membered carbocyclic or heterocyclic
ring.
13. A compound of claim 12, wherein W is N; X is CH; Y is O or S;
and A is selected from the group consisting of: ##STR137##
14. A compound of claim 1, wherein B contains a nitrogen atom at a
position two atoms away from the atom attaching B to the remainder
of the molecule.
15. A compound of claim 1, wherein B contains a nitrogen atom at
the point of attachment of B to the remainder of the molecule.
16. A compound of claim 1, wherein B is selected from the group
consisting of 1-methylimidazol-5-yl,
1-(trifluoromethyl)imidazol-5-yl, 5-methylimidazol-1-yl,
5-(trifluoromethyl)imidazol-1-yl, thiazol-5-yl, imidazol-1-yl,
1-methyl-1,3,4-triazolyl, and 4-methyl-1,2,4-triazol-3-yl.
17. A compound of claim 1, wherein B is selected from the group
consisting of substituted or unsubstituted imidazolyl, substituted
or unsubstituted thiazolyl and substituted or unsubstituted
triazolyl.
18. A compound of claim 13, wherein B contains a nitrogen atom at a
position two atoms away from the atom attaching B to the remainder
of the molecule.
19. A compound of claim 13, wherein B contains a nitrogen atom at
the point of attachment of B to the remainder of the molecule.
20. A compound of claim 13, wherein B is selected from the group
consisting of 1-methylimidazol-5-yl,
1-(trifluoromethyl)imidazol-5-yl, 5-methylimidazol-1-yl,
5-(trifluoromethyl)imidazol-1-yl, thiazol-5-yl, imidazol-1-yl,
1-methyl-1,3,4-triazolyl, and 4-methyl-1,2,4-triazol-3-yl.
21. A compound of claim 13, wherein B is selected from the group
consisting of substituted or unsubstituted imidazolyl, substituted
or unsubstituted thiazolyl and substituted or unsubstituted
triazolyl.
22. A compound of claim 1, wherein W is N; X is CH; Y is O or S; Z
is H, CH.sub.3, NH.sub.2 or NHCH.sub.3; R.sup.1 is H,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.10)heteroalkyl,
(C.sub.4-C.sub.10)cycloheteroalkyl-alkyl,
(C.sub.3-C.sub.10)cycloheteroalkyl, aryl(C.sub.1-C.sub.4)alkyl,
aryl(C.sub.1-C.sub.4)heteroalkyl, heteroaryl(C.sub.1-C.sub.4)alkyl,
heteroaryl(C.sub.1-C.sub.4)heteroalkyl, or
perfluoro(C.sub.1-C.sub.6)alkyl; R.sup.4 is H; A represents
##STR138## wherein R.sup.6 and R.sup.7 are independently selected
from the group consisting of H, halogen, CF.sub.3, CF.sub.3O,
(C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl,
(C.sub.2-C.sub.4)alkynyl, (C.sub.1-C.sub.4)heteroalkyl,
(C.sub.3-C.sub.10)cycloheteroalkyl-alkyl and cyano; and B is a
five-membered aromatic ring system containing at least one nitrogen
atom.
23. A compound of claim 22, wherein Y is S.
24. A compound of claim 22, wherein Z is NR.sup.2R.sup.3.
25. A compound of claim 22, wherein Z is NH.sub.2.
26. A compound of claim 22, wherein R.sup.1 is
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)heteroalkyl or
(C.sub.3-C.sub.10)cycloheteroalkyl-alkyl.
27. A compound of claim 22, wherein B is a five-membered aromatic
ring system containing 1-2 nitrogen atoms and 0-1 sulfur atoms.
28. A compound of claim 27, wherein B is unsubstituted or
substituted by (C.sub.1-C.sub.3)alkyl, CF.sub.3, cyano, or
halogen.
29. A compound of claim 22, wherein Z is NH.sub.2; R.sup.6 is
selected from the group consisting of H, halogen, CF.sub.3,
CF.sub.3O, (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl,
(C.sub.1-C.sub.4)heteroalkyl,
(C.sub.3-C.sub.10)cycloheteroalkyl-alkyl and cyano, wherein the
alkyl, alkenyl and heteroalkyl groups optionally bear additional
substituents selected from cyano,
carboxamido,(C.sub.1-C.sub.3)alkylsulfonyl or
(C.sub.1-C.sub.3)alkoxy; and R.sup.7 is selected from the group
consisting of H, halogen, CF.sub.3, CF.sub.3O,
(C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl,
(C.sub.2-C.sub.4)alkynyl, (C.sub.1-C.sub.4)heteroalkyl and
cyano.
30. A compound of claim 29, wherein R.sup.6 is selected from the
group consisting of CH.sub.2(CH.sub.2).sub.mCN,
CH.sub.2(CH.sub.2).sub.nSO.sub.2CH.sub.3 and
CH.sub.2(CH.sub.2).sub.nOCH.sub.3, wherein the subscript n is an
integer from 0 to 2.
31. A compound of claim 29, wherein R.sup.6 is ##STR139##
32. A compound of claim 29, wherein R.sup.7 is selected from H,
halogen, CF.sub.3 and (C.sub.1-C.sub.4)alkyl.
33. A compound of claim 29, wherein R.sup.7 is methyl.
34. A compound of claim 1, having the formula: ##STR140## wherein Y
is O, S or N--CN; W' is N(CH.sub.3), N(CF.sub.3),
N(CH.sub.2CH.sub.3), O or S; the subscripts n and n' are
independently integers from 0 to 3; R.sup.7 is H, halogen,
CF.sub.3, CF.sub.3O, (C.sub.1-C.sub.4)alkyl,
(C.sub.2-C.sub.4)alkenyl, (C.sub.2-C.sub.4)alkynyl,
(C.sub.1-C.sub.4)heteroalkyl or cyano; R.sup.9 is CN, CONH.sub.2,
CO--NH--(C.sub.1-C.sub.6)alkyl,
CO--N[(C.sub.1-C.sub.6)alkyl].sub.2,
CO--NH--(C.sub.1-C.sub.6)heteroalkyl,
CO--N[(C.sub.1-C.sub.6)heteroalkyl].sub.2,
S(O).sub.n''-(C.sub.1-C.sub.6)alkyl,
S(O).sub.n''-(C.sub.1-C.sub.6)heteroalkyl, heteroaryl,
(C.sub.1-C.sub.6)alkoxy or (C.sub.3-C.sub.6)cycloheteroalkyl,
wherein each n'' is independently an integer of 0 to 2; R.sup.1 is
NH.sub.2, NH--(C.sub.1-C.sub.6)alkyl,
N[(C.sub.1-C.sub.6)alkyl].sub.2, NH--(C.sub.1-C.sub.6)heteroalkyl,
N[(C.sub.1-C.sub.6)heteroalkyl].sub.2,
(C.sub.1-C.sub.6)heteroalkyl, S(O).sub.n''-(C.sub.1-C.sub.6)alkyl,
S(O).sub.n''-(C.sub.1-C.sub.6)heteroalkyl, aryl, heteroaryl,
O--(C.sub.1-C.sub.6)alkyl, O--(C.sub.1-C.sub.6)heteroalkyl or
(C.sub.3-C.sub.8)cycloheteroalkyl; and R.sup.11 is H, CF.sub.3,
NH.sub.2, NH--(C.sub.1-C.sub.6)alkyl,
N[(C.sub.1-C.sub.6)alkyl].sub.2, halogen or
(C.sub.1-C.sub.3)alkyl.
35. A compound of claim 34, wherein Y is O or S; W' is N--CH.sub.3;
n is 2; n' is 1-3; R.sup.9 is cyano, CONH.sub.2,
SO.sub.2-(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy or
(C.sub.3-C.sub.6)cycloheteroalkyl; R.sup.10 is
NH--(C.sub.1-C.sub.6)alkyl, N[(C.sub.1-C.sub.6)alkyl].sub.2,
NH--(C.sub.1-C.sub.6)heteroalkyl,
N[(C.sub.1-C.sub.6)heteroalkyl].sub.2, O--(C.sub.1-C.sub.6)alkyl,
O--(C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)alkoxy or
(C.sub.3-C.sub.8)cycloheteroalkyl; and R.sup.11 is H.
36. A compound of claim 22, wherein B contains a nitrogen atom at a
position two atoms away from the atom attaching B to the remainder
of the molecule.
37. A compound of claim 22, wherein B contains a nitrogen atom at
the point of attachment of B to the remainder of the molecule.
38. A compound of claim 22, wherein B is selected from the group
consisting of substituted or unsubstituted imidazolyl, substituted
or unsubstituted thiazolyl and substituted or unsubstituted
triazolyl.
39. A compound of claim 22, wherein B is selected from the group
consisting of 1-methylimidazol-5-yl,
1-(trifluoromethyl)imidazol-5-yl, 5-methylimidazol-1-yl,
5-(trifluoromethyl)imidazol-1-yl, thiazol-5-yl, imidazol-1-yl,
1-methyl-1,3,4-triazolyl, and 4-methyl-1,2,4-triazol-3-yl.
40. A compound of claim 1, wherein Y is S; Z is NH.sub.2 and
R.sup.1 is (C.sub.1-C.sub.6)alkyl.
41. A compound of claim 40, wherein R.sup.1 is methyl.
42. A compound of claim 1, wherein said compound is selected from
the group consisting of: ##STR141## ##STR142## ##STR143##
##STR144##
43. A composition comprising a pharmaceutically acceptable
excipient and a compound having the formula: ##STR145## wherein W
and X are independently selected from the group consisting of N and
CH; Y is selected from the group consisting of O, S and N(R);
wherein R is selected from the group consisting of H, CN, NO.sub.2,
(C.sub.1-C.sub.10)alkyl, (C.sub.3-C.sub.10)cycloalkyl,
(C.sub.4-C.sub.10)cycloalkyl-alkyl, (C.sub.3-C.sub.10)alkenyl and
(C.sub.2-C.sub.10)alkynyl; Z is selected from the group consisting
of H, (C.sub.1-C.sub.10)alkyl, (C.sub.3-C.sub.10)cycloalkyl,
(C.sub.4-C.sub.10)cycloalkyl-alkyl, (C.sub.2-C.sub.10)alkenyl,
(C.sub.2-C.sub.10)alkynyl and NR.sup.2R.sup.3; R.sup.1, R.sup.2 and
R.sup.3 are independently selected from the group consisting of H,
(C.sub.1-C.sub.10)alkyl, (C.sub.3-C.sub.10)alkenyl,
(C.sub.2-C.sub.10)alkynyl, (C.sub.2-C.sub.10)heteroalkyl,
(C.sub.3-C.sub.10)cycloalkyl, (C.sub.4-C.sub.10)cycloalkyl-alkyl,
(C.sub.3-C.sub.10)cycloheteroalkyl-alkyl,
(C.sub.3-C.sub.10)cycloheteroalkyl, aryl,
aryl(C.sub.1-C.sub.4)alkyl, aryl(C.sub.2-C.sub.4)heteroalkyl,
heteroaryl(C.sub.2-C.sub.4)alkyl,
heteroaryl(C.sub.2-C.sub.4)heteroalkyl and
perfluoro(C.sub.1-C.sub.6)alkyl; and wherein when Z is
NR.sup.2R.sup.3, R.sup.2 and R.sup.3 can be combined to form a 5-
to 7-membered ring; and wherein when Y is N(R), R and R.sup.1 are
optionally combined to form a 5- to 7-membered ring; R.sup.4 is
selected from the group consisting of H, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.6)cycloalkyl, (C.sub.4-C.sub.7)cycloalkyl-alkyl,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl; A is a
substituted or unsubstituted fused carbocyclic or heterocyclic ring
system, said ring system being mono- or bicyclic wherein said mono-
or bicyclic rings are selected from the group consisting of five-
and six-membered rings that are aromatic or partially or completely
saturated; and B is a substituted or unsubstituted five- or
six-membered ring which is aromatic or partially or completely
saturated, containing at least one nitrogen atom, and from 0 to 3
additional heteroatoms, wherein the B ring substituents are
selected from the group consisting of halogen, CF.sub.3, CF.sub.3O,
(C.sub.1-C.sub.6)alkyl, perfluoro(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)thioalkoxy, amino, (C.sub.1-C.sub.6)alkylamino,
di(C.sub.1-C.sub.6)alkylamino, (C.sub.3-C.sub.10)cycloalkyl,
(C.sub.4-C.sub.10)cycloalkyl-alkyl,
(C.sub.3-C.sub.10)cycloheteroalkyl, cyano, nitro, sulfonamido,
(C.sub.1-C.sub.6)acyl, (C.sub.1-C.sub.6)acylamino,
(C.sub.2-C.sub.6)alkoxycarbonyl,
(C.sub.2-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkyl, carboxamido
and (C.sub.1-C.sub.6)heteroalkoxy.
44. A composition in accordance with claim 43, wherein W is N and X
is CH.
45. A composition in accordance with claim 43, wherein W is N and X
is N.
46. A composition in accordance with claim 43, wherein W is CH and
X is N.
47. A composition in accordance with claim 43, wherein W is CH and
X is CH.
48. A composition in accordance with claim 43, wherein Y is
selected from the group consisting of O and S.
49. A composition in accordance claim 43, wherein Y is O.
50. A composition in accordance claim 43, wherein Y is S.
51. A composition in accordance claim 43, wherein Z is
NR.sup.2R.sup.3.
52. A composition in accordance with claim 48, wherein R.sup.4 is
H.
53. A composition in accordance with claim 43, wherein A is
selected from the group consisting of: ##STR146##
54. A composition in accordance with claim 43, wherein A is
selected from the group consisting of. ##STR147## wherein R.sup.5,
R.sup.6, R.sup.7 and R.sup.8 are independently selected from the
group consisting of H, halogen, CF.sub.3, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)thioalkoxy, amino, (C.sub.1-C.sub.6)alkylamino,
di(C.sub.1-C.sub.6)alkylamino, (C.sub.3-C.sub.10)cycloalkyl,
(C.sub.4-C.sub.10)cycloalkyl-alkyl,
(C.sub.3-C.sub.10)cycloheteroalkyl,
(C.sub.3-C.sub.10)cycloheteroalkyl-alkyl, cyano, nitro,
(C.sub.1-C.sub.6)acyl, (C.sub.1-C.sub.6)acylamino,
(C.sub.2-C.sub.6)alkoxycarbonyl,
(C.sub.3-C.sub.6)alkoxycarbonylalkyl, CONH.sub.2,
CO--NH--(C.sub.1-C.sub.6)alkyl,
CO--N[(C.sub.1-C.sub.6)alkyl].sub.2, SO.sub.2NH.sub.2,
SO.sub.2NH--(C.sub.1-C.sub.6)alkyl,
SO.sub.2N--[(C.sub.1-C.sub.6)alkyl].sub.2 and
(C.sub.1-C.sub.6)heteroalkoxy; or two adjacent R groups can be
linked together to form a new 5- or 6-membered carbocyclic or
heterocyclic ring.
55. A composition in accordance with claim 43, wherein W is N; X is
CH; Y is O or S; and A is selected from the group consisting of:
##STR148##
56. A composition in accordance with claim 43, wherein B contains a
nitrogen atom at a position two atoms away from the atom attaching
B to the remainder of the molecule.
57. A composition in accordance with claim 43, wherein B contains a
nitrogen atom at the point of attachment of B to the remainder of
the molecule.
58. A composition in accordance with claim 43, wherein B is
selected from the group consisting of 1-methylimidazol-5-yl,
1-(trifluoromethyl)imidazol-5-yl, 5-methylimidazol-1-yl,
5-(trifluoromethyl)imidazol-1-yl, thiazol-5-yl, imidazol-1-yl,
1-methyl-1,3,4-triazolyl, and 4 methyl-1,2,4-triazol-3-yl.
59. A composition in accordance with claim 43, wherein B is
selected from the group consisting of substituted or unsubstituted
imidazolyl, substituted or unsubstituted thiazolyl and substituted
or unsubstituted triazolyl.
60. A composition in accordance with claim 55, wherein B contains a
nitrogen atom at a position two atoms away from the atom attaching
B to the remainder of the molecule.
61. A composition in accordance with claim 55, wherein B contains a
nitrogen atom at the point of attachment of B to the remainder of
the molecule.
62. A composition in accordance with claim 55, wherein B is
selected from the group consisting of 1-methylimidazol-5-yl,
1-(trifluoromethyl)imidazol-5-yl, 5-methylimidazol-1-yl,
5-(trifluoromethyl)imidazol-1-yl, thiazol-5-yl, imidazol-1-yl,
1-methyl-1,3,4-triazolyl, and 4-methyl-1,2,4-triazol-3-yl.
63. A composition in accordance with claim 55, wherein B is
selected from the group consisting of substituted or unsubstituted
imidazolyl, substituted or unsubstituted thiazolyl and substituted
or unsubstituted triazolyl.
64. A method for treating an inflammatory, metabolic or malignant
condition, said method comprising administering to a subject in
need of such treatment, an effective amount of a compound having
the formula: ##STR149## wherein W and X are independently selected
from the group consisting of N and CH; Y is selected from the group
consisting of O, S and N(R); wherein R is selected from the group
consisting of H, CN, NO.sub.2, (C.sub.1-C.sub.10)alkyl,
(C.sub.3-C.sub.10)cycloalkyl, (C.sub.4-C.sub.10)cycloalkyl-alkyl,
(C.sub.3-C.sub.10)alkenyl and (C.sub.2-C.sub.10)alkynyl; Z is
selected from the group consisting of H, (C.sub.1-C.sub.10)alkyl,
(C.sub.3-C.sub.10)cycloalkyl, (C.sub.4-C.sub.10)cycloalkyl-alkyl,
(C.sub.2-C.sub.10)alkenyl, (C.sub.2-C.sub.10)alkynyl and
NR.sup.2R.sup.3; R.sup.1, R.sup.2 and R.sup.3 are independently
selected from the group consisting of H, (C.sub.1-C.sub.10)alkyl,
(C.sub.3-C.sub.10)alkenyl, (C.sub.2-C.sub.10)alkynyl,
(C.sub.2-C.sub.10)heteroalkyl, (C.sub.3-C.sub.10)cycloalkyl,
(C.sub.4-C.sub.10)cycloalkyl-alkyl,
(C.sub.3-C.sub.10)cycloheteroalkyl-alkyl,
(C.sub.3-C.sub.10)cycloheteroalkyl, aryl,
aryl(C.sub.1-C.sub.4)alkyl, aryl(C.sub.2-C.sub.4)heteroalkyl,
heteroaryl(C.sub.2-C.sub.4)alkyl,
heteroaryl(C.sub.2-C.sub.4)heteroalkyl and
perfluoro(C.sub.1-C.sub.6)alkyl; and wherein when Z is
NR.sup.2R.sup.3, R.sup.2 and R.sup.3 can be combined to form a 5-
to 7-membered ring; and wherein when Y is N(R), R and R.sup.1 are
optionally combined to form a 5- to 7-membered ring; R.sup.4 is
selected from the group consisting of H, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.6)cycloalkyl, (C.sub.4-C.sub.7)cycloalkyl-alkyl,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl; A is a
substituted or unsubstituted fused carbocyclic or heterocyclic ring
system, said ring system being mono- or bicyclic wherein said mono-
or bicyclic rings are selected from the group consisting of five-
and six-membered rings that are aromatic or partially or completely
saturated; and B is a substituted or unsubstituted five- or
six-membered ring which is aromatic or partially or completely
saturated, containing at least one nitrogen atom, and from 0 to 3
additional heteroatoms, wherein the B ring substituents are
selected from the group consisting of halogen, CF.sub.3, CF.sub.3O,
(C.sub.1-C.sub.6)alkyl, perfluoro(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)thioalkoxy, amino, (C.sub.1-C.sub.6)alkylamino,
di(C.sub.1-C.sub.6)alkylamino, (C.sub.3-C.sub.10)cycloalkyl,
(C.sub.4-C.sub.10)cycloalkyl-alkyl,
(C.sub.3-C.sub.10)cycloheteroalkyl, cyano, nitro, sulfonamido,
(C.sub.1-C.sub.6)acyl, (C.sub.1-C.sub.6)acylamino,
(C.sub.2-C.sub.6)alkoxycarbonyl,
(C.sub.2-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkyl, carboxamido
and (C.sub.1-C.sub.6)heteroalkoxy.
65. A method in accordance with claim 64, wherein W is N and X is
CH.
66. A method in accordance with claim 64, wherein W is N and X is
N.
67. A method in accordance with claim 64, wherein W is CH and X is
N.
68. A method in accordance with claim 64, wherein W is CH and X is
CH.
69. A method in accordance with claim 65, wherein Y is selected
from the group consisting of O and S.
70. A method in accordance with claim 65, wherein Y is O.
71. A method in accordance with claim 65, wherein Y is S.
72. A method in accordance with claim 65, wherein Z is
NR.sup.2R.sup.3.
73. A method in accordance with claim 69, wherein R.sup.4 is H.
74. A method in accordance with claim 64, wherein A is selected
from the group consisting of: ##STR150##
75. A method in accordance with claim 64, wherein A is selected
from the group consisting of: ##STR151## wherein R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are independently selected from the group
consisting of H, halogen, CF.sub.3, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)thioalkoxy, amino, (C.sub.1-C.sub.6)alkylamino,
di(C.sub.1-C.sub.6)alkylamino, (C.sub.3-C.sub.10)cycloalkyl,
(C.sub.4-C.sub.10)cycloaklyl-alkyl,
(C.sub.3-C.sub.10)cycloheteroalkyl,
(C.sub.3-C.sub.10)cycloheteroalkyl-alkyl, cyano, nitro,
(C.sub.1-C.sub.6)acyl, (C.sub.1-C.sub.6)acylamino,
(C.sub.2-C.sub.6)alkoxycarbonyl,
(C.sub.3-C.sub.6)alkoxycarbonylalkyl, CONH.sub.2,
CO--NH--(C.sub.1-C.sub.6)alkyl,
CO--N[(C.sub.1-C.sub.6)alkyl].sub.2, SO.sub.2NH.sub.2,
SO.sub.2NH--(C.sub.1-C.sub.6)alkyl,
SO.sub.2N--[(C.sub.1-C.sub.6)alkyl].sub.2 and
(C.sub.1-C.sub.6)heteroalkoxy; or two adjacent R groups can be
linked together to form a new 5- or 6-membered carbocyclic or
heterocyclic ring.
76. A method in accordance with claim 64, wherein W is N; X is CH;
Y is O or S; and A is selected from the group consisting of:
##STR152##
77. A method in accordance with claim 64, wherein B contains a
nitrogen atom at a position two atoms away from the atom attaching
B to the remainder of the molecule.
78. A method in accordance with claim 64, wherein B contains a
nitrogen atom at the point of attachment of B to the remainder of
the molecule.
79. A method in accordance with claim 64, wherein B is selected
from the group consisting of 1-methylimidazol-5-yl,
1-(trifluoromethyl)imidazol-5-yl, 5-methylimidazol-1-yl,
5-(trifluoromethyl)imidazol-1-yl, thiazol-5-yl, imidazol-1-yl,
1-methyl-1,3,4-triazolyl, and 4-methyl-1,2,4-triazol-3-yl.
80. A method in accordance with claim 64, wherein B is selected
from the group consisting of substituted or unsubstituted
imidazolyl, substituted or unsubstituted thiazolyl and substituted
or unsubstituted triazolyl.
81. A method in accordance with claim 76, wherein B contains a
nitrogen atom at a position two atoms away from the atom attaching
B to the remainder of the molecule.
82. A method in accordance with claim 76, wherein B contains a
nitrogen atom at the point of attachment of B to the remainder of
the molecule.
83. A method in accordance with claim 76, wherein B is selected
from the group consisting of 1-methylimidazol-5-yl,
1-(trifluoromethyl)imidazol-5-yl, 5-methylimidazol-1-yl,
5-(trifluoromethyl)imidazol-1-yl, thiazol-5-yl, imidazol-1-yl,
1-methyl-1,3,4-triazolyl, and 4-methyl-1,2,4-triazol-3-yl.
84. A method in accordance with claim 76, wherein B is selected
from the group consisting of substituted or unsubstituted
imidazolyl, substituted or unsubstituted thiazolyl and substituted
or unsubstituted triazolyl.
85. A method in accordance with claim 64, wherein said compound is
administered orally.
86. A method in accordance with claim 64, wherein said compound is
administered topically.
87. A method in accordance with claim 64, wherein said compound is
administered intravenously or intramuscularly.
88. A method in accordance with claim 64, wherein said compound is
administered in combination with a second therapeutic agent, said
second therapeutic agent being a member selected from the group
consisting of prednisone, dexamethasone, beclomethasone,
methylprednisone, betamethasone, hydrocortisone, methotrexate,
cyclosporin, rapamycin, tacrolimus, antihistamine drugs, TNF
antibodies, IL-1 antibodies, soluble TNF receptors, soluble IL-1
receptors, TNF or IL-1 receptor antagonists, non-steroidal
antiinflammatory agents, COX-2 inhibitors, antidiabetic agents, and
anticancer agents.
89. A method in accordance with claim 88, wherein said
administering is sequential.
90. A method in accordance with claim 64, wherein said
inflammatory, metabolic or malignant condition is selected from the
group consisting of rheumatoid arthritis, inflammatory bowel
disease, psoriasis, cancer, diabetes and septic shock.
91. A method for treating a condition or disorder mediated by IKK,
comprising administering to a subject in need thereof a
therapeutically effective amount of a compound having the formula:
##STR153## wherein W and X are independently selected from the
group consisting of N and CH; Y is selected from the group
consisting of O, S and N(R); wherein R is selected from the group
consisting of H, CN, NO.sub.2, (C.sub.1-C.sub.10)alkyl,
(C.sub.3-C.sub.10)cycloalkyl, (C.sub.4-C.sub.10)cycloalkyl-alkyl,
(C.sub.3-C.sub.10)alkenyl and (C.sub.2-C.sub.10)alkynyl; Z is
selected from the group consisting of H, (C.sub.1-C.sub.10)alkyl,
(C.sub.3-C.sub.10)cycloalkyl, (C.sub.4-C.sub.10)cycloalkyl-alkyl,
(C.sub.2-C.sub.10)alkenyl, (C.sub.2-C.sub.10)alkynyl and
NR.sup.2R.sup.3; R.sup.1, R.sup.2 and R.sup.3 are independently
selected from the group consisting of H. (C.sub.1-C.sub.10)alkyl,
(C.sub.3-C.sub.10)alkenyl, (C.sub.2-C.sub.10)alkynyl,
(C.sub.1-C.sub.10)heteroalkyl, (C.sub.3-C.sub.10)cycloalkyl,
(C.sub.4-C.sub.10)cycloalkyl-alkyl,
(C.sub.3-C.sub.10)cycloheteroalkyl-alkyl,
(C.sub.3-C.sub.10)cycloheteroalkyl, aryl,
aryl(C.sub.1-C.sub.4)alkyl, aryl(C.sub.1-C.sub.4)heteroalkyl,
heteroaryl(C.sub.1-C.sub.4)alkyl,
heteroaryl(C.sub.1-C.sub.4)heteroalkyl and
perfluoro(C.sub.1-C.sub.6)alkyl; and wherein when Z is
NR.sup.2R.sup.3, R.sup.2 and R.sup.3 can be combined to form a 5-
to 7-membered heterocyclyl ring; R.sup.4 is selected from the group
consisting of H, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.6)cycloalkyl, (C.sub.4-C.sub.7)cycloalkyl-alkyl,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl; A is a
substituted or unsubstituted fused carbocyclic or heterocyclic ring
system, said ring system being mono- or bicyclic wherein said mono-
or bicyclic rings are selected from the group consisting of five-
and six-membered rings that are aromatic or partially or completely
saturated; and B is a substituted or unsubstituted five- or
six-membered ring which is aromatic or partially or completely
saturated, containing at least one nitrogen atom, and from 0 to 3
additional heteroatoms, wherein the B ring substituents are
selected from the group consisting of halogen, CF.sub.3, CF.sub.3O,
(C.sub.1-C.sub.6)alkyl, perfluoro(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-.sub.6)thioalkoxy, amino, (C.sub.1-C.sub.6)alkylamino,
di(C.sub.1-C.sub.6)alkylamino, (C.sub.3-C.sub.10)cycloalkyl,
(C.sub.4-C.sub.10)cycloalkyl-alkyl,
(C.sub.3-C.sub.10)cycloheteroalkyl, cyano, nitro, sulfonamido,
(C.sub.1-C.sub.6)acyl, (C.sub.1-C.sub.6)acylamino,
(C.sub.1-C.sub.6)alkoxycarbonyl,
(C.sub.1-6)alkoxycarbonyl(C.sub.1-C.sub.6)alkyl, carboxamido and
(C.sub.1-C.sub.6)heteroalkoxy.
92. A method for modulating IKK, comprising contacting a cell with
a compound having the formula: ##STR154## wherein W and X are
independently selected from the group consisting of N and CH; Y is
selected from the group consisting of O, S and N(R); wherein R is
selected from the group consisting of H, CN, NO.sub.2,
(C.sub.1-C.sub.10)alkyl, (C.sub.3-C.sub.10)cycloalkyl,
(C.sub.4-C.sub.10)cycloalkyl-alkyl, (C.sub.3-C.sub.10)alkenyl and
(C.sub.2-C.sub.10)alkynyl; Z is selected from the group consisting
of H, (C.sub.1-C.sub.10)alkyl, (C.sub.3-C.sub.10)cycloalkyl,
(C.sub.4-C.sub.10)cycloalkyl-alkyl, (C.sub.2-C.sub.10)alkenyl,
(C.sub.2-C.sub.10)alkynyl and NR.sup.2R.sup.3; R.sup.1, R.sup.2 and
R.sup.3 are independently selected from the group consisting of H,
(C.sub.1-C.sub.10)alkyl, (C.sub.3-C.sub.10)alkenyl,
(C.sub.2-C.sub.10)alkynyl, (C.sub.1-C.sub.10)heteroalkyl,
(C.sub.3-C.sub.10)cycloalkyl, (C.sub.4-C.sub.10)cycloalkyl-alkyl,
(C.sub.3-C.sub.10)cycloheteroalkyl-alkyl,
(C.sub.3-C.sub.10)cycloheteroalkyl, aryl,
aryl(C.sub.1-C.sub.4)alkyl, aryl(C.sub.1-C.sub.4)heteroalkyl,
heteroaryl(C.sub.1-C.sub.4)alkyl,
heteroaryl(C.sub.1-C.sub.4)heteroalkyl and
perfluoro(C.sub.1-C.sub.6)alkyl; and wherein when Z is
NR.sup.2R.sup.3, R.sup.2 and R.sup.3 can be combined to form a 5-
to 7-membered heterocyclyl ring; R.sup.4 is selected from the group
consisting of H, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.6)cycloalkyl, (C.sub.4-C.sub.7)cycloalkyl-alkyl,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl; A is a
substituted or in substituted fused carbocyclic or heterocyclic
ring system, said ring system being mono- or bicyclic wherein said
mono- or bicyclic rings are selected from the group consisting of
five- and six-membered rings that are aromatic or partially or
completely saturated; and B is a substituted or unsubstituted five-
or six-membered ring which is aromatic or partially or completely
saturated, containing at least one nitrogen atom, and from 0 to 3
additional heteroatoms, wherein the B ring substituents are
selected from the group consisting of halogen, CF.sub.3, CF.sub.3O,
(C.sub.1-C.sub.6)alkyl, perfluoro(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)thioalkoxy, amino, (C.sub.1-C.sub.6)alkylamino,
di(C.sub.1-C.sub.6)alkylamino, (C.sub.3-C.sub.10)cycloalkyl,
(C.sub.4-C.sub.10)cycloalkyl-alkyl,
(C.sub.3-C.sub.10)cycloheteroalkyl, cyano, nitro, sulfonamido,
(C.sub.1-C.sub.6)acyl, (C.sub.1-C.sub.6)acylamino,
(C.sub.1-C.sub.6)alkoxycarbonyl,
(C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkyl, carboxamido
and (C.sub.1-C.sub.6)heteroalkoxy.
93. The method of claim 92, wherein said compound is an IKK
inhibitor.
94. The method of claim 92, wherein said compound is an IKK
activator.
95. A method for the preparation of antiinflammation agents
comprising contacting a precursor compound having the formula:
##STR155## wherein W and X are independently selected from the
group consisting of N and CH; R.sup.4 is selected from the group
consisting of H, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.6)cycloalkyl, (C.sub.4-C.sub.7)cycloalkyl-alkyl,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl; A is a
substituted or unsubstituted fused carbocyclic or heterocyclic ring
system, said ring system being mono- or bicyclic wherein said mono-
or bicyclic rings are selected from the group consisting of five-
and six-membered rings that are aromatic or partially or completely
saturated; and B is a substituted or unsubstituted five- or
six-membered ring which is aromatic or partially or completely
saturated, containing at least one nitrogen atom, and from 0 to 3
additional heteroatoms, wherein the B ring substituents are
selected from the group consisting of halogen, CF.sub.3, CF.sub.3O,
(C.sub.1-C.sub.6)alkyl, perfluoro(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)thioalkoxy, amino, (C.sub.1-C.sub.6)alkylamino,
di(C.sub.1-C.sub.6)alkylamino, (C.sub.3-C.sub.10)cycloalkyl,
(C.sub.4-C.sub.10)cycloalkyl-alkyl,
(C.sub.3-C.sub.10)cycloheteroalkyl, cyano, nitro, sulfonamido,
(C.sub.1-C.sub.6)acyl, (C.sub.1-C.sub.6)acylamino,
(C.sub.2-C.sub.6)alkoxycarbonyl,
(C.sub.2-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkyl, carboxamido
and (C.sub.1-C.sub.6)heteroalkoxy with a compound having the
formula: ##STR156## wherein Y is selected from the group consisting
of O, S and N(R); wherein R is selected from the group consisting
of H, CN, NO.sub.2, (C.sub.1-C.sub.10)alkyl,
(C.sub.3-C.sub.10)cycloalkyl, (C.sub.4-C.sub.10)cycloalkyl-alkyl,
(C.sub.3-C.sub.10)alkenyl and (C.sub.2-C.sub.10)alkynyl; Z is
selected from the group consisting of H, (C.sub.1-C.sub.10)alkyl,
(C.sub.3-C.sub.10)cycloalkyl, (C.sub.4-C.sub.10)cycloalkyl-alkyl,
(C.sub.2-C.sub.10)alkenyl, (C.sub.2-C.sub.10)alkynyl and
NR.sup.2R.sup.3; R.sup.1, R.sup.2 and R.sup.3 are independently
selected .from the group consisting of H, (C.sub.1-C.sub.10)alkyl,
(C.sub.3-C.sub.10)alkenyl, (C.sub.2-C.sub.10)alkynyl,
(C.sub.2-C.sub.10)heteroalkyl, (C.sub.3-C.sub.10)cycloalkyl,
(C.sub.4-C.sub.10)cycloalkyl-alkyl,
(C.sub.3-C.sub.10)cycloheteroalkyl-alkyl,
(C.sub.3-C.sub.10)cycloheteroalkyl, aryl,
aryl(C.sub.1-C.sub.4)alkyl, aryl(C.sub.2-C.sub.4)heteroalkyl,
heteroaryl(C.sub.2-C.sub.4)alkyl,
heteroaryl(C.sub.2-C.sub.4)heteroalkyl and
perfluoro(C.sub.1-C.sub.6)alkyl; and wherein when Z is
NR.sup.2R.sup.3, R.sup.2 and R.sup.3 can be combined to form a 5-
to 7-membered ring; and wherein when Y is N(R), R and R.sup.1 are
optionally combined to form a 5- to 7-membered ring; under
conditions sufficient to produce compounds having the formula:
##STR157## wherein each of A, B, R.sup.1, R.sup.4, W, X, Y and Z
have the meanings provided above.
96. A compound having the formula: ##STR158## wherein W and X are
independently selected from the group consisting of N and CH;
R.sup.4 is selected from the group consisting of H,
(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl,
(C.sub.4-C.sub.7)cycloalkyl-alkyl, (C.sub.2-C.sub.6)alkenyl and
(C.sub.2-C.sub.6)alkynyl; A is a substituted or unsubstituted fused
carbocyclic or heterocyclic ring system, said ring system being
mono- or bicyclic wherein said mono- or bicyclic rings are selected
from the group consisting of five- and six-membered rings that are
aromatic or partially or completely saturated; and B is a
substituted or unsubstituted five- or six-membered ring which is
aromatic or partially or completely saturated, containing at least
one nitrogen atom, and from 0 to 3 additional heteroatoms, wherein
the B ring substituents are selected from the group consisting of
halogen, CF.sub.3, CF.sub.3O, (C.sub.1-C.sub.6)alkyl,
perfluoro(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)heteroalkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)thioalkoxy, amino,
(C.sub.1-C.sub.6)alkylamino, di(C.sub.1-C.sub.6)alkylamino,
(C.sub.3-C.sub.10)cycloalkyl, (C.sub.4-C.sub.10)cycloalkyl-alkyl,
(C.sub.3-C.sub.10)cycloheteroalkyl, cyano, nitro, sulfonamido,
(C.sub.1-C.sub.6)acyl, (C.sub.1-C.sub.6)acylamino,
(C.sub.2-C.sub.6)alkoxycarbonyl,
(C.sub.2-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkyl, carboxamido
and (C.sub.1-C.sub.6)heteroalkoxy.
97. A compound of claim 96, wherein R.sup.4 is hydrogen.
98. A compound of claim 96, wherein R.sup.4 is hydrogen, Y is O or
S, and Z is NR.sup.2R.sup.3.
99. A compound of claim 96, wherein R.sup.4 is hydrogen, Y is O or
S, Z is NR.sup.2R.sup.3, and B contains a nitrogen atom at a
position two atoms away from the atom attaching B to the remainder
of the molecule.
100. A compound of claim 96, B contains a nitrogen atom at the
point of attachment of B to the remainder of the molecule.
101. A compound of claim 99, wherein B is selected from the group
consisting of 1-methylimidazol-5-yl,
1-(trifluoromethyl)imidazol-5-yl, 5-methylimidazol-1-yl,
5-(trifluoromethyl)imidazol-1-yl, thiazol-5-yl, imidazol-1-yl,
1-methyl-1,3,4-triazolyl, and 4-methyl-1,2,4-triazol-3-yl.
Description
[0001] This application claims the benefit of U.S. Ser. No.
60/243,582 filed Oct. 26, 2000 which is incorporated by reference
in its entirety
BACKGROUND OF THE INVENTION
[0002] Tumor Necrosis Factor (TNF) and interleukin-1 (IL-1) are
cytokines that have been implicated in a wide range of biological
processes, including inflammation. The recruitment of immune cells
to sites of injury involves the concerted interactions of a large
number of soluble mediators. Several cytokines appear to play key
roles in these processes, particularly IL-1 and TNF. Both cytokines
are derived from mononuclear cells and macrophages, along with
other cell types. Physiologically, they produce many of the same
proinflammatory responses, including fever, sleep and anorexia,
mobilization and activation of polymorphonuclear leukocytes,
induction of cyclooxygenase and lipoxygenase enzymes, increase in
adhesion molecule expression, activation of B-cells, T-cells and
natural killer cells, and stimulation of production of other
cytokines. Other actions include a contribution to the tissue
degeneration seen in chronic inflammatory conditions, such as
stimulation of fibroblast proliferation, induction of collagenase,
etc. They have also been implicated in the process of bone
resorption and adipose tissue regulation. Thus, these cytokines
play key roles in a large number of pathological conditions,
including rheumatoid arthritis, inflammatory bowel disease,
diabetes, obesity, bone mass loss, cancer, neurological conditions
such as ischemic stroke or closed head injuries, etc.
[0003] Cytokines trigger a variety of changes in gene expression in
their target cells by binding and activating their respective
cognate receptors. Receptor activation sets in motion certain
biochemical events, including the activation of otherwise latent
transcription factors. Members of the NF-.kappa.B Rel family of
transcription factors represent some of the most prominent of these
transcription factors, having been implicated in the regulation of
genes involved in inflammation, cell proliferation, apoptosis, and
several other basic cellular functions (Verma et al. Genes Dev. 9,
2723 (1995); Baichwal & Baeuerle, Curr. Biol. 7, 94
(1997)).
[0004] The best studied member of this family of transcription
factors is NF-.kappa.B, which generally exists in cells as a
heterodimer of two proteins: p50 (NF-.kappa.B1) and p65 (RelA),
although homodimers of these individual components are also
possible (Baeuerle and Baltimore, Cell, 53, 211 (1988); Baeuerle
and Henkel, Annu. Rev. Immunol. 12, 141 (1994)). NF-.kappa.B, in
its inactive form, resides in the cytoplasm of cells. In response
to various types of stimuli, such as proinflammatory cytokines
(e.g., TNF and IL-1), ultraviolet irradiation and viral infection
(Verma, 1995; Baichwal, 1997; Cao et al. Science, 271, 1128 (1996))
NF-.kappa.B migrates to the nucleus. TNF and IL-1 have been shown
to be two key proinflammation agents in a wide variety of
pathological conditions, including rheumatoid arthritis, septic
shock, inflammatory bowel disease, dermal sensitization disorders,
neurological trauma such as stroke or closed-head injuries,
etc.
[0005] In its inactive state, the NF-.kappa.B heterodimer is held
in the cytoplasm by association with inhibitory IkB proteins.
Recently, the three-dimensional structure of a
NF-.kappa.B/I.kappa.B ternary complex has been solved (Huxford et
al. Cell, 95, 759 (1998); Jacobs et al. Cell, 95, 749 (1998)). When
cells are treated with the appropriate stimuli, such as IL-1 or
TNF, intracellular signal transduction pathways are activated that
lead to the eventual phosphorylation of IkB proteins on two
specific residues (serines 32 and 36 in IkB.alpha., serines 19 and
23 in IkB .beta.). Mutation of one or both serine residues renders
IkB resistant to cytokine-induced phosphorylation. This
signal-induced phosphorylation targets IkB for ubiquitination and
proteosome-mediated degradation, allowing nuclear translocation of
NF-.kappa.B (Thanos and Maniatis, Cell, 80, 529 (1995)). The only
regulated step in the IkB degradation pathway is the
phosphorylation of IkB by IkB kinases (IKK) (Yaron et al. EMBO J
16, 6486 (1997)).
[0006] Several intermediate steps in the TNF- and IL-1-activated
signaling pathways that result in IkB phosphorylation have been
elucidated in recent years. Both pathways appear to merge at the
level of the protein kinase NIK (NF-.kappa.B-inducing kinase)
(Malinin et al. Nature, 385, 540 (1997); Song et al. Proc. Natl.
Acad. Sci. USA, 94, 9792 (1997)). Similarly, the protein kinases
MEKK1 and MLK3 have been implicated in the induction of IKK
activity (Lee et al. Proc. Natl. Acad. Sci. USA. 95, 9319 (1998);
Hehner et al. Mol. Cell. Biol. 20, 2556 (2000)). While the specific
details remain somewhat unclear regarding how these or other
intermediate proteins may interact with and/or stimulate IKK
activity in cells, significant progress has been made in
elucidating the enzymes responsible for IkB phosphorylation. Two
IKK enzymes, generally referred to as IKK.alpha. and IKK .beta.
(Woronicz et al. Science, 278, 866 (1997); Zandi et al. Cell, 91,
243 (1997)) or IKK-1 and IKK-2 (Mercurio et al. Science, 278, 860
(1997)) have been discovered. Both forms of IKK can exist as
homodimers and as IKK.alpha./IKK .beta. heterodimers. Another
recently discovered component of the IkB kinase complex is a
regulatory protein, known as IKK-gamma or NEMO
(NF-.kappa.B-Essential Modulator) (Rothwarf et al. Nature, 395, 297
(1998)). NEMO does not contain a catalytic domain, and thus it
appears to have no direct kinase activity and it probably serves a
regulatory function. Existing data suggest that the predominant
form of IKK in cells is an IKK.alpha./IKK .beta. heterodimer
associated with either a dimer or a trimer of NEMO (Rothwarf et al.
Nature 395, 297 (1998)).
[0007] Biochemical and molecular biology experiments have clearly
identified IKK.alpha. and IKK .beta. as the most likely mediators
of TNF- and IL-1-induced IkB phosphorylation and degradation, which
results in NF-.kappa.B activation and upregulation of families of
genes involved in inflammatory processes (Woronicz et al. Science
(1997); Karin, Oncogene 18, 6867 (1999); Karin, J. Biol. Chem. 274,
27339 (1999)). IKK.alpha. and IKK.beta. have very similar primary
structures, displaying more than 50% overall sequence identity. In
the kinase domain, their sequences are 65% identical.
[0008] Based on our present understanding of the critical role
played by TNF and IL-1 in the wide array of pathological conditions
described above, and the involvement of IKK.alpha. and IKK.beta. in
the signal transduction of both cytokines, the discovery of
compounds that potently and selectively inhibit either of these
kinases would result in a major advancement in the therapy of those
conditions. In this application we describe a novel type of
compounds which displays such desirable activity.
SUMMARY OF THE INVENTION
[0009] In one aspect, the present invention provides compounds
useful in the treatment of inflammatory, metabolic or malignant
conditions, having the formula: ##STR1##
[0010] In formula I, the letters W and X independently represent N
or CH; Y represents O, S or N(R), wherein R is H, CN, NO.sub.2,
(C.sub.1-C.sub.10)alkyl, (C.sub.3-C.sub.10)cycloalkyl,
(C.sub.4-C.sub.10)cycloalkyl-alkyl, (C.sub.3-C.sub.10)alkenyl or
(C.sub.2-C.sub.10)alkynyl; and Z represents H,
(C.sub.1-C.sub.10)alkyl, (C.sub.3-C.sub.10)cycloalkyl,
(C.sub.4-C.sub.10)cycloalkyl-alkyl, (C.sub.2-C.sub.10)alkenyl,
(C.sub.2-C.sub.10)alkynyl or NR.sup.2R.sup.3.
[0011] The symbols R.sup.1, R.sup.2 and R.sup.3 are independently
H, (C.sub.1-C.sub.10)alkyl, (C.sub.3-C.sub.10)alkenyl,
(C.sub.2-C.sub.10)alkynyl, (C.sub.1-C.sub.10)heteroalkyl,
(C.sub.3-C.sub.10)cycloalkyl, (C.sub.4-C.sub.10)cycloalkyl-alkyl,
(C.sub.4-C.sub.10)cycloheteroalkyl-alkyl,
(C.sub.3-C.sub.10)cycloheteroalkyl, aryl,
aryl(C.sub.1-C.sub.4)alkyl, aryl(C.sub.1-C.sub.4)heteroalkyl,
heteroaryl(C.sub.1-C.sub.4)alkyl,
heteroaryl(C.sub.1-C.sub.4)heteroalkyl, or
perfluoro(C.sub.1-C.sub.6)alkyl. Additionally, when Z is
NR.sup.2R.sup.3, R.sup.2 and R.sup.3 can be combined to form a
heterocyclic 5- to 7-membered ring. The symbol R.sup.4 represents
H, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl,
(C.sub.4-C.sub.7)cycloalkyl-alkyl, (C.sub.2-C.sub.6)alkenyl or
(C.sub.2-C.sub.6)alkynyl.
[0012] In formula I, the letter A represents a substituted or
unsubstituted fused carbocyclic or heterocyclic ring system, the A
ring system being mono- or bicyclic wherein the mono- or bicyclic
rings are five- or six-membered rings that are aromatic or
partially or completely saturated. The letter B represents a
substituted or unsubstituted five- or six-membered ring which is
aromatic or partially or completely saturated, containing at least
one nitrogen atom, and from 0 to 3 additional heteroatoms, wherein
the B ring substituents are selected from halogen, CF.sub.3,
CF.sub.3O, (C.sub.1-C.sub.6)alkyl, perfluoro(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)thioalkoxy, amino, (C.sub.1-C.sub.6)alkylamino,
di(C.sub.1-C.sub.6)alkylamino, (C.sub.3-C.sub.10)Cycloalkyl,
(C.sub.4-C.sub.10)cycloalkyl-alkyl,
(C.sub.3-C.sub.10)cycloheteroalkyl, cyano, nitro, sulfonamido,
(C.sub.1-C.sub.6)acyl, (C.sub.1-C.sub.6)acylamino,
(C.sub.1-C.sub.6)alkoxycarbonyl,
(C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkyl, carboxamido
and (C.sub.1-C.sub.6)heteroalkoxy.
[0013] Unless otherwise indicated, the compounds provided in the
above formula are meant to include pharmaceutically acceptable
salts and prodrugs thereof.
[0014] In another aspect, the present invention provides
pharmaceutical compositions comprising one or more compounds of
formula I in admixture with a pharmaceutically acceptable carrier
or excipient.
[0015] In yet another aspect, the present invention provides
methods for the treatment of an inflammatory, metabolic or
malignant condition, comprising administering to a subject in need
of such treatment a compound of formula I.
DETAILED DESCRIPTION OF THE INVENTION
Abbreviations and Definitions
[0016] The abbreviations used herein are conventional, unless
otherwise defined.
[0017] Unless otherwise stated, the following terms used in the
specification and claims have the meanings given below:
[0018] "Acyl" means the group --C(O)R', where R' is hydrogen,
alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, aryl-alkyl, and
variations of these groups in which one or more carbon atoms have
been rep laced with heteroatoms.
[0019] "Alkyl" means a linear saturated monovalent hydrocarbon
radical or a branched saturated monovalent hydrocarbon radical
having the number of carbon atoms indicated in the prefix. For
example, (C.sub.1-C.sub.6)alkyl is meant to include methyl, ethyl,
n-propyl, 2-propyl, tert-butyl, pentyl and the like. For each of
the definitions herein (e.g., alkyl, alkenyl, alkoxy, aralkyloxy),
when a prefix is not included to indicate the number of main chain
carbon atoms in an alkyl portion, the radical or portion thereof
will have six or fewer main chain carbon atoms.
[0020] "terfluoroalkyl" refers to an alkyl group having the
indicated number of carbon atoms, in which some of the attached
hydrogen atoms have been replaced with fluorine atoms, in a number
ranging from 1 to the maximal number of hydrogen atoms on the alkyl
group.
[0021] "Alkylene" means a linear saturated divalent hydrocarbon
radical or a branched saturated divalent hydrocarbon radical having
the number of carbon atoms indicated in the prefix. For example,
(C.sub.1-C.sub.6)alkylene is meant to include methylene, ethylene,
propylene, 2-methylpropylene, pentylene, and the like.
[0022] "Alkenyl" means a linear monovalent hydrocarbon radical or a
branched monovalent hydrocarbon radical having the number of carbon
atoms indicated in the prefix and containing at least one double
bond. For example, (C.sub.2-C.sub.6)alkenyl is meant to include,
ethenyl, propenyl, and the like.
[0023] "Alkynyl" means a linear monovalent hydrocarbon radical or a
branched monovalent hydrocarbon radical containing at least one
triple bond and having the number of carbon atoms indicated in the
prefix. For example, (C.sub.2-C.sub.6)alkynyl is meant to include
ethynyl propynyl and the like.
[0024] "Alkoxy", "aryloxy", "aralkyloxy", or "heteroaralkyloxy"
means a radical --OR where R is an alkyl, aryl, aralkyl, or
heteroaralkyl respectively, as defined herein, e.g., methoxy,
phenoxy, benzyloxy, pyridin-2-ylmethyloxy, and the like.
[0025] "Alkoxycarbonylalkyl" means a radical --R.sup.aC(O)R.sup.b
where R.sup.a is an alkylene group as defined above and R.sup.b is
an alkoxy group as defined above, e.g., methoxycarbonylethyl,
ethoxycarbonylbutyl, and the like.
[0026] "Aryl" means a monovalent monocyclic or bicyclic aromatic
hydrocarbon radical of 6 to 10 ring atoms which is substituted
independently with one to four substituents, preferably one, two,
or three substituents selected from alkyl, cycloalkyl,
cycloalkyl-alkyl, halo, nitro, cyano, hydroxy, alkoxy, amino,
acylamino, mono-alkylamino, di-alkylamino, haloalkyl, haloalkoxy,
heteroalkyl, COR (where R is hydrogen, alkyl, cycloalkyl,
cycloalkyl-alkyl, phenyl or phenylalkyl), --(CR'R'').sub.n--COOR
(where n is an integer from 0 to 5, R' and R'' are independently
hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl,
cycloalkylalkyl, phenyl or phenylalkyl) or
--(CR'R'').sub.n--CONR.sup.aR.sup.b (where n is an integer from 0
to 5, R' and R'' are independently hydrogen or alkyl, and R.sup.a
and R.sup.b are, independently of each other, hydrogen, alkyl,
cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl). More
specifically the term aryl includes, but is not limited to, phenyl
biphenyl, 1-naphthyl and 2-naphthyl, and the derivatives
thereof.
[0027] "Aralkyl" means a radical --R.sup.aR.sup.b where R.sup.a is
an alkylene group (having six or fewer main chain carbon atoms) and
R.sup.b is an aryl group as defined herein, e.g., benzyl,
phenylethyl 3-(3-chlorophenyl)-2-methylpentyl and the like.
[0028] "Aralkenyl" means a radical --R.sup.aR.sup.b where R.sup.a
is an alkenylene group and R.sup.b is an aryl group as defined
herein, e.g., 3-phenyl-2-propenyl, and the like.
[0029] "Arylheteroalkyl" means a radical --R.sup.aR.sup.b where
R.sup.a is an heteroalkylene group and R.sup.b is an aryl group as
defined herein, e.g., 2-hydroxy-2-phenyl-ethyl,
2-hydroxy-1-hydroxymethyl-2-phenyl-ethyl, and the like.
[0030] "Cycloalkyl" means a saturated monovalent cyclic hydrocarbon
radical of three to seven ring carbons. The cycloalkyl may be
optionally substituted independently with one, two, or three
substituents selected from alkyl, optionally substituted phenyl, or
--C(O)R (where R is hydrogen, alkyl, haloalkyl, amino, acylamino,
mono-alkylamino, di-alkylamino, hydroxy, alkoxy, or optionally
substituted phenyl). More specifically, the term cycloalkyl
includes, for example, cyclopropyl, cyclohexyl, phenylcyclohexyl,
4-carboxycyclohexyl, 2-carboxamidocyclohexyl,
2-dimethylaminocarbonyl-cyclohexyl, and the like.
[0031] "Cycloalkyl-alkyl" means a radical --R.sup.aR.sup.b where
R.sup.a is an alkylene group and R.sup.b is a cycloalkyl group as
defined herein, e.g., cyclopropylmethyl, cyclohexylpropyl,
3-cyclohexyl-2-methylpropyl, and the like. The prefix indicating
the number of carbon atoms (e.g., C.sub.4-C.sub.10) refers to the
total number of carbon atoms from both the cycloalkyl portion and
the alkyl portion.
[0032] "Haloalkyl" means alkyl substituted with one or more same or
different halo atoms, e.g., --CH.sub.2Cl, --CF.sub.3,
--CH.sub.2CF.sub.3, --CH.sub.2CCl.sub.3, and the like, and further
includes those alkyl groups such as perfluoroalkyl in which all
hydrogen atoms are replaced by fluorine atoms. The prefix "halo"
and the term "halogen" when used to describe a substituent, refer
to --F, --Cl, --Br and --I.
[0033] "Heteroalkyl" means an alkyl radical as defined herein with
one, two or three substituents independently selected from cyano,
--OR.sup.a, --NR.sup.bR.sup.c, and --S(O).sub.nR.sup.d (where n is
an integer from 0 to 2), with the understanding that the point of
attachment of the heteroalkyl radical is through a carbon atom of
the heteroalkyl radical. R.sup.a is hydrogen, alkyl, cycloalkyl,
cycloalkyl-alkyl, aryl, aralkyl, alkoxycarbonyl, aryloxycarbonyl,
carboxamido, or mono- or di-alkylcarbamoyl. R.sup.b is hydrogen,
alkyl, cycloalkyl, cycloalkyl-alkyl, aryl or aralkyl. R.sup.c is
hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl,
alkoxycarbonyl, aryloxycarbonyl, carboxamido, mono- or
di-alkylcarbamoyl or alkylsulfonyl. R.sup.d is hydrogen (provided
that n is 0), alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl,
amino, mono-alkylamino, di-alkylamino, or hydroxyalkyl.
Representative examples include, for example, 2-hydroxyethyl,
2,3-dihydroxypropyl, 2-methoxyethyl, benzyloxymethyl, 2-cyanoethyl,
and 2-methylsulfonyl-ethyl. For each of the above, R.sup.a,
R.sup.b,R.sup.c, and R.sup.d can be further substituted by
NH.sub.2, fluorine, alkylamino, di-alkylamino, OH or alkoxy.
Additionally, the prefix indicating the number of carbon atoms
(e.g., C.sub.1-C.sub.10) refers to the total number of carbon atoms
in the portion of the heteroalkyl group exclusive of the cyano,
--OR.sup.a, --NR.sup.bR.sup.c, or --S(O).sub.nR.sup.d portions.
[0034] "Heteroaryl" means a monovalent monocyclic or bicyclic
radical of 5 to 12 ring atoms having at least one aromatic ring
containing one, two, or three ring heteroatoms selected from N, O,
or S, the remaining ring atoms being C, with the understanding that
the attachment point of the heteroaryl radical will be on an
aromatic ring. The heteroaryl ring is optionally substituted
independently with one to four substituents, preferably one or two
substituents, selected from alkyl, cycloalkyl, cycloalkyl-alkyl,
halo, nitro, cyano, hydroxy, alkoxy, amino, acylamino,
mono-alkylamino, di-alkylamino, haloalkyl, haloalkoxy, heteroalkyl,
--COR (where R is hydrogen, alkyl, phenyl or phenylalkyl,
--(CR'R'').sub.n--COOR (where n is an integer from 0 to 5, R' and
R'' are independently hydrogen or alkyl, and R is hydrogen, alkyl,
cycloalkyl, cycloalkyl-alkyl, phenyl or phenylalkyl), or
--(CR'R'').sub.n-CONR.sup.aR.sup.b (where n is an integer from 0 to
5, R' and R'' are independently hydrogen or alkyl, and R.sup.a and
R.sup.b are, independently of each other, hydrogen, alkyl,
cycloalkyl cycloalkyl-alkyl, phenyl or phenylalkyl). More
specifically the term heteroaryl includes, but is not limited to,
pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl,
imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyridazinyl,
pyrimidinyl, benzofuranyl, tetrahydrobenzofuranyl, isobenzofuranyl,
benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl,
isoindolyl, benzoxazolyl, quinolyl, tetrahydroquinolinyl,
isoquinolyl, benzimidazolyl, benzisoxazolyl or benzothienyl, and
the derivatives thereof.
[0035] "Heteroaralkyl" means a radical --R.sup.aR.sup.b where
R.sup.a is an alkylene group and R.sup.b is a heteroaryl group as
defined herein, e.g., pyridin-3-ylmethyl,
3-(benzofuran-2-yl)propyl, and the like.
[0036] "Heteroaralkenyl" means a radical --R.sup.aR.sup.b where
R.sup.a is an alkenylene group and R.sup.b is a heteroaryl group as
defined herein, e.g., 3-(pyridin-3-yl)propen-2-yl, and the
like.
[0037] "Heterocyclyl" or "cycloheteroalkyl" means a saturated or
unsaturated non-aromatic cyclic radical of 3 to 8 ring atoms in
which one or two ring atoms are heteroatoms selected from O, NR
(where R is independently hydrogen or alkyl) or S(O).sub.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 heterocyclyl ring may be optionally substituted independently
with one, two, or three substituents selected from alkyl,
cycloalkyl, cycloalkyl-alkyl, halo, nitro, cyano, hydroxy, alkoxy,
amino, mono-alkylamino, di-alkylamino, haloalkyl, haloalkoxy, --COR
(where R is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, phenyl
or phenylalkyl), --(CR'R'').sub.n--COOR (n is an integer from 0 to
5, R' and R'' are independently hydrogen or alkyl, and R is
hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, phenyl or
phenylalkyl), or --(CR'R'').sub.n--CONR.sup.aR.sup.b (where n is an
integer from 0 to 5, R' and R'' are independently hydrogen or
alkyl, R.sup.a and R.sup.b are, independently of each other,
hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or
phenylalkyl). More specifically the term heterocyclyl includes, but
is not limited to, tetrahydropyranyl, piperidino,
N-methylpiperidin-3-yl, piperazino, N-methylpyrrolidin-3-yl,
3-pyrrolidino, 2-pyrrolidon-1-yl, morpholino, thiomorpholino,
thiomorpholino-1-oxide, thiomorpholino-1,1-dioxide, pyrrolidinyl,
and the derivatives thereof. The prefix indicating the number of
carbon atoms (e.g., C.sub.3-C.sub.10) refers to the total number of
carbon atoms in the portion of the cycloheteroalkyl or heterocyclyl
group exclusive of the number of heteroatoms.
[0038] "Heterocyclylalkyl" or "Cycloheteroalkyl-alkyl" means a
radical --R.sup.aR.sup.b where R.sup.a is an alkylene group and
R.sup.b is a heterocyclyl group as defined herein, e.g.,
tetrahydropyran-2-ylmethyl, 4-methylpiperazin-1-ylethyl,
3-piperidinylmethyl, and the like.
[0039] "Heteroalkylene" means a linear saturated divalent
hydrocarbon radical of one to six carbons or a branched saturated
hydrocarbon radical of three to six carbon atoms with one, two or
three substituents independently selected from --OR.sup.a,
--NR.sup.bR.sup.c, and --S(O).sub.nR.sup.d (where n is an integer
from 0 to 2) where, R.sup.a, Rb, Rc, and R.sup.d are as defined
herein for a heteroalkyl radical. Examples include,
2-hydroxyethan-1,2-diyl, 2-hydroxypropan-1,3-diyl and the like.
[0040] "Heterosubstituted cycloalkyl" means a cycloalkyl group
wherein one, two, or three hydrogen atoms are replaced by
substituents independently selected from the group consisting of
cyano, hydroxy, alkoxy, amino, acylamino, mono-alkylamino,
di-alkylamino, or --SO.sub.nR (where n is an integer from 0 to 2
and when n is 0, R is hydrogen or alkyl and when n is 1 or 2, R is
alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl,
amino, acylamino, mono-alkylamino, di-alkylamino, or hydroxyalkyl).
Examples include 4-hydroxycyclohexyl, 2-aminocyclohexyl etc.
[0041] "Heteroalkyl substituted cycloalkyl" means a cycloalkyl
group wherein one, two, or three hydrogen atoms are replaced
independently by heteroalkyl groups, with the understanding that
the heteroalkyl group is attached to the cycloalkyl group via a
carbon-carbon bond. Examples include
1-hydroxymethyl-cyclopent-1-yl, 2-hydroxymethyl-cyclohex-2-yl and
the like.
[0042] "Heteroalkyl substituted heterocycly" means a heterocyclyl
group wherein one, two, or three hydrogen atoms are replaced
independently by heteroalkyl groups, with the understanding that
the heteroalkyl group is attached to the heterocyclyl group via a
carbon-carbon bond. Examples include
4-hydroxymethyl-piperidin-1-yl, and the like.
[0043] "Hydroxyalkyl" means an alkyl radical as defined herein,
substituted with one or more, preferably one, two or three hydroxy
groups, provided that the same carbon atom does not carry more than
one hydroxy group. Representative examples include, but are not
limited to, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl,
1-hydroxymethyl-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl,
4-hydroxybutyl, 2,3-dihydroxypropyl,
1-hydroxymethyl-2-hydroxyethyl, 2,3-dihydroxybutyl,
3,4dihydroxybutyl and 2-hydroxymethyl-3-hydroxypropyl, preferably
2-hydroxyethyl, 2,3-dihydroxypropyl and
1-hydroxymethyl-2-hydroxyethyl. Accordingly, as used herein, the
term "hydroxyalkyl" is used to define a subset of heteroalkyl
groups.
[0044] "Optionally substituted phenyl" means a phenyl ring which is
optionally substituted independently with one to four substituents,
preferably one or two substituents selected from alkyl, cycloalkyl,
cycloalkyl-alkyl, halo, nitro, cyano, hydroxy, alkoxy, amino,
acylamino, mono-alkylamino, di-alkylamino, haloalkyl, haloalkoxy,
heteroalkyl, --COR (where R is hydrogen, alkyl, phenyl or
phenylalkyl, --(CR'R'').sub.n--COOR (where n is an integer from 0
to 5, R' and R'' are independently hydrogen or alkyl, and R is
hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or
phenylalkyl), or --CR'R'').sub.n--CONR.sup.aR.sup.b (where n is an
integer from 0 to 5, R' and R'' are independently hydrogen or
alkyl, and R.sup.a and R.sup.b are, independently of each other,
hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or
phenylalkyl).
[0045] The terms "modulate", "modulation" and the like refer to the
ability of a compound to increase or decrease the function and/or
expression of IKK, where IKK function may include kinase activity
and/or protein-binding. Modulation may occur in vitro or in vivo.
Modulation, as described herein, includes the inhibition or
activation of IKK function and/or the downregulation or
upregulation of IKK expression, either directly or indirectly. A
modulator preferably activates IKK function and/or upregulates IKK
expression. More preferably, a modulator activates or inhibits IKK
function and/or upregulates or downregulates IKK expression. Most
preferably, a modulator inhibits IKK function and/or downregulates
IKK expression. The ability of a compound to inhibit IKK function
can be demonstrated in an enzymatic assay or a cell-based assay
(e.g., inhibition of IL-1-stimulated NF-.kappa.B activation).
[0046] "Leaving group" has the meaning conventionally associated
with it in synthetic organic chemistry i.e., an atom or group
capable of being displaced by a nucleophile and includes halo (such
as chloro, bromo, iodo), alkanesulfonyloxy, arenesulfonyloxy,
alkylcarbonyloxy (e.g., acetoxy), arylcarbonyloxy, mesyloxy,
tosyloxy, trifluoromethanesulfonyloxy, aryloxy (e.g.,
2,4-dinitrophenoxy), methoxy, N,O- dimethylhydroxylamino, and the
like.
[0047] "Pharmaceutically acceptable carrier or excipient" means a
carrier or excipient that is useful in preparing a pharmaceutical
composition that is generally safe, non-toxic and neither
biologically nor otherwise undesirable, and includes a carrier or
excipient that is acceptable for veterinary use as well as human
pharmaceutical use. A "pharmaceutically acceptable carrier or
excipient" as used in the specification and claims includes both
one and more than one such carrier or excipient.
[0048] "Pharmaceutically acceptable salt" of a compound means a
salt that is pharmaceutically acceptable and that possesses the
desired pharmacological activity of the parent compound. Such salts
include:
[0049] (1) acid addition salts, formed with inorganic acids such as
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid, and the like; or formed with organic acids such as
acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic
acid, glycolic acid, pyruvic acid, lactic acid, malonic acid,
succinic acid, malic acid, maleic acid, fumaric acid, tartaric
acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid,
cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic
acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid,
benzenesulfonic acid, 4-chlorobenzenesulfonic acid,
2-napthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic
acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid,
glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid,
tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid,
glutamic acid, hydroxynapthoic acid, salicylic acid, stearic acid,
muconic acid, and the like; or
[0050] (2) salts formed when an acidic proton present in the parent
compound either is replaced by a metal ion, e.g., an alkali metal
ion, an alkaline earth ion, or an aluminum ion; or coordinates with
an organic base such as ethanolamine, diethanolamine,
triethanolamine, trimethylamine, N-methylglucamine, and the
like.
[0051] "Prodrugs" 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 I wherein a hydroxy, amino, or sulfhydryl
group in a compound of formula 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.
[0052] "Protecting group" refers to a grouping of atoms that when
attached to a reactive group in a molecule masks, reduces or
prevents that reactivity. Examples of protecting groups can be
found in T. W. Greene and P. G. Futs, Protective Groups in Organic
Chemistry, (Wiley, 2nd ed. 1991) and Harrison and Harrison et al.,
Compendium of Synthetic Organic Methods, Vols. 1-8 (John Wiley and
Sons. 1971-1996). Representative amino protecting groups include
formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ),
tert-butoxycarbonyl (Boc), trimethyl silyl (TMS),
2-trimethylsilyl-ethanesulfonyl (SES), trityl and substituted
trityl groups, alkyloxycarbonyl, 9-fluorenylmethyloxycarbonyl
(FMOC), nitro-veratryloxycarbonyl (NVOC) and the like.
Representative hydroxy protecting groups include those where the
hydroxy group is either acylated or alkylated such as benzyl and
trityl ethers as well as alkyl ethers, tetrahydropyranyl ethers,
trialkylsilyl ethers and allyl ethers.
[0053] "Treating" or "treatment" of a disease includes: [0054] (1)
preventing the disease, i.e., causing the clinical symptoms of the
disease not to develop in a mammal that may be exposed to or
predisposed to the disease but does not yet experience or display
symptoms of the disease, [0055] (2) inhibiting the disease, i.e.,
arresting or reducing the development of the disease or its
clinical symptoms, or [0056] (3) relieving the disease, i.e.,
causing regression of the disease or its clinical symptoms.
[0057] As used herein, the term "IKK-mediated condition or disease"
and related terms and phrases refer to a condition or disorder
characterized by inappropriate, e.g., less than or greater than
normal, IKK activity. Inappropriate IKK functional activity might
arise as the result of IKK expression in cells which normally do
not express IKK, increased IKK expression (leading to, e.g.,
inflammatory and immunoregulatory disorders and diseases) or
decreased IKK expression. An IKK-mediated condition or disease may
be completely or partially mediated by inappropriate IKK functional
activity. However, an IKK-mediated condition or disease is one in
which modulation of IKK results in some effect on the underlying
condition or disorder (e.g., an IKK inhibitor results in some
improvement in patient well-being in at least some patients).
[0058] The term "therapeutically effective amount" means the amount
of the subject compound that will elicit the biological or medical
response of a tissue, system, animal or human that is being sought
by the researcher, veterinarian, medical doctor or other clinician.
"A therapeutically effective amount" includes the amount of a
compound that, when administered to a mammal for treating a
disease, is sufficient to effect such treatment for the disease.
The "therapeutically effective amount" will vary depending on the
compound, the disease and its severity and the age, weight, etc.,
of the mammal to be treated.
[0059] "Optional" or "optionally" in the above definitions means
that the subsequently described event or circumstance may but need
not occur, and that the description includes instances where the
event or circumstance occurs and instances in which it does not.
For example, "heterocyclo group optionally mono- or di-substituted
with an alkyl group" means that the alkyl may but need not be
present, and the description includes situations where the
heterocyclo group is mono- or disubstituted with an alkyl group and
situations where the heterocyclo group is not substituted with the
alkyl group.
[0060] Compounds that have the same molecular formula but differ in
the nature or sequence of bonding of their atoms or the arrangement
of their atoms in space are termed "isomers". Isomers that differ
in the arrangement of their atoms in space are termed
"stereoisomers". Stereoisomers that are not mirror images of one
another are termed "diastereomers" and those that are
non-superimposable mirror images of each other are termed
"enantiomers". When a compound has an asymmetric center, for
example, it is bonded to four different groups, a pair of
enantiomers is possible. An enantiomer can be characterized by the
absolute configuration of its asymmetric center and is described by
the R- and S-sequencing rules of Cahn and Prelog, or by the manner
in which the molecule rotates the plane of polarized light and
designated as dextrorotatory or levorotatory (i.e., as (+) or
(-)-isomers respectively). A chiral compound can exist as either
individual enantiomer or as a mixture thereof. A mixture containing
equal proportions of the enantiomers is called a "racemic
mixture".
[0061] The compounds of this invention may exist in stereoisomeric
form if they possess one or more asymmetric centers or a double
bond with asymmetric substitution and, therefore, can be produced
as individual stereoisomers or as mixtures. Unless otherwise
indicated, the description is intended to include individual
stereoisomers as well as mixtures. The methods for the
determination of stereochemistry and the separation of
stereoisomers are well-known in the art (see discussion in Chapter
4 of "Advanced Organic Chemistry", 4th edition J. March, John Wiley
and Sons, New York, 1992).
[0062] The compounds of the present invention can also be produced
in radiolabeled form and are useful in assays for evaluating the
binding capabilities of compounds that interact with IKK.alpha. and
with IKK.beta..
Embodiments of the Invention
Compounds
[0063] In one aspect, the present invention provides compounds
useful in the treatment of inflammatory, metabolic or malignant
conditions, having the formula: ##STR2##
[0064] In formula I, the letters W and X independently represent N
or CH; Y represents O, S or N(R), wherein R is H, CN, NO.sub.2,
(C.sub.1-C.sub.10)alkyl, (C.sub.3-C.sub.10)cycloalkyl,
(C.sub.4-C.sub.10)cycloalkyl-alkyl, (C.sub.3-C.sub.10)alkenyl or
(C.sub.2-C.sub.10)alkynyl; and Z represents H,
(C.sub.1-C.sub.10)alkyl, (C.sub.3-C.sub.10)cycloalkyl,
(C.sub.4-C.sub.10)cycloalkyl-alkyl, (C.sub.2-C.sub.10)alkenyl,
(C.sub.2-C.sub.10)alkynyl or NR.sup.2R.sup.3.
[0065] The symbols R.sup.1, R.sup.2 and R.sup.3 are independently
H, (C.sub.1-C.sub.10)alkyl, (C.sub.3-C.sub.10)alkenyl,
(C.sub.2-C.sub.10)alkynyl, (C.sub.1-C.sub.10)heteroalkyl,
(C.sub.3-C.sub.10)cycloalkyl, (C.sub.4-C.sub.10)cycloalkyl-alkyl,
(C.sub.4-C.sub.10)cycloheteroalkyl-alkyl,
(C.sub.3-C.sub.10)cycloheteroalkyl, aryl,
aryl(C.sub.1-C.sub.4)alkyl, aryl(C.sub.1-C.sub.4)heteroalkyl,
heteroaryl(C.sub.1-C.sub.4)alkyl, heteroaryl(C.sub.1
C.sub.4)heteroalkyl or perfluoro(C.sub.1-C.sub.6)alkyl.
Additionally, when Z is NR.sup.2R.sup.3, R.sup.2 and R.sup.3 can be
combined to form a 5- to 7-membered heterocyclyl ring. The symbol
R.sup.4 represents H, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.6)cycloalkyl, (C.sub.4-C.sub.7)cycloalkyl-alkyl,
(C.sub.2-C.sub.6)alkenyl or (C.sub.2-C.sub.6)alkynyl.
[0066] In formula I, the letter A represents a substituted or
unsubstituted fused carbocyclic or heterocyclic ring system, the A
ring system being mono- or bicyclic wherein the mono- or bicyclic
rings are five- or six-membered rings that are aromatic or
partially or completely saturated.
[0067] In preferred embodiments, the letter A represents a fused
ring selected from: ##STR3## wherein R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 are independently selected from H, halogen, CF.sub.3,
CF.sub.3O, (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)heteroalkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)thioalkoxy, amino,
(C.sub.1-C.sub.6)alkylamino, di(C.sub.1-C.sub.6)alkylamino,
(C.sub.3-C.sub.10)cycloalkyl, (C.sub.4-C.sub.10)cycloalkyl-alkyl,
(C.sub.3-C.sub.10)cycloheteroalkyl,
(C.sub.3-C.sub.10)cycloheteroalkyl-alkyl, cyano, nitro,
(C.sub.1-C.sub.6)acyl, (C.sub.1-.sub.6)acylamino,
(C.sub.1-C.sub.6)alkoxycarbonyl,
(C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkyl, CONH.sub.2,
CO--NH--(C.sub.1-C.sub.6)alkyl,
CO--N[(C.sub.1-C.sub.6)aklyl].sub.2, SO.sub.2NH.sub.2,
SO.sub.2NH--(C.sub.1-C.sub.6)alkyl,
SO.sub.2N--[(C.sub.1-C.sub.6)alkyl].sub.2 and
(C.sub.1-C.sub.6)heteroalkoxy; or two adjacent R groups selected
from R.sup.5, R.sup.6, R.sup.7 and R.sup.8 can be linked together
to form a new 5- or 6-membered carbocyclic or heterocyclic ring.
Additionally, any of the R.sup.5, R.sup.6, R.sup.7 and R.sup.8
groups can be optionally substituted by 1 to 3 of the following:
CN, (C.sub.1-C.sub.6)alkyl-SO.sub.2,
(C.sub.1-C.sub.6)heteroalkyl-SO.sub.2, CONH.sub.2,
CO--NH--(C.sub.1-C.sub.6)alkyl,
CO--N[(C.sub.1-C.sub.6)alkyl].sub.2, SO.sub.2NH.sub.2,
SO.sub.2NH--(C.sub.1-C.sub.6)alkyl, or
SO.sub.2N--[(C.sub.1-C.sub.6)alkyl].sub.2.
[0068] The letter B represents a substituted or unsubstituted five-
or six-membered ring which is aromatic or partially or completely
saturated, containing at least one nitrogen atom, and from 0 to 3
additional heteroatoms, wherein the B ring substituents are
selected from halogen, CF.sub.3, CF.sub.3O, (C.sub.1-C.sub.6)alkyl,
perfluoro(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)heteroalkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)thioalkoxy, amino,
(C.sub.1-C.sub.6)alkylamino, di(C.sub.1-C.sub.6)alkylamino,
(C.sub.3-C.sub.10)cycloalkyl, (C.sub.4-C.sub.10)cycloalkyl-alkyl,
(C.sub.3-C.sub.10)cycloheteroalkyl, cyano, nitro, sulfonamido,
(C.sub.1-C.sub.6)acyl, (C.sub.1-C.sub.6)acylamino,
(C.sub.1-C.sub.6)alkoxycarbonyl,
(C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkyl, carboxamido
and (C.sub.1-C.sub.6)heteroalkoxy.
[0069] Preferably, B contains a nitrogen atom at a position two
atoms away from the atom attaching B to the remainder of the
molecule or a nitrogen atom at the point of attachment of B to the
remainder of the molecule. More preferably, B is selected from
substituted or unsubstituted imidazolyl, substituted or
unsubstituted thiazolyl and substituted or unsubstituted triazolyl.
Still more preferably, B is selected from 1-methylimidazol-5-yl,
1-(trifluoromethyl)imidazol-5-yl, 5-methylimidazol-1-yl,
5-(trifluoromethyl)imidazol-1-yl, thiazol-5-yl, imidazol-1-yl,
1-methyl-1,3,4-triazolyl, and 4-methyl-1,2,4-triazol-3-yl.
[0070] In one group of embodiments, W is N and X is CH. Within this
group of embodiments, Y is preferably O or S. More preferably,
R.sup.4 is H or CH.sub.3. Still more preferably, A is selected
from: ##STR4## wherein the symbols R.sup.5, R.sup.6 and R.sup.7
have the meanings provided above, and R.sup.8 is H. Also preferred
in this group of embodiments are those in which B contains a
nitrogen atom at a position two atoms away from the atom attaching
B to the remainder of the molecule. More preferably, B is
substituted or unsubstituted imidazolyl, substituted or
unsubstituted thiazolyl and substituted or unsubstituted triazolyl.
Still more preferably, B is selected from 1-methylimidazol-5-yl,
1-(trifluoromethyl)imidazol-5-yl, 5-methylimidazol-1-yl,
5-(trifluoromethyl)imidazol-1-yl, thiazol-5-yl, imidazol-1-yl,
1-methyl-1,3,4-triazolyl, and 4-methyl-1,2,4-triazol-3-yl.
[0071] In another group of embodiments, W is N and X is CH. Within
this group of embodiments, Y is preferably O or S. More preferably,
Z is NR.sup.2R.sup.3.
[0072] In another group of embodiments, W is N and X is N. In still
another group of embodiments, W is CH and X is N. In yet another
group of embodiments, W and X are both CH.
[0073] In yet another group of preferred embodiments, Y is S; Z is
NH2; and R.sup.1 is (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)heteroalkyl or
(C.sub.3-C.sub.10)cycloheteroalkyl-alkyl. In this group of
embodiments, preferred groups for each of A and B are the same as
have been described above.
[0074] In yet another group of preferred embodiments, Y is S; Z is
NH.sub.2; and R.sup.1 is CH.sub.3. In this group of embodiments,
preferred groups for each of A and B are the same as have been
described above.
[0075] In another group of preferred embodiments, W is N; X is CH;
Y is O or S; Z is H, CH.sub.3, NH.sub.2 or NHCH.sub.3; R.sup.1 is
H, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.10)heteroalkyl,
(C.sub.4-C.sub.10)cycloheteroalkyl-alkyl,
(C.sub.3-C.sub.10)cycloheteroalkyl, aryl(C.sub.1-C.sub.4)alkyl,
aryl(C.sub.1-C.sub.4)heteroalkyl, heteroaryl(C.sub.1-C.sub.4)alkyl,
heteroaryl(C.sub.1-C.sub.4)heteroalkyl, or
perfluoro(C.sub.1-C.sub.6)alkyl; R.sup.4 is H; A represents
##STR5## wherein R.sup.6 and R.sup.7 are independently selected
from H, halogen, CF.sub.3, CF.sub.3O, (C.sub.1-C.sub.4)alkyl,
(C.sub.2-C.sub.4)alkenyl, (C.sub.2-C.sub.4)alkynyl,
(C.sub.1-C.sub.4)heteroalkyl,
(C.sub.3-C.sub.10)cycloheteroalkyl-alkyl and cyano; B represents a
five-membered aromatic ring system containing at least one nitrogen
atom. Preferably, B contains 1-2 nitrogen atoms and 0-1 sulfur
atoms. Most preferably, B is unsubstituted or substituted by
(C.sub.1-C.sub.3)alkyl, CF.sub.3, cyano, or halogen. Most preferred
in this group of embodiments are compounds in which Z is NH.sub.2;
R.sup.6 is H, halogen, CF.sub.3, CF.sub.3O, (C.sub.1-C.sub.4)alkyl,
(C.sub.2-C.sub.4)alkenyl, (C.sub.1-C.sub.4)heteroalkyl,
(C.sub.3-C.sub.10)cycloheteroalkyl-alkyl or cyano, and the alkyl,
alkenyl and heteroalkyl groups optionally bear additional
substituents selected from cyano, carboxamido,
(C.sub.1-C.sub.3)alkylsulfonyl or (C.sub.1-C.sub.3)alkoxy; and
R.sup.7 is H, halogen, CF.sub.3, CF.sub.3O, (C.sub.1-C.sub.4)alkyl,
(C.sub.2-C.sub.4)alkenyl, (C.sub.2-C.sub.4)alkynyl,
(C.sub.1-C.sub.4)heteroalkyl or cyano.
[0076] In another group of preferred embodiments, Z is NH.sub.2;
R.sup.6 is H, halogen, CF.sub.3, CF.sub.3O, (C.sub.1-C.sub.4)alkyl,
(C.sub.2-C.sub.4)alkenyl, (C.sub.1-C.sub.4)heteroalkyl,
(C.sub.3-C.sub.10)cycloheteroalkyl-alkyl or cyano, wherein the
alkyl, alkenyl and heteroalkyl groups optionally bear additional
substituents selected from cyano,
carboxamido,(C.sub.1-C.sub.3)alkylsulfonyl or
(C.sub.1-C.sub.3)alkoxy; and R.sup.7 is H, halogen, CF.sub.3,
CF.sub.3O, (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl,
(C.sub.2-C.sub.4)alkynyl, (C.sub.1-C.sub.4)heteroalkyl or cyano.
Within this group of embodiments, R.sup.7 is preferably H, halogen,
CF.sub.3 and (C.sub.1-C.sub.4)alkyl. In particularly preferred
embodiments, R.sup.6 is CH.sub.2(CH.sub.2).sub.mCN,
CH.sub.2(CH.sub.2).sub.nSO.sub.2CH.sub.3 or
CH.sub.2(CH.sub.2).sub.nOCH.sub.3, wherein the subscript n is an
integer from 0 to 2 Also particularly preferred are embodiments in
which R.sup.6 is ##STR6##
[0077] Yet another group of preferred embodiments is represented by
the formula: ##STR7## wherein Y is O, S or N--CN; W' is
N(CH.sub.3), N(CF.sub.3), N(CH.sub.2CH.sub.3), O or S; the
subscripts n and n' are independently integers from 0 to 3;
R.sup.7is H, halogen, CF.sub.3, CF.sub.3O, (C.sub.1-C.sub.4)alkyl,
(C.sub.2-C.sub.4)alkenyl, (C.sub.2-C.sub.4)alkynyl,
(C.sub.1-C.sub.4)heteroalkyl or cyano; R.sup.9 is CN, CONH.sub.2,
CO--NH--(C.sub.1-C.sub.6)alkyl,
CO--N[(C.sub.1-C.sub.6)alkyl].sub.2,
CO--NH--(C.sub.1-C.sub.6)heteroalkyl,
CO--N[(C.sub.1-C.sub.6)heteroalkyl].sub.2,
S(O).sub.n''--(C.sub.1-C.sub.6)alkyl,
S(O).sub.n''(C.sub.1-C.sub.6)heteroalkyl, heteroaryl,
(C.sub.1-C.sub.6)alkoxy or (C.sub.3-C.sub.6)cycloheteroalkyl,
wherein each n'' is independently an integer of 0 to 2; R.sup.10 is
NH.sub.2, NH--(C.sub.1-C.sub.6)alkyl,
N[(C.sub.1-C.sub.6)alkyl].sub.2, NH--(C.sub.1-C.sub.6)heteroalkyl,
N[(C.sub.1-C.sub.6)heteroalkyl].sub.2,
(C.sub.1-C.sub.6)heteroalkyl, S(O).sub.n''--(C.sub.1-C.sub.6)alkyl,
S(O).sub.n''--(C.sub.1-C.sub.6)heteroalkyl, aryl, heteroaryl,
O--(C.sub.1-C.sub.6)alkyl, O--(C.sub.1-C.sub.6)heteroalkyl or
(C.sub.3-C.sub.8)cycloheteroalkyl; and R.sup.11 is H, CF.sub.3,
NH.sub.2, NH--(C.sub.1-C.sub.6)alkyl,
N[(C.sub.1-C.sub.6)alkyl].sub.2, halogen or (C.sub.1-C.sub.3)alkyl.
Most preferably, Y is O or S; W' is N--CH.sub.3; n is 2; n' is 1 to
3; R.sup.9 is cyano, CONH.sub.2, (C.sub.1-C.sub.6)alkoxy,
(C.sub.3-C.sub.6)cycloheteroalkyl or
SO.sub.2-(C.sub.1-C.sub.6)alkyl; R.sup.10 is
NH--(C.sub.1-C.sub.6)alkyl, N[(C.sub.1-C.sub.6)alkyl].sub.2,
NH--(C.sub.1-C.sub.6)heteroalkyl,
N[(C.sub.1-C.sub.6)heteroalkyl].sub.2, O--(C.sub.1-C.sub.6)alkyl,
O--(C.sub.1-C.sub.6)heteroalkyl, (C.sub.1-C.sub.6)alkoxy or
(C.sub.3-C.sub.8)cycloheteroalkyl; and R.sup.11 is H.
[0078] Exemplary structures within this preferred group of
embodiments are: ##STR8## ##STR9## ##STR10## ##STR11## Preparation
of Compounds of Formula I General Scheme for Synthesis
##STR12##
[0079] The synthesis of the target compounds is generally
accomplished by reaction of the appropriate aldehyde (or ketone,
when R.sup.4 is other than H) ii with the appropriately substituted
hydrazine derivative. In some cases, the aldehyde (or ketone)
intermediate ii is not fully isolated and/or characterized, but is
simply synthesized from the corresponding ester i (or similar
compound with the appropriate functional group) and utilized
directly in the final reaction. The final products can be isolated,
and purified if necessary, either by filtration, recrystallization,
and/or chromatography, as appropriate.
[0080] The starting esters can be prepared by a variety of methods
generally known to those skilled in the art of organic synthesis.
Representative methods (Methods A-O) for the synthesis of these
ester intermediates are provided in the Examples below.
[0081] In view of these preparative methods, the present invention
further provides methods of preparing antiinflammation agents,
comprising contacting a precursor compound having the formula:
##STR13## wherein W and X are independently selected from the group
consisting of N and CH; R.sup.4 is selected from the group
consisting of H, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.6)cycloalkyl, (C.sub.4-C.sub.7)cycloalkyl-alkyl,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl; A is a
substituted or unsubstituted fused carbocyclic or heterocyclic ring
system, the ring system being mono- or bicyclic wherein the mono-
or bicyclic rings are selected from the group consisting of five-
and six-membered rings that are aromatic or partially or completely
saturated; and B is a substituted or unsubstituted five- or
six-membered ring which is aromatic or partially or completely
saturated, containing at least one nitrogen atom, and from 0 to 3
additional heteroatoms, wherein the B ring substituents are
selected from halogen, CF.sub.3, CF.sub.3O, (C.sub.1-C.sub.6)alkyl
perfluoro(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)heteroalkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)thioalkoxy, amino,
(C.sub.1-C.sub.6)alkylamino, di(C.sub.1-C.sub.6)alkylamino,
(C.sub.3-C.sub.10)cycloalkyl, (C.sub.4-C.sub.10)cycloalkyl-alkyl,
(C.sub.3-C.sub.10)cycloheteroalkyl, cyano, nitro, sulfonamido,
(C.sub.1-C.sub.6)acyl, (C.sub.1-C.sub.6)acylamino,
(C.sub.2-C.sub.6)alkoxycarbonyl,
(C.sub.2-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkyl, carboxamido
and (C.sub.1-C.sub.6)heteroalkoxy; with a compound having the
formula: ##STR14## wherein Y is O, S or N(R), wherein R is H, CN,
NO.sub.2, (C.sub.1-C.sub.10)alkyl, (C.sub.3-C.sub.10)cycloalkyl,
(C.sub.4-C.sub.10)cycloalkyl-alkyl, (C.sub.3-C.sub.10)alkenyl and
(C.sub.2-C.sub.10)alkynyl; Z is H, (C.sub.1-C.sub.10)alkyl,
(C.sub.3-C.sub.10)cycloalkyl, (C.sub.4-C.sub.10)cycloalkyl-alkyl,
(C.sub.2-C.sub.10)alkenyl, (C.sub.2-C.sub.10)alkynyl or
NR.sup.2R.sup.3; R.sup.1, R.sup.2 and R.sup.3 are independently
selected from H, (C.sub.1-C.sub.10)alkyl,
(C.sub.3-C.sub.10)alkenyl, (C.sub.2-C.sub.10)alkynyl,
(C.sub.2-C.sub.10)heteroalkyl, (C.sub.3-C.sub.10)cycloalkyl,
(C.sub.4-C.sub.10)cycloalkyl-alkyl,
(C.sub.3-C.sub.10)cycloheteroalkyl,
(C.sub.3-C.sub.10)cycloheteroalkyl, aryl,
aryl(C.sub.1-C.sub.4)alkyl, aryl(C.sub.2-C.sub.4)heteroalkyl,
heteroaryl(C.sub.2-C.sub.4)alkyl,
heteroaryl(C.sub.2-C.sub.4)heteroalkyl and
perfluoro(C.sub.1-C.sub.6)alkyl; and wherein when Z is
NR.sup.2R.sup.3, R.sup.2 and R.sup.3 can be combined to form a 5-
to 7-membered ring; under conditions sufficient to produce
compounds having the formula: ##STR15## wherein each of A, B,
R.sup.1, R.sup.4, W, X, Y and Z have the meanings provided
above.
[0082] Exemplary conditions are provided in the examples below,
with the understanding that the skilled practitioner can adjust
solvents, temperature, time of reaction, workup conditions and the
like to produce the desired compounds.
[0083] In view of the methods provided herein, one of skill will
also appreciate that certain compounds are particularly useful in
the preparation of the subject antiinflammation agents.
Accordingly, the present invention provides in another aspect,
compounds of the formula: ##STR16## wherein W and X are
independently selected from N and CH; R.sup.4 is selected from H,
(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl,
(C.sub.4-C.sub.7)cycloalkyl-alkyl, (C.sub.2-C.sub.6)alkenyl and
(C.sub.2-C.sub.6)alkynyl; A is a substituted or unsubstituted fused
carbocyclic or heterocyclic ring system, the ring system being
mono- or bicyclic wherein the mono- or bicyclic rings are selected
from five- and six-membered rings that are aromatic or partially or
completely saturated; and B is a substituted or unsubstituted five-
or six-membered ring which is aromatic or partially or completely
saturated, containing at least one nitrogen atom, and from 0 to 3
additional heteroatoms, wherein the B ring substituents are
selected from halogen, CF.sub.3, CF.sub.3O, (C.sub.1-C.sub.6)alkyl,
perfluoro(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)heteroalkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)thioalkoxy, amino,
(C.sub.1-C.sub.6)alkylamino, di(C.sub.1-C.sub.6)alkylamino,
(C.sub.3-C.sub.10)cycloalkyl, (C.sub.4-C.sub.10)cycloalkyl-alkyl,
(C.sub.3-C.sub.10)cycloheteroalkyl, cyano, nitro, sulfonamido,
(C.sub.1-C.sub.6)acyl, (C.sub.1-C.sub.6)acylamino,
(C.sub.2-C.sub.6)alkoxycarbonyl,
(C.sub.2-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkyl, carboxamido
and (C.sub.1-C.sub.6)heteroalkoxy.
[0084] Compositions
[0085] In addition to the compounds provided above, the present
invention further provides pharmaceutical compositions comprising
one or more of the subject compounds in admixture with a
pharmaceutically acceptable carrier or excipient.
[0086] In one embodiment, the invention provides the subject
compounds combined with a pharmaceutically acceptable excipient
such as sterile saline, methylcellulose solutions, detergent
solutions or other medium, water, gelatin, oils, etc. The compounds
or compositions may be administered alone or in combination with
any convenient carrier, diluent, etc., and such administration may
be provided in single or multiple dosages. Useful carriers include
water soluble and water insoluble solids, fatty acids, micelles,
inverse micelles, liposomes and semi-solid or liquid media,
including aqueous solutions and non-toxic organic solvents. All of
the above formulations may be treated with ultrasounds, stirred,
mixed, high-shear mixed, heated, ground, milled, aerosolized,
pulverized, lyophilized, etc., to form pharmaceutically acceptable
compositions.
[0087] In another embodiment, the invention provides the subject
compounds in the form of a prodrug, which can be metabolically or
chemically converted to the subject compound by the recipient host.
A wide variety of prodrug derivatives are known in the art such as
those that rely on hydrolytic cleavage or oxidative activation of
the prodrug.
[0088] The compositions may be provided in any convenient form,
including tablets, capsules, lozenges, troches, hard candies,
powders, sprays, creams, suppositories, etc. As such, the
compositions, in pharmaceutically acceptable dosage units or in
bulk, may be incorporated into a wide variety of containers. For
example, dosage units may be included in a variety of containers
including capsules, pills, etc.
[0089] Still other compositions of the present invention are those
that combine two or more of the present compounds in one
formulation, or one compound from the present invention with a
second antiinflammatory, antiproliferative or antidiabetic
agent.
[0090] Methods of Use
[0091] In yet another aspect, the present invention provides
methods of treating IKK-mediated conditions or diseases by
administering to a subject having such a disease or condition, a
therapeutically effective amount of a compound of formula I above.
The "subject" is defined herein to include animals such as mammals,
including, but not limited to, primates (e.g., humans), cows,
sheep, goats, horses, dogs, cats, rabbits, rats, mice and the
like.
[0092] Diseases and conditions associated with inflammation,
infection and cancer can be treated with the present compounds and
compositions. In one group of embodiments, diseases or conditions,
including chronic diseases, of humans or other species can be
treated with inhibitors of IKK function. These diseases or
conditions include: (1) inflammatory or allergic diseases such as
systemic anaphylaxis or hypersensitivity responses, drug allergies,
insect sting allergies; inflammatory bowel diseases, such as
Crohn's disease, ulcerative colitis, ileitis and enteritis;
vaginitis; psoriasis and inflammatory dermatoses such as
dermatitis, eczema, atopic dermatitis, allergic contact dermatitis,
urticaria; vasculitis; spondyloarthropathies; scleroderma;
respiratory allergic diseases such as asthma, allergic rhinitis,
hypersensitivity lung diseases, and the like, (2) autoimmune
diseases, such as arthritis (rheumatoid and psoriatic),
osteoarthritis, multiple sclerosis, systemic lupus erythematosus,
diabetes mellitus, glomerulonephritis, and the like, (3) graft
rejection (including allograft rejection and graft-v-host disease),
and (4) other diseases in which undesired inflammatory responses
are to be inhibited (e.g., atherosclerosis, myositis, neurological
conditions such as stroke and closed-head injuries,
neurodegenerative diseases, Alzheimer's disease, encephalitis,
meningitis, osteoporosis, gout, hepatitis, nephritis, sepsis,
sarcoidosis, conjunctivitis, otitis, chronic obstructive pulmonary
disease, sinusitis and Behcet's syndrome); (5) in another group of
embodiments, diseases or conditions are treated with inhibitors of
IKK function that will promote cell death; examples of these
diseases include, but are not limited to, neoplastic diseases such
as solid tumors, skin cancer, melanoma, lymphoma, and diseases in
which angiogenesis and neovascularization play a role; (6) other
metabolic disorders that are sensitive to inhibition of TNF or IL-1
signaling, such as obesity for example.
[0093] Depending on the disease to be treated and the subject's
condition, the compounds of the present invention may be
administered by oral, parenteral (e.g., intramuscular,
intraperitoneal, intravenous, ICV, intracistemal injection or
infusion, subcutaneous injection or implant), inhalation, nasal,
vaginal, rectal, sublingual transdermal or topical routes of
administration and may be formulated, alone or together, in
suitable dosage unit formulations containing conventional non-toxic
pharmaceutically acceptable carriers, adjuvants and vehicles
appropriate for each route of administration. The present invention
also contemplates administration of the compounds of the present
invention in a depot formulation, in which the active ingredient is
released over a defined time period.
[0094] In the treatment or prevention of conditions which require
chemoline receptor modulation an appropriate dosage level will
generally be about 0.001 to 100 mg per kg patient body weight per
day which can be administered in single or multiple doses.
Preferably, the dosage level will be about 0.01 to about 25 mg/kg
per day; more preferably about 0.05 to about 10 mg/kg per day. A
suitable dosage level may be about 0.01 to 25 mg/kg per day, about
0.05 to 10 mg/kg per day, or about 0.1 to 5 mg/kg per day. Within
this range the dosage may be 0.005 to 0.05, 0.05 to 0.5 or 0.5 to
5.0 mg/kg per day. For oral administration, the compositions are
preferably provided in the form of tablets containing 1.0 to 1000
milligrams of the active ingredient, particularly 1.0, 5.0, 10.0,
15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0,
400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of
the active ingredient for the symptomatic adjustment of the dosage
to the patient to be treated. The compounds may be administered on
a regimen of 1 to 4 times per day, preferably once or twice per
day.
[0095] It will be understood, however, that the specific dose level
and frequency of dosage for any particular patient may be varied
and will depend upon a variety of factors including the activity of
the specific compound employed, the metabolic stability and length
of action of that compound, the age, body weight, general health,
sex, diet, mode and time of administration, rate of excretion, drug
combination, the severity of the particular condition, and the host
undergoing therapy.
[0096] The compounds of the present invention can be combined with
other compounds having related utilities to prevent and treat
inflammatory and immunoregulatory disorders and diseases, including
asthma and allergic diseases, as well as autoimmune pathologies
such as rheumatoid arthritis and atherosclerosis, and those
pathologies noted above.
[0097] For example, in the treatment or prevention of inflammation,
the present compounds may be used in conjunction with an
antiinflammatory or analgesic agent such as an opiate agonist, a
lipoxygenase inhibitor, such as an inhibitor of 5-lipoxygenase, a
cyclooxygenase inhibitor, such as a cyclooxygenase-2 inhibitor, an
interleukin receptor antagonist, such as an interleukin-1 receptor
antagonist, an NMDA receptor antagonist, an inhibitor of nitric
oxide or an inhibitor of the synthesis of nitric oxide, a
non-steroidal antiinflammatory agent, or a cytokine-suppressing
antiinflammatory agent, for example with a compound such as
acetaminophen, aspirin, codiene, fentanyl, ibuprofen, indomethacin,
ketorolac, morphine, naproxen, phenacetin, piroxicam, a steroidal
analgesic, sufentanyl, sulindac, tenidap, and the like. Similarly,
the instant compounds may be administered with a pain reliever, a
potentiator such as caffeine, an H2-antagonist, simethicone,
aluminum or magnesium hydroxide; a decongestant such as
phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline,
ephinephrine, naphazoline, xylometazoline, propylhexedrine, or
levo-desoxy-ephedrine; an antitussive such as codiene, hydrocodone,
caramiphen, carbetapentane, or dextramethorphan; a diuretic; and a
sedating or non-sedating antihistamine. Each of the above agents
may be administered, by a route and in an amount commonly used
therefor, contemporaneously or sequentially with a compound of the
present invention. When a compound of the present invention is used
contemporaneously with one or more other drugs, in some cases a
pharmaceutical composition containing such other drugs in addition
to the compound of the present invention may be preferred.
Accordingly, the pharmaceutical compositions of the present
invention include those that also contain one or more other active
ingredients, in addition to a compound of the present invention.
Examples of other active ingredients that may be combined with a
compound of the present invention, either administered separately
or in the same pharmaceutical compositions, include, but are not
limited to: (a) VLA-4 antagonists, (b) steroids such as
beclomethasone, methylprednisolone, betamethasone, prednisone,
dexamethasone, and hydrocortisone; (c) immunosuppressants such as
methotrexate cyclosporin, tacrolimus, rapamycin and other FK-506
type immunosuppressants; (d) antihistamines (H1-histamine
antagonists) such as bromopheniramine, chlorpheniramine,
dexchlorpheniramine, triprolidine, clemastine, diphenhydramine,
diphenylpyraline, tripelennamine, hydroxyzine, methdilazine,
promethazine, trimeprazine, azatadine, cyproheptadine, antazoline,
pheniramine pyrilamine, astemizole, terfenadine, loratadine,
cetirizine, fexofenadine, descarboethoxyloratadine, and the like;
(e) non-steroidal anti-asthmatics such as beta-adrenergic agonists
(terbutaline, metaproterenol, fenoterol, isoetharine, albuterol,
bitolterol, and pirbuterol), theophylline, cromolyn sodium,
atropine, ipratropium bromide, leukotriene antagonists
(zafirlukast, montelukast, pranlukast, iralukast, pobilukast,
SKB-106,203), leukotriene biosynthesis inhibitors (zileuton,
BAY-1005); (f) non-steroidal antiinflammatory agents (NSAIDs) such
as propionic acid derivatives (alminoprofen, benoxaprofen, bucloxic
acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen,
ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin,
pirprofen, pranoprofen, suprofen, tiaprofenic acid, and
tioxaprofen), acetic acid derivatives (indomethacin, acemetacin,
alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid,
fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac,
tiopinac, tolmetin, zidometacin, and zomepirac), fenamic acid
derivatives (flufenamic acid, meclofenamic acid, mefenamic acid,
niflumic acid and tolfenamic acid), biphenylcarboxylic acid
derivatives (diflunisal and flufenisal), oxicams (isoxicam,
piroxicam, sudoxicam and tenoxican), salicylates (acetyl salicylic
acid, sulfasalazine) and the pyrazolones (apazone, bezpiperylon,
feprazone, mofebutazone, oxyphenbutazone, phenylbutazone); (g)
cyclooxygenase-2 (COX-2) inhibitors; (h) inhibitors of
phosphodiesterase type IV (PDE-IV); (i) anti-diabetic agents such
as insulin, sulfonylureas, biguanides (metformin),
.alpha.-glucosidase inhibitors (acarbose) and glitazones
(troglitazone, rosiglitazone and pioglitazone); (j) preparations of
interferon beta (interferon beta-1.alpha, interferon beta-1.beta.);
(k) other compounds such as 5-aminosalicylic acid and prodrugs
thereof, antimetabolites such as methotrexate, azathioprine and
6-mercaptopurine, and cytotoxic cancer chemotherapeutic agents; and
(l) agents that directly or indirectly interfere with cytokine
signalling, such as soluble TNF receptors, TNF antibodies, soluble
IL-1 receptors, IL-1 antibodies, and the like. The weight ratio of
the compound of the present invention to the second active
ingredient may be varied and will depend upon the effective dose of
each ingredient. Generally, an effective dose of each will be used.
Thus, for example, when a compound of the present invention is
combined with an NSAID the weight ratio of the compound of the
present invention to the NSAID will generally range from about
1000:1 to about 1:1000, preferably about 200:1 to about 1:200.
Combinations of a compound of the present invention and other
active ingredients will generally also be within the aforementioned
range, but in each case, an effective dose of each active
ingredient should be used.
EXAMPLES
[0098] Reagents and solvents used below can be obtained from
commercial sources such as Aldrich Chemical Co. (Milwaukee, Wis.,
USA). .sup.1H-NMR spectra were recorded on a Varian Gemini 400 MHz
NMR spectrometer. Significant peaks are tabulated in the order:
multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet; br s, broad singlet), coupling constant(s) in Hertz (Hz)
and number of protons. Electron Ionization (EI) mass spectra were
recorded on a Hewlett Packard 5989A mass spectrometer. Mass
spectrometry results are reported as the ratio of mass over charge,
followed by the relative abundance of each ion (in parentheses). In
tables, a single m/e value is reported for the M+H (or, as noted,
M-H) ion containing the most common atomic isotopes. Isotope
patterns correspond to the expected formula in all cases.
Electrospray ionization (ESI) mass spectrometry analysis was
conducted on a Hewlett-Packard 1100 MSD electrospray mass
spectrometer using the HP1100 HPLC for sample delivery. Normally
the analyte was dissolved in methanol at 0.1 mg/mL and 1 microliter
(.mu.L) was infused with the delivery solvent into the mass
spectrometer, which scanned from 100 to 1500 daltons. All compounds
could be analyzed in the positive ESI mode, using 1:1
acetonitrile/water with 1% acetic acid as the delivery solvent. The
compounds provided below could also be analyzed in the negative ESI
mode, using 2 mM NH.sub.4OAc in acetonitrile/water as delivery
solvent
Preparation of Synthetic Intermediates
Method A
[0099] For compounds of the invention in which W.dbd.N and
X.dbd.CH, and the corresponding .alpha.-keto lactam (i.e., isatin)
is commercially available or can be prepared by known methods.
##STR17## Preparation of Intermediate iii ##STR18##
[0100] To a solution of the aldehyde iv (22.0 g, 98.0 mmol;
prepared according to Walters, et al. Tetrahedron Lett. 1994, 35,
8307-8310) in 200 mL of THF at 0.degree. C. was added a 3.0 M
solution of MeMgCl (39 mL, 117.0 mmol) in THF. The reaction was
stirred for 30 min and quenched with a saturated NH.sub.4Cl
solution. The solids were removed by filtration, the filtrate was
dried over Na.sub.2SO.sub.4, and concentrated to dryness to obtain
a solid. The crude product and MnO.sub.2 (36.0 g) were stirred
vigorously in 100 mL of benzene for 18 h. More MnO.sub.2 (5.0 g)
was added and the mixture was stirred for another 3 h. The reaction
was filtered through Celite, the solids were washed with EtOAc, and
the filtrate was concentrated to give a solid. The crude product
was purified by chromatography (silica gel, hexanes/acetone, 85:15)
to give the desired ketone v as a solid (16 g, 68%). .sup.1H NMR
(DMSO-d.sub.6) .delta. 8.00 (s, 1H), 3.89 (s, 3H), 2.43 (s, 3H),
0.92 (s, 9H), 0.36 (s, 6H). ##STR19##
[0101] To a mixture of isatin (1.2 g, 8.15 mmol, Aldrich Chemical
Co., Milwaukee, Wis., USA) and
5-acetyl-2-t-butyldimethylsilyl-1-methyl imidazole (2.0 g, 8.4
mmol, prepared in Step 1) in 10 mL of EtOH/water (1:1) was added
potassium hydroxide (2.0 g, 35.6 mmol). The dark-red solution was
stirred in an oil bath at 80.degree. C. for 18 h. The reaction was
cooled in an ice bath, diluted with water (5 mL) and acetic acid (2
mL) was added. The precipitate was collected by filtration, washed
with water, and dried to give the desired product vi (1.3 g).
.sup.1H NMR (DMSO-d.sub.6) .delta. 8.54 (dd, J=8.5, 1.0 Hz, 1H),
8.02 (s, 1H), 8.0 (dd, J=8.3, 1.0 Hz, 1H), 7.85 (s, 1H), 7.78 (s,
1H), 7.73 (ddd, J=8.3, 6.7, 1.4 Hz, 1H), 7.55 (ddd, J=8.3, 6.8, 1.3
Hz, 1H), 4.14 (s, 3H). ##STR20##
[0102] The acid vi (500 mg, 1.99 mmol) was dissolved in 5 mL of
MeOH and conc. H.sub.2SO.sub.4 (1.0 mL) was added. The reaction
mixture was heated at reflux for 22 h and brought to room
temperature. The mixture was concentrated and the residue was
dissolved with water and adjusted to basic pH by the addition of
solid K.sub.2CO.sub.3. The aqueous phase was extracted three times
with EtOAc. The organic extracts were washed with brine, dried over
MgSO.sub.4, filtered and concentrated to dryness to give the
desired ester iii (300 mg). .sup.1H NMR (DMSO-d.sub.6) .delta. 8.47
(d, J=8.4 Hz, 1H), 8.26 (s, 1H), 8.08 (d, J=8.4 Hz, 1H), 7.93-7.87
(br s, 2H), 7.84 (br t, J=7.0 Hz, 1H), 7.67 (br t, J=7.0 Hz, 1H),
4.15 (s, 3H), 4.02 (s, 3H).
[0103] A number of variously substituted isatins are available from
commercial sources. Alternatively, literature methods described
their preparation from the corresponding anilines (or equivalent
aromatic amines). For example, substituted isatins can be prepared
via a Sandmeyer procedure (see, Simon J. Garden, Jose C. Torres,
Alexandra A. Ferreira, Rosangela B. Silva, Angelo C. Pinto;
Tetrahedron Letters 38, 9, 1501, (1997) and references cited
therein); a formanilide method (see, Otto, et al., Tetrahedron
Letters 37, 52, 9381, (1996)); a Stolle type procedure (see Soll,
et al., J. Org. Chem. 53, 2844 (1988)); a Stolle-Becker (oxalyl
chloride) procedure (see, Baumgarten, et al., J. Org. Chem. 26,
1536 (1961)); .alpha. keto amides (see, Fumiyuki, et al., J. Org.
Chem. 51, 415, (1986)); a Gassman method (see, Gassman, et al., J.
Org. Chem. 42, 8, 1344, (1977)); ortho-lithiated anilines (see,
Hewawasam, et al., Tetrahedron Letters, 35, 7303, (1994); an
oxindole route (see, Kraynack et al., Tetrahedron Letters, 39,
7679, (1998); and via bis(alkylthio)carbenes (see Rigby, and Danca,
Tetrahedron Letters 40, 689,(1999).
Method B
[0104] Preparation of Intermediate vii ##STR21##
[0105] A solution of the amide viii (1.87 g, 10.6 mmol) in 20 mL of
THF was cooled to -78.degree. C. under nitrogen. A 2.32 M solution
of n-BuLi (11.4 mL, 26.5 mmol) in THF was added to the cold
solution, which was then stirred at -5.degree. C. for 3 h. The
reaction was cooled to -78.degree. C. and diethyl oxalate (3.65 mL,
26.5 mmol) was added. The reaction was allowed to reach room
temperature and was quenched with water, followed by EtOAc. The
aqueous phase was extracted three times with EtOAc, the organic
extracts were combined, dried over MgSO.sub.4, filtered, and
concentrated to dryness to obtain an oil (1.8 g). The crude product
was purified by chromatography (silica gel, CH.sub.2Cl.sub.2/MeOH,
97:3) to give the desired ketoester ix as an oil (680 mg, 23%).
##STR22##
[0106] A mixture of the ketoester ix (680 mg, 2.44 mmol),
5-acetyl-2-t-butyldimethylsilyl-1-methyl imidazole v (660 mg, 2.76
mmol), and potassium hydroxide (564 mg, 10.07 mmol) in 6 mL of
EtOH/water (1:1) was placed in an oil bath at 80.degree. C. for 18
h. The reaction was brought to room temperature, concentrated to
remove the EtOH, diluted with 3 mL of water, and 1 mL of AcOH was
added. The solution was refrigerated for 24 h, at which point a
solid precipitate was collected, washed with water, and dried to
give the desired acid x (200 mg, 32%). .sup.1H NMR (DMSO-d.sub.6)
.delta. 9.26 (s, 1H), 8.60 (d, J=5.7 Hz, 1H), 8.46 (d, J=5.7 Hz,
1H), 8.09 (s, 1H), 7.85 (s, 1H), 7.77 (s, 1H), 4.15 (s, 3H).
[0107] The corresponding ester of this acid can be prepared as
described in Method A, Step 3, or other standard methods known to
those of skill in the art. Alternatively, this acid can be
converted directly into the corresponding aldehyde using methods
well known in the art.
Method C
[0108] Preparation of Intermediate xi ##STR23##
[0109] This method is a variation on Method B; above. In this
method, metal-halogen exchange is used instead of direct
metallation of an aniline derivative. ##STR24##
[0110] A solution of the required carbamate xii (1.74 g, 6.37 mmol;
prepared according to Venuti et al., J. Med. Chem. 1988, 31, 2136)
in 20 mL of THF was cooled to -78.degree. C. under nitrogen. A
2.2-M solution of n-BuLi (6.1 mL, 13.4 mmol) in THF was added to
the cold solution and the mixture was stirred at -78.degree. C. for
1 h. Diethyl oxalate (1.04 mL, 7.64 mmol) was added and the
reaction was allowed to reach room temperature. The reaction was
quenched with 10% aqueous NH.sub.4Cl and diluted with EtOAc. The
organic layer was washed with water, brine, dried over MgSO.sub.4,
filtered, and concentrated to dryness to obtain an oil (1.79 g).
The crude product was purified by chromatography (silica gel,
hexanes/EtOAc, 4:1) to give the desired ketoester xiii as an oil
(1.1 g, 58%). ##STR25##
[0111] A mixture of the ketoester xiii (1.0 g, 3.4 mmol),
5-acetyl-2-t-butyldimethylsilyl-1-methyl imidazole v (882 mg, 3.7
mmol), and potassium hydroxide (760 mg, 13.6 mmol) in 8 mL of
EtOH/water (1:1) was placed in an oil bath at 80.degree. C. for 24
h. The reaction was brought to room temperature, diluted with 20 mL
of water, and 2 mL of AcOH was added. The yellow solution was
refrigerated for 4 h and the yellow needles that formed were
collected by filtration, washed with water and ether, and dried to
give the desired acid xiv (163 mg, 19%). .sup.1H NMR (DMSO-d.sub.6)
.delta. 9.02 (dd, J=4.3, 1.6 Hz, 1H), 8.55 (dd, J=8.5, 1.6 Hz, 1H),
8.46 (s, 1H), 8.01 (d, J=1.0 Hz, 1H), 7.92 (dd, J=8.5, 4.3 Hz, 1H),
7.91 (s, 1H), 4.15 (s, 3H).
[0112] The corresponding ester of this acid can be prepared as
described in Method A, Step 3, or by other methods known in the
art. Alternatively, this acid can be converted directly into the
corresponding aldehyde or ketone by known methods.
Method D
[0113] An alternative method of assembling the final framework
involves a tin-mediated coupling as indicated below. ##STR26##
[0114] To a stirred solution of 2-hydroxyquinoline-4carboxylic acid
(Lancaster, Windham, USA) (10 g, 50 mmol), anhydrous potassium
carbonate (10.35 g, 75 mmol) and anhydrous DMF (200 mL) at room
temperature under nitrogen was added iodomethane (6.14 mL, 100
mmol). The mixture was stirred for 16 h, then poured into saturated
aqueous sodium bicarbonate (150 mL). The resulting solid was washed
with water (2.times.50 mL) and dried by suction to afford the
desired product xv (9.1 g, 90%). .sup.1H NMR (DMSO-d.sub.6) .delta.
12.14 (br s, 1H), 8.05 (d, J=8 Hz, 1H), 7.55-7.60 (m, 1H), 7.39 (d,
J=8 Hz, 1H), 7.21-7.28 (m, 1H), 6.85 (s, 1H), 3.93 (s, 3H); ESI-MS
m/z 204.1 (100, M+H.sup.+).
[0115] A solution of 4-carbomethoxy-2-quinolinone xv (655 mg, 3
mmol) and POBr.sub.3 (1.9 g, 10 mmol) in toluene (20 mL) was heated
at reflux for 2 h, then allowed to cool to room temperature and
poured into ice water (25 mL). The mixture was extracted with ethyl
acetate (3.times.50 mL). The organic extract was combined, washed
with water and brine, dried (MgSO.sub.4) and concentrated in vacuo.
Flash chromatography (hexane:EtOAc 4:1) afforded the desired
product ivi (400 mg). .sup.1H NMR (DMSO-d.sub.6) .delta. 8.52-8.57
(m, 1H), 8.04-8.08 (m, 1H), 8.25 (s, 1H), 7.88-7.92 (m, 1H),
7.76-7.81 (m, 1H), 3.98 (s, 3H).
[0116] A solution of 4-tributylstannyl-1-titylimidazole (474 mg,
0.79 mmol; prepared according to Elguero et al., Synthesis, 1997,
563) and 2-bromo-4-carbomethoxy-quinoline xvi (145 mg, 0.53 mmol)
in DMF was degassed with nitrogen for 5 min. Pd.sub.2(dba).sub.3
(49 mg, 0.053 mmol), cuprous iodide (20 mg, 0.1 mmol) and triphenyl
arsine (32 mg, 0.10 mmol) were added, and the mixture was stirred
at 60.degree. C. for 16 h. The mixture was allowed to cool to room
temperature and was filtered through celite (eluting with 50 mL
ethyl acetate). Water (50 mL) was added and the organic extract was
collected and washed with water (3.times.50 mL), brine (1.times.50
mL), dried (MgSO.sub.4), filtered and concentrated in vacuo. Flash
chromatography (gradient elution: hexane to hexane:EtOAc 3:1)
afforded the desired product xvii (173 mg, 66%). .sup.1H NMR
(CDCl.sub.3) .delta. 8.62 (d, J=8 Hz, 1H), 8.36 (s, 1H), 8.20 (s,
1H), 8.04-8.07 (m, 2H), 7.17-7.76 (m, 17H), 4.04 (s, 3H); ESI-MS
m/z 496.3 (100, M+H.sup.+).
[0117] The general synthetic methodology of Method D can also be
applied to other aromatic halides. For example: Preparation of
Intermediate xix ##STR27##
[0118] To a solution of 1-methyl-5-(tributylstannyl)imidazole (9.5
g, 25.6 mmol, Gaare, et al, Acta Chem. Scand. 1993, 47(1), 57-62)
in 75 mL of anhydrous benzene which had been degassed by bubbling
nitrogen through it for 5 min. was added the chloro quinoline xviii
(4.1 g, 21.3 mmol, Hasegawa, Pharm. Bull. 1953, 47-50). To this
solution was added tetrakis(triphenylphosphine)palladium(0) (1.06
mmol, 1.23 g). The reaction was heated at reflux for 14 h, at which
time it was cooled, the volume of solvent reduced to about 15 mL
under vacuum and the solution placed on a silica gel column. The
column was eluted with 5% MeOH in methylene chloride to give 3.5 g
of the alcohol xix.
[0119] .sup.1H NMR (CDCl.sub.3) .delta. 8.02 (d, J=7.0 Hz, 1H),
.delta. 7.99 (d, J=7.0 Hz, 1H), 7.91 (s, 1H), 7.84 (s, 1H), 7.73
(t, J=7.0 Hz, 1H), 7.71 (s, 1H), 5.64 (t, J=5.6 Hz, 1H), 5.04 (d,
J=5.6 Hz, 2H), 4.15 (s, 3H).
[0120] This alcohol can then be converted into the corresponding
aldehyde as described for Example 1.9, or by other methods well
known in the art.
Method E
[0121] This method is a variation on Method D, although in this
case the fused A ring is not aromatic, and an aromatic triflate is
used in the coupling reaction. ##STR28##
[0122] A mixture of ethyl
3-cyano-2-hydroxy-5,6,7,8-tetrahydro-quinoline-4-carboxylate xx
(7.8 g, 0.032 mol; prepared according to Snyder, Org. Synth., II,
531 and Isler et al., Helv. Chim. Acta, 1955, 38, 1033) in water (9
mL) and conc. H.sub.2SO.sub.4 (9 mL) was heated at reflux for 3
days. The mixture was cooled and diluted with water. The resulting
precipitate was collected by filtration and washed with water to
give the desired carboxylic acid (4.4 g, 71%). .sup.1H NMR
(DMSO-d.sub.6) .delta. 6.34 (s, 1H), 2.10-2.20 (m, 4H), 1.61-1.70
(m, 4H); ESI-MS m/z 192.1 (100, M-H.sup.+).
[0123] To the carboxylic acid (4.4 g, 22 mmol) was added thionyl
chloride (30 mL) and the mixture was heated at reflux for 1 h, then
allowed to cool to room temperature and concentrated in vacuo. To
the residue was added ethanol (20 mL) and the mixture was stirred
at room temperature for 5 min. The mixture was concentrated in
vacuo to afford ester xxi (3.4 g, 70%). .sup.1H NMR (CDCl.sub.3)
.delta. 6.80 (s, 1H), 4.17 (q, J=7 Hz, 2H), 2.65-2.75 (m, 4H)
1.66-1.85 (m, 4H), 1.29 (t, J=7 Hz, 3H); ESI-MS m/z 222.2 (100,
M+H.sup.+).
[0124] To a stirred solution of pyridone xxi (400 mg, 1.8 mmol) in
anhydrous dichloromethane (15 mL) at 0.degree. C. under nitrogen
was added diisopropylethylamine (347 .mu.l, 1.98 mmol) and triflic
anhydride (192 .mu.l, 1.8 mmol). After 3 h, saturated aqueous
sodium bicarbonate (10 mL) was added and the organic layer was
collected, dried (Na.sub.2SO.sub.4), filtered and concentrated in
vacuo. Flash chromatography (hexane:EtOAc 95:5) afforded the
desired pyridine triflate xxii (173 mg, 27%). .sup.1H NMR
(CDCl.sub.3) .delta. 7.26 (s, 1H), 4.19 (q, J=7 Hz, 2H), 2.83-3.07
(m, 4H) 1.79-1.94 (m, 4H) 1.30 (t, J=7 Hz, 3H). ESI-MS m/z 354.0
(100, M+H.sup.+).
[0125] To a stirred solution of triflate xxii (173 mg, 0.48 mmol)
in 1,4-dioxane (5 mL) was added
tetrakis(triphenylphosphine)palladium(0) (60 mg, 0.05 mmol),
lithium chloride (67 mg, 1.5 mmol) and
1-methyl-5-(tributylstannyl)imidazole (216 mg, 0.58 mmol) and the
mixture was degassed with nitrogen for 5 min. The mixture was
heated at reflux for 18 h under nitrogen, then cooled and diluted
with dichloromethane and water. The organic layer was collected,
washed with brine, dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo. Flash chromatography (CH.sub.2Cl.sub.2 to
CH.sub.2Cl.sub.2:MeOH 1.5:98.5) afforded the desired product xxiii
(168 mg). .sup.1H NMR (CDCl.sub.3) .delta. 7.63 (s, 1H), 7.41 (s,
1H), 7.43 (s, 1H), 4.39 (q, J=7 Hz, 2H), 3.99 (s, 3H), 2.83-3.07
(m, 4H), 1.78-1.95 (m, 4H), 1.29 (t, J=7 Hz, 3H). MS m/z 286.2
(100, M+H.sup.+).
Method F
[0126] This method also illustrates a variation to Method D, but in
this case W.dbd.X.dbd.CH (utilizing a naphthalene framework).
##STR29##
[0127] To a solution of methyl 3-nitro-2-naphtholate (purchased
from TCI, 1.62 g, 7.0 mmol) in MeOH (20 mL) and EtOAc (20 mL) was
added 10% Pd--C (0.16 g) and the mixture was stirred overnight
under 1 atm H.sub.2. Filtration and concentration of the filtrate
afforded a brown solid (xxiv) that was dried under vacuum and used
directly without further purification. To the above solid was added
conc. HCl (3.1 mL), water (3.1 mL) and ice (6.5 g) and the
resulting mixture was cooled in ice bath. While maintaining the
reaction temperature below 5.degree. C., NaNO.sub.2 (0.51 g, 7.3
mmol) in water (3.3 mL) was added dropwise. After 30 min, a
solution of KI (1.17 g, 7.00 mmol) in water (3 mL) was added and
the reaction was stirred overnight at rt. The mixture was extracted
with EtOAc (3.times.30 mL) and the combined organic extracts were
sequentially washed with saturated aqueous NaHCO.sub.3,
Na.sub.2S.sub.2O.sub.3 and NaCl solutions and dried (MgSO.sub.4).
Concentration followed by column chromatography
(CH.sub.2Cl.sub.2:hexane/1:2) gave the desired naphthyl iodide xxv
as a pale yellow solid (1.15 g).
[0128] A mixture of aryl iodide xxv (758 mg, 2.4 mmol), Ph.sub.3As
(151 mg, 0.5 mmol), CuI (92 mg, 0.48 mmol), Pd.sub.2(dba).sub.3
(233 mg, 0.24 mmol) and 3-tributylstannyl-1-tritylimidazole (1.46
g, 2.40 mmol; prepared according to xx J. Org. Chem. 1991, 56,
5739) in DMF (25 mL) was purged with nitrogen for 5 min and then
heated to 65.degree. C. for 4 h. The reaction mixture was
concentrated under vacuum and partitioned between CH.sub.2Cl.sub.2
(200 mL) and aqueous sodium bicarbonate (100 mL). The organic layer
was washed with brine and dried (MgSO.sub.4). Concentration
followed by column chromatography (CH.sub.2Cl.sub.2:MeOH/100:1)
afforded the desired product xxvi as a gray solid (1.3 g).
Method G
[0129] This method illustrates the homologation of the A ring at
the stage of one of the intermediates. ##STR30##
[0130] To a solution of xxvii (2.2 g, 5.6 mmol, prepared according
to Method A from the iodoistatin) in THF (180 mL) at -78.degree. C.
was added dropwise DIBAL-H in toluene (1M, 22.4 mL, 22.4 mmol). The
reaction was warmed to 0.degree. C. After 3 h, saturated aqueous
NH.sub.4Cl (100 mL) was added and the mixture was extracted with
CH.sub.2Cl.sub.2 (10.times.200 mL). The combined organic extracts
were washed with brine and dried (MgSO.sub.4). Removal of the
solvent gave the desired alcohol xxviii as a white solid (2.0 g)
which was carried on with out purification. To a solution of the
alcohol (2.0 g, 5.5 mmol) in CH.sub.2Cl.sub.2 (200 mL) was added
Dess-Martin reagent (4.3 g, 8.8 mmol) at room temperature. After 1
h, the reaction was quenched by adding saturated aqueous
NaHCO.sub.3 (100 mL) and saturated aqueous Na.sub.2S.sub.2O.sub.3
(100 mL). The organic layer was separated, washed with brine and
dried (MgSO.sub.4). Concentration, followed by column
chromatography (CH.sub.2Cl.sub.2:MeOH/30:1) gave the corresponding
aldehyde xxix as a yellow solid (1.7 g). ##STR31##
[0131] A mixture of aldehyde xxix (195 mg, 0.54 mmol),
4-hydroxyphenylboronic acid (172 mg, 0.81 mmol),
PdCl.sub.2(dppf).sub.2 (136 mg, 0.17 mmol) and potassium carbonate
(344 mg, 2.5 mmol) in DMF (5 mL) was purged with nitrogen and
heated to 65.degree. C. overnight. The solvent was removed under
vacuum and the resulting mixture was diluted with CH.sub.2Cl.sub.2
(100 mL). After washing with brine and drying (MgSO.sub.4), removal
of the solvent followed by column chromatography
(CH.sub.2Cl.sub.2:MeOH/20:1) gave xxx as a yellow solid (56 mg),
which was utilized without further purification.
Method H
[0132] This method exemplifies yet other types of homologation of
the A ring at the stage of one of the intermediates. ##STR32##
[0133] To a solution of the ester xxvii (1.2 g, 3.05 mmol, prepared
according to Method A) in THF at -78.degree. C. under nitrogen was
added a 1.0 M solution of LiAlH.sub.4 (4 mL, 4.0 mmol) in THF. The
reaction was stirred for 1 h, quenched with water, and allowed to
reach room temperature. The aqueous layer was extracted with EtOAc
and the organic extract was washed with brine, dried over
Na.sub.2SO.sub.4, and concentrated to give a solid. The crude
product was dissolved in 50 mL of MeOH and treated with NaBH.sub.4
(200 mg, 5.3 mmol). The reaction was stirred for 15 min, water was
added, and the precipitate that formed was collected by filtration
to give an intermediate iodo-alcohol (750 mg).
[0134] A mixture of the iodo alcohol (300 mg, 0.82 mmol),
3-butyn-1-ol (0.1 mL, 1.32 mmol), Pd(PPh.sub.3).sub.4 (50 mg, 0.04
mmol), CuI (10 mg, 0.05 mmol), and triethylamine (1 mL) in 2 mL of
DMF was stirred at 80.degree. C. for 1 h. The reaction was cooled,
diluted with water, and the precipitate that formed was collected
by filtration. The crude product was dissolved in 10 mL of
EtOH/MeOH (1:1) and was hydrogenated with 10% Pd/C (100 mg) at 45
psi H.sub.2 for 3 days. The reaction was filtered and the solids
were washed with CH.sub.2Cl.sub.2 and MeOH. The filtrate was
concentrated to dryness to give the desired diol xxxi (100 mg).
.sup.1H NMR (DMSO-d.sub.6) .delta. 7.92 (d, J=8.5 Hz, 1H), 7.87 (s,
1H), 7.82 (s, 1H), 7.78 (d, J=1.4 Hz, 1H), 7.60 (dd, J=8.6, 1.8 Hz,
1H), 5.70 (br s, 1H), 5.00 (s, 2H), 4.43 (br s, 1H), 4.13 (s, 3H),
3.43 (t, J=6.4 Hz, 2H), 2.78 (t, J=7.6 Hz, 2H), 1.76-1.64 (m, 2H),
1.54-1.41 (m, 2H).
[0135] Additional examples of homologation of one of the
intermediates. ##STR33##
[0136] N-Iodosuccinimide (25.0 g, 119.5 mmol) was added to a
stirred mixture of 6-trifluoromethylisatin (10.3 g, 47.8 mmol) and
triflic acid (75 g) at 0.degree. C. under nitrogen. The ice bath
was removed and stirring at room temperature was continued for 7 h.
The mixture was poured into ice-water and was extracted with EtOAc.
The combined organic extracts were evaporated under reduced
pressure and the residue was triturated with CHCl.sub.3 to produce
a yellow-orange solid. Filtration of the crude solid and
purification by recrystallization from CHCl.sub.3 gave
5-iodo-6-trifluoromethylisatin xxxiii (10.4 g) as an orange solid.
.sup.1H NMR (DMSO-d.sub.6) .delta. 7.17(s, 1H), 8.08(s, 1H),
11.27(s, 1H); ms 340.0 (M-H). ##STR34##
[0137] A mixture of 5-iodo-6-trifluoromethylisatin (7.50 g, 22.0
mmol) and the methylketone v (5.24 g, 22.0 mmol, prepared as
described in Method A) in EtOH (50 mL) was treated with a solution
of KOH (4.93 g, 88.0 mmol) in 50 mL of water. The mixture was
heated overnight at 85.degree. C. and then cooled to 0.degree. C.
1N HCl (88 mL) was added to the mixture dropwise while a
precipitate was formed. The precipitate was collected, rinsed with
ice-water and dried under vacuum, which gave crude acid (8.0 g):
.sup.1H NMR (DMSO-d.sub.6) .delta. 4.14(s, 1H), 7.98(s, 1H),
8.03(s, 1H), 8.41(s, 1H), 8.44(s, 1H), 9.42(s, 1H); ms
448.0(M+H.sup.+).
[0138] Sulfuric acid (3.5 mL) was added to a stirred solution of
the crude acid (8.0 g) in MeOH (120 mL), and the mixture was
refluxed for 48 h. The resulting mixture was cooled and a
precipitate was collected. Rinsing with cold methanol gave the
corresponding methyl ester xxxiv (5.84 g in two steps) as a pure
off-white solid. .sup.1H NMR (DMSO-d.sub.6) .delta. 4.04(s, 1H),
4.29(s, 1H), 8.56(s, 1H), 8.57(s, 1H), 8.65(s, 1H), 9.08(s, 1H),
9.39(s, 1H); ms 462.0(M.sup.+H.sup.+). ##STR35##
[0139] To a mixture of the 6-iodo-7-trifluoromethyl methyl ester
xxxiv (615 mg, 1.33 mmol), PdCl.sub.2(PPh.sub.3).sub.2 (234 mg,
0.33 mmol), and CuI (38 mg, 0.15 mmol) in 1:1 DMF-Et.sub.3N (16
mL), methyl propargyl ether (0.34 mL, 4.02 mmol) was added at room
temperature under nitrogen. Stirring at room temperature was
continued for 4.5 h. The mixture was concentrated and the residue
was dissolved in CH.sub.2Cl.sub.2. The CH.sub.2Cl.sub.2 solution
was washed with water and brine, dried, and evaporated. Flash
chromatography of the residue over silica gel, using 1:4:5
MeOH-EtOAc-hexane, gave the crude methyl ether xxxv (300 mg).
##STR36##
[0140] The crude methyl ether xxxv (300 mg) in MeOH (15 mL) was
treated with 10% Pd/C (158 mg) and hydrogenated overnight at room
temperature. The mixture was filtered and evaporated to give the
crude saturated methyl ether xxxvi (125 mg).
[0141] Another example of homologation of the A ring of one of the
intermediates is described in the following steps: ##STR37##
[0142] To a mixture of tetrahydro-3-furanmethanol (Aldrich Chemical
Co., 3.63 g, 35.6 mmol), N-methylmorpholine oxide (6.3 g, 53.8
mmol) and 4A molecular sieves (18 g) in CH.sub.2Cl.sub.2 (70 mL) at
0.degree. C. was added TPAP (0.63 g, 1.8 mmol). After 2 h at rt,
the reaction mixture was poured on the top of a short column and
the product was eluted with ether (3.times.50 mL). Concentration
followed by column chromatography (EtOAc:Hexane/1:2 to 1:1)
afforded the aldehyde xxxvii (1.2 g) by careful concentration under
reduced pressure at 0.degree. C. To a solution of LDA [7.5 mmol,
prepared from 2.5M n-BuLi (3.0 mL, 7.5 mmol) and diisopropylamine
(1.26 mL, 9 mmol)] in THF (30 mL) at -78.degree. C. was added 2 M
TMSCHN.sub.2 (3.75 mL, 7.5 mmol). After 30 min at -78.degree. C.,
the aldehyde xxxvii (0.5 g, 5 mmol) was added and the mixture was
warmed to room temperature over 2 h Then water (20 mL) was added
and the mixture was extracted with ethyl ether (2.times.30 mL). The
combined organic layers were dried and removal of the solvent by
careful concentration under reduced pressure at 0.degree. C. gave
3-ethynyltetrahydrofuran xxxvii as a colorless liquid.
##STR38##
[0143] Compound xl was prepared by the methodology of Method H,
using iodoester xxvii and 3-ethynyltetrahydrofuran. .sup.1H-NMR
(CDCl.sub.3) .delta.: 1.59-1.66 (m, 1H), 1.84-1.88 (m, 2H),
2.08-2.18 (m, 1H), 2.23-2.37 (m, 1H), 2.79-2.93 (m, 2H), 3.44 (t,
J=7.7 Hz, 1H), 3.71-3.81 (m, 1H), 3.89-3.98 (m, 2H), 4.09 (s, 3H),
4.29 (s, 3H), 7.62 (d, J=8.6 Hz, 1H), 7.73 (s, br, 2H), 8.03 (d,
J=8.6 Hz, 1H), 8.20 (s, 1H), 8.55 (s, 1H);). ES-MS: m/z: 366
(M+1).sup.+. ##STR39##
[0144] Ester xlii was prepared by the methodology of Method H.
3-Ethynylpyridine was obtained from Aldrich Chemical Co. .sup.1H
NMR (CDCl.sub.3) .delta.: 8.18 (d, J=8.6 Hz, 1H), 8.00 (s, 1H),
7.62 (s, 1H), 7.53 (dd, J=1.8, 8.5, 1H), 7.50 (m, 1H), 7.21 (m,
1H), 4.20 (s, 3H), 4.05 (s, 3H), 3.16 (m, 2H), 3.06 (m, 2H).
Method I
[0145] This method describes additional homologation strategies for
the A ring of various intermediates. ##STR40##
[0146] A solution of the ester xxvii (500 mg, 1.27 mmol),
acrylonitrile (0.2 mL, 3.03 mmol), Pd(PPh.sub.3).sub.4 (50 mg, 0.04
mmol), and triethylamine (0.5 mL) in 4 mL of DMF was stirred at
90.degree. C. for 18 h. The reaction mixture was cooled to room
temperature, diluted with water, and the precipitate was collected
by filtration. The residue was purified by chromatography (silica,
CH.sub.2Cl.sub.2/MeOH, 96:4) to obtain the desired cyano ester xlii
(250 mg, 62%). A suspension of this ester xliii (250 mg, 0.78 mmol)
and 10% Pd/C (50 mg) in 10 mL of EtOH/MeOH (1:1) was hydrogenated
at 45 psi for 18 h. The catalyst was filtered, washed with
CH.sub.2Cl.sub.2 and MeOH, and the filtrate was concentrated to
dryness to give the desired product as a solid (250 mg,
quantitative). .sup.1H NMR (DMSO-d.sub.6) .delta. 8.36 (d, J=1.4
Hz, 1H), 8.24 (s, 1H), 8.04 (J=8.6 Hz, 1H), 7.96 (s, 1H), 7.88 (s,
1H), 7.79 (dd, J=8.6, 1.8 Hz, 1H), 4.13 (s, 3H), 4.02 (s, 3H), 3.12
(t, J=7.2 Hz, 2H), 2.94 (t, J=6.7 Hz, 2H).
[0147] Another example of the methodology illustrated by Method I:
##STR41##
[0148] To a mixture of 6-iodo-7- trifluoromethyl methyl ester xxxiv
(661 mg, 1.43 mmol, prepared in Method H), P(o-tol).sub.3 (872 mg,
2.87 mmol), NaOAc (259 mg, 3.15 mmol), and Pd(OAc).sub.2 (322 mg,
1.43 mmol) in DMF (20 mL), acrylonitrile (5.0 mL, 76 mmol) was
added at room temperature under nitrogen. The mixture was stirred
and heated to 115.degree. C. for 6 h. The mixture was cooled to
room temperature and concentrated. The residue was dissolved in
CH.sub.2Cl.sub.2, washed with water and brine, dried, and
evaporated. Flash chromatography of the residue over silica gel,
using 1:4:5 MeOH-EtOAc-hexane, gave a (Z) and (E) mixture of the
unsaturated nitrile xliv (253 mg) as a solid: .sup.1H NMR
(DMSO-d.sub.6) .delta. 4.03(s, 1.2H), 4.06(s, 1.8H), 4.17(s, 1.2H)
4.18(s, 1.8H), 6.28(d, J=12 Hz, 0.4H), 6.63(d, J=17 Hz, 0.6H),
7.78(d, J=12 Hz, 0.4H), 7.87(d, J=17 Hz, 0.6H), 7.96(s, 1H),
8.06(s, 1H), 8.48(s, 1H), 8.52(s, 1H), 8.89(s, 0.6H), 9.13(s,
0.4H); MS: 387.0(M.sup.+H.sup.+).
Method J
[0149] This method describes additional methodology for elaboration
of the A ring of one of the intermediates. ##STR42##
[0150] To a solution of the 7-iodoquinoline (440 mg, 1.12 mmol,
prepared as in Method A) in dry, degassed acetonitrile, (28 mL) was
added finely ground and dried NaCN (110 mg, 2.24 mmol), CuI (21.3
mg, 0.112 mmol), and Pd(PPh3).sub.4 (65 mg; 0.056 mmol) under
nitrogen. The mixture was stirred and heated to reflux for 1.5 h.
The reaction was diluted with ethyl acetate, filtered and the
filtrate was evaporated under reduced pressure. The residue was
purified by chromatography: (2.5% MeOH/CH.sub.2Cl.sub.2,) to yield
xlvi (161.4 mg). .sup.1H NMR (CDCl.sub.3) .delta. 4.08 (s, 3H),
4.20 (s, 3H), 7.46 (ddd J=2.8, 3.8, 5.1 Hz 1H), 7.65 (m, 1H), 8.32
(s, 1H), 8.39 (s, 1H), 8.86 (d, J=8.8 Hz, 1H). ##STR43##
[0151] To a stirred solution of the 7-cyanoquinoline xlvi (119 mg,
0.41 mmol) in THF (20 mL) was added LiBH.sub.4 (0.31 mL, 0.61 mmol,
2.0M/THF). The resulting solution was refluxed for 0.5 h, poured
into water, extracted with ethyl acetate and washed with dilute
HCl. The aqueous phase was basified and re-extracted with ethyl
acetate. The combined ethyl acetate extracts were combined and
reduced to dryness to give 34 mg of xlvii as a crude solid product,
which was used in the next step without further purification.
.sup.1H NMR (DMSO-d.sub.6) .delta. 4.13 (s, 3H), 5.02 (s, 2H),
7.81-7.89 (m, 3H), 8.06 (s, 1H), 8.21 (d, J=12 Hz, 1H), 8.53 (s,
1H). MS 265.1.0 (M+H.sup.+). ##STR44##
[0152] To a stirred solution of the crude alcohol xlvii (34 mg,
0.129 mmol) in CH.sub.2Cl.sub.2 (10 mL) was added the Dess-Martin
periodinane reagent (73 mg, 0.172 mmol). The solution was stirred
for 1 h at room temperature, poured into water, extracted with
CH.sub.2Cl.sub.2 and washed with 10% aqueous
Na.sub.2S.sub.2O.sub.3, saturated aqueous NaHCO.sub.3, and brine.
The organic solution was dried over Na.sub.2SO.sub.4. The residue
was chromatographed on silica gel (5% MeOH/CH.sub.2Cl.sub.2) to
provide the corresponding aldehyde xlviii, 34.8 mg (two steps).
.sup.1H NMR (CDCl.sub.3) .delta. 4.25 (s, 3H), 7.70(s, 1H), 7.80
(d, J=8 Hz, 1H), 7.88 (s, 1H), 8.21 (s, 1H), 8.46 (s, 1H), 9.12 (d,
J=8.8 Hz, 1H). ##STR45##
[0153] To a solution of ester xlv (430 mg, 1.09 mmol) in DMF (5 mL)
at rt was added triethylamine (0.35 mL, 2.5 mmol) followed by
dimethylamine (2.2 mL of a 2.0 M solution in THF, 4.4 mmol). The
reaction mixture was gently purged with carbon monoxide for 5 min,
Pd(PPh.sub.3).sub.4 (115 mg, 0.10 mmol) was added and the resulting
mixture was stirred under 1 atm of carbon monoxide at rt for 5 h
and then at 70.degree. C. for 3 h. The reaction mixture was cooled
to rt and concentrated under vacuum. Chromatography
(9:1/CH.sub.2Cl.sub.2:MeOH) of the residue afforded 173 mg of xlix
sufficiently pure for further use. .sup.1H NMR (CDCl.sub.3)
.delta.: 8.76 (d, J=8.7, 1H), 8.24 (s, 1H), 8.12 (s, 1H), 7.74 (s,
1H), 7.63-7.60 (m, 2H), 4.19 (s, 3H), 4.07 (s, 3H), 3.18 (s, 3H),
3.05 (s, 3H). ##STR46##
[0154] To a solution of ester xlv (225 mg, 0.57 mmol) in DMF (2 mL)
was added AsPh.sub.3 (15 mg, 0.05 mmol), CuI (11 mg, 0.06 mmol) and
Pd.sub.2dba.sub.3 (22 mg, 0.02 mmol). The reaction mixture was
purged with nitrogen for 5 min, vinyltributyltin (0.34 mL, 1.2
mmol) was added and the reaction mixture was heated to 65.degree.
C. for 3 h. After pouring onto water and saturated aqueous
NaHCO.sub.3 (15 mL each), the mixture was extracted with EtOAc
(3.times.20 mL). The combined organic extracts were washed with
saturated aqueous KF (2.times.20 mL), dried (MgSO.sub.4) and
concentrated. Chromatography (25:1/CH.sub.2Cl.sub.2:MeOH) provided
140 mg of product l. .sup.1H NMR (CDCl.sub.3) .delta.: 8.66 (d,
J=8.8 Hz, 1H), 8.15 (s, 1H), 7.99 (s, 1H), 7.71 (d, J=8.8 Hz, 1H),
6.91 (dd, J=11.0 17.6 Hz, 1H), 5.99 (d, J=17.6 Hz, 1H), 5.46 (d,
J=11.0, 1H), 4.21 (s, 3H), 4.06 (s, 3H). ##STR47##
[0155] Magnesium turnings (240 mg, 9.95 mmol) were placed in a
3-neck flask containing dry THF (2 mL) and the flask was placed in
a bath at 50.degree. C. Cyclopropylbromide (0.79 mL, 10 mmol) was
added dropwise under gentle reflux and the mixture was heated to
reflux for 1 h. After cooling to rt, the mixture was added to a
solution of zinc chloride in THF (1M, 20 mL, 10 mmol) at 0.degree.
C. and it was stirred at rt for 2 h. A solution of iodide xlv (393
mg, 1.0 mmol) in THF (5 mL) was added, followed by
PdCl.sub.2(dppf).sub.2 (41 mg, 0.05 mmol) and the resulting mixture
was stirred overnight. The reaction was quenched by addition of
saturated aqueous NH.sub.4Cl (10 mL) and saturated EDTA-sodium
aqueous solution (10 mL). The resulting mixture was extracted with
CH.sub.2Cl.sub.2 (3.times.30 mL), washed with brine and dried
(MgSO.sub.4). Concentration followed by column chromatography
(CH.sub.2Cl.sub.2:MeOH/30:1) gave the desired product li as a
yellow solid (290 mg). .sup.1H-NMR (CDCl.sub.3) .delta.: 0.91-0.94
(m, 2H), 1.13-1.16 (m, 2H), 2.12-2.15 (m, 1H), 4.08 (s, 3H), 4.28
(s, 3H), 7.37 (d, J=8.8 Hz, 1H), 7.76 (s, 1H), 7.82 (s, br, 1H),
7.95 (s, br, 1H), 8.13 (s, 1H), 8.64 (d, J=8.8 Hz). ES-MS: m/z: 308
(M+1).sup.+.
Method K
[0156] This method describes additional methodology for the
elaboration of the A ring of one of the intermediates.
##STR48##
[0157] To a stirred solution of xlv (500 mg, 1.27 mmol) in dioxane
(30 mL) under an atmosphere of nitrogen was added
1-(ethoxyvinyl)tri-n-butyl stannane (482 mg, 1.33 mmol) and
(Ph3P)4Pd (catalytic amount, .about.5 mg) and the mixture was
heated at 100.degree. C. for 12 h. Additional amounts of
1-(ethoxyvinyl)tri-n-butylstannane (482 mg, 1.33 mmol) and
(Ph3P)4Pd (catalytic amount, .about.5 mg) were added and the
mixture stirred for 12 h at 100.degree. C. The mixture was
concentrated to dryness and flash chromatography (gradient elution
CH.sub.2Cl.sub.2 to CH.sub.2Cl.sub.2:MeOH 98:2) afforded the
desired product lii (350 mg). .sup.1H NMR (CDCl.sub.3): .delta.
8.52 (d, J=8 Hz, 1H), 8.15 (s, 1H), 7.99 (s, 1H), 8.71 (d, J=8 Hz,
1H), 7.60 (s, 1H), 7.44 (s, 1H), 4.80 (s, 1H), 4.29 (s, 1H), 4.07
(s, 3H), 3.93 (s, 3H), 3.90 (q, J=6.5 Hz, 2H), 1.42 (t, J=6.5 Hz,
3H); ESI-MS m/z 338.1 (100, M+H.sup.+).
[0158] To a stirred solution of quinoline lii (350 mg, 1.0 mmol) in
dioxane (10 mL) was added conc. sulfuric acid (0.5 mL). The mixture
was stirred overnight at room temperature and quenched with
saturated aqueous sodium bicarbonate. Dichloromethane was added and
the organic phase was collected, dried (Na.sub.2SO.sub.4), filtered
and concentrated in vacuo to afford an intermediate ketone (128
mg). .sup.1H NMR (CDCl.sub.3) .delta. 8.80 (d, J=8 Hz, 1H), 8.61
(s, 1H), 8.28 (s, 1H), 8.14 (d, J=8 Hz, 1H), 7.78 (s, 1H), 7.60 (s,
1H), 4.12 (s, 3H), 4.05 (s, 3H), 2.80 (s, 3H); ESI-MS m/z 310.1
(100, M+H.sup.+).
[0159] To a stirred solution of intermediate ketone (128 mg, 0.41
mmol) in anhydrous methanol (5 mL) at 0.degree. C. was added sodium
borohydride (31 mg, 0.82 mmol) under nitrogen and the mixture was
stirred for 2 h, then quenched by the addition of saturated aqueous
ammonium chloride (10 mL) and diluted with dichloromethane (60 mL).
The organic phase was collected, washed with brine, dried
(MgSO.sub.4), filtered and concentrated in vacuo. Flash
chromatography (gradient elution --CH.sub.2Cl.sub.2 99:1 to
CH.sub.2Cl.sub.2:MeOH 97:3) afforded an intermediate alcohol (115
mg, 90%). .sup.1H NMR (CDCl.sub.3) .delta. 8.63 (d, J=8 Hz, 1H),
8.08 (s, 1H), 7.98 (s, 1H), 7.44-7.63 (m, 3H), 5.04 (q, J=7 Hz,
1H), 4.14 (s, 3H), 4.07 (s, 3H), 1.60 (d, J=7 Hz, 3H); ESI-MS m/z
312.2 (100, M+H.sup.+).
[0160] To a stirred solution of the intermediate alcohol (115 mg,
0.36 mmol) in DMF (5 mL) under an atmosphere of nitrogen was added
imidazole (63 mg, 0.93 mmol) and tert-butyldimethylsilyl chloride
(444 .mu.l of a 1.0 M solution in THF, 0.44 mmol). The mixture was
stirred at room temperature for 12 h then concentrated in vacuo.
The residue was taken up in dichloromethane and washed with
saturated aqueous ammonium chloride and brine. The organics were
dried (MgSO.sub.4), filtered and concentrated in vacuo. Flash
chromatography (gradient elution CH.sub.2Cl.sub.2 to
CH.sub.2Cl.sub.2:MeOH 97.5:2.5) afforded liii (127 mg, 84%).
.sup.1H NMR (CD.sub.3OD) .delta. 8.60 (d, J=8 Hz, 1H), 8.08 (s,
1H), 7.93 (s, 1H), 7.45-7.60 (m, 3H), 4.51 (q, J=6 Hz, 1H), 4.12
(s, 3H), 3.98 (s, 3H), 1.40 (d, J=6 Hz, 3H), 0.82 (s, 9H), 0.02 (s,
3H), -0.04 (s, 3H); ESI-MS m/z 426.2 (100, M+H.sup.+).
##STR49##
[0161] Copper powder (ca. 1 micron, 0.31 g, 4.82 mmol), and DMSO (4
mL) were charged to a resealable pressure tube and cooled to
0.degree. C. Pentafluoroethyl iodide(0.3 mL, 626 mg, 2.54 mmol) was
added and the mixture was heated at 110.degree. C.-120.degree. C.
for 4 h. After cooling to room temperature, the blue-green reagent
was removed and added to intermediate xlv(237 mg, 0.605 mmol). The
mixture was heated to 65.degree. C. for 1 h. The cooled mixture was
poured into 1N HCl (20 mL) and THF (20 mL). The organic phase was
separated, washed with water, brine, dried and evaporated Flash
chromatography of the residue over silica gel, using 1:4:5
MeOH-EtOAc-hexane, gave the pentafluoroethyl compound liv (180 mg)
as a pure solid. .sup.1H NMR (DMSO-d.sub.6) .delta. 4.03 (s, 3H),
4.15 (s, 3H), 7.88 (d, J=9.4 Hz, 1H), 7.92 (s, 1H), 7.98 (s, 1H),
8.37 (s, 1H), 8.43 (s, 1H), 8.74 (d, J=9.4 Hz, 1H); ms
386.1(M.sup.+H.sup.+).
Method L
[0162] This method describes the synthesis of compounds in which
the B ring is linked to the remainder of the molecule via a
nitrogen atom. ##STR50##
[0163] A stirred solution of 4-carbomethoxy quinolin-2-one
(prepared as shown in Method D (1.76 g, 9 mmol), POCl.sub.3 (4.6 g,
30 mmol) in toluene (40 mL) was heated at reflux for 2 h then
allowed to cool to room temperature and poured into ice water (50
mL). The mixture was extracted with ethyl acetate (3.times.50 mL).
The organics were combined, washed with water, brine, dried
(MgSO.sub.4) and concentrated in vacuo to afford the desired
2-chloro-4-carbomethoxyquinoline lv (1.50 mg). .sup.1H NMR
(DMSO-d.sub.6) .delta. 8.54 (d, J=8 Hz, 1H), 8.03-8.06 (m, 1H),
7.89-7.94 (m, 2H), 7.75-7.77 (m, 1H), 3.98 (s, 3H); ESI-MS m/z
222.1 (100, M+H.sup.+).
[0164] To a stirred solution of 2-chloro-4-carbomethoxyquinoline lv
(346 mg, 1.5 mmol) in anhydrous n-butanol (5 mL) was added
imidazole (212 mg, 3 mmol) and the mixture was heated at reflux for
48 h then imidazole (212 mg, 3 mmol) was added. The mixture was
heated at reflux for a further 12 h then cooled to room temperature
and concentrated in vacuo. Flash chromatography afforded the
desired product lvi as the n-butyl ester (152 mg, 34%); .sup.1H NMR
(CDCl.sub.3) .delta. 8.56 (d, 1H, J=8 Hz), 8.56 (s, 1H) 8.10 (d,
1H, J=8 Hz), 8.01 (s, 1H), 7.88 (s, 1H), 7.93-7.83 (m, 1H)
7.65-7.67 (m, 1H) 7.28 (s, 1H) 4.51 (t, J=8 Hz, 3H) 1.82-1.88 (m,
2H), 1.50-1.56 (m, 2H), 1.03 (t, J=8 Hz, 3H) 2.96 (s, 3H); ESI-MS
m/z 296.1 (100, M+H.sup.+). Method M ##STR51##
[0165] To a stirred solution of methyl magnesium chloride (1.6 mL
of a 3.0 M solution in THF, 4.8 mmol) in anhydrous THF (16 ml) at
-78.degree. C. under an atmosphere of nitrogen was added a solution
of zinc bromide (1.08 g, 4.8 mmol) in THF (5 mL). The mixture was
stirred at -78.degree. C. for 1 h then warmed to room temperature
whereupon a mixture of tetrakis(triphenylphosphine) palladium (0)
(228 mg, 0.20 mmol) and 2,4-dichloroquinazoline lvii (800 mg, 0.40
mmol, see Butler, et al., J. Chem. Soc. 1959, 1512) were added as a
solution in THF (11 mL). The mixture was then heated at 50.degree.
C. for 12 h then cooled to 0.degree. C. and quenched by the
addition of saturated aqueous ammonium chloride and diluted with
ethyl acetate. The organics were collected, dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. Flash
chromatography (EtOAc:hexane 1:5 afforded the desired product lviii
as a white solid (410 mg, 57%). .sup.1H NMR (CDCl.sub.3) .delta.
8.07 (d, J=9 Hz, 1H), 7.88-7.92 (m, 2H), 7.61-7.64 (m, 1H) 2.93 (s,
3H); ESI-MS m/z 179.1 (100, M+H.sup.+).
[0166] A stirred solution of 2-chloro-4-methyl quinazoline lviii
(250 mg, 1.4 mmol), 1-methyl-(5-tri-n-butylstannyl) imidazole (523
mg, 1.4 mmol, Gaare, et al., Acta Chem. Scand., 47:57 (1993)),
triphenyl arsine (43 mg, 0.14 mmol), Pd.sub.2(dba).sub.3 (63 mg,
0.07 mmol) and CuI (26 mg) in DMF (5 mL) was purged with nitrogen
gas for 5 min. then stirred under nitrogen at 60.degree. C. for 12
h. The mixture was allowed to cool to room temperature then diluted
with ethylacetate and water. The organics were collected, washed
with water, saturated aqueous KF and water then dried
(Na2SO.sub.4), filtered and concentrated in vacuo. Flash
chromatography (gradient elution CH.sub.2Cl.sub.2:MeOH 99:1 to
96:4) afforded the desired product lix as a white solid (243 mg,
77%). .sup.1H NMR (CDCl.sub.3) .delta. 8.05-8.10 (m, 2H), 7.79-7.98
(m, 2H) 7.50-7.66 (m, 2H) 4.22 (s, 3H) 2.96 (s, 3H); ESI-MS m/z
225.2 (100, M+H.sup.+).
[0167] To a stirred solution of quinazoline lvix (78 mg, 0.34 mmol)
in 1,4-dioxane (2 mL) was added selenium dioxide (54 mg, 0.48 mmol)
and the mixture was heated at reflux for 150 min. The mixture was
allowed to cool to room temperature, filtered and concentrated to
approx. 5 mL. Flash chromatography (CH.sub.2Cl.sub.2:MeOH 95:5)
afforded the aldehyde which was concentrated to 10 mL volume then
water (2 mL) and ethanol (10 mL) were added. The mixture was again
concentrated to 5 mL and ethanol (10 mL) was added and the mixture
again concentrated to 2 mL. The solution of aldehyde lx was taken
on directly to the following reaction.
Method N
[0168] The following example is a variation of Method M in which
the B ring is attached to the central ring via a nitrogen atom.
##STR52##
[0169] To a stirred solution of methyl magnesium chloride (1.62 mL
of a 3.0M solution in THF, 4.8 mmol) in THF (16 mL) at -78.degree.
C. under nitrogen was added zinc bromide (1.09 g, 4.8 mmol) in THF
(5 mL). The mixture was stirred at -78.degree. C. for 1 h and then
allowed to warm to room temperature whereupon
tetrakis(triphenylphosphine) palladium (233 mg, 0.02 mmol) and
1,3dichloroisoquinoline lxi (800 mg, 4.0 mmol, Robinson, J. Am.
Chem. Soc., 1958, 80, 5481) were added. The mixture was stirred at
50 .degree. C. for 12 h then cooled to 0.degree. C. Saturated
aqueous ammonium chloride (10 mL) and ethyl acetate (60 mL) were
added and the organics separated, dried (Na2SO.sub.4), filtered and
concentrated in vacuo. Flash chromatography (hexane:EtOAc 7:1)
afforded the desired product lxii (597 mg, 84%). .sup.1H NMR
(CDCl.sub.3) .delta. 8.03-8.05 (m, 1H), 7.52-7.55 (m, 4H) 2.92 (s,
3H); GCMS m/z 177 (100, M.sup.+).
[0170] To a stirred suspension of sodium hydride (159 mg, 6.6 mmol)
in DMF (2 mL) was added imidazole (562 mg, 8.2 mmol) in DMF (2 mL)
and the mixture was allowed to stir at room temperature for 2 h
whereupon a solution of 3-chloro-1-methyl isoquinoline lxii (293
mg, 1.6 mmol) in DMF (2 mL) was added. The mixture was then stirred
at 120.degree. C. for 48 h, cooled and quenched by the addition of
saturated aqueous ammonium chloride (20 mL) and diluted with
dichloromethane (50 mL). The organics were collected, dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. Flash
chromatography (gradient elution CH.sub.2Cl.sub.2:MeOH 99:1 to
95:5) afforded the desired product lxiii (106 mg, 32%). .sup.1H NMR
(CDCl.sub.3) .delta. 8.22 (s, 1H), 8.16 (s, 1H) 7.80-7.82 (m, 1H),
7.62-7.67 (m, 2H), 7.51-7.60 (m, 1H) 7.44 (s, 1H) 7.21 (s, 1H),
2.97 (s, 3H).
[0171] To a stirred solution of isoquinoline lxiii (165 mg, 0.78
mmol) in 1,4-dioxane (5 mL) was added selenium dioxide (438 mg, 3.9
mmol) and the mixture was heated at reflux for 14 h then cooled to
room temperature, filtered and the filtrate concentrated to approx.
5 mL. Flash chromatography (CH.sub.2Cl.sub.2:MeOH) afforded the
desired product lxiv as indicated by mass spectrometry.
Method O
[0172] This method describes additional ways of modifying the A
ring of one of the intermediates. ##STR53##
[0173] To a stirred solution of 4-nitro-2-trifluoromethylanisole
(20.4 g, 92.3 mmol, Aldrich) in MeOH (205 mL) was added Pd.C (612
mg) followed by a balloon of H.sub.2 gas. The reaction was stirred
overnight, filtered through Celite to give, after solvent removal,
the aniline lxv (17.6 g). .sup.1H NMR (CDCl.sub.3) .delta. 3.54 (br
s, 2H), 3.82 (s, 3H), 6.80 (dd, J=4, 12 Hz, 1H), 6.85 (d, J=12 Hz,
1H), 6.91 (d, J=4 Hz, 1H) ##STR54##
[0174] Di-tert-butyl dicarbonate (29.0 g, 0.133 mol) was added to a
solution of 4-methoxy-3-trifluoromethylaniline lxv (23.1 g, 0.12
mol) in THF (75 mL). The resulting solution was refluxed overnight,
cooled and the solvent removed under reduced pressure, the
resulting black oil was chromatographed (hexane/ethyl acetate as
eluant) to give 24.6 g of the product lxvi. .sup.1H NMR
(DMSO-d.sub.6) .delta. 1.48 (s, 9H), 3.82 (s, 3H), 7.17 (d, J=12
Hz, 1H), 7.61(d, J=12 Hz, 1H), 7.81(s, 1H), 9.42 (s, 1H).
##STR55##
[0175] To a stirred solution of intermediate lxvi (18.5 g, 63.5
mmol) in dry THF (200 mL) at -78.degree. C. under N.sub.2 was added
tert-BuLi (90 mL, 152 mmol, 1.7M/hexane). After 3 h diethyl oxalate
(10.3 mL, 76.2 mmol) was added at once. This mixture was stirred
for 0.5 h and kept at -30.degree. C. for 14 h. At this time all
solvent was removed and the dry residue treated with THF (250 mL)
and 3M HCl (250 mL)and subsequently refluxed for 4 h. The reaction
was cooled and the THF removed. The solid isatin precipitated out
of solution during this time. It was filtered, washed with H.sub.2O
to yield 8.2 g of pure 5-methoxy-6-trifluoromethylisatin lxvii.
.sup.1H NMR (DMSO-d.sub.6) .delta. 3.89 (s, 3H), 7.05 (s, 1H), 7.42
(s, 1H), 10.99(s, 1H). ##STR56##
[0176] To a stirred mixture of the isatin (335 mg, 1.37 mmol) under
N.sub.2 at -78.degree. C. in CH.sub.2Cl.sub.2 (3 mL) was added
BBr.sub.3 (2.5 mL, 27.4 mmol) dropwise. The mixture was allowed to
reach room temperature in the course of being stirred overnight.
The mixture was then carefully poured on ice and the residue
extracted with ethyl acetate. Chromatography (5%
MeOH/CH.sub.2Cl.sub.2) yielded 127 mg of intermediate lxviii.
.sup.1H NMR (DMSO-d.sub.6) .delta. 6.94 (s, 1H), 7.19 (s, 1H),
10.67(s, 1H), 10.92(s, 1H). ##STR57##
[0177] To a stirred solution of the isatin lxviii (256 mg, 1.1
mmol) in DMF was added TBDPSiCl (457 mg, 1.66 mmol) and imidazole
(226 mg, 3.3 mmol) then heated to 55.degree. C. for 1 h. The
mixture was poured into H.sub.2O extracted with ether and
chromatographed (4:1 hexane/ethyl acetate) yield 357 mg of lxix.
.sup.1H NMR (DMSO-d.sub.6) .delta. 0.31 (s, 6H), 0.90 (s, 9H), 7.08
(s, 2H), 11.05 (s, 1H). ##STR58##
[0178] A solution of the isatin lxix (504 mg, 2.18 mmol), imidazole
v (571 mg, 2.4 mmol) in AcOH (7 mL) and conc HCl (2.2 mL) was
refluxed for 9 days. At this time the solvents were removed, the
dry residue was dissolved in MeOH (5 mL) and conc H.sub.2SO.sub.4
(catalytic) was added, and the solution was refluxed overnight. The
majority of the solvent was removed and a saturated NaCl solution
was added. The solid precipitate was filtered and collected. Yield
of lxx: 275 mg two steps.
[0179] Alternatively:
[0180] To a stirred solution of the isatin lxix (215 mg, 0.46 mmol)
and imidazole v (109 mg, 0.46 mmol) in EtOH (1 mL) was added Et3N
(0.16 mL, 1.15 mmol) dropwise, and the resulting solution was
stirred overnight. At this time a precipitate formed which was
filtered off (88 mg). The remaining filtrate was dried under
reduced pressure and the resulting residue was combined with the
solid and subjected to THF (1.7 mL) and conc HCl (0.68 mL). This
mixture was refluxed overnight, then dried to a residue under
reduced pressure, MeOH (5.0 mL) and H.sub.2SO.sub.4 (0.2 mL) was
added and the mixture refluxed overnight. A solid precipitated,
lxx, was filtered and collected. Yield: 100 mg in three steps.
.sup.1H NMR (DMSO-d.sub.6) .delta. 4.02 (s, 3H), 4.28 (s, 3H), 8.29
(s, 1H), 8.42 (s, 1H), 8.46 (s, 1H), 8.52 (s, 1H), 9.10 (s, 1H),
11.61 (s, 1H). ##STR59##
[0181] To stirred solution of intermediate lxx (355.4 mg, 1.00
mmol) in DMF (5 mL) was added K.sub.2CO.sub.3 (152 mg, 1.10 mmol)
at 0.degree. C., after 15 min. bromoacetonitrile (0.14 mL, 2.0
mmol) was added at room temperature. After 1 h the reaction mixture
was placed in an oil bath, 55.degree. C. and heated for 1.5 h. At
this time an additional amount of bromoacetonitrile (0.14 mL, 2.0
mmol) was added. The reaction was kept for two more h at 55.degree.
C. when another 2 mmol of bromoacetonitrile was added. Heating
(40-50.degree. C.) was continued overnight. At this time the
mixture was poured into water, extracted with diethyl ether, washed
with sat. NaHCO.sub.3 and brine to give after solvent removal the
crude product lxxi. Yield: 187 mg.
Example 1
[0182] This example illustrates a procedure for the conversion of a
derivatized aromatic ester or aldehyde into a desired compound of
formula I. 1.1 Preparation of Aldehyde lxxii ##STR60##
[0183] A solution of the ester iii (1.7 g, 6.4 mmol, prepared as
described by Method A) in 20 mL of THF was cooled to -78.degree. C.
under nitrogen. A 1.0 M solution of LiAlH.sub.4 (7 mL, 7.0 mmol) in
THF was added and the reaction stirred at the same temperature for
90 min. The reaction was quenched with water, allowed to reach room
temperature, diluted with EtOAc and washed with water, brine, dried
over Na.sub.2SO.sub.4, and concentrated to give a mixture of the
corresponding aldehyde and alcohol. The crude product was purified
(SiO.sub.2, CH.sub.2Cl.sub.2/MeOH, 95:5) to obtain the aldehyde
lxxii (0.6 g, 39%) as a yellow solid. .sup.1H NMR (DMSO-d.sub.6)
.delta. 10.49 (s, 1H), 8.91 (dd, J=8.4, 1.0 Hz, 1H), 8.52 (s, 1H),
8.11 (dd, J=8.5, 1.0 Hz, 1H), 7.94 (s, 1H), 7.91 (s, 1H), 7.85
(ddd, J=8.4, 6.9, 1.5 Hz, 1H), 7.72 (ddd, J=8.4, 6.9, 1. Hz, 1H),
4.17 (s, 3H). 1.2 Preparation of Final Semicarbazone 1.1
##STR61##
[0184] A mixture of 200 mg (0.84 mmol) of the aldehyde lxxii (100
mg, 0.89 mmol, prepared in Example 1.1) of semicarbazide
hydrochloride (Aldrich Chemical Co., Milwaukee, Wis., USA), and 100
mg (0.72 mmol) of K.sub.2CO.sub.3 in 5 mL of EtOH was stirred in an
oil bath at 70.degree. C. for 18 h. The reaction mixture was cooled
and the precipitate was filtered, washed with water, and dried
under vacuum to give the desired product 1.1 (170 mg). mp
236-237.degree. C.; .sup.1H NMR (DMSO-d.sub.6) .delta. 10.6 (s,
1H), 8.65 (s, 1H), 8.39 (s, 1H), 8.25 (d, J=7.9 Hz, 1H), 8.03 (d,
J=7.5 Hz, 1), 7.99 (s, 1H), 7.84 (s, 1H), 7.78 (br t, J=7.1 Hz,
1H), 7.64 (br t, J=7.0 Hz, 1H), 6.82 (br s, 2H), 4.15 (s, 3H);
Anal. Calcd. for C.sub.15H.sub.14N.sub.6O: C, 61.22; H, 4.79; N,
28.55. Found: C, 61.12; H, 4.69; N, 28.35. 1.3 Preparation of Final
N-methylsemithiocarbazone 1.2 ##STR62##
[0185] A solution of the aldehyde lxxii (200 mg, 0.84 mmol,
prepared in Example 1.1) and 2-methyl-3-thiosemicarbazide (84 mg,
0.84 mmol) in 3 mL of EtOH was stirred at 70.degree. C. for 18 h.
The reaction brought to room temperature and the solid collected by
filtration, washed with ethanol and water and dried to obtain the
desired product 1.2 (130 mg) as a yellow solid. mp 229-230.degree.
C.; .sup.1H NMR (DMSO-d.sub.6) .delta. 8.69 (br s, 1H) 8.60 (br s,
1H), 8.55 (s, 1H), 8.54 (d, J=7.8 Hz, 1H), 8.49 (s, 1H), 8.04 (d,
J=7.4 Hz, 1H), (s, 1H), 7.85 (s, 1H), 7.80 (br t, J=8.2 Hz, 1H),
7.64 (br t, J=8.3 Hz, 1H), 4.15 (s, 3H), 3.97 (s, 3H).
[0186] The following compounds were prepared in a similar manner,
beginning with the corresponding esters prepared by Method B.
##STR63##
[0187] .sup.1H NMR (DMSO-d.sub.6) .delta. 10.54 (s, 1H). 8.53 (s,
1H), 8.48 (s, 1H) 8.40 (s, 1H), 8.28 (s, 1H), 8.05 (br s, 1H), 7.85
(br s, 1H), 6.82 (br s, 1H), 4.13 (s, 3H); ESI-MS m/z 363.0 (100,
M+H.sup.+). ##STR64##
[0188] .sup.1H NMR (d.sub.6-DMSO) .delta.: 10.53 (s, 1H), 8.66 (s,
1H), 8.31 (s, 1H), 8.00 (s, 1H), 7.93 (s, 1H), 7.85 (s, 1H), 7.82
(s, 1H), 6.82 (broad s, 2H), 4.13 (s, 3H), 3.08 (t, J=7.2 Hz, 4H),
2.13 (m, 2H).
[0189] The following compounds were prepared by similar methods
beginning with the corresponding esters prepared by Method D.
##STR65##
[0190] The starting ester was reduced by the standard procedure
described in Example 1.1 to afford a mixture of aldehyde and
alcohol. The thiosemicarbazone was prepared from this mixture by
using the standard procedure described in Example 1.3. The
trityl-protected thiosemicarbazone lxxiv (12 mg, 0.02 mmol) was
treated with TFA:DCM (1:1, 2 mL) and stirred at room temperature
for 5 h, then concentrated in vacuo. Reverse phase HPLC afforded
the desired product 1.5 (3 mg, 50%); .sup.1H NMR (CD.sub.3OD)
.delta. 8.78 (s, 1H), 8.31-8.48 (m, 3H), 8.04-8.08 (m, 1H),
7.74-7.79 (m, 1H), 7.58-7.63 (m, 1H); ESI-MS m/z 297.0 (100,
M+H.sup.+).
[0191] The following compound was prepared by the standard
procedure (see synthesis of Examples 1.1 and 1.2), using an ester
prepared according to Method E. ##STR66##
[0192] The aldehyde was prepared by LAH reduction of the ester
xxiii: .sup.1H NMR (CDCl.sub.3) .delta. 10.18 (s, 1H), 7.67 (s,
1H), 7.50 (s, 1H), 7.46 (s, 1H), 4.00 (s, 3H), 3.16-3.19 (m, 2H),
2.98-3.05 (m, 2H), 1.81-1.97 (m, 2H).
[0193] The semicarbazone was prepared by the standard procedure to
provide 1.6: .sup.1H NMR (MSO-d.sub.6) .delta. 10.45 (s, 1H). 8.09
(s, 1H), 8.01 (s, 1H) 7.67 (s, 1H), 7.57 (s, 1H), 7.65 (br s, 1H),
3.92 (s, 3H), 2.77-2.85 (m, 4H), 1.78-1.81 (m, 4H); ESI-MS m/z
299.1 (100, M+H.sup.+).
[0194] The compound below was prepared by the standard procedure
(see Example 1.2) using an ester prepared according to Method F.
##STR67##
[0195] .sup.1H NMR (d.sub.6-DMSO) .delta.: 8.61 (s, 1H), 8.57 (s,
1H), 8.50-8.52 (m, 1H), 8.39 (s, 1H), 8.29 (s, 1H), 7.98-8.00 (m,
1H), 7.92 (m, 1H), 7.82 (s, 1H), 7.55-7.57 (m, 2H), 3.97 (s,
3H).
[0196] The compound described below was prepared using the methods
above beginning with the corresponding ester compound prepared
according to Method G. ##STR68##
[0197] .sup.1H NMR (d.sub.6-DMSO) .delta.: 10.48 (s, 1H), 9.74 (s,
1H), 8.79 (s, 1H), 8.40 (s, 1H), 8.33 (s, 1H), 8.05 (s, 2H), 7.99
(s, 1H), 7.84 (s, 1H), 7.68 (d, J=8.6 Hz, 2H), 6.93 (d, J=8.6 Hz,
2H), 6.83 (s, 2H), 4.17 (s, 3H).
[0198] The compound described below was prepared using the methods
above beginning with the corresponding diol compound prepared
according to Method H.
[0199] Preparation of 1.9. ##STR69##
[0200] A mixture of the diol xxxi (100 mg, 0.32 mmol) and MnO.sub.2
(1.0 g) in 10 mL of THF was stirred at room temperature for 18 h.
The reaction was filtered over Celite, the residue washed with THF
and EtOAc, and the filtrate concentrated to give a solid. The crude
was purified (SiO.sub.2, CH.sub.2Cl.sub.2/MeOH, 95:5) to give an
intermediate aldehyde (50 mg, 50%) which was carried on
directly.
[0201] A solution of the aldehyde (50 mg, 0.16 mmol) and
2-methyl-3-thiosemicarbazide (20 mg, 0.19 mmol) in 3 mL of EtOH was
stirred at reflux for 18 h. The reaction brought to room
temperature, the precipitate filtered, washed with EtOH, and dried
to give the desired N-methyl semithiocarbazone 1.9 (28 mg, 44%).
192.6-194.7.degree. C., .sup.1H NMR (DMSO-d.sub.6) .delta. 8.71 (br
s, 1H), 8.59 (br s, 1H), 8.53 (s, 1H), 8.45 (s, 1H), 8.31 (s, 1H),
7.97 (d, J=1.o Hz, 1H), 7.96 (d, J=8.5 Hz, 1H), 7.85 (s, 1H), 7.67
(dd, J=8.6, 1.7 Hz, 1H), 4.41 (t, J=5.1 Hz, 1H), 4.13 (s, 3H), 3.98
(s, 3H), 3.50-3.40 (m, 2H), 2.83 (t, J=7.6 Hz, 2H), 1.80-1.66 (m,
2H), 1.57-1.45 (m, 2H). ##STR70##
[0202] CaCl.sub.2 (-30+80 mesh, 34.1 mg, 0.308 mmol) and NaBH.sub.4
(23.3 mg, 0.616 mmol) was added to a stirred solution of the crude
saturated methyl ether xxxvi (125 mg, 0.308 mmol) in 1:1 THF-MeOH
(10 mL) at 0.degree. C. The cold bath was removed and stirring was
continued for 1.5 h. Water (2 mL) was added and the solution was
evaporated. The residue was dried under vacuum. To the residue THF
(5 mL), CH.sub.2Cl.sub.2 (5 mL), and Dess-Martin periodinane (522
mg, 1.2 mmol) were added. The mixture was stirred for 1 h, diluted
with THF (10 mL), and poured into saturated aqueous NaHCO.sub.3 (8
mL) containing Na.sub.2S.sub.2O.sub.3 (2.5 g). The mixture was
stirred for 30 min. EtOAc (10 mL) was added, and the layers were
separated. The organic layer was washed with water and brine,
dried, and evaporated. Flash chromatography of the residue over
silica gel, using 1:4:5 MeOH-EtOAc-hexane, gave the aldehyde lxxv
(95.2 mg in two steps) as a yellow solid: MS 378.2 (MH.sup.+).
[0203] Conversion of the aldehyde lxxv to compound 1.10 was
accomplished using the methods provided above. ##STR71##
[0204] Compound 1.10 was obtained as a yellow solid: .sup.1H NMR
(DMSO-d.sub.6) .delta. 1.94(m, 2H), 2.98(t, 2H), 3.45(t, 2H),
3.92(s, 3H), 4.15(s, 3H), 7.89(s, 1H), 8.06(s, 1H), 8.32(s, 1H),
8.52(s, 1H), 8.59(s, 2H), 8.75(s, 1H); exact mass (electrospray)
m/z calcd for C.sub.21H.sub.23F.sub.3N.sub.6OS (M+H) 465.2, found
465.2.
[0205] The following compounds were prepared using methods as
provided above. ##STR72##
[0206] .sup.1H NMR (DMSO-d.sub.6) .delta. 10.64 (s, 1H). 8.58 (s,
1H), 8.37 (s, 1H) 8.25 (d, J=8.5 Hz, 1H), 8.12 (s, 1H), 7.85 (s,
1H), 7.65 (d, J=8.5 Hz, 1H), 6.82 (br s, 1H), 4.45 (s, 1H), 4.13
(s, 3H). ESI-MS m/z 319.1 (100, M+H.sup.+). ##STR73##
[0207] .sup.1H NMR (CD.sub.3OD) .delta. 8.51 (s, 1H), 8.25 (s, 1H)
8.23 (s, 1H), 7.96 (s, 1H), 7.88 (s, 1H), 7.84 (s, 1H), 4.45 (s,
1H), 4.21 (s, 3H), 4.01 (s, 3H), 3.48-3.51 (m, 2H) 3.37 (s, 3H),
2.92-2.96 (m, 2H), 2.55 (s, 3H), 1.94-1.98 (m, 2H); ESI-MS m/z
411.5 (100, M+H.sup.+). ##STR74##
[0208] .sup.1H NMR (CD.sub.3OD) .delta. 9.04 (s, 1H), 8.39 (s, 1H)
8.33 (s, 1H), 8.24 (s, 1H), 8.16 (s, 1H), 7.91 (s, 1H), 4.39 (s,
3H), 3.95 (s, 3H), 3.54-3.71 (m, 6H, 2.92-2.96 (m, 2H), 2.55 (s,
3H), 1.93-2.02 (m, 2H); ESI-MS m/z 441.2 (100, M+H.sup.+).
##STR75##
[0209] .sup.1H NMR (d.sub.6-DMSO) .delta.: 8.96 (s, 1H), 8.54 (s,
1H), 8.47 (s, 1H), 8.37 (s, 1H), 7.92-7.97 (m, 3H), 7.83 (s, 1H),
7.68 (d, J=8.2 Hz, 1H), 4.13 (s, 3H), 3.83 (t, J=7.3 Hz, 1H),
3.58-3.75 (m, 2H), 2.75-2.85 (m, 2H), 1.98-2.21 (m, 2H), 1.70-1.80
(m, 2H), 1.48-1.62 (m, 2H). ##STR76##
[0210] .sup.1H NMR (d.sub.6-DMSO) .delta.: 8.76 (s, 1H), 8.58 (s,
1H), 8.49 (s, 1H), 8.47 (s, 1H), 8.41 (m, 1H), 8.34 (s, 1H), 8.29
(s, 1H), 8.17 (s, 1H), 7.99 (d, J=8.7 Hz, 1H), 7.74-7.71 (m, 2H),
7.33 (dd, J=4.8, 7.7, 1H), 4.19 (s, 3H), 3.98 (s, 3H), 3.17 (m,
2H), 3.06 (m, 2H).
[0211] The following compounds were prepared from the corresponding
ester (prepared by Method I).
[0212] Preparation of 1.16 ##STR77##
[0213] To a solution of the ester xliii (250 mg, 0.78 mmol) in 5 mL
of THF at -78.degree. C. was added a 1.0 M solution of LiAlH.sub.4
(2 mL, 2 mmol) in THF. The reaction was stirred for 2 h and
quenched with sat. NH.sub.4Cl, warmed to room temperature, and
diluted with EtOAc. The solution was filtered, dried over
Na.sub.2SO.sub.4, and concentrated to give the crude alcohol. A
suspension of the alcohol and MnO.sub.2 (2.0 g) in 10 mL of THF was
stirred at room temperature for 3 days. The reaction mixture was
filtered through Celite, the filtrate was concentrated, and the
residue was purified (SiO.sub.2, CH.sub.2Cl.sub.2/MeOH, 96:4) to
give an oil. This was triturated with hexane/EtOAc and the solid
was filtered to give an intermediate aldehyde (60 mg, 26%).
[0214] A solution of the aldehyde (55 mg, 0.19 mmol) and
2-methyl-3-thiosemicarbazide (19 mg, 0.18 mmol) in 3 mL of EtOH was
stirred at reflux for 18 h. The reaction was cooled, the
precipitate collected, washed with EtOH, and dried to give the
desired product 1.16 (30 mg, 42%). .sup.1H NMR (DMSO-d.sub.6)
.delta. 8.72 (br s, 1H), 8.62 (br s, 1H), 8.53 (s, 1H), 8.48 (s,
1H), 8.43 (s, 1H), 8.01 (d, J=8.5 Hz, 1H), 7.98 (s, 1H), 7.48 (s,
1H), 7.76 (d, J=8.6 Hz, 1H), 4.14 (s, 3H), 3.98 (s, 3H), 3.14 (t,
J=7.2 Hz, 2H), 2.98 (t, J=7.2 Hz, 2H). ##STR78##
[0215] CaCl.sub.2 (-30+80 mesh, 109 mg, 0.983 mmol) and NaBH.sub.4
(74.4 mg, 1.97 mmol) was added to a stirred solution of the
unsaturated nitrile (253 mg, 0.655 mmol) in 1:1 THF-EtOH (30 mL) at
0.degree. C. The cold bath was removed and stirring was continued
overnight. Water (2 mL) was added and the solution was evaporated.
The residue was then dried under vacuum. To the residue THF (35
mL), CH.sub.2Cl.sub.2 (35 mL), and Dess-Martin periodinane (1.21 g,
2.86 mmol) were added. The mixture was stirred for 2 h, diluted
with THF (30 mL), and poured into saturated aqueous NaHCO.sub.3 (48
mL) containing Na.sub.2S.sub.2O.sub.3 (12.1 g). The mixture was
stirre for 30 min. EtOAc (10 mL) was added, and the layers were
separated. The organic layer was washed with water and brine,
dried, and evaporated. Flash chromatography of the residue over
silica gel, using 1:4:5 MeOH-EtOAc-hexane, gave the aldehyde lxxvi
(111.3 mg in two steps) as a yellow solid: MS 359.1 (MH.sup.+).
[0216] Conversion of aldehyde lxxvi to compound 1.16a was
accomplished using the methods described above. ##STR79##
[0217] Compound 1.16a was obtained as a yellow solid: .sup.1H NMR
(DMSO-d.sub.6) .delta. 3.03(t, J=6.0 Hz, 2H), 3.25(t, J=6.0 Hz,
2H), 3.99(s, 3H), 4.50(s, 3H), 7.89(s, 1H), 8.08(s, 1H), 8.37(s,
1H), 8.57(s, 1H), 8.48(s, 1H), 8.61(s, 1H), 8.66(s, 1H), 8.68(s,
1H), 8.76(s, 1H); MS (electrospray) m/z calcd for
C.sub.20H.sub.18F.sub.8N.sub.7S (M+H) 446.1, found 446.1.
[0218] The following compounds were prepared according to the
general methods above. ##STR80##
[0219] .sup.1H NMR (DMSO-d.sub.6) .delta. 8.69 (s, 1H). 8.58 (s,
1H), 8.50 (s, 1H) 8.40 (s, 1H), 8.34 (s, 1H), 7.95 (s, 1H), 7.86
(s, 1H), 7.83 (s, 1H) 4.13 (s, 3H), 3.97 (s, 3H), 3.12-3.15 (m,
2H), 2.93-2.96 (m, 2H), 2.54 (s, 3H); MS 392.1 (100, M+H.sup.+).
##STR81##
[0220] Compound 1.17b was obtained as a yellow solid: .sup.1H NMR
(CD3OD) .delta. 2.04(br s, 2H), 2.17(br s, 2H), 2.95(t, J=6.96 Hz,
2H), 3.17(br s, 2H), 3.36(t, J=6.96 Hz, 2H), 3.57(t, J=5.88 Hz,
2H), 3.87(br s, 2H), 4.41(s, 3H), 4.59(t, J=5.82 Hz, 2H), 8.28(s,
1H), 8.44(s, 1H), 8.45(s, 1H), 8.56(s, 1H), 8.70(s, 1H), 9.08(s,
1H); MS (electrospray) m/z calcd for C.sub.24H.sub.27ClN.sub.8O
(M+H) 479.2, found 479.2 ##STR82##
[0221] Compound 1.17c was obtained as a yellow solid: .sup.1H NMR
(DMSO-d.sub.6) .delta. 2.99(t, J=7.16 Hz, 2H), 3.24(t, J=7.14 Hz,
2H), 3.71(t, J=5.68 , 2H), 3.36(t, J=5.68 Hz, 2H), 4.13(s, 3H),
4.92(t, J=5.76 Hz, 2H), 7.88(s, 1H), 8.02(s, 1H), 8.16(s, 1H),
8.42(s, 1H), 8.46(s, 1H), 8.55(s, 1H), 8.74(s, 1H), 8.75(s, 1H); MS
(electrospray) m/z calcd for C.sub.21H.sub.22ClN.sub.7OS (M+H)
456.1, found 456.2 ##STR83##
[0222] Compound 1.17d was obtained as a yellow solid: .sup.1H NMR
(DMSO-d.sub.6) .delta. 2.49(s, 3H), 2.50(s, 3H), 2.99(t, J=7.14,
2H), 3.22(t, J=7.14 Hz, 2H), 3.28-3.30(m, 2H), 4.12(s, 3H), 4.82(t,
J=6.56 Hz, 2H), 7.86(s, 1H), 8.02(s, 1H), 8.16(s, 1H), 8.43(s, 1H),
8.48(s, 1H), 8.55(s, 1H), 8.66(s, 1H), 8.73(s, 1H); MS
(electrospray) m/z calcd for C.sub.22H.sub.25ClN.sub.8S (M+H)
469.2, found 469.2 ##STR84##
[0223] Compound 1.17e was obtained as a yellow solid: 1H NMR
(DMSO-d6) .delta. 1.92-1.65(m, 4H), 2.25(br, s, 1H), 2.36(s, 3H),
2.87(br s, 1H), 3.00(t, J=7.08 Hz, 2H), 3.09(br s, 1H), 3.19(m,
2H), 4.13(s, 3H), 4.61(br s, 1H), 4.93(m, 1H),7.86(s, 1H), 8.03(s,
1H), 8.17(s, 1H), 8.33(s, 1H), 8.48(s, 1H), 8.59(s, 1H), 8.69(s,
1H), 9.09(s, 1H); MS (electrospray) m/z calcd for
C.sub.24H.sub.28ClN.sub.8S (M+H) 495.2, found 495.2
[0224] The following compounds were prepared beginning with
intermediates provided above in Method J. ##STR85##
[0225] To a solution of the above aldehyde xliii (34.8 mg, 0.133
mmol) in EtOH (2 mL) and H.sub.2O (0.5 mL) was added the
semithiocarbazide (13.3 mg, 0.146 mmol) and 1 drop of AcOH. The
mixture was refluxed overnight. The resulting mixture was cooled
and the yellow solid filtered and washed with water. The solid was
dried and found pure by TLC, NMR and MS. Yield of 1.18: 13.5 mg.
(.sup.1H NMR, 400 MHz),: .sup.1H NMR (CDCl.sub.3) .delta. 4.15 (s,
3H), 7.89 (s, 1H), 7.95 (d, J=12 Hz, 1H), 8.08 (s, 1H), 8.32 (d,
J=12 Hz, 1H), 8.40 (s, 1H), 8.58 (m, 3H), 8.85 (s, 1H), 11.75 (s,
1H). MS 334.1 (M-H.sup.-). ##STR86##
[0226] From xlix, using the general method (Example 1.2).
[0227] .sup.1H NMR (d.sub.6-DMSO) .delta.: 11.72 (s, 1H), 8.83 (s,
1H), 8.56 (s, 1H), 8.52 (s, 1H), 8.39 (s, 1H), 8.22 (d, J=8.7, 1H),
8.02 (s, 2H), 7.86 (s, 1H), 7.65 (dd, J=1.6, 8.7 Hz, 1H), 4.15 (s,
3H), 3.06 (s, 3H), 2.99 (s, 3H). ##STR87##
[0228] From intermediate 1, using the general method (Example
1.2).
[0229] .sup.1H NMR (d.sub.6-DMSO) .delta.: 8.63 (s, 1H), 8.36 (s,
1H), 8.22 (d, J=8.8, 1H), 8.15 (s, 1H), 8.11 (s, 1H), 8.02 (s, 1H),
7.88 (d, J=8.8 Hz, 1H), 6.98 (dd, J=10.6, 17.6 Hz, 1H), 6.83 (bs,
2H), 6.11 (d, J=17.6 Hz, 1H), 5.48 (d, J=10.6 Hz, 1H), 4.19 (s,
3H). ##STR88##
[0230] From intermediate li, using the general method (Example
1.2).
[0231] .sup.1H NMR (d.sub.6-DMSO) .delta.: 10.60 (s, 1H), 8.61 (s,
1H), 8.29 (s, 1H), 8.12 (d, J=8.7 Hz, 1H), 7.95 (s, 1H),7.83 (s,
1H), 7.72. (s, 1H), 7.35 (d, J=8.7 Hz, 1H), 6.80 (s, 2H), 4.15 (s,
3H), 2.15-2.17 (m, 1H), 1.08-1.12 (m, 2H), 0.86-0.88 (m, 2H).
[0232] The following compounds were prepared beginning with the
corresponding esters prepared by Method K. ##STR89##
[0233] The aldehyde lxxiii was formed by LAH reduction of the ester
liii according to the general procedure (see Example 1). .sup.1H
NMR (CDCl.sub.3) .delta. 10.42 (s, 1H), 8.90 (s, 1H), 8.00-8.04 (m,
2H), 7.75 (s, 1H), 7.66 (d, J=7 Hz, 1H), 7.50 (s, 1H), 5.08 (q, J=6
Hz, 1H), 4.12 (s, 3H), 1.43-1.46 (m, 3H), 0.94 (s, 9H), 0.10 (s,
3H), 0.01 (s, 3H).
[0234] To a stirred solution of aldehyde lxxviii (38 mg, 0.096
mmol) in ethanol:water (5:1; 4 mL) was added semicarbazide
hydrochloride (11 mg, 0.098 mmol) and sodium acetate (24 mg, 0.28
mmol). The mixture was heated at reflux for 12 h then allowed to
cool to room temperature. The precipitate was collected and washed
with water then dissolved in TFA (2 mL). The mixture was stirred
for 36 h at room temperature then concentrated in vacuo. The
residue was purified by reverse-phase HPLC to afford the desired
product 1.22 (5 mg). .sup.1H NMR (CD.sub.3OD) .delta. 9.07 (s, 1H).
8.67 (s, 1H), 8.42 (s, 1H), 8.38 (s, 1H), 8.35 (s, 1), 8.14 (s,
1H), 7.74-7.77 (m, 1H), 5.07 (q, J=6 Hz, 1H), 4.43 (s, 3H), 1.55
(d, J=6 Hz, 3H); ESI-MS m/z 339.2 (100, M+H.sup.+). ##STR90##
[0235] LiAlH.sub.4 (1.0M in THF, 1.4 mL, 1.40 mmol) was added to a
stirred and cooled (-78.degree. C.) solution of the
pentafluoroethyl compound liv (180 mg, 0.467 mmol) in THF (10 mL).
Stirring was continued at -78.degree. C. for 3 h. Water (0.1 mL),
2N NaOH (0.1 mL), and water (0.3 mL) were added sequentially. The
cold bath was removed and the mixture was stirred for 30 min, and
then filtered through a pad of Celite. The pad was rinsed with THF
and the combined filtrates were evaporated. Flash chromatography of
the residue over silica gel, using 1:4:5 MeOH-EtOAc-hexane, gave
the crude alcohol (104 mg) for next step.
[0236] Dess-Martin periodinane (246 mg, 0.580 mmol) was added to
the alcohol (104 mg, 0.290 mmol) in 1:1 THF-CH.sub.2Cl.sub.2 (15
ML). The mixture was stirred for 2 h, diluted with TAF (30 mL), and
poured into saturated aqueous NaHCO.sub.3 (10 mL) containing
Na.sub.2S.sub.2O.sub.3 (2.5 g). The mixture was stirred for 30 min.
EtOAc (10 mL) was added, and the layers were separated. The organic
layer was washed with water and brine, dried, and evaporated. Flash
chromatography of the residue over silica gel, using 1:4:5
MeOH-EtOAc-hexane, gave the aldehyde lxxvii (84.8 mg) as a yellow
solid for the next final coupling reaction. ##STR91##
[0237] NaOAc (30.1 mg, 0.367 mmol) was added to a stirred solution
of the aldehyde lxxvii (43.5 mg, 0.123 mmol), semicarbazide
hydrochloride (13.6 mg, 0.123 mmol) in 4:1 EtOH--H.sub.2O (4.5 mL),
and the mixture was refluxed for 14 h. The resulting mixture was
cooled and precipitates were collected. Purification by rinse with
cold MeOH gave corresponding 7-pentafluoroethyl semicarbazone 1.23
(15.0 mg) as a yellow solid: .sup.1H NMR (DMSO-d.sub.6) .delta.
4.19(s, 3H), 6.85(br s, 2H), 7.88(d, J=8.8 Hz, 1H), 8.03(s, 1H),
8.15(s, 1H), 8.34(s, 1H), 8.52(s, 1H), 8.58(d, J=8.8 Hz, 1H),
8.61(s, 1H), 10.73(s, 1H); ms 413.1(M+H.sup.+).
[0238] The following compounds were prepared from the corresponding
esters prepared by the methods of Method L. ##STR92##
[0239] To a stirred solution of butyl ester lvi (152 mg, 0.5 mmol)
in anhydrous THF (3 mL) at -78.degree. C. under nitrogen was added
lithium aluminum hydride (515 .mu.l of a 1M solution in THF, 0.5
mmol). The mixture was stirred at -78.degree. C. for 30 min. then
quenched by the addition of ethyl acetate (5 mL) and water (5 mL).
The mixture was allowed to warm to room temperature, diluted with
ethyl acetate (50 mL) and water (20 mL). The organics were
collected and dried (Na.sub.2SO.sub.4), filtered and concentrated
in vacuo. Flash chromatography afforded a mixture of alcohol and
aldehyde which were taken up in THF (10 mL). Manganese dioxide (350
mg) was added and the mixture was stirred under nitrogen for 12
hours whereupon a further MnO.sub.2(350 mg) was added. The mixture
was stirred for a further 3 h then filtered and concentrated in
vacuo to afford impure aldehyde lxxix (40 mg). ESI-MS m/z
224.3(100, M+H.sup.+).
[0240] To a stirred solution of aldehyde lxxix (40 mg, 0.17 mmol)
in ethanol:water (5:1; 1 mL) was added thiosemicarbazide (20 mg,
1.2 eq.) and a drop of acetic acid. The mixture was heated at
reflux for one hour then cooled and the precipitate collected by
filtration and washed with water and cold ethanol to yield 1.24 (15
mg). .sup.1H NMR (DMSO-d.sub.6) .delta. 11.81 (s, 1H), 8.95 (s,
1H), 8.82 (s, 1H) 8.66 (s, 1H), 8.54 (s, 1H), 8.45 (s, 1H),
8.17-8.20 (m, 2H), 8.03-8.05 (m, 1H) 7.78-7.87 (m, 1H) 7.71-7.23
(m, 1H); ESI-MS m/z 297.3 (100, M+H.sup.+).
[0241] Similarly, the following compound was prepared according to
the general procedure above. ##STR93##
[0242] .sup.1H NMR (MSO-d.sub.6) .delta. 11.76 (s, 1H), 9.55 (s,
1H) 8.94 (s, 1H), 8.58 (s, 1H), 8.54 (s, 1H), 8.33-8.39 (m, 3H),
8.08 (d, J=8 Hz, 1H), 7.89-7.93 (m, 1H), 7.76-7.78 (m, 1H); ESI-MS
m/z 298.1 (100, M+H.sup.+).
[0243] The following compound was prepared from the aldehyde
described in Method M. ##STR94##
[0244] To a stirred solution of crude aldehyde lx was added
thiosemicarbazide (33 mg, 0.3 mmol) and a drop of acetic acid. The
mixture was heated at reflux for 90 min. then allowed to cool to
room temperature. The precipitate formed was collected by
filtration and purified by reverse-phase HPLC to afford the desired
product 1.26 (10 mg); .sup.1H NMR (DMSO-d.sub.6) .delta. 11.98 (br
s, 1H), 9.00 (d, J=8.5 Hz, 1H), 8.65 (br s, 1H) 8.50 (s, 1H)
7.86-7.99 (m, 5H) 7.67-7.72 (m, 1H) 4.15 (s, 3H); ESI-MS m/z 312.2
(100, M+H.sup.+).
[0245] The following compound was prepared from the aldehyde
described in Method N. ##STR95##
[0246] The solution of aldehyde lxiv was concentrated to a volume
of approx. 1 mL then ethanol (5 mL) and water (1 mL) were added and
the mixture concentrated again to approx. 1.5 mL. Ethanol (5 mL)
was added and the mixture again concentrated to approx. 1.5 mL.
Ethanol (2 mL) was added. To this'solution was added
thiosemicarbazide (72 mg) and one drop of acetic acid. The mixture
was heated at reflux for 12 h then concentrated to dryness. The
residue was purified by reverse-phase preparative HPLC to afford
isoquinoline 1.27 (2 mg, 0.8%); .sup.1H NMR (DMSO-d.sub.6) .delta.
11.92 (br s, 1H), 9.07 (d, 1H, J=8 Hz), 8.70 (s, 1H) 8.61 (br s,
1H) 8.48 (s, 1H) 7.88-8.11 (m, 6H).
[0247] The following compound was prepared in a similar manner from
the aldehyde described in Method O. ##STR96##
[0248] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 4.00 (s, 3H),
4.19 (s, 3H), 5.60 (s, 2H), 8.15 (br s, 2H), 8.26 (s, 1H), 8.43 (s,
1H), 8.48 (s, 1H), 8.61 (s, 1H), 8.64 (s,1H), 8.80 (s, 1H). ms
348.0 (M+H.sup.+).
Example 2
[0249] This example illustrates the preparation of a
2-triazolyl-quinoline semithiocarbazone.
[0250] 2.1 Preparation of 2-carboxaldehydequinoline-4-carboxylic
acid, methyl ester. ##STR97##
[0251] A solution of the quinoline ester lxxx (1.35 g, 6.7 mmol) in
dioxane was heated to reflux. SeO.sub.2 (1.49 g, 13.4 mmol) was
added and the reflux continued for 30 min. The reaction was cooled,
diluted with Et.sub.2O, filtered, and the ethereal phase was washed
with water, 10% NaHCO.sub.3 (2.times.), brine, dried over
Na.sub.2SO.sub.4, and concentrated to dryness to give the aldehyde
lxxxi as a solid (1.25 g, 87%). .sup.1H NMR (DMSO-d.sub.6) .delta.
10.16 (s, 1H), 8.73 (dd, J=8.3, 1.2 Hz, 1H), 8.35 (dd, J=8.1, 1.0
Hz, 1H), 8.33 (s, 1H), 8.02 (ddd, J=8.4, 6.9, 1.5 Hz, 1H), 7.94
(ddd, J=8.5, 6.9, 1.5 Hz, 1H), 4.03 (s, 3H).
[0252] 2.2 Preparation of Intermediate lxxxii. ##STR98##
[0253] To a solution of the aldehyde lxxxi (1.25 g, 5.81 mmol) and
sulfamic acid (1.35 g, 14.53 mmol) in 20 mL of t-butanol was added
a solution of NaClO.sub.2 (1.30 g, 14.53 mmol) and KH.sub.2
PO.sub.4 (1.97 g, 14.53 mmol) in 2 mL of water. The bi-phased
reaction was stirred vigorously for 30 min. The reaction was
quenched with AcOH (3.1 mL) and diluted with water. The mixture was
extracted with EtOAc (2.times.), and the organic layer washed with
water, brine, dried over Na.sub.2SO.sub.4, and concentrated to
dryness to give an intermediate carboxylic acid (1.24 g, 93%).
[0254] To a solution of the carboxylic acid (1.24 g, 5.4 mmol) and
DMF (0.61 mL, 7.87 mmol) in 10 mL of CH.sub.2Cl.sub.2 at 0.degree.
C. was added oxalyl chloride (1.46 mL, 16.7 mmol) dropwise. The
reaction was stirred at 0.degree. C. for 15 min and room
temperature for 30 min. The solvent was removed in vacuum to
dryness to give a yellow solid. The crude product was cooled to 0
C. and added a solution of 4-methyl-3-thiosemicarbazide (1.65 g,
15.76 mmol) in 15 mL of pyridine. The suspension was stirred at
0.degree. C. for 30 min and at room temperature for 18 h. The
reaction mixture was concentrated and a solution of EtOAc/hex
,(1:1) added. The reddish precipitate was collected by filtration
and dried to give the desired product lxxxii (1.6 g) slightly
impure. .sup.1H NMR (DMSO-d.sub.6) .delta. 10.87 (s, 1H), 0.94 (s,
1H), 8.71 (d, J=8.6 Hz, 1H); 8.84 (s, 1H), 8.24 (d, J=8.4 Hz, 1H),
8.1 (br s, 1H), 7.99 (br t, J=8.6 Hz, 1H), 7.88 (br t, J=8.4 Hz,
1H), 4.03 (s, 3H).
[0255] 2.3 Preparation of
4-methyl-3-thiomethyl-1,2,4-triazo-5-yl-quinoline-4-carboxylic acid
methyl ester. ##STR99##
[0256] Sodium metal (0.92 g, 40.2 mmol) was dissolved in 30 mL of
dry MeOH. Intermediate lxxxii (1.6 g) was added and the reaction
was refluxed for 18 h. The reaction was cooled to room temperature,
the solvent was removed and the solid residue dissolved in water.
The aqueous solution was acidified to pH 4-5 with 10% HCl, a solid
precipitated which was collected by filtration, washed with water,
and dried to give a triazolethione intermediate (1.09 g).
[0257] To a suspension of the triazolethione (1.09 g, 3.36 mmol)
was added a 1.0 N solution of NaOH (3.63 mL, 3.63 mmol) and stirred
for 10 min. Methyl iodide (0.24 mL, 3.8 mmol) was added and the
reaction stirred for 18 h. The reaction was filtered and the
filtrate concentrated to give the desired product lxxxiii. .sup.1H
NMR (DMSO-d.sub.6) .delta. 8.74 (br d, J=8.4 Hz, 1H), 8.27 (s, 1H),
8.02 (br d, J=8.4 Hz, 1H), 7.74 (ddd, J=8.3, 6.8, 1.8 Hz, 1H), 7.56
(ddd, 8.3, 6.8, 1.3 Hz, 1H), 4.11 (s, 3H), 2.72 (s, 3H).
[0258] 2.4 Preparation of Semithiocarbazone 2.1. ##STR100##
[0259] To a solution of the acid lxxxiii (750 mg, 2.5 mmol) in 20
mL of MeOH was added 2.0 mL of conc. H.sub.2SO.sub.4. The reaction
was refluxed for 18 h. The reaction was cooled, the solvent removed
in the rotavap, the residue diluted with water and the aqueous
layer neutralized with solid K.sub.2CO.sub.3 to pH 8. The aqueous
solution was extracted with EtOAc (3.times.) and CH.sub.2Cl.sub.2
(x). The organic layers were dried over Na.sub.2SO.sub.4, filtered
and concentrated to give the corresponding methyl ester (500
mg).
[0260] A suspension of the ester (500 mg) and Raney Ni (75 mg) in
30 mL of EtOH was refluxed for 18 h. The reaction was cooled,
filtered through Celite, and the filtrate was concentrated to give
the desired product (300 mg).
[0261] The methyl ester (300 mg, 0.95 mmol) was dissolved in 10 mL
of THF and cooled to -78.degree. C. A 1.0 M solution of LiAlH.sub.4
(3.0 mL, 3.0 mmol) in THF was added and the reaction was stirred
until the ester was consumed (by TLC). The reaction quenched with
10% NH.sub.4Cl at -78.degree. C., brought to room temperature and
aqueous extracted with EtOAc (3.times.). Organic layer dried over
Na.sub.2SO.sub.4, filtered, and concentrated to dryness to give the
desired alcohol (150 mg).
[0262] A suspension of the crude product (150 mg) and MnO.sub.2
(750 mg) in 20 mL of THF was stirred at room temperature for 18 h.
The suspension filtered through Celite, washed with EtOAc, and
filtrate concentrated to dryness to give the desired aldehyde (60
mg).
[0263] A solution of the aldehyde (60 mg, 0.25 mmol) and
semithiocarbazide (23 mg, 0.25 mmol) in 3 mL of EtOH was stirred at
70.degree. C. for 18 h. The reaction cooled to room temperature,
precipitate filtered, and dried to obtain the desired
semithiocarbazone (19.2 mg). MS(ES) 312 (M.sup.++1).
Example 3
[0264] The following compounds were all prepared by similar methods
to those described in Examples 1 and 2. TABLE-US-00001 ##STR101##
Compound Y R.sup.1 R.sup.6 R.sup.7 3.1 S CH.sub.3 --CH.dbd.CHCN
CH.sub.3 3.2 S CH.sub.3 --CH.dbd.CHCN H 3.3 S CH.sub.3
--CH.sub.2CH.sub.2CN H 3.4 S H --CH.sub.2CH.sub.2CN H 3.5 O H
--CH.dbd.CHCN CH.sub.3 3.6 S H --CH.dbd.CHCN CH.sub.3 3.7 S
CH.sub.3 --CH.sub.2CH.sub.2CN CH.sub.3 3.8 S H --CH.sub.2CH.sub.2CN
CH.sub.3 3.9 S H --CH.sub.2CH.sub.2CN CF.sub.3 3.10 S CH.sub.3
--CH.sub.2CH.sub.2CN CF.sub.3 3.11 S n-butyl --CH.sub.2CH.sub.2CN
CH.sub.3 3.12 S CH.sub.3 CH.sub.2CH.sub.2CN --CH.sub.2CH.sub.3 3.13
S CH.sub.3 CH.sub.2CH.sub.2SO.sub.2CH.sub.3 CH.sub.3 3.14 S
CH.sub.3 --CH.sub.2CH.sub.2CN Cl 3.15 S CH.sub.3
--CH.sub.2CH.sub.2SO.sub.2CH.sub.3 CF.sub.3 3.16 S
CH.sub.3CH.sub.2-- --CH.sub.2CH.sub.2CN Cl 3.17 S
CF.sub.3CH.sub.2-- --CH.sub.2CH.sub.2CN Cl 3.18 S
CH.sub.3CH.sub.2-- --CH.sub.2CH.sub.2CN CF.sub.3 3.19 S CH.sub.3
--CH.sub.2CH.sub.2CN --CH.sub.2CH.sub.2CH.sub.3 3.20 S CH.sub.3
--CH.sub.2CH.sub.2SO.sub.2CH.sub.3 Cl 3.21 S 2-methoxyethyl
--CH.sub.2CH.sub.2CN CF.sub.3 3.22 S 2-(4- --CH.sub.2CH.sub.2CN Cl
morpholinyl)ethyl 3.23 S 2-methoxyethyl --CH.sub.2CH.sub.2CN Cl
3.24 S 2-(4- --CH.sub.2CH.sub.2CN H morpholinyl)ethyl 3.25 S
tetrahydrofuran-3- --CH.sub.2CH.sub.2CN H ylmethyl 3.26 S
cyclopropylmethyl --CH.sub.2CH.sub.2CN H 3.27 S 2-(N,N-dimethyl-
--CH.sub.2CH.sub.2CN H amino)ethyl 3.28 S 2-(N,N-dimethyl-
--CH.sub.2CH.sub.2CN CF.sub.3 amino)ethyl 3.29 S 2-(4-
--CH.sub.2CH.sub.2CN CF.sub.3 morpholinyl)ethyl 3.30 S
3-hydroxypropyl --CH.sub.2CH.sub.2CN H 3.31 S 2-hydroxyethyl
--CH.sub.2CH.sub.2CN H 3.32 S 2-(methoxy- --CH.sub.2CH.sub.2CN H
carbonyl)ethyl 3.33 S 2-hydroxypropyl --CH.sub.2CH.sub.2CN H 3.34 S
2-(methyl- --CH.sub.2CH.sub.2CN H sulfonyl)ethyl 3.35 S
2-(2-methoxy --CH.sub.2CH.sub.2CN CF.sub.3 ethoxy)ethyl 3.36 S 2,3-
--CH.sub.2CH.sub.2CN CF.sub.3 dihydroxypropyl 3.37 S 2-(1-
--CH.sub.2CH.sub.2CN CF.sub.3 pyrrolidinyl)ethyl 3.38 S
2-(N,N-dimethyl- --CH.sub.2CH.sub.2CN Cl amino)ethyl 3.39 S 2-(1-
--CH.sub.2CH.sub.2CN Cl pyrrolidinyl)ethyl 3.40 S H
--CH.sub.2CH.sub.2CN H 3.41 S 2-(2-methoxy --CH.sub.2CH.sub.2CN H
ethoxy)ethyl 3.42 S CH.sub.3CH.sub.2 --CH.sub.2CH.sub.2CN H 3.43 S
CF.sub.3CH.sub.2 --CH.sub.2CH.sub.2CN H 3.44 S 3-(1-piperidinyl)-
--CH.sub.2CH.sub.2CN H prop-1-yl 3.45 S 2-aminoethyl
--CH.sub.2CH.sub.2CN H 3.46 S 3-(N,N-dimethyl- --CH.sub.2CH.sub.2CN
Cl amino)prop-1-yl 3.47 S 3-(N,N-dimethyl- --CH.sub.2CH.sub.2CN H
aniino)prop-1-yl 3.48 S H F H 3.49 S H CH.sub.3 H 3.50 S CH.sub.3 F
H 3.51 S CH.sub.3 CH.sub.3 H 3.52 S H CH.sub.3O-- H 3.53 O CH.sub.3
CH.sub.3O-- H 3.54 O CH.sub.3 H H 3.55 S H Ph H 3.56 O H Ph H 3.57
O H CH.sub.3O-- H 3.58 S H I H 3.59 O H I H 3.60 O H CN H 3.61 S H
--CH.dbd.CH.sub.2 H 3.62 S H H CH.sub.3 3.63 O H H CH.sub.3 3.64 O
H --CH.dbd.CH.sub.2 H 3.65 S H 3-hydroxy- H propyn-1-yl 3.66 S H Cl
H 3.67 O H Cl H 3.68 S H 3-pyridyl H 3.69 S H 2-thienyl H 3.70 O H
3-hydroxy- H propyn-1-yl 3.71 O H CH.sub.3S-- H 3.72 O H
CH.sub.3SO.sub.2-- H 3.73 O H H CH.sub.3O-- 3.74 O H H CH.sub.3S--
3.75 O H H CH.sub.3SO.sub.2-- 3.76 O H H Cl 3.77 O H H F 3.78 S H H
Cl 3.79 NH H H H 3.80 S H H Br 3.81 O H H Br 3.82 S H H F 3.83 S H
H (CH.sub.3).sub.2CH-- 3.84 S CH.sub.3 H Cl 3.85 O H 1-methyl- H
imidazol-5-yl 3.86 O H --CH.dbd.CHCONH.sub.2 H 3.87 O CH.sub.3 H Cl
3.88 O H H (CH.sub.3).sub.2CH-- 3.89 O H methylenedioxy 3.90 S
CH.sub.3 H CH.sub.3 3.91 O H NH.sub.2 H 3.92 O H --CH.dbd.CHCN H
3.93 S H CH.sub.3 CH.sub.3 3.94 O H CH.sub.3 CH.sub.3 3.95 S H
CH.sub.3 Cl 3.96 O H CH.sub.3 Cl 3.97 O H --CH.sub.2CH.sub.2CN H
3.98 S n-butyl H H 3.99 S CH.sub.3 CH.sub.3 CH.sub.3 3.100 S benzyl
H H 3.101 S CF.sub.3CH.sub.2-- H H 3.102 S CH.sub.3 2-(4-morpholin-
H yl)ethoxy 3.103 O H Cl CH.sub.3 3.104 S H Cl CH.sub.3 3.105 S
CH.sub.3 Cl CH.sub.3 3.106 S H 2-(4-morpholin- H yl)ethoxy 3.107 S
2-phenylethyl H H 3.108 S CH.sub.3 --CH.sub.2CH.sub.2CN H 3.109 S H
CH.sub.3SO.sub.2CH.dbd.CH H -- 3.110 S n-butyl H Cl 3.111 S
CH.sub.3 1,2-dihydroxy- H ethyl 3.112 S CH.sub.3
CH.sub.3SO.sub.2CH.dbd.CH H -- 3.113 S CH.sub.3 3-hydroxy- H
prop-1-yl 3.114 O H 4-hydroxy- H but-1-yl 3.115 O H
CH.sub.3SO.sub.2CH.dbd.CH H -- 3.116 S CH.sub.3
CH.sub.3SO.sub.2CH.sub.2CH.sub.2 H -- 3.117 O H
CH.sub.3SO.sub.2CH.sub.2CH.sub.2 H -- 3.118 S CH.sub.3 4-hydroxy- H
but-1-yn-1-yl 3.119 O H 4-hydroxy- H but-1-yn-1-yl 3.120 S CH.sub.3
4-morpholinyl H 3.121 S CH.sub.3 3-hydroxy-1- H propenyl 3.122 S
n-butyl --CH.sub.2CH.sub.2CN H 3.123 S H 1,2-dihydroxy- H ethyl
3.124 S H CH.sub.3SO.sub.2CH.sub.2CH.sub.2 H -- 3.125 S CH.sub.3
CH.sub.3SO.sub.2CH.sub.2CH.sub.2 CH.sub.3 -- 3.126 S CH.sub.3
2-(5-oxazolyl)- H ethyl
Example 4
[0265] The following compounds were all prepared by similar methods
to those described in Examples 1 and 2. TABLE-US-00002 ##STR102##
Compound Y Z B-ring 4.1 S --NHCH.sub.3 ##STR103## 4.2 S NH.sub.2
##STR104## 4.3 S NH.sub.2 ##STR105## 4.4 O NH.sub.2 ##STR106## 4.5
O NH.sub.2 ##STR107## 4.6 O H ##STR108## 4.7 O CH.sub.3 ##STR109##
4.8 S NH.sub.2 ##STR110##
[0266] The following compounds have also been prepared:
##STR111##
Example 5
[0267] 5.1 Preparation of Hydrazine b ##STR112##
[0268] To a solution of 3-methyl-1,3-butanediol (Fluka, 6.14 mL,
57.6 mmol) in DCM (20 mL) at 0.degree. C. under an atmosphere of
nitrogen was added triethylamine (10 mL). p-Toluenesulfonyl
chloride (11 g) in DCM (20 mL) was added dropwise over 4 h and the
mixture was stirred for a further 3 h at 0.degree. C., then allowed
to warm to room temperature overnight. The reaction mixture was
diluted with water (50 mL) and the organics were separated, washed
with 1M HCl (50 mL), sat. aq. NaHCO.sub.3 (50 mL) and water (20
mL). The organics were dried (Na.sub.2SO.sub.4), filtered and
concentrated to afford tosylate a (13.4 g) as a white solid.
.sup.1H NMR (CDCl.sub.3) .delta. 7.81 (d, J=8 Hz, 2H), 7.37 (d, J=8
Hz, 2H), 4.22 (t, J=7 Hz, 2H), 2.47 (s, 3H), 1.88 (t, J=7 Hz, 2H),
1.23 (s, 6H).
[0269] To a solution of tosylate a (6.55 g, 25 mmol) in ethanol (10
mL) was added hydrazine monohydrate (15 mL) and the mixture was
heated to 60.degree. C. for 2 h then concentrated to approx. 10 mL
volume. Saturated aq. sodium hydroxide (20 mL) and THF (50 mL) were
added and the organics collected, dried (NaSO.sub.4), filtered and
concentrated to afford hydrazine b (1.8 g) as a colorless oil.
ESI-MS m/z 119.3 (100, M+H.sup.+). .sup.1H NMR (CDCl.sub.3) .delta.
4.73 (s, 1H), 3.19 (s, 3H), 3.02-3.06 (m, 2H), 1.68 (t, J=6 Hz,
2H), 1.26 (s, 6H).
[0270] 5.2 Preparation of Semithiocarbazone 5 ##STR113##
[0271] To a stirred solution of hydrazine b (0.8 g, 6.8 mmol) in
diethyl ether (25 mL) was added triphenylmethylisothiocyanate
(Trans World Chemicals, 1.83 g, 6.0 mmol). The mixture was stirred
for 1 h and then hexanes (5 mL) was added and the mixture was
filtered to afford semithiocarbazide c as a white solid (0.62 g).
.sup.1H NMR (CDCl.sub.3) .delta. 9.51(s, 1H), 7.21-7.36 (m, 15H),
4.27 (t, J=6.5 Hz, 2H), 4.01 (s, 2H), 2.43 (s, 1H), 1.82 (t, J=6.5
Hz, 2H), 1.26 (s, 6H).
[0272] To semithiocarbazide c (284 mg, 0.68 mmol) was added
TFA:DCM/1:1 (5 mL). The mixture was stirred at room temperature for
2 h then concentrated in vacuo. Methanol (5 mL) was added and the
mixture re-concentrated. This step was repeated 3 times until a
white powder was obtained. Ethanol:water 4:1 (5 mL) and aldehyde C
(prepared from 6-chloro-5-iodo-isatin by Method I and Method A)
(199 mg, 0.61 mmol) were added and the reaction mixture was warmed
to 65.degree. C. overnight then cooled to room temperature and
concentrated in vacuo. Flash chromatography of the residue
(DCM:MeOH:NH.sub.3/98:1:1 to 96:3:1; gradient elution) afforded the
semithiocarbazone 5 as a yellow solid. ESI-MS m/z 484.1 (100,
M+H.sup.+). .sup.1H NMR (DMSO-d.sub.6) .delta. 8.72 (s, 1H), 8.69
(s, 1H), 8.60 (s, 1H), 8.53 (s, 1H), 8.43 (s, 1H), 8.17 (s, 1H),
8.07 (s, 1H), 7.88 (s, 1H), 4.95 (s, 1H), 4.79 (s, 2H), 4.15 (s,
3H), 3.24 (t, J=7 Hz, 2H), 2.98 (t, J=7 Hz, 2H), 1.73 (t, J=8 Hz,
2H), 1.27 (s, 6H).
Example 6
[0273] 6.1a Preparation of 1-Methyl-2-piperidinemethanol (d)
##STR114##
[0274] To a solution of 1-methyl-2-piperidinemethanol (20.75 mg,
160.6 mmol) in CH.sub.2Cl.sub.2 (100 mL) was added dropwise
SOCl.sub.2 (17.6 mL, 241 mmol). The solution was heated to reflux
for 12 h. The solution was then concentrated under reduced pressure
to provide 20 g which was used without further purification in the
next step. The crude material was dissolved in EtOH (100 mL) and
NH.sub.2NH.sub.2 (80 mL. 1.6 mol) was added. The solution was then
heated to reflux for 12 h, cooled to room temperature and conc.
NaOH solution (10 eq) was added, stirred for 1 h and extracted with
ether. After evaporation of the ethereal layer the residue was
distilled (reduced pressure) two fractions were recovered. Fraction
1 (95.degree. C., 7.38 g). Fraction 2 (95-98.degree. C., 1.39 g).
The hydrazine (1.07 g, 7.5 mmol) was dissolved in THF (8 mL) and
triphenylnethylisocyanate (2.16 g, 7.58 mmol) was added slowly. The
solution was then stirred overnight and the product collected by
filtration to provide 420 mg of the desired product as a yellow
solid. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.10 (m, 2H), 1.30-1.56
(m, 4H), 1.95 (t, 1H), 2.15 (s, 1H), 2.18 (s, 3H), 2.71(d, 1H),
3.25 (q, 1H), 3.55 (q, 1H), 4.80(s, 2H), 7.12-7.32 (m, 15H), 8.02
(s, 1H). ESI-MS m/z 429.4 (100, M+H). 6.1b Preparation of
(R)-(+)-1-Methyl-2-piperidinemethanol ((R)-d) ##STR115##
[0275] Following the known procedure of patent EP 0 429 984 A2
(reference example 8). The resolution was identical to the above
given procedure except that 4 rounds of crystallization were
performed instead of the two as sited above. To a mixture of
(.+-.)-1-methyl-2-piperidinemethanol (77 g, 596 mmol) in EtOH (615
mL) was added dibenzoyl-D-tartaric acid (205 g, 573 mmol). The
resulting mixture was slowly heated until a solution was obtained
at which time the solution was slowly cooled with gentle stirring.
After 12 h the crystals were isolated and dried to afford 131.6 g.
This process was repeated: (2) EtOH (533 mL) provided 92.5 g. (3)
EtOH (225 mL) provided 68 g (4) EtOH (200 mL) provided 49 g. The
resulting salt was treated with 3M HCl (200 mL) which was heated to
induce it to dissolve. The still warm solution was poured into a
separatory funnel and extracted with ethyl acetate. The remaining
aqueous layer was adjusted to pH 10 with K.sub.2CO.sub.3. The
solution was extracted with CH.sub.2Cl.sub.2, dried (MgSO.sub.4)
and concentrated to give 12 g of the alcohol. This alcohol (12 g,
92.8 mmol) was suspended in CH.sub.2Cl.sub.2 (200 mL) and
SOCl.sub.2 added. After stirring for 12 h, the solvent was removed
to provide a crude HCl salt. This salt was dissolved in EtOH (100
mL) and treated with NH.sub.2NH.sub.2 (89 mL, 1.86 mol) and heated
to reflux for 12 h. NaOH (74 g) in H2O (30 mL) was added and
stirred for 1 h. Half the solvent was removed and the residue
extracted with ether to give a crude oil. After distillation under
reduced pressure (50-60.degree. C.) the pure hydrazine product
(4.87 g) was obtained. This hydrazine (1.6 g, 11.2 mmol) was
dissolved in THF (10 mL) and triphenylmethylisocyanate (3.19 g,
11.2 mmol) was added slowly. The solution was then stirred
overnight and filtered to provide 650 mg of the desired product in
good purity. .sup.1H NMR (DMSO-d.sub.6): .delta. 1.10 (m, 2H),
1.30-1.56 (m, 4H), 1.95 (t, 1H), 2.15 (s, 1H), 2.18 (s, 3H), 2.71
(d, 1H), 3.25 (q, 1H), 3.55(q, 1H), 4.80 (s, 2H), 7.12-7.32 (m,
15H), 8.02 (s, 1H). ESI-MS m/z 429.2 (100, M+H). 6.1c Preparation
of (S)-(-)-1-Methyl-2-piperidinemethanol ((S)-d) ##STR116##
[0276] Following the known procedure of patent EP 0 429 984 A2
(reference example 8). The resolution was identical to the
procedure described above except 3 rounds of crystallization were
performed. To a mixture of (.+-.)-1-methyl-2-piperidinemethanol
(95.6 g, 740 mmol) in EtOH (840 mL) was added dibenzoyl-L-tartaric
acid (255 g, 711 mmol). The resulting mixture was slowly heated
until a solution was obtained at which time the solution was slowly
cooled with gentle stirring. After 12 h the crystals were isolated
and dried to provide 79.6 g. This process was repeated: (2) ETOH
(335 mL) provided 50.4 g. (3) EtOH (345 mL) provided 35 g. The
resulting salt was treated with 3M HCl (134 mL) which was heated to
induce it to dissolve. The still warm solution was poured into a
separatory funnel and extracted with ethyl acetate. The remaining
aqueous layer was adjusted to pH 10 with K.sub.2CO.sub.3. The
solution was extracted with CH.sub.2Cl.sub.2, dried (MgSO.sub.4)
and concentrated to give 6 g of the alcohol. This alcohol (6 g,
46.7 mmol) was suspended in CH.sub.2Cl.sub.2 (100 mL) and
SOCl.sub.2 (6.8 mL, 93.3 mmol) added dropwise. After stirring for
12 h, the solvent was removed to provide a crude HCl salt. This
salt (5.98 g) was dissolved in EtOH (100 mL) and treated with
NH.sub.2NH.sub.2 (19.5 mL, 405 mmol) and heated to reflux for 3 h.
Half the solvent was removed, the residue extracted with ether and
the extracts dried and concentrated to give 4.55 g of a crude oil.
This crude hydrazine (2.01 g, 14.06 mmol) was dissolved in THF (100
mL) and triphenylmethylisocyanate (4.0 g, 14.1 mmol) was added
slowly. The solution was then stirred overnight and the solvent
removed under reduced pressure and the residue was purified by
flash chromatography (CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH) to provide
350 mg of the desired product. .sup.1H NMR (DMSO-d.sub.6) .delta.
1.10 (m, 2H), 1.30-1.56 (m, 4H), 1.95 (t, 1H), 2.15 (s, 1H), 2.18
(s, 3H), 2.71 (d, 1H), 3.25 (q, 1H), 3.55 (q, 1H), 4.80 (s, 2H),
7.12-7.32 (m, 15H), 8.02 (s, H). ESI-MS m/z 429.2 (100, M+H). 6.2a.
Preparation of Semicarbazide 6 ##STR117##
[0277] Compound 6 was prepared from carbazide d and aldehyde C
(prepared from 6-chloro-5-iodo-isatin by Method I and Method A) by
the procedure described in Example 5. .sup.1H NMR (DMSO-d.sub.6)
.delta. 1.10-1.20 (m, 2H), 1.49 (m, 3H), 1.65 (m, 1H), 2.15 (t,
1H), 2.43 (s, 3H), 2.83 (d, 1H), 3.00 (t, 2H), 3.23 (t, 2H), 4.09
(s, 1H) 4.13 (s, 3H), 4.23 (q, 1H), 4.31 (q, 1H), 6.80-7.40 (s,
2H), 7.85 (s, 1H), 8.04 (s, 1H), 8.14 (s, 1H), 8.38 (s, 1H), 8.41
(s, 1H), 8.45 (s, 1H). ESI-MS m/z 493.2 (100, M+H). 6.2b
Preparation of Semicarbazide (S)-(-)-6 ##STR118##
[0278] Compound (S)-(-)-6 was prepared from carbazide (S)-d and
aldehyde C (prepared from 6-chloro-5-iodo-isatin by Method I and
Method A) by the procedure described in Example 5. .sup.1H NMR
(DMSO-d.sub.6) .delta. 1.10-1.30 (m, 2H), 1.49 (m, 3H), 1.64 (m,
1H), 2.09 (t, 1H), 2.38 (s, 1H), 2.41 (s, 3H), 2.83 (d, 1H), 3.00
(dd, 2H), 3.23 (dd, 2H), 4.13 (s, 3H), 4.18 (q, 1H), 4.31 (q, 1H),
6.90 (s, 1H), 7.30 (s, 1H), 7.85 (s,1H), 8.04 (s, 1H), 8.14 (s,
1H), 8.38 (s, 1H), 8.41 (s, 1H), 8.45 (s, 1H). ESI-MS m/z 493.2
(100, M+H). 6.2c Preparation of Semicarbazide (R)-(+)-6
##STR119##
[0279] Compound (R)-(+)-6 was prepared from carbazide (R)-d and
aldehyde C (prepared from 6-chloro-5-iodo-isatin by Method I and
Method A) by the procedure described in Example 5. .sup.1H NMR
(DMSO-d.sub.6) .delta. 1.10-1.30 (m, 2H), 1.49 (m, 3H), 1.64 (m,
1H), 2.09 (t, 1H), 2.38 (s, 1H), 2.41 (s, 3H), 2.83 (d, 1H), 3.00
(dd, 2H), 3.23 (dd, 2H), 4.13 (s, 3H), 4.18 (q, 1H), 4.31 (q, 1H),
6.90 (s, 1H), 7.30 (s, 1H), 7.85 (s, 1H), 8.04 (s, 1H), 8.14 (s,
1H), 8.38 (s, 1H), 8.41 (s, 1H), 8.45 (s, 1H). ESI-MS m/z493.2
(100, M+H).
Example 7
[0280] 7.1 Preparation of Ester f ##STR120##
[0281] A suspension of zinc metal (1.70 g, 26.2 mmol) in THF (2 mL)
containing 1,2-dibromoethane (190 mg, 1.0 mmol) was heated to
65.degree. C. for one minute, cooled to room temperature and
treated with TMSCl (0.10 mL, 0.80 mmol). After 15 min at room
temperature, a warm solution of 4-iodomethyltetrahydropyran (5.65
g, 25.0 mmol) in THF (10 mL) was added dropwise. Upon completion of
the addition, the reaction mixture was heated to 40.degree. C. for
12 h and then cooled to room temperature. The resulting clear
solution was transferred via cannula to a solution of iodoquinoline
e (2.0 g, 5.0 mmol) in THF (100 mL) containing
(dppf).sub.2PdCl.sub.2 (600 mg) and heated to reflux for 10 h. The
reaction mixture was treated with aq. disodium EDTA, extracted with
DCM (4.times.100 mL) and dried (Na2SO4). Concentration followed by
flash chromatography (EtOAc:hexanes:MeOH/4:4:1) afforded f as a
yellow solid (1.28 g). MS (M+1).sup.+: 380. .sup.1H NMR
(CDCl.sub.3): .delta. 8.51 (s, 1H), 8.12 (s, 1H), 7.90 (s, 1H),
4.34 (s, 3H), 4.07 (s, 3H), 3.97 (dd, J=11.0, 2.7 Hz, 2H), 3.35 (t,
J=10.1 Hz, 2H), 2.79 (d, J=7.0 Hz, 2H), 2.55 (s, 3H), 1.80-1.90 (m,
1H), 1.60-1.63 (m, 2H), 1.40-1.50 (m, 2H). 7.2 Preparation of
Semithiocarbazone 7 ##STR121##
[0282] Ester f was converted into compound 7. MS (M+1).sup.+: 494.
.sup.1H NMR (DMSO-d.sub.6): .delta. 8.69 (s, 1H), 8.67 (s, 1H),
8.49 (s, 1H), 8.37 (s, 1H), 8.05 (s, 1H), 7.92 (s, 1H), 7.84 (s,
1H), 7.81 (s, 1H), 4.75-4.85 (m, 2H), 4.11 (s, 3H), 3.80-3.83 (m,
2H), 3.20-3.24 (m, 2H), 2.73 (d, J=6.5 Hz, 2H), 2.34 (s, 6H),
1.77-1.85 (m, 1H), 1.33-1.51 (m, 2H), 1.29-1.32 (m, 2H).
Example 8
[0283] ##STR122##
[0284] Compound 8 was prepared from 2-hydroxypropylhydrazine
(obtained following the method of Gever J. Am. Chem. Soc. 1954, 76,
1283) and aldehyde C (prepared from 6-chloro-5-iodo-isatin by
Method I and Method A) following the methods in Example 5. MS
(M+1).sup.+: 456. .sup.1H NMR (DMSO-d.sub.6): .delta. 8.91 (s, 1H),
8.68 (s, 1H), 8.53 (s, 1H), 8.43 (s, 1H), 8.39 (s, 1H), 8.15 (s,
1H), 8.01 (s, 1H), 7.86 (s, 1H), 5.13 (d, J=4.6 Hz, 1H), 4.81-4.88
(m, 1H), 4.42-4.48 (m, 1H), 4.15-4.19 (m, 1H), 4.12 (s, 3H), 3.23
(t, J=7.1 Hz, 2H), 2.96 (t, J=7.8 Hz, 2H), 1.20 (d, J=6.2 Hz,
3H).
Example 9
[0285] ##STR123##
[0286] Compound 9 was obtained as a yellow solid. ESI-MS m/z 530.3
(100, M+H.sup.+). .sup.1H NMR (DMSO-d.sub.6) .delta. 8.75 (s, 1H),
8.73 (s, 1H), 8.58 (s, 1H), 8.43 (s, 1H), 8.22 (s, 1H), 7.97 (s,
1H), 7.89 (s, 1H), 7.84 (s, 1H), 4.76 (t, J=6 Hz, 2H), 4.14 (s,
3H), 3.38-3.48 (m, 2H), 3.19-3.27 (m, 2H), 3.08 (s, 3H), 2.71 (t,
J=6 Hz, 2H), 2.60 (q, J=7 Hz, 4H), 2.56 (s, 3H), 1.05 (t, J=7 Hz,
6H).
Example 10
[0287] 10.1 Preparation of Hydrazine h ##STR124##
[0288] To a stirred solution of R-(-)-1,3-butanediol (Aldrich, 5.00
g, 55.5 mmol) in dichloromethane (20 mL) at -20.degree. C. under an
atmosphere of nitrogen was added triethylamine (10 mL).
p-Toluenesulfonyl chloride (10.6 g) in a solution in
dichloromethane (30 mL) was added dropwise over 2 h and the mixture
was stirred for a further 2 h at -20.degree. C. then allowed to
warm to room temperature overnight. The mixture was diluted with
water (50 mL) and the organics were separated, washed with 1M HCl
(50 mL), sat. aq. sodium bicarbonate (50 mL) and brine (20 mL). The
organics were dried (Na.sub.2SO.sub.4), filtered and concentrated
to afford the crude tosylate g. Tosylate g was added dropwise over
30 min to a stirred solution of hydrazine monohydrate (30 mL) and
ethanol (30 mL) at 75.degree. C. The mixture was stirred at
75.degree. C. overnight and then concentrated in vacuo. Water (20
mL) was added and the mixture extracted with DCM by continuous
extraction for 48 h. The organics extracts were concentrated in
vacuo to afford hydrazine h (3.0 g for 2 steps) as a colorless oil.
.sup.1H NMR (CDCl.sub.3) .delta. 3.95-3.98 (m, 2H), 3.43 (br s,
4H), 2.97-3.04 (m, 2H), 1.61-1.68 (m, 2H), 1.91-1.20 (s, 3H).
ESI-MS m/z 105.2 (100, M+H.sup.+). 10.2 Preparation of
Semithiocarbazone 10 ##STR125##
[0289] Hydrazine h and aldehyde M (prepared from
6-chloro-5-iodo-isatin by Method I and Method A) were converted in
to semithiocarbazone 10 as described in Example 5. .sup.1H NMR
(DMSO-d.sub.6) .delta. 1.19 (d, J=7 Hz, 3H), 1.55-1.85 (m, 2H),
2.98 (t, J=7 Hz, 2H), 3.23 (t, J=7 Hz, 2H), 3.75-3.85 (m, 1H), 4.14
(s, 3H), 4.55-4.69 (m, 1H), 4.80-4.95 (m, 1H), 5.02 (d, J=4 Hz, 1H)
7.39 (s, 1H), 7.85 (s, 1H), 7.98 (s, 1H), 8.25 (s, 1H), 8.40 (s,
1H), 8.52 (s, 1H), 8.59 (s, 1H), 8.73 (s, 1H). ESI-MS m/z 450.2
(100, M+H.sup.+).
Example 11
[0290] 11.1 Preparation of Acid j ##STR126##
[0291] To a stirred solution of isatin i (30.0 g, 96.7 mmol) in
glacial acetic acid (500 mL) at room temperature was added malonic
acid (104 g, 387 mmol). The mixture was heated at 100.degree. C.
for 18 h then cooled to room temperature, filtered and washed with
acetone (3.times.100 mL) to yield acid j as an orange solid (14.4
g). .sup.1H NMR (DMSO-d.sub.6) .delta. 12.18 (s, 1H), 8.82 (s, 1H),
7.50 (s, 1H), 6.92 (s, 1H). 11.2 Preparation of Ester k
##STR127##
[0292] To a stirred solution of acid j (9.0 g, 26 mmol) and
K.sub.2CO.sub.3 (5.3 g, 39 mmol) in anhydrous DMF (200 mL) under an
atmosphere of nitrogen was added iodoethane (8.0 g, 52 mmol). The
mixture was stirred at room temperature for 18 h then poured into
saturated sodium bicarbonate solution (250 mL), filtered and washed
with H.sub.2O g(3.times.150 mL) to yield ester k as a brown solid
(7.0 g, 72%). .sup.1H NMR (DMSO-d.sub.6) .delta. 8.65 (s, 1H), 7.52
(s, 1H), 6.98 (s, 1H) 4.20 (q, J=7 Hz, 2H), 1.18 (t, J=7 Hz, 3H).
11.3 Preparation of Chloride l ##STR128##
[0293] To a stirred solution of ester k (10.0 g, 26.5 mmol) in
toluene (300 mL) was added phosphorous oxychloride (16.2 g, 106
mmol). The mixture was heated to 100.degree. C. under an atmosphere
of nitrogen for 18 h then allowed to cool to room temperature,
poured into ice water (500 mL), filtered and washed with H.sub.2O
(2.times.250 mL) to yield chloride l as a brown solid (5.3 g).
.sup.1H NMR (DMSO-d.sub.6) .delta. 9.25 (s, 1H), 8.24 (s, 1H), 7.99
(s, 1H), 4.43 (q, J=7 Hz, 2H), 1.38 (t, J=7 Hz, 3H). ESI-MS: m/z
395.9 (100%, M+H.sup.+). 11.4 Preparation of Intermediate m
##STR129##
[0294] To a stirred solution of chloride l (4.0 g, 10 mmol) in
anhydrous DMF (15 mL) was added imidazole (3.4 g, 51 mmol) and the
mixture heated at 140.degree. C. for 18 h under an atmosphere of
nitrogen. The mixture was cooled to room temperature and then
concentrated in vacuo to afford a dark oil. The residue was
dissolved in CHCl.sub.3 (150 mL) washed with H.sub.2O, saturated
sodium bicarbonate solution, brine, dried over MgSO.sub.4, filtered
and concentrated. The residue was purified by flash chromatography
(eluting with 2% MeOH in DCM) to yield m as a red brown solid (3.5
g, 81%). .sup.1H NMR (DMSO-d.sub.6) .delta. 9.17 (s, 1H), 8.81 (s,
1H), 8.39 (s, 1H), 8.22 (s, 1H), 8.18 (s, 1H), 7.21 (s, 1H), 4.56
(q, J=7 Hz, 2H), 1.48 (t, J=7 Hz, 3H). 11.5 Preparation of
Intermediate n ##STR130##
[0295] To a stirred solution of m (2.0 g, 4.7 mmol), Pd(OAc).sub.2
(210 mg, 0.94 mmol) and tri-o-tolylphosphine (640 mg, 2.16 mmol) in
1:1/triethylamine:DMF (20 mL) under an atmosphere of nitrogen at
room temperature was added acrylonitrile (1.24 g, 23.4 mmol). The
mixture was heated to 60.degree. C. for 18 h, cooled to room
temperature, concentrated in vacuo and the residue purified by
flash chromatography (gradient elution 0 to 5% MeOH in DCM) to
yield product n (730 mg) as a yellow solid and a mixture of 1:5
cis:trans isomers. .sup.1H NMR (DMSO-d.sub.6) .delta. 9.15 (cis, s,
2H), 8.85 (trans, s, 2H), 8.45 (cis, s, 1H), 8.42 (trans, s, 1H),
8.29 (cis, s, 1H), 8.25-8.20 (cis+trans, m, 1H cis, 2H trans), 8.00
(trans, d, J=16 Hz, 1H), 7.81 (cis, d, J=12 Hz, 1H), 7.23
(cis+trans, s, 1H cis, 1H trans), 6.62 (trans, d, J=16 Hz, 1H),
6.3(cis, d, J=12 Hz, 1H), 4.58-4.5 (cis+trans, m, 2H cis, 2H
trans), 1.5-1.41 (cis+trans, m, 3H cis, 3H trans). 11.6 Preparation
of Intermediate o ##STR131##
[0296] To a stirred solution of n (740 mg, 2.10 mmol) in DME (10
mL) and MeOH (1 mL) under an atmosphere of nitrogen at room
temperature was added sodium borohydride powder (800 mg, 21.0 mmol)
portionwise over 1 h. The mixture was allowed to stir for 20 h then
cooled to 0.degree. C., quenched with 1N NaOH (10 mL), diluted with
H.sub.2O (10 mL) and allowed to stir at room temperature for 2 h.
The mixture was filtered, and the filtrate extracted with 10%
isopropyl alcohol in DCM (.times.3). The organics were combined,
dried over MgSO.sub.4, filtered and concentrated. The residue was
purified by flash chromatography (gradient elution 0 to 5% MeOH in
DCM) to yield alcohol o as a pale yellow solid (260 mg). .sup.1H
NMR (DMSO-d.sub.6) .delta. 8.70 (s, 1H), 8.14 (s, 1H), 8.13 (s,
1H), 8.09 (s, 1H), 7.20 (s, 1H), 5.08 (s, 2H), 3.25 (t, J=7 Hz,
2H), 2.99 (t, J=7 Hz, 2H). ESI-MS m/z 313.0 (100%, M+H.sup.+). 11.7
Preparation of Intermediate p ##STR132##
[0297] To a stirred solution of alcohol o (260 mg, 0.83 mmol) in
DCM (10 mL) under an atmosphere of nitrogen at room temperature was
added Dess-Martin periodinane (707 mg, 1.66 mmol). After 2 h the
mixture was diluted with 5 mL saturated ammonium chloride solution
and extracted with DCM (3.times.). The combined organic extracts
were washed with saturated sodium thiosulfate solution (2.times.10
mL), H.sub.2O, brine, dried over MgSO.sub.4, filtered and
concentrated. The residue was purified by flash chromatography
(gradient elution 0 to 5% MeOH in DCM) to yield 80 mg of aldehyde p
as a yellow solid.
[0298] .sup.1H NMR (DMSO-d.sub.6) .delta. 10.52 (s, 1H), 8.96 (s,
1H), 8.61 (s, 1H), 8.20 (s, 1H), 7.95 (s, 1H), 7.89 (s, 1H), 7.38
(s, 1H), 3.34 (t, J=7 Hz, 2H), 2.81 (t, J=7 Hz, 2H). 11.8
Preparation of Semiothiocarbazone 11 ##STR133##
[0299] Compound 11 was prepared following the procedure described
in Example 5. .sup.1H NMR (DMSO-d.sub.6) .delta. 8.32 (s, 1H), 8.86
(s, 1H), 8.67 (s, 1H), 8.61 (s, 1H), 8.5 (s, 1H), 8.36 (s, 1H),
8.32 (s, 1H), 8.18 (s, 1H), 7.44 (s, 1H), 5.05 (s, 1H), 4.81-4.79
(m, 2H), 3.24 (t, J=7 Hz, 2H), 2.99 (t, J=7 Hz, 2H), 1.72 (t, J=7
Hz, 2H), 1.28 (s, 6H). ESI-MS m/z 470.2 (150, M+H.sup.+)
Example 12
[0300] This example provides an assay that is useful in evaluating
and selecting a compound that modulates IKK.
Assay Protocol for Measuring IKK.beta. Enzyme Inhibition
[0301] 96 well polystyrene microtiter plates were coated with
Neutravidin (10 .mu.g/mL in PBS, overnight at 4.degree. C.). The
coating solution was removed and in 80 .mu.L/well a kinase reaction
mixture was added (20 mM Tris-HCl, pH 7.5, 10 mM MgC.sub.2, 2 mM
EGTA, 1 mM NaF, 0.5 mM benzamidine, 1 mM DTT, 0.1% NP-40, 10 .mu.M
ATP, 1 .mu.M of biotinylated substrate peptide
KKERLLDDRHDSGLDSMKDEEYEQGK-bio, sequence derived from
I.kappa.B.alpha.). In 10 .mu.L/well in DMSO test compounds were
added covering a final concentration range from 1 nM to 30 .mu.M.
Recombinant full-length IKK.beta. enzyme produced in a baculovirus
system in insect cells was added in 10 .mu.L buffer containing
Tris-HCl pH 7.5 20 mM, EGTA 2 mM, benzamidine 0.5 mM, DTT 1 mM,
NP-40 0.1%, MgCl.sub.2 10 mM to initiate the kinase reaction. The
reaction mixture was incubated at room temperature for 45 min.
During this incubation the substrate peptide gets phosphorylated by
IKK.beta. and gets captured onto the well's surface by Neutravidin.
The plate was washed 3.times. with 150 .mu.L distilled water to
terminate the reaction and remove components of the reaction
mixture.
[0302] A conventional chemiluminescent ELISA detection technique
was initiated by adding 100 .mu.L/well primary antibody
(custom-made monoclonal antibody generated to recognize the
phosphorylated epitope in the substrate peptide; used at 1:10,000
dilution) premixed with horseradish peroxidase (HRP) conjugated
anti-mouse secondary antibody (commercially available from several
sources; used at 1:10,000 dilution) in PBS containing 2% BSA. The
solution was incubated at room temperature for 40 min on a shaker,
then washed 3.times. with 150 .mu.L of water. 100 .mu.L well
10.times. diluted SuperSignal HRP substrate (from Pierce) was added
and after 5 min incubation the chemiluminescent signal was captured
by a Labsystems LuminoSkan luminometer. The point of 50% inhibition
of IKK.beta. enzyme activity (IC.sub.50) was determined by curve
fitting with the LSW data analysis software (MDL, San Leandro,
Calif.).
[0303] The compounds provided in Examples 1-4 all displayed
IC.sub.50 values of less than or equal to about 30 .mu.M in the
above assay.
[0304] All publications and patent applications cited in this
specification are herein incorporated by reference as if each
individual publication or patent application were specifically and
individually indicated to be incorporated by reference. Although
the foregoing invention has been described in some detail by way of
illustration and example for purposes of clarity of understanding,
it will be readily apparent to those of ordinary skill in the art
in light of the teachings of this invention that certain changes
and modifications may be made thereto without departing from the
spirit or scope of the appended claims.
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