Indazole derivatives and their use as inhibitors of...

Details Indazole derivatives and their use as inhibitors of... Indazole derivatives and their use as inhibitors of...

1999-03-04

2001-07-17

Rotman, Alan L. (Department: 1812)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Para-n-benzene - sulfoxy-n containing doai, and said benzene...

C514S336000, C514S337000, C514S403000, C514S406000, C548S361100, C548S362100, C548S362500, C546S275700

Reexamination Certificate

active

06262040

ABSTRACT:

This invention relates to novel indazole analogs. The compounds are selective inhibitors of phosphodiesterase (PDE) type IV and the production of tumor necrosis factor (TNF), and as such are useful in the treatment of asthma, arthritis, bronchitis, chronic obstructive airway disease, psoriasis, allergic rhinitis, dermatitis, and other inflammatory diseases, central nervous system disorders such as depression and multi-infarct dementia, AIDS, septic shock and other diseases involving the production of TNF. This invention also relates to a method of using such compounds in the treatment of the foregoing diseases in mammals, especially humans, and to pharmaceutical compositions containing such compounds.
The following co-pending United States provisional patent applications also disclose and claim indazole derivatives that are selective inhibitors of PDE type IV and the production of TNF: U.S. provisional application No. 60/021,072, filed Jun. 27, 1996; U.S. provisional application No. 60/020,385, filed Jun. 25, 1996; and U.S. provisional application No. 60/016,861, filed May 3, 1996. The foregoing co-pending United States provisional patent applications are incorporated herein by reference in their entirety.
Since the recognition that cyclic adenosine phosphate (AMP) is an intracellular second messenger (E. W. Sutherland, and T. W. Rall,
Pharmacol. Rev.,
12, 265, (1960)), inhibition of the phosphodiesterases has been a target for modulation and, accordingly, therapeutic intervention in a range of disease processes. More recently, distinct classes of PDE have been recognized (J. A. Beavo et al.,
Trends in Pharm. Sci.
(TIPS), 11, 150, (1990)), and their selective inhibition has led to improved drug therapy (C. D. Nicholson, M. S. Hahid,
TIPS,
12, 19, (1991)). More particularly, it has been recognized that inhibition of PDE type IV can lead to inhibition of inflammatory mediator release (M. W. Verghese et al.,
J. Mol. Cell Cardiol.,
12 (Suppl. II), S 61, (1989)) and airway smooth muscle relaxation (T. J. Torphy in “Directions for New Anti-Asthma Drugs,” eds S. R. O'Donnell and C. G. A. Persson, 1988, 37 Birkhauser-Verlag). Thus, compounds that inhibit PDE type IV, but which have poor activity against other PDE types, would inhibit the release of inflammatory mediators and relax airway smooth muscle without causing cardiovascular effects or antiplatelet effects. It has also been disclosed that PDE IV inhibitors are useful in the treatment of diabetes insipidus (Kidney Int. 37:362, 1990; Kidney Int. 35:494) and central nervous system disorders such as depression and mult-infarct dementia (PCT international application WO 92/19594 (published Nov. 12, 1992)).
TNF is recognized to be involved in many infectious and auto-immune diseases (W. Friers,
Fed. of Euro. Bio. Soc.
(FEBS) Letters, 285, 199, (1991)). Furthermore, it has been shown that TNF is the prime mediator of the inflammatory response seen in sepsis and septic shock (C. E. Spooner et al., Clinical Immunology and Immunopathology, 62, S11, (1992)).
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula I
and to pharmaceutically acceptable salts thereof, wherein:
R is H, C
1
-C
9
alkyl, -(CH
2
)
m
(5 to 10 membered heterocyclyl) wherein m is 0 to 2, (C
1
-C
6
alkoxy)C
1
-C
6
alkyl, C
2
-C
6
alkenyl, or -(Z
1
(
b
(Z
2
)
c
(C
6
-C
10
aryl) wherein b and c are independently 0 or 1, Z
1
is C
1
-C
6
alkylene or C
2
-C
6
alkenylene, and Z
2
is O, S, SO
2
, or NR
12
, and wherein said R groups are optionally substituted by 1 to 3 substituents independently selected from the group consisting of halo, hydroxy, C
1
-C
6
alkyl, C
2
-C
5
alkenyl, C
1
-C
6
alkoxy, trifluoromethyl, nitro, —CO
2
R
12
, —C(O)NR
12
R
13
, —NR
12
R
13
and —SO
2
NR
12
R
13
;
R
1
is H, C
1
-C
9
alkyl, C
2
-C
3
alkenyl, or phenyl, wherein said alkyl, alkenyl and phenyl R
1
groups are optionally substituted by 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, trifluoromethyl, and halo;
R
2
is R
19
, —C(O)NR
12
(CHR
12
)
m
C(O)NR
12
O(CH
2
)
q
(C
6
-C
10
aryl), —C(═NR
32
)NH(CH
2
)
p
(C
6
-C
10
aryl), —C(O)NR
6
(CHR
12
)
m
C(O)NR
12
(CH
2
)
p
OR
12
, —C(O)NR
12
(CHR
12
)
m
S(C
1
-C
4
alkyl), —C(═NOC(O)R
25
)R
26
, —CR
17
R
18
CHR
28
NR
9
SO
2
(CH
2
)
p
A, —CR
17
R
18
CHR
28
NR
9
P(O)(OR
12
)C(O)(C
1
-C
4
alkyl), —CR
17
R
18
CHR
28
NR
9
P(O)(C
1
-C
4
alkoxy)
2
, —Z
3
-R
7
, or -(CR
17
R
18
)
m
NR
9
(C(O))
q
R
10
wherein p is 0 to 2, m is 1 to 6, and q is 1 or 2; or R
2
is
wherein in said formulas (Ia)-(Ii), the structures of formulas (If) and (Ig) are attached to formula I at carbons 5, 6, or 7 of said formulas (If) and (Ig), the dashed line in formulas (Ic) and (Id) indicates a single bond or double bond, except R
6
is absent in formulas (Ic) and (Id) where said dashed line indicates a double bond, n is 0 to 2, p is 0 to 6, and m is 0 or 1;
R
3
is —C(O)N(CH
3
)(OCH
3
) or -(CH
2
)
n
OH wherein n is 0 to 4;
R
4
and R
5
are independently selected from the group consisting of H, ethyl, —CO
2
H and —C(O)NHOH;
R
6
is H, cyano, hydroxy, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, —OC(O)(C
1
-C
6
alkyl) or —OC(O)(C
6
-C
10
aryl);
R
7
is C
6
-C
10
aryl or 5 to 10 membered heterocyclyl, wherein said R
7
groups are optionally substituted by 1 to 3 substituents independently selected from halo, trifluoromethyl, cyano, nitro, —CO
2
R
12
, C
1
-C
4
alkoxy, —OC(O)(C
1
-C
4
alkyl), —NR
12
C(O)(C
1
-C
4
alkyl), —C(O)NH
2
, —C(O)NHOH, —C(O)O(C
1
-C
4
alkyl), C
1
-C
4
alkyl, —S(O)
n
R
12
wherein n is 0 to 2, benzoyl, —NR
12
R
13
, —OR
12
, C
1
-C
6
alkanoyl, —Y
1
-(C
6
-C
10
aryl), —C(O)O(C
6
-C
10
aryl), —NH(C
6
C
10
aryl), —C(O)NH(C
6
C
10
aryl), —C(O)NR
12
O(CH
2
)
n
(C
6
-C
10
aryl) wherein n is 1 to 3, and —SO
2
NH(C
6
C
10
aryl);
R
8
is H, C
1
-C
6
alkyl, or -(CH
2
)
n
(C
6
-C
10
aryl) wherein n is 0 to 4;
R
9
is H, —OR
12
, -(CH
2
)
m
A or —CH
2
O(CH
2
)
m
A wherein m is 0 to 2;
R
10
is C
1
-C
4
alkyl, —OR
12
, —CR
12
R
13
OR
12
, —CR
12
R
13
NR
12
R
13
, —CR
12
(OR
13
)CR
12
R
13
OR
12
, 2,2-dimethyl-1,3-dioxolan-4-yl, —NR
12
C(O)NR
12
R
13
, —S(CR
12
R
13
)
n
CH
3
wherein n is 0 to 5, —NR
12
(CH
2
)
q
(pyridyl) wherein q is 0 or 1, —P(O)(C
1
-C
4
alkoxy)
2
, —NR
12
R
13
, —NR
12
OR
13
, —NR
12
NR
13
R
11
, —NR
12
CH
2
R
14
, —OCH
2
NR
12
C(O)R
14
, —OCH
2
C(O)NR
15
R
16
, —OCHR
12
OC(O)(C
1
-C
4
alkyl), —OCHR
12
C(O)(C
1
-C
3
alkoxy), —O(CH
2
)
m
R
11
, or —NR
12
(CH
2
)
m
R
11
wherein m is 0 to 2;
R
11
is H or A;
each R
12
and R
13
is independently H or C
1
-C
4
alkyl;
R
14
is methyl or phenyl;
R
15
is H, methyl, ethyl, or —CH
2
CH
2
OH;
R
16
is H, methyl, ethyl, —CH
2
C(O)NH
2
, or —CH
2
CH
2
OH;
each R
17
is independently H, hydroxy, cyano, halo, C
1
-C
3
alkyl, C
1
-C
3
alkoxy, —NR
12
R
13
, —C(O)OR
12
, —C(O)R
12
, —CH═CR
12
R
13
, —C═CR
12
, —CH
2
NR
12
R
13
, —CH
2
OR
12
, —C(O)NR
12
R
13
, —C(Y
5
)H, or —CH
2
NR
12
C(O)C(O)NR
12
R
13
, provided that when R
17
is hydroxy then R
18
is H or C
1
-C
4
alkyl;
each R
18
is independently H, fluoro, cyano, or C
1
-C
4
alkyl, wherein said methyl is optionally substituted by 1 to 3 fluoro substituents;
or R
17
and R
18
are taken together to form an oxo (═O) moiety;
R
19
is phenyl, naphthyl, pyrrolyl, furanyl, thienyl, oxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinolinyl, 5,6,7,8-tetrahydroquinolinyl, or 5,6,7,8-tetrahydroisoquinolinyl, wherein said R
19
groups, except said phenyl, are optionally substituted by 1 to 3 R
23
substituents, and wherein said phenyl R
19
group is optionally substituted by 1 to 3 substituents independently selected from R
23
and R
24
;
R
20
is —C(O)R
21
, —C(O)C(O)R
21
, —C(O)C(Y
2
)C(O)R
21
or
R
21
is H, —OR
22
, —NHR
22
, —NHOH, —NHNH
2
, -(CH
2
)
n
Y
3
(phenyl) or -(CH
2
)
n
Y
3
(pyridyl) wherein n is 0 to 4;
R
22
is H, C
1
-C
8
alkyl, -(CH
2
)
n
Y
3
(phenyl) or -(CH
2
)
n
Y
3
(pyridyl) wherein n is 0 to 4;
each R
23
is independently halo, C
1
-C
6
alkyl, C
1
-C
7
alkoxy, C
2
-C
6
alkylenedioxy,

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