Substituted indazole derivatives and related compounds

Details Substituted indazole derivatives and related compounds Substituted indazole derivatives and related compounds

1997-11-04

2001-04-03

Ramsuer, Robert W. (Department: 1613)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S361100

Reexamination Certificate

active

06211222

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to a series of novel indazole analogs that 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, 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.
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., 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.
TNF is recognized to be involved in many infectious and auto-immune diseases, W. Friers, 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 hydrogen, C
1
-C
6
alkyl, —(CH
2
)
n
(C
3
-C
7
cycloalkyl) wherein n is 0 to 2, (C
1
-C
6
alkoxy)C
1
-C
6
alkyl, C
2
-C
6
alkenyl, —(CH
2
)
n
(C
3
-C
9
heterocyclyl) wherein n is 0 to 2, or —(Z′)
b
(Z″)
c
(C
6
-C
10
aryl) wherein b and c are independently 0 or 1, Z′ is C
1
-C
6
alkylene or C
2
-C
6
alkenylene, and Z″ is O, S, SO
2
, or NR
9
, and wherein said alkyl, alkenyl, alkoxyalkyl, heterocyclyl, and aryl moieties of said R groups are optionally substituted by one or more substituents independently selected from halo, hydroxy, C
1
-C
5
alkyl, C
2
-C
5
alkenyl, C
1
-C
5
alkoxy, C
3
-C
6
cycloalkoxy, trifluoromethyl, nitro, CO
2
-R
9
, C(O)NR
9
R
10
, NR
9
R
10
and SO
2
NR
9
R
10
;
R
1
is hydrogen, C
1
-C
7
alkyl, C
2
-C
3
alkenyl, phenyl, C
3
-C
7
cycloalkyl, or (C
3
-C
7
cycloalkyl)C
1
-C
2
alkyl, wherein said alkyl, alkenyl and phenyl R
1
groups are optionally substituted with up to 3 substituents independently selected from the group consisting of methyl, ethyl, trifluoromethyl, and halo;
R
2
a
and R
2
b
are independently selected from the group consisting essentially of hydrogen and hereinafter recited substituents, provided that one, but not both of R
2
a
and R
2
b
must be independently selected as hydrogen, wherein said substituents comprise:
wherein the dashed lines in formulas (Ia) and (Ib) independently and optionally represent a single or double bond, provided that in formula (Ia) both dashed lines cannot both represent double bonds at the same time;
m is 0 to 4;
R
3
is H, halo, cyano, C
2
-C
4
alkynyl optionally mono-substituted by phenyl, pyridyl or pyrimidinyl; C
1
-C
4
alkyl optionally substituted by one or more halogens; —CH
2
NHC(O)C(O)NH
2
, cyclopropyl optionally substituted by R
11
, R
17
, CH
2
OR
9
, NR
9
R
10
, CH
2
NR
9
R
10
, CO
2
R
9
, C(O)NR
9
R
10
, C°CR
11
, C(Z)H or —CH═CR
11
R
11
; provided that R
3
is absent when the dashed line in formula (Ia) attached to the ring carbon atom to which R
3
is attached represents a double bond;
R
4
is H, R
6
, C(Y)R
14
, CO
2
R
14
, C(Y)NR
17
R
14
, CN, C(NR
17
)NR
17
R
14
, C(NOR
9
)R
14
, C(O)NR
9
NR
9
C(O)R
9
, C(O)NR
9
NR
17
R
14
, C(NOR
14
)R
9
, C(NR
9
)NR
17
R
14
, C(NR
14
)NR
9
R
10
, C(NCN)NR
17
R
14
, C(NCN)S(C
1
-C
4
alkyl), CR
9
R
10
OR
14
, CR
9
R
10
SR
14
, CR
9
R
10
S(O)
n
R
15
wherein n is 0 to 2, CR
9
R
10
NR
14
R
17
, CR
9
R
10
NR
17
SO
2
R
15
, CR
9
R
10
NR
17
C(Y)R
14
, CR
9
R
10
NR
17
CO
2
R
15
, CR
9
R
10
NR
17
C(Y)NR
17
R
14
, CR
9
R
10
NR
17
C(NCN)NR
17
R
14
, CR
9
R
10
NR
17
C(CR
9
NO
2
)S(C
1
-C
4
alkyl), CR
9
R
10
CO
2
R
15
, CR
9
R
10
C(Y)NR
17
R
14
, CR
9
R
10
C(NR
17
)NR
17
R
14
, CR
9
R
10
CN, CR
9
R
10
C(NOR
10
)R
14
, CR
9
R
10
C(NOR
14
)R
10
, CR
9
R
10
NR
17
C(NR
17
)S(C
1
-C
4
alkyl), CR
9
R
10
NR
17
C(NR
17
)NR
17
R
14
, CR
9
R
10
NR
17
C(O)C(O)NR
17
R
14
, CR
9
R
10
NR
17
O(O)C(O)OR
14
, tetrazolyl, thiazolyl, imidazolyl, imidazolidinyl, pyrazolyl, thiazolidinyl, oxazolyl, oxazolidinyl, triazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, CR
9
R
10
(tetrazolyl), CR
9
R
10
(thiazolyl), CR
9
R
10
(imidazolyl), CR
9
R
10
(imidazolidinyl), CR
9
R
10
(pyrazolyl), CR
9
R
10
(thiazolidinyl), CR
9
R
10
(oxazolyl), CR
9
R
10
(oxazolidinyl), CR
9
R
10
(triazolyl), CR
9
R
10
(isoxazolyl), CR
9
R
10
(oxadiazolyl), CR
9
R
10
(thiadiazolyl), CR
9
R
10
(morpholinyl), CR
9
R
10
(piperidinyl), CR
9
R
10
(piperazinyl), or CR
9
R
10
(pyrrolyl), wherein said heterocyclic groups and moieties for said R
4
substituents are optionally substituted by one or more R
14
substituents;
R
5
is R
9
, OR
9
, —CH
2
OR
9
, cyano, C(O)R
9
, CO
2
R
9
, C(O)NR
9
R
10
, or NR
9
R
10
, provided that R
5
is absent when the dashed line in formula (Ia) represents a double bond;
or R
4
and R
5
are taken together to form ═O or ═R
8
;
or R
5
is hydrogen and R
4
is OR
14
, SR
14
, S(O)
n
R
15
wherein n is 0 to 2, SO
2
NR
17
R
14
, NR
17
R
14
, NR
14
C(O)R
9
, NR
17
C(Y)R
14
, NR
17
C(O)OR
15
, NR
17
C(Y)NR
17
R
14
, NR
17
SO
2
NR
17
R
14
, NR
17
C(NCN)NR
17
R
14
, NR
17
SO
2
R
15
, NR
17
C(CR
9
NO
2
)NR
17
R
14
, NR
17
C(NCN)S(C
1
-C
4
alkyl), NR
17
C(CR
9
NO
2
)S(C
1
-C
4
alkyl), NR
17
C(NR
17
)NR
17
R
14
, NR
17
C(O)C(O)NR
17
R
14
, or NR
17
C(O)C(O)OR
14
;
R
6
is independently selected from methyl and ethyl optionally substituted by one or more halogens;
R
7
is OR
14
, SR
14
, SO
2
NR
17
R
14
, NR
17
R
14
, NR
14
C(O)R
9
, NR
17
C(Y)R
14
, NR
17
C(O)OR
15
, S(O)
n
R
12
wherein n is 0 to 2, OS(O)
2
R
12
, OR
12
, OC(O)NR
13
R
12
, OC(O)R
13
, OCO
2
R
13
, O(CR
12
R
13
)
m
OR
12
wherein m is 0 to 2, CR
9
R
10
OR
14
, CR
9
R
10
NR
17
R
14
, C(Y)R
14
, CO
2
R
14
, C(Y)NR
17
R
14
, CN, C(NR
17
)NR
17
R
14
, C(NOR
9
)R
14
, C(O)NR
9
NR
9
C(O)R
9
, C(O)NR
9
NR
17
R
14
, C(NOR
14
)R
9
, C(NR
9
)NR
17
R
14
, C(NR
14
)NR
9
R
10
, C(NCN)NR
17
R
14
, C(NCN)S(C
1
-C
4
alkyl), tetrazolyl, thiazolyl, imidazolyl, imidazolidinyl, pyrazolyl, thiazolidinyl, oxazolyl, oxazolidinyl, triazolyl, isoxazolyl, oxadiazolyl, or thiadiazolyl, wherein said heterocyclic groups are optionally substituted by one or more R
14
substituents;
R
8
is —NR
15
, —NCR
9
R
10
(C
2
-C
6
alkenyl), —NOR
14
, —NOR
19
, —NOCR
9
R
10
(C
2
-C
6
alkenyl), —NNR
9
R
14
, —NNR
9
R
19
, —NCN, —NNR
9
C(Y)NR
9
R
14
, —C(CN)
2
, —CR
14
CN, —CR
14
CO
2
R
9
, —CR
14
C(O)NR
9
R
14
, —C(CN)NO
2
, —C(CN)CO
2
(C
1
-C
4
alkyl), —C(CN)OCO
2
(C
1
-C
4
alkyl), —C(CN)(C
1
-C
4
alkyl), —C(CN)C(O)NR
9
R
14
, 2-(1,3-dithiane), 2-(1,3-dithiolane), dimethylthio ketal, diethylthio ketal, 2-(1,3-dioxolane), 2-(1,3-dioxane), 2-(1,3-oxathiolane), dimethyl ketal or diethyl ketal;
R
9
and R
10
are independently hydrogen or C
1
-C
4
alkyl optionally substituted by up to three fluorines;
R
11
is independently fluoro or R
10
;
R
12
is C
1
-C
6
alkyl, C
2
-C

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