1,4-substitued 4,4-diaryl cyclohexanes

Details 1,4-substitued 4,4-diaryl cyclohexanes 1,4-substitued 4,4-diaryl cyclohexanes

2002-01-24

2003-02-11

Killos, Paul J. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C560S051000, C560S059000, C560S102000, C504S172000, C568S659000

Reexamination Certificate

active

06518306

ABSTRACT:

AREA OF THE INVENTION
This invention relates to compounds which are PDE4 inhibitors particularly in regards to treating allergic and inflammatory diseases and for inhibiting the production of Tumor Necrosis Factor (TNF). They are particularly use for treating pulmonary diseases such as various forms of asthma and chronic obstructive pulmonary disease.
BACKGROUND OF THE INVENTION
The compounds of this invention can be used in treating conditions which are modulated by the inhibition of PDE4. They have particular application in regards to treating allergic and inflammatory diseases and for inhibiting the production of Tumor Necrosis Factor (TNF).
As regards anti-inflammatory activity, one target disease is chronic obstructive pulmonary disease (COPD). COPD is an umbrella term frequently used to describe two conditions of fixed airways disease, chronic bronchitis and emphysema. Chronic bronchitis and emphysema are most commonly caused by smoking; approximately 90% of patients with COPD are or were smokers. Approximately 50% of smokers develop chronic bronchitis, and about 15% of smokers develop disabling airflow obstruction. The airflow obstruction associated with COPD is progressive, may be accompanied by airway hyperactivity, and may be partially reversible. Non-specific airway hyper-responsiveness may also play a role in the development of COPD and may be predictive of an accelerated rate of decline in lung function in smokers.
Another disease treatable with PDE4 inhibitors is asthma, particularly asthma caused by extrinsic stimuli. It is a complex, multifactorial disease characterized by reversible narrowing of the airway and hyperactivity of the respiratory tract to external stimuli. Multiple mediators are responsible for the development of asthma. It seems unlikely that eliminating the effects of a single mediator will have a substantial effect on all three components of chronic asthma. An alternative to the “mediator approach” is to regulate the activity of the cells responsible for the pathophysiology of the disease. One such way is by elevating levels of cAMP (adenosine cyclic 3′,5′-monophosphate). Cyclic AMP has been shown to be a second messenger mediating the biologic responses to a wide range of hormones, neurotransmitters and drugs; [Krebs Endocrinology Proceedings of the 4th International Congress Excerpta Medica, 17-29, 1973]. When the appropriate agonist binds to specific cell surface receptors, adenylate cyclase is activated, which converts Mg
+2
-ATP to cAMP at an accelerated rate.
Cyclic AMP modulates the activity of most, if not all, of the cells that contribute to the pathophysiology of extrinsic (allergic) asthma. As such, an elevation of cAMP would produce beneficial effects including: 1) airway smooth muscle relaxation, 2) inhibition of mast cell mediator release, 3) suppression of neutrophil degranulation, 4) inhibition of basophil degranulation, and 5) inhibition of monocyte and macrophage activation. Hence, compounds that activate adenylate cyclase or inhibit phosphodiesterase should be effective in suppressing the inappropriate activation of airway smooth muscle and a wide variety of inflammatory cells. The principal cellular mechanism for the inactivation of cAMP is hydrolysis of the 3′-phosphodiester bond by one or more of a family of isozymes referred to as cyclic nucleotide phosphodiesterases (PDEs).
It has now been shown that a distinct cyclic nucleotide phosphodiesterase (PDE) isozyme, PDE 4, is responsible for cAMP breakdown in airway smooth muscle and inflammatory cells. [Torphy, “Phosphodiesterase Isozymes: Potential Targets for Novel Anti-asthmatic Agents” in New Drugs for Asthma, Barnes, ed. IBC Technical Services Ltd, 1989]. Research indicates that inhibition of this enzyme not only produces airway smooth muscle relaxation, but also suppresses degranulation of mast cells. basophils and neutrophils along with inhibiting the activation of monocytes and neutrophils. Moreover, the beneficial effects of PDE 4 inhibitors are markedly potentiated when adenylate cyclase activity of target cells is elevated by appropriate hormones or autocoids, as would be the case in vivo. Thus PDE 4 inhibitors would be effective in the asthmatic lung, where levels of prostaglandin E
2
and prostacyclin (activators of adenylate cyclase) are elevated. Such compounds would offer a unique approach toward the pharmacotherapy of bronchial asthma and possess significant therapeutic advantages over agents currently on the market.
The compounds of this invention also inhibit the production of tumor necrosis factor (TNF), a serum glycoprotein. Excessive or unregulated TNF production has been implicated in mediating or exacerbating a number of diseases including rheumatoid arthritis, rheumatoid spondylitis. osteoarthritis, gouty arthritis and other arthritic conditions: sepsis. septic shock. endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption diseases, reperfusion injury, graft vs. host reaction, allograft rejections, fever and myalgias due to infection, such as influenza, cachexia secondary to infection or malignancy, cachexia secondary to human acquired immune deficiency syndrome (AIDS), ARC (AIDS related complex). keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, or pyresis, in addition to a number of autoimmune diseases, such as multiple sclerosis, auto-immune diabetes and systemic lupus erythematosis.
This invention provides compound which are useful in treating these diseases, and others modulated by PDE4, by inhibiting one or more of the various isoforms of PDE4.
SUMMARY OF THE INVENTION
In a first aspect this invention relates to a compound of Formula(I)
wherein:
R
1
is —(CR
4
R
5
)
n
C(O)O(CR
4
R
5
)
m
R
6
, —(CR
4
R
5
)
n
C(O)NR
4
(CR
4
R
5
)
m
R
6
, —(CR
4
R
5
)
n
O(CR
4
R
5
)
m
R
6
, or —(CR
4
R
5
)
r
R
6
wherein the alkyl moieties unsubstituted or substituted with one or more halogens;
m is 0 to 2;
n is 1 to 4;
r is 0 to 6;
R
4
and R
5
are independently selected hydrogen or C
1-2
alkyl;
R
6
is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyC
1-3
alkyl, halo substituted aryloxyC
1-3
alkyl, indanyl, indenyl, C
7-11
polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C
3-6
cycloalkyl, or a C
4-6
cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl or heterocyclic moiety is unsubstituted or substituted by 1 to 3 methyl groups, one ethyl group, or an hydroxyl group;
provided that:
a) when R
6
is hydroxyl, then m is 2; or
b) when R
6
is hydroxyl, then r is 2 to 6; or
c) when R
6
is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or
d) when R
6
is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then r is 1 to 6;
e) when n is 1 and m is 0, then R
6
is other than H in —(CR
4
R
5
)
n
O(CR
4
R
5
)
m
R
6
;
X is YR
2
, fluorine, NR
4
R
5
, or formyl amine;
Y is O or S(O)
m′
,
m′ is 0, 1, or 2;
X
2
is O or NR
8
;
X
4
is H, R
9
, OR
8
, CN, C(O)R
8
, C(O)OR
8
, C(
0
)NR
8
R
8
, or NR
8
R
8
;
R
2
is independently selected from —CH
3
or —CH
2
CH
3
optionally substituted by 1 or more halogens;
s is 0 to 4;
Ar is phenyl unsubstituted or substituted by R
7
;
Z is OR
14
, OR
15
, SR
14
, S(O)
m′
R
7
, S(O)
2
NR
10
R
14
, NR
10
R
14
, NR
14
C(O)R
9
, NR
10
C(Y′)R
14
, NR
10
C(O)OR
7
, NR
10
C(Y′)NR
10
R
14
, NR
10
S(O)
2
NR
10
R
14
, NR
10
C(NCN)NR
10
R
14
, NR
10
S(O)
2
R
7
, NR
10
C(CR
4
NO
2
)NR
10
R
14
, NR
10
C(NCN)SR
9
, NR
10
C(CR
4
NO
2
)SR
9
, NR
10
C(NR
10
)NR
10
R
14
, NR
10
C(O)C(O)NR
10
R
14
,or NR
10
C(O)C(O)OR
14
;
Y′ is O or S;
R
7
is —(CR
4
R
5
)
q
R
12
or C
1-6
alkyl wherein: the R
12
or C
1-6
alkyl group is unsubstituted or substituted one or more times

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