Nicotinamide derivatives

Details Nicotinamide derivatives Nicotinamide derivatives

1999-05-27

2002-04-30

Rotman, Alan L. (Department: 1612)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S280400, C546S325000, C546S317000

Reexamination Certificate

active

06380218

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to nicotinamide derivatives that are selective inhibitors of phosphodiesterase type 4 (PDE4) and the production of tumor necrosins factor (TNF), and as such are useful in the treatment of respiratory, allergic, rheumatoid, body weight regulation, inflammatory and central nervous system disorders such as asthma, chronic obstructive pulmonary disease, adult respiratory diseases syndrome, shock, fibrosis, pulmonary hypersensitivity, allergic rhinitis, atopic dermatitis, psoriasis, weight control, rheumatoid arthritis, cachexia, crohn's disease, ulcerative colitis, arthritic conditions and other inflammatory diseases, depression, multi-infarct dementia, and AIDS.
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 tri-phosphate (cAMP) is an intracellular second messenger, 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 and their selective inhibition has led to improved drug therapy. More particularly, it has been recognized that inhibition of PDE4 can lead to inhibition of inflammatory mediator release and airway smooth muscle relaxation. Thus, compounds that inhibit PDE4, 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.
Recent molecular cloning has revealed a complexity and diversity of PDE4 enzymes. It is now known that there are four distinct PDE4 isozymes (A, B, C and D), each encoded for by a separate gene. Kinetic studies of human recombinant materials suggest that these four isozymes may differ in their Km's and Vmax's for hydrolysis of cAMP. Analysis of tissue distribution of PDE4 mRNAs suggests that each isozyme may be localized in a cell-specific pattern. For example, unlike human skeletal muscle human peripheral blood leukocytes do not express PDE4C message, and guinea pig eosinophils express predominantly PDE4D message. The structural and distribution diversity of PDE4 isozymes offers an opportunity to discover an isozyme selective inhibitor that blocks the function of inflammatory cells only. Using PDE4D isozyme selective inhibitors, we have demonstrated that the PDE4D isozyme plays a key role in regulating the activation and degranulation of human eosinophils. In a primate model of asthma, PDE4D isozyme selective compounds inhibit antigen-induced pulmonary eosinophilia. Therefore, by selectively blocking the D isozyme, PDE4D inhibitors exhibit reduced side effects and retain anti-asthmatic (anti-inflammatory) efficacy.
SUMMARY OF THE INVENTION
The present invention relates to a compound of the formula
or the pharmaceutically acceptable salt thereof, wherein the broken line represents an optional double bond;
m is 0 or 1;
n is 0 or 1;
o is 0, 1, 2, 3or 4;
p is 0 or 1;
q is 0, 1, 2 or 3;
r is 0, 1, 2, 3, or 4;
t is 0 or 1;
A is oxygen, >NH or sulfur;
B is oxygen or NH;
D is oxygen or NR
9
, wherein R
9
is hydrogen or (C
1
-C
6
)alkyl;
E is CH
2
, O, NH or S(O)
a
wherein a is 0, 1 or 2;
R
1
is hydrogen, (C
1
-C
6
)alkyl, (C
3
-C
7
)cycloalkyl, (C
3
-C
7
)cycloalkenyl, (C
6
-C
10
)aryl, bridged(C
7
-C
9
)bicycloalkyl or a saturated or unsaturated cyclic or bicyclic (C
3
-C
7
)heterocyclic group;
wherein said saturated or unsaturated cyclic or bicyclic (C
3
-C
7
)heterocyclic group contains from one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and NR
9
, wherein R
9
is as defined above;
wherein said R
1
cycloalkyl, cycloalkenyl, cycloalkanone, aryl, bicycloalkyl and heterocyclic groups are optionally substituted by one to three substituents independently selected from the substituents consisting of halo, cyano, carboxy, amino, nitro, hydroxy, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, (C
3
-C
7
)cycloalkyl, hydroxy(C
1
-C
6
)alkyl, hydroxy(C
1
-C
6
)alkylamino, (C
1
-C
6
)alkoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C
1
-C
6
)acyl, (C
1
-C
6
)acylamino, (C
1
-C
6
)acyloxy, (C
1
-C
6
)alkylamino, ((C
1
-C
6
)alkyl)
2
amino, (C
1
-C
6
)alkyl-NH—(C═O)—, ((C
1
-C
6
)alkyl
2
-N—(C═O)—, aminosulfonyl, (C
1
-C
6
)alkylaminosulfonyl, or a saturated or unsaturated cyclic or bicyclic (C
3
-C
7
) heterocycle;
wherein said saturated or unsaturated cyclic or bicyclic (C
3
-C
7
)heterocycle substituents on said R
1
cycloalkyl, cycloalkenyl, aryl, bicycloalkyl and heterocyclic groups contain from one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and NR
9
, wherein R
9
is as defined above, and wherein the heterocycles are optionally substituted by one to three substituents independently selected from halo, cyano, carboxy, amino, nitro, hydroxy, (C
1
-C
6
)alkyl, hydroxy(C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, (C
1
-C
6
)alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C
1
-C
6
)acyl, (C
6
-C
10
)aryl, (C
1
-C
6
)acylamino, (C
1
-C
6
)acyloxy, (C
1
-C
6
)alkylamino, ((C
1
-C
6
)alkyl)
2
amino, (C
1
-C
6
)alkylsulfonyl, aminosulfonyl, (C
1
-C
6
)alkylaminosulfonyl, ((C
1
-C
6
)alkyl)
2
aminosulfonyl or (C
2
-C
9
)heteroaryl;
wherein said alkyl, alkoxy or cycloalkyl substituents on said R
1
cycloalkyl, cycloalkenyl, aryl, bicycloalkyl and heterocyclic groups are optionally further independently substituted by one to three sub-substituents independently selected from halo, cyano, carboxy, amino, nitro, hydroxy, (C
1
-C
6
)alkyl, hydroxy(C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, (C
1
-C
6
)alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C
1
-C
6
)acyl, (C
6
-C
10
)aryl, (C
1
-C
6
)acylamino, (C
1
-C
6
)acyloxy, (C
1
-C
6
)alkylamino, ((C
1
-C
6
)alkyl)
2
amino, (C
1
-C
6
)alkylsulfonyl, aminosulfonyl, (C
1
-C
6
)alkylaminosulfonyl, ((C
1
-C
6
)alkyl)
2
aminosulfonyl or (C
2
-C
9
)heteroaryl;
or said R
1
cycloalkyl, cycloalkenyl, aryl, bicycloalkyl and heterocyclic groups are additionally optionally independently substituted with from one to three substituents of the formula
wherein R
10
is hydrogen, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, (C
3
-C
7
)cycloalkyl, (C
3
-C
7
)cycloalkenyl, (C
6
-C
10
)arylamino, (C
6
-C
10
)aryl, bridged(C
7
-C
9
)bicycloalkyl or a saturated or unsaturated cyclic or bicyclic (C
3
-C
7
)heterocycle;
wherein said R
10
saturated or unsaturated cyclic or bicyclic (C
3
-C
7
)heterocycle contains from one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and NR
9
, wherein R
9
is as defined above;
wherein said R
10
alkyl, alkoxy, cycloalkyl, cycloalkenyl, aryl, bicycloalkyl and heterocycle groups are optionally substituted by one to three substituents independently selected from halo, cyano, carboxy, amino, nitro, hydroxy, (C
1
-C
6
)alkyl (C
1
-C
6
)alkoxy, (C
3
-C
7
)cycloalkyl, hydroxy(C
1
-C
6
)alkyl, hydroxy(C
1
-C
6
)alkylamino, (C
1
-C
6
)alkoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C
1
-C
6
)acyl, (C
1
-C
6
)acylamino, (C
1
-C
6
)acyloxy, (C
1
-C
6
)alkylamino, ((C
1
-C
6
)alkyl)
2
amino, aminosulfonyl, (C
1
-C
6
)alkylaminosulfonyl, or a saturated or unsaturated cyclic or bicyclic (C
3
-C
7
)heterocycle;
wherein said saturated or unsaturated cyclic or bicyclic (C
3
-C
7
) heterocycle contains from one to four heteroatoms independently selected from oxygen, sulfur, nitrogen and NR
9,
wherein R
9
is as defined above; wherein the heterocycle is optionally substituted by from one to three substituents independently selected from halo, cyano, carboxy, amino, nitro, hydroxy, (C
1
-C
6
)alkyl, hydroxy(C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, (C
1
-C
6
)alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (

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