Nicotinamide derivatives useful as PDE4 inhibitors

Details Nicotinamide derivatives useful as PDE4 inhibitors Nicotinamide derivatives useful as PDE4 inhibitors

2003-02-06

2004-06-29

Aulakh, Charanjit S. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S298000, C546S296000, C546S291000, C546S290000, C546S304000, C514S346000, C514S348000, C514S352000

Reexamination Certificate

active

06756392

ABSTRACT:

This invention relates to nicotinamide derivatives of general formula:
in which R
1
, R
2
, R
3
, R
4
, X, Y, n and m have the meanings indicated below, and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such derivatives.
The 3′,5′-cyclic nucleotide phosphodiesterases (PDEs) comprise a large class of enzymes divided into at least eleven different families which are structurally, biochemically and pharmacologically distinct from one another. The enzymes within each family are commonly referred to as isoenzymes, or isozymes. A total of more than fifteen gene products is included within this class, and further diversity results from differential splicing and post-translational processing of those gene products. The present invention is primarily concerned with the four gene products of the fourth family of PDEs, i.e., PDE4A, PDE4B, PDE4C, and PDE4D. These enzymes are collectively referred to as being isoforms or subtypes of the PDE4 isozyme family.
The PDE4s are characterized by selective, high affinity hydrolytic degradation of the second messenger cyclic nucleotide, adenosine 3′,5′-cyclic monophosphate (cAMP), and by sensitivity to inhibition by rolipram. A number of selective inhibitors of the PDE4s have been discovered in recent years, and beneficial pharmacological effects resulting from that inhibition have been shown in a variety of disease models (see, e.g., Torphy et al.,
Environ. Health Perspect.,
1994, 102 Suppl. 10, p. 79-84; Duplantier et al.,
J. Med. Chem.,
1996, 39, p. 120-125; Schneider et al.,
Pharmacol. Biochem. Behav.,
1995, 50, p. 211-217; Banner and Page,
Br. J. Pharmacol.,
1995, 114, p. 93-98; Barnette et al.,
J. Pharmacol. Exp. Ther.,
1995, 273, p. 674-679; Wright et al.,
Can. J. Physiol. Pharmacol.,
1997, 75, p. 1001-1008; Manabe et al.,
Eur. J. Pharmacol.,
1997, 332, p. 97-107 and Ukita et al.,
J. Med. Chem.,
1999, 42, p. 1088-1099). Accordingly, there continues to be considerable interest in the art with regard to the discovery of further selective inhibitors of PDE4s.
Successful results have already been obtained in the art with the discovery and development of selective PDE4 inhibitors. In vivo, PDE4 inhibitors reduce the influx of eosinophils to the lungs of allergen-challenged animals while also reducing the bronchoconstriction and elevated bronchial responsiveness occurring after allergen challenge. PDE4 inhibitors also suppress the activity of immune cells (including CD4
+
T-lymphocytes, monocytes, mast cells, and basophils), reduce pulmonary edema, inhibit excitatory nonadrenergic noncholinergic neurotransmission (eNANC), potentiate inhibitory nonadrenergic noncholinergic neurotransmission (iNANC), reduce airway smooth muscle mitogenesis, and induce bronchodilation. PDE4 inhibitors also suppress the activity of a number of inflammatory cells associated with the pathophysiology of COPD, including monocytes/macrophages, CD4
+
T-lymphocytes, eosinophils and neutrophils. PDE4 inhibitors also reduce vascular smooth muscle mitogenesis and potentially interfere with the ability of airway epithelial cells to generate pro-inflammatory mediators. Through the release of neutral proteases and acid hydrolases from their granules, and the generation of reactive oxygen species, neutrophils contribute to the tissue destruction associated with chronic inflammation, and are further implicated in the pathology of conditions such as emphysema. Therefore, PDE4 inhibitors are particularly useful for the treatment of a great number of inflammatory, respiratory and allergic diseases, disorders or conditions, as well as for wounds and some of them are in clinical development mainly for treatment of asthma, COPD, bronchitis and emphysema.
The effects of PDE4 inhibitors on various inflammatory cell responses can be used as a basis for profiling and selecting inhibitors for further study. These effects include elevation of cAMP and inhibition of superoxide production, degranulation, chemotaxis, and tumor necrosis factor alpha (TNF□) release in eosinophils, neutrophils and monocytes.
As said above, the present invention relates to PDE4 inhibitors of the nicotinamide derivatives family.
Nicotinamide derivatives having a PDE4 inhibitory activity have already been synthetized. For example, the patent application No WO 98/45268 discloses nicotinamide derivatives having activity as selective inhibitors of PDE4D isozyme. These selective PDE4D inhibitors are represented by the following formula:
wherein in particular m and n may be equal to 1 and p may be equal to 0, A may be oxygen, B may be NH, r may be equal to 0, E may be O, NH or S, R
5
may be a saturated or unsaturated cyclic or bicyclic (C
3
-C
7
)heterocyclic group containing 1 to 4 heteroatoms and R
1
may be an aryl optionally substituted by various substituents.
Also, the patent application No WO 01/57036 also discloses nicotinamide derivatives which are PDE4 inhibitors useful in the treatment of various inflammatory allergic and respiratory diseases and conditions, of formula
wherein in particular: n is 1 or 2, m is 0 to 2, Y is ═C(R
E
)— or —[N→(O)]—, W is —O—, —S(═O)
t
— or —N(R
3
)—, Q represents various rings among which phenyl, Z is —OR
12
, —C(═O)R
12
or CN and R
12
is choosen from alkyl, alkenyl, cycloalkyl, phenyl, benzyl and monocyclic heterocyclic moieties.
However, there is still a huge need for additional PDE4 inhibitors showing improved therapeutic index with possibly less adverse effects such as for example emesis.
Thus, the present invention concerns new nicotinamide derivatives of general formula (1):
in which:
m is 0, 1, 2 or 3,
n is 0, 1, 2 or 3,
R
1
and R
2
are each a member independently selected from the group consisting of hydrogen atom, halo, cyano, (C
1
-C
4
)alkyl and (C
1
-C
4
)alkoxy,
X is —O—, —S— or —NH—,
R
3
is a member selected from the groups consisting of:
(a) phenyl, naphthyl, heteroaryl and (C
3
-C
8
)cycloalkyl, each optionally substituted with 1 to 3 substituents each selected from the group consisting of halo, cyano, (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy, (C
1
-C
4
)thioalkyl, —C(═O)NH
2
, —C(═O)NH((C
1
-C
4
)alkyl), hydroxy, —O—C(═O)(C
1
-C
4
)alkyl, —C(═O)—O—(C
1
-C
4
)alkyl and hydroxy(C
1
-C
4
)alkyl, or
(b) the bicyclic groups conforming to one of the following structures (1.1) to (1.4):
 where the symbol “*” indicates the point of attachment of each partial formula (1.1) through (1.4) to the remaining portion of formula (1),
Y is a member selected from the group consisting of partial formulas (1.5) through (1.11):
 where the symbol “*” indicates the point of attachment of each partial formula (1.5) through (1.11) to the remaining portions —NH— of formula (1) and “**” indicates the point of attachment of each partial formula (1.5) through (1.11) to the remaining portions —R
4
of formula (1),
and R
4
is a member selected from the groups consisting of:
(a) phenyl, naphthyl and heteroaryl, each optionally substituted with 1 to 3 substituents each selected from the group consisting of carboxylic acid, C(═O)—O—(C
1
-C
4
)alkyl, halo, cyano, —C(═O)NH
2
, (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy, (C
1
-C
4
)haloalkyl, hydroxy, and hydroxy(C
1
-C
4
)alkyl, or
(b) (C
1
-C
4
)alkyl optionally substituted with a hydroxy, carboxylic acid, C(═O)—O—(C
1
-C
4
)alkyl, phenyl, naphthyl or heteroaryl group wherein said phenyl, naphthyl and heteroaryl are each optionally substituted with 1 to 3 substituents each selected from the group consisting of carboxylic acid, C(═O)O(C
1
-C
4
)alkyl, halo, cyano, —C(═O)NH
2
, (C
1
-C
4
)alkyl or (C
1
-C
4
)alkoxy, (C
1
-C
4
)haloalkyl, hydroxy, and hydroxy(C
1
-C
4
)alkyl,
or, if appropriate, their pharmaceutically acceptable salts and/or isomers, tautomers, solvates, polymorphs, isotopic variations or metabolites thereof.
It has been found that these nicotinamide derivatives are inhibitors of PDE4 isoenzymes, particularly useful for the

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