Peptidyl heterocyclic ketones useful as tryptase inhibitors

Details Peptidyl heterocyclic ketones useful as tryptase inhibitors Peptidyl heterocyclic ketones useful as tryptase inhibitors

2000-01-13

2002-10-22

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S361000, C514S362000, C514S363000, C514S365000, C514S367000, C514S374000, C514S375000, C514S376000, C514S397000, C514S002600, C514S019300, C548S127000, C548S180000, C548S200000, C548S214000, C548S217000, C548S236000, C548S248000, C548S255000, C548S266800, C548S306100, C548S314700, C548S361100

Reexamination Certificate

active

06469036

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to a series of compounds which are peptidyl heterocyclic ketone inflammatory cell serine protease inhibitors and their compositions and methods for the prevention and treatment of a variety of immunomediated inflammatory disorders, skin hyperpigmentation, and trypsin mediated disorders. More particularly, these compounds are potent and selective inhibitors of tryptase and are therefore effective for the prevention and treatment of inflammatory diseases associated with the respiratory tract, such as asthma and allergic rhinitis, as well as other immunomediated inflammatory disorders, such as rheumatoid arthritis, conjunctivitis, psoriasis, inflammatory bowel disease, various vascular and dermatological conditions.
BACKGROUND OF THE INVENTION
Mast cells are a key cellular component of the inflammatory response and when activated, secrete numerous proinflammatory mediators, including histamine, arachidonic acid derivatives, and some serine proteases. Among these mast cell serine proteases is a unique carboxypeptidase, chymase and tryptase (Walls et al.
Eur. J. Pharmacol.
1997, 328, 89-97). Active tryptase is a structurally unique trypsin-like serine protease which exists as a tetramer that is stabilized by heparin proteoglycans which are stored and secreted with the enzyme (Bode et al.
Nature
1998, 392, 306-311). With the exception of neutrophil lactoferrin and possibly secretory leukocyte proteinase inhibitor, tryptase is generally not affected by endogenous serine protease inhibitors such as &agr;
2
-macroglobin, &agr;
2
-proteinase inhibitor, aprotinin, and antithrombin. It is postulated that in vivo tryptase activity may be regulated by the dissociation of the active tryptase tetramer into inactive monomers via the removal of heparin.
Tryptase is secreted exclusively by mast cells and comprises up to 25% of the total protein of the mast cell (Schwartz et al.,
J. Clin. Invest.
1989, 84, 1188-1195). Consequently, mast cell-derived tryptase is secreted in high concentrations at sites of tissue injury. Activated mast cells in atherosclerotic/restenotic plaque have been implicated in plaque rupture and stenosis and are also manifested in inflamed tissues of the gastrointestinal tract. Elevated tryptase levels have been detected in bronchoalveolar lavage fluid (asthma), tears (conjunctivitis), blister fluids (dermatitis), blood (anaphylaxis), cerebrospinal fluid (multiple sclerosis), synovial fluid (rheumatoid arthritis) (Rice et al. Curr. Pharm. Design. 1998, 4, 381-396). Elevated levels of tryptase have also been found in diseased arteries (atherosclerotic, restenotic) relative to normal arteries. Some cigarette smokers have elevated bronchooalveolar lavage fluid tryptase levels relative to nonsmokers, providing support for the hypothesis that mast cell proteases may contribute to lung destruction in smoker's emphysema (Kalenderian et al.
Chest
1998, 94, 119-123).
The potent bronchodilating neuropeptides, vasoactive intestinal peptide (VIP) and peptide histidine methionine (PHM) are readily cleaved by tryptase in vitro whereas substance P, a potent bronchoconstricting peptide, is not (Drazen et al.
J. Clin. Invest
1993, 91, 235-243). Tryptase has demonstrated the ability to generate bradykinin, which is known to induce bronchoconstriction in asthmatics (Zhang et al.
Mediators of Inflammation.
1997, 6, 311-317). The ability of tryptase to stimulate inflammatory eosinophils and neutophil chemotaxis in vitro and in vivo is well known (Walls et al.
J. Immunol.
1997, 159, 6216-6225). Inhaled tryptase has been shown to cause bronchoconstriction in sheep through the release of histamine (Abraham et al.
Amer. J. of Respir. and Crit. Care Med.
1996, 154, 649-654). Its ability to directly stimulate mast cell degranulation in vitro and in animal models suggests that there may be a tryptase mediated amplification mechanism of the allergic inflammatory response (Walls et al.
Eur. J. Pharmacol.
1997, 328, 89-97).
Currently, only trypsin and tryptase are known to activate the protease-activated receptor 2 (PAR-2), a cell surface G-protein-coupled receptor. The activation of PAR-2 is primarily associated with the induction of mitogenic response indicating that tryptase may have a role in pathological conditions associated with tissue hyperplasia, including the airway hyperplasia found in chronic asthmatics (Stone et al.
FEBS Letters
1997, 417, 267-269). Tryptase also has multiple effects on fibroblasts and there is in vitro evidence to suggest that tryptase may involved in the early stages of fibrotic diseases, such as fibrotic lung disease, schieroderma, atherosclerosis, and cardiomyopathic disorders (Marone et al.
Circulation
1998, 97, 971-978). Hence, an inhibitor of tryptase could provide a novel therapeutic approach for the prevention and treatment of a variety inflammatory diseases, such as vascular injury (atherosclerosis, restenosis), arthritis, inflammatory bowel disease, Crohn's disease, dermatitis, urticaria, bullous pemphigoid, psoriasis, schleroderma, fibrosis, conjunctivitis, allergic rhinitis, and particularly asthma.
Asthma is the most common chronic disease in developed countries. It is a complex disease involving multiple biochemical mediators for both its acute and chronic manifestations. Asthma is frequently characterized by the progressive development of hyperresponsiveness of the trachea and bronchi to both immunospecific allergens as well as generalized chemical or physical stimuli. The hyperresponsiveness of asthmatic bronchiolar tissue is postulated to result from chronic inflammation reactions, which irritate and damage the epithelium lining the airway wall and promote pathological thickening of the underlying tissue. Bronchial biopsy studies have indicated that even patients with mild asthma have features of inflammation in the airway wall. Mast cells have long been implicated in the pathogenesis of asthma, particularly in the acute response immediately after the exposure to allergen (Zhang et al.
Mediators of Inflammation
1997, 6, 311-317).
The therapeutic strategy of employing tryptase inhibitors as a treatment for asthma in humans has been recently validated by the selective tryptase inhibitor, APC-366 (Tanaka et al.
Am. J. Respir. Crit. Care Med.
1995, 152, 2076-2083). A recent Phase Ila study was conducted with 16 mild asthmatics who were dosed with either placebo or a nebulized dry powder formulation of APC-366 (Rice et al. Curr. Pharm. Design. 1998, 4, 381-396). Compared with placebo, the same subjects had a statistically significant improvement for the late airway response (33%; &rgr;=0.012) and a mean maximum decrease of forced expiratory volume in one second (21%; &rgr;=0.007) for late airway hyperresponsiveness. These positive results demonstrate that tryptase inhibition is a promising approach for the treatment of asthma in humans.
Currently, the most effect therapy for chronic asthma involves treatment with glucocorticoids (Barnes
New Engl. J. Med.
1995, 332, 868-875). However, glucocorticoid administration also generates a litany of local and systemic side-effects. Because of the limitations of glucocorticoids, there is an unmet medical need for improved asthma therapy. In contrast to drugs such as steroids that elicit multiple actions, tryptase inhibitors may elicit fewer side-effects through the selective inhibition of a specific inflammatory mediator (tryptase) that is exclusive to mast cells. Hence, tryptase inhibitors may offer similar efficacy in the treatment of asthma as the glucocorticoids without the same undesirable systemic side-effects.
Skin coloring has been of concern to human beings for many years. In particular, the ability to remove hyperpigmentation, such as found in age spots, freckles or aging skin generally, is of interest to individuals desiring a uniform complexion. There are also hyperpigmentation disorders that are desirable to treat. The compounds of the formula (I) have been shown to be effective in causing skin depigmentation. T

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