Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-06-04
2003-05-13
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S305700
Reexamination Certificate
active
06562854
ABSTRACT:
DESCRIPTION OF THE FIELD
Tryptase, the predominant protease secreted from human mast cells, is thought to be involved in neuropeptide processing and tissue inflammation. Tryptase concentrations are elevated in the bloodstream for several hours following anaphylaxis (Schwartz et al. (1987)
N. Eng. J. Med.
316:1622-1626), are increased in nasal and lung lavage fluid from atopic subjects following specific antigen challenge (Castells et al. (1988)
J. Allerg. Clin. Immunol.
141:563-568) and are elevated in lung lavage fluid of atopic asthmatics after endobronchial allergen challenge. Smokers often have striking elevations of bronchoalveolar lavage fluid tryptase levels, a finding that provides some support for the hypothesis that release of proteinase from activated mast cells could contribute to lung destruction in smoker's emphysema. (Celenteron et al. (1988) Chest 94:119-123). In addition, tryptase has been shown to be a potent mitogen for fibroblasts, suggesting that it is involved in pulmonary fibrosis and interstitial lung disease (Ross et al. (1991)
J. Clin. Invest.
88:493-499).
Asthma is recognized as an inflammatory disorder (Hood et al. (1984) In: Benjamin-Cummings, ed.
Immunology
2nd ed.) and frequently is characterized by progressive development of hyper-responsiveness of the trachea and bronchi to both immunospecific allergens and generalized chemical or physical stimuli. The disease involves multiple biochemical mediators in both its acute and chronic stages. The hyper-responsiveness of asthmatic bronchiolar tissue is believed to be the result of chronic inflammatory reactions, which irritate and damage the epithelium lining the airway wall and promote pathological thickening of the underlying tissue. Bronchial biopsies in patients with only mild asthma have features of inflammation in the airway wall.
Allergic responses to inhaled allergens can initiate the inflammatory sequence. For example, allergens can activate mast cells and basophils, which are present in the epithelium and underlying smooth muscle tissue by binding IgE located on the cell surface. Activated mast cells release a number of preformed or primary chemical mediators (e.g., histamine) of the inflammatory response and generate numerous other secondary mediators of inflammation (e.g., superoxide, lipid derived mediators, etc.) in situ. In addition, several large molecules (e.g., proteoglycans, tryptase, chymase, etc.) are released by degranulation of mast cells.
The release of these preformed mediators from mast cells probably accounts for the early bronchiolar constriction in the asthmatic reaction to air borne allergens. The early phase of the asthmatic reaction peaks approximately fifteen minutes after exposure to allergen and is generally followed by recovery over the ensuing one to two hours. Twenty five to thirty five percent of the patient population experience a further decline in respiratory function which maximizes six to twelve hours after exposure. This late reaction phase is accompanied by a marked increase in the number of inflammatory cells (e.g., eosinophils, neutrophils, lymphocytes, etc.) infiltrating the bronchiolar tissue. The infiltrating cells are attracted to the site by release of mast cell derived chemotactic agents and then become activated during the late reaction phase. The late asthmatic response is believed to be a secondary inflammatory reaction mediated in part by the secretory activity of granulocytes.
Tryptase is implicated in the degradation of vasodilating and bronchorelaxing neuropeptides (Caughey et al. (1988)
J. Pharmacol. Exp. Ther.
244:133-137; Franconi et al. (1988)
J. Pharmacol. Exp. Ther.
248:947-951; and Tam et al. (1990)
Am. J. Respir. Cell Mol. Biol.
3:27-32) and modulation of bronchial responsiveness to histamine (Sekizawa et al. (1989)
J. Clin. Invest.
83:175-179). These findings suggest that tryptase may increase bronchoconstriction in asthma by destroying bronchodilating peptides. Tryptase cleaves fibrinogen &agr;-chains and high molecular weight kinninogen, which suggests that tryptase plays a role with heparin as a local anticoagulant. Tryptase activates prostromelysin (pro-MMP-3) and procollagenase (pro-MMP-1) via MMP-3, which suggests that tryptase is involved in tissue inflammation and remodeling and joint destruction in rheumatoid arthritis. Further, administration of tryptase inhibitor protects against development of the late and airway hyper-responsive phases in allergen challenged sheep (Clark et al. (1995) Am.
J. Respir. Crit. Care Med.
152: 2076-2083) and inhibits the immediate cutaneous response to intradermal injection of allergen in allergic sheep (Molinari et al. (1995)
Amer. Physiol. Soc.
79(6):1966-1970). All of the above-described findings clearly indicate the applicability of tryptase inhibitors as therapeutic agents in treating asthma and other disorders associated with inflammation of the respiratory tract.
The disclosures of these and other documents, including patents and patent applications, referred to throughout this application are incorporated herein by reference.
SUMMARY OF THE INVENTION
This application relates to a compound of Formula I:
in which:
n1 is 0 or 1,
n2 is 0, 1, 2, 3 or 4;
n3 is 0, 1, 2, 3 or 4;
A together with B comprises a fused heterobicyclic radical containing 8 to 12 annular atoms, wherein each ring contains 5 to 7 annular members, each annular atom optionally is a heteroatom, X
1
and X
2
are adjacent annular members of an aromatic ring and X
1
is a heteroatom moiety selected from —N═, —NR
5
—, —O— and —S—, wherein R
5
is hydrogen, (C
1-6
)alkyl or hetero(C
2-6
)alkyl;
C comprises a fused heteropolycyclic radical containing 8 to 18 annular atoms, wherein each ring contains 5 to 7 annular members, each annular atom optionally is a heteroatom, X
4
and X
5
are adjacent annular members of an aromatic ring, X
5
is a heteroatom moiety selected from —N═, —NR
5
—, and —S—, wherein R
6
is hydrogen, a group selected from (C
1-8
)alkyl or hetero(C
2-12
)alkyl, which group optionally is substituted with one to two substituents independently selected from (C
1-6
)alkanoyloxy, (C
1-6
)alkylamino, di(C
1-6
)alkylamino, tri(C
1-6
)alkylammonio, (C
1-6
)alkylcarbamoyl, di(C
1-6
)alkylcarbamoyl, (C
1-6
)alkyloxy, (C
1-6
)alkyloxycarbonyl, (C
1-6
)alkyloxysulfonyl, amino, carboxy, carbamoyl, (C
6-14
)aryl, halo, hetero(C
5-14
)aryl, hydroxy and sulfo, or as defined below; and any carbocyclic ketone, thioketone and iminoketone derivative thereof;
X
3
is —O—, —S—, —S(O)—, —S(O)
2
—, —C(O)—, —NR
7
— or —CR
7
R
8
—, wherein R
7
is hydrogen, (C
1-6
)alkyl, hetero(C
2-12
)alkyl or together with R
6
forms (C
24
)alkylene or hetero(C
2-4
)alkylene and R
8
is hydrogen, (C
1-6
)alkyl or hydroxy or together with R
7
forms (C
2-6
)alkylene or (C
1-6
)alkylidene, wherein any aliphatic or alicyclic moiety comprising R
7
and/or R
8
optionally are substituted with one to three substituents selected from (C
1-6
)alkylamino, di(C
1-6
)alkylamino, tri(C
1-6
)alkylammonio, (C
1-6
)alkyloxy, (C
1-6
)alkyloxycarbonyl, (C
1-6
)alkanoyloxy, amino, carboxy, carbamoyl, (C
1-6
)alkylcarbamoyl, di(C
1-6
)alkylcarbamoyl, halo and hydroxy;
R
1
is amino(N
14
)azolidinyl, amino(N
1-4
)azolyl, (N
1-4
)azolidinyl, (N
1-4
)azolyl, carbamoyl, cyano, —(CH
2
)
x
NHC(NR
9
)R
9
, —(CH
2
)
x
NHC(NH)NR
9
R
9
, —(NR
9
)R
9
, —C(NH)NHR
10
, —C(NH)NR
10
R
10
or —(CR
11
R
11
)
y
NH
2
and bonded to any annular atom with an available valence comprising B, wherein x is 0 or 1, y is 0, 1, 2 or 3, each R
9
independently is hydrogen or (C
1-6
)alkyl, each R
10
is independently (C
1-6
)alkyl and each R
11
independently is hydrogen, (C
1-3
)alkyl or together with another R
11
and a carbon atom to which both are attached forms cyclopropyl, wherein any aliphatic or alicyclic moiety comprising R
1
optionally is substituted with one to two substituents independently selected from (C
1-6
)alkyloxycarbonyl, (C
1-6
)alkanoyloxy, carboxy, carbamoyl, (C
1-6
)alkylcarbamoyl, di(C
1-6
)alkylcarbamoyl, (C
1-6
)alkylsulfonyl and h
Church Timothy J.
Cutshall Neil Scott
Gangloff Anthony R.
Jenkins Thomas E.
Linsell Martin S.
Axys Pharmaceuticals Inc.
Stockton Laura L.
Towsnend and Townsend and Crew LLP
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