Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Tripeptides – e.g. – tripeptide thyroliberin – etc.
Reexamination Certificate
1999-06-03
2001-07-03
Russel, Jeffrey E. (Department: 1653)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Tripeptides, e.g., tripeptide thyroliberin , etc.
C514S018700
Reexamination Certificate
active
06255453
ABSTRACT:
BACKGROUND OF THE INVENTION
The serine proteases are a class of enzymes, which includes elastase, chymotrypsin, cathepsin G, trypsin and thrombin. These proteases have in common a catalytic triad consisting of Serine-195, Histidine-57 and Aspartic acid-102(chymotrypsin numbering system). Human neutrophil elastase (HNE) is a proteolytic enzyme secreted by polymorphonuclear leukocytes (PMNs) in response to a variety of inflammatory stimuli. This release of HNE and its extracellular proteolytic activity are highly regulated and are normal, beneficial functions of PMNs. The degradative capacity of HNE, under normal circumstances, is modulated by relatively high plasma concentrations of &agr;
1
-proteinase inhibitor (&agr;-PI). However, stimulated PMNs produce a burst of active oxygen metabolites, some of which (hypochlorous acid for example) are capable of oxidizing a critical methionine residue in &agr;-PI. Oxidized &agr;-PI has been shown to have limited potency as an HNE inhibitor and it has been proposed that alteration of this protease/antiprotease balance permits HNE to perform its degradative functions in localized and controlled environments.
Despite this balance of protease/antiprotease activity, there are several human disease states in which a breakdown of this control mechanism is implicated in the pathogenesis of the condition. Improper modulation of HNE activity has been suggested as a contributing factor in adult respiratory distress syndrome, septic shock and multiple organ failure. A series of studies also have indicated the involvement of PMNs and neutrophil elastase in myocardial ischemia-reperfusion injury. Humans with below-normal levels of &agr;
1
-PI have an increased probability of developing emphysema. HNE-mediated processes are implicated in other conditions such as arthritis, periodontal disease, glomerulonephritis, dermatitis, psoriasis, cystic fibrosis, chronic bronchitis, atherosclerosis, Alzheimer's disease, organ transplantation, corneal ulcers, and invasion behavior of malignant tumors.
There is a need for effective inhibitors of HNE as therapeutic and as prophylactic agents for the treatment and/or prevention of elastase-mediated problems.
SUMMARY OF THE INVENTION
In one embodiment, the present invention provides compounds of formula I
wherein X and Y are independently O or N;
R
1
is alkyl &agr;,&agr;-dialkylalkylaryl or &agr;,&agr;-dialkylalkyl fused aryl-cycloalkyl wherein the cycloalkyl group is optionally substituted with two or more O atoms;
R
2
and R
3
are independently H or alkyl; or together form a ring consisting of 3-5 carbons in which one or more carbon atoms of the ring can optionally be replaced with heteroatoms selected from O, S or N wherein N is optionally substituted with H or alkyl, preferably one of R
2
and R
3
is H and the other is iso-propyl; and
R
4
is alkyloxycarbonyl.
Preferably, compounds of the present invention comprise a 1,3,4 oxadiazole ring (i.e., X is N; Y is O).
In one preferred embodiment of the invention, R
1
is alkyl, such as tert-butyl. In another embodiment, R
1
is &agr;,&agr;-dialkylalkylaryl, such as an &agr;,&agr;-dimethylbenzyl group. In still another preferred embodiment, R
1
is &agr;,&agr;-dialkylalkyl fused aryl-cycloalkyl wherein the cycloalkyl group is substituted with two O atoms, such as an &agr;,&agr;-dimethyl-(3,4-methylenedioxy)benzyl group. In yet another preferred embodiment, R
2
and R
3
are independently alkyl, such as isopropyl, or H. Preferably, R
2
is isopropyl and R
3
is H.
In another embodiment, the present invention provides compounds of formula II:
wherein X and Y are independently O or N;
R
1
, R
2
, and R
3
are as above;
R′
2
and R′
3
are independently H or alkyl; or together form a ring consisting of 3-5 carbon atoms in which one or more carbon atoms of the ring can optionally be replaced by heteroatoms selected from O, S or N, wherein N is optionally substituted with H or alkyl;
A is a direct bond, —NH— or —OC(O)—NH—;
R
4
is H or halo; and
R
5
is H, alkyl or arylalkyl; or
a pharmaceutically acceptable salt thereof.
Preferably, compounds of this embodiment of the present invention comprise a 1,3,4 oxadiazole ring (i.e., X is N; Y is O).
In one preferred embodiment of the invention, R
1
is alkyl, such as tert-butyl. In another embodiment, R
1
is &agr;,&agr;-dialkylalkyl fused aryl-cycloalkyl wherein the cycloalkyl group is substituted with two O atoms, such as an &agr;,&agr;-dimethyl-(3,4-methylenedioxy)benzyl group. In yet another embodiment, R
1
is &agr;,&agr;-dialkylalkylaryl, such as an &agr;,&agr;-dimethylbenzyl group. In still another preferred embodiment, R
2
and R
3
are independently alkyl, such as isopropyl, or H. In a more preferred embodiment, R
2
is isopropyl, R
3
is H, and R
2
′ and R
3
′ are both H. Where R
4
is halo, R
4
may be Cl, F, I or Br, although preferably it is F.
As used herein, the term “optionally substituted” means, when substituted, mono to fully substituted.
As used herein, the term “independently” means that the substituents may be the same or different.
As used herein, the term “alkyl” means C
1
-C
15
, and preferably C
1
-C
8
. It will be understood that the alkyl group may be linear or branched.
As used herein, the term “&agr;,&agr;-dialkylalkylaryl” means that the alkyl groups are substituted at the &agr;-positions to the oxadiazole ring or to the aryl group or both. One such example is an &agr;,&agr;-dialkylbenzyl, wherein the &agr;-substituents are preferably methyl, ethyl or propyl. A specific example is &agr;,&agr;-dimethylbenzyl. The term “&agr;,&agr;-dialkylalkyl fused arylcycloalkyl” is defined to mean that the alkyl groups are substituted at the &agr;-positions to the oxadiazole ring or to the aryl group, and a cycloalkyl is fused to the aryl ring. One such example of an “&agr;,&agr;-dialkylalkyl fused aryl-cycloalkyl” is an &agr;,&agr;-dialkyl-3,4-methylenedioxybenzyl group, wherein the &agr;-substituents are preferably methyl, ethyl or propyl; preferably they are methyl. A specific example includes the &agr;, &agr;-dimethyl-3,4-methylenedioxybenzyl group.
As used herein, the term alkyloxycarbonyl means alkyl—O—C(O)— wherein the meaning of alkyl is defined above. One such example of an alkyloxycarbonyl is methyloxycarbonyl and is defined by the formula CH
3
—O—C(O)—.
REFERENCES:
patent: 5801148 (1998-09-01), Gyorkos et al.
patent: 6001813 (1999-12-01), Gyorkos et al.
patent: 6001814 (1999-12-01), Gyorkos et al.
Gyorkos Albert
Kawabata Kazuhito
Ohmoto Kazuyuki
Spruce Lyle
Cortech Inc.
Dechert
Russel Jeffrey E.
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