Elastase inhibitors

Details Elastase inhibitors Elastase inhibitors

2000-12-20

2004-02-17

Brumback, Brenda (Department: 1654)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S018700, C514S019300, C530S330000, C530S331000

Reexamination Certificate

active

06693072

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to compounds which are inhibitors of elastase, particularly human neutrophil elastase, useful for a variety of physiological and end-use applications. Human neutrophil elastase has been implicated as an agent contributing to the tissue destruction associated with a number of inflammatory diseases such as chronic bronchitis, cystic fibrosis, and rheumatoid arthritis. J. L. Malech and J. I. Gallin,
New Engl. J. Med.,
317(11), 687 (1987). Elastase possesses a broad range of proteolytic activity against a number of connective tissue macromolecules including elastin, fibronectin, collagen, and proteoglycan. The presence of the enzyme elastase may contribute to the pathology of these diseases.
Normal plasma contains large quantities of protease inhibitors that control a variety of enzymes involved in connective tissue turnover and inflammation. For example, &agr;-1-proteinase inhibitor &agr;-1-PI) is a serine protease inhibitor that blocks the activity of elastase. &agr;-1-PI has received considerable interest because reduction in plasma levels to less than 15% of normal is associated with the early development of emphysema. In addition to plasma derived protease inhibitors, secretory fluids, including bronchial, nasal, cervical mucus, and seminal fluid contain an endogenous protease inhibitor called secretory leukoprotease inhibitor (SLPI) that can inactivate elastase and is believed to play an important role in maintaining the integrity of the epithelium in the presence of inflammatory cell proteases. In certain pathological states &agr;-1-PI and SLPI are inactivated by neutrophil oxidative mechanisms allowing the neutrophil proteases to function in an essentially inhibitor-free environment. For example, bronchial lavage fluids from patients with adult respiratory distress syndrome (ARDS) have been found to contain active elastase and &agr;-1-PI that had been inactivated by oxidation.
In addition to oxidative mechanisms, neutrophils possess non-oxidative mechanisms for eluding inhibition by antiproteases. Neutrophils from patients with chronic granulomatous disease are capable of degrading endothelial cell matrices in the presence of excess &agr;-1-PI. There is considerable in vitro evidence that stimulated neutrophils can tightly bind to their substrates such that serum antiproteases are effectively excluded from the microenvironment of tight cell-substrate contact. The influx of large numbers of neutrophils to an inflammatory site may result in considerable tissue damage due to the proteolysis that occurs in this region.
Applicants have determined that elastase is one of the primary neutrophil proteases responsible for cartilage matrix degeneration as measured by the ability of neutrophil lysate, purified elastase and stimulated neutrophils to degrade cartilage matrix proteoglycan. Furthermore, applicants have previously discovered peptide derivatives useful as elastase inhibitors, exerting valuable pharmacological activities. For example, peptide derivatives useful as elastase inhibitors wherein the terminal carboxyl group has been replaced by a pentafluoroethylcarbonyl (—C(O)C
2
F
5
)group and in which the N-terminal amino acid is protected by various heterocycle-containing groups such as a 4-morpholinecarbonyl group are disclosed in European Patent Application OPI No. 0529568, inventors Peet et al., with a publication date of Mar. 3, 1993. Applicants have recently discovered peptidyl elastase inhibitors in which the P
2
moiety is substituted with various nitrogen-containing heterocyclic groups.
SUMMARY OF THE INVENTION
The present invention relates to compounds having the following formula I
or a hydrate, isostere, or pharmaceutically acceptable salt thereof wherein
P
4
is Ala, bAla, Leu, Ile, Val, Nva, bVal, Nle or a bond;
P
3
is Ala, bAla, Leu, Ile, Val, Nva, bVal, Nle or an N-methyl derivative, Pro, Ind, Tic or Tca, or Lys substituted on its epsilon amino group with a morpholino-B-group or Orn substituted on its delta amino group with a morpholino-B-group;
P
2
is Pip, Aze, Pro(4-OH), Pro(4-OAc) or Pro(4-OBz1);
R
1
is a side chain of Ala, Leu, Ile, Val, Nva or bVal;
X is —CF
3
, —CF
2
H, —CFH
2
, —C(═O)Y, —C(═O)P
2
′-Y, —CF
2
C(═O)P
2
′-Y, —CF
2
CH(R
1
′)C(═O)P
2
′-Y, —CF
2
CH(R
1
′)NHC(═O)R
3
, —CHFCH(R
1
 )NHC(═O)R
3
, —H, —C(═O)R
3
, —CH(R
1
)C(═O)P
2
′-Y, —CF
2
CF
3
, —CF
2
(CH
2
)
t
CH
3
, —CF
2
(CH
2
)
t
COOR4, —CHF(CH
2
)
t
CH
3
, —CF
2
(CH
2
)
t
CONHR
4
, —CF
2
(CH
2
)
t
CH
2
OR
4
, —CF
2
(CH
2
)
v
CH═CH
2
, —CH
2
Cl or —C(═O)—C(═O)—Y;
R
3
is H, C
1-6
alkyl, phenyl, benzyl, cyclohexyl, cyclohexylmethyl;
R
4
is H or C
1-6
alkyl;
R
1
′ is a side chain of Ala, Leu, Ile, Val, Nva or bVal;
P
2
′ is a bond, Ala or Val;
Y is —NHR
3
, OR
3
;
t is 2, 3 or 4;
v is 1, 2 or 3;
K is hydrogen, formyl, acetyl, succinyl, benzoyl, t-butyloxycarbonyl, carbobenzyloxy, tosyl, dansyl, isovaleryl, methoxysuccinyl, 1-adamantanesulphonyl, 1-adamantaneacetyl, 2-carboxybenzoyl, phenylacetyl, t-butylacetyl, bis((1-naphthyl)methyl)acetyl, —C(═O)N—(CH
3
)
2
,
—A—R
Z
wherein
R
Z
is an aryl group containing 6, 10 or 12 carbons suitably substituted by 1 to 3 members selected independently from the group consisting of fluoro, chloro, bromo, iodo, trifluoromethyl, hydroxy, alkyl containing from 1 to 6 carbons, alkoxy containing from 1 to 6 carbons, carboxy, alkylcarbonylamino wherein the alkyl group contains 1 to 6 carbons, 5-tetrazolyl, and acylsulfonamido containing from 1 to 15 carbons, provided that when the acylsulfonamido contains an aryl the aryl may be further substituted by a member selected from fluoro, chloro, bromo, iodo and nitro;
Z is N or CH, and
B is a group of the formulae
(the wavy line
being the attachment to the rest of the molecule, i.e., not to Z)
and wherein R′ is hydrogen or a C
1-6
alkyl group; useful as inhibitors of elastase. The compounds of formula I exhibit an anti-inflammatory effect useful in the treatment of gout, rheumatoid arthritis and other inflammatory diseases, such as adult respiratory distress syndrome, septicemia, chronic bronchitis, inflammatory bowel disease, disseminated intravascular coagulation, cystic fibrosis, and in the treatment of emphysema.
DETAILED DESCRIPTION OF THE INVENTION
Isosteres of the compounds of formula I include those wherein (a) one or more of the a-amino residues of the P
2
-P
4
substituents are in its unnatural configuration (when there is a natural configuration) or (b) when the normal peptidic amide linkage [—C(═O)NH—] is modified, such as for example, to form —CH
2
NH— (reduced), —COCH
2
— (keto), —CH(OH)CH
2
—(hydroxy), —CH(NH
2
)CH
2
— (amino), —CH
2
CH
2
— (hydrocarbon), —CH═CH—(alkene). Preferably a compound of the invention should not be in an isosteric form; particularly it is preferred that there be no modified peptidic amide group, but if there is, it is preferable to keep the isosteric modifications to a minimum.
A C
1-6
alkyl group is taken to include straight, branched, or cyclic alkyl groups, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, sec-pentyl, cyclopentyl, hexyl, isohexyl, cyclohexyl and cyclopentylmethyl.
The compounds of formua I can form pharmaceutically acceptable salts with any non-toxic, organic or inorganic acid. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulphuric and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include the mono, di and tricarboxylic acids. Illustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2-phenoxy benzoic., and sulfonic acids such as methane sulfonic acid and 2-hydroxyethane sulfo

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