Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-01-22
2001-05-15
Berch, Mark L. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S196000, C514S197000, C540S215000, C540S222000, C540S228000, C540S230000, C540S304000, C540S311000
Reexamination Certificate
active
06232305
ABSTRACT:
BACKGROUND OF INVENTION
Cysteine proteases, such as cathepsins B, H, K, L, S, and O
2
, containing a highly reactive cysteine residue with a free thiol group at the active site have been known as playing an important role in certain conditions distinguished by aberrant protein turnover such as: muscular dystrophy (Am. J. Pathol. 1986, 122, 193-198; Am. J. Pathol. 1987, 127, 461-466), myocardial infarction (J. Am. Coll. Cardiol. 1983, 2, 681-688), bone resorption (Biochem. J. 1991, 279, 167-274; J. Biol. Chem. 1996, 271, 2126-2132; and Biochem. Biophys. Acta 1992,1116, 57-66), arthritis (Arthritis Rheumatism 1994, 37, 236-247; and Biochem. Pharmacol. 1992, 44, 1201-1207),cancer, including cancer metastasis (Cancer Metastasis Rev. 1990, 9, 333-352), pulmonary emphysema (Am. Rev. Respir. Dis. 1975, 111, 579-586), septic shock (Immunol. Today 1991, 11, 404-410, Biochemistry 1994, 33, 3934-3940), cerebral ischemia, memory function, Alzheimer and cataract (TIPS 1994, 15, 412-419, Bioorg. Med. Chem. Lett. 1995 4, 387-392, Proc, Natl. Acad. Sci. USA 1991, 88,10998-11002), malaria (J. Med. Chem. 1995, 38, 5031-5037), glomerular basement membrane degradation (Biochem. Bioph. Acta 1989, 990, 246-251), bacterial infection (Nature 1989, 337, 385-386), inflammatory diseases (Protein Science 1995, 4, 3-12), parasitic infections (Annu. Rev. Microbiol. 1993, 47, 821-853; Parasitol. Today 1990, 6, 270-275), and viral infections (Biochem. 1992, 31, 7862-7869).
A variety of cysteine proteinase have been shown to be present in mammalian tissue. The most notable of these proteinase are the lysosomal cathepsins (cathepsin B, H, S, K and L) and the cytoplasmic Ca
2+
dependent enzymes, the calpains. These enzymes are, therefore, excellent targets for the development of specific inhibitors as possible therapeutic agents.
Several types of cysteine proteases inhibitors have been reported, such as peptide aldehydes (Biochim. Biophys. Acta 1991, 107-343), nitriles (Biochim. Biophys. Acta 1990, 1035, 62-70), halomethyl ketones (Anal. Biochem. 1985, 149, 461-465; Acta. Biol. Med. Ger. 1981, 40, 1503-1511; Biochem. Phar. 1992, 44, 1201-1207), diazomethyl ketones (Biochem. J. 1988, 253, 751), acyloxy methyl ketones (J. Med. Chem. 1994, 37, 1833-1840; J. Am. Chem. Soc. 1988,110, 4429-4431), ketomethylsulfonium salt (J. Biol. Chem. 1988, 263, 2768-2772), &agr;-ketocarbonyl compounds (J. Med. Chem. 1993, 36, 3472-3480; 1994, 37, 2918-2929), vinyl sulfones (J. Med. Chem. 1995, 38, 3193-3196) and epoxysuccinyl derivatives (Agric. Biol. Chem. 1978, 42, 523-527). These inhibitors, in general, have a peptidyl affinity group and a group reactive towards the thiol of the cysteine residue in cysteine proteases.
In continuation of our efforts to find low molecular weight cysteine protease inhibitors for therapeutic uses, we have focused our attention at substituted penam and cepham derivatives of which &bgr;-lactam ring is succeptible towards acylation of cysteine proteases.
SUMMARY OF THE INVENTION
The present invention is based on the discovery that certain substituted amino bicyclic-&bgr;-lactam penam derivatives and substituted amino bicyclic-&bgr;-lactam cepham derivatives exhibit excellent cysteine protease inhibitory activity which might be used for treatment of different diseases and/or conditions such as cancer (including cancer metastasis), osteoporosis, rheumatoid arthritis. muscular dystrophy, myocardial infarction, pulmonary emphysema, septic shock, cerebral ischemia, decreased memory function, Alzheimer, cataract, malaria, glomerular basement membrane degradation, bacterial infection, inflammatory diseases, parasitic infections and viral infections. Particularly important aspects of the present invention are the use of the compounds and compositions disclosed herein in the treatment of cancer, including cancer metastasis, and in the treatment of rheumatoid arthritis.
Our laboratory has been actively involved in the search for novel types of cysteine proteases inhibitors with high selectivity among the cysteine protease class of enzymes. We have found that 3,4-disubstituted azetidinone, 2-substituted oxapenam, 6-substituted oxapenam derivatives exhibit good cysteine protease inhibitory activity. Related to the present invention are inventions disclosed in U.S. patent application Ser. Nos. 08/925,459 (pending), and 08/935,259 (pending), the entire disclosures of which are hereby.
Further to optimize and enhance activity, we have designed, synthesized and evaluated the cysteine protease inhibitory activity of various substituted amino bicyclic-&bgr;-lactam penam derivatives and substituted amino bicyclic-&bgr;-lactam cepham derivatives and the findings are reported in the present invention.
In accordance with the present invention, there are provided substituted amino bicyclic-&bgr;-lactam penam derivatives and substituted amino bicyclic-&bgr;-lactam cepham derivatives of general formula I or pharmaceutically acceptable salts thereof,
wherein
R is (a) a peptidyl residue of a single natural &agr;-amino acid in either the L- or D-form, selected from the group consisting of D- or L-glycine, D- or L-alanine, D- or L-valine, D- or L-leucine, D- or L-isoleucine, D- or L-serine, D- or L-threonine, D- or L-aspartic acid, D- or L-glutamic acid, D- or L-asparagine, D- or L-glutamine, D- or L-lysine, D- or L-arginine, D- or L-phenylalanine, D- or L-tyrosine, D- or L-tryptophan, D- or L-histidine, D- or L-methionine, D- or L-proline, or
(b) a peptidyl residue of a single non-natural amino acid in either the L- or D- form, selected from D- or L-t-butyl alanine, D- or L-homophenyl alanine, D- or L-pyridyl alanine, D- or L-thienyl alanine, D- or L-naphthyl alanine, D- or L-methoxy phenylalanine, D- or L-halophenyl alanine, D- or L-e-nitro arginine, D- or L-citrulline, D- or L-indoline carboxylic acid, D- or L-cycloalkyl glycine (e.g., cyclopentyl glycine), D- or L-cycloalkyl alanine (e.g., cyclohexyl alanine), D- or L4-hydroxy-3-nitro-phenylalanine, D- or L4-amino-3,5-diiodophenyl alanine, D- or L4-hydroxy-3,5-diiodophenyl alanine, D- or L4-hydroxy-3,5-dibromo-phenyl alanine, D- or L-&bgr;-(3-benzothienyl) alanine, D- or L-3,4-dihydroxy-phenyl alanine, D- or L-3,4(methylenedioxy)phenyl alanine, D- or L-3,4(ethylenedioxy)phenyl alanine, D- or L-4,4′-biphenyl alanine, D- or L-3,4-dichlorophenyl alanine, D- or L-iodophenyl alanine, D- or L-4-nitrophenyl alanine, D- or L-pentafluorophenyl alanine, D- or L-trifluorophenyl alanine, D- or L-thiazolyl alanine, D- or L-trifluoromethylphenyl alanine, D- or L-sulfamoyl alanine, D- or L-t-butyloxy alanine, D- or L-1-t-butyloxymethylalanine, D- or L-trimethyl alanine, D- or L-3,4-diisopropyloxyphenyl alanine, D- or L-propylalanine, and D- or L-ethylalanine, in which peptidyl residue (a) or (b) the terminal —NH
2
group is unsubstituted or substituted once or twice with R
4
,
wherein R
4
is —COOR
5
, —COR
5
, —SO
2
R
5
, or —COR
6
,
wherein R
5
is (i) a C
1
-C
6
alkyl group, (ii) a C
2
-C
6
alkenyl group, (iii) a C
2
-C
6
alkynyl group, (iv) a C
3
-C
6
cycloalkyl group, (v) a phenyl group, (vi) a naphthyl group, or (vii) a monocyclic or bicyclic heterocyclic group,
which group (i), (ii), (iii), (iv), (v), (vi), or (vii) is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of hydroxy, halogen, carboxy, C
1
-C
4
alkyl (which is unsubstituted or substituted at least once with carboxy and/or amino), C
1
-C
2
alkoxy, amino, cyano, phenyl and monocyclic or bicyclic heterocyclic groups, (which phenyl and monocyclic or bicyclic heterocyclic groups are unsubstituted or substituted by 1 or 2 substituents independently selected from hydroxy, halogen, carboxy, C
1
-C
4
alkyl, C
1
-C
2
alkoxy, amino, and cyano);
and R
6
is an amino group which is unsubstituted or substituted at least once with a C
1
-C
6
alkyl group which is unsubstituted or substituted by 1 or 2 substitutents selected from the group consisting of hydroxy, halogen, cyano, amino, heterocycle, and phenyl, (wherein the heterocycle or phenyl is unsubstituted or
Guo Deqi
Micetich Ronald G.
Singh Rajeshwar
Zhou Nian
Arent Fox Kintner Plotkin & Kahn
Berch Mark L.
Naeja Pharmaceutical Inc.
LandOfFree
Substituted amino bicyclic-&bgr;-lactam penam and cepham... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Substituted amino bicyclic-&bgr;-lactam penam and cepham..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Substituted amino bicyclic-&bgr;-lactam penam and cepham... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2456726