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Peptide-containing alpha-ketoamide cysteine and serine protease inhibitorsRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) Doai, Cyclopeptides, 3 Or 4 Peptide Repeating Units In Known Peptide ChainPeptide-containing alpha-ketoamide cysteine and serine protease inhibitors description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060069037, Peptide-containing alpha-ketoamide cysteine and serine protease inhibitors. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application is a divisional of U.S. Ser. No. 10/685,923 filed Oct. 14, 2003, now allowed; which is a divisional of U.S. Ser. No. 09/879,336 filed Jun. 21, 2001, now U.S. Pat. No. 6,703,368; which is a divisional of U.S. Ser. No. 09/527,540 filed Mar. 16, 2000, now U.S. Pat. No. 6,288,231; which is a divisional of U.S. Ser. No. 09/166,808 filed Oct. 6, 1998, now U.S. Pat. No. 6,150,378; and claims benefit of U.S. Provisional Application Ser. No. 60/061,309, filed Oct. 7, 1997, the disclosure of which is hereby incorporated herein by reference in its entirety. FIELD OF THE INVENTION [0002] This invention relates to peptide-containing .alpha.-ketoamide inhibitors of cysteine and serine proteases, methods for making these compounds, and methods for using the same. BACKGROUND OF THE INVENTION [0003] Numerous cysteine and serine proteases have been identified in human tissues. A "protease" is an enzyme which degrades proteins into smaller components (peptides). The terms "cysteine protease" and "serine protease" refer to proteases which are distinguished by the presence therein of a cysteine or serine residue which plays a critical role in the catalytic process. Mammalian systems, including humans, normally degrade and process proteins via a variety of enzymes including cysteine and serine proteases. However, when present at elevated levels or when abnormally activated, cysteine and serine proteases may be involved in pathophysiological processes. [0004] For example, calcium-activated neutral proteases ("calpains") comprise a family of intracellular cysteine proteases which are ubiquitously expressed in mammalian tissues. Two major calpains have been identified; calpain I and calpain II. While calpain II is the predominant form in many tissues, calpain I is thought to be the predominant form in pathological conditions of nerve tissues. The calpain family of cysteine proteases has been implicated in many diseases and disorders, including neurodegeneration, stroke, Alzheimer's, amyotrophy, motor neuron damage, acute central nervous system injury, muscular dystrophy, bone resorption, platelet aggregation, cataracts and inflammation. Calpain I has been implicated in excitatory amino-acid induced neurotoxicity disorders including ischemia, hypoglycemia, Huntington's Disease, and epilepsy. The lysosomal cysteine protease cathepsin B has been implicated in the following disorders: arthritis, inflammation, myocardial infarction, tumor metastasis, and muscular dystrophy. Other lysosomal cysteine proteases include cathepsins C, H, L and S. Interleukin-1.beta. converting enzyme ("ICE") is a cysteine protease which catalyzes the formation of interleukin-1.beta.. Interleukin-1.beta. is an immunoregulatory protein implicated in the following disorders: inflammation, diabetes, septic shock, rheumatoid arthritis, and Alzheimer's disease. ICE has also been linked to apoptotic cell death of neurons, which is implicated in a variety of neurodegenerative disorders including Parkinson's disease, ischemia, and amyotrophic lateral sclerosis (ALS). [0005] Cysteine proteases are also produced by various pathogens. The cysteine protease clostripain is produced by Clostridium histolyticum. Other proteases are produced by Trypanosoma cruzi, malaria parasites Plasmodium falciparum and P. vinckei and Streptococcus. Hepatitis A viral protease HAV C3 is a cysteine protease essential for processing of picornavirus structural proteins and enzymes. [0006] Exemplary serine proteases implicated in degenerative disorders include thrombin, human leukocyte elastase, pancreatic elastase, chymase and cathepsin G. Specifically, thrombin is produced in the blood coagulation cascade, cleaves fibrinogen to form fibrin and activates Factor VIII; thrombin is implicated in thrombophlebitis, thrombosis and asthma. Human leukocyte elastase is implicated in tissue degenerative disorders such as rheumatoid arthritis, osteoarthritis, atherosclerosis, bronchitis, cystic fibrosis, and emphysema. Pancreatic elastase is implicated in pancreatitis. Chymase, an enzyme important in angiotensin synthesis, is implicated in hypertension, myocardial infarction, and coronary heart disease. Cathepsin G is implicated in abnormal connective tissue degradation, particularly in the lung. [0007] Given the link between cysteine and serine proteases and various debilitating disorders, compounds which inhibit these proteases would be useful and would provide an advance in both research and clinical medicine. The present invention is directed to these, as well as other, important ends. SUMMARY OF THE INVENTION [0008] The present invention is directed to selected peptide-containing .alpha.-ketoamide inhibitors of cysteine and serine proteases represented by the general formula I: wherein: [0009] Q has the formula G-B-(CHR.sup.4).sub.v where R.sup.4 is independently H or alkyl having from 1 to 4 carbons; [0010] v is 0, 1, or 2; [0011] B is selected from the group consisting of C(.dbd.O), OC(.dbd.O), S(.dbd.O).sub.m, CH.sub.2, a bond, NR.sup.5C(.dbd.O), S(.dbd.O).sub.m-A-C(.dbd.O), and C(.dbd.O)-A-C(.dbd.O), where R.sup.5 is H or lower alkyl; [0012] m is 0, 1, or 2; [0013] A is lower alkylene or cycloalkylene, optionally substituted with one or more halogen atoms, aryl, or heteroaryl groups; [0014] M is a carbon atom; [0015] G is selected from the group consisting of H, a blocking group, lower alkyl, lower alkenyl, aryl having from about 6 to about 14 carbons, heterocyclyl having from about 5 to about 14 ring atoms, heterocycloalkyl having from about 5 to about 14 ring atoms, arylalkyl having from about 7 to about 15 carbons, heteroarylalkyl, and arylheteroalkyl wherein the aryl portion can be unfused or fused with the heteroalkyl ring, said alkyl, aryl, heterocyclyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, and arylheteroalkyl groups being optionally substituted with one or more J groups; [0016] J is selected from the group consisting of halogen, CN, nitro, lower alkyl, cycloalkyl, heterocycloalkyl, heteroalkyl, halogenated alkyl, aryloxyalkyl, alkylthio, alkylsulfonyl, aryl, heteroaryl, arylalkyl, arylalkyloxy, arylsulfonyl, heteroarylsulfonyl, alkoxycarbonyl, alkoxyalkyl, acyl, alkoxy, hydroxy, carboxy, hydroxyalkyl, amino, alkylamino, and aminoalkyl, said amino group or said amino group of said aminoalkyl or alkylamino group being optionally substituted with an acyl group, an alkoxy group, or with 1 to 3 aryl, lower alkyl, cycloalkyl, or alkoxyalkyl groups; and said aryl, heteroaryl, heterocycloalkyl, and heteroalkyl groups being further optionally substituted by a J group; [0017] each Aaa is independently an amino acid which optionally contains one or more blocking groups; [0018] n is 0, 1, 2, or 3; [0019] R.sup.1 and R.sup.2 are independently selected from the group consisting of H, alkyl having from one to about 6 carbons, arylalkyl having from about 7 to about 15 carbons, heteroalkyl in which the ring contains from about 5 to about 14 ring atoms, heteroarylalkyl in which the heteroaryl ring contains from about 5 to about 14 ring atoms, alkoxyalkyl, a side chain of a naturally occurring amino acid in the R or S configuration, and (CH.sub.2).sub.pNH-L, said alkyl, arylalkyl, heteroalkyl, heteroarylalkyl, and alkoxyalkyl groups being optionally substituted with one or more J groups; [0020] p is 0, 1, 2, or 3; [0021] L is selected from the group consisting of alkoxycarbonyl having from 2 to about 7 carbons, arylalkoxycarbonyl in which the arylalkoxy group contains about 7 to about 15 carbons, and S(.dbd.O).sub.2R.sup.6; [0022] R.sup.6 is selected from the group consisting of lower alkyl, and aryl having from about 6 to about 14 carbons; [0023] R.sup.3 is selected from the group consisting of H, alkyl having from one to about 6 carbons, arylalkyl having from about 7 to about 15 carbons, heteroalkyl in which the ring contains from about 5 to about 14 ring atoms, heteroarylalkyl in which the heteroaryl ring contains from about 5 to about 14 ring atoms, alkoxyalkyl, a side chain of a naturally occurring amino acid in the R or S configuration, (CH.sub.2).sub.pNH-L, C(.dbd.O)R.sup.7, S(.dbd.O).sub.2R.sup.7, a blocking group, and when combined with the carbon atom to which R.sup.1 is attached an alkylene group having from 2 to 5 carbons, said alkylene group being optionally substituted with a group selected from the group consisting of aryl, azide, CN, a protected amino group, and OSO.sub.2-aryl, said alkyl, arylalkyl, heteroalkyl, heteroarylalkyl, and alkoxyalkyl groups being optionally substituted with one or more J groups; [0024] R.sup.7 is selected from the group consisting of aryl having from about 6 to about 14 carbons, heteroaryl having from about 5 to about 14 ring atoms, arylalkyl having from about 7 to about 15 carbons, alkyl having from 1 to about 10 carbons, said aryl, heteroaryl, arylalkyl and alkyl groups being optionally substituted with one or more J groups, heteroalkyl having from 2 to about 7 carbons, alkoxy having from about 1 to about 10 carbons, and amino optionally substituted with 1 or more alkyl groups; [0025] q is 0 or 1; [0026] Z is selected from the group consisting of C(.dbd.O)C(.dbd.O)NH--X-A.sup.1-K and [0027] X is a bond or --O--; [0028] A.sup.1 is the same as A; [0029] K is selected from the group consisting of N(R.sup.10)Y, [0030] D is a fused aryl or heteroaryl group; [0031] R.sup.11 is selected from the group consising of alkoxy, aryloxy, and NHR.sup.12; [0032] R.sup.12 is selected from the group consisting of H, alkyl, aryl, and heteroaryl, said alkyl, aryl or heteroaryl groups being optionally substituted with one or more J groups; [0033] Y is selected from the group consisting of SO.sub.2R.sup.8, C(.dbd.O)NHR.sup.9, C(.dbd.S)NHR.sup.9, C(.dbd.NCN)R.sup.11, C(.dbd.NC(.dbd.O)NHR.sup.10)R.sup.11, and CO.sub.2R.sup.8; [0034] R.sup.8 is selected from the group consisting of alkyl, alkoxy, aryl, and heterocyclyl, said alkyl, alkoxy, aryl, or heterocyclyl groups being optionally substituted with one or more J groups; [0035] R.sup.9 is selected from the group consisting of H, alkyl, aryl, and heteroaryl, said alkyl, aryl, or heteroaryl groups being optionally substituted with one or more J groups; [0036] or an R.sup.9 alkyl group may be combined with an A.sup.1 alkylene group to form a N-containing heterocyclic 5- or 6-membered ring; [0037] R.sup.10 is selected from the group consisting of H and lower alkyl; [0038] or in the moiety SO.sub.2N(R.sup.8)R.sup.10, R.sup.8 and R.sup.10 may be combined together with the N atom to which they are attached to form a N-containing heterocyclic 5- or 6-membered ring; [0039] or where A.sup.1 is an alkylene group, and K is N(R.sup.10)Y wherein R.sup.10 is alkyl, said R.sup.10 alkyl group may be combined with said A.sup.1 alkylene group to form a N-containing heterocyclic 5- or 6-membered ring; or a pharmaceutically acceptable salt thereof. [0040] In some preferred embodiments of the compounds of Formula I, n and v are each 0, q is 1, B is a bond, and G is H. In further preferred embodiments of the compounds of Formula I, R.sup.1 is the sidechain of a naturally occurring amino acid. In still further preferred embodiments of the compounds of Formula I, R.sup.3 is --S(.dbd.O).sub.2R.sup.7. [0041] In some preferred embodiments of the compounds of Formula I, R.sup.2 is benzyl or alkoxyalkyl. In more preferred embodiments, X is a bond, and Y is SO.sub.2R.sup.8. Preferably, A.sup.1 is --CH.sub.2--CH.sub.2--, --CH.sub.2--CH(CH.sub.3)--, or --(CH.sub.3)CH--CH.sub.2--. [0042] In further preferred embodiments of the compounds of Formula I, R.sup.1 is a serine sidechain, which is optionally capped with a benzyl group. Preferably, the carbon to which the serine sidechain is attached, designated "M" in Formula I, is a carbon atom in the D configuration. [0043] In preferred embodiments of the compounds of Formula I, R.sup.2 is benzyl, R.sup.7 is methyl, and R.sup.8 is substituted phenyl, unsubstituted phenyl, substituted heteroaryl, or unsubstituted heteroaryl. In particularly preferred embodiments, R.sup.8 is aryl, aryl substituted with amino, aryl substituted with heterocyclomethyl, heteroaryl, alkyl substituted with heteroaryl, or heteroaryl substituted with alkylthio, haloalkyl, alkyl, phenylsulfonyl, halogen, aminophenyl, amino, or dialkylaminoalkyl. [0044] In further preferred embodiments of the compounds of Formula I, n, v and q are each 0, B is (C.dbd.O), and G is phenyl or lower alkyl, said phenyl or lower alkyl groups being optionally substituted with one or more J groups. [0045] In more preferred embodiments of the invention, n and v are each 0, q is 1, R.sup.1 is the side chain of an amino acid in the D- or L-configuration, R.sup.3 is S(.dbd.O).sub.2R.sup.7, G is H, B is a bond, R.sup.2 is benzyl or alkoxyalkyl, X is a bond, and Y is SO.sub.2R.sup.8. [0046] In other preferred embodiments, A.sup.1 is CH.sub.2CH.sub.2, CH.sub.2CH(CH.sub.3), or (CH.sub.3)CHCH.sub.2. In more preferred embodiments, R.sup.1 is a serine side chain in the D-configuration in which the hydroxyl group is capped with benzyl, R.sup.2 is benzyl, R.sup.7 is methyl, and R.sup.8 is substituted or unsubstituted phenyl or substituted or unsubstituted heteroaryl. [0047] More preferred are the substituents shown for R.sup.1-R.sup.4, B, G, Aaa, X, A.sup.1, Y, n, q and v shown for the compounds in Tables 2, 3, 4 and 5. Especially preferred are the substituents shown for compounds 9, 13, 17, 22, and 29-151. [0048] Some especially preferred embodiments of the compounds of Formula I are shown in Tables 2, 3, 4 and 5, infra, with compounds 9, 13, 17, 22, and 29-151 being particularly preferred. [0049] Because the peptide-containing .alpha.-ketoamides of the invention inhibit cysteine proteases and serine proteases, they can be used in both research and therapeutic settings. [0050] In a research environment, preferred compounds having defined attributes can be used to screen for natural and synthetic compounds which evidence similar characteristics in inhibiting protease activity. The compounds can also be used in the refinement of in vitro and in vivo models for determining the effects of inhibition of particular proteases on particular cell types or biological conditions. [0051] In a therapeutic setting, given the connection between cysteine proteases and certain defined disorders, and serine proteases and certain defined disorders, compounds of the invention can be utilized to alleviate, mediate, reduce and/or prevent disorders which are associated with abnormal and/or aberrant activity of cysteine proteases and/or serine proteases. Continue reading about Peptide-containing alpha-ketoamide cysteine and serine protease inhibitors... Full patent description for Peptide-containing alpha-ketoamide cysteine and serine protease inhibitors Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Peptide-containing alpha-ketoamide cysteine and serine protease inhibitors patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. 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