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Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesisRelated 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, 2 Peptide Repeating Units In Known Peptide ChainAntipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060046966, Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is related to U.S. Provisional Application No. 60/098,358, filed Aug. 28, 1998, and U.S. Provisional Application No. 60/083,828, filed Apr. 30, 1998. FIELD AND INDUSTRIAL APPLICABILITY OF THE INVENTION [0002] The invention pertains to peptide-like and peptidomimetic compounds that advantageously inhibit the enzymatic activity of picornaviral 3C proteases, especially rhinovirus 3C proteases (RVPs), and that retard viral growth in cell culture. The invention also relates to the use of such compounds in pharmaceutical compositions and therapeutic treatments for rhinoviral infections. The invention further relates to processes for synthesizing such compounds and compounds useful in such syntheses. BACKGROUND OF THE INVENTION [0003] The picornaviruses are a family of tiny non-enveloped positive-stranded RNA-containing viruses that infect humans and other animals. These viruses include the human rhinoviruses, human polioviruses, human coxsackieviruses, human echoviruses, human and bovine enteroviruses, encephalomyocarditis viruses, meningitis virus, foot and mouth viruses, hepatitis A virus, and others. The human rhinoviruses are a major cause of the common cold. To date, there are no effective therapies on the market that cure the common cold, only treatments that relieve the symptoms. [0004] Picornaviral infections may be treated by inhibiting the proteolytic 3C enzymes. These enzymes are required for the natural maturation of the picornaviruses. They are responsible for the autocatalytic cleavage of the genomic, large polyprotein into the essential viral proteins. Members of the 3C protease family are cysteine proteases, where the sulfhydryl group most often cleaves the glutamine-glycine amide bond. Inhibition of 3C proteases is believed to block proteolytic cleavage of the polyprotein, which in turn can retard the maturation and replication of the viruses by interfering with viral particle production. Therefore, inhibiting the processing of this cysteine protease with selective small molecules that are specifically recognized should represent an important and useful approach to treat and cure viral infections of this nature and, in particular, the common cold. [0005] Some small-molecule inhibitors of the enzymatic activity of picornaviral 3C proteases (i.e., antipicornaviral compounds) have been recently discovered. See, for example: U.S. patent application Ser. No. 08/850,398, filed May 2, 1997, by Webber et al.; U.S. patent application Ser. No. 08/991,282, filed Dec. 16, 1997, by Dragovich et al.; and U.S. patent application Ser. No. 08/991,739, filed Dec. 16, 1997, by Webber et al. These U.S. patent applications, the disclosures of which are incorporated herein by reference, describe certain antipicornaviral compounds. There is still a desire to discover small-molecule compounds that are especially potent antipicornaviral agents. SUMMARY OF THE INVENTION [0006] Thus, an object of this invention is to discover small-molecule compounds that are especially potent antipicornaviral agents. A further object of the invention is to provide intermediates useful for the synthesis of said protease-inhibiting compounds and synthetic methods useful for such syntheses. A yet further object of the invention is to achieve pharmaceutical compositions that are highly effective for treating maladies mediated by inhibition of picornaviral 3C proteases, such as the common cold. [0007] Such objects have been attained through the discovery of compounds of the invention, which are picornaviral 3C protease inhibitors displaying particularly strong antiviral activity. It has surprisingly been discovered that peptido and peptidomimetic compounds containing a five-membered heterocyclic group have high rhinoviral-protease-inhibiting activity. It has further been surprisingly found that the rhinoviral-protease-inhibiting activity of peptido and peptidomimetic compounds may be significantly enhanced by replacing a glutamine-like moiety found in some known rhinoviral-protease-inhibiting compounds with a side-chain comprising a gamma- or delta-lactam. [0008] The inhibitors of the present invention are of the following general formula (1): wherein: [0009] Y is --N(R.sub.y)--, --C(R.sub.y)(R.sub.y)--, or --O--, where each R.sub.y is independently --H or lower alkyl; [0010] R.sub.1 is --H, --F, -alkyl, --OH, --SH, or an O-alkyl group; [0011] R.sub.2 and R.sub.3 are each independently H; where n is an integer from 0 to 5, A.sub.1 is CH or N, A.sub.2 and each A.sub.3 are independently selected from C(R.sub.41)(R.sub.41), N(R.sub.41), S, S(O), S(O).sub.2, and 0, and A.sub.4 is NH or NR.sub.41, where each R.sub.4, is independently H or lower alkyl, provided that no more than two heteroatoms occur consecutively in the above-depicted ring formed by A.sub.1, A.sub.2, (A.sub.3).sub.n, A.sub.4 and C.dbd.O, and at least one of R.sub.2 and R.sub.3 is [0012] R.sub.5 and R.sub.6 are each independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; [0013] R.sub.7 and R.sub.8 are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, --OR.sub.17, --SR.sub.17, --NR.sub.17R.sub.18, --NR.sub.19NR.sub.17R.sub.18, or --NR.sub.17OR.sub.18, where R.sub.17, R.sub.18, and R.sub.19 are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or an acyl group, provided that at least one of R.sub.7 and R.sub.8 is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, --OR.sub.17, --SR.sub.17, --NR.sub.17R.sub.18, --NR.sub.19NR.sub.17R.sub.18, or --NR.sub.17OR.sub.18; [0014] R.sub.9 is a suitable organic moiety; and [0015] Z and Z.sub.1 are each independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, --C(O)R.sub.21, --CO.sub.2R.sub.21, --CN, --C(O)NR.sub.21R.sub.22, --C(O)NR.sub.21OR.sub.22, --C(S)R.sub.21, --C(S)NR.sub.21R.sub.22, --NO.sub.2, --SOR.sub.21, --SO.sub.2R.sub.21, --SO.sub.2NR.sub.21R.sub.22, --SO(NR.sub.21)(OR.sub.22), --SONR.sub.21, --SO.sub.3R.sub.21, --PO(OR.sub.21).sub.2, --PO(R.sub.21)(R.sub.22), --PO(NR.sub.21R.sub.22)(OR.sub.23), --PO(NR.sub.21R.sub.22)(NR.sub.23R.sub.24), --C(O)NR.sub.21NR.sub.22R.sub.23, or --C(S)NR.sub.21NR.sub.22R.sub.23, where R.sub.21, R.sub.22, R.sub.23, and R.sub.24 are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an acyl group, or a thioacyl group, or where any two of R.sub.21, R.sub.22, R.sub.23, and R.sub.24, together with the atom(s) to which they are bonded, form a heterocycloalkyl group, provided that Z and Z.sub.1 are not both H; [0016] or Z.sub.1 and R.sub.1, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z.sub.1 and R.sub.1 are as defined above except for moieties that cannot form the cycloalkyl or heterocycloalkyl group; [0017] or Z and Z.sub.1, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and Z.sub.1 are as defined above except for moieties that cannot form the cycloalkyl or heterocycloalkyl group. The invention also pertains to prodrugs, pharmaceutically acceptable salts, pharmaceutically active metabolites, and pharmaceutically acceptable solvates of compounds of the formula I. [0018] In preferred embodiments of the compounds of the formula I, R.sub.2 and R.sub.3 are each independently H; where n is an integer from 0 to 5, each R.sub.41 is independently H or lower alkyl, and the stereochemistry at the carbon denoted with an asterisk may be R or S; provided that at least one of R.sub.2 and R.sub.3 is Preferably, R.sub.9 is a five-membered heterocycle having one to three heteroatoms selected from O, N, and S. Alternatively, R.sub.9 is [0019] In other preferred embodiments, the variables of formula I are as follows. Z and Z.sub.1 are each independently selected from H, F, lower alkyl, --CO.sub.2R.sub.21, and --C(O)NR.sub.21R.sub.22, provided that Z and Z.sub.1 are not both H, where R.sub.21 and R.sub.22 are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an acyl group, or a thioacyl group, or R.sub.2, and R.sub.22, together with the atom(s) to which they are bonded, form a heterocycloalkyl group. At least one of R.sub.2 or R.sub.3 is and the other is H. R.sub.5 and R.sub.6 are each independently selected from H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, and a heteroaryl group, more preferably one of R.sub.5 and R.sub.6 is H and the other is alkyl or aryl (e.g., unsubstituted or substituted phenylmethyl). R.sub.7 and R.sub.8 are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; and more preferably one of R.sub.7 and R.sub.8 is H and the other is alkyl (e.g., 2-propyl, 2-methyl-2-propyl, or 2-methyl-1-propyl) or arylmethyl (e.g., unsubstituted or substituted phenylmethyl or naphthylmethyl). R.sub.9 is a five-membered heterocycle having from one to three heteroatoms selected from O, N, and S, more preferably a five-membered heterocycle having at least one nitrogen heteroatom and at least one oxygen heteroatom (e.g., unsubstituted or substituted 1,2-oxazolyl (i.e., isoxazolyl), 1,3-oxazolyl (i.e., oxazolyl), or oxadiazolyl (1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, or 1,2,5-oxadiazolyl). When R.sub.9 is oxadiazolyl, unsubstituted and monomethyl-substituted 1,2,4-oxadiazolyl are preferred. In especially preferred embodiments, R.sub.9 is 3-isoxazolyl or 5-isoxazolyl, either unsubstituted or substituted with one or two methyl groups and/or halogens, with chlorine and fluorine being preferred halogen substituents. [0020] In a preferred embodiment, the compounds, prodrugs, pharmaceutically acceptable salts, pharmaceutically active metabolites, and solvates have an antipicornaviral activity with an EC.sub.50 less than or equal to 100 .mu.M in the H1-HeLa cell culture assay, and more preferably an antirhinoviral activity with an EC.sub.50 less than or equal to 10 .mu.M in the H1-HeLa cell culture. [0021] In another aspect, the invention is directed to intermediates of formula II, preferably of the formula II', which are useful in the synthesis of certain compounds: wherein: [0022] p is an integer of from 0 to 5; [0023] A.sub.11 is CH or N, A.sub.12 and each A.sub.13 are independently selected from C(R.sub.61)(R.sub.61), N(R.sub.61), S, S(O), S(O).sub.2, and O, and A.sub.14 is NH or NR.sub.61, where each R.sub.61 is independently H, alkyl, acyl, or aryl, provided that no more than two heteroatoms occur consecutively in the above-depicted ring in formula II formed by A.sub.11, A.sub.12, (A.sub.13).sub.n, A.sub.14 and C.dbd.O; [0024] each R.sub.141 is independently H or lower alkyl; [0025] R.sub.51, is H, alkyl, acyl, or aryl; [0026] R.sub.52, R.sub.53, and R.sub.54 are each independently selected from H, hydroxyl, alkyl, acyl, and aryl; or any two of R.sub.52, R.sub.53, and R.sub.54 together form .dbd.O or .dbd.C(R.sub.57)(R.sub.58), where R.sub.57 and R.sub.58 are each independently selected from H, alkyl, CO.sub.2(C.sub.1-C.sub.6)alkyl, C(O)N(C.sub.1-C.sub.6)alkyl, and CO.sub.2(aryl); and [0027] R.sub.55 and R.sub.56 are each independently H or a suitable protecting group for nitrogen. The invention is also directed to pharmaceutically acceptable salts of the compounds of formulae II and II'. [0028] The invention also relates to pharmaceutical compositions containing a therapeutically effective amount of at least one compound of the formula I, or a prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or solvate thereof. Additionally, the invention relates to methods of inhibiting picornaviral 3C protease by administering a therapeutically effective amount of at least one compound of the formula I, or a prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or solvate thereof. DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS [0029] The present invention relates to compounds of the formula I: wherein Y, R.sub.1, R.sub.2, R.sub.3, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, Z, and Z.sub.1 are as defined above, and to pharmaceutically acceptable salts, prodrugs, active metabolites, and solvates thereof. Preferably, such compounds, pharmaceutically acceptable salts, prodrugs, active metabolites, and solvates have antipicornaviral activity, more preferably antirhinoviral activity, corresponding to an EC.sub.50 less than or equal to 100 .mu.M in the H1-HeLa cell culture assay, more preferably corresponding to an EC.sub.50 less than or equal to 10 .mu.M in the H1-HeLa cell culture assay. [0030] The present invention additionally relates to preferred compounds of the formulas I-A, I-B, and I-C: wherein R.sub.y (in formula I-A) is H or lower alkyl, and R.sub.1, R.sub.2, R.sub.3, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, Z, and Z.sub.1 are as defined above, and to pharmaceutically acceptable salts, prodrugs, active metabolites, and solvates thereof. [0031] The inventive compounds of formulas I-A, which are referred to herein as "peptide-like" compounds, I-B, which are referred to herein as "ketomethylene-type" compounds, and I-C, which are referred to herein as "depsipeptide" compounds, differ in their backbones, which may affect the specific biodistribution or other physical properties; nonetheless each possesses a strong rhinoviral-protease-inhibiting activity. [0032] In preferred embodiments of compounds of formulas I-A, I-B, and I-C above: [0033] R.sub.1 is H, F, or an alkyl group; [0034] R.sub.y (in formula I-A) is H or methyl; [0035] R.sub.3, R.sub.5, and R.sub.8 are each H; [0036] R.sub.2 is selected from one of the following moieties: [0037] R.sub.6 is an alkyl group, which has as a preferred optional substituent an aryl group; [0038] R.sub.7 is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; [0039] R.sub.9 is a five-membered heterocycle having from one to three heteroatoms selected from O, N, and S, preferably where at least one of the heteroatoms is nitrogen, that is unsubstituted or substituted, where the optional substituents are preferably halogen or lower alkyl, and more preferably mono-chloro or -fluoro or a methyl group; and [0040] Z and Z.sub.1 are each independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, --C(O)R.sub.21, --CO.sub.2R.sub.21, --CN, --C(O)NR.sub.21R.sub.22, --C(O)NR.sub.21OR.sub.22, --C(S)R.sub.21, --C(S)NR.sub.21R.sub.22, --NO.sub.2, --SOR.sub.21, --SO.sub.2R.sub.21, --SO.sub.2NR.sub.21R.sub.22, --SO(NR.sub.21)(OR.sub.22), --SONR.sub.21, --SO.sub.3R.sub.21, --PO(OR.sub.21).sub.2, --PO(R.sub.21)(R.sub.22), --PO(NR.sub.21R.sub.22)(OR.sub.23), --PO(NR.sub.21R.sub.22)(NR.sub.23R.sub.24), --C(O)NR.sub.21NR.sub.22R.sub.23, or --C(S)NR.sub.21NR.sub.22R.sub.23, where Z and Z.sub.1 are not both H, and where R.sub.21, R.sub.22, R.sub.23, and R.sub.24 are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an acyl group, or a thioacyl group, or where any two of R.sub.21, R.sub.22, R.sub.23, and R.sub.24, together with the atom(s) to which they are bonded, form a heterocycloalkyl group, or Z and Z.sub.1 (both as defined above), together with the atoms to which they are attached, form a heterocycloalkyl group. [0041] In preferred embodiments, the compounds of the invention are of the formulae I-A', I-B', and I-C': wherein: [0042] R.sub.1, Z, and Z.sub.1 are as defined above; [0043] n is 1 or 2; [0044] R.sub.y (in formula I-A') is H or lower alkyl; [0045] R.sub.6 is alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; [0046] R.sub.7 is alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, --OR.sub.17, --SR.sub.17, --NR.sub.17R.sub.18, --NR.sub.19NR.sub.17R.sub.18, or --NR.sub.17OR.sub.18, where R.sub.17, R.sub.18, and R.sub.19 are each independently H, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or acyl; [0047] R.sub.9 is a five-membered heterocycle having one to three heteroatoms selected from O, N, and S, that is unsubstituted or substituted, where the optional substituents are preferably one or two lower alkyl groups and/or halogens; and [0048] R.sub.20 is H. [0049] The invention also relates to prodrugs, pharmaceutically acceptable salts, pharmaceutically active metabolites, and solvate of such compounds. Continue reading about Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis... Full patent description for Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis 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. Each week you receive an email with patent applications related to your keywords. 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