Substituted 1,4-diazepines and uses thereof

Abstract

The present invention is directed to novel 1,4-diazepines, pharmaceutical compositions thereof and the use thereof as inhibitors of HDM2-p53 interactions. Compounds have Formula I: or a solvate, hydrate or pharmaceutically acceptable salt thereof; wherein: R 1 , R 2 , R 9 , R 10 , R a , R d and M are defined herein; X is a bivalent radical of: an alkane, a cycloalkane, an optionally-substituted arene, an optionally-substituted heteroarene, an optionally-substituted arylalkane or an optionally-substituted heteroarylalkane; and R 3 is —CO 2 R d , —CO 2 M, —OH, —NHR d , —SO 2 R d , —NHCONHR d , optionally-substituted amidino or optionally-substituted guanidino; or R 3 —X— is hydrogen or an electron pair; R 4 is oxygen or —NR 9 R 10 ; R 5 is cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, aralkyl, heteroarylalkyl, or a saturated or partially unsaturated heterocycle, each of which is optionally substituted; and R 6 , R 7 and R 8 are independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, a saturated or partially unsaturated heterocycle, cycloalkylalkyl, aralkyl or heteroarylalkyl, each of which is optionally substituted; or R 6 and R 7 , together with the carbon atom to which they are attached form a 3- to 7-membered carbocyclic ring optionally substituted 1 to 3 times with R a .

1 - 56 . (canceled)  
   
   
       57 . A pharmaceutical composition, comprising: 
 (a) a compound of Formula II:                          or a solvate, hydrate or pharmaceutically acceptable salt thereof; wherein:    each instance of R a  is independently halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, cyano, C 3-8  cycloalkyl, hydroxy, C 1-6  alkoxy, carboxy, (C 1-6  alkoxy)carbonyl, C 1-6  acyl, carbamoyl, (C 1-6  alkyl)aminocarbonyl, alkylthio, amino or nitro;    n is 0; or n is 1 and R a  occurs at the 7- or 8-position; or n is 2 and R a  occurs at the 7- and 8-positions;    X is a bivalent radical of: a C 1-6  alkane, an optionally-substituted C 6-10  arene, an optionally-substituted 5- to 7-membered heteroarene wherein 1 or 2 ring atoms are heteroatoms, an optionally-substituted (C 6-10  aryl)C 1-6  alkane, or an optionally-substituted heteroaryl(C 1-6 ) alkane in which the heteroaryl portion contains 5 to 7 ring atoms and wherein 1 or 2 of the ring atoms are heteroatoms;    R 3  is —CO 2 R d  or —CO 2 M, where R d  is hydrogen, C 1-6  alkyl or optionally-substituted C 3-8  cycloalkyl, and M is a cation;    R 5  is C 3-8  cycloalkyl, C 6-10  aryl, 5- to 7-membered heteroaryl wherein 1 or 2 of the ring atoms are heteroatoms, (C 3-8  cycloalkyl)alkyl, (C 6-10  aryl)alkyl, (heteroaryl)alkyl in which the heteroaryl portion contains 5 to 7 ring atoms and wherein 1 or 2 of the ring atoms are heteroatoms, or 5- to 7-membered saturated or partially unsaturated heterocycle wherein 1 or 2 of the ring atoms are heteroatoms, in which each of the preceding groups is optionally substituted;    R 6  is C 3-8  cycloalkyl, C 6-10  alkyl, 5- to 7-membered heteroaryl wherein 1 or 2 of the ring atoms are heteroatoms, (C 3-8  cycloalkyl)alkyl, (C 6-10  aryl)alkyl, (heteroaryl)alkyl in which the heteroaryl portion contains 5 to 7 ring atoms and wherein 1 or 2 of the ring atoms are heteroatoms, or 5- to 7-membered saturated or partially unsaturated heterocycle wherein 1 or 2 of the ring atoms are heteroatoms, in which each of the preceding groups is optionally substituted;    R 7  is hydrogen, C 1-6  alkyl, C 3-8  cycloalkyl or (C 3-8  cycloalkyl)alkyl; and    R 8  is hydrogen or C 1-6  alkyl,    or a salt or prodrug thereof;    (b)) one or more pharmaceutically-acceptable excipients; and    (c) at least one additional substance selected from the group consisting of synergists, stabilizing substances, antineoplastic agents, anticancer agents, and cytostatic agents.    
   
   
       64 . A method of inhibiting the binding of p53 to a protein encoded by hdm2, comprising 
 contacting p53 or one or more proteins encoded by hdm2, with one or more compounds of Formula II:                          or a solvate, hydrate or pharmaceutically acceptable salt thereof; wherein:    each instance of R a  is independently halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, cyano, C 3-8  cycloalkyl, hydroxy, C 1-6  alkoxy, carboxy, (C 1-6  alkoxy)carbonyl, C 1-6  acyl, carbamoyl, (C 1-6  alkyl)aminocarbonyl, alkylthio, amino or nitro;    n is 0; or n is 1 and R a  occurs at the 7- or 8-position; or n is 2 and R a  occurs at the 7- and 8-positions;    X is a bivalent radical of: a C 1-6  alkane, an optionally-substituted C 6-10  arene, an optionally-substituted 5- to 7-membered heteroarene wherein 1 or 2 ring atoms are heteroatoms, an optionally-substituted (C 6-10  aryl)C 1-6  alkane, or an optionally-substituted heteroaryl(C 1-6 ) alkane in which the heteroaryl portion contains 5 to 7 ring atoms and wherein 1 or 2 of the ring atoms are heteroatoms;    R 3  is —CO 2 R d  or —CO 2 M, where R d  is hydrogen, C 1-6  alkyl or optionally-substituted C 3-8  cycloalkyl, and M is a cation;    R 5  is C 3-8  cycloalkyl, C 6-10  aryl, 5- to 7-membered heteroaryl wherein 1 or 2 of the ring atoms are heteroatoms, (C 3-8  cycloalkyl)alkyl, (C 6-10  aryl)alkyl, (heteroaryl)alkyl in which the heteroaryl portion contains 5 to 7 ring atoms and wherein 1 or 2 of the ring atoms are heteroatoms, or 5- to 7-membered saturated or partially unsaturated heterocycle wherein 1 or 2 of the ring atoms are heteroatoms, in which each of the preceding groups is optionally substituted;    R 6  is C 3-8  cycloalkyl C 6-10  aryl, 5- to 7-membered heteroaryl wherein 1 or 2 of the ring atoms are heteroatoms, (C 3-8  cycloalkyl)alkyl, (C 6-10  aryl)alkyl, (heteroaryl)alkyl in which the heteroaryl portion contains 5 to 7 ring atoms and wherein 1 or 2 of the ring atoms are heteroatoms, or 5- to 7-membered saturated or partially unsaturated heterocycle wherein 1 or 2 of the ring atoms are heteroatoms, in which each of the preceding groups is optionally substituted;    R 7  is hydrogen, C 1-6  alkyl, C 3-8  cycloalkyl or (C 3-8  cycloalkyl)alkyl; and    R 8  is hydrogen or C 1-6  alkyl;    or a salt or prodrug thereof.    
   
   
       65 . A method of treating a condition that results from the inhibition of one or more functions of a cellular protein that induces apoptosis, induces cellular death, or regulates the cell cycle by an HDM2 protein, comprising administering to a patient in need of such treatment a pharmaceutically-effective amount of a compound of Formula II:  
     
       
         
         
             
             
         
       
     
     or a solvate, hydrate or pharmaceutically acceptable salt thereof; wherein: 
 each instance of R a  is independently halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, cyano, C 3-8  cycloalkyl, hydroxy, C 1-6  alkoxy, carboxy, (C 1-6  alkoxy)carbonyl, C 1-6  acyl, carbamoyl, (C 1-6  alkyl)aminocarbonyl, alkylthio, amino or nitro;  
 n is 0; or n is 1 and R a  occurs at the 7- or 8-position; or n is 2 and R a  occurs at the 7- and 8-positions;  
 X is a bivalent radical of: a C 1-6  alkane, an optionally-substituted C 6-10  arene, an optionally-substituted 5- to 7-membered heteroarene wherein 1 or 2 ring atoms are heteroatoms, an optionally-substituted (C 6-10  aryl)C 1-6  alkane, or an optionally-substituted heteroaryl(C 1-6 ) alkane in which the heteroaryl portion contains 5 to 7 ring atoms and wherein 1 or 2 of the ring atoms are heteroatoms;  
 R 3  is —CO 2 R d  or —CO 2 M, where R d  is hydrogen, C 1-6  alkyl or optionally-substituted C 3-8  cycloalkyl, and M is a cation,  
 R 5  is C 3-8  cycloalkyl, C 6-10  aryl, 5- to 7-membered heteroaryl wherein 1 or 2 of the ring atoms are heteroatoms, (C 3-8  cycloalkyl)alkyl, (C 6-10  aryl)alkyl, (heteroaryl)alkyl in which the heteroaryl portion contains 5 to 7 ring atoms and wherein 1 or 2 of the ring atoms are heteroatoms, or 5- to 7-membered saturated or partially unsaturated heterocycle wherein 1 or 2 of the ring atoms are heteroatoms, in which each of the preceding groups is optionally substituted;  
 R 6  is C 3-8  cycloalkyl, C 6-10  aryl, 5- to 7-membered heteroaryl wherein 1 or 2 of the ring atoms are heteroatoms, (C 3-8  cycloalkyl)alkyl, (C 6-10  aryl)alkyl, (heteroaryl)alkyl in which the heteroaryl portion contains 5 to 7 ring atoms and wherein 1 or 2 of the ring atoms are heteroatoms, or 5- to 7-membered saturated or partially unsaturated heterocycle wherein 1 or 2 of the ring atoms are heteroatoms, in which each of the preceding groups is optionally substituted;  
 R 7  is hydrogen, C 1-6  alkyl, C 3-8  cycloalkyl or (C 3-8  cycloalkyl)alkyl; and  
 R 8  is hydrogen or C 1-6  alkyl;  
 or a salt or prodrug thereof.  
 
   
   
       66 . A method of inducing apoptosis, comprising 
 contacting an animal with a composition comprising a pharmaceutically-effective amount of at least one compound of Formula II:                          or a solvate, hydrate or pharmaceutically acceptable salt thereof; wherein:    each instance of R a  is independently halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, cyano, C 3-8  cycloalkyl, hydroxy, C 1-6  alkoxy, carboxy, (C 1-6  alkoxy)carbonyl, C 1-6  acyl, carbamoyl, (C 1-6  alkyl)aminocarbonyl, alkylthio, amino or nitro;    n is 0; or n is 1 and R a  occurs at the 7- or 8-position; or n is 2 and R a  occurs at the 7- and 8-positions;    X is a bivalent radical of: a C 1-6  alkane, an optionally-substituted C 6-10  arene, an optionally-substituted 5- to 7-membered heteroarene wherein 1 or 2 ring atoms are heteroatoms, an optionally-substituted (C 6-10  aryl)C 1-6  alkane, or an optionally-substituted heteroaryl(C 1-6 ) alkane in which the heteroaryl portion contains 5 to 7 ring atoms and wherein 1 or 2 of the ring atoms are heteroatoms;    R 3  is —CO 2 R d  or —CO 2 M, where R d  is hydrogen, C 1-6  alkyl or optionally-substituted C 3-8  cycloalkyl, and M is a cation;    R 5  is C 3-8  cycloalkyl, C 6-10  aryl, 5- to 7-membered heteroaryl wherein 1 or 2 of the ring atoms are heteroatoms, (C 3-8  cycloalkyl)alkyl, (C 6-10  aryl)alkyl, (heteroaryl)alkyl in which the heteroaryl portion contains 5 to 7 ring atoms and wherein 1 or 2 of the ring atoms are heteroatoms, or 5- to 7-membered saturated or partially unsaturated heterocycle wherein 1 or 2 of the ring atoms are heteroatoms, in which each of the preceding groups is optionally substituted;    R 6  is C 3-8  cycloalkyl, C 6-10  aryl, 5- to 7-membered heteroaryl wherein 1 or 2 of the ring atoms are heteroatoms, (C 3-8  cycloalkyl)alkyl, (C 6-10  aryl)alkyl, (heteroaryl)alkyl in which the heteroaryl portion contains 5 to 7 ring atoms and wherein 1 or 2 of the ring atoms are heteroatoms, or 5- to 7-membered saturated or partially unsaturated heterocycle wherein 1 or 2 of the ring atoms are heteroatoms, in which each of the preceding groups is optionally substituted;    R 7  is hydrogen, C 1-6  alkyl, C 3-8  cycloalkyl or (C 3-8  cycloalkyl)alkyl; and 
 R 8  is hydrogen or C 1-6  alkyl;  
 or a salt or prodrug thereof.  
   
   
   
       67 . The method according to  claim 66 , wherein said composition further comprises at least one pharmaceutically-acceptable excipient.  
   
   
       68 . A method of preventing or treating cancer or a condition that results from the uncontrolled proliferation of cells, comprising contacting an animal with (a) a composition comprising a pharmaceutically-effective amount of an antineoplastic agent, and (b) a compound of Formula II:  
     
       
         
         
             
             
         
       
     
     or a solvate, hydrate or pharmaceutically acceptable salt thereof; wherein: 
 each instance of R a  is independently halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, cyano, C 3-8  cycloalkyl, hydroxy, C 1-6  alkoxy, carboxy, (C 1-6  alkoxy)carbonyl, C 1-6  acyl, carbamoyl, (C 1-6  alkyl)aminocarbonyl, alkylthio, amino or nitro;  
 n is 0; or n is 1 and R a  occurs at the 7- or 8-position; or n is 2 and R a  occurs at the 7- and 8-positions;  
 X is a bivalent radical of: a C 1-6  alkane, an optionally-substituted C 6-10  arene, an optionally-substituted 5- to 7-membered heteroarene wherein 1 or 2 ring atoms are heteroatoms, an optionally-substituted (C 6-10  aryl)C 1-6  alkane, or an optionally-substituted heteroaryl(C 1-6 ) alkane in which the heteroaryl portion contains 5 to 7 ring atoms and wherein 1 or 2 of the ring atoms are heteroatoms;  
 R 3  is —CO 2 R d  or —CO 2 M, where R d  is hydrogen, C 1-6  alkyl or optionally-substituted C 3-8  cycloalkyl, and M is a cation;  
 R 5  is C 3-8  cycloalkyl, C 6-10  aryl, 5- to 7-membered heteroaryl wherein 1 or 2 of the ring atoms are heteroatoms, (C 3-8  cycloalkyl)alkyl, (C 6-10  aryl)alkyl, (heteroaryl)alkyl in which the heteroaryl portion contains 5 to 7 ring atoms and wherein 1 or 2 of the ring atoms are heteroatoms, or 5- to 7-membered saturated or partially unsaturated heterocycle wherein 1 or 2 of the ring atoms are heteroatoms, in which each of the preceding groups is optionally substituted;  
 R 6  is C 3-8  cycloalkyl, C 6-10  aryl, 5- to 7-membered heteroaryl wherein 1 or 2 of the ring atoms are heteroatoms, (C 3-8  cycloalkyl)alkyl, (C 6-10  aryl)alkyl, (heteroaryl)alkyl in which the heteroaryl portion contains 5 to 7 ring atoms and wherein 1 or 2 of the ring atoms are heteroatoms, or 5- to 7-membered saturated or partially unsaturated heterocycle wherein 1 or 2 of the ring atoms are heteroatoms, in which each of the preceding groups is optionally substituted;  
 R 7  is hydrogen, C 1-6  alkyl, C 3-8  cycloalkyl or (C 3-8  cycloalkyl)alkyl; and  
 R 8  is hydrogen or C 1-6  alkyl;  
 or a salt or prodrug thereof.  
 
   
   
       69 . The method of  claim 68 , wherein said cancer or condition is selected from the group consisting of breast cancer, ovarian cancer, cervical carcinoma, endometrial carcinoma, choriocarcinoma, soft tissue sarcomas, osteosarcomas, rhabdomyosarcomas, leiomyomas, leiomyosarcomas, head and neck cancers, lung and bronchogenic carcinomas, brain tumors, neuroblastomas, esophogeal cancer, colorectal adenocarcinomas, bladder cancer, urothelial cancers, leukemia, lymphoma, malignant melanomas, oral squamous carcinoma, hepatoblastoma, glioblastoma, astrocytoma, medulloblastoma, Ewing's sarcoma, lipoma, liposarcoma, malignant fibroblast histoma, malignant Schwannoma, testicular cancers, thyroid cancers, Wilms' tumor, pancreatic cancers, colorectal adenocarcinoma, tongue carcinoma, gastric carcinoma, and nasopharyngeal cancers.  
   
   
       70 . The method of  claim 68 , wherein said cancer or condition is selected from the group consisting of breast cancer, choriocarcinoma, soft tissue sarcomas, osteosarcomas, rhabdomyosarcomas, lipoma and liposarcoma.  
   
   
       71 . A method of treating an inflammatory condition, comprising administering to a patient in need of such treatment a pharmaceutically-effective amount of a compound of Formula II:  
     
       
         
         
             
             
         
       
     
     or a solvate, hydrate or pharmaceutically acceptable salt thereof; wherein: 
 each instance of R a  is independently halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, cyano, C 3-8  cycloalkyl, hydroxy, C 1-6  alkoxy, carboxy, (C 1-6  alkoxy)carbonyl, C 1-6  acyl, carbamoyl, (C 1-6  alkyl)aminocarbonyl, alkylthio, amino or nitro;  
 n is 0; or n is 1 and R a  occurs at the 7- or 8-position; or n is 2 and R a  occurs at the 7- and 8-positions;  
 X is a bivalent radical of: a C 1-6  alkane, an optionally-substituted C 6-10  arene, an optionally-substituted 5- to 7-membered heteroarene wherein 1 or 2 ring atoms are heteroatoms, an optionally-substituted (C 6-10  aryl)C 1-6  alkane, or an optionally-substituted heteroaryl(C 1-6 ) alkane in which the heteroaryl portion contains 5 to 7 ring atoms and wherein 1 or 2 of the ring atoms are heteroatoms;  
 R 3  is —CO 2 R d  or —CO 2 M, where R d  is hydrogen, C 1-6  alkyl or optionally-substituted C 3-8  cycloalkyl, and M is a cation;  
 R 5  is C 3-8  cycloalkyl, C 6-10  aryl, 5- to 7-membered heteroaryl wherein 1 or 2 of the ring atoms are heteroatoms, (C 3-8  cycloalkyl)alkyl, (C 6-10  aryl)alkyl, (heteroaryl)alkyl in which the heteroaryl portion contains 5 to 7 ring atoms and wherein 1 or 2 of the ring atoms are heteroatoms, or 5- to 7-membered saturated or partially unsaturated heterocycle wherein 1 or 2 of the ring atoms are heteroatoms, in which each of the preceding groups is optionally substituted;  
 R 6  is C 3-8  cycloalkyl, C 6-10  alkyl, 5- to 7-membered heteroaryl wherein 1 or 2 of the ring atoms are heteroatoms, (C 3-8  cycloalkyl)alkyl, (C 6-10  aryl)alkyl, (heteroaryl)alkyl in which the heteroaryl portion contains 5 to 7 ring atoms and wherein 1 or 2 of the ring atoms are heteroatoms, or 5- to 7-membered saturated or partially unsaturated heterocycle wherein 1 or 2 of the ring atoms are heteroatoms, in which each of the preceding groups is optionally substituted;  
 R 7  is hydrogen, C 1-6  alkyl, C 3-8  cycloalkyl or (C 3-8  cycloalkyl)alkyl; and  
 R 8  is hydrogen or C 1-6  alkyl;  
 or a salt or prodrug thereof.  
 
   
   
       72 . A method of treating an autoimmune disease or condition, comprising administering to a patient in need of such treatment a pharmaceutically-effective amount of a compound of Formula II:  
     
       
         
         
             
             
         
       
     
     or a solvate, hydrate or pharmaceutically acceptable salt thereof; wherein: 
 each instance of R a  is independently halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, cyano, C 3-8  cycloalkyl, hydroxy, C 1-6  alkoxy, carboxy, (C 1-6  alkoxy)carbonyl, C 1-6  acyl, carbamoyl, (C 1-6  alkyl)aminocarbonyl, alkylthio, amino or nitro;  
 n is 0; or n is 1 and R a  occurs at the 7- or 8-position; or n is 2 and R a  occurs at the 7- and 8-positions;  
 X is a bivalent radical of: a C 1-6  alkane, an optionally-substituted C 6-10  arene, an optionally-substituted 5- to 7-membered heteroarene wherein 1 or 2 ring atoms are heteroatoms, an optionally-substituted (C 6-10  aryl)C 1-6  alkane, or an optionally-substituted heteroaryl(C 1-6 ) alkane in which the heteroaryl portion contains 5 to 7 ring atoms and wherein 1 or 2 of the ring atoms are heteroatoms;  
 R 3  is —CO 2 R d  or —CO 2 M, where R d  is hydrogen, C 1-6  alkyl or optionally-substituted C 3-8  cycloalkyl, and M is a cation;  
 R 5  is C 3-8  cycloalkyl, C 6-10  aryl, 5- to 7-membered heteroaryl wherein 1 or 2 of the ring atoms are heteroatoms, (C 3-8  cycloalkyl)alkyl, (C 6-10  aryl)alkyl, (heteroaryl)alkyl in which the heteroaryl portion contains 5 to 7 ring atoms and wherein 1 or 2 of the ring atoms are heteroatoms, or 5- to 7-membered saturated or partially unsaturated heterocycle wherein 1 or 2 of the ring atoms are heteroatoms, in which each of the preceding groups is optionally substituted;  
 R 6  is C 3-8  cycloalkyl C 6-10  aryl, 5- to 7-membered heteroaryl wherein 1 or 2 of the ring atoms are heteroatoms, (C 3-8  cycloalkyl)alkyl, (C 6-10  aryl)alkyl, (heteroaryl)alkyl in which the heteroaryl portion contains 5 to 7 ring atoms and wherein 1 or 2 of the ring atoms are heteroatoms, or 5- to 7-membered saturated or partially unsaturated heterocycle wherein 1 or 2 of the ring atoms are heteroatoms, in which each of the preceding groups is optionally substituted;  
 R 7  is hydrogen, C 1-6  alkyl, C 3-8  cycloalkyl or (C 3-8  cycloalkyl)alkyl; and  
 R 8  is hydrogen or C 1-6  alkyl;  
 or a salt or prodrug thereof.  
 
   
   
       73 . The method of  claim 72 , wherein said autoimmune disease or condition is selected from the group consisting of Hashimoto's thyroiditis, Grave's disease, multiple sclerosis, pernicious anemia, Addison's disease, insulin-dependent diabetes mellitus, rheumatoid arhritis, systemic lupus erythematosus (SLE or lupus), and dermatomyositis, Crohn's disease, Wegener's granulomatosis, Anti-Glomerular Basement Membrane Disease, Antiphospholipid Syndrome, Dermatitis Herpetiformis, Allergic Encephalomyelitis, Glomerulonephritis, Membranous Glomerulonephritis, Goodpasture Syndrome, Lambert-Eaton, Myasthenic Syndrome, Myasthenia Gravis, Bullous Pemphigoid, Polyendocrinopathies, Reiter's Disease and Stiff-Man Syndrome.  
   
   
       74 . The method of  claim 72 , wherein said autoimmune disease or condition is rheumatoid arthritis or systemic lupus erythematosus.  
   
   
       75 . The method according to  claim 64 , wherein said effective amount is between about 1.0 and about 100 milligrams per kilogram per day.  
   
   
       76 . The composition of  claim 57 , wherein said compound is present in an amount between about 0.5 and about 100 milligrams.  
   
   
       77 . The composition of  claim 57 , suitable for administration by a subcutaneous, intravenous, intramuscular, intraperitoneal, buccal, or ocular route, rectally, parenterally, instrasystemically, intravaginally, topically, orally, or as an oral or nasal spray.  
   
   
       78 . The composition of  claim 57 , suitable for parenteral administration, wherein said compound is present in an amount between about 0.5 and about 100 milligrams.  
   
   
       79 . The composition of  claim 57 , suitable for parenteral administration, wherein said compound is present in an amount between about 0.5 and about 10 milligrams.  
   
   
       80 . The composition of  claim 57 , suitable for oral administration, wherein said compound is present in an amount between about 0.5 and about 100 milligrams.  
   
   
       81 . The composition of  claim 57 , suitable for oral administration, wherein said compound is present in an amount between about 25 and about 100 milligrams.