Small molecule inhibitors targeted at Bcl-2

Abstract

The present invention relates to small molecule antagonists of Bcl-2 family proteins such as Bcl-2 and/or Bcl-X L . In particular, the present invention provides non-peptide cell permeable small molecules (e.g., tricyclo-dibenzo-diazocine-dioxides) that bind to a pocket in Bcl-2/Bcl-X L that block the anti-apoptotic function of these proteins in cancer cells and tumor tissues exhibiting Bcl-2 protein overexpression. In preferred embodiments, the small molecules of the present invention are active at the BH3 binding pocket of Bcl-2 family proteins (e.g., Bcl-2, Bcl-X L , and Mcl-1). The compositions and methods of the present invention are useful therapeutics for cancerous diseases either alone or in combination with chemotherapeutic or other drugs.

1 . A method for modulating apoptosis in a subject comprising administering to said subject a therapeutically effective amount of a compound selected from a group consisting of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts and enantiomers thereof.  
     
     
         2 . The method of  claim 1 , wherein said subject is a mammal.  
     
     
         3 . The method of  claim 1 , wherein said mammal is a human.  
     
     
         4 . The method of  claim 1 , wherein the amount administered is from about 0.1 mg/kg to about 1000 mg/kg.  
     
     
         5 . The method of  claim 1 , wherein the amount of said compound administered is from about 0.5 mg/kg to about 500 mg/kg.  
     
     
         6 . The method of  claim 1 , wherein the amount of said compound administered is from about 1 mg/kg to about 100 mg/kg.  
     
     
         7 . The method of  claim 1 , wherein said compound is administered daily.  
     
     
         8 . The method of  claim 1 , wherein said compound is administered twice a week.  
     
     
         9 . The method of  claim 1 , wherein said compound is administered orally, intraorally, rectally, parenterally, epicutaneously, topically, transdermally, subcutaneously, intramuscularly, intranasally, sublingually, intradurally, intraocularly, intrarespiratorally, intravenously, intraperitoneally, intrathecal, by oral inhalation, or nasal inhalation.  
     
     
         10 . The method of  claim 1 , wherein said compound is administered in dosage forms selected from the group consisting of tablets, pills, troches, dispersions, suspensions, solutions, capsules, patches, syrups, wafers, elixirs, gels, powders, magmas, lozenges, ointments, creams, pastes, plasters, lotions, discs, suppositories, nasal sprays, oral sprays and aerosols.  
     
     
         11 . The method of  claim 1 , wherein said compound is administered together with a pharmaceutically acceptable carrier.  
     
     
         12 . The method of  claim 1 , further comprising administering one or more chemotherapeutic drugs.  
     
     
         13 . The method of  claim 12 , wherein said chemotherapeutic drugs are selected from the group consisting of Docetaxel, Paclitaxel, Cisplatin, 5-FU, Doxorubincin, Epipodophyllotoxin, and cyclophosphamide, or combinations thereof.  
     
     
         14 . The method of  claim 12 , wherein said Docetaxel is the chemotherapeutic drug.  
     
     
         15 . The method of  claim 1 , wherein said modulating apoptosis comprises promoting apoptosis in a cell line selected from the group consisting of MCF-7; MDA-231, MDA-361, MDA-468, BJ474, MDA-435 HL-60 and T47C.  
     
     
         16 . The method of  claim 1 , wherein the compound is:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts and enantiomers thereof.  
     
     
         17 . A method for treating a disease characterized by the overexpression of a Bcl-2 family protein comprising administering to a subject an effective amount of a compound selected from the group consisting of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts and enantiomers thereof.  
     
     
         18 . The method of  claim 17 , wherein the compound is:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts and enantiomers thereof.  
     
     
         19 . The method of  claim 17 , wherein said disease is selected from the group consisting of: breast cancer; prostate cancer; lung cancer; lymphomas; skin cancer; pancreatic cancer; colon cancer; melanoma; ovarian cancer; brain cancer; head and neck cancer; liver cancer; bladder cancer; non-small lung cancer; cervical carcinoma; leukemia; neuroblastoma and glioblastoma; T and B cell mediated autoimmune diseases; inflammatory diseases; infections; hyperproliferative diseases; AIDS; degenerative conditions, and vascular diseases.  
     
     
         20 . The method of  claim 17 , wherein said Bcl-2 family protein is selected from the group consisting of Bcl-2, Bcl-X L , Mcl-1, A1/BFL-1, and BOO-DIVA.  
     
     
         21 . The method of  claim 17 , wherein said subject is a mammal.  
     
     
         22 . The method of  claim 21 , wherein said mammal is a human.  
     
     
         23 . The method of  claim 17 , wherein the amount of said compound administered is from about 0.1 mg/kg to about 1000 mg/kg.  
     
     
         24 . The method of  claim 17 , wherein the amount of said compound administered is from about 0.5 mg/kg to about 500 mg/kg.  
     
     
         25 . The method of  claim 17 , wherein the amount of said compound administered is from about 1 mg/kg to about 100 mg/kg.  
     
     
         26 . The method of  claim 17 , wherein said compound is administered daily.  
     
     
         27 . The method of  claim 17 , wherein said compound is administered twice a week.  
     
     
         28 . The method of  claim 17 , wherein said compound is administered orally, intraorally, rectally, parenterally, epicutaneously, topically, transdermally, subcutaneously, intramuscularly, intranasally, sublingually, intradurally, intraocularly, intrarespiratorally, intravenously, intraperitoneally, intrathecal, by oral inhalation, or nasal inhalation.  
     
     
         29 . The method of  claim 17 , wherein said compound is administered in dosage forms selected from the group consisting of tablets, pills, troches, dispersions, suspensions, solutions, capsules, patches, syrups, wafers, elixirs, gels, powders, magmas, lozenges, ointments, creams, pastes, plasters, lotions, discs, suppositories, nasal sprays, oral sprays and aerosols.  
     
     
         30 . The method of  claim 17 , wherein the compound is administered together with a pharmaceutically acceptable carrier.  
     
     
         31 . The method of  claim 17 , further comprising administering one or more chemotherapeutic drugs.  
     
     
         32 . The method of  claim 31 , wherein said chemotherapeutic drugs are selected from the group consisting of Docetaxel, Paclitaxel, Cisplatin, 5-FU, Doxorubincin, Epipodophyllotoxin, cyclophosphamide, or combinations thereof.  
     
     
         33 . The method of  claim 32 , wherein Docetaxel is the chemotherapeutic drug.  
     
     
         34 . A pharmaceutical composition comprising a compound selected from the group consisting of: Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, and Formula VII.  
     
     
         35 . The pharmaceutical composition of  claim 34 , wherein the compound is selected from the group consisting of: Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, or pharmaceutically acceptable salts and enantiomers thereof.  
     
     
         36 . A composition comprising a compound of formula:  
       
         
           
           
               
               
           
         
       
       wherein X and Y are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine and iodine; Z 1  and Z 2  are each independently O or S; A 1  and A 2  are each independently 1 to 3 substituents and selected from the group consisting of hydrogen, hydroxy, branched or straight chain (C 1 -C 6 )-alkyl, branched or straight chain (C 2 -C 6 )-alkenyl, (C 3 -C 8 )-cycloalkyl, phenyl, aryl, (C 1 -C 6 )-alkoxy, CZ 3  (wherein Z is selected from the group consisting of F, Cl, Br and I), NH 2 , NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 , NO 2 , CN, COHO, COO(C 1 -C 6 )alkyl, COHN, COHN(C 1 -C 6 )alkyl, CON((C 1 -C 6 )alkyl) 2 , O—(C 1 -C 6 )alkyl (where one, more than one or all hydrogen(s) in the alkyl radicals may be replaced by fluorine, or one hydrogen may be replaced by OH, OC(O)CH 3 , OC(O)H, O—CH 2 -Ph, NH 2 NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 , NH—CO—CH 3  or N(COOCH 2 Ph) 2 ), SO 2 —NH 2 , SO 2 NH(C 1 -C 6 )alkyl, SO 2 N((C 1 -C 6 )alkyl) 2 , S—(C 1 -C 6 )alkyl, S—(CH 2 ) n -phenyl, SO—(C 1 -C 6 )-alkyl, SO—(CH 2 ) n -phenyl, SO 2 —(C 1 -C 6 )-alkyl, SO 2 —(CH 2 ) n -phenyl (where n is 0-6 and the phenyl radical may be substituted up to two times by F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, NH 2 , NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 ), NH(C 1 -C 7 )-acyl, phenyl, biphenylyl, O—(CH 2 ) n -phenyl (where n is 0-6), 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-furanyl, 2- or 3-thienyl (wherein the phenyl, biphenylyl, naphthyl, pyridyl, furanyl, thienyl rings may be optionally substituted up to 3 times by F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, NH 2 , NH(C 1 -C 6 )-alkyl, N((C 1 -C 6 )-alkyl) 2 , SO 2 —CH 3 , COOH, COO—(C 1 -C 6 )-alkyl or CONH 2 ), 1,2,3-triazol-5-yl (wherein the triazol ring may be optionally substituted in position 1, 2 or 3 by methyl or benzyl) or tetrazol-5-yl (wherein the tetrazol ring may be optionally substituted in position I or 2 by methyl or benzyl); B 1 , B 2 , B 3  and B 4  are each independently 1 to 2 substituents and selected from the group consisting of hydrogen, hydroxy, branched or straight chain (C 1 -C 6 )-alkyl, branched or straight chain (C 2 -C 6 )-alkenyl, (C 3 -C 8 )-cycloalkyl, phenyl, aryl, (C 1 -C 6 )-alkoxy, CZ 3  (wherein Z is selected from the group consisting of F, Cl, Br and I), NH 2 , NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 , NO 2 , CN, COOH, COO(C 1 -C 6 )alkyl, CONH 2 , CONH(C 1 -C 6 )alkyl, CON((C 1 -C 6 )alkyl) 2 , O—(C 1 -C 6 )alkyl (where one, more than one or all hydrogen(s) in the alkyl radicals may be replaced by fluorine, or one hydrogen may be replaced by OH, OC(O)CH 3 , OC(O)H, O—CH 2 -Ph, NH 2 , NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 , NH—CO—CH 3  or N(COOCH 2 Ph) 2 ), SO 2 —NH 2 , SO 2 NH(C 1 -C 6 )alkyl, SO 2 N((C 1 -C 6 )alkyl) 2 , S—(C 1 -C 6 )alkyl, S—(CH 2 ) n -phenyl, SO—(C 1 -C 6 )-alkyl, SO—(CH 2 ) n -phenyl, SO 2 —(C 1 -C 6 )-alkyl, SO 2 —(CH 2 ) n -phenyl (where n is 0-6 and the phenyl radical may be substituted up to two times by F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, NH 2 , NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 ), NH(C 1 -C 7 )-acyl, phenyl, biphenylyl, O—(CH 2 ) n -phenyl (where n is 0-6), 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-furanyl, 2- or 3-thienyl (wherein the phenyl, biphenylyl, naphthyl, pyridyl, furanyl, thienyl rings may be optionally substituted up to 3 times by F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, NH 2 , NH(C 1 -C 6 )-alkyl, N((C 1 -C 6 )-alkyl) 2 , SO 2 —CH 3 , COOH, COO—(C 1 -C 6 )-alkyl or CONH 2 ), 1,2,3-triazol-5-yl (wherein the triazol ring may be optionally substituted in position 1, 2 or 3 by methyl or benzyl) or tetrazol-5-yl (wherein the tetrazol ring may be optionally substituted in position  1  or  2  by methyl or benzyl); and pharmaceutically acceptable salts and derivatives thereof.  
     
     
         37 . The composition of  claim 36 , wherein said compound modulates apoptosis in a cell or tissue.  
     
     
         38 . The composition of  claim 37 , wherein said modulation of apoptosis comprising promoting apoptosis.  
     
     
         39 . A composition comprising a compound of formula:  
       
         
           
           
               
               
           
         
       
       wherein X and Y are each independently hydrogen, OR or OR 1 ; wherein R and R 1  are each independently hydrogen, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 3 -C 8 )-cycloalkyl, phenyl or trifluoromethyl; wherein R 2 , R 3 , R 4  and R 5  are each independently hydrogen, hydroxy, branched or straight chain (C 1 -C 6 )-alkyl, branched or straight chain (C 2 -C 6 )-alkenyl, (C 3 -C 8 )-cycloalkyl, phenyl, aryl, (C 1 -C 6 )-alkoxy, CZ 3  (wherein Z is selected from the group consisting of F, Cl, Br and I), NH 2 , NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 , NO 2 , CN, COOH, COO(C 1 -C 6 )alkyl, CONH 2 , CONH(C 1 -C 6 )alkyl, CON((C 1 -C 6 )alkyl) 2 , O—(C 1 -C 6 )alkyl (where one, more than one or all hydrogen(s) in the alkyl radicals may be replaced by fluorine, or one hydrogen may be replaced by OH, OC(O)CH 3 , OC(O)H, O—CH 2 -Ph, NH 2 , NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 , NH—CO—CH 3  or N(COOCH 2 Ph) 2 ), SO 2 —NH 2 , SO 2 NH(C 1 -C 6 )alkyl, SO 2 N((C 1 -C 6 )alkyl) 2 , S—(C 1 -C 6 )alkyl, S—(CH 2 )n-phenyl, SO—(C 1 -C 6 )-alkyl, SO—(CH 2 ) n -phenyl, SO 2 —(C 1 -C 6 )-alkyl, SO 2 —(CH2) n -phenyl (where n is 0-6 and the phenyl radical may be substituted up to two times by F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, NH 2 , NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 ), NH(C 1 -C 7 )-acyl, phenyl, biphenylyl, O—(CH 2 ) n -phenyl (where n is 0-6), 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-furanyl, 2- or 3-thienyl (wherein the phenyl, biphenylyl, naphthyl, pyridyl, furanyl, thienyl rings may be optionally substituted up to 3 times by F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, NH 2 , NH(C 1 -C 6 )-alkyl, N((C 1 -C 6 )-alkyl) 2 , SO 2 —CH 3 , COOH, COO—(C 1 -C 6 )-alkyl or CONH 2 ), 1,2,3-triazol-5-yl (wherein the triazol ring may be optionally substituted in position 1, 2 or 3 by methyl or benzyl) or tetrazol-5-yl (wherein the tetrazol ring may be optionally substituted in position  1  or  2  by methyl or benzyl); A and A 1  are each independently 1 to 3 substituents selected from the group consisting of hydrogen, hydroxy, branched or straight chain (C 1 -C 6 )-alkyl, branched or straight chain (C 2 -C 6 )-alkenyl, (C 3 -C 8 )-cycloalkyl, phenyl, aryl, (C 1 -C 6 )-alkoxy, CZ 3  (wherein Z is selected from the group consisting of F, Cl, Br and I), NH 2 , NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 , NO 2 , CN, COOH, COO(C 1 -C 6 )alkyl, CONH 2 , CONH(C 1 -C 6 )alkyl, CON((C 1 -C 6 )alkyl) 2 , O—(C 1 -C 6 )alkyl (where one, more than one or all hydrogen(s) in the alkyl radicals may be replaced by fluorine, or one hydrogen may be replaced by OH, OC(O)CH 3 , OC(O)H, O—CH 2 -Ph, NH 2 , NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 , NH—CO—CH 3  or N(COOCH 2 Ph) 2 ), SO 2 —NH 2 , SO 2 NH(C 1 -C 6 )alkyl, SO 2 N((C 1 -C 6 )alkyl) 2 , S—(C 1 -C 6 )alkyl, S—(CH 2 ) n -phenyl, SO—(C 1 -C 6 )-alkyl, SO—(CH 2 ) n -phenyl, SO 2 —(C 1 -C 6 )-alkyl, SO 2 —(CH 2 ) n -phenyl (where n is 0-6 and the phenyl radical may be substituted up to two times by F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, NH 2 , NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 ), NH(C 1 -C 7 )-acyl, phenyl, biphenylyl, O—(CH 2 ) n -phenyl (where n is 0-6), 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-furanyl, 2- or 3-thienyl (wherein the phenyl, biphenylyl, naphthyl, pyridyl, furanyl, thienyl rings may be optionally substituted up to 3 times by F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, NH 2 NH(C 1 -C 6 )-alkyl, N((C 1 -C 6 )-alkyl) 2 , SO 2 —CH 3 , COOH, COO—(C 1 -C 6 )-alkyl or CONH 2 ), 1,2,3-triazol-5-yl (wherein the triazol ring may be optionally substituted in position 1, 2 or 3 by methyl or benzyl) or tetrazol-5-yl (wherein the tetrazol ring may be optionally substituted in position  1  or  2  by methyl or benzyl); and pharmaceutically acceptable salts and derivatives thereof.  
     
     
         40 . The composition of  claim 39 , wherein said compound modulates apoptosis in a cell or tissue.  
     
     
         41 . The composition of  claim 40 , wherein said modulation of apoptosis comprises promoting apoptosis.  
     
     
         42 . A composition comprising a compound of formula:  
       
         
           
           
               
               
           
         
       
       wherein R is selected from the group consisting of NH 2 , NH((C 1 -C 6 )alkyl) and N((C 1 -C 6 )alkyl) 2 ; A 1  is 1 to 4 substituents selected from the group consisting of hydrogen, hydroxy, branched or straight chain (C 1 -C 6 )-alkyl, branched or straight chain (C 2 -C 6 )-alkenyl, (C 3 -C 8 )-cycloalkyl, phenyl, aryl, (C 1 -C 6 )-alkoxy, CZ 3  (wherein Z is selected from the group to consisting of F, Cl, Br and I), NH 2 , NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 , NO 2 , CN, COOH, COO(C 1 -C 6 )alkyl, CONH 2 , CONH(C 1 -C 6 )alkyl, CON((C 1 -C 6 )alkyl) 2 , O—(C 1 -C 6 )alkyl (where one, more than one or all hydrogen(s) in the alkyl radicals may be replaced by fluorine, or one hydrogen may be replaced by OH, OC(O)CH 3 , OC(O)H, O—CH 2 -Ph, NH 2 , NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 , NH—CO—CH 3  or N(COOCH 2 Ph) 2 ), SO 2 —NH 2 , SO 2 NH(C 1 -C 6 )alkyl, SO 2 N((C 1 -C 6 )alkyl) 2 , S—(C 1 -C 6 )alkyl, S—(CH 2 ) n -phenyl, SO—(C 1 -C 6 )-alkyl, SO—(CH 2 ) n -phenyl, SO 2 —(C 1 -C 6 )-alkyl, SO 2 —(CH 2 ) n -phenyl (where n is 0-6 and the phenyl radical may be substituted up to two times by F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, NH 2 , NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 ), NH(C 1 -C 7 )-acyl, phenyl, biphenylyl, O—(CH 2 ) n -phenyl (where n is 0-6), 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-furanyl, 2- or 3-thienyl (wherein the phenyl, biphenylyl, naphthyl, pyridyl, furanyl, thienyl rings may be optionally substituted up to 3 times by F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, NH 2 , NH(C 1 -C 6 )-alkyl, N((C 1 -C 6 )-alkyl) 2 , SO 2 —CH 3 , COOH, COO—(C 1 -C 6 )-alkyl or CONH 2 ), 1,2,3-triazol-5-yl (wherein the triazol ring may be optionally substituted in position 1, 2 or 3 by methyl or benzyl) or tetrazol-5-yl (wherein the tetrazol ring may be optionally substituted in position  1  or  2  by methyl or benzyl); A 2  is 1 to 5 substituents selected from the group consisting of hydrogen, hydroxy, branched or straight chain (C 1 -C 6 )-alkyl, branched or straight chain (C 2 -C 6 )-alkenyl, (C 3 -C 8 )-cycloalkyl, phenyl, aryl, (C 1 -C 6 )-alkoxy, CZ 3  (wherein Z is selected from the group consisting of F, Cl, Br and I), NH 2 , NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 , NO 2 , CN, COOH, COO(C 1 -C 6 )alkyl, CONH 2 , CONH(C 1 -C 6 )alkyl, CON((C 1 -C 6 )alkyl) 2 , O—(C 1 -C 6 )alkyl (where one, more than one or all hydrogen(s) in the alkyl radicals may be replaced by fluorine, or one hydrogen may be replaced by OH, OC(O)CH 3 , OC(O)H, O—CH 2 -Ph, NH 2 , NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 , NH—CO—CH 3  or N(COOCH 2 Ph) 2 ), SO 2 —NH 2 , SO 2 NH(C 1 -C 6 )alkyl, SO 2 N((C 1 -C 6 )alkyl) 2 , S—(C 1 -C 6 )alkyl, S—(CH 2 ) n -phenyl, SO—(C 1 -C 6 )-alkyl, SO—(CH 2 ) n -phenyl, SO 2 —(C 1 -C 6 )-alkyl, SO 2 —(CH 2 ) n -phenyl (where n is 0-6 and the phenyl radical may be substituted up to two times by F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, NH 2 , NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 ), NH(C 1 -C 7 )-acyl, phenyl, biphenylyl, O—(CH 2 ) n -phenyl (where n is 0-6), 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-furanyl, 2- or 3-thienyl (wherein the phenyl, biphenylyl, naphthyl, pyridyl, furanyl, thienyl rings may be optionally substituted up to 3 times by F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, NH 2 , NH(C 1 -C 6 )-alkyl, N((C 1 -C 6 )-alkyl) 2 , SO 2 —CH 3 , COOH, COO—(C 1 -C 6 )-alkyl or CONH 2 ), 1,2,3-triazol-5-yl (wherein the triazol ring may be optionally substituted in position 1, 2 or 3 by methyl or benzyl) or tetrazol-5-yl (wherein the tetrazol ring may be optionally substituted in position  1  or  2  by methyl or benzyl); or a pharmaceutically acceptable salt thereof.  
     
     
         43 . The composition of  claim 42 , wherein said compound modulates apoptosis in a cell or tissue.  
     
     
         44 . The composition of  claim 43 , wherein said modulation of apoptosis comprises promoting apoptosis.  
     
     
         45 . A composition comprising a compound of formula:  
       
         
           
           
               
               
           
         
       
       wherein, Z is O or S; X is selected from the group consisting of hydrogen and OR, wherein R is selected from the group consisting of hydrogen, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 3 -C 8 )-cycloalkyl, phenyl and trifluoromethyl; A 1  and A 2  are each independently 1 to 3 substituents selected from the group consisting of hydrogen, hydroxy, branched or straight chain (C 1 -C 6 )-alkyl, branched or straight chain (C 2 -C 6 )-alkenyl, (C 3 -C 8 )-cycloalkyl, phenyl, aryl, (C 1 -C 6 )-alkoxy, CZ 3  (wherein Z is selected from the group consisting of F, Cl, Br and I), NH 2 , NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 , NO 2 , CN, COOH, COO(C 1 -C 6 )alkyl, CONH 2 , CONH(C 1 -C 6 )alkyl, CON((C 1 -C 6 )alkyl) 2 , O—(C 1 -C 6 )alkyl (where one, more than one or all hydrogen(s) in the alkyl radicals may be replaced by fluorine, or one hydrogen may be replaced by OH, OC(O)CH 3 , OC(O)H, O—CH 2 -Ph, NH 2 , NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 , NH—CO—CH 3  or N(COOCH 2 Ph) 2 ), SO 2 —NH 2 , SO 2 NH(C 1 -C 6 )alkyl, SO 2 N((C 1 -C 6 )alkyl) 2 , S—(C 1 -C 6 )alkyl, S—(CH 2 ) n -phenyl, SO—(C 1 -C 6 )-alkyl, SO—(CH 2 ) n -phenyl, SO 2 —(C 1 -C 6 )-alkyl, SO 2 —(CH 2 ) n -phenyl (where n is 0-6 and the phenyl radical may be substituted up to two times by F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, NH 2 , NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 ), NH(C 1 -C 7 )-acyl, phenyl, biphenylyl, O—(CH 2 ) n -phenyl (where n is 0-6), 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-furanyl, 2- or 3-thienyl (wherein the phenyl, biphenylyl, naphthyl, pyridyl, furanyl, thienyl rings may be optionally substituted up to 3 times by F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, NH 2 , NH(C 1 -C 6 )-alkyl, N((C 1 -C 6 )-alkyl) 2 , SO 2 —CH 3 , COOH, COO—(C 1 -C 6 )-alkyl or CONH 2 ), 1,2,3-triazol-5-yl (wherein the triazol ring may be optionally substituted in position 1, 2 or 3 by methyl or benzyl) or tetrazol-5-yl (wherein the tetrazol ring may be optionally substituted in position  1  or  2  by methyl or benzyl); and pharmaceutically acceptable salts and derivatives thereof.  
     
     
         46 . The composition of  claim 45 , wherein said compound modulates apoptosis in a cell or tissue.  
     
     
         47 . The composition of  claim 46 , wherein said modulation of apoptosis comprises promoting apoptosis.  
     
     
         48 . A composition comprising a compound of formula:  
       
         
           
           
               
               
           
         
       
       wherein Z is O or S; A 1  and A 2  are each independently 1 or 2 substituents selected from the group consisting of hydrogen, hydroxy, branched or straight chain (C 1 -C 6 )-alkyl, branched or straight chain (C 2 -C 6 )-alkenyl, (C 3 -C 8 )-cycloalkyl, phenyl, aryl, (C 1 -C 6 )-alkoxy, CZ 3  (wherein Z is selected from the group consisting of F, Cl, Br and I), NH 2 , NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 , NO 2 , CN, COOH, COO(C 1 -C 6 )alkyl, CONH 2 , CONH(C 1 -C 6 )alkyl, CON((C 1 -C 6 )alkyl) 2 , O—(C 1 -C 6 )alkyl (where one, more than one or all hydrogen(s) in the alkyl radicals may be replaced by fluorine, or one hydrogen may be replaced by OH, OC(O)CH 3 , OC(O)H, O—CH 2 -Ph, NH 2 , NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 , NH—CO—CH 3  or N(COOCH 2 Ph) 2 ), SO 2 —NH 2 SO 2 NH(C 1 -C 6 )alkyl, SO 2 N((C 1 -C 6 )alkyl) 2 , S—(C 1 -C 6 )alkyl, S—(CH 2 ) n -phenyl, SO—(C 1 -C 6 )-alkyl, SO—(CH 2 ) n -phenyl, SO 2 —(C 1 -C 6 )-alkyl, SO 2 —(CH 2 ) n -phenyl (where n is 0-6 and the phenyl radical may be substituted up to two times by F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, NH 2 , NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 ), NH(C 1 -C 7 )-acyl, phenyl, biphenylyl, O—(CH 2 ) n -phenyl (where n is 0-6), 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-furanyl, 2- or 3-thienyl (wherein the phenyl, biphenylyl, naphthyl, pyridyl, furanyl, thienyl rings may be optionally substituted up to 3 times by F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, NH 2 , NH(C 1 -C 6 )-alkyl, N((C 1 -C 6 )-alkyl) 2 , SO 2 —CH 3 , COOH, COO—(C 1 -C 6 )-alkyl or CONH 2 ), 1,2,3-triazol-5-yl (wherein the triazol ring may be optionally substituted in position 1, 2 or 3 by methyl or benzyl) or tetrazol-5-yl (wherein the tetrazol ring may be optionally substituted in position  1  or  2  by methyl or benzyl); B 1  and B 2  are each independently I to 3 substituents selected from the group consisting of hydrogen, hydroxy, branched or straight chain (C 1 -C 6 )-alkyl, branched or straight chain (C 2 -C 6 )-alkenyl, (C 3 -C 8 )-cycloalkyl, phenyl, aryl, (C 1 -C 6 )-alkoxy, CZ 3  (wherein Z is selected from the group consisting of F, Cl, Br and I), NH 2 , NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 , NO 2 , CN, COOH, COO(C 1 -C 6 )alkyl, CONH 2 , CONH(C 1 -C 6 )alkyl, CON((C 1 -C 6 )alkyl) 2 , O—(C 1 -C 6 )alkyl (where one, more than one or all hydrogen(s) in the alkyl radicals may be replaced by fluorine, or one hydrogen may be replaced by OH, OC(O)CH 3 , OC(O)H, O—CH 2 -Ph, NH 2 , NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 , NH—CO—CH 3  or N(COOCH 2 Ph) 2 ), SO 2 —NH 2 , SO 2 NH(C 1 -C 6 )alkyl, SO 2 N((C 1 -C 6 )alkyl) 2 , S—(C 1 -C 6 )alkyl, S—(CH 2 ) n -phenyl, SO—(C 1 -C 6 )-alkyl, SO—(CH 2 ) n -phenyl, SO 2 —(C 1 -C 6 )-alkyl, SO 2 —(CH 2 ) n -phenyl (where n is 0-6 and the phenyl radical may be substituted up to two times by F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, NH 2 , NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 ), NH(C 1 -C 7 )-acyl, phenyl, biphenylyl, O—(CH 2 ) n -phenyl (where n is 0-6), 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-furanyl, 2- or 3-thienyl (wherein the phenyl, biphenylyl, naphthyl, pyridyl, furanyl, thienyl rings may be optionally substituted up to 3 times by F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, NH 2 , NH(C 1 -C 6 )-alkyl, N((C 1 -C 6 )-alkyl) 2 , SO 2 —CH 3 , COOH, COO—(C 1 -C 6 )-alkyl or CONH 2 ), 1,2,3-triazol-5-yl (wherein the triazol ring may be optionally substituted in position 1, 2 or 3 by methyl or benzyl) or tetrazol-5-yl (wherein the tetrazol ring may be optionally substituted in position  1  or  2  by methyl or benzyl); D 1  and D 2  are each independently 1 to 4 substituents selected from the group consisting of hydrogen, hydroxy, branched or straight chain (C 1 -C 6 )-alkyl, branched or straight chain (C 2 -C 6 )-alkenyl, (C 3 -C 8 )-cycloalkyl, phenyl, aryl, (C 1 -C 6 )-alkoxy, CZ 3  (wherein Z is selected from the group consisting of F, Cl, Br and I), NH 2 , NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 , NO 2 , CN, COOH, COO(C 1 -C 6 )alkyl, CONH 2 , CONH(C 1 -C 6 )alkyl, CON((C 1 -C 6 )alkyl) 2 , O—(C 1 -C 6 )alkyl (where one, more than one or all hydrogen(s) in the alkyl radicals may be replaced by fluorine, or one hydrogen may be replaced by OH, OC(O)CH 3 , OC(O)H, O—CH 2 -Ph, NH 2 , NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 , NH—CO—CH 3  or N(COOCH 2 Ph) 2 ), SO 2 —NH 2 SO 2 NH(C 1 -C 6 )alkyl, SO 2 N((C 1 -C 6 )alkyl) 2 , S—(C 1 -C 6 )alkyl, S—(CH 2 ) n -phenyl, SO—(C 1 -C 6 )-alkyl, SO—(CH 2 ) n -phenyl, SO 2 —(C 1 -C 6 )-alkyl, SO 2 —(CH 2 ) n -phenyl (where n is 0-6 and the phenyl radical may be substituted up to two times by F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, NH 2 , NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 ), NH(C 1 -C 7 )-acyl, phenyl, biphenylyl, O—(CH 2 ) n -phenyl (where n is 0-6), 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-furanyl, 2- or 3-thienyl (wherein the phenyl, biphenylyl, naphthyl, pyridyl, furanyl, thienyl rings may be optionally substituted up to 3 times by F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, NH 2 , NH(C 1 -C 6 )-alkyl, N((C 1 -C 6 )-alkyl) 2 , SO 2 —CH 3 , COOH, COO—(C 1 -C 6 )-alkyl or CONH 2 ), 1,2,3-triazol-5-yl (wherein the triazol ring may be optionally substituted in position 1, 2 or 3 by methyl or benzyl) or tetrazol-5-yl (wherein the tetrazol ring may be optionally substituted in position  1  or  2  by methyl or benzyl); and pharmaceutically acceptable salts and derivatives thereof.  
     
     
         49 . The composition of  claim 48 , wherein said compound modulates apoptosis in a cell or tissue.  
     
     
         50 . The composition of  claim 49 , wherein said modulation of apoptosis comprises promoting apoptosis.  
     
     
         51 . A composition comprising a compound of formula:  
       
         
           
           
               
               
           
         
       
       wherein X and Y are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine and iodine; A 1  and A 2  are each independently 1 to 3 substituents selected from the group consisting of hydrogen, hydroxy, branched or straight chain (C 1 -C 6 )-alkyl, branched or straight chain (C 2 -C 6 )-alkenyl, (C 3 -C 8 )-cycloalkyl, phenyl, aryl, (C 1 -C 6 )-alkoxy, CZ 3  (wherein Z is selected from the group consisting of F, Cl, Br and I), NH 2 , NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 , NO 2 , CN, COOH, COO(C 1 -C 6 )alkyl, CONH 2 , CONH(C 1 -C 6 )alkyl, CON((C 1 -C 6 )alkyl) 2 , O—(C 1 -C 6 )alkyl (where one, more than one or all hydrogen(s) in the alkyl radicals may be replaced by fluorine, or one hydrogen may be replaced by OH, OC(O)CH 3 , OC(O)H, O—CH 2 -Ph, NH 2 , NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 , NH—CO—CH 3  or N(COOCH 2 Ph) 2 ), SO 2 —NH 2 , SO 2 NH(C 1 -C 6 )alkyl, SO 2 N((C 1 -C 6 )alkyl) 2 , S—(C 1 -C 6 )alkyl, S—(CH 2 ) n -phenyl, SO-(C 1 -C 6 )-alkyl, SO—(CH 2 ) n -phenyl, SO 2 —(C 1 -C 6 )-alkyl, SO 2 —(CH 2 ) n -phenyl (where n is 0-6 and the phenyl radical may be substituted up to two times by F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, NH 2 , NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 ), NH(C 1 -C 7 )-acyl, phenyl, biphenylyl, O—(CH 2 ) n -phenyl (where n is 0-6), 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-furanyl, 2- or 3-thienyl (wherein the phenyl, biphenylyl, naphthyl, pyridyl, furanyl, thienyl rings may be optionally substituted up to 3 times by F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, NH 2 , NH(C 1 -C 6 )-alkyl, N((C 1 -C 6 )-alkyl) 2 , SO 2 —CH 3 , COOH, COO—(C 1 -C 6 )-alkyl or CONH 2 ), 1,2,3-triazol-5-yl (wherein the triazol ring may be optionally substituted in position 1, 2 or 3 by methyl or benzyl) or tetrazol-5-yl (wherein the tetrazol ring may be optionally substituted in position  1  or  2  by methyl or benzyl); B 1  and B 2  are each independently 1 to 3 substituents selected from the group consisting of hydrogen, hydroxy, branched or straight chain (C 1 -C 6 )-alkyl, branched or straight chain (C 2 -C 6 )-alkenyl, (C 3 -C 8 )-cycloalkyl, phenyl, aryl, (C 1 -C 6 )-alkoxy, CZ 3  (wherein Z is selected from the group consisting of F, Cl, Br and I), NH 2 , NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 , NO 2 , CN, COOH, COO(C 1 -C 6 )alkyl, CONH 2 , CONH(C 1 -C 6 )alkyl, CON((C 1 -C 6 )alkyl) 2 , O—(C 1 -C 6 )alkyl (where one, more than one or all hydrogen(s) in the alkyl radicals may be replaced by fluorine, or one hydrogen may be replaced by OH, OC(O)CH 3 , OC(O)H, O—CH 2 -Ph, NH 2 , NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 , NH—CO—CH 3  or N(COOCH 2 Ph) 2 ), SO 2 —NH 2 , SO 2 NH(C 1 -C 6 )alkyl, SO 2 N((C 1 -C 6 )alkyl) 2 , S—(C 1 -C 6 )alkyl, S—(CH 2 ) n -phenyl, SO—(C 1 -C 6 )-alkyl, SO—(CH 2 ) 1 -phenyl, SO 2 —(C 1 -C 6 )-alkyl, SO 2 —(CH 2 ) n -phenyl (where n is 0-6 and the phenyl radical may be substituted up to two times by F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, NH 2 , NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 ), NH(C 1 -C 7 )-acyl, phenyl, biphenylyl, O—(CH 2 ) n -phenyl (where n is 0-6), 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-furanyl, 2- or 3-thienyl (wherein the phenyl, biphenylyl, naphthyl, pyridyl, furanyl, thienyl rings may be optionally substituted up to 3 times by F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, NH 2 , NH(C 1 -C 6 )-alkyl, N((C 1 -C 6 )-alkyl) 2 , SO 2 —CH 3 , COOH, COO—(C 1 -C 6 )-alkyl or CONH 2 ), 1,2,3-triazol-5-yl (wherein the triazol ring may be optionally substituted in position 1, 2 or 3 by methyl or benzyl) or tetrazol-5-yl (wherein the tetrazol ring may be optionally substituted in position  1  or  2  by methyl or benzyl); and pharmaceutically acceptable salts and derivatives thereof.  
     
     
         52 . The composition of  claim 51 , wherein said compound modulates apoptosis in a cell or tissue.  
     
     
         53 . The composition of  claim 52 , wherein said modulation of apoptosis comprises promoting apoptosis.  
     
     
         54 . A composition comprising a compound of formula:  
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  are each independently hydrogen, OR 3  or OR4, NH 2 , NH((C 1 -C 6 )alkyl) or N((C 1 -C 6 )alkyl) 2 ; wherein R 3  and R 4  are each independently hydrogen, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 3 -C 8 )-cycloalkyl, phenyl or trifluoromethyl; A 1  and A 2  are each independently 1 to 4 substituents selected from the group consisting of hydrogen, hydroxy, branched or straight chain (C 1 -C 6 )-alkyl, branched or straight chain (C 2 -C 6 )-alkenyl, (C 3 -C 8 )-cycloalkyl, phenyl, aryl, (C 1 -C 6 )-alkoxy, CZ 3  (wherein Z is selected from the group consisting of F, Cl, Br and I), NH 2 , NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 , NO 2 , CN, COOH, COO(C 1 -C 6 )alkyl, CONH 2 , CONH(C 1 -C 6 )alkyl, CON((C 1 -C 6 )alkyl) 2 , O—(C 1 -C 6 )alkyl (where one, more than one or all hydrogen(s) in the alkyl radicals may be replaced by fluorine, or one hydrogen may be replaced by OH, OC(O)CH 3 , OC(O)H, O—CH 2 -Ph, NH 2 , NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 , NH—CO—CH 3  or N(COOCH 2 Ph) 2 ), SO 2 —NH 2 , SO 2 NH(C 1 -C 6 )alkyl, SO 2 N((C 1 -C 6 )alkyl) 2 , S—(C 1 -C 6 )alkyl, S—(CH 2 ) n -phenyl, SO—(C 1 -C 6 )-alkyl, SO—(CH 2 ) n -phenyl, SO 2 —(C 1 -C 6 )-alkyl, SO 2 —(CH 2 ) n -phenyl (where n is 0-6 and the phenyl radical may be substituted up to two times by F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, NH 2 , NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 ), NH(C 1 -C 7 )-acyl, phenyl, biphenylyl, O—(CH 2 ) n -phenyl (where n is 0-6), 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-furanyl, 2- or 3-thienyl (wherein the phenyl, biphenylyl, naphthyl, pyridyl, furanyl, thienyl rings may be optionally substituted up to 3 times by F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O-(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, NH 2 , NH(C 1 -C 6 )-alkyl, N((C 1 -C 6 )-alkyl) 2 , SO 2 —CH 3 , COOH, COO—(C 1 -C 6 )-alkyl or CONH 2 ), 1,2,3-triazol-5-yl (wherein the triazol ring may be optionally substituted in position 1, 2 or 3 by methyl or benzyl) or tetrazol-5-yl (wherein the tetrazol ring may be optionally substituted in position  1  or  2  by methyl or benzyl); B is 1 or 2 substituents selected from the group consisting of hydrogen, hydroxy, branched or straight chain (C 1 -C 6 )-alkyl, branched or straight chain (C 2 -C 6 )-alkenyl, (C 3 -C 8 )-cycloalkyl, phenyl, aryl, (C 1 -C 6 )-alkoxy, CZ 3  (wherein Z is selected from the group consisting of F, Cl, Br and I), NH 2 , NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 , NO 2 , CN, COOH, COO(C 1 -C 6 )alkyl, CONH 2 , CONH(C 1 -C 6 )alkyl, CON((C 1 -C 6 )alkyl) 2 , O—(C 1 -C 6 )alkyl (where one, more than one or all hydrogen(s) in the alkyl radicals may be replaced by fluorine, or one hydrogen may be replaced by OH, OC(O)CH 3 , OC(O)H, O—CH 2 -Ph, NH 2 , NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 , NH—CO—CH 3  or N(COOCH 2 Ph) 2 ), SO 2 —NH 2 , SO 2 NH(C 1 -C 6 )alkyl, SO 2 N((C 1 -C 6 )alkyl) 2 , S—(C 1 -C 6 )alkyl, S—(CH 2 ) n -phenyl, SO—(C 1 -C 6 )-alkyl, SO—(CH 2 ) n -phenyl, SO 2 —(C 1 -C 6 )-alkyl, SO 2 —(CH 2 ) n -phenyl (where n is 0-6 and the phenyl radical may be substituted up to two times by F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, NH 2 , NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 ), NH(C 1 -C 7 )-acyl, phenyl, biphenylyl, O—(CH 2 ) n -phenyl (where n is 0-6), 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-furanyl, 2- or 3-thienyl (wherein the phenyl, biphenylyl, naphthyl, pyridyl, furanyl, thienyl rings may be optionally substituted up to 3 times by F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, NH 2 , NH(C 1 -C 6 )-alkyl, N((C 1 -C 6 )-alkyl) 2 , SO 2 —CH 3 , COOH, COO—(C 1 -C 6 )-alkyl or CONH 2 ), 1,2,3-triazol-5-yl (wherein the triazol ring may be optionally substituted in position 1, 2 or 3 by methyl or benzyl) or tetrazol-5-yl (wherein the tetrazol ring may be optionally substituted in position  1  or  2  by methyl or benzyl); and pharmaceutically acceptable salts and derivatives thereof.  
     
     
         55 . The composition of  claim 54 , wherein said compound modulates apoptosis in a cell or tissue.  
     
     
         56 . The composition of  claim 55 , wherein said modulation of apoptosis comprises promoting apoptosis.