Dimeric small molecule potentiators of apoptosis

Abstract

Caspase activity and apoptosis are promoted using active, dimeric Smac peptide mimetics of the general formula M1-L-M2, wherein moieties M1 and M2 are monomeric Smac mimetics and L is a covalent linker. Target cancerous or inflammatory cells are contacted with an effective amount of an active, dimeric Smac mimetic, and a resultant increase in apoptosis of the target cells is detected. The contacting step may be effected by administering to a pharmaceutical composition comprising a therapeutically effective amount of The compoundic mimetic, wherein the individual may be subject to concurrent or antecedent radiation or chemotherapy for treatment of a neoproliferative pathology.

What is claimed is: 
     
       1. A pro-apoptotic Smac (second mitochondria-derived activator of caspases) peptide mimetic dimeric compound of the general formula M1-L-M2, wherein moieties M1 and M2 are monomeric Smac mimetics and L is a linker covalently linking M1 and M2 in the active dimeric compound, wherein M1-L-M2 is of formula II, 
       
         
           
           
               
               
           
         
       
       wherein:
 R1 and R1′ are selected from hydrogen, optionally substituted methyl, and hydroxyl; 
 R2 and R2′ are selected from optionally substituted methyl and optionally substituted ethyl; 
 R3 and R3′ are selected from CH2, NH, O and S; 
 R4 and R4′ are selected from CH and N; 
 R5-R8, and R5′-R8′ are selected from hydrogen, optionally hetero-, optionally substituted alkyl, optionally hetero-, optionally substituted alkenyl, optionally hetero-, optionally substituted alkynyl, optionally hetero-, optionally substituted aryl, wherein optionally either R6 and R7 as well as R6′ and R7′ or R7 and R8 as well as R7′ and R8′ are connected in 5- to 8-membered rings; and 
 L is a contiguous chain of between 2 and 200 atoms, having a MW between 20 D and 2 KD that can incorporate substitution, heteroatoms, unsaturation and cyclic aromatic and heteroaromatic portions, 
 or a pharmaceutically-acceptable salt thereof. 
 
     
     
       2. The compound of  claim 1  wherein:
 R1 and R1′ are selected from hydrogen and methyl; 
 R2 and R2′ are selected from methyl and ethyl; 
 R3 and R3′ are NH; 
 R4 and R4′ are CH; 
 R5 and R5′ are methyl, ethyl, propyl or butyl; and 
 R6 and R7, and R6 and R7, are connected in 5-membered pyrrolidinyl rings, 
 
       or a pharmaceutically-acceptable salt thereof. 
     
     
       3. The compound of  claim 1  wherein:
 R1 and R1′ are selected from hydrogen and methyl; 
 R2 and R2′ are selected from methyl and ethyl; 
 R3 and R3′ are NH; 
 R4 and R4′ are CH; 
 R5 and R5′ are methyl, ethyl, propyl or butyl; 
 R6 and R7, and R6 and R7, are connected in 5-membered pyrrolidinyl rings; 
 R8 is H; and 
 L covalently links R5, R6 or R7, with R5′, R6′ or R7′, respectively, 
 
       or a pharmaceutically-acceptable salt thereof. 
     
     
       4. The compound of  claim 1  wherein:
 R1 and R1′ are selected from hydrogen and methyl; 
 R2 and R2′ are selected from methyl and ethyl; 
 R3 and R3′ are NH; 
 R4 and R4′ are CH; 
 R5 and R5′ are methyl, ethyl, propyl or butyl; 
 R6 and R7, and R6 and R7, are connected in 5-membered pyrrolidinyl rings; 
 R8 is H; and 
 L covalently links R6 or R7, with R6′ or R7′, respectively, 
 
       or a pharmaceutically-acceptable salt thereof. 
     
     
       5. The compound of  claim 1  wherein:
 R1 and R1′ are selected from hydrogen and methyl; 
 R2 and R2′ are selected from methyl and ethyl; 
 R3 and R3′ are NH; 
 R4 and R4′ are CH; 
 R5 and R5′ are methyl, ethyl, propyl or butyl; 
 R6 and R6 are optionally substituted alkyl; 
 R7 and R7 are optionally substituted methyl; 
 R6 and R7, and R6 and R7, are connected in 5-membered pyrrolidinyl rings; 
 R8 is H; and 
 L covalently links R6 or R7, with R6′ or R7′, respectively, 
 
       or a pharmaceutically-acceptable salt thereof. 
     
     
       6. The compound of  claim 1  wherein:
 R1 and R1′ are selected from hydrogen and methyl; 
 R2 and R2′ are selected from methyl and ethyl; 
 R3 and R3′ are NH; 
 R4 and R4′ are CH; 
 R5 and R5′ are methyl, ethyl, propyl or butyl; 
 R6 and R6 are optionally substituted ethyl; 
 R7 and R7 are optionally substituted methyl; 
 R6 and R7, and R6 and R7, are connected in 5-membered pyrrolidinyl rings; 
 R8 is H; and 
 L covalently links R6 or R7, with R6′ or R7′, respectively, 
 
       or a pharmaceutically-acceptable salt thereof. 
     
     
       7. The compound of  claim 1  wherein:
 R1 and R1′ are selected from hydrogen and methyl; 
 R2 and R2′ are selected from methyl and ethyl; 
 R3 and R3′ are NH; 
 R4 and R4′ are CH; 
 R5 and R5′ are methyl, ethyl, propyl or butyl; 
 R6 and R6 are substituted ethyl; 
 R7 and R7 are substituted methyl; 
 R6 and R7, and R6 and R7, are connected in 5-membered pyrrolidinyl rings; 
 R8 is H; and 
 L covalently links R6 or R7, with R6′ or R7′, respectively, 
 
       or a pharmaceutically-acceptable salt thereof. 
     
     
       8. The compound of  claim 1  wherein:
 R1 and R1′ are selected from hydrogen and methyl; 
 R2 and R2′ are selected from methyl and ethyl; 
 R3 and R3′ are NH; 
 R4 and R4′ are CH; 
 R5 and R5′ are methyl, ethyl, propyl or butyl; 
 R6 and R6 are substituted ethyl; 
 R7 and R7 are substituted methyl; 
 R6 and R7, and R6 and R7, are connected in 5-membered pyrrolidinyl rings; 
 R8 is H; and 
 L covalently links R6, with R6′, 
 
       or a pharmaceutically-acceptable salt thereof. 
     
     
       9. The compound of  claim 1  wherein:
 R1 and R1′ are selected from hydrogen and methyl; 
 R2 and R2′ are selected from methyl and ethyl; 
 R3 and R3′ are NH; 
 R4 and R4′ are CH; 
 R5 and R5′ are methyl, ethyl, propyl or butyl; 
 R6 and R6 are linker-substituted ethyl; 
 R7 and R7 are hydroxyl-substituted methyl; 
 R6 and R7, and R6 and R7, are connected in 5-membered pyrrolidinyl rings; 
 R8 is H; and 
 L covalently links R6, with R6′, 
 
       or a pharmaceutically-acceptable salt thereof. 
     
     
       10. The compound of  claim 1  wherein:
 R1 and R1′ is methyl; 
 R2 and R2′ are selected from methyl and ethyl; 
 R3 and R3′ are NH; 
 R4 and R4′ are CH; 
 R5 and R5′ are methyl, ethyl, propyl or butyl; 
 R6 and R6 are linker-substituted ethyl; 
 R7 and R7 are hydroxyl-substituted methyl; 
 R6 and R7, and R6 and R7, are connected in 5-membered pyrrolidinyl rings; 
 R8 is H; and 
 L covalently links R6, with R6′, 
 
       or a pharmaceutically-acceptable salt thereof. 
     
     
       11. The compound of  claim 1  wherein:
 R1 and R1′ is methyl; 
 R2 and R2′ are methyl; 
 R3 and R3′ are NH; 
 R4 and R4′ are CH; 
 R5 and R5′ are methyl, ethyl, propyl or butyl; 
 R6 and R6 are linker-substituted ethyl; 
 R7 and R7 are hydroxyl-substituted methyl; 
 R6 and R7, and R6 and R7, are connected in 5-membered pyrrolidinyl rings; 
 R8 is H; and 
 L covalently links R6, with R6′, 
 
       or a pharmaceutically-acceptable salt thereof. 
     
     
       12. The compound of  claim 1  wherein:
 R1 and R1′ is methyl; 
 R2 and R2′ are methyl; 
 R3 and R3′ are NH; 
 R4 and R4′ are CH; 
 R5 and R5′ are ethyl; 
 R6 and R6 are linker-substituted ethyl; 
 R7 and R7 are hydroxyl-substituted methyl; 
 R6 and R7, and R6 and R7, are connected in 5-membered pyrrolidinyl rings; 
 R8 is H; and 
 L covalently links R6, with R6′, 
 
       or a pharmaceutically-acceptable salt thereof. 
     
     
       13. The compound of  claim 1 , wherein L is a contiguous chain of between 4 and 100 atoms, and between 40D and 1 kD. 
     
     
       14. The compound of  claim 1  wherein L incorporates heteroaromatic portions. 
     
     
       15. The compound of  claim 3  wherein L incorporates heteroaromatic portions. 
     
     
       16. The compound of  claim 11  wherein L incorporates heteroaromatic portions. 
     
     
       17. The compound of  claim 1 , wherein the dimer is symmetrical. 
     
     
       18. The compound of  claim 3 , wherein the dimer is symmetrical. 
     
     
       19. The compound of  claim 11 , wherein the dimer is symmetrical. 
     
     
       20. The compound of  claim 14 , wherein the dimer is symmetrical. 
     
     
       21. The compound of  claim 15 , wherein the dimer is symmetrical. 
     
     
       22. The compound of  claim 16 , wherein the dimer is symmetrical. 
     
     
       23. The pharmaceutical composition comprising a unit dosage of the compound of  claim 1  and a pharmaceutically acceptable excipient. 
     
     
       24. The pharmaceutical composition comprising a unit dosage of the compound of  claim 3  and a pharmaceutically acceptable excipient. 
     
     
       25. The pharmaceutical composition comprising a unit dosage of the compound of  claim 11  and a pharmaceutically acceptable excipient. 
     
     
       26. The pharmaceutical composition comprising a unit dosage of the compound of  claim 16  and a pharmaceutically acceptable excipient. 
     
     
       27. The pharmaceutical composition comprising a unit dosage of the compound of  claim 22  and a pharmaceutically acceptable excipient. 
     
     
       28. A compound of Formula II: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein:
 R1 and R1′ are selected from hydrogen and methyl; 
 R2 and R2′ are selected from methyl and ethyl; 
 R3 and R3′ are NH; 
 R4 and R4′ are CH; 
 R5 and R5′ are C1-C3 alkyl; 
 R6 and R7, and R6′ and R7′, are connected in a substituted or unsubstituted 5-membered heterocycloalkyl ring; and 
 R8 and R8′ are selected from hydrogen, optionally hetero-, optionally substituted alkyl, optionally hetero-, optionally substituted alkenyl, optionally hetero-, optionally substituted alkynyl, optionally hetero-, optionally substituted aryl; and 
 
       L is a linker covalently linking R2, R5, R6, or R7 with R2′, R5′, R6′ or R7′, wherein L
 is a contiguous chain of between 2 and 200 atoms; 
 has a molecular weight of between 20 D and 2 KD; and 
 can incorporate substitution, heteroatoms, unsaturation, cyclic aromatic or heteroaromatic moieties. 
 
     
     
       29. The compound or pharmaceutically acceptable salt of claim 28, wherein R8 and R8′ are hydrogen. 
     
     
       30. The compound or pharmaceutically acceptable salt of claim 28, wherein L incorporates substitution. 
     
     
       31. The compound or pharmaceutically acceptable salt of claim 28, wherein L incorporates substitution, and the substitution is a halogen. 
     
     
       32. The compound or pharmaceutically acceptable salt of claim 28, wherein R6 and R7, and R6′ and R7′, are connected in a substituted 5-membered heterocycloalkyl ring. 
     
     
       33. The compound or pharmaceutically acceptable salt of claim 28, wherein 
       R6 and R7, and R6′ and R7′, are connected in a substituted 5-membered heterocycloalkyl ring, and the 5-membered heterocycloalkyl ring is substituted with 1, 2, or 3 groups selected from: —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO2R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR′—SO2NR′″, —NR″CO2R′, —NH—C(NH2)═NH, —NR′C(NH2)═NH, —NH—C(NH2)═NR′, —S(O)R′, —SO2R′, —SO2NR′R″, —NR″SO2R, —CN and —NO2, and 
       wherein R′, R″ and R′″ each independently refer to hydrogen, unsubstituted (C1-C8)alkyl and heteroalkyl, unsubstituted aryl, aryl substituted with one to three halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups, or aryl-(C1-C4)alkyl groups. 
     
     
       34. The compound or pharmaceutically acceptable salt of claim 28, wherein L covalently links R6 with R6′. 
     
     
       35. A composition comprising a therapeutically effective amount of the compound or pharmaceutically acceptable salt of claim 28 and a pharmaceutically acceptable excipient or carrier.