1-deoxy analogs of vitamin d-related compounds

Abstract

This present disclosure is directed to novel prodrugs of activated vitamin D 3 compounds. The prodrugs can be designed to have one or more beneficial properties, such as selective inhibition of the enzyme CYP24, low calcemic activity, and anti-proliferative activity. Specifically, these prodrugs are 1-deoxy prohormones of active Vitamin D analogs, e.g. analogs of calcitriol. This disclosure is also directed to pharmaceutical and diagnostic compositions containing the prodrugs of the invention, and to their medical use, particularly as prodrugs in the treatment and/or prevention of diseases.

What is claimed is: 
     
         1 . A compound having Formula II, or a pharmaceutically acceptable salt, solvate, or hydrate thereof: 
       
         
           
           
               
               
           
         
         wherein each   independently is a single bond or a double bond; 
         R 1  is selected from the group consisting of OH, OC 1-6 alkyl, and halo; 
         R 2  and R 3  are each independently H or halo, or together form ═CH 2 ; 
         R 4  is C 1-6 alkyl; 
         R 5  and R 6  are each independently H, halo, C 1-4 alkyl, or can be taken, together with the carbon atom to which they are bound, to form a C 3-6 cycloalkyl ring, with the proviso that when   between carbon-23 and carbon-24 is a double bond, then R 5  is absent; 
         R 7  is selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, aryl and heteroaryl, with C 1-6 alkyl and C 2-6 alkenyl being unsubstituted or substituted with 1 to 4 groups independently selected from C 1-4 alkyl, C 2-4 alkenyl, OC 1-4 alkyl, OC 2-4 alkenyl, OH, halo, NH 2 , NHC 1-4 alkyl, NHC 2-4 alkenyl, N(C 1-4 alkyl)(C 1-4 alkyl), N(C 2-4 alkenyl)(C 1-4 alkyl), and with aryl and heteroaryl being unsubstituted or substituted with 1 to 5 groups independently selected from C 1-4 alkyl, C 2-4 alkenyl, OC 1-4 alkyl, OC 2-4 alkenyl, OH, CF 3 , OCF 3 , halo, SH, SC 1-4 alkyl, SC 2-4 alkenyl NH 2 , NHC 1-4 alkyl, NHC 2-4 alkenyl, N(C 1-4 alkyl)(C 1-4 alkyl), N(C 2-4 alkenyl)(C 1-4 alkyl)CN, C(O)OH, C(O)OC 1-4 alkyl, C(O)OC 2-4 alkenyl, C(O)NHC 1-4 alkyl, C(O)NHC 2-4 alkenyl, NHC(O)C 1-4 alkyl, NHC(O)C 2-4 alkenyl, OC(O)C 1-4 alkyl, OC(O)C 2-4 alkenyl, SOC 1-4 alkyl, SOC 2-4 alkenyl, SO 2 C 1-4 alkyl, SO 2 C 2-4 alkenyl, SO 2 NHC 1-4 alkyl, SO 2 NHC 2-4 alkenyl and SO 2 NH 2 ; and 
         R 8  is selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, cyclo(C 3 -C 6 )alkyl, cyclo(C 5 -C 6 )alkenyl, aryl, heteroaryl, aryl-C 1-6 alkyl, aryl-C 2-6 alkenyl, heteroaryl-C 1-6 alkyl, and heteroaryl-C 2-6 alkenyl with C 1-6 alkyl and C 2-6 alkenyl being unsubstituted or substituted with 1-4 groups independently selected from C 1-4 alkyl, C 2-4 alkenyl, OC 1-4 alkyl, OC 2-4 alkenyl, OH, halo, NH 2 , NHC 1-4 alkyl, NHC 2-4 alkenyl, N(C 1-4 alkyl)(C 1-4 alkyl), and N(C 2-4 alkenyl)(C 1-4 alkyl), and with cyclo(C 3 -C 6 )alkyl, cyclo(C 5 -C 6 )alkenyl aryl, heteroaryl, aryl-C 1-6 alkyl, aryl-C 2-6 alkenyl, heteroaryl-C 1-6 alkyl, heteroaryl-C 2-6 alkenyl being unsubstituted or substituted with 1-5 groups independently selected from C 1-4 alkyl, C 2-4 alkenyl, OC 1-4 alkyl, OC 2-4 alkenyl, OH, CF 3 , OCF 3 , halo, SH, SC 1-4 alkyl, SC 2-4 alkenyl, NH 2 , NHC 1-4 alkyl, NHC 2-4 alkenyl, N(C 1-4 alkyl)(C 1-4 alkyl), N(C 2-4 alkenyl)(C 1-4 alkyl), CN, C(O)OH, C(O)OC 1-4 alkyl, C(O)OC 2-4 alkenyl, C(O)NHC 1-4 alkyl, C(O)NHC 2-4 alkenyl, NHC(O)C 1-4 alkyl, NHC(O)C 2-4 alkenyl, OC(O)C 1-4 alkyl, OC(O)C 2-4 alkenyl, SOC 1-4 alkyl, SOC 2-4 alkenyl SO 2 C 1-4 alkyl, SO 2 C 2-4 alkenyl, SO 2 NHC 1-4 alkyl, SO 2 NHC 2-4 alkenyl and SO 2 NH 2 . 
       
     
     
         2 . The compound of  claim 1 , wherein
 R 1  is OH or halo;   R 2  and R 3  are either both H or together form ═CH 2 ;   R 4  is C 1-4 alkyl;   R 5  and R 6  are each independently H, halo, or C 1-2 alkyl, with the proviso that when   between carbon-23 and carbon-24 is a double bond, then R 5  is absent;   R 7  is selected from the group consisting of H, C 1-4 alkyl, C 2-5 alkenyl, aryl and heteroaryl, with C 1-4 alkyl and C 2-4 alkenyl being unsubstituted or substituted with 1 to 4 groups independently selected from C 1-4 alkyl, C 2-4 alkenyl, OC 1-4 alkyl, OC 2-4 alkenyl, OH, and halo, and with aryl and heteroaryl being unsubstituted or substituted with 1 to 5 groups independently selected from C 1-4 alkyl, C 2-4 alkenyl, OC 1-4 alkyl, OC 2-4 alkenyl, OH, CF 3 , OCF 3 , and halo; and   R 8  is selected from the group consisting of C 1-4 alkyl, C 2-4 alkenyl, cyclo(C 3 -C 6 )alkyl, cyclo(C 5 -C 6 )alkenyl, aryl, heteroaryl, with C 1-4 alkyl and C 2-4 alkenyl being unsubstituted or substituted with 1-4 groups independently selected from C 1-4 alkyl, C 2-4 alkenyl, OC 1-4 alkyl, OC 2-4 alkenyl, OH, and halo, and with cyclo(C 3 -C 6 )alkyl, cyclo(C 5 -C 6 )alkenyl aryl, and heteroaryl, being unsubstituted or substituted with 1-5 groups independently selected from C 1-4 alkyl, C 2-4 alkenyl, OC 1-4 alkyl, OC 2-4 alkenyl, OH, CF 3 , OCF 3 , and halo.   
     
     
         3 . The compound of  claim 2 , wherein
 R 1  is OH or F;   R 2  and R 3  together form ═CH 2 ;   R 4  is CH 3 ;   R 5  and R 6  are each independently H, halo, or CH 3 , with the proviso that when   between carbon-23 and carbon-24 is a double bond, then R 5  is absent;   R 7  is selected from the group consisting of H, C 1-4 alkyl, C 2-5 alkenyl, aryl and heteroaryl, with aryl and heteroaryl being unsubstituted or substituted with 1 to 5 groups independently selected from C 1-4 alkyl, OC 1-4 alkyl, OH, CF 3 , OCF 3 , and halo; and   R 8  is selected from the group consisting of C 1-4 alkyl, aryl, and heteroaryl, with aryl, and heteroaryl, being unsubstituted or substituted with 1-5 groups independently selected from C 1-4 alkyl, OC 1-4 alkyl, OH, CF 3 , OCF 3 , and halo.   
     
     
         4 . The compound of  claim 3 , wherein
 R 1  is OH;   R 5  and R 6  are each H, with the proviso that when   between carbon-23 and carbon-24 is a double bond, then R 5  is absent;   R 7  is selected from the group consisting of H, C 1-4 alkyl, C 2-5 alkenyl, aryl and heteroaryl, with aryl and heteroaryl being unsubstituted or substituted with 1 to 5 groups independently selected from C 1-4 alkyl, OC 1-4 alkyl, OH, CF 3 , OCF 3 , and halo; and   R 8  is selected from the group consisting of C 1-4 alkyl, aryl, and heteroaryl, with aryl, and heteroaryl, being unsubstituted or substituted with 1-5 groups independently selected from C 1-4 alkyl, OC 1-4 alkyl, OH, CF 3 , OCF 3 , and halo.   
     
     
         5 . The compound of  claim 4 , wherein R 7  is selected from the group consisting of H, C 1-4 alkyl, C 2-5 alkenyl, aryl and heteroaryl; and R 8  is C 1-4 alkyl or aryl. 
     
     
         6 . The compound of  claim 5  wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 1  having a relative stereochemistry as shown below: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 7  wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         9 . A method for treating diseases which benefit from an increase in the levels of 1α,25-dihydroxyvitamin D 3 , or for treating diseases which benefit from an inhibition of the catabolism of 1α,25-dihydroxyvitamin D 3 , or for treating one or more diseases detected from the group consisting of the catabolism of 1α,25-dihydroxyvitamin D 3 , or for treating breast cancer, lung cancer, prostate cancer, colon cancer, colorectal cancer, kidney cancer, head and neck cancer, pancreatic cancer, skin cancer, Kaposi's sarcoma, leukemia, and psoriasis, or for inhibiting CPY24 activity in a cell or animal, or for increasing the levels of 1α,25-dihydroxyvitamin D 3  in a cell or animal, or for inhibiting catabolism of 1α,25-dihydroxyvitamin D 3  in a cell or animal in need thereof an effective amount of a compound:
 having Formula II, or a pharmaceutically acceptable salt, solvate, or hydrate thereof: 
 
       
         
           
           
               
               
           
         
         wherein each   independently is a single bond or a double bond; 
         R 1  is selected from the group consisting of OH, OC 1-6 alkyl, and halo; 
         R 2  and R 3  are each independently H or halo, or together form ═CH 2 ; 
         R 4  is C 1-6 alkyl; 
         R 5  and R 6  are each independently H, halo, C 1-4 alkyl, or can be taken, together with the carbon atom to which they are bound, to form a C 3-6 cycloalkyl ring, with the proviso that when   between carbon-23 and carbon-24 is a double bond, then R 5  is absent; 
         R 7  is selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, aryl and heteroaryl, with C 1-6 alkyl and C 2-6 alkenyl being unsubstituted or substituted with 1 to 4 groups independently selected from C 1-4 alkyl, C 2-4 alkenyl, OC 1-4 alkyl, OC 2-4 alkenyl, OH, halo, NH 2 , NHC 1-4  alkyl, NHC 2-4  alkenyl, N(C 1-4  alkyl)(C 1-4  alkyl), N(C 2-4  alkenyl)(C 1-4  alkyl), and with aryl and heteroaryl being unsubstituted or substituted with 1 to 5 groups independently selected from C 1-4 alkyl, C 2-4 alkenyl, OC 1-4 alkyl, OC 2-4 alkenyl, OH, CF 3 , OCF 3 , halo, SH, SC 1-4 alkyl, SC 2-4 alkenyl NH 2 , NHC 1-4 alkyl, NHC 2-4 alkenyl, N(C 1-4 alkyl)(C 1-4 alkyl), N(C 2-4 alkenyl)(C 1-4 alkyl)CN, C(O)OH, C(O)OC 1-4 alkyl, C(O)OC 2-4 alkenyl, C(O)NHC 1-4 alkyl, C(O)NHC 2-4 alkenyl, NHC(O)C 1-4 alkyl, NHC(O)C 2-4 alkenyl, OC(O)C 1-4 alkyl, OC(O)C 2-4 alkenyl, SOC 1-4 alkyl, SOC 2-4 alkenyl, SO 2 C 1-4 alkyl, SO 2 C 2-4 alkenyl, SO 2 NHC 1-4 alkyl, SO 2 NHC 2-4 alkenyl and SO 2 NH 2 ; and 
         R 8  is selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, cyclo(C 3 -C 6 )alkyl, cyclo(C 5 -C 6 )alkenyl, aryl, heteroaryl, aryl-C 1-6 alkyl, aryl-C 2-6 alkenyl, heteroaryl-C 1-6 alkyl, and heteroaryl-C 2-6 alkenyl with C 1-6 alkyl and C 2-6 alkenyl being unsubstituted or substituted with 1-4 groups independently selected from C 1-4 alkyl, C 2-4 alkenyl, OC 1-4 alkyl, OC 2-4 alkenyl, OH, halo, NH 2 , NHC 1-4 alkyl, NHC 2-4 alkenyl, N(C 1-4 alkyl)(C 1-4 alkyl), and N(C 2-4 alkenyl)(C 1-4 alkyl), and with cyclo(C 3 -C 6 )alkyl, cyclo(C 5 -C 6 )alkenyl aryl, heteroaryl, aryl-C 1-6 alkyl, aryl-C 2-6 alkenyl, heteroaryl-C 1-6 alkyl, heteroaryl-C 2-6 alkenyl being unsubstituted or substituted with 1-5 groups independently selected from C 1-4 alkyl, C 2-4 alkenyl, OC 1-4 alkyl, OC 2-4 alkenyl, OH, CF 3 , OCF 3 , halo, SH, SC 1-4 alkyl, SC 2-4 alkenyl, NH 2 , NHC 1-4 alkyl, NHC 2-4 alkenyl, N(C 1-4 alkyl)(C 1-4 alkyl), N(C 2-4 alkenyl)(C 1-4 alkyl), CN, C(O)OH, C(O)OC 1-4 alkyl, C(O)OC 2-4 alkenyl, C(O)NHC 1-4 alkyl, C(O)NHC 2-4 alkenyl, NHC(O)C 1-4 alkyl, NHC(O)C 2-4 alkenyl, OC(O)C 1-4 alkyl, OC(O)C 2-4 alkenyl, SOC 1-4 alkyl, SOC 2-4 alkenyl SO 2 C 1-4 alkyl, SO 2 C 2-4 alkenyl, SO 2 NHC 1-4 alkyl, SO 2 NHC 2-4 alkenyl and SO 2 NH 2 . 
       
     
     
         10 . The method of  claim 9 , wherein the method comprises treating a disease which benefits from an increase in the levels of 1α,25-dihydroxyvitamin D 3 . 
     
     
         11 . The method of  claim 9 , wherein the method comprises treating a disease which benefits from an inhibition of the catabolism of 1α,25-dihydroxyvitamin D 3 . 
     
     
         12 . The method of  claim 9 , wherein the method comprises treating one or more diseases selected from the group consisting of breast cancer, lung cancer, prostate cancer, colon cancer, colorectal cancer, kidney cancer, head and neck cancer, pancreatic cancer, skin cancer, Kaposi's sarcoma, leukemia, and psoriasis. 
     
     
         13 . The method of  claim 9 , wherein the method comprises inhibiting CYP24 activity in a cell or animal. 
     
     
         14 . The method of  claim 9 , wherein the method comprises increasing the levels of 1α,25-dihydroxyvitamin D 3  in a cell or animal. 
     
     
         15 . The method of  claim 9 , wherein the method comprises inhibiting the catabolism of 1α,25-dihydroxyvitamin D 3  in a cell or animal. 
     
     
         16 . A method of increasing the efficacy of a vitamin D receptor agonist comprising co-administering an effective amount of the vitamin D receptor agonist and a compound having Formula II, or a pharmaceutically acceptable salt, solvate, or hydrate thereof: 
       
         
           
           
               
               
           
         
         wherein each   independently is a single bond or a double bond; 
         R 1  is selected from the group consisting of OH, OC 1-6 alkyl, and halo; 
         R 2  and R 3  are each independently H or halo, or together form ═CH 2 ; 
         R 4  is C 1-6 alkyl; 
         R 5  and R 6  are each independently H, halo, C 1-4 alkyl, or can be taken, together with the carbon atom to which they are bound, to form a C 3-6 cycloalkyl ring, with the proviso that when   between carbon-23 and carbon-24 is a double bond, then R 5  is absent; 
         R 7  is selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, aryl and heteroaryl, with C 1-6 alkyl and C 2-6 alkenyl being unsubstituted or substituted with 1 to 4 groups independently selected from C 1-4 alkyl, C 2-4 alkenyl, OC 1-4 alkyl, OC 2-4 alkenyl, OH, halo, NH 2 , NHC 1-4  alkyl, NHC 2-4  alkenyl, N(C 1-4  alkyl)(C 1-4  alkyl), N(C 2-4  alkenyl)(C 1-4  alkyl), and with aryl and heteroaryl being unsubstituted or substituted with 1 to 5 groups independently selected from C 1-4 alkyl, C 2-4 alkenyl, OC 1-4 alkyl, OC 2-4 alkenyl, OH, CF 3 , OCF 3 , halo, SH, SC 1-4 alkyl, SC 2-4 alkenyl NH 2 , NHC 1-4 alkyl, NHC 2-4 alkenyl, N(C 1-4 alkyl)(C 1-4 alkyl), N(C 2-4 alkenyl)(C 1-4 alkyl)CN, C(O)OH, C(O)OC 1-4 alkyl, C(O)OC 2-4 alkenyl, C(O)NHC 1-4 alkyl, C(O)NHC 2-4 alkenyl, NHC(O)C 1-4 alkyl, NHC(O)C 2-4 alkenyl, OC(O)C 1-4 alkyl, OC(O)C 2-4 alkenyl, SOC 1-4 alkyl, SOC 2-4 alkenyl, SO 2 C 1-4 alkyl, SO 2 C 2-4 alkenyl, SO 2 NHC 1-4 alkyl, SO 2 NHC 2-4 alkenyl and SO 2 NH 2 ; and 
         R 8  is selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, cyclo(C 3 -C 6 )alkyl, cyclo(C 5 -C 6 )alkenyl, aryl, heteroaryl, aryl-C 1-6 alkyl, aryl-C 2-6 alkenyl, heteroaryl-C 1-6 alkyl, and heteroaryl-C 2-6 alkenyl with C 1-6 alkyl and C 2-6 alkenyl being unsubstituted or substituted with 1-4 groups independently selected from C 1-4 alkyl, C 2-4 alkenyl, OC 1-4 alkyl, OC 2-4 alkenyl, OH, halo, NH 2 , NHC 1-4 alkyl, NHC 2-4 alkenyl, N(C 1-4 alkyl)(C 1-4 alkyl), and N(C 2-4 alkenyl)(C 1-4 alkyl), and with cyclo(C 3 -C 6 )alkyl, cyclo(C 5 -C 6 )alkenyl aryl, heteroaryl, aryl-C 1-6 alkyl, aryl-C 2-6 alkenyl, heteroaryl-C 1-6 alkyl, heteroaryl-C 2-6 alkenyl being unsubstituted or substituted with 1-5 groups independently selected from C 1-4 alkyl, C 2-4 alkenyl, OC 1-4 alkyl, OC 2-4 alkenyl, OH, CF 3 , OCF 3 , halo, SH, SC 1-4 alkyl, SC 2-4 alkenyl, NH 2 , NHC 1-4 alkyl, NHC 2-4 alkenyl, N(C 1-4 alkyl)(C 1-4 alkyl), N(C 2-4 alkenyl)(C 1-4 alkyl), CN, C(O)OH, C(O)OC 1-4 alkyl, C(O)OC 2-4 alkenyl, C(O)NHC 1-4 alkyl, C(O)NHC 2-4 alkenyl, NHC(O)C 1-4 alkyl, NHC(O)C 2-4 alkenyl, OC(O)C 1-4 alkyl, OC(O)C 2-4 alkenyl, SOC 1-4 alkyl, SOC 2-4 alkenyl SO 2 C 1-4 alkyl, SO 2 C 2-4 alkenyl, SO 2 NHC 1-4 alkyl, SO 2 NHC 2-4 alkenyl and SO 2 NH 2 .