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.

1 - 7 . (canceled) 
     
     
         8 . 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 . 
       
     
     
         9 . The compound of  claim 8 , 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.   
     
     
         10 . The compound of  claim 9 , 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.   
     
     
         11 . The compound of  claim 10 , 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.   
     
     
         12 . The compound of  claim 11 , 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. 
     
     
         13 . The compound of  claim 12  wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         14 . The compound of  claim 8  having a relative stereochemistry as shown below: 
       
         
           
           
               
               
           
         
       
     
     
         15 . The compound of  claim 14  wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         16 . A compound having Formula III, or a pharmaceutically acceptable salt, solvate, or hydrate thereof: 
       
         
           
           
               
               
           
         
         wherein each independently 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; 
         R 7  is selected from the group consisting of O, NH, N(C 1-6 alkyl), and NC(O)R 9 ; 
         R 8  is selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, aryl and heteroaryl, wherein each of C 1-6 alkyl, C 3-6 cycloalkyl, aryl and heteroaryl are either unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of C 1-4 alkyl, OC 1-4 alkyl, CF 3 , NO 2 , halo, OH, OCF 3 , SH, SC 1-4 alkyl, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl)(C 1-4 alkyl), and CN; and, 
         R 9  is selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, aryl-C 1-4 alkyl, aryl and heteroaryl, wherein each of C 1-6 alkyl, C 3-6 cycloalkyl, aryl and heteroaryl are either unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of C 1-4 alkyl, OC 1-4 alkyl, CF 3 , NO 2 , halo. 
       
     
     
         17 . The compound of  claim 16 , 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, or can be taken, together with the carbon atom to which they are bound, to form a C 3-4 cycloalkyl ring;   R 7  is selected from the group consisting of O, NH, and N(C 1-6 alkyl); and   R 8  is selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, aryl and heteroaryl, wherein each of C 1-6 alkyl, C 3-6 cycloalkyl, aryl and heteroaryl are either unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of C 1-4 alkyl, OC 1-4 alkyl, CF 3 , NO 2 , and halo.   
     
     
         18 . The compound of  claim 17 , 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 , or can be taken, together with the carbon atom to which they are bound, to form a C 3-4 cycloalkyl ring;   R 7  is O or NH; and   R 8  is selected from the group consisting of C 1-4 alkyl, aryl and heteroaryl, wherein each of aryl and heteroaryl are either unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of C 1-4 alkyl, OC 1-4 alkyl, CF 3 , NO 2 , and halo.   
     
     
         19 . The compound of  claim 18  selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         20 . The compound of  claim 16  having a relative stereochemistry as shown below: 
       
         
           
           
               
               
           
         
       
     
     
         21 . The compound of  claim 20  selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         22 . A pharmaceutical composition comprising a compound of  claim 8  in admixture with a pharmaceutically-acceptable excipient. 
     
     
         23 . The composition of  claim 16  comprising a unit dosage form comprising greater than 50 μg of a compound of 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 . 
       
     
     
         24 . (canceled) 
     
     
         25 . (canceled) 
     
     
         26 . A method for treating diseases which benefit from a modulation of the levels of 1α,25-dihydroxyvitamin D 3  comprising administering an effective amount of a compound of  claim 8  to a cell or animal in need thereof. 
     
     
         27 . A method for treating diseases which benefit from an inhibition of the catabolism of 1α,25-dihydroxyvitamin D 3  comprising administering an effective amount of a compound of  claim 8  to a cell or animal in need thereof. 
     
     
         28 . The method according to  claim 26 , wherein the disease is selected from the group consisting of hyperparathyroidism, hypoparathyroidism, pseudohypoparathyroidism, diabetes, medullary carcinoma, psoriasis, wound healing, sarcoidosis, tuberculosis, chronic renal disease, hypophosphatemic VDRR, vitamin D dependent rickets, convulsion, fibrogenisis imperfecta ossium, osteitits fibrosa cystica, osteomalacia, osteoporosis, osteopenia, osteosclerosis, renal osteodystrophy, rickets, breast cancer, lung cancer, and prostate cancer. 
     
     
         29 . (canceled) 
     
     
         30 . A method for inhibiting cell proliferation comprising administering an effective amount of a compound of  claim 8  to a cell or animal in need thereof. 
     
     
         31 . The method of  claim 30 , wherein the cell is a cancer cell. 
     
     
         32 . The method of  claim 31 , wherein the cancer is selected from the group consisting of breast cancer, lung cancer, and prostate cancer. 
     
     
         33 . A method for inhibiting CYP24 activity in a cell by administering an effective amount of a compound of  claim 8  to a cell or animal in need thereof. 
     
     
         34 . A method of modulating the levels of 1α,25-dihydroxyvitamin D 3  in an animal comprising administering a compound of  claim 8  to a cell or animal in need thereof. 
     
     
         35 . A method of inhibiting the catabolism of 1α,25-dihydroxyvitamin D 3  in an animal comprising administering a compound of  claim 8  to a cell or animal in need thereof. 
     
     
         36 . A method of inhibiting cell proliferation in an animal comprising administering a compound of  claim 8  to a cell or animal in need thereof. 
     
     
         37 . A method of inhibiting CYP24 activity in an animal comprising administering a compound of  claim 8  to a cell or animal in need thereof. 
     
     
         38 . A method of increasing the efficacy of a vitamin D receptor agonist comprising co-administering a compound of  claim 8  and an effective amount of the vitamin D receptor agonist. 
     
     
         39 . The method of  claim 38 , wherein the vitamin D receptor agonist is calcitriol. 
     
     
         40 . (canceled)