Method of treating prostatic diseases using active vitamin D analogues

Abstract

The invention provides therapeutic methods for inhibiting, ameliorating or alleviating the hyperproliferative cellular activity of diseases of the prostate, e.g., prostatic cancer and prostatic hyperplasia, which includes administering to a patient in need thereof an active vitamin D analogue. Cell differentiation is promoted, induced or enhanced without causing to the patient dose-limiting hypercalcemia and hypercalciuria.

1 . A method of inhibiting the hyperproliferative activity of human prostatic neoplastic or hyperplastic cells, comprising treating the cells with an effective amount of a 1α-hydroxyvitamin D compound having a hydrocarbon moiety substituted at C-24.  
     
     
         2 . The method of  claim 1 , wherein said 1α-hydroxvitamin D compound is represented by formula (I)  
       
         
           
           
               
               
           
         
       
       wherein B and C each are hydrogen or a carbon-carbon bond, thus forming a double bond between C-22 and C-23; R 1  and R 2  are identical or different and are hydrogen, hydroxyl, lower alkyl, lower fluoroalkyl, O-lower alkyl, lower alkenyl, lower fluoroalkenyl, O-lower alkenyl, O-lower acyl, O-aromatic acyl, lower cycloalkyl with the proviso that R 1  and R 2  cannot both be an alkenyl group, or taken together with the carbon to which they are bonded, form a C 3 -C 8  cyclocarbon ring; R 3  is lower alkyl, lower alkenyl, lower fluoroalkyl, lower fluoroalkenyl, O-lower alkyl, O-lower alkenyl, O-lower acyl, O-aromatic acyl or lower cycloalkyl; X 1  is hydrogen or hydroxyl, or, taken with R 3 , constitutes a bond when R 3  is an alkenyl group, and X 2  is hydrogen or hydroxyl, or, taken with R 1  or R 2 , constitutes a double bond.  
     
     
         3 . The method of  claim 2 , wherein the compound of formula (I) is 1α,24-dihydroxyvitamin D 2 , 1α,24-dihydroxyvitamin D 4 , 1α,25-dihydroxyvitamin D 2 , 1α,25-dihydroxyvitamin D 4 , 1α-hydroxyvitamin D 2  or 1α-hydroxyvitamin D 4 .  
     
     
         4 . The method of  claim 1 , wherein said treating step includes inhibiting proliferation of, and inducing and enhancing differentiation in said prostatic cells.  
     
     
         5 . A method for the treatment of prostatic diseases characterized by abnormal cell differentiation or cell proliferation, comprising administering to a male human or animal in need of such treatment an effective proliferation-inhibiting amount of a compound of formula (I)  
       
         
           
           
               
               
           
         
       
       wherein B and C each are hydrogen or a carbon-carbon bond, thus forming a double bond between C-22 and C-23; R 1  and R 2  are identical or different and are hydrogen, hydroxyl, lower alkyl, lower fluoroalkyl, O-lower alkyl, lower alkenyl, lower fluoroalkenyl, O-lower alkenyl, O-lower acyl, O-aromatic acyl, lower cycloalkyl with the proviso that R 1  and R 2  cannot both be an alkenyl group, or taken together with the carbon to which they are bonded, form a C 3 -C 8  cyclocarbon ring; R 3  is lower alkyl, lower alkenyl, lower fluoroalkyl, lower fluoroalkenyl, O-lower alkyl, O-lower alkenyl, O-lower acyl, O-aromatic acyl or lower cycloalkyl; X 1  is hydrogen or hydroxyl, or, taken with R 3 , constitutes a bond when R 3  is an alkenyl group, and X 2  is hydrogen or hydroxyl, or, taken with R 1  or R 2 , constitutes a double bond.  
     
     
         6 . The method of  claim 5 , wherein said therapeutic amount is 0.01 μg/kg/day to 2.0 μg/kg/day.  
     
     
         7 . A method of treating human prostate cancer, comprising administering to a male subject, who has prostate cancer, an effective amount of a first anticancer agent which is an active vitamin D compound to decrease or stabilize the cellular abnormal proliferative activity of the cancer, said compound or its in vivo metabolite having a VDR binding affinity substantially equivalent to the binding affinity of 1α,25-dihydroxyvitamin D 3  and a hypercalcemia risk substantially lower than that of 1α,25-dihydroxyvitamin D 3 .  
     
     
         8 . The method of  claim 7 , wherein said active vitamin D is administered in a mixture including a second anticancer agent selected from the group consisting of estramustine phosphate, prednimustine, cisplatin, 5-fluoro-uracil, melphalan, hydroxyurea, mitomycin, idarubicin, methotrexate, adriamycin and daunomycin.  
     
     
         9 . A pharmaceutical composition, comprising 
 (a) a first anticancer agent which is an active vitamin D compound, and    (b) an agent selected from the group consisting of (i) a second anticancer agent, (ii) a bone agent, (iii) an androgen control agent and (iv) a 5α-reductase inhibitor and combinations thereof.    
     
     
         10 . The pharmaceutical composition of  claim 9 , wherein said active vitamin D compound is represented by formula (I)  
       
         
           
           
               
               
           
         
       
       wherein B and C each are hydrogen or a carbon-carbon bond, thus forming a double bond between C-22 and C-23; R 1  and R 2  are identical or different and are hydrogen, hydroxyl, lower alkyl, lower fluoroalkyl, O-lower alkyl, lower alkenyl, lower fluoroalkenyl, O-lower alkenyl, O-lower acyl, O-aromatic acyl, lower cycloalkyl with the proviso that R 1  and R 2  cannot both be an alkenyl group, or taken together with the carbon to which they are bonded, form a C 3 -C 8  cyclocarbon ring; R 3  is lower alkyl, lower alkenyl, lower fluoroalkyl, lower fluoroalkenyl, O-lower alkyl, O-lower alkenyl, O-lower acyl, O-aromatic acyl or lower cycloalkyl; X 1  is hydrogen or hydroxyl, or, taken with R 3 , constitutes a bond when R 3  is an alkenyl group, and X 2  is hydrogen or hydroxyl, or, taken with R 1  or R 2 , constitutes a double bond.  
     
     
         11 . The pharmaceutical composition of  claim 9 , wherein active vitamin D compound is selected from the group consisting of 1α,24-dihydroxyvitamin D 2 , 1α,24-dihydroxyvitamin D 4 , 1α, 25-dihydroxyvitamin D 2 , 1α,25-dihydroxyvitamin D 4 , 1α-hydroxyvitamin D 2  or 1α-hydroxyvitamin D 4 .  
     
     
         12 . The pharmaceutical composition of  claim 9 , wherein said second anticancer agent is selected from the group consisting of estramustine phosphate, prednimustine, cisplatin, 5-fluoro-uracil, melphalan, hydroxyurea, mitomycin, idarubicin, methotrexate, adriamycin and daunomycin.  
     
     
         13 . The pharmaceutical composition of  claim 9 , wherein said active vitamin D compound is present in a dosage range of about 0.01 μg/kg/day to about 2.0 μg/kg/day.  
     
     
         14 . The pharmaceutical composition of  claim 10  further including a pharmaceutically acceptable carrier.  
     
     
         15 . The pharmaceutical composition of  claim 9 , wherein said androgen control agent is selected from the group consisting of an estrogen, LHRH analogue, an antiestrogen and an antiandrogen.  
     
     
         16 . The pharmaceutical composition of  claim 9 , wherein said a 5α-reductase enzyme inhibitor is finasteride.  
     
     
         17 . The pharmaceutical composition of  claim 9 , wherein said bone agent is selected from the group consisting of conjugated estrogens, antiestrogens, calcitonin, sodium fluoride, bisphosphonate, calcium supplements, cobalamin, pertussis toxin and boron.  
     
     
         18 . A method of treating a human to alleviate the hyperproliferative cellular activity of prostatic cancer or hyperplasia, comprising administering to a human in need thereof a therapeutically effective amount of an active vitamin D compound having a hydrocarbon moiety substituted at C-24.