Method of treating prostatic diseases using active vitamin D analogues

• US 5,763,429 A
• Filed: 12/30/1996
• Issued: 06/09/1998
• Est. Priority Date: 09/10/1993
• Status: Expired due to Term

• Current Assignee: Bone Care International LLC
• Original Assignee: Bone Care International LLC
• Inventors: Bishop, Charles W., Mazess, Richard B., Knutson, Joyce C.
• Primary Examiner(s): Criares, Theodore J.
• Application Number:
  US08/781,910
• Time in Patent Office: 526 Days
• Field of Search: 514/167, 514/168, 552/653
• US Class Current: 514/168
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/59 Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
• CPC Class Codes: A61K 31/592 9,10-Secoergostane derivatives, e.g. ergocalciferol, i.e. vitamin D2
• CPC Class Codes: A61K 31/593 9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
• CPC Class Codes: A61K 31/66 Phosphorus compounds
• CPC Class Codes: A61K 31/714 Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
• CPC Class Codes: A61K 33/00 Medicinal preparations containing inorganic active ingredients
• CPC Class Codes: A61K 33/06 Aluminium, calcium or magnesium; Compounds thereof , e.g. clay
• CPC Class Codes: A61K 33/16 Fluorine compounds
• CPC Class Codes: A61K 33/22 Boron compounds
• CPC Class Codes: A61K 38/23 Calcitonins
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 35/00 Antineoplastic agents

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.

Claims

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) ##STR2## wherein B and C each are hydrogen or a carbon-carbon bond, thus forming a double bond between C-22 and C-23;

R¹ and R² 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 R¹ and R² cannot both be an alkenyl group, or taken together with the carbon to which they are bonded, form a C₃ -C₈, cyclocarbon ring;

R³ is lower alkyl, lower alkenyl, lower fluoroalkyl, lower fluoroalkenyl, O-lower alkyl, O-lower alkenyl, O-lower acyl, O-aromatic acyl or lower cycloalkyl;

X¹ is hydrogen or hydroxyl, or, taken with R³, constitutes a bond when R³ is an alkenyl group, and X² is hydrogen or hydroxyl, or, taken with R¹ or R², constitutes a double bond.

3. The method of claim 2, wherein the compound of formula (I) is 1α

,24-dihydroxyvitamin D₂, 1α

,24-dihydroxyvitamin D₄, 1α

,25-dihydroxyvitamin D₂, 1α

,25-dihydroxyvitamin D₄, 1α

-hydroxyvitamin D₂ or 1α

-hydroxyvitamin D₄.

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) ##STR3## wherein B and C each are hydrogen or a carbon-carbon bond, thus forming a double bond between C-22 and C-23;

R¹ and R² 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 R¹ and R² cannot both be an alkenyl group, or taken together with the carbon to which they are bonded, form a C₃ -C₈ cyclocarbon ring;

R³ is lower alkyl, lower alkenyl, lower fluoroalkyl, lower fluoroalkenyl, O-lower alkyl, O-lower alkenyl, O-lower acyl, O-aromatic acyl or lower cycloalkyl;

X¹ is hydrogen or hydroxyl, or, taken with R³, constitutes a bond when R³ is an alkenyl group, and X² is hydrogen or hydroxyl, or, taken with R¹ or R², constitutes a double bond.

6. The method of claim 5, wherein said therapeutic amount is 0.01 μ

g/kg/day to 2.0 μ

g/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 D₃ and a hypercalcemia risk substantially lower than that of 1α

,25-dihydroxyvitamin D₃.

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 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.