CA2450942A1 - Method of treating hyperproliferative diseases using active vitamin d analogues - Google Patents

Method of treating hyperproliferative diseases using active vitamin d analogues Download PDF

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Publication number
CA2450942A1
CA2450942A1 CA002450942A CA2450942A CA2450942A1 CA 2450942 A1 CA2450942 A1 CA 2450942A1 CA 002450942 A CA002450942 A CA 002450942A CA 2450942 A CA2450942 A CA 2450942A CA 2450942 A1 CA2450942 A1 CA 2450942A1
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CA
Canada
Prior art keywords
hydrogen
compound
accordance
alpha
alkenyl
Prior art date
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Abandoned
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CA002450942A
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French (fr)
Inventor
Charles W. Bishop
Richard B. Mazess
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Bone Care International Inc
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Individual
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Publication of CA2450942A1 publication Critical patent/CA2450942A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Methods for the utilization of hypocalcemic vitamin D analogy to inhibit the hyperproliferation of malignant or neoplastic cells without incidence of hypercalcemia.

Description

METHOD

Claims (37)

CLAIM(S) What is claimed is:
1. A method of inhibiting hyperproliferation of malignant or neoplastic cells, comprising treating the cells with an antiproliferative amount of a hypocalcemic hydroxyvitamin D compound having a hydrocarbon moiety at the C24 position, the cells expressing a vitamin D receptor.
2. The method of claim 1, wherein the cells are cancers of the breast, colon, lung, neck and head, pancreas, endometrium, bladder, cervix, testes, ovaries, squamous cell carcinoma, myeloid and lymphocytic leukemia, lymphoma, medullary thyroid carcinoma, melanoma, multiple myeloma, retinoblastoma or sarcomas of the soft tissues and bone.
3. The method of claim 1, wherein the hypocalcemic vitamin D is a compound represented by formula (I) wherein A1 and A2 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, and X3 is hydrogen or hydroxyl provided that at least one of X1, X2 and X3 is hydroxyl; and Y is a methylene group if the bond to Y is a double bond or is a methyl group or hydrogen if the bond to Y is a single bond.
4. A method in accordance with claim 1 wherein the hypocalcemic vitamin D
compound is a compound of formula II
wherein A1 and A2 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, , and Y is a methylene group if the bond to Y is a double bond or is a methyl group or hydrogen if the bond to Y is a single bond.
5. A method in accordance with claim 1, wherein the hypocalcemic vitamin D
compound is a compound of formula III:
wherein A1 and A2 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. A method of inhibiting the hyperproliferative activity of malignant or neoplastic cells, comprising administering to a patient suffering therefrom, an anitproliferarive amount of a hypocalcemic hydroxyvitamin D compound.
7. A method in accordance with claim 6, wherein the hypocalcemic vitamin D
compound is administered in a daily regimen or an episodic regimen.
8. A method in accordance with claim 7, wherein the espisodic regimen is a dose once every 2 to 7 days.
9. A method in accordance with claim 7, wherein the hypocalcemic vitamin D
compound is administered daily at a dose of about 10 to 100 µg/day.
10. A method in accordance with claim 6, wherein the hypocalcemic vitamin D
compound is administered orally, is administered intravenously, is directly injected to a cancer site or is regionally delivered to a cancer site.
11. A method in accordance with claim 10, wherein the hypocalcemic vitamin D
compound is administered orally.
12. A method in accordance with claim 6, wherein the hypocalcemic vitamin D
compound is co-administered with a cytotoxic agent.
13. A method in accordance with claim 12, wherein the cytotoxic agent is an antimetabolite, and antimicrotubule agent, an alkyating agent, a platinum agent, an anthracycline, a topoisomase inhibitor, or an antibiotic.
14. A method in accordance with claim 13, wherein the antimetabolite is 5-fluoro-uracil, methotrexate or fludarabine.
15. A method in accordance with claim 13, wherein the antimicrotubule agent is vincristine, vinblastine or a taxane.
16. A method in accordance with claim 14, wherein the taxane is paclitaxel or docetaxel.
17. A method in accordance with claim 12, wherein the alkylating agent is cyclophasphamide, melphalan, biochoroethylnitrosurea or hydroxyurea.
18. A method in accordance with claim 12, wherein the platinum agent is cisplatin, carboplatin, oxaliplatin, JM-216 or CI-973.
19. A method in accordance with claim 12, wherein the anthracycline is doxrubicin or daunorubicin.
20. A method in accordance with claim 12, wherein the antibiotic is mitomycin, idarubicin, adriamycin or daunomycin.
21. A method in accordance with claim 12, wherein the topoisomerase inhibitior is etoposide or camptothecins.
22. A method in accordance with claim 12, wherein the cytotoxic agent is estramustine phosphate or prednimustine.
23. A method in accordance with claim 11, wherein an antiproliferative effective amount of the cytotoxic agent is lower than the antiproliferative effective amount of the cytotoxic agent when administered alone.
24. The method of claim 5, wherein the compound of formula (III) is 1a,24-dihydroxyvitamin D2, 1.alpha.,24-dihydroxyvitamin D4, 1.alpha.,25-dihydroxyvitamin D2, 1.alpha.,25-dihydroxyvitamin D4, 1.alpha.-hydroxyvitamin D2 or 1.alpha.-hydroxyvitamin D4.
25. A method of treating a human to alleviate the pathological effects of breast cancer, colon cancer, testicular cancer, pancreatic cancer, endometrial cancer, small cell and non-small cell cancer of the lung (including squamous, adneocarcinoma and large cell types), squamous cell of the head and neck, bladder, ovarian and cervical cancers, myeloid and lymphocyltic leukemia, lymphoma, hepatic tumors, medullary thyroid carcinoma, multiple myeloma, melanoma, retinoblastoma or sarcomas of the soft tissue and bone, comprising administering to the human an therapeutic amount of a hypocalcemic hydroxyvitamin D compound.
26. A method of claim 25, wherein said hypocalcemic vitamin D is a 1.alpha.-hydroxyvitamin D compound represented by formula (III) wherein A1 and A2 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.
27. The method of claim 26, wherein said therapeutic amount is 0.01 µg/kg/day to 2.0 µg/kg/day.
28. The method of claim 26, wherein the compound of formula (III) is 1.alpha.,24-dihydroxyvitamin D2, 1.alpha.,24-dihydroxyvitamin D4, 1.alpha.,25-dihydroxyvitamin D2, 1.alpha.,25-dihydroxyvitamin D4, 1.alpha.-hydroxyvitamin D2 or 1.alpha.-hydroxyvitamin D4.
29. A method of enhancing the antiproliferative effect of a cytotoxic agent in a patient with a disease in need of treatment by a cytotoxic agent, comprising administering to the patient a therapeutic amount of hypocalcemic vitamin D compound and the cytotoxic agent.
30. A method in accordance with claim 29, wherein the hypocalcemic vitamin D
compound is administered from 0.5 to 7 days prior to administration of the cytotoxic agent.
31. A method in accordance with claim 29, wherein the hypocalcemic vitamin D
compound is administered 2 to 4 days prior to administration of the cytotoxic agent.
32. A method of claim 29, wherein said hypocalcemic vitamin D is a 1.alpha.-hydroxyvitamin D compound represented by formula (III) wherein A1 and A2 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.
33. The method of claim 32, wherein said therapeutic amount of the vitamin D
compound is 0.01 µg/kg/day to 2.0 µg/kg/day.
34. The method of claim 32, wherein the compound of formula (III) is 1.alpha.,24-dihydroxyvitamin D2, 1.alpha.,24-dihydroxyvitamin D4, 1.alpha.,25-dihydroxyvitamin D2, 1.alpha.,25-dihydroxyvitamin D4, 1.alpha.-hydroxyvitamin D2 or 1.alpha.-hydroxyvitamin D4.
35. A method in accordance with claim 32, wherein the cytotoxic agent is an antimetabolite, and antimicrotubule agent, an alkyating agent, a platinum agent, an anthracycline, a topoisomase inhibitor, or an antibiotic.
36. A method of inducing differentiation in malignant or neoplastic cells, comprising treating to the cells with a prodifferentiative amount of a hypocalcemic vitamin D
compound.
37. A method of treating in a subject tumor or neoplasm that expresses a vitamin D
receptor, comprising administering to the subject an effective amount of hypocalcemic vitamin D compound sufficient to raise a blood level of vitamin D to a sufficiently supraphysiological level for a sufficient period of time to inhibit growth of the tumor or neoplasm without causing hypercalcemia in the subject.
CA002450942A 2001-06-26 2002-06-26 Method of treating hyperproliferative diseases using active vitamin d analogues Abandoned CA2450942A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US09/891,814 2001-06-26
US09/891,814 US6503893B2 (en) 1996-12-30 2001-06-26 Method of treating hyperproliferative diseases using active vitamin D analogues
PCT/US2002/020475 WO2003000023A2 (en) 2001-06-26 2002-06-26 Method of treating hyperproliferative diseases using active vitamin d analogues

Publications (1)

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CA2450942A1 true CA2450942A1 (en) 2003-01-03

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US (2) US6503893B2 (en)
EP (1) EP1408983A4 (en)
JP (1) JP2004535429A (en)
KR (1) KR20040015753A (en)
CN (1) CN1234366C (en)
AU (1) AU2002322346B2 (en)
CA (1) CA2450942A1 (en)
IL (1) IL159068A0 (en)
MX (1) MXPA03011307A (en)
WO (1) WO2003000023A2 (en)

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JP2004535429A (en) 2004-11-25
WO2003000023A3 (en) 2003-07-31
US20020025950A1 (en) 2002-02-28
US6680309B2 (en) 2004-01-20
US20030130242A1 (en) 2003-07-10
EP1408983A4 (en) 2007-05-09
KR20040015753A (en) 2004-02-19
MXPA03011307A (en) 2004-06-08
US6503893B2 (en) 2003-01-07
CN1520302A (en) 2004-08-11

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