.

Pharmaceutical Business Intelligence

  • Anticipate P&T budget requirements
  • Evaluate market entry opportunities
  • Find generic sources and suppliers
  • Predict branded drug patent expiration

► Plans and Pricing

Upgrade to enjoy subscriber-only features like email alerts and data export. See the Plans and Pricing

DrugPatentWatch Database Preview

Details for Patent: 6,573,256

« Back to Dashboard

Details for Patent: 6,573,256

Title: Method of inhibiting angiogenesis using active vitamin D analogues
Abstract:Methods utilizing active vitamin D analogs for the inhibition of angiogenesis associated with malignant and neoplasmic cells. Methods comprise the application of an effective amount of a hypocalcemic vitamin D compound to inhibit the angiogenesis of malignant cells, inducing the apoptosis of malignant cells, and regressing the growth of tumorous cells.
Inventor(s): Bishop; Charles W. (Madison, WI), Mazess; Richard B. (Madison, WI)
Assignee: Bone Care International, Inc. (Middleton, WI)
Filing Date:Jun 26, 2001
Application Number:09/891,805
Claims:1. A method of inhibiting angiogenesis associated with malignant or neoplastic cells, comprising treating the cells with an effective amount of a hypocalcemic hydroxy vitamin D compound having a hydrocarbon moiety at the C.sub.24 position, the cells being cancers of the breast, colon, prostate, testes, lung, neck and head, pancreas, endometrium, bladder, cervix, ovaries, squamous cell carcinomas, myeloid and lymphocytic leukemia, lymphoma, medullary thyroid carcinoma, melanoma, multiple myeloma, retinoblastoma or sarcomas of the soft tissues and bone.

2. A method of inhibiting angiogenesis associated with malignancy or neoplasm in a subject in need thereof, comprising administering to the subject an effective amount of a hypocalcemic vitamin D compound represented by formula I: ##STR4##

wherein A.sup.1 and A.sup.2 each are hydrogen or a carbon--carbon bond, thus forming a double bond between C-22 and C-23; R.sup.1 and R.sup.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.sup.1 and R.sup.2 cannot both be an alkenyl group, or taken together with the carbon to which they are bonded, form a C.sub.3 -C.sub.8 cyclocarbon ring; R.sup.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.sup.1 is hydrogen or hydroxyl, and X.sup.2 is hydrogen or hydroxyl, or, may be taken with R.sup.1 or R.sup.2, to constitute a double bond, and X.sup.3 is hydrogen or hydroxyl provided that at least one of X.sup.1, X.sup.2 and X.sup.3 is hydroxyl; and Y is a methylene group if the bond to Y is a double or is a methyl group or hydrogen if the bond to Y is a single bond sufficient to inhibit angiogenesis of the malignancy or neoplasm.

3. A method in accordance with claim 2, wherein the hypocalcemic vitamin D compound is represented by formula II: ##STR5##

wherein A.sup.1 and A.sup.2 each are hydrogen or a carbon--carbon bond, thus forming a double bond between C-22 and C-23; R.sup.1 and R.sup.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.sup.1 and R.sup.2 cannot both be an alkenyl group, or taken together with the carbon to which they are bonded, form a C.sub.3 -C.sub.8 cyclocarbon ring; R.sup.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.sup.1 is hydrogen or hydroxyl, and X.sup.2 is hydrogen or hydroxyl, or, may be taken with R.sup.1 or R.sup.2, to constitute a double bond, and Y is a methylene group if the bond to Y is a double or is a methyl group or hydrogen if the bond to Y is a single bond.

4. The method of claim 2, wherein said hypocalcemic vitamin D is a 1.alpha.-hydroxyvitamin D compound is represented by formula III: ##STR6##

wherein A.sup.1 and A.sup.2 each are hydrogen or a carbon--carbon bond, thus forming a double bond between C-22 and C-23; R.sup.1 and R.sup.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.sup.1 and R.sup.2 cannot both be an alkenyl group, or taken together with the carbon to which they are bonded, form a C.sub.3 -C.sub.8 cyclocarbon ring; R.sup.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.sup.1 is hydrogen or hydroxyl, and X.sup.2 is hydrogen or hydroxyl, or, may be taken with R.sup.1 or R.sup.2, to constitute a double bond.

5. The method of claim 4, wherein the compound of formula (I) is 1.alpha.,24-dihydroxyvitamin D.sub.2, 1.alpha.,24-dihydroxyvitamin D.sub.4, 1.alpha.,25-dihydroxyvitamin D.sub.2, 1.alpha.,25-dihydroxyvitamin D.sub.4, 1.alpha.-hydroxyvitamin D.sub.2 or 1.alpha.-hydroxyvitamin D.sub.4.

6. A method in accordance with claim 2, wherein a dosing regimen for the hypocalcemic vitamin D compound is a daily regimen or an episodic regimen.

7. A method in accordance with claim 6, wherein the espisodic regimen is a dose once every 2 to 7 days.

8. A method in accordance with claim 6, wherein the hypocalcemic vitamin D compound is administered daily at a dose of about 10 to 100 .mu.g/day.

9. A method in accordance with claim 6, wherein the hypocalcemic vitamin D compound is administered orally, is administered intravenously, is injected directly into a cancer site, or is regionally delivered to a cancer site.

10. A method in accordance with claim 9, wherein the hypocalcemic vitamin D compound is administered orally.

11. A method in accordance with claim 2, wherein the hypocalcemic vitamin D compound is co-administered with a cytotoxic agent.

12. A method in accordance with claim 11, wherein the cytotoxic agent is an antimetabolite, and antimicrotubule agent, an alkyating agent, a platinum agent, an anthracycline, a topoisomase inhibitor, or an antibiotic.

13. A method in accordance with claim 12, wherein the antimetabolite is 5-fluorouracil, methotrexate or fludarabine.

14. A method in accordance with claim 12, wherein the antimicrotubule agent isvincristine, vinblastine or a taxane.

15. A method in accordance with claim 11, wherein the taxane is paclitaxel or docetaxel.

16. A method in accordance with claim 12, wherein the alkylating agent is cyclophasphamide, melphalan, biochoroethylnitrosurea or hydroxyurea.

17. A method in accordance with claim 12, wherein the platinum agent is cisplatin, carboplatin, oxaliplatin, JM-216 or CI-973.

18. A method in accordance with claim 12, wherein the anthracycline is doxrubicin or daunorubicin.

19. A method in accordance with claim 12, wherein the antibiotic is mitomycin, idarubicin, adriamycin or daunomycin.

20. A method in accordance with claim 12, wherein the topoisomerase inhibitior is etoposide or camptothecins.

21. A method in accordance with claim 12, wherein the cytotoxic agent is estramustine phosphate or prednimustine.

22. A method of treating a human to inhibit angiogenesis associated with breast cancer, colon cancer, prostate cancer, testicular cancer, pancreatic cancer, endometrial cancer, small cell and non-small cell cancer of the lung (including squamous, adneocarcinoma 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 effective amount of a hypocalcemic vitamin D compound.

23. A method of claim 22, wherein said hypocalcemic vitamin D is a 1.alpha.-hydroxyvitamin D compound represented by formula III: ##STR7##

wherein A.sup.1 and A.sup.2 each are hydrogen or a carbon--carbon bond, thus forming a double bond between C-22 and C-23; R.sup.1 and R.sup.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.sup.1 and R.sup.2 cannot both be an alkenyl group, or taken together with the carbon to which they are bonded, form a C.sub.3 -C.sub.8 cyclocarbon ring; R.sup.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.sup.1 is hydrogen or hydroxyl, and X.sup.2 is hydrogen or hydroxyl, or, may be taken with R.sup.1 or R.sup.2, to constitute a double bond.

24. The method of claim 23, wherein said therapeutic amount is 0.01 .mu.g/kg/day to 2.0 .mu.g/kg/day.

25. The method of claim 23, wherein the compound of formula (I) is 1.alpha.,24-dihydroxyvitamin D.sub.2, 1.alpha.,24-dihydroxyvitamin D.sub.4,1.alpha.25-dihydroxyvitamin D.sub.2, 1.alpha.,25-dihydroxyvitamin D.sub.4, 1.alpha.-hydroxyvitamin D.sub.2 or 1.alpha.-hydroxyvitamin D.sub.4.

26. A method of treating a human to inhibit angiogenesis associated with malignant cells, comprising administering to the patient a hypocalcemic vitamin D compound and a cytotoxic agent.

27. A method in accordance with claim 26, wherein the hypocalcemic vitamin D compound is administered from 0.5 to 7 days prior to administration of the cytotoxic agent.

28. A method in accordance with claim 26, wherein the hypocalcemic vitamin D compound is administered 2 to 4 days prior to administration of the cytotoxic agent.

29. A method of claim 26, wherein said hypocalcemic vitamin D is a 1.alpha.-hydroxyvitamin D compound represented by formula III: ##STR8##

wherein A.sup.1 and A.sup.2 each are hydrogen or a carbon--carbon bond, thus forming a double bond between C-22 and C-23; R.sup.1 and R.sup.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.sup.1 and R.sup.2 cannot both be an alkenyl group, or taken together with the carbon to which they are bonded, form a C.sub.3 -C.sub.8 cyclocarbon ring; R.sup.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.sup.1 is hydrogen or hydroxyl, or, taken with R.sup.3, constitutes a bond when R.sup.3 is an alkenyl group, and X.sup.2 is hydrogen or hydroxyl, or, taken with R.sup.1 or R.sup.2, constitutes a double bond.

30. The method of claim 29, wherein said therapeutic amount is 0.01 .mu.g/kg/day to 2.0 .mu.g/kg/day.

31. The method of claim 29, wherein the compound of formula (I) is 1.alpha.,24-dihydroxyvitamin D.sub.2, 1.alpha.,24-dihydroxyvitamin D.sub.4, 1.alpha.,25-dihydroxyvitamin D.sub.2, 1.alpha.,25-dihydroxyvitamin D.sub.4, 1.alpha.-hydroxyvitamin D.sub.2 or 1.alpha.-hydroxyvitamin D.sub.4.

32. A method in accordance with claim 29, wherein the cytotoxic agent is an antimetabolite, and antimicrotubule agent, an alkyating agent, a platinum agent, an anthracycline, a topoisomase inhibitor, or an antibiotic.

33. A method of inducing apoptosis of malignant or neoplastic cells, comprising treating the cells with an effective amount of a hypocalcemic vitamin D compound, the cells being cancers of the breast, colon, prostate, testes, lung, neck and head, pancreas, endometrium, bladder, cervix, ovaries, squamous cell carcinoma, myeloid and lymphocytic leukemia, lymphoma, medullary thyroid carcinoma, melanoma, multiple myeloma, retinoblastoma or sarcomas of the soft tissues and bone.

34. A method of inducing the regression of tumor cells comprising treating the cells with an effective amount of a hypocalcemic vitamin D compound, which inhibits angeogenesis associated with malignancy the cells being cancers of the breast, colon, prostate, testes, lung, neck and head, pancreas, endometrium, bladder, cervix, ovaries, squamous cell carcinoma, myeloid and lymphocytic leukemia, lymphoma, medullary thyroid carcinoma, melanoma, multiple myeloma, retinoblastoma or sarcomas of the soft tissues and bone.
« Back to Dashboard

For more information try a trial or see the database preview and plans and pricing

Drugs may be covered by multiple patents or regulatory protections. All trademarks and applicant names are the property of their respective owners or licensors. Although great care is taken in the proper and correct provision of this service, thinkBiotech LLC does not accept any responsibility for possible consequences of errors or omissions in the provided data. The data presented herein is for information purposes only. There is no warranty that the data contained herein is error free. thinkBiotech performs no independent verifification of facts as provided by public sources nor are attempts made to provide legal or investing advice. Any reliance on data provided herein is done solely at the discretion of the user. Users of this service are advised to seek professional advice and independent confirmation before considering acting on any of the provided information. thinkBiotech LLC reserves the right to amend, extend or withdraw any part or all of the offered service without notice.

`abc