Low calcemic, highly antiproliferative, analogs of calcitriol

• US 9,481,646 B2
• Filed: 04/18/2008
• Issued: 11/01/2016
• Est. Priority Date: 04/18/2007
• Status: Expired due to Fees

• Current Assignee: Johns Hopkins University
• Original Assignee: Johns Hopkins University
• Inventors: Posner, Gary H., Petersen, Kimberly S., Hess, Lindsey C., Genna, Douglas T., Borella, Scott
• Primary Examiner(s): QAZI, SABIHA NAIM
• Application Number:
  US12/596,252
• Publication Number:
  US 20100137262A1
• Time in Patent Office: 3,119 Days
• Field of Search: 514/167, 552/653
• US Class Current: 1/1
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 3/02 Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 5/20 for decreasing, blocking or antagonising the activity of PTH
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 2601/16 the ring being unsaturated
• CPC Class Codes: C07C 2602/24 the ring system containing nine carbon atoms, e.g. perhydroindane
• CPC Class Codes: C07C 401/00 Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
• CPC Class Codes: C07D 307/42 Singly bound oxygen atoms

Abstract

The disclosure provides compounds, compositions and methods using these compounds and compositions to stimulate the differentiation of cells and inhibit excessive cell proliferation of certain cells, including cancer cells and skin cells, which may be useful in the treatment of diseases characterized by abnormal cell proliferation and/or cell differentiation such as leukemia, myelofibrosis and psoriasis without the well known effect on calcium metabolism, which gives rise to hypercalcemia.

Claims

1. A compound having formula I:

2. The compound of claim 1, wherein the compound of formula I has formula IV:

3. A method of treating a disorder characterized by abnormal cell-proliferation and/or cell-differentiation, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I of claim 1, wherein the disorder is selected from the group consisting of leukemia, myelofibrosis and psoriasis.

4. A method of treating secondary hyperparathyroidism, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I of claim 1.

5. A method of preparing the compound of formula I of claim 1, comprising:

6. The method of claim 5, wherein the base is an alkali metal hydride or organolithium compound;

and the protecting group is a silyl protecting group.