Low Calcemic, Highly Antiproliferative, Analogs of Calcitriol

• US 20100137262A1
• Filed: 04/18/2008
• Published: 06/03/2010
• Est. Priority Date: 04/18/2007
• Status: Active Grant

• Current Assignee: Johns Hopkins University
• Original Assignee: Johns Hopkins University
• Inventors: Borella, Scott, Genna, Douglas T., Petersen, Kimberly S., Hess, Lindsey C., Posner, Gary H.
• Granted Patent: US 9,481,646 B2
• Time in Patent Office: Days
• US Class Current: 514/167
• 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

1-42. -42. (canceled)

43. A compound having formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein;

is a single or double bond;

X is independently O, NR², S, S(O), or S(O)₂;

L₁ is independently a direct bond, or substituted or unsubstituted alkyl, wherein alkyl is optionally independently substituted with 1 to 3 R⁹ groups;

L₂ is independently a direct bond, or substituted or unsubstituted alkyl, wherein alkyl is optionally independently substituted with 1 to 3 R⁹ groups;

R¹ is independently substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroarylalkyl, wherein R¹ is optionally independently substituted with 1 to 5 R³ groups;

R² is H, alkyl, or perfluoroalkyl;

R³ is independently H, F, Cl, Br, I, OH, CN, NO₂, substituted or unsubstituted alkyl, perfluoroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, —

(CH₂)_jOR⁴, —

(CH₂)_jC(O)R⁴, —

(CH₂)_jC(NR⁷)R⁴, —

(CH₂)_jC(NNR⁷)R⁴, —

(CH₂)_jC(O)OR⁴, —

(CH₂)_jNR⁵R⁶, —

(CH₂)_jC(O)NR⁵R⁶, —

(CH₂)_jOC(O)NR⁵R⁶, —

(CH₂)_jNR⁷C(O)R⁴, —

(CH₂)_jNR⁷C(O)OR⁴, —

(CH₂)_jNR⁷C(O)NR⁵R⁶, —

(CH₂)_jS(O)_mR⁸, —

(CH₂)_jNR⁷S(O)₂R⁸, or —

(CH₂)_jS(O)₂NR⁵R⁶, wherein each j is independently an integer from 0 to 6, wherein m is independently an integer from 0 to 2, and wherein alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl are each optionally independently substituted with 1 to 3 R⁹ groups;

R⁴ is independently H, substituted or unsubstituted alkyl, perfluoroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroarylalkyl, wherein R⁴ is optionally independently substituted with 1 to 3 R⁹ groups;

R⁵, R⁶, R⁷ and R⁸ are each independently a direct bond, H, OH, —

(CH₂)_jOR⁹, substituted or unsubstituted alkyl, perfluoroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroarylalkyl, wherein R⁵, R⁶, R⁷, and R⁸ are each optionally independently substituted with 1 to 3 R⁹ groups, or

R⁷ and R⁸ are as described above, and R⁵ and R⁶, together with the N atom to which they are attached, form substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl, wherein R⁵ and R⁶ are each optionally independently substituted with 1 to 3 R⁹ groups; and

R⁹ is H, F, Cl, Br, I, OH, CN, NO₂, alkyl, perfluoroalkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —

(CH₂)_jOR¹⁰, —

(CH₂)_jC(O)R¹⁰, —

(CH₂)_jC(NR¹³)R⁴, —

(CH₂)_jC(O)OR¹⁰, —

(CH₂)_jNR¹¹R¹², —

(CH₂)_jC(O)NR¹¹R¹², —

(CH₂)_jOC(O)NR¹¹R¹², —

(CH₂)_jNR¹³C(O)R¹⁴, —

(CH₂)_jNR¹³C(O)OR¹⁰, —

(CH₂)_jNR¹³C(O)NR¹¹R¹², —

(CH₂)_jS(O)_mR¹⁵, —

(CH₂)_jNR¹³S(O)₂R¹⁵, or —

(CH₂)_jS(O)₂NR¹¹R¹²;

wherein each j is independently an integer from 0 to 6, wherein m is independently an integer from 0 to 2; and

R¹⁰, R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ are each independently H, F, Cl, Br, I, OH, CN, NO₂, alkyl, perfluoroalkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl.

44. The compound of claim 43, wherein:

X is independently O;

L₁ is independently a direct bond, or (C₁-C₆)alkyl;

L₂ is independently a direct bond, or (C₁-C₆)alkyl;

R¹ is independently substituted or unsubstituted (C₁-C₁₂)alkyl, substituted or unsubstituted (C₃-C₁₂)cycloalkyl, substituted or unsubstituted (C₂-C₁₂)alkenyl, substituted or unsubstituted (C₄-C₁₂)cycloalkenyl, or substituted or unsubstituted (C₂-C₁₂)alkynyl, wherein R¹ is optionally independently substituted with 1 to 3 R³ groups; and

R³ is independently H, F, Cl, Br, I, OH, CN, NO₂, substituted or unsubstituted alkyl, perfluoroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, —

(CH₂)_jOR⁴, —

(CH₂)₃C(O)R⁴, —

(CH₂)_jC(NR⁷)R⁴, —

(CH₂)_jC(NNR⁷)R⁴, —

(CH₂)_jC(O)OR⁴, —

(CH₂)_jNR⁵R⁶, —

(CH₂)_jC(O)NR⁵R⁶, —

(CH₂)_jOC(O)NR⁵R⁶, —

(CH₂)_jNR⁷C(O)R⁴, —

(CH₂)_jNR⁷C(O)OR⁴, —

(CH₂)_jNR⁷C(O)NR⁵R⁶, —

(CH₂)_jS(O)_mR⁸, —

(CH₂)_jNR⁷S(O)₂R⁸, or —

(CH₂)_jS(O)₂NR⁵R⁶.

45. The compound of claim 43, wherein:

X is independently O;

L₁ is independently a direct bond, or (C₁-C₆)alkyl;

L₂ is independently a direct bond, or (C₁-C₆)alkyl;

R¹ is independently substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted furanyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted thiofuranyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isooxazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, wherein R¹ is optionally independently substituted with 1 to 3 R³ groups; and

R³ is independently H, F, Cl, Br, I, OH, CN, NO₂, substituted or unsubstituted alkyl, perfluoroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, —

(CH₂)_jOR⁴, —

(CH₂)_jC(O)R⁴, —

(CH₂)_jC(NR⁷)R⁴, —

(CH₂)_jC(NNR⁷)R⁴, —

(CH₂)_jC(O)OR⁴, —

(CH₂)_jNR⁵R⁶, —

(CH₂)_jC(O)NR⁵R⁶, —

(CH₂)_jOC(O)NR⁵R⁶, —

(CH₂)₃NR⁷C(O)R⁴, —

(CH₂)_jNR⁷C(O)OR⁴, —

(CH₂)_jNR⁷C(O)NR⁵R⁶, —

(CH₂)_jS(O)_mR⁸, —

(CH₂)_jNR⁷S(O)₂R⁸, or —

(CH₂)_jS(O)₂NR⁵R⁶.

46. The compound of claim 43, wherein the compound of formula I has formula IV:

wherein;

q is independently an integer from 0 to 2;

R¹ is independently substituted or unsubstituted (C₁-C₁₂)alkyl, substituted or unsubstituted (C₃-C₁₂)cycloalkyl, substituted or unsubstituted (C₂-C₁₂)alkenyl, substituted or unsubstituted (C₄-C₁₂)cycloalkenyl, or substituted or unsubstituted (C₂-C₁₂)alkynyl, wherein R¹ is optionally independently substituted with 1 to 3 R³ groups; and

R³ is independently H, F, Cl, Br, I, OH, CN, NO₂, substituted or unsubstituted alkyl, perfluoroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, —

(CH₂)_jOR⁴, —

(CH₂)_jC(O)R⁴, —

(CH₂)_jC(NR⁷)R⁴, —

(CH₂)_jC(NNR⁷)R⁴, —

(CH₂)_jC(O)OR⁴, —

(CH₂)_jNR⁵R⁶, —

(CH₂)_jC(O)NR⁵R⁶, —

(CH₂)_jOC(O)NR⁵R⁶, —

(CH₂)_jNR⁷C(O)R⁴, —

(CH₂)_jNR⁷C(O)OR⁴, —

(CH₂)_jNR⁷C(O)NR⁵R⁶, —

(CH₂)_jS(O)_mR⁸, —

(CH₂)_jNR⁷S(O)₂R⁸, or —

(CH₂)_jS(O)₂NR⁵R⁶.

47. The compound of claim 43, wherein the compound of formula I has formula IV:

wherein;

q is independently an integer from 0 to 2;

R¹ is independently substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted furanyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted thiofuranyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isooxazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, wherein R¹ is optionally independently substituted with 1 to 3 R³ groups; and

R³ is independently H, F, Cl, Br, I, OH, CN, NO₂, substituted or unsubstituted alkyl, perfluoroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, —

(CH₂)_jOR⁴, —

(CH₂)₃C(O)R⁴, —

(CH₂)_jC(NR⁷)R⁴, —

(CH₂)_jC(NNR⁷)R⁴, —

(CH₂)_jC(O)OR⁴, —

(CH₂)_jNR⁵R⁶, —

(CH₂)_jC(O)NR⁵R⁶, —

(CH₂)_jOC(O)NR⁵R⁶, —

(CH₂)_jNR⁷C(O)R⁴, —

(CH₂)_jNR⁷C(O)OR⁴, —

(CH₂)_jNR⁷C(O)NR⁵R⁶, —

(CH₂)_jS(O)_mR⁸, —

(CH₂)_jNR⁷S(O)₂R⁸, or —

(CH₂)_jS(O)₂NR⁵R⁶.

48. The compound of claim 43, wherein the compound of formula I has formula VII:

wherein;

R¹ is independently substituted or unsubstituted (C₁-C₁₂)alkyl, substituted or unsubstituted (C₃-C₁₂)cycloalkyl, substituted or unsubstituted (C₂-C₁₂)alkenyl, substituted or unsubstituted (C₄-C₁₂)cycloalkenyl, or substituted or unsubstituted (C₂-C₁₂)alkynyl, wherein R¹ is optionally independently substituted with 1 to 3 R³ groups; and

R³ is independently H, F, Cl, Br, I, OH, CN, NO₂, substituted or unsubstituted alkyl, perfluoroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, —

(CH₂)_jOR⁴, —

(CH₂)_jC(O)R⁴, —

(CH₂)_jC(NR⁷)R⁴, —

(CH₂)_jC(NNR⁷)R⁴, —

(CH₂)_jC(O)OR⁴, —

(CH₂)_jNR⁵R⁶, —

(CH₂)_jC(O)NR⁵R⁶, —

(CH₂)_jOC(O)NR⁵R⁶, —

(CH₂)_jNR⁷C(O)R⁴, —

(CH₂)_jNR⁷C(O)OR⁴, —

(CH₂)_jNR⁷C(O)NR⁵R⁶, —

(CH₂)_jS(O)_mR⁸, —

(CH₂)_jNR⁷S(O)₂R⁸, or —

(CH₂)_jS(O)₂NR⁵R⁶.

49. The compound of claim 43, wherein the compound of formula I has formula VII:

wherein;

R¹ is independently substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted furanyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted thiofuranyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isooxazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, wherein R¹ is optionally independently substituted with 1 to 3 R³ groups; and

R³ is independently H, F, Cl, Br, I, OH, CN, NO₂, substituted or unsubstituted alkyl, perfluoroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, —

(CH₂)OR⁴, —

(CH₂)_jC(O)R⁴, —

(CH₂)_jC(NR⁷)R⁴, —

(CH₂)_jC(NNR⁷)R⁴, —

(CH₂)_jC(O)OR⁴, —

(CH₂)_jNR⁵R⁶, —

(CH₂)_jC(O)NR⁵R⁶, —

(CH₂)_jOC(O)NR⁵R⁶, —

(CH₂)_jNR⁷C(O)R⁴, —

(CH₂)_jNR⁷C(O)OR⁴, —

(CH₂)_jNR⁷C(O)NR⁵R⁶, —

(CH₂)_jS(O)_mR⁸, —

(CH₂)_jNR⁷S(O)₂R⁸, or —

(CH₂)_jS(O)₂NR⁵R⁶.

50. The compound of claim 43, wherein:

L₁ is independently a direct bond,

L₂ is independently a direct bond or CH₂; and

R¹ is independently;

wherein n is independently an integer from 0 to 2.

51. The compound of claim 43, wherein the compound of formula I has formula:

52. A pharmaceutical composition, comprising an effective amount of one or more of the compounds of formula I of claim 43, together with one or more pharmaceutically acceptable carriers, optionally in topical, oral or injectable form.

55. A method of preparing the compound of formula I of claim 43, comprising:

a) reacting the compound of formula XI with base to form the corresponding anion;

b) coupling the anion with the compound of formula XII, wherein PG is a protecting group; and

c) removing the protecting groups to provide the compound of formula I.

56. The method of claim 55, wherein the base is an alkali metal or organolithium compound;

and the protecting group is a silyl protecting group.

57. The method of claim 56, wherein the alkali metal is sodium hydride or lithium hydride;

the organolithium compound is n-butyl lithium, sec-butyl lithium or tert-butyl lithium, and the silyl protecting group is tert-butyldimethylsilane.