1-deoxy analogs of 1,25-dihydroxyvitamin D3 compounds

Patent metadata

Field	Value
Publication number	US-9775903-B2
Application number	US-201113521980-A
Country	US
Kind code	B2
Filing date	Jan 13, 2011
Priority date	Jan 13, 2010
Publication date	Oct 3, 2017
Grant date	Oct 3, 2017

Abstract

This present disclosure is directed to novel prodrugs of activated vitamin D3 compounds. The prodrugs can be designed to have one or more beneficial properties, such as selective inhibition of the enzyme CYP24, low calcemic activity, and anti-proliferative activity. Specifically, these prodrugs are 1-deoxy prohormones of active Vitamin D analogs, e.g. analogs of calcitriol. This disclosure is also directed to pharmaceutical and diagnostic compositions containing the prodrugs of the invention, and to their medical use, particularly as prodrugs in the treatment and/or prevention of diseases.

First claim

What is claimed is:

1. A compound having Formula I, or a pharmaceutically acceptable salt, solvate, or hydrate thereof:

wherein each independently is a single bond or a double bond;
n is 0, 1 or 2;
R 1 is selected from the group consisting of OH, OC 1-6 alkyl, and halo;
R 2 and R 3 are each independently H or halo, or together form ═CH 2 ;
R 4 is C 1-6 alkyl;
R 5 and R 6 are each independently H, halo, C 1-4 alkyl, or can be taken, together with the carbon atom to which they are bound, to form a C 3-6 cycloalkyl ring, with the proviso that when between carbon-23 and carbon-24 is a double bond, then R 5 is absent;
R 7 is selected from the group consisting of O, NH, N(C 1-6 alkyl), and NC(O)R 9 ;
R 8 is selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, aryl and heteroaryl, wherein each of C 1-6 alkyl, C 3-6 cycloalkyl, aryl and heteroaryl are either unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of C 1-4 alkyl, OC 1-4 alkyl, CF 3 , NO 2 , halo, OH, OCF 3 , SH, SC 1-4 alkyl, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl)(C 1-4 alkyl), and CN; and
R 9 is selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, aryl-C 1-4 alkyl, aryl and heteroaryl, wherein each of C 1-6 alkyl, C 3-6 cycloalkyl, aryl and heteroaryl are either unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of C 1-4 alkyl, OC 1-4 alkyl, CF 3 , NO 2 , halo;
with the proviso that when n is 0, then R 7 is O; and
with the proviso that when each is a single bond, n is 1, R 1 is OH, R 2 and R 3 together form ═CH 2 , R 4 is C 1 alkyl, R 5 and R 6 are each H, and R 8 is methyl, then R 7 is selected from the group consisting of NH, N(C 1-6 alkyl), and NC(O)R 9 .

2. The compound of claim 1 , wherein
n is 0 or 1;
R 1 is OH or halo;
R 2 and R 3 are either both H or together form ═CH 2 ;
R 4 is C 1-4 alkyl;
R 5 and R 6 are each independently H, halo, or C 1-2 alkyl, with the proviso that when between carbon-23 and carbon-24 is a double bond, then R 5 is absent;
R 7 is selected from the group consisting of 0, NH, and N(C 1-6 alkyl); and
R 8 is selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, aryl and heteroaryl, wherein each of C 1-6 alkyl, C 3-6 cycloalkyl, aryl and heteroaryl are either unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of C 1-4 alkyl, OC 1-4 alkyl, CF 3 , NO 2 , and halo.

3. The compound of claim 2 , wherein
R 1 is OH or F;
R 2 and R 3 together form ═CH 2 ;
R 4 is CH 3 ;
R 5 and R 6 are each independently H, halo, or CH 3 , with the proviso that when between carbon-23 and carbon-24 is a double bond, then R 5 is absent;
R 7 is O or NH; and
R 8 is selected from the group consisting of C 1-4 alkyl, aryl and heteroaryl, wherein each of aryl and heteroaryl are either unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of C 1-4 alkyl, OC 1-4 alkyl, CF 3 , NO 2 , and halo.

4. The compound of claim 3 , wherein
R 1 is OH; and,
R 5 and R 6 are each independently H, CH 3 , Cl, or F, with the proviso that when between carbon-23 and carbon-24 is a double bond, then R 5 is absent; and
R 8 is selected from the group consisting of C 1-4 alkyl and aryl, wherein aryl is either unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of C 1-4 alkyl, OC 1-4 alkyl, CF 3 , NO 2 , and halo.

5. The compound of claim 4 , selected from the group consisting of:

6. The compound of claim 1 having a relative stereochemistry as shown below:

7. The compound of claim 6 selected from the group consisting of:

8. A pharmaceutical composition comprising an admixture of a pharmaceutically-acceptable excipient and a compound:
(i) having Formula I, or a pharmaceutically acceptable salt, solvate, or hydrate thereof:

wherein each independently is a single bond or a double bond;
n is 0, 1 or 2;
R 1 is selected from the group consisting of OH, OC 1-6 alkyl, and halo;
R 2 and R 3 are each independently H or halo, or together form ═CH 2 ;
R 4 is C 1-6 alkyl;
R 5 and R 6 are each independently H, halo, C 1-4 alkyl, or can be taken, together with the carbon atom to which they are bound, to form a C 3-6 cycloalkyl ring, with the proviso that when between carbon-23 and carbon-24 is a double bond, then R 5 is absent;
R 7 is selected from the group consisting of O, NH, N(C 1-6 alkyl), and NC(O)R 9 ;
R 8 is selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, aryl and heteroaryl, wherein each of C 1-6 alkyl, C 3-6 cycloalkyl, aryl and heteroaryl are either unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of C 1-4 alkyl, OC 1-4 alkyl, CF 3 , NO 2 , halo, OH, OCF 3 , SH, SC 1-4 alkyl, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl)(C 1-4 alkyl), and CN; and
R 9 is selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, aryl-C 1-4 alkyl, aryl and heteroaryl, wherein each of C 1-6 alkyl, C 3-6 cycloalkyl, aryl and heteroaryl are either unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of C 1-4 alkyl, OC 1-4 alkyl, CF 3 , NO 2 , halo;
with the proviso that when n is 0, then R 7 is O; and
with the proviso that when each is a single bond, n is 1, R 1 is OH, R 2 and R 3 together form ═CH 2 , R 4 is C 1 alkyl, R 5 and R 6 are each H, and R 8 is methyl, then R 7 is selected from the group consisting of NH, N(C 1-6 alkyl), and NC(O)R 9 ; or
having Formula III, or a pharmaceutically acceptable salt, solvate, or hydrate thereof:

wherein is a single bond or a double bond;
R 1 is selected from the group consisting of OH, OC 1-6 alkyl, and halo;
R 2 and R 3 are each independently H or halo, or together form ═CH 2 ;
R 4 is C 1-6 alkyl;
R 5 and R 6 are each independently H, halo, C 1-4 alkyl, or can be taken, together with the carbon atom to which they are bound, to form a C 3-6 cycloalkyl ring;
R 7 is selected from the group consisting of O, NH, N(C 1-6 alkyl), and NC(O)R 9 ;
R 8 is selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, aryl and heteroaryl, wherein each of C 1-6 alkyl, C 3-6 cycloalkyl, aryl and heteroaryl are either unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of C 1-4 alkyl, OC 1-4 alkyl, CF 3 , NO 2 , halo, OH, OCF 3 , SH, SC 1-4 alkyl, NH 2 , N

Assignees

• Posner Gary H
• Hess Lindsey C
• Kalinda Alvin S
• Slack Rachel D
• Saha Uttam
• Petkovich P Martin
• Univ Johns Hopkins
• Opko Ireland Global Holdings Ltd

Inventors

• Posner Gary H
• Hess Lindsey C
• Kalinda Alvin S
• Slack Rachel D
• Saha Uttam
• Petkovich P Martin

Classifications

• A61P5/20

  for decreasing, blocking or antagonising the activity of PTH · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P5/18

  of the parathyroid hormones · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title