24-hydroxyvitamin D, analogs and uses thereof

• US 6,242,434 B1
• Filed: 05/29/1998
• Issued: 06/05/2001
• Est. Priority Date: 08/08/1997
• Status: Expired due to Term

• Current Assignee: Genzyme Corporation (Sanofi )
• Original Assignee: Bone Care International LLC
• Inventors: Bishop, Charles W., Knutson, Joyce C., Strugnell, Stephen
• Primary Examiner(s): Criares, Theodore J.
• Application Number:
  US09/086,969
• Time in Patent Office: 1,103 Days
• Field of Search: 514/167, 552/653
• US Class Current: 514/167
• CPC Class Codes: A61K 31/59 Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
• CPC Class Codes: A61K 31/592 9,10-Secoergostane derivatives, e.g. ergocalciferol, i.e. vitamin D2
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 3/02 Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 3/14 for calcium homeostasis vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 5/18 of the parathyroid hormones
• CPC Class Codes: A61P 5/20 for decreasing, blocking or antagonising the activity of PTH
• 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

Abstract

The invention provides 24-hydroxyvitamin D compounds and methods for their use in the treatment and prophylaxis of hyperparathyroidism and hyperproliferative diseases, and in the modulation of the immune and inflammatory responses as well as the treatment of bone depletive disorders.

Claims

1. A method of achieving an effect in a patient comprising administering an effective amount of a vitamin D compound which is a 24-hydroxyvitamin D wherein the effect is treating or preventing bone loss or bone mineral content, hyperparathyroidism, hyperproliferation, or modulating the immune and inflammatory responses, and wherein said 24-hydroxyvitamin D is a compound of formula (I):

wherein Z is a side chain of formula IIC, IID, or IIE;

wherein a dotted line along the side chain represents an optional additional C—

C bond;

q is zero;

R³ is hydrogen, lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl;

R⁴ and R⁷ are independently lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl;

A is carbon, oxygen, sulfur or nitrogen;

r is 1 and s is zero when A is nitrogen;

r and s are 1 when A is carbon;

r and s are zero when A is sulfur or oxygen;

R⁹ and R¹⁰ are independently hydrogen, lower alkyl, lower alkenyl, lower fluoroalkyl or lower fluoroalkenyl;

n is 1;

Y is a methylene group if Y is double bonded to the A-ring or a methyl group or hydrogen if Y is single bonded; and

X is hydrogen, lower alkyl or lower fluoroalkyl.

2. The method of claim 1 wherein Z is a side chain of formula (IIC).

3. The method of claim 1 wherein Z is a side chain of formula (IID).

4. The method of claim 1 wherein Z is a side chain of formula (IIE).

5. The method of claim 4 wherein said 24-hydroxyvitamin D compound is 24-OH-25-ene-D₂.

10. The method of claim 1 wherein said compound is administered in combination with a bone agent, a cytotoxic agent, an immune response regulating agent, an antiinflammatory agent or combinations thereof.

11. The method of claim 10 wherein said bone agent is other vitamin D compounds, conjugated estrogens, sodium fluorides, biphosphonates, cobalamin, calcium receptor agonists, pertussin toxin, boron or DHEA.

6. A 24-hydroxyvitamin D compound which is a compound of formula (I):

wherein Y is a methylene group if Y is double bonded to the A-ring or a methyl group or hydrogen if Y is single bonded;

X is hydrogen, lower alkyl or lower fluoroalkyl; and

Z is a side chain of formula (IIC);

wherein n is 1;

R³ is hydrogen, lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl;

R⁴ and R⁷ are independently lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl;

A is carbon, oxygen, sulfur or nitrogen;

r is 1 and s is zero when A is nitrogen;

r and s are 1 when A is carbon;

r and s are zero when A is sulfur or oxygen; and

R⁹ and R¹⁰ are independently hydrogen, lower alkyl, lower alkenyl, lower fluoroalkyl or lower fluoroalkenyl.

14. The compound of claim 6 in a pharmaceutical composition including a pharmaceutically acceptable carrier, adjuvant or vehicle, wherein the composition is further combined with a bone agent, a cytotoxic agent, an immune response regulating agent, an antiinflammatory agent or combinations thereof.

7. A 24-hydroxyvitamin D compound which is a compound of formula (I):

wherein Y is a methylene group if Y is double bonded to the A-ring or a methyl group or hydrogen if Y is single bonded;

X is hydrogen, lower alkyl or lower fluoroalkyl; and

Z is a side chain of formula (IIE);

wherein a dotted line along the side chain represents an optional additional C—

C bond;

q is zero;

R³ is hydrogen, lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl;

R⁴ and R⁷ are independently lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl;

A is carbon, oxygen, sulfur or nitrogen;

r is 1 and s is zero when A is nitrogen;

r and s are 1 when A is carbon;

r and s are zero when A is sulfur or oxygen; and

R⁹ and R¹⁰ are independently hydrogen, lower alkyl, lower alkenyl, lower fluoroalkyl or lower fluoroalkenyl.

13. The compound of claim 7 in a pharmaceutical composition including a pharmaceutically acceptable carrier, adjuvant or vehicle, wherein the composition is further combined with a bone agent, a cytotoxic agent, an immune response regulating agent, an antiinflammatory agent or combinations thereof.

8. A 24-hydroxyprevitamin D which is a compound of formula (III):

wherein Y is a methyl group or hydrogen;

X is hydrogen, lower alkyl or lower fluoroalkyl; and

Z is a side chain of formula (IIC);

wherein n is an integer which is 1;

R³ is hydrogen, lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl, R⁴ and R⁷ are independently lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl;

A is carbon, oxygen, sulfur or nitrogen;

r is 1 and s is zero when A is nitrogen;

r and s are 1 when A is carbon;

r and s are zero when A is sulfur or oxygen;

R⁹ and R¹⁰ are independently hydrogen, lower alkyl, lower alkenyl, lower fluoroalkyl or lower fluoroalkenyl.

12. The compound of claim 8 in a pharmaceutical composition including a pharmaceutically acceptable carrier, adjuvant or vehicle, wherein the composition is further combined with effective amounts of a bone agent, a cytotoxic agent, an immune response regulating agent, an antiinflammatory agent or combinations thereof.

9. A 24-hydroxyprevitamin D which is a compound of formula (III):

wherein Y is a methyl group or hydrogen;

X is hydrogen, lower alkyl or lower fluoroalkyl; and

Z is a side chain of formula (IIE);

wherein a dotted line along the side chain represents an optional additional C—

C bond;

q is zero or an integer which is 1;

R³ is hydrogen, lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl;

R⁴ and R⁷ are independently lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl;

A is carbon, oxygen, sulfur or nitrogen;

r is 1 and s is zero when A is nitrogen;

r and s are 1 when A is carbon;

r and s are zero when A is sulfur or oxygen;

R⁹ and R¹⁰ are independently hydrogen, lower alkyl, lower alkenyl, lower fluoroalkyl or lower fluoroalkenyl.