1 .alpha.-hydroxy-25-ene-vitamin D, analogs and uses thereof

• US 5,972,917 A
• Filed: 05/29/1998
• Issued: 10/26/1999
• Est. Priority Date: 05/29/1998
• Status: Expired due to Fees

• Current Assignee: Bone Care International Inc (Sanofi )
• Original Assignee: Bone Care International Inc (Sanofi )
• Inventors: Bishop, Charles W., Knutson, Joyce C., Strugnell, Stephen
• Primary Examiner(s): Criares, Theodore J.
• Application Number:
  US09/087,439
• Time in Patent Office: 515 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: A61K 31/593 9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
• 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 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• 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 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/18 of the parathyroid hormones

Abstract

The invention provides 1α-hydroxyvitamin D compounds in which the C-25 or equivalent position of the C-17 side chain has a double bond and method 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 represented by formula (I):

space="preserve" listing-type="equation">D-Z (I)

wherein the effect is treating or preventing bone loss or bone mineral content, hyperparathyroidism, cellular hyperproliferation, or modulating immune and inflammatory response or inflammatory response, and wherein D is D¹, D² or D³ moiety in which D¹ is a 1α

-hydroxyvitamin D moiety, D² is a 1α

-hydroxyprevitamin D moiety and D³ is a 1α

-hydroxycholesterol moiety or a 1α

-hydroxyergosterol moiety and Z is a C-17 side chain which is a saturated or unsaturated, substituted or unsubstituted, straight-chain or branched C₄ -C₈ hydrocarbon group in which the C-24 or equivalent position is bonded by a single C--C bond to a lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl, and in which the C-25 or equivalent position has a double bond.

2. The method of claim 1, wherein said 1α

-hydroxyvitamin D compound is a compound of formula (II);

##STR13## wherein Y is a methylene group if the bond to Y is a double bond or a methyl group or hydrogen if the bond to Y is a single bond; and

X is hydrogen, lower alkyl or lower fluoroalkyl.

3. The method according to claim 2, wherein said 1α

-hydroxyvitamin D compound is 1α

-hydroxy-25-ene-D₂ ;

1α

-hydroxy-25-ene-D₄ ;

1α

-hydroxy-25-oxo-D₂ ;

or 1α

-hydroxy-25-oxo-D₄.

4. The method of claim 1, wherein said 1α

-hydroxyvitamin D is a compound of formula (IIA);

##STR14## wherein Y is a methylene group if the bond to Y is a double bond or is a methyl group or hydrogen if the bond to Y is a single bond; and

X is hydrogen, lower alkyl or lower fluoroalkyl.

5. The method of claim 1, wherein said 1α

-hydroxyprevitamin D compound is a compound of formula (III);

##STR15## wherein X is hydrogen, lower alkyl or lower fluoroalkyl; and

Y is hydrogen or a methyl group.

6. The method of claim 1, wherein Z is a side chain represented by formula (VA):

##STR16## wherein n is an integer which is 1 or 2;

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

R⁴ and R⁵ are independently lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl;

A is carbon, oxygen, sulfur or nitrogen;

r and s are 1 when A is carbon;

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

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

R⁶ and R⁷ are independently hydrogen, lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl.

7. The method of claim 1, wherein Z is a side chain represented by formula (VC):

##STR17## wherein a dotted line along the side chain represents an optional additional C--C bond;

q is zero or an integer which is 1 or 2;

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

R⁴ and R⁵ 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

R⁶ and R⁷ independently are hydrogen, lower alkyl, lower alkenyl, lower fluoroalkyl or lower fluoroalkenyl.

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

15. The method of claim 14, wherein said bone agent is other vitamin D compounds, conjugated estrogens, sodium fluorides, biphosphonates, cobalamin, calcium receptor agonists, pertussin toxin, boron or DHEA.

8. A method of achieving an effect in a patient comprising administering an effective amount of a vitamin D compound which is represented by formula (I):

space="preserve" listing-type="equation">D-Z (I)

wherein the effect is increasing or maintaining bone mass or bone mineral content, lowering or maintaining lowered parathyroid hormone level, inhibiting hyperproliferative effects, inducing or enhancing cell differentiation modulating immune response, and modulating inflammatory response, and wherein D is D¹, D² or D³ moiety in which D¹ is a 1α

-hydroxyvitamin D moiety, D² is a 1α

-hydroxyprevitamin D moiety and D³ is a 1α

-hydroxycholesterol moiety or a 1α

-hydroxyergosterol moiety and Z is a C-17 side chain which is a saturated or unsaturated, substituted or unsubstituted, straight-chain or branched C₄ -C₁₈ hydrocarbon group in which the C-24 or equivalent position is bonded by a single C--C bond to a lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl, and in which the C-25 or equivalent position has a double bond.

9. The method of claim 8, wherein said vitamin D compound is a compound of formula (II):

##STR18## or of formula (III);

##STR19## wherein X is a hydrogen, lower alkyl or lower fluoroalkyl; and

Y is a methylene group if the bond to Y is a double bond or is a methyl group or hydrogen if the bond to Y is a single bond; and

wherein Z is a side chain of formula (VA);

##STR20## wherein n is an integer which is 1 or 2;

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

R⁴ and R⁵ 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

R⁶ and R⁷ are independently hydrogen, lower alkyl, lower alkenyl, lower fluoroalkyl or lower fluoroalkenyl;

or of formula (VC);

##STR21## wherein a dotted line along the side chain represents an optional additional C--C bond;

q is zero or an integer which is 1 or 2;

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

R⁴ and R⁵ 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

R⁶ and R⁷ are independently hydrogen, lower alkyl, lower alkenyl, lower fluoroalkyl or lower fluoroalkenyl.

10. A method of treating a human to alleviate the pathological effects of osteoporosis, hyperparathyroidism, psoriasis, skin cancer, breast cancer, colon cancer, prostate cancer, prostatic hyperplasia and impaired immune response, wherein the method comprises administering to the human a vitamin D compound which is represented by formula (I):

space="preserve" listing-type="equation">D-Z (I)

wherein the effect is treating or preventing bone loss or bone mineral content, hyperparathyroidism, cellular hyperproliferation, or modulating immune and inflammatory response or inflammatory response, wherein D is D¹, D² or D³ moiety in which D¹ is a 1α

-hydroxyvitamin D moiety, D² is a 1α

-hydroxyprevitamin D moiety and D³ is a 1α

-hydroxycholesterol moiety or a 1α

-hydroxyergosterol moiety and Z is a C-1 7 side chain which is a saturated or unsaturated, substituted or unsubstituted, straight-chain or branched C₄ -C₁₈ hydrocarbon group in which the C-24 or equivalent position is bonded by a single C--C bond to a lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl, and in which the C-25 or equivalent position has a double bond.

11. A pharmaceutical composition comprising an effective amount of a 1α

-hydroxyvitamin D compound which is represented by formula (I);

space="preserve" listing-type="equation">D-Z (I)

wherein the effect is treating or preventing bone loss or bone mineral content, hyperparathyroidism, cellular hyperproliferation, or modulating immune and inflammatory response or inflammatory response, wherein D is D¹, D² or D³ moiety in which D¹ is a 1α

-hydroxyvitamin D moiety, D² is a 1α

-hydroxyprevitamin D moiety and D³ is a 1α

-hydroxycholesterol moiety or a 1α

-hydroxyergosterol moiety and Z is a C-17 side chain which is a saturated or unsaturated, substituted or unsubstituted, straight-chain or branched C₄ -C₁₈ hydrocarbon group in which the C-24 or equivalent position is bonded by a single C--C bond to a lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl, and in which the C-25 or equivalent position has a double bond, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

12. The composition of claim 11, wherein the composition is orally administrable.

13. The composition of claim 11, wherein said vitamin D compound is presented in a dosage of 3.5 μ

g to about 1000 μ

g/week.

16. A 1α

-hydroxyvitamin D compound which is a compound of formula (II);

##STR22## or a compound of formula (III);

##STR23## wherein Z is a C-17 side chain which is a saturated or unsaturated, substituted or unsubstituted, straight-chain or branched C₄ -C₁₈ hydrocarbon group in which the C-24 or equivalent position is bonded by a single C--C bond to a lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl, and in which the C-25 or equivalent position has a double bond;

Y is a methylene group if the bond to Y is a double bond or a methyl group or hydrogen if the bond to Y is a single bond; and

X is hydrogen, lower alkyl or lower fluoroalkyl.

17. The compound of claim 16, wherein Z is a side chain of formula (VA):

##STR24## wherein n is an integer which is 1 or 2;

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

R⁴ and R⁵ 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

R⁶ and R⁷ are independently hydrogen, lower alkyl, lower alkenyl, lower fluoroalkyl or lower fluoroalkenyl;

or of formula (VC);

##STR25## wherein a dotted line along the side chain represents an optional additional C--C bond;

q is zero or an integer which is 1 or 2;

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

R⁴ and R⁵ 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

R⁶ and R⁷ are hydrogen, lower alkyl, lower alkenyl, lower fluoroalkyl or lower fluoroalkenyl.

18. A 1α

,24-dihydroxyvitamin D compound which is a compound of formula (II);

##STR26## or a compound of formula (III);

##STR27## or a compound of formula (IV);

##STR28## wherein Z is a side chain of formula (VE);

##STR29## wherein n is an integer which is 1 or 2;

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

R⁴ and R⁵ 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

R⁶ and R⁷ are hydrogen, lower alkyl, lower alkenyl, lower fluoroalkyl or lower fluoroalkenyl;

or of formula (VF);

##STR30## wherein q is zero or an integer which is 1 or 2;

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

R⁴ and R⁵ 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;

R⁶ and R⁷ independently are hydrogen, lower alkyl, lower alkenyl, lower fluoroalkyl or lower fluoroalkenyl.

19. The compound of claim 18, wherein Z is a side chain of formula (VG):

##STR31## or of formula (VH);

##STR32##