Method of locking 1.alpha.-OH of vitamin D compounds in axial orientation

• US 6,114,317 A
• Filed: 05/21/1998
• Issued: 09/05/2000
• Est. Priority Date: 05/21/1998
• Status: Expired due to Term

• Current Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Original Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Inventors: DeLuca, Hector F., Sicinski, Rafal R.
• Primary Examiner(s): Dees, Jose' G.
• Assistant Examiner(s): PRYOR, ALTON NATHANIEL
• Application Number:
  US09/082,776
• Time in Patent Office: 838 Days
• Field of Search: 552/653, 514/167
• US Class Current: 514/167
• CPC Class Codes: A61K 31/335 having oxygen as the only ring hetero atom, e.g. fungichromin
• CPC Class Codes: A61K 31/59 Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/10 Anti-acne agents
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• 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 25/00 Drugs for disorders of the nervous system
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 5/14 of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 5/18 of the parathyroid hormones
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07C 2601/14 The ring being saturated
• 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

Abstract

A method of modifying or altering the structure of a 1α-hydroxylated vitamin D compound to increase its biological activity by altering the conformational equilibrium of the A-ring to favor a chair conformation that presents the 1α-hydroxyl in the axial orientation. This is accomplished by either locking the A-ring chair conformation in a geometry having an axially orientated 1α-hydroxyl, or by the addition of one or more substituents to the A-ring which interact with other substituents in the molecule or on the A-ring to provide a driving force to the A-ring to adopt a chair conformation which presents the 1α-hydroxyl in the axial orientation.

Claims

1. A compound having the formula:

##STR22## where Y₁ and Y₂, which may be the same or different, are each selected from the group consisting of hydrogen and a hydroxy-protecting group;

where Y₃, Y₄, Y₅, Y₆, Y₇ and Y₈, which may be the same or different, are each selected from the group consisting of hydrogen, a methyl group or substituted methyl group of the formula --CR₁ R₂ R₃, an amino group or substituted amino group of the formula --NR₁ R₂, a phosphino group or substituted phosphino group of the formula --PR₁ R₂, an alkylsulfinyl group, an arylsulfinyl group, an alkylsulfonyl group, an arylsulfonyl group, and aryl, where R₁, R₂ and R₃ are each independently selected from the group consisting of hydrogen, C_1-5 alkyl, hydroxyalkyl, aminoalkyl, halogenalkyl, alkoxyalkyl, aryloxyalkyl, aryl, halogen, hydroxyl, protected hydroxy, alkoxyl, aryloxyl, acyl, an amino group, an alkyl substituted amino group, and an aryl substituted amino group, and where R₁ and R₂ taken together represent an oxo group or a group --(CH₂)_m -- where m is an integer having a value of from 2 to 5;

or Y₃ and Y₄ when taken together represent a methylene group;

or Y₇ and Y₈ when taken together represent a methylene group;

where Y₂ and Y₆, or Y₂ and Y₇, when taken together may represent the group --(CR₁ R₂)_n -- where n is an integer having a value of from 1 to 4 and wherein any of the groups --CR₁ R₂ -- may be replaced by an oxygen, sulfur or nitrogen atom;

where Y₅ and Y₈, or Y₅ and Y₃, or Y₃ and Y₈, when taken together may represent the group --CR₁ R₂)_r -- where r is an integer having a value of from 1 to 5 and wherein any of the groups --CR₁ R₂ -- may be replaced by an oxygen, sulfur or nitrogen atom; and

where Y₅ and Y₆ when taken together represent the group ═

CR₄ R₅ where R₄ and R₅, which may be the same or different, are each selected from the group consisting of hydrogen and Y₃ with the proviso that R₄ and R₅ cannot be a hydroxyl; and

where R₄ and Y₂ when taken together may represent the group --(CR₁ R₂)_s -- where s is an integer having a value of from 1 to 3; and

R is represented by the structure below ##STR23## where the stereochemical center at carbon 20 may have the R or S configuration, and where Z is selected from Y, --OY, --CH₂ OY, --C.tbd.CY and --CH.tbd.CHY, where the double bond may have the cis or trans geometry, and where Y is selected from hydrogen, methyl, --COR₁₀ and a radical of the structure;

##STR24## where x and y, independently, represent the integers from 0 to 5, where R₆ is selected from hydrogen, deuterium, hydroxy, protected hydroxy, fluoro, trifluoromethyl, and C_1-5 -alkyl, which may be straight chain or branched and, optionally, bear a hydroxy or protected-hydroxy substituent, and where each of R₇, R₈, and R₉, independently, is selected from deuterium, deuteroalkyl, hydrogen, fluoro, trifluoromethyl and C_1-5 alkyl, which may be straight-chain or branched, and optionally, bear a hydroxy or protected-hydroxy substituent, and where R₆ and R₇, taken together, represent an oxo group, or an alkylidene group, .tbd.CR₇ R₈, or the group --(CH₂)_p --, where p is an integer from 2 to 5, and where R₈ and R₉, taken together, represent an oxo group, or the group --(CH₂)_q --, where q is an integer from 2 to 5, and where R₁₀ represents hydrogen, hydroxy, protected hydroxy, or C_1-5 alkyl and wherein any of the CH-groups at positions 20, 22, or 23 in the side chain may be replaced by a nitrogen atom, or where any of the groups --CH(CH₃)--, --CH(R³)--, or --CH(R²)-- at positions 20, 22, and 23, respectively, may be replaced by an oxygen or sulfur atom with the proviso that when Y₃ and Y₄ are both hydrogen then Y₅ or Y₆ cannot be alkyl, hydroxyalkyl or fluoroalkyl; and

when the compound has the formula ##STR25## where R₁₀ is hydrogen or a hydroxyl group, then Y₅ and Y₆ cannot both be hydrogen;

or Y₅ cannot be hydrogen and Y₆ alkyl, alkenyl, alkynyl, an amino group, a substituted amino group of the formula --NR₁ R₂, or a substituted methyl group of the formula --CR₁ R₂ R₃ where R₁, R₂, or R₃ is an hydroxyalkyl, aminoalkyl or alkoxyalkyl;

or Y₆ cannot be hydrogen and Y₅ alkyl, alkenyl, alkynyl, an amino group, a substituted amino group of the formula --NR₁ R₂, or a substituted methyl group of the formula --CR₁ R₂ R₃ where R₁, R₂ or R₃ is an hydroxyalkyl, aminoalkyl or alkoxyalkyl; and

with the additional proviso that when the compound has the formula ##STR26## then Y₅ and Y₆ cannot both be hydrogen.

2. The compound of claim 1 having the formula:

##STR27## where U is selected from the group consisting of a methyl, a substituted methyl group described by general formula CR₁ R₂ R₃, an amino group or substituted amino group described by general formula NR₁ R₂, a phosphino group or substituted phosphino group described by general formula PR₁ R₂, an alkyl- or arylsulfinyl group, an alkyl- or arylsulfonyl group, and aryl, and where R₁, R₂ and R₃ are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, aminoalkyl, halogenalkyl, alkoxyalkyl, aryloxyakyl, aryl, halogen, hydroxyl, protected hydroxy, alkoxyl, aryloxyl, acyl, an amino group, an amino group substituted with alkyl or aryl substituents and where R₁ and R₂, taken together, represent an oxo group, or a group --(CH₂)_m -- where m is an integer having a value of from 2 to 5 with the proviso that when the compound has the formula ##STR28## then U cannot be alkyl, hydroxyalkyl or fluoroalkyl; and

with the proviso that when the compound has the formula ##STR29## where R₁₀ is hydrogen or a hydroxyl group, then U cannot be alkyl, alkenyl, alkynyl, an amino group, a substituted amino group of the formula --NR₁ R₂, or a substituted methyl group of the formula --CR₁,R₂ R₃ where R₁, R₂ or R₃ is an hydroxyalkyl, aminoalkyl or alkoxyalkyl; and

with the additional proviso that the compound cannot be ##STR30##

3. A method of treating metabolic bone disease where it is desired to maintain or increase bone mass comprising administering to a patient with said disease an effective amount of a compound as claimed in claim 1.

4. The method of claim 3 where the disease is senile osteoporosis.

5. The method of claim 3 where the disease is postmenopausal osteoporosis.

6. The method of claim 3 where the disease is steroid-induced osteoporosis.

7. The method of claim 3 where the disease is low bone turnover osteoporosis.

8. The method of claim 3 where the disease is osteomalacia.

9. The method of claim 3 where the disease is renal osteodystrophy.

10. The method of claim 3 where the disease is rickets.

11. The method of claim 3 where the disease is vitamin D resistant rickets.

12. The method of claim 3 wherein the compound is administered orally.

13. The method of claim 3 wherein the compound is administered parenterally.

14. The method of claim 3 wherein the compound is administered transdermally.

15. The method of claim 3 wherein the compound is administered in a dosage of from 0.1 μ

g to 50 μ

g per day.

16. A method of treating renal osteodystrophy where it is desired to maintain or increase bone mass comprising administering to a patient with renal osteodystrophy an effective amount of 2α

-methyl-19-nor-1α

,25-dihydroxyvitamin D₃.

17. A method of treating rickets where it is desired to maintain or increase bone mass comprising administering to a patient with rickets an effective amount of 2α

-methyl-19-nor-1α

,25-dihydroxyvitamin D₃.

18. A method of treating vitamin D resistant rickets where it is desired to maintain or increase bone mass comprising administering to a patient with vitamin D resistant rickets an effective amount of 2α

-methyl-19-nor-1α

,25-dihydroxyvitamin D₃.