Vitamin d3 lactone derivatives

• US 20060148768A1
• Filed: 01/29/2004
• Published: 07/06/2006
• Est. Priority Date: 01/30/2003
• Status: Active Grant

• Current Assignee: Teijin Limited
• Original Assignee: Teijin Pharma Limited (Teijin Limited)
• Inventors: Takenouchi, Kazuya, Okada, Kazuhisa, Kittaka, Atsushi, Ishizuka, Seiichi, Anzai, Miyuki, Saito, Nozomi, Saito, Hiroshi, Miura, Daishiro, Fujishima, Toshie, Takayama, Hiroaki
• Granted Patent: US 9,073,885 B2
• Time in Patent Office: Days
• US Class Current: 514/167
• CPC Class Codes: A61K 31/593 9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• 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 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 3/02 Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• 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 5/18 of the parathyroid hormones
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 307/58 One oxygen atom, e.g. butenolide

Abstract

A compound represented by the following Formula (1) that is effective for the treatment of Paget'"'"'s disease of bone or hypercalcemia or a medically acceptable solvate thereof;
[wherein R₁ refers to hydrogen atom, C₁-C₆ alkyl group optionally substituted with hydrogen group or C₁-C₆ alkoxy group optionally substituted with hydroxyl group, R^2a and R^2b refer to hydrogen atom, C₁-C₁₀ alkyl group optionally substituted with hydroxyl group, C₆-C₁₀ aryl group optionally substituted with hydroxyl group or C₇-C₁₂ aralkyl group optionally substituted with a hydroxyl group, or are combined to represent ethylene group. However, a compound in which R¹ is a hydrogen atom or a methyl group and R^2a and R^2b are hydrogen atoms is excluded].

Claims

1. A compound represented by the following Formula (1) or a pharmaceutically acceptable solvate thereof:

[wherein R¹ refers to hydrogen atom, C₁-C₆ alkyl group optionally substituted with hydroxyl group or C₁-C₆ alkoxy group optionally substituted with hydroxyl group;

R^2a and R^2b are identical or different and refer to hydrogen atom, C₁-C₁₀ alkyl group optionally substituted with hydroxyl group, C₆-C₁₀ aryl group optionally substituted with hydroxyl group, or C₇-C₁₂ aralkyl group optionally substituted with hydroxyl group;

alternatively, R^2a and R^2b may be combined together to form a cyclopropane ring together with the carbon atom to which they are bonded;

however, a compound in which R¹, R^2a and R^2b are all hydrogen atoms and a compound in which R¹ is methyl group and R^2a and R^2b are hydrogen atoms are excluded.]

2. The compound or the pharmaceutically acceptable solvate thereof according to claim 1, wherein the steric configuration of the 1-position of the above Formula (1) is α

configuration and that of the 3-position is β

configuration.

3. The compound or the pharmaceutically acceptable solvate thereof according to either of claims 1 or 2, wherein the steric configuration of the 2-position of the above Formula (1) is a configuration.

4. The compound or the pharmaceutically acceptable solvate thereof according to either of claims 1 or 2, wherein R¹ of the above Formula (1) is hydrogen atom.

5. The compound or the pharmaceutically acceptable solvate thereof according to any one of claims 1 to 3, wherein R¹ of the above Formula (1) is methyl group, ethyl group, propyl group, butyl group, hydroxymethyl group, 2-hydroxyethyl group, 3-hydroxypropyl group, 4-hydroxybutyl group, 2-hydroxyethoxy group, 3-hydroxypropoxy group or 4-hydroxybutoxy group.

6. The compound or the pharmaceutically acceptable solvate thereof according to any one of claims 1 to 3, wherein R¹ of the above Formula (1) is methyl group, 3-hydroxypropyl group or 3-hydroxypropoxy group.

7. The compound or the pharmaceutically acceptable solvate thereof according to any one of claims 1 to 6, wherein a combination of R^2a and R^2b of the above Formula (1) is hydrogen atom and methyl group, hydrogen atom and ethyl group, hydrogen atom and propyl group, hydrogen atom and isopropyl group, hydrogen atom and butyl group, hydrogen atom and isobutyl group, hydrogen atom and hexyl group, hydrogen atom and octyl group, hydrogen atom and phenyl group, hydrogen atom and phenethyl group, hydrogen atom and 2-hydroxyethyl group, both hydrogen atoms or both methyl groups, or alternatively R^2a and R^2b may be combined together to form a cyclopropane ring together with the carbon atom to which they are bonded.

8. The compound or the pharmaceutically acceptable solvate thereof according to any one of claims 1 to 6, wherein a combination of R^2a and R^2b of the above Formula (1) is hydrogen atom and methyl group, hydrogen atom and ethyl group, hydrogen atom and butyl group, hydrogen atom and isobutyl group, hydrogen atom and hexyl group or both methyl groups.

9. The compound or the pharmaceutically acceptable solvate thereof according to claim 4, wherein a combination of R^2a and R^2b of the above Formula (1) is hydrogen atom and methyl group, hydrogen atom and ethyl group, hydrogen atom and butyl group, hydrogen atom and isobutyl group, hydrogen atom and hexyl group or both methyl groups.

10. The compound or the pharmaceutically acceptable solvate thereof according to any one of claims 1 to 3, wherein in the above Formula (1), R¹ is methyl group and a combination of R^2a and R^2b is hydrogen atom and methyl group;

R¹ is methyl group and a combination of R^2a and R^2b is hydrogen atom and ethyl group;

R¹ is methyl group and a combination of R^2a and R^2b is hydrogen atom and butyl group;

R¹ is methyl group and a combination of R^2a and R^2b is hydrogen atom and isobutyl group;

R¹ is methyl group and a combination of R^2a and R^2b is hydrogen atom and hexyl group;

or R¹ is methyl group and both R^2a and R^2b are methyl groups.

11. The compound or the pharmaceutically acceptable solvate thereof according to any one of claims 1 to 3, wherein in the above Formula (1), R¹ is 3-hydroxypropyl group and both R^2a and R^2b are hydrogen atoms;

R¹ is 3-hydroxypropyl group and a combination of R^2a and R^2b is hydrogen atom and methyl group;

R¹ is 3-hydroxypropyl group and a combination of R^2a and R^2b is hydrogen atom and ethyl group;

R¹ is 3-hydroxypropyl group and a combination of R^2a and R^2b is hydrogen atom and butyl group;

R¹ is 3-hydroxypropyl group and a combination of R^2a and R^2b is hydrogen atom and isobutyl group;

R¹ is 3-hydroxypropyl group and a combination of R^2a and R^2b is hydrogen atom and hexyl group;

or R¹ is 3-hydroxypropyl group and both R^2a and R^2b are methyl groups.

12. The compound or the pharmaceutically acceptable solvate thereof according to any one of claims 1 to 3, wherein in the above Formula (1), R¹ is 3-hydroxypropoxy group and both R^2a and R^2b are hydrogen atoms;

R¹ is 3-hydroxypropoxy group and a combination of R^2a and R^2b is hydrogen atom and methyl group;

R¹ is 3-hydroxypropoxy group and a combination of R^2a and R^2b is hydrogen atom and ethyl group;

R¹ is 3-hydroxypropoxy group and a combination of R^2a and R^2b is hydrogen atom and butyl group;

R¹ is 3-hydroxypropoxy group and a combination of R^2a and R^2b is hydrogen atom and isobutyl group;

R¹ is 3-hydroxypropoxy group and a combination of R^2a and R^2b is hydrogen atom and hexyl group;

or R¹ is 3-hydroxypropoxy group and both R^2a and R^2b are methyl groups.

13. A therapeutic agent for Paget'"'"'s disease of bone comprising the compound or the pharmaceutically acceptable solvate thereof according to any one of claims 1 to 12 as an active ingredient.

14. A therapeutic agent for hypercalcemia comprising the compound or the pharmaceutically acceptable solvate thereof according to any one of claims 1 to 12 as an active ingredient.

15. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable solvate thereof according to any one of claims 1 to 12 and a pharmaceutically acceptable carrier.

16. A process for synthesizing a compound represented by the following Formula (4syn), wherein the relative configuration of carbon a and carbon b is syn,

comprising reacting, in the presence of divalent chromium, an aldehyde compound represented by the following Formula (2):

[wherein Z refers to any one of Formulas (2-1), (2-2), (2-3), (2-4) and (2-5);

wherein Y refers to bromine atom or iodine atom;

R³ refers to trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, acetyl group, benzoyl group, methoxymethyl group or tetrahydro-4H-pyran-2-yl group;

R⁴ or R⁵ independently refers to methyl group, ethyl group, propyl group, trichloroethyl group, or R⁴ and R⁵ are combined to refer to ethylene group or propylene group, X refers to oxygen atom or sulfur atom;

R⁶ refers to hydrogen atom, C₁-C₆ alkyl group optionally substituted with a hydroxyl group protected by a group defined by R³, or C₁-C₆ alkoxy group optionally substituted by a hydroxyl group protected by a group defined by R³], with an acrylic acid derivative represented by the following Formula (3),

[wherein R^2c refers to C₁-C₁₀ alkyl group optionally substituted with hydroxyl group protected by a group defined by R³ of the above Formula (2), C₆-C₁₀ aryl group optionally substituted with hydroxyl group protected by a group defined by R³ of the above Formula (2), or C₇-C₁₂ aralkyl group optionally substituted with hydroxyl group protected by a group defined by R³ of the above Formula (2), and R⁷ refers to C₁-C₆ alkyl group],

wherein R^2c in the above Formula (4syn) has the same definition as in the above Formula (3), and Z in the above Formula (4syn) has the same definition as in the above Formula (2).

17. A process which comprises, in the following order, the steps of:

reducing a lactone ring of a lactone compound represented by the following Formula (4syn),

[wherein R^2c has the same definition as in the above Formula (3), Z has the same definition as in the above Formula (2), and the relative configuration of carbon a and carbon b is syn];

protecting the resultant primary hydroxyl group to obtain an alcohol compound represented by the following Formula (5syn),

[wherein R^2c has the same definition as in the above Formula (3), Z has the same definition as in the above Formula (2), R⁸ refers to acetyl group, 4-oxopentanoyl group, pivaroyl group, benzoyl group, triisopropylsilyl group, t-butyldimethylsilyl group or t-butyldiphenylsilyl group and the relative configuration of carbon a and carbon b is syn];

oxidizing the secondary hydroxyl group of the alcohol compound to obtain a ketonic compound represented by the following Formula (6),

[wherein R^2c has the same definition as in the above Formula (3), Z has the same definition as in the above Formula (2), and R⁸ has the same definition as in the above Formula (5syn)];

reducing the ketone group of the ketonic compound to obtain an alcohol compound represented by the following Formula (5anti),

[wherein R^2c has the same definition as in the above Formula (3), Z has the same definition as in the above Formula (2), R⁸ has the same definition as in the above Formula (5syn), and the relative configuration of carbon a and carbon b is syn]; and

deprotecting R⁸ of the alcohol compound and then oxidizing the resultant primary hydroxyl group to form a lactone ring,

for synthesizing a lactone compound represented by the following Formula (4anti),

[wherein, R^2c has the same definition as in the above Formula (3), Z has the same definition as in the above Formula (2), and the relative configuration of carbon a and carbon b is anti].

18. A lactone compound represented by the following Formula (4),

[wherein R^2d and R^2e refer to C₁-C₁₀ alkyl group optionally substituted with hydroxyl group protected by the group defined by R³ of the above Formula (2);

C₆-C₁₀ aryl group optionally substituted with hydroxyl group protected by the group defined by R³ of the above Formula (2);

or C₇-C₁₂ aralkyl group optionally substituted with a hydroxyl group protected by the group defined by R³ of the above Formula (2);

or alternatively, R^2d and R^2e may be combined together to form a cyclopropane ring together with the carbon atom to which R^2d and R^2e are bonded; and

Z has the same definition as in the above Formula (2)].