Vitamin D3 derivative and treating agent for inflammatory respiratory disease using same

• US 6,548,489 B2
• Filed: 01/04/2002
• Issued: 04/15/2003
• Est. Priority Date: 10/23/1998
• Status: Expired due to Fees

• Current Assignee: Teijin Limited
• Original Assignee: Teijin Limited
• Inventors: Takenouchi, Kazuya, Gao, Qingzhi, Manabe, Kenji, Takano, Yasuhiro, Ishizuka, Seiichi, Sogawa, Ryo
• Primary Examiner(s): QAZI, SABIHA NAIM
• Application Number:
  US10/035,219
• Publication Number:
  US 20020091109A1
• Time in Patent Office: 466 Days
• Field of Search: 552/653, 514/167, 546/216
• US Class Current: 514/167
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• 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: 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
• CPC Class Codes: C07F 7/1804 Compounds having Si-O-C linkages Si-O-acyl linkages C07F7/1896
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

Compounds expressed by the following general formula (1),

[wherein, R₀₁ and R₀₂ are each independently a hydrogen atom or a protecting group for a hydroxyl group; Z is one out of the following formulae (1-1) to (1-5)].

The compounds can be used as active ingredients of treating agents for inflammatory respiratory diseases, malignant tumors, rheumatoid arthritis, osteoporosis, diabetes mellitus, hypertension, alopecia, acne, psoriasis, dermatitis, hypercalcemia, hypoparathyroidism and metabolic disorder of cartilage.

Claims

1. A vitamin D₃ compound expressed by the following general formula (1) or pharmaceutically permissible solvates thereof,

wherein, R₀₁ and R₀₂ are each independently a hydrogen atom, a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, an acetyl group, a methoxymethyl group or a tetrahydro-4H-pyran-2-yl group;

Z is one out of the following formulae (1-1) and (1-2),

in the above formulae (1-1) and (1-2),

m is an integer of 0 to 2;

n is 0;

X′

is NH;

R₁₁ and R₁₂ are identical to or different from each other, and express a hydrogen atom or a C₁-C₄ alkyl group;

K, L and M are each a hydrogen atom;

M is a hydrogen atom, and K and L together express a single bond and express a double bond in cooperation with the single bond already shown in the formula;

or K is a hydrogen atom, and L and M together express a single bond and express a double bond in cooperation with the single bond already shown in the formula;

R₂₁, R₂₂ and R₂₃ are identical to or different from each other, and they are a hydrogen atom, a hydroxy group, a carboxyl group, a trifluoromethyl group, a pentafluoroethyl group, a C₁-C₄ alkyloxycarbonyl group, a C₂-C₅ acyloxy group, a C₁-C₄ alkyloxy group or a C₁-C₄ alkyl group which may be substituted with a hydroxyl group, a C₂-C₅ acyloxy group or a alkyloxy group, or R₂₁ and R₂₂ together may express a C₃-C₆ cyclic alkyl group in cooperation with the carbon atom to which they are bonded,

with the proviso that the following compound (a) is excluded,

(a) a compound in which R₂₁ and R₂₂ are both hydroxy groups, both alkyloxy groups, or a hydroxy group and an alkyloxy group.

2. A vitamin D₃ compound or a pharmaceutically permissible solvate thereof described in claim 1, wherein, in the above formula (1), Z is (1-1).

3. A vitamin D₃ derivative or a pharmaceutically permissible solvate thereof described in claim 1, wherein, in the above formula (1), Z is (1-2).

4. A vitamin D₃ compound or a pharmaceutically permissible solvate thereof described in one out of claims 1, 2 and 3, wherein, in the above formula (1), R₀₁ and R₀₂ are both hydrogen atoms.

5. A vitamin D₃ compound or a pharmaceutically permissible solvate thereof described in one out of claims 1, 2 and 3, wherein, in the above formula (1), m is 0 or 1.

6. A vitamin D₃ compound or a pharmaceutically permissible solvate thereof described in one out of claims 1, 2 and 3, wherein, in the above formula (1), n is 0 or 1.

7. A vitamin D₃ compound or a pharmaceutically permissible solvate thereof described in claim 2, wherein, in the above formula (1), R₁₁ and R₁₂ are identical to or different from each other, and they are a hydrogen atom, a methyl group or an ethyl group.

8. A vitamin D₃ compound or a pharmaceutically permissible solvate thereof described in claim 1, wherein, in the above formula (1), K is a hydrogen atom, and L and M together express a single bond and express a double bond in cooperation with the single bond already shown in the formula.

9. A vitamin D₃ compound or a pharmaceutically permissible solvate thereof described in claim 3, wherein, in the above formula (1), R₂₁ and R₂₂ are identical to or different from each other, and they are a hydrogen atom, a hydroxy group or a C₁-C₄ alkyl group, or R₂₁ and R₂₂ together express a C₃-C₆ cyclic alkyl group in cooperation with the carbon atom to which they are bonded.

10. A vitamin D₃ compound or a pharmaceutically permissible solvate thereof described in claim 3, wherein, in the above formula (1), R₂₃ is a hydrogen atom or a hydroxyl group.

11. A vitamin D₃ compound or a pharmaceutically permissible solvate thereof described in claim 3, wherein, in the above formula (1), the combination of R₂₁, R₂₂ and R₂₃ is one out of

(a) R₂₁, R₂₂ and R₂₃ are all hydrogen atoms,

(b) R₂₁ and R₂₂ are methyl groups, and R₂₃ is a hydrogen atom,

(c) the combination of R₂₁ and R₂₂ is a methyl group and a hydroxyl group, and R₂₃ is a hydrogen atom,

(d) the combination of R₂₁ and R₂₂ is a methyl group and a hydroxyl group, and R₂₃ is a hydroxyl group and

(e) R₂₁ and R₂₂ together form a cyclopropyl group in cooperation with the carbon atom to which they are bonded, and R₂₃ is a hydrogen atom.

12. A pharmaceutical composition composed of a vitamin D₃ compound or pharmaceutically permissible solvate thereof described in claim 1, and a pharmaceutically permissible carrier.

13. A method for treating an inflammatory respiratory disease comprising administering to a subject a therapeutically effective amount of a vitamin D₃ compound according to claim 1.

14. A method for treating an inflammatory respiratory disease according to claim 13, wherein the inflammatory respiratory disease is at least one inflammatory respiratory disease selected from the group consisting of acute upper airway infection, chronic sinusitis, allergic rhinitis, chronic lower airway infection, pulmonary emphysema, pneumonia, bronchial asthma, tuberculosis sequela, acute respiratory distress syndrome, cystic fibrosis and pulmonary fibrosis.

15. A method of treating an inflammatory respiratory disease according to claim 14, wherein the inflammatory respiratory disease is an acute upper airway infection selected from at least one of the group consisting of common cold, acute pharyngitis, acute rhinitis, acute sinusitis, acute tonsillitis, acute epiglottis and acute bronchitis.

16. A method of treating an inflammatory respiratory disease according to claim 14, wherein the inflammatory respiratory disease is a chronic lower airway infection selected from at least one of the group consisting of chronic bronchitis, diffuse panbronchiolitis and bronchiectasis.

17. A method of treating a disease selected from the group consisting of malignant tumors, rheumatoid arthritis, osteoporosis, diabetes mellitus, hypertension, alopecia, acne, psoriasis, and dermatitis, comprising administering to a subject a therapeutically effective amount of a vitamin D₃ compound according to claim 1.

18. A method of treating hypercalcemia attributable to vitamin D excess, comprising administering to a subject a therapeutically effective amount of a vitamin D₃ compound according to claim 1.

19. A method of treating hypopararthyroidism, comprising administering to a subject a therapeutically effective amount of a vitamin D₃ compound according to claim 1.

20. A method of treating a metabolic disorder of cartilage, comprising administering to a subject a therapeutically effective amount of a vitamin D₃ compound according to claim 1.