New vitamin D derivatives with carbo-or heterocyclic substituents at C-25, a process for their production, intermediate products and their use for producing medicaments

• US 20050080058A1
• Filed: 09/10/2003
• Published: 04/14/2005
• Est. Priority Date: 04/30/1996
• Status: Active Grant

• Current Assignee: Schering Ag (Merck & Co., Inc.)
• Original Assignee: Schering Ag (Merck & Co., Inc.)
• Inventors: Thieroff-Ekerdt, Ruth, Haberey, Martin, Kirsch, Gerald, Steinmeyer, Andreas, Wiesinger, Herbert, Fahnrich, Marianne, Neef, Gunter, Schwarz, Katica
• Granted Patent: US 7,211,680 B2
• Time in Patent Office: Days
• US Class Current: 514/167
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• 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 35/00 Antineoplastic agents
• CPC Class Codes: C07C 35/32 the condensed ring system being a (4.3.0) system, e.g. indenols
• 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: C07D 207/333 Radicals substituted by oxygen or sulfur atoms
• CPC Class Codes: C07D 233/64 with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• CPC Class Codes: C07D 263/32 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 271/06 1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
• CPC Class Codes: C07D 271/10 1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
• CPC Class Codes: C07D 277/24 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 307/42 Singly bound oxygen atoms
• CPC Class Codes: C07D 333/16 by oxygen atoms

Abstract

Compounds of Formula I,
wherein Y₁, Y₂, R₁-R₆, Q and Z are as defined herein, are vitamin D derivatives. These compounds are useful for, e.g., the treatment hyperprolifierative diseases of the skin, tumor diseases and precancerous stages, auto-immune diseases, rejection reactions in the case of autologous, allogenic or xenogenic transplants, AIDS, atopic skin conditions, secondary hyperparathyroidism, renal osteodystrophia, senile and postmenopausal osteoporosis, diabetes mellitus type II, degenerative diseases of the peripheral and central nervous system, hypercalcemias, granulomatous diseases, paraneoplastic hypercalcemias, hypercalcemias in hyperparathyroidism, hirsutism, ateriosclerosis, and/or inflammatory diseases.

Claims

1-10. -10. (canceled)

11. A compound of formula I

12. A compound according to claim 11, wherein R₅ and R₆ together with carbon atom C-25 means a cyclopropyl ring.

13. A compound according to claim 11, wherein Q is hydroxymethyl or carbonylmethyl group.

14. A compound according to claim 11, wherein the compound antagonizes the action of calcitriol in HL 60 cells.

15. A compound according to claim 11, wherein Y₁ is acetyloxy, propionyloxy, butyryloxy or benzoyloxy.

16. A compound according to claim 11, wherein Y₂ is acetyl, propionyl, butyryl or benzoyl.

17. A compound according to claim 11, wherein R₃ is H and R₄ is methyl.

18. A compound according to claim 11, wherein R₃ is methyl and R₄ is H.

19. A compound according to claim 11, wherein R₃ is F and R₄ is methyl.

20. A compound according to claim 11, wherein R₃ is methyl and R₄ is F.

21. A compound according to claim 11, wherein R₃ is and R₄ together form a methylene group or together with tertiary carbon atom 20 form a cyclopropyl group.

22. A compound according to claim 11, wherein Q is an unsubstituted, unbranched alkylene having 1-3 carbon atoms.

23. A compound according to claim 11, wherein Q is hydroxymethylene in which the hydroxy group is in the α

or β

position.

24. A compound according to claim 11, wherein Q is —

CH(OH)—

CH₂—

or —

CH(OH)—

CH₂—

CH₂—

in which, in each case, the hydroxy group is in the α

or β

position.

25. A compound according to claim 11, wherein R₅ and R₆ together with carbon atom C-25 form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group.

26. A composition comprising at least one compound according to claim 11 and a pharmaceutically compatible vehicle.

27. A method of treating a patient for hyperprolifierative diseases of the skin, tumor diseases and precancerous stages, auto-immune diseases, rejection reactions in the case of autologous, allogenic or xenogenic transplants, AIDS, atopic skin conditions, secondary hyperparathyroidism, renal osteodystrophia, senile and postmenopausal osteoporosis, diabetes mellitus type II, and/or degenerative diseases of the peripheral and central nervous system comprising administering to said patient a composition according to claim 11.

28. A method according to claim 27, wherein said patient is suffering from psoriasis, acne, ichthyosis, tumors of the intestines, carcinomas of the breast, lung tumors, prostate carcinomas, leukemias, T-cell lymphomas, actinic keratoses, cervix dysplasias, multiple scleroses, diabetes mellitus type I, myasthenia gravis, lupus erythematosus, AIDS, secondary hyperparathyroidism, renal osteodystrophia, senile osteoporosis, postmenopausal osteoporosis, diabetes mellitus type II, Alzheimer'"'"'s disease and/or amyotrophic lateral schlerosis.

29. A method of treating a patient for hypercalcemias, granulomatous diseases, paraneoplastic hypercalcemias, hypercalcemias in hyperparathyroidism, hirsutism, ateriosclerosis, and/or inflammatory diseases comprising administering to said patient a composition according to claim 11, wherein the compound antagonizes the action of calcitriol in HL 60 cells.

30. A method according to claim 29, wherein said patient is suffering from hypervitaminosis D, intoxication with calcitriol or its analogues, sarcoidosis, tuberculosis, osteolytic metastases, tumors with increased synthesis of parathormone-related peptides, hypercalcemias in hyperparathyroidism, hirsutism, arterioschlerosis, rheumatoid arthritis, Crohn'"'"'s disease, ulcerative colitis, and/or granulomatous diseases.

31. A method according to claim 27, wherein said compound is administered to said patient in an amount of 0.1 μ

g/day-1000 μ

g/day.

32. A method according to claim 29, wherein said compound is administered to said patient in an amount of 0.1 μ

g/day-1000 μ

g/day.

33. A process for the production of a compound according to claim 11, said process comprising:

providing a compound of general formula II

wherein

Y′

₁ means a hydrogen atom or a protected hydroxy group and

Y′

₂ means a hydroxy protective group,

R₁ and R₂ each mean a hydrogen atom or together an exocyclic methylene group,

R₃ and R₄, independently of one another, mean a hydrogen atom, a chlorine or fluorine atom, an alkyl group with 1 to 4 carbon atoms, or together form a methylene group, or together with quaternary carbon atom 20 form a 3- to 7-membered, saturated or unsaturated carbocyclic ring,

Q means a straight-chain or branched carbon unit with up to 10 carbon atoms, which at any position can have hydroxyl groups, in α

- or β

-position, which in turn can be etherified or esterified, keto groups, amino groups or halogen atoms,

R₅ and R₆ together with carbon atom 25 mean a 3- to 7-membered, saturated or unsaturated carbocyclic ring, and

Z′

means a five- or six-membered carbocyclic ring which can be saturated, unsaturated or aromatic, and which can be substituted by one or more alkyl chains, which can be straight-chain or branched, saturated or unsaturated, and optionally interrupted by oxa, thia, aza, sulfoxide or sulfo groups or substituted by hydroxy groups or halogen atoms, wherein if Z′

is phenyl, R₅ and R₆ together with carbon atom 25 form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring; and

reacting the compound by simultaneous or successive cleavage of the hydroxy protective groups and optionally by partial or complete esterification(s) or etherification(s) of free hydroxy groups.

34. A compound selected from:

(5Z,7E,22E)-(1S,3R,24R)-25-phenyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,

(5Z,7E,22E)-(1S,3R,24S)-25-phenyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,

(5Z,7E,22E)-(1S,3R,24R)-25-(4-methylphenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,

(5Z,7E,22E)-(1S,3R,24S)-25-(4-methylphenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,

(5Z,7E,22E)-(1S,3R,24R)-25-(4-ethylphenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,

(5Z,7E,22E)-(1S,3R,24S)-25-(4-ethylphenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,

(5Z,7E,22E)-(1S,3R,24R)-25-(4-propylphenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,

(5Z,7E,22E)-(1S,3R,24S)-25-(4-propylphenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,

(5Z,7E,22E)-(1S,3R,24R)-25-(4-butylphenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,

(5Z,7E,22E)-(1S,3R,24S)-25-(4-butylphenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,

(5Z,7E,22E)-(1S,3R,24R)-25-(4-pentylphenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,

(5Z,7E,22E)-(1S,3R,24S)-25-(4-pentylphenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,

(5Z,7E,22E)-(1S,3R,24R)-25-(3-methylphenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,

(5Z,7E,22E)-(1S,3R,24S)-25-(3-methylphenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,

(5Z,7E,22E)-(1S,3R,24R)-25-(3-ethylphenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,

(5Z,7E,22E)-(1S,3R,24S)-25-(3-ethylphenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,

(5Z,7E,22E)-(1S,3R,24R)-25-(3-propylphenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,

(5Z,7E,22E)-(1S,3R,24S)-25-(3-propylphenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,

(5Z,7E,22E)-(1S,3R,24R)-25-(3-butylphenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,

(5Z,7E,22E)-(1S,3R,24S)-25-(3-butylphenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,

(5Z,7E,22E)-(1S,3R,24R)-25-(3-pentylphenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,

(5Z,7E,22E)-(1S,3R,24R)-25-(3-pentylphenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,

(5Z,7E,22E)-(1S,3R,24R)-25-[4-(1-methylethyl)phenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-25-[4-(1-methylethyl)phenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,

(5Z,7E,22E)-(1S,3R,24S)-25-[4-(1-methylethyl)phenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol, and

(5Z,7E,22E)-(1S,3R,24S)-25-[4-(1-methylethyl)phenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol.