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 6,642,218 B2
• Filed: 12/11/1998
• Issued: 11/04/2003
• Est. Priority Date: 04/30/1996
• Status: Expired due to Fees

• 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, Schwarz, Katica, Neef, Günter
• Primary Examiner(s): QAZI, SABIHA NAIM
• Application Number:
  US09/180,018
• Publication Number:
  US 20020049344A1
• Time in Patent Office: 1,789 Days
• Field of Search: 552/653, 514/167, 514/172, 514/374, 514/375, 514/378, 514/379, 548/237, 548/239
• US Class Current: 514/172
• 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

The invention relates to vitamin D derivatives of formula (I), processes for the production thereof and uses thereof:

wherein Y₁, Y₂, R₁-R₆, Q and Z are as defined herein.

Claims

1. A compound of general formula I

wherein

Y₁ means a hydrogen atom, a hydroxyl group, an alkanoyloxy group with 1 to 12 C atoms or an aroyloxy group,

Y₂ means a hydrogen atom or an alkanoyl group with 1 to 12 C atoms or an aroyl 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,

Z means an oxazole ring 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.

2. A compound according to claim 1, wherein Q has the meaning of a hydroxymethyl or carbonylmethyl group.

3. A process for the production of a compound of general formula I, according to claim 1, 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,

Z′

means an oxazole or isoxazole ring 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; and

converting said compound of formula II into a compound of formula I 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.

4. A composition comprising at least one compound according to claim 1 and a pharmaceutically acceptable carrier.

5. A method of treating 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 degenerative diseases of the peripheral and central nervous system comprising administering a composition according to claim 4.

6. A method of treating hypercalcemias, granulomatous diseases, paraneoplastic hypercalcemias, hypercalcemias in hyperparathyroidism, hirsutism, ateriosclerosis, and inflammatory diseases comprising administering a composition according to claim 4, wherein the compound antagonizes the action of calcitriol in HL 60 cells.

8. A compound according to claim 1, wherein Y₁ is acetyloxy, propionyloxy, butyryloxy or benzoyloxy.

9. A compound according to claim 1, wherein Y₂ is acetyl, propionyl, butyryl or benzoyl.

10. A compound according to claim 1, wherein R₃ is H and R₄ is methyl.

11. A compound according to claim 1, wherein R₃ is methyl and R₄ is H.

12. A compound according to claim 1, wherein R₃ is F and R₄ is methyl.

13. A compound according to claim 1, wherein R₃ is methyl and R₄ is F.

14. A compound according to claim 1, wherein R₃ is and R₄ together form a methylene group or together with tertiary carbon atom 20 form a cyclopropyl group.

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

16. A compound according to claim 1, wherein Q is hydroxymethylene in which the hydroxy group is in the α

or β

position.

17. A compound according to claim 1, 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.

18. A compound according to claim 1, wherein R₅ and R₆ together with carbon atom C-25 form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group.

19. A compound according to claim 1, wherein R₅ and R₆ together with carbon atom C-25 form a cyclopropyl group.

20. A compound according to claim 1, wherein Z is oxazole.

21. A compound according to claim 1, wherein Z is isoxazole.

22. A method of treating hyperprolifierative diseases of the skin and deficient cell differentiation diseases comprising administering to a patient an effective amount of a composition according to claim 4.

28. A process for the production of compound, according to claim 1, comprising:

providing a compound of formula II

 

wherein

Y′

₁ means a hydrogen atom or a protected hydroxy group,

Y′

₂ means a hydroxy protective group,

R₁ and R₂ each mean a hydrogen atom or together form 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 at the same time each mean a hydrogen atom, a chlorine or fluorine atom, a trifluoromethyl group, a straight-chain or branched-chain, saturated or unsaturated, hydrocarbon radical with up to 4 carbon atoms, or R₅ and R₆ together with carbon atom 25 mean a 3- to 7-membered, saturated or unsaturated, carbocyclic ring,

Z′

means an oxazole or isoxazole ring 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; and

converting said compound of formula II into a compound of formula I 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.

7. A compound, wherein the compound is selected from the group consisting of:

(5Z,7E,22E)-(1S,3R,24S)-25-(5-propyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-25-(5-methyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-25-(5-methyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-25-(5-ethyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-25-(5-ethyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-25-(5-butyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-25-(5-butyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-25-(5-pentyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-25-(4-propyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-25-(4-propyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-25-(4-methyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-25-(4-methyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-25-(4-ethyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-25-(4-ethyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-25-(4-butyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-25-(4-butyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-25-(4-pentyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-25-(4-pentyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,20S,24R)-25-(5-propyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,20S,24S)-25-(5-propyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,20S,24R)-25-(5-methyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,20S,24S)-25-(5-methyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,20S,24R)-25-(5-ethyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,20S,24S)-25-(5-ethyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,20S,24R)-25-(5-butyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,20S,24S)-25-(5-butyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,20S,24R)-25-(5-pentyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,20S,24S)-25-(5-pentyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,20S,24R)-25-(4-propyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,20S,24S)-25-(4-propyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,20S,24R)-25-(4-methyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,20S,24S)-25-(4-methyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,20S,24R)-25-(4-ethyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,20S,24S)-25-(4-ethyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,20S,24R)-25-(4-butyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,20S,24S)-25-(4-butyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,20S,24R)-25-(4-pentyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,20S,24S)-25-(4-pentyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-20-methyl-25-(5-propyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-20-methyl-25-(5-propyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-20-methyl-25-(5-methyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-20-methyl-25-(5-methyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-25-(5-ethyloxazol-2-yl)-20-methyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-25-(5-ethyloxazol-2-yl)-20-methyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-25-(5-butyloxazol-2-yl)-20-methyl-6,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-25-(5-butyloxazol-2-yl)-20-methyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-20-methyl-25-(5-pentyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-20-methyl-25-(5-pentyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-20-methyl-25-(4-propyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-20-methyl-25-(4-propyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-20-methyl-25-(4-methyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-20-methyl-25-(4-methyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-25-(4-ethyloxazol-2-yl)-20-methyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-25-(4-ethyloxazol-2-yl)-20-methyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-25-(4-butyloxazol-2-yl)-20-methyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-25-(4-butyloxazol-2-yl)-20-methyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-20-methyl-25-(4-pentyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-20-methyl-25-(4-pentyloxazol-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol.

23. A method according to claim 23, wherein said patient is suffering from psoriasis, pityriasis subia pilasis, acne, itchyosis, or combinations thereof.

24. A method according to claim 23, wherein said patient is suffering from tumors of the intestines, carcinomas of the breast, lung tumors, prostrate carcinomas, leukemias, T-cell lymphomas, melanomas, Batazell Larzin, squamos carcinomas, acetinic keratoses, cervix dysplasias, or combinations thereof.

25. A compound of formula I

wherein

Y₁ means a hydrogen atom, a hydroxyl group, an alkanoyloxy group with 1 to 12 C atoms or an aroyloxy group,

Y₂ means a hydrogen atom or an alkanoyl group with 1 to 12 C atoms or an aroyl 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 at the same time each mean a hydrogen atom, a chlorine or fluorine atom, a trifluoromethyl group, a straight-chain or branched-chain, saturated or unsaturated, hydrocarbon radical with up to 4 carbon atoms, or R₅ and R₆ together with carbon atom 25 mean a 3- to 7-membered, saturated or unsaturated, carbocyclic ring,

Z means an oxazole or isoxazole ring 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.

26. A compound according to claim 25, wherein R₅ and R₆ are each methyl or ethyl.

27. A compound according to claim 25, wherein R₅ and R₆ are each methyl or R₅ and R₆ together with carbon atom C-25 form a cyclopropyl group.