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US 2003/0149006 A1Published application
New vitamin D derivatives with cyclic substructures in the side chains, process and intermediate products for their production, and the use for the production of pharmaceutical agents
AssigneeSchering Corporation
InventorsAndreas Steinmeyer, Katica Schwarz, Claudia Giesen, Martin Haberey, Marianne Fahnrich
Life of this patent
Estimating the term…
Abstract
The invention relates to vitamin D derivatives of general formula I, 1 process for their production, intermediate products of the process as well as the use for the production of pharmaceutical agents.
Claims20
Vitamin D derivatives of general formula I,
- 36
- in which
- Y1 and Y2, independently of one another, each mean a hydrogen atom or a group —C(O)R5,
- and Y3 means a hydrogen atom or a hydroxy group, a halogen atom, a group —OC(O)R5 or an —OR5 group,
- whereby
- R5 stands for an aromatic radical with 5 to 12 C atoms or for an aliphatic, straight-chain or branched, saturated or unsaturated C1-C12 alkyl radical, which optionally is interrupted by 1-2 oxygen atoms, 1-2 sulfur atoms and/or 1-2 NH groups and/or optionally is substituted by 1-2 hydroxy groups, 1-2 amino groups, 1-2 SH groups, 1-2 COOH groups and/or 1-2 phenyl groups,
- and group Y3 can be present both in the 2α-situation and the epimeric 2β-situation,
- R1 and R2 each mean a hydrogen atom or together an exocyclic methylene group,
- R3 and R4, independently of one another, each mean a hydrogen atom, a fluorine, chlorine or bromine atom, an alkyl group with 1 to 4 carbon atoms, together a methylene group or together with quaternary carbon atom 20 a 3- to 7-membered, saturated or unsaturated carbocyclic ring,
- Q means a straight-chain alkylene group with 1 to 5 carbon atoms,
- X1 and X2 together mean a double-bound keto-oxygen atom or, independently of one another, a hydrogen atom, a hydroxy group, an —O(CO)R5 group, a fluorine, chlorine or bromine atom,
- whereby X1 and X2, not at the same time, each should be a hydroxy group or each an —O(CO)R5 group,
- Z means a carbocyclic or heterocyclic, optionally aromatic or heteroaromatic ring with 5 or 6 ring members or a condensed ring system that consists of a 5- and a 6-membered ring or two 6-membered rings, which can be substituted by one or more fluorine, chlorine, bromine or iodine atoms, one or more hydroxy groups, one or more COOR6 groups, one or more C1-C5 alkyl groups, which in turn can be substituted by one or more fluorine, chlorine, bromine or iodine atoms, C1-C6 alkoxy groups and/or COOR6 groups,
- whereby
- R6 stands for a C1-C6 alkyl group, a benzyl group or a phenyl group,
- and all possible epimers or diastereomers and mixtures thereof.
13 more elements
Process for the production of compounds of general formula IIa
- 48
- in which
- E means any side chain,
- R7, R8, independently of one another, mean a hydrogen atom, a methyl group, or together an exocyclic methylene group or a cyclopropyl ring,
- Y2 means a hydrogen atom or a group —(CO)R5,
- Y3 means a hydrogen atom or a hydroxy group, a halogen atom, a group —O(CO)R5 or an OR5 group,
- whereby
- R5 stands for an aliphatic C1-C12 alkyl radical, which optionally is interrupted by 1-2 oxygen atoms, 1-2 sulfur atoms and/or 1-2 NH groups and/or optionally is substituted by 1-2 hydroxy groups, 1-2 amino groups, 1-2 SH groups, 1-2 COOH groups and/or 1-2 phenyl groups, or for an aromatic radical with 5 to 12 C atoms,
- Y5 means a fluorine atom, a (CH2)n—OH group or a (CH2)n—O(CO) group,
- whereby n=0 to 4,
- and optionally present hydroxy groups are optionally present in protected form, which is characterized in that a ketone of general formula XIIIc
- 49
- in which
- E means any side chain
- and optionally existing keto groups and/or hydroxy groups are present in protected form
- is converted by reaction with trimethylsilylacetic ester in the presence of a base, such-as, e.g., n-butyllithium or lithium aluminum hydride or with a suitable Wittig reagent in an aprotic solvent such as toluene, tetrahydrofuran, diethyl ether or dioxane into a compound of general formula XXXIVc
- 50
- in which
- Y6 means a C1-C6 alkyl group, a benzyl group, or a phenyl group,
- the ester group is converted by reaction with a reducing agent such as Dibah, lithium aluminum hydride, diborane or RedAl in hexane, toluene, tetrahydrofuran, diethyl ether or dioxane into the allyl alcohol of general formula XXXVc
- 51
- the allyl alcohol is converted in a way that is known in the art into a compound of general formula XXXVc
- 52
- in which
- L means any leaving group (halogen, mesylate, tosylate, triflate, nonaflate),
- which is isolated or optionally produced in situ and immediately further reacted to a Wittig reagent of general formula XXXVIc,
- 53
- in which
- G means a C1-C10 alkyl group, a C1-C10 alkoxy group, a phenyl radical or a phenoxy radical,
- which then is reacted under known conditions with a ketone of general formula XXXIIIc
- 54
- in which
- Y′3 means a hydrogen atom, a halogen atom or a protected hydroxy group, a group —O(CO)R5 or an OR5 group, and
- Y5 R7 and R8 have the above-indicated meaning, and if desired, protective groups are cleaved.
31 more elements
Dependencies are inferred from the claim text.