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
First Claim
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1. A process for the production of a compounds of formula IIa in whichE is a side chain, E is a side chain, R7, R8, are each, independently of one another, a hydrogen atom or a methyl group, or together are an exocyclic methylene group or a cyclopropyl ring, Y2 is a hydrogen atom or a group —
- (CO)R5, Y3 is a hydrogen atom, a hydroxy group, a halogen atom, a group —
O(CO)R5 or an OR5 group, R5 is an aromatic radical with 5 to 12 C atoms or 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, Y5 is a fluorine atom, a (CH2)n—
OH group or a (CH2)n—
O(CO)R5 group, n is 0 to 4, and optionally present hydroxy groups are each indpendently optionally present in protected form, said process comprising;
converting a ketone of general formula XIIIc
in which E is a side chain, and optionally present keto groups and/or hydroxy groups are present in protected form, by reaction with trimethylsilylacetic ester in the presence of a base or with a Wittig reagent in an aprotic solvent into a compound of formula XXXIVc
in which Y6 is C1-C6 alkyl group, a benzyl group, or a phenyl group;
converting the ester group by reaction with a reducing agent in hexane, toluene, tetrahydrofuran, diethyl ether or dioxane to form an allyl alcohol of formula XXXVcconverting the allyl alcohol into a compound of formula XXXVc
in which L is a leaving group, which is isolated or optionally produced in situ and immediatelly further reacted to form a Wittig reagent of formula XXXVIc,
in which G is a C1-C10 alkyl group, a C1-C10 alkoxy group, a phenyl radical or a phenoxy radical;
reacting the compound of formula XXXVIc with a ketone of formula XXXIIIc
in which Y′
3 is a hydrogen atom, a halogen atom, a protected hydroxy group, a group —
O(CO)R5 or an OR5 group; and
optionally cleaving protective groups.
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Abstract
The invention relates to vitamin D derivatives of general formula I,
process for their production, intermediate products of the process as well as the use for the production of pharmaceutical agents.
10 Citations
5 Claims
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1. A process for the production of a compounds of formula IIa
in which E is a side chain, E is a side chain, R7, R8, are each, independently of one another, a hydrogen atom or a methyl group, or together are an exocyclic methylene group or a cyclopropyl ring, Y2 is a hydrogen atom or a group — - (CO)R5,
Y3 is a hydrogen atom, a hydroxy group, a halogen atom, a group —
O(CO)R5 or an OR5 group,R5 is an aromatic radical with 5 to 12 C atoms or 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, Y5 is a fluorine atom, a (CH2)n—
OH group or a (CH2)n—
O(CO)R5 group,n is 0 to 4, and optionally present hydroxy groups are each indpendently optionally present in protected form, said process comprising; converting a ketone of general formula XIIIc
in whichE is a side chain, and optionally present keto groups and/or hydroxy groups are present in protected form, by reaction with trimethylsilylacetic ester in the presence of a base or with a Wittig reagent in an aprotic solvent into a compound of formula XXXIVc
in whichY6 is C1-C6 alkyl group, a benzyl group, or a phenyl group;
converting the ester group by reaction with a reducing agent in hexane, toluene, tetrahydrofuran, diethyl ether or dioxane to form an allyl alcohol of formula XXXVc converting the allyl alcohol into a compound of formula XXXVc
in whichL is a leaving group, which is isolated or optionally produced in situ and immediatelly further reacted to form a Wittig reagent of formula XXXVIc,
in whichG is a C1-C10 alkyl group, a C1-C10 alkoxy group, a phenyl radical or a phenoxy radical;
reacting the compound of formula XXXVIc with a ketone of formula XXXIIIc
in whichY′
3 is a hydrogen atom, a halogen atom, a protected hydroxy group, a group —
O(CO)R5 or an OR5 group; and
optionally cleaving protective groups. - View Dependent Claims (2, 3, 4, 5)
- (CO)R5,
Specification
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Current AssigneeSchering Ag (Merck & Co., Inc.)
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Original AssigneeSchering Ag (Merck & Co., Inc.)
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InventorsHaberey, Martin, Steinmeyer, Andreas, Schwarz, Katica, Fähnrich, Marianne, Giesen, Claudia
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Primary Examiner(s)QAZI, SABIHA NAIM
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Application NumberUS09/624,608Time in Patent Office1,107 DaysField of Search552/653, 514/167US Class Current552/653CPC Class CodesA61P 11/00 Drugs for disorders of the ...A61P 11/06 AntiasthmaticsA61P 17/00 Drugs for dermatological di...A61P 17/02 for treating wounds, ulcers...A61P 17/04 AntipruriticsA61P 17/06 AntipsoriaticsA61P 17/14 for baldness or alopeciaA61P 19/00 Drugs for skeletal disordersA61P 19/02 for joint disorders, e.g. a...A61P 19/08 for bone diseases, e.g. rac...A61P 19/10 for osteoporosisA61P 25/00 Drugs for disorders of the ...A61P 25/02 for peripheral neuropathiesA61P 29/00 Non-central analgesic, anti...A61P 3/00 Drugs for disorders of the ...A61P 3/10 for hyperglycaemia, e.g. an...A61P 3/14 for calcium homeostasis vit...A61P 35/00 Antineoplastic agentsA61P 35/02 specific for leukemiaA61P 37/00 Drugs for immunological or ...View All
