Duphar International Research Bv

Kingdom of the Netherlands

Sebastianus J Halkes

Antonio Mourino

Jan Zorgdrager

Jose L Mascarenas

Jan-Paul Van De Velde

Maria J Valles

Robert B Koolstra

Gerhardus D Dijkstra

Eric Goethals

Wilhelmus R Overbeek

Jose P Sestelo

Luc J Vanmaele

Andrzej Kutner

Maurits E Vandewalle

Pierre J De Clercq

Juan Granja

Wolfgang Reischl

Yagamare Fall

Ana Fernandez-Gacio

Silvia Kanzler

Koen M Halkes

Benjamin Borsje

Miguel A Maestro

Wanda Wojciechowska

Jan Paul Van De Velde

Maria De Angeles Rey

Jose Antonio Martinez

Maria De Los Angeles Rey

The invention relates to vitamin D analogs of general formula (I) wherein: R,is a hydrogen atom or a substituent selected from the group consisting of hydroxy, CH,OH, CH,CH,OH, CH,CH,CH,OH, OCH,, OCH,OH, OCH,CH,OH and OCH,CH,CH,OH; R,is a hydrogen atom or a substituent selected from the group consisting of OCH,, OCH,OH, CH,(CH,OH),(CH,CH,OH),, (CH,),OH and O(CH,),OH; wherein: m is 0 or 1, p, q and n are 0-3, r is 1-3 and m&plus;n&plus;p&equals;3; with the proviso that R,and/or R,contain at least one OH group; R,is a straight or branched, saturated or unsaturated aliphatic hydrocarbon of 6-13 C atoms which may be substituted with one or more substituents from the group hydroxy or fluoro. The invention further relates to methods of preparing these compounds, a pharmaceutical composition containing these compounds and to their use in pharmacotherapy and cosmetics.

Vitamin D analogs and methods of preparing these compounds

The invention relates to a new method of preparing 16-dehydro vitamin D compounds having formula I ##STR1## wherein: R has the epi-configuration or the normal configuration and represents straight or branched C.sub.1-6 -alkyl, C.sub.2-6 -alkenyl, C.sub.3-6 -cycloalkyl, or an aromatic group optionally substituted with halogen, C.sub.1-3 -alkyl or alkoxy,

Method of preparing 16-dehydro vitamin D compounds

Vitamin D.sub.3 analogues of the formula (I): ##STR1## wherein R.sub.1 is hydrogen or hydroxy, R.sub.2 is (C.sub.1 -C.sub.3)alkyl, hydroxy(C.sub.1 -C.sub.3)alkyl, (C.sub.1 -C.sub.2)alkoxymethyl, (C.sub.2 -C.sub.3)alkenyl, or (C.sub.2 -C.sub.3)alkynyl, R.sub.3 is a branched or unbranched, saturated or unsaturated aliphatic 3- to 5- membered hydrocarbon or oxahydrocarbon biradical, having at least 3 atoms in the main chain and being optionally substituted with one or more substituents selected from epoxy, fluoro and hydroxy, R.sub.4 is sec. or tert. (C.sub.3 -C.sub.6)alkyl or (C.sub.3 -C.sub.6)cycloalkyl, A and B are each individually hydrogen or methyl, or A and B together from methylene. The compounds of the present invention exhibit pharmacotherapeutic activities, including in particular, the treatment of osteoporosis, renal osteodystrophy, osteomalacia, skin disorders such as psoriasis and other hyperproliferative skin diseases, eczema and dermatitis, nmyopathy, leukemia, breast and colon cancer, osteosarcomas, squamous cell carcinomas, melanoma, certain immunological disorders, and transplant rejections. Several methods of synthesis, including reaction of an ester compound of general formula (IX) with an inorganometallic compound of formula (III) followed by deprotection or, alternatively, first finalization of the C.sub.17 -side chain are also disclosed.

Vitamin D compounds and method of preparing these compounds

The invention relates to a new vitamin D compound, substituted in the 18-position with an alkyl group, a hydroxy group, an alkoxy group, an alkenyl group, an alkynyl group, a fluorinated alkyl group or a fluorinated alkenyl group. The invention also relates to a method of preparing said vitamin D compound and to a lactone and a hydrindane intermediate. The vitamin D compound is of the general formula ##STR1##

Synthesis of C.sub.18 -modified vitamin D compounds and compounds

The present invention relates to vitamin D compounds of the general formula ##STR1## wherein: R.sub.1 is a hydrogen atom or a hydroxy group;

Vitamin D.sub.3 analogues of the formula (I): ##STR1## wherein R.sub.1 is hydrogen or hydroxy, R.sub.2 is hydrogen, (C.sub.1 -C.sub.3) alkyl, phenyl, or trifluoromethyl, R.sub.3 is branched or unbranched (C.sub.1 -C.sub.4) alkyl, cyclopropyl or CF.sub.3, A and B are individually hydrogen or methyl, or A and B together form methylene, X is CH.sub.2 or O, and n is 2 or 3. These compounds are useful for treating various skin and bone disorders and cancers. These compounds are also useful in cosmetic applications and for diagnostic purposes. Compounds of formula (I) are prepared by reacting a C--25 ester compound with an organometallic compound or by coupling a CD ring ester moiety with a Wittig reagent or an enyne compound to form the desired diene or triene system.

Vitamin D.sub.3 analogues having an unsaturated side chain

Vitamin D compound, method of preparing this compound and intermediate

The invention relates to a new vitamin D compound of the general formula ##STR1## wherein: R.sub.1 is a hydrogen atom or a hydroxy group;

The invention relates to a new vitamin D compound, substituted in the 18-position with an alkyl group, a hydroxy group, an alkoxy group, an alkenyl group, an alkynyl group, a fluorinated alkyl group or a fluorinated alkenyl group.

The invention relates to a method of preparing a compound having an alkyl or alkoxyalkyl side-chain with a terminal 2-hydroxyprop-2-yl group, by oxidizing a compound having a terminal isopropyl group in its side-chain with a dioxirane as the oxidant.

Method of preparing hydrindane compounds and hydrindane-related compounds

The invention relates to a method for the photochemical conversion of tachysterol compounds into previtamin D compounds and of trans-vitamin D compounds into cis-vitamin D compounds under the influence of radiation, by exposing the tachysterol compound and trans-vitamin D compound, respectively, dissolved in a suitable solvent system, in the presence of a polymeric photosensitizer consisting of a polymer chain ('backbone') comprising covalently bound sensitizers suitable for the photochemical conversion, to light with a wavelength of preferably between approx. 300 and approx. 1,000 nm, and by then isolating the resulting previtamin D compound and cis-vitamin D compound, respectively, in which a polymeric photosensitizer is used, the polymer chain of which has been selected from the group consisting of a polyether chain, an amino groups-containing polymer chain and a block copolymer chain comprising polyether segments and/or amino groups-containing polymer segments, in such a manner that the polymeric photosensitizer dissolves in the solvent system during the exposure to radiation but either upon cooling precipitates from the solution and can be separated, or, in case said polymer chain comprises amino groups, can be protonated with a suitable acid substance and be removed in an after-treatment. The invention also relates to a polymeric photosensitizer to be used for the said method.

Method for the photochemical conversion of tachysterol compounds into

The invention relates to an adduct-aldehyde of the general formula ##STR1## wherein R is a hydrogen atom or an optionally etherified or esterified hydroxy group,

Adduct-aldehyde and its use for the preparation of vitamin-D compounds

The invention relates to a method of preparing 1 .alpha.-hydroxyvitamin D or 1 .alpha.-hydroxy-previtamin D compounds by hydroxylating the 1 .alpha.-position of an adduct of a previtamin D compound with a suitable dienophile, in which adduct optionally present hydroxy group or hydroxy groups is or are protected, if desired, and after removal of the protecting group or groups, isolating the 1 .alpha.-hydroxyvitamin D or 1 .alpha.-hydroxy-previtamin D compound. The invention also relates to 1 .alpha.-hydroxy-previtamin D compounds. The invention further relates to an adduct of a previtamin D or tachysterol compound with a dienophile of the general formula ##STR1## in which A' and B' are equal and represent methoxy groups or ethoxy groups, or in which A' and B' together constitute a phenylimino or o-phenylene group.

Growing community of inventors

Weesp, Netherlands

Sebastianus J Halkes