Hoffmann-la Roche Inc.

Syntex (u.s.a.) Inc.

The United States of America As Represented by the Department of

Andrew D Batcho

Milan R Uskokovic

Willy Leimgruber

Enrico G Baggiolini

John William Scott

Donald H Valentine, Jr

Bernard Michael Hennessy

Urs Oskar Hengartner

Peter Michael Wovkulich

Jerome Anthony Iacobelli

Gary A Truitt

Alfred Boris

Percy Sarwood Manchand

Ronald L Horst

Joseph L Napoli

Donald E Berger, Jr

Vitamin D3 analogs

The invention relates to a process for the preparation of vitamin D.sub.3 compounds of formula I. ##STR1## Wherein A is a single or a double bond; B is a single, cis-double, trans double or a triple bond; R.sub.1 and R.sub.2 are independently hydrogen, a lower alkyl, e.g., a C.sub.1 -C.sub.4 alkyl; R.sub.3 and R.sub.4 are independently a lower alkyl, e.g., C.sub.1 -C.sub.4 alkyl, a hydroxyalkyl, and a haloalkyl, e.g., a fluoroalkyl; and X and Y are independently hydrogen or hydroxy in the case when B is a single or a double bond.

Synthesis of 3-epi vitamin D.sub.3 metabolites and analogs

Compounds of the formula ##STR1## wherein R is hydrogen, fluorine, or hydroxyl, each R.sub.2 is lower alkyl or C(R.sub.3).sub.3 and R.sub.3 is halogen, X is .dbd.CH.sub.2 or when R is hydroxy, X is hydrogen or .dbd.CH.sub.2, and A is --C.tbd.C-- ##STR2## or --CH.sub.2 --CH.sub.2 --, which are useful in the treatment of hyperproliferative skin disorders, neoplastic diseases, and sebaceous gland diseases.

Vitamin D.sub.3 analogs

The compounds 1.alpha.,25(S), 26-trihydroxy-.DELTA..sup.22 -cholecalciferol; 1.alpha.,25(R), 26-trihydroxy-.DELTA..sup.22 -cholecalciferol; 1.alpha.,25(S),26-trihydroxyergocalciferol, 1.alpha.,25(R),26-trihydroxyergocalciferol and pharmaceutical compositions comprising the compounds as well as methods of making and using these compounds are disclosed.

Trihydroxy-cholecacliferol and trihydroxy-ergocalciferol for treating

The claimed invention relates to intermediate compounds of the formula ##STR1## wherein R is hydrogen or methyl, R.sub.1 and R.sub.2 each, independently, is hydrogen, lower alkyl or aryl, or taken together are lower alkylene of from 3 to 6 carbon atoms, and the dotted (. . . ) line is an optional bond.

Compounds, process and intermediates

Compounds of the formula ##STR1## wherein R' is hydrogen or hydroxy, epimers at the 24-position of compounds of formula I, diastereomeric mixtures of compounds of formula I which are epimeric at the 24-position, and mixtures thereof, which are useful as agents for the treatment of psoriasis, and osteoporosis, are described.

25, 28-dihydroxyergocalciferol and 1,25,28-trihydroxyergocalciferol

The invention is directed to a process and intermediates for the preparation of 1.alpha.,25-dihydroxyergocalciferol as well as substantially pure and crystalline 1.alpha.,25-dihydroxyergocolciferol. The end-product 1.alpha.,25-dihydroxyergocalciferol is useful in the treatment of disease states which are characterized by insufficient amounts of 1.alpha., 25-dihydroxycholecalciferol.

Synthesis of 1.alpha.,25-dihydroxyergocalciferol

The invention is directed to a process and intermediates for the preparation of 1.alpha.,25-dihydroxyergocalciferol as well as substantially pure and crystalline 1.alpha.,25-dihydroxyergocolciferol. The end-product 1.alpha.,25-dihydroxyergocalciferol is useful in the treatment of disease states which are characterized by insufficient amounts of 1.alpha.,25-dihydroxycholecalciferol.

7-Aminoindole is prepared from a 7-nitroindole, which in turn is prepared from a halo-substituted .beta.-dialkylamino-2-nitrostyrene.

7-Nitroindoles

The present disclosure is directed to a process for the synthesis of chenodeoxychloic acid, 25-hydroxycholesterol and 1.alpha.,25-dihydroxycholesterol from 17-keto steroids. A cholic acid side chain is stereospecifically introduced by reaction of the appropriate 17-keto steroid with ethyltriphenylphosphonium halides to produce the 17-ethylidene derivative which is allowed to react with acrylic acid esters or propiolic acid esters followed by hydrogenation.

Process and intermediates for the synthesis of Vitamin D.sub.3

The preparation of racemic and optically pure tryptophans is described. The D-enantiomers of the 6-substituted compounds possess a potent sweetening capability. Novel intermediates are also disclosed.

Pyrroles and pyrrolidines

The present disclosure is directed to a process and intermediates for the synthesis of Vitamin D.sub.3 metabolites such as 1,25-dihydroxycholecalciferol, 25-hydroxycholecalciferol and 24R,25-dihydroxycholecalciferol from 17-keto steroids via intermediates having the natural steroid configuration at the 20-position. These novel intermediates are prepared from 17-keto steroids by reaction with ethyltriphenylphosphonium halides followed by reaction with formaldehyde to form comounds having the natural steroid configuration at the 20-position and which are suitable substrates for the preparation of the aforementioned Vitamin D.sub.3 metabolites.

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North Caldwell, NJ, United States of America

Andrew D Batcho