Research Institute for Medicine & Chemistry, Inc.

Other

Robert H Hesse

Derek H Barton

Sundara Katugam Setty

Malathi Ramgopal

Gaddam Subba Reddy

Sundara Katugam Srinivasasetty Setty

Maurice Murdoch Pechet

Ezio Rizzardo

Graham Johnson

Michael Gile

Ezzio Rizzardo

Sanga Kugabalnsooriar

Novel sterol derivatives of formula (I), in which: Rrepresents a hydroxyl group or protected hydroxyl group, Rrepresents a hydrogen atom and a double bond is present at c, or Rand Rtogether represent an oxo group and a double bond is present at b or double bonds are present at a and b; Rrepresents a methyl group having &#x3b1;- or &#x3b2;-configuration; Rand R, which may be the same or different, are selected from hydrogen atoms and aliphatic, cycloaliphatic, araliphatic and aryl groups, or together with the nitrogen atom to which they are attached form a heterocyclic group; and X represents a polymethylene group containing 2&#x2013;5 carbon atoms, an oxa group-containing analogue thereof in which a methylene group other than that attached to the &#x2014;CO.NRRmoiety is replaced by an oxygen atom, or an unsaturated analogue thereof containing up to two double bonds. Active compounds of the invention exhibit potent effects on the modulation of cell growth and differentiation and possess an advantageous therapeutic ratio by virtue of their low levels of calcaemic activity.

Cholenic acid amides and pharmaceutical compositions thereof

Compounds of formula (I) in which: Rrepresents a hydrogen atom or an O-protecting group; Rrepresents a hydroxyl, lower alkoxy, carboxaldehyde, lower alk-1-enyl or hydroxy- or lower alkoxy-substituted lower alkyl group; Rrepresents a methyl group having &#x3b1;- or &#x3b2;-configuration; X represents a Calkylene group or a valence bond; Y represents a carboxaldehyde group or a group of formula &#x2014;C(R)(R)ORwhere Ris as defined above and Rand R, which may be the same or different, are each selected from hydrogen atoms, alkyl, alkenyl and alkynyl groups such that the total carbon content of Rand Rdoes not exceed three atoms, with the proviso that X is a valence bond when both Rand Rare other than hydrogen; and the dotted line signifies that a double bond may optionally be present at the 16(17)-position exhibit potent cell modulating activity, including antiproliferative and antiangiogenic effects.

2-substituted pregna-1-3,5(10) triene and chola-1,3,5(10) triene derivatives and their biological activity

Compounds of Formula (I) in which: Rand R, which may be the same or different, each represents a lower alkyl, alkenyl or alkynyl group; Rrepresents a methyl group having &#x3b1;- or &#x3b2;-configuration; Rrepresents a hydrogen atom or an etherifying or esterifying group; Rrepresents a hydrogen atom, a hydroxyl group or a lower alkoxy group; X represents a group OR, wherein Ris as defined above, or a group NRRwherein Rrepresents a hydrogen atom, an aliphatic or araliphatic organic group, or an acyl group comprising an aliphatic, araliphatic or aryl organic group linked to the nitrogen atom by way of a carbonyl group; and Ris a hydrogen atom or a lower alkyl group; Y represents a lower alkylene, alkenylene or alkynylene group optionally substituted by a hydroxyl, etherified hydroxyl or esterified hydroxyl group; and the dotted lines signify that double bonds may be present at the 16(17)-position and/or either at the 6(7)- and 8(9)-positions or at the 7(8)-position exhibit potent effects on modulation of cell growth and differentiation, while having low calcaemic activity.

Steroid compounds with a c17-alkyl side chain and an aromatic a-ring for use in therapy

1-Hydroxy pregnacalciferol derivatives of formula (I) and their corresponding 5,6-trans isomers wherein R is hydroxyl or lower alkoxy and R is optionally hydroxylated or lower alkoxylated lower alkynyl or R is C(R ) (R )CH where R is optionally hydroxylated or lower alkoxylated lower alkynyl and R is hydroxyl or lower alkoxy or R and R together represent oxo and R is hydrogen, hydroxyl or lower alkoxy, and R and R represent hydrogen atoms, exhibit anti-progesterone activity and may be useful as antineoplastic, antifertility, antiproliferative, immunosuppressive and/or antiinflammatory agents.

17-side chain alkynyl-and 20-oxopregna-derivatives of vitamin D, methods for their production and pharmaceutical compositions thereof

The present invention relates to novel 1.alpha.-hydroxy vitamin D derivatives in which the 17-position side chain carries an azide or optionally substituted 1,2,3-triazole group, including compounds of general formula (I) where R.sup.1 represents a methyl group having .alpha.- or .beta.-configuration; W represents a valence bond or a C.sub.1-5 alkylene group; X represents azide or an optionally substituted triazole group; and A.dbd. represents a cyclohexylidene moiety characteristic of the A-ring of a 1.alpha.-hydroxylated vitamin D or analogue thereof. Active compounds of the invention exhibit cell modulating activity while exhibiting a substantial lack of calcaemic effect.

Vitamin D analogues

Vitamin-D amide derivatives

Vitamin D amine and amide derivatives

Vitamin D amide derivatives

The invention pertains to vitamin D amide derivatives of formula (I). These novel 1.alpha.-hydroxy vitamin D derivatives and their 20-epi analogues comprise compounds of formula (I) and corresponding 5,6-trans isomers, where Y represents an alkylene or alkenylene group containing up to four carbon atoms; R.sup.1 and R.sup.2 independently represent a hydrogen atom or a lower alkyl or cycloalkyl group, or R.sup.1 R.sup.2 N-- represents a heterocyclic group; and R.sup.3 and R.sup.4 independently represent a hydrogen atom or an O-protecting group. Active compounds, in which R.sup.3 and R.sup.4 are hydrogen atoms or metabolically labile O-protecting groups exhibit potent cell modulating effect, but minimal effect on calcium metabolism.

The invention provides novel compositions for use in pharmaceutical and veterinary medicine which contain 1.alpha.-hydroxy vitamin D compounds. Particular compositions are described which contain steroids which induce or assist in combatting osteoporosis together with 1.alpha.-hydroxy vitamin D.sub.3 or 1.alpha.,25-dihydroxy vitamin D.sub.3. Methods of treatment of diseases are also provided including many which are resistant to vitamin D.sub.3, in particular bone diseases.

Chemical compounds and process

Compounds of the general formula ##STR1## wherein R represents a hydrogen atom or a hydroxyl protecting group, Y represents a hydrogen atom or an optionally protected hydroxyl group, X represents the residue of a dienophile and either R.sup.1 represents a halogen atom a hydrocarbylsulphonyloxy group or a group of the formula --Z--R.sup.3 (in which Z represents --O--, --S--, --SO--, --NR.sup.4 -- or --CR.sup.4 R.sup.5 -- and R.sup.3, R.sup.4 and R.sup.5, which may be the same or different, each represent a hydrogen atom or a straight or branched aliphatic group having 1-12 carbon atoms and which may optionally carry one or more substituents) and R.sup.2 represents a hydrogen atom or R.sup.1 and R.sup.2 together represent an oxo group or an optionally substituted alkylidene group, except that R.sup.1 and R.sup.2 together with the group --CH(CH.sub.3)CH-- to which they are attached do not represent a group having the branched 17.beta.-hydrocarbyl side chain skeleton of vitamin D.sub.2 or vitamin D.sub.3 or use in the preparation of novel vitamin D analogues.

The invention provides novel 1.alpha.-hydroxy vitamin D compounds and a method for their preparation from 1.alpha.-hydroxy-25-hydrogen cholesta-5,7-dienes by irradiation and isomerization techniques. The invention also includes the said 1.alpha.-hydroxy-25-hydrogen-cholesta-5,7-dienes and the corresponding cholest-5-enes. The new compounds may be obtained in a crystalline form substantially free from isomeric or other impurities arising from manufacture.

1-.alpha.-hydroxy vitamin D compounds and process for preparing same

1-unsubstituted 5,6-trans vitamin D compounds are 1.alpha.-hydroxylated by Se.sup.IV oxidation in the presence of selenous acid at a pH in the range 3-9. The oxidation is preferably effected using a 1-unsubstituted-3-trihydrocarbylsilyloxy-5,6-trans vitamin D compound in the presence of a co-oxidant.

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Cambridge, MA, United States of America

Robert H Hesse