Leo Pharmaceutical Products, Ltd.

Leo-pharma A/s

Leo Pharmaceutical Products Ltd. A/s (lovens Kemiske Fabrik

Other

Leo Pharmaceutical Products Ltd. A/s

Leo Pharmaceutical Products Ltd. A/s Kemiske Fabrik Produkionsaktiese

Leo Pharmaceutical Products Ltd. A/s (bovens Kemiske Fabrik

Martin John Calverley

Ernst T Binderup

Kai Holst Hansen

Lise Binderup

Claus Aage Svensgaard Bretting

Henrik Pedersen

Thomas Peter Sabroe

Welf Von Daehne

Gunnar Grue-Sorensen

Gunnar Grue-S&oslash;rensen

Heinz-Josef Wilhelm Deussen

Ernst Torndal Binderup

The present invention relates to intermediates useful for the synthesis of calcipotriol or calcipotriol monohydrate, to methods of producing said intermediates, and to methods of stereoselectively reducing said intermediates.

Stereoselective synthesis of vitamin D analogues

Compounds according to formula I in which formula R1 and R2, which may be the same or different, represent halogen, (C-C)hydrocarbyl, optionally substituted with one or two hydroxyl group or one or more fluorine atoms, or, together with the carbon atom to which they are both attached, R1 and R2 form a (C-C)carbocyclic ring, or one of R1 and R2 taken together with R3 forms a direct bond, such that a triple bond is constituted, or R1 and R2 represent both hydrogen; R3 when not forming a direct bond with one of R1 and R2 represents hydrogen or (C-C)hydrocarbyl; X represents (E)-ethylene, (Z)-ethylene, ethynylene, or a bond; Y and Z independently represent hydrogen or methyl; and prodrugs and stereo isomeric forms thereof are provided together with their use in therapy, and their use in the manufacture of medicaments.

Vitamin d analogues, compositions comprising said analogues and their use

Vitamin D analogues

The present invention relates to compounds of formula (I) in which formula X is hydrogen or hydroxy; R,and R,which may be the same or different, stand for hydrogen or C,-C,hydrocarbyl; or R,and R,, taken together with the carbon atom bearing the group X, can form a C,C,carbocyclic ring; Q is methylene, ethylene, tri- or tetra-methylene and may optionally be substituted with an oxy group, &mdash;OR,, in which R,is hydrogen, methyl or ethyl; Y is either a single bond or C,-C,hydrocarbylene; and one or more carbons with in R,, R,, and/or Y may optionally be substituted with one or more fluorine atoms, or with a hydroxyl group. The compounds show anti-inflammatory and immunomodulating effects as well as strong activity in inducing differentiation and inhibiting undesirable proliferation of certain cells.

##STR1## The present invention relates to compounds of formula (I), in which formula, n is 0 or 1, m is 0 or an integer from 1-7, R.sup.1 and R.sup.2 (which may be the same or different) stand for hydrogen or C.sub.1 l-C.sub.8 -hydrocarbyl, or, taken together with the carbon bearing the hydroxyl group (starred in formula I), R.sup.1 and R.sup.2 can form a saturated or unsaturated C.sub.3 -C.sub.8 carbocyclic ring. In addition, R.sup.1 and/or R.sup.2 and/or one of the m carbons designated by the '.degree.' may be optionally substituted with a hydroxyl group or one or more chlorine or fluorine atom(s); and finally one of the carbons designated '.degree.' may optionally be substituted by one or two C.sub.1 -C.sub.2 alkyl group(s); and derivatives of the compounds of formula I in which one or more hydroxy have been transformed into --O-acyl or --O-glycosyl or phosphate ester groups; such masked groups being hydrolyzable in vivo. The present compounds find use in both the human and veterinary practice in the treatment and prophylaxis of autoimmune diseases (including diabetes mellitus), hypertension, ache, alopecia, skin ageing, imbalance in the imune system, inflammatory diseases such as rheumatoid arthritis and asthma as well as diseases characterized by abnormal cell differentiation and/or cell proliferation, such as e.g. psoriasis and cancer.

##STR1## The present invention relates to compounds of formula (I), in which formula R stands for an alkyl group containing from 7 to 12 carbon atoms optionally substituted with a hydroxy group; and derivatives of the compounds of formula (I) in which one or more hydroxy groups have been transformed into --O-acyl or --O-glycosyl or phosphate ester groups, such masked groups being hydrolyzable in vivo, in pure form or in mixtures. The present compounds find use in both the human and veterinary practice in the treatment and prophylaxis of autoimmune diseases, including diabetes mellitus, hypertension, inflammatory diseases such as rheumatoid arthritis and asthma as well as diseases characterized by abnormal cell differentiation and/or cell proliferation, and/or imbalance in the immune system.

##STR1## The present invention relates to compounds of formula (I), in which formula, n is an integer from 1-7; and R.sup.1 and R.sup.2, which may be the same or different, stand for hydrogen, or lower alkyl (but with the proviso that when n=1, R.sup.1 and R.sup.2 cannot simultaneously be hydrogen, nor can R.sup.1 and R.sup.2 simultaneously be an alkyl group independently chosen from methyl, ethyl and normal-propyl, and when n=2, R.sup.1 and R.sup.2 cannot simultaneously be methyl), or lower cyclo-alkyl, or, taken together with the carbon (starred in formula I) bearing the hydroxyl group, R.sup.1 and R.sup.2 can form a saturated or unsaturated C.sub.3 -C.sub.9 carbocyclic ring; and R.sup.3 and R.sup.4 represent either simultaneously hydrogen, or when taken together constitute a bond, such that a double bond connects carbons 22 and 23; including diastereoisomeric forms (e.g. E or Z configuration of the 22,23-double bond; R or S configuration at the starred carbona atom) of the compounds of formula (I), in pure form or in mixtures. The present compounds find use in both the human and veterinary practice and show antiinflammatory and immuno-modulating effects as well as strong activity in inducing differentiation and inhibiting undesirable proliferation of certain cells, including cancer cells and skin cells.

##STR1## The present invention relates to compounds of formula (I), in which formula n is 2 or 3, m is 0 or an integer from 1-4; R.sup.1 and R.sup.2 (which may be the same or different) stand for hydrogen or C.sub.1 -C.sub.8 -hydrocarbyl, hydrocarbyl indicating the residue after removal of a hydrogen atom from a straight, branched or cyclic saturated or unsaturated hydrocarbon, or taken together with the carbon bearing the hydroxyl group (starred in formula (I)), R.sup.1 and R.sup.2 can form a saturated or unsaturated C.sub.3 -C.sub.8 carboxylic ring; in addition, R.sup.1 and/or R.sup.2 and/or one of the m carbons designated by the '.degree.' may be optionally substituted with one or more chlorine or fluorine atom(s); and finally one of the carbons designated '.degree.' may optionally be substituted by one or two C.sub.1 -C.sub.2 alkyl group(s); and derivatives of the compounds of formula (I) in which one or more hydroxy have been transformed into -O-acyl or O-glycosyl or phosphate ester groups; such masked groups being hydrolyzable in vivo. The present compounds find use in both the human and vertinary practice in the treatment and prophylaxis of autoimmune diseases (including diabetes mellitus), hypertension, acne, alopecia, skin ageing, imbalance in the immune system, inflammatory diseases such as rheumatoid arthritis and asthma as well as diseases characterized by abnormal cell differentiation and/or cell proliferation, such as e.g. psoriasis and cancer.

Growing community of inventors

Herlev, Denmark

Martin John Calverley