Yissum Research Development Company of the Hebrew University of Jerusalem Ltd.

Eli Breuer

Gershon Golomb

Reuven Reich

Claudio Salomon

Ivan Alferiev

Gordon L Amidon

Amnon Hoffman

Yiffat Katz

Naama El-Hanany Rozen

Julia Frant

Aviva Friedman-Ezra

Veerendhar Ainelly

The present invention relates to novel metalloproteinase inhibitors having an aryloxybenzenesulfonamide moiety and a carbamoylphosphonic acid moiety, to pharmaceutical compositions comprising them, and to their uses in the prevention and/or treatment of disease or disorder associated with MMP.

Carbamoylphosphonates as inhibitors and uses thereof

The present invention relates to compositions useful for treating or controlling disease states or conditions associated with zinc containing proteinases, especially metalloproteinases. The active ingredient in these compositions is an alpha-oxo- or alpha-thioxophosphonate of formula (I). Out of the phosphonates of formula (I), some are known and others are new. The novel compounds constitute another aspect of the invention.

Compositions comprising oxophosphonate-based metalloproteinase inhibitors

The present invention provides a compound of the following formula I:R&#x2014;NH&#x2014;C(&#x2550;X)&#x2014;P(&#x2550;O)ORORincluding pharmaceutically acceptable salts, solvates, hydrates and polymorphs of the compounds of formula I, as well as geometrical isomers and optically active forms of the compounds of formula I and pharmaceutically acceptable salts, solvates, hydrates and polymorphs of said isomers and forms,wherein The invention further provides pharmaceutical compositions comprising the above compounds and their use in medicine.

Carbamoyl-and thiocarbamoyl-phosphonates and pharmaceutical compositions comprising them

The present invention relates to compositions useful for treating or controlling disease states or conditions associated with zinc containing proteinases, especially metalloproteinases. The active ingredient in these compositions is an alpha-oxo- or alpha-thixophosphpnate of formula (I). Out of the phosphonates of formula (I), some are known and others are new. The novel compounds constitute another aspect of the invention.

A method for treating patients having calcium related disorders includes using di- or tripeptide derivatives of bisphosphonates to enhance oral bioavailability of such compounds.

Phosphonates, biphosphonates and pharmaceutical compositions containing them

Bisphosphonate compounds are of the Formula (I): ##STR1## wherein Y is .dbd.O or .dbd.N--OH and n is from 3 to 24, and further wherein when Y is .dbd.O, (i) R.sub.1 is hydrogen and R.sub.2 is sodium, or (ii) R.sub.1 is sodium and R.sub.2 is methyl, and when Y is .dbd.N--OH, R.sub.1 is sodium and R.sub.2 is methyl.

Bisphosphonates, processes for preparation and pharmaceutical

Novel bisphosphonates comprise compounds of the formula (I) ##STR1## wherein m and l are independently 1 or 2; R.sub.1 represents hydrogen, a lower alkyl group, or an alkali metal cation; R.sub.2 represents hydrogen, a lower alkyl group or an alkali metal cation; Y represents .dbd.0 or .dbd.N--OH, or --OH and X represents --(CH.sub.2).sub.n --, a branched alkylene group, or a branched or straight alkenylene or alkynylene chain optionally substituted by one or more oxygen or nitrogen atoms, wherein n is an integer from 3 to 24. Further definitions of X are included in the description.

Bis- and tetrakis-phosphonates useful for treating calcium related

Novel bisphosphonates comprise compounds of the formula (I) ##STR1## wherein m and l are independently 1 or 2; R.sub.1 represents hydrogen, a lower alkyl group, or an alkali metal cation; R.sub.2 represents hydrogen, a lower alkyl group or an alkali metal cation; Y represents .dbd.0 or .dbd.N--OH, or --OH; and X represents --(CH.sub.2).sub.n --, a branched alkylene group, or a branched or straight alkenylene or alkynylene chain optionally substituted by one or more oxygen or nitrogen atoms, wherein n is an integer from 3 to 24; with the provision that when l.dbd.m.dbd.1, Y is .dbd.0, and R.sub.1 and R.sub.2 denote a lower alkyl group, n represents an integer from 9 to 20; and with the provision that when l.dbd.m.dbd.2, Y is --OH and R.sub.1 and R.sub.2 are methyl groups, n represents an integer from 9-24; and with the further provision that when l.dbd.m.dbd.2, Y is --OH and R.sub.1 and R.sub.2 are hydrogen, n represents 3, 5 or an integer from 7 to 24; or X is

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Jerusalem, Israel

Eli Breuer