Hoffmann-la Roche Inc.

Sun Bio, Inc.

Other

Perry Rosen

George W Holland

Frank Kienzle

Jane L Jernow

Hans Maag

Kaspar F Burri

Patricia Kilian

John Hakimi

Ka-kong Chan

Kwang Nho

David L Coffen

Frederick Wong

Norman W Gilman

James Valentine Earley

Hugo E Gallo-Torres

W Harry Mandeville

Ann C Sullivan

James Guthrie Hamilton

Ferdinand K Lee

Kasper F Burri

Carlo Nalin

Robert Karasiewicz

John Hakini

The present invention provides novel heterobifunctional and monobifunctional polyethylene glycol derivatives for the pegylation of therapeutically active proteins. The heterobifunctional PEGs which bear two different functional groups as well as the monobifunctional PEGs which contain two similar functional groups, may be used for cross-linking purposes. The cross-linking may be intramolecular between two areas within the same molecule or intermolecular between two separate molecules. The pegylated protein conjugates that are produced, retain a substantial portion of their therapeutic activity and are less immunogenic than the protein from which the conjugate is derived. New syntheses for preparing such bifunctional derivatives are described.

Bifunctional polyethylene glycol derivatives

The present invention provides novel monofunctional polyethylene glycol aldehydes for the pegylation of therapeutically active proteins. The pegylated protein conjugates that are produced, retain a substantial portion of their therapeutic activity and are less immunogenic than the protein from which the conjugate is derived. New syntheses for preparing such aldehydes are described.

Monofunctional polyethylene glycol aldehydes

The present invention is a physiologically active, substantially non-immunogenic water soluble polyethylene glycol protein conjugate having the same utility as the protein which forms the conjugate, without having the same properties of producing an immunogenic response possessed by the protein which forms this conjugate.

Polyethylene-protein conjugates

The present invention is a polymer which may be used to produce a physiologically active, substantially non-immunogenic water soluble polyethylene glycol protein conjugate having the same utility as the protein which forms the conjugate, without having the same properties of producing an immunogenic response possessed by the protein which forms this conjugate.

Polymer for making poly(ethylene glycol)-protein conjugates

The invention relates to compounds of the formula ##STR1## wherein R.sub.1 is OR.sub.6 or NHR.sub.7, R.sub.6 and R.sub.7, which may be, the same or different, are hydrogen, lower alkyl, lower alkenyl, cycloalkyl having between 3 to 6 carbon atoms or phenyl, R.sub.2 is lower alkyl, lower alkoxy or trifluoromethyl, R.sub.3 and R.sub.4 independently, are hydrogen, chlorine, fluorine, lower alkyl or lower alkoxy, and R.sub.5 is lower alkyl or cycloalkyl having between 3 to 6 carbon atoms, and when at least one asymetric carbon is present, enantiomers, and racemates thereof, and pharmaceutically acceptable salts thereof. The compounds of formula I and pharmaceutically acceptable salts thereof are useful as bronchopulmonary agents for example in the relief of asthma and allergic reactions. In another aspect, the invention relates to pharmaceutical compositions, methods of using the compound of formula I and intermediates.

Compounds useful as dual antagonists of platelet activating factor and

Substituted PEG-interferon conjugates of formulae IA and IB where PEG is linked by means of activated linking reagents of formulae IIA, IIB, or IIB-1 to an amino group in the interferon, and activated linking reagents of formulae IIA, IIB, or IIB-1. The conjugates are not readily susceptible to in vivo hydrolytic cleavage, have enhanced in vivo half life, and reduce the immunogenicity of the interferon while maintaining biological activity.

Peg-interferon conjugates

The invention relates to compounds of the formula ##STR1## wherein R.sub.1 is OR.sub.6 or NHR.sub.7, R.sub.6 and R.sub.7, which may be, the same or different, are hydrogen, lower alkyl, lower alkenyl, cycloalkyl having between 3 to 6 carbon atoms or phenyl, R.sub.2 is lower alkyl, lower alkoxy or trifluoromethyl, R.sub.3 and R.sub.4, independently, are hydrogen, chlorine, fluorine, lower alkyl or lower alkoxy, and R.sub.5 is lower alkyl or cycloalkyl having between 3 to 6 carbon atoms, and when at least one asymetric carbon is present, enantiomers, and racemates thereof, and pharmaceutically acceptable salts thereof. The compounds of formula I and pharmaceutically acceptable salts thereof are useful as bronchopulmonary agents for example in the relief of asthma and allergic reactions. In another aspect, the invention relates to pharmaceutical compositions, methods of using the compound of formula I and intermediates.

New optically active intermediates and processes thereto are provided for use in synthesizing therapeutically active prostaglandins of the formula: ##STR1## wherein R.sup.1 is hydrogen or lower alkyl; from a compound of the formula: ##STR2## wherein R.sup.1 is as above and R.sup.2 is hydrogen or a carboxy blocking group convertible to an acid by hydrolysis.

Prostaglandin intermediates

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North Caldwell, NJ, United States of America

Perry Rosen