University of Florida Research Foundation, Incorporated

Other

Interx Research Corporation

Key Pharmaceuticals, Inc.

Schering Corporation

Otsuka Pharmaceutical Company, Limited

Merck + Co., Inc.

Abbott Laboratories Corporation

Fisons Ltd.

Soft Drugs, Inc.

Intrex Research Corporation

Nicholas S Bodor

Kenneth B Sloan

Richard H Hammer

Thorsteinn Loftsson

Stefano A Pogany

Maria B Grant

James W Simpkins

Leslie A Freiberg

Joseph Epstein

Peter W Stacpoole

Kenneth H Rand

Jack A Zupan

Kerry S Estes

Yasuo Ohshiro

Wallace Brey

Wesley R Anderson, Jr

Methods and compositions for enhancing the activity and/or duration of action of loteprednol etabonate and other soft anti-inflammatory steroids of the haloalkyl 17&#x3b1;-alkoxycarbonyloxy-11&#x3b2;-hydroxyandrost-4-en-3-one-17&#x3b2;-carboxylate type and the corresponding &#x394;-compounds are described. The enhancing agents have the formula: 

Enhancement of activity and/or duration of action of soft anti-inflammatory steroids for topical or other local application

Methods and compositions for enhancing the activity and/or duration of action of soft anti-inflammatory steroids of the haloalkyl 17&#x3b1;-alkoxy-11&#x3b2;-hydroxyandrost-4-en-3-one-17&#x3b2;-carboxylate type and the corresponding &#x394;compounds and of anti-inflammatory steroids of the hydrocortisone and prednisolone type are described. The enhancing agents have the formula: wherein R is H or C-Calkyl; Zis carbonyl or &#x3b2;-hydroxymethylene; Xis &#x2014;O&#x2014; or &#x2014;S&#x2014;; Ris &#x2014;OH, &#x2014;OR, &#x2014;OCOORor &#x2014;OCORwherein Ris C-Calkyl and Ris C-Calkyl, fluoromethyl or chloromethyl; and the dotted line in ring A indicates that the 1,2-linkage is saturated or unsaturated; with the proviso that when R is C-Calkyl, then Ris &#x2014;OH.

Enhancement of activity and/or duration of action of selected anti-inflammatory steroids for topical or other local application

The invention provides peptide derivatives designed to deliver peptides having growth factor inhibitory activity, especially somatostatin analogs, to the retina by sequential metabolism. The peptide derivatives, which comprise a dihydropyridine&#x21c4;pyridinium salt-type redox targetor moiety, a bulky lipophilic function and an amino acid/dipeptide/tripeptide spacer, are used in the prevention and treatment of diabetic retinopathy.

Compounds and method for the prevention and treatment of diabetic retinopathy

The invention provides peptide derivatives designed to deliver peptides having growth factor inhibitory activity, especially somatostatin analogs, to the retina by sequential metabolism. The peptide derivatives, which comprise a dihydropyridinepyridinium salt-type redox targetor moiety, a bulky lipophilic function and an amino acid/dipeptide/tripeptide spacer, are used in the prevention and treatment of diabetic retinopathy.

The invention provides novel soft steroidal anti-inflammatory agents, pharmaceutical compositions containing said agents, and methods of administering same to mammals in the treatment of inflammation. Preferred compounds of the invention include haloalkyl 17&agr;-alkoxycarbonyloxy-11&bgr;-hydroxyandrost-4-en-3-one-17&bgr;-carboxylates and the corresponding &Dgr; compounds, optionally bearing 6&agr;- and/or 9&agr;-fluorine and 16&agr;- or 16&bgr;-methyl substituents. Especially preferred compounds include haloalkyl 17&agr;-alkoxycarbonyloxy-9&agr;-fluoro-11&bgr;-hydroxy-16-methylandrosta-1,4-dien-3-one-17&bgr;-carboxylates.

Inactive metabolite approach to soft drug design

The invention provides new androstene derivatives having anti-inflammatory activity, pharmaceutical compositions containing them, and methods of administering them to warm-blooded animals in the treatment of inflammation. The active compounds are alkyl 17.alpha.-dichloroacetoxy-11.beta.-hydroxyandrosta-1,4-dien-3-one-17.beta. -carboxylates and related androstenes.

Androstene derivatives

The invention provides novel amino acids and peptides containing them which comprise a dihydropyridine.revreaction.pyridinium salt-type redox system and which provide site-specific and sustained delivery of pharmacologically active peptides to the brain. These new amino acids contain a redox system appended directly or via an alkylene bridge to the carbon atom adjacent to the carboxyl carbon and may be incorporated into a peptide chain at a variety of positions, including non-terminal positions.

Redox amino acids and peptides containing them

Compounds of the formula ##STR1## wherein the variables are defined in the specification; and acid addition and quaternary ammonium salts of formula (I) compounds are described. The compounds and their salts are soft anticholinergic/antisecretory agents especially useful as mydriatics and as antiperspirants.

Anticholinergic compounds, compositions and methods of treatment

The invention provides novel peptide derivatives which are designed to deliver pharmacologically active peptides into the central nervous system by sequential metabolism. The peptide is placed in a molecular environment which disguises its peptide nature and provides biolabile, lipophilic functions to penetrate the blood-brain barrier by passive transport. The design incorporates a dihydropyridine-type redox targetor moiety, an amino acid or di- or -tripeptide spacer inserted between the targetor and N-terminal amino acid unit of the peptide and a bulky, lipophilic substituent protecting the C-terminal amino acid unit of the peptide. The dihydropyridine-type targetor undergoes an enzymatically mediated oxidation to a hydrophilic, membrane-impermeable pyridinium salt. That polar targetor-peptide conjugate is trapped behind the lipoidal blood-brain barrier. Over time, cleavage of the lipophilic ester from the peptide by esterase and or lipase enzymes and enzymatic cleavage of the targetor-spacer from the peptide results in release of the desired peptide in the brain.

Brain-enhanced delivery of neuroactive peptides by sequential metabolism

The invention provides compounds of the formula ##STR1## or a pharmaceutically acceptable salt thereof, wherein [D] is the residue of a drug having a reactive functional group, said functional group being attached, directly or through a bridging group, via an oxygen-phosphorus bond to the phosphorus atom of the ##STR2## moiety; R.sub.1 is C.sub.1 -C.sub.8 alkyl, C.sub.6 -C.sub.10 aryl or C.sub.7 -C.sub.12 aralkyl; R.sub.2 is hydrogen, C.sub.1 -C.sub.8 alkyl, C.sub.6 -C.sub.10 aryl, C.sub.4 -C.sub.9 heteroaryl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.3 -C.sub.7 cycloheteroalkyl or C.sub.7 -C.sub.12 aralkyl; and R.sub.3 is selected from the group consisting of C.sub.1 -C.sub.8 alkyl; C.sub.2 -C.sub.8 alkenyl having one or two double bonds; (C.sub.3 -C.sub.7 cycloalkyl)-C.sub.r H.sub.2r -- wherein r is zero, one, two or three, the cycloalkyl portion being unsubstituted or bearing 1 or 2 C.sub.1 -C.sub.4 alkyl substituents on the ring portion; (C.sub.6 -C.sub.10 aryloxy)C.sub.1 -C.sub.8 alkyl; 2-, 3- or 4-pyridyl; and phenyl-C.sub.r H.sub.2r -- wherein r is zero, one, two or three and phenyl is unsubstituted, or is substituted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, trifluoromethyl, dialkylamino having 2 to 8 carbon atoms or alkanoylamino having 2 to 6 carbon atoms. The compounds are adapted for targeted drug delivery, especially to the brain.

Targeted drug delivery via phosphonate derivatives

Compounds of the formula ##STR1## wherein the variables are defined in the specification. The compounds and their salts are soft anticholinergic/antisecretory agents especially useful as mydriatics and as antiperspirants.

New soft .beta.-adrenergic blocking agents, useful in the treatment or prevention of cardiovascular disorders and in the treatment of glaucoma, have the formula ##STR1## wherein n is an integer from 0 to 10; R is C.sub.6 -C.sub.12 cycloalkyl-C.sub.p H.sub.2p --, C.sub.6 -C.sub.18 polycycloalkyl-C.sub.p H.sub.2p --, C.sub.6 -C.sub.18 polycycloalkenyl-C.sub.p H.sub.2p -- or C.sub.6 -C.sub.12 cycloalkenyl-C.sub.p H.sub.2p -- (wherein p is 0, 1, 2 or 3), or together with the adjacent ##STR2## group represents a variety of other complex ester groupings; R.sub.1 is C.sub.1 -C.sub.7 alkyl; and Ar is a divalent radical containing at least one aromatic nucleus. The corresponding pharmaceutically acceptable acid addition salts are also described.

Soft .beta.-drenegic blocking agents

The subject compounds, which are adapted for the site-specific/sustained delivery of centrally acting drug species to the brain, are: (a) compounds of the formula

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Gainesville, FL, United States of America

Nicholas S Bodor