Interx Research Corporation

University of Florida Research Foundation Inc

Merck + Co., Inc.

Other

Intrex Research Corporation

Kenneth B Sloan

Nicholas S Bodor

Nicolae S Bodor

Anwar A Hussain

Stefano A Pogany

Valentino J Stella

Kenneth Boone Wagener

Yu-Neng Kuo

Roy M Little

James Klein Leonard

Howard D Beall

Described herein are vitamin C prodrugs of Formula (I), (II), or (III), and pharmaceutically acceptable salts thereof. Also provided are pharmaceutical compositions, cosmetic or personal care composition, neutraceutical composition, and medical food composition thereof. Methods of using the compounds or compositions thereof for treating diseases are also provided. 

Vitamin C prodrugs and uses thereof

A poly(non-conjugated diene) based sunscreen has a plurality of repeating units where each repeating unit has at least one UV absorbing chromophore that is situated between and connected by chains to two mono-ene units where each UV absorbing chromophore absorb UVA and UVB light. The poly(non-conjugated diene) based sunscreen can be included with a vehicle for application to the skin to prevent sunburn. The poly(non-conjugated diene) based sunscreen can be prepared by acyclic diene metathesis polymerization.

Poly (non-conjugated diene) based sunscreens

A pharmaceutical composition in unit dosage form adapted for topical administration to a human or non-human animal in need thereof comprising a pharmacologically effective amount of a prodrug of 5-fluorouracil having the formula: ##STR1## wherein R.sub.3 is bonded to C=O by a carbon-to-carbon bond and is a group such that the prodrug (1) has an enhanced delivery across topical membranes and (2) hydrolyzes after delivery to 5-fluorouracil.

Topical 5-fluorouracil prodrug composition and method

Prodrugs of bio-active hydroxyaromatic drugs having the structural formula: A pharmaceutically acceptable prodrug of a biologically active, therapeutically effective hydroxyaromatic drug, said prodrug being selected from the group consisting of, (A) compounds having the structural formula:

Prodrugs of biologically active hydroxyaromatic compounds

A compound of the formula: ##STR1## wherein: R and R.sub.1 may be the same or different and are selected from the group consisting of H; cycloalkyl groups having up to 10 carbon atoms; or straight or branched chain alkyl, alkenyl or alkynyl of 1 to 10 carbon atoms;

Aminomethyl derivatives of biologically active substances and enhanced

N-methylamino derivatives of biologically active substances which have enhanced delivery across topical membranes and pharmaceutical compositions adapted for topical administration containing same.

Aminomethyl derivatives of biologically active substances, and enhanced

Novel, transient prodrug forms of biologically active agents containing mercapto groups have (i) the structural formula (I): ##STR1## wherein X is O, S, or NR.sup.5 ;

Prodrugs of 6-mercaptopurine and 6-mercaptopurine ribosides and

Novel prodrug forms of known non-steroidal anti-inflammatory agents are disclosed, said prodrugs having the structural formula ##STR1##

Mannich-base hydroxamic acid prodrugs, compositions and use

Novel derivatives of known bio-affecting carboxylic acids R-COOH are disclosed, said derivatives having the structural formula ##STR1## wherein Y and Y' are each H or C.sub.1 -C.sub.4 alkyl; n is 0 or 1; R.sub.1 and R.sub.2 are each selected from a variety of unsubstituted or substituted hydrocarbon radicals, or are combined so that --NR.sub.1 R.sub.2 represents the residue of a saturated or unsaturated heterocyclic compound containing one secondary nitrogen atom; and R.sub.3 is H or one of a variety of other substituents. Salts and N-oxides of compounds of formula (I) and the corresponding diacyloxy derivatives of known bio-affecting carboxylic acids HOOC-R'-COOH are disclosed also. The parent acids from which the subject soft tertiary amine esters can be derived include such bio-affecting agents as cephalosporin and penicillin antibiotics, amino acids and structurally related compounds, prostaglandins and their metabolites, steroidal anti-inflammatory agents, and non-steroidal anti-inflammatory/non-narcotic analgesic/antipyretic agents.

Soft tertiary amine esters of bio-affecting carboxylic acids

Novel pharmaceutically useful derivatives of selected known bio-affecting carboxylic acids are disclosed, said derivatives having the structural formula ##STR1## wherein R.sub.1 and R.sub.2, which can be the same or different, are each hydrogen, C.sub.1 -C.sub.5 alkyl, C.sub.1 -C.sub.5 alkoxy, C.sub.1 -C.sub.5 alkylthio, phenyl, or substituted phenyl having one or more substituents each of which is selected from the group consisting of C.sub.1 -C.sub.5 alkyl, C.sub.1 -C.sub.5 alkoxy, chloro and dialkylamino wherein the alkyl portions, which can be the same or different, each have 1 to 5 carbon atoms, with the proviso that when R.sub.1 is alkoxy or alkylthio, then R.sub.2 cannot be alkoxy or alkylthio; X and X', which can be the same or different, are each hydrogen, C.sub.1 -C.sub.5 alkyl, carboxy, C.sub.2 -C.sub.6 alkoxycarbonyl, halo, C.sub.1 -C.sub.5 alkoxy, dialkylcarbamyl wherein the alkyl portions, which can be the same or different, each have 1 to 5 carbon atoms, phenyl, or substituted phenyl the pyridyl ring is oriented such that it is attached to the ##STR2## portion of the molecule via a carbon-carbon bond; and R-COO- is the acyloxy residue of a monocarboxylic acid; a steroidal monocarboxylic acid; or a cephalosporin or penicillin antibiotic.

Pyridylmethyl esters of selected bio-affecting carboxylic acids

Novel, transient inotropic prodrug forms of the N-(2-phenylethyl)-.omega.-phenylalkylamines, notably of dobutamine, have (i) the structural formula (I): ##STR1## with the proviso that at least one R.sup.1, R.sup.2 or OR.sup.1, when R.sup.7 and/or R.sup.10 is OR.sup.1, must be R.sup.3 COXCH(R.sup.4)-- or R.sup.3 COXCH(R.sup.4)O--, respectively.

Novel inotropic prodrugs

Novel, transient prodrug forms of the phenolic dihydroxy sympathomimetic amines have (i) the structural formula (I): ##STR1## wherein X is O, S or NR.sup.5 ; n is 1 or 2; R.sup.1 is the monodehydroxylated residue of a phenolic, nuclear dihydroxy natural sympathetic or sympathomimetic amine when n is 1, and the didehydroxylated residue of a phenolic, nuclear dihydroxy natural sympathetic or sympathomimetic amine when n is 2; R.sup.2 is selected from the group consisting of straight or branched chain alkyl having from 1 to 20 carbon atoms; aryl having from 6 to 10 carbon atoms; cycloalkyl having from 3 to 8 carbon atoms; alkenyl having from 2 to 20 carbon atoms; cycloalkenyl having from 4 to 8 carbon atoms; alkynyl having from 2 to 20 carbon atoms; aralkyl, alkaryl, aralkenyl, aralkynyl, alkenylaryl, alkynylaryl, loweracyloxyalkyl, and carboxyalkyl, wherein alkyl, aryl, alkenyl and alkynyl are as defined above; saturated or unsaturated monoheterocyclic or polyheterocyclic, or fused heterocyclic, containing from 1 to 3 of any one or more of the hetero atoms N, S or O in each heterocyclic ring thereof and each such ring being from 3- to 8-membered; and mono-or poly-substituted derivatives of the above, each of said substituents being selected from the group consisting of lower alkyl, lower alkoxy, lower acyl, lower acyloxy, halo, haloloweralkyl, cyano, carbethoxy, loweralkylthio, amino, nitro, loweralkylamino, diloweralkylamino, carboxyl, carbamyl, loweralkylcarbamyl, diloweralkylcarbamyl and ##STR2## wherein R.sup.4 is hydrogen or alkyl having from 1 to 10 carbons; R.sup.3 is hydrogen, R.sup.2, lower acyl, cyano, haloloweralkyl, carbamyl, loweralkylcarbamyl, diloweralkylcarbamyl, --CH.sub.2 ONO.sub.2 and --CH.sub.2 OCOR.sup.2 ; R.sup.5 is hydrogen or lower alkyl; (ii) the structural formula (II): ##STR3## wherein X, R.sup.2 and R.sup.3 are as defined above and R.sup.1 is the didehydroxylated residue of a phenolic, nuclear dihydroxy natural sympathetic or sympathomimetic amine; (iii) either of the structural formulae (I) or (II) wherein ##STR4## is the residue of any naturally occurring protein amino acid, the residue of any N-substituted naturally occurring amino acid, which N-substituent is lower alkyl or any amino acid protective group cleavable via hydrogenolysis or hydrolysis, or the residue of an N, N-lower dialkyl or C.sub.4 -C.sub.7 cycloalkylamino acid; and (iv) the non-toxic, pharmaceutically acceptable salts thereof.

Novel sypathomimetic amine prodrugs

Novel, transient prodrug forms of dopa and dopamine have (i) the structural formula (I): ##STR1## wherein each R is independently selected from the group consisting of hydrogen, R.sup.3 -CO- and ##STR2## wherein X is O, S or NR.sup.6 ; R.sup.1 is hydrogen or --COOR.sup.8 ; R.sup.2 is hydrogen or OR; R.sup.3 is selected from the group consisting of straight or branched chain alkyl having from 1 to 20 carbon atoms; aryl having from 6 to 10 carbon atoms; cycloalkyl having from 3 to 8 carbon atoms; alkenyl having from 2 to 20 carbon atoms; cycloalkenyl having from 4 to 8 carbon atoms; alkynyl having from 2 to 20 carbon atoms; aralkyl, alkaryl, aralkenyl, aralkynyl, alkenylaryl, alkynylaryl, loweracyloxyalkyl, and carboxyalkyl, wherein alkyl, aryl, alkenyl and alkynyl are as defined above; saturated or unsaturated monoheterocyclic or polyheterocyclic, or fused heterocyclic, containing from 1 to 3 of any one or more of the hetero atom N, S or O in each heterocyclic ring thereof and each such ring being from 3- to 8-membered; and mono- or poly-substituted derivatives of the above, each of said substituents being selected from the group consisting of lower alkyl, lower alkoxy, lower acyl, lower acyloxy, halo, haloloweralkyl, cyano, lower alkoxycarbonyl, loweralkylthio, amino, nitro, loweralkylamino, diloweralkylamino, carboxyl, carbamyl, loweralkylcarbamyl, diloweralkylcarbamyl and ##STR3## wherein R.sup.5 is hydrogen or alkyl having from 1 to 10 carbons; R.sup.4 is hydrogen, R.sup.3, lower acyl, cyano, haloloweralkyl, carbamyl, loweralkylcarbamyl, diloweralkylcarbamyl, --CH.sub.2 ONO.sub.2 and --CH.sub.2 OCOR.sup.3 ; R.sup.6 is hydrogen or lower alkyl; R.sup.7 is hydrogen, lower alkyl, COCF.sub.3, COOC(CH.sub.3).sub.3, COOCH.sub.2 C.sub.6 H.sub.5, or other N-protective group conventional to amino acid acid chemistry; R.sup.8 is hydrogen, benzyl, or other conventional, cleavable carboxyl protective group; with the proviso that at least one R must be R.sup.3 COXCH(R.sup.4)--; (ii) the structural formula (I) wherein at least one R.sup.3 CO- moiety comprising at least one R group is the residue of any naturally occurring protein amino acid, the residue of any N-substituted naturally occurring amino acid, which N-substituent is lower alkyl or any amino acid protective group cleavable via hydrogenolysis or hydrolysis, or the residue of an N,N-lower dialkyl or C.sub.4 -C.sub.7 cycloalkylamino acid; and (ii) the non-toxic, pharmaceutically acceptable salts thereof.

Novel dopa/dopamine prodrugs

Novel 3,2'-spiro(1',3'-thiazolidine) compounds which are transient prodrug forms of known 6- and/or 9-haloglucocorticosteroids are described. The subject prodrugs provide improved delivery of the prior art steroids for therapeutic purposes, particularly in alleviating inflammation, and can be prepared by known methods, for example, by reacting the corresponding 3-keto steroids with a thiazolidine forming reagent such as an L-cysteine alkyl ester.

Prodrugs for the improved delivery of halogen-containing

Compounds of the formula: ##STR1## useful in treating dermal inflammation in warm-blooded animals are provided.

Growing community of inventors

Eudora, KS, United States of America

Kenneth B Sloan