Merck + Co., Inc.

Interx Research Corporation

Stefano A Pogany

Gaylen M Zentner

Nicholas S Bodor

Kenneth B Sloan

Takeru Higuchi

Joseph A Fix

John L Haslam

Kenneth J Himmelstein

Randall V Sparer

Gregory A McClelland

Cheryl Ringeisen

Polymers obtained by condensing polyols with divinyl orthocarbonates are useful for making bioerodible polymers for sustained release of beneficial agents.

Poly(orthocarbonate acetal) bioerodible polymers

Bioerodible, thermoset, covalently crosslinked, elastomeric poly(ortho ester)s are disclosed. These materials are comprised of polymer chains that are interlocked in a covalent, three dimensional network which imparts dimensional stability. Use of these thermoset, covalently crosslinked materials as a drug delivery device is also disclosed.

Bioerodible thermoset elastomers

The instant invention relates to a drug-delivery device for the controlled release of HMG-CoA reductase inhibitor salts, as the therapeutically active ingredient, into an environment of use which comprises:

Resin modulated drug delivery device for the delivery of HMG-CoA

The invention relates to the use of carboxylic acids incorporated as a catalyst in poly(orthoester)s and other acid labile polymers such that upon exposure to aqueous environments the acid catalyzes the erosion of the polymer matrix. The rate of release of a drug substance incorporated into or surrounded by the poly(orthoester) or other acid labile polymer can be controlled in that the drug is released as the polymer is eroded in response to the catalytic action of the acid incorporated therein.

Organic acids as catalysts for the erosion of polymers

Novel lysine esters used as absorption enhancing agents for gastrointestinally and rectally administered drugs. Also provided are processes for preparation of said lysine ester compounds as well as pharmaceutical formulations and methods for their use as absorption enhancing agents.

Novel lysine esters used as absorption

Certain novel cyclic ureas are disclosed herein as dermal penetration enhancers of drug absorption. Also disclosed herein are compositions, methods of treatment and processes for preparing said cyclic urea compounds.

Cyclic ureas as dermal penetration enhancers

The instant invention is directed to a bioerodible poly(ortho ester) thermoplastic elastomer prepared from:

Bioerodible poly(ortho ester) thermoplastic elastomer from diketene

This invention involves complexes of quinoline carboxylic acid derivatives with guanidine and guanidine carbonate. The complexes have a greater solubility and dissolution rate when compared to the parent quinoline carboxylic acid derivatives and thus are more effective anti bacterials than the parent acids.

Quinoline carboxylic acid complexes with guanidinium carbonate

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

A method and drug form enhancing the absorption of a rectally or orally administered drug from the rectal compartment into the blood stream of a warm blooded animal. The method includes the steps of preparing a drug form capable of being rectally and orally administered. The drug form comprises a therapeutically effective unit dosage amount of a selected drug of the type which is capable of being absorbed into the blood stream from the gastrointestinal area and an .alpha.-keto aldehyde or salts thereof being present in the drug form in a sufficient amount to be effective in enhancing the drug absorption rate, when administering the drug form to warm blooded animals.

.alpha.-Keto aldehydes as enhancing agents of gastro-intestinal drug

Dichloroamino acid derivatives other than .alpha.-dichloroamino acids are prepared from chlorination of corresponding amino acids, and are found to be potent germicidal and fungicidal agents.

Dichloroamino acid derivatives useful as potent germicidal and

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.

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Lawrence, KS, United States of America

Stefano A Pogany