Interx Research Corporation

Merck + Co., Inc.

Internx Research Corporation

Nicolae S Bodor

James J Kaminski

Kenneth B Sloan

Sun-Shine Yuan

Takeru Higuchi

Anwar A Hussain

Yu-Neng Kuo

Efraim Shek

Labile quaternary ammonium salts of the following formula (I) and (II) are provided: ##STR1## wherein N represents a tertiary aliphatic amine; wherein N represents an unsaturated amine; wherein R represents a member selected from the group consisting of a hydrogen atom, a C.sub.1 -C.sub.8 open chain or cyclo alkyl group, a C.sub.1 -C.sub.8 alkoxyalkyl group, a C.sub.1 -C.sub.8 acyloxyalkyl group, a C.sub.1 -C.sub.8 haloalkyl group, a C.sub.1 -C.sub.8 carboxyalkyl group, a C.sub.2 -C.sub.8 alkenylphenyl group, an aryl group, and a substituted aryl group, whose substituents are selected from the group consisting of a halogen atom, an O-lower alkyl (C.sub.1 -C.sub.4) group, an O-acyl group, a nitro group, a carboxyl group, and a carboethoxy group; wherein R.sub.1 which may be the same or different, represents any member defined by R above with the proviso that R.sub.1 cannot be a hydrogen atom; wherein X is --O-- or --S--; and wherein Y represents a member selected from the group consisting of a halogen atom or any other organic or inorganic monovalent equivalent anion; with the further proviso that N and N, respectively cannot represent trimethylamine and pyridine or quinoline when R represents a hydrogen atom and R.sub.1 represents a methyl group or a phenyl group. The compounds described above are characterized by their extreme solubility and resistance to oxidation, dealkylation, and protonation prior to chemical and/or enzymatic hydrolysis. Upon chemical and/or enzymatic hydrolysis, these compounds will 'cleave,' thus releasing their active constituent or constituents, according to the following general scheme(s): ##STR2## In other words, the title compounds hydrolyze (chemically or enzymatically) releasing a tertiary amine or unsaturated amine derivative, an aldehyde, a carboxylic acid and a hydrogen halide (HX) per the above reaction scheme.

Labile quaternary ammonium salts as prodrugs

Soft quaternary surface active agents having the formula: ##STR1## wherein ##STR2## represents a tertiary open chain or cyclic aliphatic amine; wherein ##STR3## represents an unsaturated amine; wherein R represents a member selected from the group consisting of a hydrogen atom, a C.sub.1 -C.sub.20 open chain or cyclo alkyl group, a C.sub.1 -C.sub.20 alkoxyalkyl group, a C.sub.1 -C.sub.20 acyloxyalkyl group, a C.sub.1 -C.sub.20 haloalkyl group, a C.sub.1 -C.sub.20 carboxyalkyl group, an aryl group, and a substituted aryl group, whose substituents are selected from the group consisting of a halogen atom, an O--C.sub.1 -C.sub.4 alkyl group, an O--C.sub.1 -C.sub.8 acyl group, a nitro group, a carboxyl group, and a carboethoxy group; wherein R.sub.1 represents a C.sub.9 -C.sub.22 straight or branched alkyl group, a --(CH.sub.2).sub.n -- ##STR4## wherein R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are each selected from the group consisting of a hydrogen atom, a methyl group or an ethyl group, a C.sub.0 -C.sub.22 straight or branched alkyl ##STR5## wherein n in each occurrence and m represent an integer of from 0 to 22, an ##STR6## wherein A represents a C.sub.0 -C.sub.22 straight or branched alkyl group as above or a --(CH.sub.2 CH.sub.2 O).sub.p group, wherein the p represents an integer of from 0 to 22, and the residue of any naturally occurring bile acid or synthetic derivative thereof; and wherein X represents a halogen atom or any other organic or inorganic monovalent anion are disclosed. All compounds encompassed within the above-described generic formulae find use as 'soft' antibacterial agents of extremely low toxicity.

Soft quaternary surface active agents

Soft quaternary surface active agents having the formula: ##STR1## wherein &gt;N represents a tertiary open chain or cyclic aliphatic amine; wherein &gt;N represents an unsaturated amine; wherein R represents a member selected from the group consisting of a hydrogen atom, a C.sub.1 -C.sub.20 open chain or cyclo alkyl group, a C.sub.1 -C.sub.20 alkoxyalkyl group, a C.sub.1 -C.sub.20 acyloxyalkyl group, a C.sub.1 -C.sub.20 haloalkyl group, a C.sub.1 -C.sub.20 carboxyalkyl group, an aryl group, and a substituted aryl group, whose substituents are selected from the group consisting of a halogen atom, an O--C.sub.1 -C.sub.4 alkyl group, an O--C.sub.1 -C.sub.8 acyl group, a nitro group, a carboxyl group, and a carboethoxy group; wherein R.sub.1 represents a C.sub.9 -C.sub.22 straight or branched alkyl group, a --(CH.sub.2).sub.n -- ##STR2## group, wherein R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are each selected from the group consisting of a hydrogen atom, a methyl group or an ethyl group, a C.sub.0 -C.sub.22 straight or branched alkyl-(CH.sub.2).sub.n ##STR3## (CH.sub.2).sub.m CH.sub.3 group, wherein n in each occurrence and m represents an integer of from 0 to 22, an A-CH.sub.2 ##STR4## CH.sub.2 -A-CH.sub.3 group, wherein A represents a C.sub.0 -C.sub.22 straight or branched alkyl group as above or a --(CH.sub.2 CH.sub.2 O) group, wherein the p represents an integer of from 0 to 22, and the residue of any naturally occurring bile acid or synthetic derivative thereof; and wherein X represents a halogen atom or any other organic or inorganic monovalent anion are disclosed. All compounds encompassed within the above-described generic formulae find use as 'soft' antibacterial agents of extremely low toxicity.

Soft quaternary surface active agents and method of using same

This invention deals with chemical intermediates having the formula ##STR1## wherein R.sub.1 and R.sub.2 together with the carbon atom to which they are attached form a single hetero atom member selected from the group consisting of a five-to seven-membered heterocycle containing one hetero-N-atom and a N-substituted five-to seven-membered heterocycle containing an hetero-N-atom whose substituent is C.sub.1 -C.sub.2 alkyl. These compounds are useful in the synthesis of compounds having a variety of uses as pharmaceuticals.

Intermediates useful in the preparation of optically and therapeutically

There is provided, a novel class of compounds exhibiting antibacterial activity and having the formula: ##STR1## wherein X and Y each represent a member which may be the same or different selected from the group consisting of H and Cl with the proviso that X and Y cannot represent H simultaneously;

Antibacterially active N-chloroamino ester derivatives of alkyl

Labile quaternary ammonium salts of the following formula (I) and (II) are provided: ##STR1## wherein ##STR2## represents a tertiary aliphatic amine; wherein ##STR3## represents an unsaturated amine; wherein R represents a member selected from the group consisting of a hydrogen atom, a C.sub.1 -C.sub.8 open chain or cyclo alkyl group, a C.sub.1 -C.sub.8 alkoxyalkyl group, a C.sub.1 -C.sub.8 acyloxyalkyl group, a C.sub.1 -C.sub.8 haloalkyl group, a C.sub.1 -C.sub.8 carboxyalkyl group, a C.sub.2 -C.sub.8 alkenylphenyl group, an aryl group, and a substituted aryl group, whose substituents are selected from the group consisting of a halogen atom, an O-lower alkyl (C.sub.1 -C.sub.4) group, an O-acyl group, a nitro group, a carboxyl group, and a carboethoxy group; wherein R.sub.1 which may be the same or different, represents any member defined by R above with the proviso that R.sub.1 cannot be a hydrogen atom; wherein X is --O-- or --S--; and wherein Y represents a member selected from the group consisting of a halogen atom or any other organic or inorganic monovalent equivalent anion;

Labile, non-heterocyclic quaternary ammonium salt/esters as transient

Optically and therapeutically active compounds of the formula: ##STR1## wherein R represents a member selected from the group consisting of a straight or branched alkyl group of from one to twenty carbon atoms (C.sub.1 -C.sub.5 being preferred), an ethoxycarbonyl group, a benzyloxycarbonyl group, a phenyl group, an ##STR2## WHEREIN R is as defined above and R.sub.3 is a member selected from the group consisting of a hydrogen atom, a methyl group and a phenyl group, and a 2-, 3-, or 4-pyridyl group, or the HX salts thereof, wherein X represents a pharmaceutically acceptable acid addition salt anion, are prepared optically active m-hydroxy-.alpha.-[methylamino)methyl]benzyl alcohol (phenylephrine). The compounds prepared by the process of this invention find therapeutic application to warm-blooded animals (e.g., humans) in the management of asthma, nasal congestion and as decongestants, vasoconstrictors, mydriatic agents, and anti-glaucomatous agents in the practice of ophthalmology. Upon administration, these compounds will enzymatically 'cleave,' thus releasing optically active phenylephrine (m-hydroxy-.alpha.-[(methylamino)methyl]benzyl alcohol, the therapeutically active moiety thereof.

Intermediates useful in the synthesis of optically active

Potassium is rendered nonbitter tasting by combining the same with phytic acid. The final product is useful as a nonbitter tasting potassium supplement for warm-blooded animals deficient in levels of potassium.

Nonbitter tasting potassium product for oral administration to

Free and conjugated bile acids are effectively bound in warm-blooded animals by administering thereto, a therapeutically effective bile acid binding amount of a quaternary ammonium compound having the formula: ##STR1## wherein ##STR2## represents a tertiary open chain or cyclic aliphatic amine; wherein ##STR3## represents an unsaturated amine; wherein R represents a member selected from the group consisting of a hydrogen atom, a C.sub.1 -C.sub.20 open chain or cyclo alkyl group, a C.sub.1 -C.sub.20 alkoxy-alkyl group, a C.sub.1 -C.sub.20 alkanoyloxyalkyl group, a C.sub.1 -C.sub.20 haloalkyl group, a C.sub.1 -C.sub.20 carboxyalkyl group, an aryl group, and a substituted aryl group, whose substituents are selected from the group consisting of a halogen atom, an O--C.sub.1 -C.sub.4 alkyl group, an O--C.sub.1 -C.sub.8 alkanoyl group, a nitro group, a carboxyl group, and a carboethoxy group; wherein R.sub.1, which may be the same or different, represents any member defined by R above with the proviso that R cannot be a hydrogen atom, a ##STR4## WHEREIN R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are each selected from the group consisting of a hydrogen atom, a methyl group or an ethyl group, a C.sub.0 -C.sub.22 straight or branched ##STR5## WHEREIN N IN EACH OCCURRENCE AND M REPESENT AN INTEGER OF FROM 0 TO 22, AN ##STR6## WHEREIN A represents a C.sub.0 -C.sub.22 straight or branched alkyl group as above or a --(CH.sub.2 CH.sub.2 O).sub.p group, wherein the p represents an integer of from 0 to 22, and the residue of any naturally occurring bile acid or synthetic derivative thereof; and wherein X.sup.- represents a halogen atom or any other organic or inorganic monovalent anion are disclosed. These compounds are relatively nontoxic and substantially bind bile acids in warm-blooded animals and thus reduce the ulcerogenic symptoms exhibited by those characterized as being ulcer-prone.

Labile quaternary ammonium salts useful in binding bile acids in

The compound 1,2-Diphenyl-3,5-ditrifluoroacetyloxy-4-butyl-5-hydroxy-3-pyrazoline is disclosed as an intermediate useful in the preparation of selected pro-phenylbutazone derivatives. Such selected pro-phenylbutazone derivatives are novel, transient, pro-drug forms of phenylbutazone and oxyphenbutazone having the following formulae wherein R, R.sub.2, R.sub.4, R.sub.5, X and Y are as defined herein: ##STR1## The above-identified compounds exhibit anti-inflammatory activity in warm-blooded animals. Upon administration to warm-blooded animals, these compounds pass through the gastrointenstinal tract and cleave in the bloodstream, thus releasing phenylbutazone or oxyphenbutazone in an anti-inflammatory effective amount at their therapeutic site or sites of activity.

1,2-Diphenyl-3,5-ditrifluoroacetyloxy-4-butyl-5-hydroxy-3-pyrazoline

There is provided, a novel class of compounds exhibiting antibacterial activity and having the formula: ##STR1## wherein X and Y each represent a member which may be the same or different selected from the group consisting of H and Cl with the proviso that X and Y cannot represent H simultaneously; R.sub.1 and R.sub.2 each represent a member which may be the same or different selected from the group consisting of an n- or branched alkyl group of from 1 to 20 carbon atoms, an aryl group (phenyl, naphthyl, etc.) and a ##STR2## WHEREIN M REPRESENTS AN INTEGER OF FROM 2 TO 5; N REPRESENTS AN INTEGER OF 1 TO 8; AND Z represents a member selected from the group consisting of an --OOCR.sub.3 group, an --OR.sub.3 group and an --OCH.sub.2 OR.sub.3 group, wherein R.sub.3 represents a member selected from the group consisting of an n- or branched alkyl group of 1 to 20 carbon atoms, a phenyl group, a naphthyl group, a benzyl group, ##STR3## WHEREIN X is a halogen atom (Cl, Br, I), a 2, 3 or 4 ##STR4## A 2, 3, OR 4 ##STR5## WHEREIN R.sub.4 represents a member selected from the group consisting of H, an n- or branched alkyl group, a benzyl group, an O atom, and a --(CH.sub.2).sub.p COOH group, wherein p represents an integer of 1 to 4, and wherein W.sup..crclbar. represents a non-toxic pharmaceutically acceptable inorganic or organic anion.

Novel soft N-chloroamino alcohol derivatives exhibiting antibacterial

Free and conjugated bile acids are effectively bound in warm-blooded animals by administering thereto, a therapeutically effective bile acid binding amount of a quaternary ammonium compound having the formula: ##STR1## wherein &gt;N represents a tertiary open chain or cyclic aliphatic amine; wherein &gt;N represents an unsaturated amine; wherein R represents a member selected from the group consisting of a hydrogen atom, a C.sub.1 -C.sub.20 open chain or cyclo alkyl group, a C.sub.1 -C.sub.20 alkoxyalkyl group, a C.sub.1 -C.sub.20 alkanoyloxyalkyl group, a C.sub.1 -C.sub.20 haloalkyl group, a C.sub.1 -C.sub.20 carboxyalkyl group, an aryl group, and a substituted aryl group, whose substituents are selected from the group consisting of a halogen atom, an O--C.sub.1 -C.sub.4 alkyl group, an O--C.sub.1 -C.sub.8 alkanoyl group, a nitro group, a carboxyl group, and a carboethoxy group; wherein R.sub.1, which may be the same or different, represents any member defined by R above with the proviso that R cannot be a hydrogen atom, a ##STR2## WHEREIN R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are each selected from the group consisting of a hydrogen atom, a methyl group or an ethyl group, a C.sub.0 -C.sub.22 straight or branched ##STR3## WHEREIN N IN EACH OCCURRENCE AND M REPRESENT AN INTEGER OF FROM 0 TO 22, AN ##STR4## WHEREIN A represents a C.sub.0 -C.sub.22 straight or branched alkyl group as above or a --(CH.sub.2 CH.sub.2 O).sub.p group, wherein the p represents an integer of from 0 to 22, and the residue of any naturally occurring bile acid or synthetic derivative thereof; and wherein X.sup.- represents a halogen atom or any other organic or inorganic monovalent anion are disclosed. These compounds are relatively nontoxic and substantially bind bile acids in warm-blooded animals and thus reduce the ulcerogenic symptoms exhibited by those characterized as being ulcer-prone.

Novel, transient pro-drug forms of the anti-inflammatories phenylbutazone and oxyphenbutazone are disclosed, the same having the structural formulae: ##STR1## wherein R is a member selected from the group consisting of C.sub.1 -C.sub.2 alkylsulfonyl, phenylsulfonyl, p-tolylsulfonyl and naphthylsulfonyl, and ##STR2## wherein X and Y each represent a member selected from the group consisting of a hydrogen atom and ##STR3## with the proviso that either X or Y is a hydrogen atom, R.sub.1 is selected from the group consisting of C.sub.1 -C.sub.2 alkylsulfonyl, phenylsulfonyl, p-tolylsulfonyl and naphthylsulfonyl, and R.sub.2 is selected from the group consisting of straight or branched chain C.sub.1 -C.sub.5 alkyl and phenyl.

Transient pro-drug forms of phenylbutazone

There is provided, a novel class of compounds exhibiting antibacterial activity and having the formula: ##STR1## wherein X and Y each represent a member which may be the same or different selected from the group consisting of H and Cl with the proviso that X and Y cannot represent H simultaneously; R.sub.1 and R.sub.2 each represent a member which may be the same or different selected from the group consisting of an n- or branched alkyl group of from 1 to 20 carbon atoms, an aryl group (phenyl, naphthyl, etc.) and ##STR2## WHEREIN M REPRESENTS AN INTEGER OF FROM 2 TO 5; N REPRESENTS AN INTEGER OF 1 TO 8; AND Z represents a member selected from the group consisting of an --OOCR.sub.3 group, an --OR.sub.3 group and an --OCH.sub.2 OR.sub.3 group, wherein R.sub.3 represents a member selected from the group consisting of an n- or branched alkyl group of 1 to 20 carbon atoms, a phenyl group, a naphthyl group, a benzyl group, ##STR3## WHEREIN X is a halogen atom (Cl, Br, I), ##STR4## WHEREIN R.sub.4 represents a member selected from the group consisting of H, an n- or branched alkyl group, a benzyl group, and a --(CH.sub.2).sub.p COOH group, wherein p represents an integer of 1 to 4, and wherein W.sup..crclbar. represents a non-toxic pharmaceutically acceptable inorganic or organic anion.

Antibacterial novel soft n-chloroamino alcohol derivatives

There is provided, a novel class of compounds exhibiting antibacterial activity and having the formula: ##STR1## wherein X and Y each represent a member which may be the same or different selected from the group consisting of H and Cl with the proviso that X and Y cannot represent H simultaneously; R.sub.1 and R.sub.2 each represent a member which may be the same or different selected from the group consisting of an n- or branched alkyl group of from 1 to 20 carbon atoms, an aryl group (phenyl, naphthyl, etc.) and a ##STR2## WHEREIN M REPRESENTS AN INTEGER OF FROM 2 TO 5; N REPRESENTS AN INTEGER OF 1 TO 8; AND Z represents a member selected from the group consisting of an --OOCR.sub.3 group, an --OR.sub.3 group and an --OCH.sub.2 OR.sub.3 group, wherein R.sub.3 represents a member selected from the group consisting of an n- or branched alkyl group of 1 to 20 carbon atoms, a phenyl group, a naphthyl group, a benzyl group, ##STR3## WHEREIN X is a halogen atom (Cl, Br, I), ##STR4## WHEREIN R.sub.4 represents a member selected from the group consisting of H, an n- or branched alkyl group, a benzyl group, and a --(CH.sub.2).sub.p COOH group, wherein p represents an integer of 1 to 4, and wherein W.sup..theta. represents a non-toxic pharmaceutically acceptable inorganic or organic anion.

Growing community of inventors

Lawrence, KS, United States of America

Nicolae S Bodor