Abbott Laboratories Corporation

Herman H Stein

Anthony K Fung

Raj Nandan Prasad

William R Baker

Jacob J Plattner

Steven R Crowley

Karin Rosemarie Tietje

David S Garvey

Charles W Hutchins

Steven Armen Boyd

Wang Shen

Gerard M Sullivan

Todd Warren Rockway

William J McClellan

Saul H Rosenberg

Stephen J O'Connor

Stephen A Fakhoury

Jon F Denissen

Rajnandan N Prasad

David John Augeri

David M Stout

David L Arendsen

Bruce W Horrom

B Gregory Donner

Jacob J Pattner

The present invention provides a compound of the formula ##STR1## or a pharmaceutically acceptable salt thereof, which are useful for inhibiting protein farnesyltransferase and the farnesylation of the oncogene protein Ras or inhibiting de novo squalene production resulting in the inhibition of cholesterol biosynthesis, processes for the preparation of the compounds of the invention in addition to intermediates useful in these processes, a pharmaceutical composition, and to methods of using such compounds.

Inhibitors of squalene synthase and protein farnesyltransferase

The present invention provides a compound of the formula ##STR1## or a pharmaceutically acceptable salt thereof, which are useful in inhibiting protein farnesyltransferase and the farnesylation of the oncogene protein Ras or inhibiting de novo squalene production resulting in the inhibition of cholesterol biosynthesis, processes for the preparation of the compounds of the invention in addition to intermediates useful in these processes, a pharmaceutical composition, and to methods of using such compounds.

Inhibitors of protein farnesyltransferase and squalene synthase

A renin inhibiting compound of the formula: ##STR1## wherein X is O, NH or S and G is a mimic of the Leu-Val cleavage site of angiotensinogen; or a pharmaceutically acceptable salt, ester or prodrug thereof; with the proviso that the compound is not N-(3-(4-Morpholino)propyl)-5(S)-(2(S)-(1(S)-(4-methoxymethoxy)piperidin-1- yl)carbonyl-2-phenyl)ethoxyhexanamido)-6-cyclohexyl-4(S)-hydroxy-2(S)-isopr opylhexanamide.

Renin inhibitors

A method and a composition for treating or reducing and/or controlling intraocular pressure comprising administering an effective amount of a renin inhibiting compound of the formula: ##STR1## wherein A is a substituent; W is CO or CHOH and U is CH.sub.2 or NR.sub.2 wherein R.sub.2 is hydrogen or loweralkyl; with the proviso that when W is CHOH then U is CH.sub.2 ; R.sub.1 is loweralkyl, cycloalkylmethyl, benzyl, (alpha, alpha) -dimethylbenzyl, 4-hydroxybenzyl, 4-methoxybenzyl, halobenzyl, (1-naphthyl)methyl, (2-naphthyl)methyl, 1-benzyloxyethyl, phenethyl, phenoxy, thiophenoxy or anilino; R.sub.3 is loweralkyl, loweralkenyl, ((alkoxy)alkoxy)loweralkyl, (thioalkoxy)alkyl, benzyl or heterocyclic ring substituted methyl; and R.sub.4 is substituted hydroxyalkylamino.

Glaucoma treatment

A renin inhibiting compound of the formula: ##STR1## wherein X is O NH or S and G is a mimic of the Leu-Val cleavage site of angiotensinogen; or a pharmaceutically acceptable salt, ester or prodrug thereof; with the proviso that the compound is not N-(3-(4-Morpholino)propyl)-5(S)-(2(S)-(1(S)-(4-(methoxymethoxy)piperidin-1 -yl)carbonyl-2- phenyl)ethoxyhexanamido)-6-cyclohexyl-4(S)-hydroxy-2(S)-isopropylhexanamid e.

A method and a composition for treating or reducing and/or controlling intraocular pressure comprising administering an effective amount of a renin inhibiting compound of the formula: ##STR1## wherein A is a substituent; W is CO or CHOH and U is CH.sub.2 or NR.sub.2 wherein R.sub.2 is hydrogen or loweralkyl; with the proviso that when W is CHOH then U is CH.sub.2 ; R.sub.1 is loweralkyl, cycloalkylmethyl, benzyl, (alpha, alpha)-dimethylbenzyl, 4-hydroxybenzyl, 4-methoxybenzyl, halobenzyl, (1-naphthyl)methyl, (2-naphthyl)methyl, 1-bezyloxyethyl, phenethyl, phenoxy, thiophenoxy or anilino; R.sub.3 is loweralkyl, loweralkenyl, ((alkoxy)alkoxy)loweralkyl, (thioalkoxy)alkyl, benzyl or heterocyclic ring substituted methyl; and R.sub.4 is substituted hydroxyalkylamino.

A method and a composition for treating or reducing and/or controlling intraocular pressure comprising administering an effective amount of a renin inhibiting compound of the formula: ##STR1## where A is a substituent; W is CO or CHOH and U is CH.sub.2 or NR.sub.2 wherein R.sub.2 is hydrogen or loweralkyl; with the proviso that when W is CHOH then U is Ch.sub.2 ; R.sub.1 is loweralkyl, cycloalkyl methyl, benzyl, (alpha, alpha)-dimethylbenzyl, 4-hydroxybenzyl, 4-methoxybenzyl, halobenzyl, (1-naphthyl)methyl, (2-naphthyl)methyl, 1-bezyloxyethyl, phenethyl, phenoxy, thiophenoxy or anilino; R.sub.3 is loweralkyl, loweralkenyl, ((alkoxy)alkoxy)loweralkyl, (thioalkoxy)alkyl, benzyl or heterocyclic ring substituted methyl; and R.sub.4 is substituted hydroxyalkyamino.

A method and a composition for treating or reducing and/or controlling intraocular pressure comprising administering an effective amount of a renin inhibiting compound of the formula: ##STR1## wherein A is a substituent; W is CO or CHOH and U is CH.sub.2 or NR.sub.2 wherein R.sub.2 is hydrogen or loweralkyl; with the proviso that when W is CHOH then U is CH.sub.2 ; R.sub.1 is loweralkyl, cycloalkyl, benzyl, (alpha, alpha)-dimethylbenzyl, 4-hydroxybenzyl, 4-methoxybenzyl, halobenzyl, (1-naphthyl)methyl, (2-naphthyl)methyl, (4-imidazoyl)methyl, phenethyl, 1-benzyloxyethyl, phenoxy, thiophenoxy or anilino; R.sub.3 is loweralkyl, loweralkenyl, ((alkoxy)alkoxy)alkyl, carboxyalkyl, (thioalkoxy)alkyl, benzyl or heterocyclic ring substituted methyl; and R.sub.4 is a substituted amino group; or pharmaceutically acceptable salts or esters thereof. Also disclosed are compositions, methods and kits for treating glaucoma or reducing and/or controlling intraocular pressure wherein the renin inhibiting compound is administered in combination with a beta-adrenergic antagonist, a steroidal antiinflammatory agent or an angiotensin converting enzyme inhibiting compound.

Described are compounds of the formula ##STR1## wherein Y and Z independently of one another denote hydrogen, halo or trihalomethyl, with the proviso that Y and Z cannot both be hydrogen, R is hydrogen or loweralkyl, n is 5 to 19, and pharmaceutically acceptable salts thereof. The compounds are active hypocholesterolemic agents.

Aminobenzoic acid derivatives

A method of controlling undesired animals including rodents, coyotes and birds which comprises making available to said animals an edible composition containing, as the active ingredient, a lethal dose of a compound represented by formula ##STR1## wherein R is H, loweralkyl or acetyl; R.sub.1 is H or acetyl; R.sub.2 is H, Cl or NH.sub.2 ; R.sub.3 is H, loweralkyl, alkoxy, cycloalkyl or hydroxyalkyl; R.sub.4 and R.sub.5 are each H, acetyl or propionyl, or when taken together form a p-chlorobenzylidene, a carbonate or an ethoxymethylene moiety; in a suitable carrier.

Adenosine-5'-carboxamides and method of use

A group of .beta.-blockers represented by the formula ##STR1## wherein R is ##STR2## or ##STR3## and the physiologically compatible acid addition salts thereof. These .beta.-blockers are .beta.-adrenergic receptor blocking agents which are useful in the treatment of angina pectoris, heart arrhythmia, and high blood pressure.

5-[2-Hydroxy-3-(3,4-dimethoxy phenethylamino)]-propoxy-3,4-dihydro

Adenosine-5'-carboxylic acid amides represented by the formula ##STR1## wherein R.sub.1 and R.sub.2 are each selected from the group consisting of hydrogen, loweralkyl, lowerhaloalkyl, lowerhydroxyalkyl, lowercycloalkyl, loweralkylcycloalkyl, loweralkenyl, lowerhaloalkenyl, lowerhydroxyalkenyl, loweralkynyl, lowerhaloalkynyl, benzylamino, phenyl, loweralkylphenyl, loweralkoxyloweralkyl, substituted phenyl, 2-methylfuran or di(C.sub.1 -C.sub.4)alkylamino(C.sub.1 -C.sub.4)alkyl, adamantyl or R.sub.1 and R.sub.2 taken together form a 5 or 6 membered heterocyclic moiety; R.sub.3 and R.sub.4 are hydrogen or acyl, or taken together form an isopropylidene or a benzylidene group; or a pharmaceutically acceptable acid addition salt thereof.

Adenosine-5'-carboxylic acid amides

2-Substituted adenosine-5'-carboxylates represented by the formula ##SPC1## Wherein R is amino, acetamido or hydroxy, R.sub.1 is loweralkyl, haloloweralkyl, hydroxyloweralkyl, lowercycloalkyl, loweralkenyl, loweralkynyl, loweralkyl(C.sub.3 -C.sub.6)cycloalkyl or alkoxyalkyl and R.sub.2 and R.sub.3 each are hydrogen or acyl, or R.sub.2 and R.sub.3 taken together form an isopropylidene or benzylidene moiety; and the pharmaceutically acceptable acid addition salts thereof. The compounds wherein R.sub.2 and R.sub.3 are hydrogen or acyl are useful in treating cardiovascular disorders and are particularly useful as anti-anginal agents. Compounds wherein R.sub.2 and R.sub.3 when taken together form an isopropylidene or benzylidene moiety are intermediates useful in making the final products.

2-Substituted adenosine-5'-carboxylates in the treatment of anginal pain

Adenosine-5'-carboxamides which are effective as platelet aggregation inhibitors and represented by the formula ##SPC1## Wherein R is hydrogen, loweralkyl, lowercycloalkyl, loweralkenyl, or lowerhydroxyalkyl.

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Highland Park, IL, United States of America

Herman H Stein