Merck + Co., Inc.

University of Pennsylvania

Paul S Anderson

Ben E Evans

Marcia E Christy

David C Remy

Gerald S Ponticello

Roger M Freidinger

Walfred S Saari

Douglas J Pettibone

Mark G Bock

Amos B Smith, Iii

Otto D Hensens

Peter D Williams

Ralph F Hirschmann

Jerrold M Liesch

Gideon A Rodan

Paul A Sprengeler

Thorsten E Fisher

Michael A Goetz

Lawrence R Koupal

Cheryl D Schwartz

Doug W Hobbs

Wenqing Yao

This invention relates to chemical compounds that contain adjacent carbonyl groups, which effectively inhibit the biological, chemical, and/or physical properties of enzymes and other medicinally-significant proteins. In particular, the invention relates to dicarbonyl compounds that are capable of acting as enzyme inhibitors, including irreversible inhibitors of HIV-1 protease.

Dicarbonyl-containing compounds

Compounds of the formula ##STR1## X is --O--, --NH-- and --NR.sup.8 --; Y is --CH.sub.2 --, --CHR.sup.8 -- and --C(R.sup.8).sub.2 --; R.sup.1 is camphor-10-yl, C.sub.1-5 alkoxyl, styryl, hydroxystyryl, furyl, unsubstituted or substituted thienyl, naphthyl, indolyl, tetrahydronaphthyl, unsubstituted, mono- or di-substituted pyridyl, pyrazinyl, unsubstituted or substituted cyclohexyl where the substituent is R.sup.4, and unsubstituted or substituted phenyl where the substituents on phenyl are R.sup.5, R.sup.6 and R.sup.7 ; R.sup.2 is hydrogen, C.sub.1-5 alkoxy, C.sub.1-5 alkyl, amino, C.sub.1-5 alkylcarbonylamino, nitro or halogen; R.sup.3 is hydrogen, C.sub.1-5 alkoxycarbonyl, cyano or carbamoyl; R.sup.4 is one to two of hydrogen, oxo, hydroxy, C.sub.1-5 alkoxy, C.sub.1-5 alkoxycarbonylamino-C.sub.1-5 alkyl and amino-C.sub.1-5 alkyl; R.sup.5, R.sup.6 are each independently selected from hydrogen, halogen, C.sub.1-5 alkyl, hydroxyl and C.sub.1-5 alkoxy; R.sup.7 is ##STR2## W is CO or SO.sub.2 ; and m is an integer from 0 to 1. Such compounds as useful as oxytocin and vasopressin receptor antagonists.

Benzoxazinone and benzopyrimidinone piperidinyl tocolytic oxytocin

The invention relates to acyloxymethyl esters of bisphosphonic acids, halo-bisphosphonic acids and hydroxy-bisphosphonic acids which exhibit oral bioavailability and are useful in the treatment of disturbances involving calcium or phosphate metabolism, in particular, the treatment and prevention of diseases involving bone resorption, especially osteoporosis, Paget's disease, malignant hypercalcemia, and metastatic bone disease.

Acyloxymethyl esters of bisphosphonic acids as bone resorption inhibitors

Described are new agents for treating bone disorders associated with a reduction in bone mass and abnormalities in bone resportion or bone formation including osteoporosis. Paget's disease, bone metastases and malignant hypercalcemia. The agents are hydroxyl containing steroidal hormones, having bone resportion antagonist or bone formation stimulatory activity, covalently linked through the hydroxyl group via a bond hydrolyzable in the human body, e.g. carbamate or carbonate, which is further covalently linked to an amino, or hydroxy substituted alkylidene-1,1-bisphosphonate, through the respective amino or hydroxy group. The alkyl bisphosphonate moiety confers bone affinity. The agent acts by delivering the steroidal hormone directly to the bone target site where it is released for bone resorption antagonist or bone formation stimulatory action by hydrolysis of the hydrolyzable covalent bond.

Bone acting agents

Cyclic peptides are produced by the controlled aerobic fermentation of Streptomyces silvensis, ATTCC No. 53525 or ATCC No. 53526. These compounds are antagonists of oxytocin and are useful in the treatment of preterm labor and vasopressin and are thus useful in the treatment and prevention of disease states wherein vasopressin may be involved, for example congestive heart failure, hypertension, edema and hyponatremia.

Oxytocin and vasopressin antagonists

Dibenzo[a,d]cycloocten-5,12-(and 6,12)-imines, derivatives and pharmaceutically acceptable salts thereof are useful as anxiolytics, antidepressants, anticonvulsants, muscle relaxants and in the treatment of mixed anxiety-depression, minimal brain dysfunction and extrapyramidal disorders such as Parkinson's disease.

Dibenzo[a,d]cycloocten-5,12-imines

5-Substituted-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imines, derivatives and pharmaceutically acceptable salts thereof are useful as anticonvulsants.

5-Alkyl or hydroxyalkyl

Dibenzo[a,d]cycloocten-5,12-(and 6,12)-imines

Dibenzo[a,d]cycloocten-6,12-imines

9,10-Dihydro-4H-benzo[4,5]cyclohepta [1,2-b]thiophen-4,9-imines, derivatives and pharmaceutically acceptable salts thereof are useful as antianxiety agents, as muscle relaxants and in the treatment of extrapyramidal disorders such as in Parkinson's disease.

9,10-Dihydro-4H-benzo[4,5]cyclohepta [1,2-b]thiophen-4,9-imines

1-Methyl-4-(2-carboxy-thioxanthen-9-ylidene)-piperidine is disclosed to have pharmaceutical utility as an appetite stimulant and an antihistamine with low antiserotonin and anticholinergic activity. Also disclosed are processes for the preparation of such compound; pharmaceutical compositions comprising such compound; and methods of treatment comprising administering such compound and compositions.

1-Methyl-4-(2-carboxy-thioxanthen-9-ylidene)-piperidine an appetite

Substituted 9,10-dihydroanthracen-9,10-imines are disclosed to be minor tranquilizers, anticonvulsnts, muscle relaxants, and to be useful in the treatment of extrapyramidal disorders such as Parkinson's disease; also disclosed are processes for the preparation of such compounds; pharmaceutical compositions comprising such compounds; and methods of treatment comprising administering such compounds and compositions.

Substituted 9,10-dihydroanthracen-9,10-imines

Heterocyclic dihydroanthracen imines are disclosed to be useful as minor tranquilizers, anticonvulsants, muscle relaxants and to be useful in the treatment of extrapyramidal disorders such as Parkinson's disease; also disclosed are processes for the preparation of such compounds; pharmaceutical compositions comprising such compounds; and methods of treatment comprising administering such compounds and compositions.

Heterocyclic dihydroanthracen imines

Disclosed are certain polycyclic imidazoles which are effective in inhibiting indoleamine-N-methyl transferase and thus useful in the treatment of mental aberrations, such as schizophrenia. Also disclosed are processes for the preparation of such imidazoles; pharmaceutical compositions comprising such compounds; and methods of treatment comprising administering such compounds and compositions.

Polycyclic imidazoles

Disclosed are 2,3,5,6-tetrahydro-8H-imidazo-[2,1-c][1,4]thiazines, analogues and derivatives thereof which are effective in inhibiting indoleamine-N-methyl transferase and thus useful in the treatment of mental aberrations, such as schizophrenia. Also disclosed are processes for the preparation of such imidazothiazines; pharmaceutical compositions comprising such compounds; and methods of treatment comprising administering such compounds and compositions.

Growing community of inventors

Lansdale, PA, United States of America

Paul S Anderson