Merck + Co., Inc.

Raymond S Chang

Yiu-kuen T Lam

Deborah L Zink

Otto D Hensens

Cheryl D Schwartz

Richard L Monaghan

Michael A Goetz

Mark G Bock

Roger M Freidinger

William H Parsons

Ben E Evans

Jacob M Hoffman

This invention relates to novel compounds, their synthesis and use as selective .alpha..sub.1a adrenergic receptor antagonists. One application of the compounds is in the treatment of benign prostatic hyperplasia. The compounds are selective in their ability to relax smooth muscle tissue enriched in the .alpha..sub.1a receptor subtype without at the same time inducing hypotension. One such tissue is found surrounding the urethral lining. Therefore, one utility of the instant compounds is to provide acute relief to males suffering from benign prostatic hyperplasia, by permitting less hindered urine flow. Another utility of the instant compounds is provided by combination with a human 5-alpha reductase inhibitory compound, such that both acute and chronic relief from the effects of benign prostatic hyperplasia are achieved.

.alpha..sub.1a adrenergic receptor antagonists

Pharmaceutical compositions containing Virginiamycin M.sub.1 having the Formula: ##STR1## and Virginiamycin M.sub.1 analogs having the Formulae I-IV: ##STR2## are disclosed which are useful in the treatment of panic disorder or anxiety disorder.

Fermentation analogs of Virginiamycin M.sub.1 to treat panic and anxiety

Virginiamycin M.sub.1 having the Formula: ##STR1## and virginiamycin M.sub.1 analogs having the Formulae I-IV: ##STR2## Virginiamycin M.sub.1 and the analogs I-IV are antagonists of cholecystokinin (CCK) and gastrin. Cholecystokinin antagonists are useful as analgesics and in the treatment and prevention of disorders of the gastrointestinal, central nervous and appetite regulatory systems in animals, especially humans. Gastrin antagonists are useful in blocking the receptors for gastrin in humans and may function as agents for the treatment of ulcers, tumors or other gastrointestinal disorders. The compounds of Formulae I-IV are also antibiotics and are useful as antimicrobial agents in animals including man and are useful as food additives to promote feed utilization in animals. Virginiamycin M.sub.1 and the analogs of Formula I, III and IV are produced by the controlled aerobic fermentation of a strain of Streptomyces olivaceus, ATCC No. 53527. The analog of Formula II is produced by chemical synthesis.

Therapeutic virginiamycin M.sub.1 analogs

Virginiamycin M.sub.1 having the Formula: ##STR1## and virginiamycin M.sub.1 analogs having the Formulae I-IV: ##STR2## Virginiamycin M.sub.1 and the analogs I-IV are antagonists of cholecystokinin (CCK) and gastrin. Cholecystokinin antagonists are useful as analgesics and in the treatment and prevention of disorders of the gastrointestinal, central nervous and appetite regulatory systems in animals, especially humans. Gastrin antagonists are useful in blocking the receptors for gastrin in humans and may function as agents for the treatment of ulcers, tumors or other gastrointestinal disorders. The compounds of Formulae I-IV are antibiotics and are useful as antimicrobial agents in animals including man and are useful as food additives to promote feed utilization in animals. Virginiamycin M.sub.1 and the analogs of Formula I, III and IV are produced by the controlled aerobic fermentation of a strain of Streptomyces olivaceus, ATCC No. 53527, while the analog of Formula II is produced by chemical synthesis.

Fermentation analogs of virginiamycin M.sub.1

Virginiamycin M.sub.1 having the Formula: ##STR1## and virginiamycin M.sub.1 analogs having the Formulae I-IV: ##STR2## Virginiamycin M.sub.1 and the analogs I-IV are antagonists of cholecystokinin (CCK) and gastrin. Cholecystokinin antagonists are useful as analgesics and in the treatment and prevention of disorders of the gastrointestinal, central nervous and appetite regulatory systems in animals, especially humans. Gastrin antagonists are useful in blocking the receptors for gastrin in humans and may function as agents for the treatment of ulcers, tumors or other gastrointestinal disorders. The compounds of Formulae I-IV are also antibiotics and are useful as antimicrobial agents in animals including man and are useful as food additives to promote feed utilization in animals. Virginiamycin M.sub.1 and the analogs of Formula I, II and IV are produced by the controlled aerobic fermentation of a strain of Streptomyces olivaceus, ATCC No. 53527, while the analog of Formula II is produced by chemical synthesis.

Process for preparing synthetic virginiamycin M.sub.1 analogs

Virginiamycin M.sub.1 having the Formula: ##STR1## and virginiamycin M.sub.1 analogs having the Formulae I-IV: ##STR2## Virginiamycin M.sub.1 and the analogs I-IV are antagonists of cholecystokinin (CCK) and gastrin. Cholecystokinin antagonists are useful as analgesics and in the treatment and prevention of disorders of the gastrointestinal, central nervous and appetite regulatory systems in animals, especially humans. Gastrin antagonists are useful in blocking the receptors for gastrin in humans and may function as agents for the treatment of ulcers, tumors or other gastrointestinal disorders. The compounds of Formulae I-IV are also antibiotics and are useful as antimicrobial agents in animals including man and are useful as food additives to promote feed utilization in animals. Virginiamycin M.sub.1 and the analogs of Formula I, III and IV are produced by the controlled aerobic fermentation of a strain of Streptomyces olivaceus, ATCC No. 53527, while the analog of Formula II is produced by chemical synthesis.

Compositions having fermentation analogs of virginiamycin M.sub.1 as

Synthetic virginiamycin M1 analogs

Virginiamycin M.sub.1 having the Formula: ##STR1## and virginiamycin M.sub.1 analogs having the Formulae I-IV: ##STR2## Virginiamycin M.sub.1 and the analogs I-IV are antagonists of cholecystokinin (CCK) and gastrin. Cholecystokinin antagonists are useful as analgesics and in the treatment and prevention of disorders of the gastrointestinal, central nervous and appetite regulatory systems in animals, especially humans. Gastrin antagonists are useful in blocking the receptors for gastrin in humans and may function as agents for the treatment of ulcers, tumors or other gastrointestinal disorders. The compounds of Formulae I-IV are also antibiotics and are useful as antimicrobial agents in animals including man and are useful as food additives to promote feed utilization in animals. Virginiamycin M.sub.1 and the analogs of Formula I, III, and IV are produced by the controlled aerobic fermentation of a strain of Streptomyces olivaceus, ATCC No. 53527, while the analog of Formula II is produced by chemical synthesis.

Fermentation analogs of virginiamycin M1

A process for preparing the compound having Formula I and several minor related compounds. ##STR1## The compound of Formula I and the several minor related compounds are antagonists of cholecystokinin (CCK). CCK antagonists are useful in the treatment and prevention of disorders of the gastrointestinal, central nervous and appetite regulatory systems of animals, especially humans.

Process for the preparation of cholecystokinin antagonists

A method of antagonizing the function of cholecystokinins in a disease state in mammals, especially in humans, which comprises administering a pharmaceutically-effective amount of certain 2-acylaminomethyl-1,4-benzodiazepine derivatives or their salts, alone or with a pharmaceutical carrier, with or without an adjuvant.

2-acylaminomethyl-1,4-benzodiazepine derivatives as CCK-antagonists

Benzofused lactams and their use as antagonists of cholecystokinin are disclosed.

Benzofused lactams as cholecystokinin antagonists

The compound having Formula I and several minor related compounds are produced by the aerobic fermentation of Aspergillus alliaceus Thom and Church, ATCC No. 20655 or ATCC No. 20656. ##STR1## The compound of Formula I and the several minor related compounds are antagonists of cholecystokinin (CCK). CCK antagonists are useful in the treatment and prevention of disorders of the gastrointestinal, central nervous and appetite regulatory systems of animals, especially humans.

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Lansdale, PA, United States of America

Raymond S Chang