The United States of America As Represented by the Department of Health

G.d. Searle & Company

National Institutes of Health, a Component of the US Dept. of Health & Human Services

USA As Represented by Secretary of the Navy

US Government As Represented by the Secretary of the Army

The United States of America As Represented by the Secretary of

National Institutes of Health

Arthur E Jacobson

Kenner C Rice

Patricia C Contreras

Andrew Y Thurkauf

Mariena V Mattson

Nancy M Gray

Thomas L O'Donohue

Michael Francis Rafferty

Arnold Brossi

Wayne D Bowen

Brian R De Costa

Lilian A Radesca

Fuying Li

Helmut Schmidhammer

Ralph A Lessor

Carl R Alving

Michael A Rogawski

Malliga R Iyer

Gary R Matyas

Alexander V Mayorov

James A Monn

Kejun Cheng

Eugene S Gutman

Shunichi Yamaguchi

J Michael Walker

Fu-Lian Hsu

Eric W Bow

Kenner Cralle Rice

Gutman Eugene S

The present invention is directed to a compound having Formula (I) and its enantiomer: wherein the definitions of n, R, X, Y and Y, and Z are provided in the disclosure. The invention is also directed to pharmaceutical compositions of the disclosed compounds, as well as their use as opioid-like agonists in the treatment of pain. 

Biased potent opioid-like agonists as improved medications to treat chronic and acute pain and methods of using the same

In this application is described a composition and method for inducing in a subject anti-hapten antibodies without inducing antibodies to the carrier protein. Kits for designing and making compositions with desired haptens are also described.

Induction of highly specific antibodies to a hapten but not to a carrier peptide by immunization

Nitrogen-containing cyclohetero cycloalkylaminoaryl derivatives for CNS

Compounds, compositions and methods of treatment are described to control brain damage associated with anoxia or ischemia which typically follows stroke, cardiac arrest or perinatal asphyxia. The treatment includes administration of an N-(1-thienylcycloalkyl)alkenylamine compound as an antagonist to inhibit excitotoxic actions at major neuronal excitatory amino acid receptor sites. Compounds of most interest are those of the formula ##STR1## wherein R.sup.1 is one or more groups selected from hydrido, alkyl of one to about five carbon atoms, cycloalkyl of three to about five carbon atoms, alkenyl of two to about five carbon atoms, hydroxyl and alkoxy; wherein each of R.sup.2 is one or more groups selected from hydrido, alkyl of one to about five carbon atoms, cycloalkyl of three to about five carbon atoms, alkenyl of two to about five carbon atoms, hydroxyl, oxo and alkoxy; wherein R.sup.5 is one or more groups selected from hydrido, alkyl of one to about five carbon atoms, cycloalkyl of three to about five carbon atoms, alkenyl of two to about five carbon atoms, hydroxyl and alkoxy; and wherein the broken line within the N-containing ring represents a double bond between any two adjacent carbon atoms

N-(1-thienylcycloalkyl)alkenylamines for treatment of neurotoxic injury

Compounds, compositions and methods of treatment are described to control brain damage associated with anoxia or ischemia which typically follows stroke, cardiac arrest or perinatal asphyxia. The treatment includes administration of an N-(1-thienylcycloalkyl)alkenylamine compound as an antagonist to inhibit excitotoxic actions at major neuronal excitatory amino acid receptor sites. Compounds of most interest are those of the formula ##STR1## wherein R.sup.1, R.sup.2, and R.sup.5 are defined in specification.

This invention is in the field of clinical neurology and relates specifically to compounds, compositions and methods for treatment of patients with generalized epilepsy or partial (symptomatic) epilepsy using compounds of the formula: ##STR1## This invention also relates to compounds, compositions and methods of treatment for drug craving in patients addicted to cocaine.

5-aminocarbonyl-5H-dibenzo[a.d]cyclohepten-5,10-imines for treatment of

Certain nitrogen-containing cyclohetero cycloalkylaminoaryl compounds are described for treatment of CNS disorders such as cerebral ischemia, psychotic disorders and convulsions. Compounds of particular interest are of the formula ##STR1## wherein R.sup.1 is selected from hydrido, loweralkyl, cycloalkylalkyl of four to six carbon atoms, and loweralkenylloweralkyl; wherein each of R.sup.2 and R.sup.3 is independently selected from hydrido and loweralkyl; wherein each of R.sup.4 through R.sup.7, R.sup.10 and R.sup.11 is independently selected from hydrido, hydroxy, loweralkyl, benzyl, phenoxy, benzyloxy and haloloweralkyl; wherein n is a number selected from four through six; wherein p is a number selected from zero through four; wherein q is a number selected from three through five; wherein A is selected from phenyl, naphthyl and thienyl; wherein any of the foregoing A groups can be further substituted with one or more substituents independently selected from hydrido, hydroxy, loweralkyl, loweralkoxy, halo, haloloweralkyl, amino, monoloweralkylamino and diloweralkylamino; or a pharmaceutically acceptable salt thereof.

A derivative of phencyclidine (1) bearing an isothiocyanate moiety on the meta position of the aromatic ring (3; Metaphit as methanesulfonate and HCl salt) has been synthesized and identified as a rapid and specific site-directed acylating agent of the [.sup.3 H]-phencyclidine binding site in rat brain homogenates. Additional related compounds to Metaphit are Thiophit (oxalate salt), Ethylphit (HCl salt), and Isopropylphit (HCl salt).

Metaphit and related compounds as acylating agents for the

A derivative of phencyclidine (1) bearing an isothiocyanate moiety of the meta position of the aromatic ring (2; Metaphit) has been synthesized and identified as a rapid and specific site-directed acylating agent of the [.sup.3 H]-phencyclidine binding site in rat brain homogenates.

Metaphit, a specific acylating agent for the [.sup.3 H] phencyclidine

6-Keto-hydroxymorphinans having at the 4 position a substituent which is R.sub.1 =H, O lower alkyl, or O lower acyl, and N may be substituted by R.sub.2, which for agonist properties may be lower alkyl, lower alkenyl, cyclopropylmethyl, or phenyl lower alkyl, etc. Additionally, the nitrogen may be substituted by R.sub.2, which is allyl, cyclopropylmethyl, cyclobutylmethyl, dimethylallyl, etc., which function as antagonists to the morphine-like activity of the compound. Such activity is known as antinociceptive.

6-Keto-morphinans belonging to the 14-hydroxy-series

This patent application describes the preparation and properties of novel and highly potent morphinan analgesics. The compounds include narcotic agnoists as well as narcotic antagonists and are represented by the following formula: ##STR1## R.sub.1 =OCH.sub.3, OCOCH.sub.3, H R.sub.2 =CH.sub.3, CH.sub.2 --CH.dbd.CH.sub.2, ##STR2## CH.sub.2 CH.sub.2 C.sub.6 H.sub.5

6-Keto-morphinan analgesics

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Potomac, MD, United States of America

Arthur E Jacobson