G.d. Searle & Company

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

National Institutes of Health

Patricia C Contreras

Kenner C Rice

Arthur E Jacobson

Nancy M Gray

Andrew Y Thurkauf

Mariena V Mattson

Thomas L O'Donohue

Michael Francis Rafferty

Wayne D Bowen

Brian R De Costa

Lilian A Radesca

Ralph A Lessor

J Michael Walker

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.

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.

Certain bridged tricyclic amine compounds are described as being therapeutically effective in treatments of CNS disorders resulting from neurotoxic damage or neurodegenerative diseases, particularly those CNS disorders resulting from ischemic events. Compounds of particular interest for use as neuroprotective agents are those of the formula ##STR1## wherein each of R.sup.1 and R.sup.2 is independently selected from hydrido, loweralkyl, benzyl and phenyl; wherein each of R.sup.1 through R.sup.7 is independently selected from hydrido, loweralkyl, hydroxy, benzyl, phenyl, loweralkoxy, phenoxy, benzyloxy, halo and haloloweralkyl; wherein R.sup.18 may be selected from hydrido, loweralkyl, cycloalkyl of five or six carbon atoms, cycloalkylalkyl of six or seven carbon atoms, phenyl, hydroxyloweralkyl, and heteroaryl selected from saturated or fully unsaturated heterocyclic rings containing five to seven ring members of which one or two ring members are nitrogen atom; wherein each X is independently one or more groups selected from hydrido, hydroxy, loweralkyl, benzyl, phenyl, loweralkoxy, phenoxy, haloloweralkyl, halo, and lower-alkanoyl; and wherein each of R.sup.23 through R.sup.30 is independently selected from hydrido, lower alkyl, benzyl, phenyl and halo; wherein R.sup.18 together with one of R.sup.23, R.sup.24, R.sup.29 or R.sup.30 may form a fused heterocyclic ring containing five or six ring members; or a pharmaceutically-acceptable salt thereof.

Use of bridged tricyclic amine derivatives as anti-ischemic agents

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.

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Ballwin, MO, United States of America

Patricia C Contreras