Warner-lambert Company

Anthony J Thomas

Walter H Moos

Donald E Butler

Haile Tecle

Jeffrey A Kester

David J Lauffer

Juan C Jaen

Michael R Pavia

Corinne E Augelli-Szafran

Stephen Douglas Barrett

Bradley W Caprathe

Edgardo Laborde

Stephen C Bergmeier

David M Lustgarten

Roy Douville Schwarz

Ruth Bucsh

Adam A Galan

Kathryn B Sanders

The instant invention is a selective formation of the Z-oxime and O-alkylation of 1-azabicyclo 2.2.1!heptan-3-one and 1-azabicyclo 2.2.2!heptan-3-one oximes to produce compounds with muscarinic activity. The process is capable of scale-up for industrial purposes as it provides better yields and ease of preparation. Intermediates are also described.

Preparation of stereochemically pure oximes with muscarinic activity

Pharmaceutically useful nitrogen containing cyclic oxime and amine substituted compounds are disclosed which are azabicyclo[2.2.2]oximes, azabicyclo[2.2.2]-amines, azabicyclo[3.2.1]oximes and amine containing heterocyclic oximes wherein the heterocyclic ring contains from 3 to 7 carbon atoms.

Azabicyclo and azacyclo oxime and amine cholinergic agents and methods

Substituted tetrahydropyridines and piperidinecarboxylic acids and derivatives thereof are described, as well as methods for the preparation and pharmaceutical composition of same, which muscarinic antagonists are useful as agents for inhibiting gastric acid release, for treating bradycardia, bronchoconstriction, urinary incontinence, atonic conditions of the gut and bladder, Parkinson's disease, dystonias, and Alzheimer's disease.

Substituted tetrahydropyridine and piperidine carboxylic acids as

Pharmaceutically useful nitrogen containing cyclic oxime and amine substituted compounds which are azabicyclo[2.2.1]oximes, azabicyclo[2.2.2]oximes, azabicyclo[2.2.1]amines, azabicyclo[2.2.2]amines, azabicyclo[3.2.1]oximes, and amine containing heterocyclic oximes wherein the heterocyclic ring contains from 3 to 7 carbon atoms are disclosed.

Pharmaceutically useful nitrogen containing cyclic oxime and amine substituted compounds of the following general Formulas I, II and III are disclosed: ##STR1## Specifically the compounds are azabicyclo [2.2.1] omimes, azabicyclo [2.2.2] oximes, azabicyclo [2.2.1] amines, azabicyclo [2.2.2] amines, azabicyclo [3.2.1] oximes and amine containing heterocyclic oximes wherein the heterocyclic ring contains from 4 to 5 [3 to 7] carbon atoms.

Oxime and amine substituted azabicyclo and azocyclo muscarinic agonists

Novel prodrugs or depot derivatives of 1,2,3,4-tetrahydro-9-acridinamine are described, as well as methods for the preparation and pharmaceutical compositions of same, which are useful as analgesic agents for the treatment of pain, as sleep aids and as agents for treating the symptoms of senile dementia, Alzheimer's disease, Huntington's chorea, tardive dyskinesia, hyperkinesia, mania, or similar conditions of cerebral insufficiency characterized by decreased cerebral acetylcholine production or release.

Derivatives of 1,2,3,4-tetrahydro-9-acrisinamine

4-(N-Substituted amino)-2-butynyl-1-carbamates and thiocarbamates and derivatives thereof are described, as well as methods for the preparation and pharmaceutical compositions of same, which are useful as centrally acting muscarinic agents and are useful as analgesic agents for the treatment of pain, as sleep aids and as agents for treating the symptoms of senile dementia, Alzheimer's disease, Huntington's chorea, tardive dyskinesia, hyperkinesia, mania, or similar conditions of cerebral insufficiency characterized by decreased cerebral acetylcholine production or release.

4-(N-substituted amino)-2-butynyl-1-carbamates and thiocarbamates and

4-(N-Substituted amino)-2-butynyl-1-ureas and thioureas and derivatives thereof are described, as well as methods for the preparation and pharmaceutical compositions of same, which are useful as centrally acting muscarinic agents and are useful as analgesic agents for the treatment of pain, as sleep aids and as agents for treating the symptoms of senile dementia, Alzheimer's disease, Huntington's chorea, tardive dyskinesia, hyperkinesia, mania, or similar conditions of cerebral insufficiency characterized by decreased cerebral acetylcholine production or release.

4-(N-substituted amino)-2-butynyl-1-ureas and thioureas and derivatives

A method is disclosed for the treatment or amelioration of the symptoms of cerebral insufficiency characterized by decreased central adrenergic and/or cholinergic function employing certain N-substituted aminopyridines.

Method of treating senile cognitive decline with N'-substituted

Certain trisubstituted alkyl, aryl, pyridinyl, piperidinyl, and piperazinyl urea compounds stimulate the release of acetylcholine and are thus useful agents for the treatment of senile cognitive decline characterized by decreased cerebral acetylcholine production or release. A method for treating the symptoms of senile cognitive decline is disclosed.

Method of treating the symptoms of senile cognitive decline employing

Certain tetrasubstituted alkyl, aryl, pyridinyl, piperidinyl, and piperazinyl urea compounds stimulate the release of acetylcholine and are thus useful analgesic agents for alleviating pain or as cholinergic agents which are useful for the amelioration of the symptoms of cognitive decline in the elderly. These compounds have the general formula ##STR1## wherein R.sub.1, R.sub.2 and R.sub.4 are phenyl or substituted phenyl, and R.sub.3 is pyridinyl. Pharmaceutical compositions including these compounds as well as methods for the preparation of the compounds are also disclosed.

Tetrasubstituted urea cholinergic agents

Novel derivatives of substituted pyrrolizine diones and the pharmaceutically acceptable salts and esters thereof, have therapeutic utility for reducing amnesia induced by electroconvulsive shock and for treating senility.

Pyrrolidone-2 derivatives and pharmaceutical compositions thereof

Novel derivatives of substituted pyrrolizine diones, isomers, and pharmaceutically acceptable derivatives thereof, have therapeutic utility for reducing amnesia induced by electroconvulsive shock and for treating senility.

Substituted dihydro-1H-pyrolizine-3,5(2H,6H)-diones

Certain 5-oxo-3-(unsubstituted-phenyl)- or 5-oxo-3-(substituted phenyl)-2-pyrrolidinepropanoic acids and 5-oxo-.beta.-(unsubstituted-phenyl)- or 5-oxo-.beta.-(substituted-phenyl)-2-pyrrolidinepropanoic acids, their pharmaceutically acceptable esters and metal and amine cation salts, pharmaceutical compositions employing these compounds, and a method of treating senility or of reversing amnesia are disclosed.

(Substituted-phenyl)-5-oxo-2-pyrrolidinepropanoic acids and esters

1-(Substituted-aryl)-dihydro-1H-pyrrolizine-3,5-[2H,6H]-diones are effective cognition activating agents for the treatment of senility and for reversing amnesia. Pharmaceutical compositions containing these compounds and a method of treating senility or of reversing amnesia are also disclosed.

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Ann Arbor, MI, United States of America

Anthony J Thomas