Subtype-Selective Agents: Potential Therapeutics for Neurological and Psychiatric Disorders Na Ye,† John L. Neumeyer,‡ Ross J. Baldessarini, Xuechu Zhen, and Ao Zhang*,† †CAS Key Laboratory of Receptor Research, and Synthetic Organic & Medicinal Chemistry Laboratory (SOMCL), Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China 201203 ‡Medicinal Chemistry Laboratory, McLean Hospital, Harvard Medical School, Massachusetts 02478, United States Psychopharmacology Program, McLean Hospital, Massachusetts 02478, United States Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China 215123

Update 1 of: Recent progress in development of dopamine receptor subtype-selective agents: potential therapeutics for neurological and psychiatric disorders

Thia-Michael Addition: An Emerging Strategy in Organic Synthesis

The present invention discloses compounds of formula (I) any of its enantiomers or any mixture thereof, isotopes thereof or a pharmaceutically acceptable salt thereof; wherein n is 1, 2 or 3; m is 0, 1 or 2; R represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl or aralkyl; and R1 represents aminophenyl; nitrophenyl; hydroxyphenyl, alkoxyphenyl; a monocyclic 5 to 6 membered heterocyclic group which may be substituted one or more times with substituents or R1 represents a bicyclic heterocyclic group, composed of 5 to 6 membered monocyclic heterocyclic group fused to a benzene ring, and which may be substituted one or more times with substituents. The compounds of the invention are useful as nicotinic ACh receptor ligands.

Heteroaryl diazacycloalkanes as cholinergic ligands at nicotinic acetylcholine receptors

[reaction: see text] Novel tricyclic pyrimido[4,5-b][1,4]benzothiazepines were readily prepared from 5-amino-4,6-bis(arylthio)pyrimidines and carboxylic acids via Bischler-Napieralski-type reactions. The 6-aryl sulfide group of the resulting pyrimido[4,5-b][1,4]benzothiazepines could be selectively oxidized to its corresponding sulfoxide, which underwent facile substitution reactions when treated with nucleophiles such as an amine. This synthetic strategy provides an efficient way to access a library of novel heterocyclic compounds that are of interest in drug discovery.

Synthesis of novel tricyclic pyrimido[4,5-b][1,4]benzothiazepines via Bischler-Napieralski-type reactions.

RECENT ADVANCES IN THE CHEMISTRY OF TRICHLOROMETHYL CHLOROFORMATE AND bis-(TRICHLOROMETHYL) CARBONATE

A great need exists for antipsychotic drugs which will not induce extrapyramidal symptoms (EPS) and tardive dyskinesias (TDs) These side effects are deemed to be a consequence of nonselective blockade of nigrostriatal and mesolimbic dopamine D2 receptors Nondyskinetic clozapine (1) is a low-potency D2 dopamine receptor antagonist which appears to act selectively in the mesolimbic area In this work dopamine antagonism was assessed in two mouse behavioral assays: antagonism of apomorphine-induced climbing and antagonism of apomorphine-induced disruption of swimming The potential for the liability of dyskinesias was determined in haloperidol-sensitized Cebus monkeys Initial examination of a few close cogeners of 1 enhanced confidence in the Cebus model as a predictor of dyskinetic potential Considering dibenzazepines, 2 was not dyskinetic whereas 2a was dyskinetic Among dibenzodiazepines, 1 did not induce dyskinesias whereas its N-2-(2-hydroxyethoxy)ethyl analogue 3 was dyskinetic The emergence of such distinctions presented an opportunity Thus, aromatic and N-substituted analogues of 6-(piperazin-1-yl)-11H-dibenz[b,e]azepines and 11-(piperazin-1-yl)dibenzo[b,f][1,4]thiazepines and -oxazepines were prepared and evaluated 11-(4-[2-(2-Hydroxyethoxy)ethyl]piperazin-1-yl)dibenzo[b,f][1,4]thiazepine (23) was found to be an apomorphine antagonist comparable to clozapine It was essentially nondyskinetic in the Cebus model With 23 as a platform, a number of N-substituted analogues were found to be good apomorphine antagonists but all were dyskinetic

Behavioral approach to nondyskinetic dopamine antagonists: identification of seroquel.

Compounds of formula (I): wherein R is hydrogen, C1-10alkyl, C3-8cycloalkyl, C3-8cycloalkylC1-6alkyl, phenylC1-6alkyl or phenyl; R1 is C?1-6?alkyl, C2-6alkenyl, C1-6alkoxy, halo, hydroxy, C1-6alkanoyl, haloC1-6alkyl, cyano or nitro; m is 0, 1 or 2; R?2? is C?1-6?alkyl; n is 0, 1 or 2; are empomil inhibitors and are useful in the treatment of neurological disorders such as stroke, head trauma, transient cerebral ischemic attack, and chronic neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, diabetic neuropathy, amyotrophic lateral sclerosis, multiple sclerosis, vascular dementia and AIDS-related dementia.

1,4-diazacycloheptane derivatives

The invention relates to aminotetralin derivatives of formula (I) wherein: R1 is methyl or ethyl; R2 is hydrogen, halogen, lower-alkoxy or thiolower-alkyl; R3 is hydrogen, halogen, lower-alkoxy or lower-alkyl; and the chiral center * is in the (S)(-) form; or a pharmaceutically acceptable acid-addition salt thereof, with the proviso that when R?2 and R3? are both hydrogen, R1 must be methyl; to pharmaceutical compositions containing them and to methods for the treatment or prevention of movement disorders utilizing them.

Aminotetralin derivatives and compositions and method of use thereof

Homopiperazines of formula (I), wherein R1 is hydrogen, C?1-8?alkyl, C2-8alkenyl or C2-8alkynyl substituted or unsubstituted with a variety of groups as defined herein; A is a ring selected from phenyl and naphthyl; R?2? at each occurrence is independently selected from a variety of groups as defined herein; m is an integer selected from the range 0 to 5 where at each occurrence R2 is independently selected; together with processes for their manufacture and compositions containing them. Compounds of formula (I) are pharmacologically useful in the treatment of neurological disorders.

Homopiperazine derivatives as selective emopamil inhibitors

1,4-Diazacyclo-heptanes of formula (I) wherein R is selected from hydrogen, C1-10alkyl, C2-8alkenyl, C3-8cycloalkyl, C3-8cycloalkyl C1-6alkyl, phenylC1-6alkyl and phenyl, R1 at each occurrence is independently selected from hydrogen, C?1-6?alkyl, C2-6alkenyl, C1-6alkoxy, halo, hydroxy, C1-6alkanoyl, haloC1-6alkyl, cyano and nitro, m is 4, R?2? at each occurrence is independently selected from hydrogen and C?1-6?alkyl, and n is 4, together with processes for their manufacture and compositions containing them. Compounds of formula (I) are pharmacologically useful.

Edward John Warawa

Papers

Behavioral approach to nondyskinetic dopamine antagonists: identification of seroquel.

1,4-diazacycloheptane derivatives

Aminotetralin derivatives and compositions and method of use thereof

Homopiperazine derivatives as selective emopamil inhibitors

1,4-diazacycloheptane compounds, process for their preparation, and their use as medicaments