Potential neuroleptic agents, N-((2-pyrrolidinyl)methyl)-2,3-dihydrobenzofuran-7-carboxamide derivatives.

Lu G., Yuan X., Wang J., Sun X., Cao F., Ren J., Ke Y., Mu X., Zeng B.

AbstractAn oxidative transformation from N‐substituted benzylamine into the corresponding benzamides was developed here using the oxidative system combined from the catalytic amount of PVP−I (polyinyl pyrrolidone) with TBHP. This newly developed method had the advantages of mild reaction conditions and broad substrate scope. The key intermediate of Enzalutamide as androgen receptor inhibitors was prepared using this catalytic condition starting from commercial available 2‐fluoro‐4‐nitrobenzaldehyde with the yield of 78.5 % for three‐step reactions.

Chenault H.K.

Chenault H.K.

Abstract This chapter provides an introduction to the structure, conformation, physical properties and reactivity of pyrrolidones and caprolactams. It begins with an overview of the nomenclature of lactams since there are several systems of nomenclature in practice, plus common names and various syncretisms. The chapter discusses the structures of pyrrolidone and caprolactam, starting with the X‐ray crystal structures of pyrrolidone, N‐methylpyrrolidone and caprolactam. The distinctive structural feature that dictates the physical and chemical properties of simple pyrrolidones and caprolactams is the cyclic amide moiety. The physical properties of lactams are dominated by the strong dipole moments and hydrogen bonding of their amide bonds. Pyrrolidones and caprolactams display reactivities comparable to other secondary and tertiary amides. Pyrrolidones and caprolactams display reactivities comparable to other secondary and tertiary amides. Like other amides, pyrrolidones and caprolactams are susceptible to hydrolysis, particularly at elevated temperature and extremes of pH.

Ikemoto T., Ito T., Nishiguchi A., Miura S., Tomimatsu K.

A practical method of synthesizing 7-{4-[2-(butoxy)ethoxy]phenyl}-N-(4-{[methyl(tetrahydro-2H-pyran-4-yl)amino]methyl}phenyl)-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (8), an orally active CCR5 antagonist, has been developed. Methyl 7-bromo-1-propyl-2,3-dihydro-1H-1-benzazepine-4-caboxylate (14a) was synthesized in good yield by the esterification of 4-[(4-bromo-2-formylphenyl)(propyl)amino]butanoic acid (13) followed by an intramolecular Claisen type reaction with 28% sodium methoxide in dimethyl carbonate as a solvent in one pot. The Suzuki−Miyaura reaction of 14a and 1-bromo-4-(2-butoxyethoxy)benzene (10) followed by hydrolysis and amidation gave 8. A new inexpensive method without chromatographic purification was established.

Itoh K., Kanzaki K., Ikebe T., Kuroita T., Tomozane H., Sonda S., Sato N., Haga K., Kawakita T.

A number of new carboxamide derivatives were synthesized. The affinity of these compounds for the serotoninergic 5-HT 4 receptor was evaluated by use of radioligand-binding techniques. The agonistic activity was evaluated as the contractile effect of the ascending colon isolated from guinea-pigs. Among these compounds, 4-amino-5-chloro-2-methoxy- N -[1-[2-[(methylsulfonyl)amino]ethly]-4-piperidinylmethyl]benzamide ( 24 ) showed a high affinity for the 5-HT 4 receptor ( Ki = 9.6 nM). Compound 24 displayed a higher affinity for 5-HT 4 receptors than the other receptors, including, 5-HT 3 and dopamine D 2 receptors. In addition, compound 24 was confirmed to be a potent 5-HT 4 receptor agonist (ED 50 = 7.0 nM). An interaction model between compound 24 and 5-HT 4 receptor was proposed.

Itoh K., Kanzaki K., Ikebe T., Kuroita T., Tomozane H., Sonda S., Sato N., Haga K., Kawakita T.

A number of new carboxamide derivatives were synthesized. The affinity of these compounds for the serotoninergic 5-HT 4 receptor was evaluated by use of radioligand-binding techniques. The agonistic activity was evaluated as the contractile effect of the ascending colon isolated from guinea-pigs. Among these compounds, 4-amino-5-chloro-2-methoxy- N -[1-[2-[(methylsulfonyl)amino]ethly]-4-piperidinylmethyl]benzamide ( 24 ) showed a high affinity for the 5-HT 4 receptor ( Ki = 9.6 nM). Compound 24 displayed a higher affinity for 5-HT 4 receptors than the other receptors, including, 5-HT 3 and dopamine D 2 receptors. In addition, compound 24 was confirmed to be a potent 5-HT 4 receptor agonist (ED 50 = 7.0 nM). An interaction model between compound 24 and 5-HT 4 receptor was proposed.

Reitz A.B., Scott M.K.

This chapter discusses a novel antipsychotic with unique D2/5-HT1A affinity and minimal extrapyramidal side effect liability. The term “neuroleptic” has been originally employed to distinguish agents for the treatment of schizophrenia from classical antidepressants or sedatives. Neuroleptic has come to signify the undesired neurological component of drug treatment and has been superseded by the use of the term antipsychotic. All marketed antipsychotics act by the antagonism of dopamine receptors in the brain, particularly those of the D2 subtype. Treatment with antipsychotics is often accompanied by untoward muscular effects, such as acute extrapyramidal symptoms (EPS) involving Parkinsonism, akathisia, and dystonia. There is an approximately 30% incidence of tardive dyskinesia involving abnormal movements, particularly of the face and tongue. Oxotremorine is a potent muscarinic agent in animals that exhibits peripheral effects, including diarrhea, salivation, lacrimation, and bradycardia and a bizarre set of central nervous system (CNS) effects featuring tremors, ataxia, and spasticity.

Liegéois J., Dive G., Dupont L., Delarge J.

As a further phanmacomodulation of benzamide derivatives, two structural modifications were introduced by synthesizing pyridinesulfonamides 5 and 6 (Scheme). The pharmacological profile of substituted benzamides such as metoclopramide (2) is not retained in the pyridine-sulfonarm'des 6: the latter have very low toxicity but do not exhibit any affinity for D2 and 5-HT2 receptors, and gastrointestinal prokinetic activity is weak (Table 3), Lipophilicity does not seem to be a determining factor for this lack of activity. A conformational analysis shows that the sulfonamide group in 6 is rather unfavorable for an intramolecular H-bond formation when compared to the carboxamide group of, e.g., 2. Nevertheless, the interaction remains possible and leads to a stable conformation (Fig. 1, Table 5.) Moreover, the sp3 character of the sulfonamide N-atom of 6 modifies the relative spatial orientation of one substituent in relation to each of the others. This feature seems to be more important for the observed very low activity than the H-bond formation itself.

Wise L.D., Heffner T.G.

Publisher Summary Antipsychotic drugs are not only used for the treatment of schizophrenia, but they also have limited applications in mania, schizoaffective disorder, anxiety, dementia, and drug overdose. Although available antipsychotic drugs reduce delusions and hallucinations, symptoms of schizophrenia—such as poverty of speech and social withdrawal—are less improved. In addition, some patients obtain a little benefit from these drugs and relapse occurs frequently. Available antipsychotics also produce serious neurological side effects, including extra-pyramidal syndrome (EPS) and tardive dyskinesia. These limitations have stimulated efforts to identify new drugs with improved therapeutic profiles. The history, clinical use, and pharmacokinetics of antipsychotics, as well as the biological findings on DA receptor clones and the etiology of schizophrenia, are described in this chapter. The chapter discusses dopamine (DA) D2 receptor antagonists, multiple receptor antagonists, serotonergic agents, DA autoreceptor agonists, sigma ligands, and the properties of some miscellaneous compounds. Psychotic patients who respond to DA antagonist therapy show predrug evidence of elevated brain catecholamine release. A correlation was found between negative schizophrenic symptoms and apparent brain norepinephrine release in unmedicated schizophrenic patients who relapsed. Several theories have focused on the role of brain glutamate in antipsychotic drug action and in the etiology of schizophrenia.