Nicotinic derivatives

Phenyl-1-pyrroline is useful for various purposes.10 11 In particular, its reduction product, 2-phenylpyrrolidine, is important in the synthesis of pyrroloisoquinoline antidepressants,20 12 and can be a starting point in alkaloid synthesis.13 The overall reaction sequence described here has been used to prepare nicotine derivatives such as myosmine.2a b... 

Starting from nornicotine, we were able to demonstrate the rapid construction of a small collection of nicotine derivatives using a range of readily available monomers (Scheme 2.81). In this way we were able to create compounds to probe... 

Scheme 2.82 A short synthetic sequence to nicotine derivatives.

An interesting study of conformationally mobile systems involves iodo-methylation of nicotine derivatives 47, where steric effects of substituents at position-2 and -6 modify the alkylation rate at the pyridine nitrogen and at the two nitrogens (N trans and N cis) of the pyrrolidine conformers (80JA7741 81JOC3040) (Scheme 26b). 

Myosmine (3[2-pyrrolidinyl]pyridine) and nicotine (3[l-methyl-2-pyrrolidinyl]pyridine) (Section 1, Appendix) and a number of related bioactive alkaloids occur in Nkotiana tabacum (tobacco) (Solanaceae) and variously in other Solanaceae such as Duboisia species. Nicotine and the related tobacco compounds nicotyrine and (—)-nornicotine are agonists (neurotransmitter mimics ) of the so-called (nicotine binding) nACh-R involved in neurotransmission and in neuromuscular transmission for skeletal muscle. The extraordinary addictiveness of nicotine derives from nACh-R agonists causing dopamine release and activating the mesolimbic dopamine system yielding reward effects. The antidepressant (—)-cotinine is the major nicotine metabolite in humans and a nicotinic agonist. 

Adamantanyl iso- and nicotinate derivatives were prepared by others (1) using the synthetic route of the current invention. 

Substances carcinogenic to animals (polycyclic hydrocarbons and nicotine-derived N-nitrosamines) have been identified in tobacco smoke condensates from cigarettes, cigars and pipes. Polycyclic hydrocarbons are responsible for the hepatic enzyme induction that occurs in smokers. 

Tobacco-derived nitrosamines are considered to be one of the major cancer-causing agents found in tobacco smoke and tobacco products. This is of importance as up to 90% of human lung cancers can be linked to cigarette smoking. The most potent carcinogen found in tobacco is the nicotine-derived nitrosamine 4-(me-thylnitrosamino)-l-(3-pyridyl)-l-butanone. 

Nomicotine, in which the N-methyl is replaced by hydrogen, is somewhat less potent and active than nicotine in most assays (102). R- and S-nomicotine are equipotent with R-(+)-nicotine,the less active, unnatural enantiomer, in a rat brain membrane-binding assay (103). In that study, S-(-)-nicotinewas 13 times more potent than its R- enantiomer. Replacement of the N-methyl of nicotine with ethyl or n-propyl eauses an exponential loss of peripheral nicotinic effect (102). Anabasine (51), a relatively minor alkaloidal constituent of tobacco, demonstrated approximately 1/10 the affinity of nicotine in a binding assay (104). A synthetic azetidine congener (52) of nicotine binds with the same affinity as nicotine to rat brain membrane tissue, and it displayed a greater potency than nicotine in a rat behavioral assay (105). Evaluation of a series of 6-substituted nicotine derivatives (53) led to the conclusion that affinity for rat brain... 

Nicotine Derivatives. A large number of nicotine analogs have been reported, and the SAR of nicotine derivatives has been presented in a recent review by Tonder et al. (295). Described herein are two classes of nicotine derivatives 5-substituted nicotine analogs (e.g., SIB-1508Y, 51)and pyrrolidine ring-opened nicotinoids (e.g., RJR-2403,57). 

Thus, identification of nicotine-derived electrophilic metabolites that... 

Chemically, 3-picoline is the ideal starting-material for nicotinic acid or amide the methyl group can be selectively and readily oxidized to the carboxyl derivative with few by-products or pollutants. High selectivity coupled with the low molecular weight ratio (1 1.3) compared to the end-products make picoline an attractive industrial starting-material for the production of nicotinic derivatives. 

Scheme 10.37 Diastereoselective hydrogenation of nicotinic derivatives by Pinel.

R.A., 1999a. Synthesis, receptor binding and QSAR studies on 6-substituted nicotine derivatives as cholinergic ligands. Eur. J. Med. Chem. 34, 31-40. 

Azines and their Hydro- and Benzo-derivatives Pyridines. - Synthesis. A key step in a synthesis of optically active nicotine derivatives is the hydrogen-bromide-induced cyclization of the nitrile (1) to the bromopyridine (2). ... 

The concept utilised was based on a retrosynthetic analysis comprising a nicotinic acid derivative (41) and a dihydroxychromone. The nicotinic acid moiety was prepared by lithiation of nicotinaldehyde followed by treatment with trimethyltin chloride. After benzoylation of the chromone noreugenin to protect the free phenolic group the compound was brominated to yield (42) and the two compounds formed were reacted with the nicotinic derivative to give a C-C bond with either the 6 or 8 of the chromone to give a compound such as (43) from which isoschumanniophytine or schumanniophytine respectively could be easily obtained by debenzoylation and lactonisation. 

Beilin, S.A. An evaluation of biological activity. I. Herbicidal action of nicotine derivatives and related compounds as determined by tests with Lemna Minor (Duckweed) RDR, 1964, No. 14, March 17, see www. rjrtdocs.com 500963430 -3445. 

Carmella, S.G. and S.S. Hecht High-performance liquid chromatographic analysis of the nicotine derived nitrosamines, A -nitrosonomicotine and 4-(methylnitrosamino)-l-(3-pyridinyl)-l-butanone (NNK) Anal. Biochem. 145 (1985) 239-244. 

Identification and analysis of a nicotine-derived A-nitrosamino acid and other nitrosamino acids in tobacco 42nd Tobacco Chemists Research Conference,... 

Hoffmann, D., J.D. Adams, E.J. LaVoie, and S.S. Hecht Biochemistry, pharmacokinetics and carcinogenicity of nicotine-derived nitrosamines in The pharmacology of nicotine, edited by M.J. Rand and K. Thurau, Washington, DC (1988) 43-60. 

Hoffmann, D., A. Rivenson, F.L. Chung, and S.S. Hecht Relevance of nicotine-derived A-nitrosamines in tobacco carcinogenesis in Effects of nicotine on biological systems, edited by P.X. Adlkofer and K. Thurau, Adv. Pharmacol. Sci., Biohauser Verlag, Birkhauser, Basel, Switzerland (1991) 89-101. 

S. Amin, and S.S. Hecht Cigarette smoking and adenocarcinoma of the lung. The relevance of nicotine derived Af-nitrosamines J. Smoking Related Dis. 4 (1993) 1792. 

The pharmacodynamic action of the nicotine derivatives, such as the a- and a -aminonicotines and a- and a -acetylaminonicotine, was studied by Mednikian (80). The respiratory stimulation which these substances provoke is less pronounced than that produced by nicotine but is more durable. As for the acetylated derivatives, this action is not preceded by an initial respiratory arrest which many other substances in the nicotine group presented. These substances act on the chemoceptors of the carotid body, on the respiratory center itself, and on the intrapulmonary endings of the vagus. 

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