John V. Greenhill

Amidines and guanidines in medicinal chemistry

Publisher Summary This chapter focuses on amidines and guanidines in medicinal chemistry. The drugs are classified under their main physiological activities and within each group are arranged roughly in order of increasing molecular complexity. Many of the compounds have given temporary excitement to their discoverers and then been dropped—the commonest experience in medicinal chemistry. There are important, clinically used, medicines in all the major categories of therapeutic action discussed in the chapter. This simple and very unstable compound is not only a neurotransmitter in the brain, but acts in the dilation of blood vessels and activates leucocytes to attack tumour cells, fungi, and bacteria. In addition, nitric oxide can inhibit blood coagulation by preventing platelet aggregation and appears to be the regulator of the male erection. No doubt other functions will be discovered in the future, but the interesting finding for the present chapter is that the NO is formed by nitric oxide synthetase from arginine—the only essential amino acid which carries a guanidine group. Since most of the active guanidine drugs have at least one unsubstituted =NH or NH 2 group, it is interesting to speculate that they will be shown to act by giving nitric oxide as well.

Studies on curcumin and curcuminoids. XXII: Curcumin as a reducing agent and as a radical scavenger

Abstract The function of curcumin in the reduction of Fe 3+ to Fe 2+ and in oxygen radical reactions is discussed. The presence of the diketone moiety in the curcumin molecule seems to be essential both in redox reactions and in the scavenging of oxgyen radicals.

Photodecomposition of drugs.

Publisher Summary This chapter discusses those drugs where one or more photoderivatives have been positively identified and photosensitizers which, although unchanged themselves, photocatalyse the degradations of biomolecules. Precautions against the photodegradation of drugs in storage are easily taken, but light-induced changes after the patient has taken the medicine may lead to serious side-effects––typically erythema, oedema, and vesicle formation of exaggerated sunburn. Sunlight penetrates the skin to a depth sufficient to reach blood circulating in surface capillaries. Two types of photosensitivity as a result of foreign chemicals circulating in the blood stream has been described––namely, phototoxicity and photoallergy. In phototoxicity, the excited state of the drug molecule can induce cellular damage in at least one of three ways: by inducing radical formation in an endogenous molecule, by converting oxygen from its ground (triplet) to the highly toxic singlet state, or by electron transfer, it can generate the very reactive superoxide radical. Phototoxicity occurs only in areas of skin exposed to the light and is characterized by the relief of symptoms when the drug is withdrawn. It can be effective with only one dose in combination with exposure to the sun (or an ultraviolet lamp). With a high enough dose, the phototoxic response can be elicited from all exposed individuals. Examples of drugs that can generate singlet oxygen are chloroquine, frusemide, nalidixic acid, and naproxen. Superoxide generators are chlorpromazine, mercaptopurine, some tetracyclines, and psoralens.

Tautomerism in 2-ketomethyl quinolines

Abstract The i.r.solution spectra of a series of 2-ketomethylquinolines have been studied. Tautomeric ratios have been determined by n.m.r. spectroscopy. With one exception the compounds were substantially or exclusively in the enaminone forms. The only compound carrying an α-methyl group (18) proved to be solely in the ketone form.

Photochemical stability of biologically active compounds: V. Photochemical degradation of primaquine in an aqueous medium

Quinoline antimalarials are photochemically unstable. Several of these drugs cause toxic reactions which may be ascribed to the Photochemical degradation of the substances. The effect of light of wavelengths 320–600 nm on the aminoquinoline primaquine in aqueous solution was investigated. The main photochemical degradation products were isolated by means of preparative TLC. The samples were identified by mass spectrometry (EI, CI and high-resolution), 1H-NMR spectroscopy and GC/MS.

Enaminones in the mannich reaction. Part 2. Further investigations of internal mannich reactions

The reactions of two 3-aminocyclohex-2-enones with formaldehyde have been investigated in detail. The course of each reaction has been followed by u.v. spectroscopy and the conclusions confirmed by chromatography. The gem-dimethyl group of the dimedone derivative directs the reaction to give exclusively the spiran formed by an internal Mannich reaction, but the unsubstituted cyclohexanedione enaminone gives mixtures of spiran and acridinedione derivatives. The results are rationalised on the basis of the different rates of hydrolysis of fhe enaminones.

A novel addition–rearrangement of O-(1-benzotriazolylalkyl)oximes with organolithium reagents. Convenient non-oxidative conversions of aldehydes into amides

Condensation of an aldehyde, an oxime and benzotriazole gives an O-(1-benzotriazolylalkyl)oxime which undergoes an addition–rearrangement on treatment with an organolithium reagent. This reaction provides a novel non-oxidative method for the transformation of aldehydes into amides which has afforded several new N-monosubstituted amides with crowded structures. Grignard reactions of the O-(1-benzotriazolylalkyl)oximes give alcohols as the major products.

Mannich/Friedel–Crafts preparations of 1-(arylmethyl)benzotriazoles and synthetic transformations of their lithio derivatives

The synthesis of 1-(arylmethyl)benzotriazoles by Mannich type reactions of benzene, toluene, p-xylene and chlorobenzene with 1-chloromethylbenzotriazole in the presence of aluminium halides is reported. Alkylation, of their lithio derivatives followed by the cleavage of benzotriazole from the resulting 1-(α-arylalkyl)benzotriazoles upon reduction with LiAlH4–AlCl3 or elimination by AcOH are shown to be useful procedures for the preparation of substituted arenes. An oxidative coupling of lithiated 1-(arylmethyl)benzotriazoles gave 1,2-diaryl-1,2-di(benzotriazol-1-yl)ethanes. Novel heterocyclic ring fissions of the lithio derivatives of 1-(arylmethyl)benzotriazoles afforded 1,2,4-benzotriazine and 1,2-bis(N-methylanilino)ethene derivatives.

Tautomerism in ketomethylquinolines—IV. The ultraviolet spectra of 2-ketomethylquinolines

Abstract Ultraviolet spectral data for a series of 36 2-ketomethylquinolines have been recorded. Members previously shown to be exclusively keto tautomers had spectra closely similar to that of 2-methylquinoline. Most of the rest, which were largely or exclusively in the enaminone forms, showed strong long wavelength absorptions. These are shown to be consistent with cis—s—cis enaminone structures. In aqueous acid, most of the enaminones protonated on carbon and those with electron-withdrawing groups were deprotonated in molar aqueous sodium hydroxide.

Conformational and tautomeric studies of acylguanidines. Part 1. Synthesis, ultraviolet spectroscopy, tautomeric preference, and site of protonation in some model compounds

Six of the ten possible acylguanidine conformers have been prepared as model compounds in fixed form; all protonate on the imino nitrogen. The expected close u.v. resemblance between the cations is found for the major band near 200 nm but there are complications origin to a second band at higher wavelength and of very variable intensity whose origin is traced to an electronic transition involving σ-resonance. There is a clear distinction between the u.v. spectra of the ‘through-conjugated’ and ‘cross-conjugated’ free base forms, but with unexpected complications in certain cases which are believed to be due to the co-existence of near-planar and severely twisted species. There is a large tautomeric preference for the ‘through-conjugated’ forms, the extent of which is complicated by perturbations due to the molecular scaffolding. An attempt to allow for this and to predict the pKa values for the nominal parent compounds leads to the conclusion that, for the anti-conformers, tautomeric ratio is ca. 300. Reasons are given for believing that these compounds are good models for related guanidinoheterocycles active as histamine H2-receptor antagonists.