Pyrido indoles derived from

The intramolecular cycloaddition of nitrones derived from iV-allyl-2-indolecarbaldehyde was used to an entry to pyrrolo- and pyrido[ 1,2-a]indole skeletons . For instance, the cinnamyl-substituted aldehyde 157 upon treatment with benzylhydroxylamine affords to the nitrone 158, which upon heating in refluxing toluene leads to mainly the cycloadduct 159. 

Trp-P-2 (3-amino-l-methyl-5//-pyrido[4,3-h]indole), AaC (2-amino-9//-pyrido[2,3-bJindole), MeAaC (2-amino-3-methyl-9//-pyrido[2,3- ]indole), and PhIP (2-amino-1-methyl-6-phenyl-imidazo[4,5-h]pyridine) and two /3-carbolines comutagens harman (l-methyl-9//-pyrido[4,3-h]indole) and norharman (9//-pyrido[4,3-h]indole). The optimized SPE procedure for isolation and preconcentration comprises the use of diatomaceous earth, propylsulfonyl silica gel, and C18 cartridges to separate selectively the imidazopyridine and indolpyridine derivatives from those of... 

Pal et al. [86] prepared 3H-pyrido[3,4-b]indole derivatives 130 by means of the Pictet-Spengler and Bischler-Napieralski reactions starting from a-D-xylo-pentodialdo-l,4-furanose derivatives 129 and tryptamines. Microwave-assisted reactions conducted on silica gel support under solvent-free conditions resulted in better yields than those performed under conventional conditions (Scheme 12.53, a representative example). 

Annulation Reactions. Larock et al. have described the synthesis of different heterocyclic systems using a [3+2] annulation approach. For instance, pharmaceutically important pyrido[l,2-fl]indole derivatives such as 93 are easily accessible from 2-substituted pyridines and aryne precursors (Scheme 12.48) [83]. More recently, the 1/f-indazole skeleton has been accessed through a [3+2] annulation from arynes and hydrazones. The reaction with Al-arylhy-drazones leads to 1,3-disubstituted indazoles 94 through an annulation-oxidation process (Scheme 12.48). The use of iV-tosylhydrazones also affords 3-substituted-Ai(H)-indazoles, although probably via a [3+2] cycloaddition (see Scheme 12.18) with in situ generated diazo compounds [84]. 

Decarboxylation and oxidation products of 1,2,3,4-tetrahydro-P-carbohne-3-carboxylic acids derived from formaldehyde, 9H-pyrido(3,4-fo]indole (norharmane, 2-127), and acetaldehyde, 1-methyl-9//-pyrido[3,4-fo]indole (harmane, 2-127), were identified in a number of foods at levels up to 700 mg/kg, although more typically their concentrations in smoked, cooked and fermented foods range from a few mg/kg to 1-2 orders of magnitude less. Typical norharmane and harmane findings in pan-fried, minced meat, beef patties or ground beef prepared at temperatures of 175-230 °C and... 

Many patents have been issued on the use of pyrogaUol derivatives as pharmaceuticals. PyrogaUol has been used extemaUy in the form of an ointment or a solution in the treatment of skin diseases, eg, psoriasis, ringworm, and lupus erythematosus. GaUamine triethiodide (16) is an important muscle relaxant in surgery it also is used in convulsive-shock therapy. Trimethoprim (2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine) is an antimicrobial and is a component of Bactrin and Septra. Trimetazidine (l(2,3,4-trimethoxybenzyl)piperazine (Vastarel, Yosimilon) is used as a coronary vasodilator. l,2,3,4-Tetrahydro-6-methoxy-l-(3,4,5-trimethoxyphenyl)-9JT-pyrido[3,4- ]indole hydrochloride is useful as a tranquilizer (52) (see Hypnotics, sedatives, ANTICONVULSANTS, AND ANXIOLYTICS). Substituted indanones made from pyrogaUol trimethyl ether depress the central nervous system (CNS) (53). Tyrosine-and glycine(2,3,4-trihydroxybenzyl)hydrazides are characterized by antidepressant and anti-Parkinson activity (54). 

Fischer indolization of 9-arylhydrazono-6,7,8,9-tetrahydro-4//-pyrido-[l,2-u]pyrimidin-4-ones 289 by heating in 85% phosphoric acid, or in PPA yielded 7,12-dihydropyrimido[l, 2 l,2]pyrido[3,4-Z)]indol-4(6//)-ones 290 (96JHC799, 99MI12, 00MI22). From the 3-ester and 3-carboxylic acid derivatives 289 (R = COOEt, COOH) and decarboxylated products 290 (R = H) were obtained. 

These compounds are pyrido[c,fc]indoles and the first to be identified (245) was isolated from Picrasma excelsa (78TL2777). Subsequently, the 4-methoxy derivative 246 (83CPB3198), which was a powerful inhibitor of cAMP phosphodiesterase (84CPB1872), and picrasidine 247 (85CPB4901) were also obtained. 

Of much interest is the recent discovery of substances closely related to the harmala alkaloids in animals. One of these is adrenoglomerulotropine, a hormone of the pineal body, the chemical identity of which has been indicated as 2,3,4,9-tetrahydro-6-methoxy-i-methyl-iH-pyrido (3,4,6) indole. This substance is identical to 6-methoxyletrahydroharman which has been shown to be formed in vivo from 5-methoxy tryptamine and acetaldehyde. 6-methoxytetrahydroharman is an isomer of tetrahydro-harmine, one of the alkaloids in Banisteriopsis, and in the African Leptactinia densillora. One more substance, 6-methoxyharmalan, has been shown to derive, at least in vitro, from melatonin, which results from the methylation of acetylserotonin. The enzyme which makes this possible, hydroxyindole O-methyl transferase, has only been found in the pineal body. (Naranjo, in Efron et al. 

Formation of a cation radical of the diene may catalyze Diels-Alder reactions with certain dienophiles thus oxidation of substituted vinylindoles to the cation radical in the presence of a push-pull dienophile may form different heterocyclic compounds by the Diels-Alder reaction, for instance pyrido[l,2i7]indoles from vinylindoles and yS-enamino-esters [33]. Similarly, anodic oxidation in MeCN of certain oxazolidines in presence of vinyl ether leads to derivatives of oxazepines in a catalytic reaction in which the ring-opened radical cation of the oxazolidine adds to the vinyl ether and the radical cation of the resulting oxazepine oxidizes the oxazolidine [34]. 

The benzo derivative of pyrrole-2-acetonitrile (299), the indole-2-acetonitrile (305)116 leads in high yield to the orange-red pyrido(l,2-a)indole-9-carbonitriles (308). The requirement of energy for the conversion of (306) to (307) may be smaller than the corresponding gap from (300) to (301). Consequently the thermolysis temperature is found distinctly lowered. 

Many other synthetic benzo a]quinolizidine derivatives, structurally more or less related to the alkaloids of types 72-75, have been available a number of indole alkaloids carrying the indolo[2, 3 3,4]pyrido[l,2-b][2,7]-naphthyridine ring system, structurally analogous to the A. lamarckii alkaloids 56-64, have been isolated from other plants and/or synthesized. However, this section is not intended to cover them because of the limited space. 

Quinazolin-2-one was obtained quantitatively by fusing 2-aminobenzaldehyde with urea (10 min at 150°C).76,91 Similarly, 2-amino-3-formylpyridine and urea (15 min at 160°C) gave an excellent yield of pyrido[2,3-d]pyrimidin-2-one (see 3).92 Finally, as an example from jt-excessive chemistry, 2-amino-indole-3-aldehyde was converted to its 2-benzyloxycarbonyl derivative, which benzylamine quantitatively converted to 3-benzyl-9f/-pyrimidino-[4,5- >]indol-2-one (87)93... 

In its 1985 review, published in 1986, of the various problems from exposure to numerous components in tobacco smoke, the lARC (1870) did not designate the A-heterocyclic amines as a problem. lARC did list several tryptophan-derived tobacco smoke isolates including 9A-pyrido[3,4-f>]indole (norharman) and l-methyl-9A-pyrido[3,4-f>]indole (harman). The per cigarette MSS yields of these two components were listed as 9.5 to 14.1 and 2.5 to 5.8 xg/cig, respectively. No mention was made of the A-heterocyclic amines in CSC or the degree of evidence for their carcinogenicity in animals and humans. 

Boger and Boyce synthesized l,2,9,9a-tetrahydrocyclopropa[c]pyrido[3,2-e]indol-4-one-7-carboxylate (CPyl), a parent molecular for antitumor molecular synthesis [89]. Starting from an aminophenol derivative and applied carbonylation as one of the steps, CPyl was prepared and further modified (Scheme 10.17). 

Methylthiazolidine-4-carboxylic acid, a condensation product of cysteine and acetaldehyde, occurs even in human blood as a consequence of ethanol consumption. Serine and threonine analogously produce C-2 substituted (2J S,4S)-oxazolidine-4-carboxylic acids (2-124). Heterocyclic products, C-2 substituted (2J S,4S)-pyrimidine-4-carboxylic acids, are also produced in the reaction of aldehydes with asparagine (2-125). Phenylalanine yields C-1 substituted (lJ S,3S)-tetrahydroisoquinoline-3-carboxylic acids (2-126) and analogous products arise from tyrosine. Tryptophan reacts with aldehydes under the formation of 9H-pyrido[3,4-b]indole (also known as -carboline or norharmane) derivatives, (lJ S,3S)-l,2,3,4-tetrahydro-fi-carboline-3-carboxylic acids (2-127, R = H or alkyl or residues of other aldehydes and sugars), the reaction of tryptamine yields the corresponding (lRS)-l,2,3,4-tetrahydro-P-carbolines. 

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