Papaverine isoquinoline

The position in which the veratryl residue is attached to this isoquinoline nueleus in papaveraldine and papaverine is determined by the formation of pyridine-2 3 4-tricarboxylic acid in the oxidation of papaverine by hot permanganate. On the basis of these results, Goldschmiedt assigned the following formula to papaveraldine —... 

As shown in Scheme 26, Papaverine hydrochloride yields a separable mixture of Protopapaverine (67) and the salt norpapaverinium chloride (68) when heated slightly beyond its melting point for several minutes. Molecule 67 can exist as conjugated mesomeric betaine 67A (7-hydroxy form) or as 2-substituted-2//-isoquinolin-6-one 67B (6-hydroxy form) (66TL1177). Similar structures were described as zwitterionic pentacyclic... 

Although this isoquinoline at first bears little structural resemblance to morphine (108), careful rearrangement of the structure (A) shows the narcotic to possess the benzylisoquinoline fragment within its framework. Indeed, research on the biogenesis of morphine has shown that the molecule is formed by oxidative coupling of a phenol closely related to papaverine. 

The Pictet-Gams modification of the Bischler-Napieralski synthesis has also been reviewed (5loR(6)74, 81HC(38-l)l6i). As shown in equation (32), the additional unsaturation is achieved by elimination of ROH before the cyclization. The commonest examples use j8-hydroxy or /3-methoxy substituents on the phenethylamide. Papaverine (107) is an example of an isoquinoline obtained from both precursors (09CB2943, 27AP(265)l). The precursors can be made from 5-aryloxazolines by reaction with an acid chloride and... 

Opium alkaloids are nonpeptide agonists for the opioid peptide hormone receptors. The dried latex of Papaver somniferum (opium), or the seed capsule of the plant itself, are the sources of almost 25 alkaloids. Some simple isoquinolines from opium, like papaverine (5.86), are antispasmodics. The principal alkaloid ( 10% of the total) is morphine (3.11), which is also an isoquinoline (rings C and E) but can addihonally be considered a phenanthrene derivahve (rings A, B, and C). 

The opium is obtained from the opium poppy Papaver somniferum. It contains two type of alkaloids e.g. phenanthrene derivatives (morphine, codeine thebaine) and benzyl isoquinoline derivatives (papaverine and noscapine). 

A number of naturally occurring pharmacologically active alkaloids possess quinoline and isoquinoline skeleton. For examples, papaverine from Papa-ver somniferum is an isoquinoline alkaloid and quinine from Cinchona barks is a quinoline alkaloid that has antimalarial properties. 

Isoquinoline synthesis Bischler-Napieralski synthesis is used to synthesize isoquinolines. (3-phenylethylamine is acylated, and then cyclodehy-drated using phosphoryl chloride, phosphorus pentoxide or other Lewis acids to yield dihydroisoquinoline, which can be aromatized by dehydrogenation with palladium, for example in the synthesis of papaverine, a pharmacologically active isoquinoline alkaloid. 

Isoquinolme is in fact an isomer of quinoline, and chemically known as benzo[c]pyridme or 2-benzanine. Any alkaloids that possess an isoquinoline skeleton are known as isoquinoline alkaloids, e.g. papaverine and morphine. The isoquinoline backbone is biosynthesized from the aromatic amino acid tyrosine. 

Papaverine Papaverine, molecular formula C20H21NO4, is an isoquinoline alkaloid isolated from poppy seeds Papaver somniferum, family Papaveraceae). This alkaloid is used mainly in the treatment of spasms and of erectile dysfunction. It is also used as a cerebral and coronary vasodilator. Papaverine may be used as a smooth muscle relaxant in microsurgery. In pharmaceutical preparations, papaverine is used in its salt form, e.g. hydrochloride, codecarboxylate, adenylate and teprosylate. The usual side-effects of papaverine treatment include polymorphic ventricular tachycardia, constipation, increased transaminase levels, hyperbihr-unemia and vertigo. 

Alkaloids containing the isoquinoline nucleus may be divided into two groups (1) papaverine, narcotine, cotarnine, narcine, and certain others of the opium group, and (2) the hydrastis group including hydrastine, berberine, and canadine (Figure 11.9). 

The opium alkaloids, which are obtained from Papaver somniferum, contain two groups of compounds compounds with phenanthrene derivatives, consisting of morphine, codeine, and thebaine and compounds with isoquinoline derivatives, consisting of papaverine and noscapine. 

Hanna and Shutt (146) studied the relationship between the chemical structure and the coronary dilator action of papaverine analogs on anesthetized dogs. The 6-alkoxy-, 5,6-dialkoxy-, and 6,7-dialkoxy-isoquinoline derivatives acted as dilators. The 6,7-dialkoxyisoquinoline derivatives were most effective. Optimum results were obtained when the isoquinoline nucleus was aromatic, but the 3,4-dihydro- and 1,2,3,4-... 

Isoquinolinium salts are reduced to 2-alkyl-1,2-dihydroisoquinoline derivatives by sodium dithionite,6 lithium aluminum hydride7,8 (LAH), or dialkyl aluminum hydrides.9 LAH is preferred7 to dithionite since it leads to purer products, and will reduce those salts that are inert to dithionite (e.g., papaverine methiodide). Isoquinoline itself10,11 and 3-methyl-6,7-methylenedioxyisoquinolinelz (5) can be reduced to the 1,2-dihydroisoquinoline with LAH, as can isoquinoline... 

The stereochemical removal of hydrogen from positions 3 and 4 of the isoquinoline ring during aromatization of papaverine during biosynthesis has been studied by incorporation experiments, using stereospecifically labelled [3H]nor-reticulines.24... 

We switch to a completely different kind of alkaloid made from a different kind of amino acid. The benzyl isoquinoline alkaloids have a benzyl group attached to position 2 of an isoquinoline ring. Usually the alkaloids are oxygenated on the benzene ring and many are found in opium poppies (Papaver somniferum). For all these reasons papaverine is an ideal example. 

A more interesting series of alkaloids arises when benzyl isoquinoline alkaloids cyclize by radical reactions. Phenols easily form radicals when treated with oxidizing agents such as Fe(III), and benzyl isoquinoline alkaloids with free phenolic hydroxyl groups undergo radical reactions in an intramolecular fashion through a similar mechanism. Here are the details of some methylations of a class of alkaloids closely related to papaverine. 

PictetGams preparation of isoquinolines from iV-acylated 2-hydroxyphenethylamines, e.g., the synthesis of papaverine 180 (Scheme 107), utilizes similar conditions. 

Two other closely related benzyl isoquinoline alkaloids are papaverine (94) and escholamine iodide (95). The resonance of the fully aromatic isoquinoline of papaverine, as would be expected, was observed at 297.2 ppm. In contrast, the quaternary methyl iodide salt form of escholamine iodide shifted the resonance... 

Another heterocyclic nucleus investigated as a basis for analgesics is isoquinoline with a fully reduced heterocycle moiety and carrying a 1-phenethyl substituent. The series was reported by Hoffman-La Roche in 1960(1S) but no further information has appeared since 1965, when a full account of the work appeared in deStevens book Analgetics.(16) 1-Benzyltetrahydroisoquinoline alkaloids such as papaverine occur in opium but lack analgesic properties, while others, for example, a-narcotine (noscapine), have antitussive activity. Some of the novel 1-phenethyl analogs 9 behaved as analgesics in mice after sc administration when tested by the tail-flick assay, but potency levels were mostly low and close to that of codeine. Details of the most active compounds are shown in Table 11.2. All have 6,7-methoxyls and 4 -substituents with... 

DYNOVAS ISOQUINOLINE, 6,7-DLMETHOXY-l-VERATRYL-, HYDROCHLORIDE LAPAV NCI-C56359 OPTENYL PAMEION PAPAVARINE CHLORHYDRATE PAPAVERINE CHLOROHYDRATE... 

---