Hydroxy-, derivatives 712 Subject

There are only two reports of the human evaluation of a 6-hydroxylated N,N-dialkyltryptamine. Szara and Hearst (223) studied the effects of 6-hydroxy-N,N-diethyltryptamine (6-OH-DET 56) in a single subject. Doses of 1 and 2 mg were inactive a 5-mg dose produced a short-lasting perceptual disturbance and a 10-mg dose, after 1 hr, produced some psychotomimetic disturbances. Rosenberg et al. (182) compared the activity of DMT with that of 6-OH-DMT (55) in five human subjects. While DMT was active, the 6-hydroxy derivative was found to be inactive at intramuscular doses of approximately 50 to 75 mg. At a dose of 10 mg/kg, 6-OH-DMT (55) increased spontaneous activity in mice more so than a comparable dose of DMT 6-OH-DET (36) was essentially equiactive with DET in this respect (224). In most other animal studies, however, 6-hydroxylation of DMT has been observed to result in a decrease or complete loss of behavioral activity (228,236-238). The behavioral potency of 5-OMeDMT (59) was also reduced by 6-hydroxylation (226). 7-Hydroxy-N,N-dimethyltrypt-amine (7-OH-DMT 57) has not been evaluated in man. At an intraperitoneal dose of 33 jtM/kg, 7-OH-DMT displayed no behavioral effects in rats (228). The pharmacologic effects of all four hydroxylated derivatives of DMT, psilocin (49), bufotenine (53), 6-OH-DMT (55), and 7-OH-DMT (57) have been compared in studies by Taborsky et al. (228) and by Cerletti et al. (29). 

Position 3 of anhydro 2-methyl-4-hydroxy-5,6,7,8-tetrahydropyrido[l,2-6]pyridazinium hydroxide (57) was subjected to both electrophilic and nucleophilic substitution to give 58-61 (71CPB159). Treatment of 57 with H2O2 gave the 3-hydroxy derivative 62. 

Radical reactions of enamines are the subject of another chapter in the present book. Acyloxylation of anilinomethylene dimedone to a-hydroxy derivatives of / -diketones is achieved by treating enaminediones with a diacyl peroxide. The aminomethylene group is lost in this process302 (equation 226). 

As already mentioned, the steric course of acid- or base-catalyzed conjugate additions is usually subject to thermodynamic control. An interesting example of how hydrogen bonding in the product(s) may affect the stereochemical outcome of the addition reaction is provided by ajmalicine (25). When the enoate 25 was treated with 5% aqueous sulfuric acid, the 17-hydroxy-derivative 26 was obtained as a single diastereomer in 40% yield20. The configuration of the... 

Figure 4 Polymorphic drug oxidations by cytochrome P450. A, substrates subject to debrisoquine/sparteine polymorphism. R(+)-bufuralol is I -hydroxyl-ated by P450-IID6 the S(—)-enantiomer undergoes hydroxylation at the 2- and 4-positions debrisoquine is hydroxylated at the prochiral C4-atom to S(+)-hydroxy-debrisoquine sparteine metabolism by P450-IID6 consists of N-oxidation. B, substrates subject to hydantoin polymorphism (4 -hydroxylation). Extensive metabolizers convert S(+)-mephenytoin and -nirvanol to the 4 -hydroxy derivative (indicated by the arrow). Similarly, EMs metabolize the prochiral drug phenytoin to R(+)-4 -hydroxyphenytoin. = chiral center.

The sequence of reactions nicely points out the relative reactivity of carbonyl groups at positions 3, 11 and 17. Reaction of the triketone 29-2 with a controlled amount of pyrrolidine leads to the formation of the enamine from the most reactive ketone, that at C3 (30-1) (Scheme 5.30). Treatment of this intermediate with methylmagnesium bromide leads to exclusive addition to C17. Although the ketone at Cn is virtually inert to addition reactions, it is subject to reduction. Reaction of 30-2 with lithium aluminum hydride thus leads to the corresponding j8-hydroxy derivative. The enamine is then removed by acid hydrolysis (30-4). Reaction of the newly formed alcohol with /i-toluenesulfonyl... 

The hydroxy derivatives 29, a preparatively most valuable (see Section 2.2.2) class of functionalized cyanoacetyienes, are obtained when the propargylic alcohols 28 are first subjected to the Strauss reaction and the resulting bromoacetylenes are subsequently treated with cuprous cyanide in dimethylformamide [34, 35] [Eq. (9)]. 

In the first chapter, devoted to thiazole itself, specific emphasis has been given to the structure and mechanistic aspects of the reactivity of the molecule most of the theoretical methods and physical techniques available to date have been applied in the study of thiazole and its derivatives, and the results are discussed in detail The chapter devoted to methods of synthesis is especially detailed and traces the way for the preparation of any monocyclic thiazole derivative. Three chapters concern the non-tautomeric functional derivatives, and two are devoted to amino-, hydroxy- and mercaptothiazoles these chapters constitute the core of the book. All discussion of chemical properties is complemented by tables in which all the known derivatives are inventoried and characterized by their usual physical properties. This information should be of particular value to organic chemists in identifying natural or Synthetic thiazoles. Two brief chapters concern mesoionic thiazoles and selenazoles. Finally, an important chapter is devoted to cyanine dyes derived from thiazolium salts, completing some classical reviews on the subject and discussing recent developments in the studies of the reaction mechanisms involved in their synthesis. 

In the early 1930 s, when the prime research aim was the commercial synthesis of the sex hormones (whose structures had just been elucidated), the principal raw material available was cholesterol extracted from the spinal cord or brain of cattle or from sheep wool grease. This sterol (as its 3-acetate 5,6-dibromide) was subjected to a rather drastic chromic acid oxidation, which produced a variety of acidic, ketonic and hydroxylated products derived mainly by attack on the alkyl side-chain. The principal ketonic material, 3j -hydroxyandrost-5-en-17-one, was obtained in yields of only about 7% another useful ketone, 3 -hydroxypregn-5-en-20-one (pregnenolone) was obtained in much lower yield. The chief acidic product was 3j -hydroxy-androst-5-ene-17j -carboxylic acid. All three of these materials were then further converted by various chemical transformations into steroid hormones and synthetic analogs ... 

The application of spectroscopic methods to the study of tautom-erism proved especially fruitful. The tautomerism of hydroxy and amino derivatives of isoxazole is of great interest to the chemistry of isoxazole this subject, as well as the tautomerism of functional derivatives of other five-membered heterocycles, has been reviewed by Katritzky and Lagowski. We shall therefore only... 

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