Indacrinones

Although it might seem that adrninistration of enantiomericaHy pure substances would always be preferred, the diuretic indacrinone (3), is an example of a dmg for which one enantiomer mediates the harmful effects of the other enantiomer (4). (+)-Indacrinone, the diureticaHy active enantiomer or eutomer causes uric acid retention. Fortunately, the other enantiomer distomer) causes uric acid elimination. Thus, adrninistration of a mixture of the two enantiomers, although not necessarily racemic, may have therapeutic value. 

The separation of enantiomers is a very important topic to the pharmaceutical industry. It is well recognized that the biological activities and bioavailabilities of enantiomers often differ [1]. To further complicate matters, the pharmacokinetic profile of the racemate is often not just the sum of the profiles of the individual enantiomers. In many cases, one enantiomer has the desired pharmacological activity, whereas the other enantiomer may be responsible for undesirable side-effects. What often gets lost however is the fact that, in some cases, one enantiomer may be inert and, in many cases, both enantiomers may have therapeutic value, though not for the same disease state. It is also possible for one enantiomer to mediate the harmful effects of the other enantiomer. For instance, in the case of indacrinone, one enantiomer is a diuretic but causes uric acid retention, whereas the other enantiomer causes uric acid elimination. Thus, administration of a mixture of enantiomers, although not necessarily racemic, may have therapeutic value. 

In face of the above discouraging results, recent innovative catalyst work has led to highly effective solutions for some otherwise very difficult and expensive problems. For example. Dolling and co-workers (Chapter 7) have shown that by careful choice of PTC catalyst and use of optimal reaction conditions one can obtain high chiral selectivity (greater than 90% enantiomeric excess) and have applied this chemistry to a commercial process for production of the diuretic drug candidate Indacrinone. 

There are only a few reports on chiral phase transfer mediated alkylations". This approach, which seems to offer excellent opportunities for simple asymmetric procedures, has been demonstrated in the catalytic, enantioselective alkylation of racemic 6,7-dichloro-5-methoxy-2-phenyl-l-indanone (1) to form ( + )-indacrinone (4)100. /V-[4-(tnfluoromethyl)phenylmethyl]cinchoninium bromide (2) is one of the most effective catalysts for this reaction. The choice of reaction variables is very important and reaction conditions have been selected which afford very high asymmetric induction (92% cc). A transition state model 3 based on ion pairing between the indanone anion and the benzylcinchoninium cation has been proposed 10°. 

In the mid-1980s Merck chemists developed a method for asymmetric alkylation of a cyclic ketone in the presence of a simple cinchona alkaloid (see also Section 3.1) [50-52], The resulting product 23, bearing a quaternary stereogenic center, is an intermediate in the synthesis of indacrinone 20 (Scheme 14.9). It should be noted that this impressive contribution from Merck chemists was not only the first exam-... 

In conclusion, this synthesis of the indacrinone intermediate 23 developed by Merck researchers is a highly efficient and technically feasible method for asymmetric alkylation. It not only afforded the desired drug intermediate 23 in quantitative yield and high enantioselectivity but was also found to be suitable for technical applications, as has been demonstrated on a pilot-plant scale. 

As well as an effect on the activity, different stereoisomers will also exhibit differences in other physiochemical properties, such as absorption, metabolism and elimination. For example, (—)norgestrel is absorbed at twice the rate of (+)norgestrel through buccal and vaginal membranes. The plasma half life of S-indacrinone is 2-5 hours whilst the value for the R isomer is 10-12 hours. 

Dolling UH, Davis P, Grabowski EJJ (1984) Efficient catalytic asymmetric alkylations, 1. Enantioselective synthesis of (+)-indacrinone via chiral phase-transfer catalysis. J Am Chem Soc 106 446... 

The Nazarov cyclization has also been used industrially. In the Merck synthesis of (+)-indacrinone the indanone unit is formed by an aromatic Nazarov cyclization. ... 

J. A, Tobert, V J. Cirillo, G. Hitzenberger, I. James, J. Pryor, T, Cook, A. Buntinx, I. B, Holms, and R M. Lutterbeck, "Enhancement of urisocuric properties of indacrinone by manipulation of the enantiomer ratio," Clin. Pharmacol. Ther., 79 344-350 (1981). 

Figure 18-12 Ethacrymc acid is a high-ceiling diuretic that readily reacts with many sulfhydryl-containing nucleophiles (top). Indacrinone, a structurally related high-ceiling diuretic, lacks sulfhydryl reactivity (bottom).

Dolling, U.-H. Davis, P. Grabowski, E. J. J., Efficient Catalytic Asymmetric Alkylations. 1. Enan-tioselective Synthesis of (+)-Indacrinone via Chiral Phase-Transfer Catalysis. / Am. Chem. Soc. 1984, 106, 446. 

In 1984, the first successful monumental use of cinchona PTC for asymmetric a-substitution of carbonyls was reported by Dolling and coworkers of the Merck research group (Scheme 6.1) [8], In this work, cinchoninium salt (1) was employed in the catalytic asymmetric methylation of 6,7-dichloro-5-methoxy-2-phenyl-l-indanone (2) under phase-transfer conditions. The methylated product 3, which was finally transformed to (+ )-indacrinone through three further steps, was obtained in 95% conversion with 92% enantiomeric excess (ee). Through the systematic investigation, the group reported the relationship between the chemical/optical yield and the reaction variables (e.g., amount or concentration of each chemical species, halide of... 

Indacrinone R(-)-indacrinone diuretic S(3-)-indacrinone uricosuric Drayer ... 

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