Steroid reductions

Catalytic reduction of steroid epoxides received considerable attention before the development of complex metal hydride reducing agents. Hydrogenation of 3 ,4a-epoxy steroids over platinum in acetic acid (Eq. 360), for example, gives rise to a mixture of 3 -hydroxy and 3 -acetoxy steroids.Reductive cleavage thus occur in the same direction as with lithium aluminium hydride in this particular instance —t.r. it gives an axis alcohol. 

It is worth saying that both lacking of selectivity in the A4 olefinic moiety hydrogenation and increasing of the axial epimer in 3 keto-derivatives saturation following the donor steric demand are typical aspects of steroid reduction by means of complex hydrides8. 

Ergosterol biosynthesis inhibitor, by inhibition of steroid reduction (sterol—A14—reductase) and isomerisation (A8 to A7—isomerase)... 

Inversion of 3 -hydroxy steroid. Reduction of the dihydroxy keto cholanate 1 with Raney nickel (no. 28) results in partial epimerization of the axial 3 -hydroxy group (but not the axial 7a-group). This inversion step must be fairly slow because it is not observed when reduction of a 12-ketocholanic acid group is effected within 4 hours. This reaction is the mildest method known for inversion of an axial C,-slcroidal alcohol. ... 

P-Amitto steroids. Reduction of oximes of -ketostcroids with lithium in ethyl-amine is the best procedure for preparation of 3 S-amino steroids. 

Reduction of 6 methoxy-3a -eych-S(ic-steroids. Reduction of 6)8-methoxy-3a,5-cydocholestane (1) with mixed hydride affords as the major product 3ot,5-cyclo-5 -cholestane (2). 

In pediatric renal transplantation, the tacrolimus regimen showed very favorable results in terms of patient and graft survival at 1 and 4 years, as well as in the acute rejection rate and the rate of steroid reduction or withdrawal [64]. 

Reduction of Unsaturated Steroids.—Reduction with di-imide [provided by hydrazine hydrate and copper(ii) acetate in methanol] provides a novel and stereospecific conversion of steroidal 4-en-3)5-ols into 5a-dihydro-compounds. By contrast, catalytic hydrogenation is non-stereospecific and is often accompanied by partial hydrogenolysis, so the new method offers considerable promise. Catalytic reduction of 3jS-hydroxyandrost-4-en-17-one with tritium and a Pt catalyst gave 3)5-hydroxy-5a-androstan-17-one with the tritium distribution 4a, 37% 5a, 43% and 6a, 20%. The 5jS-isomer was also formed, with tritium at 4, 29 % 5, 54 % 6, 4.7 %, and 6a, 13 %. Tritium analysis was achieved by a combination of equilibration with base, bromination-dehydrobromination, and dehydrogenation. The appearance of tritium at C-6 indicates olefinic bond migration in contact with the catalyst. ... 

Since all the complexes under discussion are ionic, it is not surprising to find that most are soluble only in polar solvents. This can be very useful in separating the desired product from the spent catalyst. For example. Professor Bill Suggs has shown that our catalyst, [Ir(cod)PCy3(py)]PF6, is useful in certain steroid reductions. Here, the reaction solvent is CH2CI2. To isolate the steroidal product, the solvent is removed and the residue extracted with hexane. The extract contains only the steroid and not the insoluble catalyst. 

U.S. subjects were enrolled using a 1 1 randomization in a 7-month double-blind core study comprised of 16 weeks of stable treatment followed by 12 weeks of attempted steroid dose reduction (Fig. 1). Patients received Xolair based on body weight and the total serum IgE level at the first visit (Fig. 2). The primary efficacy variables were the number of asthma exacerbation episodes experienced by a patient during the steroid-reduction period and during the double-blind stabilization period. There were a number of secondary efficacy variables. The secondary efficacy variables measured for the double-blind stabilization period were number of patients experiencing at least one exacerbation and the number of puffs of rescue medication taken. Secondary efficacy variables for the double-blind steroid-... 

The overall effectiveness of Xolair treatment was clearly reflected in measures of the asthma-related quality of life. Patient s self-assessment of asthma-related quality of life, using the validated asthma-related quality-of-life questionnaire (AQLQ) (16), showed a clinically significant change from baseline of 0.5 units improvement in both treatment groups for all domains at the end of both treatment stabilization and steroid-reduction periods. Importantly, a significantly greater improvement over placebo was seen in Xolair-treated patients for each of the individual domains (activities, emotions, symptoms, environmental exposure) and overall scores (p = 0.02). 

Importantly, the benefit of reduced asthma exacerbations seen in the Xolair group during the stabilization period continued during the steroid-reduction phase despite a significantly greater reduction of inhaled corticosteroid and less frequent use of rescue medication. The evidence of superior symptom control and respiratory function, which also continued throughout the steroid-reduction period, further enhances the confidence in these anti-IgE efficacy results. 

Table 5 Number of Asthma Exacerbation Episodes per Patient During the Double-Blind Stabihzation and Double-Blind Steroid Reduction Phase (all randomized patients)...

Figure 4 Clinically detectable ( 0.5) improvement in QOL scores at the end of the steroid-reduction phase (all randomized patients). Significance p < 0.05, p < 0.01.

Treatment Baseline End of add-on phase End of steroid -reduction phase... 

In all three of the pivotal phase III studies, omalizumab was significantly superior to placebo with respect to the percentage reduction in inhaled corticosteroid dose attained and the proportion of patients who achieved steroid reduction or withdrawal. 

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