Ascomycin derivative

ASM 981 is an ascomycin derivative that has been approved for topic application only. 

With another immunophilin, FK binding protein (FKBP), experiments were performed using isotope editing of the [U-13C]-labeled inhibitor ascomycin (bound to unlabeled FKBP) [34], as well as by isotope filtering with unlabeled ascomycin derivatives (bound to labeled FKBP) [35],... 

Example 2. Purification of an Ascomycin Derivative. The second example describes the use of SMB technology for the purification of a semisynthetic... 

Pimecrolimus is a non-steroidal ascomycin derivative with topical anti-inflammatory activity. In a 1% cream it is effective and safe in atopic dermatitis in infants, children, and adults (1-3), although its efficacy has been questioned (4). 

Queille-Roussel C, Paul C, Duteil L, et al. The new topical ascomycin derivative SDZ ASM 981 does not induce skin atrophy when applied to normal skin for 4 weeks a randomized, double-blind controlled study. Br J Dermatol 2001 144 507-513. 

Recently, Novartis has begun development of a new macrolide immunosuppressant, an ascomycin derivative (pimecrolimus ASM 981 Fig. 7), in a topical formulation of a 1% cream. Preliminary data presented at several international conferences suggest that it may have benefit in mild atopic dermatitis with a good safety profile, but definitive studies have not yet been published. 

Table 7.2 Depletion behavior of a certain impurity, the 19-epimer of an Ascomycin derivative, for the crystallization from different solvents.

Pimecrolimus (58 Elidel Novartis, 2001) is a novel macrolactum derivative of ascomycin, isolated as a fermentation product of Streptomyces... 

Pimecrolimus ELIDEL 2002 immunosuppressant Novartis Ascomycin 14 derivative (streptomycetes)... 

The copper-catalysed arylation reaction was recently applied to the selective functionalisation of relatively complex natural products, such as the immunosuppressive macrolides ascomycine, (104), R(31) = Me and L-683,742, (104), R(3i) = A variety of triarylbismuth derivatives substituted... 

Pimecrolimus 1% cream (Elidel), a macroMe derived from ascomycin, is FDA approved for the treatment of atopic dermatitis in patients older than 2 years of age. 

Ascomycin and derivatives (Fig. 4) were purified by QCCC. The QCCC apparams has four coils that are wound tightly on two separate bobbins on one rotor, each bobbin containing two concentrically wound coils. Optimization of solvent systems was based on solubility studies and measurements of partition coefficients for FK-506 and ascomycin. Hexane-tert-butylmethy-lether-methanol-water (1 3 6 5 v/v/v/v) showed the best solvent selectivity. Baseline separation of 25 mg of FK-506 and 50 mg of ascomycin was achieved in 6 hr. 

A similar set of incorporation studies were conducted to examine the tarbtrn backbone of the ascomycin family of immunosuppressants (30). For all three of these compounds (ascomycin, FK523, and FK506), the three methoxy carbons at Cl3, C15, and C31 were shown to be derived from methionine. All three immunosuppressants were enriched at CIO, Cl6, C18, C24, and C26 by [l-iHIl]propionate and at C8 and CZ2 by ll-i CIacetate (Figure 5). Interestingly, in the acetate incorporation study, no l C enrich-... 

As a further example, the influence of the solvent on the depletion behavior of a particular impurity during crystallization, as reported by Koch et al. [9] for a derivative of Ascomycin, is shown in Table 7.2. 

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