US 2006/0223743 A1Published application

Metabolites of cyclosporin analogs

OwnerMark Abel, Robert Foster +5inventors

InventorsMark Abel, Robert Foster, Derrick Freitag, Daniel Trepanier, Shin Sugiyama, Seetharaman Jayaraman, Randall Yatscoff

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Abstract

Isolated metabolites of the cyclosporine analog ISA247 are disclosed, including in vitro methods for their preparation. The metabolites comprise a chemical modification of ISA247, wherein the modification is at least one reaction selected from the group consisting of hydroxylation, N-demethylation, diol formation, epoxide formation, and intramolecular cyclization phosphorylation, sulfation, glucuronide formation and glycosylation. Methods of preparation include semi-synthetic methods, wherein metabolites of ISA247 are produced from the microsomal extracts of animal liver cells, or from cultures using microorganisms, and completely synthetic methods, such as chemically modifying the parent compound or isolated metabolites using organic synthetic methods.

Claims42

Dependent claims

An isolated compound represented by the following formula:

and pharmaceutically acceptable salts and solvates thereof, wherein:
each R2 is independently —H or —CH3;
each R10 is independently —H, —OH, —F, —Cl, —Br, —I, —CN, —NO2, —ORa, —C(O)Ra, —OC(O)Ra, —C(O)ORa, —S(O)Ra, —SO2Ra, —SO3Ra, —OSO2Ra, —OSO3Ra, —PO2RaRb, —OPO2RaRb, —PO3RaRb, —OPO3RaRb, —N(RaRb), —C(O)N(RaRb), —C(O)NRaNRbSO2Rc, —C(O)NRaSO2Rc, —C(O)NRaCN, —SO2N(RaRb), —SO2N(RaRb), —NRcC(O)Ra, —NRcC(O)ORa or —NRcC(O)N(RaRb);
R5, R6, R7, R8 and R9 are independently —H, —OH, —F, —Cl, —Br, —I, —CN, —NO2, —ORa, —C(O)Ra, —OC(O)Ra, —C(O)ORa, —S(O)Ra, —SO2Ra, —SO3Ra, —OSO2Ra, —OSO3Ra, —PO2RaRb, —OPO2RaRb, —PO3RaRb, —OPO3RaRb, —N(RaRb), —C(O)N(RaRb), —C(O)NRaNRbSO2Rc, —C(O)NRaSO2Rc, —C(O)NRaCN, —SO2N(RaRb), —SO2N(RaRb), —NRcC(O)Ra, —NRcC(O)ORa or —NRcC(O)N(RaRb);
or R6 and R7 are together —O—;
or R5 and R6 together, or R7 and R3 together, are independently —O—;
or R8 and R9 together are —O—;
or R5, together with the carbon to which it is bonded, is —C(═O)Ra, —CO2Ra, —CH2ORa, —CH2OC(O)Ra, —CH(ORa)2, —C(O)N(RaRb), —C(═NRb)Ra, —C(═NORb)Ra, or —C(═NNRb)Ra;
provided that one pair of R5 and R6, R6 and R7, or R7 and R8 is a carbon-carbon bond and the remainder are not all —H;
and
Ra, Rb and Rc are each independently —H or an optionally substituted aliphatic, cycloaliphatic, benzyl, or aryl, or —N(RaRb) together is an optionally substituted heterocyclic group, or —CH(ORa)2 together is a cyclic acetal group.

8 more elements

An isolated metabolite of cyclo { {(E)- and (Z)-(2S,3R,4R)-3-hydroxy-4-methyl-2-(methylamino)-6,8-nonadienoyl}-L-2-aminobutyryl-N-methyl-glycyl-N-methyl-L- leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl} (ISA247) and pharmaceutically acceptable salts and solvates thereof, wherein compared to ISA247, the isolated metabolite comprises at least one chemical modification selected from the group consisting of hydroxylation, N-demethylation, diol formation, epoxide formation, intramolecular cyclization, phosphorylation, sulfation, glucuronide formation and glycosylation.

Dependencies are inferred from the claim text.

Facts

Application: 11/313,239Filed 19 Dec 2005
Priority: 17 Dec 2004
Published: 5 Oct 2006
Term ends: Not estimatedThe source records don’t support an estimate.

Classification7 codes

A61K 38/13
Cyclic peptides , e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C: cyclosporins
A61P 37/06
Immunomodulators: immunosuppressants, e.g. drugs for graft rejection
C07K 7/64
Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof: cyclic peptides containing only normal peptide links
C07K 7/645
Cyclic peptides containing only normal peptide links: cyclosporins; Related peptides