Macrocyclic lactone compounds and methods for their use

Inventors

Yan, John • Zheng, Xiaoxia • Bhat, Vinayak D.

Assignees

Elixir Medical Corp

Abstract

A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of the formula: wherein R1, R2, R3, R5, R6, R8, M1, M2, M3, M4, M5, M6 and M7 are each independently a member selected from the group consisting of H, C1-6 alkyl, OH and C1-6 hydroxyalkyl; R4, R7 and R9 are each independently selected from the group consisting of C1-6 alkoxy and OH; R10 is a member selected from the group consisting of H, —OH, —OP(O)Me2, —O—(CH2)n—OH and —O—(CH2)m—O—(CH2)o—CH3, wherein subscripts n and m are each independently from 2 to 8 and subscript o is from 1 to 6; each of L1 and L4 are independently selected from the group consisting of: wherein each M8 is independently a member selected from the group consisting of C1-6 alkyl, OH and C1-6 hydroxyalkyl; each of L2 and L3 are independently selected from the group consisting of: and salts, isomers, or N-oxides thereof.

Core Innovation

The invention provides macrocyclic lactone compound families defined by formulas IA, IB, IC, and ID, including rapamycin-derived macrocyclic lactone analogs and 16-O-demethyl macrocyclic lactone forms with stereochemistry at the 16-position. The compounds include demethylated, hydroxylated, hydroxydemethylated, epoxidized, N-oxidized, ring-opened, and seco-macrocyclic lactone derivatives, together with salts, hydrates, isomers, metabolites, N-oxides, prodrugs, polymorphic forms, and related forms.

The disclosure specifies stereochemical and structural variations using substituent groups and includes embodiments such as demethylhydroxy macrocyclic lactones, epoxide demethyl macrocyclic lactones, and epoxide demethylhydroxy macrocyclic lactone embodiments. It also describes synthesis concepts for producing 16-O-demethyl macrocyclic lactone analogs by replacement of a C16 methoxy or alkoxy group with nucleophiles, together with epoxidation using peracids or peroxides, and optionally deuteration.

The invention further presents implant-based therapeutic compositions in which an implant surface is coated with a therapeutically effective amount of a compound of the formula, or a salt, isomer, N-oxide, or related form. The coated implant provides localized release for treatment or prevention of acute or chronic transplant rejection, and the disclosure also refers to systemic and site-specific therapeutic applications, an intracorporeal device, inhibition of cell proliferation, treatment of ophthalmic conditions, and restenosis as an intended therapeutic use.

Claims Coverage

The provided claims center on one independent method claim for treating or preventing acute or chronic transplant rejection by implanting a patient with an implant whose surface is coated with a therapeutically effective amount of a compound of the formula, including salt, isomer, or N-oxide forms. The dependent features specify release behavior, implant type, and effective amount ranges, giving five inventive feature variants in total.

Across the provided material, claim coverage is focused on implant-based delivery of a formula-defined macrocyclic lactone compound, including permitted salt, isomer, and N-oxide forms, for treating or preventing acute or chronic transplant rejection. The dependent features further define release by osmotic pressure or diffusion, biodegradable implant use, and specified effective-amount ranges.

Stated Advantages

Documented Applications