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VACUOLAR-TYPE (H+)-ATPase-INHIBITING COMPOUNDS, COMPOSITIONS, AND USES THEREOF

a technology of vacuolar-type (h+)-atpase inhibitors and compounds, applied in the field of vacuolar-type (h +)-atpase inhibitors, compositions, can solve the problems of rare h+)-atpase inhibitors, agents available for exploiting therapeutic opportunities, and purely synthetic approaches to identify novel vacuolar-type (h+)-atpase inhibitors

Inactive Publication Date: 2008-11-06
GOVERNMENT OF THE UNITED STATES OF AMERICA AS REPRESENTED BY THE SEC DEPT OF HEALTH AND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The compounds effectively inhibit vacuolar-type (H+)-ATPase activity, offering therapeutic applications in treating conditions such as osteoporosis, Alzheimer's disease, glaucoma, and cancer, by regulating biological phenomena like intra-organellar acidification, urinary acidification, and tumor cell invasiveness, and can be used to inhibit drug resistance in cancer cells.

Problems solved by technology

Among the numerous challenges faced by medicinal chemistry research is the challenge of identifying new vacuolar-type (H+)-ATPase-inhibitory leads applicable to medical treatments.
Purely synthetic approaches toward the identification of novel vacuolar-type (H+)-ATPase inhibiting agents have been typically unsuccessful, partly due to the technological and human limitations inherent in laboratory synthesis.
Although biological metabolites provide a vast resource of new structurally diverse chemical compounds, some of which have demonstrated biological activity, the agents available for exploiting therapeutic opportunities through inhibition of vacuolar-type (H+)-ATPase have heretofore been few.
The concanamycins, for example, are among the few potent inhibitors of vacuolar-type (H+)-ATPase heretofore reported, but are structurally complex and do not provide a good template from which simpler, synthetically practical vacuolar-type (H+)-ATPase inhibitors can be prepared.

Method used

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  • VACUOLAR-TYPE (H+)-ATPase-INHIBITING COMPOUNDS, COMPOSITIONS, AND USES THEREOF
  • VACUOLAR-TYPE (H+)-ATPase-INHIBITING COMPOUNDS, COMPOSITIONS, AND USES THEREOF
  • VACUOLAR-TYPE (H+)-ATPase-INHIBITING COMPOUNDS, COMPOSITIONS, AND USES THEREOF

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0105]This example illustrates a procedure for obtaining certain compounds of the present invention from marine sponges and tunicates.

[0106]The particular extract of a Haliclona sp. sponge selected from the NCI Natural Products Repository, Frederick, Md., for investigation in the present example showed an NCI 60-cell screening mean-graph (TGI) fingerprint that was highly correlated (TGI-COMPARE Pearson correlation coefficient greater than or equal to 0.7) to that of either salicylihalamide A or lobatamide A. The extract also showed proton NMR (500 MHz) resonances at chemical shift values (and multiplicities) recorded in CD3OD and referenced to residual methanol of: 6.65(d), 7.12(t), 6.72(d), 6.80(d), 5.68(d), and 6.87(dt). The selected extract was from a Haliclona sp. sponge that had been collected by P. Murphy in Southwestern Australia, 0.7 nautical miles off Rottnest Island, in March, 1989, at a depth of 15 meters. The sponge reportedly occurred as a green mass with amorphous lobe...

example 2

[0118]This example illustrates the structure proofs of particular compounds of the present invention.

[0119]Salicylihalamide A, such as obtained and characterized spectroanalytically in Example 1, was an amorphous solid with a molecular formula established by HREIMS as C26H33NO5. The 13C and DEPT NMR spectra (Table 2) showed 26 unique resonances: 5 quaternary, 14 methine, 5 methylene, and 2 methyl carbons. Chemical shift values further characterized two ester or amide carbonyls, 14 olefinic or aromatic carbons, and two oxygenated methines. Three exchangeable protons completed the proton count. The IR spectrum confirmed OH and / or NH (3288 cm−1) functionalities and suggested the presence of both an amide (1651 cm−1) and an intramolecularly hydrogen-bonded conjugated ester (1697 cm−1). The 13C (125 MHz) and 1H (500 MHz) NMR data for salicylihalamide A in C6D6 and CD3OD are illustrated below in Table 2.

TABLE 2HMBC (1H Correlation,HMBC (1H correlation,C#δc (C6D6)δH (multiplicity, Hz)(C6D6...

example 3

[0135]This example illustrates the isolation and structure of particular compounds of the present invention, Lobatamides C—F.

[0136]Lobatamides C—F were isolated from Aplidium lobatum, and the structures elucidated, according to procedures analogous to those described in Examples 1 and 2 for lobatamides A and B. Lobatamide C, was shown by HRFABMS to be isomeric with lobatamides A and B, namely C27H32N2O8. As with the latter compounds, the presence of three exchangeable protons was indicated by a CIMS deuterium exchange experiment using ND3 as the ionizing agent. The structural similarities among the three compounds were clearly evident from both the 13C and 1H NMR spectra (Tables 4-6). The 13C NMR spectrum of lobatamide C contained signals for all 27 carbons, including two ester carbonyls (δ 171.7, 169.9); an amide carbonyl (δ 164.1); 15 sp2 carbons, fourteen of which were accounted for a phenyl ring and four olefins; three oxygenated methine carbons (δ 73.7, 73.2, 72.9); three methy...

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Abstract

The present invention provides vacuolar-type (H+)-ATPase-inhibiting compounds, compositions thereof, and methods of using them to treat or prevent a condition treatable by the inhibition of a vacuolar-type (H+)-ATPase. The composition of the present invention comprises a compound of the present invention and a carrier. The method of the present invention includes administering a vacuolar-type (H+)-ATPase inhibiting-effective amount of a compound of the present invention. The compound of the present invention has the formula:wherein R1 and R2 are H, saturated or unsaturated alkyl, aryl, R6CH2—, R6CO—, or R6SO2—, wherein R6 is H, saturated or unsaturated alkyl, or aryl; R3 is H, alkyl, aryl, an oxime, or an oxime methyl ether; the aromatic ring is unsubstituted or substituted; and Z is a contiguous linker comprising a chain of 0-10 atoms which, together with the five atoms beginning with the carbon of the aromatic ring in meta-relationship with OR1 and ending with the carbon directly attached to the alkyl oxygen of the lactone, integrally form a 5-17 membered ring; or a pharmaceutically acceptable salt, an ester, or a prodrug thereof.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This patent application is a divisional of copending U.S. patent application Ser. No. 09 / 914,708, filed Dec. 20, 2001, which is the U.S. National Phase of Application No. PCT / US00 / 05582, filed on Mar. 3, 2000, claiming the benefit of U.S. Provisional Patent Application No. 60 / 122,953, filed Mar. 5, 1999, and U.S. Provisional Patent Application No. 60 / 169,564, filed Dec. 8, 1999. The disclosures of the '708, '582, '953, and '564 applications are incorporated by reference.TECHNICAL FIELD[0002]The present invention relates to vacuolar-type (H+)-ATPase-inhibiting lactones, compositions, and methods of using them.BACKGROUND OF THE INVENTION[0003]Vacuolar (or vacuolar-type, or V-type) (H+)-ATPases have been described as “a universal proton pump of eukaryotes” (Finbour and Harrison, Biochem. J., 324, 697-712 (1997)). Vacuolar-type (H+)-ATPases are present in many tissues and cells of the body. Intracellular vacuolar (H+)-ATPase activities are pr...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/335A61P19/10A61P13/02A61K31/00A61K31/336A61K31/357A61K45/06
CPCA61K31/357A61K31/365A61K31/366A61K31/39A61K31/536A61K45/06A61P13/02A61P15/08A61P15/18A61P19/00A61P19/10A61P25/28A61P27/06A61P3/00A61P35/00A61P35/04A61P43/00
Inventor BOYD, MICHAEL R.
Owner GOVERNMENT OF THE UNITED STATES OF AMERICA AS REPRESENTED BY THE SEC DEPT OF HEALTH AND