US 2006/0217427 A1Published application

Cytoskeletal active compounds, compositions and use

AssigneeInspire Pharmaceuticals, Inc.

InventorsJohn Lampe, Robert Plourde, Jin She, Jason Vittitow, Paul Watson, Michael Crimmins, David Slade

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Abstract

The present invention is directed to synthetic cytoskeletal active compounds that are related to natural Latrunculin A or Latrunculin B. The present invention is also directed to pharmaceutical compositions comprising such compounds and a pharmaceutically acceptable carrier. The invention is additionally directed to a method of preventing or treating diseases or conditions associated with actin polymerization. In one embodiment of the invention, the method treats increased intraocular pressure, such as primary open-angle glaucoma. The method comprises administering to a subject a therapeutically effective amount of a cytoskeletal active compound of Formula I or II, wherein said amount is effective to influence the cytoskeleton, for example by inhibiting actin polymerization.

Claims22

Dependent claims

A compound of Formula I, or pharmaceutically-acceptable salts, tautomers, solvates, or hydrates thereof:

wherein:
X1═S, O, NR3, or CR4R5;
Y1═S, O, or NR6;
Y2═S, O, or NR7;
Z1═S, O, NR8, or absent;
Q1 and Q2 are independently O or S;
A1 and A2 are independently hydrogen, halo, alkyl, or alkoxy, optionally substituted;
n=1, 2, or 3;
R1—R8 are independently H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, or heterocycle, optionally substituted;
with a first proviso that when Z1═S or O;
R2 is not H;
with a second proviso that when n is 1, X1 is S, Y1 is NR6, Y2 is O, Z, is absent, Q1 and Q2 are O, and if R2 is selected from one of the following groups:
methyl,
then R1 is not 3-monomethyl-substituted alkyl, or R1 is not:
where the bond marked with an arrow denotes the point of attachment of the group R1 to the rest of the molecule.

12 more elements

A compound of Formula II, or pharmaceutically-acceptable salts, tautomers, solvates, or hydrates thereof:

wherein:
Ra is an alkylene chain, from 4 to 15 atoms in length, wherein the carbon atoms of the alkylene chain are optionally replaced by from 1 to 3 O, S, or N atoms, wherein the alkylene chain optionally contains from 1 to 4 unsaturations, 1 to 2 cycloalkyl, 1 to 2 aryl, 1 to 2 heteroaryl, or 1 to 2 heterocycle rings, and is optionally substituted;
X1═S, O, NR3, or CR4R5;
Y1═S, O, or NR6;
Y2═S, O, or NR7;
Z1═S, O, NR8, or absent;
Q1 and Q2 are independently O or S;
A1 and A2 are independently hydrogen, halo, alkyl, or alkoxy, optionally substituted;
n=1, 2, or 3;
R3—R8 are independently H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, or heterocycle, optionally substituted;
with a proviso that when n is 1, X1 is S, Y1 is NR6, Y2 is O, Z1 is absent, and Q1 and Q2 are O, then either Ra is not 3-monomethyl-susbtituted, as counted from the point of attachment distal to Z1;
or Ra is not:
where in these structures the right-most bond marked with an arrow indicates the point of attachment of Ra to Z1, and the left-most bond marked with an arrow indicates the point of attachment of Ra to the pyran ring of Formula II.

10 more elements

Dependencies are inferred from the claim text.