US2015050277A1PendingUtilityA1
Compositions and methods for treating ocular diseases
Est. expiryMar 15, 2033(~6.6 yrs left)· nominal 20-yr term from priority
A61K 31/427C07D 263/32C07D 413/04A61K 31/428C07D 277/28A61K 39/3955A61K 31/10A61K 31/538C07D 277/64A61K 31/426A61K 9/0019A61K 47/40A61K 38/05A61K 31/496A61K 2039/505A61K 31/635C07D 417/14A61K 31/4439C07D 417/04C07D 277/52C07D 277/22A61K 31/513A61K 31/497C07D 417/12C07K 16/22A61K 31/04A61K 38/179
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Claims
Abstract
Disclosed herein are compositions and methods for treating ocular diseases, inter alia, diabetic macular edema, age-related macular degeneration (wet form), choroidal neovascularization, diabetic retinopathy, retinal vein occlusion (central or branch), ocular trauma, surgery induced edema, surgery induced neovascularization, cystoid macular edema, ocular ischemia, uveitis, and the like. These diseases or conditions are characterized by changes in the ocular vasculature whether progressive or non-progressive, whether a result of an acute disease or condition, or a chronic disease or condition.
Claims
exact text as granted — not AI-modified1 . A method for treating an ocular disease, comprising administering to a subject in need thereof:
a) a compound having the formula:
wherein R is a substituted or unsubstituted thiazolyl unit having the formula:
R 2 , R 3 , and R 4 are each independently:
i) hydrogen;
ii) substituted or unsubstituted C 1 -C 6 linear, C 3 -C 6 branched, or C 3 -C 6 cyclic alkyl;
iii) substituted or unsubstituted C 1 -C 6 linear, C 3 -C 6 branched, or C 3 -C 6 cyclic alkenyl;
iv) substituted or unsubstituted C 2 -C 6 linear or branched alkynyl;
v) substituted or unsubstituted C 6 or C 10 aryl;
vi) substituted or unsubstituted C 1 -C 9 heteroaryl;
vi) substituted or unsubstituted C 1 -C 9 heterocyclic; or
viii) R 2 and R 3 can be taken together to form a saturated or unsaturated ring having from 5 to 7 atoms; wherein from 1 to 3 atoms can optionally be heteroatoms chosen from oxygen, nitrogen, and sulfur;
Z is a unit having the formula:
-(L) n -R 1
R 1 is chosen from:
i) hydrogen;
ii) hydroxyl;
iii) amino;
iv) substituted or unsubstituted C 1 -C 6 linear, C 3 -C 6 branched, or C 3 -C 6 cyclic alkyl;
v) substituted or unsubstituted C 1 -C 6 linear, C 3 -C 6 branched, or C 3 -C 6 cyclic alkoxy;
vi) substituted or unsubstituted C 6 or C 10 aryl;
vi) substituted or unsubstituted C 1 -C 9 heterocyclic ring; or
viii) substituted or unsubstituted C 1 -C 9 heteroaryl ring;
L is a linking unit having the formula:
-[Q] y [C(R 5a R 5b )] x [Q 1 ] z [C(R 6a R 6b )] w —
Q and Q 1 are each independently:
i) —C(O)—;
ii) —NH—;
iii) —C(O)NH—;
iv) —NHC(O)—;
v) —NHC(O)NH—;
vi) —NHC(O)O—;
vi) —C(O)O—;
viii) —C(O)NHC(O)—;
ix) —O—;
x) —S—;
xi) —SO 2 —;
xii) —C(═NH)—;
xiii) —C(═NH)NH—;
xiv) —NHC(═NH)—; or
xv) —NHC(═NH)NH—;
R 5a and R 5b are each independently:
i) hydrogen;
ii) hydroxy;
iii) halogen;
iv) substituted or unsubstituted C 1 -C 6 linear or C 3 -C 6 branched alkyl; or
v) a unit having the formula:
—[C(R 7a R 7b )] t R 8
R 7a and R 7b are each independently:
i) hydrogen; or
ii) substituted or unsubstituted C 1 -C 6 linear, C 3 -C 6 branched, or C 3 -C 6 cyclic alkyl;
R 8 is:
i) hydrogen;
ii) substituted or unsubstituted C 1 -C 6 linear, C 3 -C 6 branched, or C 3 -C 6 cyclic alkyl;
iii) substituted or unsubstituted C 6 or C 10 aryl;
iv) substituted or unsubstituted C 1 -C 9 heteroaryl; or
v) substituted or unsubstituted C 1 -C 9 heterocyclic;
R 6a and R 6b are each independently:
i) hydrogen; or
ii) C 1 -C 4 linear or C 3 -C 4 branched alkyl;
the index n is 0 or 1; the indices t, w and x are each independently from 0 to 4; the indices y and z are each independently 0 or 1; or
a pharmaceutically-acceptable salt thereof; and
b) at least one anti-VEGF agent, wherein the anti VEGF agent is ranibizumab, bevacizumab, or aflibercept.
2 . The method according to claim 1 , wherein the ocular disease is retinopathy.
3 . The method according to claim 1 , wherein the compound or pharmaceutically-acceptable salt thereof is administered in an amount from about 0.5 mg to about 30 mg.
4 . (canceled)
5 . The method according to claim 1 , wherein the anti-VEGF agent is ranibizumab.
6 . The method according to claim 5 , wherein ranibizumab is administered in an amount from about 0.05 mg to about 1.5 mg.
7 - 11 . (canceled)
12 . The method according to claim 1 , wherein the anti-VEGF agent is bevacizumab.
13 . The method according to claim 12 , wherein bevacizumab is administered in an amount from about 0.1 mg to about 5 mg.
14 - 16 . (canceled)
17 . The method according to claim 1 , wherein the anti-VEGF agent is aflibercept.
18 . The method according to claim 17 , wherein aflibercept is administered in an amount from about 0.05 mg to about 5 mg.
19 . (canceled)
20 - 23 . (canceled)
24 . The method according to claim 1 , wherein R has the formula:
25 . The method according to claim 24 , wherein R 2 and R 3 are each independently hydrogen or substituted or unsubstituted C 1 -C 6 linear, branched, or cyclic alkyl.
26 . The method according to claim 24 , wherein R 2 is chosen from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl; and R 3 is hydrogen.
27 . The method according to claim 24 , wherein R 2 is ethyl.
28 - 29 . (canceled)
30 . The method according to claim 24 , wherein R 2 is substituted or unsubstituted heteroaryl and R 3 is hydrogen.
31 . (canceled)
32 . The method according to claim 24 , wherein R 2 is thiophen-2-yl.
33 . The method according to claim 1 , wherein R has the formula:
34 . The method according to claim 33 , wherein R 4 is hydrogen or substituted or unsubstituted C 1 -C 6 linear, branched, or cyclic alkyl.
35 . The method according to claim 33 , wherein R 4 is chosen from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl; and R 3 is hydrogen.
36 . The method according to claim 33 , wherein R 4 is ethyl.
37 - 38 . (canceled)
39 . The method according to claim 33 , wherein R 4 is substituted or unsubstituted heteroaryl.
40 . (canceled)
41 . The method according to claim 33 , wherein R 4 is thiophen-2-yl.
42 . The method according to claim 33 , wherein R 1 is hydrogen, methyl, ethyl, tert-butyl, or methyl substituted with phenyl.
43 . The method according to claim 33 , wherein L has the formula:
—C(O)[C(R 5a R 5b )] x NHC(O)—
R 5a is hydrogen, substituted or unsubstituted phenyl, and substituted or unsubstituted heteroaryl; and the index x is 1 or 2.
44 . The method according to claim 43 , wherein R 5a has the formula:
—[C(R 7a R 7b )] w R 8
each R 7a is independently hydrogen, methyl, or ethyl; each R 7b is hydrogen; R 8 is hydrogen, substituted or unsubstituted C 1 -C 4 linear, C 3 -C 4 branched, or C 3 -C 4 cyclic alkyl, or substituted or unsubstituted phenyl, wherein the substitutions are chosen from one or more hydroxy, halogen, or C 1 -C 4 alkyl; R 5b is hydrogen; and the index w is 1 or 2.
45 - 50 . (canceled)
51 . The method according to claim 33 , wherein R 1 is a substituted or unsubstituted heteroaryl unit, said substitutions chosen from:
C 1 -C 6 linear, C 3 -C 6 branched, and C 3 -C 6 cyclic alkyl.
52 . The method according to claim 33 , wherein R 1 is chosen from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or tert-butyl.
53 . The method according to claim 33 , wherein R 1 is methyl.
54 - 60 . (canceled)
61 . The method according to claim 1 , wherein the compound has the formula:
or a pharmaceutically-acceptable salt thereof.
62 . The method according to claim 1 , wherein the compound has the formula:
or a pharmaceutically-acceptable salt thereof.
63 . The method according to claim 1 , wherein the compound has the formula:
or a pharmaceutically-acceptable salt thereof.
64 . The method according to claim 1 , wherein the compound has the formula:
or a pharmaceutically-acceptable salt thereof.
65 . The method according to claim 61 , wherein the compound is in the form of a sodium salt.
66 . The method according to claim 1 , wherein the administration reduces the central foveal thickness in an eye of the subject.
67 - 108 . (canceled)
109 . The method according to claim 1 , wherein the administration improves visual acuity in an eye of the subject.
110 - 172 . (canceled)
173 . The method according to claim 1 , wherein the ocular disease is diabetic macular edema.
174 . The method according to claim 1 , wherein the ocular disease is age-related macular degeneration.
175 . The method according to claim 1 , wherein the ocular disease is wet age-related macular degeneration.
176 . The method according to claim 1 , wherein the ocular disease is diabetic retinopathy.
177 . A pharmaceutical composition comprising:
a) a compound having the formula:
wherein R is a substituted or unsubstituted thiazolyl unit having the formula:
R 2 , R 3 , and R 4 are each independently:
i) hydrogen;
ii) substituted or unsubstituted C 1 -C 6 linear, C 3 -C 6 branched, or C 3 -C 6 cyclic alkyl;
iii) substituted or unsubstituted C 1 -C 6 linear, C 3 -C 6 branched, or C 3 -C 6 cyclic alkenyl;
iv) substituted or unsubstituted C 2 -C 6 linear or branched alkynyl;
v) substituted or unsubstituted C 6 or C 10 aryl;
vi) substituted or unsubstituted C 1 -C 9 heteroaryl;
vi) substituted or unsubstituted C 1 -C 9 heterocyclic; or
viii) R 2 and R 3 can be taken together to form a saturated or unsaturated ring having from 5 to 7 atoms; wherein from 1 to 3 atoms can optionally be heteroatoms chosen from oxygen, nitrogen, and sulfur;
Z is a unit having the formula:
-(L) n R 1
R 1 is chosen from:
i) hydrogen;
ii) hydroxyl;
iii) amino;
iv) substituted or unsubstituted C 1 -C 6 linear, C 3 -C 6 branched, or C 3 -C 6 cyclic alkyl;
v) substituted or unsubstituted C 1 -C 6 linear, C 3 -C 6 branched, or C 3 -C 6 cyclic alkoxy;
vi) substituted or unsubstituted C 6 or C 10 aryl;
vii) substituted or unsubstituted C 1 -C 9 heterocyclic ring; or
viii) substituted or unsubstituted C 1 -C 9 heteroaryl ring;
L is a linking unit having the formula:
-[Q] y [C(R 5a R 5b )] x [Q 1 ] z [C(R 6a R 6b )] w —
Q and Q 1 are each independently:
i) —C(O)—;
ii) —NH—;
iii) —C(O)NH—;
iv) —NHC(O)—;
v) —NHC(O)NH—;
vi) —NHC(O)O—;
vii) —C(O)O—;
viii) —C(O)NHC(O)—;
ix) —O—;
x) —S—;
xi) —SO 2 —;
xii) —C(═NH)—;
xiii) —C(═NH)NH—;
xiv) —NHC(═NH)—; or
xv) —NHC(═NH)NH—;
R 5a and R 5b are each independently:
i) hydrogen;
ii) hydroxy;
iii) halogen;
iv) substituted or unsubstituted C 1 -C 6 linear or C 3 -C 6 branched alkyl; or
v) a unit having the formula:
—[C(R 7a R 7b )] t R 8
R 7a and R 7b are each independently:
i) hydrogen; or
ii) substituted or unsubstituted C 1 -C 6 linear, C 3 -C 6 branched, or C 3 -C 6 cyclic alkyl;
R 8 is:
i) hydrogen;
ii) substituted or unsubstituted C 1 -C 6 linear, C 3 -C 6 branched, or C 3 -C 6 cyclic alkyl;
iii) substituted or unsubstituted C 6 or C 10 aryl;
iv) substituted or unsubstituted C 1 -C 9 heteroaryl; or
v) substituted or unsubstituted C 1 -C 9 heterocyclic;
R 6a and R 6b are each independently:
i) hydrogen; or
ii) C 1 -C 4 linear or C 3 -C 4 branched alkyl;
the index n is 0 or 1; the indices t, w and x are each independently from 0 to 4; the indices y and z are each independently 0 or 1; or
a pharmaceutically acceptable salt thereof; and
b) a cyclodextrin,
wherein the compound, or a pharmaceutically-acceptable salt thereof, and the cyclodextrin are in a unit dosage form.
178 . The pharmaceutical composition of claim 177 , wherein the compound or pharmaceutically-acceptable salt thereof is administered in an amount from about 0.5 mg to about 30 mg.
179 . The pharmaceutical composition of claim 177 , wherein R has the formula:
180 . The pharmaceutical composition of claim 179 , wherein R 2 and R 3 are each independently hydrogen or substituted or unsubstituted C 1 -C 6 linear, branched, or cyclic alkyl.
181 . The pharmaceutical composition of claim 179 , wherein R 2 is chosen from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl; and R 3 is hydrogen.
182 . The pharmaceutical composition of claim 179 , wherein R 2 is ethyl.
183 . The pharmaceutical composition of claim 179 , wherein R 2 is substituted or unsubstituted heteroaryl and R 3 is hydrogen.
184 . The pharmaceutical composition of claim 179 , wherein R 2 is thiophen-2-yl.
185 . The pharmaceutical composition of claim 177 , wherein R has the formula:
186 . The pharmaceutical composition of claim 185 , wherein R 4 is hydrogen or substituted or unsubstituted C 1 -C 6 linear, branched, or cyclic alkyl.
187 . The pharmaceutical composition of claim 185 , wherein R 4 is chosen from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl; and R 3 is hydrogen.
188 . The pharmaceutical composition of claim 185 , wherein R 4 is ethyl.
189 . The pharmaceutical composition of claim 185 , wherein R 4 is substituted or unsubstituted heteroaryl.
190 . The pharmaceutical composition of claim 185 , wherein R 4 is thiophen-2-yl.
191 . The pharmaceutical composition of claim 185 , wherein R 1 is hydrogen, methyl, ethyl, tert-butyl, or methyl substituted with phenyl.
192 . The pharmaceutical composition of claim 185 , wherein L has the formula:
—C(O)[C(R 5a R 5b )] x NHC(O)—
R 5a is hydrogen, substituted or unsubstituted phenyl, and substituted or unsubstituted heteroaryl; and the index x is 1 or 2.
193 . The pharmaceutical composition of claim 192 , wherein R 5a has the formula:
—[C(R 7a R 7b )] w R 8
each R 7a is independently hydrogen, methyl, or ethyl; each R 7b is hydrogen; R 8 is hydrogen, substituted or unsubstituted C 1 -C 4 linear, C 3 -C 4 branched, or C 3 -C 4 cyclic alkyl, or substituted or unsubstituted phenyl, wherein the substitutions are chosen from one or more hydroxy, halogen, or C 1 -C 4 alkyl; R 5b is hydrogen; and the index w is 1 or 2.
194 . The pharmaceutical composition of claim 185 , wherein R 1 is a substituted or unsubstituted heteroaryl unit, said substitutions chosen from C 1 -C 6 linear, C 3 -C 6 branched, and C 3 -C 6 cyclic alkyl.
195 . The pharmaceutical composition of claim 185 , wherein R 1 is chosen from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or tert-butyl.
196 . The pharmaceutical composition of claim 185 , wherein R 1 is methyl.
197 . The pharmaceutical composition of claim 177 , wherein the compound has the formula:
or a pharmaceutically-acceptable salt thereof.
198 . The pharmaceutical composition of claim 177 , wherein the compound has the formula:
or a pharmaceutically-acceptable salt thereof.
199 . The pharmaceutical composition of claim 177 , wherein the compound has the formula:
or a pharmaceutically-acceptable salt thereof.
200 . The pharmaceutical composition of claim 177 , wherein the compound has the formula:
or a pharmaceutically-acceptable salt thereof.
201 . The pharmaceutical composition of claim 197 , wherein the compound is in the form of a sodium salt.
202 . The pharmaceutical composition of claim 177 , wherein the cyclodextrin is hydroxypropyl beta cyclodextrin.Join the waitlist — get patent alerts
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