Compounds and Compositions for the Treatment of Ophthalmic Disorders
Described herein are methods and compositions featuring a first compound that is a linear peptidic NPR-B agonist and a second compound that is a prostaglandin agonist or a β-adrenergic antagonist, which are useful in the treatment and/or prevention of ophthalmic disorders such as glaucoma.
1 . A method of treating an ophthalmic disease in a patient, said method comprising co-administering to said patient an effective amount of
a first compound that is a linear peptidic NPR-B agonist; and
a second compound that is a prostaglandin agonist or a β-adrenergic antagonist.
2 . The method of claim 1 , wherein said first compound is a compound of formula (B-1),
or a pharmaceutically acceptable salt thereof, wherein
B is selected from the group consisting of R b1 — and R b2 —C(O)—;
R b1 is selected from the group consisting of C 6 -C 10 alkyl and C 5 -C 10 alkyl substituted by NR b4 R b5 ;
R b2 is selected from the group consisting of C 5 -C 10 alkyl and C 5 -C 10 alkyl substituted by NR b4 R b5 ;
R b4 and R b5 are, independently, selected from the group consisting of H and C 1 -C 4 alkyl; and
R 11b is selected from the group consisting of H, C 1 -C 8 alkyl, C 4 -C 8 cycloalkyl, C 7 -C 12 bicycloalkyl, and C 1 -C 4 alkyl-C 4 -C 8 cycloalkyl.
3 . The method of claim 1 , wherein said first compound is Occ-Sni-Phe-orn(Me2)-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:1), or a pharmaceutically acceptable salt thereof.
4 .- 5 . (canceled)
6 . The method of claim 1 , wherein said second compound is a prostaglandin agonist that is latanoprost, bimatoprost, travoprost, or tafluprost or a β-adrenergic antagonist that is betaxolol, carteolol, levobunolol, metipranolol, or timolol.
7 .- 8 . (canceled)
9 . The method of claim 1 , wherein the ophthalmic disease is glaucoma, elevated intraocular pressure or ocular hypertension.
10 . The method of claim 1 , wherein said method comprises lowering intraocular pressure in a patient in need thereof.
11 .- 23 . (canceled)
24 . The method of claim 9 , wherein said glaucoma is primary open angle glaucoma, angle closure glaucoma, normal tension glaucoma, congenital glaucoma, neovascular glaucoma, steroid-induced glaucoma, or glaucoma related to ocular trauma.
25 .- 28 . (canceled)
29 . The method of claim 1 , wherein said single composition comprises:
said first compound in an amount that is about 0.01% (w/w) to about 0.75% (w/w);
said second compound in an amount that is about 0.0001% (w/w) to about 0.1% (w/w); and
a pharmaceutically acceptable excipient.
30 .- 44 . (canceled)
45 . The method of claim 1 , wherein said first compound and/or said second compound is topically administered.
46 .- 50 . (canceled)
51 . A pharmaceutical composition comprising:
a first compound that is a linear peptidic NPR-β agonist;
a second compound that is a prostaglandin agonist or a β-adrenergic antagonist; and
a pharmaceutically acceptable excipient.
52 . The pharmaceutical composition of claim 51 , wherein said first compound is a compound of formula (B-1),
or a pharmaceutically acceptable salt thereof, wherein
B is selected from the group consisting of R b1 — and R b2 —C(O)—;
R b1 is selected from the group consisting of C 6 -C 10 alkyl and C 6 -C 10 alkyl substituted by NR b4 R b5 ;
R b2 is selected from the group consisting of C 6 -C 10 alkyl and C 6 -C 10 alkyl substituted by NR b4 R b5 ;
R b4 and R b5 are, independently, selected from the group consisting of H and C 1 -C 4 alkyl; and
R 11b is selected from the group consisting of H, C 1 -C 8 alkyl, C 4 -C 8 cycloalkyl, C 7 -C 12 bicycloalkyl, and C 1 -C 4 alkyl-C 4 -C 8 cycloalkyl.
53 . The pharmaceutical composition of claim 51 , wherein said first compound is Occ-Sni-Phe-orn(Me2)-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:1), or a pharmaceutically acceptable salt thereof.
54 .- 55 . (canceled)
56 . The pharmaceutical composition of claim 51 , wherein said second compound is a prostaglandin agonist that is latanoprost, bimatoprost, travoprost, or tafluprost or a β-adrenergic antagonist that is betaxolol, carteolol, levobunolol, metipranolol, or timolol.
57 .- 60 . (canceled)
61 . The pharmaceutical composition of claim 51 , wherein
said first compound, or a pharmaceutically acceptable salt thereof, is present in an amount that is about 0.01% (w/w) to about 0.15% (w/w); and
said second compound is present in an amount that is about 0.001% (w/w) to about 0.05% (w/w).
62 .- 64 . (canceled)
65 . The pharmaceutical composition of claim 51 , wherein said pharmaceutical composition is formulated for ophthalmic use.
66 . The pharmaceutical composition of claim 51 , wherein said pharmaceutical composition is formulated for topical administration.
67 .- 76 . (canceled)
77 . A method of treating an ophthalmic disease in a patient, said method comprising administering to said patient an effective amount of the pharmaceutical composition of claim 51 .
78 . A method of lowering intraocular pressure in a patient in need thereof, said method comprising administering to said patient an effective amount of the pharmaceutical composition of claim 51 .
79 . A method of treating glaucoma in a patient in need thereof, said method comprising administering to said patient an effective amount of the pharmaceutical composition of claim 51 .
80 .- 81 . (canceled)
82 . A compound that is:
a compound of formula (I),
or a pharmaceutically acceptable salt thereof, wherein
X 1 is a covalent bond, —O—, —S—, or —NR X1 —,
R 1 is H, optionally substituted C 1 -C 12 alkyl, or optionally substituted C 7 -C 16 aralkyl;
R X1 is H or optionally substituted C 1 -C 12 alkyl;
L represents a linker that is a covalent bond, optionally substituted C 1 -C 12 alkylene, or optionally substituted 2- to 12-membered heteroalkylene, or
L represents a linker having the structure -(L 1 )-L 2 -(L 3 )-, wherein
each of L 1 and L 3 is independently a covalent bond, optionally substituted C 1 -C 5 alkylene, or optionally substituted 2- to 6-membered heteroalkylene; and
L 2 is optionally substituted C 5 -C 10 arylene or optionally substituted 5- to 10-membered heteroarylene;
or
a compound of formula (III),
or a pharmaceutically acceptable salt thereof, wherein
R 2 is H, optionally substituted C 1 -C 12 alkyl, or optionally substituted C 7 -C 16 aralkyl;
X 1 is a covalent bond, —O—, —S—, or —NR X1 —,
X 2 is a covalent bond, —O—, —S—, or —NR X2 —,
each of R X1 and R X2 is independently H or optionally substituted C 1 -C 12 alkyl;
L represents a linker that is a covalent bond, optionally substituted C 1 -C 12 alkylene, or optionally substituted 2- to 12-membered heteroalkylene, or
L represents a linker having the structure -(L 1 )-L 2 -(L 3 )-, wherein
each of L 1 and L 3 is independently a covalent bond, optionally substituted C 1 -C 5 alkylene, or optionally substituted 2- to 6-membered heteroalkylene; and
L 2 is optionally substituted C 5 -C 10 arylene or optionally substituted 5- to 10-membered heteroarylene.
83 .- 92 . (canceled)
93 . The compound of claim 82 , wherein said compound is of formula (II),
or a pharmaceutically acceptable salt thereof, wherein
R 1 is H, optionally substituted C 1 -C 12 alkyl, or optionally substituted C 7 -C 16 aralkyl.
94 .- 107 . (canceled)
108 . The compound of claim 82 , wherein said compound is of formula (IV):
or a pharmaceutically acceptable salt thereof, wherein
L represents a linker that is optionally substituted C 1 -C 12 alkylene or optionally substituted 2- to 12-membered heteroalkylene.
109 . (canceled)
110 . The compound of claim 82 , having the following structure,
or a pharmaceutically acceptable salt thereof.
111 . A pharmaceutical composition comprising
the compound of claim 82 , and
a pharmaceutically acceptable excipient.
112 . The pharmaceutical composition of claim 111 , comprising the compound in an amount that is
about 0.001% (w/v) to about 1.000% (w/v), about 0.001% (w/v) to about 0.500% (w/v), about 0.001% (w/v) to about 0.250% (w/v), about 0.001% to about 0.150%, about 0.001% to about 0.100%, about 0.001% to about 0.090%, about 0.001% to about 0.075%, about 0.001% to about 0.050%, or about 0.001% to about 0.010%;
about 0.005% (w/v) to about 1.000% (w/v), about 0.005% (w/v) to about 0.500% (w/v), about 0.005% (w/v) to about 0.250% (w/v), about 0.005% to about 0.150%, about 0.005% to about 0.100%, about 0.005% to about 0.090%, about 0.005% to about 0.075%, about 0.005% to about 0.050%, or about 0.005% to about 0.010%;
about 0.010% (w/v) to about 2.000% (w/v), about 0.010% (w/v) to about 1.500% (w/v), about 0.010% (w/v) to about 1.000% (w/v), about 0.010% (w/v) to about 0.900% (w/v), about 0.010% (w/v) to about 0.800% (w/v), about 0.010% (w/v) to about 0.700% (w/v), about 0.010% (w/v) to about 0.600% (w/v), about 0.010% (w/v) to about 0.500% (w/v), about 0.010% (w/v) to about 0.250% (w/v), about 0.010% to about 0.150%, about 0.010% to about 0.100%, about 0.010% to about 0.090%, about 0.010% to about 0.075%, or about 0.010% to about 0.050%;
about 0.050% (w/v) to about 2.000% (w/v), about 0.050% (w/v) to about 1.500% (w/v), about 0.050% (w/v) to about 1.000% (w/v), about 0.050% (w/v) to about 0.500% (w/v), about 0.050% (w/v) to about 0.250% (w/v), about 0.050% (w/v) to about 0.200% (w/v), about 0.050% to about 0.150%, or about 0.050% to about 0.125%; or
about 0.075% (w/v) to about 2.000% (w/v), about 0.075% (w/v) to about 1.500% (w/v), about 0.075% (w/v) to about 1.250% (w/v), about 0.075% (w/v) to about 1.000% (w/v), about 0.075% (w/v) to about 0.750% (w/v), about 0.075% (w/v) to about 0.500% (w/v), about 0.075% (w/v) to about 0.250% (w/v), about 0.075% (w/v) to about 0.200% (w/v), or about 0.075% (w/v) to about 0.150% (w/v).
113 . The pharmaceutical composition of claim 111 , wherein said pharmaceutical composition is formulated for ophthalmic use.
114 . The pharmaceutical composition of claim 111 , wherein said pharmaceutical composition is formulated for topical administration.
115 .- 124 . (canceled)
125 . A method of treating an ophthalmic disease in a patient, said method comprising administering to said patient an effective amount of the pharmaceutical composition of claim 111 .
126 . A method of lowering intraocular pressure in a patient in need thereof, said method comprising administering to said patient an effective amount of the pharmaceutical composition of claim 111 .
127 . A method of treating glaucoma in a patient in need thereof, said method comprising administering to said patient an effective amount of the pharmaceutical composition of claim 111 .
128 .- 129 . (canceled)