Compounds and compositions for eye treatments
This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt and/or hydrate and/or prodrug of the compound) that that generates cross-linking in the cornea in response to exposure to an electromagnetic irradiation. This disclosure also features compositions containing the same as well as other methods of using and making the same. The chemical entities are useful, e.g., for treating a subject (e.g., a human) having a disease, disorder, or condition in which in which abnormal shaping of the cornea (e.g., thinning of the cornea, e.g., bilateral thinning of the cornea, e.g., bilateral thinning of the central, paracentral, or peripheral cornea; or steepening (e.g., bulging) of the cornea) contributes to the pathology and/or symptoms and/or progression of the disease, disorder, or condition. Non-limiting examples of such diseases, disorders, or conditions include: (i) corneal ectatic disorders; (ii) vision conditions; and (iii) diseases, disorders, or conditions that are sequela or comorbid with any of the foregoing or any disclosed herein. More particular non-limiting examples of such diseases, disorders, or conditions include keratoconus, keratoglobus, pellucid marginal degeneration, corneal ectasia (e.g., post-operative ectasia, e.g., post-LASIK ectasia), Terrien's marginal degeneration, myopia, hyperopia, astigmatism, irregular astigmatism, and presbyopia.
1 . A compound having formula (I):
or a pharmaceutically acceptable salt thereof;
wherein:
X is C 1 -C 6 alkyl;
Y is selected from the group consisting of:
(i) C(O)NR 4Y R 5Y ;
(ii) heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-2 independently selected R c ; and
(iii) heterocycloalkenyl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R 4 ), O, and S, and wherein one or more of the heterocycloalkenyl ring carbon atoms are optionally substituted with from 1-2 independently selected R b ;
Z is selected from the group consisting of:
(i) H,
(ii) NR 4Z R 5Z ,
(iii) OR 6Z ,
(iv) OC(O)R 7Z ,
(v) OP(O)OR 8Z OR 9Z , and
(vi) heterocyclyl including from 4-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), and O, and wherein one or more of the heterocyclyl ring carbon atoms are optionally substituted with from 1-4 independently selected R h ;
each Z x is H; or each Z x together with the carbon to which each is attached forms C═O;
each of R 1 , R 2 , and R 3 is R 6A ;
ach of R 4Y and R 5Y is independently selected from the group consisting of:
(i) H;
(ii) C 1-12 alkyl, which is optionally substituted with 1-6 R a ;
(iii) heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected R h ;
(iv) —(W 1 —W 2 ) n —W 3 , wherein:
W 1 is in each occurrence is independently C 1-3 alkylene optionally substituted with from 1-4 R a ;
W 2 is in each occurrence independently —N(H)—, —N(R d )—, —O—, or —S—;
W 3 is H or C 1-7 alkyl optionally substituted with from 1-4 R a ; and
n is 2-4;
and
(v) R 4Y and R 5Y together with the nitrogen atom to which each is attached forms a ring including from 3-8 ring atoms, wherein the ring includes: (a) from 1-7 ring carbon atoms, each of which is substituted with from 1-2 substituents independently selected from H and C 1-3 alkyl; and (b) from 0-3 ring heteroatoms in addition to the nitrogen atom attached to R 4Y and R 5Y , which are each independently selected from the group consisting of N(H), N(R d ), O, and S;
each of R 4Z and R 5Z is independently selected from the group consisting of:
(i) H; and
(ii) C 1-10 alkyl optionally substituted with 1-6 independently selected R a ;
R 6A in each occurrence is H;
R 6Z is independently selected from the group consisting of:
(i) H;
(ii) C 1-10 alkyl optionally substituted with from 1-6 independently selected R a ;
(iii) —(C 0-2 alkylene)-(C 6-10 aryl), wherein the C 6-10 aryl is optionally substituted with from 1-2 independently selected R h ;
(iv) —(C 0-2 alkylene)-(heteroaryl), wherein the heteroaryl includes from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(C 1-3 alkyl), O, and S, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected R h , and
(v) —(C 1-2 alkylene)-C(═O)NH—(C 1-3 alkylene)-R 6Z′ ;
R 6Z′ is selected from the group consisting of:
C(═O)OH, N(C 1-4 alkyl) 2 , NH 2 , NH(C 1-4 alkyl), and heterocyclyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), and O, and wherein one or more of the heterocyclyl ring carbon atoms are optionally substituted with from 1-4 independently selected C 1-3 alkyl;
each of R 7Z at each occurrence, is independently C 1-10 alkyl optionally substituted with from 1-6 independently selected R a ;
each of R 8Z and R 9Z in each occurrence is H;
each occurrence of R a is independently selected from the group consisting of: —OH; NR e R f ; C 1-4 alkoxy; —C(═O)OH; —CON(R′)(R″); C(═NH)N(R′)(R″);
each occurrence of R b is C 1-6 alkyl;
each occurrence of R c is independently selected from the group consisting of:
(i) C 1-10 alkyl;
(ii) C 1-10 alkyl substituted with from 1-6 independently selected R a ;
(iii) —NR e R f ,
(iv) —C(═O)OH; and
(v) —C(═O)N(R′)(R″);
R d is C 1-6 alkyl optionally substituted with from 1-3 independently selected R g ;
each occurrence of R e and R f is independently selected from the group consisting of: H and C 1-6 alkyl;
or R e and R f together with the nitrogen atom to which each is attached forms a ring including from 3-8 ring atoms, wherein the ring includes: (a) from 1-7 ring carbon atoms, each of which is substituted with from 1-2 substituents independently selected from H and C 1-3 alkyl; and (b) from 0-3 ring heteroatoms in addition to the nitrogen atom attached to R e and R f , which are each independently selected from the group consisting of N(H), N(R d ), O, and S;
each occurrence of R h is C 1-3 alkyl;
and
each occurrence of R′ and R″ is H;
with the proviso that the compound is not:
2 . The compound of claim 1 , wherein Z is OR 6Z .
3 . The compound of claim 2 , wherein R 6Z is selected from H and C 1-3 alkyl, optionally substituted with 1 R a .
4 . The compound of claim 3 , wherein R 6Z is H.
5 . The compound of claim 1 , wherein Y is CONR 4Y R 5Y .
6 . The compound of claim 5 , wherein each of R 4Y and R 5Y is independently H or C 1-4 alkyl optionally substituted with from 1-2 independently selected R a .
7 . The compound of claim 6 , wherein each of R 4Y and R 5Y is independently H or
8 . The compound of claim 7 , wherein R 4Y is H; and R a on R 5Y is selected from —OH and —NR e R f —.
9 . The compound of claim 8 , wherein R 5Y is
10 . The compound of claim 1 , wherein Y is heteroaryl including from 5 ring atoms wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-2 independently selected R c .
11 . The compound of claim 10 , wherein Y is selected from tetrazolyl, triazolyl, oxadiazolyl, and oxazolyl, wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-2 independently selected R c ; and one of the heteroaryl ring nitrogen atoms is optionally substituted with R d .
12 . The compound of claim 1 , wherein each Z x is H.
13 . The compound of claim 1 , wherein each Z x together with the carbon to which each is attached forms C═O.
14 . The compound of claim 1 , wherein the compound is selected from:
Example #
Compound
Name/ID #
8
Compound 15
14
Compound 31
15
Compound 37
16
Compound 40
17
Compound 43
18
Compound 50
19
Compound 52
20
Compound 54
21
Compound 56
22
Compound 59
23
Compound 61
24
Compound 63
25
Compound 65
28
Compound 71
29
Compound 73
30
Compound 75
31
Compound 79
32
Compound 78
33
Compound 83
34
Compound 84
35
Compound 92
36
Compound 97
37
Compound 99
38
Compound 104
39
Compound 105
40
Compound 110
41
Compound 113
42
Compound 116
43
Compound 117
44
Compound 121
45
Compound 129
46
Compound 132
47
Compound 135
48
Compound 137
49
Compound 141
50
Compound 143
51
Compound 145
52
Compound 147
53
Compound 150
54
Compound 153
55
Compound 158
56
Compound 160
57
Compound 161
58
Compound 162
59
Compound 163
60
Compound 165
61
Compound 167
63
Compound 171
64
Compound 173
65
Compound 175
66
Compound 177
67
Compound 180
68
Compound 181
69
Compound 183
or a pharmaceutically acceptable salt thereof.
15 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
16 . A method for applying treatment to a cornea of an eye, comprising:
administering a compound of claim 1 , or a pharmaceutically acceptable salt thereof, to the cornea of a subject in need thereof; and
applying an electromagnetic radiation to the cornea, thereby generating cross-linking in the cornea.
17 . The method according to claim 16 , wherein the method is used to treat one or more corneal ectatic disorders selected from the group consisting of keratoconus, keratoglobus, pellucid marginal degeneration, post-operative ectasia, and Terrien's marginal degeneration.
18 . The method according to claim 16 , wherein the electromagnetic radiation is selected from the group consisting of ultraviolet light and laser radiation.
19 . The method according to claim 16 , further comprising administering to the cornea an additional cross-linking agent; administering to the cornea one or more additives that are different from the cross-linking agent; administering to the cornea an additional ophthalmic therapeutic for inflammation, cataracts, or lens disorder and/or applying a selected concentration of oxygen to the eye, where the selected concentration is greater than a concentration of oxygen in atmosphere.
20 . The compound of claim 11 , wherein Y is selected from the group consisting of:
wherein R a is selected from —OH, —OMe, and —NMe 2 .