US 12,673,925 B2 · Compounds and compositions for eye treatments

Abstract

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.

A compound having formula (I):

or a pharmaceutically acceptable salt thereof;
wherein:
X is C1-C6 alkyl;
Y is selected from the group consisting of:
(i) C(O)NR4YR5Y;
(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(Rd), O, and S, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-2 independently selected Rc;
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(R4), O, and S, and wherein one or more of the heterocycloalkenyl ring carbon atoms are optionally substituted with from 1-2 independently selected Rb;
Z is selected from the group consisting of:
(i) H,
(ii) NR4ZR5Z,
(iii) OR6Z,
(iv) OC(O)R7Z,
(v) OP(O)OR8ZOR9Z, 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(Rd), and O, and wherein one or more of the heterocyclyl ring carbon atoms are optionally substituted with from 1-4 independently selected Rh;
each Zx is H;
or each Zx together with the carbon to which each is attached forms C═O;
each of R1, R2, and R3 is R6A;
ach of R4Y and R5Y is independently selected from the group consisting of:
(i) H;
(ii) C1-12 alkyl, which is optionally substituted with 1-6 Ra;
(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(Rd), O, and S, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected Rh;
(iv) —(W1—W2)n—W3, wherein:
W1 is in each occurrence is independently C1-3 alkylene optionally substituted with from 1-4 Ra;
W2 is in each occurrence independently —N(H)—, —N(Rd)—, —O—, or —S—;
W3 is H or C1-7 alkyl optionally substituted with from 1-4 Ra;
and
n is 2-4;
and
(v) R4Y and R5Y 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 C1-3 alkyl;
and (b) from 0-3 ring heteroatoms in addition to the nitrogen atom attached to R4Y and R5Y, which are each independently selected from the group consisting of N(H), N(Rd), O, and S;
each of R4Z and R5Z is independently selected from the group consisting of:
(i) H;
and
(ii) C1-10 alkyl optionally substituted with 1-6 independently selected Ra;
R6A in each occurrence is H;
R6Z is independently selected from the group consisting of:
(i) H;
(ii) C1-10 alkyl optionally substituted with from 1-6 independently selected Ra;
(iii) —(C0-2 alkylene)-(C6-10 aryl), wherein the C6-10 aryl is optionally substituted with from 1-2 independently selected Rh;
(iv) —(C0-2 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(C1-3 alkyl), O, and S, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected Rh, and
(v) —(C1-2 alkylene)-C(═O)NH—(C1-3 alkylene)-R6Z′;
R6Z′ is selected from the group consisting of:
C(═O)OH, N(C1-4 alkyl)2, NH2, NH(C1-4 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(Rd), and O, and wherein one or more of the heterocyclyl ring carbon atoms are optionally substituted with from 1-4 independently selected C1-3 alkyl;
each of R7Z at each occurrence, is independently C1-10 alkyl optionally substituted with from 1-6 independently selected Ra;
each of R8Z and R9Z in each occurrence is H;
each occurrence of Ra is independently selected from the group consisting of:
—OH;
NReRf;
C1-4 alkoxy;
—C(═O)OH;
—CON(R′)(R″);
C(═NH)N(R′)(R″);
each occurrence of Rb is C1-6 alkyl;
each occurrence of Rc is independently selected from the group consisting of:
(i) C1-10 alkyl;
(ii) C1-10 alkyl substituted with from 1-6 independently selected Ra;
(iii) —NReRf,
(iv) —C(═O)OH;
and
(v) —C(═O)N(R′)(R″);
Rd is C1-6 alkyl optionally substituted with from 1-3 independently selected Rg;
each occurrence of Re and Rf is independently selected from the group consisting of:
H and C1-6 alkyl;
or Re and Rf 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 C1-3 alkyl;
and (b) from 0-3 ring heteroatoms in addition to the nitrogen atom attached to Re and Rf, which are each independently selected from the group consisting of N(H), N(Rd), O, and S;
each occurrence of Rh is C1-3 alkyl;
and
each occurrence of R′ and R″ is H;
with the proviso that the compound is not:

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Compounds and compositions for eye treatments

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Compounds and compositions for eye treatments

Life of this patent

Abstract

Claims20