Bis(diazirine) derivatives as photo-crosslinker for treating corneal ectatic disorders

Patent metadata

Field	Value
Publication number	US-12344598-B2
Application number	US-202017424413-A
Country	US
Kind code	B2
Filing date	Jan 24, 2020
Priority date	Jan 25, 2019
Publication date	Jul 1, 2025
Grant date	Jul 1, 2025

Abstract

This disclosure features bis(diazirine) derivatives of the formulae (I) (1-a) or (1-b) that generate cross-linking in the cornea in response to exposure to an electromagnetic irradiation (e.g. UV-light). The compounds are useful, e.g. for treating a subject (e.g. a human) having a disease, disorder or condition 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. 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 examples of such diseases, disorders or conditions include keratoconus, keratoglobus, pellucid marginal degeneration, corneal ectasia (e.g. postoperative ectasia, e.g. post-LASIK ectasia), Terrien's marginal degeneration, myopia, hyperopia, astigmatism, irregular astigmatism and presbyopia. In some embodiments, the claimed methods can be performed in the absence of added or supplemental oxygen levels, which can be advantageous in some applications. Preferred exemplary compounds are e.g. bis(diazirine) amino acid derivatives, such as e.g. example 1 :

First claim

What is claimed is:

1. A compound of Formula II

or a pharmaceutically acceptable salt thereof,
wherein:
each of B 1 and B 2 is independently —Z 1 —Z 2 —Z 3 , wherein:
Z 1 is C 1-3 alkylene;
Z 2 is a bond; and
Z 3 is H;
each of E 1 and Q 1 is C 1 -C 6 alkylene, which is optionally substituted with 1-3 R a ;
each occurrence of R 2 is independently selected from the group consisting of:
(i) R a ;
(ii) C 1 -C 6 alkyl, which is substituted with 1-3 R a ;
(iii) L 2 -heterocyclyl, wherein the heterocyclyl includes from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N(R d ), O, and S; and wherein one or more of the heterocyclyl ring carbon atoms are optionally substituted with from 1-4 independently selected R b ,
(iv) L 2 -C 6 -C 10 aryl, which is optionally substituted with from 1-4 R c ;
(v) L 2 -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(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 c ; and
(vi) H; or
(vii) R 2 and R d1 , in the —C(═O)CH(R 2 )N(R d1 )— group, combine to form a ring including from 5-8 ring atoms, wherein the ring includes: (a) from 3-6 ring carbon atoms (in addition to CH(R 2 )), 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 d1 ), which are each independently selected from the group consisting of N(R d1 ), O, and S;
each occurrence of R a is independently selected from the group consisting of: —OH; —SH; —F; —Cl; —Br; —NR e R f ; C 1-4 alkoxy; C 1-4 haloalkoxy; —C(═O)O(C 1-4 alkyl); —C(═O)(C 1-4 alkyl); —C(═O)OH; —CON(R′)(R″); —S(O) 1-2 (NR′R″); —S(O) 0-2 (C 1-4 alkyl); cyano; —NR′C(═NR′)NR′R″; and C 3-6 cycloalkyl optionally substituted with from 1-4 independently selected R b ;
each occurrence of R b is independently selected from the group consisting of: —OH; —SH; —F; —Cl; —Br; —NR e R f ; C 1-4 alkyl; C 1-4 haloalkyl; C 1-4 alkoxy; C 1-4 haloalkoxy; —C(═O)O(C 1-4 alkyl); —C(═O)(C 1-4 alkyl); —C(═O)OH; —CON(R′)(R″); oxo; —S(O) 1-2 (NR′R″); —S(O) 0-2 (C 1-4 alkyl); cyano; —NR′C(═NR′)NR′R″; and C 3-6 cycloalkyl optionally substituted with from 1-4 independently selected C 1-4 alkyl;
each occurrence of R c is independently selected from the group consisting of: —OH; —SH; —F; —Cl; —Br; —NR e R f ; C 1-4 alkyl; C 1-4 haloalkyl; C 1-4 alkoxy; C 1-4 haloalkoxy; —C(═O)O(C 1-4 alkyl); —C(═O)(C 1-4 alkyl); —C(═O)OH; —CON(R′)(R″); —S(O) 1-2 (NR′R″); —S(O) 0-2 (C 1-4 alkyl); cyano; —NR′C(═NR′)NR′R″; and C 3-6 cycloalkyl optionally substituted with from 1-4 independently selected C 1-4 alkyl;
each occurrence of R d is selected from the group consisting of: H; C 1-6 alkyl; C 3-6 cycloalkyl; —C(O)(C 1-4 alkyl); —C(O)O(C 1-4 alkyl); —CON(R′)(R″); —S(O) 1-2 (NR′R″); —S(O) 1-2 (C 1-4 alkyl); —OH; and C 1-4 alkoxy;
each occurrence of R e and R f is independently selected from the group consisting of: H; C 1-6 alkyl; C 3-6 cycloalkyl; —C(O)(C 1-4 alkyl); —C(O)O(C 1-4 alkyl); —CON(R′)(R″); —S(O) 1-2 (NR′R″); —S(O) 1-2 (C 1-4 alkyl); —OH; and C 1-4 alkoxy; and
each occurrence of R′ and R″ is independently selected from the group consisting of: H and C 1-4 alkyl; or R′ and R″ 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′ and R″), which are each independently selected from the group consisting of N(R 4 ), O, and S;
each occurrence of R d1 is selected from the group consisting of: H, C 1-6 alkyl; C 3-6 cycloalkyl; —C(O)(C 1-4 alkyl); —C(O)O(C 1-4 alkyl); —CON(R′)(R″); —S(O) 1-2 (NR′R″); —S(O) 1-2 (C 1-4 alkyl); —OH; and C 1-4 alkoxy; or R 2 and R d1 , in the —C(═O)CH(R 2 )N(R d1 )— group, combine to form a ring including from 5-8 ring atoms as defined above;

each of L 2 in each occurrence is independently a single bond or a C 1 -C 6 alkylene optionally substituted with 1-3 substituents independently selected from oxo and R a ; and
F 1 is —N(R d1 )—, —O—, or —S—; and
each of H 1 , G 1 , L 1 , and M 1 is independently selected from:
a bond;
—N(R d1 )—,
—O—;
S(O) p , wherein p is 0, 1, or 2;
C(═O);
C(═S);
CHR 2 ;
—C(═O)CH(R 2 )N(R d1 )—; and
—C(═O)CH(R 2 )CH 2 N(R d1 )—.

2. The compound according to claim 1 , wherein each of L 1 and M 1 is a bond; each of G 1 and H 1 is a bond; and F 1 is —N(R 4 )— or —O—.

3. The compound according to claim 1 , wherein each occurrence of R 2 independently is selected from:
H;
C 1 -C 6 alkyl optionally substituted with 1-2 substituents selected from —NH 2 , —OH, —SH, —SMe, —NH(C═NH)NH 2 , CO 2 H, and CO 2 NH 2 ;
(C 1 -C 6 alkylene)-phenyl, optionally substituted with 1-2-OH;
(C 1 -C 6 alkylene)-indolyl; and
(C 1 -C 6 alkylene)-imidazolyl; or
R 2 and R d1 , in the —CH(R 2 )N(R d1 )— group, combine to form a pyrrolidine ring.

4. The compound according to claim 1 , wherein each of B 1 and B 2 is independently selected from CH 3 .

5. The compound according to claim 1 , wherein each occurrence of R d1 is H.

6. The compound according to claim 1 , wherein the compound is a compound of formula (II-a), Formula (II-c1), Formula (II-c2), Formula (II-d), or Formula (II-e):

or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1 , wherein each occurrence of R 2 is independently selected from:
H;

8. The compound according to claim 1 , wherein:
each of E 1 and Q 1 is independently C 1 -C 6 alkylene;
R 2 is independently selected from the group consisting of:
(i) C 1 -C 6 alkyl, which is substituted with 1 R a ; and
(ii) H;
R a is independently selected from the group consisting of: —C(═O)OH and —NR′C(═NR′)NR′R″;
each occurrence of R′ and R″ is H;
each occurrence of R d1 is H; and
each of H 1 , G 1 , L 1 , and M 1 is independently selected from:
a bond;
—C(═O)CH(R 2 )N(R d1 )—; and
—C(═O)CH(R 2 )CH 2 N(R d1 )—.

9. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

10. 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.

11. A compound of Formula (III):

or a pharmaceutically acceptable salt thereof,
wherein:
each of B 1 and B 2 is independently —Z 1 —Z 2 —Z 3 , wherein:
Z 1 is C 1-3 alkylene;
Z 2 is a bond; and
Z 3 is H;
each of E 1 , F 1 , H 1 , L 1 , M 1 , and Q 1 is independently selected from:
a bond; and
C 1 -C 6 alkylene;
provided that at least one of

Assignees

• Avedro Inc

Inventors

• Hill Jason
• Adler Desmond

Classifications

• C07D403/14

  containing three or more hetero rings · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D229/02 Primary

  containing three-membered rings · CPC title

• A61P27/10

  for accommodation disorders, e.g. myopia · CPC title

• A61P27/02

  Ophthalmic agents · CPC title