Compounds and methods for treating eye disorders

Abstract

The present invention provides compositions and methods for treating ocular surface disorders, including meibomian gland dysfunction, blepharitis, dry eye diseases, and other inflammatory / infectious diseases of the anterior surface of the eye. [Solution] A pharmaceutical composition for eye drops or dermatological use is provided, comprising a compound having the structure of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof. JPEG2026102607000083.jpg6966

Claims

1. A compound having the structure of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, 【Chemistry 1】 During the ceremony, Each R is independently H, R', a substituted or unsubstituted alkyl, or a substituted or unsubstituted heteroalkyl, and at least one R is R'. R' is D-L-, D is a keratolytic agent, L is a linker compound, or a pharmaceutically acceptable salt or solvate thereof.

2. A compound having the structure of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, 【Chemistry 2】 During the ceremony, R' is D-L-, D is a keratolytic agent, L is a linker compound, or a pharmaceutically acceptable salt or solvate thereof.

3. The compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt or solvate thereof, wherein L comprises one or more linker groups, each linker group selected from the group consisting of single bond, -O-, alkyl (alkylenyl), heteroalkyl (heteroalkylenyl), ester, and carbonyl (>C=O).

4. The keratolytic agent comprises one or more groups (for example, keratolytic groups such as groups that impart keratolytic activity), each group being selected from the group consisting of thiols, disulfides, selenium (e.g., selenides, diselenides), and carboxylic acids, and is a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate thereof, wherein R' is an alkyl or heteroalkyl compound substituted with at least one oxo, and is further optionally substituted.

6. R' is 【Transformation 3】 And, During the ceremony, m is 1 to 6, R ８ and R ９ Each of these is independently H, halo, alkoxy, alkyl, heteroalkyl, or haloalkyl, R １０ The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, wherein is H, -OH, alkyl, heteroalkyl, or aryl, and the alkyl, heteroalkyl, or aryl is optionally substituted.

7. The aforementioned R １０ The compound according to claim 6, or a pharmaceutically acceptable salt or solvate thereof, wherein the alkyl or heteroalkyl of is substituted with one or more substituents, each substituent independently selected from the group consisting of alkyl, heteroalkyl, hydroxyl, thiol, thioether, disulfide, seleno, seleno, sulfone, amide, ester, halo, oxo, heterocyclyl, and cycloalkyl, and the heterocyclyl and cycloalkyl (for example, by one or more substituents selected from the group consisting of alkyl, heteroalkyl, hydroxyl, thiol, thioether, disulfide, seleno, sulfone, amide, halo, and oxo) are optionally substituted.

8. R'は、-C(O)CH ２ OH、-C(O)CH(CH ３ )OH、-C(O)CH ２ (OCH) ２ CH ２ ) ４ OH、-C(O)CH ２ CH ２ (OCH) ２ CH ２ ) ４ Oh, 【Chemistry 4】 A compound according to any one of claims 1 to 7, selected from the group consisting of the above, or a pharmaceutically acceptable salt or solvate thereof.

9. R' is -C(O)CH(R １ ) (Caution ２ ) and R １ is H, -OH, optionally substituted -O-C(O)alkyl, optionally substituted phenyl, -X(OCH) ２ CH ２ ) ｎ OR ３ , or optionally substituted alkyl-heterocyclines, R ２ is H or C １ -C ４ It is alkyl, X is replaced by C by direct joining or optional substitution. １ -C ３ It is alkylene, R ３ is H, or C which is optionally replaced. １ -C ３ It is alkyl, and A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 to 20.

10. R １ The compound according to claim 9, or a pharmaceutically acceptable salt or solvate thereof, wherein the heterocyclyl is an alkyl-heterocyclyl, the heterocyclyl comprising a disulfide in its cyclic structure.

11. The compound according to claim 10, or a pharmaceutically acceptable salt or solvate thereof, wherein the heterocyclyl is dithiolane.

12. R １ but 【Transformation 5】 The compound according to claim 11, or a pharmaceutically acceptable salt or solvate thereof.

13. R １ The compound according to claim 9, wherein the hyphen is -OH, or a pharmaceutically acceptable salt or solvate thereof.

14. R １ The compound according to claim 9, or a pharmaceutically acceptable salt or solvate thereof, wherein is optionally substituted with phenyl.

15. R １ is -X(OCH) ２ CH ２ ) ｎ OR ３ The compound according to claim 9, or a pharmaceutically acceptable salt or solvate thereof.

16. The compound according to claim 15, or a pharmaceutically acceptable salt or solvate thereof, wherein X is a direct bond.

17. X is replaced by C of any choice. １ -C ３ The compound according to claim 15, which is an alkylene, or a pharmaceutically acceptable salt or solvate thereof.

18. R ３ A compound according to any one of claims 15 to 17, wherein is hydrogen, or a pharmaceutically acceptable salt or solvate thereof.

19. R ３ C is replaced by an optional substitution. １ -C ３ A compound according to any one of claims 15 to 17, which is alkyl, or a pharmaceutically acceptable salt or solvate thereof.

20. A compound according to any one of claims 15 to 19, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 4.

21. R ２ A compound according to any one of claims 9 to 20, wherein is H, or a pharmaceutically acceptable salt or solvate thereof.

22. R ２ C １ -C ４ A compound according to any one of claims 9 to 20, which is alkyl, or a pharmaceutically acceptable salt or solvate thereof.

23. R ２ CH ３ The compound according to claim 22, or a pharmaceutically acceptable salt or solvate thereof.

24. (2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl 2-hydroxyacetate, (2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl(R)-2-hydroxypropanoate, (2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl2-(4-methoxyphenyl)acetate, (2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl14-hydroxy-3,6,9,12-tetraoxatetradecanoate, and (2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl1-hydroxy-3,6,9,12-tetraoxapentadecane-15-oate A compound selected from the group consisting of the above, or a pharmaceutically acceptable salt or solvate thereof. 【Request Item 25】 【Chemistry 6】 A compound selected from the group consisting of the above, or a pharmaceutically acceptable salt or solvate thereof.

26. A pharmaceutical composition comprising a compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient (e.g., a carrier or solvent).

27. The pharmaceutical composition according to claim 26, which is suitable for ocular administration.

28. A pharmaceutical composition according to any one of claims 26 to 27, suitable for topical ocular administration.

29. A method for treating a disease or disorder of an individual (e.g., an eye disease), comprising the step of administering to the individual a composition comprising a compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof.

30. The aforementioned eye diseases or disorders include inflammatory diseases of the eyelids (e.g., styes, blepharitis, lid wiper corneal epitheliopathy, and chalazion), the ocular surface (e.g., dry eye diseases including evaporative dry eye syndrome and dehydrative dry eye syndrome, and anterior uveitis), and / or the posterior part of the eye (e.g., posterior and panuveitis), abnormalities of the periocular glands (e.g., meibomian gland dysfunction (MGD) and lacrimal gland disorders), allergic diseases (e.g., eczema, atopic dermatitis, atopic keratoconjunctivitis resistant to topical steroids, and vernal keratoconjunctivitis), parasitic infections (e.g., Demodex mite eyelid infection), and surgical complications (e.g., corneal keratoconjunctivitis). The method according to claim 29, which is selected from disorders including membrane transplant rejection, post-corneal transplant glaucoma, cataract associated with phakic corneal transplantation, fungal infections in corneal transplant patients, and post-LASIK dry eye and / or low refractive outcome), corneal abnormalities (e.g., inflammatory corneal ulcer, rheumatic corneal ulcer, contact lens discomfort, Thygeson punctate superficial keratitis, and common keratitis), conjunctival abnormalities (e.g., iridocyclitis, lignite conjunctivitis), ocular complications due to systemic therapy and / or autoimmune diseases (e.g., minor-joint juvenile rheumatoid arthritis, graft-versus-host disease, and Sjögren's syndrome), and / or infections of the anterior surface of the eye.

31. The method according to claim 29, wherein the skin disease or disorder is selected from disorders including inflammatory skin diseases (e.g., dermatitis (eczema), rosacea, seborrheic dermatitis, and psoriasis), hyperkeratosis of the skin (e.g., keratosis pilaris, acne comedones, and basal hyperkeratosis), parasitic disorders (e.g., demodex mite-associated rosacea, acne, and herpes zoster), allergies (e.g., urticaria, contact dermatitis, and diaper rash), injuries (e.g., sunburn), and / or autoimmune diseases (e.g., vitiligo).

32. A compound having the structure of formula (II), or a pharmaceutically acceptable salt or solvate thereof, 【Transformation 7】 During the ceremony, Z is -O- or -(CR ８ R ９ ) ｍ - and m is 1 to 6, R ８ and R ９ Each of these is independently H, halo, alkoxy, alkyl, heteroalkyl, or haloalkyl, R １０ is a compound in which the alkyl, heteroalkyl, heteroalkyl, -O(C=O) heteroalkyl, -O(C=O) alkyl, or aryl is optionally substituted, or a pharmaceutically acceptable salt or solvate thereof.

33. Z is -CR ８ R ９ - The compound according to claim 32, or a pharmaceutically acceptable salt or solvate thereof.

34. R ８ is H or methyl, R ９ A compound according to any one of claims 32 to 33, or a pharmaceutically acceptable salt or solvate thereof, wherein is H.

35. R １０ The compound according to any one of claims 32 to 34, or a pharmaceutically acceptable salt or solvate thereof, wherein is -OH, alkyl (e.g., methyl), heteroalkyl, -O(C=O)alkyl, or aryl, and the alkyl of the alkyl, heteroalkyl, aryl, or -O(C=O)alkyl is substituted with one or more substituents, each substituent independently selected from the group consisting of -OH, alkyl (e.g., alkylene), oxo, halo, alkoxy, alkylamide, thiol, and heterocycle, and each of the alkyl, alkoxy, alkylamide, or heterocycle is independently optionally substituted.

36. R １０ is an -O(C=O)alkylene, wherein the alkylene is substituted with one or more substituents, each substituent independently being methyl, -SH, -OH, or -NHCOCH ３ A compound according to any one of claims 32 to 35, selected from the group consisting of the above, or a pharmaceutically acceptable salt or solvate thereof.

37. R １０ The compound according to any one of claims 32 to 36, or a pharmaceutically acceptable salt or solvate thereof, wherein the aryl is substituted with methoxy.

38. R １０ is an alkyl or heteroalkyl group, wherein the alkyl or heteroalkyl group is substituted with one or more substituents, each substituent independently being -OH, alkoxy (e.g., OCH) ２ CH ２ A compound according to any one of claims 32 to 37, selected from the group consisting of ), and heterocycloalkyls (e.g., dithiolanes), or a pharmaceutically acceptable salt or solvate thereof.

39. R １０ は-OH、-(OCH ２ CH ２ ) ４ OH、-H ２ (OCH) ２ CH ２ ) ４ OH、-(C=O)CH ３ 、 【Transformation 8】 The compound according to any one of claims 32 to 38, or a pharmaceutically acceptable salt or solvate thereof.

40. The compound according to claim 32, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is -O-.

41. R １０ teeth 【Chemistry 9】 The compound according to claim 40, or a pharmaceutically acceptable salt or solvate thereof.

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