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Compounds and compositions for eye treatments

A compound and selected technology, applied in the direction of drug combination, compound of group 5/15 elements of the periodic table, treatment, etc., can solve the problem of weakening and reversing the expected effect of reshaping the cornea

Pending Publication Date: 2022-02-18
艾弗德罗股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Although the treatment may initially achieve the desired corneal remodeling, if the collagen fibrils within the cornea continue to change after the desired remodeling is achieved, the desired effect of remodeling the cornea may be attenuated or reversed, at least in part

Method used

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  • Compounds and compositions for eye treatments
  • Compounds and compositions for eye treatments
  • Compounds and compositions for eye treatments

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0802] In certain embodiments of [1]-[7], Z is as defined in claims 6-15.

[0803] In certain embodiments of [1]-[7], Z is as defined in claim 6.

[0804] In certain embodiments of [1]-[7], Z is as defined in claim 7 (i.e., Z is NR 4Z R 5Z ).

[0805] In some of these embodiments, R 4Z and R 5Z as defined in claim 8. In some of these embodiments, R 4Z and R 5Z as defined in claim 9. In some of these embodiments, R 4Z and R 5Z as defined in claim 10. In some of these embodiments, R 4Z and R 5Z as defined in claim 11. In some of the foregoing embodiments, when R 4Z and R 5Z each independently selected from H and when R a as defined in claim 12. In some embodiments of [1]-[7], R 4Z and R 5Z each independently selected from H and

[0806] In certain embodiments of [1]-[7], Z is NR 4Z R 5Z ; and R 4Z and R 5Z as defined in claim 14.

[0807] In certain embodiments of [1]-[7], Z is NR 4Z R 5Z ; and R 4Z and R 5Z as defined in claim 15.

[0808] In c...

Embodiment 1

[1136] To a suspension of compound (2) (1.5 g, 4.3 mmol) in 100 mL of MeOH was added neat SOCl dropwise at ambient temperature 2 (0.51 g, 4.3 mmol). The reaction mixture was stirred overnight at reflux and evaporated to dryness. The residue was passed through a pad of silica gel eluting with 20% MeOH in chloroform to afford 1.0 g of compound (3) (Example 1).

[1137] 1 H-NMR (DMSO-d 6 , δ, ppm): 2.30(s, 3H), 2.38(s, 3H), 3.41-3.49(m, 1H), 3.55-3.65(m, 3H), 4.07-4.14(m, 1H), 4.18(br .d, 1H, J = 14.0Hz), 4.47 (dd, 1H, J 1 =J 2 =5.8Hz), 4.59(dd,1H,J 1 = 3.6Hz,J 2 = 14.0 Hz), 4.72 (d, 1H, J = 5.8 Hz), 4.82 (d, 1H, J = 2.7 Hz), 4.97 (d, 1H, J = 4.3 Hz), 7.61 (br.s, 2H).

[1138] 13 C-NMR (DMSO-d 6 , δ, ppm): 18.63, 20.33, 44.50, 52.61, 63.51, 68.60, 72.76, 73.83, 116.26, 129.66, 129.96, 132.34, 132.68, 142.20, 147.65, 152.41, 164.54.

[1139] LCMS, m / z: 367.0 (M+H) + , 389.5 (M+Na) + .

[1140] Compound 4 (Example 5)

[1141] Compound (2) (2.5 g, 7.1 mmol) was susp...

Embodiment 2

[1161] Compound (9) (3.6 g, 7.7 mmol) was dissolved in MeCN (50 mL). The solution was purged with nitrogen, and Pd(PPh 3 ) 4 (0.89 g, 0.77 mmol), followed by addition of pyrrolidine (0.66 g, 9.2 mmol). After 16 hours at room temperature, MeCN was evaporated, EtOAc was added and the particles formed were filtered off and washed with EtOAc. The particles were dissolved in water and the pH was adjusted to 2 by adding 10% HCl. The particles formed were filtered off, washed with water and dried, yielding 1.56 g of compound (10) (Example 2).

[1162] 1 H-NMR (DMSO-d 6 , δ, ppm): 1.10 (dd, 6H, J 1 = 1.7Hz,J 2 =7.1Hz), 2.32(s, 3H), 2.40(s, 3H), 2.52-2.59(m, 1H), 3.60-3.62(m, 1H), 3.81-3.88(m, 1H), 4.02(dd, 6H,J 1 =7.0Hz,J 2 =10.9Hz), 4.10-4.12(m, 1H), 4.20-4.30(m, 2H), 4.58(dd, 6H, J 1 =10.2Hz,J 2 =13.7Hz), 4.82-4.89 (m, 1H), 5.12-5.23 (m, 2H), 7.60 (s, 1H), 7.65 (s, 1H), 13.98 (br.s, 1H).

[1163] 13 C-NMR (DMSO-d 6 , δ, ppm): 18.67, 18.91 (2×), 20.38, 33.31, 44.84, 66...

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Abstract

The 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. The disclosure also features compositions containing the chemical entities 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 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.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Provisional Application Serial No. 62 / 775,305, filed December 4, 2018, which is incorporated herein by reference in its entirety. technical field [0003] The disclosure features chemical entities (eg, compounds or pharmaceutically acceptable salts and / or hydrates and / or prodrugs of compounds) that produce crosslinks in the cornea in response to exposure to electromagnetic radiation. The disclosure also features compositions comprising the chemical entities and other methods of using and making the same. The chemical entity can be used, for example, to treat a subject (e.g., a human) suffering from a disease, disorder, or condition in which the abnormal shape of the cornea (e.g., corneal thinning, e.g., bilateral corneal thinning, e.g., central, paracentral, or peripheral cornea or corneal steepening (e.g., bulging)) leading to the pathology and / or symptoms and / or progression ...

Claims

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Application Information

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IPC IPC(8): A61K31/498C07D241/44C07D401/12C07D403/04C07D413/04C07D417/04A61P27/02
CPCC07D241/44C07D403/04C07D413/04C07D417/04C07D401/12A61K31/498A61K31/5377A61K31/519A61K9/0048A61K41/00A61P27/02A61P27/10A61N5/0613C07D403/14C07D401/14A61N2005/0661A61F9/0079A61F9/008A61K31/506A61K31/525A61K31/675A61K33/00A61K45/06C07F9/6524
Inventor J·希尔D·阿德勒M·D·弗里德曼P·卡梅弗E·谢尔
Owner 艾弗德罗股份有限公司
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