# US 10,117,950 B2 · Compounds and compositions for the treatment of ocular disorders

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- Number: US 10,117,950 B2
- Document ID: US10117950B2
- Status: Granted
- Kind: B2
- Application number: 15/782,749
- Filed: 2017-10-12
- Published: 2018-03-08
- Granted: 2018-11-06
- Earliest claimed: 2015-09-22
- Assignees: Graybug Vision, Inc.
- Applicants: Graybug Vision, Inc.
- Inventors: Jeffrey L. Cleland; Ming Yang; John G. Bauman; Nu Hoang; Emmett Cunningham
- Web page: https://patentgrep.com/patent/US10117950B2

## CPC

- A61K 47/59: obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K 47/54: the modifying agent being an organic compound
- A61K 47/542: {Carboxylic acids, e.g. a fatty acid or an amino acid}
- A61K 47/543: {Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine}
- A61K 47/55: the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug
- A61K 47/593: {Polyesters, e.g. PLGA or polylactide-co-glycolide}
- A61K 47/60: the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 27/02: Ophthalmic agents
- A61P 27/06: Antiglaucoma agents or miotics
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C 69/73: of unsaturated acids
- C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 495/04: Ortho-condensed systems
- C07D 513/04: Ortho-condensed systems
- C07C 2601/08: the ring being saturated
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The disclosure describes prodrugs and derivatives of prostaglandins, carbonic anhydrase inhibitors, kinase inhibitors, beta-adrenergic receptor antagonists and other drugs, as well as controlled delivery formulations containing such prodrugs and derivatives, for the treatment of ocular disorders.

## Claims

### Claim 1

A compound of Formula XV:
or a pharmaceutically acceptable salt thereof;
wherein:
R32 is R35;
R35 is selected from
R51 is
R15 is R17;
R17 is selected from H and —C(O)A;
A is selected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkyloxy, and alkyloxy; and
x and y are independently selected from an integer between 1 and 30.

### Claim 2 (depends on 1)

The compound of claim 1, wherein x and y are independently selected from 1, 2, 3, 4, 5, and 6.

### Claim 3 (depends on 2)

The compound of claim 2, wherein x is 1 and y is selected from 1, 2, 3, and 4.

### Claim 4 (depends on 2)

The compound of claim 2, wherein x is 2 and y is selected from 1, 2, 3, and 4.

### Claim 5 (depends on 3)

The compound of claim 3, wherein x is 1 and y is 3.

### Claim 6 (depends on 3)

The compound of claim 3, wherein x is 1 and y is 4.

### Claim 7 (depends on 1)

The compound of claim 1, wherein R15 is hydrogen.

### Claim 8 (depends on 1)

The compound of claim 1, wherein R35 is

### Claim 9 (depends on 8)

The compound of claim 8, wherein R15 is hydrogen.

### Claim 10 (depends on 9)

The compound of claim 9, wherein x and y are independently selected from 1, 2, 3, and 4.

### Claim 11 (depends on 10)

The compound of claim 10, wherein x is 1 or 2 and y is selected from 2, 3, and 4.

### Claim 12 (depends on 11)

The compound of claim 11, wherein x is 2 and y is 3.

### Claim 13 (depends on 11)

The compound of claim 11, wherein x is 2 and y is 4.

### Claim 14 (depends on 11)

The compound of claim 11, wherein x is 1 and y is 3.

### Claim 15 (depends on 11)

The compound of claim 11, wherein x is 1 and y is 4.

### Claim 16 (depends on 1)

The compound of claim 1, wherein R35 is

### Claim 17 (depends on 16)

The compound of claim 16, wherein R15 is hydrogen.

### Claim 18 (depends on 17)

The compound of claim 17, wherein x and y are independently selected from 1, 2, 3, and 4.

### Claim 19 (depends on 18)

The compound of claim 18, wherein x is 1 or 2 and y is selected from 2, 3, and 4.

### Claim 20 (depends on 19)

The compound of claim 19, wherein x is 2 and y is 3.

### Claim 21 (depends on 19)

The compound of claim 19, wherein x is 2 and y is 4.

### Claim 22 (depends on 19)

The compound of claim 19, wherein x is 1 and y is 3.

### Claim 23 (depends on 19)

The compound of claim 19, wherein x is 1 and y is 4.

### Claim 24 (depends on 1)

The compound of claim 1 of the formula
or a pharmaceutically acceptable salt thereof.

### Claim 25 (depends on 1)

The compound of claim 1 of the formula
or a pharmaceutically acceptable salt thereof.

### Claim 26 (depends on 1)

The compound of claim 1 of the formula
or a pharmaceutically acceptable salt thereof.

### Claim 27

The compound of formula
or a pharmaceutically acceptable salt thereof.

### Claim 28 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 in a pharmaceutically acceptable carrier.

### Claim 29 (depends on 24)

A pharmaceutical composition comprising a compound of claim 24 in a pharmaceutically acceptable carrier.

### Claim 30 (depends on 25)

A pharmaceutical composition comprising a compound of claim 25 in a pharmaceutically acceptable carrier.

### Claim 31 (depends on 26)

A pharmaceutical composition comprising a compound of claim 26 in a pharmaceutically acceptable carrier.

### Claim 32 (depends on 27)

A pharmaceutical composition comprising a compound of claim 27 in a pharmaceutically acceptable carrier.

### Claim 33 (depends on 1)

A method for the treatment of an ocular disorder treatable with both a tyrosine kinase inhibitor and a carbonic anhydrase inhibitor comprising administering a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof of claim 1 to a host in need thereof wherein the disorder is selected from glaucoma, age-related macular degeneration (AMD), a disorder related to an increase in intraocular pressure (IOP), a disorder related to neuroprotection, or diabetic retinopathy.

### Claim 34 (depends on 33)

The method of claim 33, wherein the host is a human.

### Claim 35 (depends on 34)

The method of claim 34, wherein the disorder is optic nerve damage caused by high intraocular pressure (IOP).

### Claim 36 (depends on 34)

The method of claim 34, wherein the compound is administered via intravitreal, intrastromal, intracameral, sub-tenon, sub-retinal, retro-bulbar, peribulbar, suprachoroidal, choroidal, subchoroidal, conjunctival, subconjunctival, episcleral, posterior juxtascleral, circumcorneal, or tear duct injection.

### Claim 37 (depends on 33)

The method of claim 33, wherein the compound is administered via intravitreal injection.

### Claim 38 (depends on 27)

A method for the treatment of an ocular disorder treatable with both a tyrosine kinase inhibitor and a carbonic anhydrase inhibitor comprising administering a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof of claim 27 to a host in need thereof wherein the disorder is selected from glaucoma, age-related macular degeneration (AMD), a disorder related to an increase in intraocular pressure (IOP), a disorder related to neuroprotection, or diabetic retinopathy.

### Claim 39 (depends on 38)

The method of claim 38, wherein the host is a human.

### Claim 40 (depends on 39)

The method of claim 39, wherein the disorder is optic nerve damage caused by high intraocular pressure (IOP).

### Claim 41 (depends on 39)

The method of claim 39, wherein the compound is administered via intravitreal, intrastromal, intracameral, sub-tenon, sub-retinal, retro-bulbar, peribulbar, suprachoroidal, choroidal, subchoroidal, conjunctival, subconjunctival, episcleral, posterior juxtascleral, circumcorneal, or tear duct injection.

### Claim 42 (depends on 38)

The method of claim 38, wherein the compound is administered via intravitreal injection.

### Claim 43 (depends on 34)

The method according to claim 34, wherein the disorder is glaucoma.

### Claim 44 (depends on 34)

The method according to claim 34, wherein the disorder is related to an increase in intraocular pressure (IOP).

### Claim 45 (depends on 34)

The method according to claim 34, wherein the disorder is related to neuroprotection.

### Claim 46 (depends on 39)

The method according to claim 39, wherein the disorder is glaucoma.

### Claim 47 (depends on 39)

The method according to claim 39, wherein the disorder is related to an increase in intraocular pressure (IOP).

### Claim 48 (depends on 39)

The method according to claim 39, wherein the disorder is related to neuroprotection.