# US 11,028,081 B2 · Dual mechanism inhibitors for the treatment of disease

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- Number: US 11,028,081 B2
- Document ID: US11028081B2
- Status: Granted
- Kind: B2
- Application number: 16/730,058
- Filed: 2019-12-30
- Published: 2020-04-30
- Granted: 2021-06-08
- Earliest claimed: 2009-05-01
- Assignees: Aerie Pharmaceuticals, Inc.
- Applicants: Aerie Pharmaceuticals, Inc.
- Inventors: Mitchell A. deLong; Jill Marie Sturdivant; Susan M. Royalty
- Web page: https://patentgrep.com/patent/US11028081B2

## CPC

- C07D 417/12: linked by a chain containing hetero atoms as chain links
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 9/00: Drugs for disorders of the cardiovascular system
- 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 9/12: Antihypertensives
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/02: Nasal agents, e.g. decongestants
- A61P 13/10: of the bladder
- A61P 13/12: of the kidneys
- A61P 15/18: Feminine contraceptives
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/14: for baldness or alopecia
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 27/00: Drugs for disorders of the senses
- A61P 27/02: Ophthalmic agents
- A61P 27/04: Artificial tears; Irrigation solutions
- A61P 27/06: Antiglaucoma agents or miotics
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C 237/20: the carbon skeleton containing six-membered aromatic rings
- C07C 237/42: having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
- C07D 217/00: Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D 217/02: with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D 217/04: with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
- C07D 217/22: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D 217/24: Oxygen atoms
- C07D 333/38: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 333/40: Thiophene-2-carboxylic acid
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07C 2601/08: the ring being saturated
- C07C 2601/14: The ring being saturated
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

Provided are compounds that are inhibitors of both rho kinase and of a monoamine transporter (MAT) act to improve the disease state or condition. Further provided are compositions comprising the compounds. Further provided are methods for treating diseases or conditions, the methods comprising administering compounds according to the invention. One such disease may be glaucoma for which, among other beneficial effects, a marked reduction in intraocular pressure (IOP) may be achieved.

## Claims

### Claim 1

A method of treating glaucoma or ocular hypertension, comprising administration of a composition comprising a Rho kinase inhibitor and a pharmaceutically acceptable carrier to a subject in need thereof,
wherein the administration is daily administration, weekly administration, or monthly administration,
wherein the Rho kinase inhibitor is:
or a pharmaceutically acceptable salt thereof,
wherein
R1, R2, and R3 are independently hydrogen, C1-C4 alkyl, aryl, C1-C4 alkyl aryl, C1-C4 alkyl heteroaryl, C1-C4 alkyl heterocyclyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 carbonyl, C1-C4 carbonylamino, C1-C4 alkoxy, C1-C4 sulfonyl, C1-C4 sulfonylamino, C1-C4 thioalkyl, C1-C4 carboxyl, or form a ring with each other or with A;
A is C1-C4 alkyl, C1-C4 alkyl aryl, C1-C4 alkyl heteroaryl, or forms a ring structure with R1, R2 or R3;
B is hydrogen, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, C1-C22 alkyl, C1-C22 alkyl aryl, C1-C22 alkyl heteroaryl, C2-C22 alkenyl, C2-C22 alkynyl, C1-C22 carbonyl, C1-C22 carbonylamino, C1-C22 alkoxy, C1-C22 sulfonyl, C1-C22 sulfonylamino, C1-C22 thioalkyl, or C1-C22 carboxyl;
X1, X2, and X3 are, independently, hydrogen, hydroxyl, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, aminocarbonyl, nitro, cyano, C1-C4 carbonyl, C1-C4 carbonylamino, C1-C4 alkoxy, C1-C4 sulfonyl, C1-C4 sulfonylamino, C1-C4 thioalkyl, or C1-C4 carboxyl;
the double circle
indicates an aromatic or heteroaromatic ring; and
each Z is independently a bond, is C1-C4 alkyl, heteroalkyl, or an O atom.

### Claim 2 (depends on 1)

The method of claim 1, wherein the administration is ocular administration.

### Claim 3 (depends on 1)

The method of claim 1, wherein the amount of the compound administered is about 0.001 to about 100 mg/kg subject body weight.

### Claim 4 (depends on 1)

The method of claim 1, wherein the administration is daily administration once daily, twice per day, or 4 times per day.

### Claim 5 (depends on 2)

The method of claim 2, wherein the administration is daily administration once daily, twice per day, or 4 times per day.

### Claim 6 (depends on 3)

The method of claim 3, wherein the administration is daily administration once daily, twice per day, or 4 times per day.

### Claim 7 (depends on 1)

The method of claim 1, wherein the administration is weekly administration once weekly or twice weekly.

### Claim 8 (depends on 2)

The method of claim 2, wherein the administration is weekly administration once weekly or twice weekly.

### Claim 9 (depends on 3)

The method of claim 3, wherein the administration is weekly administration once weekly or twice weekly.

### Claim 10 (depends on 1)

The method of claim 1, wherein the administration is monthly administration once a month.

### Claim 11 (depends on 2)

The method of claim 2, wherein the administration is monthly administration once a month.

### Claim 12 (depends on 3)

The method of claim 3, wherein the administration is monthly administration once a month.

### Claim 13

A method of treating glaucoma or ocular hypertension, comprising administration of a composition comprising a Rho kinase inhibitor and a pharmaceutically acceptable carrier to a subject in need thereof,
wherein the administration is daily administration, weekly administration, or monthly administration,
wherein the Rho kinase inhibitor is:
or a pharmaceutically acceptable salt thereof.

### Claim 14 (depends on 13)

The method of claim 13, wherein the administration is ocular administration.

### Claim 15 (depends on 13)

The method of claim 13, wherein the amount of the compound administered is about 0.001 to about 100 mg/kg subject body weight.

### Claim 16 (depends on 13)

The method of claim 13, wherein the administration is daily administration once daily, twice per day, or 4 times per day.

### Claim 17 (depends on 14)

The method of claim 14, wherein the administration is daily administration once daily, twice per day, or 4 times per day.

### Claim 18 (depends on 15)

The method of claim 15, wherein the administration is daily administration once daily, twice per day, or 4 times per day.

### Claim 19 (depends on 13)

The method of claim 13, wherein the administration is weekly administration once weekly or twice weekly.

### Claim 20 (depends on 14)

The method of claim 14, wherein the administration is weekly administration once weekly or twice weekly.

### Claim 21 (depends on 15)

The method of claim 15, wherein the administration is weekly administration once weekly or twice weekly.

### Claim 22 (depends on 13)

The method of claim 13, wherein the administration is monthly administration once a month.

### Claim 23 (depends on 14)

The method of claim 14, wherein the administration is monthly administration once a month.

### Claim 24 (depends on 15)

The method of claim 15, wherein the administration is monthly administration once a month.