# US 10,188,641 B2 · Compositions and methods for treatment

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- Number: US 10,188,641 B2
- Document ID: US10188641B2
- Status: Granted
- Kind: B2
- Application number: 14/045,159
- Filed: 2013-10-03
- Published: 2014-06-12
- Granted: 2019-01-29
- Earliest claimed: 2005-05-17
- Assignees: Sarcode Bioscience Inc.
- Applicants: Sarcode Bioscience Inc.
- Inventors: Thomas Gadek; John Burnier
- Web page: https://patentgrep.com/patent/US10188641B2

## CPC

- A61K 31/4725: containing further heterocyclic rings
- A61B 3/101: {for examining the tear film}
- A61B 3/145: {by video means}
- A61K 9/0014: {Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00)}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/0043: {Nose}
- A61K 9/0048: {Eye, e.g. artificial tears}
- A61K 9/0051: {Ocular inserts or implants}
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 31/197: the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid (carnitine A61K31/205)
- A61K 31/198: Alpha-amino acids, e.g. alanine or edetic acid [EDTA] (betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00)
- A61K 31/275: Nitriles; Isonitriles
- A61K 31/341: not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
- A61K 31/381: having five-membered rings
- A61K 31/40: having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K 31/404: Indoles, e.g. pindolol
- A61K 31/405: Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
- A61K 31/4162: condensed with heterocyclic ring systems
- A61K 31/4184: condensed with carbocyclic rings, e.g. benzimidazoles
- A61K 31/4192: 1,2,3-Triazoles
- A61K 31/44: Non condensed pyridines; Hydrogenated derivatives thereof
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 31/472: Non-condensed isoquinolines, e.g. papaverine
- A61K 31/4745: condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48)
- A61K 31/495: having six-membered rings with two {or more} nitrogen atoms as the only ring heteroatoms, e.g. piperazine {or tetrazines}(A61K31/48 takes precedence {; with three nitrogen atoms A61K31/53})
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/517: ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/54: having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K 31/541: Non-condensed thiazines containing further heterocyclic rings
- A61K 33/00: Medicinal preparations containing inorganic active ingredients
- A61K 33/06: Aluminium, calcium or magnesium; Compounds thereof {, e.g. clay}
- A61K 38/07: Tetrapeptides
- A61K 38/08: Peptides having 5 to 11 amino acids {(A61K38/043 - A61K38/046 take precedence)}
- A61K 38/12: Cyclic peptides {, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C (A61K38/043 - A61K38/046 take precedence)}
- A61K 38/1703: {from vertebrates}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 11/06: Antiasthmatics
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 27/00: Drugs for disorders of the senses
- A61P 27/02: Ophthalmic agents
- A61P 27/04: Artificial tears; Irrigation solutions
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C 279/28: having nitrogen atoms of guanidine groups bound to cyano groups, e.g. cyanoguanidines, dicyandiamides
- C07C 317/50: at least one of the nitrogen atoms being part of any of the groups [IMAGE cpc-sch-C07C-0976.gif], X being a hetero atom, Y being any atom
- C07D 207/06: with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
- 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 217/06: with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
- C07D 217/20: with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine
- C07D 217/26: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D 307/52: Radicals substituted by nitrogen atoms not forming part of a nitro radical
- 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 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 405/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 405/14: containing three or more hetero rings
- C07D 409/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- G01N 33/5011: {for testing antineoplastic activity}
- G01N 33/5032: {on intercellular interactions}
- G01N 33/5047: {Cells of the immune system}
- G01N 33/566: using specific carrier or receptor proteins as ligand binding reagents {where possible specific carrier or receptor proteins are classified with their target compounds}
- G01N 33/6872: {Intracellular protein regulatory factors and their receptors, e.g. including ion channels}
- G01N 2333/705: Assays involving receptors, cell surface antigens or cell surface determinants
- G01N 2333/70525: ICAM molecules, e.g. CD50, CD54, CD102
- G01N 2333/70546: Integrin superfamily, e.g. VLAs, leuCAM, GPIIb/GPIIIa, LPAM
- G01N 2500/02: Screening involving studying the effect of compounds C on the interaction between interacting molecules A and B (e.g. A = enzyme and B = substrate for A, or A = receptor and B = ligand for the receptor)
- G01N 2500/04: Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
- G01N 2500/10: involving cells
- G01N 2500/20: cell-free systems
- G01N 2800/16: Ophthalmology
- 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)
- A61B: DIAGNOSIS; SURGERY; IDENTIFICATION (usefulness limited to only animals A61D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

The present invention provides compounds and methods for the treatment of LFA-1 mediated diseases. In particular, LFA-1 antagonists are described herein and these antagonists are used in the treatment of LFA-1 mediated diseases. One aspect of the invention provides for diagnosis of an LFA-1 mediated disease and administration of a LFA-1 antagonist, after the patient is diagnosed with a LFA-1 mediated disease. In some embodiments, the LFA-1 mediated diseases treated are dry eye disorders. Also provided herein are methods for identifying compounds which are LFA-1 antagonists.

## Claims

### Claim 1

A method of treating dry eye disease in a subject in need thereof comprising administering to the subject an effective amount of a lymphocyte function associated antigen-1 (LFA-1) antagonist or a pharmaceutically acceptable salt or ester thereof, wherein the LFA-1 antagonist is

### Claim 2 (depends on 1)

The method of claim 1, wherein the subject does not have Sjogren's syndrome.

### Claim 3 (depends on 1)

The method of claim 1, where the subject has Sjogren's syndrome.

### Claim 4 (depends on 1)

The method of claim 1, wherein the administering comprises topical administration of the LFA-1 antagonist to the outer surface of the eyelid, lacrimal tissues, conjunctival tissue or ocular surface of the eye via a carrier vehicle selected from the group consisting of liquid drops, liquid wash, gel, ointment, spray, and liposome.

### Claim 5 (depends on 4)

The method of claim 4, wherein the topical administration comprises infusion of the LFA-1 antagonist to an eye of the subject via a device selected from the group consisting of a pump-catheter system, a continuous or selective release system, and a contact lens.

### Claim 6 (depends on 1)

The method of claim 1, wherein the administering involves systemically administering a liquid or liquid suspension of the LFA-1 antagonist via nose drops of nasal spray or nebulized liquid to oral or nasopharylngeal airways of the subject, such that an effective amount of the LFA-1 antagonist contacts one or more of a lacrimal gland, conjunctival tissue, tears, or ocular surface of an eye of the subject.

### Claim 7 (depends on 1)

The method of claim 1, wherein the administering involves administering an oral form of the LFA-1 antagonist, such that an effective amount of the LFA-1 antagonist contacts one or more of the lacrimal gland, conjunctival tissue, tears, or ocular surface of the eye of the subject via systemic absorption and circulation.

### Claim 8 (depends on 1)

The method of claim 1, wherein the administering is accomplished by administering an injectable form of the LFA-1 antagonist, such that an effective amount of the LFA-1 antagonist contacts one or more of the lacrimal tissues, conjunctival tissue, tears, or ocular surface of the eye of the subject via systemic absorption and circulation.

### Claim 9 (depends on 1)

The method of claim 1, wherein the administering is accomplished by administering a suppository form of the LFA-1 antagonist, such that an effective amount of the LFA-1 antagonist contacts one or more of the lacrimal tissues, conjunctival tissue, tears, or ocular surface of the eye of the subject via systemic absorption and circulation.

### Claim 10 (depends on 1)

The method of claim 1, wherein the administering is accomplished by administering an intraocular instillation of a gel, cream, powder, foam, crystals, liposomes, spray or liquid suspension form of the LFA-1 antagonist.

### Claim 11 (depends on 1)

The method of claim 1, wherein the LFA-1 antagonist is administered to the ocular surfaces of the subject in an amount sufficient to achieve concentrations thereof of from about 1×10−7 to about 1×10−1 moles/liter.

### Claim 12 (depends on 1)

The method of claim 1, wherein the administering is via a sustained release insert or implant, subconjunctival injection, intraocular injection, periocular injection, retrobulbar injection, or intracameral injection.

### Claim 13 (depends on 1)

The method of claim 1, wherein the administering involves delivery of a liquid or liquid suspension of the LFA-1 antagonist via nose drops or nasal spray or nebulized liquid to oral or nasopharyngeal airways of the subject, such that an effective amount of said compound contacts one or more of the lacrimal gland, conjunctival tissue, or ocular surface of the eye of the LFA-1 antagonist via nasolacrimal ducts.

### Claim 14 (depends on 1)

The method of claim 1, wherein the administering is accomplished by administering an injectable form of the LFA-1 antagonist, such that a therapeutically effective amount of the LFA-1 antagonist contacts one or more of the lacrimal tissues, conjunctival tissue or ocular surface of the eye of the subject via local delivery.

### Claim 15 (depends on 5)

The method of claim 5, wherein the continuous or selective release device is an ocular insert or implant.

### Claim 16 (depends on 1)

The method of claim 1, wherein an effective amount of the LFA-1 antagonist is distributed regionally to one or more of a nose, nasal passages, and nasal cavity of the subject.

### Claim 17 (depends on 1)

The method of claim 1, wherein the administering comprises controlled release of the LFA-1 antagonist from a biocompatible polymer.

### Claim 18

A method of treating dry eye disorder in a subject in need thereof comprising administering to an eye of the subject an effective amount of a pharmaceutical composition comprising a LFA-1 antagonist or a pharmaceutically acceptable salt or ester thereof, wherein the LFA-1 antagonist is
and whereby the administering is effective in promoting tear secretion or mucin production in said eyes in said subject.

### Claim 19

A method of treating dry eye disease in a subject comprising performing a dry eye diagnostic test on the subject; determining whether the subject suffers from a dry eye disease based on the results of the diagnostic step; and upon diagnosis of the dry eye disease, administering to the subject an effective amount of a LFA-1 antagonist or a pharmaceutically acceptable salt or ester thereof, wherein the LFA-1 antagonist is

### Claim 20

A method of treating dry eye disorder in a subject in need thereof comprising administering to an eye of the subject a therapeutically effective amount of a pharmaceutical composition comprising an LFA-1 antagonist and/or its pharmaceutically acceptable salts or ester, wherein said LFA-1 antagonist is
wherein the administering comprising administering the LFA-1 antagonist in liquid drops topically to a surface of the subject's eyes.