# US 8,771,715 B2 · Compositions and methods for treatment

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- Number: US 8,771,715 B2
- Document ID: US8771715B2
- Status: Granted
- Kind: B2
- Application number: 13/011,760
- Filed: 2011-01-21
- Published: 2011-07-07
- Granted: 2014-07-08
- Earliest claimed: 2005-05-17
- Assignees: Sarcode Bioscience Inc.
- Applicants: Johan Oslob; Wang Shen; Kenneth Barr; Min Zhong
- Inventors: Johan Oslob; Wang Shen; Kenneth Barr; Min Zhong
- Web page: https://patentgrep.com/patent/US8771715B2

## 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 pharmaceutical composition comprising an effective amount of a compound having the following formula:
or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle,
wherein the composition is in the form of liquid drops, liquid wash, gel, ointment, liposomes, solution, cream, powder, foam, crystals, spray, aerosol, or liquid suspension.

### Claim 2

A pharmaceutical composition comprising an effective amount of a compound having the following formula:
or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle,
wherein the pharmaceutically acceptable vehicle is suitable for ocular administration,
wherein the composition is formulated as an insert or implant, subconjunctival injection, intraocular injection, periocular injection, retrobulbar injection, or intracameral injection.

### Claim 3 (depends on 2)

The pharmaceutical composition of claim 2 wherein the insert or implant comprises a selective release device comprising a formulation wherein the compound is released in a sustained fashion.

### Claim 4 (depends on 3)

The pharmaceutical composition of claim 3 wherein the formulation comprises a biocompatible polymer.

### Claim 5 (depends on 2)

The pharmaceutical composition of claim 2, further comprising a preservative.

### Claim 6 (depends on 1)

The pharmaceutical composition of claim 1, further comprising a preservative.

### Claim 7 (depends on 1)

The pharmaceutical composition of claim 1, wherein the composition is in the form of liquid drops.

### Claim 8 (depends on 1)

The pharmaceutical composition of claim 1, wherein the composition is in the form of a liquid wash.

### Claim 9 (depends on 1)

The pharmaceutical composition of claim 1, wherein the composition is in the form of a gel.

### Claim 10 (depends on 1)

The pharmaceutical composition of claim 1, wherein the composition is in the form of an ointment.

### Claim 11 (depends on 1)

The pharmaceutical composition of claim 1, wherein the composition is in the form of liposomes.

### Claim 12 (depends on 1)

The pharmaceutical composition of claim 1, wherein the composition is in the form of a solution.

### Claim 13 (depends on 1)

The pharmaceutical composition of claim 1, wherein the composition is in the form of a cream.

### Claim 14 (depends on 1)

The pharmaceutical composition of claim 1, wherein the composition is in the form of a powder.

### Claim 15 (depends on 1)

The pharmaceutical composition of claim 1, wherein the composition is in the form of a foam.

### Claim 16 (depends on 1)

The pharmaceutical composition of claim 1, wherein the composition is in the form of crystals.

### Claim 17 (depends on 1)

The pharmaceutical composition of claim 1, wherein the composition is in the form of a spray.

### Claim 18 (depends on 1)

The pharmaceutical composition of claim 1, wherein the composition is in the form of an aerosol.

### Claim 19 (depends on 1)

The pharmaceutical composition of claim 1, wherein the composition is in the form of a liquid suspension.