# US 8,080,562 B2 · Crystalline pharmaceutical and methods of preparation and use thereof

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- Number: US 8,080,562 B2
- Document ID: US8080562B2
- Status: Granted
- Kind: B2
- Application number: 12/386,361
- Filed: 2009-04-15
- Published: 2009-12-03
- Granted: 2011-12-20
- Earliest claimed: 2008-04-15
- Assignees: Sarcode Bioscience Inc.
- Inventors: John Burnier; Thomas Gadek; Frederic Naud
- Web page: https://patentgrep.com/patent/US8080562B2

## CPC

- C07D 405/06: linked by a carbon chain containing only aliphatic carbon atoms
- A61K 9/06: Ointments; Bases therefor; {Other semi-solid forms, e.g. creams, sticks, gels (composition of ointments, creams or gels A61K47/00)}
- A61K 9/08: Solutions {(composition of solutions A61K47/00)}
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 31/4725: containing further heterocyclic rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/02: Inorganic compounds
- A61K 47/06: Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
- A61K 47/14: Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
- A61K 47/22: Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
- A61K 47/38: Cellulose; Derivatives thereof
- A61P 11/02: Nasal agents, e.g. decongestants
- A61P 11/06: Antiasthmatics
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/06: Antipsoriatics
- A61P 17/08: Antiseborrheics
- A61P 17/14: for baldness or alopecia
- A61P 27/02: Ophthalmic agents
- A61P 27/04: Artificial tears; Irrigation solutions
- A61P 27/14: Decongestants or antiallergics
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C07C 317/48: the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- 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 217/26: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D 405/10: linked by a carbon chain containing aromatic rings
- A61K 47/183: {Amino acids, e.g. glycine, EDTA or aspartame}
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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

## Abstract

Novel crystalline polymorphic forms, Forms A, B, C, D, and E of a compound of Formula I, which has been found to be a potent inhibitor of LFA-1, are disclosed. Methods of preparation and uses thereof in the treatment of LFA-1 mediated diseases are also disclosed in this invention.

## Claims

### Claim 1

A compound of the formula:
or its pharmaceutically acceptable salts.

### Claim 2

A compound of the formula:
or its pharmaceutically acceptable salts.

### Claim 3

A compound of the formula:

### Claim 4

A compound of the formula:
or its pharmaceutically acceptable salts.

### Claim 5 (depends on 1, 2)

A reaction mixture comprising the compound of claim 1 or 2, a solvent, and a coupling reagent.

### Claim 6 (depends on 5)

The reaction mixture of claim 5 further comprising a base.

### Claim 7 (depends on 6)

The reaction mixture of claim 6 comprising the compound of
or its pharmaceutically acceptable salts.

### Claim 8 (depends on 7)

The reaction mixture of claim 7 wherein a compound of the formula:
is produced.

### Claim 9 (depends on 5)

The reaction mixture of claim 5 wherein the solvent is DMF.

### Claim 10 (depends on 5)

The reaction mixture of claim 5 wherein the coupling reagent is 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU).

### Claim 11 (depends on 6)

The reaction mixture of claim of claim 6 wherein the base is triethylamine.

### Claim 12

A compound of the formula:

### Claim 13 (depends on 4)

A reaction mixture comprising the compound of claim 4, a solvent, and an acid.

### Claim 14 (depends on 4)

The reaction mixture of claim 4 wherein a compound of the formula:
is produced.

### Claim 15 (depends on 13)

The reaction mixture of claim 13 wherein the solvent is dioxane.

### Claim 16 (depends on 13)

The reaction mixture of claim 13 wherein the acid is HCl.

### Claim 17 (depends on 12)

A reaction mixture comprising the compound of claim 12, a solvent, and a base.

### Claim 18 (depends on 17)

The reaction mixture of claim 17 further comprising benzofuranoyl chloride.

### Claim 19 (depends on 18)

The reaction mixture of claim 18 wherein a compound of the formula:
is produced.

### Claim 20 (depends on 17)

The reaction mixture of claim 17 wherein the solvent is methylene chloride.

### Claim 21 (depends on 17)

The reaction mixture of claim 17 wherein the base is diisopropylethylamine.