# US 11,028,077 B2 · Crystalline pharmaceutical and methods of preparation and use thereof

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- Number: US 11,028,077 B2
- Document ID: US11028077B2
- Status: Granted
- Kind: B2
- Application number: 15/235,572
- Filed: 2016-08-12
- Published: 2016-12-22
- Granted: 2021-06-08
- Earliest claimed: 2008-04-15
- Assignees: Novartis Pharmaceuticals Corporation
- Applicants: Novartis Pharmaceuticals Corporation
- Inventors: John Burnier; Thomas Gadek; Frederic Naud
- Web page: https://patentgrep.com/patent/US11028077B2

## 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 crystalline form of the compound of Formula I:
or a pharmaceutically acceptable salt thereof, having an X-ray powder diffraction pattern comprising the following peaks, in terms of 2θ, of about 18.2°, 21.4° and 22.7°.

### Claim 2 (depends on 1)

A composition comprising the crystalline form of claim 1, and a pharmaceutically acceptable carrier.

### Claim 3 (depends on 2)

The composition of claim 2, wherein the composition is substantially free of other crystalline forms of the compound of Formula I.

### Claim 4

A crystalline form of the compound of Formula I:
or a pharmaceutically acceptable salt thereof, having a differential scanning calorimetry thermogram comprising an endothermic peak at about 145° C.

### Claim 5 (depends on 4)

A composition comprising the crystalline form of claim 4, and a pharmaceutically acceptable carrier.

### Claim 6 (depends on 5)

The composition of claim 5, wherein the composition is substantially free of other crystalline forms of the compound of Formula I.

### Claim 7

A crystalline form of the compound of Formula I:
or a pharmaceutically acceptable salt thereof, having a thermogravimetric analysis spectrum comprising a mass loss of about 2.5% between room temperature and 180° C.

### Claim 8 (depends on 7)

The crystalline form of claim 7, having a thermogravimetric analysis spectrum substantially as shown in FIG. 7.

### Claim 9 (depends on 7)

A composition comprising the crystalline form of claim 7.

### Claim 10 (depends on 9)

The composition of claim 9, wherein the composition is substantially free of other crystalline forms of the compound of Formula I.

### Claim 11

A crystalline form of the compound of Formula I:
or a pharmaceutically acceptable salt thereof, having a Raman chromatograph substantially as shown in FIG. 5.

### Claim 12 (depends on 11)

A composition comprising the crystalline form of claim 11.

### Claim 13 (depends on 12)

The composition of claim 12, wherein the composition is substantially free of other crystalline forms of the compound of Formula I.

### Claim 14 (depends on 1)

The crystalline form of claim 1, wherein the X-ray powder diffraction pattern further comprises two or more of the following peaks, in terms of 2θ, of about 5.7°, 7.6°, 9.7°, 10.1°, 17.5°, 18.8°, 19.4°, 20.0°, 21.1°, 23.2° and 24.6°.

### Claim 15 (depends on 1)

The crystalline form of claim 1, wherein the X-ray powder diffraction pattern further comprises the following peaks, in terms of 2θ, of about 5.7°, 7.6°, 9.7°, 10.1°, 17.5°, 18.8°, 19.4°, 20.0°, 21.1°, 23.2° and 24.6°.

### Claim 16 (depends on 1)

The crystalline form of claim 1, wherein the X-ray powder diffraction pattern is substantially as shown in FIG. 6.

### Claim 17 (depends on 4)

The crystalline form of claim 4, wherein the differential scanning calorimetry thermogram is substantially as shown in FIG. 8.