# US 8,541,451 B2 · Crystalline freebase forms of a biphenyl compound

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- Number: US 8,541,451 B2
- Document ID: US8541451B2
- Status: Granted
- Kind: B2
- Application number: 12/835,964
- Filed: 2010-07-14
- Published: 2011-01-20
- Granted: 2013-09-24
- Earliest claimed: 2009-07-15
- Assignees: Theravance, Inc.
- Applicants: Grahame Woollam
- Inventors: Grahame Woollam
- Web page: https://patentgrep.com/patent/US8541451B2

## CPC

- C07D 211/62: attached in position 4
- A61K 9/124: {characterised by the propellant}
- A61K 9/1623: {Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules}
- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 11/08: Bronchodilators
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- 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
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

The invention provides two crystalline freebase forms of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester. The invention also provides pharmaceutical compositions comprising the crystalline freebase or prepared using the crystalline freebases; processes and intermediates for preparing the crystalline freebases; and methods of using the crystalline freebases to treat a pulmonary disorder.

## Claims

### Claim 1

A crystalline freebase of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester characterized by a powder x-ray diffraction comprising diffraction peaks at 2θ values of 6.6±0.1, 13.1±0.1, 18.6±0.1, 19.7±0.1, and 20.2±0.1, and further characterized by having five or more additional diffraction peaks at 2θ values selected from 8.8±0.1, 10.1±0.1, 11.4±0.1, 11.6±0.1, 14.8±0.1, 15.2±0.1, 16.1±0.1, 16.4±0.1, 16.9±0.1, 17.5±0.1, 18.2±0.1, 19.3±0.1, 19.9±0.1, 20.8±0.1, 21.1±0.1, 21.7±0.1, and 22.3±0.1; designated as Form III; and having a melting point of about 125° C.

### Claim 2 (depends on 1)

The crystalline compound of claim 1, characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2θ values selected from 6.6±0.1, 11.4±0.1, 13.1±0.1, 16.1±0.1, 17.5±0.1, 18.2±0.1, 18.6±0.1, 19.3±0.1, 19.7±0.1, 19.9±0.1, 20.2±0.1, 20.8±0.1, 21.1±0.1, 21.7±0.1, and 22.3±0.1.

### Claim 3 (depends on 1)

The crystalline compound of claim 1, further characterized by a powder x-ray diffraction pattern in which the peak positions are substantially in accordance with the peak positions of the pattern shown in FIG. 1.

### Claim 4 (depends on 1)

The compound of claim 1, further characterized by a differential scanning calorimetry thermogram substantially in accordance with that shown in FIG. 4.

### Claim 5

A crystalline freebase of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester characterized by a powder x-ray diffraction comprising diffraction peaks at 2θ values of 6.6±0.1, 13.1±0.1, 18.6±0.1, 19.7±0.1, and 20.2±0.1, and further characterized by having five or more additional diffraction peaks at 2θ values selected from 10.6±0.1, 15.0±0.1, 16.0±0.1, 17.3±0.1, 17.7±0.1, 20.9±0.1, 21.4±0.1, 22.6±0.1, 24.6±0.1, and 27.8±0.1; designated as Form IV; and having a melting point of about 119° C.

### Claim 6 (depends on 5)

The crystalline compound of claim 5, further characterized by a powder x-ray diffraction pattern in which the peak positions are substantially in accordance with the peak positions of the pattern shown in FIG. 2.

### Claim 7 (depends on 5)

The compound of claim 5, further characterized by a differential scanning calorimetry thermogram substantially in accordance with that shown in FIG. 5.

### Claim 8 (depends on 1)

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 1.

### Claim 9 (depends on 8)

The composition of claim 8, which further comprises an agent selected from β2 adrenergic receptor agonists, steroidal anti-inflammatory agents, phosphodiesterase-4 inhibitors, and combinations thereof; wherein the crystalline form and the agent are formulated together or separately.

### Claim 10 (depends on 9)

The composition of claim 9, which comprises a β2 adrenergic receptor agonist and a steroidal anti-inflammatory agent.

### Claim 11 (depends on 1)

The compound of claim 1 in micronized form.

### Claim 12 (depends on 5)

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 5.

### Claim 13 (depends on 12)

The composition of claim 12, which further comprises an agent selected from β2 adrenergic receptor agonists, steroidal anti-inflammatory agents, phosphodiesterase-4 inhibitors, and combinations thereof; wherein the crystalline form and the agent are formulated together or separately.

### Claim 14 (depends on 13)

The composition of claim 13, which comprises a β2 adrenergic receptor agonist and a steroidal anti-inflammatory agent.

### Claim 15 (depends on 5)

The compound of claim 5 in micronized form.

### Claim 16 (depends on 1)

A process for preparing the crystalline freebase Form III of claim 1, comprising contacting biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester with a solvent consisting of acetonitrile, wherein the ratio of milligrams of the ester to total milliliters of acetonitrile is about 100:1, and the acetonitrile is added in two steps.

### Claim 17 (depends on 5)

A process for preparing the crystalline freebase Form IV of claim 5, comprising a) forming a seed crystal of the crystalline freebase Form III by contacting biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester with a solvent consisting of acetonitrile, wherein the ratio of milligrams of the ester to total milliliters of acetonitrile is about 100:1, and the acetonitrile is added in two steps; b) dissolving the crystalline freebase Form III in acetonitrile to form a solution; c) and adding the seed crystal to the solution.