# US 2013/0158013 A1 · Processes for the preparation of 5-ht2c receptor agonists

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- Number: US 2013/0158013 A1
- Document ID: US20130158013A1
- Status: Published application
- Kind: A1
- Application number: 13/701,471
- Filed: 2011-06-01
- Published: 2013-06-20
- Earliest claimed: 2010-06-02
- Assignees: Arena Pharmaceuticals, Inc.
- Inventors: Anthony C. Blackburn; Anna Shifrina
- Web page: https://patentgrep.com/patent/US20130158013A1

## CPC

- C07D 223/16: Benzazepines; Hydrogenated benzazepines
- A61K 31/137: Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine {or methadone}
- A61K 31/55: having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61P 3/04: Anorexiants; Antiobesity agents
- 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

## Abstract

Processes and intermediates for preparing salts of the 5-HT2C-receptor agonist (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, and pharmaceutically acceptable solvates and hydrates thereof, that are useful for, inter alia, weight management.

## Claims

### Claim 1

A process for preparing (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride salt hemihydrate Form III, comprising slurrying a first mixture comprising: (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride salt Form IV; and a first solvent; to form said (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride salt hemihydrate Form III.

### Claim 2 (depends on 1)

The process according to claim 1, wherein said first mixture has a water activity of greater than about 0.15.

### Claim 3 (depends on 1)

The process according to claim 1, wherein said first mixture has a water activity of greater than about 0.20.

### Claim 4 (depends on 1)

The process according to claim 1, wherein said (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride salt Form IV is prepared by slurrying a second mixture comprising: a starting material selected from (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride salt Form I, (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride salt Form II, and mixtures thereof; and a second solvent; to form said (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride salt Form IV.

### Claim 5 (depends on 4)

The process according to claim 4, further comprising isolating said (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride salt Form IV.

### Claim 6 (depends on 4)

The process according to claim 4, wherein said second mixture further comprises seed crystals, wherein said seed crystals comprise (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride salt Form IV.

### Claim 7 (depends on 4)

The process according to claim 4, wherein said starting material comprises (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride salt Form I.

### Claim 8 (depends on 4)

The process according to claim 4, wherein said starting material comprises (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride salt Form II.

### Claim 9 (depends on 4)

The process according to claim 4, wherein said second mixture has a water activity of less than about 0.20.

### Claim 10 (depends on 4)

The process according to claim 4, wherein said second mixture has a water activity of less than about 0.10.

### Claim 11 (depends on 4)

The process according to claim 4, wherein said second mixture has a water activity of less than about 0.05.

### Claim 12 (depends on 4)

The process according to claim 4, wherein said second solvent comprises an anhydrous solvent selected from: acetonitrile, isobutanol, acetone, and isopropanol.

### Claim 13 (depends on 4)

The process according to claim 4, wherein said second solvent comprises acetonitrile.

### Claim 14 (depends on 1)

A crystalline salt produced by the process according to claim 1.

### Claim 15 (depends on 1)

A process according to claim 1, further comprising admixing said (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride salt hemihydrate Form III with a pharmaceutically acceptable carrier.

### Claim 16 (depends on 15)

A composition produced by the process according to claim 15.

### Claim 17 (depends on 1)

A process according to claim 1, further comprising formulating said (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride salt hemihydrate Form III into a pharmaceutical composition.

### Claim 18 (depends on 17)

A pharmaceutical composition produced by the process according to claim 17.

### Claim 19

A salt which is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride salt Form IV.

### Claim 20 (depends on 19)

The salt according to claim 19, having an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at about 20.2316°, about 15.3400°, about 17.7719°, about 25.1334°, about 23.2759°, about 18.2736°, about 35.8226°, about 19.8388°, about 10.6724°, and about 24.2509°.

### Claim 21 (depends on 19)

A composition comprising a salt according to claim 19.

### Claim 22 (depends on 19)

A pharmaceutical composition comprising a salt according to claim 19.

### Claim 23 (depends on 19)

A method for weight management, comprising administering to an individual in need thereof, a therapeutically effective amount of a salt according to claim 19.

### Claim 24 (depends on 23)

The method according to claim 23, wherein said weight management comprises weight loss.

### Claim 25 (depends on 23)

The method according to claim 23, wherein said weight management comprises maintenance of weight loss.

### Claim 26 (depends on 23)

The method according to claim 23, wherein said weight management further comprises a reduced-calorie diet.

### Claim 27 (depends on 23)

The method according to claim 23, wherein said weight management further comprises a program of regular exercise.

### Claim 28 (depends on 23)

The method according to claim 23, wherein said weight management further comprises both a reduced-calorie diet and a program of regular exercise.

### Claim 29 (depends on 23)

The method according to claim 23, wherein said individual in need of weight management is an obese patient with an initial body mass index ≧30 kg/m2.

### Claim 30 (depends on 23)

The method according to claim 23, wherein said individual in need of weight management is an overweight patient with an initial body mass index ≧27 kg/m2 in the presence of at least one weight related comorbid condition selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance, and sleep apnea.

### Claim 31 (depends on 23)

The method according to claim 23, further comprising administering phentermine to said individual.

### Claim at position 32

-50. (canceled)