# US 2019/0315673 A1 · 5-BROMO-2-(alpha-HYDROXYPENTYL)BENZOIC ACID SODIUM SALTS IN DIFFERENT CRYSTAL FORMS, AND PREPARATION METHOD THEREOF

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- Number: US 2019/0315673 A1
- Document ID: US20190315673A1
- Status: Published application
- Kind: A1
- Application number: 16/452,905
- Filed: 2019-06-26
- Published: 2019-10-17
- Earliest claimed: 2013-07-17
- Assignees: Zhejiang Ausun Pharmaceutical Co., Ltd.
- Applicants: Zhejiang Ausun Pharmaceutical Co., Ltd.
- Inventors: Junbiao Chang; Chuanjun Song
- Web page: https://patentgrep.com/patent/US20190315673A1

## CPC

- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- C07C 63/70: Monocarboxylic acids
- A61P 25/00: Drugs for disorders of the nervous system
- C07C 51/09: from carboxylic acid esters or lactones
- C07C 51/60: by conversion of carboxylic acids or their anhydrides {or esters, lactones, salts} into halides with the same carboxylic acid part
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

The present invention discloses 5-bromo-2-(α-hydroxypentyl)benzoic acid sodium salt in different crystal forms and the preparation methods thereof, and belongs to the field of pharmaceutical chemistry. Said different crystal forms of 5-bromo-2-(α-hydroxypentyl)benzoic acid sodium salt include: amorphous 5-bromo-2-(α-hydroxypentyl)benzoic acid sodium salt, crystal form A of 5-bromo-2-(α-hydroxypentyl)benzoic acid sodium salt, and crystal form B of 5-bromo-2-(α-hydroxypentyl)benzoic acid sodium salt. The different crystal forms of 5-bromo-2-(α-hydroxypentyl)benzoic acid sodium salt obtained according to the present invention have better stability and water-solubility than the mixed forms of 5-bromo-2-(α-hydroxypentyl)benzoic acid sodium salt, thus is advantageous for pharmaceutical use. Moreover, the different crystal forms of 5-bromo-2-(α-hydroxypentyl)benzoic acid sodium salt possess much better therapeutic effect than 5-bromo-2-(α-hydroxypentyl)benzoic acid potassium salt.

## Claims

### Claim 1

Crystal form B of 5-bromo-2-(α-hydroxypentyl)benzoic acid sodium salt, defined by a XRPD pattern with the diffraction peaks at 2θ values of 5.72, 6.69, 9.93, 11.09, 11.84, 14.55, 16.42, 17.27, 17.80, 18.28, 19.86, 20.98, 22.21, 23.43, and 23.88, wherein the error range of 2θ value is ±0.2.

### Claim 2 (depends on 1)

A method for preparing the crystal form B of 5-bromo-2-(α-hydroxypentyl)benzoic acid sodium salt of claim 1, the method comprising:
dissolving amorphous 5-bromo-2-(α-hydroxypentyl)benzoic acid in a tetrahydrofuran solvent,
stirring the resulting solution at room temperature, and
adding an aqueous solution of sodium hydroxide dropwise to the solution;
wherein after evaporation of the tetrahydrofuran and water solvents, the resulting solids are dried under a vacuum.

### Claim 3 (depends on 1)

A method for preparing the crystal form B of 5-bromo-2-(α-hydroxypentyl)benzoic acid sodium salt of claim 1, the method comprising:
weighing and placing 6-bromo-3-butyl-1(3H)-isobenzofuranone and sodium hydroxide in a flask,
adding methanol to the flask,
heating the resulting mixture under reflux to react the contents,
evaporating and removing the methanol,
adding ethyl acetate,
shaking the resulting mixture and filtering and removing the undissolved solids,
evaporating and removing the ethyl acetate to yield a solid compound,
adding anhydrous diethyl ether to dissolve the solid compound, and
filtering the resulting solution after standing overnight.

### Claim 4 (depends on 1)

A method of reducing brain tissue injury induced by obstruction of cerebral arteries comprising administering the crystal form B of 5-bromo-2-(α-hydroxypentyl)benzoic acid sodium salt of claim 1.

### Claim 5 (depends on 1)

A method of reducing brain infarction volume comprising administering the crystal form B of 5-bromo-2-(α-hydroxypentyl)benzoic acid sodium salt of claim 1.

### Claim 6 (depends on 1)

A method of reducing brain edema volume comprising administering the crystal form B of 5-bromo-2-(α-hydroxypentyl)benzoic acid sodium salt of claim 1.

### Claim 7 (depends on 1)

A method of preventing and treating heart and brain ischemic diseases comprising administering the crystal form B of 5-bromo-2-(α-hydroxypentyl)benzoic acid sodium salt of claim 1.

### Claim 8 (depends on 1)

A method of improving heart and brain circulatory disorders comprising administering the crystal form B of 5-bromo-2-(α-hydroxypentyl)benzoic acid sodium salt of claim 1.

### Claim 9 (depends on 1)

A method of producing antithrombotic effects comprising administering the crystal form B of 5-bromo-2-(α-hydroxypentyl)benzoic acid sodium salt of claim 1.

### Claim 10 (depends on 1, 4)

The method of claim 4 wherein administration of the crystal form B of 5-bromo-2-(α-hydroxypentyl)benzoic acid sodium salt of claim 1 comprises intravenous administration.

### Claim 11 (depends on 1, 4)

The method of claim 4 wherein administration of the crystal form B of 5-bromo-2-(α-hydroxypentyl)benzoic acid sodium salt of claim 1 comprises intragastric administration.

### Claim 12 (depends on 1, 5)

The method of claim 5 wherein administration of the crystal form B of 5-bromo-2-(α-hydroxypentyl)benzoic acid sodium salt of claim 1 comprises intravenous administration.

### Claim 13 (depends on 1, 5)

The method of claim 5 wherein administration of the crystal form B of 5-bromo-2-(α-hydroxypentyl)benzoic acid sodium salt of claim 1 comprises intragastric administration.

### Claim 14 (depends on 1, 6)

The method of claim 6 wherein administration of the crystal form B of 5-bromo-2-(α-hydroxypentyl)benzoic acid sodium salt of claim 1 comprises intravenous administration.

### Claim 15 (depends on 1, 6)

The method of claim 6 wherein administration of the crystal form B of 5-bromo-2-(α-hydroxypentyl)benzoic acid sodium salt of claim 1 comprises intragastric administration.

### Claim 16 (depends on 1, 7)

The method of claim 7 wherein administration of the crystal form B of 5-bromo-2-(α-hydroxypentyl)benzoic acid sodium salt of claim 1 comprises intravenous administration.

### Claim 17 (depends on 1, 7)

The method of claim 7 wherein administration of the crystal form B of 5-bromo-2-(α-hydroxypentyl)benzoic acid sodium salt of claim 1 comprises intragastric administration.

### Claim 18 (depends on 1, 8)

The method of claim 8 wherein administration of the crystal form B of 5-bromo-2-(α-hydroxypentyl)benzoic acid sodium salt of claim 1 comprises intravenous administration.

### Claim 19 (depends on 1, 8)

The method of claim 8 wherein administration of the crystal form B of 5-bromo-2-(α-hydroxypentyl)benzoic acid sodium salt of claim 1 comprises intragastric administration.

### Claim 20 (depends on 1, 9)

The method of claim 9 wherein administration of the crystal form B of 5-bromo-2-(α-hydroxypentyl)benzoic acid sodium salt of claim 1 comprises intravenous administration or intragastric administration.