# US 2019/0315698 A1 · Crystalline salts and polymorphs of a p2x3 antagonist

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- Number: US 2019/0315698 A1
- Document ID: US20190315698A1
- Status: Published application
- Kind: A1
- Application number: 16/468,992
- Filed: 2017-12-15
- Published: 2019-10-17
- Earliest claimed: 2016-12-20
- Assignees: Afferent Pharmaceuticals, Inc.
- Applicants: Afferent Pharmaceuticals, Inc.
- Inventors: Prabha Ibrahim; Ronald Charles Hawley; Anthony P. Ford; Steven A. Smith
- Web page: https://patentgrep.com/patent/US20190315698A1

## CPC

- A61P 11/14: Antitussive agents
- C07D 239/48: Two nitrogen atoms
- A61K 9/2095: {Tabletting processes}
- A61K 31/191: having two or more hydroxy groups, e.g. gluconic acid
- C07C 59/255: Tartaric acid
- C07C 59/265: Citric acid
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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)
- 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

Provided are novel salts and polymorphs of 5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzenesulfonamide, which are potentially useful for modulating a condition mediated by a P2X3 or P2X2/3 receptor. Also provided are pharmaceutical formulations and methods of administration and dosing of these salts and polymorphs to subjects in need thereof.

## Claims

### Claim 1

A crystalline citrate Form A of 5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzenesulfonamide having an X-ray powder diffraction pattern, collected using copper Kα radiation, corresponding to d-spacings of approximately: 11.7, 16.2 and 21.1 angstroms.

### Claim 2 (depends on 1)

The crystalline citrate Form A of claim 1, further characterized by d-spacings of approximately: 9.4 and 26.3 angstroms.

### Claim 3 (depends on 2)

The crystalline citrate Form A of claim 2, further characterized by d-spacings of approximately: 14.4 and 19.5 angstroms.

### Claim 4 (depends on 1)

The crystalline citrate Form A of claim 1, which is substantially similar to the X-ray powder diffraction pattern, collected using copper Kα radiation, of FIG. 3.

### Claim 5 (depends on 1)

The crystalline citrate Form A of claim 1, further characterized by proton nuclear magnetic resonance (NMR) data showing a 1:1 Compound A to citrate ratio.

### Claim 6 (depends on 1)

The crystalline citrate Form A of claim 1, further characterized by DSC and TGA thermograms showing negligible weight loss up to 160° C., and stepwise weight loss of about 24 wt % between 160° C. and 250° C.

### Claim 7 (depends on 6)

The crystalline citrate Form A of claim 6, which is substantially similar to the DSC/TGA thermograms of FIG. 4.

### Claim 8 (depends on 1)

A pharmaceutical composition comprising the crystalline citrate Form A of claim 1 and a pharmaceutically acceptable carrier.

### Claim 9 (depends on 1)

A method of modulating a condition mediated by a P2X3 or P2X2/3 receptor, said method comprising administering an effective amount of the crystalline citrate Form A of claim 1 to a subject in need thereof.

### Claim 10 (depends on 9)

The method of claim 9, wherein the condition mediated by a P2X3 or P2X2/3 receptor is selected from cough, chronic cough and urge to cough.

### Claim 11

A crystalline tartrate Form F of 5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzenesulfonamide having an X-ray powder diffraction pattern, collected using copper Kα radiation, corresponding to d-spacings of approximately: 11.3, 18.7, and 22.7 angstroms.

### Claim 12 (depends on 11)

The crystalline tartrate Form F of claim 11, further characterized by d-spacings of approximately: 12.1 and 17.7 angstroms.

### Claim 13 (depends on 12)

The crystalline tartrate Form F of claim 12, further characterized by d-spacings of approximately: 9.2 and 26.5 angstroms.

### Claim 14 (depends on 11)

The crystalline tartrate Form F of claim 11, which is substantially similar to the X-ray powder diffraction pattern, collected using copper Kα radiation, of FIG. 11.

### Claim 15 (depends on 11)

The crystalline tartrate Form F of claim 11, further characterized by proton nuclear magnetic resonance (NMR) data showing a 2:1 Compound A to tartrate ratio.

### Claim 16 (depends on 11)

The crystalline tartrate Form F of claim 11, further characterized by DSC and TGA thermograms showing an initial weight loss step of about 6.6 wt % between 27-100° C. by TGA and a broad endotherm by DSC at 125° C.

### Claim 17 (depends on 16)

The crystalline tartrate Form F of claim 16, which is substantially similar to the DSC/TGA thermograms of FIG. 12.

### Claim 18 (depends on 11)

A pharmaceutical composition comprising the crystalline tartrate Form F of claim 11 and a pharmaceutically acceptable carrier.

### Claim 19 (depends on 11)

A method of modulating a condition mediated by a P2X3 or P2X2/3 receptor, said method comprising administering an effective amount of the crystalline tartrate Form F of claim 11 to a subject in need thereof.

### Claim 20 (depends on 19)

The method of claim 19, wherein the condition mediated by a P2X3 or P2X2/3 receptor is selected from cough, chronic cough and urge to cough.