# US 12,006,319 B2 · Monohydrate and crystalline forms of 6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-tetrahydropyran-4-yl-7H-imidazo[1,5-a]pyrazin-8-one

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- Number: US 12,006,319 B2
- Document ID: US12006319B2
- Status: Granted
- Kind: B2
- Application number: 17/110,000
- Filed: 2020-12-02
- Published: 2021-04-15
- Granted: 2024-06-11
- Earliest claimed: 2018-05-25
- Assignees: Cardurion Pharmaceuticals, LLC
- Applicants: Cardurion Pharmaceuticals, Inc.
- Inventors: Suzanne Buttar; Mateusz Pitak; Adam Ross Patterson; Samuel Alexander Stratford; Ioana Sovago; Jun Xu; Peng Zhou; Haojuan Wei; Kuangchu Dai
- Web page: https://patentgrep.com/patent/US12006319B2

## CPC

- A61K 31/4985: Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
- C07D 487/04: Ortho-condensed systems
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- 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)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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 present disclosure relates to crystalline polymorph forms of 6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-tetrahydropyran-4-yl-7H-imidazol[1,5-a]pyrazin-8-one.

## Claims

### Claim 1

A monohydrate crystalline form of 6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-tetrahydropyran-4-yl-7H-imidazo[1,5-a]pyrazin-8-one

### Claim 2

A monohydrate crystalline form of Compound 1
wherein the monohydrate crystalline form is Monohydrate Form 1 (MH1), having an XRPD pattern comprising peaks of 2θ angles at 9.1, 11.5, 16.2, 16.7, 18.2, 18.9, 19.8, 22.6, and 26.4 degrees 2θ, each ±0.2 degrees 2θ.

### Claim 3 (depends on 2)

The monohydrate crystalline form of claim 2, having an XRPD pattern substantially the same as shown in FIG. 2A.

### Claim 4 (depends on 2)

The monohydrate crystalline form of claim 2, having a dehydration endothermic peak at 40-100° C. and a melting endothermic peak at about 184.4° C. in a differential scanning calorimetry (DSC) thermogram.

### Claim 5 (depends on 2)

The monohydrate crystalline form of claim 2, having a DSC thermogram substantially in accordance with FIG. 5.

### Claim 6 (depends on 2)

The monohydrate crystalline form of claim 2, exhibiting dehydration between ambient and about 90° C. with a weight loss of about 3.8% in a thermogravimetric analysis (TGA).

### Claim 7 (depends on 2)

The monohydrate crystalline form of claim 2, having a TGA substantially in accordance with FIG. 5.

### Claim 8 (depends on 2)

The monohydrate crystalline form of claim 2, having characteristic absorptions at about 782 cm−1, 1123 cm−1, 1562 cm−1 and 1655 cm−1 in an infrared (IR) spectrum.

### Claim 9 (depends on 2)

The monohydrate crystalline form of claim 2, having an infrared spectrum substantially in accordance with FIG. 3.

### Claim 10

A monohydrate crystalline form of Compound 1
wherein the monohydrate crystalline form is Monohydrate Form 2 (MH2), having an XRPD pattern comprising peaks of 2θ angles at 9.0, 11.6, 15.0, 16.0, 18.6, 19.1, 20.4, or 20.6 degrees 2θ, each ±0.2 degrees 2θ.

### Claim 11 (depends on 10)

The monohydrate crystalline form of claim 10, having an XRPD pattern substantially the same as the XRPD pattern shown in FIG. 7A.

### Claim 12 (depends on 10)

The monohydrate crystalline form of claim 10, having an endothermic peak at 59.1° C. (±5° C.) and at 184.7° C. (±5° C.) in a differential scanning calorimetry (DSC) thermogram.

### Claim 13 (depends on 10)

The monohydrate crystalline form of claim 10, having a DSC thermogram substantially in accordance with FIG. 9.

### Claim 14 (depends on 10)

The monohydrate crystalline form of claim 10, exhibiting dehydration at about 25° C. to about 100° C. with a weight loss of about 4.4% in a thermogravimetric analysis (TGA).

### Claim 15 (depends on 10)

The monohydrate crystalline form of claim 10, having a TGA substantially in accordance with FIG. 9.

### Claim 16 (depends on 2)

The monohydrate crystalline form of claim 2, which is at least 95, 96, 97, 98, or 99% purified.

### Claim 17 (depends on 2)

A pharmaceutical composition comprising the monohydrate crystalline form of claim 2, and a pharmaceutically acceptable excipient.

### Claim 18 (depends on 17)

The pharmaceutical composition of claim 17, wherein the monohydrate crystalline form is present in an amount of at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% by weight.

### Claim 19 (depends on 10)

A pharmaceutical composition comprising the monohydrate crystalline form of claim 10, and a pharmaceutically acceptable excipient.

### Claim 20 (depends on 19)

The pharmaceutical composition of claim 19, wherein the monohydrate crystalline form is present in an amount of at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% by weight.