# US 12,006,318 B2 · Crystalline forms of C-C chemokine receptor type 4 antagonist and uses thereof

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- Number: US 12,006,318 B2
- Document ID: US12006318B2
- Status: Granted
- Kind: B2
- Application number: 17/098,157
- Filed: 2020-11-13
- Published: 2021-05-13
- Granted: 2024-06-11
- Earliest claimed: 2019-11-13
- Assignees: Rapt Therapeutics, Inc.
- Applicants: Rapt Therapeutics, Inc.
- Inventors: David J. Arnold; Omar Robles; Duane E. Rudisill; David J. Wustrow; Mikhail Zibinsky; Sami Karaborni
- Web page: https://patentgrep.com/patent/US12006318B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 9/2018: {Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates}
- A61K 9/2054: {Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose}
- A61K 9/284: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone}
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- C07K 16/2818: {against CD28 or CD152}
- 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
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

Crystalline forms of a C-C chemokine receptor type 4 (CCR4) antagonist, oral dosage forms of same and methods of using and preparing same, are provided.

## Claims

### Claim 1

Compound 2-((R)-3-(1-(1-((R)-1-(2,4-Dichlorophenyl)ethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-13]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol benzene sulfonate in crystalline form.

### Claim 2 (depends on 1)

The compound of claim 1, comprising characteristic absorption peaks (2θ) at 18.4°±0.3°, 22.9°±0.3°, 21.2°±0.3°, and 15.9°±0.3° in an X-ray powder diffractogram using Cu Kα radiation.

### Claim 3 (depends on 2)

The compound of claim 2, further comprising characteristic absorption peaks (2θ) at 12.2°±0.3°, 23.8°±0.3°, and 25.6°±0.3° in an X-ray powder diffractogram using Cu Kα radiation.

### Claim 4 (depends on 1)

The compound of claim 1, further comprising characteristic absorption peaks (2θ) at 23.1°±0.3°, 20.0°±0.3°, and 16.2°±0.3° in an X-ray powder diffractogram using Cu Kα radiation.

### Claim 5 (depends on 1)

The compound of claim 1, having an X-ray powder diffractogram using Cu Kα radiation illustrated in FIG. 1.

### Claim 6 (depends on 1)

The compound of claim 1, having a melting point between about 170° C. and about 173° C. as determined by differential scanning calorimetry at a scan rate of 5° C./minute.

### Claim 7 (depends on 2)

The compound of claim 2, further comprising a characteristic absorption peak (2θ) at 12.2°±0.3° in an X-ray powder diffractogram using Cu Kα radiation.

### Claim 8 (depends on 2)

The compound of claim 2, further comprising a characteristic absorption peak (2θ) at 23.8°±0.3° in an X-ray powder diffractogram using Cu Kα radiation.

### Claim 9 (depends on 2)

The compound of claim 2, further comprising a characteristic absorption peak (2θ) at 25.6°±0.3° in an X-ray powder diffractogram using Cu Kα radiation.

### Claim 10 (depends on 2)

The compound of claim 2, further comprising a characteristic absorption peak (2θ) at 23.1°±0.3° in an X-ray powder diffractogram using Cu Kα radiation.

### Claim 11 (depends on 2)

The compound of claim 2, further comprising a characteristic absorption peak (2θ) at 20.0°±0.3° in an X-ray powder diffractogram using Cu Kα radiation.

### Claim 12 (depends on 2)

The compound of claim 2, further comprising a characteristic absorption peak (2θ) at 16.2°±0.3° in an X-ray powder diffractogram using Cu Kα radiation.

### Claim 13 (depends on 1)

The compound of claim 1, comprising characteristic absorption peaks (2θ) at 12.5°±0.3°, 14.6°±0.3°, 22.3°±0.3°, and 13.3°±0.3° in an X-ray powder diffractogram using Cu Kα radiation.

### Claim 14 (depends on 13)

The compound of claim 13, further comprising characteristic absorption peaks (2θ) at 15.8°±0.3°, 24.5°±0.3°, and 4.5°±0.3° in an X-ray powder diffractogram using Cu Kα radiation.

### Claim 15 (depends on 14)

The compound of claim 14, further comprising characteristic absorption peaks (2θ) at 22.8°±0.3°, 10.6°±0.3°, and 18.6°±0.3° in an X-ray powder diffractogram using Cu Kα radiation.

### Claim 16 (depends on 13)

The compound of claim 13, having an X-ray powder diffractogram using Cu Kα radiation illustrated in FIG. 3.

### Claim 17 (depends on 13)

The compound of claim 13, having a melting point between about 116° C. and about 119° C. as determined by differential scanning calorimetry at a scan rate of 5° C./minute.

### Claim 18 (depends on 13)

The compound of claim 13, further comprising a characteristic absorption peak (2θ) at 15.8°±0.3° in an X-ray powder diffractogram using Cu Kα radiation.

### Claim 19 (depends on 13)

The compound of claim 13, further comprising a characteristic absorption peak (2θ) at 24.5°±0.3° in an X-ray powder diffractogram using Cu Kα radiation.

### Claim 20 (depends on 13)

The compound of claim 13, further comprising a characteristic absorption peak (2θ) at 4.5°±0.3° in an X-ray powder diffractogram using Cu Kα radiation.

### Claim 21 (depends on 13)

The compound of claim 13, further comprising a characteristic absorption peak (2θ) at 22.8°±0.3° in an X-ray powder diffractogram using Cu Kα radiation.

### Claim 22 (depends on 13)

The compound of claim 13, further comprising a characteristic absorption peak (2θ) at 10.6°±0.3° in an X-ray powder diffractogram using Cu Kα radiation.

### Claim 23 (depends on 13)

The compound of claim 13, further comprising a characteristic absorption peak (2θ) at 18.6°±0.3° in an X-ray powder diffractogram using Cu Kα radiation.

### Claim 24 (depends on 1)

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

### Claim 25 (depends on 2)

A pharmaceutical composition comprising the crystalline compound of claim 2 and a pharmaceutically acceptable vehicle.

### Claim 26 (depends on 13)

A pharmaceutical composition comprising the crystalline compound of claim 13 and a pharmaceutically acceptable vehicle.

### Claim 27 (depends on 24)

The pharmaceutical composition of claim 24, wherein the composition is an oral tablet dosage form.

### Claim 28 (depends on 27)

The pharmaceutical composition of claim 27, wherein the composition comprises 75 mg of the crystalline compound.

### Claim 29 (depends on 27)

The pharmaceutical composition of claim 27, wherein the composition comprises 25 mg of the crystalline compound.

### Claim 30 (depends on 24)

The pharmaceutical composition of claim 24, wherein the composition comprises a wetting agent.

### Claim 31 (depends on 30)

The pharmaceutical composition of claim 30, wherein the wetting agent is sodium lauryl sulfate.

### Claim 32 (depends on 24)

The pharmaceutical composition of claim 24, wherein the composition comprises a water soluble excipient.

### Claim 33 (depends on 32)

The pharmaceutical composition of claim 32, wherein the water soluble excipient is lactose mono-hydrate.

### Claim 34 (depends on 32)

The pharmaceutical composition of claim 32, wherein the water soluble excipient is at least 50% by weight of said pharmaceutical composition.

### Claim 35 (depends on 24)

The pharmaceutical composition of claim 24, wherein the composition comprises a disintegrant.

### Claim 36 (depends on 35)

The pharmaceutical composition of claim 35, wherein the disintegrant is cros-carmellose sodium.

### Claim 37 (depends on 1)

A method of treating an immune-, inflammatory-, or cancer-related disease or disorder, comprising administering to a patient in need of such treatment the crystalline compound of claim 1.

### Claim 38 (depends on 24)

A method of treating an immune-, inflammatory-, or cancer-related disease or disorder, comprising administering to a patient in need of such treatment the pharmaceutical composition of claim 24.

### Claim 39 (depends on 37)

The method of claim 37, wherein the disease or disorder is selected from allergy-related disorders, hypersensitivity, anaphylactic responses, gastrointestinal disorders, respiratory allergic diseases, hypersensitivity lung diseases, autoimmune diseases, inflammatory dermatoses, graft rejection, allograft rejection, transplant rejection, cancer, metastatic cancer, and neurodegenerative disease.

### Claim 40 (depends on 37)

The method of claim 37, wherein the disease or disorder is selected from inflammatory bowel disease, Crohn's disease, ulcerative colitis, ileitis, enteritis, psoriasis, dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, dermatomyositis, urticaria, pruritus, vasculitis, scleroderma, asthma, COPD, allergic rhinitis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, systemic lupus erythematosus, type I diabetes, glomerulonephritis, leukemia, lymphoma, gastric cancer, atherosclerosis, Alzheimer's disease, encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis, allergic conjunctivitis, otitis, and sinusitis, idiopathic pulmonary fibrosis, contact dermatitis, pulmonary fibrosis, hepatic inflammation, asthma, thyroid carcinoma, cholangiocarcinoma, pancreatic adenocarcinoma, skin cutaneous melanoma, colon adenocarcinoma, rectum adenocarcinoma, stomach adenocarcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, nasopharangeal carcinoma, Hodgkin lymphoma, breast invasive carcinoma, lung adenocarcinoma, lung squamous cell carcinoma and granuloma development.

### Claim 41 (depends on 37)

The method of claim 37, wherein the crystalline compound is co-administered with another therapeutic agent.

### Claim 42 (depends on 41)

The method of claim 41, wherein the another therapeutic agent is pembrolizumab.

### Claim 43 (depends on 38)

The method of claim 38, wherein the disease or disorder is selected from allergy-related disorders, hypersensitivity, anaphylactic responses, gastrointestinal disorders, respiratory allergic diseases, hypersensitivity lung diseases, autoimmune diseases, inflammatory dermatoses, graft rejection, allograft rejection, transplant rejection, cancer, metastatic cancer, and neurodegenerative disease.

### Claim 44 (depends on 38)

The method of claim 38, wherein the disease or disorder is selected from inflammatory bowel disease, Crohn's disease, ulcerative colitis, ileitis, enteritis, psoriasis, dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, dermatomyositis, urticaria, pruritus, vasculitis, scleroderma, asthma, COPD, allergic rhinitis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, systemic lupus erythematosus, type I diabetes, glomerulonephritis, leukemia, lymphoma, gastric cancer, atherosclerosis, Alzheimer's disease, encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis, allergic conjunctivitis, otitis, and sinusitis, idiopathic pulmonary fibrosis, contact dermatitis, pulmonary fibrosis, hepatic inflammation, asthma, thyroid carcinoma, cholangiocarcinoma, pancreatic adenocarcinoma, skin cutaneous melanoma, colon adenocarcinoma, rectum adenocarcinoma, stomach adenocarcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, nasopharangeal carcinoma, Hodgkin lymphoma, breast invasive carcinoma, lung adenocarcinoma, lung squamous cell carcinoma and granuloma development.

### Claim 45 (depends on 38)

The method of claim 38, wherein the crystalline compound is co-administered with another therapeutic agent.

### Claim 46 (depends on 45)

The method of claim 45, wherein the another therapeutic agent is pembrolizumab.