# US 10,308,658 B2 · Salt of EGFR inhibitor, crystalline form and uses thereof

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- Number: US 10,308,658 B2
- Document ID: US10308658B2
- Status: Granted
- Kind: B2
- Application number: 15/769,065
- Filed: 2016-10-18
- Published: 2018-10-18
- Granted: 2019-06-04
- Earliest claimed: 2015-10-19
- Assignees: Sunshine Lake Pharma Co., Ltd.
- Applicants: Sunshine Lake Pharma Co., Ltd.
- Inventors: Bing Liu; Weihong Zhang; Yingjun Zhang
- Web page: https://patentgrep.com/patent/US10308658B2

## CPC

- C07D 491/056: with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
- A61K 31/517: ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/04: specific for metastasis
- A61K 31/337: having four-membered rings, e.g. taxol
- A61K 31/427: not condensed and containing further heterocyclic rings
- A61K 31/436: the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
- A61K 31/5355: Non-condensed oxazines and containing further heterocyclic rings
- A61K 31/573: substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
- A61K 31/7072: having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
- A61K 2300/00: Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
- 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

The invention relates to a salt, a hydrate or a crystalline form of an EGFR inhibitor, and use thereof. Specifically it relates to 4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-[3-[(1R,6S)-2,5-dioxa-8-azabicyclo [4.3.0] nonan-8-yl] propoxy] quinazoline dimethanesulfonate, hydrate and a crystalline form thereof; the invention also relates to a preparation method of the crystalline form disclosed herein, a pharmaceutical composition containing the crystalline form, and uses thereof for treating proliferative disorders.

## Claims

### Claim 1

A compound having Formula (I):

### Claim 2

A hydrate of a compound having formula (I).

### Claim 3 (depends on 2)

The hydrate of claim 2, wherein the hydrate is a monohydrate of the compound having formula (I).

### Claim 4

A crystalline form of a monohydrate of a compound having formula (I):
wherein the crystalline form is form I having one or more of following characteristics:
i) an X-ray powder diffraction (XRPD) pattern comprising peaks expressed in degrees 2θ at 14.88°±0.2°, 18.05°±0.2°, 20.84°±0.2°, 21.34°±0.2°, 24.39°±0.2° and 25.18°±0.2°; or/and
ii) the following structure parameters analyzed from monocrystalline:
Crystallographic System:
monoclinic system
Space Groups:
C2/c;
Cell Parameters:
a = 27.3004(5) Å, α = 90°,
b = 16.2882(3) Å, β = 103.3439(17)°,
c = 14.3529(2) Å, γ = 90°;
Volume:
6210.01(18) Å3;
Molecules number of
8.
each unit cell (Z):

### Claim 5 (depends on 4)

The crystalline form of claim 4 having an X-ray powder diffraction (XRPD) pattern comprising peaks expressed in degrees 2θ at 9.47°±0.2°, 14.88°±0.2°, 16.58°±0.2°, 17.15°±0.2°, 17.46°±0.2°, 18.05°±0.2°, 20.46°±0.2°, 20.84°±0.2°, 21.34°±0.2°, 22.71°±0.2°, 23.16°±0.2°, 24.39°±0.2°, 25.18°±0.2°, 25.46°±0.2°, 26.29°±0.2° and 28.01°±0.2°.

### Claim 6 (depends on 4)

The crystalline form of claim 4 having an X-ray powder diffraction (XRPD) pattern comprising peaks expressed in degrees 2θ at 6.36°±0.2°, 6.66°±0.2°, 9.47°±0.2°, 10.82°±0.2°, 11.70°±0.2°, 13.31°±0.2°, 14.88°±0.2°, 15.86°±0.2°, 16.58°±0.2°, 17.15°±0.2°, 17.46°±0.2°, 18.05°±0.2°, 19.30°±0.2°, 20.46°±0.2°, 20.84°±0.2°, 21.34°±0.2°, 21.76°±0.2°, 22.28°±0.2°, 22.71°±0.2°, 23.16°±0.2°, 24.07°±0.2°, 24.39°±0.2°, 25.18°±0.2°, 25.46°±0.2°, 26.29°±0.2°, 26.78°±0.2°, 27.15°±0.2°, 28.01°±0.2°, 28.80°±0.2°, 29.77°±0.2°, 30.44°±0.2°, 31.06°±0.2°, 32.05°±0.2°, 33.01°±0.2°, 33.51°±0.2°, 33.84°±0.2°, 34.90°±0.2°, 38.03°±0.2°, 38.58°±0.2° and 39.48°±0.2°.

### Claim 7 (depends on 4)

The crystalline form of claim 4 having an X-ray powder diffraction (XRPD) pattern as shown in FIG. 1.

### Claim 8 (depends on 4)

The crystalline form of claim 4 having a monocrystalline structure as shown in FIG. 3.

### Claim 9 (depends on 1)

A pharmaceutical composition comprising the compound of claim 1, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

### Claim 10 (depends on 9)

The pharmaceutical composition of claim 9 further comprising a therapeutic agent, wherein the therapeutic agent is a chemotherapeutic agent used for treating proliferative disease or cancer, an antiproliferative agent, a cytotoxic agent, a signal transduction inhibitor, an agent used for treating non-small cell lung cancer or skin cancer or a combination thereof; and wherein the therapeutic agent is adriamycin, rapamycin, temsirolimus, everolimus, ixabepilone, gemcitabine, cyclophosphamide, dexamethasone, etoposide, fluorouracil, imatinib mesylate, dasatinib, nilotinib, erlotinib, lapatinib, gefitinib, sorafenib, sunitinib, interferon, carboplatin, topotecan, paclitaxel, vinblastine, vincristine, temozolomide, tositumomab, trabedectin, bevacizumab, trastuzumab, cetuximab, panitumumab, icotinib, icotinib hydrochloride, matuzmab, neratinib, canertinib, vandetanib, cediranib, vatalanib, axitinib, motesanib, nimotuzumab, theliatinib, epitinib, simotinib, poziotinib, varlitinib, rociletinib, pelitinib, osimertinib, PKI-166, PD 158780, MDX447, Mab425, HM-61713, TAS-121, seribantumab, naquotinib, or a combination thereof.

### Claim 11 (depends on 1)

A method of inhibiting EGFR in a subject, comprising administering to the subject a therapeutically effective amount of the compound of claim 1.

### Claim 12 (depends on 1)

A method of treating a proliferative disorder in a patient, comprising administering to the patient a therapeutically effective amount of the compound of claim 1; wherein the proliferative disorder is colon cancer lung cancer or malignant glioma.

### Claim 13 (depends on 2)

A pharmaceutical composition comprising the hydrate of claim 2; and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

### Claim 14 (depends on 4)

A pharmaceutical composition comprising the crystalline form of claim 4; and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

### Claim 15 (depends on 13)

The pharmaceutical composition of claim 13 further comprising a therapeutic agent, wherein the therapeutic agent is a chemotherapeutic agent used for treating proliferative disease or cancer, an antiproliferative agent, a cytotoxic agent, a signal transduction inhibitor, an agent used for treating non-small cell lung cancer or skin cancer or a combination thereof; and wherein the therapeutic agent is adriamycin, rapamycin, temsirolimus, everolimus, ixabepilone, gemcitabine, cyclophosphamide, dexamethasone, etoposide, fluorouracil, imatinib mesylate, dasatinib, nilotinib, erlotinib, lapatinib, gefitinib, sorafenib, sunitinib, interferon, carboplatin, topotecan, paclitaxel, vinblastine, vincristine, temozolomide, tositumomab, trabedectin, bevacizumab, trastuzumab, cetuximab, panitumumab, icotinib, icotinib hydrochloride, matuzmab, neratinib, canertinib, vandetanib, cediranib, vatalanib, axitinib, motesanib, nimotuzumab, theliatinib, epitinib, simotinib, poziotinib, varlitinib, rociletinib, pelitinib, osimertinib, PKI-166, PD 158780, MDX447, Mab425, HM-61713, TAS-121, seribantumab, naquotinib, or a combination thereof.

### Claim 16 (depends on 14)

The pharmaceutical composition of claim 14 further comprising a therapeutic agent, wherein the therapeutic agent is a chemotherapeutic agent used for treating proliferative disease or cancer, an antiproliferative agent, a cytotoxic agent, a signal transduction inhibitor, an agent used for treating non-small cell lung cancer or skin cancer or a combination thereof; and wherein the therapeutic agent is adriamycin, rapamycin, temsirolimus, everolimus, ixabepilone, gemcitabine, cyclophosphamide, dexamethasone, etoposide, fluorouracil, imatinib mesylate, dasatinib, nilotinib, erlotinib, lapatinib, gefitinib, sorafenib, sunitinib, interferon, carboplatin, topotecan, paclitaxel, vinblastine, vincristine, temozolomide, tositumomab, trabedectin, bevacizumab, trastuzumab, cetuximab, panitumumab, icotinib, icotinib hydrochloride, matuzmab, neratinib, canertinib, vandetanib, cediranib, vatalanib, axitinib, motesanib, nimotuzumab, theliatinib, epitinib, simotinib, poziotinib, varlitinib, rociletinib, pelitinib, osimertinib, PKI-166, PD 158780, MDX447, Mab425, HM-61713, TAS-121, seribantumab, naquotinib, or a combination thereof.

### Claim 17 (depends on 4)

A method of inhibiting EGFR in a subject, comprising administering to the subject a therapeutically effective amount of the crystalline form of claim 4.

### Claim 18 (depends on 14)

A method of inhibiting EGFR in a subject, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 14.

### Claim 19 (depends on 4)

A method of treating the severity of a proliferative disorder in a patient, comprising administering to the patient a therapeutically effective amount of the crystalline form of claim 4, wherein the proliferative disorder is colon cancer lung cancer, or malignant glioma.

### Claim 20 (depends on 14)

A method of treating a proliferative disorder in a patient, comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition of claim 14; wherein the proliferative disorder is colon cancer, lung cancer, or malignant glioma.