# US 9,751,859 B2 · Process for preparing an anti-cancer agent, 1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine, its crystalline form and its salts

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- Number: US 9,751,859 B2
- Document ID: US9751859B2
- Status: Granted
- Kind: B2
- Application number: 15/143,630
- Filed: 2016-05-02
- Published: 2016-11-10
- Granted: 2017-09-05
- Earliest claimed: 2015-05-04
- Assignees: Advenchen Pharmaceuticals, LLC
- Applicants: Advenchen Pharmaceuticals, LLC
- Inventors: Guoqing Paul Chen; Changren Yan
- Web page: https://patentgrep.com/patent/US9751859B2

## CPC

- C07D 401/12: linked by a chain containing hetero atoms as chain links
- A61K 31/337: having four-membered rings, e.g. taxol
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 31/555: containing heavy metals, e.g. hemin, hematin, melarsoprol
- A61K 33/243: Platinum; Compounds thereof
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 27/02: Ophthalmic agents
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- C07C 55/10: Succinic acid
- C07C 57/145: Maleic acid
- C07K 16/22: against growth factors {; against growth regulators}
- A61K 31/4745: condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48)
- A61K 2039/505: {comprising antibodies}
- A61K 2300/00: Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- 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
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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)

## Abstract

The present invention relates a new process to synthesize 1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine (AL3818). A stable crystalline form of Al3818 has been prepared. Salts and their crystalline forms of AL3818 have been also prepared. Anti-cancer and optometric activities of AL3818 and its salts have been further tested. New process has been outlined in Scheme I.

## Claims

### Claim 1

A crystalline form of 1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquino-lin-7-yloxy)methyl)cyclopropanamine of AL3818 exhibiting at least one of following characters:
a melting point at 208° C.-210° C.;
a DSC Melting Range (Endo): 207-220° C. with Peak Temp=216° C., pattern shown in FIG. 1;
a TGA thermogram that doesn't exhibit significant weight loss until at 205-215° C., pattern shown in FIG. 2.

### Claim 2 (depends on 1)

A crystalline form of 1-((4-(4-Fluoro-1-methyl-1H-indol-5-yloxy)-6-methoxyquino-lin-7-yloxy)methyl)cyclopropanamine according claim 1 exhibiting a XRPD having pattern shown in FIG. 3 comprising 10 characteristic peaks with intensity % greater than 10% expressed in d values and angles as follows:
Angle
d value
13.344
6.62986
15.858
5.58405
16.799
5.27326
17.640
5.02377
18.770
4.72373
20.650
4.29771
21.633
4.10463
23.087
3.84934
25.128
3.54112
26.607
3.34755.

### Claim 3 (depends on 1)

A crystalline form of 1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquino-lin-7-yloxy)methyl)cyclopropanamine according claim 1 exhibiting a XRPD having pattern shown in FIG. 3 comprising 26 characteristic peaks with all intensity % expressed in d values and angles as follows:
d
Intensity
NO.
Angle
value
(%)
1
10.892
8.11623
2.1
2
11.589
7.62991
6.1
3
12.195
7.25174
5.9
4
13.344
6.62986
36.2
5
15.858
5.58405
31.5
6
16.799
5.27326
77.9
7
17.640
5.02377
18.8
8
18.770
4.72373
11.9
9
19.987
4.43884
7.2
10
20.650
4.29771
42.0
11
21.633
4.10463
15.3
12
23.087
3.84934
100.0
13
24.356
3.65157
3.5
14
25.128
3.54112
14.6
15
25.669
3.46768
3.8
16
26.607
3.34755
18.0
17
26.607
3.34755
3.1
18
29.050
3.07132
5.7
19
29.797
2.99602
1.5
20
30.681
2.91167
4.3
21
31.853
2.80718
1.2
22
33.524
2.67095
2.8
23
34.789
2.57667
2.6
24
35.873
2.50131
2.2
25
37.391
2.40313
3.9
26
38.637
2.32846
1.4.

### Claim 4 (depends on 1)

A pharmaceutical composition that comprises as an active ingredient a compound as defined in claim 1 of the compound and a pharmaceutically acceptable carrier.

### Claim 5 (depends on 1)

A method of treating an optometric disease, said method comprising administering a compound as defined in claim 1.

### Claim 6 (depends on 5)

A method of treating as claimed in claim 5, wherein an optometric disease is AMD and the combing anti-VEGF antibody is ranibizumab, or the VEGF trap is aflibercep.

### Claim 7 (depends on 1)

A method of treating an optometric disease, said method comprising administering a pharmaceutical composition comprising a compound as defined in claim 1 and pharmaceutically acceptable excipients to a subject in need thereof.

### Claim 8 (depends on 1)

A method of treating an optometric disease, said method comprising administering a pharmaceutical composition comprising the compound as defined claim 1 with an anti-VEGF antibody or VEGF trap to a subject in need thereof.

### Claim 9 (depends on 1)

A process to synthesize 1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquino-lin-7-yl-oxy)methyl)cyclopropanamine (AL3818) according to claim 1 where AL3818 can be prepared according to Process A1 when R is H by deprotecting intermediate (Z-1) with HCOONH4 (ammonium formate) and Pd/C in an alcoholic solvent at 25° C.-80° C. for 0.1-4 hours (Z-1) can be prepared by reacting intermediate (X1) with (Y1-1) at the presence of KI or NaI with K2CO3 in acetone or DMF at a temperature of 60° C.−160° C. for 2-24 hours.