Process of manufacture of a compound for inhibiting the activity of SHP2, as well as products resulting from acid addition

Patent metadata

Field	Value
Publication number	US-12138262-B2
Application number	US-201917280637-A
Country	US
Kind code	B2
Filing date	Sep 18, 2019
Priority date	Sep 29, 2018
Publication date	Nov 12, 2024
Grant date	Nov 12, 2024

Abstract

The invention relates to a method for the manufacture of a compound of Formula I as mentioned above, or a pharmaceutically acceptable salt, acid co-crystal, hydrate or other solvate thereof, said method comprising reacting a compound of the formula II with a compound of the formula III according to the following reaction scheme: wherein A, LG, n and m are as defined in the Summary of the Invention.

First claim

The invention claimed is:

1. A compound, wherein said compound is (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine monosuccinate salt, or a hydrate thereof, in crystalline form.

2. The compound of claim 1 which is (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine monosuccinate hydrate.

3. The compound of claim 1 which is (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine, succinate (1:1) in anhydrous form.

4. The compound of claim 1 which is (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine, succinate (2:1) hydrate.

5. The compound of claim 1 which is (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine, succinate (2:1) anhydrate.

6. A pharmaceutical composition comprising the compound of claim 1 and at least one pharmaceutically acceptable carrier.

7. The composition according to claim 6 , wherein the compound is (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine succinate (1:1) hydrated form H A .

8. A method of treatment comprising administering the compound of claim 1 to a patient in need of such treatment in an effective amount for the prophylactic or therapeutic treatment of a disease or disorder which is mediated by the activity of SHP2.

9. The method of claim 8 , wherein the disease or disorder mediated by the activity of SHP2 is selected from Noonan Syndrome, Leopard Syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, squamous-cell carcinoma of the head and neck, gastric carcinoma, anaplastic large-cell lymphoma and glioblastoma.

10. A combination comprising the compound of claim 1 , and one or more other pharmacologically active compounds for simultaneous, sequential or separate administration.

11. The combination of claim 10 , wherein the one or more other pharmacologically active compounds is an antiproliferative agent.

12. The compound of claim 2 , characterized by an XRPD pattern with at least three of the following 2-theta values; 8.1°, 16.3°, 17.5°, 22.5° and 26.8°.

13. The compound of claim 2 , characterized by an XRPD pattern substantially as shown in FIG. 1 .

14. The compound of claim 2 , in form H A .

Assignees

• Novartis Ag

Inventors

• Fei Zhongbo
• Lu Gang
• Wan Yinbo
• Wang Jianhua
• Wu Quanbing
• Zhang Hao

Classifications

• C07D491/107 Primary

  with only one oxygen atom as ring hetero atom in the oxygen-containing ring · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D211/62

  attached in position 4 · CPC title

• C07D211/22

  by oxygen atoms · CPC title