Water soluble adjuvant and composition containing same

Patent metadata

Field	Value
Publication number	US-12427192-B2
Application number	US-202017600919-A
Country	US
Kind code	B2
Filing date	Apr 3, 2020
Priority date	Apr 5, 2019
Publication date	Sep 30, 2025
Grant date	Sep 30, 2025

Abstract

The present invention relates to a compound useful as a vaccine adjuvant for cancer vaccine, a preparation process thereof, a pharmaceutical composition comprising the compound, and use of the compound as a vaccine adjuvant for cancer vaccine.

First claim

The invention claimed is:

1. A compound of formula (1):

or a pharmaceutically acceptable salt thereof, wherein
X is methylene, oxygen atom, sulfur atom, SO, SO 2 , or NR 5 , wherein R 5 is hydrogen or C 1-6 alkyl,
R 1 is C 1-6 alkyl which is optionally substituted with 1-5 substituents selected independently from the group consisting of halogen, hydroxy, and C 1-6 alkoxy,
R 2 and R 3 are independently hydrogen or C 1-6 alkyl which is optionally substituted with 1-5 substituents selected independently from the group consisting of halogen, hydroxy, and C 1-6 alkoxy,
R 4 is hydrogen, halogen, hydroxy, C 1-6 alkyl, which is optionally substituted with 1-3 the same or different halogens, C 1-6 alkoxy, which is optionally substituted with 1-3 the same or different halogens, or cyano,
L is a linker, and
Y 1 is —(CH 2 CH 2 O) m —R 6 , wherein R 6 is hydrogen or C 1-6 alkyl, and m is an integer from 3-100.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X is methylene.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1-3 alkyl which is optionally substituted with 1-3 independently selected halogens.

4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein R 1 is methyl.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen, hydroxy, C 1-3 alkyl, or C 1-3 alkoxy.

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen, hydroxy, or methoxy.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is C 1-6 alkyl.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen, or C 1-3 alkyl which is optionally substituted with 1-3 hydroxy.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
L is a linker selected from —O—, —NR Y —, —C(O)—, —C(O)O—, —OC(O)—, —C(O) NR Y —,—NR Y C(O)—, —CH 2 NR Y —, —CH 2 O—, —OC(O)O—, —NR 7 C(O)O—, —OC(O)NR Y —, —NR 7 C(O)NR Y —, —OC(S)NR Y —, and —NR 7 C(S)NR Y —; wherein R 7 is hydrogen or C 1-6 alkyl; and R Y is hydrogen, C 1-6 alkyl, or Y 2 ; wherein Y 2 is —(CH 2 CH 2 O) n —R 8 ; and wherein R 8 is hydrogen atom or C 1-6 alkyl, and n is an integer from 3-100.

10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein L is —C(O)NR Y —, —CH 2 NR Y —, —C(O)O—, or —CH 2 O—.

11. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein
L is —CH 2 NR Y —, and
R Y is hydrogen, C 1-6 alkyl, or Y 2 .

12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
Y 1 is —(CH 2 CH 2 O) m —R 6 ,
R 6 is hydrogen or C 1-6 alkyl, and
m is an integer from 3-40.

13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (2):

or formula (3):

wherein
R 2 is C 1-6 alkyl,
R 3 is hydrogen or C 1-3 alkyl, which is optionally substituted with 1-3 hydroxy,
R 4 is hydrogen, hydroxy, or methoxy,
L is —CH 2 NR Y —,
R Y is hydrogen or C 1-6 alkyl,
Y 1 is —(CH 2 CH 2 O) m —R 6 ,
R 6 is hydrogen or C 1-6 alkyl, and
m is an integer from 3-20.

14. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (2):

wherein
R 2 is C 1-6 alkyl,
R 3 is hydrogen or C 1-3 alkyl, which is optionally substituted with one hydroxy,
R 4 is hydrogen or methoxy,
L is —CH 2 NR Y —,
R Y is hydrogen or C 1-6 alkyl,
Y 1 is —(CH 2 CH 2 O) m —R 6 ,
R 6 is hydrogen or C 1-6 alkyl, and
m is selected from 3-40.

15. The compound of claim 1 or a pharmaceutically acceptable salt thereof, which is selected from:
1-(4- {[2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl]methyl}-3-methoxyphenyl)-2-methyl-5,8, 11, 14-tetraoxa-2-azahexadecan-16-ol;
1-{4-[(2-amino-4- {[(3S)-1-hydroxyhexan-3-yl]amino}-6-methylpyrimidin-5-yl)methyl]-3-methoxyphenyl}-2-methyl-5,8,11,14-tetraoxa-2-azahexadecan-16-ol;
1-(3- {[2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl]methyl}-4-methoxyphenyl)-2-methyl-5,8, 11, 14-tetraoxa-2-azahexadecan-16-ol;
1-(3- {[2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl]methyl}-4-hydroxyphenyl)-2-methyl-5,8, 11, 14-tetraoxa-2-azahexadecan-16-ol;
4-[(2-amino-4- {[(2S)-1-hydroxypentan-2-yl]amino}-6-methylpyrimidin-5-yl)methyl]-N-(20-hydroxy-3,6,9,12,15, 18-hexaoxaicosan-1-yl)-3-methoxybenzamide;
2,5,8, 11-tetraoxatridecan-13-yl 4-[(2-amino-4- {[(2S)-1-hydroxypentan-2-yl]amino}-6-methylpyrimidin-5-yl)methyl]-3-methoxybenzoate;
5- {[2-methoxy-4-(2,5,8,11,14-pentaoxapentadecan-1-yl)phenyl]methyl}-6-methyl-N4-pentylpyrimidine-2,4-diamine;
1-(4- {[2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl]methyl}-3-methoxyphenyl)-2-methyl-5,8, 11, 14, 17,20,23,26,29-nonaoxa-2-azahentriacontan-31-ol;
1-(4- {[2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl]methyl}-3-methoxyphenyl)-2-methyl-5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71-tricosaoxa-2-azatriheptacontan-73-ol;
1-(4- {[2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl]methyl}-3-methoxyphenyl)-2-methyl-

5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71,74,77,80,83,86,89,92,95,98, 101,104, 107-pentatriacontaoxa-2-azanonahectan-109-ol; and
12-[(4- {[2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl]methyl}-3-methoxyphenyl)methyl]-3,6,9,15,18,21-hexaoxa-12-azatricosan-1,23-diol.

16. The compound of claim 1 or a pharmaceutically acceptable salt thereof, which is selected from:
1-(4- {[2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl]methyl}-3-methoxyphenyl)-2-methyl-5,8, 11, 14-tetraoxa-2-azahexadecan-16-ol;
1-(4- {[2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl]methyl}-3-methoxyphenyl)-2-methyl-5,8,11, 14,17,20,23,26,29-nonaoxa-2-azahentriacontan-31-ol;
1-(4- {[2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl]methyl}-3-methoxyphenyl)-2-methyl-5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71-tricosaoxa-2-azatriheptacontan-73-ol;
1-(4- {[2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl]methyl}-3-methoxyphenyl)-2-methyl-5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71,74,77,80,83,86,89,92,95,98, 101,104, 107-pentatriacontaoxa-2-azanonahectan-109-ol; and
12-[(4- {[2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl]methyl}-3-methoxyphenyl)methyl]-3,6,9,15,18,21-hexaoxa-12-azatricosan-1,23-diol.

17. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

18. The pharmaceutical composition of claim 17 , which is an emulsion formulation, an oil-based suspension, a hydrogel formulation, or a lipid formulation.

19. The pharmaceutical composition of claim 18 , which is an emulsion formulation.

20. The pharmaceutical composition of claim 19 , wherein the emulsion formulation is a water-in-oil emulsion.

21. The pharmaceutical composition of claim 20 , wherein the emulsion formulation comprises (1) e

Assignees

• Sumitomo Pharma Co Ltd

Inventors

• Ban Hitoshi
• Takanashi Yosuke
• Goto Masashi
• Suginobe Natsuko
• Imazaki Yusuke
• Iwata Yoshiko

Classifications

• A61K39/001153

  Wilms tumor 1 [WT1] · CPC title

• C07D239/49 Primary

  with an aralkyl radical, or substituted aralkyl radical, attached in position 5, e.g. trimethoprim · CPC title

• A61K2039/55566

  Emulsions, e.g. Freund's adjuvant, MF59 · CPC title

• A61K39/0011

  Cancer antigens · CPC title

• A61P35/00

  Antineoplastic agents · CPC title