antimalarial drugs
Patent Information
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Current Assignee / Owner
- MERCK SHARP & DOHME LLC
- Filing Date
- 2024-06-10
- Publication Date
- 2026-06-25
Smart Images
Figure 2026520957000001_ABST
Abstract
Claims
1. Structural formula I: 【Chemistry 1】 [During the ceremony, A is at least 1 -CH ２ - Saturated or unsaturated (C) linear or branched polymers containing the - group ３ -C １０ ) is an alkylene, where one or more further -CH in A ２ - The bases are independently O, S, NR, CONR, NRCO, SO ２ and SO ２ It may be replaced by a substructure selected from the group consisting of NR, and here, one or more of the hydrogens along A are hydroxyl, halogen and C １－３ It can be replaced with a group independently selected from the haloalkyl group; X is, (a) a linear or branched saturated or unsaturated (C ３ -C １０ ) alkylene, 【Chemistry 2】 (A single wavy line here) 【change】 The double dash represents the bond point to the nitrogen atom of the tetrahydropyrimidinyl ring, and the double dash represents the bond point to the nitrogen atom of the tetrahydropyrimidinyl ring. 【change】 (This represents a connection point to Z.) Selected from; J is a six-membered aryl or heteroaryl selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, and pyrazinyl, where phenyl, pyridyl, pyrimidinyl, pyridazinyl, and pyrazinyl are either unsubstituted or substituted with 1 to 3 groups independently selected from R; G is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, bicyclobutanil, bicyclopentanil, bicyclohexyl, bicycloheptyl, bicyclononanil, pyridyl, pyrimidinil, benzylpyrimidinil, pyrazolyl, and imidazolyl, where the group may be substituted with one to three of the groups of R; R stands for hydrogen, halogen, C １ -C ６ Alkyl COOH, COOH, C ３ -C ６ Cycloalkyl, C １ -C ６ Alkyl, Halo C １ -C ６ Alkyl, -O-halo C １ -C ６ Alkyl, C １ -C ６ Alkyl OH, C １ -C ６ Alkoxy, COC １ -C ６ Alkyl, C １ -C ６ Alkyl O-C １ -C ６ Alkyl, heteroaryl, or COOC １ -C ６ It is alkyl; Z is a bond, -(CH ２ ) ｐ C(O)(CH ２ ) ｐ -, -phenyl-, -C １－１０ A heteroaryl compound, where the phenyl and heteroaryl compounds may be substituted with R1-3 groups; Q is, 【Transformation 3】 [Here, a single wavy line] 【change】 The symbol represents the connection point to A, and the double wavy line 【change】 [This represents a connection point to Z.] Selected from; R １ is hydrogen, halogen, CN, OH, C １ -C ６ Alkoxy, C １ -C ６ Alkyl OC １ -C ６ Alkyl, C １ -C ６ Alkyl COOH, COOH, Oxo, COOC １ -C ６ Alkyl, C １ -C ６ Alkyl COOC １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, C １ -C ６ Alkyl C ３ -C ６ Cycloalkyl, C １ -C ６ Alkyl, -C １ -C ６ Alkyl O Halo C １ -C ６ Alkyl, Halo C １ -C ６ Alkyl, C １ -C ６ AlkylOH, CON(R) ２ ) (Caution ３ ), N (R ２ ) (Caution ３ ) or C １ -C ６ Alkyl N(R) ２ ) (Caution ３ ) and; R ２ is hydrogen, C １ -C ６ -alkyl COOH, COOH, C ３ -C ６ -cycloalkyl, C １ -C ６ -alkyl, halo C １ -C ６ -alkyl, C １ -C ６ -alkyl OH, COC １ -C ６ -alkyl or COOC １ -C ６ -alkyl; R ３ is hydrogen, C １ -C ６ -alkyl COOH, COOH, C ３ -C ６ -cycloalkyl, C １ -C ６ -alkyl, halo C １ -C ６ -alkyl, C １ -C ６ -alkyl OH, COC １ -C ６ -alkyl or COOC １ -C ６ -alkyl and is; k is an integer from 0 to 4; and, p is an integer independently selected from 0 to 4. A compound having or a pharmaceutically acceptable salt thereof.
2. A is a linear or branched saturated or unsaturated (C ３ -C ６ ) The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is alkylene.
3. Q is, 【Chemistry 4】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof.
4. Q is, 【Transformation 5】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof.
5. Q is, 【Transformation 6】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof.
6. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein Z is a bond.
7. Z is -C(O)(CH ２ ) ｐ - The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.
8. Z is -phenyl- and -C ３－１０ A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, selected from heteroaryl compounds (wherein these may be substituted with R1 to R3 groups).
9. X is a linear or branched saturated or unsaturated (C) ３ -C １０ ) A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, which is an alkylene.
10. X, 【Transformation 7】 The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein J is a condensed aromatic ring selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, and pyrazinyl (wherein phenyl, pyridyl, pyrimidinyl, pyridazinyl, and pyrazinyl are either unsubstituted or substituted with 1 to 3 groups selected from R).
11. X, 【Transformation 8】 The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.
12. X, 【Chemistry 9】 [Here, G is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclobutanil, bicyclopentanil, bicyclohexyl, bicycloheptyl, and bicyclononanil, where cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclobutanil, bicyclopentanil, bicyclohexyl, bicycloheptyl, and bicyclononanil are either unsubstituted or substituted with groups 1 to 3 of R.] The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.
13. Structural formula II: 【Chemistry 10】 [In the formula, n is an integer between 0 and 4.] A compound according to any one of claims 1 to 5 and 9 to 12, or a pharmaceutically acceptable salt thereof, as represented by [formula].
14. Q is, 【Chemistry 11】 [Here, R １ is hydrogen, halogen, OH, C １ -C ６ Alkoxy, C １ -C ６ Alkyl, -C １ - HaroC １ -C ６ Alkyl and C １ -C ６ Selected from alkylOH groups. The compound according to claim 13 or a pharmaceutically acceptable salt thereof.
15. Q is, 【Chemistry 12】 [Here, R １ is hydrogen, halogen, OH, C １ -C ６ Alkoxy, C １ -C ６ Alkyl, -C １ - HaroC １ -C ６ Alkyl and C １ -C ６ Selected from alkylOH groups. The compound according to claim 14 or a pharmaceutically acceptable salt thereof.
16. Q is, 【Chemistry 13】 [Here, R １ is hydrogen, halogen, OH, C １ -C ６ Alkoxy, C １ -C ６ Alkyl, -C １ - HaroC １ -C ６ Alkyl and C １ -C ６ Selected from alkylOH groups. The compound according to claim 14 or a pharmaceutically acceptable salt thereof.
17. X is a linear or branched saturated or unsaturated (C) ３ -C ６ ) The compound according to claim 14 or a pharmaceutically acceptable salt thereof, which is alkylene.
18. X, 【Chemistry 14】 The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein J is selected from phenyl, pyridyl, and pyrimidinyl (wherein phenyl, pyridyl, and pyrimidinyl are either unsubstituted or substituted with 1 to 3 groups selected from R).
19. X, 【Chemistry 15】 The compound according to claim 14.
20. X, 【Chemistry 16】 [Here, G is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclobutanil, bicyclopentyl, phenyl, pyridyl, pyrimidinyl, benzylpyrimidinyl, pyrazolyl, and imidazolyl, where cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclobutanil, bicyclopentyl, phenyl, pyridyl, pyrimidinyl, benzylpyrimidinyl, pyrazolyl, and imidazolyl are either unsubstituted or substituted with groups 1 to 3 of R.] The compound according to claim 14 or a pharmaceutically acceptable salt thereof.
21. R is hydrogen, CH ２ COOH, (CH ２ ) ２ COOH, CH(CH ３ ) COOH, CH ３ ,CH ２ CH ３ , (CH ２ ) ２ OCH ３ , (CH ２ ) ３ OCH ３ , (CH ２ ) ２ OCH ２ CH ３ , (CH ２ ) ３ OCH ２ CH ３ ,CH ２ F, CHF ２ CF ３ , (CH ２ ) ２ OH and (CH ２ ) ３ A compound according to any one of claims 1 to 20, selected from OH, or a pharmaceutically acceptable salt thereof.
22. below 【Chemistry 17】 【change】 【change】 【change】 【change】 A compound selected from or a pharmaceutically acceptable salt thereof.
23. A method for treating a malaria parasitic infection or a method for treating malaria, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof to a person in need of such treatment.
24. A method for inhibiting plasmmepsin X, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof to a subject in need of such treatment.
25. A method for inhibiting plasmmepsin IX, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof to a subject in need of such treatment.
26. A method for dually inhibiting plasmmepsin X and plasmmepsin IX, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof to a subject in need of such treatment.
27. Use of a compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof for treating malaria parasitic infection or malaria in patients who require treatment for malaria parasitic infection or malaria.
28. Use of a compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof for inhibiting plasmmepsin X in patients for whom inhibition of plasmmepsin X is necessary.
29. Use of a compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof for inhibiting plasmmepsin IX in patients for whom inhibition of plasmmepsin IX is necessary.
30. Use of a compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof for inhibiting plasmepsin IX and plasmepsin X in patients for whom inhibition of plasmepsin IX and plasmepsin X is necessary.
31. A pharmaceutical composition comprising a compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
32. A pharmaceutical composition comprising a compound according to any one of claims 1 to 22 and a pharmaceutically acceptable carrier.
33. A method for treating a malaria parasitic infection or a method for treating malaria, comprising administering a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 22 and an effective amount of one or more additional antimalarial drugs.
34. A method for treating malaria by inhibiting plasmmepsin X, plasmmepsin IX, and by at least one other mechanism, comprising administering a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 22 and an effective amount of one additional antimalarial agent, wherein the additional antimalarial agent acts by a mechanism different from the inhibition of plasmmepsin IX or plasmmepsin X.