Medicine for treating eye diseases
阅读说明：本技术 治疗眼部疾病的药物 (Medicine for treating eye diseases ) 是由 苏里亚·坎塔·德 G·斯里达尔·普拉萨德 马歇尔·克拉克·彼得曼 伯纳德·科林斯 于 2019-04-05 设计创作，主要内容包括：提供了在有需要的受试者中治疗老花眼或白内障的方法。所述方法需要向所述受试者施用有效量的组合物,所述组合物包含抑制人α-A-晶状体蛋白的高分子量聚集体形成的化合物。据信含有某些化合物的组合物也有效治疗转甲状腺素蛋白(TTR)相关的淀粉样变性和帕金森病。(Methods of treating presbyopia or cataract in a subject in need thereof are provided. The method entails administering to the subject an effective amount of a composition comprising a compound that inhibits the formation of high molecular weight aggregates of human alpha-a-crystallin. Compositions containing certain compounds are also believed to be effective in Treating Transthyretin (TTR) -associated amyloidosis and Parkinson's disease.)
1. A method for treating presbyopia or cataract in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition comprising a compound having formula (VII)
Or a solvate or pharmaceutically acceptable salt thereof, wherein
R1Independently selected from the group consisting of: hydrogen; (C)1-C3) An alkyl group; halo (C)1-C3) An alkyl group; (C)3-C6) A cycloalkyl group; halo (C)3-C6) A cycloalkyl group; (C)1-C3) An alkoxy group; and R4C ═ O; wherein R is4Is selected from (C)1-C6) An alkyl group; halo (C)1-C6) An alkyl group; (C)3-C6) A cycloalkyl group; halo (C)3-C6) A cycloalkyl group; an aryl group; a halogenated aryl group; and wherein R is7Is (C)1-C6) Alkyl and R8Is (C)1-C6) Alkyl, aryl or polyethylene glycol groups;
R2independently selected from the group consisting of: hydrogen, R5、OR5、N(R5)(R6) Halide, CN, NO2、C(O)OR5、CON(R5)(R6)、S(O)NR5 2、SO3H、SO2CH3Phenyl, biphenyl, phenoxy-phenyl and polyethylene glycol groups, wherein R is5And R6Independently selected from hydrogen atoms, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl group, (C)3-C6) Cycloalkyl (C)1-C6) Alkyl, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkyl and (C)3-C6) Cycloalkyl halo (C)1-C6) An alkyl group; wherein R is2Can occupy 0-2 positions of the ring in which it appears; and wherein any two vicinal radicals selected are OR5In the case of radicals, two OR5The group may optionally pass through R thereof5The functional groups crosslink to form additional rings; and
R3selected from the group consisting of: hydrogen, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl group, (C)2-C6) Alkenyl, halo (C)2-C6) Alkenyl and hydroxy (C)2-C6) An alkenyl group.
2. The method of claim 1, wherein the compound is
Wherein
R1Selected from the group consisting of: wherein R is7Is (C)1-C6) Alkyl and R8Is (C)1-C6) Alkyl, aryl or polyethylene glycol groups.
3. The method of claim 1, wherein each R1Is a hydrogen atom.
4. The method of claim 1, wherein each R1Is an alkyl group.
5. The method of claim 1, wherein the first and second light sources are selected from the group consisting of,wherein one R is1Is hydrogen or alkyl, and the other R1Is carboxy, benzoyloxy or methoxy.
6. The method of claim 1, wherein the compound is
7. A method for treating presbyopia or cataract in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition comprising a compound having formula (I)
Or a solvate or pharmaceutically acceptable salt thereof, wherein
R1Is R8Or R8C ═ O, where R8Selected from hydrogen, (C)1-C6) Alkyl and (C)3-C6) Cycloalkyl, wherein alkyl and cycloalkyl are optionally substituted with one or more fluorine atoms;
R2is aryl, (C)1-C3) Alkylaryl, heteroaryl, (C)1-C3) Alkyl heteroaryl alkyl, (C)1-C3) (iii) alkylheterocyclyl, each of which is optionally substituted with up to 3 independently selected from R11Substituted with a group of (1);
R3、R4、R5、R6and R7Independently selected from hydrogen, R9、OR9、N(R9)(R10) Halogen, CN, NO2、C(O)OR9、CON(R9)(R10)、S(O)NR9 2、SO3H、SO2CH3Phenyl, biphenyl, phenoxy-phenyl and polyethylene glycol groups, wherein R is9And R10Independently selected from a hydrogen atom,(C1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl group, (C)3-C6) Cycloalkyl (C)1-C6) Alkyl, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkyl and (C)3-C6) Cycloalkyl halo (C)1-C6) An alkyl group; wherein R is3、R6And R7Can occupy 0-2 positions of its respective ring; and wherein at a position selected from R3、R4、R5、R6And R7Any two adjacent groups of (A) are OR9In the case of radicals, two OR9The group may optionally pass through R thereof9The functional groups crosslink to form additional rings; and
R11selected from the group consisting of: oxo, halo, cyano, nitro, amino, hydroxy, carboxy, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl, hydroxy (C)3-C6) Cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, (C)1-C6) Alkyl heteroaryl, halo (C)1-C6) Alkyl heteroaryl, hydroxy (C)1-C6) Alkyl heteroaryl, (C)3-C6) Cycloalkyl heteroaryl, halo (C)3-C6) Cycloalkyl heteroaryl, hydroxy (C)3-C6) Cycloalkyl heteroaryl, heterocyclyl heteroaryl, (C)1-C6) Alkylheterocyclylheteroaryl, halo (C)1-C6) Alkyl heterocyclic heteroaryl, hydroxy (C)1-C6) Alkylheterocyclylheteroaryl, heteroalkyl, heterocyclylalkyl, (CH)2)1-3COOH、(C1-C3) Alkylcarbonyloxy, (C)3-C6) Cycloalkyl (C)1-C6) Alkyl, (C)2-C6) Alkenyl, halo (C)2-C6) Alkenyl, hydroxy (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)3-C6) Cycloalkyl (C)2-C4) Alkynyl, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkyl, (C)1-C6) Alkoxy group, (C)3-C6) Cycloalkoxy, (C)3-C6) Cycloalkyl (C)1-C6) Alkoxy, halo (C)1-C6) Alkoxy, halo (C)3-C6) Cycloalkoxy, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkoxy group, (C)1-C6) Alkylthio, (C)3-C6) Cycloalkylthio, (C)3-C6) Cycloalkyl (C)1-C6) Alkylthio, halo (C)1-C6) Alkylthio, halo (C)3-C6) Cycloalkylthio, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkylthio, (C)1-C6) Alkylsulfinyl (C)3-C6) Cycloalkylsulfinyl, (C)3-C6) Cycloalkyl (C)1-C6) Alkylsulfinyl, halo (C)1-C6) Alkylsulfinyl, halo (C)3-C6) Cycloalkylsulfinyl, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkylsulfinyl (C)1-C6) Alkylsulfonyl group, (C)3-C6) Cycloalkylsulfonyl group, (C)3-C6) Cycloalkyl (C)1-C6) Alkylsulfonyl, halo (C)1-C6) Alkylsulfonyl, halo (C)3-C6) Cycloalkylsulfonyl, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkylsulfonyl group, (C)1-C6) Alkylamino radical, di (C)1-C6) Alkylamino radical, (C)1-C6) Alkoxycarbonyl, H2NCO、H2NSO2、(C1-C6) Alkylaminocarbonyl, di (C)1-C6) Alkylaminocarbonyl and (C)1-C3) Alkoxy (C)1-C3) An alkylaminocarbonyl group.
8. The method of claim 7, wherein R7Is hydrogen.
9. The method of claim 7, wherein R6Is hydrogen.
10. The method of claim 7, wherein R3Is hydrogen.
11. The method of claim 7, wherein R5Is hydrogen.
12. The method of claim 7, wherein R4Is hydrogen.
13. The method of claim 7, wherein R2Is a heteroaryl group having one ring nitrogen.
14. The method of claim 7, wherein R2Is a heteroaryl group having two ring nitrogen atoms.
15. The method of claim 7, wherein R2Is heteroaryl having one or two ring nitrogens, said rings optionally being interrupted by up to two (C)1-C6) Alkyl substitution.
16. The method of claim 7, wherein R2Is heteroaryl having one or two ring nitrogens, said rings optionally being interrupted by up to two (C)1-C6) Alkyl and oxo groups.
17. The method of claim 7, wherein the compound is one of the following compounds
18. A method for treating presbyopia or cataract in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition comprising a compound having formula (II)
Or a solvate or pharmaceutically acceptable salt thereof, wherein
X is CH2Or C ═ O
n is 1 or 2
R1、R4And R5Independently selected from hydrogen, R6、OR6、N(R6)(R7) Halide, CN, NO2、C(O)OR6、CON(R6)(R7)、S(O)NR6 2、SO3H、SO2CH3Phenyl, biphenyl, phenoxy-phenyl and polyethylene glycol groups, wherein R is6And R7Independently selected from hydrogen, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl group, (C)3-C6) Cycloalkyl (C)1-C6) Alkyl, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkyl and (C)3-C6) Cycloalkyl halo (C)1-C6) An alkyl group; wherein R is1、R4And R5Can occupy 0-2 positions of its respective ring; and wherein at a position selected from R1、R4And R5Any two adjacent groups of (A) are OR6In the case of radicals, two OR6The group may optionally pass through R thereof6The functional groups crosslink to form additional rings; and
R2selected from the group consisting of: hydrogen, (C)1-C6) Alkyl, halo (C)1-C6) Alkane (I) and its preparation methodRadical, hydroxy (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl, hydroxy (C)3-C6) Cycloalkyl and (C)1-C6) Alkoxy (C)1-C6) An alkyl group;
R3is aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by up to 3 independently selected from R8Substituted with a group of (1); and
R8selected from the group consisting of: oxo, halo, cyano, nitro, amino, hydroxy, carboxy, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl, hydroxy (C)3-C6) Cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, (C)1-C6) Alkyl heteroaryl, halo (C)1-C6) Alkyl heteroaryl, hydroxy (C)1-C6) Alkyl heteroaryl, (C)3-C6) Cycloalkyl heteroaryl, halo (C)3-C6) Cycloalkyl heteroaryl, hydroxy (C)3-C6) Cycloalkyl heteroaryl, heterocyclyl heteroaryl, (C)1-C6) Alkylheterocyclylheteroaryl, halo (C)1-C6) Alkyl heterocyclic heteroaryl, hydroxy (C)1-C6) Alkylheterocyclylheteroaryl, heteroalkyl, heterocyclylalkyl, (CH)2)1-3COOH、(C1-C3) Alkylcarbonyloxy, (C)3-C6) Cycloalkyl (C)1-C6) Alkyl, (C)2-C6) Alkenyl, halo (C)2-C6) Alkenyl, hydroxy (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)3-C6) Cycloalkyl (C)2-C4) Alkynyl, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkyl, (C)1-C6) Alkoxy group, (C)3-C6) Cycloalkoxy, (C)3-C6) Cycloalkyl (C)1-C6) Alkoxy, halo (C)1-C6) Alkoxy, halo (C)3-C6) Cycloalkoxy, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkoxy group, (C)1-C6) Alkylthio, (C)3-C6) Cycloalkylthio, (C)3-C6) Cycloalkyl (C)1-C6) Alkylthio, halo (C)1-C6) Alkylthio, halo (C)3-C6) Cycloalkylthio, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkylthio, (C)1-C6) Alkylsulfinyl (C)3-C6) Cycloalkylsulfinyl, (C)3-C6) Cycloalkyl (C)1-C6) Alkylsulfinyl, halo (C)1-C6) Alkylsulfinyl, halo (C)3-C6) Cycloalkylsulfinyl, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkylsulfinyl (C)1-C6) Alkylsulfonyl group, (C)3-C6) Cycloalkylsulfonyl group, (C)3-C6) Cycloalkyl (C)1-C6) Alkylsulfonyl, halo (C)1-C6) Alkylsulfonyl, halo (C)3-C6) Cycloalkylsulfonyl, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkylsulfonyl group, (C)1-C6) Alkylamino radical, di (C)1-C6) Alkylamino radical, (C)1-C6) Alkoxycarbonyl, H2NCO、H2NSO2、(C1-C6) Alkylaminocarbonyl, di (C)1-C6) Alkylaminocarbonyl and (C)1-C3) Alkoxy (C)1-C3) An alkylaminocarbonyl group.
19. The method of claim 18, wherein R1Is (C)3-C6) Cycloalkyl and substitutes one or two ring hydrogen atoms.
20. The method of claim 18, wherein R1Is cyclopropyl and replaces one ring hydrogen atom.
21. The method of claim 18, wherein R1Is (C)3-C6) Cycloalkyl (C)1-C6) An alkyl group.
22. The method of claim 18, wherein R1Is cyclopropylmethyl.
23. The method of claim 18, wherein R5Is hydrogen.
24. The method of claim 18, wherein R5Is hydrogen, R1Is (C)3-C6) Cycloalkyl, and substituting one or two ring hydrogen atoms.
25. The method of claim 18, wherein R5Is hydrogen and R1Is (C)3-C6) Cycloalkyl (C)1-C6) An alkyl group.
26. The method of claim 18, wherein X is CH2And R is2Is (C)1-C6) Alkoxy (C)1-C6) An alkyl group.
27. The method of claim 18, wherein R3Is an aryl group.
28. The method of claim 18, wherein R3Is a heteroaryl group.
29. The method of claim 18, wherein the compound is one of the following compounds
30. A method for treating presbyopia or cataract in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition comprising a compound having formula (III)
Or a solvate or pharmaceutically acceptable salt thereof, wherein
X is N;
p is 0 or 1;
n is 0, 1 or 2;
R1、R4and R5Independently selected from hydrogen, R6、OR6、N(R6)(R7) Halide, CN, NO2、C(O)OR6、CON(R6)(R7)、S(O)NR6 2、SO3H、SO2CH3Phenyl, biphenyl, phenoxy-phenyl and polyethylene glycol groups, wherein R is6And R7Independently selected from hydrogen atoms, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl group, (C)3-C6) Cycloalkyl (C)1-C6) Alkyl, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkyl and (C)3-C6) Cycloalkyl halo (C)1-C6) An alkyl group; wherein R is1、R4And R5Can occupy 0-2 positions of its respective ring; and wherein at a position selected from R1、R4And R5Any two adjacent groups of (A) are OR6In the case of radicals, two OR6May optionally pass through R thereof6The functional groups crosslink to form additional rings;
R2selected from the group consisting of: hydrogen, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl, hydroxy (C)3-C6) Cycloalkyl and (C)1-C6) Alkoxy (C)1-C6) An alkyl group;
R3is hydrogen, R8And SO2R8Wherein R is8Selected from the group consisting of: aryl, heteroaryl or heterocyclyl, each of which is optionally substituted with up to 3 independently selected from R9Substituted with a group of (1);
R9selected from the group consisting of: oxo, halo, cyano, nitro, amino, hydroxy, carboxy, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl, hydroxy (C)3-C6) Cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, (C)1-C6) Alkyl heteroaryl, halo (C)1-C6) Alkyl heteroaryl, hydroxy (C)1-C6) Alkyl heteroaryl, (C)3-C6) Cycloalkyl heteroaryl, halo (C)3-C6) Cycloalkyl heteroaryl, hydroxy (C)3-C6) Cycloalkyl heteroaryl, heterocyclyl heteroaryl, (C)1-C6) Alkylheterocyclylheteroaryl, halo (C)1-C6) Alkyl heterocyclic heteroaryl, hydroxy (C)1-C6) Alkylheterocyclylheteroaryl, heteroalkyl, heterocyclylalkyl, (CH)2)1-3COOH、(C1-C3) Alkylcarbonyloxy, (C)3-C6) Cycloalkyl (C)1-C6) Alkyl, (C)2-C6) Alkenyl, halo (C)2-C6) Alkenyl, hydroxy (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)3-C6) Cycloalkyl (C)2-C4) Alkynyl, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkyl, (C)1-C6) Alkoxy group, (C)3-C6) Cycloalkoxy, (C)3-C6) Cycloalkyl (C)1-C6) Alkoxy, halo (C)1-C6) Alkoxy, halo (C)3-C6) Cycloalkoxy, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkoxy group, (C)1-C6) Alkylthio, (C)3-C6) Cycloalkylthio, (C)3-C6) Cycloalkyl (C)1-C6) Alkylthio, halo (C)1-C6) Alkylthio, halo (C)3-C6) Cycloalkylthio, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkylthio, (C)1-C6) Alkylsulfinyl (C)3-C6) Cycloalkylsulfinyl, (C)3-C6) Cycloalkyl (C)1-C6) Alkylsulfinyl, halo (C)1-C6) Alkylsulfinyl, halo (C)3-C6) Cycloalkylsulfinyl, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkylsulfinyl (C)1-C6) Alkylsulfonyl group, (C)3-C6) Cycloalkylsulfonyl group, (C)3-C6) Cycloalkyl (C)1-C6) Alkylsulfonyl, halo (C)1-C6) Alkylsulfonyl, halo (C)3-C6) Cycloalkylsulfonyl, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkylsulfonyl group, (C)1-C6) Alkylamino radical, di (C)1-C6) Alkylamino radical, (C)1-C6) Alkoxycarbonyl, H2NCO、H2NSO2、(C1-C6) Alkylaminocarbonyl, di (C)1-C6) Alkylaminocarbonyl and (C)1-C3) Alkoxy (C)1-C3) An alkylaminocarbonyl group.
31. The method of claim 30, wherein R1Is hydrogen.
32. The method of claim 30, wherein R1Is hydrogen and p and n are each zero.
33. The method of claim 30, wherein X is N.
34. The method of claim 30, wherein X is N and R2Is cyclopropyl.
35. The method of claim 30, wherein R1、R4And R5Each is hydrogen.
36. The method of claim 30, wherein R3Is a heteroaryl group.
37. The method of claim 30, wherein R3Is heteroaryl substituted with heterocyclyl.
38. The method of claim 30, wherein R3Is SO2R8Wherein R is8Is a heteroaryl group.
39. The method of claim 30, wherein the compound is one of the following compounds
40. A method for treating presbyopia or cataract in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition comprising a compound having formula (IV)
Or a solvate or pharmaceutically acceptable salt thereof, wherein
R1And R3Independently of each other, hydrogen, (C)1-C3) Alkyl, halo (C)1-C3) Alkyl, (C)3-C6) Cycloalkyl and halo (C)3-C6) A cycloalkyl group;
R2selected from the group consisting of: hydrogen, (C)1-C3) Alkyl, halo (C)1-C3) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl and R5C ═ O, where R5Is selected from (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl, aryl and haloaryl;
x is O, S or NH; and
R4selected from the group consisting of: hydrogen, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl group, (C)2-C6) Alkenyl, halo (C)2-C6) Alkenyl and hydroxy (C)2-C6) An alkenyl group.
41. The method of claim 40, wherein X is O.
42. The method of claim 40, wherein X is NH.
43. The method of claim 40, wherein X is NH and R4Is (C)2-C6) An alkenyl group.
44. The method of claim 40, wherein R1Is methyl.
45. According to claim 40The process of (1), wherein R2Is hydrogen.
46. The method of claim 40, wherein R3Is methyl.
47. The method of claim 40, wherein the compound is one of the following compounds
48. A method for treating presbyopia or cataract in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition comprising a compound having formula (V)
Or a solvate or pharmaceutically acceptable salt thereof, wherein
R1Independently selected from hydrogen, R5、OR5、N(R5)(R6) Halide, CN, NO2、C(O)OR5、CON(R5)(R6)、S(O)NR6 2、SO3H、SO2CH3Phenyl, biphenyl, phenoxy-phenyl and polyethylene glycol groups, wherein R is5And R6Independently selected from hydrogen, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl group, (C)3-C6) Cycloalkyl (C)1-C6) Alkyl, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkyl and (C)3-C6) Cycloalkyl halo (C)1-C6) An alkyl group; wherein R is1Capable of occupying the ring in which it appears0-2 positions; and wherein any two vicinal radicals selected are OR5In the case of radicals, two OR5May optionally pass through R thereof5The functional groups crosslink to form additional rings;
R2is aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by up to 3 independently selected from R7Substituted with a group of (1);
R7selected from the group consisting of: oxo, halo, cyano, nitro, amino, hydroxy, carboxy, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl, hydroxy (C)3-C6) Cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, (C)1-C6) Alkyl heteroaryl, halo (C)1-C6) Alkyl heteroaryl, hydroxy (C)1-C6) Alkyl heteroaryl, (C)3-C6) Cycloalkyl heteroaryl, halo (C)3-C6) Cycloalkyl heteroaryl, hydroxy (C)3-C6) Cycloalkyl heteroaryl, heterocyclyl heteroaryl, (C)1-C6) Alkylheterocyclylheteroaryl, halo (C)1-C6) Alkyl heterocyclic heteroaryl, hydroxy (C)1-C6) Alkylheterocyclylheteroaryl, heteroalkyl, heterocyclylalkyl, (CH)2)1-3COOH、(C1-C3) Alkylcarbonyloxy, (C)3-C6) Cycloalkyl (C)1-C6) Alkyl, (C)2-C6) Alkenyl, halo (C)2-C6) Alkenyl, hydroxy (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)3-C6) Cycloalkyl (C)2-C4) Alkynyl, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkyl, (C)1-C6) Alkoxy group, (C)3-C6) Cycloalkoxy, (C)3-C6) Cycloalkyl (C)1-C6) Alkoxy, halo (C)1-C6) Alkoxy radicalHalo (C)3-C6) Cycloalkoxy, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkoxy group, (C)1-C6) Alkylthio, (C)3-C6) Cycloalkylthio, (C)3-C6) Cycloalkyl (C)1-C6) Alkylthio, halo (C)1-C6) Alkylthio, halo (C)3-C6) Cycloalkylthio, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkylthio, (C)1-C6) Alkylsulfinyl (C)3-C6) Cycloalkylsulfinyl, (C)3-C6) Cycloalkyl (C)1-C6) Alkylsulfinyl, halo (C)1-C6) Alkylsulfinyl, halo (C)3-C6) Cycloalkylsulfinyl, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkylsulfinyl (C)1-C6) Alkylsulfonyl group, (C)3-C6) Cycloalkylsulfonyl group, (C)3-C6) Cycloalkyl (C)1-C6) Alkylsulfonyl, halo (C)1-C6) Alkylsulfonyl, halo (C)3-C6) Cycloalkylsulfonyl, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkylsulfonyl group, (C)1-C6) Alkylamino radical, di (C)1-C6) Alkylamino radical, (C)1-C6) Alkoxycarbonyl, H2NCO、H2NSO2、(C1-C6) Alkylaminocarbonyl, di (C)1-C6) Alkylaminocarbonyl and (C)1-C3) Alkoxy (C)1-C3) An alkylaminocarbonyl group;
R3selected from the group consisting of: hydrogen, (C)1-C3) Alkyl, halo (C)1-C3) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl and R8C ═ O, where R8Is selected from (C)1-C6) Alkyl, halo (C)1-C6) Alkyl group (a)C3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl, aryl and haloaryl; and
R4selected from the group consisting of: (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl group, (C)2-C6) Alkenyl, halo (C)2-C6) Alkenyl and hydroxy (C)2-C6) An alkenyl group.
49. The method of claim 48, wherein R1Is hydrogen.
50. The method of claim 48, wherein R2Is an aryl group.
51. The method of claim 48, wherein R2Is a heteroaryl group.
52. The method of claim 48, wherein R4Is (C)1-C6) An alkyl group.
53. The method of claim 48, wherein R3Is hydrogen.
54. The method of claim 48, wherein the compound is
55. A method for treating presbyopia or cataract in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition comprising a compound having formula (VI)
Or a solvate or pharmaceutically acceptable salt thereof, wherein
X is H OR OR1；
R1Independently selected from the group consisting of: hydrogen, (C)1-C3) Alkyl, halo (C)1-C3) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl and R3C ═ O, where R3Is selected from (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl, aryl and haloaryl; and
R2independently selected from hydrogen, R4、OR4、N(R4)(R5) Halide, CN, NO2、C(O)OR4、CON(R4)(R4)、S(O)NR4 2、SO3H、SO2CH3Phenyl, biphenyl, phenoxy-phenyl and polyethylene glycol groups, wherein R is4And R5Independently selected from hydrogen, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl group, (C)3-C6) Cycloalkyl (C)1-C6) Alkyl, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkyl and (C)3-C6) Cycloalkyl halo (C)1-C6) An alkyl group; wherein R is2Can occupy 0-2 positions of the ring in which it appears.
56. The method of claim 55 wherein in the unfused phenyl ring, X is hydrogen.
57. The method of claim 55 wherein in the unfused phenyl ring, X is hydroxyl.
58. The method of claim 55, wherein R1Is hydrogen.
59. The method of claim 55, wherein R2Is hydrogen.
60. The method of claim 55, wherein the compound is one of the following compounds
61. A method for treating presbyopia or cataract in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition comprising a compound having formula (VIII)
Or a solvate or pharmaceutically acceptable salt thereof, wherein
R1Selected from hydrogen, halogen, hydroxy, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl group, (C)2-C6) Alkenyl and halo (C)2-C6) An alkenyl group;
R2selected from hydrogen, R3、OR3、N(R3)(R4) Halide, CN, NO2、C(O)OR3、CON(R3)(R4)、S(O)NR3 2、SO3H、SO2CH3Phenyl, biphenyl, phenoxy-phenyl and polyethylene glycol groups, wherein R is3And R4Independently selected from hydrogen atoms, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl group, (C)3-C6) Cycloalkyl (C)1-C6) Alkyl, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkyl and (C)3-C6) Cycloalkyl halo (C)1-C6) An alkyl group; wherein R is2Can occupy 0-2 positions in the ring; and wherein any two vicinal radicals selected are OR3In the case of radicals, two OR3The group may optionally pass through R thereof3The functional groups crosslink to form additional rings; and
n is an integer of 0 to 4.
62. The method of claim 61, wherein R1Is a halogen atom.
63. The method of claim 61, wherein R1Is (C)2-C6) An alkenyl group.
64. The method of claim 61, wherein R2Is a halogen atom.
65. The method of claim 61, wherein R1And R2Each is a halogen atom.
66. The method of claim 61, wherein the compound is one of the following compounds
67. A method for treating presbyopia or cataract in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition comprising a compound having formula (IX)
Or a solvate or pharmaceutically acceptable salt thereof, wherein
R1Selected from the group consisting of: hydrogen, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl group, (C)2-C6) Alkenyl, halo (C)2-C6) Alkenyl and hydroxy (C)2-C6) An alkenyl group;
x is hydrogen, halogen, hydroxy or (C)1-C6) An alkyl group; and
R2selected from hydrogen, R3、OR4、N(R3)(R4) Halide, CN, NO2、C(O)OR3、CON(R3)(R4)、S(O)NR3 2、SO3H、SO2CH3Phenyl, biphenyl, phenoxy-phenyl and polyethylene glycol groups, wherein R is3And R4Independently selected from hydrogen atoms, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl group, (C)3-C6) Cycloalkyl (C)1-C6) Alkyl, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkyl and (C)3-C6) Cycloalkyl halo (C)1-C6) An alkyl group; wherein R is2Can occupy 0-2 positions of the ring in which it appears; and wherein any two vicinal radicals selected are OR3In the case of radicals, two OR3The group may optionally pass through R thereof3The functional groups crosslink to form additional rings.
68. The method according to claim 67, wherein X is halogen.
69. The method of claim 67, wherein R1Is an alkyl group.
70. The method of claim 67, wherein R2Is hydrogen.
71. The method of claim 67, wherein the compound is
72. A method for treating presbyopia or cataract in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition comprising a compound having formula (X)
Or a solvate or pharmaceutically acceptable salt thereof, wherein,
x is O, S or N;
n and p are each an integer of 1 to 3;
R1is aryl, heteroaryl, cyclyl or heterocyclyl, each of which is optionally substituted with up to 3 independently selected from R3Substituted with a group of (1);
R2selected from the group consisting of: hydrogen, R4、OR4、N(R4)(R5) Halide, CN, NO2、C(O)OR4、CON(R4)(R5)、S(O)NR4 2、SO3H、SO2CH3Phenyl, biphenyl, phenoxy-phenyl and polyethylene glycol groups, wherein R is4And R5Independently selected from the group consisting of: hydrogen, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl group, (C)3-C6) Cycloalkyl (C)1-C6) Alkyl, halo (C)3-C6) CycloalkanesRadical (C)1-C6) Alkyl and (C)3-C6) Cycloalkyl halo (C)1-C6) An alkyl group; wherein R is2Can occupy 0-2 positions in the ring; and wherein any two vicinal radicals selected are OR4In the case of radicals, two OR4The group may optionally pass through R thereof4The functional groups crosslink to form additional rings; and
R3selected from the group consisting of: (C)1-C3) Alkyl, halo (C)1-C3) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl and R6C ═ O, where R6Is selected from (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl, aryl and haloaryl.
73. The method of claim 72, wherein X is an oxygen atom.
74. The method of claim 72, wherein X is an oxygen atom and n and p are each 1.
75. The method of claim 72, wherein R1Is an aryl group.
76. The method of claim 72, wherein R2Is hydrogen.
77. The method of claim 72, wherein the compound is
78. A method for treating presbyopia or cataract in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition comprising a compound having formula (XI)
Or a solvate or pharmaceutically acceptable salt thereof, wherein
R1Selected from the group consisting of: hydrogen, (C)1-C3) Alkyl, halo (C)1-C3) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl and R3C ═ O, where R3Is selected from (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl, aryl and haloaryl;
x is hydrogen, halogen, hydroxy or (C)1-C6) An alkyl group; and
R2selected from the group consisting of: hydrogen, R4、OR4、N(R4)(R5) Halide, CN, NO2、C(O)OR4、CON(R4)(R5)、S(O)NR4 2、SO3H、SO2CH3Phenyl, biphenyl, phenoxy-phenyl and polyethylene glycol groups, wherein R is4And R5Independently selected from hydrogen atoms, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl group, (C)3-C6) Cycloalkyl (C)1-C6) Alkyl, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkyl and (C)3-C6) Cycloalkyl halo (C)1-C6) An alkyl group; wherein R is2Can occupy 0-2 positions in the ring; and wherein any two vicinal radicals selected are OR4In the case of radicals, two OR4The group may optionally pass through R thereof4The functional groups crosslink to form additional rings.
79. The method of claim 78, wherein R1Is (C)1-C3) An alkyl group.
80. The method of claim 78, wherein R2Is hydrogen.
81. The method of claim 78, wherein X is halogen.
82. The method of claim 78, wherein the compound is
83. A method for treating presbyopia or cataract in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition comprising a compound having formula (XVII) or (XVIII)
Or a solvate or pharmaceutically acceptable salt thereof, wherein
Or OH;
or SO3H
R2Is H, X-R, CH3Lower alkyl, OCH3、OH、F、Cl、Br、NR、-CN、CO2R、CH2OH or CF3，
R is OH, And
x is NH, O, S, SO2Or N (C)1-C6) An alkyl group.
84. The method of claim 83, wherein the compound is
85. A method for treating presbyopia or cataract in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition comprising a compound having formula (XII)
Or a solvate or pharmaceutically acceptable salt thereof, wherein
R1And R2Independently selected from the group consisting of: hydrogen, (C)1-C3) An alkyl group; halo (C)1-C3) An alkyl group; (C)3-C7) A cycloalkyl group; halo (C)3-C7) A cycloalkyl group; and phenyl (C)1-C3) Alkyl, aminophenyl (C)1-C3) Alkane (I) and its preparation methodPhenyl or indanyl, wherein phenyl or indanyl is optionally substituted by halogen and amino is optionally substituted by one or two (C)1-C3) Alkyl substitution;
R3selected from the group consisting of: hydrogen, (C)3-C10) A cycloalkyl group; halo (C)3-C10) A cycloalkyl group; (C)3-C10) Cycloalkyl (C)1-C6) An alkyl group; halo (C)3-C10) Cycloalkyl (C)1-C6) An alkyl group; (C)1-C20) An alkyl group; halo (C)1-C20) An alkyl group; an aryl group; a halogenated aryl group; aryl radical (C)1-C6) An alkyl group; halogenated aryl group (C)1-C6) An alkyl group; and (C)3-C10) Heterocyclyl and halo (C)3-C10) Heterocyclyl, each of which is optionally interrupted by R at a heteroatom7CO substitution, wherein R7Selected from the group consisting of: (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C10) Cycloalkyl, halo (C)3-C10) Cycloalkyl, aryl, haloaryl, aryl (C)1-C6) Alkyl, halogenated aryl (C)1-C6) Alkyl, (C)1-C6) Alkylaryl and halo (C)1-C6) An alkylaryl group; and
R4each position at which it occurs is independently selected from the group consisting of: hydrogen; halogen; (C)1-C3) An alkyl group; halo (C)1-C3) An alkyl group; (C)1-C3) An alkoxy group; halo (C)1-C3) An alkoxy group; OH, mercapto, amino and nitro.
86. The method of claim 85, wherein R4Is hydrogen and R1And R2Each is methyl or hydrogen.
87. The method of claim 85, wherein R4Is hydrogen and R3Is (C)3-C10) Cycloalkyl or (C)3-C10) Cycloalkyl (C)1-C3) An alkyl group.
88. The method of claim 87, wherein R1Or R2Or both are hydrogen.
89. The method of claim 86, wherein R4Is hydrogen and R3Is a six-membered nitrogen-containing heterocyclic group.
90. The method of claim 89, wherein nitrogen is substituted with phenylcarbonyl or benzylcarbonyl, and wherein phenyl is optionally substituted with one or more fluorine atoms.
91. The method of claim 85, wherein the compound is selected from the group consisting of:
92. a method for treating presbyopia or cataract in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition comprising a compound having formula (XIII)
Or a solvate or pharmaceutically acceptable salt thereof, wherein
R1Independently at each position of its occurrence is hydrogen OR OR2Wherein R is2Selected from the group consisting of: hydrogen, (C)1-C3) An alkyl group; halo (C)1-C3) An alkyl group; (C)3-C7) A cycloalkyl group; halo (C)3-C7) A cycloalkyl group; phenyl (C)1-C3) Alkyl, aminophenyl (C)1-C3) Alkyl and indanyl, wherein phenyl or indanyl is optionally substituted by halogen and amino is optionally substituted by one or two (C)1-C3) Alkyl substitution;
R3selected from the group consisting of: hydrogen, (C)1-C3) An alkyl group; halo (C)1-C3) An alkyl group; (C)3-C7) A cycloalkyl group; halo (C)3-C7) A cycloalkyl group; phenyl (C)1-C3) Alkyl, aminophenyl (C)1-C3) Alkyl and indanyl, wherein phenyl or indanyl is optionally substituted by halogen and amino is optionally substituted by one or two (C)1-C3) Alkyl substitution;
R4each position at which it occurs is independently selected from the group consisting of: hydrogen; halogen; (C)1-C3) An alkyl group; halo (C)1-C3) An alkyl group; (C)1-C3) An alkoxy group; halo (C)1-C3) An alkoxy group; OH, mercapto, amino and nitro;
n is an integer of 0 to 5; and
m is an integer of 0 to 3.
93. The method of claim 92, wherein R2And R3One or both of which are methyl and n is 2 or 3.
94. The method of claim 93, wherein R4Is hydrogen.
95. The method of claim 92, wherein the compound is selected from the group consisting of:
96. a method for treating presbyopia or cataract in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition comprising a compound having formula (XIV)
Or a solvate or pharmaceutically acceptable salt thereof, wherein
R1And R2Independently selected from the group consisting of: hydrogen, (C)1-C3) An alkyl group; halo (C)1-C3) An alkyl group; (C)3-C7) A cycloalkyl group; halo (C)3-C7) A cycloalkyl group; phenyl (C)1-C3) Alkyl, aminophenyl (C)1-C3) Alkyl and indanyl, wherein phenyl or indanyl is optionally substituted by halogen and amino is optionally substituted by (C)1-C3) Alkyl and R3One or two of CO substituted, wherein R3Selected from the group consisting of: hydrogen, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C10) Cycloalkyl and halo (C)3-C10) A cycloalkyl group;
R4each position at which it occurs is independently selected from the group consisting of: hydrogen; halogen; (C)1-C3) An alkyl group; halo (C)1-C3) An alkyl group; (C)1-C3) An alkoxy group; halo (C)1-C3) An alkoxy group; OH, mercapto, amino and nitro; and
R5selected from the group consisting of: hydrogen, (C)3-C10) A cycloalkyl group; halo (C)3-C10) A cycloalkyl group; (C)3-C10) Cycloalkyl (C)1-C6) An alkyl group; halo (C)3-C10) Cycloalkyl (C)1-C6) An alkyl group; (C)1-C20) An alkyl group; halo (C)1-C20) An alkyl group; (C)3-C10) Heterocyclic radicalAnd halo (C)3-C10) Heterocyclyl, each of which is optionally interrupted by R at a heteroatom6CO substitution, wherein R6Selected from the group consisting of: (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C10) Cycloalkyl, halo (C)3-C10) Cycloalkyl, aryl, haloaryl, aryl (C)1-C6) Alkyl, halogenated aryl (C)1-C6) Alkyl, (C)1-C6) Alkylaryl and halo (C)1-C6) An alkylaryl group.
97. The method of claim 96, wherein R1And R2Each is hydrogen, methyl or CH3A CO group and R4Is hydrogen.
98. The method of claim 97, wherein R1And R2Each is CH3A CO group.
99. The method of claim 97, wherein R1And R2Each is CH3A group.
100. The method of claim 97, wherein R1And R2Each is hydrogen.
101. The method of claim 97, wherein R5Is hydrogen or carboxyl.
102. The method of claim 96, wherein the compound is selected from the group consisting of:
103. a method for treating presbyopia or cataract in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition comprising a compound having formula (XV)
Or a solvate or pharmaceutically acceptable salt thereof, wherein
R1And R2Independently selected from the group consisting of: hydrogen, (C)1-C3) An alkyl group; halo (C)1-C3) An alkyl group; (C)3-C7) A cycloalkyl group; halo (C)3-C7) A cycloalkyl group; phenyl (C)1-C3) Alkyl, aminophenyl (C)1-C3) Alkyl and indanyl, wherein phenyl or indanyl is optionally substituted by halogen and amino is optionally substituted by one or two (C)1-C3) Alkyl substitution;
R3each position at which it occurs is independently selected from the group consisting of: hydrogen; halogen; (C)1-C3) An alkyl group; halo (C)1-C3) An alkyl group; (C)1-C3) An alkoxy group; halo (C)1-C3) An alkoxy group; OH, mercapto, amino and nitro;
R4selected from the group consisting of: (C)1-C3) Alkyl, OH, NR5R6Wherein R is5And R6Each independently selected from the group consisting of: (C)1-C3) An alkyl group; halo (C)1-C3) Alkyl, (C)3-C7) A cycloalkyl group; halo (C)3-C7) A cycloalkyl group; and phenyl (C)1-C3) Alkyl, wherein phenyl is optionally substituted by halogen, (C)1-C3) Alkyl or hydroxy substitution;
x is hydrogen or nitro; and
y is H or CN.
104. The method of claim 103, wherein R1And R2Is hydrogen.
105. The method of claim 104, wherein X is nitro.
106. The method of claim 105, wherein Y is cyano.
107. The method of claim 106, wherein R4Is NR5R6，R5Is hydrogen.
108. The method of claim 107, wherein R4Is alkyl, dialkylamine or hydroxy.
109. A method according to claim 103, wherein said compound is one of the following compounds
110. A method for treating presbyopia or cataract in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition comprising a compound having formula (XVI)
Or a solvate or pharmaceutically acceptable salt thereof, wherein
R1Is hydrogen OR OR3Wherein R is3Selected from the group consisting of: hydrogen, (C)1-C3) An alkyl group; halo (C)1-C3) An alkyl group; (C)3-C7) A cycloalkyl group; halo (C)3-C7) A cycloalkyl group; phenyl (C)1-C3) Alkyl, aminophenyl (C)1-C3) Alkyl and indanyl, in which phenyl or indanyl isOptionally substituted by halogen and amino optionally substituted by one or two (C)1-C3) Alkyl substitution; and
R2each position at which it occurs is independently selected from the group consisting of: hydrogen; halogen; (C)1-C3) An alkyl group; halo (C)1-C3) An alkyl group; (C)1-C3) An alkoxy group; halo (C)1-C3) An alkoxy group; OH, sulfonyl, mercapto, amino and nitro.
111. The method of claim 110, wherein R1Is hydrogen.
112. The method of claim 110, wherein R2Is hydrogen.
113. The method of claim 110, wherein the compound is one of the following compounds
114. A method for treating presbyopia or cataract in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition comprising a compound selected from the group consisting of
115. A method for preventing and/or Treating Transthyretin (TTR) -associated amyloidosis in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition comprising a compound having the formula
Or a pharmaceutically acceptable salt thereof,
wherein R is1Selected from the group consisting of: wherein R is7Is (C)1-C6) Alkyl and R8Is (C)1-C6) Alkyl, aryl or polyethylene glycol groups.
116. The method of claim 115, wherein the compound is
117. A method for treating Parkinson's disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition comprising a compound having the formula
Wherein R is1Selected from the group consisting of: wherein R is7Is (C)1-C6) Alkyl and R8Is (C)1-C6) Alkyl, aryl or polyethylene glycol groups.
118. The method of claim 117, wherein the compound is
Background
Presbyopia is the loss of the eye's ability to accommodate, resulting in the inability to focus on near objects. Presbyopia affects everyone over the age of 45 and has a significant negative impact on quality of life. Current treatments for presbyopia include: (i) non-invasive methods that utilize devices to help improve near and distance vision, but do not restore the natural accommodative process and require continuous use of the device, and (ii) invasive surgery, which is associated with major complications including vision quality degradation, degenerative effects, refractive error, corneal ectasia, and cloudiness. Most importantly, none of these methods can reverse presbyopia. Furthermore, there are no treatment options available that can prevent or delay the onset of presbyopia.
It has been proposed that stiffening of the lens of the eye, as well as changes in lens capsule elasticity, lens size, zonule attachment size, and Ciliary Muscle (CM) contraction are all factors contributing to presbyopia. However, human and non-human primate studies indicate that CM function is normal after the onset of presbyopia. In contrast, the stiffness of the human lens increases with age in a manner directly related to the loss of accommodation (fig. 1). The loss of accommodation ability can be restored by implanting an intraocular lens made of a flexible polymer, which indicates that restoration of lens flexibility is sufficient to restore accommodation. Therefore, drugs that can prevent or reverse lens sclerosis would provide a promising avenue for novel non-invasive treatment of presbyopia.
At the molecular level, proteins called crystallins play an important role in ocular lens sclerosis. Crystallins comprise three isoforms α, β and γ and account for 90% of the eye's crystallin content. Alpha Crystallin (AC) is an ATP-independent chaperone protein and a small heat shock protein (stsp) family member, constituting 40% of the crystallin content. It exists as a heterogeneous oligomer of the two subunits, α a crystallin (AAC) and α B crystallin (ABC), and its expression is mainly restricted to the eye lens. It recognizes and isolates exposed conformational features in partially unfolded lens proteins from each other, thereby reducing the population of species prone to aggregation that would otherwise lead to various age-related visual impairments.
Several studies have established a link between stiffening of the human lens and AC function. Dynamic mechanical analysis measurements showed a significant increase in lens stiffness with age, and in particular a 500 to 1000 fold decrease in elasticity was observed in the lens nucleus (fig. 1A). This increase in lens stiffness was associated with an age-related decrease in free AC chaperone concentration, as most AC was incorporated into High Molecular Weight (HMW) aggregates by the age of 40-50 years (fig. 2). This conversion of soluble AC to HMW aggregates was accompanied by a large increase in lens stiffness (fig. 1A), presumably because the low levels of soluble AC present were insufficient to chaperone the denatured proteins. The age-related reduction in free AC chaperone protein is responsible for lens stiffness, which is supported by experiments in which the human lens is heated to mimic the age-related transformation of soluble AC to HMW aggregates and an increase in lens stiffness is observed. Similarly, purified soluble AC forms HMW aggregates with a loss of chaperone-like activity when exposed to ultraviolet radiation. HMW aggregates are formed as a result of intermolecular crosslinks, particularly S-S bonds, which are generated by the oxidation of cysteine sulfhydryls (-SH). The formation of this disulfide-crosslinked HMW aggregate is believed to be a major factor in increasing lens stiffness and loss of accommodative amplitude of the lens.
Presbyopia has been shown to be the earliest observable symptom of age-related nuclear (ARN) cataracts, which are the leading cause of blindness in the world.
Given the need for non-invasive treatments that can protect and restore lost ocular accommodation in presbyopia, and given that the formation of HMW AC aggregates is a major cause of presbyopia, there is a need to develop drugs that can selectively delay and/or reverse HMW AC aggregate formation.
Disclosure of Invention
Provided herein is a rational structure activity relationship-based method for identifying Small Molecule Depolymerases (SMDs) that inhibit the formation of HMW aggregates, human acc (haac). Several SMDs were identified based on this approach. These SMDs are believed to be useful for the treatment of presbyopia and the treatment of cataracts. Cataracts can be age-related (nuclear sclerosing cortex and posterior subcapsular), congenital, secondary, traumatic and radioactive cataracts.
In one aspect, provided herein is a method for treating presbyopia or cataract in a subject in need thereof. The method comprises administering to a subject an effective amount of a composition comprising a compound having formula (VII)
Or a solvate or pharmaceutically acceptable salt thereof, wherein
R1Independently selected from the group consisting of: hydrogen; (C)1-C3) An alkyl group; halo (C)1-C3) An alkyl group; (C)3-C6) A cycloalkyl group; halo (C)3-C6) A cycloalkyl group; (C)1-C3) An alkoxy group; and R4C ═ O; wherein R is4Is selected from (C)1-C6) An alkyl group; halo (C)1-C6) An alkyl group; (C)3-C6) A cycloalkyl group; halo (C)3-C6) A cycloalkyl group; an aryl group; a halogenated aryl group; and wherein R is7Is (C)1-C6) Alkyl and R8Is (C)1-C6) Alkyl, aryl or polyethylene glycol groups;
R2independently selected from the group consisting of: hydrogen, R5、OR5、N(R5)(R6) Halide, CN, NO2、C(O)OR5、CON(R5)(R6)、S(O)NR5 2、SO3H、SO2CH3Phenyl, biphenyl, phenoxy-phenyl and polyethylene glycol groups, wherein R is5And R6Independently selected from hydrogen atoms, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl group, (C)3-C6) Cycloalkyl (C)1-C6) Alkyl, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkyl and (C)3-C6) Cycloalkyl halo (C)1-C6) An alkyl group; wherein R is2Can occupy 0-2 positions of the ring in which it appears; and wherein any two vicinal radicals selected are OR5In the case of radicals, two OR5The group may optionally pass through R thereof5The functional groups crosslink to form additional rings; and
R3selected from the group consisting of: hydrogen, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl group, (C)2-C6) Alkenyl, halo (C)2-C6) Alkenyl and hydroxy (C)2-C6) An alkenyl group.
In one embodiment of the method where a compound having formula (VII) is desired, the compound is
Wherein
R1Selected from the group consisting of: wherein R is7Is (C)1-C6) Alkyl and R8Is (C)1-C6) Alkyl, aryl or polyethylene glycol groups.
In one embodiment of a process requiring a compound having formula (VII), each R is1Is a hydrogen atom. In another embodiment, each R1Is an alkyl group. In yet another embodiment, one R1Is hydrogen or alkyl, and the other R1Is carboxy, benzoyloxy or methoxy. In one embodiment, the compound is
In another aspect, provided herein is a method for treating presbyopia or cataract in a subject in need thereof. The method comprises administering to a subject an effective amount of a composition comprising a compound having formula (I)
Or a solvate or pharmaceutically acceptable salt thereof, wherein
R1Is R8Or R8C ═ O, where R8Selected from hydrogen, (C)1-C6) Alkyl and (C)3-C6) Cycloalkyl radicals in which the alkyl radicalAnd cycloalkyl is optionally substituted by one or more fluorine atoms;
R2is aryl, (C)1-C3) Alkylaryl, heteroaryl, (C)1-C3) Alkyl heteroaryl alkyl, (C)1-C3) (iii) alkylheterocyclyl, each of which is optionally substituted with up to 3 independently selected from R11Substituted with a group of (1);
R3、R4、R5、R6and R7Independently selected from hydrogen, R9、OR9、N(R9)(R10) Halogen, CN, NO2、C(O)OR9、CON(R9)(R10)、S(O)NR9 2、SO3H、SO2CH3Phenyl, biphenyl, phenoxy-phenyl and polyethylene glycol groups, wherein R is9And R10Independently selected from hydrogen atoms, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl group, (C)3-C6) Cycloalkyl (C)1-C6) Alkyl, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkyl and (C)3-C6) Cycloalkyl halo (C)1-C6) An alkyl group; wherein R is3、R6And R7Can occupy 0-2 positions of its respective ring; and wherein at a position selected from R3、R4、R5、R6And R7Any two adjacent groups of (A) are OR9In the case of radicals, two OR9The group may optionally pass through R thereof9The functional groups crosslink to form additional rings; and
R11selected from the group consisting of: oxo, halo, cyano, nitro, amino, hydroxy, carboxy, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl, hydroxy (C)3-C6) Cycloalkyl, heterocyclyl, aryl,Arylalkyl, heteroaryl, (C)1-C6) Alkyl heteroaryl, halo (C)1-C6) Alkyl heteroaryl, hydroxy (C)1-C6) Alkyl heteroaryl, (C)3-C6) Cycloalkyl heteroaryl, halo (C)3-C6) Cycloalkyl heteroaryl, hydroxy (C)3-C6) Cycloalkyl heteroaryl, heterocyclyl heteroaryl, (C)1-C6) Alkylheterocyclylheteroaryl, halo (C)1-C6) Alkyl heterocyclic heteroaryl, hydroxy (C)1-C6) Alkylheterocyclylheteroaryl, heteroalkyl, heterocyclylalkyl, (CH)2)1-3COOH、(C1-C3) Alkylcarbonyloxy, (C)3-C6) Cycloalkyl (C)1-C6) Alkyl, (C)2-C6) Alkenyl, halo (C)2-C6) Alkenyl, hydroxy (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)3-C6) Cycloalkyl (C)2-C4) Alkynyl, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkyl, (C)1-C6) Alkoxy group, (C)3-C6) Cycloalkoxy, (C)3-C6) Cycloalkyl (C)1-C6) Alkoxy, halo (C)1-C6) Alkoxy, halo (C)3-C6) Cycloalkoxy, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkoxy group, (C)1-C6) Alkylthio, (C)3-C6) Cycloalkylthio, (C)3-C6) Cycloalkyl (C)1-C6) Alkylthio, halo (C)1-C6) Alkylthio, halo (C)3-C6) Cycloalkylthio, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkylthio, (C)1-C6) Alkylsulfinyl (C)3-C6) Cycloalkylsulfinyl, (C)3-C6) Cycloalkyl (C)1-C6) Alkylsulfinyl, halo (C)1-C6) Alkylsulfinyl, halo (C)3-C6) Cycloalkylsulfinyl, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkylsulfinyl (C)1-C6) Alkylsulfonyl group, (C)3-C6) Cycloalkylsulfonyl group, (C)3-C6) Cycloalkyl (C)1-C6) Alkylsulfonyl, halo (C)1-C6) Alkylsulfonyl, halo (C)3-C6) Cycloalkylsulfonyl, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkylsulfonyl group, (C)1-C6) Alkylamino radical, di (C)1-C6) Alkylamino radical, (C)1-C6) Alkoxycarbonyl, H2NCO、H2NSO2、(C1-C6) Alkylaminocarbonyl, di (C)1-C6) Alkylaminocarbonyl and (C)1-C3) Alkoxy (C)1-C3) An alkylaminocarbonyl group.
In one embodiment of a method where a compound having formula (I) is desired, R7Is hydrogen. In another embodiment, R6Is hydrogen. In yet another embodiment, R3Is hydrogen. In one embodiment, R5Is hydrogen. In one embodiment, R4Is hydrogen. In one embodiment, R2Is a heteroaryl group having one ring nitrogen. In one embodiment, R2Is a heteroaryl group having two ring nitrogen atoms. In one embodiment, R2Is heteroaryl having one or two ring nitrogens, optionally substituted by up to two (C)1-C6) Alkyl substitution. In one embodiment, R2Is heteroaryl having one or two ring nitrogens, optionally substituted by up to two (C)1-C6) Alkyl and oxo groups. In one embodiment, the compound is one of the following compounds
In yet another aspect, provided herein is a method for treating presbyopia or cataract in a subject in need thereof. The method comprises administering to a subject an effective amount of a composition comprising a compound having formula (II)
Or a solvate or pharmaceutically acceptable salt thereof, wherein
X is CH2Or C ═ O
n is 1 or 2
R1、R4And R5Independently selected from hydrogen, R6、OR6、N(R6)(R7) Halide, CN, NO2、C(O)OR6、CON(R6)(R7)、S(O)NR6 2、SO3H、SO2CH3Phenyl, biphenyl, phenoxy-phenyl and polyethylene glycol groups, wherein R is6And R7Independently selected from hydrogen, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl group, (C)3-C6) Cycloalkyl (C)1-C6) Alkyl, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkyl and (C)3-C6) Cycloalkyl halo (C)1-C6) An alkyl group; wherein R is1、R4And R5Can occupy 0-2 positions of its respective ring; and wherein at a position selected from R1、R4And R5Any two adjacent groups of (A) are OR6In the case of radicals, two OR6The group may optionally pass through R thereof6The functional groups crosslink to form additional rings; and
R2selected from the group consisting of: hydrogen, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl, hydroxy (C)3-C6) Cycloalkyl and (C)1-C6) Alkoxy (C)1-C6) An alkyl group;
R3is aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by up to 3 independently selected from R8Substituted with a group of (1); and
R8selected from the group consisting of: oxo, halo, cyano, nitro, amino, hydroxy, carboxy, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl, hydroxy (C)3-C6) Cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, (C)1-C6) Alkyl heteroaryl, halo (C)1-C6) Alkyl heteroaryl, hydroxy (C)1-C6) Alkyl heteroaryl, (C)3-C6) Cycloalkyl heteroaryl, halo (C)3-C6) Cycloalkyl heteroaryl, hydroxy (C)3-C6) Cycloalkyl heteroaryl, heterocyclyl heteroaryl, (C)1-C6) Alkylheterocyclylheteroaryl, halo (C)1-C6) Alkyl heterocyclic heteroaryl, hydroxy (C)1-C6) Alkylheterocyclylheteroaryl, heteroalkyl, heterocyclylalkyl, (CH)2)1-3COOH、(C1-C3) Alkylcarbonyloxy, (C)3-C6) Cycloalkyl (C)1-C6) Alkyl, (C)2-C6) Alkenyl, halo (C)2-C6) Alkenyl, hydroxy (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)3-C6) Cycloalkyl (C)2-C4) Alkynyl, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkyl, (C)1-C6) Alkoxy group, (C)3-C6) Cycloalkoxy, (C)3-C6) Cycloalkyl (C)1-C6) Alkoxy, halo (C)1-C6) Alkoxy, halo (C)3-C6) Cycloalkoxy, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkoxy radical、(C1-C6) Alkylthio, (C)3-C6) Cycloalkylthio, (C)3-C6) Cycloalkyl (C)1-C6) Alkylthio, halo (C)1-C6) Alkylthio, halo (C)3-C6) Cycloalkylthio, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkylthio, (C)1-C6) Alkylsulfinyl (C)3-C6) Cycloalkylsulfinyl, (C)3-C6) Cycloalkyl (C)1-C6) Alkylsulfinyl, halo (C)1-C6) Alkylsulfinyl, halo (C)3-C6) Cycloalkylsulfinyl, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkylsulfinyl (C)1-C6) Alkylsulfonyl group, (C)3-C6) Cycloalkylsulfonyl group, (C)3-C6) Cycloalkyl (C)1-C6) Alkylsulfonyl, halo (C)1-C6) Alkylsulfonyl, halo (C)3-C6) Cycloalkylsulfonyl, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkylsulfonyl group, (C)1-C6) Alkylamino radical, di (C)1-C6) Alkylamino radical, (C)1-C6) Alkoxycarbonyl, H2NCO、H2NSO2、(C1-C6) Alkylaminocarbonyl, di (C)1-C6) Alkylaminocarbonyl and (C)1-C3) Alkoxy (C)1-C3) An alkylaminocarbonyl group.
In one embodiment of the method where a compound having formula (II) is desired, R1Is (C)3-C6) Cycloalkyl and substitutes one or two ring hydrogen atoms. In one embodiment, R1Is cyclopropyl and replaces one ring hydrogen atom. In one embodiment, R1Is (C)3-C6) Cycloalkyl (C)1-C6) An alkyl group. In one embodiment, R1Is cyclopropylmethyl. In one embodiment, R5Is hydrogen. In one embodiment，R5Is hydrogen, R1Is (C)3-C6) Cycloalkyl, and substituting one or two ring hydrogen atoms. In one embodiment, R5Is hydrogen and R1Is (C)3-C6) Cycloalkyl (C)1-C6) An alkyl group. In one embodiment, X is CH2And R is2Is (C)1-C6) Alkoxy (C)1-C6) An alkyl group. In one embodiment, R3Is an aryl group. In one embodiment, R3Is a heteroaryl group. In one embodiment, the compound is one of the following compounds
In another aspect, provided herein is a method for treating presbyopia or cataract in a subject in need thereof. The method comprises administering to a subject an effective amount of a composition comprising a compound having formula (III)
Or a solvate or pharmaceutically acceptable salt thereof, wherein
X is N;
p is 0 or 1;
n is 0, 1 or 2;
R1、R4and R5Independently selected from hydrogen, R6、OR6、N(R6)(R7) Halide, CN, NO2、C(O)OR6、CON(R6)(R7)、S(O)NR6 2、SO3H、SO2CH3Phenyl, biphenyl, phenoxy-phenyl and polyethylene glycol groups, wherein R is6And R7Independently selected from hydrogen atoms, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl group, (C)3-C6) Cycloalkyl (C)1-C6) Alkyl, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkyl and (C)3-C6) Cycloalkyl halo (C)1-C6) An alkyl group; wherein R is1、R4And R5Can occupy 0-2 positions of its respective ring; and wherein at a position selected from R1、R4And R5Any two adjacent groups of (A) are OR6In the case of radicals, two OR6May optionally pass through R thereof6The functional groups crosslink to form additional rings;
R2selected from the group consisting of: hydrogen, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl, hydroxy (C)3-C6) Cycloalkyl and (C)1-C6) Alkoxy (C)1-C6) An alkyl group;
R3is hydrogen, R8And SO2R8Wherein R is8Selected from the group consisting of: aryl, heteroaryl or heterocyclyl, each of which is optionally substituted with up to 3 independently selected from R9Substituted with a group of (1);
R9selected from the group consisting of: oxo, halo, cyano, nitro, amino, hydroxy, carboxy, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl, hydroxy (C)3-C6) Cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, (C)1-C6) Alkyl heteroaryl, halo (C)1-C6) Alkyl heteroaryl, hydroxy (C)1-C6) Alkyl heteroaryl, (C)3-C6) Cycloalkyl heteroaryl, halo (C)3-C6) Cycloalkyl heteroaryl, hydroxy (C)3-C6) Cycloalkyl heteroaryl, heterocyclyl heteroaryl, (C)1-C6) Alkylheterocyclylheteroaryl, halo (C)1-C6) Alkyl heterocyclic heteroaryl, hydroxy (C)1-C6) Alkylheterocyclylheteroaryl, heteroalkyl, heterocyclylalkyl, (CH)2)1-3COOH、(C1-C3) Alkylcarbonyloxy, (C)3-C6) Cycloalkyl (C)1-C6) Alkyl, (C)2-C6) Alkenyl, halo (C)2-C6) Alkenyl, hydroxy (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)3-C6) Cycloalkyl (C)2-C4) Alkynyl, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkyl, (C)1-C6) Alkoxy group, (C)3-C6) Cycloalkoxy, (C)3-C6) Cycloalkyl (C)1-C6) Alkoxy, halo (C)1-C6) Alkoxy, halo (C)3-C6) Cycloalkoxy, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkoxy group, (C)1-C6) Alkylthio, (C)3-C6) Cycloalkylthio, (C)3-C6) Cycloalkyl (C)1-C6) Alkylthio, halo (C)1-C6) Alkylthio, halo (C)3-C6) Cycloalkylthio, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkylthio, (C)1-C6) Alkylsulfinyl (C)3-C6) Cycloalkylsulfinyl, (C)3-C6) Cycloalkyl (C)1-C6) Alkylsulfinyl, halo (C)1-C6) Alkylsulfinyl, halo (C)3-C6) Cycloalkylsulfinyl, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkylsulfinyl (C)1-C6) Alkylsulfonyl group, (C)3-C6) Cycloalkylsulfonyl group, (C)3-C6) Cycloalkyl (C)1-C6) Alkylsulfonyl, halo (C)1-C6) Alkylsulfonyl, halo (C)3-C6) Cycloalkylsulfonyl, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkylsulfonyl group, (C)1-C6) Alkylamino radical, di (C)1-C6) Alkylamino radical, (C)1-C6) Alkoxycarbonyl, H2NCO、H2NSO2、(C1-C6) Alkylaminocarbonyl, di (C)1-C6) Alkylaminocarbonyl and (C)1-C3) Alkoxy (C)1-C3) An alkylaminocarbonyl group.
In one embodiment of a method where a compound having formula (III) is desired, R1Is hydrogen. In one embodiment, R1Is hydrogen and p and n are each zero. In one embodiment, X is N. In one embodiment, X is N and R2Is cyclopropyl. In one embodiment, R1、R4And R5Each is hydrogen. In one embodiment, R3Is a heteroaryl group. In one embodiment, R3Is heteroaryl substituted with heterocyclyl. In one embodiment, R3Is SO2R8Wherein R is8Is a heteroaryl group. In one embodiment, the compound is one of the following compounds
In another aspect, provided herein is a method for treating presbyopia or cataract in a subject in need thereof. The method comprises administering to a subject an effective amount of a composition comprising a compound having formula (IV)
Or a solvate or pharmaceutically acceptable salt thereof, wherein
R1And R3Independently of each other, hydrogen, (C)1-C3) Alkyl, halo (C)1-C3) Alkyl, (C)3-C6) CycloalkanesAlkyl and halo (C)3-C6) A cycloalkyl group;
R2selected from the group consisting of: hydrogen, (C)1-C3) Alkyl, halo (C)1-C3) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl and R5C ═ O, where R5Is selected from (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl, aryl and haloaryl;
x is O, S or NH; and
R4selected from the group consisting of: hydrogen, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl group, (C)2-C6) Alkenyl, halo (C)2-C6) Alkenyl and hydroxy (C)2-C6) An alkenyl group.
In one embodiment of the method where a compound having formula (IV) is desired, X is O. In one embodiment, X is NH. In one embodiment, X is NH and R4Is (C)2-C6) An alkenyl group. In one embodiment, R1Is methyl. In one embodiment, R2Is hydrogen. In one embodiment, R3Is methyl. In one embodiment, the compound is one of the following compounds
In another aspect, provided herein is a method for treating presbyopia or cataract in a subject in need thereof. The method comprises administering to a subject an effective amount of a composition comprising a compound having formula (V)
Or a solvate or pharmaceutically acceptable salt thereof, wherein
R1Independently selected from hydrogen, R5、OR5、N(R5)(R6) Halide, CN, NO2、C(O)OR5、CON(R5)(R6)、S(O)NR6 2、SO3H、SO2CH3Phenyl, biphenyl, phenoxy-phenyl and polyethylene glycol groups, wherein R is5And R6Independently selected from hydrogen, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl group, (C)3-C6) Cycloalkyl (C)1-C6) Alkyl, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkyl and (C)3-C6) Cycloalkyl halo (C)1-C6) An alkyl group; wherein R is1Can occupy 0-2 positions of the ring in which it appears; and wherein any two vicinal radicals selected are OR5In the case of radicals, two OR5May optionally pass through R thereof5The functional groups crosslink to form additional rings;
R2is aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by up to 3 independently selected from R7Substituted with a group of (1);
R7selected from the group consisting of: oxo, halo, cyano, nitro, amino, hydroxy, carboxy, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl, hydroxy (C)3-C6) Cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, (C)1-C6) Alkyl heteroaryl, halo (C)1-C6) Alkyl heteroaryl, hydroxy (C)1-C6) Alkyl heteroaryl, (C)3-C6) Cycloalkyl heteroaryl, halo (C)3-C6) Cycloalkyl heteroaryl, hydroxy (C)3-C6) Cycloalkyl heteroaryl, heterocyclyl heteroaryl, (C)1-C6) Alkylheterocyclylheteroaryl, halo (C)1-C6) Alkyl heterocyclic heteroaryl, hydroxy (C)1-C6) Alkylheterocyclylheteroaryl, heteroalkyl, heterocyclylalkyl, (CH)2)1-3COOH、(C1-C3) Alkylcarbonyloxy, (C)3-C6) Cycloalkyl (C)1-C6) Alkyl, (C)2-C6) Alkenyl, halo (C)2-C6) Alkenyl, hydroxy (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)3-C6) Cycloalkyl (C)2-C4) Alkynyl, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkyl, (C)1-C6) Alkoxy group, (C)3-C6) Cycloalkoxy, (C)3-C6) Cycloalkyl (C)1-C6) Alkoxy, halo (C)1-C6) Alkoxy, halo (C)3-C6) Cycloalkoxy, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkoxy group, (C)1-C6) Alkylthio, (C)3-C6) Cycloalkylthio, (C)3-C6) Cycloalkyl (C)1-C6) Alkylthio, halo (C)1-C6) Alkylthio, halo (C)3-C6) Cycloalkylthio, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkylthio, (C)1-C6) Alkylsulfinyl (C)3-C6) Cycloalkylsulfinyl, (C)3-C6) Cycloalkyl (C)1-C6) Alkylsulfinyl, halo (C)1-C6) Alkylsulfinyl, halo (C)3-C6) Cycloalkylsulfinyl, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkylsulfinyl (C)1-C6) Alkylsulfonyl group, (C)3-C6) Cycloalkylsulfonyl group, (C)3-C6) Cycloalkyl (C)1-C6) Alkylsulfonyl, halo (C)1-C6) Alkylsulfonyl, halo (C)3-C6) Cycloalkylsulfonyl, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkylsulfonyl group, (C)1-C6) Alkylamino radical, di (C)1-C6) Alkylamino radical, (C)1-C6) Alkoxycarbonyl, H2NCO、H2NSO2、(C1-C6) Alkylaminocarbonyl, di (C)1-C6) Alkylaminocarbonyl and (C)1-C3) Alkoxy (C)1-C3) An alkylaminocarbonyl group;
R3selected from the group consisting of: hydrogen, (C)1-C3) Alkyl, halo (C)1-C3) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl and R8C ═ O, where R8Is selected from (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl, aryl and haloaryl; and
R4selected from the group consisting of: (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl group, (C)2-C6) Alkenyl, halo (C)2-C6) Alkenyl and hydroxy (C)2-C6) An alkenyl group.
In one embodiment of the method where a compound having formula (V) is desired, R1Is hydrogen. In one embodiment, R2Is an aryl group. In one embodiment, R2Is a heteroaryl group. In one embodiment, R4Is (C)1-C6) An alkyl group. In one embodiment, R3Is hydrogen. In one embodiment, the compound is
In another aspect, provided herein is a method for treating presbyopia or cataract in a subject in need thereof. The method comprises administering to a subject an effective amount of a composition comprising a compound having formula (VI)
Or a solvate or pharmaceutically acceptable salt thereof, wherein
X is H OR OR1；
R1Independently selected from the group consisting of: hydrogen, (C)1-C3) Alkyl, halo (C)1-C3) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl and R3C ═ O, where R3Is selected from (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl, aryl and haloaryl; and
R2independently selected from hydrogen, R4、OR4、N(R4)(R5) Halide, CN, NO2、C(O)OR4、CON(R4)(R4)、S(O)NR4 2、SO3H、SO2CH3Phenyl, biphenyl, phenoxy-phenyl and polyethylene glycol groups, wherein R is4And R5Independently selected from hydrogen, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl group, (C)3-C6) Cycloalkyl (C)1-C6) Alkyl, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkyl and (C)3-C6) Cycloalkyl halo (C)1-C6) An alkyl group; wherein R is2Can occupy 0-2 positions of the ring in which it appears.
In one embodiment of a method where a compound having formula (VI) is desired, in the unfused phenyl ring, X is hydrogen. In one embodiment, in the unfused phenyl ring, X is hydroxy. In one embodiment, R1Is hydrogen. In one embodiment, R2Is hydrogen. In one embodiment, the compound is one of the following compounds
In another aspect, provided herein is a method for treating presbyopia or cataract in a subject in need thereof. The method comprises administering to a subject an effective amount of a composition comprising a compound having formula (VIII)
Or a solvate or pharmaceutically acceptable salt thereof, wherein
R1Selected from hydrogen, halogen, hydroxy, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl group, (C)2-C6) Alkenyl and halo (C)2-C6) An alkenyl group;
R2selected from hydrogen, R3、OR3、N(R3)(R4) Halide, CN, NO2、C(O)OR3、CON(R3)(R4)、S(O)NR3 2、SO3H、SO2CH3Phenyl, biphenyl, phenoxy-phenyl and polyethylene glycol groups, wherein R is3And R4Independently selected from hydrogen atoms, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl group, (C)3-C6) Cycloalkyl (C)1-C6) Alkyl, halo (C)3-C6) Ring (C)Alkyl radical (C)1-C6) Alkyl and (C)3-C6) Cycloalkyl halo (C)1-C6) An alkyl group; wherein R is2Can occupy 0-2 positions in the ring; and wherein any two vicinal radicals selected are OR3In the case of radicals, two OR3The group may optionally pass through R thereof3The functional groups crosslink to form additional rings; and
n is an integer of 0 to 4.
In one embodiment of a process requiring a compound having formula (VIII), R1Is a halogen atom. In one embodiment, R1Is (C)2-C6) An alkenyl group. In one embodiment, R2Is a halogen atom. In one embodiment, R1And R2Each is a halogen atom. In one embodiment, the compound is one of the following compounds
In another aspect, provided herein is a method for treating presbyopia or cataract in a subject in need thereof. The method comprises administering to a subject an effective amount of a composition comprising a compound having formula (IX)
Or a solvate or pharmaceutically acceptable salt thereof, wherein
R1Selected from the group consisting of: hydrogen, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl group, (C)2-C6) Alkenyl, halo (C)2-C6) Alkenyl and hydroxy (C)2-C6) An alkenyl group;
x is hydrogen, halogen, hydroxy or (C)1-C6) An alkyl group; and
R2selected from hydrogen, R3、OR4、N(R3)(R4) Halide, CN, NO2、C(O)OR3、CON(R3)(R4)、S(O)NR3 2、SO3H、SO2CH3Phenyl, biphenyl, phenoxy-phenyl and polyethylene glycol groups, wherein R is3And R4Independently selected from hydrogen atoms, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl group, (C)3-C6) Cycloalkyl (C)1-C6) Alkyl, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkyl and (C)3-C6) Cycloalkyl halo (C)1-C6) An alkyl group; wherein R is2Can occupy 0-2 positions of the ring in which it appears; and wherein any two vicinal radicals selected are OR3In the case of radicals, two OR3The group may optionally pass through R thereof3The functional groups crosslink to form additional rings.
In one embodiment of the method where a compound having formula (IX) is desired, X is halogen. In one embodiment, R1Is an alkyl group. In one embodiment, R2Is hydrogen. In one embodiment, the compound is
In another aspect, provided herein is a method for treating presbyopia or cataract in a subject in need thereof. The method comprises administering to a subject an effective amount of a composition comprising a compound having formula (X)
Or a solvate or pharmaceutically acceptable salt thereof, wherein,
x is O, S or N;
n and p are each an integer of 1 to 3;
R1is aryl, heteroaryl, cyclyl or heterocyclyl, each of which is optionally substituted with up to 3 independently selected from R3Substituted with a group of (1);
R2selected from the group consisting of: hydrogen, R4、OR4、N(R4)(R5) Halide, CN, NO2、C(O)OR4、CON(R4)(R5)、S(O)NR4 2、SO3H、SO2CH3Phenyl, biphenyl, phenoxy-phenyl and polyethylene glycol groups, wherein R is4And R5Independently selected from the group consisting of: hydrogen, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl group, (C)3-C6) Cycloalkyl (C)1-C6) Alkyl, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkyl and (C)3-C6) Cycloalkyl halo (C)1-C6) An alkyl group; wherein R is2Can occupy 0-2 positions in the ring; and wherein any two vicinal radicals selected are OR4In the case of radicals, two OR4The group may optionally pass through R thereof4The functional groups crosslink to form additional rings; and
R3selected from the group consisting of: (C)1-C3) Alkyl, halo (C)1-C3) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl and R6C ═ O, where R6Is selected from (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl, aryl and haloaryl.
In one embodiment of the method where a compound having formula (X) is desired, X is an oxygen atom. In one embodiment, X is an oxygen atom and n and p are each 1. In one embodimentIn, R1Is an aryl group. In one embodiment, R2Is hydrogen. In one embodiment, the compound is
In another aspect, provided herein is a method for treating presbyopia or cataract in a subject in need thereof. The method comprises administering to a subject an effective amount of a composition comprising a compound having formula (XI)
Or a solvate or pharmaceutically acceptable salt thereof, wherein
R1Selected from the group consisting of: hydrogen, (C)1-C3) Alkyl, halo (C)1-C3) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl and R3C ═ O, where R3Is selected from (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl, aryl and haloaryl;
x is hydrogen, halogen, hydroxy or (C)1-C6) An alkyl group; and
R2selected from the group consisting of: hydrogen, R4、OR4、N(R4)(R5) Halide, CN, NO2、C(O)OR4、CON(R4)(R5)、S(O)NR4 2、SO3H、SO2CH3Phenyl, biphenyl, phenoxy-phenyl and polyethylene glycol groups, wherein R is4And R5Independently selected from hydrogen atoms, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl, halo (C)3-C6) Cycloalkyl group, (C)3-C6) Cycloalkyl (C)1-C6) Alkyl, halo (C)3-C6) Cycloalkyl (C)1-C6) Alkyl and (C)3-C6) Cycloalkyl halo (C)1-C6) An alkyl group; wherein R is2Can occupy 0-2 positions in the ring; and wherein any two vicinal radicals selected are OR4In the case of radicals, two OR4The group may optionally pass through R thereof4The functional groups crosslink to form additional rings.
In one embodiment of the process where a compound having formula (XI) is desired, R1Is (C)1-C3) An alkyl group. In one embodiment, R2Is hydrogen. In one embodiment, X is halogen. In one embodiment, the compound is
In another aspect, provided herein is a method for treating presbyopia or cataract in a subject in need thereof. The method comprises administering to the subject an effective amount of a composition comprising a compound having formula (XVII) or (XVIII)
Or a solvate or pharmaceutically acceptable salt thereof, wherein
R is Or OH;
R1is that Or SO3H
R2Is H, X-R, CH3Lower alkyl, OCH3、OH、F、Cl、Br、NR、-CN、CO2R、CH2OH or CF3。
R is OH, And
x is NH, O, S, SO2Or N (C)1-C6) An alkyl group.
In one embodiment of the method where a compound having formula (XVII) or (XVIII) is desired, the compound is
In another aspect, provided herein is a method for treating presbyopia or cataract in a subject in need thereof. The method comprises administering to the subject an effective amount of a composition comprising a compound having formula (XII)
Or a solvate or pharmaceutically acceptable salt thereof, wherein
R1And R2Independently selected from the group consisting of: hydrogen, (C)1-C3) An alkyl group; halo (C)1-C3) An alkyl group; (C)3-C7) A cycloalkyl group; halo (C)3-C7) A cycloalkyl group; and phenyl (C)1-C3) Alkyl, aminophenyl (C)1-C3) Alkyl and indanyl, wherein phenyl or indanyl is optionally substituted by halogen and amino is optionally substituted by one or two (C)1-C3) Alkyl substitution;
R3selected from the group consisting of: hydrogen, (C)3-C10) A cycloalkyl group; halo (C)3-C10) A cycloalkyl group; (C)3-C10) Cycloalkyl (C)1-C6) An alkyl group; halo (C)3-C10) Cycloalkyl (C)1-C6) An alkyl group; (C)1-C20) An alkyl group; halo (C)1-C20) An alkyl group; an aryl group; a halogenated aryl group; aryl radical (C)1-C6) An alkyl group; halogenated aryl group (C)1-C6) An alkyl group; and (C)3-C10) Heterocyclyl and halo (C)3-C10) Heterocyclyl, each of which is optionally interrupted by R at a heteroatom7CO substitution, wherein R7Selected from the group consisting of: (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C10) Cycloalkyl, halo (C)3-C10) Cycloalkyl, aryl, haloaryl, aryl (C)1-C6) Alkyl, halogenated aryl (C)1-C6) Alkyl, (C)1-C6) Alkylaryl and halo (C)1-C6) An alkylaryl group; and
R4each position at which it occurs is independently selected from the group consisting of: hydrogen; halogen; (C)1-C3) An alkyl group; halo (C)1-C3) An alkyl group; (C)1-C3) An alkoxy group; halo (C)1-C3) An alkoxy group; OH, mercapto, amino and nitro.
In one embodiment of a process requiring a compound having formula (XII), R4Is hydrogen and R1And R2Each is methyl or hydrogen. In a related embodiment, R4Is hydrogen and R3Is a six-membered nitrogen-containing heterocyclic group. Further, the nitrogen may be substituted with phenylcarbonyl or benzylcarbonyl, and the phenyl group may be optionally substituted with one or more fluorine atoms.
In one embodiment, R4Is hydrogen and R3Is (C)3-C10) Cycloalkyl or (C)3-C10) Cycloalkyl (C)1-C3) An alkyl group. In a related embodiment, R1Or R2Or both are hydrogen.
In one embodiment, the compound is selected from the group consisting of:
in another aspect, provided herein is a method for treating presbyopia or cataract in a subject in need thereof. The method comprises administering to a subject an effective amount of a composition comprising a compound having formula (XIII)
Or a solvate or pharmaceutically acceptable salt thereof, wherein
R1Independently at each position of its occurrence is hydrogen OR OR2Wherein R is2Selected from the group consisting of: hydrogen, (C)1-C3) An alkyl group; halo (C)1-C3) An alkyl group; (C)3-C7) A cycloalkyl group; halo (C)3-C7) A cycloalkyl group; phenyl (C)1-C3) Alkyl, aminophenyl (C)1-C3) Alkyl and indanyl, wherein phenyl or indanyl is optionally substituted by halogen and amino is optionally substituted by one or two (C)1-C3) Alkyl substitution;
R3selected from the group consisting of: hydrogen, (C)1-C3) An alkyl group; halo (C)1-C3) An alkyl group; (C)3-C7) A cycloalkyl group; halo (C)3-C7) A cycloalkyl group; phenyl (C)1-C3) Alkyl, aminophenyl (C)1-C3) Alkyl and indeneAn alkynyl group wherein the phenyl or indanyl group is optionally substituted by halogen and the amino group is optionally substituted by one or two (C)1-C3) Alkyl substitution;
R4each position at which it occurs is independently selected from the group consisting of: hydrogen; halogen; (C)1-C3) An alkyl group; halo (C)1-C3) An alkyl group; (C)1-C3) An alkoxy group; halo (C)1-C3) An alkoxy group; OH, mercapto, amino and nitro;
n is an integer of 0 to 5; and
m is an integer of 0 to 3.
In one embodiment of a process requiring a compound having formula (XIII), R2And R3One or both of which are methyl and n is 2 or 3. In a related embodiment, R4Is hydrogen.
In one embodiment, the compound is selected from the group consisting of:
in another aspect, provided herein is a method for treating presbyopia or cataract in a subject in need thereof. The method comprises administering to the subject an effective amount of a composition comprising a compound having formula (XIV)
Or a solvate or pharmaceutically acceptable salt thereof, wherein
R1And R2Independently selected from the group consisting of: hydrogen, (C)1-C3) An alkyl group; halo (C)1-C3) An alkyl group; (C)3-C7) A cycloalkyl group; halo (C)3-C7) A cycloalkyl group; phenyl (C)1-C3) Alkyl, aminophenyl (C)1-C3) Alkyl and indanyl, wherein phenyl or indanyl is optionally substitutedHalogen substituted and amino optionally substituted by (C)1-C3) Alkyl and R3One or two of CO substituted, wherein R3Selected from the group consisting of: hydrogen, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C10) Cycloalkyl and halo (C)3-C10) A cycloalkyl group;
R4each position at which it occurs is independently selected from the group consisting of: hydrogen; halogen; (C)1-C3) An alkyl group; halo (C)1-C3) An alkyl group; (C)1-C3) An alkoxy group; halo (C)1-C3) An alkoxy group; OH, mercapto, amino and nitro; and
R5selected from the group consisting of: hydrogen, (C)3-C10) A cycloalkyl group; halo (C)3-C10) A cycloalkyl group; (C)3-C10) Cycloalkyl (C)1-C6) An alkyl group; halo (C)3-C10) Cycloalkyl (C)1-C6) An alkyl group; (C)1-C20) An alkyl group; halo (C)1-C20) An alkyl group; (C)3-C10) Heterocyclyl and halo (C)3-C10) Heterocyclyl, each of which is optionally interrupted by R at a heteroatom6CO substitution, wherein R6Selected from the group consisting of: (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)3-C10) Cycloalkyl, halo (C)3-C10) Cycloalkyl, aryl, haloaryl, aryl (C)1-C6) Alkyl, halogenated aryl (C)1-C6) Alkyl, (C)1-C6) Alkylaryl and halo (C)1-C6) An alkylaryl group.
In one embodiment of the method where a compound having formula (XIV) is desired, R1And R2Each is hydrogen, methyl or CH3A CO group and R4Is hydrogen. In a related embodiment, R1And R2Each is CH3A CO group. In another related embodiment, R1And R2Each is CH3A group. In another related embodiment, R1And R2Each is hydrogen. In another related embodiment, R5Is hydrogen or carboxyl.
In one embodiment, the compound is selected from the group consisting of:
in another aspect, provided herein is a method for treating presbyopia or cataract in a subject in need thereof. The method comprises administering to a subject an effective amount of a composition comprising a compound having formula (XV)
Or a solvate or pharmaceutically acceptable salt thereof, wherein
R1And R2Independently selected from the group consisting of: hydrogen, (C)1-C3) An alkyl group; halo (C)1-C3) An alkyl group; (C)3-C7) A cycloalkyl group; halo (C)3-C7) A cycloalkyl group; phenyl (C)1-C3) Alkyl, aminophenyl (C)1-C3) Alkyl and indanyl, wherein phenyl or indanyl is optionally substituted by halogen and amino is optionally substituted by one or two (C)1-C3) Alkyl substitution;
R3each position at which it occurs is independently selected from the group consisting of: hydrogen; halogen; (C)1-C3) An alkyl group; halo (C)1-C3) An alkyl group; (C)1-C3) An alkoxy group; halo (C)1-C3) An alkoxy group; OH, mercapto, amino and nitro;
R4selected from the group consisting of: (C)1-C3) Alkyl, OH, NR5R6Wherein R is5And R6Each independently selected from the group consisting ofGroup (2): (C)1-C3) An alkyl group; halo (C)1-C3) Alkyl, (C)3-C7) A cycloalkyl group; halo (C)3-C7) A cycloalkyl group; and phenyl (C)1-C3) Alkyl, wherein phenyl is optionally substituted by halogen, (C)1-C3) Alkyl or hydroxy substitution;
x is hydrogen or nitro; and
y is H or CN.
In one embodiment of a method where a compound having formula (XV) is desired, R1And R2Is hydrogen. Further, X may be nitro. Further, Y may be cyano. Further, R4May be NR5R6，R5Is hydrogen. Further, R4May be an alkyl, dialkylamine or hydroxyl group.
In one embodiment, the compound is one of the following compounds
In another aspect, provided herein is a method for treating presbyopia or cataract in a subject in need thereof. The method comprises administering to the subject an effective amount of a composition comprising a compound having formula (XVI)
Or a solvate or pharmaceutically acceptable salt thereof, wherein
R1Is hydrogen OR OR3Wherein R is3Selected from the group consisting of: hydrogen, (C)1-C3) An alkyl group; halo (C)1-C3) An alkyl group; (C)3-C7) A cycloalkyl group; halo (C)3-C7) A cycloalkyl group; phenyl (C)1-C3) Alkyl, aminophenyl (C)1-C3) Alkyl and indanyl, wherein phenyl or indanyl is optionally substituted by halogen and aminoOptionally one or two (C)1-C3) Alkyl substitution; and
R2each position at which it occurs is independently selected from the group consisting of: hydrogen; halogen; (C)1-C3) An alkyl group; halo (C)1-C3) An alkyl group; (C)1-C3) An alkoxy group; halo (C)1-C3) An alkoxy group; OH, sulfonyl, mercapto, amino and nitro.
In one embodiment of a process requiring a compound having formula (XVI), R1Is hydrogen. In one embodiment, R2Is hydrogen. In one embodiment, the compound is one of the following compounds
In another aspect, provided herein is a method for treating presbyopia or cataract in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition comprising a compound selected from the group consisting of
In another aspect, provided herein is a method for preventing and/or Treating Transthyretin (TTR) -associated amyloidosis in a subject in need thereof. The method comprises administering to a subject an effective amount of a composition comprising a compound having the formula
Or a pharmaceutically acceptable salt thereof,
wherein R is1Selected from the group consisting of: wherein R is7Is (C)1-C6) Alkyl and R8Is (C)1-C6) Alkyl, aryl or polyethylene glycol groups.
In one embodiment, the compound is
In another aspect, provided herein is a method for treating parkinson's disease in a subject in need thereof. The method comprises administering to a subject an effective amount of a composition comprising a compound having the formula
Wherein R is1Selected from the group consisting of: wherein R is7Is (C)1-C6) Alkyl and R8Is (C)1-C6) Alkyl, aryl or polyethylene glycol groups.
In one embodiment, the compound is
Drawings
FIGS. 1A-1D show the results of experiments described in the prior art. Fig. 1A and 1B depict graphs of the stiffness (1A) and loss of accommodation (diopter) (1B) of the lens cortex and nucleus as a function of age. The figure represents a summary of four independent human regulatory studies. Fig. 1C depicts the mass distribution of the water soluble fraction in young (19 years) (solid and filled circles) and old (83 years) (dotted and open circles) human lenses using SEC-MALS (multi-angle light scattering). Fig. 1D shows the change in soluble AC (open circles) and high molecular weight protein (closed circles) content in the lens nucleus as a function of age.
FIG. 2A shows the effect of exposing 500. mu.g/ml of hAAC to UVC. FIG. 2B shows subjecting hAAC to Ca+2Heat 0, 5, 15 and 30 minutes. The absorbance at 360/400nm was measured at each time point. Mean ± SEM of measurements are shown.
Figures 3A and 3B show representative data of the extent to which a compound (or DMSO control) protected hAAC from aggregation. Aggregation was monitored by absorbance at 360nm for 120 minutes for UV induced aggregation (3A), or by absorbance at 400nm for 120 minutes for heat induced aggregation (3B). Mean ± SEM of measurements are shown.
FIGS. 4A-4F show the structure-activity relationship (SAR) -based classification of compounds found from UV and heat-induced hAAC aggregation assays. Compounds were divided into three series, series 1: a macrocycle; series 2: "covalent", and series 3: catechol. FIGS. 4A, 4C and 4E show the EC of a compound from the macrocyclic, covalent and catechol series, respectively50Curve line. Figures 4B, 4D and 4F show the percentage of 200 μ M compound from the macrocycle, covalent and catechol series, respectively, protected from aggregation. Measurements to assess protection were performed in triplicate.
Fig. 5 shows the results of biochemical tests of SMD participation in the target (i.e., hACC). hACC (500ug/ml) was treated with 200. mu.M CAP1613 and CAP1614 overnight and exposed to UV at 0, 5, 15 or 30. Samples from each time point were run on SDS-PAGE under non-reducing conditions. The top and bottom boxes of the gel show insoluble and soluble HMW aggregates, respectively.
Fig. 6A shows a sequence alignment of mammalian AAC. Conserved Cys (Cys131) is highlighted. Cys (Cys142) present only in human and chimpanzees is also highlighted. The 3D model structure of hAAC (inset) is shown on the right, showing the positions of residues Cys131 and Cys 142. Figure 6B shows a reaction scheme for the modification of cysteine with cysteine-reactive acrylamide (a) and chloroacetamide (B).
Figure 7A shows the results of viability of HLE cells (B3 and SRA 01/04) exposed to UV (left) or heat (right), evaluated 24 hours after exposure. Alamar blue was used to assess viability. Mean ± SEM of measurements are shown.
Figure 7B shows the protection of SRA 01/04 cells (human lens epithelial cell line) pre-incubated with different concentrations of compound two hours prior to UV exposure. Relative protection was measured as percent viability compared to vehicle control at 24 hours post UV exposure. The effect from each of the three different chemical series (macrocyclic, covalent and catechol) is shown. Mean ± SEM of measurements are shown.
FIG. 8A shows ectopic expression of AAC-EGFP in B-3 cells, which forms inclusion bodies (arrows) co-localized with p 62. Figure 8B shows automated image analysis results for >2500 cells. A statistically significant increase in GFP positive inclusion bodies due to AAC overexpression was observed. Mean ± SEM and p-values of the measurements are shown (t-test).
FIGS. 9A-9F show the EC for selected compounds50Curve, depicts hAAC vs. UVC and Ca+2Fold change in protection of induced aggregation.
Fig. 10A-10C are graphs showing dose-dependent protection of human lens epithelial cells (HLE) from UV radiation-induced cell death. SRA 01/04HLE cells were preincubated with different concentrations of compounds for 3 hours and exposed to UV light (9600 mJ/cm)2254 nm). After 24 hours, the percent viability was assessed by alamar blue compared to the unirradiated control. Mean ± SD and linear regression curve fit values generated using Graphpad software are provided, along with the calculated EC50(μ M).
FIGS. 11A-11D show the effect of CAP1159 on the exposure of the lens of the eye to UVC radiation.
FIG. 11A shows the exposure to 480mJ/cm in the presence or absence of varying concentrations of CAP11592Representative dark field digital images of porcine eye lenses at 2 hours of UVC irradiation per minute (from a set of n-12 lens experiments). The first row of the figure corresponds to lenses that were not exposed to UVC but contained the same percentage of DMSO as those exposed to UVC. After exposure to UVC, the lenses were monitored and imaged for three days. No drug was added to the lens after UVC exposure.
Fig. 11B shows the results scored for cataractous lenses on days 1, 2 and 3 after exposure to UVC radiation in the study shown in fig. 11A (n-12). Fig. 11A shows the scale (0-9) for grading.
Fig. 11C shows the progression of cataract within three days after UVC exposure.
Fig. 11D is a bar graph showing soluble protein content from the treatment group (CAP1159) and the control group measured at 280nm at the end of the three day period. The lenses of each group were lysed and the supernatants were pooled to measure the total soluble protein content of each group.
FIGS. 12A-12D show the effect of CAP1160 on exposure of the lens of the eye to UVC radiation.
FIG. 12A shows the exposure to 480mJ/cm in the presence or absence of various concentrations of CAP11602Representative dark field digital images of porcine eye lenses at 2 hours of UVC irradiation per minute (from a set of n-12 lens experiments). The first row of the figure corresponds to lenses that were not exposed to UVC but contained the same percentage of DMSO as those exposed to UVC. After exposure to UVC, the lenses were monitored and imaged for three days. No drug was added to the lens after UVC exposure.
Fig. 12B shows the results scored for cataractous lenses on days 1, 2 and 3 after exposure to UVC radiation in the study shown in fig. 12A (n-12). Fig. 12A shows the scales (0-9) used for grading.
Fig. 12C shows the progression of cataract monitored over three days following UVC exposure.
Fig. 12D is a bar graph showing soluble protein content from the treatment group (CAP1160) and the control group measured at 280nm at the end of the three day period. The lenses of each group were lysed and the supernatants were pooled to measure the total soluble protein content of each group.
Detailed Description
Compounds and definitions
As used herein, the terms "halo" and "halogen" refer to an atom selected from the group consisting of fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I).
The term "alkyl", employed alone or as part of a larger moiety, such as, for example, "haloalkyl", means, unless otherwise stated, a saturated monovalent straight or branched chain hydrocarbon radical having from 1 to 10 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like. "monovalent" means attached at one point to the rest of the molecule.
The term "cycloalkyl", employed alone or as part of a larger moiety, means, unless otherwise stated, a saturated cyclic aliphatic monocyclic, bicyclic, or tricyclic ring system having 3 to 10 carbon ring atoms as described herein. Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, and cyclooctyl. Bicyclic cycloalkyl groups include, for example, cycloalkyl fused to another cycloalkyl group such as decalin, or cycloalkyl fused to an aryl (e.g., phenyl) or heteroaryl group, such as tetrahydronaphthyl, indanyl, 5,6,7, 8-tetrahydroquinoline, and 5,6,7, 8-tetrahydroisoquinoline. An example of a tricyclic ring system is adamantane. It is understood that the point of attachment of the bicyclic cycloalkyl can be on the cycloalkyl moiety, or can be on an aryl (e.g., phenyl) or heteroaryl group, thereby forming a stable structure. It will also be understood that when indicated, the optional substituents on the cycloalkyl groups may be present at any substitutable position and include, for example, the position at which the cycloalkyl group is attached.
The term "heterocyclyl" refers to 4, 5,6 and 7 membered saturated or partially unsaturated heterocyclic rings containing 1 to 4 heteroatoms independently selected from N, O and S. The terms "heterocycle", "heterocyclyl ring", "heterocyclyl group", "heterocyclic moiety" and "heterocyclyl" may be used interchangeably. The heterocyclyl ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. Examples of such saturated or partially unsaturated heterocyclyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, oxetanyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, and tetrahydropyrimidinyl. The heterocyclic group may be monocyclic or bicyclic. Unless otherwise specified, bicyclic heterocyclic groups include, for example, unsaturated or saturated heterocyclic groups fused to another unsaturated heterocyclic group or an aromatic or heteroaryl ring, such as, for example, chromanyl, 2, 3-dihydrobenzo [ b ] [1,4] dioxinyl, tetrahydronaphthyridinyl, indolonyl, dihydropyrrolotriazolyl, imidazopyrimidinyl, quinolinonyl, dioxaspirodecyl. It is understood that the point of attachment of the bicyclic heterocyclic group may be on the heterocyclic or aromatic ring, thereby creating a stable structure. It will also be understood that when indicated, the optional substituents on the heterocyclyl group may be present at any substitutable position and include, for example, the position at which the heterocyclyl group is attached.
The term "heteroaryl", used alone or as part of a larger moiety such as "heteroarylalkyl", "heteroarylalkoxy", or "heteroarylaminoalkyl", refers to a 5-to 10-membered aromatic group containing 1 to 4 heteroatoms selected from N, O and S, and includes, for example, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "heteroaryl group" or "heteroaromatic". As used herein, the terms "heteroaryl" and "heteroaryl-" also include groups in which a heteroaryl ring is fused to one or more aryl rings, where the radical or point of attachment is on the heteroaryl ring. Non-limiting examples include indolyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, quinazolinyl, and quinoxalinyl. Heteroaryl groups may be monocyclic or bicyclic. It is to be understood that when specified, optional substituents on the heteroaryl group can be present at any substitutable position, and include, for example, the position at which the heteroaryl group is attached. As used herein, the term "aryl", used alone or in combination with other terms, refers to a 6 to 14 membered aromatic ring containing only ring carbon atoms. The aryl ring may be monocyclic, bicyclic or tricyclic. Non-limiting examples include phenyl, naphthyl, or anthracenyl and the like. It is also understood that when indicated, optional substituents on the aryl groups may be present at any substitutable position. In one embodiment, the aryl group is unsubstituted or mono-or disubstituted.
As used herein, the terms "subject" and "patient" are used interchangeably and refer to a mammal in need of treatment, such as companion animals (e.g., dogs, cats, etc.), farm animals (e.g., cows, pigs, horses, sheep, goats, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). Typically, the subject is a human in need of treatment.
The compounds of the invention may be present in the form of pharmaceutically acceptable salts. For use in medicine, salts of the compounds of the present invention are referred to as non-toxic "pharmaceutically acceptable salts". Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts.
Pharmaceutically acceptable basic/cationic salts include sodium, potassium, calcium, magnesium, diethanolamine, n-methyl-D-glucamine, L-lysine, L-arginine, ammonium, ethanolamine, piperazine, and triethanolamine salts.
Pharmaceutically acceptable acid/anion salts include, for example, acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, carbonate, citrate, dihydrochloride, gluconate, glutamate, glycolamidophenylarsonate, hexylisophthalate, hydrobromide, hydrochloride, malate, maleate, malonate, methanesulfonate, nitrate, salicylate, stearate, succinate, sulfate, tartrate, and tosylate.
Route of delivery
Methods for delivering the compounds described herein to the eye include topical, subconjunctival, intravitreal, and systemic.
Local: topical ocular drug administration is typically accomplished by eye drops. The contact time of the ocular surface is short, but can be extended with specific formulations (e.g., gels, gelling formulations, ointments, and inserts). Typically, the basic nature of the solution comprising the pharmaceutical composition is aqueous, and thus agents aimed at increasing the viscosity of the solution may be used. Such agents include, for example, hydroxypropylmethylcellulose, carbomer, polyvinyl alcohol, and the like.
Subconjunctival administration: traditionally, subconjunctival injection has been used to deliver drugs to the uvea at increased levels. This mode of administration can be used to deliver drugs in a controlled release formulation to the posterior segment and to guide the healing process after surgery.
Intravitreal administration: direct drug administration to the vitreous provides the advantage of more direct access to the vitreous and retina. However, delivery from the vitreous to the choroid is more complicated by the obstruction of the RPE (retinal pigment epithelium) barrier. Small molecules are able to diffuse rapidly in the vitreous, but the migration of large molecules (particularly positively charged) is limited. Injectable compositions suitable for intraocular injection typically comprise a drug solution or fine particle suspension, which may enable sustained delivery to the eye. The formulations are typically aqueous and may generally include solubilizing agents such as, but not limited to, polyvinyl alcohol, Tween 80, solutol, cremophore, and cyclodextrins. These solubilizers may be used in combination. The formulation is typically in the pH range of 3 to 8, which is considered acceptable for intravitreal formulations. To achieve an acceptable pH, buffer systems are sometimes used. These include, but are not limited to, citrate and phosphate based buffer systems. The tonicity of the intravitreal formulation can be adjusted to remain within the desired range, typically 250 to 360 mOsm/kg. The adjustment of tonicity can be achieved, for example, by the addition of sodium chloride. Typically, intravitreal formulations are produced by aseptic preparation for single use. Preservative formulations, for example formulations containing preservatives such as benzyl alcohol, may be used. The dosage of the active agent in the compositions of the invention will depend on the nature and extent of the condition, the age and condition of the patient, and other factors known to those skilled in the art. Administration may be as a single injection, without further administration, or may be as multiple injections.
The system comprises the following steps: posterior segment therapy and supplemental topical therapy of the anterior segment require systemic medication. The posterior segment always requires systemic treatment because most topical drugs do not penetrate the posterior segment. Retrobulbar and orbital tissues were treated systemically.
Prodrug formulation and permeability enhancer
In some embodiments, the present technology provides a method of treating presbyopia or cataract that entails administering an effective amount of a composition comprising a compound described herein in a prodrug form or converted to a prodrug form. Prodrug formulations use pharmacologically inactive derivatives of drug molecules that are able to penetrate the cornea better (e.g., they are more lipophilic) than standard formulations of drugs. See Brian G.Short, diagnostic Pathology,36:49-62,2008 for a review. As described in this review and the references cited therein, the prodrug is metabolized chemically or enzymatically to the active parent compound, either within the cornea or after corneal penetration. Enzyme systems identified in ocular tissues include esterases, ketoreductases, and steroid 6 β -hydroxylases.
Most prodrugs are routinely delivered by topical application, for example the antiviral prodrugs ganciclovir (ganciclovir) and acyclovir (acyclovir), although ganciclovir has also been delivered intravitreally by injection or as a non-biodegradable depot (see below). The systemic delivery of drugs in the cornea using non-native enzymes is achieved by local 5-fluorocytosine (a prodrug of 5-fluorouracil) after subconjunctival transplantation of cells containing the invertase cytosine deaminase. Increased corneal penetration to the anterior segment is achieved by adding a permeability enhancer to the pharmaceutical formulation. Surfactants, bile acids, chelating agents and preservatives have all been used. Cyclodextrins are cylindrical oligonucleotides having a hydrophilic outer surface and a lipophilic inner surface and forming complexes with lipophilic drugs, which are the most popular permeability enhancers. They have improved chemical stability and bioavailability and reduced local irritation, and they have been used with corticosteroids, chloramphenicol, diclofenac, cyclosporine, and sulfonamide carbonic anhydrase inhibitors. The present invention includes Small Molecule Depolymerases (SMDs) synthesized as prodrugs, allowing them better ability to penetrate the cornea.
Examples of the invention
Example 1: recombinant hAAC forms HMW aggregates upon exposure to UV and heat
Factors that lead to age-related loss of soluble functional AAC include post-translational modifications of amino acid residues due to UV and heat exposure. Thus, to identify effective SMDs, experimental conditions were developed under which haacs formed HMW aggregates upon exposure to UV-C radiation or heating to 50 ℃ (fig. 2A-2D). Consistent with published reports, hAAC HMW aggregates formed under UV-C irradiation remained insoluble compared to thermally induced HMW (FIGS. 2C and 2D). The system described herein summarizes the factors that lead to the formation of presbyopia.
Example 2: identification of Small Molecule Depolymerase (SMD) of hAAC:
large numbers of small molecule compounds were screened for their ability to protect haacs from forming HMW aggregates. In the screening based on UV-induced aggregation, 310 compounds were tested, while in the screening based on Ca2+In the screening for heat-induced aggregation, 206 compounds were tested. Each compound was used at a concentration of 200 uM. In view of the fact that almost 40% of the lens of the eye is composed of AC, high concentrations of recombinant hAAC (500ug/ml for UV and 400ug/ml for heat) were used in the screening. Screening led to the identification of various compounds that showed efficacy in protecting haacs from forming HWM aggregates (table 1). These compounds are called SMDs. Representative data sets are shown in FIGS. 3A-3B. Details of the procedure for identifying SMDs are described below.
In order to identify compounds that are effective in preventing the accumulation of human AAC in the lens of the eye and that can act or develop as a drug for the treatment of presbyopia, it is important that the biochemical screening method (i) is based on non-enzymatic conditions leading to the loss of AAC function and the formation of HMW aggregates, and (ii) uses the relevant species of AAC, in particular because human AAC contains a unique cysteine residue (Cys 142). Thus, the screening methods employed herein take these factors into account.
Library design: since the SMDs of the present disclosure are intended for ophthalmic applications, the key factors are those that act as transcellular drug penetration. These factors are logP, pKa and MW. LogP is the most important feature of a drug because it determines whether SMD can cross the epithelial layer. 2-3LogP provides the optimal chemical composition for absorption through the corneal layer. SMDs must also have sufficient water solubility because it must diffuse through a water-filled matrix, and it is the initial drug concentration in the tear film that determines the driving force for corneal penetration. Thus, a library of compounds for screening SMDs is assembled such that the included compounds have physicochemical properties of drugs known to have high tissue permeability. See table 1 below for details.
For screening, 200 μ M concentration of each compound (0.5% DMSO) was incubated with hAAC (500ug/ml for UV-induced aggregation and 400ug/ml for heat-induced aggregation) at room temperature for 30 min and absorbance was measured at various time points (0, 30, 60, 90 and 120 min). Compounds that show greater than 50% protection relative to untreated compounds were retested and sequenced to provide dose-dependent EC50And (4) measuring the value. Table 2 below shows the distribution of the compounds and the extent to which they protect the hAAC from aggregation.
Structural analysis of the identified SMDs indicates that compounds that prevent hAAC aggregation under UV exposure can be divided into two classes, macrocyclic and"covalent", and those that act as catechol to prevent heat-induced aggregation. The molecular structure of hits and their percent protection for each series are shown in FIGS. 4A-4F. Also shown are dose-dependent efficacy curves and ECs for one compound from each series50The value is obtained. The fact that the identified SMDs prevent hAAC aggregation when exposed to UV demonstrates their ability to participate directly in hAAC.
Example 3: SMD prevention of HMW formation of covalent bonds with ACC hAAC aggregate formation
AAC contains two cysteine residues, which are known to undergo post-translational modification to form an intramolecular/intermolecular disulfide bond, resulting in HMW aggregate formation. Therefore, it is hypothesized that disulfide bond formation can be prevented using a structure-directed design, employing covalent bonds that target two cysteines to form cysteine-reactive drug-like compounds, in order to develop efficient and selective SMD of hAAC. Thus, irreversible electrophilic cysteine-reactive compounds comprising acrylamide and chloroacetamide functionalities are included in the screening assay for SMD. These compounds were prepared using the synthetic route shown in scheme 1 below.
Screening resulted in the identification of multiple compounds (FIGS. 4C-4D). Given their potential to form covalent bonds with cysteine residues, these compounds are referred to as "covalent" (fig. 6A and 6B).
Example 4: cell-based assays using Human Lens Epithelial (HLE) cells
Cell-based assays using human lens epithelial cell lines SRA 01/04 and B3 were also performed. Cells were exposed to UV or heat and cell viability was assessed 24 hours after exposure by alamar blue staining. The results are shown in FIGS. 7A and 7B. In another experiment, SRA 01/04 cells were preincubated with different concentrations of compound for two hours prior to UV exposure. Relative protection was measured as percent viability compared to vehicle control at 24 hours post UV exposure. The effect of compounds from each of the three different chemical series (macrocyclic, covalent and catechol) is shown in figure 7B. Mean ± SEM of measurements are shown.
Ectopic expression of AAC-EGFP in B-3 cells revealed inclusion bodies (arrows) where AAC formation was co-localized with p62 (FIG. 8A). Automated image analysis of greater than 2500 cells is shown in fig. 8B. A statistically significant increase in GFP positive inclusion bodies due to AAC overexpression was observed. Mean ± SEM and p-values of the measurements are shown (t-test). The results show that the high-content screen can be used for evaluating the cytopharmacodynamics effect of SMD measurement of AAC cell aggregates.
Example 5: synthesis of catechol derivatives
The catechol derivatives described herein may be synthesized using the reaction scheme shown below. Specific examples of the synthesized derivatives are described in terms of reaction schemes.
Scheme 1
Reagents and conditions for scheme 1: (a) grignard reaction conditions, diethyl ether, 0 ℃ to r.t.; (b) oxidation, PCC, CH2Cl2，r.t.，(c)Pd/C，H2Methanol, r.t.; (d) 0% HNO3，r.t.；(e)BBr3，CH2Cl2R.t.; (f) PEG-acid, EDC, DMAP, r.t. In this reaction scheme, a variety of different substituents may be used as different R groups. R6、R7、R8、R9And R10May independently be, for example, H, alkyl, aryl, halogen, nitro, amino, trifluoromethyl and trifluoromethoxy.
Scheme 2
Reagents and conditions for scheme 2: (g) EDC, HOBt, DIEA, DMF, rt, 16 h. In thatIn this reaction scheme, a variety of different substituents may be used as different R groups. R17、R18And R19May independently be, for example, H, alkyl, aryl, halogen, nitro, amino, methoxy, trifluoromethyl and trifluoromethoxy. R20May be an alkyl or aryl group.
Scheme 3
Reagents and conditions for scheme 3: (h) EDC, HOBt, DIEA, DMF, rt, 16 h; (i) TFA, CH2Cl2Rt, 6 h; (j) arylamine, EDC, HOBt, DIEA, DMF, rt, 20 h. In this reaction scheme, a variety of different substituents may be used as different R groups. R17、R18、R19、R21、R22、R23、R24And R25And may independently be, for example, hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, and trifluoromethyl.
Scheme 4
Scheme 4: reagents and conditions for scheme 4: (k) EDC, HOBt, DIEA, DMF, rt, 15 h; (l) TFA, CH2Cl2，rt，6h；(m)R26-CO2H, EDC, HOBt, DIEA, DMF, rt, 22H. In this reaction scheme, a variety of different substituents may be used as different R groups. R17、R18And R19And may independently be, for example, hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, and trifluoromethyl. R26May be an alkyl or aryl group.
Synthesis of N- [2- (3, 4-dimethoxyphenyl) ethyl ] cyclobutanecarboxamide (CAP1226)
As shown in scheme 2 above, CAP1226 is synthesized using appropriate reagents and starting materials. Briefly, 3, 4-dimethoxyphenethyl ether was reacted at room temperatureA mixture of amine (1mmol), cyclobutanecarboxylic acid (1mmol), EDC (1.2mmol), HOBt (1.2mmol) and DIEA (1.5mmol) in DMF (3mL) was stirred for 16 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate solution, water and brine, respectively. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel using ethyl acetate hexane solvent system to give the pure product CAP1226 as a solid (82%). The compound was characterized by NMR and mass spectrometry.1H NMR(500MHz,DMSO-d6) δ 1.92-2.05(m,4H),2.44-2.46(m,2H),2.91-3.15(m,3H),6.68(dd, J ═ 8 and 2Hz,1H),6.73(d, J ═ 1.7Hz,1H),6.82(d, J ═ 7.8Hz,1H),7.56(t, J ═ 5.4Hz,1H, NH); ESI-MS M/z 264(M + H)+Other compounds were selected using scheme 2,3 or 4.
N, N' -bis [2- (3, 4-dimethoxyphenyl) ethyl ] hexanediamine (CAP1225)
CAP1225 was prepared using scheme 2 shown above. The compound was characterized by NMR and mass spectrometry.
1H NMR(500MHz,DMSO-d6)δ1.45-1.48(m,4H),1.98-2.01(m,4H),2.56-2.57(m,4H),3.01-3.09(m,4H),3.76(s,6H),3.79(s,6H),6.67(d,J＝7.2Hz,1H),6.69(d,J＝7.2Hz,2H),6.75(d,J＝7,5Hz,2H),6.79(d,J＝1.2Hz,2H),6.81(d,J＝1.2Hz,2H),7.72(t,J＝5.4Hz,2H,NH)；ESI-MS m/z 474(M+H)+.
N- [2- (3, 4-Dimethoxyphenyl) ethyl ] -1 (phenylacetyl) -4-piperidinecarboxamide (CAP1227)
CAP1227 was prepared using scheme 2 shown above. The compound was characterized by NMR and mass spectrometry.
1H NMR(500MHz,DMSO-d6) δ 1.41-1.52(m,4H),2.32-2.38(m,1H),2.61-2.68(m,3H),2.88-2.92(m,1H),3.21-3.29(m,2H),3.62(s,2H),3.72(s,3H),3.75(s,3H),3.92-3.95(m,1H),4.41-4.45(m,1H),6.61(dd, J ═ 7.8 and 1.7, 1H),6.72(d, J ═ 1.7Hz,1H),6.81(d, J ═ 8Hz,1H),7.19-7.25(m,3H),7.28-7.32(m,2H),7.68(t, J ═ 5.2, 1H, NH, 1H); ESI-MS M/z 412(M + H)+.
N, N' -bis [2- (3, 4-dimethoxyphenyl) ethyl ] pentanediamine (CAP1228)
CAP1228 was prepared using scheme 3 shown above. The compound was characterized by NMR and mass spectrometry.
1H NMR(500MHz,DMSO-d6) δ 1.61-162(m,2H),1.98-2.10(m,4H),2.65-2.70(m,4H),3.30-3.39(m,4H),3.78(s,6H),3.79(s,6H),6.67(dd, J ═ 8 and 1.6Hz,2H),6.77(d, J ═ 1.6Hz,2H),6.82(d, J ═ 8Hz,2H),7.71(t, J ═ 5.4Hz,2H, NH); ESI-MS M/z 460(M + H)+.
N- [2- (3, 4-Dimethoxyphenyl) ethyl ] cyclopropanecarboxamide (CAP1230)
CAP1230 was prepared using scheme 2 shown above. The compound was characterized by NMR and mass spectrometry.
1H NMR(500MHz,DMSO-d6) δ 0.58-0.67(m,4H),1.46-1.53(m,1H),2.62-2.68(m,2H),3.21-3.27(m,2H),3.76(s,3H),3.77(s,3H),6.67(d, J ═ 8 and 1.6Hz,1H),6.75(d, J ═ 1.6Hz,1H),6.81(d, J ═ 8Hz,1H),7.98(t, J ═ 5.6.1h, NH); ESI-MS M/z 250(M + H)+.
N- [2- (3, 4-Dimethoxyphenyl) ethyl ] cyclopentanecarboxamide (CAP1231)
CAP1231 was prepared using scheme 2 shown above. The compound was characterized by NMR and mass spectrometry.
1H NMR(500MHz,DMSO-d6) δ 1.48-1.78(m,5H),2.58-2.61(m,4H),3.27-3.35(m,4H),3.75(s,3H),3.76(s,3H),6.72(dd, J ═ 7.8 and 1.6Hz,1H),6.79(d, J ═ 1.6Hz,1H),6.84(d, J ═ 8Hz,1H),7.77(t, J ═ 5.4Hz,1H, NH); ESI-MS M/z 278(M + H)+.
N- [2- (3, 4-Dimethoxyphenyl) ethyl ] -1- (4-fluorophenyl) -4-piperidinecarboxamide (CAP1232)
CAP1232 was prepared using scheme 2 shown above. The compound was characterized by NMR and mass spectrometry.
1H NMR(500MHz,DMSO-d6) δ 1.47-1.71(m,4H),2.37-2.41(m,1H),2.62-2.71(m,3H),2.80-2.88(m,2H),3.23-3.32(m,3H),3.75(s,3H),3.76(s,3H),6.65(dd, J ═ 8 and 1.6Hz,1H),6.72(d, J ═ 1.6Hz,1H),6.78(d, J ═ 7.8Hz,1H),7.16-7.22(,2H),7.41-7.46(m,2H),7.72(t, J ═ 5.2Hz,1H, NH); ESI-MS M/z 415(M + H) +.
+2Example 6: selected neighborsUse of benzenediol derivatives for preventing Ca and UVC induced aggregation of alpha-A crystallin Effectiveness of
Table 3 below shows selected catechol derivatives and their use in Ca prevention+2And effectiveness of UVC-induced aggregation of a-a crystallins.
TABLE 3
Table 4 below provides selected catechol derivatives for Ca inhibition+2And UVC-induced aggregation of alpha-A crystallin50The value is obtained.
TABLE 4
Example 7: selected tolcapone derivatives against UV and heat induced polymerization of alpha-A crystallin Centralized availability
Table 5 below lists selected tolcapone derivatives and their effectiveness in preventing UV and heat induced aggregation of alpha-a crystallin.
TABLE 5
Example 8: prodrugs of tolcapone
As mentioned above, topical administration is the preferred route for ophthalmic drugs because of its local drug action in the anterior segment of the eye. However, poor permeability and rapid loss of therapeutic agents following topical administration are major limitations of the topical route. This problem is further amplified and exacerbated if the water solubility of a given drug is poor. Formulation methods have been widely used to address and overcome poor ocular bioavailability. In addition to formulations, chemical methods such as prodrugs have been used to optimize the physicochemical and biochemical properties of drug molecules to increase their ocular bioavailability. The important steps in effective prodrug therapy are the activation of the prodrug and the release of the free active therapeutic agent. Important enzymes involved in the activation and biotransformation of prodrugs include phosphatases, paraoxonase, carboxylesterase, acetylcholinesterase and cholinesterase.
The use of tolcapone can involve side effects, particularly liver injury. For example, increasing the solubility of tolcapone by administering it as a prodrug may result in the drug being effective at lower doses. To improve the water solubility of tolcapone, the prodrug CAP4196 of tolcapone was synthesized. It is believed that an increase in the solubility of the prodrug will result in a more effective treatment of ocular diseases (presbyopia or cataracts), parkinson's disease, amyloid diseases, and the prevention and/or Treatment of Transthyretin (TTR) -associated amyloidosis.
Synthesis of CAP4196
Scheme 1:
sodium 2-hydroxy-5- (4-methylbenzoyl) -3-nitrophenyl phosphate (CAP 4196):to a cold solution of tolcapone (20g) in THF (100mL) and pyridine (25mL) over 20 minutes, POCl was added dropwise via addition funnel3(20 mL). The reaction mixture was stirred at room temperature overnight and cooled to below 10 ℃. The reaction was quenched with 50% aqueous phosphoric acid and stirring was continued at RT for 10 h. The reaction mixture was further washed with THF (100mL) and water (1)00mL), the precipitated solid was filtered, washed with ethyl acetate (2 × 50mL) and dried to give the intermediate 2 tolcapone monophosphate (8.0g) as an off-white solid.
To a stirred suspension of tolcapone monophosphate (2) (15g) in EtOH (300ml) was added NaOEt/EtOH (2.5eq) and the suspension was stirred for 1 hour. The resulting orange-red solid was filtered, washed with EtOH (2 × 100ml) and dried to give 14g tolcapone monophosphate disodium salt CAP4196 as an orange-red solid.
Solubility: CAP1160 and CAP4196 were tested for solubility with various FDA approved excipients, such as cyclodextrin, PEG-b-PCL, Kolliphor-EL, Kolliphor-40, sorbitol, propylene glycol, sodium phosphate, and the like. Only a 10-fold increase in the solubility of CAP1160 (1.5mg/ml) was observed with (2-hydroxypropyl) - β -cyclodextrin. On the other hand, the phosphate prodrug CAP4196 showed a solubility increase of over 660-fold (100mg/ml) with water alone as the solvent, and the pH of the formulation was 6.65, in the pH range of tears (6.5-7.6). This makes the formulation safe for topical use (see table 6).
Table 6: solubility of CAP1160 and CAP4196
Example 9: ocular safety in New Zealand White Rabbits (NZWR) with repeated dosing of prodrug CAP 41967 days:
prodrug CAP4196 was well tolerated in new zealand white rabbits at concentrations up to 10%. The initial maximum tolerated dose study (MTD) helped identify observable signs of toxicity and provided a basis for establishing dose levels in later definitive studies. Thus, the MTD of CAP4196 was evaluated in new zealand white rabbits. Four animals per group were dosed with increasing concentrations (0.25, 2.5, 8 and 10%) of CAP4196 four times daily in 50 μ l volumes at 2 hour intervals. Following dosing, animals were assessed for mortality and morbidity, ophthalmic examination, body weight, and clinical pathology prior to initiation of dosing, then on days 2, 4, 6 and 7 prior to the first dose instillation, and one hour after the last dose instillation.
Based on the results, it was concluded that administration of CAP4196 at a dose concentration of 10% w/v (4 times daily, 50 μ L, 2 hours between each dose) produced only few transient local reactions such as excessive rubbing of the eyes and redness, and did not produce any systemic toxicity in new zealand white rabbits conducted in this MTD study. Therefore, the highest dose concentration of 10% is considered the MTD. See table 7.
Table 7: toxicity results for CAP4196
Example 9: tocapone derivatives for the prevention or treatment of transthyretin and Parkinson's disease
Transthyretin (TTR) is a plasma homotetrameric protein that plays a role in fatal systemic amyloidosis (Sant' Anna, R. et al (2016) nat. Commun.7:10787doi:10.1038/ncomms 10787). Dissociation of TTR tetramer precedes pathological TTR aggregation. Natural state stabilizers of TTR tetramers are promising drugs for the treatment of TTR amyloidosis. Tolcapone is an FDA-approved molecule for parkinson's disease and is a potent TTR aggregation inhibitor (Sant' Anna, r. et al (2016)). Tolcapone specifically binds to TTR in human plasma, stabilizing the native tetramer and inhibiting TTR cytotoxicity in vivo in mice and humans (Sant' Anna, r. et al (2016)). Thus, tolcapone is considered a powerful candidate for the treatment of TTR amyloidosis. Since tolcapone use is associated with side effects, particularly liver damage, and improving the solubility of tolcapone, e.g., by administering it as a prodrug, can result in the drug being effective at lower doses, it can be expected that the tolcapone prodrugs described herein may be better therapeutic agents against TTR amyloidosis and parkinson's disease.
Example 10: structure-activity relationship of naphthalene analogs
The structure-activity relationships of the naphthalene analogs are summarized in table 8 below.
TABLE 8
Equivalent scheme
All features disclosed in this specification may be combined in any combination. Each feature disclosed in this specification may be replaced by alternative features serving the same, equivalent or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features.
From the above description, one skilled in the art can easily ascertain the essential characteristics of the present invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. Accordingly, other embodiments are within the scope of the following claims.