calcium channel inhibitors
阅读说明：本技术 钙通道抑制剂 (calcium channel inhibitors ) 是由 托马斯·E·理查森 米歇尔·希金 蒂莫西·麦克唐纳 于 2018-02-15 设计创作，主要内容包括：本公开内容描述了米贝拉地尔(mibefradil)的氨基甲酸酯类似物,以及它们的组合物和使用方法。所述化合物阻断电压门控钙通道的一种或多种亚型的活性并且可用于治疗疾病,包括例如癌症。(The present disclosure describes carbamate analogs of mibefradil (mibefradil), as well as compositions and methods of use thereof. The compounds block the activity of one or more subtypes of voltage-gated calcium channels and are useful for treating diseases, including, for example, cancer.)
1. A compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
X is O or CH 2;
y is CR1R2, NR3, C (═ O) NH, or NH (C ═ O);
Z is C (═ O) ORZ1 or C (═ O) NRZ2RZ 3;
n is 0, 1, 2 or 3;
RN is H or optionally substituted C1-4 alkyl;
r1 is H or optionally substituted C1-4 alkyl;
r2 is H or optionally substituted C1-4 alkyl; or
R1 and R2 combine to form C2-4 alkylene, which C2-4 alkylene together with the carbon atom to which R1 and R2 are attached forms a 3-6 membered optionally substituted cycloalkyl ring;
r3 is H or optionally substituted C1-4 alkyl;
RZ1 is optionally substituted C1-4 alkyl;
RZ2 is H or optionally substituted C1-4 alkyl;
RZ3 is H or optionally substituted C1-4 alkyl; or
RZ2 and RZ3 combine with the nitrogen atom to which they are attached to form an optionally substituted 4-6 membered heterocycloalkyl ring; and is
Ar is optionally substituted C6-10 aryl or 5-10 membered optionally substituted heteroaryl;
Wherein each substituted C1-4 alkyl is substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 alkoxy, OH, CN, NO2, amino, C1-4 alkylamino, di (C1-4 alkyl) amino, oxo, optionally substituted C3-10 cycloalkyl, optionally substituted C6-10 aryl, optionally substituted 4-10 membered heterocycloalkyl, and optionally substituted 5-10 membered heteroaryl;
each substituted cycloalkyl and heterocycloalkyl is substituted with 1, 2, 3, 4 or 5 substituents each independently selected from halo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 alkoxy, OH, CN, NO2, amino, C1-4 alkylamino, di (C1-4 alkyl) amino and oxo; and is
each of the substituted aryl and heteroaryl is substituted with 1, 2, 3, 4 or 5 substituents each independently selected from halo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 alkoxy, OH, CN, NO2, amino, C1-4 alkylamino and di (C1-4 alkyl) amino.
2. the compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X is O.
3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X is CH 2.
4. a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein Y is CR1R 2.
5. a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein RN is unsubstituted C1-4 alkyl.
6. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein RN is methyl or ethyl.
7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R1 is H or unsubstituted C1-4 alkyl.
8. the compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R1 is H or methyl.
9. the compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R2 is H or unsubstituted C1-4 alkyl.
10. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R2 is H or methyl.
11. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are each H.
12. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are each unsubstituted C1-4 alkyl.
13. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are each methyl.
14. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 combine to form C2-4 alkylene, which C2-4 alkylene, together with the carbon atom to which R1 and R2 are attached, forms a 3-6 membered optionally substituted cycloalkyl ring.
15. the compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 combine to form an ethylene group that, together with the carbon atom to which R1 and R2 are attached, forms an unsubstituted cyclopropyl ring.
16. the compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein n is 1.
17. The compound according to any one of claims 1 to 3 and 5 to 16, or a pharmaceutically acceptable salt thereof, wherein R3 is H or unsubstituted C1-4 alkyl.
18. The compound according to any one of claims 1 to 3 and 5 to 16, or a pharmaceutically acceptable salt thereof, wherein R3 is H.
19. a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein Z is C (═ O) ORZ 1.
20. the compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein RZ1 is unsubstituted C1-4 alkyl.
21. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein RZ1 is methyl.
22. A compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein Z is C (═ O) NRZ2RZ 3.
23. The compound of any one of claims 1 to 18 and 22, or a pharmaceutically acceptable salt thereof, wherein RZ2 is H or unsubstituted C1-4 alkyl.
24. The compound according to any one of claims 1 to 18 and 22, or a pharmaceutically acceptable salt thereof, wherein RZ2 is H or methyl.
25. the compound of any one of claims 1 to 18 and 22 to 24, or a pharmaceutically acceptable salt thereof, wherein RZ3 is optionally substituted C1-4 alkyl.
26. The compound of any one of claims 1 to 18 and 22 to 24, or a pharmaceutically acceptable salt thereof, wherein RZ3 is C1-4 alkyl optionally substituted with 1, 2, or 3 groups independently selected from amino, C1-4 alkylamino, di (C1-4 alkyl) amino, C1-4 alkoxy, and 4-6 membered heterocycloalkyl.
27. The compound according to any one of claims 1 to 18 and 22 to 24, or a pharmaceutically acceptable salt thereof, wherein RZ3 is methyl, N-dimethylaminoethyl, N-diethylaminoethyl, methoxyethyl, or pyrrolidinylethyl.
28. The compound according to any one of claims 1 to 18 and 22 to 24, or a pharmaceutically acceptable salt thereof, wherein RZ3 is methyl, 2- (N, N-dimethylamino) ethyl, 2- (N, N-diethylamino) ethyl, 2-methoxyethyl, or 2- (pyrrolidin-1-yl) ethyl.
29. The compound of any one of claims 1 to 18 and 22, or a pharmaceutically acceptable salt thereof, wherein RZ2 and RZ3, in combination with the nitrogen atom to which they are attached, form an optionally substituted 4-6 membered heterocycloalkyl ring.
30. The compound of any one of claims 1 to 18 and 22, or a pharmaceutically acceptable salt thereof, wherein RZ2 and RZ3, in combination with the nitrogen atom to which they are attached, form an unsubstituted 4-6 membered heterocycloalkyl ring.
31. the compound according to any one of claims 1 to 18 and 22, or a pharmaceutically acceptable salt thereof, wherein RZ2 and RZ3, in combination with the nitrogen atom to which they are attached, form a morpholinyl ring.
32. The compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein Ar is optionally substituted phenyl, optionally substituted naphthyl, or 5-10 membered optionally substituted heteroaryl.
33. The compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein Ar is 5-10 membered optionally substituted heteroaryl.
34. the compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein Ar is 5-10 membered heteroaryl optionally substituted with 1, 2, 3, or 4 groups independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, and C1-4 alkoxy.
35. the compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein Ar is 5-10 membered heteroaryl optionally substituted with 1, 2, 3, or 4 groups independently selected from chloro, methyl, methoxy, and trifluoromethyl.
36. the compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein Ar is:
37. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:
x is O or CH 2;
y is CR1R 2;
Z is C (═ O) ORZ1 or C (═ O) NRZ2RZ 3;
RN is unsubstituted C1-4 alkyl;
R1 is H or unsubstituted C1-4 alkyl;
R2 is H or unsubstituted C1-4 alkyl; or
R1 and R2 combine to form C2-4 alkylene, which C2-4 alkylene together with the carbon atom to which R1 and R2 are attached forms a 3-6 membered optionally substituted cycloalkyl ring;
n is 0, 1, 2 or 3;
RZ1 is unsubstituted C1-4 alkyl;
RZ2 is H or unsubstituted C1-4 alkyl;
RZ3 is optionally substituted C1-4 alkyl; or
RZ2 and RZ3 combine with the nitrogen atom to which they are attached to form an optionally substituted 4-6 membered heterocycloalkyl ring; and is
Ar is optionally substituted phenyl, optionally substituted naphthyl, or 5-10 membered optionally substituted heteroaryl.
38. the compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:
X is O or CH 2;
Y is CR1R 2;
Z is C (═ O) ORZ1 or C (═ O) NRZ2RZ 3;
RN is unsubstituted C1-4 alkyl;
r1 is H or unsubstituted C1-4 alkyl;
R2 is H or unsubstituted C1-4 alkyl; or
r1 and R2 combine to form C2-4 alkylene, which C2-4 alkylene together with the carbon atom to which R1 and R2 are attached forms a 3-6 membered optionally substituted cycloalkyl ring;
n is 1;
RZ1 is unsubstituted C1-4 alkyl;
RZ2 is H or unsubstituted C1-4 alkyl;
RZ3 is C1-4 alkyl optionally substituted with 1, 2, or 3 groups independently selected from amino, C1-4 alkylamino, di (C1-4 alkyl) amino, C1-4 alkoxy, and 4-6 membered heterocycloalkyl, RZ2 and RZ3 combine with the nitrogen atom to which they are attached to form an optionally substituted 4-6 membered heterocycloalkyl ring; and is
ar is a 5-10 membered optionally substituted heteroaryl.
39. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:
x is O or CH 2;
Y is CR1R 2;
Z is C (═ O) ORZ1 or C (═ O) NRZ2RZ 3;
RN is unsubstituted C1-4 alkyl;
r1 is H or methyl;
r2 is H or methyl; or
r1 and R2 combine to form an ethylene group which together with the carbon atom to which R1 and R2 are attached forms a cyclopropyl ring;
n is 1;
RZ1 is unsubstituted C1-4 alkyl;
RZ2 is H or unsubstituted C1-4 alkyl;
RZ3 is C1-4 alkyl optionally substituted with 1, 2, or 3 groups independently selected from amino, C1-4 alkylamino, di (C1-4 alkyl) amino, C1-4 alkoxy, and 4-6 membered heterocycloalkyl, RZ2 and RZ3 combine with the nitrogen atom to which they are attached to form an optionally substituted 4-6 membered heterocycloalkyl ring; and is
Ar is a 5-10 membered heteroaryl group optionally substituted with 1, 2, 3 or 4 groups independently selected from halo, C1-4 alkyl, C1-4 haloalkyl and C1-4 alkoxy.
40. the compound of claim 1, wherein the compound of formula I is a compound of formula II:
or a pharmaceutically acceptable salt thereof.
41. The compound of claim 1, wherein the compound of formula I is a compound of formula III:
Or a pharmaceutically acceptable salt thereof.
42. The compound of claim 1, wherein the compound of formula I is a compound of formula IV:
Or a pharmaceutically acceptable salt thereof, wherein each RAr is independently selected from H, halo, C1-4 alkyl, C1-4 haloalkyl, and C1-4 alkoxy.
43. The compound of claim 1, wherein the compound of formula I is a compound of formula V:
Or a pharmaceutically acceptable salt thereof, wherein each RAr is independently selected from H, halo, C1-4 alkyl, C1-4 haloalkyl, and C1-4 alkoxy.
44. The compound of claim 1, wherein the compound of formula I is a compound of formula I-a, I-b, II-a, II-b, III-a, III-b, IV-a, IV-b, V-a, or V-b:
Or a pharmaceutically acceptable salt thereof, wherein each RAr is independently selected from H, halo, C1-4 alkyl, C1-4 haloalkyl, and C1-4 alkoxy.
45. the compound of claim 1, wherein the compound is selected from the group consisting of:
Methylcarbamic acid 2- (2- ((3- (1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
Methyl carbonate 2- (2- ((3- (1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
methylcarbamic acid 2- (2- ((3- (4, 7-dimethyl-1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester
(2- (dimethylamino) ethyl) carbamic acid 2- (2- ((3- (4, 7-dimethyl-1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
Methylcarbamic acid 2- (2- ((3- (4, 7-dimethoxy-1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
(2-methoxyethyl) carbamic acid 2- (2- ((3- (4, 7-dimethoxy-1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
Dimethyl carbamic acid 2- (2- ((3- (7-chloro-4-methoxy-1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
Morpholine-4-carboxylic acid 2- (2- ((3- (4, 6-bis (trifluoromethyl) -1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
Morpholine-4-carboxylic acid 2- (2- ((3- (1H-benzo [ d ] imidazol-2-yl) -3-methylbutyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
Methylcarbamic acid 2- (2- ((3- (1H-benzo [ d ] imidazol-2-yl) -3-methylbutyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
(2- (dimethylamino) ethyl) carbamic acid 2- (2- ((3- (1H-benzo [ d ] imidazol-2-yl) -3-methylbutyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
(2-methoxyethyl) carbamic acid 2- (2- ((3- (1H-benzo [ d ] imidazol-2-yl) -3-methylbutyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
2- (2- ((3- (1H-benzo [ d ] imidazol-2-yl) -3-methylbutyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl) 2- (2- (pyrrolidin-1-yl) ethyl) carbamate;
(2- (diethylamino) ethyl) carbamic acid 2- (2- ((3- (1H-benzo [ d ] imidazol-2-yl) -3-methylbutyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
Morpholine-4-carboxylic acid 2- (2- ((3- (4, 7-dimethyl-1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
2- (2- ((3- (4, 7-dimethyl-1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl) carbamate;
Morpholine-4-carboxylic acid 2- (2- ((4- ((2-amino-3, 6-dimethylphenyl) amino) -4-oxobutyl) (ethyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
Morpholine-4-carboxylic acid 2- (2- ((2- (1- (1H-benzo [ d ] imidazol-2-yl) cyclopropyl) ethyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
Methylcarbamic acid 3- (2- ((3- (1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -7-fluoro-4-isopropyl chroman-3-yl ester; and
Methylcarbamic acid 3- (2- ((3- (4, 7-dimethyl-1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -7-fluoro-4-isopropyl chroman-3-yl ester;
Or a pharmaceutically acceptable salt thereof.
46. the compound of claim 1, wherein the compound is selected from the group consisting of:
(1S, 2S) -methylcarbamic acid 2- (2- ((3- (1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
(1S, 2S) -methyl carbonic acid 2- (2- ((3- (1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
(1S, 2S) -methylcarbamic acid 2- (2- ((3- (4, 7-dimethyl-1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
(1S, 2S) - (2- (dimethylamino) ethyl) carbamic acid 2- (2- ((3- (4, 7-dimethyl-1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
(1S, 2S) -methylcarbamic acid 2- (2- ((3- (4, 7-dimethoxy-1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
(1S, 2S) - (2-methoxyethyl) carbamic acid 2- (2- ((3- (4, 7-dimethoxy-1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
(1S, 2S) -dimethylcarbamic acid 2- (2- ((3- (7-chloro-4-methoxy-1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
(1S, 2S) -morpholine-4-carboxylic acid 2- (2- ((3- (4, 6-bis (trifluoromethyl) -1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
(1S, 2S) -morpholine-4-carboxylic acid 2- (2- ((3- (1H-benzo [ d ] imidazol-2-yl) -3-methylbutyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
(1S, 2S) -methylcarbamic acid 2- (2- ((3- (1H-benzo [ d ] imidazol-2-yl) -3-methylbutyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
2- (2- ((3- (1H-benzo [ d ] imidazol-2-yl) -3-methylbutyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl) (1S, 2S) - (2- (dimethylamino) ethyl) carbamate;
(1S, 2S) - (2-methoxyethyl) carbamic acid 2- (2- ((3- (1H-benzo [ d ] imidazol-2-yl) -3-methylbutyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
(1S, 2S) - (2- (pyrrolidin-1-yl) ethyl) carbamic acid 2- (2- ((3- (1H-benzo [ d ] imidazol-2-yl) -3-methylbutyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
2- (2- ((3- (1H-benzo [ d ] imidazol-2-yl) -3-methylbutyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl) carbamate (1S, 2S) - (2- (diethylamino) ethyl) carbamate;
(1S, 2S) -morpholine-4-carboxylic acid 2- (2- ((3- (4, 7-dimethyl-1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
(1S, 2S) -dimethylcarbamic acid 2- (2- ((3- (4, 7-dimethyl-1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
(1R, 2R) -morpholine-4-carboxylic acid 2- (2- ((3- (4, 7-dimethyl-1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
(1S, 2S) -morpholine-4-carboxylic acid 2- (2- ((4- ((2-amino-3, 6-dimethylphenyl) amino) -4-oxobutyl) (ethyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
(1S, 2S) -morpholine-4-carboxylic acid 2- (2- ((2- (1- (1H-benzo [ d ] imidazol-2-yl) cyclopropyl) ethyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
(3S, 4S) -methylcarbamic acid 3- (2- ((3- (1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -7-fluoro-4-isopropyl chroman-3-yl ester;
(3R, 4S) -methylcarbamic acid 3- (2- ((3- (1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -7-fluoro-4-isopropyl chroman-3-yl ester;
(3S, 4S) -methylcarbamic acid 3- (2- ((3- (4, 7-dimethyl-1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -7-fluoro-4-isopropyl chroman-3-yl ester; and
(3R, 4S) -methylcarbamic acid 3- (2- ((3- (4, 7-dimethyl-1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -7-fluoro-4-isopropyl chroman-3-yl ester;
Or a pharmaceutically acceptable salt thereof.
47. A pharmaceutical composition comprising a compound according to any one of claims 1 to 46, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
48. A method of treating a disease associated with, or in which inhibition of, the activity of one or more subtypes of voltage-gated calcium channels is beneficial in a subject, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 46, or a pharmaceutically acceptable salt thereof.
49. A method of treating a disease associated with or in which inhibition of the activity of one or more subtypes of T-type calcium channels is beneficial comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 46, or a pharmaceutically acceptable salt thereof.
50. The method of claim 49, wherein the disease is associated with activity of the CaV3.2 subtype of T-type voltage-gated calcium channels in the subject, or wherein inhibition of activity of the CaV3.2 subtype of T-type voltage-gated calcium channels is beneficial.
51. A method of treating a cell proliferative disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 46, or a pharmaceutically acceptable salt thereof.
52. The method of claim 51, wherein the cancer is selected from the group consisting of: brain cancer, breast cancer, colon cancer, glioma, glioblastoma, melanoma, ovarian cancer, and pancreatic cancer.
53. The method of claim 51, wherein the cancer is glioma or glioblastoma.
Technical Field
The present application relates to pharmaceutically useful compounds. The present disclosure provides novel compounds, as well as compositions and methods of use thereof. The compounds of the invention block the activity of one or more subtypes of voltage-gated (voltage-gated) calcium channels and are therefore useful for treating diseases associated with aberrant activity of voltage-gated calcium channels, such as cancer.
Background
T-type calcium channels are low voltage activated calcium channels that open during membrane depolarization and mediate calcium influx into cells following an action potential or depolarization signal. T-type calcium channels are known to be present in the myocardium and smooth muscle, and also in many neuronal cells within the central nervous system. T-type calcium channels (transient open calcium channels) differ from L-type calcium channels (long-acting calcium channels) due to their ability to be activated by a more negative membrane potential, their small single-channel conductance, and their non-responsiveness to traditional calcium channel antagonist drugs that target L-type calcium channels.
T-type calcium channels open following the depolarization of the small membrane. T-type calcium channels have been studied primarily in the context of neuronal and cardiomyocyte function, and have been implicated in hyperexcitability disorders (hyperexcitability disorders), such as epilepsy (epilesys) and cardiac dysfunction (cardiac dysfunction). Voltage-gated calcium channels are not normally expressed in non-excitable cells, but there is evidence that T-type calcium channels are expressed in cancer cells of the non-excitable lineage.
T-type calcium channels are activated and inactivated by the depolarization of the small membrane and exhibit a slow inactivation rate. Thus, these channels can carry depolarizing currents at low membrane potentials and mediate cellular "window" currents that occur within the voltage overlap between activation and steady-state inactivation at low or resting membrane potentials. T-type calcium channels can sustain a window current at non-stimulated or resting membrane potential, allowing a sustained inward calcium current carried by a fraction of the channels that are not inactivated. Modulation of the window current allows T-type calcium channels to modulate intracellular calcium levels in both electrically stimulated cells (such as neurons) and non-excitable tissues under non-stimulated or resting cell conditions.
Voltage-gated calcium channels are composed of several subunits. The α 1 subunit is the major subunit of the transmembrane pore forming the channel. The α 1 subunit also determines the type of calcium channel. The β, α 2 δ and γ subunits, which are only present in some types of calcium channels, are accessory subunits that play a minor role in the channel. The α 1 subunit is composed of four domains (I-IV), wherein each domain contains 6 transmembrane segments (S1-S6), and the hydrophobic loop between the S5 and S6 segments of each domain forms the pore of the channel. The subtype of T-type calcium channels is defined by the specific α 1 subunit, as shown in table 1.
TABLE 1 type T calcium channel subtypes
Name (R)
1Alpha 1 subunit
gene
CaV3.1
α1G
CACNA1G
CaV3.2
α1H
CACNA1H
CaV3.3
α1I
CACNA1I
T-type calcium channels are implicated in pathologies associated with a variety of diseases and conditions, including epilepsy, essential tremor (essential diabetes), pain, neuropathic pain (neuropathic pain), schizophrenia (schizophrenia), Parkinson's disease, depression, anxiety, sleep disorders (sleep disorders), psychosis (psychoses), schizophrenic patients (schizophrenic), cardiac arrhythmia (cardiac arrhythmia), hypertension, pain, cancer, diabetes, infertility (infertility), and sexual dysfunction (sextual dysfunction). Neuroscience, 1994, 14, 5485; drugs Future, 2005, 30(6), 573-580; EMBO j., 2005, 24, 315-; drug Discovery Today, 2006, 11(5-6), 245-.
compounds that inhibit T-type calcium channels and the use of such compounds are described in Giordanetto et al, "T-type calcium channels inhibitors: a patent review, "Expert opin. the r. Pat. No., 2011, 21, 85-101, WO2004035000, WO9304047, WO2006098969, WO2009009015, WO2007002361, WO2007002884, WO2007120729, WO2009054982, WO2009054983, WO 2009054544, US 2002709090413, WO2008110008, WO2009146539, WO2009146540, US8,133,998, WO2010083264, WO 2009160281, WO2006023883, WO2005007124, WO2005009392, US2005245535, WO 200707349749749749752, WO 2007033333333333333333320080456, WO2008033460, WO 200803333464, WO2008033465, WO 200908117148, WO 2009020090497, WO 20020120120120120120120120143564143564178, WO 2008043563543564187307, WO 20080435635435641307, WO 200807543564356439748, WO 200804356354356435643449, WO 200804356355646, WO 2008043563556354356435635, WO 2008043563556435643564356439798, WO 2008043563543564356435635, and WO 2008075563543563543564356435643307, as a whole body, and WO 200807556354320080755631, incorporated herein.
SUMMARY
the present disclosure provides, inter alia, compounds of formula I:
Or a pharmaceutically acceptable salt thereof; wherein the variables are defined as follows.
the present disclosure also provides compositions comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
the present disclosure also provides methods of treating cancer comprising administering to a patient a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.
The details of one or more embodiments are set forth in the description below. Other features, objects, and advantages will be apparent from the description and from the claims.
Detailed description of the invention
It is to be understood that certain features are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.
I. Definition of
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs, in view of the context provided by this disclosure.
The concomitant phrase "and not limited to" should be understood as referring to the terms "for example" and "such as" and grammatical equivalents thereof, unless otherwise expressly specified.
the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise.
The term "about" means "about" (e.g., plus or minus about 10% of the indicated value).
the term "n-membered" (where n is an integer) generally describes the number of ring-forming atoms in a moiety, where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridinyl is an example of a 6-membered heteroaryl ring, and 1, 2, 3, 4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl ring. When the term is used to refer to a carbocyclic ring (e.g., aryl or cycloalkyl), all ring atoms are carbon atoms. When the term is used to refer to a heterocyclic ring (e.g., heteroaryl or heterocycloalkyl), one or more (e.g., 1, 2, 3, or 4) of the ring atoms is a heteroatom (e.g., nitrogen, oxygen, or sulfur) and the remainder (e.g., n-1, n-2, n-3, or n-4) are carbon atoms.
In various places in this specification, divalent linking substituents are described. It is specifically intended that each divalent linking substituent includes both forward and backward forms of the linking substituent. For example, -NR (CR 'R') n-includes both-NR (CR 'R') n-and- (CR 'R') nNR-. Where a linking group is explicitly required for a structure, then the markush variables listed for that group are understood to be linking groups.
the phrase "optionally substituted" means unsubstituted or substituted. The substituents are independently selected, and the substituents can be in any chemically accessible position. The term "substituted" means that a hydrogen atom is removed and replaced with a substituent. A single divalent substituent (e.g., oxo) may replace two hydrogen atoms. It is understood that substitution at a given atom is limited by valence number. Exemplary substituents include, but are not limited to, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, OH, CN, NO2, amino, C1-6 alkylamino, di (C1-6 alkyl) amino, oxo, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl. In some embodiments, the C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl groups forming substituents may be optionally substituted, for example, optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, OH, CN, NO2, amino, C1-6 alkylamino, di (C1-6 alkyl) amino, and oxo.
the term "Cn-m" denotes a range including endpoints, where n and m are integers and denote the number of carbon atoms present in a chemical group. Examples include C1-2, C1-4, and the like. Whenever the term is used with the intent to describe each member included in the group, Cn through Cm are as if each member had been explicitly set forth. For example, the term C1-6 is intended to describe each of members C1, C2, C3, C4, C5, and C6.
the term "Cn-m alkyl" refers to a saturated hydrocarbon group having n to m carbons that may be straight or branched. The term "alkyl" refers to a saturated hydrocarbon group, which may be linear or branched, and may include Cn-m alkyl. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, and the like. In some embodiments, the alkyl group contains 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms.
The term "Cn-m alkoxy" refers to a group of the formula-O-alkyl, wherein the alkyl has n to m carbons. The term "alkoxy" refers to an-O-alkyl group, and may include a Cn-m alkoxy group. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tert-butoxy), and the like. In some embodiments, the alkyl group has 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms.
The term "amino" refers to a group of formula-NH 2.
The term "Cn-m alkylamino" refers to a group of formula-NH (alkyl), wherein alkyl has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of alkylamino include, but are not limited to, N-methylamino, N-ethylamino, N-propylamino (e.g., N- (N-propyl) amino and N-isopropylamino), N-butylamino (e.g., N- (N-butyl) amino and N- (tert-butyl) amino), and the like.
The term "di (Cn-m-alkyl) amino" refers to a group of formula-N (alkyl) 2, wherein the two alkyl groups each independently have N to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Exemplary dialkylamino groups include, but are not limited to, dimethylamino, ethylmethylamino, diethylamino, methylpropylamino, ethylpropylamino, dipropylamino, dibutylamino, butylpropylamino, and the like.
The term "aryl", used alone or in combination with other terms, refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings). The term "Cn-m aryl" refers to an aryl group having n to m ring carbon atoms. Aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, indanyl, indenyl, and the like. In some embodiments, aryl groups have from 6 to about 20 carbon atoms, from 6 to about 15 carbon atoms, or from 6 to about 10 carbon atoms. In some embodiments, aryl is optionally substituted phenyl. In some embodiments, aryl is unsubstituted phenyl. In some embodiments, aryl is optionally substituted naphthyl. In some embodiments, aryl is unsubstituted naphthyl.
"halo" or "halogen" refers to F, Cl, Br, or I. In some embodiments, halo is F or Cl. In some embodiments, halo is Cl.
The term "haloalkyl" refers to an alkyl group substituted with one or more halogen atoms, and may include "Cn-m haloalkyl". The term "Cn-m haloalkyl" refers to an alkyl group having from 1 halogen atom to 2s +1 halogen atoms, which may be the same or different, wherein "s" is the number of carbon atoms in the alkyl group, wherein the alkyl group has from n to m carbon atoms. In some embodiments, the haloalkyl is fluorinated only. In some embodiments, the alkyl group has 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. The number of halogen atoms may be, for example, 1, 2 or 3. In some embodiments, the haloalkyl is trifluoromethyl (-CF 3).
"cycloalkyl" refers to a non-aromatic cyclic hydrocarbon, including cyclized alkyl and/or alkenyl groups. Cycloalkyl groups may include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spiro rings. Cycloalkyl groups may have 3, 4, 5, or 6 ring-forming carbons (e.g., C3-6 cycloalkyl). In some embodiments, the cycloalkyl is a C3-6 monocyclic cycloalkyl. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
"heteroaryl" refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen, and nitrogen. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, heteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8, or 9 carbon atom ring members and 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, heteroaryl is an 8-10 membered bicyclic fused heteroaryl having 4, 5, 6, 7, 8, or 9 carbon atom ring members and 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. Exemplary 5-membered ring heteroaryl groups are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1, 2, 3-triazolyl, tetrazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-triazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 4-oxadiazolyl, 1, 3, 4-triazolyl, 1, 3, 4-thiadiazolyl, and 1, 3, 4-oxadiazolyl. Exemplary six membered ring heteroaryl groups are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl. Exemplary nine membered ring heteroaryl groups are 1H-benzo [ d ] imidazole, 1H-benzo [ d ] [1, 2, 3] triazole, 3H-imidazo [4, 5-b ] pyridine, 1H-imidazo [4, 5-b ] pyrazine, and the like.
"heterocycloalkyl" refers to a non-aromatic monocyclic or polycyclic heterocycle having one or more ring-forming heteroatoms selected from O, N or S. Included among heterocycloalkyl groups are monocyclic 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl groups. Heterocycloalkyl groups may also include spiro rings. Exemplary heterocycloalkyl groups include pyrrolidin-2-one, 1, 3-isoxazolidin-2-one, pyranyl, tetrahydropyranyl (tetrahydropuran), oxetanyl (oxolanyl), azetidinyl (azetidinyl), morpholinyl (morpholino), thiomorpholinyl (thiomorpholino), piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl (azepanyl), benzazepanyl (benzazapene), and the like. The ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group may be optionally substituted by oxo or thio (sulfido) (e.g., c (o), s (o), c(s), or s (o)2, etc.). The heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring-forming heteroatom (e.g., a ring-forming nitrogen atom). In some embodiments, heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having 1, 2, 3, 4, or 5 carbon atom ring members and 1 or 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
In certain positions, these definitions or embodiments refer to particular rings (e.g., pyrrolidine rings, etc.). Unless otherwise specified, the rings may be attached to any ring member, provided that the valency of the atoms is not exceeded. For example, the pyrrolidinyl ring may be attached at any position on the ring, while the pyrrolidin-1-yl ring is attached at the 1-position.
the compounds described herein can be asymmetric (e.g., having one or more stereogenic centers). Unless otherwise indicated, all stereoisomers (e.g., enantiomers and diastereomers) are contemplated. The compounds of the present invention containing asymmetrically substituted carbon atoms may be isolated in optically active or racemic forms. Methods are known in the art as to how to prepare optically active forms from optically inactive starting materials, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C ═ N double bonds, and the like may also be present in the compounds described herein, and all such stable isomers are encompassed by the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as mixtures of isomers or as individual isomers. In some embodiments, the compound has the (R) -configuration. In some embodiments, the compound has the (S) -configuration. In some embodiments, the compounds have the (R, R) -configuration. In some embodiments, the compounds have the (R, S) -configuration. In some embodiments, the compounds have the (S, S) -configuration. In some embodiments, the compounds have the (S, R) -configuration.
resolution of racemic mixtures of compounds can be carried out by any of a variety of methods known in the art. One exemplary method includes fractional recrystallization using a chiral resolving acid, which is an optically active salt-forming organic acid. Suitable resolving agents for use in the fractional recrystallization process are, for example, optically active acids, such as tartaric acid in the D and L forms, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acids (e.g. β -camphorsulfonic acid). Other resolving agents suitable for fractional crystallization processes include stereoisomerically pure forms of α -methylbenzylamine (e.g., S and R forms or diastereomerically pure forms), 2-phenylglycinol, norephedrine (norephedrine), ephedrine, N-methylephedrine, cyclohexylethylamine, 1, 2-diaminocyclohexane, and the like.
Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent, for example dinitrobenzoylphenylglycine. Suitable elution solvent compositions can be determined by those skilled in the art.
The compounds provided herein also include tautomeric forms. The tautomeric form results from the exchange of a single bond with an adjacent double bond along with the accompanying proton migration. Tautomeric forms include proton transfer tautomers, which are isomeric protonated states with the same empirical formula and total charge. Exemplary proton transfer tautomers include keto-enol pairs, amide-imide pairs, lactam-lactam pairs, enamine-imine pairs, and cyclic forms in which a proton may occupy more than two positions of a heterocyclic ring system, such as 1H-and 3H-imidazoles, 1H-, 2H-, and 4H-1, 2, 4-triazoles, 1H-and 2H-isoindoles, and 1H-and 2H-pyrazoles. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
all compounds and pharmaceutically acceptable salts thereof may be present with other materials such as water and solvents (e.g., hydrates and solvates), or may be isolated.
In some embodiments, preparation of the compounds may include addition of an acid or base to affect, for example, catalysis of the desired reaction or formation of a salt form (e.g., an acid addition salt).
Exemplary acids may be inorganic or organic acids and include, but are not limited to, strong and weak acids. Exemplary acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, 4-nitrobenzoic acid, methanesulfonic acid, benzenesulfonic acid, trifluoroacetic acid, nitric acid, acetic acid, propionic acid, butyric acid, benzoic acid, tartaric acid, valeric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, and capric acid.
Exemplary bases include, but are not limited to, hydroxides, alkoxides, metal amides, metal hydrides, metal dialkylamides, and arylamines, wherein: hydroxides include lithium hydroxide, sodium hydroxide and potassium hydroxide; alkoxides include lithium, sodium and potassium salts of methyl, ethyl and t-butyl oxides; metal amides include sodium amide, potassium amide, and lithium amide; metal hydrides including sodium hydride, potassium hydride and lithium hydride; and metal dialkylamides include lithium, sodium, and potassium salts of methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, trimethylsilyl, and cyclohexyl substituted amides.
in some embodiments, a compound provided herein or a salt thereof is substantially isolated. By "substantially isolated" is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial isolation may include, for example, compositions enriched in the compounds provided herein. Substantial separation can include a composition comprising at least about 50 wt.%, at least about 60 wt.%, at least about 70 wt.%, at least about 80 wt.%, at least about 90 wt.%, at least about 95 wt.%, at least about 97 wt.%, or at least about 99 wt.% of a compound provided herein, or a salt thereof. Methods for isolating compounds and salts thereof are conventional in the art.
Unless the context indicates otherwise, the term "compound" includes all stereoisomers, geometric isomers, tautomers and isotopes of the indicated structures. Unless otherwise indicated, a compound identified herein by name or structure as one particular tautomeric form is intended to include other tautomeric forms.
the phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and/or dosage forms that: it is suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio, within the scope of sound medical judgment.
The present application also includes pharmaceutically acceptable salts of the compounds described herein. The invention also includes pharmaceutically acceptable salts of the compounds described herein. The term "pharmaceutically acceptable salt" refers to derivatives of the disclosed compounds wherein the parent compound is modified by conversion of an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues (e.g., amines); alkali or organic salts of acidic residues (e.g., carboxylic acids); and the like. The pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media such as ether, ethyl acetate, alcohols (e.g., methanol, ethanol, isopropanol, or butanol), or acetonitrile are preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17 th edition, Mack Publishing Company, Easton, Pa., 1985, page 1418 and Journal of Pharmaceutical Science, 66, 2(1977), each of which is incorporated herein by reference in its entirety.
The expressions "ambient temperature" (abbreviated "rt") and "room temperature" generally refer to a temperature (e.g., reaction temperature) that is about the temperature of the room in which the reaction is conducted, e.g., a temperature of about 20 ℃ to about 30 ℃, typically a temperature of about 25 ℃.
by "cell proliferative disorder" is meant a disorder in which the body produces cells at an atypically accelerated rate.
The term "contacting" means bringing at least two moieties together, whether in an in vitro system or in an in vivo system.
The terms "individual" or "patient" used interchangeably refer to (e.g., as a subject of treatment) any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and most preferably humans.
The phrase "therapeutically effective amount" refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, subject, or human that is being sought by a researcher, veterinarian, medical doctor, or other clinician.
The term "treatment" or "treating" refers to one or more of the following: (1) inhibiting the disease; for example, inhibiting a disease, condition, or disorder in an individual who is experiencing the disease, condition, or disorder, or is presenting with a pathology or symptom of the disease, condition, or disorder (i.e., arresting further development of the pathology and/or symptom); and (2) relief from disease; for example, ameliorating a disease, condition, or disorder (i.e., reversing pathology and/or symptoms) in an individual who is experiencing the disease, condition, or disorder or is presenting with pathology or symptoms of the disease, condition, or disorder (i.e., reversing pathology and/or symptoms), such as reducing the severity of the disease. In one embodiment, treating or managing comprises preventing or reducing the risk of developing a disease; for example, preventing or reducing the risk of developing a disease, condition, or disorder in an individual who may be predisposed to the disease, condition, or disorder but has not yet experienced the disease or presented with the pathology or symptomology of the disease.
The following abbreviations may be used herein: AcOH (acetic acid); (aqueous); br (wide); d (bimodal); dd (doublet of doublets); DCM (dichloromethane); DIAD (N, N' -diisopropylazidodiformate); DIC (N, N' -diisopropylcarbodiimide); DIPEA (N, N-diisopropylethylamine); DMAP (4-dimethylaminopyridine); DMF (N, N-dimethylformamide); eq. (eq); et (ethyl); EtOAc (ethyl acetate); g (grams); h (hours); HATU (N, N' -tetramethyl-O- (7-azabenzotriazol-1-yl) urea hexafluorophosphate); HCl (hydrochloric acid); HPLC (high performance liquid chromatography); hz (hertz); j (coupling constant); LCMS (liquid chromatography-mass spectrometry); m (multiplet); m (mole); MS (mass spectrometry); me (methyl); MeCN (acetonitrile); MeOH (methanol); mg (milligrams); min. (minutes); mL (milliliters); mmol (millimole); n (standard); NaHCO3 (sodium bicarbonate); NaOH (sodium hydroxide); na2SO4 (sodium sulfate); NH4Cl (ammonium chloride); nm (nanometers); nM (nanomolar); NMR (nuclear magnetic resonance spectroscopy); PPTS (pyridinium p-toluenesulfonate); RP-HPLC (reverse phase high performance liquid chromatography); rt (room temperature); s (single multiplet); t (triplet or tertiary); tert (tertiary); tt (triplet); /-Bu (tert-butyl); THF (tetrahydrofuran); μ g (μ g); μ L (microliters); μ M (micromolar); wt% (weight percent).
II. Compound
The present application provides, inter alia, compounds of formula I:
Or a pharmaceutically acceptable salt thereof, wherein:
X is O or CH 2;
y is CR1R2, NR3, C (═ O) NH, or NH (C ═ O);
Z is C (═ O) ORZ1 or C (═ O) NRZ2RZ 3;
n is 0, 1, 2 or 3;
RN is H or optionally substituted C1-4 alkyl;
R1 is H or optionally substituted C1-4 alkyl;
R2 is H or optionally substituted C1-4 alkyl; or
r1 and R2 combine to form C2-4 alkylene, said C2-4 alkylene forming, together with the carbon atom to which R1 and R2 (which are attached), a 3-6 membered optionally substituted cycloalkyl ring;
r3 is H or optionally substituted C1-4 alkyl;
RZ1 is optionally substituted C1-4 alkyl;
RZ2 is H or optionally substituted C1-4 alkyl;
RZ3 is H or optionally substituted C1-4 alkyl; or
RZ2 and RZ3 combine with the nitrogen atom to which they are attached to form an optionally substituted 4-6 membered heterocycloalkyl ring; and is
ar is optionally substituted C6-10 aryl or 5-10 membered optionally substituted heteroaryl.
in some embodiments, each substituted C1-4 alkyl is substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 alkoxy, OH, CN, NO2, amino, C1-4 alkylamino, di (C1-4 alkyl) amino, oxo, optionally substituted C3-10 cycloalkyl, optionally substituted C6-10 aryl, optionally substituted 4-10 membered heterocycloalkyl, and optionally substituted 5-10 membered heteroaryl;
Each substituted cycloalkyl and heterocycloalkyl is substituted with 1, 2, 3, 4 or 5 substituents each independently selected from halo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 alkoxy, OH, CN, NO2, amino, C1-4 alkylamino, di (C1-4 alkyl) amino and oxo; and is
Each of the substituted aryl and heteroaryl is substituted with 1, 2, 3, 4 or 5 substituents each independently selected from halo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 alkoxy, OH, CN, NO2, amino, C1-4 alkylamino and di (C1-4 alkyl) amino.
In some embodiments, X is O.
In some embodiments, X is CH 2.
in some embodiments, Y is CR1R 2.
in some embodiments, Y is NR3, C (═ O) NH, or NH (C ═ O).
In some embodiments, R3 is H or unsubstituted C1-4 alkyl, e.g., methyl or ethyl.
in some embodiments, R3 is H.
In some embodiments, RN is H or unsubstituted C1-4 alkyl.
In some embodiments, RN is unsubstituted C1-4 alkyl.
In some embodiments, RN is methyl or ethyl.
In some embodiments, R1 is H or unsubstituted C1-4 alkyl, e.g., methyl or ethyl.
In some embodiments, R1 is H or methyl.
In some embodiments, R2 is H or unsubstituted C1-4 alkyl, e.g., methyl or ethyl.
In some embodiments, R2 is H or methyl.
In some embodiments, R1 is H or optionally substituted C1-4 alkyl, such as methyl or ethyl, and R2 is H or optionally substituted C1-4 alkyl, such as methyl or ethyl.
In some embodiments, R1 and R2 are each H.
In some embodiments, R1 and R2 are each unsubstituted C1-4 alkyl, e.g., methyl or ethyl.
In some embodiments, R1 and R2 are each methyl.
In some embodiments, R1 and R2 combine to form a C2-4 alkylene (e.g., -CH2) 2-4-group) that, together with the carbon atom to which R1 and R2 are attached, forms a 3-6 membered optionally substituted cycloalkyl ring.
In some embodiments, R1 and R2 combine to form a C2-4 alkylene group, which C2-4 alkylene group together with the carbon atom to which R1 and R2 are attached forms a 3-6 membered unsubstituted cycloalkyl ring, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, the cycloalkyl ring may be unsubstituted. In some embodiments, the cycloalkyl ring may be substituted.
In some embodiments, R1 and R2 combine to form an ethylene group, which together with the carbon atom to which R1 and R2 are attached forms an unsubstituted cyclopropyl ring.
in some embodiments, n is 0.
In some embodiments, n is 1.
In some embodiments, n is 2.
In some embodiments, n is 3.
in some embodiments, Z is C (═ O) ORZ 1.
In some embodiments, RZ1 is an unsubstituted C1-4 alkyl group, such as methyl or ethyl.
In some embodiments, RZ1 is methyl.
In some embodiments, Z is C (═ O) NRZ2RZ 3.
in some embodiments, RZ2 is H or unsubstituted C1-4 alkyl, e.g., methyl or ethyl.
In some embodiments, RZ2 is H or methyl.
In some embodiments, RZ3 is optionally substituted C1-4 alkyl, e.g., methyl or ethyl.
In some embodiments, RZ3 is C1-4 alkyl optionally substituted with 1, 2, or 3 groups independently selected from amino, C1-4 alkylamino, di (C1-4 alkyl) amino, C1-4 alkoxy, and 4-6 membered heterocycloalkyl.
In some embodiments, RZ3 is methyl, N-dimethylaminoethyl, N-diethylaminoethyl, methoxyethyl, or pyrrolidinylethyl.
In some embodiments, RZ3 is methyl, 2- (N, N-dimethylamino) ethyl, 2- (N, N-diethylamino) ethyl, 2-methoxyethyl, or 2- (pyrrolidin-1-yl) ethyl.
In some embodiments, RZ2 is H or optionally substituted C1-4 alkyl, and RZ3 is H or optionally substituted C1-4 alkyl.
In some embodiments, RZ2 is H or unsubstituted C1-4 alkyl, e.g., methyl or ethyl, and RZ3 is optionally substituted C1-4 alkyl, e.g., methyl or ethyl.
in some embodiments, RZ2 and RZ3, in combination with the nitrogen atom to which they are attached, form an optionally substituted 4-6 membered heterocycloalkyl ring.
In some embodiments, RZ2 and RZ3 combine with the nitrogen atom to which they are attached to form an unsubstituted 4-6 membered heterocycloalkyl ring.
In some embodiments, RZ2 and RZ3 combine with the nitrogen atom to which they are attached to form a morpholinyl ring.
In some embodiments, Ar is optionally substituted phenyl, optionally substituted naphthyl, or 5-10 membered optionally substituted heteroaryl.
In some embodiments, Ar is aryl (e.g., phenyl), naphthyl, or 5-10 membered heteroaryl, each optionally substituted with 1, 2, 3, or 4 independently selected RAr groups, wherein each RAr is independently selected from the group consisting of: halo, C1-4 alkyl, C1-4 haloalkyl, and C1-4 alkoxy.
In some embodiments, Ar is unsubstituted phenyl, unsubstituted naphthyl, or 5-10 membered optionally substituted heteroaryl.
in some embodiments, Ar is 5-10 membered optionally substituted heteroaryl.
In some embodiments, Ar is an 8-10 membered optionally substituted heteroaryl. In some embodiments, the 8-10 membered optionally substituted heteroaryl is an 8-10 membered fused bicyclic heteroaryl.
in some embodiments, Ar is a 5-10 membered heteroaryl optionally substituted with 1, 2, 3, or 4 groups independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, and C1-4 alkoxy.
in some embodiments, Ar is an 8-10 membered heteroaryl optionally substituted with 1, 2, 3, or 4 groups independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, and C1-4 alkoxy.
In some embodiments, Ar is 5-10 membered heteroaryl optionally substituted with 1, 2, 3, or 4 groups independently selected from chloro, methyl, methoxy, and trifluoromethyl.
In some embodiments, Ar is an 8-10 membered heteroaryl optionally substituted with 1, 2, 3, or 4 groups independently selected from chloro, methyl, methoxy, and trifluoromethyl.
In some embodiments, Ar is a group of formula Ar-1:
Wherein each RAr is independently selected from the group consisting of: h. halo, C1-4 alkyl, C1-4 haloalkyl, and C1-4 alkoxy.
In some embodiments, each RAr is independently selected from the group consisting of: h. chloro, methyl, methoxy and trifluoromethyl.
In some embodiments, Ar is a group selected from the group consisting of formulas Ar-2 and Ar-3:
Wherein each RAr is independently selected from the group consisting of: halo, C1-4 alkyl, C1-4 haloalkyl, and C1-4 alkoxy.
in some embodiments, each RAr is independently selected from the group consisting of: chloro, methyl, methoxy and trifluoromethyl.
In some embodiments, Ar is:
in some embodiments:
x is O or CH 2;
Y is CR1R 2;
Z is C (═ O) ORZ1 or C (═ O) NRZ2RZ 3;
RN is unsubstituted C1-4 alkyl;
R1 is H or unsubstituted C1-4 alkyl;
R2 is H or unsubstituted C1-4 alkyl; or
R1 and R2 combine to form C2-4 alkylene, which C2-4 alkylene together with the carbon atom to which R1 and R2 are attached forms a 3-6 membered optionally substituted cycloalkyl ring;
n is 0, 1, 2 or 3;
RZ1 is unsubstituted C1-4 alkyl;
RZ2 is H or unsubstituted C1-4 alkyl;
RZ3 is optionally substituted C1-4 alkyl; or
RZ2 and RZ3 combine with the nitrogen atom to which they are attached to form an optionally substituted 4-6 membered heterocycloalkyl ring; and is
ar is optionally substituted phenyl, optionally substituted naphthyl, or 5-10 membered optionally substituted heteroaryl.
In some embodiments:
x is O or CH 2;
Y is CR1R 2;
z is C (═ O) ORZ1 or C (═ O) NRZ2RZ 3;
RN is unsubstituted C1-4 alkyl, for example methyl or ethyl;
r1 is H or unsubstituted C1-4 alkyl, e.g., methyl or ethyl;
R2 is H or unsubstituted C1-4 alkyl, e.g., methyl or ethyl; or
r1 and R2 combine to form C2-4 alkylene, which C2-4 alkylene together with the carbon atom to which R1 and R2 are attached forms a 3-6 membered optionally substituted cycloalkyl ring;
n is 1;
RZ1 is unsubstituted C1-4 alkyl, e.g., methyl or ethyl;
RZ2 is H or unsubstituted C1-4 alkyl, e.g., methyl or ethyl;
RZ3 is C1-4 alkyl optionally substituted with 1, 2, or 3 groups independently selected from amino, C1-4 alkylamino, di (C1-4 alkyl) amino, C1-4 alkoxy, and 4-6 membered heterocycloalkyl, RZ2 and RZ3 combine with the nitrogen atom to which they are attached to form an optionally substituted 4-6 membered heterocycloalkyl ring; and is
Ar is a 5-10 membered optionally substituted heteroaryl.
in some embodiments:
x is O or CH 2;
y is CR1R 2;
z is C (═ O) ORZ1 or C (═ O) NRZ2RZ 3;
RN is unsubstituted C1-4 alkyl, for example methyl or ethyl;
R1 is H or methyl;
R2 is H or methyl; or
R1 and R2 combine to form an ethylene group which together with the carbon atom to which R1 and R2 are attached forms a cyclopropyl ring;
n is 1;
RZ1 is unsubstituted C1-4 alkyl, e.g., methyl or ethyl;
RZ2 is H or unsubstituted C1-4 alkyl, e.g., methyl or ethyl;
RZ3 is C1-4 alkyl optionally substituted with 1, 2, or 3 groups independently selected from amino, C1-4 alkylamino, di (C1-4 alkyl) amino, C1-4 alkoxy, and 4-6 membered heterocycloalkyl, RZ2 and RZ3 combine with the nitrogen atom to which they are attached to form an optionally substituted 4-6 membered heterocycloalkyl ring; and is
Ar is a 5-10 membered heteroaryl group optionally substituted with 1, 2, 3 or 4 groups independently selected from halo, C1-4 alkyl, C1-4 haloalkyl and C1-4 alkoxy.
in some embodiments, the compound of formula I is a compound of formula II:
Or a pharmaceutically acceptable salt thereof, wherein the variables Y, Z, RN and Ar are defined herein with respect to the definition provided for the compound of formula I.
In some embodiments, the compound of formula I is a compound of formula III:
Or a pharmaceutically acceptable salt thereof, wherein the variables Z, R1, R2, and Ar are defined herein with respect to the definition provided for the compound of formula I.
in some embodiments, the compound of formula I is a compound of formula IV:
Or a pharmaceutically acceptable salt thereof, wherein the variables Z, R1 and R2 are defined herein with respect to the definition of the compound of formula I; and is
Each RAr is independently selected from H, halo, C1-4 alkyl, C1-4 haloalkyl and C1-4 alkoxy.
In some embodiments, the compound of formula I is a compound of formula V:
Or a pharmaceutically acceptable salt thereof, wherein the variables RZ2, RZ3, R1, and R2 are defined as provided herein for compounds of formula I; and is
each RAr is independently selected from H, halo, C1-4 alkyl, C1-4 haloalkyl and C1-4 alkoxy.
In some embodiments, the compound of formula I is a compound of formula VI:
Or a pharmaceutically acceptable salt thereof, wherein the variables RZ1, R1, and R2 are defined as provided herein for compounds of formula I; and is
Each RAr is independently selected from H, halo, C1-4 alkyl, C1-4 haloalkyl and C1-4 alkoxy.
In some embodiments, the compound of formula I is a compound of formula VII:
Or a pharmaceutically acceptable salt thereof, wherein the variables Z, R1 and R2 are defined herein with respect to the definition of the compound of formula I; and is
Each RAr is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl and C1-4 alkoxy.
In some embodiments, the compound of formula I is a compound of formula VIII:
Or a pharmaceutically acceptable salt thereof, wherein the variables Z, R1 and R2 are defined herein with respect to the definition of the compound of formula I.
each RAr is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl and C1-4 alkoxy.
in some embodiments, the compound of formula I is a compound of formula IX:
or a pharmaceutically acceptable salt thereof, wherein the variables Z, R1 and R2 are defined herein with respect to the definition of the compound of formula I; and is
Each RAr is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl and C1-4 alkoxy.
In some embodiments, the compound of formula I is a compound of formula X:
Or a pharmaceutically acceptable salt thereof, wherein the variables Z, R1 and R2 are defined herein with respect to the definition of the compound of formula I; and is
Each RAr is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl and C1-4 alkoxy.
In some embodiments, the compound of formula I is a compound of formula XI:
Or a pharmaceutically acceptable salt thereof, wherein the variables Z, R1 and R2 are defined herein with respect to the definition of the compound of formula I; and is
Each RAr is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl and C1-4 alkoxy.
in some embodiments, the compound of formula I is a compound of formula I-a, I-b, I-c, II-a, II-b, II-c, III-a, III-b, III-c, IV-a, IV-b, IV-c, V-a, V-b, V-c, VI-a, VI-b, VI-c, VII-a, VII-b, VII-c, VIII-a, VIII-b, VIII-c, IX-a, IX-b, IX-c, X-a, X-b, X-c, XI-a, XI-b, or XI-c:
Or a pharmaceutically acceptable salt thereof, wherein the variables X, Y, Z, RN, n, R1, R2, Ar and RAr are defined herein with respect to the definition provided for the compound of formula I.
In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, is selected from:
Methylcarbamic acid 2- (2- ((3- (1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
Methyl carbonate 2- (2- ((3- (1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
methylcarbamic acid 2- (2- ((3- (4, 7-dimethyl-1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester
(2- (dimethylamino) ethyl) carbamic acid 2- (2- ((3- (4, 7-dimethyl-1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
Methylcarbamic acid 2- (2- ((3- (4, 7-dimethoxy-1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
(2-methoxyethyl) carbamic acid 2- (2- ((3- (4, 7-dimethoxy-1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
Dimethyl carbamic acid 2- (2- ((3- (7-chloro-4-methoxy-1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
Morpholine-4-carboxylic acid 2- (2- ((3- (4, 6-bis (trifluoromethyl) -1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
morpholine-4-carboxylic acid 2- (2- ((3- (1H-benzo [ d ] imidazol-2-yl) -3-methylbutyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
Methylcarbamic acid 2- (2- ((3- (1H-benzo [ d ] imidazol-2-yl) -3-methylbutyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
(2- (dimethylamino) ethyl) carbamic acid 2- (2- ((3- (1H-benzo [ d ] imidazol-2-yl) -3-methylbutyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
(2-methoxyethyl) carbamic acid 2- (2- ((3- (1H-benzo [ d ] imidazol-2-yl) -3-methylbutyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
2- (2- ((3- (1H-benzo [ d ] imidazol-2-yl) -3-methylbutyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl) 2- (2- (pyrrolidin-1-yl) ethyl) carbamate;
(2- (diethylamino) ethyl) carbamic acid 2- (2- ((3- (1H-benzo [ d ] imidazol-2-yl) -3-methylbutyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
Morpholine-4-carboxylic acid 2- (2- ((3- (4, 7-dimethyl-1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
2- (2- ((3- (4, 7-dimethyl-1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl) carbamate;
morpholine-4-carboxylic acid 2- (2- ((4- ((2-amino-3, 6-dimethylphenyl) amino) -4-oxobutyl) (ethyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
Morpholine-4-carboxylic acid 2- (2- ((2- (1- (1H-benzo [ d ] imidazol-2-yl) cyclopropyl) ethyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
Methylcarbamic acid 3- (2- ((3- (1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -7-fluoro-4-isopropyl chroman-3-yl ester; and
methylcarbamic acid 3- (2- ((3- (4, 7-dimethyl-1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -7-fluoro-4-isopropyl chroman-3-yl ester;
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, is selected from:
(1S, 2S) -methylcarbamic acid 2- (2- ((3- (1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
(1S, 2S) -methyl carbonic acid 2- (2- ((3- (1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
(1S, 2S) -methylcarbamic acid 2- (2- ((3- (4, 7-dimethyl-1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
(1S, 2S) - (2- (dimethylamino) ethyl) carbamic acid 2- (2- ((3- (4, 7-dimethyl-1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
(1S, 2S) -methylcarbamic acid 2- (2- ((3- (4, 7-dimethoxy-1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
(1S, 2S) - (2-methoxyethyl) carbamic acid 2- (2- ((3- (4, 7-dimethoxy-1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
(1S, 2S) -dimethylcarbamic acid 2- (2- ((3- (7-chloro-4-methoxy-1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
(1S, 2S) -morpholine-4-carboxylic acid 2- (2- ((3- (4, 6-bis (trifluoromethyl) -1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
(1S, 2S) -morpholine-4-carboxylic acid 2- (2- ((3- (1H-benzo [ d ] imidazol-2-yl) -3-methylbutyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
(1S, 2S) -methylcarbamic acid 2- (2- ((3- (1H-benzo [ d ] imidazol-2-yl) -3-methylbutyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
2- (2- ((3- (1H-benzo [ d ] imidazol-2-yl) -3-methylbutyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl) (1S, 2S) - (2- (dimethylamino) ethyl) carbamate;
(1S, 2S) - (2-methoxyethyl) carbamic acid 2- (2- ((3- (1H-benzo [ d ] imidazol-2-yl) -3-methylbutyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
(1S, 2S) - (2- (pyrrolidin-1-yl) ethyl) carbamic acid 2- (2- ((3- (1H-benzo [ d ] imidazol-2-yl) -3-methylbutyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
2- (2- ((3- (1H-benzo [ d ] imidazol-2-yl) -3-methylbutyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl) carbamate (1S, 2S) - (2- (diethylamino) ethyl) carbamate;
(1S, 2S) -morpholine-4-carboxylic acid 2- (2- ((3- (4, 7-dimethyl-1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
(1S, 2S) -dimethylcarbamic acid 2- (2- ((3- (4, 7-dimethyl-1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
(1R, 2R) -morpholine-4-carboxylic acid 2- (2- ((3- (4, 7-dimethyl-1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
(1S, 2S) -morpholine-4-carboxylic acid 2- (2- ((4- ((2-amino-3, 6-dimethylphenyl) amino) -4-oxobutyl) (ethyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
(1S, 2S) -morpholine-4-carboxylic acid 2- (2- ((2- (1- (1H-benzo [ d ] imidazol-2-yl) cyclopropyl) ethyl) (methyl) amino) ethyl) -6-fluoro-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl ester;
(3S, 4S) -methylcarbamic acid 3- (2- ((3- (1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -7-fluoro-4-isopropyl chroman-3-yl ester;
(3R, 4S) -methylcarbamic acid 3- (2- ((3- (1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -7-fluoro-4-isopropyl chroman-3-yl ester;
(3S, 4S) -methylcarbamic acid 3- (2- ((3- (4, 7-dimethyl-1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -7-fluoro-4-isopropyl chroman-3-yl ester; and
(3R, 4S) -methylcarbamic acid 3- (2- ((3- (4, 7-dimethyl-1H-benzo [ d ] imidazol-2-yl) propyl) (methyl) amino) ethyl) -7-fluoro-4-isopropyl chroman-3-yl ester;
Or a pharmaceutically acceptable salt thereof.
With respect to other compounds that may be disclosed in the art, the compounds of the present invention exhibit unexpected properties, such as with respect to duration of action and/or metabolism, such as increased metabolic stability, enhanced oral bioavailability or absorption, and/or reduced drug-drug interactions. The compounds of the invention may exhibit a reduced propensity for side effects (e.g., with respect to cardiovascular side effects such as those associated with inhibition of the hERG potassium channel).
synthesis of
The compounds provided herein (including salts thereof) can be prepared using known organic synthesis techniques and can be synthesized according to any of a variety of possible synthetic routes.
For example, a compound provided herein (e.g., a compound of any of formulas I-XI) or a pharmaceutically acceptable salt thereof, can be prepared according to the procedure shown in scheme 1, wherein Ag1 is a hydroxyl activating group (e.g., tosyl, mesyl, etc.), R' is an alkyl group (e.g., C1-4 alkyl, such as methyl or t-butyl), and the variables X, Y, Z, RN, Ar, and n are defined herein as provided for the compound of formula I.
Scheme 1.
For example, the compounds provided herein, or pharmaceutically acceptable salts thereof, can also be prepared according to the procedures shown in scheme 2, R' is alkyl (e.g., C1-4 alkyl, such as methyl or t-butyl), and the variables X, Y, Z, RN, Ar, and n are defined herein with respect to the definition provided for the compound of formula I.
Scheme 2.
As shown in scheme 3 below, the compounds provided herein, or pharmaceutically acceptable salts thereof, can also be prepared from the commercially available starting material mibefradil (mibefradil).
Scheme 3.
The preparation of the compounds described herein may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the choice of an appropriate protecting group, can be readily determined by those skilled in the art. The chemical nature of the Protecting Group may be found, for example, in Protecting Group Chemistry, 1 st edition, Oxford University Press, 2000; march's Advanced Organic chemistry: reactions, Mechanisms, and Structure, 5 th edition, Wiley-Interscience Publication, 2001; and Petursion et al, "protective Groups in Carbohydrate Chemistry," J.chem.Educ., 1997, 74(11), 1297.
the reaction for preparing the compounds as described herein may be carried out in a suitable solvent, which may be readily selected by one skilled in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperatures at which the reaction is carried out (e.g., temperatures that can range from the freezing temperature of the solvent to the boiling temperature of the solvent). A given reaction may be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, the skilled person can select a suitable solvent for the particular reaction step.
The reaction may be monitored by any suitable method known in the art. For example, product formation may be monitored by spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g. 1H or 13C), infrared spectroscopy, spectrophotometry (e.g. UV-visible light), mass spectrometry, or by chromatographic methods such as High Performance Liquid Chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS) or Thin Layer Chromatography (TLC). The compounds can be purified by a variety of methods by those skilled in the art, including High Performance Liquid Chromatography (HPLC) ("Preparative LC-MS Purification: Improved Compound Specific Method Optimization" Blom et al, J.Combi.chem.2004, 6(6)874-883) and normal phase silica gel chromatography (Still et al, J.Org.chem., 1978, 43(14), 2923-25).
It will be understood by those skilled in the art that the methods described herein are not exclusive methods by which the compounds provided herein may be synthesized, and that a wide collection of synthetic organic reactions may be used to potentially synthesize the compounds provided herein. The skilled person knows how to select and implement an appropriate synthetic route. Suitable synthetic methods for starting materials, intermediates and products can be determined by reference, including reference sources such as: advances in Heterocyclic Chemistry, Vols.1-107(Elsevier, 1963-; journal of Heterocyclic Chemistry Vols.1-49(Journal of Heterocyclic Chemistry, 1964-; carreira et al (eds.) Science of Synthesis, Vols.1-48 (2001-; 2011/1-4; 2012/1-2(Thieme, 2001-; katritzky et al, (ed) Comprehensive Organic Functional Group Transformations, (Pergamon Press, 1996); katritzky et al (editors); comprehensive Organic Functional Group Transformations II (Elsevier, 2 nd edition, 2004); katritzky et al (ed.), Comprehensive Heterocyclic Chemistry (Pergamon Press, 1984); katritzky et al, Comprehensive Heterocyclic Chemistry II, (Pergamon Press, 1996); smith et al, March's Advanced Organic Chemistry: reactions, Mechanisms, and Structure, 6 th edition (Wiley, 2007); trost et al (ed.), Comprehensive Organic Synthesis (Pergamon Press, 1991).
Method of use
A. inhibition of calcium channels
the present application also provides methods of blocking one or more subtypes of voltage-gated calcium channels. In some embodiments, the method is an in vitro method. In some embodiments, the method is an in vivo method.
in some embodiments, the method comprises blocking one or more subtypes of a voltage-gated calcium channel in a cell sample or tissue sample, the method comprising contacting the cell sample or tissue sample with a compound provided herein (e.g., a compound of any of formulas I-XI), or a pharmaceutically acceptable salt thereof.
In some embodiments, the method comprises blocking one or more subtypes of T-type voltage-gated calcium channels in the cell sample or tissue sample.
In some embodiments, the subtype is cav3.1, cav3.2, cav3.3, or any combination thereof.
In some embodiments, the method comprises blocking a cav3.2 subtype of T-type voltage-gated calcium channels in a cell sample or a tissue sample.
The present application also provides methods of blocking one or more subtypes of a voltage-gated calcium channel in a subject. The term "subject" refers to any animal, including mammals. Exemplary subjects include, but are not limited to, mice, rats, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, and humans. In some embodiments, the subject is a human. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a compound provided herein (e.g., a compound of any one of formulas I-XI), or a pharmaceutically acceptable salt thereof.
In some embodiments, the method comprises blocking one or more subtypes of a T-type voltage-gated calcium channel in the subject.
in some embodiments, the subtype is cav3.1, cav3.2, cav3.3, or any combination thereof.
in some embodiments, the method comprises blocking a cav3.2 subtype of T-type voltage-gated calcium channel in the subject.
The present application also provides methods of treating a disease associated with aberrant activity of one or more subtypes of voltage-gated calcium channels in a subject. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a compound provided herein (e.g., a compound of any one of formulas I-XI), or a pharmaceutically acceptable salt thereof.
in some embodiments, the disease is associated with abnormal activity of one or more subtypes of T-type voltage-gated calcium channels in the subject.
In some embodiments, the disease is associated with abnormal activity of cav3.1, cav3.2, cav3.3, or any combination thereof in the subject.
in some embodiments, the disease is associated with abnormal activity of the cav3.2 subtype of T-type voltage-gated calcium channels in the subject.
B. cancer treatment
Provided herein are methods of treating a cell proliferative disorder in a patient. The method comprises administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or any of its embodiments.
The cell proliferative disorder may include cancer. Non-limiting examples of cancer include bladder cancer, brain cancer, breast cancer, colorectal cancer, cervical cancer, gastrointestinal cancer, genitourinary cancer, head and neck cancer, lung cancer, ovarian cancer, prostate cancer, kidney cancer, skin cancer, and testicular cancer.
More particularly, cancers that may be treated by the compounds, compositions and methods described herein include, but are not limited to, the following:
1) Nervous system cancers, including, for example, cancers of the skull, such as osteoma, hemangioma, granuloma, xanthoma, and osteitis deformans; meningeal cancers, such as meningioma, meningeal sarcoma, and glioma; brain cancers, such as astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors (pinealomas), gliomas (gliomas ), glioblastoma multiforme, oligodendrogliomas, schwannomas, retinoblastomas, and congenital tumors; and spinal cord cancers such as neurofibromas, meningiomas, gliomas, and sarcomas.
2) Breast cancers including, for example, ER + breast cancer, ER-breast cancer, her 2-breast cancer, her2+ breast cancer, interstitial tumors such as fibroadenoma, phyllodes tumors, and sarcomas, and epithelial tumors such as ductal papillomas; breast carcinomas include carcinoma in situ (non-invasive) including ductal carcinoma in situ (including Paget's disease) and lobular carcinoma in situ, and aggressive (invasive) cancers including, but not limited to, invasive ductal carcinoma, invasive lobular carcinoma, medullary carcinoma, glue (mucus) carcinoma, tubular carcinoma, and invasive papillary carcinoma; and confounding malignancies. Other examples of breast cancer may include luminal a, luminal B, basal a, basal B, and triple breast cancers, which are estrogen receptor negative (ER-), progesterone receptor negative, and her2 negative (her 2-). In some embodiments, the breast cancer may have a high risk of cancer type (Oncotype) score.
3) Heart cancers including, for example, sarcomas, such as angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma; myxoma; rhabdomyoma; fibroids; lipomas and teratomas.
4) Lung cancer, including, for example, bronchial cancers, such as squamous cells, undifferentiated small cells, undifferentiated large cells, and adenocarcinoma; alveolar and bronchiolar carcinomas; bronchial adenoma; a sarcoma; lymphoma; cartilage hamartoma (chondromatous hamartoma); and mesothelioma.
5) Gastrointestinal cancers including, for example, esophageal cancers such as squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma; gastric cancers, such as carcinoma, lymphoma and leiomyosarcoma; pancreatic cancers, such as ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors (carcinoid tumors), and vipoma (vipoma); small bowel cancers, such as adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, and fibroma; large bowel cancers such as adenocarcinoma, tubular adenoma, villous adenoma, hamartoma (hamartoma) and leiomyoma.
6) genitourinary tract cancers, including, for example, renal cancers, such as adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, and leukemia; bladder and urinary tract cancers, such as squamous cell carcinoma, transitional cell carcinoma, and adenocarcinoma; prostate cancers, such as adenocarcinoma and sarcoma; testicular cancers such as seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors (adenomatoid tumors), and lipomas.
7) liver cancer, including, for example, hepatoma, such as hepatocellular carcinoma; biliary epithelial cancer; hepatoblastoma; angiosarcoma; hepatocellular adenoma; and hemangiomas.
8) Bone cancers include, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrosarcoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulosarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondrochromyoma) (osteochondrochondral exostosis), benign chondroma, chondroblastoma fibrosus (chondromomyoxofibroma), osteoid osteoma, and giant cell tumor.
9) Gynecological cancers, including, for example, uterine cancers, such as endometrial cancers; cervical cancers, such as cervical cancer and pre-neoplastic cervical dysplasia (pre cervical dysplasia); ovarian cancers, such as ovarian cancers, including serous cystadenocarcinoma, myxocystic adenocarcinoma, unclassified carcinoma, granulosa thecal cell tumors (granulosa thecal cells), Sertoli Leydig cell tumors (Sertoli Leydig cell tumors), dysgerminoma, and malignant teratoma; vulvar cancers, such as squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, and melanoma; vaginal cancers such as clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma, and embryonal rhabdomyosarcoma; and fallopian tube cancer, such as carcinoma.
10) Hematologic cancers, including, for example, hematologic cancers, such as acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma and myelodysplastic syndrome (myelodysplastic syndrome), Hodgkin's lymphoma, non-Hodgkin's lymphoma (malignant lymphoma), and waldenstrom's macroglobulinemia (macroglobulinemia).
11) skin cancers, including, for example, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, kaposi's sarcoma, dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloids (keloids), and psoriasis.
12) Adrenal cancer, including, for example, neuroblastoma.
13) pancreatic cancer, including, for example, exocrine pancreatic cancer, such as adenocarcinoma (M8140/3), adenosquamous carcinoma, signet ring cell carcinoma, hepatoid, colloid-like, undifferentiated, and undifferentiated with osteoclast-like giant cells; and exocrine pancreatic tumors.
The cancer may be a solid tumor, which may or may not be metastatic. Cancer can also occur as diffuse tissue, as in leukemia. Thus, the term "tumor cell" as provided herein includes cells that suffer from any of the disorders identified above.
the compounds described herein may also be useful for the treatment of non-cancer cell proliferative disorders such as hemangiomatosis, secondary progressive multiple sclerosis, chronic progressive myelodegenerative diseases, neurofibromatosis, gangliomasis, keloid formation, paget's disease of bone, fibrocystic disease of the breast, uterine fibroids, peloniosis (Peyronie's disease), diesterren's disease, restenosis (restenosis) and cirrhosis of the liver in newborns.
in some embodiments, the cancer is selected from the group consisting of: brain cancer, breast cancer, colon cancer, glioma, glioblastoma, melanoma, ovarian cancer, and pancreatic cancer.
in some embodiments, the cancer is glioma or glioblastoma.
The present invention also provides a compound described herein (e.g., a compound of any one of formulas I-XI), or a pharmaceutically acceptable salt thereof, for use in any one of the methods described herein.
The invention also provides the use of a compound described herein (e.g. a compound of any one of formulae I-XI), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in any one of the methods described herein.
C. other diseases
in addition to cancer, T-type calcium channels are involved in a wide range of biological functions. This suggests that these receptors have potential roles in various disease processes in humans or other species. The compounds of the present invention are useful in the treatment, prevention, alleviation, control, or reduction of risk of various neurological and psychiatric disorders associated with calcium channels, including one or more of the following conditions or diseases: movement disorders (dyskinesias), including akinesia and akinesia-tonic syndrome (including Parkinson's disease, drug-induced parkinsonism, postencephalitic parkinsonism, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, parkinsonism-ALS dementia complex and basal ganglial calcification), chronic fatigue syndrome, fatigue, including parkinsonism, multiple sclerosis fatigue, fatigue caused by sleep disorders or circadian rhythm disturbances, drug-induced parkinsonism (such as neuroleptic-induced parkinsonism, antipsychotic malignancy syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia (dyskinesia) and drug-induced tremor in-situ), gilles de la Tourette's syndrome, seizure disorders (seizure disorder), epilepsy (epilepsy) and movement disorders [ including tremors (e.g. resting tremor, essential tremor, postural tremor and intention tremor) ], chorea (e.g. Sydenham's chorea), Huntington's chorea, benign hereditary chorea, neuroacanthocytosis, symptomatic chorea, drug-induced chorea and hemiballism (hemibali) ], myoclonus (including systemic myoclonus and myoclonus), tic (including simple tic, complex and symptomatic tic), restless leg syndrome and dystonia (including systemic dystonia, such as dystonia (dystonia), drug-induced dystonia and dystonia), and focal dystonia, such as blepharospasm, oromandibular dystonia, spasmodic dysphonia, spasmodic torticollis, axial dystonia, dystonic writer's cramp, and hemiplegic dystonia); angelman's Syndrome, Prader-Willi Syndrome, heart disease, abnormal heart rhythm and arrhythmia, myocardial infarction, congestive heart failure, coronary heart disease, sudden death, stroke, sexual and reproductive dysfunction, such as impaired fertility, infertility, diseases or conditions in which abnormal oscillatory activity occurs in the brain, including depression, migraine, neuropathic pain, parkinson's disease, psychosis and schizophrenia, and diseases or conditions in which there is abnormal coupling of activity (particularly via the thalamus); enhancing cognitive function; enhancing memory; memory retention is improved; the training performance is improved; increase the immune response; improving the immune function; hot flashes; night sweat; the service life is prolonged; schizophrenia; muscle-related disorders controlled by the excitation/relaxation rhythms imposed by the nervous system, such as heart rhythm and other disorders of the cardiovascular system; conditions associated with cell proliferation, such as vasodilation or vasoconstriction and blood pressure; cardiac arrhythmia; hypertension; congestive heart failure; conditions of the genital/urinary system; sexual dysfunction and fertility disorders; sufficient renal function; responsiveness to an anesthetic; sleep disorders, including enhancing sleep quality, improving sleep quality, increasing sleep efficiency, enhancing sleep maintenance; increasing a value calculated by dividing the sleep time of the subject by the time the subject attempts to sleep; improving sleep onset; reducing sleep latency or onset (time required to fall asleep); reducing difficulty in falling asleep; increasing sleep continuity; reducing the number of awakenings during sleep; reducing intermittent arousals during sleep; reducing nighttime arousal; reducing the time taken to wake up after the initial sleep has begun; increasing total sleep; reducing sleep fragmentation; altering the time, frequency or duration of REM sleep episodes; altering the time, frequency or duration of slow wave (i.e. stage 3 or 4) sleep onset; increasing the amount and percentage of stage 2 sleep; promoting slow wave sleep; enhancing EEG-delta activity during sleep; increasing the amount of delta sleep in the early stages of the sleep cycle and REM sleep in the late stages of the sleep cycle; reducing nighttime arousal, particularly morning arousal; increasing daytime alertness; reducing daytime sleepiness; treating or reducing excessive daytime sleepiness; increasing satisfaction with sleep intensity; increase sleep maintenance; idiopathic insomnia; sleep problems; insomnia, hypersomnia, idiopathic hypersomnia, repetitive hypersomnia, endogenous hypersomnia, narcolepsy, sleep interruption, sleep apnea, obstructive sleep apnea, insomnia, nocturnal myoclonus, REM sleep interruption, jet lag, shift worker sleep disorders, sleep abnormalities, night terrors, insomnia associated with depression, mood/mood disorders, Alzheimer's disease or cognitive disorders, and sleep walking and enuresis, and sleep disorders with aging; alzheimer's sunset syndrome (Alzheimer's sundowning); conditions associated with circadian rhythms and mental and physical disorders associated with cross-time zone travel and shift work schedules, conditions caused by drugs that cause a reduction in REM sleep as a side effect; fibromyalgia; syndromes manifested as non-restorative sleep and muscle pain or sleep apnea (associated with breathing disturbances during sleep); conditions resulting from decreased sleep quality; mood disorders, such as depression or more particularly depression, e.g. single-or recurrent major depression and dysthymic disorder, or bipolar affective disorders, e.g. bipolar I affective disorder, bipolar II affective disorder and circulatory affective disorder, mood disorders resulting from general medical conditions and substance-induced mood disorders; anxiety disorders including acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive compulsive disorder, panic attacks, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, specific phobias, substance-induced anxiety disorder, and anxiety disorder resulting from medical conditions in general; acute neurological and psychiatric disorders such as brain defects following heart bypass surgery and transplantation, stroke, ischemic stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage; huntington's chorea; amyotrophic lateral sclerosis; multiple sclerosis; eye damage; retinopathy; cognitive disorders; idiopathic and drug-induced parkinson's disease; muscle spasms and disorders associated with muscle spasticity, including tremors, epilepsy, tics; cognitive disorders including dementia (associated with alzheimer's disease, ischemia, trauma, vascular problems or stroke, aids, parkinson's disease, huntington's disease, Pick's disease, Creutzfeldt-Jacob disease, perinatal hypoxia, other general medical conditions or substance abuse); delirium, amnestic disorders or age-related cognitive decline; schizophrenia or psychosis, including schizophrenia (paranoid, disorganized, catatonic or undifferentiated), schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder resulting from a general medical condition, and substance-induced psychotic disorder; substance-related disorders and addictive behaviors (including substance-induced delirium, persisting dementia, persisting amnestic disorder, psychotic disorder or anxiety; tolerance to, dependence on, or withdrawal from substances including alcohol, amphetamine, cannabis, ***e, hallucinogens, inhalants, nicotine, opioids, phencyclidine, sedatives, hypnotics, or anxiolytics); attention deficit/hyperactivity disorder (ADHD); conduct disorder; migraine (including migraine headache); urinary incontinence; overactive bladder (OAB); urge Urinary Incontinence (UUI); lower Urinary Tract Symptoms (LUTS); substance tolerance, substance withdrawal (including substances such as opiates, nicotine, smoking products, alcohol, benzodiazepines, ***e, sedatives, hypnotics, etc.); psychosis; schizophrenia; anxiety (including generalized anxiety disorder, panic disorder, and obsessive compulsive disorder); mood disorders (including depression, mania, bipolar disorder); trigeminal neuralgia; hearing loss; tinnitus; neuronal damage, including eye damage; retinopathy; macular degeneration of the eye; vomiting; cerebral edema; pain, including acute pain, chronic pain, acute pain, intractable pain, inflammatory pain, chronic inflammatory pain, diabetic neuropathy, chronic neuropathic pain, post-traumatic pain, osteoarticular pain (osteoarthritis), repetitive motion pain, dental pain, cancer pain, myofascial pain (muscle injury, fibromyalgia), perioperative pain (general surgery, gynecology), chronic pain, neuropathic pain, post-traumatic pain, trigeminal neuralgia, migraine and migraine headache. Thus, in some embodiments, a compound described herein, or any embodiment or example thereof, may be used in a method of treating, controlling, ameliorating, or reducing the risk of any of the foregoing diseases by administering to an individual in need of such treatment a therapeutically effective amount of a drug.
In some embodiments, the compounds described herein, or any embodiment or example thereof, may be used in methods of treating, controlling, ameliorating, or reducing the risk of epilepsy (including absence epilepsy); treating or managing parkinson's disease; treating essential tremor; treating or controlling pain, including neuropathic pain; enhancing sleep quality; enhancing sleep maintenance; increasing REM sleep; increasing slow wave sleep; reducing fragmentation in sleep mode; treating insomnia; enhancing cognition; memory retention is improved; treating or controlling depression; treating or controlling psychosis; or treating, controlling, ameliorating or reducing the risk of schizophrenia in a mammalian patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of the present invention. The compounds of the present invention are also useful in methods of preventing, treating, controlling, ameliorating, or reducing the risk of diseases, disorders, and conditions described herein. The method is carried out by administering to an individual in need of such treatment a therapeutically effective amount of the compound.
D. Developing method
In some embodiments, the compounds described herein or any examples or embodiments thereof may be used to enhance the efficacy of imaging agents for diseases such as cancer or pre-cancerous diseases or cell proliferative disorders, for example, according to the methods described in WO 2011/109262. The methods can be used to image various diseases or conditions, including unstable angina, hypertension, epilepsy, neuropathic pain, petit mal seikations (petit mal seikations), absence seikations (absence seikations), age-related macular degeneration, cancer, and pre-cancerous conditions. In other embodiments, the methods can be used to image tumors and pre-cancerous tumors.
Although not limited thereto, a method for imaging a disease or condition, a T-type calcium channel inhibitor (which may be any compound described herein or any embodiment or example thereof) is first administered in an effective amount to stop proliferation of eukaryotic cells at a cell cycle checkpoint between the G1 phase and the S phase (G1/S). The different lengths of the cell cycle depend primarily on the time taken for the G1 phase. The lengths of the S, G2 and M phases are relatively unchanged. Thus, any particular cell in the cell population will remain in G1 for a period of time before the cell enters the S phase of the cell cycle. To prevent the cell cycle from continuing beyond the cell cycle checkpoint, a T-type calcium channel inhibitor may be administered. Administration of cell cycle inhibitors results in the accumulation of asynchronously proliferating cancer cells in the cell population at G1/S as they travel through the cell cycle, as their ability to travel to the S phase is prevented by the cell cycle inhibitor. In order for cells to move from G1 phase to S phase through cell cycle checkpoints, the cells require a large influx of extracellular calcium to trigger the biochemical cascade necessary for progression. Removal of calcium from the extracellular medium blocks the cell cycle transition of individual cells. Thus, as long as it is facing extracellular calcium, the individual cells remain at stage G1, but become locked in place when reaching G1/S in the absence of calcium, thereby synchronizing the cells at G1/S. Calcium influx into cells is essential for proliferation and turnover through the cell cycle.
Administration of a T-type calcium channel inhibitor increased the percentage of cells at G1/S. To take advantage of the increase in cells at G1/S, a T-type calcium channel inhibitor can be administered to a subject during the time period prior to imaging. The time period can be from about 1 day to about 10 days (e.g., from about 5 days to about 7 days, inclusive). Following administration of the T-type calcium channel inhibitor, there may be a period of time (e.g., a period of time of about 30 minutes to about 72 hours) during which no T-type calcium channel inhibitor is administered. This time period can allow cells accumulated at G1/S to enter the S phase of the cell cycle (e.g., about 5% to about 25% can accumulate at G1/S). The increase in the number of cells in S phase makes the subsequently administered dose of the imaging marker more effective, since a large proportion of the cells will take up the imaging marker in each dose.
Following administration of the T-type calcium channel inhibitor, an imaging marker targeted for uptake in the S phase of the cell cycle is administered. The time period between the first administration of the cell cycle inhibitor and the imaging label allows the cells to accumulate at G1/S of the cell cycle. This method increases the percentage of cells in S phase, thereby increasing the uptake of imaging markers by those cells, and thus increasing the sensitivity of imaging.
Some examples of possible imaging labels include 11C methionine, 2-deoxy-2- (18F) fluoro-D-glucose, tritiated 2-deoxy-2-fluoro-D-glucose, and fluorodeoxythymidine such as [18F ] -3 '-fluoro-3' -deoxy-L-thymidine).
the mammal is subsequently imaged after the imaging marker is applied to the mammal. The imaging label may be administered at any suitable dose (e.g., about 100mBq to about 600 mBq). The mammal may be imaged using any suitable imaging device, such as a device capable of acquiring Magnetic Resonance Images (MRI), positron emission tomography (PET scan) or computed tomography (CT scan). The images collected by a suitable imaging device will be more sensitive than images taken of a mammal that has not been pre-treated with a cell cycle inhibitor. The scan performed after administration of the cell cycle inhibitor will be more sensitive because the diseased cells will have a higher uptake of the imaging marker than the uptake of the phenomenon marker by cells not administered with the cell cycle inhibitor.
Combination therapy
The compounds of the invention may be used in combination with one or more other drugs for the treatment, prevention, control, alleviation or risk of a disease or condition in which the compounds of the invention or the other drugs may have utility, wherein the drugs in combination are safer or more effective than either drug alone. Such one or more other drugs may be administered together with the compounds of the present invention, either simultaneously or sequentially, by the route and amount in which they are normally used. When a compound of the invention is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of the invention is contemplated. However, combination therapy may also include therapies in which a compound of the invention and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used alone. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients in addition to the compounds of the present invention. The above combinations include not only combinations of the compounds of the invention with one other active compound but also combinations with two or more other active compounds.
Likewise, the compounds of the present invention may be used in combination with other drugs that are useful in the prevention, treatment, control, alleviation or reduction of the risk of diseases or conditions for which the compounds of the present invention are useful. Such other drugs may be administered, either simultaneously or sequentially with the compounds of the present invention, by the routes and amounts normally used therefor. When a compound of the present invention is used contemporaneously with one or more other drugs, pharmaceutical compositions containing such other drugs in addition to the compound of the present invention are contemplated. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients in addition to the compounds of the present invention.
the weight ratio of the compound of the present invention to the second active ingredient may vary and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent is generally in the range of from about 1000: 1 to about 1: 1000 (including from about 200: 1 to about 1: 200). Combinations of the compounds of the invention and other active ingredients will generally also be within the above ranges, but in each case an effective dose of each active ingredient should be used. In such combinations, the compounds of the present invention and other active agents may be administered alone or in combination. In addition, one component may be administered before, simultaneously with, or after the other agent or agents.
One or more additional therapeutic agents such as, for example, steroids, immunosuppressive agents, chemotherapeutic agents, radiation therapy, and anesthetic agents (e.g., for use in combination with surgery) can be used in combination with the compounds and salts provided herein.
exemplary steroids include, but are not limited to, corticosteroids such as cortisone (cortisone), dexamethasone (dexamethasone), hydrocortisone (hydrocortisone), methylprednisolone (methylprednisone), prednisolone (prednisone), and prednisone (prednisone).
Exemplary immunosuppressive agents include, but are not limited to, azathioprine (azathioprine), chlorambucil (chlorambucil), cyclophosphamide (cyclophosphamide), cyclosporine (cyclosporine), daclizumab (daclizumab), infliximab (infliximab), methotrexate (methotrexate), and tacrolimus (tacrolimus).
Exemplary chemotherapeutic agents include, but are not limited to, temozolomide (temozolomide), 5-fluorouracil (5-fluorouracil), 6-mercaptopurine (6-mercaptoprine), bleomycin (bleomycin), carboplatin (carboplatin), cisplatin (cissplatin), dacarbazine (dacrbazine), doxorubicin (doxobicin), epirubicin (epirubicin), etoposide (etoposide), hydroxyurea (hydroxyurea), ifosfamide (ifosfamide), irinotecan (irinotecan), topotecan (topotecan), methotrexate, mitoxantrone (mitoxantrone), oxaliplatin (oxaliplatin), paclitaxel (paclitaxel), docetaxel (docetaxel), vindesine (vinblastine), vincristine (vinristine), vinorelbine (vinorelbine), and mitomycin (mitomycin C).
Exemplary anesthetics include, but are not limited to, local anesthetics (e.g., lidocaine (lidocaine), procaine (procain), ropivacaine (ropivacaine)) and general anesthetics (e.g., desflurane (desflurane), enflurane (enflurane), halothane (halothane), isoflurane (isoflurane), methoxyflurane (methoxyflurane), nitrous oxide (nitrous oxide), sevoflurane (sevoflurane), amobarbital (mbobarbital), methohexital (methohexital), thiopentobarbital (thiopental), thiopentasodium (thiopenepen), diazepam (diazepam), lorazepam (lorazepam), midazolam (midazolam), etomidate (etomidate), ketamine (ketamine), propofol (propyphenol), naloxone (naloxonol), oxyphenirane (morphine), levorphanol (morphine), naloxone (morphine), levorphanol (morphine), naloxone), levorphanol (morphine), morphine (morphine), levorphanol (morphine), morphine (morphine), morphine (morphine), morphine (morphine), morphine (morphine), nalbuphine (nalbuphine), oxymorphone (oxymorphone), pentazocine (pentazocine)).
For example, one or more of the following agents may be used in combination with the compounds provided herein, and are provided as a non-limiting list: alkylating agents, cytostatic agents, cisplatin, doxorubicin, taconazole (taxol), etoposide, irinotecan, topotecan, paclitaxel, docetaxel, epothilones (epothilones), tamoxifen (tamoxifen), 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, tipifarnib (tipifarnib), gefitinib (gefitinib), erlotinib hydrochloride (erlotinib hydrochloride), antibodies to EGFR, imatinib mesylate (imatinib mesylate), gemcitabine (gemcitabine), uracil mustard (uracil murard), nitrogen mustard (chlorethine), ifosfamide, melphalan (melphalland), chlorambucil (chlorembucil), pipobroman (pipobroman), tritetramine (trietylamine), thiovinphospine (triacetylcarbamine), streptozocin (carmustine), streptozocin (carbapenem), streptozocin (streptozocin), streptozocin (streptozocine), streptozocin (streptozocine), thiofenacin), streptozocin (streptozocine), streptozocin (streptozocine (streptozocin (streptozocine), streptozocin (streptozocin) and other (streptozocin) can), mitomycin (streptozocin) can, Cytarabine (cytarabine), 6-mercaptopurine, 6-thioguanine (6-thioguanine), fludarabine phosphate (fludarabine phosphate), oxaliplatin, folinic acid (folinic acid), pentostatin (pentostatin), vinblastine, vincristine, vindesine, bleomycin, dactinomycin (dactinomycin), daunorubicin (daunorubicin), epirubicin, idarubicin (idarubicin), mithramycin (mithramycin), deoxyfumycin (deoxynomycin), mitomycin C, L-asparaginase (L-asparginine), teniposide (teniposide), 17 alpha-ethinylestradiol (17 alpha-ethinyldione), diethylstilbestrol (diethylstilbestrol), testosterone (testosterone), prednisone (testosterone), medoxolone (ketolide), testosterone (ketosteroid), prednisolone (ketolide), medoxolone (medoxolone acetate), medoxolone (medrysone), medrysone (acetate (medrysone), medrysone (medrysone), clenbuterol (chlorendanisene), hydroxyprogesterone (hydroxyprogesterone), aminoglutethimide (aminoglutethimide), estramustine (estramustine), medroxyprogesterone acetate (medroxyprogesterone), leuprolide (leuprolide), flutamide (flutamide), toremifene (toremifene), goserelin (goserelin), carboplatin, hydroxyurea, amsacrine (amsacrine), procarbazine (procarbazine), mitotane (mitoxantrone), mitoxantrone (levamisole), vinorelbine, anastrozole (anastrozole), letrozole (letrozole), capecitabine (capecitabine), raloxifene (relexane), hexamethylmelamine (hexetitrolene), trimebutine (hexetiracetam), melphalan (xxoxime), melphalan (loxacin), melphalan (valnemadex (loxacin), melphalan (e), melphalan (loxacin (e), melphalan (e (loxacin), melphalan (e (loxacin (e), melphalan (e), mellituracilexetine (e), mellithamabolizine (e), mellituracilexetine (e), mellithamabolizumab), rituximab (rituximab), alemtuzumab (alemtuzumab), clofarabine (clofarabine), cladribine (cladribine), aphidicolin (aphidicin), sunitinib (sunitinib), dasatinib (dasatinib), tizacitabine (tezacitabine), triapine, didox, trimido, amidix, bendamustine (bendamustine), ofatumumab (ofatumumab), and idelalisib (idelalisib).
the compounds described herein may also be used in combination with other methods of treating cancer, for example, by chemotherapy, radiation, or surgery. The compounds may be administered in combination with one or more anti-cancer drugs such as the chemotherapeutic drugs abarelix (abarelix), aldesleukin (aldesleukin), alemtuzumab, alitretinoin (alitretinin), allopurinol (allopurinol), altretamine, anastrozole (anastrozole), arsenic trioxide (arsenic trioxide), asparaginase, azacitidine (azacitidine), bevacizumab, bexarotene (bexatene), bleomycin, bortezomib (bortezombi), bortezomib (bortezomib), intravenous busulfan, oral busulfan, carroterone, capecitabine, carboplatin, carmustine, cetuximab (cetuximab), chlorambucil, cisplatin, farabine, clorabine, cyclophosphamide, aspartame, adapalysin, dacarbazine (dacarbazine), dacarbazine (gentamycin), dactinomycin (dactinomycin), dactinomycin (e), dactinomycin (e, dactinomycin), dactinomycin, dinil interleukin-toxin linker (denileukin diftotox), dexrazoxane (dexrazoxane), docetaxel, doxorubicin, dromostanolone propionate (dromostanolone propionate), eculizumab (eculizumab), epirubicin, erlotinib (erlotinib), estramustine (estramustine), etoposide phosphate (etoposide phosphate), etoposide, exemestane (exemestane), fentanyl citrate (fentanyl citrate), filgrastim (filgrastim), floxuridine, fludarabine (fludarabine), fluorouracil (flurouracil), fulvestrant (fulvestrant), gefitinib, oxford, tuzumab ozimab ozagrosticin (gemmazogamimib), sertralin acetate (serelin acetate), histidinine acetate (acetate), imatinib (imatinib), irubicin, imatinib sulfonate (isoxatilin), imatinib sulfonate (imatinib), imatinib 2, imatinib sulfonate (imatinib), imatinib 2, imatinib sulfonate, imatinib, and a, Lenalidomide (lenalidomide), letrozole (letrozole), leucovorin (leucovorin), leuprolide acetate (leuprolide acetate), levamisole (1evamisole), lomustine, mecloethymene (meclorethamine), megestrol acetate, melphalan, mercaptopurine (mercaptoprine), methotrexate, methoxsalen (methoxsalen), mitomycin C, mitotane (mitotane), mitoxantrone, nandrolone (nandrolone phenproprione), nelarabine (nellabine), norfebuxomab (nofetumumab), oxaliplatin, paclitaxel, pamidronate (pamidronate), panitumomab (panitumomab), pemetrexen (pegargatropine), pefilgrastim (peggpentin), pemetrexed (pemetrexed), pefurazone (clavine), pefurazosin (clavine), pefurazomycin (clavulan (clavine), pefurazomycin (clavine), pefurazomycin (e, pefurazomycin), pefurazomycin (e, pefurazoline, Sunitinib, sunitinib maleate, tamoxifen (tamoxifen), temozolomide (temozolomide), teniposide, testolactone (testolactone), thalidomide (thalidomide), thioguanine (thioguanine), thiotepa (thiotepa), topotecan (topotecan), toremifene (toremifene), tositumomab (tositumomab), trastuzumab, tretinoin (tretinoin), uracil mustard (uracil) valrubicin, vinblastine, vincristine, vinorelbine, vorinostat (vorinostat) and zoledronate (zoledronate).
In some embodiments, the additional therapeutic agent is administered concurrently with the compound or salt provided herein. In some embodiments, the additional therapeutic agent is administered after administration of the compound or salt provided herein. In some embodiments, the additional therapeutic agent is administered prior to administration of the compound or salt provided herein. In some embodiments, the compounds or salts provided herein are administered during surgery. In some embodiments, the compounds or salts provided herein are administered in combination with an additional therapeutic agent during surgery.
In some embodiments, the compounds described herein or any examples or embodiments thereof may be used to enhance the efficacy of chemotherapeutic agents or radiation in the treatment of cell proliferative disorders (such as cancer, e.g., any type of cell proliferative disorder or cancer described above) to kill proliferating cells, e.g., according to the methods described in WO 2010/141842.
While not being bound by any theory, it is believed that administration of a T-type calcium channel inhibitor may result in asynchronous progression in the cell population or accumulation of proliferating cancer cells at the G1/S checkpoint as they travel through the cell cycle, as their ability to travel to the S phase is prevented by the cell cycle inhibitor. In order for cells to move from G1 phase to S phase through cell cycle checkpoints, the cells require a large influx of extracellular calcium to trigger the biochemical cascade necessary for progression. Removal of calcium from the extracellular medium blocks the cell cycle transition of individual cells. This blocking can be accomplished by administering a T-type calcium channel inhibitor. Thus, each cell remains in stage G1 as long as it will be in the presence of extracellular calcium, but becomes locked in place when reaching G1/S in the absence of calcium, thereby synchronizing the cells at G1/S.
administration of the cell cycle inhibitor increased the percentage of cells at G1/S. Following this administration, a dose of at least one chemotherapeutic agent, a dose of radiation, or a dose of both, may be administered that targets cells in the S phase of the killer cell cycle. The dose of the at least one chemotherapeutic agent may be administered before, after, or during the firing of the dose. The dose of radiation may be administered before, after or during the dose of the at least one chemotherapeutic agent. The method increases the percentage of cells in S-phase or M-phase, thereby increasing the effectiveness of the dose of at least one chemotherapeutic agent, the dose of radiation, or both, and subsequently decreasing the toxicity burden required to kill a predetermined amount of eukaryotic cells. The chemotherapeutic agent may be any of the cancer chemotherapeutic agents described above or a combination thereof.
the compounds described herein may be used in combination with anti-seizure agents such as carbamazepine (carbamazepine), clonazepam (clonazepam), divalproex (divaprox), ethosuximide (ethosuximide), felbamate (felbamate), phenytoin (fosphenynyloin), gabapentin (gabapentin), lamotrigine (lamotrigine), levetiracetam (1 ethyliracetam), lorazepam, midazolam, oxcarbazepine (oxcarbazepine), phenobarbital (phenobarbital), phenytoin (phenyloin), primidone (primidone), tiagabine (tiagabine), topiramate (topiramate), valproate (valpropropionate), vigabatrin (vigabatrin), or nisamide (azoniazole). In another embodiment, the compounds of the invention may be combined with acetophenazine (acetophenazine), alendronate (alendronate), benzhexol (benzhexyl), bromocriptine (bromocriptine), biperiden (biperiden), chlorpromazine (chlorpromazine), chlorprothixene (chlorprothixene), clozapine (clozapine), diazepam, fenoldopam (fenoldopam), fluphenazine (fluphenazine), haloperidol (haloperidol), levodopa (levodopa), levodopa and benserazide (levodopa with benserazide), levodopa and carbidopa (levodopa with carbidopad), ethylurea (lisuride), saproline (loxapine), mesoridazine (meperidoline), pramipeline (piperazine), homopterazine (piperazine), piperazinone (piperazinone), piperazinone (piperazinone, piperazinone (piperazinone), piperazinone (piperazinone, thioxanthine (thioxene), trifluoperazine (trifluoperazine) or valproic acid (valproic acid) are used in combination.
In another embodiment, the compounds of the invention may be used in combination with levodopa (1evodopa) (with or without selective extracerebral decarboxylase inhibitors such as carbidopa (carbidopa) or benserazide), anticholinergics such as biperiden (biperiden) (optionally as its hydrochloride or lactate) and trihexyphenidyl (trihexyphenidyl) hydrochloride, COMT inhibitors such as entacapone (entacapone), MOA-B inhibitors, antioxidants, A2a adenosine receptor antagonists, cholinergic agonists, hydroxytryptamine (serotonin) receptor antagonists and dopamine receptor agonists such as alemtimomol (serotonin), bromocriptine (bromocriptine), fenoldopam (feldopam), lisuride (lisuride), naxagolide (nagelilide), pergolide (pergolide) and pramipexole (pramipexole). It will be appreciated that dopamine agonists may be in the form of pharmaceutically acceptable salts, for example, alendronate (alendronate), bromocriptine mesylate (bromocriptine mesylate), fenoldopam mesylate (fenoldopam mesylate), naxagolide hydrochloride (nagalalide hydrochloride) and pergolide mesylate (pergolide mesylate). Lisuride and pramipexole are used by being in non-salt form.
in another embodiment, the compounds of the present invention may be used in combination with a compound selected from the phenothiazine (phenothiazine), thioxanthene (thioxanthe), heterocyclic dibenzoazepine (heterocyclic dibenzozapine), butyrophenone (butyrophenone), diphenylbutylpiperidine (diphenylbutylpiperidine) and indolinone classes of neuroleptic agents. Suitable examples of phenothiazines include chlorpromazine (chlorpromazine), mesoridazine (mesoridazine), thioridazine (thioridazine), acetophenazine (acetophenazine), fluphenazine (fluphenazine), perphenazine (perphenazine), and trifluoperazine (trifluoperazine). Suitable examples of thioxanthenes include chlorprothixene and thiothixene. An example of a dibenzoazepine is clozapine (clozapine). An example of butyrophenone is haloperidol (haloperidol). An example of a diphenylbutylpiperidine is pimozide (pimozide). An example of an indolone is molindolone (molindolone). Other neuroleptic agents include loxapine (loxapine), sulpiride (sulpiride) and risperidone (risperidone). It will be appreciated that when used in combination with the compounds of the invention, the neuroleptic agent may be in the form of a pharmaceutically acceptable salt, for example chlorpromazine hydrochloride (chlorpromazine hydrochloride), mesoridazine besylate (mesoridazine besylate), thioridazine hydrochloride (thioridazine hydrochloride), acetophenazine maleate (acetophenazine maleate), fluphenazine hydrochloride (fluphenazine hydrochloride), fluphenazine enanthate (flurphenazine hydrochloride), fluphenazine hydrochloride (trifluoperazine hydrochloride), thiothixene hydrochloride (thiothidiazepine hydrochloride), haloperidol decanoate (haloperidol decanoate), haloperidol hydrochloride (trifluoperazine hydrochloride), thalidomide succinate (loxapine hydrochloride) and molindone hydrochloride (dihydrochlonide hydrochloride). Perphenazine, chlorprothixene, clozapine, haloperidol, pimozide and risperidone are commonly used in non-salt forms.
In another embodiment, the compounds of the present invention may be used in combination with an opiate agonist, a lipoxygenase inhibitor (e.g., a 5-lipoxygenase inhibitor), a cyclooxygenase inhibitor (e.g., a cyclooxygenase-2 inhibitor), an interleukin inhibitor (e.g., an interleukin-1 inhibitor), an NMDA antagonist, a nitric oxide inhibitor or an inhibitor of nitric oxide synthesis, a non-steroidal anti-inflammatory agent, or a cytokine-suppressing anti-inflammatory agent, for example, in combination with a compound such as acetaminophen (acetaminophen), aspirin (asprin), codeine (codeine), fentanyl (fentanyl), ibuprofen (ibuprofen), indomethacin (indomethacin), ketorolac (ketorolac), morphine (morphine), naproxen (naproxen), phenacetin (phenacetin), piroxicam (piroxicam), a steroidal analgesic, sufentanil (sufentanyl), sulindac (sunlindac), tenidap (teidap), and the like. Similarly, the subject compounds may be administered with: analgesic agents; synergists, such as caffeine, H2-antagonists, simethicone (simethicone), aluminum hydroxide or magnesium hydroxide; decongestants (decongestants), such as phenylephrine (phenylephrine), phenylpropanolamine (phenylpropanolamine), pseudoephedrine (pseudoephedrine), oxymetazoline (oxymetazoline), norepinephrine (ephinephine), naphazoline (naphazoline), xylometazoline (xylometazoline), cyclohexylpropylmethanamine (propylhexidine) or levo-deoxy-ephedrine (levo-desoxy-epinephrine); antitussives such as codeine (codeine), hydrocodone (hydrocodone), caramiphen (caramiphen), pentoxyverine (carbetasentane) or dextromethorphan (dextromethorphan); a diuretic; and sedating or non-sedating antihistamines. In another embodiment, the compounds of the present invention may be used in combination with an L-type calcium channel antagonist such as amlodipine (amlodipine). In another embodiment, the compounds of the present invention may be used in combination with NK-1 receptor antagonists, beta-3 agonists, 5-alpha reductase inhibitors such as finasteride or dutasteride, M3 muscarinic receptor antagonists such as darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine or troxipide or duloxetine.
in another embodiment, the compounds of the present invention may be administered in combination with compounds known in the art to be useful for enhancing sleep quality and preventing and treating sleep disorders and sleep disturbances, including, for example, sedatives, hypnotics, anxiolytics (anxinolytics), antipsychotics, anxiolytics (antanxiety agents), antihistamines, benzodiazepines, barbiturates, cyclopyrrolones, GABA agonists, 5HT-2 antagonists (including 5HT-2A antagonists and 5HT-2A/2C antagonists), histamine antagonists (including histamine H3 antagonists), histamine H3 inverse agonists, imidazopyridines, weakly-analeptics (minor transquilibrizzers), melatonin (melatonin) agonists and antagonists), melatoninergic agents (melatonergic agents), other orexin (orexin) antagonists, orexin agonists, prokinetin agonists (prokinetin) agonists and antagonists, Pyrazolopyrimidines, other T-type calcium channel antagonists, triazolopyridines, and the like, such as: adizolam (adinazolam), amobarbital (alloparbital), alomiprone (alonimid), alprazolam (alprazolam), amitriptyline (amitriptyline), amobarbital (amobarbital), amoxapine (amoxapine), armodafinil (armodafinil), APD-125, phencyclam (bentazopam), benzzocetamine (benzonatamine), brotizolam (brotizololam), bupropion (bupropion), buspirone (buspirone), sec-butyl barbital (butatialbital), butalbital (butalbital), carpropriline (capromopril), carpuride (capride), carbochloral (carboplorelar), chlorambucil (chlorazeclavine), chlorambucil (chlorazaclavine), chloracil (chloracil), chloracil (chloracil, Chloraldiline (diphenxazone), divalproex sodium, diphenhydramine (diphenhydramine), doxepin (doxepin), EMD-281014, eprinorine (eplerenerin), estazolam (estazolam), dexzopiclone (eszopiclone), ethopropionol (ethchrynol), etomidate (etomidate), fenoban (fenobam), flunitrazepam (flunitrazepam), flurazepam (fluzepam), fluvoxamine (fluvoxamine), fluoxetine (fluoxetine), fosazepam (fosazepam), gaxadol (gaboprodol), gelsemide (glutethimide), halazepam (halazepam), hydroxyzine (hydroxyziprazine), ziprasidone (ibamide), meprobamate (meprobamate), meprobamate (mdalomenam), meprobamate (mdlam (meprobamate), meprobamate (mefon (mebendazone), meprobamate (mefon (mexil), meprobamate), mexil (mexil), mexil (mexil), midazolam (midaflur), midazolam, modafinil (modafinil), nefazodone (nefazodone), NGD-2-73, nisolone (nisobamate), nitrazepam (nitrazepam), nortriptyline (nortriptyline), oxazepam (oxazepam), paraldehyde (paraldehyde), paroxetine (parotid), pentobarbital (pentobarbital), perlapine (perlapine), perphenazine, phenelzine (phenobarbital), phenobarbital, prazepam (prazepam), promethazine (promethazine), propofol (propofol), protiline (protriptylazine), pramipeline (rametratretrazone), repaclozepam (procarbazine), thimide (procarbazine), thiurazole (tazone), thiuracil (tazobactam), thiuracil (tazone (r), thiuracil (r), thiurazone (s (tazone), thiurazone(s), thiuracils(s), thiuracils(s), thiuracils(s), thiuracils (r), thiuracils, Trapipeam (trepepam), tricresyl amide (tricetamide), triclofos (triclofos), trifluoperazine (trifluoroperazine), trimetazidine (trimetazine), trimipramine (trimipramine), udazepam (uldazepam), venlafaxine (venlafaxine), zaleplon (zaleplon), zolazepam (zolazepam), zopiclone (zopiclone), zolpidem (zolpidem) and salts thereof and combinations thereof, and the like, or the compounds of the present invention may be administered in combination with the use of physical means such as light therapy or electrical stimulation.
in another embodiment, the compounds of the present invention may be used in combination with an antidepressant or anxiolytic agent, including norepinephrine reuptake inhibitors (including tertiary amine tricyclics and secondary amine tricyclics), Selective Serotonin Reuptake Inhibitors (SSRIs), monoamine oxidase inhibitors (MAOI), monoamine oxidase Reversible Inhibitors (RIMA), Serotonin and Norepinephrine Reuptake Inhibitors (SNRI), Corticotropin Releasing Factor (CRF) antagonists,. alpha. -adrenoceptor antagonists, neurokinin-1 receptor antagonists, atypical antidepressants, benzodiazepines, 5-HT1A agonists or antagonists (particularly 5-HT1A partial agonists), and Corticotropin Releasing Factor (CRF) antagonists. Specific agents include: amitriptyline, clomipramine, doxepin, imipramine and trimipramine; amoxapine, desipramine, maprotiline, nortriptyline and protriptyline; fluoxetine, fluvoxamine, paroxetine, and sertraline; isocarboxazid (isocarboxazid), phenelzine (phenelzine), tranylcyclopropylamine (tranylcyclopromine) and selegiline (selegiline); moclobemide (moclobemide): venlafaxine (venlafaxine); aprepitant (aprepitant); bupropion, lithium, nefazodone, trazodone, and viloxazine (viloxazine); alprazolam, clonazepam salts (chlorazepates), diazepam, halazepam, lorazepam, oxazepam and pramipepam; buspirone, fluocinolone, gepirone and ixabepilone and their pharmaceutically acceptable salts.
In another embodiment, the compounds of the invention may be administered with an anti-alzheimer agent; inhibitors of beta-secretase; gamma-secretase inhibitors; growth hormone secretase; recombinant growth hormone; HMG-CoA reductase inhibitors; NSAIDs (including ibuprofen); a vitamin E; an anti-amyloid antibody; a CB-1 receptor antagonist or a CB-1 receptor inverse agonist; antibodies (such as doxycycline and rifampin); N-methyl-D-aspartate (NMDA) receptor antagonists (e.g., memantine); cholinesterase inhibitors (e.g., galantamine (galantamine), rivastigmine (rivastigmine), donepezil (donepezil), and tacrine (tacrine)); growth hormone secretagogues (e.g., ibulamen (ibutamoren), ibulamen mesylate (ibutamoren mesylate), and capromorelin); histamine H subtype 3 antagonists; an AMPA agonist; a PDE IV inhibitor; GABA subtype a inverse agonist; or a combination of neuronal nicotinic agonists.
Formulation, dosage form and administration
when used as a medicament, the compounds and salts provided herein may be administered in the form of a pharmaceutical composition. These compositions may be prepared as described herein or elsewhere and may be administered by various routes depending on whether local or systemic treatment is desired and on the site to be treated. Administration can be topical (including transdermal, epidermal, ocular, and to mucosal membranes, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral, or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, or injection or infusion; or intracranial, (e.g., intrathecal or intraventricular administration). Parenteral administration may be in the form of a single bolus dose, or may be, for example, by continuous infusion pump. In some embodiments, the compounds, salts, and pharmaceutical compositions provided herein are suitable for parenteral administration. In some embodiments, the compounds, salts, and pharmaceutical compositions provided herein are suitable for intravenous administration.
pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, aerosols, liquids and powders. Conventional pharmaceutical carriers, aqueous solutions, powders or oily bases, thickeners and the like may be necessary or desirable.
also provided are pharmaceutical compositions containing a compound provided herein, or a pharmaceutically acceptable salt thereof, as an active ingredient in combination with one or more pharmaceutically acceptable carriers (e.g., excipients). In preparing the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted with an excipient or encapsulated in such a carrier, for example, in a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material that serves as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
Some examples of suitable excipients include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Formulations may additionally include, but are not limited to, lubricants, such as talc, magnesium stearate, and mineral oil; a wetting agent; emulsifying and suspending agents; preservatives, such as methyl and propyl hydroxybenzoate; a sweetener; a flavoring agent, or a combination thereof.
The active compounds may be effective over a wide dosage range and are generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual subject, the severity of the subject's symptoms, and the like.
examples
the following examples are provided for illustrative purposes and are not intended to limit the invention.
Intermediate 1.4-Methylbenzenesulfonic acid 2- ((1S, 2S) -6-fluoro-2-hydroxy-1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-yl) ethyl ester
To a solution of (1S, 2S) -6-fluoro-2- (2-hydroxyethyl) -1-isopropyl-1, 2, 3, 4-tetrahydronaphthalen-2-ol (160g, 627.45mmol, 1.0 eq) in DCM (1600mL) was added triethylamine (132.5mL, 941.17mmol, 1.5 eq), DMAP (7.66g, 62.74mmol) and tosyl chloride (155.5g, 815.68mmol, 1.3 eq) at room temperature. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was taken up in saturated NaHCO3 solution (5000mL) and extracted with DCM (1500mL X2). The combined organics were dried over Na2SO4 and concentrated to give intermediate 1 as a clear semi-solid which solidified upon standing overnight. (180g, 70%). MS: 424.4M/z (M + NH4) +.
Intermediate 2 (1S, 2S) -6-fluoro-1-isopropyl-2- (2- (methylamino) ethyl) -1, 2, 3, 4-tetrahydronaphthalen-2-ol
a mixture of intermediate 1(180g, 443.34mmol) and methylamine 2M in MeOH (900mL) was stirred at 40 ℃ for 12 h under an autoclave. The reaction mixture was put into ice-cold water (4000mL) to obtain a solid precipitate. The precipitate was filtered, washed with water, and dried under vacuum to give intermediate 2(115g, 97%). MS: 266.3M/z (M + H) +.
Intermediate 3.3- (1H-benzo [ d ] imidazol-2-yl) -3-methylbutyraldehyde
Step 1.3, 3-Dimethyldihydrofuran-2 (3H) -one
To a solution of dihydrofuran-2 (3H) -one (2.0g, 0.023mol, 1.0 equiv.) in anhydrous THF was added sodium hydride (3.34g, 0.069mol, 3.0 equiv.) portionwise at 0 deg.C and refluxed for 30 min. MeI (11.5g, 0.081mol, 3.5 equiv.) was slowly added to the reaction mixture over 1 hour at reflux. After 2 hours, the reaction mixture was diluted with Et2O and acidified with 1N HCl and stirred overnight. The organic layer was separated and concentrated under reduced pressure. The crude product (350mg) was used in the next step without any purification.
Step 2.3- (1H-benzo [ d ] imidazol-2-yl) -3-methylbutan-1-ol
The crude mixture from step 1 (5.0g, 0.046mol, 1.0 equiv) and o-phenylenediamine (10.5g, 0.92mol, 2 equiv) were placed in a flask at room temperature and 25mL of 5.5M HCl was added, followed by stirring at 90 ℃ for 12 hours. The reaction mixture was diluted with acetone and neutralized with saturated NaHCO3, dried over Na2SO 4. The organic layer was concentrated under reduced pressure and purified by flash column on 230-400 mesh silica gel to give 3- (1H-benzo [ d ] imidazol-2-yl) -3-methylbutan-1-ol (1.5g, 17%) as a grey solid. MS: 205.0M/z (M + H) +.
Step 3.3- (1H-benzo [ d ] imidazol-2-yl) -3-methylbutyraldehyde
To a solution of 3- (1H-benzo [ d ] imidazol-2-yl) -3-methylbutan-1-ol (1g, 0.005mol, 1 eq) in DCM (20mL) was added Dess Martin oxidant (3.1g, 0.007mmol, 1.5 eq) at 0 ℃. The reaction was warmed to room temperature and stirred at room temperature for 3 hours. The reaction mass was then quenched with saturated NaHCO3 solution and extracted with DCM (100mL × 2). The combined organics were collected, washed with brine, dried over Na2SO4, and evaporated to dryness. The residue was purified by flash column chromatography on silica gel with DCM/MeOH to give intermediate 3(0.84g, 84.84%) as a grey solid. MS: 203.2M/z (M + H) +.
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