Anticholinergic agents
Compounds shown in Formula (I), pharmaceutical compositions, and methods of using related to muscarinic acetylcholine receptors. The compounds herein are typically muscarinic acetylcholine receptor antagonists, such as M 3 antagonists, which can be used for treating a variety of disorders, conditions or diseases such as hyperhidrosis.
1 . A salt having Formula I:
wherein:
X − is a counterion;
R 1 is hydrogen;
L 1 is null, C 1-4 alkylene, or C 1-4 heteroalkylene;
R 2 is C 3-8 carbocyclyl, 4-8 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl, each of which is optionally substituted;
R 3 and R 4 are each independently hydrogen or C 1-6 alkyl; and
j is 0, 1 or 2.
2 . The salt of claim 1 , which has a formula according to Formula I-1 or Formula I-2:
3 . The salt of claim 1 , wherein L 1 is null or a C 1-4 alkylene.
4 . The salt of claim 1 , wherein L 1 is CH 2 .
5 . The salt of claim 1 , wherein R 2 is C 3-6 cycloalkyl, which is optionally substituted with one or more substituents independently selected from F, OH, R A , and OR A , wherein R A at each occurrence is independently a C 1-4 alkyl or C 3-6 cycloalkyl, which is optionally substituted with one or more substituents independently selected from F, OH, C 1-4 alkyl, fluorine-substituted C 1-4 alkyl, C 1-4 alkoxy, and fluorine-substituted C 1-4 alkoxy; (ii) C 4-7 cycloalkenyl, such as cyclopentenyl, which is optionally substituted with one or more substituents independently selected from F, OH, R A , and OR A , wherein R A at each occurrence is independently a C 1-4 alkyl or C 3-6 cycloalkyl, which is optionally substituted with one or more substituents independently selected from F, OH, C 1-4 alkyl, fluorine-substituted C 1-4 alkyl, C 1-4 alkoxy, and fluorine-substituted C 1-4 alkoxy; (v) (iii) phenyl, which is optionally substituted with one or more substituents independently selected from F, Cl, OH, C 1-4 alkyl, fluorine-substituted C 1-4 alkyl, C 1-4 alkoxy, and fluorine-substituted C 1-4 alkoxy; (iv) a 5-membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O, and S, which is optionally substituted with one or more substituents independently selected from F, Cl, OH, C 1-4 alkyl, fluorine-substituted C 1-4 alkyl, C 1-4 alkoxy, and fluorine-substituted C 1-4 alkoxy; or (v) a 6-membered heteroaryl having 1-2 ring heteroatoms independently selected from N, O, and S, which is optionally substituted with one or more substituents independently selected from F, Cl, OH, C 1-4 alkyl, fluorine-substituted C 1-4 alkyl, C 1-4 alkoxy, and fluorine-substituted C 1-4 alkoxy.
6 . The salt of claim 1 , wherein R 3 is methyl.
7 . The salt of claim 1 , wherein R 4 is methyl.
8 . The salt of claim 1 , wherein j is 1.
9 . The salt of claim 1 , wherein X − is a pharmaceutically acceptable counterion.
10 . A salt selected from those shown in Table 1 or 2, wherein X − is a pharmaceutically acceptable counterion:
TABLE 1
TABLE 2
11 . A pharmaceutical composition comprising the salt of claim 9 and optionally a pharmaceutically acceptable carrier.
12 . The pharmaceutical composition of claim 11 , which is formulated for topical administration.
13 . The pharmaceutical composition of claim 11 , which is in the form of a topical solution, cream, ointment, mousse, gel, lotion, or powder.
14 . A method of treating hyperhidrosis, reducing drooling, reducing secretions in stomach or airway, protecting heart and nervous system, treating chronic obstructive pulmonary disease, inducing pupil dilation, or treating abdominal pain in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the salt of claim 9 .
15 . The method of claim 14 , wherein the method is for treating hyperhidrosis, and the administering is a topical administration.
16 . A compound having Formula II, or a salt thereof:
wherein:
R 1 is hydrogen;
L 1 is null, C 1-4 alkylene, or C 1-4 heteroalkylene;
R 2 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 carbocyclyl, 4-8 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl, each of which is optionally substituted;
R 3 is hydrogen or C 1-6 alkyl; and
j is 0, 1 or 2.
17 . The compound of claim 16 , or a salt thereof, which has a formula according to Formula II-1 or Formula II-2:
18 . The salt of claim 5 , wherein L 1 is CH 2 .
19 . The salt of claim 18 , wherein j is 1.