Prodrugs of quinuclidine ring-containing muscarinic agonists and compositions and methods thereof
The present invention is directed to compounds of the formula and salts or esters thereof. The present invention is further directed to ophthalmological compositions comprising a therapeutically effective amount of a compound of the present invention and one or more pharmaceutically acceptable excipients. The present invention is further directed to a methods of treating presbyopia or glaucoma or reducing hyperemia comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention.
1. A compound of formula (I),
wherein:
m is an integer of 0 or 1, when m is 0, R 1 is absent;
p is an integer of 0 or 1, when p is 0, X is a bond;
q is an integer of 0 or 1, when q is 0, R 2 is a bond;
X is CH 3 ;
Y is C, N, O, S or
wherein when Y is C, an alkyne is optionally formed, when Y is N, an optionally substituted imine or an oxime is formed together with R 2 , and when Y is O, a carbonyl is formed;
R 1 has the formula —CH 2 —R 3 —O—R 4 ,
R 2 is selected from
with the proviso when Y is N and an oxime is formed together with R 2 , then R 2 is OH; or
when Y is
R 2 is H;
R 3 is selected from a bond between CH 2 and O of R 1 or an alkyl; and
R 4 is selected from a phosphate, a sulfate, a trifluoroacetate or a polar amino acid,
or any pharmaceutically acceptable salt or ester thereof.
2. The compound of claim 1 wherein:
m is 0;
p and q are 1;
X is C; and
Y is N, wherein Y forms an optionally substituted imine or an oxime with R 2 .
3. The compound of claim 2 selected from
4. The compound of claim 1 wherein:
m and p are 1;
q is 0;
X is C; and
Y is O.
5. The compound of claim 1 selected from
6. A compound of formula II,
or a pharmaceutically acceptable salt or ester thereof.
7. A compound of formula (III),
or a pharmaceutically acceptable salt or ester thereof.
8. An ophthalmological composition comprising a therapeutically effective amount of a compound of claim 1 .
9. The composition of claim 8 further comprising a cyclodextrin.
10. The composition of claim 9 wherein the cyclodextrin is selected from an alpha-cyclodextrin, a beta-cyclodextrin and a gamma-cyclodextrin.
11. A method of treating presbyopia or glaucoma comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 .
12. A method of reducing hyperemia comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 .
13. An ophthalmological composition comprising a therapeutically effective amount of a compound of claim 6 .
14. The composition of claim 13 further comprising a cyclodextrin.
15. The composition of claim 14 wherein the cyclodextrin is selected from an alpha-cyclodextrin, a beta-cyclodextrin and a gamma-cyclodextrin.
16. A method of treating presbyopia or glaucoma comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 6 .
17. A method of reducing hyperemia comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 6 .
18. An ophthalmological composition comprising a therapeutically effective amount of a compound of claim 7 .
19. The composition of claim 18 further comprising a cyclodextrin.
20. The composition of claim 19 wherein the cyclodextrin is selected from an alpha-cyclodextrin, a beta-cyclodextrin and a gamma-cyclodextrin.
21. A method of treating presbyopia or glaucoma comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 7 .
22. A method of reducing hyperemia comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 7 .