Muscarinic antagonists
View Patent ↗The invention described herein are compounds in accordance with formula I: wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 2 , R 8 , R 9 , n, X, and Z are as defined herein, pharmaceutical compositions containing at least one compound of formula I, methods of preparation thereof, and methods of treating disorders with at least one compound of formula I or at least one compound of formula I in association with at least one acetylcholinesterase inhibitor.
1. A compound having the structural formula (I):
or pharmaceutically acceptable salts or solvates thereof; wherein:
R 1 is selected from the group consisting of H alkyl, alkenyl and alkynyl;
R 2 is
p is 0-4;
m is 0-4;
n is 0-4;
R 3 is selected from the group consisting of H, alkyl, halo, alkoxy, hydroxy, nitro, aminoalkyl, and acyl, wherein R 3 can be the same or different and is independently selected when m is 2-4;
R 4 and R 5 , which can be the same or different, are each independently selected from the group consisting of H and halogen;
R 6 is selected from the group consisting of H, halo, alkyl, hydroxy, hydroxyalkyl, arylalkyl, aminoalkyl, haloalkyl, and thioalkyl, wherein R 6 can be the same or different and is independently selected when n is 2-4;
R 7 is selected from the group consisting of hydrogen, acyl, alkyl, alkoxy, alkenyl, cycloalkyl, cycloalkyl substituted with 0-2 alkyl groups which can be the same or different and are independently selected, cycloalkenyl, bicycloalkyl, arylalkenyl and arylalkyl;
R 8 is selected from the group consisting of H, alkyl, aryl, heteroaryl, halo, and cycloalkyl;
R 9 is selected from the group consisting of H, alkyl, aryl, halo, hydroxy and cycloalkyl, wherein R 9 can be the same or different and is independently selected when (p) is 2-4, or two R 9 groups can be joined together to form the group —(CH 2 ) r —, wherein r is 1 to 6;
R 10 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, with the proviso that when R 10 is a substituted or unsubstituted heteroaryl, the bond to M is from a carbon atom in the R 10 group;
Z is N;
X is selected from the group consisting of —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, -alkylene-, —C(S)—, —C(alkyl) 2 - and —C(H)(alkyl)-; and
M is —S(O) 2 — or —C(O)—.
2. The compound according to claim 1 , wherein R 7 is —CH(CH 3 ) 2 .
3. The compound according to claim 1 , wherein R 3 is H.
4. The compound according to claim 1 , wherein R 6 is H.
5. The compound according to claim 1 , wherein R 1 is H or methyl.
6. The compound according to claim 1 , wherein X is —O—.
7. The compound according to claim 1 , wherein R 8 is H.
8. The compound according to claim 1 , wherein R 9 is H.
9. The compound according to claim 1 , wherein R 10 is a substituted or unsubstituted alkyl, or a substituted or unsubstituted aryl.
10. The compound according to claim 9 , wherein R 10 is a substituted aryl.
11. The compound according to claim 10 , wherein said substituted aryl is substituted with one or more groups selected from the group consisting of alkyl, halogen and amino.
12. The compound according to claim 1 , wherein the compound of formula I is:
and wherein R 1 , R 2 , R 4 and R 5 are defined in the following table for the compounds shown:
Com-
pound #
R 1
R 2
R 4
R 5
1
H
Cl
Cl
2
H
Cl
Cl
3
H
Cl
Cl
4
H
Cl
Cl
5
H
Cl
Cl
6
H
Cl
Cl
7
H
H
H
8
H
H
H
9
H
H
H
10
CH 3
H
H
11
CH 3
H
H
12
CH 3
H
H
13
H
Cl
Cl
14
H
Cl
Cl
15
H
Cl
Cl
16
H
Cl
Cl
17
H
Cl
Cl.
13. The compound according to claim 1 having the following formula:
14. The compound according to claim 1 having the following formula:
15. The compound according to claim 1 having the following formula:
16. The compound according to claim 1 having the following formula:
17. A pharmaceutical composition consisting of at least one compound according to claim 1 .
18. The pharmaceutical composition according to claim 17 , further comprising at least one pharmaceutically acceptable carrier.
19. A method of making the pharmaceutical composition according to claim 18 comprising mixing at least one compound according to claim 1 with at least one pharmaceutically acceptable carrier.
20. A method of treating Senile Dementia or Alzheimer's disease comprising administering to a patient suffering from said disease at least one compound according to claim 1 .
21. The method of treating Senile Dementia or Alzheimer's disease according to claim 20 , wherein the amount of compound of formula I administered is a therapeutically effective amount for treatment of the cognitive or neurological disease.
22. The method of treating Senile Dementia or Alzheimer's disease according to claim 21 , wherein the amount of compound of formula I administered is from about 0.00001 mg/kg to about 40 mg/kg of body weight.
23. The method of treating Senile Dementia or Alzheimer's disease according to claim 21 , wherein said cognitive or neurodegenerative disease is Alzheimer's disease.
24. A method of treating Senile Dementia or Alzheimer's disease comprising administering to a patient suffering from said disease a combination of at least one compound according to claim 1 with at least one acetylcholinesterase inhibitor.
25. The method of treating Senile Dementia or Alzheimer's disease according to claim 24 , wherein the amount of compound of formula I and amount of inhibitor administered is a therapeutically effective amount.
26. The method of treating Senile Dementia or Alzheimer's disease according to claim 24 , wherein the amount of compound of formula I and amount of inhibitor administered are each independently from about 0.001 mg/kg to about 100 mg/kg of body weight.