Substituted 4-amino-1-(pyridylmethyl)piperidine and related compounds
This invention provides 4-amino-1-(pyridylmethyl)piperidine and related compounds and pharmaceutically acceptable salts thereof which are useful as muscarinic receptor antagonists. This invention also provides pharmaceutical compositions containing such compounds; processes and intermediates useful for preparing such compounds; and methods for treating disease conditions mediated by muscarinic receptors, such as overactive bladder, irritable bowel syndrome and chronic obstructive pulmonary disease, using such compounds.
1. A compound of formula V:
wherein G is selected from the group consisting of:
—CHO;
—CH(OR m ) 2 , where R m is C 1-6 alkyl, or both R m groups are joined to form C 2-6 alkylene;
—COOH;
—CH═CH 2 ; and
—CH 2 -L, where L is a leaving group;
each R a and R b is independently selected from the group consisting of C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, cyano, halo, —OR f , —SR f , —S(O)R f , —S(O) 2 R f and —NR g R h ; or two adjacent R a groups or two adjacent R b groups are joined to form C 3-6 alkylene, —(C 2-4 alkylene)—O — or —O—(C 1-4 alkylene)—O—; wherein each alkyl, alkylene, alkenyl, alkynyl and cycloalkyl group is optionally substituted with 1 to 5 fluoro substituents;
each R c is independently selected from the group consisting of C 1-4 alkyl and fluoro; wherein each alkyl group is optionally substituted with 1 to 5 fluoro substituents;
each R e is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 6-10 aryl, C 2-9 heteroaryl, C 3-6 heterocyclic, —CH 2 —R i and —CH 2 CH 2 —R j ; or both R e groups are joined together with the nitrogen atom to which they are attached to form C 3-6 heterocyclic; wherein each alkyl, alkenyl, alkynyl and cycloalkyl group is optionally substituted with 1 to 5 fluoro substituents; and each aryl, heteroaryl and heterocyclic group is optionally substituted with 1 to 3 substituents independently selected from R k ;
each R f is independently selected from the group consisting hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl and C 3-6 cycloalkyl; wherein each alkyl, alkenyl, alkynyl and cycloalkyl group is optionally substituted with 1 to 5 fluoro substituents;
each R g and R h is independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl and C 3-6 cycloalkyl; or R g and R h are joined together with the nitrogen atom to which they are attached to form C 3-6 heterocyclic; wherein each alkyl, alkenyl, alkynyl and cycloalkyl group is optionally substituted with 1 to 5 fluoro substituents, and the heterocyclic group is optionally substituted with 1 to 3 substituents independently selected from C 1-4 alkyl and fluoro;
each R i is independently selected from the group consisting of C 3-6 cycloalkyl, C 6-10 aryl, C 2-9 heteroaryl and C 3-6 heterocyclic; wherein aryl, cycloalkyl, heteroaryl and heterocyclic group is optionally substituted with 1 to 3 substituents independently selected from R k ;
each R j is independently selected from the group consisting of C 3-6 cycloalkyl, C 6-10 aryl, C 2-9 heteroaryl, C 3-6 heterocyclic, —OH, —O(C 1-6 alkyl), —O (C 3-6 cycloalkyl), —O(C 6-10 aryl), —O(C 2-9 heteroaryl), —S(C 1-6 alkyl), —S(O)(C 1-6 alkyl), —S(O) 2 (C 1-6 alkyl), —S(C 3-6 cycloalkyl), —S(O)(C 3-6 cycloalkyl), —S(O) 2 (C 3-6 cycloalkyl), —S(C 6-10 aryl), —S(O)(C 6-10 aryl), —S(O) 2 (C 6-10 aryl), —S(C 2-9 heteroaryl), —S(O)(C 2-9 heteroaryl) and —S(O) 2 (C 2-9 heteroaryl); wherein each alkyl group is optionally substituted with 1 to 5 fluoro substituents; and each aryl, cycloalkyl, heteroaryl and heterocyclic group is optionally substituted with 1 to 3 substituents independently selected from R k ;
each R k is independently selected from the group consisting of C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, cyano, halo, —OR f , —SR f , —S(O)R f , —S(O) 2 R f and —NR g R h ; or two adjacent R k groups are joined to form C 3-6 alkylene, —(C 2-4 alkylene)—O— or —O—(C 1-4 alkylene)—O—; wherein each alkyl, alkylene, alkenyl and alkynyl group is optionally substituted with 1 to 5 fluoro substituents;
a is an integer from 2 to 7;
b is 0 or 1;
c is an integer from 2 to 7; provided that a +b +c equals 7, 8 or 9;
m is an integer from 0 to 3;
n is an integer from 0 to 3;
p is 1;
q is an integer from 0 to 4;
or a salt or stereoisomer thereof.
2. The compound of claim 1 , wherein b is 0.
3. The compound of claim 1 , wherein b is 1.
4. The compound of claim 1 , wherein a +b +c equals 7.
5. The compound of claim 1 , wherein G is —CHO.
6. The compound of claim 1 , wherein G is —CH(OR m ) 2 .
7. The compound of claim 1 , wherein G is —COOH.
8. The compound of claim 1 , wherein G is —CH═CH 2 .
9. The compound of claim 1 , wherein G is —CH 2 -L.
10. A compound of the formula:
wherein
G is selected from —CHO; —CH(OR m ) 2 , where R m is C 1-6 alkyl, or both R m groups are joined to form C 2-6 alkylene; —COOH; —CH═CH 2 ; and —CH 2 -L, where L is a leaving group;
a is an integer from 2 to 7;
b is 0 or 1;
c is an integer from 2 to 7; provided that a +b +c equals 7, 8 or 9;
or a salt or stereoisomer thereof.
11. The compound of claim 10 , wherein b is 0.
12. The compound of claim 10 , wherein b is 1.
13. The compound of claim 10 , wherein G is —CHO.
14. The compound of claim 10 , wherein G is —CH(OR m ) 2 .
15. The compound of claim 10 , wherein G is —COOH.
16. The compound of claim 10 , wherein G is —CH═CH 2 .
17. The compound of claim 10 , wherein G is —CH 2 -L.
18. The compound of claim 10 , wherein G is —CH 2 —Cl.
19. The compound of claim 10 , wherein G is —CH 2 —Br.
20. The compound of claim 10 , wherein G is —CH 2 —I.
21. The compound of claim 10 , wherein G is —CH 2 —O—S(O) 2 CH 3 .
22. The compound of claim 10 , wherein G is —CH 2 —O—S(O) 2 (4-methylphenyl).
23. A compound of the formula:
or a salt thereof.
24. A compound of the formula:
or a salt thereof.