Pharmacokinetically Improved Compounds
A compound of formula A having improved non-specific binding characteristics and pharmacokinetic properties is provided: or pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein R 1 is lower alkyl, R 2 and R 3 are independently selected from lower alkyl, and lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO 2 , amino, acylamino, amido, carbonyl, and alkylthio, A is N or C—H, B is N, C—H, C—(SO 2 —R 4 ), or C—CO—R 4 , D is N, C—H, C—(SO 2 —R 4 ) or C—CO—R 4 , E is N or C—H, wherein only one of A, B or E may be N, and one of B or D is C—(SO 2 —R 4 ) or C—CO—R 4 , R 4 is a group having the formula: in which each R 5 , R 6 , R 7 and R 8 are independently selected from H and lower alkyl, wherein the lower alkyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO 2 , amino, acylamino, amido, carbonyl, and alkylthio; and additionally or alternatively R 6 and R 5 together form a 5- or 6-membered ring, or R 6 and R 7 together form a 3 to 6 membered ring; R 9 is independently selected from H and lower alkyl, wherein the lower alkyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO 2 , amino, acylamino, amido, carbonyl, and alkylthio; alternatively R 8 and R 9 together with the nitrogen to which they are attached form a 5- or 6-membered ring; n is 1 to 4; and m is 1 to 6.
1 . A compound of formula A
or pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein
R 1 is lower alkyl;
R 2 and R 3 are independently selected from lower alkyl, and lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO 2 , amino, acylamino, amido, carbonyl, and alkylthio;
A is Nor C—H;
B is N, C—H, C—(SO 2 —R 4 ), or C—CO—R 4 ;
D is N, C—H, C—(SO 2 —R 4 ) or C—CO—R 4 ;
E is Nor C—H;
wherein only one of A, B or E may be N, and one of B or D is C—(SO 2 —R 4 ) or C—CO—R 4 ;
R 4 is a group having the formula:
wherein
each R 5 , R 6 , R 7 and R 8 are independently selected from H and lower alkyl, wherein the lower alkyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO 2 , amino, acylamino, amido, carbonyl, and alkylthio; and additionally or alternatively R 6 and R 5 together form a 5- or 6-membered ring, or R 6 and R 7 together form a 3 to 6 membered ring;
R 9 is independently selected from H and lower alkyl, wherein the lower alkyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO 2 , amino, acylamino, amido, carbonyl, and alkylthio;
alternatively R 8 and R 9 together with the nitrogen to which they are attached form a 5- or 6-membered ring; n is 1 to 4; and m is 1 to 6.
2 . The compound of claim 1 wherein:
A is C—H;
B is C—H;
D is C—(SO 2 —R 4 ); and
E is C—H.
3 . The compound of claim 2 , wherein nm is 1 or 2.
4 . The compound of claim 3 , wherein n is 1.
5 . The compound of claim 1 , wherein:
R 1 is ethyl
R 2 is methyl
R 3 is propyl
A is C—H;
B is C—H;
D is C—(SO 2 —R 4 ); and
E is C—H.
6 . The compound of claim 1 having the formula:
wherein,
R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 9 are as defined in claim 1 for formula A.
7 . The compound of claim 5 having the formula:
wherein,
R 1 , R 2 and R 3 are independently selected from H and lower alkyl, wherein the lower alkyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO 2 , amino, acylamino, amido, carbonyl, and alkylthio.
8 . The compound of claim 1 having the formula:
wherein,
R 1 is lower alkyl;
R 2 and R 3 are independently selected from lower alkyl, and lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO 2 , amino, acylamino, amido, carbonyl, and alkylthio;
R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are independently selected from H and lower alkyl, wherein the lower alkyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO 2 , amino, acylamino, amido, carbonyl, and alkylthio;
and additionally or alternatively R 6 and R 5 , or R 8 and R 10 together form a 5- or 6-membered ring, or R 6 and R 7 , or R 10 and R 11 together form a 3 to 6 membered ring; and R 9 and R 12 together with the nitrogen to which they are attached form a 5- or 6-membered ring.
9 . The compound of claim 8 having the formula:
wherein,
R 1 , R 2 , R 3 R 5 , R 8 , R 9 and R 12 are as defined in claim 8 .
10 . The compound of claim 9 having the formula:
wherein,
R 1 is lower alkyl; and
R 2 and R 3 are independently selected from lower alkyl, and lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO 2 , amino, acylamino, amido, carbonyl, and alkylthio.
11 . The compound of claim 1 , having the formula selected from:
12 . A compound of formula D
or pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein:
R 1 is lower alkyl;
R 2 and R 3 are independently selected from lower alkyl, and lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO 2 , amino, acylamino, amido, carbonyl, and alkylthio;
A is Nor C—H;
B is N, C—H, C—(SO 2 —NH—R 13 ), or C—CO—NH—R 13 ;
D is N, C—H, C—(SO 2 —NH—R 13 ) or C—CO—NH—R 13 ;
E is N or C—H;
wherein only one of A, B or E may be N, and one of B or D is C—(SO 2 —NH—R 13 ) or C—CO—NH—R 13 ;
R 13 is lower alkyl.
13 . The compound of claim 12 , wherein R 13 is methyl.
14 . The compound of claim 12 , wherein R 2 and R 3 are independently selected from lower alkyl.
15 . The compound of claim 12 , having the formula D 1 :
or pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein
R 1 is lower alkyl;
R 2 and R 3 are independently selected from lower alkyl, and lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO 2 , amino, acylamino, amido, carbonyl, and alkylthio; and
R 13 is selected from lower alkyl.
16 . The compound of claim 15 , wherein R 13 is methyl.
17 . The compound of claim 15 , wherein R 2 and R 3 are independently selected from lower alkyl.
18 . The compound of claim 15 having the formula
19 . A pharmaceutical compositions comprising a compound according to claim 1 or claim 12 and a pharmaceutically acceptable carrier.
20 . A methods for the treating erectile dysfunction, comprising administering to a human or animal an effective amount of a compound according to claim 1 or claim 12 and a pharmaceutically acceptable carrier.