US2010324037A1PendingUtilityA1
Pharmacokinetically improved compounds
Est. expiryAug 24, 2026(~0.1 yrs left)· nominal 20-yr term from priority
Inventors:Stewart CampbellDavid C. DuffyMichael J. GroganSteven A. KatesEmanuele OstuniOlivier SchuellerPaul Sweetnam
A61P 9/12A61P 9/02A61P 9/10A61P 9/00A61P 43/00C07D 487/04A61P 15/10C07D 257/08C07D 403/04A01N 43/90
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Claims
Abstract
A compound of formula A having improved non-specific binding characteristics and pharmacokinetic properties is provided: or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof.
Claims
exact text as granted — not AI-modified1 . A compound of the formula A:
or pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein
R 1 is lower alkyl;
R 2 is selected from lower alkyl, 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 3 is selected from lower alkyl, 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:
R 41 is selected from C 3 -C 6 alkyl, C 2 -C 3 alkyl-OH, —(CH 2 ) a —N(H)(R 51 ) and —(CH 2 ) a —N(R 52 )(R 53 );
R 51 is selected from alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;
R 52 and R 53 are taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which is substituted at a ring carbon with one or two oxo groups and which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group,
a is 1 to 6;
R 42 is selected from alkyl, and C 2 -C 6 alkyl-O-alkyl;
R 43 is selected from alkyl, C 2 -C 6 alkyl-NH-alkyl, C 2 -C 6 alkyl-O-alkyl, alkyl-CO 2 H, C 2 -C 6 alkyl-CH(O-alkyl)(O-alkyl), C 2 -C 6 alkyl-CH 2 (O-alkyl)-alkyl-O-alkyl, —(CH 2 ) a —N(H)(R 51 ) and —(CH 2 ) a —N(R 52 )(R 53 );
R 44 is selected from is selected from the group consisting of —(CH 2 ) q —N(R 12 )(R 13 ), —(CH 2 ) r —N(R 11 )—(CH 2 ) s C(O)R 14 , —(CH 2 ) q —C(O)R 14 , —(CH 2 ) r —C(O)—(CH 2 ) s OR 11 , —(CH 2 ) r —C(O)—(CH 2 ) s N(R 12 )(R 13 ), and —(CH 2 ) r O—(CH 2 ) s —C(O)R 14 ,
each R 11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;
each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R 12 and R 13 may be taken together with the nitrogen to which they are attached foam a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group;
each R 14 is independently selected from H, alkyl, —OH, —O-alkyl, —O-aryl, —O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;
q is 1 to 6;
r is 0 to 6;
s is 0 to 6;
R 45 is selected from is selected from the group consisting of —(CH 2 ) v —N(R 25 )(R 26 ), —(CH 2 ) v —N(R 21 )—(CH 2 ) w —C(O)R 24 , —(CH 2 ) v —C(O)R 24 , —(CH 2 ) t —C(O)—(CH 2 ) w OR 21 , —(CH 2 ) t —C(O)(CH 2 ) w —N(R 22 )(R 23 ), —(CH 2 ) v —O—(CH 2 ) w —C(O)R 24 ;
each R 21 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;
each R 22 and R 23 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R 22 and R 23 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group,
each R 24 is independently selected from H, alkyl, —OH, —O-alkyl, —O-aryl, —O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;
R 25 and R 26 taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group;
t is 0 to 6;
v is 1 to 6;
w is 0 to 6;
x is 1 or 2;
y is 1 or 2; and
R 46 are both selected from C 2 -C 6 alkyl-OH, and C 2 -C 6 alkyl-O—C 2 -C 6 alkyl.
2 . A compound of claim 1 , having the formula A 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;
R 4 is a group having the formula:
R 41 is selected from C 3 -C 6 alkyl, C 2 -C 3 alkyl-OH, —(CH 2 ) a —N(H)(R 51 ) and —(CH 2 ) a —N(R 52 )(R 53 );
R 51 is selected from alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;
R 52 and R 53 are taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which is substituted at a ring carbon with one or two oxo groups and which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group,
a is 1 to 6;
R 42 is selected from alkyl, and C 2 -C 6 alkyl-O-alkyl;
R 43 is selected from alkyl, C 2 -C 6 alkyl-NH-alkyl, C 2 -C 6 alkyl-O-alkyl, alkyl-CO 2 H, C 2 -C 6 alkyl-CH(O-alkyl)(O-alkyl), C 2 -C 6 alkyl-CH 2 (O-alkyl)-alkyl-O-alkyl, —(CH 2 ) a —N(H)(R 51 ) and —(CH 2 ) a —N(R 52 )(R 53 );
R 44 is selected from is selected from the group consisting of —(CH 2 ) q —N(R 12 )(R 13 ), —(CH 2 ) r —N(R 11 )—(CH 2 ) s C(O)R 14 , —(CH 2 ) q —C(O)R 14 , —(CH 2 ) r —C(O)—(CH 2 ) s OR 11 , —(CH 2 ) r —C(O)—(CH 2 ) S N(R 12 )(R 13 ), and —(CH 2 ) r O—(CH 2 ) s —C(O)R 14 ,
each R 11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;
each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R 12 and R 13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group;
each R 14 is independently selected from H, alkyl, —OH, —O-alkyl, —O-aryl, —O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;
q is 1 to 6;
r is 0 to 6;
s is 0 to 6;
R 45 is selected from is selected from the group consisting of —(CH 2 ) v —N(R 25 )(R 26 ), —(CH 2 ) v —N(R 21 )—(CH 2 ) w —C(O)R 24 , —(CH 2 ) v —C(O)R 24 , —(CH 2 ) t —C(O)—(CH 2 ) w OR 21 , —(CH 2 ) t —C(O)(CH 2 ) w —N(R 22 )(R 23 ), —(CH 2 ) v —O—(CH 2 ) w —C(O)R 24 ;
each R 21 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;
each R 22 and R 23 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R 22 and R 23 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group,
each R 24 is independently selected from H, alkyl, —OH, —O-alkyl, —O-aryl, —O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;
R 25 and R 26 taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group;
t is 0 to 6;
v is 1 to 6;
w is 0 to 6;
x is 1 or 2;
y is 1 or 2; and
R 46 are both selected from C 2 -C 6 alkyl-OH, and C 2 -C 6 alkyl-O—C 2 -C 6 alkyl.
3 . The compound of claim 2 , having the formula A 2 :
or pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein
R 4 is a group having the formula:
R 41 is selected from C 3 -C 6 alkyl, C 2 -C 3 alkyl-OH, —(CH 2 ) n —N(H)(R 51 ) and —(CH 2 ) a —N(R 52 )(R 53 );
R 51 is selected from alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;
R 52 and R 53 are taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which is substituted at a ring carbon with one or two oxo groups and which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group,
a is 1 to 6;
R 42 is selected from alkyl, and C 2 -C 6 alkyl-O-alkyl;
R 43 is selected from alkyl, C 2 -C 6 alkyl-NH-alkyl, C 2 -C 6 alkyl-O-alkyl, alkyl-CO 2 H, C 2 -C 6 alkyl-CH(O-alkyl)(O-alkyl), C 2 -C 6 alkyl-CH 2 (O-alkyl)alkyl-O-alkyl, —(CH 2 ), N(H)(R 51 ) and —(CH 2 ) a —N(R 52 )(R 53 );
R 44 is selected from is selected from the group consisting of —(CH 2 ) q —N(R 12 )(R 13 ), —(CH 2 ) r —N(R 11 )—(CH 2 ) s C(O)R 14 , —(CH 2 ) q —C(O)R 14 , —(CH 2 ) r —C(O)—(CH 2 ) s OR 11 , —(CH 2 ) r —C(O)—(CH 2 ) s N(R 12 )(R 13 ), and —(CH 2 ) r O—(CH 2 ) s —C(O)R 14 ,
each R 11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;
each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R 12 and R 13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group;
each R 14 is independently selected from H, alkyl, —OH, —O-alkyl, —O-aryl, —O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;
q is 1 to 6;
r 0 to 6;
s is 0 to 6;
R 45 is selected from is selected from the group consisting of —(CH 2 ) v —N(R 25 )(R 26 ), —(CH 2 ) v —N(R 21 )—(CH 2 ) w —C(O)R 24 , —(CH 2 ) v —C(O)R 24 , —(CH 2 ) t —C(O)—(CH 2 ) w OR 21 , —(CH 2 ) r —C(O)(CH 2 ), —N(R 22 )(R 23 ), —(CH 2 ) v —O—(CH 2 ) w —C(O)R 24 ;
each R 21 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;
each R 22 and R 23 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R 22 and R 23 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group,
each R 24 is independently selected from H, alkyl, —OH, —O-alkyl, —O-aryl, —O-aralkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;
R 25 and R 26 taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group;
t is 0 to 6;
v is 1 to 6;
w is 0 to 6;
x is 1 or 2;
y is 1 or 2; and
R 46 are both selected from C 2 -C 6 alkyl-OH, and C 2 -C 6 alkyl-O—C 2 -C 6 alkyl.
4 . The compound of claim 1 , having the formula B 1 :
wherein,
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;
R 41 is selected from C 3 -C 6 alkyl, C 2 -C 3 alkyl-OH, —(CH 2 ) a —N(H)(R 51 ) and —(CH 2 ) a —N(R 52 )(R 53 );
R 51 is selected from alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;
R 52 and R 53 are taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which is substituted at a ring carbon with one or two oxo groups and which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group,
a is 1 to 6;
R 22 and R 23 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;
or R 22 and R 23 may be taken together with the nitrogen to which they are attached foam a 5-to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; and
v is 1 to 6.
5 . The compound of claim 4 , having the formula B 2 :
wherein,
R 41 is selected from C 3 -C 6 alkyl, C 2 -C 3 alkyl-OH, —(CH 2 ) a —N(H)(R 51 ) and —(CH 2 ) a —N(R 52 )(R 53 );
R 51 is selected from alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;
R 52 and R 53 are taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which is substituted at a ring carbon with one or two oxo groups and which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group,
a is 1 to 6;
R 22 and R 23 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;
or R 22 and R 23 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; and
v is 1 to 6.
6 . The compound of claim 1 , the having a structure selected from:
7 . The compound of claim 1 , having the formula C 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;
R 42 is selected from alkyl, and C 2 -C 6 alkyl-O-alkyl;
R 43 is selected from alkyl, C 2 -C 6 alkyl-NH-alkyl, C 2 -C 6 alkyl-O-alkyl, alkyl-CO 2 H, C 2 -C 6 alkyl-CH(O-alkyl)(O-alkyl), C 2 -C 6 alkyl-CH 2 (O-alkyl)-alkyl-O-alkyl, —(CH 2 ) a —N(H)(R 51 ) and —(CH 2 ) a —N(R 52 )(R 53 );
R 22 and R 23 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;
or R 22 and R 23 may be taken together with the nitrogen to which they are attached form a 5-to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; and
v is 1 to 6.
8 . The compound of claim 7 having the formula C 2 :
or pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein
R 42 is selected from alkyl, and C 2 -C 6 alkyl-O-alkyl;
R 43 is selected from alkyl, C 2 -C 6 alkyl-NH-alkyl, C 2 -C 6 alkyl-O-alkyl, alkyl-CO 2 H, C 2 -C 6 alkyl-CH(O-alkyl)(O-alkyl), C 2 -C 6 alkyl-CH 2 (O-alkyl)-alkyl-O-alkyl, —(CH 2 ) a —N(H)(R 51 ) and —(CH 2 ) a —N(R 52 )(R 53 );
R 22 and R 23 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;
or R 22 and R 23 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; and
v is 1 to 6.
9 . The compound of claim 1 , the having a structure selected from:
10 . The compound of claim 1 , 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;
R 44 is selected from is selected from the group consisting of —(CH 2 ) q —N(R 12 )(R 13 ), —(CH 2 ) r —N(R 11 )—(CH 2 ) s C(O)R 14 , —(CH 2 ) q —C(O)R 14 , —(CH 2 ) r —C(O)—(CH 2 ) s OR 11 , —(CH 2 ) r —C(O)—(CH 2 ) s N(R 12 )(R 13 ), and —(CH 2 ) r —O—(CH 2 ) s —C(O)R 14 ,
each R 11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;
each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R 12 and R 13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group;
each R 14 is independently selected from H, alkyl, —OH, —O-alkyl, —O-aryl, —O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;
q is 1 to 6;
r is 0 to 6;
s is 0 to 6; and
x is 1 or 2.
11 . The compound of claim 10 having the 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;
R 44 is selected from is selected from the group consisting of —(CH 2 ) q —N(R 12 )(R 13 ), —(CH 2 ) r —N(R 11 )—(CH 2 ) s C(O)R 14 , —(CH 2 ) q —C(O)R 14 , —(CH 2 ) r —C(O)—(CH 2 ) s OR 11 , —(CH 2 ) r —C(O)—(CH 2 ) S N(R 12 )(R 13 ), and —(CH 2 ) r —O—(CH 2 ) s —C(O)R 14 ,
each R 11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;
each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R 12 and R 13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group;
each R 14 is independently selected from H, alkyl, —OH, —O-alkyl, —O-aryl, —O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;
q is 1 to 6;
r is 0 to 6;
s is 0 to 6.
12 . The compound of claim 11 having the formula D 3 :
or pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein
R 44 is selected from is selected from the group consisting of —(CH 2 ) q —N(R 12 )(R 13 ), —(CH 2 ) r —N(R 11 )—(CH 2 ) n C(O)R 14 , —(CH 2 ) q —C(O)R 14 , —(CH 2 ) r —C(O)—(CH 2 ) s OR 11 , —(CH 2 ) r —C(O)—(CH 2 ) s N(R 12 )(R 13 ), and —(CH 2 ) r O—(CH 2 ) s —C(O)R 14 ,
each R 11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;
each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R 12 and R 13 may be taken together with the nitrogen to which they are attached foam a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group;
each R 14 is independently selected from H, alkyl, —OH, —O-alkyl, —O-aryl, —O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;
q is 1 to 6;
r is 0 to 6;
s is 0 to 6.
13 . The compound of claim 12 , the having a structure:
14 . The compound of claim 1 having the formula E 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;
R 45 is selected from is selected from the group consisting of —(CH 2 ) v —N(R 25 )(R 26 ), —(CH 2 ) v —N(R 21 )—(CH 2 ) w —C(O)R 24 , —(CH 2 ) v —C(O)R 24 , —(CH 2 ) t —C(O)—(CH 2 ) w OR 21 , —(CH 2 ) t —C(O)(CH 2 ) w —N(R 22 )(R 23 ), —(CH 2 ) v O—(CH 2 ) w —C(O)R 24 ;
each R 21 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;
each R 22 and R 23 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R 22 and R 23 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group,
each R 24 is independently selected from H, alkyl, —OH, —O-alkyl, —O-aryl, —O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;
R 25 and R 26 taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group;
t is 0 to 6;
v is 1 to 6; and
w is 0 to 6.
15 . The compound of claim 14 having the formula E 2 :
or pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein
R 45 is selected from is selected from the group consisting of —(CH 2 ) v —N(R 25 )(R 26 ), —(CH 2 ) v —N(R 21 )—(CH 2 ) w —C(O)R 24 , —(CH 2 ) v —C(O)R 24 , —(CH 2 ) t —C(O)—(CH 2 ) w OR 21 , —(CH 2 ) t —C(O)(CH 2 ) w —N(R 22 )(R 23 ), —(CH 2 ) v —O—(CH 2 ) w —C(O)R 24 ;
each R 21 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;
each R 22 and R 23 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R 22 and R 23 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group,
each R 24 is independently selected from H, alkyl, —OH, —O-alkyl, —O-aryl, —O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;
R 25 and R 26 taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group;
t is 0 to 6;
v is 1 to 6; and
w is 0 to 6.
16 . The compound of claim 1 , having a structure selected from:
17 . The compound of claim 1 having the formula:
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;
R 46 are both selected from C 2 -C 6 alkyl-OH, and C 2 -C 6 alkyl-O—C 2 -C 6 alkyl.
18 . The compound of claim 17 having the formula:
or pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein
R 46 are both selected from C 2 -C 6 alkyl-OH, and C 2 -C 6 alkyl-O—C 2 -C 6 alkyl.
19 . A method of treating erectile dysfunction comprising:
administering a therapeutically effective amount of a compound according to claims 1 - 18 in combination with a pharmaceutically acceptable excipient to a patient suffering from erectile disfunction.
20 . A method of treating cardiovascular disorders comprising:
administering a therapeutically effective amount of a compound according to claims 1 - 18 in combination with a pharmaceutically acceptable excipient to a patient suffering from a cardiovascular disorder.
21 . The method of claim 20 , wherein the cardiovascular disorder is hypertension.Cited by (0)
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