Methods for treating cognitive/attention deficit disorders using tetrahydroindolone analogues and derivatives
View Patent ↗The present specification discloses tetrahydroindolone derivatives or analogues and methods for treating cognitive/attention deficit disorders using such tetrahydroindolone derivatives and analogues.
1. A compound of Formula (I) comprising:
wherein A is
wherein, R 5 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkanoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, NH 2 , NHQ 1 , NQ 1 Q 2 , OH, OQ 1 , or SQ 1 , where Q 1 and Q 2 are alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, alkanoyl, aroyl, aralkanoyl, heteroaralkanoyl, heteroaroyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, or heteroaralkylsulfonyl in which the alkyl portions can be cyclic and can contain from 1 to 3 heteroatoms which can be N, O, or S, and when Q 1 and Q 2 are present together and are alkyl, they can be taken together to form a 5 or 6 member ring which may contain 1 other heteroatom which can be N, O, or S, of which the N may be further substituted with Y 2 , where Y 2 is alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkanoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl, or heteroaralkylaminocarbonyl, in which the alkyl portions can be cyclic and can contain from 1 to 3 heteroatoms which can be N, O, or S;
R 5′ is hydrogen unless R 5 is alkyl, in which case R 5′ is hydrogen or the same alkyl as R 5 ;
R 5 and R 5′ can be taken together as a double bond to C 5 and can be O, S, NQ 3 , or C which can be substituted with one or two groups R 5 , where Q 3 is alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, alkanoyl, aroyl, aralkanoyl, heteroaralkanoyl, or heteroaroyl in which the alkyl portions can be cyclic and can contain from 1 to 3 heteroatoms which can be N, O, or S;
R 6 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, NH 2 , NHQ 4 , NQ 4 Q 5 , OH, OQ 4 , or SQ 4 , where Q 4 and Q 5 are alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, alkanoyl, aroyl, aralkanoyl, heteroaralkanoyl, heteroaroyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, or heteroaralkylsulfonyl in which the alkyl portions can be cyclic and can contain from 1 to 3 heteroatoms which can be N, O, or S, and when Q 1 and Q 2 are present together and are alkyl, they can be taken together to form a 5 or 6 member ring which may contain 1 other heteroatom which can be N, O, or S, of which the N may be further substituted with Y 2 , where Y 2 is alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkanoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl, or heteroaralkylaminocarbonyl, in which the alkyl portions can be cyclic and can contain from 1 to 3 heteroatoms which can be N, O, or S;
R 6′ is hydrogen unless R 6 is alkyl, in which case R 6′ is hydrogen or the same alkyl as R 6 ;
R 6 and R 6′ can be taken together as a double bond to C 5 and can be O, S, NQ 6 , or C which can be substituted with one or two groups R 5 , and where Q 6 is alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, alkanoyl, aroyl, aralkanoyl, heteroaralkanoyl, heteroaroyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, or heteroaralkylsulfonyl in which the alkyl portions can be cyclic and can contain from 1 to 3 heteroatoms which can be N, O, or S;
where N is bonded to L;
L is a hydrocarbyl moiety of 1 to 6 carbon atoms optionally substituted with one or more substituents selected from the group consisting of lower alkyl, amino, hydroxy, lower alkoxy, lower alkylamino, lower alkythio, and oxo; and
B is —OZ or N(Y 1 )-D, where Z is hydrogen or alkyl and Y 1 is hydrogen or alkyl which, when taken with D, can form a cyclic 5- or 6-membered saturated structure which can contain one other heteroatom which can be O, N, or S, of which N can be further substituted with Y 2 , where Y 2 is alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkanoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl, or heteroaralkylaminocarbonyl, in which the alkyl portions can be cyclic and can contain from 1 to 3 heteroatoms which can be N, O, or S.
2. The compound of claim 1 , wherein L has the structure —(CH 2 ) n — wherein n is an integer from 1 to 6.
3. The compound of claim 2 , wherein n is 2.
4. The compound of claim 1 , wherein the moiety B is N(Y 1 )-D.
5. The compound of claim 4 , wherein Y 1 is hydrogen.
6. The compound of claim 4 , wherein Y 1 is lower alkyl.
7. The compound of claim 6 , wherein Y 1 is methyl.
8. The compound of claim 1 , wherein D is
9. The compound of claim 4 , wherein D is
10. A pharmaceutical composition comprising:
a) a compound of Formula (I)
wherein A is
wherein, R 5 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkanoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, NH 2 , NHQ 1 , NQ 1 Q 2 , OH, OQ 1 , or SQ 1 , where Q 1 and Q 2 are alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, alkanoyl, aroyl, aralkanoyl, heteroaralkanoyl, heteroaroyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, or heteroaralkylsulfonyl in which the alkyl portions can be cyclic and can contain from 1 to 3 heteroatoms which can be N, O, or S, and when Q 1 and Q 2 are present together and are alkyl, they can be taken together to form a 5 or 6 member ring which may contain 1 other heteroatom which can be N, O, or S, of which the N may be further substituted with Y 2 , where Y 2 is alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkanoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl, or heteroaralkylaminocarbonyl, in which the alkyl portions can be cyclic and can contain from 1 to 3 heteroatoms which can be N, O, or S;
R 5′ is hydrogen unless R 5 is alkyl, in which case R 5′ is hydrogen or the same alkyl as R 5 ;
R 5 and R 5′ can be taken together as a double bond to C 5 and can be O, S, NQ 3 , or C which can be substituted with one or two groups R 5 , where Q 3 is alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, alkanoyl, aroyl, aralkanoyl, heteroaralkanoyl, or heteroaroyl in which the alkyl portions can be cyclic and can contain from 1 to 3 heteroatoms which can be N, O, or S;
R 6 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, NH 2 , NHQ 4 , NQ 4 Q 5 , OH, OQ 4 , or SQ 4 , where Q 4 and Q 5 are alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, alkanoyl, aroyl, aralkanoyl, heteroaralkanoyl, heteroaroyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, or heteroaralkylsulfonyl in which the alkyl portions can be cyclic and can contain from 1 to 3 heteroatoms which can be N, O, or S, and when Q.sub.1 and Q.sub.2 are present together and are alkyl, they can be taken together to form a 5 or 6 member ring which may contain 1 other heteroatom which can be N, O, or S, of which the N may be further substituted with Y 2 , where Y 2 is alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkanoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl, or heteroaralkylaminocarbonyl, in which the alkyl portions can be cyclic and can contain from 1 to 3 heteroatoms which can be N, O, or S;
R 6′ is hydrogen unless R 6 is alkyl, in which case R 6′ is hydrogen or the same alkyl as R 6 ;
R 6 and R 6′ can be taken together as a double bond to C 5 and can be O, S, NQ 6 , or C which can be substituted with one or two groups R 5 , and where Q 6 is alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, alkanoyl, aroyl, aralkanoyl, heteroaralkanoyl, heteroaroyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, or heteroaralkylsulfonyl in which the alkyl portions can be cyclic and can contain from 1 to 3 heteroatoms which can be N, O, or S;
where N is bonded to L;
L is a hydrocarbyl moiety of 1 to 6 carbon atoms optionally substituted with one or more substituents selected from the group consisting of lower alkyl, amino, hydroxy, lower alkoxy, lower alkylamino, lower alkythio, and oxo; and
B is —OZ or N(Y 1 )-D, where Z is hydrogen or alkyl and Y 1 is hydrogen or alkyl which, when taken with D, can form a cyclic 5- or 6-membered saturated structure which can contain one other heteroatom which can be O, N, or S, of which N can be further substituted with Y 2 , where Y 2 is alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkanoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl, or heteroaralkylaminocarbonyl, in which the alkyl portions can be cyclic and can contain from 1 to 3 heteroatoms which can be N, O, or S; and
b) a pharmaceutically acceptable carrier.
11. The compound of claim 10 , wherein L has the structure —(CH 2 ) n — wherein n is an integer from 1 to 6.
12. The compound of claim 11 , wherein n is 2.
13. The compound of claim 10 , wherein the moiety B is N(Y 1 )-D.
14. The compound of claim 13 , wherein Y 1 is hydrogen.
15. The compound of claim 13 , wherein Y 1 is lower alkyl.
16. The compound of claim 13 , wherein Y 1 is methyl.
17. The compound of claim 10 , wherein D is
18. The compound of claim 14 , wherein D is
19. The pharmaceutical composition of claim 10 , wherein the pharmaceutical composition further comprises a preservative, a stabilizing agent, a wetting agent, an emulsifying agent, a buffering agent, an antioxidant, a suspending agent, a thickening agent, a solubilizer, a bacteriostatic agent, or any combination thereof.
20. The pharmaceutical composition of claim 10 , wherein the pharmaceutical composition is an oral formulation.
21. The pharmaceutical composition of claim 10 , wherein the pharmaceutical composition is a parenteral formulation.
22. The pharmaceutical composition of claim 10 , wherein the pharmaceutical composition is a solid formulation.
23. The pharmaceutical composition of claim 10 , wherein the pharmaceutical composition is a liquid formulation.
24. The pharmaceutical composition of claim 10 , wherein the pharmaceutical composition is a suspension formulation.
25. The pharmaceutical composition of claim 10 , wherein the pharmaceutical composition is an aerosol formulation.
26. The pharmaceutical composition of claim 10 , wherein the pharmaceutical composition is an injection formulation.