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US 6,605,621 B1Granted
Monomeric and dimeric heterocycles, and therapeutic uses thereof
AssigneeGeorgetown University
InventorsAlan P. Kozikowski, Gian Luca Araldi, Amir P. Tamiz
Life of this patent
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Abstract
The invention provides compounds of formula(I): X—L—X1 (I) wherein X, L, and X1 have any of the meanings defined in the specification; as well a pharmaceutical composition comprising a compound of formula I; intermediates and methods useful for preparing a compound of formula I; and therapeutic methods for treating drug addiction, Parkinson's disease, depression, or a disease wherein the administration of cocaine is indicated, comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof to a mammal in need of such treatment.
Claims3
A radiolabeled compound, comprising a radionuclide and a compound represented by formula I:
- X—L—X1 (I)
- wherein X and X1 each independently represent a compound of formula II:
- wherein
- Y is NR6, —C(R4)(R5)—, or —O—;
- R1 is —C(═O)ORa, —C(═O)N(Ra)2, cyano, (C1-C6)alkyl, (C1-C6)alkanoyl, (C2-C6)alkenyl, (C2-C6)alkynyl, or 1,2,4-oxadiazol-5-yl unsubstituted or substituted at the 3-position by W, wherein any (C1-C6)alkyl, (C1-C6)alkanoyl, (C2-C6)alkenyl, or (C2-C6)alkynyl is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, (C1-C6)alkoxy, (C2-C6)acyloxy, trifluoromethyl, C(═O)ORb, C(═O)NRcRd, NReRf, and S(═O)nRg;
- and R3 is (C6-C10)aryl, 5-10 membered heteroaryl, (C6-C10)aryl(C1-C6)alkyl, 5-10 membered heteroaryl(C1-C6)alkyl, (C6-C10)arylcarbonyl, biphenyl, or 5-10 membered heteroarylcarbonyl, wherein any aryl, biphenyl, or heteroaryl substituent is unsubstituted or substituted on cabon with 1, 2 or 3 substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C2-C6)acyloxy, trifluoromethyl, C(═O)ORb, C(═O)NRcRd, NRcRf, and S(═O)nRg;
- or
- R1 is —CH2—, or —CH2CH2—, wherein R1 is attached to a carbon at the ortho position of R3;
- and R3 is (C6-C10)aryl, or 5-10 membered heteroaryl;
- R2 is hydrogen or (C1-C6)alkyl;
- R4 and R5 are independently hydrogen or (C1-C6)alkyl;
- R6 is hydrogen, (C1-C6)alkyl, (C1-C6)alkanoyl, (C2-C6)alkenyl, (C2-C6)alkynyl, trifluoromethyl, aryl, heteroaryl, aryl(C1-C4)alkyl, heteroaryl(C1-C4)alkyl, aryl(C1-C4)alkanoyl, or heteroaryl(C1-C4)alkanoyl;
- wherein any (C2-C6)alkyl, (C2-C6)alkanoyl, (C2C6)alkenyl, or (C2-C6)alkynyl is unsubstituted or substituted on a carbon other than the carbon attached to the piperidine nitrogen with 1, 2 or 3 substituents independently selected from the group consisting of nitro, cyano, hydroxy, (C1-C6)alkoxy, (C2-C6)acyloxy, trifluoromethyl, C(═O)ORb, C(═O)NRcRd, and S(═O)nRg;
- each n is independently 0, 1 or 2;
- W is (C1-C6)alkyl, or aryl, unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, (C1-C6)alkoxy, (C2-C6)acyloxy, trifluoromethyl, C(═O)ORb, C(═O)NRcRd, NReRf, and S(═O)nRg;
- Ra is L, hydrogen, (C1-C4)alkyl, aryl, heteroaryl, aryl(C1-C4)alkyl, or heteroaryl(C1-C4)alkyl;
- each Rb is independently hydrogen, (C1-C4)alkyl, aryl, heteroaryl, aryl(C1-C4)alkyl, or heteroaryl(C1-C4)alkyl;
- each Rc and Rd is independently hydrogen, (C1-C4)alkyl, aryl, heteroaryl, aryl(C1-C4)alkyl, or heteroaryl(C1-C4)alkyl;
- or, independently, each NRcRd together is piperidino, pyrrolidino, or morpholino;
- each Re and Rf is independently hydrogen, (C1-C4)alkyl, (C1-C4)alkanoyl, (C1-C4)alkoxycarbonyl, aryl, heteroaryl, aryl(C1-C4)alkyl, heteroaryl(C1-C4)alkyl, aryl(C1-C4)alkanoyl, or heteroaryl(C1-C4)alkanoyl;
- or, independently, each NReRf together is piperidino, pyrrolidino, or morpholino;
- each Rg is independently hydrogen, (C1-C4)alkyl, aryl, heteroaryl, aryl(C1-C4)alkyl, or heteroaryl(C1-C4)alkyl;
- and
- L is an unbranched (C2-C12)alkylene chain, unsubstituted or substituted with one, two, or three substituents selected from the group consisting of (C1-C4)alkyl, (C1-C4)alkoxy, hydroxy, oxo, and halo;
- or L is an unbranched (C2-C10)alkylene chain including, within the chain, at least one divalent radical selected from the group consisting of non peroxide oxy (—O—), thio (—S—), sulfinyl, sulfonyl, —OC(═O)—, and —N(Rm)C(═O)—;
- or L is Ri—(C2-C10alkylene)—Rk wherein Ri and Rk are each independently —N(Rm)—, —O—, or —S—;
- each Rm is independently hydrogen or (C1-C4)alkyl;
- or a pharmaceutically acceptable salt thereof.
25 more elements
A method of imaging the brain of a mammal, comprising administering, to a mammal a radiolabeled compound comprising a radionuclide and a compound represented by formula I:
- X—L—X1 (I)
- wherein X and X1 each independently represent a compound of formula II:
- wherein
- Y is NR6, —C(R4)(R5)—, or —O—;
- R1 is —C(═O)ORa, —C(═O)N(Ra)2, cyano (C1-C6)alkyl, (C1-C6)alkanoyl, (C2-C6)alkenyl, (C2-C6)alkynyl or 2,2,4-oxadiazol-5-yl unsubstituted or substituted at the 3-position by W, wherein any (C1-C6)alkyl, (C1-C6)alkanoyl, (C2-C6)alkenyl, or (C2-C6)alkynyl is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, (C1-C6)alkoxy, (C2-C6)acyloxy, trifluoromethyl, C(═O)ORb, C(═O)NRcRd, NReRf, and S(═O)nRg;
- and R3 is (C6-C10)aryl, 5-10 membered heteroayl, (C6-C10)aryl(C1-C6)alkyl, 5-10 membered heteroaryl(C1-C6)alkyl, (C6-C10)arylcarbonyl, biphenyl, or 5-10 membered heteroarylcarbonyl, wherein any aryl, biphenyl, or heteroaryl substituent is unsubstituted or substituted on carbon with 1, 2 or 3 substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C2-C6)acyloxy, trifluoromethyl, C(═O)ORb, C(═O)NRcRd, NReRf, and S(═O)nRg;
- or
- R1 is —CH2—, or —CH2CH2—, wherein R1 is attached to a carbon at the ortho position of R3;
- and R3 is (C6-C10)aryl, or 5-10 membered heteroaryl;
- R2 is hydrogen or (C1-C6)alkyl;
- R4 and R5 are independently hydrogen or (C1-C6)alkyl;
- R6 is hydrogen (C1-C6)alkyl, (C2-C6)alkaneyl, (C2-C6)alkenyl, (C2-C6)alkyhyl, trifluoromethyl, aryl, heteroaryl, aryl(C1-C4)alkyl, heteroaryl(C1-C4)alkyl, aryl(C1-C4)alkanoyl, or heteroaryl(C1-C4)alkanoyl;
- wherein any (C2-C6)alkyl, (C2-C6)alkanoyl, (C2-C6)alkenyl, or (C2-C6)alkynyl is unsubstituted or substituted on a carbon other than the carbon attached to the piperidine nitrogen with 1, 2 or 3 substituents independently selected from the group consisting of nitro, cyano, hydroxy, (C1-C6)alkoxy, (C2-C6)acyloxy, trifluoromethyl, C(═O)ORb, C(═O)NRcRd, and S(═O)nRg;
- each n is independently 0, 1 or 2;
- W is (C1-C6)alkyl, or aryl, unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, (C1-C6)alkoxy, (C2-C6)acyloxy, trifluoromethyl, C(═O)ORb, C(═O)NRcRd, NReRf, and S(═O)nRg;
- Ra is L, hydrogen, (C1-C4)alkyl, aryl, heteroaryl, aryl(C1-C4)alkyl, or heteroaryl(C1-C4)alkyl;
- each Rb is independently hydrogen, (C1-C4)alkyl, aryl, heteroaryl, aryl(C1-C4)alkyl, or heteroaryl(C1-C4)alkyl;
- each Rc and Rd is independently hydrogen, (C1-C4)alkyl, aryl, heteroaryl, aryl(C1-C4)alkyl, or heteroaryl(C1-C4)alkyl;
- or, independently, each NRcRd together is piperidino, pyrrolidino, or morpholino;
- each Re and Rf is independently hydrogen, (C1-C4)alkyl, (C1-C4)alkanoyl, (C1-C4)alkoxycarbonyl, aryl, heteroaryl, aryl(C1-C4)alkyl, heteroaryl(C1-C4)alkyl, aryl(C1-C4)alkanoyl, or heteroaryl(C1-C4)alkanoyl;
- or, independently, each NReRf together is piperidino, pyrrolidino, or morpholino;
- each Rg is independently hydrogen, (C1-C4)alkyl, aryl, heteroaryl, aryl(C1-C4)alkyl, or heteroaryl(C1-C4)alkyl;
- and
- L is an unbranched (C2-C2)alkylene chain, unsubstituted or substituted with one, two, or three substituents selected from the group consisting of (C1-C4)alkyl, (C1-C4)alkoxy, hydroxy, oxo, and halo;
- or L is an unbranched (C2-C10)alkylene chain including, within the chain, at least one divalent radical selected from Me group consisting of non peroxide oxy (—O—), thio (—S—), sulfinyl, sulfonyl, —OC(═O)═, and —N(Rm)C(═O)—;
- or L is Ri—(C2-C10alkylene)—Rk wherein Ri and Rk are each independently —N(Rm)—, —O—, or —S—;
- each Rm is independently hydrogen or (C1-C4)alkyl;
- or a pharmaceutically acceptable salt thereof;
- and
- detecting the presence of the radiolabeled compound in the brain of the mammal.
27 more elements
Dependencies are inferred from the claim text.