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US 2003/0144322 A1Published application
Analogs of cocaine
AssigneeGeorgetown University
InventorsAlan P. Kozikowski, Gian Luca Araldi
Life of this patent
Estimating the term…
Abstract
The invention provides a compound of formula (I): 1 wherein R1, R2, R3, and Y 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 or depression comprising administering a compound of formula I, to a mammal in need of such treatment.
Claims26
A compound of formula I:
- 4
- wherein
- Y is NR6, —C(4)(R5)—, or —O—;
- R1 is —C(═O)OFa, cyano, (C1-C6)alkyl, (C1-C6)alkanoyl, (C2-C6)alkenyl, (C2-C6)alkynyl, or 1, 2, 4-oxadiazol-5-yl optionally substituted at the 3-position by W, wherein any (C1-C6)alkyl, (C1-C6)alkanoyl, (C2-C6)alkenyl, or (C2-C6)alkynyl may optionally be substituted by 1, 2 or 3 Z, wherein each Z is independently nitro, cyano, (C1-C6)alkoxy, (C2-C6)acyloxy, C(═O)ORb, C(═O)NRcRd, or 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, or 5-10 membered heteroarylcarbonyl, wherein any aryl or heteroaryl substituent may optionally be substituted on carbon by 1, 2 or 3 Z;
- or
- R1 is —CH2—, or —CH2CH2—, wherein R1 is attached to a carbon at the ortho position of R3;
- and R3is (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, or S(O)2Rh;
- n is 0, 1 or 2;
- W is (C1-C6)alkyl, or phenyl, optionally substituted by 1, 2, or 3 Z;
- Ra to Rg are independently hydrogen or (C1-C4)alkyl;
- and
- Rh is H, (C1-C4)alkyl, or phenyl;
- or a pharmaceutically acceptable salt thereof;
- provided that R3 is not phenyl, when R1 is methoxycarbonyl or acetoxymethyl, R2 is hydrogen, Y is NR6, and R6 is methyl.
15 more elements
A compound of formula I:
- 5
- wherein
- Y is NR6, —C(R4)(R5)—, or —O—;
- R1 is —C(═O)ORa, cyano, (C1-C6)alkyl, (C1-C6)alkanoyl, (C2-C6)alkenyl, (C2-C6)alkynyl, or 1, 2, 4-oxadiazol-5-yl optionally substituted at the 3-position by W, wherein any (C1-C6)alkanoyl, (C2-C6)alkenyl, or (C2-C6)alkynyl may optionally be substituted by 1, 2 or 3 Z, wherein each Z is independently halo, nitro, cyano, hydroxy, (C1-C6)alkoxy, (C2-C6)acyloxy, C(═O)ORb, C(═O)NRcRd, NReRf, or 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, or 5-10 membered heteroarylcarbonyl, wherein any aryl or heteroaryl substituent may optionally be substituted on carbon by 1, 2 or 3 Z;
- 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, or S(O)2Rh;
- n is 0, 1 or 2;
- W is (C1-C6)alkyl, or phenyl, optionally substituted by 1, 2, or 3 Z;
- Ra to Rg are independently hydrogen or (C1-C4)alkyl;
- and
- Rh is H, (C1-C4)alkyl, or phenyl;
- or a pharmaceutically acceptable salt thereof;
- provided that R3 is not phenyl, when R1 is methoxycarbonyl, R2 is hydrogen, Y is NR6, and R6 is methyl.
15 more elements
A compound of formula I:
- 6
- wherein
- Y is —C(R4)(R5)—, or —O—;
- R1 is —C(═O)ORa, cyano, (C1-C6)alkyl, (C1-C6)alkanoyl, (C2-C6)alkenyl, (C2-C6)alkynyl, or 1, 2, 4-oxadiazol-5-yl optionally substituted at the 3-position by W, wherein any (C1-C6)alkyl, (C1-C6)alkanoyl, (C2-C6)alkenyl, or (C2-C6)alkynyl may optionally be substituted by 1, 2 or 3 Z, wherein each Z is independently halo, nitro, cyano, hydroxy, (C1-C6)alkoxy, (C2-C6)acyloxy, C(═O)ORb, C(═O)NRcRd, NReRf, or 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, or 5-10 membered heteroarylcarbonyl, wherein any aryl or heteroaryl substituent may optionally be substituted on carbon by 1, 2 or 3 Z;
- 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, or S(O)2Rh;
- n is 0, 1 or 2;
- W is (C1-C6)alkyl, or phenyl, optionally substituted by 1, 2, or 3 Z;
- Ra to Rg are independently hydrogen or (C1-C4)alkyl;
- and
- Rh is H, (C1-C4)alkyl, or phenyl;
- or a pharmaceutically acceptable salt thereof.
14 more elements
A pharmaceutical composition comprising a compound of formula I:
- 7
- wherein
- Y is NR6, —C(R4)(R5)—, or —O—;
- R1 is —C(═O)ORa, cyano, (C1-C6)alkyl, (C1-C6)alkanoyl, (C2-C6)alkenyl, (C2-C6)alkynyl, or 1, 2, 4-oxadiazol-5-yl optionally substituted at the 3-position by W, wherein any (C1-C6)alkyl, (C1-C6)alkanoyl, (C2-C6)alkenyl, or (C2-C6)alkynyl may optionally be substituted by 1, 2 or 3 Z, wherein each Z is independently halo, nitro, cyano, hydroxy, (C1-C6)alkoxy, (C2-C6)acyloxy, C(═O)ORb, C(═O)NRcRd, NReRf, or S(═O)nRg;
- and R3is (C6-C10)aryl, 5-10 membered heteroaryl, (C6-C10)aryl(C1-C6)alkyl, 5-10 membered heteroaryl(C1-C6)alkyl, (C6-C10)arylcarbonyl, or 5-10 membered heteroarylcarbonyl, wherein any aryl or heteroaryl substituent may optionally be substituted on carbon by 1, 2 or 3 Z;
- 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, or S(O)2Rh;
- n is 0, 1 or 2;
- W is (C1-C6)alkyl, or phenyl, optionally substituted by 1, 2, or 3 Z;
- Ra to Rg are independently hydrogen or (C1-C4)alkyl;
- and
- Rh is H, (C1-C4)alkyl, or phenyl;
- or a pharmaceutically acceptable salt thereof;
- and a pharmaceutically acceptable diluent or carrier.
15 more elements
A method comprising treating drug addiction in a human by administering a pharmaceutically effective dose of a compound of formula I:
- 8
- wherein
- Y is NR6, —C(R4)(R5)—, or —O—;
- R1 is —C(═O)ORa, cyano, (C1-C6)alkyl, (C1-C6)alkanoyl, (C2-C6)alkenyl, (C2-C6)alkynyl, or 1, 2, 4-oxadiazol-5-yl optionally substituted at the 3-position by W, wherein any (C1-C6)alkyl, (C1-C6)alkanoyl, (C2-C6)alkenyl, or (C2-C6)alkynyl may optionally be substituted by 1, 2 or 3 Z, wherein each Z is independently halo, nitro, cyano, hydroxy, (C1-C6)alkoxy, (C2-C6)acyloxy, C(═O)ORb, C(═O)NRcRd, NReRf, or 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, or 5-10 membered heteroarylcarbonyl, wherein any aryl or heteroaryl substituent may optionally be substituted on carbon by 1, 2 or 3 Z;
- 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, or S(O)2Rh;
- n is 0, 1 or 2;
- W is (C1-C6)alkyl, or phenyl, optionally substituted by 1, 2, or 3 Z;
- Ra to Rg are independently hydrogen or (C1-C4)alkyl;
- and
- Rh is H, (C1-C4)alkyl, or phenyl;
- or a pharmaceutically acceptable salt thereof.
14 more elements
A method comprising treating a disease or condition in a mammal in which the activity of dopamine or serotonin is implicated and modulation of dopamine or serotonin reuptake is desired comprising administering a compound of formula I:
- 9
- wherein
- Y is NR6, —C(R4)(R5)—, or —O—;
- R1 is —C(═O)ORa, cyano, (C1-C6)alkyl, (C1-C6)alkanoyl, (C2-C6)alkenyl, (C2-C6)alkynyl, or 1, 2, 4-oxadiazol-5-yl optionally substituted at the 3-position by W, wherein any (C1-C6)alkyl, (C1-C6)alkanoyl, (C2-C6)alkenyl, or (C2-C6)alkynyl may optionally be substituted by 1, 2 or 3 Z, wherein each Z is independently halo, nitro, cyano, hydroxy, (C1-C6)alkoxy, (C2-C6)acyloxy, C(═O)ORb, C(═O)NRcRd, NReRf or 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, or 5-10 membered heteroarylcarbonyl, wherein any aryl or heteroaryl substituent may optionally be substituted on carbon by 1, 2 or 3 Z;
- 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, or S(O)2Rh;
- n is 0, 1 or 2;
- W is (C1-C6)alkyl, or phenyl, optionally substituted by 1, 2, or 3 Z;
- Ra to Rg are independently hydrogen or (C1-C4)alkyl;
- and
- Rh is H, (C1-C4)alkyl, or phenyl;
- or a pharmaceutically acceptable salt thereof.
14 more elements
A radio labeled compound comprising a radionuclide and a compound of formula I:
- 10
- wherein
- Y is NR6, —C(R4)(R5)—, or —O—;
- R1 is —C(═O)ORa, cyano, (C1-C6)alkyl, (C1-C6)alkanoyl, (C2-C6)alkenyl, (C2-C6)alkynyl, or 1, 2, 4-oxadiazol-5-yl optionally substituted at the 3-position by W, wherein any (C1-C6)alkyl, (C1-C6)alkanoyl, (C2-C6)alkenyl, or (C2-C6)alkynyl may optionally be substituted by 1, 2 or 3 Z, wherein each Z is independently halo, nitro, cyano, hydroxy, (C1-C6)alkoxy, (C2-C6)acyloxy, C(═O)ORb, C(═O)NRcRd, NReRf or 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, or 5-10 membered heteroarylcarbonyl, wherein any aryl or heteroaryl substituent may optionally be substituted on carbon by 1, 2 or 3 Z;
- 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, or S(O)2Rh;
- n is 0, 1 or 2;
- W is (C1-C6)alkyl, or phenyl, optionally substituted by 1, 2, or 3 Z;
- Ra to Rg are independently hydrogen or (C1-C4)alkyl;
- and
- Rh is H, (C1-C4)alkyl, or phenyl;
- or a pharmaceutically acceptable salt thereof.
14 more elements
A method comprising imaging the brain of a mammal by administering a radiolabeled compound comprising a radionuclide and a compound of formula I:
- 11
- wherein
- Y is NR6, —C(R4)(R5)—, or —O—;
- R1 is —C(═O)ORa, cyano, (C1-C6)alkyl, (C1-C6)alkanoyl, (C2-C6)alkenyl, (C2-C6)alkynyl, or 1, 2, 4-oxadiazol-5-yl optionally substituted at the 3-position by W, wherein any (C1-C6)alkyl, (C1-C6)alkanoyl, (C2-C6)alkenyl, or (C2-C6)alkynyl may optionally be substituted by 1, 2 or 3 Z, wherein each Z is independently halo, nitro, cyano, hydroxy, (C1-C6)alkoxy, (C2-C6)acyloxy, C(═O)ORb, C(═O)NRcRd, NReRf or 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, or 5-10 membered heteroarylcarbonyl, wherein any aryl or heteroaryl substituent may optionally be substituted on carbon by 1, 2 or 3 Z;
- 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, or S(O)2Rh;
- n is 0, 1 or 2;
- W is (C1-C6)alkyl, or phenyl, optionally substituted by 1, 2, or 3 Z;
- Ra to Rg are independently hydrogen or (C1-C4)alkyl;
- and
- Rh is H, (C1-C4)alkyl, or phenyl;
- or a pharmaceutically acceptable salt thereof;
- and detecting the presence of the radiolabeled compound in the brain.
15 more elements
Dependencies are inferred from the claim text.