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US 7,115,767 B2Granted
Tetraline derivatives as ghrelin receptor modulators
AssigneeAbbott Laboratories
InventorsBo Liu, Gang Liu, Lissa T. J. Nelson, Jyoti R. Patel, Hing L. Sham, Zhili Xin, Hongyu Zhao
Life of this patent
Estimating the term…
Abstract
The present invention is related to compounds of formula (I), or a therapeutically suitable salt or prodrug thereof, the preparation of the compounds, compositions containing the compounds and the use of the compounds in the prevention or treatment of disorders regulated by ghrelin including anorexia, cancer cachexia, eating disorders, age-related decline in body composition, weight gain, obesity, and diabetes mellitus.
Claims21
A compound according to formula (I),
- or a therapeutically suitable salt or prodrug thereof, wherein
- R1 is selected from the group consisting of hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle, heterocyclealkyl;
- R2 is selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle, heterocyclealkyl;
- or
- R1 and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle;
- R3, R4, R5, and R6 are each independently a member selected from the group consisting of hydrogen, alkoxyalkyl, alkyl, alkenyl, alkenylalkoxy, aryl, cyano, cycloalkyl, halo, haloalkyl, heterocycle, hydroxy, hydroxyalkyl, nitro, sulfonyl, RaRbN—, RaRbNalkyl, RaRbNcarboxyalkyl, RaRbNcarboxyalkenyl and RaRbNsulfonyl;
- R7 is a member selected from the group consisting of alkenyl, alkoxy, alkoxycarbonyl, aryl, haloalkyl, cycloalkyl, heterocycle, RcRdN—, RcRdNcarboxy and RcRdNsulfonyl;
- R8, R9, R10, and R11 are each independently a member selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, alkyl, alkenyl, alkenylalkoxy, aryl, cyano, halo, haloalkyl, heterocycle, hydroxy, hydroxyalkyl, RaRbN—, RaRbNalkyl, RaRbNcarboxyalkyl;
- R12 and R13 are each independently a member selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, alkyl, alkenyl, alkenylalkoxy, aryl halo, haloalkyl, heterocycle, hydroxy, hydroxyalkyl, RaRbN—, RaRbNalkyl, RaRbNcarboxyalkyl;
- Ra and Rb are each independently a member selected from the group consisting of hydrogen, alkenyloxycarbonyl,alkoxyalkyl, alkyl, alkylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkylalkoxyalkoxycarbonyl, alkylsulfonyl, alkynyloxycarbonyl, aryl, arylalkyl, arylalkoxycarbonyl, aryloxyalkyl, aryloxyalkylcarbonyl, cycloalkyl, cycloalkoxycarbonyl, cycloalkylalkyl, cycloalkylalkoxycarbonyl, heterocycle, heterocyclecarbonyl, heterocyclealkyl, heterocyclealkoxylcarbonyl, hydroxyalkoxycarbonyl, haloalkoxycarbonyl, RcRdNcarbonyl, RcRdNcarbonylalkyl, RcRdNalkyl, RcRdNalkoxycarbonyl;
- Rc and Rd are each independently a member selected from the group consisting of hydrogen, alkenyloxycarbonyl, alkoxyalkyl, alkyl, alkylcarbonyl, alkylNHalkylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl,alkoxyalkoxycarbonyl, alkylsulfonyl, alkynyloxycarbonyl, aryl, arylalkyl, arylalkoxycarbonyl, aryloxyalkyl, aryloxyalkylcarbonyl, cycloalkyl, cycloalkoxycarbonyl, cycloalkylalkyl, cycloalkylalkoxycarbonyl, heterocycle, heterocyclecarbonyl, heterocyclealkyl, heterocyclealkoxylcarbonyl, hydroxyalkoxycarbonyl, haloalkoxycarbonyl, nitroalkoxycarbonyl, ReRfNcarbonyl, ReRfNcarbonylalkyl, ReRfNalkyl, ReRfNalkoxycarbonyl;
- Re and Rf are each independently a member selected from the group consisting of hydrogen, alkyl.
9 more elements
A compound according to formula (Ia),
- or a therapeutically suitable salt or prodrug thereof, wherein
- R1 is selected from the group consisting of hydrogen, alkyl, aryl, arylalkyl, heterocycle, and heterocyclealkyl;
- R2 is selected from the group consisting of alkyl, aryl, arylalkyl, heterocycle, and heterocyclealkyl;
- or
- R1 and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle;
- R3, R4, R5, and R6 are each independently a member selected from the group consisting of hydrogen, alkoxyalkyl, alkyl, alkenyl, alkenylalkoxy, aryl, cyano, cycloalkyl, halo, haloalkyl, heterocycle, hydroxy, hydroxyalkyl, nitro, sulfonyl, RaRbN—, RaRbNalkyl, RaRbNcarboxyalkyl, RaRbNcarboxyalkenyl, RaRbNsulfonyl;
- R7 is a member selected from the group consisting of alkenyl, alkoxy, alkoxycarbonyl, aryl, haloalkyl, cycloalkyl, heterocycle, RcRdN—, RcRdNcarboxy and RcRdNsulfonyl;
- R8, R9, R10, and R11 are each independently a member selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, alkyl, alkenyl, alkenylalkoxy, aryl, cyano, halo, haloalkyl, heterocycle, hydroxy, hydroxyalkyl, RaRbN—, RaRbNalkyl, RaRbNcarboxyalkyl;
- R12 and R13 are each independently a member selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, alkyl, alkenyl, alkenylalkoxy, aryl halo, haloalkyl, heterocycle, hydroxy, hydroxyalkyl, RaRbN—, RaRbNalkyl, RaRbNcarboxyalkyl;
- Ra and Rb are each independently a member selected from the group consisting of hydrogen, alkenyloxycarbonyl,alkoxyalkyl, alkyl, alkylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkylalkoxyalkoxycarbonyl, alkylsulfonyl, alkynyloxycarbonyl, aryl, arylalkyl, arylalkoxycarbonyl, aryloxyalkyl, aryloxyalkylcarbonyl, cycloalkyl, cycloalkoxycarbonyl, cycloalkylalkyl, cycloalkylalkoxycarbonyl, heterocycle, heterocyclecarbonyl, heterocyclealkyl, heterocyclealkoxylcarbonyl, hydroxyalkoxycarbonyl, haloalkoxycarbonyl, RcRdNcarbonyl, RcRdNcarbonylalkyl, RcRdNalkyl, RcRdNalkoxycarbonyl;
- Rc and Rd are each independently a member selected from the group consisting of hydrogen, alkenyloxycarbonyl, alkoxyalkyl, alkyl, alkylcarbonyl, alkylNHalkylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl,alkoxyalkoxycarbonyl, alkylsulfonyl, alkynyloxycarbonyl, aryl, arylalkyl, arylalkoxycarbonyl, aryloxyalkyl, aryloxyalkylcarbonyl, cycloalkyl, cycloalkoxycarbonyl, cycloalkylalkyl, cycloalkylalkoxycarbonyl, heterocycle, heterocyclecarbonyl, heterocyclealkyl, heterocyclealkoxylcarbonyl, hydroxyalkoxycarbonyl, haloalkoxycarbonyl, nitroalkoxycarbonyl, ReRfNcarbonyl, ReRfNcarbonylalkyl, ReRfNalkyl, ReRfNalkoxycarbonyl;
- Re and Rf are each independently a member selected from the group consisting of hydrogen, alkyl.
9 more elements
A compound according to formula (II),
- or a therapeutically suitable salt or prodrug thereof, wherein
- R1 is selected from the group consisting of hydrogen, alkyl, aryl, arylalkyl, heterocycle, and heterocyclealkyl;
- R3, R4, R5, and R6 are each independently a member selected from the group consisting of hydrogen, alkoxyalkyl, alkyl, alkenyl, alkenylalkoxy, aryl, cyano, cycloalkyl, halo, haloalkyl, heterocycle, hydroxy, hydroxyalkyl, nitro, sulfonyl, RaRbN—, RaRbNalkyl, RaRbNcarboxyalkyl, RaRbNcarboxyalkenyl, RaRbNsulfonyl;
- R7 is a member selected from the group consisting of alkenyl, alkoxy, alkoxycarbonyl, aryl, haloalkyl, cycloalkyl, heterocycle, RcRdN—, RcRdNcarboxy and RcRdNsulfonyl;
- R8, R9, R10, and R11 are each independently a member selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, alkyl, alkenyl, alkenylalkoxy, aryl, cyano, halo, haloalkyl, heterocycle, hydroxy, hydroxyalkyl, RaRbN—, RaRbNalkyl, RaRbNcarboxyalkyl;
- R12 and R13 are each independently a member selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, alkyl, alkenyl, alkenylalkoxy, aryl halo, haloalkyl, heterocycle, hydroxy, hydroxyalkyl, RaRbN—, RaRbNalkyl, RaRbNcarboxyalkyl;
- R14 is alkyl;
- Ra and Rb are each independently a member selected from the group consisting of hydrogen, alkenyloxycarbonyl,alkoxyalkyl, alkyl, alkylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkylalkoxyalkoxycarbonyl, alkylsulfonyl, alkynyloxycarbonyl, aryl, arylalkyl, arylalkoxycarbonyl, aryloxyalkyl, aryloxyalkylcarbonyl, cycloalkyl, cycloalkoxycarbonyl, cycloalkylalkyl, cycloalkylalkoxycarbonyl, heterocycle, heterocyclecarbonyl, heterocyclealkyl, heterocyclealkoxylcarbonyl, hydroxyalkoxycarbonyl, haloalkoxycarbonyl, RcRdNcarbonyl, RcRdNcarbonylalkyl, RcRdNalkyl, RcRdNalkoxycarbonyl;
- Rc and Rd are each independently a member selected from the group consisting of hydrogen, alkenyloxycarbonyl, alkoxyalkyl, alkyl, alkylcarbonyl, alkylNHalkylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl,alkoxyalkoxycarbonyl, alkylsulfonyl, alkynyloxycarbonyl, aryl, arylalkyl, arylalkoxycarbonyl, aryloxyalkyl, aryloxyalkylcarbonyl, cycloalkyl, cycloalkoxycarbonyl, cycloalkylalkyl, cycloalkylalkoxycarbonyl, heterocycle, heterocyclecarbonyl, heterocyclealkyl, heterocyclealkoxylcarbonyl, hydroxyalkoxycarbonyl, haloalkoxycarbonyl, nitroalkoxycarbonyl, ReRfNcarbonyl, ReRfNcarbonylalkyl, ReRfNalkyl, ReRfNalkoxycarbonyl;
- Re and Rf are each independently a member selected from the group consisting of hydrogen, alkyl.
7 more elements
A compound according to formula (IIb),
- or a therapeutically suitable salt or prodrug thereof, wherein
- R1 is selected from the group consisting of hydrogen, alkyl, aryl, arylalkyl, heterocycle, and heterocyclealkyl;
- R3, R4, R5, and R6 are each independently a member selected from the group consisting of hydrogen, alkoxyalkyl, alkyl, alkenyl, alkenylalkoxy, aryl, cyano, halo, haloalkyl, heterocycle, hydroxy, hydroxyalkyl, nitro, sulfonyl, RaRbN—, RaRbNalkyl, RaRbNcarboxyalkyl;
- R7 is a member selected from the group consisting of alkenyl, alkyl, alkoxy, aryl, haloalkyl, cycloalkyl, heterocycle and RcRdN-;
- R8, R9, R10, and R11 are each independently a member selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, alkyl, alkenyl, alkenylalkoxy, aryl, cyano, halo, haloalkyl, heterocycle, hydroxy, hydroxyalkyl, RaRbN—, RaRbNalkyl, RaRbNcarboxyalkyl;
- R12 and R13 are each independently a member selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, alkyl, alkenyl, alkenylalkoxy, aryl halo, haloalkyl, heterocycle, hydroxy, hydroxyalkyl, RaRbN—, RaRbNalkyl, RaRbNcarboxyalkyl;
- R14 is alkyl;
- Ra and Rb are each independently a member selected from the group consisting of hydrogen, alkenyloxycarbonyl,alkoxyalkyl, alkyl, alkylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkylalkoxyalkoxycarbonyl, alkylsulfonyl, alkynyloxycarbonyl, aryl, arylalkyl, arylalkoxycarbonyl, aryloxyalkyl, aryloxyalkylcarbonyl, cycloalkyl, cycloalkoxycarbonyl, cycloalkylalkyl, cycloalkylalkoxycarbonyl, heterocycle, heterocyclecarbonyl, heterocyclealkyl, heterocyclealkoxylcarbonyl, hydroxyalkoxycarbonyl, haloalkoxycarbonyl, RcRdNcarbonyl, RcRdNcarbonylalkyl, RcRdNalkyl, RcRdNalkoxycarbonyl;
- Rc and Rd are each independently a member selected from the group consisting of hydrogen, alkenyloxycarbonyl, alkoxyalkyl, alkyl, alkylcarbonyl, alkylNHalkylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl,alkoxyalkoxycarbonyl, alkylsulfonyl, alkynyloxycarbonyl, aryl, arylalkyl, arylalkoxycarbonyl, aryloxyalkyl, aryloxyalkylcarbonyl, cycloalkyl, cycloalkoxycarbonyl, cycloalkylalkyl, cycloalkylalkoxycarbonyl, heterocycle, heterocyclecarbonyl, heterocyclealkyl, heterocyclealkoxylcarbonyl, hydroxyalkoxycarbonyl, haloalkoxycarbonyl, nitroalkoxycarbonyl, ReRfNcarbonyl, ReRfNcarbonylalkyl, ReRfNalkyl, ReRfNalkoxycarbonyl;
- Re and Rf are each independently a member selected from the group consisting of hydrogen, alkyl.
7 more elements
A compound according to formula (IIc),
- or a therapeutically suitable salt or prodrug thereof, wherein
- R1 is selected from the group consisting of hydrogen, alkyl, aryl, arylalkyl, heterocycle, and heterocyclealkyl;
- R3, R4, R5, and R6 are each independently a member selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, alkyl, alkenyl, alkenylalkoxy, aryl, cyano, halo, haloalkyl, heterocycle, hydroxy, hydroxyalkyl, nitro, sulfonyl, RaRbN—, RaRbNalkyl, RaRbNcarboxyalkyl;
- R7 is a member selected from the group consisting of alkoxycarbonyl, RcRdNcarboxy and RcRdNsulfonyl;
- R14 is alkyl;
- R8, R9, R10, R11, are each independently a member selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, alkyl, alkenyl, alkenylalkoxy, aryl, cyano, halo, haloalkyl, heterocycle, hydroxy, hydroxyalkyl, RaRbN—, RaRbNalkyl, RaRbNcarboxyalkyl;
- R12 and R13 are each independently a member selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, alkyl, alkenyl, alkenylalkoxy, aryl halo, haloalkyl, heterocycle, hydroxy, hydroxyalkyl, RaRbN—, RaRbNalkyl, RaRbNcarboxyalkyl;
- Ra and Rb are each independently a member selected from the group consisting of hydrogen, alkenyloxycarbonyl,alkoxyalkyl, alkyl, alkylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkylalkoxyalkoxycarbonyl, alkylsulfonyl, alkynyloxycarbonyl, aryl, arylalkyl, arylalkoxycarbonyl, aryloxyalkyl, aryloxyalkylcarbonyl, cycloalkyl, cycloalkoxycarbonyl, cycloalkylalkyl, cycloalkylalkoxycarbonyl, heterocycle, heterocyclecarbonyl, heterocyclealkyl, heterocyclealkoxylcarbonyl, hydroxyalkoxycarbonyl, haloalkoxycarbonyl, RcRdNcarbonyl, RcRdNcarbonylalkyl, RcRdNalkyl, RcRdNalkoxycarbonyl;
- Rc and Rd are each independently a member selected from the group consisting of hydrogen, alkenyloxycarbonyl, alkoxyalkyl, alkyl, alkylcarbonyl, alkylNHalkylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl,alkoxyalkoxycarbonyl, alkylsulfonyl, alkynyloxycarbonyl, aryl, arylalkyl, arylalkoxycarbonyl, aryloxyalkyl, aryloxyalkylcarbonyl, cycloalkyl, cycloalkoxycarbonyl, cycloalkylalkyl, cycloalkylalkoxycarbonyl, heterocycle, heterocyclecarbonyl, heterocyclealkyl, heterocyclealkoxylcarbonyl, hydroxyalkoxycarbonyl, haloalkoxycarbonyl, nitroalkoxycarbonyl, ReRfNcarbonyl, ReRfNcarbonylalkyl, ReRfNalkyl, ReRfNalkoxycarbonyl;
- Re and Rf are each independently a member selected from the group consisting of hydrogen, alkyl.
7 more elements
Dependencies are inferred from the claim text.