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US 12,643,907 B2Granted
Opioid receptor antagonists
AssigneeUniversity of Southern California
InventorsVsevolod Katritch, Valery V. Fokin, Saheem Zaidi, Joice Thomas
Life of this patent
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Abstract
The first selective SuFEx antagonists to μ-opioid receptors (MOR) were developed by functionalizing an opioid scaffold with an SO2—F warhead. Our model, based on a MOR structure with antagonist β-FNA, indicates the naloxone carbonyl as an advantageous point for derivatization as it is chemically accessible and is not involved in interaction with receptors. Of the three accessible Tyr residues in MOR pocket, Tyr77, Tyr130 and Tyr150, Tyr150 in proximity to the carbonyl of the docked naloxone was selected as a target, which resulted in the development of highly potent antagonists.
Claims18
A compound of Formula I:
- wherein
- G is CHNRbRc, CHRx, CHORa, or C═O;
- Rx is H or —(C1-C8)alkyl;
- Ra is H, —(C1-C8)alkyl, or —(C3-C8)cycloalkyl;
- Rb and Rc are each independently —(C1-C8)alkyl, H, —(C3-C8)cycloalkyl, —C(═O)Rd, or —S(═O)2Re;
- or Rb and Rc taken together are —CH2—CH2—SO2—;
- Rd and Re are each independently —(C1-C8)alkyl, —(C3-C8)cycloalkyl, or phenyl, wherein —(C1-C8)alkyl, —(C3-C8)cycloalkyl, or phenyl is substituted with —OS(═O)2F, —S(═O)2F, or unsaturated or saturated —(C1-C8)alkyl-S(═O)2F;
- J is ORa, H, or NRbRc, or J is a two-carbon alkyl bridge connected to the carbon atom of G and G is CHNRbRc, CHRx, or CHORa;
- R1 is —(C1-C8)alkyl, H, —(C1-C8)alkyl(C3-C8)cycloalkyl, —C(═O)Rd, or —S(═O)2Re;
- R2 is H, OH, ORf, —(C0-C5)C(═O)Rf, —(C0-C5)C(═O)ORf, —(C0-C5)OC(═O)ORf;
- Rf is —(C1-C8)alkyl wherein —(C1-C8)alkyl is optionally substituted with amine;
- R3 and R4 taken together form a single bond;
- or
- R3 is H, —(C1-C8)alkyl, or —(C3-C8)cycloalkyl;
- and R4 is H;
- wherein —(C1-C8)alkyl is unsaturated or saturated and unbranched or branched, and at least of one of J or G comprises —S(═O)2F.
13 more elements
A compound of Formula IIA:
- wherein
- R1 is —(C1-C3)alkyl-CZ═CZ2 wherein Z is H, Me, or CF3, —CH(Me)-CH═CH2, —(C1-C3)alkyl-cyclopropyl, —CH(Me)-cyclopropyl, propargyl, arylsulfonamide-substituted triazole, or —CH2-cyclopropyl wherein the cyclopropyl is substituted with hydroxymethyl and RF wherein RF is H, Me, F, or CF3;
- R2 is OR10 wherein R10 is H, —C(═O)R11, —C(═O)OR11, —CH2O—C(═O)R11, —CH(Me)-O—C(═O)R11, —CH2O—C(═O)OR11, or —CH(Me)-O—C(═O)OR11, and R11 is unbranched or branched —(C1-C8)alkyl, —CH2NH2, —CH2NMe2, or —CH2—N-morpholinyl;
- Rb is H, Me, —CH2CF3, —OH, —(C3-C8)cycloalkyl, or propargyl;
- and
- Rc is —S(═O)2F, —(C1-C8)alkyl-S(═O)2F wherein the alkyl is optionally further substituted with bromo or chloro, —CH═CH—S(═O)2F, phenyl substituted with —S(═O)2F, tetrahydropyran substituted with —S(═O)2F, or —(C3-C8)cycloalkyl substituted with —S(═O)2F and optionally further substituted by two fluorine atoms on a ring carbon;
- or Rb and Rc taken together are —CH2—CH2—SO2—.
4 more elements
A compound of Formula IIB:
- wherein
- R1 is allyl or —CH2-cyclopropyl;
- J is OH or OMe;
- Rb is Me, —CH2CF3, —OH, —(C3-C8)cycloalkyl, or propargyl;
- and
- Rc is —S(═O)2F, —(C1-C8)alkyl-S(═O)2F wherein the alkyl is optionally further substituted with bromo or chloro, —CH═CH—S(═O)2F, phenyl substituted with —S(═O)2F, tetrahydropyran substituted with —S(═O)2F, or —(C3-C8)cycloalkyl substituted with —S(═O)2F and optionally further substituted by two fluorine atoms on a ring carbon;
- or Rb and Rc taken together are —CH2—CH2—SO2—.
4 more elements
A compound of Formula IIC:
- wherein
- R1 —(C1-C3)alkyl-CZ═CZ2 wherein Z is H, Me, or CF3, —CH(Me)-CH═CH2, —(C1-C3)alkyl-cyclopropyl, —CH(Me)-cyclopropyl, propargyl, arylsulfonamide-substituted triazole, —CH2-cyclopropyl wherein the cyclopropyl is substituted with hydroxymethyl and RF wherein RF is H, Me, F, or CF3, —(C1-C8)alkyl-S(═O)2F, phenyl substituted with —S(═O)2F, phenyl substituted with —OS(═O)2F, —CH═CH-Ph substituted with —S(═O)2F, —CH═CH-Ph substituted with —OS(═O)2F, or phenyl substituted with —CH═CH—S(═O)2F;
- R2 is OR10 wherein R10 is H, —C(═O)R11, —C(═O)OR11, —CH2O—C(═O)R11, —CH(Me)-O—C(═O)R11, —CH2O—C(═O)OR11, or —CH(Me)-O—C(═O)OR11, and R11 is unbranched or branched —(C1-C8)alkyl, —CH2NH2, —CH2NMe2, or —CH2—N-morpholinyl;
- Rb is Me;
- and
- Rc is —(C1-C8)alkyl-S(═O)2F.
3 more elements
A compound of Formula IIIA:
- wherein
- R1 is allyl or —CH2-cyclopropyl;
- Rb is H;
- Rc is —C(═O)—R12 or —S(═O)2—R13;
- R12 is —(C1-C3)alkyl-CZ═CZ2 wherein Z is H, Me, or CF3, —CH(Me)-CH═CH2, —(C1-C3)alkyl-cyclopropyl, —CH(Me)-cyclopropyl, propargyl, arylsulfonamide-substituted triazole, —CH2-cyclopropyl wherein the cyclopropyl is substituted with hydroxymethyl and RF wherein RF is H, Me, F, or CF3, —(C1-C8)alkyl-S(═O)2F, phenyl substituted with —S(═O)2F, phenyl substituted with —OS(═O)2F, —CH═CH-Ph substituted with —S(═O)2F, —CH═CH-Ph substituted with —OS(═O)2F, or phenyl substituted with —CH═CH—S(═O)2F;
- R13 is —(C1-C8)alkyl-S(═O)2F, phenyl substituted with —S(═O)2F, phenyl substituted with —OS(═O)2F, —CH═CH-Ph substituted with —S(═O)2F, —CH═CH-Ph substituted with —OS(═O)2F, or phenyl substituted with —CH═CH—S(═O)2F;
- R20 is H or —(C1-C8)alkyl;
- and R21 is H or —C(═O)NH2.
5 more elements
Dependencies are inferred from the claim text.