Metallo-oxidoreductase inhibitors using metal binding moieties in combination with targeting moieties
AssigneeViamet Pharmaceuticals, Inc.
InventorsRobert J. Schotzinger, William J. Hoekstra
Life of this patent
Estimating the term…
Abstract
The presently disclosed subject matter is directed to metallo-oxidoreductase inhibitors having metal binding moities linked to a targeting moiety through a linking group or a direct bond, methods for screening for metallo-oxidoreductase inhibitors, and methods of treating an oxidoreductase related disorder by administering a metallo-oxidoreductase inhibitor to a subject in need of treatment thereof.
Claims58
A metallo-oxidoreductase inhibitor, wherein the metallo-oxidoreductase inhibitor is a lanosterol demethylase inhibitor comprising a targeting moiety, a metal binding moiety, and optionally a linker, and wherein the inhibitor has a formula selected from the group consisting of:
- wherein:
- hal1 and hal2 are each independently halogen;
- X1 is CH or N;
- A1 is selected from the group consisting of H, alkyl, branched alkyl, —C(═O)—CH3, or a moiety having a structure selected from the group consisting of:
- wherein:
- R1 is H or alkyl;
- R2 is alkyl or —CR3R4,
- wherein R3 is H or alkyl;
- and R4 is selected from the group consisting of H, alkyl, —OH and —O—C(═O)—R5;
- wherein R5 is selected from the group consisting of —CH2NH2;
- —CH(CH2-phenyl)-NH2;
- —CH2N(CH2CH3)2;
- —CH(CH2(CH3)2)—NH2;
- —CH(CH2CH(CH3)2)—NH2;
- wherein:
- m is an integer from 1 to 5;
- p is an integer from 1 to 4;
- R6 is H or alkyl;
- R7 is selected from the group consisting of H, alkyl, halogen, —CN, —OCF3;
- —S—CF3;
- —CF3;
- —S(═O)—CF3;
- —CF3;
- —C(═O)—NH2;
- and combinations thereof;
- wherein:
- p is an integer from 0 to 2;
- A2 is H or halogen;
- R8 is H or alkyl;
- and
- R9 is selected from the group consisting of H, alkyl, —O—CF3;
- and —CF3;
- R10 is selected from the group consisting of:
- halogen, 4-fluorophenyl-piperazinyl, 3,4-methylenedioxy, 3-methoxypropylamino, 4-benzyloxycarbonylamino, 4-NO2-phenyl-piperazinyl, and 4-methoxyimino;
- X2 is O or S;
- a dashed line indicates that a bond is present or absent;
- and
- Ar is selected from the group consisting of -phenyl-S-phenyl;
- halo- or dihalophenyl;
- halothienyl;
- halophenoxymethyl;
- and halo-3-benzothienyl;
- wherein:
- R11 is H or P(═O)O2;
- R12 is selected from the group consisting of H and alkyl;
- R13 is a nitrogen-containing heterocyclic ring or a nitrogen-containing fused heterocyclic ring selected from the group consisting of:
- wherein:
- R13 is H or alkyl;
- X3 is —S—(CH2)q— or —NR16—C(═O)—, wherein q is an integer from 1 to 8 and R16 is H or alkyl;
- R15 is selected from the group consisting of:
- wherein:
- t is an integer from 1 to 2;
- and
- R17 is H or halogen:
- and
- each R18 is halogen;
- wherein:
- u is an integer from 1 to 3;
- R19 is H or P(═O)(OH)2;
- and
- R20 is H or alkyl;
- wherein:
- t is an integer from 1 to 2;
- each R21 is halogen;
- wherein:
- t is an integer from 1 to 2;
- each R22 is independently halogen;
- and
- R23 is selected from the group consisting of:
- wherein:
- MBM is a metal binding moiety;
- Ln is a linker, wherein n is an integer from 0 to 1;
- under the proviso that the metal binding moiety is not a metal binding moiety selected from the group consisting of:
- wherein:
- R is an attachment site through which the metal binding moiety can be attached to the targeting moiety, optionally through linker, Ln;
- and
- hal, hal1, hal2, hal3, and hal4 are each independently halogen;
- and pharmaceutically acceptable salts thereof.
A metallo-oxidoreductase inhibitor, wherein the metallo-oxidoreductase inhibitor is a 5-lipoxygenase inhibitor comprising a targeting moiety, a metal binding moiety, and optionally a linker, and wherein the inhibitor has a formula selected from the group consisting of:
- wherein R24 and R25 are each independently selected from the group consisting of —OH and Ln-MBM, wherein Ln is a linking group, n is an integer from 0 to 1, and MBM is a metal binding moiety, provided that at least one of R25 and R25 is Ln-MBM;
- wherein:
- MBM is a metal binding moiety;
- Ln is a linker, wherein n is an integer from 0 to 1;
- under the proviso that the metal binding moiety is not a metal binding moiety selected from the group consisting of:
- wherein:
- R is an attachment site through which the metal binding moiety can be attached to the targeting moiety, optionally through linker, Ln.
(canceled)
A metallo-oxidoreductase inhibitor, wherein the metallo-oxidoreductase inhibitor is an aromatase inhibitor comprising a targeting moiety, a metal binding moiety, and optionally a linker, and wherein the inhibitor has a formula selected from the group consisting of:
- wherein:
- R26 and R27 are each independently selected from the group consisting of —OH, ═O, and Ln-MBM, and combinations thereof, wherein Ln is a linking group, wherein n is an integer from 0 to 1, and MBM is a metal binding moiety, provided that at least one of R26 and R27 is Ln-MBM;
- R28 is H or ═O;
- and
- a dashed line indicates that a bond is present or absent;
- wherein:
- R29 is alkyl;
- and
- X4 is CH or N;
- wherein:
- MBM is a metal binding moiety;
- Ln is a linker, wherein n is an integer from 0 to 1;
- under the proviso that the metal binding moiety is not a metal binding moiety selected from the group consisting of:
- wherein:
- R is an attachment site through which the metal binding moiety can be attached to the targeting moiety, optionally through linker, Ln.
(canceled)
A metallo-oxidoreductase inhibitor, wherein the metallo-oxidoreductase inhibitor is a cyclooxygenase inhibitor comprising a targeting moiety, a metal binding moiety, and optionally a linker, and wherein the inhibitor has a formula selected from the group consisting of:
- wherein:
- R30 is alkyl;
- X5 is CH or N;
- and
- A3 is selected from the group consisting of:
- wherein:
- R31 and R32 are H or —CH2-Ln-MBM, provided at least one of R31 and R32 is —CH2l -Ln-MBM;
- wherein R33 and R34 are selected from the group consisting of hal, —CH2-Ln-MBM, and
- provided at least one of R33 and R34 is —CH2-Ln-MBM;
- wherein R35 and R36 are selected from the group consisting of H, —CH2-(phenyl)m-Ln-MBM, wherein m and n are integers from 0 to 1;
- and provided at least one of R36 and R36 is —CH2-(phenyl)m-Ln-MBM;
- wherein:
- R37 is alkyl;
- and
- R38 is —(CH2)y—CH—(R39)—CH2—(O—CH2—C(═O))z-Ln-MBM;
- wherein:
- n, y, and z are each independently an integer from 0 to 1;
- R39 is straight-chain or branched alkyl;
- and
- wherein:
- R40 is H or —CH2-Ln-MBM;
- R41 is CH3 or —CH2-Ln-MBM, provided that at least one of R40 and R41 is —CH2-Ln-MBM;
- wherein:
- MBM is a metal binding moiety;
- Ln is a linker, wherein n is an integer from 0 to 1;
- under the proviso that the metal binding moiety is not a metal binding moiety selected from the group consisting of:
- wherein:
- R is an attachment site through which the metal binding moiety can be attached to the targeting moiety, optionally through linker, Ln.
(canceled)
A metallo-oxidoreductase inhibitor, wherein the metallo-oxidoreductase inhibitor is a heme oxygenase inhibitor comprising a targeting moiety, a metal binding moiety, and optionally a linker, and wherein the inhibitor has a formula selected from the group consisting of:
- wherein:
- R42 is H or —NH2;
- and
- R43 is H or halogen;
- and
- wherein:
- MBM is a metal binding moiety;
- Ln is a linker, wherein n is an integer from 0 to 1;
- under the proviso that the metal binding moiety is not a metal binding moiety selected from the group consisting of:
- wherein:
- R is an attachment site through which the metal binding moiety can be attached to the targeting moiety, optionally through linker, Ln.
(canceled)
A metallo-oxidoreductase inhibitor, wherein the metallo-oxidoreductase inhibitor is a xanthine oxidase inhibitor comprising a targeting moiety, a metal binding moiety, and optionally a linker, and wherein the inhibitor has a formula selected from the group consisting of:
- wherein at least one of R45 and R46 is -Ln-MBM;
- wherein R46 is H or alkyl;
- and
- wherein at least one of R47, R48, and R49 is -Ln-MBM;
- wherein:
- MBM is a metal binding moiety;
- Ln is a linker, wherein n is an integer from 0 to 1;
- under the proviso that the metal binding moiety is not a metal binding moiety selected from the group consisting of:
- wherein:
- R is an attachment site through which the metal binding moiety can be attached to the targeting moiety, optionally through linker, Ln.
(canceled)
A metallo-oxidoreductase inhibitor, wherein the metallo-oxidoreductase inhibitor is a 17a-hydroxylase inhibitor comprising a targeting moiety, a metal binding moiety, and optionally a linker, and wherein the inhibitor has a formula selected from the group consisting of:
- wherein:
- R50 is selected from the group consisting of (═O) and —OR51, wherein R51 is alkyl;
- wherein:
- R52 and each R53 are independently H and alkyl;
- R54 is H or OH;
- wherein:
- MBM can be fused to cyclic hydrocarbon;
- R55=H, halogen, alkyl, CONHR57, wherein R57 is alkyl;
- and
- R56 is H or OH;
- wherein:
- MBM can be fused to cyclic hydrocarbon;
- R58=H, halogen, alkyl, CONHR60, wherein R60 is alkyl;
- and
- R59 is H or OH;
- wherein:
- R61 and R62 are each independently -Ln-MBM or unsubstituted phenyl or phenyl substituted with halogen, alkyl, or alkoxyl;
- wherein R63 and R64 are each independently selected from the group consisting of H, halogen, alkyl, and alkoxy;
- wherein R65 is H or halogen;
- wherein:
- R66 is H or alkyl;
- and
- R67 is H or OH;
- wherein:
- R68 is H or halogen;
- R69 and R70 are H or alkyl;
- wherein:
- MBM is a metal binding moiety;
- Ln is a linker, wherein n is an integer from 0 to 1;
- under the proviso that the metal binding moiety is not a metal binding moiety selected from the group consisting of:
- wherein:
- R is an attachment site through which the metal binding moiety can be attached to the targeting moiety, optionally through linker, Ln.
(canceled)
A metallo-oxidoreductase inhibitor, wherein the metallo-oxidoreductase inhibitor is an aldosterone synthase inhibitor comprising a targeting moiety, a metal binding moiety, and optionally a linker, and wherein the inhibitor has a formula selected from the group consisting of:
- wherein:
- n1 is an integer from 0 to 2;
- t is an integer from 0 to 2;
- R71 is selected from the group consisting of H, cyano, halogen, alkyl, and aryl;
- R72 is selected from the group consisting of H, cyano, halogen, alkyl, and aryl;
- R73 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, alkoxy, and CF3;
- wherein:
- R74 is selected from the group consisting of cyano, halogen, and alkyl;
- and a dashed line indicates that a bond can be present or absent;
- wherein:
- R75 and R76 are each independently H or alkyl;
- and
- R77 is selected from the group consisting of H, cyano, halogen, and alkyl.
- wherein:
- n1 is an integer from 0 to 1;
- X6 is O or NR, wherein R is selected from the group consisting of H, alkyl, acyl, and aryl;
- Z1 is selected from the group consisting of O, NR, and —CH2—;
- and
- X7 is O or —CH2—;
- wherein:
- n1 is an integer from 0 to 1;
- R79 is selected from the group consisting of cyano, halogen, and alkyl;
- X8 is O or NR80, wherein R80 is selected from the group consisting of H, alkyl, acyl, and aryl;
- n1 is an integer from 0 to 1;
- R81 is selected from the group consisting of cyano, halogen, and alkyl;
- X9 is O or NR82, wherein R82 is selected from the group consisting of H, alkyl, acyl, and aryl;
- n1 is an integer from 0 to 1;
- X10 is O or NR83, wherein R83 is selected from the group consisting of H, alkyl, acyl, and aryl;
- and
- Z2 is selected from the group consisting of O, NR84, —CH2—, wherein R84 is selected from the group consisting of H, alkyl, acyl, and aryl;
- wherein:
- R85 and R86 are each independently H, halogen, cyano, alkyl, and alkoxyl;
- R87 is selected from the group consisting of OR88, NR89R90, wherein R88, R89, and R90 are each independently selected from the group consisting of H, alkyl, and aryl;
- wherein:
- R91 and R92 are each independently selected from the group consisting of H, halogen, cyano alkyl, alkoxyl, and aryl;
- and
- Z3 is O or —CH2—;
- wherein:
- X11 is selected from the group consisting of O, S, and NH;
- and
- R93 is selected from the group consisting of H, cyano, halogen, alkyl, and aryl;
- wherein:
- R94 and R95 are each independently H or alkyl;
- R96 is selected from the group consisting of H, cyano, halogen, alkyl;
- or R96 is part of a fused aromatic ring structure;
- and
- wherein:
- X12 is O or S;
- and
- R97 is alkyl;
- wherein:
- MBM is a metal binding moiety;
- Ln is a linker, wherein n is an integer from 0 to 1;
- under the proviso that the metal binding moiety is not a metal binding moiety selected from the group consisting of:
- wherein:
- R is an attachment site through which the metal binding moiety can be attached to the targeting moiety, optionally through linker, Ln.
(canceled)
A metallo-oxidoreductase inhibitor, wherein the metallo-oxidoreductase inhibitor is a retinoic acid hydroxylase (CYP26) inhibitor comprising a targeting moiety, a metal binding moiety, and optionally a linker, and wherein the inhibitor has a formula selected from the group consisting of:
- wherein:
- R99=H or alkyl;
- and
- R100 and H101 are each selected from the group consisting of H, alkyl, and cycloalkyl;
- wherein:
- R102 is H or alkyl;
- and
- R103 and R104 are each independently H, alkyl, cycloalkyl;
- wherein R105 is H or alkyl;
- and
- wherein R106 is H or alkyl;
- and
- wherein:
- MBM is a metal binding moiety;
- Ln is a linker, wherein n is an integer from 0 to 1;
- under the proviso that the metal binding moiety is not a metal binding moiety selected from the group consisting of:
- wherein:
- R is an attachment site through which the metal binding moiety can be attached to the targeting moiety, optionally through linker, Ln.
(canceled)
A metallo-oxidoreductase inhibitor, wherein the metallo-oxidoreductase inhibitor is an alcohol dehydrogenase inhibitor comprising a targeting moiety, a metal binding moiety, and optionally a linker, and wherein the inhibitor has a formula selected from the group consisting of:
- wherein R107, R108, R109, and R110 are each independently H or alkyl;
- and
- wherein R111 is alkyl;
- wherein:
- MBM is a metal binding moiety;
- Ln is a linker, wherein n is an integer from 0 to 1;
- under the proviso that the metal binding moiety is not a metal binding moiety selected from the group consisting of:
- wherein:
- R is an attachment site through which the metal binding moiety can be attached to the targeting moiety, optionally through linker, Ln.
(canceled)
A metallo-oxidoreductase inhibitor, wherein the metallo-oxidoreductase inhibitor is a 1-deoxy-d-xylulose-5-phosphate reductoisomerase inhibitor comprising a targeting moiety, a metal binding moiety, and optionally a linker, and wherein the inhibitor has a formula selected from the group consisting of:
- wherein n1 is an integer from 1 to 2;
- and
- wherein n1 an integer from 1 to 2;
- wherein:
- MBM is a metal binding moiety;
- Ln is a linker, wherein n is an integer from 0 to 1;
- under the proviso that the metal binding moiety is not a metal binding moiety selected from the group consisting of:
- wherein:
- R is an attachment site through which the metal binding moiety can be attached to the targeting moiety, optionally through linker, Ln.
(canceled)
A metallo-oxidoreductase inhibitor, wherein the metallo-oxidoreductase inhibitor is an indoleamine 2,3-dioxygenase inhibitor comprising a targeting moiety, a metal binding moiety, and optionally a linker, and wherein the inhibitor has a formula selected from the group consisting of:
- wherein:
- R114 is selected from the group consisting of H, alkyl, CO-alkyl, and CO-aryl;
- R112 and R113 are each selected from the group consisting of H, alkyl, halogen, and alkoxy;
- and
- Ar is a substituted phenyl or heteroaryl;
- wherein R115 and R116 are each independently selected from the group consisting of H, alkyl, CO-alkyl, and CO-aryl;
- and
- wherein:
- MBM is a metal binding moiety;
- Ln is a linker, wherein n is an integer from 0 to 1;
- R117 and R118 are independently selected from the group consisting of H, alkyl, —C(═O)-alkyl, and —C(═O)-aryl;
- under the proviso that the metal binding moiety is not a metal binding moiety selected from the group consisting of:
- wherein:
- R is an attachment site through which the metal binding moiety can be attached to the targeting moiety, optionally through linker, Ln.
(canceled)
A metallo-oxidoreductase inhibitor, wherein the metallo-oxidoreductase inhibitor is a nitric oxide synthase inhibitor comprising a targeting moiety, a metal binding moiety, and optionally a linker, and wherein the inhibitor has a formula selected from the group consisting of:
- wherein:
- n1 is an integer from 0 to 1;
- R119 and R121 are each independently selected from the group consisting of H, acyl, and alkyl;
- and
- R120 and R122 are each independently H or alkyl;
- and
- wherein:
- R123 is selected from the group consisting of H, acyl, and alkyl;
- R124 is H or alkyl;
- and
- Z4 and Z5 are each independently O or null;
- wherein:
- MBM is a metal binding moiety;
- Ln is a linker, wherein n is an integer from 0 to 1;
- under the proviso that the metal binding moiety is not a metal binding moiety selected from the group consisting of:
- wherein:
- R is an attachment site through which the metal binding moiety can be attached to the targeting moiety, optionally through linker, Ln.
(canceled)
A metallo-oxidoreductase inhibitor, wherein the metallo-oxidoreductase inhibitor is a vascular adhesion protein-1 inhibitor comprising a targeting moiety, a metal binding moiety, and optionally a linker, and wherein the inhibitor has a formula selected from the group consisting of:
- wherein:
- R125 is selected from the group consisting of H, acyl, and alkyl;
- and
- R126 is selected from the group consisting of H, alkyl, and aminoalkyl;
- wherein:
- R127 is selected from the group consiting of H, halogen, and alkyl;
- R128 is selected from the group consisting of H, alkyl, acyl, and aralyl;
- wherein:
- R129 is H or halogen;
- X13 is N or CH;
- and
- Ar is substituted phenyl;
- wherein:
- n1 is an integer from 0 to 2;
- R130 is H or CONHR132;
- R131 is selected from the group consisting of H, CONHR133COalkyl, and CO2alkyl;
- and
- R132 and R133 are each independently selected from the group consisting of H, alkyl, and aralkyl;
- wherein:
- MBM is a metal binding moiety;
- Ln is a linker, wherein n is an integer from 0 to 1;
- under the proviso that the metal binding moiety is not a metal binding moiety selected from the group consisting of:
- wherein:
- R is an attachment site through which the metal binding moiety can be attached to the targeting moiety, optionally through linker, Ln.
(canceled)
53-73. (canceled)
Dependencies are inferred from the claim text.