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US 2010/0323999 A1Published application
Therapeutic Molecules and Methods-1
OwnerEric Francis Morand, Magdy Naguib Iskander +1inventors
InventorsEric Francis Morand, Magdy Naguib Iskander, Basil Danylec
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Abstract
Methods of inhibiting the cytokine or biological activity of Macrophage Migration Inhibitory Factor (MIF) comprising contacting MIF with a compound of formula (I) as defined herein, is provided. The invention also relates to methods of treating diseases or conditions where MIF cytokine or biological activity is implicated comprising administration of compounds of formula (I), either alone or as part of a combination therapy. Novel heterocyclic compounds are also provided for.
Claims38
A method of inhibiting cytokine or biological activity of MIF comprising contacting MIF with a cytokine or biological activity inhibiting effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof
- wherein
- X is selected from —O—, —S—, —C(R5)(R5′)— or —N(R6)—;
- Y is selected from —N(R7)—, —O—, —S— or —C(R7)2—;
- Z is selected from —C(O)—, —C(S)—, —C(═NR6)—, —S(O)— or —S(O)2—;
- R1 is selected from hydrogen, C1-3alkyl, (CR5R5′)nOR7, (CR5R5′)nSR7, (CR5R5′)nN(R6)2 and (CR5R5′)nhalo;
- R2 is selected from C1-C20alkyl, C2-C20alkenyl, C2-C20alkynyl, (CR12R12′)mC(O)R9, (CR12R12′)mC(S)R8, (CR12R12′)mS(O)R8, (CR12R12′)mS(O)2R8, (CR12R12′)mOR9, (CR12R12′)mSR9, (CR12R12′)mNR10R11, (CR12R12′)mC(═NR24)R22 and (CR12R12′)mR13;
- R3 is selected from hydrogen, C1-C6alkyl, (CR16R16′)pNR14R15, (CR16R16′)pOR17, (CR16R16′)pSR17, (CR16R16′)phalo, (CR16R16′)pNO2, (CR16R16′)nC(O)R28, (CR16R16′)nC(═NR24)R22, (CR16R16′)S(O)R17, (CR16R16′)nS(O)2R17, (CR16R16′)nS(O)3R17 and (CR16R16′)pC(R18)3;
- R4 is selected from hydrogen, halogen C1-C3alkyl, C2-3alkenyl, C2-3alkynyl and (CR12R12′)nC(R8)3;
- Each R5 and R5′ is independently selected from hydrogen, C1-C3alkyl, halo, OR7, SR7 and N(R6)2;
- Each R6 is independently selected from hydrogen, C1-C3alkyl and OR7;
- Each R7 is independently selected from hydrogen and C1-C3alkyl;
- R8 is selected from hydrogen, C1-C20alkyl, C2-C20alkenyl, C2-C20alkynyl, OR19, SR19, N(R20)2, [NH—CH(R21)—C(O)]q—OR29, [sugar]q and (CR12R12′)tR13;
- R9 is selected from hydrogen, C1-C20alkyl, C2-C20alkenyl, C2-C20alkynyl, (CR12R12′)tR13, C(O)R23, CO2R23, C(S)R23, C(S)OR23, S(O)R23, S(O)2R23, [C(O)CH(R21)NH]q—R23 and [sugar]q;
- R10 and R11 are independently selected from hydrogen, C1-C20alkyl, C2-C20alkenyl, C2-C20alkynyl, (CR12R12′)mR13, C(O)R23, C(S)R23, S(O)R23, S(O)2R23, [C(O)CH(R21)NH]q—R23, -[sugar]q and NHC(═NR25)—NH2;
- Each R12 and R12′ is independently selected from hydrogen, C1-C6alkyl, C2-C6 alkenyl, C2-C6alkynyl, OR24, SR24, halo, N(R24)2, CO2R24, CN, NO2, aryl or heterocyclyl;
- R13 is selected from OR25, SR25, halo, N(R25)2, C(O)R31, CN, C(R8)3, aryl or heterocyclyl;
- R14 and R15 are independently selected from hydrogen, C1-C3alkyl, OR17, (CR16R16′)pC(R18)3;
- Each R16 and R16′ is independently selected from hydrogen, C1-C3alkyl, halo, OR17, SR17 and N(R17)2;
- Each R17 is independently selected from hydrogen and C1-C3alkyl;
- Each R18 is independently selected from hydrogen and halo;
- R19 and each R20 are independently selected from hydrogen, C1-C20alkyl, C2-C20alkenyl, C2-C20alkynyl, (CR26R26′)tR27;
- R21 is the characterising group of an amino acid;
- R22 is selected from C1-C6alkyl, NH2, NH(C1-6alkyl), N(C1-6alkyl)2, OR29 or SR29;
- R23 is selected from hydrogen, C1-C20alkyl, C2-C20alkenyl, C2-C20alkynyl, aryl (CR26R26′)tR27;
- Each R24 is independently selected from hydrogen and C1-C6alkyl;
- Each R25 is independently selected from hydrogen, C1-C6alkyl, C1-3alkoxyC1-3alkyl, aryl and heterocyclyl;
- Each R26 and R26′ is independently selected from hydrogen, C1-C6 allyl, C2-C6alkenyl, C2-C6alkynyl, OR29, SR29, halo, N(R29)2, CO2R29, CN, NO2, aryl and heterocyclyl;
- R27 is selected from hydrogen, OR30, SR30, halo, N(R30)2, CO2R30, aryl and heterocyclyl;
- R28 is selected from hydrogen, C1-6alkyl, OR29, SR29 or N(R29)2;
- Each R29 is independently selected from hydrogen and C1-C3alkyl;
- Each R30 is independently selected from hydrogen, C1-C3alkyl, aryl and heterocyclyl;
- R31 is selected from C1-3alkyl, OH, C1-3alkoxy, aryl, aryloxy, heterocyclyl and heterocyclyloxy;
- n is 0 or an integer from 1 to 3;
- m is 0 or an integer from 1 to 20;
- p is 0 or an integer from 1 to 6;
- q is an integer from 1 to 5;
- t is an integer from 1 to 10;
- wherein alkyl, alkenyl, alkynyl, aryl and heterocyclyl may be optionally substituted.
35 more elements
A compound of formula (III) or a pharmaceutically acceptable salt or prodrug thereof:
- wherein
- X is —O—, —NH— or —CH2—;
- Y is —NH—, —O—, —S— or —CH2—;
- Z is —C(O)—, —C(S)— or —S(O)—;
- R101 is selected from hydrogen, C1-3alkyl, OH, SH, NH2, NHC1-3alkyl, F, Cl or Br;
- R102 is selected from C1-20alkyl, C2-20alkenyl, CO2H, F, Cl, Br, CO2R105, (CH2)wR106, C(O)N(R107)2, C(═N)NHC1-6alkyl, SO2C1-6alkyl, C(O)[NHCH(R108)C(O)]q—OR109, NH2, C(O)sugar, CONH(CH2)naryl, NHC(O)(CH2)nSheterocyclyl, C(O)SC1-6alkyl, C(O)(CH2)nCO2H, SO2OC1-10alkyl and SO2NHC1-10alkyl;
- R103 is selected from hydrogen, F, Cl, Br, C1-6alkyl, —(CH2)nNH2, —(CH2)nNO2, —(CH2)—OH, —(CH2)n—CF3, —(CH2)nC(O)C1-3alkyl or —(CH2)n—SH;
- R104 is selected from hydrogen, methyl, ethyl, CH2C(R110)3, C(R110)3, —CH2═CH2, fluoro, chloro or bromo;
- R105 is selected from hydrogen, C1-20alkyl, C2-20alkenyl or (CH2)tOC1-3alkyl;
- R106 is selected from SH, SC1-6alkyl, OH, OC1 ialkyl, sugar, CO2H, NH2, heterocyclyl or aryl;
- Each R107 is independently selected from hydrogen, C1-20alkyl, C2-20alkenyl, (CH2)taryl and (CH2)theterocyclyl;
- R108 is the characterising group of an amino acid;
- R109 is hydrogen, C1-3alkyl;
- Each R110 is independently selected from hydrogen and halo;
- and
- n is 0 or an integer from 1 to 3, q is an integer from 1 to 5, w is an integer from 1 to 6;
- t is an integer from 1 to 10;
- wherein each alkyl, alkenyl, alkynyl, aryl and heterocyclyl may be optionally substituted.
15 more elements
A compound of formula (IV) or a pharmaceutically acceptable salt or prodrug thereof:
- wherein
- R101 is selected from hydrogen, CH3, OH, SH, NH2, NHCH3, F, Cl or Br;
- R102 is selected from C1-20alkyl, C2-20alkenyl, CO2H, F, Cl, Br, CO2R105, (CH2)wR106, C(O)N(R107)2, C(═N)NHC1-6alkyl, SO2C1-6alkyl, C(O)[NHCH(R108)C(O)]q—OR109, NH2, C(O)sugar, CONH(CH2)naryl, NHC(O)(CH2)nSheterocyclyl, C(O)SC1-6alkyl, C(O)(CH2)nCO2H, SO2OC1-10alkyl and SO2NHC1-10alkyl.
- R103 is selected from hydrogen, F, Cl, Br, C1-6alkyl, (CH2)nNH2, —(CH2)nNO2, —(CH2)n—OH, —(CH2)n—CF3, CH2C(O)CH3 or —(CH2)n—SH;
- R104 is selected from hydrogen, methyl, ethyl, CH2CF3, —CH2═CH2 fluoro, chloro or bromo;
- R105 is selected from hydrogen, C1-10alkyl, C2-10alkenyl, (CH2)tOC1-3alkyl;
- R106 is selected from SH, SC1-6alkyl, OH, OC1-6alkyl, sugar, CO2H, NH2, heterocyclyl or aryl;
- Each R107 is independently selected from hydrogen, C1-10alkyl, C2-10alkenyl, (CH2)taryl and (CH2)theterocyclyl;
- R108 is the characterising group of an amino acid;
- R109 is hydrogen, C1-3alkyl;
- Each R110 is independently selected from hydrogen and halo;
- and
- n is 0 or an integer from 1 to 3, q is an integer from 1 to 5, w is an integer from 1 to 6, t is an integer from 1 to 10;
- wherein each alkyl, alkenyl, alkynyl, aryl and heterocyclyl may be optionally substituted.
11 more elements
A compound of formula (I) selected from the group consisting of:
- benzimidazole-2-one-5-n-pentanoate,
- 5-[2-(1-oxy-2-hydroxyethyl)ethyl]benzimidazol-2-one-5-carboxylate,
- benzimidazole-2-one-5-methanoate,
- benzimidazole-2-one-5-ethanoate,
- 3,4,5-tris(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-2-yl-benzimidazole-2-one-5-carboxylate,
- 5-bromo-6-methylbenzimidazol-2-one,
- 5-hydroxy-6-methylbenzimidazol-2-one,
- 5-dodecanylbenzoimidazol-2-one,
- 4,5,7-tribromo-6-methylbenzimidazol-2-one,
- 4,5,6,7-tetrabromobenzimidazol-2-one,
- 5-methyl-6-nitrobenzimidazol-2-one,
- 5-amino-6-methylbenzimidazol-2-one,
- N-(6-methylbenzimidazol-5-yl)-2-pyrimnidin-2-yl-sulfanyl-axetamide,
- pentyl-benzimidazol-2-one-5-carbothioate,
- 5-(benzimidazol-2(3H)-one-6-yl)-5-oxopentanoic acid,
- 2(3H)-benzimidazolone-5-sulfonic acid pentyl ester,
- 2(3H)-benzimidazolone-5-sulfonic acid pentyl amide,
- N-butyl-2-oxo-2,3-dihydro-1H-1,3-benzimidazole-5-carboximidamide,
- 5-heptanoylbenzofuran-2(3H)-one,
- methyl 3-hydroxy-2-{[(2-oxo-2,3-dihydro-1H-1,3-benzimiidazol-5-yl)carbonyl]amino}propanoate,
- 3-hydroxy-2-{[(2-oxo-2,3-dihydro-1H-1,3-benzimidazol-5-yl)carbonyl]amino}propanoic acid,
- methyl 2-{[(2-oxo-2,3-dihydro-1H-1,3-benzimidazol-5-yl)carbonyl]amino}-3-phenyl propanoate,
- 2-{[(2-oxo-2,3-dihydro-1H-1,3-benzimidazol-5-yl)carbonyl]amino}-3-phenyl propanoic acid, and
- N-(3,4-dihydroxyphenethyl)-2-oxo-2,3-dihydro-1H-1,3-benzimidazole-5-carboxamide.
21 more elements
Dependencies are inferred from the claim text.