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US 2019/0276481 A1Published application
Liver Prodrugs of Mitochondrial Proton Ionophores
OwnerMagnus Joakim Hansson, Eskil Elmer +2inventors
InventorsMagnus Joakim Hansson, Eskil Elmer, Matthew Alan Gregory, Steven James Moss
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Abstract
The present invention provides novel liver-targeted prodrugs of mitochondrial proton ionophores. These compounds have utility in medicine including their use in treatment of diseases such as NASH and NAFLD.
Claims17
1:
- A compound of Formula (I)
- wherein:
- X and X′ can independently be NH or O;
- Y is absent, —CR3R4O—, —C(═O)O—, or
- (X is phenyl substituent, Z connects to O);
- Y′ is absent, —CR3R4O—, —C(═O)O—, or
- (X′ is phenyl substituent, Z′ connects to O);
- Z is formula (II)
- Z′ is CHR2′ (C═O)OR1′, Me, Et, iPr, Ph or formula (II)
- R1 and R1′ are independently Me, Et, iPr, nPr, tBu, iBu, sBu or
- CH2CMe3
- R2 and R2′ are independently H, Me, Et, iPr, Ph, Bn
- R3 is H, Me, Et
- R4 is H, Me, Et
- wherein:
- R5 is H, NO2 or
- R6 is H, NO2, Cl, Br or I
- R7 is H, Me, Et, iPr, tBu, sBu, iBu, Cl, Br or I
- R8 is H, NO2, Cl, Br, C(CN)H(C6H4)-p-Cl
- R9 is H, Cl, OH or CH3
- R10 is H or Cl
- R5 and R6 cannot both be H;
- when R6 is Cl, R5 cannot be H or NO2;
- when Z′ is CHR2′ (C═O)OR1′, Me, Et, iPr then Y′ must be absent;
- when Z′ is CHR2′ (C═O)OR1′ then X′ must be NH;
- when Z′ is Me, Et or iPr then X′ must be O;
- when Z is Formula II and R6 is NO2 then Y cannot be absent
- when Z′ is Formula II and R6 is NO2 then Y′ cannot be absent
- when Z is formula II and R6 is NO2 and Z′ is CHR2′ (C═O) OR1′
- then R2 and R2′ cannot be H or Me;
- or a pharmaceutically acceptable salt thereof.
28 more elements
2:
- The A compound according to claim 1, wherein
- Z and/or Z′ are formula (II) and R5 is
3:
- The A compound according to claim 1, wherein Z and/or Z′ are formula (II) and R5 is
- and R6, R7, R8, R9 and R10 are all H.
4:
- The A compound according to claim 1, wherein
- Z and/or Z′ are formula (II);
- R5 is
- and R6 is Cl, R7 is H or tBu, R8 is Cl and R9 is NO2, and R10 is H.
1 more element
5:
- The A compound according to claim 1, wherein Z′ is CHR2′ (C═O) OR1′ and Z is formula (II)
- and R5 is
6:
- The A compound according to claim 1, wherein Z′ is CHR2′ (C═O)OR1′
- R1 and R1′ are iPr
- R2 and R2′ are Me or Bn
- Z is formula (II)
- R5 is
- and R6, R7, R8, R9 and R10 are all H.
3 more elements
7:
- The compound according to claim 1, wherein Z′ is CHR2′ (C═O) OR1′
- R1 and R1′ are iPr
- R2 and R2′ are Me or Bn
- Z is formula (II)
- R5 is
- and R6 is Cl, R7 is H or tBu, R8 is Cl and R9 is NO2, and R10 is H.
3 more elements
8:
- The compound according to claim 1 having one of the following formulas:
9:
- The compound according to claim 1, wherein the compound is selected from:
10:
- The compound according to claim 1 selected from
(canceled)
(canceled)
13:
- A method of preventing or treating a disorder or disease where liver targeted mitochondrial uncoupling is useful, the method comprising administering to the subject an effective amount of a compound according to claim 1.
14:
- A method of preventing or treating a disorder or disease where liver targeted mitochondrial uncoupling is useful, the method comprising administering to the subject an effective amount of salicylanilide.
15:
- A pharmaceutical composition comprising a compound according to claim 1 together with one pharmaceutically acceptable excipients.
16:
- A method of treating a subject suffering from non-alcoholic steatohepatitis (NASH) or non-alcoholic fatty liver disease (NAFLD), the method comprising administering to the subject an effective amount of a compound according to claim 1.
17:
- The method of claim 14, wherein said disorder or disease is non-alcoholic steatohepatitis (NASH) or non-alcoholic fatty liver disease (NAFLD).
Dependencies are inferred from the claim text.