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EP-4126905-B1 - CYCLOPHILIN INHIBITORS AND USES THEREOF

EP4126905B1EP 4126905 B1EP4126905 B1EP 4126905B1EP-4126905-B1

Inventors

  • MAK, CHING-PONG
  • FLIRI, HANS
  • MA, Fashu
  • PEEL, MICHAEL

Dates

Publication Date
20260513
Application Date
20210325

Claims (15)

  1. A compound according to Formula 4, or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 2 are independently selected from H, C 1 to C 6 alkyl or wherein R 1 and R 2 are joined together to form a C 3 to C 6 cycloalkyl or heterocycloalkyl ring; X and Z are both alkyl, or wherein X is alkyl, e.g. C 1 to C 6 alkyl and Z is H, or wherein X and Z are joined together to form a C 3 to C 6 cycloalkyl or heterocycloalkyl ring; A is selected from: - NR 3 R 4 , wherein R 3 and R 4 are independently selected from H, or C 1 to C 6 alkyl; and - N=C(R 5 )NR 6 R 7 , wherein R 5 , R 6 and R 7 are independently selected from H, C 1 to C 6 alkyl, and optionally wherein R 6 and R 7 are joined together to form a C 3 to C 6 cycloalkyl or heterocycloalkyl ring; R 8 is ethyl, 1-hydroxyethyl, isopropyl, or n-propyl; R 9 is Formula 1a or 1b
  2. A compound according to Formula 1 or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 2 are independently selected from H, C 1 to C 6 alkyl or wherein R 1 and R 2 are joined together to form a C 3 to C 6 cycloalkyl or heterocycloalkyl ring; A is selected from: - NR 3 R 4 , wherein R 3 and R 4 are independently selected from H or C 1 to C 6 alkyl; and - N=C(R 5 )NR 6 R 7 , wherein R 5 , R 6 and R 7 are independently selected from H, C 1 to C 6 alkyl, and optionally wherein R 6 and R 7 are joined together to form a C 3 to C 6 cycloalkyl or heterocycloalkyl ring; R 8 is ethyl, 1-hydroxyethyl, isopropyl, or n-propyl; R 9 is Formula 1a or 1b provided that if R 1 and R 2 are both H, or if R 1 is methyl and R 2 is H, and R 8 is selected from ethyl, isopropyl, and n-propyl, R 9 is Formula 1a, and A is NR 3 R 4 , then R 3 and R 4 are not H, C 1 -C 4 alkyl.
  3. The compound according to claim 1 or 2, wherein: a. R 1 and R 2 are both hydrogen; or b. at least one of R 1 or R 2 is C 1 to C 6 alkyl; or c. R 1 and R 2 are joined together to form a C 3 to C 6 cycloalkyl or heterocycloalkyl ring.
  4. The compound according to any one of the preceding claims wherein R 8 is ethyl.
  5. The compound according to any one of the preceding claims, wherein R 9 is Formula 1a.
  6. The compound according to any one of the preceding claims, wherein A is NR 3 R 4 .
  7. The compound according to claim 6 wherein R 3 and R 4 are both -CH 3 .
  8. The compound according to any one of claims 1 to 5, wherein A is - N=C(R 5 )NR 6 R 7 ; optionally wherein R 5 , R 6 and R 7 are independently selected from H, C 1 to C 6 alkyl or optionally, substituted C 1 to C 6 alkyl.
  9. The compound according to claim 8, wherein R 5 is H or CH 3 and wherein R 6 and R 7 are CH 3 .
  10. The compound according to claims 8 or 9, wherein R 8 is ethyl.
  11. The compound according to claims 1 to 10, wherein the compound is of Formula 4, and wherein X is C 1 to C 6 alkyl (e.g. methyl), and Z is H.
  12. The compound according to claim 2, wherein the compound, or a pharmaceutically acceptable salt thereof is of Formula 3: wherein: R 1 and R 2 are independently selected from H, C 1 to C 6 alkyl, or wherein R 1 and R 2 are joined together to form a C 3 to C 6 cycloalkyl or heterocycloalkyl ring; wherein R 5 , R 6 and R 7 are independently selected from H, C 1 to C 6 alkyl, and optionally wherein R 6 and R 7 are joined together to form a C 3 to C 6 cycloalkyl or heterocycloalkyl ring; R 8 is ethyl, 1-hydroxyethyl, isopropyl, or n-propyl; and R 9 is Formula 1a or 1b
  13. The compound according to claim 12 wherein: a. R 1 and R 2 are both hydrogen; or b. at least one of R 1 or R 2 is C 1 to C 6 alkyl; or c. R 1 and R 2 are joined together to form a C 3 to C 6 cycloalkyl or heterocycloalkyl ring; wherein R 8 is ethyl; and optionally wherein R 5 , R 6 and R 7 are independently selected from H, C 1 to C 6 alkyl, and optionally, substituted C 1 to C 6 alkyl; further optionally wherein R 5 is H or CH 3 and wherein R 6 and R 7 are CH 3 .
  14. The compound according to claim 1 or 2, wherein the compound, or pharmaceutically acceptable salt thereof is selected from the group consisting of the following compounds of Formula I or pharmaceutically acceptable salts thereof: Compound R 1 R 2 A R 8 R 9 2 H H -N(CH 3 ) 2 -CH(OH)CH 3 5 H H -N(CH 3 ) 2 -CH(CH 3 ) 2 9 H H -N=C(CH 3 )N(CH 3 ) 2 -CH 2 CH 3 10 H H -N=C(H)N(CH 3 ) 2 -CH 2 CH 3 11 CH 3 CH 3 -N(CH 3 ) 2 -CH 2 CH 3 12 -CH 2 - -CH 2 - -N(CH 3 ) 2 -CH 2 CH 3 13 -CH 2 - -CH 2 - N=C(CH 3 )N(CH 3 ) 2 -CH 2 CH 3 or selected from a compound of Formula 4 or a pharmaceutically acceptable salt thereof, wherein R 9 is Formula 1a, R 8 is ethyl, Z is H, and X is methyl, R 1 and R 2 are both H, and A is -N(CH 3 ) 2 or wherein the compound, or a pharmaceutically acceptable salt thereof is selected from the group consisting of: and
  15. A compound or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 14 for use as a medicine; optionally wherein said compound or pharmaceutically acceptable salt thereof is for use in the: - prevention and/or treatment of a disease or condition of the kidney; - prevention and/or treatment of a cyclophilin-mediated disease condition, e.g. cyclophilin A and/or D, e.g. a cyclophilin-mediated disease or condition of the kidney; or - prevention and/or treatment of a disease or condition associated with cell injury or cell death, optionally wherein said disease condition is organ injury or organ failure, wherein the organ is selected from the group consisting of kidney, liver, heart, lung, pancreas, intestine, cornea, skin, brain and nerve tissue; further optionally wherein the disease or condition is ischemia-reperfusion injury, e.g. renal reperfusion injury, or wherein the disease or condition is acute kidney injury; e.g. acute kidney injury is associated with, or a consequence of kidney transplantation.

Description

BACKGROUND OF THE INVENTION The present invention relates to cyclosporin analogues, and their use for the treatment or prevention of disease or disorders, in particular disease or conditions associated with cellular injury or cell death, which can be caused by a number of different reasons, such as ischemia or ischemia reperfusion injury, toxins, infection or mechanical trauma. In particular, the invention relates to compounds which may be provided as potent cyclophilin D inhibitors. Acute inflammation is well recognized to involve the complex interaction of various cellular (neutrophils, macrophages) and extracellular (complement, histamine) factors that act in response to PAMP (pathogen-activated molecular patterns) and DAMP (damage-activated molecular patterns) signals to resolve the originating insult. Cyclophilin A has been demonstrated to function as a chemokine to facilitate leukocyte migration in support of an inflammatory response and blockade of cyclophilin A was shown to be beneficial in animal models of acute inflammation. More recently a severe form of inflammation that is accompanied by cell death and tissue necrosis has been described. A significant body of evidence now supports the opening of a pore at the mitochondrial membrane, termed the Mitochondrial Permeability Transition Pore (MPTP), as being critical to the onset and maintenance of this necrotic inflammation. A key regulator of this MPTP opening is Cyclophilin D (CypD), and inhibitors of CypD have shown good activity in preventing tissue damage associated with necrotic inflammation. Opening of the MPTP, and subsequent initiation of necrotic cell death, is triggered by elevated intracellular calcium levels that result from a variety of factors including excessive physiological signals (e.g. noise trauma, excitotoxicity), oxidative stress, hypoxia, bile salt toxins, etc. Notably, genetic ablation, or pharmacological inhibition, of CypD was found to be protective toward tissue degradation due to ischemia-reperfusion injury of cardiac tissue suggesting that CypD inhibition is a viable drug target for ischemia-reperfusion injury more generally. In mouse models cyclophilin D deletion was shown to have a significant protective effect against damage caused to the kidney by a severe ischemia-reperfusion insult (Am J Physiol Renal Physiol 297: F749-F759, 2009). This protective effect was evident in improved renal function, as measured by serum creatinine levels, and in tissue damage (measured by histology) in the cyclophilin D knockout animals compared to wild type controls. Similarly, in a mouse model of kidney damage caused by administration of a nephrotoxic drug (Am J Physiol Renal Physiol. 2019 Sep 1;317(3):F683-F694), animals in which cyclophilin D was knocked out were more resistant to oxidative stress and hypomethylation and had lower indications of renal toxicity than wild type animals. In studies carried out using cyclophilin D knockout mice as well as pharmacological strategies with cyclophilin inhibitors it has been unambiguously demonstrated that opening of the mitochondrial permeability transition pore (MPTP), a non-specific channel in the inner mitochondrial membrane, is a fundamental event in cell death that results from a variety of insults. Further, inhibition of cyclophilin D can prevent opening of the mPTP which is protective toward mitochondrial function and preserves cell viability. Cyclosporin A is a compound well known for its immunosuppressive properties, but other biological properties have also been described. Cyclosporin A has the following chemical structure: Biologically active derivatives of Cyclosporin A have also been made. For example, US 6,583,265, EP0484281, EP0194972 describes cyclosporin derivatives having various properties including immunosuppressive, antiparasitic and antiviral properties. US 6,583,265 describes cyclosporin derivatives with modifications made at position 3 of the cyclosporin macrocycle. In particular, US 6,583,265 discloses WO2019/016572 A1 also describes Compound 1 for use in the treatment or prevention of acute or chronic inflammatory disorders. It is an object of the present invention to provide further cyclosporin analogues, in particular analogues which may be useful for inhibition of cyclophilins, e.g. cyclophilin A, B, and D, and diseases and conditions associated therewith. Further objects of the invention will be clear on the basis of the following description of the invention, examples and claims. SUMMARY OF THE INVENTION In a first aspect, the invention relates to the compounds as defined by the present claims, and relates to compounds as defined in the detailed description, i.e. compounds of Formula 1, Formula 2 or Formula 3, or Formula 4. In a further aspect, the present invention provides for the use of said compounds as defined in the claims. The compounds may be used as cyclophilin inhibitors. In yet a further aspect, the invention provides for use of said compounds in a