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WO2024245384A1 - Inhibiteurs de cyclophiline et leurs utilisations - Google Patents

Inhibiteurs de cyclophiline et leurs utilisations Download PDF

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Publication number
WO2024245384A1
WO2024245384A1 PCT/CN2024/096567 CN2024096567W WO2024245384A1 WO 2024245384 A1 WO2024245384 A1 WO 2024245384A1 CN 2024096567 W CN2024096567 W CN 2024096567W WO 2024245384 A1 WO2024245384 A1 WO 2024245384A1
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Prior art keywords
compound
alkyl
cyclophilin
item
compounds
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English (en)
Inventor
Fashu MA
Ching Pong Mak
Junchao SHAO
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Farsight Medical Technology Shanghai Co Ltd
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Farsight Medical Technology Shanghai Co Ltd
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Priority to PCT/CN2024/136541 priority Critical patent/WO2025246257A1/fr
Publication of WO2024245384A1 publication Critical patent/WO2024245384A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/64—Cyclic peptides containing only normal peptide links
    • C07K7/645—Cyclosporins; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • Acute and chronic 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 and chronic inflammation.
  • cyclophilin A has been implicated in the treatment of various diseases and conditions including cardiovascular disease, viral infections including human immunodeficiency virus (HIV) , influenza virus, and severe acute respiratory syndrome coronavirus (SARS-CoV) , cancer including breast cancer, small cell lung cancer, non-small cell lung cancer, and renal cell carcinoma, kidney diseases including acute kidney injury, nephritis, and renal fibrosis, rheumatoid arthritis, sepsis, asthma, colitis, ulcerative colitis, Crohn's disease, allergic rhinitis, atherosclerosis, vascular smooth muscle cell disease, myocarditis, cardiac fibrosis, central nervous system diseases, Alzheimer's disease, and amyotrophic lateral sclerosis.
  • cardiovascular disease cardiovascular disease
  • viral infections including human immunodeficiency virus (HIV) , influenza virus, and severe acute respiratory syndrome coronavirus (SARS-CoV)
  • cancer including breast cancer, small cell lung cancer, non-small cell lung cancer, and renal cell carcinoma
  • 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:
  • Cyclosporin A Biologically active derivatives of Cyclosporin A have also been made.
  • US 6,583,265, EP0484281, EP0194972 describe cyclosporin derivatives having various properties including immunosuppressive, antiparasitic and antiviral properties.
  • US 6,583,265 describes cyclosporin derivatives with modifications made at position 3 (sarcosine) of the cyclosporin macrocycle.
  • US 6,583,265 discloses Compound 0:
  • WO2019/016572 A1 also describes Compound 0 for use in the treatment or prevention of acute or chronic inflammatory disorders.
  • WO2021/190601 A1 and WO 2021/190603 A1 describe cyclosporin derivatives for use in the treatment or prevention of a disease or condition such as organ injury or organ failure.
  • 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.
  • the disclosure relates to compounds which may be provided as potent cyclophilin A inhibitors, cyclophilin D inhibitors, or both cyclophilin A and D inhibitors.
  • the disclosure related to compounds which may be provided as potent cyclophilin A inhibitors. Further objects of the disclosure will be clear on the basis of the following description, examples, and claims.
  • the disclosure relates to compounds as defined in the detailed description, i.e., compounds of Formulas 1-6.
  • the present disclosure provides for the use of said compounds as cyclophilin inhibitors.
  • the disclosure provides for use of said compounds in a method of preventing and/or treating cyclophilin-mediated diseases or conditions, such as cyclophilin A-or cyclophilin D-mediated diseases or conditions, specifically cyclophilin A-mediated diseases or conditions.
  • the present disclosure relates to a compound of Formula 1, or a pharmaceutically acceptable salt thereof:
  • n 0, 1, 2, 3, or 4;
  • c, d, and e are each 0 or 1;
  • Y is CH 2 or NR x ;
  • R x is H or C 1 to C 6 alkyl
  • R 1 and R 2 are each independently selected from H, aryl, arylalkyl, C 1 to C 6 alkyl, C 6 to C 10 bicyclyl, (C 1 to C 6 alkyl) C (O) 2 R 9 , or wherein R 1 and R 2 are joined together to form a C 3 to C 6 cycloalkyl ring;
  • R 3 and R 4 are each independently selected from H, C 1 to C 6 alkyl, or wherein R 3 and R 4 are joined together to form a C 3 to C 6 cycloalkyl ring;
  • R 5 and R 6 are each independently selected from H or C 1 to C 6 alkyl
  • R 7 is O-R 8 ;
  • R 8 is selected from H, C 1 to C 6 alkyl, CHR 10 OC (O) CHNH 2 R 11 , CHR 12 OC (O) R 13 , CH 2 CH 2 OH, CH 2 CH (OH) CH 2 OH or wherein m is 0-20;
  • R 9 , R 10 , R 11 , and R 12 are each independently selected from H or C 1 to C 6 alkyl;
  • R 13 is selected from O (C 1 to C 6 alkyl) or C 1 to C 6 alkyl;
  • R 14 is selected from H, NR 15 R 16 , a heteroalkyl ring, or a heteroaryl ring;
  • R 15 and R 16 are each independently selected from H or C 1 to C 6 alkyl, or wherein R 15 and R 16 are joined together to form a C 3 to C 6 cycloalkyl or C 3 to C 6 heterocycloalkyl ring.
  • the present disclosure relates to a compound of Formula 1, or a pharmaceutically acceptable salt thereof:
  • n 0, 1, 2, or 3;
  • R 1 and R 2 are each independently selected from H, C 1 to C 6 alkyl, (C 1 to C 6 alkyl) C (O) 2 R 9 , or wherein
  • R 1 and R 2 are joined together to form a C 3 to C 6 cycloalkyl ring;
  • R 3 and R 4 are each independently selected from H, C 1 to C 6 alkyl, or wherein R 3 and R 4 are joined together to form a C 3 to C 6 cycloalkyl ring;
  • R 8 is selected from H, C 1 to C 6 alkyl, CHR 10 OC (O) CHNH 2 R 11 , CHR 12 OC (O) R 13 , CH 2 CH 2 OH, or
  • R 9 , R 10 , R 11 , and R 12 are each independently selected from H or C 1 to C 6 alkyl
  • R 13 is selected from O (C 1 to C 6 alkyl) or C 1 to C 6 alkyl.
  • the cyclosporin compound according to the disclosure is a cyclosporin A compound comprising a substituent at the sarcosine residue at position 3 of the macrocyclic ring such as defined in any one or combination of the embodiments described herein.
  • the position numbering as used herein refers to commonly used nomenclature and number assignment of the eleven amino acid residues featured in the cyclosporin core.
  • the amino acids residues may be numbered as follows: methyl-butenyl-threonine, which may be abbreviated as MeBmt (1) , aminobutyric acid (2) ) , sarcosine, which may be abbreviated as Sar (3) , N-methyl leucine (4) , valine (5) , N-methyl leucine (6) , alanine (7) , D-alanine (8) , N-methyl leucine (9) , N-methyl leucine (10) , N-methyl valine (11) .
  • H refers to hydrogen.
  • alkyl as used herein is defined as a saturated or unsaturated alkyl hydrocarbon moiety in any isomeric configuration. Included are straight-chain, linear alkyl, such as methyl, ethyl, n-propyl, n-butyl, 1-pentyl, n-hexyl.
  • branched alkyl e.g., branched C 3 to C 6 alkyl
  • cyclic isomers such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • unsaturated alkyl examples include but are not limited to vinyl, allyl, butenyl, pentenyl, and hexenyl, and other alkenyl or alkylene moieties, for example comprising one or more double bonds e.g., pentadienyl.
  • C 1 to C 6 is defined as a moiety comprising a range of 1 to 6 carbon atoms.
  • C 3 to C 6 ’ and ‘C 6 to C 10 ’ are to be understood analogously but denoting a moiety comprising a range of 3 to 6 carbon atoms or a range of 6 to 10 carbon atoms, respectively.
  • the C 1 to C 6 alkyl refers to an unsubstituted hydrocarbon moiety such as defined above.
  • the C 1 to C 6 alkyl may be substituted with one or more substituents, whereby one or more hydrogen atoms are replaced with a bond to said substituent or moiety other than hydrogen.
  • aryl refers to a monocyclic or polycyclic aromatic ring assembly typically containing 6-14 ring atoms where all the ring atoms are carbon atoms. Typically, the aryl is a 6-membered (ring atoms) monocyclic, a 10-to 12-membered bicyclic, or a 14-membered fused tricyclic aromatic ring system. Examples include, but are not limited to, phenyl, biphenyl, naphthyl, and anthracenyl.
  • the term ‘aryl’ is represented along with another radical such as ‘arylalkyl’ , the aryl portion shall have the same meaning as the definition of ‘aryl’ and is bonded to the other radical.
  • hydroxyl refers to a -OH radical.
  • the hydrogen may be substituted, for example with a hydroxy protecting group within the art or a prodrug moiety.
  • alkoxyl or the like means an alkylated hydroxyl substituent, i.e., in which the hydrogen is replaced by an alkyl group.
  • C 1 to C 6 alkoxy refers to the replacement of hydroxy hydrogen with a C 1 to C 6 alkyl such as defined above. Examples include methoxy, isopropoxy, phenoxy, or t-butoxy.
  • amino may refer to an -NH 2 radical.
  • the hydrogen (s) may be substituted, for example with a protecting group, or one or more further substituent such as alkyl.
  • monoalkylamino refers to an amino radical in which one of the hydrogens is replaced with alkyl, e.g., C 1 to C 6 alkyl such as defined above (i.e. -NHR, wherein R is alkyl) .
  • Dialkylamino refers to an amino radical whereby both hydrogens are replaced independently with alkyl (i.e. -NRR’ , where R and R' are alkyl, which may be the same (e.g., dimethylamino) , or different) .
  • Thioalkyl may refer to the radical -SR” , wherein R” is alkyl, e.g., C 1 to C 6 alkyl such as defined above.
  • the term ‘carboxyl’ as used herein refers to the radical -C (O) -R a , wherein R a may be selected from hydrogen, alkyl, aryl, hetaryl, hydroxy, alkoxy (e.g. -OCH 3 ) , amino, alkylamino, dialkyl amino, thioalkyl and the like.
  • alkoxycarbonyl may refer to the radical -OC (O) -R a , wherein R a is selected from alkyl (e.g., C 1 to C 6 alkyl, e.g., methyl) , aryl, hetaryl, alkoxy, amino, alkylamino, dialkyl amino, thioalkyl, etc.
  • hetero when used to describe a compound or substituent means that one or more carbon atoms are replaced by an oxygen, nitrogen, or sulfur atom.
  • the substituents R 1 and R 2 may be joined together to form a heterocycloalkyl ring, for example a C 3 to C 6 heterocycloalkyl ring.
  • heterocycloalkyl refers to a saturated, or unsaturated non-aromatic ring forming at least part of a cyclic structure and where at least one or more carbon atoms are replaced by oxygen, nitrogen, or sulfur atom (and in the case of a C 3 to C 6 heterocycloalkyl comprising between 3 to 6 carbon atoms) .
  • the substituents R 1 and R 2 may be joined together to form a 4-, 5-or 6-member saturated, non-aromatic ring comprising at least one heteroatom.
  • the heterocycloalkyl ring may comprise at least one heteroatom selected from O, N, or S.
  • the substituent R 8 of a compound of Formula 1 may be selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, CHR 10 OC (O) CHNH 2 R 11 , CH 2 OC (O) CHNH 2 CH (CH 3 ) 2 , CHR 12 OC (O) R 13 , CH 2 OC (O) OCH (CH 3 ) 2 , CH (CH 3 ) OC (O) OCH (CH 3 ) 2 , CH 2 OC (O) C (CH 3 ) 3 , CH (CH 3 ) OC (O) C (CH 3 ) 3 , CH (CH 3 ) OC (O) C (CH 3 ) 3 , CH 2 CH 2 OH, CH 2 CH (OH) CH 2 OH, (CH 2 ) (CH 2 ) m R 14 , (CH 2 ) (CH 2
  • the substituent R 8 of a compound of Formula 1 may be selected from the group consisting of hydrogen, methyl, tert-butyl, CHR 10 OC (O) CHNH 2 R 11 , CH 2 OC (O) CHNH 2 CH (CH 3 ) 2 , CHR 12 OC (O) R 13 , CH 2 OC (O) C (CH 3 ) 3 , CH 2 CH 2 OH, CH 2 CH (OH) CH 2 OH, (CH 2 ) (CH 2 ) m R 14 , (CH 2 ) (CH 2 ) m NR 15 R 16 , (CH 2 ) 2 NR 15 R 16 , (CH 2 ) 2 N (CH 3 ) 2 , and (CH 2 ) 2 N (CH 2 ) 4 N (CH 3 ) (e.g., (CH 2 ) 2 N-methylpiperazinyl) .
  • CHR 10 OC (O) CHNH 2 R 11 CH 2 OC (O) CHNH 2 CH (CH 3 ) 2 ,
  • Prodrugs of a compound of Formula 1 as disclosed herein are contemplated.
  • the term ‘prodrug’ refers to a drug substance that after intake is metabolized into a pharmacologically active drug by a metabolic or physicochemical transformation.
  • a compound of Formula 1 comprises one or more hydroxyl groups (-OH)
  • any of the one or more hydroxyl groups may be optionally converted to a prodrug moiety.
  • the substituent R 8 of a compound of Formula 1 is hydrogen or if the substituent R 8 comprises a hydroxyl group (-OH)
  • the hydrogen of any hydroxyl group present in the compound may be optionally converted to a prodrug moiety.
  • the prodrug moiety may be selected from the group consisting of CHR 10 OC (O) CHNH 2 R 11 , CH 2 OC (O) CHNH 2 CH (CH 3 ) 2 , CHR 12 OC (O) R 13 , CH 2 OC (O) OCH (CH 3 ) 2 , CH (CH 3 ) OC (O) OCH (CH 3 ) 2 , CH 2 OC (O) C (CH 3 ) 3 , CH (CH 3 ) OC (O) C (CH 3 ) 3 , and CH 2 CH (OH) CH 2 OH.
  • the prodrug moiety may be selected from the group consisting of CHR 10 OC (O) CHNH 2 R 11 , CH 2 OC (O) CHNH 2 CH (CH 3 ) 2 , CHR 12 OC (O) R 1313 , CH 2 OC (O) C (CH 3 ) 3 , and CH 2 CH (OH) CH 2 OH.
  • the prodrug compound is a compound as disclosed in example compounds 47, 48, and 49.
  • the compound is a compound of Formula 2
  • R 1 and R 2 are each H. In other embodiments, R 1 and R 2 are each C 1 to C 6 alkyl. In other embodiments, R 1 is H and R 2 is C 1 to C 6 alkyl. In other embodiments, R 1 is C 1 to C 6 alkyl and R 2 is H. In some embodiments, R 1 is H and R 2 is (C 1 to C 6 alkyl) C (O) 2 R 9 . In other embodiments, R 1 is (C 1 to C 6 alkyl) C (O) 2 R 9 and R 2 is H.
  • R 1 and R 2 are joined together to form a C 3 to C 6 cycloalkyl ring.
  • R 3 and R 4 are each H.
  • R 3 and R 4 are each C 1 to C 6 alkyl.
  • R 3 is H and R 4 is C 1 to C 6 alkyl.
  • R 3 is C 1 to C 6 alkyl and R 2 is H.
  • R 3 and R 4 are joined together to form a C 3 to C 6 cycloalkyl ring.
  • any recited R 1 and R 2 combination may be combined with any recited R 3 and R 4 combination.
  • a stereocenter defined by -CR 1 R 2 - is a racemic mixture or any mixture of (R) and (S) enantiomers, an (R) enantiomer, or an (S) enantiomer.
  • a stereocenter defined by -CR 3 R 4 - is a racemic mixture or any mixture of (R) and (S) enantiomers, an (R) enantiomer, or an (S) enantiomer.
  • any R 8 substituent disclosed herein may be combined with any of the above recited combinations.
  • R 5 and R 6 are each H. In other embodiments, R 5 and R 6 are each C 1 to C 6 alkyl. In other embodiments, R 5 is H and R 6 is C 1 to C 6 alkyl. In other embodiments, R 5 is C 1 to C 6 alkyl and R 6 is H. In some embodiments, each stereocenter defined by -CHR 5 -and -CHR 6 -are a racemic mixture or any mixture of (R) and (S) enantiomers, an (R) enantiomer, or an (S) enantiomer. In other embodiments, any R 8 substituent disclosed herein may be combined with any of the above recited combinations.
  • Y is CH 2 .
  • each potential stereocenter present in the X group is a racemic mixture or any mixture of (R) and (S) enantiomers, an (R) enantiomer, or an (S) enantiomer.
  • X is In other embodiments, Y is NR x and R x is H, C 1 to C 6 alkyl, or CH 3 .
  • the compound is a compound of Formula 5
  • Y is CH 2 .
  • each potential stereocenter present in the X group is a racemic mixture or any mixture of (R) and (S) enantiomers, an (R) enantiomer, or an (S) enantiomer.
  • X is In other embodiments, Y is NR x and R x is H, C 1 to C 6 alkyl, or CH 3 .
  • the compound is a compound of Formula 6
  • each potential stereocenter present in the X group is a racemic mixture or any mixture of (R) and (S) enantiomers, an (R) enantiomer, or an (S) enantiomer.
  • X is .
  • m e.g., (CH 2
  • n is 1, wherein R 1 and R 2 are each H and R 3 and R 4 are each H, CH 3 , or joined together to form a C 3 cycloalkyl ring; R 1 and R 2 are each CH 3 and R 3 and R 4 are each H; R 1 is H and R 2 is C 1 to C 6 alkyl, CH 3 , or CH 2 CH 3 and R 3 and R 4 are each H; or R 1 and R 2 are each H, R 3 is H and R 4 is C 1 to C 6 alkyl or CH 3 .
  • a stereocenter defined by -CR 1 R 2 - is a racemic mixture or any mixture of (R) and (S) enantiomers, an (R) enantiomer, or an (S) enantiomer.
  • a stereocenter defined by -CR 3 R 4 - is a racemic mixture or any mixture of (R) and (S) enantiomers, an (R) enantiomer, or an (S) enantiomer.
  • n 2
  • R 1 , R 2 , R 3 , and R 4 are each H.
  • n 3 wherein R 1 , R 2 , R 3 , and R 4 are each H.
  • each stereocenter defined by -CHR 5 -and -CHR 6 - is a racemic mixture or any mixture of (R) and (S) enantiomers, an (R) enantiomer, or an (S) enantiomer.
  • the compound is of Formula 2; n is 0, 1, 2, or 3; R 1 is wherein f and g are each independently 0 to 4; and R 2 is H.
  • the compound is of Formula 2; n is 0, 1, 2, or 3; the stereocenter defined by -CR 1 R 2 -is the (S) enantiomer; R 1 is selected from the group consisting of R 2 is H; and R 8 is selected from the group consisting of
  • the compound is of Formula 2; n is 0, 1, 2, or 3; the stereocenter defined by -CR 1 R 2 -is the (S) enantiomer; R 1 is selected from the group consisting of R 2 is H; and R 8 is
  • the compound is of Formula 2; n is 0, 1, 2, or 3; the stereocenter defined by -CR 1 R 2 -is the (S) enantiomer; R 1 is selected from the group consisting of R 2 is H; and R 8 is
  • X is selected from the group consisting of and R 8 is
  • the compounds according to the disclosure may be selected from Compound 1, 2, 3, 4, et seq. or a pharmaceutically acceptable salt thereof as defined in Table 1:
  • the compounds of present disclosure may exist in various stereoisomeric forms and mixtures. It may be understood that the disclosure may include, in addition to stereocenters as designated or depicted in the formulae, all their enantiomers, diastereomers, racemates or other mixtures, as well as polymorphs, solvates, hydrates, complexes, free form, or salt forms. Unless otherwise indicated, the compounds within the scope of the current disclosure comprising one or more asymmetric centers which have not been designated or depicted in the formulae, or which have not been specifically named/described may also include all enantiomers, diastereomers, or their mixtures, racemic or otherwise thereof.
  • the representation of double bonds in the current disclosure refers to the isomer as depicted, however may be considered as also including the other Z (or E) isomer. Also included is the use of any optically pure or stereochemically pure stereoisomers, as well as any combination of stereoisomers, as determined or prepared by methods well-known in the art.
  • the compounds of the disclosure may also include their isotopes, such compounds wherein an atom is replaced with an isotope, such as hydrogen with a deuterium, or a carbon with carbon-13.
  • the compounds of the present disclosure comprise a cyclosporin ring, wherein the substituent at the 4-position, e.g., the isobutyl group of the cyclosporin ring is substituted with at least one hydroxyl (-OH) substituent.
  • the at least one hydroxyl (-OH) substituent is present at the carbon atom substituted by two methyl groups (e.g., -CH 2 C (OH) (CH 3 ) 2 ) .
  • the compounds of the present disclosure comprise a cyclosporin ring, wherein the substituent at the 8-position, e.g., the methyl group of the cyclosporin ring is substituted with at least one hydroxyl (-OH) substituent (e.g., 8-D serine-cyclosporin) .
  • -OH hydroxyl
  • L-ascorbic) L-aspartic, benzoic, 4-acetamidobenzoic, butanoic, (+) camphoric, camphor-sulfonic, (+) - (1S) -camphor-10-sulfonic, capric, caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulfuric, ethane-1, 2-disulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, formic, fumaric, galactaric, gentisic, glucoheptonic, gluconic (e.g. D-gluconic) , glucuronic (e.g.
  • acid addition salts may include those derived from mineral acids such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids; from organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, and arylsulfonic acids.
  • mineral acids such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids
  • organic acids such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, and arylsulfonic acids.
  • the compounds of the present disclosure may be useful for the prevention and/or treatment of diseases or medical conditions, or in the manufacture of a medicament for prevention and/or treating a disease or medical condition.
  • the compounds of the present disclosure e.g., any compound of Formulas 1-6 or any compound disclosed in Table 1, or a pharmaceutically acceptable salt thereof, may be used as a medicament.
  • the medicament may be used to prevent and/or treat diseases or medical conditions.
  • the compounds of the present disclosure may be used in methods for prevention and/or treating a disease or condition comprising administering any compound of Formulas 1-6 or any compound disclosed in Table 1, or a pharmaceutically acceptable salt thereof, to a subject in need thereof; preferably wherein the subject is a human subject.
  • a therapeutically effect amount of any compound of Formulas 1-6 or any compound disclosed in Table 1, or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof; preferably wherein the subject is a human subject.
  • treatment which may be used synonymously with the term ‘treatment’ , as used herein, relates to a therapeutic intervention capable of effecting a cure, improvement, amelioration, control, control of progression, prevention of progression, prevention of reoccurrence of a disease, condition or symptom associated with said disease or condition.
  • prevention refers to the use of a compound, or composition, for preventing the occurrence of a disease, condition, or symptom, or significantly reducing the likelihood of occurrence of a disease, condition, or symptom, as well as the prevention of, for example, a further reoccurrence of a disease, condition, or associated symptom. Also included within the meaning of the term is the prevention of progression of a disease, condition, or associated symptom, after an initial improvement or after initial removal of the cause of the disease, condition, or symptom.
  • the compound according to the disclosure may be used for the prevention, as well as the treatment of cyclophilin-mediated disease or condition.
  • the compounds as described herein may be used as inhibitors of cyclophilin, especially cyclophilin A (CypA) and/or cyclophilin D (CypD) .
  • the compound is used as an inhibitor of cyclophilin A, for example, provided or administered at a therapeutically relevant amount for the inhibition of cyclophilin A.
  • the term ‘therapeutically effective amount’ is an amount of e.g., a compound which when administered to a subject (e.g., human subject) for treating and/or preventing a disease or condition, is sufficient to affect such treatment and/or prevention thereof.
  • 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 oxidative stress, hypoxia, bile salt toxins, etc.
  • Pharmacological inhibition of CypD may therefore be protective toward tissue degradation due to ischemia-reperfusion injury of organ tissue.
  • certain compounds according to the present disclosure are surprisingly effective as inhibitors of cyclophilin, in particular, cyclophilin A, but are surprisingly non-immunosuppressive.
  • the compounds may be useful for the treatment or prevention of disease or conditions, wherein raised levels or activity of cyclophilin is associated with, contributing to, or resulting in said disease or condition.
  • the cyclophilin-mediated disease or condition which may be treated or prevented according to the disclosure may be a cyclophilin A-or cyclophilin D-mediated disease or condition.
  • Such compounds bear high CypA /D binding affinity and high mitochondrial function protection. Examples of such compounds include compounds 53, 58 and 59.
  • certain compounds according to the present disclosure are surprisingly effective as inhibitors of cyclophilin, in particular, cyclophilin A, but surprisingly possess anti-inflammatory activities, are non-immunosuppressive, and have little or no effect on mitochondrial activities.
  • Such compounds may be used to treat patients having chronic inflammation, who in certain embodiments require long-term drug intake. Examples of such compounds include compounds 10, 29, 51, and 62.
  • the compounds according to the present disclosure inhibit cyclophilin intracellularly. In other embodiments, the compounds according to the present disclosure inhibit cyclophilin extracellularly. In yet other embodiments, the compounds according to the present disclosure inhibit cyclophilin both intracellularly and extracellularly. In certain embodiments, elevated levels of extracellular cyclophilins may contribute to diseases or conditions that may be treated with the compounds of the present disclosure, such as, for example, diseases or conditions that are associated with elevated levels of extracellular cyclophilin A.
  • Cyclophilin-mediated diseases or conditions are typically diseases and conditions associated with inflammatory response, cellular damage, injury and/or cell death (e.g., necrosis) and may include, but are not limited to, the diseases and conditions as further described below.
  • the term ‘subject’ or ‘patient’ may be used interchangeably, and refer in one embodiment, to a human subject.
  • the subject or patient is a human.
  • These terms may also refer to other animals, such as other mammals.
  • the disclosure in further embodiments may also have application, for instance, in farm animals or other veterinary subjects, in particular mammals such cats, dogs, primates, horses, cows, and pigs.
  • the compound of the present disclosure may optionally be administered together with one or more further active substances.
  • Intervals between doses may be, for example, two doses administered approximately every 12 hours, or three doses administered approximately every 8 hours.
  • a dose of a compound may refer to a unit dose of Compounds of Formulas 1-6 or a pharmaceutically acceptable salt thereof, but may also be applicable to a medicament, or composition or dosage form comprising said unit dose of compound or a pharmaceutically acceptable salt thereof.
  • the term ‘about’ or the like in connection with an attribute or value such as dose amount includes the exact attribute or precise value, as well as any attribute or value typically considered to fall within the normal or accepted variability associated with the technical field, and methods of measuring or determining said attribute or value.
  • the term allows for any variation which in the common practice would allow for the product being evaluated to be considered bioequivalent in a mammal to the recited strength or dose of a claimed product.
  • a compound or a pharmaceutically acceptable salt thereof according to the present disclosure may be administered enterally or parenterally to a subject.
  • a compound of Formulas 1-6 or a composition or a medicament comprising said compound or a pharmaceutically acceptable salt thereof may be adapted for administration or may be administered parenterally, for example by intravenous injection or by sub-cutaneous, or intramuscular injection, or by intravenous or subcutaneous infusion.
  • the compound, or a composition or medicament comprising the compound may be adapted for administration, or may be administered to a subject enterally, for example orally.
  • the present disclosure may also relate to a medicament, or a pharmaceutical composition comprising a compound according to any one or combination of the embodiments described herein above, e.g., a compound of Formulas 1-6 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
  • the medicament or composition may comprise a therapeutically effective amount or unit dose (s) of said compound.
  • the medicament, or pharmaceutical composition comprising said compound may be formulated in a dosage form suitable or adapted for injection or infusion by any of the administration methods above.
  • the medicament or pharmaceutical composition comprising a compound according to the present disclosure may be provided in a dosage form suitable or adapted for oral administration, for example such as, but not limited to a tablet, capsule, gel cap, or film.
  • Said medicament, or pharmaceutical composition may be used in accordance with any of the methods of treatment or prevention or uses described herein.
  • n 0, 1, 2, 3, or 4;
  • c, d, and e are each 0 or 1;
  • Y is CH 2 or NR x ;
  • R 3 and R 4 are each independently selected from H, C 1 to C 6 alkyl, or wherein R 3 and R 4 are joined together to form a C 3 to C 6 cycloalkyl ring;
  • R 5 and R 6 are each independently selected from H or C 1 to C 6 alkyl
  • R 7 is O-R 8 ;
  • R 8 is selected from H, C 1 to C 6 alkyl, CHR 10 OC (O) CHNH 2 R 11 , CHR 12 OC (O) R 13 , CH 2 CH 2 OH, CH 2 CH (OH) CH 2 OH or wherein m is 0-20;
  • R 9 , R 10 , R 11 , and R 12 are each independently selected from H or C 1 to C 6 alkyl;
  • R 13 is selected from O (C 1 to C 6 alkyl) or C 1 to C 6 alkyl;
  • R 14 is selected from H, NR 15 R 16 , a heteroalkyl ring, or a heteroaryl ring;
  • R 15 and R 16 are each independently selected from H or C 1 to C 6 alkyl, or wherein R 15 and R 16 are joined together to form a C 3 to C 6 cycloalkyl or C 3 to C 6 heterocycloalkyl ring;
  • n 0, 1, 2, or 3;
  • R 1 and R 2 are each independently selected from H, C 1 to C 6 alkyl, (C 1 to C 6 alkyl) C (O) 2 R 9 , or wherein R 1 and R 2 are joined together to form a C 3 to C 6 cycloalkyl ring;
  • R 3 and R 4 are each independently selected from H, C 1 to C 6 alkyl, or wherein R 3 and R 4 are joined together to form a C 3 to C 6 cycloalkyl ring;
  • R 5 and R 6 are each independently selected from H or C 1 to C 6 alkyl
  • R 7 is O-R 8 ;
  • R 8 is selected from H, C 1 to C 6 alkyl, CHR 10 OC (O) CHNH 2 R 11 , CHR 12 OC (O) R 13 , CH 2 CH 2 OH, or CH 2 CH (OH) CH 2 OH;
  • R 9 , R 10 , R 11 , and R 12 are each independently selected from H or C 1 to C 6 alkyl
  • R 13 is selected from O (C 1 to C 6 alkyl) or C 1 to C 6 alkyl.
  • R 8 is CH 2 OC (O) OCH (CH 3 ) 2 or CH (CH 3 ) OC (O) OCH (CH 3 ) 2 .
  • R 8 is CH 2 OC (O) C (CH 3 ) 3 or CH (CH 3 ) OC (O) C (CH 3 ) 3 .
  • n 0.
  • n 1.
  • n 3.
  • a compound or a pharmaceutically acceptable salt thereof as defined in any one of items 1 to 81, the compound or pharmaceutically acceptable salt thereof comprises a cyclosporin ring; and wherein an isobutyl group at a 4-position of the cyclosporin ring is substituted with at least one hydroxyl substituent.
  • a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof as defined in any one of items 1 to 82, and one or more pharmaceutically acceptable excipients.
  • a method of treatment and/or prevention of a disease or condition comprising administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as defined in any one of items 1 to 83.
  • cyclophilin A-mediated disease or condition is selected from the group consisting of cardiovascular disease, viral infection, cancer, kidney disease, rheumatoid arthritis, sepsis, asthma, colitis, ulcerative colitis, Crohn’s disease, allergic rhinitis, atherosclerosis, vascular smooth muscle cell disease, myocarditis, cardiac fibrosis, central nervous system diseases, Alzheimer’s disease, and amyotrophic lateral sclerosis.
  • cancer is selected from the group consisting of breast cancer, small cell lung cancer, non-small cell lung cancer, and renal cell carcinoma.
  • kidney disease is selected from the group consisting of acute kidney injury, nephritis, and renal fibrosis.
  • cyclophilin D-mediated disease or condition is a disease or condition associated with cell injury or cell death, e.g., cell injury or cell death in an organ.
  • any one of items 97 to 98 wherein the organ is selected from the group consisting of kidney, liver, heart, lung, pancreas, intestine, cornea, skin, brain, and nerve tissue.
  • intravenous injection or infusion is selected from the group consisting of subcutaneous, intramuscular or intravenous injection, and intravenous or subcutaneous infusion.
  • the compounds as described herein may be obtainable in accordance to the general synthesis route as depicted below, comprising: a first step of reacting a cyclosporin compound (for example, cyclosporin A, C, D, G, etc. ) with dipyridyl disulphide to form a thiopyridyl intermediate ( [ (2’- (2-thiopyridyl) -Sar] 3 -cyclosporin A or C, or D, or G, etc. ) , such as a compound of formula II as depicted below, followed by a second step comprising the reaction of this intermediate with a hydroxylalkylcarboxylate ester compound (HO-X-C (O) OR) in the presence of copper triflate.
  • a hydroxylalkylcarboxylate ester compound used include, but are not limited to, methyl glycolate or 2-tert-butyl glycolate.
  • analogues may be prepared using different hydroxylalkylcarboxylate ester compounds (HO-X-C (O) OR) in the second step, for example, where the -X-group varies in alkyl chain length and/or structure or where the carboxylate ester substituent -R varies in alkyl chain length and/or structure.
  • HO-X-C (O) OR hydroxylalkylcarboxylate ester compounds
  • the first flask with Cu (OTf) 2 or AgOTf was dried at 120 °C under vacuum for 4 hours. After being cooled to room temperature, the reactor was placed into a dry ice bath, followed by slow addition of THF under a nitrogen atmosphere. To the second flask was added compound II, an hydroxylalkylcarboxylate ester compound (HO-X-C (O) OR) , and THF under a nitrogen atmosphere. This solution was then added dropwise into the first reactor flask with Cu (OTf) 2 or AgOTf/THF at room temperature, followed by addition of trimethylsilyl chloride (TMSCl) . The reaction mixture was maintained stirring at the same temperature for another 16 hours.
  • TMSCl trimethylsilyl chloride
  • Compound VI was prepared analogously to Compound III, above, where R is a -tert-butyl group. To the solution of ZnCl 2 in THF (1 M) was added compound VI. The stirred mixture was warmed up to 40 °C under N 2 and maintained for 18 hours. After being checked by HPLC, the mixture was added 1 M HCl aq., extracted by DCM. The organic phase was dried over Na 2 SO 4 , concentrated to obtain crude. The crude was further purified by preparative TLC or by preparative HPLC to afford the desired compound VII as white solid. Compounds 11 and 30 were prepared by this methodology.
  • Terfenadine (stored at 4 °C) , tolbutamide (stored at 4 °C) , NaH 2 PO 4 ⁇ 2 H 2 O (stored at room temperature) , Na 2 HPO 4 ⁇ 12 H 2 O (stored at room temperature) , and NaCl (stored at room temperature) were obtained from Sigma-Aldrich.
  • FaSSIF, FeSSIF, FaSSGF, and FaSSIF-V2 were obtained from Biorelevant and stored at 4 °C.
  • a filter plate was obtained from Merck Millipore and stored at room temperature. Mass spectra were obtained on a Q Trap 4500 mass spectrometer obtained from AB Sciex.
  • the LC-MS/MS analysis was carried out in ESI, positive ionization mode using an ACE Excel 5 C4 50*2.1 mm column with a mobile phase A of 0.1%formic acid in H 2 O and a mobile phase B of 0.1%formic acid in acetonitrile with a run time of 3 minutes.
  • a solution of FaSSIF with pancreatin was prepared in a maleic acid buffer solution.
  • the maleic acid buffer solution was prepared from 0.695 g NaOH, 1.115 g maleic acid, and 2.005 g NaCl dissolved in 0.49 L distilled water. The pH was adjusted to 6.8 with HCl and the volume was brought to 0.5 L with distilled water. The maleic acid buffer solution was filtered through a 0.22 ⁇ m filter.
  • FaSSIF-V2 powder (89.5 mg) was dissolved in the maleic acid buffer and the volume was brought to 50 mL and stored at 4 °C for future use.
  • pancreatin powder 100 mg was dissolved in 10 mL of the above FaSSIF-V2 solution.
  • a solution of FaSSGF with pepsin was prepared in a NaCl/HCl buffer solution.
  • the NaCl/HCl buffer solution was prepared from 1.0 g NaCl dissolved in 0.49 L distilled water. The pH was adjusted to 1.2 with HCl and the volume was brought to 0.5 L with distilled water. The NaCl/HCl buffer solution was filtered through a 0.22 ⁇ m filter.
  • FaSSGF powder (3.0 mg) was dissolved in the NaCl/HCl buffer and the volume was brought to 5O mL and stored at 4 °C for future use.
  • pepsin powder 32 mg was dissolved in 10 mL of the above FaSSGF solution.
  • Stock solutions of compounds 2, 47, 48, and 49 were prepared at a concentration of 50 mM in DMSO. From these 50 mM stock solutions, 200 ⁇ M working solutions of compounds 2, 47, 48, and 49 were prepared by diluting the stock solutions with DMSO.
  • a stock solution of terfenadine was prepared at 1/1 mg/mL in DMSO. From this 1/1 mg/mL stock solution, a 5/10 ng/mL quenching solution of terfenadine was prepared by diluting the stock solution with acetonitrile. The same procedure was used to prepare a 1/1 mg/mL stock solution of tolbutamide in DMSO and a 5/10 ng/mL quenching solution of tolbutamide in acetonitrile.
  • FaSSIF with pancreatin solution or the FaSSGF with pepsin solution was added 1.0 ⁇ L of the test compound/control working solution at 0, 5, 15, 30, 60, and 120 minutes and incubated for 120, 60, 30, 15, 5, and 0 minutes, respectively. After 120 minutes, 600 ⁇ L of quenching solution is added to the 200 ⁇ L reaction mixture.
  • a 1 ⁇ M standard solution of compound 2 was prepared by adding of 199 ⁇ L of the buffer solution to 600 ⁇ L of the quenching solution. Subsequently, 1.0 ⁇ L of the working solution of compound 2 was added to prepare the standard solution of compound 2.
  • test solutions and standard solution of compound 2 were vortexed vigorously for 1 minute and centrifuged at 4000 rpm at 4 °C for 15 min.
  • the supernatants (300 ⁇ L) of each sample were removed for LC-MS/MS analysis.
  • Sprague-Dawley (male) rat plasma was obtained from BIOIVT and stored at -20 °C. Mass spectra were obtained on a Q Trap 4500 or API 4000 mass spectrometer obtained from AB Sciex.
  • the LC-MS/MS analysis was carried out in ESI, positive ionization mode using an ACE Excel 5 C4 50*2.1 mm column (run time 3 minutes) or a Kinetex 2.6 ⁇ m C18 column (2.1 mm *30 mm, run time 1.5 minutes) with a mobile phase A of 0.1%formic acid in H 2 O and a mobile phase B of 0.1%formic acid in acetonitrile.
  • the rat plasma was thawed in a 37 °C water bath and the pH was adjusted to 7.4 with an aqueous HCl or NaOH solution as needed.
  • a stock solution of terfenadine was prepared at 1/1 mg/mL in DMSO. From this 1/1 mg/mL stock solution, a 5/10 ng/mL quenching solution of terfenadine was prepared by diluting the stock solution with acetonitrile. The same procedure was used to prepare a 1/1 mg/mL stock solution of tolbutamide in DMSO and a 5/10 ng/mL quenching solution of tolbutamide in acetonitrile.
  • Stock solutions of compounds 2, 47, 48, and 49 were prepared at a concentration of 50 mM in DMSO. From these 50 mM stock solutions, 200 ⁇ M working solutions of compounds 2, 47, 48, and 49 were prepared by diluting the stock solutions with DMSO.
  • the rat plasma was pre-warmed in a 37 °C water bath for 15 min.
  • the working solution of the control/test compound (2 ⁇ L) was added to 398 ⁇ L of plasma and mixed well by pipetting. From the reaction mixture at each time point (0, 5, 15, 30, 60 and 120 min) , 30 ⁇ L was removed and added to 300 ⁇ L of the quenching solution.
  • DMSO (3 ⁇ L) was added to the above solutions to ensure the same concentration in DMSO as the standard solution of compound 2.
  • a 1 ⁇ M standard solution of compound 2 was prepared by adding 30 ⁇ L plasma to 300 ⁇ L quenching solution to which a working solution of compound 2 (3 ⁇ L, 10 ⁇ M) was added.
  • test samples and standard solution of compound 2 were mixed well by vortexing for 1 minute and centrifuged at 4,000 rpm for 15 minutes at 4 °C.
  • the supernatants (100 ⁇ L) of each sample were mixed with 100 ⁇ L of distilled water for LC-MS/MS analysis.
  • Rat (male) intestinal S9 without phenylmethyl sulfonyl fluoride (PMSF) was obtained from BioreclamationIVT and stored at -80 °C.
  • Terfenadine, tolbutamide, and tetracaine were obtained from Sigma-Aldrich.
  • K 2 HPO 4 was obtained from SCR.
  • NADPH was obtained from ACROS.
  • Mass spectra were obtained on a Q Trap 4500 or API 4000 mass spectrometer obtained from AB Sciex.
  • the LC-MS/MS analysis was carried out in ESI, positive ionization mode using an ACE Excel 5 C4 50*2.1 mm column with a mobile phase A of 0.1%formic acid in H 2 O and a mobile phase B of 0.1%formic acid in acetonitrile with a run time of 3 minutes.
  • a phosphate buffer solution (50 mM K 2 HPO 4 , pH 7.4) was prepared by dissolving 8.709 g K 2 HPO 4 in 950 mL of water. The pH was adjusted to 7.4 using an HCl solution. The final volume was adjusted to 1000 mL with water, filtered through a 0.22 ⁇ m filter, and stored at 4 °C for future use.
  • a stock solution of terfenadine was prepared at 1/1 mg/mL in DMSO. From this 1/1 mg/mL stock solution, a 5/10 ng/mL quenching solution of terfenadine was prepared by diluting the stock solution with acetonitrile. The same procedure was used to prepare a 1/1 mg/mL stock solution of tolbutamide in DMSO and a 5/10 ng/mL quenching solution of tolbutamide in acetonitrile.
  • Stock solutions of compounds 47, 48, and 49 were prepared at a concentration of 50 mM in DMSO. From these 50 mM stock solutions, 200 ⁇ M working solutions of compounds 47, 48, and 49 were prepared by diluting the stock solutions with DMSO.
  • the intestinal S9 was thawed in a 37 °C water bath.
  • a 5 mM NADPH working solution was prepared with the phosphate buffer solution.
  • the working solution of the control/test compound (1.5 ⁇ L) was added to the intestinal S9 working solution (238,5 ⁇ L) in a 1.1 mL tube and gently mixed.
  • the tube was pre-incubated in a 37 °C shaking water bath for 5 minutes.
  • the reaction is started by adding the NADPH working solution (60 ⁇ L) to the tube and mixed by pipetting. From the reaction mixture at each time point (0, 5, 15, 30, and 60 min) , 30 ⁇ L was transferred to 300 ⁇ L of the quenching solution and mixed well by pipetting.
  • DMSO (3 ⁇ L) was added to the above solutions to ensure the same concentration in DMSO as the standard solution of compound 2. The samples were vortexed vigorously for about 1 minute.
  • a standard solution of compound 2 was prepared at a concentration of 50 mM in DMSO. From this 50 mM stock solution, a 10 ⁇ M working solution of compound 2 was prepared by diluting the standard solution of compound 2 with DMSO. The intestinal S9 working solution (24 ⁇ L) and the NADPH working solution (6 ⁇ L ) was added to the quenching solution (300 ⁇ L) , then 3 ⁇ L of the compound 2 working solution was added and mixed well.
  • test samples and standard solution of compound 2 were centrifuged at 4000 rpm at 4 °C for 15 minutes. Each supernatant (100 ⁇ L) was mixed with distilled water (100 ⁇ L) for LC-MS/MS analysis.
  • Prodrug compounds 47, 48, and 49 were tested in different matrices for stability and ability to generate parent compound 2.
  • the assay results obtained are summarized in Tables 2 and 3 below.
  • the prodrug glycerol linker moiety may be used to increase the stability of the prodrug compounds without compromising the biological activity of parent compound.
  • Such prodrug glycerol linker moieties may be utilized to develop prodrugs of carboxylic acid containing parent drugs which may increase the absorption of the parent compound.
  • Example 1 The compounds as prepared in Example 1 are evaluated in cyclophilin A and D peptidyl-prolyl isomerase functional assays using human recombinant enzymes (PPIase assay) , as well as in a calcineurin inhibition assay with and without cyclophilin A.
  • PPIase assay human recombinant enzymes
  • calcineurin inhibition assay with and without cyclophilin A.
  • the compounds are also evaluated in a calcium retention capacity (CRC) assay in permeabilized HepG2. Cyclosporin A is used as a control in all assays.
  • CPC calcium retention capacity
  • the compounds are supplied as a dry powder or oils and made up as a 10 mM stock solution in 100%DMSO. Subsequent dilutions were made in 100%DMSO for use in all assays.
  • This colorimetric 96 well assay is designed for inhibitor screening of recombinant Calcineurin (CaN) .
  • Activity is determined using the RII phosphopeptide substrate, the most efficient and selective peptide known for calcineurin, and detection of free phosphate released is based on the classic malachite green assay.
  • CypA and CsA form a complex which binds CaN/calmodulin, which will inhibit dephosphorylation of the RII peptide.
  • cyclosporine-like cyclophilin inhibitors were screened in the assay to determine inhibition of calcineurin phosphatase activity.
  • CRC Calcium Retention Capacity
  • HepG2 cells were permeabilised with 100 ⁇ M digitonin for 10 min in ice cold buffer containing 1 mM EGTA. Following two wash steps to remove the digitonin, the cells were plated into 96 well black and clear plates at 1e 6 cell per well in 180 ⁇ L assay buffer containing 0.5 ⁇ M Calcium Green 5N. Compounds dilutions were made in DMSO to 1000-fold the final concentration, diluted 1 ⁇ 100 in assay buffer and added to the assay as 20 ⁇ L per well.
  • the assay buffer contained 5mM glutamate and 2.5mM malate.
  • the cell plate was immediately run on the FLIPR Tetra TM which added 5 ⁇ L of 200 ⁇ M (5 ⁇ M) calcium chloride every 5 minutes whilst reading the plate every 3 seconds. The area under the curve at each concentration of compound was calculated. EC 50 values were calculated. The use of Area Under the Curve (AUC) rather than the number of Calcium additions before buffering is lost was determined to be a more accurate way of analysing the
  • a 10 mM stock solution of each representative compound of the present disclosure was diluted with DMSO to a concentration of 2 mM, then were further diluted 33.33x with the 10%FBS 1640 medium to a concentration of 60 ⁇ M. Then 25 ⁇ L of the test compound solution was added to the corresponding well. The test compound final concentration was 10 ⁇ M and a total of 10 concentrations were investigated (3-fold dilution per concentration) and each concentration point was set two replicate wells. The compounds were incubated at 37°C for 6 hours. After incubation, 120 ⁇ L supernatant from each well was transferred to a new 96 well plate and stored at 4°C overnight. Coating ELISA plate: the capture antibody was prepared with coating buffer in the Elisa kit, 100 ⁇ L/well coating 96 well plate and stored in 4°C overnight.
  • IL-2 ELISA determination Each well was aspirated and the ELISA plate washed with wash buffer. The process was repeated two times for a total of three washes. Block buffer (200 ⁇ L) was added to each well. The plates were incubated at room temperature for 1 hour. The aspiration/wash steps were repeated and 100 ⁇ L of sample or standards in the reagent diluent, or an appropriate diluent, was added per well. The wells were covered with an adhesive strip and incubated for 2 hours at room temperature. The aspiration/wash steps were repeated with 5 total washes and 100 ⁇ L of the working detector (Detection Antibody + Streptavidin-HRP reagent) was added to each well.
  • the working detector Detection Antibody + Streptavidin-HRP reagent
  • the wells were covered with an adhesive strip and incubated for 1 hour at room temperature.
  • the aspiration/wash steps were repeated with 7 total washes and 100 ⁇ L of substrate solution was added to each well.
  • the plate was covered and incubated for 30 minutes at room temperature out of direct light.
  • a stop solution 50 ⁇ L was added to each well, gently tapping the plate to ensure thorough mixing. The OD450/570 nm was recorded.
  • CsA While some compounds exhibit similar immunosuppressive properties as CsA, they may have surprisingly improved, and increased water solubility as e.g. compared to CsA.
  • CsA is a poorly water soluble active pharmaceutical ingredient which poses a drug formulation and delivery problem. It has required in many instances, and across different therapeutic applications, the development of specific (and complex) formulation strategies to solubilize it and to facilitate its delivery.
  • the water solubilities of selected compounds disclosed herein were determined and compared to Compound 0 and cyclosporin A (CsA) in Table 5.
  • An Ultimate 3000 HPLC from Thermo Scientific was used for the analysis using a Hypersil GOLDTM 5 ⁇ m, 4.6 ⁇ 250 mm column with a mobile phase A: 0.05%formic acid in H 2 O and a mobile phase B: 0.05%formic acid in acetonitrile.
  • the column temperature was 40 °C with a flow rate of 1.0 mL/min and 210 nm wavelength.
  • the mobile phase (A ⁇ B) composition was 95 ⁇ 5, 95 ⁇ 5, 5 ⁇ 95, 5 ⁇ 95, 95 ⁇ 5, and 95 ⁇ 5, respectively.
  • Standard solutions were prepared as follows. First, the test compound was accurately weighed to obtain weight data (m STD , ⁇ g) . Second, the test compound was dissolved in acetonitrile. Acetonitrile was added to adjust to the final volume in a volumetric flask to obtain the standard solution and its volume data (V STD , mL) . The standard solution was analyzed by HPLC to obtain the data of the injection volume (V STDInj , ⁇ L) and the peak area in HPLC spectrum (A STD , mAU*min) .
  • the standard solution concentration was calculated as follows:
  • the water solubility was calculated as follows:

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Abstract

L'invention concerne des composés tels que définis par les formules 1 à 6 et leurs utilisations en tant qu'inhibiteurs de la cyclophiline, pour la prévention ou le traitement de maladies ou d'affections telles que des maladies ou des affections médiées par la cyclophiline, en particulier, des maladies ou des affections médiées par la cyclophiline A.
PCT/CN2024/096567 2023-06-02 2024-05-31 Inhibiteurs de cyclophiline et leurs utilisations Pending WO2024245384A1 (fr)

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Citations (11)

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WO1999065933A1 (fr) * 1998-06-12 1999-12-23 C-Chem Ag Nouvelles cyclosporines
WO2007041631A1 (fr) * 2005-09-30 2007-04-12 Scynexis, Inc. Derives d'arylalkyle et d'heteroarylalkyle de cyclosporine a utilises pour traiter et prevenir une infection virale
WO2007136759A2 (fr) * 2006-05-19 2007-11-29 Scynexis, Inc. Procédé de traitement et de prévention de troubles oculaires
WO2008143996A1 (fr) * 2007-05-18 2008-11-27 Scynexis, Inc. Nouveaux procédés chimiques
WO2011082289A1 (fr) * 2009-12-30 2011-07-07 Scynexis Inc. Analogues de cyclosporine
WO2012009715A2 (fr) * 2010-07-16 2012-01-19 S&T Global Inc. Nouveaux dérivés de la cyclosporine destinés à traiter et à prévenir une infection virale
WO2012079172A1 (fr) * 2010-12-15 2012-06-21 Isotechnika Pharma Inc. Molécules analogues de cyclosporine modifiées au niveau des acides aminés 1 et 3
WO2014145686A2 (fr) * 2013-03-15 2014-09-18 Zhuang Su Nouveaux dérivés de cyclosporine et leurs utilisations
WO2016112321A1 (fr) * 2015-01-08 2016-07-14 Allergan, Inc. Dérivés de cyclosporine dans lesquels la chaîne latérale mebmt a été cyclisée
WO2019016572A1 (fr) * 2017-07-21 2019-01-24 Cypralis Ltd Analogues de la ciclosporine et leurs utilisations
WO2021190601A1 (fr) * 2020-03-26 2021-09-30 Farsight Medical Technology (Shanghai) Co., Ltd. Inhibiteurs de cyclophiline et leurs utilisations

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999065933A1 (fr) * 1998-06-12 1999-12-23 C-Chem Ag Nouvelles cyclosporines
WO2007041631A1 (fr) * 2005-09-30 2007-04-12 Scynexis, Inc. Derives d'arylalkyle et d'heteroarylalkyle de cyclosporine a utilises pour traiter et prevenir une infection virale
WO2007136759A2 (fr) * 2006-05-19 2007-11-29 Scynexis, Inc. Procédé de traitement et de prévention de troubles oculaires
WO2008143996A1 (fr) * 2007-05-18 2008-11-27 Scynexis, Inc. Nouveaux procédés chimiques
WO2011082289A1 (fr) * 2009-12-30 2011-07-07 Scynexis Inc. Analogues de cyclosporine
WO2012009715A2 (fr) * 2010-07-16 2012-01-19 S&T Global Inc. Nouveaux dérivés de la cyclosporine destinés à traiter et à prévenir une infection virale
WO2012079172A1 (fr) * 2010-12-15 2012-06-21 Isotechnika Pharma Inc. Molécules analogues de cyclosporine modifiées au niveau des acides aminés 1 et 3
WO2014145686A2 (fr) * 2013-03-15 2014-09-18 Zhuang Su Nouveaux dérivés de cyclosporine et leurs utilisations
WO2016112321A1 (fr) * 2015-01-08 2016-07-14 Allergan, Inc. Dérivés de cyclosporine dans lesquels la chaîne latérale mebmt a été cyclisée
WO2019016572A1 (fr) * 2017-07-21 2019-01-24 Cypralis Ltd Analogues de la ciclosporine et leurs utilisations
WO2021190601A1 (fr) * 2020-03-26 2021-09-30 Farsight Medical Technology (Shanghai) Co., Ltd. Inhibiteurs de cyclophiline et leurs utilisations

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