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WO2011144924A1 - Amine ou analogues d'amide de sanglifehrine - Google Patents

Amine ou analogues d'amide de sanglifehrine Download PDF

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Publication number
WO2011144924A1
WO2011144924A1 PCT/GB2011/050928 GB2011050928W WO2011144924A1 WO 2011144924 A1 WO2011144924 A1 WO 2011144924A1 GB 2011050928 W GB2011050928 W GB 2011050928W WO 2011144924 A1 WO2011144924 A1 WO 2011144924A1
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compound according
hcv
carbon atoms
alkyl
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Steven James Moss
Barrie Wilkinson
Ming-Qiang Zhang
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Biotica Technology Ltd
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Biotica Technology Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0215—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing natural amino acids, forming a peptide bond via their side chain functional group, e.g. epsilon-Lys, gamma-Glu
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention relates to sanglifehrin analogues, that are useful as cyclophilin inhibitors, e.g. in the treatment of viral infection especially infection by RNA viruses such as Hepatitis C virus (HCV) and HIV and muscular dystrophy.
  • RNA viruses such as Hepatitis C virus (HCV) and HIV and muscular dystrophy.
  • HCV Hepatitis C virus
  • the present invention also provides methods for their use in medicine, in particular for the treatment of HCV infection.
  • Hepatitis C virus is a positive strand RNA virus, and infection is a leading cause of post-transfusional hepatitis.
  • HCV is the most common chronic blood borne infection, and the leading cause of death from liver disease in United States.
  • the World Health Organization estimates that there are more than 170 million chronic carriers of HCV infection, which is about 3% of the world population.
  • the un-treated HCV-infected patients about 70%-85% develop chronic HCV infection, and are therefore at high risk to develop liver cirrhosis and hepatocellular carcinoma.
  • 50-76% of all cases of liver cancer and two- thirds of all liver transplants are due to chronic HCV infection (Manns et al, 2007).
  • HCV infection causes non-liver complications such as arthralgias (joint pain), skin rash, and internal organ damage predominantly to the kidney. HCV infection represents an important global health-care burden, and currently there is no vaccine available for hepatitis C (Strader et al., 2004;
  • SoC The current standard of care
  • pIFNa pegylated interferon-a
  • SVR sustained virologic response
  • HCV RNA levels Patients with genotype 2 and 3 are more likely to respond to SoC than patients infected with genotype 1 (Melnikova, 2008; Jacobson et al., 2007).
  • SoC is also contraindicated in some patients who are not considered candidates for treatment, such as patients with past significant episodes of depression or cardiac disease. Side effects of the SoC, which frequently lead to discontinuation of treatment include a flu-like illness, fever, fatigue, haematological disease, anaemia, leucopaenia, thrombocytopaenia, alopecia and depression (Manns et al., 2007).
  • HCV has a short life cycle and therefore development of drug resistance during drug therapy is common.
  • Novel, specifically targeted antiviral therapy for hepatitis C (STAT-C) drugs are being developed that target viral proteins such as viral RNA polymerase NS5B or viral protease NS3 (Jacobson et al, 2007; Parfieniuk et al., 2007).
  • novel compounds also are being developed that target human proteins (e.g. cyclophilins) rather than viral targets, which might be expected to lead to a reduction in incidence of resistance during drug therapy (Manns et al., 2007; Pockros, 2008; Pawlotsky J-M, 2005).
  • Cyclophilins are a family of cellular proteins that display peptidyl-prolyl cis-trans isomerase activity facilitating protein conformation changes and folding. CyPs are involved in cellular processes such as transcriptional regulation, immune response, protein secretion, and mitochondrial function. HCV virus recruits CyPs for its life cycle during human infection.
  • CyPs stimulate the RNA binding activity of the HCV non-structural protein NS5B RNA polymerase that promotes RNA replication, although several alternative hypotheses have been proposed including a requirement for CyP PPIase activity.
  • the ability to generate knockouts in mice Coldgan et al., 2000
  • human T cells Braaten and Luban, 2001 ) indicates that CyPA is optional for cell growth and survival..
  • Cyclosporine A (Inoue et al. 2003) ("CsA") and its closely structurally related non- immunosuppressive clinical analogues DEBIO-025 (Paeshuyse et al. 2006; Flisiak et al. 2008), NIM81 1 (Mathy et al. 2008) and SCY-635 (Hopkins et al., 2009) are known to bind to cyclophilins, and as cyclophilin inhibitors have shown in vitro and clinical efficacy in the treatment of HCV infection (Crabbe et al., 2009; Flisiak et al. 2008; Mathy et al.
  • DEBIO-025 the most clinically advanced cyclophilin inhibitor for the treatment of HCV, has shown in vitro and in vivo potency against the four most prevalent HCV genotypes (genotypes 1 , 2, 3, and 4). Resistance studies showed that mutations conferring resistance to DEBIO-025 were different from those reported for polymerase and protease inhibitors, and that there was no cross resistance with STAT-C resistant viral replicons. More importantly, DEBIO-025 also prevented the development of escape mutations that confer resistance to both protease and polymerase inhibitors (Crabbe et al., 2009).
  • CsA-based cyclophilin inhibitors in clinical development have a number of issues, which are thought to be related to their shared structural class, including: certain adverse events that can lead to a withdrawal of therapy and have limited the clinical dose levels; variable pharmacokinetics that can lead to variable efficacy; and an increased risk of drug-drug interactions that can lead to dosing issues.
  • AEs adverse events
  • Peg-IFN can cause profound thrombocytopaenia and combination with DEBIO-025 could represent a significant clinical problem.
  • Both an increase in bilirubin and decrease in platelets have also been described in early clinical studies with NIM-81 1 (Ke et al., 2009).
  • DEBIO-025 and cyclosporine A are known to be inhibitors of biliary transporters such as bile salt export pumps and other hepatic transporters (especially MRP2/cMOAT/ABCC2) (Crabbe et al., 2009). It has been suggested that the interaction with biliary transporters, in particular MRP2, may be the cause of the hyperbilirubinaemia seen at high dose levels of DEBIO-025 (Nelson et al., 2009).
  • DEBIO-025 and cyclosporine A are substrates for metabolism by cytochrome P450 (especially CYP3A4), and are known to be substrates and inhibitors of human P- glycoprotein (MDR1 ) (Crabbe et al., 2009). Cyclosporine A has also been shown to be an inhibitor of CYP3A4 in vitro (Niwa et al., 2007). This indicates that there could be an increased risk of drug-drug interactions with other drugs that are CYP3A4 substrates, inducers or inhibitors such as for example ketoconazole, cimetidine and rifampicin. In addition, interactions are also expected with drugs that are subject to transport by P-glycoprotein (e.g.
  • CsA digoxin
  • CsA is also known to have highly variable pharmacokinetics, with early formulations showing oral bioavailability from 1 -89% (Kapurtzak et al., 2004). Without expensive monitoring of patient blood levels, this can lead to increased prevalence of side effects due to increased plasma levels, or reduced clinical response due to lowered plasma levels.
  • Sanglifehrin A and its natural congeners belong to a class of mixed non-ribosomal peptide/polyketides, produced by Streptomyces sp. A92-3081 10 (also known as DSM 9954) (see WO 97/02285), which were originally discovered on the basis of their high affinity to cyclophilin A (CyPA). SfA is the most abundant component in fermentation broths and exhibits approximately 20-fold higher affinity for CyPA compared to CsA. This has led to the suggestion that sanglifehrins could be useful for the treatment of HCV (WO2006/138507).
  • Sanglifehrins have also been shown to exhibit a lower immunosuppressive activity than CsA when tested in vitro (Sanglier et al., 1999; Fehr et al., 1999). SfA binds with high affinity to the CsA binding site of CyPA (Kallen et al., 2005;).
  • the immunosuppressive mechanism of action of SfA is different to that of other known immunophilin-binding immunosuppressive drugs such as CsA, FK506 and rapamycin.
  • SfA does not inhibit the phosphatase activity of calcineurin, the target of CsA (Zenke et al. 2001 ), instead its immunosuppressive activity has been attributed to the inhibition of interleukin-6 (Hartel et al., 2005), interleukin-12 (Steinschulte et al., 2003) and inhibition of interleukin-2- dependent T cell proliferation (Zhang & Liu, 2001 ).
  • the molecular target and mechanism through which SfA exerts its immunosuppressive effect is hitherto unknown.
  • SfA The molecular structure of SfA is complex and its interaction with CyPA is thought to be mediated largely by the macrocyclic portion of the molecule.
  • a macrocyclic compound hydroxymacrocycle derived from oxidative cleavage of SfA has shown strong affinity for CyPA (Sedrani et al., 2003).
  • X-ray crystal structure data has shown that the hydroxymacrocycle binds to the same active site of CyPA as CsA.
  • Analogues based on the macrocycle moiety of SfA have also been shown to be devoid of immunosuppressive properties (Sedrani et al., 2003), providing opportunity for design of non-immunosuppressive CyP inhibitors for potential use in HCV therapy.
  • These molecules will have lower molecular weight than SfA and are expected to possess improved physico-chemcial properties suitable for drug development.
  • Cyclophilin inhibitors such as CsA and DEBIO-025 have also shown potential utility in inhibition of HIV replication.
  • the cyclophilin inhibitors are thought to interfere with function of CyPA during progression/completion of HIV reverse transcription (Ptak et al., 2008).
  • Cyclophilin inhibitors such as DEBIO-025 have shown utility in animal models of muscular dystrophy, in particular Ullrich congenital muscular dystrophy and Bethlem myopathy (WO2008/084368). Specifically, they were seen to reduce mitochondrial swelling and necrotic disease manifestation in mdx mice, a model of Duchenne Muscular Dystrophy (Millay et al., 2008). They are thought to exert their effect through inhibition of cyclophilin D.
  • cyclophilin inhibitors which may have utility, particularly in the treatment of HCV infection, but also in the treatment of other disease areas where inhibition of cyclophilins may be useful, such as HIV infection, Muscular Dystrophy or aiding recovery after myocardial infarction.
  • cyclophilin inhibitors have improved properties over the currently available cyclophilin inhibitors, including one or more of the following properties: improved water solubility, improved pharmacological profile, such as high exposure to target organ (e.g. liver in the case of HCV) and/or long half life (enabling less frequent dosing), reduced drug-drug interactions, such as via reduced levels of CYP3A4 metabolism and inhibition and reduced (Pgp) inhibition (enabling easier multi-drug
  • the present invention discloses novel sanglifehrin analogues which may have one or more of the above properties.
  • the present invention discloses novel amine derivatives, which are anticipated to have improved solubility, and therefore improved formulation.
  • the present invention provides novel macrocyclic sanglifehrin analogues, which have been generated by semisynthetic modification of native sanglifehrins. These analogues may be generated by dihydroxylation of a sanglifehrin, such as SfA, followed by cleavage to generate the aldehydic macrocycle, followed by further chemistry, such as reductive amination or oxidation followed by amidation, to generate molecules with a variety of substituents to replace the aldehyde.
  • SfA dihydroxylation of a sanglifehrin
  • cleavage to generate the aldehydic macrocycle
  • further chemistry such as reductive amination or oxidation followed by amidation
  • the present invention provides macrocylic amine and amide analogues of SfA, methods for the preparation of these compounds, and methods for the use of these compounds in medicine or as intermediates in the production of further compounds.
  • the present invention provides macrocylic amines, macrocyclic amides and derivatives thereof according to formula (I) below, or a
  • X represents CH 2 or CO
  • Ri and R 2 independently represent hydrogen; or an alkyl or alkenyl group which may optionally be joined to form a saturated or unsaturated heterocyclic ring containing the nitrogen atom shown and wherein one or more carbon atoms of Ri and/or R 2 are optionally replaced by a heteroatom selected from O, N and S(0) p in which p represents 0, 1 or 2 and wherein one or more carbon atoms of Ri and/or R 2 are optionally replaced by carbonyl; or one of Ri and R 2 represents -alkylaryl, -alkenylaryl, -alkylheteroaryl or -alkenylheteroaryl and the other represents H, alkyl or alkenyl;
  • analogue means one analogue or more than one analogue.
  • analogue(s) refers to chemical compounds that are structurally similar to another but which differ slightly in composition (as in the replacement of one atom by another or in the presence or absence of a particular functional group).
  • sanglifehrin(s) refers to chemical compounds that are structurally similar to sanglifehrin A but which differ slightly in composition (as in the
  • sanglifehrin-like compounds discussed in WO97/02285 and WO98/07743, such as sanglifehrin B.
  • HCV Hepatitis C Virus
  • RNA RNA
  • enveloped virus in the viral family Flaviviridae.
  • HIV Human Immunodeficiency Virus
  • the causative agent of Human Acquired Immune Deficiency Syndrome the causative agent of Human Acquired Immune Deficiency Syndrome.
  • bioavailability refers to the degree to which or rate at which a drug or other substance is absorbed or becomes available at the site of biological activity after administration. This property is dependent upon a number of factors including the solubility of the compound, rate of absorption in the gut, the extent of protein binding and metabolism etc. Various tests for bioavailability that would be familiar to a person of skill in the art are described herein (see also Egorin et al. 2002).
  • water solubility refers to solubility in aqueous media, e.g. phosphate buffered saline (PBS) at pH 7.4, or in 5% glucose solution. Tests for water solubility are given below in the Examples as “water solubility assay”.
  • PBS phosphate buffered saline
  • macrocyclic amine or “macrocyclic amide” refers to a macrocylic amine or amide referred to above as representing the invention in its broadest aspect, for example a compound according to formula (I) above, or a pharmaceutically acceptable salt thereof. These compounds are also referred to as “compounds of the invention” or
  • the pharmaceutically acceptable salts of compounds of the invention include conventional salts formed from pharmaceutically acceptable inorganic or organic acids or bases as well as quaternary ammonium acid addition salts. More specific examples of suitable acid salts include hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, perchloric, fumaric, acetic, propionic, succinic, glycolic, formic, lactic, maleic, tartaric, citric, palmoic, malonic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methanesulfonic, naphthalene-2-sulfonic, benzenesulfonic hydroxynaphthoic, hydroiodic, malic, steroic, tannic and the like.
  • Hydrochloric acid salts are of particular interest.
  • Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable salts.
  • More specific examples of suitable basic salts include sodium, lithium, potassium, magnesium, aluminium, calcium, zinc, ⁇ , ⁇ '- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N- methylglucamine and procaine salts.
  • References hereinafter to a compound according to the invention include both compounds of formula (I) and their pharmaceutically acceptable salts.
  • alkyl represents a straight chain or branched alkyl group, containing typically 1 -8 carbon atoms, for example a Ci -6 alkyl group.
  • Alkenyl refers to an alkyl group containing two or more carbons (for example 2-8 carbons e.g. 2-6 carbons) which is unsaturated with one or more double bonds.
  • alkyl groups examples include d ⁇ alkyl groups such as methyl, ethyl, n-propyl, i-propyl, and n-butyl.
  • aryl groups include phenyl and naphthyl, especially phenyl which groups may optionally be substituted e.g. with one or more (e.g. 1 , 2 or 3) substituents e.g. selected from alkyl (eg halogen, alkoxy (e.g. nitro, -S0 2 Me, cyano or -CONH 2 .
  • alkyl e.g halogen, alkoxy (e.g. nitro, -S0 2 Me, cyano or -CONH 2 .
  • heteroaryl groups include monocyclic groups (e.g. 5 and 6 membered rings) and bicyclic rings (e.g. 9 and 10 membered rings) which are aromatic or (in the case of bicyclic rings contain at least one aromatic ring) and contain one or more heteroatoms (e.g. 1 , 2, 3 or 4) heteroatoms selected from N, O and S.
  • heteroatoms e.g. 1 , 2, 3 or 4
  • Examples of 5 membered heteroaryl rings include pyrrole, furan, thiophene, oxazole, oxadiazole, thiazole and triazole.
  • 6 membered heteroaryl rings include pyridine, pyrimidine and pyrazine.
  • bicyclic rings examples include quinoline, quinazoline, isoquinoline, indole, indane, cinnoline and quinoxaline.
  • Monocyclic heteroaryl groups are preferred.
  • the aforementioned heteroaryl groups may be optionally substituted as described above for aryl groups.
  • treatment includes prophylactic as well as therapeutic treatment.
  • the present invention provides sanglifehrin macrocylic analogues, as set out above, methods for preparation of these compounds and methods for the use of these compounds in medicine.
  • the compound is a methanol adduct thereof in which a ketal is formed by the combination of the C-53 keto and the C-15 hydroxyl groups and methanol. In another embodiment it is not.
  • Variable p suitably represents 0 or 1. In one embodiment p represents 0 in another embodiment p represents 1 . In another embodiment p represents 2.
  • R-i or R 2 represents -alkylaryl
  • an example includes Ci -2 alkylaryl e.g. benzyl.
  • R-i or R 2 represents -alkenylaryl
  • an example includes C 2-3 alkenylaryl e.g. - ethenylphenyl.
  • R-i or R 2 represents -alkylheteroaryl
  • an example includes Ci -2 alkylheteraryl e.g. -methylpyridinyl.
  • R-i or R 2 represents -alkenylheteroaryl
  • an example includes C 2- 3 alkenylheteroaryl e.g. -ethenylpyridinyl.
  • Ri and R 2 independently represent hydrogen; or an alkyl or alkenyl group which may optionally be joined to form a saturated or unsaturated heterocyclic ring containing the nitrogen atom shown and wherein one or more carbon atoms of Ri and/or R 2 are optionally replaced by a heteroatom selected from O, N and S(0) p in which p represents 0, 1 or 2 and wherein one or more carbon atoms of Ri and/or R 2 are optionally replaced by carbonyl.
  • R-i and R 2 may independently represent hydrogen; or an alkyl or alkenyl group which may optionally be joined to form a saturated or unsaturated heterocyclic ring containing the nitrogen atom shown and wherein one or more (e.g. one or two, such as one) carbon atoms of Ri and/or R 2 are optionally replaced by a heteroatom selected from O, N and S(0) p in which p represents 0, 1 or 2 and wherein one or more (e.g.
  • Ri and/or R 2 are optionally replaced by carbonyl or one of Ri and R 2 represents -alkylaryl, -alkenylaryl, -alkylheteroaryl or -alkenylheteroaryl and the other represents H, alkyl or alkenyl.
  • R-i and R 2 independently represent hydrogen; or an alkyl or alkenyl group wherein one or more (e.g. one or two such as one) carbon atoms of Ri and/or R 2 are optionally replaced by a heteroatom selected from O, N and S(0) p and wherein one or more (e.g. one or two such as one) carbon atoms of Ri and/or R 2 are optionally replaced by carbonyl;
  • examples include:
  • R-i represents hydrogen and R 2 represents an alkyl group and wherein one or more (e.g. one or two, such as one) carbon atoms of Ri and/or R 2 are replaced by carbonyl;
  • R-i represents hydrogen and R 2 represents an alkyl group and wherein one or more (e.g. one or two, such as one) carbon atoms of Ri and/or R 2 are replaced by a heteroatom selected from O, N and S(0) p ;
  • R-i represents hydrogen and R 2 represents an alkyl group and wherein one or more (e.g. one or two, such as one) carbon atoms of Ri and/or R 2 are replaced by a heteroatom selected from O, N and S(0) p ; and wherein one or more (e.g. one or two, such as one) carbon atoms of Ri and/or R 2 are replaced by a heteroatom selected from O, N and S(0) p .
  • Ri and R 2 represents -alkylaryl, -alkenylaryl, -alkylheteroaryl or - alkenylheteroaryl and the other represents H, alkyl or alkenyl; examples include:
  • Ri and R 2 independently represent an alkyl or alkenyl group which is joined to form a saturated or unsaturated heterocyclic ring containing the nitrogen atom shown and wherein one or more (e.g. one or two, such as one) carbon atoms of Ri and/or R 2 are optionally replaced by a heteroatom selected from O, N and S(0) p in which p represents 0, 1 or 2 and wherein one or more (eg one or two, such as one) carbon atoms of Ri and/or R 2 are optionally replaced by carbonyl;
  • examples include:
  • Ri and R 2 independently represent an alkyl or alkenyl group which are joined to form a saturated or unsaturated heterocyclic ring containing the nitrogen atom shown and wherein one or more (e.g. one or two, such as one) carbon atoms of Ri and/or R 2 are replaced by a heteroatom selected from O, N and S(0) p ;
  • Ri and R 2 independently represent an alkyl or alkenyl group which are joined to form a saturated or unsaturated heterocyclic ring containing the nitrogen atom shown and wherein one or more (e.g. one or two, such as one) carbon atoms of Ri and/or R 2 are replaced by carbonyl; and
  • R-i and R 2 independently represent an alkyl or alkenyl group which are joined to form a saturated or unsaturated heterocyclic ring containing the nitrogen atom shown and wherein one or more (e.g. one or two, such as one) carbon atoms of Ri and/or R 2 are replaced by a heteroatom selected from O, N and S(0) p and wherein one or more (e.g. one or two, such as one) carbon atoms of Ri and/or R 2 are replaced by carbonyl.
  • Ri or R 2 When a carbon atom of Ri or R 2 is replaced by a heteroatom, it is suitably replaced by O or N, especially N.
  • carbonyl When a carbon atom of Ri or R 2 is replaced by a carbonyl, the carbonyl is suitably located adjacent to another carbon atom or a nitrogen atom. Suitably carbonyl groups are not located adjacent to sulphur or oxygen atoms. Heterocyclic rings formed when R-i and R 2 are joined typically contain 4-8 ring atoms, e.g. 5-7 ring atoms, particularly 5 or 6 ring atoms.
  • Heterocyclic rings formed when R-i and R 2 are joined typically contain only the nitrogen atom shown or one or two (e.g. one) additional heteroatom, especially a nitrogen or oxygen atom.
  • R-i and/or R 2 contain more than one heteroatom, these should typically be separated by two or more carbon atoms.
  • nitrogen atoms within R-i and R 2 may be primary, secondary or tertiary nitrogen atoms.
  • R-i represents hydrogen. In another embodiment, neither R-i nor R 2 represents hydrogen. In another embodiment R-i and R 2 are not both hydrogen.
  • R-i and R 2 are selected from hydrogen, C i -4 alkyl and C i -4 alkenyl.
  • R-i and R 2 are selected from hydrogen, C i -4 alkyl and C i -4 alkenyl
  • R-i and R 2 do not both represent hydrogen.
  • R-i and R 2 together with the nitrogen to which they are attached represent a 5-7 membered heterocyclic ring, such as a pyrrolidine, piperidine, morpholine or piperazine ring in which the 4-nitrogen of piperazine is optionally substituted by
  • R-i and R 2 together with the nitrogen to which they are attached represent a 5-7 membered heterocyclic ring, such as a pyrrolidine, piperidine, morpholine or piperazine ring in which the 4-nitrogen of piperazine is optionally substituted by C1 - 4alkyl, and in which a carbon atom adjacent to a nitrogen atom within the ring is replaced with carbonyl.
  • R-i and R 2 together with the nitrogen to which they are attached represent piperidinone.
  • X represents CH 2 . In another embodiment X represents CO.
  • R-i and R 2 represent CH 3 e.g. as represented by the following structure:
  • the compounds of the invention are prepared by semi-synthetic derivatisation of a sanglifehrin.
  • Sanglifehrins may be prepared using methods described in WO97/02285 and WO98/07743, which documents are incorporated in their entirety, or additional methods described herein.
  • Semisynthetic methods for generating the sanglifehrin macrocylic aldehyde are described in US6,124,453, Metternich et al., 1999, Banteli et al., 2001 and Sedrani et al., 2003.
  • a process for preparing certain compounds of formula (I) or a pharmaceutically acceptable salt thereof comprises:
  • a process for preparing compounds of the invention comprises reducing the product of reacting a compound of formula R 1 R 2 NH with aldehydic macrocycle.
  • a sanglifehrin such as SfA
  • modified Sharpless conditions catalytic osmium tetroxide
  • the use of the chiral ligands aids in promoting selectivity.
  • the resultant 26,27-dihydroxylsanglifehrin can then be cleaved oxidatively, using for instance sodium periodate.
  • the resultant aldehydic macrocycle can then be used as a substrate for reductive amination.
  • the aldehyde is treated with an amine before the introduction of a reducing agent, typically sodium cyanoborohydride.
  • the imine that results from the coupling of the aldehyde and amine is then reduced to an amine.
  • the use of the correct stoichiometeries of amine and / or reducing agent is necessary in order to prevent reaction at the less reactive C-53 ketone.
  • Reductive amination is typically performed by combining the aldehydic macrocycle with the primary or secondary amine R 1 R 2 NH to form an imine in an inert organic solvent (such as THF) and then treating with a reducing agent such as sodium cyanoborohydride or sodium
  • the reaction may typically be performed at room temperature in one pot so that imine formation and reduction occur concurrently.
  • the amine R 1 R 2 NH may typically be employed in the form of an acid salt such as the HCI salt.
  • the reaction mixture may be worked up with acidic aqueous medium such as ammonium chloride.
  • carboxylic acid may be employed in the form of an activated derivative, such as an anhydride or acid halide.
  • a process for preparing certain compounds of the invention comprises reacting a compound of formula R-
  • the acid macrocycle can be prepared from the aldehydic macrocycle. The preparation of the aldehydic macrocycle has been described previously (Metternich et al. 1999) and is described above.
  • the acid macrocycle can then be coupled to an amine by standard peptide bond forming reactions. Exemplary conditions include combination of the reagents in an organic solvent (e.g. methylene chloride, dimethylformamide (DMF) or tetrahydrofuran ( THF)) in the presence of acid or base catalysis followed by aqueous work-up.
  • an organic solvent e.g. methylene chloride, dimethylformamide (DMF) or tetrahydrofuran ( THF)
  • protecting groups may be employed to protect functionality in the aldehydic macrocycle, acid macrocycle or the amine, as described in T. W. Green, P. G. M. Wuts, Protective Groups in Organic Synthesis, Wiley-lnterscience, New York, 1999, 49-54, 708-71 1 .
  • the methanol adduct may be prepared by fermentation and isolation from broth, or may be prepared from sanglifehrin A (WO97/02285).
  • Amine compounds of formula R 1 R 2 NH are either known or may be prepared by conventional methods.
  • a sanglifehrin macrocycle may be administered alone or in combination with other therapeutic agents.
  • Co-administration of two (or more) agents allows for lower doses of each to be used, thereby reducing side effect, can lead to improved potency and therefore higher SVR, and a reduction in resistance.
  • the sanglifehrin macrocycle is co-administered with one or more therapeutic agent s for the treatment of HCV infection, taken from the standard of care treatments.
  • a sanglifehrin macrocycle is co-administered with one or more other anti-viral agents, such as a STAT-C (specifically targeted agent for treatment of HCV), which could be one or more of the following: Non-nucleoside Polymerase inhibitors (e.g. IDX375, VCH-222, Bl 207127, ANA598, VCH-916), Nucleoside or nucleotide polymerase inhibitors (e.g. 2'- C-methylcytidine, 2'-C-methyladenosine, R1479, PSI-6130, R7128, R1626), Protease inhibitors (e.g. BILN-2061 , VX-950(Telaprevir), SCH503034(Boceprevir), TMC435350, MK-7009,
  • Non-nucleoside Polymerase inhibitors e.g. IDX375, VCH-222, Bl 207127, ANA598, VCH-916
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient (compound of the invention) with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • the compounds of the invention will normally be administered orally in the form of a pharmaceutical formulation comprising the active ingredient, optionally in the form of a nontoxic organic, or inorganic, acid, or base, addition salt, in a pharmaceutically acceptable dosage form.
  • a pharmaceutical formulation comprising the active ingredient, optionally in the form of a nontoxic organic, or inorganic, acid, or base, addition salt, in a pharmaceutically acceptable dosage form.
  • compositions may be administered at varying doses.
  • the compounds of the invention can be administered orally, buccally or sublingually in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed- or controlled-release applications.
  • Such tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxy-propylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.
  • Solid compositions of a similar type may also be employed as fillers in gelatin capsules.
  • Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols.
  • lactose lactose
  • starch a cellulose
  • milk sugar or high molecular weight polyethylene glycols.
  • compounds of the invention may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g. povidone, gelatin, hydroxypropyl methyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g. sodium starch glycolate, cross-linked povidone, cross-linked sodium
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethylcellulose in varying proportions to provide desired release profile.
  • Formulations in accordance with the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets, each containing a
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
  • agents such as preservatives and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • the dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.
  • the dosage to be administered of a compound of the invention will vary according to the particular compound, the disease involved, the subject, and the nature and severity of the disease and the physical condition of the subject, and the selected route of administration.
  • the appropriate dosage can be readily determined by a person skilled in the art.
  • compositions may contain from 0.1 % by weight, preferably from 5-60%, more preferably from 10-30% by weight, of a compound of invention, depending on the method of administration.
  • the optimal quantity and spacing of individual dosages of a compound of the invention will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the age and condition of the particular subject being treated, and that a physician will ultimately determine appropriate dosages to be used. This dosage may be repeated as often as appropriate. If side effects develop the amount and/or frequency of the dosage can be altered or reduced, in accordance with normal clinical practice.
  • RNA virus infections such as HCV or HIV infection or other diseases such as muscular dystrophy
  • -A pharmaceutical composition comprising a compound according to the invention together with a pharmaceutically acceptable diluent or carrier
  • -A pharmaceutical composition comprising a compound according to the invention together with a pharmaceutically acceptable diluent or carrier further comprising a second or subsequent active ingredient, especially an active ingredient indicated for the treatment of viral infections such as HCV or HIV infection or muscular dystrophy;
  • RNA virus infections such as HCV or HIV infection or muscular dystrophy
  • administering to a subject a therapeutically effective amount of a compound according to the invention
  • -Use of a compound according to the invention for the manufacture of a medicament for the treatment of viral infections such as HCV or HIV infection or muscular dystrophy.
  • the sanglifehrin producer Streptomyces sp. A92-3081 10 (DSM no 9954, purchased from DSMZ, Braunschweig, Germany) also termed BIOT-4253 and BIOT-4370 is maintained on medium oatmeal agar, MAM, or ISP2 (see below) at 28 °C.
  • Streptomyces sp. A92-3081 10 was grown on oatmeal agar at 28 °C for 7-10 days. Spores from the surface of the agar plate were collected into 20% w/v sterile glycerol in distilled and stored in 0.5-ml aliquots at -80 °C. Frozen spore stock was used for inoculating seed media SGS or SM25- 3. The inoculated seed medium was incubated with shaking between 200 and 300 rpm at 5.0 or 2.5 cm throw at 27 °C for 24 hours. The fermentation medium SGP-2 or BT6 were inoculated with 2.5%- 10% of the seed culture and incubated with shaking between 200 and 300 rpm with a 5 or 2.5 cm throw at 24 °C for 4-5 days. The culture was then harvested for extraction.
  • yeast extract (Becton Dickinson, 212770) 1.35 g
  • potato starch (soluble) (Signma, S2004) 7.50 g NZ-amine A (Sigma, C0626) 2.50 g toasted soy flour, Nutrisoy (ADM, 063-160) 2.50 g
  • Glycerol (Fisher scientific, G/0650/25) 40.00 g
  • Solvent B is Acetonitrile + 0.1 % Formic Acid
  • LCMS is performed on an integrated Agilent HP1 100 HPLC system in combination with a Bruker Daltonics Esquire 3000+ electrospray mass spectrometer operating in positive ion mode using the chromatography and solvents described above.
  • Solvent A is Water + 0.1 % Formic Acid
  • Solvent B is Acetonitrile + 0.1 % Formic Acid MS conditions
  • MS operates in switching mode (switching between positive and negative), scanning from 150 to 1500 amu.
  • Antiviral efficacy against genotype 1 HCV may be tested as follows: One day before addition of the test article, Huh5.2 cells, containing the HCV genotype 1 b l389luc-ubi-neo/NS3- 375.1 replicon (Vrolijk et al., 2003) and subcultured in cell growth medium [DMEM (Cat No.
  • microtitre plates are incubated overnight (37°C, 5% C0 2 , 95-99% relative humidity), yielding a non-confluent cell monolayer. Dilution series are prepared; each dilution series is performed in at least duplicate. Following assay setup, the microtitre plates are incubated for 72 hours (37°C, 5% C0 2 , 95-99% relative humidity).
  • the assay medium is aspirated, replaced with 75 ⁇ _ of a 5% MTS (Promega) solution in phenol red-free medium and incubated for 1 .5 hours (37°C, 5% C0 2 , 95-99% relative humidity). Absorbance is measured at a wavelength of 498nm (Safire 2 , Tecan) and optical densities (OD values) are converted to percentage of untreated controls.
  • assay medium is aspirated and the cell monolayers are washed with PBS.
  • the wash buffer is aspirated, 25 ⁇ _ of Glo Lysis Buffer (Cat. N°. E2661 , Promega) is added after which lysis is allowed to proceed for 5min at room temperature.
  • 50 ⁇ of Luciferase Assay System (Cat. N°. E1501 , Promega) is added and the luciferase luminescence signal is quantified immediately (1000ms integration time/well, Safire 2 , Tecan). Relative luminescence units are converted to percentage of untreated controls.
  • the EC50 and EC90 represent the concentrations at which respectively 50% and 90% inhibition of viral replication would be observed.
  • the CC50 value derived from the dose-response curve
  • the selectivity index (SI), indicative of the therapeutic window of the compound, is calculated as CC50/EC50.
  • a concentration of compound is considered to elicit a genuine antiviral effect in the HCV replicon system when, at that particular concentration, the anti-replicon effect is above the 70% threshold and no more than 30% reduction in metabolic activity is observed.
  • Water solubility may be tested as follows: A 10 mM stock solution of the sanglifehrin analogue is prepared in 100% DMSO at room temperature. Triplicate 0.01 mL aliquots are made up to 0.5 mL with either 0.1 M PBS, pH 7.3 solution or 100% DMSO in amber vials. The resulting 0.2 mM solutions are shaken, at room temperature on an IKA® vibrax VXR shaker for 6 h, followed by transfer of the resulting solutions or suspensions into 2 mL Eppendorf tubes and centrifugation for 30 min at 13200 rpm. Aliquots of the supernatant fluid are then analysed by the LCMS method as described above.
  • Cell permeability may be tested as follows: The test compound is dissolved to 10mM in DMSO and then diluted further in buffer to produce a final 10 ⁇ dosing concentration. The fluorescence marker lucifer yellow is also included to monitor membrane integrity. Test compound is then applied to the apical surface of Caco-2 cell monolayers and compound permeation into the basolateral compartment is measured. This is performed in the reverse direction (basolateral to apical) to investigate active transport. LC-MS/MS is used to quantify levels of both the test and standard control compounds (such as Propanolol and Acebutolol). In vivo assessment of pharmacokinetics
  • In vivo assays may also be used to measure the bioavailability of a compound.
  • a compound is administered to a test animal (e.g. mouse or rat) both intravenously (i.v.) and orally (p.o.) and blood samples are taken at regular intervals to examine how the plasma concentration of the drug varies over time.
  • a test animal e.g. mouse or rat
  • intravenously i.v.
  • orally p.o.
  • blood samples are taken at regular intervals to examine how the plasma concentration of the drug varies over time.
  • the time course of plasma concentration over time can be used to calculate the absolute bioavailability of the compound as a percentage using standard models.
  • An example of a typical protocol is described below.
  • Activation is calculated from the vanadate sensitive increase in ATPase activity. Inhibition is determined by decrease in verapamil/sulfasalazine mediated ATPase activity.
  • the 80:20 methanokwater fraction was then dried under reduced pressure to yield a crude dry extract which contained SfA and SfB.
  • This extract was dissolved in methanol (100 ml), mixed with 15 g Silica gel and dried to a powder.
  • the powder was loaded into a silica gel column (5 x 20 cm) packed in 100% CHCI 3 .
  • the methanol concentration was increased stepwise by 1 % and 250 ml fractions collected. After three litres of solvent elution the methanol concentration was increased stepwise by 2% up to 8%.
  • Fractions containing SfA and / or SfB were combined and reduced in vacuo to dryness and SfA and SfB purified by preparative HPLC.
  • sanglifehrin A SFA
  • 5 26, 27-dihydroxysanglifehrin, 9
  • DHQ DHQ 2 PHAL
  • 2.5 wt % solution of osmium tetroxide in ie f-butyl alcohol 47 uL, 0.0037 mmol
  • methanesulfonamide 23.6 mg, 0.2476 mmol
  • ie f-butyl alcohol 4 ml.
  • Example 6 Biological data - In vitro evaluation of HCV antiviral activity in the replicon system Compounds were analysed in the replicon assay as described in the General Methods. Cyclosporine A, 1 and sanglifehrin B, 7 were included as a comparison.
  • Hepatitis C virus NS5A protein is a substrate for the Peptidyl-Prolyl cis/trans isomerase activity of Cyclophilins A and B. J Biol Chem.

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Abstract

La présente invention concerne des analogues macrocycliques de sanglifehrine qui sont utiles comme inhibiteurs de cyclophilines, par exemple dans le traitement d'infections virales, notamment d'une infection par des virus à ARN, tels que le virus de l'Hépatite C (VHC) et le VIH, et de la dystrophie musculaire. La présente invention concerne également des méthodes pour leur utilisation en médecine, en particulier pour le traitement d'une infection par le VHC.
PCT/GB2011/050928 2010-05-17 2011-05-16 Amine ou analogues d'amide de sanglifehrine Ceased WO2011144924A1 (fr)

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Cited By (4)

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WO2013185103A1 (fr) * 2012-06-08 2013-12-12 Gilead Sciences, Inc. Inhibiteurs macrocycliques des virus flaviviridae
US9642889B2 (en) 2012-06-08 2017-05-09 Gilead Sciences, Inc. Macrocyclic inhibitors of Flaviviridae viruses
US9873716B2 (en) 2012-06-08 2018-01-23 Gilead Sciences, Inc. Macrocyclic inhibitors of flaviviridae viruses
WO2018091634A1 (fr) 2016-11-18 2018-05-24 Neurovive Pharmaceutical Ab Utilisation d'analogues macrocycliques de sangliféhrine en tant que composés anticancéreux

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