WO2019020767A1 - Macrolides de séquanamycine utiles dans le traitement de la tuberculose - Google Patents

Macrolides de séquanamycine utiles dans le traitement de la tuberculose Download PDF

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WO2019020767A1
WO2019020767A1 PCT/EP2018/070342 EP2018070342W WO2019020767A1 WO 2019020767 A1 WO2019020767 A1 WO 2019020767A1 EP 2018070342 W EP2018070342 W EP 2018070342W WO 2019020767 A1 WO2019020767 A1 WO 2019020767A1
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methyl
oxy
compound
hydroxy
tetrahydropyran
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PCT/EP2018/070342
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English (en)
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Yannick Benedetti
Frank Halley
Jidong Zhang
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Sanofi
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
    • 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
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives

Definitions

  • the present invention relates to macrolides, and to the preparation and therapeutic use thereof.
  • the compounds according to the present invention have substantial antimicrobial activity on mycobacteria, and are useful especially in the treatment of tuberculosis.
  • Tuberculosis is a disease which, at the present time, is still a worldwide health threat.
  • tuberculosis killed approximately 1 .8 million people in 2015, including 0.4 million of Mycobacterium tuberculosis and HIV co-infected patents, and its global incidence increases by 1 % per year, with an estimation in 2015 of 10.4 million annual new cases of declared disease.
  • the common treatment protocols for combating sensitive strains of M. tuberculosis are mainly based on a combination of three or, more frequently, of four molecules: isoniazide (INH), rifampicin (RIF), pyrazinamide (PZA) and ethambutol (EMB). These drugs constitute the "first-line” treatment.
  • MDR-TB multi-resistant
  • Another therapeutic drawback in the treatment of tuberculosis is the interaction of rifampicin with treatments for combating HIV (human immunodeficiency virus), which represents an obstacle in the treatment of patients co-infected with tuberculosis and HIV.
  • HIV human immunodeficiency virus
  • the current anti-HIV therapeutic recommendations favour, as a first-line treatment, an anti-retroviral triple therapy combining a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI) with two nucleoside reverse transcriptase inhibitors (NRTI).
  • PI and NNRTI are metabolized by CYP3A4. Metabolic interactions between anti-retrovirals (ATRV) and certain combined drugs have been demonstrated.
  • the novel anti-tuberculosis treatments should be capable of satisfying one or more of the following criteria:
  • This compound is described therein as an antimicrobial agent and especially enables the treatment of tuberculosis.
  • this compound may show instability, in particular in acidic or basic aqueous medium, and/or may also show metabolic instability, which makes it difficult to use as a drug.
  • WO 2014/044645 describes sequanamycin compounds of formula:
  • a subject of the present invention is in particular new macrolides, which have bacteriostatic and/or bactericidal action, on mycobacteria, especially against strains of sensitive Mycobacterium tuberculosis that are resistant to the first-line antibiotics, and the preparation and therapeutic uses thereof.
  • the present invention thus concerns a compound of formula (I) :
  • - Y1 and Y2 identical or different, independently represents a hydrogen atom or a group -Ci.p-alkyl provided that at least one of Y1 and Y2 is not H ;
  • R 4 independently represents a group chosen from:
  • the compounds of general formula (I) may comprise one or more asymmetric carbons. They may therefore exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, and also mixtures thereof, including racemic mixtures, form part of the invention.
  • the compounds of formula (I) may exist in the form of bases or acid-addition salts. Such addition salts form part of the invention.
  • Pharmaceutically acceptable salts of the compounds of formula (I) do form part of the invention.
  • distinguished compounds are those of formula (I) wherein Y1 and Y2 are different, and where one of Y1 and Y2 represents a -Ci- 6 -alkyl, then the other of Y1 and Y2 represents a hydrogen atom.
  • distinguished compounds are those of formula (I) wherein Y1 and Y2 are different, and where one of Y1 and Y2 represents a methyl, then the other of Y1 and Y2 represents a hydrogen atom.
  • distinguished compounds are those of formula (I) wherein Y1 and Y2 independently represent an identical or different -C 1 6 -alkyl.
  • distinguished compounds are those of formula (I) wherein Y1 and Y2, identical, represent a methyl. According to another embodiment, distinguished compounds are those of formula (I) wherein Y1 represents a hydrogen atom and Y2 represents a -Ci 6 -alkyl.
  • distinguished compounds are those of formula (I) wherein Y2 represents a hydrogen atom and Y1 represents a -Ci- 6 -aikyl.
  • distinguished compounds are those of formula (I) wherein Y1 represents a hydrogen atom and Y2 represents a methyl.
  • distinguished compounds are those of formula (I) wherein Y2 represents a hydrogen atom and Y1 represents a methyl.
  • distinguished compounds are those of formula (I) wherein Z represents a cyclobutyl, a methyl, a methoxyethyl, 2-methyl-butyl, 2,2-dimethyl- propyl or 2-hydroxy-2-methyl-propyl. According to another embodiment, distinguished compounds are those chosen from the compounds of formu -A):
  • distinguished compounds are those of formula (l-A) wherein Y1 and Y2 are different, and where one of Y1 and Y2 represents a -C :. 6 -alkyl, then the other of Y1 and Y2 represents a hydrogen atom.
  • distinguished compounds are those of formula (l-A) wherein Y1 and Y2 are different, and where one of Y1 and Y2 represents a methyl, then the other of Y1 and Y2 represents a hydrogen atom.
  • distinguished compounds are those of formula (l-A) wherein Y1 and Y2 independently represent an identical or different -Ci 6 -alkyl.
  • distinguished compounds are those of formula (l-A) wherein Y1 and Y2, identical, represent a methyl.
  • distinguished compounds are those of formula (l-A) wherein Y1 represents a hydrogen atom and Y2 represents a -d 6 -alkyl. According to another embodiment, distinguished compounds are those of formula (I- A) wherein Y2 represents a hydrogen atom and Y1 represents a -Ci. 6 -alkyl.
  • distinguished compounds are those of formula (I- A) wherein Y1 represents a hydrogen atom and Y2 represents a methyl.
  • distinguished compounds are those of formula (I- A) wherein Y2 represents a hydrogen atom and Y1 represents a methyl.
  • distinguished compounds are those of formula (l-A) wherein Z represents a cyclobutyl, a methyl, a methoxyethyl, 2-methyl-butyl, 2,2-dimethyl- propyl or 2-hydroxy-2-methyl-propyl.
  • the compound of formula (I) or (l-A) corresponds to one of the following compounds:
  • the compound of the invention is:
  • an alkyl group a saturated, linear or branched hydrocarbon-based aliphatic group comprising, unless otherwise mentioned, from 1 to 6 and preferably from 1 to 4 carbon atoms. Examples that may be mentioned include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, etc. groups;
  • a cycloalkyl group a cyclic alkyl group comprising, unless otherwise mentioned, from 3 to 6 carbon atoms. Examples that may be mentioned include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. groups;
  • alkoxy group a radical -O-alkyl in which the alkyl group is as defined previously, including -O-methyl, -O-ethyl, -O-propyl, -O-isopropyl, -O-butyl, -O-isobutyl, -O-tert-butyl, - O-pentyl, -O-isopentyl, -O-hexyl.
  • the present invention also concerns the process of preparation of the compound of formula (I).
  • the usual organic chemistry reactions may be followed, especially those described in "Comprehensive Organic Transformations: A Guide to Functional Group Preparations” by Richard C. Larock, published by John Wiley & Sons Inc.
  • the protecting groups are preferably chosen from those described in "Protective Groups in Organic Chemistry, J.F.W. McOmie, Plenum Press, 1973 or in “Greene's Protective Groups in Organic Synthesis", by Theodora W. Greene, published by John Wiley & Sons Inc., 2006.
  • the processes for the protection and deprotection of the protecting groups are typically those described in these books.
  • protecting group PG means a group that can, firstly, protect a reactive function such as a hydroxyl or an amine during the synthesis and, secondly, regenerate the intact reactive function at the end of the synthesis. Examples of protecting groups and also protection and deprotection methods are given in particular in Protective Groups in Organic Synthesis, supra.
  • leaving group LG means a group that can be readily cleaved from a molecule by breaking a heterolytic bond, with loss of an electron pair. This group may thus be readily replaced with another group, for example during a substitution reaction.
  • Such leaving groups are, for example, halogens or an activated hydroxyl group such as a methanesulfonate, benzenesulfonate, p-toluenesulfonate, triflate, acetate, etc. Examples of leaving groups and also references for their preparation are given in Advanced Organic Chemistry, M.B. Smith and J. March, 6th Edition, Wiley Interscience, 2007, pp. 496-501 .
  • steps of protection/deprotection of the various hydroxyl groups present on the sequanamycin compounds may be added before or after each of the steps mentioned above (or between two steps). Determining the order of the steps and the need or otherwise to protect the hydroxyl functions are routine operations for a person skilled in the art, who knows, in the light of his general knowledge, whether or not a hydroxyl group is liable to react during the steps below and whether or not it needs to be protected.
  • the preparation of the compounds may be achieved by either of the two following routes: route A called the "oxime-mycarose route", and
  • route B called the "oxime oxazepan route”.
  • the compound of formula (I) may be obtained by an oxidative cleavage and reductive amination from a corresponding 7-carbamate, oxime compound of formula (VI):
  • the present invention thus concerns the process of preparation of a compound of formula (I) comprising reacting the corresponding compound of formula (VI)
  • This reaction may be conducted by reacting an oxidative reagent such as sodium periodate (Nal0 4 ) followed by reacting a reducing reagent such as Sodium cyanoborohydride (NaBH 3 CN), or NaBH(OAc) 3 .
  • an oxidative reagent such as sodium periodate (Nal0 4 )
  • a reducing reagent such as Sodium cyanoborohydride (NaBH 3 CN), or NaBH(OAc) 3 .
  • the reaction may be conducted in two successive steps, in a solvent such as tetrahydrofuran (THF) or methanol (MeOH).
  • a solvent such as tetrahydrofuran (THF) or methanol (MeOH).
  • the reaction may be conducted in a basic medium, such as potassium carbonate (K 2 C0 3 ) in MeOH/H 2 0.
  • a basic medium such as potassium carbonate (K 2 C0 3 ) in MeOH/H 2 0.
  • K 2 C0 3 potassium carbonate
  • the compound (VII) may be obtained from the corresponding 7 imidazole carbamate compound of formula (VIII):
  • the reaction may be conducted in the presence of N-hydrosuccinimide (NHS), in an organic solvent such as acetonitrile.
  • NHS N-hydrosuccinimide
  • the compound of formula (VIII) may be obtained from the corresponding imidazole carbamate-compound of formula (IX):
  • the reaction may be conducted in an acidic medium, e.g. by adding an aqueous solution of hydrochloric acid (HCI).
  • HCI hydrochloric acid
  • the reaction may be conducted in an organic solvent such as THF, THF- cyclohexane, or acetonitrile.
  • the compound (IX) may be obtained from the corresponding oxime compound of formula
  • GDI ⁇ , ⁇ '-carbonyldiimidazole
  • the reaction may be conducted in an organic solvent such as toluene, or cyclohexane, or cyclohexane-THF or cyclohexane- methyl- THF.
  • the compound (V) may be obtained from sequanamycin (A) by an oximation reaction. Said oximation reaction may be conducted by reacting the compound of formula (D):
  • This reaction may be typically carried out in the presence of a base, generally an organic base, such as triethylamine (Et 3 N) in an organic solvent such as methanol.
  • a base generally an organic base, such as triethylamine (Et 3 N) in an organic solvent such as methanol.
  • Sequanamycin (A) may be obtained by application of the process disclosed in the examples.
  • the compound of formula (I) may be obtained from the corresponding 7 imidazole carbamate compound of formula (II):
  • the present invention also concerns the process of preparation of a compound of formula (I) comprising reacting a compound of formula (II)
  • reaction may be conducted by:
  • the compound of formula (II) may be obtained by hydrolysis of the corresponding imidazole carbamate compound of formula (III):
  • Said hydrolysis may be conducted by adding an aqueous solution of an acid (such as HCI) to a solution of compound (II) in an organic solvent such as THF, THF-Cyclohexane.
  • an acid such as HCI
  • a solution of compound (II) in an organic solvent such as THF, THF-Cyclohexane.
  • the compound of formula (III) may be obtained from the corresponding 7-membered oxazepan compound of formula (IV):
  • Z is defined as in formula (I) by reacting with N.N'-carbonyldiimidazole (GDI).
  • GDI N.N'-carbonyldiimidazole
  • the reaction may be conducted in an organic solvent such as toluene, or cyclohexane, or cyclohexane-THF or cyclohexane- methyl-THF.
  • the compound of formula (IV) may be obtained from the corresponding oxime compound of formula (V):
  • This reaction may be conducted by reacting an oxidative reagent such as NalCv followed by reacting a reducing reagent such as NaBH 3 CN, or NaBH(OAc) 3 .
  • an oxidative reagent such as NalCv
  • a reducing reagent such as NaBH 3 CN, or NaBH(OAc) 3 .
  • reaction may be conducted in two successive steps, in a solvent such as THF or
  • oxime compound (V) may be obtained from sequanamycin (A) by an oximation reaction, as disclosed above
  • the processes of preparation of the invention may further comprise the step of isolating and/or purifying the obtained compound of formula (I).
  • the present invention also concerns novel intermediates involved in the above synthetic processes.
  • MgS0 4 magnesium sulfate
  • the progress of the synthetic reactions is monitored by TLC.
  • the plates are made of glass and are coated with Merck 60 F 254 silica gel. After elution, the plates are observed under ultraviolet light at 254 nm and then revealed by spraying with a 5M sulfuric acid/water solution followed by heating.
  • the microwave reactions were performed using a Biotage Initiator 8 EXP microwave machine.
  • the spectra were acquired on a Waters UPLC-SQD machine;
  • Ionization electrospray in positive and/or negative mode (ES+/-);
  • Solvents A: H 2 0 (0.1 % formic acid) B: CH 3 CN (0.1 % formic acid),
  • Ionization electrospray in positive and/or negative mode (ES+/-);
  • Ionization electrospray in positive and/or negative mode (ES+/-);
  • Ionization electrospray in positive and/or negative mode (ES+/-);
  • Ionization electrospray in positive and/or negative mode (ES+/-);
  • ⁇ Ionization electrospray in positive and/or negative mode (ES+/-);
  • Ionization electrospray in positive and/or negative mode (ES+/-);
  • the 1 H NMR spectra were recorded on a Bruker Avance and/or Varian G spectrometer (300 MHz, 400 MHz, 500 MHz or 600 MHz) in deuterated DMSO. The chemical shifts are expressed in units ⁇ (ppm) using tetramethylsilane (TMS) as internal reference.
  • TMS tetramethylsilane
  • s singlet
  • d doublet
  • t triplet
  • q quartet
  • quint quintet
  • sext sextet
  • dd doubled doublet
  • ddd doublet of doubled doublets
  • m multiplet
  • ax. axial
  • equat. equatorial.
  • NRRL 3892 The strain described in FR 2 126 108 deposited at the Northern Regional Research Laboratory (NRRL) under the number NRRL 3892 may be used to prepare sequanamycin.
  • the fermentation and purification processes may also be conducted using Allokutzneria albata to isolate sequanamycin (A).
  • DSMZ Deutsche Sammlung Von Mikroorganismen und Zellkulturen GmbH
  • Sanofi- Aventis Sanofi Aventis Deutschland GmbH, Industriepark Hochst H831 , 65926 Frankfurt am Main
  • the order number DSM24416 may also be used to prepare sequanamycin.
  • the free culture medium (known as "5294 medium") used is typically as follows:
  • the pH of the medium before sterilization is 7.2.
  • the main culture medium (known as "5254-Seq01 medium") used is typically as follows:
  • the fermentation process is typically as follows:
  • Step 1 Preculture 1
  • the fermentation process described above was performed for 500 liters, but may be adapted for smaller or larger proportions. It was, for example, used on a scale of 7000 liters as follows, using the same culture media:
  • Preculture 1 250 ml_, inoculum: one vial of WCB
  • Preculture 2 5 L in the flasks (2 x 2.5 L), inoculum of 0.5% starting with Preculture 1
  • Preculture 3 400 L of medium in a 600 L bioreactor, seeding proportion of 1 .25% starting with Preculture 2
  • Main culture 7000 L of medium in a 10 000 L bioreactor, seeding proportion of 5.7% starting with Preculture 3.
  • Fermentation process is followed by the purification process below (performed on the 500 liters fermentation broth described above).
  • the fermentation broth was separated as a culture supernatant and mycelium using a cylindrical seeding sorter. The separation gave about 440L of culture supernatant.
  • the fractions comprising sequanamycin (A) were combined and the 2-propanol was evaporated off.
  • the pH of the solution obtained was adjusted to above 7.5 and the solution was then extracted twice with ethyl acetate. The organic phases were combined and the solvents were evaporated off.
  • the oil obtained (about 10 grams per 100 L of culture supernatant) was purified on silica gel (40 mm ⁇ 260 mm column), eluting with a column with gradient from n-heptane to 30/70 n-heptane/ethyl acetate over 45 minutes, and then 30/70 n-heptane/ethyl acetate maintained for about 40 minutes (at a flow rate of 100 ml/minute).
  • Monitoring of the purification may be performed by thin-layer chromatography, eluting with ethyl acetate and revealing the sequanamycins (in the form of blue spots) with a reagent such as vanillin.
  • the sequanamycin (A) may be repurified by reverse-phase chromatography on a WatersAtlantis machine with a 50x 100 mm, 5 ⁇ column. An elution gradient of H 2 0 (A) and acetonitrile (B) and 1 vol% NH 4 Ac 50 g/L adjusted to pH 7 was used (40-60% B over 30 minutes, flow rate of 140 ml/minute). The chromatography was monitored by the light scattering electrical signal. The fractions comprising sequanamycin (A) were combined and freeze-dried after evaporating off the acetonitrile. The yield of sequanamycin (A) after this final purification step was 57% with an 85% pure compound according to the NMR analyses.
  • Sequanamycin (A) serves as starting materials for synthesizing the compounds of formula (I) according to the invention.
  • the medium is saturated with NaCI and filtered, and the filtrate is extracted with DCM (3x200 ml).
  • the organic phases are combined, washed with saturated aqueous NaCI solution, dried over MgS0 4 , filtered and finally concentrated under reduced pressure.
  • the oily residue obtained is dissolved, under argon, in 680 ml of MeOH. The pH is adjusted to
  • Example 1 A [(2R,3S,4R,5R,7S,9S,10S,1 1 R,12S,13R)-2-[(1 S)-2-[(2R,3R,4R,5R,6R)-5- hydroxy-3,4-dimethoxy-6-methyl-tetrahydropyran-2-yl]oxy-1 -methyl-ethyl]-10
  • Example 2A [(2R,3S,4R,5R,7S,9S,10S,1 1 R,12S,13R)-2-[(1 S)-2-[(2R,3R,4R,5R,6R)-5- hydroxy-3,4-dimethoxy-6-methyl-tetrahydropyran-2-yl]oxy-1 -methyl-ethyl]-10- [(2S,3R,4E,6R)-3-hydroxy-4-methoxyimino-6-methyl-tetrahydropyran-2-yl]oxy- 3,5,7,9,1 1 ,13-hexamethyl-4-(3-methylbutanoyloxy)-6,14-dioxo-12-[[(2S,5R,7R)-2,4,5- trimethyl-1 ,4-oxazepan-7-yl]oxy]-oxacyclotetradec-7-yl] (2S,6R)-2,6-dimethylmorpholine- 4-
  • Example 3A & 3A' [(2R,3S,4R,5R,7S,9S,10S,1 1 R,12S,13R)-12-[[(2S,5R,7R)-4- cyclobutyl-2,5-dimethyl-1 ,4-oxazepan-7-yl]oxy]-2-[(1 S)-2-[(2R,3R,4R,5R,6R)-5-hydroxy- 3,4-dimethoxy-6-methyl-tetrahydropyran-2-yl]oxy-1 -methyl-ethyl]-10-[(2S,3R,4E,6R)-3- hydroxy-4-methoxyimino-6-methyl-tetrahydropyran-2-yl]oxy-3,5,7,9,1 1 ,13-hexamethyl-4- (3-methylbutanoyloxy)-6, 14-dioxo-oxacyclotetradec-7-yl] (2S)-2-
  • the reaction was diluted with EtOAc (20 ml), washed with NaHC0 3 solution (15 ml), dried with anhydrous MgS0 4 , filtered. The filtrate was concentrated under reduced pressure to afford 0.268 g of crude product.
  • the residue was purified by silica gel column (20 g SiOH 15-40 ⁇ , EtOAC-TEA 98.5/1 .5) to afford 0,180 g of mixture 3A and 3A'.
  • the mixture was purified by silica gel column (10 g of 15-40 ⁇ silica) eluted with the following elution solvent: DCM-MeOH- NH 4 OH 96/4/0.2) to afford 65 mg of the desired compound example 3A and 17 mg of 3A'.
  • Example 4A [(2R,3S,4R,5R,7S,9S,10S,1 1 R,12S,13R)-2-[(1 S)-2-[(2R,3R,4R,5R,6R)-5- hydroxy-3,4-dimethoxy-6-methyl-tetrahydropyran-2-yl]oxy-1 -methyl-ethyl]-10- [(2S,3R,4E,6R)-3-hydroxy-4-methoxyimino-6-methyl-tetrahydropyran-2-yl]oxy-12- [[(2S,5R,7R)-4-(2-hydroxy-2-methyl-propyl)-2,5-dimethyl-1 ,4-oxazepan-7-yl]oxy]-
  • Example 5A [(2R,3S,4R,5R,7S,9S,10S,1 1 R,12S,13R)-2-[(1 S)-2-[(2R,3R,4R,5R,6R)-5- hydroxy-3,4-dimethoxy-6-methyl-tetrahydropyran-2-yl]oxy-1 -methyl-ethyl]-10-
  • Example 7A [(2R,3S,4R,5R,7S,9S,10S,1 1 R,12S,13R)-12-[[(2S,7R)-4-cyclobutyl-2,5- dimethyl-1 ,4-oxazepan-7-yl]oxy]-2-[(1 S)-2-[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6- methyl-tetrahydropyran-2-yl]oxy-1 -methyl-ethyl]-10-[(2S,3R,4E,6R)-3-hydroxy-4- methoxyimino-6-methyl-tetrahydropyran-2-yl]oxy-3, 5,7,9,1 1 ,13-hexamethyl-4-(3- methylbutanoyloxy)-6,14-dioxo-oxacyclotetradec-7-yl] (2S,6R)-2,6-dimethyl
  • Example 8A [(2R,3S,4R,5R,7S,9S,10S,1 1 R,12S,13R)-2-[(1 S)-2-[(2R,3R,4R,5R,6R)-5- hydroxy-3,4-dimethoxy-6-methyl-tetrahydropyran-2-yl]oxy-1 -methyl-ethyl]-10- [(2S,3R,4E,6R)-3-hydroxy-4-methoxyimino-6-methyl-tetrahydropyran-2-yl]oxy- 3,5,7,9,1 1 ,13-hexamethyl-4-(3-methylbutanoyloxy)-6,14-dioxo-12-[[(2S,5R,7R)-2,4,5- trimethyl-1 ,4-oxazepan-7-yl]oxy]-oxacyclotetradec-7-yl] (2R)-2-methylmorpholine-4- carboxylate
  • Step 8A.1 A mixture of Step 8A.1 (3.00 g, 2.62 mmol) and K 2 C0 3 (1 .09 g, 7.86 mmol) in MeOH (30.00 mL) and H 2 0 (3.00 mL) was stirred at 25 °C for 2 hour.
  • the reaction mixture was diluted with EtOAc (100 mL), then washed with brine (50 mL x 3), dried over anhydrous Na 2 S0 4 , filtered. The filtrate was concentrated under reduced pressure to give 2.9 g of the desired crude product as yellow solid.
  • Step 8A.2 To a mixture of Step 8A.2 (2.90 g, 2.59 mmol) in THF (35 mL) was added a solution of Nal0 4 (2.77 g, 12.95 mmol) in H 2 0 (19.00 mL) at 0 °C over 10 min. The resulting mixture was stirred at 25 °C for 1 hr. Then the reaction mixture was filtered and the cake was washed with THF (20 mL). Then to the above combined filtrate was added methanamine (2 M, 6.48 mL) and AcOH (1 .79 g, 29.79 mmol). The resulting mixture was stirred at 25 °C for 1 hr.
  • Example 9A [(2R,3S,4R,5R,7S,9S,10S,1 1 R,12S,13R)-2-[(1 S)-2-[(2R,3R,4R,5R,6R)-5- hydroxy-3,4-dimethoxy-6-methyl-tetrahydropyran-2-yl]oxy-1 -methyl-ethyl]-10- [(2S,3R,4E,6R)-3-hydroxy-4-methoxyimino-6-methyl-tetrahydropyran-2-yl]oxy- 3,5,7,9,1 1 ,13-hexamethyl-4-(3-methylbutanoyloxy)-6,14-dioxo-12-[[(2S,5R,7R)-2,4,5- trimethyl-1 ,4-oxazepan-7-yl]oxy]-oxacyclotetradec-7-yl] (2S,6S)-2,6-dimethylmorpholine-4-
  • Step 9A.1 To a solution of Step 9A.1 (2.90 g, 2.50 mmol) in MeOH (30.00 mL) and H 2 0 (3.00 mL) was added K 2 C0 3 (1 .04 g, 7.50 mmol). Then the mixture was stirred at 20 °C for 1 .5 hour. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to remove most of MeOH. The residue was diluted with EtOAc (50 mL), then washed with H 2 0 (20 mL x 3), brine (20 mL x 3), dried over anhydrous Na 2 S0 4 , filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was used into next step without purification. 2.90 g of the desired crude compound was obtained as a yellow solid.
  • Step 9.A2 (2.90 g, 2.56 mmol) in THF (30.00 mL) was added dropwise a solution of Nal0 4 (2.74 g, 12.79 mmol) in H 2 0 (18.00 mL) at 0 °C, then the mixture was stirred at 35 °C for 2 h. Then the mixture was filtered, the filter cake was washed with THF (20.00 mL). The resulting filtrate was added AcOH (1 .77 g, 29.43 mmol) and then MeNH 2 (2 M in MeOH, 6.40 mL) was added dropwise at 25 °C. The resulting mixture was stirred at 25 °C for 1 h.
  • the compounds corresponding to the general formula (I) that are the subject of the invention underwent microbiological trials which showed their value as therapeutically active substances. Specifically, they have bacteriostatic and/or bactericidal action on mycobacteria, especially against strains of Mycobacterium, in particular strains of Mycobacterium which are sensitive and resistant to the first-line antibiotics.
  • the compounds corresponding to the general formula (I) which are the subject of the invention are used for the prevention and/or treatment of bacterial infections caused by mycobacteria.
  • R2 Receiver quantity of compound after 2 hours (corresponding peak area or
  • Alamar blue is a colorimetric test which makes it possible to determine the MIC (minimum inhibitory concentration) of antibacterial agents.
  • Alamar blue is a redox indicator which changes from blue to pink in the case of bacterial growth. Resazurin (blue and non-fluorescent) is reduced to resorufin (pink and fluorescent) by live bacteria. The plate is thus read visually or by fluorescence measurement. The fluorescence intensity is proportional to the number of live bacteria.
  • the fluorimetric MIC value tends towards zero, the less the amount of product necessary to inhibit the total growth of the bacteria.
  • the experiments performed demonstrate that the compounds according to the present invention have activity on inhibiting the growth of M. tuberculosis.
  • the MIC values are typically between 0.1 and 10 ⁇ , or even between 0.1 and 1 ⁇ .
  • the compounds presented as examples in the present patent application generally have MIC values of less than 1 ⁇ .
  • example 78 with an unsubstitued morpholine was less potent in terms of inhibitory activity with a less favorable Caco2 parameter.
  • the compounds according to the invention i.e. the compounds corresponding to formula (I), furthermore show good microbiological properties and are particularly suitable for use for the preparation of medicaments, in particular antibiotics with a narrow spectrum for the treatment and/or prevention of tuberculosis.
  • antibiotics have antimicrobial action against M. tuberculosis for the treatment and/or prevention of tuberculosis.
  • a subject of the invention is medicaments that comprise a compound of formula (I), or an addition salt with a pharmaceutically acceptable acid or base of the compound of formula (I).
  • the present invention relates to pharmaceutical compositions comprising, as active principle, a composition according to the invention.
  • These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt of said compound, and also at least one pharmaceutically acceptable excipient.
  • Said excipients are chosen, according to the pharmaceutical form and the desired mode of administration, from the usual excipients known to those skilled in the art.
  • compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration the active principle of formula (I) above or the salt thereof may be administered in unit administration form, as a mixture with standard pharmaceutical excipients, to man and animals for the prophylaxis or treatment of the above disorders or diseases.
  • the appropriate unit forms of administration include oral-route forms such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular, intranasal and inhalation administration forms, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants.
  • oral-route forms such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions
  • sublingual, buccal, intratracheal intraocular, intranasal and inhalation administration forms
  • topical, transdermal, subcutaneous, intramuscular or intravenous administration forms rectal administration forms and implants.
  • the compounds according to the invention may be used in creams, gels, ointments or lotions.
  • a unit administration form of a compound according to the invention in tablet form may comprise the following components:
  • the dosage that is appropriate to each patient is determined by the doctor according to the mode of administration and the weight and response of said patient.
  • the present invention also relates to the compounds of formula (I), or a pharmaceutically acceptable salt thereof, for use for the treatment and/or prevention of bacterial infections caused by mycobacteria.
  • one of the aspects of the invention concerns the compounds of formula (I), or a pharmaceutically acceptable salt thereof, for use for the treatment and/or prevention of infectious diseases such as to tuberculosis, pulmonary mycobacterial infection, cutaneous mycobacterial infection, atypical mycobacterial infection and mycobacteriosis.
  • tuberculosis includes infections caused by bacilli of the tuberculosis complex (M. tuberculosis, M. bovis and M. africanum), which are all pathogens to man.
  • Pulmonary tuberculosis is far and away the most common and the most widespread: this is tuberculosis of the lungs, of the larynx, of the trachea and of the bronchi, tuberculosis of the intrathoracic lymphatic ganglions, respiratory tuberculosis of the pleura, primary respiratory tuberculosis and any other respiratory tuberculosis.
  • tuberculosis of the nervous system such as tuberculous meningitis, tuberculous leptomeningitis, cerebral tuberculoma and any other tuberculosis of the nervous system, or alternatively bone or articular tuberculosis, tuberculosis of the genitourinary system, lymphadenopathic peripheral tuberculosis, intestinal or peritoneal tuberculosis and/or tuberculosis of the mesenteric glands, tuberculosis of the skin and of the subcutaneous tissues, tuberculosis of the eyes, of the ears or of the adrenal glands, and also disseminated tuberculosis, exist.
  • the present invention also relates to a method for treating the pathologies indicated above, which comprises the administration, to a patient in need thereof, of an effective dose of a compound of formula (I).
  • the compounds of the invention are suitable for combined administration with one or more other active agent useful for treating and/or preventing bacterial infections caused by mycobacteria, especially caused by bacilli of the tuberculosis complex (M. tuberculosis, M. bovis and/or M. africanum).

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Abstract

La présente invention concerne des composés de formule (I), leur procédé de préparation et leurs utilisations thérapeutiques. Les macrolides de séquanamycine sont utiles dans le traitement de la tuberculose.
PCT/EP2018/070342 2017-07-26 2018-07-26 Macrolides de séquanamycine utiles dans le traitement de la tuberculose WO2019020767A1 (fr)

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EP17306003.9 2017-07-26

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021162196A1 (fr) * 2020-02-14 2021-08-19 서울대학교산학협력단 Composition pharmaceutique contenant un composé macrolide, sa méthode de production et méthode l'utilisant

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2126108A1 (fr) 1971-02-25 1972-10-06 Rhone Poulenc Sa
WO2014044645A1 (fr) 2012-09-18 2014-03-27 Sanofi Dérivés de macrolide, leur préparation et leur utilisation thérapeutique

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2126108A1 (fr) 1971-02-25 1972-10-06 Rhone Poulenc Sa
WO2014044645A1 (fr) 2012-09-18 2014-03-27 Sanofi Dérivés de macrolide, leur préparation et leur utilisation thérapeutique

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
ARNOUX ET AL., JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 102, no. 10, 1980, pages 3605
J.F.W. MCOMIE: "Protective Groups in Organic Chemistry", 1973, PLENUM PRESS
M.B. SMITH; J. MARCH: "Advanced Organic Chemistry", 2007, WILEY INTERSCIENCE, pages: 496 - 501
RICHARD C. LAROCK: "Comprehensive Organic Transformations: A Guide to Functional Group Preparations", JOHN WILEY & SONS INC.
THEODORA W. GREENE: "Greene's Protective Groups in Organic Synthesis", 2006, JOHN WILEY & SONS INC.

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021162196A1 (fr) * 2020-02-14 2021-08-19 서울대학교산학협력단 Composition pharmaceutique contenant un composé macrolide, sa méthode de production et méthode l'utilisant

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