WO2019018890A1 - Nouveaux composés spirocycliques - Google Patents

Nouveaux composés spirocycliques Download PDF

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Publication number
WO2019018890A1
WO2019018890A1 PCT/AU2018/050771 AU2018050771W WO2019018890A1 WO 2019018890 A1 WO2019018890 A1 WO 2019018890A1 AU 2018050771 W AU2018050771 W AU 2018050771W WO 2019018890 A1 WO2019018890 A1 WO 2019018890A1
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Prior art keywords
alkyl
compound
formula
independently selected
heteroalkyl
Prior art date
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PCT/AU2018/050771
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English (en)
Inventor
Guillaume Lessene
William Hawkins
Original Assignee
The Walter And Eliza Hall Institute Of Medical Research
University Of Otago
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Publication date
Priority claimed from AU2017902925A external-priority patent/AU2017902925A0/en
Application filed by The Walter And Eliza Hall Institute Of Medical Research, University Of Otago filed Critical The Walter And Eliza Hall Institute Of Medical Research
Publication of WO2019018890A1 publication Critical patent/WO2019018890A1/fr

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • the present invention relates to new spirocyclic compounds that may be useful as anticancer and anti-microbial agents, to the preparation of the compounds, and to compositions including the compounds.
  • the present invention also relates to the use of the compounds, as well as compositions including the compounds, in treating or preventing cancer, and treating or preventing microbial infections.
  • the present invention relates to a compound of formula (I):
  • R 1 and R 2 are each independently selected from H, OH, O-alkyl, NH 2 , NH-alkyl, N(alkyl) 2 , alkyl, N0 2 and halogen;
  • R 3 is selected from H, OC(0)-alkyl, NH-alkyl, N(alkyl) 2 and S-alkyl;
  • R 4 and R 6 are each independently selected from H, alkyl and heteroalkyl
  • R 5 is selected from O, NH, N-alkyl and N-heteroalkyl
  • n 0, 1 , 2, 3, 4, 5 or 6;
  • R 7 is selected from alkyl, aryl and heteroaryl, which groups are optionally substituted, wherein the compound of formula (I) is not spiroleucettadine:
  • the present invention relates to a compound of formula (I):
  • R 1 and R 2 are each independently selected from H, OH, O-alkyl, NH 2 , NH-alkyl, N(alkyl) 2 , alkyl, N0 2 and halogen;
  • R 3 is selected from H, OC(0)-alkyl, NH-alkyl, N(alkyl) 2 and S-alkyl;
  • R 4 and R 6 are each independently selected from H, alkyl and heteroalkyl
  • R 5 is selected from NH, N-alkyl and N-heteroalkyl
  • n 0, 1 , 2, 3, 4, 5 or 6;
  • R 7 is selected from alkyl, aryl and heteroaryl, which groups are optionally substituted.
  • the present invention relates to a compound of formula (I):
  • R 1 and R 2 are each independently selected from H, OH, O-alkyl, NH 2 , NH-alkyl, N(alkyl) 2 , alkyl, N0 2 and halogen;
  • R 3 is selected from H, OC(0)-alkyl, NH-alkyl, N(alkyl) 2 and S-alkyl;
  • R 4 and R 6 are each independently selected from H, alkyl and heteroalkyl
  • R 5 is selected from O, NH, N-alkyl and N-heteroalkyl
  • n 0, 1 , 2, 3, 4, 5 or 6;
  • R 7 is selected from alkyl, aryl and heteroaryl, which groups are optionally substituted.
  • R 1 and R 2 may both be H.
  • the halogen may be bromine or chlorine.
  • R 3 may be H.
  • R 3 may be OC(0)-alkyl (e.g. OC(O)-methyl).
  • R 3 may be NH-alkyl (e.g. NH- methyl).
  • R 4 and R 6 may both be alkyl (e.g. methyl).
  • R 5 may be NH.
  • m may be 1 .
  • R 7 may be an aryl group.
  • the aryl group may be substituted.
  • the substituent may be heteroalkyl (e.g. methoxy).
  • the compound may be a compound of formula (III):
  • the present invention relates to a pharmaceutical composition including a compound of formula (I) (according to the first, second or third aspect of the invention) together with a pharmaceutically acceptable carrier, diluent or excipient.
  • the present invention may be suitable for treating and/or preventing cancer, and microbial infections. Accordingly, in another aspect, the present invention relates to a method of treating and/or preventing cancer or microbial infection in a subject, the method including administering to the subject an effective amount of a compound of formula (I) according to the first, second or third aspect of the invention or a pharmaceutical composition according to the fourth aspect of the invention.
  • the present invention relates to the use of a compound of formula (I) according to the first, second or third aspect of the invention or a pharmaceutical composition according to the fourth aspect of the invention in the manufacture of a medicament for treating and/or preventing cancer or microbial infection.
  • the present invention relates to the use of a compound of formula (I) according to the first, second or third aspect of the invention or a pharmaceutical composition according to the fourth aspect of the invention for the treatment and/or prevention of cancer or microbial infection in a subject.
  • the present invention relates to a compound of formula (I) according to the first, second or third aspect of the invention or a pharmaceutical composition according to the fourth aspect of the invention for use in the treatment and/or prevention of cancer or microbial infection in a subject.
  • the compounds of formula (I) may be used in therapy alone or in combination with one or more other therapeutic agents, for example, as part of a combination therapy.
  • the present invention relates to a process for making a compound of formula (I):
  • R 1 and R 2 are each independently selected from H, OH, O-alkyl, NH 2 , NH-alkyl, N(alkyl) 2 , alkyl, N0 2 and halogen;
  • R 3 is selected from H, OC(0)-alkyl, NH-alkyl, N(alkyl) 2 and S-alkyl;
  • R 4 and R 6 are each independently selected from H, alkyl and heteroalkyl
  • R 5 is selected from O, NH, N-alkyl and N-heteroalkyl
  • n 0, 1 , 2, 3, 4, 5 or 6;
  • R 7 is selected from alkyl, aryl and heteroaryl, which groups are optionally substituted, the process including treating a compound of formula (II):
  • the present invention relates to a process for making a compound of formula (I):
  • R 1 and R 2 are each independently selected from H, OH, O-alkyl, NH 2 , NH-alkyl, N(alkyl) 2 , alkyl, N0 2 and halogen;
  • R 3 is selected from H, OC(0)-alkyl, NH-alkyl, N(alkyl) 2 and S-alkyl;
  • R 4 and R 6 are each independently selected from H, alkyl and heteroalkyl
  • R 5 is selected from O, NH, N-alkyl and N-heteroalkyl
  • n 0, 1 , 2, 3, 4, 5 or 6;
  • R 7 is selected from alkyl, aryl and heteroaryl, which groups are optionally substituted, the process including treating a compound of formula (II):
  • the present invention relates to a process for making a compound of formula (I):
  • R 1 and R 2 are each independently selected from H, OH, O-alkyl, NH 2 , NH-alkyl, N(alkyl) 2 , alkyl, N0 2 and halogen;
  • R 3 is selected from H, OC(0)-alkyl, NH-alkyl, N(alkyl) 2 and S-alkyl;
  • R 4 and R 6 are each independently selected from H, alkyl and heteroalkyl
  • R 5 is selected from NH, N-alkyl and N-heteroalkyl
  • n 0, 1 , 2, 3, 4, 5 or 6;
  • R 7 is selected from alkyl, aryl and heteroaryl, which groups are optionally substituted, the process including treating a compound of formula (II):
  • the hypervalent iodine reagent may be selected from an organic iodine (III) compound, such as an aryliodine(lll) carboxylate (e.g. phenyliodine ⁇ 11 l)-bis ⁇ trif luoroacetate) (PIFA) or phenyliodine(lll)-difluoroacetate (PIDA)).
  • III organic iodine
  • PIFA phenyliodine ⁇ 11 l)-bis ⁇ trif luoroacetate
  • PIDA phenyliodine(lll)-difluoroacetate
  • the hypervalent iodine reagent may be selected from an organic iodine (V) compound, such as a periodinane (e.g. Dess-Martin periodinane), PIFA or PIDA.
  • V organic iodine
  • Recited compounds are further intended to encompass compounds in which one or more atoms are replaced with an isotope, i.e., an atom having the same atomic number but a different mass number.
  • isotopes of hydrogen include tritium and deuterium and isotopes of carbon include 11 C, 13 C, and 14 C.
  • a “pharmaceutically acceptable salt” of a compound disclosed herein is an acid or base salt that is generally considered in the art to be suitable for use in contact with the tissues of human beings or animals without excessive toxicity or carcinogenicity, and preferably without irritation, allergic response, or other problem or complication.
  • Such salts include mineral and organic acid salts of basic residues such as amines, as well as alkali or organic salts of acidic residues such as carboxylic acids.
  • Suitable pharmaceutically acceptable salts include, but are not limited to, salts of acids such as hydrochloric, phosphoric, hydrobromic, malic, glycolic, fumaric, sulfuric, sulfamic, sulfanilic, formic, toluenesulfonic, methanesulfonic, benzenesulfonic, ethane disulfonic, 2- hydroxyethylsulfonic, nitric, benzoic, 2-acetoxybenzoic, citric, tartaric, lactic, stearic, salicylic, glutamic, ascorbic, pamoic, succinic, fumaric, maleic, propionic, hydroxymaleic, hydroiodic, phenylacetic, alkanoic (such as acetic, HOOC-(CH 2 )n-COOH where n is any integer from 0 to 6, i.e., 0, 1 , 2, 3, 4, 5 or 6), and the like.
  • acids such as hydroch
  • pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium.
  • a pharmaceutically acceptable acid or base salt can be synthesized from a parent compound that contains a basic or acidic moiety by any conventional chemical method. Briefly, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two.
  • nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile, is preferred.
  • each compound of formula (I) may, but need not, be present as a hydrate, solvate or non-covalent complex.
  • the various crystal forms and polymorphs are within the scope of the present invention, as are prodrugs of the compounds of formula (I) provided herein.
  • a “prodrug” is a compound that may not fully satisfy the structural requirements of the compounds provided herein, but is modified in vivo, following administration to a subject or patient, to produce a compound of formula (I) provided herein.
  • a prodrug may be an acylated derivative of a compound as provided herein.
  • Prodrugs include compounds wherein hydroxy, carboxy, amine or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxy, carboxy, amino, or sulfhydryl group, respectively.
  • prodrugs include, but are not limited to, acetate, formate, phosphate and benzoate derivatives of alcohol and amine functional groups within the compounds provided herein.
  • Prodrugs of the compounds provided herein may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved in vivo to generate the parent compounds.
  • a “ring substituent” may be a moiety such as a halogen, alkyl group, heteroalkyi group, haloalkyi group or other substituent described herein that is covalently bonded to an atom, preferably a carbon or nitrogen atom, that is a ring member.
  • substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated substituents, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound, i.e., a compound that can be isolated, characterized and tested for biological activity.
  • a pyridyl group substituted by oxo is a pyridone.
  • suitable substituents include aryl (e.g. phenyl), heteroaryl (e.g. pyridine), alkyl-aryl (e.g. benzyl), and alkyl-heteroaryl (e.g. CH 2 -pyridine).
  • alkyl refers to a saturated, straight-chain or branched hydrocarbon group that contains from 1 to 20 carbon atoms, preferably from 1 to 10 carbon atoms, for example a n-octyl group, especially from 1 to 6, i.e., 1 , 2, 3, 4, 5, or 6, carbon atoms.
  • alkyl groups are methyl, ethyl, propyl, / ' so-propyl, n-butyl, / ' so-butyl, sec-butyl, ferf-butyl, n-pentyl, iso- pentyl, n-hexyl and 2,2-dimethylbutyl.
  • heteroalkyi refers to an alkyl group as defined above that contains one or more heteroatoms selected from oxygen, nitrogen and sulphur (especially oxygen and nitrogen).
  • Specific examples of heteroalkyi groups are methoxy, trifluoromethoxy, ethoxy, n- propyloxy, / ' so-propyloxy, butoxy, ferf-butyloxy, methoxymethyl, ethoxymethyl, -CH 2 CH 2 OH, - CH 2 OH, methoxyethyl, 1 -methoxyethyl, 1 -ethoxyethyl, 2-methoxyethyl or 2-ethoxyethyl, methylamino, ethylamino, propylamino, / ' so-propylamino, dimethylamino, diethylamino, iso- propyl-ethylamino, methylamino methyl, ethylamino methyl, di-
  • aryl refers to an aromatic group that contains one or more rings containing from 6 to 14 ring carbon atoms, preferably from 6 to 10 (especially 6) ring carbon atoms. Examples are phenyl, naphthyl and biphenyl groups.
  • heteroaryl refers to an aromatic group that contains one or more rings containing from 5 to 14 ring atoms, preferably from 5 to 10 (especially 5 or 6) ring atoms, where one or more of the ring atoms are replaced with one or more (preferably 1 , 2, 3 or 4) oxygen, nitrogen, phosphorus or sulfur ring atoms (preferably O, S or N).
  • Examples are pyridine, imidazole, thiazole, / ' so-thiazole, 1 ,2,3-triazole, 1 ,2,4-triazole, oxadiazole, thiadiazole, indole, indazole, tetrazole, pyrazine, pyrimidine, pyridazine, oxazole, isoxazole, triazole, tetrazole, isoxazole, indazole, benzimidazole, benzoxazole, benzisoxazole, benzthiazole, pyridazine, quinoline, isoquinoline, pyrrole, purine, carbazole, acridine, and / ' so-quinoline groups.
  • halogen or "halogen atom” as used herein means fluorine, chlorine, bromine, or iodine.
  • halogen is chlorine or bromine.
  • halogen for example, fluorine, chlorine, bromine or iodine atoms
  • This expression also refers to a group that is substituted by one, two, three or more alkyl or heteroalkyl (e.g. OMe) groups. These groups may themselves be substituted.
  • an alkyl group substituent may be substituted by one or more halogen atoms ⁇ i.e., may be a haloalkyl group).
  • a wording defining the limits of a range of length such as, for example, "from 1 to 5" means any integer from 1 to 5, i. e. 1 , 2, 3, 4 and 5.
  • any range defined by two integers explicitly mentioned is meant to comprise and disclose any integer defining said limits and any integer comprised in said range.
  • R 1 and R 2 are each independently selected from H, OH, O-alkyl, NH 2 , NH-alkyl, N(alkyl) 2 , alkyl, N0 2 and halogen;
  • Ft 3 is selected from H, OC(0)-alkyl, NH-alkyl, N(alkyl) 2 and S-alkyl;
  • R 4 and R 6 are each independently selected from H, alkyl and heteroalkyi;
  • R 5 is selected from O, NH, N-alkyl and N-heteroalkyl
  • n 0, 1 , 2, 3, 4, 5 or 6;
  • R 7 is selected from alkyl, aryl and heteroaryl, which groups are optionally substituted, wherein the compound of formula (I) is not spiroleucettadine:
  • the present invention also relates to a compound of formula (I):
  • R 1 and R 2 are each independently selected from H, OH, O-alkyl, NH 2 , NH-alkyl, N(alkyl) 2 , alkyl, N0 2 and halogen;
  • R 3 is selected from H, OC(0)-alkyl, NH-alkyl, N(alkyl) 2 and S-alkyl;
  • R 4 and R 6 are each independently selected from H, alkyl and heteroalkyi;
  • R 5 is selected from NH, N-alkyl and N-heteroalkyl
  • n 0, 1 , 2, 3, 4, 5 or 6;
  • R 7 is selected from alkyl, aryl and heteroaryl, which groups are optionally substituted.
  • the present invention also relates to a compound of formula (I):
  • R 1 and R 2 are each independently selected from H, OH, O-alkyl, NH 2 , NH-alkyl, N(alkyl) 2 , alkyl, N0 2 and halogen;
  • R 3 is selected from H, OC(0)-alkyl, NH-alkyl, N(alkyl) 2 and S-alkyl;
  • R 4 and R 6 are each independently selected from H, alkyl and heteroalkyl
  • R 5 is selected from O, NH, N-alkyl and N-heteroalkyl
  • n 0, 1 , 2, 3, 4, 5 or 6;
  • R 7 is selected from alkyl, aryl and heteroaryl, which groups are optionally substituted.
  • R 1 and R 2 may both be H.
  • the halogen may be bromine or chlorine.
  • R 3 may be H.
  • R 3 may be OC(0)-alkyl (e.g. OC(O)-methyl).
  • R 3 may be NH-alkyl (e.g. NH- methyl).
  • R 4 and R 6 may both be alkyl (e.g. methyl).
  • R 5 may be NH.
  • m may be 1 .
  • R 7 may be an aryl group.
  • the aryl group may be substituted.
  • the substituent may be heteroalkyl (e.g. methoxy).
  • the compound may be a compound of formula (III):
  • the present inventors have developed a synthetic procedure that is efficient (having less steps than previously-reported syntheses of the related natural product spiroleucettadine), can be used for a number of different analogues, and utilises a readily-available starting material ((L)- tyrosine).
  • the present invention also relates to a process for making a compound of formula (I):
  • R 1 and R 2 are each independently selected from H, OH, O-alkyl, NH 2 , NH-alkyl, N(alkyl) 2 , alkyl, N0 2 or halogen;
  • R 3 is selected from NH-alkyl, N(alkyl) 2 and S-alkyl;
  • R 4 and R 6 are each independently selected from H, alkyl and heteroalkyl;
  • R 5 is selected from O, NH, N-alkyl and N-heteroalkyl;
  • n 0, 1 , 2, 3, 4, 5 or 6;
  • R 7 is selected from alkyl, aryl and heteroaryl, which groups are optionally substituted, the process including treating a compound of formula (II):
  • the present invention also relates to a process for making a compound of formula (I):
  • R 1 and R 2 are each independently selected from H, OH, O-alkyl, NH 2 , NH-alkyl, N(alkyl) 2 , alkyl, N0 2 and halogen;
  • R 3 is selected from H, OC(0)-alkyl, NH-alkyl, N(alkyl) 2 and S-alkyl;
  • R 4 and R 6 are each independently selected from H, alkyl and heteroalkyl
  • R 5 is selected from O, NH, N-alkyl and N-heteroalkyl
  • n 0, 1 , 2, 3, 4, 5 or 6; and R 7 is selected from alkyl, aryl and heteroaryl, which groups are optionally substituted, the process including treating a compound of formula (II):
  • the present invention also relates to a process for making a compound of formula (I):
  • R 1 and R 2 are each independently selected from H, OH, O-alkyl, NH 2 , NH-alkyl, N(alkyl) 2 , alkyl, N0 2 and halogen;
  • R 3 is selected from H, OC(0)-alkyl, NH-alkyl, N(alkyl) 2 and S-alkyl;
  • R 4 and R 6 are each independently selected from H, alkyl and heteroalkyl;
  • R 5 is selected from NH, N-alkyl and N-heteroalkyl
  • n 0, 1 , 2, 3, 4, 5 or 6;
  • R 7 is selected from alkyl, aryl and heteroaryl, which groups are optionally substituted, the process including treating a compound of formula (II):
  • the compound of formula (I la) is the compound that cyclises to give the compound of formula (III) under the oxidative conditions.
  • the hypervalent iodine reagent that may be used to convert the compound of formula (II) into the corresponding spirocyclic compound may be an organic iodine compound that acts as a selective oxidizing agent.
  • Suitable agents in this regard would be known to a person skilled in the art and include iodine (III) compounds, such as (difluoroiodo)arenes, (dichloroiodo)arenes, iodosylarenes, [bis(acyloxy)iodo]arenes, aryliodine(lll) organosulfonates, and five-membered iodine heterocylces (e.g.
  • Preferred agents are [bis(acyloxy)iodo]arenes, or aryliodine(lll) carboxylates, such as (diacetoxyiodo)benzene (also referred to as phenyliodine diacetate or PI DA) and [bis(trifluoroacetoxy)iodo]benzene (also referred to as phenyliodine bis(trifluoroacetate) or PIFA).
  • the reaction may be performed under any suitable conditions known to the person skilled in the art.
  • the reaction is carried out in a dry atmosphere, at room temperature in the presence of diethylisopropylamine, and in an acetonitrile/CF 3 CH20H solvent mixture.
  • the process may include the further step of treating the compound of formula (III) with a hypervalent iodine reagent to produce a compound of formula (IV):
  • the hypervalent iodine reagent that may be used to convert the compounds of formula (III) into the corresponding acylated compound may be an organic iodine compound that acts as a selective oxidizing agent.
  • Suitable agents in this regard would be known to a person skilled in the art and include iodine (V) compounds, such as periodinanes (e.g. Dess-Martin periodinane or 2-iodoxybenzoic acid), or iodine (III) compounds, such as PIDA or PIFA.
  • the preferred reagent is Dess-Martin periodinane.
  • the reaction may be performed under any suitable conditions known to the person skilled in the art.
  • the reaction is carried out in a dry atmosphere and in a halogenated solvent.
  • compositions including a therapeutically effective amount of the compounds of formula (I), or its pharmaceutically acceptable salt, prodrug, solvate or hydrate thereof, and one or more pharmaceutically acceptable excipients, carriers or diluents.
  • Pharmaceutical compositions may be formulated for any appropriate route of administration including, for example, topical (for example, transdermal or ocular), oral, buccal, nasal, vaginal, rectal or parenteral administration.
  • parenteral as used herein includes subcutaneous, intradermal, intravascular (for example, intravenous), intramuscular, spinal, intracranial, intrathecal, intraocular, periocular, intraorbital, intrasynovial and intraperitoneal injection, as well as any similar injection or infusion technique.
  • Suitable oral forms include, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Aqueous suspensions contain the active ingredient(s) in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as naturally-occurring phosphatides (for example, lecithin), condensation products of an alkylene oxide with fatty acids such as polyoxyethylene stearate, condensation products of ethylene oxide with long chain aliphatic alcohols such as heptadecaethyleneoxycetanol, condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol mono-oleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides such as polyethylene sorbitan monooleate.
  • Aqueous suspensions may also comprise one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl, or n-propyl p-hydroxybenzoate
  • colouring agents for example ethyl, or n-propyl p-hydroxybenzoate
  • flavouring agents such as sucrose or saccharin.
  • sweetening agents such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and/or flavoring agents may be added to provide palatable oral preparations.
  • Such suspensions may be preserved by the addition of an antioxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol,
  • compositions may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil such as olive oil or arachis oil, a mineral oil such as liquid paraffin, or a mixture thereof.
  • Suitable emulsifying agents include naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides such as sorbitan monoleate, and condensation products of partial esters derived from fatty acids and hexitol with ethylene oxide such as polyoxyethylene sorbitan monoleate.
  • An emulsion may also comprise one or more sweetening and/or flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also comprise one or more demulcents, preservatives, flavouring agents and/or colouring agents.
  • sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also comprise one or more demulcents, preservatives, flavouring agents and/or colouring agents.
  • a composition may further include one or more components adapted to improve the stability or effectiveness of the applied formulation, such as stabilizing agents, suspending agents, emulsifying agents, viscosity adjusters, gelling agents, preservatives, antioxidants, skin penetration enhancers, moisturizers and sustained release materials.
  • stabilizing agents such as hydroxymethylcellulose or gelatin-microcapsules, liposomes, albumin microspheres, microemulsions, nanoparticles or nanocapsules.
  • a pharmaceutical composition may be formulated as inhaled formulations, including sprays, mists, or aerosols.
  • inhalation formulations the compounds provided herein may be delivered via any inhalation methods known to a person skilled in the art.
  • inhalation methods and devices include, but are not limited to, metered dose inhalers with propellants such as CFC or HFA or propellants that are physiologically and environmentally acceptable.
  • propellants such as CFC or HFA or propellants that are physiologically and environmentally acceptable.
  • Other suitable devices are breath operated inhalers, multidose dry powder inhalers and aerosol nebulizers.
  • Aerosol formulations for use in the subject method typically include propellants, surfactants and co-solvents and may be filled into conventional aerosol containers that are closed by a suitable metering valve.
  • Inhalant compositions may comprise liquid or powdered compositions containing the active ingredient that are suitable for nebulization and intrabronchial use, or aerosol compositions administered via an aerosol unit dispensing metered doses.
  • Suitable liquid compositions comprise the active ingredient in an aqueous, pharmaceutically acceptable inhalant solvent such as isotonic saline or bacteriostatic water.
  • the solutions are administered by means of a pump or squeeze-actuated nebulized spray dispenser, or by any other conventional means for causing or enabling the requisite dosage amount of the liquid composition to be inhaled into the patient's lungs.
  • Suitable formulations, wherein the carrier is a liquid, for administration, as for example, a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient.
  • compositions may also be prepared in the form of suppositories such as for rectal administration.
  • Such compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable excipients include, for example, cocoa butter and polyethylene glycols.
  • compositions may be formulated as sustained release formulations such as a capsule that creates a slow release of modulator following administration.
  • sustained release formulations such as a capsule that creates a slow release of modulator following administration.
  • Such formulations may generally be prepared using well-known technology and administered by, for example, oral, rectal or subcutaneous implantation, or by implantation at the desired target site.
  • Carriers for use within such formulations are biocompatible, and may also be biodegradable.
  • the formulation provides a relatively constant level of modulator release.
  • the amount of modulator contained within a sustained release formulation depends upon, for example, the site of implantation, the rate and expected duration of release and the nature of the condition to be treated or prevented.
  • the dose of the biologically active compound according to the invention may vary within wide limits and may be adjusted to individual requirements.
  • Active compounds according to the present invention are generally administered in a therapeutically effective amount. Preferred doses range from about 0.1 mg to about 140 mg per kilogram of body weight per day ⁇ e.g., about 0.5 mg to about 7 g per patient per day).
  • the daily dose may be administered as a single dose or in a plurality of doses.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between about 1 mg to about 500 mg of an active ingredient.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination (i.e., other drugs being used to treat the patient), and the severity of the particular disorder undergoing therapy.
  • terapéuticaally effective amount refers to an amount of the compound of formula (I) that results in an improvement or remediation of the disorder.
  • Preferred compounds of the invention will have certain pharmacological properties. Such properties include, but are not limited to oral bioavailability, such that the preferred oral dosage forms discussed above can provide therapeutically effective levels of the compound in vivo.
  • the compounds of the present invention are preferably administered to a patient (for example, a human) orally, and are present within at least one body fluid or tissue of the patient. Accordingly, the present invention further provides methods for treating and/or preventing cancer, and methods for treating and/or preventing microbial infections.
  • treatment encompasses both disorder-modifying treatment and symptomatic treatment. It refers to therapeutic treatment, i.e., after the onset of symptoms, in order to reduce the severity and/or duration of symptoms, and/or to cure the condition or disorder.
  • prevention encompasses prophylactic treatment, i.e., before the onset of symptoms, in order to prevent, delay or reduce the severity of symptoms and/or the condition or disorder.
  • Patients may include but are not limited to primates, especially humans, domesticated companion animals such as dogs, cats, horses, and livestock such as cattle, pigs, sheep, and poultry, with dosages as described herein.
  • the present invention may be useful for the treatment and/or prevention of cancer, and for the treatment and/or prevention of microbial infections, in a subject. Accordingly, the present invention also relates to a method of treating or preventing cancer, or treating or preventing microbial infection, in a patient including administration to the patient of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically-acceptable salt, solvate or hydrate thereof. The present invention also relates to the use of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically-acceptable salt, solvate or hydrate thereof, for treating or preventing cancer, or treating or preventing microbial infection.
  • the present invention also provides a pharmaceutical composition for use in treating or preventing cancer, or treating or preventing microbial infection, in any of the embodiments described in the specification.
  • the present invention also relates to the use of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof, for the manufacture of a medicament for treating or preventing cancer, or treating or preventing microbial infection.
  • the present invention also relates to a compound of formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof, when used in a method of treating or preventing cancer, or treating or preventing microbial infection.
  • the present invention also relates to a composition having an active ingredient for use in treating or preventing cancer, or treating or preventing microbial infection, wherein the active ingredient is a compound of formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof.
  • the present invention also relates to the use of a pharmaceutical composition containing a compound of the formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof, in treating or preventing cancer, or treating or preventing microbial infection, such as described above.
  • the compound of formula (I) is essentially the only active ingredient of the composition.
  • the compounds according to the invention are used as or for the manufacture of a diagnostic agent, whereby such diagnostic agent is for the diagnosis of the disorders and conditions which can be addressed by the compounds of the present invention for therapeutic purposes as disclosed herein.
  • the compounds of the invention can be labelled by isotopes, fluorescence or luminescence markers, antibodies or antibody fragments, any other affinity label like nanobodies, aptamers, peptides etc., enzymes or enzyme substrates.
  • These labelled compounds of this invention are useful for mapping the location of receptors in vivo, ex vivo, in vitro and in situ such as in tissue sections via autoradiography and as radiotracers for positron emission tomography (PET) imaging, single photon emission computerized tomography (SPECT) and the like, to characterize those receptors in living subjects or other materials.
  • PET positron emission tomography
  • SPECT single photon emission computerized tomography
  • the labelled compounds according to the present invention may be used in therapy, diagnosis and other applications such as research tools in vivo and in vitro, in particular the applications disclosed herein.
  • Compound 12 was prepared according to a literature procedure (Ko et al. (201 1 ) Org. Lett., pages 980-983).
  • Compound 13 A solution of Weinreb amide 12 (1 .489 g, 3.59 mmol) in THF (15 mL) was stirred at 0°C, to which was added a solution of 4-methoxybenzylmagnesium chloride (10.8 mmol, 0.36 M) dropwise over 10 min. The resulting solution was stirred at room temperature until the observed disappearance of starting material as monitored by TLC. The solution was cooled to 0°C, and quenched with sat. NH 4 CI and partitioned between EtOAc (45 mL) and distilled water (30 mL).

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

La présente invention concerne de nouveaux composés spirocycliques qui peuvent être utiles en tant qu'agents anticancéreux et antimicrobiens, la préparation des composés, et des compositions comprenant les composés. La présente invention concerne également l'utilisation des composés, ainsi que des compositions comprenant les composés, pour le traitement ou la prévention du cancer, et le traitement ou la prévention d'infections microbiennes.
PCT/AU2018/050771 2017-07-26 2018-07-25 Nouveaux composés spirocycliques WO2019018890A1 (fr)

Applications Claiming Priority (2)

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AU2017902925A AU2017902925A0 (en) 2017-07-26 Novel Spirocyclic Compounds
AU2017902925 2017-07-26

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WO2019018890A1 true WO2019018890A1 (fr) 2019-01-31

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Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
ELYASHBERG, M. ET AL.: "Structural revisions of natural products by Computer-Assisted Structure Elucidation (CASE) systems", NATURAL PRODUCT REPORTS, vol. 27, no. 9, 2010, pages 1296 - 1328, XP055569287, Retrieved from the Internet <URL:DOI:10.1039/C002332A> *
LAMB, R. A. ET AL.: "Strategies, Setbacks, and Successes in the Synthesis of (-)- Spiroleucettadine", JOURNAL OF ORGANIC CHEMISTRY, vol. 83, no. 17, 13 July 2018 (2018-07-13), pages 10120 - 10133, XP055569298, Retrieved from the Internet <URL:DOI:10.1021/acs.joc.8b01404> *
LAMB, R. A. ET AL.: "Total Synthesis of (-)-Spiroleucettadine", ANGEWANDTE CHEMIE , INTERNATIONAL EDITION, vol. 56, no. 46, 27 September 2017 (2017-09-27), pages 14663 - 14666, XP055569301, Retrieved from the Internet <URL:https://doi.org/10.1002/anie.201708110> *
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NAGASAWA, Y. ET AL.: "Spironaamidine, a new spiroquinone-containing alkaloid from the marine sponge Leucetta microraphis", TETRAHEDRON LETTERS, vol. 52, no. 41, 12 October 2011 (2011-10-12), pages 5342 - 5344, XP028286466, Retrieved from the Internet <URL:https://doi.org/10.1016/j.tetlet.2011.08.026> *
RALIFO, P. ET AL.: "A New Structural Theme in the Imidazole-Containing Alkaloids from a Calcareous Leucetta Sponge", JOURNAL OF ORGANIC CHEMISTRY, vol. 69, no. 26, 10 November 2004 (2004-11-10), pages 9025 - 9029, XP055569284, Retrieved from the Internet <URL:DOI:10.1021/jo048789+> *
WHITE, K. N. ET AL.: "Structure Revision of Spiroleucettadine, a Sponge Alkaloid with a Bicyclic Core Meager in H-Atoms", JOURNAL OF ORGANIC CHEMISTRY, vol. 73, no. 22, 16 October 2008 (2008-10-16), pages 8719 - 8722, XP055569280, Retrieved from the Internet <URL:DOI:10.1021/jo800960w> *
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