WO2012145678A1 - Composés parthénolides anticancéreux et anti-inflammatoire - Google Patents

Composés parthénolides anticancéreux et anti-inflammatoire Download PDF

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WO2012145678A1
WO2012145678A1 PCT/US2012/034527 US2012034527W WO2012145678A1 WO 2012145678 A1 WO2012145678 A1 WO 2012145678A1 US 2012034527 W US2012034527 W US 2012034527W WO 2012145678 A1 WO2012145678 A1 WO 2012145678A1
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alkyl
aryl
heteroaryl
cycloalkyl
compound
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Daniel A. HARKI
Dan Wang
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University of Minnesota Twin Cities
University of Minnesota System
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University of Minnesota Twin Cities
University of Minnesota System
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/92—Naphthofurans; Hydrogenated naphthofurans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

Definitions

  • the natural product parthenolide (PTL, 1):
  • DMAPT dimethylamino-parthenolide
  • DMAPT (also known as LC-1) is a water-soluble analogue and a clinical drug candidate with efficacy against AML stem and progenitor cells in vivo (canines), and has substantially improved bioavailability as compared to PTL.
  • LC-1 water-soluble analogue
  • canines AML stem and progenitor cells in vivo
  • a Phase I trial with DMAPT has been recently initiated in the United Kingdom for the treatment of AML (Guzman, M. L., et al. Blood 2007, 110, 4427-4435; and Neelakantan, S., et al. Bioorg. Med. Chem. Lett. 2009, 19, 4346-4349).
  • PTL has also been shown to affect other cellular processes, such as blocking STAT3 phosphorylation of IL-6, inhibiting c-Jun N-terminal kinase (JNK), depleting cellular glutathione levels, increasing cellular oxidative stress by the generation of reactive oxygen species (ROS), activation of p53 and cellular caspases, and inhibition of Hsp70.
  • JNK c-Jun N-terminal kinase
  • ROS reactive oxygen species
  • the present invention provides novel compounds that possess anti-cancer and antiinflammatory properties and that are useful for treating cancer and cardiovascular diseases. Accordingly there is provided a compound of the invention which is a compound of formula I, formula II, formula III, formula IV, or formula V:
  • X is O or C3 ⁇ 4, is absent, or taken together with the carbons to which it is attached forms a double bond;
  • Z is O or CH 2 or taken together with the carbons to which it is attached forms a double bond; the bond represented by— is a single or a double bond;
  • R 1 is H, halo, cyano, nitro, hydroxy, carboxy, trifluoromethyl, trifluoromethoxy, (C 1 -C 6 )alkyl,
  • any alkyl of R 1 is optionally substituted with one or more R a ; and wherein any aryl, heteroaryl, or any aryl or heteroaryl portion of any aryloxy, or heteroaryloxy of R 1 is optionally substituted with one or more R b ;
  • R is H, phosphate, trifluoromethyl, (C 1 -C 6 )alkyl, (C!-C6)alkoxycarbonyl, aryl, heteroaryl, aryl(Ci-C6)alkyl, or heteroaryl(CrC6)alkyl; wherein any alkyl of R 2 is optionally substituted with one or more R a ; and wherein any aryl, heteroaryl, or any aryl or heteroaryl portion of any aryl(C 1 -C 6 )alkyl or heteroaryl(C 1 -C6)alkyl of R 2 is optionally substituted with one or more R b ;
  • R is H, halo, cyano, nitro, hydroxy, carboxy, trifluoromethyl, trifluoromethoxy, (Ci-C 6 )alkyl,
  • any alkyl of R 3 is optionally substituted with one or more R a ; and wherein any aryl, heteroaryl, or any aryl or heteroaryl portion of any aryloxy, or heteroaryloxy of R 3 is optionally substituted with one or more R b ;
  • R 4 is H or OR v ;
  • R 5 is H or OR v ;
  • R 6 is H or OR v ;
  • R 7 is H or OR v ;
  • R 8 is H or OR v ;
  • R 9 is H or OR v ;
  • each R a is independently selected from halo, cyano, nitro, hydroxy, carboxy, oxo, (C 1 -C6)alkyl,
  • each R° and R d is independently selected from H, (d-C ⁇ alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -
  • each R g and R h is independently selected from H, (C 1 -C6)alkyl, (C3-C 6 )cycloalkyl, (C 3 - C 6 )cycloalkyl(C]-C 6 )alkyl, aryl, heteroaryl, ar l(CrC6) alkyl and heteroaryl(d-C 6 ) alkyl; or R 8 andR h together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino; wherein any (d-C 6 )alkyl, (C 3 -C6)cycloalkyl, (C 3 - C 6 )cycloalkyl(d-C 6 )alkyl, aryl, heteroaryl, aryl(d-C6) alkyl or heteroaryl(C 1 -C6)alkyl of R 8 and R h is optionally substituted with one or more
  • each R k is independently selected from H, (C 1 -C )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -
  • each R m and R n is independently selected from H, (d-C 6 )alkyl, (C 3 -C6)cycloalkyl, (C 3 - C 6 )cycloalkyl(CrC 6 )alkyl, aryl, heteroaryl, aryl(d-C 6 ) alkyl and heteroaryl(d-C 6 ) alkyl; or R m andR n together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino; wherein any (d-C )alkyl, (C 3 -C6)cycloalkyl, (C 3 - C 6 )cycloalkyl(Ci-C 6 )alkyl, aryl, heteroaryl, aryl(d-C 6 ) alkyl or heteroaryl(C r C 6 )alkyl of R m and R" is optionally substituted
  • each R l and R u is independently selected from H, (d-C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 - C 6 )cycloalkyl(d-C 6 )alkyl, aryl, heteroaryl, aryl(C r C 6 ) alkyl and heteroaryl(d-C 6 ) alkyl; or R'andR" together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino; and
  • each R v is H, (d-C 6 )alkyl, phosphate, (d-C 6 )alkoxycarbonyl, aryl, heteroaryl, aryl(C 1 -C6)alkyl, or heteroaryl(C 1 -C 6 )alkyl; wherein any alkyl of R v is optionally substituted with one or more R a ; and wherein any aryl, heteroaryl, or any aryl or heteroaryl portion of any aryl(C 1 -C6)alkyl or heteroaryl(d- C )alkyl of R v is optionally substituted with one or more R b ; or a salt thereof.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I, formula II, formula III, formula IV, or formula V, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
  • the invention also provides a method for treating cancer in a mammal, comprising administering a compound of formula I, formula II, formula III, formula IV, or formula V, or a pharmaceutically acceptable salt thereof, to the mammal.
  • the invention also provides a method for treating a cardiovascular diseases (e.g. atherosclerosis) in a mammal, comprising administering a compound of formula I, formula II, formula III, formula IV, or formula V, or a pharmaceutically acceptable salt thereof, to the mammal.
  • a cardiovascular diseases e.g. atherosclerosis
  • the invention also provides a method for inhibiting the NF- ⁇ signaling pathway in a cell, comprising contacting the cell in vitro or in vivo with an effective amount of a compound of formula I, formula II, formula III, formula IV, or formula V, or a pharmaceutically acceptable salt thereof.
  • the invention provides a therapeutic method for preventing or treating a pathological condition or symptom in a mammal, such as a human, wherein the activity of the NF-KB signaling pathway is implicated and antagonism of its action is desired comprising administering to a mammal in need of such therapy, an effective amount of a compound of formula I, formula II, formula III, formula IV, or formula V, or a pharmaceutically acceptable salt thereof.
  • the invention provides a compound of formula I, formula II, formula III, formula IV, or formula V, or a pharmaceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment of cancer.
  • the invention provides a compound of formula I, formula II, formula III, formula IV, or formula V, or a pharmaceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment of a cardiovascular disease.
  • the invention provides a compound of formula I, formula ⁇ , formula III, formula IV, or formula
  • V or a pharmaceutically acceptable salt thereof, for use in medical therapy (e.g. for use in treating cancer or a cardiovascular diseases such as atherosclerosis).
  • the invention provides the use of a compound of formula I, formula II, formula ⁇ , formula IV, or formula V, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful for the treatment of cancer in a mammal, such as a human.
  • the invention provides the use of a compound of formula I, formula II, formula III, formula IV, or formula V, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful for the treatment of a cardiovascular disease (e.g. atherosclerosis) in a mammal, such as a human.
  • a cardiovascular disease e.g. atherosclerosis
  • the invention also provides synthetic processes and synthetic intermediates disclosed herein that are useful for preparing compounds formula I, formula II, formula HI, formula IV, or formula V, or salts thereof.
  • halo is fluoro, chloro, bromo, or iodo.
  • Alkyl, alkoxy, alkenyl, alkynyl, etc. denote both straight and branched groups; but reference to an individual radical such as propyl embraces only the straight chain radical, a branched chain isomer such as isopropyl being specifically referred to.
  • Aryl denotes a phenyl radical or an ortho-fused bicyclic carbocyclic radical having about nine to ten ring atoms in which at least one ring is aromatic.
  • Heteroaryl encompasses a radical of a monocyclic aromatic ring containing five or six ring atoms consisting of carbon and one to four heteroatoms each selected from the group consisting of non- peroxide oxygen, sulfur, and N(Y) wherein Y is absent or is H, O, (C 1 -C4)alkyl, phenyl or benzyl, as well as a radical of an ortho-fused bicyclic heterocycle of about eight to ten ring atoms comprising one to four heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and N(Y).
  • (d-C ⁇ alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl;
  • (C 3 -C 6 )cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
  • (C 1 -C 6 )alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec- butoxy, pentoxy, 3-pentoxy, or hexyloxy;
  • (CrC ⁇ alkanoyl can be acetyl, propanoyl or butanoyl;
  • (Q-C ⁇ alkoxycarbonyl can be methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxy
  • a s ecific compound of the invention is a compound of formula la, Ila, or Ilia:
  • a s ecific compound of the invention is a compound of formula lb, Ic, or Id:
  • a s ecific compound of the invention is a compound of formula le, If, or I :
  • a specific compound of the invention is a compound of formula Im, In, or Io:
  • a s ecific compound of the invention is a compound of formula Ip, Iq, or Ir:
  • a specific compound of the invention is a compound of formula lib, lie, or lid:
  • a specific value for R 4 is H.
  • a specific value for R 5 is H.
  • a specific value for R 6 is H.
  • a specific value for R 4 is OH.
  • a specific value for R 5 is OH.
  • a specific value for R 6 is OH.
  • a specific value for R 7 is H.
  • a specific value for R 8 is H.
  • a specific value for R 9 is H.
  • a specific value for R 7 is OH.
  • a specific value for R 8 is OH.
  • a specific value for R 9 is OH.
  • a specific value for R 1 is H.
  • R 1 A specific value for R 1 is -NR c R d .
  • a specific value for R 2 is H.
  • R 2 is (C 1 -C 6 )alkyl, that is optionally substituted with one or more (e.g. 1 , 2, 3, or 4) R a .
  • a specific value for R 3 is H.
  • a specific value for R 3 is -NR c R d .
  • a specific compound of the invention is a compound of formula I, formula II, or formula III:
  • X is O or CH 2 , is absent, or taken together with the carbons to which it is attached forms a cis- double bond;
  • Z is O or C3 ⁇ 4 or taken together with the carbons to which it is attached forms a double bond; the bond represented by— is a single or a double bond;
  • R 1 is H, halo, cyano, nitro, hydroxy, carboxy, trifluoromethyl, trifluoromethoxy, (Ci-C ⁇ alkyl, (C 3 -C 6 )cycloalkyl, (CrC 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, a group of formula:
  • any alkyl of R 1 is optionally substituted with one or more R a ; and wherein any aryl, heteroaryl, or any aryl or heteroaryl portion of any aryloxy, or heteroaryloxy of R 1 is optionally substituted with one or more R b ;
  • R is H, trifluoromethyl, (C 1 -C 6 )alkyl, (Q-C ⁇ alkoxycarbonyl, aryl, heteroaryl, arylid-C ⁇ alkyl, or heteroary ⁇ CrC ⁇ alkyl; wherein any alkyl of R 2 is optionally substituted with one or more R a ; and wherein any aryl, heteroaryl, or any aryl or heteroaryl portion of any aryl(Ci-C )alkyl or heteroary ⁇ C C 6 )alkyl of R is optionally substituted with one or more R ; R is H, halo, cyano, nitro, hydroxy, carboxy, trifluoromethyl, trifluoromethoxy, (Q-C ⁇ alkyl, (C3-C )cycloalkyl, (d-C 6 )alkoxy, (Ci-C6)alkoxycarbonyl, (Q-Csialkanoyloxy, aryl, heteroaryl, ary
  • any alkyl of R 3 is optionally substituted with one or more R a ; and wherein any aryl, heteroaryl, or any aryl or heteroaryl portion of any aryloxy, or heteroaryloxy of R 3 is optionally substituted with one or more R b ;
  • R 4 is H or OR v ;
  • R 5 is H or OR v ;
  • R 6 is H or OR v ;
  • R 7 is H or OR v ;
  • R 8 is H or OR v ;
  • R 9 is H or OR v ;
  • each R a is independently selected from halo, cyano, nitro, hydroxy, carboxy, oxo, (Ci-C 6 )alkyl, (C 3 -C )cycloalkyl, (C 1 -C6)alkoxy, (CrC ⁇ alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, (C 1 -C 6 )alkylthio, -S(0)R k , -S(0) 2 R k , -S(0) 3 R k , -S(0) 2 NR e R f , and -NR R f ; wherein each aryl, heteroaryl, aryloxy, and heteroaryloxy is optionally substituted with one or more groups independently selected from halo, cyano, nitro, hydroxy, carboxy, trifluoromethyl, trifluoromethoxy, (C!-C6)alkyl,
  • each R b is independently selected from halo, cyano, nitro, hydroxy, carboxy, trifluoromethyl, trifluoromethoxy, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C]-C6)alkoxy, (Ci-C 6 )alkoxycarbonyl, (Q- C 6 )alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, (C 1 -C 6 )alkylthio, -S(0)R k , -S(0) 2 R k , -S(0) 3 R k , -S(0) 2 NR m R n , and -NR m R n ; wherein each aryl, heteroaryl, aryloxy, and heteroaryloxy is optionally substituted with one or more groups independently selected from halo, cyano, nitro, hydroxy, carboxy, trifluoromethyl, trifluorometh
  • each R c and R d is independently selected from H, (CrC ⁇ alkyl, (C 3 -C6)cycloalkyl, (C 3 - C 6 )cycloalkyl(C 1 -C6)alkyl, hydroxy, aryl, heteroaryl, ary ⁇ Q-Ce) alkyl and heteroaryliCrCe) alkyl; or R c and R d together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino; wherein any (C 1 -C 6 )alkyl, (C 3 -C6)cycloalkyl, (C 3 - C 6 )cycloalkyl(C 1 -C )alkyl, aryl, heteroaryl, aryl(C C 6 ) alkyl or heteroaryl(C 1 -C6)alkyl of R c and R d is optionally substituted
  • each R e and R f is independently selected from H, (C C ⁇ alkyl, (C3-C6)cycloalkyl, (C 3 - C 6 )cycloalkyl(C 1 -C 6 )alkyl, aryl, heteroaryl, aryl(CrC6) alkyl and heteroaryliCi-Ce) alkyl; or R e andR f together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino; wherein any (C3-C 6 )cycloalkyl, (C 3 - C )cycloalkyl(C 1 -C 6 )alkyl, aryl, heteroaryl, aryl(CrC 6 ) alkyl or heteroaryliQ-C ⁇ alkyl of R e and R f is optionally substituted with one or more groups independently selected from hydroxy, carboxy, and
  • each R 8 and R h is independently selected from H, (C C ⁇ alkyl, (C3-C6)cycloalkyl, (C 3 - C 6 )cycloalkyl(C 1 -C 6 )alkyl, aryl, heteroaryl, aryl(C r C 6 ) alkyl and heteroary C Ce) alkyl; or R g andR h together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino; wherein any (C 3 -C6)cycloalkyl, (C 3 - C f cycloalky CrC f alkyl, aryl, heteroaryl, aryl(Ci-C 6 ) alkyl or heteroaryl(C 1 -C 6 )alkyl of R g and R h is optionally substituted with one or more groups independently selected from hydroxy, carboxy, and NR l
  • each R k is independently selected from H, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -
  • each R m and R n is independently selected from H, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 - C 6 )cycloalkyl(C 1 -C 6 )alkyl, aryl, heteroaryl, aryl(CrC 6 ) alkyl and heteroarylCCrCe) alkyl; or R m and R n together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino; wherein any (C !
  • R m and R n is optionally substituted with one or more groups independently selected from hydroxy, carboxy, and NR l R u ;
  • each R l and R u is independently selected from H, (CrC ⁇ alkyl, (C 3 -C 6 )cycloalkyl, (C 3 - C ⁇ cycloalkylCC C ⁇ alkyl, aryl, heteroaryl, aiyl(Ci-C 6 ) alkyl and heteroarylCd-Ce) alkyl; or R l andR u together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino; and
  • each R v is H, (d-C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl, aryl, heteroaryl, aryl(Ci-C6)alkyl, or heteroary ⁇ d-C ⁇ alkyl; wherein any alkyl of R v is optionally substituted with one or more R a ; and wherein any aryl, heteroaryl, or any aryl or heteroaryl portion of any aryliC C ⁇ alkyl or heteroaryl(C ! - C 6 )alkyl of R v is optionally substituted with one or more R b ;
  • the compound when a compound is shown with a wedged (up) or dashed (back) bond the compound may be enriched by about 60%, 80%, 90%, 95%, 98%, or 99% in the absolute stereoisomer represented.
  • a specific compound of the invention is compound 3, 4, 6, 8, 13, 14, 15, or 16, or a salt thereof.
  • a specific compound of the invention is compound 3, 4, 14, or 15, or a salt thereof.
  • the compound of the invention is not compound 1, 2, 5, 7,
  • a salt of a compound of formula I, formula II, formula III, formula IV, or formula V can be useful as an intermediate for isolating or purifying a compound of formula I.
  • administration of a compound of formula I, formula II, formula III, formula IV, or formula V as a pharmaceutically acceptable acid or base salt may be appropriate.
  • pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, fumarate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, a-ketoglutarate, and a- glycerophosphate.
  • Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.
  • salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.
  • a sufficiently basic compound such as an amine
  • a suitable acid affording a physiologically acceptable anion.
  • Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
  • the compounds of formula I, formula II, formula III, formula IV, or formula V can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes.
  • the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet.
  • a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier.
  • the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • Such compositions and preparations should contain at least 0.1 % of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2% to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.
  • the tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as com starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added.
  • a liquid carrier such as a vegetable oil or a polyethylene glycol.
  • any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
  • the active compound may be incorporated into sustained-release preparations and devices.
  • the active compound may also be administered intravenously or intraperitoneally by infusion or injection.
  • Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes.
  • the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage.
  • the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization.
  • the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
  • the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.
  • Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like.
  • Useful liquid carriers include water, alcohols or glycols or water- alcohol/ glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.
  • Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use.
  • the resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
  • Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
  • Examples of useful dermatological compositions which can be used to deliver the compounds to the skin are known to the art; for example, see Jacquet et al. (U.S. Pat. No.4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman (U.S. Pat. No. 4,820,508).
  • Useful dosages of the compounds can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949.
  • the amount of the compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.
  • a suitable dose will be in the range of from about 0.5 to about 100 mg/kg, e.g., from about 10 to about 75 mg/kg of body weight per day, such as 3 to about 50 mg per kilogram body weight of the recipient per day, preferably in the range of 6 to 90 mg/kg/day, most preferably in the range of 15 to 60 mg/kg/day.
  • the compound is conveniently formulated in unit dosage form; for example, containing 5 to 1000 mg, conveniently 10 to 750 mg, most conveniently, 50 to 500 mg of active ingredient per unit dosage form.
  • the invention provides a composition comprising a compound of the invention formulated in such a unit dosage form.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
  • the invention also provides a composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent, and a pharmaceutically acceptable diluent or carrier.
  • the invention also provides a kit comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent, packaging material, and instructions for administering the compound of the invention or the pharmaceutically acceptable salt thereof and the other therapeutic agent or agents to an animal to treat cancer.
  • cytotoxicity of a compound of the invention may be determined using pharmacological models which are well known, or using Test A described below.
  • CCRF-CEM acute lymphoblastic leukemia cells (ATCC, CCL-119) were cultured in RPMI- 1640 media (ATCC, 30-2001) supplemented with 10% fetal bovine serum (FBS, Gibco), penicillin (100 I.U./mL), and streptomycin (100 ⁇ g/mL) (ATCC, 30-2300) at a density of 2 10 5 - 2 10 6 cells/mL.
  • HL-60 acute promyelocytic leukemia cells (ATCC, CCL-240) were cultured in IMDM media (ATCC, 30-2005) supplemented with 10% FBS, penicillin (100 I.U./mL), and streptomycin (100 ⁇ g/mL) at a density of 1 10 5 - 1 10 6 cells/mL.
  • DU- 145 prostate cancer cells (ATCC, HTB-81 ) were cultured in EMEM media (ATCC, 30-2003) supplemented with 10% FBS, penicillin (100 I.U./mL), and streptomycin (100 ⁇ g/mL).
  • U-87 MG glioblastoma cells (ATCC, HTB-14) were cultured in EMEM media (ATCC, 30-2003) supplemented with 10% FBS, penicillin (100 I.U./mL), and streptomycin (100 ⁇ g/mL).
  • GBM6 primary glioblastoma cells (a gift from Professor John Ohlfest, University of Minnesota) were cultured under serum-free conditions utilizing Neural Stem Cell (NSC) complete growth media. This media was prepared by treating a 500 mL bottle of DMEM/F12 (1 : 1) media containing L-glutamine (ThermoSci.
  • SH3027101 with B-27 supplement without Vitamin A (10 mL of a 50X solution; Gibco 12587-010), N-2 supplement (5 mL of a 100X solution; Gibco 17502- 048), normocin (100 ⁇ g/mL; Invivogen ant-nr-1), penicillin (50 I.U./mL; Cellgro 30-001-CI), and streptomycin (50 pg/mL; Cellgro 30-001-CI).
  • cytokines human EGF (20 ng/ ⁇ , in 0.1% BS A/PBS solution; PeptroTech; 100-15) and human FGF-basic (20 ng pL in 0.1% BS A/PBS solution; PeproTech; 100-18B), were added to aliquots of the NSC media prior to splitting and plating the cell cultures. Trypsinization of GBM6 cells was achieved with the use of TrypLE Express solution (Gibco 12604013) in place of trypsin.
  • CCRF-CEM and HL-60 cells were seeded at a density of 10,000 cells/well in cell culture media (50 ⁇ ) in standard 96-well plates (Costar) 24 h prior to treatment.
  • DU- 145, U87-MG, and GBM6 cells were seeded at a density of 5,000 cells/well in cell culture media (50 L) in standard 96-well plates (Costar).
  • Blank (no cells) wells and control (vehicle control treated) wells were prepared with each experiment.
  • Alamar Blue (Invitrogen) cell viability reagent was added to each well (10 ⁇ ). This procedure yields a quantitative measure of cell viability by evaluating the ability of metabolically active cells (which are proportional to the number of living cells) to convert resazurin (non-fluorescent dye) to red-fluorescent resorufin. Fluorescence data were obtained on either a Molecular Devices SpectraMax M2 plate reader or an LJL BioSystems HT Analyst plate reader.
  • Murine Cytotoxicity Assays The anti-leukemic activities of 1-19 were studied in murine cell culture models of drug-resistant acute myeloid leukemia (AML).
  • the cell lines used are B 117P, B 117H, B 140P and B140H.
  • Bl 17P and B140P are murine AML cell lines derived from a BXH-2 strain of mice that develop AML (J Virol 1995, 69, 5095). These cell lines are cytarabine-sensitive models of AML. Continuous low-dose culturing of Bl 17P and B140P cell lines with cytarabine yielded Bl 17H and B140H, respectively, which can tolerate cytarabine concentrations 500-1000 times greater than the parental cell lines (Exp.
  • AML Colony Forming Assay AML proliferation is dependent on the existence of the cancer stem cell population, and drug-mediated elimination of AML CSCs will prohibit colony formation (Nat. Immunol. 2004, 5, 738).
  • a colony-forming assay with 5 was performed.
  • a low concentration of primary murine leukemia cells (harboring MII/AF9 and N/L4S G/2F transgenes) were treated with vehicle control or 38 ⁇ 5 and then plated in methylcellulose semi-solid media containing IL-3, IL-6, GM-CSF, and SCF.
  • individual cells were suspended in the media, and therefore, resulting colonies represent the outgrowth from single cells with replicative capacity (stem cells). Colonies were then counted for both vehicle control and 5.
  • Dosing of the vehicle control yields approximately 26 colonies per 10,000 nucleated cells in this assay. Repeating this experiment with 5 revealed no colony formation, suggesting the
  • the pharmacokinetic properties of a compound of the invention may be determined using pharmacological models which are well known, or using Test B described below.
  • PK Pharmacokinetics
  • the signal was optimized for each compound by ESI positive or negative ionization mode.
  • An MS2 scan or a SIM scan was used to optimize the fragmenter voltage and a product ion analysis was used to identify the best fragment for analysis, and the collision energy was optimized using a product ion or MRM scan.
  • An ionization ranking was assigned indicating the compound's ease of ionization.
  • Plasma and brain samples were thawed on ice and kept at 4 °C during processing. Brain tissues were homogenized in 50 mM potassium phosphate, pH 7.4. An aliquot of plasma or brain homogenate sample or calibration sample were mixed with three volumes of methanol containing internal standard, incubated on ice for 5 min, and centrifuged. The protein-free supernatant was used for analysis.
  • Test Article Formulation Test articles were formulated in 0.5% methylcellulose; the dosing solution was freshly made on the dosing day and dosed the animals immediately: PO at 100 mg/Kg, (10 mg/mL, 10 mL/kg). The following is the study table:
  • mice were provided a single dose by body weight via oral gavage at 100 mg/Kg (10 mg/mL, 10 mL/kg) Sampling. Blood samples were collected into K 2 EDTA microtainer tubes for plasma separation. Blood samples were centrifuged at 4 °C at 6,000 RPM for 5 minutes. Decanted plasma samples were stored at -80 °C until analysis. Brains were perfused and collected for the oral study. The tissue samples were stored at -80 °C until analysis.
  • brain ng/g
  • brain ng/g
  • DMAPT Dimethylamino parthenolide
  • a 0.20 M solution of Zn(CH 2 I) 2 DME complex was made in the following manner: diethyl zinc (1.0 M solution in hexanes, 4.0 mL, 4 mmol) was added to CH 2 C1 2 (20 mL) and DME (0.50 mL) at 0 °C under N 2 . Diiodomethane (0.80 mL, 9.92 mmol) was added and the mixture was stirred for 10 minutes. This material was added dropwise over 10 minutes to a solution of parthenolide (1, 90 mg, 0.36 mmol) in CH 2 C1 2 (2 mL) at 0 °C. The mixture was stirred for 1 hour at 0 °C, and the stirring was continued overnight with gradual warming to room temperature.
  • the crude material was quenched by pouring into NH 4 CI (saturated, aq., 20 mL) and then extracted with CH 2 C1 2 (20 mL, 4x). The combined organic layers were washed with NaHC0 3 (saturated, aq., 20 mL), brine (saturated, aq., 20 mL) and then dried over Na 2 S0 4 .
  • the crude material was MPLC purified using Si0 2 (10-30% EtOAc in hexanes over 15 minutes) to yield compound 3 (36 mg, 40%) as a colorless oil and recovered 1 (37 mg, 41%).
  • Cyclopropyl parthenolide (3, 35.0 mg, 0.134 mmol) was dissolved in anhydrous MeOH (1 mL). Dimethylamine (2.0 M solution in methanol, 100.0 ⁇ , 0.200 mmol) was added and the mixture was allowed to stir overnight at room temperature. The solvent and excess dimethylamine were removed in vacuo, and the crude material was MPLC purified using Si0 2 (5-30% MeOH in CH 2 C1 2 over 15 minutes) to afford 4 (34.0 mg, 83%).
  • This molecule was synthesized from melampomagnolide B (9) by photochemical isomerization of the CI -CIO olefin. A protocol for this reaction is described for a related molecule in Eur. J. Org. Chem. 2003, 2003, 3969.
  • This molecule was synthesized from melampomagnolide B (9) by incorporation of the dimethylamino group as described in the synthesis of 4.
  • This molecule is the C 1 -C 10 isomer of parthenolide and was prepared according to the known method in Eur. J. Org. Chem. 2003, 2003, 3969. HRMS calcd for (C 17 H 27 N0 4 + H) + 310.2018, found 310.2019
  • This molecule is dimethylamino costunolide. It was synthesized by addition of a dimemylamino group to costunolide (commercial) according to the method described in the synthesis of 4. Example 10. Preparation of Compound 12.
  • This molecule is a glutathione adduct of parthenolide and was prepared by reacting parthenolide
  • Example 17 The following illustrate representative pharmaceutical dosage forms, containing a compound of the invention, or a pharmaceutically acceptable salt thereof ('Compound X'), for therapeutic or prophylactic use in humans.

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Abstract

L'invention porte sur des composés de la formule I, de la formule II, de la formule III, de la formule IV et de la formule V : et sur des sels de ceux-ci, où X, Z, ---, et R1-R9 ont n'importe laquelle des valeurs définies dans la description, ainsi que sur des compositions comprenant les composés et sur leurs procédés d'utilisation dans une thérapie. Les composés sont utiles pour le traitement du cancer, le traitement de maladies anti-inflammatoires et le traitement de maladies cardiovasculaires.
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EP3003317A4 (fr) * 2013-06-06 2017-04-19 University Of Rochester Dérivés de parthénolide, leurs procédés de préparation et leur utilisation en tant qu'agents anticancéreux
DE102015117882A1 (de) * 2015-10-21 2017-04-27 Mehrdad Ghashghaeinia Pharmazeutische Zusammensetzung
CN108484550A (zh) * 2018-05-07 2018-09-04 中国人民解放军第四军医大学 一种含笑内酯衍生物及其制备方法和用途
CN109897022A (zh) * 2017-12-07 2019-06-18 中国医学科学院药物研究所 含笑内酯衍生物、其药物组合物及其制备方法和用途
US10428082B2 (en) 2016-01-29 2019-10-01 Bioventures, Llc Triazole derivatives of melampomagnolide B and methods of use thereof
CN111303099A (zh) * 2018-12-12 2020-06-19 天津尚德药缘科技股份有限公司 含笑内酯二甲基胺富马酸盐晶型f及其制备方法
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CN109897022A (zh) * 2017-12-07 2019-06-18 中国医学科学院药物研究所 含笑内酯衍生物、其药物组合物及其制备方法和用途
CN108484550A (zh) * 2018-05-07 2018-09-04 中国人民解放军第四军医大学 一种含笑内酯衍生物及其制备方法和用途
CN111303099A (zh) * 2018-12-12 2020-06-19 天津尚德药缘科技股份有限公司 含笑内酯二甲基胺富马酸盐晶型f及其制备方法
CN111303099B (zh) * 2018-12-12 2022-12-02 天津尚德药缘科技股份有限公司 含笑内酯二甲基胺富马酸盐晶型f及其制备方法
CN119707897A (zh) * 2023-09-28 2025-03-28 鄂尔多斯市尚德艾康药业有限公司 含笑内酯衍生物的制备方法
CN120860013A (zh) * 2025-08-08 2025-10-31 华中科技大学同济医学院附属协和医院 一种用于缓解主动脉夹层的Micheliolide药物及其应用

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