WO2010060098A1 - Dérivés antioxydants de la camptothécine et leurs nanosphères antioxydantes antinéoplasiques - Google Patents

Dérivés antioxydants de la camptothécine et leurs nanosphères antioxydantes antinéoplasiques Download PDF

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WO2010060098A1
WO2010060098A1 PCT/US2009/065776 US2009065776W WO2010060098A1 WO 2010060098 A1 WO2010060098 A1 WO 2010060098A1 US 2009065776 W US2009065776 W US 2009065776W WO 2010060098 A1 WO2010060098 A1 WO 2010060098A1
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compound
formula
group
camptothecin
hydrogen
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PCT/US2009/065776
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English (en)
Inventor
John S. Yu
Bong Seop Lee
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Cedars-Sinai Medical Center
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Priority to EP09828387.2A priority Critical patent/EP2370435B1/fr
Priority to JP2011537722A priority patent/JP5564512B2/ja
Priority to ES09828387.2T priority patent/ES2529060T3/es
Priority to KR1020117011757A priority patent/KR101493125B1/ko
Publication of WO2010060098A1 publication Critical patent/WO2010060098A1/fr
Priority to US13/114,539 priority patent/US8697743B2/en
Priority to US14/109,777 priority patent/US20140105822A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D491/22—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 four or more hetero rings

Definitions

  • This invention relates to antioxidant camptothecin derivatives and na ⁇ ospheres thereof.
  • AIi publications herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.
  • the following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
  • Camptothecin is a plant alkaloid first isolated from the wood and barks of Camptotheca acuminate (Nyssaceae), and exhibits its antineoplastic effect by the inhibition of DNA relaxation by DNA topoisomerase I.
  • camptothecin is essentially insoluble in water, and therefore, numerous derivatives have been developed to increase the water solubility (Thomas et al., Camptothecin: Current perspectives. BIOORG. MED. CHEM.. 12, 2004, 1585-1604: PizzoJato et a!..
  • Camptothecin consists of a pentacyclic structure having a lactone in the E- ring.
  • ⁇ -Lipoic acid ⁇ thioctic acid, 1 ,2-d ⁇ th ⁇ olane-3-pentano ⁇ c acid), which has dithiolane ring in its molecule is a widely distributed natural substance which was originally discovered as a growth factor Physiologically it acts as a coenzyme of the oxidative decarboxylation of o>keto carboxylic acid (e g , pyruvates) and as an antioxidant, and it is able to regenerate vitamin C, vitamin E, glutathione and coenzyme Q10
  • lipoic acid is applied in the treatment of diabetic polyneuropathy, liver cirrhosis and metal intoxications
  • Lipoic acid and dihydrolipoic acid are capable of trapping a number of radicals both in a lipid and in an aqueous environment
  • Lipoic acid and dihydrolipoic acid act as antioxidants not only by direct radical trapping and/or metal chelation but also by recycling other antioxidants (e g , vitamin C vitamin E) and by reducing glutathione, which in turn recycles vitamin E
  • the two thiol groups present in [1 ,2]-d ⁇ th ⁇ olane ring system confer it a unique antioxidant potential
  • the disulfides with a cyclic five- member ring such as lipoic acid have been found to be more effective in reductive and/or nucleophilic attack than open-chain derivatives such as cystine or glutathione
  • the antioxidant potential of a compound may be evaluated based on the properties such as (1 ) specificity of free radical scavenging, (2) interaction with other antioxidants, (3) metal-chelating activity, (4) effects on gene expression (5) absorption and bio
  • NO-synthase and trapping the reactive oxygen species Various conditions or disease conditions have demonstrated a potential role of nitric oxide (NO) and the ROS's and the metabolism of glutathione in their physiopathology
  • Conditions or disease conditions where nitrogen monoxide and the metabolism of glutathione as well as the redox status of thiol groups are involved include but are not limited to cardiovascular and cerebrovascular disorders (e g , atherosclerosis, migraine, arterial hypertension, septic shock, ischemic or hemorrhagic cardiac or cerebral infarctions, ischemias and thromboses), disorders of the central or peripheral nervous system (e g , neurodegenerative nervous system), neurodegenerative diseases including cerebral infarctions, sub-arachnoid hemorrhaging, ageing, senile dementias (e g , Alzheimer's disease), Huntmgton's chorea, Parkinson's disease, prion disease (e g , Creutzfeld Jacob disease),
  • 6,605,637, 6,887,891 , and 6.936,715 disclose that lipoic acid derivatives inhibit the activity of NOsynthase enzymes producing nitrogen monoxide NO and regenerate endogenous antioxidants which trap the ROS and which intervene in a more general fashion in the redox status of thiol groups.
  • U.S. Pat. Nos. 5,693,664, 5,948,810, and 6,884,420 disclose the use of racemic ⁇ -iipo ⁇ c acid or their metabolites, salts, amides or esters for the synthesis of drugs for the treatment of diabetes meil ⁇ tus of types i and II.
  • 5,925,668 discloses a method of treating free radical mediated diseases, and/or reducing the symptoms associated with such diseases whereby the compounds with antioxidant activity contain 1 ,2-dithiolane, reduced or oxidized forms.
  • U.S. Pat. No. 6,251 ,935 discloses methods for the prevention or treatment of migraine comprising the administration of an active ingredient selected from the group consisting of racemic alpha-lipoic acid, enantiomers and pharmaceutically acceptable salts, amides, esters or thioesters thereof.
  • U S. Pat. Nos. 6,472,432 and 6,586,472 disclose the treatment of a chronic inflammatory disorder rosacea by application of a composition containing lipoic acid and/or lipoic acid derivatives.
  • a and B may be independently selected from the group consisting of — OC(O)--, --OC(O)O-. and -OC(O)N(R)-, wherein R may be a hydrogen atom, or a substituted, unsubstituted, branched or unbranched chain of carbon atoms.
  • X and Y may be linkers, each independently comprising a substituted, unsubstituted, branched or unbranched chain of carbon atoms and may optionaily contain a heteroatom
  • R 1 , R 2 , R 3 , R 4 , and R 5 may each be independently selected from the group consisting of hydrogen, alkyl, aryl, cycioaiiphatic, and aralkyl and may each optionally contain a hetero atom.
  • the compound may be represented by
  • L 1 may be a moiety formed by esterification of two free esterifiable hydroxy! groups on a diol
  • R 1 , R 2 , R 3 , R 4 , and R 5 may each be independently selected from the group consisting of hydrogen, alkyl, aryl. cycioaiiphatic. and aralkyl group, and may optionally contain a hetero atom.
  • the diol may be selected from the group consisting of
  • W is a hydrocarbon group, wherein n is an
  • n is an integer between 2 and 12
  • the compound may be selected from the group consisting of Formula V
  • Another embodiment of the present invention also provides for a compound,
  • A may be selected from the group consisting of — OC(O)- , -OC(O)O-. and -OC(O)N(R) — , wherein R may be a hydrogen atom, or a substituted, unsubstituted, branched or unbranched chain of carbon atoms, P may be selected from the group consisting of — OC(O) — , and — N(R)C(O) — , wherein R may be a hydrogen atom, or a substituted, unsubstituted, branched or unbranched chain of carbon atoms; X may be a linker comprising a substituted, unsubstituted, branched or unbranched chain of carbon atoms and may optionally contain a heteroatom; and R 1 , R 2 , R 3 , R 4 , and R 5 may each be independently selected from the group consisting of hydrogen, alky!, aryl, cycloalipha
  • the compound may be any organic compound.
  • the compound may be any organic compound.
  • Formula Xl wherein L 2 may be a moiety formed by using a diamine as a linker in the process of producing the compound; and R 1 , R 2 , R 3 , R 4 , and R 5 may each be independently selected from the group consisting of hydrogen, alkyl, aryl, cycloaliphatic, and aralky! group, and may optionally contain a hetero atom.
  • the diamine may be selected from the group consisting of: wherein X is a hydrocarbon group,
  • n is an integer between 1 and 100, and wherein n is an integer between 2 and 12
  • the compound may be selected from the group consisting of Formula XLVfi
  • the compound may be represented as follows
  • L 3 may be a moiety formed by using an ammoalcohol as a linker in the process of producing the compound
  • R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen, alkyl, aryl, cycloaliphatic, and aralkyl, and may each contain a hetero atom
  • ammoalcohol may be selected from the group consisting of wherein the Y is a hydrocarbon group, and may
  • n is an integer between
  • n is an integer between 2 and 12
  • the compound may be selected from the group consisting of Formula XIX
  • Another embodiment of the present invention also provides for a compound produced by conjugation of an ⁇ -l ⁇ po ⁇ c acid and camptothecin or a camptothecin analog modified by reacting with succinic anhydride or glutaric anhydride, wherein the camptothecin analog is represented by Formula I
  • R 1 , R 2 , R 3 , R 4 , and R 5 may each be independently selected from the group consisting of hydrogen, alkyl, aryl, cycloaiiphatic, and araikyl, and may optionally contain a hetero atom
  • the compound may be selected from the group consisting of
  • R 1 , R 2 R 3 , R 4 and R 5 may each be independently selected from the group consisting of hydrogen, alkyl, aryl, cycloaliphatic, and aralkyl, and may optionally contain a hetero atom
  • R 1 , R 2 R 3 , R 4 and R 5 may each be independently selected from the group consisting of hydrogen, alkyl, aryl, cycloaliphatic, and aralkyl, and may optionally contain a hetero atom
  • the present invention also provides a nanosphere, comprising a compound of the present invention.
  • the nanosphere may further comprise a compound selected from the group consisting of: a multiple ⁇ -lipoic acid- containing hydrophobic compound, ⁇ -tocopherol, a nonsteroidal anti-inflammatory drug (NSAID) derivative, and combinations thereof.
  • NSAID nonsteroidal anti-inflammatory drug
  • the present invention also provides for a method of treating cancer in a subject in need thereof, comprising: providing a composition comprising a compound of the present invention; and administering a therapeutically effective amount of the composition to the subject to treat the cancer.
  • the present invention also provides a method of treating cancer in a subject in need thereof, comprising: providing a nanosphere of the present invention: and administering a therapeutically effective amount of the nanosphere to the subject to treat the cancer.
  • the present invention also provides a pharmaceutical composition, comprising: a pharmaceutically acceptable carrier or excipient; and a compound of the present invention.
  • Figure 1 depicts the 1 H spectrum of the compound ALA-TEG-OH in accordance with an embodiment of the present invention
  • Figure 2 depicts the 13 C spectrum of the compound ALA-TEG-OH in accordance with an embodiment of the present invention
  • Figure 3 depicts the 1 H spectrum of the compound ALA 2 (1 , 12-dodecaned ⁇ ol) in accordance with an embodiment of the present invention
  • Figure 4 depicts the 13 C spectrum of the compound ALA 2 (I 12-dodecaned ⁇ ol) in accordance with an embodiment of the present invention
  • Figure 5 depicts the effect of nanospheres comprising Compound 10 on glioma cell viability in accordance with an embodiment of the present invention
  • Control nanospheres prepared from ⁇ -tocopherol only in the absence of Compound 10 (Toco) are treated with nanospheres prepared from a mixture of ⁇ - tocopherol and Compound 10, which contained 0 1-2 0 ⁇ M of Compound 10
  • Error bar represents ⁇ S D calculated from triplicate determinations
  • Figure 6 depicts the effect of nanospheres comprising Compound 10 on glioma cell viability in accordance with an embodiment of the present invention
  • Error bar represents ⁇ S D calculated from triplicate determinations
  • Figure 7 depicts the effect of nanospheres comprising Compound 10 and IbU 2 TEG on glioma cell viability Cells treated with nanospheres prepared from a mixture of IbU 2 TEG and Compound 10, which contained 0 1-2 0 ⁇ M of Compound 10
  • Error bar represents ⁇ S. D. calculated from triplicate determinations.
  • Figure 8 depicts the effect of nanospheres containing IbU 2 TEG on glioma cell viability
  • Cells were treated with nanospheres prepared from IbU 2 TEG only which contained 16-160 ⁇ M of IbU 2 TEG.
  • the amount of IbU 2 TEG in this experiment is equal to the amount of IbU 2 TEG contained in the nanospheres prepared from a mixture of IbU 2 TEG and Compound 10 (Fig. 7).
  • the results serve as a control for the experiment of Fig. 7 in the absence of Compound 10.
  • Error bar represents ⁇ S.D. calculated from triplicate determinations.
  • CPT camptothecin ⁇ (S)-4-ethyl-4- hydroxy-1 H-pyrano-[3', 4':6, 7]indolizino[1 ,2-b]quinoline-3, 14(4H, 12H)-dione ⁇ , which is shown below.
  • the compound is commercially available from numerous sources: e.g., from Sigma Chemical Co. (St. Louis, Mo).
  • R 1 , R 2 , R 3 , R 4 , and R 5 may each be independently selected from hydrogen or a substituent selected from an alkyl, aryf, cycloaliphatic, and aralkyl group, may be saturated or unsaturated, and may contain hetero atoms (e g , nitrogen, oxygen, sulfur, halogens, etc)
  • Antioxidant derivative of camptothecin and “antioxidant camptothecin derivative” as used herein refer to a derivative of camptothecin that contains an antioxidant [1 ,2]-d ⁇ th ⁇ olane ring
  • Antioxidant derivative of a camptothecin analog and “antioxidant camptothecin analog derivative” as used herein refer to a derivative of a camptothecin analog that contains an antioxidant [1 ,2]-d ⁇ th ⁇ olane ring
  • camptothecin nanosphere and " camptothecin nanosphere prodrug” as used herein refer to a nanosphere comprising an antioxidant derivative of camptothecin or an antioxidant derivative of a camptothecin analog
  • the nanosphere may further comprise a multiple ⁇ -iipoic acid-containing hydrophobic compound, ⁇ -tocopherol, a nonsteroidal anti-inflammatory drug (NSAID) derivative, or combinations thereof
  • NSAID nonsteroidal anti-inflammatory drug
  • Cancer and ' cancerous refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth
  • examples of cancer include, but are not limited to breast cancer, colon cancer, lung cancer, prostate cancer, hepatocellular cancer, gastric cancer, pancreatic cancer, cervical cancer ovarian cancer, liver cancer, bladder cancer, cancer of the urinary tract, thyroid cancer, renal cancer, carcinoma, melanoma head and neck cancer, and brain cancer, including, but not limited to, gliomas, glioblastomas, glioblastoma multiforme (GBM), oligodendrogliomas primitive neuroectodermal tumors, low, mid and high grade astrocytomas ependymomas (e g , myxopapiltary ependymoma papillary ependymoma, subependymoma anaplastic ependymoma), oligodendrogliomas, medulloblastomas meningi
  • “Mammal” as used herein refers to any member of the class Mammalia, including, without limitation, humans and nonhuman primates such as chimpanzees and other apes and monkey species, farm animals such as cattle, sheep, pigs, goats and horses, domestic mammals such as dogs and cats, laboratory animals including rodents such as mice, rats and guinea pigs, and the like The term does not denote a particular age or sex Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be included within the scope of this term "Nanosphere” as used herein refers to a particle with a size, in at least one dimension, between about 10 nm to about 1000 nm, and may also include a nanoernulsion
  • Non-steroidal as used herein distinguishes the anti-inflammatory drugs from steroids, which have a similar anti-inflammatory action
  • NSAID derivative refers to a compound in which as least one NSAID molecule is coupled to a polyol, for example, through este ⁇ fication
  • Polyol as used herein refers to a compound that contains at least two free este ⁇ fiable hydroxyl groups
  • Therapeutic agent refers to any substance used internally or externally as a medicine for the treatment, cure, prevention slowing down, or lessening of a disease or disorder, even if the treatment, cure, prevention, slowing down, or lessening of the disease or disorder is ultimately unsuccessful
  • “Therapeutically effective amount' as used herein refers to an amount which is capable of achieving beneficial results in a patient with a condition or a disease condition in which treatment is sought
  • a therapeutically effective amount can be determined on an individual basis and will be based, at least in part, on consideration of the physiological characteristics of the mammal, the type of delivery system or therapeutic technique used and the time of administration relative to the progression of the disease
  • Treatment and treating, ' as used herein refer to both therapeutic treatment and prophylactic or preventative measures wherein the object is to prevent slow down and/or alleviate the disease or disease condition even if the treatment is ultimately unsuccessful
  • the present invention provides for antioxidant derivatives of camptothecin and antioxidant derivatives of camptothecin analogs These derivatives are useful for treating various types of cancer
  • the present invention provides antioxidant-antineoplastic nanospheres comprising the antioxidant derivatives of camptothecin or antioxidant derivatives of camptothectn analogs and methods of preparing the antioxidant-antineoplastic nanospheres
  • These nanospheres can operate as prodrugs
  • the camptothecin nanosphere prodrugs are capable of releasing camptothecin or a camptothecin analog for a prolonged period of time
  • the camptothecin nanosphere prodrugs are capable of serving as a vehicle for the delivery of additional pharmaceuticals
  • an antioxidant derivative of camptothecin and/or an antioxidant derivative of a camptothecin analog may be represented by Formula Il
  • a and B may be independently selected from the group consisting of -OC(O)- -OC(O)O-, and -OC(O)N(R)-, wherein R may be a hydrogen atom, or a substituted, unsubstituted, branched or unbranched chain of carbon atoms and may contain heteroatoms (e g , nitrogen, oxygen, sulfur, etc ), wherein X and Y may be each be a linker that may be a substituted, unsubstituted, branched or unbranched chain of carbon atoms and may contain heteroatoms (e g , nitrogen, oxygen, sulfur, etc ) and wherein R 1 , R 2 , R 3 , R 4 , and R 5 may each be independently selected from hydrogen or a substituent selected from an alkyl aryl, cycloaliphatic, and aralkyl group may be saturated or unsaturated and may contain hetero atoms (e g , nitrogen oxygen, sulfur, halogens, etc
  • an antioxidant derivative of camptothecin and/or antioxidant derivative of a camptothecin analog is prepared by the conjugation of a camptothecin or a camptothecin analog and an ⁇ -lipoic acid and is represented by Formula III: ⁇ v wherein A may be selected from the group consisting of — OC(O) — , — OC(O)O — .
  • R may be a hydrogen atom, or a substituted, unsubstituted, branched or unbranched chain of carbon atoms and may contain heteroatoms (e.g., nitrogen, oxygen, sulfur, etc.); wherein P may be selected from the group consisting of — OC(O) — , and — N(R)C(O) — , wherein R may be a hydrogen atom, or a substituted, unsubstituted, branched or unbranched chain of carbon atoms and may contain heteroatoms (e.g., nitrogen, oxygen, sulfur, etc.); wherein X may be a linker that may be a substituted, unsubstituted, branched or unbranched chain of carbon atoms and may contain heteroatoms (e.g...
  • R 1 , R 2 , R 3 , R 4 , and R 5 may each be independently selected from hydrogen or a substituent selected from an alky!, aryl, cycloaliphatic, and aralkyl group, may be saturated or unsaturated, and may contain hetero atoms (e.g., nitrogen, oxygen, sulfur, halogens, etc).
  • an antioxidant derivative of camptothecin and/or antioxidant derivative of a camptothecin analog is prepared by the conjugation of camptothecin or a camptothecin analog and ⁇ -lipoic acid via a diol and is represented Formula IV:
  • Li may be a moiety formed by esterification of two free esterifiable hydroxy! groups on a diol; and wherein R 1 , R 2 , R 3 , R 4 , and R 5 may each be independently selected from hydrogen or a substituent selected from an alky!, aryl, cycloai ⁇ phatic. and aralkyl group, may be saturated or unsaturated, and may contain hetero atoms (e.g. , nitrogen, oxygen, sulfur, halogens, etc).
  • dtols that are useful in the present invention include, but are not limited to commercially available one as follows wherein n is an integer between 1 and 100 wherein n is an integer between 2 and 12 1 ,4-B ⁇ s ⁇ 2-hydroxyethyl)-p ⁇ peraz ⁇ ne 1 ,3-CycIopentaned ⁇ ol
  • antioxidant derivatives of camptothecin and/or antioxidant derivatives of camptothecin analogs of this embodiment are represented by the following formulas
  • R 1 R 2 R 3 , R 4 , and R 5 may each be independently selected from hydrogen or a substttuent selected from an alkyl aryl cycloaliphatic and arafkyf group may be saturated or unsaturated, and may contain hetero atoms (e g , nitrogen, oxygen, sulfur halogens, etc)
  • an antioxidant derivative of a camptothecin and/or antioxidant derivative of a camptothecin analog is prepared by the conjugation of camptothecin or a camptothecin analog and an ⁇ -lspoic acid vsa a diamine and is represented by Formula Xl wherein L 2 may be a moiety formed by using a diamine as the linker in the process of producing the antioxidant camptothecin derivative or the antioxidant camptothecin analog derivative; and wherein R 1 , R 2 , R 3 , R 4 , R5 may each be independently selected from hydrogen or a substituent selected from an alkyl, aryl, cycloaliphatic, and aralkyl group, may be saturated or unsaturated, and may contain hetero atoms (e g , nitrogen, oxygen, sulfur, halogens, etc).
  • hetero atoms e g , nitrogen, oxygen, sulfur, halogens, etc.
  • diamines that are useful in the present invention may be represented by the following formula:
  • X may be a hydrocarbon group; for example, an alkyl, aryl, cycloaliphatic or aralkyl group; and may be saturated or unsaturated. X may also contain hetero atoms (e.g., nitrogen, oxygen, sulfur, etc.). in other embodiments, diamines that are useful in the present inventive compounds include, but are not limited to commercially available ones as follows: wherein n is an integer between 1 and 100 wherein n is an integer between 2 and 12. Examples of particularly useful antioxidant derivatives of camptothecin and/or antioxidant derivatives of camptothe ⁇ n analogs of this embodiment are represented by the following formulas: Formula XIl
  • R 1 , R 2 , R 3 , R A , and R 5 may each be independently selected from hydrogen or a substftuent selected from an alkyl aryt, cycloaliphatic, and aralkyl group, may be saturated or unsaturated, and may contain hetero atoms (e g , nitrogen, oxygen sulfur halogens, etc)
  • hetero atoms e g , nitrogen, oxygen sulfur halogens, etc
  • an antioxidant derivative of camptothecin and/or antioxidant derivative of a camptothecin analog is prepared by the conjugation of camptothectn or a camptothecin analog and an ⁇ -lipoic acid via an aminoaicohoi and is represented by Formula XVIH:
  • L 3 may be a moiety formed by using an aminoaicohoi as the linker in the process of producing the antioxidant camptothecin derivative or the antioxidant camptothecin analog derivative; and wherein R 1 , R 2 , R 3 , R 4 , and R 5 may each be independently selected from hydrogen or a substituent selected from an alky!, aryl, cycloaltphatic, and aralkyl group, may be saturated or unsaturated, and may contain hetero atoms (e.g., nitrogen, oxygen, sulfur, halogens, etc).
  • hetero atoms e.g., nitrogen, oxygen, sulfur, halogens, etc.
  • Aminoalcohols that are useful in the present invention may be represented by the following formula wherein Y may be a hydrocarbon group, for example, an alkyl, aryl, cycloaliphatic or aralkyl group, and may be saturated or unsaturated Y may also contain hetero atoms ⁇ e g , nitrogen, oxygen sulfur, etc )
  • antioxidant derivatives of camptothecin and/or antioxidant derivatives of camptothecin analogs of this embodiment are represented by the following formulas Formula XIX
  • R 1 , R 2 , R 3 , R 4 , and R 5 may each be independently selected from hydrogen or a substituent selected from an alky!, aryl, cycloaliphatic, and aralkyl group, may be saturated or unsaturated and may contain hetero atoms (e g , nitrogen, oxygen, sulfur, halogens, etc)
  • camptothecin analogs are modified by reaction with succinic anhydride or gluta ⁇ c anhydride and an antioxidant derivative of camptothecin and/or antioxidant derivative of a camptothecin analog is prepared by the conjugation of an ⁇ -lipo ⁇ c acid and the modified camptothecin or camptothecin analog
  • succinic anhydride or gluta ⁇ c anhydride an antioxidant derivative of camptothecin and/or antioxidant derivative of a camptothecin analog is prepared by the conjugation of an ⁇ -lipo ⁇ c acid and the modified camptothecin or camptothecin analog
  • R 1 , R 2 , R 3 , R 4 , and R 5 may each be independentiy selected from hydrogen or a substituent selected from an alkyl, aryl, cyctoaliphatic, and aralkyl group may be saturated or unsaturated, and may contain hetero atoms (e g nitrogen, oxygen, sulfur, halogens, etc)
  • R 1 R 2 R 3 R 4 , and R 5 may each be independently selected from hydrogen or a substituent selected from an alky! aryi cycloalsphatic and araikyl group may be saturated or unsaturated, and may contain hetero atoms (e g , nitrogen, oxygen, sulfur, halogens, etc)
  • each of R 1 through R 5 of the formulas and/or compounds described above is H, and is shown below
  • the present invention also provides for methods of treating cancer
  • the antioxidant camptothecin derivatives and the antioxidant camptothecin analog derivatives are used for treating cancer
  • the method comprises providing a pharmaceutical composition comprising an antioxidant camptothecin derivative or an antioxidant camptothecin analog derivative of the present invention, and administering a therapeutically effective amount of the pharmaceutical composition to a subject in need thereof
  • the pharmaceutical composition comprises a pharmaceutically acceptable carrier or excipient
  • the antioxidant camptothecin derivatives and the antioxidant camptothecin analog derivatives are used to treat a brain tumor
  • the method comprises providing a pharmaceutical composition comprising an antioxidant camptothecm derivative or an antioxidant camptothecin analog derivative of the present invention, and administering a therapeutically effective amount of the pharmaceutical composition to a subject in need of treatment for a brain tumor
  • Additional embodiments of the present invention provide for methods of preparing the camptothecin nanosphere prodrugs from the antioxidant derivatives of camptothecin and antioxidant derivatives of camptothecin analogs
  • the antioxidant derivatives of camptothecin and antioxidant derivatives of camptothecin analogs are prepared into antioxidant-antineoplastic nanoparticles (e g., nanospheres) by blending with other antioxidant ⁇ -Iipoic acid-containing hydrophobic compounds.
  • antioxidant-antineoplastic nanoparticles e g., nanospheres
  • antioxidant ⁇ -Iipoic acid-containing hydrophobic compounds include, but are not limited to the following :
  • Antioxidant ⁇ -lipoic acid-containing hydrophobic compounds represented by Formula Ia represented by Formula Ia
  • X may be selected from the group consisting of a substituted, unsubstituted, branched or unbranched chain of carbon atoms, and may optionally contain a heteroatom
  • Y may be selected from the group consisting of a branched and unbranched alkyl, branched and unbranched alkenyl, branched and unbranched alkynyl, heteroatom-containing branched and unbranched alkyl, heteroatom-containing branched and unbranched alkenyl, heteroatom- containing branched and unbranched alkynyl, aryl.
  • cyclic aliphatic, cyclic aromatic, heterocyclic, and aromatic heterocyclic group; and n may be an integer of at least one.
  • n may be an integer from 1 to 4; and X may be an unsubstituted, unbranched chain of 1 to 6 carbon atoms.
  • the dithiolane moiety in Formula Ia may be an ⁇ -lipoic acid and is represented by Formula Ha:
  • Y may be a moiety formed by este ⁇ fication of the hydroxyl groups of a polyol
  • the polyol may be selected from the group consisting of wherein n is an integer between 1 and 4 and wherein n is an integer between 3 and 16
  • the antioxidant derivatives of camptothecin and antioxidant derivatives of camptothecin analogs are prepared into nanoparticles (e g , nanospheres) by blending with a non-steroidal anti-inflammatory drug (NSAID) derivative disclosed in International Application No PCT/US09/39956, filed on April 8, 2009, which is incorporated by reference in its entirety as though fully set forth
  • NSAID non-steroidal anti-inflammatory drug
  • n may be an integer of at least two
  • A may be a moiety that is formed by esterifi cation of at least two free esterifiable hydroxyl groups on a polyol
  • the polyol may be , wherein n on the polyol may be an integer between 1
  • the polyo) may be , wherein n on the polyol may be an integer between 3 and 16
  • A may be formed from esterifi cation of a polyol selected from group consisting of an ethylene glycol (Methylene glycol, t ⁇ ethylene glycol, tetraethylene glycol, pentaethylene glycol, hexaethylene glycol, 1 ,3- propanediol, and 1 ,4-butaned ⁇ ol
  • a polyol selected from group consisting of an ethylene glycol (Methylene glycol, t ⁇ ethylene glycol, tetraethylene glycol, pentaethylene glycol, hexaethylene glycol, 1 ,3- propanediol, and 1 ,4-butaned ⁇ ol
  • the NSAID may be selected from the group consisting of aspirin, ibuprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen, naproxen, indomethacin, diclofenac, ketorolac, tolmetin, flufenamic acid, mefenamic acid, tolfenamic aod, meclofenamic acid niflumic acid, sulindac, sulindac sulfide and combinations thereof
  • X may be selected from the group consisting of a substituted, unsubstituted, branched or unbranched chain of carbon atoms and may optionally contain a heteroatom
  • A may be selected from the group consisting of branched and unbranched alkyl, branched and unbranched alkenyl, branched and unbranched alkynyl, heteroatom-containing branched and unbranched alkyl, heteroatom-containing branched and unbranched alkenyl, heteroatom- containing branched and unbranched alkynyl, aryl, cyclic aliphatic, cyclic aromatic, heterocyclic, and aromatic heterocyclic groups, n may be an integer of at least one, and m may be an integer of at least one
  • A may be a moiety that is formed by esterificatfon of at least two free esterifiable hydroxyl g olyol
  • the polyol may be , wherein n on the polyol may be an integer
  • n on the polyol may be an integer between 3 and 16
  • the NSAID may be selected from the group consisting of aspirin, ibuprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen naproxen indomethacm, diclofenac, ketorolac, tolmetin, flufenamic acid, mefenamic acid, tolfenamic acid, meclofenamic acid, niflumic acid, sulindac, sulindac sulfide and combinations thereof
  • the dithiolane moiety may be an ⁇ -l ⁇ po ⁇ c acid ("ALA') and is represented by formula 11 Ib
  • the antioxidant derivatives of camptothecm and antioxidant derivatives of camptothecm analogs are prepared into nanopartides by blending with an antioxidant ⁇ -l ⁇ po ⁇ c acid-containing hydrophobic compound and a non-steroidal anti-inflammatory drug (NSAID) derivative disclosed in U S Provisional Application Serial No 61/018,749, filed January 3, 2008, and International Application Publication No WO 2009/086547, filed December 30, 2008, and in International Application No PCT/US09/39956, filed on April 8, 2009, respectively, which are incorporated by reference in their entirety as though fully set forth
  • NSAID non-steroidal anti-inflammatory drug
  • camptothecm nanospheres described above can be used for treating cancer They can operate as prodrugs as discussed above
  • the method comprises providing a composition comprising a camptothecm nanosphere of the present invention, and administering a therapeutically effective amount of the composition to a subject in need thereof
  • the camptothecin nanospheres are used to treat a brain tumor
  • the method comprises providing a composition comprising a camptothecin nanosphere, and administering a therapeutically effective amount of the composition to a subject in need of treatment for a brain tumor
  • the camptothecin nanospheres may be used as a carrier of an additional therapeutic agent
  • the second therapeutic agent is a chemotherapeutic agent that is useful for cancer treatment Accordingly, one embodiment provides for a composition comprising a camptothecin nanosphere of the present invention and an additional therapeutic agent
  • the present invention provides for a method to enhance the cytotoxicity of an antineoplastic drug for treatment of a disorder of abnormal ceil proliferation
  • the method comprises providing a composition comprising a camptothecin nanosphere of the present invention, and administering a therapeutically effective amount of the composition and an antineoplastic drug to a subject in need of the treatment to enhance the cytotoxicity of the antineoplastic drug
  • the present invention provides pharmaceutical compositions including a pharmaceutically acceptable excipient along with a therapeutically effective amount of the antioxidant derivatives of camptothecin and/or antioxidant derivatives of camptothecin analogs, or the camptothecin nanosphere prodrugs
  • “Pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and desirable, and includes excipients that are acceptable for veterinary use as well as for human pharmaceutical use Such excipients may be solid, liquid, semisolid, or, in the case of an aerosol composition, gaseous
  • the pharmaceutical compositions according to the invention may be formulated for delivery via any route of administration 'Route of administration” may refer to any administration pathway known in the art, including but not limited to aerosol nasal, oral, transmucosal transdermal, parenteral enteral or ocular "Transdermal" administration may be accomplished using a topical cream or ointment or by means of a transdermal patch 'Parenteral” refers to a route of administration that is generally associated with injection, including intraorbital infusion, intraarterial, intracapsular, intracardiac, intradermal, intramuscular, intraperitoneal, intra pulmonary, intraspinal, intrasternal, intrathecal, intrauterine, intravenous, subarachnoid, subcapsular, subcutaneous, transmucosat, or transtracheal Via the parenteral route, the compositions may be in the form of solutions or suspensions for infusion or for injection, or as lyophiltzed powders Via the enteral route,
  • compositions according to the invention can also contain any pharmaceutically acceptable carrier "Pharmaceutically acceptable carrier' as used herein refers to a pharmaceutically acceptable material composition, or vehicle that is involved in carrying or transporting a compound of interest from one tissue organ, or portion of the body to another tissue, organ, or portion of the body
  • the carrier may be a liquid or solid filler, diluent, exctpsent, solvent, or encapsulating material, or a combination thereof
  • Each component of the carrier must be 'pharmaceutically acceptable” in that it must be compatible with the other ingredients of the formulation It must also be suitable for use in contact with any tissues or organs with which it may come in contact, meaning that it must not carry a risk of toxicity, irritation, allergic response, immunogenicity, or any other complication that excessively outweighs its therapeutic benefits
  • compositions according to the invention can also be encapsulated, tabfeted or prepared in an emulsion or syrup for oral administration
  • Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition
  • Liquid carriers include syrup, peanut oil, olive oil, glycerin, saline, alcohols and water
  • Solid carriers include starch, lactose, calcium sulfate, dihydrate, terra alba magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin
  • the earner may also include a sustained release material such as glyceryl monostearate or glyceryl distearate alone or with a wax
  • the pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulation, and compressing, when necessary, for tablet forms, or milling, mixing and filling for hard gelatin capsule forms
  • a liquid carrier When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension
  • Such a liquid formulation may be administered directly p o or filled into a soft gelatin capsule
  • the pharmaceutical compositions according to the invention may be delivered in a therapeutically effective amount
  • the precise therapeutically effective amount is that amount of the composition that will yield the most effective results in terms of efficacy of treatment in a given subject This amount will vary depending upon a variety of factors including but not limited to the characteristics of the therapeutic compound (including activity, pharmacokinetics, pharmacodynamics, and bioavailability), the physiological condition of the subject (including age, sex, disease type and stage, general physical condition, responsiveness to a given dosage, and type of medication), the nature of the pharmaceutically acceptable carrier or carriers in the formulation, and the route of administration
  • One skilled in the clinical and pharmacological arts will be able to determine a therapeutically effective amount through routine experimentation, for instance by monitoring a subject's response to administration of a compound and adjusting the dosage accordingly For additional guidance, see Remington The Science and Practice of Pharmacy (Gennaro ed 20th edition Williams & Wilkins PA, USA) (2000) Typical dosages of an effective amount of the antioxidant derivatives of campto
  • the present invention is also directed to a kit to treat cancer
  • the kit is an assemblage of materials or components, including at least one of the inventive compositions
  • the kit contains a composition including antioxidant derivatives of camptothecin and/or antioxidant derivatives of camptothecin analogs, or the camptothecin nanospheres of the present invention as described above
  • kits configured for the purpose of treating cancer
  • the kit is configured particularly for the purpose of treating mammalian subjects
  • the kit is configured particularly for the purpose of treating human subjects
  • the kit is configured for veterinary applications treating subjects such as, but not limited to, farm animals, domestic animals, and laboratory animals
  • kits Instructions for use typically include a tangible expression describing the technique to be employed in using the components of the kit to effect a desired outcome, such as to treat cancer
  • the kit also contains other useful components, such as, diluents, buffers, pharmaceutically acceptable carriers, syringes, catheters applicators, pipetting or measuring tools, or other useful paraphernalia as will be readily recognized by those of skill in the art
  • the materials or components assembled in the kit can be provided to the practitioner stored in any convenient and suitable ways that preserve their operability and utility
  • the components can be in dissolved, dehydrated, or lyophilized form, they can be provided at room, refrigerated or frozen temperatures
  • the components are typically contained in suitable packaging mate ⁇ al(s)
  • packaging material refers to one or more physical structures used to house the contents of the kit, such as inventive compositions and the like
  • the packaging material is constructed by well known methods, preferably to provide a sterile, contaminant
  • HPLC/UV detector system with CAPCELL PAK 1 Type SG 120 (phenomenex) Ci 8 reversed phase column (250/4.6 mm, 5 ⁇ m).
  • the composition of the mobile phase acetonitrile/water mixture containing 0.1 % (v/v) trifluoroacetic acid
  • camptothecin and ⁇ -lipoic acid derivatives were adjusted for camptothecin and ⁇ -lipoic acid derivatives, multiple ⁇ -lipoic acid-containing compounds and NSAID derivatives in order to provide an appropriate retention time and separation.
  • Example 2 Synthesis of the camptothecin and ⁇ -lipoic acid derivatives
  • a ⁇ -L ⁇ poic acid (ALA, 2.06 g, 10 mmol ) and a diol compound (tetraethylene glycol, TEG) (30 mmol) in 50 mL of anhydrous dichSoromethane (DCM) were reacted with 4 ⁇ (dimethylamino)-pyridine (DMAP, 15 mmol) in the presence of a molecular sieve (60 ⁇ , 10-20 mesh beads) for 10 min at room temperature, N-(S- Dimethylamfnopropyl)-N-ethyfcarbod ⁇ mide hydrochloride (EDCI, 2,3 g, 12 mmol) was added portionwise over 10 min and the reaction mixture was stirred for 5 h at room temperature in the dark, filtered, and then concentrated under vacuum to reduce the volume. The resulting reaction mixture was purified using silica gel by direct loading onto the column without further preparation. The solvent was removed under
  • Mono-ALA-TEG was prepared as described in Example 1 Mono-ALA-TEG (10 mmol) and succinic anhydride (100 mmot) were dissolved in 100 mL of pyridine and the reaction mixture was stirred for 3 h at room temperature The reaction mixture was concentrated under vacuum to reduce the volume The resulting reaction mixture was purified using silica gel by direct loading onto the column without further preparation The solvent was removed under reduced pressure to give the products.
  • Nanospheres were prepared according to the method using spontaneous emuisification with slight modification Briefly, 15 mg of the compounds (mixture of camptothecin derivatives and ALA 2 (1 , 12-dodecanediol) were dissolved in acetone (5 HnL 1 0 1% polysorbate 80) The organic solution was poured under moderate stirring on a magnetic plate into an aqueous phase prepared by dissolving 25 mg of Pluronic F68 in 10 mL bidistilled water (0 25% w/v) Following 15 mm of magnetic stirring, the acetone was removed under reduced pressure at room temperature The nanospheres were filtered through 0 8 ⁇ m hydrophilic syringe filter and stored at 4 °C The hydrodynamic size measurement and size distribution of the nanospheres was performed by the dynamic light scattering (DLS) using a Coulter N4 ⁇ Pius Submicron Particle Sizer (Coulter Corporation, Miami FL)
  • the hydrodynamic size measurement and size distribution of the nanospheres was performed by the dynamic light scattering (DLS) using a Coulter N4-P!us Submicron Particle Sizer (Coulter Corporation, Miami, FL).
  • Control nanosphere was prepared from multiple u- lipoic acid containing compounds and ⁇ -tocopheroi in the absence of camptothecin derivatives.
  • Nanospheres were prepared according to the method described in Example 5 using spontaneous emulsification from 25 mg of the compounds (mixture of camptothecin derivatives and ⁇ tocopherol). Control nanosphere was prepared from ⁇ -tocopherol or IbU 2 TEG in the absence of camptothecin derivatives.
  • Nanospheres were prepared according to the method described in Example 5 using spontaneous emulsification from 25 f th compounds (mixture of camptothecin derivatives, derivatives of non-steroidal antiinflammatory drugs (NSAIDs) and ⁇ -tocophero! Control nanosphere was prepared from ⁇ -tocopherol or a mixture of ⁇ -tocopherol and derivatives of NSAIDs in the absence of camptothecin derivatives
  • the U87-MG human glioma cell line was obtained from American Type Culture Collection (ATCC) (Rockville, Maryland, USA) The cells were grown and maintained in Minimum Essential Medium (MEM) (Invitrogen) containing antibiotics 100 U/mL penicillin (Invitrogen) and 100 ⁇ g/mL streptomycin (Invitrogen), and supplemented with 10% fetal bovine serum (FBS) (Invitrogen) Cells were kept at 37°C in a humidified atmosphere including 5% CO 2
  • MEM Minimum Essential Medium
  • FBS fetal bovine serum
  • Nanospheres were prepared from the mixture of Compound 10 (1 mg), ⁇ - tocopherol (25 mg), and multiple ⁇ -lipoic acid containing compound (ALA ⁇ Glycerol, or Compound 10 (1 mg) and ⁇ -tocopherol (25 mg), or Compound 10 (1 mg), ⁇ - tocophero! (25 mg), and NSAID derivative IbU 2 TEG as described in Examples 5, 6, and 7, and dialyzed in phosphate buffered saline (PBS) overnight
  • PBS phosphate buffered saline
  • the human glioma cells U87-MG were seeded in a 6-wel!
  • Example 9 Synthesis of bifunctional derivatives of ⁇ -lipoic acid and NSAlDs ⁇ -Lipoic acid (ALA, 10 mrnol) and tetraethylene glycol (TEG, 30 mmof) in 50 ml of anhydrous dichloromethane (DCM) were reacted with 4-(dimethylamino)- pyridine (DMAP, 15 mmot) in the presence of a motecufar sieve (Fluka, 3 A, 10-20 rnesh beads) for 10 min at room temperature.
  • DCM anhydrous dichloromethane
  • NSAIDs (6 mmoi) and TEG (2.5 mmoi) in 40 ml of anhydrous DCM were reacted with DMAP (6 mmoi) in the presence of molecular sieve for 10 min at room temperature.
  • EDC! (6 mmoi) was added portionwise over 10 min and the reaction mixture was stirred for 5 h at room tem t i the dark, filtered, and then concentrated under vacuum The products were purified (column chromatography, 100 0 5 CH3CI MeOH) and characterized as described above

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Abstract

L’invention concerne des dérivés antioxydants de la camptothécine et des dérivés antioxydants d’analogues de la camptothécine et la préparation de promédicaments à base de camptothécine de taille nanométrique. L’invention concerne également des procédés de synthèse des dérivés antioxydants de la camptothécine et des dérivés antioxydants d’analogues de la camptothécine, l’émulsification ou la nanoprécipitation spontanée de ceux-ci afin de produire des promédicaments nanosphériques à base de camptothécine et leur utilisation pour traiter les maladies cancéreuses. Selon un autre aspect, l’invention permet d’utiliser ces promédicaments nanosphériques à base de camptothécine pour préparer des dispositifs d’administration d’autres substances pharmaceutiques et/ou médicaments.
PCT/US2009/065776 2008-11-24 2009-11-24 Dérivés antioxydants de la camptothécine et leurs nanosphères antioxydantes antinéoplasiques WO2010060098A1 (fr)

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EP09828387.2A EP2370435B1 (fr) 2008-11-24 2009-11-24 Dérivés antioxydants de la camptothécine et leurs nanosphères antioxydantes antinéoplasiques
JP2011537722A JP5564512B2 (ja) 2008-11-24 2009-11-24 抗酸化カンプトセシン誘導体及びその抗酸化、抗新生物ナノスフェア
ES09828387.2T ES2529060T3 (es) 2008-11-24 2009-11-24 Derivados antioxidantes de la camptotecina y nanoesferas antineoplásicas antioxidantes de los mismos
KR1020117011757A KR101493125B1 (ko) 2008-11-24 2009-11-24 항산화성 캠토테신 유도체 및 이들의 항산화성 항종양성 나노구체
US13/114,539 US8697743B2 (en) 2008-11-24 2011-05-24 Antioxidant camptothecin derivatives and antioxidant antineoplastic nanospheres thereof
US14/109,777 US20140105822A1 (en) 2008-11-24 2013-12-17 Nanospheres comprising tocopherol, an amphiphilic spacer and a therapeutic or imaging agent

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WO2013067881A1 (fr) * 2011-11-11 2013-05-16 南京美西宁医药科技有限责任公司 Médicament anticancer amphiphile, modifié par un dérivé de vitamine e, soluble dans l'eau, et préparation, procédé de préparation du composé et son application
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