WO2014114183A1 - Composé de platine (ii) pour traiter la maladie à prolifération de cellules tumorales - Google Patents

Composé de platine (ii) pour traiter la maladie à prolifération de cellules tumorales Download PDF

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WO2014114183A1
WO2014114183A1 PCT/CN2014/000061 CN2014000061W WO2014114183A1 WO 2014114183 A1 WO2014114183 A1 WO 2014114183A1 CN 2014000061 W CN2014000061 W CN 2014000061W WO 2014114183 A1 WO2014114183 A1 WO 2014114183A1
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alkyl
water
add
cycloalkyl
compound
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PCT/CN2014/000061
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English (en)
Chinese (zh)
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陈小平
高泽军
孟小平
温守明
闫亚矢
赵锋
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北京市丰硕维康技术开发有限责任公司
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Priority to CN201480002915.4A priority Critical patent/CN104995201B/zh
Publication of WO2014114183A1 publication Critical patent/WO2014114183A1/fr

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    • 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
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
    • C07F15/0086—Platinum compounds
    • C07F15/0093—Platinum compounds without a metal-carbon linkage

Definitions

  • the present invention relates to a platinum compound against cell proliferative diseases, in particular to a type of leaving group malonate derivative
  • Cancer malignant tumor is one of the most important diseases that currently threaten human life. In recent years, the incidence and mortality of tumors have risen sharply. The trend of tumor development disclosed by the World Health Organization shows that since 1996, the number of newly diagnosed tumor patients worldwide has exceeded 10 million. By the end of 1999, the total number of cancer patients worldwide has exceeded 4,000. 10,000 people, about 7 million people die of various tumors every year in the world. In 2001, the world cancer morbidity and mortality rate increased by 22% compared with 1990, which is the second leading cause of death after cardiovascular and cerebrovascular diseases.
  • the cancers are lung cancer, breast cancer, colorectal cancer, stomach cancer, liver cancer, cervical cancer, esophageal cancer and bladder cancer.
  • Anti-tumor drugs are the most common treatment method. In 2008, global anti-cancer drug market sales were US$48 billion. At present, clinical anti-tumor drugs are mainly divided into sputum agents, antimetabolites, metal platinum, plant alkaloids and other natural drugs, cytotoxic antibiotics and other major categories. Platinum antineoplastic agents are one of the most important antitumor drugs, and were the first anticancer drugs developed in the 1960s. An important difference from traditional cytotoxic anti-tumor drugs is that they have a unique mechanism of action and good anti-tumor selectivity.
  • DNA which is interlinked between DNA strands and chains, forms platinum complexes ⁇ DNA complexes, interferes with DNA replication, or binds to nuclear proteins and cytoplasmic proteins. It is a cyclic non-specific drug.
  • platinum complexes ⁇ DNA complexes, interferes with DNA replication, or binds to nuclear proteins and cytoplasmic proteins. It is a cyclic non-specific drug.
  • platinum antitumor drugs are currently more toxic, such as myelosuppression, renal toxicity, nerve damage, etc., poor solubility, relatively narrow anticancer spectrum, and drug resistance. Therefore, the design and synthesis of novel platinum antitumor drugs is still one of the main directions of anticancer drug research (MA Jakuper, M. Galanski, BK Keppler. Tumour-inhibit ing platinum complexes-state of art and future perspect ives, Rev. Physiol Biochem Pharmacol, 2003, 146, 1-53).
  • the solubility of oxaplatin is 2.65 mg/ml
  • the solubility of later oxaliplatin is 7.9 mg/ml
  • the solubility of nedaplatin is 8 mg/ml
  • the solubility of carboplatin is 17.8 mg/ml.
  • the solubility is 27 mg/ml, and the toxic side effects of oxaliplatin and carboplatin are lower than that of cisplatin.
  • the present invention provides a class of platinum compounds for treating proliferative diseases, in particular, a leaving group containing a primary amino group, a secondary amino group, a tertiary amino group, a quaternary amino group, a malonate derivative, which is pharmaceutically acceptable.
  • a leaving group containing a primary amino group, a secondary amino group, a tertiary amino group, a quaternary amino group, a malonate derivative which is pharmaceutically acceptable.
  • the salt, the solvate, the stereoisomer or the prodrug thereof have strong anti-tumor effect in vivo and in vitro, and the solubility is greatly improved, and the toxic and side-effect is significantly reduced. Unexpected technical effects.
  • the structure of this class of compounds is shown in formula A:
  • R includes, but is not limited to, hydrogen, fluorenyl, cyclodecyl, decyloxyalkyl, alkylaminoindolyl, heterocyclic, alkenyl, alkynyl, above alkyl, cyclodecyl, alkenyl,
  • the alkynyl, alkoxyfluorenyl, anthranylamino and heterocyclic rings may be unsubstituted or optionally substituted, preferably by halogen, hydroxy, alkoxy, decyl, alkoxyalkyl, Substituted by cycloalkyl, nonylamino, amino, heterocyclic.
  • Ro may or may not exist, as R.
  • the compounds of the invention are quaternary ammonium salts and must have corresponding negative ions present simultaneously.
  • R. When present, the compound of the invention is a tertiary amine, a secondary amine or a primary amine compound; when R. When present, R.
  • an anthracenyl group a cycloalkyl group, an alkoxyalkyl group, an alkylaminoalkyl group, a heterocyclic ring, an alkenyl group, an alkynyl group, a above fluorenyl group, a cycloalkyl group, an alkenyl group, an alkynyl group,
  • the decyloxy group, the alkylaminoalkyl group and the heterocyclic ring may be unsubstituted or optionally substituted, preferably by halogen, hydroxy, alkoxy, alkyl, alkoxyalkyl, cyclodecyl, a hydrazine amino group, an amino group, a heterocyclic ring;
  • R 2 may be the same or different and include, but are not limited to, hydrogen, alkyl, cycloalkyl, decyloxy, fluorenylamino, heterocyclic, alkenyl, alkynyl, fluorenyl, fluorenyl
  • the base, alkenyl group, chain block group, alkoxyfluorenyl group, nonylamino group and heterocyclic ring may be unsubstituted or optionally substituted, preferably by halogen, hydroxy, alkoxy, fluorenyl, Alkoxycarbonyl, cyclodecyl, alkylamino, amino, heterocyclic substituted under the condition of R. Or if it contains an unsaturated bond, the atom of the unsaturated bond cannot be directly connected to the nitrogen atom;
  • R 2 and the nitrogen atom to which they are attached may also form a closed saturated or unsaturated heterocyclic ring, for example, may be a ternary, quaternary, five-membered, six-membered, seven-membered or eight-membered ring, and the above ring may also be It is optionally fused to other rings and may be optionally substituted by halogen, hydroxy, alkoxy, decyl, decyloxy, cyclodecyl, heterocyclic, aryl, provided that! If ⁇ or ⁇ contains an unsaturated bond, the atom of the unsaturated bond cannot be directly connected to the nitrogen atom;
  • anthracenyl group, a cyclodecyl group, -R 31 -0-R 32 -, R 3 , and 2 are independently selected from a bond or a hydrocarbon group, and R 31 is bonded to a nitrogen atom in the formula, provided that If R 31 contains an unsaturated bond, the atom of the unsaturated bond cannot be directly bonded to the nitrogen atom; the above alkyl or cycloalkyl group may be unsubstituted or optionally substituted, preferably by halogen or hydroxy group. Substituted with methoxy, decyl, alkoxyalkyl, cycloalkyl, alkylamino, amino, heterocyclic, etc.;
  • R, R. , R, R 2 and the atoms to which they are attached may also form a closed saturated or unsaturated ring, for example, may be a ternary, quaternary, five-membered, six-membered, seven- or eight-membered ring, the above ring It may also optionally be fused to other rings, and may be optionally substituted by halogen, hydroxy, decyloxy, decyl, decyloxy, cycloalkyl, heterocyclic, aryl; for example, ! ⁇ And!
  • ⁇ and their commonly associated atoms together can also form a closed saturated or unsaturated ternary, quaternary, five-membered, six-membered, seven- or eight-membered ring; it can also be connected to its common
  • the atoms together form a closed saturated or unsaturated ternary, quaternary, five-membered, six-membered, seven-membered or eight-membered ring; or an atom connected to 1 ⁇ and its co-phase to form a closed saturated or unsaturated three Yuan, quaternary, five-yuan, six-member, seven- or eight-membered ring; or ⁇ and R, and
  • the atoms connected together form a closed saturated or unsaturated ternary, quaternary, five-membered, six-membered, seven-membered or eight-membered ring; and R 5 may be the same or different and may be, but not limited to: hydrogen, hydroxyl , fluorenyl
  • R 5 and the atoms to which they are attached may also form a closed ring, such as a five-, six-, seven-, or eight-membered ring, which may optionally be fused to other rings, and may Optionally replaced.
  • R is selected from the group consisting of hydrogen, alkyl, cycloalkyl; R. And and are selected from the group consisting of hydrogen, C, -8 alkyl, cyclodecyl, alkoxy fluorenyl, amino, hydrazinoalkyl, heterocyclic; R 3 may be, but not limited to: C, s s decyl, hydrazine R; and R 5 are selected from the group consisting of hydrogen, hydroxy, C, -s decyl, cyclodecyl, alkoxy, decyloxy, heterocyclic.
  • R is selected from substituted or unsubstituted indenyl, cycloalkyl, nonyloxyindenyl, alkylaminoindenyl, heterocyclic, alkenyl, alkynyl, R.
  • R, R 2 , R 3 , and R 5 are as described above.
  • R is H
  • ⁇ And! The atoms they are connected together form a closed saturated or unsaturated ternary, quaternary, five-, six-, seven- or eight-membered ring; or! ⁇ Together with R, , ⁇ and their associated atoms form a closed saturated or unsaturated ternary, quaternary, quaternary, hexavalent, seven- or eight-membered ring.
  • the present invention also provides a compound of the formula C and a pharmaceutically acceptable salt thereof, that is, a compound obtained when R 4 and R 5 and the atom to which they are bonded form a closed ring, as follows:
  • R, R. , R, R 2 . R 3 is selected from the group as described above
  • w is preferred but not limited to:
  • Preferred compounds are (s) trans 1,2-hexyl, pentane, butyl and propyl Amine platinum (ruthenium).
  • the hydrogen may be substituted by halogen, thiol, hydroxy, hydroxydecyl or alkoxy.
  • hydroxymethyl group (F) is preferred.
  • Rn may be, but not limited to, hydrogen, halogen, hydroxyalkyl, alkane, alkoxy, heterocyclic, etc., R,.
  • ⁇ may be the same or different, and a hydroxymethyl group is preferred.
  • R 13 may be -CH 2 - or -0-, preferably -CH 2 -.
  • ⁇ may be hydrogen, halogen, fluorenyl, decyloxy, hydroxydecyl or hydroxy, and R 14 is preferably hydrogen.
  • Preferred compounds have the following structure:
  • the term "mercapto" refers to a straight or branched saturated monovalent hydrocarbon group.
  • the fluorenyl group has 1-20 (C 1-2 ), 1-15 (d- 15 ), 1-10 (C, - 10 ) , a linear saturated monovalent hydrocarbon group of 7 (Cw) or ⁇ (CH) carbon atoms, or 3 - 20 (C 3 - 20 ), Branched saturated monovalent hydrocarbon groups of 3- 15 (C 3 - 15 ) , 3- 10 (C 3 - , .), 3-7 (C 3 - 7 ) or 3- 4 (C 3 - 4 ) carbon atoms .
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl (including all isomeric forms), hexyl (including all isomeric forms), heptyl (including all isomeric forms), octyl (including all isomeric forms), thiol (including all isomeric forms), thiol (including all isomers) Form), undecyl (including all isomeric forms), dodecyl (including all isomeric forms), tridecyl (including all isomeric forms), tetradecyl (including all isoforms)
  • a structure fifteen fluorenyl (including all isomeric forms), hexadecyl (including all isomeric forms), heptadecyl (including all isomeric forms), octadecy
  • “Mercapto” may be optionally substituted by one, two, three or four of the following substituents: halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, cyclodecyloxy, heteroepoxy Base, oxo, chain decanoyl, aryloxy, decanoyloxy, amino, alkylamino, arylamino, arylmethylamino, cyclodecylamino, heterocyclic amino, substituted tertiary ammonia (of which 2 nitrogen).
  • the substituent is selected from decyl, aryl or aryl fluorenyl, alkanoylamino, aroylamino, aryl decanoylamino, substituted alkanoylamino, substituted arylamino, substituted aryl decanoyl, thiol, hydrazine Thiothio, arylthio, aralkylthio, cycl
  • alkoxy refers to a straight one having 1 ⁇ OO ⁇ 1-15 (CBu 15 ), 1-10 ((:, —, .), l_7 (Cw) or 1- 4 (C ⁇ ) carbon atoms. or a saturated monovalent hydrocarbon chain of 3-20 (C 3 2.), 3- 15 (- 3-10 (C: MO), 3-7 (C 3 - 7) or 3- 4 (C M) carbon atoms a branched group of a saturated monovalent hydrocarbon group bonded to an oxygen atom.
  • Examples of the decyloxy group include, but are not limited to, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a n-butoxy group, and an isobutyl group.
  • alkylamino means that 1 or 2 of H of - 2 are each having 1 - 10 ⁇ ⁇ ), 1-6 or 1-4 (C, - 4 ) a linear sulfhydryl group of a carbon atom or a branched group substituted with 3-10 (C :M .), 3- 6 (C) or 3-4 (C) carbon atoms; when the above two H are simultaneously When substituted, the substituents may be the same or different.
  • alkylamino groups include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, dipropylamino, isopropylamino, diisopropylamino, n-butylamino, isobutylamino, t-butylamino, Di-n-butylamino, diisobutylamino, di-tert-butylamino, pentylamino, dipentylamino, hexylamino, dihexylamino, heptylamino, diheptylamino, octylamino, dioctylamino, decylamino, dinonylamino, Amidino, di-amino, N-methyl-N-ethylamino, N-methyl-N-propylamino, N-methyl-N-isopropylamin
  • halogen refers to fluoro, chloro, bromo and iodo.
  • hydrocarbyl refers to a functional group containing only two atoms of carbon and hydrogen.
  • aryl refers to a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 12 carbon atoms in the ring portion, such as phenyl, naphthyl, biphenylyl and diphenyl, each of which may be substituted.
  • Aryl may be optionally substituted by the following substituents: for example, fluorenyl, halogen, trifluoromethoxy, trifluoromethyl, hydroxy, decyloxy, cycloalkoxy, heterocyclooxy, alkanoyl , chain decanoyloxy, amino, alkylamino, aralkylamine Base, cyclodecylamino, heterocyclic amino, dinonylamino, decanoylamino, thiol, decylthio, cyclodecylthio, heterocyclic thio, ureido, nitro, cyano, carboxy And a carboxy fluorenyl group, a carbamoyl group, a decyloxycarbonyl group, a fluorenylthiocarbonyl group, an arylthiocarbonyl group, a decylsulfonyl group, a sulfinylamino group, an
  • aryl refers to an aryl group bonded directly through a thiol group, such as benzyl, phenethyl, phenylpropyl.
  • alkenyl refers to a straight or branched chain hydrocarbon radical having from 2 to 20 carbon atoms, preferably from 2 to 10 carbon atoms, most preferably from 2 to 6 carbon atoms, having from one to four double bonds, and also includes Groups having "cis” and “trans” configurations, or "E” and “Z” configurations, will be understood by those skilled in the art.
  • Alkenyl may be optionally substituted by, for example, halogen, hydroxy, alkoxy, alkanoyl. Alkanoyloxy, amino, mercaptoamino, dinonylamino, alkanoylamino, thiol, alkylthio, decylthiocarbonyl, alkylsulfonyl, sulfinamide, nitro, a cyano group, a carboxyl group, a carbamoyl group, a substituted carbamoyl group, a fluorenyl group, and a heterocyclic group, such as a fluorenyl group, an imidazolyl group, a furyl group, a thienyl group, a thiazolyl group, a pyrrolidinyl group, a pyridyl group, a pyrimidinyl group, etc. .
  • alkynyl refers to a straight or branched chain hydrocarbon radical having from 2 to 20 carbon atoms, preferably from 2 to 10 carbon atoms, and most preferably from 2 to 6 carbon atoms, having from one to four triple bonds.
  • the groups also include groups having the "cis” and “trans” configurations, or the “E” and “Z” configurations, as will be understood by those skilled in the art.
  • Alkynyl may be optionally substituted by the following substituents: halogen, hydroxy, alkoxy, alkanoyl, decanoyloxy, amino, decylamino, dimethylamino, decanoylamino, sulphur Hydroxy, alkylthio, decylthiol, alkylsulfonyl, sulfinamido, nitro, cyano, carboxy, carbamoyl, substituted carbamoyl, fluorenyl and heterocyclic, eg imidazole A group, a furyl group, a thienyl group, a thiazolyl group, a pyrrolidinyl group, a pyridyl group, a pyrimidinyl group or the like.
  • cycloalkyl refers to an optionally substituted, saturated ring containing preferably from 1 to 3 rings and each ring (which may be further fused to an unsaturated C 3 -C 7 carbocycle) containing from 3 to 7 carbons.
  • Cyclic hydrocarbon ring system Exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododedecyl and adamantyl.
  • substituents include one or more sulfhydryl groups as described above, or one or more thiol substituents as described above.
  • heterocyclic refers to an optionally substituted, fully saturated or unsaturated, aromatic or non-aromatic ring group, for example, the ring is a 4-7 membered monocyclic ring, A 7- to 11-membered bicyclic or 10-15 membered tricyclic system containing at least one heteroatom on a ring containing at least one carbon atom.
  • the hetero atom-containing heterocyclic group may have 1, 2, 3 or 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom on each ring, wherein the nitrogen and sulfur hetero atoms may also optionally be The oxidized and nitrogen heteroatoms can also optionally be quaternized.
  • the heterocyclic group can be attached to any hetero atom or carbon atom.
  • Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, indenyl, pyrazolyl, oxabutyryl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolyl, oxazolyl, Oxazolidine, isoxazolinyl, isoxazolyl, thiazolyl, thiadipine Azyl, thiazolyl, isothiazolyl, isothiazolyl, furyl, tetrahydrofuranyl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperrazinyl, 2-oxo Piperidinyl, 2-oxopyrrolenyl, 2-oxoazepine, azetyl, 4-piperidinone, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimi
  • bicyclic heterocyclic groups include benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl, iso Quinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromenyl, coumarinyl, 1,2-naphthyridinyl, quinoxalinyl, anthracene Azyl, pyrrolopyridyl, furopyridinyl (eg, furo[2,3-c]pyridyl, furo[3,1-b]pyridyl or furo[2,3-b]pyridinyl) , dihydroisoindolyl, dihydroquinazolinyl (eg 3,4-dihydro-4-oxo-quinazolinyl),
  • heteroatom includes oxygen, sulfur and nitrogen.
  • pharmaceutically acceptable salt includes salts of the active compounds which are prepared according to the particular substituents present on the compounds described herein using relatively non-toxic acids or bases.
  • a base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired base, either alone or in a suitable inert solvent.
  • the salt derived from a pharmaceutically acceptable inorganic base include aluminum, ammonium, calcium, copper, ferric iron, ferrous iron, lithium, magnesium, manganese, divalent manganese, potassium, sodium, zinc, and the like.
  • Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, natural amines and the like, such as arginine, betaine, caffeine, choline, N, N'-dibenzylethylenediamine, diethylamino, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, Glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methyl glucosamine, morpholine, piperazine, piperidine, polyamine resin, procaine, guanidine , theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • arginine betaine
  • caffeine choline
  • N N
  • the acid addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired acid, either alone or in a suitable inert solvent.
  • suitable inert solvent examples include those derived from inorganic acids, such as nitrates, carbonates, bicarbonates, phosphates, hydrogen phosphates, dihydrogen phosphates, sulfates, Hydrogen sulphate, phosphite, hydrochloride, hydrobromide, hydroiodide, etc.; from relatively non-toxic organic acids a derivative salt, such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluene Sulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like
  • salts of amino acids such as arginine and the like
  • salts of organic acids such as glucuronic acid or galactonic acid.
  • the leaving group of the compound of the present invention contains a basic group which can be salted with an acid, and a salt of the platinum (I I) compound can be prepared by a method well known to those skilled in the art.
  • Corresponding salts can also be formed with inorganic acids such as nitric acid, carbonic acid, sulfuric acid or phosphoric acid.
  • the acids which can be used include organic acids, inorganic acids and the like.
  • a lower sulfonic acid such as methanesulfonic acid or trifluoromethanesulfonic acid can form a methanesulfonate or a triflate; and an arylsulfonic acid such as benzenesulfonic acid or p-toluenesulfonic acid.
  • the form of the compound of the present invention and its salt can be converted into each other by a conventional method in the art, for example, by contacting the salt with a base or an acid and then separating the compound in a free form in a conventional manner, or by adding the compound to an acid or a base.
  • the salt form is isolated by conventional methods.
  • the invention provides a compound in the form of a prodrug ester.
  • prodrugs of the compounds described herein are those compounds which readily undergo chemical changes under physiological conditions to give the compounds of the invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an ex vivo environment.
  • a prodrug can be slowly converted to a compound of the invention when placed in a transdermal patch reservoir containing a suitable enzyme or chemical reagent.
  • Prodrugs are often pharmacologically inert compounds prior to conversion to the active drug, but this is not required.
  • the "precursor moiety" of the active drug can be obtained by masking a functional group of the drug that may be required for the active moiety with a "precursor group” (defined below) to form a functional group that can be converted (eg, cleaved under specific conditions of use) to release the functional group. ", get a prodrug.
  • the precursor moiety can be catalyzed or induced, for example, by a hydrolysis reaction, or by another substrate (such as an enzyme, light, acid or base) or physical or environmental parameter changes (such as temperature changes) or exposure to physical or environmental parameters. , for spontaneous lysis.
  • the agent may be endogenous to the environment of use, such as an enzyme present in the cells to which the prodrug is administered or an acidic environment of the stomach, or may be provided by an exogenous source.
  • Precursor group refers to a class of protecting groups that are capable of converting a drug into a prodrug when used to mask a functional group in the active drug to form a "precursor moiety.”
  • the precursor group is typically linked to the functional group of the drug by a bond which is cleavable under the particular conditions of use.
  • the precursor group is part of a precursor moiety that is cleaved under specific conditions of use and released Functional group.
  • the formula -NH-C (0) CH 3 amide promoiety comprising a precursor group - C (0) CH 3.
  • precursor groups suitable for masking functional groups in the active compound to give prodrugs and the resulting precursor moieties are well known in the art.
  • the hydroxy functionality can be masked to a sulfonate, ester (e.g., acetate or maleate) or carbonate precursor moiety which can be hydrolyzed in vivo to provide a hydroxyl group.
  • the amino functional group can be masked to an amide, carbamate, imine, urea, phenylphosphino, pity acyl or oxythio precursor moiety which can be hydrolyzed in vivo to give an amino group.
  • the carboxyl group can be masked as an ester (including methyl, ethyl, pivaloyloxymethyl, silicylide, and thioester), an amide or a hydrazide precursor which can be hydrolyzed in vivo to give a carboxyl group.
  • the present invention includes those esters and acyl groups known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations. Specific examples of suitable precursor groups and their corresponding precursor moieties will be apparent to those skilled in the art.
  • Certain compounds of the invention may exist in unsolvated as well as solvated forms including hydrated forms.
  • “Solvate” means a complex formed by the combination of a solvent molecule and a molecule or ion of a solute.
  • the solvent may be an organic compound, an inorganic compound or a mixture of the two.
  • Some examples of solvents include, but are not limited to, methanol, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, and water.
  • the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention.
  • Certain compounds of the invention may exist in a polymorphic or amorphous form. In general, all physical forms are the same and are within the scope of the invention for the purposes contemplated by the present invention.
  • Certain compounds of the invention have asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, regioisomers, and individual isomers (eg, isolated enantiomers) All are included in the scope of the invention. These isomers may be resolved or asymmetrically synthesized by conventional methods to render the isomer "optically pure", i.e., substantially free of other isomers thereof. For example, if a particular enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved.
  • the pure desired enantiomer is obtained.
  • a basic functional group such as an amino group or an acidic functional group such as a carboxyl group
  • an asymmetrically active salt is formed with a suitable optically active acid or base, and then the resulting non-form is formed by fractional crystallization or chromatographic methods well known in the art.
  • the enantiomers are resolved and the pure enantiomers are recovered.
  • the compounds of the invention may also contain an unusual proportion of atomic isotopes in one or more of the atoms that make up the compound.
  • the compound can be labeled with a radioactive isotope such as hydrazine (3 ⁇ 4), iodine-125 ( '25 1) or carbon-14 ( 14 C). All isotopic forms of the compounds of the invention, whether or not they are radioactive, are included within the scope of the invention.
  • Another object of the present invention is to provide a process for the preparation of the aforementioned compounds.
  • the preparation method of the formula (A) comprises the following steps:
  • the preferred preparation method is as follows:
  • reaction solution (3) The reaction solution is cooled to below 20 ° C, dissolved in R 5 NH 2 with water, added dropwise to the reaction solution of (2), and reacted in a water bath at 40-60 ° C for 30-60 min, and a large amount of yellow precipitate is formed.
  • the temperature in the reaction liquid was cooled to 20 ° C or less and filtered under suction, and washed with water, anhydrous ethanol and diethyl ether to obtain diiododiamine platinum (11).
  • the product obtained above can also be further prepared as a chiral compound and other pharmaceutically acceptable salts by conventional methods in the art.
  • the obtained product is made into a free base at a pH of 9-11, dissolved in an organic solvent such as methanol or ethanol, and reacted with a different acid to form a corresponding salt; or
  • the obtained compound is dissolved by adding water, cooled, and then filled with an anion exchange resin (0H type) column to be converted into a quaternary ammonium hydroxide obtained by replacing the other anion radicals with a hydroxyl group, and the corresponding salt is obtained by adding an acid;
  • the obtained compound can also be made into a free base under the condition of pH 9-11, dissolved in a small molecule alcohol such as methanol, ethanol and the like, and an appropriate amount of chiral mandelic acid solution is obtained.
  • the chiral mandelic acid salt crystallizes and can be obtained by repeated operations to obtain a pure chiral product.
  • the present invention also provides a pharmaceutical composition comprising the above compound, a pharmaceutically acceptable salt, a stereoisomer, a prodrug or a solvate thereof, and a pharmaceutically acceptable carrier and/or excipient.
  • the composition contains from 0.01% to 100%, preferably from 0.1% to 100%, more preferably from 1% to 100%, still more preferably from 20% to 100% by weight, of one or more compounds of the invention, the remainder Part of it consists of a suitable pharmaceutical carrier and/or excipient.
  • Compositions of the compounds of the invention may be combined with the routes of administration by methods well known in the art using suitable carriers and/or excipients.
  • the amount of active compound in a unit dosage formulation may vary from 0.001 mg to 1000 mg, preferably from 0.1 mg to 500 tng, more preferably from 1 mg to 100 mg, most preferably from 10 mg to 50 mg.
  • Administration can be, for example, oral, topical, intravenous, subcutaneous, transdermal, transdermal, intramuscular, intra-articular, parenteral, intra-arterial, intradermal, intraventricular, intracranial, intraperitoneal, intralesional, intranasal, intranasal , rectal, vaginal, inhaled or through an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques.
  • the composition is administered intravenously.
  • the formulations of the invention may be designed to be fast acting, immediate release or long lasting.
  • compositions of the invention may be formulated as a medicament for administration to a mammal, preferably a human.
  • composition comprising one or more of the invention may be administered repeatedly, for example at least 2, 3, 4, 5, 6, 7, 8 or more times, or the composition may be administered by continuous infusion.
  • Suitable sites for administration include, but are not limited to, blood vessels, muscles, skin, bronchi, gastrointestinal, anus, vagina, eyes and ears.
  • the preparation may be in the form of a liquid dosage form, a lyophilized powder form, a solid or a semi-solid, such as a solution, a suspension, an emulsion, a tablet, a pill, a capsule, a powder, a suppository, a retention enema, a cream, an ointment, a lotion
  • a gelling agent, an aerosol, or the like is preferably suitable for simply administering an accurate dosage unit dosage form.
  • compositions may be in the form of a sterile injectable solution and a sterile packaged powder.
  • the injection is prepared in 114. 5-7.
  • compositions of the invention in sterile injectable form are aqueous or oily suspensions. These suspensions may be formulated with suitable dispersing or wetting agents and suspending agents according to techniques known in the art.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension or dispersion in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, non-volatile oils are often used as solvents. Or suspending the matrix.
  • any brand of non-volatile oil including synthetic mono- or diglycerides can be used.
  • natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated form
  • fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectable preparations.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethylcellulose or similar dispersions typically used in formulations of pharmaceutically acceptable dosage forms including emulsions and suspensions. Agent.
  • compositions for parenteral administration by injection for example, bolus injection or continuous infusion, can be formulated.
  • Unit dosage forms for injection can be in ampoules or in multi-dose containers.
  • compositions of the invention may also be provided in lyophilized form.
  • Such compositions may comprise a buffer such as a hydrogencarbonate for reconstitution prior to administration, or a buffer may be included in the lyophilized composition for, for example, water reconstitution.
  • the lyophilized composition may also contain a suitable vasoconstrictor, such as epinephrine.
  • the lyophilized composition can be provided by syringe, optionally packaged with a buffer for reconstitution, so that the reconstituted composition can be administered to the patient immediately.
  • the pharmaceutical composition of the present invention may also be in any orally acceptable dosage form, including tablets, capsules, cachets, emulsions, suspensions, solutions, syrups, elixirs, sprays, pills, troches, powders. , granules and sustained release preparations.
  • Suitable excipients for oral administration include pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, gelatin, sucrose, magnesium carbonate and the like.
  • commonly used carriers include lactose and corn starch.
  • a lubricant such as magnesium stearate is usually also added.
  • useful diluents include lactose and dried corn starch.
  • the active ingredient is mixed with emulsifying and suspending agents.
  • Some sweeteners, flavoring agents or coloring agents may also be added as appropriate.
  • a liquid or composition is prepared by topical or intravenous administration of a solution or suspension.
  • Pharmaceutical preparations in the form of liquid suspensions or solutions may be prepared using sterile liquids such as oil, water, ethanol, and combinations thereof.
  • a suitable surfactant, suspending agent or emulsifier may be added to the agent.
  • the suspension may contain oils such as peanut oil, sesame oil, cottonseed oil, corn oil and olive oil.
  • the suspension formulation may also contain esters of fatty acids such as ethyl oleate, isopropyl myristate; fatty acid glycerides and acetyl fatty acid glycerides.
  • the suspension formulation may contain an alcohol such as ethanol, isopropanol, cetyl alcohol, glycerol and propylene glycol.
  • Ethers such as poly(ethylene glycol); petroleum hydrocarbons such as mineral oil and petrolatum, water can also be used in suspension formulations.
  • the composition may be in the form of a pill, a tablet or a capsule, and thus, the composition may contain one or more diluents such as lactose, sucrose, dicalcium phosphate, etc.; a disintegrating agent such as starch or a derivative thereof; Lubricants, such as magnesium stearate, and the like; and/or binders such as starch, gum arabic, polyvinylpyrrolidone, gelatin, cellulose, and derivatives thereof. Tablets can be prepared by any compression or molding process known to those skilled in the art.
  • diluents such as lactose, sucrose, dicalcium phosphate, etc.
  • a disintegrating agent such as starch or a derivative thereof
  • Lubricants such as magnesium stearate, and the like
  • binders such as starch, gum arabic, polyvinylpyrrolidone, gelatin, cellulose, and derivatives thereof. Tablets can be prepared by any compression or molding process known to those skilled in the art
  • a compressed tablet of the present invention in a free-flowing form e.g., powder or granule
  • admixture e.g., a binder, a lubricant, a diluent, a disintegrant, or a dispersing agent
  • Molded tablets may be made by molding in a suitable machine a powder mixture of the compound of the invention and any suitable carrier.
  • compositions of the invention may be in the form of a suppository for rectal administration.
  • suppositories can be prepared by admixing the drug with suitable suitable non-irritating excipients which are solid at room temperature but liquid at the rectal temperature and thereby release the drug in the rectum.
  • suitable suitable non-irritating excipients include cocoa butter, beeswax, polyethylene glycol, hard fat and/or hydrogenated cocoglyceride.
  • Compositions suitable for rectal administration may also contain rectal enema units containing one or more compounds of the invention and a pharmaceutically acceptable vehicle (for example, a 50% aqueous solution of ethanol or saline), such vehicles and rectal and / or the colon is physiologically compatible.
  • a pharmaceutically acceptable vehicle for example, a 50% aqueous solution of ethanol or saline
  • the rectal enema unit contains an applicator tip protected by an inert lid which preferably consists of polyethylene, lubricated with a lubricant such as white petrolatum, preferably protected by a one-way valve to prevent backflow of the ejected drug.
  • the rectal enema unit is also of sufficient length, preferably 2 inches, to be inserted through the anus into the colon.
  • compositions of the present invention may also be in the form of topical administration, especially when the therapeutic target includes areas or organs which are easily accessible by topical application, and diseases of these organs include diseases of the eyes, skin or lower intestinal tract. Suitable topical formulations for use in these areas or organs or organs in these organs are readily prepared.
  • compositions containing one or more compounds of the invention may be in the form of emulsions, lotions, gels, foams, creams, jellies, solutions, suspensions, ointments and transdermal patches. .
  • Topical administration in the lower intestinal tract can be achieved by a rectal suppository formulation or a suitable enema formulation. Topical transdermal patches can also be used.
  • a pharmaceutical composition in the form of a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers may be formulated.
  • Carriers for topical administration of the compounds of the invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • a pharmaceutical composition in the form of a suitable lotion or cream may be formulated containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include mineral oil, Span-60, Tween-60, cetyl ester, wax, cetyl alcohol, 2-octyl decadiol, benzyl alcohol and water.
  • compositions of this invention may also be administered by nasal aerosol or inhalation.
  • a dry powder or liquid form of the composition can be delivered by a nebulizer.
  • Such compositions are prepared according to techniques known in the art of pharmaceutical formulation, and may be employed in saline, with benzyl alcohol or other suitable preservatives, bioavailability absorption enhancers, fluorocarbons and/or other conventional solubilizing agents or A dispersant prepares a composition in the form of a solution.
  • compositions include ion exchangers, alumina, aluminum stearate, lecithin; serum proteins such as human serum albumin; buffer substances such as phosphate; glycine, sorbic acid, potassium sorbate a mixture of partial glycerides of saturated plant fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silica, magnesium trisilicate, polyvinylpyrrolidone , Cellulosic materials, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin.
  • ion exchangers alumina, aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • buffer substances such as phosphate
  • excipients include, but are not limited to, water, saline, lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline Cellulose, polyvinylpyrrolidone, cellulose, syrup, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, and polyacrylic acid, such as carbopol.
  • compositions may also contain lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifiers; suspending agents; preservatives such as methyl-, ethyl- and propyl-hydroxy-benzoates; Regulators such as inorganic and organic acids and bases; sweeteners; and flavoring agents.
  • lubricants such as talc, magnesium stearate and mineral oil
  • wetting agents such as talc, magnesium stearate and mineral oil
  • emulsifiers such as methyl-, ethyl- and propyl-hydroxy-benzoates
  • preservatives such as methyl-, ethyl- and propyl-hydroxy-benzoates
  • Regulators such as inorganic and organic acids and bases; sweeteners; and flavoring agents.
  • compositions may further comprise other active ingredients for the treatment or adjuvant treatment of proliferative diseases, or in combination with other drugs for the treatment or adjuvant treatment of proliferative diseases.
  • an anti-proliferative agent, an immunomodulator, an anticancer drug, a cytotoxic agent, and an antitumor auxiliary drug other than the present invention are used in combination.
  • anti-proliferative agents such as methotrexate, FK506 ( Futomycin , Pro gra f), mycophenolic mofetil; cytotoxic drugs such as azathioprine and cyclophosphamide; TNF- ⁇ inhibitors, such as tenidap; anti-TNF antibodies or soluble TNF receptors, such as etanercept (Enbrel); rapamycin, Ieflunimide, and cyclooxygenase-2 (C0X-2) inhibitors, such as Celecoxib and rofecoxib, or derivatives thereof; and PTK inhibitors disclosed in the prior art.
  • anti-proliferative agents such as methotrexate, FK506 ( Futomycin , Pro gra f), mycophenolic mofetil
  • cytotoxic drugs such as azathioprine and cyclophosphamide
  • TNF- ⁇ inhibitors such as tenidap
  • Typical types of anticancer and cytotoxic agents include, but are not limited to, alkylating agents such as nitrogen mustard, alkyl sulfonates, nitroureas, aziridines and triazene; antimetabolites such as folic acid Salt antagonists, purine analogs and pyrimidine analogs; antibiotics such as anthracycline, bleomycin, mitomycin, dactinomycin and plenummycin, enzymes such as L-asparaginase; Nylon protein transferase inhibitors; hormone agents, for example, glucocorticoids, estrogens/antiestrogens, androgens/antiandrogens, progesterone, luteinizing hormone releasing hormone antagonists, acetic acid, and microtubule destruction Agents such as echinosin or analogues and derivatives thereof; microtubule stabilizers, such as paclitaxel, docetaxel, and othi lone or analogs or derivatives thereof; plant-derived products
  • anticancer and cytotoxic agents include, but are not limited to, nitrogen mustard, cyclophosphamide, chlorambucil, anti-tumorine, ifosfamide, busulfan, carmustine, ring Nitrosourea, nitrosourea, streptozotocin, thiotepa, dacarbazine, methotrexate, thiopterin, guanidinium, fludarabine, pentastat in, claripine, a Sugar Cytidine, fluorouracil, doxorubicin hydrochloride, daunorubicin, demethoxydaunorubicin, bleomycin sulfate, mitomycin (:, actinomycin D, safracins, small nomiline, quinocarcins , discodermol ides, vincristine, vinblastine, vinorelbine tartrate, etoposide, podophyllotoxin, paclit
  • Preferred members of these categories include, but are not limited to: paclitaxel, cisplatin, carboplatin, doxorubicin, noredamycin, daunorubicin, aminoguanidine, methotrexate, methylhydrazine, silk Mycomycin (:, ecteinascidin, buffomycin, 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytarabine, podophyllotoxin or podophyllotoxin derivatives such as etoposide, etoposide phosphate or ghost Lethiophene glycosides, anti-tyrosine, vinblastine, vincristine, isovinblastine, vindesine, and vinorelbine.
  • antineoplastic agents and other cytotoxic agents include: US6262094, DE4138042, W097/19086, W098/2246K W098/25929, W098/38192, W099/01124, W099/02224 W099/02514, W099/03848, W099/07692, W099/27890, W099/28324> W099/43653, W099/54330 W099/54318, W099/54319, W099/65913, W099/67252, W099/67253, and epothi lone derivatives in WOOO/00485; W099/24416 Cyclin dependent kinase inhibitors; and isoprenyl protein transferase inhibitors such as W097/30992 and W098/54966.
  • the invention also provides a method of treating a cell proliferative disorder comprising administering to a patient in need thereof an effective amount of a compound of formula A.
  • Cell proliferative disorder refers to a disorder characterized by abnormal proliferation of cells. Proliferative disease does not imply any limitation on the rate of cell growth, but merely indicates loss of normal control of growth and cell division. Thus, cells of proliferative disease can have the same rate of cell division as normal cells, but do not respond to signals that limit this growth. “Cell proliferative disease” is in the range of neoplasms or tumors, and neoplasms or tumors are abnormal growth of tissues. “Cancer” refers to any of a variety of malignant tumors characterized by cell proliferation that have the ability to invade surrounding tissues and/or metastasize to new colonization sites.
  • cell proliferative disorders that can be treated with the compounds disclosed herein involve any disorder characterized by abnormal cell proliferation.
  • disorders include a variety of benign or malignant, metastatic or non-metastatic tumors and cancers.
  • the specific properties of cancer, such as tissue invasiveness or metastasis, can be combated by the methods described herein.
  • Cell proliferative diseases include a variety of cancers, including but not limited to: cancer: including bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, ovarian cancer, prostate cancer, pancreatic cancer, esophageal cancer, Gastric cancer, gallbladder cancer, cervical cancer, thyroid cancer, skin cancer, and squamous cell carcinoma; Hematopoietic tumors of the lymphatic system: including leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, beta-cell lymphoma, T-cell lymphoma, Hodgkins' lymphoma, non-Hodgkins' lymphoma, villous cell lymphoma and Burketts'lymphoma;
  • cancer including bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, ovarian cancer, prostate cancer, pancreatic cancer, esophageal cancer, Gastric cancer, gallbladder cancer, cervical cancer, thyroid cancer, skin
  • Hematopoietic tumors of the myeloid system including acute and chronic myeloid leukemia, myelodysplastic syndrome, and promyelocytic leukemia;
  • Tumors of the central and peripheral nervous system including astrocytoma, neuroblastoma, glioma, and schwannomas; interstitial-derived tumors: including fibrosarcoma, rhabdomyosarcoma, and osteosarcoma;
  • tumors include melanoma, xenoderma pigmentos aminated acanthoma, seminoma, thyroid follicular carcinoma and teratocarcinoma.
  • a cell proliferative disorder that can be treated with the compound is a blood tumor that is a cell malformation of the hematopoietic system.
  • Hematological tumors include lymphomas in which abnormal cells are derived from lymphoid cell lineage cells and/or exhibit a characteristic phenotype of lymphoid cell lineage cells.
  • Lymphoid cell tumors can be subdivided into B cell tumors, T and NK cell tumors, and Hodgkin's lymphoma.
  • B cell tumors can be subdivided into primordial B cell tumors and mature/peripheral B cell tumors.
  • B-cell tumor is precursor B lymphocytic leukemia/lymphoma (precursor B-cell acute lymphoblastic leukemia), mature/peripheral B-cell tumor is B-cell chronic lymphocytic leukemia/small lymphoma, B-cell Lymphocytic leukemia, lymphoplasmic lymphoma, spleen border B-cell lymphoma, hairy cell leukemia, plasma cell myeloma/plasma tumor, MALT-type pan-domain B-cell lymphoma, marginal zone B-cell lymphoma , Follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, mediastinal large B-cell lymphoma, primary osmotic lymphoma, and Burkitt's lymphoma/Burkitt cell leukemia.
  • T cells and Nk cell tumors are subdivided into precursor T cell carcinoma and mature (peripheral) T cell tumors.
  • Precursor T-cell tumor is precursor T-lymphocytic lymphoma/leukemia (precursor T-cell acute lymphoblastic leukemia), mature (peripheral) T-cell tumor is T-cell lymphocytic leukemia, T-cell granulosa leukemia, aggressive NK cell leukemia, adult T-cell lymphoma/leukemia (HTLV-1), extranodal nasal type NK/T-cell lymphoma; nasal type, pathogenic T-cell lymphoma, hepatosplenic sputum - ⁇ sputum cell lymphoma, subcutaneous Panniculitis-like sputum cell lymphoma, early granuloma/Sessley syndrome, degenerative large cell lymphoma; sputum/ineffective cells, primary cutaneous peripheral sputum cell lymphoma
  • Hodgkin's lymphoma also known as Hodgkin's disease.
  • the diagnosis of such diseases that can be treated with the compounds includes, but is not limited to, nodular lymphocyte super-dominant Hodgkin's lymphoma and various classical forms of Hodgkin's disease, wherein the sclerosing hardening Hodgkin's lymphoma (Grade 1 and Grade 2), classical Hodgkin's lymphoma enriched in lymphocytes, mixed cells constitute Hodgkin's lymphoma and lymphocytes deplete Hodgkin's lymphoma.
  • Hematological tumors also include myeloma.
  • Such tumors include a large class of cell proliferative disorders that are involved in or display characteristic phenotypes of myeloid lineage cells.
  • Myeloid cells can be subdivided into myeloproliferative diseases, myelodysplastic/myeloproliferative diseases, myelodysplastic syndromes, and acute myeloid leukemia.
  • Myeloproliferative diseases are chronic myelogenous leukemia, chronic neutrophil white blood Disease, chronic eosinophilic leukemia/eosinophilic syndrome, chronic spontaneous myelofibrosis, erythrocytosis, and essential thrombocytosis.
  • Myelodysplastic/myeloproliferative disorders are chronic mononuclear myeloid leukemia, atypical chronic myelogenous leukemia and adolescent mononuclear myeloid leukemia.
  • Myelodysplastic syndrome is a refractory anemia with ring-like high-iron red blood cells and non-circular high-iron red blood cells, refractory cytopenia with multiple dysplasia (myelodysplastic syndrome), and stubbornness with excessive blasts Anemia (myelodysplastic syndrome), 5ci-syndrome and myelodysplastic syndrome. Any myeloma can be treated and treated with the compounds of the invention.
  • the compounds can be used to treat acute myeloid leukemia (AML), which represents a large class of myeloid tumors with re-segmentable conditions.
  • AML acute myeloid leukemia
  • These branches include, but are not limited to, AM with polymorphic dysplasia with recurrent cytogenetic translocation and other unclassified AML.
  • AML with recurrent cellular genetic translocations includes, but is not limited to, AML with t (8; 21 ) (q22 ; q22), AML1 (CBF-a) / ET0, acute promyelocytic leukemia (with t (15; 17) (q22 ; ql l- 12) AML and variants, PML/RAR-a), with abnormal bone marrow eosinophils (inv (16) (pl 3q22) or t (16; 16) (pl 3 ; qll ) CBFb /MLHl lX) AML and AML with ll q23 (MLL) exception.
  • AML with multiple dysplasia is those associated with or not associated with premyelodysplastic syndrome.
  • Other acute myeloid leukemias not classified in any definable class include minimally differentiated AML, immature AML, mature AML, acute mononuclear myeloid leukemia, acute mononuclear leukemia, acute erythroid leukemia, acute megakaryocyte type Leukemia, acute basophilic leukemia, and acute whole myeloid leukemia with myelofibrosis.
  • Preferred tumors to be treated are breast cancer, lung cancer, colon cancer, gastric cancer, esophageal cancer, ovarian cancer, osteosarcoma, cervical cancer, liver cancer, brain tumor, prostate cancer, melanoma.
  • Treatment in the context of the present invention means alleviating the symptoms associated with the condition or disease, or terminating the further development or worsening of those symptoms, or preventing or preventing the disease or condition.
  • pharmaceutically effective amount refers to a subject compound that is being sought by a researcher, veterinarian, physician, or other clinical technician to cause a biological or medical response to a tissue, system, animal, or human. the amount.
  • therapeutically effective amount includes an amount of a compound which, after administration, is sufficient to prevent the development or alleviation of one or more symptoms of the disease or condition being treated to some extent.
  • the therapeutically effective amount will vary with the compound, condition or condition and its severity, as well as the age, weight, etc. of the mammal being treated.
  • a "patient” as defined herein includes animals, such as mammals, including but not limited to primates (eg, humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, and the like.
  • the patient is a human.
  • An effective amount of a compound of the present invention can be determined by one of ordinary skill in the art. For an adult dose of 0.0001-100 mg of active compound per kg body weight per day, it can be administered in a single dose or in divided doses, for example, 1 per day. -4 times.
  • the specific dosage level and number of administrations may vary for any particular subject, depending on a number of factors, including the activity of the particular compound employed, the metabolic stability of the compound, and the length of action, the subject's Species, age, weight, health profile, gender and eating habits, manner and timing of medication, rate of excretion, combination of medications, and severity of specific conditions.
  • the free compound of the present invention has a markedly improved solubility relative to the antitumor platinum compound of the prior art, and has a solubility in water of 50 mg/ml or more, particularly those of the preferred embodiments of the present invention, each having 90 mg/ml or even 100 mg/ Solubility above ml.
  • the prior art platinum compound cannot form a salt, and the compound of the present invention can be formed into a salt form, which is more advantageous for its preparation into a stable preparation form.
  • the therapeutically effective dose can be adjusted depending on the route of administration and the dosage form.
  • Representative compounds of the invention are those which exhibit a high therapeutic index.
  • the therapeutic index is the dose ratio between toxicity and efficacy, which can be LD 5 .
  • the index is expressed as the ratio of in vivo antitumor activity (ED 5 .) or in vitro cytotoxicity (IC 5 .).
  • LD 5 To make a 50% population lethal dose, ED 5 . To achieve a therapeutically effective dose in 50% of the population. LD 5 is determined in animal cell culture media or experimental animals by standard pharmaceutical methods. And ED 5 . .
  • the compound of the present invention represents a toxic LD 50 (a dose of mmol/kg causing half of animal death) is much higher than the platinum compounds of the prior art, such as cisplatin and carboplatin, and an effective dose of antitumor activity in vivo and an inhibitory cytotoxic concentration in vitro. IC 5 .
  • the value is comparable to or lower than carboplatin, so it can be used for patients who cannot tolerate treatment with existing platinum compounds such as carboplatin and cisplatin, and achieve good technical results.
  • the compounds of the invention may be used alone or in combination with each other, and/or in combination with other suitable therapeutic agents useful in the treatment of proliferative diseases.
  • Inorganic salts compounds in the form of these salts can also be obtained as a free base compound by an anion exchange resin, and can be easily converted into other kinds of organic or inorganic salts by the addition of the corresponding acid.
  • Step 1 2-( 3-Bromopropanyl)-malonic acid diethyl ester Take 15.15 g (0. lmol) of diethyl malonate and 50. 5 g (0.25 mol) of 1, 3-dibromopropene in a 150 ml three-necked flask, and add K 2 C0 3 15.12 g (0. llmol).
  • Step 5 trans-cyclohexanediamine* platinum (ruthenium) sulfate dihydrate
  • Step 6 2-(3-(1-piperidinyl)-propanyl)-malonic acid*cis-(1,2-trans-cyclohexanediamine)platinum(II) phosphate;
  • the product was dissolved in water, the pH was adjusted to 10-11 with EtOAc and then ethyl acetate (10 ml X 3 times), and the organic layer was combined, and the mixture was adjusted to pH 5-7 by adding H 3 P0 4 (1M) to give the final product 131 mg.
  • the compound is easily soluble in water and has a solubility of more than 100 mg/ml. It can be easily converted into other kinds of organic or inorganic salts by being free, and can be, but not limited to, sulfate, methanesulfonate, tartrate, succinate, B. Acid salts, decanoates, p-toluenesulfonates, fumarates, and the like. Analysis of free alkali elements: C38.24% (theoretical 38.06%); H5.93% (theoretical 5.78%); N7.72% (theoretical 7.84%).
  • Step 1 Same as [Example 3] Step 1.
  • Step 4 5 Same as [Example 1] Step 4 5
  • Step 6 2-(3-(1-tetrahydropyrrole)-propionyl)-malonic acid ⁇ cis-(1 2 trans-cyclohexanediamine) platinum (ruthenium) phosphate;
  • the compound is easily soluble in water and has a solubility of more than 100 mg/ml. It can be easily converted into other kinds of organic or inorganic salts by free, and can be, but not limited to, sulfate, methanesulfonate, tartrate, succinate, acetic acid. Salt, citrate, p-toluenesulfonate, fumarate, and the like. Analysis of free alkali elements: C36.73% (theoretical 36.78%) H5.39% (theoretical 5.56%) N8.18% (theory 8.05%).
  • Example 3 2-methyl-2-(2-methylaminoethyl)-malonic acid. cis-diaminoplatinum (II) phosphate;
  • Step 1 2-(2-Bromoethyl)-2-methyl-propionic acid ethyl ester
  • Step 5 Diamine ⁇ Platinum (II) sulfate dihydrate
  • H 2 0-NH 2 takes Ag 2 S0 4 625 mg (2 sec ol ) in a 100 ml three-necked flask, and 30 ml of water is added to stir, and diammine ⁇ diiodoplatinum (11) 0. 96 g (2 mmol) is added to the reaction solution. Then add 40ml of water to react, N 2 protection, protected from light, water bath 40 ⁇ 6 (4 ⁇ 8h reaction under TC). The Agl precipitate is removed by suction filtration to obtain the filtrate, which is the aqueous solution of the product.
  • Step 6 2-Methyl-2-(2-methylaminoethenyl)-malonic acid*cis-diammineplatinum (ruthenium) phosphate
  • reaction solution 40 ⁇ 75°C reaction for 4-6h, the reaction solution is filtered and concentrated to a certain volume, static crystallized, the product is dissolved in water, adjusted to pH 10-11 with NaOH, extracted with ethyl acetate (10ml ⁇ 3 times), combined organic The layer was added with P0 4 (1M) to adjust the pH to 5-7 to obtain 115 mg of 2-(2-methylaminoethylhydrazinyl)-3-hydroxy-propionic acid ⁇ cis diaminoplatinum(II) phosphate.
  • the compound is easily soluble in water and has a solubility of more than 100 mg/ml. It can be easily converted into other kinds of organic or inorganic salts by being free, and can be, but not limited to, sulfate, methanesulfonate, tartrate, succinate, phosphate. , citrate, p-toluenesulfonate, fumarate, and the like. Analysis of free alkali elements: C20.45% (theory 20.90%); H4.43% (theoretical 4.23%); N10.58% (theoretical 10.45%).
  • Step 4 Same as [Example 3] Step 4.
  • Step 5 Same as [Example 3] Step 5.
  • Step 6 2-methyl-2-(-triethylaminoethane)-malonic acid, cis-diaminoplatinum(II) methanesulfonate;
  • solubility 386mg / ml can be converted into various organic or inorganic salts by ion exchange, which can be, but not limited to, sulfate, phosphate, tartrate, succinate, acetate, strontium Acid salt, p-toluenesulfonate, fumarate, and the like. Elemental analysis: 28.79% (theory 28.97%); H5.25% (theoretical 5.35%) ; N7.15% (theoretical 7.24%); S5.36% (theoretical 5.52%).
  • Example 5 3-piperidinyl-1,1-cyclobutane-dicarboxylic acid diethyl ester, cis-diamino-platinum (ruthenium) phosphate
  • Step 1 3-piperidinyl-1, 1-cyclobutane-dicarboxylic acid diethyl ester
  • Step 2 3-piperidinyl-1, 1-cyclobutane-dicarboxylic acid disodium salt
  • Step 3 Same as [Example 3] Step 4.
  • Step 4 Same as [Example 3] Step 5.
  • Step 5 3-piperidinyl-1, 1-cyclobutane-dicarboxylic acid, cis-diaminoplatinum (ruthenium) phosphate;
  • the compound is easily soluble in water and has a solubility of 219 mg/ml. It can be easily converted into other kinds of organic or inorganic salts by liberation, and may be, but not limited to, sulfate, methanesulfonate, tartrate, succinate, acetic acid. Salt, citrate, p-toluenesulfonate, fumarate, and the like. Analysis of free alkali elements: C29.18% (theoretical 29.01%); H4.73% (theoretical 4.84%); N9.52% (theoretical 9.23%).
  • Step 3 Same as [Example 1] Step 4.
  • Step 4 Same as Step 5 of [Example 1].
  • Step 5 3-piperidinyl-1, 1-cyclobutane-dicarboxylic acid * cis diaminoplatinum (ruthenium) phosphate;
  • the compound is easily soluble in water and has a solubility of 309 mg/ml. It can be easily converted into other kinds of organic or inorganic salts by free, and can be, but not limited to, sulfate, methanesulfonate, tartrate, succinate, acetic acid. Salt, citrate, p-toluenesulfonate, fumarate, and the like. Analysis of free alkali elements: C38.25% (theoretical 38.20%); H5.48% (theoretical 5.43%); N7.88% (theoretical 7.87%).
  • Example 7 2-(4-piperidinyl)-propionic acid ⁇ cis-(1,2-trans-cyclopentanediamine) platinum (ruthenium) phosphate;
  • Step 4 1, 2-trans-cyclopentadiamine*diiodoplatinum (ruthenium)
  • Step 5 1, 2-trans-cyclopentanediamine ⁇ platinum(II) sulfate dihydrate
  • Step 6 2-(4-Piperidinyl)-malonic acid ⁇ cis-(1,2-trans-cyclopentanediamine) Platinum (II) phosphate
  • the compound is easily soluble in water and has a solubility of 322 mg/ml. It can be easily converted into other kinds of organic or inorganic salts by free, and can be, but not limited to, sulfate, methanesulfonate, tartrate, succinate, acetic acid. Salt, citrate, p-toluenesulfonate, fumarate, and the like. Analysis of free alkali elements: C32. 58% (theoretical 32. 5%); H4. 57% (theory 4. 79%); N8. 61% (theory 8. 75%)
  • Example 8 2-methyl-(4-piperidyl)-propionic acid ⁇ cis-(1,2-trans-cyclopentadiamine)-platinum (II) phosphate; Step 1: 2 -methyl-(4-piperidinyl)-dipropyl malonate
  • Steps 3, 4, and 5 Same as [Example 7] Steps 3, 4, and 5.
  • Step 6 2-((4-piperidinyl)-malonic acid ⁇ cis-(1,2-trans-cyclopentanediamine) platinum (II) phosphate
  • the compound is easily soluble in water and has a solubility of 307 mg/ml. It can be easily converted into other kinds of organic or inorganic salts by free, and can be, but not limited to, sulfate, methanesulfonate, tartrate, succinate, acetic acid. Salt, citrate, p-toluenesulfonate, fumarate, and the like. Free base element analysis: C34. 18% (theoretical 34. 01%); H5. 16% (theoretical 5.06%); N8. 62% (theoretical 8.50%).
  • Step 4 1, 2-Ethylenediamine, Diiodoplatinum (II)
  • Step 6 2-methyl-(N-ethyl-4-piperidyl)-malonic acid 'cis- 1,2-ethylenediamine platinum (ruthenium) phosphate;
  • Ethyl ester (10ml X3 times) is extracted, combined with extract, adjusted to pH 5 ⁇ 7 with 1 ⁇ 0 4 (1M), static, crystallized product, crystal product dissolved in water, pH adjusted to 10-11 with NaOH It was extracted with ethyl acetate (10 ml ⁇ 3 ⁇ ), and the organic layer was combined, and the mixture was adjusted to pH 5 to 7 by adding H 3 P0 4 (1M) to obtain 135 mg of the final product.
  • the compound is readily soluble in water and has a solubility of 290 mg/ral and can be converted into various organic or inorganic salts, which may be, but not limited to, sulfate, methanesulfonate, tartrate, succinate, acetate, citric acid. Salt, p-toluenesulfonate, fumarate, and the like. Analysis of free alkali elements: C32.51% (theoretical 32.37%); H5.33% (theoretical 5.19%); N8.56% (theoretical 8.71%).
  • Step 3 Same as [Example 9] Step 3.
  • Step 4 1, 3-propanediamine, diiodoplatinum (ruthenium)
  • Step 6 2-((N-Ethyl-4-piperidinyl)-malonic acid 'cis-1,3-1,3-diamine-platinum(II) phosphate
  • the compound is readily soluble in water and has a solubility of 276 mg/ml and can be converted into various organic or inorganic salts, which may be, but not limited to, sulfate, methanesulfonate, tartrate, succinate, acetate, citric acid. Salt, p-toluenesulfonate, fumarate, and the like. Analysis of free alkali elements: C33. 63% (theoretical 33. 87%); H5. 51% (theory 5. 44%); N8. 36% (theory 8. 47%).
  • Step 3 Same as [Example 9] Step 3.
  • Step 4 1, 4-butanediamine, diiodoplatinum (II)
  • Step 5 1, 4-butanediamine, platinum (II) sulfate dihydrate
  • Step 6 2-Methyl-(N-ethyl-4-piperidinyl)-malonic acid ⁇ cis- 1, 3-propanediamine platinum (II) phosphate
  • the compound is readily soluble in water and has a solubility of 279 mg/ml and can be converted into various organic or inorganic salts, which may be, but not limited to, sulfate, methanesulfonate, tartrate, succinate, acetate, citric acid. Salt, p-toluenesulfonate, fumarate, and the like.
  • Free base element analysis . 35.43% (theoretical 35.29%); H5.57% (theoretical 5.69%); N8.39% (theory 8.24%).
  • Steps 1, 2 Same as [Example 8] Steps 1, 2.
  • Step 3 Same as [Example 9] Step 3.
  • Step 4 1 3- (2 2-Hydroxymethyl-propylenediamine' Iodine Platinum (II)
  • Step 5 1 3- (2-hydroxymethyl)-propylenediamine ⁇ Platinum ( ⁇ ) sulfate dihydrate
  • Step 6 2-Methyl-(N-ethyl-4-piperidinyl)-malonic acid ⁇ cis- 1 3-(2,2-hydroxymethyl)-propanediamine-platinum (phosphonium) phosphate Salt
  • Soluble in water, solubility 389mg/ml can be converted into various organic or inorganic salts, which can be, but are not limited to, sulfate, methanesulfonate, tartrate, succinate, acetate, citrate, Tosylate, fumarate, and the like. Analysis of free alkali elements: C34.48% (theoretical 34.53%); H5.47% (theoretical 5.58%) N7.36% (theoretical 7.55%)
  • Example 13 2-(2-Dimethylaminoethane)-3-hydroxy-propionic acid 'cis- 1, 4-(trans-2, 3-cyclobutyl)-butanediamine Platinum (phosphonium) phosphate;
  • Steps 1, 2 Same as [Example 5] steps 1, 2.
  • Step 3 1, 4- (trans -2, 3-cyclobutyl) - butanediamine - diiodoplatinum (II)
  • Step 4 1, 4- (trans-2, 3-cyclobutyl)-butanediamine* platinum (II) sulfate dihydrate
  • Step 5 3-piperidinyl-1,1-cyclobutane-dicarboxylic acid ⁇ cis-1,4-(trans-2, 3-cyclobutyl)-butanediamine platinum (II) phosphate Salt
  • volume, static, crystallized product, crystallized product is dissolved in water, pH is adjusted to 10-11 with NaOH, extracted with ethyl acetate (10 ml X 3 times), the organic layer is combined, and methanesulfonic acid (1M) is added to adjust the pH to 5 ⁇ 7, the final product is 145mg.
  • the compound is easily soluble in water and has a solubility of 278 mg/ml. It can be easily converted into other kinds of organic or inorganic salts by free, and can be, but not limited to, sulfate, methanesulfonate, tartrate, succinate, acetic acid. Salt, citrate, p-toluenesulfonate, fumarate, and the like. Analysis of free alkali elements: C38.29% (theoretical 38.20%); H5.39% (theoretical 5.43%); N7.65% (theory 7.87%).
  • Steps 1, 2 Same as [Example 5] steps 1, 2.
  • Step 4 1, 3- (2, 2- (4- ) - Propanediamine ⁇ Platinum ( ⁇ ) sulfate dihydrate
  • Step 5 3-piperidinyl-1, 1-cyclobutane-dicarboxylic acid ⁇ cis-1, 3-(2,2-(4-oxocyclohexyl))-propanediamine platinum (II Phosphate
  • the crystalline product After concentration to a certain volume, static, to obtain a crystalline product, the crystalline product is dissolved in water, the pH is adjusted to 10-11 with NaOH, and then extracted with ethyl acetate (10 ml X 3 times), the organic layer is combined, and methanesulfonic acid (1M) is added. The pH was adjusted to 5-7 to give a final product of 151 mg.
  • the compound is easily soluble in water and has a solubility of 311 mg/ml. It can be easily converted into other kinds of organic or inorganic salts by liberation, and can be, but not limited to, sulfate, methanesulfonate, tartrate, succinate, acetic acid. Salt, citrate, p-toluenesulfonate, fumarate, and the like. Analysis of free alkali elements: C37.12% (theoretical 37.09%); H5.45% (theoretical 5.31%); N7.81% (theoretical 7.63%).
  • the toxic effects of the platinum compounds of the examples on tumor cells were observed by applying the MTT colorimetric method.
  • Several tumor cells in the exponential growth phase were prepared as single cell suspensions, seeded in 96-well plates at a density of 4 X 107 wells, and cultured in 1640 medium (complete medium) containing 10% fetal bovine serum at 37 °C. The cells were allowed to adhere for 24 hours, and the final volume was 100 ⁇ l. After 24 hours of culture, the morphology of the cells was observed.
  • platinum compound For the amount of platinum compound, the following concentrations were determined by preliminary tests due to different IC50 of various cells: cisplatin 200, 60, 20, 6, 2, 0.64 g/ml, carboplatin 200, 60, 20, 6, 2, 0.6 g/ml, the platinum compounds of the examples were appropriately adjusted according to their sensitivity to each cell, and the results are shown in Table 2-5 below:
  • the present invention also provides phosphates of the following compounds:

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Abstract

L'invention concerne un composé de platine avec le substituant en position 2 de dérivé malonique de groupe partant contenant une amine primaire, une amine secondaire, une amine tertiaire, une amine quaternaire et un sel pharmaceutiquement acceptable ainsi que son procédé de préparation, et une composition pharmaceutique contenant le composé. L'invention concerne également des utilisations de ce composé pour le traitement de maladies à prolifération de cellules, en particulier des cancers. Le composé de platine de la présente invention a une haute solubilité dans l'eau et une faible toxicité.
PCT/CN2014/000061 2013-01-23 2014-01-17 Composé de platine (ii) pour traiter la maladie à prolifération de cellules tumorales WO2014114183A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020043144A1 (fr) 2018-09-01 2020-03-05 北京硕佰医药科技有限责任公司 Phosphate de composé de platine et son procédé de préparation
WO2021218892A1 (fr) * 2020-04-27 2021-11-04 威海海岭生物科技有限公司 Composé de platine bivalent ayant une nouvelle structure et son utilisation

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011006908A2 (fr) * 2009-07-16 2011-01-20 Royal College Of Surgeons In Ireland Complexes métalliques ayant une double activité inhibitrice d'histone désacétylase et de liaison à l'adn
CN102781478A (zh) * 2010-02-03 2012-11-14 米韦林有限公司 用于细胞内靶向增殖和蛋白质合成的聚阴离子多价大分子
CN102863474A (zh) * 2011-07-09 2013-01-09 陈小平 一类治疗细胞增殖性疾病的铂化合物、其制备方法和应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011006908A2 (fr) * 2009-07-16 2011-01-20 Royal College Of Surgeons In Ireland Complexes métalliques ayant une double activité inhibitrice d'histone désacétylase et de liaison à l'adn
CN102781478A (zh) * 2010-02-03 2012-11-14 米韦林有限公司 用于细胞内靶向增殖和蛋白质合成的聚阴离子多价大分子
CN102863474A (zh) * 2011-07-09 2013-01-09 陈小平 一类治疗细胞增殖性疾病的铂化合物、其制备方法和应用

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GIBSON, D. ET AL.: "Anthraquinone intercalators as carrier molecules for second-generation platinum anticancer drugs", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 32, no. 10, 31 December 1997 (1997-12-31), pages 823 - 831, XP004172153, DOI: doi:10.1016/S0223-5234(99)80068-3 *
ZHAO, JIAN ET AL.: "Antitumor Platinum (11) Complexes Containing Platinum-Based Moieties of Present Platinum Drugs and Furoxan Groups as Nitric Oxide Donors: Synthesis, DNA Interaction, and Cytotoxicity", INORGANIC CHEMISTRY, vol. 51, no. 19, 7 September 2012 (2012-09-07), pages 10317 - 10324 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020043144A1 (fr) 2018-09-01 2020-03-05 北京硕佰医药科技有限责任公司 Phosphate de composé de platine et son procédé de préparation
US11661434B2 (en) 2018-09-01 2023-05-30 Beijing Showby Pharmaceutical Co., Ltd. Phosphate of platinum compound and preparation method therefor
WO2021218892A1 (fr) * 2020-04-27 2021-11-04 威海海岭生物科技有限公司 Composé de platine bivalent ayant une nouvelle structure et son utilisation

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