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WO2019052477A1 - Composé de tanshinone et son utilisation pour traiter un hémangiome - Google Patents

Composé de tanshinone et son utilisation pour traiter un hémangiome Download PDF

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Publication number
WO2019052477A1
WO2019052477A1 PCT/CN2018/105278 CN2018105278W WO2019052477A1 WO 2019052477 A1 WO2019052477 A1 WO 2019052477A1 CN 2018105278 W CN2018105278 W CN 2018105278W WO 2019052477 A1 WO2019052477 A1 WO 2019052477A1
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group
substituted
unsubstituted
alkyl
acyl
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Chinese (zh)
Inventor
吴晔明
叶阳
武志祥
姚胜
蔡翊鸿
谭敏佳
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Shanghai Institute of Materia Medica of CAS
XinHua Hospital Affiliated To Shanghai JiaoTong University School of Medicine
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Shanghai Institute of Materia Medica of CAS
XinHua Hospital Affiliated To Shanghai JiaoTong University School of Medicine
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
    • C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
    • C07J73/003—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by oxygen as hetero atom
    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C50/00—Quinones
    • C07C50/16—Quinones the quinoid structure being part of a condensed ring system containing three rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
    • A61K36/537—Salvia (sage)

Definitions

  • the present invention relates to the field of medicine, and in particular, the present invention provides a class of tanshinone compounds and their use for treating hemangiomas.
  • Aneurysm hemangiomas is the most common benign tumor in infants and young children. It is a true hemangioma caused by abnormal proliferation of vascular endothelial cells. Its incidence rate is about 5%-10%, and the ratio of male to female is 1:3-5. The disease is difficult to be discovered at birth. A recent cohort study suggests that the peak growth period of infantile hemangiomas is mostly 5.5-7.5 weeks, with an average of about 4 weeks. Then the lesions gradually become visible and enter a period of rapid growth, which is slow. , from a few months to as many as seven to ten years. A small number of children have a large area of hemangioma, leaving pigmentation, accompanied by signs of shallow scars, skin atrophy and sagging, and even lifelong unhealed.
  • the pathogenesis of IH has been blurred to this day.
  • Early theory suggests that mother's behavior during pregnancy leads to the occurrence of hemangioma or vascular malformation, and strawberry hemangioma is even thought to be caused by the mother taking red fruit.
  • the mechanism of hemangioma mainly includes the following theories: abnormal vascular development during embryogenesis, angiogenic diseases, and effects of estrogen.
  • Recent research on hemangiomas has focused on the recruitment of progenitor cells, interstitial tumor cells, abnormalities in extracellular matrices, and factors that promote angiogenesis.
  • More than half of IH can resolve on its own. It is generally advocated to hold a wait-and-see attitude and palliative attitude in the early stage of hemangioma.
  • the occurrence and development of hemangioma may affect the life of the child. As the age increases, the self-awareness increases, and the child often shows a deficiency. Self-confidence, anxiety and guilt, especially when the growth of hemangioma endangers the life or function of the child, should be treated promptly.
  • Current treatments include oral or topical medications, surgical resection, cryotherapy, radionuclide therapy, and laser therapy.
  • a ring is selected from the group consisting of a substituted or unsubstituted 3-10 membered carbocyclic ring, a substituted or unsubstituted 3-10 membered heterocyclic ring, a substituted or unsubstituted C 6 -C 10 aromatic ring, substituted or unsubstituted 5-12 yuan heteroaryl ring;
  • R 2 is selected from the group consisting of H, oxygen atom, O-R';
  • the R' is selected from the group consisting of H, a substituted or unsubstituted C 2 -C 10 acyl group, a fluorenylmethoxycarbonyl group (Fmoc), or a substituted or unsubstituted C 1 -C 10 alkyl group; Ground, R' is H;
  • R 3 is selected from the group consisting of H, halogen, oxygen atom, cyano group, hydroxyl group, carboxyl group, C 1 -C 4 alkoxy group, C 1 -C 4 alkyl group, C 1 -C 4 haloalkyl group, substitution Or an unsubstituted C 2 -C 10 acyl group, a substituted or unsubstituted C 2 -C 10 ester group, -OC(O)-R, -NH-R; wherein R is selected from the group consisting of H, C 1 -C 4 acyl group, a substituted or unsubstituted C 1 -C 4 alkyl group;
  • R 4 is selected from the group consisting of H, halogen, oxygen atom, cyano group, hydroxyl group, carboxyl group, C 1 -C 4 alkoxy group, C 1 -C 4 alkyl group, C 1 -C 4 haloalkyl group, substitution Or an unsubstituted C 2 -C 10 acyl group, a substituted or unsubstituted C 2 -C 10 ester group, -OC(O)-R, -NH-R; wherein R is selected from the group consisting of H, C 1 -C 4 acyl group, a substituted or unsubstituted C 1 -C 4 alkyl group;
  • any two of R 1 , R 2 , R 3 and R 4 together with an adjacent carbon atom constitute a group selected from the group consisting of a substituted or unsubstituted C 3 -C 10 membered carbocyclic ring, substituted or unsubstituted a substituted 3-10 membered heterocyclic ring, a substituted or unsubstituted C 6 -C 10 aromatic ring, a substituted or unsubstituted 5-12 membered heteroaryl ring;
  • R 5 is selected from the group consisting of H, halogen, cyano, hydroxy, C 1 -C 4 alkoxy, -COOR, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 1 -C a 10 haloalkyl group, a substituted or unsubstituted C 2 -C 10 acyl group, a substituted or unsubstituted C 2 -C 10 ester group; wherein R is selected from the group consisting of H, C 2 -C 4 acyl groups, substitutions Or an unsubstituted C 1 -C 4 alkyl group;
  • R 6 is selected from the group consisting of H, halogen, oxygen atom, cyano group, carboxyl group, hydroxyl group, C 1 -C 4 alkoxy group, -COOR, substituted or unsubstituted C 1 -C 10 alkyl group, substituted or unsubstituted C 1 -C 10 haloalkyl, substituted or unsubstituted C 2 -C 10 acyl, substituted or unsubstituted C 2 -C 10 ester group; wherein R is selected from the group consisting of H, C 2 -C 4 is an acyl group, a substituted or unsubstituted alkyl group of C 1 -C 4;
  • R 5 and R 6 together form -R"-OR"-, wherein said R" is none or a substituted or unsubstituted C 1 -C 4 alkylene group;
  • R 7 is a group selected from the group consisting of H, hydroxy, amino, substituted or unsubstituted C 1 -C 10 alkoxy, -COOR, substituted or unsubstituted C 2 -C 10 Acyl, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 2 -C 10 ester group; wherein R is selected from the group consisting of H, C 2 -C 4 acyl, substituted or not Substituted C 1 -C 4 alkyl;
  • n 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
  • one or more hydrogen atoms on the substituent group are substituted with a substituent selected from the group consisting of a carboxyl group, a phenyl group, a C 3 -C 6 cycloalkyl group, and a C 2 -C 10 ester.
  • a substituent selected from the group consisting of a carboxyl group, a phenyl group, a C 3 -C 6 cycloalkyl group, and a C 2 -C 10 ester.
  • a halogen a C 1 -C 10 alkyl-oxy group, a C 2 -C 10 acyl group, a hydroxyl group, a hydroxy-C 1 -C 10 alkylene group;
  • the R 3 is selected from the group consisting of H, halogen, oxygen atom, cyano group, hydroxyl group, carboxyl group, C 1 -C 4 alkyl group, C 1 -C 4 haloalkyl group;
  • R 4 is selected from the group consisting of H, halogen, oxygen atom, cyano group, hydroxyl group, carboxyl group, C 1 -C 4 alkyl group, C 1 -C 4 haloalkyl group;
  • R 3 and R 4 together constitute a group selected from the group consisting of a substituted or unsubstituted 3-8 membered heterocyclic ring, a substituted or unsubstituted 5-7 membered heteroaryl ring.
  • the A ring is selected from the group consisting of a substituted or unsubstituted 5-7 membered carbocyclic ring, a substituted or unsubstituted 5-7 membered heterocyclic ring, a substituted or unsubstituted 6 membered aromatic ring.
  • a substituted or unsubstituted 5-7 membered heteroaryl ring is selected from the group consisting of a substituted or unsubstituted 5-7 membered carbocyclic ring, a substituted or unsubstituted 5-7 membered heterocyclic ring, a substituted or unsubstituted 6 membered aromatic ring.
  • a substituted or unsubstituted 5-7 membered heteroaryl ring is selected from the group consisting of a substituted or unsubstituted 5-7 membered carbocyclic ring, a substituted or unsubstituted 5-7 membered heterocyclic ring, a substituted or unsubstit
  • R 7 is one or more groups selected from the group consisting of H, hydroxy, amino, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C Alkoxy group of 4 , -COOR; wherein R is selected from the group consisting of H, C 1 -C 4 acyl group, substituted or unsubstituted C 1 -C 4 alkyl group.
  • the R 3 is a C 1 -C 4 alkyl group or a C 1 -C 4 haloalkyl group
  • R 4 is selected from the group consisting of H and an oxygen atom
  • R 3 and R 4 together constitute a group selected from the group consisting of a substituted or unsubstituted furan ring, a substituted or unsubstituted dihydrofuran ring, a substituted or unsubstituted tetrahydrofuran ring.
  • the compound of formula I is selected from the group consisting of:
  • the effective amount of the compound of formula I in the pharmaceutical composition is from 0.1 to 50 mg/kg body weight, preferably from 1 to 20 mg/kg body weight.
  • the pharmaceutical composition is a dosage form selected from the group consisting of an oral dosage form and an injectable dosage form.
  • the pharmaceutical composition is also for inhibiting angiogenesis of hemangioendothelial cells.
  • FIG. 1 - Figure 3 Dihydrotanshinone I and propranolol at a corresponding drug concentration (3uM, 50uM) and fixed time (48h), cell apoptosis in a time- and concentration-dependent manner;
  • Figure 4 Protein results of apoptosis of dihydrotanshinone I and propranolol
  • tanshinone compounds have good hemangio cell inhibitory activity and are superior in activity to the conventional general drug propranolol.
  • the compounds inhibit proliferation of hemangio cells in vivo or in vitro in a time- and dose-dependent manner. Based on the above findings, the inventors completed the present invention.
  • C 1 -C 4 alkyl or “C 1 -C 10 alkyl” as used herein refers to a straight or branched alkyl group having from 1 to 4 or 1 to 10 carbon atoms, such as methyl, Ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like.
  • C 3 -C 6 cycloalkyl refers to a cycloalkyl group having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, methylcyclobutyl, cyclopentyl, or the like.
  • C 1 -C 10 acyl or “C 1 -C 4 acyl” refers to a straight or branched alkyl/cycloalkyl group having the form of 0 to 9 or 0 to 3 carbon atoms. Substituents for the /aryl-carbonyl" structure, such as acetyl, propionyl, butyryl, or the like.
  • C 2 -C 10 ester group refers to a substituent such as a "linear or branched alkyl/cycloalkyl/aryl-carbonyl-oxygen atom having 1 to 9 carbon atoms" structure, such as an acetyl group. , propionyl, butyryl, or the like.
  • C 1 -C 4 alkylene refers to a group formed after the C1 to C4 alkyl group has lost a hydrogen atom as described above, for example, -CH 2 -, -CH 2 -CH 2 -, or the like. .
  • halogen refers to F, Cl, Br and I.
  • C 6 -C 10 aryl refers to an aryl group having 6 to 10 carbon atoms, such as phenyl, naphthyl and the like.
  • C 1 -C 10 heteroaryl refers to a heteroaryl group having from 1 to 10 carbon atoms and one or more heteroatoms selected from O, S and/or N.
  • the terms "containing”, “comprising” or “including” mean that the various ingredients may be used together in the mixture or composition of the present invention. Therefore, the terms “consisting essentially of” and “consisting of” are encompassed by the term “contains.”
  • the term "pharmaceutically acceptable” ingredient means a substance which is suitable for use in humans and/or animals without excessive adverse side effects (such as toxicity, irritation, and allergic reaction), that is, a reasonable benefit/risk ratio.
  • the term "effective amount" means an amount of a therapeutic agent that treats, alleviates or prevents a target disease or condition, or an amount that exhibits a detectable therapeutic or prophylactic effect.
  • the precise effective amount for a subject will depend on the size and health of the subject, the nature and extent of the condition, and the combination of therapeutic and/or therapeutic agents selected for administration. Therefore, it is useless to specify an accurate effective amount in advance. However, for a given condition, routine experimentation can be used to determine the effective amount that the clinician can determine.
  • substituted means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, unsubstituted or halogenated C1-C6 alkyl, unsubstituted. Substituted or halogenated C 2 -C 6 acyl, unsubstituted or halogenated C1-C6 alkyl-hydroxy.
  • each of the chiral carbon atoms may be optionally in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.
  • compound of the invention refers to a compound of formula I.
  • the term also encompasses various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula I.
  • the term "pharmaceutically acceptable salt” refers to a salt of the compound of the invention formed with an acid or base suitable for use as a medicament.
  • Pharmaceutically acceptable salts include inorganic and organic salts.
  • a preferred class of salts are the salts of the compounds of the invention with acids.
  • Suitable acids for forming salts include, but are not limited to, mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzoic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.
  • mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid,
  • Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid,
  • Salvia miltiorrhiza is the root component of the plant of the Labiatae family. It is contained in the "Shen Nong's Herbal Classic” and is a commonly used traditional Chinese medicine for activating blood circulation, removing stasis and stasis.
  • a series of tanshinones were isolated from the fat-soluble extract of Salvia miltiorrhiza (tanshinone extract). In vitro activity screening showed that tanshinone compounds significantly inhibited the proliferation of hemangio cells (positive control: Propranolol) Among them, Dihydrotanshinone I (DHTS) is the most effective and superior to Propranolol in inhibiting hemangio cells.
  • DHTS Dihydrotanshinone I
  • the tanshinone compound of the present invention has a structure represented by the following formula:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are the corresponding groups in the specific compounds of the present invention.
  • Preferred tanshinone compounds of the invention include compounds selected from the group consisting of:
  • the compound of the present invention has excellent inhibitory activity against hemangio cells
  • the compound of the present invention and various crystal forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and compounds containing the present invention are mainly
  • the pharmaceutical composition of the active ingredient can be used for the treatment, prevention, and alleviation of diseases caused by hemangio cell production, such as fatty liver and the like.
  • compositions of the present invention comprise a safe or effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
  • safe and effective amount it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical compositions contain from 1 to 3000 mg (active dose range 3-30 mg/kg) of a compound/agent of the invention, more preferably from 10 to 2000 mg of a compound/agent of the invention.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By “compatibility” it is meant herein that the components of the composition are capable of intermingling with the compounds of the invention and with each other without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid).
  • magnesium stearate magnesium stearate
  • calcium sulfate vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier (such as Tween ), a wetting agent (such as sodium lauryl sulfate), a coloring agent, a flavoring agent, a stabilizer, an antioxidant, a preservative, a pyrogen-free water, and the like.
  • vegetable oil such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyol such as propylene glycol, glycerin, mannitol, sorbitol, etc.
  • emulsifier such as Tween
  • a wetting agent such as sodium lauryl sulfate
  • a coloring agent such as a flavoring agent, a stabilizer, an antioxidant, a preservative
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration. .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) Absorbing accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethyl
  • compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for the compounds of the invention for topical administration include ointments, powders, patches, propellants and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or, if necessary, propellants.
  • the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight
  • the dose to be administered is usually from 1 to 2000 mg, preferably from 6 to 600 mg.
  • specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
  • the tanshinone compound of the present invention can effectively inhibit hemangio cells to promote apoptosis, and can also inhibit angiogenesis of hemangioendothelial cells;
  • the compound of the present invention is effective in vitro and in vivo, and has a low active dose, and can exhibit an antitumor effect at a dose as low as 10 mg/kg, which is far lower than the effective dose of propranolol.
  • Nuclear magnetic resonance spectrum Varian INOVA 600 nuclear magnetic resonance spectrometer, Bruker AM-500, AM-400, AM-300 nuclear magnetic resonance spectrometer, ⁇ (ppm), with TMS as internal standard;
  • Analytical HPLC Waters 2690 Separate Model, Waters PDA 996 detector coupled Alltch ELSD 2000 detector, Millennium 2000 operating system, Waters RP18 column (5.0 x 125 mm, 5 ⁇ m, Waters), flow rate 1.0 ml/min, CH3CN (Merck, Germany) , H2O (Rapex); Jasco HPLC (Chiralcel IA column, 5 ⁇ m, 150 ⁇ 4.6 mm), flow rate 0.6 ml / min, hexane / ethanol (7:3).
  • HPLC-MS Waters 2695 Separate Model, Waters PDA 2998 detector coupled with Alltch ELSD 2424 detector, 3100 Ms detector, SunFireTM C-18 column (4.6 x 100 mm, 3.5 ⁇ m, Waters), flow rate 1.0 ml/min, CH3CN (Merck, Germany) , H2O (Rapex); Jasco HPLC (Chiralcel IA column, 5 ⁇ m, 150 ⁇ 4.6 mm), flow rate 0.6 ml / min, hexane / ethanol (7:3).
  • TLC thin layer preparation board HSGF254 is produced by Yantai Chemical Plant;
  • MCI resin CHP20P (75-150 ⁇ m) is produced by Mitsubishi Corporation;
  • Color developing agent 10% sulfuric acid-vanillin solution, potassium permanganate aqueous solution;
  • Main biological reagents 1640 medium, fetal bovine serum (Gibco, USA); double antibody (Sigma, USA); antibody: Caspase 3, Caspase 8, Caspase 9, AIF, PARP, Bax, FADD, Cyst3 (Abclonal/China Cyclodextrin (Medchem, USA); Flow Apoptosis Fluorescent Reagent (FITC-Annexin, PI) (BD, USA); Matrigel (Corning, USA); Western Blot Glue Reagent, Secondary Antibody, CCK8 Reagent, Enhanced chemiluminescence agent, Tween-20 and crystal violet ( ⁇ / ⁇ ); protease inhibitor (Roche, Switzerland); experimental animals are nude mice, weighing 20 ⁇ 5g, purchased from Xinhua Hospital affiliated to Shanghai Jiao Tong University, animals are stored in Xinhua Hospital SPF animal room.
  • fraction S6 (4.32g) was subjected to silica gel column chromatography (petroleum ether: ethyl acetate 100:3 to 10:1) to obtain 5 fractions of S6A-S6E; fraction S6A (152mg) was subjected to Sephadex LH-20 gel column chromatography. (Chloroform: methanol 1:1) and then purified by preparative silica gel plate (dichloromethane) to obtain the compound Danshenxin (5 mg); fraction S6C (311 mg) was subjected to ODS column chromatography (methanol-water, 65%-95) %) Purified compound saponin ⁇ A (10 mg).
  • the 800 mg fraction S10 (6.5 g) was separated by ODS column chromatography (methanol-water, 65%-95%), and the fraction S10C was purified by preparative silica gel plate (dichloromethane) to give the compound isopropyl orthophenanthrene. ⁇ (10mg).
  • Fraction S13 (10.89 g) was recrystallized from petroleum ether-ethyl acetate to give tanshinone I (3.2 g).
  • Fraction S14 (17.72 g) was recrystallized from petroleum ether-ethyl acetate to afford ss.
  • Fraction S15 (3.61g) was separated by silica gel column chromatography (petroleum ether: acetone 30:1 to 0:1) to obtain 5 fractions S15A-S15E; 25mg of S15D was passed through Sephadex LH-20 (chloroform:methanol 1:1) Column gel chromatography gave the compound tanshinone methyl ester (15 mg).
  • the fraction obtained by purifying the fraction S16 (20 g) through a silica gel column (petroleum ether: acetone 100:3 to 100:10) was subjected to MCI column chromatography (ethanol-water 80% to 95%) and Sephadex LH-20 (chloroform:methanol 1).
  • Tanshinone IIA Tanshinone IIA, cherry red needle crystal.
  • Example 2 Cell proliferation inhibitory activity of tanshinones on hemangio cells
  • the EOMA cell line originated from the spontaneous hemangio cells of the 129/J line.
  • the cell culture was carried out in 1640 medium containing 10% fetal calf serum, and mixed with 100 mg/l of penicillin and 100 ug/l of streptomycin.
  • the cells were cultured in an incubator containing 5% CO 2 at 37 °C. The medium was changed every other day and passage was carried out at a cell density of 80%.
  • Dissolution of the drug The drug powder was dissolved in DMSO, stored at a concentration of 10 uM, and stored at -20 degrees.
  • CCK8 detection IC 50 Before dosing treatment, the cells were plated in a 96-well plate, and the cells were counted so that the cell concentration of each well reached 2000-3000/ul. After the cells were attached, the medium was aspirated and added. Different concentrations of dihydrotanshinone I. After 72 h, the medium containing the drug was aspirated, cck8 was added, and three blank control wells were set at the same time, and the absorbance at 450 wavelength was measured around 2 h.
  • the cell proliferation inhibitory activity of the tanshinone compound on hemangio cells is shown in Table 1 below.
  • the activity test results showed that the tanshinone compound can significantly inhibit the proliferation of hemangio cells.
  • Table 1 Inhibitory activity of tanshinones on proliferation of hemangio cells
  • Example 3 Effect of dihydrotanshinone I on apoptosis of hemangio cells
  • Cell clone formation experiment 1000 cells / 2 ml cells were added to a six-well plate. After the cells were attached to the cells, different drug concentrations were added for treatment. The blank group was treated with DMSO (solvent) for comparison. (24h, 48h), replaced with fresh medium, and after 10 days, the crystals were stained and photographed.
  • DMSO solvent
  • test results are shown in the following figure 1-3: dihydrotanshinone I and propranolol at the corresponding drug concentration (3uM, 50uM) and fixed time (48h), cell apoptosis time and concentration-dependent, analysis of variance The results suggest that the difference is statistically significant.
  • DHTS can act on hemangio cells through FAS/FASL and mitochondrial pathways at the same time.
  • the mitochondrial pathway is dominant at low concentrations, and the FASL pathway is dominant at high concentrations.
  • PropranololZ is at low concentrations.
  • the FASL pathway is dominant, and the mitochondrial pathway is dominant at high concentrations.
  • Example 4 Tube formation observes the effect of drugs on cell formation:
  • the unsolidified Matrigel was placed on a 96-well plate in an amount of 10 ul per well, and the 96-well plate was placed in an incubator for 1 h to completely coagulate the colloid.
  • EOMA cells (3 ⁇ 10 4 /well) were added to the 96-well plate, and The medium with or without drug was placed on the surface of the colloid and cells, and was placed in the incubator. After 2 hours, it was observed under a microscope and photographed and retained.
  • the tube-forming experiment reflects the angiogenesis of cells in vivo, including the action of vascular endothelial growth factor (VEGF), the degradation of intercellular matrix (mmp9), and the migration of endothelial cells.
  • VEGF vascular endothelial growth factor
  • mmp9 intercellular matrix
  • Example 5 In vivo experiments in animals to explore the effect of drugs on hemangioma
  • the body weight of nude mice 4 weeks later, the nude mice were sacrificed, the tumor was cut and measured, and some tissues were immunohistochemically analyzed for changes in CD31, CD34, vWF, Glut1, Caspase3, MMP9 and VEGFR2.

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Abstract

L'invention concerne l'utilisation d'une classe de composés de tanshinone pour traiter un hémangiome ; en particulier, l'invention concerne l'utilisation d'une classe de composés tels que représentés dans la formule I ci-dessous ou un sel pharmaceutiquement acceptable de ceux-ci. Les composés de tanshinone ont une activité inhibitrice des cellules d'hémangiome et peuvent être utilisés pour préparer une composition pharmaceutique pour traiter un hémangiome.
PCT/CN2018/105278 2017-09-12 2018-09-12 Composé de tanshinone et son utilisation pour traiter un hémangiome Ceased WO2019052477A1 (fr)

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