Classifications

• • 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
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
  • C07J1/0051—Estrane derivatives
  • C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
  • C07J1/007—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
  • C07J1/0074—Esters
• • 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
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
  • A61P5/32—Antioestrogens
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
  • C07J1/0051—Estrane derivatives
  • C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
  • C07J1/007—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
  • C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003

Definitions

• the invention belongs to the field of medicine, and particularly relates to a preparation method of the compound of the general formula A, in particular, to 7- ⁇ -[9-(4, 4, 5, 5, 5-pentafluoropentylsulfinyl) hydrazine.
• estrogen receptors are found on tumor cells in many breast cancer patients, and that tumor growth is stimulated by estrogen, thereby reducing the concentration of estrogen or blocking the binding of estrogen to its receptor. It can inhibit the growth and reproduction of tumor cells and is one of the main methods for the treatment of breast cancer. Fulvestrant can compete with the estrogen receptor for similarity, and its affinity is similar to that of estradiol; it can also block receptors, inhibit estrogen binding, stimulate morphological changes in receptors, reduce ER concentration and damage tumors. cell. Fulvestrant can down-regulate ER protein in human breast cancer cells, and down-regulate ER in tumor cells to minimize tumor growth.
• fulvestrant is poorly stable and is an easily degradable drug. It is generally stored at -20 ° C. It should not be too long at normal temperature, otherwise it will affect its purity. Its down The mechanism of the solution is unclear. It is generally believed that the main reason for its stability is the presence of -OH at the C-3 and C-17 positions. At the same time, the presence of -OH at the 3-, 17-position increases the polarity of the drug, increases the stimulation of the drug to the gastrointestinal tract, and can only be used as an injection.
• fulvestrant has certain physical properties that are difficult to formulate, a particularly lipophilic molecule with minimal water solubility of about 10 ng/mL.
• Solubility (mg/mL, 25 °C) is given in US5183514 and CN1394141A (water 0.001, peanut oil 0.45, sesame oil 0.58, castor oil 20, Migloyl 810 3.06, Migloyl 812 2.72, ethyl oleate 1.25, benzyl benzoate Ester 6.15, isopropyl myristate 0.80, Span 85 3.79, ethanol > 200, phenyl decyl alcohol > 200).
• the object of the present invention is to improve the -OH at the C-3 position and the C-17 position in the fulvestrant structure to esterify it into an ester having 2 to 22 carbon atoms at the C-17 position.
• the present invention provides a compound represented by the following formula A,
• the substituent R' is selected from the group consisting of H, an alkanoyl group having 2 to 4 carbon atoms and an enoyl group,
• the substituent R is selected from the group consisting of H, an alkanoyl group having 2 to 22 carbon atoms and an enoyl group.
• the substituent R' is H, and the substituent R is selected from the group consisting of alkanoyl and enoyl groups having from 11 to 22 carbon atoms;
• the substituent R is selected from alkanoyl groups having from 11 to 22 carbon atoms, preferably undecanoyl, hexadecanoyl, dodecanoyl or 2-[(3', 3')-dioxin ⁇ - ⁇ -fluorenyl]butyl-5-mercapto-(7,7)-dimercapto-octanoyl.
• the substituent R is selected from an enoyl group having 1 to 6 carbon-carbon double bonds and having 11 to 22 carbon atoms, wherein the carbon-carbon double bond may be distributed in the main chain or may be distributed in the branch. On the chain; preferably,
• the substituent R is selected from the group consisting of undec-2-enoyl, eicos-(5, 8, 11, 14, 17)-pentenoyl and docosa- (4, 7, 10, 13, 16, 19) -hexaenoyl.
• the substituent R' is selected from alkanoyl groups having 2 to 4 carbon atoms, it is an acetyl group or a butyryl group.
• the substituent R' is selected from alkanoyl groups having 2 to 4 carbon atoms, it is an acetyl group or a butyryl group.
• the substituent R is selected from alkanoyl and enoyl groups having from 11 to 22 carbon atoms, preferably 2-[(3',3')-dimercapto-indenyl]butyl-5-anthracene Base - (7,7)-dimercapto-octanoyl or undec-2-enoyl.
• the compound may have a structure represented by the following formula, and the structural formula of fluviglicine I to XI is shown below:
• the present invention provides a method of preparing the above compound, the method comprising the steps of:
• acylation of -OH at the C-17 position of the compound of formula B The compound of formula B is stirred with an alkaline reagent, an organic acid, and a catalyst in a solvent at room temperature to form a reaction mixture, and the reaction is carried out to obtain a formula A.
• Formula B b) purifying the crude product obtained in the step a), removing the by-product hydrazine, hydrazine-bicyclic urea, to obtain an acylated purified product at the C-17 position of the compound of the formula;
• the method further comprises the step c) performing the acyl-purified product at the C-17 position prepared in the step b) at the C-3 position.
• the acylated purified product at the C-17 position prepared in the step b) is stirred with a basic reagent, an organic acid and a catalyst in a solvent at room temperature to obtain a compound C-17 and C- of the formula A.
• step a) Purifying the crude product obtained in step c) to obtain a purified product of the compound of formula A.
• the alkaline reagent is selected from the group consisting of pyridine, 2-mercaptopyridine, 3-mercaptopyridine, 4-mercaptopyridine, 2-ethylpyridine, 3-ethylpyridine, 4-ethylidene Pyridine, 5-ethylpyridine, 2-mercapto-5-ethylpyridine, 2-diaminopyridine, 4-diaminopyridine, preferably selected from 4-diaminopyridine;
• the solvent is selected from the group consisting of Chlorodecane, dichlorodecane, trichloromethane;
• the catalyst is a dehydrating agent, preferably N, N-dicyclohexylcarbodiimide;
• the organic acid is an alkane having 2 to 22 carbon atoms a base acid or an olefinic acid; in the step b), the pur
• the alkaline reagent is selected from the group consisting of pyridine, 2-mercaptopyridine, 3-mercaptopyridine, 4 - mercaptopyridine, 2-ethylpyridine, 3-ethylpyridine, 4-ethylpyridine, 5-ethylpyridine, 2-mercapto-5-ethylpyridine 2-diaminopyridine, 4-diaminopyridine, preferably selected from 4-diaminopyridine;
• the solvent is selected from tetrahydrofuran, ethyl acetate, preferably tetrahydrofuran;
• the catalyst is a dehydrating agent, preferably N, N-dicyclohexylcarbodiimide;
• the organic acid is an alkyl acid or an alkenoic acid having 2 to 4 carbon atoms; in step d), the purification is performed
• the present invention provides a composition comprising the compound of the above formula A, wherein the composition is an oil agent, a fat agent or a microsphere.
• the present invention provides a use of a composition comprising a compound of the above formula A or a compound comprising the formula A for the preparation of a medicament for the treatment of cancer; the medicament preferably for inhibiting cancer with an estrogen receptor
• the cells are particularly preferably used for inhibiting breast cancer cells.
• the invention also provides a method for treating cancer, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula A as described above;
• a method of inhibiting breast cancer cells is particularly preferred; preferably, the compound of formula A is administered by injection.
• the compound of the present invention is prepared as an oily agent, it is injected subcutaneously into a mouse bearing human breast cancer MCF-7 tumor, and the tumor inhibition rate is examined. The results show that the derivative has anticancer activity and is used for Treatment of breast cancer. detailed description
• alkaline agent selected in the following examples is 4-diaminopyridine
• pyridine, 2-mercaptopyridine, 3-mercaptopyridine, 4-mercaptopyridine, 2-ethyl may also be used.
• a reagent such as pyridine, 3-ethylpyridine, 4-ethylpyridine, 5-ethylpyridine, 2-mercapto-5-ethylpyridine or 2-diaminopyridine is used as an alkaline reagent in the following examples. .
• Example 1 Synthesis and Structure Confirmation of Compound II
• the reaction solution was filtered to remove the precipitated by-product N, N, -dicyclohexylurea (DCU).
• the filtrate was washed with saturated sodium hydrogen carbonate solution, washed with water until neutral, and the solvent was evaporated to remove the solvent.
• the gelatinous liquid was 8.8 g, which was dissolved in an appropriate amount of ethyl acetate, and frozen in a refrigerator (for example, a freezing temperature of -15 ⁇ 3 ° C), and a small amount of a white solid was washed out and removed by filtration, and this was repeated three times. Thereafter, the filtrate was evaporated to remove ethyl acetate to give a colorless, transparent, gelatinous liquid.
• the colorless transparent liquid was dissolved in a small amount of tetrahydrofuran, and added to n-hexane to form a large amount of white solid, which was allowed to stand and filtered.
• the filter cake was repeatedly dissolved in the above tetrahydrofuran and n-hexane sedimentation method three times to obtain a white powdery product.
• Pure compound II dried under vacuum at 60 ° C to obtain 1.5 g II (HPLC purity: 99.88%, C18 column, mobile phase 67% aqueous THF, flow rate 1.0 mL/min, detection wavelength 220 nm), molar yield 22% .
• the reaction system was first frozen, and the by-product DCU of the reaction was precipitated as much as possible.
• the solid of DCU was filtered off, the filtrate was washed with saturated sodium bicarbonate solution, washed with water until neutral, and dichloromethane was removed by rotary evaporation to obtain a colorless transparent gel. Liquid.
• the gelatinous liquid is dissolved in a small amount of ethyl acetate and frozen in a refrigerator (for example, the freezing temperature may be -15 ⁇ 3 ° C) until no white solid DCU is precipitated.
• the reaction liquid was treated in the same manner as in the post-treatment method of Example 2 to obtain a white solid powder.
• the reaction solution was treated with reference to the post-treatment method in Example 2 to give a colorless gum.
• the reaction mixture was treated with reference to the post-treatment method of Example 2 to give a pale-yellow oil.
• the purity was 96.010%) (Methods refer to Example 3), that is, Compound V, the yield was 21.5%.
• the reaction solution was treated in the same manner as in the after-treatment of Example 8 to obtain a milky white gummy liquid, i.e., Compound IX.
• the reaction solution was treated in the same manner as in the post-treatment of Example 8 to obtain a milky white gummy liquid, i.e., Compound X.
• Test drug fulvestrant and compound II and X are prepared by dispersing in oil and sterilizing to prepare an oil.
• Negative control group is blank solvent (oil), single subcutaneous injection

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• Health & Medical Sciences (AREA)
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• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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• Diabetes (AREA)
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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 2013
  • 2013-04-18 US US14/781,650 patent/US20160060288A1/en not_active Abandoned
  • 2013-04-18 WO PCT/CN2013/074363 patent/WO2014169462A1/zh not_active Ceased
  • 2013-04-18 CA CA2909418A patent/CA2909418A1/en not_active Abandoned
  • 2013-04-18 KR KR1020157033007A patent/KR102046415B1/ko not_active Expired - Fee Related
  • 2013-04-18 EP EP13882193.9A patent/EP2987799B1/en active Active
  • 2013-04-18 JP JP2016507969A patent/JP6356218B2/ja not_active Expired - Fee Related
  • 2013-04-18 CN CN201380069374.2A patent/CN104936971B/zh active Active
  • 2013-04-18 AU AU2013386732A patent/AU2013386732B2/en not_active Ceased

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