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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
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  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/81—Amides; Imides
  • C07D213/82—Amides; Imides in position 3
• • C—CHEMISTRY; METALLURGY
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  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

• the invention belongs to the technical field of medicine and relates to a series of Combretastatin A4 derivatives and preparation methods thereof, and the use thereof in the preparation of tubulin inhibitors. Background technique
• the Combretastatins series of compounds were originally extracted from the trunk of Combretum caffrum in South Africa. It has anti-tumor activity and can directly act on endothelial cells to induce proliferation of endothelial cells, thereby inhibiting tumor angiogenesis and achieving tumor elimination.
• the Combretastatins series of compounds have a cis 1,2-stilbene structure.
• combretastatin A-4 [CA-4, Compris, cis-1 -(3,4,5-trimethoxy)phenyl-2-(3'-hydroxy-4'-methoxy)benzene Ethylene has the strongest inhibition of microtubule polymerization (Pettit G, et al. J. Med.
• CA-4 as a tumor vascular targeting agent, has shown its excellent properties for blocking tumor blood vessels (Thorpe PE. Clin Cancer Res. 2004 Jan 15, 10(2): 41 5-27; West CM, Price P Anticancer Drugs. 2004 Mar, 15(3): 179-87; Young SL, Chaplin DJ. Expert Opin Invest ig Drugs. 2004 Sep, 13(9): 1 171-82 ⁇ ).
• Oxigene, Inc. of the United States has used CA-4 as a new anti-tumor drug and has entered Phase III clinical studies.
• Ajinomoto Co., T. Hatanaka et al. found that the modification of the hydroxyl group at the 3' position of CA-4 to an amino group greatly improved the anticancer activity (USP5674906).
• the Combretastatins series of compounds are poorly water soluble, which limits their clinical application.
• the usual method of converting CA-4 to its phosphate after the conversion of the hydroxyl group at the 3' position of CA-4 to an amino group is not applicable.
• Ajinomoto has modified amino CA-4 with amino acids, it has increased its water solubility, making it an injection for cancer patients.
• the present invention provides a novel amino CA-4 derivative which is absorbed through the digestive tract and transmitted to various parts of the body through blood, and has a certain therapeutic effect on various tumors, particularly liver cancer and colon cancer. Summary of the invention
• the present invention provides a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof:
• R 1 is independently selected from the group consisting of a fluorenyl group of a d-Cg, a halogenated fluorenyl group;
• R 2 is independently selected from the group consisting of hydrogen, methyl, ethyl, and halogen
• R 3 is a heterocyclic or heterocyclic fluorenyl group containing one or more hetero atoms which may be optionally substituted, wherein at least one of the hetero atoms is N.
• R 1 is independently selected from the group consisting of a fluorenyl group of a d-Cg, a halogenated fluorenyl group;
• R 2 is independently selected from the group consisting of hydrogen, methyl, ethyl, and halogen
• R 4 is independently selected from the group consisting of hydrogen, dC 3 fluorenyl, halo fluorenyl, cyclodecyl, aryl, heterocyclic aryl, heterocycloalkyl, decanoyl, decyloxycarbonyl;
• R 5 is independently selected from the group consisting of hydrogen, thiol, fluorenyl, cyclodecyl, decyloxy, alkenyl, alkynyl, hydroxy, decyl, amino, nitro, cyano, NR a R b , N d C (O c , C(O)NR a R b , S(O) 2 NR a R b , N d S(O) 2 c , NR d (CH 2 ) n R c , (CH 2 ) n NR a R b , NHC(O)NH R c , (CH 2 ) n NHC(O)R
• R a , R b are each independently selected from hydrogen, fluorenyl, cyclodecyl, or may form a 5, 6 or 7 membered heterocyclic or heterocyclic fluorenyl group with the N, O, S atom;
• R e is independently selected from the group consisting of an indenyl group, a cycloalkyl group, an aryl group, a heterocyclic aryl group, a heterocyclic fluorenyl group;
• R d is independently selected from the group consisting of hydrogen, fluorenyl, cyclodecyl, aryl, heterocyclic aryl;
• the compound of the formula (I) of the present invention may be a pharmaceutically acceptable inorganic or organic acid, including a mineral acid: hydrochloric acid, in a pharmaceutically acceptable salt, or an acid containing at least one basic salt-forming group. , sulfuric acid, phosphoric acid; organic carboxylic acid: acetic acid, propionic acid, trifluoroacetic acid, glycolic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, oxalic acid, various natural or synthetic amino acids , benzoic acid, salicylic acid, 4-aminosalicylic acid, mandelic acid, cinnamic acid, nicotinic acid, isonicotinic acid; organic sulfonic acid: methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, 2-hydroxyethyl Sulfonic acid, benzenesulfonic acid, p-tol
• the compounds of the invention and pharmaceutically acceptable salts also include the solvates or hydrates.
• the solvate or hydrate form is equivalent to the unsolvated or non-hydrated form and is intended to be encompassed within the scope of the invention.
• Some of the compounds of the present invention are likely to exist in a polycrystalline or amorphous form. In general, all physical forms have equivalent utility and are encompassed within the scope of the invention.
• the invention encompasses all stereoisomers of the compounds of the invention in admixture or in pure form.
• the definition of a compound of the invention encompasses all possible stereoisomers and mixtures thereof. It very specifically comprises a racemic form and an isolated optical isomer having a specific activity.
• the racemic form can be resolved by physical methods such as fractional crystallization of the diastereomer derivatives, separation or separation by chiral column chromatography.
• the individual optical isomers can be obtained from the racemate by conventional methods such as the formation of a salt followed by crystallization of the optically active acid form.
• the invention also provides a process for the synthesis of a compound of formula (I).
• the process is as follows:
• the synthesis method of the present invention obtains the corresponding phosphorus salt by reacting the bromination of the compound vn with triphenylphosphine, and then reacting the phosphorus salt with the compound to obtain the cis stilbene structure (IV) o
• the styrene is reduced to an amino group by using dibromodioctylbipyridine and metal ruthenium powder as a reducing agent to obtain an amino group.
• the invention further relates to a pharmaceutical composition
• a pharmaceutical composition comprising an effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier, which composition is suitable for topical, enteral or parenteral administration, and may be inorganic or organic , solid or liquid.
• a pharmaceutically acceptable carrier for oral administration, especially tablets or capsules.
• the tablet or capsule contains the active ingredient and a diluent (eg lactose, glucose, sucrose, mannitol, sorbitol, fiber) , glycerol), lubricants (such as talc, stearate), polyethylene glycol.
• a diluent eg lactose, glucose, sucrose, mannitol, sorbitol, fiber
• glycerol e.glycerol
• lubricants such as talc, stearate
• polyethylene glycol e.glycerol
• the tablet may further comprise a binder, starch, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and if necessary, a pulverizing agent (such as starch, agar, alginic acid and Salt), effervescent mixture, or adsorbent, dye, flavoring, sweetener.
• pulverizing agent such as starch
• Such dosage forms are preferably isotonic aqueous solutions or emulsions, such as in the case of lyophilized compositions consisting only of the active ingredient and a carrier such as mannitol, such solutions may be prepared before use.
• These pharmaceutical compositions may be sterile, or contain excipients, or dosing, adjusting the osmotic pressure
• the invention further relates to the use of a compound of formula (I) for the manufacture of a medicament for the treatment of a disease caused by abnormal neovascularization.
• Diseases caused by abnormal neovascularization include various tumors, including: lung cancer, small cell lung cancer, liver cancer, pancreatic cancer, gastric cancer, bone cancer, esophageal cancer, breast cancer, kidney cancer, cholangiocarcinoma, prostate cancer, testicular cancer, colon Cancer, ovarian cancer, bladder cancer, cervical cancer, bronchial carcinoma, melanoma, adenocarcinoma, sweat gland cancer, papillary carcinoma, papillary adenocarcinoma, squamous cell carcinoma, basal cell carcinoma, cystic adenocarcinoma, glioma , astrocytoma, medulloblastoma, neuroblastoma, craniopharyngioma, ependymoma, pineal tumor, hemangioblastom
• Diseases caused by abnormal neovascularization include: rheumatoid arthritis, diabetic retinopathy, precocious retinopathy, retinal vein occlusion, psoriasis, rosacea, Kaposi's sarcoma, specific reactive keratitis, epidemic keratoconjunctivitis, Neovascular glaucoma, bacterial ulcer, fungal ulcer, herpes simplex infection, herpes zoster infection, protozoal infection, mycobacterial infection, polyarteritis, sarcoidosis, scleritis, flushing, dry mouth arthritis Syndrome, systemic lupus erythematosus, AIDS syndrome, syphilis.
• the invention also relates to the use of a compound of formula (I) for the preparation of a tubulin aggregation inhibitor.
• the invention also provides an animal test method by which a compound can be verified (I) Absorption in animals and ability to inhibit tumors. detailed description
• mercapto refers to a straight or branched unsubstituted hydrocarbon group having from 1 to 20 carbon atoms, preferably from 1 to 6 carbon atoms, especially methyl, ethyl, propyl ( Including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, t-butyl) and the like.
• alkenyl refers to a hydrocarbon group having one or more carbon-carbon double bonds, such as ethenyl, propenyl, 1,3-butadiene, cis-butene, anti-butene, and the like.
• alkynyl refers to a hydrocarbon radical having one or more carbon-carbon triple bonds, such as ethynyl, propynyl, and the like.
• halogen or “halo” refers to fluoro (fluoro), chloro (chloro), bromo (bromo), iodine (iodo).
• aryl refers to a monocyclic or polycyclic aromatic hydrocarbon such as benzene, naphthalene, anthracene, phenanthrene, and the like.
• heterocyclic aryl refers to an optionally substituted aromatic cyclic group wherein at least one carbon atom is replaced by another heteroatom, and the hetero atom includes nitrogen, oxygen, sulfur.
• the nitrogen and sulfur heteroatoms may also optionally be oxidized, and the nitrogen heteroatoms may also optionally be quaternized.
• the heterocyclic group can be attached at any hetero atom or carbon atom.
• Preferred heterocyclic aryl groups include, but are not limited to, pyridine, pyrazine, pyrimidine, pyridazine, triazine, furan, thiophene, imidazole, triazole, tetrazole, thiazole, isothiazole, pyrrole, pyrazole, oxazole, iso Oxazole, benzofuran, benzothiazole, benzothiophene, anthracene, quinoline, isoquinoline, indole, oxazole, benzimidazole, pyrrolopyridine, pyrrolopyrimidine, and the like.
• cycloalkyl refers to a non-aromatic carbocyclic ring, including monocyclic, fused or spiro rings.
• the cyclic fluorenyl group also includes a ring having one or more aromatic rings fused (ie, having a common bond), and the fluorenyl group having one or more aromatic rings fused through the aromatic ring or the non-aromatic ring moiety and other groups The group is connected.
• heterocyclic fluorenyl refers to a non-aromatic heterocyclic ring wherein one or more of the ring-forming atoms are heteroatoms such as oxygen, nitrogen, sulfur.
• Heterocyclic fluorenyl groups may include monocyclic or polycyclic (eg, 2, 3, 4 fused rings), spiro rings.
• Preferred heterocyclic fluorenyl groups include aziridine, azetidinium, tetrahydrofuran, tetrahydrothiophene, pyridyl Rhodium, oxazolidine, thiazolium, isothiazolium, imidazolium, pyrazolium, morpholine, thiomorpholine, piperazine, piperidine, and the like.
• Heterocyclic fluorenyl also includes heterocyclic rings having one or more aromatic rings fused, such as 2,3-dihydrobenzofuran, 1,3-benzodioxolane, benzo-1,4-dioxin Bismuth, phthalic acid amide, etc.
• a heterocyclic fluorenyl group having one or more aromatic rings fused may be bonded to other groups through an aromatic ring or a non-aromatic ring moiety.
• cyano refers to the group -CN.
• nitro refers to the group -NO 2 .
• mercapto refers to the group -SH.
• decyloxy refers to the group -OR 7 wherein R 7 refers to fluorenyl.
• pharmaceutically acceptable carrier includes all core solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like.
• the use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agent is incompatible with the active ingredient, its use in therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
• Example 5 (Z)-l-(345-Trimethoxyphenyl)-2-(3-(N-methylpiperidino-4-formyl)amino 4-Trifluoroethoxyphenyl)ethylene
• Example 6 (Z)-l-(345-Trimethoxyphenyl)-2-(3-(N-ethylpiperidin-4-yl)amino 4-methoxyphenyl) Ethylene
• Example 7 (Z)-l-(345-Trimethoxyphenyl)-2-(3-(N-hydroxymethylpiperidin-4-yl)amino- 4-methoxyphenyl)ethylene
• Example 8 (Z)-l-(345-Trimethoxyphenyl)-2-(3-(N-hydroxyethylpiperidine-4-formyl)ammonia Benzyl-4-methoxyphenyl)ethylene
• Example 9 (Z)-l-(345-Trimethoxyphenyl)-2-(3-(
• the present invention provides a formulation of a pharmaceutical composition for several diseases associated with dysplasia of neovascularization, the pharmaceutical composition of which is mainly an oral preparation such as a tablet or a capsule.
• the compound represented by the present invention is represented by "active compound”.
• the cells were cultured in a culture medium containing 10% fetal bovine serum to keep the cells in the logarithmic growth phase.
• the cells were seeded in a 96-well plate at a density of 4-7 X l OVmK HUVEC at a density of 3 X 10 4 /ml.
• a 5 % CO 2 incubator was pre-incubated for 24 hours, and the drug was set at 6 concentrations, each concentration. Two double holes were set and acted continuously for 72 hours. After the end of the drug, the cells were fixed with trichloroacetic acid, washed and added to the SRB working solution.
• the positive control drug selected CA-4.
• the cell growth inhibition rate was calculated based on the OD value.
• Inhibition rate (%) (control group OD value - medication group OD value) / control group OD value 100
• IC 5Q values were calculated by Logitech method according to the inhibition rate of cells on cell growth at different concentrations.
• EACA is the compound described in Example 1 of the present invention.
• the compounds of the present invention have obvious anti-tumor activity against a variety of tumor cells cultured in vitro; and have significant inhibitory effects on the proliferation of human umbilical vein endothelial cells; EACA inhibition is significantly stronger than the positive control CA-4.
• Example 33 Efficacy experiment of nude mice xenografts
• mice BALB/cA-nude nude mice, 6-7 weeks, ⁇ , purchased from Shanghai Slack Laboratory Animals Co., Ltd.
• the nude mice were subcutaneously inoculated with human hepatoma Bel-7402 cells, colon cancer HT-29 cells, gastric cancer SGC-7901 cells and non-small cell lung cancer A549 cells. After the tumors were grown to 100-250 mm 3 , the animals were randomly divided into groups (d0). . The tumor volume was measured 2-3 times a week, the rats were weighed, and the data were recorded.
• the tumor volume (V) is calculated as:
• V l/2xaxb2 where a and b represent length and width, respectively;
• T/C(%) (T-T0)/(C-C0) l 00
• T and C are the tumor volumes at the end of the experiment
• T0 and CO are the tumor volumes at the beginning of the experiment.
• the samples tested were each diluted to the desired concentration with 50% PEG 400 distilled water.
• the method of administration was once a day, and it was administered by intragastric administration for 21 days.
• Therapeutic effects of the compounds shown in Examples 1, 3, 4, 17, 23 on nude mice xenografts of human liver cancer Bel-7402, colon cancer HT-29 cells, gastric cancer SGC-7901 cells and non-small cell lung cancer A549 cells The test was carried out, and the results are shown in Table 2.
• the compound of the present invention can significantly inhibit the growth of human liver cancer Bel-7402, colon cancer HT-29 cells, gastric cancer SGC-7901 cells and non-small cell lung cancer A549 cells in nude mice under the conditions of intragastric administration. .

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