WO2014108066A1 - 氨基康普立停衍生物的合成及其作为口服抗肿瘤药物的应用 - Google Patents

氨基康普立停衍生物的合成及其作为口服抗肿瘤药物的应用 Download PDF

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WO2014108066A1
WO2014108066A1 PCT/CN2014/070286 CN2014070286W WO2014108066A1 WO 2014108066 A1 WO2014108066 A1 WO 2014108066A1 CN 2014070286 W CN2014070286 W CN 2014070286W WO 2014108066 A1 WO2014108066 A1 WO 2014108066A1
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acid
group
amino
cancer
trimethoxyphenyl
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PCT/CN2014/070286
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English (en)
French (fr)
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王建平
王建国
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浙江大德药业集团有限公司
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • 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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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • 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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    • C07D213/04—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
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    • 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
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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. .

Abstract

本发明公开了式（Ⅰ）所示的用于抑制肿瘤新生血管生成的化合物、及其可药用盐或其构型异构体。其中取代基 R1、 R2、 R3 如说明书中所定义。本发明还公开了包括所示式（Ⅰ）化合物的制备方法、药物组合物，以及这些化合物作为微管蛋白抑制剂在抑制肿瘤新生血管方面的用途，尤其是作为口服制剂方面的应用。

Description

氨基康普立停衍生物的合成及其作为口服抗肿瘤药物的应用 技术领域
本发明属于医药技术领域， 涉及一系列的康普立停（Combretastatin ) A4 衍生物及其制备方法， 及其在制备微管蛋白抑制剂中的用途。 背景技术
Combretastatins系列化合物最初是从南非 Combretum caffrum树干中提 取分离得到的。 它具有抗肿瘤活性， 可以直接作用于内皮细胞， 诱导增殖的 内皮细胞凋亡， 从而抑制肿瘤新生血管的生成， 达到消灭肿瘤的目的。 Combretastatins系列化合物具有顺式 1，2-二苯乙烯结构。 其中 combretastatin A— 4[CA-4， 康普立停， 顺式 - 1 - ( 3，4，5-三甲氧基） 苯基 -2-(3 '-羟基 -4'-甲氧基) 苯基乙烯] 具有最强的抑制微管聚合作用（Pettit G , et al. J.Med. Chem( \ 995) 38 1666- 1672 ) 。 最近， 由于 CA-4作为肿瘤血管靶向试剂， 显示出其阻断肿 瘤血管的优良特性（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·)。 美国 Oxigene, Inc.公司用 CA-4作为抗肿瘤新药， 已进入 III期临床研究。 1997年 日本味之素株式会社 （Ajinomoto Co. ) T.Hatanaka 等人发现把 CA-4的 3 ' 位的羟基改造成氨基， 其抗癌活性大大提高 （USP5674906 ) 。
但是， Combretastatins 系列化合物的水溶性很差， 使其临床应用受到 很大的限制。而且将 CA-4的 3 ' 位的羟基改造成氨基后，目前通常的将 CA-4 改造成其磷酸盐的方法并不适用。虽然日本味之素株式会社已经将氨基 CA-4 用氨基酸进行了修饰， 增加了其水溶性， 使其成为针剂能对癌症病人使用。 但其使用方法还是有诸多不便。 因此， 本发明将提供一种新的氨基 CA-4衍 生物， 该化合物通过消化道吸收， 并通过血液传输到全身各部位， 对各种肿 瘤都有一定的疗效， 尤其是肝癌和结肠癌。 发明内容
本发明提供了一种含有下面通式 （ I ) 表示的化合物或其药学上可接受 的盐：
Figure imgf000003_0001
(I)
R1独立地选自 d-Cg的垸基， 卤代垸基；
R2独立地选自氢， 甲基， 乙基， 卤素；
R3是可被任意取代的含有一个或多个杂原子的杂环或杂环垸基， 其中 至少有一个杂原子为 N。
在本发明所述式 （ I ) 化合物中， 优选是具有通式 II (a)或 11 (b)化合物：
Figure imgf000003_0002
Figure imgf000003_0003
R1独立地选自 d-Cg的垸基， 卤代垸基；
R2独立地选自氢， 甲基， 乙基， 卤素；
R4独立地选自氢， d-C3的垸基， 卤代垸基， 环垸基， 芳基， 杂环芳基， 杂环垸基， 垸酰基， 垸氧羰基； R5独立地选自氢， ^素， 垸基， 环垸基， 垸氧基， 烯基， 炔基， 羟基， 巯 基，氨基，硝基，氰基， NRaRb， N dC(O) c, C(O)NRaRb， S(O)2NRaRb， N dS(O)2 c, NRd(CH2)nRc， （CH2)nNRaRb， NHC(O)NH Rc， （CH2)nNHC(O)Rc， NHC(NH)RC;
Ra、 Rb分别独立地选自氢， 垸基， 环垸基， 或可与 N、 O、 S原子形成一个 5、 6或 7元的杂环或杂环垸基；
Re独立地选自垸基， 环垸基， 芳基， 杂环芳基， 杂环垸基；
Rd独立地选自氢， 垸基， 环垸基， 芳基， 杂环芳基；
以上所述的垸基， 环垸基， 垸氧基， 烯基， 炔基， 杂环基， 杂环垸基可以被 以下任意一个或多个基团取代： 卤素， 氨基， 垸氨基， 二垸基胺， 酰胺， 芳基， 杂环基， 硝基， 氰基， 羧基， 垸氧羰基， 羟基， 垸氧基， 酰氧基， =0， =S， =NH。
本发明所述式 （ I ) 化合物或其药学上可接受的盐， 其中所述的化合物更优 选自：
(Z)-l-(3，4，5-三甲氧基苯基 )-2-(3-(N-甲基哌啶 -4-甲酰基)氨基 -4-乙氧基 苯基）乙烯；
(Z)-l-(3,4,5 甲氧基苯基) -2-(3-(N-甲基哌啶 -4-甲酰基)氨基 -4-甲氧基 苯基）乙烯；
(Z)-l-(3，4，5 甲氧基苯基) -2-(3-(N-甲基哌啶 -4-甲酰基)氨基 -4-二氟甲 氧基苯基）乙烯；
(Z)-l-(3，4，5 甲氧基苯基) -2-(3-(N-甲基哌啶 -4-甲酰基)氨基 -4-三氟乙 氧基苯基）乙烯；
(Z)-l-(3，4，5 甲氧基苯基) -2-(3-(N-羟甲基哌啶 -4-甲酰基)氨基 -4-甲氧 基苯基)乙稀；
(Z)-l-(3，4，5 甲氧基苯基) -2-(3-(2-吡咯基哌啶 -4-甲酰基））氨基 -4-甲氧 基苯基)乙稀；
(Z)-l-(3,4,5 甲氧基苯基) -2-(3- (吡啶 -3-甲酰基)氨基 -4-甲氧基苯基）乙 烯；
(Z)-l-(3，4，5 甲氧基苯基) -2-(3-(2-乙酰氨基吡啶 -5-甲酰基)氨基 -4-甲 氧基苯基）乙烯；
(Z)-l-(3，4，5 甲氧基苯基) -2-(3-(2-三氟甲基吡啶 -5-甲酰基))氨基 -4-甲 氧基苯基）乙烯；
(Z)-l-(3，4，5 甲氧基苯基) -2-(3-(2-氟吡啶 -5-甲酰基)氨基 -4-甲氧基苯 基)乙烯；
(Z)-l-氟 - 1- (3，4，5-三甲氧基苯基 )-2-(3-(N-甲基哌啶 -4-甲酰基)氨基 -4-甲 氧基苯基）乙烯；
(Z)-l-甲基 - 1- (3，4，5-三甲氧基苯基 )-2-(3-(N-甲基哌啶 -4-甲酰基)氨基 -4- 甲氧基苯基)乙烯。
本发明所述式 （ I ) 化合物在药学上可接受的盐， 或含至少一个碱性成盐 基团，与其成盐的酸可以是药学上常用的无机酸或有机酸，包括无机酸：盐酸、 硫酸、 磷酸； 有机羧酸： 乙酸、 丙酸、 三氟乙酸、 乙醇酸、 琥珀酸、 马来酸、 富马酸、 苹果酸、 酒石酸、 柠檬酸、 草酸、 各种天然的或合成的氨基酸、 苯甲 酸、 水杨酸、 4-氨基水杨酸、 扁桃酸、 肉桂酸、 烟酸、 异烟酸； 有机磺酸： 甲 磺酸、 三氟甲磺酸、 乙磺酸、 2-羟基乙磺酸、 苯磺酸、 对甲苯磺酸、 2-萘磺酸。 当存在多个碱性基团时， 可以生成多酸加成盐。
本发明的化合物和药学上可接受的盐还包括溶剂化物或水合物的形式。 一般来说， 溶剂化物或水合物的形式与非溶剂化的或非水合的形式等同， 一 并涵盖在本发明的范围内。 本发明中的有些化合物有可能存在多晶体或无定 形的形式。 总的来说， 所有的物理形式具有同等的用途， 并且涵盖在本发明 的范围内。
本发明涵盖呈混合物形式或者呈纯形式的本发明化合物的所有立体异 构体。 本发明化合物的定义包含所有可能的立体异构体及其混合物。 其非常 具体地包含外消旋形式和分离的具有特定活性的光学异构体。 外消旋形式可 通过物理方法来进行拆分， 所述物理方法诸如对非对映异构体衍生物进行分 级结晶、 分离或者通过手性柱色谱进行分离。 可通过常规方法例如光学活性 酸形式成盐接着结晶而从外消旋体得到单独的光学异构体。
此外， 本发明还提供了合成式 （ I ) 化合物的方法。 其工艺过程如下所 示：
Figure imgf000006_0001
本发明所述的合成方法通过化合物 vn的溴代、 与三苯基膦反应后得到相 应的磷盐， 再将磷盐与化合物珊通过 wittig 反应得到顺式的二苯乙烯结构 (IV) o 二苯乙烯用二溴二辛基联吡啶和金属钐粉作为还原剂将结构中的硝基 还原成氨基， 就得到了氨基康普立停 Α-4(ΠΙ)。 然后以氨基康普立停 A-4 为 原料， 与吡啶甲酸或哌啶甲酸通过酰氯或活性酯的方法连接成酰胺（结构 II a 或 li b), 最后与酸成盐得到最终产物。 本发明还涉及包含有效量的式 （ I ) 化合物和药理上可接受的载体的药 物组合物， 该组合物适用于局部的、 肠内的或肠外的给药， 可以是无机的或 有机的， 固态的或液态的。 对于口服， 尤其用片剂或胶囊。 这种片剂或胶囊 包含活性成分和稀释剂 （如乳糖、 葡萄糖、 蔗糖、 甘露糖醇、 山梨醇、 纤维 素、 丙三醇） ， 润滑剂 （如滑石、 硬脂酸盐） ， 聚乙二醇。 片剂还可包含粘 合剂， 淀粉， 明胶， 甲基纤维素， 羧甲基纤维素钠和 /或聚乙烯吡咯垸酮， 必 要时还可包含粉碎剂 （如淀粉、 琼脂、 藻酸及其盐） ， 泡腾混合物， 或吸附 剂， 染料， 调味剂， 增甜剂。 这些组合物还可以肠胃外给药的形式或以针剂 的形式被适用。 此类剂型优选等渗水溶液或乳液， 如在仅由活性成分和一种 载体（如甘露醇）组成的冻干组合物的情况下， 此类溶液可以在使用前制备。 这些药物组合物可以是无菌的， 或包含赋形剂的， 或加溶剂、 调节渗透压的 ±卜
本发明还涉及式 （ I ) 化合物在制备治疗非正常新生血管引起的疾病的 药物中的应用。 非正常新生血管引起的疾病包括各种肿瘤， 主要有： 肺癌、 小细胞肺癌、 肝癌、 胰腺癌、 胃癌、 骨癌、 食道癌、 乳房癌、 肾癌、 胆管癌、 前列腺癌、 睾丸癌、 结肠癌、 卵巢癌、 膀胱癌、 子宫颈癌、 支气管癌、 黑色 素瘤、 腺癌、 汗腺癌、 乳头状癌、 乳头状腺癌、 鳞状细胞癌、 基底细胞癌、 囊性腺癌、 胶质细胞瘤、 星型细胞瘤、 成神经管细胞瘤、 成神经细胞瘤、 颅 咽管瘤、 室管膜瘤、 松果体瘤、 成血管细胞瘤、 少突神经胶质瘤、 脑膜瘤、 神经纤维瘤、 纤维肉瘤、 成纤维细胞瘤、 纤维瘤、 粘液肉瘤、 粘液囊瘤、 脂 肪瘤、 脂肪腺瘤、 软骨肉瘤、 软骨瘤、 软骨肌瘤、 脊索瘤、 绒毛膜腺瘤、 绒 毛血管瘤、 绒毛上皮瘤、 成绒毛膜细胞瘤、 骨肉瘤、 成骨细胞瘤、 破骨细胞 瘤、 骨软骨纤维瘤、 骨软骨肉瘤、 股囊瘤、 骨牙质瘤、 骨纤维瘤、 骨纤维肉 瘤、 血管瘤、 血管肉瘤、 淋巴管肉瘤、 淋巴管瘤、 淋巴瘤、 内皮瘤、 滑膜瘤、 滑膜肉瘤、 间皮瘤、 结缔组织瘤、 尤因瘤、 平滑肌瘤、 平滑肌肉瘤、 横纹肌 瘤、 横纹肌肉瘤、 急性淋巴性白血病、 急性骨髓性白血病、 慢性白血病、 红 细胞增多症、 多发性骨髓瘤。
非正常新生血管引起的疾病还包括： 风湿性关节炎、 糖尿病视网膜病、 早熟视网膜病、 视网膜静脉闭塞、 牛皮癣、 红斑痤疮、 卡波济肉瘤、 特异性 反应性角膜炎、 流行性角膜结膜炎、 新生血管性青光眼、 细菌性溃疡、 真菌 性溃疡、 单纯性疱疹感染、 带状疱疹感染、 原生动物感染、 分支杆菌感染、 多动脉炎、 肉样瘤、 巩膜炎、 潮红、 口干眼燥关节炎综合症、 全身性红斑狼 疮、 艾滋病综合症、 梅毒。
本发明还涉及了式 （ I ) 化合物在制备微管蛋白聚集抑制剂中的应用。 本发明还提供了一种动物试验的方法， 通过这种方法可以验证化合物 ( I ) 在动物体内的吸收和对肿瘤的抑制能力。 具体实施方式
下面将详细描述本发明的示例性实施方案。 然而， 这些实施方案仅为说 明目的， 并不旨在限制本发明的范围。
以下是可在本说明书中使用的术语的定义。 除非另有说明， 本专利就基 团或术语而言提供的初始定义适用于在说明书通篇中的所述基团或者术语， 不论是单独使用还是作为另一基团的部分使用。
术语"垸基"是指直链的或支链的未取代的烃基，其具有 1-20个碳原子， 优选的是 1-6个碳原子，尤其是指甲基、 乙基、丙基（包括正丙基和异丙基）、 丁基 （包括正丁基、 异丁基、 叔丁基） 等。
术语 "烯基"是指具有一个或多个碳碳双键的烃基， 如乙烯基、 丙烯基、 1，3-丁二烯、 顺丁烯、 反丁烯等。
术语 "炔基"是指具有一个多个碳碳三键的烃基， 如乙炔基、 丙炔基等。 术语 "卤素"或者 "卤代"是指氟 （氟代） 、 氯 （氯代） 、 溴 （溴代） 、 碘 （碘代） 。
术语 "芳基" 是指单环或多环的芳香族碳氢化合物， 例如苯、 萘、 蒽、 菲等。
术语 "杂环芳基" 是指任选取代的芳香族环状基团， 其中至少含有一个 碳原子被其它杂原子取代， 杂原子包括氮、 氧、 硫。 该氮和硫杂原子也可任 选被氧化， 氮杂原子也可任选被季铵化。 该杂环基团可在任何杂原子或碳原 子处连接。 优选的杂环芳基包括但不限于， 吡啶、 吡嗪、 嘧啶、 哒嗪、 三嗪、 呋喃、 噻吩、 咪唑、 三唑、 四唑、 噻唑、 异噻唑、 吡咯、 吡唑、 噁唑、 异噁 唑、 苯并呋喃、 苯并噻唑、 苯并噻吩、 吲哚、 喹啉、 异喹啉、 嘌呤、 咔唑、 苯并咪唑、 吡咯并吡啶、 吡咯并嘧啶等。
术语 "环垸基" 是指非芳香族的碳环， 包括单环、 稠环或螺环。 环垸基 还包括具有一个或多个芳香环稠合 （即有一个共同的键） 的环， 有一个或多 个芳香环稠合的环垸基可以通过芳香环或非芳香环部分与其他基团相连接。
术语"杂环垸基"是指非芳香杂环， 其中一个或多个成环原子是杂原子， 如氧、氮、硫原子。杂环垸基可以包括单环或多环（如有 2、 3、 4个稠合环）、 螺环。 优选的杂环垸基包括氮丙啶、 氮杂环丁垸、 四氢呋喃、 四氢噻吩、 吡 咯垸、 噁唑垸、 噻唑垸、 异噻唑垸、 咪唑垸、 吡唑垸、 吗啉、 硫代吗啉、 哌 嗪、 哌啶等。 杂环垸基还包括具有一个或多个芳香环稠合的杂环， 例如 2，3- 二氢苯并呋喃、 1，3-苯并二氧戊环、 苯并 - 1，4-二噁垸、 苯二甲酰胺等。 具有 一个或多个芳香环稠合的杂环垸基可以通过芳香环或非芳香环部分与其它 基团连接。
术语 "氰基" 是指基团 -CN。
术语 "硝基" 是指基团 -NO2。
术语 "巯基" 是指基团 -SH。
术语 "垸氧碳基" 是指基团 -C(=O)OR6， 其中 R6是指垸基。
术语 "垸氧基" 是指基团 -OR7， 其中 R7是指垸基。
术语 "酰氧基" 是指基团 -OC(=O)R8， 其中 R8是指垸基。
"可选的" 意味着随后描述的事件或情况可以发生或者不发生， 所述描 述摆阔其中所述事件或情况发生的例子和其中它不发生的例子。
本文所用的 "药学可接受的载体"包括任何核全部的溶剂、 分散介质、 包 衣、 抗细菌和抗真菌药剂、 等渗和吸收延迟剂等。 这样的介质和药剂用于药学 活性物质在本领域是众所周知的。 除非任何常规介质或药剂与活性成分不相容， 其在治疗组合物中的应用时可预期的。 补充的活性成分也可并入组合物中。 实施例 1
(z)-i-(3，4，5-三甲氧基苯基 )-2-(3-(N-甲基哌啶 -4-甲酰基)氨基 -4-乙氧基 苯基 乙烯的合成
Figure imgf000009_0001
步骤 1 : 溴化三甲氧基苄基三苯基膦的合成
将 3，4，5-三甲氧基苯甲醛 4Kg溶于无水乙醇， 搅拌， 在 35 °C以下少量多 次加入硼氢化钠 1.4Kg。 加完后反应过夜。 反应完成后， 旋转蒸发除去乙醇。 加入乙酸乙酯 （10L X 4 ) 萃取， 合并乙酸乙酯层， 无水硫酸镁干燥， 过滤， 减压蒸去乙酸乙酯， 得到 3200ml产物。 将 3，4，5-三甲氧基苄醇 3200ml溶于 20L甲苯中， 搅拌， 降温到 -5— 0°C， 滴加三溴化磷 1L， 同时控温在 -5— 0°C。 滴加完成后， 低温反应 2h， 恢复到 室温， 反应过夜。
加入纯化水 14L终止反应， 搅拌 30min， 分液， 分出水层。 有机层用饱 和碳酸氢钠溶液洗涤到 Ph值 7.5-8， 无水硫酸镁干燥， 过滤， 得到三甲氧基 苄溴的甲苯溶液。
在此溶液中加入三苯基磷 5.6Kg， 搅拌 48h 以上， 有固体析出， 过滤， 即得到产物粗品， 湿重 13Kg。 产品用无水乙醇重结晶。 步骤 2 : (Z)-l-(3，4，5-三甲氧基苯基 )-2- (3-氨基 -4-甲氧基苯基）乙烯的合 成
在化学合成器中， 氩气保护下， 将溴化三甲氧基苯基亚甲基三苯鳞 15g(28.7mmol.)悬浮于 300ml THF中， 冷却到 -15 °C左右。 滴入 1.6mol/L的正 丁基锂环己垸溶液 22ml， 反应 1小时。然后， 将 5.7克 (29mmol.) 4-乙氧基 -3- 硝基苯甲醛 24ml THF溶液， 缓慢滴加入反应中。 TLC跟踪， 搅拌过夜， 反 应温度升到室温。 次日， 将溶液温度降到 -5 °C， 加入饱和食盐水中止反应。 分出有机层， 除去溶剂。 经常压柱层析 （硅胶柱， 4 : 1 正己垸 /乙酸乙酯） 分离得到 6.5克浅黄色晶体， 即为 (Z)-l-(3，4，5-三甲氧基苯基 )-2- (3-硝基 -4-乙 氧基苯基）乙烯， 产率 63 %。
在干燥的 5L四颈瓶中加入 3.5L新蒸异丙醇， 二溴二辛基联吡啶 50g， 金属钐粉 120g， 最后加入 (Z)-l-(3，4，5-三甲氧基苯基 )-2- (3-硝基 -4-乙氧基苯 基）乙烯 50g， 搅拌， 加热至回流。 TLC点板跟踪， 直至反应结束。 反应完成 后， 抽滤， 浓缩， 柱色谱分离， 洗脱剂石油醚 /乙酸乙酯 =4/1。 收率 30〜40%。 步骤 3 : (Z)-l-(3，4，5-三甲氧基苯基 )-2-(3-(N-甲基哌啶 -4-甲酰基)氨基 -4- 乙氧基苯基)乙烯的合成
1-甲基哌啶 -4-甲酸盐酸盐 （10g， 55.6mmol ) ， 加入 100ml 二氯亚砜， 搅拌， 加热回流 12h， 冷却， 减压蒸去二氯亚砜， 得到类白色固体。 加入 50ml 干燥的 THF， 蒸干溶剂， 再重复此操作 2次， 得到的固体直接用于下一步反 应。
将上一步反应得到的固体溶于 100ml吡啶， 加入氨基 CA-4 ( 12.2g, 37mmol ) ， 搅拌， 加热到 60°C， 反应 6h。 反应结束后， 将反应液倒入 500ml 水中， 加入 NaOH溶液调节 pH值到 9， 有固体析出， 过滤， 得到的固体经 过柱 （洗脱剂： 氯仿 /甲醇 =9/0.3 ) 提纯后得到产物 (Z)-l-(3 4 5-三甲氧基苯 基 )-2-(3-(N-甲基哌啶—4-甲酰基)氨基 -4-乙氧基苯基）乙烯 14g， 收率 83% MS(M+1)=455.5 实施例 2
(Z)-l-(3 4 5-三甲氧基苯基 )-2-(3-(N-甲基哌啶 -4-甲酰基)氨基 -4-乙氧基 苯基)乙烯柠檬酸盐的制备
将 (z)-i-(3 4 5-三甲氧基苯基 )-2-(3-(N-甲基哌啶 -4-甲酰基)氨基 -4-乙 氧基苯基）乙烯 20g加入到 200ml丙酮中， 加热溶解， 加入柠檬酸 10g， 继续 加热回流 3h， 冷却后过滤析出的沉淀， 并用乙醇重结晶后得到标题所示化合 物。 利用不同的原料， 通过实施例 1类似的方法， 分别合成了以下各种化合
Figure imgf000011_0001
实施例 5 (Z)-l-(345-三甲 氧基苯基） -2- (3-(N-甲基哌啶 o -4-甲酰基)氨基
Figure imgf000012_0001
-4-三氟乙氧基苯 基)乙烯 实施例 6 (Z)-l-(345-三甲 氧基苯基） -2- (3-(N-乙基哌啶 -4-甲酰基)氨基
Figure imgf000012_0002
-4-甲氧基苯基） 乙烯 实施例 7 (Z)-l-(345-三甲 氧基苯基） -2- (3-(N-羟甲基哌 啶 -4-甲酰基)氨 基 -4-甲氧基苯 基)乙烯 实施例 8 (Z)-l-(345-三甲 氧基苯基） -2- (3-(N-羟乙基哌 啶 -4-甲酰基)氨
Figure imgf000012_0003
基 -4-甲氧基苯 基)乙烯 实施例 9 (Z)-l-(345-三甲 氧基苯基） -2- (3-(N-异丙基哌 啶 -4-甲酰基)氨
Figure imgf000012_0004
基 -4-甲氧基苯 基)乙烯 实施例 (Z)-l-(3，4，5-三甲
10 氧基苯基） -2- (3-(N-环己基哌
0 啶 -4-甲酰基)氨
〇
基 -4-甲氧基苯 基)乙烯 实施例 (Z)-l-(3，4，5-三甲
1 1 氧基苯基） -2- (3— (N-( 4-哌啶基） 哌啶— 4-甲酰基）
Figure imgf000013_0001
氨基 -4-甲氧基 苯基）乙烯 实施例 (Z)-l-(3，4，5-三甲
12 氧基苯基） -2- (3-(N-乙基哌啶 -4-甲酰基)氨基 -4-乙氧基苯基）
Figure imgf000013_0002
乙烯 实施例 (Z)-l-(3，4，5-三甲 13 氧基苯基） -2- (3-(N-异丙基哌 啶 -4-甲酰基)氨 基 -4-乙氧基苯 基)乙烯 实施例 (Z)-l-(3，4，5-三甲 14 氧基苯基） -2- (3-(N-羟甲基哌 啶 -4-甲酰基)氨 基 -4-乙氧基苯
Figure imgf000014_0001
Figure imgf000015_0001
甲氧基苯基）乙烯 实施例 (Z)-l-(345-三甲
25 氧基苯基） -2- (3-(2-氯吡啶 -5-
Figure imgf000016_0001
甲酰基)氨基 -4- 甲氧基苯基）乙烯 实施例 (Z)-l-(345-三甲 26 氧基苯基) -2- (3- (2-硝基吡啶 -5-甲
Figure imgf000016_0002
酰基)氨基 -4-甲 氧基苯基）乙烯 实施例 (Z)-l-(345-三甲 27 氧基苯基) -2- (3-
(2-三氟甲基吡吡 啶 -5-甲酰基)氨
Figure imgf000016_0003
基 -4-甲氧基苯 基)乙烯 实施例 (Z)-l-氟 -1- 28 (345-三甲 氧基 苯基) -2- (3-(N-甲 基哌啶 -4-甲酰
Figure imgf000016_0004
基)氨基 -4-甲氧 基苯基)乙稀 实施例 (Z)-l-甲基 -1- 29 (345-三甲氧基 苯基) -2- (3-(N-甲 基哌啶 -4-甲酰
Figure imgf000016_0005
基)氨基 -4-甲氧 基苯基)乙稀 实施例 (Z)-l-乙基 -1-
30 (3，4，5-三甲氧基 苯基) -2- (3-(N-甲 基哌啶 -4-甲酰 基)氨基 -4-甲氧
Figure imgf000017_0001
基苯基)乙稀 实施例 31 药物制剂配方
本发明提供了几种与新生血管异常增生相关的疾病的药物组合物的配 方， 其药物组合物主要有片剂、 胶囊等口服制剂。 以下以 "活性化合物 " 表 示本发明所示的化合物。
(a)片剂 I ( mg)
活性化合物 100 乳糖 188.75
微晶纤维素 100
交联羧甲基纤维素钠 6
淀粉 2.25
硬脂酸镁 3
(b)片剂 II ( mg)
活性物质 50 乳糖 218
交联羧甲基纤维素钠 12
淀粉 15
聚乙烯吡咯垸酮 2
硬脂酸镁 3 (c)胶囊 ( mg )
活性物质 10 乳糖 487.5
硬脂酸镁 2.5 实施例 32 对体外培养的肿瘤细胞的抗肿瘤活性试验
细胞以含 10%胎牛血清的培养液培养， 使细胞一直处于对数生长期。 细 胞接种于 96培养板，密度 4-7 X l OVmK HUVEC密度 3 X 104/ml ) .37 °C ， 5 %CO2 培养箱预培养 24 小时加药， 药物设 6个浓度， 每个浓度设两个复孔， 连续 作用 72小时。 药物作用结束后， 用三氯乙酸固定细胞， 清洗后加入 SRB工 作液， 1 5min后， 用 1 %醋酸溶液洗涤， 用 Tris base溶解与蛋白结合的 SRB， NOCOstar 酶标仪 545nm 波长下测定每个小孔的 OD 值。 阳性对照药选择 CA-4。
根据 OD值， 计算细胞生长抑制率。
抑制率(％)= (对照组 OD值-用药组 OD值) /对照组 OD值 100
根据不同浓度下药物对细胞生长的抑制率，以 Logitech方法计算 IC5Q值。
表 1 活性化合物对体外培养肿瘤细胞的抗肿瘤活性
Figure imgf000018_0001
注： EACA为本发明实施例 1所述化合物。
结论： 本发明所示化合物对多种体外培养的肿瘤细胞均具有明显的抗肿 瘤活性； 对人脐静脉内皮细胞增殖也有显著的抑制作用； EACA抑制作用显 著强于阳性对照物 CA-4。 实施例 33 裸小鼠移植瘤的疗效实验
BALB/cA-nude裸小鼠， 6-7 周， ¥， 购自上海斯莱克实验动物有限责任公 司。 裸小鼠皮下分别接种人肝癌 Bel-7402 细胞、 结肠癌 HT-29 细胞、 胃癌 SGC-7901细胞和非小细胞肺癌 A549细胞， 待肿瘤生长至 100-250mm3后， 将动 物随机分组 (d0)。 每周测 2— 3次瘤体积， 称鼠重， 记录数据。 肿瘤体积 （V) 计 算公式为：
V= l/2xaxb2 其中 a、 b分别表示长、 宽；
T/C(%)=(T-T0)/(C-C0) l 00 其中 T、 C为实验结束时的肿瘤体积； T0、 CO为实验开始时的肿瘤体积。
将所试样品均用 50 %PEG400蒸馏水稀释成所需浓度。 用药方式为每天给 药 1次， 灌胃给药， 连用 21天。 分别对实施例 1， 3， 4， 17， 23所示化合物对 人肝癌 Bel-7402、结肠癌 HT-29细胞、胃癌 SGC-7901细胞和非小细胞肺癌 A549 细胞的裸小鼠移植瘤的疗效进行了试验， 其结果如表 2所示。
表 2活性化合物多种癌细胞裸小鼠移植瘤的疗效
Figure imgf000019_0001
结论： 本发明所示化合物可以在灌胃给药的条件下明显抑制人肝癌 Bel-7402, 结肠癌 HT-29细胞、 胃癌 SGC-7901细胞和非小细胞肺癌 A549细 胞裸小鼠移植瘤的生长。

Claims

权 利 要 求
1. 一种含有下面通式 （ I ) 表示的化合物或其药学上可接受的盐:
Figure imgf000020_0001
(I)
R1独立地选自 d-Cg的垸基， 卤代垸基；
R2独立地选自氢， 甲基， 乙基， 卤素；
R3是可被任意取代的含有一个或多个杂原子的杂环或杂环垸基， 其中 至少有一个杂原子为 N。
面通式 II (a)或 11 (b) :
Figure imgf000020_0002
Figure imgf000020_0003
R1独立地选自 d-Cg的垸基， ^代垸基; R2独立地选自氢， 甲基， 乙基， 卤素；
R4独立地选自氢， d-C3的垸基， 卤代垸基， 环垸基， 芳基， 杂环芳基， 杂环垸基， 垸酰基， 垸氧羰基；
R5独立地选自氢， ^素， 垸基， 环垸基， 垸氧基， 烯基， 炔基， 羟基， 巯 基，氨基，硝基，氰基， NRaRb， N dC(O) c , C(O)NRaRb， S(O)2NRaRb， N dS(O)2 c, NRd(CH2)nRc， （CH2)nNRaRb， NHC(O)NH Rc， （CH2)nNHC(O)Rc， NHC(NH)RC ;
Ra、 Rb分别独立地选自氢， 垸基， 环垸基， 或可与 N、 O、 S原子形成一个 5、 6或 7元的杂环或杂环垸基；
Re独立地选自垸基， 环垸基， 芳基， 杂环芳基， 杂环垸基；
Rd独立地选自氢， 垸基， 环垸基， 芳基， 杂环芳基；
以上所述的垸基， 环垸基， 垸氧基， 烯基， 炔基， 杂环基， 杂环垸基可以被 以下任意一个或多个基团取代： 卤素， 氨基， 垸氨基， 二垸基胺， 酰胺， 芳基， 杂环基， 硝基， 氰基， 羧基， 垸氧羰基， 羟基， 垸氧基， 酰氧基， =0， =S， =NH。
3. 根据权利要求 2所示化合物， 其中
R1是甲基， 乙基， 二氟甲基， 2，2，2-三氟乙基；
R2是氢， 氟， 甲基， 乙基；
R4是氢， 甲基， 乙基， 氯甲基， 环己基， 苯基， 吡啶基， 噻吩基， 呋喃 基， 吡咯基， 哌啶基， 四氢呋喃基， 哌嗪基， 乙酰基， 叔丁氧羰基；
R5独立地选自氢， 氟， 氯， 溴， 碘， 甲基， 乙基， 异丙基， 环丙基， 甲氧 基， 乙氧基， 羟基， 巯基， 氨基， 硝基， 氰基， 胺甲酰基。
4.根据权利要求 1 -3任一项所述的化合物或其药学上可接受的盐， 其中所述 的化合物优选自：
(Z)- l -(3，4，5-三甲氧基苯基 )-2-(3-(N-甲基哌啶 -4-甲酰基)氨基 -4-乙氧基 苯基）乙烯；
(z)- i -(3，4，5-三甲氧基苯基 )-2-(3-(N-甲基哌啶 -4-甲酰基)氨基 -4-甲氧基 苯基）乙烯；
(Z)- l -(3，4，5-三甲氧基苯基 )-2-(3-(N-甲基哌啶 -4-甲酰基)氨基 -4-二氟甲 氧基苯基）乙烯；
(Z)- l -(3，4，5-三甲氧基苯基 )-2-(3-(N-甲基哌啶 -4-甲酰基)氨基 -4-三氟乙 氧基苯基）乙烯；
(Z)- l -(3，4，5-三甲氧基苯基 )-2-(3-(N-羟甲基哌啶 -4-甲酰基)氨基 -4-甲氧 基苯基)乙稀；
(Z)-l-(3，4，5-三甲氧基苯基 )-2-(3-(2-吡咯基哌啶 -4-甲酰基））氨基 -4-甲氧 基苯基)乙稀；
(Z)-l-(3，4，5-三甲氧基苯基 )-2-(3- (吡啶 -3-甲酰基)氨基 -4-甲氧基苯基）乙 烯；
(Z)-l-(3，4，5-三甲氧基苯基 )-2-(3-(2-乙酰氨基吡啶 -5-甲酰基)氨基 -4-甲 氧基苯基）乙烯；
(Z)-l-(3，4，5-三甲氧基苯基 )-2-(3-(2-三氟甲基吡啶 -5-甲酰基))氨基 -4-甲 氧基苯基）乙烯；
(Z)-l-(3，4，5-三甲氧基苯基 )-2-(3-(2-氟吡啶 -5-甲酰基)氨基 -4-甲氧基苯 基)乙烯；
(Z)-l-氟 - 1- (3，4，5-三甲氧基苯基 )-2-(3-(N-甲基哌啶 -4-甲酰基)氨基 -4-甲 氧基苯基）乙烯；
(Z)-l-甲基 - 1- (3，4，5-三甲氧基苯基 )-2-(3-(N-甲基哌啶 -4-甲酰基)氨基 -4- 甲氧基苯基）乙烯。
5. 根据权利要求 1-4所述的化合物在药学上可接受的盐， 或含至少一个 碱性成盐基团， 与其成盐的酸可以是药学上常用的无机酸或有机酸， 包括无 机酸： 盐酸、 硫酸、 磷酸； 有机羧酸： 乙酸、 丙酸、 三氟乙酸、 乙醇酸、 琥 珀酸、 马来酸、 富马酸、 苹果酸、 酒石酸、 柠檬酸、 草酸、 各种天然的或合 成的氨基酸、 苯甲酸、 水杨酸、 4-氨基水杨酸、 扁桃酸、 肉桂酸、 烟酸、 异 烟酸； 有机磺酸： 甲磺酸、 三氟甲磺酸、 乙磺酸、 2-羟基乙磺酸、 苯磺酸、 对甲苯磺酸、 2-萘磺酸。 当存在多个碱性基团时， 可以生成多酸加成盐。
6. 一种药物组合物， 其特征在于， 它含有治疗有效量的如权利要求 1 -5 所述的化合物和药学上可接受的载体。
7.根据权利要求 6所述， 药学上可接受的载体主要包括口服制剂所使用 的稀释剂， 润滑剂， 聚乙二醇。 片剂还可包含粘合剂， 淀粉， 明胶， 甲基纤 维素， 羧甲基纤维素钠和 /或聚乙烯吡咯垸酮， 必要时还可包含粉碎剂， 泡腾 混合物， 或吸附剂， 染料， 调味剂， 增甜剂。
8.—种如权利要求 1 -5 所述的化合物在制备微管蛋白聚集抑制剂中的应 用。
9.一种如权利要求 1 -5 所述的化合物在制备治疗非正常新生血管引起的 疾病的药物中的应用。
10.根据权利要求 9所述， 非正常新生血管引起的疾病包括各种肿瘤， 主 要有： 肺癌、 小细胞肺癌、 肝癌、 胰腺癌、 胃癌、 骨癌、 食道癌、 乳房癌、 肾癌、 胆管癌、 前列腺癌、 睾丸癌、 结肠癌、 卵巢癌、 膀胱癌、 子宫颈癌、 支气管癌、 黑色素瘤、 腺癌、 汗腺癌、 乳头状癌、 乳头状腺癌、 鳞状细胞癌、 基底细胞癌、 囊性腺癌、 胶质细胞瘤、 星型细胞瘤、 成神经管细胞瘤、 成神 经细胞瘤、 颅咽管瘤、 室管膜瘤、 松果体瘤、 成血管细胞瘤、 少突神经胶质 瘤、 脑膜瘤、 神经纤维瘤、 纤维肉瘤、 成纤维细胞瘤、 纤维瘤、 粘液肉瘤、 粘液囊瘤、 脂肪瘤、 脂肪腺瘤、 软骨肉瘤、 软骨瘤、 软骨肌瘤、 脊索瘤、 绒 毛膜腺瘤、 绒毛血管瘤、 绒毛上皮瘤、 成绒毛膜细胞瘤、 骨肉瘤、 成骨细胞 瘤、 破骨细胞瘤、 骨软骨纤维瘤、 骨软骨肉瘤、 股囊瘤、 骨牙质瘤、 骨纤维 瘤、 骨纤维肉瘤、 血管瘤、 血管肉瘤、 淋巴管肉瘤、 淋巴管瘤、 淋巴瘤、 内 皮瘤、 滑膜瘤、 滑膜肉瘤、 间皮瘤、 结缔组织瘤、 尤因瘤、 平滑肌瘤、 平滑 肌肉瘤、 横纹肌瘤、 横纹肌肉瘤、 急性淋巴性白血病、 急性骨髓性白血病、 慢性白血病、 红细胞增多症、 多发性骨髓瘤。
1 1.根据权利要求 9所述， 非正常新生血管引起的疾病还包括： 风湿性关 节炎、 糖尿病视网膜病、 早熟视网膜病、 视网膜静脉闭塞、 牛皮癣、 红斑痤 疮、 卡波济肉瘤、 特异性反应性角膜炎、 流行性角膜结膜炎、 新生血管性青 光眼、 细菌性溃疡、 真菌性溃疡、 单纯性疱疹感染、 带状疱疹感染、 原生动 物感染、 分支杆菌感染、 多动脉炎、 肉样瘤、 巩膜炎、 潮红、 口干眼燥关节 炎综合症、 全身性红斑狼疮、 艾滋病综合症、 梅毒。
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