WO2011131135A1 - 芳杂（烷基）氨基二硫代甲酸酯类化合物、其制备方法和应用 - Google Patents

芳杂（烷基）氨基二硫代甲酸酯类化合物、其制备方法和应用 Download PDF

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WO2011131135A1
WO2011131135A1 PCT/CN2011/073118 CN2011073118W WO2011131135A1 WO 2011131135 A1 WO2011131135 A1 WO 2011131135A1 CN 2011073118 W CN2011073118 W CN 2011073118W WO 2011131135 A1 WO2011131135 A1 WO 2011131135A1
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compound
ethyl ester
cyano
group
pyridinemethylaminodithiocarbamate
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PCT/CN2011/073118
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English (en)
French (fr)
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李润涛
葛泽梅
崔景荣
孙兴义
王仲清
闫旭
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北京大学
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Priority to US13/642,298 priority Critical patent/US20130136794A1/en
Priority to JP2013505324A priority patent/JP2013530130A/ja
Priority to EP11771588.8A priority patent/EP2562157A4/en
Publication of WO2011131135A1 publication Critical patent/WO2011131135A1/zh

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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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
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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
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    • C07D213/72—Nitrogen atoms
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    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
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    • C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Definitions

  • Aromatic (fluorenyl) aminodithioformate compound preparation method and application thereof
  • the present invention relates to a novel class of aromatic (indenyl) aminodithioformate compounds, which are novel tyrosine kinase inhibitors which are useful as antitumor agents.
  • the epidermal growth factor receptor (EAB) family belongs to the family of type I receptor tyrosine kinases, which have four members: ErbB-1 (EGFR), ErbB-2 (HER-2), ErbB-3 and ErbB-4 .
  • EGFR ErbB-1
  • HER-2 ErbB-2
  • ErbB-3 ErbB-4
  • EGFR and HER-2 are highly expressed in tumor cells such as bladder cancer, breast cancer, colon cancer, and lung cancer, and there is a strong correlation between solid tumors and their high expression. Therefore, in recent years, research on targeted anti-tumor drugs targeting EGFR and HER-2 has been highly valued.
  • EGFR and HER-2 inhibitors have been found to be the following five types, namely 4-aminoquinazoline, 4-amino-3-cyanoquinoline, benzylidenemalononitrile, Salicylamides and pyrrole triterpenes.
  • the most studied among the five structures are 4-aminoquinazolines and 4-amino-3-cyanoquinolines, as disclosed in, for example, Chinese Patent Application No. CN200610023526.7 and International Application Publication No. WO 2008/0033748 and WO 2008/0033749. Compound.
  • Some compounds with good anti-tumor activity have been discovered, and some have entered the clinic.
  • Aminodithioformate compounds are another class of compounds having antitumor activity, and WO2007/050963A1 discloses a class of aminodithioformate compounds:
  • R 1 is cyclodecyl, aryl or benzopyrrolyl, furyl or thienyl; the compound is useful as an antitumor drug; Li Runtao et al. CN01118399.3, CN200410054686.9 and CN200910143757.5 also disclosed a variety of such compounds, of the compound R 1 and R 2 groups classes vary.
  • A is a substituted or unsubstituted five- or six-membered heterocyclic group having one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur,
  • the heterocyclic group may be substituted by one or more substituents selected from the group consisting of halogen, d- 4 fluorenyl, d- 4 methoxy, phenyl, phenoxy, furyl, morpholinyl, D- 6 mercaptoamide group and d- 4 ⁇ oxycarbonyl group; when the heterocyclic group is a pyridyl group, the pyridyl group may also be fused to a benzene ring or a heterocyclic ring, or the fused benzene ring or a heterocyclic ring which is unsubstituted or substituted by a thiol group;
  • R 1 is hydrogen, phenyl or d- 4 alkyl
  • R 2 is hydrogen or 4 fluorenyl
  • R 3 is cyano, boronic acid, oxime oxycarbonyl, aminosulfonyl, benzylsulfinyl or d- 4- mercaptosulfinyl; or R 2 and R 3 are bonded together to form a nitrogen atom and a sulfur atom, a saturated or unsaturated five- or six-membered heterocyclic ring which is unsubstituted or substituted by one or more hydroxyl or thiol groups;
  • n is an integer from 0-3.
  • the group A is a substituted or unsubstituted heterocyclic group; preferably, the group A is a substituted or unsubstituted pyridyl group, a pyrimidinyl group, a pyridyl group, a furyl group, an oxazole.
  • a pyrazole group a thiazolyl group or an oxadiazolyl group
  • the heterocyclic group may be substituted by one or more substituents selected from the group consisting of halogen, d- 4 fluorenyl, d- 4 oxo a phenyl group, a phenoxy group, a furyl group, a morpholinyl group, a d- 6 fluorenyl amide group, and a d- 4 methoxycarbonyl group; or, when the heterocyclic group is a pyridyl group, the pyridyl group is further It may be fused to a benzene ring or a heterocyclic ring which is unsubstituted or substituted by a thiol group.
  • the term "mercapto" as used refers to a saturated straight or branched hydrocarbon fluorenyl group having 1 to 4 carbon atoms, preferably a linear chain having 1 to 3 carbon atoms. Or a branched fluorenyl group such as a methyl group, an ethyl group, a propyl group or an isopropyl group; more preferably a methyl group and an ethyl group, most preferably a methyl group.
  • d- 4 methoxy means a saturated linear or branched decyloxy group having 1 to 4 carbon atoms, such as methoxy group, ethoxy group. Or a methoxy or isopropoxy group; preferably a methoxy group or an ethoxy group; more preferably a methoxy group.
  • embankment oxycarbonyl group refers to a saturated, having embankment oxycarbonyl group, linear or branched 1-4 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxy Oxycarbonyl or isopropoxycarbonyl; preferably methoxycarbonyl or ethoxycarbonyl; more preferably methoxycarbonyl.
  • d- 6 amide group means a saturated linear or branched oxime amide group having 1 to 6 carbon atoms, such as a formamide group or an acetamide. a base, a propionamide group, or various isomeric butanamide groups, pentanoamide groups or hexanoamide groups; preferably a branched oxime amide group having 4 to 6 carbon atoms, more preferably various isomers of a pentanoamide group Most preferred are isovaleryl or pivalamide groups.
  • halogen means a fluorine, chlorine, bromine and iodine atom, preferably a fluorine, chlorine or bromine atom, more preferably a bromine atom.
  • preferred A groups are substituted or unsubstituted pyridyl groups.
  • a preferred R 3 group is a cyano group.
  • the pharmaceutically acceptable salt of the compound of the formula (I) of the present invention means an acid addition salt of the compound of the present invention, and includes an inorganic acid addition salt or an organic acid addition salt, and the inorganic acid is, for example, sulfuric acid, hydrochloric acid, or sub Sulfuric acid, boric acid, phosphoric acid, sulfonic acid, hydrobromic acid or hydrofluoric acid, etc.; the organic acid is, for example, acetic acid, valeric acid, maleic acid, fumaric acid, oxalic acid, oleic acid, lactic acid, palmitic acid, lauric acid , stearic acid, citric acid, succinic acid, tartaric acid, benzoic acid, methanesulfonic acid, toluenesulfonic acid
  • substituted or unsubstituted means a group which is mono- or polysubstituted by the substituent at any position which may be substituted.
  • the above compound of the present invention is an epidermal growth factor receptor inhibitor (EGFR inhibitor), which is useful for treating tumors, and is particularly suitable for treating diseases mediated by protein tyrosine kinases, such as breast cancer, liver cancer, non-small cell lung cancer, gastric cancer. , colon cancer, leukemia, nasal cancer, etc.
  • EGFR inhibitor epidermal growth factor receptor inhibitor
  • Preferred compounds of the invention are:
  • Another object of the present invention is to provide a process for the preparation of a compound of the above formula (I) or a pharmaceutically acceptable salt thereof, said formula
  • the pharmaceutically acceptable salts of the compounds can be prepared by conventional salt formation methods in the chemical arts.
  • the preparation method described above is a method for preparing an aminodithioformate known in the chemical arts. Specifically, the preparation method is to use a compound of the formula ( ⁇ ) in the presence of anhydrous potassium phosphate in an organic solvent such as acetone, first reacted with a stoichiometric amount of carbon disulfide, and then stirred and stoichiometric with a suction. The electron-based olefin or bromopropionitrile is subjected to a reaction, and after the completion of the reaction, the reaction product can be purified according to a conventional method in the chemical field to obtain the desired compound of interest.
  • the preparation method may be as follows: 1 equivalent of the compound of the formula ( ⁇ ) is dissolved in acetone, 1 equivalent of anhydrous potassium phosphate is added, and after a few minutes, 4 equivalents of carbon disulfide are added, and after 20 minutes, 1 equivalent is added. After stirring at room temperature for several hours, the solvent is distilled off, diluted with water, extracted with ethyl acetate, and the organic solvent is removed to obtain a crude product which is purified by column chromatography to obtain the desired objective.
  • 1 equivalent of the compound of the formula ( ⁇ ) is dissolved in acetone, 1 equivalent of anhydrous potassium phosphate is added, and after a few minutes, 4 equivalents of carbon disulfide are added, and after 20 minutes, 1 equivalent is added. After stirring at room temperature for several hours, the solvent is distilled off, diluted with water, extracted with ethyl acetate, and the organic solvent is removed to obtain a crude product which is purified by column chromatography to obtain the desired objective.
  • the starting compound ( ⁇ ), the olefin-linked olefin and the bromopropionitrile used therein may be commercially available or prepared according to methods known in the art.
  • reaction conditions and auxiliary reagents to be used may be appropriately adjusted depending on the compound to be prepared, and the change in the reaction conditions is easily determined by a person skilled in the art by a routine experiment.
  • the synthesis may be carried out by reacting furan (Cw) decylamine with carbon disulfide and 3-bromopropionitrile, The reaction can be carried out in the presence of potassium phosphate in acetone at room temperature.
  • the furyl group described therein may be substituted or unsubstituted.
  • the corresponding boronic acid ester compound can be first prepared.
  • the borate ester compound can be prepared by reacting dibromofluorenyl with n-butyllithium under nitrogen atmosphere to form 2-bromoindole at -76 ° C using anhydrous tetrahydrofuran as a solvent. Lithium base, the compound can be directly reacted with trimethyl borate without isolation to obtain the corresponding 2-bromodecyl borate, and then the above-mentioned synthesis of the compound of the general formula (I) can be carried out as a raw material to obtain the target compound. .
  • the group R 4 is a substituent on the group A described above, and the group is one or more substituents selected from the group consisting of halogen, d- 4 fluorenyl, d- 4 methoxy, phenyl a phenoxy group, a furyl group, a morpholinyl group, a d- 6 amide amide group, and a d- 4 methoxycarbonyl group; or the pyridine group is fused to a benzene ring or a heterocyclic ring, preferably fused to a pyridyl group.
  • a benzene ring or a morpholine ring the fused benzene ring or heterocyclic ring is unsubstituted or substituted with a - 4 fluorenyl group, preferably unsubstituted or substituted with a methyl group.
  • the specific preparation method is as follows: 3-aminopyridine is dissolved in diethyl ether, triethylamine is added thereto, and after a few minutes, carbon disulfide is added, and after reacting for a certain period of time, bromopropionitrile is added thereto, and stirred at room temperature for several hours; Method The compound is subjected to post-treatment, for example, purification by column chromatography to give the desired compound.
  • the compound can be synthesized by the following method:
  • the furyl group may have a substituent as described in the above formula.
  • the preparation method comprises the steps of: stirring the reaction of paraformaldehyde, acetone and dimethylamine hydrochloride in a mixed solution of water and isopropyl alcohol for several hours, and then post-treating with 50% NaOH, and not concentrating the organic phase.
  • the reaction is directly carried out with carbon disulfide and 2-furanmethylamine to obtain the above compound in which the aminodithioformate moiety is a cyclic group.
  • various other compounds of the formula (I) wherein the aminodithioformate moiety is a cyclic group can be prepared.
  • the preparation of the pharmaceutically acceptable salt of the compound of the formula (I) of the present invention can be carried out in the process of preparing the compound, or after the preparation of the compound, the compound can be reacted with the corresponding acid according to a conventional method to obtain a corresponding salt.
  • Another object of the present invention is to provide a pharmaceutical composition which is a tyrosine kinase inhibitor which can be used for the treatment of diseases mediated by protein tyrosine kinases, for example, for treating tumors, in particular Suitable for the treatment of breast cancer, liver cancer, non-small cell lung cancer, gastric cancer, colon cancer, leukemia or nasal cancer.
  • the composition contains the compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient, and may optionally contain a pharmaceutically acceptable carrier.
  • the composition contains a therapeutically effective amount of a compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
  • the active ingredient is present in the compositions of the invention in an amount of from 0.5% to 99%, and the pharmaceutically acceptable carrier is from 1% to 99.5%, based on the total weight of the composition.
  • composition of the present invention can be formulated into various conventional pharmaceutical dosage forms, for example, in the form of oral or parenteral administration, for example, various injection administration, topical administration, inhalation administration.
  • compositions are, for example, tablets, capsules, granules or other pharmaceutically acceptable liquid form preparations such as solutions, emulsions, suspensions and the like.
  • Preferred oral preparations are tablets, and the tablets may be in the form of a coating, enteric, sustained release or quantitative release.
  • one or more pharmaceutically acceptable carriers may be added to the active ingredient as needed, including such conventional pharmaceutical adjuvants such as excipients, fillers, diluents, A disintegrant, a surfactant, a wetting agent, a preservative, a sweetener, a pigment, and the like.
  • the appropriate dosage form and administration dose are selected according to the type of the disease, the severity of the disease, and the condition of the patient, such as sex, age, body weight, etc., usually, the dosage is from 1 to 200 mg/kg body weight/day, preferably from 1 to 50 mg/kg body weight. / between days.
  • compositions of the present invention and the various formulations of the compositions can be prepared according to conventional methods known in the pharmaceutical art.
  • Another object of the present invention is to provide a pharmaceutical use of the compound of the formula (I) or an acceptable salt thereof, and the present invention discloses a compound of the above formula (I) or an acceptable salt thereof, and a pharmaceutical combination containing the same
  • the antitumor drug is particularly useful for treating tumors such as breast cancer, liver cancer, non-small cell lung cancer, gastric cancer, colon cancer, leukemia or nasal cancer.
  • Another object of the present invention is to provide a method of treating a tumor comprising administering a therapeutically effective amount of a compound of the formula ⁇ ), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, to a patient in need of such treatment.
  • the organic phase was combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate
  • the column was separated by column chromatography with ethyl acetate- petroleum ether as eluent to give a pale-yellow solid, which crystallised as pale yellow needle crystals, yield 34%, mp 42-43 °C.
  • the compound is placed in the air, and the color gradually becomes darker over time, so the seal is preferably stored.
  • This compound was prepared in substantially the same manner as in Example 1, except that methyl acrylate was used in place of acrolein, and the target compound was obtained as white crystals, yield 81%, melting point 50-52 °C.
  • This compound was prepared in the same manner as in Example 1, except that 2-bromopropionitrile was used instead of acrolein, and the target compound was obtained as a white solid, yield 61%, m.p.
  • acetone (1.2 mol) and dimethylamine hydrochloride (0.6 mol) and water (150 mL) were placed in a 500 mL round bottom flask, and paraformaldehyde (0.8 mol) and isopropanol (15) were added with stirring at room temperature. (mL), the reaction was stirred under reflux for 6 hours, the reaction was stopped, and most of the solvent was evaporated under reduced pressure. Then, 25 g of 50% aqueous sodium hydroxide solution was slowly added to the ice bath, and the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (25mLx4) The organic phase was combined, dried over anhydrous sodium sulfate, and then evaporated.
  • the catalyst aluminum oxide (4.0 mmol) was added to a solution of 2-chloroethylsulfonyl chloride (4.0 mmol) in dioxane (30 mL), and slowly stirred with ammonia gas. During the process, the formation of white mist was observed. After stirring for 2 hours, the reaction was stopped. The mixture was filtered under suction, and a portion of solvent was evaporated under reduced pressure. 50 mL of water was then evaporated, ethyl acetate (25mL ⁇ 3), and the organic phase was combined. Drying over sodium sulfate and concentrating under reduced pressure gave a pale-yellow liquid succinimide, which was directly reacted with furanamine and carbon disulfide without purification to give the corresponding product as an oil.
  • This compound was prepared in substantially the same manner as in Example 7 except that the methyl isothiouronium salt was replaced with a benzylisothiouronium salt.
  • the obtained product was obtained as a white solid, yield 77%, m.p.
  • the preparation method of the compound is basically the same as the preparation method of the furanthranamine derivative corresponding to the examples 1-8, and the corresponding pyridinium amine can be replaced by the corresponding pyridinium amine.
  • the prepared compounds and structural confirmation data are as follows:
  • Examples 31-33 Preparation of Compound 31-33
  • the preparation method of the compound is basically the same as the preparation method of the furanthylamine derivative corresponding to the third embodiment, except that the pyridylamine is replaced by the corresponding pyridinium amine, and the prepared compound and structure are prepared.
  • the data are as follows: thioformic acid-(2-cyano)ethyl ester (31)
  • the compound was prepared in substantially the same manner as the corresponding furyl mercaptoamine derivative of Example 3 except that the corresponding heterocyclic mercaptoamine was used in place of the furoylamine as a starting compound.
  • the prepared compounds and structural confirmation data are as follows:
  • the compounds of the present invention are evaluated for the inhibition rate of proliferation of four different tumor cells using a conventional antitumor activity test method in the pharmaceutical field, for example, by the method described in the following literature: (. Immunol Method, 1983, 65, 55). The test results are shown in Table 1 below.
  • test model is: A: MTT method (HL-60 human leukemia); B: SRB method (BGC-823 human gastric cancer); C: SRB method (Bel-7402 human liver cancer); D: SRB method (KB human nose) Pharyngeal cancer);
  • the test concentration is 10 ⁇ .
  • ED 5 of the compounds of the invention against human leukemia HL-60 cells and Bel7402 cells The value can be measured by the following method, and the results are shown in Table 2 below.
  • Test method for ED 50 of human leukemia HL-60 cells Human leukemia HL-60 cells were cultured in vitro. After the cells were grown to logarithmic growth phase, the cells were collected, centrifuged at 0.01 rpm for 5 minutes, the supernatant was discarded, the appropriate medium was suspended, and the cell concentration was adjusted to 1.2 ⁇ 10 4 /mLo. The cell suspension was inoculated into a 96-well cell culture plate. 90 ⁇ per well, add the drug diluted in the cell culture medium to each well of the drug group, add the same amount of cell culture medium to the blank control group, set three replicate wells for each drug, and set the control hole with only drug (no cells). Three, negative control groups were 0.5% DMSO medium.
  • the compounds of Examples 11, 16, and 47 of the present invention were selected by the following methods to evaluate the protein tyrosine kinase EGFR inhibitory activity of the compound of the present invention, and the selected small molecule EGFR, erbB2 double receptor tyrosine kinase inhibitor was selected.
  • Lapatinib is used as a positive control. Clinical trials have confirmed that the drug has significant efficacy in the treatment of invasion, recurrence, inflammatory, and metastatic breast cancer.
  • the experimental method is: Cell line: EGFR overexpressing cell line MDA-MB-468, erbB2 overexpressing cell line SK-BR-3, and EGFR and erbB2 low expressing cell line HCT116 were selected as controls;
  • the present invention requires the patented compound of the general formula (I) to have superior protein butyrate kinase inhibitory activity and anticancer activity than the known drug lapatinib, and is expected to be developed into a class.
  • New anti-tumor drugs of new structure type Particularly, the group ⁇ is a pyridyl group, and the R 3 group is a cyano group, a fluorenyloxy group, a boronic acid group or a benzylsulfinyl group, which exhibits better antitumor activity.

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Description

芳杂（垸基）氨基二硫代甲酸酯类化合物、 其制备方法和应用 技术领域
本发明涉及一类新的芳杂 （垸基） 氨基二硫代甲酸酯类化合物， 其制备方法和应用， 本发 明化合物是一类新的酪氨酸激酶抑制剂， 可作为抗肿瘤药物。
背景技术
表皮生长因子受体 （EAB ) 家族属于 I 型受体酪氨酸激酶家族， 该家族有四个成员： ErbB- l(EGFR), ErbB-2(HER-2), ErbB-3 和 ErbB-4。 研究表明， 在膀胱癌、 乳腺癌、 结肠癌、 肺癌等肿瘤细胞中， EGFR和 HER-2均有高表达， 实体瘤与它们的高表达之间有很强的相关 性。 因此， 近年来以 EGFR和 HER-2作为靶点进行靶向抗肿瘤药物研究受到高度重视。
目前， 己发现的 EGFR和 HER-2抑制剂的主要结构类型有以下 5种， 即 4-氨基喹唑啉类、 4-氨基 -3-氰基喹啉、 苯亚甲基丙二腈类、 水杨酰胺类和吡咯并三嗉类。 这 5种结构中研究最多 的是 4-氨基喹唑啉类和 4-氨基 -3-氰基喹啉类， 例如中国专利申请 CN200610023526.7及国际申 请公开 WO2008/0033748和 WO2008/0033749所公开的化合物。 己发现了一些抗肿瘤活性很好 的化合物， 有些己进入临床。
氨基二硫代甲酸酯类化合物是另外一类具有抗肿瘤活性的化合物， WO2007/050963A1 公 开了一类氨基二硫代甲酸酯类化合物：
S
' CH 2.)n II . 其中的 R1 为环垸基、 芳基或苯并的吡咯基、 呋喃基或噻吩基； 所述化合物可用作抗肿瘤 药物 ； 李润涛等人在 中 国发 明专利 申请 CN01118399.3 、 CN200410054686.9 和 CN200910143757.5 中也公开了多种此类化合物， 所述化合物中的 R1和 R2基团的类别各不相 同。
基于现有技术对氨基二硫代甲酸酯类化合物的研究结果和表皮生长因子受体抑制剂 (EGFR inhibitor)的研究进展， 本发明人经过大量实验， 发现了一类结构全新的、 活性强、 选择性高、 毒性低的表皮生长因子受体抑制剂。
发明内容
牛 1 W H'、J H Η \) τεΐ¾1Λ 类具有全新结构的下述通式 （I) 化合物或其药用盐：
A'
Figure imgf000003_0001
八, R
^ (I)
其中：
A是取代或未取代的、 具有一个或多个选自氮、 氧和硫的杂原子的五元或六元杂环基， 所 述的杂环基可以被一个或多个选自下述的取代基所取代： 卤素、 d— 4垸基、 d— 4垸氧基、 苯 基、 苯氧基、 呋喃基、 吗啉基、 d— 6垸基酰胺基和 d— 4垸氧羰基； 当所述的杂环基是吡啶基 时， 所述吡啶基还可以与苯环或杂环稠合， 所述稠合的苯环或杂环是未取代的或是被 垸基 取代的；
R1是氢、 苯基或 d— 4垸基；
R2是氢或 4垸基；
R3是氰基、 硼酸基、 垸氧羰基、 氨基磺酰基、 苄基亚磺酰基或 d— 4垸基亚磺酰基； 或 R2与 R3连接在一起形成含有氮原子和硫原子的、 饱和或不饱和的五或六元杂环， 所述 的杂环是未取代的， 或被一个或多个羟基或 垸基所取代； 和
m是 0-3的整数。
在本发明的化合物中， 所述的基团 A是取代或未取代的杂环基； 优选的， 基团 A是取代或 未取代的吡啶基、 嘧啶基、 吡嗉基、 呋喃基、 噁唑基、 吡唑基、 噻唑基或噁二唑基； 其中所述 的杂环基可以被一个或多个选自下述的取代基所取代： 卤素、 d— 4垸基、 d— 4垸氧基、 苯基、 苯氧基、 呋喃基、 吗啉基、 d— 6垸基酰胺基和 d— 4垸氧羰基； 或者， 当所述的杂环基是吡啶基 时， 所述吡啶基还可以与苯环或杂环稠合， 所述稠合的苯环或杂环是未取代的或是被 垸基 取代的。
在本发明化合物的上述定义中， 所用的术语" 垸基"是指饱和的、 具有 1-4个碳原子的 直链或支链的烃基垸基， 优选具有 1-3 个碳原子的直链或支链的垸基， 例如甲基、 乙基、 丙基 或异丙基等； 更优选甲基和乙基， 最优选甲基。
在本发明化合物的上述定义中， 所用的术语 " d— 4垸氧基"是指饱和的、 具有 1-4个碳原子 的直链或支链的垸氧基， 例如甲氧基、 乙氧基、 丙氧基或异丙氧基； 优选甲氧基或乙氧基； 更 优选甲氧基。
在本发明化合物的上述定义中， 所用的术语 4垸氧羰基" 是指饱和的、 具有 1-4个碳 原子的直链或支链的垸氧羰基， 例如甲氧羰基、 乙氧羰基、 丙氧羰基或异丙氧羰基； 优选甲氧 羰基或乙氧羰基； 更优选甲氧羰基。
在本发明化合物的上述定义中， 所用的术语" d— 6垸酰胺基"是指饱和的、 具有 1-6个碳原 子的直链或支链的垸酰胺基， 例如甲酰胺基、 乙酰胺基、 丙酰胺基、 或各种异构的丁酰胺基、 戊酰胺基或己酰胺基； 优选具有 4-6 个碳原子的支链垸酰胺基， 更优选戊酰胺基的各种异构 体， 最优选异戊酰胺基或特戊酰胺基。
在本发明化合物的上述定义中， 所用的术语 "卤素" 是指氟、 氯、 溴和碘原子， 优选为 氟、 氯或溴原子， 更优选溴原子。
在本发明所述的化合物中， 优选的 A基团是取代或未取代的吡啶基。
在本发明所述的化合物中， 优选的 R3基团是氰基。
在本发明所述的化合物中， 优选化合物的 A基团是取代或未取代的吡啶基以及 R3基团是 氰基。 本发明所述通式 （I) 化合物的药用盐是指本发明化合物的酸加成盐， 包括无机酸加成盐或 有机酸加成盐， 所述的无机酸例如是硫酸、 盐酸、 亚硫酸、 硼酸、 磷酸、 磺酸、 氢溴酸或氢氟 酸等； 所述的有机酸例如是乙酸、 戊酸、 马来酸、 富马酸、 草酸、 油酸、 乳酸、 棕榈酸、 月桂 酸、 硬脂酸、 柠檬酸、 琥珀酸、 酒石酸、 苯甲酸、 甲磺酸、 甲苯磺酸、 葡萄糖酸、 乳糖酸或月 桂基磺酸等； 在所述的盐之中还可以有碱金属或碱土金属阳离子， 例如锂、 钠、 钾、 钙、 镁等 的阳离子， 以及各种有机铵阳离子， 例如四甲基胺、 四乙基胺、 甲胺、 二甲胺、 乙胺等形成的 铵盐阳离子。
本发明化合物定义中， 使用了术语 "取代或未取代的"， 其中所述的 "取代" 是指在可取 代的任意位置上被所述取代基单取代或多取代的基团。
本发明的上述化合物是表皮生长因子受体抑制剂 (EGFR inhibitor), 可用于治疗肿瘤， 特别 适用于治疗由蛋白酪氨酸激酶介导的疾病， 如乳腺癌、 肝癌、 非小细胞肺癌、 胃癌、 结肠癌、 白血病、 鼻癌等。
本发明优选的化合物是：
3-(2-呋喃甲基) -4-羟基 -1,3-噻嗉垸 -2-硫酮 (化合物 1);
2-呋喃甲氨基二硫代甲酸 -(2-甲氧甲酰)乙酯 (化合物 2);
2-呋喃甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 3);
3- (2-呋喃甲基) -4-羟基 -4,5-二甲基 -3， 4-二氢 -1,3-噻嗉 -2-硫酮 (化合物 4);
2-呋喃甲氨基二硫代甲酸 -(2-氨基磺酰基)乙酯 (化合物 5);
2-呋喃甲氨基二硫代甲酸 -(2-硼酸基)乙酯 (化合物 6);
2-呋喃甲氨基二硫代甲酸 -(2-甲亚磺酰基)乙酯 (化合物 7);
2-呋喃甲氨基二硫代甲酸 -(2-苄基亚磺酰基)乙酯 (化合物 8);
3- (3-吡啶甲基) -4-羟基 -1,3-噻嗉垸 -2-硫酮 (化合物 9);
3-吡啶甲氨基二硫代甲酸 -(2-甲氧甲酰基)乙酯 (化合物 10);
3-吡啶甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 11);
3-(3-吡啶甲基) -4-羟基 -4,5-二甲基 -3,4-二氢 -1,3-噻嗉 -2-硫酮 (化合物 12);
3-吡啶甲氨基二硫代甲酸 -(2-氨基磺酰基)乙酯 (化合物 13);
3-吡啶甲氨基二硫代甲酸 -(2-硼酸基)乙酯 (化合物 14);
3-吡啶甲氨基二硫代甲酸 -(2-甲基亚磺酰基)乙酯 (化合物 15);
3-吡啶甲氨基二硫代甲酸 -(2-苄基亚磺酰基)乙酯 (化合物 16);
3-(4-特戊酰胺基)吡啶甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 17);
3-喹啉甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 18);
3-吡啶甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 19);
3-(2-甲氧基)吡啶甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 20);
3-(6-甲氧甲酰基)吡啶甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 21); 3-(4,6-二甲基)吡啶甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 22);
3-(5-甲氧基)吡啶甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 23);
3-(5-溴)吡啶甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 24);
3-[6-(2-呋喃基)]吡啶甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 25);
7-(4-甲基 -3,4,4a,8a-四氢 -2H-吡啶并 [3,2-b][l,4]噁嗉）甲氨基二硫代甲酸 -(2-氰
);
3- (6-苯氧基)吡啶甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 27);
4-吡啶甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 28);
N-甲基 -3-吡啶甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 29);
3-吡啶氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 30);
3-吡啶苯甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 31);
1 - (3-吡啶)乙氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 32);
3- (6-甲氧基)吡啶甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 33);
5- (4-甲基 -2-苯基)噁唑甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 34);
4- (5-甲基 -1-苯基) -1H-吡唑甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 35);
5-嘧啶甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 36);
5-(1,3-二甲基) -1H-吡唑甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 37)；
2-噻唑甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 38);
2-吡嗉甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 39);
2- (5-苯基) -1,3,4-噁二唑甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 40);
5-(2-吗啉基)嘧啶甲氨基二硫代甲酸 -(2-氰基)乙酯（化合物 41);
3-吡啶丙基氨基二硫代甲酸 -(2-氰基)乙酯 （化合物 42);
3-吡啶甲氨基二硫代甲酸 -(2-氰基)乙酯盐酸盐 （化合物 43);
3-吡啶乙氨基二硫代甲酸 -(2-氰基)乙酯盐酸盐 （化合物 44);
2- (5-苯基) -1,3,4-噻二唑甲氨基二硫代甲酸 -(2-氰基)乙酯 （化合物 45);
(1H-吡咯 -2-基)甲基氨基二硫代甲酸 -(2-氰基)乙酯 （化合物 46); 和
3- (吡啶 -3-基甲基氨基二硫代甲酸酯基)丙酸丁酯 （化合物 47)。
本发明的另一目的是提供了上述通式 （I) 化合物或其药用盐的制备方法， 所述的通式
Figure imgf000006_0001
其中通式 ω和 (π)中各基团的定义如上文所述；
如果需要， 可按化学领域常规的成盐方法制备所述化合物的药用盐。
上文所述的制备方法是化学领域己知的制备氨基二硫代甲酸酯的方法。 具体地， 所述制备 方法是使用式 (Π)化合物在无水磷酸钾存在下， 在有机溶剂如丙酮中， 首先与化学计量的二硫 化碳反应， 然后再在搅拌下与化学计量的、 连有吸电子基的烯烃或溴丙腈进行反应， 反应结束 后可按照化学领域的常规方法对反应产物进行精制， 得到所需的目的化合物。
更具体的， 所述制备方法可以是： 将 1当量的式 (Π)化合物溶于丙酮中， 加入 1当量的无水 磷酸钾， 数分钟后， 加入 4当量的二硫化碳， 20分钟后加入 1当量的连有吸电子基的烯烃或溴 丙腈， 在室温下搅拌数小时后， 蒸除溶剂， 加水稀释， 乙酸乙酯萃取， 除去有机溶剂后得到粗 品， 经柱层析纯化后得到所需目的化合物。
其中所使用的原料化合物 （π)、 连有吸电子基的烯烃和溴丙腈可在市场上购买， 或按照本 领域己知方法制备。
根据所制备的化合物不同， 可对所使用的具体反应条件和辅助试剂作适当调整， 所述反应 条件的变化是本领域技术人员通过常规试验很容易确定的。
例如， 当目的化合物中的 Α基团是呋喃基， R3基团是氰基时， 所述的合成方法可以是使呋 喃 （Cw ) 垸基胺与二硫化碳和 3-溴丙腈反应， 所述反应可以在磷酸钾存在下， 在丙酮中， 于 室温下进行。 其中所述的呋喃基可以是取代或未取代的。
又如， 当目的化合物中的 R3是硼酸基时， 可以首先制备对应的硼酸酯化合物。 例如， 所 述硼酸酯类化合物可按照下述方法制备： 在 -76°C条件下， 以无水四氢呋喃作为溶剂， 使二溴垸 基与正丁基锂在氮气保护下反应生成 2-溴垸基锂， 该化合物可不经分离直接与硼酸三甲酯反应 得到对应的 2-溴垸基硼酸酯， 然后以此为原料， 进行上述合成通式 （I ) 化合物的反应， 即可 得到目的化合物。
又如， 当本发明通式 （I ) 化合物中的 A基团为取代或未取代的吡啶基、 m=0和 R3是氰基 时， 所述的化合物可按照下述方法制备：
Figure imgf000007_0001
然后根据需要， 按照化学领域常规的成盐方法制备所述化合物的药用盐；
其中基团 R4是前文所述基团 A上的取代基， 该基团是一个或多个选自下述的取代基： 卤 素、 d— 4垸基、 d— 4垸氧基、 苯基、 苯氧基、 呋喃基、 吗啉基、 d— 6垸基酰胺基和 d— 4垸氧羰 基； 或者， 所述吡啶基与苯环或杂环稠合， 优选与吡啶基稠合的是苯环或吗啉环； 所述稠合的 苯环或杂环是未取代的或是被 — 4垸基取代的， 优选是未取代的或是被甲基取代的。
具体的制备方法例如： 将 3-氨基吡啶溶于乙醚中， 向其中加入三乙胺， 数分钟后加入二硫 化碳， 反应一定时间后向其中加入溴丙腈， 于室温下搅拌数小时； 然后按照常规方法对该化合 物进行后处理， 例如经柱层析纯化， 得到所需目的化合物。 当本发明化合物中的 A基团为 2-呋喃基、 m=l 以及甲氨基二硫代甲酸酯部分为环状基团 时， 所述的化合物可以通过下述方法合成：
0
( HCHO) n + 义 + Me2 NHHCI »
Figure imgf000008_0001
其中， 所述呋喃基上可以带有上文通式定义中所述的取代基。
具体地， 所述制备方法是将多聚甲醛、 丙酮与二甲胺盐酸盐在水和异丙醇混合溶液中回流 搅拌反应数小时， 然后用 50% NaOH进行后处理， 有机相浓缩后不经纯化直接与二硫化碳和 2- 呋喃甲胺进行反应， 得到其中的氨基二硫代甲酸酯部分为环状基团的上述化合物。 参照上述方 法， 可以制备氨基二硫代甲酸酯部分为环状基团的其它各种通式 （I ) 化合物。
本发明通式 （I ) 化合物的药用盐的制备可在制备该化合物的过程中完成， 也可以在制备得 到该化合物后， 按照常规方法， 使该化合物与相应的酸反应可制得对应的盐。
本发明的另一目的是提供了一种药物组合物， 该药物组合物是一种酪氨酸激酶抑制剂， 可 用于治疗由蛋白酪氨酸激酶介导的疾病， 例如可用于治疗肿瘤， 特别适用于治疗乳腺癌、 肝 癌、 非小细胞肺癌、 胃癌、 结肠癌、 白血病或鼻癌等。 该组合物以本发明的通式 （I ) 化合物或 其药用盐为活性成分， 其中还可以任意地含有药用载体。
具体的， 该组合物含有治疗有效量的本发明通式 （I ) 化合物或其药用盐， 以及一种或多种 药学上可接受的载体。 优选的， 以组合物的总重量计， 本发明组合物中活性成分的含量是 0.5 % -99%, 药用载体的含量是 1 %-99.5 %。
本发明的组合物可以制成各种常规的药用剂型， 例如制成口服、 肠胃外给药的形式， 所述 肠胃外给药的形式例如是各种注射给药、 局部给药、 吸入给药、 直肠给药或植入给药的形式。
适于药用的口服给药制剂例如是片剂、 胶囊、 颗粒剂或其它适于药用的液体形式的制剂如 溶液、 乳液、 悬浮剂等。 优选的口服制剂是片剂， 并且所述片剂可以制成包衣、 肠溶、 缓释或 定量释放的形式。
为了制备适用的剂型， 可根据需要在活性成分中添加一种或多种药用载体， 所述的药用载 体包括各种常规的药用辅剂， 例如赋形剂、 填充剂、 稀释剂、 崩解剂、 表面活性剂、 湿润剂、 防腐剂、 甜味剂、 色素等。
根据疾病的类型、 严重的程度以及患者的状况， 例如性别、 年龄、 体重等选用合适的剂型 和施用剂量， 通常成人施用剂量在 l-200mg/kg体重 /天， 优选为 l-50mg/kg体重 /天之间。
本发明的药用组合物和该组合物的各种制剂可按照制药领域己知的常规方法制备。
本发明的另一目的是提供了通式 （I ) 化合物或其可接受盐的药用用途， 本发明公开了上述 通式 （I ) 化合物或其可接受的盐， 以及含有上述化合物的药物组合物在制备酪氨酸激酶抑制剂 中的应用， 特别是在制备抗肿瘤药物中的应用。 所述的抗肿瘤药物特别适用于治疗乳腺癌、 肝 癌、 非小细胞肺癌、 胃癌、 结肠癌、 白血病或鼻癌等肿瘤。
通过对本发明化合物的活性进行筛选， 包括进行体外抗肿瘤活性测试和蛋白酪氨酸激酶抑 制活性筛选试验， 由所得到的结果可以看出， 本发明的通式 （I ) 的化合物或其药用盐具有优异 的蛋白酪酸激酶抑制活性和抗癌活性， 有望开发成为一类新结构类型的抗肿瘤新药。
本发明的另一目的是提供了一种治疗肿瘤的方法， 该方法包括将治疗有效量的通式 α ) 化 合物或其药用盐或上述药物组合物施用于需要这种治疗的患者。
具体实施方式
下面通过具体的实施方式对本发明的技术方案作进一步的说明， 其中例举的实施例是对本 发明的说明， 而不以任何方式限制其保护范围。
实施 喃甲基) -4-羟基 -1,3-噻嗪垸 -2-硫酮 （1 ) 的制备
Figure imgf000009_0001
将呋喃苄胺 （4 mmol ) 与二硫化碳 (5 mmolM衣次加入 15mL 水中， 接着加入三乙胺
(8mmol),室温下搅拌反应 10分钟后， 溶液淡黄色， 缓慢滴加丙烯醛 （4 mmol) , 很快可见白色 浑浊产生。 继续反应 1小时后 TLC检测原料点消失， 停止反应， 加入 20mL水后， 用乙酸乙酯 ( 15mLx3 ) 萃取， 合并有机相， 依次用水， 饱和食盐水洗， 无水硫酸镁干燥， 有机溶液浓缩 后直接上柱， 以乙酸乙酯 -石油醚为洗脱剂进行加压柱层析分离， 得到淡黄色固体， 重结晶可得 淡黄色针状结晶， 收率 34%， 熔点 42-43 °C。 该化合物在空气中放置， 可随时间延长颜色慢慢 变深， 因此密封保存为宜。
^NMR (300MHz, CDC13): 82.20 (m, IH), 2.45 (m, IH), 2.63 (m, IH), 3.39-3.54 (m, 2H),
5.02-5.07(d, IH), 5.38 (s, IH), 5.71-5,76 (m, 2H), 6.38-6.51 (bs, NH), 7.39 (m, IH). Anal Calcd. for C9HuN02S2: C, 47.14; H, 4.83; N, 6.11. Found: C, 47.43; H, 5.14; N, 5.90.
实施 硫代甲酸 -(2-甲氧甲酰基)乙酯 （2) 的制备
Figure imgf000009_0002
该化合物的制备方法与实施例 1 基本相同， 只是需要用丙烯酸甲酯代替其中的丙烯醛， 所 得目标化合物为白色晶体， 收率 81%， 熔点 50-52 °C。
^NMR (300MHz, CDC13): δ 2.79 (t, 2H, J = 6.6 Hz); 3.53 (t, 2H, J = 6.6 Hz); 3.70 (s, 3H); 4.87 (s, 2H); 6.33-6.36 (m, 2H); 7.18 (bs, NH); 7.39 (s, IH). Anal Calcd. for C10H13NO3S2: C, 46.31 ; H, 5.05; N, 5.40. Found: C, 46.43; H, 5.24; N, 5.70.
实施 氨基二硫代甲酸 -(2-氰基)乙酯 （3) 的制备
Figure imgf000009_0003
该化合物的制备方法与实施例 1基本相同， 只是需要用 2-溴丙腈代替其中的丙烯醛， 所得 到目标化合物为白色固体， 收率 61%， 熔点 53-54 °C。
^NMR (300MHz, CDC13): δ 2.89 (t, 2H, J = 6.9Hz), 3.56 (t, 2H, J = 6.9 Hz), 4.88 (s, 2H), 7.12 (bs, NH), 7.33-7.41 (m, 3H). Anal Calcd. for C8H8N2OS2: C, 45.26; H, 3.80; N, 13.20. Found: C 45.61 ; H, 3.97; N, 13.12.
Figure imgf000010_0001
首先， 丙酮 （1.2 mol ) 与二甲胺盐酸盐 （0.6 mol )、 水 （150 mL ) 置于 500 mL圆底瓶 中， 室温搅拌下加入多聚甲醛 （0.8 mol) 与异丙醇 （15 mL )， 回流搅拌反应 6 小时， 停止反 应， 减压蒸去大部分溶剂后， 在冰浴条件下缓慢加入 25g 50%氢氧化钠水溶液， 分离有机相， 水相用乙酸乙酯 （25mLx4 ) 萃取， 合并有机相， 无水硫酸钠干燥， 减压浓缩后直接用于下一 步反应。
然后， 按照与实施例 1 相同的合成操作步骤， 取上一步反应的浓缩液与相应的二硫化碳、 呋喃甲胺反应， 得到白色固体目标化合物， 收率 57%， 熔点 88-89 °C。
^NMR (300MHz, CDC13): δ 2.37 (s, 3H), 3.10-3.15 (m, 3H), 3.59-3.62(m, 1H), 3.65-3.78 (m， 1H), 5.12-5.17(d, 1H), 5.47-5.52 (d, 1H), 6.36-6.47 (m, 2H), 7.40 (m, 1H). Anal Calcd. for CuH13N02S2: C, 51.74; H, 5.13; N, 5.49. Found: C, 51.46; H, 5.67; N, 5.12.
实施 硫代甲酸 -(2-氨基磺酰基)乙酯 （5) 的制备
Figure imgf000010_0002
冰浴条件下， 将催化剂三氧化二铝 （4.0 mmol) 加入溶有 2-氯乙基磺酰氯 （4.0 mmol) 的 二氧六环 （30 mL ) 溶液中， 搅拌下缓慢通入氨气， 反应过程中可观察到白雾的生成， 保持搅 拌反应 2 小时后停止反应， 抽滤， 减压蒸去部分溶剂后加 50 mL 水， 用乙酸乙酯萃取 (25mLx3 ) , 合并有机相， 用无水硫酸钠干燥， 减压浓缩得到淡黄色液体乙烯磺酰胺， 不经纯 化直接与呋喃甲胺、 二硫化碳反应得到相应的产物， 为油状物， 总收率 35%。
^NMR (300MHz, CDC13): δ 3.51-3.55 (m, 2Η), 4.08-4.13 (m, 2H), 4.74(s, 2H), 4.88-4.90(m, 2H), 6.35-6.38(m, 2H), 7.18(bs, NH), 6.36-6.47(m, 2H), 7.40-7.41(m, 1H). Anal Calcd. for C8H12N203S3: C, 34.27; H, 4.31 ; N, 9.99. Found: C, 34.35; H, 4.56; N, 10.13.
实施 二硫代甲酸 -(2-硼酸基)乙酯 （6) 的制备
Figure imgf000010_0003
在 -76°C条件下， 以无水四氢呋喃为溶剂， 二溴乙垸与正丁基锂在氮气保护下反应生成 2- 溴乙基锂， 不经分离直接与硼酸三甲酯反应得到对应的 2-溴乙基硼酸二甲酯， 然后用盐酸乙醚 饱和溶液处理， 得到关键中间体 2-溴乙基硼酸。 未经纯化与二硫化碳和呋喃甲胺直接进行下一 步反应， 操作步骤同实施例 1， 得淡黄色固体目标化合物， 总收率 19%， 熔点 73-75 °C。
HNMR (300MHz, CDC13): δ 3.51 -3.55 (m, 2H), 4.08-4.13 (m, 2H), 4.74 (s, 2H), 4.88-4.90
(m, 2H), 6.35-6.38 (m, 2H), 7.18 (bs, NH), 6.36-6.47 (m, 2H), 7.40-7.41 (m, 1H). Anal Calcd. for C8H12BN203S3: C, 34.27; H, 4.31 ; N, 9.99. Found: C, 34.35; H, 4.56; N, 10.13. 实施 二硫代甲酸 -(2-甲亚磺酰基)乙酯 （7) 的制备
Figure imgf000011_0001
将二溴乙垸 （10 mmol) 与氢氧化钠 （30 mmol) 加入到 10 mL水中， 搅拌下加入相转移 催化剂四丁基溴化铵 （TBAB ) (2 mmol) ，继续搅拌 10分钟后向反应体系中加入甲基异硫脲硫 酸盐 （10 mmol) 的水溶液 （10 mL ), 室温下继续搅拌反应 1小时； 加入二氯甲垸 （15 mL ), 室温反应过夜。 从反应体系中分出二氯甲垸层， 加入 80%甲酸溶液 （1.5 g )， 室温搅拌下滴加 30%双氧水 （2.0 g )， 滴加完毕后保持搅拌反应 4 小时， 可观察到溶液逐渐由无色变为淡黄 色。 停止反应， 静置分层， 有机相用 5%碳酸钠水溶液调节 pH到 7左右， 再用适当二氯甲垸进 行萃取， 有机相经无水硫酸钠干燥处理后， 减压浓缩即可得到相应的粗品， 2-溴代乙基甲基亚 砜。 该粗品未经纯化， 直接用于下一步反应， 然后按照实施例 1 的方法， 与呋喃甲胺和二硫化 碳反应， 制得目标化合物。 白色固体， 收率 65%， 熔点 43-45 °C。
^NMR (300MHz, CDC13): δ 1.55 (s, 3H), 3.25 (t, 2H), 4.05 (t, 2H), 4.66 (bs, NH), 4.96 (s, 2H), 6.29-6.40 (m, 2H), 6.36-6.47(m, 2H), 7.36-7.41 (m, 1H). Anal Calcd. for C9H13N02S3: C, 41.04; H, 4.97; N, 5.32. Found: C, 40.96; H, 4.85; N, 5.12.
实施 甲酸 -(2-苄基亚磺酰基)乙酯 （8) 的制备
Figure imgf000011_0002
该化合物的制备方法基本上与实施例 7相同， 只是要用苄基异硫脲盐替代其中的甲基异硫 脲盐， 所得产物为白色固体， 收率 77%， 熔点 51-52 °C。
^NMR (300MHz, CDC13): δ 3.28 (m, 2H), 4.03 (m, 2H), 4.68 (bs, NH), 4.94 (s, 2H), 6.29- 6.40 (m, 2H), 7.18(bs, NH), 6.36-6.47(m, 2H), 7.37-7.45(m, 6H). Anal Calcd. for C15H17N02S3: C, 53.07; H,5.05; N, 4.13. Found: C, 53.26; H, 5.13; N, 4.02。
实施例 9-29 化合物 9-29的制备
所述化合物的制备方法基本上与实施例 1-8 相应的呋喃垸基胺类衍生物的制备方法相同， 用相应的吡啶垸基胺代替其中的呋喃垸基胺即可。 所制备的化合物以及结构确证数据如下：
) -4-羟基 -1,3-噻嗪垸 -2-硫酮 （9)
Figure imgf000011_0003
淡黄色固体， 收率 58%; 熔点： 56-57 °Co
^NMR (CDC13, 300 MHz): δ 2.22 (m, 1Η), 2.48 (m, 1H), 2.66 (m, 1H), 3.40-3.56 (m, 2H), 5.03-5.08 (d, 1H), 5.38 (s, 1H), 6.21 -6.32(m, 1H), 6.38-6.51 (bs, NH), 7.39 (m, 3H). Anal Calcd. for C10H12N2OS2: C, 49.97; H, 5.03; N, 11.66. Found: C, 49.42; H, 5.16; N, 11.23.
3-吡啶甲氨基二硫代甲酸 -(2-甲氧甲酰基)乙酯 （10)
Figure imgf000012_0001
白色晶体， 收率 72%; 熔点： 50-52 °C。
^NMR (CDCI3, 300 MHz): δ 2.80 (t, 2H, J = 6.9 Hz), 3.53 (t, 2H, J = 6.9 Hz), 3.70 (s, 3H), 4.94 (s, 2H), 7.28-7.32 (m, IH), 7.70 (m, IH), 7.73 (bs, NH), 8.53-8.56 (m, 2H). Anal Calcd. for CuH14N202S2: C, 48.87; H, 5.22; N, 10.36. Found: C, 48.55; H, 5.24; N, 10.70.
酸 -(2-氰基)乙酯 （11)
Figure imgf000012_0002
白色固体， 收率 77%; 熔点： 58-60°C。
^NMR (CDCI3, 300 MHz): δ 2.87 (t, 2Η, J = 6.6Hz), 3.54 (t, 2H, J = 6.6 Hz), 4.88 (s, 2H): 7.12 (bs, NH), 7.23 (m, IH), 7.53-7.64 (m, 3H). Anal Calcd. for C10HUN3S2: C, 50.60; H, 4.67; N 17.70. Found: C, 50.72; H, 4.93; N, 17.62.
-羟基 -4,5-二甲基 -3,4-二氢 -1,3-噻嗪 -2-硫酮 （12)
Figure imgf000012_0003
白色固体， 收率 41%; 熔点： 71-72°C。
^NMR (CDCI3, 300 MHz): δ 2.38 (s, 3Η), 3.12-3.16 (m, 3H), 3.59-3.64 (m, IH), 3.65-3.78 (m, IH), 5.12-5.17 (d, IH), 5.47-5.52 (d, IH), 6.46-6.48 (m, IH), 7.40-7.42 (m, 3H). Anal Calcd. for C12H14N2OS2: C, 54.11 ; H, 5.30; N, 11.52 Found: C, 54.47; H, 5.66; N, 11.33.
酸 -(2-氨基磺酰基)乙酯 （13)
Figure imgf000012_0004
油状物， 收率 41%。
^NMR (CDCI3, 300 MHz): δ 3.52-3.55 (m, 2H),4.10-4.15 (m, 2H), 4.76 (s, 2H), 4.84-4.91 (m, 2H), 6.25-6.35 (m, 2H), 7.18 (bs, NH), 6.36-6.47 (m, IH), 7.40-7.42 (m, 3H). Anal Calcd. for C9H13N303S3: C, 37.09 H, 4.50; N, 14.42 Found: C, 37.35; H, 4.58; N, 14.16.
酸 -(2-硼酸基)乙酯 （14)
Figure imgf000012_0005
白色固体， 收率 48%; 熔点： 49-50 °C。
^NMR (CDCI3, 300 MHz): δ 3.49-3.51 (m, 2Η),4.10-4.15 (m, 2Η), 4.74 (s, 2H), 4.88-4.90 (m, 2H), 6.35-6.38 (m, 2H), 7.20 (bs, NH), 6.36-6.47 (m, IH), 7.40-7.41(m, 3H). Anal Calcd. for (61)騸 2(¾ -z)-邈 二
Figure imgf000013_0001
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Figure imgf000014_0001
淡黄色固体， 收率： 74%; 熔点： 82-84°C。
^NMR (CDC13,400 MHz): δ 8.50 (m， 1H)， 8.39 (m， 2H )， 7.56 (d， 1H， J = 7.6 Hz), 7.25 (dd， 1H， = 7.6， 5.2 Hz), 4.04 (dd， 2H， = 12.8, 6.4 Hz), 3.53 (t， 2H， J = 6.8 Hz), 3.04 (t， 2H， = 6.4 Hz), 2.87 (t， 2H， = 6.8 Hz) .
13CNMR(CDC13,100 MHz): δ 196， 149， 147， 136, 134, 123, 118， 47， 31, 30, 18.
3-(2-甲氧基)吡啶甲氨基二硫代甲酸 -(2-氰基)乙酯 （ 20)
Figure imgf000014_0002
白色固体， 收率： 67%; 熔点： 88-92°C。
^NMR (CDC13,400 MHz): δ 8.10 (dd， 1H， J= 1.6， 3.6 Hz), 7.71 (m， 1H)， 7.59 (dd， 1H， =1.6, 7.2 Hz), 6.83 (dd， 1H， J= 3.6, 7.2 Hz), 4.86 (d， 2H， J= 5.2 Hz), 3.90 (s, 3H), 3.47 (t， 2H， = 6.8 Hz), 2.82 (t， 2H， = 6.8 Hz) .
13CNMR(CDC13,100 ΜΗζ):δ 195， 162， 146， 139, 118， 118， 116， 54， 46， 30, 18. 3-(6-甲氧甲酰基)吡啶甲氨基二硫代甲酸 -(2-氰基)乙酯 （21)
Figure imgf000014_0003
白色固体， 收率： 30%; 熔点： 106-112°C。
^NMR (d6DMSO,400 MHz): δ 10.72 (m， 1H)， 8.63 (d， 1H， J=\.6 Hz), 8.
1H， J= 8.0 Hz), 7.85 (dd， 1H， J= 1.6， 8.0 Hz), 4.93 (d， 2H, J= 5.2 Hz), 3 3H), 3.47 (t， 2H， = 6.8 Hz), 2.90 (t， 2H， = 6.8 Hz) .
13CNMR (d6DMSO,100 MHz): δ 196， 165， 150， 147， 137, 136, 125, 118， 5 30, 18.
氨基二硫代甲酸 -(2-氰基)乙酯 （22)
Figure imgf000014_0004
淡黄色固体， 收率： 76%; 熔点： 138-142°C。
^NMR (d6DMSO,400 MHz): δ 8.22 (s, 1H)， 7.04 (s, 1H)， 4.75 (s, 2H)， 3.44 (t， 2H, = 6.8 Hz), 2.87 (t， 2H, = 6.8 Hz), 2.37 (s, 3H), 2.22 (s， 3H) .
13CNMR (d6DMSO,100 MHz): δ 195， 157， 149， 146， 128, 125, 119， 46， 30, 24， 19， 18.
3-(5-甲氧基)吡啶甲氨基二硫代甲酸 -(2-氰基)乙酯 （23)
Figure imgf000015_0001
白色固体， 收率： 73%; 熔点： 86-90°C。
^NMR (CDC13,400 MHz): δ 8.22 (s, 1H)， 8.14 (s, 1H)， 8.02 (m， 1H)， 7.21 (s， 1H)， 4.92 (d， 2H, = 5.6 Hz), 3.81 (s， 3H), 3.53 (t， 2H, = 6.8 Hz), 2.87 (t， 2H, J = 6.8 Hz) .
13CNMR(CDC13,100 MHz): δ 196， 149， 149， 146， 122, 122, 118， 49， 30, 18， 17. 3-(5-溴)吡啶甲氨基二硫代甲酸 -(2-氰基)乙酯 （24)
Figure imgf000015_0002
淡黄色固体， 收率： 71%; 熔点： 102-108°C。
^NMR (CDC13,400 MHz): δ 8.53 (d， 1H， J -- 1.6 Hz), 8.49 (d， 1H， = 1.6 Hz), 8.46 (d， 1H， J = 1.6 Hz), 7.84 (s， 1H)， 4.91 (d， 2H, J = 5.6 Hz), 3.51 (t， 2H, J = 6.8 Hz), 2.86 (t， 2H, J = 6.8 Hz) .
13CNMR (CDC13,100 MHz): δ 196, 156， 150， 147， 138, 134, 120， 47， 31， 18.
基二硫代甲酸 -(2-氰 ；)乙酯 (25)
Figure imgf000015_0003
淡黄色固体， 收率： 78%; 熔点： 118-120°C。
^NMR (CDC13,400 ΜΗζ):δ 8.43 (m， 2Η)， 7.66 (dd, 1Η， J= 1.6， 7.6 Hz), 7.58 (d， 1H， J = 7.6 Hz), 7.50 (s, 1H)， 7.00 (d， 1H， J = 3.2 Hz), 6.51 (dd, 1H， J = 1.6， 3.2 Hz), 4.89 (d， 2H, = 5.2 Hz), 3.51 (t， 2H, = 6.8 Hz), 2.86 (t， 2H, = 6.8 Hz) .
13CNMR (CDC13,100 MHz): δ 196， 153, 149， 149， 143, 137, 130, 118， 118， 112, 109， 48， 31, 18.
7-(4-甲基 -3，4，4a，8a-四氢 -2H-吡啶并 [3，2-b][l，4]噁嗪） 甲氨基二硫代甲酸 -(2-氰基）乙酯 (26
Figure imgf000015_0004
淡黄色固体， 收率： 79%; 熔点： 117-118°C。
^NMR (CDC13,400 ΜΗζ): δ 8.63 (s, 1H)， 7.50 (s, 1H)， 6.73 (s, 1H)， 4.57 (d， 2H， J = 4.0 Hz), 4.15 (t， 2H， J = 3.6 Hz), 3.45 (t， 2H， J = 6.8 Hz), 3.37 (t， 2H， J = 3.6 Hz), 3.02 (s, 3H), 2.81 (t， 2H， = 6.8 Hz) .
13CNMR (CDC13,100 MHz): δ 194， 148， 139, 139, 121, 120， 118， 64， 49， 48， 36, 30, 19. 二硫代甲酸 -(2-氰基)乙酯 （27)
Figure imgf000016_0001
油状物， 产率： 33%。
^NMR (CDC13,400 MHz): δ 8.13 (s, 0.5Η), 8.05 (s, 0.5H), 7.73 (m， 1H)， 7.41
(t， 2HJ= 7.6 Hz) 7.22(t,lH, = 7.2 Hz), 7.11 (d， 1H， = 7.6 Hz), 6.90 (d， 1H， = 7.6
Hz), 5.28 (m， 1H)， 4.83 (m， 1H)， 3.50 (t， 2H， = 6.8 Hz), 2.83 (t， 2H， = 6.8 Hz) .
13CNMR (CDC13,100 MHz): δ 197, 154， 147， 140， 130, 125, 121, 121, 118， 111, 111, 56， 32, 18.
代甲酸 -(2-氰基)乙酯 （28)
Figure imgf000016_0002
油状物， 产率： 69%。
^NMR (CDC13,400 MHz): δ 10.27 (m， 1Η)， 8.34 (d， 2Η， = 5.6 Hz), 7.16 (d， 2H， J = 5.6 Hz), 4.88 (d， 2H, J = 5.2 Hz), 3.43 (t， 2H, J = 6.8 Hz), 2.78 (t， 2H, J = 6.8 Hz) .
N-甲基 -3-吡啶甲氨基二硫代甲酸 -(2-氰基)乙酯 （29)
Figure imgf000016_0003
油状物， 产率： 72%。
^NMR (CDC13,400 MHz): δ 8.49 (s, 2H)， 7.57 (m， 1H)， 7.23 (m， 1H)， 5.23 (s,
1.45H), 4.90 (s, 0.45H), 3.50 (t， 2H, = 6.8 Hz), 3.36 (s, 0.85H), 3.20 (s, 2.02H), 2.88 (t， 2H, = 6.8 Hz) .
13CNMR(CDC13,100 MHz): δ 197， 149， 149， 135, 131, 124， 118， 57， 39, 32, 18. 实施例 30 3-吡啶氨基二硫代甲酸 -(2-氰基)乙酯 （30) 的制备
Figure imgf000016_0004
将 3-氨基吡啶（lmmol)溶于乙醚 (25mL)中， 向其中加入三乙胺（lmmol), 数分钟后加入二 硫化碳 (4 mmol)， 反应 20分钟后， 向其中加入溴丙腈 （lmmol), 于室温下搅拌 24小时； 然后 按照常规方法对该化合物进行后处理， 得到所需目的化合物。
白色固体， 收率： 20%; 熔点： 80-82°C。
^NMR (CDC13, 400 MHz): δ 10.81 (s, 1Η)， 8.68 (d， 1Η， = 1.6 Hz), 8.51 (d， 1H， J = 4.4 Hz), 8.27 (s， 1H)， 7.38 (dd， 1H， J = 1.6， 4.4 Hz), 3.54 (t， 2H, J= 6.8 Hz), 2.88 (t， 2H, J = 6.8 Hz) .
实施例 31-33 化合物 31-33的制备 所述化合物的制备方法基本上与实施例 3 相应的呋喃垸基胺类衍生物的制备方法相同， 只 是用相应的吡啶垸基胺代替其中的呋喃垸基胺即可， 所制备的化合物以及结构确证数据如下： 硫代甲酸 -(2-氰基)乙酯 （31)
Figure imgf000017_0001
白色固体， 收率： 65%; 熔点： 118-120°C。
^NMR (CDC13,400 MHz): δ 9.46 (d， 1H， = 6.8 Hz), 8.36 (d， 2H， = 6.8 Hz), 7. (d， 1H， J = 6.8 Hz), 7.36 (m， 3H), 7.23 (m， 3H), 6.94 (d， 1H， J = 6.8 Hz), 3. (t， 2H， = 6.8 Hz), 2.85 (t， 2H， = 6.8 Hz) .
13CNMR (CDC13,100 MHz): δ 195， 149， 148， 139, 136, 129， 128， 128， 124， 118 62， 31, 18.
二硫代甲酸 -(2-氰基)乙酯 （32)
Figure imgf000017_0002
油状物， 产率： 63%。
^NMR (CDC13,400 MHz): δ 8.79 (d， 1Η， = 5.2 Hz), 8.60 (m， 2H)， 7.69 (d， 1H， J = 5.2 Hz), 7.36 (s， 1H)， 5.80 (s， 1H)， 3.50 (t， 2H, = 6.8 Hz), 2.85 (t， 2H, = 6.8 Hz) .
3-(6-甲氧基)吡啶甲氨基二硫代甲酸 -(2-氰基)乙酯 （ 33)
S
J ^NI S〜CN
MeO N'
白色固体， 收率： 68%; 熔点： 90-92°C。
^NMR (CDC13,400 MHz): δ 8.10 (d， 1H， = 2.4 Hz), 7.75 (s， 1H)， 7.58 (dd， 1H， J = 2.4， 8.4 Hz), 6.72 (d， 1H， J = 8.4 Hz), 4.82 (d， 2H， J = 4.8 Hz), 3.90 (s， 3H), 3.50 (t， 2H， = 6.8 Hz), 2.85 (t， 2H， = 6.8Hz) .
13CNMR(CDC13,100 MHz): δ 197， 149， 149， 147， 123, 122, 118， 49， 30, 18， 17. 实施例 34-42 化合物 34-42的制备
所述化合物的制备方法基本上与实施例 3 相应的呋喃基垸基胺类衍生物相同， 只是需要用 相应的杂环垸基胺代替其中的呋喃垸基胺作为原料化合物。 所制备的化合物以及结构确证数据 如下：
5-(4-甲基 -2-苯基)噁唑甲氨基二硫代甲酸 -(2-氰基)乙酯 （34)
Figure imgf000017_0003
黄色固体， 收率： 85%; 熔点： 221-224 °C。
^NMR (CDC13,400 MHz): δ 2.29 (s, 3H), 2.80-2.89 (t, J = 6.8 Hz, 2H), 3.53-3.59 (t, = 6.8 Hz, 2H), 4.97 (s, 2H), 8.31 (bs, IH), 7.46-8.01 (m, 5H).
4- (5-甲基 -1-苯基） -IH-吡唑甲氨基二硫代甲酸 -(2-氰基)乙酯 （35)
Figure imgf000018_0001
白色晶体， 收率： 87%; 熔点： 135- 138 °C。
^NMR (CDC13,400 ΜΗζ): δ 2.33 (s, 3H), 2.86-2.89 (t, J = 6.8 Hz, 2H), 3.52-3.56 (t, = 6.8 Hz, 2H), 4.77 (s, 2H), 8.31 (bs, NH), 7.10 (bs, IH), 7.48-7.64 (m, 6H).
代甲酸 -(2-氰基)乙酯 （36)
Figure imgf000018_0002
白色晶体， 收率： 81%; 熔点： 168- 170°C。
^NMR (CDC13,400 MHz): δ 2.88-2. 91 (t, J = 6.8 Hz, 2H), 3.57-3.61 (t, J = 6.8 Hz, 2H), 4.65 (s, 2H), 5.04 (m, IH), 5.35 (m, IH), 7.12-7.14 (m, IH).
5-(l，3-二甲基) -IH-吡唑甲氨基二硫代甲酸 -(2-氰基)乙酯 （37)
厂 CN
/ 」」 白色晶体， 收率： 82%; 熔点： 112- 116°C。
^NMR (CDC13,400 ΜΗζ): δ 2.23 (s, 3H), 2.85-2.88 (t, J = 6.8 Hz, 2H), 3.52-3.55 (t, = 6.8 Hz, 2H), 3.76 (s, 3H); 4.90 (s, 2H), 6.04 (s, IH), 8.31 (bs, IH).
2-噻唑甲氨基二硫代甲酸 -(2-氰基)乙酯 （38)
广 CN
S」
N
黄色固体， 收率： 78%; 熔点： 76-78°C。
^NMR (CDC13,400 MHz): δ 2.85-2.88 (t, = 6.8 Hz, 2H), 3.52-3.56 (t, = 6.8 Hz, 2H), 5.23 (s, 2H), 7.36-7.37 (s, IH), 7.77-7.78 (s, IH), 8.47 (bs, IH).
2-吡嗪甲氨基二硫代甲酸 -(2-氰基)乙酯 （39)
Figure imgf000018_0003
白色晶体， 收率： 69%; 熔点： 96-99°C。
^NMR (CDC13,400 MHz): δ 2.85-2.93 (t, = 6.8 Hz, 2H), 3.55-3.63 (t, = 6.8 Hz, 2H), 5.05 (s, 2H), 8.31 (bs, IH), 8.56-8.78 (m, 3H).
基二硫代甲酸 -(2-氰基)乙酯 （40)
Figure imgf000019_0001
白色固体， 收率： 54%; 熔点： 148- 152°C。
^NMR (CDC13,400 MHz): δ 2.85-2.89 (t, = 6.8 Hz, 2H), 3.53-3.58 (t, = 6.8 Hz, 2H), 5.24 (s, 2H), 7.50-7.55 (m, 3H), 8.02-8.04 (m, 2H), 8.23 (bs, IH).
硫代甲酸 -(2-氰基)乙酯 （41 )
Figure imgf000019_0002
白色晶体， 收率： 90%; 熔点： 151- 154°C。
^NMR (CDC13,400 MHz): δ 2.84-2.87 (t, J = 6.8 Hz, 2H), 3.50-3.53 (t, J = 6.8 Hz, 2H) 3.76-3.81 (m, 4H), 4.73 (s, 2H), 8.31-8.34 (s, 2H).
酸- (2-氰基） 乙酯 （42)
Figure imgf000019_0003
白色晶体， 收率： 77%， 熔点: 81-83 °C
^ NMR (CDC13,400 MHz): δ 2.01-2.04 (m, 2H), 2.70 (t, = 6.8 Hz, 2H), 2.85-2.87 (m, 2H), 3.47-3.51 (t, J = 6.8 Hz, 2H), 3.76-3.80 (m, 2H), 7.24-7.26 (m, IH), 7.52-7.54 (m, IH), 8.43-8.46 (m, 2H), 8.84 (bs, IH).
实施 代甲酸 -(2-氰基)乙酯盐酸盐 （43) 的制备
Figure imgf000019_0004
将 3-吡啶甲氨基二硫代甲酸 -(2-氰基）乙酯溶于乙酸乙酯中， 加入 1.38 M氯化氢乙醚溶 液， 放置过夜， 出现大量沉淀， 过滤， 得白色固体产物， 熔点 118-120°C。
^NMR (D2O,400 MHz): δ 2.84 ( s， 2H ) , 3.44 ( s， 2H) , 5.00 ( s, 2H) , 7.95 ( s, IH) , 8.45 ( s， IH) , 8.61 ( s， IH ) , 8.67 ( s， IH) .
实施例 44 3-吡啶乙氨基二硫代甲酸 -(2-氰基)乙酯盐酸盐 （44) 的制备 ■(HI 'sq) 0Γ6 m '∞) O '(HI '∞) L9.L '(HI '∞) Ο Α-9ΓΑ 'ZH -s =/ 'P) 06 Xm 'ZH 9'9 = / ¾ o 'ΖΗ 8·9 = / ¾ ^v£ X 'ΖΗ 8·9 = / ' LI 'ΖΗ 8·9 = / ¾ 9' ι
-917Ί '( Z 'ZH i'L '9'W = / 'bp) Z£'l '( £ 'ZH YL = / Ί) 88Ό g ： (2腦 Οθ ΐ α ) ¾ΙΜΝΗ1
°a9S-l7S '%88 'φ固
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Figure imgf000020_0001
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Figure imgf000020_0002
'ψ(Ί∞ςΖ)醒 缀 ( raraO^^聲焉- £ ¾
Figure imgf000020_0003
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°a68-A8 : 'Φ固
Figure imgf000020_0004
(917) 騸 二 ¾ ( -z- W-Hi)
'(HI 'sq) OL'8 '(H '∞)
Figure imgf000020_0005
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°a8SI-9SI :% 'φ固
Figure imgf000020_0006
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'∞) 96 '(HI '∞) 68'L '(HI '∞) 017·8 '(HZ '∞) "·8 g ： (zHIM 00ΐ7'Οζα) ¾ΙΜΝΗ1
。嗨 每 腺 ' 2(聲 難 二聲焉 ¾ ϋ
-e (聲 ϋ- )-難 二聲焉 ' ^\ m ^ mm^ m
81·
8llC.0/llOZN3/X3d 本发明化合物对四种不同肿瘤细胞增殖抑制率的评价采用药学领域常规的抗肿瘤活性试验 方法， 例如采用下述文献描述的方法： （ . Immunol Method, 1983, 65, 55 )。 试验结果见下表 1。
部分化合物在 Ι ΟμΜ浓度下对四种肿瘤细胞增殖的抑制作用 （％)
Figure imgf000021_0001
说明:
1、 测试模型为： A : MTT法 （HL-60人白血病）； B : SRB法 （BGC-823 人胃癌）； C : SRB法 （Bel-7402人肝癌）； D : SRB法 （KB人鼻咽癌）；
2、 测试浓度为 10μΜ。
试验实施例 2 本发明化合物对不同肿瘤细胞增殖的抑制作用评价 （2)
本发明化合物对人白血病 HL-60 细胞和 Bel7402细胞的 ED5。值可采用下述方法进行测 定， 结果见下表 2。
对人白血病 HL-60细胞 ED50的测试方法： 体外培养人白血病 HL-60细胞。 细胞生长至对 数生长期后， 收集细胞， l OOOrpm离心 5 分钟， 弃上清， 适量培养基悬浮， 调整细胞浓度至 1.2x l 04/mLo 将细胞悬液接种到 96孔细胞培养板中， 每孔 90μί， 用药组每孔加入细胞培养基 稀释的药物 Ι Ομί, 空白对照组加入等量的细胞培养基， 每种药物设三个复孔， 同时设仅加药物 (无细胞） 的对照孔三个， 阴性对照组为含 0.5% DMSO培养基。 培养箱中培养 48h后， 每孔 加入 5mg/mL的 MTT 10μ1,37°Ο 放置 3h。 每孔加入三联液 （5% SDS, 10mM HC1,5%异丙醇） Ι ΟΟμί , 37°C过夜。 595nm/620nm测吸光度 （OD )。 运用 Prism Graphpad统计软件计算 EC50 值。
对人 Bel7402细胞 ED5。的测试方法： 细胞加药培养 48小时后， 取出培养板， 每孔加预冷
500 g/L三氯醋酸 50 μL (终浓度为 100 g/L )， 静置 5分钟后， 将培养板移入 4°C冰箱中静置 1 小时， 取出培养板用去离子水洗 5 遍， 空气中干燥， 待完全干燥后每孔加入 0.4%的 SRB lOOuL ( 1%乙酸配制）， 染色 20分钟后倒掉染液， 用 1%乙酸洗 5次， 去除未结合的染料。 空 气中干燥后用 pH 10.5的 lOmmol/L的非缓冲 Tris碱液 150uL溶解， 在平板振荡器上振荡 5分 钟， 在 TECAN 酶标仪上测定各孔在 490nm 的光吸收。 本底对照板的细胞同样处理测定 OD490。 运用 Prism Graphpad统计软件计算 EC5()值。
表 2 本发明化合物抑制 HL-60和 Bel7402细胞生长的 EC5。(nmol)
Figure imgf000022_0001
试验实施例 3 本发明的化合物对蛋白酪氨酸激酶 EGFR抑制活性评价
采用下述方法选择本发明实施例 11、 16和 47的化合物对本发明化合物的蛋白酪氨酸激酶 EGFR抑制活性进行评价， 选择己上市的小分子 EGFR、 erbB2双受体酪氨酸激酶抑制剂一拉帕 替尼 （Lapatinib ) 作为阳性对照药。 临床实验己证实， 该药物在治疗侵袭、 复发、 炎性、 脑转 移乳癌具有显著的疗效。
实验方法是： 细胞株： 选择了 EGFR过表达细胞株 MDA-MB-468 , erbB2过表达细胞株 SK-BR-3， 以及 EGFR、 erbB2均低表达细胞株 HCT116作为对照；
阳性对照药： 拉帕替尼 （Lapatinib );
实验操作 ： 体外培养人乳腺癌 SK-BR-3、 MDA-MB-468细胞， 人结肠癌 HCT116细胞。 细胞生长至对数生长期后， 收集细胞， lOOOrpm离心 5分钟， 弃上清， 适量培养基悬浮， 调整 细胞浓度至 3.5x l 03/mL。 将细胞悬液接种到 96孔细胞培养板中， 每孔 ΙΟΟμί, 放置细胞培养 箱 （37°C， 5 %C02) 中培养 24h后， 加入待测药物， 阴性对照组加入终浓度为 0.5% DMSO , 各组均设 3个复孔。 培养箱中培养 72h后， 每孔加入 5mg/ml的 MTT 20μ1, 37°C 放置 4h。 每孔 加入 200 μΐ DMSO , 37 °C摇床振荡 30min， 492nm/620nm 测吸光度 （ OD )。 运用 Prism Graphpad统计软件计算 EC5。值。
试验结果见表 3 :
表 3 化合物 16对蛋白酪氨酸激酶 EGFR抑制活性
Figure imgf000023_0001
从上述试验结果可以清楚地看出， 本发明要求获得专利保护的通式 （I ) 化合物具有比己知 药物拉帕替尼更优异的蛋白酪酸激酶抑制活性和抗癌活性， 有望开发成为一类新结构类型的抗 肿瘤新药。 特别是其中的基团 Α为吡啶基， R3基团为氰基、 垸氧羰基、 硼酸基或苄基亚磺酰基 时显示了更好的抗肿瘤活性。
现在己经详细描述了本发明的实施方案， 对本领域技术人员来说很明显可以做很多改进和 变化而不会背离本发明的基本精神， 所有这些变化和改进都在是本发明的范围之内， 其特征由 上述说明书确定。

Claims

权利要求书
1.一种具有通式 （I ) 结构的氨基二硫代甲酸酯类化合物或其药用盐:
A '
Figure imgf000024_0001
( I )
其中：
A是取代或未取代的、 具有一个或多个选自氮、 氧和硫的杂原子的五元或六元杂环基， 所 述的杂环基可以被一个或多个选自下述的取代基所取代： 卤素、 d— 4垸基、 d— 4垸氧基、 苯 基、 苯氧基、 呋喃基、 吗啉基、 d— 6垸基酰胺基和 d— 4垸氧羰基； 当所述的杂环基是吡啶基 时， 所述吡啶基还可以与苯环或杂环稠合， 所述稠合的苯环或杂环是未取代的或是被 d— 4垸基 取代的；
R1是氢、 苯基或 d— 4垸基；
R2是氢或 4垸基；
R3是氰基、 硼酸基、 垸氧羰基、 氨基磺酰基、 苄基亚磺酰基或 d— 4垸基亚磺酰基； 或 R2与 R3连接在一起形成含有氮原子和硫原子的、 饱和或不饱和的五或六元杂环， 所述 的杂环是未取代的， 或被一个或多个羟基或 — 4垸基所取代； 和
m是 0-3的整数。
2、 根据权利要求 1 所述的化合物， 其中所述的基团 A是取代或未取代的杂环基， 所述的 杂环基选自吡啶基、 嘧啶基、 吡嗉基、 呋喃基、 噁唑基、 吡唑基、 噻唑基和噁二唑基； 优选所 述的基团 A是取代或未取代的吡啶基， 或所述的吡啶基与苯环或吗啉环稠合， 所述稠合的苯环 或吗啉环是未取代的或是甲基取代的。
3、 根据权利要求 2所述的化合物， 其中所述的 d— 4垸基是甲基， 所述的 d— 4垸氧基是甲 氧基， 所述的 d— 4垸氧羰基是甲氧羰基， 和 /或所述的 d— 6垸基酰胺基的戊酰胺基。
4、 根据权利要求 3所述的化合物， 其中所述的 R3基团是氰基。
5、 根据权利要求 1 -4任意一项所述的化合物， 其中所述的化合物是：
3-(2-呋喃甲基) -4-羟基 - 1 ,3-噻嗉垸 -2-硫酮 (化合物 1) ;
2-呋喃甲氨基二硫代甲酸 -(2-甲氧甲酰)乙酯 (化合物 2) ;
2-呋喃甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 3) ;
3- (2-呋喃甲基) -4-羟基 -4,5-二甲基 -3， 4-二氢 - 1 ,3-噻嗉 -2-硫酮 (化合物 4) ;
2-呋喃甲氨基二硫代甲酸 -(2-氨基磺酰基)乙酯 (化合物 5) ;
2-呋喃甲氨基二硫代甲酸 -(2-硼酸基)乙酯 (化合物 6) ;
2-呋喃甲氨基二硫代甲酸 -(2-甲亚磺酰基)乙酯 (化合物 7) ; 2-呋喃甲氨基二硫代甲酸 -(2-苄基亚磺酰基)乙酯 (化合物 8);
3- (3-吡啶甲基) -4-羟基 -1,3-噻嗉垸 -2-硫酮 (化合物 9);
3-吡啶甲氨基二硫代甲酸 -(2-甲氧甲酰基)乙酯 (化合物 10);
3-吡啶甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 11);
3-(3-吡啶甲基) -4-羟基 -4,5-二甲基 -3,4-二氢 -1,3-噻嗉 -2-硫酮 (化合物 12);
3-吡啶甲氨基二硫代甲酸 -(2-氨基磺酰基)乙酯 (化合物 13);
3-吡啶甲氨基二硫代甲酸 -(2-硼酸基)乙酯 (化合物 14);
3-吡啶甲氨基二硫代甲酸 -(2-甲基亚磺酰基)乙酯 (化合物 15);
3-吡啶甲氨基二硫代甲酸 -(2-苄基亚磺酰基)乙酯 (化合物 16)
3-(4-特戊酰胺基)吡啶甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 17);
3-喹啉甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 18);
3-吡啶甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 19);
3-(2-甲氧基)吡啶甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 20);
3-(6-甲氧甲酰基)吡啶甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 21);
3-(4,6-二甲基) B比啶甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 22);
3-(5-甲氧基)吡啶甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 23);
3-(5-溴)吡啶甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 24);
3-[6-(2-呋喃基)]吡啶甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 25);
7-(4-甲基 -3,4,4a,8a-四氢 -2H-吡啶并 [3,2-b][l,4]噁嗉）甲氨基二硫代甲酸 -(2-氰基）乙酯 (化合 物 26);
3- (6-苯氧基)吡啶甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 27);
4-吡啶甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 28);
N-甲基 -3-吡啶甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 29);
3-吡啶氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 30);
3-吡啶苯甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 31);
1 - (3-吡啶)乙氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 32);
3- (6-甲氧基)吡啶甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 33);
5- (4-甲基 -2-苯基)噁唑甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 34);
4- (5-甲基 -1-苯基) -1H-吡唑甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 35);
5-嘧啶甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 36);
5- (1,3-二甲基) -1H-吡唑甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 37)；
2-噻唑甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 38); 2-吡嗉甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 39);
2- (5-苯基) - 1,3,4-噁二唑甲氨基二硫代甲酸 -(2-氰基)乙酯 (化合物 40) ;
5-(2-吗啉基)嘧啶甲氨基二硫代甲酸 -(2-氰基)乙酯（化合物 41);
3-吡啶丙基氨基二硫代甲酸 -(2-氰基)乙酯 （化合物 42 ) ;
3-吡啶甲氨基二硫代甲酸 -(2-氰基)乙酯盐酸盐 （化合物 43 );
3-吡啶乙氨基二硫代甲酸 -(2-氰基)乙酯盐酸盐 （化合物 44 );
2- (5-苯基) - 1,3,4-噻二唑甲氨基二硫代甲酸 -(2-氰基)乙酯 （化合物 45 ) ;
(1H-吡咯 -2-基)甲基氨基二硫代甲酸 -(2-氰基)乙酯 （化合物 46 ); 和
3- (吡啶 -3-基甲基氨基二硫代甲酸酯基)丙酸丁酯 （化合物 47 )。
6、 根据权利要求 1-5任意一项所述化合物或其药用盐的制备方法， 该方法包括首先按照下 述方法制备所述的通式 （I ) 化合物， 然后按照化学领域常规的成盐方法制备所述化合物的药用
Figure imgf000026_0001
(II) (I) 其中通式 (I)和 (II)中各基团的定义如权利要求 1 -5所述；
如果需要， 可按化学领域常规的成盐方法制备所述化合物的药用盐。
7、 根据权利要求 1-5 任意一项所述化合物或其药用盐的制备方法， 其中通式 （I ) 化合物 的 Α基团为取 或未取代的吡啶基， R3基团是氰基时， 此类 ：
Figure imgf000026_0002
如果需要， 可按化学领域常规的成盐方法制备所述化合物的药用盐；
其中基团 R4是所述基团 A 的取代基， 所述的取代基是一个或多个选自下述的基团： 卤 素、 d— 4垸基、 d— 4垸氧基、 苯基、 苯氧基、 呋喃基、 噁嗉基、 酰胺基和 d— 4垸氧羰基； 或是与 所述吡啶环稠合的苯环或吗啉环。
8、 药物组合物， 其中含有治疗有效量的权利要求 1-5 任意一项所述的通式 （I ) 化合物或 其药用盐为活性成分， 和任选的含有一种或多种药用载体； 优选以所述组合物的总重量计， 该 组合物中活性成分的含量是 0.5 %-99%， 药用载体的含量是 1 %-99.5 %。
9、 根据权利要求 8 所述的药物组合物， 其中所述的组合物被制成口服或肠胃外给药的形 式， 所述肠胃外给药的形式包括注射给药、 局部给药、 吸入给药、 直肠给药或植入给药的形 式； 所述的口服给药的剂型是片剂、 胶囊、 颗粒剂或适于药用的液体形式的制剂； 优选所述的 片剂是包衣、 肠溶、 缓释或定量释放的形式。
10、 权利要求 1 -5任意一项所述的化合物或权利要求 8或 9所述的药物组合物在制备酪氨 酸激酶抑制剂中的应用； 其中所述的酪氨酸激酶抑制剂是抗肿瘤药物； 优选的， 其中所述的抗 肿瘤药物是用于治疗乳腺癌、 肝癌、 非小细胞肺癌、 胃癌、 结肠癌、 白血病或鼻癌的药物。
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CN103508930B (zh) * 2012-06-25 2016-01-27 北京大学 双(氨基二硫代甲酸)-1,3-丙二酯类化合物及其合成方法、药物组合物和用途

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