Ferrocene derivative, preparation method and use thereof

Abstract

The present invention relates to the ferrocene derivative represented by formula (IA) or formula (IB), or to the pharmaceutically acceptable salt or solvate thereof and to the pharmaceutical composition thereof. Wherein, R is independently selected from H, halogen, cyano, nitro, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, hydroxy-C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkoxy or C.sub.1-C.sub.6 alkoxy-C.sub.1-C.sub.6 alkoxy; Z is selected from O, S or NR.sub.1, wherein R.sub.1 is independently H or C.sub.1-C.sub.6 alkyl; n is an integer from 0 to 5. The present invention also provides a method and the pharmaceutical application thereof for preparing the compounds represented by formula (IA) or formula (IB) or the pharmaceutically acceptable salts thereof. The compounds have a strong inhibitory activity against human lung cancer cell line A549, colorectal cancer cell line HCT116 and/or breast cancer cell line MCF-7. ##STR00001##

Claims

1. A ferrocene derivative of formula (IA) or formula (IB), and a pharmaceutically acceptable salt or solvate thereof: ##STR00046## wherein: Z is O, S or NR.sub.1, wherein R.sub.1 is independently H or C.sub.1-C.sub.6 alkyl; R is independently selected from the group consisting of H, halogen, cyano, nitro, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, hydroxy-C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkoxy, and C.sub.1-C.sub.6 alkoxy-C.sub.1-C.sub.6 alkoxy; and n is an integer from 0 to 5, and where n is more than 1, the R groups are the same or different.

2. The ferrocene derivative and the pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein: Z is O or NR.sub.1, wherein R.sub.1 is independently H or C.sub.1-C.sub.4 alkyl; R is independently selected from the group consisting of H, halogen, cyano, nitro, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, hydroxy-C.sub.1-C.sub.3 alkyl, and halo-C.sub.1-C.sub.4 alkyl; n is an integer from 0 to 5.

3. The ferrocene derivative and the pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein said ferrocene derivative is ##STR00047## ##STR00048## ##STR00049## ##STR00050## ##STR00051## ##STR00052## ##STR00053## ##STR00054## ##STR00055## ##STR00056## ##STR00057## ##STR00058## ##STR00059## ##STR00060## ##STR00061##

4. The ferrocene derivative and the pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein the pharmaceutically acceptable salt comprises a salt formed with an inorganic acid.

5. A pharmaceutical composition, comprising: the ferrocene derivative according to claim 1, or the pharmaceutically acceptable salt or solvate thereof according to claim 1, or both, and at least one pharmaceutically acceptable excipient, carrier or diluent.

6. The pharmaceutical composition according to claim 5, wherein said pharmaceutical composition is in the form of a solid oral preparation, a liquid oral preparation or an injection.

7. A method of treating a tumor or a cancer, comprising: preparing a medicament comprising the ferrocene derivative according to claim 1, or the pharmaceutically acceptable salt or solvate thereof according to claim 1, or both; and administering the medicament to a patient in need thereof, wherein said tumor or cancer is associated with overexpression and/or overactivity of EGFR.

8. The method according to claim 7, wherein the medicament inhibits the overexpression and/or overactivity of EGFR.

9. A method for preparing said ferrocene derivative according to claim 1, comprising: A) carrying out a condensation reaction between a compound of formula (III) and a compound of formula (II) in a system of an organic solvent and an alkaline acid binding reagent to obtain the compound of formula (IA): ##STR00062## wherein, X is optionally OH or Cl; or, B) carrying out a condensation reaction between 1,1′-ferrocenedicarboxylic acid and a compound of formula (II) in a system of an organic solvent and an alkaline catalyst to obtain the compound of formula (IB): ##STR00063##

10. The pharmaceutical composition according to claim 5, wherein the pharmaceutically acceptable excipient, carrier, or diluent is selected from the group consisting of a filler, a disintegrating agent, a lubricant, a glidant, an effervescent agent, a flavoring agent, a preservative, and a coating material.

11. The pharmaceutical composition according to claim 6, wherein said preparation is a tablet, a dispersible tablet, an enteric coated tablet, a chewable tablet, an orally disintegrating tablet, a capsule, a granule, an oral soluble formulation, water for injection, a lyophilized powder for injection, a large volume infusion, or a small volume infusion.

12. The method according to claim 7, wherein said tumor or cancer is bladder cancer, non-small cell lung cancer, ovarian cancer, breast cancer, stomach cancer, esophageal cancer, lung cancer, head and neck cancer, colon cancer, pharyngeal cancer, pancreatic cancer, or non-small cell lung cancer.

13. The ferrocene derivative and the pharmaceutically acceptable salt or solvate thereof according to claim 4, wherein the inorganic acid is hydrochloride, phosphate, diphosphate, hydrobromide, sulfate, sulfinate, nitrate, and similar salts thereof; and also includes a salt formed with an organic acid, such as lactate, oxalate, malate, maleate, fumarate, tartrate, succinate, citrate, sulfonate, p-toluene sulfonate, 2-hydroxyethyl sulfonate, benzoate, salicylate, trifluoroacetate, amino acid salt, or alkanoate (such as acetate, stearate), or HOOC—(CH.sub.2).sub.m—COOH salt, wherein m is an integer from 1 to 4.

14. The ferrocene derivative and the pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein: Z is O or NH; R is independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, methyl, ethyl, t-butyl, methoxy, nitro, cyano, and trifluoromethyl; and n is 0, 1, 2, or 3.

15. The method for preparing said ferrocene derivative according to claim 9, further comprising: protecting a functional group in formula (II) with a protecting reagent; and removing the protective reagent from the compound of formula (IA) or formula (IB).

16. The method for preparing said ferrocene derivative according to claim 9, further comprising: forming a pharmaceutically acceptable salt of the compound of formula (IA) or formula (IB).

17. The method for preparing said ferrocene derivative according to claim 9, wherein the compound of formula (II) is a compound of formula (II-A), a compound of formula (II-B), or a compound of formula (II-C), wherein formula (II-A) is prepared by a method comprising: when Z is O, converting a compound of formula (1) to a compound of formula (2), and converting a compound of formula (2) to the compound of formula (II-A) via 1,3-dipolar cycloaddition reaction: ##STR00064## wherein formula (II-C) is prepared by a method comprising: when Z is S, converting a compound of formula (1) to a compound of formula (2), and converting a compound of formula (2) to the compound of formula (II-C) via 1,3-dipolar cycloaddition reaction: ##STR00065## wherein formula (II-B) is prepared by a method comprising: when Z is NH, 1) converting a compound of formula (II-A) via methylsulfonyl-esterification reaction, azidation and reduction to the compound of formula (II-A) to the compound of formula (II-B): ##STR00066## or, 2) reacting a compound of formula (2) and propargylamine via 1,3-dipolar cycloaddition reaction to obtain the compound of formula (II-B): ##STR00067## or, 3) reacting a compound of formula (2) and 3-halo-propynyl via 1,3-dipolar cycloaddition reaction to obtain the compound of formula (5), followed by amine substitution reaction to obtain the compound of formula (II-B): ##STR00068##

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) The object of the present invention is to provide novel structure ferrocene derivative represented by formula (IA) or formula (TB). The research results of in-vitro inhibitory activity against colorectal cancer cell line HCT116, human lung cancer cell line A549, and/or breast cancer cell line MCF-7 show that the compounds have strong inhibitory activity against colorectal cancer cell line HCT116, human lung cancer cell line A549, and/or breast cancer cell line MCF-7, and can be used as candidate compounds or lead compounds for anticancer drugs.

(2) The invention is realized by the following technical solutions:

(3) A ferrocene derivative represented by formula (IA) or formula (TB), or the pharmaceutically acceptable salt or solvate thereof,

(4) ##STR00003##

(5) wherein:

(6) Z is selected from O, S or NR.sub.1, wherein R.sub.1 is independently H or C.sub.1-C.sub.6 alkyl; R is independently selected from H, halogen, cyano, nitro, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, hydroxy-C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkyl, halo-C.sub.1-C.sub.6 alkoxy or C.sub.1-C.sub.6 alkoxy-C.sub.1-C.sub.6 alkoxy;

(7) n is an integer from 0 to 5, when n is more than 1, the R group may be the same or different.

(8) According to the preferred technical solution of the present invention, in formula (IA) or formula (TB):

(9) Z is selected from O or NR.sub.1, wherein R.sub.1 is independently H or C.sub.1-C.sub.4 alkyl;

(10) R is independently selected from H, halogen, cyano, nitro, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, hydroxy-C.sub.1-C.sub.3 alkyl, halo-C.sub.1-C.sub.4 alkyl;

(11) n is an integer from 0 to 5.

(12) According to the more preferred technical solution of the present invention, in formula (IA) or formula (IB):

(13) Z is selected from 0 or NH;

(14) R is independently selected from hydrogen, fluoro, chloro, bromo, methyl, ethyl, t-butyl, methoxy, nitro, cyano or trifluoromethyl;

(15) n is an integer of 0, 1, 2, or 3.

(16) According to the present invention, said ferrocene derivative represented by formula (IA) or formula (TB) is selected from any of the following compounds:

(17) ##STR00004## ##STR00005## ##STR00006## ##STR00007## ##STR00008## ##STR00009## ##STR00010## ##STR00011## ##STR00012## ##STR00013## ##STR00014## ##STR00015## ##STR00016## ##STR00017## ##STR00018##

(18) In the present invention, the ferrocene derivative represented by formula (IA) or (IB) may be respectively selected to form a pharmaceutically acceptable salt with a pharmaceutically acceptable acid. Wherein, the term “pharmaceutically acceptable salt” includes, but is not limited to a salt formed with an inorganic acid, such as hydrochloride, phosphate, diphosphate, hydrobromide, sulfate, sulfinate, nitrate, and similar salts thereof; and also includes a salt formed with an organic acid, such as lactate, oxalate, malate, maleate, fumarate, tartrate, succinate, citrate, sulfonate, p-toluene sulfonate, 2-hydroxyethyl sulfonate, benzoate, salicylate, stearate, trifluoroacetate, amino acid salt, or alkanoate such as acetate, HOOC—(CH.sub.2).sub.m—COOH salt (wherein, the m is an integer from 1 to 4), and similar salts thereof. Similarly, a pharmaceutically acceptable cation includes, but is not limited to sodium, potassium, calcium, aluminum, lithium and ammonium.

(19) The term “solvate” includes a hydrate and an alcoholate.

(20) The present invention also provides a pharmaceutical composition comprising the ferrocene derivative represented by formula (IA) or (IB), or the pharmaceutically acceptable salt or solvate thereof, and comprising at least one pharmaceutically acceptable, inert, non-toxic excipient, carrier or diluent.

(21) According to said pharmaceutical composition, wherein, said pharmaceutical composition also comprises one or more pharmaceutically acceptable auxiliaries selected from a filler, a disintegrating agent, a lubricant, a glidant, an effervescent agent, a flavoring agent, a preservative and a coating material.

(22) The present invention also provides a pharmaceutical preparation comprising the ferrocene derivative represented by formula (IA) or (IB), or the pharmaceutically acceptable salt or solvate thereof, and comprising at least one pharmaceutically acceptable, inert, non-toxic excipient, carrier or diluent.

(23) The present invention provides a pharmaceutical preparation, wherein, said pharmaceutical preparation is preferably a solid oral preparation, a liquid oral preparation or an injection.

(24) According to the pharmaceutical preparation of the present invention, said preparation is selected from a tablet, a dispersible tablet, an enteric coated tablet, a chewable tablet, an orally disintegrating tablet, a capsule, a granule, an oral soluble formulation, water for injection, a lyophilized powder for injection, large volume infusion or small volume infusion.

(25) The present invention also provides any of the above-mentioned of the ferrocene derivative represented by formula (IA) or (IB), or the pharmaceutically acceptable salt or solvate thereof for medicament, which is particularly utilized in the preparation of antitumor drugs for the effective treatment of inhibiting the overexpression and/or overactivity of EGFR.

(26) The present invention also provides any of the above-mentioned of the ferrocene derivative represented by formula (IA) or (IB), or the pharmaceutically acceptable salt or solvate thereof, which is used in the preparation of antitumor or anticancer drugs.

(27) According to said application of the present invention, wherein, said tumor or cancer is selected from: bladder cancer, non-small cell lung cancer, ovarian cancer, breast cancer, stomach cancer, esophageal cancer, lung cancer, head and neck cancer, colon cancer, pharyngeal cancer and pancreatic cancer, and so on, more preferably is non-small cell lung cancer.

(28) The present invention also provides any of the above-mentioned of the ferrocene derivative represented by formula (IA) or (IB), or the pharmaceutically acceptable salt or solvate thereof, which is used in the preparation of an inhibitor for inhibiting the overexpression and/or overactivity of EGFR.

(29) The present invention also provides a method for preparing the ferrocene derivative represented by formula (IA) or (IB), wherein, said method includes the following steps:

(30) A) carrying out a condensation reaction between a compound of formula (III) and a compound of formula (II) in a system of an organic solvent (preferably a dry organic solvent) and an alkaline acid binding reagent to obtain the compound of formula (IA):

(31) ##STR00019##

(32) wherein, X is optionally OH or Cl; Z, R and n are as defined above;

(33) or,

(34) B) carrying out a condensation reaction between 1,1′-ferrocenedicarboxylic acid and a compound of formula (II) in a system of an organic solvent (preferably a dry organic solvent) and an alkaline catalyst to obtain the compound of formula (IB):

(35) ##STR00020##

(36) wherein, Z, R and n are as defined above;

(37) any functional group in the compound of formula (II), if desired, can be protected.

(38) And thereafter, if necessary (in any order):

(39) (1) removing any protective reagent, and

(40) (2) forming a pharmaceutically acceptable salt or solvate of the compound of formula (IA) or formula (IB).

(41) According to the present invention, said reaction temperature is from −20° C. up to reflux conditions, preferably from 0° C. to room temperature.

(42) According to the present invention, said reaction is carried out in an organic solvent, preferably a dry organic solvent. Said organic solvent can be benzene, toluene, xylene, dichloromethane, chloroform, acetonitrile, dioxane, tetrahydrofuran or DMF, more preferably tetrahydrofuran.

(43) According to the present invention, said alkaline catalyst is an organic base or an inorganic base, said organic base is preferably selected from triethylamine, tripropylamine, DMAP, potassium tert-butoxide, and so on; said inorganic base is preferably selected from potassium carbonate, sodium hydride, sodium carbonate, and so on. Said alkaline acid binding reagent can also be the above-mentioned alkaline catalyst, the preferred acid binding reagent is DMAP. In the above-described condensation reaction, a condensation reagent, such as DCC, HOBt (1-hydroxybenzotriazole), and so on, can also be added.

(44) According to the present invention, a compound of formula (II), when Z is O, can be prepared by the following method:

(45) ##STR00021##

(46) wherein, R and n are as defined above;

(47) converting substituted benzaldehyde (a compound of formula (1)) to substituted benzaldoxime (a compound of formula (2)) (such as adding NH.sub.3OH.HCl and sodium carbonate, reacting at 25° C.), and converting substituted benzaldoxime (a compound of formula (2)) to the compound of formula (II-A) via 1,3-dipolar cycloaddition reaction (such as adding propynol, NCS and Et.sub.3N, refluxing at 0° C.).

(48) A compound of formula (II), when Z is S, can be prepared by the following method:

(49) ##STR00022##

(50) wherein, R and n are as defined above;

(51) converting substituted benzaldehyde (a compound of formula (1)) to substituted benzaldoxime (a compound of formula (2)), and converting substituted benzaldoxime (a compound of formula (2)) to the compound of formula (II-C) via 1,3-dipolar cycloaddition reaction (propargyl-mercaptan).

(52) A compound of formula (II), when Z is NH, can be prepared by the following method:

(53) 1) converting a compound of formula (II-A) via methylsulfonyl-esterification reaction (such as adding MSCl and Et.sub.3N, reacting at 0° C.), azidation (such as adding NaN.sub.3, reacting at 60° C.), and reduction (such as adding Zn and NH.sub.4Cl, refluxing) to the compound of formula (II-B):

(54) ##STR00023##

(55) wherein, R and n are as defined above;

(56) or

(57) 2) reacting substituted benzaldoxime (a compound of formula (2)) and propargylamine via 1,3-dipolar cycloaddition reaction (such as adding NCS and Et.sub.3N, refluxing at 0° C.) to obtain the compound of formula (II-B);

(58) ##STR00024##

(59) wherein, R and n are as defined above;

(60) or

(61) 3) reacting substituted benzaldoxime (a compound of formula (2)) and 3-halo-propynyl via 1,3-dipolar cycloaddition reaction (such as adding NCS and Et.sub.3N, refluxing at 0° C.) to obtain the compound of formula (5), followed by amine substitution reaction (such as adding ammonia) to obtain the compound of formula (II-B);

(62) ##STR00025##

(63) wherein, R and n are as defined above.

(64) A compound of formula (II), when Z is NR.sub.1, R.sub.1 is C.sub.1-C.sub.6 alkyl, can be prepared by substitution reaction of a compound of formula (II-B) with an amino group.

(65) The ferrocene derivative represented by formula (IA) or formula (IB) of the present invention include, but is not limited to their optical isomers, racemates and the mixtures.

(66) The term “an effective amount” refers to the amount of at least one compound and/or at least one pharmaceutically acceptable salt that is effective for the “treatment” of an individual's disease or discomfort. If it is a cancer, the effective amount may reduce the number of cancer or tumor cells; shrink the size of the tumor; inhibit or prevent the tumor cell infiltration into peripheral organs, for example, when tumors spread into soft tissue or bone; inhibit or prevent tumor metastasis; inhibit or prevent tumor growth; to certain extent, relieve one or more symptoms associated with the cancer; reduce morbidity and mortality; improve quality of life; or a combination of the above-mentioned effects. The effective amount can be an amount which decreases the symptoms of a disease via inhibiting EGFR activity. For the treatment of cancer, the effect of in-vivo experiment can be measured by assessing, such as the duration of survival, time to disease progression (TTP), response rates (RR), the duration of sustained response and/or quality of life.

(67) The effective amount may vary, as recognized by those professionals, along with a route of administration, a dosage of excipient, and co-usage with other drugs.

(68) The term “an effective amount” may also refer to the dosage of at least one said compound and/or at least one pharmaceutically acceptable salt that is effective to inhibit the overexpression and/or overactivity of EGFR.

(69) The ferrocene derivative of the present invention have an antitumor and anticancer activity, especially to human lung cancer cell line A549, colorectal cancer cell line HCT116 and/or breast cancer cell line MCF-7 with a strong inhibitory activity. IC.sub.50 of the compound YJP-8 against the three tumor cell lines, A549, HCT116 and MCF-7, are 142.4 μM, 236.0 μM, 137.8 μM, respectively; IC.sub.50 of the compound YJP-12 against the three tumor cell lines, A549, HCT116 and MCF-7, are 167.5 □M, 148.9 μM, 158.8 μM, respectively; IC.sub.50 of the compound YJP-13 against the three tumor cell lines, A549, HCT116 and MCF-7, are 690.3 μM, 486.2 μM, 169.1 μM, respectively; IC.sub.50 of the compound YJP-14 against the three tumor cell lines, A549, HCT116 and MCF-7, are 450.0 μM, 227.6 μM, 171.7 μM, respectively; IC.sub.50 of the compound YJP-15 against the three tumor cell lines, A549, HCT116 and MCF-7, are 222.4 μM, 233.5 μM, 189.8 μM, respectively; IC.sub.50 of the compound YJP-16 against the three tumor cell lines, A549, HCT116 and MCF-7, are 250.7 μM, 63.9 μM, 155.8 μM, respectively; IC.sub.50 of the compound YJP-19 against the three tumor cell lines, A549, HCT116 and MCF-7, are 530.5 μM, 157.0 μM, 178.0 μM, respectively.

(70) Most of the compounds are shown to have a strong inhibitory activity against the three tumor cell lines. The ferrocene derivative of the present invention can be used as candidate compounds or lead compounds for the treatment of tumors and cancers.

DETAILED DESCRIPTION OF VARIOUS EXAMPLES

(71) In the following, the present invention will be further illustrated by means of specific examples. It should be understood that the examples are only intended to illustrate the invention, rather than to constitute a limitation of the scope of the present invention. In addition, it should be understood that such various changes or modifications as may be made by those skilled in the art after reading the description of the present invention would be considered to be equivalent fall equally within the scope of the present invention.

(72) Among them, the synthetic processes of intermediates and target compounds are represented by the examples in EXAMPLES, and the synthetic processes of the other intermediates and target compounds are the same as those of the representative compounds.

(73) Instruments and reagents: AVANCE III NMR (400 MHz, DMSO-d.sub.6, TMS as an internal standard), ion trap liquid-mass spectrometer (DECAX-30000 LCQ Deca XP), XT5 micro melting point detector with digital display (Beijing Tech-Instrument Lighting Manufacturing, temperature without correction), wavelength-tunable microplate reader (Molecular Devise SPECTRAMAX190). Chemical reagents are commercially analytical reagents or chemically pure reagents, RPMI1640 (Gibco), MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] (Sigma), other reagents are commercially analytical reagents and untreated before use unless otherwise specified, and tetrahydrofuran is treated with dry molecular sieves before use.

Example 1 The Synthesis of the Intermediate of 3-substituted phenyl-5-hydroxymethyl-isoxazole of Formula (II-A) or the Intermediate of 3-substituted phenyl-5-Aminomethyl-isoxazole of Formula (II-B)

(74) using substituted benzaldehyde as a raw material via oxime formation, 1,3-dipolar cycloaddition reaction, methylsulfonyl-esterification reaction, azidation and reduction to obtain the compound of formula (II-A) and formula (II-B) (R and n are as described above), as specifically described in the following scheme:

(75) ##STR00026##

(76) The specific synthesis processes for the intermediate of 3-substituted phenyl-5-hydroxymethyl-isoxazole of formula (II-A) or the intermediate of 3-substituted phenyl-5-aminomethyl-isoxazole of formula (II-B) are disclosed by the applicant in the publication numbers of the previous applications as CN103360382A, CN103664991A and CN103601762A, which is herein incorporated by reference in its entirety.

Example 2 the Synthesis of the Ferrocene Derivative Represented by Formula (IA) (Wherein Z Represents O.)

(77) Wherein, the reaction of 1,1′-ferrocenedicarboxylic acid and 3-phenyl-5-hydroxymethyl-isoxazole is illustrated as an example:

(78) the synthesis of the ferrocene-dicarboxylate derivative (YJP-1):

(79) ##STR00027##

(80) adding 1,1′-ferrocenedicarboxylic acid (0.274 g, 1 mmol) and DCC (0.412 g, 2 mmol) into a 50 mL round-bottom flask and adding 10 mL of dry THF; after stirring the solution in an ice bath for 30 minutes, slowly dropwise adding 10 mL THF solution of 3-phenyl-5-hydroxymethyl-isoxazole (0.35 g, 2 mmol) and DMAP (0.244 g, 2 mmol) into the reaction system; after stirring the reaction in an ice bath for 30 minutes, the reaction temperature being naturally increased to room temperature. When TLC detection showing that the reaction was complete, condensing the reaction solution under reduced pressure; directly separating the residue by using column chromatography (petroleum ether:ethyl acetate=5:1-2:1, volume ratio) to obtain the desired ferrocene-dicarboxylate derivative (YJP-1).

(81) The rest of the ferrocene-dicarboxylate compounds represented by the formula (IA), when Z was O, were synthesized according to the synthetic process of the ferrocene-dicarboxylate derivative (YJP-1).

Example 3 the Synthesis of the Ferrocene Derivative Represented by Formula (IA) (Wherein Z Represents NH.)

(82) Wherein, the reaction of 1, 1′-ferrocenedicarboxylic acid and 3-phenyl-5-aminomethyl-isoxazole is illustrated as an example:

(83) the synthesis of the ferrocene-dicarboxamide derivative (YJP-20):

(84) ##STR00028##

(85) adding 1,1′-ferrocenedicarboxylic acid (0.274 g, 1 mmol), DCC (0.412 g, 2 mmol) and HOBt (0.270 g, 2 mmol) into a 50 mL round-bottom flask and adding 10 mL of dry THF; after stirring the solution in an ice bath for 30 minutes, slowly dropwise adding 10 mL THF solution of 3-phenyl-5-aminomethyl-isoxazole (0.348 g, 2 mmol) and DMAP (0.244 g, 2 mmol) into the reaction system; after stirring the reaction in an ice bath for 30 minutes, the reaction temperature being naturally increased to room temperature. When TLC detection showing that the reaction was complete, condensing the reaction solution under reduced pressure; directly separating the residue by using column chromatography (petroleum ether:ethyl acetate=5:1-2:1, volume ratio) to afford the desired ferrocenedicarboxamide derivative (YJP-20).

(86) The rest of the ferrocene-dicarboxamide compounds were synthesized according to the synthetic process of the compound (YJP-20).

Example 4 the Synthesis of the Ferrocene Derivative Represented by Formula (IB) (Wherein Z Represents O.)

(87) Wherein, the reaction of 1, 1′-ferrocenedicarboxylic acid and 3-phenyl-5-hydroxymethyl-isoxazole is illustrated as an example:

(88) the synthesis of the ferrocene derivative (YJP-41):

(89) ##STR00029##

(90) adding 1,1′-ferrocenedicarboxylic acid (0.274 g, 1 mmol) and DCC (0.206 g, 1 mmol) into a 50 mL round-bottom flask and adding 10 mL of dry THF; after stirring the solution in an ice bath for 30 minutes, slowly dropwise adding 10 mL THF solution of 3-phenyl-5-hydroxymethyl-isoxazole (0.125 g, 1 mmol) and DMAP (0.122 g, 1 mmol) into the reaction system; after stirring the reaction in an ice bath for 30 minutes, the reaction temperature being naturally increased to room temperature. When TLC detection showing that the reaction was complete, condensing the reaction solution under reduced pressure; directly separating the residue by using column chromatography (petroleum ether:ethyl acetate=5:1-0:1, volume ratio) to afford the desired ferrocene-dicarboxylate derivative (YJP-41).

(91) The rest of the ferrocene-dicarboxylate derivatives were synthesized according to the synthetic process of the ferrocene derivative (YJP-41).

Example 5 the Synthesis of the Ferrocene Derivative Represented by Formula (IB) (Wherein Z Represents NH.)

(92) Wherein, the reaction of 1, 1′-ferrocenedicarboxylic acid and 3-phenyl-5-aminomethyl-isoxazole is illustrated as an example:

(93) the synthesis of the ferrocene derivative (YJP-61):

(94) ##STR00030##

(95) adding 1,1′-ferrocenedicarboxylic acid (0.274 g, 1 mmol), DCC (0.206 g, 1 mmol) and HOBt (0.135 g, 1 mmol) into a 50 mL round-bottom flask and adding 10 mL of dry THF; after stirring the solution in an ice bath for 30 minutes, slowly dropwise adding 10 mL THF solution of 3-phenyl-5-aminomethyl-isoxazole (0.174 g, 1 mmol) and DMAP (0.122 g, 1 mmol) into the reaction system; after stirring the reaction in an ice bath for 30 minutes, the reaction temperature being naturally increased to room temperature. When TLC detection showing that the reaction was complete, condensing the reaction solution under reduced pressure; directly separating the residue by using column chromatography (petroleum ether:ethyl acetate=5:1-2:1, volume ratio) to afford the desired ferrocene derivative (YJP-61).

(96) The rest of the ferrocene derivatives represented by the formula (IB) were synthesized according to the synthetic process of the compound (YJP-61).

(97) The structures were characterized by IR, .sup.1H NMR, ESI-MS and other analytical methods. The physical constants and spectral data of preferred compounds are indicated in the tables.

(98) The structures and numbers of the preferred compounds are as follows:

(99) ##STR00031## ##STR00032## ##STR00033## ##STR00034## ##STR00035## ##STR00036## ##STR00037## ##STR00038## ##STR00039## ##STR00040## ##STR00041## ##STR00042## ##STR00043## ##STR00044## ##STR00045##

(100) The numbers and the physical constants of the preferred compounds are shown as follows:

(101) TABLE-US-00001 TABLE 1 .sup.1H NMR data of the preferred compounds Number .sup.1H NMR (400 MHz, CDCl.sub.3) YJP-1  4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 1.6 Hz), 5.41 (s, 4H, 2 × CH.sub.2 of isoxazole- CH.sub.2), 6.73 (s, 2H, 2 × 1H of isoxazole), 7.47-7.49 (m, 2 × 3H), 7.83-7.86 (m, 2 × 2H). YJP-2  2.42 (s, 6H, 2 × CH.sub.3), 4.46 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.40 (s, 4H, 2 × CH.sub.2 of isoxazole-CH.sub.2), 6.70 (s, 2H, 2 × 1H of isoxazole), 7.28 (2 × 2H, d, J = 4.8 Hz), 7.74 (2 × 2H, d, J = 8.0 Hz). YJP-3  1.29 (6H, 2 × CH.sub.3, t, J = 7.6 Hz), 2.72 (4H, 2 × CH.sub.2, q, J = 7.6 Hz), 4.46 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.40 (s, 4H, 2 × CH.sub.2 of isoxazole-CH.sub.2), 6.70 (s, 2H, 2 × 1H of isoxazole), 7.32 (2 × 2H, d, J = 8.0 Hz), 7.74 (2 × 2H, d, J = 8.4 Hz). YJP-4  1.37 (s, 18H, 2 × 3CH.sub.3), 4.46 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.40 (s, 4H, 2 × CH.sub.2 of isoxazole-CH.sub.2), 6.71 (s, 2H, 2 × 1H of isoxazole), 7.51 (2 × 2H, d, J = 8.4 Hz), 7.78 (2 × 2H, d, J = 6.8 Hz). YJP-5  2.17 (s, 12H, 4 × CH.sub.3), 2.34 (s, 6H, 2 × CH.sub.3), 4.47 (2 × 2H, t, J = 2.0 Hz), 4.89 (2 × 2H, t, J = 2.0 Hz), 5.43 (s, 4H, 2 × CH.sub.2 of isoxazole-CH.sub.2), 6.71 (s, 2H, 2 × 1H of isoxazole), 6.96 (s, 2 × 2H). YJP-6  3.88 (s, 6H, 2 × OCH.sub.3), 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.39 (s, 4H, 2 × CH.sub.2 of isoxazole-CH.sub.2), 6.67 (s, 2H, 2 × 1H of isoxazole), 7.00 (d, 2 × 2H, J = 5.2 Hz), 7.79 (d, 2 × 2H, J = 9.2 Hz). YJP-7  3.92 (s, 6H, 2 × OCH.sub.3), 4.46 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.41 (s, 4H, 2 × CH.sub.2 of isoxazole-CH.sub.2), 6.92 (s, 2H, 2 × 1H of isoxazole), 7.01-7.08 (m, 2 × 2H), 7.42- 7.46 (m, 2 × 1H), 7.91 (2 × 1H, dd, J = 1.6, 2.0 Hz). YJP-8  3.89 (s, 6H, 2 × OCH.sub.3), 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.40 (s, 4H, 2 × CH.sub.2 of isoxazole-CH.sub.2), 6.71 (s, 2H, 2 × 1H of isoxazole), 7.00-7.04 (m, 2 × 1H), 7.38- 7.41 (m, 2 × 3H). YJP-9  4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.42 (s, 4H, 2 × CH.sub.2 of isoxazole- CH.sub.2), 6.71 (s, 2H, 2 × 1H of isoxazole), 7.76 (2 × 2H, d, J = 8.4 Hz), 7.98 (2 × 2H, d, J = 8.4 Hz). YJP-10 3.92 (s, 6H, 2 × OCH.sub.3), 4.46 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.41 (s, 4H, 2 × CH.sub.2 of isoxazole-CH.sub.2), 6.92 (s, 2H, 2 × 1H of isoxazole), 7.01-7.08 (m, 2 × 2H), 7.42-7.46 (m, 2 × 1H), 7.91 (2 × 1H, dd, J = 1.6, 2.0 Hz). YJP-11 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.40 (s, 4H, 2 × CH.sub.2 of isoxazole- CH.sub.2), 6.69 (s, 2H, 2 × 1H of isoxazole), 7.20 (2 × 2H, d, J = 8.8 Hz), 7.85 (2 × 2H, d, J = 8.8 Hz). YJP-12 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.42 (s, 4H, 2 × CH.sub.2 of isoxazole- CH.sub.2), 6.87 (s, 2H, 2 × 1H of isoxazole), 7.18-7.26 (m, 2 × 2H), 7.43-7.49 (m, 2 × 1H), 7.99-8.04 (m, 2 × 1H). YJP-13 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.40 (s, 4H, 2 × CH.sub.2 of isoxazole- CH.sub.2), 6.70 (s, 2H, 2 × 1H of isoxazole), 7.47 (2 × 2H, d, J = 8.8 Hz), 7.79 (2 × 2H, d, J = 8.8 Hz). YJP-14 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.43 (s, 4H, 2 × CH.sub.2 of isoxazole- CH.sub.2), 6.90 (s, 2H, 2 × 1H of isoxazole), 7.35-7.44 (m, 2 × 2H), 7.52 (dd, 2 × 1H, J = 1.2, 1.2 Hz), 7.77 (dd, 2 × 1H, J = 2.0 , 2.0 Hz). YJP-15 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.42 (s, 4H, 2 × CH.sub.2 of isoxazole- CH.sub.2), 6.89 (s, 2H, 2 × 1H of isoxazole), 7.37 (dd, 2 × 1H, J = 2.0 , 2.0 Hz), 7.54 (2 × 1H, d, J = 2.0 Hz), 7.73 (2 × 1H, d, J = 8.4 Hz). YJP-16 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.40 (s, 4H, 2 × CH.sub.2 of isoxazole- CH.sub.2), 6.70 (s, 2H, 2 × 1H of isoxazole), 7.63 (2 × 2H, d, J = 8.8 Hz), 7.79 (2 × 2H, d, J = 8.4 Hz). YJP-17 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.42 (s, 4H, 2 × CH.sub.2 of isoxazole- CH.sub.2), 6.87 (s, 2H, 2 × 1H of isoxazole), 7.18-7.26 (m, 2 × 2H), 7.43-7.49 (m, 2 × 1H), 7.99- 8.04 (m, 2 × 1H). YJP-18 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.40 (s, 4H, 2 × CH.sub.2 of isoxazole- CH.sub.2), 6.71 (s, 2H, 2 × 1H of isoxazole), 7.00-7.04 (m, 2 × 1H), 7.38-7.41 (m, 2 × 3H). YJP-19 4.48 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.43 (s, 4H, 2 × CH.sub.2 of isoxazole- CH.sub.2), 6.80 (s, 2H, 2 × 1H of isoxazole), 8.04 (2 × 2H, d, J = 8.8 Hz), 7.79 (2 × 2H, d, J = 8.4 Hz). YJP-20 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 1.6 Hz), 5.41 (s, 4H, 2 × CH.sub.2 of isoxazole- CH.sub.2), 5.66 (2H, t, 2 × NH—CO—, J = 4.6 Hz), 6.73 (s, 2H, 2 × 1H of isoxazole), 7.47-7.49 (m, 2 × 3H), 7.83-7.86 (m, 2 × 2H). YJP-21 2.42 (s, 6H, 2 × CH.sub.3), 4.46 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.40 (s, 4H, 2 × CH.sub.2 of isoxazole-CH.sub.2), 5.66 (2H, t, 2 × NH—CO—, J = 4.6 Hz), 6.70 (s, 2H, 2 × 1H of isoxazole), 7.28 (2 × 2H, d, J = 4.8 Hz), 7.74 (2 × 2H, d, J = 8.0 Hz). YJP-22 1.29 (6H, 2 × CH.sub.3, t, J = 7.6 Hz), 2.72 (4H, 2 × CH.sub.2, q, J = 7.6 Hz), 4.46 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.40 (s, 4H, 2 × CH.sub.2 of isoxazole-CH.sub.2), 5.66 (2H, t, 2 × NH—CO—, J = 4.6 Hz), 6.70 (s, 2H, 2 × 1H of isoxazole), 7.32 (2 × 2H, d, J = 8.0 Hz), 7.74 (2 × 2H, d, J = 8.4 Hz). YJP-23 1.37 (s, 18H, 6 × CH.sub.3), 4.46 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.40 (s, 4H, 2 × CH.sub.2 of isoxazole-CH.sub.2), 5.66 (2H, t, 2 × NH—CO—, J = 4.6 Hz), 6.71 (s, 2H, 2 × 1H of isoxazole), 7.51 (2 × 2H, d, J = 8.4 Hz), 7.78 (2 × 2H, d, J = 6.8 Hz). YJP-24 2.17 (s, 12H, 4 × CH.sub.3), 2.34 (s, 6H, 2 × CH.sub.3), 4.47 (2 × 2H, t, J = 2.0 Hz), 4.89 (2 × 2H, t, J = 2.0 Hz), 5.43 (s, 4H, 2 × CH.sub.2 of isoxazole-CH.sub.2), 5.66 (2H, t, 2 × NH—CO—, J = 4.6 Hz), 6.71 (s, 2H, 2 × 1H of isoxazole), 6.96 (s, 2 × 2H). YJP-25 3.88 (s, 6H, 2 × OCH.sub.3), 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.39 (s, 4H, 2 × CH.sub.2 of isoxazole-CH.sub.2), 5.66 (2H, t, 2 × NH—CO—, J = 4.6 Hz), 6.67 (s, 2H, 2 × 1H of isoxazole), 7.00 (d, 2 × 2H, J = 5.2 Hz), 7.79 (d, 2 × 2H, J = 9.2 Hz). YJP-26 3.92 (s, 6H, 2 × OCH.sub.3), 4.46 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.41 (s, 4H, 2 × CH.sub.2 of isoxazole-CH.sub.2), 5.66 (2H, t, 2 × NH—CO—, J = 4.6 Hz), 6.92 (s, 2H, 2 × 1H of isoxazole), 7.01-7.08 (m, 2 × 2H), 7.42-7.46 (m, 2 × 1H), 7.91 (2 × 1H, dd, J = 1.6, 2.0 Hz). YJP-27 3.89 (s, 6H, 2 × OCH.sub.3), 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.40 (s, 4H, 2 × CH.sub.2 of isoxazole-CH.sub.2), 5.66 (2H, t, 2 × NH—CO—, J = 4.6 Hz), 6.71 (s, 2H, 2 × 1H of isoxazole), 7.00-7.04 (m, 2 × 1H), 7.38-7.41 (m, 2 × 3H). YJP-28 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.42 (s, 4H, 2 × CH.sub.2 of isoxazole- CH.sub.2), 5.66 (2H, t, 2 × NH—CO—, J = 4.6 Hz), 6.71 (s, 2H, 2 × 1H of isoxazole), 7.76 (2 × 2H, d, J = 8.4 Hz), 7.98 (2 × 2H, d, J = 8.4 Hz). YJP-29 4.46 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.41 (s, 4H, 2 × CH.sub.2 of isoxazole- CH.sub.2), 5.66 (2H, t, 2 × NH—CO—, J = 4.6 Hz), 6.92 (s, 2H, 2 × 1H of isoxazole), 7.01-7.08 (m, 2 × 2H), 7.42-7.46 (m, 2 × 1H), 7.91 (2 × 1H, dd, J = 1.6, 2.0 Hz). YJP-30 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.40 (s, 4H, 2 × CH.sub.2 of isoxazole- CH.sub.2), 5.66 (2H, t, 2 × NH—CO—, J = 4.6 Hz), 6.69 (s, 2H, 2 × 1H of isoxazole), 7.20 (2 × 2H, d, J = 8.8 Hz), 7.85 (2 × 2H, d, J = 8.8 Hz). YJP-31 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.42 (s, 4H, 2 × CH.sub.2 of isoxazole- CH.sub.2), 5.66 (2H, t, 2 × NH—CO—, J = 4.6 Hz), 6.87 (s, 2H, 2 × 1H of isoxazole), 7.18-7.26 (m, 2 × 2H), 7.43-7.49 (m, 2 × 1H), 7.99-8.04 (m, 2 × 1H). YJP-32 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.40 (s, 4H, 2 × CH.sub.2 of isoxazole- CH.sub.2), 5.66 (2H, t, 2 × NH—CO—, J = 4.6 Hz), 6.70 (s, 2H, 2 × 1H of isoxazole), 7.47 (2 × 2H, d, J = 8.8 Hz), 7.79 (2 × 2H, d, J = 8.8 Hz). YJP-33 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.43 (s, 4H, 2 × CH.sub.2 of isoxazole- CH.sub.2), 5.66 (2H, t, 2 × NH—CO—, J = 4.6 Hz), 6.90 (s, 2H, 2 × 1H of isoxazole), 7.35-7.44 (m, 2 × 2H), 7.52 (dd, 2 × 1H, J = 1.2, 1.2 Hz), 7.77 (dd, 2 × 1H, J = 2.0 , 2.0 Hz). YJP-34 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.42 (s, 4H, 2 × CH.sub.2 of isoxazole- CH.sub.2), 5.66 (2H, t, 2 × NH—CO—, J = 4.6 Hz), 6.89 (s, 2H, 2 × 1H of isoxazole), 7.37 (dd, 2 × 1H, J = 2.0 , 2.0 Hz), 7.54 (2 × 1H, d, J = 2.0 Hz), 7.73 (2 × 1H, d, J = 8.4 Hz). YJP-35 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.40 (s, 4H, 2 × CH.sub.2 of isoxazole- CH.sub.2), 5.66 (2H, t, 2 × NH—CO—, J = 4.6 Hz), 6.70 (s, 2H, 2 × 1H of isoxazole), 7.63 (2 × 2H, d, J = 8.8 Hz), 7.79 (2 × 2H, d, J = 8.4 Hz). YJP-36 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.42 (s, 4H, 2 × CH.sub.2 of isoxazole- CH.sub.2), 5.66 (2H, t, 2 × NH—CO—, J = 4.6 Hz), 6.87 (s, 2H, 2 × 1H of isoxazole), 7.18-7.26 (m, 2 × 2H), 7.43-7.49 (m, 2 × 1H), 7.99-8.04 (m, 2 × 1H). YJP-37 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.40 (s, 4H, 2 × CH.sub.2 of isoxazole- CH.sub.2), 5.66 (2H, t, 2 × NH—CO—, J = 4.6 Hz), 6.71 (s, 2H, 2 × 1H of isoxazole), 7.00-7.04 (m, 2 × 1H), 7.38-7.41 (m, 2 × 3H). YJP-38 4.48 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.43 (s, 4H, 2 × CH.sub.2 of isoxazole- CH.sub.2), 5.66 (2H, t, 2 × NH—CO—, J = 4.6 Hz), 6.80 (s, 2H, 2 × 1H of isoxazole), 8.04 (2 × 2H, d, J = 8.8 Hz), 7.79 (2 × 2H, d, J = 8.4 Hz). YJP-39 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.40 (s, 4H, 2 × CH.sub.2 of isoxazole- CH.sub.2), 6.70 (s, 2H, 2 × 1H of isoxazole), 7.63 (2 × 2H, d, J = 8.8 Hz), 7.79 (2 × 2H, d, J = 8.4 Hz). YJP-40 4.48 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.43 (s, 4H, 2 × CH.sub.2 of isoxazole- CH.sub.2), 5.66 (2H, t, 2 × NH—CO—, J = 4.6 Hz), 6.80 (s, 2H, 2 × 1H of isoxazole), 8.04 (2 × 2H, d, J = 8.8 Hz), 7.79 (2 × 2H, d, J = 8.4 Hz). YJP-41 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 1.6 Hz), 5.41 (s, 2H, isoxazole-CH.sub.2), 6.73 (s, 1H, 1H of isoxazole), 7.47-7.49 (m, 3H), 7.83-7.86 (m, 2H), 10.8 (brs, 1H, —COOH). YJP-42 2.42 (s, 3H, CH.sub.3), 4.46 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.40 (s, 2H, isoxazole-CH.sub.2), 6.70 (s, 1H, 1H of isoxazole), 7.28 (2H, d, J = 4.8 Hz), 7.74 (2H, d, J = 8.0 Hz), 10.8 (brs, 1H, —COOH). YJP-43 1.29 (3H, CH.sub.3, t, J = 7.6 Hz), 2.72 (2H, CH.sub.3CH.sub.2, q, J = 7.6 Hz), 4.46 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.40 (s, 2H, isoxazole-CH.sub.2), 6.70 (s, 1H, 1H of isoxazole), 7.32 (2H, d, J = 8.0 Hz), 7.74 (2H, d, J = 8.4 Hz), 11.0 (brs, 1H, —COOH). YJP-44 1.37 (s, 9H, 3 × CH.sub.3), 4.46 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.40 (s, 2H, isoxazole-CH.sub.2), 6.71 (s, 1H, 1H of isoxazole), 7.51 (2H, d, J = 8.4 Hz), 7.78 (2H, d, J = 6.8 Hz), 11.0 (brs, 1H, —COOH). YJP-45 2.17 (s, 6H, 2 × CH.sub.3), 2.34 (s, 3H, CH.sub.3), 4.47 (2 × 2H, t, J = 2.0 Hz), 4.89 (2 × 2H, t, J = 2.0 Hz), 5.43 (s, 2H, isoxazole-CH.sub.2), 6.71 (s, H, 1H of isoxazole), 6.96 (s, 2H), 11.0 (brs, 1H, —COOH). YJP-46 3.88 (s, 3H, OCH.sub.3), 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.39 (s, 2H, isoxazole-CH.sub.2), 6.67 (s, 1H, 1H of isoxazole), 7.00 (d, 2H, J = 5.2 Hz), 7.79 (d, 2H, J = 9.2 Hz), 11.0 (brs, 1H, —COOH). YJP-47 3.92 (s, 3H, OCH.sub.3), 4.46 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.41 (s, 2H, isoxazole-CH.sub.2), 6.92 (s, 1H, 1H of isoxazole), 7.01-7.08 (m, 2H), 7.42-7.46 (m, 1H), 7.91 (1H, dd, J = 1.6, 2.0 Hz), 11.0 (brs, 1H, —COOH). YJP-48 3.89 (s, 3H, OCH.sub.3), 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.40 (s, 2H, isoxazole-CH.sub.2), 6.71 (s, 1H, 1H of isoxazole), 7.00-7.04 (m, 1H), 7.38-7.41 (m, 3H), 11.0 (brs, 1H, —COOH). YJP-49 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.42 (s, 2H, isoxazole-CH.sub.2), 6.71 (s, 1H, 1H of isoxazole), 7.76 (2H, d, J = 8.4 Hz), 7.98 (2H, d, J = 8.4 Hz), 11.0 (brs, 1H, —COOH). YJP-50 3.92 (s, 3H, OCH.sub.3), 4.46 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.41 (s, 2H, isoxazole-CH.sub.2), 6.92 (s, 1H, 1H of isoxazole), 7.01-7.08 (m, 2H), 7.42-7.46 (m, 1H), 7.91 (1H, dd, J = 1.6, 2.0 Hz), 11.0 (brs, 1H, —COOH). YJP-51 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.40 (s, 2H, isoxazole-CH.sub.2), 6.69 (s, 1H, 1H of isoxazole), 7.20 (2H, d, J = 8.8 Hz), 7.85 (2H, d, J = 8.8 Hz), 11.0 (brs, 1H, —COOH). YJP-52 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.42 (s, 2H, isoxazole-CH.sub.2), 6.87 (s, 1H, 1H of isoxazole), 7.18-7.26 (m, 2H), 7.43-7.49 (m, 1H), 7.99-8.04 (m, 1H), 11.0 (brs, 1H, —COOH). YJP-53 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.40 (s, 2H, isoxazole-CH.sub.2), 6.70 (s, 1H, 1H of isoxazole), 7.47 (2H, d, J = 8.8 Hz), 7.79 (2H, d, J = 8.8 Hz), 11.0 (brs, 1H, —COOH). YJP-54 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.43 (s, 2H, isoxazole-CH.sub.2), 6.90 (s, 1H, 1H of isoxazole), 7.35-7.44 (m, 2H), 7.52 (dd, 1H, J = 1.2, 1.2 Hz), 7.77 (dd, 1H, J = 2.0 , 2.0 Hz), 11.0 (brs, 1H, —COOH). YJP-55 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.42 (s, 2H, isoxazole-CH.sub.2), 6.89 (s, 1H, 1H of isoxazole), 7.37 (dd, 1H, J = 2.0, 2.0 Hz), 7.54 (1H, d, J = 2.0 Hz), 7.73 (1H, d, J = 8.4 Hz), 11.0 (brs, 1H, —COOH). YJP-56 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.40 (s, 2H, isoxazole-CH.sub.2), 6.70 (s, 1H, 1H of isoxazole), 7.63 (2H, d, J = 8.8 Hz), 7.79 (2H, d, J = 8.4 Hz), 11.0 (brs, 1H, —COOH). YJP-57 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.42 (s, 2H, isoxazole-CH.sub.2), 6.87 (s, 1H, 1H of isoxazole), 7.18-7.26 (m, 2H), 7.43-7.49 (m, 1H), 7.99-8.04 (m, 1H), 11.0 (brs, 1H, —COOH). YJP-58 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.40 (s, 2H, isoxazole-CH.sub.2), 6.71 (s, 1H, 1H of isoxazole), 7.00-7.04 (m, 1H), 7.38-7.41 (m, 3H), 11.0 (brs, 1H, —COOH). YJP-59 4.48 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.43 (s, 2H, isoxazole-CH.sub.2), 6.80 (s, 1H, 1H of isoxazole), 8.04 (2H, d, J = 8.8 Hz), 7.79 (2H, d, J = 8.4 Hz), 11.0 (brs, 1H, —COOH). YJP-60 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.40 (s, 2H, isoxazole-CH.sub.2), 6.70 (s, 1H, 1H of isoxazole), 7.63 (2H, d, J = 8.8 Hz), 7.79 (2H, d, J = 8.4 Hz), 11.0 (brs, 1H, —COOH). YJP-61 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.40 (s, 2H, isoxazole-CH.sub.2), 5.66 (1H, t, NH—CO—, J = 4.6 Hz), 6.69 (s, 1H, 1H of isoxazole), 7.20 (2H, d, J = 8.8 Hz), 7.85 (2H, d, J = 8.8 Hz), 11.0 (brs, 1H, —COOH). YJP-62 2.42 (s, 3H, CH.sub.3), 4.46 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.40 (s, 2H, isoxazole-CH.sub.2), 5.66 (1H, t, NH—CO—, J = 4.6 Hz), 6.70 (s, 1H, 1H of isoxazole), 7.28 (2H, d, J = 4.8 Hz), 7.74 (2H, d, J = 8.0 Hz), 11.0 (brs, 1H, —COOH). YJP-63 1.29 (3H, CH.sub.3, t, J = 7.6 Hz), 2.72 (2H, CH.sub.3CH.sub.2, q, J = 7.6 Hz), 4.46 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.40 (s, 2H, isoxazole-CH.sub.2), 5.66 (1H, t, NH—CO—, J = 4.6 Hz), 6.70 (s, 1H, 1H of isoxazole), 7.32 (2H, d, J = 8.0 Hz), 7.74 (2H, d, J = 8.4 Hz), 11.0 (brs, 1H, —COOH). YJP-64 1.37 (s, 9H, 3 × CH.sub.3), 4.46 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.40 (s, 2H, isoxazole-CH.sub.2), 5.66 (1H, t, NH—CO—,J = 4.6 Hz), 6.71 (s, 1H, 1H of isoxazole), 7.51 (2H, d, J = 8.4 Hz), 7.78 (2H, d, J = 6.8 Hz), 11.0 (brs, 1H, —COOH). YJP-65 2.17 (s, 6H, 2 × CH.sub.3), 2.34 (s, 3H, CH.sub.3), 4.47 (2 × 2H, t, J = 2.0 Hz), 4.89 (2 × 2H, t, J = 2.0 Hz), 5.43 (s, 2H, isoxazole-CH.sub.2), 5.66 (1H, t, NH—CO—, J = 4.6 Hz), 6.71 (s, 1H, 1H of isoxazole), 6.96 (s, 2H), 11.0 (brs, 1H, —COOH). YJP-66 3.88 (s, 3H, OCH.sub.3), 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.39 (s, 2H, isoxazole-CH.sub.2), 5.66 (1H, t, NH—CO—, J = 4.6 Hz), 6.67 (s, 1H, 1H of isoxazole), 7.00 (d, 2H, J = 5.2 Hz), 7.79 (d, 2H, J = 9.2 Hz), 11.0 (brs, 1H, —COOH). YJP-67 3.92 (s, 3H, OCH.sub.3), 4.46 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.41 (s, 2H, isoxazole-CH.sub.2), 5.66 (1H, t, NH—CO—, J = 4.6 Hz), 6.92 (s, 1H, 1H of isoxazole), 7.01- 7.08 (m, 2H), 7.42-7.46 (m, 1H), 7.91 (1H, dd, J = 1.6, 2.0 Hz), 11.0 (brs, 1H, —COOH). YJP-68 3.89 (s, 3H, OCH.sub.3), 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.40 (s, 2H, isoxazole-CH.sub.2), 5.66 (1H, t, NH—CO—, J = 4.6 Hz), 6.71 (s, 1H, 1H of isoxazole), 7.00- 7.04 (m, 1H), 7.38-7.41 (m, 3H), 11.0 (brs, 1H, —COOH). YJP-69 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.42 (s, 2H, isoxazole-CH.sub.2), 5.66 (1H, t, NH—CO—, J = 4.6 Hz), 6.71 (s, 1H, 1H of isoxazole), 7.76 (2H, d, J = 8.4 Hz), 7.98 (2H, d, J = 8.4 Hz), 11.0 (brs, 1H, —COOH). YJP-70 4.46 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.41 (s, 2H, isoxazole-CH.sub.2), 5.66 (1H, t, NH—CO—, J = 4.6 Hz), 6.92 (s, 1H, 1H of isoxazole), 7.01-7.08 (m, 2H), 7.42-7.46 (m, 1H), 7.91 (1H, dd, J = 1.6, 2.0 Hz), 11.0 (brs, 1H, —COOH). YJP-71 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.40 (s, 2H, isoxazole-CH.sub.2), 5.66 (1H, t, NH—CO—, J = 4.6 Hz), 6.69 (s, 1H, 1H of isoxazole), 7.20 (2H, d, J = 8.8 Hz), 7.85 (2H, d, J = 8.8 Hz), 11.0 (brs, 1H, —COOH). YJP-72 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.42 (s, 2H, isoxazole-CH.sub.2), 5.66 (1H, t, NH—CO—, J = 4.6 Hz), 6.87 (s, 1H, 1H of isoxazole), 7.18-7.26 (m, 2H), 7.43-7.49 (m, 1H), 7.99-8.04 (m, 1H), 11.0 (brs, 1H, —COOH). YJP-73 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.40 (s, 2H, isoxazole-CH.sub.2), 5.66 (1H, t, NH—CO—, J = 4.6 Hz), 6.70 (s, 1H, 1H of isoxazole), 7.47 (2H, d, J = 8.8 Hz), 7.79 (2H, d, J = 8.8 Hz), 11.0 (brs, 1H, —COOH). YJP-74 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.43 (s, 1H, isoxazole-CH.sub.2), 5.66 (1H, t, NH—CO—, J = 4.6 Hz), 6.90 (s, 1H, 1H of isoxazole), 7.35-7.44 (m, 2H), 7.52 (dd, 1H, J = 1.2, 1.2 Hz), 7.77 (dd, 1H, J = 2.0 , 2.0 Hz), 11.0 (brs, 1H, —COOH). YJP-75 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.42 (s, 2H, isoxazole-CH.sub.2), 5.66 (1H, t, NH—CO—, J = 4.6 Hz), 6.89 (s, 1H, 1H of isoxazole), 7.37 (dd, 1H, J = 2.0, 2.0 Hz), 7.54 (1H, d, J = 2.0 Hz), 7.73 (1H, d, J = 8.4 Hz), 11.0 (brs, 1H, —COOH). YJP-76 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.40 (s, 2H, isoxazole-CH.sub.2), 5.66 (1H, t, NH—CO—, J = 4.6 Hz), 6.70 (s, 1H, 1H of isoxazole), 7.63 (2H, d, J = 8.8 Hz), 7.79 (2H, d, J = 8.4 Hz), 11.0 (brs, 1H, —COOH). YJP-77 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.42 (s, 2H, isoxazole-CH.sub.2), 5.66 (1H, t, NH—CO—, J = 4.6 Hz), 6.87 (s, 1H, 1H of isoxazole), 7.18-7.26 (m, 2H), 7.43- 7.49 (m, 1H), 7.99-8.04 (m, 1H), 11.0 (brs, 1H, —COOH). YJP-78 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.40 (s, 2H, isoxazole-CH.sub.2), 5.66 (1H, t, NH—CO—, J = 4.6 Hz), 6.71 (s, 1H, 1H of isoxazole), 7.00-7.04 (m, 1H), 7.38- 7.41 (m, 3H), 11.0 (brs, 1H, —COOH). YJP-79 4.48 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.43 (s, 2H, isoxazole-CH.sub.2), 5.66 (1H, t, NH—CO—, J = 4.6 Hz), 6.80 (s, 1H, 1H of isoxazole), 8.04 (2H, d, J = 8.8 Hz), 7.79 (2H, d, J = 8.4 Hz), 11.0 (brs, 1H, —COOH). YJP-80 4.47 (2 × 2H, t, J = 2.0 Hz), 4.88 (2 × 2H, t, J = 2.0 Hz), 5.40 (s, 2H, isoxazole-CH.sub.2), 6.70 (s, 1H, 1H of isoxazole), 7.63 (2H, d, J = 8.8 Hz), 7.79 (2H, d, J = 8.4 Hz), 11.0 (brs, 1H, —COOH).

Example 6 In Vitro Anticancer Activity Assay

(102) Colorectal cancer cell line HCT-116, human lung cancer cell line A549 and breast cancer cell line MCF-7 were screened by MTT assay.

(103) Specific experimental procedure is as follows:

(104) (1) seeding colorectal cancer cell line HCT-116 which is in logarithmic growth phase in 96-well culture plates, when the cells grew to 90%, adding 1 μL of the test sample at a concentration of 1×10.sup.−4M, using three replicate wells of the concentration, and designing positive control (Gefitinib) and 1 μL of negative control (DMSO+cell culture medium+MTT), culturing the cells for 48 h at 37° C. in 5% CO.sub.2; (2) then adding 20 μL of 5 mg/mL MTT solution into each well, after gently shaking for a few minutes incubating for 3 to 4 hours, removing the culture fluid; (3) adding 100 μL of DMSO into each well, shaking at low speeds on a shaker for 10 minutes, fully dissolving the crystals. Using a wavelength-tunable microplate reader absorbance value (A595) was measured at 595 nm. Inhibitory ratio was calculated with the following formula:

(105) $\mathrm{Inhibitory}\mathrm{ratio}\left(\%\right)=\frac{A_{595\mathrm{control}\mathrm{group}}-A_{595\mathrm{treated}\mathrm{group}}}{A_{595\mathrm{control}\mathrm{group}}}\times 100\%$

(106) wherein, IC.sub.50 values were calculated using the GraphPad Prism 5 software.

(107) Experimental procedure for inhibition of human lung cancer cell line A549 and breast cancer cell line MCF-7 are the same as the procedure of colorectal cancer cell line HCT-116.

(108) The inhibitory activity results of the preferred ferrocene derivative against human lung cancer cell line A549 and breast cancer cell line MCF-7 are shown in Table 2.

(109) TABLE-US-00002 TABLE 2 Testing results of inhibitory activity of some exemplified ferrocene derivatives in Table 1 against A549, HCT116 and MCF-7 IC.sub.50 (μM) Compound A549 HCT116 MCF-7 YJP-1  252.2 1.038 × 10.sup.11 990 YJP-2  198.1 220.1 135.8 YJP-3  1.925 × 10.sup.12 6.086 × 10.sup.10 86.76 YJP-4  220.3 2180 149.7 YJP-5  188.6 2.952 × 10.sup.10 142.0 YJP-6  9.377 × 10.sup.8  3.807 × 10.sup.7  182.5 YJP-7  868.4 1.318 × 10.sup.15 157.3 YJP-8  142.5 236.0 137.8 YJP-9  4.795 × 10.sup.−5 982062 132.8 YJP-11 2863 1.060 × 10.sup.8  138.0 YJP-12 167.5 148.9 158.8 YJP-13 690.3 486.2 169.1 YJP-14 450.0 227.6 171.7 YJP-15 222.4 233.5 189.8 YJP-16 250.7 63.9 155.8 YJP-19 530.5 157.0 178.0 Gefitinib 21.55 17.9 20.68

(110) The foregoing description refers to the examples of this invention. However, the present invention is not limited to the above-described examples. Any change such as modification, equivalent replacement, improvement, and so on, which may be made to these examples within the spirit and principles of the present invention, is intended to be embraced within the scope of the invention.