TW399053B - Acrylamide derivatives and process for the preparation - Google Patents

Abstract

Acrylamide derivatives represented by the general formula (1) formula (1) ((S, S)-3, 3'-[3, 3'-1, 4-phenylenediacryloyl]bis-[1-chloromethyl-5-hydroxy-7-trifluoromethyl-1, 2, 3, 6-tetrahydropyrrolo[3, 2-e] indole-8-carboxylic acid methyl ester is a concrete example for the general formula (1)). Acrylamide derivatives represented by the general formula (1) exhibit excellent antineoplastic effects against solid tumor and further has high selectivity to cancer cells with low toxicity.

Description

Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 ___________-________ --- --- --- 5th, invention (I) [Detailed description of the invention] [Technical field of the invention] The present invention relates to Antitumor activity of the novel acrylamide derivative 'its optical activity, and its pharmacologically acceptable salts. [Previous technology] '' Antibiotic cc_1065 with antibacterial and antitumor activity is shown in "J. Antibiotics" Volume 31, page 1211 (1978), same volume 34, page 1119 (1981), In USP 4169888, duocaimycin A and its analogs with similar structures are shown in WO 87/06255, EP 0318 05 6, and "J. Antibiotics" "Vol. 42, p. 1229 (1989), No. 4-99774. Moreover, the derivatives of CC-1065 are disclosed in EP 0359454, Japanese Patent Application Publication No. 60-193989, and Japanese Patent Application Publication No. 2-502005. No. 7287, Japanese Patent Application No. 3-128379, EP 0354583, EP 0406749. The basic framework of these natural products is used as it is, or induced by chemical modification of natural products. Although a compound having two tetrahydropyrroloindole skeletons in one kind of compound is included in the scope of patent applications of JP-A-Sho 60-193989 (EP 0154445) and JP-A No. 2-502005 (W08804659), but Examples are not specifically described and disclosed. And the 'bridged part is -Rs_T_RV5 (R5' R's is a phenyl, heterocyclic group, benzene heterocyclic group, etc. substituted by a forging group, etc.'T is an amine group, a tramine group, a oxo group, an oxo group, etc. ) The compound ^ is contained in the special table Pingbu 50066 ^ 1 ^ "0 90027 46") and the bridge part is based on the Chinese paper standard (CNS) A4 size (210x297 mm) (please first Read the notes on the back and fill in this page again) Packing! ----- Order ------ Tip-- A7 B7 Printed by the Consumers 'Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. The invention is bound (1';-0 1! | Carbonylbis (imino- 1H -Π introdo 2-carbonyl) 5, 5 ί mono [(1, 2--oxy-1, 2 1 1 1 -ethanediyl) diamine Group] bis-1H-Π bow 丨 II-carbonyl compound and the like are M and X--N 1 Examples revealed 0 Please read 1 I | 2 have 7 Ξ: fluoromethyl-8 ~ methoxycarbonyl -1, 2, 3, 6 -tetrahydropyrrolo [read back 1 II 3, 2- e] indene ring with carbonyl bis (imino-1H-π bow | dish | disk-2- Note JI means 1 I carbonyl) The compound has been disclosed by the applicant (Japanese Patent Application Laid-Open No. 6-116269) ° Matter 1 I Re 1 | However, the acrylamide derivative of the compound of the present invention is previously unknown. Fill out this k [Problems to be Solved by the Invention] In page 1, the treatment method for cancer of 外科 I has been used clinically by surgical resection M X-ray and other 1 1 1 radiation therapy and M chemotherapeutic drug therapy. Among them, chemical 1 1 Therapeutic drug therapy is the only order for a wide range of cancers and end-stage cancers in various parts of the body --- Therapeutic method 0 This kind of drug therapy that M m thinks has the least burden on patients 9 1 | Due to the strong side effects in patients The pain of this disease is also> 1 I. Many current chemotherapeutic agents show efficacy against leukemia with fast cell proliferation. 1 1 1 Low tumor effectiveness 〇K This reason is not based on chemical treatment of cancer treatment of chemotherapeutic agents.-__. Selective implementation 〇1 The present invention is based on the rules of such chemotherapy. 1 The purpose is to select compounds that are highly selective and effective on solid tumors and that have low toxicity. 1 1 [Means for solving problems] 1 1 The present inventors and others committed to solve the above-mentioned problems and found that new 1 1 The compounds of the present invention are selective for cancer cells and have low toxicity to 1 1 solid tumors. The invention is completed by the activity of Ⅱ. The present invention is to provide the acrylamide derivative represented by the following formula (1): 1 1 | Optically active substance, pharmacologically acceptable salt thereof, and manufacturing method thereof 0 1 1 Standard (CNS) Λ4 specification (210X297 mm) 5. The invention will be clear (:) 〇X1 X2 0 (1) A7 B7 (where X1 and X2 are independently of each other a hydrogen atom, a halogen atom, an amine group, and an alkylamine Group, amine alkyl group, hydroxyl group, OR3 (R3 is a linear or branched "-% alkyl group, or an aryl group which may be substituted), OCOR3 (R3 is the same as above), or straight or branched Ci-Ce is low Alkyl. X1 and X2 can also be combined with each other. Ring A is a pyrrolidine ring, a pyran ring, a thieno ring, a stupid ring, a pyridine ring, a daikon ring, pyrimidine, hexahydropyridine , Biphenyl ring, a pyridine ornamentation, two pyrimidine ring, a naphthalene ring, recreational ring, a quinone ring or lip .R1 and R2 each independently is

---------- install ------- order ------- " line ------- (Please read the precautions on the back before filling this page) Economy Printed by the Ministry of Standards and Staff ’s Consumer Cooperatives (R4 is a hydrogen atom, a protective group for a hydroxyl group, or a substituent that can be decomposed in the body, Y is a halogen atom, an aromatic alkoxy group, a lower alkoxy group, Alkoxy, or azide,

： B is a thick ring, or H. H- The paper size is applicable to the Chinese National Standard (CNS) Λ4 specification (210X297) 牦 or 6 A7 B7 V. Description of the invention (.})

Here, in the substituents defined by X1 and X2, the so-called halogen atom means a fluorine atom, an atmospheric atom, a bromine atom, an iodine atom, and the so-called alkylamino group means a straight or branched (^- Examples of the Cb alkyl-substituted amino group include methylamino, dimethylamino, ethylamino, diethylamino, isopropylamino, and diisopropylamino groups. The so-called amine alkyl group refers to an amine group. Bonding amidine:-% amine alkyl of straight or branched alkyl, and exemplified by amine methyl, 1-aminoethyl, 2-amineethyl, 1-amine isopropyl, 2-aminopropyl, 3 -Aminopropyl, etc. The so-called substitutable aryl group means an aryl group which can be substituted by a halogen atom, an alkyl group, an amine group, an alkylamino group, an amine alkyl group, a hydroxyl group, and the like, and examples thereof include arylbenzyl , Methylbenzyl, aminephenyl, methylaminebenzyl, aminetolyl, hydroxybenzyl, etc. Also, the so-called X1 and X2 are bonded to each other, which means that on the ring A, it is bonded to K and contains a condensation alkylene Chain or 1 to 2 oxygen atoms, the case of an alkylene ring of an amine group, an ester group, or a carbamoyl group, for example, 1-1-v ^ n ^^^^ 1 ml —HI— ml «i mu n nn V ~ r —m In— mu n ^ i · t ^ n (Please read the notes on the back before filling out this page) Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

This paper size applies to China's National Standards (CNS) Λ4 specification (210X297 mm) 7 A7 B7 V. Description of the invention (:))

HN: 〇 etc. The so-called (. · Β • Ji and the manuscripts shown) are aromatic or non-aromatic hydrocarbons or heterofused rings, such as Μθνλ V-? 1 " Μθ〇2〇 \ 7,

xs H

F3Cw,

H

H The staff of the Central Bureau of Standards of the Ministry of Economic Affairs has printed a thick ring of cooperatives and so on. The term “substitutable group decomposable in the living body” herein means a substituent which decomposes in the living body to generate a hydroxyl group. Examples of the substituent include an alkylamino group, an allyl salt, a lower alkoxycarbonyl group, and a substituted or unsubstituted group. Aryloxycarbonyl groups can be substituted aminocarbamyl, α-aminoacid fluorenyl residues, and the like. Specific examples of lower alkylsulfonyl include methylsulfenyl, ethylsulfonyl, propionyl, butanyl, trimethylethylsulfonyl, pentamyl, hexyl, and the like. Specific examples of arylfluorenyl include noon Fluorenyl, phenethylfluorenyl, naphthyl ether and the like. Specific examples of the lower alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, and hexyloxycarbonyl. Examples of the so-called substituted or unsubstituted aryloxycarbonyl include phenoxycarbonyl and p-chloro. Phenoxycarbonyl, p-methoxyphenoxycarbonyl, p-aminephenoxycarbonyl m ^ i — ^ nm · ^^^^ 1 ^^^^ 1 «HI — ^ — vh ^^^^ 1 In n · ^ ^^^^ 1 f— ^ ϋ \ y ml n 1 ^^ 1- fn nn at * —— (Please read the precautions on the back before filling this page) This paper size is applicable to Chinese valve standards (('NS) Λ4 specification U10X 297 漦) 8-V. Description of the invention () carbonyloxycarbonyl benzyloxy, benzylamino fluorenylmethylamine alkylcarbonylalkane or Λ7 B7 pair, carbonylcarbonyl nitrogen-low pair For example, Gilead can be oxidized, for example; Substitute for body oxygen with methyl-methylmethylamine. Printed on Keluo by the Central Standards Bureau Shellfish Consumer Cooperative. ------- Order ------ Into (please read the precautions on the back before filling this page). Pyrididine Aminopyridine: :: Low Substituted hexahydropyridine carbonyls such as methylamine methylamine ra, diylpyridinium hexa-4 // 1, or hexahydropyridyl) carbonyl, (4-methyl-1-hexahydro "biryl) Carbonyl, [4- [2- (dimethylamino) ethyl] -1-hexahydropyridyl] carbonyl, [4- (2- (hydroxyethoxy) -1-hexahydropyridyl] carbonyl, Or [4- [2- [2- (dimethylamino) ethoxy] ethyl] -l-hexahydropyridyl] carbonyl and the like may be substituted hexahydropyridine carbonyl, or may be substituted Bufo fluorene carbonyl, pyrrolidine carbonyl, silyl substituted by alkyl, etc. Examples of α-amino acid fluorenyl residues are amine oxycarbonyl, fluorenylmethoxycarbonyl, or tertiary butane. Glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, protected by carbonyl groups, etc. Asparagine residues, asparagine, glutamine, ammonium, arginine, stuplanine, tick, histidine, tryptophan, proline and hydroxyproline Specific examples of the arylsulfonyloxy group include benzenesulfonyloxy, methylbenzylsulfonyloxy, and the like. Examples of the group include methanesulfonyloxy group, ethanesulfonyloxy group, and propanesulfonyloxy group, and further examples of the haloalkylfluorenyl group include trifluoromethanesulfonyloxy group, trichloromethanesulfonyloxy group, and the like. [Implementation Mode of the Invention] The present invention is a manufacturing method according to the following method | providing the compound represented by the above formula (1). This paper size is applicable to Chinese national standards (CNS> Λ4 specification (210 > < 297) ) -9 — V. Invent sharp (V) A7 B7 That is, let the carboxylic acid represented by the following formula (2α)

(In the formula, R5 is 0Η. Ring A, X1 and X2 are the same as described above.) A compound represented by the following formula (4) or (5) or a salt thereof

Printed by the Employees 'Cooperatives of the Central Standardization Bureau of the Ministry of Economic Affairs (in the formula (· 日. ([, (C' (, R4, and Υ are the same as above).) Use of dihexylcarbodiimide (DCC) or 3-ethyl Condensation agents such as -1- (3-dimethylaminopropyl) carbodiimide hydrochloride, or with halides of carboxylic acids shown in (2b), oxazolidinyl carboxylic acids of carboxylic acids, Mixture of active ester and carboxylic acid or symmetrical anhydride reaction (2b) 0x1 V ο (where V is a halogen atom, reactivity of 1-imidazolyl, 4-nitrophenoxy, succinimidyloxy, etc. Residues.) -10-This paper size is applicable to China National Standard (CNS) Λ4 specification (210 × 297 males) ---------- installation ------, 1T ------ ^ -------- (Please read the notes on the back before filling out this page) A7 B7 Printed by the Central Standards of the Ministry of Economic Affairs and printed by the Employee Consumer Cooperative V. Invention Description (发明) The following formula (la) or (Lb)

(1a) (1b) (wherein ring A, (B trans, :: C bis, R4 λ χ, χ2, and Υ are the same as the foregoing 0). The condensation reaction can be carried out in triethylamine, diisopropylethylamine, Organic bases such as pyridine and dimethylaminopyridine, inorganic bases such as sodium bicarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, etc., in the presence or absence of dibasic methane, toluene, acetonitrile, Ν , N-dimethylformamide, dimethyl sub code I, tetrahydrofuran and other solvents, can be easily cell-treated at -20 ~ 50TC for 30 minutes to 48 hours. Also, the following formula (lc) Compound

(1c) The size of this paper is applicable to the Chinese National Standard (CNS) Λ4 specification (210X297) 牦 I ------------------------------- I ---. (Please read the notes on the back before filling out this page) 11 Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Labor A7 B7 V. Invention Description (ί)) ['X1, X2 and Y are the same as above.) Via M low alkylfluorenyl chloride, allylsulfonyl gas, low alkoxycarbonyl gas, substituted or unsubstituted aryloxycarbonyl atmosphere, α-amino acid atmosphere, can Treatment with a substituted carbamoyl chloride, or an active ester thereof, can lead to a compound represented by the following formula (Id)

(1d) This reaction can be in the presence of an organic base such as triethylamine, diisopropylethylamine, pyridine, dimethylaminopyridine, etc., an inorganic base such as sodium bicarbonate, potassium carbonate, or in the absence of inert In the solvent, M-20 ~ 1001C, preferably 0 ~ 50Ϊ: Implementation. Furthermore, if the compound represented by the above formula (lc) undergoes ring closure in the presence of a base, it can be led to the compound represented by the above formula (1 b). This reaction is carried out by mixing the compound of the formula (1 c) in 1 to 10 equivalents, preferably 1 to 5 equivalents of an organic base such as diazine, triethylamine, or the like. In the presence of an inorganic base such as potassium carbonate, potassium chloride, etc., in an inert solvent such as dichloromethane, toluene, acetonitrile, Ν, Ν-dimethylformamide, dimethylsulfine, tetrahydrofuran, or a mixed solvent thereof, in -78 ~ 100t :, preferably at 0 ~ 50C, after 10 minutes to 24 hours, preferably 20 minutes to 5 hours. In addition, the compound represented by the above formula (1 b) passes the scale of hydrogen chloride, hydrogen bromide, hydrochloric acid, hydroxamic acid, toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, and azide. Applicable for domestic valve treatment (CNS) Λ4 specification (210X 297 public potential) ^ 1 ^ 1 1 ^ 1 ^ 1 mV 1 —JJ mv ^ m tl ^^ i aJ— ml Hit---(please first Read the notes on the back and fill in this page) -12-Printed A7 B7 printed by M Industrial Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs 5. Description of the invention (1 η) In the presence of acids such as ethyl acetate, dichloromethane, acetonitrile, Ν , N-dimethylformamide, tetrahydrofuran and other inert solvents, the temperature of -20 <0 to the boiling point of the solvent, preferably 0 to 50 TC, can be converted into the compound represented by the above formula (lc) . The use of excess acid in this reaction is preferred in order to shorten the reaction time. Also, the following formula U) OHC-Vy-CH0 V = &lt; (9) Latch 11 (wherein, R 11 is a linear or branched "-% lower alkyl group." And the two shown by the following formula (7) Aldehyde derivative r12oc-^)-cor, 2 0 0, (7) R14 (wherein R 12 is OR 13 (R 13 is a straight branched Ci-Ce lower alkyl group), a dialkylamino group, R 14 is a linear or branched d-% lower alkyl group, or R 14 is a methylene group, an ethyl group, or a propyl group which form a ring with each other.) It can be manufactured, for example, by the following method. This valve is applicable to a valve. Family Sample Respect (CNS) Λ4 specification (210X 297 public repair) ---------- E ----- 1ΪΤ ------ ^ (Please read the precautions on the back before filling this page ) -13-V. Description of the invention (丨 1) A7 B7

Second process A'i-n10 Rl, z, ^ i Three processes MeO OMe (4)

Fourth process R10 卩 1 V) (Zz) 〇, ΆΝ + rr \ 'N 七, 〇

〇- Fifth process ^ 0HC CH0 R ^ Rn ⑼ (R9 is a hydroxyl or reactive residue, Rle is a hydrogen atom, straight or branched (^ -Cb lower alkyl, R 15 is methyl, ethyl, benzyl The base and R11 are printed with the aforementioned Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (first process). This process is to condense a compound represented by formula (10) and a compound represented by formula (11) to produce formula (12 ). In the case where R9 is 0 碳, this reaction uses dicyclohexylcarbodiimide (DCC) or 3-ethyl-bu (3-dimethylaminepropyl) carbodiimide hydrochloride. In the case where a condensing agent is used to condense or R9 is a reactive residue such as a halogen atom, the reaction can be easily performed in the presence or absence of a base such as pyridine, triethylamine, diisopropylethylamine, or the like. (Second process) In this process, a compound represented by the following formula (4) is produced through ring closure of a compound represented by the formula (1 2). This ring closure reaction is carried out by reacting with polyphosphoric acid and a polyphosphate-- ----- Installation ------- Order ------ Line ------- (Please read the precautions on the back before filling this page) This paper standard is applicable to China valve house standard rate (CNS) Λ4格 （2 丨 0 × 297 公 牦） 14 Printed A7 B7 by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (丨?), Sulfuric acid, sulfurous acid, etc. are processed in 30 minutes to 24 hours at 0 ~ 100¾ It can be easily implemented. (Third process) In this process, a compound represented by the formula (4) is reacted with an organic gold compound represented by the following formula (13) R11 Z1 (13) (wherein Z1 is Li, MgCil, MgBr, Ru are the same as above.) The compound represented by formula (5) is produced. This reaction is carried out in tetrahydrofuran, diethyl ether, dimethoxyethane, methylbenzyl, hexane, or a mixed solvent thereof. At -20 ~ 50t: it can be easily implemented after 30 minutes to 24 hours treatment. (Fourth process) This process is to react a compound represented by formula (5) with a compound represented by formula (14) by R 15 Z2 (14) (wherein Z 2 is C, B r, I, 0 S 0 2 C Η 3, and 0S02Me R 15 is the same as above.) To produce a compound represented by formula (15). This reaction is performed at Nitromethane, dimethyl methyl ether amine, dioxane, or other solvents, or without using a solvent, at 0 to 1001C for 30 minutes to 24 hours (Fifth process) This process is to produce a dialdehyde derivative represented by the formula (9) by converting the compound represented by the formula (15) into an original compound. Korihara used in this reaction Agents can be listed as hydrogenated. The paper size is applicable to Chinese National Standards (CNS) Λ4 specifications (210X297 cm). Order (^ Please read the precautions on the back before filling this page) -15-Staff Consumption of Central Standards Bureau, Ministry of Economic Affairs Cooperate with Du printed the paper standard applicable to the national valve standard (CNS) Λ4 specification (210X297 mm) Λ7 B7 V. Description of the invention (! : j) Diisobutylaluminum, lithium aluminum hydride, sodium bis (methoxyethoxy) aluminum hydride, sodium borohydride, sodium cyanoborohydride, lithium borohydride, etc. This reaction is carried out in toluene, ether, tetrahydrofuran, methanol, acetic acid or the like, or a mixed solvent thereof, and it is smoothly performed at -78t: to 50TC.

r ^ 〇c ^ \. c〇ri2 R ^ Z3 (16) ^ OC-^-CO ^ _ ^ OHC-^-CHO HO OH Sixth process Seventh process $ 4 (6) (7) (8) (No. Six processes) In this process, a phenol derivative represented by the formula (6) is alkylated in the presence of carbonic acid, and a compound represented by the following formula (丨 6) is alkylated. R 14 Z3 (16) (where Z Z is Cl, Br, I, OS02CH3, 〇02- &lt; ^) ~ Me R 14 are the same as described above. ) To produce a compound represented by formula (7). This reaction is carried out by using 1 to 5 equivalents, preferably 2 equivalents, in a solvent such as dimethylformamide, dimethylethylamine, N-methylpyrrolidine, dimethylene oxide and the like. Carbonic acid is absolutely carried out, and it can be easily implemented after 30 minutes to 24 hours treatment at 0 to 100 Torr. (Seventh process) This process is to make the compound represented by formula (7) into original formula (8) -16-1. 111 11¾ ^. I order III (Please read the precautions on the back before (Fill in this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Λ7 B7 V. The dialdehyde derivative shown in the description of the invention (M). Examples of rhenium agents used in this reaction include diisobutylaluminum hydride, lithium aluminum hydride, lithium bis (methoxyethoxy) aluminum hydride, and sodium bis (2-methoxyethoxy) aluminum hydride / N- Methylhexahydropyridine and the like. This reaction is carried out in toluene, ether, IVf), tetrahydrofuran, etc., or a mixed solvent thereof, and the reaction is carried out in a round shape at −78 to 50 °. Here, Rie is straight or branched (^-(: 6 specific examples of lower alkyl include methyl, ethyl, propyl, butyl, isopropyl, etc.) R11 is straight or branched (^ -(^ Specific examples of lower alkyl include methyl, ethyl, propyl, butyl, isopropyl, etc .. Linear or branched R13 (: 1-(: 6 specific examples of lower alkyl) Methyl, ethyl, propyl, butyl, isopropyl, and the like. Specific examples of the dialkylamino group include dimethylamino, diethylamino, dibutylamino, diisopropylamino, and pyrrolidinyl. , Hexahydropyridyl and the like. Specific examples of straight or branched R14 (^-(: 6 lower alkyl) include methyl, ethyl, propyl, butyl, isopropyl, etc. The beginning of the present invention A compound represented by the following formula (2a)

(In the formula, X1, X2, and ring A and R5 are the same as described above.) It is also an important intermediate product of the present invention, and can be produced, for example, according to the method described below. This paper size applies to Chinese National Standard (CNS) Λ4 specification (210 × 297 mm). Appropriate water1, one tongue ^ (Please read the notes on the back before filling this page) -17-A7 B7 f. Cooperative print 5. V. Invention Description (li &gt;)

Y

(20) (2a) (Eighth process) In this process, a compound represented by formula (17) (wherein Y1 is Br, I, OS02CF3, X1, X2, and 瑁 A are the same as described above) and formula ( 18) an acrylic acid derivative (wherein R 16 is a methoxy group, an ethoxy group, a benzyloxy group, and Y 2 is a hydrogen atom, a trimethylstannyl group, and a tributylstannyl group.) A tight coupling reaction is carried out under the conditions of the solvent to produce a diacrylate derivative represented by the formula (19). This reaction can be carried out according to a known method (for example, "Lecture on Experimental Chemistry, 4th edition, pages 396 ~ 427, (1991), Jiushan"). (Ninth process) In this process, the diacrylic acid ester represented by formula (19) is derived and the ester of the product is removed, and the diacrylic acid derivative represented by formula (2a) is produced. This reaction can be carried out according to a known method ("Protective Groups in Organic Synthese", pp. 231 to 265, (1991), Johan W i 1 y & Suns). (Tenth process) _This process is to condense the dialdehyde derivative shown in formula (20) and malonic acid. This paper size applies the Chinese National Standard (CNS) Λ4 specification (210X297 mm) I gutter (please Read the notes on the back before filling out this page.) 18 — A7 Printed by the Consumers Cooperative of the Central Standards Bureau, Ministry of Economic Affairs, B7 ——! V. The invention is clear (Η;) 1 1 1 and the manufacturing method (2 a) is shown The second acrylic acid derivative 〇 This reaction can be performed according to the known method 1 1 〇 [Properties please i racemic compounds of the compounds represented by the above formulas (4) and (5) »and its optical activity 1 | According to well-known methods (e.g., &quot; T etrahedr ο η Le 11 · J 27 vol. 4103 p. A back 1 1 9 (1 986), the journal of medicine ib science (j. He d. Che m.) J 37 Attention to Volume 1 1 I 2 32 pages (1 994) r Bioorganic and "Pharmaceutical Chemistry" (Βί〇Μβ &lt; 1 • Ch e η * Matter 1 I and then IL e tt.) J Volume 2, page 755 * ( 1992), Factory Beauty Journal of the Chemical Society of China (fill in 1 pack j. A m. Ch em «S oc.) J 115 Vol. 9025 pages (1993) t Plant Chemicals I Journal (J * 0 rg. Che m.) J 57, p. 2873 (1992) Japanese Patent Application Laid-Open No. 1 1 3- 128379 * Japanese Patent Application Laid-Open No. 6-116269) = 1 1 The compound represented by formula (I) can be used alone or in combination with--more than one conventional% cocoon content 1 Order Xu auxiliary ribs are commonly used as antibacterial and antitumor compositions and can be used in the form of lozenges &gt; gum 1 1 capsules, powders, ampoules, etc. for oral or non-oral administration 0 1 1 I For non-oral use In some cases, it can be administered intravenously Λ intra-arterial administration 1 1 intraperitoneal administration, subcutaneous administration, intramuscular administration, intrathoracic administration, or local first-line administration, etc. 0 1 For example, the formula (1) The compound or its salt is dissolved in a physiological saline solution and glucose 1 &gt; manganese, lactose and other aqueous solutions to form an appropriate B drug composition 1 1 1 substance 0 The salt of the compound represented by formula (1) may also be used as usual Freeze-dried, and add 1 gasification sodium powder to make a powder injection. 0 more »this m composition 1 1 material may contain additives known in the formulation field> For example, the formulation allows salts 1 I, etc. 〇1 I injection Although the dose varies depending on the patient's age and symptoms9, for human breastfeeding 1 1 | Animals M 0 · 00001 to 100 mg / kg / day 0 Dosage is, for example, 1 time 1 times 1 1-1 η _ paper The Zhang scale is applicable to the Chinese threshold family apple (ΓΝ5) Λ4 specification (210X 297 mm) 19 V. Description of the invention u Week A7 B7 Reproduced by the Ming Dynasty, the origin of the issue, or other examples. The actual number of executions of the series is dependent on or within 2 weeks and 4 innings. 〇 It is not voted and the answer is made.

F3 Tris-n-methylfluorotri-7-ylhydroxy-5 I-methylchloro I-ylcarbonyloxopyrrolidine tetra / | \ 60 5 3 1X ester carboxylic acid carboxyl-8 I indole (Please read the precautions on the back first (Fill in this page again) Packing. Order u Allyl acid and slag residue are hydrogenated. Chlorine agent M? 3 dissolved in addition to distillation (1 in mg, 丨 after 3 ij. Shi Xiao and \ 1 / A ο In w base temperature Η base chamber Ξ 叾 /, / 彳-i-3 迨 4-IV) / 殳 (1 base m-芍 6 ο 3 'amine glM Formaldehyde 2 Dicha acid vinegar awarded dioxin carbon wire. The hydrochloride amine was printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Printing. Water is not dissolved in the water and added to remove the middle mash. It should be dried and then dried. The acid late sulfur is mixed with water without water and extracted in a warm room. 1) Flow: gas (5 enzymes) Formazan imitation m Chlorine residue Residues Obtain 03 pillars with yellow coloration layer ¾) Glue 25 sand g

Refined \) / 1A Benzene UA— / Benzene allyl bis tetrazolium tetrafluoromethylene trifluoride ο ___ _ 7 kuyl methoic acid 5-postyl -8 formyl nitrogen ° 3 | Paper size Applicable to Chinese National Standard (CNS) Λ4 specification (2lOX297 mm) 20 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (1 [a] 24D = — 2 1. (c = 0.20, Tetrahydrofuran) NMR (DMSO dg) δ: 3. 48 (2H. T. J = 8Hz), 3. 8 3 (2H. D, J = 8Hz). 3. 88 (611, s), 4 .28 (2H , br), 4. 40-4. 4 9 (4H, m). 7. 30 (2H, d. J = 15IIz). 7. 70 (211. d. J = 6Hz), 7. 8 7 ( 4It, s), 8. 11 (2H. Brs). 10. 52 (211, br). 13. 02 (ZIl.br). Example 2

(S) -3-Third-butoxycarbonyl-benzoylmethyl-5-hydroxy-7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3,21] indole-8 -To methyl carboxylate 13.511 ^ (30 wmOA) was added 3M hydrogen chloride-ethyl acetate 0.43 mA and left in the chamber for 2 hours, and then the solvent was distilled off. The obtained residue was mixed with 3,3 '-(9,10-cyclodiyl) diacrylic acid (4.8 mg (15 W mOA)) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride iiU. SmgOOw moil) was stirred at room temperature under an argon stream in anhydrous dimethylformamide 0.3 m Λ. Water was added to the reaction solution, and the deposited precipitate was decanted and purified by silica gel column chromatography (tetrahydrofuran: chloroform = 2: 1) to obtain 3.7 mg (25: U of yellow crystal (S, S) -3,3'- [3,3 '-(9, 10-Allium diyl) dipropenyl] bis- [1-chloromethyl-5-hydroxy-7-trifluoromethyl-1,2,3,6-tetrahydro η is better than pyrro [3,2-e] indole-8-carboxylic acid methyl ester]. This paper size is applicable to the National Standard for Valves (CNS) Λ4 specification (210X 297 male f) I -------- -Install one --- order ------ line (please read the precautions on the back before filling out this page) 21 Printed by the KK Industrial Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. The invention is sharp (JJ) 2 9 C a] D = -144 ° (c = 〇-〇5 'tetrahydrofuran) NMR (DM SO dg) δ: 3. 56 (2H, t. J = 10l! Z), 3. 7 9 -3. 8 5 (2H. M), 3. 87 (6H, s), 4. 22-4. 2 9 (2H. M). 4. 33-4. 47 (411. m). 7. 0 5 (211. d, J = 16Hz), 7. 66 (411, dd. J = 4 ^ 7Ilz). 8. 22 (211, s). 8. 3 7 (d! I. Dd. J = 7 yj 4Hz), 8. 5 5 (2H, d, J = 16Ilz), 10. 6 4 (2H. S). 13. 11 (2H. S). Example 3

In the same way, (S) -3-Third-butoxycarbonyl-buchloromethyl-5-hydroxy-7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3,2 -e] indole-8-carboxylic acid methyl ester 13.51 ^ (30 / «111〇] 1) and 3,3 '-(5,8-dimethoxy-1,4-naphthalenediyl) diacrylic acid 4.9 mgi (15w m〇A), and obtained 2.2mg (15S!) of (SS) -3,3'- [3,3 ·-(5,8 -dimethoxy-1,4 -bi-diyl) di Propylene group] Bis-[[Bloromethyl-5-hydroxy-7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3, 2-e]) indole-8-carboxylic acid ester. [a] D3 () =-56. (C = 0.05, tetrahydrofuran) NMR (DMSO dg) δ: 3. 5 2 (2Η, dd. J = 9 and llllz). 3. 80-3. 87 (211, m), 3. 88 (6H , s), 3.89 (6H.s). 4.23 — 4.31 (2H.m), 4.40-1.47Ull, m), 6.77 (2H, d, J = 15Hz), 7.10 (2H.s). 7.75 (2H.s). 8.16 (2II, s), 8.77 (2II.d, J = lSHz). 10.54 (211.s), 13.06 (2Il, s) Examples ---------- t -丨 ----- IT ------ A (Please read the precautions on the back before filling out this page) This paper size applies to Chinese National Standard (CNS) Λ4 specification (21〇X 297 cm) 22 OO -Μ Β7 Economic Lang Central Standard _Printed by Bureau Consumer Consumption Cooperative V. Invention Description (; j (丨)

In the same way, (S) -3-Third-butoxycarbonyl-1-chloromethyl-5-hydroxy-7-trifluoromethyl-1,2,3,6-tetrahydro "pyrrolo [ 3,2-e] indole-8-carboxylic acid methyl ester 26.911 ^ (60 / ^ 111〇) 1) and 3,3 '-(2,3- (ethylenedioxylene) -1,4-benzene Based] diacrylic acid 8.31! ^ (30 / ^ 111〇) 1), obtain 4.111 ^ (15: 1!) Of (5,5) -3,3 '-[3,3'- (2,3- ( Ethylenedioxane) -1,4-phenylene) dipropylfluorenyl] bis- [1-lanemethyl-5-hydroxy-7-trifluoromethyl-1,2,3,6-tetrahydro Called: Paro [3, 2-e] indole-8-carboxylic acid methyl ester] [α] 〇3 ° = -12 ° (c = 〇. Ο 5. Tetrahydrofuran) NM R (D Μ S 〇 dg) δ: 3. 5 1 (2H, t. J-1 ΟΗζ), 3. 7 9-3. 8 5 (2Η. In), 3. 88 (611, s), 4. 2 3 -4. 3 2 (ZΗ, m), 4. 38-4. 4 4 (4 Η, m). 4. 46 (4 Η. S). 7. 25 (2Η, d, J = 16Hz), 7 5 2 (2H, s). 7. 8 9 (2H.d. J = 16! Iz), 8. 10 (211. S). 10. 56 (211, s). 13. 07 (211. S ) Example 5

_According to the same method, the paper size of (S) -3-third butoxycarbonyl-1-chloromethyl-5-hydroxyl applies to the Chinese National Standard (CNS) Λ4 specification (210X297). ----- ------ install l · ----- order ------ line (please read the notes on the back before filling this page) -23-Printed by the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention Ul) 1-7 mg of tris-7-trifluoromethyl-1,2,3,6-tetrahydron ratio to pyrro [3,2-e] indole-8-carboxylic acid methyl ester 3〇w moil) and 3,3 '-[2,3- (methyldioxy building) -1,4-phenylene] diacrylic acid 3.9mg (15w m〇A) to obtain (S, S) -3 , 3 '-[3,3'-(2,3- (methyldioxy) -1,4-phenylene) dipropenyl] bis- [1-chloromethyl-5 -hydroxy-7- Trifluoromethyl-1,2,3,6-tetrahydrocarbo [3,2-e] indole-8-carboxylic acid methyl]. "1 30. — L a JD = — 12 (c = 0.05, tetrahydrofuran) NMR (DMSO dg) δ: 3. 52 (2H, dd. J = 9 / ¾ 11 Hz), 3. 78-3. 85 (ZH, m). 3 88 (6H. S). 4. 2 4-4. 3 2 (211. m). 32H.i5 (4H,,). 6. 38 (211. s), 7. 28 (211.d .; = 16Hz). 737 (2H.s), 7.65 (2II.d. J = 16HZ). 8.10 (21 !, s), 10.58 (2H, s), 13. 17 (211 s). Example 6

In the same way, (S) -3-Third-butoxycarbonyl-1-aminomethyl-5-hydroxy-7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3 , 2-6] Indole-8-carboxylic acid methyl ester 26.9mg (60w moil) and 3,3 '-(2,3-diethyl-1,4-phenylene) diacrylic acid 8.2mg (3〇 w moil) to obtain 5.5 mg (20! U) of (S, S) -3,3 '-[3,3'-(2,3-diethyl-1,4-phenylene) dipropenose Propyl] bis- [1-naphthylmethyl-5 -hydroxy-7-trifluoromethyl-1,2,3,6-tetrahydro "than pyrro [3,2-e] indole-8-carboxylic acid Methyl ester]. This paper size applies to Chinese National Standards (CNS) Λ4 specification (210X297 cm) ----------- installation --------- order ------ silk--1 (please (Please read the notes on the back before filling this page) -24-Μ Β7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (发明) [a] D31 = -16e (c = 0.05, tetrahydrofuran)

NMR (DMSO d.) Δ: 1. 18 (G H. t. J = 8 Hz). 2. 8 5 (4 H, q, J = 8Ηζ), 3. 51 (2Η, t. J 6

= 10Hz). 3. 7 2-3. 8 5 (2H. M). 3. 88 (6H, s). 4. 2 2-4. 32 (211. m), 4. 38-4. 48 ( 4H.m). 7. 12 (2 HdJ = 16Hz). 7.78 (2H.s), 7.99 (211, d, J = 16Hz). 8.11 (2H, s). 10.54 (2H, s), 13.06 (2H , s). Example 7

In the same way, from (S) -3 -Third-butoxycarbonyl-1-chloromethyl-5-hydroxy-7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3, 21] Indole-8-carboxylic acid methyl ester 13.511 ^ (30 «1! 1〇] 1) and 3,3 '-(2,3-dimethoxy-1,4-phenylene) diacrylic acid 4.2 mg (15 «moil) to obtain 2.1 fflg (15! 〇 of (SS) -3,3'- [3,3 ·-(2,5-dimethoxy-1,4-benzyl) dipropylene Fluorenyl] bis- [1-lanemethyl-5 -hydroxy-7-trifluoromethyl-1,2,3,6-tetrahydro is called: pyrro [3, 2-e] ind ° -8- Methyl carboxylate]. Ί η C a] D =-56. (c = 0.05, tetraargon) NMR (DMSO d 6) 5: 3. 52 (2H, dd. J = 8 and 11 Hz), 3 78-3. 90 (211, m), 3. 88 (G! I. S). 3. 98 (6H, s). 4. 2 3 -4. 3 3 (211. m). -1. 38-4. 48 (4H. M). 7. 30 (2H, d, J = 16Hz), 7. 53 (2H. S). 7. 96 (211, d. J = 16Hz), 8. 10 ( 211. s), 10. 56 (2H, s). 13. 07 (211, s). Example 8 This paper size applies to the Chinese National Standard (CNS) Λ4 specification (210X297mm t) I Gutter (please read first Note on the back, please fill out this page) 25 A7 B7 Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

In the same way, (S) -3 -Third-butoxycarbonyl-1-aminomethyl-5 -hydroxy-7-trifluoromethyl-1,2,3,6-tetrahydro 13.5 mg of 3,21] indole-8-carboxylic acid methyl ester (30 wm0A) and 4.2 mg of 3,3 '-(2,5-dimethoxy-1,4-phenylene) diacrylic acid (15w moil) to obtain 1.1 mg (8S!) 2 (S, S) -3,3'- [3,3 '-(2, 3-dimethoxy-1,4-phenylene) di Allyl] bis- [1-chloromethyl-5-hydroxy-7-trifluoromethyl-1,2,3,6-tetrahydro "it pyrro [3, 2-e] indole-8- Methyl carboxylate]. [a] D32 = — 26. (C = 0.05, tetrahydrofuran) NMR (DMSO d J δ: 3.51 (2H, del, J = 9/1 10Hz). 3. 7 9-3. 94 (2H, in), 3. 6 88 ( 6H. S), 3. 90 (6H, s), 4. 24-4. 3 3 (2H.ni). 4. 3 9-4. 4 9 (411, m), 7. 31 (2H, d , J = 16Hz), 7. 78 (2H, s), 7.88 (2H, dJ = 16IIz), 8.11 (2H.s). 10.57 (2H, s), 13.08 (2H.s). Example 9

According to the same method, (S) -3 -Third-butoxycarbonyl-bufamylmethyl-5 -hydroxy-7-trifluoromethyl-1,2,3,6-tetrahydropyrene [3] , 2-6] indole-8-carboxylic acid methyl ester 13.511 ^ (30/1 (111〇) 1) and 3,3 '-(1,1'-diphenyl-4,4'-diyl) This paper size applies the Chinese National Standard (CNS) Λ4 specification (210X 297 cm) binding line (please read the notes on the back before filling this page) 26 Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention 4.4 mg (15 u mOA) of diacrylic acid, 1.7 mg (12! U of (S, S) -3,3 '-[3,3'-(1,1 · -diphenyl-4.4'-di Propyl) dipropenyl] bis- [chlorochloro-5-hydroxy-7-trifluoromethyl-1,2,3,6-tetrahydro% pyrrolo [3, 2-e] indole-8 -Methyl carboxylate]. [(^ / 2 = -36 ° (c = 0.05, tetrahydrofuran) NMR (DMS 0 d,) δ: 3.50 (211. dd. J = 9 / ¾ 11Hz). 3. 78-3. 90 (2H. M). 3. 0 88 (611, s), 4. Z3-4. 32 (211. M), 4. 3 8-4. 5 2 (4 11, in ), 7. 29 (2H, d, J = 15Hz), 7. 71 (2H. D, J = 1 5Hz). 7. 84 (4H, d, J = 8Hz), 7. 9 3 (4H, d , J = 8IIz), 8. 11 (2H, s), 10. 5 8 (2H, s), 13. 07 (ZH, s). Example 1 0

In the same way, (S) -3 -Third-butoxycarbonyl-bufamylmethyl-5 -hydroxy-7-trifluoromethyl-1,2,3.6-tetrahydropyrrolo [3,2- e) Indole-8-carboxylic acid methyl ester 13.511 ^ (30 // 111〇) 1) and 3,3 '-(1,4-naphthalenediyl) dipropionate (LonigdSii mOA), 3.0 mg was obtained (22S!) Of (S, S) -3,3,-[3,3 '— (1,4-naphthalenediyl) dipropenylfluorenyl] bis- [1-chloromethyl-5-hydroxy-7 -Trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3,2-e] indole-8-carboxylic acid methyl ester]. This paper size is applicable to China National Standard (CNS) Λ4 specification (210X297 Gongkang) ---------- ^-丨 -----, order ------. ^ (Please read the back first Please pay attention to this page, please fill in this page) 27 Consumer Cooperation of Central Standards Bureau, Ministry of Economic Affairs, Du printed A7 B7 V. Description of Invention (⑸) [«] =-4 1 ° (c = 0 · 0 5, Tetrahydrofuran) NMR (DMS 〇 d,) δ: 3. 53 (2Η.t, J = 1 〇Ηζ), 3. 78-3. 9 2 (2Η.m) 3.88 (6Η.s), 〇 4. 2 5-4. 34 (2H.in). 4. 4 5-4. 54 (iH.m). 7. 3 6 (2H, d. J = 15IIz). 7. 7 4 (ZII.dd, J = 3 jk 6

Hz). 8. 16 (2H. S). 8. 20 (211. S). 8. 36 (2il. Dd. J = 6/5 31! Z). 8. 51 (211.d, J = 15Hz ). 10 .60 (2H, s). 13.09 (2H, s). Example 1 1

In the same way, (S) -3-Third-butoxycarbonyl-1-nitromethyl-5-hydroxy-7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3, 2-e] ind «-8-carboxylic acid methyl ester 13.511 ^ (30; 1 &lt; 111〇 and) and 3,3 '-(1,4-cyclodiyl) diacrylic acid 4.8 mg (15 μm〇A), (2.3! (16! U of (S, S) -3,3 '-[3,3'-(l, 4-allium diyl) dipropenylfluorenyl] bis- [1-chloromethyl-5- Hydroxy-7-trifluoromethyl-1,2,3,6-tetrahydro 0H: pyrro [3,2-e] indole-8-carboxylic acid methyl ester].-36. (c = 0.05 , Tetragas sulfonation) NMR (DMSO d J δ: 3. 5 4 (2II. T, J = 1 ΟΙΙζ), 3. 7 8-3. 9 3 (211. π), 3. 8 9 (611. s), 6 4. 27-4. 36 (211, m), 4. 4 6 -4. 5 7 (4Η. m). 7. 43 (2H, d. J = 15Hz), 7. 62 (211 dd, J = 3} l 6 Hz). 8. 19 (411, s), 8. 30 (2H, dd. J = 6 3 Hz), 8. 6 7 (211, d, J = 15 Hz) , 9. 0 4 (ZH, s), 1 〇.60 (211, s), 13. 07 (2H, s). Implementation 洌 1 2 Wood paper standard applies the mid-threshold national standard (CRS) Λ4 specification (210X297)漦) _ 2 8-I Order (Please read the precautions on the back before filling this page) A7 B7 Printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs Description (:%)

In the same way, from (S) -3 -Third-butoxycarbonyl-1-aminomethyl, 5-hydroxy-7-trifluoromethyl-1,2,3,6-tetrahydroterm: 3,2-e] indole-8-carboxylic acid methyl ester 40.4 | 118 (90 &lt; / 111〇) 1) and 3,3 '-(9,10-dihydro_9.10-dioxy_1,4 -Didiyl) 15.7mg (45w moil) of diacrylic acid, 1.6mg (4n of (S, S) -3, 3 '-[3,3'-(9,10-dihydro-9,10-di) Oxy-1,4-allium diyl) dipropenylfluorenyl] bis- [1-chloromethyl-5-hydroxy-7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [ 3,2-e] indole-8-carboxylic acid methyl ester] 3 7 [a] D = -48 ° (c = 0.05, tetrahydrofuran) NMR (DMS 0 dg) δ: 3. 53 (2Η. Dd. J-9 Mo 10Hz), 3. 79-3. 91 (2H, m). 3. 88 (6H, s). 4. 2 4-4. 3 4 (211. m), 4. 41-4. 51 (4H. M), 7. 11 (211, d, J = 16ilz), 7. 95 (211. dd. J = 3 Jl 6Hz). 8. 10-8. 19 (411 , m). 8. 21 (21 !, s), 8. 5 3 (211. d, J = 16IIz), 10. 61 (211, s), 13 .10 (2H, s). Example 13

This paper size applies to Chinese National Standard (CNS) Λ4 specification (210X 297 mm) I -------- 1 —----- IT ------ g (Please read the notes on the back first (Fill in this page again) 29 A7 B7 printed by the Employees' Cooperative of the Shiyang Standard Bureau of the Ministry of Economic Affairs. 5. Description of the Invention (: Γ /) In the same way, (S) -3-Third-butoxycarbonyl-Puccino Methyl-5-hydroxy-7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3,2-e] indole-8-carboxylic acid methyl ester 13.511 ^ (3 (^ 111〇1 ) And 3,3 '-(2,2'-di (1 than pyridyl-5,5'-diyl) diacrylic acid 4.4mg (15; u moil), to obtain 2.4mg (17! «) Of (SS ) -3,3 '-[3,3'-(2,2'-Diamidinyl-5,5'-diyl) dipropenyl ether] bis- [1-chloromethyl-5 -hydroxy- 7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3,2-e] indole-8-carboxylic acid methyl ester] 〇] n32 = -35 ° (c = 0.05, Tetrahydrofuran)

D N M R (D M S Ο d J δ: 3.51 (211, dd, J = 9 / ¾ 10Hz), 3. 7 7-3. 9 2 (2H. M). 3.

D 88 (61i.s), 4.25-4_33 (211.m), 4.39-4_55UH, m), 7.47 (2il, d, J = 15Hz). 7.78 (2H, dJ = l 5Hz), 8. 13 (211 s). 8. 51 (4H, s). 9. 08 (2H, s), 10. 60 (2H, s), 13. 09 (2H. s). Example 14

In the same way, from (S) -3 -Third-butoxycarbonyl-buchloromethyl-5 -hydroxy-7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3, 2-6] Indole-8-carboxylic acid methyl ester 13.51 ^ (30 &quot; 111〇) 1) and 3,3 '-(1,3-phenylene) diacrylic acid 3.3 tng (15 / i moil), obtained 3.5ing (27: i :) of (S, S) -3,3,-[3,3 '-(l, 3-phenylene) dipropenyl] bis- [1-chloromethyl-5 -Hydroxy-7-trifluoromethyl- This paper size applies to China's National Standards (CNS) Λ4 specification (210X 297 public momentum). Yi Yi ^ (Please read the precautions on the back before filling this page) -30- Fifth, invention invention (; 3) A7 B7 1,2,3,6-tetrahydro friends: pyrro [3,2-e] indole-8-carboxylic acid methyl ester]. [a] D27 = —28. (C = 0.05, tetrahydrofuran) NMR (DMS Ο d.) Δ: 3.51 (2H.dd, J = 9 and 10 Hz), 3. 75-3. 93 (2 II, η), 3. Ο 88 (6Η, s), 4. 2 4-4. 3 3 (2 Η. M), 4. 38-4. 5 3 (4H, m). 7. 3 3 (2H.d, J = 16Hz), 7. 52 (1H, t. J = 8 Hz), 7. 7 3 (2H, d. J = 16 Hz), 7. 88 (2H. D. J = 8 Hz). 8. 1 2 (2H, s) , 8. 25 (1II. S), 10. 56 (2H, s), 13. 06 (2H, s). Example 1 5

Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs in the same way, from (S) -3 -Third-butoxycarbonyl-1-ammoniamethyl-5 -hydroxy-7-trifluoromethyl-1,2,3 , 6-tetrahydro "than pyrro [3,2-6] indole-8-carboxylic acid methyl_13.51 ^ (30" moil) and 3,3 '-(1,2-phenylene) diacrylic acid 3.3 mg (15w moil) to obtain 3,9mg (30S;) of (S, S) -3,3 '-[3,3'-(l, 2-phenylene) dipropenyl] bis- [1 -Chloromethyl-5-hydroxy-7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3,2-6] indole-8-carboxylic acid methyl ester] 28 10 7 0.05, Tetrahydrofuran NMR (DMSO d6) 6: 3. 51 (2Ii. T. J = 9! Iz). 3. 7 5-3. 9 2 (2H. &Gt; n). 3. 87 (6H s). 4 .2 2-4. 3 2 (2H. m). 4. 38-4. 50 (411. m), 7. 16 (211. d. J = 15Ilz), 7. 5 2 ( EN, dd. J = 4 fk 6H z), 7. 97 (2H.ro). 8. 0 5 (211. d, J = 15Hz). 8. 11 (EN. S). 10. 57 (2H. s), 13. 0 6 (2H, s). This paper size applies Chinese National Standard (CNS) Λ4 specification (210X297 cm) ---------- ^ 1: ----- ir- ----- M --------- (Please read the precautions on the back before filling out this page) -〇1 31 A7 B7 Central Ministry of Economic Affairs of the People's Republic of China, printing bag for consumer cooperatives 16 illustrates an embodiment Ming

In the same way, from (S) -3 -Third-butoxycarbonyl-1-aminomethyl-5 -hydroxy-7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3, 2-6] Indole-8-carboxylic acid methyl ester 27.011 (60 // 111〇AI) and 3,3 '-(4,4'-(1,1 ': 4,, 1,' -Bitriphenyl)) 11.2 mg (30w moil) of diacrylic acid, to obtain 3.1 ng (10iU) of (S, S) -3,3,-[3,3 '-(3,3 "-(1,1, : 4 ', 1 ”-bitriphenyl)) dipropenyl] bis- [1-chloromethyl-5 -hydroxy-7-trifluoromethyl-1,2,3,6 -tetrahydro" And [3, 2-e] indodol-8-carboxylic acid methyl ester]. 28 C *] D = one 19. (C = 0.5, tetrahydrofuran) NMR (DMSO dg) δ: 3. 51 (2 (1, dd. J = 9 ^ 10Hz), 3. 78-3. 94 (211. m). 3. 8 8 (611. S). 4. 2 4-4. 3 4 (2H, m). 4. 3 9-4. 54 (4H.m). 7. 37 (2H, d, J = 15Hz), 7 58 (211.t, J = 8 Hz). 7. 78 (2H, d. J = 15Hz). 7. 81 (211, d. J = 8Hz). 7. 8 3 (2H. D. J = 8Hz). 7. 9 2 (411. S). 8. 13 (2H. S). 8. 18 (2H, s). 10. 5 6 (2 (1. S). 1 3. 07 (2H, s). Example 1 7 This paper size applies the Chinese National Standard (CNS) Λ4 specification (210X297 mm) I — ^ Packing, one swallow (please read the precautions on the back before filling this page) 32 A7 B7 Ministry of Economic Affairs Printed by the Consumer Standards Cooperative of the Central Bureau of Standards

In the same way, from (S) -3-Third-butoxycarbonyl-azepinemethyl-5-hydroxy-7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3,2 -e] ind ««-8-carboxylic acid methyl ester 40.5π ^ (180 «moil) and 3,3 '-(4,4'-(1,1 ': 4 ·· 1” -terphenyl)) 2 5.6mg (15w moil) of valproic acid, 4.9mg (32X) of (S, S) -3,3 '-[3,3'-(4,4 "-(1,1 ': 4', 1) Bitriphenyl)) Dipropenyl] bis- [1-chloromethyl-5-hydroxy-7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo [3, 2-e] Indole-8-carboxylic acid formaldehyde]. [α] / 8 = -17 ° (c = 0.05, tetrahydrofuran i ') NMR (DMS 0 d J δ: 3. 50 (211, t, J = 1 〇Hz), 3. 7 9 -3. 9 3 (2H, m), 3. 88 (6H. S), 0 4. 2 3 -4. 3 3 (2H, m). 4. 3 8 -4. 5 3 (4H, m) , 7. 29 (211, d. J = 16ilz). 7. 72 (2H, d, J = 16Hz). 7. 83 (4H, d. J = 8IIz), 7. 88 (4H, s). 7 9 3 (411, d. J = 8Hz), 8. 13 (211, s), 10. 56 (211, s). 13. 06 (ZH, s). Example 18

This paper size is applicable to China Standard (CNS) Λ4 specification (21〇X 297 mm) --------- installation ------ order ------ line—Γ (please first Read the note on the back of the page and fill in this page) 33 A7 B7 printed by the staff of the Central Standards Bureau of the Ministry of Economic Affairs F5. Invention description (: u) In the same way, from (S) -3-third butoxycarbonyl -1-nitromethyl-5-hydroxy-7-methyl-1,2,3.6-tetrahydro "than methyl [3,2-e] indole-8-carboxylic acid methyl ester 31.611 ^ (8 (^ 111〇] 1) with 3,3 '-(1,4-benzyl) diacrylic acid 8.7 mg (40iu moil), 8.8 mg (29! U of (S, S) -3,3,-[3 , 3,-(I group in 1,4 -1) dipropenyl] bis-Π-chloromethyl-5-hydroxy-7-methyl-1,2,3,6-tetrahydropyracolo [ 3,2-e] Earthworm-8-methyl carboxylate]. [A] D28 =-15. (c = 0.05, tetrahydrofuran ') NMR (DMS Ο ¢ 1,) δ: 2. 61 (611, s ), 3. 41-3. 47 (2Η. M). 3. 80 (6H, s). 3. 77-3. 6 90 (2H, m), 4. 2 9 -4. 5 0 (611. m), 7. 30 (211, d. J = 15Hz), 7. 66 (ZII, d, J = 15Hz), 7. 87 (4H, s), 7. 93 (211. s). 10. 11 (211, s), 11. 88 (211, s). Example 19

In the same way, (S) -3 -Third-butoxycarbonyl-1-fluorenylmethyl-5 -hydroxy-8-methyl-1,2,3,6-tetrahydropyrrolo [3,2 -6] Indole 27, 〇1 ^ (80 M moil) and 3,3 '-(1,4-phenylene) diacrylic acid 8.7mg (40w moil), obtaining 13.01 ^ (50%) (5, $)-3,3 '-[3,3'-(1,4-benzyl) dipropenyl] bis- [1-chloromethyl-5 -hydroxy-8 -methyl-1 , 2,3,6-tetrahydropyrrolo [3,2-e] Π3Ι π 朵]. This paper size is applicable to Chinese standard rate (CNS) Λ4 specification (210 × 297 public repair) 0, -34- I i Binding-stitching (please read the notes on the back before filling this page) A7 B7 V. Description of the invention (： 丨 2) α] -42. c = 0. 05 、 Working with the Central Standards Bureau of the Ministry of Economics, Ministry of Economic Affairs and Consumer Cooperation Du printed NMR (DMS 〇 de) δ: 2. 3 5 (6 H. s), 3. 5 4-3. 6 3 (2 H. m). 3. 8 4-3. 9 1 (2 !!. M), 4. 6 00-4. 10 (2Η, m), 4. 3 4-4. 5 4 (4Η. m). 7. 03 (211. s), 7. ZO9 (2Η, d, J = 16Hz), 7. 6 5 (2H, d, J = 1 6Hz), 7. 78 (2H. s), 7 86 (4H, s), 9. 7 5 (211, s). 10. 68 (2H. S). Example 20

In the same way, (S) -3-Third-butoxycarbonyl-1-aminomethyl-5-hydroxy-1,2-dihydropyrrolo [3,2-3] pyrazole 14.91 ^ (40 « 100%) and 4.4 mg (20w mOA) of 3,3 ·-(1,4-benzyl) dipropanoic acid to obtain 1.5mg (10,00 of (3,3) -3,3 '-[3,3'-(1,4-phenylene) dipropenylfluorenyl] bis-Π-nitromethyl-5 -hydroxy-1,2-dihydropyridine. Each of [3,2-a ] 4azole]. [«] D28 =-4 Γ e (c = 0.05 'tetrahydrofuran)

NMR (DMSO dg) δ: 3.83 (21 !. dd, J = 8 shoulder 11Hz), 3. 98-4. 05 (211, m). 4. 34-4. 4 2 (2H, tn), 4. 53-4. 64 (4H.m), 7. 18 (ZH, t. J = TH2), 7. 34 (ZH, d. J = 15Hz), 7. 39 (2H.t. J = 7Hz ). 7. 51 (2H. D, J = 7Hz). 7. 6 9 (2H. D, J = 15IIz), 7. 90 (4H. S), 7. 91 (211, d, J = 7!) lz), 8. 11 (2H. s). 10. 08 (2H, s). 11. 20 (211, s). Example 21 The paper and paper scales are applicable to the standard Chinese standard (CNS) Λ4 specification ( 2 丨 0X297 公 漦) _ΒΙ ^ 1 · m ^ i ^ mf tm «i / f / m ^ i Huff n ^ in ^ i · — ^ ϋ J US. Ί 矣 (Please read the notes on the back before filling in this Page) 35 A7 B7 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs V. Invention Description (: 丨: 3)

In the same way, from (S) -3 -Third-butoxycarbonyl-1-aminomethyl-5-hydroxy-1,2,3,6-tetrahydro-pyrrolo [3,2-e] ind Indole-8-carboxylic acid methyl ester 9.5mg (25w mOA) and 3,3 '-(1,4-phenylene) diacrylic acid 2.71 ^ (12.5 wmOA), to obtain 2.8mg (30: C) Of (5,5) -3,3 '-[3,3'-(1,4-phenylene) dipropenyl ether] bis- [1-lanemethyl-5 -hydroxy-1,2,3 , 6-tetrahydropyrrolo [3,2-e] indole-8-carboxylic acid methyl ester]. Γ α 1 26 = -8. (C = 0.20, tetrahydrofuran)

LD NMR (DMS〇d 6) δ: 3.4 5-3. 5 8 (2 11, m), 3. 80 (611. s), 3. 7 2-3. 88 (211, m). 3 94 (211, d, J = 8. 8Hz), -1. 31-4. 44 (211. m). 4. Ί8 (2H, d. J = 8. 8Hz). 7. 31 (2H. D , J = 15Hz), 7. 67 (211. D, J = 15Hz), 7. 88 (411, s), 7. 9 3 (211. D, J = 2. 9Hz). 7. 9 7 (2H , brs). 10. Zl (2il. s). 1 2.03 (2H. s). Example 22

Me〇2〇

Wood paper scale is applicable to the Mid-Threshold Home Standard (CNS) Λ4 specification (210X297 male f). (Please read the precautions on the back before filling out this page) 2. Description of the invention (: l ·)) According to the same method, from (S) -3-third butoxycarbonyl-1-aminomethyl-5-hydroxy-1,2,3,6-tetrahydro >> [3,2-6] Indole-7-carboxylic acid methyl ester 38.11〇8 (100 μm〇A) and 3,3 '-(1,4-benzyl) diacrylic acid 10.911 ^ (50 «moil) To obtain 2.2 mg (6a;) of (5, $)-3,3 '-[3,3'-(1,4-phenylene) dipropenyl] bis- [1-aeromethyl-5 -Hydroxy-1,2,3,6-tetrahydropyrrolo [3,2-e] indole-7-carboxylic acid methyl ester]. [a] D28 = + 21. (C = 0.05, tetrahydrofuran) NMR (DMS Ο d J δ: 3. 87 (611. S), 3. 90-3. 99 (2H. M), 4. 02-4. 16 (4H. M ), 4. 6 28-4. 37 (2H, m). 4. 5 2-4. 6 3 (2H. M). 7. 26 (211. D. J = 15Hz). 7. 22-7. 30 (2H.m) 7. G6 (2H, d.J = 15Hz). 7. 85 (411, s). 7. 9 2 (211, s). 9. 79 (211. S), 11. 61 (211. s). Reference Example 1

Tf0- / ~ VTfo was added to 100 mg (0.62 mm) of naphthoquinone, and 10! «Pd / c 10. 0 mg and 2 ml of anhydrous tetrahydrofuran were stirred under a hydrogen stream at room temperature for 2 hours. Under ice cooling, add 2,4,6-trimethylpyridine 0.4〇 !! 1 meaning (3.03111111〇] 1) and anhydrous trifluoromethanesulfonic acid 0.261 ^ (1.55 «1111〇 again), in the chamber under the radon air Stir at warm for 2 hours. The reaction solution was purged, and the solvent was distilled off. Then, digas methane was added, and M water, 1N hydrochloric acid, and saturated brine were successively washed and dried over anhydrous sodium sulfate. The solvent was distilled off, and the silica gel column chromatography (hexane: ethyl acetate = 10: 1) was purified to obtain 78.7 mg (30S;). Colorless oil 1,4-bis-(((trifluoromethyl) sulfonic acid) Stuffed) oxy) naphthalene. This paper size applies to China's National Standards (CNS) Λ4 specification (210X 297 cm) — binding line (please read the precautions on the back before filling out this page) -37-Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (: 丨 5) High resolution mass spectrum MC i 2 H e H e 0 e S z Calculated value: 423. 95 1 0 Found: 423. 95 1 2 Reference example

TfO

In the same way, OTf obtained 450 mg (66! L!) Of 1,4-bis-(((trifluoromethyl) sulfonic acid) oxy) from 300 mg of 1,4-quinone (1.44 mmOA). . Melting point 1 52.5-153. Elemental analysis Based on C, Calculated: C, 40.51; Thallium, 1.70 Found: C, 40.31; Thallium, 1.54 Mass spectrum (m / z): 474 (Μ +) Reference Example 3

In the same way, 163 mg (15: n of 1,4-bis-(((trifluoromethyl) sulfonyl)) was obtained from 5,8-dimethoxyquinone 50〇11 ^ (2.29111111〇yi). Oxy) -5, 8-dimethoxy ban. This paper size is suitable for medium valve valve standard (CNS) Λ4 size (210X 297 cm) III,-^ (Please read the precautions on the back before (Fill in this page) 38-A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (36) Melting point 1 45. 5-1 46. 5 TC elemental analysis MC14H1DFG〇BS2 Calculated value: C, 34.72; Η, 2.08 Found: C, 34.88; Η, 1.82 Mass spectrum (m / z): 484 (Μ +) Reference example 2

Tf〇- ^ OT, MeO OMe According to the same method, from 2,3-dimethoxybenzoquinone 1001 ^ (0.59111111〇 殳), 218mg (84! N of 1,4-bis-((tri Fluoromethyl) i) oxy) -2,3-dimethoxybenzene. High resolution mass spectrum W C, Q H B F s 0 B S 2 Calculated value: 433.9565 Found value: 433.9564 Reference example 5

TfO

In the same manner, 567 mg (84: n of 5,5 · -bis-(((trifluoromethyl))) was obtained from 280 mg (l, 49 mmOjl) of 5,5-dihydroxy-2,2'-dipyridyl. Base) 硪 醢) oxy) -2,2 dipyridyl. Melting point 158.0-162.0Ό This paper size is applicable to China National Standards (CNS) Λ4 specifications (210X297). — 一 ----- Order ------ line (please read the notes on the back before filling out this page) 39 A7 B7 printed by the Staff Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (: 丨 7) Elemental analysis MClzHeFeN20BS2 Calculated value: C, 31.87; Η &gt;1.34; Ν, 6.19 found · C, 31.72: Η, 1.14; Ν-6.40 Mass spectrum (m / z): 452 (Μ +) Reference Example 6

Et02C— ^ CO, Et

1,4-Bis-(((trifluoromethyl) sulfofluorenyl) oxy) was banned from 30.0 mg (71 / z moil) with triethylamine 0.041 mil (0.29 mm) and ethyl acrylate 0.16 mA ), 2.9 mg (7.0w moil) of 1,3-diphenyltenyl propane and 1.6 mg (7.1 «niOl) of barium acetate were suspended in anhydrous dimethylformamide 5mA and 80t under argon atmosphere: Stir overnight. Dichloromethane was added, K535 hydrochloric acid, water and saturated brine were successively washed, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was subjected to silica gel column chromatography (dichloromethane: hexane = 1: 1) and purified * to obtain 19.5 mg (85; U) of yellow crystals 3,3 '-(1,4_naphthalene di Based) ethyl diacrylate.

Melting point 84.0-87.0 1C

Elemental analysis MC 0 Calculated value: C, 74.06; Η, 6.21 Measured value: C, 73.89; Η, 6.21 Reference example 7 This paper size applies to the Chinese National Standard (CNS) Λ4 specification (210X 297 public dust) ----- ----------- ΪΤ ------. ^ (Please read the notes on the back before filling this page) 40 A7 B7

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

V. Invention Description (38)

EtQ2C In the same way, 300 mg (0.63 min) of 1,4-bis-(((trifluoromethyl) fluorene) oxy) onion was obtained to obtain 169 mg (7U) of 3,3 ·-(1, 4-Di-diyl) ethyl diacrylate. Melting point 98. 5-99.5 υ Elemental analysis M CZ4H2Z0 «Calculated: C, 76.99; Η, 5.92 Found: C, 76.76; Η, 6.04 Mass spectrum (m / z): 3 7 4 (Μ +) Reference Example 8

Et02C In the same way, from 1,4-bis-(((trifluoromethyl) fluorene) oxy-9,10-dihydro-9,10-dioxybenzene 1001118 (0.2〇1111 〇〇 ^ {1), 49.0 1 ^ (61%) of 3,3 '-(9,10-dihydro-9,10-dioxy-1,4-cyclodiyl) diacrylate was obtained. Melting point 222.5-224.5t Elemental analysis M C2 «H2 () 0b This paper size is applicable to Chinese National Standard (CNS) Λ4 specification (2 丨 OX 297 mm) Gutter (please read the precautions on the back before filling this page) -41-V. Description of the invention (: ⑼ A7 B7 Calculated value: C, 71.28; H, 4.98 Found: C, 71 · 09; Η, 4.93 Mass spectrum (m / z): 404 (Μ +) Reference example 9 sto2c

MeO OMe co2et According to the same method, 300 mg (0.62 mmol) of 1,4-bis-(((trifluoromethyl) sulfonyl) oxy) -5,8-dimethoxynaphthalene * was obtained 219ng ( 92S!) Ethyl 3,3 '-(5,8-dimethoxy-1,4-Mdiyl) diacrylate. Melting point 1 19. 0-122. 0¾ Elemental analysis K C22H240b Calculated value: C, 68.74; Er, 6.29 Found: C, 68.50: Er, 6.29 Mass spectrum (m / z): 384 (Μ +) Reference example 10- ----------- install ------- order ------ line --- (Please read the precautions on the back before filling out this page) Staff Consumption of the Central Standards Bureau of the Ministry of Economic Affairs Printed by a cooperative

Et02C

In the same way, CO2B was prepared from 5,5 '-(1,4-bis-(((trifluoromethyl) sulfonyl) oxy))-2,2'-dicaryl 83.2mg (0.18mm〇A). ), 54.3mg (8430 of 3,3 |-(2,2'-dipyridyl-5, 5'-diyl) ethyl diacrylate. This paper size applies the Chinese National Standard (CNS) Λ4 specification ( 210X297 mm) -42-Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (:! 0), melting point 1 7 3. 5- 1 7 5. OTC elemental analysis WC 2 n H 2 DH z 0 4 Calculated: C * 68.17; Η, 5.72; N, 7.95 Found: C, 67,89; Η, 5.64; N, 7.93 Mass spectrum U / z): 35 2 (Μ +) Reference Example 11 ε, 〇 2〇ά_ ^ ~ ^ γ C〇zEt

MeO 〇Me Suspended 1,4-bis-(((trifluoromethyl) sulfonyl) oxy) -2,3-dimethoxybenzene 200rag (0.46mmojl) and 58.5mg (1.38mmoJl) chloride In 2.3 mA of anhydrous dimethylformamide, after degassing by blowing in argon, 16.1 mg (23 mg) of bis (triphenylphosphine) palladium difluoride was added and stirred for 30 minutes at 100 t :. A solution of 537 mg (1.38 mm) of ethyl 3- (tributylmethylstannyl) acrylate in anhydrous dimethylamidine 0.5 mA was added, and the mixture was stirred at 100 t for 30 minutes. Dichloromethane was added, M water, 5% potassium fluoride were successively washed, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 6) to obtain 18.61 ^ (145 ° of colorless prisms 3,3 '-(2,3-dimethoxy). -1,4-dibenzyl) ethyl diacrylate. Melting point 88. 5 -8 9. 5 1C Elemental analysis MC10H22Ob Calculated value: C, 64.66; Η, 6.63 Found: C, 64.45; Η, 6.66 paper Standards apply to Chinese National Standards (CNS) Λ4 specifications (210X 297 mm) One 4 3 One I gutter (please read the precautions on the back before filling this page) A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

V. Description of the invention UJL) Mass spectrum U / Z): 334 (M +) Reference example 12

H02C 115 mg (0.35 mmoil) of ethyl 3,3 '_ (1,4-M diyl) diacrylate and 196 mg (3.49 mm) of potassium hydroxide were dissolved in acetic acid 2 mA and refluxed for 2 hours. 1 N hydrochloric acid was added to make p Η = 1, and the precipitated crystal water and acetic acid were sequentially washed and dried to obtain 90.2 mg (95! U) of 3,3 '-(1,4-naphthalenediyl) diacrylic acid. Melting point 350. 0 -3 5 5. 0 1C High resolution energy mass spectrum MC i β H i 2 0 4 Calculated value: 268.0736 Found value: 268.0743 Reference example 13 Plant co2h According to the same method, from 3,3 '-(1,4 -Xijiji) Ethyl diacrylate 200 1 ^ (0.53111111〇] 1), 3152 '^ (89: «) 3,3'-(1,4-Xijiji) two paper sizes are applicable to Chinese national standards (CNS) Λ4 specification (210X 297 mm) ---------- installation ------- ΐτ ------. ^ (Please read the precautions on the back before filling this page) 44-Printing of A7 B7 by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs V. Invention # 明 (42) Acrylic acid. Melting point 328.5-338.Ot: Θ toughness> High resolution energy mass spectrum M C 2 D H i «0 &lt; Calculated value: 3 1 8. 0 8 9 2 Found: 318.0894 Reference example 14

In the same way, from 3,3 '-(9,10-dihydro-9,10-dioxy-1,4-cyclodiyl) diacrylate 250〇 ^ (0.621! 1111〇), Obtained 2151118: (100%) of 3,3 '-(9,10-digas-9,10-dioxy-1,4-diphenyl) dipropionic acid. Melting point 323.0-338.Ot: 岵) Elemental analysis M C2aH120s Calculated value: C, 68.97; Η, 3.47 Measured value: C, 68.71; Η, 3.31 Reference example 15 Gutter (Please read the precautions on the back before filling this page )

The size of this paper is suitable for China National Standard (CNS) Λ4 specification (210 × 297 mm) 45 _ &gt; 1 I; _ Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (U) According to the same method 100 mg (0.26 mm) of 3,3 '-(5,8-dimethoxy-1,4-diadiyl) diacrylate was obtained from 3,3'-(5,8-dimethoxy-1,4-diadiyl) diacrylate to obtain 39.5 of 79.5 mg (93! K) -(5,8-dimethoxy-1,4-diphenyl) dipropionic acid. Melting point 290. 0-299. 5 υ (decomposition) High resolution mass spectrum MC1BH1S0B Calculated value: 327.0864 Found value: 327.0934 Reference example 1 6

h〇2Cav_ ^ v ^-/ ac〇2H According to the same method * from 3,3 '-(2,2'-diamidinyl-5,5-diyl) ethyl diacrylate 100mg (0.28mm〇A) ) To obtain 73.8ms (88S :) of 3,3 '-(2, 2'-dipyridyl-5,5'-diyl) diacrylic acid. Melting point 447.0-454. 0 ICC (Gao Cui) 髙 Decomposition energy mass spectrum M C, s H i 2 N 2 Calculated value: 2 9 7. 0 8 7 5 Found: 297.0875 Reference Example 17

MeO OMe This paper size is applicable to Chinese National Standard (CNS) Λ4 specification (210X297mm) _ — Binding — Thread (please read the precautions on the back before filling this page) 46 Printed by the staff of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (a) According to the same method, 44.5 mg (0.13 mm) of 3,3 '-(2,3-dimethoxy-1,4-benzyl) diacrylate was prepared from ethyl diacrylate. ) To obtain 36.3 mg: (98! L :) of 3,3 '-(2,3-dimethoxy-1,4-phenylene) diacrylic acid. Melting point 304.0-315. 5 ¾ (decomposition) High resolution mass spectrum MC ^ HhOb Calculated value: 278.0790 Found value: 278.0802 Reference example 18 ho2c

co2h According to the same method, 161 mg (963, 3, 3 '-(9, 1〇-) of 3,3'-(9, 10-diethyl) diacrylate, 200 mg (0.53 mm) was obtained in the same way. Onion diyl) diacrylic acid. Melting point 310. 5-31?. OTC (decomposition) High decomposition energy mass spectrum MC 2 D Η, 4 Calculated value: 318.0892 Found: 3 1 8. 0 9 1 5 Reference example 19 This paper applies to the standard China National Standard (CNS) Λ4 specification (210X297 public capital) ---------- ^ ------ ir ---------- (Please read the precautions on the back before (Fill in this page) -47-A7 B7 Jiro Lang Central Standards Bureau, Consumers and Consumers Cooperatives, Printing and Printing Co., Ltd. 5. Description of Invention (4 5) OHC- ^ ^ -CHO MeO OMe in hydrogenated bis (2-methoxyethoxy) aluminum Sodium (70¾ methylbenzyl solution) 13.6g (47.1111111〇yi) added ^ -methylhexahydropyridine 5,20 g (51.9111111〇yi) of anhydrous toluene 23mA solution to prepare the reagent. 2,3-dimethyl 3.00 g (11.8 mmOA) of methyl oxy-1,4-benzenedicarboxylate was dissolved in 120 mA of anhydrous toluene, and the above reagent was added while keeping it at -20 to -171, followed by stirring for 10 minutes. Water was added to the reaction solution to remove insoluble matters, and then 1N hydrochloric acid and water Saturated saline solution was successively washed and dried over anhydrous sodium sulfate. The solvent was distilled off and purified by silica gel column chromatography (dichloromethane) to obtain 1.84 g (80¾) of colorless crystals 2,3-dimethoxy- 1,4-Benzenedicarboxylic aldehyde. Melting point 99.5-1 00.5 Ό Elemental analysis is C: DH i. 0 &lt; Calculated value: C, 61.85; Η, 5.19 Found: C, 61.74; Η, 5.18 Mass spectrum (m / z ): 194 (Μ +) Reference Example 20 OHC-^^-CHO Ο Ο This paper size applies the Chinese National Standard (CNS) Λ4 specification (210X297 mm) _ — I order. Line (Please read the precautions on the back first (Fill in this page) 48 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Λ7 B7 V. Description of the invention (· Η;) In the same way, 2,3- (ethylenedioxy) -1,4-benzyldicarboxylate Methyl ester 3.00 g (11.9 | 11111〇; 1) to obtain 371 | 118 (16 »:) 2,3- (ethylenediamino) -1,4-benzyldicarboxyaldehyde. Melting point 139.0-140.5t: Elemental analysis MC i aH B0 «Calculated value: C, 62.50; Η, 4.20 Found: C, 62.47; Η, 4.26 Mass spectrum (m / z): 192 (Μ +) Reference example 21

OHC-H ^^-CHO According to the same method, 1.52 g (683 :) of 2,3- (methyldioxy) -1,4-benzenedicarboxylic acid methyl ester 3.00 g (12.6 mm) was obtained. 2,3- (methyldioxy) -1,4-benzenedicarboxyaldehyde.

Melting point 151.5-152.0 ° C Elemental analysis WC s H s (U Calculated value: C, 60.68; Europium, 3.39 Found: C, 60.59; Europium, 3.40 Mass spectrum (π / ζ): 178 (Μ +) Reference example 2 2 This paper size is applicable to Chinese National Standard (CNS) Λ4 specification (210 × 2 &lt; Π 公 牦) I '~ .. Order I line (please read the precautions on the back before filling this page) 49 V. Inventive wishes (47) Η〇2〇-

MeO OMe Λ7 B7 co2h will be 2,3-dimethoxy-1,4-benzyldicarboxyaldehyde 1.0 (^ (5.15111111〇) 1) and malonic acid 2.37 to 22.8 | 11111〇] 1) and hexamidine The suspension of 0.1111] 1 and | 1 ratio pyridine 7.〇111 ai was refluxed for 16 hours. The reaction solution was ice-cooled, and IN hydrochloric acid was added so that pH = 2.析 Collect the precipitated crystals and wash them with water, ethanol, and dichloromethane successively. 3,3 '-(2,3-dimethoxy-1,4-phenylene) diacrylic acid was obtained as 1.348 (943!) Colorless crystals. Reference example 2 3 ho2c

Factory co2h I order (please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, the same method is used for 2,3- (ethylenedioxy) -1,4-benzene Dicarboxylic aldehyde 1.018 (5.26111111 〇 meaning), obtain 1.398 (96, 〇 3,3 '-(2,3- (ethoxy) -1,4-phenylene) diacrylic acid. Melting point 344.5-348.5 ° C High resolution energy mass spectrum C i 4 H iz 0 6 Calculated value: 276.0634 Measured value: 276.0634 Reference example 24_ _ C Λ _ This paper size applies to the Chinese National Standard (CNS) Λ4 specification (210X297 mm) 50 A7 B7

co2h Ο. .0 ho2c

Et Et 5. Description of the invention ('1S) ho2c In the same way, from 2,3- (methyldioxy) -1,4-benzyldicarboxylic aldehyde 1.0008 (5.61111111〇) 1), 1.398 (94 »:) of 3,3 '-(2,3- (methyldioxy) -1, 4-phenylene) diacrylic acid. Melting point 334.0-338. 0 T: High decomposition energy mass C13H1D0B Calculated value: 262.0477 Found value: 2 6 2. 0 4 6 2 Reference example 25 co2h In the same way * from 2,3 -diethyl-1, 4-Benzenedicarboxylic aldehyde 59.8rag (0.31mm), to obtain 62.6g (74; n of 3,3 '-(2,3-diethyl-1,4 phenylene) diacrylic acid. Melting point 26 4 0-268. 0 ¾ (Decomposition) Calculated value of high resolution energy mass spectrum: 274.1205 This paper size is applicable to China National Standard Apple (CNS) Λ4 specification (210X297 public dream) -------------- installation ------ Order ------ Line --- (Please read the notes on the back before filling out this page) Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 51 Λ7 B7 V. Description of the invention (1! «Found: 274.1160 Reference Example 26

H〇2C

co2h

According to the same method, (1,1 '; 4,4 ”-bitriphenyl) -4,4” -dicarboxyaldehyde 80.0 mg (0.28 mm), to obtain 96.4 g (93S!) Of 3,3 '-(4,4 ”-(1,1': 4 ·, 4” -bitriphenyl)) diacrylic acid. Melting point 340.0-345.0 ° C Elemental analysis WC 2 4 H t B 0 4 Calculated value: C, 7 7. 8 2; Η .39 Found: C, 77.72; Η, 5,10 Reference Example 27 ----- ---- install ------- order ------ line_ "(Please read the precautions on the back before filling this page) Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

H02C

οο2η &gt; In the same way, from (1,1 ′: 4 ′, 4 ”-bitriphenyl) -3, 3” -dicarboxyaldehyde 859! ^ (3.00 «1111〇1), 1.068 (95! 1 :) of 3,3 '-(3,3 "-(1, 1': 4 ', 4" -liansanben)) diacrylic acid. Melting point 337. 0-343. 0 Ό High resolution energy mass spectrometry with C ^ 4 H t 7 0 4 This paper size is applicable to the valve standard (CNS) Λ4 specification (210XM7 male) -52-A7 B7 V. Invention Explanation (5 ()) Calculated value: 3 6 9. 1 1 2 7 Found: 369. 1 2 1 4 Reference example 28

Me〇2〇 — ((^ ~ C〇2Mr MeO OMe dissolves methyl 2,3-dihydroxy-1,4-benzenedicarboxylate 5.0 (^ (22.110111〇; 1) in anhydrous dimethyl In 50 mil formamidine, 17.3 g (53.1 mnioil) of europium carbonate was added, and the mixture was stirred at room temperature under an argon atmosphere for 30 minutes. Methyl iodide 3.31 mA (53.2 ^ 01) was added and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, dichloromethane was added, and the mixture was sequentially washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 5.55 g (99Si) of brown oil 2,3 methoxy-1,4. -Methylbenzenedicarboxylate mass spectrum (m / z): 2 5 4 (Μ +) Reference example 29 ---------------- 装 -------- Order-- ---- Line I. (Please read the notes on the back before filling out this page) Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

MeO? Cc〇2Me 0 〇 According to the same method, from 2,5.00-dihydroxy-1,4-benzenedicarboxylic acid methyl ester 5.00g (22.1mnioJl), 5.548 (99¾) of 2,3- (ethylene Oxygen) -1,4-Benzene paper size applies Chinese National Standard (CNS-) Λ4 specification (210X 297 mm) 53-Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (51) 2 Methyl carboxylate. Melting point 107, 5-110. Ου Mass spectrum (m / z): 25 2 (Μ +) Reference example 30

MeQ2C—CQ2Me ° v / ° According to the same method, from 5.00 g (22.1nm〇jl) of 2,3-dihydroxy-1,4-benzenedicarboxylic acid methyl ester, 5.14g (98! U of 2,3 -(Methyldioxy) 1,4-benzyl dicarboxylic acid. Melting point 208.0 0-2 1 0. 0 1C Mass spectrum '(m / z): 238 (M +) Reference example 3 1

6.06 g (68.0 mm) of 2-amino-2-methyl-1-propanol was dissolved in 8 mil of anhydrous dichloromethane, and 2,3-dimethoxy-1,4-benzenedicarboxylic acid was dissolved. An 8 ml solution of anhydrous dichloromethane with an atmosphere of 4.47 g (17.0 μπιι ΑΑ) was kept at an internal temperature of 5-10 TC. After the addition, the mixture was stirred at room temperature for 2 hours. The reaction solution was filtered and washed with water, and then the mash and the washing solution were combined and shrunk under reduced pressure. Applicable to China National Standards (CNS) Λ4 Appearance (210 × 297 cm) at the size of the obtained scrap paper '-54-------------- ^ ------ 1Τ ---- -^ 1 '(Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs, printed A7 B7 V. Description of the invention (5.?) Dichloromethane is added to the slag, and anhydrous sulfuric acid is added. Let it dry. The solvent was decanted and recrystallized from benzene to obtain 6.27 g (100 m of colorless prisms of N, N'-bis- (2-hydroxy-1,1-dimethylethyl) -2,3-dimethylformaldehyde. Oxy-1,4-phenylenedicarboxylic acid amine. Melting point 151.0-153. Ot Elemental analysis KC, BH2BN20e Calculated value: C, 58.68; Η, 7.66; N, 7.60 Found: C, 58.65; Η * 7.79; Ν, 7.44 Mass spectrum (m / z): 36 8 (Μ +) Reference example 32

MeO OMe in N'-bis- (2-hydroxy-1,1-dimethylethyl) -2,3-dimethoxy-1,4-phenylenedicarboxylic acid amine 6.00g (16.3mnIol ) 7.0mA (96. OmmoA) of human thionyl chloride, and search at room temperature for 3 hours * and then add 7.0mA (96.0mm) tellurium gas, and stir at room temperature for 1 hour. The reaction solution was poured into 50 mils of ether, and the supernatant solution M was decanted and removed. To the residue were added water and 10 ¾ aqueous sodium hydroxide solution to make ρΗ = 8. K ether was extracted and dried on anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (dichloromethane: ethyl acetate = 20: 1) to obtain 2.52 g (47! «) Of colorless crystals of 2,2 '-(2, 3-dimethoxy). -1,4-phenylene) bis- (4,4-dimethyl-2-pizoline). The size of this paper applies to Chinese National Standard (CNS) Λ4 specification (2I0X297 mm) --------- ^ -Packing ------- Order ------ M-„--- 1 (Please read the precautions on the back before filling out this page) -55-Printed by the Economist Central Standards Bureau Shellfish Consumer Cooperative A7 B7 V. Description of the invention (5: j) Melting point 84.5-85. 5 t: Element Analyze MC1BH24N204. Calculated value: C, 65.04; Η, 7.28; N, 8.43. Found: C, 64.96; Η · 7.16; Ν, 8.41 Mass spectrum (m / Z): 3 32 (Μ +) Reference Example 33

2.00 g (6.02 mm) of 2,2 '-(2,3-dimethoxy-1,4-phenylene) bis- (4,4-dimethyl-2-benzolidine) was dissolved Ethylmagnesium bromide was added dropwise to the tetrahydrofuran 20mA under ice-cooling for 30 minutes, while the 0.92M tetrahydrofuran solution 16.4mil (15.1mm〇A) was added dropwise, followed by stirring at room temperature for 2 hours. . To the reaction solution were sequentially added a saturated ammonium chloride aqueous solution of 10 m Λ and water of 30 mil, and extracted with M ether. After being washed with M saturated brine, it was dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by M silica gel column chromatography (ethyl acetate: hexane = 2: 1) to obtain 1.988 (100! «) Colorless spindle crystals of 2,2 '-(2,3-diethyl- 1,4-phenylene) bis- (4,4-dimethyl-2-oxazolyl) &gt; Melting point 49. 0-50. OTC Elemental analysis MC2DH2BN20z Calculated value: C, 73.14; 59 * 8.59; Ν -8.53 ---------- install ------ order ------ marry (please read the notes on the back before filling this page) Measured value: C, 72.97; Η .56 ; Ν .46 This paper size applies Chinese National Standard (CNS) Λ4 specification (210 × 297 gongjie) 56-A7 B7 V. Description of the invention (54) Mass spectrum (m / 2): 3 2 8 (M + Reference Example 34

Me Me

Me Me Γ Me Me ^

Et Et Consumption cooperation between employees of the Central Bureau of Standards of the Ministry of Economic Affairs Du printed at 2,2 '-(2,3-diethyl-1,4-phenylene) bis- (4, 4-dimethyl-2- 喟To azole (1.86 g) (5.66 min), nitromethane 5.0 mA and methyl iodide 7.0 mil (122 mm) were added, and the mixture was stirred at 801 C for 4 hours. The reaction solution was poured into ether 30 mA, and the precipitated crystals were collected by filtration and recrystallized from ethanol to obtain 2.62 g (763!) Of colorless prisms of 2,2 '-(2,3-diethyl-1,4-elongation. Phenyl) bis- (3,4,4-trimethyl-2-oxazoline hydrazone iodide) Melting point 28 1. 0-285. Ot: Elemental analysis MC22H34I2H20z Calculated value: C, 43.15; Hf, 5.60; N , 4.57 Found: C, 43.05; Η · 5.41; Ν, 4.72 Mass spectrum (m / Z): 329 (M ++ l-2MeI) Reference Example 35 Let OHC-Λν / &gt;-CHO Et El The degree of paper Applicable to China National Standard (CNS) Λ4 specification (2IOX297 mm) ---------- &quot; -installation ------- order ------ pie--i ---- (Please read the notes on the back before filling out this page) 57 Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A 7 B7 V. Invention Description (5: J) will be 2,2 '-(2,3- 二Ethyl-1,4-benzyl) bis- (3,4,4-trimethyl-2-oxazolium iodide) 2,45 g (4.00 mm) was suspended in acetic acid 50 mA, one side Sodium borohydride (70.4 ms (20.4 in m OA)) was dripped over 1 hour under ice-cooling, and then stirred at 5 ° C for 3 hours. After adding 2 N hydrochloric acid to the reaction solution, it was extracted with ether, washed with saturated brine, and dried over anhydrous sodium sulfate. Add activated carbon, and dilute the solvent to obtain 102mg (13! U colorless prisms of 2,3-diethyl-1,4-benzenecarboxylaldehyde. Melting point 32.0-34.5 Ό High decomposition energy mass spectrometry MC12H1402 calculation Value: 190.0994 Found: 190.0990 Experimental Example 1 H e L a cell proliferation inhibitory activity:

HeLa S3 cells were prepared as single cells in Eagle's Minimal Medium (Nigsui Pharmaceutical Co., Ltd., Tokyo) containing 2 mM glutamic acid, 100 ug / mil Conamin sulfate, and 105 K non-activated fetal bovine serum. The layer was cultured in a carbon dioxide incubator and maintained at 37t :. 1.8X103 cells were seeded into a 96-well plate and contacted with the test compound for 72 hours from the next day. According to the method of Mosmann et al. (Mosmann, T., J. Imunol. Meth., 6f, 55-63, 1983), W Kanyuan 3-U, 5-dimethylthiazol-2-yl] -2,5 -Diphenyltetrazolium bromide (MTT) capability, which measures the number of viable cells after compound treatment and culture. The ratio of the growth of untreated fine-growth compound-treated cells to the ratio of the compound to the concentration of the compound was calculated as M 50. The inhibitory cell proliferation inhibitory activity is shown in Table 1. _ This paper size applies to China National Standard (CNS) Λ4 specification (210X 297 male f) -5 8 _ ---------- installed! (Please read the precautions on the back first to fill in this page), va 5. Description of the invention (ίΚ;) A7 B7 Experimental Example 2 Effect on Colon26 Mice Colon Cancer: IX 106 Collon 26 cells were transplanted to An 8-year-old female CDFt mouse (Ellus Co., Ltd., Hamamatsu, Japan) was subcutaneously in the axillary region and the tumor was confirmed by M finger touch. The compound was administered once through the tail vein 6 days after transplantation. The weight of tumors extracted from the compound administered for 1 week was measured, and the tumor proliferation inhibition rate obtained from the ratio (T / C) of the average tumor weight (T) of the compound administration group to the average tumor weight (C) of the control group ( TGI% = (1-T / C) x 100) is shown in Table 1 as the antitumor effect. Still, the maximum tolerated dose for mice (Μ TD, mg / kg) and the tumor growth inhibition rate (TGI) for colon cancer in mice of C ο 1 ο η 2 6 is 50 ¾ (TGI5D, mg / kg) The ratio of) is used as the chemotherapy coefficient (M TD / TG 15.) and is shown in Table 1. --\ '' 卩 (Please read the notes on the back before filling this page) Printed by the Central Consumers Bureau of the Ministry of Economic Affairs, Consumer Cooperatives This paper is printed in accordance with the Chinese National Standard (CNS) Λ4 specification (210 × 297 male feet) 59 39- 905S a? B7 V. Description of the invention (57) [Table 1] Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, No. of printed cells, cell proliferation inhibition, HeLaSa ICW (ng / ml), antitumor activity, Colon26 TGI% (μg / kg ) Chemotherapy coefficient MTD / TGIbo 1 0.0031, 92 (7.81) 21.9 3 '0.00934 ― 4 0.00276 91 (0.488) 9 5. 0.00595 90 (1.95) — 6 0.0318-― 8 0.00158 89 (0.977) 4.6 10 0.011 85 (0.977 ) 7.4 13 0.0198 88 (3.91) 3.6 18 0.000459 丨 — 19 0.0134 — 20 0.0716 — — 21 0.00035 — — 22 0.0227 — From the results of M, the compound of the present invention shows excellent antitumor activity. This paper size applies to Chinese National Standard (CNS) Λ4 specification (210X 297 mm) I- In HI m I 1 ^ 1-ί — Vi I V ..-- 1 n (Please read the precautions on the back before reading Fill in this page) Thread 60 Λ7 B7 V. Description of the invention ("θ) [Effect of the invention] The compound of the present invention has excellent antibacterial activity and antitumor activity, and has a high k and low toxicity to cancer cells. The present invention Since the compound has been confirmed to have strong cytocidal activity and anti-tumor activity in a wide range of safety areas, it is not only effective for tumors with low sensitivity to anticancer agents, but also expected to reduce the burden of chemotherapy on cancer patients. I. IIII! ^ 衣 n I. I 1 Order '1 II! R', (Please read the notes on the back before filling out this page) Printed by the Central Consumers Bureau of the Ministry of Economic Affairs, Consumer Cooperatives This paper is printed in accordance with Chinese national standards (_ Λ Side training means official performance) —

Claims (1)

399053 A8 B8 C8 D8 89. 4. Amend this VI. Patent application scope 1. An acrylamide derivative represented by the following formula (1), its optically active substance and its pharmacologically acceptable salt: --------- ------ ⑴ (wherein X1 and X2 are each independently a hydrogen atom, OR3 (R3 is a straight bond or a branched Cj-Cs lower alkyl group), or a straight 鐽 or branched lower alkyl group; X1 and X2 may also be combined with each other, and Forms methylene dioxy or ethylene dioxy; ring A is benzene ring, biphenyl ring, bipyridine ring, naphthalene ring, rest ring, rattanone ring or bitriphenyl ring; R1 and R2 are independent of each other as R4. (Please read the note on the back? Matters before filling out this page.) Packing-· IIII line, printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs (R4 is a hydrogen atom, Y is a halogen atom 2x is Ηί〇Γ or ( It can be substituted by 1 or 2 straight-chain or branched Ci-C3 lower alkyl groups, or straight-chain or branched (^-(: 3 lower alkoxycarbonyl group, trihalomethyl group, K substituted))) 2. — A method for manufacturing a compound represented by the following formula (3) i B \ This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1 399053 A8 B8 C8 D8 89. 4. Amend this six, Patent application scope 1. An acrylamide derivative represented by the following formula (1), its optically active substance and its pharmacologically acceptable salt: --------------- ⑴ (wherein X1 and X2 are each independently a hydrogen atom, OR3 (R3 is a straight bond or a branched Cj-Cs lower alkyl group), or a straight 鐽 or branched lower alkyl group; X1 and X2 may also be combined with each other, and Forms methylene dioxy or ethylene dioxy; ring A is benzene ring, biphenyl ring, bipyridine ring, naphthalene ring, rest ring, rattanone ring or bitriphenyl ring; R1 and R2 are independent of each other as R4. (Please read the note on the back? Matters before filling out this page.) Packing-· IIII line, printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs (R4 is a hydrogen atom, Y is a halogen atom 2x is Ηί〇Γ or ( It can be substituted by 1 or 2 straight-chain or branched Ci-C3 lower alkyl groups, or straight-chain or branched (^-(: 3 lower alkoxycarbonyl group, trihalomethyl group, K substituted))) 2. —A method for manufacturing a compound represented by the following formula (3) i B \ This paper size is applicable to the Chinese National Standard (CNS) A4 (210 X 297 mm) 1 S99053 VI. Application scope A8 B8 C8 D8 (3) (Where (R4, Υ, and (·?.! [Same as below) are characterized by printing the dicarboxylic acid derivative shown by the following formula (2) (2) printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs (where, X1 and X2 are each independently a hydrogen atom, OR3 (R3 is a linear or branched Ci-Ca lower alkyl group), or a linear or branched "-^^ low alkyl group; X1 and X2 may also be combined with each other, and Form methylenedioxy or ethylenedioxy; ring A is benzene ring, biphenyl ring, bipyridine ring, naphthalene ring, anthracene ring, onion ring or bitriphenyl ring; R5 is 0H, or reactive Residue) K a compound represented by the formula or a salt thereof: (R4 is a hydrogen atom and Y is a halogen atom; this paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ^ ------------ ^ ------ --Order --------- line. (Please read the note 2 on the back before filling out this page) 389053 g D8 6. Scope of patent application (M can be substituted by 1 ~ 2 straight or branched (^-(: 3 lower alkyl, linear or branched (^-(: 3 lower alkoxycarbonyl, trihalomethyl, M substituted)) (I will be M). .-- I I--Order --I --- --- (Please read the notes on the back before filling this page) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economy 3 paper sizes Applicable to China National Standard (CNS) A4 (210 X 297 mm)