TW464649B - Oxazolone derivatives and their use - Google Patents

Abstract

An anti-Helicobacter pylori agent comprising a compound represented by the formula: wherein A represents an aromatic ring group which may be substituted; R1 and R2, whether identical or not, each represent a hydrogen atom or a hydrocarbon group which may be substituted; R3 and R4, whether identical or not, each represent a hydrogen atom, a hydrocarbon group which may be substituted, an acyl group, a carbamoyl group which may be substituted, or a carboxyl group which may be esterified; or a salt thereof.

Description

464649 A7 B7 V. Description of the invention (1) Fang Yicheng (please read the precautions on the back before filling this page) The present invention is an anti-Helicobacter pylori agent, including: The substance is used as a therapeutic agent for ulcer and duodenal ulcer. Xishu holds a therapeutic agent for ulcers, has developed antacids, anticholinergics, anti-M secretin agents, gastrointestinal hormones, anti-pepsin agents, histamine 2 receptor antagonists, tissue repair Agents, mucosal protective agents, microcirculation agents, proton capsule inhibitors, etc. Histamine 2 is affected by hip antagonists and proton capsule inhibitors, both of which have a strong ability to restrict acid secretion, and its development can especially promote the treatment of ulcers. However, these agents for treating ulcers are unsatisfactory in terms of the curative effect on recurrent ulcers. On the other hand, Helicobacter pylori, a Gram-negative trace aerobic bacterium of the genus Helicolacter, has been regarded as a possible main cause of recurrence of gastritis, duodenal ulcers, and gastric ulcers. Although many antibacterial agents can easily inhibit the proliferation of individual microorganisms of the genus Helicobacter in vitro, the effects in human and animal tests are very low if they are administered alone in vivo. The Consumer Cooperative of the Central Bureau of Standards in the Ministry of Economic Affairs prints a variety of diseases caused by Helicobacter pylori bow I, all of which are treated with chemotherapeutics, for example, double chemotherapy with bismuth preparations and antibiotics, and bismuth preparations, metronidazole (metr ο nida ζ ο 1 e, U.S. Patrin 2, 9 4 4, 0 6 1 鲅), and tetracycline (such as U.S. Pat No. 2,712,51?) or amoxicillin (amoxicillin, U.S. Patent 3) , 19 2, 198)). Metronidazole, an oxazole derivative t with anti-Helicobacter pylori activity, is used in combination with antibiotics. These bismuth paintings, antibiotics, and antipyretic paper sizes are applicable to the Chinese National Standard (CMS) A4 specifications (210X297 mm > 1 39 221 464649 A7 ______ ^ _ B7_ V. Description of the invention (2) Fan etc. are orally administered And clinical studies have shown that the eradication of this microorganism will lead to healing and reduce the recurrence rate of ulcers. However, these bismuth preparations, antibiotics, metronidazole, etc. must be administered in high daily doses to maintain sufficient concentrations in the pylorus The site where H. pylori multiplies inhibits H. pylori proliferation, resulting in many problems, including adverse effects such as vomiting and chancre. Many compounds with anti-H. Pylori activity have been developed. For example, Japanese Patent Laid-Open Publication No. 1 1 726 8/1 993 No. 掲 shows pyridine derivatives having anti-Helicobacter pylori activity, and European Patent No. EP0535528A1 discloses oxazole derivatives having anti-Helicobacter pylori activity. After extensive research on the above problems, the inventors discovered that a mold is particularly The oxazoline-4-one derivative exhibits extremely excellent antibacterial activity against Helicobacter bacteria represented by Helicobacter pylori. Based on this finding, The inventor carried out further research and developed the present invention. Therefore, the present invention has the following features: Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs ^ ϋ-. ^ 1 ^ 1 ml I nn i nn (. 1 ^ 1- i II · I:--— ^ n BJ (Please read the precautions on the reverse side before filling out this page) (1) An anti-Helicobacter pylori composition, including: a compound of the following formula or its salt, and pharmacological Acceptable diluents, excipients or carriers, R1 R2 0

In the formula, A represents an aromatic group which may be substituted, and R1 and R2 each represent a hydrogen atom or may be used. The paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 2 3 9 22 1 4 6 4649

A7 B7 V. Description of the invention (3) Substituted hydrocarbyl groups, R3 and R4 each show a hydrogen atom, a substituted hydrocarbyl group, a fluorenyl group, a substituted carbatenyl group, or a carboxyl group that can be modified, (2 ) The Helicobacter pylori composition according to (1) above, wherein A is an aromatic heterocyclic group which may be substituted, (3) The Helicobacter pylori composition according to (1) above, wherein A is of the formula Group, | less, '(II) where ring B is a 6-membered aromatic ring that can be substituted, X is CH or N, Y is 0, 3, or-»(-1 {5 (!? 5 shows hydrogen Atomic or substituted hydrocarbon group), (4) anti-Helicobacter pylori composition according to U) above, where A is the following formula, (please read the precautions on the back before filling this page)

In the Indo-Public Cooperative of the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, B 瑁 is a 6-membered aromatic ring which can be substituted, R 5 represents a hydrogen atom or a substituted hydrocarbon group, (5) The anti-pylorus screw according to (1) above Bacteria composition (wherein A represents indyl and may be substituted by 1 to 3 selected from hydroxyl, halo, nitro, cyano, lower alkyl substituted by 1 to 5 halogen, and may be substituted by 1 to 5 A halogen-substituted lower alkoxy group is substituted by a substituent, R1 and R2 each represent hydrogen or a lower alkyl group which may be substituted by 1 to 5 halogens, and R3 and R4 each represent hydrogen or a lower paper size Applicable to China National Standard (CNS) A4 specification (210X297 mm) 3 3922 1 A7 4 6 4 6 4 9 __B7_ V. Description of the invention (4) Alkyl, (Please read the precautions on the back before filling this page) (6 ) The anti-Helicobacter pylori composition according to the above (5), wherein A is an indyl group, R1 and R3 are hydrogen, and R2 and "are"-·? Alkyl groups, (7) the anti-pylorus according to (6) above Spirulina composition, wherein A is 3-indino, R2 and R4 are methyl, (8) The anti-Helicobacter pylori composition according to (1) above, wherein the compound is indigo Undolmycin), (9) The anti-Helicobacter pylori composition according to (1) above, which is a preventive or therapeutic agent for diseases related to Helicobacter pylori infection, (10) the anti-Helicobacter pylori adult product according to (9) above In which, the disease related to Helicobacter pylori infection is gastric or duodenal ulcer, rickets or gastric cancer, (id according to the above α) anti-spirospira composition, used in combination with antibacterial agents, (12) According to the above (1 The anti-Helicobacter pylori composition is used in combination with an anti-ulcer agent. (13) The anti-Helicobacter pylori composition according to (1) above is used in combination with an anti-bacterial agent and an anti-ulcer agent. Central Standards Bureau, Ministry of Economic Affairs The use of the compound (14) of the following formula or its salt printed by employee consumer cooperatives is for the preparation of anti-Helicobacter pylori agents,

39221 This paper size applies to Chinese national standards (CNS > A4 size (210X297 mm) 464649 A7 B7 V. Description of the invention (5) In the formula, A represents a substituted aromatic group, and R1 and R2 each show a hydrogen atom Or a substituted hydrocarbon group, R3 and R4 each show a hydrogen atom, a substituted hydrocarbon group, a fluorenyl group, a substituted carbamoyl group, or an esterified carboxyl group, (15) a mammalian pylorus A method for preventing or treating a bacillus infection-related disease, comprising: administering a compound of formula (I) or a salt thereof in an effective amount to an individual in need thereof, R1 R2 0

R3 R4 (Please read the notes on the back before filling this page) (I) In the formula, A represents a substituted aromatic group, R1 and R2 each represent a hydrogen atom or a substituted hydroxyl group, and R3 and R4 each Do not show a hydrogen atom, a hydrocarbyl group which may be substituted, a fluorenyl group, a carbamoyl group which may be substituted, or a carboxyl group which may be tritiated, (16) A method for preparing an anti-Helicobacter pylori composition, comprising: using a compound of the formula Or its salt mixed with a pharmacologically acceptable diluent, excipient or / and carrier, printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

(I) R3 R4 In the formula, A represents an aromatic group which may be substituted, R1 and R2 each represents a hydrogen atom or a substituted hydrocarbon group, and R3 and R4 each represents a hydrogen atom, a substituted hydrocarbon group, and the paper. The scale is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 5 3 922 1 46 4649 A7 B7 V. Description of the invention (6) fluorenyl group, carbamoyl group which can be substituted, or carboxyl group which can be converted, (17) A compound of the formula or a salt thereof, R1 R2.

VI,) R3 · R4 'wherein A represents a substituted aromatic group, R1 and R2 each represent a hydrogen atom or a substituted hydrocarbon group, and R3' and Ri each represent a hydrogen atom or a substituted hydrocarbon group, However, (1) if A is a 3-indino group, R1 and R3 'are hydrogen, and R2 is a methyl group, then U4' is neither a C3-6 cycloalkyl group nor a group selected from halogen, hydroxyl, Lower alkoxy, lower sulfanyl, aryl, or unsaturated mono-substituted Ci-4 alkyl with 2 to 4 carbon atoms in the side chain, and (2) if A is 3 -P? 丨Fluorenyl, R1 and R3 'are hydrogen, and R2 is Ci-3 alkyl, then R4' is not selected from hydrogen, phenyl, methoxyphenyl, tolylamino, and d-4 alkyl, (18) A compound of the following formula or its salt, ----------- / ^ /-(Please read the notes on the back before filling out this page) Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economy

(ΐ'Ί RJ R4, where A represents a substituted aromatic group, R1 and R2 each represent a hydrogen atom or a substituted hydrocarbon group, R3 'is a hydrogen atom or a substituted hydrocarbon group, R4 " is Alkyl or substituted aminocarbamyl, however, if A is 3-indyl, R1 is the paper standard and applies Chinese National Standard (CNS) A4 (2I0X297 mm) 6 39 2 21 464649 Central Ministry of Economic Affairs A7 B7 printed by the Consumers' Cooperative of the Bureau of Standards and Administration V. Description of the invention (7) Hydrogen, and R2 and f are methyl, then R4 "is neither a C2-5 alkyl group or a mono-substituted C2-5 alkyl group ( The substituent is selected from amine, halogen, phenyl, p-hydroxyphenyl, or lower alkoxy), and is not substituted by (^ -4 alkyl, C3-6 cycloalkyl, or phenyl Carbamate, (19) A compound of the formula or its salt, R1 R2 0

In the formula, A represents a substituted aromatic group, Ri and R2 each represent an argon atom or a substituted hydrocarbon group, R3 'is a hydrogen atom or a substituted hydrocarbon group, and R4' '' is an ester group Carboxyl, (20) The compound according to (19) above, where A is a sulfonyl group, Ri and R2 each represent a hydrogen atom or a methyl group, R3 'is a methyl group and R4' '' is an esterified carboxyl group 9 (21) A method for preparing indigoxin, which is cultivating Streptoroyces sp. HC-21 strain in culture medium, and manufacturing and accumulating indigoxin in culture medium, and harvesting the indigoxin Indrugin, and (22) a Streptomyces saccharum HC-21 strain, which is used as L-rhaanose and has a tadpole-shaped surface. In the chemical formula (I), " an aromatic group which may be substituted ",

Examples are monocyclic or fused polycyclic aromatic hydrocarbon groups or aromatic heterocyclic groups. These aromatic hydrocarbon groups include: for example, benzyl, naphthyl, aryl, phenanthrene, and pinene naphthyl, K This paper size applies to China National Standard (CNS) A4 (210X297 mm) 3922 1 (Please read (Notes on the back then fill out this page) --0

464649 A7 B7 Annex 5 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the Invention (3) Phenyl, 1-tapyl, 2-naphthyl, etc. are preferred. Aromatic heterocyclyls include, for example, aromatic monocyclic heterocyclyls such as furyl, phenophyl, pyrrolyl, oxazolyl, isoxazolyl, oxazolyl, isophasyl, oxazolyl, H pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-diadiazolyl, 1,3,4-morphadiazolyl, furyl, 1,2,3-pyridine Oxazolyl, 1,2,4-®diazolyl, 1,3,4-diaphlyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridine Base, daphthyl, pyrimidinyl, pyridyl, and trigyl; and aromatic fused heterocyclic groups, such as benzofuranyl, isobenzofuranyl ', benzo [6] sulfanyl, fluorenyl , Isoindiolyl, 1 Η-oxazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzoisoxazolyl, benzopyrazolyl, 1,2-benzoisopyrazole Base, 1Η-benztriazolyl, oxolinyl, isohumidyl, carbolinyl, HIoxazolyl, Bfpyridinyl, amidinyl, amidinyl, purinyl, pyridinyl, Oxazolyl, α-carbolinyl, / 3-carbolinyl, 7-carolinyl, acridine, phlefinyl Pyrimidinyl, morpholinyl, indolyl, pyridine Acyl [1,2-a] dalophenyl, pyrrolo [1,5-a] pyridyl, oxazo [1,2-b] pyridyl, imidazo [l, 5-a] pyridyl, hoof Zolo [1,2-b] dalophenyl, oxazo [1,2-a] pyrimidinyl, 1,2,4-trimile [4,3-a] pyridyl, and lf2,4-tris Wow [4, 3-b] Da Gengji. Among the aromatic condensed fluorenyl ring groups, the K indyl group is preferred, and the M 3 -indyl group is more preferred. In the chemical formula (I), the substituent in the "optionally substituted aromatic ring group or aromatic heterocyclic group" shown by A includes: for example, a hydroxyl group, a halogen (eg, gas, atmosphere, bromine, iodine) , Nitro, cyano, lower alkyl which can be substituted with 1 to 5 halogens (eg, fluorine, chlorine, bromine, iodine), and 1 to 5 halogens (if this paper's inversion applies the China National Standard ( CNS > A4 specification (210 X 297 mm) 8 (correction page) 3 9 2 2 1 --- Rj (Please read the notes on the back before filling this page)

Alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl). These lower alkyl groups include, for example, alkyl groups having 1 to 4 pseudo carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second butyl, and third Butyl, M methyl and ethyl are preferred. These lower alkoxy groups include: alkoxy groups having 1 to 4 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, Dibutoxy and tertiary butoxy, Kmethoxy and ethoxy are preferred. Preferably, there are 1 to 3 of these substituents (preferably 1 to 2) which are the same or different. In the "optionally substituted aromatic ring group or aromatic heterocyclic group" shown by A, the substituents also include butanedioxo, such as methylenedioxy and ethylenedioxy. In the formula (I), the "optionally substituted hydrocarbon group" represented by R1 and R2 includes an aliphatic chain hydrocarbon group, an alicyclic hydrocarbon group and an aryl group, and an M aliphatic fluorene hydrocarbon group is preferred. (Please read the precautions on the back before filling out this page.) Employees of the Intellectual Property Bureau of the Ministry of Economic Affairs, Consumer Cooperatives, etc. Printed bases such as propyl, phenyl, phenyl, phenyl, alkoxy, e.g., acetyl, ethyl-3, and Propane, butyl, isobutyl, C1, alkenyl, triethylene, trimethyl, trimethyl, -1 hydrocarbon, trimethyl, such as methyl group, hexamethylene group, melene methyl n-3- . Ethyl ethyl 2-fluorene grades such as butane, 3, alkane such as, branched, diyl, hept-2, alkynyl, or propyl n-C1 alkenyl alkenyl, butyl and allyl straight alkane ~ 7 Methyl methyl group Jia-61-: Grade C but 1 methyl butan C, containing low, iso, and di groups, the base package is, for example, 2-ethyl, such as propyl, pentyl 2,2-propion Olefin special: Dingxin,, and: based on fluorene. Contains n- and alkynyl groups, including methyl group groups, butyl butadiene groups, 2-alithynylpentyl groups, groups, etc., and alkylpropylisomethylalkenyl groups. Base 1-3- such as low propionate. Pentyl 13. Different paper sizes apply the Chinese national standard < CNS > A4 specification (210 X 297 mm) 9 (correction page) 3 9 22 1 6 4649 'A7 __B7_ V. Description of the invention (10), 2-methyl-2-propene Base, i-butenyl, 2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4 -Methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl, preferably C2-salkenyl, such as Vinyl, allyl, isopropenyl, 2-methylallyl, 2-methyl-propenyl, 2-methyl-2-propenyl, and 3-methyl-2-butenyl. Lower alkynyl includes, for example, C2-6 alkynyl, such as ethynyl, 1-propenyl. 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentamyl, 3-pentynyl, 4-pentynyl, 1- Hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl, preferably C2-4 alkynyl, such as ethynyl, 1-propynyl and 2-propynyl Alkynyl. The alicyclic hydrocarbon group includes: a saturated or unsaturated alicyclic hydrocarbon group, such as a cycloalkyl group, an original heptane carbocyclic group, a 9 group to a hexyl ring group, a base group, a cyclopentyl group, an alkylcyclobutane group. Ring group, alkenyl dipropane ring and ring-based alkenyl naphthenes, ^ ϋ · ί ^ ί. Nn 1 «l I ami ^ ^ (Please read the precautions on the back before filling this page) Nonane, Kissinyl, Hexyl, and 7-Based Pentapentyl Rings I, 2 Jiruki, Central Bureau of Standards, Ministry of Economic Affairs, Consumer Cooperatives, Printed Alkenyl, Hexahedral and Base Rings

Dipentyl 7 is better. T ring group, alkenyl ring E-6 ring C3 such as-such as alkane: the ring contains -6 packets C3 group is alkenyl--alkenyl ring t 2 'group and 2 groups such as 1-yl-ene-1 Alkenyl dipentacyclocycloene bicyclic ο radicals such as 丨, the radicals of the alkyl radicals are better aromatic and polycyclic. Hechatyl fused alkenes 1- or and. Cyclomonophenyl and fluorenyl-containing phenanthryl, aryl, yinzhong, -1-based olefin naphthalene, hexylcyclophenylnaphthalene, etc. \ / I / m \ formula learned in the substitution of alkenyl hexyl hydrocarbons can be replaced by 2 R or alkane ring can be replaced by can be aromatic and can be included in the paper. Chinese paper standards are applicable to Chinese standards (CNS) A4 specification (2 丨 0X297 mm) 10 3922 1 4 ο 4 6 4 9 Α7 __ ^ _ Β7_ V. Description of invention (11) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back first) Please fill in this page for more details) Cycloalkenyl, heterocyclic group which can be substituted, amine group which can be substituted, hydroxyl group which can be substituted, fluorenyl group which can be substituted, and halogen (such as fluorine, chlorine, bromine, iodine ). These optional substituents may exist in 1 to 5 (preferably 1 to 3). The aryl group which may be substituted includes: phenyl group, pyridyl group, alkyl group, phenanthryl group, and pinencainyl group, preferably phenyl group, 1-naphthyl group, and 2-naphthyl group. In the aryl group which may be substituted, the substituent includes: an alkoxy group (e.g., methoxy, ethoxy, propoxy), a halogen atom (e.g., fluorine, chlorine, bromine, Iodine) and alkyl groups (eg, methyl, ethyl, propyl) having 1 to 3 carbon atoms; these optionally selected substituents may exist in 1 to 2 groups. Cycloalkyl which may be substituted includes: C3-7 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The kind and number of the substituents used in the optionally substituted cycloalkyl group are the same as those in the aforementioned substituted aryl group. Cycloalkenyl which may be substituted includes: C 3-6 cycloalkenyl, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl. The kind and number of the substituents used in the cycloalkenyl group which may be substituted are the same as those in the above-mentioned substituted aryl group. An optionally substituted heterocyclic group includes: an aromatic fluorene ring group having at least one heteroatom selected from oxygen, sulfur, or nitrogen as a ring constituent atom (ring atom), and a saturated or unsaturated non-aromatic heterocyclic group ( Aliphatic heterocyclic group), preferably an aromatic heterocyclic group. Aromatic heterocyclyls include: aromatic monocyclic heterocyclyls (e.g., furyl, pyranyl, pyrrolyl, azolyl, isoyl, i? Azolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3 -morphazolyl, 1,2,4-B-oxadiazolyl, 1,3,4-oxadiazolyl, furyl, 1,2,3-oxadiazolyl, 1 , 2,4-¾diazolyl, 1,3,4-diadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, datrayl The basic paper sizes of pyrimidyl, pyrazinyl, and triple wells are applicable to the Chinese National Standard (CNS) A4 (210X297 mm) 1 1 3 922 1 ο 4 6 49 Α7 Β7 This year $ 1 £ 1 5. Description of the invention ( l2)) and aromatic fused heterofluorenyl groups (eg, benzofuranyl, isobenzofuranyl, benzo [b] fluorenyl, indino, isoinfluorenyl, 1 fluoren-influorenyl, Benzozozozolium Bnf Acetyl \ Acylazolyl benzophenazine ¥ nu Isophenylazole 0 Isophenylphenoline BI Isomorpholine tit, Triazole benzopyridine purine, Pyridoxine 'Ji Geng 呔' 基 喏 喏 喏 of '咐 咐 f Df, 啉 啉, ί ί, 基 并 啉 啉 耕 耕 耕, 耕, 电, 、, 、 Glycogen, α, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl G.A. 1 // 9, I, pyridyl, 5pyridine, Γ1 pyridopyridinopyrimidazolium pyrimidine tri-a.], 4-5 base 2 1 'pyridyl 1, rL pyridyl, oxazolyl Pyridazine apyrazolidine (please read the precautions on the back before filling out this page) r * and 2'sal hydrazine 4 azole 2, hoof 1 ', hydrazine DD bld base 3 Deng Dtt N-based fluorene B3I heterocyclic, cladyl fluorinated ring heterocyclic, non-phasic aryl phenone, etc., and the like aminopyrimidine furimidine, carbidine pyridine, pyridine, tetramethylpyridine, cyclopropylpyridine thiopyridine '' Hydroxyhexabutane, cycloheterophenoxine, hydrogen tetrapyridine, butyl acryl, furylhydroethylenetetroxy, cyclic group, pyrimidine, such as the example of pyridyl hydrocarbon Each of the six 3 and 1 bases is instructed to include: thiosulfan, phenyl, phenyl, and chloro. Benzyl, cyclic, and cyclic heteropyranyl. Printed by the Bureau's Consumer Cooperatives

Coryl and alkane, 3-yl 1-hydroxyl (substituting C 'for alkoxy group: R amine containing the package. Substituting group 丨 Substituting for acetyl group, 0 in} group i, ^ ^ S propyl group, substitution The lower grades of two, two, five, five, and three percent of propyl and acetyl are shown below. For example, R2 is an example of a basic hydrocarbon cycloaliphatic alkane. The subgeneration of the original hydrocarbon carbon 3 is taken to 1 and can be substituted by 1 Take Beijifang or Jipropyl, Jiyi% Jiyi and

Substitute R element), halogen T- (each formula 5 learns to chemical 1 in Jingguan can be 2 R is a combination of formulas, better as compared to argon as the basis of the alkane paper standard applicable Chinese National Standards (CNS) A4 specification (210 X 297 mm) 12 (revised page) 3 92 2 1 4646 ^ 9 Printed by A7, B7, Consumer Work Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (13) R3 in chemical formula (I) or R4, and in the chemical formula (indicated by R3 'or R4 \ in "II" may be substituted hydrocarbon group ", the hydrocarbon groups and substituents used are, for example, the same hydrocarbon groups and substituents used in the above R1 and R2. About the chemical formula (I ), And R4 is a preferred combination in which R3 is hydrogen and R4 is C i -3 alkyl. In the chemical formula (I), examples of the fluorenyl group represented by R3 or R4 are aliphatic fluorenyl groups, such as fluorenyl, Alkenyl, cycloalkylcarbonyl, and alkylsulfonyl groups; aromatic fluorenyl groups, such as arylfluorenyl, aralkylfluorene, arenefluorenyl, and aromatic sulfonyl groups; fluorene aromatic aromatic groups, such as aromatic heterocyclic rings Carbonyl and aromatic heterocyclic fluorenyl groups; and non-aromatic heterocyclic carbonyl groups (aliphatic heterocyclic carbonyl groups). &Quot; Alkyl group " means an alkylcarbonyl group. Preferred examples include: Lower fluorenyl groups of 1 to 8 carbon atoms, such as formamyl, acetamyl, propionyl, butylamyl, isobutylamyl, pentylase, isopentamyl, trimethylacetamyl and hexamethylene. "Alkenyl" refers to alkenylcarbonyl, and preferred examples include: C3-6 alkenyl, such as propenyl, methacryl, crotonyl, and isocrotonyl. "Cycloalkoxy" refers to cycloalkane Preferable examples include: those having 4 to 7 carbon atoms, such as cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl and cyclohexanecarbonyl. "Alkylsulfonyl" refers to alkylsulfonyl, Examples of p include: those having 1 to 4 carbon atoms, such as methylsulfonyl, ethylsulfonyl, and sulfonylsulfonyl. &Quot; Arylfluorenyl " refers to arylcarbonyl, and preferred examples include: Those with 7 to 11 carbon atoms, such as benzamyl, p-toluenyl, 1-naphthyl and 2-naphthyl. -------------- 1T (Please read the notes on the back before filling out this page) This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 13 392 2 1 A7 464649 B7 V. Description of the invention (14) (Please read first Note on the back, please fill in this page again) "Aralkyl" refers to alkoxy substituted by aryl, and its preferred examples include: C6-8aryl-C2-5 alkyl, such as phenethylfluorenyl, benzene Propionyl, hydrogen atomyl and phenbutylfluorenyl. "" Arylene "refers to an alkenyl group substituted with an aryl group. Preferred examples include: C6-8aryl-C3-5 alkenyl, such as cinnamon "Aromatic sulfonyl" refers to arylsulfonyl, and preferred examples thereof include those having 6 to 8 carbon atoms, such as benzenesulfonyl and p-toluenesulfonyl. "Aromatic heterocyclic carbonyl" More examples of fluorene, including: furanomethane, I * phenformamyl, nicotinyl, isonicotinylfluorenyl, pyrrolylcarbonyl, Bfazolecarbonyl, 1 «azolecarbonyl, An oxazole carbonyl and a pyrazole carbonyl. "Aromatic sulfonylcycloalkyl" refers to an alkylcarbonyl group substituted with an aromatic heterocyclic group, and preferred examples thereof include: aromatic sulfonyl-C2-5 alkylsulfonyl, such as 1 «phenethylfluorenyl, 1« phenpropylfluorenyl, furan ethylfluorenyl, dozosylethyl, 1,2,4-ridiazolidine, and pyridylacetinyl. &Quot; Non-aromatic heterocycles Preferred examples of carbonyls include: aliphatic heterocyclic carbonyls such as azetidinyl carbonyl, pyrrolidine carbonyl, and hexahydropyridine carbonyl. Economy, Qiu Central Standard Bureau Staff Consumer Cooperative R3 printed in Chemical Formula (I) And R4, and a substituted carbamoyl group represented by R4 'in Chemical Formula (I), such as " N-monosubstituted carbamoyl "and" N, N-disubstituted carbamoyl " &Quot; M and unsubstituted carbamoyl. "" -Mono-substituted carbamoyl "refers to a carbamoyl group having 1 substituted Hua on the nitrogen. Examples of the '/ substituted fluorene' include: Cl-6 alkyl (eg, methyl, ethyl, propane, isopropyl, butyl, tertiary butyl, pentyl, hexyl), C3-6 naphthene (Eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), aryl (eg, phenyl, I-naphthyl, 2-naphthyl), aralkyl (eg, benzyl, Phenyl) and miscellaneous paper sizes are applicable to Chinese National Standard (CNS) A4 (210X297 mm) 1 4 39 221 A6 A649 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (15) Ring base (For example, in the "optionally substituted hydrocarbon residues" shown by R1 and R2 above, the "substituent" is exemplified by the "ring ring group"). These aryl groups, aralkyl groups, and heterocyclic groups May be substituted. The substituent such as hydroxy may be substituted by 1 or 2 lower alkyl (for example, those having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, and butyl) or Amines (such as formamyl, ethyl, propyl, propyl, and benzyl) substituted amines, halogens (eg, fluorine, chlorine, bromine, iodine), nitro, and aryl, which can pass through 1 to 5 halogens (eg, , Chlorine, bromine, iodine) substituted lower alkyl groups and lower alkoxy groups that may be substituted with 1 to 5 halogens (eg, fluorine, chlorine, bromine, iodine). These lower alkyl groups include, for example, 1 to The fluorenyl group of 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second butyl and third butyl, is preferably methyl and ethyl. Lower alkoxy contains alkoxy groups with 1 to 4 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, Dibutoxy and tertiary butoxy, preferably methoxy and ethoxy. Preferably there are 1 to 3 (preferably 1 to 2) of these substituents which are the same or different. "H, N- "Disubstituted carbamoyl" refers to carbamoyl having 2 substituents on the nitrogen atom. An example of such a substituent includes the same substituents as used in the above-mentioned "N-monosubstituted carbamoyl"; Examples of other substituents include Cl-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, third butyl, pentyl, hexyl), C3-6 cycloalkyl ( Such as (, cyclopropyl, cyclobutyl Cyclopentyl, cyclohexyl) and C6-l0 aralkyl (eg, benzyl, phenethyl). Two substituents can be bonded to the nitrogen atom to form a cyclic amine group. In this example, a cyclic amine group Examples of formazanyl include: 1-azetidine carbonyl, 1-pyrrolidinyl carbonyl, hexahydropyridine carbonyl, morpholine carbonyl, 1-hexahydropyridine carbonyl, and the Chinese standard (CNS) applicable to this paper standard A4 specifications (210X297 mm) 15 3 ^ 22 1 1 order (please read the precautions on the back before filling out this page) 464649 Α7 Β7 V. Description of the invention (16) Hexahydrophenyl carbonyl, and in the fourth position Has a lower alkyl group, such as Ci-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, third butyl, pentyl, hexyl), arylfluorenyl such as benzyl and benzyl Ethyl, aryl such as phenyl, 1-naphthyl and 2-naphthyl, and the like. R3 and R4 in the chemical formula (I) and R 4 '' 'in the chemical formula (I''1), shown as "the carboxyl group which can be quenched", for example, "lower oxocarbonyl" ", "Aryloxycarbonyl" and "aralkoxycarbonyl", as well as free carboxyl groups. "Lower alkoxycarbonyl" preferred examples include those having 2 to δ carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, The second butoxycarbonyl group, the third butoxycarbonyl group, the pentyloxycarbonyl group, the isopentyloxycarbonyl group, the neopentyloxycarbonyl group and the third pentyloxycarbonyl group are preferably those having 2 to 4 carbon atoms, for example, a methoxycarbonyl group, Ethoxycarbonyl and propoxycarbonyl. &Quot; Aryloxycarbonyl " Preferred examples include: 7 to 12 carbon atoms (please read the notes on the back before filling this page), ιτ group 0: oxygen content check Bao-1Α 9, the best examples of oxygen based benzene are better than U such as base carbonyl, oxyalkylnaphthyl naphthalene I 2 and aryl to 8 exemplified by the original carbon of the Ministry of Economic Affairs Central Standards Bureau Staff Consumer Cooperatives The alkyl aryl sulfonium and methylamine carbonyl oxon aryl are printed at the carbonyl aromatic oxygen department. versus . The basic group and the carbonyl phase oxygen are taken as the radical of the radical B and the radical is taken; the radical obtained by the carbonyl radical is replaced by the alkyl radical, which can be replaced by the alkyl radical as the radical 6 β can be represented by the substitution of the ring benzene in the ring B. As an example, the script can be replaced by the ring B. If the ring is exposed, 3 is replaced by the substitution of the family member 6 and the formula β is shown below. This paper size applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm) 16 3922 1 46 4649 A7 B7 V. Description of the invention (17) φζΓ (called (where C ring can be replaced; X and Y definitions It is as above. If the B ring represents a 6-membered aromatic heterocyclic ring which can be substituted, the base represented by the chemical formula (II) includes: For example, the base of the formula, (Please read the precautions on the back before filling in this page)

Printed by the Consumer Cooperatives of the Central Sample Bureau of the Ministry of Economic Affairs In these chemical formulas, the D ring can be replaced; the definitions of X and Υ are as described above. Regarding the above chemical formula, the substituents of the C and D rings are the same as those exemplified in the "Aromatic cyclic group which may be substituted" shown in A. These substituents may be bonded to any carbon atom of the C and D rings. In the chemical formula (II-1), an example of the "substitutable hydrocarbyl group" represented by R5 is the same hydrocarbyl group exemplified as the hydrocarbyl group represented by R1 or R2 which may be substituted.阚 于 Chemical formula (I), A, reverse 1 ,! ^, R3 and R4 are a preferred combination, in which A is indyl, 1 ^ and 1 {3 are hydrogen, and R2 and R4 are Ci-3 alkyl groups. The special examples of the above-mentioned oxazoline-4-fluorene derivatives, where h contains indene and flavin. This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 1 7 39 221 A7 __B7. V. Description of the invention (18) Chemical formula (I), (I '), (I' ') or (Γ u ) The salt of the compound shown includes pharmacologically acceptable acid addition salts; the acids used for the acid addition salts include: acetic acid, lactic acid, succinic acid, maleic acid, tartaric acid, and betulinic acid , Gluconic acid, ascorbic acid, stearic acid, methanesulfonic acid, p-formamic acid, cinnamic acid, fumaric acid, phosphonic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, aminesulfonic acid and sulfonic acid. Examples of the compound represented by the chemical formula (I) are as follows. — ^ Ϋ tLtr nn 1 I 1 ^ 1 ml 1 ^ 1 ^ 1 \ OJ (Please read the precautions on the back before filling this page) Printed by the Central Standards Bureau of the Ministry of Economic Affairs, Consumer Cooperatives This paper is sized to Chinese national standards (CNS) A4 specification (2 丨 0X297 mm) 18 39 2 2 1 464649 A7 B7 V. Description of the invention (19) R1 R2 〇

Printed by the Central Bureau of Standards of the Ministry of Economic Affairs, β Shelley Consumer Cooperative, R4 Compound No. A R1 R2 R3 R4 1) Η Η Η HH 2) Η Η Η H ch3 3) Η Η Η H CH2CH3 4) Η Η Η H (ch2) 2ch3 5) Η Η CH H CH (CH3) 2 6) Η Η Η H ~ < j 7) Η Η Η H (CH2) 3CH3 8) Η ch3 HH 9) 〇 / Η ch3 H ch3 1〇) 〇 / Η ch3 H CH2CH3 11) Η ch3. Ϊ́- H (ch2) 2ch3 12) Η ch3 H CH (CH3) 2 (Please read the precautions on the back before filling out this page) This paper applies Chinese national standard Rate (CNS) A4 specification (210X297 mm) 19 39 2 2 1 464649 A7 B7 V. Description of the invention (2) R1 R2 〇

Printed Compound No. A R1 R2 R3 R4 13) Η ch3 H 14) Η ch3 H (CH2) 3CS3 15) 〇 / Η ch3 H CH2CH (CH3) 2 16) Η ch ch3 H 17) Η. Η ch3 H ch2- ^ Q 18) w Η Η ch3 H (CH2) 2 ^ Q 19} Η Η ch3 ch3 ch3 20) Η ch3 CH2CH3 CH2CH3 21) Η ch3 H CH2CH2OH 22) 〇 / Η ch3 H CH2CH2OCH3 23} Η ch3 H ch2ch2cn 24) Ος / Η ch3 ch3 H CH3 (Please read the precautions on the back before filling out this page) The paper size applies to the Chinese National Standard (CNS) Α4 size (210 × 297) %) 20 39221 4646 ^ 9 A7 _B7 V. Description of the invention (2 1) R1 R2 〇

Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economy R4 Compound No. A R1 R2 R3 R4 25) Η ch3 ch3 ch3 ch3 26) Η Η CH2CH3 H ch3 27) Η Η CH2CH3 H ch3 28) w Η Η (CH2) 2CH3 H ch3 29) 〇 / Η CH (CH2) 2CH3 ch3 ch3 30) Η Η CH (CH3) 2 H ch3 31) Η Η CH (CH3) 2 ch3 ch3 32) Η Η ch3 ch3 COCH3 33) Η ch3 ch3 COCH2CH3 34) Η Η CH3 CH3 < CO (CH2) 2CH3 35) W Η Η ch3 ch3 COCH (CH3) 2 36) 〇 / Η Η ch3 ch3 CO (CH2) 3CH3 ---------- ^ 1 '^ -(Please read the notes on the back before filling out this page) This paper size applies to China National Standard (CNS) A4 (210X297 mm) 21 39221

T 464649 A7 B7 V. Description of the invention (22) R1 R2 〇

R4 Compound Number A, R2, R2, R3, R4 37) Η Η CH3 ch3 CO (CH2) 4CH3 38) 〇 / Η ch3 CO (CH2) 5CH3 39) Η ch3 ch3 CO ^ ) 40) 〇 / Η Η CH3 CH3 coch2 — 41) Η ch3 ch3 C〇 (CH2) 2 ^ Q) 42) Η Η ch3 ch3 co ~ G ^ ~ ci 43) Η ch3 ch3 CO-^ Br 44) 〇 / Η ch ch3 ch3 C〇 — ^^ ~ F 45) 'Η Η CH3 ch3 C0 CF3 46) Η Η ch3 ch3 ΐ C0 ~ h〇-CH3 47) Η Η ch3 ch3 co—och3 48) W Η Η HH coch3 ------------ (Please read the notes on the back before filling in this page) The size of the paper is applicable to the Chinese National Standard (CNS) A4 (210X297 mm) 22 3922 1 464649 A7

7 B V. Description of the invention (23) R1 R2 〇

Printed Compound No. A R1 R2 R3 μ 49) 中央 Η Η Η co- ^) 50) w Η Η ^ Η Η CONHCH3 51) Η Η Η Η CONHCH2CH3 52) 〇 / Η Η Η Η CONH (CH2) 2CH3 53) Η Η Η Η CONHCH (CH3) 2 54) 〇 / Η Η Η 〇 C〇NH (CH2) 3CH3 55) Η Η Η Η CONH (CH2) 5〇H3 56) Η Η Η Η CONH— 57) Η Η Η Η c〇nhch2 — < (3 58) Η Η Η Η CONH— 59) Η Η Η Η CONH —F 60) Ος Η Η ch3 Η CONHCH3 (Please read the first Please fill in this page for the matters needing attention) This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297mm) 23 39 22 1 4 6 4 6 4 9 a? B7 5

Description of the invention (2 4) R1 V

Printed Compound No. A R1 R2 R3 R4 61) W Η Η ch3 H conhch2ch3 62) Η Η ch3 H CONH (CH2) 2CH3 63) Η ch3 H CONHCH (CH3) 2 64) Η ch3 H conh (ch2) 3ch3 65) Η ch3 H conh (ch2) 5ch3 66) Η ch3 H CONH— (h) 67} W Η ch3 H c〇nhch2 — < ^ y 68) Η Η ch3 H CONH— 69) Η Η ch3 H CONH —F 70) Η Η ch3 ch3 CONHCH3 71) W Η Η ch3 \ · ch3 CONHCH2CH3 72) Η Η CH3 ch3 CONHCH (CH3) 2 (Please read the precautions on the back first (Fill in this page) This paper size is in accordance with China National Standard (CNS) A4 (210X297 mm) 2 4 3 9 22 1 ''46 4649 A7 B7

V. Description of the invention (25) R1 R2 〇 A

Printed by the Employees' Cooperatives of the China History Standards Bureau, Ministry of Economic Affairs

Compound No. A R1 R2 R3 R4 73) Η ch3 ch3 CONH (CH2) 2CH3 74) Η ch3 ch3 CONH (CH2) 3CH3 75) Η ch3 ch3 CONH (CH2) 4CH3 76) Η ch3 ch3 CONH (CH2 ) 5CH3 77) Η Η ch3 ch3 CONH 乂 78} Οςί Η ch3 ch3 com ^ y 79) Η Η ch3 ch3 CONH -— (T) 80) W Η Η ch3 ch3 c〇nhch2 — {3 81) 〇 / Η Ch ch3 ch3 CONH— .82) Η .Η ch3 ch3 i. CONH —C1 83) Η ch3 ch3 CONHBr 84) 〇 / Η ch3 ch3 CONH F (please read the precautions on the back before filling in this page) The paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 25 39 2 2 1 94 6 4 Ό 4 Printed by the Consumer Cooperatives of the Central Standardization Bureau of the Ministry of Economic Affairs 5. Description of the invention (26) R1 R2 〇

%

Compound number A R1 R2 R3 R4 85) Ogr Η Η ch3 ch3 CONH —CH3 86) Η Η ch3 ch3 CONH—0CH3 87) 〇 ί ch ch3 ch3 CONH —CF3 88) W Η ch3 ch3 ch3 CONHCH3 89} W Η Η ch3 ch3 CH3 CONHCH2CH3 90) Η ch3 ch3 ch3 CONH — 91) 〇 / Η ch3 CH3 ch3 CONH Cl 92) Η Η HH 93) Η Η HH Λ co > 94) W Η Η HH .. ΐ 95) Η Η HH Λ ccy 96) Η Η H .H coO (Please read the notes on the back before filling this page) This paper size is applicable to China National Standard (CNS) A4 (210X297 mm) 26 3922 1, V 4 6 4- 6 4 9 A7 B7 V. Description of the invention (27) R1A:

Central Standards Bureau of the Ministry of Economic Affairs—Industrial and Consumer Cooperatives printed compound numbers Ά R1 R2 R3 R4 97) Η Η Η HC〇J〇I 98) Η Η Η H coO 99) Η ch ch3 ch3 100) O? Η Η ch3 ch3 Λ co ^ 101) Η Η ch3 ch3 co ^ 102) Η ch ch3 ch3 Λ CO " 103) Η ch ch3 ch3 CO 104) Η ch3 ch3 C0O 105) Η Η ch3 ch3 co ^ 106) Η Η ch3 ch3 jl JJ C0CH2 s' 107) Η Η ch3. ch3 A coch / 108) Η ch3 ch3 C0JCH3!--I----I--nx ^-n-(Please read the notes on the back before filling this page) Paper size applies Chinese National Standard (CNS) A4 specification (210 × 297 mm) 27 39 22 1 ^ 464649 A7 B7 V. Description of invention (28)

Printed Compound No. A R1 R2 R3 R4 109) by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs CONH ~ S '113} W Η Η ch3 ch3 A CONH, 1X4) Η Η ch3 ch3 X Jl CONH 115) Η Η ch3 ch3 Λ CONH ^ 116) Η Η ch3 ch3 Jl J] conhch2 s 117) Η ch3 ch3 A conhch2〆118) Ος Η HHH 119) Η HH 120) 〇 / Η HH C0NH— (Please read the precautions on the back before filling out this page) This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) ) 28 3 922 1 44 1 I si ^ ^ nzw ^ > ^ sv? ^

WQ w (flw2 3 2

Hu

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KC offlu nffiw ΠΟZZΚ o

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H nw3 nw3 oo o

KC

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MH mw

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Hw

MH

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002HH OK3 OH 3 owww R.

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nHWW nww nwrtu

R 3 oohy no w

iJ 4u4549 A7 B7 V. Description of the invention (30) R1 R2 〇

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

Compound number A R1 R2 R3 R4 133) Orr Η ch3 ch3 ji ii CONH S 134) W Η Η Η HH 135) Ogii Η Η Η H CO— 136) Η Η Η H CONH- 137) Η ch3 ch3 H 138) Η Η ch3 ch3 co ^ D 139) Η Η ch3 ch3 c.卩 140) Η ch3 ch3 rsn CO " 141) W Η ch3 ch3 CH3 CONH— 142) Η ch3 ch3 ch3 1 J CONH S 143) Η ch3 ch3 CO JCH3 144) Η ch3 ch3 C0_ ^ D {Please read first Note on the back, please fill in this page again.) This paper size applies Chinese National Standard (CNS) A4 specification (2 丨 0 × _297 mm) 30 39 2 2 1 46 4649 A7 B7 V. Description of the invention (31) R1 R2 0

Printed compound number A R1 R2 R3 R4 145) Η Η ch3 ch3 C00CH3 146) w Η Η ch3 ch3 COOCH2CH3 147) Η Η ch3 ch3 COO (CH2) 2CH3 148) Η Η ch3 ch3 COO (CH3) 2 149) Η Η ch3 ch3 COO (CH3) 3CH3 150) Η ch3 ch3 COOCH2CH (CH3) 3 151) Η ch3 ch3 COOC (CH3) 3 152) Η ch3 ch3 COO (CH2) 4CH3 153) Η ch3 ch3 coo (ch2) 5ch3 X54) Η ch3 ch3 COOCH2 155) Η ch3. \ Ch3 S02CH3 156) Η ch3 ch3 so2ch2ch3 (Please read the notes on the back before filling out this page) This paper is for China National Standard (CNS) A4 specification (2l0X: 2i »7mm) 3 922 1 4 6 4649 A7 B7 V. Description of the invention (32) R1 R2 0

Printed by the Central Laboratories of the Ministry of Economic Affairs and Consumer Cooperatives — Compound No. A R1 R2 R3 R4 157) Η Η ch3 ch3 S〇2 (CH2) 2CH3 158) w Η Η ch3 ch3 S〇2 (CH2) 3CH3 159) Η ch ch3 ch3 S〇2 (CH2) 4CH3 160) Η Η ch3 ch3 S〇2 (CH2) 5CH3 161) S〇2- ^ 164) Η Η ch3 ch3 S〇2-Cl 165) Η ch3 ch3 S〇2 ^ G >-CH3 166) Η Η ch3 ch31 S02xo (Please read the notes on the back before filling this page) This paper size applies Chinese National Standard (CNS) A4 specification (2I0X 2S> 7 mm) 32 3 92 2 1 6 46 49 A7 B7 V. Description of the invention (33). The above compounds can be racemates or optical isomers . Because the compound (I) or its salt used in the present invention has antibacterial activity, (please read the precautions on the back before filling in this page). It is especially effective against Helicobacter bacteria such as K. pylori. Bacterial activity, and effectively used as an antibacterial agent, K to prevent or treat the above-mentioned "duodenal ulcer, gastric ulcer, gastritis (including chronic gastritis), cancer, etc." caused by Helicobacter pylori infection. I) or a pharmacologically acceptable salt thereof, which can be administered orally or parenterally to mammals as an antibacterial or antiulcer agent (eg, human, dog, cat, monkey, mouse, mouse, horse, cow) Among them, K is better for oral administration. Examples of dosage forms for oral administration include: lozenges (including sugar-coated tablets and film-coated lozenges), pills, granules, powders, capsules (including soft capsules) ), Slurry, emulsion and suspension. Examples of dosage forms for parenteral administration include injection preparations, infusions, drip infusions and suppositories. In the preparation of the present invention, compound (I) or a salt thereof Content, usually 2 to 85% by weight, preferably 5 to 70% by weight. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs to make compound (I) or its salts into the above-mentioned dosage forms. • The known manufacturing methods commonly used in the related fields are used. Appropriate amounts of excipients, binders, disintegrating agents, lubricants, sweeteners, surfactants, suspending agents, emulsions, etc. commonly used in the pharmaceutical field can be added, and can be added in appropriate amounts. For example, if the compound (I ) Or its salt is prepared into lozenges, which may contain excipients, binders, disintegrating agents, lubricants, etc .; if compound (I) or its salt is prepared into nine agents or granules, it may contain excipients and binders , Disintegrating agent, etc. If the k-scale of the compound is applicable to the Chinese National Standard (CNS) A4 specification (2 丨 OX297 mm) 33 39 2 2 1 6 4649 A7 B7 V. Description of the invention (34) Object (I) or its Salts are prepared into powders or capsules, which can contain excipients, etc .; if compound (I) or its salts are prepared into slurry, sweeteners, etc .; if compound (I) or its tincture is prepared into emulsion or tincture float The agent may contain a flocculant, a surfactant, an emulsion, etc. Examples of the excipient include Lactose, sucrose, glucose, starch, sucrose, microcrystalline cellulose, licorice powder, mannose, sodium bicarbonate, calcium phosphate and calcium sulfate. Examples of binders include: 5 to 10% by weight starch gum solution, 10 to 20% by weight Aberber gum solution or gelatin solution, 1 ~ 5% by weight Xanthan gum solution, Carboxymethyl pavidin solution, Sodium alginate solution and glycerin. Examples of disintegrants include: starch and calcium carbonate Examples of lubricants include magnesium stearate, stearic acid, calcium stearate, and purified talc. Examples of sweeteners include glucose, fructose, invert sugar, sorbase, xylitol, glycerin, and Simple syrup. Examples of surfactants include: Sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid and polyoxystearate 40. Examples of (stearic acid polyoxyl 40) suspending agents include acacia, sodium alginate, sodium carboxymethyl cellulose, methyl cellulose and bentonite. Examples of emulsifiers include: gum arabic, tragacanth, gelatin, and polysorbate 80. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs {Please read the precautions on the back before filling this page} In order to prepare the compound (I) or its salt into the above dosage form, you can add an appropriate amount of coloring agents commonly used in the pharmaceutical field , Preservatives, flavoring agents, tinctures, stabilizers, thickeners, etc. The disadvantages of the present invention are that it contains a compound of general formula U) or a pharmaceutically acceptable salt thereof, and is stable and has low toxicity, and can be used safely. Depending on the patient's condition and weight, the type of compound, the route of administration, etc., the daily dose of the preparation of the present invention, when administered orally to a patient with 1 ulcer caused by Helicobacter pylori infection, the content of M active ingredient (compound This paper size applies the Chinese National Standard (CNS) A4 specification (21〇 ×: 297 mm) 34 3 9 22 1 6 4649 A7 B7 V. Description of invention (35) (I) or its salt) In terms of each adult (Weighing about 60 kg) is usually 1 to 500 mg, preferably about 10 to 200 g. Although it is in the above range, it is not toxic. Moreover, in the preparation of the present invention, the compound (I) or a salt thereof can be used in combination with other antibacterial agents and antiulcer agents. Other antibacterial agents that can be used in combination with compound (I) or a salt thereof include, for example, nitropyrazole antibiotics [eg, tinidazole and methoxazole

ffl 8 (Γ honey e drop U class prime ring four C y X ο d / TV Suspension strength strong cyclotetracycline amine too ring A and two, and e as in (Please read the precautions on the back before filling in this (Page) m / t \ Sui Susu Huiqing penicillin ammonia hydroxyl such as ___ class mycocyanin * 1 P 0 9 Spore head

Such as rL chloro C ί £, {Φ Taisu (C spores order Acetozole IB Cefuroxime cephalosporin benzylamine hydroxyl Γ head a oxime furosemide X a β ra • 1 ο Γ U ΛΙ e Cephalosporin V TX spore cephalosporin ah sindupa cephalosporin X ο e ο cephalin Ritaspora jl jxtn Special spores sold 0 and \ — / Θ 1 Printed by the Central Bureau of Standards of the Ministry of Economic Affairs and Industry and Consumer Cooperatives C / 1. Class Λν7 Ning with bakaersu M κ ¢ 1 Ninglong with bano, ο ο Γ a is too red as ft

C prime emblem 立 o B Ning C (\ with β vinegar rice U inner ring, Gan Daru sugar, rL P-1 > group > s η m amine i β cn ^ y Θ --Lffl p) o Rice and ο Γ prime emblem Soly and a prime grade sora ο Mycelium mycelium chloride such as 1__ phytosanitary anti-level welfare benefits such as the paper size applicable to Chinese national standards (CNS > A4 specifications (210X297 mm) 35

C Θ Rusheng Anti-Xicolin a 39 2 2 1 Η 6 4 6 49 Α7 Β7

5. Description of the invention (36) and Uuinolone) antibiotics [eg, ciprofloxacin, ofloxacin] nitrofurantoin. Anti-ulcer agents that can be used in combination with compound (I) or a salt thereof include, for example, proton capsule inhibitors [eg, lansoprazole, o.meprazole, pantopeline ( pantoprazole), rabeprazole, histamine H2 antagonists [eg, ranitidine, cimetidine, and famotidine] and mucosal anti-ulcer agents [ For example, sofaicone, plaunotol, teprenone, sucralfate]. The other antibacterial agents and antiulcer agents mentioned above can be used by mixing two kinds of M. According to this example, the dosage of an antibacterial agent is usually 1 to 500 g per adult per day, preferably 5 to 200 mg when administered orally; while the dosage of an antiulcer agent is usually administered orally It is 0.5 to 1,000 mg per adult per day, preferably 1 to 500 g. The compound of the formula (I) or a salt thereof can be produced, for example, by the following methods A to E. Method A R1 R2 into (III)

(IV) m (I) In the above chemical formula, B atom is represented by _ atom or -0-S〇2R6 (Rs indicates low grade) This paper size is applicable to China National Standard (CNS) A4 (210X 297 mm) 36 3 92 2 1 (Please read the notes on the back before filling this page) 〇 4 6 4 9 A7 B7 V. Description of the invention (37) Alkyl or substituted phenyl); the definitions of other symbols are as above. In the chemical formula (III), a halogen atom represented by B, for example, gas, chlorine, bromine and iodine. Lower alkyl represented by R6, for example, alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, second butyl, third butyl , Pentyl, isopentyl, neopentyl, third pentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2, 2-dimethylbutyl, 3 , 3-dimethylbutyl and 2-ethylbutyl, preferably alkyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl and isobutyl . Useful substituents in the substituted phenyl group represented by R6 include, for example, a lower alkyl group (the same as exemplified at the lower alkyl group shown by R6 above), a lower alkoxy group (for example, having 1 to 4 carbons) Atomic alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, and butoxy), halogen atoms (for example, fluorine, chlorine, bromine, iodine), nitro, cyano, and carboxyl . Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) This method is performed by reacting compound (III) or its salt with compound (IV) in the presence of a base. The salt of the compound (III) is, for example, an acid addition salt formed by the acid in the acid example of each of them and the compound (I). This reaction is usually performed in a solvent; a solvent is a solvent which is suitably selected so as not to interfere with the reaction. These solvents include, for example, enzymes such as methanol, ethanol, propionate, isopropanol, butanol, and tertiary butanol; ethers such as dioxin, tetrahydrofuran, acetamidine, tertiary butyl methyl ether, and diisopropyl ether. And ethylene glycol-dimethyl ether; esters such as ethyl formate, ethyl acetate and n-butyl acetate; toothed hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichloroethylene, and 1,2- Dichloroethane; hydrocarbons such as n-hexane, benzyl, and methylbenzyl; amines such as formamide, Ν, Ν-dimethylformamide, and this paper size are applicable to China National Standard (CNS) A4 specifications (210 × 297) (%) 37 39 22 1 4 6 4 6 4 9 A7 B7 V. Description of the invention (38) Η, N-dimethylacetamide; hydrazones such as propane, methyl ethyl ketone and methyl isobutyl ketone; nitrile Such as acetonitrile and propionitrile; dimethyl arylene, dioxetane, hexamethylphosphamide and water; these solvents can be used alone or as a mixed solvent. Printed by the Central Standards Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperatives (please read the notes on the back, and then fill in this page) Useful ones include: for example, Ci-6 alkyl or aryl lithium such as methyl bell, ethyl lithium , N-butyllithium, second butyllithium, third butyllithium and phenyllithium; lithium alkylammonium amines having 2 to 6 carbon atoms, such as lithium dimethylammonium amine, diethylammonium amine Lithium and lithium diisopropylammonium, metal hydrides such as lithium hydride and sodium hydride; metal alkoxides having 1 to 6 carbon atoms, such as lithium ethionate, lithium third butoxide, sodium formate, Sodium ethoxide and potassium tert-butoxide; fermented amines such as lithium amide, potassium amide, and sodium amide; phosphonium bases such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, and argon carbonate Sodium; and tertiary amines such as triethylamine, tri (n-propyl) amine, tri (n-butyl) amine, diisopropylethylamine, hexamethylenedimethylamine, pyridine, dimethylpyridine, 7 i -Collidine, N, N-dimethylaniline, N-methylhexahydropyridine, N-methylpyridine and N-methylmorpholine. When this reaction proceeds, the compound (IV) is used in an amount of 1 to 5 moles, preferably 1 to 3 moles per mole. The reaction temperature is usually about -80 to 100 ¾, preferably -50 to 60 ¾. The reaction time is usually 1 minute to 72 hours, preferably 15 minutes to 24 hours, depending on the kinds of the compounds (III) and (IV), the kind of the solvent, the reaction temperature and the like. This paper size applies to Chinese national standards (CNS > A4 size (2 丨 0 X: 297 mm) 38 39 2 2 1

464649 V. Description of the invention (39) Method R A7 B7 R1 R2, N: HN = C. R3 Ή4

(I) OR8 (VIII) (Please read the precautions on the back before filling out this page)

The 7 R-based hydroxyl or hydrogen is shown. 8 R-based alkane hydrazone. A The low-level method or the upper hydrogen is as shown in the example os, and the alkane-type academic symbol in the fixed base reduces his description. The alkane-level low-level indicator 6 R The employee of the Central Standards Bureau of the Ministry of Economic Affairs Consumption cooperatives do not just base their protection on what can be a base. Protective group, alkyl-protecting, low-grade, low-molecular-weight rm CMM. Phase-a-R as described in 'Methoxybutane: three containing the first, the basic example of methyl ethyl oxy good methane is relatively stupid _' , Methylcothyl three is methyl I. oxy-2 transmethylmethoxyethyloxymethyltoluenemethyl, methylmethyl benzopyridine argon nitrate 3 --Eg pairs such as thios s; ott S Oxygen Hydroxyl protection_ Sibao 22- of, Cheng. * Base form of methylthiomethoxymethoxyethoxy para- 'dimethylbenzyl, thiofurfuryl tetramethyltoluene three and dimethylbenzyl nitrate I adjacent to the paper size Applicable to Chinese National Standards (CNS > ΑΊ specifications (210X297 mm) 39 392 2 1 4 6 4 S 4 9 Δ7 Α7 B7 V. Description of the invention (40); Silyl ether-protective groups such as trimethylsilyl , Triethylsilyl, triisopropylsilyl, isopropyldimethylsilyl, diethylisosilyl, third butyldimethylsilyl, third butyldiphenylsilyl, trityl Silyl groups, tribenzyl silyl groups and methyl diphenyl silyl groups; and the protective groups formed by _-, such as methyl, ethyl, and ethyl ethyl groups Dioxoethenyl, trichloroethenyl, trimethylethylglycosyl, and benzamidine. If Rs in formula (V) is hydrogen, compound (V) or a salt thereof reacts with compound (VI). Salts of compounds (V), such as the acid addition salts described with the acids described in the section where they form acid addition salts with compound (I). The reaction is usually carried out in a solvent, if necessary, in the presence of a tank. These solvents and amidines are the same as those described in the above method A. When this reaction is carried out, the compound (V 1) is used in the range of 1 to 10 moles per mole, preferably 1 To 5 moles. The reaction temperature is usually about -30 to 20010, preferably -10 to 1501C. The reaction time is usually 1 minute to 120 hours, preferably 15 minutes to 48 hours, depending on the types of compounds (V) and (VI). , Solvent, and the type of osmium, reaction temperature, etc. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Carp (please read the precautions on the back before filling this page). Manufacture of compound (I), also from compound (V ) And (VII) to obtain compound (VIII), and then cyclizing compound (VIII) to obtain it. This method And compound (VII) or a salt thereof and a compound (V), a salt thereof or a reactive derivative thereof. ≪ Specifically, a free acid (V), a salt thereof (inorganic salt, organic salt) Or • Its anti-fluorinated derivatives (for example, fluorenyl halide, enzyme-based azide, acid anhydride, mixed acid anhydride, active ammonium amine, active fat, active sulfur, etc.) for the amidine reaction. Inorganic salts include: starved gold靥 Salts (for example, sodium salt, potassium salt) and basic paper size are applicable to Chinese National Standard (CNS) A4 (210 X 297 mm) 40 3 92 2 1 464649 A7 _ B7 V. Description of the invention (41) Gold tincture salts (for example, calcium salts). Organic salts include, for example, trimethylamine salt, triethylamine salt, third butyldimethylamine salt, benzylmethylamine salt, benzyldimethylamine salt, N, H-dimethylaniline salt , Pyridine salts and phosphonium salts. The fluorenyl halides include, for example, fluorenyl chloride and fluorenyl bromide. Mixed acid anhydrides include: Mono-Ci-4 alkyl carbonate mixed acid anhydrides (for example, free acid (V) and monomethyl carbonate, monoethyl carbonate, monoisopropyl carbonate, monoisobutyl carbonate, Mixed anhydrides of butyl carbonate, monobenzylmethyl carbonate, mono (p-nitrobenzylmethyl) carbonate, monoallyl carbonate, etc.), Ci-6 aliphatic carboxylic acid mixed anhydrides (for example, free acid ( V) Mixed anhydrides with acetic acid, cyanoacetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, trimethylacetic acid, trifluoroacetic acid, trichloroacetic acid, acetic acid, etc.), C7- H aromatic carboxylic acid mixed acid anhydrides (for example, mixed acid anhydrides of free acid (V) and benzoic acid, p-toluic acid, p-chlorobenzoic acid, etc.) and organic sulfonic acid mixed acid anhydrides (for example, with methanesulfonic acid Acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and other mixed anhydrides). Please read the precautions on the back before filling this page) and packages} Rings (V-Amino acid nitrogen 醢 is a formed product containing self-identifying amines 三 t-trimethylated cyclic aza nitrogen η The content can be combined with a substance containing P, such as the base of the example. Forms such as azole, tris, benzo, imimidazole, amine, and hydrazone, etc. This base is printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. Isopropylglycidyl group, base oxobutane 6-, C1 based triglycyl group, base diglycyl isobutyl group Propionyloxyethyl Λ oxymethyl bromide r chlorofluoro, for example, / «V · type protohalooxythioethyl 'methyl thiomethyl example, / f \ type sulfane examples containing encapsulating esters, etc. Substitute all kinds of ester acids, esters, phosphorous oxybenzenes, diesters, phosphoric acid, etc. For example, esters, esters, etc. 4 2 Phosphonic acid, ethyl nitrate, dibenzyl paper This paper applies the Chinese National Standard (CNS) A4 specification (210X297) (Mm) 4 1 392 2 1 4.6 4649 A7 B7 V. Description of the invention ( 42) ester, cyanomethyl, pentachlorobenzyl ester, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxybenzotriazole, 6-chloro-1-hydroxyl Ben Bingsan, Ministry of Economic Affairs, Central Standards Bureau, Consumer Cooperatives, Printed Family, J D ¾ Class 2 and 二 Η · _ > Alkane contains 4 bases including 1-D = iso-fermented, sulfur; * properties ㈣ live ㈣,. $ Isopropyl acetone iso® esters, other radicals in two bis-forms, -1 alkynyl ethoxylation, 1 zymo and thiomethyl ring, oxazolyl, isopropyl) -oxypropyl isotriazine Benzyl bromide, butyl chloride, butyl bromide, butyl chloride, propyl sulfide, propyl thiophene, 〇 Γ -1 compounds to form oxazolyl lithium salts to form acid and oxyalkyloxy Radical, oxygen monomethyl, oxygen such as butyl example 3 1 (class radical, radical such as radical ft instead of --► etc. radicals such as ethyl radical / t \ proton halogen sulfanylthioethylthiomethyl as example Esters Thiolidine Dtt and S-3 Sodium 'Potassium as examples Examples of compounding with acid and salting into acids are where salt forming and acid forming are mixed and the solution should be disturbed instead of traveling. Rong Ding et al. 选. Ethyl ether, ethyl ethyl and chloroester triethyl, acid carbon ethylation, chlorotetraethyl, acid methyl chloride such as', such as amine ketones, etc. ;; Aminobenzoic acid ethyl and benzoic acid, dioxane N-hexane R, propyl butane and fluorenone isopropenoic acid furfuryl hydrogen tetraether, methane di n§ii dioxane such as ethyl and ether ether alkyl n-methyl Such as chlorinated dihydrocarbons such as · '-type alkane ethyl chloride halides, 2 S > 1 and ketoamine butyl isopropyl methyl methyl and 20 HV. Ethyl nitro, methylamine, methyl hexa

Compounding and phenochemistry. Sleep with hydrogen to make four doses of oxygen-soluble dioxin, mixed hunting, or methylene monodimerization., Acetonitrile, molybdenum, etc. are nitriles, and the amount of ethyl water is the same as that of amine-like nitriles (I). •, disc V ear Mo ο 1 to Changtong V / IV comparison (please read the precautions on the back before filling this page) This paper size applies Chinese National Standard (CNS) A4 (210X297 mm) 42 3 922 1 464649 A7 B7 V. Description of the invention (43) Preferably 1 to 5 moles. The reaction is usually performed at -80 to 20 °, preferably -40 to 150¾, and most preferably -30 to 100¾. The reaction time is usually 1 minute to 72 hours, preferably 15 minutes to 24 hours, depending on the compound (V) and ( The type of VII), the type of the solvent (if it is a mixed solvent, also the mixing ratio), the reaction temperature, etc. are different. If the compound (V) M is used, the reaction is carried out in the presence of a deoxidizing agent, and M is reacted automatically. The hydrogen halide released is removed from the system. These deoxidants include, for example, inorganic lysines such as sodium carbonate, potassium carbonate, osmium carbonate and sodium carbonate: tertiary amines such as triethylamine, tripropylamine, Butylamine, cyclohexyldimethylamine, pyridine, dimethylpyridine, 7-collidine, N, N-dimethylaniline, H-methylhexahydropyridine, N-methylpyrrolidine and N-methyl Modal orders; and epoxy such as propylene oxide and epichlorohydrin. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page). The hydroxyl protecting group R8 should be removed if necessary. Then, compound (VIII) is cyclized to obtain compound (I). Depending on the type of protecting group, this deprotection reaction It is carried out according to a known method selected by Dee. The deprotection reaction is achieved, for example, if it is an ether-protecting group, using an acid (for example, formic acid, acetic acid, propionic acid, hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, methanesulfonic acid). , Ethanesulfonic acid, p-toluenesulfonic acid) or catalyzed rhenium reactions [for example, using Raney nickel, platinum, palladium, rhodium, etc. at constant pressure or high pressure (2 to 100 atmospheres) as a catalyst ]; For a silyl ether-forming protective group, use one of the above acids or Lewis acid (eg, zinc chloride, zinc bromide, aluminum chloride 'titanium chloride) or a gaseous product (eg, potassium fluoride , Sodium fluoride, tetraethylammonium fluoride, tetra-n-butylammonium fluoride); or if it is an ester-forming protective group, use a base (for example, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, lithium hydroxide , Potassium hydroxide, sodium hydroxide). The reaction is usually carried out in a solvent; these solvents, such as those used in Method A, are applicable to Chinese national standards (CNS > A4 size (2I0X297 mm)) 43 3 922 1 4 6 4649 A7 B7 V. Description of the invention (44) 0 If it is an ether-forming protective group or a silane-based protective group, the amount of acid or Lewis acid is usually from 0.001 to 100 moles per mole of compound (V), preferably 0.01 To 50 mol. The reaction temperature is usually -50 to 150P, preferably -20 to 100t: ° The reaction time is usually 1 minute to 72 hours, preferably 15 minutes to 48 hours. If it is a protective group formed, the base The most commonly used is that 0,01 to 50 moles, preferably 0.1 to 20 moles per mole of compound (V). The reaction temperature is usually -20 to 150 ° F, preferably -10 to. The reaction time is usually 1 Minutes to 72 hours, preferably 15 minutes to 48 hours. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the note on the back before filling out this page) The deprotected compound (VIII) is given to Μ Cyclization to compound U) ° This reaction is usually carried out in a solvent. Such solvents are exemplified by methods Solvent. The reaction temperature is usually -10 to 200C, preferably -5 to 150 ¾. At this reaction, a base can be used as a catalyst; these bases are exemplified by the age of Method A. To promote the reaction, for example, 2-chloro Tetrafluoromethyl salt, 2-chloro-3-ethylbenzoxazole tetrafluoroborate, 2-chloro-3-methylbenzo1 Tetrafluoroammonium salt, 2-chloro-3-ethylbenzimidazole fluoroborate, 2-chloro-1-methylpyridine tetrafluoroborate, and 2-chloro-1-ethylpyridine Tetrafluoroborate. The amount of the reaction accelerator is usually 1 to 10 moles, preferably 1 to 3 moles per mole of the compound (VIII). If a reaction accelerator is used, osmium can also be used. Examples of these include The reaction temperature at 醮 ° as used in Method A is usually -30 to 1501, preferably -20 to 100¾. The reaction time is usually 1 minute to 72 hours, preferably 15 minutes to 48 hours. If one of R3 and R4 is available, Substituted fluorenyl groups and esterified carboxyl paper sizes are applicable to China National Examination (CNS) A4 specifications (210X297 mm) 44 39 2 21 464649 A7 B7 V. Description of the invention (45) or carbamoyl groups, Compound (I) Method C was prepared to follow the above methods C, D and E in the chemical 0 in formula (I) compounds of the compound (LB) (wherein R3 or R4 group having Niang) to give the.

R4bCOOH (IX)

R4bS03H (X) In these chemical formulas, 1-4 & shows a fluorenyl group; R4b shows a group after removing a carbonyl or sulfonyl group from a fluorenyl group; the definitions of other symbols are as described above. The base shown by R4a refers to the base shown by R4; R4bm shows "the base after removing the ape or sulfo base from the base" " refers to the base shown by R4. Offset consumption of the Central Standards Bureau of the Ministry of Economic Affairs Cooperative printed (please read the notes on the back before filling this page)

R3 R4a R1 R2 〇

According to this reaction, compound (la) or a salt thereof can be compounded with compound (IX) or (X) or a reactive derivative thereof to obtain compound Ub). The salt of the compound (la) is exemplified by the same acid addition salt as described for the salt of the compound (I). The reactive derivative of the compound (IX) is exemplified by the reactive derivative described in Method B. Examples of the reactive derivative of the compound (X) include sulfonium (e.g., sulfonium bromide, sulfonium chloride) and sulfonic anhydride; this reaction is carried out according to the method described in Method B or a modified method thereof. Among the compounds of formula (I). Compound (Ic) (where R4 has an esterified carboxyl group) can be prepared according to method D. This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) 45 3 9 22 1 464649 V. Description of invention (46) Method 1) A7 B7 (la) QR4c (Xi) R1 R2 Ο

R3 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. In these chemical formulas, R4e indicates a carboxyl carboxyl group; Q indicates a tooth atom; other symbols .. Among the carboxyl groups which R4c and R4 can be esterified, any group other than the free carboxyl group K is used. Examples of _ elements shown by Q include fluorine, chlorine, bromine and iodine. This reaction is carried out by reacting the compound (la) or a salt thereof with the compound (XI). The salt of the compound (la) is exemplified by the acid addition salt of the compound (la) of the reaction D described above. This reaction is usually performed in a solvent; the solvent is exemplified as the solvent used in the method B. At this reaction, hydrogen halide is released. To remove the hydrogen halide, the reaction may be performed in the presence of an acid scavenger. Acid scavengers include, for example, inorganic bases such as sodium carbonate, potassium carbonate, calcium carbonate and sodium bicarbonate; tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, pyridine, dimethyl Pyridine, 7-hour collidine, d, N-dimethylaniline, N-methylhexahydropyridine, K-methylpyrrolidine and N-methylmorpholine; and propylene oxide and epichloromethane. The compound (XI) is used in an amount of usually 1 to 20 moles, preferably 1 to 10 moles per mole of the compound Ua). The reaction temperature is usually -30 to 120 t :, preferably -20 to 80¾. The reaction time is usually 1 minute to 72 hours, preferably 15 minutes to 48 hours. (Please read the precautions on the back before filling this page) The paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 46 3 922 1 46 4649 A7 B7 2. Description of the invention (47) Among the compounds of the formula (I), the compound (Ic |) (which may have a substituted carbamoyl group may be prepared according to method E).

Method E

In these chemical formulae, R4d represents a carbamoyl group which may be substituted; R3, R10 and R11 are the same or different, showing hydrogen or the same as described in the substituent in the carbamoyl group which may be substituted. Substituents; other symbols are as defined above. According to this method, the compound (Ic) or a salt thereof can be reacted with the compound (XII) to obtain the compound (Id). The salt of the compound (Ic) is exemplified by the same acid addition salt as described for the salt of the compound (I). This reaction is usually performed in a solvent; the solvent is exemplified as the solvent used in the method A. The compound (XII) is used in an amount of usually 1 to 100 moles, preferably 1 to 30 moles per mole of the compound (Ic). The reaction temperature is usually -30 to 200 ° C, preferably -10 to 100 $. The reaction time is usually 1 minute to 72 hours, preferably 15 minutes to 48 hours. The compound (Id) can also be prepared by reacting the compound (la) with an isocyanate derivative (XIII). This reaction is usually carried out in a solvent. The solvent may be any solvent as long as it does not interfere with the reaction. For example, ethers such as dimer -------- Ί) ^-C- (Please read the precautions on the back before filling out this page) The size of the paper is applicable to China National Standard (CNS) Α4 specifications (2 丨 〇 × 297mm) 47 3 9 22 1. 4b4b4 ^ 4 6 46 49 a? B7 V. Description of the invention (48), tetrahydrofuran, acetamidine, tertiary butyl ether, diisopropyl ether and ethylene glycol- Dimethyl ether; esters such as ethyl formate, ethyl acetate and n-butyl acetate; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichloroethylene and 1,2-dichloroethane; hydrocarbons Such as n-hexane, benzene, and toluene; amines such as formamide, Ν, Ν-dimethylformamide, and Ν, 二 -dimethylacetamide; ketones such as acetone, methyl ethyl ketone, and methyl Isobutyrium; nitriles such as acetonitrile and propionitrile; dimethylarylene, dioxolane 18 phen, hexamethylphosphonium amine; these solvents are used alone or as a mixed solvent in the amount of compound (XIII), 1 to 30 moles, preferably 1 to 15 moles per mole of compound (la) is used. The reaction temperature is usually -20 to 150 t, preferably -10 to 100 υ. The reaction time is usually 1 minute to 72 hours, more preferably 15 minutes to 48 hours.

Method F (Please read the notes on the back before filling this page) η

(XVI) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Carpling Hydrolysis or Hydrolysis R 12

R3 R4 Heating (I) In these chemical formulas, R12 shows hydrogen, lower alkyl, cyclofluorenyl, and aromatic paper. The paper size is applicable to China National Standard (CNS) A4 (210X297 mm) 48 39 2 2 1 Central Standard of the Ministry of Economic Affairs Printed by the Bureau ’s Consumer Cooperatives 4 6 4 6 49 Α7 Β7 V. Description of the Invention (49) \ Alkyl or fluorenyl; R 13 and R14 are the same or different and show hydrogen or lower alkyl; R15 shows argon and lower Alkyl or aralkyl R16 represents a lower alkyl or aryl group; the definitions of other symbols are as described above. In the chemical formula (XIV), examples of the lower alkyl group represented by R12 include alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and second Butyl, third butyl, pentyl, isopentyl, neopentyl, third pentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2- Dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl, preferably alkyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl , Butyl and isobutyl. The cycloalkyl group represented by R12 is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclononyl, preferably cyclopropyl, cyclobutyl, cyclopentyl And cyclohexyl. Examples of the aralkyl group represented by R12 include benzyl, benzyl, and phenylpropyl. The fluorenyl group represented by R12 is exemplified by aliphatic radicals such as alkylfluorenyl, alkenyl, / cycloalkylcarbonyl, and alkylsulfonyl; aromatic fluorenyl such as arylfluorenyl, aralkylfluorenyl, and arenefluorenyl And aromatic hydrocarbon sulfonyl groups; heterocyclic aromatic fluorenyl groups such as aromatic heterocyclic carbonyl groups and aromatic heterocycloalkanoyl groups; and non-aromatic heterocyclic carbonyl groups (aliphatic heterocyclic carbonyl groups). " Alkino " refers to fluorenyl carbonyl. Preferred examples include: lower alkyl fluorenyl having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, propyl, butyl, isobutyl, and pentyl. Base, isoamyl, 3methylacetamyl and hexamethylene. " Alkenyl " refers to alkenyl carbonyl, and its preferred examples include: C3-6 alkenyl, such as acryl, methacryl, methacryl and isocrotonyl. 0 This paper is applicable to China National Standard (CNS) Α4 Specification (210X297 mm) 4 9 3 92 2 1 (Please read the precautions on the back before filling this page)

A7 B7 164649 V. Description of the invention (50) (Please read the notes on the back before filling out this page) "Cycloalkylcarbonyl" refers to cycloalkylcarbonyl, and its preferred examples include: cycloalkylcarbonyl with 4 to 7 carbon atoms , Such as cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl and cyclohexylcarbonyl. "Alkylsulfonyl" refers to alkylsulfonyl, and preferred examples thereof include alkylsulfonyl having 1 to 4 carbon atoms, such as methylsulfonyl, ethylsulfonyl, and sulfonylsulfonyl. "Aromatic" refers to an arylcarbonyl group, and preferred examples thereof include an arylcarbonyl group having 7 to 11 carbon atoms, such as benzamyl, p-methylbenzyl, 1-naphthylmethyl, and 2- Forbidden. " Aralkylfluorenyl "refers to fluorenyl carbonyl substituted with aryl. Examples include: C6-8aryl-C2-5 alkyl alcohol, such as benzyl, phenylpropanyl, and hydrogen atomol. "Phenyl" and "phenylalkenyl" refers to an alkenyl group substituted with an aryl group, and preferred examples thereof include: C6-8 aryl C3-5 alkenyl groups, such as epithelyl and atropyl. "Aromatic sulfonyl" refers to arylsulfonyl. Preferred examples include: arylsulfonyl having 6 to 8 carbon atoms, such as benzylsulfonyl and p-toluenesulfonyl. Central standard of the Ministry of Economic Affairs Preferable examples of "aromatic heterocyclic carbonyl" printed by local consumer cooperatives include: furanomethane, phenphenamidine, nicotinemethane, isonicotinylmethyl, pyrrolecarbonyl, oxazole carbonyl, Pyrazole carbonyl, oxazole carbonyl, and pyrazole carbonyl. "Aromatic heterocycloalkyl" refers to an alkylcarbonyl substituted with an aromatic heterocyclic group, and preferred examples include: aromatic heterocyclic-C2-5 alkyl , Such as 1¾ phenethylfluorenyl, phenpropylfluorenyl, furan acetylfluorenyl, oxazolidinyl, 1,2,4- «diazolethylfluorenyl, and pyridylacetinyl. This paper size applies to Chinese national standards (CNS) A4 specification (210X297 mm) 5 0 3 922 1 46A649 A7 B7 V. Description of the invention (51) " Non-aromatic heterocyclic carbonyl "Preferred examples include: aliphatic heterocyclic carbonyl, such as azetidine carbonyl , Pyrrolidine carbonyl and hexahydropyridine carbonyl. In other formulae (XIV), (XV) and (XVI), the lower alkyl group represented by R13, Ri4, R15 or R16 is exemplified by the lower alkyl group represented by R12. The aralkyl group shown in 1MS is exemplified as the aralkyl group shown in R12. Examples of the aryl group represented by R16 include phenyl, naphthyl, aryl, phenanthryl, and pinenaphalyl, and phenyl is more than phenyl and naphthyl. These aryl groups may have 1 to 5 substituents. These substituents include: alkyl groups with 1 to 3 carbon atoms (eg, methyl, ethyl, propyl), alkoxy groups with 1 to 3 carbon atoms (eg, methoxy, ethoxy Group, propoxy group) and halogen atoms (eg, fluorine, fluorine, bromine, iodine). According to this method, compounds UIV) and (XV) are reacted in the presence of compound (XVI) to obtain compound (XVII). Ministry of Economic Affairs Printed by the Consumer Standards Cooperative of the Central Bureau of Standards (please read the notes on the back before filling this page) This reaction is usually performed in a solvent; the solvent is a suitable solvent that does not interfere with the reaction. These solvents include: for example, alcohols such as Formic acid, acetic acid, propanol, isopropanol, butanol, and tertiary butanol; ethers such as diming tincture, tetrahydrofuran, ether, tertiary butyl methyl ether, diisopropyl ether, and ethylene glycol-dimethyl ether; Esters such as ethyl formate, ethyl acetate and n-butyl acetate; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichloroethylene and 1,2-dioxane; hydrocarbons such as n-hexane, Benzene and toluene; amidines such as formamide, amidine, N-dimethylformamide and Ν, Ν-dimethylacetamide; amidines such as propyl Ketones, methyl ethyl ketones, and methyl isobutyl ketones; eyes such as acetonitrile and propionitrile; dimethyl arylene, dioxotetrahydro! Phen, hexamethylammonium, and water; these solvents can be used alone or Mixed solvents are used. The reaction temperature is usually -80 to 1501C, preferably -50 to 120¾. The use of each compound (XV) and (XVI) is usually per Xerium compound (XIV). This paper is applicable to China. Standard (CNS) A4 specification (2! 0X297 mm) 51 39 2 2 1 4. 6 4 6 4 9 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (52) 1 I 1 to 5 Mo Ear »Preferable 1 to 3 M Ear 0 1 1 Then the ester of compound (XV II) is hydrolyzed > m etc. f to obtain the compound 1 1 (XVIII) > 1 I This hydrogenolysis reaction is usually carried out in a solvent ♦ Solvents are suitable. Please read 1 1 I Solvents that interfere with the reaction 0 These solvents contain X For example 9 Ferments such as methanol% Ethanol Read back 1 ί Propanol% isopropanol butanol and dibutanol; Ethers Such as Precautions for di-doxane tetrahydro 1 1 Furan ether > Third butyl methyl ether, diisopropyl ether and oxalase-dimethyl ether; 1 1 Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride > (Trichloroethylene and 1,2-fill in this)) Diazine 9 hydrocarbons such as n-hexane and toluene * amines such as formamide, page 1 1 H, N-dimethylformamide and hydrazone, Ν-dimethylacetamidone such as acetone, methyl 1 1 methyl ethyl and methyl isobutyl ketone * nitriles such as acetonitrile and propionitrile dimethyl sulfite, di 1 I oxytetrahydrophenone% methyl Solvents such as phosphatidylamine and water > λ Solvents used alone or in mixtures 〇1 1 | This reaction is performed in the presence of a base. The base used preferably contains: metal 1 1 I hydroxide such as lithium hydroxide hydrogen Potassium oxide sodium hydroxide and barium hydroxide; 1 " X and gold carbonates such as potassium carbonate Λ sodium carbonate and barium carbonate The use of alkali >> 3 1 is usually 1 to 30 moles per mole of compound (XVII) »preferably 1 to 10 moles 1 1 ear 0 Anti-US 'fishy temperature is usually -30 to 15〇υ f is more preferably -10 to 120υ. The inverse 1 I response time is usually 15 minutes to 48 hours, preferably 30 minutes to 24 hours. 1 I If the compound (XVIII) M is produced by a hydrogenolysis reaction, this reaction is usually carried out with a catalyst of 1 1 I. This catalyst is a better catalyst for catalyzing the prinogen reaction. 1 1 Platinum catalysts (for example, platinum oxide, 'Platinum Black 4 Na-Carbon), Palladium Catalyst 1 1 (eg, Palladium Chloride, Palladium-Carbon \ Palladium-Calcium Carbonate, Palladium-Barium Sulfate), Rhodium Catalyst 1 1 (eg, Rhodium-Carbon Samarium-alumina) and ruthenium catalysts (eg, oxidation 1 1) This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 5 2 3 9 2 2 1 A7 B7 4 6 46 49 5. Description of the invention ( 53) (Please read the notes on the back before filling out this page) Ruthenium, Ruthenium-Carbon), preferably palladium catalysts. This reaction is usually carried out in a solvent; a solvent is a solvent which is suitably selected so as not to interfere with the reaction. These solvents include, for example, alcohols such as methanol, ethanol, propanol, isopropanol, butanol, and tertiary butyrate; ethers such as dioxane, tetrahydrofuran, ether, third butyl methyl ether, diisopropyl ether, and Glyoxal-dimethylformamide; esters such as ethyl formate, ethyl acetate, and n-butyl acetate; hydrocarbons such as n-hexane, benzyl, and toluene; amidines such as formamidine, K, N-dimethylformamide Amidine and Ν, Ν-dimethylacetamide and water; these solvents M are used alone or in a mixed solvent. The reaction temperature is usually -10 to 120 ° F, preferably 0 to 100t :. Although this reaction is usually carried out under normal pressure, it should sometimes be carried out under high pressure. The pressure is preferably 1 to 200 atmospheres. The compound (XV III) printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs can be decarburized by heating to obtain compound (I). This reaction is usually carried out in a solvent; a solvent is a solvent which is suitable for a non-drying reaction. These solvents include, for example, alcohols such as formazan, ethylase, propionase, isopropanol, butanol, and tertiary butanol; ethers such as dimethyl, tetrahydrofuran, ether, tertiary butyl methyl ether, diisopropyl Ethers and ethylene glycol-dimethyl ether; bribes such as ethyl formate, ethyl acetate and n-butyl acetate; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichloroethylene and 1,2- Dichloroethane; hydrocarbons such as hexane, benzene and toluene; ammoniums such as formamide, amidine, N-dimethylformamide and K, N-dimethylacetamide; ketones such as acetone, Methyl ethyl ring and isobutyl ketone; nitriles such as acetonitrile and propionitrile; dimethylarylene, dioxetane, hexamethylphosphamide and water; these solvents K are used alone or in a mixed solvent. The reaction temperature is usually 0 to 1801C, and preferably 10 to 150¾. The reaction time is usually 5 minutes to 24 hours, preferably 10 minutes to 12 hours. This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 53 39 22 1 c / i 5 49 A7 '___ B7 V. Description of the invention (5 4) If the compounds involved in the above reactions have amine groups, The carboxyl or hydroxyl group is used by the Central Standards Bureau of the Ministry of Economic Affairs to print the substrate protection and protection of the consumer cooperatives. It is often necessary to obtain him, and the bases and protections can be merged in addition to peptide transfer. The basic needs of the progeny should be taken from the trans-methyl fluorenyl for example, containing carbonyl amines for protecting the stilbylamine. Carbonylbenzene > carbonylcarbonylpropenylcarbonyloxymethyl 0 carbonylcarbonyloxyethyl 'carbonyloxymethyl 9'yl S carbonyloxycarbonyloxyalkane) carbonyl carbonyl such as methyl carbonyl phthalate, methyl phthalide, methyl toluene trifluoro such as yi. The original halogens 3 to 3 containing the protective base protecting the base 3 to 3, the first base, etc., this base. Carboxypropyl isopropyl, alkenyl and propyl, methyl bromide 7 (e.g. carbonylcarbonylarylarylmethylene, methyl) > Ammonium bromide, dichlorobenzene This is substituted for isopropylnitroethyl 'methyl a Such as / ί, alkyl alkyl benzene, halogen benzene, chloro, fluoroalkane, silicon (Please read the precautions on the back before filling out this page). Examples of hydroxy groups include carbonyl such as fv, aryl, aryl, tolyl, methyltriylcarbonyl, alkyl-6, C1, alkenyl, and carbonyl such as tolyl. Aryl 10 alkane 7-sand C-based, alkane tri- and sulfanyl, carbonyl ethanyl,). Ethyl bromide 'chloro 7 ′ gas groups such as propane (itl heterogen, primary halopropyl, 3 groups) To B1, via carbamoyl », such as base 8 (¾yl-6yl C1Η, three I

Use the encapsulation method to improve the method or the method of the method, and know the ^ B group as a methyl-phenylene, such as hydration and protection, etc. This IX I 7 C-based alkane is aromatically substituted to obtain the methyl nitrite sodium methylamine thiodiyl group. Formazan-except, transfer hydrazine * benzene method, hydrazine, isoline palladium-exogen acid violet ethyl, \ ortho ammonium kantin, tetrabasic, fluoric acid, this paper size applies Chinese National Standard (CNS) A4 specifications ( 210X297 mm) 54 39 22 1 A7 ____B7_ V. Description of the invention (55) The compound obtained by the above reactions of the present invention can be converted into salt according to conventional methods; if salt is obtained, it can be converted into salt according to conventional methods Free form or another salt. The obtained compound (I) can be isolated and purified from the reaction mixture according to generally known methods, such as extraction, concentration, neutralization, purification, recrystallization, column chromatography and thin-layer chromatography. The salt of the compound (I) can be prepared in a generally known manner, for example, by adding one of the aforementioned inorganic acids or organic acids to the compound (I). The compounds (III) and (IV) used as the starting compounds in the above method A can be prepared according to, for example, the method described in U.S. Patent No. 4,584,385, or a method like M thereof. The compound (V) used as the starting compound in the above method B can be printed according to, for example, the Journal of Medicinal Chemistry, the Central Standards Bureau, Ministry of Economic Affairs, and the Consumers' Cooperatives (please read the precautions on the back first) (Fill in this page again) 21, 82 (1978) or Chemical Letters, 166 (1980) or a similar method, prepared; compound (VI) can be obtained according to, for example, Journal of Organic Chemistry (Issue), Issue 360, p. 8 (1979), or a method similar thereto; compound (VII) can be obtained according to the Journal of the Chemical Society), 9 5, 132 (1909), or a method similar to that of M, was prepared. (In addition to the above method, compound (I) can also be prepared according to the method described in US Patent No. 4,584,385 or a similar method. Although compound (I) can be prepared according to the above-mentioned chemical method, it can also be prepared using microorganisms In the compound of formula (I), indole may be applied in accordance with the Chinese paper standard (CNS) A4 specification (210X297 mm) according to this paper size. 5 5 3 9 2 2 1 4649 Α7 Β7 Employees of the Central Bureau of Standards, Ministry of Economic Affairs Printed by Consumer Cooperatives 5. Description of Invention (56) Literature [KVRao, Antibiotics and Cheaotherapy (Washington), ULSS, 312 pages (1960); WS Marsh et al., Id., No. 10, 316. (1960); Schach von Wittenau, M. et al., Journal of the American Chemical Society (J, Am. Chem. Soc.) 6_3JI, 467 8 pages (1961), same book, 3 425 pages (1 9 6 3 years)], using the producer strain Streptomyces grisftiis subsp. Griseus ΐ ATCC 1 264 [American Type Calture Collection Catalogue of Bacteria & Bacteriophages), No. 18, 1992], etc., prepared HC-21, a new strain, can also be used as a producer strain. The withdrawn organism used in the method for producing indocyanin of the present invention is a strain of HC- *. · 21 strain (hereinafter also referred to as "" HC-") isolated from soil samples of Tenninfcyo, Asahikawa, Hokkaido 21 strains ">. According to the International Journal of Bacteriology

Journal of SysteBatic Bacteriology), Lfi_ (3), pages 313 ~ 3 40 (1960), the special emblem of the HC-21 strain is as follows: Unless otherwise specified, culture medium observations are cultivated on 14 days Period and under 281. (I) Morphology: The aerial mycelium has been extended and the branched basal fungi's body has been extended into simple branches, with a slightly wavy or spore-like spore spread at its apex (usually 10 to 50 brussels). . No infusion was seen. The spores are columnar (1 · 1 to υχ (please read the precautions on the back before filling out this page) > -Order. The size of this note is in accordance with Chinese National Standard (CNS) A4 (210x297 mm) 5 6 3922 1 'Λ 6 46 49 Α7 B7 V. Description of the invention (57) 1.4 to 1.5 microns) and a spiny surface. (I I) Cultivation properties The growth degree (G) of each medium, the growth condition and hue of aerial mycelium (Am), the presence or absence of soluble pigment (SP), and the hue are described below. When describing colors, the standard tone symbols in parentheses and the Color * Harmony Manual of Container Corporation of America, 4th edition, 1958 are used as the basis. Table 1 U) Sucrose-G: Inferior, milky white (2ca) Nitrate-Am: Agar-free medium R: Milky white (2ca) SP: None {Please read the precautions on the back before filling in this I)-Amine sugar Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs of the Ministry of Economic Affairs of the People's Republic of China. Bn Jean G: Good, milky white (2ea) Am: Good, milky white (2ea) R: Light yellow (2ia) to yellow brown (3na ) SP: None-based amine cultivation > Anthracite oil winter fat Gan Tianqiong This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) G: Good, yellow-brown (3ic) Am: Good, yellowish-gray (2sc) R: yellow-brown (3 la) to brown (41a) SP: no δΐ 39 22 1 46 4649 a? B7 V. Description of the invention (58) (d) Starch-G: Medium, milky white (2ec) inorganic salt -Am: medium, light greenish gray (2cb) agar medium R: light yellowish brown (2ga) to light yellowish gray (2gc) SP: no (e) glycine-G: good, light yellowish brown (2ga) agar medium Am: milky white (2ea) R: light yellow brown (21a) to yellow brown (31c) SP: no (f) nutrient fortified agar G: medium, light gray red brown (5ic) medium Am: inferior White R: light gray-brown (4s a) to red-brown (6〗 a) SP: no (g) yeast extract G: good, yellow-brown (4ia) printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read first Note on the back, please fill out this page again) ——Malt extract Am: Medium, light gray brown (5ga) to gray yellow brown (4ge)-Agar medium R: yellow brown (31a) to red yellow brown (5pa) SP : No (h) oats-G: Good, light gray brown (4gc) Agar medium Am: Medium, light red white (5ea) to gray Paper size Applicable to Chinese National Standard (CNS) A4 specification (2i0 × 297 mm) 58 3922 1 464649 A7 B7 V. Description of the invention (59 brown (5 gc) bright red ochre (6ia) to gray grazing (5gc) SP: no (i) protein aging-yeast extract A * ti-iron-agar medium (Please read the notes on the back before filling in this X) G: Medium, Milky white (2ea >, Partial Am: No R: Light yellow building color (2ga) to yellow-gray brown (3U SP: None (11 I) Physiological properties (a) Growth temperature range: 11 to 29¾ Optimum growth temperature range: 18 to 24 (b) Nitric acid reduction reaction: weak positive (c) gelatin liquefaction: negative (glucose) Glucose-Protein-Gelatin Media) (d) Starch hydrolysis: negative (e) Skim milk coagulation: negative Skimmed milk glandification printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs: negative (f) melanin-like pigment formation Tyrosine-agar medium: negative protein Chen-yeast extract iron-agar medium: negative U) carbon source assimilation [agar medium containing pridham and sotlieb] This paper is applicable to China National Standard (CNS) A4 specification (2I0X297 mm) 59 39 22 1) 4649 A7 B7 V. Description of the invention (60) L-arabinose D-xylose D-glucose D-fructose sucrose inositol L-rhamnose cotton Seed sugar D-mannose alcohol photo group (Note) +: (Please read the precautions on the back before filling out this page) The central government bureau of the Ministry of Economic Affairs's consumer co-operative prints have excellent growth and significant growth + or one cannot Confirmation :: Immune (I) (IV) cell analysis According to the method of Hasegawa et al. [Journal of General Applied Microbiology 29th issue, pages 319 ~ 322 (1983), hydrochloride hydrolysate identified in the cells Diamine Pimelic acid as LL- configuration. Judging from the above results, especially based on light yellow-brown to gray-brown aerial cryptofilaments, slightly undulating or transmissive spore chains, surface of spinous spores, diaminopimelate into LL-configuration, and other findings, It was proved that this strain was streptomyces; and this strain was named Streptomyces HC-21 strain (Strept 〇mycessp. HC-2 1) 〇 The paper size of the paper is applicable to Chinese national standards (CNS > A4 specification (210X297 mm) 60 39 22 1 d 6 4 6 4 9 A7 B7 V. Description of the invention (ei) This streptococcus sp. HC-21 strain t special emblem has the ability to assimilate with L-channeling sugar and The surface of spinous spores. This chain emblem H C-21 strain was deposited at the Institute for Fermentation, Osaka (foundation) under the deposit number IF0-15984 on June 12, 1996. Biao deposited with the National Institute of Bioscience and Human Technology, Agency of Industrial under the registration number FERM BP-5571 on June 25, 1996 at the National Institute of Bioscience and Human Technology, Agency for Industrial Science and Technology, Ministry of International Trade and Industry, Japan. Science and Technology, Mini stry of International Trade and Industry of the Japan) [1-3, Higashi-l-chome, yatabe, Tsukuba City (1-3, Higashi-l-chome, yatabe, Tsukuba City, Tsukuba City, Ibaraki Prefecture (Please read the precautions on the back before filling out (This page), • 11 The Central Aggregate Bureau of the Ministry of Economic Affairs, the Consumers ’Cooperative Co., Ltd. prints ag products, and requires a large shed, ia ransu only to adapt, but the line emblem is better than sugar self-emission or solidification. Buds can be cultivated with x ^ g · ind, wheat can be cultivated by h method, S3-line produced liquid glucosides can be used for liquid camps, and can be used as δ and only base but The sugar is the same as that of the nutrient. It is cultivated by the same method. The milk is cultivated in the form of cocoa, and the material is cultivated by β. The sugar is supplemented by sugar. The amount of Portuguese re is the same. 1 ^ Each of each. The combination of micro, tu is different, the method of cultivation can be reached, such as the ec fungus, the hair base, such as ef, the fine nutrient properties obtained by the line ΓΓ 靥Into M medicine, Ming Yi Ke Pei Wu contains .1 bacteria agent containing hair, strain. Machine package ak emblem change, change the nature of mycological passive ar chain process M method, although the use of the use, carbon lb use f management / can-the model source >. Or γ all contain regular nitrogen This paper size applies China National Standard (CNS) A4 specification (210 X 297 mm) 6 1 392 2 1 464649 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (62) 1 I refined starch glycerol mannose fermented sorbose Fermented oils and fats (eg, 1 1 soybean oil, olive oil, rice bran oil, sesame oil, refined lard, chicken oil); 1 1 nitrogen sources include: for example, 1 meat extract, yeast extract, dry yeast, soybean 1 I please 1 1 powder \ Corn syrup a »Protein scented cotton seed powder red sugar molasses urea ammonium cyanide (eg, Longyue 1 | read I ammonium sulfate aerated ammonium% m ammonium acid, ammonium acetate) and others = also suitable for use on the back [1 of 1 inclusive > Salts of potassium, calcium, magnesium, etc. Ϊ Metal salts such as iron, manganese, zinc \ 1 、 Injector 1 matters such as nickel salts, phosphoric acid and other salts * and organic acids such as acetic acid and propionic acid. 1 1 Salt 0 In addition, it can also contain amino acids (such as glutamic acid, > asparagine) Acids, Propionate Page 1 Amino Acid% Leucine Valine Methyl Thiuran Proline), Vitamins 1 (eg, B 1, B 2 '> Nicotinic Acid' B 12 C) Nucleic Acids (For example, purine, pyridine and its derivatives), etc. Of course, in general implementation, it will add inorganic or organic acids, 1 1 Yuanyuan solution and other K to adjust the pH value of the culture medium »and a suitable amount of fat, order | Surfactants etc. lambda defoaming 0 1 I The culture method can be from 1 to 10 for stationary culture, shaking culture, bell culture, etc. For large-scale processing 9 Of course, immersed spin culture (S ubmerged 1 i SP i η ner salt ure) is ideal 0 〇 Although 1 culture conditions depend on the conditions of the medium And composition strain types, 1 1 and culture methods are different but usually the temperature and initial pH are 15 to 1 1 26 and about 5 to 9 respectively. It is preferred that the temperature and initial pH of the middle stage of incubation 1 I be 20 to 25 and about 6 to 8 〇 The incubation period is also different from the above conditions. 1 1 I push m to continue incubation until the concentration of the desired biologically active substance reaches a maximum of 0 1 1 1 When shaking culture or rotary culture is performed using liquid medium t Usually about 1 to 1 1 10 days 0 1 1 The biologically active substance ketinin 9 obtained can be based on its chemical properties, 1 1 β This paper size applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm) 62 69 2 2 1 4 4649 A7 B7 V. Description of the invention (63) Extraction and purification from the cultivating substance. Since indigoxin is produced in culture medium and cells, the purification of this indole hormone can be carried out from culture K or by centrifugation of the culture solution and cells, and the organic solvent is used to extract from the obtained solution or centrifuged supernatant. Or use organic solvents to extract from cells, and separate from each extract or mixed extracts. For industrial manufacturing purposes, it is preferred to directly add an organic solvent such as formazan, acetone, butanol, or ethyl acetate to the culture to purify the indrugin from the resulting extract, and omit the cell isolation operation. Because indigoxin is a weakly alkaline and oil-soluble substance, when collecting it from the culture medium, it is possible to use the separation and purification methods commonly used in collecting related metabolites of microorganisms. For example, a method based on the difference in the solubility of impurities and chromatography using various carriers such as activated carbon nonionic porous resin, silica gel, alumina, and dextran gel can be used alone or in combination. Printed by J Industry Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs (please read and read the notes on the reverse side, and then fill out this page). The method for the isolation and collection of indigo emblem from the culture medium is detailed below. First, the cells are removed by filtration from the culture solution; the resulting supernatant solution is adjusted to a suitable pH value; a solvent such as ethyl acetate is added, and then vigorously searched to obtain an ethyl acetate layer. The obtained organic layer was sequentially washed with alkali, acid, and water, and then concentrated; the obtained concentrate was subjected to silica gel column chromatography. Useful developing solvents include, for example, a chloroform-methanol or hexane-acetone mixed solvent, which effectively distinguishes the concentrate after collection and concentration, and performs Sephadex LH-20 chromatography. Useful development solvents are formic acid and mixed solvents such as hexane-toluene-methanol and hexane-dichloroformamidine-methanol. After concentration, the eluate containing effective differentiation was purified by preparative high performance liquid chromatography. The packing column used here is ODS-S Η 3 43 S-15 (manufactured by Yainamura Kagaku Kenkyujo); the solvent used is the paper standard applicable to the Chinese National Standard {CNS) A4 specification (2! 0X 297 mm) ft 3 3 9 2 2 1 4 b 46 4-9 A7 B7 V. Description of the invention (64) is a mixture of 0.02M phosphate buffer (pH6.3 >) and 26% acetonitrile. 官 旆 本 发明 ^ 最 住 椹 忒 ( Please read the precautions on the reverse side before filling out this page) The following examples, test examples, and formulation examples are used to describe the present invention in detail, but the scope of the present invention is not limited by this. In the following, "room temperature" refers to 15 to 3 0t) 〇 [Example] 謇 抡 Example 1 The consumption cooperation of employees of the Central Bureau of Standards of the Ministry of Economic Affairs, Du-printing-the amount of platinum ring is preliminarily sufficient on the slanted medium composed of yeast extract-malt extract-agar The growing Streptomyces HC-21 strain was inoculated into a sterile 2 liter Sakaguchi flask containing 500 ml of inoculation medium (PH7.0) (this inoculation medium consists of 2% glucose, 3% soluble starch, 1 Composition of% corn pulp, 1% fresh soybean flour, 0.5% polyprotein, 0.3% sodium gasification and 0.5% precipitated calcium sulphate) The reciprocal shaking at 24¾ the oscillator incubated for 2 days. In this 500 ml culture medium, 120 liters of basic medium (P Η 7.0) was injected, and the basic medium was composed of 2.0% glucose, 3.0% soluble starch, 1.0% defatted soybean flour, 0.3% corn pulp, 0.1 % Yeast Extract, 0.5% Polyprotein, 0.2% Oatmeal Agar, 0.3% Sodium Chloride, 0.5% Precipitated Calcium Phosphate, 0.05% ACTC0L 31-56 (manufactured by Takeda Pharmaceutical Industry Co., Ltd.) and 0.05% Polycarbonate The composition of silicon and oxygen was then transplanted into a sterile 200 liter fermentation tank, and cultivated under the conditions of temperature, 1. 厘米 kg / cm2 internal pressure, 120 liters / minute aeration rate, and 120 pm mixing rate. The obtained 120 liters of the culture solution was filtered with Hyflo Super Cel to obtain 110 liters of filtrate. This filtrate was adjusted to pH 3.0 with dilute sulfuric acid; an equivalent amount of ethyl acetate was added. The size of the paper was adapted to Chinese National Standard (CNS) A4 specifications (210 X 297 mm) 64 39 2 2 1 Stone 4 6 4 · 9 a7 B7 V. Description of the invention (65) (Please read the precautions on the back before filling in this page), then stir vigorously to obtain 80 liters of ethyl acetate The ethyl acetate layer was washed with 30 liters of 2% sodium bicarbonate solution, and then 30 liters of 0.02H hydrochloric acid was dissolved. After washing, washing with K water was completed, and then reduced under reduced pressure to obtain about 30 g of concentrate. This Ma shrink was passed through a silica gel column (0.8 liter) to adsorb the active ingredient, followed by K 4 liters of hexane-acetone (80: 20), 4 liters of hexane-propanone (50:50) and 4 liters of hexane-acetone (20:80). Effectively distinguish after mixing, and reduce the pressure to obtain 1.53 g of concentrate. This concentration The product was dissolved in methanol; the resulting solution was passed through a Sephadex LH-20 (manufactured by Pharmacia, Sweden) column (2 liters), and washed in advance; the effective dissolution from 1.3 liters to 1.7 liters was mixed with K, and concentrated under reduced pressure to obtain 49 0 mg powder. This powder is K 0.02H osmate buffer solution (PH6.3) and a solvent system of 26% acetonitrile. Preparative liquid chromatography (Hitachi model L-6 2 50, Detector 1- 4000, ¥ »10 Pack, ODS SH343 S-15 120A, 214 nm) is further expanded (20 ml / min, 20 ml division) to obtain a valid distinction (differentiation between 30 and 39). After removing acetonitrile, effective discrimination It was washed with water and extracted with ethyl acetate; the ethyl acetate layer was concentrated under reduced pressure to obtain 315 mg of crystalline indigoxin. Analysis of Printed Elements of Employees' Cooperatives of the Central Bureau of Standards of the Ministry (C 14H 15N302): Calculated: C, 65.35; 35, 5.δ8; H.16.33 Measured: C, 65, 14; H, 5.87; N, 16.p7 The physicochemical properties are consistent with those of indigoxin. When Example 2 (5S) -2- (N-benzyloxycarbonyl-N-methyl) amino-5 [(1R) -1- (b3 丨 睬 -3-yl) ethyl] -2 -_ Oxazoline-4-鬭 This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) 65 3 92 2 1 a 4 6 4 9 A7 B7 V. Description of the invention (66) (Please read the note on the back first Please fill in this page again) Solution of Indigo Huixin Π 100 mg) in tetrahydrofuran (5 ml), cooled to -30t :. In this cooled solution, triethylamine (0.217 ml) and benzooxycarbonyl chloride (0.167 ml) were added dropwise at -30¾. Warm all to 0¾ and stir for 80 minutes. Ethyl acetate was added to the reaction mixture. The mixture was washed with water, a saturated aqueous sodium hydrogen carbonate solution and a common salt solution, respectively, and then the ethyl acetate solution was dried over magnesium sulfate. The organic solvent was removed, and the obtained residue was recrystallized from isopropyl ether to obtain the title compound (115 mg, 75.5%). The melting point was 136 to 138C. IRtKBrJcm-1: 3299, 1748. 1 Η-NMR (CDC 1 3) δ: 1.3 9 (3 H, d, J = 7. 2 Η z), 3.34 (3Η, s), 3.81-3.93 (1Η , m), 5.10 (1Η, d, J = 2. 8Ηζ), 5.31 (2H, s), 6.97-7.40 (8H, m), 7.62 (lH, d, J = 7.4Hz), 7 '95 (1Η , Bs) Example 3 The consumer cooperative of the Central Standards Bureau of the Ministry of Economic Affairs printed the same procedure as in Example 2 to prepare the following compounds. (5S) -2- (H-ethoxycarbonyl-K-methyl) amino-5 [(1R) -1_ (indio-3-yl) ethyl] -2-oxazolam-4 -fluorene, IR (KBr) ciB-1: 329 3, 1 769, 1 7 38. 1 H-HHR (CDC Is) θ: 1. 3 4 (3 Η, d, J = 7 0 Η ζ), 1.41 (3H, t , J = 7.2Hz), 3.32 (3H, s), 3.88 (1Η, ιπ), 4.35 (2H, q, J = 7.2Hz), 5.10 (lH, d, J = 2.6Hz), 7.07-7.26 (3H , m), 7.36 (lH, d, J = 8.2Hz), 7.67 (1H, d, J = 8.2Hz), 8.15 (lH, bs). This paper size applies to China National Standard (CNS) A4 specification (210X297 Mm) 66 39 22 1 4 υ 4 6 4 9 a? B7 V. Description of the invention (67) (5S)-5- [(1R) -1- (indio-3-yl) ethyl] -2- (N-isopropoxycarbonyl-N-methyl) amino-2-η and other oxazol-4-ones, IR (KBr) cnr 1: 3 2 7 2, 1 73 2. 1 H-HHR (CDC 1 3) 5: 1.36 (6H, d, J = 6.4Hz), 1.43 (3H, d, J = 7.4Hs), 3.31 (3H, s), 3.91 (1 H, m), 5.08 (1H, ib), 5.12 (lH, d, J = 2.6Hz), 7.07-7.35 (3H, i), 7.37 (lH, d, J = 8.0Hz), 7.67 (1H, d, J = 7.8Hz), 8.17 (lH, bs). (5S) -2- [it- (2-ethylhexyloxycarbonyl) -H-methyl] amino-5-[(lR) -1- (B3Ifluoren-3-yl) Ethyl] -2 -b oxazoline-4 -fluorene, IR (KBr) cm-1: 32 9 8, 1 769, 1 742. iH-HMRCCDClajS: 0.90 (6H, t, J = 7.6Hz), 1.26-1.60 (9H, m), 3.29 (3H, s), 3.90 (lH, m), 4.19 (2H, d, J = 5.8Hz), 5.12 (lH, d, J = 3.0Hz), 7.06-7.38 (4H, m), 7.66 (lH, d, J = 7.6H2), 8.14 (1H, bs). Central standard of the Ministry of Economic Affairs Printed by the Bureau's Consumer Cooperative (please read the precautions on the back before filling out this page) (5S) -2- [N- (4-Ethyloxybenzyloxycarbonyl) -N-methyl] amino-5- [(IR) -1-(Indino-3-yl) ethyl] -2-oxazolin-4-one, IR (KBr) c®-1: 3 3 33, 1 746. ^ -NHRiCDCls) ^ : 1.24 (3H, d, J = 7, .4Hz), 2.41 (3H, s), 3.50 (3H, s), 3.80 (lH, m), 5.09 (lH, d, J = 2.8Hz), 5.30 ( 2H, s), 6.52 (lH, d, J = 2.2Hz), 7.03-7.46 (7H, m), 7.57 (1H, d, J = 7.6Hz), 8.56 (lH, bs). This paper is applicable to China National Standard (CNS) A4 Specification (210X297 mm) 67 39 22 1 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 464649 V. Description of Invention (68) '(5S) -5-[(1R) -1- (b Preferred 3-yl) ethyl] -2- [N- (4-nitrobenzyloxycarbonyl) -N-methyl] amino-2-umolinolin-4-one, IR (KB r) cb -1: 3 2 9 9, 1 7 7 3, 1 7 4 6 · iH-HMR (CDC 1 3) 5: 1.44 (3H, d, J = 7. 2 Ηζ), 3.35 (3H, s), 3.90 (1Η, ιι), 5. .1 5 (1 Η, d, J = 2. 6 Η ζ), 5. 37 (2Η, s), 7 . 0 3-7. 2 4 (3 Η, m), 7.37 (lH, d, J = 8.2Hz), 7.47 (2H, d, J = 8.8Hz), 7.64 (1Η, d, J = 8 4Ηζ), 8.10 (lH, bs), 8.14 (2H, d, J = 6.8Hz). (5S) _5-[(lli) -1- (indio-3-yl) ethyl] -2- ( N-methyl-N-benzyloxycarbonyl) amino-2 -oxazolyl-4 -fluorene, IR (RBr) car 1: 328 1, 1 77 9, 1 746. IH-HHR (CDCla) δ: 1.45 (3Η, d, J = 7.2Ηε), 3.47 (3H, s), 3.91 (lH, m), 5.15 (lH, d, J = 3.0Hz), 7.03-7.49 (9H, m), 7.67 (lH, (d, J = 7.4 Hz), 8 · 05 (1H, bs). Example 4 (5 S) -5-[(lR) -l- (B fluoren-3-yl) ethyl] -2- [N- (N- (4-methoxybenzyl) aminomethyl) -N-methyl] amino-2 -n-oxazoline-4-indigoxin (150 mg) and dichloromethane To the (3-stretched) mixture was added 4-methoxyphenyl isocyanate (261 mg >) under ice-cooling. After the mixture was stirred at room temperature for 2 hours, the solvent was removed by distillation to obtain a residue. After adding isopropyl ether to the residue, the title compound was obtained as a crystal (213 mg, 89.9%). — ^ 1- ^^ 1 «^^ 1 ^^ 1 ^^ 1 ^^^ 1.--N ^ im In V, (Please read the precautions on the back before filling this page) This paper size is applicable to China Standard (CNS) A4 size (210X 297 mm) 68 392 2 1 '' 464649 A7 B7 Printed by the Consumers ’Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of invention (69) (CDCl3) δ: 1.48 (3H, d, J = 7.0Hz), 3.34 (3H, s), 3.78 (3H, s), 3.95 (1 H, m), 5.08 (lH, d, J = 3.0Hz) , 6.83 (2H1d, J = 9.2Hz), 7.11- 7.40 (6H, m), 7,67 (lH, d, J = 8.4Hz), 8.21 (lH.bs), 11.21 (lH, bs). When skimming Example fi According to the same procedure as described in Example 4, the following compound was prepared. (5S) -2- [N- (H- (4-chlorophenyl) aminomethylmethyl) -N-methyl] amino-5 -[(lR) -2- (indio-3-yl) ethyl] -2-oxazolin-4-one, IR (KBr) cm-1: 337 2, 1 7 1 3. 1H-HMR ( CDC 1 3) a: 1.49 (3H, d, J = 7.4Hz), 3.34 (3H, s), 3.97 (lH, m), 5.09 (1H, d, J = 3.2Hz), 7.15-7.47 (8H, m) t 7.67 (lH, d, J = 7.4Hz), 8. 17 (lH.bs), 1 1 .48 (1H, bs). (5S) -5-[(lR) -l- (ind -3-yl) ethyl] -2- [NU- (2-phenethyl) aminomethyl) -N-methyl] amino-2 -B, etc. -4- plane, IR (KBr) cm-1: 3 243, 1 7 1 3. ^ -NHR (CDCls) 8: 1. 4 4 (3 Η, d, J = 7.4 Η z), 2.82 ( 2H, t, J = 8.0Hz), 3,28 (311,3) (, 3.47 (2H, ra), 3.91 (1H, id), 5.02 (lH, d, J = 3. 0Hz), 7.11 -7.40 (9H, m), 7.65 (lH, d, J = 7.8Hz), 8.15 (1H, bs), 9.33 (1H, bs). (5S) -2- [H- (N- (2,4 -Dimethoxyphenyl) aminoformyl) -N-methyl] (Please read the precautions on the back before filling this page)

This paper size applies Chinese national standards (CNS > A4 size (210 × 2ί »7mm) 69 39 22 1 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 4 6 4 6 4 9 Α7 Β7 V. Description of the invention (70) Amine -5-[('1 R) _- l- (i) -3-yl) ethyl.]-2-Df Porphyrin-4- _, IR (KB r) c 1-1: 3 3 9 7, 1 7 1 1. ^ -NHRCCDCls) ^: l, 45 (3H, d, J = 7.2Hz), 3.37 (3H, s), 3.79 (3H, s), 3.89 (3H, s), 3.92 (lH, m), 5.07 (lH, d, J = 2.8Hz), 6.42 ~ 6.47 (2H, m), 7.14-7.26 (3H, m), 7.39 (lH # d, J = 7.4Hz), 7.69 ( lH, d, J = 6.8Hz), 7.90 (lH, d, J = 9.2Hz), 8.14 (lH, bs), 11.45 (lH, bs). (5S) -2- [N- (N- (7 -Ethoxycarbonylheptyl) carbamoyl) -N-methyl] amino-5-[(lR) -1- (indio-3-yl) ethyl] -2-morphazoline-4- Ketone, IR (KBr) cm " 1: 3 235, 1 7 1 6. ^ -NMRtCDCU) d: 1.17-1.32 (9Htm), 1.45 (3H, d, J = 7.4Hz), 1.50-1.72 (4H, m ), 2.30 (2H, t, J = 7.4Hz), 3.20 (2H, m), 3.28 (3H, s), 4.13 (2H, q, J = 7.0Hz), 5.02 (lH, d, J = 3.0HE ), 7.10-7,25 (3H, m), 7 * 38 (lH, d, J = 7.6Hz), 7.65 (lH, d, J = 7.8Hz), 8.34 (lH, bs), 9.18 (lH, bs). Examples of β (5S) -5-[(lR) -l- (indio-3-yl) ethyl] -2- (H- ( 4-trifluoromethylbenzyl) -fluorene-methyl] amino-2-B and other oxazoline-4-_ < indoxacin (150 mg), triethylamine (325 μl), To a fully stirred mixture of 4-dimethylaminopyridine (39.8 mg) and tetrahydrofuran (10 ml), add 4-trifluoromethylbenzidine chloride (260 µl) under ice cooling and stir the mixture at 0¾ for 30 minutes Add ethyl acetate. All are water and saturated respectively (please read the notes on the back before filling this page) The size of the paper is applicable to the Chinese National Standard (CNS) A4 specification U10X297 mm) 7 0 3922 1 A7 B7 V. Description of the Invention (Ή) (Please read note f on the back before filling out this page} Wash with sodium bisulfate aqueous solution and common salt solution, then dry the ethyl acetate solution with magnesium sulfate. The organic solvent was removed, and the obtained residue was subjected to silica gel chromatography. Isolation with hexane-propane (4: 1>) to obtain the title compound (176 mg, 70.4%), melting point 146 to 148 ° C. IRiKBrJcm'1: 3390, 1749, 1714. ^ -HMR (CDCla) δ: 1 42 (3Η, d, J = 7.2Hz), 3. 41 (3Η, s), 3.7 7-3.8 9 (1 Η, m), 4.92 (lHfd, J = 2.8Hz), 6.64 (lH, d , J = 2.0Hz), 7.13-7.56 (8Η, m), 8.03 (1Η, bs). Fendam 7 According to the same procedure as described in Example 6, the following compounds were prepared. (5S > -5-[( lR) -l- (indio-3-yl) ethyl] -2- (N ~ (2-trifluoromethylbenzyl) -K-methyl] amino-2 -oxazoline-4 -Ketone, IR (KBr) cm-1: 3287, 1 7 48, 1 7 1 7. ^ -NMRiCDCls) ^ 1.23 (3H, d, J = 7.2Hz), 3.51 (3H, s), 3.68 (1H , b), 4.87 (1 Η, d, J = 2.8Hz), 6.60 (lh, d, J = 1.8Hz), 7.08-7.26 (3H, m), printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs7. 36-7.61 (5H, m) t 8. 02 (1H, bs). (5S) -5-[(lR) -1- (indio-3-yl) ethyl] -2- [N- (3 -Trifluoromethyl i-methylfluorenyl-methyl] amino- 2-D oxazolidine-4, IR (KBr) cm-1: 3 33 5, 1 7 1 5. 1 Η-Η MR (CDC 1 3) S: 1. 3 7 (3 Η, d, J = 7. 2 Η z) · 3.41 (3H, s), 3.78 (lH, ra), 4.91 (1 , dJ = 3.4Hz), 6.62 (lH, d, J = 2.2Hz), 7.11-7.40 (5H, m), this paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 71 39 22 1 4 6 4 6 4 9 A7 B7 V. Description of the invention (72) 7.51 (lH, d, J = 8.0Hz), 7.73 (lH, d, J = 7.4Hz), 7.78 (1H, s) v 8.00 (1H , bs). (Please read the precautions on the back before filling this page) (5S) -2- [N- (4-fluorobenzyl) -U-methyl] amino- 5-[(lR) -l-(Xiayi-3 -yl) ethyl] -2-Bfazole command-4-_, IR (KBr) cm ~ 1: 3300, 17 4 1, 1 707.1 1H-NHR (CDCla) δ: 1.44 (3H, d, J = 7.4Hz), 3.38 (3H, s), 3.76-3.90 (1H, m), 4.93 (lH, d, J = 3.0Hz), 6.76 (lH, d, J = 2.4Hz ), 6.92-7.00 (2H, m), 7.09-7.27 (4H, m), 7.40 (lH, d, J = 8.0Hz), 7.56 (lH, dtJ = 7.2Hz), 8.13 (1H, bs) (5S) -2- [N- (4-Azobenzyl) -N-methyl] amino- 5-[(lR) -l-(»51 Preferred-3-yl) ethyl]- 2-Zoxazolin-4-one, IRUBrOc®- 1: 3296, 1746, 1705.. 1 H-HMR (CDC Is) δ: 1.42 (3Η (d, J = 7.4Hz), 3.38 (3H, s), 3.75-3.86 (lH, m), 4.93 (lH, d, J = 3.0Hz), 6.70 (lH, d, J = 2.6Hz), printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 7.09-7.28 ( 6H, a), 7.40 (lH, d, J = 7.8Hz), 7.55 (1H, d, J = 8.OHe), 8.09 (lH, bs). (5S) -5-[(1R) -1- (b3 丨 睬 -3-yl) ethyl] '-2 -[N- (4-methylbenzaldehyde) -N-methyl] amino-2-D and other oxazolin-4-ones, IR (KBr) cm-1 ^ 3 300, 17 44, 1 703. 1 H-HMR (CDC Is) δ: 1.36 (3H, d, J = 7.4Hz), 2.39 (3H, s), 3.38 (3H, s), 3. 7 1-3.83 (1 H, m), this paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 72 3 922 1 A7 B7 4 6 4 6 4 Φ 5. Description of the invention (73) 4.89 (lH, d, J = 3.0Hz) , 6.59 (lH, d, J = 2.2Hz), 7.06- 7.38 (7 H, id), 7.50 (lH, d, J = 8.4Hz), (Please read the precautions on the back before filling this page) 8.00 (1 Η, bs). (5S) -5-[(lR) -1- (indio-3-yl) ethyl] -2- [N- (4-methoxybenzyl) -N-form Amine] amino_2-D, etc., _4__, IR (KBr) cm-1: 329 9, 1 744, 1 7 01. ^ -NHR (CDCla) δ: 1. 39 (3Η, d, J = 7.4Hz), 3.38 (3Hts), 3.82 (3H, s), 4.91 (1 Η, d, J = 2.8 Ηζ), 6.67 (lH, d, J = 2.2Hz), 6.81 (2H, d, J = 8.8Hz), 7.06- 7.26 (3H, m), 7.36 (2H, d, J = 8.8Hz), 7.52 (1Η, d, J = 7.4Ηζ), 8.01 (lH, bs). (5S)- 2- (N-Cinnamonyl-N-methyl) amino-5-[(1R)- 1- (b3 丨 taste-3 -yl) ethyl] -2-oxazol-4-one, IR (KBr) cm * 1: 339 5, 1 753, 1 6 8 2, 1 6 1 5. (CDC 1 s) δ: 1.46 (3Η, d, J = 7.2Ηζ), 3.38 (3Η, s), 3.88-3 · 99 (1Η, m), 5 · 1 4 (1 Η, d, J = 3. 0 Η ζ), 7.0 6-7. 8 2 (1 2 Η, ιη), printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 7.96 (1Η, bs). (5S) -5 -[(lR) -l- (indio-3-yl) ethyl] -2- (N-methyl-N-nicotinylfluorenyl) amino-2-oxazoline-4-one,, 1 IR (KBr) cm-1: 3277, 1 748, 1 703. ^ -NHRfCDCls) ^: 1.48 (3H, d, J = 7.4Hz), 3.37 (3H, s), 3.79-3.92 (lH (m), 4.95 (lH, d, J = 3.4Hz), 6.80 (lH, d, J = 2.2Hz), this paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 73 3 922 1 Λ7 B7 464649 V. Description of the invention (74)? .09-7.58 (6H, nt), 8.12 (lH, d, J = 2.2Hz), (Please read the precautions on the back before filling this page) 8.40 (lH, bs), 8.63 (lH, dd, J = 1.8 & 4.8Hz). (5S) -5-[(lR) -l- (indio-3-yl) ethyl] -methyl-N-phenethylfluorenyl) amine 1-2-oxazoline-4-one, IRUBrOcm · 1: 3 300, 1 724.1 1 H-NMR (CDC U) δ 1.45 (3Η, d, J = 7.0 Hz), 3.25 (3Η, s), 3.8 5 -3.99 (1 Η, a), 4.10 (lH, d, J = 16.6Hz), 4.25 (lH, d , J = 16.6Hz), 5.05 (lH, d, J = 2.8Hz), 6.98-7.39 (9H, m), 7.63 (lH, d, J = 8.6Hz), 8.18 (lH, bs). (5S) -5-[(lR > -l- (indio-3-yl) ethyl] -2- (K-methyl-H- (2-«pan) carbonyl] amino-2 -oxazoline-4 -Ketone, IR (KBr) cm- 1: 329 8, 1 739, 1 672.1 1H-NHR (CDC13) δ: 1.48 (3H, d, J = 7.4Hz), 3.37 (3H, s), 3. 81 -3. 90 (1 Η, m), 4.99 (lH, d, J = 3.0Hz), 6.87-7.66 (8H, m), 8.08 (1 Η, bs). Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (5S) -5-[(lR) -l- (indyl-3-yl) ethyl] -2- (fluorene-methyl-fluorene- (2 -1 * phenyl) ethylfluorenyl] amino- 2-oxazoline- 4- _, IR (KBr) cm- 1: 3 289, 1 726. ≪ ^ -NHRCCDCUJS: 1.49 (3H, d, J = 7.2Hz), 3.26 (3H, s), 3.88 -3.99 (lH, m), 4.34 (lH, d, J = 17.6Hz), 4.51 (lH, d, J = 17.6Hz), 5.09 (lH, d, J = 3.2Hz), 6.80-7.22 (6H , m), this paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 3922 1 74 4 6 4649 at B7 V. Description of the invention (75) 7.38aH, < j, J = 7.4Hz), 7.64 (lH, d, J = 7.6Hz), 8.17 (1H, bs) (5S) -2- (N-heptyl-K-methyl) amino- 5-[(lR) -l- (indyl-3 -yl) ethyl] -2-BMoxazoline-4 -Ketone, IRCKBricm-1: 3275, 1732. ^ -NMRiCDClsJS: 0.88 (3H, t, J = 6.2Hz), 1.18-1.33 (6H, m), 1.47 (3H, d, J = 7.2Hz), 1.55- 1.63 (2H, m), 2.84 (2H, q, J = 5.4Hz), 3.26 (3H, s), 3.87-3.99 (lH, m), 5.07 (lH, d, J = 3.0Hz), 7.09-7.25 (3H, i), 7.38 (lH, d, J = 7.4Hz), 7,65 (lH, d, J = 7.4Hz), 8.14 (lh, bs). (5S) -2- (N -Hex Carbonyl-N-methyl) amino-5-[(lR) -l- (indio-3-yl) ethyl] -2-oxazolin-4-one, IRtKBrici-1: 3320, 1717. 1 Η-_ (CDC 1 3) δ: 1. U-1, 3 9 (6 Η, m), 1.50 (3H, dtJ = 7.2Hz), 1.53-1.83 (4H, m), employees of the Central Standards Bureau of the Ministry of Economic Affairs Printed by a consumer cooperative (please read the precautions on the back before filling out this page) 3.23 (3H, s), 3.46 -3. 60 (1 H, m), 3.8 5-3.99 (1 H, m), 5.06 (lH , d, J = 3.0Hz), 7.09-7.24 (3Htm), 7.37 (lH, d, J = 7.0Hz), 7. 6 5 (1 H, d, J (= 7.6 Hz), 8.11 ( lH, bs). (5S) -5 ~ [(1R) _1- (b Induction-3-yl) ethyl] _2_ (N_methyl-N_dimethylacetamido) amino-2-11 Perylene-4- ·, IR (KBr) cm " 1: 3 287, 1 7 3 6, 1 6 24. This paper size applies to China National Standard (CNS) A4 (210X297 mm) 75 39 22 1 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 6 4649 A7 B7 V. Description of the invention (76) 1H-NMR (CDC 1 3) δ: 1.12 (9Η, s), 1.47 (3H, d, J = 7.4Hz), 3.16 (3H, s), 3.90 (lH, m), 5.02 (lH, d, J = 3.0Hz), 7.08-7.26 (3H, m), 7.36 (lH, d, J = 7.2Hz), 7.64 (lH, d, J = 7.2Hz), 8. 2 7 (1H, bs). (5S) -2- (N-B Aldehyde-H-methyl) amino-5-[(lR) -l- (n3 丨 3-3 -yl) ethyl] -2-11sulfazol-4-one, IRtKBrJcm-1: 3378, 1750, 1722. ^ -NMR (CDCU) δ: 1.47 (3Η, d, J = 7.0 Hz), 2.48 (3Hts), 3.25 (3H, s), 3.94 (lH, m), 5.08 (lH, d, J = 3.4Hz), 7.09-7.22 (3H, ia) t 7.38 (lK, d, J = 7.4Hz) f 7.65 (lH, d, J = 8.0Hz), 8.15 (1H, bs). (5S ) -5-[(lR) -l- (indio-3-yl) ethyl] -2- (N-isobutyl-N-methyl) amino-2 -oxazolin-4-one, IR (KBr) cm-1: 3 300, 1 736, 1 7 25. 1 H-NMR (CDC 1 3) 5 ί 0. 86 (3Η, d, J = 7.〇Ηζ), 1.07 (3H, d, J = 6.8Hz), 1.50 (3H, d, J = 7.4Hz), 3. 2 4 (3 Η, s), 3. 8 6 (1 Η, m), 3. 9 4 (1 Η, m) , 5.05 (lH, d, J = 3.0Hz), 7.09-7.2 3 (3 ^, 11), 7.36 (lH, d, J = 7.4Hz), 7.64 (lH, d, J = 7.4Hz), 8.13 (1H, bs). (5S) -5-[(1R ) -1- (b-fluoren-3-yl) ethyl] -2MN-methyl-N-propionyl) amino-2-imidazolin-4-one, this paper size applies to Chinese National Standard (CNS ) A4 specification (2! 0X297 mm) 76 39221 (Please read the notes on the back before filling this page) Order • \ Ly— A7 464649 B7 V. Description of the invention (77) IR (KBr) cia-1: 33 8 1, 1736, 1 7 2 3. ^ -NMRiCDCls) δ: 1.05 (3H, t, J = 7.2Hz), (Please read the notes on the back before filling this page) 1. 47 (3Η, dtJ = 7.2 Hz), 2.87 (2H, m), 3.26 (3H, s), 3.88-4.00 (lH, m), 5.06 (lH, d, J = 3.0Hz), 7.09-7.25 (3H, m), 7.38 ( lH, d, J = 7.4Hz), 7.64 (1 H, d, J = 7.4Hz), 8.13 (lH, bs). (5S) -5-[(1R) -1- (b3 丨 味 -3- (Yl) ethyl] _2- (N-methyl-N-pyridyl) amino-2 -oxazolyl-4 -one, IRiKBricf1: 3370, 1726. 1 H-NHR (CDC 1 a) 5: 0. 88 (3Η, t, J = 6.6Hz), 1.16-1.19 (26H, m), 1.46 (3H, d, J = 7.2Hz), 2.82 (2H, m), 3.25 (3H, s), 3 9 1 (1 Η, m), 5.06 (1Η, d, J = 3_2Hz), 7.09-7. 21 (3Η, m), 7.37 (lH, d, J = 7.4Hz), 7 .64 (lH, d, J = 7,8Hz), 8. 12 (1H, bs). Examples: "Peace Consumer Consumption Cooperation of the Central Standards Bureau of the Ministry of Economic Affairs. Printed by the agency (5S) -2- [N- ( 2-benzyl benzamidine) -H-methyl] amino-5-[(lR) -1_ (b3 丨 3-3-yl) ethyl] -2-B _ The complete mixture of indigoxin (400 mg), triethylamine (888 microliters) and 4-dimethylaminopyridine (106 mg) in tetrahydrofuran (20 ml) was added. Under ice cooling, add 2-benzyloxybenzoate (1.15 g). The mixture was stirred at Ot; for 40 minutes, ethyl acetate was added. The whole was washed with water, a saturated sodium bicarbonate aqueous solution and a common salt solution, and then the ethyl acetate solution was dried over magnesium sulfate. The organic solvent was removed, and the obtained residue was subjected to silica gel chromatography. Applicable to China Papers (CMS) A4 specification (210X297 mm) on this paper scale 77 39 22 1 4 6 4 6 4 9 A7 'B7 V. Description of the invention (78) Hexane-Bing Gu I (5: 1) Dissolve to obtain the title compound (534 mg, 73.3%). IR (KBr) cm-1: 3 3 0 3, 1 744 t 1701. 1H-NMR (CDC13) δ: 1.15 (3H, d, J = 7. OHz), 3. 40 (3 H, s), 3.65 (1 H, m), 4.68 (1 H, d, J = 2. 6 Hz), 4.97 (2H, s), 6.28 (1H, d, J = 2.6Hz), 6.89 (lH, dtJ = 8.4Hz), 7.04-7.50 (12H, m), 7.85 C1H, bs). Example 9 (5S) -2- [ N- (2-hydroxybenzyl) -N-methyl] amino-5-[(1R) -1- (b3 [fluoren-3-yl) ethyl] -2 -nfazole-4- Keto (5S) -2- [N- (2-benzylbenzyl) methyl] amino-5-_ [(11 {)-1- (hr 丨 睬 -3-yl) ethyl] To a solution of -2-Dizoxan-4-one (420 mTorr) in tetrahydrofuran (10 ml) was added 10% rake-sulfur (300 mg). The gold portion undergoes a hydrogenation reaction, and then the catalyst is removed by filtration. This filtrate was removed by distillation to obtain a residue, which was treated with diethyl ether to obtain the title compound (104 mg, 30.7%), which was crystallized. Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back before filling (This page) IRUBrOcm-1: 3430, 3250, 1752, 1649. 1 H-HHR (DMSO-de) δ: 1.38 (3 Η, d, J = 7.4 Ηζ), 2.59 (3H, s), 3.56 ( lH, m), 4.77 (lff, d, J = 3.0Hz), 6.89-7.8.4 (9 9, πm), 10.62 (lH, bs), 1 0. 8 7 (1 Η, bs) Example 1 10 (5S) -5-[(1I〇-1- (b3 丨 fluoren-3-yl) ethyl] -2- [N- (1-hexahydropyridylcarbonyl) -fluoren-methyl ] Amine-2-Biazolin-4-one This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) 78 3 922 1 4 6 4649 A7 B7 V. Description of the invention (79) (Please read first Note on the back page, please fill in this page again) Indigoxin (150 mg) and triethylamine (324 liters) in a mixture of tetrahydrofuran (7.0 ml), in Ot: aerated 4-nitrophenyl formate ( 353 mg). The mixture was stirred at 0¾ floor for 15 minutes, then hexahydropyridine (173 liters) was added. The gold part was stirred at 0 ° C for another 8 After 20 minutes, ethyl acetate was added. All were washed with water, saturated aqueous sodium hydrogen sulfonate solution, and common salt solution, and then the ethyl acetate solution was dried over magnesium sulfate. The organic solvent was removed, and the obtained residue was subjected to silica gel chromatography. Dissolved in hexane-propanol I (3: 1) to obtain the title compound (154 mg, 71.6%). IR (KBr) cm " 1: 327 9, 1 6 98. 1 H-HMR (CDC 1 3) δ: 1.20-1.75 (9 Η, m), 3.09 -3.35 (5 Η, m), 3.40-3.70 (2 Η, ra), 3.88 (1Η, ι) , 4.99 (lH, d, J = 2.6Hz), 7.10-7.19 (3H, m), 7.34 (1 Η, dtJ = 7.4Ηζ), 7.67 (1 Η, d, J = 8 · 4Hz) , 8.17 (1Η, bs). 啻 抡 M 1 (5 3) -2- [1 (-(11-benzyl carbonyl-[-propylaminoaldehyde bumethyl] amino-5-[(1 {〇-1- (indio-3-yl) ethyl] -2-oxazoline-4-_ printed by N-benzylcarbonyl-L-alanine (893 Mg) and triethylamine (1.11 ml) in a mixture of tetrahydrofuran (10 ml), and ethyl formate (381 tL) was aerated at -15¾. Mix the mixture at -15C for 5 minutes, then add indoxin (257 mg). After all stirring at 0¾ for another 8 minutes, ethyl acetate was added. All were warmed to room temperature and stirred for 40 minutes. Ethyl acetate was added to the mixture. This mixture was washed with water, a saturated aqueous sodium sulfonate solution and a common salt solution, respectively, and then the ethyl acetate solution was dried over magnesium sulfate. The organic solvent is removed, and the paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) 79 3 9 22 1 4 6 46 49 A1 B7 5. The residue obtained by the invention (SO) is subjected to silica gel chromatography. Dissolve in hexane-acetone (4: 1) to obtain the title compound (387 mg, 83.3%). (Please read the notes on the back before filling in this page) IR (KBr) cm- 1 ί 3233, 1 7 1 5. XH-NMR (CDC13) δ: 1.26-1.6 0 (6Η, m), 2.20 (3H , s), 4.14 (lH, m), 5.05-5, 2 4 (4Η, in), 6.69 (lH, s), 7.U-7.36 (9H, m), 7.64 (lH, bs) , 8.11 (lH, s). Fluorene 1 2 According to the same procedure as described in Example 11, the following compounds were prepared. (5S) -2- [N- (H-Benzyloxycarbonylglycinyl) -K-methyl] amino-5-[(lR) -l- (indio-3-yl) ethyl] 2-Hipazolin-4-one, IR (KBr) cm'1: 3 277, 1 7 1 7. iH-NMR (CDC la) δ: 1. 55 (3H, d, J = 7.8 Hz) , _ 2. 44 (3H, s), 3.9niH, d, J = 15.8Hz), 4. 01 (1H, d, J = 15.8Hz), 4.53 (lH, m), 5.11 (2H, s), 5. 2 0 (1 H, m), 6. 6 1 (1 H, s), 7. 1 5-7, 3 4 (9 H, m), 7.62 (1H, m), 8.13 (1H, bs ). Printed by (5S) -2- [N- (H-Benzylcarbonyl-L-leucineamido) -N-methyl] amino- 5-[(lR ) -l- (indio-3-yl) ethyl] -2-Dizolamidine-4-_, IR (KBr) cm-1: 3 300, 1 7 1 7. ^ -NMRfCDClsiS: 0.75 (6H, m), 1.4 4-1.8 1 (6 Η, m), 2.19 (3H, s), 4.14 (lH, m), 5.0 1-5.27 (4 Η, m), 6.67 (lH, s), 7.07 -7.22 (4H, m), 7.33 (5H, m), 7.60 (1H, m), 8.11 (lH.bs).

(5S) -2- [N- (N-benzyl carbonyl-L-amphetamine fluorenyl) -N-methyl] I This paper size applies to China National Standard (CNS) A4 specification (2 丨 0X297 mm) 80 39 2 2 1 Consumption printed by the Central Bureau of Standards of the Ministry of Economic Affairs, including printed by the company 4 6 4 6 49 A.7 B7 V. Description of the invention (SI) Amino-5-[(lR) -l- (B 引 睬 -3 -Yl) ethyl] -2-oxazoline- 4- _, IRtKBricni-1: 337 5, 1719. 1H-HHR (CDC13) 5: 1.31 (1H, d, J ^ 7.4Hz), 1.45 (2H, d, J = 7.2Hz), 3.13 (3H, s), 3.50 (2H, m), 4.42 (lH, m), 4.52 (lH, m), 5.08-5.44 (3H, m), 6.70-7.60 (15H, m), 8.04 (lH, s). (5S) -2- [N- (N-benzyloxycarbonyl-L-proline) -N-methyl] amino-5 -[(lR) -l- (indio-3-yl) ethyl] -2-D | oxazolin-4-one, 332 4, 1 70 1. 1 H-NHR (CDC Is) δ: 1. 28 (1.5., D, J = 7.2Hz), 1.42 (1.5Η, d, J = 5.2Hz), 1.90 (3Htm), 2.39 (lH, m), 3.11 (1.5H, s), 3.30 (1.5H, s), 3.51-3.66 (2H, m), 3.89 (lH, m), 4.89-5.21 (3 Η, m), 5.40-5.52 (1 Η, m), 7. 01-7.36 ( 9H, m), 8.01 (0.5 Η, bs), 8, 1 9 (0.5 Η, bs). (5S) -2- [N- (N-benzyloxycarbonyl-L-7 benzyl Glutaminyl) -11-methyl] amine 5--5-[(11〇-1-(»induction-3-yl) ethyl] -2-oxazolin-4-one, IR (KBr) cm ~ 1: 33 5 4, 1 7 1 9 1 H-NMR (CDC 13) δ: 1.56 (3H, m), 1.75 (2Η, m), 2.17 (3H, s), 2.40 (2H, m), 3.73 (1Ήμ〇), 4. 25 (1 Η, m), 5.00-5.22 (5Η, m), 7.11 -7.34 (14Η, m), 7.64 (lH, m), 8.10 (lH, bs). Examination example 1: ¾ (5S) -2- [H- (N- (L-propylaminofluorenyl) -fluorenyl-methyl] amino- 5-[(lR) -l- (Please read the precautions on the back before filling this page ) 4, ιτ This paper size is applicable to China National Standard (CNS) A4 specification (210 × 297 mm) 81 3 9 22 1 464649 a? B7 V. Description of the invention (82) (Indino-3 -yl) ethyl]- 2-Diazole command -4-_ (5S)-2- [N- (N-benzyloxycarbonylpropylaminoamidino) -H-methyl] amino-5-[(lR) -l- (ind -3-yl) ethyl] -2-Bf oxazoline-4- (387 mg) was added to a solution of tetrahydrofuran (4 ml), and 10% palladium-sulfonic acid (100 mg) was added. All were hydrogenated and then the catalyst was removed by filtration. The filtrate was distilled to remove the residue, and the residue was treated with diethyl ether to obtain the title compound (141 mg, 51.6%) as crystals. IRiKBrJcm-1: 3372, 3287, 1736, 1633.iH-NMRtCDCUJS: 1.26 (3H, dtJ = 7.0Hz), 1.52 (3H, d, J = 7.0Hz), 3.13 (3H, s), 3.80 (lH , m), 4.22 (lH, q, J = 7.0Hz), 4.53 (lH, bs), 7.07-7.22 (2 H, m), 7.36 (lH, d, J = 7.2Hz), 7.72 (lH, d , J = 7.0 Hz), 8.02 (lH, bs), 9.09 (lH, bs). Example 1 4 Following the same procedure as described in Example 13, the following compounds were prepared. (5S) -2- (N-Glycinyl-N-methyl) amino-5-[(lR) -1- (indio-3-yl) ethyl] -2 -_, Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs (please read the precautions on the back before filling this page) IR (KBr) cm-1: 33 33, 1 7 48, 1 63 0. iH-NMR (CDC la) δ: 1.27 (3H, d, J = 7.2Hz), 3.14 (3H, s), 3.80 (lH, m), 4.15 (2H <, s), 4.54 (lH, dtJ = 2.8Hz) , 7.08-7.22 (2H, m), 7.36 (1H, d, J = 7.2Hz), 7.72 (lH, d, J = 7.4Hz), 8.03 (1H, bs), 9 .02 (1H, bs). (5S) -5-[(lR) -l-(«Indene-3-yl) ethyl] -2- (if-L-leucine) The paper size is applicable to Chinese National Standard (CNS) A4 Specifications (210 X 297 mm) 82 3 92 2 1 4 6 4649 A7 ._B7_ V. Description of the invention (83) -N-methyl) amino-2B and other oxazoline-4-_, IRtKBrJci-1 : 3368, 1759, 1644. 1H-NM8 (CDC 1 3) 5: 1.00 (6Η, d, J = 4.8Hz), 1.27 (3Η, d, J = 7.0Hz), 1.63 (lH, m), 1.77 ( 2 Η (m), 3.13 (3Η, s), 3.80 (1 Η, m), 4.18 (lH, dd, J = 3.8 & 9.2Hz), 4.52 (lH, d, J = 2.6Hz), 7.07- 7.21 (2H, m), 7.36 (lH, d, J = 7.4Hz), 7.72 (1Η, d, J = 7.4Ηζ), 8.02 (lH, bs), 9.18 (lH, bs). (5S ) -5-[(lfi) -Bu (indio-3-yl) ethyl]-2-UL-amphetamine-N-methyl) amino-2-oxazoline-4-one, IRCKBricm- 1: 3380, 1707, 1637. 1 H-NMR (CDC 1 3) δ: 1.22 (3Η, d, J = 7.〇Ηζ), 2.93 (1Η, dd, J = 14 · 0 & 8 · 4Ηζ), 3, 04 (3Η, s), 3.32 (lH, d, J = 14.0 & 4.0Hz), 3.95 (lH, m), 4.37 (lH, dd, J = 8.4 & 4.0Hz), 7.07 -7.41 (9H, m), 7.70 (1H, d, J = 8.0Hz), 8.01 (lH, bs). (5S) -5-[(lR) -l- (indio-3-yl) Ethyl] -2-UL-proline 醯 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) 4-ketone, IR (KBr) cm- 1: 3 289, 1 707.1 H-NHR (CDC 1 3) δ: 1.5 1 (3Η, d, J = 7. (4Ηζ), 1.89 (2Η, π), 2.06 (2H, m), 2.78 (3H, s) (3.00 (lH, m), 3.25 (lH, m), 3.80 (2Η, ι), 4. 83 (1 Η, d, J = 3.2 Ηz), 6.59 (lH, s), 7.09-7.21 (3H, m), 7.38 (lH, d, J = 7.4Hz), 7.64 (lH, d, J = 7.8Hz), this paper size applies to Chinese national standards (CNS) A4 specifications (210X297 mm) 83 3 9 22 1 4 6 4649 A? B7 V. Description of the invention (84) 8.13 (1H, bs). 5S) -2- (NL-glutamine-N-methyl) amino-5-((lR) -1- (indio-3-yl) ethyl] -2 -oxazoline-4- Ketone, IRtKBrJcm-1: 3299, 1724, 1623. 1 H-NMR (DMSO-de) δ: 1. 18 (3Η, d, J = 6.8Hz), 2.03 (2H, a), 2.22 (2H, m ), 2.99 (3H, s), 3.66 (1 Η, m), 4.27 (2H, m), 6.91 -7.12 (3H, m), 7.32 (lH, d, J = 7.4Hz), 7.58 (lH , d, J = 6.6Hz), 9.57 (lli, bs). Example of window 1 5 (5S) -5-[(1R) -1- (ii) -3-methyl) ethyl-2- (N-Methanesulfonyl-N-methyl) amino-2-imidazolin-4-one printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Huixin (100 mg) and triethylamine (217 liters) in a mixture of tetrahydrofuran (5 ml), and methanesulfonyl chloride (90. 3 liters) were added at -30 ° C. The whole was stirred at -30¾ for 5 minutes and then at 0 for another hour. Add ethyl acetate to the mixture. The mixture was washed with water, a saturated aqueous solution of sodium bisulfate, and a common salt solution, and then the ethyl acetate solution was dried over magnesium sulfate. The organic solvent was removed to obtain a residue, and isopropyl ether was added to obtain the title compound (74 mg, 57.0%). IR (KBr) cm ~ 1: 330 3, 1 7 48. '. 1 Η-Η MR (CDC 1 3) δ: 1.5 3 (3 H, d, J = 7.4 Η z), 2.88 (3H, s), 3.33 (3H, s), 3.88-3.97 (lH, m), 5.06 (lH, d, J = 3.4Hz) t 7.10-7.25 (3H, m), 7,37 (lH, d, J = 7.0Hz), 7.67 (lH, d, J = 7.8Hz), this paper size applies to Chinese national standards (CNS > A4 size (210X 297 mm) 84 3 9 2 2 1 4 6 4649 A7 B7 V. Description of the invention (85) 8.28 (1 Η, bs). Example 1 β (Please read the precautions on the back before filling this page) According to the same procedure as described in Example 15, the following compounds were prepared. (5S) -2- (N-benzenesulfonyl-N-methyl) amino-5-[(lR) -l- (a3l odor-3-yl) ethyl] -2 -oxazol-4-one IR (KBr) cm-1: 3 300, 1 7 48. VH-NMRCCDClsiS: 1.23 (3H, < i, J = 7.2H ?.), 3. 5 4 (3 Η, s), 3 · 7 6-3. 8 9 (1 Η, m), 4.99 (lH, d, J = 2.6Hz), 7.15-7.78 (10H, i) f 8.12 (1H, bs). Example of window 17 / Consumer Cooperatives of the Central Standards Bureau, Ministry of Economic Affairs Print

A solution of 5- [l- (6-fluoroB3 丨） -3-yl) ethyl] -2-methylamino-2-tazolyl-4-ketonealdehyde (1.0 g) in toluene (7 ml) Add isopropylamine (1.3 g). The mixture was dried over magnesium sulfate and filtered. The resulting filtrate was added to a solution of 6-fluoroindole (3.32 g) in acetic acid (20 ml) under ice-cooling. All were stored in the refrigerator for 3 days and poured into ice water. The mixture was neutralized with 25% ammonia water. All were extracted with ethyl acetate. The obtained extract was washed with a common salt solution and then dried over magnesium sulfate. The solvent was removed to obtain a residue. Ethyl acetate and diethyl ether and the mixture were added to obtain 6-fluoro-3- (1-isopropylamino) ethylindole (1.31 g) as crystals. V 1 H-HHR (CDC Is) S: 1.07 (6H, m), 1. 4 9 (3 Η, d, J = 6. 6 Η z), 2. 8 5 (1 Η, in > , 4.23 (lH, q, 6.6Hz), 6.80-7.10 (3H, m), 7.62 (lH, dd, J = 5.4 & 8.4Hz), 8.12 (lH, bs). The paper size applies to Chinese national standards ( CNS) A4 specification (210X297 mm) 85 3 9 2 2 1 A7 B7 464649 V. Description of invention (86) (Please read the precautions on the back before filling this page) 6 -Fluoro- 3- (1-isopropylamine Methyl) ethyl indene (435 mg), 2-dimethylamino-4-oxo-2-oxazoline-5-carboxylic acid benzyl ester (ΰ 18 mg) in acetonitrile (15 ml) To the mixture was added tri-n-butyl acetone (492 liters). The mixture was refluxed for 2.5 hours. The solvent was removed to obtain a residue, and a mixture of ethyl acetate and ether (10: 1) was added to obtain 2-dimethylformate. Amino-5- [1- (6-fluoro11? 丨 睬 -3 -yl) ethyl] -4-oxo-2-oxazolyl-5-carboxylic acid benzyl ester (509 mg) is Crystallization. ^ -NMR (CDC U) 5: 1.28 (2Η, d, J = 7.2Hz), 1.51 (lH, d, J = 7.2Hz), 2.84-3.26 (6H, ra), 4.24 (1H , ra), 4.99 (1.4H, ABq, J = 4.8Hz), 5.32 (0.7H, ABq, J = 4.8Hz), 6.70-7.70 (9H, m), 8. 14 (0.7H, bs), 8.45 (0.35 H, bs). 2-dimethylamino-5- [1- (6-fluoro hours 丨 except-3-yl) printed by the Central-Quasi Bureau Employee Consumer Cooperative of the Ministry of Economic Affairs ) Ethyl] -4-oxo-2-benzazoline-5-carboxylic acid benzyl ester (500 mg) was dissolved in 15 ml of ethanol and tetrahydrofuran (5: 1). Add 10% palladium-rhenium ( 170 mg). All were subjected to a hydrogenation reaction at normal temperature and pressure for 1.5 hours. All were stirred under 80 scoops of nitrogen for 1 hour, and then the catalyst was removed by filtration. The filtrate was concentrated to obtain 2-dimethylamino-5- [1 -(6-fluoroindio-3-yl) ethyl] -2-Doxazolin-4-one (340 mg). ^ -NMRiCDCla) ^: 1.4 3 (1, 2 Η, d, J = &7; 2 Η z), 1.62 (1.8H, d, J = 7.2Hz), 2.97-3.06 (6H, m),

I 3.60-3.80 (lH, n), 4.90 (0.6H, d, J = 1.5Hz), 4.97 (0.4H, d, J = 1.5Hz), 6.85 (lH, m), 6.90 -7.30 (2H, m ), 7.58 (lH, m), 8.66 (0.4 Η, bs), this paper size applies Chinese National Standard (CNS) A4 specification (2I0X297 mm) 86 3 922 1 A7 B7 4 6 4649 V. Description of the invention (87) 8.67 (0.6H, bs). (Please read the precautions on the back before filling this page) 2-Dimethylamino-5-C1-C6-fluoroindio-3-yl) ethyl] -2-π etc. Zazolin-4-one (340 mg) was dissolved in -10¾ in methylamine (5 ml). The mixture was stirred at the same temperature for 3 hours. The mixture was concentrated, and the obtained residue was subjected to column chromatography. The residue was dissolved in hexane-acetone (1: 1) to obtain the title compound (254 mg). IR (KBr) cm_1: 3195, 1733, 1644, 1627. 1 H-HHR (DHSO-de) δ; 1. 8 (0.9 Η, d, J = 7.2 Ηζ), 1.27 (0.4H, d, J = 7.4Hz), 1.43 (l.lH, d, J = 7.2Hz), 1.49 (0.6H, d, J = 7.2Hz), 2.60-2.80 (3Η, ·) · 3.40-3. 60 (lH, m), 4.80-5.00 (1 Η, t), 6.81 (1Η, «), 7.00-7.2 0 (2Η, m), 7.55 (1 Η, m), 8.50-8. 70 (1 Η, bs), 10.9-11.0 (1 Η, ι). Guan Lunli 1 8 According to the same procedure as described in Example 11, the following compounds were prepared. (5S) -2- [N- (3-Benzyloxycarbonylfluorenal) -H-methylamino] -5-[(lR) -1- (indio-3-yl) ethyl]- 2-oxazolin-4-one, IRUBrOcn-1: 3327, 2 971, 1715, 1557, 1539, printed by Zhengong Consumer Cooperative, Central Standards Bureau of the Ministry of Economic Affairs, printed 1456, 1397, 1316, 1246, 1200, 1 138. NHR (CDCI3) δ 1. 48 (3Η, d, J = 7.4Ηζ), 2. 76-3. 07 (2Η, m), 3.20 (3H, s), 3. ^ 3 0-3. 4 2 (2 Η, πι), 3.93 (lH, m), 5.06 (lH, d, J = 3.2Hz), 5.11 (2H, s), 7.07-7.22 (3H, mJ, 7.30-7.40 (6H, m), 7.62 (1H, d, J = 7.8Hz), 8.24 (lH, bs). (5S) -5-[(1I〇-1- (b3 丨 睬 -3-yl) ethyl] -2- [ N- [3- (N-Benzene paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 87 3922 1 4 6 4 6 49 A7 'B7 V. Description of the invention (88) Carbonyl-N- (Methyl) amino] propanal-methylamino] -2-η and other azoles-4-m, IRUBHcb-1: 3296, 1 700-1 750, 1 646.1 1H-NHR (CDC la) 5 : 1. 38-1.50 (3 Η, π), 2.86 (1.2H, s), 2.90 (1.8H, s), 2.97-3.U (2H, m), 3.16 (1.8H, s), 3.22 ( 1.2H, s), 3.4-3.6 (2H, i), 3.92 (1H, b), 5.04 (lH, d, J = 2.8Hz), 5.13 (2H, s), 6.9-7. 4 (9H, ra), 7.61 (lH, d, J = 7.4Hz), 8.1-8.3 (lH, bs). (5S) -2- [N- (4-Benzylcarbonylaminobutanyl)>-N -Methylamino] -5-[(lR) -l- (indio-3-yl) ethyl] -2-bsilazolin-4-one, 'IR (KBr) cm " 1: 3 3 37 , 2969, 2940, 1 7 1 1, 1 56 1, 1 53 7, 1 45 4, 1 4 3 3, 1 3 97, 1 3 1 4, 1 252, 1 1 92. 1H-NHR (CDC Is) δ: 1.48 (3Η, d, J = 7.4Ηz), 1.64 (2H, m), 2.76 (2H, b), 3.12 (2H, n), 3.23 (3H, s), 3.93 (1H, b), 4.82 (lH, bs), 5.05 (1H, d, J = 3.2Hz), 5.12 (2H, s), 7.00-7.41 (9H, m), 7.62 (1H, d, J = 6.8Hz), 8.35 (lH, bs). Printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) (5S) -2- [N- (4-Benzylbutyryl) -N- Methylamino] -5-[(lR) -1- (b3 丨 fluoren-3-yl) ethyl] -2-Bfoxazolin-4-one, IRtKBrJcm-1: 3400, 1733, 1558, < 1538 , 1456, 1432, 1394, 1209, 1166. ^ -HMRtCDClsiS: 1.46 (3H, d, J = 7.3Hz), 2.52-2.66 (2H, m), 2.99-3.34 (2H, m), 3.24 (3H, s), 3.93 (lH, dq, J = 7.3 & 3.0Hz), 5.06 (lH, d, J = 3.0Hz), this paper size applies Chinese national standard (CNS > A4 specification (210X297) ) 88 3 9 2 2 1 A7 B7 464649 V. Description of the invention (89) 5.12 (2H, s), 7.0 7 -7.38 (9H, m), (Please read the precautions on the back before filling this page) 7. 6 3 (1 H, d, J = 7.2 H z), 8. 1 0 (1 Η, bs). (5S) -2- [N-[(2S) -2,5-double (N- Benzylcarbamyl) pentamyl] -bromomethyl-5-[(11〇-1- (indio-3-yl) ethyl] -2-11 (KBr) cm-1: 3327, 30 64, 303 3, 29 68, 29 39, 2877, 1 7 1 8, 1 52 3, 1 455, 1 388, 1 3 45, 1 26 3, 1 2 2 0 iH-NMRiCDCla) δ: 1.25-1.55 (4 Η, ra), 1.57 (3Η, d, J = 6Hz), 2.33 (3H, s), 2.7 0-2.90 (2 Η, a ), 4.15-4.30 (2H, m), 4.83-5.29 (7Η, ιι), 7. 0 7 -7. 68 (1 5Η, m), 8.12 (1Η, bs). (5S) -2- [N-[(S) -4-benzyl (H-benzylamido) aspartyl] -N-methylamino] -5-[(1 R)-1-(»3 丨Fluoren-3 -yl) ethyl] -2-oxazoline'-4-one, IRUBrOcn-1: 3396, 3064, 3035, 2970, 2937, 1722, 1455, 1423, 1386, 1344, 1311. 1 Η- Η MR (CDC 1 3) S: 1. 3 6, 1 · 6 0 (all 3 H, d, J = 7.8 Η z), 2. 1 9 (3 Η, s), 2.2 8-3. 1 8 (2 Η, β >, 3. 7 8 (1 Η, η), 4.21 (1Η, m), 4.29 -4.47 (1 Η, η), 4.99 -5.32 ί5 Η, ο), 6.70-7.47 (14H, m), 7.68 (lH, d, J = 8.2Hz), 8.10 (1Η, bs)., (5S) -5-[(1R)- 1- (b3I favors 3-yl) ethyl] -2- [N-[(S) -4 -methyl [N-benzylcarbonylamino] aspartamido] -N-methylamino ] -2-11 Isoxazolin-4-one, IR (KBr) cm-1: 3402, 3060, 3037, 2954, 2937, This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) 89 3922 1 464649 A7 B7 V. Description of the invention (90) 1 7 2 2, 1 45 7, 1 436, 1 37 6, 1 344, 1 3 1 3. UMlUCDCls) ^: 1.36 · 1.61 (all 3H, d, J = 7.6Hz), 2.20 (3H, s), 2.82-3.82 (3H, m), 3.57, 3.60 (all 311,8 >, 4.18-4.50 (211, 《1), 5.02- 5.32 (3H, b), 6.85 -7.36 (9H, m), 7-45, 7.68 (gold part lH, d, J = 7.2Hz), 8,14 (lH, bs). (5S) -2- [N- (2 -Third Ding Dimethylsilyl octyl) -N-methylamino] -5-[(lR) -1- (indio-3-yl) ethyl] -2-oxazoline-4-one, 1 H-NMR (CDCI3) δ: -0. 1-0. 1 (6Η, m) f 0.85 (4.5 Η, s) , 0. 87 (4.5 Η, s), 1. 0-1.2 (10 Η, m), 1.46 (3H, t, J = 7.0Hz), 3.25 (1.5H, s), 3.26 (1.5H, s), 3.93 (1H, dq, J = 3.0 & 7.0 Hz), 5.05 (0.5H, d, J = 3.0Hz), 5.07 (0.5H, d, J = 3.0Hz), 5.40-5.48 ( lH, m), 7.1-7.7 (5H, n), 8.13 (lH, bs). (5S) -2- [N- (2-benzyloxyoctanylmethylamino) -5-[(lR) -1 -(Indino-3-yl) ethyl] -2-B | oxazol-4-one IRUBrOcm · 1: 181 0, 1 733, 1704, 1634. Printed by Zhengong Consumer Cooperative, Central Standards Bureau, Ministry of Lithium Economy ( Please read the notes on the back before filling this page) ^ -NMR (CDCla) δ: 0.8-0.9 (3 Η, m), 1.1-1.4 (9 Η, η), 1.45 (3H, d, J = 7.2Hz), 1.5-1.83 (lH, m), 3.2- 3.3 (3Η, β), 3.89 (lH, dq, J = 3. 0 < & 7. 2 Η ζ) t 3.97 -4.73 (3 Η, m), 5.03 (0.5Η, m), 5.11-5.17 (0.5Η, π), 6.9-7.7 (10 Η, ιπ), 8.11 (0.5H, bs), 8.16 (0.5H, bs ). (5S) -2- (H-benzyloxyacetaldehyde group) -fluorene-methylamino group) -5-[(lR) -l- This paper size applies to Chinese national standards (CNS > A4 specifications (210X297 (Mm) 90 39221 A7 B7 464649 V. Description of the invention (91) (Indino-3 -yl) ethyl] -2 -oxazoline-4 -one, IR (KBr) c m-33 47, 1 7 3 3, 1 627, 1 55 7. (Please read the notes on the back before filling this page) 1 H-HMR (CDC 1 3) 5 J 1.46 (3Η, d, J = 7.2 Hz), 3.26 (3H, s), 3,92 (1Η, dq, J = 3.4 & 7.2Hz), 4.42, 4.66 (2H, ABq, J = 18.0Hz), 4.55 (2H, s), 5.05 ( lH, d, J = 3.4Hz), 7.0-7.7 (10H, iD), 8.09 (1H, bs). (5S) -2- [H- (2-benzyloxy-4-methylpentanyl) ) -N-methylamino] -5-[(1R) -1- (b-triol-3-yl) ethyl] -2-BM ® 4--4-one, IR (KBr) cm-1: 1 742, 1 72 9, 1 5 57, 1 5 38. l-NMMCDClsJS: 0.66, 0.7 8 (each 3H, d, J = 6, 6Hz), 0.88, 0.93 (3 H, dtJ = 7.0Hz ), 1.3-1.6 (3H, m), 3. 2-3. 3 (3H, m), 3.91 (1 H, m), 3.8 ~ 4.6 (2.5 H, m) , 5.00-5.05 (lH, m), 5. 2 5 (0.5H, m), 7.0-7.7 (10H, m), 8.09-8.2 (1H, m).

Example 1 Q Printed by the Consumer Cooperatives of the Central Standards Bureau, Ministry of Economic Affairs According to the same procedure as described in Example 6, the following compounds were prepared. (5S) -5-[(lR) -l- (n3 | fluoren-3-yl) ethyl] -2- [K-lauryl-N-methylamino] -2-BMazoline-4- _, IR (KBr) cm-1: 32 98, 2925, 2854, 1 7 29, 1 558, 1538, 1455, 1394, 1195. 1H-NMR (CDC13) δ: 0.83 (3Η, t, J = 6.6Ηζ ), 1.23-1.35 (16Η, ιη), 1.46 (3Hfd, J = 7.2Hz), 1,51-1.64 (2Η, ι), 2.85 (2Η, π), 3.25 (3H, s) f Applicable to this paper size China National Standard (CNS) A4 specification (2 丨 0X297 mm) 91 3 92 21 464649 A7 __B7_ V. Description of the invention (9 2) 3.93 (1H, b), 5.06 (lH, d, J = 3.0Hz >, 7.09 -7.25 (3H.a), 7.37 (lH, d, J = 7.8Hz), 7.64 (1Η, d, J: 7.8Hz), 8.14 (1Η, bs). (5S) -2- [N- Chloroethenyl-N-methylamino] -5-[(lR)-: l- (indio-3-yl) ethyl] -2 -oxazolin-4-one, IR (RBr) cm- 1: 338 3, 2972, 1 73 3, 1 5 58, 1 45 5, 1 436, 1 3 9 8, 1 340, 1 3 1 7, 1 203. ^ -NMR (CDCla) δ: 1.5 2 (3 Η, d, J = 7. 3 Η ζ), 3.28 (3H, s), 3.95 (lH, m), 4. 48 (1 Η, dtJ = 16. 5 Ηζ), 4.72 (lH, d , J = 16.5Hz), 5.08 (lHfd, J = 3.3Hz), 7.08-7.26 (3H, a) f 7.38 (lH, d, J = 7.4Hz), 7.62 (1H, d, J = 7.6Hz ), 8.25 (lH, bs). (5S) -2- [N- [2- (5-amino -Diazol-3-yl) -2 (Z)-Ethyleneimine-acetaldehyde] -N-methylamino] -5- (1R > -1- (b5 丨 Chen-3-yl) ethyl] -2-Miconazole commanded 4-one, IRUBrOcm · 1: 3400, 2 976, 17 47, 1 7 1 4, 1 6 1 6, 1538, 1455, 1403, 1245, 1224. Consumption by employees of the Central Standards Bureau of the Ministry of Economic Affairs Cooperative cooperative policy (please read the notes on the back before filling in this page) 1 H-NMR (CDC 1 3) 5: 1. 14 (3Η, t, J = 7.1 Hz), 1, 2 3 (3 Η, in ), 3 '5 6 (3 Η, s), 3. 7 9 (1 Η m), 5.0 8 (1 Η, m), 6.85-7.25 (5Η, π), 7.33 (lH, d, J = ^. 2Hz), 7.56 (lH, d, J = 7.0Hz), 8.60 (lH, bs). (5S) -2- (N-allyloxalyl-N-methylamino) -5- [ (lR) -l- (Indole-3 -yl) ethyl] -2 -oxazoline-4-one, IR (KBr) cm'1: 1746, 1704, 1634, 1 6 1 5. Size of this paper Applicable to China National Standard (CMS) A4 specification (210X297 mm) 92 39 2 2 1 4 6 4649 A7 B7 V. Description of the invention (93) iH-HMMCDClaM: 1.2 5-1. 4 5 (3 Η, η) , 3.00- 3.U (3H, m), 3.76ilH, dq, J = 3.46.7.2Hz), 4.90-5.01 (3H, b), 5.40 (lH, d, J = 11.2Hz), 5.5 1 (1 H, dd, J = 1.2 & 1 7.0 H z), 5.9 5-6. 1 5 ( 1 H, m). 7.1- 7.7 (5H.n), 8.46 (1H, bs). Guan Yanli 20 According to the same procedure as described in Example 13, the following compounds were prepared. (5S) -2- [N- (3-Alaninyl) -N-methylamino] -5-[(lR) -1- (indyl-3-yl) ethyl] -2 Command-4- 阙, IRUBrOcm · 1: 3266, 2969, 2928, 1705, 1622, 1 584, 1 495, 1 456 t 1 399, 1 34 1, 1 308, 1236. 1 H-NHR (CDC 1 3) 5: 1.27 (3H, d, J = 7.0 Hz), 2.78 (2H, t, J = 7.0 Hz), 3.30 (3H, s), 3.56 (2H, t, J = 7.0Hz) , 3.65 (2H, bs), 3.77 (lH, m), 4.48 (1H, ra), 7.06-7.21 (3 Η, m), 7.35 (lH, d, J = 7.6Hz), 7.71 (lH, d, J = 7.0Hz), 8.08 (1H, bs). Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) (5S) -5-[(lR) -l -〇3 丨 睬 -3-yl) ethyl] -2- [N-[(S) -4 -methylaspartamidinyl] -N -methylamyl] -2 -B -Ketone, IRiKBrJcm-1: 3352, 2966, 1735,4643, 1577, 1488, 1 457, 1 438, 1 40 3, 1 32 2, 1 25 5, 1 0 99. ^ -HMRiCDCls) ^: 1.27 (3H , d, J = 7.1Hz), 2.73 (1H, dd, J = 17.6 & 9. 0Hz), 3.07 (lH, dd, J = 17.6 & 3.4Hz), 3.15 (3H, s), This paper size applies to Chinese National Standard (CNS) A4 specification (21 OX 297 mm) 93 392 2 1 4 64649 A7 B7 V. Description of the invention 9 4) 3 · 5 7 (1 H, bs), 3 · 7 6 (3 Η, s), 3. 8 2 (1 Η, in), 4.46 (lH, ddtJ = 9.0 & 3.4Hz), 4.54 (1Η, ι), (Please read the notes on the back before filling in this page) 7.03-7.27 (3 Η, m), 7.36 (lH, d, J = 7.0Hz), 7.73 (1Η, d, J = 7.4Hz), 8.07 (lH, bs), 9.12 (lH, bs). (5S) -2- [N-[(S) -aspartylamino] -N-methylamino] -5 -[(lR) -1- (Indide-3-yl) ethyl] -2-noxazolidine-4-one, IR (KBr) ci ~ 1: 3400, 1720, 1629, 1560, 1425, 1 39 9, 1 3 42. 1 H-NMR (DMSO-de) 5: 1.1 7 (3 Η, d, J = 7. 0 Ηζ), 2. 3 0-2.7 0 (2 Η, m), 2.99 (3H, s), 3.64 (1 Η, m), 4.24-4.38 (2H, m), 6.93-7.36 (4H, m), 7.60 (1Η, d, J = 8.〇Ηζ), 10.78 ( lHfbs) (5S) -5-[(1R) -1- (b3 丨 睬 -3 -yl) ethyl] -2- [Η -methyl-N- (3-methylaminepropylamino) amino] Azole command-4-_, IRUBrOcm- 1: 3 244, 1 73 3, 16 0 7 ′ -NMR (CDCls) δ: 1. 49 (2. OH, d, J = 7. 4Ηζ), 1.54 (1 .OH, d, J = 7.4Hz), 1.9-2.5 (2Η, ι), printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economy 2.59 (1.0H, d, J = 2.4Hz), 2.71 (2.0H, d, J = 2.4Hz), 2.97 (2.OH, s), 3.00 (1.0Hts), 3.4 ~ 3.6 ( lH, a), 3.6-3.8 (1H, m), 3.86 (lH, dq, J = 3.0 '& 7.4Hz), 4.80 (0.33H, bs), 4.98 (lH, d, J = 3.0Hz), 6.08 (0.67 H, bs), 7.0-7.7 (5 Η, m), 8.6 4 (0.67 Η, bs), 8.7 0 (0.33 H, bs). Wmm 2i Paper size applies Chinese national standard (CNS > A4 size (210X297 mm) 94 3 922 1 4 6 4 6 49 a? B7 V. Description of the invention (95) (5S) -2- [N- (2-Benzyl Phthalofluorenyl)-} (-methylamino] -5-[(lR) -1- (indyl-3-yl) ethyl] -2-oxazoline-4-one phthalic acid monobenzyl ( 1.60 g) of a solution of toluene (20 ml) was added with sulfuric acid gas (1 ml). At 80t: After stirring for 1 hour, the mixture was concentrated under reduced pressure to obtain a residue. Add tetrahydrofuran (20 ml) to the residue, and then add indigoxin (400 mg) at -15¾. After adding triethylamine (1.74 ml), the mixture was stirred at room temperature for 21 hours. All were diluted with ethyl acetate (100 ml). The mixture was washed with water (35 ml), a saturated aqueous solution of sodium hydrogensulfonate (35 ml x 3), and a common salt solution (35 ml), and then the ethyl acetate solution was dried over magnesium sulfate. The solution was concentrated by subtracting E, and the obtained residue was subjected to column chromatography. It was dissolved in ethyl acetate-hexane, and the eluate was collected and concentrated. The contents are solidified in their own hospital. This solid product was collected by filtration and dried to obtain the title compound (161 mg). IRCKBricm-1: 3400, 1714, 1538, 1455, 1399, 1278, 1222. 1H-NMR (CDC la) 5: 1.07 (3 Η, d, J = 7. 1 Ηζ) t 3.44 (3H, s), 3.60 (lH, m), 4.72 (1 Η, d, J = 2. 6 Ηζ), printed by the Consumers' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs and printed by the company (please read the precautions on the back before filling out this page) 5.17 (lH, d, J = 12.0Hz), 5.26 (lH, d, J = 12.0Hz), 6.31 (lH, d, J = 2.4Hz), 7.06-7.52 (12H, m), 7.86 (1 Η , bs), 7.95 (1Η, dd, J = 7.4Hz). ^ W Μ 2 7 (5S) -5-[(lR) -1- (indio-3-yl) ethyl] -2 -U -Methyl-N-trifluoroacetaldehyde amino group> -2 -D | oxazolin-4-one »3 睬 素 Anhui hormone (401 mg) was dissolved in tetrahydrofuran (38 ml). The size of the paper used here is in accordance with Chinese National Standard (CNS) A4 (2 丨 OX297 mm) 95 3 9 22 1 464649 A7 B7 V. Description of the invention (9 6) Add triethylamine (1.5 ml > and difluoroacetic anhydride (1.0 ml). The whole was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate (100 ml). All were washed with water and food liquid and dried over magnesium sulfate. The solution was It was concentrated, and the obtained residue was subjected to silica gel chromatography, and the title compound (375 mg) was obtained by dissociation with hexane-acetone (1: 1). IR (KBr) cb-1: 1733, 1652, 1634, 1615. ^- HMRiCDCls) ^: 1.33 (0.45H, d, J = 7.0Hz), 1.34 (2.55H, d, J = 7.0Hz), 2.97-3.13 (3H, m), 3.77 (lH, dq, J = 2.2fi [ 7.0Hz), 4.85 (0.15H, d, J = 2.2Hz), 4.97 (0.85 H, d, J = 2.2Hz), 7.3-7.7 (5H, m), 8.4- 8.51 (lH.bs).

曹 抡 例 M 2-Methylamino-5-[(5-helium indole-3-yl) methyl] -2-acetazolin-4-® printed by employee consumer cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please first Read the notes on the back and fill in this page again.) .5-Amino-3-formyl indene (5.00 g) in a solution of tetrahydrofuran (135 ml), add sodium argon (60% oil suspension, 3.53 g) ). The mixture was stirred at room temperature for 20 minutes. Add benzyl carbonyl (6.64 ml) to the mixture. After stirring at room temperature for 1 hour, all was poured into ice water. The mixture was extracted with ethyl acetate. The obtained extract was washed with a common salt solution and dried over magnesium sulfate. The solution was concentrated, and the obtained residue was subjected to silica gel chromatography. Dissolve with hexane-ethyl acetate (5: 1) to obtain 1-benzylcarbonyl-5 -amino-3 -formamidineindole (5 * 74 g) as crystals. ^ -NMR (CDCla) 5: 5.51 (2H, s), 7. 3 6-7. 5 2 (6 Η, m), 8.10 (lH, d (J = 9.2Hz), 8.27 (lH, s), 8.30 (1H, d, J = 2.2Hz), 10.06 (lH, s). This paper size is applicable to China National Standard (CNS) A4 (2 丨 OX297 mm) 96 3 9 2 2 1 A7 B7 464649 V. Description of the invention (9? (Please read the precautions on the back before filling out this page) 1-Benzyl gas carbonyl-5-amino-3-methylamidoindene (2. 00 g) in methanol (13 ml) In the solution, sodium borohydride (241 mg) was added at 0 T. After the mixture was stirred at the same temperature for 15 minutes, ice water was added to the mixture. Potassium sulfonate was added to saturate the mixture. The whole was extracted with ether, and the resulting extract was made with magnesium sulfate. It was dried. The mixture was concentrated, and hexane was added to the obtained residue to obtain 1-benzylcarbonyl-6-amino-3-hydroxymethylindole (1.80 g) as a crystal. 1 H-HMR (CDC 1 3) a: 1.63 (1H, t, J = 5.0 Hz), 4.79 (2H, d, J = 5.0Hz), 5.44 (2H, s), 7.2 6-7.45 (6H fm), 7.63 (2H, s), 8.09 (1H, d, J = 8.8flz). 1-benzylcarbonyl-5-amino-3-hydroxymethyl S3 丨 睬 (1.45 g) in two gases Methane (23 ml) In the solution, sulfur aldehyde gas (0.797 liters) was added at -78¾. After the mixture was stirred at room temperature for 1.5 hours, the reaction mixture was concentrated under reduced pressure to obtain a hydrazone residue. Hexane was added to the residue to obtain 1-benzene. Methanecarbonyl-5-aeroyl-3-aeromethylindole (1.43 g), which is crystalline. ^ -HMR (CDCls) 5: 4.70 (2H, s), 5.44 (2H, s), 7.32 (lH, dd, J = 8.8 & 1.8Hz) t 7.39-7.46 (5H, m), Central Standards Bureau of the Ministry of Economic Affairs-Industrial and Consumer Cooperation Du printed ί n-amine plus propane-isobutadiene is cold at V 8 7 to cold The material greenhouse is mixed with the material, mixed ο liquid η volume liter 4 milliliter 4 2 liters 5. / | \ (2 dissolved 6M furan 1. hydrogen tetrahydroxane in hexanox) in "? Lithium liter milliliter Ben 8 Pa 7 脞-¥ to Τ But 2 ^-cold base and amine, 1 minute 2 ο 2 3 stir, stir ketone

V Jiagjia 07 Benzoyl methyl chloride-3-Chlorochloride-5 Molyl carbonyl oxygen in all branches ο The paper size is applicable to the Chinese National Standard (CNS) Α4 size (210X297 mm) 97 3 922 1 464649 A7 B7 V. Description of the invention (98) t: to -40 t: search and mix for 30 minutes, search and mix for 2 hours, and stir at room temperature for 40 minutes. Water was added to the reaction mixture, and the gold portion was extracted with ethyl acetate. The obtained extract was dried over magnesium sulfate, concentrated, and the obtained residue was subjected to silica gel decantation. Dissolve in hexane-ethyl acetate (1: 1) to obtain 5- [(5-ammonium [fluoren-3-yl) methyl-2 -dimethylamino-2-floxazoline-4 -one (232 mg) as crystals. 1 H-NMR (CDC I 3) δ: 2.96 (3H, s), 2.98 (3H, s), 3.22 (1H, dd, J = 15.8 & 4.0 Hz), 3,45 (lH, dd, J = 15.86 <4.0Hz;), 4'98 (lH, t, J = 4.0Hz) 7.07 (lH, s), 7.09 (1H, d, J = 8.8Hz), 7.29 (1 H, d, J = 8.8 Hz), 7.59 (lH, s), 8.64 (lH, bs). In [(5-chloroindio-3-yl) methyl] -2-dimethylamino- 21¾ Zolamine-4-_ (200 mg) was added with methylamine (20 ml). The mixture was refluxed at -6¾ for 1 hour. The methylamine was removed and ether was added to the obtained residue to obtain the title compound (120 mg) as crystals. IR (KBr) cm " 1: 29 86, 1 6 4 1, 1413, 1 39 0, 1 3 0 4, 1242, 1103. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before (Fill in this page) 1H-NHR (DMSO-de) 5: 2.73 (3H, s), 3.01 (1Η, ι), 3.19 (lH, m), 4.95 (lH, i), 7.03 (1 H, d, J = 8.8Hz), 7.20 (lH, s), 7.34 (lH, dd, J = 8.8 & l. «Hz), 7.58 (1H, d, J = 1.8Hz), 8.31 (lH, bs ). Example 24 According to the same procedure as described in Example 23, the following compound was prepared. 2-Methylamino-5-[(2-methylindio-3-yl) methyl] -2-! 1 and other oxazolines. 4- This paper is sized to Chinese National Standard (CNS) A4 specifications (2 丨0X297 mm) 98 3 9 22 1 464649 A7 B7 V. Description of the invention (9 9) ketone, IR (KBr) cm-15 2912, 1 655, 1508, 1408, 1305, 1251, 1238, 746. iH-NHRiDHSO- de) ^: 2.50 (3H, s), 2.70 (3H, s), 2.93-3.20 (2H, b), 4.86 (1H, b), 6.86-7.00 (2H, m), 7.20 (lH, d, J = 7.2Hz), 7.40 (lH, d, J = 6.9Hz), 8.48 (lH, bs), 10.76 (lH, bs). 5-[(5-Benzyloxyindan-3-yl) methyl ] -2-Methylamino-2-Mesobutanthine -4-Brown, IR (KBr) cm " 1: 1667, 1640, 1485, 1 41 2, 1304. 1 H-NHR (DMSO-de) δ: 2 68 (1 .5 Η, s), 2.99 (1Η, η), 3.21 (lH, m), 4.95 (lH, dd, J = 7.0 & 3.4Hz), 6. 79 (1 Η, d, J = 8.8Hz), 7.08-7.5.2 (8 H, m), 10.78 (1H, bs). 2-methylamino-5-[(5, 6-methylenediazine ind Favor 3-yl) methyl] -2-oxazolin-4-one, ^ -HMR (DMSO-de) δ: 2.7 3 (3 Η, d, J = 5.0 Η ζ). Central Ministry of Economic Affairs Printed by the Consumer Bureau of Standards Bureau (Please read the notes on the back before filling out this page) 2 '9 6 -3. 1 5 (2 Η, βι), 4.8 9-4. 9 1 (1 H, m), 5.9 2 (2 Η, s), 6.85 (lH, s), 6.96 (lH, s), 6.99 (lH, s), 8.58 (lH, bs). (Window Example 25 2-Methylamino-5- (1Η-pyrrolo [2,3-b] pyridin-3-yl) methyl -2-Miconazole is instructed to be 4-ketodiisopropylamine (0.75 ml) in a solution of tetrahydrofuran (35 ml). The paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) gg 392 2 1 6 4649 A7 B7. Λ '' J _ ._τ. 'Ding-1 wide .... under r | ._ ^ T, ".U1 V. Description of the invention (100) Under ice cooling, add n-butyl to 1.6 in hexane. M solution (3.35 ml). All were cooled to -7 ** C plus 2-dimethylamino-2-Hizolam-4-4-one (666 mg), and then all were stirred at room temperature for 30 minutes. The mixture was cooled to -78¾ again, and 3 -gasmethyl-1H-leptro [2,3-b] pyridine (230 mg) was added. All were stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the whole was extracted with ethyl acetate. The obtained extract was dried over magnesium sulfate and concentrated, and the obtained residue was subjected to silica gel chromatography. Dissolve in ethyl acetate-ethanol (10: 1) to obtain 2-dimethylamino-5- (1Η-pyrrolo [2,3-b] pyridin-3-yl) methyl-2-bazolyl 4-one (51 mg). 1 Η-HHR (CDC 1 3) δ: 2.9 5 (3 IK s), 3.0 3 (3 H, s), 3. 26 (1Η, dd, J = 15. 9 & 5.5 Hz), 3.48 (1Η, dd, J = 15. 9 & 4. 3Ηζ), 4, 9 7 (1 Η, dd, J = 5. 5 & 4 '3 Η ζ), 7.09 (lH, dd, J = 7.9 & 4.8Hz), 7.24 (lH, s), 7.98 (1Η, dd, J = 7.9 & 1.5Ηζ), ι 8.29 (lH, J = 4.8 & 1.5Hz), 9.64 (lH, bs). Economy Printed by the Ministry of Standards and Labor ’s Consumer Cooperatives (please read the precautions on the back before filling out this page) Methyl-2 -D and other oxazolones (50 mg) were added to methylamine (1 ml). After the mixture was refluxed for 1 hour, methylamine was removed, and the obtained residue was subjected to silica gel chromatography. Ethyl acetate-ethanol was used to dissociate and concentrate, and the obtained residue was solidified by imitation. This solid was washed with diethyl ether and dried under reduced pressure to obtain the title compound (32 mg). IR (KBr) cm-1 i 32 1 5, 1645 1 5 1 6. U-NMlUDMSO-dsiS: 2'71, 2.73 (Gold Department 3H, each s), this paper size applies Chinese National Standard (CNS ) A4 specification (2IO × 297 mm) 100 3 9 22 1 4 64649 A7 B7 V. Description of the invention (101) 2.99-3.32 (2H, m), 4.97 (lH, dd, J = 6.7 & 3.9Hz), 7.03 ( lH, dd, J = 7.8 & 4.7Hz), 7.24 (lH, d, J = 2.1Hz), 7.96 (lH, d, J = 7.8Hz), 8.18 (lH, d, J = 4.7Hz), 8.58 (lH, bs), 11.43 (lH, bs).

Sound Example PR According to the same procedure as described in Example 25, the following compounds were prepared. 5- (Benzo [b] l «pan-3-yl) methyl-2-methylamino-2-B and other oxazoline-4-ones, IRiKBrJcm-1: 3210, 1768, 1678. UMiUDMSO-ddS: 2.68, 2.79 (all 3H, each s), 3. 18 (lH, dd, J = 15.78, 8.4Hz), 3.42 (lH, m), 5.06 (lH, m), 7.35-7.45 {2H, ia) , 7.51 (lH ,, s), 7.82 -7.99 (2 H, m), 8.69 (1H, bs). 5-[(l-benzylindolin-3-yl) methyl] -2-methylamine 2--2-oxazolium-4-one, IRUBrOcm, 1: 1 6 6 3, 1 50 8, 1 41 0, 1402, 1 298, 7 2 9. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (Please Read the precautions on the back before filling this page) 1 Η ~ ΗΗ1ί (DMSO-de) 5: 2.68 (lH, s), 2.72 (2H, s), 3.07 (1H, m), 3.30 (1H · m), 4.98 (lH, dd, J = 6.2 & 2.4Hz), 5.37 (2fl, s), 6.96-7.38 (9H, m), 7.56 (lH, d, J = 7.0Hz), 8.55 (1H, bs ). Example 27 According to the same procedure as described in Example 17, the following compound was prepared. This paper size is applicable to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 101 3 92 2 1 4 6 4649 A7 B7 V. Description of the invention (102) 5-[(1- (4-methylindionium- 3-yl) ethyl] -2 -methylamino-2-oxazoline-4 -one, (Please read the notes on the back before filling this page} IR (KBr) ci-1: 3183, 1733, 1623 lH-NHR (CDCla) 5: 1.25-1.50 (3Η, a), 2.69-3.0 (3Η, m), 4.05-4.25 (1 Η, m), 4.86 (0.5H, d, J = 3.6Hz), 4.96 (0.5H, d, J-2.6Hz), 6.84 (lH, m), 6.9 8-7.25 (3 Η, 1), 8.29 (0.5 Η, bs), 8 38 (0. 5Η, bs), 9. 30 (1Η, bs). 5-[(1- (4-benzyloxyindio-3-yl) ethyl] -2-methylamino-2 -B-oxazol-4-one, IR (KBr) cm- 1: 3 1 9 9, 1 733, 16 52, 1 6 1 5. ^ -NMRiCDCis) ^: 1.22-1.37 (3H, m), 2.82 -3. 0 (3Η, n), 4.1-4.4 (1 Η, m), 5.0 8 (0.5 Η, d, J = 4. 8 Η ζ), 5. 1 9 (1. 5 Η , β), 5 · 2 6 (1 Η, s), 6, 5 6 (1 Η, 麄), 6 · 9-7.1 (3 Η, m), 7.2 9-7.6 (5 Η, m), 8.23 (0.5H, bs), 8.37 (0.5H, bs), 9.25 (lH, bs). Staff Consumer Cooperatives, Central Bureau of Standards, Ministry of Economic Affairs Preparation of 2-methylamino-5- [1- (7-methylindio-3-yl) ethyl] -2-_ isoxazoline-4-b, IRiKBricn * 1! 3357, 3214, 1733, 1 652, 1615. UMMDMSO-deM: 1.18 (0.96H, d ', J = 7.4Hz), 1.25 (0.45H, d, J = 7.0Hz), 1.42 (0.96H, d, J = 7.2Hz), 1.50 ( 0.63H, d, J = 7.6Hz), 2.41 (1.5H, s), 2.44 (1.5H, s), 2.65-2.8 (3H, m), 3.5-3.7 (1 Η, m), 4.8-4.95 (1H, m), 6.8-6,9 (2 Η, b), 7.0-7.15 (1 Η,), this paper size applies China National Standard (CNS) A4 specification (210 X 297 mm) 102 3 92 2 1 464649 A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (103) 7.3 5 -7.45 (lH, m), 8.55 (lH.bs). 5- [lU-methylcarbonyl Indino-3-yl) ethyl] -2-methylamino-2-oxazoline-4-one, IR (KBr) cm-1: 3278, 3203, 1713, 1 635. ^ -NHR (DMSO- de) δ: 1.06 (1.33 3, d, J = 7.00 .z), 1.14 (0, 67Htd, J = 7.0Hz), 1.32 (0.67H, d, J = 7.0Hz) , 1.41 (0.33H, dfJ = 7.6Hz), 2.7-2.85 (3H, i), 3.86 (1.08H, s), 3.91 (1.92H, s), 3.95-4.2 (lHtm) (4.65 -4. 85 (1 H, m), 7.0-7.2 (1 Η, i), 7.3-7.5 (2 H, nt), 7.5 5-7. 6 5 (1 H, ra), 11.40 (lH.bs). 5- [1- (4-isopropylindio-3-yl) ethyl] -2-methylamino-2- 1 isoxazoline-4-ϋ IRUB r) c]-1: 3 2 6 6, 3 2 1 6, 1 7 2 5, 1 6 3 4. ^ -HMR (DHSO-de) δ: 1. 1- 1.5 (9 H, id), 2.75-2. 9 (3H, m), 3.6-3.9 (1 H, m), 4.8-4.95 (1 Htm), 6.8-7 · 1 (2 H, b), 7. 1-7. 2 5 (2 H, legs), 8. 6 7 (1 H, bs). Fen Li Li 5- [l- (4-hydroxyindio-3-yl) Ethyl] -2-methylamino-2-B quinazoline-4-one 5- [1- (4-benzylaminoindan-3-yl) ethyl] -2-methylamino-2 -Miconazole is instructed to be dissolved in a mixture of ethanol and tetrahydrofuran (氲: 1.6 ml). Add 10% rake-sulfur (45 mg), and perform all hydrogenation at room temperature and normal pressure for 24 hours. The catalyst was removed from the mixture by filtration, and 10¾ palladium-rhenium (45 mg) was added. The gold part was hydrogenated again at room temperature and normal pressure for 24 hours. The reaction mixture was filtered to remove the catalyst. The obtained filtrate is concentrated, and the obtained residue is f factory, (please read the precautions on the back before filling this page), ν #

This paper size is in accordance with Chinese National Standard (CMS) A4 specification (21 × 297 mm) 103 39 22 1 Λ 6 4649 Α7 Β7 5. Description of the invention (10 4) The silica gel chromatography is performed. Dissolve in hexane-propane (1: 1) to obtain the title compound (72 mg). {Please read the notes on the back before filling this page) IR (KBr) cm-1: 3 1 89, 1 733, 1 6 9 8, 1 6 1 5. 1H-NHR (DMS0-d6) S * · 1.0-1.15 (1.92H, m), 1.3 .0-1.3 .5 (1.0 8 Η, m), 2 · 7-2. 8 5 (3 Η, in), 3.7-4.0 (lH, m), 4.92 (0.12Htd, J = 6.0Hz), 5.02 (0.31H, d, J = 6.0Hz), 5.08 (0.20H, d, J = 2.2Hz), 5.13 (0.37H, d, J = 2.2 Hz), 6.32 (lH, d, J = 5.2Hz) t 6. 7-7. 0 (3H, m), 8.58 (lHtbs) t 9.40 (lHtbs). Example 29 5- [l- (4- Methenyl group "3 丨 基 -3-yl) ethyl] -2-methylamino-2-B and other oxazol-4-ones Printed by 5- [lU-benzene" Methazinyl-3-yl) ethyl] -2-dimethylamino-2-B and other oxazoline-4- (268 mg) were dissolved in a mixture of ethanol and tetrahydrofuran (7: 3.10 ml). 10% rake-shuo (80 mg), all hydrogenated at room temperature and atmospheric pressure for 5 hours. The catalyst was removed from the mixture, and 0% rake-sulfur (80 mg) was added. All were hydrogenated again at room temperature and normal pressure for 24 hours. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated to obtain 2-dimethylamino-5-[[1-U-hydroxyindio-3-yl) ethyl] -2-oxazol-4-yl (125 mg). 1 H-NHR (DMSO-de) δ: 1.02-1.15 (3Hs m), 3.00-3.10 (6H, m), 3'98 (lH, m), 4.97-5.16 (lH, m), 6.30-6.34 ( 1 H, m), 6.77-6.83 (2 H, m), 6.95 (1 Ηtm), 9.40 (1H t bs), 10.69 (1H, bs). 2-dimethylamino-5- [l- (4 -Hydroxyindox-3-yl) ethyl] -2-B oxazole This paper is sized to the Chinese National Standard (CNS) A4 (210 X 297 mm) 104 3 922 1 464649 A7 B7 V. Description of the invention (105 ) The 4--4-one (120 mg) was dissolved in dimethylformamide (3 ml). Add potassium sulphate (115 ml) and indylmethane (ί 56 liters). The mixture was stirred at room temperature for 3 hours, and then indanemethane (78 liters) was added. The mixture was stirred at room temperature for 36 hours. Water was added to the reaction mixture, and the whole was extracted with ethyl acetate. The obtained extract was washed with a common salt solution and dried over magnesium sulfate. The ethyl acetate solution was concentrated, and the obtained residue was subjected to silica gel chromatography. Dissolve with hexane-acetone (1: 1) to obtain 2-dimethylamino-5- [1- (4-methylaminoinden-3-yl) ethyl] -2-B, etc. -Ketones (54 mg). 1 H-NMR (CDC 1 3) δ: 1.26 (2.6Η, d, J = 7.0 Hz), 1.45 (0.4H, d, J = 7.2Hz), 2,96 (0.4H, s), 3. 00 (2.6H, s), 3.17 (2.6H, s), 3.19 (0.4H, s), 3.90 (0.4H, s), 3.93 (2.6H, s), 4.25 (lH, m), 4.98 (0.13H, d, J = 3.4Hz). 5.24 (0.87H, d, J = 2.2Hz), printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the note on the back first) Please fill in this page again for matters) 6.51 (d, J = 7,8Hz), 6.95-7.14 (3H, m), 8.16 (lH, bs). 2-dimethylamino-5- [l- (4-methyl gas Indox-3-yl) ethyl] -2-oxazoline-4-_ (50 mg) was added to methylamine (5 ml). The mixture was refluxed for 5 hours and methylamine (5 ml) was added. All again refluxed for 2.5 hours. Methylamine was removed by distillation, and the obtained residue was subjected to silica gel chromatography and eluted with hexane-acetone (1: 1) to obtain the title compound (32 mg). IR (KBr) cm * 1: 328 6, 3 1 99, 1 7 33, 1 6 2 3. ^ -NMRiDHSO-de) ^: 1.0-1.15 (3H, m) f 2. 7-2. 8 5 ( 3 Η, m), 3 · 8 4 (3 Η, s), 3 · 7-3.9 (1 Η, m), 4.98 (0.33H, d, J = 2.2Hz), 5.01 (0.67H, d , J = 2.2Hz), 6.46 (lH, m), 6.9-7.1 (3H, m), 8.60 (lH, bs), this paper size applies Chinese National Standard (CNS) A4 specification (2! 0X297 (Mm) 105 3 9 2 2 1 464649 A7 B7 V. Description of the invention (106) 1 0. 8 δ (1 Η, bs). Example 30 (Please read the notes on the back before filling this page) 5- [l- (4-Gaindino-3-yl) ethyl] -2-methylamino-2-Bcurazol-4-one 3-ketoindene (500 mg) and trans-2, Ethyl 3-tritium butyrate (472 mg) was dissolved in digas methane (5 ml). In this mixture, it took 30 minutes at -90 to add tetragas titanium. Stir all at -9 10 for 1 hour. Add trans-2,3-cyclobutyric acid ethyl ester (405 mg) and titanium tetragas (40 5 liters). All was stirred for an additional hour at -9t. The reaction mixture was concentrated, and ethyl acetate was added to the obtained residue. The mixture was washed with a common salt solution, and the dried solution was concentrated with magnesium sulfate, and the obtained residue was subjected to silica gel chromatography. Dissolve in hexane-ethyl acetate (1: 3) to obtain 2S *, 3l ^)-3- (4-aminoindan-3-yl) -2-hydroxybutyric acid ethyl ester (200 mg) . »H-NMR (CDC Is) 5: 1.27 (3H, d, J = 7.2 Ηz), 1.33 (3H, t, J = 7.0Hz), 2.81 (lH, d, J = 5.2Hz), 4 · 2 5-4, 4 0 (4 H, m), 4. 6 4 (1 H, dd, J = 5. 2 & 2. 6 H z), 7.06-7.10 (2H, id), 7.24-7.29 (2Hti), 8.22 (lH, bs). Sodium (100 mg) was dissolved in ethanol (5 ml). Plus (2S *, 3R *)-3- Printed by (4-Amino-Inden-3-yl) -2-Hydroxybutyric Acid (200 mg) and Ν, Ν printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs '-Dimethylguanidine bromate (143 mg). All were refluxed for 16 hours. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The obtained extract was washed with a common salt solution and dried over magnesium sulfate. The solution was concentrated, and the obtained residue was subjected to silica gel layer analysis. Dissolve in hexane-acetone (1: 1) to obtain the title compound (25 mg). 1 H-HMR (CDC Is) 5: 1.27-1.44 (3 Η, m), 2.84-3.00 (3Η, ιιι), 4.36-4.58 (lH, m), this paper size applies Chinese national standard ( CNS) A4 specification (210 × 297 mm) 106 39 2 2 1 464649 A7 B7 V. Description of the invention (10?). 4.99-5.11 (lH, m), 5.88 (lH, m), 7.0,0-7.30 (4Η , π >), 8. 6 0 -8. 80 (1 Η, m). Examination Example 3 1 5- [1- (Indyl-3-yl) -2,2,2-trifluoroethyl] 2-Methylamino-2-1! _Oxazoline-4-sodium ethoxide (580 mg) was added to 4,4,4-trifluoro-2-hydroxy-3- (indol-3-yl) A solution of methyl butyrate (980 mg) and N, fT-dimethylguanidine bromate (630 mg) in ethanol (2.5 ml). The mixture was refluxed for 1.5 hours and then cooled. Add ice water (20 ml) to the cooled reaction mixture. After the pH of the mixture was adjusted to 7 with acetic acid, the whole was extracted with ethyl acetate. The obtained extract was washed with a saturated aqueous solution of sodium hydrogen sulfonate, and then dried over magnesium sulfate. The solution was concentrated under reduced pressure, and the obtained residue was subjected to silica gel decantation, and the residue was separated with ethyl acetate-hexane, and collected and concentrated to obtain Title compound (218 mg). IR (KBr) cm]: 3283, 1769, 1717, 1659, 1541, 1 H-NMR (DMSO-de) δ: 2.38-2.5 4 (3 Η, m), 3'65-4.61 (2H, m), 6.24-6.33 (1Η, ια), printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back before filling out this page) 6. 9 4-7. 9 8 (5 Η, m), 11 · 1 0-1 1. 1 8 (1 Η, m), butanidine: ¾¾ 2-diethylamidoamino-5-[1- (indio-3-yl) ethyl] -2-oxazole The 4-keto-2-amino- 5- [l- (n3 睬 睬 -3-yl) ethyl] -2-doxazolin-4-one (300 mg) was dissolved in tetrahydrofuran (2 ml). Add triethylamine (344 liters) and aceton gas (123 μl) under ice cooling. The mixture was stirred at 0¾ for 2 hours. Add triethylamine (3 44 microliters) and aceton gas (123 Chel). All are stirred again. The paper size is in accordance with Chinese national standard (CNS > A4 size (210 X 297 mm) 107 3 922 1 464649 A7 B7. 5. Description of the invention (108) 2 hours. Add water to the reaction mixture, all with ethyl acetate. Extraction. The obtained extract was washed with a common salt solution and dried over magnesium sulfate. The solution was concentrated, and the obtained residue was subjected to silica gel chromatography, which was separated with hexane-propane (1: 1), collected and concentrated to obtain Title compound (40 mg). 1 Η-Η Μ ϋ (CDC 1 3 Μ: 1. 4 5 (1.92 Η, d, J = 7.2 Η z), 1. 57 (1 · 08 Η, d , J = 7. 2Ηζ), 2. 17 (6Η, s), 3.7-3.9 (1Η, β), 4.99 (0.36H, d, J = 2.4Hz), 5.07 (0.64H, d, J = 2.8Hz ), 7.0-7.4 (4H, m), 7. 6-7. 7 (1Η, a), 8.32 (1H, bs). Printed by the Central Standards Bureau of the Ministry of Economic Affairs, Industrial and Consumer Cooperatives (please read the back first) Please pay attention to this page before filling in this page) This paper size is applicable to Chinese National Standard (CNS) A1 2 3 specifications (2 410X596 mm) 108 39 22 1 1 ^ -NHRfCDCls) ^: 1.42 (1.95H, d, J '= 7.2 Hz), 2 1.62 (1.05H, d, J = 7.2Hz), 2.1-2.3 (3H, m), 3.88 (lH dq, J = 2.2 & 7.2Hz), 5.00 (0.35H, d, J = 2.2Hz) 3, 5.04 (0.6 5H, d, J = 2.2Hz), 7.0-7.4 (5H, m), 4 IR (KBr) cm " 7: 1 742, 1 69 8. 5 -Amino-5- [l- (n-preferred-3-yl) ethyl] zolam-4-_ (100 mg) is soluble in pyridine (0.5 ml). Add acetic anhydride (117 liters). Stir the mixture at 80 ° C for 2 hours. Add water to the reaction mixture. This mixture is acidified with 4N hydrochloric acid. The whole is extracted with ethyl acetate. The resulting extract is a common salt solution It was washed and dried over magnesium sulfate. The solution was concentrated, and the obtained residue was subjected to silica gel chromatography. It was isolated with hexane-acetone (1: 1), collected and concentrated to obtain the title compound (16 mg). 6. 67 (1H, d, J = 8.4Hz), 8.19 (lH, bs). 7 2-Ethylamino-5- [1- (great-3-yl) ethyl] -2-〇l -4-keto A7 464649 B7 V. Description of the invention (10 9) Test example 1 In vitro anti-percutaneous biological test: (Please read the precautions on the back before filling out this page) Pave the pylorus 蜾 蜾 榭 榭 榭 生物 biological: > Live 牛 external resistance to cattle 袢 测 测 Test using 5 kinds of Helicobacter pylori a strain, 19 other fine worms and 2 kinds of yeast Strains, anti thorough measurement of the biological activity of various compounds in accordance with the following methods (Ai aliphatic dilution). The test compound was dissolved in dimethyl isocyanate; this solution was slowly diluted twice with sterile distilled water to form a test sample. 2 ml of each test sample was mixed with 18 ml of Brucella agar supplemented with 7% horse blood as a culture medium to prepare a petri dish for measurement. Helicobacter pylori was aerated in S [] containing Campy PakTW (BBLR Beckton Dickinson Microbial System), and cultured with Brucella broth supplemented with 2.5% fetal bovine serum at 30¾ for 20 hours with shaking to form seed in oclan ). The other tested organisms were cultured in Brusella medium at 37t each: 20 hours of incubation to form inoculation bacteria. The Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs printed 5 liters of each inoculum, adjusted in advance to 106 CFU / ml with 2.5% fetal bovine serum supplemented with Brucella broth, and inoculated it into each measuring dish Inflated cylinders containing Campy PakTM and absorbent cotton absorbent were incubated at 37¾ for 4 days. After incubation, check the growth of the strain with the naked eye; when the sterile strain grows, the minimum concentration (minimum inhibitory concentration) of the test compound is used as the HIC value. 'The results are shown in Tables 2 and 3. This paper size applies to China National Standard (CNS) A4 (2I0X297mm) 109 3 92 2 1 464649 A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (110) Table 2 133 丨 睬Anti-biological activity of Huimin on various withdrawn organisms [(MIC (Chek / ml)] 1 Escherichia coli K12 > 100 2 Escherichia coli IH J JC-2 > 100 3 Proteus mirabilis ATCC 21100 > 100 4 Common Proteus IF0 3045 > 100 5 Mogni Proteus IF0 3168 > 100 6 Pneumoniae IF0 3317 > 100 7 Serratia marcescens IF0 3046 > 100 8 Salmonella typhimurium IF0 1 252 9 > 100 9 Salmonella enteritidis IF0 3313 > 100 10 C. freundii IF0 1 268 1 > 100 11 Pseudomonas aeruginosa IF0 3080 > 100 12 Alkali-producing bacteria IF0 13111 > 100 13 Bacillus thuringiensis PCI 219 > 100 14 Bacillus saccharus IFO 3514 > 100 15 Bacillus pumilus IFO 3813 > 100 16 Bacillus macrobiosis IFO 12108 > 100 17 Golden yellow Staphylococcus FDA 209 P > 100 18 S. luteus IFO 1 27 0 8 12.5 19 S. flavus IFO 32 42 > 100 20 H. pylori NCTC 11637 0.006 21 Candida albicans IFO 05 8 3 > 100 22 Winemaking ntMf Yeast IFO 02 09 > 100 ΤΠΓ (Please read the back. Note before filling out this page) _ -e Γ

3 9 2 2T This paper scale is applicable to China National Standards (CNS) A4 specifications (210X: 297 mm) 4 # ^ 4 # ^ A7 B7 Supplement 464649 V. Description of the invention (111 Table 3 Anti-microbial of various Helicobacter pylori Activity (live mic identification of H. pylori H. pylori H. pylori H. pylori butterfly # H. pylori 11637 11916 CPY433 TN2 TN58 indolin 0.006 0.013 0.013 0.006 0.025 N-desmethylindolin + 0.05-0.2 0.1 0,2 Refinement of Example 2 0.025-0.05 0.025 0.05 Compound of Example 17 0.78-1.56 0.78 3.13 Compound of Example 27 0.1-0.2 0.1 0.39 Compound of Example 28 6.25-6.25 3,13 6.25 Implementation The compound of Example 29 3.13-6.25 1.56 6.25 The compound of Example 30 0.39-0.39 0.2 0.78 'Please fill in the matter of the army I}. Chemical formula of desmethylindoxin:

Me

Η Ν Agar dilution method. M 1C value was printed with Bruce La Agar supplemented with 7 jealous horse blood · 1 Employee Cooperative of Intellectual Property Bureau of Ministry of Economic Affairs. It is known from Tables 2 and 3 that the compound (I) shows extremely selective antimicrobial activity against Helicobacter bacteria represented by M. pylori. Test 2 (in vivo antimicrobial activity test) Mongolian gerbils (raongoHan gerbils, MGS / Sea, male, 6 weeks old) After fasting for 24 hours, Helicobacter pylori TK2dF4M was used per Ronggu gerbil. 7.08 inoculation to its window. After 11 days of infection, the test compound was at 5%. 392 2 1 This paper size applies the Chinese National Standard (CNS) A4 specification (2 × 297 mm) 1 1 1 (correction page) 4 6 4 6 49 a7 B7 V. Invention Explanation] 2) n &-* * --------- I. ·. (Please read the precautions on the back before filling in this page) Methyl cellulose aqueous solution becomes 3, 10, 30 or 100 mg / A kilogram of suspension is administered orally, twice a day (early morning), for 3 days. After the last day of administration, the shoulders of each infected Mongolian gerbil were resected and ruptured; a 10-fold serial dilution of the gastric homogenate was inoculated into modified Scroox supplemented with activated carbon. (Skirr ο ν The culture medium was cultured for 4 days under 37 a trace aerobic conditions, and then the removal effect was evaluated based on the presence or absence of bacteria growth. The results are shown in Table 4. After Dunnett's test with the control group, the mean K value of the bacterial cells was expressed as the standard deviation. In Table 4, ^ means p < 0.01. Table 4 Test compound dosage (mg / kg) Clearance (96) Bacterial detection value (log / CFU / gastric wall) Control group (0.5% methyl cellulose solution)-0/4 (0) 6.36 ± 0.19 indole Huisu 3 0/5 (0) 4.61 ± 1.84 10 0/5 (0) 2.76 ± l, 04ss 30 1/4 (25) 1.96 ± 0,783 ^ 100 4/5 (80) 1,48 ± O.OO * * From Table 4, it is known that indoxin above 10 mg / kg will cause the bacterial cell count of the rat crotch printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs of Mongolia to decrease in a dose-dependent manner, and the resulting clearance rate is 30. Mg / kg is 25%, while 100 mg / kg is 80%. These findings prove that the preparation of the present invention is effective against peripheral ulcers, inflammation, and gastric cancer caused by Helicobacter pylori infection. Test example: ¾ (in vivo antimicrobial activity test) The paper size is applicable to the Chinese National Standard (CNS) A4 specification (2! 0X297 mm) 112 (correction page) 3922 1 I ---------- ------ 464649 A7 B7 V. Description of the invention 1 1 1 (Please read the precautions on the back before filling this page)

Isf ancient gerbils (mongolian gerbils, MON / Jms / Gb.s, male, 5 weeks old) were fasted for 24 hours, and each Mongolian gerbil of Helicobacter pylori TN2GF4M was inoculated to its stomach with 10.56. After 11 days of infection, the test compound was dissolved in a 0.5% methylcellulose aqueous solution into a 50 mg / kg tincture floating solution and administered orally, twice a day (early mucus) for 2 days. After the last day of administration, each infected tight gerbil rat was removed and ruptured; a 10-fold dilution of the homogenate homogenate was inoculated into modified Skrowrow's supplemented with activated carbon. The culture medium was cultured for 5 days under 37 a microaerobic conditions, and then the removal effect was evaluated based on the presence or absence of bacteria growth. The results are shown in Table 5. The mean value of the bacterial cell count and the standard deviation were shown after the unnett's test with the control group. In Table 5, ss refers to p < 0.01. Table 5 Test compound dose (mg / kg) Clearance (96) Bacterial detection value (log / CFU / gastric wall) Control group (0.5% methylcellulose solution) N-desmethylindoxin 50 50 / 4 (0) 0/4 (0) 6.21 ± 0.06 2.13 ± 0.22 Material _I Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, as shown in Table 5, N-desmethylindene favors emblematin at 50 mg / kg M The above results in a significant reduction in Mongolian gerbil's stomach bacterial cell count. These findings prove that the preparation of the present invention is effective against stroke ulcer, qi inflammation and gastric cancer caused by Helicobacter pylori infection. (In vivo antimicrobial activity test) Mice (Cr i: ICR, male, 5 weeks old) fasted for 20 hours. Pylori paper size applies Chinese national standard (CNS > A4 size (2ΙΟχ29ϋ) ~ 1 1 2 -1 (^ iE Η) 39221 4 6 4 649

The stalk fungus TN2GP4M was inoculated to each mouse with 108'05. Infection 11 (Please read the precautions on the reverse side before filling out this page) Days later, the test compound is administered as a 50 mg / kg suspension in 0.5% methylcellulose aqueous solution and administered orally, twice a day (morning and evening) For 2 days. After the last day of administration, the stomachs of each infected mouse were excised and a 10-fold dilution of the flail homogenate was inoculated into the modified supplemented activated carbon. Good Skirrov's medium t Incubate for 4 days under 1 / ^ trace aerobic conditions, and then evaluate the removal effect based on the presence or absence of bacteria growth. The results are shown in Table 6. After Dunnett's test with the control group, the bacterial cell count was expressed as the mean ± standard deviation. In Table 6, s: s: refers to ρ < 0 · 01 0 Table 6 Test compound dose (mg / kg) Elimination rate has been eliminated / total (%) Bacterial detection (log / CFU / stomach wall) Control Group (0.25% methylcellulose solution)-0/4 (0) 4.73 ± 0.18 The first compound of Example 3 50 0 / 4⑼ 2.94 ± 1.21 ** The fifth compound of Example 3 50 1/4 (25) 2.43 ± 0.78 ** The sixth compound of Example 3 50 0/4 (0) 1.96 ± 0.16 ** _group (0.25% methyl cellulose solution)-0/4 (0) 4.55+ 0.46 implementation The second chemical decoration of Example 3 50 0 / 4⑼ 2.55+ 0.75 ** The third compound of Example 3 50 0 / 4⑼ 2.79+ 0.55 ** The fourth compound of Example 3 50 0/4 (0) 2.74 ± 0.64 ** Examples of preparations printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs are used as a therapeutic agent for Helicobacter pylori infection. The preparation of the present invention containing a compound of formula (I) or a salt thereof can be prepared according to the following formula . 1. Capsules __ 112-2 (correction page) 39 22 1 This paper size applies to Chinese National Standards (CNS) A4 specifications (210 × 297 mm) A7 B7 V. Description of the invention (113) (1) B§ | 睬 emblem (2) Lactose (3) Microcrystalline cellulose (4) Total magnesium stearate 100 mg 90 mg 70 mg 10 mg Per capsule tincture 270 mg Ingredients (1), (2) and (3) and half The ingredients (4) are mixed and granulated. To these granules, the remaining component (4) is added, and the whole mixture is filled into gelatin capsules. 2. Lozenges (1) indigoxin (2) lactose (3) corn starch (4) scopolamine androgen (5) total magnesium stearate 100 mg 35 mg 150 mg 30 mg 5 mg per tablet Agent 3 20 mg of ingredients (1), (2) and (3), 2/3 parts of ingredient (4) and half of ingredient (5) are mixed and granulated. In these granules, add the rest of the ingredients (4) and ((Please read the precautions on the back before filling this page) Order the printed tablets of the Consumer Cooperatives of the Central Standard Bureau of the Ministry of Economic Affairs to produce tablets for the French tablets Jingwu I and W mixed parts are used in the entire brake department: industry · 5¾. The genus Bacteria is replaced by the sclerotium snail, which is resistant to salt or the combination of bright hair and natural viable bacteria. It is effective to show the bacteria's fine and long-distance dosage. I It is a rational agent. The stalk spirulina anti-drug salt or the bacterial bacterial resistance is known. Bacterium sclerotiorum bacillus snail agent is effective in proportion to the size of the paper. Applicable to China National Standard (CNS) A4 (2! 0X297 mm) 113 3 92 2 1 Printed by the Consumers ’Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs : 6 4 9 A7 B7 V. Description of the invention 14) Compound (I) or a salt thereof is effective for preventing or treating various diseases caused by Helicobacter pupae bacteria such as duodenal ulcer, gastric ulcer, chronic gastritis, and pimple cancer, and, Due to pylorus Bacteria main cause of the ulcer complications Buc, therefore, compound (I) or a salt thereof for preventing the recurrence of ulcer disease is also effective. In addition, the compound (I) or a salt thereof is effective against Gram-positive bacteria such as Staphy lococcus and Bacillus bacteria, and Gram-negative bacteria such as Escherichia, False Pseudomonas, Proteus, Klebsiella, Serratia, Salmonella, Citrobacter, and production test Alcaligenes bacteria have no antibacterial effect. Therefore, the compound (I) or a salt thereof has a selective effect for preventing or treating a disease caused by Helicobacter pupae bacteria, has little effect on other bacteria and fungi, and can be used as a safe medicine without adverse effects. Compound (I) or a salt thereof is stable and has low toxicity. Therefore, the present invention provides an excellent anti-Helicobacter pylori agent without adverse effects. (Please read the notes on the back before filling this page)

This paper size applies to Chinese national standards (CNS > A4 size (210X297 mm) 114 392 2 1

Claims (1)

464649 H3 Patent Application No. 86114531 f Amendment to the scope of patent application (September 10, 1990 | »| pieces | Two kinds of anti-helicospira composition, including compounds of the following formula or their salts Diluent, excipient or vehicle, In the formula, A shows the following formula: In the formula, Q is a hydrogen atom, a halogen atom, a Cl-4 alkyl group, a Cl-4 alkoxy group, or a hydroxyl group * R 1 represents a hydrogen atom; 82 represents a hydrogen atom or a lower alkyl group having 1 to 7 carbon atoms, R 3 Shows a hydrogen atom or a lower fluorenyl group having 1 to 7 carbon atoms, and the staff welfare committee of the Central Standards Bureau of the Ministry of Economic Affairs prints R4 (1) a hydrogen atom t (2) a lower alkyl group having 1 to 7 carbon atoms, ( 15) a lower alkoxycarbonyl group having 2 to 9 broken atoms, (16) an aryloxycarbonyl group having 7 to 12 carbon atoms, or (17 > having 8 to 10 valences which may be substituted by ethoxy or nitro groups Aryloxycarbonyl group of carbon atom 2. For example, the composition of anti-Helicobacter pylori in item 1 of the scope of patent application, wherein R4 represents a hydrogen atom or a lower alkyl group having 1 to 7 carbon atoms. The anti-Helicobacter pylori composition of item 2, wherein Q is a hydrogen atom, R3 is a hydrogen atom, and R2 and R4 are each a Ci-7 alkyl group. 3 922 1 This paper size applies to China National Standard (CNS) A4 specifications (210 X 297 public love) 1 464649 H3 4. For the composition of anti-Helicobacter pylori in item 3 of the patent application scope, in which R2 and R4 are methyl groups. The anti-Helicobacter pylori composition in item 1 of the patent scope, the compound of which is indigoxin. 6. If the anti-Helicobacter pylori composition in item 1 of the patent scope is applied, it is used as a disease related to Helicobacter pylori infection. Prophylactic or therapeutic agents. 7. If the anti-Helicobacter pylori composition in item 6 of the scope of application is applied, wherein the disease associated with Helicobacter pylori infection is Seoul or duodenal ulcer, gastritis or cancer. 8. If the scope of application is The anti-Helicobacter pylori composition of item 1 is used in combination with an antibacterial agent. 9. If the anti-Helicobacter pylori composition in item 1 of the patent application scope is used in combination with an anti-ulcer agent. The anti-helicobacter composition of item 1 is used in combination with an antibacterial agent and an antiulcer agent. 11.-a compound of the formula or a salt thereof, In the printed format of the Staff Welfare Committee of the Central Bureau of Standards of the Ministry of Economic Affairs, Q is a hydrogen atom, a hydrogen atom, a Ci-4 alkyl group, a Ci-4 alkoxy group, or a hydroxyl group. • This paper size applies the Chinese National Standard (CNS) A4 specification ( 210X 297 male cage) 2 392 2 1 464649 H3 価 7ί 7 to 1 -1 with or with ㉟ 子 f + 原 原 原 S ί chlorohydrogen show, / t 2 3 RRR low-grade son Protons with low alkane radicals Protons with low alkane radicals 7-7 1 have ν) Γ 2 / V or protohydrogen νιν ί for protohydrogen is Q when but 2 R and proton hydrogen are The time-based alkane is an aprotogen, and the hydrogen is an alkynyl salt, or the combination thereof is as follows 3 R \ / I / 1 Basic formula A Chinese style is shown below The proton halide and the proton hydrogen are the basic hydroxy alkane or alkoxy alkane in the Q. 1 S S printed by the Staff Welfare Committee of the Central Standards Bureau of the Ministry of Economic Affairs. M 7M71M 1 * 2 R has a lower ortho atom, a lower hydrogen radical, a lower carbon radical, a lower carbon radical, a lower carbon radical, a lower carbon radical, a lower carbon radical, a lower radical, a lower carbon radical, and a lower radical. 9 to 2 The original carbon of the carbonyloxy aryl group 2 1 to 7 has the original carbon of the carbonyl oxyalkyl aryl group to the salt or its ^ 3 compound R chemistry and the M group of the 12th or the second group of the original carbon has a favorable hydrogen Please refer to the application on behalf of the applicant. Jiruzixian 2 Jijia is the paper standard applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 public goods) 3 The original hydrogen is Q of which 3 922 1 Alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl). These lower alkyl groups include, for example, alkyl groups having 1 to 4 pseudo carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second butyl, and third Butyl, M methyl and ethyl are preferred. These lower alkoxy groups include: alkoxy groups having 1 to 4 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, Dibutoxy and tertiary butoxy, Kmethoxy and ethoxy are preferred. Preferably, there are 1 to 3 of these substituents (preferably 1 to 2) which are the same or different. In the "optionally substituted aromatic ring group or aromatic heterocyclic group" shown by A, the substituents also include butanedioxo, such as methylenedioxy and ethylenedioxy. In the formula (I), the "optionally substituted hydrocarbon group" represented by R1 and R2 includes an aliphatic chain hydrocarbon group, an alicyclic hydrocarbon group and an aryl group, and an M aliphatic fluorene hydrocarbon group is preferred. (Please read the precautions on the back before filling out this page.) Employees of the Intellectual Property Bureau of the Ministry of Economic Affairs, Consumer Cooperatives, etc. Printed bases such as propyl, phenyl, phenyl, phenyl, alkoxy, e.g., acetyl, ethyl-3, and Propane, butyl, isobutyl, C1, alkenyl, triethylene, trimethyl, trimethyl, -1 hydrocarbon, trimethyl, such as methyl group, hexamethylene group, melene methyl n-3- . Ethyl ethyl 2-fluorene grades such as butane, 3, alkane such as, branched, diyl, hept-2, alkynyl, or propyl n-C1 alkenyl alkenyl, butyl and allyl straight alkane ~ 7 Methyl methyl group Jia-61-: Grade C but 1 methyl butan C, containing low, iso, and di groups, the base package is, for example, 2-ethyl, such as propyl, pentyl 2,2-propion Olefin special: Dingxin,, and: based on fluorene. Contains n- and alkynyl groups, including methyl group groups, butyl butadiene groups, 2-alithynylpentyl groups, groups, etc., and alkylpropylisomethylalkenyl groups. Base 1-3- such as low propionate. Pentyl 13. Different paper sizes apply the Chinese national standard < CNS > A4 specification (210 X 297 mm) 9 (correction page) 3 9 22 1 4 6 4 6 49 a7 B7 V. Description of the invention 2) n &-* *- ------- I ... (Please read the precautions on the back before filling out this page) Methyl cellulose aqueous solution into 3, 10, 30 or 100 mg / kg suspension, administered orally, each夭 2 times (early 晩) for 3 days. After the last day of administration, the shoulders of each infected Mongolian gerbil were resected and ruptured; a 10-fold serial dilution of the gastric homogenate was inoculated into modified Scroox supplemented with activated carbon. (Skirr ο ν The culture medium was cultured for 4 days under 37 a trace aerobic conditions, and then the removal effect was evaluated based on the presence or absence of bacteria growth. The results are shown in Table 4. After Dunnett's test with the control group, the mean K value of the bacterial cells was expressed as the standard deviation. In Table 4, ^ means p < 0.01. Table 4 Test compound dosage (mg / kg) Clearance (96) Bacterial detection value (log / CFU / gastric wall) Control group (0.5% methyl cellulose solution)-0/4 (0) 6.36 ± 0.19 indole Huisu 3 0/5 (0) 4.61 ± 1.84 10 0/5 (0) 2.76 ± l, 04ss 30 1/4 (25) 1.96 ± 0,783 ^ 100 4/5 (80) 1,48 ± O.OO * * From Table 4, it is known that indoxin above 10 mg / kg will cause the bacterial cell count of the rat crotch printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs of Mongolia to decrease in a dose-dependent manner, and the resulting clearance rate is 30. Mg / kg is 25%, while 100 mg / kg is 80%. These findings prove that the preparation of the present invention is effective against peripheral ulcers, inflammation, and gastric cancer caused by Helicobacter pylori infection. Test example: ¾ (In vivo antimicrobial activity test) The paper size is applicable to the Chinese National Standard (CNS) A4 specification (2! 0X297 mm) 112 (correction page) 3922 1 I ---------- ------ 464649 A7 B7 V. Description of the invention 1 1 1 (Please read the notes on the back before filling this page) Isf Ancient gerbil (mongolian gerbils, MON / Jms / Gb.s, male, 5 weeks old) ) After fasting for 24 hours, each Mongolian gerbil of H. pylori TN2GF4M was inoculated to its stomach with 107.56. After 11 days of infection, the test compound was dissolved in a 0.5% methylcellulose aqueous solution into a 50 mg / kg tincture floating solution and administered orally, twice a day (early mucus) for 2 days. After the last day of administration, each infected tight gerbil rat was removed and ruptured; a 10-fold dilution of the homogenate homogenate was inoculated into modified Skrowrow's supplemented with activated carbon. The culture medium was cultured for 5 days under 37 a microaerobic conditions, and then the removal effect was evaluated based on the presence or absence of bacteria growth. The results are shown in Table 5. The mean value of the bacterial cell count and the standard deviation were shown after the unnett's test with the control group. In Table 5, ss refers to p < 0.01. Table 5 Test compound dose (mg / kg) Clearance (96) Bacterial detection value (log / CFU / gastric wall) Control group (0.5% methylcellulose solution) N-desmethylindoxin 50 50 / 4 (0) 0/4 (0) 6.21 ± 0.06 2.13 ± 0.22 Material _I Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, as shown in Table 5, N-desmethylindene favors emblematin at 50 mg / kg M The above results in a significant reduction in Mongolian gerbil's stomach bacterial cell count. These findings prove that the preparation of the present invention is effective against stroke ulcer, qi inflammation and gastric cancer caused by Helicobacter pylori infection. (In vivo antimicrobial activity test) Mice (Cr i: ICR, male, 5 weeks old) fasted for 20 hours. Pylori paper size applies Chinese national standard (CNS > A4 size (2ΙΟχ29ϋ) ~ 1 1 2 -1 (^ iE Η) 39221 4 6 4 649 The stalk fungus TN2GP4M was inoculated to each mouse with 108'05. Infection 11 (Please read the precautions on the reverse side before filling out this page) Days later, the test compound is administered as a 50 mg / kg suspension in 0.5% methylcellulose aqueous solution and administered orally, twice a day (morning and evening) For 2 days. After the last day of administration, the stomachs of each infected mouse were excised and a 10-fold dilution of the flail homogenate was inoculated into the modified supplemented activated carbon. Good Skirrov's medium t Incubate for 4 days under 1 / ^ trace aerobic conditions, and then evaluate the removal effect based on the presence or absence of bacteria growth. The results are shown in Table 6. After Dunnett's test with the control group, the bacterial cell count was expressed as the mean ± standard deviation. In Table 6, s: s: refers to ρ < 0 · 01 0 Table 6 Test compound dose (mg / kg) Elimination rate has been eliminated / total (%) Bacterial detection (log / CFU / stomach wall) Control Group (0.25% methylcellulose solution)-0/4 (0) 4.73 ± 0.18 The first compound of Example 3 50 0 / 4⑼ 2.94 ± 1.21 ** The fifth compound of Example 3 50 1/4 (25) 2.43 ± 0.78 ** 6th compound of Example 3 50 0/4 (0) 1.96 ± 0.16 ** _group (0.25% methyl cellulose solution)-0/4 (0) 4.55+ 0.46 implementation The second chemical decoration of Example 3 50 0 / 4⑼ 2.55+ 0.75 ** The third compound of Example 3 50 0 / 4⑼ 2.79+ 0.55 ** The fourth compound of Example 3 50 0/4 (0) 2.74 ± 0.64 ** Examples of preparations printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs are used as a therapeutic agent for Helicobacter pylori infection. The preparation of the present invention containing a compound of formula (I) or a salt thereof can be prepared according to the following formula . 1 .Capsules __ 112-2 (correction page) 39 22 1 This paper size applies to China National Standard (CNS) A4 specification (210 × 297 mm) 464649 H3 Patent Application No. 86114531 f Amendment to the scope of patent application (September 10, 1990 | »| pieces | Two kinds of anti-helicospira composition, including compounds of the following formula or their salts Diluent, excipient or vehicle, In the formula, A shows the following formula: In the formula, Q is a hydrogen atom, a halogen atom, a Cl-4 alkyl group, a Cl-4 alkoxy group, or a hydroxyl group * R 1 represents a hydrogen atom; 82 represents a hydrogen atom or a lower alkyl group having 1 to 7 carbon atoms, R 3 Shows a hydrogen atom or a lower fluorenyl group having 1 to 7 carbon atoms, and the staff welfare committee of the Central Standards Bureau of the Ministry of Economic Affairs prints R4 (1) a hydrogen atom t (2) a lower alkyl group having 1 to 7 carbon atoms, ( 15) a lower alkoxycarbonyl group having 2 to 9 broken atoms, (16) an aryloxycarbonyl group having 7 to 12 carbon atoms, or (17 > having 8 to 10 valences which may be substituted by ethoxy or nitro groups Aryloxycarbonyl group of carbon atom 2. For example, the composition of anti-Helicobacter pylori in item 1 of the scope of patent application, wherein R4 represents a hydrogen atom or a lower alkyl group having 1 to 7 carbon atoms. The anti-Helicobacter pylori composition of item 2, wherein Q is a hydrogen atom, R3 is a hydrogen atom, and R2 and R4 are each a Ci-7 alkyl group. 3 922 1 This paper size applies to China National Standard (CNS) A4 specifications (210 X 297 public love) 1