TW200417367A - Antitussive - Google Patents

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Publication number
TW200417367A
TW200417367A TW092126013A TW92126013A TW200417367A TW 200417367 A TW200417367 A TW 200417367A TW 092126013 A TW092126013 A TW 092126013A TW 92126013 A TW92126013 A TW 92126013A TW 200417367 A TW200417367 A TW 200417367A
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TW
Taiwan
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group
bak
production example
synthesis
title compound
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TW092126013A
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Chinese (zh)
Inventor
Tomoko Hibino
Junzo Kamei
Katsuyuki Aoki
Toru Okubo
Yasushi Igarashi
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Tsumura & Co
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Publication of TW200417367A publication Critical patent/TW200417367A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A—HUMAN NECESSITIES
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    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/223—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of alpha-aminoacids
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    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
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    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4425—Pyridinium derivatives, e.g. pralidoxime, pyridostigmine
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5355—Non-condensed oxazines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/536—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/60—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
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    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
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    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
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    • C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
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    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
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Abstract

This invention discloses antitussives containing as the active ingredient compounds represented by the general formula (I) or salts thereof: (I) (in which A is alkoxycarbonylalkyl, carboxylalkyl, pyridylalkyl, oxypyrrolidylalkyl, quinolylalkyl, indolylalkyl, pyrrolidylalkyl, furanylalkyl, thiophenylalkyl, pyrrolylalkyl, imidazylalkyl, pyrazylalkyl, thiazylalkyl, aminocarbonylalkyl, cyanylalkyl, or carboxylbenzyl, and R is optionally protected hydroxyl, or A and R may be united to form a six- or seven-membered oxygenic ring; B is carbonyl or sulfonyl; R1 and R2 are each hydrogen, alkoxyl, benzoyl, halogen atoms, alkyl, hydroxyl, alkoxylcarbonylalkoxyl, or carboxylalkoxyl; R3 and R4 are each hydrogen, alkoxyl, benzoyl, halogen atoms, alkyl, hydroxyl, alkoxylcarbonylalkoxyl, carboxylalkoxyl, cyanylalkoxyl, aminosulfonyl, hydroxylalkoxyl, or aminocarbonylalkoxyl, or R3 and R4 may be united to from alkylenedioxy; and n is 1 or 2). The invention provides novel compounds having antitussive activity, particularly peripheral antitussive activity.

Description

200417367 (1) 玖、發明說明 【發明所屬之技術領域】 本發明係有關止咳藥，更詳而言係具有強力鎭咳作用 之止咳藥及可使用於其之化合物者。 【先前技術】 止咳藥係被廣爲使用於治療倂發有感冒症候群、支氣 管炎、肺炎等呼吸器疾病之咳嗽者，可分類爲作用於咳嗽 中E之中樞性止咳藥，及在末梢（氣道、肺或呼吸肌等） 阻斷傳入咳嗽刺激或傳出來自中樞之興奮的末梢性止咳藥 。惟現今被使用的幾乎均爲中樞性者。 中樞性止咳藥更可分爲麻醉性與非麻醉性者、麻醉性 止咳藥有磷酸可待因、磷酸二氫可待因等、非麻醉性止咳 藥有羥苯醯苯酸齊培啶、氫溴酸美沙芬等化合物係爲人所 知考。 其中’麻醉性止咳藥雖鎭咳作用強，但亦被認爲有便 秘、噁心、嘔吐、頭痛、思睡等副作用，連續服用時會產 生耐性、依賴性等問題。又，非麻醉性止咳藥雖無耐性、 依賴性之副作用較弱’但仍無法避免對咳中樞以外之影謹 ’仍會有思睡、暈眩、頭痛等副作用發生、鎭咳作用亦較 麻醉性止咳藥弱。 所以極希望能提供具有強力之鎭咳作用，且對中樞性 之副作用殆無，具有末梢性鎭咳作用之物質，惟實際上這 種物質迄今幾乎無人提出報告。 ~ 6 - (2) 200417367 本發明係有鑑於上述之實情而開發者’以提供具有鎭 咳作用之化合物，尤其具有末梢性鎭咳作用之新穎化合物 做爲其課題者。 【發明內容】200417367 (1) 发明 Description of the invention [Technical field to which the invention belongs] The present invention relates to an antitussive agent, and more specifically, to an antitussive agent having a strong antitussive effect and a compound that can be used therefor. [Previous technology] Antitussive drugs are widely used to treat cough patients with respiratory symptoms such as cold syndrome, bronchitis, pneumonia, etc., which can be classified as central cough medicines that act in the cough of the cough, and , Lung, or respiratory muscles, etc.) Peripheral cough suppressants that block afferent cough stimuli or excitement from the center. However, almost all of them are used today. Central cough medicines can be further divided into narcotic and non-narcotic people, narcotic cough medicines include codeine phosphate, dihydrocodeine, and so on. Compounds such as methadine bromate are well known. Among them, the narcotic cough medicine has a strong antitussive effect, but it is also considered to have side effects such as constipation, nausea, vomiting, headache, and sleepiness, and it may cause problems such as tolerance and dependence when continuously taken. In addition, although non-narcotic cough medicines have no tolerance and have weak side effects 'but still cannot avoid the effects on the cough center', there will still be side effects such as sleepiness, dizziness, and headache, and the antitussive effect is also more narcotic Sexual cough medicines are weak. Therefore, it is highly desirable to provide a substance with a strong antitussive effect and no central side effects, and a peripheral antitussive effect, but in fact, almost no report has been made of this substance so far. ~ 6-(2) 200417367 The present invention has been developed by the present invention in view of the above-mentioned facts, and has provided a compound having an antitussive effect, especially a novel compound having a peripheral antitussive effect as its subject. [Summary of the Invention]

本發明人等係爲解決上述課題’爲得到具有優異鎭咳 作用之化合物，合成許多化合物進行檢索，結果發現具有 一定構造化合物具有鎭咳作用，其中還包含對中樞性不具 副作用之具有末梢性鎭咳作用者，遂完成了本發明。 即，本發明可提供以下式（I )所示化合物或藥理學 上可被容許之鹽做爲有效成份之止咳藥In order to solve the above-mentioned problem, the present inventors synthesized a number of compounds and searched for compounds having excellent antitussive effects. As a result, it was found that compounds with certain structures have antitussive effects, and they also have peripheral properties with no side effects on centrality The person who coughed, then completed the present invention. That is, the present invention can provide a cough medicine having the compound represented by the following formula (I) or a pharmacologically acceptable salt as an active ingredient

(式中A示烷氧羰基烷基、羧基烷基、吡啶基烷基、氧 化吡啶-基烷基、喳啉基烷基、吲哚烷基、吡咯啶烷基、 呋喃烷基、噻吩烷基、吡咯烷基、咪唑烷基、吡唑烷基、 噻唑烷基、胺羰基烷基、氰烷基、羧基苯甲基' R示可被 保護之羥基、或A與R —起形成爲含氧之六或七節環、B 不鑛基或磺醒基、1^及R2示氫原子、院氧基、苯甲氧基 、鹵素原子、烷基、羥基、烷氧羰基烷氧基、羧基烷氧基 、R3及R4係分別獨立示氫原子、烷氧基、苯甲氧基、鹵 素原子、烷基、羥基、烷氧羰基烷氧基、羧基烷氧基、氰 -7- (3) 200417367 基烷氧基、胺磺醯基、羥基烷氧基、胺羰基烷氧基，或此 等一起示伸烷二氧基、η示1或2之數）。 又，本發明可提供以下式（IA )或（IΒ )所示新穎化 合物者(Wherein A represents an alkoxycarbonylalkyl group, a carboxyalkyl group, a pyridylalkyl group, a pyridyl-oxyalkyl group, a fluorinylalkyl group, an indolealkyl group, a pyrrolidinyl group, a furylalkyl group, and a thienylalkyl group. , Pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, aminocarbonylalkyl, cyanoalkyl, carboxybenzyl 'R shows a hydroxyl group that can be protected, or A and R together form oxygen 6 or 7-membered ring, B is non-mineral or sulfo, 1 ^ and R2 represent a hydrogen atom, a hydroxy group, a benzyloxy group, a halogen atom, an alkyl group, a hydroxyl group, an alkoxycarbonylalkoxy group, a carboxyalkane Oxygen, R3 and R4 are each independently a hydrogen atom, an alkoxy group, a benzoyloxy group, a halogen atom, an alkyl group, a hydroxyl group, an alkoxycarbonylalkoxy group, a carboxyalkoxy group, or a cyano-7- (3) 200417367 Alkoxy, sulfamolyl, hydroxyalkoxy, aminecarbonylalkoxy, or these together show alkanedioxy, η shows a number of 1 or 2). In addition, the present invention can provide a novel compound represented by the following formula (IA) or (IB)

(IA) (IB) (式中，Y示亞甲基、伸乙基、羰基或亞甲羰基、R’示可 被保護之羥基、A ’示烷氧羰基烷基、羧基烷基、吡啶基烷 基、氧化吡啶-基烷基、喹啉基烷基、吲哚基烷基、D比咯 啶基烷基、呋喃基烷基、噻吩基烷基、吡咯基烷基、咪唑 基烷基、吡唑基烷基、噻唑基烷基、胺羰基烷基、氰烷基 、幾基苯甲基、B、Ri、R2、R3、R4及η係分別如上述所 定義）。 【實施方式】 本發明之式（I )所示化合物雖包含一部份化合物，但大 部份係新穎化合物。 上述化合物（I )所含新穎化合物，大體上可分爲上 述式（ΙΑ )及（ΙΒ )所示以下二群。 (4)200417367(IA) (IB) (In the formula, Y represents methylene, ethylene, carbonyl or methylenecarbonyl, R ′ represents a hydroxyl group which can be protected, and A ′ represents an alkoxycarbonylalkyl group, a carboxyalkyl group, and a pyridyl group. Alkyl, pyridyl-oxyalkyl, quinolinylalkyl, indolylalkyl, D-pyrrolidinylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl, imidazolylalkyl, Pyrazolylalkyl, thiazolylalkyl, aminecarbonylalkyl, cyanoalkyl, phenylbenzyl, B, Ri, R2, R3, R4 and η are as defined above). [Embodiment] Although the compound represented by formula (I) of the present invention includes a part of the compound, most of it is a novel compound. The novel compounds contained in the compound (I) can be roughly classified into the following two groups represented by the above formulae (IA) and (IB). (4) 200417367

(ΙΑ) (式中Β、R!、R2、R3、R4、γ及η係分別如上述定義）(ΙΑ) (wherein B, R !, R2, R3, R4, γ and η are as defined above)

(ΙΒ) (式中 義）。(ΙΒ) (in the formula).

上述式（ΙΑ)及（ΙΒ )中，烷氧基係以乙氧基、甲氧 基等C !〜C 4左右之可被取代的低級烷氧基爲宜，烷基亦以 甲基、乙基等C !〜C4左右之可被取代的低級烷基爲宜。此 等之取代基係以甲基或氟原子、氯原子等鹵素原子爲宜。 又，伸烷二氧基係以亞甲二氧基、伸乙二氧基、伸丙二氧 基等爲宜。 另外，烷氧羰基烷基、羰基烷基、吡啶基烷基、氧化 D比啶-基烷基、胺羰基烷基等中之烷氧基或烷基亦以如上 述之之低級烷氧基或低級烷基爲宜。 又，爲保護羥基其保護基則可爲苯甲基、低級烷基、 乙醯基等。 上述式（IA )及（IB )化合物可依例如以下所記載之 反應式製造。 (a)式（IA)中，基γ爲亞甲基之化合物（m) 冬 (5) 200417367 可依例如以下式，使式（Π)所示化合物與甲醛或其衍生 物（例如聚甲醛、二甲氧基甲烷）反應，即可製得。In the above formulae (IA) and (IB), the alkoxy group is preferably a lower alkoxy group which can be substituted with C! ~ C 4 such as ethoxy and methoxy, and the alkyl group is also methyl or ethyl. Substitutable lower alkyl groups such as C! ~ C4 are preferred. These substituents are preferably a halogen atom such as a methyl group, a fluorine atom, or a chlorine atom. The alkylene dioxy group is preferably methylene dioxy, ethylene dioxy or propylene dioxy. In addition, the alkoxy group or alkyl group in alkoxycarbonylalkyl, carbonylalkyl, pyridylalkyl, oxidized pyridinyl-based alkyl, aminecarbonylalkyl, etc. is also a lower alkoxy or Lower alkyl is preferred. The protecting group for protecting the hydroxyl group may be benzyl, lower alkyl, ethenyl, and the like. The compounds of the formulae (IA) and (IB) can be produced by, for example, the following reaction formulae. (a) In the formula (IA), the compound (m) in which the group γ is methylene (5) 200417367 The compound represented by the formula (Π) and formaldehyde or a derivative thereof (for example, polyoxymethylene, Dimethoxymethane) reaction can be obtained.

(Π) (式中，R"示羥基、B、Ri、R2、R3、R4及η係分別(Π) (In the formula, R " shows hydroxyl, B, Ri, R2, R3, R4 and η are respectively

如上述所定義）。 上述反應係對1莫耳化合物（11 )，使用1〜1 〇 〇莫耳 甲醒或其衍生物，在氯仿、二氧甲院、甲苯、DMF、 DMSO、1，4_二噁烷等溶媒存在或不存在下，於_5(rc至 1 〇〇 °C溫度，使用對甲苯磺酸、硫酸等酸予以環化。 (b )式（IA )中，基γ爲伸乙基之化合物（ia-2 ) 可依例如以下式，使式（II )所示化合物與丨_溴氯乙 烷等反應’得化合物（III )，然後閉環即可製得。As defined above). The above reaction is based on 1 mole compound (11), using 1 to 1000 moles of methyl formaldehyde or its derivative, in a solvent such as chloroform, dioxane, toluene, DMF, DMSO, 1,4-dioxane, etc. In the presence or absence, cyclization is performed with an acid such as p-toluenesulfonic acid, sulfuric acid, etc. at a temperature of -5 (rc to 100 ° C.) (B) In the formula (IA), the compound in which the group γ is an ethylidene group ia-2) can be obtained by reacting a compound represented by formula (II) with bromochloroethane and the like according to the following formula to obtain compound (III), and then ring closure can be obtained.

(式中X示鹵素原子、B、r，，、r】、r2、r3、]^4及η -10 - (6) 200417367 係分別如上述定義）。 上述反應係對1莫爾化合物（II )，使用1至1 〇莫 耳 1-溴-2-氯乙烷，在丙酮、DMF、DMSO、甲苯等溶媒存 在下，於-5 0 °C至1 5 0。(：溫度反應後，於-5 0 t：〜1 5 (TC溫度 ’使用碳酸鉀、氫氧化鈉、氫化鈉等鹼予以閉環者。(Wherein X represents a halogen atom, B, r, ,, r], r2, r3,] ^ 4 and η-10-(6) 200417367 are as defined above). The above reaction is performed on 1 mole compound (II) using 1 to 10 mole 1-bromo-2-chloroethane in the presence of a solvent such as acetone, DMF, DMSO, toluene, etc. at -50 ° C to 1 5 0. (: After temperature reaction, at -50 t: ~ 1 5 (TC temperature 'using alkalis such as potassium carbonate, sodium hydroxide, sodium hydride for ring closure.

(Ο式（IA)中，基Y爲羰基之化合物（IA_3 )係 例如依以下式，使式（Π )所示化合物與N，N-羰基二咪 唑等反應即可製得。(In the formula (IA), the compound (IA_3) in which the group Y is a carbonyl group can be prepared by reacting a compound represented by the formula (Π) with N, N-carbonyldiimidazole or the like according to the following formula, for example.

N，N-羰基二咪唑 (II) (1Α·3) (式中Β，R”，l ’ R2，R3，r4，χ及^係分別如上 述定義）。 上述反應係對1莫耳化合物（II)使用1〜1()莫爾Ν ，Ν-羰基二咪唑等化合物，在氯仿、二氯甲院、甲苯、 DMF、DMSO等溶媒存在或不存在下，於^^(^至15〇。匸予 以環化即可得。 (d)式（ΙΑ)中，基Υ爲伸乙基羰基（·από·) 之化合物（IA-4)可以依例如以下式，使式（π)所示化 合物與氯乙醯基氯等反應’得化合物（IV )，繼而予以閉 環即可製得。 (7) 200417367N, N-carbonyldiimidazole (II) (1A · 3) (wherein B, R ", l 'R2, R3, r4, χ and ^ are as defined above). The above reaction is performed on a mole compound ( II) Use 1 ~ 1 () Moore N, N-carbonyldiimidazole and other compounds in the presence or absence of a solvent such as chloroform, dichloromethane, toluene, DMF, DMSO, etc. at ^ (^ to 150).匸 can be obtained by cyclization. (D) In the formula (IA), the compound (IA-4) in which the group Υ is an ethylcarbonyl group (· από ·) can be a compound represented by the formula (π) according to the following formula, for example. The compound (IV) can be obtained by reacting with chloroethenyl chloride and the like, and then it can be prepared by ring closure. (7) 200417367

(式中R”不趙基、B、R!、R2、R3、R4及η係分別如(Where R "is not Zhao Ji, B, R !, R2, R3, R4, and η are respectively

上述）。 上述反應係對1莫爾化合物（II )使用1〜10莫爾氯 乙醯基氯等化合物，於氯仿、二氯甲烷、甲苯、：DMF、 DMSO等溶媒存在或不存在下，於·5(Γ(：至i5(rc溫度反應 ，於〇°C至100 °C溫度使用碳酸鉀、氯化鈉等鹼予以閉環 者0 (e )式（IA )中，基γ爲伸乙基之化合物（lA-2 ) 可依例如以下式，使式（V )所示化合物或其反應性衍生Above). The above reaction system uses 1 to 10 moles of chloroethenyl chloride and other compounds for 1 mole compound (II) in the presence or absence of a solvent such as chloroform, dichloromethane, toluene, DMF, DMSO, etc. Γ (: to i5 (rc temperature reaction, ring closure with a base such as potassium carbonate, sodium chloride, etc. at a temperature of 0 ° C to 100 ° C. 0 (e) In the formula (IA), the group γ is an ethylidene compound ( 1A-2) The compound represented by formula (V) or its reactive derivative can be derived according to the following formula, for example

物’與式（VI )所示二取代胺化合物反應，經閉環即可製 得。The substance 'can be obtained by reacting with a disubstituted amine compound represented by the formula (VI) through ring closure.

(V) R·(V) R

(式中Z示鹵素原子、B、R，、Ri、R2、R3、r4、χ 及 係分別如上述所定義）。 上述反應係對1莫爾化合物（V )，以1至1 〇莫爾二 -12 - (8) 200417367 取代胺（VI)，在乙醯乙酯等溶媒存在或不存在下，於-5〇C至150°C溫度，於DBU等鹼存在下反應即可製得。 (f )式（I B )所示化合物可以使式（v丨丨）所示化合 物或其反應性衍生物，與式（VIII )所示二取代胺化合物 反應’視其需要改變其取代基即可製得。(In the formula, Z represents a halogen atom, B, R ,, Ri, R2, R3, r4, χ, and are each as defined above). The above reaction is to replace 1 mol of compound (V) with 1 to 10 mol of di-12-(8) 200417367 to replace amine (VI) in the presence or absence of a solvent such as ethyl acetate. It can be prepared by reacting at a temperature of C to 150 ° C in the presence of a base such as DBU. (f) The compound represented by the formula (IB) can react the compound represented by the formula (v 丨 丨) or a reactive derivative thereof with a disubstituted amine compound represented by the formula (VIII), and its substituents may be changed as necessary. be made of.

(式中A’’ B、R’、R!、R2、R3、以4及^係分別如上(Where A ’’ B, R ’, R !, R2, R3, and 4 and ^ are as above, respectively

述）。 上述反應係對1莫耳化合物（V 11 )、使甩！〜丨〇莫爾 二取代胺（viii)，於氯仿、二氯甲烷、甲苯苯、DMF等 溶媒存在或不存在下，於-5 0 °C〜1 5 0。(：縮合即可製得。 由以上方法所得化合物，可以採用一般的處理方法， 例如再結晶，各種層析等方法予以精製，視其需要使其成 爲其鹽，即可使用做爲止咳藥。 含有式（I )所示化合物之本發明止咳藥的投予形態 並不特別被限制，可以適當地選擇一般之醫藥投予形態。 這類投予形態可爲例如爲錠劑、膠囊劑、顆粒劑、細粒劑 、粉劑或液劑之類的口服劑、或注射劑、栓劑、吸入劑等 非口服劑。 · 本發明之止咳藥的投予方法以口服投予爲最適宜，這 時製劑中之化合物（I )的投予量係依病人之年齡、性別 、體重或疾病之程度而異，通常對成人係以每日iHOOmg -13- (9) (9)200417367 範圍，以此每日分數次投予爲最理想。 調製適於口服之固體口服劑時可單獨使用本發明化合 物，或使用例如澱粉、乳糖、白糖、甘露糖醇、羧甲基纖 維素、玉米殿粉或無機鹽類之類的賦形劑，依常法製造。 上述賦形劑之外，還可以適當地選擇結合劑、散解劑、界 面活性劑、滑澤劑、促進流動劑、改味劑、著色劑或香料 等予以使用。 調製此固體口服劑時所使用之結合劑可爲澱粉、糊精 、阿拉伯橡嘐粉末、明膠、羥丙基澱粉、甲基纖維素、羧 甲基纖維素鈉、羥丙基纖維素、結晶纖維素、乙基纖維素 、聚乙嫌卩比略院_或聚乙二醇（m a c r 〇 g 〇 1 )。又，散解劑 可爲例如澱粉、羥丙基澱粉、羧甲基纖維素鈉、羧甲基纖 維素鈣、羧甲基纖維素或低取代羥丙基纖維素。另外，界 面活性劑則可爲月桂基硫酸鈉、大豆卵憐脂、蔗糖脂肪酸 酯或聚山梨糖醇酯8 0。 另外’滑澤劑有滑石、蠟類、氫化植物油、蔗糖脂肪 酸酯、硬脂酸鎂、硬脂酸鈣、硬脂酸鋁或聚乙二醇、流動 性促進劑有例如輕質矽酸酐、乾燥氫氧化鋁膠、合成矽酸 鋁或矽酸鎂。 除此外，本發明之止咳藥還可以做爲懸浮液、乳液劑 、糖漿劑或酏劑之液狀口服劑投予。這類劑形中亦可含有 改味去臭劑或著色劑。 另一方面，本發明之止咳藥還可爲非口服劑。這時化 合物（I)之投予量係依病人之年齡、體重、疾病程度而 -14 - (10) (10)200417367 異，通常對成人每日爲1〜3 0 Omg範圍，藉由靜脈注射' 點滴注射、皮下注射或肌肉注射投予爲宜。 調製非口服劑時可用適當之稀釋劑稀釋使用。稀釋劑 可用一般之注射用蒸餾水、生理食鹽水、葡萄糖水溶液、 注射用植物油、麻油、花生油、大豆油、玉米油、丙二醇 或聚乙二醇。非口服劑中更可視其需要加入殺菌劑、防腐 劑或安定劑。 此等中，尤其對注射劑保存安定之觀點，以塡充於小 藥瓶等後經冷凍，以一般之凍結乾燥技術除去水份，做爲 冷凍乾燥物保存’於使用之前再自冷凍乾燥物再調製爲液 劑使用。注射劑中還可視其需要加入等張劑、安定劑、防 腐劑、無痛化劑等。 其他之非口服劑還有例如外用液劑、軟膏等塗劑或投 予直腸內用之栓劑，此等製劑可依常法製造。 如以上說明，本發明止咳藥可以廣泛應用於治療倂發 感冒症候群、支氣管炎、肺炎等呼吸器疾病之咳嗽。 實施例 以下舉出製造例及試驗例，更詳細說明本發明，惟本 發明並不受此等之任何限制。 製造例1 合成2-羥基-4-甲氧基_N]3,4_亞甲二氧基）苯甲基〕 苯甲醯胺 -15- (11) 200417367 於150°C攪拌3小時3.12g ( 17.1毫莫爾）甲氧基 柳酸甲酯，4 · 3 ml ( 3 4 · 3毫莫爾）向日葵基胺。所得粗生 成物以砂膠管柱層析（己院： 收率3 8 %得1 . 9 6 g標題化合物 乙酸乙酯=4 : 1 )精製，以 (B AK-G202 )。As described). The above reaction is based on 1 mole compound (V 11). ~ 丨 〇 Moore Disubstituted amine (viii), in the presence or absence of chloroform, dichloromethane, toluene, DMF and other solvents, at -50 ° C ~ 150. (: Condensation can be obtained. The compound obtained by the above method can be purified by general processing methods, such as recrystallization, various chromatography and other methods, and can be used as a cough medicine if necessary to make it into its salt. The administration form of the cough medicine of the present invention containing the compound represented by the formula (I) is not particularly limited, and a general pharmaceutical administration form can be appropriately selected. Such administration forms may be, for example, tablets, capsules, and granules. Oral preparations such as agents, fine granules, powders, or liquids, or parenteral preparations such as injections, suppositories, and inhalants. · The method of administration of the cough medicine of the present invention is most suitable for oral administration. The amount of Compound (I) to be administered varies depending on the age, sex, weight or disease of the patient. Generally, it is divided into iHOOmg -13- (9) (9) 200417367 daily for adults. Administration is optimal. The compound of the present invention can be used alone when preparing a solid oral preparation suitable for oral administration, or using, for example, starch, lactose, white sugar, mannitol, carboxymethyl cellulose, corn flour or inorganic salts. Excipients of this type are manufactured by conventional methods. In addition to the above-mentioned excipients, a binding agent, a disintegrating agent, a surfactant, a slip agent, a flow-promoting agent, a flavor modifier, a coloring agent, or a fragrance can be appropriately selected. The binding agent used in the preparation of this solid oral preparation may be starch, dextrin, Arabian oak powder, gelatin, hydroxypropyl starch, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl fiber Cellulose, crystalline cellulose, ethyl cellulose, polyethylene glycol, or polyethylene glycol (macr 〇g 〇1). In addition, the disintegrating agent may be, for example, starch, hydroxypropyl starch, carboxymethyl Cellulose sodium, carboxymethyl cellulose calcium, carboxymethyl cellulose or low-substituted hydroxypropyl cellulose. In addition, the surfactant may be sodium lauryl sulfate, soybean egg fat, sucrose fatty acid ester or polysorbate Sugar alcohol ester 8 0. In addition, "slip agents" include talc, waxes, hydrogenated vegetable oils, sucrose fatty acid esters, magnesium stearate, calcium stearate, aluminum stearate or polyethylene glycol, and fluidity promoters. For example, light silicic anhydride, dry aluminum hydroxide glue, synthetic aluminum silicate In addition to magnesium silicate, the cough medicine of the present invention can also be administered as a liquid oral preparation in the form of a suspension, emulsion, syrup or elixir. Such dosage forms may also contain taste-modifying deodorants or colorants On the other hand, the cough suppressant of the present invention may also be a non-oral agent. At this time, the amount of the compound (I) to be administered depends on the age, weight, and degree of the disease of the patient. -14-(10) (10) 200417367 varies, It is usually in the range of 1 to 300 mg per day for adults. It is suitable to be administered by intravenous injection, drip injection, subcutaneous injection or intramuscular injection. When preparing a non-oral preparation, it can be diluted with a suitable diluent. The diluent can be used by ordinary injection Distilled water, physiological saline, dextrose aqueous solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol or polyethylene glycol. For non-oral preparations, bactericides, preservatives or stabilizers can be added as needed. Among them, especially for the stability of injections, they are filled with vials and frozen, and then the water is removed by ordinary freeze-drying techniques, and stored as freeze-dried products. Prepared for liquid use. Isotonic agents, stabilizers, preservatives, and analgesics can also be added to the injections as needed. Other parenteral preparations include preparations such as topical solutions, ointments, and suppositories for intrarectal administration. These preparations can be produced by conventional methods. As described above, the antitussive agent of the present invention can be widely applied to the treatment of cough in respiratory diseases such as a cold syndrome, bronchitis, and pneumonia. Examples The present invention will be described in more detail below with reference to production examples and test examples, but the present invention is not limited to these. Production Example 1 Synthesis of 2-hydroxy-4-methoxy_N] 3,4_methylenedioxy) benzyl] benzamide-15- (11) 200417367 3.12 g at 150 ° C with stirring for 3 hours (17.1 millimoles) methyl methoxysalicylate, 4.3 ml (34. 3 millimoles) sunflower sunflower amine. The obtained crude product was purified by silica gel column chromatography (Yiyuan: yield of 38% to obtain 1.96 g of the title compound ethyl acetate = 4: 1), and was (B AK-G202).

】H-NMR (CDC13) δ:] H-NMR (CDC13) δ:

3.8 1 (s5 3H)? 4.5 1 (d5 J 6.3 1 (brs5 1H)? 6.38 (dd5 (m5 3H)? 7.23 (d?J = 8.9Hz? MS (El) E/Z 301 (M + ) = 5.6 Hz, 2H)5 5.9 6 (s，2H)5 J = 2.5，8.9Hz5 1H)，6.75-6.85 H)? 12.63 (s? 1H) 製造例2 合成2，3-二氫-7-甲氧基-3-〔3，4-(亞甲二氧基）苯甲 基〕-4H-1，3-苯并哼哄-4-酮 於室溫攪拌2小時209.9mg(0.697毫莫爾）製造例1 所得 BAK-G202、105mg ( 3.49毫莫爾）三聚甲醛、 13211^( 0.69 7毫莫爾）對甲苯磺酸1水合物、41111二氯甲 烷。反應液中加入飽和碳酸氫鈉水溶液，以二氯甲烷萃取 ，有機層以無水硫酸鈉乾燥。濃縮後以矽膠管柱層析（己 烷：乙酸乙酯=2 : 1 )精製粗生成物，以收率27%得 59.9mg 標題化合物（BAK-G 2 0 3 )。 -16_ 2004173673.8 1 (s5 3H)? 4.5 1 (d5 J 6.3 1 (brs5 1H)? 6.38 (dd5 (m5 3H)? 7.23 (d? J = 8.9Hz? MS (El) E / Z 301 (M +) = 5.6 Hz, 2H) 5 5.9 6 (s, 2H) 5 J = 2.5, 8.9Hz5 1H), 6.75-6.85 H)? 12.63 (s? 1H) Production Example 2 Synthesis of 2,3-dihydro-7-methoxy -3- [3,4- (Methylenedioxy) benzyl] -4H-1,3-benzoxan-4-one stirred at room temperature for 2 hours 209.9mg (0.697 mmol) 1 The obtained BAK-G202, 105 mg (3.49 mmol) of paraformaldehyde, 13211 ^ (0.69 7 mmol) p-toluenesulfonic acid monohydrate, 41111 dichloromethane. To the reaction solution was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. After concentration, the crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain 59.9 mg of the title compound (BAK-G 2 0 3) in a yield of 27%. -16_ 200417367

BAK-G202BAK-G202

BAK-G203 ]H-NMR (CDC13) δ: 3·83 (s5 3H)，4.64 (s，2H)，5·09 (s，2H)，5.95(s，2H)， 6.43 (d? J = 2.4 Hz, 1 H)? 6.67 (dd，J = 2.4，8.7Hz5 1 H)? 6.7 5 -6.8 5 (m? 3H)? 7.93 (d? J= 8.7Hz? 1H) M S (El) E/Z 3 1 3 (M + ) 製造例3 合成 7-甲氧基-3-〔3，4-(亞甲二氧基）苯甲基〕-2H-1 ，3•苯并 Df D井-2，4 ( 3H)-二酮 冰冷下攪拌1小時22 1.7 mg ( 0.73 7毫莫爾）製造例1 所得 BAK-G202、179mg ( 1.10 毫莫爾）1，1、羰基二咪 唑、4ml二氯甲烷。反應液中力□入水，以二氯甲烷萃取， 有機層以無水硫酸鈉乾燥。濃縮後以矽膠管柱層析（二氯 甲烷：己烷=2 : 1 )精製粗生成物，以收率 84%得 202.6mg 標題化合物（BAK-G219)。 I I ^ ^BAK-G203] H-NMR (CDC13) δ: 3.83 (s5 3H), 4.64 (s, 2H), 5.09 (s, 2H), 5.95 (s, 2H), 6.43 (d? J = 2.4 Hz, 1 H)? 6.67 (dd, J = 2.4, 8.7Hz 5 1 H)? 6.7 5 -6.8 5 (m? 3H)? 7.93 (d? J = 8.7Hz? 1H) MS (El) E / Z 3 1 3 (M +) Production Example 3 Synthesis of 7-methoxy-3- [3,4- (methylenedioxy) benzyl] -2H-1,3 • benzo Df D well-2,4 (3H) -dione was stirred under ice-cooling for 1 hour 22 1.7 mg (0.73 7 mmol) of BAK-G202 obtained in Production Example 1, 179 mg (1.10 mmol) of 1, 1, carbonyldiimidazole, 4 ml of dichloromethane. Water was poured into the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. After concentrating, the crude product was purified by silica gel column chromatography (dichloromethane: hexane = 2: 1) to obtain 202.6 mg of the title compound (BAK-G219) in a yield of 84%. I I ^ ^

BAK-G219BAK-G219

B.AX-G202 〇 - 〇 " ^ H-NMR (CDCls) δ: (13) 200417367 3·89 (s，3H)，5.08 (s，2H)，5.92 (s5 2H), 6.68 (d5 J = 2.3Hz，1H)，6.75 (d，J= 8.5Hz，1H)，6.88 (d5 J = 8.8, 2.3Hz，1 H )，7.0 0 - 7 · 0 5 (m，2 H)，7.9 8 (d，J = 8 · 8 Hz， 1H) MS (El) E/Z 3 27(M + ) 製造例4B.AX-G202 〇- 〇 " ^ H-NMR (CDCls) δ: (13) 200417367 3.89 (s, 3H), 5.08 (s, 2H), 5.92 (s5 2H), 6.68 (d5 J = 2.3Hz, 1H), 6.75 (d, J = 8.5Hz, 1H), 6.88 (d5 J = 8.8, 2.3Hz, 1 H), 7.0 0-7 · 0 5 (m, 2 H), 7.9 8 (d , J = 8 · 8 Hz, 1H) MS (El) E / Z 3 27 (M +) Manufacturing Example 4

合成2，4，6 -三（苯甲氧基）-N-〔 3，4-(亞甲二氧基） 苯甲基〕苯甲醯胺 在460mg(1.05毫莫爾）2，4，6-三（苯甲氧基）苯 甲醯胺及1〇1111甲苯中加入8411^(2.1毫莫爾）60%油狀 之氫化鈉，於1 〇 〇 °C再攪拌2小時。反應液中加入水，以 乙酸乙酯萃取，有機層以無水硫酸鈉乾燥。濃縮後以矽膠 管柱層析（己院··乙酸乙醋=3 : 1 )精製粗生成物，以收 率43%得256mg標題化合物（BAK-G232-2)。Synthesis of 2,4,6-tris (benzyloxy) -N- [3,4- (methylenedioxy) benzyl] benzamide in 460mg (1.05 mmol), 2,4,6 -Tris (benzyloxy) benzamide and 101111 toluene were added with 8411 ^ (2.1 mmol) of 60% oily sodium hydride and stirred at 1000 ° C for another 2 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After concentrating, the crude product was purified by silica gel column chromatography (Kiyain ·· ethyl acetate = 3: 1) to obtain 256 mg of the title compound (BAK-G232-2) in a yield of 43%.

BnOBnO

BAK-G232-2BAK-G232-2

H-NMR (CDC13) δ: 4·49 (d5 J = 5.7Hz，2Η)，4.97 (s，2Η)5 5·05 (s，4Η)，5.89 (s5 2H), 5.95 (t; J = 5.7Hz5 ]H)，6.23(s，2H)，6.54(d， J = 7.9Hz; 1H)， 6.69 (dd; J = 1 .6; 7.9Hz; 1H); 6.77 (d? J = . 6 H z , 1 H )，7.2 5 - 7.4 5 (m，] 5 H ) -18 - (14) 200417367 MS (El) E/Z 5 7 3 (M + ) 製造例5 合成2，4 -雙（苯甲氧基）-6 -經基-N-〔 3，4-(亞甲二氧 基）苯甲基〕苯甲醯胺H-NMR (CDC13) δ: 4.49 (d5 J = 5.7Hz, 2Η), 4.97 (s, 2Η) 5 5.05 (s, 4Η), 5.89 (s5 2H), 5.95 (t; J = 5.7 Hz5] H), 6.23 (s, 2H), 6.54 (d, J = 7.9Hz; 1H), 6.69 (dd; J = 1.6, 7.9Hz; 1H); 6.77 (d? J = .6 H z , 1 H), 7.2 5-7.4 5 (m,] 5 H) -18-(14) 200417367 MS (El) E / Z 5 7 3 (M +) Production Example 5 Synthesis of 2, 4-bis (benzyl) (Oxy) -6-Cyclo-N- [3,4- (methylenedioxy) benzyl] benzamide

在284mg ( 0.495毫莫爾）製造例4所得BAK-G232-2 及1 0 m 1 1，4 -二H惡院中加入1 m 1濃鹽酸，於8 0 °C攪样3 0 分鐘。反應液中加入水，以乙酸乙酯萃取，.有機層以無水 硫酸鈉乾燥。濃縮後以矽膠管柱層析（己烷：乙酸乙酯=5 :1 )精製粗生成物，以收率60%得143. lg標題化合物（ B AK-G23 8 )。To 284 mg (0.495 mmol) of BAK-G232-2 obtained in Production Example 4 and 10 m 1 of 1,4-diH, a 1 m 1 concentrated hydrochloric acid was added, and the sample was stirred at 80 ° C for 30 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. After concentration, the crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain 143. lg of the title compound (B AK-G23 8) in a yield of 60%.

BAK-G232-2 BAK-G238BAK-G232-2 BAK-G238

JH-NMR (CDC13) δ: 4·34 (d5 J = 5.4Hz，2Η)，4.99(s，2Η)，5.05 (s5 2Η)5 5.95 (s，2H)5 6.13 (d5 J =2·3 Hz，1H)，6.24(d，J = 2.3Hz， 1H)5 6.5 0 - 6.6 0 (m5 2H)5 6.6 6 (d5 J = 7.8Hz5 1H), 7.25- 7.45(m5 l〇H) 5 8.3 7 (t5 J = 5.4 Hz? 1H)? 14.29 (s? 1H) MS (El) E/Z 4 8 3 (M + ) 製造例6 合成5，7 >雙（苯甲氧基（-3 -〔 3，4 -(亞甲二氧基）苯 -19- (15) 200417367 甲基〕-2H-1，3 -苯并噚畊-2，4-(3H)-二酮 與製造例3 —樣之方法，以收率62%得標題化合物（ BAK-G246 ) 〇JH-NMR (CDC13) δ: 4 · 34 (d5 J = 5.4Hz, 2Η), 4.99 (s, 2Η), 5.05 (s5 2Η) 5 5.95 (s, 2H) 5 6.13 (d5 J = 2 · 3 Hz , 1H), 6.24 (d, J = 2.3Hz, 1H) 5 6.5 0-6.6 0 (m5 2H) 5 6.6 6 (d5 J = 7.8Hz5 1H), 7.25- 7.45 (m5 l〇H) 5 8.3 7 ( t5 J = 5.4 Hz? 1H)? 14.29 (s? 1H) MS (El) E / Z 4 8 3 (M +) Production Example 6 Synthesis of 5, 7 > bis (benzyloxy (-3-[3 , 4- (Methylenedioxy) benzene-19- (15) 200417367 methyl] -2H-1,3-benzopyrene-2,4- (3H) -dione and Manufacturing Example 3-the same Method to obtain the title compound (BAK-G246) in a yield of 62%.

BAK-G238 BAK-G246 ]H-NMR (CDC13) δ: 5.06 (s? 4H) 5 5.2 2 (s5 2H)? 5.91 (s，2 H) 5 6 · 3 7 (d， J == 2.2 Η z ? 1H)，6.4 3 ( d 5 J = 2.2 Η z 5 1H)，6.7 4 ( d d ? J = 〇 . 9 ? 7.5Hz? 1H)? 7.00-7.10 (m? 2H)5 7.3 0 - 7.5 5 (m? 10H) MS (El) E/Z 509(M + ) 製造例7 合成 5，7-二羥基-3-〔3，4-(亞甲二氧基）苯甲基〕_ 2H-1，3 -苯并鸣啡-2，4-(3H)-二酮 於氫氣氛下攪拌6小時45mg ( 0.0 8 8毫莫爾·）製造例 6所得BAK-G246，10ml乙酸乙酯及5mg 10%Pd-C。以矽 藻上過濾反應液後濃縮，以收率92%得26.8mg標題化合 物（BAK-G248) 〇BAK-G238 BAK-G246] H-NMR (CDC13) δ: 5.06 (s? 4H) 5 5.2 2 (s5 2H)? 5.91 (s, 2 H) 5 6 · 3 7 (d, J == 2.2 Η z ? 1H), 6.43 (d 5 J = 2.2 Η z 5 1H), 6.74 (dd? J = 0.9? 7.5Hz? 1H)? 7.00-7.10 (m? 2H) 5 7.3 0-7.5 5 ( m? 10H) MS (El) E / Z 509 (M +) Production Example 7 Synthesis of 5,7-dihydroxy-3- [3,4- (methylenedioxy) benzyl] -2H-1, 3-Benzomorphin-2,4- (3H) -dione was stirred under a hydrogen atmosphere for 6 hours and 45 mg (0.0 8 8 mmol) of BAK-G246 obtained in Production Example 6, 10 ml of ethyl acetate and 5 mg of 10% Pd-C. The reaction solution was filtered through diatom and concentrated to obtain 26.8 mg of the title compound (BAK-G248) in a yield of 92%.

BAK-G246 BAK-G248 (16) 200417367 ]H-NMR (丙酮-d6) δ: 5.02 (s5 2H)，5.97 (s5 2H), 6.24 (d，J = 2.1Hz，1H)5 6.26 (d? J =2.1Hz5 1H) 5 6.7 8 (d3 J = 8.5 Hz? 1H)? 6.95-7.00 (m，2H)，10.95 (s，1H) MS (El) E/Z 3 29(M + ) 製造例8 合成4-氯-2-羥基-N-〔3，4-(亞甲二氧基）苯甲基〕苯 甲醯胺 與製造例1 一樣之方法，以收率49%得標題化合物（ BAK-G2 5 9 )。BAK-G246 BAK-G248 (16) 200417367] H-NMR (acetone-d6) δ: 5.02 (s5 2H), 5.97 (s5 2H), 6.24 (d, J = 2.1 Hz, 1H) 5 6.26 (d? J = 2.1Hz5 1H) 5 6.7 8 (d3 J = 8.5 Hz? 1H)? 6.95-7.00 (m, 2H), 10.95 (s, 1H) MS (El) E / Z 3 29 (M +) Manufacturing Example 8 Synthesis 4-Chloro-2-hydroxy-N- [3,4- (methylenedioxy) benzyl] benzamide was prepared in the same manner as in Production Example 1 to obtain the title compound (BAK-G2) in a yield of 49%. 5 9).

BAK-G256BAK-G256

^-NMR (CDC13) δ: 4.52 (d3 J = 5.6Hz5 2H) 5 5.9 6 (s5 2H)? 6.42 (brs5 1H)5 6.75-6.85 (m5 4H)，7.01 (d5 J = 2.1Hz5 1H)5 7.2 4 (d，J = 7.4 Hz? 1H)? 12.48 (s5 1H) MS (El) E/Z 3 0 5 (M + ) 製造例9 合成7-氯-2，3-二氫-3-〔 3，4-(亞甲二氧基）苯甲基〕-4 Η - 1，3 -苯并哼D并-4 -二酮 -21 - (17) 200417367 與製造例2 —樣之方法，以收率9 1 %得標題化合物（ BAK-G25 7 )。^ -NMR (CDC13) δ: 4.52 (d3 J = 5.6Hz5 2H) 5 5.9 6 (s5 2H)? 6.42 (brs5 1H) 5 6.75-6.85 (m5 4H), 7.01 (d5 J = 2.1Hz5 1H) 5 7.2 4 (d, J = 7.4 Hz? 1H)? 12.48 (s5 1H) MS (El) E / Z 3 0 5 (M +) Production Example 9 Synthesis of 7-chloro-2,3-dihydro-3- [3 , 4- (Methylenedioxy) benzyl] -4 fluorene-1,3-benzobenzo-D-4-4dione-21-(17) 200417367 The same method as in Production Example 2 The title compound (BAK-G25 7) was obtained at a yield of 91%.

BAK-G256 BAK-G257 'H-NMR (CDC13) δ: 4.65 (s5 2H)? 5.11 (s? 2H)? 5.95 (s? 2H)5 6.7 5 - 6.8 5 (m? 3H)，6.98 (d，J = 1.9Hz5 1 H)? 7.11 (dd，J= 1 .9? 8.4Hz5 1H)，7.94(d? J = 8.4Hz? 1 H) MS (E I) E/Z 3 1 7 (M + ) 製造例1 〇 合成7-氯-3-〔3，4-(亞甲二氧基）苯甲基〕-2H-1，3-苯 并哼畊，4- ( 3H )-二酮 與製造例3 —樣之方法，以收率93 %得標題化合物（ B AK-G260 )。BAK-G256 BAK-G257 'H-NMR (CDC13) δ: 4.65 (s5 2H)? 5.11 (s? 2H)? 5.95 (s? 2H) 5 6.7 5-6.8 5 (m? 3H), 6.98 (d, J = 1.9Hz5 1 H)? 7.11 (dd, J = 1.9? 8.4Hz5 1H), 7.94 (d? J = 8.4Hz? 1 H) MS (EI) E / Z 3 1 7 (M +) Manufacturing Example 1 〇 Synthesis of 7-chloro-3- [3,4- (methylenedioxy) benzyl] -2H-1,3-benzone, 4- (3H) -dione and Production Example 3 In the same way, the title compound (B AK-G260) was obtained in a yield of 93%.

H-NMR (CDCh) δ: 5.09 (s，2Η)，5.93 (s，2H)，6.75 (d; J = 8.4Hz，1Η); 7.00-7.05 (m? 2H)? 7.29(d, J-].9Hz; 1H); 7.34 (dd: -22- (18) (18)200417367 J=1.9，8·3Ηζ，1H)，8.〇2(d，J = 8 3Hz, iH) M S (El) E/Z 33 1 (M + ) 製造例1 1 合成2 -經基-3-甲氧基〔3，4_ (亞甲二氧基）苯甲基 〕苯甲醯胺 與製造例1 一樣之方法，以收率52%得標題化合物（ B AK-G26 1 )。H-NMR (CDCh) δ: 5.09 (s, 2Η), 5.93 (s, 2H), 6.75 (d; J = 8.4Hz, 1Η); 7.00-7.05 (m? 2H)? 7.29 (d, J-) .9Hz; 1H); 7.34 (dd: -22- (18) (18) 200417367 J = 1.9, 8.3Ηζ, 1H), 8.02 (d, J = 8 3Hz, iH) MS (El) E / Z 33 1 (M +) Production Example 1 1 Synthesis of 2-Ethyl-3-methoxy [3,4- (methylenedioxy) benzyl] benzidine. The same method as in Production Example 1, The title compound (B AK-G26 1) was obtained in a yield of 52%.

]H-NMR (CDC13) δ: 3.90(s? 3H)? 4.54 (d? J = 5.6Hz? 2H) 5 5.9 5 (s5 2H)? 6.70- 6.85 (m，5H)，6.98(dd，j=1.4，8.0 Hz，1H)，7.07(dd5 J=1.4? 8.1Hz? 1H)5 1 1.7〇(s5 1H) MS (El) E/Z 301 (M + ) 製造例12 合成2’ 3-二氫-8-甲氧基、3-〔 3，4·(亞甲二氧基）苯甲 基〕-4H-1 ’ 3 -苯并D等哄.4-酮 與製造例2 —樣之方法，以收率9 7 %得標題化合物（ B AK-G26 3 )。 -ZO - (19) 200417367 、〇 Ο] H-NMR (CDC13) δ: 3.90 (s? 3H)? 4.54 (d? J = 5.6Hz? 2H) 5 5.9 5 (s5 2H)? 6.70- 6.85 (m, 5H), 6.98 (dd, j = 1.4, 8.0 Hz, 1H), 7.07 (dd5 J = 1.4? 8.1Hz? 1H) 5 1 1.7〇 (s5 1H) MS (El) E / Z 301 (M +) Production Example 12 Synthesis of 2 '3-dihydrogen -8-methoxy, 3- [3,4 · (methylenedioxy) benzyl] -4H-1'3-benzoD, etc. 4-keto is the same method as in Production Example 2, The title compound (B AK-G26 3) was obtained in a yield of 97%. -ZO-(19) 200417367, 〇 〇

BAK-G261BAK-G261

〇 BAK-G263 ο H-NMR (CDC13) δ:〇 BAK-G263 ο H-NMR (CDC13) δ:

3.89 (s? 3Η)? 4.67 (s? 2Η)5 5.16 (s5 2Η)? 5.94(s, 2Η)? 6.7 0 -6.8 5 (m? 3Η)? 7.00-7.1 5 (m5 2Η)? 7.61 (dd? J = 2.7? 6.6Ηζ5 lH) MS (El) Ε/Ζ 3 1 3 (Μ + ) 製造例1 3 合成2-羥基-3-甲基-Ν-〔 3，4-(亞甲二氧基）苯甲基〕 苯甲醯胺3.89 (s? 3Η)? 4.67 (s? 2Η) 5 5.16 (s5 2Η)? 5.94 (s, 2Η)? 6.7 0 -6.8 5 (m? 3Η)? 7.00-7.1 5 (m5 2Η)? 7.61 (dd ? J = 2.7? 6.6Ηζ5 lH) MS (El) E / Z 3 1 3 (Μ +) Production Example 1 3 Synthesis of 2-hydroxy-3-methyl-N- [3,4- (methylenedioxy ) Benzyl] benzamidine

與製造例1 一樣之方法，以收率46%得標題化合物（ B AK-G2 6 5 )。In the same manner as in Production Example 1, the title compound (B AK-G2 6 5) was obtained in a yield of 46%.

BAK-G265 ^-NMR (CDCI3) δ: 2.27(s，3H) 5 4.5 3 (d，J = 5.6Hz，2H) 5 5.9 6 (s，2Η)，6·48 (brs? 1Η); 6.65-6.85 (m; 4Η), 7.10-7.30 (m5 2Η)? 12.51 (s; 1Η) -24 - (20) 200417367 MS (El) E/Z 2 8 5 (M + ) 製造例1 4 合成2，3-二氫-8-甲基-3-〔3，4-(亞甲二氧基）苯甲基 〕-4H-1，3 -苯并哼畊-4-酮 與製造例2 —樣之方法，以收率82%得標題化合物（ BAK-G26 7)。BAK-G265 ^ -NMR (CDCI3) δ: 2.27 (s, 3H) 5 4.5 3 (d, J = 5.6Hz, 2H) 5 5.9 6 (s, 2Η), 6.48 (brs? 1Η); 6.65- 6.85 (m; 4Η), 7.10-7.30 (m5 2Η)? 12.51 (s; 1Η) -24-(20) 200417367 MS (El) E / Z 2 8 5 (M +) Manufacturing Example 1 4 Synthesis 2, 3 -Dihydro-8-methyl-3- [3,4- (methylenedioxy) benzyl] -4H-1,3-benzophenone-4-one and Production Example 2-the same method The title compound (BAK-G26 7) was obtained in a yield of 82%.

BAK-G265 BAK-G267BAK-G265 BAK-G267

^-NMR (CDC13) δ: 2.21 (s5 3H)? 4.66(s? 2H)5 5.12(s5 2H)? 5.95(s? 2H)5^ -NMR (CDC13) δ: 2.21 (s5 3H)? 4.66 (s? 2H) 5 5.12 (s5 2H)? 5.95 (s? 2H) 5

6.7 0 -6.8 5 (m5 3H)5 7.0 2 (t5 J = 7.7Hz? 1H)? 7.29 (dd? J = 1.4，7·7 Hz，1H)，7.85 (dd5 J=1.4, 7.7Hz5 1H) MS (El) E/Z 297 (M + ) 製造例15 合成8-甲氧基-3-〔3，4-(亞甲二氧基）苯甲基〕-2H-1 ，3 -苯并鸣啡-2，4-(3H)-二酮 與製造例3 —樣之方法，以收率94 %得標題化合物（ B A K - G 2 6 8 )。 - 25- (21) 2004173676.7 0 -6.8 5 (m5 3H) 5 7.0 2 (t5 J = 7.7Hz? 1H)? 7.29 (dd? J = 1.4, 7.7 Hz, 1H), 7.85 (dd5 J = 1.4, 7.7Hz5 1H) MS (El) E / Z 297 (M +) Production Example 15 Synthesis of 8-methoxy-3- [3,4- (methylenedioxy) benzyl] -2H-1,3-benzobenphine -2,4- (3H) -dione was prepared in the same manner as in Production Example 3 to obtain the title compound (BAK-G 2 6 8) in a yield of 94%. -25- (21) 200417367

^-NMR (CDC13) δ: 3.95 (s5 3H)，5.11 (s，2H)，5.92 (s5 2H) 5 6,7 4 (d， J = 8.4Hz5 1H)5 7.00-7.05 (m.? 2H)? 7.15-7.35 (m? 2H)? 7.63 (dd，J=1 .9，7.5Hz，1H) MS (El) E/Z 3 2 7 (M + ) 製造例1 6 合成8-甲基- 3-〔3，4-(亞甲二氧基）苯甲基〕-2H-1，3-苯并 Df 畊-2，4- ( 3H )-二酮 與製造例3 —樣之方法，以收率93 %得標題化合物（ B A K - G 2 6 9 )。^ -NMR (CDC13) δ: 3.95 (s5 3H), 5.11 (s, 2H), 5.92 (s5 2H) 5 6,7 4 (d, J = 8.4Hz5 1H) 5 7.00-7.05 (m.? 2H) 7.15-7.35 (m? 2H)? 7.63 (dd, J = 1.9, 7.5Hz, 1H) MS (El) E / Z 3 2 7 (M +) Production Example 1 6 Synthesis of 8-methyl-3 -[3,4- (Methylenedioxy) benzyl] -2H-1,3-benzo Df phen-2,4- (3H) -dione and the same method as in Manufacturing Example 3 to collect The title compound (BAK-G 2 6 9) was obtained at a rate of 93%.

Ο BAK-G265〇 BAK-G265

】H-NMR (CDC13) δ: 2.41 (s? 3H)5 5.12 (s; 2H)5 5.92 (s? 2H), 6.75 (d; J = 8.4 Hz, 1 H)5 7.0 0 - 7.1 0 〇 ; 2 H )，7.2 4 (t; J = 7.3 H z， 1 H ); 7.52 ( d d : J 二].4， 7.3 H z， 1 H)r 7.92 (dd: J 二 1 . 4， -26 - (22) 200417367 7.3Hz，1H) MS (El) E/Z 3 1 1 (M + ) 製造例1 7 合成N- (3，4 -二甲氧苯甲基）-2 -羥基-3-甲氧基苯甲醯 胺 與製造例1 一樣之方法，以收率5 1 %得標題化合物（ BAK-G3 20 )。】 H-NMR (CDC13) δ: 2.41 (s? 3H) 5 5.12 (s; 2H) 5 5.92 (s? 2H), 6.75 (d; J = 8.4 Hz, 1 H) 5 7.0 0-7.1 0 〇; 2 H), 7.24 (t; J = 7.3 H z, 1 H); 7.52 (dd: J two). 4, 7.3 H z, 1 H) r 7.92 (dd: J two 1.4, -26- (22) 200417367 7.3 Hz, 1H) MS (El) E / Z 3 1 1 (M +) Production Example 1 7 Synthesis of N- (3,4-dimethoxybenzyl) -2 -hydroxy-3-methyl In the same manner as in Production Example 1, oxybenzamide was used to obtain the title compound (BAK-G3 20) in a yield of 51%.

BAK-G320 ^-NMR (CDC13) δ: 3.87 (s5 6Η) 5 3.9 0 (s5 3Η)， 4.5 7 (d， J = 5.6Hz， 2Η)， 6.75 -6.95 (m, 5H)，6.98(dd，J=l，4，8.1Hz5 1H)，7.0 7 (dd? J = 1.4? 8.1Hz? 1H)5 11.81 (s? 1H) MS (El) E/Z 317 (M + ) 製造例18 合成5-氯-N-(3，4-二甲氧苯甲基）·八羥基苯甲醯胺 與製造例1 一樣之方法，以收率7 9 %得標題化合物（ BAK-G 3 3 2 )。 200417367BAK-G320 ^ -NMR (CDC13) δ: 3.87 (s5 6Η) 5 3.9 0 (s5 3Η), 4.5 7 (d, J = 5.6Hz, 2Η), 6.75 -6.95 (m, 5H), 6.98 (dd, J = 1, 4, 8.1Hz5 1H), 7.0 7 (dd? J = 1.4? 8.1Hz? 1H) 5 11.81 (s? 1H) MS (El) E / Z 317 (M +) Manufacturing Example 18 Synthesis 5- Chloro-N- (3,4-dimethoxybenzyl) · octahydroxybenzamide was prepared in the same manner as in Production Example 1 to obtain the title compound (BAK-G 3 3 2) in a yield of 79%. 200417367

]H-NMR (CDC13) δ: 3.89 (s? 6H)? 4.56 (d5 J = 5.5Hz5 2H)? 6.44 (brs5 1H)?] H-NMR (CDC13) δ: 3.89 (s? 6H)? 4.56 (d5 J = 5.5Hz5 2H)? 6.44 (brs5 1H)?

6.8 0 -6.90 (m，3H)，6.95 (d，J = 8.8Hz，1H)5 7.31 (d5 J = 2.5Hz，1H)，7.34(dd5 J = 2.5，8·8Ηζ5 1H)，12.24 (s， 1H) MS (El) E/Z 321 (M + ) 製造例1 9 合成5-氯·2-羥基-N-〔 3，4-(亞甲二氧基）苯甲基〕苯 甲醯胺 與製造例1 一樣之方法，以收率26%得標題化合物（ BAK-G293 )。6.8 0 -6.90 (m, 3H), 6.95 (d, J = 8.8Hz, 1H) 5 7.31 (d5 J = 2.5Hz, 1H), 7.34 (dd5 J = 2.5, 8 · 8Ηζ5 1H), 12.24 (s, 1H) MS (El) E / Z 321 (M +) Production Example 1 9 Synthesis of 5-chloro · 2-hydroxy-N- [3,4- (methylenedioxy) benzyl] benzidine and In the same manner as in Production Example 1, the title compound (BAK-G293) was obtained in a yield of 26%.

〇 BAK-6293 ^-NMR (CDCI3) δ: (s, 2H)5 6.4 3 (brs5 1H)5 J = 8.7Hz3 1 H)? 7.25-7.40 4.53 (d，J = 5.6Hz，2Η)5 5·98 6.8 0-6.8 5 (m5 3Η)? 6.95 (d5 (m; 2H); 12.22 (s? 1H) MS (El) E/Z 3 0 5 (M + ) -28- (24) 200417367 製造例20 合成3- (3，4-二甲氧苯甲基）-2，3-二氫-8-甲氧基- 4H-1 ，3-苯并哼哄-4-酮 與製造例2 —樣之方法，以收率94 %得標題化合物（ BAK-G321 )。〇 BAK-6293 ^ -NMR (CDCI3) δ: (s, 2H) 5 6.4 3 (brs5 1H) 5 J = 8.7Hz3 1 H)? 7.25-7.40 4.53 (d, J = 5.6Hz, 2Η) 5 5 · 98 6.8 0-6.8 5 (m5 3Η)? 6.95 (d5 (m; 2H); 12.22 (s? 1H) MS (El) E / Z 3 0 5 (M +) -28- (24) 200417367 Manufacturing example 20 Synthesis of 3- (3,4-dimethoxybenzyl) -2,3-dihydro-8-methoxy-4H-1,3-benzoxan-4-one and Production Example 2-the same This method gave the title compound (BAK-G321) in a yield of 94%.

BAK-G320 BAK-G321BAK-G320 BAK-G321

^-NMR (CDC13) δ: 3.86 (s5 3H) 5 3.8 7 (s? 3H) 5 3.8 9 (s? 3H)5 4.7 0 (s5 2H)5 5 .17(s， 2H)5 6.80-6.90(m5 3H)5 7.00-7.15 (m5 2H)5 7.62 (dd5 J = 2.7? 6.7Hz，1H)^ -NMR (CDC13) δ: 3.86 (s5 3H) 5 3.8 7 (s? 3H) 5 3.8 9 (s? 3H) 5 4.7 0 (s5 2H) 5 5 .17 (s, 2H) 5 6.80-6.90 ( m5 3H) 5 7.00-7.15 (m5 2H) 5 7.62 (dd5 J = 2.7? 6.7Hz, 1H)

MS (El) E/Z 3 29 (M + ) 製造例2 1 合成6-氯-3- (3，4-二甲氧苯甲基）-2，3-二氫- 4H-1，3-苯并啤D井-4 -酮 與製造例2 —樣之方法，以收率72 %得標題化合物（ BAK-G3 3 3 )。 -29- 200417367MS (El) E / Z 3 29 (M +) Production Example 2 1 Synthesis of 6-chloro-3- (3,4-dimethoxybenzyl) -2,3-dihydro-4H-1,3- Benzo beer D well-4 -one was the same as in Production Example 2 to obtain the title compound (BAK-G3 3 3) in a yield of 72%. -29- 200417367

BAK-G332BAK-G332

BAK-G333 】H-NMR (CDC13) δ: 3.86 (s5 3H)? 3.87 (s? 3H)? 4.69 (s5 2H)? 5.10 (s? 2H), 6.8 0-6.9 0 (m5 3H)5 6.91(d? J = 8.7Hz5 1H) 5 7.3 9 (dd? J = 2.6? 8.7 Hz, 1H)，7.99 (d，J = 2.6Hz，1H) MS (El) E/Z 3 3 3 (M + ) 製造例22 合成6-氯-2，3-二氫- 3-〔3，4-(亞甲二氧基）苯甲基〕-4 Η - 1，3 -苯并Df畊-4 -酮 與製造例2 —樣之方法，以收率94 %得標題化合物（ BAK-G3 3 0 )。BAK-G333】 H-NMR (CDC13) δ: 3.86 (s5 3H)? 3.87 (s? 3H)? 4.69 (s5 2H)? 5.10 (s? 2H), 6.8 0-6.9 0 (m5 3H) 5 6.91 ( d? J = 8.7Hz5 1H) 5 7.3 9 (dd? J = 2.6? 8.7 Hz, 1H), 7.99 (d, J = 2.6Hz, 1H) MS (El) E / Z 3 3 3 (M +) Manufacturing Example 22 Synthesis of 6-chloro-2,3-dihydro- 3- [3,4- (methylenedioxy) benzyl] -4 pyrene-1,3-benzo-Df phen-4-one and its manufacture Example 2-In the same manner, the title compound (BAK-G3 3 0) was obtained in a yield of 94%.

〇H〇H

BAK-G293BAK-G293

BAK-G330 ]H-NMR (CDC13) δ: 4.65 (s5 2H)? 5.10 (s5 2H)? 5.95 (s5 2H), 6.7 5 - 6.8 5 (m5 3H)5 6.9 0 (d5 J = 8.7 Hz5 1H) 5 7.3 9 (dd? J = 2.65 8.7 Hz5 1 H)，7.98(d? J = 2.6Hz; 1 H) MS (El) E/Z 3 1 7 (M + ) -30 - (26) 200417367 製造例23 合成3- ( 3，4-二甲氧苯甲基）-8-甲氧基- 2H-1，3-苯并哼 畊-2，4 ( 3H )-二酮 與製造例3 —樣之方法，以收率95 %得標題化合物（ BAK-G3 22 )。BAK-G330] H-NMR (CDC13) δ: 4.65 (s5 2H)? 5.10 (s5 2H)? 5.95 (s5 2H), 6.7 5-6.8 5 (m5 3H) 5 6.9 0 (d5 J = 8.7 Hz5 1H) 5 7.3 9 (dd? J = 2.65 8.7 Hz 5 1 H), 7.98 (d? J = 2.6 Hz; 1 H) MS (El) E / Z 3 1 7 (M +) -30-(26) 200417367 Manufacturing example 23 Synthesis of 3- (3,4-dimethoxybenzyl) -8-methoxy-2H-1,3-benzohumen-2,4 (3H) -dione and Production Example 3-the same Method: The title compound (BAK-G3 22) was obtained in a yield of 95%.

〇 〇 BAK-G320 BAK-G322〇 〇 BAK-G320 BAK-G322

I Ο aH-NMR (CDC13) δ: 3,85 (s，3Η)，3.88 (s，3Η)，3·95 (s5 3Η)5 5.1 5(s，2Η)5 6.80 (d5 J = 8.7 Hz5 1H)? 7.10-7.35 (m5 4H) 5 7.6 4 (dd? J=1 .9，7.5Hz，1H) MS (El) E/Z 3 43 (M+ )I 〇 aH-NMR (CDC13) δ: 3,85 (s, 3Η), 3.88 (s, 3Η), 3.95 (s5 3Η) 5 5.1 5 (s, 2Η) 5 6.80 (d5 J = 8.7 Hz5 1H )? 7.10-7.35 (m5 4H) 5 7.6 4 (dd? J = 1 .9, 7.5Hz, 1H) MS (El) E / Z 3 43 (M +)

製造例24 合成6-氯-3- (3，4-二甲氧苯甲基）-2H-1，3-苯并哼哄-2 ，4 ( 3H)-二酮 與製造例3 —樣之方法，以收率75 %得標題化合物（ BAK-G3 40 )。 -31 - 200417367Production Example 24 Synthesis of 6-Chloro-3- (3,4-dimethoxybenzyl) -2H-1,3-benzoxanthone-2,4 (3H) -dione and Production Example 3-the same The title compound (BAK-G3 40) was obtained in 75% yield. -31-200417367

iH-NMR (CDC13) δ: 3.86 (s5 3H) 5 3.8 8 (s? 3H)? 5.13 (s5 2H)? 6.81 (d5 J = 8.8 Hz? 1H)? 7.10-7.20 (m? 2H) 5 7.2 3 (d? J = 8.8Hz9 1 H)? 7.63 (dd? J = 2.5，8·8Ηζ5 1H)，8.06 (d，J =2.5 Hz， 1H) MS (El) E/Z 3 47 (M + ) 製造例25 合成5-氯-2- (2-氯乙氧基）-N-(3，4-二甲氧苯甲基）苯 甲醯胺 於4 0 °C攪拌2 0小時1 · 1 5 g ( 3 · 5 7毫莫爾）製造例1 8 所得BAK-G332，0·59ml(7·15毫莫爾）l-溴-2-氯乙烷， 1.48g ( 10.71毫莫爾）20ml DMF。反應液中加入水，以 乙酸乙酯萃取’有機層以無水硫酸鈉乾燥。濃縮後以矽膠 管柱層析（己烷：乙酸乙酯=1 : 1 )精製粗生成物，以收 率8 6 %得1 · 1 8 g標題化合物（b A K - G 3 3 4 )。 - 32 - (28) 200417367iH-NMR (CDC13) δ: 3.86 (s5 3H) 5 3.8 8 (s? 3H)? 5.13 (s5 2H)? 6.81 (d5 J = 8.8 Hz? 1H)? 7.10-7.20 (m? 2H) 5 7.2 3 (d? J = 8.8Hz9 1 H)? 7.63 (dd? J = 2.5, 8 · 8Ηζ5 1H), 8.06 (d, J = 2.5 Hz, 1H) MS (El) E / Z 3 47 (M +) Manufacturing Example 25 Synthesis of 5-chloro-2- (2-chloroethoxy) -N- (3,4-dimethoxybenzyl) benzamide. Stir at 40 ° C for 20 hours. 1 · 1 5 g (3.57 mmoles) Production Example 18 BAK-G332, 0.59 ml (7.15 mmoles) of 1-bromo-2-chloroethane, 1.48 g (10.71 mmoles) of 20 ml of DMF. Water was added to the reaction solution, and the organic layer was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After concentrating, the crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain 1.18 g of the title compound (b A K-G 3 3 4) in a yield of 86%. -32-(28) 200417367

ClCl

BAK-G332BAK-G332

ο BAK-G334 】Η-ΝΜΙΙ (CDC13) δ: 3.77(t5 J = 4.8Hz? 2H) 5 3.8 7 (s5 3H)? 3.88(s5 3H)5 4.3 0 (t5 J = 4.8Hz5 2H)? 4.58(d，J = 5.6Hz，2H)? 6.8 0-6.95 (m5ο BAK-G334] Η-ΝΜΙΙ (CDC13) δ: 3.77 (t5 J = 4.8Hz? 2H) 5 3.8 7 (s5 3H)? 3.88 (s5 3H) 5 4.3 0 (t5 J = 4.8Hz5 2H)? 4.58 ( d, J = 5.6Hz, 2H)? 6.8 0-6.95 (m5

4H) 5 7.3 7 (dd5 J = 2.8，8.8Hz，1H)，8.18 (brs，1H)5 8.22 (d? J =2.8 Hz5 1H) MS (El) E/Z 3 8 3 (M + ) 製造例26 合成5-氯-2- (2-氯乙氧基）3，4-(亞甲二氧基）苯 甲基〕苯甲醯胺 與製造例25 —樣之方法，以收率82%得標題化合物 (B AK-G294 )。 ⑩4H) 5 7.3 7 (dd5 J = 2.8, 8.8Hz, 1H), 8.18 (brs, 1H) 5 8.22 (d? J = 2.8 Hz5 1H) MS (El) E / Z 3 8 3 (M +) Manufacturing example 26 Synthesis of 5-chloro-2- (2-chloroethoxy) 3,4- (methylenedioxy) benzyl] benzidine. The same method as in Production Example 25 was obtained at a yield of 82%. The title compound (B AK-G294). ⑩

BAK-G293 BAK-G294 JH-NMR (CDC13)6: 3.80 (t，J = 4.8Hz5 2H)，4.31 (t5 J = 4.8Hz5 2H)，4.55 (d， J = 5.6Hz，2H); 5.94 (s5 2H)，6.70-6.9 0 (m5 4H)5 7.37 -33- (29) 200417367 (dd，J = 2.8，8.8Hz，H)，8.20 (b r s，1 H)，8.2 1 (d，J = 2 · 8 Hz5 1H) MS (El) E/Z 3 67(M + ) 製造例27 合成2- ( 2 -氣乙氧基）3 -甲氧基-N-〔 3 ’ 4-(亞甲一氧基 )苯甲基〕苯甲醯胺 與製造例25 —樣之方法，以收率1 00%得標題化合物 (BAK-G2 8 8 )。BAK-G293 BAK-G294 JH-NMR (CDC13) 6: 3.80 (t, J = 4.8Hz5 2H), 4.31 (t5 J = 4.8Hz5 2H), 4.55 (d, J = 5.6Hz, 2H); 5.94 (s5 2H), 6.70-6.9 0 (m5 4H) 5 7.37 -33- (29) 200417367 (dd, J = 2.8, 8.8 Hz, H), 8.20 (brs, 1 H), 8.2 1 (d, J = 2 · 8 Hz5 1H) MS (El) E / Z 3 67 (M +) Production Example 27 Synthesis of 2- (2 -Gaethoxy) 3 -methoxy-N- [3 '4- (Methylene monooxy ) Benzyl] benzamidine The same method as in Production Example 25 was used to obtain the title compound (BAK-G2 8 8) in a yield of 100%.

BAK-G261 BAK-G288 ^-NMR (CDC13) δ:BAK-G261 BAK-G288 ^ -NMR (CDC13) δ:

3.71 (t? J = 5.1Hz5 2H)? 4.27(t? J = 5.1Hz? 2H) 5 4.5 6 (d5 J = 5·8 Hz5 2H)，5.93 (s，2H)，6·75 (d，J = 7.8Hz，1H)， 6.83(dd? J=1.6，7.8Hz5 1H)? 6.87 (d，J=1.6Hz，1H)， 7.04 (dd? J=1.7? 7.9Hz? 1H)? 7.18 (t? J =7.9 Hz5 1H)? 7.74 (dd，J 二 1·7，7·9Ηζ，1H)5 8·28 (brs5 1H) MS (El) E/Z 3 63 (M + ) 製造例2 8 合成2-(2-氯乙氧基）-4-甲氧基-N- (3，4-(亞甲二氧基 )苯曱基〕苯甲醯胺 -34 - (30) 200417367 與製造例25 —樣之方法，以收率72%得標題化合物 (BAK-G27 8 )。3.71 (t? J = 5.1Hz5 2H)? 4.27 (t? J = 5.1Hz? 2H) 5 4.5 6 (d5 J = 5 · 8 Hz5 2H), 5.93 (s, 2H), 6.75 (d, J = 7.8Hz, 1H), 6.83 (dd? J = 1.6, 7.8Hz5 1H)? 6.87 (d, J = 1.6Hz, 1H), 7.04 (dd? J = 1.7? 7.9Hz? 1H)? 7.18 (t? J = 7.9 Hz5 1H)? 7.74 (dd, J 2 1 · 7, 7 · 9Ηζ, 1H) 5 8 · 28 (brs5 1H) MS (El) E / Z 3 63 (M +) Manufacturing Example 2 8 Synthesis 2 -(2-chloroethoxy) -4-methoxy-N- (3,4- (methylenedioxy) phenylfluorenyl] benzamide-34-(30) 200417367 and Production Example 25 — In the same manner, the title compound (BAK-G27 8) was obtained in a yield of 72%.

BAK-G202BAK-G202

BAK-G278 tNMR (CDC13) δ: 3.79 (t5 J = 4.9Hz? 2H)5 3.8 4 (s? 3H)5 4.3 0 (t5 J= 4.9Hz? 2H)? 4.55(d，J = 5.6Hz，2H)，5.93 (s，2H)，6.40 (d，J = 2.3Hz? 1 H)? 6.64 (dd5 J = 2.3? 8.8Hz? 1H)，6.76 (d? J = 7.8 Hz, 1H)，6.85 (dd5 J = 1.6，7.8Hz，1H)，6.88 (d，J = 1.6Hz，1H)5 8.13 (brs，1H)，8.21 (d，J = 8.8 Hz, 1H) 製造例29 合成7-氯-4- (3，4-二甲氧苯甲基）-3，4-二氫-1，4-苯 幷哼吖庚因-5 ( 2H )-酮 961mg(2.50毫莫爾）製造例25所得BAK-G334之 30瓜1甲苯中加入20011^(5.00毫莫爾）氫化鈉（60%油狀 )，於1 〇 〇 °C攪拌2 0小時。反應液中加入水，以乙酸乙 酯萃取，有機層以無水硫酸鈉乾燥。濃縮後以矽膠管柱層 析（己烷··乙酸乙酯=3 : 2 )精製粗生成物，以收率90% 得78 3mg標題化合物（BAK-G3 3 5 )。 -35- (31) 200417367 α 广ClBAK-G278 tNMR (CDC13) δ: 3.79 (t5 J = 4.9Hz? 2H) 5 3.8 4 (s? 3H) 5 4.3 0 (t5 J = 4.9Hz? 2H)? 4.55 (d, J = 5.6Hz, 2H ), 5.93 (s, 2H), 6.40 (d, J = 2.3Hz? 1 H)? 6.64 (dd5 J = 2.3? 8.8Hz? 1H), 6.76 (d? J = 7.8 Hz, 1H), 6.85 (dd5 J = 1.6, 7.8 Hz, 1H), 6.88 (d, J = 1.6 Hz, 1H) 5 8.13 (brs, 1H), 8.21 (d, J = 8.8 Hz, 1H) Production Example 29 Synthesis of 7-chloro-4- (3,4-Dimethoxybenzyl) -3,4-dihydro-1,4-phenylazepine-5 (2H) -one 961 mg (2.50 mmol) obtained in Production Example BAK- Add Glycol 30, 30 melon, 1 toluene, 20011 ^ (5.00 mmol) sodium hydride (60% oily), and stir at 1000 ° C for 20 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After concentration, the crude product was purified by silica gel column chromatography (hexane · ethyl acetate = 3: 2) to obtain 78 3 mg of the title compound (BAK-G3 3 5) in a yield of 90%. -35- (31) 200417367 α Wide Cl

ο BAK-G334ο BAK-G334

BAK-G335 ^-NMR (CDCls) δ: 3.45 (t? J = 5.3Hz? 2H)? 3.88 (s? 3H)? 3.89 (s? 3H)? 4.13 (t5 J = 5 .3Hz? 2H)? 4.76 (s·，2H)5 6.8 0 - 6 · 9 5 (m，4 H)，BAK-G335 ^ -NMR (CDCls) δ: 3.45 (t? J = 5.3Hz? 2H)? 3.88 (s? 3H)? 3.89 (s? 3H)? 4.13 (t5 J = 5.3Hz? 2H)? 4.76 (s ·, 2H) 5 6.8 0-6 · 9 5 (m, 4 H),

7.36 (dd5 J = 2.7? 8.6Hz? 1H)? 7.85(d? J = 2.7 Hz5 1H) MS (El) E/Z 347 (M + ) 製造例3 0 合成7-氯-3，4-二氫-4-〔3，4-(亞甲二氧基）苯甲基〕-1，4-苯并鸣吖庚因-5 ( 2H )-酮 與製造例2 9 —樣之方法，以收率7 5 %得標題化合物 (BAK-G295 )。7.36 (dd5 J = 2.7? 8.6Hz? 1H)? 7.85 (d? J = 2.7 Hz5 1H) MS (El) E / Z 347 (M +) Manufacturing Example 3 0 Synthesis of 7-chloro-3,4-dihydro -4- [3,4- (Methylenedioxy) benzyl] -1,4-benzylazepine-5 (2H) -one and Production Example 29 9 in the same manner as the yield 75% gave the title compound (BAK-G295).

BAK-G294 BAK-G295 H-NMR (CDC13) δ: 3.44 (t? J = 4.9Hz5 2H)5 4.18 (t5 J = 4.9Hz5 2H)? 4.71 (s5 2H)， 5.9 7 (s5 2H)， 6.7 5 - 6.90 (m， 3H)， 6.93 (d5 J = 8.6Hz，1H)，7.36 (dd，J二 2.75 8.6 Hz5 ]H)5 7·85 (d，J = 2.7 Hz，1H) -36- (32) 200417367 MS (El) E/Z 331 (M + ) 製造例31 合成3，4-二氫-9-甲氧基- 4-〔 3，4-(亞甲二氧基）苯甲 基〕-1，4-苯并Df吖庚因- 5(2H)-酮 與製造例29 —樣之方法，以收率75 %得標題化合物 (B AK-G290 )。BAK-G294 BAK-G295 H-NMR (CDC13) δ: 3.44 (t? J = 4.9Hz5 2H) 5 4.18 (t5 J = 4.9Hz5 2H)? 4.71 (s5 2H), 5.9 7 (s5 2H), 6.7 5 -6.90 (m, 3H), 6.93 (d5 J = 8.6Hz, 1H), 7.36 (dd, J = 2.75 8.6 Hz5) H) 5 7 · 85 (d, J = 2.7 Hz, 1H) -36- (32 200417367 MS (El) E / Z 331 (M +) Production Example 31 Synthesis of 3,4-dihydro-9-methoxy-4- [3,4- (methylenedioxy) benzyl]- 1,4-benzo Dfazepine-5 (2H) -one was prepared in the same manner as in Production Example 29 to obtain the title compound (B AK-G290) in a yield of 75%.

BAK-G288BAK-G288

BAK-G290 ^-NMR (CDC13) δ: 3.42 (t5 J = 5.3Hz5 2H) 5 3.8 7 (s5 3H)5 4.20 (t, J = 5.3Hz5 2H)，4.74 (s5 2H)，5.95 (s，2H)，6.70-6.85 (m5 2H)， 6.89 (d? J=1.2Hz? 1H)? 7.03(dd? J =1 -7? 7.7 Hz? 1H)? 7.14 (t5 J = 7.7 Hz5 1H) 5 7.3 9 (dd? J= 1.7 5 7.7 Hz5 1H) MS (El) E/Z 3 2 7(M + ) 製造例32 合成3，4-二氫-8-甲氧基- 4-〔3，4-(亞甲二氧基）苯甲 基〕-1，4·苯并鳄吖庚因- 5(4H)-酮 與製造例29 —樣之方法，以收率87%得標題化合物 (BAK-G2 8 2 )。 -37- (33) 200417367 广ClBAK-G290 ^ -NMR (CDC13) δ: 3.42 (t5 J = 5.3Hz5 2H) 5 3.8 7 (s5 3H) 5 4.20 (t, J = 5.3Hz5 2H), 4.74 (s5 2H), 5.95 (s, 2H ), 6.70-6.85 (m5 2H), 6.89 (d? J = 1.2Hz? 1H)? 7.03 (dd? J = 1 -7? 7.7 Hz? 1H)? 7.14 (t5 J = 7.7 Hz5 1H) 5 7.3 9 (dd? J = 1.7 5 7.7 Hz5 1H) MS (El) E / Z 3 2 7 (M +) Production Example 32 Synthesis of 3,4-dihydro-8-methoxy- 4- [3,4- ( Methylenedioxy) benzyl] -1,4 · benzocropin-5 (4H) -one was prepared in the same manner as in Production Example 29 to obtain the title compound (BAK-G2 8 in a yield of 87%). 2 ). -37- (33) 200417367 Guang Cl

BAK- G282 2H) 5 3.8 2 (s5 5.95(s? 2H)? 8.8 Hz? jH-NMR (CDCI3) δ: 3,46(t，J = 4.7Hz5 2H)5 4.7 1 (s，2H)5 1H)? 6.71 (dd5 J = 2.5 7.88(d，J = 8.8Hz，1 H) MS (El) E/Z 327(M + ) 3H)? 4.20(t? J = 4.7Hz? 6.48(d，J = 2.5 Hz， 1H)5 6.75 -6.9 0(m? 3H)5BAK- G282 2H) 5 3.8 2 (s5 5.95 (s? 2H)? 8.8 Hz? JH-NMR (CDCI3) δ: 3,46 (t, J = 4.7Hz5 2H) 5 4.7 1 (s, 2H) 5 1H )? 6.71 (dd5 J = 2.5 7.88 (d, J = 8.8Hz, 1 H) MS (El) E / Z 327 (M +) 3H)? 4.20 (t? J = 4.7Hz? 6.48 (d, J = 2.5 Hz, 1H) 5 6.75 -6.9 0 (m? 3H) 5

製造例3 3 合成氯化乙酸3-甲氧基-5-〔 〔3，4-(亞甲二氧基）苯甲 基〕胺甲醯基〕苯酯Production Example 3 3 Synthesis of 3-methoxy-5-[[3,4- (methylenedioxy) benzyl] aminemethylamido] phenyl chloride

冰冷 5 1 1 .3mg ( 1 .70毫莫爾）製造例1 Κ-ΒΑΚ-G202，0.59ml (3·40 毫莫爾（DIEa) ，10ml 二氯甲烷， 在其中滴下0· 1 6ml氯乙醯基氯，冰冷下攪拌2小時。反 應液中加入稀鹽酸，以二氯甲烷萃取，有機層以無水硫酸 鈉乾燥。濃縮後，得粗生成物之標題化合物（B A K - G 2 7 2 -38 - (34) 200417367Ice-cold 5 1 1.3 mg (1.70 mmoles) Manufacturing Example 1 Κ-ΒΑΚ-G202, 0.59 ml (3.40 mmoles (DIEa), 10 ml of dichloromethane, 0.16 ml of chloroethyl Phenyl chloride was stirred under ice-cooling for 2 hours. Dilute hydrochloric acid was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. After concentration, the title compound (BAK-G 2 7 2 -38 was obtained as a crude product. -(34) 200417367

Ο ΟΟ Ο

H-NMR (CDC13) δ: 3·83 (s5 3Η)5 4.18 (s5 2Η)5 4。48 (d，J = 5.7Hz，2Η)，5·95 (s，2Η)，6·45 (brs，1Η) 5 6.6 6 (d，J = 2.5Hz，1Η)，6·75-6.85 (m? 3Η)? 6 8 5 (dd5 J = 2.5，8.7Hz，1Η)5 7.7 6 (d5 J = 8.7Hz, 1Η) 製造例3 4 合成 8 -甲氧基-4-〔 （3，4-亞甲二氧基）苯甲基〕-1，4- 苯并噚吖庚因-3，5(2H，4H)-二酮 於室溫攪拌1小時製造例3 3中做爲粗生成物所得 BAK-G272，469mg(3.4 毫莫爾）碳酸鉀，5 0ml DMF。反 應液中追加1 g碳酸鉀，再於室溫攪拌1小時。反應液中 加入水，以乙酸乙酯萃取，有機層以無水硫酸鈉乾燥。濃 縮後以矽膠管柱層析（己烷：乙酸乙酯=5 : 1 )精製粗生 成物，以收率56%得3 27.3 mg標題化合物（BAK-G2 73 ) -39- (35) 200417367H-NMR (CDC13) δ: 3.83 (s5 3Η) 5 4.18 (s5 2Η) 5 4.48 (d, J = 5.7Hz, 2Η), 5.95 (s, 2Η), 6.45 (brs , 1Η) 5 6.6 6 (d, J = 2.5Hz, 1Η), 6.75-6.85 (m? 3Η)? 6 8 5 (dd5 J = 2.5, 8.7Hz, 1Η) 5 7.7 6 (d5 J = 8.7 Hz, 1Η) Production Example 3 4 Synthesis of 8-methoxy-4-[(3,4-methylenedioxy) benzyl] -1,4-benzopyreneazepine-3,5 (2H , 4H) -diketone was stirred at room temperature for 1 hour. BAK-G272 obtained as a crude product in Production Example 3, 469 mg (3.4 mmol) of potassium carbonate, 50 ml of DMF. An additional 1 g of potassium carbonate was added to the reaction solution, followed by stirring at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. After concentration, the crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain 3 27.3 mg of the title compound (BAK-G2 73) -39- (35) 200417367 in a 56% yield.

^-NMR (CDC13) δ:^ -NMR (CDC13) δ:

3.85 (s，3H)5 4·75 (s5 2H)，5.08 (s，2H)5 5.91 (s5 2H)， 6.53 (d，J = 2.5Hz，1H)，6·70-6·80(ιη5 2H)，6.8 5 - 6.95 (m， 2H)? 8.14(d? J = 9.1Hz? 1H) 製造例3 5 合成4- (3，4 -二甲氧苯甲基）-9 -甲氧基-i，4_苯并啤口丫 庚因-3，5 ( 2H，4H )-二酮 冰冷611.2mg(1.93毫莫爾）製造例17所得BAK-G320、〇.67ml (3.86 毫莫爾）DIEA，12ml 二氯甲院，滴 下〇.19ml (2.33毫莫爾）氯乙醯基氯於其中，於室溫攪 拌2小時。反應液中加入稀鹽酸，以二氯甲烷萃取，以無 水硫酸鈉乾燥有機層。濃縮後溶解粗生成物於D M F，再 加入2 g碳酸鉀，於3 0 °C攪拌2小時。反應液中加入水， 以乙酸乙酯萃取，有機層以無水硫酸鈉乾燥。濃縮後以矽 膠管柱層析（己烷：乙酸乙酯=3 : 2 )精製粗生成物，以 收率64%得442.7mg標題化合物（BAK-G3 2 3 )。 -40 - (36) 2004173673.85 (s, 3H) 5 4.75 (s5 2H), 5.08 (s, 2H) 5 5.91 (s5 2H), 6.53 (d, J = 2.5Hz, 1H), 6.70-6 · 80 (ιη5 2H ), 6.8 5-6.95 (m, 2H)? 8.14 (d? J = 9.1Hz? 1H) Production Example 3 5 Synthesis of 4- (3,4-dimethoxybenzyl) -9-methoxy-i , 4-benzophenone yamphenin-3,5 (2H, 4H) -dione ice-cooled 611.2 mg (1.93 mmol), BAK-G320 obtained in Production Example 17, 0.67 ml (3.86 mmol) DIEA, In 12 ml of dichloromethane, 0.19 ml (2.33 mmol) of chloroacetamidinyl chloride was dropped and stirred at room temperature for 2 hours. Dilute hydrochloric acid was added to the reaction solution, extraction was performed with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate. After concentration, the crude product was dissolved in DM, 2 g of potassium carbonate was added, and the mixture was stirred at 30 ° C for 2 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After concentration, the crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2) to obtain 442.7 mg of the title compound (BAK-G3 2 3) in a yield of 64%. -40-(36) 200417367

BAK-G320BAK-G320

]H-NMR (CDC13) δ: 3.85 (s? 3H) 5 3 8 7 (s5 3H) 5 3.9 0 (s5 3H)? 4 8 3 (s? 2H)? 5.14 (s，2H)5 6.7 9 (d，J = 8.8 Hz，1H)，7.00-7.20(m? 4H)? 7.64(dd? J = 2.0，7.7Hz，1H) MS (El) E/Z 3 5 7 (M + ) 製造例3 6 合成7-氯- 4-(3，4-二甲氧苯甲基）-1，4-苯并噚吖庚因-3，5 ( 2H，4H )-二酮 與製造例35 —樣之方法，以收率33 %得標題化合物 (BAK-G3 3 9 )。] H-NMR (CDC13) δ: 3.85 (s? 3H) 5 3 8 7 (s5 3H) 5 3.9 0 (s5 3H)? 4 8 3 (s? 2H)? 5.14 (s, 2H) 5 6.7 9 ( d, J = 8.8 Hz, 1H), 7.00-7.20 (m? 4H)? 7.64 (dd? J = 2.0, 7.7Hz, 1H) MS (El) E / Z 3 5 7 (M +) Manufacturing Example 3 6 Synthesis of 7-Chloro- 4- (3,4-dimethoxybenzyl) -1,4-benzopyreneazepine-3,5 (2H, 4H) -dione and Manufacturing Example 35-the same method The title compound (BAK-G3 3 9) was obtained in a yield of 33%.

Ο BAK-G332 BAK-G339 JH-NMR (CDCI3) δ: 3.85 (s? 3H)? 3.87 (s5 3H)? 4.77 (s5 2H)? 5.13(s? 2H)? 6.79(d? J = 8.7Hz? 1H); 6.95-7.10 (m; 3H)5 7.4 5 (dd5 J = 2.6，8.7 Hz, 1H)5 8.13 (d5 J = 2.6Hz? 1H) MS (El) E/Z 361 (M + ) -41 - (37) 200417367 製造例3 7 合成9-甲氧基-4-〔3，4-(亞甲二氧基）苯甲基〕-1’ l 苯并噚吖庚因-3，5 ( 2H，4H )-二酮 與製造例3 5 —樣之方法，以收率72 %得標題化合物 (B AK-G287 )。〇 BAK-G332 BAK-G339 JH-NMR (CDCI3) δ: 3.85 (s? 3H)? 3.87 (s5 3H)? 4.77 (s5 2H)? 5.13 (s? 2H)? 6.79 (d? J = 8.7Hz? 1H); 6.95-7.10 (m; 3H) 5 7.4 5 (dd5 J = 2.6, 8.7 Hz, 1H) 5 8.13 (d5 J = 2.6Hz? 1H) MS (El) E / Z 361 (M +) -41 -(37) 200417367 Production Example 3 7 Synthesis of 9-methoxy-4- [3,4- (methylenedioxy) benzyl] -1 'l Benzopyrazine-3,5 (2H , 4H) -diketone in the same manner as in Production Example 3 5 to obtain the title compound (B AK-G287) in a yield of 72%.

〇 BAK-G261 Ο〇 BAK-G261 〇

^-NMR (CDC13) δ: 3.90 (s5 3H)? 4.82 (s5 2H)5 5.11 (s? 2H)? 5.91 (s5 2H)5 6.73(d，J = 8.5Hz5 1H)，6.90-6.9 5 (m，2H) 5 7.0 9 (dd?^ -NMR (CDC13) δ: 3.90 (s5 3H)? 4.82 (s5 2H) 5 5.11 (s? 2H)? 5.91 (s5 2H) 5 6.73 (d, J = 8.5Hz5 1H), 6.90-6.9 5 (m , 2H) 5 7.0 9 (dd?

J = 2.0，7.6Hz，1H)，7.16 (t5 J = 7.6，1H)，7.64 (dd5 JJ = 2.0, 7.6 Hz, 1H), 7.16 (t5 J = 7.6, 1H), 7.64 (dd5 J

= 2.0? 7.6 Hz5 1H) MS (El) E/Z 341 (M + ) 製造例3 8 合成 1· (2，3-二氫·1，4-苯并二噁因-6-基）甲基胺鹽酸 化物 於1 3 0 t攪拌6小時4 · 9 3 g ( 3 0 . 1毫莫爾）3，4 -伸乙 基二氧苯甲醛，15ml甲醯胺，10ml甲酸。以飽和碳酸氫 鈉水溶液洗淨，以無水硫酸鈉乾燥。濃縮後，以矽膠管柱 -42 - (38) 200417367 層析（己烷··乙酸乙酯=1 ·· 1 )精製，以4 1 %收率得2.3 6 g 卜（2，3-二氫-1，4-苯并二噁因-6-基）甲基胺（BAK-G3 6 6 )。 回流3小時1 .3 0g ( 6.74毫莫爾）所得BAK-G3 66， 1 0 m 1乙醇及1 m 1濃鹽酸。於室溫在反應液中加入2 0 m 1乙 醚，濾取析出之結晶，以乙醚洗淨後，乾燥，以收率7 8 % 得1.06g標題化合物（BAK-G369)。= 2.0? 7.6 Hz5 1H) MS (El) E / Z 341 (M +) Production Example 3 8 Synthesis of 1 · (2,3-dihydro · 1,4-benzodioxin-6-yl) methyl The amine hydrochloride was stirred at 130 t for 6 hours 4.93 g (30.1 mmol) of 3,4-ethylenedioxybenzaldehyde, 15 ml formamidine, 10 ml formic acid. It was washed with a saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. After concentration, it was purified by silica gel column -42-(38) 200417367 chromatography (hexane ·· ethyl acetate = 1 ·· 1) to obtain 2.3 6 g (2,3-dihydrogen) in a 41% yield. -1,4-benzodioxin-6-yl) methylamine (BAK-G3 6 6). Under reflux for 3 hours, 1.3 g (6.74 mmol) of the obtained BAK-G3 66, 10 ml 1 ethanol and 1 ml 1 concentrated hydrochloric acid. 20 m 1 of diethyl ether was added to the reaction solution at room temperature, and the precipitated crystals were collected by filtration, washed with diethyl ether, and dried to obtain 1.06 g of the title compound (BAK-G369) at a yield of 78%.

OHCOHC

XCOXCO

BAK-G369 BAK-G366 iH-NMR (DMSO-d6) δ: 3.88 (s5 2H)? 4.24 (s5 4H)? 6.85 -6.9 5 (m? 2H)? 7.02 (d? J=1 .6Hz，1H)? 8.21 (brs，3H) 製造例39 合成4 -苯甲氧基-3-甲氧基苯甲胺氯化氮 與製造例3 8 —樣之方法，以收率3 8 °/〇得標題化合物 (BAK-G3 8 8 )。BAK-G369 BAK-G366 iH-NMR (DMSO-d6) δ: 3.88 (s5 2H)? 4.24 (s5 4H)? 6.85 -6.9 5 (m? 2H)? 7.02 (d? J = 1 1.6 Hz, 1H) ? 8.21 (brs, 3H) Preparation Example 39 Synthesis of 4-benzyloxy-3-methoxybenzylamine nitrogen chloride The same method as in Manufacturing Example 38 was used to obtain the title compound in a yield of 38 ° / °. (BAK-G3 8 8).

H-NMR (DMSO-d6) δ: 3.79 (s; 3H); 3.92 (s? 2H)? 5.10 (s5 2H); 6.95(dd; -43 - (39) 200417367 J=1.8? 8.3Hz3 1H)? 7.04(d? J = 8.3Hz? 1H) 5 7.2 3 (d? J=1.8Hz，1H)，7.2 5 -7.45 (m5 5H)，8.34 (brs5 3H) 製造例4 0 合成N-〔 （2，3-二氫-1，4-苯并二噁因-6-基）甲基〕-2- 羥基-4-甲氧苯苯甲醯胺 於 140°C攪拌 3小時 3 0 7.7mg ( 1.69毫莫爾）， 341mg ( 1.69 毫莫爾）製造例 38 所得 BAK-G369，466mg (毫莫爾）碳酸紳，及5ml DMSO。反應液中加入水，以 乙酸乙酯萃取，有機層以無水硫酸鈉乾燥。濃縮後以矽膠 管柱層析（己烷：乙酸乙酯=3 ·· 1 )精製粗生成物，以收 率37%得196mg標題化合物（BAK-G371)。H-NMR (DMSO-d6) δ: 3.79 (s; 3H); 3.92 (s? 2H)? 5.10 (s5 2H); 6.95 (dd; -43-(39) 200417367 J = 1.8? 8.3Hz3 1H)? 7.04 (d? J = 8.3Hz? 1H) 5 7.2 3 (d? J = 1.8Hz, 1H), 7.2 5 -7.45 (m5 5H), 8.34 (brs5 3H) Manufacturing Example 4 0 Synthesis of N- [(2, 3-Dihydro-1,4-benzodioxin-6-yl) methyl] -2-hydroxy-4-methoxybenzamide, stirred at 140 ° C for 3 hours 3 0 7.7mg (1.69 mmol Moore), 341 mg (1.69 mmoles) of BAK-G369 obtained in Example 38, 466 mg (mmoles) carbonate, and 5 ml DMSO. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After concentration, the crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 3 ·· 1) to obtain 196 mg of the title compound (BAK-G371) in a yield of 37%.

BAK-G371 JH-NMR (CDC13) δ: 3.81 (s，3Η)，4.25 (s，4Η)，4.50 (d5 J = 5.5Hz，2Η)，6·32 (brs， 1H)? 6.38 (dd5 J = 2.5? 8.8Hz? 1H)? 6.47 (d5 J = 2.5Hz? 1H)? 6.7 0 -6.90 (m5 3H) 5 7.2 3 (d5 J =8.8 Hz5 1H)? 12.68 (s5 1H) MS (El) E/Z 315 (M + ) 製造例4 1 -44 - (40) 200417367 合成5-氯- N-〔 （2，3-二氫-1，4-苯并二噁因-6-基）甲基 〕-2-羥基苯甲醯胺 與製造例4 0 —樣之方法，以收率6 1 %得標題化合物 (BAK-G378 )。BAK-G371 JH-NMR (CDC13) δ: 3.81 (s, 3Η), 4.25 (s, 4Η), 4.50 (d5 J = 5.5Hz, 2Η), 6.32 (brs, 1H)? 6.38 (dd5 J = 2.5? 8.8Hz? 1H)? 6.47 (d5 J = 2.5Hz? 1H)? 6.7 0 -6.90 (m5 3H) 5 7.2 3 (d5 J = 8.8 Hz5 1H)? 12.68 (s5 1H) MS (El) E / Z 315 (M +) Production Example 4 1 -44-(40) 200417367 Synthesis of 5-chloro-N-[(2,3-dihydro-1,4-benzodioxin-6-yl) methyl] 2-Hydroxybenzidine was produced in the same manner as in Production Example 40 to obtain the title compound (BAK-G378) in a yield of 61%.

BAK-G378 'H-NMR (CDC13) δ: 4.24(s5 4Η)，4.51 (d，J = 5.8Hz，2Η)5 6.7 5 - 6.9 0 (m，3Η)， 6.94(d? J = 8.9Hz5 1H)5 7.42 (dd5 J = 2.5， 8.9Hz， 1H)， 7.88 (d? J = 2.5Hz? 1H)5 8 · 7 0 (b r s 5 1 H) 5 1 2 · 8 0 (b r s，1 H) MS (El) E/Z 3 1 9 (M + ) 製造例42 合成N-( 4-苯甲氧基-3-甲氧苯甲基）-2-羥基-4-甲氧苯甲 酿胺 與製造例4 0 —樣之方法，以收率3 1 %得標題化合物 (BAK-G391 )。BAK-G378 'H-NMR (CDC13) δ: 4.24 (s5 4Η), 4.51 (d, J = 5.8Hz, 2Η) 5 6.7 5-6.9 0 (m, 3Η), 6.94 (d? J = 8.9Hz5 1H ) 5 7.42 (dd5 J = 2.5, 8.9Hz, 1H), 7.88 (d? J = 2.5Hz? 1H) 5 8 · 7 0 (brs 5 1 H) 5 1 2 · 8 0 (brs, 1 H) MS (El) E / Z 3 1 9 (M +) Production Example 42 Synthesis of N- (4-benzyloxy-3-methoxybenzyl) -2-hydroxy-4-methoxybenzamide and production Example 40: In the same manner, the title compound (BAK-G391) was obtained in a yield of 31%.

BAK-G391 H-NMR (CDC13) δ: -45- (41) 200417367 3.81 (s, 3H)，3·89 (s5 3H)5 4.5 3 (d，J = 5.5Hz，2H)5 5.16 (s5 2H)? 6.29 (brs5 1 H) 5 6 · 3 8 ( d d 5 J = 2.5，8.9 H z，1 H )， 6.47 (d5 J = 2.5 Hz? 1H)? 7.22 (d? J = 8.9Hz5 1H)? 7.25-7.50(m, 5H)5 12.68 (s? 1H) * MS (El) E/Z 3 9 3 (M + ) 製造例43 合成N-(4-苯甲氧基-3-甲氧苯甲基）-5_氯-2-羥基苯甲醯 胺 與製造例40 —樣之方法，以收率54%得標題化合物 (B AK-G3 9 5 )。BAK-G391 H-NMR (CDC13) δ: -45- (41) 200417367 3.81 (s, 3H), 3.89 (s5 3H) 5 4.5 3 (d, J = 5.5Hz, 2H) 5 5.16 (s5 2H )? 6.29 (brs5 1 H) 5 6 · 3 8 (dd 5 J = 2.5, 8.9 H z, 1 H), 6.47 (d5 J = 2.5 Hz? 1H)? 7.22 (d? J = 8.9Hz5 1H)? 7.25-7.50 (m, 5H) 5 12.68 (s? 1H) * MS (El) E / Z 3 9 3 (M +) Production Example 43 Synthesis of N- (4-benzyloxy-3-methoxybenzyl) Group) -5-chloro-2-hydroxybenzidine was prepared in the same manner as in Production Example 40 to obtain the title compound (B AK-G3 9 5) in a yield of 54%.

^-NMR (DMSO d6) δ: 3.76 (s? 3H)5 4.4 2 (m? 2H) 3 5.0 6 (s5 2H) 5 6.8 2 (dd9 J=1.9，8.2Hz? 1 H)? 6.90-7.00(1X1，3H)，7.3 0 - 7.5 0 (m， 6H)，7·96 (d5 J = 2.6Hz，1H)，9.36 (brt5 1H)，12.56 (brs， 1H) MS (El) E/Z 3 9 7 (M + ) 製造例44 合成N- ( 3，4-二甲氧基苯乙基）-2-羥基-4-甲氧基苯甲 -46- (42) 200417367 醯胺 與製造例1 一樣之方法，以收率24 %得標題化合物（ BAK-G3 8 6 )。^ -NMR (DMSO d6) δ: 3.76 (s? 3H) 5 4.4 2 (m? 2H) 3 5.0 6 (s5 2H) 5 6.8 2 (dd9 J = 1.9, 8.2Hz? 1 H)? 6.90-7.00 ( 1X1, 3H), 7.3 0-7.5 0 (m, 6H), 7.96 (d5 J = 2.6Hz, 1H), 9.36 (brt5 1H), 12.56 (brs, 1H) MS (El) E / Z 3 9 7 (M +) Production Example 44 Synthesis of N- (3,4-dimethoxyphenethyl) -2-hydroxy-4-methoxybenzyl-46- (42) 200417367 The same as in Production Example 1 In this way, the title compound (BAK-G3 8 6) was obtained in a yield of 24%.

αχχ;η〇 0αχχ; η〇 0

^-NMR (CDC 2.87(t5 J = 6.8Hz5 2H) 5 3.6 7 (q5 J = 6.8Hz? 2H)? 3.80 (s5 3H)，3.85 (s，3H)，3.88(s，3H)5 6.12(brs，1H)5 6.3 6 (dd5 J = 2.5? 8.9Hz5 1H)，6.46(d，J = 2.5Hz，1H)，6.70-6.90 (m5 3H)5 7.0 8 (d5 J = 8.9Hz? 1H)? 12.71 (s5 1H) MS (El) E/Z 33 1 (M + ) 製造例4 5 合成5-氯-N-(3，4-二甲氧基苯乙基）-2-羥基苯甲醯胺 · 與製造例1 一樣之方法，以收率47%得標題化合物（ BAK-G403 ) 〇^ -NMR (CDC 2.87 (t5 J = 6.8Hz5 2H) 5 3.6 7 (q5 J = 6.8Hz? 2H)? 3.80 (s5 3H), 3.85 (s, 3H), 3.88 (s, 3H) 5 6.12 (brs , 1H) 5 6.3 6 (dd5 J = 2.5? 8.9Hz5 1H), 6.46 (d, J = 2.5Hz, 1H), 6.70-6.90 (m5 3H) 5 7.0 8 (d5 J = 8.9Hz? 1H)? 12.71 (s5 1H) MS (El) E / Z 33 1 (M +) Production Example 4 5 Synthesis of 5-chloro-N- (3,4-dimethoxyphenethyl) -2-hydroxybenzidine · The title compound (BAK-G403) was obtained in the same manner as in Production Example 1 with a yield of 47%.

〇 W-NMR (CDC1 2.88(t，J=6.8Hz，2H)，3.68(q，J = 6.8Hz，2H);3.8 7(s: -47 _ (43) 200417367 3H)? 3.88 (s? 3H)? 6.28 (b r s，1 H )，6.7 0 - 6 · 9 0 (m，3 H)， 6.9 3 (d，J =8.9 Hz， 1H)5 7.17 (d5 J =2.5 Hz， 1H)，7.32 (d d? J = 2.5, 8.9 Hz, 1H)5 12.24 (s5 1H) MS (El) E/Z 3 3 5 (M + ) 製造例46 合成3-〔 （2，3-二氫-1，4-苯并二噁因-6-基）甲基〕-2 ，3-二氫-7-甲氧基- 4H-1，3-苯并噚吖庚因-4-酮 與製造例2 —樣之方法，以收率37%得標題化合物（ BAK-G3 74 )。〇W-NMR (CDC1 2.88 (t, J = 6.8Hz, 2H), 3.68 (q, J = 6.8Hz, 2H); 3.87 (s: -47 _ (43) 200417367 3H)? 3.88 (s? 3H )? 6.28 (brs, 1 H), 6.70-6 · 9 0 (m, 3 H), 6.9 3 (d, J = 8.9 Hz, 1H) 5 7.17 (d5 J = 2.5 Hz, 1H), 7.32 ( dd? J = 2.5, 8.9 Hz, 1H) 5 12.24 (s5 1H) MS (El) E / Z 3 3 5 (M +) Production Example 46 Synthesis of 3-[(2,3-dihydro-1,4- Benzodioxin-6-yl) methyl] -2,3-dihydro-7-methoxy-4H-1,3-benzofluorenazepine-4-one and Production Example 2-the same The title compound (BAK-G3 74) was obtained in 37% yield.

BAK-G371BAK-G371

BAK-G374 ^-NMR (CDC13) δ: 3.83(s? 3H)? 4.24(s5 4H)? 4.63(s5 2H)5 5.09 (s5 2H)5 6.42 (d，J =2.4 Hz? 1 H)? 6.67 (dd5 J = 2.49 8.7 Hz? 1 H)? 6.8 0-6.90(m，3H)，7.92(d，J = 8.7Hz5 1 H) 製造例47 合成6-氯-3〔 （2，3-二氫-1，4-苯并二噁因-6-基）甲基 〕-2，3-二氫- 4H-1，3-苯并卩f吖庚因-4-酮 與製造例2 —樣之方法，以收率76%得標題化合物（ BAK-G3 7 9 )。 >48 - (44) 200417367BAK-G374 ^ -NMR (CDC13) δ: 3.83 (s? 3H)? 4.24 (s5 4H)? 4.63 (s5 2H) 5 5.09 (s5 2H) 5 6.42 (d, J = 2.4 Hz? 1 H)? 6.67 (dd5 J = 2.49 8.7 Hz? 1 H)? 6.8 0-6.90 (m, 3H), 7.92 (d, J = 8.7 Hz 5 1 H) Production Example 47 Synthesis of 6-chloro-3 [(2,3-dihydro -1,4-benzodioxin-6-yl) methyl] -2,3-dihydro-4H-1,3-benzofluorene fazepine-4-one is the same as in Production Example 2 The title compound (BAK-G3 7 9) was obtained in 76% yield. > 48-(44) 200417367

BAK-G378 BAK-G379 'H-NMR (CDC13) δ: 4.25 (s? 4H)? 4.64 (s5 2H)5 5.10 (s? 2H)? 6.7 5 -6.90 (m? 3H)5 6.9 0 (d，J = 8.7Hz，1H)，7.38(dd，J = 2.6，8·7 Hz， 1H) 5 7.9 7 (d，J = 2.6 Hz，1H) φ MS (El) E/Z 33 1 (M + ) 製造例4 8 合成3-〔 （2，3-二氫-1，4-苯并二噁因-6-基）甲基〕-7- 甲氧基- 2H-1，3-苯并鸣吖庚因-2，4(3H)-二酮 與製造例3 —樣之方法，以收率6 1 %得標題化合物（ BAK-G3 77 )。BAK-G378 BAK-G379 'H-NMR (CDC13) δ: 4.25 (s? 4H)? 4.64 (s5 2H) 5 5.10 (s? 2H)? 6.7 5 -6.90 (m? 3H) 5 6.9 0 (d, J = 8.7Hz, 1H), 7.38 (dd, J = 2.6, 8.7 Hz, 1H) 5 7.9 7 (d, J = 2.6 Hz, 1H) φ MS (El) E / Z 33 1 (M +) Production Example 4 8 Synthesis of 3-[(2,3-dihydro-1,4-benzodioxin-6-yl) methyl] -7-methoxy-2H-1,3-benzodiazepine Heptane-2,4 (3H) -dione was produced in the same manner as in Production Example 3 to obtain the title compound (BAK-G3 77) in a yield of 61%.

0 〇 BAK-G371 BAK-G377 H-NMR (CDC13) δ: 3.89 (s5 3H)5 4.2 2 (s? 4H)? 5.07 (s5 2H)? 6.68(d? J = 2.4Hz，1 H)5 6.80(d5 J = 8.2Hz，1H)，6.88(dd5 J = 2.4; 8.8Hz? 1H)5 6.9 5 - 7.1 0 (m? 2H); 7.97 (d5 J=8.8Hz? 1H) -49^ (45) 200417367 MS (El) E/Z 341 (M + ) 製造例49 合成 6-氯-3-〔 （2，3-二氫-1，4-苯并二噁因-6-基）甲基 〕-2H-1，3 -苯并噚吖庚因-2，4(3H)-二酮 與製造例3 —樣之方法，以收率73 %得標題化合物（ B AK-G3 82 )。0 〇BAK-G371 BAK-G377 H-NMR (CDC13) δ: 3.89 (s5 3H) 5 4.2 2 (s? 4H)? 5.07 (s5 2H)? 6.68 (d? J = 2.4Hz, 1 H) 5 6.80 (d5 J = 8.2Hz, 1H), 6.88 (dd5 J = 2.4; 8.8Hz? 1H) 5 6.9 5-7.1 0 (m? 2H); 7.97 (d5 J = 8.8Hz? 1H) -49 ^ (45) 200417367 MS (El) E / Z 341 (M +) Production Example 49 Synthesis of 6-chloro-3-[(2,3-dihydro-1,4-benzodioxin-6-yl) methyl]- 2H-1,3-benzobenzoazepine-2,4 (3H) -dione was prepared in the same manner as in Production Example 3 to obtain the title compound (B AK-G3 82) in a yield of 73%.

BAK-G378BAK-G378

BAIMJ382 H-NMR (CDC13) δ: 4.23 (s5 4Η)，5.09 (s， 2H)，6.80 (d，J = 8.2Hz，1H)? J = 8.8Hz，1H)5 7.6 2 (dd? J = 2.6Hz5 1H) 6.95 -7.05 (m5 2H)5 7.2 2 (d5 J = 2.6 ? 8.8Hz5 1H)5 8.〇5(d， MS (El) E/Z 3 45 (M + ) 製造例5 0 合成3- ( 4-苯甲氧基-3BAIMJ382 H-NMR (CDC13) δ: 4.23 (s5 4Η), 5.09 (s, 2H), 6.80 (d, J = 8.2Hz, 1H)? J = 8.8Hz, 1H) 5 7.6 2 (dd? J = 2.6 Hz5 1H) 6.95 -7.05 (m5 2H) 5 7.2 2 (d5 J = 2.6? 8.8Hz5 1H) 5 8.〇5 (d, MS (El) E / Z 3 45 (M +) Manufacturing Example 5 0 Synthesis 3 -(4-Benzyloxy-3

合成3-(心本甲氧基甲氧苯甲基） 苯并鸣吖庚因-2，4 ( 3H)、二酬 與製造例3 —樣之方法，N -7-甲氧基-2H-1，3- 以收率94%得標題化合物（ BAK-G3 93 )。 200417367Synthesis of 3- (Heartylmethoxymethoxybenzyl) Benzoazepine-2,4 (3H), Diary and Production Example 3-The same method, N-7-methoxy-2H- 1,3- The title compound (BAK-G3 93) was obtained in a yield of 94%. 200417367

'H-NMR (CDCI3) δ: 3.89 (s? 6H)? 5.10 (s? 2H)5 5.13 (s? 2H)? 6.68(d? J = 2.3Hz5 1 H)? 6.8 1 (d? J = 8.2Hz，1H)，6.88 (dd5 J = 2.4? 8.8 Hz? 1H)5 7.0 4 (d d? J = 2.05 8.2 Hz? 1H)? 7.14 (d5 J = 2.0 Hz? 1H)5 7.2 5 - 7.4 5 (m5 5 H)5 7.9 7 (d5 J = 8.8 Hz? 1 H) MS (El) E/Z 419 (M + ) 製造例5 1 合成3- (4-苯甲氧基-3-甲氧苯甲基）-6-氯- 2H-1，3-苯并 口署吖庚因-2，4(3H)-二酮 與製造例3 —樣之方法，以收率94%得標題化合物（ BAK-G3 97 )。'H-NMR (CDCI3) δ: 3.89 (s? 6H)? 5.10 (s? 2H) 5 5.13 (s? 2H)? 6.68 (d? J = 2.3Hz5 1 H)? 6.8 1 (d? J = 8.2 Hz, 1H), 6.88 (dd5 J = 2.4? 8.8 Hz? 1H) 5 7.0 4 (dd? J = 2.05 8.2 Hz? 1H)? 7.14 (d5 J = 2.0 Hz? 1H) 5 7.2 5-7.4 5 (m5 5 H) 5 7.9 7 (d5 J = 8.8 Hz? 1 H) MS (El) E / Z 419 (M +) Production Example 5 1 Synthesis of 3- (4-benzyloxy-3-methoxybenzyl) ) -6-Chloro-2H-1,3-benzohexidine-2,4 (3H) -dione was prepared in the same manner as in Production Example 3 to obtain the title compound (BAK-G3 97 in 94% yield) ).

BAK-G395 BAK-G397 H-NMR (CDC13) δ: 3.89(s， 3H)5 5.11 (s， 2H)， 5. 1 3(s; 2H), 6.8 1 (d;BAK-G395 BAK-G397 H-NMR (CDC13) δ: 3.89 (s, 3H) 5 5.11 (s, 2H), 5. 1 3 (s; 2H), 6.8 1 (d;

J = 8.2 H z，1 H); 7.0 4 (d d ; J = 2.0，8.2 H z，] H )，7.13 ( d，J - 51 - (47) 200417367 = 2.0 Hz5 1H)? 7.22 (d? J =8.8 Hz? 1H)5 7.2 5 - 7.4 5 (m? 5H)5 7.6 3 (dd? J = 2.5? 8.8Hz? 1 H)? 8.05 (d5 J= 2.5 Hz? 1H) MS (El) E/Z 423 (M + ) 製造例52 合成3- (3，4-二甲氧基苯乙基）-7-甲氧基- 2H-1，3-苯并 哼吖庚因-2，4 ( 3H )-二酮 與製造例3 —樣之方法，以收率82%得標題化合物（ B AK-G3 90 )。J = 8.2 H z, 1 H); 7.0 4 (dd; J = 2.0, 8.2 H z,] H), 7.13 (d, J-51-(47) 200417367 = 2.0 Hz5 1H)? 7.22 (d? J = 8.8 Hz? 1H) 5 7.2 5-7.4 5 (m? 5H) 5 7.6 3 (dd? J = 2.5? 8.8Hz? 1 H)? 8.05 (d5 J = 2.5 Hz? 1H) MS (El) E / Z 423 (M +) Production Example 52 Synthesis of 3- (3,4-dimethoxyphenethyl) -7-methoxy-2H-1,3-benzoazepine-2,4 (3H ) -Dione The same method as in Production Example 3 was used to obtain the title compound (B AK-G3 90) in a yield of 82%.

BAK-G386BAK-G386

】H-NMR (CDC13) δ: 2.95 (m，2H)5 3.8 6 (s，3Η)，3·87 (s，3Η)5 3.91 (s，3Η)， 4.21 (m5 2H)5 6·71 (d，J =2·4 Hz5 1H)，6.7 5 - 6.8 5 (m， 3H)? 6.90(dd? J = 2.45 8.8Hz? 1 H)，7 · 9 7 (d，J = 8 · 8 Hz, 1H) MS (El) E/Z 3 5 7 (M + ) 製造例5 3 合成6-氯3- (3，4-二甲氧基苯乙基）-2H-1，3-苯并鸣吖 庚因-2，4 ( 3H )-二酮 >52- (48) 200417367 與製造例3 —樣之方法，以收率8 1 %得標題化合物（ BAK-G405 )。H-NMR (CDC13) δ: 2.95 (m, 2H) 5 3.8 6 (s, 3Η), 3.87 (s, 3Η) 5 3.91 (s, 3Η), 4.21 (m5 2H) 5 6.71 ( d, J = 2 · 4 Hz5 1H), 6.7 5-6.8 5 (m, 3H)? 6.90 (dd? J = 2.45 8.8Hz? 1 H), 7 · 9 7 (d, J = 8 · 8 Hz, 1H) MS (El) E / Z 3 5 7 (M +) Production Example 5 3 Synthesis of 6-Chloro 3- (3,4-dimethoxyphenethyl) -2H-1,3-benzopyrazine Heptane-2,4 (3H) -dione> 52- (48) 200417367 The same method as in Production Example 3 was used to obtain the title compound (BAK-G405) in a yield of 81%.

^-NMR (CDC13) δ:^ -NMR (CDC13) δ:

2.95 (m，2Η) 5 3.8 6 (s5 3Η) 5 3.8 8 (s5 3Η)，4.23(m，2Η)， 6.75 -6.90 (m，3Η)，7·24 (d，J= 8.8Hz，1Η)，7.65 (dd， J = 2.5, 8.8Hz5 1H)? 8.04 (d? J = 2.5Hz? 1H) MS (El) E/Z 361 (M + ) 製造例54 合成 3-(4-羥基-3-甲氧基苯甲基）-7_甲氧基-211，3-苯 并噚吖庚因-2，4 ( 3H)-二酮2.95 (m, 2Η) 5 3.8 6 (s5 3Η) 5 3.8 8 (s5 3Η), 4.23 (m, 2Η), 6.75 -6.90 (m, 3Η), 7.24 (d, J = 8.8Hz, 1Η) , 7.65 (dd, J = 2.5, 8.8Hz5 1H)? 8.04 (d? J = 2.5Hz? 1H) MS (El) E / Z 361 (M +) Production Example 54 Synthesis of 3- (4-hydroxy-3- Methoxybenzyl) -7-methoxy-211,3-benzopyreneazepine-2,4 (3H) -dione

在 370mg (0.883毫莫爾），14ml乙酸乙酯及 10ml 二氯甲烷中加入37mg 10%Pd-C，於氫氣氛下，在室溫攪 拌3小時。以矽藻土過濾反應液，自12ml乙酸乙酯-12ml 己烷再結晶濃縮後之粗生成物，以65%收率得188.5mg標 題化合物（BAK-G3 94 )。 -53- (49) 20041736737 mg of 10% Pd-C was added to 370 mg (0.883 mmol), 14 ml of ethyl acetate and 10 ml of dichloromethane, and stirred at room temperature for 3 hours under a hydrogen atmosphere. The reaction solution was filtered through celite, and the crude product was recrystallized from 12 ml of ethyl acetate to 12 ml of hexane and concentrated to obtain 188.5 mg of the title compound (BAK-G3 94) in a 65% yield. -53- (49) 200417367

BAK-G393BAK-G393

Ο BAK-G394 JH-NMR (CDC 13) δ:〇 BAK-G394 JH-NMR (CDC 13) δ:

3.88 (s5 3H)? 3.89 (s? 3H)? 5.1 0 (s5 2H)? 5.60 (s? 1H)5 6.68(d? J = 2.3Hz? 1H)，6.8 0-6.95 (m，2H)5 7。05-7。15 (m? 2H)? 7.98 (d，J = 8.8Hz，1H) MS (El) E/Z 3 29(M + ) 製造例55 合成 6-氯-3- (4-羥基-3-甲氧基苯甲基3-苯并鸣 吖庚因-2，4 ( 3H)-二酮 與製造例54 —樣之方法，以收率85%得標題化合物 (B AK-G400 )。3.88 (s5 3H)? 3.89 (s? 3H)? 5.1 0 (s5 2H)? 5.60 (s? 1H) 5 6.68 (d? J = 2.3Hz? 1H), 6.8 0-6.95 (m, 2H) 5 7 05-7.15 (m? 2H)? 7.98 (d, J = 8.8Hz, 1H) MS (El) E / Z 3 29 (M +) Production Example 55 Synthesis of 6-chloro-3- (4-hydroxyl -3-methoxybenzyl 3-benzylazepine-2,4 (3H) -dione was prepared in the same manner as in Production Example 54 to obtain the title compound (B AK-G400) in a yield of 85%. .

BAK-G397 BAK-G400 ^-NMR (CDC 13) δ: 3.89(s5 3H)5 5.11 (s? 2H)? 5.62 (s5 1H)? 6.85(d5 J = 8.3 Hz5 1H)? 7.05-7.10 (m? 2H)? 7.22 (d? J-8.8Hz, 1H)5 7.63 (dd5 J = 2.5，8·8Ηζ; 1H); 8.05 (d”T= 2.5 Hz, 1H) -54- (50) 200417367 MS (El) E/Z 3 3 3 (M + ) 製造例5 6 合成N-(4-苯甲氧基-3-甲氧基苯甲基）-2，4，6-三甲氧 基苯甲醯胺BAK-G397 BAK-G400 ^ -NMR (CDC 13) δ: 3.89 (s5 3H) 5 5.11 (s? 2H)? 5.62 (s5 1H)? 6.85 (d5 J = 8.3 Hz5 1H)? 7.05-7.10 (m? 2H)? 7.22 (d? J-8.8Hz, 1H) 5 7.63 (dd5 J = 2.5, 8 · 8Ηζ; 1H); 8.05 (d ”T = 2.5 Hz, 1H) -54- (50) 200417367 MS (El ) E / Z 3 3 3 (M +) Production Example 5 6 Synthesis of N- (4-benzyloxy-3-methoxybenzyl) -2,4,6-trimethoxybenzamide

冰冷 198.9mg( 0.938毫莫爾）2，4，6 -三甲氧基苯 甲酸，263mg(0.9 38毫莫爾）製造例39所得BAK-G388 ，0.3 92ml ( 2.25毫莫爾）及 4ml DMF，在其中加入 0.17ml ( 1.13毫莫爾）二乙基磷酸氰化物，冰冷下攪拌2 小時，於室溫攪拌1小時。反應液中加入稀鹽酸，以乙酸 乙酯萃取，有機層以碳酸氫鈉水溶液洗淨，以無水硫酸鈉 乾燥。濃縮後以矽膠管柱層析（己烷：乙酸乙酯=2 : 1 ) 精製粗生成物，以收率60%得244.5 g標題化合物（BAK-G401 )。198.9 mg (0.938 mmol) of 2,4,6-trimethoxybenzoic acid, 263 mg (0.9 38 mmol) of BAK-G388 obtained in Preparation Example 39, 0.3 92 ml (2.25 mmol) and 4 ml of DMF, To this was added 0.17 ml (1.13 mmol) of diethyl phosphate cyanide, followed by stirring under ice-cooling for 2 hours and at room temperature for 1 hour. Dilute hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. After concentration, the crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain 244.5 g of the title compound (BAK-G401) in a yield of 60%.

]H-NMR (CDC13) δ: 3.78 (s5 6H)? 3.81 (s? 3H)? 3.90 (s5 3H) 5 4.5 7 (d? J =5.8 Hz5 2H)5 5.15 (s? 2H)? 5.98 (brt5 1H)? 6.10 (s5 2H)? 6.83 (m? 2H)? 6.97 (s5 1H) 5 7.2 5 - 7.5 0 (m5 5H) MS (El) E/Z 4 3 7 (M + ) -55- (51) (51)200417367 製造例5 7 合成N- (4 -苯甲氧基-3-甲氧基苯甲基）-2 -羥基-4，6 -二 甲氧基苯甲醯胺 在5 7 2mg ( 1 .3 1毫莫爾）製造例56所得BAK-G401 及12ml 1，4-二噁烷中加入878mg(6.55毫莫爾）碘化鋰 ，回流2 0小時。反應液中加入水，以乙酸乙酯萃取，有 機層以無水硫酸鈉乾燥。濃縮後以矽膠管柱層析（己烷： 乙酸乙酯=1 : 1 )精製粗生成物，以收率58%得324mg標 題化合物（B AK-G402 )。] H-NMR (CDC13) δ: 3.78 (s5 6H)? 3.81 (s? 3H)? 3.90 (s5 3H) 5 4.5 7 (d? J = 5.8 Hz5 2H) 5 5.15 (s? 2H)? 5.98 (brt5 1H)? 6.10 (s5 2H)? 6.83 (m? 2H)? 6.97 (s5 1H) 5 7.2 5-7.5 0 (m5 5H) MS (El) E / Z 4 3 7 (M +) -55- (51 ) (51) 200417367 Production Example 5 7 Synthesis of N- (4-benzyloxy-3-methoxybenzyl) -2-hydroxy-4,6-dimethoxybenzamide in 5 7 2mg (1.31 mmoles) BAK-G401 obtained in Production Example 56 and 12 ml of 1,4-dioxane were charged with 878 mg (6.55 mmoles) of lithium iodide and refluxed for 20 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After concentration, the crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain 324 mg of the title compound (B AK-G402) in a yield of 58%.

BAK-G401 BAK-G402 ^-NMR (CDC13) δ: 3.80 (s5 3Η)，3.83 (s5 3Η)，3.89 (s5 3H)5 4.5 4 (d， J = 5.6Hz，2Η)5 5.15(s，2Η)，5.95(d, J = 2.4 Ηζ5 1Η)， 6.14 (d，J = 2·4 Hz，1H)，6.8 0-6.95 (m，3H)5 7.2 5 - 7.5 0 (m5 5H) 5 8.3 6 (brt5 1H)5 14.29(s? 1H) MS (El) E/Z 423 (M + ) 製造例5 8 合成3-(4-苯甲氧基-3-甲氧基苯甲基）_5，7_二甲氧基_ 2H-1，3-苯并哼吖庚因-2，4 ( 3H) _二酬 與製造例3 —樣之方法，以收率9 2 %得標題化合物（ ^ 56 - (52) 200417367 B AK-G404 )。BAK-G401 BAK-G402 ^ -NMR (CDC13) δ: 3.80 (s5 3Η), 3.83 (s5 3Η), 3.89 (s5 3H) 5 4.5 4 (d, J = 5.6Hz, 2Η) 5 5.15 (s, 2Η ), 5.95 (d, J = 2.4 Ηζ5 1Η), 6.14 (d, J = 2.4 Hz, 1H), 6.8 0-6.95 (m, 3H) 5 7.2 5-7.5 0 (m5 5H) 5 8.3 6 ( brt5 1H) 5 14.29 (s? 1H) MS (El) E / Z 423 (M +) Production Example 5 8 Synthesis of 3- (4-benzyloxy-3-methoxybenzyl) _5,7_ Dimethoxy_ 2H-1,3-benzylazepine-2,4 (3H) _ diluent was the same as that in Production Example 3 to obtain the title compound (^ 56-( 52) 200417367 B AK-G404).

BAK-G402 BAK-G404 'H-NMR (CDC13) δ:BAK-G402 BAK-G404 'H-NMR (CDC13) δ:

3.86 (s，3H)，3.89 (s5 3H)，3.94 (s，3H)，5.05(s，2H)5 5.12 (s5 2H)5 6.31 (s? 2H), 6.79 (d? J = 8.2Hz5 1H)5 7.06 (dd5 J = 2.0? 8..2Hz? 1 H)5 7。14 (d5 J = 2.0Hz，1 H)? 7.25-7.45 (m，5H) MS (El) E/Z 404 (M + ) 製造例5 9 合成3- (4-羥基-3-甲氧基苯甲基）-5，7-二甲氧基-2 H-l ，3-苯并Df吖庚因-2，4(3H)-二酮 與製造例54 —樣之方法，以收率76%得標題化合物 (BAK-G406 ) 〇3.86 (s, 3H), 3.89 (s5 3H), 3.94 (s, 3H), 5.05 (s, 2H) 5 5.12 (s5 2H) 5 6.31 (s? 2H), 6.79 (d? J = 8.2Hz5 1H) 5 7.06 (dd5 J = 2.0? 8..2Hz? 1 H) 5 7.14 (d5 J = 2.0Hz, 1 H)? 7.25-7.45 (m, 5H) MS (El) E / Z 404 (M + ) Production Example 5 9 Synthesis of 3- (4-hydroxy-3-methoxybenzyl) -5,7-dimethoxy-2 Hl, 3-benzoDfazepine-2,4 (3H) -Diketone was the same as in Production Example 54 to obtain the title compound (BAK-G406) in a yield of 76%.

BAK-G406 H-NMR (CDC13) δ: 3.87 (s，3Η)，3.89 (s5 3Η); 3.95 (s，3Η)，5.05 (s5 2Η)， -57 - (53) 200417367 5.58 (s，1H)，6.31 (s，2Η)5 6·83 (d，j = 8.6Hz，1H)， 7.05-7.15 (m? 2H) M S (El) E/Z 3 5 9 (M + ) 製造例6 0 合成2，4-雙（苯甲氧基）+ (厂氯乙氧基）j〔 3，4_ 亞甲基二氧）苯甲基〕苯甲醯月安 與製造例2 5 —樣之方法，以收率8 4 %得標題化合物 (BAK - G3 64 ) 〇BAK-G406 H-NMR (CDC13) δ: 3.87 (s, 3Η), 3.89 (s5 3Η); 3.95 (s, 3Η), 5.05 (s5 2Η), -57-(53) 200417367 5.58 (s, 1H) , 6.31 (s, 2Η) 5 6 · 83 (d, j = 8.6Hz, 1H), 7.05-7.15 (m? 2H) MS (El) E / Z 3 5 9 (M +) Manufacturing Example 6 0 Synthesis 2 , 4-Bis (benzyloxy) + (factory chloroethoxy) j [3,4_ methylenedioxy) benzyl] benzidine Yuean and Manufacturing Example 2 5-The same method to collect The title compound (BAK-G3 64) was obtained at a yield of 84%.

BAK-G238 BAK-G364 ^-NMR (CDC13) δ:BAK-G238 BAK-G364 ^ -NMR (CDC13) δ:

3.74 (t? J = 5.9Hz? 2H)5 4.19 (t5 J = 5.9Hz? 2H)5 5.9 2 (s? 2H)5 6.04 (t? J = 5.8Hz? 1 H )，6 · 1 5 ( d，J = 2 · 0 Η z，1 H)? 6.25 (d5 J = 2.0 Hz, 1H)， 6.66 (d5 J = 7.9Hz， 1H)5 6.77 (dd5 J=1.5，7.9Hz5 1H)，6.86(d，J=1.5Hz，1H)，7.25-7.40(m5 1 OH) M S (El) E/Z 5 45 (M + ) 製造例6 1 合成6，8 -雙（苯甲氧基-3，4 -二氫-4-〔3，4-(亞甲二氧 )苯甲基〕-]，4 -苯并Df吖庚因- 5(2H)-酮 -58- (54) 200417367 與製造例2 9 —樣之方法，以收率7 6 %得標題化合物 (B AK-G3 67 )。3.74 (t? J = 5.9Hz? 2H) 5 4.19 (t5 J = 5.9Hz? 2H) 5 5.9 2 (s? 2H) 5 6.04 (t? J = 5.8Hz? 1 H), 6 · 1 5 (d , J = 2 · 0 Η z, 1 H)? 6.25 (d5 J = 2.0 Hz, 1H), 6.66 (d5 J = 7.9Hz, 1H) 5 6.77 (dd5 J = 1.5, 7.9Hz5 1H), 6.86 (d , J = 1.5Hz, 1H), 7.25-7.40 (m5 1 OH) MS (El) E / Z 5 45 (M +) Production Example 6 1 Synthesis of 6,8 -bis (benzyloxy-3,4- Dihydro-4- [3,4- (methylenedioxy) benzyl]-], 4-benzoDfazepine-5 (2H) -one-58- (54) 200417367 and Production Example 2 9 In the same manner, the title compound (B AK-G3 67) was obtained in a yield of 76%.

广CICanton CI

OBn 0 BAK-G364OBn 0 BAK-G364

BAK-G367 0BAK-G367 0

^-NMR (CDC13) δ:^ -NMR (CDC13) δ:

3.39 (t5 J = 5.6Hz? 2H)? 3.98 (t? J = 5.6Hz? 2H)? 4.74 (s? 2H)，4.99 (s，2H)5 5.16 (s，2H) 5 5.9 5 (s5 2H) 5 6.2 6 (d5 J = 2.3 Hz, 1H)? 6.44 (d5 J-=2.3 Hz? 1H)? 6.75 (d5 J = 7.9 Hz5 1H)? 6.83 (dd5 7.9Hz? 1H)? 6.94(d? J=1 .5Hz5 1H)? 7.2 5 -7.5 0 (m5 1〇h) MS (El) E/Z 5 0 9 (M + ) 製造例62 合成3，4 -二氫-6，8-一羥基-4、〔 3，4_(甲氧基二氫）苯 甲基〕-1，4 -苯并吗吖庚因-5 (2H)-酮 在660mg ( 1.30毫莫爾）製造例61所得BAK-G367 ，及12ml乙酸乙醋中加入66mg 10% Pd-C，氫氣氛下， 於室溫攪拌2 0小時。以矽藻土過濾反應液，濃縮後粗生 成物以矽膠管柱層析（己烷··乙酸乙酯=1 : 1 )精製，以 83%收率得3 5 7.3 mg標題化合物（BAK-G3 72 )。 - 59- (55) 2004173673.39 (t5 J = 5.6Hz? 2H)? 3.98 (t? J = 5.6Hz? 2H)? 4.74 (s? 2H), 4.99 (s, 2H) 5 5.16 (s, 2H) 5 5.9 5 (s5 2H) 5 6.2 6 (d5 J = 2.3 Hz, 1H)? 6.44 (d5 J- = 2.3 Hz? 1H)? 6.75 (d5 J = 7.9 Hz5 1H)? 6.83 (dd5 7.9Hz? 1H)? 6.94 (d? J = 1.5 Hz5 1H)? 7.2 5 -7.5 0 (m5 1〇h) MS (El) E / Z 5 0 9 (M +) Production Example 62 Synthesis of 3,4-dihydro-6,8-monohydroxy-4 [3,4_ (methoxydihydro) benzyl] -1,4-benzonazepine-5 (2H) -one at 660 mg (1.30 mmol) BAK-G367 obtained in Production Example 61, 66 mg of 10% Pd-C was added to 12 ml of ethyl acetate, and the mixture was stirred at room temperature for 20 hours under a hydrogen atmosphere. The reaction solution was filtered through celite, and the crude product was purified by silica gel column chromatography (hexane ·· ethyl acetate = 1: 1) to obtain 3 5 7.3 mg of the title compound (BAK-G3) in 83% yield. 72). -59- (55) 200417367

ΒΑΚ·Ό367 BAK-G372 iH-NMR (CDC13) δ:ΒΑΚ · Ό367 BAK-G372 iH-NMR (CDC13) δ:

3.46(t? J = 4.9Hz? 2H)? 4.20(t? J = 4.9Hz? 2H)? 4.68 (s? 2H) 5 5.3 0 (s，1H)，5。97 (s，2H) 5 6.0 3 (d，J-2.5Hz? 1H)， 6.20 (d5 J = 2.5Hz，1H) 5 6.7 5 - 6.8 5 (m，3H) 1 1.80 (s5 1H) MS (El) E/Z 3 29 (M + ) 製造例6 3 合成 4-苯甲氧基-N- (3，4-二甲氧基苯甲基）-2-羥基苯 甲醯胺 與製造例1 一樣之方法，以收率1 8%得標題化合物（ B AK-G44 1 )。3.46 (t? J = 4.9Hz? 2H)? 4.20 (t? J = 4.9Hz? 2H)? 4.68 (s? 2H) 5 5.3 0 (s, 1H), 5.97 (s, 2H) 5 6.0 3 (d, J-2.5Hz? 1H), 6.20 (d5 J = 2.5Hz, 1H) 5 6.7 5-6.8 5 (m, 3H) 1 1.80 (s5 1H) MS (El) E / Z 3 29 (M + ) Production Example 6 3 Synthesis of 4-benzyloxy-N- (3,4-dimethoxybenzyl) -2-hydroxybenzamide in the same manner as in Production Example 1 in a yield of 18% The title compound (B AK-G44 1) was obtained.

BnOBnO

BAK-G365-1BAK-G365-1

BnOv OH H I Γ Y BAK-G441 H-NMR (CDC13) δ: 3.88 (s; 6H)5 4.54 (d5 J = 5.5Hz，2H)5 5.06 (s; 2H)，6.33 (brt; 1H); 6.45 (dd? J = 2.5? 8.5Hz; 1H); 6.56 (d? -60- (56) 200417367 J = 2.5Hz? 1 H)? 6.8 0 - 6.9 5 (m? 3H)? 7.24 (d5 J= 8.8Hz? 1H)， 7.30-7.45 (m， 5H)， 12.67 (s5 1H) MS (El) E/Z 3 9 3 (M + ) 製造例64 合成4·苯甲氧基-2- (2-氯乙氧基）-N- (3，4-二甲氧基苯 甲基）苯甲醯胺 與製造例25 —樣之方法，以收率92%得標題化合物 (B AK-G442 )。BnOv OH HI Γ Y BAK-G441 H-NMR (CDC13) δ: 3.88 (s; 6H) 5 4.54 (d5 J = 5.5Hz, 2H) 5 5.06 (s; 2H), 6.33 (brt; 1H); 6.45 ( dd? J = 2.5? 8.5Hz; 1H); 6.56 (d? -60- (56) 200417367 J = 2.5Hz? 1 H)? 6.8 0-6.9 5 (m? 3H)? 7.24 (d5 J = 8.8Hz 1H), 7.30-7.45 (m, 5H), 12.67 (s5 1H) MS (El) E / Z 3 9 3 (M +) Production Example 64 Synthesis of 4 · Benzyloxy-2- (2-chloroethyl Oxy) -N- (3,4-dimethoxybenzyl) benzamide was prepared in the same manner as in Production Example 25 to obtain the title compound (B AK-G442) in a yield of 92%.

BAK-G441 BAK-G442 ^-NMR (CDC13) δ: 3.7 4 (t5 J = 4.8Hz，2Η)，3.86 (s5 3Η)，3·8 7 (s，3Η)，4·26BAK-G441 BAK-G442 ^ -NMR (CDC13) δ: 3.7 4 (t5 J = 4.8Hz, 2Η), 3.86 (s5 3Η), 3.87 (s, 3Η), 4.26

(t，J = 4.8Hz5 2Η) 5 4.5 8 (d，J = 5.6Hz，2Η)? 5.09(s，2Η)， 6.48.(d5 J = 2.3Hz, 1H)，6.7 1 (dd5 J = 2.3 5 8.8 Hz，1H)5 6.82(d? J = 8.7Hz? 1H)? 6.9 0 - 7.00 (m5 2H)5 7.3 0 - 7.4 5 (m，5H)，8.14(brt，1H)，8.22 (d，J= 8·8 Hz5 1H) MS (El) E/Z 4 5 5 (M + ) 製造例65 合成8-苯甲氧基- 4-(3，4-二甲氧基苯甲基）-3，4-二氫-1，4-苯并哼吖庚因-5 ( 2H )-酮 -61 - (57) 200417367 與製造例2 9 —樣之方法，以收率9 1 %得標題化合物 (B AK-G444 )。(t, J = 4.8Hz5 2Η) 5 4.5 8 (d, J = 5.6Hz, 2Η)? 5.09 (s, 2Η), 6.48. (d5 J = 2.3Hz, 1H), 6.7 1 (dd5 J = 2.3 5 8.8 Hz, 1H) 5 6.82 (d? J = 8.7Hz? 1H)? 6.9 0-7.00 (m5 2H) 5 7.3 0-7.4 5 (m, 5H), 8.14 (brt, 1H), 8.22 (d, J = 8 · 8 Hz5 1H) MS (El) E / Z 4 5 5 (M +) Production Example 65 Synthesis of 8-benzyloxy-4- (3,4-dimethoxybenzyl) -3, 4-Dihydro-1,4-benzoazepine-5 (2H) -one-61-(57) 200417367 The same method as in Production Example 2 9 was used to obtain the title compound (B in a yield of 91%) AK-G444).

^-NMR (CDC13) δ:^ -NMR (CDC13) δ:

3.46(t? J = 5.2Hz? 2H), 3„87(s? 3H)? 3.88(s? 3H)? 4.14 (t? J = 5.2Hz5 2H)5 4.7 5 (s? 2H) 5 5.0 7 (s? 2H) 5 6.7 5 - 6.95(m5 4H)? 7.3 0 - 7.45 (m5 5H) 5 7.8 7 (d? J- 8.8 Hz? 1H) MS (El) E/Z 419 (M + ) 製造例663.46 (t? J = 5.2Hz? 2H), 3 „87 (s? 3H)? 3.88 (s? 3H)? 4.14 (t? J = 5.2Hz5 2H) 5 4.7 5 (s? 2H) 5 5.0 7 ( s? 2H) 5 6.7 5-6.95 (m5 4H)? 7.3 0-7.45 (m5 5H) 5 7.8 7 (d? J- 8.8 Hz? 1H) MS (El) E / Z 419 (M +) Manufacturing example 66

合成 3，4-二氫- 4-(3，4-二甲氧基苯甲基）-8-羥基-1， 4-苯并哼吖庚因-5 ( 2H)-酮 在48 0mg ( 1.15毫莫爾）製造例65所得BAK-G444 及10ml乙酸乙酯中加入48mg 10% Pd-C，於氫氣氛下攪 拌2 0小時。以矽藻土過濾反應液，濃縮後粗生成物以矽 膠管柱層析（己烷：乙酸乙酯=1 : 2 )精製，以88%收率 得3 3 4.5 mg標題化合物（BAK-G44 5 )。 -62- (58) 200417367Synthesis of 3,4-dihydro- 4- (3,4-dimethoxybenzyl) -8-hydroxy-1,4-benzonezepine-5 (2H) -one at 48 0mg (1.15 (Mole) BAK-G444 obtained in Production Example 65 and 10 ml of ethyl acetate were added with 48 mg of 10% Pd-C and stirred under a hydrogen atmosphere for 20 hours. The reaction solution was filtered through celite, and the crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2) to obtain 3 3 4.5 mg of the title compound (BAK-G44 5 in 88% yield). ). -62- (58) 200417367

〇、 〇〆 ^-NMR (CDC13) δ:〇, 〇〆 ^ -NMR (CDC13) δ:

： 3.46 (t5 J = 5.2Hz5 2H)? 3.86 (s5 3H)? 3.88 (s? 3H), 4.13 (t5 J-5.2Hz5 2H)? 4.75 (s5 2H)? 6.39(s? 1H)? 6.45(d?: 3.46 (t5 J = 5.2Hz5 2H)? 3.86 (s5 3H)? 3.88 (s? 3H), 4.13 (t5 J-5.2Hz5 2H)? 4.75 (s5 2H)? 6.39 (s? 1H)? 6.45 (d ?

J = 2.5Hz? 1 H)? 6.62(dd5 J = 2.5? 8.6Hz5 1H)， 6.75- 6.95(m，3H) 5 7.7 8 (d，J = 8.6Hz? 1H) MS (El) E/Z 3 29 (M + ) 製造例67 合成乙酸〔〔4-(3，4-二甲氧基苯甲基）-2’ 3，4，5-四 氫-5-氧基-1，4-苯并哼吖庚因-8-基〕氧基〕甲酯J = 2.5Hz? 1 H)? 6.62 (dd5 J = 2.5? 8.6Hz5 1H), 6.75- 6.95 (m, 3H) 5 7.7 8 (d, J = 8.6Hz? 1H) MS (El) E / Z 3 29 (M +) Production Example 67 Synthesis of acetic acid [[4- (3,4-dimethoxybenzyl) -2 '3,4,5-tetrahydro-5-oxy-1,4-benzo Humazepine-8-yl] oxy] methyl ester

於室攪拌4小時259.3mg(0.788毫莫爾）製造例66 所得 BAK-G445，326mg(2.36 毫莫爾）碳酸鉀，0·15χη1 (1.58毫莫爾）溴化乙酸甲酯及4 ml DMF。反應液中加 入水，以乙酸乙酯萃取，有機層以無水硫酸鈉乾燥。濃縮 後以矽膠管柱層析（己烷：乙酸乙酯=1 : 1 )精製粗生成 物，以收率1〇〇%得323.3mg標題化合物（BAK-G460 )。259.3 mg (0.788 mmol) of BAK-G445 obtained in Preparation Example 66, 326 mg (2.36 mmol) of potassium carbonate, 0.15 × η1 (1.58 mmol) of methyl bromide and 4 ml of DMF were stirred in the chamber for 4 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After concentration, the crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain 323.3 mg of the title compound (BAK-G460) in a yield of 100%.

BAK-G445 BAK-G460 ΟBAK-G445 BAK-G460 Ο

A^o ^ •63 - (59) 200417367 ^-NMR (CDCI3) δ: 3.47(t，J = 5.1Hz， 2H)，3.81 (s5 3H)， 3.87 (s， 3H)5 3.88(s，3H)，4.14(t，J = 5.1Hz，2H)，4·65 (s，2H)，4.75 (s? 2H)? 6.49 (d? J = 2.5Hz5 1H)? 6.72(dd5 J = 2.5? 8.8Hz? 1H)，6.7 5 -6.9 5 (m，3 H)，7·89 (d5 J =8.8 Hz，1H) MS (El) E/Z 401 (M + )A ^ o ^ • 63-(59) 200417367 ^ -NMR (CDCI3) δ: 3.47 (t, J = 5.1Hz, 2H), 3.81 (s5 3H), 3.87 (s, 3H) 5 3.88 (s, 3H) , 4.14 (t, J = 5.1Hz, 2H), 4.65 (s, 2H), 4.75 (s? 2H)? 6.49 (d? J = 2.5Hz5 1H)? 6.72 (dd5 J = 2.5? 8.8Hz? 1H), 6.7 5 -6.9 5 (m, 3 H), 7.89 (d5 J = 8.8 Hz, 1H) MS (El) E / Z 401 (M +)

製造例6 8 合成〔〔4-(3，4-二甲氧基苯甲基）-2，3，4，5-四氫-5 -氧基-1，4 -苯并卩琴卩丫庚因-8-基〕氧基〕乙酸Production Example 6 8 Synthesis of [[4- (3,4-dimethoxybenzyl) -2,3,4,5-tetrahydro-5 -oxy-1,4-benzobenzopyrene In-8-yl] oxy] acetic acid

在3 1 5mg ( 0.7 8 6毫莫爾）製造例67所得BAK-G460 之7ml甲醇溶液中，加入400mg氫氧化鈉及3ml水，回 流3小時。反應液中加入稀鹽酸使其爲酸性，以乙酸乙酯 萃取，有機層以無水硫酸鈉乾燥。經濃縮後，自1 0 m 1乙 醇再結晶粗生成物，以收率75 %得227.2mg標題化合物（ BAK-G462 ) 〇To 3 15 mg (0.7 8 6 mmol) of 7 ml of a methanol solution of BAK-G460 obtained in Production Example 67 was added 400 mg of sodium hydroxide and 3 ml of water, and the mixture was refluxed for 3 hours. Dilute hydrochloric acid was added to the reaction solution to make it acidic, extraction was performed with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After concentration, the crude product was recrystallized from 10 m 1 of ethanol to obtain 227.2 mg of the title compound (BAK-G462) in a yield of 75%.

]H-NMR (DMSO-d6) δ: 3.49 (t5 J = 4.6Hz? 2H)? 3.72 (s5 3H) 5 3.7 3 (s? 3H)? 4.19 (t? J = 4.6Hz? = 2H)? 4.65 (s; 2H); 4.72(s? 2H)5 6.5 0 (d5 J = 2.5Hz，1H)，6·73 (dd; J = 2.5; 8·8 Hz; 1H)，6.80-6.95 -64 - (60) 200417367 (m，3H)，7·6 9 (d，J = 8.8Hz5 1H) MS (El) E/Z 38 7 (M + ) 製造例6 9 合成 3-〔 （4-苯甲氧基-3-甲氧基）苯甲基〕-6-氯-2，3- 二氫- 4H-1，3 -苯并Df畊-4-酮 與製造例1 一樣之方法，以收率88%得標題化合物（ B AK-G4 5 4 )。] H-NMR (DMSO-d6) δ: 3.49 (t5 J = 4.6Hz? 2H)? 3.72 (s5 3H) 5 3.7 3 (s? 3H)? 4.19 (t? J = 4.6Hz? = 2H)? 4.65 (s; 2H); 4.72 (s? 2H) 5 6.5 0 (d5 J = 2.5Hz, 1H), 6.73 (dd; J = 2.5; 8 · 8 Hz; 1H), 6.80-6.95 -64-( 60) 200417367 (m, 3H), 7 · 6 9 (d, J = 8.8Hz5 1H) MS (El) E / Z 38 7 (M +) Production Example 6 9 Synthesis of 3- [(4-benzyloxy -3-methoxy) benzyl] -6-chloro-2,3-dihydro-4H-1,3-benzo-Df phen-4-one The same method as in Production Example 1 was used to obtain a yield of 88%. The title compound (B AK-G4 5 4) was obtained.

BAK-G395BAK-G395

BAK-G454 Ή-NMR (CDC13) δ: 3.87(s5 3H)? 4.68(s5 2H) 5 5.0 9 (s? 2H)? 5.15(s? 2H)5 6.7 5 -6.9 5 (m，4H)，7.3 0 -7.5 0 (m，6H)? 7.98(d? J = 2.6Hz5 1H) MS (El) E/Z 409(M + ) 製造例70 合成6-氯-2，3-二氫-3-〔 （4-羥基-3-甲氧基）苯甲基〕- 4 Η - 1，3 -苯并卩f哄-4 -酮 與製造例66 —樣之方法，以收率71 %得標題化合物 (B AK-G4 5 6 ) (61) 200417367BAK-G454 Ή-NMR (CDC13) δ: 3.87 (s5 3H)? 4.68 (s5 2H) 5 5.0 9 (s? 2H)? 5.15 (s? 2H) 5 6.7 5 -6.9 5 (m, 4H), 7.3 0 -7.5 0 (m, 6H)? 7.98 (d? J = 2.6Hz5 1H) MS (El) E / Z 409 (M +) Production Example 70 Synthesis of 6-chloro-2,3-dihydro-3- [ (4-Hydroxy-3-methoxy) benzyl] -4 fluorene-1,3-benzofluorene f co-4-one was prepared in the same manner as in Production Example 66 to obtain the title compound in a yield of 71% ( B AK-G4 5 6) (61) 200417367

BAK-G454 BAK-G456 】H-NMR (CDC13) δ: 3.87 (s? 3H)? 4.67 (s5 2H) 5 5.0 9 (s5 2H)? 5.64(s, 1H)? 6.7 5 - 6.9 5 (m5 4H)5 7.3 9 (dd5 J = 2.6, 8.7 Hz, 1H)5 7.98 (d? J = 2.6 Hz? 1H) φ MS (El) E/Z 3 1 9 (M + ) 製造例7 1 合成〔4-〔 〔 6-氯-4-氧基- 2H-1，3-苯并Df哄-3 (4H)-基 〕甲基〕-2-甲氧基苯氧基〕乙酸甲酯 與製造例67 —樣之方法，以收率100%得標題化合物 (B AK-G45 9 )。BAK-G454 BAK-G456】 H-NMR (CDC13) δ: 3.87 (s? 3H)? 4.67 (s5 2H) 5 5.0 9 (s5 2H)? 5.64 (s, 1H)? 6.7 5-6.9 5 (m5 4H ) 5 7.3 9 (dd5 J = 2.6, 8.7 Hz, 1H) 5 7.98 (d? J = 2.6 Hz? 1H) φ MS (El) E / Z 3 1 9 (M +) Manufacturing Example 7 1 Synthesis (4- [[6-Chloro-4-oxy-2H-1,3-benzo Df co-3-(4H) -yl] methyl] -2-methoxyphenoxy] methyl acetate with Production Example 67 — In the same way, the title compound (B AK-G45 9) was obtained in a yield of 100%.

Ο BAK-G456 BAK-G459 ]H-NMR (CDC13) δ: 3.80 (s3 3H) 5 3.8 7 (s5 3H)5 4.6 9 (s5 4H)5 5.10 (s5 2H)5 6.7 5 -6.9 5 (m，4H)，7.40(dd5 J = 2.6 5 8.7 Hz，1H)5 7.9 8 (d， J = 2.6 H z，1 H) MS (El) E/Z 391 (M + ) -66 - (62) 200417367 製造例72 合成〔4-〔 〔 6 -氯-4-氧基- 2H-1，3 -苯并鸣畊-3 (4H)-基 〕甲基〕-2 -甲氧基苯氧基〕乙酸 與製造例6 8 —樣之方法，以收率6 7 %得標題化合物 (B AK-G46 1 )。〇 BAK-G456 BAK-G459] H-NMR (CDC13) δ: 3.80 (s3 3H) 5 3.8 7 (s5 3H) 5 4.6 9 (s5 4H) 5 5.10 (s5 2H) 5 6.7 5 -6.9 5 (m, 4H), 7.40 (dd5 J = 2.6 5 8.7 Hz, 1H) 5 7.9 8 (d, J = 2.6 H z, 1 H) MS (El) E / Z 391 (M +) -66-(62) 200417367 Manufacturing Example 72Synthesis of [4- [[6 -Chloro-4-oxy-2H-1,3-benzobenzopentine-3 (4H) -yl] methyl] -2 -methoxyphenoxy] acetic acid and Production Example 68 The same method was used to obtain the title compound (B AK-G46 1) in a yield of 67%.

BAK-G459 BAK-G461BAK-G459 BAK-G461

^-NMR (DMSO-d6) δ: 3.75 (s，3Η)5 4·61 (s，2Η)，4.62 (s，2Η)，5.33(s，2Η)5 6.82 (m5 2Η)? 6.96 (s5 1Η)5 7.12 (d5 J = 8.7Hz? 1Η)5^ -NMR (DMSO-d6) δ: 3.75 (s, 3Η) 5 4.61 (s, 2Η), 4.62 (s, 2Η), 5.33 (s, 2Η) 5 6.82 (m5 2Η)? 6.96 (s5 1Η ) 5 7.12 (d5 J = 8.7Hz? 1Η) 5

7.59 (dd，J =2.6，8·7Ηζ，1Η) 5 7.7 8 (d，J = 2.6Hz，1Η) MS (El) E/Z 3 7 7 (M + ) 製造例73 合成N-〔 （ 4-苯甲氧基-3-甲氧基）苯甲基〕_5_氯_2_ ( 2- 氯化乙氧基）苯甲醯胺 與製造例25 —樣之方法，以收率88%得標題化合物 (B AK-G47 1 )。 -67 - 2004173677.59 (dd, J = 2.6, 8.7 · ζ, 1Η) 5 7.7 8 (d, J = 2.6Hz, 1Η) MS (El) E / Z 3 7 7 (M +) Production Example 73 Synthesis of N- [(4 -Benzyloxy-3-methoxy) benzyl] _5_chloro_2_ (2-chloroethoxy) benzamide and the same method as in Production Example 25. The title was obtained with a yield of 88%. Compound (B AK-G47 1). -67-200417367

iH-NMR (CDC13) δ: 3.73(t? J = 4.8Hz? 2H) 5 3.8 8 (s5 3H), 4.29(t5 J = 4.8Hz5iH-NMR (CDC13) δ: 3.73 (t? J = 4.8Hz? 2H) 5 3.8 8 (s5 3H), 4.29 (t5 J = 4.8Hz5

2H)? 4.57(d? J = 5.6Hz, 2H)5 5.15 (s5 2H)? 6.75 - 6.9 5 (m5 4H)? 7.25-7.5 0(m? 6H)5 8.18 (brt? 1H)5 8.21 (d? J = = 2.8 Hz，1H) MS (El) E/Z 45 9(M + ) 製造例74 合成4〔 （I苯甲氧基甲氧基）苯甲基〕-八氯二 氫d，4_苯井噚吖庚因-5 ( 2h) _嗣2H)? 4.57 (d? J = 5.6Hz, 2H) 5 5.15 (s5 2H)? 6.75-6.9 5 (m5 4H)? 7.25-7.5 0 (m? 6H) 5 8.18 (brt? 1H) 5 8.21 (d ? J = = 2.8 Hz, 1H) MS (El) E / Z 45 9 (M +) Production Example 74 Synthesis of 4 [(IBenzylmethoxymethoxy) benzyl] -octachlorodihydro d, 4 _Benzene 噚 Azine-5 (2h) _ 嗣

與製造例29 一樣之方法’以收率86%得標題化合物 (B AK-G472 )。The title compound (B AK-G472) was obtained in the same manner as in Production Example 29 'in a yield of 86%.

BAK-G471 BAK-G472 H-NMR (CDC13) δ: 88 (s5 3H)? 4.12(t? 2H)? 6.75-7.00 J = 4.9Hz5 (in， 4 H)， 3.44(t5 J = 4.9Hz? 2H)5 2H)，4.7 4 (s，2H)5 5. -68 - (64) 200417367 7.2 5 - 7.5 0 (m? 6H)，7.84 (d? J = 2.7Hz，1H) MS (El) E/Z 423 (M + ) 製造例7 5 合成7-氯-3，4-二氫-4-〔 （4-羥基-3-甲氧基）苯甲基〕- i，4-苯井Df吖庚因-5 ( 2H )-酮 與製造例66 —樣之方法，以收率89%得標題化合物 (B AK-G473 )。BAK-G471 BAK-G472 H-NMR (CDC13) δ: 88 (s5 3H)? 4.12 (t? 2H)? 6.75-7.00 J = 4.9Hz5 (in, 4 H), 3.44 (t5 J = 4.9Hz? 2H ) 5 2H), 4.7 4 (s, 2H) 5 5. -68-(64) 200417367 7.2 5-7.5 0 (m? 6H), 7.84 (d? J = 2.7Hz, 1H) MS (El) E / Z 423 (M +) Production Example 7 5 Synthesis of 7-chloro-3,4-dihydro-4-[(4-hydroxy-3-methoxy) benzyl] -i, 4-benzene well Df acryl The title compound (B AK-G473) was obtained in a yield of 89% due to the same method as that of Production Example 66 for -5 (2H) -one.

BAK-G472 BAK-G473 ^-NMR (CDC13) δ:BAK-G472 BAK-G473 ^ -NMR (CDC13) δ:

3.45(t? J = 4.9Hz? 2H) 5 3.8 8 (s5 3H)? 4.12(t? J = 4.9Hz? 2H)，4.7 3 (s，2H)，5.65 (s5 1H)，6.80(dd，J=1.8，8.0Hz, 1H)，6.8 5 -7.00 (m? 3H)? 7.36 (dd? J = 2.75 8.7 Hz? 1H)5 7.84 (d5 J = 2.7 Hz5 1H) MS ( El ) E/Z 3 3 3 (M + ) 製造例76 合成〔4-〔 〔7-氯-2，3-二氫-5-氧基-1，4-苯井Df吖庚因- 4 ( 5H )-基〕甲基〕-2-甲氧基苯氧基〕乙酸甲酯 與製造例67 —樣之方法，以收率100 %得標題化合物 -69- (65) 200417367 (BAK-G474 )。3.45 (t? J = 4.9Hz? 2H) 5 3.8 8 (s5 3H)? 4.12 (t? J = 4.9Hz? 2H), 4.7 3 (s, 2H), 5.65 (s5 1H), 6.80 (dd, J = 1.8, 8.0Hz, 1H), 6.8 5 -7.00 (m? 3H)? 7.36 (dd? J = 2.75 8.7 Hz? 1H) 5 7.84 (d5 J = 2.7 Hz5 1H) MS (El) E / Z 3 3 3 (M +) Production Example 76 Synthesis of [4- [[7-Chloro-2,3-dihydro-5-oxy-1,4-Benzene Dfazepine-4 (5H) -yl] methyl ] Methyl-2-methoxyphenoxy] acetate was prepared in the same manner as in Production Example 67 to obtain the title compound -69- (65) 200417367 (BAK-G474) in a yield of 100%.

BAK-G473 BAK-G474 Ο 0-Λ〇/ 〇/ ]H-NMR (CDC13) δ: 3.45(t? J = 5.3Hz5 2H)? 3.80(s? 3H) 5 3.8 8 (s? 3H)? 4.14BAK-G473 BAK-G474 〇 0-Λ〇 / 〇 /] H-NMR (CDC13) δ: 3.45 (t? J = 5.3Hz5 2H)? 3.80 (s? 3H) 5 3.8 8 (s? 3H)? 4.14

(t，J = 5.3Hz，2H)5 4.70 (s5 2H)，4.75 (s5 2H)，6.77 (d，J =8. 1Hz5 1H)? 6.8 3 (dd? J=1 .7, 8·1Ηζ，1H)，6.94(d5 J = 8.6Hz，1H)，6.95(d，J=1.7Hz5 1H)，7.37 (dd，J = 2.7, 8.6Hz? 1H)，7.84(d，J = 2.7Hz，1 H) MS (El) E/Z 405 (M + ) 製造例77 合成〔4-〔 〔7-氯-2，3-二氫-5-氧基-1，4-苯井哼吖庚因· 4 (5H)-基〕甲基〕-2-甲氧基苯氧基〕乙酸 與製造例68 —樣之方法，以收率79%得標題化合物 (B AK-G4 7 5 )。(t, J = 5.3Hz, 2H) 5 4.70 (s5 2H), 4.75 (s5 2H), 6.77 (d, J = 8. 1Hz5 1H)? 6.8 3 (dd? J = 1 .7, 8 · 1Ηζ, 1H), 6.94 (d5 J = 8.6Hz, 1H), 6.95 (d, J = 1.7Hz5 1H), 7.37 (dd, J = 2.7, 8.6Hz? 1H), 7.84 (d, J = 2.7Hz, 1 H ) MS (El) E / Z 405 (M +) Production Example 77 Synthesis of [4- [[7-Chloro-2,3-dihydro-5-oxy-1,4-benzyl azepine] 4 (5H) -yl] methyl] -2-methoxyphenoxy] acetic acid was obtained in the same manner as in Production Example 68 to obtain the title compound (B AK-G4 7 5) in a yield of 79%.

BAK-G474 BAK-G475 H-NMR (DMSO-d6) δ: 3.52 (t，J=4.8Hz5 2Η); 3.76 (s，3Η)，4.22 (t，J = 4.8Hz， (66) 200417367 2H)? 4.64 (s? 2H)? 4.67 (s? 2H)? 6.83(brs? 1H)? 6.97 (brs? 1H)? 7.07(d5 J = 8.7Hz? 1H)? 7.5 3 (dd? J = 2.7? 8.7 Hz? 1H) 5 7.6 9 (d5 J = 2.7Hz9 1H) MS (El) E/Z 391 (M + ) 製造例7 8 合成 3，5-二氯-N-〔 （2，3-二氫-1，4-苯井二噁因-6-基BAK-G474 BAK-G475 H-NMR (DMSO-d6) δ: 3.52 (t, J = 4.8Hz5 2Η); 3.76 (s, 3Η), 4.22 (t, J = 4.8Hz, (66) 200417367 2H)? 4.64 (s? 2H)? 4.67 (s? 2H)? 6.83 (brs? 1H)? 6.97 (brs? 1H)? 7.07 (d5 J = 8.7Hz? 1H)? 7.5 3 (dd? J = 2.7? 8.7 Hz 1H) 5 7.6 9 (d5 J = 2.7Hz9 1H) MS (El) E / Z 391 (M +) Production Example 7 8 Synthesis of 3,5-dichloro-N- [(2,3-dihydro-1 , 4-Benzene dioxin-6-yl

〕-2-羥基-苯磺醯胺 於室溫攪拌16.5小時l.OOg ( 3.82毫莫爾）3，5-二 氯-2-羥基苯磺醯氯，771mg(3.82毫莫爾）製造例38所 得 BAK-G369，1·60πι1(11·5 毫莫爾）三乙胺，40.0ml 氯 仿。反應液中加入2莫爾/1鹽酸，以氯仿萃取，以飽和食 鹽水洗淨有機層。以無水硫酸鎂乾燥，濃縮後以矽膠管柱 層析（己烷：乙酸乙酯=2 : 1 )精製粗生成物，以收率 97%得 1.45g 標題化合物（ΒΑΚ-ΚΑ254 )。] 2-Hydroxy-benzenesulfonamide was stirred at room temperature for 16.5 hours. 1,000 g (3.82 mmol) of 3,5-dichloro-2-hydroxybenzenesulfon chloride, 771 mg (3.82 mmol) Production Example 38 The obtained BAK-G369, 1.60 μm (11.5 mmol) triethylamine, 40.0 ml of chloroform. To the reaction solution was added 2 mol / 1 hydrochloric acid, followed by extraction with chloroform, and the organic layer was washed with saturated brine. The crude product was dried over anhydrous magnesium sulfate, concentrated, and then purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain 1.45 g of the title compound (ΒΑΚ-ΚΑ254) in a yield of 97%.

]H-NMR (CDC13) δ: 4.09 (s5 2H)5 4.2 2 (s5 4H)5 6.5 8 - 6.7 6 (m 5 3H)5 7.5 0 (brs5 1H) MS (El) E/Z 3 8 9 (M + )，391 (M + 2)，3 9 3 (M + 4) -71 - (67) 200417367 製造例79 合成1，1-二氧化5，7-二氯-2-〔（2，3-二氫-1，4-苯并 二噁因-6-基）甲基〕-2，3-二氫-4，1，2-苯并鸣噻D并] H-NMR (CDC13) δ: 4.09 (s5 2H) 5 4.2 2 (s5 4H) 5 6.5 8-6.7 6 (m 5 3H) 5 7.5 0 (brs5 1H) MS (El) E / Z 3 8 9 ( M +), 391 (M + 2), 3 9 3 (M + 4) -71-(67) 200417367 Manufacturing Example 79 Synthesis of 1,1-dioxide 5,7-dichloro-2-[(2,3 -Dihydro-1,4-benzodioxin-6-yl) methyl] -2,3-dihydro-4,1,2-benzothiazepine

加熱回流1 4小時4 3 9 mg ( 1 . 1 2毫莫爾）製造例7 8所 得BAK-KA254，214mg(1.12毫莫爾）對甲苯磺酸-水合 物，1·0πι1二甲氧基甲烷，10.0ml甲苯。反應液中加入2 莫爾/1鹽酸，以乙酸乙酯萃取，以飽和食鹽水洗淨有機層 。以無水硫酸鎂乾燥，濃縮後以矽膠管柱層析（己烷：乙 酸乙酯=3 : 1 )精製粗生成物，以收率92 %得41 6mg標題 化合物（B AK-KA25 5 - 1 )。 〇2 〇2Heated to reflux for 4 hours 4 3 9 mg (1.22 mmoles) BAK-KA254 obtained in Preparation Example 7 8, 214 mg (1.12 mmoles) of p-toluenesulfonic acid-hydrate, 1.0 μm 1 dimethoxymethane , 10.0 ml of toluene. 2 mol / 1 hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine. The crude product was dried over anhydrous magnesium sulfate, concentrated, and then purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain 41.6 mg of the title compound (B AK-KA25 5-1) in a yield of 92%. . 〇2 〇2

^-NMR (CDC13) δ:^ -NMR (CDC13) δ:

4.27 (s? 4H)? 4.29 (s5 2H)? 5.48 (s? 2H)? 6.86-6.89 (m? 3H) 5 7.5 5 (d5 J = 2.5Hz5 1H) 7.67 (d? J= 2.5Hz5 1H) MS (El) E/Z 401 (M + ) 5 4 0 3 (m + 2)5 40 5 (M + 4) 製造例8 0 合成1，1-二氧化5，7_二氯-2-〔 （ 2，3-二氫·丨，肛苯并 二噁因-6-基）甲基〕·4，丨，2-苯并噚噻哄_3(2H)-酮 於室溫攪拌21小時3〇〇mg ( 〇.77毫莫爾）製造例78 所得 BAK-KA2 54，249mg ( 1.53 毫莫爾）N，N•碳化二咪 -72- (68) (68)200417367 唑，94.Omg (0.77毫莫爾）二甲基胺基吡啶，500ml無水 二甲基甲醯胺。反應液中加入2莫爾/1鹽酸，以乙酸乙酯 萃取，以飽和碳酸氫鈉水溶液及飽和食鹽水洗淨有機層。 以無水硫酸鎂乾燥，濃縮後以矽膠管柱層析（己烷：乙酸 乙酯=4 : 1 )精製粗生成物，以收率69%得222mg標題化 合物（BAK-KA2 5 7 )。4.27 (s? 4H)? 4.29 (s5 2H)? 5.48 (s? 2H)? 6.86-6.89 (m? 3H) 5 7.5 5 (d5 J = 2.5Hz5 1H) 7.67 (d? J = 2.5Hz5 1H) MS (El) E / Z 401 (M +) 5 4 0 3 (m + 2) 5 40 5 (M + 4) Production Example 8 0 Synthesis of 1,1-dioxide 5,7_dichloro-2- [( 2,3-dihydro · 丨, anal benzodioxin-6-yl) methyl], 4, 丨, 2-benzofluorenthiazine_3 (2H) -one was stirred at room temperature for 21 hours3. 〇mg (.77 mmol) BAK-KA2 obtained in Production Example 78, 54249 mg (1.53 mmol) N, N • carbodiimide-72- (68) (68) 200417367 azole, 94.0 mg (0.77 Millimolar) dimethylaminopyridine, 500ml anhydrous dimethylformamide. To the reaction solution was added 2 mol / 1 hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate aqueous solution and a saturated saline solution. The crude product was dried over anhydrous magnesium sulfate and concentrated, and then purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain 222 mg of the title compound (BAK-KA2 5 7) in a yield of 69%.

】H-NMR (CDC13) δ: 4.23 (s? 4H)? 4.94 (s? 2H)? 6.82(d5 J = 8.2Hz? 1H)， 6.98(dd，J = 2.1? 8.2Hz? 1 H) 5 7 · 0 0 ( d，J = 2 · 1 Η z 5 1H) 7.72 (d5 J = 2.4Hz，1H)? 7.75 (d? J = 2.4Hz? 1H) MS (El) E/Z 415 (M + )，417 (M + 2)5 419 (M + 4) 製造例81 合成N-〔4-(苯甲氧基）-3-甲氧基苯甲基〕-3，5-二氯_ 2-羥基苯磺醯胺 與製造例7 8 —樣之方法，以收率8 8 %得標題化合物 (B AK-KA26 6 )。 (69) 200417367】 H-NMR (CDC13) δ: 4.23 (s? 4H)? 4.94 (s? 2H)? 6.82 (d5 J = 8.2Hz? 1H), 6.98 (dd, J = 2.1? 8.2Hz? 1 H) 5 7 · 0 0 (d, J = 2 · 1 Η z 5 1H) 7.72 (d5 J = 2.4Hz, 1H)? 7.75 (d? J = 2.4Hz? 1H) MS (El) E / Z 415 (M +) ， 417 (M + 2) 5 419 (M + 4) Production Example 81 Synthesis of N- [4- (benzyloxy) -3-methoxybenzyl] -3,5-dichloro-2-hydroxyl Tolasulfazone was prepared in the same manner as in Production Example 78 to obtain the title compound (B AK-KA26 6) in a yield of 88%. (69) 200417367

]H-NMR (CDC13) δ: 4·09 (s5 3H)，4.13 (d，2H·)，5·08 (t5 1H)，5.12 (s5 2H)， 6.61-6.78 (m，3H)，7.3 1-7.53 (m，7H) MS (El) E/Z 46 7 (M + )，469 (M + 2)，471 (M + 4) 製造例8 2 合成1，卜二氧化2-〔4-(苯甲氧基）-3_甲氧基苯甲基 〕-5，7-二氯-2，3-二氫-4，1，2-苯并噚噻哄 與製造例79 —樣之方法，以收率74%得標題化合物 (BAK-KA26 8- 1 )。] H-NMR (CDC13) δ: 4.09 (s5 3H), 4.13 (d, 2H ·), 5.08 (t5 1H), 5.12 (s5 2H), 6.61-6.78 (m, 3H), 7.3 1 -7.53 (m, 7H) MS (El) E / Z 46 7 (M +), 469 (M + 2), 471 (M + 4) Production Example 8 2 Synthesis 1, Dioxo 2- [4- ( Benzyloxy) -3_methoxybenzyl] -5,7-dichloro-2,3-dihydro-4,1,2-benzobenzothiazine and the same method as in Production Example 79, The title compound (BAK-KA26 8-1) was obtained in a yield of 74%.

JH-NMR (CDC13) δ: 3.90 (s? 3H)? 4.32 (s? 2H)? 5.17 (s5 2H)5 5.4 7 (s5 2H), 6.86-6.91 (m，3H)5 7.3 1 (m5 7H) MS (El) E/Z 479 (M + )，481 (M + 2)，4 8 3 (M + 4) -74 - (70) 200417367 製造例8 3 合成 5，7-二氯-2，3-二氫-2- (4-羥基-3-甲氧基苯甲基 〕-4，1，2 -苯并Df噻啡-1，1-二氧化物 於氫氣流下，室溫下攪拌3小時604mg ( 1.22毫莫爾 )製造例 82 所得 BAK-KA2 6 8 - 1，60.0mg 10%鈀-碳， 10.0ml乙酸乙酯。濾別觸媒，濃縮後，自二氯甲烷-己烷 再結晶，以收率82%得3 90mg標題化合物。 〇2 〇2JH-NMR (CDC13) δ: 3.90 (s? 3H)? 4.32 (s? 2H)? 5.17 (s5 2H) 5 5.4 7 (s5 2H), 6.86-6.91 (m, 3H) 5 7.3 1 (m5 7H) MS (El) E / Z 479 (M +), 481 (M + 2), 4 8 3 (M + 4) -74-(70) 200417367 Production Example 8 3 Synthesis of 5,7-dichloro-2,3 -Dihydro-2- (4-hydroxy-3-methoxybenzyl] -4,1,2,2-benzo Df thienine-1,1-dioxide under a stream of hydrogen and stirred at room temperature for 3 hours 604 mg (1.22 mmol) of Production Example 82 BAK-KA2 6 8-1, 60.0 mg 10% palladium-carbon, 10.0 ml of ethyl acetate. The catalyst was filtered, concentrated, and recrystallized from dichloromethane-hexane. 90 mg of the title compound was obtained in a yield of 82%. 〇2 〇2

^-NMR (CDCI3) δ: 3.91 (s5 3H)? 4.32 (s? 2H)? 5.48 (s5 2H)? 5.69(s5 1H)? 6.8 5 -6.94(m5 3H)5 7.5 6 (d? J = 2.5 Hz, 1H)5 7.6 8 (t? J = 2.5Hz，1 H)^ -NMR (CDCI3) δ: 3.91 (s5 3H)? 4.32 (s? 2H)? 5.48 (s5 2H)? 5.69 (s5 1H)? 6.8 5 -6.94 (m5 3H) 5 7.5 6 (d? J = 2.5 Hz, 1H) 5 7.6 8 (t? J = 2.5Hz, 1 H)

MS (El) E/Z 3 8 9 (M +) 5 3 9 1 (M + 2 ) 5 3 9 3 (M + 4 ) 製造例84 合成1，卜二氧化2-〔4-(苯甲氧基）-3 -甲氧基苯甲基 〕-5，7 -二氯-4，1，2 -苯并噚噻畊-3 (2H)-酮 與製造例80 —樣之方法，以收率85%得標題化合物 (B AK-KA267 )。 75- (71) (71)200417367MS (El) E / Z 3 8 9 (M +) 5 3 9 1 (M + 2) 5 3 9 3 (M + 4) Production Example 84 Synthesis of 1, 2-dioxo-2- [4- (benzyloxy) ) -3 -methoxybenzyl] -5,7-dichloro-4,1,2-benzobenzothiagen-3 (2H) -one as in Production Example 80 in the same manner as the yield 85% gave the title compound (B AK-KA267). 75- (71) (71) 200417367

製造例8 5 合成1，1-二氧化5，7 -二氯- 2-(4 -羥基-3-甲氧基苯甲基 〕-4，1，2 -苯并 Df 噻畊- 3(2H)-酮 與製造例83 —樣之方法，以收率42 %得標題化合物 (B AK-KA27 1 )。Production Example 8 5 Synthesis of 1,1-dioxide 5,7-dichloro-2- (4-hydroxy-3-methoxybenzyl] -4,1,2-benzo Df Thiogen-3 (2H ) -Ketone was the same as in Production Example 83 to obtain the title compound (B AK-KA27 1) in a yield of 42%.

^-NMR (CDC13) δ: 3.89 (s, 3H)? 4.98 (s? 2H); 5.66 (brs，1H)5 6.8 5 - 7.04 (m，3H) 5 7.7 2 (d5 J = 2.4Hz5 1H)，7.74(t，J = 2.4Hz5 1H) MS (El) E/Z 4 0 3 (M + )，405 (M + 2)，407(M + 4) 製造例8 6 合成3，5-二氯-2-羥基-N-〔 3，4-(亞甲二氧基）苯甲基 〕苯磺醯胺 與製造例7 8 —樣之方法，以收率7 8 %得標題化合物 -76- (72) 200417367 (B AK-KA27 5 )。^ -NMR (CDC13) δ: 3.89 (s, 3H)? 4.98 (s? 2H); 5.66 (brs, 1H) 5 6.8 5-7.04 (m, 3H) 5 7.7 2 (d5 J = 2.4Hz5 1H), 7.74 (t, J = 2.4Hz5 1H) MS (El) E / Z 4 0 3 (M +), 405 (M + 2), 407 (M + 4) Production Example 8 6 Synthesis of 3,5-dichloro- 2-Hydroxy-N- [3,4- (methylenedioxy) benzyl] benzenesulfonamide was prepared in the same manner as in Production Example 78 to obtain the title compound -76- (72 200417367 (B AK-KA27 5).

C K^^so2c\ 〇2C K ^^ so2c \ 〇2

'H-NMR (CDC13) δ:'H-NMR (CDC13) δ:

4.10 (d? J = 6.0Hz5 2H)? 5 · 0 9 (t，J = 6 · 0 H z，1 H) 5 5 · 9 4 (s， 2H)，6.59-6.71(m，3H) 5 7.5 2 (s，2H)，8.34 (brs5 1H) MS (El) E/Z 3 7 5 (M + )? 3 77 (M + 2 )5 3 7 9 (M + 4) 製造例8 7 合成1，1-二氧化5，7-二氯-2-〔3，4-(亞甲二氧基）苯 甲基〕-4，1，2-苯并噚噻哄-3 (2H)-酮 與製造例80 —樣之方法，以收率82%得標題化合物 (BAK-KA2 7 7 )。4.10 (d? J = 6.0Hz5 2H)? 5 · 0 9 (t, J = 6 · 0 H z, 1 H) 5 5 · 9 4 (s, 2H), 6.59-6.71 (m, 3H) 5 7.5 2 (s, 2H), 8.34 (brs5 1H) MS (El) E / Z 3 7 5 (M +)? 3 77 (M + 2) 5 3 7 9 (M + 4) Production Example 8 7 Synthesis 1, 1-Dioxide 5,7-dichloro-2- [3,4- (methylenedioxy) benzyl] -4,1,2-benzobenzothiazine-3 (2H) -one and manufacturing Example 80-In the same manner, the title compound (BAK-KA2 7 7) was obtained in a yield of 82%.

^-NMR (CDCI3) δ: 4.96 (s? 2H)? 5.95 (s5 2H)5 6.74 - 6.9 9 (m5 3H)5 7.7 3 (d5 J =2.4 Hz? 1H)? 7.75 (d? J =2.4 Hz; 1H) MS (El) E/Z 401 (M + )? 4 03 (M + 2)? 405 (M + 4) >77- (73) (73)200417367 製造例8 8 合成1，卜二氧化5，7 -二氯-2，3·二氫-2_〔3，4_ (亞甲 二氧基）苯甲基〕-4，1，2-苯并嗎嘻畊 與製造例7 9 —樣之方法，以收率4 2 %得標題化合物 (Β ΑΚ-ΚΑ2 8 8 ) 〇^ -NMR (CDCI3) δ: 4.96 (s? 2H)? 5.95 (s5 2H) 5 6.74-6.9 9 (m5 3H) 5 7.7 3 (d5 J = 2.4 Hz? 1H)? 7.75 (d? J = 2.4 Hz ; 1H) MS (El) E / Z 401 (M +)? 4 03 (M + 2)? 405 (M + 4) > 77- (73) (73) 200417367 Manufacturing Example 8 8 Synthesis 1, Bu Er Oxidation of 5,7-dichloro-2,3 · dihydro-2_ [3,4_ (methylenedioxy) benzyl] -4,1,2-benzobenzyl and production example 7 9 In this way, the title compound (ΒΑΚ-ΚΑ2 8 8) was obtained in a yield of 42%.

^-NMR (CDC13) δ: 4.31 (s? 2H)? 5.48 (s5 2H)? 5.99 (s? 2H)? 6.7 8 -6.8 8 (m5 3H)，7.56 (d，J = 2.5Hz，1H)，7.67 (d5 J =2.5 Hz，1H) MS (El) E/Z 3 8 7 (M + )? 3 8 9 (M + 2)? 391 (M + 4) 製造例8 9 合成2，4，6 -三甲氧基苯磺醯氯 在5.00ml氯代磺酸中逐以少量加入2.0g( 11.9毫莫 爾）間苯三酚三甲醚，再於室溫攪拌1 . 5小時，於5 0 °C攪 拌1小時。將反應液倒入200ml冰中，以氯仿萃取，有機 層以無水硫酸鎂乾燥。濃縮後以矽膠管柱層析（己烷：乙 酸乙酯=4 : 1 — 1 : 1 )精製粗生成物，以收率3 9 %得1 .2 3 g 標題化合物（BAK-KA260- 1 )。 -78 - (74) 200417367^ -NMR (CDC13) δ: 4.31 (s? 2H)? 5.48 (s5 2H)? 5.99 (s? 2H)? 6.7 8 -6.8 8 (m5 3H), 7.56 (d, J = 2.5Hz, 1H), 7.67 (d5 J = 2.5 Hz, 1H) MS (El) E / Z 3 8 7 (M +)? 3 8 9 (M + 2)? 391 (M + 4) Manufacturing Example 8 9 Synthesis 2, 4, 6 -Trimethoxybenzenesulfonyl chloride in 5.00 ml of chlorosulfonic acid, add 2.0 g (11.9 mmol) of resorcinol trimethyl ether in small portions, and stir at room temperature for 1.5 hours at 50 ° C Stir for 1 hour. The reaction solution was poured into 200 ml of ice, extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. After concentration, the crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1—1: 1) to obtain 1.2% of the title compound (BAK-KA260-1) at a yield of 39%. . -78-(74) 200417367

·>-· ≫-

^-NMR (CDC13) δ: 2.89 (s5 3H)5 3.9 6 (s5 6H)5 6.12 (s5 2H) MS (El) E/Z 266 (M + )^ -NMR (CDC13) δ: 2.89 (s5 3H) 5 3.9 6 (s5 6H) 5 6.12 (s5 2H) MS (El) E / Z 266 (M +)

製造例90 合成 N-〔 （2，3 -二氫-1，4 -苯并二噁因-6-基）甲基〕-2 ，4，6 -三甲氧基苯磺醯胺 與製造例78 —樣之方法，以收率78%得標題化合物 (B AK-KA26 1 )。Production Example 90 Synthesis of N-[(2,3-dihydro-1,4-benzodioxin-6-yl) methyl] -2,4,6-trimethoxybenzenesulfonamide and Production Example 78 In the same manner, the title compound (B AK-KA26 1) was obtained in a yield of 78%.

BAK-KA261BAK-KA261

^--NMR (CDCI3) δ: 3.85 (s5 9Η)5 4.0 2 (d，J = 6.3Hz，2Η)5 4.21 (s5 4Η)5 5.31 (t? J = 6.3Hz5 1H)? 6.09 (s? 2H)5 6.6 8 - 6.7 6 (m? 3H) MS (El) E/Z 3 95 (M + ) 製造例9 1 合成N-〔4-(苯甲氧基）-3 -甲氧苯甲基〕-2，4，6 -三甲 -79- (75) 200417367 氧基苯磺醜胺 與製造例78 —樣之方法，以收率86%得標題化合物 (B AK-KA290 )。^-NMR (CDCI3) δ: 3.85 (s5 9Η) 5 4.0 2 (d, J = 6.3Hz, 2Η) 5 4.21 (s5 4Η) 5 5.31 (t? J = 6.3Hz5 1H)? 6.09 (s? 2H ) 5 6.6 8-6.7 6 (m? 3H) MS (El) E / Z 3 95 (M +) Production Example 9 1 Synthesis of N- [4- (benzyloxy) -3 -methoxybenzyl] -2,4,6-trimethyl-79- (75) 200417367 The same method as in Production Example 78 was used to obtain the title compound (B AK-KA290) in a yield of 86%.

BAK-KA260-1BAK-KA260-1

^-NMR (CDC13) δ: 3.81 (s5 6H)? 3.82(s? 3H)? 3.83(d? J = 3.7Hz, 2H), 3.84 (s5 3H)，.5.12 (s，2H) 5 5.3 2 (t5 J = 3.7Hz，1H )，6.09 (s， 2H)，6.6 0- 6.79 (m，3H)，7.29-7.44 (m，5H) MS (El) E/Z 473 (M + ) 製造例92 合成N-〔 （2，3-二氫-1，4-苯并二噁因-6-基）甲基〕-2- 羥基_4，6-二甲氧基苯磺醯胺 加熱回流2 4小時1 · 2 6 g ( 3 · 1 9毫莫爾）製造例9 0所 得BAK-KA26 1，2.13g(15.9毫莫爾）碘化鋰，30ml無水 二噁烷。反應液中加入水’以乙酸乙酯萃取’以飽和食鹽 水洗淨有機層。以無水硫酸鎂乾燥，濃縮後以砂膠管柱層 析（己烷：乙酸乙酯=4 ·· 1 — 1 ·· 1 )精製粗生成物’以收 率 78%得 94 6.5mg 標題化合物（BAK-KA262 )。 -80 - (76) 200417367^ -NMR (CDC13) δ: 3.81 (s5 6H)? 3.82 (s? 3H)? 3.83 (d? J = 3.7Hz, 2H), 3.84 (s5 3H), 5.12 (s, 2H) 5 5.3 2 ( t5 J = 3.7Hz, 1H), 6.09 (s, 2H), 6.60- 6.79 (m, 3H), 7.29-7.44 (m, 5H) MS (El) E / Z 473 (M +) Manufacturing Example 92 Synthesis N-[(2,3-dihydro-1,4-benzodioxin-6-yl) methyl] -2-hydroxy-4,6-dimethoxybenzenesulfonamide is heated under reflux for 2 4 hours 1 · 2 6 g (3.91 mmol) BAK-KA26 obtained in Production Example 9 1.2.13 g (15.9 mmol) of lithium iodide, 30 ml of anhydrous dioxane. Water was added to the reaction solution and extracted with ethyl acetate, and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate and concentrating, the crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 4 ·· 1 — 1 ·· 1) to obtain 94 6.5 mg of the title compound (BAK in 78% yield). -KA262). -80-(76) 200417367

Ή-NMR (CDC13) δ:Ή-NMR (CDC13) δ:

3.78 (s5 3H)? 3.81 (s5 3H)? 3.98(d? 2H)5 4.21(s? 4H)? 5.94 (d5 J = 2.2Hz5 1H)? 6.11 (d? J = 2.2Hz5 1H)5 6.61-6·76 (m，3H)，9.84 (s，1H) M S (El) E/Z 381 (M + ) 製造例93 合成 2-〔 （2，3 -二氫-1，4 -苯并二噁因-6-基）甲基〕-2 ，.3 -二氨-6，8 -二甲氧基-4，1，2 -苯并D琴嚷D井-1，1- 一氧 化物3.78 (s5 3H)? 3.81 (s5 3H)? 3.98 (d? 2H) 5 4.21 (s? 4H)? 5.94 (d5 J = 2.2Hz5 1H)? 6.11 (d? J = 2.2Hz5 1H) 5 6.61-6 76 (m, 3H), 9.84 (s, 1H) MS (El) E / Z 381 (M +) Production Example 93 Synthesis of 2-[(2,3-dihydro-1,4-benzodioxin -6-yl) methyl] -2, .3-diamino-6,8-dimethoxy-4,1,2,2-benzo-D-phenylene-D-well-1,1-monoxide

加熱回流69.5小時436mg ( 1.14毫莫爾）製造例92 所得 BAK-KA262，10.0ml 福嗎啉，〇.50ml 乙酸，20ml 無 水甲醇。反應液中加入1 〇莫爾/1氫氧化鈉水溶液，以乙 酸乙酯萃取，以飽和食鹽水洗淨有機層。以無水硫酸鎂乾 燥，濃縮後以矽膠管柱層析（己烷：乙酸乙酯=3 : 1 —氯 仿）精製粗生成物，以收率60%得272mg標題化合物（ BAK-KA264 )。 -81 ^ (77) 200417367Heated to reflux for 69.5 hours, 436 mg (1.14 mmol) of BAK-KA262 obtained in Production Example 92, 10.0 ml of morpholine, 0.50 ml of acetic acid, and 20 ml of anhydrous methanol. A 10 mol / 1 sodium hydroxide aqueous solution was added to the reaction solution, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The crude product was purified by drying over anhydrous magnesium sulfate and then concentrated by silica gel column chromatography (hexane: ethyl acetate = 3: 1-chloroform) to obtain 272 mg of the title compound (BAK-KA264) in a yield of 60%. -81 ^ (77) 200417367

】H-NMR (CDC 13) d: 3.81 (s? 3H)? 3.94 (s5 3H)5 4.2 7 (s5 4H)5 4.3 4 (s5 2H)5 5.24(s? 2H)? 6.09 (d5 J = 2.3Hz5 1H)，6.15 (d，J = 2.3Hz5 1 H)5 6.8 7 - 6.9 3 (m，3H) MS (El) E/Z 3 9 3 (M + ) 製造例94 合成 2-〔 （2，3 -二氫-1，4 -苯并二噁因-6-基）甲基〕-6 ，8 -二甲氧基-4，1，2 -苯并哼噻畊-3(2H)-酮-1，1-二 氧化物 與製造例80 —樣之方法，以收率87%得標題化合物 (B AK-KA26 5 )。】 H-NMR (CDC 13) d: 3.81 (s? 3H)? 3.94 (s5 3H) 5 4.2 7 (s5 4H) 5 4.3 4 (s5 2H) 5 5.24 (s? 2H)? 6.09 (d5 J = 2.3 Hz5 1H), 6.15 (d, J = 2.3Hz5 1 H) 5 6.8 7-6.9 3 (m, 3H) MS (El) E / Z 3 9 3 (M +) Manufacturing Example 94 Synthesis 2- [(2, 3-dihydro-1,4-benzodioxin-6-yl) methyl] -6,8-dimethoxy-4,1,2-benzothien-3 (2H) -one -1,1-dioxide was prepared in the same manner as in Production Example 80 to obtain the title compound (B AK-KA26 5) in a yield of 87%.

H-NMR (CDC13) d: 3.85 (s5 3H)? 3.97 (s5 3H)5 4.2 2 (s5 4H)? 4.92(s5 2H), 6.32 (d，J = 2.2 Hz; 1H), 6.3 5 (d; J =2·2Ηζ，1H) 6.80 (d，J = 8.2 Hz，1H): 7.01 (dd，J二2.0，8.2Hz; 1H); 7.06 -82 - (78) (78)200417367 (d，J = 2.0Hz，1H) MS (El) E/Z 407 (M + ) 製造例9 5 合成 N-〔 4-苯甲氧基-3-甲氧苯甲基〕-2-羥基-4，6-二甲 氧苯擴胺 與製造例92 —樣之方法，以收率定量得2.2 0g標題 化合物（B AK-KA292 )。H-NMR (CDC13) d: 3.85 (s5 3H)? 3.97 (s5 3H) 5 4.2 2 (s5 4H)? 4.92 (s5 2H), 6.32 (d, J = 2.2 Hz; 1H), 6.3 5 (d; J = 2 · 2Ηζ, 1H) 6.80 (d, J = 8.2 Hz, 1H): 7.01 (dd, J = 2.0, 8.2 Hz; 1H); 7.06 -82-(78) (78) 200417367 (d, J = 2.0Hz, 1H) MS (El) E / Z 407 (M +) Production Example 9 5 Synthesis of N- [4-benzyloxy-3-methoxybenzyl] -2-hydroxy-4,6-di Methoxyamphetamine was the same as in Production Example 92, and 2.20 g of the title compound (B AK-KA292) was quantitatively obtained in a yield.

BAK-KA290 BAK-KA292 iH-NMR (CDC13) (5 : 3.68 (s5 3H) 5 3.8 0 (s5 3H)? 3.83 (s? 3H)5 4.0 3 (d? 2 H)5 5.12 (s， 2H)? 5.90 (d5 J = 2.3 Hz， 1 H)? 6.11 (d5 J = 2.3Hz? 1H)5 6.5 7 - 6.7 7 (m? 3H)? 7.29- 7.4 5 (m5 5H)5 9.86 (s? 1H) MS (El) E/Z 45 9(M + ) 製造例96 合成2-〔 4-(苯甲氧基）-5-3 -甲氧苯甲基〕-2，3-二氫-6 ，8 -二甲氧基-4，1，2 -苯并哼噻哄-1，1-二氧化物 加熱回流19·5小時1 .00g ( 2.18毫莫爾）製造例95 所得 B AK-KA2 92，2 0.0ml福馬啉水溶液，1 .00ml乙酸， - 83 - (79) 200417367 20.0ml無水甲醇。反應液中加入10%氫氧化鈉水溶液，以 乙酸乙醋萃取’有機層以飽和碳酸氫鈉水溶液及飽和食鹽 水洗淨，以無水硫酸鎂乾燥。濃縮後，以矽膠管柱層析（ 己烷：乙酸乙酯=4 : 1 — 2 : 1 )精製，以5 5 %收率得 566mg 標題化合物（BAK-KA294)。BAK-KA290 BAK-KA292 iH-NMR (CDC13) (5: 3.68 (s5 3H) 5 3.8 0 (s5 3H)? 3.83 (s? 3H) 5 4.0 3 (d? 2 H) 5 5.12 (s, 2H) ? 5.90 (d5 J = 2.3 Hz, 1 H)? 6.11 (d5 J = 2.3 Hz? 1H) 5 6.5 7-6.7 7 (m? 3H)? 7.29- 7.4 5 (m5 5H) 5 9.86 (s? 1H) MS (El) E / Z 45 9 (M +) Production Example 96 Synthesis of 2- [4- (benzyloxy) -5-3 -methoxybenzyl] -2,3-dihydro-6,8 -Dimethoxy-4,1,2, benzobenzothiazine-1,1-dioxide heated and refluxed 19.5 hours 1.00 g (2.18 mmoles) Manufactured from 95 obtained B AK-KA2 92, 2 0.0ml formalin water solution, 1.00 ml acetic acid, -83-(79) 200417367 20.0 ml anhydrous methanol. 10% sodium hydroxide aqueous solution was added to the reaction solution, and the organic layer was extracted with ethyl acetate to saturate the sodium bicarbonate aqueous solution and The solution was washed with saturated brine, and dried over anhydrous magnesium sulfate. After concentrating, it was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1—2: 1) to obtain 566mg of the title compound (55% yield). BAK-KA294).

KA294 製造例97 合成2，3 -一氫- 2_(4 -羥基甲氧基苯甲基）_6，8_二甲 氧基-4，1，2-苯并Ilf噻哄-丨，κ二氧化物 與製造例83 —樣之方法，以收率42%得標題化合物 (Β ΑΚ-ΚΑ296 )。 〇KA294 Production Example 97 Synthesis of 2,3 -monohydro-2_ (4-hydroxymethoxybenzyl) _6,8_dimethoxy-4,1,2-benzoIlfthiazine- 丨, κdioxide The same method as in Production Example 83 was used to obtain the title compound (ΒΑΚ-ΚΑ296) in a yield of 42%. 〇

ΚΑ294ΚΑ294

ΚΑ296 ]H-NMR (CDC13) δ: 3.81 (s，3Η)，3.91 (s5 3Η); 3 9 5 (s，3Η)，4 3 7 (s，2Η)5 5.23 (s，2H)，5·66 (s5 1H)，6 1〇 (d，J = 2 2Hz，1H)，6 17 (d? J-2.2Hzr 1H)? 6.84^6.94 (m 3H) -84 - (80) 200417367 MS (El) E/Z 381(M + ) 製造例9 8 氧苯甲基〕-6，8-二甲氧 -酮-1，1 -二氧化物 ，得標題化合物（ΒΑΚ- 合成 2-〔 4-(苯甲氧基）-3-甲 基-4，1，2 -苯并Df噻畊-3 ( 2 Η ) 與製造例 80 —樣之方法 ΚΑ2 95 )。ΚΑ296] H-NMR (CDC13) δ: 3.81 (s, 3Η), 3.91 (s5 3Η); 3 9 5 (s, 3Η), 4 3 7 (s, 2Η) 5 5.23 (s, 2H), 5. · 66 (s5 1H), 6 1〇 (d, J = 2 2Hz, 1H), 6 17 (d? J-2.2Hzr 1H)? 6.84 ^ 6.94 (m 3H) -84-(80) 200417367 MS (El) E / Z 381 (M +) Production Example 9 8 oxybenzyl] -6,8-dimethoxy-one-1,1-dioxide to obtain the title compound (ΒΑΚ- Synthesis of 2- [4- (benzene (Methoxy) -3-methyl-4,1,2-benzo-Df thiagen-3 (2 fluorene) The same method as in Production Example 80 (KA 2 95).

ΚΑ295 製造例99 合成 6 ’ 8 - 一甲氧基-2 - ( 4 -經基-3 -甲氧苯甲基〕-4，1， 2-苯并鳄噻哄-3 ( 2Η )-酮-1，1-二氧化物 與製造例8 3 —樣之方法，以收率1 8 % (二步驟）得 標題化合物（ΒΑΚ-ΚΑ297)。ΚΑ295 Production Example 99 Synthesis of 6 '8-monomethoxy-2-(4-Ethyl-3 -methoxybenzyl] -4,1,2-benzocrotidine-3 (2Η) -one- 1,1-dioxide was produced in the same manner as in Production Example 83, with the yield of 18% (two steps) to obtain the title compound (ΒΑΚ-ΚΑ297).

ΚΑ295 ΚΑ297 H-NMR (CDC13) δ: 3.85 (s，3Η) 3.S8 (s5 3Η)，3.98 (s，3H)5 4.9 5 (s，2Η); -85- (81) 200417367 5.6 1 (s5 1H)? 6.32 (d，J = 2.2 Hz? 1H)? 6.36 (t J = 2.2Hz? 1H)5 6.8 3 - 7.1 0 (m5 3H) MS (El) E/Z 3 95 (M + ) 製造例100 合成 3，5-二氯-N-〔 2- (2，3-二氫-1，4-苯并二噁因- 6· 基）乙基〕-2 -淫基苯礦釀胺ΚΑ295 ΚΑ297 H-NMR (CDC13) δ: 3.85 (s, 3Η) 3.S8 (s5 3Η), 3.98 (s, 3H) 5 4.9 5 (s, 2Η); -85- (81) 200417367 5.6 1 (s5 1H)? 6.32 (d, J = 2.2 Hz? 1H)? 6.36 (t J = 2.2Hz? 1H) 5 6.8 3-7.1 0 (m5 3H) MS (El) E / Z 3 95 (M +) Manufacturing example 100 Synthesis of 3,5-dichloro-N- [2- (2,3-dihydro-1,4-benzodioxin-6 · yl) ethyl] -2 -pyroxybenzamine

與製造例78 —樣之方法，以收率78%得標題化合物 (B AK-E57 )。The title compound (B AK-E57) was obtained in the same manner as in Production Example 78 in a yield of 78%.

製造例101Manufacturing example 101

合成 6，8 -二氯-2-〔 2- ( 2，3 -二氫-1，4-苯并二噁因-6-基）乙基〕-4，1，2 -苯并D等噻畊-3 (2H)-酮 與製造例8 0 —樣之方法，以收率4 7 %得標題化合物 (B AK - E60 )。Synthesis of 6,8-dichloro-2- [2- (2,3-dihydro-1,4-benzodioxin-6-yl) ethyl] -4,1,2-benzoD, etc. Geng-3 (2H) -one was prepared in the same manner as in Manufacturing Example 80 to obtain the title compound (B AK-E60) in a yield of 47%.

86 - (82) 200417367 ^-NMR (CDC13) δ: 2.92-3.00 (m? 2H)? 4.03-4.14 (m? 2H) 5 4.2 2 (s? 4H)3 6.65 (dd5 J =2.0，8·5 Hz5 1H)，6.67 (d，J = 2.0Hz，1H)5 6.74 (d，J = 8.5Hz，1H)，7.69 (d5 J = 2.4Hz，1H)，7.74 (d5 J = 2.4Hz5 1 H) 製造例1 0 286-(82) 200417367 ^ -NMR (CDC13) δ: 2.92-3.00 (m? 2H)? 4.03-4.14 (m? 2H) 5 4.2 2 (s? 4H) 3 6.65 (dd5 J = 2.0, 8 · 5 Hz5 1H), 6.67 (d, J = 2.0Hz, 1H) 5 6.74 (d, J = 8.5Hz, 1H), 7.69 (d5 J = 2.4Hz, 1H), 7.74 (d5 J = 2.4Hz5 1 H) Manufacturing Example 1 0 2

合成3，5-二氯-N_(3，4-二甲氧基苯乙基）_2_羥基苯磺 醯胺 與製造例78 —樣之方法，以收率86%得標題化合物 (BAK-E6 7 )。Synthesis of 3,5-dichloro-N_ (3,4-dimethoxyphenethyl) _2_hydroxybenzenesulfonamide was carried out in the same manner as in Production Example 78 to obtain the title compound (BAK-E6 in a yield of 86%). 7).

^-NMR (CDCI3) δ: φ 2.73 (t, J = 0.6Hz5 2Η) 5 3.2 8 (t，6·6Ηζ，2Η)，3.84 (s5 3H) 5 3.8 6 (s? 3H)? 6.57 (d? j = 2.〇Hz? 1H)? 6.61 (dd5 J = 2.0，8.0Hz，1H)，6.78 (d，j = 8〇Hz，1H)，7.51 (d5 J = 2.5Hz5 1H) 5 7.5 3 (d5 J-2.5Hz5 1H) MS (El) E/Z 405 (M + ) 製造例1 0 3 合成5，7-二氯- 2-(3，4-二甲氧基苯乙基苯 > 87 - 200417367 并哼噻畊-3 ( 2H )-酮 與製造例80 —樣之方法，以收率93 %得標題化合物 (BAK-E68 )。^ -NMR (CDCI3) δ: φ 2.73 (t, J = 0.6Hz5 2Η) 5 3.2 8 (t, 6 · 6Ηζ, 2Η), 3.84 (s5 3H) 5 3.8 6 (s? 3H)? 6.57 (d? j = 2.〇Hz? 1H)? 6.61 (dd5 J = 2.0, 8.0Hz, 1H), 6.78 (d, j = 8〇Hz, 1H), 7.51 (d5 J = 2.5Hz5 1H) 5 7.5 3 (d5 J-2.5Hz5 1H) MS (El) E / Z 405 (M +) Production Example 1 0 3 Synthesis of 5,7-dichloro- 2- (3,4-dimethoxyphenethylbenzene) 87- 200417367 Phenoxythiamine-3 (2H) -one was prepared in the same manner as in Production Example 80 to obtain the title compound (BAK-E68) in a yield of 93%.

^-NMR (CDC13) δ: 3.03 (m，2Η)，3.84 (s，3Η)5 3.8 6 (s5 3H)5 4.12(m5 2Η)5 6.70 (s5 1H)? 6.72 (s5 2H) 5 7.6 5 (d? J = 2.4Hz? 1H)? 7.73 (d5 J-2.4Hz? 1H) MS (El) E/Z 431 (M + ) 製造例104 合成3-〔 N- ( 2 -苯甲氧基-3，5 -二氯苯甲酿基）-N- ( 3， 4_二甲氧基苯乙基）胺基〕丙酸乙酯〕 在 667.3 mg(2.25毫莫爾）2-苯甲氧基-3，5-二氯苯 甲酸，681mg(2.25毫莫爾）3-〔 〔2-(3，4-二甲氧基苯 基）乙基〕胺基〕丙酸乙酯鹽酸鹽，0.94ml (5.4毫莫爾 )DIEA，1 3ml DMF 中，加入 41ml ( 2.7 毫莫爾）DEPC， 於室溫攪拌2小時。反應液中加入水，以乙酸乙酯萃取， 有機層以無水硫酸鈉乾燥。濃縮後以矽膠管柱層析（己烷 ••乙酸乙酯=2 : 1 )精製粗生成物，以收率100%得1 .27g 標題化合物（BAK-G492)。 (84) 200417367^ -NMR (CDC13) δ: 3.03 (m, 2Η), 3.84 (s, 3Η) 5 3.8 6 (s5 3H) 5 4.12 (m5 2Η) 5 6.70 (s5 1H)? 6.72 (s5 2H) 5 7.6 5 ( d? J = 2.4Hz? 1H)? 7.73 (d5 J-2.4Hz? 1H) MS (El) E / Z 431 (M +) Manufacturing Example 104 Synthesis of 3- [N- (2 -benzyloxy-3 , 5-dichlorobenzyl) -N- (3,4-dimethoxyphenethyl) amino] ethyl propionate] at 667.3 mg (2.25 mmoles) 2-benzyloxy- 3,5-dichlorobenzoic acid, 681 mg (2.25 mmol) 3-[[2- (3,4-dimethoxyphenyl) ethyl] amino] propanoic acid ethyl ester hydrochloride, 0.94 ml (5.4 mmoles) DIEA, 1 3 ml of DMF, 41 ml (2.7 mmoles) of DEPC was added, and stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. After concentration, the crude product was purified by silica gel column chromatography (hexane •• ethyl acetate = 2: 1) to obtain 1.27 g of the title compound (BAK-G492) in a yield of 100%. (84) 200417367

MS (El) E/Z 5 5 9 (M + ) 製造例1 〇 5MS (El) E / Z 5 5 9 (M +) Production Example 1 05

合成〔N-(2-苯甲氧基-3，5-二氯苯甲醯基）-N-(3，4-二甲氧基苯乙基）胺基〕乙酸甲酯 與製造例1 04 —樣之方法，以收率99%得標題化合物Synthesis of [N- (2-Benzyloxy-3,5-dichlorobenzyl) -N- (3,4-dimethoxyphenethyl) amino] acetate and Production Example 1 04 —The same method, the title compound was obtained in a yield of 99%

(B AK-G494 )。 CI(B AK-G494). CI

BAK-G484 CI ΟBAK-G484 CI Ο

MS (El) E/Z 531 (M + ) 製造例106 合成〔N-(2-苯甲氧基-3，5-二氣苯甲酿基）-N-(3，4-二甲氧基苯甲基）胺基〕乙酸甲酯 與製造例1 04 —樣之方法，以7 3 %之收率得標題化合 物(B AK-G4 9 9 )。 -89 - 200417367MS (El) E / Z 531 (M +) Production Example 106 Synthesis of [N- (2-Benzyloxy-3,5-digas benzyl) -N- (3,4-dimethoxy In the same manner as in Production Example 104, benzyl) amino] methyl acetate, the title compound (B AK-G4 9 9) was obtained in a yield of 73%. -89-200417367

BAK-G484BAK-G484

BAK-G499 MS ( El) E/Z 5 1 7 (M + ) 製造例107 合成 3·〔Ν-(3，5-二氯-2-羥基苯甲醯基）-N-(3，4-二 甲氧基苯乙基）胺基〕丙酸乙酯 與製造例6 6 —樣之方法，以9 1 %之收率得標題化合 物(B AK-G49 3 ) 〇 C! O Cl ΟBAK-G499 MS (El) E / Z 5 1 7 (M +) Production Example 107 Synthesis of 3 · [N- (3,5-dichloro-2-hydroxybenzyl) -N- (3,4- Dimethoxyphenethyl) amino] ethyl propionate was prepared in the same manner as in Production Example 66 to obtain the title compound (B AK-G49 3) in a yield of 91%. OC! O Cl 〇

BAK-G492 BAK-G493 MS (El) E/Z 469 (M + ) 製造例1 0 8 合成〔N- (3，5-二氯-2-羥基苯甲醯基）-N- (3，4-二甲 氧基苯乙基）胺基〕乙酸甲酯 與製造例6 6 —樣之方法，以9 1 %之收率得標題化合 物（B AK-G49 5 ) (86) 200417367BAK-G492 BAK-G493 MS (El) E / Z 469 (M +) Production Example 1 0 8 Synthesis of [N- (3,5-dichloro-2-hydroxybenzyl) -N- (3,4 -Dimethoxyphenethyl) amino] acetic acid methyl ester was prepared in the same manner as in Production Example 66 to obtain the title compound (B AK-G49 5) (86) 200417367 in a yield of 91%.

Cl ΟCl Ο

BAK-G494BAK-G494

Cl ΟCl Ο

]H-NMR (CDC13) δ:] H-NMR (CDC13) δ:

2.81 (t，J = 7.0Hz，2H) 5 3.6 2 (t5 J = 7.0Hz，2H)，3.81 (s5 3H) 5 3.8 2 (s，3H)，3.87(s53H)，4.19(s，2H)，6.50- 6.65(m? 2H)5 6.7 5 - 6.8 5 (m5 2H)? 7.37 (d5 J = 2.5Hz? 1 H) MS (El) E/Z 441 (M + ) 製造例1 〇 9 合成〔3- (3，5-二氯-2-羥基苯甲醯基）-N- (3，4-二甲 氧苯甲基）胺基〕乙酸甲酯2.81 (t, J = 7.0Hz, 2H) 5 3.6 2 (t5 J = 7.0Hz, 2H), 3.81 (s5 3H) 5 3.8 2 (s, 3H), 3.87 (s53H), 4.19 (s, 2H), 6.50- 6.65 (m? 2H) 5 6.7 5-6.8 5 (m5 2H)? 7.37 (d5 J = 2.5Hz? 1 H) MS (El) E / Z 441 (M +) Manufacturing Example 1 〇9 Synthesis [3 -(3,5-Dichloro-2-hydroxybenzyl) -N- (3,4-dimethoxybenzyl) amino] acetic acid methyl ester

與製造例66 —樣之方法，以90%之收率得標題化合 物(B AK-G5 00 )。In the same manner as in Manufacturing Example 66, the title compound (B AK-G500) was obtained in a yield of 90%.

BAK-G499 BAK-G500 H-NMR (CDC13) δ: 3.78 (s5 3Η)，3.87 (s5 3Η) 5 3.8 9 (s，3Η)5 4.10 (s，2Η)5 4.64 (s? 2H)? 6.7 0- 6.90 (m5 3H); 7.26 (d; J = 2.5 Hz5 1H)，7.43 (d，J = 2.5 Hz, 1H) -91 - (87) 200417367 MS (El) E/Z 427(M + ) 製造例1 1 〇 合成3-〔1(3，5-二氯-2-羥基苯甲醯基）-]^(3，4-二 甲氧基苯乙基）胺基〕丙酸 與製造例6 8 —樣之方法，以9 8 %之收率得標題化合 物(BAK-G4 97 )。 CI 〇BAK-G499 BAK-G500 H-NMR (CDC13) δ: 3.78 (s5 3Η), 3.87 (s5 3Η) 5 3.8 9 (s, 3Η) 5 4.10 (s, 2Η) 5 4.64 (s? 2H)? 6.7 0 -6.90 (m5 3H); 7.26 (d; J = 2.5 Hz5 1H), 7.43 (d, J = 2.5 Hz, 1H) -91-(87) 200417367 MS (El) E / Z 427 (M +) Manufacturing example 1 1 0 Synthesis of 3- [1 (3,5-dichloro-2-hydroxybenzyl)-] ^ (3,4-dimethoxyphenethyl) amino] propanoic acid and Production Example 6 8 In the same way, the title compound (BAK-G4 97) was obtained in a yield of 98%. CI 〇

BAK-G497BAK-G497

]H-NMR (CDC13) δ: 2.65 -2.8 5 (m5 4H)? 3.59(m5 2H)? 3.79(m5 2H)? 3.80(s? 3H)， 3.8 7(s5 3H)， 6·45-6·60(ιη， 2H)5 6.7 5 - 6.8 0 (m5 2H)，7.3 1 (d，J = 2.5Hz，1 H)] H-NMR (CDC13) δ: 2.65 -2.8 5 (m5 4H)? 3.59 (m5 2H)? 3.79 (m5 2H)? 3.80 (s? 3H), 3.8 7 (s5 3H), 6.45-6 · 60 (ιη, 2H) 5 6.7 5-6.8 0 (m5 2H), 7.3 1 (d, J = 2.5Hz, 1 H)

MS (El) E/Z 441 (M + ) 製造例1 1 1 合成〔Ν· (3，5-二氯-2-羥基苯甲醯基）-N- (3，4-二甲 氧苯乙基）胺基〕乙酸 與製造例68 —樣之方法，以100%之收率得標題化合 物(B AK-G496 )。 -92- (88) 200417367MS (El) E / Z 441 (M +) Production Example 1 1 1 Synthesis of [N · (3,5-dichloro-2-hydroxybenzyl) -N- (3,4-dimethoxyphenethyl (Amino) amino] acetic acid was prepared in the same manner as in Production Example 68 to obtain the title compound (B AK-G496) in a yield of 100%. -92- (88) 200417367

BAK-G495 BAK-G496BAK-G495 BAK-G496

NN

^-NMRCCDCls) δ: 2.81 (t9 J = 6.7Hz? 2H)? 3.62 (t5 J = 6.7Hz? 2H)? 3.82 (s? 3H)? 3.87 (s，3H)? 4.22 (s? 2H) 6 · 5 0 - 6 · 6 5 (m，2 H)，^ -NMRCCDCls) δ: 2.81 (t9 J = 6.7Hz? 2H)? 3.62 (t5 J = 6.7Hz? 2H)? 3.82 (s? 3H)? 3.87 (s, 3H)? 4.22 (s? 2H) 6 · 5 0-6 · 6 5 (m, 2 H),

6.7 5 - 6.8 5 (m5 2H)，7.37 (d，J= 2·5Ηζ，1H) MS (El) E/Z 427 (M + ) 製造例1 1 2 合成〔N- (3，5-二氯-2-羥基苯甲醯基）-N- (3，4-二甲 氧苯甲基）胺基〕乙酸 與製造例68 —樣之方法，以100%之收率得標題化合 物(B AK-G50 1 )。6.7 5-6.8 5 (m5 2H), 7.37 (d, J = 2 · 5Ηζ, 1H) MS (El) E / Z 427 (M +) Production Example 1 1 2 Synthesis [N- (3,5-dichloro -2-Hydroxybenzyl) -N- (3,4-dimethoxybenzyl) amino] acetic acid was prepared in the same manner as in Production Example 68 to give the title compound (B AK- G50 1).

BAK-G500 BAK-G501BAK-G500 BAK-G501

H-NMR (CDC13) δ: 3·87 (s5 3Η)，3·89 (s5 3Η); 4·14 (s，2H)5 .4.63 (s，2Η)， 6.70-6.90 (m5 3Η); 7.26 (d，J = 2.5Hz，1Η)，7.43 (d，J = 2.5 Hz; 1 H) -93 - (89) 200417367 MS (El) E/Z 413 (M + ) 製造例1 1 3 合成〔（3，4-二甲氧基苯甲基）胺基〕乙酸甲酯 於室溫攪拌5小時1 . 6 6 g ( 1 0 · 0毫莫爾）3，4 -二甲氧 基苯甲醛，1.3 8g ( 1 1.0毫莫爾）甘胺酸甲酯，1.6ml ( 11.4毫莫爾）三乙胺，4.2g(19.8毫莫爾）三乙醯胺基氫 硼化鈉，8 0ml二氯甲烷，反應液中加入飽和碳酸氫鈉水 溶液，以氯仿萃取，以無水硫酸鈉乾燥，有機層濃縮後， 以矽膠管柱層析（己烷：乙酸乙酯=1 : 1 —氯仿：甲醇=3 〇 :1 )精製，以收率95%得2.2 7g標題化合物。H-NMR (CDC13) δ: 3.87 (s5 3Η), 3.89 (s5 3Η); 4.14 (s, 2H) 5.4.63 (s, 2Η), 6.70-6.90 (m5 3Η); 7.26 (d, J = 2.5 Hz, 1Η), 7.43 (d, J = 2.5 Hz; 1 H) -93-(89) 200417367 MS (El) E / Z 413 (M +) Production Example 1 1 3 Synthesis [( 3,4-Dimethoxybenzyl) amino] acetic acid methyl ester was stirred at room temperature for 5 hours 1.66 g (10.0 mmol) of 3,4-dimethoxybenzaldehyde, 1.3 8g (1 1.0 mmoles) methyl glycine, 1.6 ml (11.4 mmoles) of triethylamine, 4.2 g (19.8 mmoles) of sodium triethylammonium borohydride, 80 ml of dichloromethane, A saturated sodium bicarbonate aqueous solution was added to the reaction solution, and the mixture was extracted with chloroform, dried over anhydrous sodium sulfate, and the organic layer was concentrated, followed by silica gel column chromatography (hexane: ethyl acetate = 1: 1-chloroform: methanol = 3): 1) Purification yielded 2.27 g of the title compound in a yield of 95%.

BAK-KA316 h-NMR (CDC13) δ: 3.42 (s5 3Η)5 3.91 (s5 3Η)，3·74 (s5 2Η)5 3.8 7 (s5 3Η)5 3.89(s? 3Η) 5 6 8 3 - 6.8 9 (m，3Η) MS (El) E/Z 23 9 (Μ) 製造例1 1 4 合成〔〔3，5-二氯-2-羥苯基）硕基〕（3，4-二甲氧苯甲 基）胺基〕乙酸甲酯 於室溫攪拌]7·5小時2.22 g ( 8.52毫莫爾）3，5-苯 -94 - (90) 200417367 磺醯氯，2.04g(8.52毫莫爾）製造例113所得6八1^ KA316，3.57ml(25.6毫莫爾）三乙胺，85ml氯仿。反應 液中加入1莫爾/1鹽酸，以氯仿萃取’有機層以飽和碳酸 氫鈉水溶液及飽和食鹽水洗淨’以無水硫酸鎂乾燥，濃縮 後，以矽膠管柱層析（己烷··乙酸乙酯=1 ·· 1 )精製，以 83%收率得3.28g標題化合物（BAK-KA317)。BAK-KA316 h-NMR (CDC13) δ: 3.42 (s5 3Η) 5 3.91 (s5 3Η), 3.74 (s5 2Η) 5 3.8 7 (s5 3Η) 5 3.89 (s? 3Η) 5 6 8 3-6.8 9 (m, 3Η) MS (El) E / Z 23 9 (Μ) Production Example 1 1 4 Synthesis of [[3,5-dichloro-2-hydroxyphenyl] sulfonyl] (3,4-dimethoxy Benzyl) amino] methyl acetate stirred at room temperature] 7.5 hours 2.22 g (8.52 mmoles) 3,5-benzene-94-(90) 200417367 sulfonyl chloride, 2.04 g (8.52 mmoles) ) 680 obtained from Preparation Example 113, KA316, 3.57 ml (25.6 mmol) triethylamine, 85 ml chloroform. 1 mol / 1 hydrochloric acid was added to the reaction solution, and the organic layer was extracted with chloroform and washed with a saturated sodium bicarbonate aqueous solution and a saturated saline solution, dried over anhydrous magnesium sulfate, concentrated, and then subjected to silica gel column chromatography (hexane ··· Ethyl acetate = 1..1) was purified to obtain 3.28 g of the title compound (BAK-KA317) in 83% yield.

^-NMR (CDC13) δ: 3.67 (s5 3H)? 3.84 (s? 3H)? 3.87 (s? 3H) 3.98 (s? 2H)? 4.37 (s5 2H) 6.74-6.81 (m5 3H)，7.58 (d，J=1.5Hz，1H)5 7.66(d，J = 1.5Hz，lH)^ -NMR (CDC13) δ: 3.67 (s5 3H)? 3.84 (s? 3H)? 3.87 (s? 3H) 3.98 (s? 2H)? 4.37 (s5 2H) 6.74-6.81 (m5 3H), 7.58 (d , J = 1.5Hz, 1H) 5 7.66 (d, J = 1.5Hz, lH)

MS (E I) E/Z 4 63 (M)? 465 (M + 2) 製造例1 1 5 合成〔〔3，5-二氯-2-甲氧苯基）碾基〕（3，4-二甲氧苯 甲基）胺基〕乙酸甲酯 於ll〇°C攪拌1小時92 9mg ( 2.0毫莫爾）製造例114 所得BAK-KA3 17，0.2 9ml ( 2.2毫莫爾）二甲基甲醯胺二 甲基縮醛，〇. 7 ml二甲基甲醯胺。反應液中加入1莫爾/1 鹽酸，以乙酸乙酯萃取，有機層以飽和碳酸氫鈉水溶液及 -95- (91) (91)200417367 飽和食鹽水洗淨，以無水硫酸鎂乾燥，濃縮後，以矽膠管 柱層析（己烷：乙酸乙酯=2 : 1 )精製，以 72%收率得 6 9 2mg 標題化合物（BAK-KA319)。MS (EI) E / Z 4 63 (M)? 465 (M + 2) Production Example 1 1 5 Synthesis of [[3,5-dichloro-2-methoxyphenyl) phenyl] (3,4-di Methoxybenzyl) amino] methyl acetate was stirred at 110 ° C. for 1 hour 92 9 mg (2.0 mmoles) BAK-KA3 17, obtained in Production Example 114, 0.2 9 ml (2.2 mmoles) dimethylformamidine Amine dimethyl acetal, 0.7 ml dimethylformamide. 1 mol / 1 hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and -95- (91) (91) 200417367, and dried over anhydrous magnesium sulfate. The product was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain 692 mg of the title compound (BAK-KA319) in a 72% yield.

】H-NMR (CDC13) δ: 3.62 (s? 3H)? 3.82 (s? 3H) 5 3.9 9 (s5 2H)5 4.01 (s5 3H)? 4.52 (s? 2H)，6.75 (m? 3H)? 7.57 (d? J = 2.6Hz，1H)， 7.7 9 (d5 J = 2.6Hz? 1H) MS (El) E/Z 47 7 (M)5 4 7 9 (M + 2) 製造例1 1.6 合成〔〔（3，5-二氯-2-甲氧苯基）硕基〕（3，4-二甲氧 苯甲基）胺基〕乙酸 於室溫攪拌15小時 692mg ( 1·45毫莫爾）製造例 1 15所得ΒΑΚ-ΚΑ3 19，174mg ( 4·35毫莫爾）氫氧化鈉， 5 ml甲醇，5ml水。反應液中加入1莫爾/1鹽酸，以氯仿 萃取，以飽和食鹽水洗淨有機層。以無水硫酸鎂乾燥，濃 縮後，自二氯甲烷·己烷再結晶，以收率52%得35 Omg標 題化合物（BAK-KA3 20 )。 -96- (92) 200417367】 H-NMR (CDC13) δ: 3.62 (s? 3H)? 3.82 (s? 3H) 5 3.9 9 (s5 2H) 5 4.01 (s5 3H)? 4.52 (s? 2H), 6.75 (m? 3H)? 7.57 (d? J = 2.6Hz, 1H), 7.7 9 (d5 J = 2.6Hz? 1H) MS (El) E / Z 47 7 (M) 5 4 7 9 (M + 2) Manufacturing Example 1 1.6 Synthesis [ [(3,5-Dichloro-2-methoxyphenyl) sulfonyl] (3,4-dimethoxybenzyl) amino] acetic acid was stirred at room temperature for 15 hours and 692 mg (1.45 mmol) 19,174 mg (4.35 mmol) of sodium hydroxide, 5 ml of methanol, and 5 ml of water. To the reaction solution was added 1 mol / 1 hydrochloric acid, followed by extraction with chloroform, and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate and concentration, it was recrystallized from dichloromethane · hexane to obtain 35 Omg of the title compound (BAK-KA3 20) in a yield of 52%. -96- (92) 200417367

or 、Q〇or 、 Q〇

BAK-KA320 'H-NMR (CDC13) δ:BAK-KA320 'H-NMR (CDC13) δ:

3.81 (s? 3H)? 3.86 (s5 3H)? 4.03 (s? 3H)5 4.0 6 (s5 2H)? 4.49 (s5 2H)? 6.71-6.76 (m? 3H)? 7.57 (d? J= 2.6 Hz? 1H)，7.79 (d5 J = 2.6 Hz，1H) MS (El) E/Z 463 (M) 5 4 6 5 (M + 2) 製造例1 1 7 合成〔〔（3，5-二氯-2-羥苯基）硕基〕（3，4-二甲氧基 苯甲基）胺基〕乙酸 與製造例1 1 6 —樣之方法， 物(B AK-KA3 23 )。 以5 3 %之收率得標題化合3.81 (s? 3H)? 3.86 (s5 3H)? 4.03 (s? 3H) 5 4.0 6 (s5 2H)? 4.49 (s5 2H)? 6.71-6.76 (m? 3H)? 7.57 (d? J = 2.6 Hz ? 1H), 7.79 (d5 J = 2.6 Hz, 1H) MS (El) E / Z 463 (M) 5 4 6 5 (M + 2) Production Example 1 1 7 Synthesis [[(3,5-dichloro- 2-hydroxyphenyl) sulfonyl] (3,4-dimethoxybenzyl) amino] acetic acid was the same as in Production Example 1 16 (B AK-KA3 23). The title compound is obtained with a yield of 53%

^-NMR (CDCI3) δ: 04 (s5 2H) 5 4.3 8 (s，2H)， J = 2.5 Η z 5 1H)，7.79 (d? 3·83 (s5 3Η) 5 3.8 7 (s，3Η), 4, 6.7 2-6.7 8 (m; 3H)， 7.5 7 (d; -97- (93) 200417367 J = 2.5Hz, 1 Η) MS (El) E/Z 449 (M)，451 (M + 2) 製造例118 合成N-(3，4-二甲氧基苯甲基）-1-(3-吼啶基）甲胺 於室溫攪拌3小時5.00g ( 30.0毫莫爾）3，4-二甲氧 基苯甲醛，3.1ml ( 30.4毫莫爾）3-胺甲基吡啶，5g無水 硫酸鎂，20ml無水二乙醚。過濾硫酸鎂，濃縮後，加入 1 . 1 g ( 2 9.0毫莫爾）四氫硼化鈉，於室溫攪拌3小時。反 應液中加入飽和碳酸氫鈉水溶液，以乙酸乙酯萃取，有機 層以無水硫酸鈉乾燥，濃縮後，以矽膠管柱層析（己烷： 乙酸乙酯=1 : 1—氯仿：甲醇=20 : 1 )精製，以 5 9%收率 得 4.59g 標題化合物（BAK-KA331-2)。^ -NMR (CDCI3) δ: 04 (s5 2H) 5 4.3 8 (s, 2H), J = 2.5 Η z 5 1H), 7.79 (d? 3.83 (s5 3Η) 5 3.8 7 (s, 3Η) , 4, 6.7 2-6.7 8 (m; 3H), 7.5 7 (d; -97- (93) 200417367 J = 2.5Hz, 1 Η) MS (El) E / Z 449 (M), 451 (M + 2) Preparation Example 118 Synthesis of N- (3,4-dimethoxybenzyl) -1- (3-armidinyl) methylamine, stirred at room temperature for 3 hours, 5.00 g (30.0 mmol), 3, 4 -Dimethoxybenzaldehyde, 3.1 ml (30.4 mmol) of 3-aminomethylpyridine, 5 g of anhydrous magnesium sulfate, 20 ml of anhydrous diethyl ether. After filtering magnesium sulfate, concentrating, adding 1.1 g (2 9.0 mmol) (G) Sodium tetrahydroborate, stirred at room temperature for 3 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated, and then subjected to silica gel column chromatography (hexane). Alkane: ethyl acetate = 1: 1-chloroform: methanol = 20: 1) was purified to give 4.59 g of the title compound (BAK-KA331-2) in a 59% yield.

CHOCHO

】H-NMR (CDC13) δ: 3 75 (s? 2H)? 3.81 (s? 2H) 5 3.8 8 (s? 3H)? 3.89(s? 3H), 6.84-6.89(m? 3H)5 7.2 7 (dd5 J = 4.8? 7.8Hz5 1H)? 7.69 (ddd5 J = 1 .7，2.0，7·8Ηζ5 1H)5 8.51 (d d，J = 1 · 7 5 4 · 8 H z， 1H)? 8.58 (d? J = 2.0Hz? 1H) MS (El) E/Z 25 8 (M) -98- (94) 200417367 製造例1 1 9 合成3，5-二氯-N- ( 3，4-二甲氧基苯甲基）-2-羥基-N-〔（3 -吡啶基）甲基〕苯磺醯胺 於室溫攪拌15小時5 0 6mg ( 1.94毫莫爾）3，5-苯磺 醯氯，5 0 0mg ( 1.94毫莫爾）製造例118所得8八艮-KA331-2，0.8ml (5.73毫莫爾）三乙胺’ 20ml氯仿。反 應液中加入飽和碳酸鈉水溶液.，以氯仿萃取’有機層以無 水硫酸鈉乾燥，濃縮後’以矽膠管柱層析（氯仿：甲醇 =20 : 1 )精製，再自二氯甲烷-己烷-乙醇予以再結晶，得 收率爲73%之6 8 3 mg標題化合物（BAK-KA3 3 7 )。】 H-NMR (CDC13) δ: 3 75 (s? 2H)? 3.81 (s? 2H) 5 3.8 8 (s? 3H)? 3.89 (s? 3H), 6.84-6.89 (m? 3H) 5 7.2 7 (dd5 J = 4.8? 7.8Hz5 1H)? 7.69 (ddd5 J = 1. 7, 2.0, 7 · 8Ηζ5 1H) 5 8.51 (dd, J = 1 · 7 5 4 · 8 H z, 1H)? 8.58 (d J = 2.0 Hz? 1H) MS (El) E / Z 25 8 (M) -98- (94) 200417367 Manufacturing Example 1 1 9 Synthesis of 3,5-dichloro-N- (3,4-dimethoxy Benzylmethyl) -2-hydroxy-N-[(3-pyridyl) methyl] benzenesulfonamide was stirred at room temperature for 15 hours, 506 mg (1.94 mmol) of 3,5-benzenesulfonyl chloride, 500 mg (1.94 mmoles) of the obtained product 118 in Example 118 was obtained, 0.8 ml (5.73 mmoles) of triethylamine '20 ml of chloroform. A saturated sodium carbonate aqueous solution was added to the reaction solution, and the organic layer was extracted with chloroform, dried over anhydrous sodium sulfate, and concentrated, and then purified by silica gel column chromatography (chloroform: methanol = 20: 1), and then purified from methylene chloride-hexane. -Ethanol was recrystallized to give 6 8 3 mg of the title compound (BAK-KA3 37) in a 73% yield.

〇〇ητ〇 ΒΑΚ-ΚΑ331-2 ΒΑΚ-ΚΑ337〇〇ητ〇 ΒΑΚ-ΚΑ331-2 ΒΑΚ-ΚΑ337

分子量；483.365 (C21H12N205S) 熔點；1 47- 1 48 °C (自 H2Cl2-hexane-EtOH 再結晶） ^-NMR (CDC13) δ: 3.74 (s? 3H) 5 3.8 5 (s5 3H)? 4.31 (s? 2H)? 4.39(s? 2H)? 5.30 (s? 1H)5 6.51-6.75 (m? 3H)? 7.49- 7.5 7 (m3 3H), 8.34 (d5 1H) 5 8.5 2 (dd5 1H) MS (El) E/Z 4 82 (M)5 4 8 4 (M + 2) 製造例1 2 0 合成卜氧化〔〔〔（3，5 -二氯-2 -羥苯基）磺醯基〕（3 -99- 200417367 ，4_二甲氧基苯甲基）胺基〕吡啶 於室溫攪拌3.5小時3 0 0mg ( 0.66毫莫爾）製造例 1 19 所得 BAK-KA337，1 14mg ( 0.97 毫莫爾）m-CPBA， 1 2 m 1二氯甲院。反應液中加入飽和碳酸氫鈉水溶液，以 氯仿萃取。有機層以無水硫酸鎂乾燥，濃縮後，以二氯甲 烷-己烷-甲醇予以再結晶，以收率79%得244mg標題化合 物(B AK-KA34 1 )。Molecular weight; 483.365 (C21H12N205S) melting point; 1 47- 1 48 ° C (recrystallized from H2Cl2-hexane-EtOH) ^ -NMR (CDC13) δ: 3.74 (s? 3H) 5 3.8 5 (s5 3H)? 4.31 (s 2H)? 4.39 (s? 2H)? 5.30 (s? 1H) 5 6.51-6.75 (m? 3H)? 7.49- 7.5 7 (m3 3H), 8.34 (d5 1H) 5 8.5 2 (dd5 1H) MS ( El) E / Z 4 82 (M) 5 4 8 4 (M + 2) Production Example 1 2 0 Synthesis [[[(3,5-dichloro-2 -hydroxyphenyl) sulfonyl]] (3 -99- 200417367, 4-dimethoxybenzyl) amino] pyridine was stirred at room temperature for 3.5 hours 300 mg (0.66 mmol) of Production Example 1 19 BAK-KA337, 1 14 mg (0.97 mmol) ) M-CPBA, 12 m 1 dichloromethane hospital. A saturated sodium bicarbonate aqueous solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, concentrated, and then recrystallized from dichloromethane-hexane-methanol to obtain 244 mg of the title compound (B AK-KA34 1) in a yield of 79%.

BAK-KA337 BAK-KA341 ^-NMR (CDC13) δ: 3.71 (s，3Η)，3.83 (s，3Η)，4·24 (s5 2Η)，4.42(s，2Η)， 6.51-6.69(m? 3H)? 7.20(d? 2H)? 7.57(d? J- 2.5 Hz5 1H)，7.69 (d，J = 2.5 Hz，1H)，8·10〇，1H)，8.28 (s，1H) MS (E I) E/Z 482 (M^O) MS (FAB) +FAB 499· 1 (M + l)， -FAB 497.0 (M-1) 製造例1 2 1 合成〔〔2-(3，4-二甲氧苯基）乙基〕胺基〕乙酸甲酯 於8 0 °C攪拌2 4小時3 . 3 8 in 1 ( 2 0.0毫莫爾）3，4 -二 甲氧基苯乙基胺，19ml (20.0毫莫爾）2-溴化乙酸甲酯， -100- (96) 200417367 3.48ml(20.0毫莫爾）二異丙基乙胺，240ml無水乙腈。 濃縮反應液後以矽膠管柱層析（己烷：乙酸乙酯=1 : 1 — 氯仿··甲醇=30 : 1 )精製，以收率77%得3.8 9g標題化合 物（B AK-KA3 4 8 ) 〇BAK-KA337 BAK-KA341 ^ -NMR (CDC13) δ: 3.71 (s, 3Η), 3.83 (s, 3Η), 4.24 (s5 2Η), 4.42 (s, 2Η), 6.51-6.69 (m? 3H )? 7.20 (d? 2H)? 7.57 (d? J- 2.5 Hz5 1H), 7.69 (d, J = 2.5 Hz, 1H), 8.10〇, 1H), 8.28 (s, 1H) MS (EI) E / Z 482 (M ^ O) MS (FAB) + FAB 499.1 (M + l), -FAB 497.0 (M-1) Production Example 1 2 1 Synthesis [[2- (3,4-Dimethoxy Phenyl) ethyl] amino] methyl acetate was stirred at 80 ° C for 2 4 hours 3.38 in 1 (2 0.0 mmol) 3,4-dimethoxyphenethylamine, 19 ml (20.0 Mmol) methyl 2-bromoacetate, -100- (96) 200417367 3.48 ml (20.0 mmol) diisopropylethylamine, 240 ml anhydrous acetonitrile. The reaction solution was concentrated, and then purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1—chloroform ·· methanol = 30: 1) to obtain 3.79 g of the title compound (B AK-KA3 4 8 in a yield of 77%). ) 〇

'H-NMR (CDC13) δ: 2.72-2.91 (m，4Η)，3.43 (s5 2Η)，3.71 (s5 3Η) 5 3.8 6 (s5 3H)? 3.88 (s5 3H)5 6.7 4 - 6.8 3 (m? 3H) MS (El) E/Z 25 3 (M) 製造例122'H-NMR (CDC13) δ: 2.72-2.91 (m, 4Η), 3.43 (s5 2Η), 3.71 (s5 3Η) 5 3.8 6 (s5 3H)? 3.88 (s5 3H) 5 6.7 4-6.8 3 (m 3H) MS (El) E / Z 25 3 (M) Manufacturing example 122

合成3-〔〔 2-(3，4-二甲氧苯基）乙基〕胺基〕丙酸乙 酯鹽酸 於室溫攪拌2小時3.00ml(17.2毫莫爾）3，4-二甲 氧基苯乙基胺，186ml ( 17.2毫莫爾）丙烯酸乙酯， 5.00ml無水乙醇。反應液中加入2.0ml濃鹽酸，自丙酮-二乙醚予以結晶化後，經濾取，以二乙醚洗淨結晶，以收 率81%得4.24g標題化合物（BAK-KA3 5 0 )。Synthesis of ethyl 3-[[2- (3,4-dimethoxyphenyl) ethyl] amino] propanoate Hydrochloric acid, stirred at room temperature for 2 hours 3.00 ml (17.2 mmol) 3,4-dimethoxy Phenylethylamine, 186 ml (17.2 mmol) ethyl acrylate, 5.00 ml absolute ethanol. To the reaction solution was added 2.0 ml of concentrated hydrochloric acid, which was crystallized from acetone-diethyl ether, and then filtered and washed with diethyl ether to obtain 4.24 g of the title compound (BAK-KA3 50) in a yield of 81%.

-101 - (97) 200417367 ^-NMR (DMSO-d6) δ: 1·21 (t，J = 7.1Hz，3H)，2.75-2.91 (m5 4H)，3.14 (m， 4H)? 3.72 (s5 3H) 5 3.7 5 (s? 3H)? 4.11 (q5 7.1Hz? 2H) 5 6.7 5 - 6.9 2 (m，3H)，9·〇2 (brs，2H) MS (El) E/Z 279 (M-HC1) 製造例123-101-(97) 200417367 ^ -NMR (DMSO-d6) δ: 1.21 (t, J = 7.1Hz, 3H), 2.75-2.91 (m5 4H), 3.14 (m, 4H)? 3.72 (s5 3H ) 5 3.7 5 (s? 3H)? 4.11 (q5 7.1Hz? 2H) 5 6.7 5-6.9 2 (m, 3H), 9.02 (brs, 2H) MS (El) E / Z 279 (M- HC1) Manufacturing example 123

合成3-〔〔 3，5-二氯-2-羥苯基）硕基〕〔（3，二甲 氧苯基）乙基〕胺基〕丙酸乙酯 於室溫攪拌1.5小時500mg (2.89毫莫爾）3，5 -苯Synthesis of ethyl 3-[[3,5-dichloro-2-hydroxyphenyl) sulfonyl] [(3, dimethoxyphenyl) ethyl] amino] propionate, stirred at room temperature for 1.5 hours, 500 mg (2.89 Millimolar) 3,5-benzene

磺醯氯，8 7 8 mg ( 2.89毫莫爾）製造例122所得BAK-KA350’ 1.2ml (8_59毫旲爾）三乙胺，3〇ml氯仿。反應 液中加入1莫爾/1鹽酸，以氯仿萃取，有機層以飽和碳酸 氫鈉水溶液及飽和食鹽水洗淨，以無水硫酸鈉乾燥，濃縮 後，以矽膠管柱層析（己烷··乙酸乙酯=1 : 1 )精製，以 64%收率得 942mg標題化合物（BAK：-K352)。Sulfonium chloride, 878 mg (2.89 mmol), BAK-KA350 '1.2 ml (8-59 mmol) triethylamine obtained in Preparation Example 122, and 30 ml of chloroform. 1 mol / 1 hydrochloric acid was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with a saturated sodium bicarbonate aqueous solution and a saturated saline solution, dried over anhydrous sodium sulfate, concentrated, and then subjected to silica gel column chromatography (hexane ··· Ethyl acetate = 1: 1) was purified to obtain 942 mg of the title compound (BAK: -K352) in a 64% yield.

]H-NMR (CDC13) δ: 1.27(t? J = 7.1Hz? 3H)? 2.62(t5 J = 7.0Hz5 2H)5 2.7 8 (t5 J = 8.1Hz? 2H)? 3.46(t5 J = 8.1Hz5 2H)? 3.56(t? J = 7.1Hz5 2H); 3.86 (s，3H)，3.8 7 (s5 3H)，4.15(q，J = 7.1Hz，2 H)5 -102 - (98) (98)200417367 7.43 (d，J = 2.5Hz，1H)，7·53 (d，J = 2.5 Hz，1H) MS (El) E/Z 5 05 (M)5 5 0 7 (M + 2) 製造例124 合成2- (3，4 -二甲氧苯基）-N-〔 （4 -D比D定基）甲基〕乙 胺 於室溫攪拌17小時2.5ml ( 26.8毫莫爾）吡啶-4-羧 醛，4.50ml (26.8毫莫爾）3，4 -二甲氧基苯乙基胺， 1.35g(21.5毫莫爾）氰基三氫硼化鈉，40ml無水甲醇， 濃縮反應液，加入飽和碳酸氫鈉水溶液，以乙酸乙酯萃取 ，有機層以飽和食鹽水洗淨，以無水硫酸鈉乾燥，濃縮後 ，以矽膠管柱層析（氯仿：甲醇=40 : 1—氯仿：甲醇=20 :1 )精製，以52%收率得3.78g標題化合物（BAK-KA 3 5 3 - 2 )。] H-NMR (CDC13) δ: 1.27 (t? J = 7.1Hz? 3H)? 2.62 (t5 J = 7.0Hz5 2H) 5 2.7 8 (t5 J = 8.1Hz? 2H)? 3.46 (t5 J = 8.1Hz5 2H)? 3.56 (t? J = 7.1Hz5 2H); 3.86 (s, 3H), 3.87 (s5 3H), 4.15 (q, J = 7.1Hz, 2 H) 5 -102-(98) (98) 200417367 7.43 (d, J = 2.5Hz, 1H), 7.53 (d, J = 2.5 Hz, 1H) MS (El) E / Z 5 05 (M) 5 5 0 7 (M + 2) Manufacturing example 124 Synthesis of 2- (3,4-dimethoxyphenyl) -N-[(4-D to D amidyl) methyl] ethylamine, stirred at room temperature for 17 hours, 2.5 ml (26.8 mmoles) of pyridine-4-carboxyl Aldehyde, 4.50 ml (26.8 mmoles) of 3,4-dimethoxyphenethylamine, 1.35 g (21.5 mmoles) of sodium cyanotrihydroborate, 40 ml of anhydrous methanol, the reaction solution was concentrated, and saturated carbonic acid was added Aqueous sodium hydrogen solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and then subjected to silica gel column chromatography (chloroform: methanol = 40: 1-chloroform: methanol = 20: 1). ), And 3.78 g of the title compound (BAK-KA 3 5 3-2) was obtained in a yield of 52%.

BAK-KA353-2 】H-NMR (CDC13) δ: 2.7 8 -2.8 9 (m? 4H)? 3.81 (s5 2H) 5 3.8 7 (s5 6H) 5 6.7 0 - 6.84 (m? 3H)? 7.21 (d? J = 6.〇Hz? 2H) 5 8.5 3 (d5 J- 6.0 Hz? 2H) MS (El) E/Z 2 72 (M) 製造例1 2 5 ^ 103 - (99) 200417367 合成 3-〔 〔3，5-二氯-2-羥苯基）硕基〕〔（3，4-二甲 氧苯基）乙基〕胺基〕丙酸 於室溫攪拌3小時5 2 9mg ( 1·04毫莫爾）製造例123 所得 ΒΑΚ-ΚΑ352，3.00ml 濃鹽酸，6.00ml 甲酸，3.00ml 水，再於60 °C攪拌2.5小時。反應液中加入1莫爾/1鹽酸 ，以氯仿萃取。有機層以無水硫酸鎂乾燥，濃縮後自二 氯甲烷-己烷再結晶，以收率73 %得3 64mg標題化合物（BAK-KA353-2】 H-NMR (CDC13) δ: 2.7 8 -2.8 9 (m? 4H)? 3.81 (s5 2H) 5 3.8 7 (s5 6H) 5 6.7 0-6.84 (m? 3H)? 7.21 ( d? J = 6.〇Hz? 2H) 5 8.5 3 (d5 J- 6.0 Hz? 2H) MS (El) E / Z 2 72 (M) Manufacturing Example 1 2 5 ^ 103-(99) 200417367 Synthesis 3- [[3,5-Dichloro-2-hydroxyphenyl) sulfoyl] [(3,4-dimethoxyphenyl) ethyl] amino] propionic acid was stirred at room temperature for 3 hours 5 2 9 mg (1 · (04 millimoles) Production Example 123 ΒΑΚ-ΚΑ352, 3.00 ml of concentrated hydrochloric acid, 6.00 ml of formic acid, 3.00 ml of water, and stirred at 60 ° C for 2.5 hours. 1 mol / 1 hydrochloric acid was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and concentrated after recrystallization from dichloromethane-hexane to obtain 3 64 mg of the title compound in a yield of 73% (

BAK-KA3 5 4 )。BAK-KA3 5 4).

BAK-KA354 ]H-NMR (CDC13) δ: 2.68 (t? J = 7.0Hz? 2H)5 2.7 9 (t5 J = 7.2Hz? 2H) 5 3.4 7 (t5 J-7.2Hz? 2H) 5 3.5 5 (t，J = 7.0Hz5 2H)，3.86 (s5 6H)5BAK-KA354] H-NMR (CDC13) δ: 2.68 (t? J = 7.0Hz? 2H) 5 2.7 9 (t5 J = 7.2Hz? 2H) 5 3.4 7 (t5 J-7.2Hz? 2H) 5 3.5 5 (t, J = 7.0Hz5 2H), 3.86 (s5 6H) 5

6.64-6.81 (m? 3H)5 7.4 4 (d5 J = 2.5 Hz? 1H)? 7.54 (d? J =2.5 H z ? 1 H) MS (El) E/Z 47 7 (M)，479 (M + 2) 製造例126 合成〔〔（3，5-二氯-2-羥苯基）碾基〕〔（3，4-二甲氧 苯基）乙基〕胺基〕乙酸甲酯 於室溫攪拌1小時5 00m g ( 2.89毫莫爾）3，5-苯磺 醯氯，7 3 2nig ( 2·89毫莫爾）製造例121所得BAK-KA348 -104 - (100) 200417367 ，1.2ml三乙胺，30ml氯仿。反應液中加入1莫爾/1鹽酸 ，以氯仿萃取，有機層以飽和碳酸氫鈉水溶液及飽和食鹽 水洗淨，以無水硫酸鈉乾燥，濃縮後，以矽膠管柱層析（ 己烷：乙酸乙酯=1 : 1 )精製，以55%收率得7 62mg標題 化合物（B AK-KA3 5 6 )。6.64-6.81 (m? 3H) 5 7.4 4 (d5 J = 2.5 Hz? 1H)? 7.54 (d? J = 2.5 H z? 1 H) MS (El) E / Z 47 7 (M), 479 (M + 2) Production Example 126 Synthesis of [[(3,5-dichloro-2-hydroxyphenyl) yl] [(3,4-dimethoxyphenyl) ethyl] amino] acetic acid methyl ester at room temperature Stir for 1 hour 5,000 mg (2.89 mmoles) 3,5-benzenesulfonyl chloride, 7 3 2nig (2.89 mmoles) BAK-KA348 -104-(100) 200417367 obtained in Production Example 121, 1.2 ml three Ethylamine, 30 ml of chloroform. 1 mol / 1 hydrochloric acid was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and then subjected to silica gel column chromatography (hexane: acetic acid). Ethyl ester = 1: 1) was purified to obtain 7 62 mg of the title compound (B AK-KA3 5 6) in a 55% yield.

^-NMR (CDCI3) δ: 2.79 (t5 J = 7.2Hz5 2H)5 3.4 9 (t5 J = 7.2Hz5 2H)? 3.70 (s5 3H) 5 3.8 6 (s5 3H)? 3.87 (s5 3H)? 4.02(s? 2H) 5 6.6 0 - 6.79(m? 3H)? 7.53(s? 2H)5 9.0 0 (s5 1H) MS (El) E/Z 477 (M)? 4 7 9 (M + 2)^ -NMR (CDCI3) δ: 2.79 (t5 J = 7.2Hz5 2H) 5 3.4 9 (t5 J = 7.2Hz5 2H)? 3.70 (s5 3H) 5 3.8 6 (s5 3H)? 3.87 (s5 3H)? 4.02 ( s? 2H) 5 6.6 0-6.79 (m? 3H)? 7.53 (s? 2H) 5 9.0 0 (s5 1H) MS (El) E / Z 477 (M)? 4 7 9 (M + 2)

製造例1 2 7 合成〔〔3，5-二氯-2-羥苯基）硕基〕〔2-(3，4-二甲氧 苯基）乙基〕胺基〕乙酸 與製造例1 1 6 —樣之方法，以8 7 %之收率得標題化合 物(B AK-KA3 5 7 ) 〇 -105 - (101) 200417367Production Example 1 2 7 Synthesis of [[3,5-dichloro-2-hydroxyphenyl] shutyl] [2- (3,4-dimethoxyphenyl) ethyl] amino] acetic acid and Production Example 1 1 6 —The same method, the title compound (B AK-KA3 5 7) was obtained in a yield of 87% 〇-105-(101) 200417367

!H-NMR (CDCIb) δ:! H-NMR (CDCIb) δ:

2.79 (t? J = 7.2Hz? 2H)? 3.51 (t3 J = 7.2Hz? 2H) 5 3.8 5 (s5 3H)，3.86(s，3H)5 4.0 9 (s，2H)，6.4 8 -6.7 5 (m，3H)，7.51 (d5 J = 2.5Hz? 1H) 5 7.5 3 (d? J = 2.5 Hz? 1H) MS (El) E/Z 463 (M)，465 (M + 2) 製造例1 2 8 合成3，5-二氯-N-〔 2-(3，4-二羥苯基）乙基〕-2·羥基-N-〔 （ 4-吡啶基）甲基〕苯磺醯胺2.79 (t? J = 7.2Hz? 2H)? 3.51 (t3 J = 7.2Hz? 2H) 5 3.8 5 (s5 3H), 3.86 (s, 3H) 5 4.0 9 (s, 2H), 6.4 8 -6.7 5 (m, 3H), 7.51 (d5 J = 2.5Hz? 1H) 5 7.5 3 (d? J = 2.5 Hz? 1H) MS (El) E / Z 463 (M), 465 (M + 2) Manufacturing example 1 2 8 Synthesis of 3,5-dichloro-N- [2- (3,4-dihydroxyphenyl) ethyl] -2 · hydroxy-N- [(4-pyridyl) methyl] benzenesulfonamide

於室溫攪拌4.5小時1 .00g ( 5.79毫莫爾）3，5-苯磺 醯氯，1.50g(5.50毫莫爾）製造例124所得BAK-KA353 ，2.4 2ml ( 17.3毫莫爾）三乙胺，60ml氯仿。反應液加 入飽和碳酸氫鈉水溶液，以氯仿萃取。有機層以飽和食鹽 水洗淨，以無水硫酸鈉乾燥，濃縮後以矽膠管柱層析（氯 仿：甲醇=50 : 1 )精製，再以二氯甲烷-己烷予以再結晶 ，以收率29%得821mg標題化合物（BAK-KA3 5 8 )。 -106 - (102) 200417367Stir at room temperature for 4.5 hours. 1.00 g (5.79 mmoles) of 3,5-benzenesulfonyl chloride, 1.50 g (5.50 mmoles) of BAK-KA353 obtained in Preparation Example 124, 2.4 2 ml (17.3 mmoles) of triethyl Amine, 60 ml of chloroform. The reaction solution was added with a saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and then purified by silica gel column chromatography (chloroform: methanol = 50: 1), and then recrystallized from dichloromethane-hexane to obtain a yield of 29 % To give 821 mg of the title compound (BAK-KA3 5 8). -106-(102) 200417367

\S、C丨十\ S, C 丨 十

BAK-KA353-2 BAK-KA358 』H-NMR (CDC13) δ: 2.64 (t5 J = 7.2Hz， 2Η)， 3.44 (t5 J = 7.2Hz5 2H)， 3.81 (s5 3H)5 3.8 5 (s5 3H)5 4.42 (s5 2H)? 6.48-6.7 5 (m5 3 H), 7.19 (d? J = 6.0 Hz? 2H)? 7.47 (d? J = 2.5Hz? 1H)? 7.55 (d? J = 2.5Hz? 1H)? 8.60 (d? J = 6.0Hz? 2H) MS (El) E/Z 496 (M)? 49 8 (M + 2) 製造例1 2 9 合成卜氧化4-〔〔〔 （3，5-二氯-2-羥苯基）硕基〕〔2- (3，4-二甲氧苯基）乙基〕胺基〕甲基〕吡啶 於室溫攪拌4小時3 00mg ( 0.60毫莫爾）製造例128 所得 BAK-KA358，156mg( 0.90 毫莫爾）m-CPBA，12ml 二氯甲烷。反應液中加入二乙醚，濾取析出之結晶，以二 乙醚洗淨結晶，以收率83%得257mg標題化合物（BAK-KA3 60 )。BAK-KA353-2 BAK-KA358 "H-NMR (CDC13) δ: 2.64 (t5 J = 7.2Hz, 2Η), 3.44 (t5 J = 7.2Hz5 2H), 3.81 (s5 3H) 5 3.8 5 (s5 3H) 5 4.42 (s5 2H)? 6.48-6.7 5 (m5 3 H), 7.19 (d? J = 6.0 Hz? 2H)? 7.47 (d? J = 2.5Hz? 1H)? 7.55 (d? J = 2.5Hz? 1H)? 8.60 (d? J = 6.0Hz? 2H) MS (El) E / Z 496 (M)? 49 8 (M + 2) Production Example 1 2 9 Synthesis of oxidized 4-[[[(3, 5 -Dichloro-2-hydroxyphenyl) sulfoyl] [2- (3,4-dimethoxyphenyl) ethyl] amino] methyl] pyridine, stirred at room temperature for 4 hours 300 mg (0.60 mmol) ) BAK-KA358 obtained in Preparation Example 128, 156 mg (0.90 mmol) of m-CPBA, 12 ml of dichloromethane. Diethyl ether was added to the reaction solution, and the precipitated crystals were collected by filtration, and the crystals were washed with diethyl ether to obtain 257 mg of the title compound (BAK-KA3 60) in a yield of 83%.

BAK-KA358 BAK-KA360 107- (103) 200417367 】H-NMR (CDC13) δ: 2.63 (t5 J = 7.2Hz5 2H)? 3.44 (t? J = 7.2Hz? 2H)? 3.83(s3 3H) 5 3.8 5 (s5 3H)5 4.3 4 (s5 2H)? 6.45 -6.73 (m5 3 H)5 7.18 (d5 J =7.0 Hz, 2H)，7.54 (d5 J = 2.5Hz，1H)5 7.5 7 (d5 J 2.5Hz5 1H)? 8.19 (d? J = 7.0Hz5 2H) MS (FAB) +FAB 5 13.1 (M+l) -FAB 5 11.0 (M-l) 製造例1 3 0 合成〔〔（2，3-二氫-1，4-苯并二噁因-6-基）甲基〕胺 基〕乙酸甲酯 於室溫攪拌23小時2.00g ( 12.2毫莫爾）3，4-乙烯 二氧基苯甲醛，1.53g(12.2毫莫爾）甘胺酸甲酯鹽酸鹽 ，61 3mg氰基三氫硼鈉，200ml無水甲醇。反應液濃縮後 加入飽和碳酸氫鈉水溶液，以二乙醚萃取。有機層以無水 硫酸鈉乾燥，經濃縮後，以矽膠管柱層析（己烷：乙酸乙 酯=1 ·· 1—氯仿：甲醇=20 : 1 ^精製，以收率28%得8 04 mg 標題化合物（BAK-KA3 7 5 )。BAK-KA358 BAK-KA360 107- (103) 200417367】 H-NMR (CDC13) δ: 2.63 (t5 J = 7.2Hz5 2H)? 3.44 (t? J = 7.2Hz? 2H)? 3.83 (s3 3H) 5 3.8 5 (s5 3H) 5 4.3 4 (s5 2H)? 6.45 -6.73 (m5 3 H) 5 7.18 (d5 J = 7.0 Hz, 2H), 7.54 (d5 J = 2.5Hz, 1H) 5 7.5 7 (d5 J 2.5 Hz5 1H)? 8.19 (d? J = 7.0Hz5 2H) MS (FAB) + FAB 5 13.1 (M + l) -FAB 5 11.0 (Ml) Production Example 1 3 0 Synthesis [((2,3-dihydro- 1,4-Benzodioxin-6-yl) methyl] amino] acetic acid methyl ester stirred at room temperature for 23 hours 2.00 g (12.2 mmol) 3,4-ethylenedioxybenzaldehyde, 1.53 g (12.2 mmoles) methyl glycine hydrochloride, 61 3 mg sodium cyanotrihydroborate, 200 ml anhydrous methanol. After the reaction solution was concentrated, a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, concentrated, and then purified by silica gel column chromatography (hexane: ethyl acetate = 1 ·· 1-chloroform: methanol = 20: 1 ^) to obtain 8 04 mg in a yield of 28%. The title compound (BAK-KA3 7 5).

BAK-KA375 】H-NMR (CDC]3) δ: 3.40 (s; 2H) 5 3.6 9 (s5 2H)? 3.72 (s; 3H); 4.24(s5 4H)5 -108- (104) (104)200417367 6.79-6.84 (m5 3H) MS (El) E/Z 23 7 (M) 製造例1 3 1 合成2，3-二氫-6-〔 （E) -2-甲氧基乙烯基〕-1，3-苯并 二噁因及2，3-二氫-6-〔 （Z) -2-甲氧基乙烯基〕-1，3- 苯并二噁因 氮氣氛中於〇°C在54ml無水甲醇中加入1.06g(26.5 毫莫爾）氫化鈉（油中60%)，再滴下8.27g ( 24.1毫莫 爾）亞甲二氧基三苯膦氯之50ml無水甲醇溶液，於室溫 攪拌3 0分鐘。濃縮反應液後，共沸除去含有苯之甲醇， 減壓乾燥。所得粗生成物中加入3 · 0 g ( 1 8.3毫莫爾）3， 4-乙烯二氧化苯甲醛之64ml苯溶液，加熱回流3小時， 再於室溫攪拌1 9小時。濃縮反應液後以矽膠管柱層析（ 己烷：乙酸乙酯=1 〇 : 1 )精製，以定量收率做爲混合物得 3.81g 標題化合物（BAK-KA3 77 )。BAK-KA375】 H-NMR (CDC) 3) δ: 3.40 (s; 2H) 5 3.6 9 (s5 2H)? 3.72 (s; 3H); 4.24 (s5 4H) 5 -108- (104) (104) 200417367 6.79-6.84 (m5 3H) MS (El) E / Z 23 7 (M) Production Example 1 3 1 Synthesis of 2,3-dihydro-6-[(E) -2-methoxyvinyl] -1 , 3-Benzodioxin and 2,3-Dihydro-6-[(Z) -2-methoxyvinyl] -1,3-Benzodioxine in a nitrogen atmosphere at 54 ° C at 54ml Add 1.06 g (26.5 mmoles) of sodium hydride (60% in oil) to anhydrous methanol, and drop 8.27 g (24.1 mmoles) of methylene dioxytriphenylphosphine chloride in 50 ml of anhydrous methanol and stir at room temperature 30 minutes. After the reaction solution was concentrated, methanol containing benzene was removed azeotropically and dried under reduced pressure. To the obtained crude product was added 3.0 g (18.3 mmol) of 64 ml of a benzene solution of 3,4-ethylene benzaldehyde, and the mixture was heated under reflux for 3 hours, and then stirred at room temperature for 19 hours. The reaction solution was concentrated, and then purified by silica gel column chromatography (hexane: ethyl acetate = 1: 0: 1), and the quantitative yield was used as a mixture to obtain 3.81 g of the title compound (BAK-KA3 77).

BAK-KA377 ^-NMR (CDC13) δ: 3.65，3.74 (s，3Ηχ2)，4.23，4.24 (s5 4Hx2)，5.11(d， J = 7.0Hz， 1H)? 5.70 (d5 J = 1 2.9 H z 5 1 H)? 6.04 (d5 J = 7.0Hz，1 H); 6.71-6.79 (m5 4H); 6.90 (d? J = 12.9Hz? -10S- (105) 200417367 1H)? 6.98-7.21 (τη? 2H) MS (El) E/Z 3 84 (M) 製造例1 3 2 合成〔〔（3，5 -二氯-2-羥苯基）硕基〕〔（2，3 -二氫-1 ，4 -苯并二噁因-6-基）甲基〕胺基〕乙酸 於室溫攪拌3.5小時585mg(3.39毫莫爾）3，5 -苯 磺醯氯，8 04mg ( 3.39毫莫爾）製造例13〇所得BAK-KA375，1.42ml (10.2毫莫爾）三乙胺，35ml氯仿。反應 液中加入飽和碳酸氫鈉水溶液，以氯仿萃取。有機層以飽 和食鹽水洗淨，以無水硫酸鎂乾燥濃縮後，以矽膠管層析 (己烷：乙酸乙酯=2 : 1—己烷：乙酸乙酯=i : 1 )精製， 以收率62%得971mg標題化合物甲酯體（BAK-KA3 79 ) 〇 於室溫攪拌4 · 5小時9 7 1 m g ( 2 · 1 0毫莫爾）上述所得 BAK-KA379，252mg(6.30毫莫爾）氫氧化鈉，5ml .甲醇 ，5 ml水。反應液中加入1莫爾/1鹽酸，以氯仿萃取，有 機層以無水硫酸鎂乾燥，濃縮後自二氯甲烷-己烷再結晶 ，以收率81%得762mg標題化合物（BAK-KA3 8 0 )。BAK-KA377 ^ -NMR (CDC13) δ: 3.65, 3.74 (s, 3Ηχ2), 4.23, 4.24 (s5 4Hx2), 5.11 (d, J = 7.0Hz, 1H)? 5.70 (d5 J = 1 2.9 H z 5 1 H)? 6.04 (d5 J = 7.0Hz, 1 H); 6.71-6.79 (m5 4H); 6.90 (d? J = 12.9Hz? -10S- (105) 200417367 1H)? 6.98-7.21 (τη? 2H ) MS (El) E / Z 3 84 (M) Production Example 1 3 2 Synthesis of [[(3,5-dichloro-2-hydroxyphenyl) sulfonyl] [(2,3-dihydro-1,4 -Benzodioxin-6-yl) methyl] amino] acetic acid stirred at room temperature for 3.5 hours 585 mg (3.39 mmoles) of 3,5-benzenesulfonyl chloride, 8 04 mg (3.39 mmoles) Production Example 130. BAK-KA375 obtained, 1.42 ml (10.2 mmol) of triethylamine, 35 ml of chloroform. A saturated sodium bicarbonate aqueous solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated, and then purified by silica gel tube chromatography (hexane: ethyl acetate = 2: 1-hexane: ethyl acetate = i: 1) to obtain a yield. 62% yielded 971 mg of the title compound methyl ester (BAK-KA3 79) 〇 stirred at room temperature for 4 · 5 hours 9 7 1 mg (2 · 10 mmol) BAK-KA379 obtained above, 252 mg (6.30 mmol) Sodium hydroxide, 5 ml. Methanol, 5 ml water. 1 mol / 1 hydrochloric acid was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated after recrystallization from methylene chloride-hexane to obtain 762 mg of the title compound (BAK-KA3 8 0) ).

BAK-KA379 BAK-KA380 BAK-KA375 -110- (106) (106)200417367 W-NMR (CDC13) δ: 4.05 (s? 2H)? 4.25 (s5 4H)5 4.3 5 (s5 2H)? 6.68(dd? J = 2.1，8.2Hz5 1H)? 6.74(d? J = 2.1Hz? 1H)? 6.82 (d? J = 8.2 Hz? 1H)? 7.56 (d5 J = 2.5Hz? 1 H)，7 · 6 0 (d，J = 2.5 Hz, 1H) MS (El) E/Z 446 (M) 製造例1 3 3 合成（2，3-二氫-1，4-苯并氧-6-基）乙醛 加熱回流5小時3 · 8 1 g ( 1 9.8毫莫爾）製造例1 3 1所 得BAK-KA377，1.82ml硫酸，95ml無水四氫卩夫喃，18ml 水。反應液濃縮加入水，以二乙醚萃取，有機層以飽和食 鹽水洗淨無水硫酸鈉乾燥。濃縮後以矽膠管柱層析（己烷 ••乙酸乙酯=5 : 1 )精製粗生成物，以收率.76%得 2.67g 標題化合物（BAK-KA381)。BAK-KA379 BAK-KA380 BAK-KA375 -110- (106) (106) 200417367 W-NMR (CDC13) δ: 4.05 (s? 2H)? 4.25 (s5 4H) 5 4.3 5 (s5 2H)? 6.68 (dd ? J = 2.1, 8.2Hz5 1H)? 6.74 (d? J = 2.1Hz? 1H)? 6.82 (d? J = 8.2 Hz? 1H)? 7.56 (d5 J = 2.5Hz? 1 H), 7 · 6 0 (d, J = 2.5 Hz, 1H) MS (El) E / Z 446 (M) Production Example 1 3 3 Synthesis of (2,3-dihydro-1,4-benzooxy-6-yl) acetaldehyde heating Reflux for 5 hours. 3.81 g (19.8 mmol) of BAK-KA377 obtained in Production Example 1 31, 1.82 ml of sulfuric acid, 95 ml of anhydrous tetrahydrofuran, and 18 ml of water. The reaction solution was concentrated, water was added, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the crude product was purified by silica gel column chromatography (hexane •• ethyl acetate = 5: 1) to obtain 2.67 g of the title compound (BAK-KA381) in a yield of .76%.

BAK-KA377 BAK-KA381 】H-NMR (CDC13) δ: 3.57 (d，J = 2.4Hz，1Η)，4·26 (s5 4Η)，6.64-6.8 8 (m5 3H)5 9.7 0 (d，J = 2.4Hz? 1 H) MS (El) E/Z 178 (M) -111 - (107) (107)200417367 製造例1 3 4 合成〔〔2- (2，3-二氫-1，4-苯并二噁因-6-基）乙基〕 胺基〕乙酸甲酯 於室溫攪拌14.5小時2.67g ( 15.0毫莫爾）製造例 133所得BAK-KA381，2.50g ( 19.9毫莫爾）甘胺酸甲酯 鹽酸鹽，754mg( 12.0毫莫爾）氰基三氫硼化鈉，200ml 無水甲醇。反應液中加入飽和碳酸氫鈉水溶液，以二乙醚 萃取。有機層以飽和食鹽水洗淨，以無水硫酸鈉乾燥，濃 縮後以矽膠管柱層析（己烷：乙酸乙酯=1 : 1 -氯仿：甲 醇=10 : 1 )精製，以收率 60%得 2.25g標題化合物（ BAK-KA3 8 3 )。BAK-KA377 BAK-KA381】 H-NMR (CDC13) δ: 3.57 (d, J = 2.4Hz, 1Η), 4.26 (s5 4Η), 6.64-6.8 8 (m5 3H) 5 9.7 0 (d, J = 2.4Hz? 1 H) MS (El) E / Z 178 (M) -111-(107) (107) 200417367 Production Example 1 3 4 Synthesis [[2- (2,3-dihydro-1,4- Benzodioxin-6-yl) ethyl] amino] methyl acetate was stirred at room temperature for 14.5 hours 2.67 g (15.0 mmol) of BAK-KA381 obtained in Production Example 133, 2.50 g (19.9 mmol) of glycine Methyl urethane hydrochloride, 754 mg (12.0 mmol) sodium cyanotrihydroborate, 200 ml anhydrous methanol. To the reaction solution was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and then purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1-chloroform: methanol = 10: 1) at a yield of 60%. This gave 2.25 g of the title compound (BAK-KA3 8 3).

BAK-KA381 BAK-KA383 ^-NMR (CDC13) δ: 2.66-2.74 (m? 2H)? 2.80-2.8 8 (m5 2H)5 3.4 2 (s? 2H)5 3.72 (s5 2H)5 4.24 (s? 4H)5 6.6 5 - 6.8 1 (m? 3H) MS (El) E/Z 251 (M) 製造例1 3 5 合成〔〔3，5-二氯-2-羥苯基）碾基〕〔2-(2，3-二氫-1 ，4-苯并二噁因-6-基）乙基〕胺基〕乙酸甲酯 於室溫攪拌16小時1 .54g ( 8.95毫莫爾）3，5-苯磺 -112 - (108) 200417367 醯氯，2.25g ( 8.95毫莫爾）製造例134所得BAK-KA383 ，3.7 5ml (26.9毫莫爾）三乙胺，89ml氯仿。反應液中 加入1莫爾/1鹽酸，以氯仿萃取，有機層以飽和碳酸氫鈉 水溶液及飽和食鹽水洗淨，以無水硫酸鈉乾燥，濃縮後， 以矽膠管柱層析（己烷：乙酸乙酯=2 : 1 )精製，以52% 收率得2.21g標題化合物（BAK-KA3 84 )。BAK-KA381 BAK-KA383 ^ -NMR (CDC13) δ: 2.66-2.74 (m? 2H)? 2.80-2.8 8 (m5 2H) 5 3.4 2 (s? 2H) 5 3.72 (s5 2H) 5 4.24 (s? 4H) 5 6.6 5-6.8 1 (m? 3H) MS (El) E / Z 251 (M) Production Example 1 3 5 Synthesis of [[3,5-dichloro-2-hydroxyphenyl] yl] [2 -(2,3-dihydro-1,4-benzodioxin-6-yl) ethyl] amino] acetic acid methyl ester stirred at room temperature for 16 hours 1.54 g (8.95 mmol) 3,5 -Benzenesulfonyl-112- (108) 200417367 gadolinium chloride, 2.25 g (8.95 mmol) of BAK-KA383 obtained in Production Example 134, 3.75 ml (26.9 mmol) triethylamine, 89 ml chloroform. 1 mol / 1 hydrochloric acid was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated, followed by silica gel column chromatography (hexane: acetic acid) Ethyl ester = 2: 1) was purified to obtain 2.21 g of the title compound (BAK-KA3 84) in a yield of 52%.

JH-NMR (CDCh) δ: 2.74(t5 J = 7.2Hz? 2H)? 3.45(t? J = 7.2Hz5 2H)? 3.69 (s? 3H)，4.04 (s，2H)，4.24 (s，4H)，6.54-6.78 (m5 3H)， 7.54 (s5 2H) MS (El) E/Z 475 (M)JH-NMR (CDCh) δ: 2.74 (t5 J = 7.2Hz? 2H)? 3.45 (t? J = 7.2Hz5 2H)? 3.69 (s? 3H), 4.04 (s, 2H), 4.24 (s, 4H) , 6.54-6.78 (m5 3H), 7.54 (s5 2H) MS (El) E / Z 475 (M)

製造例1 3 6 合成〔〔（3，5-二氯-2-羥苯基）硕基〕〔2-(2，3-二 氫-1，4-苯并二噁因-6-基）乙基〕胺基〕乙酸 與製造例1 16 —樣之方法，以90%之收率得標題化合 物（BAK-3 8 5 )。 113 - (109) 200417367Production Example 1 3 6 Synthesis of [[(3,5-dichloro-2-hydroxyphenyl) sulfonyl] [2- (2,3-dihydro-1,4-benzodioxin-6-yl) Ethyl] amino] acetic acid was obtained in the same manner as in Production Example 16 to obtain the title compound (BAK-3 8 5) in a yield of 90%. 113-(109) 200417367

^-NMR (CDCI3) δ:^ -NMR (CDCI3) δ:

2.74 (t5 J = 7.1Hz? 2H)? 3.47 (t5 J = 7.1Hz? 2H)? 4.02 (s? 2H)5 4.2 4 (s? 4H)5 6 5 4 - 6.7 8 (m5 3H)? 7.52 (d? J = 2.5Hz? 1H)5 7.5 5 (d5 J = 2.5Hz5 1H) MS (El) E/Z 461 (M) 製造例137 合成 2-〔 （3，5-二氯-2-羥苯基）砸基〕（3，4-二甲氧 基苯乙基）胺基甲基乙醯胺 於室溫攪拌17小時2.7 6g ( 5.7毫莫爾）製造例135 所得BAK-KA384，5.00ml甲胺甲醇溶液，5.00ml甲醇。 反應液中加入1莫爾/1鹽酸，以氯仿萃取，有機層以無水 硫酸鎂乾燥，濃縮後自二氯甲烷-已烷再結晶’得 1 · 9 5 g 標題化合物（BAK-KA3 8 9 )。 再將濾液濃縮後，以矽膠管柱層析（氯仿：甲醇=3 0 :1 )精製，以 8 4 %收率得 3 5 8 m g相同之標題化合物（ BAK-KA3 8 9 )。 -114- (110) 2004173672.74 (t5 J = 7.1Hz? 2H)? 3.47 (t5 J = 7.1Hz? 2H)? 4.02 (s? 2H) 5 4.2 4 (s? 4H) 5 6 5 4-6.7 8 (m5 3H)? 7.52 ( d? J = 2.5Hz? 1H) 5 7.5 5 (d5 J = 2.5Hz5 1H) MS (El) E / Z 461 (M) Production Example 137 Synthesis of 2-[(3,5-dichloro-2-hydroxybenzene Group) stilbene] (3,4-dimethoxyphenethyl) aminomethylacetamidine, stirred at room temperature for 17 hours, 2.7 6 g (5.7 mmol), Production Example 135, BAK-KA384, 5.00 ml of formazan Amine methanol solution, 5.00 ml methanol. 1 mol / 1 hydrochloric acid was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated after recrystallization from dichloromethane-hexane to give 1.95 g of the title compound (BAK-KA3 8 9). . After the filtrate was concentrated, the residue was purified by silica gel column chromatography (chloroform: methanol = 3 0: 1) to obtain the same title compound (BAK-KA3 8 9) with a yield of 84% in 35.8 mg. -114- (110) 200417367

^-NMR (CDCI3) δ: 1.59 (t? J = 7.6Hz5 2H)5 2.8 0 (d5 J = 4.9Hz5 3H) 5 3.4 8 (t5 J = 7.6Hz? 2H)? 3.86 (s5 8H)5 6.6 2 (brs? 1H)? 6.63-6.80 (m? 3H)5 7.5 6 (s? 2H)5 9.17(s? 1H) MS (El) E/Z 476( M + ) 製造例1 3 8 合成2-〔 4-〔 〔 7-氯-5-氧基-2，3-二氫-1，4-苯并Df吖庚 因-4(5H)-基〕甲基〕-2-甲氧苯氧基〕乙酸乙酯 在 201.6mg( 0.604毫莫爾）製造例 75所得8入[ G47 3，167mg ( 1·21毫莫爾）碳酸鉀，4ml DMF中，加入 0.13ml ( 1.21毫莫爾）2-溴化乙酸乙酯，於室溫攪拌24 小時。反應液中加入水，以乙酸乙酯萃取，有機層以無水 硫酸鈉乾燥。濃縮後以矽膠管柱層析（己烷：乙酸乙酯=4 :3 )精製粗生成物，以收率86%得21 9mg標題化合物（ B AK-G6 8 7 )。^ -NMR (CDCI3) δ: 1.59 (t? J = 7.6Hz5 2H) 5 2.8 0 (d5 J = 4.9Hz5 3H) 5 3.4 8 (t5 J = 7.6Hz? 2H)? 3.86 (s5 8H) 5 6.6 2 (brs? 1H)? 6.63-6.80 (m? 3H) 5 7.5 6 (s? 2H) 5 9.17 (s? 1H) MS (El) E / Z 476 (M +) Manufacturing Example 1 3 8 Synthesis 2- ( 4- [[7-Chloro-5-oxy-2,3-dihydro-1,4-benzoDfazepine-4 (5H) -yl] methyl] -2-methoxyphenoxy] Ethyl acetate was added to 201.6 mg (0.604 mmol) of Production Example 75. [G47 3,167 mg (1.21 mmol) of potassium carbonate, 4 ml of DMF was added to 0.13 ml (1.21 mmol) of 2-bromo Ethyl acetate was stirred at room temperature for 24 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After concentration, the crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 3) to obtain 21 9 mg of the title compound (B AK-G6 8 7) in a yield of 86%.

BAK-G473 BAK-G687 115 - (111) 200417367 】H-NMR (CDC13) (5 : 2.10 (s5 3H)，3·45 (t5 J 5·3Ηζ，2H)，3.86 (s5 3H)，4·13 (t5 J = 5.3Hz? 2H)? 4.23 (m5 2H)5 4.44 (m5 2H)? 4.75 (s5 2H)，6.8 0- 7.00 (m5 4H) 5 7.3 6 (dd，J = 2.6，8.7Hz，1H)， 7.85 (d? J = 2.6Hz? 1Hz) 製造例1 3 9 合成 7-氯- 4-〔4-(2-羥乙氧基）-3-甲氧苯甲基〕-3，4-二氫-1，4 -苯并哼吖庚因-5 ( 2 Η )-酮 在 200m g ( 0.476毫莫爾）製造例 138所得 ΒΑΚ -G68 7，4ml甲醇中，加入 2 m 11 0 %氫氧化鈉水溶液，於室 溫攪拌2小時。反應液中加入稀鹽酸，以乙酸乙酯萃取， 有機層以無水硫酸鈉乾燥。濃縮後以矽膠管柱層析（己烷 ••乙酸乙酯=1 : 2 )精製粗生成物，以收率92%得165mg 標題化合物（BAK-G692 )。BAK-G473 BAK-G687 115-(111) 200417367】 H-NMR (CDC13) (5: 2.10 (s5 3H), 3.45 (t5 J 5. · 3Ηζ, 2H), 3.86 (s5 3H), 4.13 (t5 J = 5.3Hz? 2H)? 4.23 (m5 2H) 5 4.44 (m5 2H)? 4.75 (s5 2H), 6.8 0- 7.00 (m5 4H) 5 7.3 6 (dd, J = 2.6, 8.7Hz, 1H ), 7.85 (d? J = 2.6 Hz? 1 Hz) Production Example 1 3 9 Synthesis of 7-Chloro-4- [4- (2-hydroxyethoxy) -3-methoxybenzyl] -3,4- Dihydro-1,4-benzoazepine-5 (2 Η) -one in 200 mg (0.476 mmol) of ΒΑΚ-G68 obtained in Production Example 138, 4 ml of methanol, and 2 m of 11 0% hydrogen Aqueous sodium oxide solution was stirred at room temperature for 2 hours. Dilute hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. After concentration, it was subjected to silica gel column chromatography (hexane •• ethyl acetate = 1). : 2) The crude product was purified to obtain 165 mg of the title compound (BAK-G692) in a yield of 92%.

ΒΑΚΌ687 ΒΑΚΌ692 H-NMR (CDC13) δ ： 2.89 (brs? 1H) 5 3.4 5 (t5 J = 5.3Hz, 2H) 5 3.8 5 (s? 3H)5 3.94 (brs5 2H)? 4.05 -4.20 (m? 4H)? 4.75 (s? 2H)? 6.80^ 7.00 (m; 4H)，7.36 (dd5 J = 2.7，8·7Ηζ，1H)5 7.84 (d5 J 二2.7H z, 1 H) > 116- (112) 200417367 MS (El) E/Z 3 7 7(M + ) 製造例140 合成〔4-〔 〔 7-氯-5-氧基-2，3-二氫-1，4-苯并Df吖庚因— 4(5H)-基〕甲基〕-2 -甲氧苯氧基〕乙腈 在 202.3 mg( 0.606毫莫爾）製造例 75所得 BAK-G473，167mg(1.21毫莫爾）碳酸鉀，4ml DMF中，加入 0.08 5ml ( 1.21毫莫爾）溴化乙腈，於室溫攪拌2小時。 反應液中加入水，以乙酸乙酯萃取，有機層以無水硫酸鈉 乾燥。濃縮後以矽膠管柱層析（己烷：乙酸乙酯=1 : 1 ) 精製粗生成物，以收率99%得224mg標題化合物（BAK-G6 8 9 ) 〇ΒΑΚΌ687 ΒΑΚΌ692 H-NMR (CDC13) δ: 2.89 (brs? 1H) 5 3.4 5 (t5 J = 5.3Hz, 2H) 5 3.8 5 (s? 3H) 5 3.94 (brs5 2H)? 4.05 -4.20 (m? 4H )? 4.75 (s? 2H)? 6.80 ^ 7.00 (m; 4H), 7.36 (dd5 J = 2.7, 8.7Ηζ, 1H) 5 7.84 (d5 J 2.7H z, 1 H) > 116- (112 200417367 MS (El) E / Z 3 7 7 (M +) Production Example 140 Synthesis [4- [[7-Chloro-5-oxy-2,3-dihydro-1,4-benzo Df acryl — 4 (5H) -yl] methyl] -2-methoxyphenoxy] acetonitrile in 202.3 mg (0.606 mmol) of BAK-G473 obtained in Example 75, 167 mg (1.21 mmol) of potassium carbonate, 4 ml To DMF, 0.08 5 ml (1.21 mmol) of acetonitrile bromide was added and stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. After concentrating, the crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain 224 mg of the title compound (BAK-G6 89) in a yield of 99%.

BAK-G473 BAK>G689 ^-NMR (CDC13) δ: 3.47(t5 J = 5 .0Hz5 2H)，3 · 8 8 ( s 5 3 H)，4.1 7 (t，J = 5 · 0 H z， 2H)5 4.7 7 (s5 2H)，4.83 (s5 2H) 5 6.8 8 (d d，J = 2.0, 8.1Hz? 1H)? 6.95 (d? J = 8.6Hz5 1H)? 7.00(d5 J = 2.0Hz? 1H)? 7.03(d? J = 8.1Hz? 1H) 5 7.3 7 (dd? J = 2.75 8.6Hz5 1H) 7.85 (d? 2.7Hz? 1H) MS (El) E/Z 3 72 (M + ) -117- (113) (113)200417367 製造例1 4 1 合成〔4-〔 〔7 -氯·5 -氧基-2，3 -二氫-1, 4 -苯并卩f吖庚因_ 4 (5H)-基〕甲基〕-2_甲氧苯氧基〕二氟化乙酸 在2〇〇mg ( 0.5 9 9毫莫爾）製造例75所得BAK - G473 ’ 414mg(3.00毫莫爾.）碳酸鉀，4rni DMF中，加入 〇,39ml(3.〇〇毫莫爾）溴化二氟化乙酸乙酯，於5(Γ(：攪 拌2 4小時。反應液中加入水，以乙酸乙酯萃取，有機層 以無水硫酸鈉乾燥。濃縮後以矽膠管柱層析（己烷··乙酸 乙醋=2: 1)精製粗生成物，以收率72%得i977xng乙酯 體。 在 180mg(0.395毫莫爾）此乙酯體，4ml甲醇中， 加入2ml 10%氫氧化鈉水溶液，於室溫攪拌3小時。反應 液中加入稀鹽酸，以乙酸乙酯萃取，有機層以無水硫酸鈉 乾燥。濃縮後得188mg標題化合物（BAK-G69 3 )(未精 製）BAK-G473 BAK> G689 ^ -NMR (CDC13) δ: 3.47 (t5 J = 5.0 Hz 5 2H), 3 · 8 8 (s 5 3 H), 4.1 7 (t, J = 5 · 0 H z, 2H ) 5 4.7 7 (s5 2H), 4.83 (s5 2H) 5 6.8 8 (dd, J = 2.0, 8.1Hz? 1H)? 6.95 (d? J = 8.6Hz5 1H)? 7.00 (d5 J = 2.0Hz? 1H )? 7.03 (d? J = 8.1Hz? 1H) 5 7.3 7 (dd? J = 2.75 8.6Hz5 1H) 7.85 (d? 2.7Hz? 1H) MS (El) E / Z 3 72 (M +) -117 -(113) (113) 200417367 Production Example 1 4 1 Synthesis of [4- [[7 -Chloro-5 -oxy-2,3-dihydro-1, 4-benzobenzofazepine_ 4 (5H ) -Yl] methyl] -2-methoxyphenoxy] difluoroacetic acid in 200 mg (0.5 9.9 mmol) of BAK-G473'414 mg (3.00 mmol) obtained in Preparation Example 75 To potassium and 4rni DMF, 0.39 ml (3.0 mmol) of ethyl bromide difluoride was added, and the mixture was stirred at 5 ° C (2: 4 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. After concentration, the crude product was purified by silica gel column chromatography (hexane ·· ethyl acetate = 2: 1) to obtain i977xng ethyl ester body in a yield of 72%. 180 mg (0.395 Mmol) of this ethyl ester in 4 ml of methanol, add 2 ml of 10% Aqueous sodium hydroxide solution, stirred at room temperature for 3 hours. The reaction mixture was added dilute hydrochloric acid, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate. And concentrated to give the title compound 188mg (BAK-G69 3) (unpurified) was

H-NMR (CDC13) 5 ： 3.49(t5 J = 5.2Hz5 2H)5 3.81 (s? 3H)5 4.19(t? J = 5.2Hz5 2H)5 4.7 9 (s5 2H)? 6.85(dd5 J- 1.9 5 8.1 Hz? 1H)5 6.9 6 (d5 J = 8.7H.z， 1 H)? 6.99 (d? J = 1 .9 H z 5 1 H); 7.2.1 (d? -118- (114) (114)200417367 J = 8.1Hz? 1H)? 7.39 (dd? J = 2.65 8.7Hz5 1H)? 7.83(d J = 2.6Hz? 1 H) MS (El) E/Z 427(M + ) 製造例142 合成〔4-〔 〔 7 -氣-5-氧基-2，3 -二氫-1，4 -苯并Hf吖庚因_ 4 ( 5H )-基〕甲基〕苯氧基〕乙酸甲酯 在10.00g(81.97毫莫爾）4 -羥基苯甲醛，22.62g( 163.9毫莫爾）碳酸鉀，l〇〇ml丙酮中，加入 9·3ιη1( 9 8 · 3 6毫莫爾）溴化乙酸甲酯。過濾反應液後，濃縮濾液 ，殘渣中加入水，以乙酸乙酯萃取，有機層之無水硫酸鈉 乾燥。濃縮後以矽膠管柱層析（己烷：乙酸乙酯=2 : 1 ) 精製粗生成物，以收率93 %得14.74 g ( 4-甲醯苯氧基）乙 酸甲酯（BAK-G6 8 8 )。 於室溫攪拌30分鐘2.04g(10.5毫莫爾）所得BAK-G688，20ml乙醇，2.44g(21毫莫爾）2-氯乙基胺鹽酸鹽 ，0.6ml乙酸。冰冷反應液，加入279mg(7.35毫莫爾） 氫化硼鈉，於室溫攪拌1小時。濾取析出之結晶’減壓乾 燥，得1.75g (收率57% )氯化（2-氯乙基）〔4-〔甲氧 羰基）甲氧基〕苯甲基〕銨。 冰冷1.23g(4.18毫莫爾）所得BAK-G699，12ml乙 酸乙酯，3.1ml(20.9毫莫爾）DBU，在其中滴入 Ug( 8.36毫莫爾）氯化5-氯化柳酸之16ml乙酸乙酯溶液。於 室溫攪拌4小時反應液。反應液中加入稀鹽酸’以乙酸乙 -119 - (115) (115)200417367 酯萃取，有機層以無水硫酸鈉乾燥。濃縮後以矽膠管柱層 析（己烷：乙酸乙酯=2 : 1 )精製粗生成物，以收率45% 得702.7mg標題化合物（BAK-G701)。H-NMR (CDC13) 5: 3.49 (t5 J = 5.2Hz5 2H) 5 3.81 (s? 3H) 5 4.19 (t? J = 5.2Hz5 2H) 5 4.7 9 (s5 2H)? 6.85 (dd5 J- 1.9 5 8.1 Hz? 1H) 5 6.9 6 (d5 J = 8.7Hz, 1 H)? 6.99 (d? J = 1. 9 H z 5 1 H); 7.2.1 (d? -118- (114) (114) 200417367 J = 8.1Hz? 1H)? 7.39 (dd? J = 2.65 8.7Hz5 1H)? 7.83 (d J = 2.6Hz? 1 H) MS (El) E / Z 427 (M +) Manufacturing Example 142 Synthesis (4) -[[7 -Ga-5-oxy-2,3-dihydro-1,4- benzoHfazepine-4 (5H) -yl] methyl] phenoxy] methyl acetate in 10.00g (81.97 mmoles) 4-hydroxybenzaldehyde, 22.62 g (163.9 mmoles) of potassium carbonate, 100 ml of acetone, and 9.3 μηι (98.36 mmoles) of methyl bromide were added. After the reaction solution was filtered, the filtrate was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. After concentrating, the crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain 14.74 g (4-formamylphenoxy) methyl acetate (BAK-G6 8 in 93% yield). 8 ). Stir at room temperature for 30 minutes. 2.04 g (10.5 mmol) of the obtained BAK-G688, 20 ml of ethanol, 2.44 g (21 mmol) of 2-chloroethylamine hydrochloride, 0.6 ml of acetic acid. The reaction solution was ice-cooled, and 279 mg (7.35 mmol) of sodium borohydride was added, followed by stirring at room temperature for 1 hour. The precipitated crystals were filtered and dried under reduced pressure to obtain 1.75 g (yield: 57%) of (2-chloroethyl) chloride [4- [methoxycarbonyl) methoxy] benzyl] ammonium. 1.23 g (4.18 mmoles) of BAK-G699, 12 ml of ethyl acetate, 3.1 ml (20.9 mmoles) of DBU, and 16 ml of Ug (8.36 mmoles) of chlorinated 5-chlorosalicylic acid were added dropwise thereto. Ethyl acetate solution. The reaction solution was stirred at room temperature for 4 hours. Dilute hydrochloric acid 'was added to the reaction solution, followed by extraction with ethyl acetate -119-(115) (115) 200417367, and the organic layer was dried over anhydrous sodium sulfate. After concentration, the crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain 702.7 mg of the title compound (BAK-G701) in a yield of 45%.

BAK-G699 BAK-G701 ^-NMR (CDC 15) δ : 3.43 (t5 J = 5.1Hz? 2H)5 3.81 (s5 3H)5 4.1 5 (t5 J-5.1Hz? 2H)5 4.64 (s? 2H)? 4.75(s? 2H)? 6.89(d5 J = 8.7Hz9 2H)5 6.93(d? J = 8.6Hz? 1H) 7.28(d，J = 8.7Hz，2H)? 7.35 (dd? J = 2.7? 8.6Hz5 1H) 5 7.8 5 (d3 J = 2.7Hz? 1H) MS (El) E/Z 3 75 (M + ) 製造例143 合成〔5-〔 〔 7-氯·5-氧基-2，3-二氫-1，4-苯并Df吖庚因- 4 (5H)-基〕甲基〕-2-甲氧苯氧基〕乙酸甲酯 與製造例142 —樣之方法，得標題化合物（BAK-G7 02 )。 -120 - (116) 200417367BAK-G699 BAK-G701 ^ -NMR (CDC 15) δ: 3.43 (t5 J = 5.1Hz? 2H) 5 3.81 (s5 3H) 5 4.1 5 (t5 J-5.1Hz? 2H) 5 4.64 (s? 2H) 4.75 (s? 2H)? 6.89 (d5 J = 8.7Hz9 2H) 5 6.93 (d? J = 8.6Hz? 1H) 7.28 (d, J = 8.7Hz, 2H)? 7.35 (dd? J = 2.7? 8.6 Hz5 1H) 5 7.8 5 (d3 J = 2.7Hz? 1H) MS (El) E / Z 3 75 (M +) Production Example 143 Synthesis [5- [[7-chloro · 5-oxy-2,3- Dihydro-1,4-benzo Dfazepine-4 (5H) -yl] methyl] -2-methoxyphenoxy] methyl acetate was prepared in the same manner as in Preparation Example 142 to give the title compound (BAK -G7 02). -120-(116) 200417367

'H-NMR (CD C 1 3) δ : 3.42(t，J = 5.0Hz, 2H)5 3.76(s，3H)，3.88(s，3H)，4.12〇, J = 5.0Hz? 2H)5 4.7 0 (s? 2H)? 4.72(s? 2H)5 6.8 0 - 6.9 3 (m, 3H)，6.93 (d，J = 8.7Hz5 1H)，7.36 (dd，J = 2.7，8.7Hz， 1H)? 7.84 (d? J = 2.7Hz? 1H) MS (El) E/Z 405 (M + ) 製造例144 合成〔4-〔 〔 7 -氯-5-氧基-2，3_二氫-i，4_苯并鸣吖庚因_ 4(5H)-基〕甲基〕苯氧基〕乙酸 與製造例68 —樣之方法，得標題化合物（BAK-G703 °'H-NMR (CD C 1 3) δ: 3.42 (t, J = 5.0Hz, 2H) 5 3.76 (s, 3H), 3.88 (s, 3H), 4.12〇, J = 5.0Hz? 2H) 5 4.7 0 (s? 2H)? 4.72 (s? 2H) 5 6.8 0-6.9 3 (m, 3H), 6.93 (d, J = 8.7Hz5 1H), 7.36 (dd, J = 2.7, 8.7Hz, 1H)? 7.84 (d? J = 2.7 Hz? 1H) MS (El) E / Z 405 (M +) Production Example 144 Synthesis [4- [[7 -Chloro-5-oxy-2,3_dihydro-i, 4-Benzoazepine_4 (5H) -yl] methyl] phenoxy] acetic acid was prepared in the same manner as in Preparation Example 68 to obtain the title compound (BAK-G703 °

ΟΟ

BAK-G703 ^-NMR (CDC13) (5 : 3.44 (t5 J = 5.0Hz; 2H); 4.15 (t5 J = 5.0Hz 2H)? 4.66 (s? 2H); 4.76 (s; 2H); 6.9〇 (d； j = 8.7Hz; 2H), 6.93 (d; -121 - (117) 200417367 J = 8.7Hz5 1H)? 7.28 (d， J = 8.7Hz? 2H)5 7.36 (dd? J = 2.7, 8.7Hz5 1H) 5 7.8 5 (d? J = 2.7Hz5 1H) MS (El ) E/Z 361 (M + ) 製造例145 合成 2-〔4-〔 〔7 -氯-5-氧基-2，3 -二氫-1，4 -苯并卩f吖庚 因- 4(5H)-基〕甲基〕-2-甲氧苯氧基〕甲基乙醯胺BAK-G703 ^ -NMR (CDC13) (5: 3.44 (t5 J = 5.0Hz; 2H); 4.15 (t5 J = 5.0Hz 2H)? 4.66 (s? 2H); 4.76 (s; 2H); 6.9〇 ( d; j = 8.7Hz; 2H), 6.93 (d; -121-(117) 200417367 J = 8.7Hz5 1H)? 7.28 (d, J = 8.7Hz? 2H) 5 7.36 (dd? J = 2.7, 8.7Hz5 1H) 5 7.8 5 (d? J = 2.7Hz5 1H) MS (El) E / Z 361 (M +) Production Example 145 Synthesis of 2- [4- [[7 -Chloro-5-oxy-2,3- Dihydro-1,4-benzofluorene fazepine-4 (5H) -yl] methyl] -2-methoxyphenoxy] methylacetamide

於室溫攪拌3 0分鐘1 · 0 1 g ( 2 · 5 8毫莫爾）製造例7 7 所得 BAK-G47 5，1 .35ml ( 7.74 毫莫爾）DIEA，627mg ( 3.87毫莫爾）1，1’-羰基二咪唑，20ml DMF。反應液中加 入351mg ( 5.16毫莫爾）甲基胺鹽酸鹽，於室溫攪拌30 分鐘。反應液中加入稀鹽酸，以乙酸乙酯萃取，有機層以 無水硫酸鈉乾燥。濃縮後以矽膠管柱層析（乙酸乙酯）精 製粗生成物，以收率86%得8 93.9mg標題化合物（BAK-G719 )。Stir at room temperature for 30 minutes. 1.01 g (2.88 mmol) of Production Example 7 BAK-G47 5, 1.35 ml (7.74 mmol) DIEA, 627 mg (3.87 mmol) 1 , 1'-carbonyldiimidazole, 20 ml DMF. To the reaction solution was added 351 mg (5.16 mmol) of methylamine hydrochloride, and the mixture was stirred at room temperature for 30 minutes. Dilute hydrochloric acid was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After concentration, the crude product was purified by silica gel column chromatography (ethyl acetate) to obtain 8 93.9 mg of the title compound (BAK-G719) in a yield of 86%.

BAKG475 BAK-G719BAKG475 BAK-G719

]h-nmr (CDCls) 5 : 2.91 (d5 J = 5.0Hz? 3H)? 3.46(t? J = 5.0Hz, 2H)? 3.88 (s5 3H)，4.16 (t，J = 5.0.Hz，2H)，4.52 (s，2H)，4.76 (s， 2H); 6.80-7.00 (m, 5H)，7.37 (dd，J = 2.7，8·6Ηζ，1H)， -122- (118) 200417367 7.85 (d，J = 2.7Hz5 1H) MS (El) E/Z 404 (M + ) 製造例1 4 6 合成〔2-甲氧基-4-〔 〔7-甲氧基-5-氧基-2，3-二氫-1，4- 苯并噚吖庚因-4 ( 5H )-基〕甲基〕-苯氧基〕乙酸甲酯] h-nmr (CDCls) 5: 2.91 (d5 J = 5.0Hz? 3H)? 3.46 (t? J = 5.0Hz, 2H)? 3.88 (s5 3H), 4.16 (t, J = 5.0.Hz, 2H) , 4.52 (s, 2H), 4.76 (s, 2H); 6.80-7.00 (m, 5H), 7.37 (dd, J = 2.7, 8.6Ηζ, 1H), -122- (118) 200417367 7.85 (d, J = 2.7Hz5 1H) MS (El) E / Z 404 (M +) Production Example 1 4 6 Synthesis of [2-methoxy-4- [[7-methoxy-5-oxy-2,3- Dihydro-1,4-benzopyreneazepine-4 (5H) -yl] methyl] -phenoxy] acetic acid methyl ester

與製造例 142 —樣之方法，得標題化合物（BAK-G706 )。The title compound (BAK-G706) was obtained in the same manner as in Production Example 142.

】Η-ΝΜΙΙ (CDC13) (5 ：Η-NMIL (CDC13) (5:

3.42 (t? J = 5.5Hz? 2H)? 3.80 (s5 3H) 5 3.8 3 (s? 3H) 3.88 (s5 3H)? 4.07 (t? J = 5.5Hz5 2H)5 4.7 0 (s? 2H)? 4.77 (s5 2H)5 6.7 5 - 7.0 0 (m，5H) 7.3 1 (dd，J = 0.45 2.5 Hz? 1H) MS (El) E/Z 401 (M + ) 製造例147 合成〔2 -甲氧基-4-〔〔 7 -甲基-5-氧基-2，3 -二氫-1，4 -苯 并噚吖庚因-4 ( 5H)-基〕甲基〕-苯氧基〕乙酸甲酯 與製造例142 —樣之方法，得標題化合物（BAK-G 7 0 8 )。 -123 - (119) (119)2004173673.42 (t? J = 5.5Hz? 2H)? 3.80 (s5 3H) 5 3.8 3 (s? 3H) 3.88 (s5 3H)? 4.07 (t? J = 5.5Hz5 2H) 5 4.7 0 (s? 2H)? 4.77 (s5 2H) 5 6.7 5-7.0 0 (m, 5H) 7.3 1 (dd, J = 0.45 2.5 Hz? 1H) MS (El) E / Z 401 (M +) Production Example 147 Synthesis [2-Methoxy 4-([7-methyl-5-oxy-2,3-dihydro-1,4-benzobenzoazepine-4 (5H) -yl] methyl] -phenoxy] acetic acid The methyl ester was prepared in the same manner as in Preparation Example 142 to obtain the title compound (BAK-G 7 0 8). -123-(119) (119) 200417367

'H-NMR (CDC13) δ : 2.35(s? 3H) 5 3.4 2 (t5 J = 5.3Hz? 2H)? 3.80(s5 3H)? 3.88(s? 3H)? 4.11 (t5 J = 5.3Hz，2H)，4.69(s? 2H)，4.76 (s，2H)? 6.77 (d5 J = 8. 1 Hz? 1 H)? 6.80 (dd? J=1.7，8.1Hz? 1H)? 6.89 (d，J=8.3.Hz，1H)5 6.9 7 (d，J=1.7Hz，1H)，7.22 (dd5 J = 2.1 5 8.3Hz5 1H)，7.63 (d5 J = 2·1Ηζ5 1H) MS (El) E/Z 3 8 5 (M + ) 製造例1 4 8 合成〔4-〔 〔 8-氯-5-氧基_2，3-二氫-1，4-苯并Hf吖庚因- 4(5H)-基〕甲基〕-2-甲氧苯氧基〕乙酸甲酯 與製造例 142 —樣之方法，得標題化合物（BAK-G7 1 0 )。'H-NMR (CDC13) δ: 2.35 (s? 3H) 5 3.4 2 (t5 J = 5.3Hz? 2H)? 3.80 (s5 3H)? 3.88 (s? 3H)? 4.11 (t5 J = 5.3Hz, 2H ), 4.69 (s? 2H), 4.76 (s, 2H)? 6.77 (d5 J = 8. 1 Hz? 1 H)? 6.80 (dd? J = 1.7, 8.1Hz? 1H)? 6.89 (d, J = 8.3.Hz, 1H) 5 6.9 7 (d, J = 1.7Hz, 1H), 7.22 (dd5 J = 2.1 5 8.3Hz5 1H), 7.63 (d5 J = 2 · 1Ηζ5 1H) MS (El) E / Z 3 8 5 (M +) Production Example 1 4 8 Synthesis of [4- [[8-Chloro-5-oxy_2,3-dihydro-1,4-benzoHfazepine-4 (5H) -yl ] Methyl] -2-methoxyphenoxy] methyl acetate was prepared in the same manner as in Production Example 142 to give the title compound (BAK-G7 1 0).

BAK-G710 H-NMR (CDC13) δ: > 124- (120) (120)200417367 3.46(t，J = 5.2Hz，2H)，3.80(s，3H) 5 3.8 7 (s，3H)，4.18(t5 J = 5.2Hz? 2H)5 4.7 0 (s? 2H)? 4.75(s5 2H)? 6.7 0- 6.8 5 (m? 2H)? 6.94 (d5 J=1.6Hz? 1H)5 7.01 (d5 J = 2.0Hz? 1H)5 7.15(dd? J = 2.0? 8.4Hz? 1H)? 7.84 (d5 J = 8.4Hz? 1H) MS (El) E/Z 405 (M + ) 製造例149 合成〔2-甲氧基-4-〔 〔5-氧基-2，3-二氫-1，4-苯并哼吖 庚因- 4(5H)-基〕甲基〕苯氧基〕乙酸甲酯 與製造例142 —樣之方法，得標題化合物（BAK-G7 16) 〇BAK-G710 H-NMR (CDC13) δ: > 124- (120) (120) 200417367 3.46 (t, J = 5.2Hz, 2H), 3.80 (s, 3H) 5 3.8 7 (s, 3H), 4.18 (t5 J = 5.2Hz? 2H) 5 4.7 0 (s? 2H)? 4.75 (s5 2H)? 6.7 0- 6.8 5 (m? 2H)? 6.94 (d5 J = 1.6Hz? 1H) 5 7.01 (d5 J = 2.0Hz? 1H) 5 7.15 (dd? J = 2.0? 8.4Hz? 1H)? 7.84 (d5 J = 8.4Hz? 1H) MS (El) E / Z 405 (M +) Manufacturing Example 149 Synthesis (2- Methoxy-4-[[5-oxy-2,3-dihydro-1,4-benzylazepine-4 (5H) -yl] methyl] phenoxy] acetic acid methyl ester and manufacture Example 142-The same method as the above, to give the title compound (BAK-G7 16).

BAKG716 ^-NMR (CDC13) δ: 3.45(t5 J = 5.4Hz，2Η)，3,80(s，3H)5 3.8 7 (s，3Η)5 4.15 (t? J = 5.4Hz5 2H)5 4.7 0 (s5 2H)? 4.77 (s5 2H) 5 6.7 8 (d5 J = 8.1Hz，1H) 5 6.8 4 (d d? J =1 .7, 8.1Hz? 1H)? 6.97 (d5 J=1.7Hz, 1H)? 6.99 (dd? J=1.8? 7.7 Hz, 1H)? 7.19 (dt5 1.8，7·7 Hz5 1H) 5 7.4 3 (dt，J= 1.8 5 7·7Ηζ，1H)，7.86 (dd5 J=1.8? 7.7Hz5 1H) MS (El) E/Z 371 (M + ) -125- (121) 200417367 製造例1 5 0 合成〔2 -甲氧基-4-〔〔 7 -甲氧基-5-氧基-2，3 - 一·氯-1，4_ 苯并噚吖庚因-4 ( 5H )-基〕甲基〕-苯氧基〕乙酸 與製造例68 —樣之方法，得標題化合物（BAK-G711BAKG716 ^ -NMR (CDC13) δ: 3.45 (t5 J = 5.4Hz, 2Η), 3,80 (s, 3H) 5 3.8 7 (s, 3Η) 5 4.15 (t? J = 5.4Hz5 2H) 5 4.7 0 (s5 2H)? 4.77 (s5 2H) 5 6.7 8 (d5 J = 8.1Hz, 1H) 5 6.8 4 (dd? J = 1.7, 8.1Hz? 1H)? 6.97 (d5 J = 1.7Hz, 1H) ? 6.99 (dd? J = 1.8? 7.7 Hz, 1H)? 7.19 (dt5 1.8, 7 · 7 Hz5 1H) 5 7.4 3 (dt, J = 1.8 5 7 · 7Ηζ, 1H), 7.86 (dd5 J = 1.8? 7.7Hz5 1H) MS (El) E / Z 371 (M +) -125- (121) 200417367 Production Example 1 5 0 Synthesis of [2-methoxy-4-[[7-methoxy-5-oxy -2,3 -monochloro-1,4-benzobenzoazepine-4 (5H) -yl] methyl] -phenoxy] acetic acid was prepared in the same manner as in Production Example 68 to obtain the title compound (BAK- G711

BAK-G706 BAK-G711 iH-NMR (DMSO-d6) δ: 3.44 (t? J = 5.2Hz? 2H) 5 3.7 6 (s5 6H)? 4.11 (t5 J = 5.2Hz5 2H)? 4.63 (s5 2H)? 4.66 (s? 2H)5 6.8 0- 7.0 0 (m5 4H)5BAK-G706 BAK-G711 iH-NMR (DMSO-d6) δ: 3.44 (t? J = 5.2Hz? 2H) 5 3.7 6 (s5 6H)? 4.11 (t5 J = 5.2Hz5 2H)? 4.63 (s5 2H) ? 4.66 (s? 2H) 5 6.8 0- 7.0 0 (m5 4H) 5

7.05 (dd，J = 2.8，8.8Hz，1H)? 7.14 (d5 J = 2.8Hz，1H). MS( E I) E/Z 3 8 7 (M + ) 製造例1 5 1 合成〔2-甲氧基-4-〔 〔7-甲基-5-氧基-2，3-二氫-1，4-苯 并哼吖庚因-4 ( 5H)-基〕甲基〕苯氧基〕乙酸 與製造例68 —樣之方法，得標題化合物（BAK-G712 -126- (122) (122)2004173677.05 (dd, J = 2.8, 8.8Hz, 1H)? 7.14 (d5 J = 2.8Hz, 1H). MS (EI) E / Z 3 8 7 (M +) Production Example 1 5 1 Synthesis [2-methoxy Methyl-4-[[7-methyl-5-oxy-2,3-dihydro-1,4-benzoazepine-4 (5H) -yl] methyl] phenoxy] acetic acid and Preparation Example 68: The same method as described above was used to obtain the title compound (BAK-G712 -126- (122) (122) 200417367

BAK-G708 BAK-G712 ^-NMR (DMSO-d6) δ: 2.30 (s? 3H)? 3.45 (t5 J = 5„1Hz5 1H)? 3.76 (s5 3H)5 4.15 (t? J = 5.1Hz? 2H) 5 4.6 3 (s5 2 H)? 4.66 (s? 2 H)? 6.83 (brs，2H)， 6.92 (d5 J=8.2Hz， 1H)， 6.98 (brs， 1H)， 7.27(dd，J = 2.1，8.2Hz? 1H)，7 · 4 7 ( d，J = 2.1 Η z 5 1H) MS (El) E/Z 371 (M + ) 製造例1 5 2 合成〔4-〔 〔 8 -氯-5-氧基-2，3 -二氫-1，4 -苯并Df吖庚因· 4(5H)-基〕甲基〕-2-甲氧苯氧基〕乙酸 與製造例68 —樣之方法，得標題化合物（BAK-G713BAK-G708 BAK-G712 ^ -NMR (DMSO-d6) δ: 2.30 (s? 3H)? 3.45 (t5 J = 5 „1Hz5 1H)? 3.76 (s5 3H) 5 4.15 (t? J = 5.1Hz? 2H ) 5 4.6 3 (s5 2 H)? 4.66 (s? 2 H)? 6.83 (brs, 2H), 6.92 (d5 J = 8.2Hz, 1H), 6.98 (brs, 1H), 7.27 (dd, J = 2.1 , 8.2Hz? 1H), 7 · 4 7 (d, J = 2.1 Η z 5 1H) MS (El) E / Z 371 (M +) Production Example 1 5 2 Synthesis [4- [[8 -chloro-5 -Oxy-2,3-dihydro-1,4-benz Dfazepine · 4 (5H) -yl] methyl] -2-methoxyphenoxy] acetic acid was the same as in Production Example 68. To give the title compound (BAK-G713

BAK-G710 BAK-G713 WNMR (DMSO-d6) δ: 3.52 (t5 J = 5.0Hz5 2H), 3.76 (s； 3H)? 4.24 (t? J = 5.0Hz, -127 - (123) 200417367 2H)，4·63 (s5 2H)，4.66 (s，2H)，6.83 (brs5 2 Η), 6·97 (brs，1H)，7.13 (d5 J =2·1Ηζ，1H)，7.24 (dd5 J = 2.1， 8.4Hz，1H)，7.74(d，J = 8.4Hz5 1H) MS (El) E/Z 391 (M + ) 製造例1 5 3 合成〔2 -甲氧基-4-〔 〔 5 -氧基，3·二氫q，4_苯并哼吖 庚因_4(5H)-基〕甲基〕苯氧基〕乙酸 與製造例68 —樣之方法，得標題化合物（BAK-G717BAK-G710 BAK-G713 WNMR (DMSO-d6) δ: 3.52 (t5 J = 5.0Hz5 2H), 3.76 (s; 3H)? 4.24 (t? J = 5.0Hz, -127-(123) 200417367 2H), 4.63 (s5 2H), 4.66 (s, 2H), 6.83 (brs5 2 Η), 6.97 (brs, 1H), 7.13 (d5 J = 2 · 1Ηζ, 1H), 7.24 (dd5 J = 2.1, 8.4Hz, 1H), 7.74 (d, J = 8.4Hz5 1H) MS (El) E / Z 391 (M +) Production Example 1 5 3 Synthesis of [2-methoxy-4- [[5-oxy, 3. Dihydroq, 4-benzobenzepine_4 (5H) -yl] methyl] phenoxy] acetic acid was prepared in the same manner as in Preparation Example 68 to obtain the title compound (BAK-G717

^-NMR (DMSO-d6) δ: 3.48(t5 J = 5.0Hz? 2H)5 3.7 6 (s5 3H)5 4.19(t5 J = 5.0Hz? 2H)，4.63 (s，2H)，4.67 (s，2h) 5 6.8 3 (brs5 2H), 6·98 (brs5 1H)，7.03 (dd，J=i 8，7 7Ηζ，ih)，7.19 (dt5 J = 1.8，7.7Hz，1H)，7.47 ⑷，J=l.8 5 7.7 Hz，1H)，7.70 (dd，J=1 .8，7.7Hz，1H) MS (El) E/Z 3 5 7(M + ) 製造例1 5 4 -128- (124) 200417367 合成 4-〔 4-(苯甲氧基）-3 -甲氧苯甲基〕-7-氯-1，4-苯 并哼吖庚因-3，5 ( 2H，4H )-二酮 冰冷下，在8 1 0.9mg ( 2.04毫莫爾）製造例43所得 BAK-G395，113g(8.16 毫莫爾）碳酸鉀，l6mlDMF 中， 滴下1.13g(8.16毫莫爾）氯乙醯基氯，於室溫攪拌2小 時，40 °C攪拌20小時。反應液中加入水，以乙酸乙酯萃 取，有機層以無水硫酸鈉乾燥。濃縮後以矽膠管柱層析（ 己烷：乙酸乙酯=4 : 1 )精製粗生成物，以收率 84%得 7 5 4.3 mg 標題化合物（BAK-G695 )。^ -NMR (DMSO-d6) δ: 3.48 (t5 J = 5.0Hz? 2H) 5 3.7 6 (s5 3H) 5 4.19 (t5 J = 5.0Hz? 2H), 4.63 (s, 2H), 4.67 (s, 2h) 5 6.8 3 (brs5 2H), 6.98 (brs5 1H), 7.03 (dd, J = i 8, 7 7Ηζ, ih), 7.19 (dt5 J = 1.8, 7.7Hz, 1H), 7.47 ⑷, J = l.8 5 7.7 Hz, 1H), 7.70 (dd, J = 1 .8, 7.7Hz, 1H) MS (El) E / Z 3 5 7 (M +) Manufacturing Example 1 5 4 -128- (124 200417367 Synthesis of 4- [4- (Benzyloxy) -3 -methoxybenzyl] -7-chloro-1,4-benzoazepine-3,5 (2H, 4H) -dione Under ice-cooling, 1.13 g (8.16 mmol) of chloroacetamidyl chloride was dripped into 8 1 0.9 mg (2.04 mmol) of BAK-G395 obtained in Production Example 43, 113 g (8.16 mmol) of potassium carbonate, and 16 ml of DMF. Stir at room temperature for 2 hours and 40 ° C for 20 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. After concentration, the crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain 7 5 4.3 mg of the title compound (BAK-G695) in a yield of 84%.

Ο BAK-G395 BAK-G695 ]Η-ΝΜΚ (CDC13) δ: 3.88(s5 3H) 5 4.7 6 (s? 2H)5 5.11 (s? 2H)5 5.12(s? 2H)5 6.79 (d5 J = 8.3Hz5 1 H) 5 6.8 5 -7.1 0 (m? 3H)5 7.25 - 7.5 0 (m5 6H)，8.13 (d，J = 2.6Hz，1H) MS (El) E/Z 43 7 (M + ) 製造例1 5 5 合成7-氯-4- (4-羥基-3-甲氧苯甲基）-1，4-苯并鸣吖庚 因-3，5 ( 2H，4H )-二酮 在 7 46.3mg ( 1.70毫莫爾）製造例154所得BAK-G695，15ml乙酸乙酯中，加入74mg 10% Pd-C，氫氣氛 -129- (125) 200417367 下，於室溫攪拌2小時。以矽藻土過濾反應液後，濃縮濾 ，得6 5 8.3 mg標題化合物（BAK-G696 )(未精製）。〇 BAK-G395 BAK-G695] Η-NMK (CDC13) δ: 3.88 (s5 3H) 5 4.7 6 (s? 2H) 5 5.11 (s? 2H) 5 5.12 (s? 2H) 5 6.79 (d5 J = 8.3 Hz5 1 H) 5 6.8 5 -7.1 0 (m? 3H) 5 7.25-7.5 0 (m5 6H), 8.13 (d, J = 2.6Hz, 1H) MS (El) E / Z 43 7 (M +) Manufacturing Example 1 5 5 Synthesis of 7-Chloro-4- (4-hydroxy-3-methoxybenzyl) -1,4-benzopyreneazepine-3,5 (2H, 4H) -dione at 7 46.3 mg (1.70 mmol) of BAK-G695 obtained in Production Example 154, 15 ml of ethyl acetate, 74 mg of 10% Pd-C, hydrogen atmosphere -129- (125) 200417367 were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was filtered through celite and concentrated to obtain 6 5 8.3 mg of the title compound (BAK-G696) (unrefined).

】H-NMR (CDC13) δ: 3.88(s? 3H)? 4.76(s? 2H)? 5.11 (s? 2H)? 5.58(s? 1H)? 6.80-7.10 (m3 4H)5 7.44 (dd5 J = 2.65 8.7 Hz5 1H)5 8.13 (d5 J = 2.6Hz，1H) MS (El) E/Z 347 (M + ) 製造例1 5 6 合成〔4-〔 〔7-氯-3，5-二氧基-2，3-二氫-1，4-苯并曙吖 庚因-4(5H)-基〕甲基〕-2-甲氧苯氧基〕乙酸苯甲酯 於640mg ( 1.84毫莫爾）製造例155所得BAK-G696 ，508mg.(3.68毫莫爾）碳酸鉀，l〇ml DMF中，加入 0.5 8ml ( 3.68毫莫爾）溴代乙酸苯甲酯，於室溫攪拌3小 時。反應液中加入水，以乙酸乙酯萃取，有機層以無水硫 酸鈉乾燥。濃縮後以矽膠管柱層析（己烷：乙酸乙酯=2 : 1 )精製粗生成物，以收率81%得7 3 7mg標題化合物（ BAK-G722 )。 > 130- (126) (126)200417367】 H-NMR (CDC13) δ: 3.88 (s? 3H)? 4.76 (s? 2H)? 5.11 (s? 2H)? 5.58 (s? 1H)? 6.80-7.10 (m3 4H) 5 7.44 (dd5 J = 2.65 8.7 Hz5 1H) 5 8.13 (d5 J = 2.6Hz, 1H) MS (El) E / Z 347 (M +) Production Example 1 5 6 Synthesis of [4- [[7-chloro-3,5-dioxy -2,3-dihydro-1,4-benzoazepine-4 (5H) -yl] methyl] -2-methoxyphenoxy] phenylacetate in 640 mg (1.84 mmol) BAK-G696 obtained in Preparation Example 155, 508 mg. (3.68 mmoles) of potassium carbonate, 10 ml of DMF, 0.5 8 ml (3.68 mmoles) of benzyl bromoacetate were added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After concentration, the crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain 7 37 mg of the title compound (BAK-G722) in a yield of 81%. > 130- (126) (126) 200417367

】H-NMR (CDC13) δ: 3.85(s5 3H)? 4.70(s? 2H)5 4.7 7(s5 2H)? 5.12(s5 2H)? 5.21 (s5 2H)，6.71(d，J = 8.2Hz，1 H) 5 6 · 9 3 (d d 5 J = 8 · 2， 2.0Hz，1 H), 7.04 (d，J = 2.0Hz，1H)? 7.05(d? J = 8.7Hz5 1 H)? 7.25-7.40(m，5H)，7.45(dd，J = 2.75 8·7Ηζ，1H)， 8. 1 3(d5 J =2·6Ηζ5 1H) MS (El) E/Z 495 (M + ) 製造例1 5 7 合成〔4-〔 〔7-氯-3，5-二氧基-2，3-二氫-1，4-苯并卩琴吖 庚因- 4(5H)-基〕甲基〕-2-甲氧苯氧基〕乙酸 在720mg ( 1.45毫莫爾）製造例155所得BAK-G722 ，10ml乙酸乙酯中加入70mg 10% Pd-C，氫氣氛下於室 溫攪拌2小時。以矽藻土過濾反應液，濃縮濾液，殘渣則 自乙醇予以再結晶，得3 04.8 mg (收率52% )標題化合物 (B AK-G723 )。 (127) 200417367 Λ Λ] H-NMR (CDC13) δ: 3.85 (s5 3H)? 4.70 (s? 2H) 5 4.7 7 (s5 2H)? 5.12 (s5 2H)? 5.21 (s5 2H), 6.71 (d, J = 8.2Hz, 1 H) 5 6 · 9 3 (dd 5 J = 8 · 2, 2.0Hz, 1 H), 7.04 (d, J = 2.0Hz, 1H)? 7.05 (d? J = 8.7Hz5 1 H)? 7.25- 7.40 (m, 5H), 7.45 (dd, J = 2.75 8 · 7Ηζ, 1H), 8. 1 3 (d5 J = 2 · 6Ηζ5 1H) MS (El) E / Z 495 (M +) Manufacturing Example 1 5 7 Synthesis of [4- [[7-Chloro-3,5-dioxy-2,3-dihydro-1,4-benzopyreneazepine-4 (5H) -yl] methyl] -2 -Methoxyphenoxy] acetic acid was added to 720 mg (1.45 mmol) of BAK-G722 obtained in Production Example 155, 70 mg of 10% Pd-C was added to 10 ml of ethyl acetate, and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The reaction solution was filtered through celite, and the filtrate was concentrated. The residue was recrystallized from ethanol to obtain 304.8 mg (yield 52%) of the title compound (B AK-G723). (127) 200417367 Λ Λ

BAK-G722 BAK-G723 iH-NMR (DMSO-d6) δ: 3.73(s，2Η)，4.60(s，2H), 5.00(s，4H)，6.75(brs，2H)5 6.93 (brs? 1H)，7.25 (d，J = 8.7Hz，1H)，7.68 (dd，J = 2.7? 8.7Hz? 1H)，8.01 (d5 J = 2.7Hz, 1 H)5 13.00 (brs? 1H) MS (El) E/Z 405 (M + ) 製造例1 5 8 合成〔〔2-(4-氯苯基）乙基〕〔（3，5-二氯-2-羥苯基 )硕基〕胺基〕乙酸甲酯 與製造例 1 14 一樣之方法，得標題化合物（BAK-KA424 )。BAK-G722 BAK-G723 iH-NMR (DMSO-d6) δ: 3.73 (s, 2Η), 4.60 (s, 2H), 5.00 (s, 4H), 6.75 (brs, 2H) 5 6.93 (brs? 1H) , 7.25 (d, J = 8.7Hz, 1H), 7.68 (dd, J = 2.7? 8.7Hz? 1H), 8.01 (d5 J = 2.7Hz, 1 H) 5 13.00 (brs? 1H) MS (El) E / Z 405 (M +) Production Example 1 5 8 Synthesis of [[2- (4-chlorophenyl) ethyl] [(3,5-dichloro-2-hydroxyphenyl) sulfonyl] amino] methyl acetate The ester was prepared in the same manner as in Preparation Example 14 to obtain the title compound (BAK-KA424).

BAK-KA424 ]H-NMR (CDC13) δ: 2.83 (t5 J = 7.1Hz5 2H)5 3.4 9 (t? J = 7.1Hz5 2H) 5 3.7 0 (s; 3H), 4.34 (s? 2H); 7.04 (d，J = 8.4Hz, 2H) 7.2 1 (d? -132 - (128) (128)200417367 J = 8.4 Hz，2 H)，7.5 1 (d5 J =2·5 Ηζ，1Η)，7·53 (d，J = 2.5 Hz, 1H) MS (El) E/Z 451 (M)，4 5 3 (M + 2)，4 5 5 (M + 4) 製造例1 5 9 合成 3，5-二氯-N-〔 2-(3，4-二甲氧苯基）乙基〕-2-羥 基-N-(吲哚-3-基甲基）苯磺醯胺 與製造例114 一樣之方法，得標題化合物（BAK-KA42 5 )。BAK-KA424] H-NMR (CDC13) δ: 2.83 (t5 J = 7.1Hz5 2H) 5 3.4 9 (t? J = 7.1Hz5 2H) 5 3.7 0 (s; 3H), 4.34 (s? 2H); 7.04 (d, J = 8.4 Hz, 2H) 7.2 1 (d? -132-(128) (128) 200417367 J = 8.4 Hz, 2 H), 7.5 1 (d5 J = 2 · 5 Ηζ, 1Η), 7 · 53 (d, J = 2.5 Hz, 1H) MS (El) E / Z 451 (M), 4 5 3 (M + 2), 4 5 5 (M + 4) Production Example 1 5 9 Synthesis 3, 5- Dichloro-N- [2- (3,4-dimethoxyphenyl) ethyl] -2-hydroxy-N- (indol-3-ylmethyl) benzenesulfonamide was prepared in the same manner as in Production Example 114 To give the title compound (BAK-KA42 5).

BAK-KA425 ^-NMR CDC13) δ: 2.67(t? J = 7.3Hz? 2H)? 3.45(t5 J = 7.3Hz5 2H)? 3.78 (s5 3H) 5 3.8 3 (s5 3H)，6.44 (d5 J=1.9Hz，1H) 5 6.5 3 (dd5 J= 1.9 5 8.1 Hz5 1H)? 6.71 (d5 J = 8.1Hz5 1H)5 7.10-7.41 (m，7H)，8.16 (brs5 1H)，9.27 (brs5 1H) MS (El) E/Z 5 3 4 (M) 5 5 3 6 (M + 2) 製造例1 6 0 合成〔〔2-( 4-氯苯基）乙基〕〔3，5-二氯-2-羥苯基） 碼基〕胺基〕乙酸 -133- (129) 200417367 與製造例116 —樣之方法，得標題化合物（BAK-KA426 )。BAK-KA425 ^ -NMR CDC13) δ: 2.67 (t? J = 7.3Hz? 2H)? 3.45 (t5 J = 7.3Hz5 2H)? 3.78 (s5 3H) 5 3.8 3 (s5 3H), 6.44 (d5 J = 1.9Hz, 1H) 5 6.5 3 (dd5 J = 1.9 5 8.1 Hz5 1H)? 6.71 (d5 J = 8.1Hz5 1H) 5 7.10-7.41 (m, 7H), 8.16 (brs5 1H), 9.27 (brs5 1H) MS (El) E / Z 5 3 4 (M) 5 5 3 6 (M + 2) Production Example 1 6 0 Synthesis of [[2- (4-chlorophenyl) ethyl] [3,5-dichloro-2 -Hydroxyphenyl) code group] amino group] acetic acid-133- (129) 200417367 The same method as in Production Example 116 was used to obtain the title compound (BAK-KA426).

ΒΑΚ-ΚΑ426 V V。、 a ο ΒΑΚ-ΚΑ424ΒΑΚ-ΚΑ426 V V. , A ο ΒΑΚ-ΚΑ424

'H-NMR (CDC13) δ: 2.83 (t，J = 7.2Hz5 2H)5 3.51 (t，J = 7.2Hz5 2H)5 4.11 (s， 2H) 5 7.0 3 (d，J = 8.4Hz? 2H) 5 7.2 3 (d，J = 8.4Hz5 2H)， 7.5 1 (d? J = 2.5Hz, 1H) 7.53 (d5 J = 2.5Hz, 1H) MS (El) E/Z 43 7 (M)? 43 9 (M + 2)? 441 (M + 4) 製造例1 6 1 合成4〔 〔 〔 （3，5-二氯-2-羥苯基）硕基〕〔2-(3，4-'H-NMR (CDC13) δ: 2.83 (t, J = 7.2Hz5 2H) 5 3.51 (t, J = 7.2Hz5 2H) 5 4.11 (s, 2H) 5 7.0 3 (d, J = 8.4Hz? 2H) 5 7.2 3 (d, J = 8.4Hz5 2H), 7.5 1 (d? J = 2.5Hz, 1H) 7.53 (d5 J = 2.5Hz, 1H) MS (El) E / Z 43 7 (M)? 43 9 (M + 2)? 441 (M + 4) Production Example 1 6 1 Synthesis of 4 [[[((3,5-Dichloro-2-hydroxyphenyl) sulfonyl]] [2- (3,4-

二甲氧苯基）乙基〕胺基〕甲基〕苯甲酸甲酯 與製造例 1 14 一樣之方法，得標題化合物（BAK-KA443 )。Dimethoxyphenyl) ethyl] amino] methyl] methylbenzoate In the same manner as in Production Example 114, the title compound (BAK-KA443) was obtained.

ClCl

BAK-KA443 0 ^-NMR (CDCI3) δ: 2.6 1 (t5 J = 7.2Hz; 2Η)，3.3 9(t，J = 7.2Hz5 2Η)，3.8](s5 -134- (130) 200417367 3H)5 3.8 4 (s? 3H)? 3.93(s5 3H)? 4.45(s5 2H)? 6.45- 6.74(m3 3H)? 7.33(t? J = 8.3Hz? 2H)5 7.44 (d? J= 2.5 Hz? 1H)? 7.54 (d? J= 2.5 Hz? 1H) 8.01 (t5 J = 8.3Hz5 2H)? 9.04 (s，1H) MS (El) E/Z 5 5 3 (M) 5 5 5 5 (M + 2)? 5 5 7 (M + 4) 製造例162 合成4〔〔〔 （ 3，5-二氯-2-羥苯基）硕基〕〔2- ( 3，4- 二甲氧苯基）乙基〕胺基〕甲基〕苯甲酸 與製造例116 —樣之方法，得標題化合物（BAK-KA445 )。BAK-KA443 0 ^ -NMR (CDCI3) δ: 2.6 1 (t5 J = 7.2Hz; 2Η), 3.3 9 (t, J = 7.2Hz5 2Η), 3.8] (s5 -134- (130) 200417367 3H) 5 3.8 4 (s? 3H)? 3.93 (s5 3H)? 4.45 (s5 2H)? 6.45- 6.74 (m3 3H)? 7.33 (t? J = 8.3Hz? 2H) 5 7.44 (d? J = 2.5 Hz? 1H )? 7.54 (d? J = 2.5 Hz? 1H) 8.01 (t5 J = 8.3Hz5 2H)? 9.04 (s, 1H) MS (El) E / Z 5 5 3 (M) 5 5 5 5 (M + 2 )? 5 5 7 (M + 4) Production Example 162 Synthesis of 4 [[[((3,5-dichloro-2-hydroxyphenyl) sulfonyl]] [2- (3,4-dimethoxyphenyl) ethyl In the same manner as in Production Example 116, the group] amino] methyl] benzoic acid gave the title compound (BAK-KA445).

BAK-KA443 BAK-KA445 aH-NMR (CDC13) δ: 2.64 (t5 J = 7.0Hz? 2H)? 3.42 (t5 J = 7.0Hz? 2H)5 3.81 (s? 3H)， 3.84(s， 3H)5 4.4 7 (s， 2H)5 6.4 6 -6.7 5 (m， 3H)， 7.37(t，J = 8.0Hz? 2H)，7.44(d? J = 2.4Hz? 1H)5 7.5 4 (d? J = 2.4 Η z 5 1H) 5 8.0 7 (t，J = 8.0Hz, 2H)，9.00 (brs，1H) MS (El) E/Z 5 3 9 (M) 5 5 4 1 (M + 2)，54 3 (M + 4) 製造例1 6 3 -135- (131) 200417367 合成3，5-二氯-N-〔 2-(3，4-二甲苯基）乙基〕-2-羥基-N-〔 （2-噻吩基）甲基〕苯磺醯胺 與製造例1 14 一樣之方法，得標題化合物（BAK-KA4 5 0 )。BAK-KA443 BAK-KA445 aH-NMR (CDC13) δ: 2.64 (t5 J = 7.0Hz? 2H)? 3.42 (t5 J = 7.0Hz? 2H) 5 3.81 (s? 3H), 3.84 (s, 3H) 5 4.4 7 (s, 2H) 5 6.4 6 -6.7 5 (m, 3H), 7.37 (t, J = 8.0Hz? 2H), 7.44 (d? J = 2.4Hz? 1H) 5 7.5 4 (d? J = 2.4 Η z 5 1H) 5 8.0 7 (t, J = 8.0Hz, 2H), 9.00 (brs, 1H) MS (El) E / Z 5 3 9 (M) 5 5 4 1 (M + 2), 54 3 (M + 4) Production Example 1 6 3 -135- (131) 200417367 Synthesis of 3,5-dichloro-N- [2- (3,4-xylyl) ethyl] -2-hydroxy-N- [(2-Thienyl) methyl] benzenesulfonamide was prepared in the same manner as in Production Example 1 14 to give the title compound (BAK-KA4 50).

BAK-KA450 ^-NMR (CDC13) δ: 2.75(t，J = 7.2Hz5 2H)5 3.4 4 (t，J = 7.2Hz5 2Η)，3.85(s， 6H) 5 4.5 7 (s，2H)，6.5 7-7.29(m，6H)5 7.36 (d，J = 2.5Hz， 1H)? 7.51 (d? J = 2.5Hz5 1H)? 9.1 2 (s? 1H) MS (El) E/Z501 (M + )? 5 0 3 (M + 2)，5 0 5 (M + 4)BAK-KA450 ^ -NMR (CDC13) δ: 2.75 (t, J = 7.2Hz5 2H) 5 3.4 4 (t, J = 7.2Hz5 2Η), 3.85 (s, 6H) 5 4.5 7 (s, 2H), 6.5 7-7.29 (m, 6H) 5 7.36 (d, J = 2.5Hz, 1H)? 7.51 (d? J = 2.5Hz5 1H)? 9.1 2 (s? 1H) MS (El) E / Z501 (M +) ? 5 0 3 (M + 2), 5 0 5 (M + 4)

製造例164 合成 3，5-二氯-N-〔2-(3，4-二甲苯基）乙基〕-N-〔（ 2-呋喃基）甲基〕-2-羥苯磺醯胺 與製造例1 14 一樣之方法，得標題化合物（BAK-KA45 1 )。Production Example 164 Synthesis of 3,5-dichloro-N- [2- (3,4-xylyl) ethyl] -N-[(2-furyl) methyl] -2-hydroxybenzenesulfonamide and The same method as in Production Example 14 was used to obtain the title compound (BAK-KA45 1).

BAK-KA451 -136 - (132) 200417367 ]H-NMR (CDC13) δ: 2.79(t5 J = 7.2Hz5 2H)5 3.4 2 (t? J = 7.2Hz5 2H) 5 3.8 6 (s5 3H) 5 3.8 7 (s，3H)，4.40 (s5 2H)，6.24-6.81 (m5 6H)， 7.34(d5 J = 2.5Hz，1H)，7.48(d，J = 2.5Hz，1H)，9.2 1 (s5 1 H) MS (E I) E/Z 4 8 5 (M)，4 8 7(M + 2)，48 9 (M + 4)BAK-KA451 -136-(132) 200417367] H-NMR (CDC13) δ: 2.79 (t5 J = 7.2Hz5 2H) 5 3.4 2 (t? J = 7.2Hz5 2H) 5 3.8 6 (s5 3H) 5 3.8 7 (s, 3H), 4.40 (s5 2H), 6.24-6.81 (m5 6H), 7.34 (d5 J = 2.5Hz, 1H), 7.48 (d, J = 2.5Hz, 1H), 9.2 1 (s5 1 H) MS (EI) E / Z 4 8 5 (M), 4 8 7 (M + 2), 48 9 (M + 4)

製造例165 合成3，5-二氯- N-〔 2-(3，4-二甲苯基）乙基〕-2-羥基-N-(吡咯-2-基甲基）苯磺醯胺 與製造例1 14 一樣之方法，得標題化合物（BAK- KA4 5 2 ) 〇Production Example 165 Synthesis and production of 3,5-dichloro-N- [2- (3,4-xylyl) ethyl] -2-hydroxy-N- (pyrrole-2-ylmethyl) benzenesulfonamide Example 1 14 The same method was used to obtain the title compound (BAK-KA4 5 2).

!H-NMR (CDC13) δ: 2.63(t5 J = 7.1Hz? 2H)5 3.4 0 (t? J = 7.1Hz5 2H)? 3.83(s? 3H) 5 3.8 5 (s5 3H)5 4.3 4 (s? 2H)? 6.12-6.83 (m5 6H)? 7.32 (d5 J = 2.5Hz，1H)，7.52 (d，J = 2.5Hz，1H) 5 8.5 8 (brs5 1H)，8.96 (s5 1H) MS (El) E/Z 484(M + )5 486 (M + 2)，4 8 8 (M + 4) -137- (133) 200417367 製造例166 合成〔〔（3，5·二氯-2-羥苯基）硕基〕〔2-(2，5 -二甲 氧苯基）乙基〕胺基〕乙酸甲酯 與製造例 1 14 一樣之方法，得標題化合物（BAK-KA45 6 )。! H-NMR (CDC13) δ: 2.63 (t5 J = 7.1Hz? 2H) 5 3.4 0 (t? J = 7.1Hz5 2H)? 3.83 (s? 3H) 5 3.8 5 (s5 3H) 5 4.3 4 (s 2H)? 6.12-6.83 (m5 6H)? 7.32 (d5 J = 2.5Hz, 1H), 7.52 (d, J = 2.5Hz, 1H) 5 8.5 8 (brs5 1H), 8.96 (s5 1H) MS (El ) E / Z 484 (M +) 5 486 (M + 2), 4 8 8 (M + 4) -137- (133) 200417367 Production Example 166 Synthesis [[(3,5 · Dichloro-2-hydroxybenzene Group) masteryl] [2- (2,5-dimethoxyphenyl) ethyl] amino] acetic acid methyl ester was prepared in the same manner as in Production Example 1 14 to give the title compound (BAK-KA45 6).

]H-NMR (CDC13) δ: 2.79(t，J = 7.0Hz，2H) 5 3.4 7 (t，J = 7 · 0 H z，2 H)，3 · 7 3 (s 5 6H)? 3.75(s? 3H)? 4.14(s5 2H)? 6.60-6.7 0(m? 3H)5 7.50(d，J = 2.5Hz，1H)5 7 5 4 (d，J = 2.5Hz，1H)5 9.14 (s， 1H) MS (El ) E/Z 477 (M)，479 (M + 2) · 製造例167 合成〔〔（3，5-二氯-2-羥苯基）硕基〕〔2-(4-甲苯基 )乙基〕胺基〕乙酸甲酯 與製造例1 14 一樣之方法，得標題化合物（BAK-KA45 7 )。 -138- (134) 200417367] H-NMR (CDC13) δ: 2.79 (t, J = 7.0 Hz, 2H) 5 3.4 7 (t, J = 7 · 0 H z, 2 H), 3 · 7 3 (s 5 6H)? 3.75 ( s? 3H)? 4.14 (s5 2H)? 6.60-6.7 0 (m? 3H) 5 7.50 (d, J = 2.5Hz, 1H) 5 7 5 4 (d, J = 2.5Hz, 1H) 5 9.14 (s , 1H) MS (El) E / Z 477 (M), 479 (M + 2) · Preparation Example 167 Synthesis [[(3,5-Dichloro-2-hydroxyphenyl) sulfonyl] [2- (4 -Tolyl) ethyl] amino] methyl acetate The same method as in Production Example 14 was used to obtain the title compound (BAK-KA45 7). -138- (134) 200417367

BAK-KA457 ]H-NMR (CDC13) δ: 2.30(s? 3H)? 2.80(t5 J = 7.0Hz? 2H)5 3.4 9 (t? J = 7.0Hz?BAK-KA457] H-NMR (CDC13) δ: 2.30 (s? 3H)? 2.80 (t5 J = 7.0Hz? 2H) 5 3.4 9 (t? J = 7.0Hz?

2H)，3.70 (s，3H)，4·04 (s，2H)，6.98 (d，J = 8.0Hz，2H)， 7.07 (d5 J = 8.0Hz5 2H)? 7.52(s? 2H) 5 8.9 8 (s5 1H) MS (El) E/Z 43 1 (M) 製造例1 6 8 合成3，5-二氯-N-〔 2-(3，4-二甲氧苯基）乙基〕-2-羥 基-N-〔 （1，3-噻唑-2-基）甲基〕苯磺醯胺2H), 3.70 (s, 3H), 4.04 (s, 2H), 6.98 (d, J = 8.0Hz, 2H), 7.07 (d5 J = 8.0Hz5 2H)? 7.52 (s? 2H) 5 8.9 8 (s5 1H) MS (El) E / Z 43 1 (M) Production Example 1 6 8 Synthesis of 3,5-dichloro-N- [2- (3,4-dimethoxyphenyl) ethyl] -2 -Hydroxy-N-[(1,3-thiazol-2-yl) methyl] benzenesulfonamide

與製造例114 一樣之方法，得標題化合物（BAK-KA465 )。The title compound (BAK-KA465) was obtained in the same manner as in Production Example 114.

H-NMR (CDC13) δ: 2.77(t，J = 7.1Hz，2Η), 3.51 (t5 J = 7.2Hz5 2Η) 5 3.8 4 (s5 3H), 3.85 (s5 3H)5 4.78 (s; 2H)? 6.57-6.76 (m5 3H); 7.3 6 (d，J 二 3 · 3 H z，1 H); 7.4 8 (d ; J = 2 · 6 H z，1 H )，7.5 1 > 139- (135) 200417367 (d? J =2.6 Hz5 1H)? 7.7 3 (d? J = 3.3Hz? 1H) MS (El) E/Z 5 02 (M), 5 04 (M + 2) 製造例1 6 9 合成〔〔（3，5-二氯-2-羥苯基）碾基〕〔2-(2，5-二甲 氧苯基）乙基〕胺基〕乙酸H-NMR (CDC13) δ: 2.77 (t, J = 7.1Hz, 2Η), 3.51 (t5 J = 7.2Hz5 2Η) 5 3.8 4 (s5 3H), 3.85 (s5 3H) 5 4.78 (s; 2H)? 6.57-6.76 (m5 3H); 7.3 6 (d, J 2 3 · 3 H z, 1 H); 7.4 8 (d; J = 2 · 6 H z, 1 H), 7.5 1 > 139- (135 ) 200417367 (d? J = 2.6 Hz5 1H)? 7.7 3 (d? J = 3.3Hz? 1H) MS (El) E / Z 5 02 (M), 5 04 (M + 2) Manufacturing example 1 6 9 Synthesis [[(3,5-Dichloro-2-hydroxyphenyl) yl] [2- (2,5-dimethoxyphenyl) ethyl] amino] acetic acid

與製造例1 1 6 —樣之方法，得標題化合物（BAK-KA459)。The title compound (BAK-KA459) was obtained in the same manner as in Production Example 1 16.

BAK-KA456BAK-KA456

CI 〇 BAK-KA459 ]H-NMR (CDC13) δ:CI 〇 BAK-KA459] H-NMR (CDC13) δ:

2.79(t? J = 7.0Hz? 2H) 5 3.4 9 (t, J = 7.0Hz5 2H)? 3.74 (s5 3H)? 3.74 (s5 3H)5 4.19 (s? 2H)? 6.5 9- 6.6 9 (m5 3H)? 7.49 (d? J = 2.5Hz5 1H)? 7.53 (d? J = 2.5Hz5 1H) MS (El) E/Z 463 M5 46 5 (M + 2) 製造例1 7 0 合成〔〔（3，5 -二氯-2-經苯基）5風基〕〔2-(4 -甲苯基 )乙基〕胺基〕乙酸 與製造例1 16 —樣之方法，得標題化合物（BAK_ KA460 )。 -140- (136) 2004173672.79 (t? J = 7.0Hz? 2H) 5 3.4 9 (t, J = 7.0Hz5 2H)? 3.74 (s5 3H)? 3.74 (s5 3H) 5 4.19 (s? 2H)? 6.5 9- 6.6 9 (m5 3H)? 7.49 (d? J = 2.5Hz5 1H)? 7.53 (d? J = 2.5Hz5 1H) MS (El) E / Z 463 M5 46 5 (M + 2) Manufacturing Example 1 7 0 Synthesis [((3 5,5-Dichloro-2-transphenyl) 5-yl] [2- (4-tolyl) ethyl] amino] acetic acid was prepared in the same manner as in Production Example 16 to give the title compound (BAK_KA460). -140- (136) 200417367

BAK-KA457BAK-KA457

α ο BAK4CA460 JH-NMR (CDC13) δ:α ο BAK4CA460 JH-NMR (CDC13) δ:

2.31 (s5 3Η)? 2.81 (t? J = 7.2Hz5 2Η) 5 3.5 0 (t? J = 7.2Hz? 2H)? 4.09(s5 2H)? 6.97(d5 J=8. 1 Hz5 2H)? 7.06 (d， J = 8.0Hz5 2H)? 7.50 (d5 J = 2.5Hz? 1 H)5 7.5 2 (d? J -2.5Hz5 1H) MS (El) E/Z 417 (M) 製造例1 7 1 合成〔〔2-〔 4-(胺硕基）苯基〕乙基〕〔（3，5-二氯-2-羥苯基）硕基〕胺基〕乙酸甲酯 與製造例114 一樣之方法，得標題化合物（BAK-KA464 )。2.31 (s5 3Η)? 2.81 (t? J = 7.2Hz5 2Η) 5 3.5 0 (t? J = 7.2Hz? 2H)? 4.09 (s5 2H)? 6.97 (d5 J = 8. 1 Hz5 2H)? 7.06 ( d, J = 8.0Hz5 2H)? 7.50 (d5 J = 2.5Hz? 1 H) 5 7.5 2 (d? J -2.5Hz5 1H) MS (El) E / Z 417 (M) Manufacturing Example 1 7 1 Synthesis [ [2- [4- (Aminosulfonyl) phenyl] ethyl] [(3,5-dichloro-2-hydroxyphenyl) sulfonyl] amino] methyl acetate was prepared in the same manner as in Production Example 114 to obtain The title compound (BAK-KA464).

]H-NMR (CDCI3) δ: 2.97(t? J = 7.1Hz? 2H)? 3.54(t, J = 7.1Hz; 2H)? 3.70 (s? -141 - (137) (137)200417367 3H)5 4.0 5 (S? 2H)5 4.8 0 (brs? 2H)? 7.30 (d5 J = 8.3Hz5 2H)，7.55(s5 2H)，7.85(d，J = 8.3Hz，2H)5 8.81 (s，1H) MS (El) E/Z 496 (M)，498 (M + 2) 製造例172 合成〔〔2-〔 4-(胺硕基）苯基〕乙基〕〔（3，5-二氯-2-羥苯基）硕基〕胺基〕乙酸 與製造例1 16 —樣之方法，得標題化合物（BAK-KA466)。] H-NMR (CDCI3) δ: 2.97 (t? J = 7.1Hz? 2H)? 3.54 (t, J = 7.1Hz; 2H)? 3.70 (s? -141-(137) (137) 200417367 3H) 5 4.0 5 (S? 2H) 5 4.8 0 (brs? 2H)? 7.30 (d5 J = 8.3Hz5 2H), 7.55 (s5 2H), 7.85 (d, J = 8.3Hz, 2H) 5 8.81 (s, 1H) MS (El) E / Z 496 (M), 498 (M + 2) Production Example 172 Synthesis of [[2- [4- (Aminosulfo) phenyl] ethyl] [(3,5-dichloro-2 -Hydroxyphenyl) sulfonyl] amino] acetic acid was prepared in the same manner as in Production Example 16 to give the title compound (BAK-KA466).

UMR (CDC13) δ: 2.93(t? J = 7.1Hz, 2H) 5 3.5 4 (t5 J = 7.1Hz? 2H)? 4.04 (s3 2H)? 5.99 (s? 2H)5 7.2 6 (d5 J = 8.3Hz? 2H)? 7.52 (d? J = 2.6Hz? 1H), 7.66 (d5 J = 2.6 Hz5 1H)? 7.83 (d5 J = 8.3Hz5 2H) MS (Q-TOF) E/Z +ESI 483.0 (M)? 4 8 5 (M) -ESI 481.0 (Μ-1)，4 8 3·0 (M + l) 製造例1 7 3 合成〔〔（3，5-二氯-2-羥苯基）硕基〕〔2-(4-氟苯基 -142- (138) 200417367 )乙基〕胺基〕乙酸甲酯 與製造例114 一樣之方法，得標題化合物（BAK-KA469 )。UMR (CDC13) δ: 2.93 (t? J = 7.1Hz, 2H) 5 3.5 4 (t5 J = 7.1Hz? 2H)? 4.04 (s3 2H)? 5.99 (s? 2H) 5 7.2 6 (d5 J = 8.3 Hz? 2H)? 7.52 (d? J = 2.6Hz? 1H), 7.66 (d5 J = 2.6 Hz5 1H)? 7.83 (d5 J = 8.3Hz5 2H) MS (Q-TOF) E / Z + ESI 483.0 (M )? 4 8 5 (M) -ESI 481.0 (M-1), 4 8 3 · 0 (M + 1) Production Example 1 7 3 Synthesis of [[(3,5-dichloro-2-hydroxyphenyl) Methyl] [2- (4-fluorophenyl-142- (138) 200417367) ethyl] amino] acetic acid methyl ester was prepared in the same manner as in Production Example 114 to obtain the title compound (BAK-KA469).

iH-NMR (CDC13) δ: 2.84 (t5 J = 7.2Hz5 2H)5 3.0 0 (t? J = 7.2Hz? 2H)? 3.70 (s5 3H)? 4.03 (s? 2H)5 6.91-7.1 2 (m? 4H)? 7.53 (s5 2H)? 8.92 (s5 1H) MS (E I) E/Z 43 5 (M) 製造例174iH-NMR (CDC13) δ: 2.84 (t5 J = 7.2Hz5 2H) 5 3.0 0 (t? J = 7.2Hz? 2H)? 3.70 (s5 3H)? 4.03 (s? 2H) 5 6.91-7.1 2 (m (4H)? 7.53 (s5 2H)? 8.92 (s5 1H) MS (EI) E / Z 43 5 (M) Manufacturing example 174

合成 3，5-二氯-N-〔 2-(3，4-二甲氧苯基）乙基〕-2-羥 基_N- ( D奎啉基甲基）苯磺醯胺鹽酸鹽 與製造例 1 14 一樣之方法，得標題化合物（BAK-KA470 )。Synthesis of 3,5-dichloro-N- [2- (3,4-dimethoxyphenyl) ethyl] -2-hydroxy_N- (D-quinolinylmethyl) benzenesulfonamide hydrochloride with In the same manner as in Production Example 14, the title compound (BAK-KA470) was obtained.

BAK-KA470 H-NMR (CDC13)5: -143 - (139) (139)200417367 2.80 (t5 J = 7.0Hz，2H) 5 3.6 4 (t，J = 7.0Hz5 2H)，3.68 (s， 3H)? 3.71 (s5 3H)? 5.53 (s5 2H)? 6.41-6.63 (m? 3H)? 7.58 (d5 J = 2.5Hz5 1H)? 7.72 (d5 J = 2.5Hz? 1H)? 7.89- 7.94 (m5 2H)5 8·03·8·10(χη，2H)，8.59(d，1H)，8.83.(d， 1H) MS (Q-TOF) E/Z +ESI 5 45.1 (M-HC1 + 1) -ESI 546.1 (M-HC1-1)BAK-KA470 H-NMR (CDC13) 5: -143-(139) (139) 200417367 2.80 (t5 J = 7.0Hz, 2H) 5 3.6 4 (t, J = 7.0Hz5 2H), 3.68 (s, 3H) ? 3.71 (s5 3H)? 5.53 (s5 2H)? 6.41-6.63 (m? 3H)? 7.58 (d5 J = 2.5Hz5 1H)? 7.72 (d5 J = 2.5Hz? 1H)? 7.89- 7.94 (m5 2H) 5 8 · 03 · 8 · 10 (χη, 2H), 8.59 (d, 1H), 8.83. (D, 1H) MS (Q-TOF) E / Z + ESI 5 45.1 (M-HC1 + 1) -ESI 546.1 (M-HC1-1)

製造例1 7 5 合成3，5-二氯-N-(氰甲基）-N-〔 2-(3，4-二甲氧苯基 )乙基〕-2-羥苯基磺醯胺 與製造例1 14 一樣之方法’得標題化合物（BAK-KA47 1 )。Production Example 1 7 5 Synthesis of 3,5-dichloro-N- (cyanomethyl) -N- [2- (3,4-dimethoxyphenyl) ethyl] -2-hydroxyphenylsulfonamide and The same method as in Production Example 14 was used to obtain the title compound (BAK-KA47 1).

BAK-KA471 ^-NMR (CDC13) δ: 2.88 (t? J = 7.0Hz? 2H) 5 3.5 5 (t? J = 7.0Hz? 2H) 5 3.8 7 (s5 2H)，4.15(s，2H)5 6.6 8 - 6.8 1 (m5 3H)5 7.5 6 (d5 J = 2.5Hz， 1H) 5 7.5 8 (d5 J = 2.5Hz5 1H)5 8.10 (brs5 1H) MS (El) E/Z 444 (M)，446 (M + 2) 製造例1 7 6 -144- (140) 200417367 合成〔〔（3，5-二氯-2-羥苯基）碾基〕〔2-(4-氟苯基 )乙基〕胺基〕乙酸 與製造例 1 16 —樣之方法，得標題化合物（BAK-KA472 )。BAK-KA471 ^ -NMR (CDC13) δ: 2.88 (t? J = 7.0Hz? 2H) 5 3.5 5 (t? J = 7.0Hz? 2H) 5 3.8 7 (s5 2H), 4.15 (s, 2H) 5 6.6 8-6.8 1 (m5 3H) 5 7.5 6 (d5 J = 2.5Hz, 1H) 5 7.5 8 (d5 J = 2.5Hz5 1H) 5 8.10 (brs5 1H) MS (El) E / Z 444 (M), 446 (M + 2) Production Example 1 7 6 -144- (140) 200417367 Synthesis of [[(3,5-dichloro-2-hydroxyphenyl) pentyl] [2- (4-fluorophenyl) ethyl ] Amine] Acetic acid was prepared in the same manner as in Production Example 16 to give the title compound (BAK-KA472).

BAK-KA469 BAK-KA472 ^-NMR (CDC13) δ: 2.83(t，J = 7.2Hz，2H) 5 3.4 9 (t，J = 7.2Hz，2Η)5 4.10 (s5 2H)5 6.91-7.11 (m5 4H)? 7.52 (s? 2H) MS (El) E/Z 421 (M), 423 (M + 2) 製造例1 7 7 合成〔〔（3，5-二氯-2-羥苯基）硕基〕〔2-(4-氟苯基 )乙基〕胺基〕乙酸 與製造例 142 —樣之方法，得標題化合物（BAK-KA479)。BAK-KA469 BAK-KA472 ^ -NMR (CDC13) δ: 2.83 (t, J = 7.2Hz, 2H) 5 3.4 9 (t, J = 7.2Hz, 2Η) 5 4.10 (s5 2H) 5 6.91-7.11 (m5 4H)? 7.52 (s? 2H) MS (El) E / Z 421 (M), 423 (M + 2) Production Example 1 7 7 Synthesis of [[(3,5-dichloro-2-hydroxyphenyl)] Group] [2- (4-fluorophenyl) ethyl] amino] acetic acid was prepared in the same manner as in Production Example 142 to give the title compound (BAK-KA479).

BAK-KA479 -145- (141) 200417367 ^-NMR (CDC13) δ: 3.66 (t? J = 4.3Hz? 2H)? 3.79(s? 3H)? 3.87(s? 3H)? 4.16 (s5 2H)? 4.21 (t5 J = 4.3Hz? 2H)5 4.69 (s? 2H)? .6.74- 6.89 (m，3H)，7.59(d，J = 2.5Hz, 1H)，7.78 (d5 J = 2.5Hz， 1H) MS (El) E/Z 4 7 5 (M)，477 (M + 2)BAK-KA479 -145- (141) 200417367 ^ -NMR (CDC13) δ: 3.66 (t? J = 4.3Hz? 2H)? 3.79 (s? 3H)? 3.87 (s? 3H)? 4.16 (s5 2H)? 4.21 (t5 J = 4.3Hz? 2H) 5 4.69 (s? 2H)? .6.74- 6.89 (m, 3H), 7.59 (d, J = 2.5Hz, 1H), 7.78 (d5 J = 2.5Hz, 1H) MS (El) E / Z 4 7 5 (M), 477 (M + 2)

製造例1 7 8 合成1，1-二氧化2-〔4-羧甲氧基）-3-甲氧苯甲基〕-6’ 8 -二氯-3，4 -二氫- 2H-5，1，2 -苯并哼吖庚因 與製造例 68 —樣之方法，得標題化合物（BAK- KA48 1 )。Production Example 1 7 8 Synthesis of 1,1-dioxide 2- [4-carboxymethoxy] -3-methoxybenzyl] -6 '8-dichloro-3,4-dihydro-2H-5, In the same manner as in Production Example 68 for 1,2-benzylazepine, the title compound (BAK-KA48 1) was obtained.

]H-NMR (CDCI3) δ: 3.67(t? J = 4.2Hz? 2H)? 3.90(s? 3H)5 4.17(s? 2H)5 4.24(t? J = 4.2Hz? 2H)5 4.6 8 (s? 2H)? 6.79-6.94 (m5 3H)? 7.60(d? J = 2.5Hz? 1H)，7.78(d，J = 2.5Hz，1H) MS (El) E/Z 461 (M) 5 4 6 3 (M + 2) 試驗例] 確認對於辣椒素引起之咳嗽試驗動物具有鎭咳作用之 -146- (142) (142)200417367 試驗（1 ) 將Hartley系天竺鼠（東京實驗動物，雄，5週齡） 放入 body-Plethymography箱形裝置之圓筒中，自圓筒前 方連接超音波噴霧器，使其吸入7〜1 〇分鐘之辣椒素生理 食鹽水溶液，引起咳嗽，以多種波動描記器記錄body-Plethymography之內壓變化，同時觀察多種波動描記器記 錄之變化與動物之胸部動靜，計測咳嗽之發生次數。 鎭咳作用係由被檢化合物投服前之咳嗽發生次數（ pre値），與經口投服被檢化合物1小時後咳嗽發生次數 (p 〇 st値），依以下計算式算出咳嗽抑制率予以表示。 咳嗽抑制率（％) =(pre値-pos値）/pre値χΙΟΟ 又，爲確認被檢化合物之鎭咳作用係對中樞性作用， 或封末梢性作用’在投予被檢化合物之1 5分鐘前，在腹 腔內投予3mg/kg之美麥角醯胺（methy.sergide )，調查其 對被檢化合物之鎭咳作用的影響。 曾有報告指出胞突接合後膜的血淸素（serotonill )受 體（5 - Η TIA )之活化會干與中樞性鎭咳藥之作用表現（ Nippon Yokurigaku Zasshi，111 ( 6) ，p345 ( 1 998 )) ，由於已知中樞性鎭咳作用係可以藉由血淸素受體拮抗劑 之美麥角醯胺而消失或減弱，所以有無此影響即可知爲中 樞性或末梢性。 (結果） -147 - (143) 200417367 表1 被檢化合物 (30mg/k^ 咳嗽抑制率(A) 美麥角 醯胺前處理 作用機作 咳嗽抑制率(B) 鎭咳作用之殘留率(％) 製造例2 56.7 nt 一 — 製造例3 69.6 68.8 98.9 末梢性 製造例34 63.0 nt 一 一 moguistein 59.5 67.0 112.6 末梢性 殘留率（％) =咳嗽抑制率（B)/咳嗽抑制率（Β)χ100 經口投服30mg/kg三種被檢化合物（製造例2，3， 3 4 )後示鎭咳作用。 又，製造例3之化合物係對於以美麥角醯胺前處理之 天竺鼠亦示有鎭咳作用（鎭咳作用之殘留率係9 8.9 % )。 所以與m 〇 g u i s t e i η —樣可能示有末梢性鎭咳作用。 試驗例2 確認對於使用辣椒素引發咳嗽之實驗動物的鎭咳作用 (2) 與試驗例1 一樣之方法，調查投予量1 〇 m g / k g被檢化 合物之鎭咳作用。作用機作係以對美麥角醯胺前處理之天 竺鼠的鎭咳作用殘留率70%以上之被檢化合物判定爲具有 末梢性鎭咳作用。做爲對照，使用二氫可待因爲中樞性鎭 咳藥。 (結果） -148- (144)200417367 表2 被檢化合物 咳嗽抑制率(％) 美麥角醯胺前處理 (10mg/kg) 鎭咳作用之殘留率(％) 作用機作 製造例102 69.2 nt — 製造例22 53.5 nt — 製造例48 67.6 121.4 末梢性 製造例47 86.5 77.7 末梢性 製造例49 56.0 94.2 末梢性 製造例52 71.5 98.9 末梢性 製造例54 62.7 102.1 末梢性 製造例55 44.5 nt — 製造例59 65.7 99.1 末梢性 製造例79 69.8 87.2 末梢性 製造例80 63.3 80.6 末梢性 製造例93 82.1 86.5 末梢性 製造例94 74.6 70.2 末梢性 製造例83 76.4 nt — 製造例85 83.5 75.8 末梢性 製造例87 71.5 nt — 製造例97 66.5 34.9 中樞性 製造例99 66.8 80.1 末梢性 製造例72 71.3 51.6 中樞性 製造例68 64.4 nt — 製造例77 62.8 93.8 末梢性 製造例116 46.9 nt — 製造例117 68.8 76.7 末梢性 製造例119 61.9 69.5 中樞性 製造例120 64.5 nt — 製造例125 62.2 65.9 中樞性 製造例127 82.1 72.4 末梢性 製造例129 73.3 67.9 中樞性 製造例132 67.6 nt — 製造例136 71.9 nt — 二氫可待因 65.6 24.5 中樞性 對照（媒體） 28.7 — —] H-NMR (CDCI3) δ: 3.67 (t? J = 4.2Hz? 2H)? 3.90 (s? 3H) 5 4.17 (s? 2H) 5 4.24 (t? J = 4.2Hz? 2H) 5 4.6 8 ( s? 2H)? 6.79-6.94 (m5 3H)? 7.60 (d? J = 2.5Hz? 1H), 7.78 (d, J = 2.5Hz, 1H) MS (El) E / Z 461 (M) 5 4 6 3 (M + 2) Test Example] -146- (142) (142) 200417367 Test (1) The Hartley guinea pig (Tokyo laboratory animal, male, 5 weeks) Age) Put it into the cylinder of the body-Plethymography box device, connect the ultrasonic sprayer from the front of the cylinder, and let it inhale the capsaicin physiological saline solution for 7 ~ 10 minutes to cause cough. The internal pressure changes, while simultaneously observing the changes recorded by a variety of plethysmographs and the animal's chest movements, and measuring the number of coughs. The antitussive effect is based on the number of coughs (pre 値) before the administration of the test compound and the number of coughs (ppst 値) after 1 hour of oral administration of the test compound, and the cough suppression rate is calculated according to the following formula: Means. Cough inhibition rate (%) = (pre 値 -pos 値) / pre 値 χΙΟΟ In addition, in order to confirm that the cough effect of the test compound is a central effect, or a peripheral effect, it is 1 in 5 of the test compound administered Minutes ago, 3 mg / kg methysergide (methy.sergide) was administered intraperitoneally to investigate its effect on the antitussive effect of the test compound. It has been reported that the activation of the serotonill receptor (5-Η TIA) of the membrane after the synaptic junction will act as a central and antitussive drug (Nippon Yokurigaku Zasshi, 111 (6), p345 (1 998)), because the central cough effect is known to disappear or be weakened by ergosterol, a hemagglutinin receptor antagonist, the presence or absence of this effect can be known as central or peripheral. (Results) -147-(143) 200417367 Table 1 Test compounds (30mg / k ^ cough suppression rate (A) cough suppression rate of mekeroxamine pretreatment machine (B) cough suppression rate (%) ) Manufacturing Example 2 56.7 nt 1 — Manufacturing Example 3 69.6 68.8 98.9 Peripheral Manufacturing Example 34 63.0 nt-moguistein 59.5 67.0 112.6 Peripheral residual rate (%) = Cough inhibition rate (B) / Cough inhibition rate (B) χ100 Oral administration of 30 mg / kg of three test compounds (Production Examples 2, 3, 3 4) showed an antitussive effect. The compound of Production Example 3 also exhibited an antitussive effect on guinea pigs pretreated with ergotamine Effect (residual rate of antitussive effect is 9 8.9%). Therefore, it may show peripheral antitussive effect similar to m 〇guistei η. Test Example 2 Confirmed antitussive effect on experimental animals with capsaicin (2 ) Investigate the antitussive effect of the test compound at the dosage of 10 mg / kg in the same manner as in Test Example 1. The action mechanism is to give a residual rate of more than 70% of the antitussive effect in guinea pigs pretreated with ergotamine. Test compound was judged to have peripheral cough action As a control, dihydrocodeine was used as a central antitussive agent. (Result) -148- (144) 200417367 Table 2 Cough Inhibition Rate of Test Compounds (%) Pretreatment with Mergotamine (10mg / kg) Residual rate of cough action (%) Action mechanism Manufacturing example 102 69.2 nt — Manufacturing example 22 53.5 nt — Manufacturing example 48 67.6 121.4 Peripheral manufacturing example 47 86.5 77.7 Peripheral manufacturing example 49 56.0 94.2 Peripheral manufacturing example 52 71.5 98.9 Peripheral Manufacturing Example 54 62.7 102.1 Peripheral Manufacturing Example 55 44.5 nt — Manufacturing Example 59 65.7 99.1 Peripheral Manufacturing Example 79 69.8 87.2 Peripheral Manufacturing Example 80 63.3 80.6 Peripheral Manufacturing Example 93 82.1 86.5 Peripheral Manufacturing Example 94 74.6 70.2 Manufacturing Example 83 76.4 nt — Manufacturing Example 85 83.5 75.8 Peripheral Manufacturing Example 87 71.5 nt — Manufacturing Example 97 66.5 34.9 Central Manufacturing Example 99 66.8 80.1 Peripheral Manufacturing Example 72 71.3 51.6 Central Manufacturing Example 68 64.4 nt — Manufacturing Example 77 62.8 93.8 Peripheral Manufacturing Example 116 46.9 nt — Manufacturing Example 117 68.8 76.7 Peripheral Manufacturing Example 119 61.9 69.5 Central Manufacturing Example 120 64.5 nt — Manufacturing Example 12 5 62.2 65.9 Centrality Manufacturing Example 127 82.1 72.4 Peripheral Manufacturing Example 129 73.3 67.9 Central Manufacturing Example 132 67.6 nt — Manufacturing Example 136 71.9 nt — Dihydrocodeine 65.6 24.5 Centrality Control (Media) 28.7 — —

-149- (145) 200417367 大約全部之被檢化合物在l〇mg/kg經口投予時均可以 示有與二氫可待因同等以上之鎭咳作用。又，約一半之 1 5種化合物可能示有末梢性鎭咳作用。 試驗例3 確認使用辣椒素引發咳嗽之實驗動物的鎭咳作用試驗 (3 ) 與試驗例1 一樣之方法，調查3mg/kg投予量之被檢 化合物的鎭咳作用。做爲對照係使用中樞性鎭咳藥之二氫 可待因^ (結果） 表3 被檢化合物 咳嗽抑制率（％ ) (3 mg/kg ) 製造例4 8 59.6 製造例47 57.8 製造例52 77.5 製造例54 56.4 製造例93 62.7 製造例94 57.5 製造例85 59.1 二氫可待因 52.4 對照（媒體） 2 8.7 -150- (146) (146)200417367 於試驗例2中示有末梢性之鎭咳作用的七種被檢化合 物係在3mg/kg經口投予時可示有與二氫可待因同等以上 的鎭咳作用。 產業上之可利用性 本發明化合物係具有優異之鎭咳作用者，其中還包含 具有末梢性之鎮咳作用者。因此，此等化合物係具有與現 有之中樞性鎭咳藥不同之作用機作，可做爲幾乎沒有中樞 性之副作用的極優異鎭咳藥作用。 以這種化合物做爲有效成份之本發明止咳藥可以極有 利地使用於抑制或緩和會咳嗽的大多數疾病，例如感冒、 支热B炎、肺炎、氣D而、上热道發炎、胸膜發炎、百日咳 等呼吸器疾病的咳嗽者。-149- (145) 200417367 Approximately all of the test compounds exhibited an antitussive effect equivalent to or more than that of dihydrocodeine when administered orally at 10 mg / kg. In addition, about one-fifth of the 15 compounds may show peripheral cough. Test Example 3 Test for cough effect in experimental animals using capsaicin to cough (3) In the same manner as in Test Example 1, the cough effect of the test compound at a dose of 3 mg / kg was investigated. As a control system, dihydrocodeine, a central cough medicine, was used. (Results) Table 3 Cough inhibition rate (%) (3 mg / kg) of the test compound Manufacturing Example 4 8 59.6 Manufacturing Example 47 57.8 Manufacturing Example 52 77.5 Manufacturing Example 54 56.4 Manufacturing Example 93 62.7 Manufacturing Example 94 57.5 Manufacturing Example 85 59.1 Dihydrocodeine 52.4 Control (media) 2 8.7 -150- (146) (146) 200417367 In Test Example 2, there was a peripheral cough The seven test compounds that acted showed an antitussive effect equivalent to or more than that of dihydrocodeine when administered orally at 3 mg / kg. Industrial Applicability The compounds of the present invention have excellent antitussive effects, and also include those with peripheral antitussive effects. Therefore, these compounds have a different action mechanism from existing central cough medicines, and can be used as excellent cough medicines with almost no central side effects. The antitussive of the present invention containing this compound as an active ingredient can be extremely advantageously used to suppress or alleviate most diseases that may cough, such as colds, bronchitis B, pneumonia, qi D, upper hot airway inflammation, pleural inflammation Cough for respiratory diseases such as pertussis.

151 -151-

Claims (1)

200417367 Π) 拾、申請專利範圍 L 一種止咳藥，其特徵爲含有以下式（I)所示化合 物或藥理學上可被容許之鹽做爲有效成份者，200417367 Π) Patent application scope L An antitussive, which is characterized by containing a compound represented by the following formula (I) or a pharmacologically acceptable salt as an active ingredient, ⑴⑴ (式中 A示烷氧羰基烷基、羧基烷基、吡啶基烷基、氧 化吡啶-基烷基、喹啉基烷基、吲哚烷基、吡咯啶烷基、 呋喃烷基、噻吩烷基、吡咯烷基、咪唑烷基、吡唑烷基、 噻唑烷基、胺羰基烷基、氰烷基、羧基苯甲基、R示可被 保護之羥基、或A與R —起形成爲含氧之六或七節環、B 示羰基或磺醯基、尺：及R2示氫原子、烷氧基、苯甲氧基 、鹵素原子、烷基、羥基、烷氧羰基烷氧基、羧基烷氧基 、R3及R4係分別獨立示氫原子、烷氧基、苯甲氧基、鹵 素原子、烷基、羥基、烷氧羰基烷氧基、羧基烷氧基、氰 基烷氧基、胺磺醯基、羥基烷氧基、胺羰基烷氧基，或此 等一起示伸烷二氧基、η示1或2之數）。 2· —種以下式（ΙΑ)所示化合物，(Wherein A represents an alkoxycarbonylalkyl group, a carboxyalkyl group, a pyridylalkyl group, a pyridyl-oxyalkyl group, a quinolinylalkyl group, an indolealkyl group, a pyrrolidinyl group, a furylalkyl group, and a thienylalkyl group. , Pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, aminocarbonylalkyl, cyanoalkyl, carboxybenzyl, R represents a hydroxyl group that can be protected, or A and R together form oxygen 6 or 7-membered ring, B is carbonyl or sulfonyl, ruler: and R2 is hydrogen atom, alkoxy group, benzyloxy group, halogen atom, alkyl group, hydroxyl group, alkoxycarbonylalkoxy group, carboxyalkoxy group R3, R3 and R4 each independently represent a hydrogen atom, an alkoxy group, a benzoyloxy group, a halogen atom, an alkyl group, a hydroxyl group, an alkoxycarbonylalkoxy group, a carboxyalkoxy group, a cyanoalkoxy group, or an sulfamidine Group, hydroxyalkoxy group, aminecarbonylalkoxy group, or these together show the alkylene dioxy group, η shows the number of 1 or 2). 2. a compound represented by the following formula (IA), (式中Β示羰基或磺醯基，Υ示亞甲基、伸乙基、羰基或 亞甲羰基，R】及R2示氫原子、烷氧基、苯甲氧基、鹵素 -152- (2) 200417367 原子、烷基、羥基、烷氧羰基烷氧基、羧基烷氧基、r3 及R4係分別獨立示氫原子、院氧基、苯甲氧基、鹵素原 子、丨兀基、經基、院氧鑛基院氧基、殘基院氧基、氰基院 氧基、胺磺醯基、羥基烷氧基、胺羰基烷氧基，或此等一 起不伸院二氧基、η示1或2之數）。 3· —種以下式（ΙΒ)所示化合物(Wherein B represents a carbonyl group or a sulfonyl group, and R represents a methylene group, an ethyl group, a carbonyl group, or a methylenecarbonyl group, and R] and R2 represents a hydrogen atom, an alkoxy group, a benzyloxy group, and halogen -152- (2 ) 200417367 Atom, alkyl, hydroxyl, alkoxycarbonylalkoxy, carboxyalkoxy, r3 and R4 are each independently a hydrogen atom, a phenyloxy group, a benzyloxy group, a halogen atom, a carbamoyl group, a meridian group, Oxygen-based oxygen, radical-oxyl, cyano-oxyl, sulfamoyl, hydroxyalkoxy, aminocarbonyl-alkoxy, or these are not extended to the dioxy group, η is shown as 1 Or 2). 3 · —a compound represented by the following formula (IB) (式中 A ’示烷氧羰基烷基、羧基烷基、吡啶基烷基、氧 化吡啶-基烷基、喹啉基烷基、吲哚基烷基、吡咯啶基烷 基丨呋喃基烷基、噻吩基烷基、毗咯基烷基、咪唑基烷基 、吡唑基烷基、噻唑基烷基、胺羰基烷基、氰烷基、羰基 苯甲基’ B示羰基或磺醯基，R’示可被保護之羥基，Rl& R2示氫原子、烷氧基、苯甲氧基、鹵素原子、烷基、羥 基、烷氧羰基烷氧基、羧基烷氧基、R3及R4係分別獨立 示氫原子、烷氧基、苯甲氧基、鹵素原子、烷基、羥基、 烷氧羰基烷氧基、羧基烷氧基、氰基烷氧基、胺磺醯基、 键基Ί氧基、胺鑛基垸氧基，或此等一起不伸院二氧基、 η不1或2之數）。 -153- 200417367 柒、（一）、本案指定代表圖為：無 (二）、本代表圖之元件代表符號簡單說明··無(Wherein A 'represents an alkoxycarbonylalkyl group, a carboxyalkyl group, a pyridylalkyl group, a pyridyl-oxyalkyl group, a quinolinylalkyl group, an indolylalkyl group, a pyrrolidylalkyl group, and a furylalkyl group. , Thienylalkyl, pyrrolylalkyl, imidazolylalkyl, pyrazolylalkyl, thiazolylalkyl, aminocarbonylalkyl, cyanoalkyl, carbonylbenzyl'B shows a carbonyl or sulfonyl group, R 'represents a hydroxyl group that can be protected, and Rl & R2 represents a hydrogen atom, an alkoxy group, a benzoyloxy group, a halogen atom, an alkyl group, a hydroxyl group, an alkoxycarbonylalkoxy group, a carboxyalkoxy group, R3 and R4 are respectively Independently shown as hydrogen atom, alkoxy group, benzyloxy group, halogen atom, alkyl group, hydroxyl group, alkoxycarbonylalkoxy group, carboxyalkoxy group, cyanoalkoxy group, sulfamoyl group, bond fluorenyloxy group , Amine-based fluorenyloxy group, or these are not extended to the dioxy group, η is not a number of 1 or 2). -153- 200417367 柒, (1), the designated representative of this case is: None (二), a brief description of the representative symbols of the components of this representative ... 捌、本案若有化學式時，請揭示最能顯示發明特徵的化學 式··捌 、 If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention ...
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