TW391960B

TW391960B - Pharmaceutical composition containing tachykinin antagonistic piperazine derivatives

Info

Publication number: TW391960B
Application number: TW085106105A
Authority: TW
Inventors: Takashi Manabe; Hiroshi Matsuda; Masaaki Matsuo; Hiroshi Miyake; Kenji Murano
Original assignee: Fujisawa Pharmaceutical Co
Priority date: 1995-05-25
Filing date: 1996-05-23
Publication date: 2000-06-01
Also published as: IL118369A0; JPH11505830A; NZ307625A; HUP9900822A2; AU5703196A; HUP9900822A3; IL118369A; ZA964101B; AU706021B2; WO1996037489A1; EA199700425A1; TR199600438A2; CN1072220C; EP0846116A1; CA2222041A1; KR19990021857A; CN1191533A; EA000669B1; JP3071829B2

Abstract

This invention relates to (2R) -1-[3, 5-bis (trifluoromethyl)benzoyl] -2-(1H-indol-3-ylmethyl)-4-[N-(4-methyl-1-piperazinyl) carbamoylmethyl]piperazine or fumarate.

Description

五、聲明説明（本發明為有關新穎哌畊衍生物或其製藥容許鹽。詳言之，為有關具有如急速激素（Tachykinin)拮抗作用，尤其物質P括抗作兩，神經激素(Neurokinin A)拮抗作用，神經激素B拮抗作用等藥理作用之新穎喊畊衍生物及其製藥容許鹽，其製法，其醫藥組成物，及其當作醫藥之用途。故本發明之目的為提供具有如急速激素拮抗作用，尤其物質P拮抗作用，神經激素A拮抗作用，神經激素B 括抗作用等藥理作用之新穎哌阱衍生物及其製藥容許鹽本發明之另一目的為提供該哌阱衍生物及其鹽之製法本發明之另一目的為提供以該哌阱衍生物及其製藥容許鹽為有效成分之醫藥組成物。本發明之另一目的為提供以該呃阱衍生物及其製藥容 Ιΐ鹽當作急速激素拮抗劑，尤其物質P拮抗劑，神經激素Α拮抗劑或神經激素Β拮抗劑，可用以防治a或動物之急速激素仲介疾病，如氣喘，支氣管炎，箅炎，咳嗽，咳疲等呼吸器病；如結膜炎，春季結膜炎等眼病；如經濟部中央標準局員工消費合作杜印製接觸皮慮炎，異位皮慮炎，蓴麻瘆及其他類濕疹皮虜炎等皮虜病；如風濕性關節炎，骨關節炎等炎症；如偏頭痛，頭，牙痛，癌痛，背痛等疼痛。兜前技術：USP 5,670,505掲示如下式（I)化合物之自由體及富馬酸鹽以外之鹽。本紙張尺度適用中國國家標準（CNS ) A4規格（210X2.97公釐）五、聲明説明（本發明為有關新穎哌畊衍生物或其製藥容許鹽。詳言之，為有關具有如急速激素（Tachykinin)拮抗作用，尤其物質P括抗作兩，神經激素(Neurokinin A)拮抗作用，神經激素B拮抗作用等藥理作用之新穎喊畊衍生物及其製藥容許鹽，其製法，其醫藥組成物，及其當作醫藥之用途。故本發明之目的為提供具有如急速激素拮抗作用，尤其物質P拮抗作用，神經激素A拮抗作用，神經激素B 括抗作用等藥理作用之新穎哌阱衍生物及其製藥容許鹽本發明之另一目的為提供該哌阱衍生物及其鹽之製法本發明之另一目的為提供以該哌阱衍生物及其製藥容許鹽為有效成分之醫藥組成物。本發明之另一目的為提供以該呃阱衍生物及其製藥容 Ιΐ鹽當作急速激素拮抗劑，尤其物質P拮抗劑，神經激素Α拮抗劑或神經激素Β拮抗劑，可用以防治a或動物之急速激素仲介疾病，如氣喘，支氣管炎，箅炎，咳嗽，咳疲等呼吸器病；如結膜炎，春季結膜炎等眼病；如經濟部中央標準局員工消費合作杜印製接觸皮慮炎，異位皮慮炎，蓴麻瘆及其他類濕疹皮虜炎等皮虜病；如風濕性關節炎，骨關節炎等炎症；如偏頭痛，頭，牙痛，癌痛，背痛等疼痛。兜前技術：USP 5,670,505掲示如下式（I)化合物之自由體及富馬酸鹽以外之鹽。本紙張尺度適用中國國家標準（CNS ) A4規格（210X2.97公釐） A7 Β7 修，下.，、 , 五、發明説明（) 補无經濟部中央標準局員工消費合作社印製腫瘤，尤其小胞肺癌（SCLC);如野葛等過敏症；纖維變性膠辱病，如鞏皮症及嗜伊紅性瓜仁蟲病；反射交感性營養不良，如扃手症候群；瘸病，如酒精中毒；窘迫相關身體毛病；風濕病，如纖維組織炎等。治療上，本發明之目的物（I)及其製藥容許鹽以一種該化合物為舌性成分摻和製藥容許載體，如適合口服，非口服，局部外用，腸内，靜脈内，肌肉内，吸入，# 内，關節内，脊椎内，經氣管或經眼投予之有機或無機固體或液體賦.形劑之劑型使用。此製劑可為固體，半固體或溶液，如膠囊，錠，粒，丸，顆粒，栓劑，軟菊=，霜劑，洗液，吸入劑，注射，硬膏，凝膠，膠帶，點眼藥，溶液，糖漿，氣溶膠，懸浮液，乳液等。必要時可再加輔肋劑，安定劑，潤濕或乳化劑，缓衝劑或其他習用添加劑。化合物（I)之劑量雖視病人之年龄及體況而異，但化合物（I)之平均單一劑量為約Q.l, 1, 10, 50, 100, 250, 5QG及lOOQmg,可有效治療急速激素仲介疾病，如氣喘等。每人每日可投予〇 . 1〜約1 , Q 〇〇 in g。為說明目的物（I)及其製藥容許鹽之有用性，其代表化合物之藥理數據如下。下列試驗化合物以0, 1 w g/ ml之濃度時對h-NKi ( human neurokinin-1)受體結合 125 I-B H (Bolton Hunter-) -物質P之抑制率90¾以上。試驗化合物：例2之目的物。 125 I_BH_物質p結合h-NlU受體 -1 3- 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210Χ 297公釐） (諳先閔讀背面之注意事項再本頁)V. Statement (The present invention relates to novel piperin derivatives or pharmaceutically acceptable salts thereof. In particular, it is related to having antagonistic effects such as rapid hormones (Tachykinin), especially substance P including anti-drugs and neurokinin A) Novel pharmacological derivatives such as antagonism, neurohormone B antagonism, and their pharmacologically acceptable salts, their preparation methods, their pharmaceutical compositions, and their use as medicines. Therefore, the object of the present invention is to provide compounds having rapid hormones Antagonism, especially substance P antagonism, neurohormone A antagonism, neurohormone B and other pharmacological effects of pharmacological effects and its pharmacologically acceptable salts Another object of the present invention is to provide the piperidine derivative and its Method for producing salt Another object of the present invention is to provide a medicinal composition containing the piperidine derivative and a pharmaceutically acceptable salt thereof as an active ingredient. Another object of the present invention is to provide the uranium derivative and a pharmaceutically acceptable salt thereof. As rapid hormone antagonists, especially substance P antagonists, neurohormone A antagonists or neurohormone B antagonists, they can be used to prevent or prevent a rapid hormone in animals or animals. Intermediate diseases, such as asthma, bronchitis, rickets, cough, fatigue, and other respiratory diseases; such as conjunctivitis, spring conjunctivitis, and other eye diseases; such as consumer cooperation with the Central Standards Bureau of the Ministry of Economic Affairs Dermatitis such as inflammation, ramie rash and other eczema-like dermatitis; inflammation such as rheumatoid arthritis, osteoarthritis; pain such as migraine, head, tooth pain, cancer pain, back pain and so on. USP 5,670,505 shows the free body of the compound of formula (I) and salts other than fumarate. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X2.97 mm) 5. Statement (The invention is related to novelty Piperin derivative or its pharmaceutically acceptable salt. Specifically, it is related to pharmacological effects such as the antagonistic action of Tachykinin, especially the substance P, including the antagonistic action of neurokinin A, the antagonistic action of neurohormone B, etc. The novel novel derivatives and pharmacologically acceptable salts thereof, their preparation methods, their medicinal compositions, and their use as medicines. Therefore, the object of the present invention is to provide hormonal antagonistic effects. In particular, novel piperidine derivatives of pharmacological effects such as substance P antagonism, neurohormone A antagonistic effects, neurohormone B including antitumor effects, and their pharmaceutically acceptable salts. Another object of the present invention is to provide the piperidine derivatives and their salts. Preparation method Another object of the present invention is to provide a pharmaceutical composition using the pipe trap derivative and a pharmaceutically acceptable salt thereof as an active ingredient. Another object of the present invention is to provide the pipe trap derivative and a pharmaceutically acceptable salt thereof as Rapid hormone antagonists, especially substance P antagonists, neurohormone A antagonists or neurohormone B antagonists, can be used to prevent acute hormone-mediated diseases such as asthma, bronchitis, rickets, cough, fatigue, etc. Organ diseases; such as conjunctivitis, spring conjunctivitis and other eye diseases; such as dermatitis such as contact printing dermatitis, ectopic dermatitis, ramie rash and other types of eczema dermatitis; Such as rheumatoid arthritis, osteoarthritis and other inflammation; such as migraine, head, toothache, cancer pain, back pain and other pain. Front-end technology: USP 5,670,505 shows the free compounds of compounds of formula (I) and salts other than fumarate. This paper size applies Chinese National Standard (CNS) A4 specification (210X2.97 mm) A7 Β7 Repair, down. ,,,, V. Description of invention () Complementary printing of tumors by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, especially small Cell lung cancer (SCLC); allergies such as kudzu; fibrotic gum disease such as sclera and eosinophilia; reflex sympathetic malnutrition such as chiropody syndrome; rickets such as alcoholism ; Distress-related physical problems; Rheumatism, such as fibrosis. For therapeutic purposes, the object of the present invention (I) and a pharmaceutically acceptable salt thereof are compounded with a pharmaceutically acceptable carrier with one of the compounds as a tongue component, if suitable for oral, parenteral, topical, enteral, intravenous, intramuscular, inhalation ， # Intra-articular, intra-spine, intra-tracheal or intraocular administration of organic or inorganic solid or liquid excipients. This preparation can be solid, semi-solid or solution, such as capsules, tablets, granules, pills, granules, suppositories, chrysanthemums, creams, lotions, inhalants, injections, plasters, gels, tapes, eye drops, Solutions, syrups, aerosols, suspensions, emulsions, etc. If necessary, co-ribs, stabilizers, wetting or emulsifying agents, buffers or other conventional additives can be added. Although the dosage of compound (I) varies depending on the age and physical condition of the patient, the average single dose of compound (I) is about Ql, 1, 10, 50, 100, 250, 5QG and 100Qmg, which can effectively treat rapid hormone intermediation Diseases such as asthma. Each person can administer from 0.1 to about 1.0 Q g in. Per day. To illustrate the usefulness of the target compound (I) and its pharmaceutically acceptable salts, the pharmacological data of the representative compounds are as follows. The following test compounds inhibit h-NKi (human neurokinin-1) receptor binding to 125 I-B H (Bolton Hunter-)-substance P at a concentration of 0,1 w g / ml of more than 90¾. Test compound: the object of Example 2. 125 I_BH_ Substance p binds h-NlU receptor -1 3- This paper is in accordance with Chinese National Standard (CNS) Λ4 specification (210 × 297 mm) (Notes on the back of Min Xian Min are on this page)

、1T A7 B7 經濟部中央標準局員工消費合作社印製1T A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

A7 B7 __ 丨· _' 五、發明説明（I» ) 修正 4 補充本緣求試驗方法125 I-BH-物質P結合h-NK ~-' (a )粗製C Η 0細胞膜收集永久表不h-NKi受體之CHO(Chinese Hamster Ovary)細胞，而用Dounce均化機均化於4°C緩衝液（Q.25M蔗糖，25mM Tris-HC1，PH 7 . 4 , 1 0 m Μ M g C 1 2 ，1 m Μ 乙二胺四乙酸，5"苷/1111?- A P M S F )，而離心（5 0 0 X g， 1 0分）。所得粒子再懸浮於同樣緩衝液，而予以均化及離心。合併二上澄液而離心（ 1 0 0 , 0 0 0 X g , 1小時）。所得粗製細胞膜再懸浮於緩衝液（25mM Tris-HCl，pH7.4， 10mM MgCl2 ，lmM乙二胺四乙酸，5//g/ml p-APMSF),而在-80-C貯存備用。 (b). 125 I-BH-物質P結合粗製膜將細胞膜6 #g/ml與usuh-物質ρ 〇·1ηΜ有或無試A7 B7 __ 丨 · _ 'V. Description of the invention (I ») Amendment 4 Supplementary original test method 125 I-BH-substance P combined with h-NK ~-' (a) Crude C Η 0 Permanent surface of cell membrane collection h -NKi receptor CHO (Chinese Hamster Ovary) cells, and homogenized in 4 ° C buffer (Q.25M sucrose, 25mM Tris-HC1, pH 7.4, 10 m Μ M g C 1 2 1 M ethylenediaminetetraacetic acid, 5 " glycoside / 1111? -APMSF), and centrifuged (500 x g, 10 minutes). The particles obtained were resuspended in the same buffer, homogenized and centrifuged. The two supernatants were combined and centrifuged (100, 000 X g, 1 hour). The resulting crude cell membrane was resuspended in a buffer solution (25 mM Tris-HCl, pH 7.4, 10 mM MgCl2, 1 M ethylenediamine tetraacetic acid, 5 / g / ml p-APMSF), and stored at -80-C until use. (b). 125 I-BH-substance P combined with crude membrane. Cell membrane 6 # g / ml and usuh-substance ρ 〇 · 1ηΜ with or without test.

驗化合物之 0.25ml培養液 2(50mM Tris-HCl，pH7.4, 5mM Μ n C 1 2 , 2 0 μ g / m 1 chyffl〇statin，40；ug/ml 制·菌素， 4Ag/lnl白胃消化素，5Aίg/mlp-APMSI^20(Ug/Bll BSA)保溫22°C 90分。然後迅速吸引濾經Whatman GF/C 經濟部中央標準局員工消费合作社印製玻璃濾器（使用前以0.1 %聚乙烯亞胺預處理3小時。各濾液以 5 m 1 鍰衝液（5 0 m Μ T r i s - H C 1，p Η 7 . 4，Μ n C 1 2 )洗 4 次後，用自動y計數器（Packerd RIASTAR 5 4 2 0 Α)計數放射活性。所有之數據為可由3# M未標幟物質P代替之專一性結合。且本發明目的物，尤其化合物（If)安定性也優異。下面舉製備例及實例說明本發明。料備例1 -1 4 -本紙張尺度適用中國國家標準（CNS ) Λ4規格（2ίΟΧ297公釐）. A7 B70.25 ml of culture solution 2 (50 mM Tris-HCl, pH 7.4, 5 mM M n C 1 2, 20 μ g / m 1 chyffl0statin, 40; ug / ml bacteriocin, 4Ag / lnl white Gastrin, 5Aίg / mlp-APMSI ^ 20 (Ug / Bll BSA) at 22 ° C for 90 minutes. Then quickly filtered through a Whatman GF / C printed glass filter by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. % Polyethyleneimine pretreatment for 3 hours. Each filtrate was washed 4 times with 5 m 1 锾 flushing solution (50 m Μ Tris-HC 1, p Η 7.4, Mn C 1 2), and then used an automatic y counter (Packerd RIASTAR 5 4 2 0 A) Counts radioactivity. All data are specific combinations that can be replaced by 3 # M unmarked substance P. And the object of the present invention, especially the compound (If), also has excellent stability. Preparation examples and examples illustrate the present invention. Material preparation examples 1 -1 4-This paper size is applicable to Chinese National Standard (CNS) Λ4 specifications (2ίΟ × 297 mm). A7 B7

-A-R 五、發明説明（即（21〇-1-〔3,5-雙（三氟甲基）苄醯基]-2-(1}1-?3丨呤甲基）-4-〔 N-(4-甲基-卜哌阱基）胺甲醯甲基）-哌阱，或其富馬酸鹽〔以下簡稱化合物（I f )],以及如下式（I g ) 化合物或其製藥容許鹽 (Ig) 式中R1為三鹵低烷基； R 2為三鹵低烷基， R 3為吲呤低烷基& 為 -或 _C_Cfi (請先閲讀背面之注意事項再填寫本頁) 為r5-AR V. Description of the invention (that is, (21〇-1- [3,5-bis (trifluoromethyl) benzylfluorenyl] -2- (1} 1-? 3 丨 methinylmethyl) -4- [N -(4-methyl-bupiperinyl) carbamidinemethyl) -piperazine, or its fumarate salt [hereinafter referred to as compound (I f)], and a compound of the following formula (I g) or its pharmaceutically acceptable Salt (Ig) where R1 is a trihalo-lower alkyl; R 2 is a trihalo-lower alkyl; R 3 is an indino-lower alkyl & is-or _C_Cfi (Please read the precautions on the back before filling this page ) Is r5

N R \R7 6N R \ R7 6

經濟部中央標隼局員工消費合作社印製其中R5為H或低垸氧羰基， R 6為H或低烷醯基， R7為Η,低烷基，低烷醯基，低烷氧羰基，低烷氧低烷醯基，環低烷羰基，芳醯基或低烷磺醯基。依本發明，目的物或其鹽可由如下圖製法製造。製法1Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs where R5 is H or low-alkoxycarbonyl, R 6 is H or low-alkoxycarbonyl, R7 is fluorene, low-alkyl, low-alkylfluorenyl, low-alkoxycarbonyl, low Alkoxy low alkyl fluorenyl, cyclic low alkyl carbonyl, aryl fluorenyl or low alkyl sulfonyl. According to the present invention, an object or a salt thereof can be produced by the following method. Method 1

(II) 或其在羧基之反應性衍生物或其鹽 H2N-N NCH-3 (III) 或其在胺基之反應性衍生物或其鹽本紙張尺度適用中國國家標隼（CNS ) Λ4規格（21〇'Χ297公t ) Β7五、發明説明0沉）經濟部中央標準局員工消費合作社印製詳言之，化合物（If )(以下稱富馬酸鹽）比非此鹽之鹽酸鹽5水合物（以下簡稱鹽酸鹽）具有種種優點。即如下表所示，富馬酸鹽在吸水性，固態安定性及溶解性等理化性質確比鹽酸鹽為優，故以此富馬酸鹽為主藥則可得更安定之醫藥組成物。試驗項目化合物 - 富馬酸鹽鹽酸鹽吸水性水分 250C,7 日 u%ms 0.60¾ 5.68¾ 33^RH* 0.93% 8.53¾ 53^RHr 1.38% 10.54¾ 75%RH* 2.34¾ 14.86¾ 固態安定性外觀 .初日白晶粉白粉 70 Ό, 9曰白晶粉（稍帶黃）稍帶褐色黃色粉分析初日 100¾ 100¾ 70 *C , 9 B 100.3¾ 92.7¾ . 溶解性' 水11 ^ 200 mg/ml 174 mg/ml 食鹽水r: S 200 mg/ml 177 mg/ml * : R Η =相對濕度 ^ :在室溫振盪30分下面舉製備例及實例說明本發明。製備例1 -14 a - 本紙張尺度適用中國國家標準（CNS ) A4規格（210Χ29?公釐） (請先閱讀背面之注意事項^/氟本頁) 五、發明説明（々） mm?. A7 B7(II) or its reactive derivative at the carboxyl group or its salt H2N-N NCH-3 (III) or its reactive derivative at the amine group or its salt The paper size applies to the Chinese National Standard (CNS) Λ4 specification (21〇′297297 t) B7 V. Description of the Invention 0) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. In detail, the compound (If) (hereinafter referred to as fumarate) is a hydrochloride salt other than this salt. 5 hydrate (hereinafter referred to as the hydrochloride) has various advantages. That is, as shown in the following table, fumarate is better than hydrochloride in physicochemical properties such as water absorption, solid stability and solubility. Therefore, using fumarate as the main drug can obtain a more stable pharmaceutical composition. . Test project compound-Fumarate hydrochloride water absorption 250C, 7% u% ms 0.60¾ 5.68¾ 33 ^ RH * 0.93% 8.53¾ 53 ^ RHr 1.38% 10.54¾ 75% RH * 2.34¾ 14.86¾ Solid state stability Appearance of white crystal powder at the beginning of the day 70 9, white crystal powder (slightly yellow), brownish yellow powder analysis at the beginning of the day 100¾ 100¾ 70 * C, 9 B 100.3¾ 92.7¾. Solubility 'Water 11 ^ 200 mg / ml 174 mg / ml saline r: S 200 mg / ml 177 mg / ml *: R Η = relative humidity ^: shake at room temperature for 30 minutes The following preparation examples and examples illustrate the invention. Preparation Example 1 -14 a-This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210 × 29? Mm) (Please read the notes on the back ^ / Fluorine page first) 5. Description of the invention (々) mm ?. A7 B7

(工）或其鹽(Work) or its salt

h〇2cch hcco2h (I) 或其富馬酸鹽以外之鹽經濟部中央標準局員工消費合作社印製 Ηh〇2cch hcco2h (I) or its salt other than fumarate. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. Η

H〇2CCH h!：C〇2H (If) (請先閲讀背面之注意事項再填寫本頁)H〇2CCH h !: C〇2H (If) (Please read the precautions on the back before filling this page)

本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X297公釐） A7 B7 五、發明説明（4 靱法3This paper size applies to Chinese National Standard (CNS) Λ4 specification (210X297 mm) A7 B7 V. Description of invention (4)

W-Aj-R4 (V) 或其鹽W-Aj-R4 (V) or its salt

或其在亞胺基之反應性衍生物或其鹽餺法4Or its reactive derivative or its salt in an imine group

Ug·) 或其翰 —5Λί 7Ν ΧΐΤΐUg ·) or Han — 5Λί 7Ν ΧΐΤΐ

(IV) HOOC-A^^-R^ (VI) 或其在羧基之反應性衍生物或其鹽(IV) HOOC-A ^^-R ^ (VI) or its reactive derivative at the carboxyl group or its salt

ι-R" 或其鹽或其在亞胺基之反前同各 4 R S及鹽彐其 R 或， 2 物 R 生’ 衍R1 性中應其為經濟部中央標準局員工消費合作杜印製鹽毒無用習為鹽許容藥 K S9 及鹽鹽酸當機適有之如物 , 的鹽。目成基及加離物酸為 '發括 W 出包鹽酸乙氟三鹽酸乙如鹽酸® 石), 酒等 -鹽鹽酸酸磺來苯馬甲甲鹽酸機，碘鹽氫酸，甲鹽，酸鹽溴酸氫磺，苯鹽，酸鹽鹽酸如磺ί (請先閲讀背面之注意事項再填寫本頁)ι-R " or its salt or its 4 or RS before the imide group, its R or R 2, R 1, R 1 should be printed for the consumer cooperation of the Central Standards Bureau of the Ministry of Economic Affairs The use of salt poisoning is the salt of salt, salt, salt, and salt. The basis of the base and the added acid is' Faucet W, Ethyl Hydrochloride, Ethyl Trifluoride, Ethyl Hydrochloride, etc.), wine, etc.-Hydrochloric acid, sulfenylmethyl methyl chloride hydrochloride machine, iodohydrochloric acid, methyl salt, acid Hydrogen sulfonate, benzene salt, hydrochloride such as sulfonium (Please read the precautions on the back before filling this page)

本紙張尺度適用中國國家標隼（CNS ) Λ4規格（2!0X297公釐〉經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明（r ) 酸鹽，硫酸鹽，硝酸鹽，磷酸鹽等），或與胺基酸（如精胺酸，天冬胺酸，麩胺酸等）之鹽，或金屬鹽，如鹼金屬鹽（如鈉.鹽，鉀鹽等），及鹼土金屬鹽（如鈣鹽，鎂鹽），有機鹼鹽（如三甲胺鹽，三乙胺鹽，咄啶鹽，甲基毗啶鹽，二環己胺鹽，N,tr-二苄基乙二胺鹽等）等。本文中包括在本發明内之種種定義之適例詳述如下。除另行規定外，「低」乃指C i - 6，宜C i - 4。適當之「低烷基」及在「吲哚低烷基」及「低烷磺醯基」中「低烷基J為直或分枝Ci - 6者，可為甲基，乙基，丙基，異丙基，丁基，異丁基，戊基，己基等。適當之「三鹼低烷基」可為三氯甲基，三溴甲基，三氟甲基等。適當之「低烷氧基」及在「低烷氧羰基j及「低烷氣低烷醯基」中「低烷氣基J可為甲氣基，乙氧基，異丙氧基，丁氣基等。適當之「低烷醯基」及在「低烷氣低烷醯基」中「低烷醯基」可為甲醯基，乙醯基，丙醯基，丁醯基，異丁醯基，戊醯基，己醯基，特戊醯基等。在「環低烷羰基」中適當之「環低烷基」可為環丙基，環丁基，環戊基，環己基等。適當之芳醯基可為苄醯基，甲苄醯基，萊甲醯基等。適當之「離基」可為羥基，從羥基衍生之反應性基。適當之「從羥基衍生之反應性基」可為酸殘基等。適當之「酸殘基」為鹵素（如氟，氯，溴，碘），醯氧 -7 - 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X 297公釐） (請先閱讀背面之注意事項再填寫本頁) d A7 B7 五、發明説明（k ) 基（如乙醯氧基，甲苯磺醯氧基，甲磺醯氧基等）等。本發明目的物之製法1〜4詳述如下/ 製法1 化合物（I)或其鹽可令化合物（II)或其在羧基之反應性衍生物或其鹽與化合物（III)或其在胺基之反應性衍生物或其鹽反應來製造。化合物（II)在羧基之適當反應性衍生物可包括醯鹵，酐，活化醯胺，活化酯.，低烷酯等。例如醯氣；醯基壘氮；與下列酸之混合酐；如取代磷酸〔如二烷基磷酸，苯基磷酸，二苯基磷酸，二苄基磷酸，鹵化磷酸等〕，二烷基亞磷酸，亞硫酸，硫代硫酸，硫酸，磺酸〔如甲磺酸等〕，脂族羧酸〔如乙酸，丙酸，丁酸，異丁酸，特戊酸，戊酸，異戊酸，2 -乙基丁酸，三氣乙酸等〕或芳族羧酸〔如苯甲酸等〕；對稱酐；與眯唑，4-取代眯唑，二甲基毗唑，***，四唑之活化醯胺；或活化酯〔如氣甲酯，甲氣甲酯，二甲亞胺甲酯〔（CH3)2N+ =CH-〕經濟部中央標隼局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) ，乙烯酯，丙炔酯，對硝苯酯，2, 4 -二硝苯酯，三氣苯酯，五氯苯酯，甲磺醯苯酯，苯偶氤苯酯，苯硫酯，對硝苯硫酯，對甲酚硫酯，羧甲硫酯，吡喃酯，毗啶酯，哌啶酯，8-IS啉硫酯等〕.，或與N-羥基化合物〔如N，N-二甲基羥胺，卜羥基-2-(1Η)-吡啶酮，N-羥基丁二醯亞胺，N-羥基酞醯亞胺，1-羥基-1H-苯駢***等〕之酯等。這些反應衍生物可依所用化合物（II)之種類任意選擇。化合物（III)在胺基之適當反應性衍生物包括令化合 -8 -本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X 297公釐） A7 B7 經濟部中央標準局員工消費合作杜印製This paper size applies to Chinese National Standard (CNS) Λ4 specification (2! 0X297 mm) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. Description of the invention (r) Acid, sulfate, nitrate, phosphate Etc.), or with amino acids (such as arginine, aspartic acid, glutamic acid, etc.), or metal salts, such as alkali metal salts (such as sodium, potassium, etc.), and alkaline earth metal salts (Such as calcium salt, magnesium salt), organic base salts (such as trimethylamine salt, triethylamine salt, pyridine salt, methylpyridine salt, dicyclohexylamine salt, N, tr-dibenzylethylenediamine salt) and many more. Suitable examples of the various definitions included in the invention herein are detailed below. Unless otherwise specified, "low" refers to Ci-6, preferably Ci-4. Appropriate "low alkyl" and "indol low alkyl" and "low alkylsulfonyl" "low alkyl J is straight or branched Ci-6, which may be methyl, ethyl, propyl , Isopropyl, butyl, isobutyl, pentyl, hexyl, etc. Suitable "tribase lower alkyl" may be trichloromethyl, tribromomethyl, trifluoromethyl and the like. Appropriate "low alkoxy" and "low alkoxycarbonyl j" and "low alkoxy low alkyl" may be methyl, ethoxy, isopropoxy, butane The appropriate "lower alkyl" and the "lower alkyl" in the "lower alkyl" may be methyl, ethyl, propyl, propyl, butyl, isobutyl, pentyl Base, hexamyl, tamyl, etc. Suitable "cyclo-lower alkyl" in "cyclo-lower alkylcarbonyl" may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. Suitable arylfluorenyl groups may be benzylfluorenyl, methylbenzylfluorenyl, lymefluorenyl and the like. A suitable "free radical" may be a hydroxyl group, a reactive group derived from a hydroxyl group. A suitable "reactive group derived from a hydroxyl group" may be an acid residue or the like. Appropriate "acid residues" are halogens (such as fluorine, chlorine, bromine, and iodine), and oxygen-7.-This paper size applies the Chinese National Standard (CNS) Λ4 specification (210X 297 mm) (Please read the note on the back first) Please fill in this page for matters) d A7 B7 V. Description of the invention (k) group (such as ethoxyl, tosylsulfonyloxy, methanesulfonyloxy, etc.). The production methods 1 to 4 of the object of the present invention are detailed below. Production method 1 The compound (I) or a salt thereof allows the compound (II) or a reactive derivative thereof at a carboxyl group or a salt thereof with the compound (III) or an amine group thereof. It is produced by reacting a reactive derivative or a salt thereof. Suitable reactive derivatives of the compound (II) at the carboxyl group may include halogen halides, anhydrides, activated amidines, activated esters, lower alkyl esters, and the like. For example tritium gas; tritium barrier nitrogen; mixed anhydride with the following acids; such as substituted phosphoric acid [such as dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, etc.], dialkyl phosphorous acid , Sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid [such as methanesulfonic acid], aliphatic carboxylic acid [such as acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, valeric acid, isovaleric acid, 2 -Ethyl butyric acid, trigas acetic acid, etc.] or aromatic carboxylic acids such as benzoic acid, etc .; symmetric anhydride; with oxazole, 4-substituted oxazole, dimethylpyrazole, triazole, tetrazole, etc. Amine; or activated esters [such as methyl methyl, methyl methyl, dimethyl imine [(CH3) 2N + = CH-] printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back first) Fill out this page again), vinyl esters, propynyl esters, p-nitrophenyl esters, 2, 4-dinitrophenyl esters, trisylphenyl esters, pentachlorophenyl esters, mesyl sulfonyl phenyl, benzophenidyl phenyl, benzene Thioesters, p-n-phenylthioesters, p-cresol thioesters, carboxymethylthioesters, pyranyl esters, pyridinyl esters, piperidinyl esters, 8-IS phosphonium thioesters, etc.], or with N-hydroxy compounds [such as N, N-two Methylhydroxylamine, hydroxy-2- (1Η) -pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzenetriazole, etc.] and the like. These reaction derivatives can be arbitrarily selected depending on the kind of the compound (II) to be used. Appropriate reactive derivatives of compound (III) in the amine group include chemical compounds -8-This paper size applies Chinese National Standard (CNS) Λ4 specification (210X 297 mm) A7 B7 Consumption cooperation printed by employees of the Central Standards Bureau of the Ministry of Economic Affairs

五、發明説明 ( 7 ) 1 1 物 (I II )與如醛，酮等羰基化合物反應所生成之許夫氏 1 鹼型亞胺 t 或其互變烯胺型異構物 9 由化合物 (I II )與 1 I 如雙 (Ξ ξ甲基矽烷基）乙 m pun 胺 9 αα 早 (三甲基矽烷基）乙醯胺 y---v 請 1 9 雙 (三甲基矽烷基）脲等矽烷基化合物反應而成之矽烷先閱 1 | 讀 1 基衍生物由化合物 (I II )與三氣化磷或光氣反應而成背 1 1 之衍生物等〇之注 1 I 意 I 反應常在習用溶劑 9 如水醇 [ 如甲醇 » 乙醇等 ), 事項 1 I 再 1 I 丙酮 9 二 U咢烷 9 乙腈 9 氣仿 9 二氯甲烷，二氯乙烷 ,四 f ( 叫氫呋喃 9 乙酸乙酯 9 N , N- 二甲基甲醯胺吡啶 9 或對反本頁 1 應無不良影 m 之任何其他有機傾溶劑 Ο 這習用溶劑也可 1 1 與水混合〇 1 | 在此反應中 9 若化合物 (I I)以商由酸或其鹽使用，反 1 1 應宜在如下列習用縮合劑之存在下進行 9 如 N , N ' -二二環訂 | 己基 m 化二亞胺 1 N- 環己基 -N '_ 嗎啉乙基磺化二亞胺； 1 I N- 環己基 -N ! (4 -二乙胺基己基） m 化二亞胺 N , N ' -二 1 1 乙基碩化二亞胺 9 N , N ' -二異丙基碩化二亞胺 N -乙基 1 | -N « _ (3 -二甲胺丙基）硝化二亞胺五亞甲基烯酮 -N -璟 '·] ..^ 己基亞胺 9 二苯烯酮 -N -環己亞胺；乙氣基乙炔 1 -院 1 1 氣基 -1 _院氧基- 1 - 氯乙烯亞 m 酸三院酯 9 聚 m 酸乙酯 1 1 9 聚磷酸異丙酯 9 氧氯化磷（磷醯氣 ); 二氯化磷二苯 1 1 基磷醯叠氮亞磺醛氯草 m 氯；齒甲酸低院酯 C 如氣 1 1 甲酸乙酯氣甲酸異丙酯等 ] ，二苯 m ； 2- 乙基 -7 -羥 1 I 基苯駢異唑 m 鹽；氫氧化 2 - -乙基 - 5 - :間磺酸苯基 )異 1 1 Kg 唑 m 分子内鹽 9 1 -(對氯苯磺醯氧 -9 - 基）-6-氯- -1H-苯駢 1 1 Ί 1 1 I 本紙張尺度適用中國國家標準（CNS ) Λ4規格（2丨0X 297公釐） A7 B7 經濟部中央標準局員工消費合作社印製五、發明説明 ( ) I 二脞 » 1 - 羥基苯駢三唑 * 如碘化 2- 氯 -1 -甲基吡錠等 1 Mu k a iy am a試劑； 1 -( 3- 二甲胺丙基 )-3- 乙基碩化二亞 1 I 胺本身或與 1 - 羥基苯駢三唑之合劑 » 由N N -二甲基甲醯 —V 1 I 請 | 胺與亞磺醯氯 $ 光氣 » 氯甲酸三氣甲酯，氧氣化 m 等反先閲 1 I 讀 1 應製得之 Vi Is hi e i e r試劑等，或這些之混合物。背面 1 I 反應也可在如鹼金屬重碩酸鹽 9 — 低烷胺，吡啶 > N- 之注 1 1 意 | 低烷基嗎啉 1 N， N- 二低院苄胺等無機或有機鹼之存在下事項 1 I 再 I I 進行 0 If 反應溫度無關緊要，常在冷卻〜加溫下進行。頁 1 製法 2 1 1 百的物 (I η 可令化合物 (I )或其富馬酸以外之鹽與富 1 I 馬酸反應來製造〇 1 1 反應常在習用溶劑 > 如水 9 醇 [ 如甲醇 ,乙醇等 ] 9 訂 I 丙酮 9 2- 丁 m 二 m 院 > 乙腈 > 氣仿 ,二氛甲院 * 二氣 1 1 乙院 9 四氩咲喃 9 乙酸乙酯 9 Ν， N- 二甲基甲醯胺 9 吡旋 1 1 或對反應無不良影鎏之任何其他有機溶劑。這習用 1 I 溶劑也可與水混合〇反應溫度無駸定 ί 常在冷卻 t 室溫或加溫下反應 Ο 1 1 製法 3 1 I 百的物 (Ig ' )或其鹽可令化合物< ‘Π r)或其在亞胺基之 1 1 反應性衍生物或其鹽與化合物 (V)或其鹽反應1 K製ΐ S C 1 1 化合物 (IV)在胺基之適田反應性衍生物包括令化合物 1 | (] V) 與如醛 $ m 等羰基化合物反應所生成之許夫氏鹼型 1 1 亞胺或其互變烯胺型異構物由化合物 (IV >與如雙 ( 1 -] 10- 1 1 1 本紙張尺度適州中國國家標準（CNS ) Λ4規格（2丨0X297公漦.) A7 B7 五、發明説明（9 ) ' 三甲基矽烷基）乙醯胺，單（三甲基矽烷基）乙醯胺，雙 (三甲基矽烷基）脲等矽烷基化合物反應而成之矽烷基衍生物；由化合物（IV)與三氯化磷或光氣反應而成之衍生物等。此反應常在如醇〔如甲醇，乙醇等〕，二氛甲烷，苯 ,Ν,Ν -二甲基甲醯胺，四氫呋喃，***或任何其他對反應無不良影ϋ之任何其他溶劑中進行。反應可在無機或有機鹾之存在下進行，諸如鹼金屬氫氧化物〔如NaOH，KOH等],鹼金屬硪酸鹽〔如磺酸鈉，碩酸鉀等〕，鹼金屬重磺酸鹽〔如重碩酸鈉，重磺酸鉀等〕，鹼金屬氫化物〔如NaH,KH等〕，三低烷胺〔如三甲胺，三乙胺，二異丙基乙胺等〕，吡啶或其衍生物〔如甲基吡啶，二甲基吡啶，4 -二甲胺基吡啶等]等。若所用鹼為液體，也可當作溶劑。反應溫度無嚴定，可在冷卻，室溫，加溫或加熱下反應。製法4 經濟部中央標準局員工消費合作社印裝 (請先閲讀背面之注意事項再填寫本頁) 目的物（Ig")或其鹽可令化合物（IV)或其在亞胺基之反應性衍生物或其鹽與化合物（VI)在羧基之反應性衍生物或其鹽反應來製造。此反應可仿製法1 Q進行。目的物（I)及其製藥容許鹽具有藥理活性，如拮抗急速激素，尤其物質P，神經激素A或B ,故可用以防治急速激素，尤其物質P仲介疾病，例如呼吸糸疾病，如氣 _ 1 1 _ 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210 X 297公釐） A7 B7 五、發明説明（…） (請先閲讀背面之注意事項再填寫本頁) 喘，枝氣管炎（如慢性及急性枝氣管炎，及全細枝氣管炎等），#炎，咳痰等；眼疾，如結膜炎，春季結膜炎等；皮慮病，如接觸皮慮炎，異位皮癢炎，莽痳疹，及其他類濕疹皮慮炎等；炎症，如類風濕性關節炎，骨關節炎等；疼痛（如偏頭痛，頭痛，簇頭痛，牙痛，癌痛，背痛，神經痛等）等。本發明之目的物（I)及其製藥容許鹽又可望防治眼疾，如青光眼，葡萄膜炎等；胃腸病，如潰瘍，潰瘍性大腸炎，剌激性腹症候群，食物過敏等；炎症，如腎炎等；循環糸病，如高血壓，狹心症，心臓衰竭，栓塞，雷諾氏病等；癲癇；痙孿性痲痺；頻尿；膀胱炎，迫尿肌反射過強；尿失禁；痴呆症；愛滋病相關痴呆症；阿滋海黙症；Down氏症候群；亨丁頓氏舞蹈症，類癌症候群；免疫增強或抑制相關疾病等。本發明之目的物（I)及其製藥容許鹽更可望防治慢性肺阻塞，尤其慢性肺氣腫；虹膜炎；增殖性玻璃狀體視網膜病；牛皮癖；腸炎，尤其Crohn氏病；肝炎；凍傷，灼傷，帶狀庖疹或糖尿病性神經病上表面痛；附於高經濟部中央標準局員工消費合作社印製陰氣；裂化胞女枝性分硬小 ;.; 變神索；後炎維精側腫· 術喉纖及性浮手咽囊劣縮之房；；惡萎起乳蘚核情肌引. 其苔結心及傷尤平肺，症熱，扁；鬱化由腫，咳.抑硬如經癢日，性，2-神之百盧發腫-1 後伴.，焦多浮術隨病其如；手析著尤，弱 ;透沈，病衰痛液埃病失之腱血塵神脱啉之；；精鞘嗎症炎 '張；髓禁血庭擴吐；.，脂前管嘔症症本紙張尺度適用中國國家標準（CNS ) Λ4規格（2丨0X 297公釐） A7 Β7 修，下.，、 , 五、發明説明（) 補无經濟部中央標準局員工消費合作社印製腫瘤，尤其小胞肺癌（SCLC);如野葛等過敏症；纖維變性膠辱病，如鞏皮症及嗜伊紅性瓜仁蟲病；反射交感性營養不良，如扃手症候群；瘸病，如酒精中毒；窘迫相關身體毛病；風濕病，如纖維組織炎等。治療上，本發明之目的物（I)及其製藥容許鹽以一種該化合物為舌性成分摻和製藥容許載體，如適合口服，非口服，局部外用，腸内，靜脈内，肌肉内，吸入，# 内，關節内，脊椎内，經氣管或經眼投予之有機或無機固體或液體賦.形劑之劑型使用。此製劑可為固體，半固體或溶液，如膠囊，錠，粒，丸，顆粒，栓劑，軟菊=，霜劑，洗液，吸入劑，注射，硬膏，凝膠，膠帶，點眼藥，溶液，糖漿，氣溶膠，懸浮液，乳液等。必要時可再加輔肋劑，安定劑，潤濕或乳化劑，缓衝劑或其他習用添加劑。化合物（I)之劑量雖視病人之年龄及體況而異，但化合物（I)之平均單一劑量為約Q.l, 1, 10, 50, 100, 250, 5QG及lOOQmg,可有效治療急速激素仲介疾病，如氣喘等。每人每日可投予〇 . 1〜約1 , Q 〇〇 in g。為說明目的物（I)及其製藥容許鹽之有用性，其代表化合物之藥理數據如下。下列試驗化合物以0, 1 w g/ ml之濃度時對h-NKi ( human neurokinin-1)受體結合 125 I-B H (Bolton Hunter-) -物質P之抑制率90¾以上。試驗化合物：例2之目的物。 125 I_BH_物質p結合h-NlU受體 -1 3- 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210Χ 297公釐） (諳先閔讀背面之注意事項再本頁)V. Description of the invention (7) 1 Schiff's 1 formed by the reaction of a compound (I II) with a carbonyl compound such as aldehyde, ketone, etc. 1 Basic imine t or its tautomeric enamine isomer 9 From compound (I II) and 1 I such as bis (Ξ ξ methylsilyl) ethyl m pun amine 9 αα early (trimethylsilyl) acetamidamine y --- v please 1 9 bis (trimethylsilyl) urea etc. Silanes made by reaction of silane compounds. Read 1 | Read 1 Derivatives. Compounds (I II) react with phosphorus trioxide or phosgene to form derivatives of 1 1 etc. Note 1 I means I reaction often Common solvents 9 such as hydroalcohol [such as methanol »ethanol, etc.], Matter 1 I then 1 I Acetone 9 DiUxane 9 Acetonitrile 9 Aeroform 9 Dichloromethane, dichloroethane, tetraf (called hydrofuran 9 ethyl acetate) Esters 9 N, N-dimethylformamidine pyridine 9 or any other organic solvent which should have no adverse effect on the reverse page 1 〇 This conventional solvent can also be mixed with water 1 1 | In this reaction 9 If compound (II) is used commercially as an acid or its salt, trans 1 1 should be carried out in the presence of the following conventional condensing agent 9 N, N '-Dibicyclodine | Hexylmethanediimine 1 N-cyclohexyl-N' _morpholineethylsulfonimide; 1 I N-cyclohexyl-N! (4 -diethylamine Hexyl) m-diamine N, N'-di 1 1 Ethyl-diimine 9 N, N'-diisopropyl-per-imide N-ethyl 1 | -N _ (3 -Dimethylaminopropyl) nitrated diimidepentamethyleneketene-N-璟 '·] .. ^ hexylimine 9 benzophenone-N -cycloheximide; 1 1 Gas-based-1 _Hydroxy-1-Trichloroethylene methylene acid triethyl ester 9 Polymethane ethyl ester 1 1 9 Isopropyl polyphosphate 9 Phosphorus oxychloride (phosphorus tritium); Phosphorus dichloride Diphenyl 1 1 phosphonium azide sulfinaldehyde chloral chloride m chloride; dentate formic acid low ester C such as gas 1 1 ethyl formate Isopropyl formate, etc.], diphenyl m; 2-ethyl-7-hydroxy1 I phenylbenzisoxazole m salt; 2-ethyl-5-hydroxide: phenyl m-sulfonic acid) iso-1 1 Kg azole m Intramolecular salt 9 1-(p-chlorobenzenesulfonyloxy-9-yl) -6-chloro- -1H-benzene hydrazone 1 1 1 1 1 I This paper size applies the Chinese National Standard (CNS) Λ4 specification ( 2 丨 0X 297 mm) A7 B7 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention () I Difluorene »1-Hydroxybenzotriazole * such as 2-chloro-1 -methylpyridine Etc. 1 Mu ka iy am a reagent; 1-(3-dimethylaminopropyl) -3-ethylsulfonated diimide 1 I amine itself or a mixture with 1-hydroxybenzotriazole »by NN -dimethyl Methyl hydrazone—V 1 I Please | Amine and sulfenyl chloride $ Phosgene »Trimethyl chloroformate, oxygenated m, etc. Read first 1 I Read 1 Vi Is hi eier reagents, etc., or these Of a mixture. The 1 I reaction on the back can also be performed on inorganic or organic compounds such as alkali metal bisulfate 9 — low alkylamine, pyridine &N; Note 1 1 | low alkylmorpholine 1 N, N-di-lower benzylamine Matters in the presence of a base 1 I then II. 0 If the reaction temperature does not matter, it is usually carried out under cooling to heating. Page 1 Preparation method 2 1 1 100 (I η can make compound (I) or its salt other than fumaric acid and 1 1 fumaric acid to react. 0 1 1 reactions are often used in conventional solvents> such as water 9 alcohols [such as Methanol, ethanol, etc.] 9 Order I Acetone 9 2-Butan m 2 m House > Acetonitrile > Gas-form, Erhuang Jiayuan * Di gas 1 1 E Yuan 9 Tetrahydrofuran 9 Ethyl acetate 9 Ν, N- Dimethylformamide 9 Pyridine 1 1 or any other organic solvent that does not adversely affect the reaction. This customary 1 I solvent can also be mixed with water. The reaction temperature is not fixed. It is usually cooled at room temperature or warmed. 〇 1 1 Preparation method 3 1 I Hundred things (Ig ') or its salt can make compound <' Π r) or its 1 1 reactive derivative or its salt with imine group and compound (V) or Its salt reacts with 1 K to make SC 1 1 and the amine-based Shida reactive derivative includes the compound 1 | (] V) and Schiff ’s base type 1 1 imine or its tautoenyl isomer formed by the reaction of carbonyl compounds such as aldehydes and m is composed of compounds (IV > and bis (1-) 10- 1 1 1 Shizhou Chinese National Standard (CNS) Λ4 specification (2 丨 0X297 gong.) A7 B7 V. Description of the invention (9) 'Trimethylsilyl) acetamide, mono (trimethylsilyl) acetamide, Silyl derivatives derived from the reaction of bis (trimethylsilyl) urea and other silyl compounds; derivatives derived from the reaction of compound (IV) with phosphorus trichloride or phosgene, etc. (Such as methanol, ethanol, etc.), dichloromethane, benzene, Ν, Ν-dimethylformamide, tetrahydrofuran, ether, or any other solvent that does not adversely affect the reaction. The reaction can be performed in inorganic or organic solvents. In the presence of, for example, alkali metal hydroxides [such as NaOH, KOH, etc.], alkali metal phosphonates [such as sodium sulfonate, potassium sulfonate, etc.], alkali metal heavy sulfonates [such as sodium bisulfate, heavy Potassium sulfonate, etc.], alkali metal hydride [such as NaH, KH, etc.] , Tri-lower alkylamine [such as trimethylamine, triethylamine, diisopropylethylamine, etc.], pyridine or its derivatives [such as methylpyridine, dimethylpyridine, 4-dimethylaminopyridine, etc.] and the like. If the base used is a liquid, it can also be used as a solvent. The reaction temperature is not critical and can be reacted under cooling, room temperature, heating or heating. Method 4 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) The target substance (Ig ") or its salt can be derived from the compound (IV) or its imino group A substance or a salt thereof is produced by reacting a reactive derivative of a compound (VI) with a carboxyl group or a salt thereof. This reaction can be carried out by imitation 1 Q. The target substance (I) and its pharmacologically acceptable salts have pharmacological activities, such as antagonizing rapid hormones, especially substance P, neurohormones A or B, so it can be used to prevent and cure rapid hormones, especially substance P, such as respiratory diseases, such as qi. 1 1 _ This paper size applies the Chinese National Standard (CNS) Λ4 specification (210 X 297 mm) A7 B7 V. Description of the invention (…) (Please read the precautions on the back before filling this page) Asthma, bronchitis ( Such as chronic and acute bronchitis, and panbronchiolitis, etc.), # inflammation, sputum, etc .; eye diseases, such as conjunctivitis, spring conjunctivitis, etc .; skin anxiety, such as contact dermatitis, ectopic dermatitis, rash Eczema, and other eczema-like dermatitis; inflammation, such as rheumatoid arthritis, osteoarthritis, etc .; pain (such as migraine, headache, cluster headache, toothache, cancer pain, back pain, neuralgia, etc.) Wait. The object of the present invention (I) and its pharmaceutically acceptable salts are also expected to prevent and treat eye diseases such as glaucoma and uveitis; gastrointestinal diseases such as ulcers, ulcerative colitis, irritable abdominal syndrome, food allergies, etc .; inflammation, Such as nephritis; circulatory rickets, such as hypertension, angina, heart palpitations, embolism, Raynaud's disease, etc .; epilepsy; spastic paralysis; frequent urination; cystitis, hyperuric detrusor reflex; urinary incontinence; dementia AIDS-related dementia; Alzheimer's disease; Down's syndrome; Huntington's disease, carcinoid syndrome; immune-enhancing or suppression-related diseases. The object of the present invention (I) and its pharmacologically acceptable salt are more expected to prevent and treat chronic pulmonary obstruction, especially chronic emphysema; irisitis; proliferative vitreoretinopathy; psoriasis; enteritis, especially Crohn's disease; hepatitis; Frostbite, burns, shingles, or diabetic neuropathy; upper surface pain; attached to the Consumer Cooperative of the Central Bureau of Standards of the Ministry of High Economics; printed Yin Qi; Spermoid swelling · The room where the laryngeal fiber and the floating pharyngeal sac are inferior; the malignant atrophy is caused by the lichen moss nucleus and the muscles. The moss, the heart and the injury are flat, the lungs are hot, and the flatness; the depression is caused by the swelling, the cough . Stiff as hard as menstruation, sex, 2-God's Bailu swollen -1 after accompanied by, Jiao Duo Fu surgery as the disease; hand analysis, especially weak; Shen Shen, illness and pain fluid loss Tendons of blood and dust from the dermatophyte; dermatophytitis; Zhang; myeloablative dilation;., Pre-lipitia vomiting; this paper applies Chinese National Standard (CNS) Λ4 specification (2 丨 0X 297 (Mm) A7 Β7 repair, next. ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, _______ ,,,,,,,,,,,,,,,,,,,,,-,-,-,-,,,,,,,,,,,,,,,,,-,-,-,-,-,-,-,,,,,,,,,,,,,,,-,,,-,,,-,,,-,,-,,-,,-,,,,,,,,,,-,,-,,-,,-,,,,- In particular, small cell lung cancer (SCLC); allergies such as kudzu; fibrotic gum disease, such as sclera and eosinophilia; reflex sympathetic malnutrition such as chiropody syndrome; rickets, Such as alcoholism; distress-related physical problems; rheumatism, such as fibrosis. For therapeutic purposes, the object of the present invention (I) and a pharmaceutically acceptable salt thereof are compounded with a pharmaceutically acceptable carrier with one of the compounds as a tongue component, if suitable for oral, parenteral, topical, enteral, intravenous, intramuscular, inhalation ， # Intra-articular, intra-spine, intra-tracheal or intraocular administration of organic or inorganic solid or liquid excipients. This preparation can be solid, semi-solid or solution, such as capsules, tablets, granules, pills, granules, suppositories, chrysanthemums, creams, lotions, inhalants, injections, plasters, gels, tapes, eye drops, Solutions, syrups, aerosols, suspensions, emulsions, etc. If necessary, co-ribs, stabilizers, wetting or emulsifying agents, buffers or other conventional additives can be added. Although the dosage of compound (I) varies depending on the age and physical condition of the patient, the average single dose of compound (I) is about Ql, 1, 10, 50, 100, 250, 5QG and 100Qmg, which can effectively treat rapid hormone intermediation Diseases such as asthma. Each person can administer from 0.1 to about 1.0 Q g in. Per day. To illustrate the usefulness of the target compound (I) and its pharmaceutically acceptable salts, the pharmacological data of the representative compounds are as follows. The following test compounds inhibit h-NKi (human neurokinin-1) receptor binding to 125 I-B H (Bolton Hunter-)-substance P at a concentration of 0,1 w g / ml of more than 90¾. Test compound: the object of Example 2. 125 I_BH_ Substance p binds h-NlU receptor -1 3-This paper size applies Chinese National Standard (CNS) Λ4 specification (210 × 297 mm)

、1T A7 B7 __ 丨· _' 五、發明説明（I» ) 修正 4 補充本緣求試驗方法125 I-BH-物質P結合h-NK ~-' (a )粗製C Η 0細胞膜收集永久表不h-NKi受體之CHO(Chinese Hamster Ovary)細胞，而用Dounce均化機均化於4°C緩衝液（Q.25M蔗糖，25mM Tris-HC1，PH 7 . 4 , 1 0 m Μ M g C 1 2 ，1 m Μ 乙二胺四乙酸，5"苷/1111?- A P M S F )，而離心（5 0 0 X g， 1 0分）。所得粒子再懸浮於同樣緩衝液，而予以均化及離心。合併二上澄液而離心（ 1 0 0 , 0 0 0 X g , 1小時）。所得粗製細胞膜再懸浮於緩衝液（25mM Tris-HCl，pH7.4， 10mM MgCl2 ，lmM乙二胺四乙酸，5//g/ml p-APMSF),而在-80-C貯存備用。 (b). 125 I-BH-物質P結合粗製膜將細胞膜6 #g/ml與usuh-物質ρ 〇·1ηΜ有或無試、 1T A7 B7 __ 丨 · _ 'V. Description of the invention (I ») Amendment 4 Supplementary original test method 125 I-BH-substance P combined with h-NK ~-' (a) Crude C Η 0 Cell membrane collection permanent table H-NKi receptor-free CHO (Chinese Hamster Ovary) cells were homogenized in a 4 ° C buffer (Q.25M sucrose, 25mM Tris-HC1, pH 7.4, 10 m MM) using a Dounce homogenizer. g C 1 2, 1 μM ethylenediaminetetraacetic acid, 5 " glycoside / 1111? -APMSF), and centrifuged (500 X g, 10 minutes). The particles obtained were resuspended in the same buffer, homogenized and centrifuged. The two supernatants were combined and centrifuged (100, 000 X g, 1 hour). The resulting crude cell membrane was resuspended in a buffer solution (25 mM Tris-HCl, pH 7.4, 10 mM MgCl2, 1 M ethylenediamine tetraacetic acid, 5 / g / ml p-APMSF), and stored at -80-C until use. (b). 125 I-BH-substance P combined with crude membrane. Cell membrane 6 # g / ml and usuh-substance ρ 〇 · 1ηΜ with or without test.

驗化合物之 0.25ml培養液 2(50mM Tris-HCl，pH7.4, 5mM Μ n C 1 2 , 2 0 μ g / m 1 chyffl〇statin，40；ug/ml 制·菌素， 4Ag/lnl白胃消化素，5Aίg/mlp-APMSI^20(Ug/Bll BSA)保溫22°C 90分。然後迅速吸引濾經Whatman GF/C 經濟部中央標準局員工消费合作社印製玻璃濾器（使用前以0.1 %聚乙烯亞胺預處理3小時。各濾液以 5 m 1 鍰衝液（5 0 m Μ T r i s - H C 1，p Η 7 . 4，Μ n C 1 2 )洗 4 次後，用自動y計數器（Packerd RIASTAR 5 4 2 0 Α)計數放射活性。所有之數據為可由3# M未標幟物質P代替之專一性結合。且本發明目的物，尤其化合物（If)安定性也優異。下面舉製備例及實例說明本發明。料備例1 -1 4 -本紙張尺度適用中國國家標準（CNS ) Λ4規格（2ίΟΧ297公釐）. Β7五、發明説明0沉）經濟部中央標準局員工消費合作社印製詳言之，化合物（If )(以下稱富馬酸鹽）比非此鹽之鹽酸鹽5水合物（以下簡稱鹽酸鹽）具有種種優點。即如下表所示，富馬酸鹽在吸水性，固態安定性及溶解性等理化性質確比鹽酸鹽為優，故以此富馬酸鹽為主藥則可得更安定之醫藥組成物。試驗項目化合物 - 富馬酸鹽鹽酸鹽吸水性水分 250C,7 日 u%ms 0.60¾ 5.68¾ 33^RH* 0.93% 8.53¾ 53^RHr 1.38% 10.54¾ 75%RH* 2.34¾ 14.86¾ 固態安定性外觀 .初日白晶粉白粉 70 Ό, 9曰白晶粉（稍帶黃）稍帶褐色黃色粉分析初日 100¾ 100¾ 70 *C , 9 B 100.3¾ 92.7¾ . 溶解性' 水11 ^ 200 mg/ml 174 mg/ml 食鹽水r: S 200 mg/ml 177 mg/ml * : R Η =相對濕度 ^ :在室溫振盪30分下面舉製備例及實例說明本發明。製備例1 -14 a - 本紙張尺度適用中國國家標準（CNS ) A4規格（210Χ29?公釐） (請先閱讀背面之注意事項^/氟本頁) A7 B7 五、發明説明（<〇0.25 ml of culture solution 2 (50 mM Tris-HCl, pH 7.4, 5 mM M n C 1 2, 20 μ g / m 1 chyffl0statin, 40; ug / ml bacteriocin, 4Ag / lnl white Gastrin, 5Aίg / mlp-APMSI ^ 20 (Ug / Bll BSA) at 22 ° C for 90 minutes. Then quickly filtered through a Whatman GF / C printed glass filter by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. % Polyethyleneimine pretreatment for 3 hours. Each filtrate was washed 4 times with 5 m 1 锾 flushing solution (50 m Μ Tris-HC 1, p Η 7.4, Mn C 1 2), and then used an automatic y counter (Packerd RIASTAR 5 4 2 0 A) Counts radioactivity. All data are specific combinations that can be replaced by 3 # M unmarked substance P. And the object of the present invention, especially the compound (If), also has excellent stability. Preparation examples and examples illustrate the present invention. Preparation examples 1 -1 4-This paper size is applicable to the Chinese National Standard (CNS) Λ4 specification (2 ΙΟ × 297 mm). Β7 V. Description of the Invention 0) Employees ’Cooperatives, Central Standards Bureau, Ministry of Economic Affairs Printed in detail, the compound (If) (hereinafter referred to as fumarate) Hydrochloride) has various advantages. As shown in the following table, fumarate is better than hydrochloride in physicochemical properties such as water absorption, solid stability and solubility, so fumarate is the main drug. A more stable pharmaceutical composition can be obtained. Test Item Compound-Fumarate hydrochloride water absorbent 250C, 7% u% ms 0.60¾ 5.68¾ 33 ^ RH * 0.93% 8.53¾ 53 ^ RHr 1.38% 10.54¾ 75 % RH * 2.34¾ 14.86¾ The appearance of solid stability. The first day white crystal powder and white powder 70 Ό, 9th white crystal powder (slightly yellow) and the brownish yellow powder analysis. First day 100¾ 100¾ 70 * C, 9 B 100.3¾ 92.7¾. Solubility 'water 11 ^ 200 mg / ml 174 mg / ml saline r: S 200 mg / ml 177 mg / ml *: R Η = relative humidity ^: shake at room temperature for 30 minutes The following are examples of preparation and examples Invention. Preparation Example 1 -14 a-This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210 × 29? Mm) (Please read the precautions on the back ^ / Fluorine page) A7 B7 V. Description of the invention (< 〇

o-ch2 ---------〇 — (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製混合N2 -(第三丁氧羰基）-Ν'-甲醯基-D-色胺酸3. 99克 ,Ν -苄基甘胺酸苄酯鹽酸鹽3 . 5 Q克及二氣甲烷7 Q m 1，在氮大氣下加三乙胺5.85ml。在室溫碘化2 -氯-1-甲基咄錠3.67克，攪拌2小時。反應完成後，加二氯甲烷30ml 及水30ml。分取有機層，依序以0.5N鹽酸10ml,水10ml ，重碳酸鈉水1 〇 πι 1及食鹽水2 0 m 1洗淨，以硫酸鎂乾燥，蒸除溶劑，在140克矽膠柱層析（甲苯：乙酸乙酯=4: 1) ，得（2R)-N -苄基-N-苄氣羰甲基- 2- (第三丁氧羰胺基） -3 - ( N -甲醯基-1 Η - P3丨卩采-3 -基）丙醯胺6 . 4 1克，油狀。 IR (CHC13) : 3300, 2970, 1740, 1700, 1644, 1604 cm-1 NMR (DMSO-dg, δ) : 0.89, 1.22 &1.29(9H,3s); 2.80-3.10 (2H,-m); 3.95-4.25 (2H, m); 4.40-4.90 (3H, m); 4.95-5.20 (2H, m); 7.05-7.75 (15H, ra); 7.98 及 8.22 (1H, 2 br s); 9.22 及 9.61 (1.Π, ? ht s) MASS : 570 (M+l) -1 5 -本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X297公釐.) 五、發明説明（K ) A7 B7o-ch2 --------- 〇— (Please read the notes on the back before filling out this page) Printed Mixed N2 by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs-(Third Butoxycarbonyl) -N ' -Formamyl-D-tryptophan 3.99 g, N-benzyl glycinate benzyl ester hydrochloride 3.5 Q g and digas methane 7 Q m 1, triethylamine 5.85 was added in a nitrogen atmosphere ml. 2.67 g of 2-chloro-1-methylphosphonium iodide was iodized at room temperature and stirred for 2 hours. After the reaction was completed, 30 ml of dichloromethane and 30 ml of water were added. The organic layer was separated, washed sequentially with 0.5N hydrochloric acid 10ml, water 10ml, sodium bicarbonate water 100m1 and brine 2m1, and dried over magnesium sulfate. The solvent was distilled off, and chromatography was performed on a 140 g silica gel column. (Toluene: ethyl acetate = 4: 1) to obtain (2R) -N-benzyl-N-benzylcarbonylcarbonyl-2- (third butoxycarbonylamino) -3-(N-formamyl) -1 Η-P3 卩 -3 -yl) propylamine 6.4 g, oily. IR (CHC13): 3300, 2970, 1740, 1700, 1644, 1604 cm-1 NMR (DMSO-dg, δ): 0.89, 1.22 & 1.29 (9H, 3s); 2.80-3.10 (2H, -m); 3.95-4.25 (2H, m); 4.40-4.90 (3H, m); 4.95-5.20 (2H, m); 7.05-7.75 (15H, ra); 7.98 and 8.22 (1H, 2 br s); 9.22 and 9.61 (1.Π,? Ht s) MASS: 570 (M + l) -1 5-This paper size applies the Chinese National Standard (CNS) Λ4 specification (210X297 mm.) V. Description of the invention (K) A7 B7

0 經濟部中央標隼局員工消費合作社印製於製備例1之目的物6.39克與二氯甲烷5Gml之冰*** 液加4N HC1/二鸣烷5Qml,在同溫攪拌30分後，在室溫攪拌1小時，蒸除溶劑。殘渣分配在二氯甲烷50ml及重磺酸鈉水3Qml。分取有機層，以硫酸鎂乾燥而過濾。濾液在室溫加三乙胺1 . 6 7 in 1 ,攪拌1 . 5小時後，蒸發而以二異丙醚碾製，濾集而乾燥，得（3R)-1-苄基-3-(N-甲醯基-111-113丨呤-3-基甲基）哌阱-2,5-二酮3.93克。 mp : 176-178 °C IR(石蟠油）：3250 ,1709 ,1648 ,1630(^-1 NMR (DMSO-d6, δ) : .2.95-3.30 &3.35-3.70(4H,2m); 4.22 (1H, d, J=14.6Hz); 4.30-4.40 (1H, m); 4.54 (1H, d, J=14.9Hz); 6.80-7.75 (9H, m); 7.95-8.^0 (2H, m); 9.20 及 9.65 (1H, 2 br s) 製備例30 Printed by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs, 6.39g of the object in Preparation Example 1 and 5Gml of dichloromethane in an ice-cold solution, plus 4N HC1 / dioxane 5Qml, stirred at the same temperature for 30 minutes, and stirred at room temperature After 1 hour, the solvent was evaporated. The residue was partitioned between 50 ml of dichloromethane and 3 Q ml of sodium bisulfate water. The organic layer was separated, dried over magnesium sulfate, and filtered. The filtrate was added with triethylamine 1.67 in 1 at room temperature, and stirred for 1.5 hours. After evaporation, it was triturated with diisopropyl ether, collected by filtration, and dried to obtain (3R) -1-benzyl-3- ( N-formamyl-111-113-purin-3-ylmethyl) piperidin-2,5-dione 3.93 g. mp: 176-178 ° C IR (stone oil): 3250, 1709, 1648, 1630 (^ -1 NMR (DMSO-d6, δ): 2.95-3.30 & 3.35-3.70 (4H, 2m); 4.22 (1H, d, J = 14.6Hz); 4.30-4.40 (1H, m); 4.54 (1H, d, J = 14.9Hz); 6.80-7.75 (9H, m); 7.95-8. ^ 0 (2H, m); 9.20 and 9.65 (1H, 2 br s) Preparation Example 3

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本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X297公漦） (請先閲讀背面之注意事項再填寫本頁)This paper size applies Chinese National Standard (CNS) Λ4 specification (210X297 cm) (Please read the precautions on the back before filling this page)

、1T X ! A7 B7 五、發明説明（β ) 將製備例2之目的物3.89克在冰冷下溶在甲醇175ml 及四氫呋喃50ml之混液，加0. IN NaOH水108ml,在同溫攪拌3 0分後，在室溫攪拌1 . 5小時，蒸除溶劑。殘渣以二氯甲烷萃取而以水及食鹽水洗淨，以硫酸鎂乾燥，褰除溶劑，得（3 R ) - 1 -苄基-3 - ( 1 Η -吲哚-3 -基甲基）哌畊-2 ，5-二酮 3 · 68 克。 fflp: 207-208 °C I R (石蠘油）：3 4 0 2，1 6 5 0 c m ―1 NMR (DMSO-d6/ δ) : 2.68 (1H, d, J-17.2Hz); 3.04 (1H, dd, J=14.4 及 4.4Hz); 3.20-3.40 (2H, m); 4.24 (1H, s); 4.10-4.40 (2H, m) ; 6.75-7.60 (10H, m); 8.35 (1H, s); 10.94 (1H, s) MASS : 334 (M+l) (請先間讀背面之注意事項再填寫本頁)1T X! A7 B7 V. Description of the invention (β) 3.89 g of the object of Preparation Example 2 was dissolved in a mixture of 175 ml of methanol and 50 ml of tetrahydrofuran under ice-cooling, and 108 ml of 0.1 NaOH water was added, and stirred at the same temperature for 30 minutes. Then, it was stirred at room temperature for 1.5 hours, and the solvent was distilled off. The residue was extracted with dichloromethane, washed with water and brine, dried over magnesium sulfate, and the solvent was decanted to obtain (3 R)-1 -benzyl-3-(1 Η -indole-3 -ylmethyl). Pipen-2,5-dione 3.68 g. fflp: 207-208 ° CIR (stone oil): 3 4 0 2, 1 6 50 cm -1 NMR (DMSO-d6 / δ): 2.68 (1H, d, J-17.2Hz); 3.04 (1H, dd, J = 14.4 and 4.4Hz); 3.20-3.40 (2H, m); 4.24 (1H, s); 4.10-4.40 (2H, m); 6.75-7.60 (10H, m); 8.35 (1H, s) ; 10.94 (1H, s) MASS: 334 (M + l) (Please read the precautions on the back before filling this page)

經濟部中央標隼局員工消費合作社印製將氫化鋰鋁0.77克懸浮於四氫呋喃40ml,在0°C氮大氣下滴加製備例3之目的物3 . 4 Q克與四氫呋喃4 0 m 1之溶液。在室溫攪拌5 0分後，在回流溫度搜拌1小時。次以四氫呋喃6 0 m 1稀釋，冷卻至0 °C ,徐徐加水3 . 0 nt 1及 1 5 % MaOH 0.8ml,濾除不溶解之無機物而以四氫呋喃洗淨。 -17-本紙張尺度適用中國國家標準（CNS ) Λ4現格（2丨OX 297公漦） A7 B7 五、發明説明（靱備例ftPrinted by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs, suspended 0.77 g of lithium aluminum hydride in 40 ml of tetrahydrofuran, and added dropwise a solution of 3.4 Q g and tetrahydrofuran 40 m 1 in a nitrogen atmosphere at 0 ° C. . After stirring at room temperature for 50 minutes, it was stirred at reflux temperature for 1 hour. It was diluted with 60 m 1 of tetrahydrofuran, cooled to 0 ° C, and 3.0 ml of water and 0.8% MaOH 0.8 ml were added slowly. The insoluble inorganic matter was filtered off and washed with tetrahydrofuran. -17- This paper size applies to Chinese National Standards (CNS) Λ4 is present (2 丨 OX 297 public 漦) A7 B7 V. Description of invention (靱 Example ft

、N NH 經濟部中央標準局員工消費合作社印製 CF3 混合（21?)-4-苄基-1-〔3,5-雙（三氟甲基）苄醯基〕-2-(1H -吲卩朵-3-基甲基）哌阱5.20克，甲酸銨1.50克，10% P d - C 0 . 5 2克及乙醇5 0 m 1，在氮大氣下回流7 . 5小時後，冷卻至室溫，濾經矽藻土 H,減壓濃縮，在矽膠柱層析 (二氣甲烷：甲醇= 20: 1),得（2R)-l-〔3,5 -雙（三氟甲基）苄醯基〕-2-(lH -吲哚甲基）哌阱2.67克，糖漿。 IR (CHC13) ： 3280, 2900, 1622 cm-1 NMR (DMSO-dg, δ) : 2.50-3.50 (9H, m); 3.6-4.8 (1H, m); 6.55-7.40 (5H, m) ; 7.50-8.22 (3H, m) ; 10.84 (1H, s) MASS : 456 (M+l) 剪備例7 混合製備例6之産物1.5克，2 -溴乙酸苄酯0.79克，三乙胺0.55ml及四氫呋喃15ml,在室溫攪拌過夜後，濾除不溶物，減壓濃縮，在矽膠.柱層析（二氣甲烷：甲醇 =30:1),得（21〇-4-(苄氧羰甲基）-1-〔3,5-雙（三氟甲基）苄醯基〕-2 - ( 1 Η - η引呤-3 -基甲基）哌阱1 . 9 2克。 19 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X 297.公釐） (請先閱讀背面之注意事項再填寫本頁) 訂 dlsJJSrluLi:.. A 7 B7 五、發明説明（4 ) 含併濾液及洗液，減壓蒸發，得（3 R ) - 1 -苄基-3 - ( 1 Η -吲呤-3-基甲基）哌畊3. 68克，油狀。 (請先閱讀背面之注意事項再填寫本頁) IR (CHC13) : 3240, 3040, 2900 cm-1 NMR (DMSO-dg, δ) : 1.70-2.00 &2.30-2.45(2H,2m); 2.50-3.00 (7H, m); 3.25-3.60 (3H, m); 6.80-7.60 (10H, m); 10.80 (1H, s) MASS ： 306 (M+l) 靱備例5, N NH Printed CF3 by Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs (21?)-4-benzyl-1- [3,5-bis (trifluoromethyl) benzylfluorenyl] -2- (1H -ind 5.20 g of pidol-3-ylmethyl) pipe trap, 1.50 g of ammonium formate, 10% P d-C 0 .52 g and ethanol 50 m 1, refluxed under nitrogen atmosphere for 7.5 hours, and cooled to At room temperature, filtered through diatomaceous earth H, concentrated under reduced pressure, and subjected to silica gel column chromatography (methane: methanol = 20: 1) to obtain (2R) -l- [3,5-bis (trifluoromethyl). Benzylfluorenyl] -2- (lH-indolyl) piperidine 2.67 g, syrup. IR (CHC13): 3280, 2900, 1622 cm-1 NMR (DMSO-dg, δ): 2.50-3.50 (9H, m); 3.6-4.8 (1H, m); 6.55-7.40 (5H, m); 7.50 -8.22 (3H, m); 10.84 (1H, s) MASS: 456 (M + 1) Shearing example 7 1.5 g of the product of the mixed preparation example 6, 0.79 g of 2-bromobenzyl acetate, 0.55 ml of triethylamine and 15 ml of tetrahydrofuran, stirred at room temperature overnight, filtered off the insolubles, concentrated under reduced pressure, and concentrated on silica gel. Column chromatography (dichloromethane: methanol = 30: 1) to obtain (21〇-4- (benzyloxycarbonylmethyl ) -1- [3,5-bis (trifluoromethyl) benzylfluorenyl] -2-(1 Η-ηopterin-3 -ylmethyl) piperidine 1. 9 2 g. 19 This paper size applies Chinese National Standard (CNS) Λ4 specification (210X 297.mm) (Please read the precautions on the back before filling this page) Order dlsJJSrluLi: .. A 7 B7 V. Description of the invention (4) Containing filtrate and washing liquid, Evaporate under reduced pressure to get (3 R)-1 -benzyl-3-(1 Η -indin-3-ylmethyl) pipen 3.68 g, oily. (Please read the notes on the back before filling (This page) IR (CHC13): 3240, 3040, 2900 cm-1 NMR (DMSO-dg, δ): 1.70-2.00 & 2.30-2.45 (2H, 2m); 2.50-3.00 (7H, m); 3.25- 3.60 (3H, m); 6.80-7.60 (10H, m); 10.80 (1H, s) MASS: 306 (M + l) 靱 Example 5

HH

CF3 混合3 , 5 -雙（三氟甲基）苯甲酸1 · 1 5克，（3 R ) - 1 -苄基 -3-(lH-B3| B朵一3-基甲基）呢畊1.61克及二氣甲院80ml, 在室溫氮大氣下加三乙胺1.55ml,加碘化2 -氯-1-甲基吡錠1 . 3 7克。在室溫攪拌2 . 5小時後，倒入水2 0 m 1中。有機層先後以0.5N鹽酸，水，重磺酸鈉水及食鹽水洗淨 ,以硫酸鎂乾燥，減壓蒸發，在矽膠層析（甲苯：乙酸乙酯=4: 1)，得（2R)-4 -苄基-卜〔3,5 -雙（三氟甲基）苄醯基〕-2-(1Η -吲時-3-基甲基）哌畊0.87克，糖接。 IR (CHC13) ： 3430, 3300, 3000, 2910, 2800, 1630-1610 cm-1 NMR (DMSO-dg, δ) : 1.90-2.40 (2H, m); 2.70-3.90 (8H, in); 4.25-4.40 及 4.75-4.90 (1H, m); 6.50-7.45 (10H, m); 7.50-8.25 (3H, m); 10.77 (1H, s) MASS : 546 (M+l) -18- 本紙張尺度適用中國國家標準（CNS ) Λ4規格（.210 X 297公漦） A7 B7 五、發明説明（、？） [α]^1 : -11.6。（C=1.0, MeOH) IR (淨丨：3600-3100, 1735, 1626, 1275, 1129, 900 cm-1 NMR (DMS〇-d6, δ) : 2.20-5.20 (13H, m); 6.60-8.20 (13H, m) ; 10.85 (1H, br s) MASS ： 604 (M+l), 454 . 靱備例8 混合製備例7之産物1.86克，10% Pd-C 0.186克及四氫呋喃93ml，在氫大氣下Μ拌17小時後，濾除觸媒而濃縮，以***碾製，得（21〇-4-(羧甲基）-1-〔3,5-雙（三氟甲基）苄醯基〕-2-UH -吲Β朵-3 -基甲基）哌阱0.83克，白色粉末。 [a]J9 : -3.0° (C=0.5, DMF)CF3 mixed 3, 5 -bis (trifluoromethyl) benzoic acid 1.5 g, (3 R)-1 -benzyl-3- (lH-B3 | Grams and 80ml of Erqi Jiayuan, add 1.55ml of triethylamine and 1.37g of 2-chloro-1-methylpyridine iodide under nitrogen atmosphere at room temperature. After stirring at room temperature for 2.5 hours, it was poured into 20 ml of water. The organic layer was washed with 0.5N hydrochloric acid, water, sodium disulfonate water and brine, dried over magnesium sulfate, evaporated under reduced pressure, and subjected to silica gel chromatography (toluene: ethyl acetate = 4: 1) to obtain (2R). -4 -benzyl-bu [3,5-bis (trifluoromethyl) benzylfluorenyl] -2- (1Η-indol-3-ylmethyl) piperin 0.87 g, sugar-linked. IR (CHC13): 3430, 3300, 3000, 2910, 2800, 1630-1610 cm-1 NMR (DMSO-dg, δ): 1.90-2.40 (2H, m); 2.70-3.90 (8H, in); 4.25- 4.40 and 4.75-4.90 (1H, m); 6.50-7.45 (10H, m); 7.50-8.25 (3H, m); 10.77 (1H, s) MASS: 546 (M + l) -18- Applicable to this paper size Chinese National Standard (CNS) Λ4 specification (.210 X 297 gong) A7 B7 5. Description of the invention (,?) [Α] ^ 1: -11.6. (C = 1.0, MeOH) IR (Net 丨: 3600-3100, 1735, 1626, 1275, 1129, 900 cm-1 NMR (DMS〇-d6, δ): 2.20-5.20 (13H, m); 6.60-8.20 (13H, m); 10.85 (1H, br s) MASS: 604 (M + 1), 454. Preparation Example 8 1.86 g of the product of Preparation Example 7 mixed, 0.186 g of 10% Pd-C and 93 ml of tetrahydrofuran, in hydrogen After 17 hours of stirring in the air, the catalyst was filtered off and concentrated, and then triturated with diethyl ether to obtain (21〇-4- (carboxymethyl) -1- [3,5-bis (trifluoromethyl) benzylfluorenyl ] 0.8 Ug of 2-UH-ind-Bido-3-ylmethyl) piperidine, white powder. [A] J9: -3.0 ° (C = 0.5, DMF)

mp : 152-156°C IR(石.油蠟）：3600-3100, 1654, 1630, 1277, 1196, 1130 cm_1 NMR (DMSO-dg, δ) : 2.20-5.20 (11Η, m); 6.60-8.20 (8H, m) ; 10.85 (1H, s) MASS : 514 (M+l) 剪備例9 經濟部中央標準局員工消費合作社印製 I-------0 ! (讀先閱讀背面之注意事項再填寫本頁) 冰冷混合（2R)-2 -节基-1-〔3,5 -雙（三氟甲基）苄醛基] 哌哄0.3克，三乙胺0.39ml及二甲基甲醯胺8ml,加3-(氣甲基）吡啶鹽酸鹽0 . 1 2克，在同溫攪拌3 0分後，在室溫攪拌2小時。追加三乙胺Q.39ml及3-(氯甲基）吡啶鹽酸鹽0.12克。攪拌過夜後，過濾而濃縮，在矽膠層析（甲苯 :乙酸乙酯=5: 1),溶出液以4N HC1/乙酸乙酯處理，得（2ΪΟ-2 -苄基-卜〔3,5 -雙（三氟甲基）苄醯基]-4-((¾ -2 0 -本紙張尺度適用中國國家標隼（CNS ) Λ4規格（210X 297公漦） A7 B7 五、發明説明（) 啶-3-基甲基）哌阱二鹽酸鹽mp: 152-156 ° C IR (stone. oil wax): 3600-3100, 1654, 1630, 1277, 1196, 1130 cm_1 NMR (DMSO-dg, δ): 2.20-5.20 (11Η, m); 6.60-8.20 (8H, m); 10.85 (1H, s) MASS: 514 (M + l) Cutting example 9 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economy I --------- 0! Note: Please fill in this page again.) Cold-mix (2R) -2 -Benyl-1- [3,5-bis (trifluoromethyl) benzaldehyde]] 0.3 g of piperidine, 0.39 ml of triethylamine and dimethyl 8 ml of formamidine, 0.12 g of 3- (aeromethyl) pyridine hydrochloride was added, and after stirring at the same temperature for 30 minutes, it was stirred at room temperature for 2 hours. Triethylamine Q.39ml and 3- (chloromethyl) pyridine hydrochloride 0.12g were added. After stirring overnight, it was filtered and concentrated, and subjected to silica gel chromatography (toluene: ethyl acetate = 5: 1). The eluate was treated with 4N HC1 / ethyl acetate to obtain (2Ϊ-2--2benzyl-bu [3,5- Bis (trifluoromethyl) benzylfluorenyl] -4-((¾ -2 0 -This paper size is applicable to the Chinese National Standard (CNS) Λ4 specification (210X 297 g)) A7 B7 V. Description of the invention () 3-ylmethyl) piperidine dihydrochloride

mp : 164-168°Cmp: 164-168 ° C

[α]§5 : +9.1。（C=1.0, MeOH) τ η / -r- >4, ^ λ 3700-3100, 2700-2000, 1630, 1270, 1120, 900 cm-1 NMR (DMSO-d6, δ) : 2.80-5.40 (11Η, m); 6.85-6.90 (1Η, in); 7.10-7.40 (4H, m) ; 7.46 (1H, s); 7.75 (1H, s); 7.90-8.00 (1H, m); 8.19-8.23 (1H, m); 8.66-8.70 (1H, m); 8.88-8.91 (1H, m); 9.09 (1H, s) MASS: 508(M+1)(自由）餺備例1 0 (請先閲讀背面之注意事項再填寫本頁) X)[α] §5: +9.1. (C = 1.0, MeOH) τ η / -r- > 4, ^ λ 3700-3100, 2700-2000, 1630, 1270, 1120, 900 cm-1 NMR (DMSO-d6, δ): 2.80-5.40 ( 11Η, m); 6.85-6.90 (1Η, in); 7.10-7.40 (4H, m); 7.46 (1H, s); 7.75 (1H, s); 7.90-8.00 (1H, m); 8.19-8.23 ( 1H, m); 8.66-8.70 (1H, m); 8.88-8.91 (1H, m); 9.09 (1H, s) MASS: 508 (M + 1) (free) 馎 Example 1 0 (Please read the back first (Please fill in this page again) X)

、1Τ 經濟部中央標準局員工消費合作社印製攪拌混合（21〇-2-苄基-1-〔3,5-雙（三氟甲基）苄醯基] 哌阱0.3克及2-(lH -吲呤-3-基）乙酸0.13克於含三乙胺 0.25ml之二氯甲烷8ml,在室溫氮大氣下加碘化2-氯-1-甲基吡錠0.22克，攪拌5小時後，以二氯甲烷稀釋，以 0.1N鹽酸，飽和重碩酸鈉水及食鹽水洗淨，以硫酸鎂乾燥，蒸除溶劑，在矽膠柱層析（氯仿：甲醇= 50: 1)，得（2叼-2-苄基-卜〔3,5-雙（三氟甲基）苄醯基〕-4-〔2-(1 Η - B引呤-3 -基）乙醯基〕哌阱〇 . 3 4克，白色粉末。 -21- 本紙張尺度適用中國國家標準（CNS )八4^格（210Χ297公釐） A7 B7 五、發明説明（w ), 1T printed and mixed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (21〇-2-benzyl-1- [3,5-bis (trifluoromethyl) benzylfluorenyl] piperidine 0.3 g and 2- (lH -Indolin-3-yl) acetic acid 0.13 g in 0.25 ml triethylamine 8 ml methylene chloride, 0.22 g of 2-chloro-1-methylpyridine iodide was added at room temperature under nitrogen, and stirred for 5 hours , Diluted with dichloromethane, washed with 0.1N hydrochloric acid, saturated sodium bisulfate water and brine, dried over magnesium sulfate, distilled off the solvent, and subjected to silica gel column chromatography (chloroform: methanol = 50: 1) to obtain ( 2 叼 -2-benzyl-bu [3,5-bis (trifluoromethyl) benzylfluorenyl] -4- [2- (1 Η-Binopterin-3-yl) ethenyl] piperazine. 3 4 grams, white powder. -21- This paper size applies to Chinese National Standard (CNS) 8 4 ^ grid (210 × 297 mm) A7 B7 V. Description of invention (w)

mp : 201-210°Cmp: 201-210 ° C

[α]§7 : +27.6。（C=1.0, MeOH) IR(石油蠛）：3270, 1630, 1276, 1115, 900, 737 citT1 NMR (DMSO-dg, δ) : 2.60-5.00 (11H, m); 6.70-7.70 (12H, ra); 8.10-8.20 (1H, m); 10.85-11.10 (1H, m) MASS : 574 (M+l), 417 製備例1 1 將（2 R ) - 1 -〔 3 , 5 -雙（三氟甲基）苄醯基〕-2 - ( 1 H -吲H朵 -3 -基甲基）贿阱0.1克溶在二氣甲烷10ml,在〇°C加O HC1 /二枵烷溶液〇.〇5ml。在同溫攪拌50分後，減壓濃縮，濾集粉末，以***洗淨，得（2R)-l-〔3,5 -雙（三氟甲基）苄醯基〕-2 - ( 1 Η - Ο引II朵-3 -基甲基）哌阱鹽酸鹽0 . 1克。 I R (石油蠟）：3 3 4 0，1 6 4 8 c m-1 NMR (DMS〇-d6, δ) : 2.9-3.9 (8Η, m); 3.9-5.2 (1Η, m); 6.57-7.50 (5H, m); 7.50-8.30 (3H, m); 9.40-10.00 (2H, m); 10.96 (1H, s) MASS : 456(M+1)(自由）製備例1 2 攪拌混合（2R)-4-(2-胺乙基）-卜〔3,5 -雙（三氟甲基）經濟部中央標準局員工消費合作社印製 ----------Λ丨- (請先閲讀背面之注意事項再填寫本頁) 节醯基〕-2 - ( 3，4 -二甲苄基）哌畊二鹽酸鹽1 1 0 in g ,三乙胺0.2 1!11及二氛甲烷101111，在0°(：加甲磺醯氯0.11111。攪拌 1小時後，倒入冰水中。次以乙酸乙酯萃取，先後以飽和重碩酸鈉水及食鹽水洗淨，乾燥而真空蒸除溶劑，在矽膠柱層析（二氯甲烷：甲醇= 40: 1)，以4N HC1/乙酸乙酯處理，得（2 R ) - 1 -〔 3，5 -雙（三氟甲基）苄醯基] -2 2 -本紙張尺度適用中國國家標準（CNS ) A4^格（210X297公釐）經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明（.>1 ) -2-(3,4-二甲苄基）-4-〔2-(甲磺醯胺基）乙基〕哌阱鹽酸鹽5 0 rog。[α] §7: +27.6. (C = 1.0, MeOH) IR (petroleum thallium): 3270, 1630, 1276, 1115, 900, 737 citT1 NMR (DMSO-dg, δ): 2.60-5.00 (11H, m); 6.70-7.70 (12H, ra ); 8.10-8.20 (1H, m); 10.85-11.10 (1H, m) MASS: 574 (M + l), 417 Preparation Example 1 1 (2 R)-1-[3, 5 -bis (trifluoro (Methyl) benzylfluorenyl] -2-(1 H -indH-do-3 -ylmethyl) brittle trap was dissolved in 10ml of digas methane, and O HC1 / dioxane solution was added at 0 ° C. 5ml. After stirring at the same temperature for 50 minutes, the solution was concentrated under reduced pressure, and the powder was collected by filtration and washed with ether to obtain (2R) -l- [3,5-bis (trifluoromethyl) benzylfluorenyl] -2-(1 Η -0.1 g of II-3 -ylmethyl) piperidine hydrochloride. IR (petroleum wax): 3 3 4 0, 1 6 4 8 c m-1 NMR (DMS〇-d6, δ): 2.9-3.9 (8Η, m); 3.9-5.2 (1Η, m); 6.57-7.50 (5H, m); 7.50-8.30 (3H, m); 9.40-10.00 (2H, m); 10.96 (1H, s) MASS: 456 (M + 1) (free) Preparation example 1 2 Stir and mix (2R) -4- (2-aminoethyl) -bu [3,5 -bis (trifluoromethyl) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ---------- Λ 丨-(please first Read the notes on the back and fill in this page) Section 醯]]-2-(3,4-Dimethylbenzyl) piperine dihydrochloride 1 1 0 in g, triethylamine 0.2 1! 11 and dichloromethane 101111, at 0 ° (: add methanesulfonium chloride 0.11111. After stirring for 1 hour, pour into ice water. Extract with ethyl acetate, wash with saturated sodium bisulfate water and brine, dry and evaporate under vacuum. The solvent was subjected to silica gel column chromatography (dichloromethane: methanol = 40: 1) and treated with 4N HC1 / ethyl acetate to obtain (2 R)-1-[3,5-bis (trifluoromethyl) benzylhydrazone. Base] -2 2-This paper size applies Chinese National Standard (CNS) A4 ^ (210X297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (. &Gt; 1) 2- (3,4-dimethylbenzyl) -4- [2- (methanesulfonylamino) ethyl] piperidine hydrochloride 50 rog.

mp : >220°Cmp: > 220 ° C

[α]§2 : +0.2。（C=0.5, DMF) I R(石油蠟）：3350, 2700-2400, 1645, 1500, 1450, 1380 cm-1 NMR (DMSO-d6, δ) : 2.10 and 2.18 (6H, 2 s); 2.7-5.2 {17H, m); 6.6-7.7 (5H, m); 8.1-8.2 (1H, m); 11.05-11.4 (1H, m) MASS : 566(M+1)(自由）例1 將（2R)-4-(羧甲基）-1-〔3, 5-雙（三氟甲基）苄醯基〕 -2-UH-B引哚-3-基甲基）哌阱1克攪拌溶在乾二甲基甲醯胺Ιϋηιΐ,在室溫加卜羥基苯駢***0.29克及1-(3 -二甲胺丙基）.-3 -乙基磺化二亞胺鹽酸鹽0.41克。在室溫攪拌15分後，加1-胺基-4-甲基哌阱32 O.mg。在同溫攪拌5 小時後。倒入重碩酸鈉1 . 8克與水1 Ο Ο π 1之溶液中。次以乙酸乙酯（20mlX 3)萃取而合併以食鹽水30ml洗淨，以硫酸鎂乾燥，過濾而以回轉式蒸發器蒸除溶劑，在矽膠層析（二氯甲烷：甲醇=5: 1),得（2R)-1-〔 3, 5-雙（三氟甲基）苄醯基〕-2-(lH-H引P朵-3-基甲基）-4-〔 N-(4-甲 .基-1-哌哄基）胺甲醯甲基）-哌阱0.94克，帶黃色粉末。 IR(石油蠟）：3180, 1680, 1630, 1276, 1170, 1130, 1005, 8 97 cm-·*· NMR (DMSO-dg, δ) : 2.16 (3Η, s); 2.0-5.0 (19Η, m); 6.6-8.2 (8H, m) ; 8.47, 8.77 (1H, 2 s); 10.85 (1H, s) -23- 本紙張尺度適用中國國家標準（CNS ) A4規格（2IOX297公釐）讓1 (請先閲讀背面之注意事項再填寫本頁) 乂 .[α] §2: +0.2. (C = 0.5, DMF) IR (petroleum wax): 3350, 2700-2400, 1645, 1500, 1450, 1380 cm-1 NMR (DMSO-d6, δ): 2.10 and 2.18 (6H, 2 s); 2.7- 5.2 (17H, m); 6.6-7.7 (5H, m); 8.1-8.2 (1H, m); 11.05-11.4 (1H, m) MASS: 566 (M + 1) (free) Example 1 will be (2R) 4- (carboxymethyl) -1- [3,5-bis (trifluoromethyl) benzylfluorenyl] -2-UH-B indol-3-ylmethyl) piperidine 1g was stirred and dissolved in the dry Dimethylformamide I ϋηΐ was added at room temperature to 0.29 g of hydroxybenzotriazole and 0.41 g of 1- (3-dimethylaminepropyl) .- 3 -ethylsulfodiimide hydrochloride. After stirring at room temperature for 15 minutes, 32 mg of 1-amino-4-methylpiperidine was added. After stirring at the same temperature for 5 hours. Pour into a solution of 1.8 g of sodium bisulfate and 1 00 π 1 of water. It was extracted with ethyl acetate (20ml × 3), washed with 30ml of brine, dried over magnesium sulfate, filtered, and the solvent was distilled off on a rotary evaporator. Chromatography on silica gel (dichloromethane: methanol = 5: 1) To give (2R) -1- [3, 5-bis (trifluoromethyl) benzylfluorenyl] -2- (lH-H-P-D-3-ylmethyl) -4- [N- (4- A.methyl-1-piperazinyl) carboxamidomethyl) -piperazine 0.94 g, with yellow powder. IR (petroleum wax): 3180, 1680, 1630, 1276, 1170, 1130, 1005, 8 97 cm-** NMR (DMSO-dg, δ): 2.16 (3Η, s); 2.0-5.0 (19Η, m ); 6.6-8.2 (8H, m); 8.47, 8.77 (1H, 2 s); 10.85 (1H, s) -23- This paper size applies Chinese National Standard (CNS) A4 specification (2IOX297 mm) Let 1 ( (Please read the notes on the back before filling out this page) 乂.

'1T A7 B7 五''發明説明（將（2R)-l-〔3,5-雙（三氟甲基）苄酵基〕-2_(1H_叫丨時甲基）-4-〔 N-(4 -甲基-1-呢畊基）胺甲醯甲基）_哌哄10.89 克及富馬酸2.07克溶在70°0乙醇5〇!111。冷卻後，減壓濃縮，得粉末13.18克。將此粉末9.68克在回流溫度溶在 2 - 丁酮1 9 4 π 1，在室溫攪拌。濾集結晶而乾燥，得（2 R ) -1-〔3,5-雙（三氟甲基）节醒基〕-2~(1}{-113丨|1朵甲基）-4-_ 〔H-(4-甲基-1-哌阱基）胺甲醒甲基）-哌哄富馬酸鹽7.94 克0 mp : 16 9-5-171。。 IR(石油蠟）：3220, 1700, 1653, 1630, 1275, 1217, 1168, 1122, 979, 894, 730 cm~! NMR (DMSO-dg, δ) : 2.23, 2.26 (3Η, 2 s); 2.10-4.93 (19H, m); 6.60 (2H, s); 6.54-8.23 (8H, m); 8.50, 8.85 (1H, 2 s); 10.85 (1H, s： m 依如下流程也可得化合物（I f )，即（2 R ) i _〔 3 5 _雙 (三氟甲基）Y醯基〕-2-UH-B引呤甲基卜4_〔N (4甲基 (請先閲讀背面之注意事項再填寫本頁) I©'1T A7 B7 Five' invention description (will be (2R) -l- [3,5-bis (trifluoromethyl) benzyl]]-2_ (1H_called 丨 Methyl) -4- [N- 10.89 g of (4-methyl-1-naphthyl) carbamylmethyl) -piperamide and 2.07 g of fumaric acid were dissolved in 70 ° ethanol 50% 111. After cooling, it was concentrated under reduced pressure to obtain 13.18 g of powder. 9.68 g of this powder was dissolved in 2-butanone 1 9 4 π 1 at reflux temperature and stirred at room temperature. The crystals were collected by filtration and dried to obtain (2 R) -1- [3,5-bis (trifluoromethyl) benzyl group] -2 ~ (1} {-113 丨 | 1 methyl) -4-_ [H- (4-methyl-1-piperidyl) aminomethyl) -piperate fumarate 7.94 g 0 mp: 16 9-5-171. . IR (petroleum wax): 3220, 1700, 1653, 1630, 1275, 1217, 1168, 1122, 979, 894, 730 cm ~! NMR (DMSO-dg, δ): 2.23, 2.26 (3Η, 2 s); 2.10 -4.93 (19H, m); 6.60 (2H, s); 6.54-8.23 (8H, m); 8.50, 8.85 (1H, 2 s); 10.85 (1H, s: m) The compound (I f), that is (2 R) i _ [3 5 _bis (trifluoromethyl) Yfluorenyl] -2-UH-B priming methyl group 4_ [N (4 methyl group (please read the note on the back first) (Please fill in this page for matters) I ©

、1T -哌阱基〉胺甲醯甲基）-呢阱富馬酸鹽 Η Η 經濟部中央標準局0貝工消費合作社印製, 1T -piperazinyl> carbamoylmethyl) -fumarate fumarate Η 印 Printed by the Central Laboratories of the Ministry of Economic Affairs

ch3ohch3oh

cich2cocicich2coci

οf II Cl、 JZοf II Cl, JZ

g^C〇2CH3 mp : 243°C (分解) mp : 224-225°C (分解） CH2NH2 -2 4 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X 297公着） A7 B7 五、發明説明（w.) 經濟部中央標準局員工消費合作社印製g ^ C〇2CH3 mp: 243 ° C (decomposed) mp: 224-225 ° C (decomposed) CH2NH2 -2 4-This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297) A7 B7 Five 2. Description of invention (w.) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

—25— (請先閲讀背面之注意事項再填寫本頁)—25— (Please read the notes on the back before filling this page)

本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X297公釐）五、發明説明（外 A7 B7This paper size applies to Chinese National Standard (CNS) Λ4 specification (210X297 mm) V. Description of invention (outside A7 B7

(請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製(Please read the notes on the back before filling out this page) Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

H02CfH HCC〇2< —26 — 本紙張尺度適用中國國家標準（CNS ) Λ4規格（2IOX297公釐） A7 B7___ 五、發明説明（>〇例4 混合（21〇-1-〔3,5-雙（三氟甲基）苄醯基〕-2-(111-吲 H朵-3-基甲基）哌畊120mg, 4-氯甲基- 2- (2 -甲氧乙羰胺基）喀唑70mg,粉化重磺酸鈉27mg及乾二甲基甲醯胺，在6 (T C攪拌5小時2 0分後，倒入水中，濾集沈澱，在矽顧柱層析（二氯甲烷：甲醇=30: 1),減壓蒸發，以 17.6% HC1/ 乙醇 0.12ml 處理，得（2R)-l-〔3,5-雙（三氟甲基）苄酷.基〕-2-( 1H-吲B朵-3-基甲基）-4-〔〔 2-(3-甲氧丙醯胺基）喀脞-4-基〕甲基〕哌阱鹽酸鹽140mg。 [α]§2 : -34.0。（Ο0·5, MeOH> IR (石: 3650-3100, 2750-2000, 1635, 1275, 1130, 900 cm-1 NMR (DMS〇-d6, δ) : 2.60-5.20 (18H, m); 6.60-8.21 (9H, m) ; 10.90-11.00 (1H, m); 11.20-12.00 (1H, m); 12.19 (1H, s) MASS:654(M+1)(自由）例5 下列哌阱衍生物（表1 )可仿「製法」稱所示各例或製備例來製造。此目的物之理化性質如表後。 (請先閱讀背面之注意事項再填寫本頁) © 訂經濟部中央標準局員工消費合作社印製本紙張尺度適用中國國家標隼（CNS ) A4現格（210 X 297公釐） Β7 五、發明説明（4) J, 表1H02CfH HCC〇2 < —26 — This paper size applies to Chinese National Standard (CNS) Λ4 specification (2IOX297mm) A7 B7___ V. Description of the invention (> 〇 Example 4 Hybrid (21〇-1- [3,5-double (Trifluoromethyl) benzylfluorenyl] -2- (111-indHdo-3-ylmethyl) piperin 120mg, 4-chloromethyl-2- (2-methoxyethylcarbonylamino) carbazole 70mg, 27mg of pulverized sodium disulfonate and dry dimethylformamide, stirred at 6 ° C for 5 hours and 20 minutes, poured into water, collected the precipitate by filtration, and subjected to silica gel column chromatography (dichloromethane: methanol = 30: 1), evaporated under reduced pressure, and treated with 17.6% HC1 / ethanol 0.12ml to obtain (2R) -l- [3,5-bis (trifluoromethyl) benzyl.-2-yl] -2- (1H- IndoB-3-ylmethyl) -4-[[2- (3-methoxypropanylamino) carbam-4-yl] methyl] piperidine hydrochloride 140mg. [Α] §2: -34.0. (0 · 5, MeOH > IR (Stone: 3650-3100, 2750-2000, 1635, 1275, 1130, 900 cm-1 NMR (DMS〇-d6, δ): 2.60-5.20 (18H, m) ; 6.60-8.21 (9H, m); 10.90-11.00 (1H, m); 11.20-12.00 (1H, m); 12.19 (1H, s) MASS: 654 (M + 1) (free) Example 5 The following pipe trap Derivatives (Table 1) can imitate the examples shown in the "preparation method" or The physical and chemical properties of this object are as shown in the table below. (Please read the notes on the back before filling this page) ) A4 (210 X 297 mm) B7 V. Description of the invention (4) J, Table 1

---------© ^ (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作杜印製例 No. 目的物起始物製法 -A-R4 鹽 5-1) -CH2 N 〈nhcoch3 S HC1 製備例 6 例4 5-2) 2 ( ^-NHCOOC2H5 s HCl 裂備例 6 例4 5-3) -CHo—τ—N t__. HC1 製備例 6 例4 5-4) -CH N NHCOC(CH3) 3 HCl 製備例 6 例4 5-5) -CH2—TT-N HCl 製備例 6 例4 <δτ -28 -本紙張尺度適用中國國家標準（CNS ) Λ4規格（210Χ 297公釐） A7 B7 五、發明説明（巧）表1 (鑲）經濟部中央標隼局員工消費合作社印製例 No. 目的物起始物裂法 -A-r4 鹽. 5-6) -CH2T"1 —khcoc3h7 S HC1 製備例 6 例4 5-71 -CH2—y—-N ^s>-nhcoc2h5 HC1 製備例 6 例4 5-8) _CH L ii >—NHCHO 、s’ HC1 製備例 6 例4 5-9) -CHo—NHCOCHo XT 2HC1 製傲例 6 例4 5-10) CH2// 5， /^V^NHCOCH 3 dooc2H5 HC1 製備例 6 例4 5-11) -CH〇—7—N h Χ8^ΝΗ2 - 製備例 6 例9 5-12) -CHo—t—N 、s 广'"NH2 2HC1 例.5-11) 例11 5-13) 21T i XS/^NHS〇2CH3 HC1 例·5-11) 例12 5-14) -COCHo—N 丁 k XS/^NHC0CH3 - 製備例 6 例10 本紙張尺度適用中國國家標隼（CNS ) Λ4規格（210X 297公釐） -29 - (請先閱讀背面之注意事項再填寫本頁) A7 B7 五、發明説明（W )表1 (壤）例 No. 目的物起始物製法 -A- R4 鹽 5-15) vSy^NHCOCH3 HC1 製備例 6 例4 5-16) -CH N xs/xN-coc2H5 ch3 HC1 製備例 6 例4 I---------¾ (請先閲讀背面之注意事項再填寫本頁) 經濟部中夬標準局員工消費合作社印製例5之化合物之理化性質： ^ 5-Ί > mp : 185-189°C [α]^4 : 30.2。（C=0.5, MeOH) I R (石油蠟）：3660-3100, 2800-2000, 1635, 1545, 1276, 1183, 1130, 900 cm-1 NMR (DMSO-dg, δ) ： 1.36-5.10 (14H, m); 6.59-8.22 (10H, ra); 10.90-11.0Q (1H, m); 12.15 (1H, s) MASS : 610 (M+l)(自由），456 例 5-21 [α]^2 : -33.4° (C=0.5, MeOH) I R(石油蠑）：3650-3100, 2800-2000, 1715, 1635, 1555, 1274, 1130, 900 cm-1 NMR (DMSO-d6, δ) ： 1.25 (3H, tf J=7.1Hz); 2.73-5.10 (13H, m); 6.60-8.30 (9H, m) ; 10.90-11.00 (1H, m); 11.81 (1H, br s) MASS : 640 (M+l)(自由），456 5-3) [a]§2 : -42.0e (C=0.5, MeOH} I R(石油描）：3600-3100, 2750-2000, 1635, 1540, 1277, 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X 297公釐） -30 ---------- © ^ (Please read the precautions on the back before filling out this page) Employees ’Cooperative Cooperation of the Central Bureau of Standards, Ministry of Economic Affairs, Du Printed Example No. Method for the Preparation of Targets-A-R4 Salt 5 -1) -CH2 N <nhcoch3 S HC1 Preparation Example 6 Example 4 5-2) 2 (^ -NHCOOC2H5 s HCl Cracking Preparation Example 6 Example 4 5-3) -CHo—τ—N t__. HC1 Preparation Example 6 Example 4 5-4) -CH N NHCOC (CH3) 3 HCl Preparation Example 6 Example 4 5-5) -CH2—TT-N HCl Preparation Example 6 Example 4 < δτ -28-This paper standard applies Chinese National Standard (CNS) Λ4 specification (210 × 297 mm) A7 B7 V. Description of the invention (ingenious) Table 1 (inlaid) Printed case No. of the target starting material splitting method-A-r4 salt. 5 -6) -CH2T " 1 —khcoc3h7 S HC1 Preparation Example 6 Example 4 5-71 -CH2—y—-N ^ s > -nhcoc2h5 HC1 Preparation Example 6 Example 4 5-8) _CH L ii > -NHCHO, s 'HC1 Preparation Example 6 Example 4 5-9) -CHo—NHCOCHo XT 2HC1 Preparation Example 6 Example 4 5-10) CH2 // 5 ， / ^ V ^ NHCOCH 3 dooc2H5 HC1 Preparation Example 6 Example 4 5-11)- CH〇—7—N h χ8 ^ ΝΗ2-Preparation Example 6 Example 9 5-12) -CHo—t—N, s Guang '" NH2 2HC1 .5-11) Example 11 5-13) 21T i XS / ^ NHS〇2CH3 HC1 Example · 5-11) Example 12 5-14) -COCHo-N Ding XS / ^ NHC0CH3-Preparation Example 6 Example 10 Paper The scale applies to the Chinese National Standard (CNS) Λ4 specification (210X 297 mm) -29-(Please read the precautions on the back before filling this page) A7 B7 V. Description of the invention (W) Table 1 (Soil) Example No. Preparation method of target starting material-A- R4 salt 5-15) vSy ^ NHCOCH3 HC1 Preparation Example 6 Example 4 5-16) -CH N xs / xN-coc2H5 ch3 HC1 Preparation Example 6 Example 4 I ------ --- ¾ (Please read the notes on the back before filling out this page) Physicochemical properties of the compound printed in Example 5 of the Consumer Cooperatives of the China Standards Bureau of the Ministry of Economic Affairs: ^ 5-Ί > mp: 185-189 ° C [ α] ^ 4: 30.2. (C = 0.5, MeOH) IR (petroleum wax): 3660-3100, 2800-2000, 1635, 1545, 1276, 1183, 1130, 900 cm-1 NMR (DMSO-dg, δ): 1.36-5.10 (14H, m); 6.59-8.22 (10H, ra); 10.90-11.0Q (1H, m); 12.15 (1H, s) MASS: 610 (M + l) (free), 456 cases 5-21 [α] ^ 2 : -33.4 ° (C = 0.5, MeOH) IR (petroleum thallium): 3650-3100, 2800-2000, 1715, 1635, 1555, 1274, 1130, 900 cm-1 NMR (DMSO-d6, δ): 1.25 ( 3H, tf J = 7.1Hz); 2.73-5.10 (13H, m); 6.60-8.30 (9H, m); 10.90-11.00 (1H, m); 11.81 (1H, br s) MASS: 640 (M + l ) (Free), 456 5-3) [a] §2: -42.0e (C = 0.5, MeOH) IR (petroleum): 3600-3100, 2750-2000, 1635, 1540, 1277, this paper size applies China National Standard (CNS) Λ4 specification (210X 297 mm) -30-

、tT 五、發明説明（θ ) 1175, 1130 cm-1 NMR (DMSO-d6/ δ) : 2.73-5.20 (11H, m); 6.59-8.21 (14H, m); 10.90-11.00· (1H, m}; 12.69 (1H, s) MASS : 672 (M+l)(自由），456 例 5-4¾ 1 [a]g2 : -24.2* (C=0.5, MeOH) I R(石油蠟）：3650-3100, 2750-2000, 1635, 1540, 1276, 1170, 1129, 900 cnT1 NMR (DMSO-d6, δ) : 1.23 (9H, s); 2.73-5.10 (llH,m); 6.50-8.20 (9H, m)； 10.80-11.00 (1H, m); 11.84 (1H, S) MASS : 652 {M+l) {自由），456 例 5-51 [a]g2 : -35.88 (C=0.5, MeOH) IR(石油蟠）：3650-3100, 2750-2000, 1635, 1540, 1276, 1170, 1130, 900 cm-1 NMR (DMSO-d6/ δ) ： 0.80-1.00 (4H, m); 1.90-2.00 (1H, m) ; 2.73-5.15 (11H, m); 6.60-8.21 (9H, m) ; 10.90-11.00 (1H, ra); 12.43 (1H, m) MASS : 636 (M+l)(自由），456 例—5-61 經濟部中央標準局員工消費合作社印製 [cl]%2 : -30.4。（C=〇. 5, MeOH) I R (石油豳）：3650-3100, 2750-2000, 1635, 1542, 1275, 1170, 1131, 900 cm—1 NMR (DMSO-d6, δ) : 0.89 (3H, t, J=7.4Hz); 1.56-1.67 (2H, m)； 2.40-2.50 (2H, m); 2.73-5.15 (11H, ra); 6.56-8.21 (9H,m); 10.90-10.94 (1H, m); 12.12 (1H, s) MASS : 638 (M+l)(自由} 例 s-7) [α]π2 ： -34.0° (0=0.5, MeOH) 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210 X彳97公漦） -31 - 乜.II (請先閲讀背面之注意事項再填寫本頁) 經濟部中央樣隼局員工消費合作社印製 S91960 ^ 五、發明説明（w) IR(石油蠟）：3650-3100, 2750-2000, 1635, 1543, 1277, 1170, 1130, 900 cnT1, NMR (DMSO-d6f δ) : 1.08 (3Hf t, J=7.4Hz); 2.43-2.50 (2H, m); 2.73-5.15 (11H, ra); 6.55-8.21 (9H, m); 10.90-10.94 (1H/ ra)/ 12.11 (1H, a) MASS ： 624 (M+l)(自由）例 5二8、 [a]g2 : -15.2。（00.5, MeOH) I R(石油蟠）：3600-3100, 2750-2000, 1635, 1278, 1172, 1130, 900 cm-1 NMR (DMSO-dg, δ) : 2.73-5.20 (11H, m) / 6.60-8.52 (11H, m) / 10.94 (1H, s) MASS ： 596 (M+l)(自由），456 例 5-91 [a]g2 : -20.6。（C=0.5, MeOH) IR (石油蟠）：3650-3100., 2750-2000, 1635, 1276, 1170,. 1129, 900 cm-1 NMR (DMSO-d6, δ) : 2.09 (3H, s); 2.73-5.20 (11H, m); 6.60-8.20 (11H, m); 10.46 (1H, s); 10.91 (1H, s) MASS : 604 (H+l)(自由} 例 5-Ί0ί [a]^2 : -13.0° (C=0.5, MeOH) I R(石油蠟）：3650-3050, 2750-2000, 1685, 1636, 1524, 1275, 1130, 900 cm-1 NMR (DMSO-dg, δ) : 1.31 (3H, t, J=6.5Hz); 2.24 (3H, s); 2.73-5.20 (13H, m); 6.66-8.25 (8H, m); 10.94 (1H, s}, 12.71 (1H, s} MASS : 682 (M+l)(自由）例 5-11\ 【a】J8 ·· -20.8* (00.5, MeOH) IR(淨）： 3700-3000, 1615, 1515, 1272, 1125,_ 本紙張尺度適用中國國家標準（CNS ) Λ4現格（2丨〇X W7公釐） -32 - (請先閲讀背面之注意事項再填寫本頁) 訂經濟部中央標隼局員工消費合作杜印製 391960_^__________ 五、發明説明（w ) 900 cm_l NMR (DMS〇-d6, δ) : 2.00-5.00 (13H, in); 6.38-8.20 (9H, •m) ; 10.80 (1H, s) MASS : 568 (M+l), 456 1.5-121 [a]g2 : -10.4° (00.5, MeOH) IR(石油蠟）：3650-3100, 2750-2000, 1635, 1277, 1130 cm-1 NMR (DMS〇-d6, δ) : 3.00-5.20 (11H, m); 6.60-8.30 (11H, m); 10.95 (1H, s) MASS : 568 (M+l)(自由），456 例 5-131 [a]g2 : -31.8° (C=0.5, MeOH) . I R(石油蟠）：3270, 2750-2000, 1637, 1531, 1279, 1124, 964 cm-1 NMR (DMSO-dg, δ) : 2.73-5.15 (14H, m); 6.60-8.25 (10H, ia); 10.89 (1H, s) MASS : 646 (M+l)(自由），568, 456 例 5-14) [a]g3 : 11.8e (0=0.5, MeOH) IR(石油蠟）：3650-3100, 1625, 1543, 127 5, 1130 cm-]L NMR (DMS〇-d6/ δ) : 2.09-2.11 (3H, m); 2.52-5.00 (11H, m), 6.63-8.20 (9H, m); 10.85 (1H, s); 12.07 (1H, s) HASS ： 638 (M+l), 456 例 5-15、 [01]¾8 : -51.6e (00.5, MeOH) I R(石油蟠）：3650-3100, 2750-2000, 1634, 1540, 1274, 1170, 1127, 900 cm-1 NMR (DMS〇-d6, δ) : 2.31 (3H, s) ; 2.73-5.35 (11H, m); 6.63-8.25 (8H, m)； 10.94-11.00 (1H, m); 13.20 (1H, 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X 297公釐） -33 - (請先閲讀背面之注意事項再填寫本頁), TT 5. Description of the invention (θ) 1175, 1130 cm-1 NMR (DMSO-d6 / δ): 2.73-5.20 (11H, m); 6.59-8.21 (14H, m); 10.90-11.00 · (1H, m }; 12.69 (1H, s) MASS: 672 (M + 1) (free), 456 cases 5-4¾ 1 [a] g2: -24.2 * (C = 0.5, MeOH) IR (petroleum wax): 3650-3100 , 2750-2000, 1635, 1540, 1276, 1170, 1129, 900 cnT1 NMR (DMSO-d6, δ): 1.23 (9H, s); 2.73-5.10 (llH, m); 6.50-8.20 (9H, m) ; 10.80-11.00 (1H, m); 11.84 (1H, S) MASS: 652 {M + l) {free), 456 cases 5-51 [a] g2: -35.88 (C = 0.5, MeOH) IR (petroleum蟠): 3650-3100, 2750-2000, 1635, 1540, 1276, 1170, 1130, 900 cm-1 NMR (DMSO-d6 / δ): 0.80-1.00 (4H, m); 1.90-2.00 (1H, m ); 2.73-5.15 (11H, m); 6.60-8.21 (9H, m); 10.90-11.00 (1H, ra); 12.43 (1H, m) MASS: 636 (M + l) (free), 456 cases— 5-61 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs [cl]% 2: -30.4. (C = 0.5, MeOH) IR (petroleum thallium): 3650-3100, 2750-2000, 1635, 1542, 1275, 1170, 1131, 900 cm-1 NMR (DMSO-d6, δ): 0.89 (3H, t, J = 7.4Hz); 1.56-1.67 (2H, m); 2.40-2.50 (2H, m); 2.73-5.15 (11H, ra); 6.56-8.21 (9H, m); 10.90-10.94 (1H, m); 12.12 (1H, s) MASS: 638 (M + l) (free) Example s-7) [α] π2 ： -34.0 ° (0 = 0.5, MeOH) This paper standard is applicable to Chinese National Standard (CNS) Λ4 specification (210 X 彳 97mm) -31-乜 .II (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Central Bureau of Samples of the Ministry of Economic Affairs S91960 ^ V. Description of Invention (w) IR (Petroleum wax): 3650-3100, 2750-2000, 1635, 1543, 1277, 1170, 1130, 900 cnT1, NMR (DMSO-d6f δ): 1.08 (3Hf t, J = 7.4Hz); 2.43-2.50 (2H , m); 2.73-5.15 (11H, ra); 6.55-8.21 (9H, m); 10.90-10.94 (1H / ra) / 12.11 (1H, a) MASS: 624 (M + l) (free) Example 5 2: 8. [a] g2: -15.2. (00.5, MeOH) IR (petroleum thallium): 3600-3100, 2750-2000, 1635, 1278, 1172, 1130, 900 cm-1 NMR (DMSO-dg, δ): 2.73-5.20 (11H, m) / 6.60 -8.52 (11H, m) / 10.94 (1H, s) MASS: 596 (M + 1) (free), 456 cases 5-91 [a] g2: -20.6. (C = 0.5, MeOH) IR (petroleum thallium): 3650-3100., 2750-2000, 1635, 1276, 1170,. 1129, 900 cm-1 NMR (DMSO-d6, δ): 2.09 (3H, s) ; 2.73-5.20 (11H, m); 6.60-8.20 (11H, m); 10.46 (1H, s); 10.91 (1H, s) MASS: 604 (H + l) (free) Example 5-Ί0ί [a] ^ 2: -13.0 ° (C = 0.5, MeOH) IR (petroleum wax): 3650-3050, 2750-2000, 1685, 1636, 1524, 1275, 1130, 900 cm-1 NMR (DMSO-dg, δ): 1.31 (3H, t, J = 6.5Hz); 2.24 (3H, s); 2.73-5.20 (13H, m); 6.66-8.25 (8H, m); 10.94 (1H, s), 12.71 (1H, s) MASS: 682 (M + l) (free) Example 5-11 \ [a] J8 ·· -20.8 * (00.5, MeOH) IR (net): 3700-3000, 1615, 1515, 1272, 1125, _ This paper Standards are applicable to Chinese National Standards (CNS). Λ4 is now (2 丨〇X W7mm) -32-(Please read the precautions on the back before filling out this page). ^ __________ V. Description of the invention (w) 900 cm_l NMR (DMS〇-d6, δ): 2.00-5.00 (13H, in); 6.38-8.20 (9H, • m); 10.80 (1H, s) MASS: 568 ( M + l), 456 1.5-121 [a] g2: -10.4 ° (00.5, MeOH) IR (petroleum wax): 3650-310 0, 2750-2000, 1635, 1277, 1130 cm-1 NMR (DMS〇-d6, δ): 3.00-5.20 (11H, m); 6.60-8.30 (11H, m); 10.95 (1H, s) MASS: 568 (M + 1) (free), 456 cases 5-131 [a] g2: -31.8 ° (C = 0.5, MeOH). IR (petroleum thallium): 3270, 2750-2000, 1637, 1531, 1279, 1124 , 964 cm-1 NMR (DMSO-dg, δ): 2.73-5.15 (14H, m); 6.60-8.25 (10H, ia); 10.89 (1H, s) MASS: 646 (M + l) (free), 568, 456 Examples 5-14) [a] g3: 11.8e (0 = 0.5, MeOH) IR (petroleum wax): 3650-3100, 1625, 1543, 127 5, 1130 cm-] L NMR (DMS〇-d6 / δ): 2.09-2.11 (3H, m); 2.52-5.00 (11H, m), 6.63-8.20 (9H, m); 10.85 (1H, s); 12.07 (1H, s) HASS: 638 (M + l), 456 cases 5-15, [01] ¾8: -51.6e (00.5, MeOH) IR (petroleum tincture): 3650-3100, 2750-2000, 1634, 1540, 1274, 1170, 1127, 900 cm-1 NMR (DMS〇-d6, δ): 2.31 (3H, s); 2.73-5.35 (11H, m); 6.63-8.25 (8H, m); 10.94-11.00 (1H, m); 13.20 (1H, this paper Standards are applicable to Chinese National Standards (CNS) Λ4 specifications (210X 297 mm) -33-(Please read the precautions on the back before filling this page)

- gl-l .—1C -.391960 at B7 五、發明説明（V ) S) MASS : 611 (M+1)(自由） ^ 5-16> [a】g2 : -23.4* (C-0.5, MeOH) IR(石油蠟）：3650-3000, 2750-2000, 1620, 1274, 1175, 1128, 900 cm-1 • NMR (DMSO-d6, δ) : 1.10 (3H, t, J=7.2Hz), 2.60-5.10 (16H, m); 6.50-8.21 (9H, m); 10.91 (1H, s); 11.50-11.90 (1H, br s) MASS ： 638 (M+1)(自由） ---------d ! (請先閱讀背面之注意事項再填寫本頁)-gl-l .—1C -.391960 at B7 V. Description of the invention (V) S) MASS: 611 (M + 1) (free) ^ 5-16 > [a] g2: -23.4 * (C-0.5, MeOH) IR (petroleum wax): 3650-3000, 2750-2000, 1620, 1274, 1175, 1128, 900 cm-1 • NMR (DMSO-d6, δ): 1.10 (3H, t, J = 7.2Hz), 2.60-5.10 (16H, m); 6.50-8.21 (9H, m); 10.91 (1H, s); 11.50-11.90 (1H, br s) MASS: 638 (M + 1) (free) ----- ---- d! (Please read the notes on the back before filling this page)

、1T 經濟部中央標準局員工消費合作社印製 -34 - 本纸張尺度適用中國國家標隼（CNS )人4規格（210乂297公浇）、 1T Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs -34-This paper size is applicable to China National Standards (CNS) Person 4 specifications (210 乂 297 mm)

Claims

Β919β0 A8 B8 C8 D8 修正申請專利範圍第85106105號「具有急速激素桔抗作用之哌哄系醫藥組成物」專利案名案告农 (8 9年2月3日修正） __^ A申請專利範圍： 1. 一種用於急速Jlt_素-挂JS劑之醫藥組成物，其係含如下 —式/化冶物爲有效成分:二Β919β0 A8 B8 C8 D8 Amends the scope of patent application No. 85106105 "Pipeline medicinal composition with rapid hormone orange resistance" Patent case filed (Amended on February 3, 1989) __ ^ The scope of patent application: 1. A medicinal composition for rapid Jlt_sugar-hanging JS agent, which contains the following formulas / chemicals as active ingredients:

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c=〇經濟部智慧財產局員工消費合作社印製c = 〇 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

(請先閱讀背面之注意事項再填寫本頁) 、tT 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） Β919β0 A8 B8 C8 D8 修正申請專利範圍第85106105號「具有急速激素桔抗作用之哌哄系醫藥組成物」專利案名案告农 (8 9年2月3日修正） __^ A申請專利範圍： 1. 一種用於急速Jlt_素-挂JS劑之醫藥組成物，其係含如下 —式/化冶物爲有效成分:二(Please read the precautions on the back before filling this page), tT This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) Β919β0 A8 B8 C8 D8 Amendment application patent scope No. 85106105 "The role of pipe pipe is a pharmaceutical composition" patent case filed (revised on February 3, 1989) __ ^ A patent application scope: 1. A pharmaceutical composition for rapid Jlt Its system contains the following formulas / chemicals as active ingredients:

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(請先閱讀背面之注意事項再填寫本頁) 、tT 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）(Please read the precautions on the back before filling this page), tT This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm)