TW448173B

TW448173B - N-substituted piperidinyl bicyclic benzoate derivatives

Info

Publication number: TW448173B
Application number: TW84109382A
Authority: TW
Inventors: Daele Georges Henri Paul D Van; Jean-Paul Rene Marie A Bosmans; Den Keybus Frans Maria Alf Van
Original assignee: Janssen Pharmaceutica Nv
Priority date: 1995-05-31
Filing date: 1995-09-08
Publication date: 2001-08-01

Abstract

The present invention is concerned with novel benzoate derivatives having the formula, the N-oxide forms, the salts and the stereochemically isomeric forms thereof, wherein: R1 is halo or C1-6 alkylsulfonylamino; A represents a bivalent radical of formula -CH2-CH2- (a), -CH2-CH2-CH2- (b), -CH=CH- (c), in the radicals (a), (b) and (c) one or two hydrogen atoms may be replaced by a C1-6alkyl; R2 is hydrogen or C1-6alkyloxy; L is a radical of formula: -Alk-R4 (d), -Alk-O-R5 (e), -Alk-NR6R7 (f), Alk is C1-12alkanediyl; R4 is hydrogen; cyano; C1-6alkylcarbonyl; C1-6alkyloxycarbonyl; C3-7cycloalkyl; C1-6alkylsulfinyl; C1-6alkylsulfonyl; phenyl or phenyl substituted with halo, C1-6alkyl or C1-6alkyloxy; tetrahydrofuran; dioxolane; dioxolane substituted with C1-6alkyl; dioxane; dioxane substituted with C1-6alkyl; pyridine; pyridine substituted with halo or C1-6alkyl; pyridazine; pyridazine substituted with one or two substituents selected from halo, C1-6alkyl, hydroxy or an optionally substituted benzimidazolone or an optionally substituted imidazolone; R5 is hydrogen; C1-6alkyl; hydroxy C1-6alkyl; C1-6alkylcarbonyl; phenyl or phenyl substituted with up to three substituents selected from halo, C1-6alkyl, C1-6alkyloxy; R6 is hydrogen or C1-6alkyl; R7 is hydrogen; C1-6alkyl; C1-6alkylcarbonyl; C1-6alkyloxycarbonyl; pyridazine; pyridazine substituted with one or two substituents selected from halo, C1-6alkyl, hydroxy; pyrazine; pyrazine substituted with one or two substituents selected from halo, C1-6alkyl, hydroxy. Pharmaceutical compositions comprising said compounds, processes for preparing compounds and compositions as well as the use as a medicine, in particular for the treatment of gastrointestinal disorders involving a decreased colon motility are described.

Description

448173 A7 B7 經濟部中央標準局員工消费合作社印製五、發明説明（1 ) 本發明係有關新穎之苯甲酸醋衍生物類、包含該等靳穎化合物之醫藥組合物、製備該等化合物與組合物之方法，及其作爲藥物之用途，特定言之，用於治療涉及結腸蠕動降低之疾病。在吾等於1990年9月26日出版之EP-〇,389,037-A中曾揭示N-(3-羥基-4-六氫啶基）（二氫苯並蚨喃或二氫-2H-苯並砒喃）羧醯胺衍生物類具有刺激胃腸蠕動之性質。吾等於1991年9月11日出版之EP-0,445,862-A中亦揭示N-(4-六氫蚍啶基）（二氫苯並蚨喃或二氳-2H-苯並蚨喃）羧醯胺衍生物類具有刺激胃腸蠕動之性質。1993年3月4日出版之WO 93/03725(SmithKline Beecham)曾揭示如通式X-CO-Y-Z之酯作爲5HT4受體拮抗劑之用途，其中X可爲經取代之苯基，Y可爲氧，Z可爲經取代之六氫mt啶基。1994年4月 28 日出版之 94/08995(SmithKline Beecham)曾揭示例如經取代之7-苯並蚨喃羧酸酯亦具有5HT4拮抗劑之活性。後兩項專利申請案説明5HT4拮抗劑化合物於治療刺激性腸部症候群（IBS)，特定言之，IBS之腹瀉病症上之用途。吾等已意外發現，本新穎化合物具有腸動力原活性。因此本發明揭示之化合物具有治療涉及腸，尤指結腸，蠕動降低之疾病。本發明係有關新穎之如下式苯甲酸酯衍生物類 (請先閱讀背面之注意事項再^ 乂本頁) -裝. 訂線 —3** 本紙張尺度適用中國國家樣準（CNS ) A4規格（210X297公釐〉 448173 A7 B7 五、發明説明（2 R2448173 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the invention (1) The present invention is related to novel benzoic acid vinegar derivatives, pharmaceutical compositions containing these Jin Ying compounds, preparation of these compounds and combinations. The method of biotechnology, and its use as a medicament, in particular, is used to treat diseases involving reduced colonic motility. N- (3-hydroxy-4-hexahydropyridyl) (dihydrobenzopyran or dihydro-2H-benzo) was disclosed in EP-〇, 389,037-A published on September 26, 1990. Aromatic) carboxamide derivatives have the property of stimulating gastrointestinal motility. It is also disclosed in EP-0,445,862-A, published on September 11, 1991, that N- (4-hexahydropyridinyl) (dihydrobenzopyran or difluorene-2H-benzopyran) carboxypyramine Derivatives have the property of stimulating gastrointestinal motility. WO 93/03725 (SmithKline Beecham) published on March 4, 1993 has disclosed the use of esters of the general formula X-CO-YZ as a 5HT4 receptor antagonist, where X may be a substituted phenyl group and Y may be Oxygen, Z may be substituted hexahydromtyl. 94/08995 (SmithKline Beecham) published on April 28, 1994 (SmithKline Beecham) has disclosed, for example, that substituted 7-benzopyranocarboxylates also have 5HT4 antagonist activity. The latter two patent applications describe the use of 5HT4 antagonist compounds in the treatment of irritable bowel syndrome (IBS), and in particular, the diarrheal condition of IBS. We have unexpectedly discovered that this novel compound has enteric motility activity. The compounds disclosed in the present invention are therefore useful in treating diseases involving the bowel, especially the colon, with reduced peristalsis. The present invention is related to novel benzoate derivatives of the following formula (please read the notes on the back before ^ 乂 this page)-binding. Threading-3 ** This paper size is applicable to China National Standard (CNS) A4 Specifications (210X297 mm) 448173 A7 B7 V. Description of the invention (2 R2

L——NL——N

NH2 (I), 經濟部中央標準局負工消費合作杜印製其N-氧化物型、其醫藥上可接受之酸加成鹽類及主體化學異構型，其中： R 1爲S素或C 1 _ 6烷磺醯胺基； A代表如下式之二價自由基： -CH2 -CH2 -(a)、 -CH2 -CH2 -CH2 -(b) ^ -CH=CH-(c), 自由基（a)、（b)與（c)中一或二個氫原子可被C 基置換； R2爲氫或C 1 — 6烷氧基； L爲如下式自由基： -Alk-ΙΜ ⑷、 Alk-0-R5 (e). -Alk-NR6 R 7 (f), Aik 爲C i _ i2 烷二基； ΪΜ爲氫；氰基；Ci _ 6烷羰基；C] C3 _ 7環烷基；C 1 _ 6烷亞磺醯基苯基或經卣素、Cl _ 6烷基或Cl _ ;四氫酜喃；二氧戊環；經Cl - 6烷基取代之二氧戊環; 二氧陸環；經C! _ 6烷基取代之二氧陸環；ott啶；經鹵素或Cl - 6烷基取代之她啶；嗒畊；經一或二個選自下列之取代基取代之嗒畊：#素、C 1 _ 6烷基、羥基；或烷 .6烷氧羰基； C 1 _ 6燒續龜基；垸氧基取代之苯基本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 448173 五、發明説明（3 如下式自由基： R8NH2 (I), the Ministry of Economic Affairs, Central Bureau of Standards, Consumer and Consumer Cooperation Du printed its N-oxide type, its pharmaceutically acceptable acid addition salts and its main chemical isomers, where: R 1 is S element or C 1 _ 6 alkylsulfonamido; A represents a divalent radical of the formula: -CH2 -CH2-(a), -CH2 -CH2 -CH2-(b) ^ -CH = CH- (c), free One or two hydrogen atoms in the groups (a), (b) and (c) may be replaced by a C group; R2 is hydrogen or a C 1-6 alkoxy group; L is a radical of the formula: -Alk-IM ⑷, Alk-0-R5 (e). -Alk-NR6 R 7 (f), Aik is Ci_i2 alkanediyl; ； Μ is hydrogen; cyano; Ci_6 alkylcarbonyl; C] C3_7 cycloalkyl ; C 1 _ 6 alkyl sulfenyl phenyl or via halogen, Cl _ 6 alkyl or Cl _; tetrahydrofuran; dioxolane; dioxolane substituted by Cl-6 alkyl; two Oxygen ring; dioxo ring substituted with C! _6 alkyl; ottidine; tampidine substituted with halogen or Cl-6 alkyl; daquan; substituted with one or two substituents selected from Da Geng: # prime, C 1 _ 6 alkyl, hydroxyl; or alkane. 6 alkoxycarbonyl; C 1 _ 6 stilbyl; phenyloxy substituted phenyl This paper is applicable to China Of Standards (CNS) A4 size (210X297 mm) 448 173 V. described invention (3 radical of the formula: R8

AA

0 ㈤或Rs—N八N_ W Φ) 經濟部中央標準局員工消費合作社印製其中R 8爲氳或c R5爲氳；c 、6烷基；基；苯基~ 6垸基；羥基-至多素、Cl-_c R6爲氳或Cl代疋苯基； r7爲氳“d 基；嗒峤.經疋基’ C 1 - 6燒毅基；c 1 _ 6燒氧默素、Cl ’ 一或二個選自下列之取代基取代之嗒嵴；鹵取代基取代6之：、'基;•井;經-或二個選自下列之，上述定義A井，_素、C 1 _ e烷基、羥基。中，鹵素一般係指氟、氣、漠與破；Cl· 4 ^ 0 δ 1至4個碳原子之直鏈及分支飽和烴基，如， •甲基、乙基、丙基、丁基、1-甲基乙基、2-甲基丙基、等等，Cl - 6烷基係包括C 1 _ 4烷基及其具有5或 6個碳原子之較高碳數同系物，如，例如：2-甲基丁基、戊基、己基、等等，- 7烷基係指環两基、環丁基、環戊基、環己基及環庚基；Cl _ 12烷二基係指含有1至 12個碳原子之直鏈及分支二償烴基如，例如：12_乙二基、1，3-丙二基、1,4-丁二基、1,5-戊二基、1，6-己二基、1,7-庚二基、1,8-辛二基、1,9-壬二基、1，10-癸二基 ' 烷基；C 1 _ 6烷羰 _ 6垸氧基中 I I I __ I I 訂線 (請先閲讀背面之注意事項再(^>本貫) ) 本紙張尺度適用中國國家標隼（CNS ) A4規格（210X 297公釐） 448 448 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明（4 ) ι，π-十一烷二基、1,12-十二烷二基及其分支異構物。上述醫藥上可接受之酸加成鹽包括式（I )化合物可形成之具醫療活性之無毒酸加成鹽型。後者由此等適當酸處理其鹼型即可得到。適當酸包括例如：無機酸，如，氫鹵酸，例如：鹽酸或氫溴酸、硫酸、硝酸、磷酸、等等；或有機酸，如，例如：乙酸、丙酸、羥乙酸、乳酸、丙酮酸、草酸、丙二酸、琥珀酸、馬來酸、富馬酸、蘋果酸、酒石酸、檸檬酸、曱磺酸、乙磺酸、苯磺酸、對甲苯磺酸、環己胺磺酸、水楊酸、對胺基水楊酸、帕馬酸（Pamoic acid) 、等等。本文所使用之加成鹽一詞亦包括式（I )化合物及其鹽類可形成之溶劑化物。此等溶劑化物爲例如：水合物、醇鹽、等等。反之，鹽型可經鹼處理，轉化成游離鹼型〇本文所使用之"立體化學異構型''一詞係指式（I )化合物可能出現之所有異構型。除非另外説明或指示，否則化合物之化學式均代表所有可能出現之立體化學異構型之混合物，該混合物包括基本分子結構之所有非對映異構物與對映異構物。更特定言之，立體中心可呈R-或S-組態；雙價環狀（部份）飽和自由基可呈順式或反式組態。本發明範園當然包括式（I )化合物之立體化學異構型。有些式（I )化合物亦可呈其互變異構型。上式中雖然未明確説明此等型式，但均包括在本發明範園内。例如，式 (I)化合物，其中R4爲3-或6-羥基嗒畊基，或式（g)或 (h)中，R8爲氫者，可呈其相應之互變異構型。 -6— 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） ----------^------1T------^ (請先間讀背面之注意事項再本頁) j 448173 經濟部中央標準局員工消費合作社印裝 Α7 Β7 五、發明説明（5 ) 式（I )化合物之N-氧化物型包括彼等式（I )化合物中一個或數個氮中心氧化成所謂之N-氧化物者，特定言之，彼等其中六氫砒啶-氮已N-氧化之N-氧化物。 R1最好爲鹵素，以氣較佳； ίί 2最好爲氫或C 1 _ 4烷氧基，以氫或甲氧基較佳； Α 最好爲式（a)或（b)之二價自由基，當A經取代時，以甲基取代較佳；當A爲式（a)或（b)二價自由基時，以同一個碳上之二甲基取代較佳，尤其位於與氧原子相鄰之碳原子上；當L爲式（d)自由基時，爲氫、氰基、c〗„ 6烷羰基，Cl - 6燒氧默基，C3 -7環烷基，Cl -6燒續罐基，四氫她喃、經C 1 _ 6烷基取代之二氧戊環、Hit啶、如式 (g)自由基，其中R8爲Cl _ 6烷基，經鹵素與嬅基取代之嗒D井；當L爲式（e)自由基時，R5爲氯、Ci — 6统基、澤基 Cl、6烷基、或經卣素取代之苯基較佳；當L爲式（f)自由基時，R6爲氫較佳，R 7爲氫或經 C1、6烷基、C 1 _ 6垸氧羰基取代之嗒ο井較佳。較佳式（I )化合物爲彼等式Ri爲氣者。亦較佳式（I )化合物爲彼等式中R 2爲氫或甲氧基者。更佳式（I )化合物爲彼等式中A爲如式（a)或（b)之二償自由基者。較佳式（I )化合物爲： 4 -胺基-5-氯-2,3 -二氫-7-苯並枝喃羧酸1-[(四氫-2-α夫喃本紙張尺度適用中國國家標準（CNS > Α4規格（2丨0Χ297公釐） ----------赛------ΪΤ------,a (請先閲讀背面之注意事項再、^本頁) >. _κ .K____ __............. 448 17 經濟部中央標準局員工消費合作社印製 Α7 Β7 五、發明説明（6) 基）甲基]-4-六氫毗啶基酯； 5-胺基-6-氣-3,4-二氫-2,2-二甲基-21^1-苯並〇夫喃-8-羧酸1-[(四氫-2-蚨喃基）曱基]-4-六氫mt啶基酯； 4-胺基-5-氣-2,3-二氫-7-苯並〇夫喃羧酸1-(3-甲氧丙基）_ 4 六氫她咬基自旨； 4-胺基-5-氣-2,3-二氫-7-苯並〇夫喃羧酸1-[3-(2-甲基-1， 3- 二氧戌環-2-基）丙基]-4-六氬mt唉基自旨； 4 -胺基-5-氣-2,3 -二氫-7-苯並α夫哺後酸1-[3-(1-甲基乙氧基）丙基]-4-六氫她咬基酷； 4- 胺基-5-氣-2,3-二氫-7-苯並σ夫喃羧酸卜[2-(2-嬅乙氧基）乙基]-4-六氫砒啶基酯； 4-胺基-5-氣-2,二氫苯並σ夫喃竣酸1-[3-(3-氣-6-氧 _ 1 (6H)-塔β井基）两基]-4 -六氫〇比咬基S旨； 4-胺基-5-氣-2，3_二氫-7-苯並蚨喃狻酸1-(4-氧戊基）-4-六氫她唉基醋； 4-[[(4-胺基-5-氣-2,3-二氫-7-苯並〇夫喃基）羰基]氧]-卜六氫ott啶丁酸乙酯；及 4_胺基_5_氣_2,3_二氫_7-.苯並蚨喃羧酸卜[2-(四氫-2·〇夫喃基）乙基]-六氫oit交基醋；及其可能之立體化學異構型與醫藥上可接受之酸加成鹽。爲了簡化式（I )化合物及其某些起始物質與中間物之結構式，下文中將以代號D代表如下式自由基。 —8 — 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐）裝------訂-------線 (請先閱讀背面之注意事項再本頁) '} 4 4 0 1 7 A7 B7 五、發明説明（ R20 ㈤ or Rs—N 八 N_ W Φ) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs where R 8 is 氲 or c R5 is 氲; c, 6 alkyl; radical; phenyl ~ 6 fluorenyl; hydroxyl-up to R6 is fluorene or Cl substituted fluorenyl group; r7 is fluorene "d group; hydrazone. Fluorenyl group 'C 1-6 alkyl group; c 1 -6 oxygen oxymethoxin, Cl' one or Two substituents selected from the following: substituted by halogen; halogen substituted by 6 :, ';; well; via-or two selected from the following, the above definition A well, _ prime, C 1 _ e alkane In general, halogen refers to fluorine, gas, indifference and destruction; Cl · 4 ^ 0 δ linear and branched saturated hydrocarbon groups of 1 to 4 carbon atoms, such as: methyl, ethyl, propyl, Butyl, 1-methylethyl, 2-methylpropyl, etc., Cl-6 alkyl system includes C 1-4 alkyl and its higher carbon number homologues having 5 or 6 carbon atoms, For example, for example: 2-methylbutyl, pentyl, hexyl, etc., -7 alkyl refers to cyclodiyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl; Cl-12 alkyl diyl system Refers to straight-chain and branched compensating hydrocarbon groups containing 1 to 12 carbon atoms, such as: 12_B Base, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl, 1,7-heptanediyl, 1,8-octanediyl, 1,9-nonanediyl, 1,10-decanediyl 'alkyl; C 1_ 6 alkylcarbonyl-6 methoxy group III __ II (Please read the precautions on the back first (^ > this (Continued)) This paper size applies to China National Standard (CNS) A4 (210X 297 mm) 448 448 A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (4) ι, π-undecane Diyl, 1,12-dodecanediyl and its branched isomers. The above-mentioned pharmaceutically acceptable acid addition salts include medically active non-toxic acid addition salt forms which can be formed by compounds of formula (I). The latter Such bases can be obtained by treating them with a suitable acid. Suitable acids include, for example, inorganic acids such as hydrohalic acids such as hydrochloric or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or organic acids such as, For example: acetic acid, propionic acid, glycolic acid, lactic acid, pyruvate, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, sulfonic acid, ethanesulfonic acid, benzenesulfonic acid acid , P-toluenesulfonic acid, cyclohexylaminesulfonic acid, salicylic acid, p-aminosalicylic acid, Pamoic acid, etc. The term addition salt as used herein also includes compounds of formula (I) And its salts can form solvates. These solvates are, for example: hydrates, alkoxides, etc. Conversely, the salt form can be treated with a base to convert it into a free base form. The term `` configuration '' refers to all isomeric forms that may occur with a compound of formula (I). Unless otherwise stated or indicated, the chemical formula of a compound represents a mixture of all stereochemically isomeric forms that may occur, and the mixture includes all diastereomers and enantiomers of the basic molecular structure. More specifically, the stereocenter can assume an R- or S-configuration; the bivalent cyclic (partially) saturated radicals can assume a cis or trans configuration. The invention encompasses, of course, the stereochemically isomeric forms of the compounds of formula (I). Some compounds of formula (I) may also be in their tautomeric form. Although these types are not explicitly described in the above formula, they are all included in the scope of the present invention. For example, a compound of formula (I), in which R4 is 3- or 6-hydroxydacrotyl, or in formula (g) or (h), R8 is hydrogen, which may be in its corresponding tautomeric form. -6— This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) ---------- ^ ------ 1T ------ ^ (Please read first Note on the back page) j 448173 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (5) The N-oxide type of the compound of formula (I) includes one of the compounds of formula (I) Or, several nitrogen centers are oxidized to so-called N-oxides, specifically, N-oxides in which hexahydropyridine-nitrogen has been N-oxidized. R1 is preferably halogen, preferably gas; ί 2 is preferably hydrogen or C 1 _ 4 alkoxy group, preferably hydrogen or methoxy group; A is preferably divalent of formula (a) or (b) Free radicals, when A is substituted, methyl substitution is preferred; when A is a divalent radical of formula (a) or (b), dimethyl substitution on the same carbon is preferred, especially if it is located with oxygen On adjacent carbon atoms of the atom; when L is a radical of formula (d), it is hydrogen, cyano, or c 6 alkylcarbonyl, Cl-6 alkoxymeryl, C3-7 cycloalkyl, Cl-6 Burning of a canister group, tetrahydrobutan, dioxolane substituted with C 1 -6 alkyl, Hitidine, such as a radical of formula (g), wherein R 8 is Cl -6 alkyl, substituted with halogen and fluorenyl Well D; When L is a radical of formula (e), R5 is chlorine, Ci-6, Benzyl Cl, 6 alkyl, or halogen-substituted phenyl; When L is formula ( f) In the case of free radicals, R6 is preferably hydrogen, and R7 is preferably hydrogen or substituted by a C1, 6 alkyl group, or C1-6 oxocarbonyl group. Preferred compounds of formula (I) are their formulas Ri is a gas. Also preferred is a compound of formula (I) in which R 2 is hydrogen or methoxy. More preferably, the compound of formula (I) The compounds are those in which A is a free radical such as formula (a) or (b). Preferred compounds of formula (I) are: 4-amino-5-chloro-2,3-dihydro-7 -Benzofurancarboxylic acid 1-[(tetrahydro-2-αfuran) The paper size applies to Chinese national standards (CNS > A4 specification (2 丨 0 × 297 mm) ---------- sai ------ ΪΤ ------, a (Please read the precautions on the back, ^ this page) >. _κ .K ____ __............. 448 17 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (6) methyl] -4-hexahydropyridinyl ester; 5-amino-6-gas-3,4-dihydro -2,2-dimethyl-21 ^ 1-benzofran-8-carboxylic acid 1-[(tetrahydro-2-fluoranyl) fluorenyl] -4-hexahydromtpyridyl ester; 4 -Amino-5-Gas-2,3-dihydro-7-benzofranocarboxylic acid 1- (3-methoxypropyl) _ 4 hexahydrohexatyl motif; 4-amino-5 -Ga-2,3-dihydro-7-benzoxancarboxylic acid 1- [3- (2-methyl-1,3-dioxocyclo-2-yl) propyl] -4-hexa Argon mt fluorenyl motif; 4-amino-5-gas-2,3-dihydro-7-benzo-α-ferrous acid 1- [3- (1-methylethoxy) propyl]- 4-Hexahydroquinone; 4-Amino-5-Ga-2,3-dihydro-7-benzosigmafuran [2- (2-fluorenylethoxy) ethyl] -4-hexahydropyridinyl ester; 4-amino-5-gas-2, dihydrobenzoσfrancoic acid 1- [3 -(3-Gas-6-Oxygen-1 (6H) -Tower β-well base) two radicals] -4 -Hexahydro octadecyl S; 4-amino-5-gas-2,3-dihydro -7-benzopyranoic acid 1- (4-oxopentyl) -4-hexahydrotartaric acid vinegar; 4-[[((4-amino-5-gas-2,3-dihydro-7) -Benzobenzofuranyl) carbonyl] oxy] -ethyl hexahydroottidine butyrate; and 4-amino-5_gas_2,3_dihydro-7-. [2- (Tetrahydro-2 · 0furanyl) ethyl] -hexahydrooit cross-linked vinegar; and its possible stereochemically isomeric forms and pharmaceutically acceptable acid addition salts. In order to simplify the structure of the compound of formula (I) and some of its starting materials and intermediates, the radical D will be represented by the following formula with the code D. —8 — This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X 297mm). Packing ---------------- line (Please read the precautions on the back before this page) '' } 4 4 0 1 7 A7 B7 V. Description of the invention (R2

NH2 下列製法中，可自反應混合物中單離反應產物，且若需要時，再根據相關技藝上已知之方法純化，如，例如：萃取法、蒸餾法、結晶法、研磨法及層析法。製備式（I)化合物時，可由式（π)六氫oit啶與式（m)中間物進行N-烷化反應，其中，wi爲適當之釋離基，如，例如：南素，例如：氣、溴或破，或續酿氧基，例如：曱磺醯氧基、曱苯磺醢氧基，等等。U )與（m )之N-垸化反應宜依相關技藝上已知之烷化製程進行。 L-W1 + H-D N-烷化反應 (ffl ) (Π ) -----> (I ) 製備式（I)化合物時，亦可由式（IV)醇與式（V)羧酸或其官能衍生物，如醯基自化物、對稱或混合酸酐或酯，以活化蜡較佳，依相關技藝上已知之製程進行酯形成作用。 R2 R1NH2 In the following production methods, the reaction product can be isolated from the reaction mixture and, if necessary, purified according to methods known in the relevant art, such as, for example, extraction, distillation, crystallization, grinding, and chromatography. In the preparation of compounds of formula (I), hexahydrooitidine of formula (π) and an intermediate of formula (m) can be used for N-alkylation reaction, where wi is an appropriate release group, such as, for example, nansin, for example: Gas, bromine or broken, or continue to make oxygen, such as: sulfonylsulfonyloxy, sulfonylsulfonyloxy, and so on. The reaction of U) with (m) should be carried out according to alkylation processes known in the related art. L-W1 + HD N-alkylation reaction (ffl) (Π) ----- > (I) When the compound of formula (I) is prepared, the alcohol of formula (IV) and the carboxylic acid of formula (V) or its Functional derivatives, such as fluorenyl autogenates, symmetrical or mixed anhydrides or esters, are preferably activated waxes, and perform ester formation according to processes known in the relevant art. R2 R1

L—N (TV) 請k, 閱讀背面之注項再 D 本頁裝 I 訂經濟部中央標準局員工消費合作社印製L—N (TV) Please read the note on the back and then D. This page is bound to be printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs.

-0H-0H

nh2 (Ο 反應過程中，宜保護胺基或雞基，即非反應性之m基，以避免不必要之副反應。待酯形成反應完成後，即脱除該等胺基或m基之保護基團。合適之保護基團包括容易脱除之基團，如Cl _ 4烷羰基、Cl _4烷氧羰基、苯甲基等 *9- 本紙張尺度適用中國國家榇準（CNS ) A4規格（210X297公釐） II 線 -ςί 經濟部中央標準局員工消費合作社印製nh2 (〇 During the reaction, it is advisable to protect the amine or chicken group, that is, the non-reactive m group, to avoid unnecessary side reactions. After the ester formation reaction is completed, the protection of the amine or m group is removed. Groups. Suitable protective groups include groups that can be easily removed, such as Cl _ 4 alkoxycarbonyl, Cl _ 4 alkoxycarbonyl, benzyl, etc. * 9- This paper size applies to China National Standard (CNS) A4 specifications ( 210X297 mm) Line II-Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

A7 B7 五、發明説明（8 ) 等保護基團。製備式（I)化合物時，亦可由式（I)化合物轉化成另一種式（I )化合物。式（I )化合物，其中L爲式（f)自由基，其中β 7不爲氫，該化合物由式（I-f-2)代表，其製法可由式（I)化合物，其中R7爲氫，該化合物由式（I-f-l)代表，與式0V) 試劑，其中W 2爲適當之釋離基，如，例如：卣素，例如：氯、溴或碘，或磺醴氧基，例如：甲磺醯氧基、甲苯磺醯氧基，等等，依相關技藝上已知烷化製程進行反應。 + HN - Aik—N R6 (VI) 製備式（I )化合物，其中L爲式（d)自由基，Aik爲1， 2-乙二基且R4爲氰基時，可由式（H)中間物與丙烯觭依相關技藝上已知製程進行反應。製備式（I )化合物，其中L爲式（e)自由基，Aik爲1， 2- 乙二基且R5爲氫時，可由式（Π)中間物與環氧乙垸依相關技藝上已知製程進行反應。製備式（I )化合物，其中L爲式（f)自由基，Aik爲1, 3- 丙二基且K6與R7爲氫時，可由式（I)化合物，其中L 爲式（d)自由基，Aik爲1,2-乙二基且R 4爲氰基，進行氫化反應。式（I )化合物亦可依相關技藝上已知使三價氮轉化成其一 10_ 本紙張尺度適用中國國家標準（CNS )八4規格（210Χ：297公釐） ----------^------ΐτ------^ (請先閱讀背面之注意事項再1}?本頁) } 五、發明説明（9 A7 B7 N-氧化物之製轉化成其N_氧化物 ◊進行該N-氧化反應時，通常由式（I)起始物質與適當有機或無機過氧化物反應。適當無機過氧化物包括例如：過氧化氫、鹼金屬或鹼土金屬過氧化物，例如：過氧化鈉、過氧化鉀；適當有機過氣、物匕括過氧酸類，如，例如：苯織過氧酸或經卣素取代之苯㈣氧酸，例如，3-氣《過氧酸，過紐酸，例如：過氧乙酸，垸基氫過氧化物，例如：三級丁基氫過氧化物。合適之溶劑爲例如：水低碳數垸醇，例如乙醇二等等，煙類，例如：甲苯，酮類，例如：2-丁酮，_化經類，例如：二氣f烷，及此等溶劑之混合物。式（K )中間物可由式（VB)經適當取代之六氫毗啶與式 (V)酸中間物或其官能衍生物依相關技藝上已知之酯形成製程進行反應製得，随後依相關技藝上已知之製程脱除保護基團P ° P代表容易脱除之保護基，如：C 1 _ 4繞羰基 -4 垸氧羰基、苯甲基等等保護基國A7 B7 V. Description of invention (8) and other protecting groups. In the preparation of a compound of formula (I), a compound of formula (I) can also be converted into another compound of formula (I). A compound of formula (I), wherein L is a radical of formula (f), wherein β 7 is not hydrogen, the compound is represented by formula (If-2), and a preparation method thereof may be a compound of formula (I), wherein R 7 is hydrogen, the compound Represented by the formula (Ifl) and the reagent of formula 0V), wherein W 2 is an appropriate releasing group, such as, for example, halogen, such as: chlorine, bromine or iodine, or sulfonyloxy, such as: methanesulfonyloxy Base, tosylsulfonyloxy, etc., are reacted according to known alkylation processes in the related art. + HN-Aik—N R6 (VI) To prepare a compound of formula (I), where L is a radical of formula (d), Aik is 1,2-ethylenediyl and R4 is a cyano group, an intermediate of formula (H) It reacts with a process known in propylene conversion. When the compound of formula (I) is prepared, where L is a radical of formula (e), Aik is 1,2-ethylenediyl and R5 is hydrogen, the intermediates of formula (Π) and ethylene oxide can be known in the related art. The process is reacted. When a compound of formula (I) is prepared, where L is a radical of formula (f), Aik is 1,3-propanediyl and K6 and R7 are hydrogen, a compound of formula (I) can be obtained, where L is a radical of formula (d) Aik is 1,2-ethylenediyl and R 4 is cyano, and a hydrogenation reaction is performed. The compound of formula (I) can also be used to convert trivalent nitrogen into one of the 10_ according to the known technology. This paper size is applicable to China National Standard (CNS) 8-4 specification (210 ×: 297 mm) -------- -^ ------ ΐτ ------ ^ (Please read the notes on the back first and then 1}? This page)} 5. Description of the invention (9 A7 B7 N-oxide system into its N_oxide◊ When performing this N-oxidation reaction, the starting material of formula (I) is usually reacted with a suitable organic or inorganic peroxide. Suitable inorganic peroxides include, for example, hydrogen peroxide, alkali metal or alkaline earth metal peroxides. Oxides, such as: sodium peroxide, potassium peroxide; suitable organic peroxides, peroxo acids, such as, for example, phenylperoxyacid or phenylarsinic acid substituted with halogens, such as 3-gas "Peroxy acid, peronic acid, for example: peroxyacetic acid, fluorenyl hydroperoxide, for example: tertiary butyl hydroperoxide. Suitable solvents are, for example, water lower carbon alcohols, such as ethanol, etc. And so on, such as: toluene, ketones, such as: 2-butanone, chemical compounds, such as: digas fane, and a mixture of these solvents. Formula (K) Intermediates can be prepared by reacting a suitably substituted hexahydropyridine of formula (VB) with an acid intermediate of formula (V) or a functional derivative thereof according to an ester formation process known in the related art, and then according to the known technology Removal of the protective group P ° P in the process represents a protective group that can be easily removed, such as: C 1 _ 4 around carbonyl-4 oxocarbonyl, benzyl, etc.

R2 Γ P-NR2 Γ P-N

•0H + (VH) 經濟部中央標準局員工消費合作社印製• 0H + (VH) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

2.脱除P 酸形成作用2.Removal of P acid formation

(H ^v/Ol xL 製備式（vr)中間物，PI代表p及氫時，可由式（调）中間物依相闞技藝上已知之方法進行還原反應製得。製備式（別，）中間物，其中口爲^ _ 4燒氧基，該中間物以式（vr-a)代表，且其與4_嬅基呈順式组態時 -11- 本紙張尺度適用中國國家標準（CNS ) A4規格（210x297公釐} 448 1 7 A7 B7 經濟部中央標準局負工消費合作社印製五、發明説明（10 ) ，可使用還原劑，如：經取代之氫碉化物，例如：參-二級丁基氫硼化鋰、參-二級丁基氫硼化鉀、經取代之氫化鋁、參-三級丁氧基氳化鋁鋰，等等還原式(VH-a)中間物。可依立體專一性方式，使用純立體化學性試刑進行該還原反應。 R2 P1—^—OH (VH) (vm-a): R2為Cw鄉基 (VII-.a):R2^witS^ 式（I)化合物之頬式輿反式非對映異構性消旋物，或其它任何中間物亦可依相關技藝上已知之方法解析成其旋光異構物，順式（+)、順式（-)、反式（+)輿反式（-)。非對映異構物可利用物理分離法分離，如：選擇性結晶法與層析法，例如，进流分佈法，且對映異構物可利用其非對映異構性鹽與純對映異構性酸或其純對映異構性衍生物進行選擇性結晶法互相分離。式（I )化合物及其式（I )中間物、N-氧化物型、醫樂上可接受之簠類輿立髏異構型具有有利之刺激胃腸蠕動之性質。特定言之，本化合物對小腸及大腸展現顯著之促進蠕動性質。後項性質可由”天竺鼠迴腸同軸刺激"（Guinea Pig Ileum Coaxial Stimulation)試驗及"有意識的狗之結腸綠動"（Colon motility in conscious dog)試驗證實。這兩種試驗均説明於下文中。其中有些化合物亦在••狗之利達脒試驗"（Lidamidine test in dogs)中具有活性。(H ^ v / Ol xL when the intermediate of formula (vr) is prepared, and PI represents p and hydrogen, the intermediate of formula (tune) can be prepared by a reduction reaction according to a method known in the art of phase mixing. When the mouth is ^ _ 4 alkoxy, the intermediate is represented by the formula (vr-a), and when it is in cis configuration with the 4_ 嬅 group -11- This paper size applies to the Chinese National Standard (CNS) A4 specifications (210x297 mm) 448 1 7 A7 B7 Printed by the Consumers ’Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (10), reducing agents can be used, such as: substituted hydrogen hydrides, such as: Grade butyl lithium borohydride, ginseng-secondary butyl potassium borohydride, substituted aluminum hydride, ginseng-tertiary butoxy lithium aluminum halide, and the like (VH-a) intermediates. The reduction reaction is performed in a stereospecific manner using pure stereochemical test sentences. R2 P1 — ^ — OH (VH) (vm-a): R2 is Cw township (VII-.a): R2 ^ witS ^ (I) The hydrazone, trans-diastereomeric racemate of the compound, or any other intermediates can also be resolved into its optical isomers according to methods known in the relevant art, cis (+), cis (-), Trans (+) and trans (-). Diastereomers can be separated by physical separation methods, such as: selective crystallization and chromatography, for example, inflow distribution method, and enantiomers. Isomers can be separated from each other by selective crystallization using their diastereomeric salts and pure enantiomeric acids or their pure enantiomeric derivatives. Compounds of formula (I) and formula (I) Intermediate, N-oxide type, medically acceptable stilbene stereoisotope isoform has favorable properties for stimulating gastrointestinal peristalsis. In particular, this compound exhibits significant peristaltic properties for the small and large intestines. This property can be confirmed by the "Guinea Pig Ileum Coaxial Stimulation" test and the "Colon motility in conscious dog" test of guinea pigs. Both tests are described below. Some of these compounds are also active in the Lidamidine test in dogs.

(請先閲讀背面之注意事項再'Θ本頁) -5 丁本紙張尺度適用中_國家樣率（〇^>人4规格（2丨0父297公釐） 4 4 8 彳 7:: 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明（11 ) 由於其具有促進腸蠕動之有利性質，本發明化合物因此可調配成供投藥用之各種不同型式。製備本發明之醫禁組合物時，由有效量之特定化合物（可呈鹼或酸加成鹽型）作爲活性成份，與醫藥上可接受之載體組合成均句混合物，該载體依投禁時所需之製劑型式而定，可呈各種不同型式。此等醫藥組合物需呈最好適合口服、經直腸投藥或非經腸式注射之單位劑型。例如，製備口服劑型組合物時，若爲口服液體製劑，如懸浮液、糖漿、酊劑及溶液時，可使用任何習知醫禁介質，如，例如 :水、二醇類、油類、醇類，等等；或若爲散劑、丸劑、膠囊及禁錠時，可使用固體載體如：糖、高嶺土、潤滑劑、結合劑、崩解劑，等等。由於禁錠與膠囊容易投藥，因此爲最有甩之口服單位劑型，此時當然使用固體醫禁載體。用於非經腸式組合物之載體通常至少包含大量無菌水，但亦可包含其它成份，以便例如促進溶解。例如製備注射溶液時，載體可包含生理食鹽溶液、葡萄糖溶液或生理食鹽水與葡萄糖溶液之混合物。亦可製備注射懸浮液，此時可使用適當液體載體、懸浮劑，等等。適於經皮唐投藥之組合物中，載體可視需要包含滲透加強劑與/或合適之濕化劑，可視需要與少量之任何性質之合通添加物组合，但該等添加物不可對皮膚引起顯著之不良反應。該等添加物可促進對皮膚之投禁且/或有助於製成所需之組合物。此等組合物可由各種方式投禁，例如：經皮式貼布、定點投藥（spot-on)、軟膏。由於（I )或（Π )之酸加成鹽之水溶 —13— 本紙張尺度適用中國囤家標準（CNS ) A4規格（210X297公釐） ~~ n n n I u 1 I ^ p (請先閲讀背面之注意事項再本頁} j 13 13 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明（12 ) 性高於相應之鹼型，因此當然較適合製備水性組合物。上述醫藥組合物尤其有利於配成容易投藥且劑量均一之單位劑型。本説明書及申請專利範園所使用之單位劑型係指適於呈單一劑型之物理性分離單位，每單位包含經計算可產生所需醫療效果之預定量活性成份，及所需之醫藥載體。此等單位劑型之實例爲藥錠（包括有刻度或包衣之蔡錠）、膠囊、丸劑、散劑包、扁囊錠、注射用溶液或懸浮液、茶匙量、湯匙量，等等，及其分開之多重單位。由於本化合物可以刺激腸系蠕動且特别可以促進結腸蠕動’因此適於爲罹患與蠕動障礙有關之症狀，例如：僅小腸與大腸之蠕動降低或合併出現胃延遲排空之患者改善腸運動或使之正常化。由於本發明化合物具有此等用途，因此可提供一種爲溫血動物治療罹患腸系蠕動異常之方法，· 例如：便秘、假性阻塞、腸弛缓、手術後之腸弛缓、刺激性腸部症候群（IBS)、禁物引起之運動延遲，特定言之，結腸運動受損。該方法包括爲溫血動物全身投與刺激腸有效量之式（I )化合物、其N-氧化物、醫藥上可接受之酸加成鹽或其可能出現之立體化學異構物。因此提供式（I )化合物作爲禁物之用途，特定言之，式（I)化合物於製造用於治療涉及結腸蠕動降低之病症之禁物上之用途。通常醫療有效量爲約0.001毫克/欠斤至约10毫克/公斤體重，以約0.002毫克/公斤至約5毫克/欠斤體重較佳。治療方法亦包括每日在兩次或四次攝食之間投與活性成份療程〇 -*14 — 本纸張尺度適用中國國家標準（CNS ) A4规格（210X 297公釐) ----------^------,訂------1 (請先閱讀背面之注意事項再本頁) J ./' 448173 A7 B7 五、發明说明（13 ) 下列實例係説明本發明，且完全未加以限制。下文中， ” ΤΗΓ’係指四氫〇夫喃，且"DIPE"指二異丙基鰱。奮驗部份 A.中間物之鷇法實例1 a) 取含3-甲氧基-1-(苯基甲基）-4-六氫砒啶酮（4.4克）之 THF溶液冷卻至-75eC。滴加參-二級丁基氫硼化叙，於 -7(TC下攪拌反應混合物2小時。於室溫下滴加1〇%乙酸 (100毫升）。蒸發有機溶劑。以ΝΗ 4 ΟΗ鹸化水性殘質後，以DIPE萃取兩次。分離之有機層以水洗滌，以恥3〇4脱水，過濾及蒸發溶劑。殘質經短矽膠管柱層析純化（溶離液： 012(：丨2八：1[3(^95/5逐漸提高至98/2)，產生1.3克（29.4%)觸式-3-甲氧基-1-(苯基甲基）-4-六氫毗啶酵（中間物1)。經濟部t央標隼局爲工消费合作杜印製 b) 取含中間物(1)(11.5克）輿甲醇（150毫升）之混合物於常壓及室溫下，與2克Pd/C 10%觸媒氳化兩小時。待已吸收計算之氬氣後，濾出觸媒，蒸發濾液。殘質經矽膠管柱層析纯化（溶離液：CHCl 3 /(CH3 0H/NH3 )85/15)。收集純溶離份，蒸發溶出液，產生3.6克（53%)順式-3-甲氧基-4-六氫战啶醇之油殘質（中間物2 )。 0滴加含雙（1,1，-二甲基乙基）二碳酸酯（65.5克）之 CHCI 3 (100毫升）溶液至含中間物⑵（34克）之CHC1 3 (350 毫升）溶液中，反應混合物於室溫下攪拌3小時。反應混合物依序以水、氨及水洗滌。分雜之有機層以MgS04脱水，過濾及蒸發溶劑。殘質（79克）經發藤管柱層析妹化（溶 -15-本紙張尺度遑用中國國家樣準（CNS > A4规格（2丨〇>;297公釐） 448173 A7 B7 五、發明説明（14 ) 離液：CH2 Cl 2 /(CH3 〇H/NH3 )97/3逐漸提高 95/5)。收集純溶離份，蒸發溶劑，產生58克（士）_順式-4-羥基-3-甲氧基-1-六氫ojfc啶羧酸1，1-二甲基乙酯（96.4%粗殘質） (中間物3 )。 d) 添加氫化鈉（6·2克）至含中間物⑶（30克）之TEF(1000毫升）溶液中。混合物於氮氣流下回流攪拌3小時後，冷卻 (溶液I ) »添加1，1’1炭基雙-1Η-咪唑（21克）至含4-胺基-5-氣-2,3-二氳-7-苯並蚨喃羧酸（31.4克）之乙胯（1000毫升)溶液中，混合物於室溫下攪拌2小時。蒸發溶劑。殘質溶於THF(1000毫升）中，形成溶液I。於室溫下，將溶液 II倒至溶液I中，反應混合物於室溫下攪拌2小時。蒸發溶劑。殘質分配在CH2CI2與H2〇之間。分離有機層，以 CH 2 C1 2萃取水層兩次。分離之有機層以MgSO 4脱水，過濾及蒸發溶劑。殘質經矽膠管柱層析純化（溶離液： CH2 Cl 2 /CH3 0H 98/2)。收集所需之溶離份，蒸發溶劑，產生50克（士）-順式-4-[[(4-胺基-5-氣-2,3-二氳-2,2-二甲基苯並〇夫喃基）_默基]氧]-3 -甲氧基-1-六氫她咬談酸1,1-二甲基乙S旨（85%)(中間物4 )。經濟部中央標準局員工消費合作社印製 e) 取含中間物⑷（50克）之THF(600毫升）與鹽酸（60毫升）之混合物回流挽拌30分鐘〇反應混合物冷卻，以NH4 0H驗化。分離之水層以THF萃取。卒液蒸發，殘寶經梦膠管柱層析純化（溶離液：CH2 Cl 2 /(CH3 〇H/M3 )93/7)。收華純溶離份，蒸發溶劑。殘質於沸騰之DIPE中攪拌。混合物冷卻，濾出所得沉澱，溶於2-丙醇中，以乙二酸（0 6克）轉 —16— 本紙張尺度適用中國國家標準（CNS ) A4规格（2!〇Χ297公釐） 448173 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明（15 ) 化成乙二酸鹽（1:1)。混合物煮沸，冷卻，濾出所得沈殿，乾燥，產生16克（±)-順式-4-胺基-5-氣-2,3-二氫-2,2 -二甲基-7-苯並酜喃羧酸3-甲氧基-4-六氫她啶基酯乙二酸鹽（1:1)(33%);熔點 193.2ec(中間物5 )。依類似方法亦製得： 4-胺基-5-氣-2,3-二氫-2,2-二甲基-7-苯並〇夫喃羧酸4-六氫毗啶基酯；熔點161.0Τ〇(中間物6 )。 (士）-順式-4-胺基-5-氣-2,3-二氫-2,2-二甲基-7-苯並〇夫喃羧酸3-甲氧基-4-六氫毗啶基酯（中間物7 )。 ' 4-胺基-5-氣-2,3-二氫-7-苯並蚨喃羧酸4-六氫砒啶基酯；熔點161.0°C(中間物8 )。 B,終化合物之铟法實例2 取含1-[3-(卜甲基乙氧基）丙基]-4-六氫mt啶醇（2.5克）與Ν,Ν-二甲基-4-她啶胺（2克）之二氣甲烷（1〇〇毫升）混合物於室溫下攪拌。添加4-(乙釀胺基）-5-氣-2,3-二氫-7-苯並蚨喃羰基氯（2.7克）。反應混合物於室溫下攪拌72小時。蒸發溶劑。殘質經矽膠管柱層析純化（溶離液： CH 2 Cl 2 /CH 3 0H 95/5)。收集所需之溶離份，蒸發溶劑。殘質（3.2克）溶於THF(100毫升）中，以鹽酸（1〇毫升）處理◊反應混合物挽拌回流2小時。反應混合物冷卻，以 NH4 OH鹼化。蒸發有機溶劑，以CEbCh萃取水性殘質兩次。分離之有機層以MgSO 4聪水，過濾及蒸發溶劑。殘質經短矽膠管柱層析純化（溶離液：CH2CI2 /(CH3OH/NH3 4)97 -17- 本紙張尺度適用中國國家標準（CNS ) A4规格（210X297公釐） (請先.閱讀背面之注意事項再iv.本頁) -裝. 訂 448173 經濟部中央標準局員工消費合作社印繁 A7 B7 五、發明説明（l6 ) /3)。收集所需之溶離份，蒸發溶劑。殘質（2.9克）經高效液相層析法純化（溶離液：CH2 C1 2 /(CH3 0H/NH3 )/ CH 3 OH 97/1/2)。收禁純溶離份，蒸發溶劑。殘質溶於2-丙醇中，i5<HC1/2-丙醇轉化成鹽酸鹽（1:1)。混合物煮洙，冷卻，濾出沉澱乾燥（眞空；80·〇)，產生0.50克4-胺基-5-氣-2,3-二氫-7-苯並〇夫喃羧酸1-[3-(卜甲基乙氧基）丙基]-4-六氫ait啶基酯單鹽酸鹽（12%);熔點208.6eC(化合物4 ) 〇實例3 取含中間物⑻（3克）、2-(3-氣丙基）-2-甲基-1,3-二氧戊環（2.5克）、碳酸鈉（2.1克）與碘化鉀（觸媒量）之4-甲基 -2-戊酮（150毫升）混合物回流攪拌一夜。混合物冷卻，以水洗滌，脱水（MgS04 ),過濾及蒸發溶劑。殘質經矽膠管· 柱層析純化（溶離液：CH2 C1 2 /(CH3 0H/NH3 )97/3)。收集純溶離份，蒸發溶劑。殘質於沸騰之DIPE中攪拌，冷卻，攪拌，過濾並自CH3CN/DIPE中再結晶。濾出沉澱，乾燥，產生1.00克4-胺基-5-氣-2,3-二氫-7-苯並蚨喃羧酸 1-[3-(2-甲基-1,3-二氧戊環-2-基）两基】-4-六氫毗啶基酯（24%);熔點128.1eC(化合物6 )。實例4 取含中間物⑸（10克）與2-丙烯骑（2毫升）之2-丙醇（150 毫升）混合物攪拌回流一夜。再添加2-丙烯胩（1毫升），反應混合物攪拌回流20小時〇蒸發溶劑。殘質經矽膠管柱層析純化（溶離液：CH2 C1 2 /(CH3 〇H/NH3 )97/3)。收集 -18- 本紙張尺度適用中國國家標準（CNS ) A4说格（210X297公釐） I ~- — — —II . ... I 訂 * 1 I I 矣 ί请先閱讀背面之注意事項存本貫) 1 448173 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明（17 ) 純溶離份。殘質於沸騰之DIPE中攪拌，冷卻，擾拌濾出沉澱，乾燥（眞空；80°C)，產生10.7克（士）-順式-4-胺基 -5-氯-2,3-二氫-2,2-二甲基-7-苯並α夫喃羧酸1-(2-氰乙基）-3-甲氧基-4-六氫mt啶基酯（94%);熔點180.3eC (化合物27)。實例5 於室溫下，使環氧乙垸（氣體）通過含中間物⑹（3.3克）之甲醇（80毫升）溶液3小時，並保持301〇以下之溫度。蒸發溶劑，殘質經矽膠管柱層析純化（溶離液：CH2C1 2 / (CH3 011/冊3 )93/7)。收集純溶離份，蒸發溶劑。殘質於沸騰之DIPE中攪拌，冷卻至室溫，濾出沉澱，乾燥（眞空； 80¾)，產生1.66 克 4-胺基-5-氣-2,3-二氫-2,2-二甲基-7 -苯並蚨喃羧酸1-(2-羥基乙基）-六氫砒啶基酯（45%);熔，點166.310(化合物21)。實例6 取含化合物⑹（2克）之THF(50毫升）與鹽酸（5毫升）之混合物攪拌回流30分鐘。反應混合物冷卻，以NIU0H鹼化。分離之水層以THF萃取。合併之有機層蒸發，殘質經矽膠管柱層析純化（溶離液：CH2 C1 2 /(CH3 0Η/ΝΗ3 )97/3) 。收集純溶離份，蒸發溶劑。殘質於沸騰之DIPE中攪拌。濾出所得沉澱，乾燥，殘質再經矽膠管柱層析純化（溶離液:CH2 C1 2 /CH3 0H 90/10)。收集純溶離份，蒸發溶劑。產生0.90克4-胺基-5-氣-2,3-二氫-7-苯並蚨喃羧酸1-(4_氧戊基）-4-六氫毗啶基酯（47%);熔點104·8eC(化合物 -19- 本纸張尺度適用中國國家操準（⑽）八4麟_ ( 21〇><297公着）裝-------訂------線 (請先閔讀背面之注意事項再ΐ}本頁) 丨 448173 Α7 Β7 五、發明説明（is ) 8) 〇實例7 取舍化合物⑼（8.5克)之THF(500毫升）混合物經阮來鎳觸媒（觸媒量）氫化。吸收Η 2 (2當量）後，濾出觸媒，蒸發濾液。殘質再經矽膠管拄層析純化（溶離液：CH2C1 2 /(CH3 OH/NH3 )90/10)。收禁純溶離份，蒸發溶劑。殘質於沸騰之DIPE中攪拌，冷卻後，濾出所得沉激，乾燥，產生5.2克（士）-順式-4-胺基-5-氣-2,3-二氫-7-苯並蚨喃羧酸卜（2-胺乙基）-3-甲氧基-4-六氫毗啶基酯（61%);熔點 133.9eC(化合物 11)。實例8 取化合物（11)(4克）、2-氣-3-甲基σΜ井（2_8克）與N，N- 經濟部中央標隼局員工消費合作社印製二乙基己胺（2.8毫升）於120¾挽拌24小時。混合物冷卻，· 溶於CH2 C1 2中。有機溶液經矽膠管柱層析純化兩次（溶離液：CH2 C1 2 /(CH3 0H/NH3 )95/5)。收集純溶離份，蒸發溶劑。殘質於沸騰之DIPE中攪拌，冷卻後，濾出所得沉殿，乾燥，產生0.53克（士）-順式-4-胺基_5-氣-2,3-二氫-7-苯並α夫喃狻酸3-甲氧基-l-[2-[(3-甲基-2-毗碑基）胺基]乙基]-4-六氫砒啶基酯（π. 5%;熔點124. Γ〇 (化合物 12)。口實例9 取化合物（38)(4.5克）、2-氣-3-甲基毗11#(3.3克）與 Ν,Ν-二乙基乙胺（2.1毫升）於i2〇eC攪拌20小時。反應混合物冷卻，經矽膠管柱層析純化（溶離液：（：Η2{：ΐ2Λ(^3(Η 本紙張尺度適用中國國家標毕{ CMS ) Α4規格（210X297公釐） 448 Ί Α7 Β7 五、發明説明（19 ) /NH 3 )95/5)。收集純溶離份，蒸發溶劑。殘質經矽膠管柱層析純化（溶離液：CH2 Cl 2 /CH3 0H 90/10)。收集純溶離份，蒸發溶劑，殘質於DIPE中固化。濾出沉澱，乾燥，產生2.10克4-胺基-5-氣-2,3-二氫-7-苯並蚨喃羧酸1-[ 2-[(3-曱基-2-oftη井基）胺基]乙基]-4-六氫她啶基酯（38%) ;熔點108.6eC(化合物39)。類似上述方法之一，製備表1至3所列之化合物。表1(Please read the precautions on the back of this page before 'Θ this page) -5 Dimensions of this paper are in use_Country sample rate (〇 ^ > People 4 specifications (2 丨 0 Father 297 mm) 4 4 8 彳 7 :: Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (11) Because of its beneficial properties of promoting bowel movements, the compounds of the present invention can be formulated into various types for pharmaceutical use. In the composition, an effective amount of a specific compound (which may be in the form of an alkali or an acid addition salt) is used as an active ingredient, and a pharmaceutically acceptable carrier is combined into a homologous mixture, which is in accordance with the formulation type required at the time of prohibition. It may take a variety of different forms. These pharmaceutical compositions need to be in unit dosage forms that are best suited for oral, rectal, or parenteral injection. For example, when preparing oral dosage form compositions, if they are oral liquid formulations, such as For suspensions, syrups, tinctures and solutions, any conventional medically prohibited medium can be used, such as, for example, water, glycols, oils, alcohols, etc .; or for powders, pills, capsules and tablets , Can use solid carrier Such as: sugar, kaolin, lubricants, binding agents, disintegrants, etc. Because the forbidden tablets and capsules are easy to administer, it is the most popular oral unit dosage form. Of course, a solid medical carrier is used at this time. The carrier of the enteric composition usually contains at least a large amount of sterile water, but may also include other ingredients to, for example, promote dissolution. For example, when preparing an injection solution, the carrier may include a physiological saline solution, a glucose solution, or a mixture of a physiological saline solution and a glucose solution. Injectable suspensions can also be prepared, in which case appropriate liquid carriers, suspending agents, etc. can be used. In compositions suitable for transdermal administration, the carrier can optionally include a penetration enhancer and / or a suitable wetting agent, as needed Combined with a small amount of Hetong additives of any nature, but these additives must not cause significant adverse reactions to the skin. These additives can promote the prohibition of skin and / or help to make the desired composition These compositions can be banned by various means, such as: transdermal patch, spot-on, ointment. Due to the acid of (I) or (Π) Water soluble salt—13— This paper size is in accordance with China's standard (CNS) A4 size (210X297 mm) ~~ nnn I u 1 I ^ p (Please read the precautions on the back before this page} j 13 13 Economy Printed by A7 B7 of the Consumer Cooperatives of the Ministry of Standards and Standards of the People's Republic of China 5. The invention description (12) is higher than the corresponding basic type, so it is certainly more suitable for the preparation of aqueous compositions. The above pharmaceutical composition is particularly conducive to easy formulation and uniform dosage. Unit dosage form. The unit dosage form used in this specification and the patent application range refers to a physically separated unit suitable for a single dosage form. Each unit contains a predetermined amount of active ingredients calculated to produce the required medical effect, and the required Pharmaceutical carriers. Examples of such unit dosage forms are medicinal tablets (including scaled or coated zeolites), capsules, pills, powder packs, cachets, solutions or suspensions for injection, teaspoon amounts, tablespoons, etc. , And its separate multiple units. Since the compound can stimulate peristalsis of the intestine and especially promote colonic peristalsis, it is suitable for patients with symptoms related to peristaltic disorders, such as reduced peristalsis of the small and large intestines or patients with delayed gastric emptying or improved bowel movement Of normalization. Because the compounds of the present invention have these uses, they can provide a method for treating warm-blooded animals suffering from abnormal peristalsis of the intestine, such as: constipation, pseudo-obstruction, intestinal relaxation, intestinal relaxation after surgery, irritating bowel syndrome ( IBS), delayed movement caused by immobilization, and in particular, impaired colon movement. The method includes systemically administering a warm-blooded animal with an intestinal stimulating effective amount of a compound of formula (I), its N-oxide, a pharmaceutically acceptable acid addition salt, or a stereochemical isomer thereof that may occur. Accordingly, the use of a compound of formula (I) as a contraindication is provided, in particular, the use of a compound of formula (I) in the manufacture of a contraindication for the treatment of a condition involving a reduction in colonic motility. Generally a medically effective amount is about 0.001 mg / kg to about 10 mg / kg of body weight, preferably about 0.002 mg / kg to about 5 mg / kg of body weight. The treatment method also includes the administration of active ingredients between two or four daily meals. 0- * 14 — This paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 mm) ------ ---- ^ ------, order ------ 1 (Please read the precautions on the back before this page) J. / '448173 A7 B7 V. Description of the invention (13) The following examples are illustrations The present invention is not limited at all. In the following, "T'Γ 'refers to tetrahydrofuran, and" DIPE "refers to diisopropylfluorene. Trial section A. Example of a method for intermediates 1 a) Take 3-methoxy-1 -(Phenylmethyl) -4-hexahydropyridone (4.4 g) in THF was cooled to -75 eC. Ginseng-secondary butyl hydroboron was added dropwise, and the reaction mixture was stirred at -7 (TC 2 Hours. 10% acetic acid (100 ml) was added dropwise at room temperature. The organic solvent was evaporated. The aqueous residue was extracted with NH 4 0 and extracted with DIPE twice. The separated organic layer was washed with water and treated with 304. Dehydrate, filter, and evaporate the solvent. The residue was purified by short silica gel column chromatography (eluent: 012 (: 丨 28: 1 [3 (^ 95/5 gradually increased to 98/2), yielding 1.3 g (29.4% ) Tactyl-3-methoxy-1- (phenylmethyl) -4-hexahydropyridine (Intermediate 1). Printed by the Ministry of Economic Affairs and the Central Bureau of Standards for industrial and consumer cooperation. B) Inclusion The mixture of intermediate (1) (11.5 g) and methanol (150 ml) was tritiated with 2 g of Pd / C 10% catalyst for two hours at normal pressure and room temperature. After the calculated argon was absorbed, it was filtered The catalyst was removed and the filtrate was evaporated. The residue was purified by silica gel column chromatography (solvent Leaving solution: CHCl 3 / (CH3 0H / NH3) 85/15). Collect the pure fractions and evaporate the eluate to produce 3.6 g (53%) of cis-3-methoxy-4-hexahydrocolidol. Oily residue (Intermediate 2). 0 Dropwise add a solution of bis (1,1, -dimethylethyl) dicarbonate (65.5 g) in CHCI 3 (100 ml) to intermediate ⑵ (34 g). In a solution of CHC1 3 (350 ml), the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was sequentially washed with water, ammonia and water. The separated organic layer was dehydrated with MgS04, filtered and the solvent was evaporated. The residue (79 G) Chromatographic column chromatography (solvent-15- this paper size uses Chinese national standards (CNS > A4 size (2 丨〇 > 297 mm)) 448173 A7 B7 V. Description of the invention ( 14) Leaving liquid: CH2Cl2 / (CH3OH / NH3) 97/3 is gradually increased by 95/5). The pure soluble fractions are collected, and the solvent is evaporated, yielding 58 g (±) _cis-4-hydroxy-3- Methoxy-1-hexahydroojfc pyridinecarboxylic acid 1,1-dimethylethyl ester (96.4% crude residue) (Intermediate 3). D) Add sodium hydride (6.2 g) to intermediate containing ⑶ (30 g) of TEF (1000 ml). The mixture was subjected to a nitrogen stream. After stirring at reflux for 3 hours, cool (Solution I) »Add 1,1'1 carbon-based bis-1'-imidazole (21 g) to 4-amino-5-gas-2,3-difluorene-7-benzene In a solution of sulfanylcarboxylic acid (31.4 g) in acetamidine (1000 ml), the mixture was stirred at room temperature for 2 hours. The solvent was evaporated. The residue was dissolved in THF (1000 ml) to form solution I. At room temperature, solution II was poured into solution I, and the reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated. Residues were allocated between CH2CI2 and H2O. The organic layer was separated and the aqueous layer was extracted twice with CH 2 C1 2. The separated organic layer was dried over MgSO4, filtered and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: CH2Cl2 / CH3OHH / 2/2). The required fractions were collected and the solvent was evaporated to yield 50 g (±) -cis-4-[[(4-amino-5-gas-2,3-difluorene-2,2-dimethylbenzo) 〇furanyl) -Meryl] oxy] -3-methoxy-1-hexahydro She talked about acid 1,1-dimethylethyl S (85%) (Intermediate 4). Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs e) Take a mixture of THF (600 ml) containing intermediate ⑷ (50 g) and hydrochloric acid (60 ml) and reflux for 30 minutes. The reaction mixture is cooled and tested with NH4 0H . The separated aqueous layer was extracted with THF. The effluent was evaporated, and Canbao was purified by column chromatography on a dream gel (eluent: CH2Cl2 / (CH3OH / M3) 93/7). The pure fractions were collected and the solvent was evaporated. The residue was stirred in boiling DIPE. The mixture was cooled, and the resulting precipitate was filtered off, dissolved in 2-propanol, and converted to oxalic acid (0.6 g) —16— This paper is in accordance with the Chinese National Standard (CNS) A4 specification (2.0 × 297 mm) 448173 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of Invention (15) Formed into oxalate (1: 1). The mixture was boiled, cooled, and the resulting Shen Dian was filtered off and dried to produce 16 g (±) -cis-4-amino-5-gas-2,3-dihydro-2,2-dimethyl-7-benzo 3-methoxy-4-hexahydrotamidinyl ester oxalate (1: 1) (33%); melting point 193.2ec (intermediate 5). A similar method was also prepared: 4-Amino-5-Ga-2,3-dihydro-2,2-dimethyl-7-benzofranocarboxylic acid 4-hexahydropyridyl ester; melting point 161.0TO (Intermediate 6). (±) -cis-4-amino-5-gas-2,3-dihydro-2,2-dimethyl-7-benzoxancarboxylic acid 3-methoxy-4-hexahydro Pyridinyl ester (Intermediate 7). '4-Amino-5-gas-2,3-dihydro-7-benzopyranocarboxylic acid 4-hexahydropyridinyl ester; melting point 161.0 ° C (intermediate 8). B, Example 2 of the indium method of the final compound: Take 1- [3- (bumethylethoxy) propyl] -4-hexahydromtidinol (2.5 g) and N, N-dimethyl-4-tamidine A mixture of amine (2 g) in methane (100 ml) was stirred at room temperature. 4- (Ethylamino) -5-gas-2,3-dihydro-7-benzopyranylcarbonyl chloride (2.7 g) was added. The reaction mixture was stirred at room temperature for 72 hours. The solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: CH 2 Cl 2 / CH 3 0H 95/5). The required fractions were collected and the solvent was evaporated. The residue (3.2 g) was dissolved in THF (100 ml), and the reaction mixture was treated with hydrochloric acid (10 ml) and stirred under reflux for 2 hours. The reaction mixture was cooled and basified with NH4OH. The organic solvent was evaporated and the aqueous residue was extracted twice with CEbCh. The separated organic layer was filtered with MgSO4, and the solvent was evaporated. The residue is purified by short silica gel column chromatography (eluent: CH2CI2 / (CH3OH / NH3 4) 97 -17- This paper size is applicable to the Chinese National Standard (CNS) A4 size (210X297 mm) (please read first. Note iv. Again on this page)-Binding. Order 448173 Employees' Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs, India and India A7 B7 V. Invention Description (l6) / 3). The required fractions were collected and the solvent was evaporated. The residue (2.9 g) was purified by high performance liquid chromatography (eluent: CH2 C1 2 / (CH3 0H / NH3) / CH 3 OH 97/1/2). The pure solvents were banned and the solvent was evaporated. The residue was dissolved in 2-propanol, and i5 < HC1 / 2-propanol was converted into the hydrochloride (1: 1). The mixture was boiled, cooled, and the precipitate was filtered off to dry (empty; 80 · 〇), yielding 0.50 g of 4-amino-5-gas-2,3-dihydro-7-benzofurancarboxylic acid 1- [3 -(Bumethylethoxy) propyl] -4-hexahydroaitinyl ester monohydrochloride (12%); melting point 208.6eC (compound 4) 〇 Example 3 Take the intermediate ⑻ (3 g), 2- (3-Gaspropyl) -2-methyl-1,3-dioxolane (2.5 g), sodium carbonate (2.1 g) and potassium iodide (catalyst amount) 4-methyl-2-pentanone ( 150 ml) of the mixture was stirred at reflux overnight. The mixture was cooled, washed with water, dehydrated (MgS04), filtered and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: CH2 C1 2 / (CH3 0H / NH3) 97/3). The pure fractions were collected and the solvent was evaporated. The residue was stirred in boiling DIPE, cooled, stirred, filtered and recrystallized from CH3CN / DIPE. The precipitate was filtered off and dried to yield 1.00 g of 4-amino-5-gas-2,3-dihydro-7-benzopyrancarboxylic acid 1- [3- (2-methyl-1,3-dioxo Pentyl-2-yl) diyl] -4-hexahydropyridinyl ester (24%); melting point 128.1 eC (compound 6). Example 4 A mixture of 2-propanol (150 ml) containing intermediate hydrazone (10 g) and 2-propene (2 ml) was stirred and refluxed overnight. Additional 2-propenehydrazone (1 ml) was added and the reaction mixture was stirred at reflux for 20 hours. The solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: CH2C1 2 / (CH3 0H / NH3) 97/3). Collection-18- This paper size applies the Chinese National Standard (CNS) A4 format (210X297 mm) I ~-— — —II. ... I Order * 1 II 矣 ί Please read the notes on the back to save the original ) 1 448173 A7 B7 printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (17) Pure soluble ion. The residue was stirred in boiling DIPE, cooled, stirred to filter out the precipitate, dried (empty; 80 ° C), yielding 10.7 g (±) -cis-4-amino-5-chloro-2,3-di Hydrogen-2,2-dimethyl-7-benzo-α-furancarboxylic acid 1- (2-cyanoethyl) -3-methoxy-4-hexahydromtpyridyl ester (94%); melting point 180.3 eC (compound 27). Example 5 Ethylene oxide (gas) was passed through a methanol (80 ml) solution containing intermediate rhenium (3.3 g) at room temperature for 3 hours, and maintained at a temperature below 3010. The solvent was evaporated, and the residue was purified by silica gel column chromatography (eluent: CH2C1 2 / (CH3 011 / Vol. 3) 93/7). The pure fractions were collected and the solvent was evaporated. The residue was stirred in boiling DIPE, cooled to room temperature, the precipitate was filtered off, and dried (empty; 80¾), yielding 1.66 g of 4-amino-5-gas-2,3-dihydro-2,2-dimethyl 1- (2-hydroxyethyl) -hexahydropyridinyl ester (45%); fused, point 166.310 (compound 21). Example 6 A mixture of the compound IX (2 g) in THF (50 ml) and hydrochloric acid (5 ml) was stirred under reflux for 30 minutes. The reaction mixture was cooled and basified with NIUOH. The separated aqueous layer was extracted with THF. The combined organic layers were evaporated, and the residue was purified by silica gel column chromatography (eluent: CH2 C1 2 / (CH3 0Η / ΝΗ3) 97/3). The pure fractions were collected and the solvent was evaporated. The residue was stirred in boiling DIPE. The resulting precipitate was filtered off, dried, and the residue was purified by silica gel column chromatography (eluent: CH2 C1 2 / CH3 0H 90/10). The pure fractions were collected and the solvent was evaporated. Generated 0.90 g of 4-amino-5-gas-2,3-dihydro-7-benzopyrancarboxylic acid 1- (4-oxopentyl) -4-hexahydropyridinyl ester (47%); Melting point: 104 · 8eC (Compound-19- This paper size is applicable to Chinese national standard (⑽) 4 4 Lin_ (21〇 > < 297)) ------------ Order ----- -Line (please read the precautions on the back of the page before proceeding to this page) 丨 448173 Α7 Β7 V. Description of the invention (is) 8) 〇 Example 7 The mixture of compound 8.5 (8.5g) in THF (500ml) was contacted by Ruanlai nickel The catalyst (catalyst amount) is hydrogenated. After hydrazone 2 (2 equivalents) was absorbed, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by silica gel tube chromatography (eluent: CH2C1 2 / (CH3 OH / NH3) 90/10). The pure solvents were banned and the solvent was evaporated. The residue was stirred in boiling DIPE. After cooling, the resulting precipitate was filtered and dried to produce 5.2 g (±) -cis-4-amino-5-gas-2,3-dihydro-7-benzo. (2-Aminoethyl) -3-methoxy-4-hexahydropyridinyl carboxylate (61%); melting point 133.9eC (compound 11). Example 8 Take compound (11) (4 g), 2-gas-3-methyl σM well (2-8 g) and N, N- printed diethylhexylamine (2.8 ml) by the Consumer Cooperative of the Central Standardization Bureau of the Ministry of Economic Affairs ) Stir at 120¾ for 24 hours. The mixture was cooled and dissolved in CH2C12. The organic solution was purified twice by silica gel column chromatography (eluent: CH2C1 2 / (CH3 0H / NH3) 95/5). The pure fractions were collected and the solvent was evaporated. The residue was stirred in boiling DIPE. After cooling, the obtained sink was filtered and dried to produce 0.53 g (±) -cis-4-amino_5-gas-2,3-dihydro-7-benzo. Alpha uranoic acid 3-methoxy-l- [2-[(3-methyl-2-pyridyl) amino] ethyl] -4-hexahydropyridinyl ester (π. 5%; Melting point 124. Γ (compound 12). Example 9 Take compound (38) (4.5 g), 2-gas-3-methylpyridine 11 # (3.3 g), and Ν, Ν-diethylethylamine (2.1 Ml) was stirred at i20eC for 20 hours. The reaction mixture was cooled and purified by silica gel column chromatography (eluent: (: Η2 {: ΐ2Λ (^ 3 (Η) This paper size applies to China National Standards {CMS) Α4 specifications ( 210X297 mm) 448 Ί Α7 B7 V. Description of the invention (19) / NH 3) 95/5). The pure fractions were collected and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: CH2 Cl 2 / CH3 0H 90/10). The pure fractions were collected, the solvent was evaporated, and the residue was solidified in DIPE. The precipitate was filtered off and dried to produce 2.10 g of 4-amino-5-gas-2,3-dihydro-7-benzo. Aromatic carboxylic acid 1- [2-[(3-fluorenyl-2-oftη well group) amino] ethyl] -4-hexahydrotamidinyl ester (38%); melting point 108.6eC (combined Compound 39). A method similar to the above one, prepared listed in Table 1-3. Table 1

Ll-(CH2)n~N R2Ll- (CH2) n ~ N R2

----------批衣------1T------i (請先閱讀背面之注意事項再本頁) } 經濟部中央標準局員工消費合作杜印製本紙張尺度適用中國國家標準（CNS ) Α4规格（2! Ο X 297公釐） 4 4 8 1 7 3 A7 B7 五、發明説明（20 ) 經濟部中央標準局員工消費合作社印製化莨陳0， R2 η Ll 物理数據 1 3 Η 2 3-乙基-2*3-二氫-2-氧 1H-苯並眯唑-1-基 mp. 191.7°C 2 2 Η 3 3-乙基-2,3-二氣-2-氧苯並眯唑-1-基 mp. 150.2°C 3 2 Η 1 四氣-2-呋喃拣 mp. 147.0°C/(±) 4 2 Η 3 -0-CH(CH3)2 mp.208.6oC/HCl 5 2 Η 3 3-fl-甲基乙基）-2.3-二氫 -2-氧-11丨-¾並咪啤-1-基 mp. 165.2°C 6 3 Η 3 塞-1,3-二氧戊環-2-基 /* mp. 128.1°C 7 3 Η 3 3-氛-6-氧Μ (6H)嗒畊基 mp* 134.0°C 8 6 Η 3 -C(=0)域 mp. 104.8°C 9 3 och3 1 -CN mp. 178.4°C/(±)順式 10 3 0CH3 2 -H mp. 138.2°C/(±)顒式 11 7 OCH3 2 -nh2 mp. 133.9°C/(±)頗式 12 8 OCH3 2 CC ? mp. 124.1°C/(±)順式 13 3 OCH3 1 2-毗啶基 mp. d3°C/(±)順式 14 3 Η 2 -0-(CH2)2-〇H mp. 171.6°C 15 3 Η 3 -O-CH3 mp. 117.4°C 33 3 Η 3 -C(=0)O-CH2-CH3 mp. 115.2°C 34 3 Η 1 瑱丙基 mp. 183.2°C 35 3 Η 3 四氫-2-呋喃基 mp. 122.4°C/(±) 36 3 Η 2 四氫-2-呋喃基 mp. 123.7°C/(±) 37 3 Η 1 -CN mp. 1693°C 38 39 7 Η 2 2 -nh2 mp. 139.80C 9 Η mp. 108.6°C 人 CH3 40 2 och3 1 四S -2-呋喃基 mp. 189.9°C/ ' _賦/(COOH)2 41 3 OCH3 3 -o-ch3 mp. 92.6eC/ (±)順式 42 3 OCH3 3 3-(1-甲基乙基）-2,3-二氫 -2-氧-1H-苯並咪唑-卜基 mp· 177.3°C/(±)晡式 43 8 OCH3 2 -0-(CH2)2-〇H mp. 145.1°C/(±)噸式 44 3 OCH3 1 環丙基 mp. 133.0°C/(士)顒式 45 3 OCH3 2 四氫-2-呋喃基 mp. 119.4°C/(±)順式 46 3 OCH3 3 2-甲基Μ , 3-二氣戍瑁-2-塞 gitip. 121.9°C/(±)噸式 47 3 OCH3 3 -0-CH(CH3)2 mp.76.4°C/(±)順式 Ο (請先聞讀背面之注意事項再本頁) 裝' 訂1 -線· 張紙本 CN /IX 準橾家國國中用適---------- batch of clothes ------ 1T ------ i (please read the precautions on the back first and then this page) This paper size applies the Chinese National Standard (CNS) A4 specification (2! 〇 X 297 mm) 4 4 8 1 7 3 A7 B7 V. Description of the invention (20) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs , R2 η Ll Physical data 1 3 Η 2 3-ethyl-2 * 3-dihydro-2-oxo 1H-benzoxazol-1-yl mp. 191.7 ° C 2 2 Η 3 3-ethyl- 2,3-Digas-2-oxobenzoxazol-1-yl mp. 150.2 ° C 3 2 Η 1 Tetragas-2-furan mp. 147.0 ° C / (±) 4 2 Η 3 -0- CH (CH3) 2 mp.208.6oC / HCl 5 2 Η 3 3-fl-methylethyl) -2.3-dihydro-2-oxo-11 丨 -¾Bimi-1-yl mp. 165.2 ° C 6 3 Η 3 plug-1,3-dioxolane-2-yl / * mp. 128.1 ° C 7 3 Η 3 3-aqueous-6-oxy M (6H) daikonyl mp * 134.0 ° C 8 6 Η 3 -C (= 0) domain mp. 104.8 ° C 9 3 och3 1 -CN mp. 178.4 ° C / (±) cis 10 3 0CH3 2 -H mp. 138.2 ° C / (±) Equation 11 7 OCH3 2 -nh2 mp. 133.9 ° C / (±) po 12 8 OCH3 2 CC? Mp. 124.1 ° C / (±) cis 13 3 OCH3 1 2-pyridinyl mp. D3 ° C / (±) Along 14 3 Η 2 -0- (CH2) 2-〇H mp. 171.6 ° C 15 3 Η 3 -O-CH3 mp. 117.4 ° C 33 3 Η 3 -C (= 0) O-CH2-CH3 mp. 115.2 ° C 34 3 Η 1 瑱 propyl mp. 183.2 ° C 35 3 Η 3 tetrahydro-2-furyl mp. 122.4 ° C / (±) 36 3 Η 2 tetrahydro-2-furyl mp. 123.7 ° C / (±) 37 3 Η 1 -CN mp. 1693 ° C 38 39 7 Η 2 2 -nh2 mp. 139.80C 9 Η mp. 108.6 ° C human CH3 40 2 och3 1 tetraS -2-furyl mp. 189.9 ° C / '_ Fu / (COOH) 2 41 3 OCH3 3 -o-ch3 mp. 92.6eC / (±) cis 42 3 OCH3 3 3- (1-methylethyl) -2,3-dihydro -2-Oxygen-1H-benzimidazole-butyl mp177.3 ° C / (±) 晡 43 8 OCH3 2 -0- (CH2) 2-〇H mp. 145.1 ° C / (±) ton 44 3 OCH3 1 cyclopropyl mp. 133.0 ° C / (±) formula 45 3 OCH3 2 tetrahydro-2-furyl mp. 119.4 ° C / (±) cis 46 3 OCH3 3 2-methyl M, 3 -Two gas 戍瑁 -2-plug gitip. 121.9 ° C / (±) tons 47 3 OCH3 3 -0-CH (CH3) 2 mp.76.4 ° C / (±) cis 〇 (Please read the back first (Notes on this page) Pack 'Order 1-Line · Sheet of paper CN / IX

AA

釐公 7 29 X 44 8 1 7 ο Α7 Β7 五、發明説明（21) ibo^No, 宵例No. R2 η U 物理數據 48 6 〇ch3 3 -C(=0)-CH3 mp. 115.8°C/(±)順式 49 3 och3 3 四氫-2-呋喃基 .mp.943°C/(±)·順式 '50 3 och3 3 3-氯-6-氣-1 (6H)嗒阱基 mp, 138.3°C/(±)順式 51 3 OCH3 3 -C(=0)-0-CH2-CH3 inp. 170.9°C/ (±WW (COOID2 表2Centimeter 7 29 X 44 8 1 7 ο Α7 Β7 V. Description of the invention (21) ibo ^ No, Example No. R2 η U Physical data 48 6 〇ch3 3 -C (= 0) -CH3 mp. 115.8 ° C / (±) cis 49 3 och3 3 tetrahydro-2-furanyl.mp.943 ° C / (±) · cis '50 3 och3 3 3-chloro-6-gas-1 (6H) mp, 138.3 ° C / (±) cis 51 3 OCH3 3 -C (= 0) -0-CH2-CH3 inp. 170.9 ° C / (± WW (COOID2 Table 2

C1 (請先聞讀背面之注意事項再一本頁) 裝. 經濟部中央標準局員工消費合作杜印製 ib細 \\o. 實例 Ho. R2 n Ll 物Μ数撺 16 3 H 2 -H mp. 186*1°C 17 3 H 3 -CN mp. 127.1°C 18 3 H 3 -S(0)2-CH3 mp, 140.8°C 19 3 H 1 四冠_2-映喃_ mp. 142.9°C/(±) 20 3 H 4 -NH-C(=0)-0-CH2-CH3 mp. 116.2°C 21 5 H 2 -OH mp· 166.3。C 22 3 OCH3 1 四氫-2-呋喃基 mp. 152.7°C/(±)-H0 式 23 3 〇CH3 3 -CN mp, 134.9°C/(±)-_ 式 24 5 OCH3 2 -OH ηφ. 126.6°C/ (±)-順式 25 3 OCH3 4 -NH-C(=0)-0-CH2-CH3 mp. 135，C/(±)-順式 26 3 〇CH3 2 -H. mp·—139.6。(：/(±)-順式 27 4 〇CH3 2 -CN mp. 180.3oC/(±)-_ 式 28 7 〇CH3 3 -NH2 mp. 111.2°C/(±)-順式 29 3 〇CH3 3 -S(0)2-CH3 mp_ 145-7°C/(±)-賴式 52 8 H 2 -0-(CH2)2-〇H mp. 152.2°C 53 3 H 3 2-甲基-1,3-二氧戊瑁-2-S mp. 104.7°C 54 3 H 3 -O-CH3 mp. 113.1°C 55 3 H 3 -C(=0)-0-CH2-CH3 mp. 79.2°C 56 3 H 3 -o-ch(ch3)2 mp. 84.7°C 57 3 H 3 3-(1-甲基乙基）-2,3-二氫 -2-氣-1H-苯並咪唑_-卜基 mp. 226.4°C —23" 訂線本紙張尺度適用中國國家標準（CNS ) A4规格（2Ι0Χ：297公釐） 4 4 8 17 A7 B7 五、發明説明（没: 經濟部中央標準局員工消費合作社印製實例 R2 η Ll 物理数據 No. No. 58 3 Η 1 _丙基 mp. 161.5°C 59 3 Η 3 3-氯-6-氣-1 (β|| >唂阱耦 nip. 172.4°C 60 3 Η 3 四® - 2 -咲喃基 mp. 88.2°C/(COOH)2/(+) 61 3 Η 2 四氣-2-呋喃基 mp. Π 8°C / (COOH)2 / (+) 62 3 Η 1 -CN mp. 196.6°C 63 7 Η 2 -νη2 mp. 135.8°C 64 9 Η 2 /Ν …ΝΗ— if γ mp. 134.7°C 65 3 〇ch3 2 四氫呋喃.箱 mp. 126.8°C/(±)順式 66 3 och3 3 3-Π-甲基乙基）-2,3-二基 -2-氣-1H-苯並咪唑-卜基 mp.239‘9°C/(±)順式 67 3 och3 1 環丙基 mp. 143.3°C/(±)順式 68 3 OCH3 3 -0-CH3 mp. 128.0°C/(±> 順式 69 8 〇CH3 2 -0-(GH2)2-〇H mp. 107.8°C/(±)順式 70 3 OCH3 3 -0-CH(CH3)2 mp. 89.2°C/ ' (±)|1 献(COOH)2 71 3 OCH3 3 3-氛-6-氣-1 (6H)嗒哄基 mp. 167.5°C/(±)嚼式 72 3 OCH3 3 -C(=0)-0-CH2-CH3 mp. 105.1°C/ (±)贼(COOH)2 73 3 OCH3 3 四氣-2™映喃基 mp. 185.4°C/ (±)_(COOH)2 74 3 〇CH3 3 2-甲基-1,3-二氧戊環-2-S ξπιρ. 180.8°C/(±)順式 (COOH)2 75 3 OCH3 1 -CN mp. 144.2°C/(±)順式 76 6 〇CH3 3 -C(=0)-CH3 mp. 153.0°C/(±)順式 77 7 OCH3 2 -NH2 mp. 142.8°C/(±)順式 78 9 〇CH3 2 N HH- mp.l49.7°C/(±)順式 ^N^CH3 表3C1 (Please read the precautions on the back and read this page again.) Packing. Consumption cooperation by employees of the Central Standards Bureau of the Ministry of Economic Affairs, printed ib \\ o. Example Ho. R2 n Ll Material number 撺 16 3 H 2 -H mp. 186 * 1 ° C 17 3 H 3 -CN mp. 127.1 ° C 18 3 H 3 -S (0) 2-CH3 mp, 140.8 ° C 19 3 H 1 Four Crown_2-yingnan_ mp. 142.9 ° C / (±) 20 3 H 4 -NH-C (= 0) -0-CH2-CH3 mp. 116.2 ° C 21 5 H 2 -OH mp · 166.3. C 22 3 OCH3 1 tetrahydro-2-furyl mp. 152.7 ° C / (±) -H0 formula 23 3 〇CH3 3 -CN mp, 134.9 ° C / (±) -_ formula 24 5 OCH3 2 -OH ηφ 126.6 ° C / (±) -cis 25 3 OCH3 4 -NH-C (= 0) -0-CH2-CH3 mp. 135, C / (±) -cis 26 3 〇CH3 2 -H. Mp -139.6. (: / (±) -cis 27 4 〇CH3 2 -CN mp. 180.3oC / (±) -_ formula 28 7 〇CH3 3 -NH2 mp. 111.2 ° C / (±) -cis 29 3 〇CH3 3 -S (0) 2-CH3 mp_ 145-7 ° C / (±) -lai 52 8 H 2 -0- (CH2) 2-〇H mp. 152.2 ° C 53 3 H 3 2-methyl- 1,3-dioxolane-2-S mp. 104.7 ° C 54 3 H 3 -O-CH3 mp. 113.1 ° C 55 3 H 3 -C (= 0) -0-CH2-CH3 mp. 79.2 ° C 56 3 H 3 -o-ch (ch3) 2 mp. 84.7 ° C 57 3 H 3 3- (1-methylethyl) -2,3-dihydro-2-gas-1H-benzimidazole_ -Bu Ji mp. 226.4 ° C —23 " Dimensions of the paper are applicable to the Chinese National Standard (CNS) A4 (2Ι0 ×: 297 mm) 4 4 8 17 A7 B7 V. Description of the invention (No: Central Bureau of Standards, Ministry of Economic Affairs Printed example of employee consumer cooperative R2 η Ll Physical data No. 58 3 Η 1 _propyl mp. 161.5 ° C 59 3 Η 3 3-chloro-6-gas-1 (β || > nip. 172.4 ° C 60 3 Η 3 Tetra®-2 -pyranyl mp. 88.2 ° C / (COOH) 2 / (+) 61 3 Η 2 Tetraki-2-furyl mp. Π 8 ° C / ( COOH) 2 / (+) 62 3 Η 1 -CN mp. 196.6 ° C 63 7 Η 2 -νη2 mp. 135.8 ° C 64 9 Η 2 / Ν… ΝΗ — if γ mp. 134.7 ° C 65 3 〇ch3 2 Tetrahydrofuran. Box mp. 126.8 ° C / (±) cis 66 3 och3 3 3-Π-methylethyl) -2,3-diyl-2-gas-1H-benzimidazole-butyl mp. 239'9 ° C / (±) cis 67 3 och3 1 cyclopropyl mp. 143.3 ° C / (±) cis 68 3 OCH3 3 -0-CH3 mp. 128.0 ° C / (± > cis 69 8 〇CH3 2 -0- (GH2) 2-〇H mp. 107.8 ° C / (±) cis 70 3 OCH3 3 -0-CH (CH3) 2 mp. 89.2 ° C / '(±) | 1 (COOH) 2 71 3 OCH3 3 3-Amote-6-air-1 (6H) dacoyl mp. 167.5 ° C / (±) chewing formula 72 3 OCH3 3 -C (= 0) -0-CH2-CH3 mp. 105.1 ° C / (±) thief (COOH) 2 73 3 OCH3 3 tetraki-2 ™ enanyl mp. 185.4 ° C / (±) _ (COOH) 2 74 3 〇CH3 3 2-methyl- 1,3-dioxolane-2-S ξπιρ. 180.8 ° C / (±) cis (COOH) 2 75 3 OCH3 1 -CN mp. 144.2 ° C / (±) cis 76 6 〇CH3 3- C (= 0) -CH3 mp. 153.0 ° C / (±) cis 77 7 OCH3 2 -NH2 mp. 142.8 ° C / (±) cis 78 9 〇CH3 2 N HH- mp.l49.7 ° C / (±) cis ^ N ^ CH3 Table 3

L1—(CH2)n—NL1— (CH2) n—N

NH2 -24- (請先閱讀背面之注意事項再本頁) -裝-NH2 -24- (Please read the precautions on the back before this page) -pack-

、1T 線本紙浪尺度適用中國國家標準（CNS ) A4規格（2丨OX297公釐）五發明説明（23 ) A7 B7 30 3132 實例 No. R2 η -OA Li 物理數撺 2 OCH3 3 -0-C(CH3)=CH- 2,3-二氫-3-(1-甲基乙基）-2-氧-1H-苯並眯唑-1-基 mp.221.8°C/ i (±)-順式^ 2 OCH3 3 -0-C(CH3)=CH- 2,3-二氳-3-乙基-2-氧-1H-苯並咪睡-1-基 mp. 192.5°C/ (±)-顒式 2 Η 1 -0-C(CH3)2-(CH2)2" 四氫-2-呋喃基 mp. 146*7°C/ (±)/(COOH)9 讀先聞讀背面之注 I 項再蔡實例复例10:夭竺鼠迴腸同軸刺激取雄性與雌性之登肯-哈利（Dunkin-Hartley)天竺鼠（體重±500克），以斷頭法殺死。取出迴腸，以溫暖且充氧氣之克氏-亨來（Krebs-Henseleit)溶液洗淨。取天竺鼠之長公分，非末端完整迴腸段，先承載1克重量，垂直懸淳於100毫升克氏-亨來（Krebs-Henseleit)溶液中（37.5 °C),通入含95%02與5%C〇2之混合氣體。利用兩隻白金電極，陽極通過迴腸腔，陰極浸在溶液中，對整條迴腸段進行穿透腸壁刺激。使用來自可調整之刺激器之單一矩型刺激[lmsec; 0.1Hz;次於最大程度之刺激（電流調至最大反應之80%)]激發標本。測定等量性收縮。在30分鐘之穩定期期間，重覆拉長迴腸條至2克之張力，以便得到1克之穩定張力狀態。開始電擊刺激之前，先測定乙醢膽鹼之累積劑量反應曲線。以次於最大程度之電流開始電擊刺激，測定痙攣之最大振幅。當此等反應穩定時，施予可得到 *25— 本紙張尺度it财賴家榡準（CNS > Α4規格（2似297公瘦） i 線鯉濟部中央橾準局員Η消費合作社印製 448 1 A7 B7 五經濟部中央標隼局員工消費合作社印製 #利申請案第84109382號；補^ ROC Patent Appln. N〇.84109382 U一- 弋各敦明書修正第26-29頁-附件一發明説明（24)、 1T line paper wave scale is applicable to Chinese National Standard (CNS) A4 specification (2 丨 OX297 mm) Five invention description (23) A7 B7 30 3132 Example No. R2 η -OA Li Physical number 撺 2 OCH3 3 -0-C (CH3) = CH- 2,3-dihydro-3- (1-methylethyl) -2-oxo-1H-benzoxazol-1-yl mp. 221.8 ° C / i (±) -cis Formula 2 OCH3 3 -0-C (CH3) = CH-2,3-difluoren-3-ethyl-2-oxo-1H-benzimid-1-yl mp. 192.5 ° C / (±) -Formula 2 Η 1 -0-C (CH3) 2- (CH2) 2 " Tetrahydro-2-furyl mp. 146 * 7 ° C / (±) / (COOH) 9 Read the notes on the back Item I and Cai example Example 10: guinea pig ileum coaxial stimulation Take male and female Dunkin-Hartley guinea pigs (weight ± 500 g) and kill them by decapitation. The ileum was removed and washed with a warm and oxygenated Krebs-Henseleit solution. Take the length of guinea pig, non-terminal intact ileum, first load 1g, and suspend vertically in 100ml Krebs-Henseleit solution (37.5 ° C), pass 95% 02 and 5% CO2 mixed gas. Using two platinum electrodes, the anode passed through the ileum cavity, and the cathode was immersed in the solution to stimulate the entire ileum segment through the intestinal wall. A single rectangular stimulus from an adjustable stimulator [lmsec; 0.1 Hz; second to the maximum stimulus (current adjusted to 80% of the maximum response)] was used to excite the specimen. Determination of isometric contraction. During the 30-minute stabilization period, repeatedly stretch the ileum strip to a tension of 2 grams to obtain a stable tension of 1 gram. Before starting electric shock stimulation, measure the cumulative dose-response curve of acetylcholine. Shock stimulation was started with a current that was below the maximum level, and the maximum amplitude of the spasm was measured. When these reactions are stable, giving can be obtained * 25—this paper size it is Lai Jiazheng Standard (CNS > A4 size (2 like 297 male thin) i printed by the Central Government Bureau of the Ministry of Economic Affairs and Consumer Cooperatives 448 1 A7 B7 Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs # 利应用案号 84109382; Supplement ^ ROC Patent Appln. N〇.84109382 U 一-Amendments to the Official Documents, pages 26-29-Attachments A description of the invention (24)

Amended Pages ^6~29 of the Chinese Specification - End τ " (民興JJ7年$ 2 h修 (Amended & Submitted on March 2 , 1998) 最大反應之80%之次於最大程度之刺激，直到痙攣反應維持恆定至少15分鐘，隨後在溶液浴中添加單一刼量之試驗化合物。比較投與試驗化合物5分鐘後之痙孿反應振幅及投與試驗化合物前之痙攣反應振幅。編號1 、4、6j、 32-36、39、46與50之化合物於3χ：ι〇-9Μ之濃度時之痙攣反應振幅調提高5¾以上。實例Π:有意識的狗之結腊蠕動在接受普通麻醉與止痛之雌性小猟犬（體重7-17公斤）體内植入等量性力轉換器。研究結腸蠕動時，在距離迴腸〜育腸瓣膜8、16、24及32公分處鏠合結腸。讓狗至少休養2 週。在禁食20;小時後開始試驗，此期間可自由飲水。試驗期間，藉由遙感（無線）系統，允許狗自由離籠活動。狗籠建在一間特定屋子内，裝有單向透光之玻璃，亦即觀察者可，見狗，而狗卻看不見人。利用此系統觀察狗之行爲變化，判斷是否有苹陷現象。轉換器之數據經由小型特製之傳導器盒數字化傳送。此傳導器盒置於穿在狗身上之外套内。利用每一個籠子上之麥克風接收訊號，並傳至中央電腦系統。狗之排便現象爲此試驗之一個變數。投與試驗化合物後頭3個小時内，觀察狗是否出現及何時出現排便。在此頭3個小時内，本發明化合物會謗發試驗動物排便本紙張尺度適用中國國家標準（CNS ) A4规格（210X297公釐） ..裝訂 r-1 {請先閲讀背面之注意事項再填寫本頁j 448 1 kl B7 五、發明説明（25 修」補充. 〇_31毫克斤劑量之化合物6，15，21，35，36，38 ，39，41至47及49謗發至少50%之試驗動物在前三小時内排便。1.25毫克/欠斤.劑量之化合物2，4，8，10， 16，19，22，26，32及33誘發至少5〇%之試驗動物在前三小時内排便。 D.組合物會例下列調配物爲適於根據本發明爲溫血動物進行全身或局部投蔡之呈單位劑型之典型醫蔡組合物實例。本文實例中之"活性成份"（Α.Ι.)係指式（η化合物、其 Ν-氧化物型、醫蔡上可接受之酸加成鹽或立體化學異構型〇實例12: 口服浚取9克4-羥基苯曱酸甲酯與1克4-羥基苯平酸丙酯溶於 4升沸騰之純水中。取3升此溶液，依序溶解1〇克2J-二輕基丁二酸及20克Α· I 後項溶液再與前項剩餘溶液合併，並添加12升1,2,3-丙三醇及3升山梨糖醇70%溶液。取 40克糖情鈉溶於0.5升水中，添加2毫升覆盆子香精與2 毫升醋栗香精。後項溶液再與前項溶液合併，並添加適量水至20升之體積，製成每茶匙（5毫升）含有5毫克^丨之口服液。所得溶液裝入合適容器内。實例13:膠愈取20克Α.Ι.、6克月桂基硫酸納、56克毁粉、56克乳糖、0.8克二氧化矽膠體及1‘2克硬脂酸鎂激烈攪拌混合。所 -27-Amended Pages ^ 6 ~ 29 of the Chinese Specification-End τ " (Minxing JJ7 $ 2 h repair (Amended & Submitted on March 2, 1998) 80% of the maximum response is next to the maximum stimulation until the spasm The reaction was kept constant for at least 15 minutes, and then a single amount of test compound was added to the solution bath. The amplitude of the spasm response 5 minutes after the test compound was administered and the amplitude of the spasm response before the test compound was administered. Numbers 1, 4, 6j , 32-36, 39, 46, and 50 compounds at a concentration of 3x: ιOM-9M, the amplitude of the spastic response was increased by more than 5¾. Example Π: Conscious dog's waxing peristalsis in females receiving general anesthesia and analgesia Small Mastiff (7-17 kg) is implanted with an isometric force converter. When studying colonic peristalsis, the colon is closed at 8, 16, 24, and 32 cm from the ileum to the intestinal valve. Let the dog rest for at least 2 Week. Start the test after fasting for 20 hours, during which time you can drink freely. During the test, the remote sensing (wireless) system allows the dog to move freely from the cage. The dog cage is built in a specific room with a one-way Glass of light That is, the observer can see the dog, but the dog can't see the person. Use this system to observe the behavior change of the dog and determine whether there is a trapping phenomenon. The data of the converter is digitally transmitted through a small specially-made transmitter box. This transmitter The box is placed in a jacket worn on the dog. The microphones in each cage receive signals and transmit them to the central computer system. The defecation of dogs is a variable in this test. Observe within the first 3 hours after the test compound is administered Whether and when dogs have defecation. Within the first 3 hours, the compounds of the present invention will defame the defecation of test animals. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm). Binding r-1 {Please Read the notes on the back before filling in this page j 448 1 kl B7 V. Description of the invention (25 revisions) Supplement. __31 mg of compound dose 6,15,21,35,36,38, 39,41 to 47 And 49 defamated that at least 50% of the test animals defecate within the first three hours. 1.25 mg / kg. Dose of Compounds 2, 4, 8, 10, 16, 19, 22, 26, 32 and 33 induce at least 50% Test animals in the top three Defecation within hours. D. Composition Examples The following formulations are examples of typical medical and pharmaceutical compositions suitable for systemic or local administration of Cai Zhi to a warm-blooded animal according to the present invention in a unit dosage form. The "active ingredients" in the examples herein (A.I.) refers to the compound of the formula (η, its N-oxide type, medically acceptable acid addition salt, or stereochemically isomeric form. Example 12: Oral extraction of 9 grams of 4-hydroxybenzene Methyl gallate and 1 g of propyl 4-hydroxyphenylpine acid were dissolved in 4 liters of boiling pure water. Take 3 liters of this solution, and sequentially dissolve 10 g of 2J-diphenylsuccinic acid and 20 g of Α · I. The latter solution is then combined with the remaining solution of the preceding item, and 12 liters of 1,2,3-propanetriol and 3 liters of sorbitol 70% solution. Take 40 g of sodium sugar and dissolve in 0.5 liter of water, add 2 ml of raspberry flavor and 2 ml of gooseberry flavor. The latter solution is combined with the former solution, and an appropriate amount of water is added to a volume of 20 liters to prepare an oral solution containing 5 mg ^ 5 per teaspoon (5 ml). The resulting solution is filled into a suitable container. Example 13: Gum Healing 20 grams of A.I., 6 grams of sodium lauryl sulfate, 56 grams of crushed powder, 56 grams of lactose, 0.8 grams of silica colloid, and 1'2 grams of magnesium stearate were vigorously stirred and mixed. Place -27-

Jd,------訂----,---1 (請先閲讀背面之注意事項再填寫本頁) 經濟部中央操隼局員工消費合作衽印製 ?^· J? fiF· lit |4-» Mil «Π 1 ^ 1·__ κ / «*Α· JJaJd, ------ Order ----, --- 1 (Please read the notes on the back before filling out this page) Printed by the consumer cooperation of the Central Operation Bureau of the Ministry of Economic Affairs? ^ J? FiF · lit | 4- »Mil« Π 1 ^ 1 · __ κ / «* Α · JJa

I % y 448 1 7 A7 B7 經濟部中央標準爲貝工消費合作社印製五 '發明説明（26 ) 得遂合物裝入ioob.個合逍硬明膝甚内，每個含艰·毫克 A.I. 〇复鼓]4:包膜辏錠蔡疑核心之製法取100克A.I.、570克乳糖與2〇〇克澱粉混合均勻後，以含5克十二烷基硫酸鈉及1〇克衆乙醯毗咯啶酮之約2〇〇毫升水溶液濕化。濕粉末混合物過篩，乾燥，再過篩一次。然後添加100克微晶纖維素與15克氫化植物油◊全部混合均勻，壓成錠劑，製成1〇,〇〇〇個各含10毫克活性成份之藥鍵。 . 、核心添加含5克乙基纖維素之150毫升二氣曱垸溶液至含1〇克甲基纖維素之75毫升變性乙醇溶液中。隨後添加乃克二甲燒與2.5毫升1，2,3-丙三醇。取克聚乙二醇溶化並溶於75亳升二氣甲烷中。後項溶液加至前項溶液中然後添加2.5克十八烷酸鎂、5克聚乙醯咣咯啶酮及毫升濃縮色素懸浮液，全麵合均勻^於包覆設備上所得之混合物包覆蔡錠核心。 f倒1互^射液’ 、取U克4-雞基苯曱酸甲s旨與0.2克4_經基苯甲酸丙錯溶於约0.5料射狀滞水卜冷卻至糊.⑽，齡添加4 克乳酸、〇.〇5克丙二醇及4克A.I·。溶液冷卻至室溫，龙補充適量水至〗升之體積，製成4毫克/毫升Α ι之溶液。溶液過祕則以上則以⑴絲人無菌容器内〇本紙張尺度適用中國國家榇準（CNS ) Α4規格（21〇χ297公釐）裝------订----1--身一 (請先閱讀背面之注意事項再填寫本頁) A7I% y 448 1 7 A7 B7 The central standard of the Ministry of Economic Affairs printed the Fifth 'Invention Note for Shellfish Consumer Cooperatives (26) The successful compound was loaded into ioob. Each of them contained a hard knee, each containing a hard milligram AI. Re-drum] 4: Preparation method of coated cymbal tablet Cai Sui core Take 100 grams of AI, 570 grams of lactose and 200 grams of starch, mix them, and then add 5 grams of sodium dodecyl sulfate and 10 grams of acetamidine Wet about 200 ml of aqueous solution of pyridone. The wet powder mixture is sieved, dried, and sieved again. Then 100 grams of microcrystalline cellulose and 15 grams of hydrogenated vegetable oil were added and mixed uniformly, pressed into tablets, and made into 10,000 drug bonds each containing 10 mg of active ingredient. . Core Add 150 ml of diradin solution containing 5 g of ethyl cellulose to 75 ml of denatured ethanol solution containing 10 g of methyl cellulose. Then add dimethyldimethylbenzene and 2.5 ml of 1,2,3-propanetriol. Take a gram of polyethylene glycol and dissolve it in 75 liters of digas methane. Add the latter solution to the former solution and then add 2.5 grams of magnesium octadecanoate, 5 grams of polyacetrolidone and milliliter of concentrated pigment suspension, and make it fully homogeneous. Ingot core. f inverted 1 ^ ejaculate ', take U grams of 4-chisylbenzoic acid methyl ester s purpose and 0.2 grams of 4-propanyl benzoate dissolved in about 0.5 material projectile stagnant water to cool to a paste. ⑽, age 4 g of lactic acid, 0.05 g of propylene glycol and 4 g of AI · were added. The solution was cooled to room temperature, and the dragon was replenished with an appropriate amount of water to a volume of 1 liter to make a 4 mg / ml solution. If the solution is too secret, the above is in a sterile container. The paper size is applicable to China National Standard (CNS) A4 specification (21 × 297 mm). I (Please read the notes on the back before filling this page) A7

448173 B7 五、發明説明（27 )448173 B7 V. Description of the invention (27)

. S 補實例16:棠劑 — 取3克A.I.溶於舍3克2,3-二羥基-丁二酸之25毫升聚乙二醇400之溶液中◊取12克界面活性劑與適量加至300克之三酸甘油S旨共同熔化。後項混合物與前項溶液均句混合。所得混合物倒入37-38ti溫度之模型中，形成1〇〇個各含 30毫克活性成份之塞劑。 (請先閲讀背面之注意事項再填寫本頁) \裝.S Supplement Example 16: Tang agent-take 3 grams of AI dissolved in a solution of 3 grams of 2,3-dihydroxy-succinic acid in 25 ml of polyethylene glycol 400, take 12 grams of surfactant and add the appropriate amount to 300 grams of triglyceride S are intended to co-melt. The latter mixture is mixed with the former solution. The resulting mixture was poured into a model at a temperature of 37-38ti to form 100 suppositories each containing 30 mg of active ingredient. (Please read the precautions on the back before filling this page)

rIT 經濟部中央標準局負工消費合作社印製 29 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）rIT Printed by the Central Standards Bureau, Ministry of Economic Affairs, Consumer Cooperatives 29 This paper size applies to China National Standard (CNS) A4 (210X297 mm)

Claims

448 1 73 ABCD 申請專利範5 r-\/ 公夺利申請案第84109382號 v*R0C No.84109382 »修·巧今节笋參利砝固中文本-附件二 unended Claims in Chinese - Rnrl.ff777¾¾57^ (bubmitted on Mai 2 March 1. 一種如下式化合物 R2448 1 73 ABCD Patent Application No. 5 r-\ / Public Profits Application No. 84109382 v * R0C No. 84109382 »Revision · Qiao This section of bamboo shoots and weights Chinese text-Annex II Unended Claims in Chinese-Rnrl.ff777¾¾57 ^ (bubmitted on Mai 2 March 1. A compound of the formula R2

NH2 (I), 經濟部中央標準局員工消費合作社印製 t)〇\ 其醫禁上可接受之酸加成鹽類及立體化學異構型，其中： R1爲鹵素； A 代表如下式之二價自由基： -CH2_CH2-(a)、 -CH2-CH2-,CH2-(b)、 -CH=CH-(c),. 自由基（a)、（b)與(c)中一或二個氫原子可被^^烷基置換； R2爲氫或(：1-6垸氧基； L 爲如下式自由基： -Allt-E4(d) > -Alk-0-R5(e)、 30 - 本紙張尺度適财酬家辟（CNS)从雜（加心7公酱） 87-9JMSEN.241A-1 1^1 1!- tn I— — III I- - HI m » - i '一nJ (請先閱讀背面之注意事項再填寫本頁} a 4 b t > - a 4 b t > - 經濟部中央標準局員工消费合作杜印製 AS B8 ' C8 D8 六、申请專利範園 -Alk-NR6R7(f), Aik 爲 C1-12 稼二基； R4爲氫；氰基；Ci-6烷羰基；Cl-6烷氧默基；C3-7環烷基；Cl_6燒確链基；四氫吱喊；二氧戌環；經Cl-6院基取代之二氧戊環；Qjt咬；經自素或C〗-6燒基取代之地啶.；嗒嘈；經一或二個選自下列之取代基取代之嗒畊 :鹵素、Ci-e燒基、羥基；或如下式之基： 0 人 · R8—N — Cg)NH2 (I), printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs t) 〇 \ Acceptable acid addition salts and stereochemically isomeric forms of their medical confinement, where: R1 is halogen; A represents the following formula two Valent radicals: -CH2_CH2- (a), -CH2-CH2-, CH2- (b), -CH = CH- (c) ,. One or two of the radicals (a), (b) and (c) A hydrogen atom may be replaced by ^^ alkyl; R2 is hydrogen or (: 1-6 alkoxy; L is a radical of the formula: -Allt-E4 (d) > -Alk-0-R5 (e), 30-This paper scales CNS from miscellaneous (plus 7 male sauce) 87-9JMSEN.241A-1 1 ^ 1 1!-Tn I— — III I--HI m »-i '一nJ (Please read the notes on the back before filling in this page} a 4 bt >-a 4 bt >-Consumer Co-operation by the Central Bureau of Standards of the Ministry of Economic Affairs, printed AS B8 'C8 D8 VI. Patent Application Park-Alk -NR6R7 (f), Aik is C1-12 carbadiyl; R4 is hydrogen; cyano; Ci-6 alkylcarbonyl; Cl-6 alkoxymer; C3-7 cycloalkyl; Cl_6 alkyl chain; four Hydrogen squeak; Dioxolane ring; Dioxolane substituted by Cl-6 courtyard; Qjt bite; Dipyridine substituted by autogen or C〗 -6 alkyl. Substituted with one or two substituents selected from the farming of despair: halo, Ci-e burned group, a hydroxyl group; or a group of the formula: and 0 · R8-N - Cg)

其中如爲氫或Cl-6垸基； R5爲氫；Cl-6烷基；嬅基Cl-6燒基； R6爲氫； K7爲氫；Ci-β燒氧羰基；毗嘈；經一成二個選自Cl-6燒基之取代基取代之她τ»井。 2.根據申請專利範園第j項之化合物，其中： R4爲氳；氰基；Cl-6垸羰基；Cl-6烷磺醢基；四氳呋喃 :二氧戊環；經Ci-S烷基取代之二氧戊環；嘛啶；經南素或Cl-6烷基取代之〇*啶；嗒崎；經一或二個選自下列之取代基取代之嗒蜡：鹵素、Cl-6烷基、羥基；或如下式之基： -31 - utflx騰t,)--------一~ .(請先閲讀背面之注意事項再填寫本買) 一裝- 8 4 A8 B8 C8 D8 六、申請專利範圍 0 X . R8—N^N——Cg) \=y 〇〇^) 其中K8爲氫或Cl-6烷基。 3. 根據申請專利範園第1項之化合物，其中Ri爲氣。 4. 根據申請專利範園第1項之化合物，其中R2爲氫或甲氧基。 5. 根據申請專利範園第1項之化合物，其中該化合物係選自：胺基-5-氣-2,3-二氫-7-苯並”夫喃竣破1-[(四氫-2-呋喃基）甲基]-4-六氫毗啶基酯； 5-胺基-6-氣-3,4-二氫-2,2-二甲基-2H-l-苯並毗喃-8-竣酸l-[(四氫-2-吱喃基）甲基]-4-六氫σ^t唉基S旨； 4-胺基-5-氣-2,3-二氫-7-苯並呋喃欸酸1-(3-甲氧丙 -基）-4-六氫毗啶基酯； 4-胺基-5-氣」’2,3-二氫-7-苯並"夫喃駿酸1- [3-(2-甲基-1,3-二氧戊環-2-基）丙基卜4-六氫漱咬基a旨；-4 -胺基-5-氯-2，3-二氫-7-苯並”夫喃竣酸1-[3-(1-甲基乙氧基）丙基]-4-六氫被唉基醋； 4-胺基-5-氯-2，3-二氫苯並咬喃羧酸1-[2-(2-羥乙氧基）乙基]-4-六氫毗啶基酯； « m nn n i\ I —y* m f^i m· —，肯 _ (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t合作社印製本紙張尺度適用中國國家標华（CNS ) Λ4規格（210X297公釐.） 44 8 1 A8 B8 C8 D8 經濟部中央標準局員工消費合作社印製申請專利範圍 4-胺基-5-氣-2,3-二氳苯並'^喃羧酸[3-(3-氣-6 -氧-1(6H)_嗒姘基）丙基]—[六氫毗啶基酯； 4-胺基-5-氣-2,3-二氫苯並咳喃羧酸1_(4-氧戊基） -4-六氫毗啶基酯； 4_[[(4_胺基-5-氣_2,3-二氫_7-苯並吱喃基）缓基]氧] -1_六氨0Λ咬丁酸乙暗；及 4-胺基-5-氣-2,3-二氫-7-苯並呋喃羧酸卜[2-(四氫-2 _咬喃基）乙基]_4~六氳此咬基酷；及其可能之立體化學異構型與醫蔡上可接受之酸加成鹽。 6. —種用於治療涉及結腸蠕動降低之腸病症之醫禁組合物，其包含醫療有效量之根據申請專利範園第1項之化合物及醫藥上可接受之載體。 7. 根據申請專利範圍第1項之化合物，其用以製造用於治療涉及結腸蠕動降低之腸病症之藥物。 8‘一種式（VT-a)中間物，其中R2爲Ci-e燒氧基，pi爲氳或容易脱除之保課基图，其係選自包括Ci-4烷羰基、貌氧羰基及苯甲基，且其中R2與鏵基呈順式組態，或其對映異構物。 R2Wherein it is hydrogen or Cl-6 fluorenyl; R5 is hydrogen; Cl-6 alkyl; fluorenyl Cl-6 alkynyl; R6 is hydrogen; K7 is hydrogen; Ci-β oxycarbonyl carbonyl; Two τ »wells substituted with two substituents selected from Cl-6 alkyl. 2. The compound according to item j of the patent application park, wherein: R4 is fluorene; cyano; Cl-6 fluorene carbonyl; Cl-6 alkanesulfonyl; tetrafuran: dioxolane; via Ci-S alkane Dioxolane substituted with aryl; oxidine; oxidine substituted with nansin or Cl-6 alkyl; dazaki; diwax substituted with one or two substituents selected from: halogen, Cl-6 Alkyl, hydroxy; or the base of the formula: -31-utflx 腾 t,) -------- 一 ~ (Please read the precautions on the back before filling in this purchase) One pack-8 4 A8 B8 C8 D8 6. Application scope 0 X. R8—N ^ N——Cg) \ = y 〇〇 ^) where K8 is hydrogen or Cl-6 alkyl. 3. The compound according to item 1 of the patent application park, wherein Ri is gas. 4. The compound according to item 1 of the patent application park, wherein R2 is hydrogen or methoxy. 5. The compound according to item 1 of the patent application park, wherein the compound is selected from the group consisting of: amine-5-gas-2,3-dihydro-7-benzo "furan 1-[(tetrahydro- 2-furyl) methyl] -4-hexahydropyridinyl ester; 5-amino-6-gas-3,4-dihydro-2,2-dimethyl-2H-l-benzopyranyl -8- Junic acid l-[(tetrahydro-2-creanyl) methyl] -4-hexahydroσ ^ t fluorenyl radical; 4-amino-5-amino-2,3-dihydro- 7-benzofuran sulfonic acid 1- (3-methoxyprop-yl) -4-hexahydropyridinyl ester; 4-amino-5-gas "'2,3-dihydro-7-benzo & quot Furanoic acid 1- [3- (2-methyl-1,3-dioxolane-2-yl) propylbutanyl 4-hexahydrostilbyl a; -4 -amino-5- Chloro-2,3-dihydro-7-benzo "fumaric acid 1- [3- (1-methylethoxy) propyl] -4-hexahydrofluorenyl acetate; 4-amino- 5-chloro-2,3-dihydrobenzopyrancarboxylic acid 1- [2- (2-hydroxyethoxy) ethyl] -4-hexahydropyridinyl ester; «m nn ni \ I —y * mf ^ im · —, Ken _ (Please read the notes on the back before filling this page) Printed by the staff of the Central Bureau of Standards of the Ministry of Economic Affairs, Co-operative Society This paper is printed in accordance with China National Standard (CNS) Λ4 specification (210X297 mm) .) 44 8 1 A8 B8 C8 D8 Printed by the Consumers 'Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs for the application of patents. 4-Amino-5-Gas-2,3-Dipyridobenzo' ^ carboxylic acid [3- (3-Ga-6-Oxygen-1 (6H ) _Damidyl) propyl]-[Hexahydropyridinyl ester; 4-Amino-5-Ga-2,3-dihydrobenzocarbancarboxylic acid 1_ (4-oxopentyl) -4- Hexahydropyridinyl ester; 4 _ [[(4_Amine-5-Ga_2,3-dihydro_7-benzocreanyl) branyl] oxy] -1_Hexamine 0ΛEthyl butyrate Dark; and 4-amino-5-gas-2,3-dihydro-7-benzofurancarboxylic acid [2- (tetrahydro-2 _anyl) ethyl] _4 ~ hexamethyl And its possible stereochemically isomeric forms and medically acceptable acid addition salts. 6. A medically incontinent composition for the treatment of intestinal disorders involving reduced colonic motility, comprising a medically effective amount of evidence The compound of the patent application Fanyuan No. 1 and the pharmaceutically acceptable carrier. 7. The compound according to the patent application No. 1 is used for the manufacture of a medicament for the treatment of intestinal disorders involving reduced colonic motility. 8'A formula (VT-a) Intermediate, in which R2 is Ci-e alkoxy, pi is fluorene or easily removed, and it is selected from the group consisting of Ci-4 alkylcarbonyl, Carbonyl and benzyl, and wherein the R2 group is cis to the plow configuration, or an enantiomer thereof. R2

)—OH f (VD’-a) : R2爲Ci-6烷氧基 -33 - 本紙張尺度適用中國國家標準（CNS ) Μ規格（21〇x297公釐 ^^1 1 - - HI »^^1 n^l\^—/· 士-- —^ϋ >—^1 tu—J. 0¾ 、-u (請先聞讀背面之注意事項再填寫本頁) 8 4 4 ABCD 申請專利範圍 9.一種製備根據申請專利範園第1項之化合物之方法，其中： a)由式（I )六氫她啶與式（HI )中間物進行N-垸化反應， L-Wi + H-D N-垸化反應(Μ) (Π) -MI ) 其中L如申請專利範園第1項之定義，Wi爲合適之釋離基且D爲如下式之自由基 R2) —OH f (VD'-a): R2 is Ci-6 alkoxy-33-This paper size is applicable to Chinese National Standard (CNS) M specifications (21 × 297 mm ^^ 1 1--HI »^^ 1 n ^ l \ ^ — / · 士-— ^ ϋ > — ^ 1 tu—J. 0¾, -u (Please read the precautions on the back before filling out this page) 8 4 4 ABCD patent application scope 9 A method for preparing a compound according to item 1 of the patent application park, wherein: a) N-fluorination reaction of hexahydroteridine of formula (I) and intermediate of formula (HI), L-Wi + HD N- Tritiation reaction (Μ) (Π) -MI) where L is as defined in the first patent application, Wi is a suitable release group and D is a radical R2 of the formula

nh2 其中R1、N與A如申請專利範園第1項之定義； b)由如式(IV)醇與如式（V)羧酸或其官能衍生物，如醯基鹵化物、對稱或混合酸酑或酯反應： .(請先間讀背面之注意事項再填寫本頁) 經濟部中央標—局員工消費合作社印製 L—Nnh2 wherein R1, N and A are as defined in the first patent application; b) the alcohol of formula (IV) and the carboxylic acid or functional derivative of formula (V), such as fluorenyl halide, symmetry or mixed Acid or ester reaction: (Please read the precautions on the back before filling this page) Printed by L-N

0H (TV) R10H (TV) R1

NH2 ο 〇b 0) 其中R1、R2、L與A如申請專利範圍第1項之定義；並 -34 - 本紙張尺度適用中國国家標準（CNS ) A4規格（210X297公釐） 448 A8 Β8 C8 D8 六、申請專利範園視需要，利用官能基轉化反應，使式（I )化合物轉化成另一種式（I )化合物；且若需要時，使式（I )化合物轉化成具醫療活性之無毒酸加成鹽類，或反之，使酸加成鹽類經鹼轉化成游離鹼型；及/或製備其立體化學異構型。 _(請先閱讀背面之注意事項再填寫本頁) 裝. -β 經濟部中央標隼局員工消費合作社印製本紙張尺度適用中國國家標準（CNS ) Λ4規格（2丨0X297公t ) 448 1 A7 B7 五經濟部中央標隼局員工消費合作社印製 #利申請案第84109382號；補^ ROC Patent Appln. N〇.84109382 U一- 弋各敦明書修正第26-29頁-附件一發明説明（24) Amended Pages ^6~29 of the Chinese Specification - End τ " (民興JJ7年$ 2 h修 (Amended & Submitted on March 2 , 1998) 最大反應之80%之次於最大程度之刺激，直到痙攣反應維持恆定至少15分鐘，隨後在溶液浴中添加單一刼量之試驗化合物。比較投與試驗化合物5分鐘後之痙孿反應振幅及投與試驗化合物前之痙攣反應振幅。編號1 、4、6j、 32-36、39、46與50之化合物於3χ：ι〇-9Μ之濃度時之痙攣反應振幅調提高5¾以上。實例Π:有意識的狗之結腊蠕動在接受普通麻醉與止痛之雌性小猟犬（體重7-17公斤）體内植入等量性力轉換器。研究結腸蠕動時，在距離迴腸〜育腸瓣膜8、16、24及32公分處鏠合結腸。讓狗至少休養2 週。在禁食20;小時後開始試驗，此期間可自由飲水。試驗期間，藉由遙感（無線）系統，允許狗自由離籠活動。狗籠建在一間特定屋子内，裝有單向透光之玻璃，亦即觀察者可，見狗，而狗卻看不見人。利用此系統觀察狗之行爲變化，判斷是否有苹陷現象。轉換器之數據經由小型特製之傳導器盒數字化傳送。此傳導器盒置於穿在狗身上之外套内。利用每一個籠子上之麥克風接收訊號，並傳至中央電腦系統。狗之排便現象爲此試驗之一個變數。投與試驗化合物後頭3個小時内，觀察狗是否出現及何時出現排便。在此頭3個小時内，本發明化合物會謗發試驗動物排便本紙張尺度適用中國國家標準（CNS ) A4规格（210X297公釐） ..裝訂 r-1 {請先閲讀背面之注意事項再填寫本頁j 448 1 kl B7 五、發明説明（25 修」補充. 〇_31毫克斤劑量之化合物6，15，21，35，36，38 ，39，41至47及49謗發至少50%之試驗動物在前三小時内排便。1.25毫克/欠斤.劑量之化合物2，4，8，10， 16，19，22，26，32及33誘發至少5〇%之試驗動物在前三小時内排便。 D.組合物會例下列調配物爲適於根據本發明爲溫血動物進行全身或局部投蔡之呈單位劑型之典型醫蔡組合物實例。本文實例中之"活性成份"（Α.Ι.)係指式（η化合物、其 Ν-氧化物型、醫蔡上可接受之酸加成鹽或立體化學異構型〇實例12: 口服浚取9克4-羥基苯曱酸甲酯與1克4-羥基苯平酸丙酯溶於 4升沸騰之純水中。取3升此溶液，依序溶解1〇克2J-二輕基丁二酸及20克Α· I 後項溶液再與前項剩餘溶液合併，並添加12升1,2,3-丙三醇及3升山梨糖醇70%溶液。取 40克糖情鈉溶於0.5升水中，添加2毫升覆盆子香精與2 毫升醋栗香精。後項溶液再與前項溶液合併，並添加適量水至20升之體積，製成每茶匙（5毫升）含有5毫克^丨之口服液。所得溶液裝入合適容器内。實例13:膠愈取20克Α.Ι.、6克月桂基硫酸納、56克毁粉、56克乳糖、0.8克二氧化矽膠體及1‘2克硬脂酸鎂激烈攪拌混合。所 -27- Jd,------訂----,---1 (請先閲讀背面之注意事項再填寫本頁) 經濟部中央操隼局員工消費合作衽印製 ?^· J? fiF· lit |4-» Mil «Π 1 ^ 1·__ κ / «*Α· JJa I % y 448 1 7 A7 B7 經濟部中央標準爲貝工消費合作社印製五 '發明説明（26 ) 得遂合物裝入ioob.個合逍硬明膝甚内，每個含艰·毫克 A.I. 〇复鼓]4:包膜辏錠蔡疑核心之製法取100克A.I.、570克乳糖與2〇〇克澱粉混合均勻後，以含5克十二烷基硫酸鈉及1〇克衆乙醯毗咯啶酮之約2〇〇毫升水溶液濕化。濕粉末混合物過篩，乾燥，再過篩一次。然後添加100克微晶纖維素與15克氫化植物油◊全部混合均勻，壓成錠劑，製成1〇,〇〇〇個各含10毫克活性成份之藥鍵。 . 、核心添加含5克乙基纖維素之150毫升二氣曱垸溶液至含1〇克甲基纖維素之75毫升變性乙醇溶液中。隨後添加乃克二甲燒與2.5毫升1，2,3-丙三醇。取克聚乙二醇溶化並溶於75亳升二氣甲烷中。後項溶液加至前項溶液中然後添加2.5克十八烷酸鎂、5克聚乙醯咣咯啶酮及毫升濃縮色素懸浮液，全麵合均勻^於包覆設備上所得之混合物包覆蔡錠核心。 f倒1互^射液’ 、取U克4-雞基苯曱酸甲s旨與0.2克4_經基苯甲酸丙錯溶於约0.5料射狀滞水卜冷卻至糊.⑽，齡添加4 克乳酸、〇.〇5克丙二醇及4克A.I·。溶液冷卻至室溫，龙補充適量水至〗升之體積，製成4毫克/毫升Α ι之溶液。溶液過祕則以上則以⑴絲人無菌容器内〇本紙張尺度適用中國國家榇準（CNS ) Α4規格（21〇χ297公釐）裝------订----1--身一 (請先閱讀背面之注意事項再填寫本頁) A7NH2 ο 〇b 0) Among them, R1, R2, L and A are as defined in the first patent application scope; and -34-This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 448 A8 Β8 C8 D8 6. Apply for a patent. If necessary, use a functional group conversion reaction to convert a compound of formula (I) into another compound of formula (I); and if necessary, convert a compound of formula (I) into a non-toxic acid with medical activity Addition salts, or vice versa, convert acid addition salts into free base forms via bases; and / or prepare stereochemically isomeric forms thereof. _ (Please read the precautions on the back before filling this page). -Β This paper is printed by the Employees' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. The paper size is applicable to the Chinese National Standard (CNS) Λ4 specification (2 丨 0X297mmt) 448 1 A7 B7 Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs # 利应用案号 84109382; Supplement ^ ROC Patent Appln. N〇.84109382 U 一-Amendments to the Official Documents, page 26-29-Annex I Inventions Explanation (24) Amended Pages ^ 6 ~ 29 of the Chinese Specification-End τ " (Minxing JJ7 $ 2 h repair (Amended & Submitted on March 2, 1998) 80% of the maximum response is second to the maximum Stimulate until the spasm response remains constant for at least 15 minutes, and then add a single amount of test compound to the solution bath. Compare the spasm response amplitude 5 minutes after the test compound administration and the spasm response amplitude before the test compound administration. Number 1 , 4, 6j, 32-36, 39, 46, and 50 compounds at a concentration of 3x: ιOM-9M, the amplitude of the spastic response was increased by more than 5¾. Example Π: The consciousness of the dog's wax motility is under general anesthesia versus An equal amount of force converter is implanted in the painful female mastiff (weight 7-17 kg). When studying colonic peristalsis, the colon is closed at 8, 16, 24, and 32 cm from the ileum to the intestinal valve. Let the dog Rest for at least 2 weeks. Start the test after fasting for 20 hours, during which time you can drink freely. During the test, the dogs are allowed to move freely from the cage by using a remote sensing (wireless) system. The dog cage is built in a specific room and installed There is one-way transparent glass, that is, the observer can see the dog, but the dog can't see the person. Use this system to observe the behavior change of the dog and determine whether there is a sag phenomenon. The data of the converter is passed through a small specially-made transmitter The box is digitally transmitted. The transmitter box is placed in the outer casing of the dog. The microphone is used in each cage to receive the signal and transmit it to the central computer system. Dog defecation is a variable of this test. The test compound is administered In the first 3 hours, observe whether and when the dog has defecation. Within the first 3 hours, the compound of the present invention will defame the defecation of the test animal. The paper size is applicable to Chinese national standards (CN S) A4 size (210X297 mm) .. Binding r-1 {Please read the notes on the back before filling in this page j 448 1 kl B7 V. Description of the invention (25 repairs) Supplement. 〇_31 mg kg compound 6, 15, 21, 35, 36, 38, 39, 41 to 47, and 49 defame that at least 50% of the test animals defecate within the first three hours. 1.25 mg / kg. Dose of Compounds 2, 4, 8, 10, 16, 19, 22, 26, 32, and 33 induced at least 50% of the test animals to defecate within the first three hours. D. Composition Examples The following formulations are examples of typical medical and pharmaceutical compositions suitable for systemic or local administration of Cai Zhi in unit dosage form to warm-blooded animals according to the present invention. The "active ingredient" (A.I.) in the examples herein refers to the compound of formula (η, its N-oxide type, medically acceptable acid addition salt, or stereochemically isomeric form. Example 12: Orally take 9 g of methyl 4-hydroxybenzoate and 1 g of propyl 4-hydroxybenzepine in 4 liters of boiling pure water. Take 3 liters of this solution and dissolve 10 g of 2J-dichlorobenzene sequentially. The succinic acid and 20 grams of A · I solution of the latter item were combined with the remaining solution of the preceding item, and 12 liters of 1,2,3-glycerol and 3 liters of sorbitol 70% solution were added. 40 grams of sodium sugar solution was taken In 0.5 liters of water, add 2 ml of raspberry flavor and 2 ml of gooseberry flavor. The latter solution is then combined with the previous solution, and an appropriate amount of water is added to a volume of 20 liters, and each teaspoon (5 ml) contains 5 mg ^ 丨Oral solution. The resulting solution was filled into a suitable container. Example 13: Gum heal 20 g of A.I., 6 g of sodium lauryl sulfate, 56 g of powder, 56 g of lactose, 0.8 g of silicon dioxide colloid and 1 ' 2 grams of magnesium stearate are vigorously stirred and mixed. So-27- Jd, -------- Order ----, --- 1 (Please read the precautions on the back before filling this page) Central operation of the Ministry of Economic Affairs Bureau staff Printed by consumer cooperation? ^ · J? FiF · lit | 4- »Mil« Π 1 ^ 1 · __ κ / «* Α · JJa I% y 448 1 7 A7 B7 Description of the "Five" invention (26) The obtained compound was loaded into the ioob. Each of them contained hard and hard knees, each containing hard · mg AI 〇 re-drum] 4: The method of making the coated cymbals Cai Sui core took 100 grams of AI After mixing 570 g of lactose and 200 g of starch, it was wetted with about 200 ml of an aqueous solution containing 5 g of sodium lauryl sulfate and 10 g of diethylpyrrolidone. The wet powder mixture was sieved , Dried, and sieved again. Then 100 grams of microcrystalline cellulose and 15 grams of hydrogenated vegetable oil tincture were added and mixed uniformly, pressed into tablets, and made into 10,000 drug bonds each containing 10 mg of active ingredient. 1. Add 150 ml of dikidone solution containing 5 g of ethyl cellulose to 75 ml of denatured ethanol solution containing 10 g of methyl cellulose. Then add gram of dimethylbenzene and 2.5 ml of 1,2, 3-Glycerol. Take 1 gram of polyethylene glycol to dissolve and dissolve in 75 liters of digas methane. Add the latter solution to the former solution and then add 2.5 g of magnesium octadecanoate, 5 g of polyacetrolidone and milliliter of concentrated pigment suspension were uniformly mixed ^ The mixture obtained on the coating equipment was used to coat the core of Cai ingot. ', Take U grams of 4-chityl benzoic acid methyl s purpose and 0.2 grams of 4-Chlorobenzoic acid propionate dissolved in about 0.5 material spray stagnant water to cool to a paste. 龄, add 4 grams of lactic acid, 0. 0.05 g of propylene glycol and 4 g of AI ·. The solution was cooled to room temperature, and the dragon was replenished with an appropriate amount of water to a volume of 1 liter to make a 4 mg / ml solution. If the solution is too secret, the above is in a sterile container. The paper size is applicable to China National Standard (CNS) A4 specification (21 × 297 mm). I (Please read the notes on the back before filling this page) A7

448173 B7 五、發明説明（27 ) . S 補實例16:棠劑 — 取3克A.I.溶於舍3克2,3-二羥基-丁二酸之25毫升聚乙二醇400之溶液中◊取12克界面活性劑與適量加至300克之三酸甘油S旨共同熔化。後項混合物與前項溶液均句混合。所得混合物倒入37-38ti溫度之模型中，形成1〇〇個各含 30毫克活性成份之塞劑。 (請先閲讀背面之注意事項再填寫本頁) \裝. rIT 經濟部中央標準局負工消費合作社印製 29 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 448 1 73 ABCD 申請專利範5 r-\/ 公夺利申請案第84109382號 v*R0C No.84109382 »修·巧今节笋參利砝固中文本-附件二 unended Claims in Chinese - Rnrl.ff777¾¾57^ (bubmitted on Mai 2 March 1. 一種如下式化合物 R2448173 B7 V. Description of the invention (27). S Supplement Example 16: Tang agent—Take 3 grams of AI and dissolve 3 grams of 2,3-dihydroxy-succinic acid in 25 ml of polyethylene glycol 400 solution. 12 grams of surfactant are melted together with an appropriate amount of triglyceride S added to 300 grams. The latter mixture is mixed with the former solution. The resulting mixture was poured into a model at a temperature of 37-38ti to form 100 suppositories each containing 30 mg of active ingredient. (Please read the notes on the back before filling in this page) \ Installation. RIT Printed by the Central Standards Bureau of the Ministry of Economic Affairs, Printed by the Consumers' Cooperatives 29 This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 448 1 73 ABCD Patent Application No. 5 r-\ / Public Profits Application No. 84109382 v * R0C No. 84109382 »Revision · Qiaojin Festival bamboo shoots weights Chinese text-Annex II Unended Claims in Chinese-Rnrl.ff777¾¾57 ^ (bubmitted on Mai 2 March 1. A compound of the formula R2

NH2 (I), 經濟部中央標準局員工消費合作社印製 t)〇\ 其醫禁上可接受之酸加成鹽類及立體化學異構型，其中： R1爲鹵素； A 代表如下式之二價自由基： -CH2_CH2-(a)、 -CH2-CH2-,CH2-(b)、 -CH=CH-(c),. 自由基（a)、（b)與(c)中一或二個氫原子可被^^烷基置換； R2爲氫或(：1-6垸氧基； L 爲如下式自由基： -Allt-E4(d) > -Alk-0-R5(e)、 30 - 本紙張尺度適财酬家辟（CNS)从雜（加心7公酱） 87-9JMSEN.241A-1 1^1 1!- tn I— — III I- - HI m » - i '一nJ (請先閱讀背面之注意事項再填寫本頁}NH2 (I), printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs t) 〇 \ Acceptable acid addition salts and stereochemically isomeric forms of their medical confinement, where: R1 is halogen; A represents the following formula two Valent radicals: -CH2_CH2- (a), -CH2-CH2-, CH2- (b), -CH = CH- (c) ,. One or two of the radicals (a), (b) and (c) A hydrogen atom may be replaced by ^^ alkyl; R2 is hydrogen or (: 1-6 alkoxy; L is a radical of the formula: -Allt-E4 (d) > -Alk-0-R5 (e), 30-This paper scales CNS from miscellaneous (plus 7 male sauce) 87-9JMSEN.241A-1 1 ^ 1 1!-Tn I— — III I--HI m »-i '一nJ (Please read the notes on the back before filling this page}