TW593320B

TW593320B - Tetrahydro imidazonaphthyridine compounds

Info

Publication number: TW593320B
Application number: TW87104064A
Authority: TW
Inventors: Joerg Senn-Bilfinger; Gerhard Grundler; Wolfgang-Alexander Simon; Stefan Postius; Richard Riedel
Original assignee: Byk Gulden Lomberg Chem Fab
Priority date: 1997-03-24
Filing date: 1998-03-19
Publication date: 2004-06-21
Also published as: HRP980147B1; PE61999A1; GEP20012445B; SA98190059B1; CO4940425A1; HRP980147A2; MY116727A; AR011460A1

Abstract

Compounds of the formula I, in which the substituents have the meanings mentioned in the description, are suitable for the prevention and treatment of gastrointestinal diseases. A compound of the formula I, in which R1 is 1-4C-alkyl, R2 is 1-4C-alkyl or hydroxy-1-4C-alkyl, R3 is hydrogen or halogen, one of the substituents R4a and R4b is hydrogen and the other is hydrogen, hydroxyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy or 1-4C-alkylcarbonyloxy, or in which R4a and R4b together are O (oxygen), one of the substituents R5a and R5b is hydrogen and the other is hydrogen, hydroxyl, 1-4C-alkoxy or 1-4C-alkylcarbonyloxy, or in which one of the substituents R4a and R4b on the one hand and one of the substituents R5a and R5b on the other hand is in each case hydrogen, and the other substituents in each case together form a methylenedioxy radical (-O-CH2-O-) or an ethylenedioxy radical (-O-CH2-CH2-O), where R4a, R4b, R5a and R5b are not simultaneously hydrogen, R6 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy or trifluoromethyl and R7 is hydrogen, halogen, 1-4C-alkyI or 1-4C-alkoxy, or its salts.

Description

593320 A7 B7 第087104064號專利申請案中文說明書替換頁(92年12月）五、發明説明（1 ) 本發明之應用範圍本發明係關於新穎之化合物，其在醫藥工業上被用為製備藥劑之活性化合物。已决口之技術背景美國專利4,468,400描述有不同環狀系統稠合至咪唑并吡啶母結構之三環咪唑并[l，2-a]吡啶，其應適於治療消化性潰癌病。發明敘述本發明係描述式L化合物和其鹽593320 A7 B7 Patent Application No. 087104064 Chinese Specification Replacement Page (December 1992) V. Description of the Invention (1) Scope of Application of the Invention The present invention relates to novel compounds which are used in the pharmaceutical industry to prepare pharmaceuticals Active compound. Background of the U.S. Patent No. 4,468,400 describes a tricyclic imidazo [1,2-a] pyridine having different ring systems fused to the imidazopyridine parent structure, which should be suitable for the treatment of digestive cancer. DESCRIPTION OF THE INVENTION The present invention describes compounds of formula L and their salts

其中 R1為1-4C-烷基， R2為1-4C-烷基或羥基-1-4C-烷基， R3為氫或鹵素，取代基R4a和R4b其中之一為氫而另一者為氫、羥基、1-4C-烷氧基、1-4C-烷氧基-1-4C_烷氧基或1-4C-烷基羰氧基，或R4a和R4b共同為0(氧），取代基R5a和R5b其中之一為氫而另一者為氫、羥基、1-4C-烷氧基，1-4C-烷氧基-1-4C-烷氧基或1-4C-烷基羰氧本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 593320 92. 4. 17 A7 _____B7 五、發明説明（2 ) 基，或R5a和R5b共同為0(氧），或其中一方面取代基R4a和R4b中之一而另一方面取代基R5a和 R5b中之一為氫，而另一取代基一起形成亞甲二氧基卜〇_ CH2-O-)或伸乙二氧基（-O-CH2-CH2-O-)，其中R4a，R4b，R5a和R5b不會同時為氫， R6為氫、齒素、1-4C-统基、1-4C-烷氧基、i_4C-烷氧羰基胺基、l-4C-:fe氧基-l-4C-fe氧羰基胺基或三氟甲基和 R7為氫、鹵素、1-4C-烷基或1-4C-烷氧基。 1-4C-烷基代表含1至4個碳原子之直鏈或支鏈燒基。可提及之例子為丁基、異丁基、第二丁基、第三丁基、丙基、異丙基、乙基和甲基。較佳為甲基。羥基1-4C-烷基代表上述之1-4C-烷基，其可經經基取代。可知之例子為羥甲基、2 -羥乙基和3 -羥丙基。較佳為羥甲基。. 本發明中之自素為溴、氯或氟。 1-4C-烷氧基代表除了氧原子外含1至4個碳原子之直鏈或支鏈烷基之基團。可提及之例子為丁氧基、異丁氧基、第二丁氧基、第三丁氧基、丙氧基、異丙氧基、而較佳為乙氧基和甲氧基。 1-4C-烷氧基-1-4C-烷氧基代表上述之經更多1-4C-烷氧基取代之1-4C-烷氧基之一。可敘及之例子為2-(甲氧基）乙氧基（CH3-0-CH2-CH2-〇）和 2_(乙氧基）乙氧基（CH3-CH2-0-CH2-CH2-0-)。 -5- 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 593320 oCi. 4. ί Ί Α7 Β7 1-4C-燒基羰氧基代表羰基與上述l-4C-、烷基中之一者鍵結。可敘及之例為乙醯氧基（CH3C0-0-)。 1-4C-烷氧基羰胺基代表經上述1-4C-烷氧羰基取代之胺基。可敘及之例為乙氧基羰胺基和甲氧基羰胺基。 1 - 4 C - 元氧基-1 - 4 C ·坑氧基談基代表談基上鍵結上述ί、4 C « 坑氧基-1-4C-燒氧基中之一。可敘及之例子為2_(甲氧基）乙氧羰基（CH3-0-CH2CH2-〇-C0-)和2-(乙氧基）乙氧羰基 (CH3CH2-〇-CH2CH2-0-C0_)。 1-4C-烷氧基-1-4C-烷氧基羰胺基代表經上述1_4C-烷氧基-1-4C-烷氧羰基中之一取代之胺基。可敘及之例子為2_ (甲氧基）乙氧基羰胺基和2-(乙氧基）乙氧基羰胺基。式I化合物適合之鹽依賴於取代基，特別是所有之酸加成鹽。特別提及慣用於製藥業上所製造之醫藥學上無機和有機酸之可耐受鹽。適合者為含例如氫氯酸、氫溴酸、磷酸、硝酸、硫酸、醋酸、檸檬酸、D _葡糖酸、苯甲酸、2_ (4-羥苯甲醯基）苯甲酸、丁酸、磺基水楊酸、馬來酸、月桂酸、蘋果酸、富馬酸、琥珀酸、草酸、酒石酸、氯溴銀酸、硬脂酸、甲苯磺酸、甲基磺酸或羥基_2_莕酸之水溶性和非水溶性之酸加成鹽，其中製備鹽中所使用之酸端 #員万、疋否干係到一兀或多兀酸與端賴於需要何種鹽，而以等莫耳量之比例或不同方式。當處理產物時，開始可得到醫藥非耐受鹽，例如，以工業尺度依據本發明製備化合物時，其可經熟諳此技藝者處理轉化成醫藥上可耐受之鹽。Where R1 is 1-4C-alkyl, R2 is 1-4C-alkyl or hydroxy-1-4C-alkyl, R3 is hydrogen or halogen, and one of the substituents R4a and R4b is hydrogen and the other is hydrogen , Hydroxy, 1-4C-alkoxy, 1-4C-alkoxy-1-4C_alkoxy or 1-4C-alkylcarbonyloxy, or R4a and R4b together are 0 (oxy), the substituent One of R5a and R5b is hydrogen and the other is hydrogen, hydroxyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy or 1-4C-alkylcarbonyloxy Paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 593320 92. 4. 17 A7 _____B7 V. Description of the invention (2) group, or R5a and R5b together are 0 (oxygen), or one of the substituents One of R4a and R4b and one of the substituents R5a and R5b on the other hand is hydrogen, and the other substituents together form a methylenedioxy group (CH2-O-) or ethylenedioxy (-O -CH2-CH2-O-), where R4a, R4b, R5a and R5b will not be hydrogen at the same time, R6 is hydrogen, halo, 1-4C-alkyl, 1-4C-alkoxy, i_4C-alkoxycarbonyl Amine, l-4C-: feoxy-l-4C-feoxycarbonylamino or trifluoromethyl and R7 are hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy. 1-4C-alkyl represents a straight or branched chain alkyl group containing 1 to 4 carbon atoms. Examples which may be mentioned are butyl, isobutyl, second butyl, third butyl, propyl, isopropyl, ethyl and methyl. Methyl is preferred. The hydroxy 1-4C-alkyl group represents the above-mentioned 1-4C-alkyl group, which may be substituted by a group. Known examples are hydroxymethyl, 2-hydroxyethyl and 3-hydroxypropyl. Preferred is hydroxymethyl. The autogen in the present invention is bromine, chlorine or fluorine. 1-4C-alkoxy represents a group of a linear or branched alkyl group containing 1 to 4 carbon atoms in addition to the oxygen atom. Examples which may be mentioned are butoxy, isobutoxy, second butoxy, third butoxy, propoxy, isopropoxy, and preferably ethoxy and methoxy. 1-4C-alkoxy-1-4C-alkoxy represents one of the above-mentioned 1-4C-alkoxy groups substituted with more 1-4C-alkoxy groups. Examples that can be mentioned are 2- (methoxy) ethoxy (CH3-0-CH2-CH2-〇) and 2- (ethoxy) ethoxy (CH3-CH2-0-CH2-CH2-0- ). -5- This paper size applies to China National Standard (CNS) A4 specifications (210X297 mm) 593320 oCi. 4. ί Α7 Β7 1-4C-alkoxycarbonyloxy represents the carbonyl group and the above l-4C- and alkyl groups. One of them is bound. A reproducible example is ethoxyl (CH3C0-0-). The 1-4C-alkoxycarbonylamino group represents an amine group substituted with the aforementioned 1-4C-alkoxycarbonyl group. Illustrative examples are ethoxycarbonylamino and methoxycarbonylamino. 1-4 C -membered oxy-1-4 C · Phenyloxy represents a bond to one of the above ί and 4 C «Phenoxy-1-4C-alkyloxy. Illustrative examples are 2- (methoxy) ethoxycarbonyl (CH3-0-CH2CH2-O-C0-) and 2- (ethoxy) ethoxycarbonyl (CH3CH2-O-CH2CH2-0-C0_). The 1-4C-alkoxy-1-4C-alkoxycarbonylamino group represents an amine group substituted with one of the aforementioned 1-4C-alkoxy-1-4C-alkoxycarbonyl groups. Illustrative examples are 2- (methoxy) ethoxycarbonylamino and 2- (ethoxy) ethoxycarbonylamino. Suitable salts of the compounds of the formula I depend on the substituents, especially all acid addition salts. Special mention is made of tolerable salts of inorganic and organic acids that are customarily used in the pharmaceutical industry. Suitable are those containing, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2- (4-hydroxybenzyl) benzoic acid, butyric acid, and sulfonic acid. Salicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, chlorobromosilicic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid, or hydroxy_2_arsinic acid The water-soluble and non-water-soluble acid addition salts, in which the acid end used in the preparation of the salt is not related to the mono- or poly-acid and the end depends on what kind of salt is required, and so on. The proportion of the amount or different ways. When the product is processed, medically intolerable salts begin to be obtained, for example, when a compound is prepared on an industrial scale in accordance with the present invention, it can be converted into a pharmaceutically tolerable salt by those skilled in the art.

裝訂Binding

-6- A7 B7 第087104064號專利申請案中文說明書替換頁(92年12月）五、發明説明（4 ) 式I化合物有3個對掌中心。本發明是有關所有八種可想像的鏡像異構物以任何所須比例彼此混合，其包括純鏡像異構物，而此為本發明較佳之主題。假若一方面為取代基R4a和R4b中之一而另一方面為取代基R5a和R5b中之一形成亞甲二氧基或伸乙二氧基，則此二取代基形成之亞甲二氧基或伸乙二氧基較佳為彼此為順式。所強調之化合物為式I化合物和其鹽，其中 R1為1-4C-烷基， R2為1-4C-烷基或羥基-1-4C-烷基， R3為氫，取代基R4a和R4b中之一為氫而另一為氫、羥基或1-4C-烷氧基，或其中R4a和R4b共同為0(氧），取代基R5a和R5b中之一為氫而另一為氫、羥基或1-4C-烷氧基，或其中R5a和R5b共同為0(氧），其中R4a、R4b、R5a和R5b不是同時為氫， R6為氫、鹵素或三氟甲基而 R7為氫或鹵素。所強調之本發明具體實施例為式I #化合物和其鹽-6- A7 B7 Patent Application No. 087104064 Patent Replacement Page of Chinese Specification (December 1992) 5. Description of the Invention (4) The compound of formula I has 3 palm centers. The present invention is related to all eight imaginable mirror isomers mixed with one another in any desired ratio, including pure mirror isomers, and this is a preferred subject of the present invention. If methylenedioxy or ethylenedioxy is formed by one of the substituents R4a and R4b on the one hand and by one of the substituents R5a and R5b on the other hand, the methylenedioxy group formed by this disubstituted group Or ethylenedioxy is preferably cis to each other. The compounds highlighted are compounds of formula I and their salts, where R1 is 1-4C-alkyl, R2 is 1-4C-alkyl or hydroxy-1-4C-alkyl, R3 is hydrogen, and the substituents R4a and R4b One is hydrogen and the other is hydrogen, hydroxy or 1-4C-alkoxy, or where R4a and R4b are together 0 (oxygen), one of the substituents R5a and R5b is hydrogen and the other is hydrogen, hydroxy or 1-4C-alkoxy, or where R5a and R5b are collectively 0 (oxygen), where R4a, R4b, R5a and R5b are not both hydrogen, R6 is hydrogen, halogen or trifluoromethyl and R7 is hydrogen or halogen. Emphasized embodiments of the invention are compounds of formula I # and salts thereof

本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 593320 92· 4 Α7 Β7 五、發明説明（5 ) 其中 R1為1-4C-烷基， R2為1-4C-烷基或羥基-1-4C-烷基， R3為氫，取代基R4 a和R4b中之一為氫而另一為氫、經基或1-4 C-烷氧基，取代基R5a和R5b中之一為氫而另一為氫、羥基或1-4C-烷氧基，其中R4a、R4b、R5a和R5b不是同時為氫， R6為氫、鹵素或三氟甲基而 R7為氫或鹵素。特別強調之本發明具體實施例為式Γ化合物和其鹽，其中 R1為1-4C-烷基， R2為1-4C-烷基或羥曱基， R3為氫， R4a為氫， R4b為羥基或1-4C-烷氧基， R5a為氫，羥基或1-4C-烷氧基， R5b為氫， R6為氫、鹵素或三氟甲基而 R7為氫或鹵素。本發明較佳具體實施例為式Γ化合物和其鹽，其中 R1為1-4C-烷基， -8- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 593320 4- i 1 A7 B7 五、發明説明（6 ) R2為1-4C-烷基， R3為氫， R4a為氫， 1141)為 #i 基， R5a為經基， R5b為氫， R6為氫、鹵素或三氟甲基而 R7為氫或鹵素。藉由通式Γ，可經由下表1之取代基意義及所示取代基 R3、R6和R7之位置而真正提出依據本發明之下述範例化合物和在表1所述化合物之鹽。 -9- 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐） 593320 第087104064號專利申請案中文說明書替換頁(92年12月） A? B7 五、發明説明（7 ) 表1This paper size applies to China National Standard (CNS) A4 specifications (210X 297 mm) 593320 92 · 4 Α7 Β7 5. Description of the invention (5) where R1 is 1-4C-alkyl and R2 is 1-4C-alkyl or Hydroxy-1-4C-alkyl, R3 is hydrogen, one of the substituents R4a and R4b is hydrogen and the other is hydrogen, mesityl or 1-4C-alkoxy, one of the substituents R5a and R5b Is hydrogen and the other is hydrogen, hydroxy or 1-4C-alkoxy, wherein R4a, R4b, R5a and R5b are not both hydrogen, R6 is hydrogen, halogen or trifluoromethyl and R7 is hydrogen or halogen. Particularly emphasized embodiments of the present invention are compounds of formula Γ and salts thereof, wherein R1 is 1-4C-alkyl, R2 is 1-4C-alkyl or hydroxyfluorenyl, R3 is hydrogen, R4a is hydrogen, and R4b is hydroxyl Or 1-4C-alkoxy, R5a is hydrogen, hydroxy or 1-4C-alkoxy, R5b is hydrogen, R6 is hydrogen, halogen or trifluoromethyl and R7 is hydrogen or halogen. The preferred embodiment of the present invention is a compound of formula Γ and a salt thereof, in which R1 is 1-4C-alkyl, -8- This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) 593320 4- i 1 A7 B7 V. Description of the invention (6) R2 is 1-4C-alkyl, R3 is hydrogen, R4a is hydrogen, 1141) is #i group, R5a is warp group, R5b is hydrogen, R6 is hydrogen, halogen or Trifluoromethyl and R7 is hydrogen or halogen. By the general formula Γ, the following exemplary compounds according to the present invention and the salts of the compounds described in Table 1 can be really proposed through the meaning of the substituents and the positions of the substituents R3, R6, and R7 shown in Table 1 below. -9- This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210X 297 mm) 593320 Patent Application No. 087104064 Chinese Specification Replacement Page (December 1992) A? B7 V. Description of Invention (7) Table 1

R1 R2 R3 R4a R4b R5a R5b RB y R7 CHa CHa H 0 H H Ή H CHS CHa H H OH H H H H CKa CHa H 0 H H 2-C1 H CHa CH3 H H OH H H 2-Cl · H CH3 ch3 H 0 H H 2-CI 6-CI CHa Chfc H H OH H H 2-CJ 6-CI ch3 CH3 H H OCHn H t H H H ch3 ch3 H H OC2H5 H .H H A CH3 ch3 ，H 0 H H 2-CF5 H CH3 ch3 • H OH H H 2-CF3 H ch3 Ή 〇 OH H H H ch3 Cht H H OH · OH H H H CH, CHa 6-Br ^ 〇 H H H H ch3 ch3 6-Br H OH H H H H ch3 CHa 6-C) H OH H H H •丨 H ch3 ch3 6-Cl H OH OH H H H ch3 ch3 H H OH OH H 2-CI H ch3 Chb H H OH OH H 2-CI S-C! Chb CHa H H OH OH H 4-a H CH3 ch3 H H OH OH H 2-CF3 H CHi CHa H H . OH OH H 2-NHCOOCH3v e-CHs CHo ch3 H H OH OH H ^-NHCOOC^KrOCH^ 6-CHa 〜1 H 0 H H H H H H OH H H H h -10- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 593320 A7 B7 五、發明説明（8 ) 續表1 R1 RZ R3 R4a R4b R5a R5b R6 R7 Chh ch2oh H 〇 H H H ch3 ch2〇h H H OH .H H 2-Ci ' H CH^ ch2oh H . 〇 H，；H 2-C( 5-CI Ch3 ChbOH H H OH H 、H 2-Ci S-Ci ch3 ch2〇h H H 〇CH^ H -H H H CHo CH^OH H H OC^Hs • H H H H ch3 ch2〇h H 0 H H 2-CF3 H CHy ch3oh H H OH H H 2-CF3 H CHi ch2oh H 〇 .OH H H · CHa CHi〇H H H OH OH H〆 H H ch3 CH：〇H 5-Br 0 H . .H H H CH】 CH2〇H 6-Br H OH H H H H ch3 ch2oh 5-C! H OH H H . H ’ H CH) ch2oh θ-CI H OH •OH H H H CK, ch^oh H H OH OH H 1 2-Ci H ch3 CH^OH H H OH OH \ H 2C\ 5-CI CH： CHz〇H H • H OH OH H M ch3 • CHz〇H H H OH OH H 2-CF3 叫 ch3 ch2〇h .H 1 H OH OH H 2-NHCO-OCH3 6-CH3 CH] ch2oh H H OH OH H ^NHCO-OC^KrOC^ 根據本發明之化合物因而可以以下例子之描述法或由適當之起始化合物開始之類似法製備。起始化合物為已知或可以製備類似於已知化合物。端賴於位置7和8之取代方式（R4a/R4b或R5a/R5b)，製備根據本發明化合物可由已知或以已知法製備之N -經保護 8 -胺咪唑并[l，2-a]吡啶（見例如歐洲專利ΕΡ-Α-0 299 470或卡米斯期（Kaminski)等人，J· Med. Chem. 1985, 28, 876-892) 開始依以下反應圖製備： -11 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐） 2.593320 A7 B7 五、發明説明（9 ) 圖1 :R1 R2 R3 R4a R4b R5a R5b RB y R7 CHa CHa H 0 HH Ή H CHS CHa HH OH HHHH CKa CHa H 0 HH 2-C1 H CHa CH3 HH OH HH 2-Cl · H CH3 ch3 H 0 HH 2-CI 6 -CI CHa Chfc HH OH HH 2-CJ 6-CI ch3 CH3 HH OCHn H t HHH ch3 ch3 HH OC2H5 H .HHA CH3 ch3, H 0 HH 2-CF5 H CH3 ch3 • H OH HH 2-CF3 H ch3 Ή 〇 OH HHH ch3 Cht HH OH · OH HHH CH, CHa 6-Br ^ 〇HHHH ch3 ch3 6-Br H OH HHHH ch3 CHa 6-C) H OH HHH • 丨 ch3 ch3 6-Cl H OH OH HHH ch3 ch3 HH OH OH H 2-CI H ch3 Chb HH OH OH H 2-CI SC! Chb CHa HH OH OH H 4-a H CH3 ch3 HH OH OH H 2-CF3 H CHi CHa HH. OH OH H 2-NHCOOCH3v e- CHs CHo ch3 HH OH OH H ^ -NHCOOC ^ KrOCH ^ 6-CHa ～ 1 H 0 HHHHHHH OH HHH h -10- This paper size applies to China National Standard (CNS) A4 specifications (210 X 297 mm) 593320 A7 B7 5 Description of the invention (8) Continued Table 1 R1 RZ R3 R4a R4b R5a R5b R6 R7 Chh ch2oh H 〇HHH ch3 ch2 0h HH OH .HH 2-Ci 'H CH ^ ch2oh H. 〇H,; H 2-C ( 5-CI Ch3 ChbOH HH OH H 、 H 2-Ci S-Ci ch3 c h2〇h HH 〇CH ^ H -HHH CHo CH ^ OH HH OC ^ Hs • HHHH ch3 ch2〇h H 0 HH 2-CF3 H CHy ch3oh HH OH HH 2-CF3 H CHi ch2oh H OHHH CHA CHi 〇HHH OH OH H〆HH ch3 CH: 〇H 5-Br 0 H.. HHH CH] CH2〇H 6-Br H OH HHHH ch3 ch2oh 5-C! H OH HH. H 'H CH) ch2oh θ-CI H OH • OH HHH CK, ch ^ oh HH OH OH H 1 2-Ci H ch3 CH ^ OH HH OH OH \ H 2C \ 5-CI CH: CHz〇HH • H OH OH HM ch3 • CHz〇HHH OH OH H 2-CF3 is called ch3 ch2〇h. H 1 H OH OH H 2-NHCO-OCH3 6-CH3 CH] ch2oh HH OH OH H ^ NHCO-OC ^ KrOC ^ The compounds according to the present invention can therefore be described by the following examples Alternatively, they can be prepared analogously starting with the appropriate starting compound. The starting compounds are known or can be prepared similar to known compounds. Depending on the substitutions (R4a / R4b or R5a / R5b) at positions 7 and 8, the compounds according to the invention can be prepared from known or prepared N-protected 8-amine imidazo [l, 2-a ] Pyridine (see, for example, European Patent EP-A-0 299 470 or Kaminski et al., J. Med. Chem. 1985, 28, 876-892) began to be prepared according to the following reaction scheme: -11-This Paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) 2.593320 A7 B7 V. Description of invention (9) Figure 1:

NHPivNHPiv

-R1-R1

R6R6

•R1 在第7位置去質子化之N -經保護（如圖和以下各圖之Piv 代表一般之保護基，較佳為三甲基乙醯基），8 -胺咪唑并 [1，2-a]说啶與肉桂醛反應。加成產物開始被氧化（例如，以二氧化錳）再環氧化（例如，以過氧化氫）。在強鹼，接著再強酸條件下，移除保護基而造成閉環。若須要可接著進行酮基之還原作用，例如利用氫硼化物。 -12 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 593320 A7 B7• N-protected by deprotonation of R1 at the 7th position (Piv in the figure and the following figures represents a general protecting group, preferably trimethylacetamido), 8-aminoimidazo [1,2- a] Say pyridine reacts with cinnamaldehyde. The addition product begins to be oxidized (for example, with manganese dioxide) and then epoxidized (for example, with hydrogen peroxide). Under strong base and then strong acid conditions, the protecting group is removed to cause ring closure. If necessary, the reduction of the ketone group can be followed by, for example, the use of borohydride. -12 This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 593320 A7 B7

裝訂Binding

593320 A7 B7 五、發明説明（11 ) 圖3 ··593320 A7 B7 V. Description of the invention (11) Figure 3 ··

RR

R1 〇 R7R1 〇 R7

R6^) R7 上圖代表鏡像選擇製造例，同圖1，以相同之N -經保護咪唑并[l，2-a]吡啶為起始物質。去質子式之咪唑[l，2-a]吡啶與純鏡像二呤烷反應，剛開始產生縮合產物，在強酸條件下，將保護基移除而加以環化。續而以氫硼化鈉還原酮基（亦見圖1)以產生顯示有超過90%鏡像純度之終產物。 -14 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 593320 A7 B7 五、發明説明（12 ) 圖4 :R6 ^) R7 The figure above represents an example of mirror-selection manufacturing. As in Figure 1, the same N-protected imidazo [l, 2-a] pyridine is used as the starting material. The deprotonated imidazole [1,2-a] pyridine reacts with pure mirror dipyridinane, which initially produces condensation products. Under strong acid conditions, the protecting group is removed and cyclized. The ketone group was also reduced with sodium borohydride (see also Figure 1) to produce a final product showing over 90% mirror purity. -14-This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 593320 A7 B7 5. Description of the invention (12) Figure 4:

由上述之8 -胺基咪唑并[1，2-A]吡啶開始，經由利用烷化劑攜帶取代基（如R8a=氫，R8b=鹵素）之烷化作用或經由與適當經取代酮[R8a和R8b共同為0(氧）]在例如氰基氫硼化鈉之還原劑輔助下之還原烷化作用，而在鹼或酸之催化下，其為環閉合，產生環酮，其在適當化學變換下可轉化成所需標的化合物（例如見圖1和2 )。若需要，C〇2R在環化前亦可開始還原（醛階段），因而形成經取代7 -羥基衍生物其經由氧化/還原作用可轉化成適當標的化合物。 -15- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 593320 A7 B7Starting from the above 8-aminoimidazo [1,2-A] pyridine, via alkylation using an alkylating agent to carry a substituent (eg R8a = hydrogen, R8b = halogen) or via an appropriately substituted ketone [R8a And R8b together are 0 (oxygen)] reductive alkylation with the aid of a reducing agent such as sodium cyanoborohydride, and under the catalysis of a base or an acid, it is a ring closure, producing a cyclic ketone, which is in a suitable chemistry Transformation can be converted into the desired target compound (see Figures 1 and 2 for example). If necessary, Co2R can also be reduced before cyclization (aldehyde stage), thus forming a substituted 7-hydroxy derivative which can be converted to the appropriate target compound via oxidation / reduction. -15- This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) 593320 A7 B7

593320593320

發明説明上圖4所列出不同方法中R5a*R8a = H (氫）而R5b和R8b共同=〇(氧），8_胺基咪唑并比啶開始與環氧肉桂酸酯衍生物反應成選擇區之環氧化物開啟（A )，在非親質子鹼條件下，環化產物（C)。另一種為，可水解混合物而在酸性條件下環化游離羧酸衍生物（D )。在此二種方法中，酮基可如圖1所示再被還原成醇（G)，例如，利用氫硼化鈉。假若8-胺基咪唑并[i，2_a]吡啶與保護之環氧肉桂醛衍生物（B)反應，則在移除縮醛保護基後，在酸性條件下，此產物可成閉環（F)。酯還原成醛與酸環化同樣可能（£)。酮之還原作用與醛階段之閉環二者可鏡像選擇性地進行，如此當利用相對應之鏡像純環氧衍生物時，則可能鏡像選擇性地製造。 -17- 本紙張又度適用巾國國家標準(CNS) A4規格(210 X 297公D ------------ 593320 ¥)2. 4. IT B7Description of the invention In the different methods listed in Figure 4 above, R5a * R8a = H (hydrogen) and R5b and R8b together = 0 (oxygen), 8-aminoimidazopyridine starts to react with the epoxy cinnamate derivative to choose The epoxide is turned on (A), and the product (C) is cyclized under non-protonic base conditions. The other is to hydrolyze the mixture to cyclize the free carboxylic acid derivative (D) under acidic conditions. In these two methods, the keto group can be reduced to an alcohol (G) as shown in Fig. 1, for example, using sodium borohydride. If 8-aminoimidazo [i, 2_a] pyridine reacts with the protected epoxy cinnamaldehyde derivative (B), the product can be closed-looped (F) under acidic conditions after removing the acetal protecting group. . Reduction of esters to aldehydes is also possible (£) with acid cyclization. Both the reduction of the ketone and the ring closure of the aldehyde stage can be mirror-selectively performed, so that when the corresponding mirror-pure epoxy derivative is used, it is possible to selectively manufacture the mirror. -17- This paper is again applicable to the national standard (CNS) A4 size of the towel (210 X 297 male D ------------ 593320 ¥) 2. 4. IT B7

593320593320

A7A7

基後而活化。因it卜P + ± H i* 、仔<產物與8-胺基咪唑并[i，2-a]吡And then activated. Because it is P + ± H i *, Aberdeen < products and 8-aminoimidazo [i, 2-a] pyridine

•反應’再進行閉5學 1 L·. ±L 如在鹼性條件下。若須要，再進行類似圖3足步驟（還原作用）。圖7 :• The reaction ’is performed for 5 more cycles 1 L ·. ± L as in alkaline conditions. If necessary, perform steps similar to Figure 3 (reduction). Figure 7:

8 -鹵基咪唑并[1，2-a]吡啶（X =鹵素）在重金屬催化（較佳為Pd)下，與適當之經取代/3-苯基-/3-胺基酸反應，產生經取代胺，其再依圖4環化。醛基亦可代替COOR基使用 (如在圖4已提及），若須要則成縮醛之形式。γ為Η (氫）或保護基，其可在閉環後移除。 -19- 本紙張尺度適用中國國家標準(CNS) Α4規格(21〇Χ297公董) 593320 A7 B7 五、發明説明（17 圖8 : R38-haloimidazo [1,2-a] pyridine (X = halogen) is reacted with a suitably substituted / 3-phenyl- / 3-amino acid under heavy metal catalysis (preferably Pd) to produce The substituted amine is cyclized according to FIG. 4. An aldehyde group can also be used in place of the COOR group (as mentioned in Figure 4), if necessary, in the form of an acetal. γ is europium (hydrogen) or a protecting group, which can be removed after the ring is closed. -19- This paper size is in accordance with Chinese National Standard (CNS) A4 specification (21〇297297) 593320 A7 B7 V. Description of the invention (17 Figure 8: R3

N 、R1 〇 Ά2 R丨N 、 R1 〇 Ά2 R 丨

COOR R3COOR R3

N〆 ,R2N〆, R2

3H ROOC〆丫 R6-j 0 R7 尸〇< X HCT R3- ό •R1 由已知或可以類似法製備之咪唑開始，閉環易於成婦胺結構（平衡）。經氧化作用加入雙键後，酮基還原成醇可如圖1所示進行。上圖中，nR”為1-4C-烷基。例中提及之酯基（-COOR或 -C〇2R)可由另外之脫離基替代-OR基或亦可由有關機能之另外基團代替酯基。式I化合物中R4a/R4b或R5a/R5b為1-4C-烷氧基、1-4C-烷 20- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 593320 .發明説明（18 ) 氧基-1-4C-烷氧基或烷基羰氧基可由例者所熟知之-般衍生之法（如燒化或酶Μ此技蟄 R4a/R4«R5a/R5b為㈣之相對應化合物’由其中以已知法分離並純化依據本發明之物質备餾除去溶劑並再結晶由適當溶劑所得之在真二内在適當載質之管柱層析法之—般純化法。'"物或以例如將游離化合物溶在適當溶劑，如氯化之烴，或氯仿，或含所需酸或續而將所需之酸加：：乙醇’異丙醇)’即可得鹽。經過遽、再沈爽：:; 洛劑沈澱加成鹽或經蒸發而獲取鹽。所得 ^而轉化成游離化合物，其反之可轉化成鹽ί 裝藥上非耐受鹽可轉化成醫藥可耐受鹽。純鏡像異構物，㈣是本發明較^之有_灯異構物可以熟諳此技藝者所熟知之法而獲得，例如，：鏡像選擇製造法（例見圖3)、經在對掌分離管柱之層析轉法’經與對掌性佐劑產生衍生物再分離非鏡像異構物並移除對掌性輔助基’經與對掌性酸形成鹽再分離鹽並由鹽中釋出所需化合物，或經由適當溶劑（分餾）結晶。本發明更是有關以上各圖所描述之方法和㈣中間物’ 特別是圖丨小^小咖之過程巾間^其可在環化步驟前分離。以下例子用以更進一步說明本發明而非限定之。同樣地，製備法並無明確描述之更多式〗化合物可以類似或用此技蟄中所熟諳之一般操作技術之相同法製備。 -21 - 本紙張尺度咖家標準(CNS) A4規格(210X297公釐 5933203H ROOC〆 R R6-j 0 R7 〇 < X HCT R3- ό • R1 starts from imidazole, which is known or can be prepared in a similar way, and the closed loop is easy to form the femine structure (equilibrium). After the double bond is added by oxidation, the reduction of the keto group to an alcohol can proceed as shown in FIG. In the figure above, "nR" is 1-4C-alkyl. The ester group (-COOR or -C02R) mentioned in the example may be replaced by another leaving group or the OR group or another group may be used instead of the ester. In the compound of formula I, R4a / R4b or R5a / R5b is 1-4C-alkoxy, 1-4C-alkane 20- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 593320. Description of the invention (18) The oxy-1-4C-alkoxy or alkylcarbonyloxy group can be derived by methods well known to the examples (such as calcination or enzymes. This technique R4a / R4 «R5a / R5b is Corresponding compound of ㈣, from which a substance according to the present invention is separated and purified by a known method, the solvent is distilled off, and recrystallized from a suitable solvent, a column chromatography method in which a proper carrier is contained in Shinji, a general purification method '&Quot; or, for example, dissolve the free compound in a suitable solvent, such as a chlorinated hydrocarbon, or chloroform, or contain the desired acid or continue and add the required acid: ethanol' isopropanol) ' Salt is obtained. After 遽, and then cooler ::; Luo agent precipitation addition salt or evaporation to obtain salt. The resulting ^ is converted into free compounds, and vice versa can be converted into salt. Non-tolerant salts can be converted into pharmaceutical tolerable salts. Pure mirror image isomers, 较 is the comparative of the present invention._ Lamp isomers can be obtained by familiarizing with the methods familiar to this artisan, for example, mirror image selection (For example, see Figure 3), the chromatographic conversion method on the separation column of the opposite palm is used to generate derivatives and then separate non-mirror isomers and remove the opposite palm auxiliary group by the opposite adjuvant. Palmitic acid forms a salt, and then separates the salt and releases the desired compound from the salt, or crystallizes it through a suitable solvent (fractionation). The present invention is more related to the method and intermediates described in the above figures', especially the figure 丨 small ^ The process of the small coffee can be separated before the cyclization step. The following examples are used to further illustrate the present invention without limiting it. Similarly, more compounds not specifically described in the preparation method can be similar or used here. It is prepared in the same way as the general operating techniques familiar to the technology. -21-This paper size is a standard of CNS A4 (210X297 mm 593320)

」終彦物 1 * 苯基- 咪唑并奈啶-7· m 將30毫升二，燒中含4·5克2,3-二甲基^(3_苯基小氧基I丙烯基）_8-三甲基乙醯基-胺基咪唑幷[l，2-a]吡啶之溶液以2 0毫升濃鹽酸處理，回流8小時，在冷卻下以2N氫氧化鈉調整至pH 7.〇並以5〇亳升乙酸乙酯萃取二次。合併之萃取物以水洗滌並以碳酸鉀乾燥再在真 2内濃縮乾燥。殘留黏稠油狀物以乙酸乙酯/石油醚 (1 : 1)為溶離液在矽凝膠上層析。可得26克熔點138_4〇 °(：之標題化合物。 2 · 乳冬基）-2,3_二 bl「l.71 嘧啶-7·酮 , 類似於例1 ’可由7-[3-(2-氯苯基M•氧基_2_丙埽基]8-三甲基乙醯基胺基-2,3-二甲基咪唑并n，2_a]吡啶得到73%產量，熔點80-2°C之標題化合物。 9-(2,6--一亂冬基）-2,3 - — 甲基-7,8.9,10-四氣味 hin.71嘧啶-7-酮類似於例1，可由7-[3-(2,6-二氯苯基卜^氧基_2_丙缔基]8-三甲基乙酸基胺基-2,3-二甲基咪哇并[i，2-a]^ — 得到41%產量，熔點248-9°C之標題化合物。 4 · 9-(2-三氣甲 i + 基）-2，—3二—，—$ 基-7·8Ή_ 四 <氣^ 「1,2-111「1,71啥_淀-7-酮類似於例1，可由7-[3-(2-三氟甲基苯基）-；μ氧基·2_兩 -22-”Endogenous substance 1 * Phenyl-imidazolopyridine-7 · m 30 ml of dioxin, containing 4.5 grams of 2,3-dimethyl ^ (3-phenyl small oxygen I propenyl) _8 -Trimethylacetamido-amino imidazolium [1,2-a] pyridine solution was treated with 20 ml of concentrated hydrochloric acid, refluxed for 8 hours, and adjusted to pH 7.0 with 2N sodium hydroxide under cooling and 50 亳 L of ethyl acetate was extracted twice. The combined extracts were washed with water and dried over potassium carbonate and concentrated to dryness in Celite. The residual viscous oil was chromatographed on a silica gel using ethyl acetate / petroleum ether (1: 1) as the eluent. 26 g can be obtained with a melting point of 138_40 ° (: the title compound. 2 · Lactyl) -2,3-dibl "1.71 pyrimidine-7 · ketone, similar to Example 1 'can be 7- [3- (2 -Chlorophenyl M • oxy-2-propanyl] 8-trimethylethylamidoamino-2,3-dimethylimidazon, 2_a] pyridine yields 73%, melting point 80-2 ° The title compound of C. 9- (2,6--monochatyl) -2,3--methyl-7,8.9,10-tetraodorant hin.71 pyrimidin-7-one is similar to Example 1, and can be obtained by 7 -[3- (2,6-dichlorophenylbutoxy-2-propenyl] 8-trimethylacetamido-2,3-dimethylimidazo [i, 2-a ] ^ — 41% yield of the title compound with a melting point of 248-9 ° C. 4 · 9- (2-tris-methyl i + radical) -2, -3 di-,-$ radical-7 · 8Ή_ tetra- < Gas ^ "1,2-111" 1,71_Yodo-7-one is similar to Example 1 and can be determined by 7- [3- (2-trifluoromethylphenyl)-; twenty two-

裝訂Binding

k 埽基]-8-三甲基乙醯基胺基-2,3-二甲基咪唑并[^“吡哫得到41%產量，熔點184-5°Ct標題化合物。 5 ’ 基-2,3::甲 -四氡咪唑并 hl「l，71 嘧啶在室溫下，將15毫升甲醇中含1克2，弘二甲基·9_苯基-7,8,9，10-四氫咪唑并[nh][1，7]喑啶i酮之懸浮液以少量之450毫克氫硼化鈉處理。攪拌所得淡黃溶液2 小時再以冰水稀釋。以吸滤法遽出沈積之沈澱物再以一些冷的2-丙醇洗滌，可得熔點為21〇_i2<ti8〇〇亳克標題化合物。 Π,2-ίι1Π·71-4 啶類似於例5，可由9_(2_氯苯基）_2,3_二曱基_7,8,9 ι〇_ 四氯味吐并[l，2-h][1，7],奈咬_7_酮得到73%產量，’溶 150-2°C之標題化合物。 . me-二四氤味^ 并 fl.2-hl「l,71-喵啶類似於例5，可由9-(2,6_二氯笨基^，弘二甲基· 7,8,9，1〇-四氫咪唑并喑啶1酮得到72^產量，熔點155-7°C之標題化合物。 8. 1_(2-三氟甲i 苯^1〇_ 四新1 唑并 fl,2-hl「l,71-崦哇類似於例5，可由9-(2-三氟甲基苯基）_2,3_二甲基· 7,8,9，10-四氫咪峻并[mnu]峰啶_7_酮得到72%"產 -23-k fluorenyl] -8-trimethylethylfluorenylamino-2,3-dimethylimidazo [^ "pyridinium yields 41% yield, melting point 184-5 ° Ct. The title compound. 5'yl-2, 3 :: methyl-tetrahydroimidazo hl "1,71 pyrimidine at room temperature, containing 1 g of 2,2-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazole in 15 ml of methanol The suspension of [nh] [1,7] pyridinone was treated with a small amount of 450 mg of sodium borohydride. The resulting yellowish solution was stirred for 2 hours and then diluted with ice water. The deposited precipitate was decanted by suction filtration. After washing with some cold 2-propanol, the title compound having a melting point of 2〇_i2 < ti80000 g was obtained. Π, 2-ίι1Π · 71-4 A pyridine was similar to Example 5 and was obtained from 9- (2-chlorobenzene Base) _2,3_diamidino_7,8,9 ι〇_ Tetrachlorotantrol [l, 2-h] [1,7], naphthalene_7_one yielded 73% yield, 'solvent 150 -2 ° C title compound.. Me- 二四氤味 ^ and fl.2-hl 「1,71-Meridine is similar to Example 5 and can be obtained from 9- (2,6_dichlorobenzyl ^, dimethyl dimethylbenzene • 7,8,9,10-tetrahydroimidazopyridinone 1 ketone yields the title compound with a yield of 72 ^ and a melting point of 155-7 ° C. 8. 1_ (2-trifluoromethyl i benzene ^ 1〇_ tetra New 1 Zolo fl, 2-hl, l, 71- 崦 Wa Example 5: 72% can be obtained from 9- (2-trifluoromethylphenyl) _2,3_dimethyl · 7,8,9,10-tetrahydroimido [mnu] peak pyridin_7_one " Production -23-

593320 第0871〇4〇64號專利申請者中文說明書替換頁(92年12月） a? '! -—------------- -_____ B7 五、發明説明（21 ^ " -- I ’溶點145-7°c之標題化合物。 9· 苯基-7,8,9,10-四氫生1并 n h_iru7i^ 將5晕升無水乙醇中含500毫克2,3-二甲基_7_(2,3_環氧基-1-氧基-3-苯基丙基）三甲基乙醯基-胺基咪嗤 [1’2-a] p比淀之溶液以9 6毫克氫氧化鐘劇烈攪拌之處理，1：溫攪拌2小時後，在冰浴冷卻至〇它。以吸濾法濾出沈積之結晶並以一些冷的乙醇洗滌。在高真空乾媒後’在室溫下將固體加入5毫升之9〇%強度之硫酸中並攪拌1小時。再以4〇%強度之冷氫氧化鈉溶液於冰冷條件下中和。操作過程中沈澱之沈澱物在真空中濾出並乾燥。可得145毫克，熔點232-4°C之標題化合物。 1〇·工』-二轉茱基-9-茉某_7·8·9·10-四氤呋4并 LI，2-hl[l，71 喊哈 700亳克8-羥基-2,3-二甲基-9-苯基-7,8,9，10·四氫咪唑并n，2-h][l，7]喑啶-7-酮懸浮於1 5毫升甲醇中並在室溫以部份200毫克氫硼化鈉攪拌處理。攪捽2小時後，將混合物倒入1〇〇毫升冰冷水中。濾出沈積之沈澱物再於真空短暫乾燥並由一些2_丙醇再結晶。可得5〇〇毫克，熔點為150-2°C之標題化合物。 11·腿，9R)-2,3-二甲基|蕤甚冬苯某_7,8,91〇_四氤咪唑幷 Il，—2-hl「1.71 喵啶-7-酮將 10.8 克（24 毫莫耳）2,3-二甲基-7-[(2S，3R)-2,3-0-亞異丙基-3-苯基丙-1-醯-1基]三甲基乙醯基咪唑并 -24- 本紙張尺度適财國國家標準(CNS) A4規格(210X29?公愛) 593320 θ2· “7 Α7593320 Replacement page of Chinese manual for patent applicant No. 0871〇4〇64 (December 1992) a? '! ------------- -_____ B7 V. Description of the invention (21 ^ "-I 'The title compound has a melting point of 145-7 ° C. 9 · Phenyl-7,8,9,10-tetrahydrogen 1 and n h_iru7i ^ 5 mg of absolute ethanol containing 500 mg 2, 3-dimethyl_7_ (2,3_epoxy-1-oxy-3-phenylpropyl) trimethylacetamido-aminoimido [1'2-a] p The solution was treated with violent stirring with 96 mg of hydroxide. 1: After 2 hours of warm stirring, it was cooled to 0 in an ice bath. The deposited crystals were filtered off by suction filtration and washed with some cold ethanol. Drying under high vacuum After the reaction, the solid was added to 5 ml of 90% strength sulfuric acid at room temperature and stirred for 1 hour. Then it was neutralized with 40% strength cold sodium hydroxide solution under ice-cold conditions. The precipitate precipitated during the operation The material was filtered off in vacuo and dried. 145 mg of the title compound with a melting point of 232-4 ° C were obtained. 1〇工』-二转 Ju 基 -9- 茉某 _7 · 8 · 9 · 10-Tetrapyrene Furo 4-Lio, 2-hl [l, 71 700 gram 8-hydroxy-2,3-dimethyl-9-phenyl-7,8,9,10 · tetrahydroimid And n, 2-h] [l, 7] pyrimidin-7-one was suspended in 15 ml of methanol and stirred at room temperature with a portion of 200 mg of sodium borohydride. After stirring for 2 hours, the mixture was poured Into 100 ml of ice-cold water. The deposited precipitate was filtered off, dried briefly under vacuum and recrystallized from some 2-propanol. 500 mg of the title compound having a melting point of 150-2 ° C was obtained. ， 9R) -2,3-dimethyl | Nandong Benzene_7,8,91〇_tetra-imidazolium Il, 2-2-hl "1.71 meridin-7-one will 10.8 g (24 mmol) Ear) 2,3-dimethyl-7-[(2S, 3R) -2,3-0-isopropylidene-3-phenylpropan-1-yl-1yl] trimethylacetamidoimidazole -24- This paper is suitable for National Standards (CNS) A4 size (210X29? Public love) of the country of wealth 593320 θ2 · "7 Α7

發明説明 [1，2-a]P比咬（ee : >95% HPLC)在4分鐘之間於冰冷條件下加入5 0毫升7〇%強度硫酸中。在此期間形成懸浮液’其在3 0分鐘後轉為橘色溶液。加成完成後，移除冰洛並在室溫攪掉混合物。5 〇小時後做TLC檢測。將逐漸元成之反應溶液加入冰水中再將二氯甲燒加入，再用6 N氫氧化鈉溶液和飽和碳酸氫鈉調整混合物至pH 8 °分離出有機相。以二氯甲烷萃取水相兩次。合併有機相再以一些蒸餾水洗滌。再以無水硫酸鈉乾燥有機層’過濾並在真空旋轉蒸發器内濃縮。以溶離劑：二氯甲燒/甲醇1 00/ 1在急騾碎凝膠層析濃縮殘留物。濃縮主要之部份並以乙酸乙酯處理，在此時結晶黃色固體之I越化合物。以吸濾、法遽出沈澱物並在5 〇 °c之真空乾燥烤箱乾燥至恆重量。質量：4 22克（57 2%理論值），ee : >95% (HPLC)，熔點：231-4C。 12.^111，811，91〇-2.3-二甲基-7,8-二蕤某-9-艾甚-7,8,9.10-四 1咪唑并「l，2-hl「1.71硌凃將6克（19·52毫莫耳）（8R，9R)-2,3-二甲基-8-羥基-9-苯基-7,8,9，10-四氫咪唑并[1，2-11][1，7]喑啶-7-酮（66:>90% HPLC)懸浮在6 0毫升甲醇並在冰甲醇浴中冷卻至乃。c至 0C。在此溫度’將氫测化鋼（〇.81克，21.47毫莫耳）在 0 · 5小時間以藥匙加入（釋出氣體）。完全加入後，再攪拌混合物1 0分鐘再在40 °C浴溫於真空旋轉蒸發器中濃縮。所得油狀殘留物溶在蒸餾水中並以氯仿萃取三次。合併有機相並以一些水洗滌再以無水硫酸鈉乾燥 -25- 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐)Description of the invention [1,2-a] P specific bite (ee: > 95% HPLC) was added to 50 ml of 70% strength sulfuric acid under ice-cooling conditions within 4 minutes. During this time a suspension ' was formed which turned to an orange solution after 30 minutes. After the addition is complete, remove the ice cream and stir off the mixture at room temperature. TLC was performed after 50 hours. The gradual reaction solution was added to ice water, and then dichloromethane was added. Then, the mixture was adjusted to pH 8 ° with 6 N sodium hydroxide solution and saturated sodium bicarbonate to separate the organic phase. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with some distilled water. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in a vacuum rotary evaporator. The residue was concentrated with eluent: dichloromethane / methanol 1 00/1 in a flash gel chromatography. The main part was concentrated and treated with ethyl acetate, at which point the crystalline compound as a yellow solid crystallized. The precipitate was decanted by suction filtration and dried in a vacuum drying oven at 50 ° C to constant weight. Mass: 4 22 g (57 2% of theory), ee: > 95% (HPLC), melting point: 231-4C. 12. ^ 111,811,91〇-2.3-dimethyl-7,8-dioxo-9-aiseven-7,8,9.10-tetra1imidazo "1,2-hl" 1.71 6 g (19.52 mmol) (8R, 9R) -2,3-dimethyl-8-hydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo [1,2- 11] [1,7] Pyridin-7-one (66: > 90% HPLC) suspended in 60 ml of methanol and cooled to 50 ° C in an ice-methanol bath. C to 0C. At this temperature 'the hydrogen was measured Steel (0.81 g, 21.47 mmol) was added with a spoon (releasing gas) over 0.5 hours. After the addition was complete, the mixture was stirred for another 10 minutes and then at 40 ° C bath temperature on a vacuum rotary evaporator. It was concentrated in water. The obtained oily residue was dissolved in distilled water and extracted three times with chloroform. The organic phases were combined and washed with some water and then dried over anhydrous sodium sulfate. -25- This paper applies to Chinese National Standard (CNS) A4 (210X297) (Centimeter)

裝訂Binding

k W320 92. i.，11k W320 92. i., 11

，過濾。濾液在真空旋轉蒸發器中濃縮並與丙酮共同必發’在此時結晶出標題化合物。以吸濾法濾出沈澱物並以丙酮和二***洗滌再在5〇。〇之真空乾燥烤箱乾爍至2重。可得熔點：2〇6-9。(：之無色結晶之標題化合物。質量：5·15克（85.3%理論值）；化合物有97 4%之非鏡像異構純度和鏡像異構純度超過ee : 93 8% (HpL 合物,filter. The filtrate was concentrated in a vacuum rotary evaporator and combined with acetone to crystallize the title compound at this time. The precipitate was filtered off with suction and washed with acetone and diethyl ether and then at 50 ° C. 〇In a vacuum drying oven, dry to 2 weights. Available melting point: 20-6-9. (: Title compound of colorless crystals. Mass: 5.15 g (85.3% of theoretical value); 97% of the compound has a non-mirromeric purity and a mirror-isomeric purity exceeding ee: 93 8% (HpL compound

裝 Α· 氧基-2-丙烯基）_8_三甲某乙醢 [吡啶(A · oxy-2-propenyl) _8_trimethyl acetamidine [pyridine

方法A a) 7 - 一丁錫烷基-2,3_二甲基_8_三甲基乙醯基胺基咪唑并 [l，2-a]吡啶Method A a) 7-Butyltinyl-2,3-dimethyl-8-trimethylethylamidoaminoimidazo [l, 2-a] pyridine

在-78°C將40亳升二***含1克2,3-二甲基三甲基乙醯基胺基咪唑并[丨，2_a]吡啶之溶液以8毫升之正戊烷中含第二丁基鋰之丨·5莫耳溶液滴加處理。攪摔混合物1 $ 刀I里再以3 · 3毫升二_正·丁基錫化氯處理。再使内部溫度升土 ▲溫’將混合物倒入冰水中再以乙酸乙酯萃取二次’合併之萃取液以一些水洗滌再以碳酸鉀乾燥，在真空吸除溶劑而所得油狀物以溶離劑乙酸乙酯/石油醚（1 : 3)在矽凝膠上層析。可得13克之黏稠油狀物7_三丁錫烷基-2,3-二甲基三甲基乙醯基胺基咪唑并 ρ比淀。 b) 2,3-二甲基-7-(3-苯基_丨_氧基丙晞基）-8_三甲基乙醯基胺基味峻并[1，2 - a] p比淀 -26-At -78 ° C, a solution of 40 liters of diethyl ether containing 1 g of 2,3-dimethyltrimethylethylamidoimidazo [丨, 2-a] pyridine was added in 8 ml of n-pentane. 5 Molar solution of butyllithium was added dropwise. Stir the mixture for $ 1 and then treat it with 3.3 ml di-n-butyltin chloride. Then the internal temperature was raised. The mixture was poured into ice water and extracted twice with ethyl acetate. The combined extracts were washed with some water and dried with potassium carbonate. The solvent was removed under vacuum to dissolve the oil. The solvent was ethyl acetate / petroleum ether (1: 3) and chromatographed on a silica gel. 13 grams of 7-tributyltin alkyl-2,3-dimethyltrimethylethylamidoamidoimidazopyridine was obtained as a viscous oil. b) 2,3-Dimethyl-7- (3-phenyl_ 丨 _oxypropylfluorenyl) -8_trimethylethylfluorenylamino and [1,2-a] p ratio -26-

593320 A7 B7 五、發明説明（24 將15愛升四氫呋喃中含1克7-三丁基錫烷基_2,3 •二甲基-8-二甲基乙醒基胺基咪唑并[丨，]^]吡啶之溶液依次以85毫克氯化鐘、6〇亳克雙（乙腈）氯化鈀和34〇亳克肉桂酿氯處理。在60它攪拌混合物3小時。冷卻至〇後’以吸濾法濾出淡黃色沈澱物並以一些四氫吱喃和二乙基酸洗條。在真空乾燥後，可得720毫克熔點263_5 °C (分解作用）之氧氯化物之鹽的標題化合物。593320 A7 B7 V. Description of the invention (24 15 liters of tetrahydrofuran contains 1 gram of 7-tributyltinalkyl_2,3 • dimethyl-8-dimethylethoxyaminoimidazolo [丨,] ^ ] The pyridine solution was treated with 85 mg of bell chloride, 60 g of bis (acetonitrile) palladium chloride, and 3400 g of cinnamon chloride in order. The mixture was stirred at 60 for 3 hours. After cooling to 0, it was filtered by suction. The pale yellow precipitate was filtered off and the strip was washed with some tetrahydrocondensation and diethyl pickling. After vacuum drying, 720 mg of the title compound of the salt of oxychloride having a melting point of 263_5 ° C (decomposition) were obtained.

方法B a) 2,3-二甲基-7-(3-苯基_1_羥基_2-丙晞基）_8-三甲基乙醯基胺基咪唑并[1，2-a]吡啶在-78°C ’將劇烈攪摔之41克8_三甲基乙醯基胺基_ 2,3-一甲基咪唑并[i，2_a]吡啶於氬保護氣下，以320毫升可用商品之第三丁基鋰含於正-戊烷之1.5莫耳溶液滴加處理以使溫度不超過-7〇它。在_78°c再攪拌1 5分鐘後，將50毫升無水二***中含61克肉桂醛之溶液滴加入（内部溫度<-68。<3)。再使混合物回溫至室溫，再小心地倒入冰水並以總共500毫升乙酸乙酯萃取三次，以蒸餘水洗滌淡紅色有機相並以硫酸鈉乾燥並在真空除去落劑。殘留之淡黃色懸浮液以二***處理。所得結晶以吸濾法濾出。可得30克熔點194-5°C之2,3-二甲基 (3-苯基-1-羥基-2-丙缔基三甲基乙醯基胺基咪唑并 [l，2-a]吡啶。 b) 2,3-二甲基-7-(3-苯基-1-氧基-2-丙晞基）-8-三甲基乙醯基胺基咪唑并[l，2-a]吡啶 -27-Method B a) 2,3-dimethyl-7- (3-phenyl_1_hydroxy_2-propanyl) _8-trimethylethylamidoaminoimidazo [1,2-a] pyridine 41 grams of 8_trimethylethylamidoamino_ 2,3-monomethylimidazo [i, 2_a] pyridine will be vigorously stirred at -78 ° C under 320 ml of available commercial product The third butyl lithium containing 1.5 mol of n-pentane was added dropwise so that the temperature did not exceed -70 ° C. After stirring for an additional 15 minutes at -78 ° C, a solution containing 61 g of cinnamaldehyde in 50 ml of anhydrous diethyl ether was added dropwise (internal temperature < -68. &Lt; 3). The mixture was warmed to room temperature again, carefully poured into ice water and extracted three times with a total of 500 ml of ethyl acetate. The pale red organic phase was washed with distilled water and dried over sodium sulfate and the falling off agent was removed in vacuo. The remaining pale yellow suspension was treated with diethyl ether. The obtained crystals were filtered off by suction filtration. 30 g of 2,3-dimethyl (3-phenyl-1-hydroxy-2-propenyltrimethylethylamidoamidoimidazo [l, 2-a] having a melting point of 194-5 ° C can be obtained Pyridine. B) 2,3-dimethyl-7- (3-phenyl-1-oxy-2-propanyl) -8-trimethylethylamidoaminoimidazo [1,2-a ] Pyridine-27-

A7A7

將900毫升三氯甲烷中含35 5克2,3_二甲基·7 — (3_苯基_ 1-¾基-2-丙晞基）-8-三甲基乙醯基胺基咪唑并[ny吡啶之岭液以6 0克一氧化錳處理並在室溫劇烈攪拌2 〇小時再過濾混合物，濾液在真空濃縮至乾燥而所得油狀物以一些二異丙醚處理。此過程中所得結晶以吸濾法遽出。可得31.5克熔點i〇8-i〇°c之標題化合物。 β. 丙烯某1-8-三甲其广致基胺羞二平基咪唑并毗冷類似於例A，方法A，經與2 -氯肉桂醯氯相對應之反應，可得產量42%，熔點158-60°C之氫氯化物的標題化合物。 C· - 一氧+某）-1 -氣基-2-丙婦基1 -8-三曱甚乙赫莘胺羞^ -2，3 -—甲基-味咬并f 1，2 - a 1 p比淀類似於例A，方法A，經與2,6-二氯肉桂醯氯相對應之反應’可得產量51%，熔點21 8-191之氫氯化物的標題化合物。 D. 7二氣甲基笨某）_ι·氣基_2_丙烯基1 -8_三〒莘乂^ 酿基胺基-2,3·二甲某味峻并flj-alp比咬類似於例A，方法A，經與2-三氟甲基肉桂醯氯相對應之反應’可得產量12%，熔點206-8。(：之氫氯化物的標題化合物。 E. 2，3 - —里―基- 7- (2,3 -環氧基-1-氣基-3-笨基丙基）-8-= 乙酿基胺基咪嗅并「1,2-aV比咬 60毫升丙酮含4克2,3-二甲基-7-(3-苯基-1-氧基-2-丙 -28-In 900 ml of trichloromethane, 35.5 g of 2,3-dimethyl · 7 — (3-phenyl — 1-¾yl-2-propenyl) -8-trimethylacetamidoimidazole The pyridine solution was treated with 60 g of manganese monoxide and stirred vigorously at room temperature for 20 hours. The mixture was then filtered and the filtrate was concentrated in vacuo to dryness and the resulting oil was treated with some diisopropyl ether. The crystals obtained in this process were decanted by suction filtration. 31.5 g of the title compound having a melting point of 108-100 ° C were obtained. β. Propyl-1-8-trimethylpropionylamine diamidinediimidazole is similar to Example A, Method A. After a reaction corresponding to 2-chlorocinnamonium chloride, a yield of 42% can be obtained. Melting point The title compound was hydrochloride at 158-60 ° C. C · -monooxy + a) -1 -Gas-2-propenyl 1 -8-Tris-methyl ethylhexylamine ^ -2,3--methyl-taste and f 1,2 -a The 1 p ratio is similar to Example A, Method A. The title compound was obtained in a yield of 51% and melting point of 21 8-191 by reaction with 2,6-dichlorocinnamonium chloride. D. 7 Digas, methylbenzyl) _ι · Gas_2_propenyl 1 -8_triamyl ^ Bakerylamino-2,3 · Dimethyl is savory and flj-alp is similar to bite Example A, Method A, through reaction corresponding to 2-trifluoromethylcinnamonium chloride, a yield of 12% and a melting point of 206-8 can be obtained. (: The title compound of hydrochloride. E. 2,3--Li-yl- 7- (2,3 -Epoxy-1-airyl-3-benzylpropyl) -8- = ethyl alcohol Aminoamido smells, "1,2-aV ratio bite 60 ml of acetone contains 4 g of 2,3-dimethyl-7- (3-phenyl-1-oxy-2-propan-28-

本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 593320 A7 _____ B7 五、發明説明（26 ) 蹄基）-8-三甲基乙醯基胺基咪唑并比啶與1 2毫升水中含400毫克氳氧化鈉之混合物在3〇。〇以5.6毫升可用商品之30%強度過氧化氫水溶液以劇烈攪拌滴加處理 (2 0分鐘）。在30°C另外攪拌3 〇分鐘後，將混合物冷卻至0 °C並以6 0毫升水、i 3克硫代硫酸鈉和3 0毫升乙酸乙酿混合物處理。經相分離後，水相以2 〇亳升乙酸乙酿萃取。合併有機相，以一些水處理並以碳酸鉀乾燥。在真空去除溶劑後，在高真空中乾燥殘留油狀物。可得無定形物質之4克標題化合物。 F. ^^甲基二?二「（2.§^1〇-2.3-0-砟異丙某-3-笨基丙-1-醯-[基乙酸基脖甚咪吐并map比淀在除去水份並在氬氣下，將6〇克（0.245莫耳）2,3-二甲基-8-三甲基乙醯基胺基咪唑并[ij-a]吡啶溶於1.5升無水二***中並在無水冰丙酮冷卻浴中冷卻至-75。〇。以曲針將408毫升（0.6 12莫耳）第三-丁基鋰溶液（1.5 Μ 含於正-戊烷）滴加入以使溫度不超過_65。〇 (3()分鐘）。形成紅色懸浮液。完全加入後，在-75°C再攪拌懸浮液 3 0分鐘。再在溫度低於-65°c，在3 〇分鐘間，將1/ 3之 150毫升無水THF中含145克甲基（23,311)-2,3-0-亞異丙基-3-苯丙酸鹽（ee : 99.05%)緩緩滴加。再將剩餘量隨意地滴加（5分鐘），其使溫度升至-6〇°c。完全加入後，移除冷卻浴。内部溫度達到-30°C時，將2〇毫升甲醇加入並在内部溫度0C時，加入2〇〇毫升蒸顧水。以分液漏斗分離出水相而有機相以每次1 〇〇毫升蒸餾水洗滌5 -29- 本紙張尺度適用中國國家標準(CNS) A4規格(2l〇^r^^y 装訂This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 593320 A7 _____ B7 V. Description of the invention (26) Foot base) 8-trimethylacetamidoimidazopyridine and 1 A mixture of 400 mg of sodium sulfonium oxide in 2 ml of water was added at 30. 〇 Add 5.6 ml of a 30% strength hydrogen peroxide aqueous solution of a commercially available product to the solution under vigorous stirring (20 minutes). After stirring for an additional 30 minutes at 30 ° C, the mixture was cooled to 0 ° C and treated with 60 ml of water, 3 g of sodium thiosulfate and 30 ml of acetic acid. After phase separation, the aqueous phase was extracted with 2.0 liters of ethyl acetate. The organic phases were combined, treated with some water and dried over potassium carbonate. After removing the solvent in vacuo, the residual oil was dried in high vacuum. 4 g of the title compound were obtained as an amorphous material. F. ^^ methyl bis (2.§ ^ 10-2.3-0- 砟 isopropyl-3-benzylpropan-1- 醯-[ylacetate) Remove the water and dissolve 60 g (0.245 mole) of 2,3-dimethyl-8-trimethylethylamidoamidoimidazo [ij-a] pyridine in 1.5 liters of anhydrous di under argon. In ether and cooled to -75 in an ice-acetone cooling bath, 408 ml (0.6 12 mol) of a tertiary-butyl lithium solution (1.5 M in n-pentane) was added dropwise with a curved needle so that The temperature does not exceed _65. 0 (3 () minutes). A red suspension is formed. After the addition is complete, the suspension is stirred for a further 30 minutes at -75 ° C. The temperature is then lower than -65 ° c for 30 minutes In the meantime, 145 g of methyl (23,311) -2,3-0-isopropylidene-3-phenylpropionate (ee: 99.05%) in 150 ml of anhydrous THF of 1/3 was slowly added dropwise. The remaining amount was added dropwise randomly (5 minutes), which brought the temperature to -60 ° C. After the addition was complete, the cooling bath was removed. When the internal temperature reached -30 ° C, 20 ml of methanol was added and internally At a temperature of 0C, 200 ml of distilled water was added. The aqueous phase was separated with a separatory funnel and the organic phase was added at a time of 100 ° C. 5-29- washed ml of distilled water suitable for the present paper China National Standard Scale (CNS) A4 size (2l〇 ^ r ^^ y bookbinding

593320 A7 _______B7__— 五、發明説明（27 ) 次，再以10%強度硫酸（200毫升，50毫升，50毫升）萃取 3次。合併硫酸相，以200毫升二氯甲烷處理並以氫氧化鈉溶液以劇烈調整至pH 2.3 (校正電極）。分離除去有機相。以3 0毫升二氯甲烷萃取水相。以一些蒸餾水洗滌合併之二氯甲烷相兩次。再於無水硫酸鈉乾燥有機相並在真空完全去除溶劑。可得棕色油，再以5 0毫升二***處理之。放入晶種後，靜置隔夜，濾出所形成之結晶並以二***洗滌。在真空中乾燥後，可得熔點 76-80 °C之淡黃粉末之標題化合物。質量：57.7克 (52.5%理論值），ee > 99% (HPLC)。 13. 1118,811,91〇-2,3-二甲某-7.8-二衮篡-9-苯基-7,8,9.10-^蘅生唑并H,2-hl「1.7l4啶在矽凝膠層析（溶離劑··乙酸乙酯/甲醇19/1)例12之 2克母液以產生0.35克之油狀標題化合物，其在加入乙酸乙酯後結晶。熔點：199-200°C(乙酸乙酯）。 14· H9RV3-甲醯基-8-羥基-2-甲基-7-氣基-9- 1 I -miO-四氤咪唑并「i.2-hl「l,71唼啶將（8R，9R)-8-羥基-2,3_二甲基-7-氧基冬苯基-7,8,9，1〇-四氫咪唑并[1，2-11][1，7]喑啶（1克）溶於2〇毫升無水氯仿中，再將5克高錳酸鉀加入。在室溫揽拌反應混合物4 0天後，濾出固體。在矽凝膠層析（溶離劑：二氣甲fe /甲醇13/1)濾液兩次以產生〇·〇7克半固體之標題化合物。 15· 幾甲基_7,8-二與基-2-甲基-9-笨基- -30- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) ^3320593320 A7 _______ B7 __— 5. Description of the invention (27) times, and then extracted 3 times with 10% strength sulfuric acid (200 ml, 50 ml, 50 ml). The sulfuric acid phases were combined, treated with 200 ml of dichloromethane and adjusted vigorously to pH 2.3 with a sodium hydroxide solution (calibration electrode). Separate and remove the organic phase. The aqueous phase was extracted with 30 ml of dichloromethane. The combined dichloromethane phases were washed twice with some distilled water. The organic phase was dried over anhydrous sodium sulfate and the solvent was completely removed in vacuo. A brown oil was obtained and treated with 50 ml of diethyl ether. After the seed crystals were put in, they were left overnight, and the crystals formed were filtered off and washed with diethyl ether. After drying in vacuo, the title compound was obtained as a pale yellow powder with a melting point of 76-80 ° C. Mass: 57.7 g (52.5% of theory), ee > 99% (HPLC). 13. 1118,811,91〇-2,3-Dimethyl-7.8-dioxine-9-phenyl-7,8,9.10- ^ pyrazoloH, 2-hl Gel chromatography (eluent ·· ethyl acetate / methanol 19/1) 2 g of mother liquor of Example 12 to give 0.35 g of the title compound as an oil, which crystallized after adding ethyl acetate. Melting point: 199-200 ° C ( Ethyl acetate). 14 · H9RV3-methylfluorenyl-8-hydroxy-2-methyl-7-oxyl-9- 1 I -miO-tetrahydroimidazolium "i.2-hl" l, 71 pyridine Add (8R, 9R) -8-hydroxy-2,3-dimethyl-7-oxytolyl-7,8,9,10-tetrahydroimidazo [1,2-11] [1, 7] Pyridine (1 g) was dissolved in 20 ml of anhydrous chloroform, and 5 g of potassium permanganate was added. After the reaction mixture was stirred at room temperature for 40 days, the solid was filtered off. Eluent: Dichloromethane / methanol 13/1) The filtrate was twice to give 0.07 g of the title compound as a semi-solid. 15 · Chloromethyl-7,8-di-amino-2-methyl-9- BenQ--30- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) ^ 3320

HA10-四氫咮吨并n.2-hin.7l4啶將0.07克（8R，9R)-3 -甲醯基-8-幾基-2 -甲基-7 -氧基- 9·» 苯基-7,8,9，1〇-四氫咪唑并[1，24][1，7]喑啶溶在5毫升無水甲醇中再將0·1克氫硼化鈉加入。攪拌混合物3 0分鐘再在真2中濃縮。油狀殘留物在水和氯仿間分佈。分離有機層’以無水硫酸鈉乾燥並濃縮。產物經碎凝膠急驟層析（溶離劑：二氯甲烷/甲醇9/1)純化以產生〇〇5 克半固體之標題化合物。 1H-NMR (CD30H，400 MHz) 5=1.90(s，3H，2-CH3)，3.87 (dd，J8,9=9.5 Hz，J8,7=8.0 Hz，1H，8-H)，4.45(d，J9,8=9.4 Hz, 1H，9-H)，4.79(bs，2H，3-CH2)，5.42(d，J7,8=8.0 Hz，1H，7-H)， 7.03(d，J6,5=6.9 Hz，1H，6-H)，7.35-7.42(m，3H，9-Ph)，7.55(d， J=7.0 Hz，2H，9-Ph)，7.77(d，J5,6=7.0 Hz，1H，5-H)。 16· ai^，9R)-7,8-亞異而某二最篡3_二甲篡冬笨基-四氫咪唑并n.2-hl「l,71嘧啶將〇·3 克（73,8匕911)-2,3-二甲基-7,8_二羥基-9-苯基-7,8,9，10-四氫咪唑并[1，2-1!][1，7]嗉啶溶在5毫升無水丙酮和1 0毫升無水Ν，Ν-二甲基甲醯胺中。將2,2-二甲氧丙烷（20毫升）和對-甲苯磺酸-水合物（〇68克）加入，再在室溫擅:拌混合物2 0小時。分離有機層，以水洗滌並以操水硫酸鋼乾燥。蒸發溶劑後，在碎凝膠層析（落離劑：乙酸乙酯/甲醇20/1)殘留物，可得熔點23 1-232°C (分解=***）之如無色針狀物之0.2克標題化合物。商業用途 -31 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)HA10-tetrahydroxanthene and n.2-hin.7l4 pyridine will be 0.07 g of (8R, 9R) -3 -methylamido-8-quinyl-2 -methyl-7 -oxy-9 · »phenyl -7,8,9,10-tetrahydroimidazo [1,24] [1,7] pyridine was dissolved in 5 ml of anhydrous methanol and then 0.1 g of sodium borohydride was added. The mixture was stirred for 30 minutes and concentrated in true 2. An oily residue was distributed between water and chloroform. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated. The product was purified by flash gel flash chromatography (eluent: dichloromethane / methanol 9/1) to give 0.05 g of the title compound as a semi-solid. 1H-NMR (CD30H, 400 MHz) 5 = 1.90 (s, 3H, 2-CH3), 3.87 (dd, J8, 9 = 9.5 Hz, J8, 7 = 8.0 Hz, 1H, 8-H), 4.45 (d , J9,8 = 9.4 Hz, 1H, 9-H), 4.79 (bs, 2H, 3-CH2), 5.42 (d, J7, 8 = 8.0 Hz, 1H, 7-H), 7.03 (d, J6, 5 = 6.9 Hz, 1H, 6-H), 7.35-7.42 (m, 3H, 9-Ph), 7.55 (d, J = 7.0 Hz, 2H, 9-Ph), 7.77 (d, J5, 6 = 7.0 Hz, 1H, 5-H). 16 · ai ^, 9R) -7,8-subisomeric and some two most usable 3_ dimethyl usbbenzyl-tetrahydroimidazolium n.2-hl, l, 71 pyrimidine will be 0.3 g (73, 8 911) -2,3-dimethyl-7,8-dihydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo [1,2-1!] [1,7] Pyridine was dissolved in 5 ml of anhydrous acetone and 10 ml of anhydrous N, N-dimethylformamidine. 2,2-Dimethoxypropane (20 ml) and p-toluenesulfonic acid-hydrate (〇68 G) Add, and then mix at room temperature: mix the mixture for 20 hours. Separate the organic layer, wash with water and dry with hydrated sulfuric acid steel. After evaporating the solvent, chromatograph the gel (eluent: ethyl acetate / Methanol 20/1) residue, 0.2 g of the title compound with a melting point of 23 1-232 ° C (decomposition = ether) can be obtained as colorless needles. Commercial Use-31-This paper applies Chinese National Standard (CNS) A4 Specifications (210 X 297 mm)

裝訂Binding

kk

、發明説明（29 式I化合物和其鹽的有益之醫藥特上。特別是其在溫血動物上顯示顯著抑制=可、用於商業 …保護作用。本文中，根據本發明之泌與極佳擇性之作用、有利之延犀作用、極佳之物可由高選副作用與寬廣之治療範園而區分出。内活性、無顯著意為胃腸病之預防和治療，特別是瘍、胃炎、二害(:ί像例如f潰瘍、十二指腸潰由例如微生：(如二二樂二關之官能性胃病)，其可土 W (如幽π螺旋囷）、細菌毒辛、么抗發炎劑和抗風濕劑）、化乙 ” 口力所引發。予栾如乙醇）、f酸或壓裝前：：本發明之化合物的優良特性已被證實顯然優於由先合物X不冋棱式所得之已確定抗生成潰癌和抗分泌之化別適用於於此些特性’式1化合物和其醫藥可耐受之鹽特別通用於人類和獸醫學，其中胃和/輕心 ί、特別用於治療和/或預防因此，本發明更進而有關根據本發明之化合物用在治療和/或預防上述疾病。 *、本發明還包含使用根據本發明之化合物以製備用於治療和/或預防上述疾病之藥劑。本發明更進而有關含—或多種幻化合物和/或其醫藥可耐雙之鹽的藥劑。藥劑經原本已知之方法製備，其對熟諳此技藝者為熟悉的。 ’ _______ _- 32 _ 本紙張尺歧用t目@家鮮(CNS) A4祕五、發明説明（3〇 ) 人：用'為樂劑之根據本發明之醫藥活性化合物卜活性化 )可以原本（樣式或較佳為與適當之醫藥佐劑組合成叙劑、塗被錠劑、膠量、縣、囊栓劑、貼劑（例如TTS)、乳液、 …二錢，其中活性化合物成份較佳為介在(U和95% 〈間，而其經由適當選擇佐劑與賦形劑可得真正適合活性 :合物和/或所需引發作用之醫藥投藥式(例或腸型）。又土 U技蟄者以其專業知冑熟悉適於所需醫藥配方之佐 =或賦形劑。除溶劑、成膠劑、栓劑基質、錠劑佐劑和其 w性化合物載劑外’彳能使用例如抗氧化劑、分散劑了防；;末劑、調味劑、防腐劑、溶解化劑、色劑別為滲透促進劑和絡合劑（例如環糊精）。活性化合物可經口、非經腸或經皮投藥。已證明在人類醫學上，_般以每日劑量之經口投藥投藥活性化合物為約〇〇1至約2〇，較佳為〇〇5至5，特別為〇.1至1^克/公斤體重’ #適於以數次之形式，則較佳為1至4次之個別劑量以獲得所需結果。一般非經腸治療之 =式二可用相似或（特別是靜脈内投藥活性化合物）較低劑 I。每-情況所需活性化合物之適合劑量和投藥方式可由任何熟讀此技蟄者依其專業知識而訂定。若使用根據本發明之化合物和/或其鹽治療上述疾病，則此醫藥製劑亦可含一或多種其它醫藥物之醫藥活性組成物。可提及之例有：鎮靜劑（例如，由苯并二氮平 (benzodiazapines)類之如待思片（Diazepam)),解痙劑（如五、發明説明（31 ) 畢塔明凡潤（bietamivedne)或卡米羅發（camyl〇fin)，抗副交感神經劑（如氧芬環亞胺（oxyphencycHmine)或苯脲 (phenycarbamide))，局部麻醉劑（如丁卡因（戈普魯卡因（procaine)，與若適合則亦有酵素、維生素或胺基酸。此中特別要強調的是根據本發明化合物與抑制酸分泌之醫藥製劑，例如像Η:阻斷劑（如希每得定（ cimetidine)、雷尼得定（ranitidine)，H+/K+-ATPase抑制劑（如歐米瑞卓 (omeprazole)，片多瑞卓（pantoprazole)，或更進而與所謂之周圍抗副交感神經劑（如皮瑞周片（pirenzepine)、泰樂周片 (telenzepine)，與為增加加強或附加感覺之主要作用與/或減低副作用之與胃泌素拮抗劑之組合劑，或另外與抗細菌活性物質（如頭芽孢菌素（cephalosporin)、四環素、盤尼西林、大環内酯、硝基咪唑、或其它鉍鹽）以控制幽門螺旋菌之組合劑。可提及之活性組合成份為例如每洛黴素 (mezlocillin)、胺芊青黴素（ampicillin)、保黴素 (amoxycillin)、西彿洛辛（cefalothin)、西福斯汀 (cefoxitin)、西福達塞（cefotaxime)、意米盤尼（imipenem)、健大黴素（gentamycin)、艾米康絲菌素（amikacin)、紅黴素、塞普沙辛（ciprofloxacin)、硝基甲p密峻乙醇 (metronidazole)、那鈴錠黴素（clarithromycin)、日舒黴素 (azithromycin)、和其組合劑（如那鈴鍵黴素 (clarithromycin)+ 硝基甲喊吐乙醇）（metronidazole))。藥理學 -34- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) A72. Description of the invention (29) The beneficial pharmaceutical properties of the compound of formula I and its salts are particularly beneficial. In particular, it shows significant inhibition on warm-blooded animals = can be used for commercial ... protection. Selective effects, favorable rhinoplasty effects, and excellent materials can be distinguished from high-selection side effects and broad treatment paradigms. Internal activity, no significant meaning for the prevention and treatment of gastrointestinal diseases, especially ulcers, gastritis, two Harm (: such as f ulcer, duodenal ulcer caused by, for example, micro-birth: (such as Er Er Le Er Guan's functional gastric disease), which can be W (such as the pi spiral pimple), bacterial toxins, anti-inflammatory agents and Anti-rheumatic agent), acetic acid "caused by the mouth force. Yu Luan such as ethanol), f acid or before pressing: The excellent properties of the compound of the present invention have been proved to be significantly better than those obtained from the unformed compound X It has been determined that anti-carcinogenic and anti-secretory chemical compounds are suitable for these properties. The compounds of formula 1 and their pharmaceutically tolerable salts are particularly useful in human and veterinary medicine, of which the stomach and / Treatment and / or prevention The compounds according to the present invention are used for the treatment and / or prevention of the aforementioned diseases. *. The present invention also includes the use of the compounds according to the present invention to prepare a medicament for the treatment and / or prevention of the aforementioned diseases. The present invention further relates to-or- A variety of magic compounds and / or pharmaceuticals that are resistant to double salts. The pharmaceuticals are prepared by known methods and are familiar to those skilled in the art. '_______ _- 32 _ This paper rule is used t 目 @ 家鲜(CNS) A4 Secret V. Explanation of the invention (30) Human: The active pharmaceutical compound according to the present invention can be activated by using as a fungicide (form or preferably combined with a suitable medical adjuvant to form a remedy) , Coated tablets, gum volume, county, capsules, suppositories, patches (such as TTS), emulsions, ... two dollars, of which the active compound component is preferably between (U and 95% <, and it is through the appropriate choice of adjuvant With excipients can be truly suitable for the active: the compound and / or the pharmaceutical dosage form (such as intestinal type) required to trigger the effect. The skilled person is familiar with the expertise suitable for the required pharmaceutical formula = Or excipient. In addition to solvents, gelling In addition to suppository base, lozenge adjuvant, and its w-type compound carrier, it is possible to use anti-oxidants, dispersants, etc .; the final agent, flavoring agents, preservatives, dissolving agents, colorants are not penetration enhancers. And complexing agents (such as cyclodextrin). The active compound can be administered orally, parenterally or transdermally. It has been proven in human medicine that the active compound is usually administered orally at a daily dose of about 0.001 to About 20, preferably from 0.05 to 5, especially from 0.1 to 1 ^ g / kg body weight '#suitable in the form of several times, preferably 1 to 4 individual doses to obtain the required Results. General parenteral treatment = formula II can be used similarly or (especially for intravenous administration of the active compound) a lower dose of I. The appropriate dosage and method of administration of the active compound required in each case can be determined by anyone skilled in the art. Defined by its expertise. If a compound according to the present invention and / or a salt thereof is used to treat the above-mentioned diseases, the pharmaceutical preparation may also contain one or more other medicinal active ingredients. Examples that can be mentioned are: sedatives (for example, benzodiazapines such as Diazepam), antispasmodics (for example, V. Description of the Invention (31) bitamivedne ) Or camilofin, antiparasympathetic agents (such as oxyphencycHmine or phenycarbamide), local anesthetics (such as tetracaine (procaine) And, if appropriate, enzymes, vitamins or amino acids. Special emphasis here should be given to compounds according to the invention and pharmaceutical preparations that inhibit acid secretion, such as for example: Η: blockers (such as cimetidine) Ranitidine, H + / K + -ATPase inhibitors (such as omeprazole, pantoprazole), or even with so-called peripheral antiparasympathetic agents (such as pirrizone tablets) (Pirenzepine), Telenzepine, and a combination with gastrin antagonists to increase the main effect of enhancing or additional sensation and / or reduce side effects, or in addition to antibacterial active substances (such as cephalosporins) (Cephalosporin), tetracycline , Penicillin, macrolide, nitroimidazole, or other bismuth salts) to control Helicobacter pylori. Active combination ingredients that can be mentioned are, for example, mezlocillin, ampicillin, Amoxycillin, cefalothin, cefoxitin, cefotaxime, imipenem, gentamycin, amikacillin Amikacin, erythromycin, ciprofloxacin, metronidazole, clarithromycin, azithromycin, and combinations thereof ( Such as clarithromycin + metronidazole). Pharmacology-34- This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) A7

:據本發明化合物之極佳胃保護作用和抑制分泌胃酸之菸明：：動物實驗模式加以說明。以下所示模式之根據本 " s物 < 研究所提供之數目相當於此些化合物之數目。注之大白鼠胃之測試以下表Α顯示根據本發明化合物於活體内灌注之大白鼠同在靜脈内投藥後對刺激之五肽胃泌素酸分泌之影響。表A 貫例編號劑量 (微莫耳/公斤）靜脈内抑制酸分泌 5 3 100 6 3 100 10 3 100 12 3 100 方法: According to the compound of the present invention, it has an excellent gastric protective effect and inhibits the secretion of gastric acid. Based on the model shown below, the number provided by the Institute is equivalent to the number of these compounds. Tests on the stomach of injected rats The following Table A shows the effects of the rats perfused with a compound according to the present invention in vivo on the stimulation of pentagastrin acid secretion after intravenous administration. Table A Convention No. Dose (μmol / kg) Intravenous Inhibition of Acid Secretion 5 3 100 6 3 100 10 3 100 12 3 100 Method

裝訂Binding

麻醉之大白鼠（CD大白鼠、雌性’ 200-250克，·肌肉内注射尿烷1 · 5克/公斤）在氣管切開後，在正中之上腹部打開腹腔，在食道經口固定PVC導管而另一端則經幽門以使導管末端正好***胃腔。由幽門引出之導管經側端開口引至外部進入右腹腔壁。徹底濕潤（約50-100毫升）後，37°C溫熱生理食鹽水繼續流過胃（〇·5毫升/分鐘，pH 6.8-6.9 ;布朗-優尼塔I (Braun-Unita 1))。以1 5分鐘間隔收集流出液以測定pH(pH儀632，玻璃電極EA 147; φ=5毫米，曼卓（Metrohm))和經由以新鮮配製0.01 N NaOH溶液滴定至pH 7(多氏梅特665曼卓 -35- I紙張尺度k用中國國家標準(CNS)A4規格(21〇x 297公釐) 593320 第087104064號專利申請案 ' 中文說明書替換頁(92年12月） A7 B7 五、發明説明（33 ) (Dosimat 665 Metrohm))以測定分泌之 HC1。手術結束後（例如測定開始之2部份後），經連續靜脈内注射1微克/公斤（=1.65毫升/小時）五肽胃泌素（左股靜脈）3 0分鐘以刺激胃分泌。測試物質在開始五肽胃泌素連續注射後，以1毫升/公斤液體體積靜脈内投藥6 0分鐘。動物體溫以紅外線照射和熱墊維持在恆定之37.8至38°C (以肛溫感應器之自動，非分段之控制）。本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)Anesthetized rats (CD rats, females' 200-250 g, · intramuscular injection of urethane 1.5 g / kg), after tracheotomy, open the abdominal cavity in the middle above the abdomen, and fix the PVC catheter through the esophagus through the mouth The other end passes through the pylorus so that the end of the catheter fits into the gastric cavity. The catheter leading from the pylorus is guided to the outside through the side opening and enters the right abdominal wall. After being thoroughly moistened (approximately 50-100 ml), warm physiological saline at 37 ° C continued to flow through the stomach (0.5 ml / min, pH 6.8-6.9; Braun-Unita 1). The effluent was collected at 15-minute intervals to determine the pH (pH meter 632, glass electrode EA 147; φ = 5 mm, Metrohm) and titrated to pH 7 by freshly prepared 0.01 N NaOH solution (Dossmet) 665 Mandro-35-I paper size uses the Chinese National Standard (CNS) A4 specification (21 × 297 mm) 593320 Patent Application No. 087104064 'Chinese manual replacement page (December 1992) A7 B7 V. Invention (33) (Dosimat 665 Metrohm)) to determine the secreted HC1. After the operation (for example, after the second part of the measurement), continuous intravenous injection of 1 microgram / kg (= 1.65 ml / hour) of pentagastrin (left femoral vein) for 30 minutes to stimulate gastric secretion. After starting the continuous injection of pentagastrin, the test substance was administered intravenously at a liquid volume of 1 ml / kg for 60 minutes. Animal body temperature is maintained at a constant 37.8 to 38 ° C with infrared radiation and a heat pad (automatic, non-segmented control with anal temperature sensor). This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)

Claims

593320 8 8 8 8 A B c D 9as.2〇第087104064號專利申請案中文申請專利範圍替換本(93年5月) 六、申請專利範圍 1. 一種式I化合物或其鹽 R2593320 8 8 8 8 A B c D 9as.2〇 Patent application No. 087104064 Chinese patent application scope replacement (May 1993) VI. Application scope of patent 1. A compound of formula I or its salt R2

其中 R1為1-4C-烷基， R2為1-4C-烷基或羥基-1-4C-烷基， R3為氫或鹵素，取代基R4a和R4b之一為氫，而另一者為氫、羥基、1-4C-烷氧基、1-4C-烷氧基-1-4C-烷氧基或1-4C-烷基羰基氧基，或其中R4a和R4b共同為0(氧），取代基R5 a和R5b之一為氫，而另一者為氫、羥基'Ι-βί：-烷氧基或 1-40烷基羰基氧基，或其中一方面取代基R4a和R4b之一及另一方面取代基R5a和 R5b之一於各情況中為氫，而在各情況中之另一取代基共同形成亞甲二氧基（-0-CH2-〇-)或伸乙二氧基（-〇-CH2-CH2-〇-)。其中R4a、R4b、R5a和R5b不同時為氫，本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 593320 A 8 B8 C3 D8 申請專利範圍 R6為氫、鹵素、1-4C-烷基、1-4C-烷氧基或三氣甲基和 R7為氫、鹵素、1-4C-烷基或1-4C-烷氧基。 2 .根據申請專利範圍第1項之化合物或其鹽，其中 R1為1-4C-烷基， R2為1-4C-烷基或羥基-1-4C-烷基， R3為氫，Where R1 is 1-4C-alkyl, R2 is 1-4C-alkyl or hydroxy-1-4C-alkyl, R3 is hydrogen or halogen, one of the substituents R4a and R4b is hydrogen, and the other is hydrogen , Hydroxy, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, or 1-4C-alkylcarbonyloxy, or wherein R4a and R4b together are 0 (oxy), substituted One of the groups R5a and R5b is hydrogen, and the other is hydrogen, hydroxy'l-βί: -alkoxy or 1-40 alkylcarbonyloxy, or one of the substituents R4a and R4b and the other On the one hand one of the substituents R5a and R5b is hydrogen in each case, and the other substituent in each case together forms a methylenedioxy (-0-CH2-〇-) or ethylenedioxy (- O-CH2-CH2-o-). Among them, R4a, R4b, R5a, and R5b are not hydrogen at the same time. This paper size applies Chinese National Standard (CNS) A4 specifications (210 X 297 mm) 593320 A 8 B8 C3 D8. The scope of patent application R6 is hydrogen, halogen, 1-4C -Alkyl, 1-4C-alkoxy or tris-methyl and R7 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy. 2. The compound or its salt according to item 1 of the scope of the patent application, wherein R1 is 1-4C-alkyl, R2 is 1-4C-alkyl or hydroxy-1-4C-alkyl, and R3 is hydrogen,

取代基R4a和R4b之一為氫，而另一者為氫、羥基或卜 4C-玟'氧基，或其中R4a和R4b共同為〇（氧），取代基R5 a和R5b之一為氫，而另一者為氫、羥基或Ι-βΟ烷氧基，其中R4a、R4b、R5a和R5b不同時為氫， R6為氫、鹵素或三氟甲基和 R7為氫或鹵素。 3.根據_請專利範圍第1項之化合物或其鹽，其具有式ΓOne of the substituents R4a and R4b is hydrogen, and the other is hydrogen, hydroxy, or 4C-fluorenyloxy, or wherein R4a and R4b are together 0 (oxy), and one of the substituents R5a and R5b is hydrogen, The other is hydrogen, hydroxy or 1-β0 alkoxy, wherein R4a, R4b, R5a and R5b are not hydrogen at the same time, R6 is hydrogen, halogen or trifluoromethyl and R7 is hydrogen or halogen. 3. The compound or its salt according to item 1 of the patent scope, which has the formula Γ

R 1為1 - 4 C -燒基， R2為1-4C-烷基或羥基-1-4C-烷基，各畝張尺度通用中國國家標準(CNS) A4規格（210 X 297公釐） 593320 A3 B8 C8 D8 々、申請專利範圍 R3為氫，取代基R4a和R4b之一為氫，而另一者為氫、經基或卜 4 C -烷氧基，取代基R5a和R5b之一為氫而另一者為氫、羥基或1-4C-烷氧基，其中R4a、R4b、R5a和R5b不同時為氫，R 1 is 1-4 C -alkyl, R2 is 1-4C-alkyl or hydroxy-1-4C-alkyl, and the common Chinese National Standards (CNS) A4 specifications (210 X 297 mm) for each acre size are 593320 A3 B8 C8 D8 々, the scope of the patent application R3 is hydrogen, one of the substituents R4a and R4b is hydrogen, and the other is hydrogen, meridian or B4C-alkoxy, and one of the substituents R5a and R5b is hydrogen And the other is hydrogen, hydroxy, or 1-4C-alkoxy, where R4a, R4b, R5a, and R5b are not hydrogen at the same time,

R6為氫、鹵素或三氟甲基而 R7為'氩·或_素。 4 .根據申請專利範圍第3項之化合物或其鹽，其中 R1為1-4C-烷基， R2為1-4C-烷基或羥甲基， R3為氫， R4a為氫， R4b為羥基或1-4C-烷氧基， R5a為氫，羥基或1-4C-烷氧基，R6 is hydrogen, halogen, or trifluoromethyl and R7 is 'argon · or'. 4. The compound or its salt according to item 3 of the scope of the patent application, wherein R1 is 1-4C-alkyl, R2 is 1-4C-alkyl or hydroxymethyl, R3 is hydrogen, R4a is hydrogen, and R4b is hydroxy or 1-4C-alkoxy, R5a is hydrogen, hydroxy or 1-4C-alkoxy,

R5b為氫， R6為氫、鹵素或三氟甲基和 R7為氫或鹵素。 5 .根據申請專利範圍第3項之化合物或其鹽，其中 R1為1-4C-烷基， R2為1-4C-烷基， R3為氫， R4a為氫，衣纸*尺度通用中國圏$：標準(CMS) A4規格（210X 297公寶） 593320R5b is hydrogen, R6 is hydrogen, halogen or trifluoromethyl and R7 is hydrogen or halogen. 5. The compound or its salt according to item 3 of the scope of the patent application, wherein R1 is 1-4C-alkyl, R2 is 1-4C-alkyl, R3 is hydrogen, R4a is hydrogen, and paper and paper * standards are generally in Chinese. : Standard (CMS) A4 Specification (210X 297 Gem) 593320

R4b為羥基， R5a為羥基， R5b為氫， R6為氫、鹵素或三氟甲基和 R7為氣或齒素。 6 ·根據申請專利範圍第丨項之化合物或其鹽，其係選自包括7,8-二羥基_2,3_二甲基_9_苯基_7,8,9，1〇_四氫咪唑并 Π’2 h] [1，7]口奈咬、2,3-二甲基-9-苯基-7,8,9,10-四氫咪唑并[l，2-h] [1，7]嗱啶酮、9_(2_氯苯基>2,3_二甲基_ 二8,9，1〇_四氫咪唑并奈啶酮、9_(2,6-二氯苯基）-2,3-二甲基-7,8,9，1〇-四氫咪唑并[1，2_}1][1，7]嗉啶-7-酮、9-(2-三氟甲基）-2,3_二甲基-7,8,9，1〇-四氫咪唑并 [1，2-11][1，7]峰淀-7-酮、7-羥基-2,3-二甲基-9_苯基- 7,8,9，1〇-四氫咪唑并n，2-hni，7]嗱啶、9_(2_氯苯基）·7_ 羥基-2,3-二甲基-7,8,9，10-四氫咪唑并嗉啶、、（2,6-二氯苯基）-7_羥基_2,3_二甲基-7,8,9，1〇/四氫咪唑并[l，2-hni，7]喑啶、9-(2-三氟甲基苯基）_7•羥基J，夂二甲基-7,8,9，10-四氫咪唑并嗉啶和8•羥基_2,3_ 二甲基苯基-7,8,9，10-四氫咪唑并喑啶·7_ 嗣。 7 ·根據申請專利範圍第1項之化合物或其鹽，其具有化學名（711，811，911)-7,8-二羥基-2,3-二甲基-9-苯基_7,891〇四氫咪唑并[l，2-h][l，7]喑啶。 ’ 8 · 種用於治療θ細疾病之醫藥組成物’其含有根據.、主 1 p月 -4 中國國家標準(CNS) A4規格(210 X 297公董）R4b is hydroxy, R5a is hydroxy, R5b is hydrogen, R6 is hydrogen, halogen or trifluoromethyl, and R7 is gas or dentition. 6. The compound or a salt thereof according to item 丨 of the scope of the patent application, which is selected from the group consisting of 7,8-dihydroxy_2,3_dimethyl_9_phenyl_7,8,9,1〇_ Hydroimidazolium'2 h] [1,7] Oral anaesthesia, 2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo [l, 2-h] [ 1,7] pyrimidone, 9_ (2_chlorophenyl)> 2,3_dimethyl_di 8,9,1__tetrahydroimidazolidinone, 9_ (2,6-dichlorobenzene) ) -2,3-dimethyl-7,8,9,10-tetrahydroimidazo [1,2_} 1] [1,7] pyrimidin-7-one, 9- (2-trifluoro (Methyl) -2,3-dimethyl-7,8,9,10-tetrahydroimidazo [1,2-11] [1,7] peak lake-7-one, 7-hydroxy-2, 3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazolo n, 2-hni, 7] pyridine, 9_ (2-chlorophenyl) · 7_hydroxy-2,3 -Dimethyl-7,8,9,10-tetrahydroimidazopyridine, (2,6-dichlorophenyl) -7_hydroxy_2,3_dimethyl-7,8,9, 10 / tetrahydroimidazo [l, 2-hni, 7] pyridine, 9- (2-trifluoromethylphenyl) _7 • hydroxyJ, pyrenedimethyl-7,8,9,10-tetram Hydroimidazolopyridine and 8 • hydroxy_2,3_dimethylphenyl-7,8,9,10-tetrahydroimidazolopyridine · 7_ 嗣. 7 · Combination according to item 1 of the scope of patent application Or its salt, which has the chemical name (711,811,911) -7,8-dihydroxy-2,3-dimethyl-9-phenyl_7,891〇tetrahydroimidazo [l, 2-h] [1,7] Pyridine. '8 · A pharmaceutical composition for the treatment of θ fine disease', which contains the basis according to the Chinese National Standard (CNS) A4 (210 X 297)

裝 593320Fit 593320

申請專利範般醫藥佐劑供使用於預其係用於製 =園第1項之化合物和/或其鹽，以及和/或職形劑。 •根據申凊專利範圍第1項之化合物或其碌防胃腸病。 I 10 據申請專利範圍第工項之化合物或其鹽造預防和治療胃腸病之藥劑。據申Μ專利範圍第1項之化合物或其鹽，其係 (’8R’9R)-7,8-亞異丙基二氧基-2,3_二甲基冬苯基· 7’8,9，1〇_四氫咪唑并[1，24][1，7]喑啶化合物或其鹽。 12·根據申請專利範圍第1項之化合物或其鹽，其係裝 (7R’8R，9R)-2,3·二甲基-8-羥基-7-(2-甲氧基乙氧基苯基·7,8,9，1〇_四氫咪唑并嗉啶化合物或其鹽。 -5- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)Patented generic pharmaceutical adjuvants are intended for use in the preparation of compounds and / or salts thereof, and / or formulations. • The compound according to item 1 of the patent application or its prevention of gastrointestinal diseases. I 10 The compound or a salt thereof according to the item of the scope of patent application for the prevention and treatment of gastrointestinal diseases. The compound or its salt according to item 1 of the scope of the patent application, which is ('8R'9R) -7,8-isopropylidenedioxy-2,3-dimethyltolyl 7'8, 9,10-tetrahydroimidazo [1,24] [1,7] pyridine compound or a salt thereof. 12. The compound or its salt according to item 1 of the scope of patent application, which is (7R'8R, 9R) -2,3 · dimethyl-8-hydroxy-7- (2-methoxyethoxybenzene • 7,8,9,10_tetrahydroimidazopyridine compound or its salt. -5- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)