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TW201034667A - N-[(6-azabicyclo[3.2.1]oct-1-yl)arylmethyl]benzamide derivatives, preparation and therapeutic use thereof - Google Patents

N-[(6-azabicyclo[3.2.1]oct-1-yl)arylmethyl]benzamide derivatives, preparation and therapeutic use thereof Download PDF

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TW201034667A
TW201034667A TW099104006A TW99104006A TW201034667A TW 201034667 A TW201034667 A TW 201034667A TW 099104006 A TW099104006 A TW 099104006A TW 99104006 A TW99104006 A TW 99104006A TW 201034667 A TW201034667 A TW 201034667A
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azabicyclo
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trifluoromethyl
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Gihad Dargazanli
Genevieve Estenne-Bouhtou
Florence Medaisko
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Sanofi Aventis
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Abstract

The present invention relates to N-[(6-azabicyclo[3.2.1]oct-1-yl)arylmethyl]benzamide derivatives of general formula (I): - R represents a hydrogen atom or a (C1-C6)alkyl or (C3-C7) cycloalkyl group, optionally substituted with one or more of the following: fluorine, (C3-C7)cycloalkyl, (C2-C4)alkenyl, phenyl, (C1-C6)alkoxy or hydroxy; R1 represents a phenyl or naphtyl, optionally substituted with one or more of the following: halogen, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, NR4R5, (C1-C6) alkylthio, (C1-C6)alkyl-SO2, phenyl or heteroaryl; R2 represents one or more hydrogen or halogen atoms, halo(C1-C6)alkyl, (C1-C6) alkyl, (C3-C7)cycloalkyl or (C3-C7)cycloalkyl(C1-C3)alkyl; R3, R4 and R5 represent, independently of one another, a hydrogen atom or a (C1-C6)alkyl group; R6 represents a (C1-C6)alkyl group; R4 and R5 may together form a ring chosen from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine or azepine rings, optionally substituted with a (C1-C6)alkyl group. Therapeutic use and method of synthesis.

Description

201034667 六、發明說明： 【發明所屬之技術領域】 本發明係關於一種N-[(6-氮雜雙環[3.2.1]辛-1-基）芳基甲 基]苯曱醯胺之衍生物、其製備及其於治療或預防涉及 GlyT 1甘胺酸轉運體的疾病之治療用途。 【先前技術】 本發明之化合物相當於通式（I):201034667 VI. Description of the Invention: [Technical Field of the Invention] The present invention relates to a derivative of N-[(6-azabicyclo[3.2.1]oct-1-yl)arylmethyl]benzoguanamine And its preparation and its therapeutic use in the treatment or prevention of diseases involving the GlyT 1 glycine transporter. [Prior Art] The compound of the present invention corresponds to the general formula (I):

其t : -R表不氫原子或選自（C]-C6)烷基或（c3_c7)環烷基之基 團，此等基團係視需要經一或多個相互獨立地選自氟原子Its t: -R represents a hydrogen atom or a group selected from (C)-C6)alkyl or (c3_c7)cycloalkyl, and such groups are optionally selected from fluorine atoms independently of one or more of them.

145867.doc 201034667 基、（CVC6)烷氧基、鹵（Cl_C6)烷基、NR4R5、NR3C(0)0R4、 nr3so2r4 ' nr3c(o)r6、羥基、_ (Ci_c6)烷氧基、（C1_C6) 烷硫基及（CrC：6)烷基-S〇2基團，該雜芳基視需要經一或多 個獨立地選自以下之取代基取代：鹵素原子及（Ci_c6)烷 基、（CVC6)烧氧基、i(Cl_C6)烧基或NR4R5; _R2表示一或多個選自以下之取代基：氫原子、鹵素原 子及（CVC6)烧基、（c3-c7)環燒基、（C3_C7)環院基（c〗_c3) 烷基、鹵（C「C6)烷基、（CVC6)烷氧基、NR4R5、苯基、雜 芳基、氰基、乙醯基、（CVC6)硫烷基、（CVC6)烷基磺醯 基、羧基或（C^-C：6)烷氧基羰基；該苯基視需要經一或多個 獨立地選自以下之取代基取代：鹵素原子及（C〗_C6)烷基、 (CVC6)烧氧基、鹵（CVQ)；)^ 基、NR4R5、NR3C(0)0R4、 NR3S02R4、NR3C(0)R6、羥基、鹵（Cl-c6)烷氧基、（Ci_C6) 烧硫基及（C^-C6)烧基-S〇2基團，該雜芳基視需要經—或多 個獨立選自鹵素原子及（Cl_C6)烷基、（Cl-C6)烷氧基、齒 (Ci-C0)烧基或NR4R5之取代基取代； -R3、R4及Rs相互獨立地表示氫原子或（Cl_C6)烷基； -R_6表不（Ci_C6)烧基； -R4及R5可與其所附接之氮原子一起形成選自氮雜環丁 烷、吡咯啶、哌啶、嗎啉、硫嗎啉、哌嗪或氮呼環之環， 其視需要經（CKCd烷基取代； -R_3及R4可與其所附接之原子一起形成5-貝或6-員環· -R·3及Re可與其所附接之原子一起形成5-貝或6-員環； 其呈驗形式或與酸之加成鹽形式。 145867.doc 201034667 式⑴化合物包括三個不對稱磁 e 禆妷原子。其因此存在非對映 ”構體之形式及對映異構體 ' 开馎媸之形式。此等對映異構體 括外消旋混合物）係本發明的一部份。 該式⑴化合物可呈驗形式或與酸形成之加成鹽形式存 在。該等加成鹽係本發明的一部份。 、此等鹽宜利用醫藥上可接受酸製備，然而可(例如)用於 式（I)化合物之純化或單離的其他酸之鹽亦係本發明之 份。145867.doc 201034667, (CVC6) alkoxy, halo(Cl_C6)alkyl, NR4R5, NR3C(0)0R4, nr3so2r4 'nr3c(o)r6, hydroxy, _(Ci_c6)alkoxy, (C1_C6) alkane a thio group and a (CrC:6)alkyl-S〇2 group which is optionally substituted by one or more substituents independently selected from the group consisting of a halogen atom and a (Ci_c6)alkyl group, (CVC6) Alkoxy, i(Cl_C6)alkyl or NR4R5; _R2 represents one or more substituents selected from the group consisting of a hydrogen atom, a halogen atom and a (CVC6) alkyl group, (c3-c7) a cycloalkyl group, (C3_C7) Ring base (c _c3) alkyl, halo (C "C6" alkyl, (CVC6) alkoxy, NR4R5, phenyl, heteroaryl, cyano, ethyl sulfonyl, (CVC6) sulfanyl, (CVC6) alkylsulfonyl, carboxy or (C^-C:6) alkoxycarbonyl; the phenyl optionally substituted by one or more substituents independently selected from: halogen atom and (C) _C6)alkyl, (CVC6) alkoxy, halogen (CVQ);), NR4R5, NR3C(0)0R4, NR3S02R4, NR3C(0)R6, hydroxy, halo(Cl-c6)alkoxy, ( Ci_C6) a sulfur-based group and a (C^-C6)alkyl-S〇2 group, which may optionally be-- Substituent independently selected from a halogen atom and a (Cl-C6) alkyl group, a (Cl-C6) alkoxy group, a dentate (Ci-C0) alkyl group or NR4R5; -R3, R4 and Rs independently of each other represent a hydrogen atom or (Cl_C6)alkyl; -R_6 represents (Ci_C6)alkyl; -R4 and R5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine a ring of piperazine or a nitrogen ring, which is optionally substituted by a CKCd alkyl group; -R_3 and R4 may form a 5-shell or a 6-membered ring together with the atom to which they are attached. -R·3 and Re may The attached atoms together form a 5-shell or 6-membered ring; in the form of a test or an acid addition salt. 145867.doc 201034667 The compound of formula (1) includes three asymmetric magnetic e 禆妷 atoms. The form of the diastereomeric construct and the enantiomeric form of the enantiomers. These enantiomers, including racemic mixtures, are part of the present invention. The compound of the formula (1) may exist in the form of an assay or an addition salt formed with an acid. Such addition salts are part of the invention. Preferably, such salts are prepared using pharmaceutically acceptable acids, however, salts of other acids which may, for example, be used for the purification or isolation of the compound of formula (I) are also within the scope of the invention.

CC

在本發明之上下文内，以下定義可適用： -Ct_Cz，其中t&z可取丨至6之值：可能具有丨至2個碳原 子之以碳為主的鏈，例如Ci_C6係具有丨至6個碳原子 之以碳為主的鏈； _烷基：直鏈或分支鏈飽和脂族基；例如C1C6_烷基表 示具有1至6個碳原子之直鏈或分支之以碳為主的鏈， 諸如甲基、乙基、丙基、異丙基、丁基、異丁基、第 三丁基、戊基或己基； -稀基：直鏈或分支鏈單不飽和或多不飽和脂族基，其 包括（例如）一或二個乙烯系不飽和基團； -胺基：NH2基； -烷氧基：-〇-烷基； -乙醯基：-c(0)-基； -氰基：-CN基； -羥基：-OH基； -硫燒基：經烧1基取代之硫原子； 145867.doc 201034667 _鹵素原子：氟、氯、溴或碘； -鹵烷基.-或多個氫原子經鹵素取代之烷基。其實例 可提及三氟甲基、三氟乙基或五氟乙基；及 雜芳基：包括1至3個選自氮、氧及硫之雜原子的5_或 6-員芳族單環基團。可提及之料基實例n各、咬 味、嗟吩坐、三〇坐、四 <、嚼唾、異嗔 唑…惡二嗤、嚷吐、異嗟嗤、嗟二唾、吼咬、喷咬、 °比嗪、噠嗪或三嗪基。 【發明内容】 在本發明主題之通式⑴化合物中，第—類化合物係由此 等化合物構成，其中R表示氫原子或（Ci_C6)烷基；尺丨、 R2、R3、R4及R5係如上定義。 *在本發明主題之通式⑴化合物中，第二類化合物係由此 等化合物構成，其中R表示氫原子或甲基或乙基； R1、R2、R3、r4、115及r6係如上定義。 *在本發明主題之通式⑴化合物中，第三類化合物係由此 等化合物構成，其中Rj示苯基，其視需要經—或多個相 互獨立地選自鹵素原子、（Ci_C6)烷基、烷基、 (Ci-C0)烷氧基或羥基之取代基取代； R、、r3、114及r5係如上定義。 在本發明主題之通式（1)化合物中，第四類化合物係由此 等化合物構成，其中1表示苯基，其視需要經一或多個相 互獨立地選自齒素原子、甲基'乙基、三氟曱基、甲氧基 或經基之取代基取代； 145867.doc 201034667Within the context of the present invention, the following definitions are applicable: -Ct_Cz, where t&z can take values up to 6: carbon-based chains which may have up to 2 carbon atoms, for example Ci_C6 has 丨 to 6 a carbon-based chain of carbon atoms; _alkyl: a linear or branched saturated aliphatic group; for example, a C1C6-alkyl group means a linear or branched carbon-based chain having 1 to 6 carbon atoms, Such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl or hexyl; - dilute: linear or branched monounsaturated or polyunsaturated aliphatic groups , which includes, for example, one or two ethylenically unsaturated groups; - an amine group: NH2 group; - an alkoxy group: - fluorenyl-alkyl group; - an ethyl group: -c(0)- group; Base: -CN group; -Hydroxyl group: -OH group; - Sulfur group: Sulfur atom substituted by calcination 1 group; 145867.doc 201034667 _Het atom: fluorine, chlorine, bromine or iodine; -haloalkyl.- or An alkyl group in which a plurality of hydrogen atoms are replaced by a halogen. Examples thereof may include a trifluoromethyl group, a trifluoroethyl group or a pentafluoroethyl group; and a heteroaryl group: a 5- or 6-membered aromatic single comprising 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur. Ring group. Examples of materials that can be mentioned are n, bite, sputum, three squats, four lt; chewing saliva, isoxazole, dioxin, vomiting, sputum, sputum, bite, Bite, ° azine, pyridazine or triazine. SUMMARY OF THE INVENTION In the compound of the formula (1) of the present invention, the first compound is composed of a compound such as R, wherein R represents a hydrogen atom or a (Ci_C6)alkyl group; and a ruthenium, R2, R3, R4 and R5 are as defined above. definition. * In the compound of the formula (1) which is the subject of the present invention, the second compound is composed of a compound such as R, wherein R represents a hydrogen atom or a methyl group or an ethyl group; and R1, R2, R3, r4, 115 and r6 are as defined above. * Among the compounds of the formula (1) which are the subject of the present invention, the third type of compound is composed of such compounds, wherein Rj is a phenyl group which may optionally be selected from a halogen atom or a (Ci_C6) alkyl group independently of one another. Substituting a substituent of an alkyl group, a (Ci-C0) alkoxy group or a hydroxyl group; R, r3, 114 and r5 are as defined above. In the compound of the formula (1) of the present invention, the fourth compound is composed of the same compound, wherein 1 represents a phenyl group, which is optionally selected from a dentate atom, a methyl group, independently of one or more Ethyl, trifluoromethyl, methoxy or substituted with a substituent; 145867.doc 201034667

Ri、R2、R3、R4、115及116係如上定義。 在本發明主題之通式⑴化合物中，第五類化合物係^ 專化合物構成，其中R2表示—或多個選自氫原子、齒素房 子、齒（cvC6m基、（Cl_C6m基、（Ci_C6)貌氧基或⑹ C6)烷基-S〇2基之取代基； R、R1、R3、R4及R5係如上定義。 ΟRi, R2, R3, R4, 115 and 116 are as defined above. In the compound of the formula (1) which is the subject of the present invention, the fifth compound is composed of a specific compound, wherein R2 represents - or a plurality of selected from a hydrogen atom, a dentate house, a tooth (cvC6m group, (Cl_C6m group, (Ci_C6) appearance) a substituent of an oxy group or a (6) C6)alkyl-S〇2 group; R, R1, R3, R4 and R5 are as defined above.

在本發明主題之通式⑴化合物中，第六類化合物係由此 等化合物構成，其中R2表示-或多個選自氫原子、函素原 子、三氟曱基、曱基、甲氧基或乙基磺醯基之取代基； R、Ri、R3、r4及r5係如上定義。 々在本發明主題之通式⑴化合物中，第七類化合物係由此 等呈鹼形式或與酸之加成鹽形式之化合物構成，其中： -R表示氫原子或曱基或乙基；In the compound of the formula (1) of the present invention, the sixth compound is composed of a compound such as R 2 or a plurality selected from a hydrogen atom, a functional atom, a trifluoromethyl group, a decyl group, a methoxy group or a substituent of the ethylsulfonyl group; R, Ri, R3, r4 and r5 are as defined above. In the compound of the formula (1) which is the subject of the present invention, the seventh compound is constituted by a compound which is in the form of a base or an acid addition salt, wherein: -R represents a hydrogen atom or a fluorenyl group or an ethyl group;

Ri表不笨基，其視需要經一或多個相互獨立地選自鹵 素原子或甲基、乙基、三氟甲基、甲氧基或經基之取代基 取代；及 -I表示一或多個選自氫原子、鹵素原子或三氟曱基、 甲基、曱氧基或乙基績酿基之取代基。 以上定義之第一至第七類之組合物亦係本發明之一部 份。 σ 在本發明主題之通式（I)化合物中，可特別提及以下化合 物： Ν-[(6·氮雜雙環基）苯基曱基](2_甲基_3_三氟 甲基）苯甲酿胺； U5867.doc 201034667 N-[(6-氮雜雙環[3.2.1;^_5_基）苯基甲基](3甲氧基_2_甲 基）苯曱醯胺； #N-[(6-氮雜雙環[3.2n5_基）苯基曱基](2,6_二氯冬三 氟甲基）本甲酿胺及其鹽酸鹽； N-[6-氮雜雙環[3.21]辛_5基）苯基甲基](2_氯_3_三氣甲 基）苯甲醯胺及其鹽酸鹽； 尸（+)-N-[(6-氮雜雙環[3 21]辛-5_基）苯基甲基阶氯^三 氟曱基）本甲酿胺及其鹽酸鹽； -㈠-N修氮雜雙環[3.21]辛_5_基）苯基曱基](2 6_二氯_3_ 二氟甲基）苯曱醯胺及其鹽酸鹽； 斤〇例（6-氮雜雙環[3.2·^ _5_基）苯基甲基](2氣小三 氟曱基）苯甲醯胺及其鹽酸鹽； ( + )-N-[(6-氮雜雙環基）苯基甲基](2,6_二氯 _3_二氟甲基）苯甲醯胺及其鹽酸鹽； N-K6-氮雜雙環[3.2.^:基）苯基曱基]&氣：乙基磺 酿基-2-曱氧基）苯甲醯胺及其鹽酸鹽； N-[(6-氮雜雙環基）苯基甲基](2_氯_5•三氟甲 基）苯甲醯胺及其鹽酸鹽； Ν·[(6-氮雜雙環基）苯基甲基](2,6_二氣）苯曱 醯胺； N-U6-氮雜雙環[3.2.1]辛_5_基）苯基曱基](3_氯_2_甲基） 苯甲酿胺； Ν [(6-氮雜雙環[3.2.1]辛-5-基）_(4-氟苯基）甲基](2_氯_3_ 三氟曱基）苯甲醯胺； I45867.doc •10· 201034667 N_[(6-氮雜雙環[3.2.1]辛-5_基）-(4_氟苯基）曱基](2,6-二 氣_3_二氟曱基）苯曱醯胺； N_[(6-氤雜雙環[3.2.1]辛-5-基）-(3-甲氧基苯基）甲 基](2,6_二氯-3-三氟甲基）苯甲醯胺； N_[(6·氮雜雙環[3.2.1]辛-5-基-(3·甲氧基苯基）曱基](2_ 氯-3_二氟甲基）苯曱醯胺； • N-[6-氮雜雙環[3·2·1]辛-5-基-(3-羥基苯基）甲基](2-氯_3_ Θ 二氣曱基）笨甲醯胺； Ν-[(6-氮雜雙環[3.2.1]辛-5-基）-(3-羥基苯基）曱基](2,6_ 二氯-3-三氟曱基）苯曱醯胺； N-[(6-氮雜雙環[3.2.1]辛-5-基）-間曱苯基曱基](2-氯_3-二氟甲基）笨甲醯胺及其鹽酸鹽； 2-氣-N-[(6_乙基_6_氮雜雙環[321]辛_5_基）苯基甲基](3_ 二氟^曱基）笨曱醢胺； N_[(6-氮雜雙環[3 21]辛-5_基-間曱苯基甲基](2,6_二氯_ 〇 3_二氟甲基）苯曱醯胺； 2_氣-N-[(6_甲基_6_氮雜雙環[3 2丨]辛_5_基）苯基甲基](3_ 一氟甲基）苯甲醯胺及其鹽酸鹽； N_[(6-氮雜雙環[3 21]辛_5基）_(3_溴苯基）甲基](2_氣-3_ 二氟甲基）笨甲醯胺及其鹽酸鹽； N-[⑻氮雜雙環[3.2」]辛_5_基）(3_漠苯基）甲基](2,6_二 氯3 一氟甲基）笨甲醯胺及其鹽酸鹽； /七遣雜雙環[3·2.1]辛i基-(3-三氟甲基苯基）甲基](2_ 氯-3-二氟甲基）苯甲酿胺及其鹽酸鹽； 145867.doc -11 - 201034667 (+)-2,6-二氣-N-[(6-乙基_6_氮雜雙環[3 21]辛_5_基）笨基 甲基](3-三氟甲基）苯甲醯胺及其鹽酸鹽； 2-氣-N-[(6-乙基-6-氮雜雙環[3.21]辛_5_基）_(3_三氟甲基 苯基）甲基](3-三氟曱基）苯甲醯胺及其鹽酸鹽。 本發明之化合物具有作為GlyT1甘胺酸轉運體之抑制劑 的特定活性，尤其是經改良之活性及安全性質。 该等通式（I)化合物可藉由闡述於下之反應圖方法製 備。 反應囷1Ri is not a stupid group, and is optionally substituted with one or more substituents independently selected from a halogen atom or a methyl group, an ethyl group, a trifluoromethyl group, a methoxy group or a trans group; and -I represents one or A plurality of substituents selected from a hydrogen atom, a halogen atom or a trifluoromethyl group, a methyl group, a decyloxy group or an ethyl group. Compositions of the first to seventh categories defined above are also part of the present invention. σ Among the compounds of the formula (I) which are subject of the present invention, the following compounds may be specifically mentioned: Ν-[(6-azabicyclo)phenylindolyl](2-methyl-3-trifluoromethyl) Benzoylamine; U5867.doc 201034667 N-[(6-Azabicyclo[3.2.1;^_5_yl)phenylmethyl](3methoxy-2-methyl)benzamide; # N-[(6-azabicyclo[3.2n5-yl)phenylindenyl](2,6-dichlorodongtrifluoromethyl)benylamine and its hydrochloride; N-[6-aza Bicyclo[3.21]oct-5yl)phenylmethyl](2_chloro-3-3-trimethylmethyl)benzamide and its hydrochloride; cadaveric (+)-N-[(6-azabicyclo) [3 21] oct-5-yl) phenylmethyl-methyl chlorotrifluoromethyl) benzylamine and its hydrochloride; -(a)-N diazabicyclo[3.21]oct-5-yl)benzene (2 6_Dichloro_3_difluoromethyl)phenyl hydrazine and its hydrochloride; 〇 ( (6-azabicyclo[3.2·^ _5_yl)phenylmethyl] 2 gas small trifluoromethyl benzyl benzyl amide and its hydrochloride; ( + )-N-[(6-azabicyclo)phenylmethyl] (2,6-dichloro_3_difluoromethyl) Benzobenzamide and its hydrochloride; N-K6-azabicyclo[3.2.^:yl)phenylindenyl]& gas: ethylsulfonyl-2-pyrene Oxyphenyl)benzamide and its hydrochloride; N-[(6-azabicyclo)phenylmethyl](2_chloro-5(trifluoromethyl)benzamide and its hydrochloride Ν·[(6-Azabicyclo)phenylmethyl](2,6_di-p-phenyl)benzamine; N-U6-azabicyclo[3.2.1]oct-5-yl)phenyl曱[]](3_chloro-2-methyl)benzamide; Ν [(6-azabicyclo[3.2.1]oct-5-yl)-(4-fluorophenyl)methyl](2 _Chloro_3_trifluoromethyl)benzamide; I45867.doc •10· 201034667 N_[(6-azabicyclo[3.2.1]oct-5-yl)-(4-fluorophenyl)fluorenyl (2,6-digas_3_difluoroindolyl)benzamine; N_[(6-indolobicyclo[3.2.1]oct-5-yl)-(3-methoxyphenyl) Methyl](2,6-dichloro-3-trifluoromethyl)benzamide; N_[(6·azabicyclo[3.2.1]oct-5-yl-(3.methoxyphenyl) (曱)](2_chloro-3-difluoromethyl)phenylhydrazine; • N-[6-azabicyclo[3·2·1]oct-5-yl-(3-hydroxyphenyl) A (2-Chloro_3_ Θ dihalofluorenyl) benzoate; Ν-[(6-azabicyclo[3.2.1]oct-5-yl)-(3-hydroxyphenyl)indolyl] (2,6-dichloro-3-trifluoromethyl)benzamide; N-[(6-azabicyclo[3.2.1]oct-5-yl) - m-phenylphenyl hydrazino](2-chloro-3-trifluoromethyl) benzoic acid and its hydrochloride; 2-gas-N-[(6-ethyl-6-azabicyclo[321] ] 辛_5_yl)phenylmethyl](3_difluoro(fluorenyl) hydrazinamine; N_[(6-azabicyclo[3 21]oct-5-yl-m-phenylenemethyl] (2,6-dichloro- 〇3_difluoromethyl)benzamide; 2_gas-N-[(6-methyl-6-azabicyclo[3 2丨]oct-5_yl) Phenylmethyl](3-monofluoromethyl)benzamide and its hydrochloride; N_[(6-azabicyclo[3 21]oct-5)-(3-bromophenyl)methyl] (2_Gas-3_difluoromethyl) benzomethamine and its hydrochloride; N-[(8)azabicyclo[3.2"]octyl-5-yl)(3_indolyl)methyl](2 , 6-dichloro-3-fluoromethyl) benzoic acid and its hydrochloride; / seven heterobicyclo[3.2.1] octyl-(3-trifluoromethylphenyl)methyl] (2_ Chloro-3-difluoromethyl)benzamide and its hydrochloride; 145867.doc -11 - 201034667 (+)-2,6-digas-N-[(6-ethyl_6_aza Bicyclo[3 21]octyl-5-yl) phenylmethyl](3-trifluoromethyl)benzamide and its hydrochloride; 2-gas-N-[(6-ethyl-6-nitrogen) Heterobicyclo[3.21]octyl-5-yl)-(3-trifluoromethylphenyl)methyl](3-trifluoromethyl) A Amides and its hydrochloride. The compounds of the present invention have specific activities as inhibitors of GlyT1 glycine transporters, especially improved activity and safety properties. The compounds of the formula (I) can be prepared by the reaction schemes set forth below. Reaction 囷1

利用熟悉此項技術者已知之方法將通式（11)二胺（其中R 及1係如上定義，尤其係當R表示氫原子或烯丙基或苯基 曱基時）與通式（III)之活化酸偶合，例如經由混合酸酐或酸 乳化物’纟中γ表示自（例如）苯并三嗤、酿基脈或_素原 子衍生之離去基團且R2係如上定義。 通式（I)化合物（其中R表示氫原子）亦可自其中尺表示下者 之通式（I)化合物製備： -苯基甲基，藉由氫解反應脫除氮之保護基； 145867.doc 12· 201034667 烯基較佳為烯丙基，其係根據熟悉此項技術者已 知之方法，例如：經由鈀（〇)錯化物脫除氮之保護基。The diamine of the formula (11) wherein R and 1 are as defined above, especially when R represents a hydrogen atom or an allyl or phenylfluorenyl group, and the formula (III) are known by a method known to those skilled in the art. The activated acid coupling, for example via a mixed anhydride or acid emulsion 'gamma', represents a leaving group derived from, for example, a benzotriazole, a cyclyl or a sulfonium atom and R2 is as defined above. The compound of the formula (I) wherein R represents a hydrogen atom can also be prepared from a compound of the formula (I) wherein the ruthenium represents the following: - phenylmethyl, a protecting group for the removal of nitrogen by hydrogenolysis; 145867. Doc 12· 201034667 The alkenyl group is preferably an allyl group, which is a method known to those skilled in the art, for example, a protecting group for removing nitrogen via a palladium (hydrazine) complex.

及等通式（I)中R不為氫原子之化合物亦可根據熟悉此項 技術=已知之方法’自通式⑴中尺表示氫原子之化合物開 始，藉由在礦物鹼的存在下（例如碳酸鉀之乙腈溶液），與 RX類型之函化物或甲磺酸鹽進行烷基化（其中尺係如上定 義且X係甲磺酸根或鹵素），或經由埃謝偉勒-克萊克 (Eschweiler-Clarke)反應或與適宜醛或酮進行還原性胺化 作用而製備。 該等通式（1)中1為經羥基取代之苯基之化合物可利用熟 悉此項技術者已知之方法，自相應的經甲氧基取代之通式 (I)化合物獲得。 通式（II)二胺可藉由以下針對胺（IIa)及（IIb)的反應圖2及 針對胺（lie)的反應圖3所說明之方法製備。 反應圖2And a compound of the formula (I) wherein R is not a hydrogen atom can also be started according to a method known in the art = known method from a compound having a hydrogen atom in the formula (1), in the presence of a mineral base (for example Alcoholization of potassium carbonate in acetonitrile) with RX type of methanide or methanesulfonate (where the ruler is as defined above and X system mesylate or halogen), or via Eschweiler-Eckweiler- Clarke) is prepared or reacted with a reductive amination of a suitable aldehyde or ketone. The compound of the formula (1) wherein 1 is a hydroxy-substituted phenyl group can be obtained from the corresponding methoxy-substituted compound of the formula (I) by a method known to those skilled in the art. The diamine of the formula (II) can be produced by the following method for the reaction of the amines (IIa) and (IIb) and the reaction of the amine (lie) shown in Fig. 3. Reaction diagram 2

❹ 145867.doc •13- 201034667 根據反應圖2，可於醚類溶劑中（諸如四氫呋喃或乙 醚），在低溫下（例如在-7〇°C下），使式（IVa)腈與通式（v)之 經化芳族化合物反應’其中心係如上定義。如此獲得亞 胺，其特定言之係於質子溶劑（諸如甲醇），佶田、署sλ τ并J，使用還原劑（諸 如硼氫化鈉）進行非立體選擇性還原，以得到通式（na)之 胺。該胺（Ha)可在把觸媒的存在下經由氫化反應脫除节 基，提供脫除保護基之胺（IIb)(反應圖2)。 根據反應圖3 ’亦可於醚類溶劑中（諸如四氣吱。南或乙 醚）’在低溫下（例如在-70°C下），使式（IVc)腈與通式⑺之 鋰化芳族化合物反應’其中R】係如上定義。如此獲得亞 胺，其係於質子溶劑（諸如甲醇）中經還原劑（諸如硼氫化 鈉）還原，以得到通式（lie)之胺（反應圖3)。 此外’通式（I)之對掌性化合物可藉由外消旋化合物經由 對掌性管柱進行高效液相層析法（HPLC)分離，或經由通式 (Ila)胺之對掌性非對映異構體進行矽膠層析法分離，繼而 脫除苄基而獲得，如反應圖2中所述。 式（IVa)腈係根據闡述於 Tetrahedron : Asymmetry，2006 (17) ’ 252-258中之方法而製備，且式（IVc)腈係根據此相 同的參考文獻，使用烯丙基胺合成。 通式（V)之經化芳基化合物可根據熟悉此項技術者已知 之方法製備。 此等通式（III)之酸及酸氣化物係可購得或藉由類似於熟 悉此項技術者已知之方法而製備。 【實施方式】 145867.doc •14- 201034667 以下實例闡釋某些本發明化合物之製備。在此等實例 中： -元素微量分析法、IR&NMR光譜與對掌性管柱HPLC可 確定所獲得化合物之結構及對映異構體純度。 -對於NMR說明書中，「m」表示多重峰，「s」表示單重 峰，「t」表示三重峰，「d」表示雙重峰，「q」表示四重 峰，dxd表示雙組雙重峰’ txt表示三組三重峰，dxt表示雙 組三重峰等。 -實例標題之括弧中所指出的數字對應於下表的第一 欄。 -術語「decomp.」表示「分解」。 -圓括弧中之羅馬數字對應於在合成反應圖中所指出之 相應通式。 -所用系統命名法係根據IUPAC(國際純粹與應用化學聯 合會(International Union 〇f pure and Applied Chemistry))建議之系統 命名法。 在化合物的名稱中，短折號r _」係單詞的一部份且該 短折號「-」僅用於在該列的末端中斷時；若沒有中斷時 應將其刪除，且不應改用常見短折號或空格替代。 實例1(第3號化合物）：义[(6-氮雜雙環[3.2.1]辛-5-基）苯基 甲基](2,6-二氯-3-三氟甲基）苯甲醯胺鹽酸鹽（丨：丨）。 1.1苯基_[6-((R)-l-苯基乙基）_6_氮雜雙環[3 2…辛基】 甲基胺（Ila)。 將含1层6-((11)-1-苯基乙基）_6-氮雜雙環[3.2.1]辛烷_5-甲 145867.doc -15- 201034667 腈（IVa)(4.16 mmol)之35 ml無水四氫咬喃溶液置於_7〇。〇及 氬氣下之100 ml三頸燒瓶中。逐滴添加7.4 ml苯基鋰（8.32 mmol)之1.13M溶液（環己烷/乙醚）。 該混合物在-7 0 C下放置兩個半小時，之後在_ 2 〇 t下用 15 ml的水水解。 在萃取之後，將有機相在減壓下濃縮，用2〇 ml甲醇提 取殘質。逐份添加0.79 g硼氫化鈉（20.8 mmol)。將反應介 質在周圍溫度下攪拌過夜。 在減壓下蒸發之後’用50 ml乙醚及50 ml水提取殘質。 用1N鹽酸溶液酸化介質，之後萃取。水相經氨水驗化，隨 後用50 ml的二氣甲烷再萃取兩次。將有機相合併，用硫 酸鈉乾燥，過濾及在減壓下蒸發。因此獲得丨·5 g的油，其 在矽膠管柱上層析（藉由使用二氣甲烷與甲醇之混合物洗 提）而純化。因此，獲得呈油形式之丨.15 g的苯基 1-苯基乙基）-6-氮雜雙環[3.2.1]辛-5-基]甲基胺（Ila)，係2 種對掌性非對映異構體之混合物。 1.2 (6-氮雜雙環【3.2.1】辛-5-基）苯基甲基胺（nb)。 將於80 ml的甲醇中之4 g的式（Ila)化合物（12.5 mmol)在 一刮勺尖_的20%氫氧化把之存在下’於4大氣麼氫氣下， 且在周圍溫度下，置於帕爾（parr)燒瓶中6小時。 在將觸媒過濾及在減壓下蒸發該濾液之後，殘質用1〇 ml的二氯曱烷及20 ml的氨水提取。在萃取之後，將有機 相用氣化鈉飽和溶液沖洗，用硫酸鈉乾燥，過濾，隨後將 該溶劑在減壓下蒸發，因此，獲得1 g呈油形式之式 145867.doc -16- 201034667 (nb)(6-氮雜雙環基）苯基甲基胺’其可在隨後 的步驟中以粗製形式使用。 藉由鹼與2N鹽酸之乙醚溶液之成鹽作用，及隨後於乙醚 中研磨而獲得分析樣品。145 145867.doc •13- 201034667 According to the reaction scheme 2, the nitrile of the formula (IVa) can be obtained from the formula (IVa) in an ether solvent (such as tetrahydrofuran or diethyl ether) at a low temperature (for example, at -7 ° C). The trans-aromatic reaction of v) 'the center is as defined above. The imine is thus obtained, in particular, in a protic solvent (such as methanol), in the field, in the s λ τ and J, using a reducing agent (such as sodium borohydride) for non-stereoselective reduction to obtain the general formula (na) Amine. The amine (Ha) can be subjected to a hydrogenation reaction to remove a unit group in the presence of a catalyst to provide a deprotecting amine (IIb) (Reaction Figure 2). According to the reaction diagram 3', it is also possible to make the nitrile of the formula (IVc) and the lithiated formula of the formula (7) at a low temperature (for example, at -70 ° C) in an ether solvent (such as tetrakis. South or diethyl ether). The compound reaction 'where R' is as defined above. The imine is thus obtained, which is reduced in a protic solvent such as methanol by a reducing agent such as sodium borohydride to give an amine of the formula (Reaction Figure 3). Further, the 'preferable compound of the formula (I) can be separated by high performance liquid chromatography (HPLC) on the palmar column by a racemic compound, or via a palm of the formula (Ila). The enantiomers were separated by gel electrochromatography followed by removal of the benzyl group as described in Figure 2. The nitrile of the formula (IVa) is prepared according to the method described in Tetrahedron: Asymmetry, 2006 (17) '252-258, and the nitrile of the formula (IVc) is synthesized according to the same reference using allylamine. The arylated compound of the formula (V) can be prepared according to methods known to those skilled in the art. The acids and acid vapors of the formula (III) are commercially available or can be prepared by methods analogous to those known to those skilled in the art. [Examples] 145867.doc • 14- 201034667 The following examples illustrate the preparation of certain compounds of the invention. In these examples: - Elemental microanalysis, IR& NMR spectroscopy and HPLC on the column to determine the structure and enantiomeric purity of the obtained compound. - For the NMR specification, "m" indicates a multiplet, "s" indicates a singlet, "t" indicates a triplet, "d" indicates a doublet, "q" indicates a quadruple, and dxd indicates a double peak. Txt represents three sets of triplet, and dxt represents two sets of triplet. - The numbers indicated in parentheses in the instance header correspond to the first column of the table below. - The term "decomp." means "decomposition". - Roman numerals in parentheses correspond to the corresponding general formulas indicated in the synthetic reaction scheme. - The system nomenclature used is based on the system nomenclature recommended by the IUPAC (International Union 〇f pure and Applied Chemistry). In the name of the compound, the short suffix r _" is part of the word and the short apos "-" is only used when the end of the column is interrupted; if there is no interruption, it should be deleted and should not be changed. Replace with a common short apos or space. Example 1 (Compound No. 3): [[6-Azabicyclo[3.2.1]oct-5-yl)phenylmethyl](2,6-dichloro-3-trifluoromethyl)benzene Indoleamine hydrochloride (丨:丨). 1.1 Phenyl_[6-((R)-l-phenylethyl)-6-azabicyclo[3 2...octyl]methylamine (Ila). Will contain 1 layer of 6-((11)-1-phenylethyl)-6-azabicyclo[3.2.1]octane-5-methyl 145867.doc -15- 201034667 nitrile (IVa) (4.16 mmol) A 35 ml anhydrous tetrahydrogenate solution was placed at _7 Torr. 〇 and 100 ml three-necked flask under argon. A solution of 7.4 ml of phenyllithium (8.32 mmol) in 1.13 M (cyclohexane / diethyl ether) was added dropwise. The mixture was allowed to stand at -7 0 C for two and a half hours before being hydrolyzed with 15 ml of water at _ 2 〇 t. After the extraction, the organic phase was concentrated under reduced pressure and residue was taken from 2 hrs of methanol. 0.79 g of sodium borohydride (20.8 mmol) was added portionwise. The reaction medium was stirred overnight at ambient temperature. After evaporation under reduced pressure, the residue was extracted with 50 ml of diethyl ether and 50 ml of water. The medium was acidified with a 1 N hydrochloric acid solution and then extracted. The aqueous phase was verified by aqueous ammonia and then extracted twice with 50 ml of di-methane. The organic phases were combined, dried over sodium sulfate, filtered and evaporated. Thus, 5 g of oil was obtained which was purified by chromatography on a ruthenium column (by elution with a mixture of di-methane and methanol). Thus, 15 g of phenyl 1-phenylethyl)-6-azabicyclo[3.2.1]oct-5-yl]methylamine (Ila) is obtained in the form of an oil, which is a pair of palms. a mixture of diastereomers. 1.2 (6-Azabicyclo[3.2.1]oct-5-yl)phenylmethylamine (nb). 4 g of the compound of formula (Ila) (12.5 mmol) in 80 ml of methanol was placed in the presence of 20% hydroxide in a spatula tip at 4 atmospheres of hydrogen and at ambient temperature. In a parr flask for 6 hours. After filtering the catalyst and evaporating the filtrate under reduced pressure, the residue was extracted with 1 ml of dichloromethane and 20 ml of aqueous ammonia. After the extraction, the organic phase was washed with a saturated solution of sodium sulphate, dried over sodium sulfate, filtered, and then the solvent was evaporated under reduced pressure, thus yielding 1 g of the formula 145867.doc -16 - 201034667 in oil form ( Nb) (6-Azabicyclo)phenylmethylamine 'which can be used in the crude form in the subsequent step. An analytical sample was obtained by salt formation of a base with 2N hydrochloric acid in diethyl ether and then trituration in diethyl ether.

MP=215-225〇C H NMR (400 MHz, DMSO-d6) δ ppm 9.14 (m，4H)，7.76 (m，2H) ’ 7.56-7.43 (m，4H)，5,09 (寬 s，1H)，3.49 (m， 0 1H) ’ 3-U (m，1H) ’ 2.72 (m, 1H)，2.19 (m, 1H)，1.87 (m, 1H) ’ 1.83-1.37 (m, 8H)。 1.3 N-[(6-氮雜雙環卩丄”辛^•基）苯基甲基](26二氣_3_ 三氟甲基）苯曱醢胺鹽酸鹽（1: p。 將含240 mg的（2,6-二氯-3-三氟甲基）苯甲酸（0.92 mmol)、124 mg的羥基苯并三唑（〇92 mmol)及180 mg的1- [3-(二曱基胺基）丙基]·3_乙基碳化二亞胺鹽酸鹽（〇 92 mmol)之5 ml的二氣甲烷溶液置於25 ml的圓底燒瓶中，並 Q 將該混合物在周圍溫度下攪拌15分鐘。將200 mg(0.92 mmol)的式（IIb)(6-氮雜雙環[3.2.1]辛-5-基）苯基甲基胺添 加至5 ml的二氣甲烷溶液中，並將該混合物在周圍溫度下 攪拌過夜。 之後用10 ml的二氯曱烷稀釋該反應介質，隨後連續用 水（5 ml)、1N氫氧化鈉（5 ml)及氣化鈉飽和溶液（5 ml)洗 滌。 將有機相用硫酸納乾燥，過遽並在減壓下蒸發。 殘質在矽膠管柱上層析（以二氯甲烷與甲醇之混合物洗 145867.doc 201034667 提）而純化該殘質。因此，獲得180 mg的N-[(6-氮雜雙環 [3.2.1]辛-5 -基）苯基曱基](2,6-二氯-3 -三氟甲基）苯曱醯 胺’其係藉由將驗溶於二氣甲炫中，添加過量的鹽酸之乙 醚溶液，之後在減壓下濃縮，形成鹽酸鹽形式。MP=215-225〇CH NMR (400 MHz, DMSO-d6) δ ppm 9.14 (m, 4H), 7.76 (m, 2H) ' 7.56-7.43 (m, 4H), 5, 09 (width s, 1H) , 3.49 (m, 0 1H) ' 3-U (m,1H) ' 2.72 (m, 1H), 2.19 (m, 1H), 1.87 (m, 1H) ' 1.83-1.37 (m, 8H). 1.3 N-[(6-Azabicycloindole) octyl)phenylmethyl](26 digas_3_trifluoromethyl)phenylhydrazine hydrochloride (1: p. Will contain 240 mg (2,6-Dichloro-3-trifluoromethyl)benzoic acid (0.92 mmol), 124 mg of hydroxybenzotriazole (〇92 mmol) and 180 mg of 1-[3-(didecylamine) 5 ml of a di-methane solution of propyl]·3_ethylcarbodiimide hydrochloride (〇92 mmol) was placed in a 25 ml round bottom flask, and Q was stirred at ambient temperature. 15 minutes. Add 200 mg (0.92 mmol) of the formula (IIb) (6-azabicyclo[3.2.1]oct-5-yl)phenylmethylamine to 5 ml of di-methane solution and The mixture was stirred overnight at ambient temperature. The reaction medium was then diluted with 10 ml of dichloromethane, followed by continuous washing with water (5 ml), 1N sodium hydroxide (5 ml) and saturated sodium sulfate (5 ml) The organic phase was dried over sodium sulfate, dried and evaporated under reduced pressure. The residue was chromatographed on a silica gel column (washed with a mixture of dichloromethane and methanol 145867.doc 201034667) to purify the residue. , obtaining 180 mg of N-[(6-azabicyclo[3.2.1] octane -5-yl)phenylindolyl](2,6-dichloro-3-trifluoromethyl)benzoguanamine' is prepared by dissolving the test in dioxane and adding an excess of diethyl ether. The solution was then concentrated under reduced pressure to give the hydrochloride salt.

MP=249.5-250.5°C NMR (400 MHz，DMSO-d6) δ ppm 9.79 (m，1H)，9_66 (d，J=9 Hz，1H)，8.86 (m，1H)，8.01 (m，1H)，7·84 (m， 1H)，7.69 (m，2H)，7.50 (m，2H)，7.42 (m，1H)，5.79 (d， J=9.1 Hz, 1H)，3.57 (m，1H)，3.16 (m，1H)，2.69 (m, 1H) ’ 2.16-1.84 (m，3H)，1.77-1.38 (m, 5H)。 實例2(第8號化合物）：（+)_N_[(6_氮雜雙環丨3 2…辛^基） 苯基甲基】-(2,6-二氣-3-三氟甲基）苯甲醢胺鹽酸鹽（1: 2·1·苯基-[6-((R)-l-苯基乙基）_6_氮雜雙環[3 2…辛^基]甲 基胺（Ilal)之第一非對映異構體。 藉由於矽膠上使用二氣曱烷與甲醇之混合物作為洗提液 之分離法，將兩種非對映異構體（IIa)分離。最低極性化合 物係苯基-[6-((R)-l-笨基乙基）_6_氮雜雙環[3 2辛_5_基] 甲基胺（Ilal)。 lH NMR (400 MHz, DMSO-d6) δ ppm 7.47 (m, 4H) > 7.39-7.17 (m，6H) ’ 4.26 (s，1H)，4.23 (m，1H)，3.17 (m, 1H)，3.56 (d，J=8.7 Hz, 1H)，2.28 (m，1H)，2.07 (m, 1H) ’ 2.00 (m，2H)，1.65 (m, ih)，1.54 (d，J=6.8 Hz, 3H)，1.28-0.86 (m，6H)。 2·2· (+)-(6-氮雜雙環丨3.21】辛_5基）苯基甲基胺對映 145867.doc -18- 201034667 異構體。 該化合物係根據實例12，以式（IIal)化合物 ’吳始物而 獲得。 式（Ilbl)化合物係呈鹼形式。 MP=84-85〇C ee= 1 00% [aD] 2〇°c CHCl3=+55.2 c=0.80 g/100 ml H NMR (400 MHz, CDCI3) δ ppm 7.29-7.13 (m 5H) 3.72 (s，1H)，3.01 (m, J=5.4 Hz及 10 Hz, 1H)，2.87 (m J=1〇MP=249.5-250.5°C NMR (400 MHz, DMSO-d6) δ ppm 9.79 (m, 1H), 9_66 (d, J=9 Hz, 1H), 8.86 (m, 1H), 8.01 (m, 1H) ,7·84 (m, 1H), 7.69 (m, 2H), 7.50 (m, 2H), 7.42 (m, 1H), 5.79 (d, J = 9.1 Hz, 1H), 3.57 (m, 1H), 3.16 (m, 1H), 2.69 (m, 1H) ' 2.16-1.84 (m, 3H), 1.77-1.38 (m, 5H). Example 2 (Compound No. 8): (+)_N_[(6-azabicycloindole 3 2...indolyl)phenylmethyl]-(2,6-dioxa-3-trifluoromethyl)benzene Formamide hydrochloride (1: 2·1·phenyl-[6-((R)-l-phenylethyl)-6-azabicyclo[3 2...indolyl]methylamine (Ilal) The first diastereomer. The separation of the two diastereomers (IIa) is carried out by using a mixture of dioxane and methanol as the eluent on the tannin. The lowest polar compound is benzene. -[6-((R)-l-stylethyl)_6-azabicyclo[3 2 octyl-5-yl]methylamine (Ilal). lH NMR (400 MHz, DMSO-d6) δ ppm 7.47 (m, 4H) > 7.39-7.17 (m,6H) ' 4.26 (s,1H), 4.23 (m,1H), 3.17 (m, 1H), 3.56 (d, J=8.7 Hz, 1H), 2.28 (m,1H), 2.07 (m, 1H) ' 2.00 (m, 2H), 1.65 (m, ih), 1.54 (d, J = 6.8 Hz, 3H), 1.28-0.86 (m, 6H). · 2 · (+)-(6-azabicycloindole 3.21) octyl-5 phenylmethylamine enantiomer 145867.doc -18- 201034667 isomer. This compound is according to Example 12, with formula (IIal The compound 'Ilbl' is obtained in the form of a base. MP=84-85 C ee = 1 00% [aD] 2〇°c CHCl3=+55.2 c=0.80 g/100 ml H NMR (400 MHz, CDCI3) δ ppm 7.29-7.13 (m 5H) 3.72 (s,1H), 3.01 ( m, J=5.4 Hz and 10 Hz, 1H), 2.87 (m J=1〇

Hz及 1 Hz，1H), 2.25 (m, 1H)，1.83 (m，1H)，i.7〇 (m，3H) 1.58 (m，1H)，1.52-1.39 (m，2H), 1.31-1.08 (m，4H)。 2.3 (+)-Ν-[(6·氮雜雙環[3.2.1】辛-5-基）苯基甲基】（26二氣· 3-三氟甲基）苯甲醢胺鹽酸盥（1 : 該化合物係根據實例1.3 ’以式（ilbl)化合物為起始物而 獲得。獲得呈鹽酸鹽形式之分析樣品’其藉由將驗溶於二 氯曱烷中、添加過量的1N鹽酸之乙醚溶液，之後在減壓下 濃縮而獲得。 MP: 241-242〇C ee ： 95% [aD] 2〇c MeOH=+30.7 c=0.75 g/100 ml *H NMR (400 MHz, DMSO-d6) δ ppm 9.62 (d; j=8.9 Hz, 1H)，9_42 (m，1H)，8,84 (m，1H)，7.97 (m, lH), 7 8〇 (m, 1H)，7.59 (m，2H), 7.46 (m, 2H)，7.39 (m，1H)，5.70 (寬d， J=9 Hz，1H), 3.49 (m，1H), 3.13 (m，1H)，2.65 (m, 1H), •19- 145867.doc 201034667 2.11-1.20 (m, 9H) 實例3(第6號化合物）：（_)_沁丨(6_氮雜雙環[3.2.1】辛-5-基） 苯基甲基卜(2,6-二氣-3-三氟甲基）苯甲醢胺鹽酸鹽q : i)。 3.1苯基-[6-((R)-l-苯基乙基）_6_氮雜雙環[3.2.1】辛_5_基j甲 基胺（IIa2)之第二非對映異構體。 藉由於矽膠上使用二氯甲烷與曱醇之混合物作為洗提液 之分離法’將該2種式（na)非對映異構體分離。最高極性 化合物為苯基-C-[6-((R)-l -笨基乙基）-6-氮雜雙環[3.2.1] 辛-5-基]甲基胺（Ila2)。 !H NMR (400 MHz, DMSO-d6) δ ppm 7.46 (m, 2H), 7.34 (m, 2H), 7.29-7.14 (m, 6H), 4.23 (q, J=6.8 Hz, 1H), 3.56 (m, 1H), 3.21 (m, 1H), 3.06 (m, 1H), 2.26 (m, 1H), 2.19 (m, 2H), 1.75 -1.16 (m，10H)，0.89 (m，2H)。 3.2 (-)-(6-氮雜雙環[3.2.1】辛_5_基）苯基甲基胺（IIb2)對映 異構體。 該化合物係根據實例1.2，以式（na2)化合物為起始物而 獲得。 式（IIb2)化合物係呈鹼形式。 MP = 82.5-83.5〇C ee=93% [α〇] 2〇c CHC13=-18.30 c=0.58 g/l〇〇 ml 'H NMR (400 MHz, CDC13) δ ppm 7.29-7.13 (m, 5H), 3.72 (s, 1H), 3.02 (m, J = 5.4 Hz及 10 Hz, 1H), 2.88 (m, J=10 Hz及 1 Hz, 1H)，2.25 (m，1H), 1.83 (m, 1H), 1.70 145867.doc -20· 201034667 (m, 3H), 1.59 (m, 1H)> ^52-1.39 (m, 2H), 1.33-1.08 (m, 4H)。 ’ 3·3 (_)_N_[(6-氮雜雙環[3.2.1]辛-5·基）苯基甲基](2,6-二氣_ 3_二氟甲基）苯甲醢胺鹽酸鹽（1: 1)。 該化合物係根據實例1.3 ’以式（IIb2)化合物為起始物而 獲得。Hz and 1 Hz, 1H), 2.25 (m, 1H), 1.83 (m, 1H), i.7〇(m, 3H) 1.58 (m, 1H), 1.52-1.39 (m, 2H), 1.31-1.08 (m, 4H). 2.3 (+)-Ν-[(6·Azabicyclo[3.2.1]oct-5-yl)phenylmethyl](26 digas·3-trifluoromethyl)benzamide guanidine hydrochloride (1 This compound was obtained according to the example 1.3' starting from the compound of the formula (ilbl). An analytical sample in the form of the hydrochloride salt was obtained, which was dissolved in dichloromethane by adding an excess of 1N hydrochloric acid. A solution of diethyl ether was obtained after concentration under reduced pressure. MP: 241-242 〇C ee : 95% [aD] 2 〇 MeOH = +30.7 c = 0.75 g / 100 ml *H NMR (400 MHz, DMSO-d6 δ ppm 9.62 (d; j=8.9 Hz, 1H), 9_42 (m, 1H), 8, 84 (m, 1H), 7.97 (m, lH), 7 8 〇 (m, 1H), 7.59 (m) , 2H), 7.46 (m, 2H), 7.39 (m, 1H), 5.70 (width d, J = 9 Hz, 1H), 3.49 (m, 1H), 3.13 (m, 1H), 2.65 (m, 1H) ), • 19- 145867.doc 201034667 2.11-1.20 (m, 9H) Example 3 (Compound No. 6): (_)_沁丨(6_Azabicyclo[3.2.1]oct-5-yl) Benzene Methyl bromide (2,6-dioxa-3-trifluoromethyl)benzamide hydrochloride q : i). 3.1 phenyl-[6-((R)-l-phenylethyl)-6-azabicyclo[3.2.1] osin-5-yl-j-methylamine (IIa2) second diastereomer . The two diastereomers of the formula (na) are separated by the separation of the mixture of methylene chloride and decyl alcohol as the eluent. The most polar compound is phenyl-C-[6-((R)-l-phenylethyl)-6-azabicyclo[3.2.1]oct-5-yl]methylamine (Ila2). !H NMR (400 MHz, DMSO-d6) δ ppm 7.46 (m, 2H), 7.34 (m, 2H), 7.29-7.14 (m, 6H), 4.23 (q, J=6.8 Hz, 1H), 3.56 ( m, 1H), 3.21 (m, 1H), 3.06 (m, 1H), 2.26 (m, 1H), 2.19 (m, 2H), 1.75 -1.16 (m, 10H), 0.89 (m, 2H). 3.2 (-)-(6-Azabicyclo[3.2.1]oct-5-yl)phenylmethylamine (IIb2) enantiomer. This compound was obtained according to Example 1.2 using the compound of formula (na2) as a starting material. The compound of the formula (IIb2) is in the form of a base. MP = 82.5-83.5〇C ee=93% [α〇] 2〇c CHC13=-18.30 c=0.58 g/l〇〇ml 'H NMR (400 MHz, CDC13) δ ppm 7.29-7.13 (m, 5H) , 3.72 (s, 1H), 3.02 (m, J = 5.4 Hz and 10 Hz, 1H), 2.88 (m, J=10 Hz and 1 Hz, 1H), 2.25 (m, 1H), 1.83 (m, 1H) ), 1.70 145867.doc -20· 201034667 (m, 3H), 1.59 (m, 1H)> ^52-1.39 (m, 2H), 1.33-1.08 (m, 4H). ' 3·3 (_)_N_[(6-Azabicyclo[3.2.1]oct-5-yl)phenylmethyl](2,6-digas_3_difluoromethyl)benzamide Hydrochloride (1: 1). This compound was obtained according to the Example 1.3' starting from the compound of the formula (IIb2).

MP: 192-193〇C ee = 92% [aD]2〇°c Me〇H=-40.5o c=0.194 g/100 ml lU NMR (400 MHz, DMSO-d6) δ ppm 9.61 (d, J=8.6 Hz, 1H)，9.54 (m，1H)，8.83 (m，1H), 7.97 (m, J=8.8 Hz, 1H), 7.79 (m, 1H), 7.60 (m, 2H), 7.46 (t, J=7.7 Hz, 2H), 7.38 (m, 1H), 5.71 (d, J=8.5 Hz, 1H), 3.49 (m, 1H), 3.13 (m, 1H), 2.65 (m，1H)，2.11-1.78 (m, 3H), 1.71-1.22 (m，6H)。 實例4(第20號化合物）.2-氣-N-[(6-乙基-6-氣雜雙環[3.2.1】 辛_5_基）苯基甲基】（3_三氟甲基）苯甲醢胺。 將於4 ml乙腈中之0.17 g的N-[(6-氮雜雙環[3.2.1]辛-5-基）笨基甲基](2-氯-3-三氟甲基）苯甲酿胺（0.40 mmol)及 0.084 g的碳酸鉀（0.60 mmol)置於25 ml的圓底燒瓶中，並 將50 μΐ的峨乙烧（0.60 mmol)添加至其中。 將反應介質在周圍溫度下授拌過夜，之後在5〇下授摔 3小時’隨後在減壓下濃縮。繼而用1 〇 m丨的二氣曱烷稀釋 殘質，隨後用水（5 ml)洗務。 在萃取之後’將有機相用硫酸鈉乾燥、過遽及在減壓下 145867.doc -21 - 201034667 濃縮。因此，獲得158 mg的油，其係藉由在矽膠管柱上層 析（藉由使用二氯甲烷與曱醇之混合物洗提）而純化。因 此，獲得84 mg呈粉狀形式之2_氣^_[(6_乙基_6_氮雜雙環 [3.2.1]辛-5-基）苯基甲基](3-三氟甲基）苯甲醯胺。MP: 192-193 〇C ee = 92% [aD]2〇°c Me〇H=-40.5oc=0.194 g/100 ml lU NMR (400 MHz, DMSO-d6) δ ppm 9.61 (d, J=8.6 Hz, 1H), 9.54 (m, 1H), 8.83 (m, 1H), 7.97 (m, J = 8.8 Hz, 1H), 7.79 (m, 1H), 7.60 (m, 2H), 7.46 (t, J =7.7 Hz, 2H), 7.38 (m, 1H), 5.71 (d, J=8.5 Hz, 1H), 3.49 (m, 1H), 3.13 (m, 1H), 2.65 (m,1H),2.11-1.78 (m, 3H), 1.71-1.22 (m, 6H). Example 4 (Compound No. 20). 2-Gas-N-[(6-ethyl-6-oxabicyclo[3.2.1]oct-5-yl)phenylmethyl](3-trifluoromethyl) Benzoguanamine. 0.17 g of N-[(6-azabicyclo[3.2.1]oct-5-yl)phenylmethyl](2-chloro-3-trifluoromethyl)benzene in 4 ml of acetonitrile Amine (0.40 mmol) and 0.084 g of potassium carbonate (0.60 mmol) were placed in a 25 ml round bottom flask, and 50 μM of succinimide (0.60 mmol) was added thereto. The reaction medium was stirred overnight at ambient temperature and then dropped for 3 hours at 5 Torr' followed by concentration under reduced pressure. The residue was then diluted with 1 〇 m丨 of dioxane and then washed with water (5 ml). After the extraction, the organic phase was dried over sodium sulfate, dried and concentrated under reduced pressure 145867.doc -21 - 201034667. Thus, 158 mg of oil was obtained which was purified by layering on a ruthenium tube column (by eluting with a mixture of dichloromethane and decyl alcohol). Thus, 84 mg of 2_gas^_[(6-ethyl-6-azabicyclo[3.2.1]oct-5-yl)phenylmethyl](3-trifluoromethyl) is obtained in powder form. Benzoguanamine.

MP: 160-162〇C H NMR (400 MHz, DMSO-d6) δ ppm 8.60 (d, J=7.7 Hz, 1H), 7.92 (m, 1H), 7.63 (m, 2H), 7.43-7.21 (m, 5H), 4.93 (d, J=7.7 Hz, 1H), 3.41 (m, 1H), 2.82 (m, 1H), 2.62-2.39 (m，2H), 2·20 (m, 2H), 1.72 (m, 1H), 1.53-0.84 (m, 9H)。 實例5(第22號化合物）：2_氣-]\-[(6-甲基-6-氮雜雙環[3.2.1] 辛-5-基）苯基甲基](3-三氟甲基）苯甲醯胺鹽酸鹽（1 : 將含0.127 g N-[(6-氮雜雙環[3.2.1]辛-5-基）苯基甲基](2-氣-3-三氟甲基）苯甲酿胺（〇.3〇 mmol)及1 ml曱酸之2 ml甲 酸置於25 ml圓底燒瓶中。將反應混合物在1 〇〇°c下加熱過 夜。冷卻後，將介質水解，用氨水鹼化至pH 9，隨後用乙 酸乙酯萃取。將有機相用硫酸鈉乾燥、過濾並在減壓下蒸 發。 殘質於矽膠管柱上藉由層析（使用二氯曱烷與甲醇之氨 溶液之混合物洗提）而純化。因此獲得113 mg油狀物，其 係藉由將驗溶於二氣甲烧中，添加過量的1N鹽酸之乙鍵溶 液，之後減壓濃縮，形成鹽酸鹽形式。MP: 160-162〇CH NMR (400 MHz, DMSO-d6) δ ppm 8.60 (d, J=7.7 Hz, 1H), 7.92 (m, 1H), 7.63 (m, 2H), 7.43-7.21 (m, 5H), 4.93 (d, J=7.7 Hz, 1H), 3.41 (m, 1H), 2.82 (m, 1H), 2.62-2.39 (m, 2H), 2·20 (m, 2H), 1.72 (m , 1H), 1.53-0.84 (m, 9H). Example 5 (Compound No. 22): 2_gas-]\-[(6-methyl-6-azabicyclo[3.2.1]oct-5-yl)phenylmethyl](3-trifluoromethyl) Benzomethane hydrochloride (1: will contain 0.127 g of N-[(6-azabicyclo[3.2.1]oct-5-yl)phenylmethyl](2-a-3-trifluoro) Methyl)benzamide (〇.3〇mmol) and 1 ml of citric acid 2 ml of formic acid were placed in a 25 ml round bottom flask. The reaction mixture was heated overnight at 1 ° C. After cooling, the medium was cooled. Hydrolysis, basification with aqueous ammonia to pH 9, followed by extraction with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and evaporated under reduced pressure. It was purified by eluting with a mixture of methanolic ammonia solution. Thus, 113 mg of an oil was obtained by dissolving the test in a gas-fired methane, adding an excess of 1 N hydrochloric acid in a solution of the ethyl bond, followed by concentration under reduced pressure. The hydrochloride form is formed.

MP: 186-188〇C 'Η NMR (400 MHz, DMSO-d6) δ ppm 10.20 (m，1H)， 9.34 (d, J=9.8 Hz, 1H), 8.06 (d, J=7.7 Hz, 1H), 7.97 (d, J=7.7 Hz, 1H), 7.68 (m, 3H), 7.53-7.38 (m, 3H), 5.74 (d, 145867.doc -22· 201034667 J=9.8 Hz, 1H), 4.16 (m, 1H), 3.10 (m, 1H), 2.73-2.50 (m, 4H)，2.40 (m，1H), 2.10-1.38 (m, 7H)。 實例6(第23號化合物）：N-丨(6-氮雜雙環【3.2.1]辛-5-基）_(3_ 溴苯基）甲基】(2-氣-3-三氟甲基）苯甲醯胺鹽酸鹽（1 : 1)。 6.1. 6-烯丙基-6-氮雜雙環[3.2.1】辛烷-5-甲腈（IVc)。 將0.5 g 3 -氣甲基環己酮（3.4 mmol)、3 ml無水甲醇、 0.93 ml丙酮氰醇（ίο.2 mmol)及0.26 ml的烯丙基胺（3 4 mmol)置於在氬氣下之5 ml密封管中。反應混合物在ι〇(Γ(： 下加熱3天。在冷卻之後，將該反應介質傾至10加的1^^氫 氧化鈉水溶液中。在用二氯甲烷萃取兩次之後，將合併的 有機相用氣化鈉飽和溶液沖洗，用硫酸鈉乾燥，過攄，隨 後將該溶劑在減壓下蒸發。殘質於矽膠管柱上藉由層析 (使用石油醚與乙酸乙酯之混合物洗提）而純化。因此，獲 得426 mg呈油狀之6_烯丙基_6_氮雜雙環[3 2.丨]辛烷_5_甲腈 (IVc)。 〇 !H NMR (400 MHz, DMSO-d6) δ ppm 8.60 (d, J=7.7 Hz 1H)，7.92 (m，1H)，7.63 (m，2H)，7.43-7.21 (m, 5H)，4.93 (d, J=7.7 Hz, 1H), 3.41 (m，1H), 2.82 (m，1H), 2.62-2.39MP: 186-188〇C 'Η NMR (400 MHz, DMSO-d6) δ ppm 10.20 (m,1H), 9.34 (d, J=9.8 Hz, 1H), 8.06 (d, J=7.7 Hz, 1H) , 7.97 (d, J=7.7 Hz, 1H), 7.68 (m, 3H), 7.53-7.38 (m, 3H), 5.74 (d, 145867.doc -22· 201034667 J=9.8 Hz, 1H), 4.16 ( m, 1H), 3.10 (m, 1H), 2.73-2.50 (m, 4H), 2.40 (m, 1H), 2.10-1.38 (m, 7H). Example 6 (Compound No. 23): N-indole (6-azabicyclo[3.2.1]oct-5-yl)-(3-bromophenyl)methyl](2-a-3-trifluoromethyl) Benzoguanamine hydrochloride (1:1). 6.1. 6-Allyl-6-azabicyclo[3.2.1]octane-5-carbonitrile (IVc). 0.5 g of 3-methylcyclohexanone (3.4 mmol), 3 ml of anhydrous methanol, 0.93 ml of acetone cyanohydrin (ίο. 2 mmol) and 0.26 ml of allylamine (34 mmol) were placed in argon Under the 5 ml sealed tube. The reaction mixture was heated under 〇 (: (3 days). After cooling, the reaction medium was poured into 10 mL of 1% aqueous sodium hydroxide solution. After extraction twice with dichloromethane, the combined organic The mixture was washed with a saturated solution of sodium sulphate, dried over sodium sulfate, and then evaporated, and then evaporated and evaporated under reduced pressure. The residue was eluted on a silica gel column by chromatography (using a mixture of petroleum ether and ethyl acetate) Purification. Thus, 426 mg of 6-allyl-6-azabicyclo[3.indol]octane-5-carbonitrile (IVc) was obtained as an oil. 〇!H NMR (400 MHz, DMSO -d6) δ ppm 8.60 (d, J=7.7 Hz 1H), 7.92 (m, 1H), 7.63 (m, 2H), 7.43-7.21 (m, 5H), 4.93 (d, J=7.7 Hz, 1H) , 3.41 (m,1H), 2.82 (m,1H), 2.62-2.39

胺（lie)。Amine (lie).

經及5當量硼氫化鈉為起始物而獲得 方法’以1 g 6-稀丙 :)、2.5當量3-溴苯基 。於矽膠管柱上藉由 145867.doc •23· 201034667 層析（使用一氣甲娱•與甲醇之氨溶液之混合物洗提）純化， 獲得含140 mg的（6-烯丙基_6_氮雜雙環[3.2.1]辛-5-基）-(3-溴苯基）甲基胺（IIc)(0.42 mmol)之260 mg油狀物，隨後即 用於接續步驟中。 6.3 N-[(6-烯丙基_6_氮雜雙環[3.2.1】辛_5-基）-(3-溴苯基）甲 基】（2-氣-3-三氟甲基）苯甲醯胺。 將含260 mg (6-烯丙基-6-氮雜雙環[3.2.1]辛-5-基）-(3-溴 苯基）甲基胺（IIc)(0.42 mmol))之8 ml二氣甲烷置於0。(：且在 118 mg碳酸鉀（0.78 mmol)存在下之25 ml圓底燒瓶中。 之後添加189 mg (2-氯-3-三氟）苯曱酸之酸氣化物（0.78 mmol)。反應介質在周圍溫度下授摔過夜。在水解及萃取 之後’將有機相用1N氫氧化鈉沖洗，用硫酸鈉乾燥，過 慮，之後在減壓下濃縮。在碎膠管柱上層析（使用二氯甲 烷與曱醇之氨溶液之混合物洗提）純化後，獲得146 mg呈 油形式之N-[(6-烯丙基-6-氮雜雙環[3.2.1]辛-5-基）-(3-臭苯 基）曱基](2-氣-3-三氟甲基）苯甲醯胺。 H NMR (400 MHz, DMSO-d6) δ ppm 8.68 (d, J=7.7 Hz, 1H), 7,91 (d, J=7.7 Hz, 1H), 7.63 (m, 2H), 7.58 (m, 1H), 7.44 (m, 1H), 7.40 (m, 1H), 7.28 (d, J=7.8 Hz, 1H), 5.81 (m, 1H), 5.22 (m, 1H), 5.00 (m, 1H), 4.97 (d, J=7.7 Hz, 1H), 3.53 (m, 1H), 3.34 (m, 1H), 3.07 (m, 1H), 2.37 (m, 1H)，2.18 (m, 1H), 1.77 (m, 1H), 1.54-0.77 (m, 7H)。 6·4 N-丨(6-氮雜雙環[3.2.1】辛-5-基H3-溴苯基）曱基】（2_氣_ 3-三氟甲基）苯甲醢胺鹽酸鹽。 145867.doc -24- 201034667 將 3 19 mg.(三苯基膦）把（〇 〇2 mmol)及 0.078 g Ν,Ν-二 甲基巴比妥酸（0.5 mmol)之3 ml二氣甲烷溶液置入氬氣下 之密封管中。反應介質先在40t下加熱後，再添加0.09 g 烯丙基-6-氮雜雙環[3.2.1]辛_5_基）-(3-漠苯基）甲 基](2-氣-3-三氟曱基）苯甲醯胺（〇17 mni〇l)至3 ml二氣曱烷 中。冷卻後，用10 ml二氯甲烷稀釋，隨後用5 mi碳酸鈉溶 液水解。 將有機相分離，並用5 ml 1 n鹽酸沖洗兩次。將水相合 併’隨後用氨水鹼化為pH 9，之後用25 ml二氣甲烷萃取 兩次。將有機相用硫酸鈉乾燥，過濾並減壓蒸發。殘質於 矽膠管柱上層析（使用二氯甲烧與曱醇之氨溶液之混合物 洗提）純化。因此，獲得62 mg N-[(6-氮雜雙環[3.2.1]辛-5-基）-(3-溴苯基）甲基](2-氣_3_三氟曱基）苯甲醢胺’其係藉 由將驗溶解於二氯曱烧中，添加過量的1N鹽酸之乙_溶 液’在減壓下濃縮，於乙喊中研製之後，過遽，形成鹽酸 鹽形式。The procedure was carried out with 5 equivalents of sodium borohydride as the starting material to give 1 g 6-dil-propyl :), 2.5 equivalents of 3-bromophenyl. Purification on a ruthenium tube column by 145867.doc •23· 201034667 chromatography (extracted with a mixture of a gas and a solution of ammonia in methanol) to obtain 140 mg of (6-allyl-6-aza Bicyclo[3.2.1]oct-5-yl)-(3-bromophenyl)methylamine (IIc) (0.42 mmol) in 260 mg of oil, which was subsequently used in the next step. 6.3 N-[(6-Allyl-6-azabicyclo[3.2.1]oct-5-yl)-(3-bromophenyl)methyl](2-a-3-trifluoromethyl) Benzoylamine. Will contain 260 mg (6-allyl-6-azabicyclo[3.2.1]oct-5-yl)-(3-bromophenyl)methylamine (IIc) (0.42 mmol)) of 8 ml The methane is placed at zero. (: and in a 25 ml round bottom flask in the presence of 118 mg of potassium carbonate (0.78 mmol). Then add 189 mg (2-chloro-3-trifluoro)benzoic acid acid anhydride (0.78 mmol). After the hydrolysis and extraction, the organic phase was washed with 1N sodium hydroxide, dried over sodium sulfate, and then concentrated under reduced pressure. After elution with a mixture of sterol ammonia solution, 146 mg of N-[(6-allyl-6-azabicyclo[3.2.1]oct-5-yl)-(3) is obtained as an oil. -odorophenyl)indenyl](2-a-3-trifluoromethyl)benzamide. H NMR (400 MHz, DMSO-d6) δ ppm 8.68 (d, J = 7.7 Hz, 1H), 7 , 91 (d, J=7.7 Hz, 1H), 7.63 (m, 2H), 7.58 (m, 1H), 7.44 (m, 1H), 7.40 (m, 1H), 7.28 (d, J=7.8 Hz, 1H), 5.81 (m, 1H), 5.22 (m, 1H), 5.00 (m, 1H), 4.97 (d, J=7.7 Hz, 1H), 3.53 (m, 1H), 3.34 (m, 1H), 3.07 (m, 1H), 2.37 (m, 1H), 2.18 (m, 1H), 1.77 (m, 1H), 1.54-0.77 (m, 7H). 6·4 N-丨(6-azabicyclo[ 3.2.1] oct-5-yl H3-bromophenyl)fluorenyl](2_gas_3-trifluoromethyl)benzamide Hydrochloride. 145867.doc -24- 201034667 3 19 mg. (triphenylphosphine) 3 ml (〇〇2 mmol) and 0.078 g Ν, Ν-dimethylbarbituric acid (0.5 mmol) The two-gas methane solution was placed in a sealed tube under argon. The reaction medium was heated at 40 t, and then 0.09 g of allyl-6-azabicyclo[3.2.1]octyl-5-yl)-(3) was added. - Desert phenyl)methyl](2-a-3-trifluoromethyl)benzamide (〇17 mni〇l) to 3 ml of dioxane. After cooling, it was diluted with 10 ml of dichloromethane and then hydrolyzed with 5 mi of sodium carbonate solution. The organic phase was separated and washed twice with 5 mL 1 n hydrochloric acid. The water was combined and subsequently basified to pH 9 with aqueous ammonia and then extracted twice with 25 ml of di-methane. The organic phase was dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography on a silica gel column (extracted with a mixture of methylene chloride and methanol in methanol). Thus, 62 mg of N-[(6-azabicyclo[3.2.1]oct-5-yl)-(3-bromophenyl)methyl](2-gas_3_trifluorodecyl)benzate was obtained. Indoleamine was prepared by dissolving it in dichlorohydrazine, adding an excess of 1N hydrochloric acid to a solution of 'B', and concentrating under reduced pressure.

MP: 250.5-251.5°C ]H NMR (400 MHz, DMSO-d6) δ ppm 9.62 (m, 1H), 9.45 (d，J=9.2 Hz，1H)，8.94 (m，1H)，7.97 (dxd，及 1.5 Hz, 1H)，7.91 (m, 1H) 7.77 (dxd，J=7.8及 1.4 Hz，1H)，7.67 (t， J=7.6 Hz, 2H)，7.59 (m, J=8 Hz，1H), 7.43 (t，J=7.9 Hz, 2H), 5.74 (d, J=9.1 Hz, 1H), 3.50 (m, 1H), 3.15 (m, 1H), 2.64 (m, 1H), 2.08 (m，1H) 1.94 (m, 1H)，1.80 (m，1H), 1.72-1.40 (m, 5H)。 145867.doc •25· 201034667 列於表1中之其他化合物係根據闡述於實例丨至6中之方 法’自式（Ila)、（lib)、（lic)胺、式（v)裡化化合物、式⑴工) 之竣酸衍生物或適宜炫化劑獲得。 下表1闡述本發明某些化合物之化學結構。 在欄中： -「鹽」攔中之「-」係指呈鹼形式之化合物，「Hc丨」表 示鹽酸鹽，圓括弧中之數字係指（酸：鹼）比率； -該表之化合物係呈經一或多分子水溶劑化之鹽酸鹽形 式。 在此等R、1^及112欄中： -「CI」表示氯； -「CH3」表示甲基； -「NH2」表示胺基； 「OCH3」表示甲氧基； _「Ph」表不苯基； -「S02C2H5」表示乙基續醯基； _「CF3」表示三說甲基；及 -在「R2」行中，取代基前面的數字係指其在通式⑴中 之位置。 表2出示表1中化合物之物理特性、熔點及旋光度。 在表2中： . -「[aD]2〇t：」攔出示在589 nm波長及2〇<t溫度下分析表 中化合物之旋光度結果。圓括弧中所指溶劑相當於用於測 量旋光度（以「度」表示）之溶冑，以及字母「〜係指溶劑 145867.doc -26- 201034667 之濃度，以g/l 〇〇 ml表示。「N.A.」意指無法測得旋光度； -「m/z」櫊係指藉由質譜測定法分析產物而觀察到之 分子態離子（M+H+)或（M+)，其係於以正ESI模式之Agilent LC-MSD Trap型裝置上實施的LC-MS(液相層析偶聯質譜分 析），或直接採用於使用DCI-NH3技術之Autospec Μ (EBE) 裝置上或於使用電子衝擊技術之Waters GCT型裝置上的 MS(質譜分析）。MP: 250.5-251.5 ° C ]H NMR (400 MHz, DMSO-d6) δ ppm 9.62 (m, 1H), 9.45 (d, J = 9.2 Hz, 1H), 8.94 (m, 1H), 7.97 (dxd, And 1.5 Hz, 1H), 7.91 (m, 1H) 7.77 (dxd, J=7.8 and 1.4 Hz, 1H), 7.67 (t, J=7.6 Hz, 2H), 7.59 (m, J=8 Hz, 1H) , 7.43 (t, J = 7.9 Hz, 2H), 5.74 (d, J = 9.1 Hz, 1H), 3.50 (m, 1H), 3.15 (m, 1H), 2.64 (m, 1H), 2.08 (m, 1H) 1.94 (m, 1H), 1.80 (m, 1H), 1.72-1.40 (m, 5H). 145867.doc •25· 201034667 Other compounds listed in Table 1 are based on the methods set forth in Examples 丨 to 6 'from the formula (Ila), (lib), (lic) amine, formula (v) chlorinated compound, Obtained by a decanoic acid derivative of the formula (1) or a suitable stimulator. Table 1 below illustrates the chemical structures of certain compounds of the invention. In the column: - "-" in "salt" means a compound in the form of a base, "Hc" means a hydrochloride, and the number in a parentheses means the ratio of (acid: base); - a compound of the table It is in the form of the hydrochloride salt solvated with one or more molecules of water. In the columns R, 1^ and 112: - "CI" means chlorine; - "CH3" means methyl; - "NH2" means amine; "OCH3" means methoxy; _ "Ph" means benzene Base; - "S02C2H5" means ethyl sulfonate; _ "CF3" means trimethyl; and - in the "R2" row, the number preceding the substituent means its position in the formula (1). Table 2 shows the physical properties, melting point and optical rotation of the compounds in Table 1. In Table 2: . - "[aD]2〇t:" blocks the optical rotation results of the compounds shown in the 589 nm wavelength and 2 〇 <t temperature. The solvent referred to in the parentheses corresponds to the solvent used to measure the optical rotation (in degrees), and the letter "~ refers to the concentration of solvent 145867.doc -26- 201034667, expressed in g/l 〇〇ml. "NA" means that the optical rotation cannot be measured; - "m/z" 櫊 refers to the molecular state ion (M+H+) or (M+) observed by mass spectrometry analysis, which is based on positive ESI LC-MS (liquid chromatography coupled mass spectrometry) performed on a model Agilent LC-MSD Trap type device, or directly on an Autospec® (EBE) device using DCI-NH3 technology or using electron impact technology MS (mass spectrometry) on a Waters GCT type device.

表1Table 1

編號 R Ri r2 鹽 立體化學 1 Η Ph 2-CH3, 3-CF3 - 非對映異構體1， 外消旋 2 Η Ph 2-CH3, 3-OCH3 - 非對映異構體1， 外消旋 3 Η Ph 2,6(C1)2, 3-CF3 HC1 (1:1) 非對映異構體1， 外消旋 4 Η Ph 2-C1, 3-CF3 HC1 (1:1) 非對映異構體1， 外消旋 5 Η Ph 2-C1, 3-CFs HC1 (1:1) 對掌性右旋 6 Η Ph 2,6-(Cl)2, 3- CF3 HC1 (1:1) 對掌性左旋 145867.doc -27- 201034667 7 Η Ph 2-C1, 3-CF3 HC1 (1:1) 對掌性左旋 8 Η Ph 2,6-(Cl)2, 3- CF3 HC1 (i) 對掌性右旋 9 Η Ph 2-OCH3, 4-C1, 5- so2c2h5 HC1 (1:1) 非對映異構體1， 外消旋 10 Η Ph 2-C1, 5-CF3 HC1 (1:1) 非對映異構體1， 外消旋 11 Η Ph 2,6-(Cl)2 - 非對映異構體1， 外消旋 12 Η Ph 2-CH3, 3-C1 非對映異構體1， 外消旋 13 Η 4-F-Ph 2-C1, 3-CF3 - 非對映異構體1， 外消旋 14 Η 4-F-Ph 2,6-(Cl)2, 3-CF3 - 非對映異構體1， 外消旋 15 Η 3-OCH3- Ph 2,6-(Cl)2, 3-CF3 - 非對映異構體1， 外消旋 16 Η 3-OCH3- Ph 2-C1, 3-CF3 - 非對映異構體1， 外消旋 17 Η 3-OH-Ph 2-C1, 3-CF3 - 非對映異構體1， 外消旋 18 Η 3-OH-Ph 2,6-(Cl)2, 3-CF3 - 非對映異構體1， 外消旋 19 Η 3-CH3-Ph 2-C1, 3-CF3 HC1 (1:1) 非對映異構體1， 外消旋 20 c2h5 Ph 2-C1, 3-CF3 - 非對映異構體1， 外消旋 21 Η 3-CH3-Ph 2,6-(Cl)2, 3-CF3 - 非對映異構體1， 外消旋 22 ch3 Ph 2-C1, 3-CF3 HC (1:1) 非對映異構體1， 外消旋 145867.doc -28- 201034667 23 Η 3-Br-Ph 2-C1, 3-CF3 HC1 (1:1) 非對映異構體1， 外消旋 24 Η 3-Br-Ph 2,6-(Cl)2, 3-CF3 HC1 (1:1) 非對映異構體1， 外消旋 25 Η 3-CFrPh 2-C1, 3-CF3 HC1 (1:1) 非對映異構體1， 外消旋 26 c2h5 Ph 2,6-(Cl)2, 3-CF3 HC1 (1:1) 對掌性右旋 27 c2h5 3-CFrPh 2-C1, 3-CF3 HC1 (1:1) 非對映異構體1， 外消旋 表2 編號 MP(°C) [«d]2〇C (°) LCMS 1 58.5-59.5 N.A. 403 2 233-234 N.A. 365 3 249.5-250.5 N.A. 457 4 260-262 N.A. 423 5 265.5-266.5 32.0 (MeOH, c=0.66 g/100 ml) 423 6 192-193 -40.5 (MeOH, c=0.196 g/100 ml) 457 7 266.5-267.5 -26.4 (MeOH, c=0.73 g/100 ml) 423 8 241-242 30.7 (MeOH, c=0.75 g/100 ml) 457 9 185-187 N.A. 477 10 188-190 N.A. 423 11 172-174 N.A. 389 12 132-134 N.A. 369 13 244-246 N.A. 441 14 188-190 N.A. 475 15 208-210 N.A. 487 145867.doc -29- 201034667 16 67-69 N.A. 453 17 180-182 N.A. 439 18 208-210 N.A. 473 19 257-259 N.A. 437 20 160-162 N.A. 451 21 186-188 N.A. 471 22 186-188 N.A. 437 23 250-251 N.A. 501 24 278.5-279 N.A. 535 25 236-238 N.A. 491 26 270.5-272.5 +55.37 (CHC13, c=0.736 g/ 100 ml) 485 27 147-148 N.A. 519 本發明化合物已進行一系列醫藥學試驗，該等試驗已經 證實其作為具有治療活性之物質的優勢。 在表現天然人類轉運體GlyTl之SK-N-MC細胞中甘胺酸轉 運之研究。 在受試化合物存在或不存在下測量所吸收的放射性，在 表現天然人類轉運體GlyTl之SK-N-MC細胞（人類神經上皮 細胞）中研究[14C]甘胺酸之吸收。該等細胞在經0.02%纖維 網蛋白預處理之培養皿中培養48小時形成單層。在試驗的 當天，移除培養介質，並於pH 7.4下，用Krebs-HEPES (4-(2-羥基乙基）哌嗪-1-乙磺酸）緩衝液沖洗細胞。在37°C下， 在缓衝液（對照組）存在下或各種濃度的受試化合物存在 下，或10 mM的甘胺酸（測定非特異性吸收）的存在下，預 培養1 0分鐘之後，繼而添加1 0 μΜ的[14C]甘胺酸（比活性 145867.doc -30- 201034667 112 mCi/mmol)。在37t：下持續培養1〇分鐘’用pH 74之 Krebs-HEPES緩衝液沖洗兩次，中止反應。添加1〇〇沁的 閃爍計數液及攪拌丨小時之後，估計細胞所併入的放射 性。用Microbeta Tri-LuX™計數器進行計數。以IC5〇(使甘 胺酸特異性吸收量減少50%時之化合物濃度）來測定化合物 的效力’其係藉由對照組與接受1 〇 mM甘胺酸處理組之間 所吸收的放射性差異而界定。 〇 本發明之化合物在此檢測中的IC50為〇.〇01至10 μΜ。 表3顯示根據本發明化合物的1(：5〇之某些實例結果。 表3 化合物 1。5〇 (μΜ) 2 1 4 0.020 5 0.04 7 0.29 11 0.90 16 0.163 17 0.045 20 0.006 23 0.036 25 ---- 0.547 於本發明通式（I)對掌性化合物及其消旋物（其中r2特定 δ之表示一或多個函原子或三氟曱基）進行檢測之結果顯 示’其等為存在於腦中之GlyT 1甘胺酸轉運體的抑制劑。 145867.doc -31- 201034667 該等結果顯示，本發明化合物可用於治療與神經退化性 疾病及癡呆症相關之認知及/或行為失冑；用⑨治療精神 病，尤其係精神分裂症（不足形式（deficit f〇rm)及多發形式 (productive f0rm))及急性或慢性精神抑制劑引起的錐體外 徑症狀m療各種形式的㈣、職發作、恐懼及強 迫症，用於治療各種形式的抑#，包括精神用於治 療雙極症、躁症及情緒障礙；用於治療歸因於㈣或戒酒 的失調、性行為障礙、進食障礙及偏頭痛疾病；疼痛；及 睡眠障礙。 根據本發明之化合物 w ㈠於U /ηNo. R Ri r2 Salt Stereochemistry 1 Η Ph 2-CH3, 3-CF3 - Diastereomer 1, Racemic 2 Η Ph 2-CH3, 3-OCH3 - Diastereomer 1, Exogenous旋 3 Η Ph 2,6(C1)2, 3-CF3 HC1 (1:1) diastereomer 1, racemic 4 Η Ph 2-C1, 3-CF3 HC1 (1:1) non-pair Isomer 1, racemic 5 Η Ph 2-C1, 3-CFs HC1 (1:1) palmar dextrorotatory 6 Η Ph 2,6-(Cl)2, 3- CF3 HC1 (1:1 ) palmar left-handed 145867.doc -27- 201034667 7 Η Ph 2-C1, 3-CF3 HC1 (1:1) palmar left-handed 8 Η Ph 2,6-(Cl)2, 3- CF3 HC1 (i ) to palmar dextrorotatory 9 Η Ph 2-OCH3, 4-C1, 5- so2c2h5 HC1 (1:1) diastereomer 1, racemic 10 Η Ph 2-C1, 5-CF3 HC1 (1 :1) diastereomer 1, racemic 11 Η Ph 2,6-(Cl) 2 - diastereomer 1, racemic 12 Η Ph 2-CH3, 3-C1 diastereomeric Isomer 1, racemic 13 Η 4-F-Ph 2-C1, 3-CF3 - diastereomer 1, racemic 14 Η 4-F-Ph 2,6-(Cl) 2, 3-CF3 - diastereomer 1, racemic 15 Η 3-OCH3- Ph 2,6-(Cl)2, 3-CF3 - diastereomer 1, racemic 16 Η 3- OCH3- Ph 2-C1, 3-CF3 - diastereoisomer 1, racemic 17 Η 3-OH-Ph 2-C1, 3-CF3 - diastereomer 1, racemic 18 Η 3-OH-Ph 2,6-(Cl)2, 3-CF3 - diastereomer 1, racemic 19 Η 3-CH3-Ph 2-C1, 3-CF3 HCl (1:1) diastereomer 1, racemic 20 c2h5 Ph 2-C1, 3-CF3 - diastereomer 1, racemic 21 Η 3-CH3-Ph 2,6-(Cl) 2, 3-CF3 - diastereomer 1, racemic 22 ch3 Ph 2 -C1, 3-CF3 HC (1:1) diastereomer 1, racemic 145867.doc -28- 201034667 23 Η 3-Br-Ph 2-C1, 3-CF3 HC1 (1:1) Diastereomer 1, racemic 24 Η 3-Br-Ph 2,6-(Cl) 2, 3-CF3 HCl (1:1) diastereomer 1, racemic 25 Η 3 -CFrPh 2-C1, 3-CF3 HC1 (1:1) diastereomer 1, racemic 26 c2h5 Ph 2,6-(Cl)2, 3-CF3 HC1 (1:1) Right-handed 27 c2h5 3-CFrPh 2-C1, 3-CF3 HC1 (1:1) Diastereomer 1, Racemic Table 2 No. MP(°C) [«d]2〇C (°) LCMS 1 58.5-59.5 NA 403 2 233-234 NA 365 3 249.5-250.5 NA 457 4 260-262 NA 423 5 265.5-266.5 32.0 (MeOH, c=0.66 g/100 ml) 423 6 192-193 -40.5 (MeOH, c=0.196 g/100 ml) 457 7 266.5-267.5 -26.4 (MeOH, c=0.73 g/100 ml) 423 8 241-242 30.7 (MeOH, c=0.75 g/100 ml) 457 9 185-187 NA 477 10 188-190 NA 423 11 172-174 NA 389 12 132-134 NA 369 13 244-246 NA 441 14 188-190 NA 475 15 208-210 NA 487 145867.doc -29- 201034667 16 67-69 NA 453 17 180-182 NA 439 18 208-210 NA 473 19 257-259 NA 437 20 160-162 NA 451 21 186-188 NA 471 22 186-188 NA 437 23 250-251 NA 501 24 278.5-279 NA 535 25 236-238 NA 491 26 270.5-272.5 +55.37 ( CHC13, c=0.736 g/100 ml) 485 27 147-148 NA 519 The compounds of the invention have been subjected to a series of medicinal tests which have proven their advantage as therapeutically active substances. Glycine transfer in SK-N-MC cells expressing the native human transporter GlyTl. The absorbed radioactivity was measured in the presence or absence of the test compound, and the absorption of [14C]glycine was investigated in SK-N-MC cells (human neuroepithelial cells) expressing the native human transporter GlyTl. The cells were cultured for 48 hours in a 0.02% fibrin pretreated dish to form a monolayer. On the day of the experiment, the culture medium was removed, and the cells were washed with Krebs-HEPES (4-(2-hydroxyethyl) piperazine-1-ethanesulfonic acid) buffer at pH 7.4. After pre-incubation for 10 minutes at 37 ° C in the presence of buffer (control) or in the presence of various concentrations of test compound, or 10 mM glycine (determination of non-specific absorption), Then, 10 μM of [14C]glycine (specific activity 145867.doc -30- 201034667 112 mCi/mmol) was added. Incubation was continued for 1 min at 37 t: and washed twice with Krebs-HEPES buffer at pH 74 to stop the reaction. After adding 1 闪烁 of scintillation counter and stirring for 丨 hours, the radioactivity incorporated by the cells was estimated. Counting was performed using a Microbeta Tri-LuXTM counter. The potency of the compound was determined by IC5 〇 (the concentration of the compound when the specific absorption of glycine was reduced by 50%), which was determined by the difference in radioactivity absorbed between the control group and the group treated with 1 mM mM glycine. Defined. IC The IC50 of the compound of the present invention in this assay is 〇.〇01 to 10 μΜ. Table 3 shows the results of some examples of 1 (: 5 化合物) of the compound according to the present invention. Table 3 Compound 1. 5 〇 (μΜ) 2 1 4 0.020 5 0.04 7 0.29 11 0.90 16 0.163 17 0.045 20 0.006 23 0.036 25 -- - 0.547 The results of the general formula (I) of the present invention for the palm compound and its racemate (wherein r2 specific δ represents one or more functional atoms or trifluoromethyl) are shown to be present in Inhibitors of GlyT 1 glycine transporters in the brain. 145867.doc -31- 201034667 These results show that the compounds of the invention are useful for the treatment of cognitive and/or behavioral disorders associated with neurodegenerative diseases and dementia; Treating psychosis with 9 diseases, especially schizophrenia (deficit f〇rm and product form f0rm) and acute or chronic psychosuppressive symptoms of pyramidal edema m treatment in various forms (4), occupational seizures, Fear and obsessive-compulsive disorder, used to treat various forms of depression, including the spirit for the treatment of bipolar disorder, snoring and mood disorders; for the treatment of disorders attributed to (4) or abstinence, sexual behavior disorders, eating disorders and migraine disease; Pain; and sleep disorders. The compound w (a) according to the invention is U / η

GlyTl甘胺酸轉運體的抑制劑之藥劑 从因此，根據本發明之另一態樣，本發明之—主題係一種 樂劑，其包含式（I)化合物，或後者與醫藥上可接受酸之加 成鹽或式（I)化合物的水合物或溶劑化物。 本發明之另一主題係一種醫藥組合物， 的呈驗形式或醫藥上可接受鹽形式的根據本發明L; 一 種化合物，以及若適宜時，鱼 物。 ，、適且的賦形劑形成之混合 該等賦形劑係根據醫藥形式及所需投藥方法 根據本發明之醫藥組合物可因此用& 下、肌肉内、靜脈内、局部、氣管内、鼻服、，劑1 或眼内投藥。 、，友皮、直丹 單位投藥形式可為(例如)鍵劑、明膠膠囊 Η 用於口服或注射之溶液或縣纟 "； 乂心汙液、貼片或栓劑。車 145867.doc •32- 201034667 膏、洗劑及洗眼劑用於局部投藥。 根據醫藥劑型而定’該單位形式之劑量允許每天每公斤 體重投與0.01至20 mg的活性成份。 為製備錠劑，可將由稀釋劑（諸如乳糖、微晶形纖維素 或澱粉）、及調配佐劑（諸如黏合劑（聚乙烯吡咯啶酮，羥丙 .&曱基纖維素等））、㈣劑（諸如氧切）、㈣滑劑（諸如 • 硬月曰酉夂鎂、硬脂酸、二山蓊酸甘油酯或硬脂富馬酸鈉)組 〇 A之醫藥載劑添加至微粉化或未經微粉化的活性成份中。 亦可添加濕化劑或界面活性劑，諸如月桂基硫酸鈉。 製備技術可經直接製錠、乾式造粒、濕式造粒或熱熔。 錠劑可不包覆包衣、包覆糖衣（例如嚴糖）、或包覆各種 聚合物或其他適宜材料。其等可設計成藉由聚合物基質或 在包衣中使用特定聚合物，使活性成份進行可能的快速、 延遲或持續釋放。 β為製備明膠膠囊’可使活性成份與乾燥醫藥載體（簡單 ◎ ❿合、乾式或濕式造粒或熱炫）或液體或半固體醫藥載體 混合。 明膠膠囊可為硬式或軟式，且可包覆或未包覆薄膜，以 具有快速、持續或延遲活性（例如腸溶形式）。 呈糖漿或驰劑形式或呈滴劑形式用於投藥之組合物可包 ^與甜味劑（較佳為不含卡路里之甜味劑）、作為防腐劑之 广基苯甲酸甲酯或對羥基苯甲酸丙酯、香味增強劑及著 色劑結合之活性成份。 水可分散粉末及顆粒可包含活性成份與分散劑、或濕潤 145867.doc 33- 201034667 劑或刀政劑（諸如聚乙烯°比σ各咬酮）、及甜味劑及香味橋正 劑之混合物。 對於直腸投藥’採用在直腸溫度下熔化之黏合劑（例如 可可脂或聚乙二醇)製備栓劑。 對於非胃腸道投藥，可使用水性懸浮液、等滲生理食鹽 扒或滅菌〆主射液’其包括醫藥相容之分散劑及/或濕潤 劑，例如丙二醇或丁二醇。 ，㈣成份亦可視需要使用—或多種載體或添加劑調配成 囊$式’或另外使用聚合物基質或使用環糊精（用於 貼片或持續釋放形式）。 ::本發明之局部組合物包括可與皮膚相容之介質。其 :::::可呈水、醇或水，醇溶液形式、凝膠形式或具有 膠或微乳液或喷霧劑外觀之油包水或水包油乳液 彳接祉, 千i及/或非離子型脂質）形 > ”。此等醫藥劑型係根據相Μ β + π 爆相關領域中習知方法製備。 舉例而言，呈錠劑形式 形式可… 式之根據本發明化合物之單位投藥 々八力包括以下組分： 50.0 mg 223.75 mg 6.0 mg 15.0 mg 2.25 mg 3.0 mg 根據本發明之化合物 甘露醇 交聯鲮甲基纖維素鈉 玉米戰粉 經丙基甲基纖維素 硬脂酸鎂 145867.doc -34- 201034667 經由口服途徑，每天經投與之活性成份之劑量可在0. J 至2〇 mg/kg的範圍内，服用一劑或多劑。 可能會出現需要較高或較低劑量才適宜之特定情況，此 等劑量仍在本發明範疇内。根據標準操作法，對每個患者 適宜之劑量係由醫生根據投藥模式及該患者之體重及反應 而決定。 根據本發明之另一態樣，本發明亦關於一種用於治療以 〇 所指不病症之方法’其包括對患者投與有效劑量的根據 本發明化合物或其醫藥可接受鹽。 〇 145867.doc -35-Agent for Inhibitor of GlyTl Glycine Transporter Thus, in accordance with another aspect of the present invention, the subject matter of the present invention is an agent comprising a compound of formula (I), or a pharmaceutically acceptable acid An addition salt or a hydrate or solvate of a compound of formula (I). A further subject of the invention is a pharmaceutical composition, in the form of a test or a pharmaceutically acceptable salt, according to the invention L; a compound, and if appropriate a fish. Mixture of suitable excipients formed according to the pharmaceutical form and the desired administration method. The pharmaceutical composition according to the present invention can be used as follows, under, intramuscularly, intravenously, locally, intratracheally, Nasal, dose 1 or intraocular administration. , Youpi, Zhidan unit dosage form can be (for example) key agent, gelatin capsule Η for oral or injection solution or county 纟 "; 乂 heart stain, patch or suppository. Car 145867.doc •32- 201034667 Creams, lotions and eye washes for topical administration. Depending on the pharmaceutical dosage form, the dosage form of the unit form allows from 0.01 to 20 mg of active ingredient per kilogram of body weight per day. For the preparation of a tablet, a diluent such as lactose, microcrystalline cellulose or starch, and a formulation adjuvant such as a binder (polyvinylpyrrolidone, hydroxypropyl. & thiol cellulose, etc.), (4) The agent (such as oxygen cut), (4) slip agent (such as • hard magnesium, stearic acid, glyceryl dibehenate or stearyl fumarate), the pharmaceutical carrier of 〇A is added to the micronized Or active ingredients that have not been micronized. Wetting agents or surfactants such as sodium lauryl sulfate may also be added. The preparation technique can be directly ingot, dry granulation, wet granulation or hot melt. Tablets may be uncoated, coated (e.g., sugar), or coated with various polymers or other suitable materials. They can be designed to effect a rapid, delayed or sustained release of the active ingredient by the use of a polymer matrix or a specific polymer in the coating.为 is a gelatin capsule' which allows the active ingredient to be mixed with a dry pharmaceutical carrier (simple, dry or wet granulation or heat) or a liquid or semi-solid pharmaceutical carrier. Gelatin capsules can be either hard or soft and can be coated or uncoated to provide rapid, sustained or delayed activity (e.g., enteric form). The composition for administration in the form of a syrup or a granule or in the form of a drop may comprise a sweetener (preferably a calorie-free sweetener), a broad-based methyl benzoate or a para-hydroxyl group as a preservative. Active ingredient in combination with propyl benzoate, aroma enhancer and color former. The water-dispersible powders and granules may comprise an active ingredient and a dispersing agent, or a mixture of wet 145867.doc 33- 201034667 or a knifeing agent (such as a polyethylene ratio σ ket), and a mixture of a sweetener and a flavoring agent. . For rectal administration, suppositories are prepared using a binder that melts at the rectal temperature, such as cocoa butter or polyethylene glycol. For parenteral administration, aqueous suspensions, isotonic saline salts or sterile sputum priming agents can be employed which comprise pharmaceutically compatible dispersing agents and/or wetting agents, such as propylene glycol or butylene glycol. (4) Ingredients may also be used as needed - or a variety of carriers or additives may be formulated into a capsule or additionally using a polymer matrix or using a cyclodextrin (for patch or sustained release forms). The topical compositions of the present invention comprise a medium compatible with the skin. Its::::: may be in the form of water, alcohol or water, in the form of an alcohol solution, in the form of a gel or a water-in-oil or oil-in-water emulsion having the appearance of a glue or microemulsion or spray, 千, and/or Non-ionic lipids)>" These pharmaceutical dosage forms are prepared according to conventional methods in the art of phase Μ β + π blasting. For example, in the form of a tablet form, the unit can be administered according to the compound of the present invention. 々力力 includes the following components: 50.0 mg 223.75 mg 6.0 mg 15.0 mg 2.25 mg 3.0 mg The compound according to the invention mannitol cross-linked 鲮methylcellulose sodium corn powder by propylmethylcellulose magnesium stearate 145867 .doc -34- 201034667 The dosage of the active ingredient administered daily via the oral route may be in the range of 0. J to 2 〇 mg/kg, taking one or more doses. It may occur that the need is higher or lower. In the particular case where the dosage is appropriate, such dosages are still within the scope of the invention. According to standard practice, the appropriate dosage for each patient is determined by the physician based on the mode of administration and the weight and response of the patient. In one aspect, the invention is also closed A method for treating a disorder of the square method is not referred to 'comprising administering to a patient an effective dose of a compound according to the present invention or a pharmaceutically acceptable salt thereof. Billion 145867.doc -35-

Claims (1)

201034667 七、申請專利範圍： 1. 一種呈鹼形式或與酸之加成鹽形式之通式⑴化合物：201034667 VII. Scope of application: 1. A compound of the formula (1) in the form of a base or an acid addition salt: O R表示氫原子或選自（Ci_C6)烷基或（cvc：7)環烷基之基 團，此等基團係視需要經一或多個相互獨立地選自氟原 子及（C3-C7)環烷基、（c2_c4)烯基、笨基、（Ci_C6)烷氧基 或羥基之基團取代；該苯基可視需要經一或多個烷氧基 取代； Ri表示苯基或萘基，其視需要經一或多個相互獨立地 選自以下之取代基取代：鹵素原子及（Ci_c6)烷基、（Ci_ C6)烷氧基、鹵（Cl-c6)烷基、NR4R5、NR3c(〇)〇R4、 〇 NR3S〇2R4、nr3c(〇)r6、羥基、鹵（Ci_C6)烷氧基、（Ci_ C：6)烷硫基、（C^C：6)烷基-S〇2、苯基或雜芳基，該苯基視 需要經一或多個獨立地選自以下之取代基取代：鹵素原 子及（cvc6)烷基、（Cl_c6)烷氧基' i(Ci_C6)烷基、 NR4R5 ' nr3c(o)〇r4、NR3so2R4、顺3C(〇)R6、羥基、 鹵（Ci-CJ烷氧基、（CrCe)烷硫基及（Ci_c6)烷基_s〇2基 團，該雜芳基視需要經一或多個獨立地選自以下之取代 基取代：鹵素原子及（CVC6)烷基、（Ci_c6)烷氧基、鹵 145867.doc 201034667 (CVC6)烷基或 NR4R5 ; R2表示一或多個選自以下之取代基：氫原子、鹵素原 子及（CVC6)烷基、（c3-c7)環烷基、（C3_C7)環烷基（Ci_c3) 炫基、鹵（CVC6)烷基、（Ci-CJ烷氧基、NR4R5、苯基、 雜芳基、氰基、乙醯基、（C丨-C6)硫烷基、（CrCd烷基磺 醯基、羧基或烷氧基羰基；該苯基視需要經一或 多個獨立地選自以下之取代基取代：_素原子及（Ci_C6) 烷基、（CVC6)烷氧基、鹵（Cl_C6)烷基、Nr4R5、 NR3C(0)OR4、NR3S〇2R4、NR3C(〇)R6、羥基、_ (Ci C6) 烷氧基、（(VCd烷硫基及（Cl_c0)烷基_s〇2基團，該雜芳 基視需要經一或多個獨立選自鹵素原子及（Ci_c6)烷基、 (C!-C6)炫氧基、鹵（Ci-C6)烧基或NRA5之取代基取代； R3、R4及Rs相互獨立地表示氫原子或（C1_C6)烷基； 尺6表不（Ci-C6)烧基； R4及RS可與其所附接之氮原子—起形成一個選自氮雜 環丁烧、料。定K、㈣、硫嗎H秦或氮呼環 之環，其視需要經（CrC6)烷基取代； 可與其所附接之原子_起形成5員或6員環； R3及R0可與其所附接之原子一起形成5員或6員環。 2.如請求们之通式⑴化合物，其特徵為R表示氫原子或 (Ci-C6)烧基。 3·如請求項！或2之通式⑴化合物，其特徵為Ri表示苯基’ 其可視需要經一或多個相互獨立地選自函素原子及⑹_ c6)院基、_(cvc6m基、（Cl_C6)院氧基或經基之取代 145867.doc 201034667 基取代。 4.如請求項1至3中任一項之通式⑴化合物，其特徵為化表 示一或多個選自氫原子、鹵素原子及鹵（Ci_c6)烷基、 (C丨-C6)烷基、（CVC6)烷氧基或（Cl_c6)烷基_s〇2之取代 基。 5·如請求項1至4中任一項之通式（I)化合物，其特徵為： R表示氫原子或甲基或乙基； ❹ Rl表不苯基，其視需要經一或多個相互獨立地選自鹵 素原子及甲基、乙基、三氟甲基、甲氧基或羥基之取代 基取代；及 R2表示一或多個選自氫原子、鹵素原子及三氟甲基、 甲基、甲氧基或乙基磺醯基之取代基； 且该化合物係呈鹼形式或與酸之加成鹽形式。 6_如請求項1至5中任一項之化合物，其特徵為其係選自以 下化合物： 〇 N-K6-氮雜雙環基）苯基甲基](2_曱基_3三 氟甲基）笨甲酿胺； N-[(6-氮雜雙環基）苯基甲基](3_甲氧基_2_ 甲基）苯甲醯胺； N-[(6-氮雜雙環基）苯基甲基](2 6_二氯％ 二I曱基）笨曱醯胺及其鹽酸鹽； N-[6-氮雜雙環基）苯基甲基](2_氣_3_三氟 甲基）笨甲醯胺及其鹽酸鹽； (+)力-[(6_氮雜雙環[3.21]辛_5_基）苯基甲基](2_氯_3_ I45867.doc 201034667 二氟甲基）苯曱醯胺及其鹽酸鹽； ㈠1[(6-氮雜雙環[3·2辛_5_基）苯基甲基](2芥二 氯3-一氟甲基）苯甲醯胺及其鹽酸鹽； 氮雜雙環[3.21]辛_5_基）笨基甲基](2_氣_3_三 氟曱基）苯甲醯胺及其鹽酸鹽； > 氮雜雙環[3 2辛·5·基）苯基甲基狀卜二 氯3-二氟甲基）苯甲醯胺及其鹽酸鹽； 氮雜雙環[3.2.1]辛_5_基）苯基f基](4-氣-5_乙基 石尹、醯基-2-曱氧基）苯曱醯胺及其鹽酸鹽； 氮雜雙環 曱基）苯甲醯胺及其鹽酸鹽； N-[(6-氮雜雙環[3.21]辛_5_基）苯基曱基](2,6_二氯）苯 曱醯胺； 队[(6_氮雜雙環[3.21]辛_5_基）苯基曱基](3_氣_2_曱基） 苯甲酿胺； N-[(6-氮雜雙環[3 21]辛_5基）_(4_氟苯基）曱基](2_ 氣-3-三氟甲基）苯甲醯胺； N-K-6-氮雜雙環[32」]辛_5_基）(4氟苯基）甲基Κ2,6_ 二氣-3-三氟曱基）苯甲醯胺； Ν-[(-6-氮雜雙環[3 21]辛_5_基）_(3_曱氧基苯基）甲 基](2,6-二氣_3_三氟曱基）苯甲醯胺； Ν_[(6-氮雜雙環[3 2丨^辛乃-基彳、甲氧基苯基）曱基](2_ 氣-3-三氟甲基）苯甲醯胺； Ν_[6-氮雜雙環[3 2辛_5_基_(3_羥基苯基）曱基Η]· 145867.doc 201034667 虱-3-二氟甲基）苯甲醢胺； N_[(6-氮雜雙環[m]辛j基）_(3_羥基苯基）甲 基](2,6_二氯-3-三氟甲基）苯甲醯胺； 叫(6德雜雙環間曱苯基曱基](2_氯_3_ 二氟甲基）笨甲醯胺及其鹽酸鹽； 2氯Ν·[(6-乙基-6-氮雜雙環[321]辛_5·基）苯基甲 , 基](3-二氟甲基）苯曱醯胺； ❹ Ν_[^氮雜雙環[3.2.Π辛-5-基-間甲苯基曱基](2,6_二 氣-3-二氟甲基）苯甲醯胺； 2_氯士-[(6_曱基冬氮雜雙環[3 2丨]辛_5_基）苯基甲 基](3_三氟曱基）苯甲醯胺及其鹽酸鹽； N-[(6德雜雙環[3·21]辛_5_基）_(3_漠苯基）甲基似_ 氣-3-二氟甲基）苯甲醯胺及其鹽酸鹽； Ν-[(6-氮雜雙環基Η3_演苯基）甲基](μ· 二氣-3-三氟曱基）苯曱醯胺及其鹽酸鹽； 〇 Ν·[6；氮雜雙環[3·2·1]辛-5-基-(3-三氟甲基苯基）甲 基](2-氯-3-三氟甲基）苯甲醯胺及其鹽酸鹽； (+)-2,6-二氯·Ν_[(6_乙基_6_氮雜雙環[32.丨]辛_^基）笨 基曱基](3-三氟甲基）苯甲醯胺及其鹽酸鹽； 2-氯-Ν-[(6_乙基_6_氮雜雙環[321]辛_5_基Η〗·三氟甲 基笨基）曱基](3-三氟甲基）笨曱醯胺及其鹽酸鹽。 7. —種製備如請求項丨之通式⑴化合物之方法，其 使通式（II)化合物： ~ 145867.doc 201034667OR represents a hydrogen atom or a group selected from (Ci_C6)alkyl or (cvc:7)cycloalkyl, and such groups are optionally selected from one or more fluorine atoms and (C3-C7) independently of one another. a group substituted with a cycloalkyl group, a (c2_c4)alkenyl group, a phenyl group, a (Ci_C6) alkoxy group or a hydroxy group; the phenyl group may be optionally substituted with one or more alkoxy groups; Ri represents a phenyl group or a naphthyl group, Substituted by one or more substituents independently selected from the group consisting of: a halogen atom and (Ci_c6) alkyl group, (Ci_C6) alkoxy group, a halogen (Cl-c6) alkyl group, NR4R5, NR3c (〇) 〇R4, 〇NR3S〇2R4, nr3c(〇)r6, hydroxy, halo(Ci_C6)alkoxy, (Ci_C:6)alkylthio, (C^C:6)alkyl-S〇2,phenyl Or a heteroaryl group which is optionally substituted by one or more substituents independently selected from the group consisting of a halogen atom and (cvc6)alkyl group, (Cl_c6) alkoxy group 'i(Ci_C6)alkyl group, NR4R5' Nr3c(o)〇r4, NR3so2R4, cis 3C(〇)R6, hydroxy, halo(Ci-CJ alkoxy, (CrCe)alkylthio and (Ci_c6)alkyl_s〇2 groups, the heteroaryl Depending on the need, one or more substituents independently selected from the following Generation: halogen atom and (CVC6) alkyl group, (Ci_c6) alkoxy group, halogen 145867.doc 201034667 (CVC6) alkyl group or NR4R5; R2 represents one or more substituents selected from the group consisting of a hydrogen atom, a halogen atom and (CVC6)alkyl, (c3-c7)cycloalkyl, (C3_C7)cycloalkyl (Ci_c3) leumino, halo(CVC6)alkyl, (Ci-CJ alkoxy, NR4R5, phenyl, heteroaryl , cyano, ethyl hydrazino, (C丨-C6) sulfanyl, (CrCd alkylsulfonyl, carboxy or alkoxycarbonyl; the phenyl optionally needs to be substituted by one or more of the following Substituent substitution: _ atom atom and (Ci_C6) alkyl group, (CVC6) alkoxy group, halogen (Cl_C6) alkyl group, Nr4R5, NR3C(0)OR4, NR3S〇2R4, NR3C(〇)R6, hydroxyl group, _ (Ci C6) an alkoxy group, ((VCd alkylthio group and (Cl_c0)alkyl group ss2), the heteroaryl group optionally being selected from one or more independently selected from a halogen atom and a (Ci_c6) alkyl group, (C) !-C6) a methoxy group, a halogen (Ci-C6) group or a substituent of NRA5; R3, R4 and Rs independently of each other represent a hydrogen atom or a (C1_C6) alkyl group; and a ruler 6 indicates (Ci-C6) Burning base; R4 and RS can be combined with the nitrogen atom attached thereto a ring selected from the group consisting of azetidin, feed, K, (d), sulphur H or nitrogen ring, which is optionally substituted by (CrC6) alkyl; can form 5 members with the attached atom Or 6-membered ring; R3 and R0 can form a 5- or 6-membered ring with the atoms attached to them. 2. A compound of the formula (1) as claimed, characterized in that R represents a hydrogen atom or a (Ci-C6) alkyl group. 3. If requested! Or a compound of the formula (1), characterized in that Ri represents a phenyl group which may optionally be selected from one or more mutually independently selected from a functional atom and (6) _ c6), _(cvc6m, (Cl_C6) alkoxy Or a substitution of a radical 145867.doc 201034667. 4. A compound of the formula (1) according to any one of claims 1 to 3, characterized in that one or more selected from the group consisting of a hydrogen atom, a halogen atom and a halogen (Ci_c6) a substituent of an alkyl group, (C丨-C6)alkyl group, (CVC6) alkoxy group or (Cl_c6)alkyl group ss2. 5. The formula (I) according to any one of claims 1 to 4 a compound characterized by: R represents a hydrogen atom or a methyl group or an ethyl group; ❹ R1 represents a phenyl group which, if necessary, is independently selected from a halogen atom and a methyl group, an ethyl group, a trifluoromethyl group by one or more a substituent substituted with a methoxy group or a hydroxy group; and R 2 represents one or more substituents selected from a hydrogen atom, a halogen atom, and a trifluoromethyl group, a methyl group, a methoxy group or an ethyl sulfonyl group; The compound is in the form of a base or a salt with an acid. The compound of any one of claims 1 to 5 is characterized by being selected from the following compounds 〇N-K6-azabicyclo)phenylmethyl](2_fluorenyl-3-trifluoromethyl) benzoate; N-[(6-azabicyclo)phenylmethyl](3 _Methoxy-2_methyl)benzamide; N-[(6-azabicyclo)phenylmethyl](2 6-dichloro% diindolyl) alum and its hydrochloric acid Salt; N-[6-azabicyclo)phenylmethyl](2_gas_3_trifluoromethyl) benzoic acid and its hydrochloride; (+) force-[(6-aza Bicyclo[3.21] osin-5_yl)phenylmethyl](2_chloro_3_ I45867.doc 201034667 difluoromethyl)phenylguanamine and its hydrochloride; (a) 1[(6-azabicyclo[3] · 2 辛_5_yl)phenylmethyl](2 mustard dichloro 3-fluoromethyl)benzamide and its hydrochloride; azabicyclo[3.21]octyl-5-yl) (2_Gas_3_Trifluoromethyl)benzamide and its hydrochloride; > Azabicyclo[3 2 辛·5·yl)phenylmethyldichloro-3-difluoro Methyl)benzamide and its hydrochloride; azabicyclo[3.2.1]octyl-5-yl)phenylf-yl](4-a-5-ethylpyramine, fluorenyl-2-oxime Benzoamine and its hydrochloride; azabicyclononyl)benzamide and its hydrochloride; N-[(6-aza) Bicyclo[3.21]octyl-5-yl)phenylindenyl](2,6-dichloro)benzoquinone; team [(6-azabicyclo[3.21]oct-5-yl)phenylindenyl] (3_气_2_曱基) Benzoylamine; N-[(6-Azabicyclo[3 21]octyl-5)-(4-fluorophenyl)indenyl](2_气-3- Trifluoromethyl)benzamide; NK-6-azabicyclo[32"]octyl-5-yl)(4fluorophenyl)methylhydrazine 2,6_dioxa-3-trifluoromethyl)benzamide Guanidine; Ν-[(-6-azabicyclo[3 21]octyl-5-yl)-(3-methoxyphenyl)methyl](2,6-digas_3_trifluoromethyl) Benzoguanamine; Ν_[(6-azabicyclo[3 2丨^ octyl-hydrazinyl, methoxyphenyl)indolyl](2-nitro-3-trifluoromethyl)benzamide; Ν_[6-Azabicyclo[3 2 octyl-5-yl-(3-hydroxyphenyl)indenyl]] 145867.doc 201034667 虱-3-difluoromethyl)benzamide; N_[(6 -azabicyclo[m]octyl)-(3-hydroxyphenyl)methyl](2,6-dichloro-3-trifluoromethyl)benzamide; Phenyl fluorenyl] (2_chloro-3-3 difluoromethyl) benzoic acid and its hydrochloride; 2 chloropurine · [(6-ethyl-6-azabicyclo[321] octyl] Phenylmethyl, yl](3-difluoromethyl)benzoquinone Amine; ❹ Ν _ [^ azabicyclo[3.2. oxime-5-yl-m-tolyl fluorenyl] (2,6-di--3-difluoromethyl)benzamide; 2_Chlores- [(6_Indolyl-azabicyclobicyclo[3 2丨]octyl-5-yl)phenylmethyl](3-trifluoromethyl)benzamide and its hydrochloride; N-[(6-de Heterobicyclo[3·21]octyl-5_yl)_(3_ lyophilyl)methyl-like _ gas-3-difluoromethyl)benzamide and its hydrochloride; Ν-[(6- Azabicycloindole _3_ phenyl)methyl](μ·di-3-trifluoromethyl)benzamide and its hydrochloride; 〇Ν·[6; azabicyclo[3·2· 1] oct-5-yl-(3-trifluoromethylphenyl)methyl](2-chloro-3-trifluoromethyl)benzamide and its hydrochloride; (+)-2,6 - Dichloro-indole _[(6-ethyl_6_azabicyclo[32.oxime] octyl) phenylamino](3-trifluoromethyl)benzamide and its hydrochloride; 2-Chloro-indole-[(6-ethyl-6-azabicyclo[321]octyl-5-ylindole]trifluoromethylindolyl]indolyl](3-trifluoromethyl) alum Amine and its hydrochloride. 7. A process for the preparation of a compound of the formula (1) as claimed, which comprises a compound of the formula (II): ~ 145867.doc 201034667 其中尺及!^係如請求項丨所定義’與通式（ΠΙ)化合物反 應： 8. 9. 10. 11. 12. 中表示/舌化之〇Η基或氣原子，且r2係如請求項1 所定義。 一種藥劑’其特徵為其包括如請求項1至6中任一項之式 (I)化合物或該化合物與醫藥上可接受酸之加成鹽。 一種醫藥組合物’其特徵為其包括如請求項1至6中任一 項之式（I)化合物或該化合物之加成鹽，及至少一種醫藥 上可接受的賦形劑。 種如凊求項1至6中任一項之式⑴化合物之用途，其係 用於製備意欲治療與神經退化性疾病以及癡呆症相關的 έ忍知及/或行為失調之藥劑。 種如凊求項1至6中任一項之式⑴化合物之用途，其用 於袋備意欲治療精神病、精神分裂症（不足形式（defich f〇rm)及多發形式（pr〇ductive f贿））及急性或慢性精神抑 制背彳弓丨起的錐體外徑症狀之藥劑。 種如晴求項1至6中任一項之式⑴化合物之用途，其係 145867.doc 201034667 用於製備意欲治療各種形式的焦慮、恐慌發作、恐懼及 強迫症之藥劑。 13. —種如請求項i至6中<壬一項之式⑴化合物於製備意欲治 療以下疾病之藥劑之用途：各種形式的抑t(包括精神抑 ^ )又極症、知症及情緒障礙；由酗酒或戒酒引發的疾 病、性行為障礙、進食障礙及偏頭痛疾病。 Ο 14. —種如請求項1至6中任一項之式⑴化合物於製備意欲治 療疼痛之藥劑之用途。 15. 16. —種如請求項1至6中任一項之式⑴化合物於製備意欲治 療睡眠障礙之藥劑之用途。 如請求項!至6中任一項之化合物，其係用於治療與神經 退化性疾病及癡呆症相關的認知及/或行為失調。 17·如請求項⑴中任一項之化合物，其係用於治療精神 病、精神分裂症(不足形式及多發性形式)及急性或慢性 精神抑制劑引起的錐體外徑症狀。 18. 如請求項!至6中任一項之化合物，其係用於治療各種形 式的焦慮 '恐慌發作、恐懼及強迫症。 19. 如請求項…中任一項之化合物，其係用於治療各種形 式的抑镫（包括精神抑鬱）；雙極症、躁症及情緒障礙； 由驗酒或成酒引發的疾病、性行為障礙、進食障礙及偏 頭痛疾病。 其係用於治療疼痛。 其係用於治療睡眠障 2〇‘如請求項1至6中任一項之化合物， 2 1 ·如請求項1至6中任一項之化合物， 礙。 145867.doc 201034667 四、指定代表圖： (一) 本案指定代表圖為：（無） (二) 本代表圖之元件符號簡單說明： 五、本案若有化學式時，請揭示最能顯示發明特徵的化學式：Wherein the ruler and !^ are as defined in the request item ' with the compound of the formula (ΠΙ): 8. 9. 10. 11. 12. Indicates the thiol or gas atom of the tongue, and r2 is as requested Item 1 is defined. A pharmaceutical agent is characterized in that it comprises a compound of the formula (I) according to any one of claims 1 to 6 or an addition salt of the compound with a pharmaceutically acceptable acid. A pharmaceutical composition which is characterized by comprising a compound of the formula (I) according to any one of claims 1 to 6 or an addition salt of the compound, and at least one pharmaceutically acceptable excipient. The use of a compound of the formula (1) according to any one of claims 1 to 6 for the preparation of a medicament intended for the treatment of sputum tolerance and/or behavioral disorders associated with neurodegenerative diseases and dementia. The use of a compound of the formula (1) according to any one of claims 1 to 6, which is intended for the treatment of psychosis, schizophrenia (defich f〇rm) and multiple forms (pr〇ductive bri bribe) And an agent that acutely or chronically suppresses the symptoms of the outer diameter of the cone caused by the sacral arch. Use of a compound of the formula (1) according to any one of items 1 to 6, which is 145867.doc 201034667 for the preparation of a medicament intended for the treatment of various forms of anxiety, panic attacks, fear and obsessive-compulsive disorder. 13. The use of a compound of the formula (1) in claims i to 6 for the preparation of a medicament intended for the treatment of various forms of depression (including mental depression), extreme illness, knowledge and mood Disorders; diseases caused by alcohol or alcohol withdrawal, sexual behavior disorders, eating disorders, and migraine disorders. Ο 14. The use of a compound of the formula (1) according to any one of claims 1 to 6 for the preparation of a medicament intended to treat pain. 15. Use of a compound of formula (1) according to any one of claims 1 to 6 for the preparation of a medicament intended for the treatment of sleep disorders. A compound according to any one of claims 6 to 6 for use in the treatment of cognitive and/or behavioral disorders associated with neurodegenerative diseases and dementia. The compound according to any one of the preceding claims, wherein the compound is used for the treatment of psychiatric disorders, schizophrenia (deficient forms and multiple forms) and symptoms of pyramidal outer diameter caused by acute or chronic psychotropic agents. 18. The compound of any one of claims 6 to 6 for use in the treatment of anxiety, panic attacks, fear and obsessive-compulsive disorder in various forms. 19. A compound according to any one of the claims, for use in the treatment of various forms of depression (including depression); bipolar disorder, snoring and mood disorders; diseases caused by alcohol or alcohol, sexual behaviour Disorders, eating disorders and migraine disorders. It is used to treat pain. It is used to treat a sleep disorder. The compound of any one of claims 1 to 6 is a compound of any one of claims 1 to 6. 145867.doc 201034667 IV. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbolic symbol of the representative figure is simple: 5. If there is a chemical formula in this case, please reveal the best indication of the characteristics of the invention. Chemical formula: 145867.doc145867.doc
TW099104006A 2009-02-10 2010-02-09 N-[(6-azabicyclo[3.2.1]oct-1-yl)arylmethyl]benzamide derivatives, preparation and therapeutic use thereof TW201034667A (en)

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JP2012517412A (en) 2012-08-02
SG173607A1 (en) 2011-09-29
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FR2941954A1 (en) 2010-08-13
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IL214487A0 (en) 2011-09-27

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