TW200410693A

TW200410693A - Therapeutic agents

Info

Publication number: TW200410693A
Application number: TW091136670A
Authority: TW
Inventors: Johan Michael Wilstermann; Anna Ingrid Kristina Berggren
Original assignee: Astrazeneca Uk Ltd
Priority date: 2001-12-19
Filing date: 2002-12-19
Publication date: 2004-07-01
Also published as: AU2002352420A1; WO2003051850A1; SE0104332D0

Abstract

The present invention relates to compound of formula I, and pharmaceutically acceptable salts, solvates and crystalline forms thereof, in which R1 represents cyclohexyl, 1-piperidinyl or phenyl; R2 represents H, chloro, bromo, methyl or methoxy; and when R3 represents H, R4 represents H or chloro; and when R3 represents C1, R4 represents H or chloro; to processes for preparing such compounds, to their use in the treatment of obesity, psychiatric and neurological disorders particularly obesity, to methods for their therapeutic use and to pharmaceutical compositions containing them.

Description

200410693 ⑴ 玫、發明說明 - (發明說明應敘明：發明所屬之技術領域、先前技術、内容、實施方式及圖式簡單說明) 技術領域本發明係關於某些式I哦畊羧醯胺化合物，製備此等化合物之方法，其用於治療肥胖、精神及神經病症之用途，其治療使用方法以及含有該等化合物之醫藥組成物。先前技術已知某些CB!調節劑（稱作拮抗劑或反相激動劑）可用於治療肥胖、精神及神經病症（W001/70700及EP 656354)。但需要具有改良物理化學性質及/或DMPK性質及/或藥效學性質之08丨調節劑。曾報告吡啡羧醯胺類具有抗血栓性質（WO 92/02513)。5,6-二苯基-2-吼□井羧酸揭示於CH 458 36 1。發明内容本發明係有關通式（I)化合物200410693 ⑴ Rose, description of the invention-(the description of the invention should state: the technical field to which the invention belongs, the prior art, the content, the embodiments and the simple description of the drawings) TECHNICAL FIELD The present invention relates to certain formula I compounds, A method for preparing these compounds, its use in the treatment of obesity, mental and neurological disorders, its method of therapeutic use, and pharmaceutical compositions containing these compounds. It is known in the prior art that certain CB! Modulators (called antagonists or inverse agonists) can be used to treat obesity, mental and neurological disorders (W001 / 70700 and EP 656354). However, 08 modulators with improved physicochemical properties and / or DMPK properties and / or pharmacodynamic properties are required. The antithrombotic properties of pyridoxamine have been reported (WO 92/02513). 5,6-Diphenyl-2-hydrocarbon carboxylic acid is disclosed in CH 458 36 1. SUMMARY OF THE INVENTION The present invention relates to compounds of general formula (I)

及其醫藥可接受性鹽、溶劑合物及結晶形式，其中 R1表示環己基、1-哌啶基或苯基； R2表示Η、氯、溴、甲基或甲氧基；以及當R3表示Η時，R4表示Η或氯；以及 200410693 Ρ) Γ發明說明續頁式I化合物中R1之其它代表值說明如後。但須瞭解此等值於適當時可用於前文所述或後文之定義、申請專利範圍或具體實施例。一組式I化合物中，R1表示環己基。第二組式I化合物中，R1表示1 -哌啶基。第三組式I化合物中，R1表示苯基。當可形成鹽類時「醫藥可接受性鹽」包括醫藥可接受性酸及鹼加成鹽。適當式I化合物之醫藥可接受性鹽例如為具有足夠鹼性之式I化合物之酸加成鹽例如與無機或有機酸（如氫氯酸、氫溴酸、硫酸、三氟乙酸、檸檬酸或順丁稀二酸生成之酸加成鹽）；或例如充分酸性之式I化合物之鹽，例如驗金屬或驗土金屬鹽（如鈉、I弓或鎭鹽）、或敍鹽、或與有機鹼（例如曱基胺、二曱基胺、三甲基胺、哌啶、嗎啉或參-(2 -羥基乙基）胺）生成之鹽。全文說明書及隨附之申請專利範圍中，指定化學式或化學名將涵蓋其全部立體及光學異構物以及外消旋混合物、以及（當存在有此等異構物及對映異構物時）個別對映異構物以不同比例混合之混合物，及其醫藥可接受性鹽及溶劑合物例如水合物。異構物可使用習知技術（例如層析術或分選結晶）分離。對映異構物例如可經由分選結晶、光學分割或HP LC經由分離外消旋混合物而被單離。非對映異構物例如可藉分選結晶、Η P L C或急速層析術藉分離異構物混合物而單離。另外，立體異構物可從對掌起始物料於不會造成外消旋化或差向異構化之條件下，藉對掌合 200410693 (3) 發明說明續頁成製造；或經由使用對掌反應劑藉衍生製造。全部立體真構物皆係含括於本發明之範圍。特定本發明化合物為： N - ( 1 -哌啶基）-5,6 -二笨基-2 -哦□井羧醯胺； N - ( 1 -哌啶基）-5，6 -貳（4 -溴苯基）-2 -吡哄羧醯胺； N-(l-哌啶基）-5,6-貳（4 -曱基苯基）-2-吡畊羧醯胺； N-(l-哌啶基）-5,6-貳（4·曱氧基笨基）-2-吡畊羧醯胺； N-(l-哌啶基）-5,6-貳（4-氯苯基）-2-吡哄羧醯胺； N-(卜哌啶基）-5，6-貳（2-氯苯基）-2-吡啡羧醯胺； N-環己基-5,6-二苯基-2吡畊羧醯胺； N-環己基-5,6-貳（4-溴苯基）-2吡啡羧醯胺； N-環己基-5,6-貳（4-甲基笨基）-2吡哄羧醯胺； N-環己基- 5,6-貳（4 -甲氧基苯基）-2吡畊羧醯胺； N-環己基-5,6-貳（4-氣苯基）-2吡畊羧醯胺； N-環己基-5,6-貳（2-氣苯基）-2吡啡羧醯胺； N , 5,6 -三笨基-2吡哄羧醯胺； N -笨基-5,6-貳（4 -曱基苯基）-2 [I比啡羧醯胺； N-苯基- 5,6-貳（4 -甲氧基苯基）-2吡哄羧醯胺； N-笨基-5,6-貳（4-氣苯基）-2吡哄羧醯胺； N-笨基-5,6-貳（2-氯苯基）-2吡哄羧醯胺； N-(l-哌啶基）-5-(4-氣苯基）-6-(2,4-二氣苯基）-2吡哄羧醯胺；以及 N-(l-哌啶基）-6-(4-氯笨基）-5-(2,4-二氣笨基）-2吡畊羧醯胺； 200410693 (4) 發明說明續頁以及當適用時，其光學異構物、互變異構物、立體異構物及外消旋混合物，以及其醫藥可接受性鹽類、溶劑合物及結晶形式。製備方法本發明化合物可根據後述任一種方法製備，摘述如後。但本發明絕非囿限於此等方法，化合物也可如先前技藝對結構相關化合物所述方式製備。式I化合物之製法可經由式II化合物And pharmaceutically acceptable salts, solvates, and crystalline forms thereof, wherein R1 represents cyclohexyl, 1-piperidinyl, or phenyl; R2 represents fluorene, chlorine, bromine, methyl, or methoxy; and when R3 represents Η R4 represents rhenium or chlorine; and 200410693 P) Γ Description of the invention Continuing the description of other representative values of R1 in the compound of formula I are as follows. However, it should be understood that these values may be used in the definitions, patent application scope, or specific embodiments described above or later, as appropriate. In a group of compounds of formula I, R1 represents cyclohexyl. In the second group of compounds of formula I, R1 represents 1-piperidinyl. In the third group of compounds of formula I, R1 represents phenyl. "Pharmaceutically acceptable salts" when salts can be formed include pharmaceutically acceptable acid and base addition salts. Suitable pharmaceutically acceptable salts of compounds of formula I are, for example, acid addition salts of compounds of formula I with sufficient basicity, for example, with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid, citric acid or Acid addition salt of maleic acid); or, for example, a salt of a compound of formula I that is sufficiently acidic, such as a metal or earth metal salt (such as sodium, bow or sulfonium salt), or salt, or organic A salt formed by a base (eg, fluorenylamine, difluorenylamine, trimethylamine, piperidine, morpholine, or p- (2-hydroxyethyl) amine). In the full description and the scope of the attached patent application, the specified chemical formula or chemical name will cover all its stereo and optical isomers and racemic mixtures, and (when such isomers and enantiomers are present) individually Enantiomers are mixed in different ratios, and their pharmaceutically acceptable salts and solvates such as hydrates. Isomers can be separated using conventional techniques such as chromatography or sorted crystals. Enantiomers can be isolated, for example, by sorting crystals, optical segmentation, or HP LC by separating racemic mixtures. Diastereomers can be isolated, for example, by separation crystals, ΗPLC, or flash chromatography by separating a mixture of isomers. In addition, stereoisomers can be produced from the starting material of the palmetto by the pairing of palms under conditions that do not cause racemization or epimerization. 200410693 (3) Continued pages of the description of the invention; Palm reactants are manufactured by derivation. All stereostructures are included in the scope of the present invention. Specific compounds of the invention are: N-(1 -piperidinyl) -5,6 -dibenzyl-2 -oh @ carboxamidine; N-(1 -piperidinyl) -5,6 -fluorene (4 -Bromophenyl) -2-pyridinecarboxamide; N- (l-piperidinyl) -5,6-fluorenyl (4-methylphenyl) -2-pyridoxamine; N- (l -Piperidinyl) -5,6-fluoren (4 · methoxybenzyl) -2-pyridoxamine; N- (l-piperidinyl) -5,6-fluoren (4-chlorophenyl ) -2-pyridinecarboxamidine; N- (piperidinyl) -5,6-pyrene (2-chlorophenyl) -2-pyridinecarboxamide; N-cyclohexyl-5,6-di Phenyl-2 pyridocarboxamidine; N-cyclohexyl-5,6-fluoren (4-bromophenyl) -2 pyridocarboxamide; N-cyclohexyl-5,6-fluoren (4-methyl Benzyl) -2pyridinecarboxamidine; N-cyclohexyl-5,6-fluorenyl (4-methoxyphenyl) -2 piracetamidine; N-cyclohexyl-5,6-fluorene (4 -Phenylphenyl) -2 pyridocarboxamide; N-cyclohexyl-5,6-pyridine (2-phenyl) -2pyridinocarboxamide; N, 5,6 -tribenzyl-2pyridine Carboxamidine; N-benzyl-5,6-fluoren (4-fluorenylphenyl) -2 [I-biffin Carboxamide; N-phenyl-5,6-fluoren (4-methoxybenzene Yl) -2pyridinecarboxamide; N-benzyl-5,6-pyridine (4-aerophenyl) -2pyridinecarboxamide; N-benzylcarboxamide N- (l-piperidinyl) -5- (4-phenyl) -6- (2,4-bis Phenyl) -2pyridinecarboxamide; and N- (l-piperidinyl) -6- (4-chlorobenzyl) -5- (2,4-diaphthyl) -2 Amidine; 200410693 (4) Description of the invention, and, where applicable, its optical isomers, tautomers, stereoisomers, and racemic mixtures, and their pharmaceutically acceptable salts, solvates, and Crystalline form. Preparation method The compound of the present invention can be prepared according to any one of the methods described below, and is summarized below. However, the present invention is by no means limited to these methods, and compounds can also be prepared as described in the prior art for structure-related compounds. Compounds of formula I can be prepared via compounds of formula II

其中R2、R3及R4定義如前與式Π I胺Where R2, R3 and R4 are as defined above and amines of formula II

R丨NH 於惰性溶劑（如二氯甲烷），於偶合劑（如曱二醯亞胺如 1-(3-二曱基胺基丙基）-3-乙基曱二醯亞胺）存在下以及視情況需要，於催化劑（如鹼性催化劑例如4 -二曱基胺基吡啶）存在下，於-25°C至150°C範圍之溫度反應而製備。式II及III化合物可如實施例所述以及經由熟諳技藝人士已知之其它方法製備。某些式II化合物其中R2、R3及R4定義如前，相信該等式II 化合物為新穎且於此處請求專利作為本發明之另一特色 -9- 200410693 (5) I發明說明續頁，但5,6-二笨基-2吡啡羧酸及5,6-貳（4 -甲氧基苯基）-2吔啡羧酸除外。本發明化合物可使用習知技術由反應混合物單離。熟諳技藝人士瞭解為了以另一種方式且於某些情況下以更方便之方式獲得本發明化合物，前文敘述之個別方法步驟可以不同順序進行，及/或個別反應可於整體途徑之不同階段進行（亦即可對前文就特定反應所述之中間物之不同中間物進行化學轉變）。「惰性溶劑」之表示法表示一種溶劑其不會以對所需產物產率造成不良影響之方式與起始物料、反應劑、中間物或產物起反應。醫藥製劑本發明化合物通常係經口、腸道外、靜脈、肌肉、皮下或其它注射途徑、經頰、經直腸、經***、經皮及/或經鼻途徑投藥，及/或透過吸入途徑投藥，投藥形式為包含活性成分或醫藥可接受性有機或無機鹼加成鹽呈醫藥可接受性劑型之醫藥製劑形式投予。依據欲治療之病症及病人以及投藥途徑而定，組成物可以不同劑量投藥。本發明化合物用於人類治療性處理之適當每日劑量為約0.00 1-10毫克/千克體重且較佳為0.0 1-1毫克/千克體重。口服調配劑為較佳，特別為錠劑或膠囊劑，口服調配劑可藉熟諳技藝人士已知方法調配，提供0.5毫克至500毫克範圍之活性化合物劑量，例如1毫克、3毫克、5毫克、1 0 毫克、25毫克、50毫克' 100毫克及250毫克。 200410693 (6) 發明說明續頁本發明化合物也可組合其它抗肥胖劑例如歐立史達特 < (Orlistat)或單胺再吸收抑制劑例如西布徹明（Sibutramine)使用。此外，本發明化合物也可組合治療劑使用，該等治療劑係可用於治療肥胖相關病症或病情（例如第II型糖尿病、代謝症候群、血中脂肪代謝障礙、葡萄糖耐性受損、高血壓、冠心病、非酒精性脂漏性肝炎、骨關節炎以及某些癌症）以及精神及神經疾病。根據本發明之又一特色，也提供一種醫藥調配物，其包括任一種本發明化合物或其醫藥可接受性衍生物混合醫藥可接受性佐劑、稀釋劑及/或載劑。藥理性質式’（I)化合物可用於治療肥胖、精神病症例如精神錯亂、精神***、兩極性躁鬱症、焦慮症、焦慮-憂鬱症、憂· 鬱症、認知障礙、記憶障礙、強迫症、厭食症、貪食症、注意力障礙例如ADHD、癲癇及相關疾病、以及神經病症例如癡呆、神經發炎病症（例如多發性硬化）、雷氏症候群、帕金森氏病、亨丁頓氏舞蹈症及阿茲海默氏病。該等化合物也可用於治療免疫、心血管、生殖及内分泌病症、敗血性休克以及呼吸系統及胃腸系統相關疾病（例如腹瀉）。該等化合物也可用作為治療劑用於治療長期濫用、成癮及/或復發適應症例如治療藥物（尼古丁、酒精、古柯驗、雅片劑等）依賴性及/或治療藥物（尼古丁、酒精、古柯鹼、雅片劑等）戒斷症狀。該等化合物也可去除通常伴隨著戒菸時的體重增加。 200410693 (7) 發明說明績頁於另一特色，本發明提供如前述式I化合物用作為藥滅之用途。又另一特色，本發明提供式I化合物用於製備下列疾病之治療或預防用藥：肥胖、精神病症例如精神錯亂、精神 ***、兩極性躁鬱症、焦慮症、焦慮-憂鬱症、憂鬱症、認知障礙、記憶障礙、強迫症、厭食症、貪食症、注意力障礙例如ADHD、癲痛及相關疾病、神經病症例如癡呆、神經發炎病症（例如多發性硬化）、帕金森氏病、亨丁頓氏舞蹈症及阿茲海默氏病、免疫、心血管、生殖及内分泌病症、敗血性休克以及呼吸系統及胃腸系統相關疾病（例如腹瀉）以及長期濫用、成癮及/或復發適應症例如治療藥物 (尼古丁、酒精、古柯鹼、雅片劑等）依賴性及/或治療藥物（尼古丁、酒精、古柯鹼、雅片劑等）戒斷症狀。本發明之又另一方面提供一種治療肥胖、精神病症例如精神錯亂如精神***及兩極性躁鬱症、焦慮症、焦慮•憂餐症、憂鬱症、認知障礙、記憶障礙、強迫症、厭食症、貪食症、注意力障礙例如ADHD、癲癇及相關疾病、神經病症例如癡呆、神經發炎病症（例如多發性硬化）、帕金森氏病、亨丁頓氏舞蹈症及阿茲海默氏病、免疫、心血管、生殖及内分泌病症、敗血性休克以及呼吸系統及胃腸系統相關疾病（例如腹瀉）以及長期濫用、成癮及/或復發適應症例如治療藥物（尼古丁、酒精、古柯驗、雅片劑等）依賴性及/或治療藥物（尼古丁、酒精、古柯鹼、雅片劑等）戒斷症狀之方法，該方法包含對有需要之病人投予藥理有效 200410693 (8) 發明說明續頁量之式I化合物。本發明化合物特別適合用於治療肥胖，例如藉由降低食慾及體重、維持體重減輕以及預防回復發胖而治療肥胖。實施例縮寫 DCM-二氯甲烷 DMF-二甲基甲醯胺 DMAP - 4-二甲基胺基吡啶 EDC-l-(3-二曱基胺基丙基）-3-乙基曱二醯亞胺 TEA-三乙基胺 TFA-三氟乙酸 DMSO-二曱亞 DEA-二乙基胺 PCC-氣鉻酸吡啶 DCM-二氣曱烷 t 三峰 S 單峰 d 雙峰 q 四峰 q vint 五峰 m 多峰 b r 見 b s 寬單峰 dm 多峰之雙峰 200410693 (9) 發明說明續頁 bt 寬三峰 - dd 雙峰之雙峰概略實驗程序質譜係記錄於微質量（Micr⑽ass) ZQ單一四極質譜儀或微質量LCZ早一四極質譜儀，二儀器皆配備有氣動式輔助電噴霧介面（LC-MS)。iH NMR測量係於微麗安汞（VaHan Mercury) j〇〇或Μ麗安英諾瓦（In〇va) 500進行，二儀器分別係於300及 500百萬赫兹之ιΗ頻率操作。化學移位係以CDCl3作為内部標準品，以ppm表示。純化係於半製備性Ηριχ進行，帶有質量觸發之洗提分收集器’島津QP 8000單一四極質譜儀，其配備有19 X 1 〇〇毫米C8管柱。若未做額外陳述，使用之動相為乙腈及緩衝液（0· 1 Μ乙酸氨：乙腈95:5)。供分離異構物，使用克羅斯美瑟（Kromasil) CN Ε9344 (250 X 20毫米内徑）管柱。使用庚烷：乙酸乙酯：DEA 95:5:0.1作為動相（1毫升/分鐘）。洗提分之收集係使用紫外光偵測器 (330奈米）導引。中間物之合成下列中間物並非市面上可得，因此係如製備例A所述合成（Chem. Ber·，100, 1967, ρ· 555)。R 丨 NH in an inert solvent (such as dichloromethane), in the presence of a coupling agent (such as fluorene diimide such as 1- (3-diamidinoaminopropyl) -3-ethyl fluorene diimide) And if necessary, it is prepared by reacting in the presence of a catalyst (such as a basic catalyst such as 4-diamidoaminopyridine) at a temperature ranging from -25 ° C to 150 ° C. Compounds of formulae II and III can be prepared as described in the examples and via other methods known to those skilled in the art. Certain compounds of formula II in which R2, R3, and R4 are as defined above. It is believed that these compounds of formula II are novel and patented here as another feature of the invention. 9-200410693 (5) I Description of the invention continued, but Except 5,6-dibenzyl-2pyridinecarboxylic acid and 5,6-fluorene (4-methoxyphenyl) -2fluorenecarboxylic acid. The compounds of the invention can be isolated from the reaction mixture using conventional techniques. Those skilled in the art understand that in order to obtain the compounds of the invention in another way and in some cases in a more convenient manner, the individual method steps described above can be performed in different orders, and / or individual reactions can be performed at different stages of the overall pathway ( That is to say, chemical conversion can be performed on different intermediates of the intermediates described in the previous specific reaction). The expression "inert solvent" means a solvent that does not react with the starting materials, reagents, intermediates or products in a manner that adversely affects the desired product yield. Pharmaceutical formulations The compounds of the invention are generally administered orally, parenterally, intravenously, intramuscularly, subcutaneously or by other injection routes, buccal, rectal, vaginal, transdermal and / or nasal routes, and / or by inhalation routes, The dosage form is a pharmaceutical preparation containing an active ingredient or a pharmaceutically acceptable organic or inorganic base addition salt in a pharmaceutically acceptable dosage form. Depending on the condition and patient to be treated and the route of administration, the composition may be administered in different doses. A suitable daily dose of a compound of the invention for therapeutic treatment in humans is about 0.00 1-10 mg / kg body weight and preferably 0.0 1-1 mg / kg body weight. Oral formulations are preferred, especially lozenges or capsules. Oral formulations can be formulated by methods known to those skilled in the art to provide dosages of the active compound in the range of 0.5 mg to 500 mg, such as 1 mg, 3 mg, 5 mg, 10 mg, 25 mg, 50 mg ', 100 mg and 250 mg. 200410693 (6) Description of the invention continuation sheet The compounds of the present invention can also be used in combination with other anti-obesity agents such as Orlistat or monoamine reuptake inhibitors such as Sibutramine. In addition, the compounds of the present invention can also be used in combination with therapeutic agents that are useful in the treatment of obesity-related disorders or conditions (eg, type II diabetes, metabolic syndrome, impaired lipid metabolism, impaired glucose tolerance, hypertension, coronary disease). Heart disease, nonalcoholic lipidarrhoidal hepatitis, osteoarthritis, and some cancers) and mental and neurological diseases. According to still another feature of the present invention, there is also provided a pharmaceutical formulation comprising any one of the compound of the present invention or a pharmaceutically acceptable derivative thereof, a mixed pharmaceutically acceptable adjuvant, a diluent and / or a carrier. Pharmacological properties Compounds of formula '(I) are useful in the treatment of obesity, mental disorders such as schizophrenia, schizophrenia, bipolar disorder, anxiety, anxiety-depression, depression, depression, cognitive impairment, memory disorders, obsessive-compulsive disorder, anorexia Bulimia, attention disorders such as ADHD, epilepsy and related diseases, and neurological conditions such as dementia, neuroinflammatory conditions (such as multiple sclerosis), Reye syndrome, Parkinson's disease, Huntington's disease, and Alzheimer's Moore's disease. These compounds can also be used to treat immune, cardiovascular, reproductive and endocrine disorders, septic shock, and diseases related to the respiratory and gastrointestinal systems (such as diarrhea). These compounds can also be used as therapeutic agents for the treatment of chronic abuse, addiction and / or relapse indications such as therapeutic drugs (nicotine, alcohol, coca test, astatin, etc.) dependence and / or therapeutic drugs (nicotine, alcohol , Cocaine, refined tablets, etc.) withdrawal symptoms. These compounds can also remove weight gain usually associated with quitting smoking. 200410693 (7) Summary page of the invention In another feature, the present invention provides the use of the compound of formula I as a medicament. In yet another feature, the present invention provides a compound of formula I for use in the preparation of a therapeutic or prophylactic agent for the following diseases: obesity, mental disorders such as insanity, schizophrenia, bipolar disorder, anxiety, anxiety-depression, depression, cognition Disorders, memory disorders, obsessive-compulsive disorder, anorexia, bulimia, attention disorders such as ADHD, epilepsy and related disorders, neurological disorders such as dementia, neuroinflammatory disorders (such as multiple sclerosis), Parkinson's disease, Huntington's Chorea and Alzheimer's disease, immune, cardiovascular, reproductive and endocrine disorders, septic shock, and diseases related to the respiratory and gastrointestinal systems (such as diarrhea) and chronic abuse, addiction and / or relapse indications such as therapeutic drugs (Nicotine, alcohol, ***e, astatin, etc.) withdrawal and / or treatment drugs (nicotine, alcohol, ***e, astatin, etc.) withdrawal symptoms. Yet another aspect of the present invention provides a method for treating obesity, mental disorders such as schizophrenia such as schizophrenia and bipolar disorder, anxiety, anxiety • anxiety, depression, depression, cognitive impairment, memory disorder, obsessive-compulsive disorder, anorexia, Bulimia, attention disorders such as ADHD, epilepsy and related diseases, neurological disorders such as dementia, neuroinflammatory disorders (such as multiple sclerosis), Parkinson's disease, Huntington's disease and Alzheimer's disease, immunity, Cardiovascular, reproductive and endocrine disorders, septic shock and diseases related to the respiratory and gastrointestinal systems (such as diarrhea) and indications for chronic abuse, addiction and / or relapse such as therapeutic drugs (nicotine, alcohol, coca test, agar tablets) Etc.) Method for dependence and / or treatment of withdrawal symptoms of nicotine, alcohol, ***e, astatin, etc., which method comprises pharmacologically effective administration to patients in need 200410693 (8) Description of the Continued Page Formula I. The compounds of the present invention are particularly suitable for the treatment of obesity, for example, by reducing appetite and weight, maintaining weight loss, and preventing obesity. Example abbreviation DCM-dichloromethane DMF-dimethylformamidine DMAP-4-dimethylaminopyridine EDC-l- (3-diamidinoaminopropyl) -3-ethylphosphonium difluorene Amine TEA-triethylamine TFA-trifluoroacetic acid DMSO-dihydrazene DEA-diethylamine PCC-pyrochromic acid DCM-difluoromethane t triplet S singlet d doublet q fourt q vint fivet m Multimodal br See bs wide singlet dm multimodal doublet 200410693 (9) Description of the Invention Continued bt Broad Trimodal-dd Doublet Doublet Summary Experimental Procedure The mass spectrometer is recorded in the micro mass (Micr⑽ass) ZQ single quadrupole mass spectrometer The mass LCZ has a quadrupole mass spectrometer and both instruments are equipped with a pneumatically assisted electrospray interface (LC-MS). iH NMR measurements were performed on VaHan Mercury jOO or Mli Inova 500. The two instruments were operated at 300 and 500 megahertz frequencies. Chemical shifts are based on CDCl3 as an internal standard, expressed in ppm. Purification was performed in a semi-preparative Ηρχχ with a mass-triggered elution fraction collector 'Shimadzu QP 8000 single quadrupole mass spectrometer equipped with a 19 X 100 mm C8 column. Unless otherwise stated, the mobile phases used are acetonitrile and buffer (0.1 M ammonia acetate: acetonitrile 95: 5). For separation of isomers, a Kromasil CN Ε9344 (250 X 20 mm ID) column was used. Heptane: ethyl acetate: DEA 95: 5: 0.1 was used as the mobile phase (1 ml / min). Elution fractions were collected using a UV detector (330 nm). Synthesis of Intermediates The following intermediates are not commercially available and were synthesized as described in Preparation A (Chem. Ber ·, 100, 1967, ρ · 555).

製備例A (a) 5,6-二笨基吼畊-2-羧酸 2,3-二胺基丙酸一鹽酸鹽（500毫克，3.56毫莫耳）以及聯苯醯（ 890毫克，4.23毫莫耳）添加至氫氧化鈉溶液（677毫克，16.93 毫莫耳）於甲醇（1〇毫升）之溶液。加入另一份曱醇（5毫升） 200410693 (ίο) 發明說明續頁，反應混合物回流2 0分鐘。混合物冷卻至2 5 °C，通空氣Μ 3 0分鐘時間。加入鹽酸（水性2 Μ)至反應混合物達pH 2。溶液以***萃取。合併***相經脫水（硫酸鎂），過濾及於減壓下蒸發獲得粗產物。MS m/z 277 (M+H)+。粗產物未經進一步純化即用於下述步驟。 (b) 5,6-貳- (4-溴苯基μ比畊-2-羧酸Preparation Example A (a) 5,6-dibenzyl-2-carboxylic acid 2,3-diaminopropionic acid monohydrochloride (500 mg, 3.56 mmol) and biphenylhydrazone (890 mg, 4.23 mmol) was added to a solution of sodium hydroxide solution (677 mg, 16.93 mmol) in methanol (10 ml). Another portion of methanol (5 ml) was added. 200410693 (ίο) Description of the Invention Continued The reaction mixture was refluxed for 20 minutes. The mixture was cooled to 25 ° C and ventilated for 30 minutes. Hydrochloric acid (aqueous 2M) was added until the reaction mixture reached pH 2. The solution was extracted with ether. The combined ether phases were dehydrated (magnesium sulfate), filtered and evaporated under reduced pressure to obtain the crude product. MS m / z 277 (M + H) +. The crude product was used in the following steps without further purification. (b) 5,6-fluorene- (4-bromophenyl)

標題化合物大致係如製備例Α步驟（a)所述製備，但使用 2,3 -二胺基丙酸一鹽酸鹽（600毫克，4.26毫莫耳）以及4,4’-二溴聯苯醯（1 · 7 4 5克，4.2 6毫莫耳，9 0 %)作為起始物料。反應混合物回流2小時，通空氣1小時。加入鹽酸（水性，2 Μ)至p Η 2。混合物於減壓下蒸發，殘餘物溶解於水。溶液以***萃取，合併***相經脫水（硫酸鎂），過濾及於減壓下蒸發。粗產物（5 0 0毫克，2 7 % )未經進一步純化即用於後述步驟。MS m/z 435, 437, 439 (Μ+Η)+。 (c) 5,6-二-對甲苯基吡畊-2-羧酸The title compound was prepared roughly as described in step (a) of Preparation A, but using 2,3-diaminopropionic acid monohydrochloride (600 mg, 4.26 mmol) and 4,4'-dibromobiphenyl Tritium (1.745 grams, 4.26 millimoles, 90%) was used as the starting material. The reaction mixture was refluxed for 2 hours and allowed to air for 1 hour. Hydrochloric acid (aqueous, 2M) was added to pΗ2. The mixture was evaporated under reduced pressure and the residue was dissolved in water. The solution was extracted with ether, and the combined ether phases were dehydrated (magnesium sulfate), filtered and evaporated under reduced pressure. The crude product (500 mg, 27%) was used in the next step without further purification. MS m / z 435, 437, 439 (Μ + Η) +. (c) 5,6-Di-p-tolyl pyridine-2-carboxylic acid

標題化合物係如製備例A步驟（a)所述使用4,4’-二曱基聯苯醯（8 4 8毫克，3 . 5 6毫莫耳）製備。但反應混合物回流1 小時以及反應混合物通空氣約7小時。混合物經蒸發及殘餘物溶解於水。加入鹽酸（水性，2 Μ)至達到p Η 2。溶液以***萃取。合併***相經脫水（硫酸鎂），過濾及減壓蒸發。粗產物（9 1 8毫克，8 5 %)未經進一步純化即用於後述步驟。MS m/z 305 (Μ + Η)+。 (d) 5,6-貳- (4 -曱氧基笨基吡畊-2-羧酸標題化合物係如製備例A步驟（c )所述使用4,4 ’ -二曱氧 -15 - 200410693 (11) 發明說明續頁基聯苯醯（9 6 1毫克，3 . 5 6毫莫耳）作為起始物料製備。皮應混合物回流隔夜，混合物通空氣8小時。粗產物（4 3 5毫克，36%)表經進一步純化即用於後述步驟。MS m/z 335 (Μ + Η). 〇 (e) 5,6-貳-(4-氣苯基）-吡畊-2-羧酸標題化合物係如製備例A步驟（c )所述使用4，4 ’ -二氯聯苯醯（9 9 3毫克，3 . 5 6毫莫耳）製備。回流1小時直接獲得粗產物（9 2 3毫克，7 5 % )，其未經進一步純化即用於後述步驟。MS m/z 343, 345, 347 (M-Η)·。 (f) 5,6-貳- (2-氯苯基）-吡畊-2-羧酸標題化合物係如製備例A步驟（c )所述使用2，2 ’ -二氯聯笨醯（9 9 3毫克，3 . 5 6毫莫耳）製備。粗產物（8 9 5毫克，7 3 % ) ，其未經進一步純化即用於後述步驟。MS m/z 343, 345, 347 (M-H)· 〇 (g) 2-(4-氯苯基）-1-(2,4-二氯笨基）乙酮 (4-氯笨基）乙醯氣（7.0克，73.0毫莫耳），1,3-二氯-苯（42 毫升，3 7 0毫莫耳）及氣化鋁（6 · 9克，5 1 · 8毫莫耳）之混合物於2 5 °C攪拌隔夜。水性後續處理及管柱層析術（矽膠，曱笨：庚烷1 : 1 )獲得標題化合物（2.70克，24%)。MS m/z 297, 299, 301 (M-Η).。 (h) 1-(4-氣本基）-2-(2,4-二氣本基）乙烧-1,2 -二嗣 2-(4-氯笨基）-1-(2，4·二氣笨基）乙酮（2.7克，9.01毫莫耳）溶解於1，2-二氣乙烷（25毫升），加入新鮮製備之PCC (3.89 克，18.02毫莫耳），ίΐ比啶（1.43克，18.02毫莫耳）及分子篩。 200410693 (12) 發明說明續頁反應混合物於惰性氣氛回流隔夜。溶液冷卻至2 5 °C，經矽膠過濾，然後於減壓下蒸發去除溶劑。粗產物（1.9克，66%) 直接用於次一步驟。WNMR (500MHz) 5 7,97 (d，2H)，7.84 (d， 1H), 7.52 (d，2H)，7.46 (s, 1H)，7.44 (d, 1H)。 (i) 5-(4 -氯苯基）-6-(2,4-二氯苯基）□比畊-2-羧酸以及6-(4-氯苯基）-5-(2，4-二氯苯基）吼啡-2-羧酸標題化合物係如製備例A步驟（a)所述製備，但使用得自製備例A步驟（h)之1-(4-氯苯基）-2-(2，4-二氯苯基）乙烷-1,2-二酮（1.85克；5.90毫莫耳）及2,3-二胺基丙酸一鹽酸鹽 (0.61克，5.90毫莫耳）作為起始物料。混合物回流30分鐘然後只接後續處理。讓粗產物放置隔夜進行芳香化。急速層析（矽膠，二氣甲烷：曱醇1 〇 ; 1，1 %乙酸）獲得異構物混合物（0.2 克，10%)。MS m/z 377, 379, 38 1 (M-Η)·。本發明實施例實施例1 N - ( 1 -吡啶基）-5，6 -二苯基-2 -吼畊羧醯胺得自製備例A步驟（a)之5,6-二苯基J比畊-2 ·羧酸（5 0 0毫克，1 ·8 1毫莫耳）溶解於DCM (4毫升）及DMF (150微升）。加入DMAP (22毫克，0.18毫莫耳）及1-胺基吼啶（218毫克， 2 . 1 7毫莫耳），混合物冷卻至。逐滴加入E D C料漿（1.99 毫莫耳，於DCM及100微升DMF)。反應混合物於25°C攪拌。17小時後又加入1-胺基D比咬（40毫克，0.40毫莫耳）及 EDC (76毫克，0_40毫莫耳），混合物又攪拌3小時。粗產物以D C Μ ( 5毫升）稀釋，以飽和碳酸氫鈉溶液洗條。有機 •17- 200410693 發明說明續頁相經脫水（硫酸鎮），過；慮及蒸發。急速層析術〇夕膠，6 酸乙酯：己烷2 : 1 )獲得小標題化合物（1 6 0毫克，2 5 % )，呈白色固體。丨HNMR (300MHz)5 9.41 (s，1H)，8.52 (s，1H)，7.50-7.29 (m，10H)， 2.94 (t，4H)，1.81 (m，4H)，1.50 (m，2H)。 MS m/z 359 (M + H)+。實施例2 N-(l-吡啶基）-5,6-貳（4-溴苯基）-2-吡畊羧醯胺The title compound was prepared as described in Step (a) of Preparation A using 4,4'-difluorenylbiphenylphosphonium (8.88 mg, 3.56 mmol). However, the reaction mixture was refluxed for 1 hour and the reaction mixture was allowed to air for about 7 hours. The mixture was evaporated and the residue was dissolved in water. Hydrochloric acid (aqueous, 2M) was added until pΗ2 was reached. The solution was extracted with ether. The combined ether phases were dehydrated (magnesium sulfate), filtered and evaporated under reduced pressure. The crude product (918 mg, 85%) was used in the steps described below without further purification. MS m / z 305 (M + H) +. (d) The title compound of 5,6-fluorenyl- (4-methoxybenzylopyridine-2-carboxylic acid is 4,4'-dioxo-15-200410693 as described in step (c) of Preparation A. (11) Description of the invention Continuing phenylbiphenylhydrazone (96 1 mg, 3.56 mmol) was prepared as a starting material. The skin should be refluxed overnight, and the mixture was allowed to air for 8 hours. The crude product (4 3 5 mg (36%) Table was further purified and used in the steps described below. MS m / z 335 (M + Η). 〇 (e) 5,6- 贰-(4-Gaphenyl) -pyracine-2-carboxylic acid The title compound was prepared as described in Step (c) of Preparation A using 4,4'-dichlorobiphenylhydrazone (993 mg, 3.56 mmol). The crude product was obtained by refluxing for 1 hour (9 2 3 mg, 75%), which was used in the following steps without further purification. MS m / z 343, 345, 347 (M-Η) ·. (F) 5,6- 贰-(2-chlorophenyl) ) -Pycnogenol-2-carboxylic acid The title compound was prepared as described in Step (c) of Preparation A using 2,2'-dichlorobibenzamine (993 mg, 3.56 mmol). Crude The product (895 mg, 73%) was used in the following steps without further purification. MS m / z 343, 345, 347 (MH) · (g) 2- (4-chlorophenyl) -1- (2,4-dichlorobenzyl) ethanone (4-chlorobenzyl) acetone gas (7.0 g, 73.0 mmol), 1,3 -A mixture of dichloro-benzene (42 ml, 370 mmol) and vaporized aluminum (6.9 g, 5 1.8 mmol) was stirred overnight at 25 ° C. Aqueous post-treatment and column Chromatography (silica gel, heptane: heptane 1: 1) gave the title compound (2.70 g, 24%). MS m / z 297, 299, 301 (M-Η). (H) 1- (4- (Gasyl) -2- (2,4-digasbenzyl) ethane-1,2-dihydrazine 2- (4-chlorobenzyl) -1- (2,4 · digasbenzyl) acetone (2.7 g, 9.01 mmol) dissolved in 1,2-digas ethane (25 ml), and freshly prepared PCC (3.89 g, 18.02 mmol) was added, and pyridine (1.43 g, 18.02 mmol) ) And molecular sieves. 200410693 (12) Description of the invention Continuation page The reaction mixture was refluxed overnight in an inert atmosphere. The solution was cooled to 25 ° C, filtered through silica gel, and then the solvent was removed by evaporation under reduced pressure. Crude product (1.9 g, 66%) Used directly in the next step. WNMR (500MHz) 5 7,97 (d, 2H), 7.84 (d, 1H), 7.52 (d, 2H), 7.46 (s, 1H), 7.44 (d, 1H). (i) 5- (4-Chlorophenyl) -6- (2,4-dichlorophenyl) □ Phen-2-carboxylic acid and 6- (4-chlorophenyl) -5- (2,4 -Dichlorophenyl) rophine-2-carboxylic acid The title compound was prepared as described in Step (a) of Preparation A, but using 1- (4-chlorophenyl) from Step (h) of Preparation A 2- (2,4-dichlorophenyl) ethane-1,2-dione (1.85 g; 5.90 mmol) and 2,3-diaminopropionic acid monohydrochloride (0.61 g, 5.90 mmol) Mol) as starting material. The mixture was refluxed for 30 minutes and then subjected to subsequent processing only. The crude product was allowed to stand overnight for aromatization. Rapid delamination (silica gel, digasmethane: methanol 10; 1.1% acetic acid) to obtain a mixture of isomers (0.2 g, 10%). MS m / z 377, 379, 38 1 (M-Η). Examples of the present invention Example 1 N-(1 -pyridyl) -5,6-diphenyl-2 -crotocarboxamidine is obtained from the 5,6-diphenyl J ratio in step (a) of Preparation Example A Geng-2 · carboxylic acid (500 mg, 1.81 mol) was dissolved in DCM (4 ml) and DMF (150 µl). Add DMAP (22 mg, 0.18 mmol) and 1-aminopyridine (218 mg, 2. 17 mmol) and cool the mixture to. Add the E DC slurry (1.99 millimoles in DCM and 100 μl DMF) dropwise. The reaction mixture was stirred at 25 ° C. After 17 hours, 1-amino D specific bite (40 mg, 0.40 mmol) and EDC (76 mg, 0-40 mmol) were added, and the mixture was stirred for another 3 hours. The crude product was diluted with DC (5 ml) and the bars were washed with a saturated sodium bicarbonate solution. Organic • 17- 200410693 Description of the Invention Continued The phase is dehydrated (sulphuric acid), too; taking into account evaporation. Flash chromatography gelatin, ethyl acetate: hexane 2: 1) to obtain the subtitled compound (160 mg, 25%) as a white solid. HNMR (300MHz) 5 9.41 (s, 1H), 8.52 (s, 1H), 7.50-7.29 (m, 10H), 2.94 (t, 4H), 1.81 (m, 4H), 1.50 (m, 2H). MS m / z 359 (M + H) +. Example 2 N- (l-pyridyl) -5,6-fluorene (4-bromophenyl) -2-pyroxycarboxamide

於得自製備例A步驟（b ) 5，6 -貳-(4 -溴苯基）-吡畊-2 -羧酸（108毫克，0.25毫莫耳），加入DM AP (0.025毫莫耳，於 5 0 0微升D C Μ )，1 -胺基吡啶（0 · 2 5毫莫耳，於1 1 0 0微升D C Μ) ，EDC (0.27毫莫耳，於1100微升DCM及冷卻至8°C)。反應混合物於2 5 t攪拌2 0小時，然後以飽和碳酸氫鈉溶液洗滌，脫水（硫酸鎂），過濾及蒸發。半製備性HPLC (0.01% TEA 於緩衝相）獲得小標題化合物（6.7毫克，5.4%)。丨HNMR (300MHz) 5 9.41 (s, 1H)，8.48 (s，1H), 7.54 (d，2H)，7·5 1 (d， 2H)，7.36 (d，2H)，7.34 (d，2H)，2·94 (t, 4H)，1.81 (m，4H)，1·55·1·45 (m, 2H)。 MS m/z 5 1 5，5 1 7，5 19 (M + H)' 實施例3 N-(l-吡啶基）-5,6-貳（4-曱基苯基）-2-吡啡羧醯胺；得自製備例A步驟（c )之5，6 -二-對曱笨基-吡哄-2 -羧酸 7 6毫克，0.2 5毫莫耳）如實施例2所示用以獲得標題化合物 (2 7 毫克，2 8 % )。 -18 - 200410693 (14) 發明說明續頁 !HNMR (300MHz) (5 9.3 5 (s，1H)，8.57 (s，1H)，7.3 8 (d，4H)，7· 18 (d, 2H), 7.13 (d, 2H), 2.92 (t? 4H), 2.40 (s, 3H)? 2.37 (s, 3H)? 1.86-1.75 (m, 4H), 1.54-1.44 (m, 2H)。 MS m/z 387 (M+H)+。實施例4 N-(l-吡啶基）-5，6-貳（4 -甲氧基苯基）-2-吡哄羧醯胺；To step (b) 5,6 -fluorene- (4-bromophenyl) -pyracin-2-carboxylic acid (108 mg, 0.25 mmol) obtained from Preparation Example A, DM AP (0.025 mmol, At 500 μl DC Μ), 1-aminopyridine (0.25 mM, at 110 μl DC Μ), EDC (0.27 mM, at 1100 μl DCM and cooled to 8 ° C). The reaction mixture was stirred at 25 t for 20 hours, then washed with saturated sodium bicarbonate solution, dehydrated (magnesium sulfate), filtered and evaporated. Semi-preparative HPLC (0.01% TEA in buffer phase) gave the subtitled compound (6.7 mg, 5.4%).丨 HNMR (300MHz) 5 9.41 (s, 1H), 8.48 (s, 1H), 7.54 (d, 2H), 7.5.1 (d, 2H), 7.36 (d, 2H), 7.34 (d, 2H) , 2.94 (t, 4H), 1.81 (m, 4H), 1.55 · 1 · 45 (m, 2H). MS m / z 5 1 5, 5 1 7, 5 19 (M + H) 'Example 3 N- (l-pyridinyl) -5,6-fluorene (4-fluorenylphenyl) -2-pyridine Carboxamidine; 5,6-di-p-pyridinyl-pyridine-2-carboxylic acid (76 mg, 0.2 5 mmol) from step (c) in Preparation Example A) was used as shown in Example 2 The title compound was obtained (27 mg, 28%). -18-200410693 (14) Description of the invention continued! HNMR (300MHz) (5 9.3 5 (s, 1H), 8.57 (s, 1H), 7.38 (d, 4H), 7. 18 (d, 2H), 7.13 (d, 2H), 2.92 (t? 4H), 2.40 (s, 3H)? 2.37 (s, 3H)? 1.86-1.75 (m, 4H), 1.54-1.44 (m, 2H). MS m / z 387 (M + H) +. Example 4 N- (l-pyridyl) -5,6-fluorene (4-methoxyphenyl) -2-pyridazolamide;

得自製備例A步驟（d)之5,6-貳- (4 -甲氧基苯基）-吡啡- 2-羧酸（8 4毫克，0.2 5毫莫耳）如實施例2所示用以獲得標題化合物（2 0毫克，1 9 % )。 lHNMR (3 00MHz) 5 9.3 1 (s, 1 Η), 8.5 7 (s, 1Η), 7.46 (d, 2H), 7.44 (d, 2H), 6.90 (d, 2H), 6.86 (d, 2H), 3.86 (s, 3H)? 3.84 (s, 3H), 2.93 (t, 4H). 1.80 (m, 4H), 1.54-1.45 (m, 2H)· MS m/z 419 (M + H)' 實施例5 N-(l-吡啶基）-5,6-貳（4-氣苯基）-2-吡啡羧醯胺；5,6-fluorene- (4-methoxyphenyl) -pyrphin-2-carboxylic acid (84 mg, 0.2 5 mmol) obtained in step (d) of Preparation A as shown in Example 2 To obtain the title compound (20 mg, 19%). lHNMR (3 00MHz) 5 9.3 1 (s, 1 Η), 8.5 7 (s, 1 Η), 7.46 (d, 2H), 7.44 (d, 2H), 6.90 (d, 2H), 6.86 (d, 2H) , 3.86 (s, 3H)? 3.84 (s, 3H), 2.93 (t, 4H). 1.80 (m, 4H), 1.54-1.45 (m, 2H) MS m / z 419 (M + H) 'Implementation Example 5 N- (l-pyridyl) -5,6-fluorene (4-phenyl) -2-pyridinecarboxamide

得自製備例A步驟（e)之5,6-貳- (4 -氯苯基）-吡啡-2-羧酸 (8 6毫克，0.2 5毫莫耳）如實施例2所示用以獲得標題化合物（1 6毫克，1 5 % )。 'HNMR (300MHz) 5 9.40 (s, 1H), 8.49 (s, 1H), 7.45-7.31 (m, 8H), 2.94 (t, 4H), 1.80 (m, 4H), 1.54- 1.45 (m, 2H). MS m/z 427, 429, 43 1 (M + H)+。實施例6 N-(1-吡啶基）-5,6-貳（2-氯笨基）-2-吡哄羧醯胺；得自製備例A步驟（f)之5,6-貳-(2-氯笨基）-吡啡-2-羧酸 -19 - 200410693 (15) 發明說明續頁 (8 6毫克，0.2 5毫莫耳）如實施例2所示用以獲得標題化4 物（6毫克，6 %)。 ^NMR (300MHz) 5 9.52 (s, 1H), 8.52 (s5 1H)? 7.44-7.17 (d? 8H)? 2.94-2.88 (t, 4H)，1.85- 1.70 (m，4H), 1.52-1.44 (m，2H). MS m/z 427, 429, 43 1 (M+H) + . 實施例7 N - ( 1 -環己基）-5，6 -二苯基-2 - [I比哄羧醯胺得自製備例A步驟（a)之5，6-二苯基-吼畊-2-羧酸（70毫克，0.2 5毫莫耳）大致如實施例2所述，但與環己基胺（0.2 5 毫莫耳，於1毫升DCM)，DMAP (0.025毫莫耳，於0.5毫升DCM) ，EDC(0·28毫莫耳，於1毫升DCM及冷卻至8°C)及DMF(100 微升）反應。半製備性HPLC (0.15% TFA/水：乙腈95··5替代緩衝相），經以碳酸鈉溶液洗題後獲得標題化合物（7毫克，8%)〇 ^NMR (300MHz)(5 9.41 (s, 1H)? 7.78 (d, 1H)? 7.49-7.28 (m? 10H), 4.12-3.97 (m，1H)，2.13-1.23 (m，10H)。 MS m/z 358 (M + H)+。實施例8 N-(l-環己基）-5,6-貳（4-溴苯基）-2-吡畊羧醯胺得自製備例A步驟（b)之5,6-貳- (4-溴苯基）-吡畊-2-羧酸 (1 0 9毫克，0.2 5毫莫耳）如實施例7所述使用。半製備性 HPLC (0.15% TFA/水：乙腈95:5替代緩衝相），使用碳酸鈉溶液洗提後獲得標題化合物（7毫克，8%)。 !HNMR (3 00MHz) 5 9.4 1 (s, 1 Η), 7.68 (s, lH), 7.54 (d, 2H), 7.5 0 (d, 200410693 (16) 發明說明續頁 2H), 7.36 (d，2H)，7.34 (d，2H)，4.11-3.96 (m, 1H), 2.12-1.20 (m， 10H). MS m/z 514, 516, 518 (M + H)' 實施例9 N-(l-環己基）-5，6-貳（4 -曱基笨基）-2-吡哄羧醯胺得自製備例A步驟（c )之5,6 -二-對曱苯基-吡畊-2 -羧酸 (7 6毫克，0.2 5毫莫耳）如實施例7所述使用。半製備性HPLC (0.01% TEA於緩衝相）獲得小標題化合物（4毫克，4%)。 ^NMR (3 00MHz) 5 9.3 6 (s, 1H), 7.77 (d, 1 H), 7.39 (d, 4H), 7.1 8 (d; 2H), 7.13 (d, 2H), 4.10-3.96 (m, 1H), 2.40 (s, 3H), 2.37 (s, 3H), 2.09- 1.20 (m, 10H)。 MS m/z 386 (M + H)+。實施例1 0 N-(l-環己基）-5,6-貳（4-甲氧基苯基）-2-吡啡羧醯胺得自製備例A步驟（d)之5,6-貳- (4·甲氧基笨基）-吡D井- 2-羧酸（7 6毫克，0.2 5毫莫耳）大致如實施例7所述使用，但首先反應混合物攪拌隔夜，然後加入額外量環己基胺（2 5 毫克，0.2 5毫莫耳），混合物又攪拌二曰隨後後續處理。半製備性HPLC (0.15% TFA於緩衝相）獲得標題化合物（1 2毫克，1 1 % )。 'HNMR (3 00MHz) ό 9.3 2 (s, 1H), 7.76 (d, 1 H), 7.4 7 (d, 2H), 7.4 5 (d. 2H), 6.90 (d, 2H), 6.86 (d, 2H), 4.10-3.96 (m, 1H), 3.86 (s, 3H). 3.84 (s, 3H), 2.09-1.17 (m, 10H). MS m/z 418 (M+H)' 200410693 發明說明續頁 (17) 實施例1 1 N-( 1-環己基）-5,6-貳（4-氣苯基）-2-吡哄叛Si胺得自製備例A步驟（e)之5，6 -貳-(4 -氯笨基）-吡哄-2 -竣酸 (8 6毫克，0.2 5毫莫耳）如實施例1 〇所述使用，以碳酸納溶液洗提後獲得標題化合物（7毫克，8 %)。丨HNMR (300MHz)5 9.41 (s，1H)，7.69 (d，1H)，7.47-7.30 (m，8H)， 4.10-3.97 (m? 1H), 2.10-1.18 (m, 10H). MS m/z 426, 428, 430 (M+H) + . 實施例1 2 N - ( 1 -環己基）-5，6 -貳（2 -氣苯基）-2 -吡D井羧醯胺得自製備例A步驟（f)之5，6-貳- (2-氣苯基）-吡哄-2-羧酸 (86毫克，0.25毫莫耳）如實施例10所述使用，獲得標題化合物（14毫克，13%)。 iHNMR (300MHz)5 9.51 (s，1H)，7.74 (s，1H)，7.41-7.18 (m，8H), 4.10-3.97 (m, 1H), 2.07-1.14 (m, 10H). MS m/z 426, 428, 430 (M+H)+. m 實施例1 3 N , 5,6 -三笨基-2 - □比啡羧醯胺於得自製備例A步驟（a)之5，6 -二笨基-吡哄-2 -羧酸（7 0 毫克，0.25毫莫耳），加入DMAP (0.025毫莫耳，於〇·5毫升 DCM),笨胺（〇·25毫莫耳，於1毫升DCM)，EDC(0.28毫莫耳，於1毫升DCM，冷卻至8t )及DMF (1〇〇微升）。反應混合物於2 :> C攪拌隔夜，然後如實施例2所述後續處评 ^ , 備性HPLc(0.15%TFA/水：乙腈95:5替代緩衝相二:+製 )M蛟醆鈉 -22- 200410693 (18) 發明說明續頁溶液洗提後獲得標題化合物（27毫克，30%)。 — lHNMR (300MHz)5 9.75 (s, 1H), 9.52 (d? 1H), 7.80 (d, 2H), 7.55-7.32 (m, 12H), 7.20 (ΐ, 1H). MS m/z 352 (M+H) + . 實施例1 4 N -笨基- 5,6-貳（4 -甲基苯基）-2-吡畊羧醯胺5,6-fluorene- (4-chlorophenyl) -pyridine-2-carboxylic acid (86 mg, 0.2 5 mmol) from step (e) of Preparation A was used as shown in Example 2 The title compound (16 mg, 15%) was obtained. 'HNMR (300MHz) 5 9.40 (s, 1H), 8.49 (s, 1H), 7.45-7.31 (m, 8H), 2.94 (t, 4H), 1.80 (m, 4H), 1.54- 1.45 (m, 2H ). MS m / z 427, 429, 43 1 (M + H) +. Example 6 N- (1-pyridyl) -5,6-fluorenyl (2-chlorobenzyl) -2-pyridinecarboxamidine; 5,6-fluorene- (from Step (f) of Preparation Example A) 2-chlorobenzyl) -pyridine-2-carboxylic acid-19-200410693 (15) Description of the invention Continuation sheet (86 mg, 0.2 5 mmol) was used as shown in Example 2 to obtain the title compound ( 6 mg, 6%). ^ NMR (300MHz) 5 9.52 (s, 1H), 8.52 (s5 1H)? 7.44-7.17 (d? 8H)? 2.94-2.88 (t, 4H), 1.85- 1.70 (m, 4H), 1.52-1.44 ( m, 2H). MS m / z 427, 429, 43 1 (M + H) +. Example 7 N-(1 -cyclohexyl) -5,6-diphenyl-2-[I The amine was obtained from the 5,6-diphenyl-growth-2-carboxylic acid (70 mg, 0.2 5 mmol) in step (a) of Preparation Example A, but was substantially as described in Example 2, but with cyclohexylamine ( 0.2 5 mmoles in 1 ml of DCM), DMAP (0.025 mmoles in 0.5 ml of DCM), EDC (0.28 mmoles in 1 ml of DCM and cooling to 8 ° C) and DMF (100 µm L) response. Semi-preparative HPLC (0.15% TFA / water: acetonitrile 95 · 5 instead of buffer phase). The title compound (7 mg, 8%) was obtained after washing the title with sodium carbonate solution. NMR (300 MHz) (5 9.41 (s , 1H)? 7.78 (d, 1H)? 7.49-7.28 (m? 10H), 4.12-3.97 (m, 1H), 2.13-1.23 (m, 10H). MS m / z 358 (M + H) +. Example 8 N- (l-cyclohexyl) -5,6-fluoren (4-bromophenyl) -2-pyroxycarboxamide is obtained from 5,6-fluorene- (4) in step (b) of Preparation Example A -Bromophenyl) -pyroxy-2-carboxylic acid (109 mg, 0.2 5 mmol) was used as described in Example 7. Semi-preparative HPLC (0.15% TFA / water: acetonitrile 95: 5 instead of buffer Phase), and the title compound (7 mg, 8%) was obtained after extraction with sodium carbonate solution.! HNMR (300 MHz) 5 9.4 1 (s, 1 H), 7.68 (s, 1H), 7.54 (d, 2H) , 7.50 (d, 200410693 (16) Description of the invention continued on 2H), 7.36 (d, 2H), 7.34 (d, 2H), 4.11-3.96 (m, 1H), 2.12-1.20 (m, 10H). MS m / z 514, 516, 518 (M + H) 'Example 9 N- (l-cyclohexyl) -5,6-fluoren (4-methylbenzyl) -2-pyridamidine Example A Step 5, (c) of 5,6-di-p-Phenyl-pyroxy-2-carboxylic acid (76 mg, 0.2 5 mmol) Ear) was used as described in Example 7. Semi-preparative HPLC (0.01% TEA in buffer phase) gave the subtitled compound (4 mg, 4%). NMR (300 MHz) 5 9.3 6 (s, 1H), 7.77 (d, 1 H), 7.39 (d, 4H), 7.18 (d; 2H), 7.13 (d, 2H), 4.10-3.96 (m, 1H), 2.40 (s, 3H), 2.37 (s, 3H ), 2.09- 1.20 (m, 10H). MS m / z 386 (M + H) +. Example 1 0 N- (l-cyclohexyl) -5,6-fluorene (4-methoxyphenyl) -2-pyridinecarboxamide is obtained from 5,6-fluorene- (4 · methoxybenzyl) -pyridine D--2-carboxylic acid (76 mg, 0.2 5 mmol) in step (d) of Preparation Example A Mol) was used as described in Example 7 except that the reaction mixture was stirred overnight, and then an additional amount of cyclohexylamine (25 mg, 0.2 5 mmol) was added, and the mixture was stirred for two days and subsequently processed. Semi-preparative HPLC (0.15% TFA in buffer phase) gave the title compound (12 mg, 11%). 'HNMR (3 00MHz) ό 9.3 2 (s, 1H), 7.76 (d, 1 H), 7.4 7 (d, 2H), 7.4 5 (d. 2H), 6.90 (d, 2H), 6.86 (d, 2H), 4.10-3.96 (m, 1H), 3.86 (s, 3H). 3.84 (s, 3H), 2.09-1.17 (m, 10H). MS m / z 418 (M + H) '200410693 Description of the invention continued Page (17) Example 1 1 N- (1-Cyclohexyl) -5,6-fluorene (4-Gaphenyl) -2-pyridine coerced Si amine, obtained from steps 5 and 6 of Preparation Example A -贰-(4-chlorobenzyl) -pyridine-2 -junic acid (86 mg, 0.2 5 mmol) was used as described in Example 10, and the title compound was obtained after elution with a sodium carbonate solution (7 Mg, 8%).丨 HNMR (300MHz) 5 9.41 (s, 1H), 7.69 (d, 1H), 7.47-7.30 (m, 8H), 4.10-3.97 (m? 1H), 2.10-1.18 (m, 10H). MS m / z 426, 428, 430 (M + H) +. Example 1 2 N-(1 -Cyclohexyl) -5,6 -fluorene (2-Gaphenyl) -2 -pyridine D-carboxamidine is obtained from the preparation Example A Step (f) of 5,6-fluorene- (2-aminophenyl) -pyridine-2-carboxylic acid (86 mg, 0.25 mmol) was used as described in Example 10 to obtain the title compound (14 Mg, 13%). iHNMR (300MHz) 5 9.51 (s, 1H), 7.74 (s, 1H), 7.41-7.18 (m, 8H), 4.10-3.97 (m, 1H), 2.07-1.14 (m, 10H). MS m / z 426, 428, 430 (M + H) +. M Example 1 3 N, 5,6 -Tribenzyl-2-□ -biffonylcarboxamide in step 5, 6-from Preparation Example A Dibenzyl-pyridine-2-carboxylic acid (70 mg, 0.25 mmol), DMAP (0.025 mmol, 0.5 ml DCM), benzylamine (0.25 mmol, 0.5 ml) Ml DCM), EDC (0.28 millimoles in 1 ml DCM, cooled to 8t) and DMF (100 μl). The reaction mixture was stirred at 2: C overnight, and then evaluated as described in Example 2 below. Preparative HPLc (0.15% TFA / water: acetonitrile 95: 5 instead of buffer phase two: +) M sodium sodium- 22-200410693 (18) Description of the invention The title compound (27 mg, 30%) was obtained after elution of the solution on the next page. — LHNMR (300MHz) 5 9.75 (s, 1H), 9.52 (d? 1H), 7.80 (d, 2H), 7.55-7.32 (m, 12H), 7.20 (ΐ, 1H). MS m / z 352 (M + H) +. Example 1 4 N -Bentyl-5,6-fluoren (4-methylphenyl) -2-pyridoxamine

得自製備例A步驟（c )之5，6 -二-對甲苯基-吡啡-2 -羧酸 (7 7毫克，0.2 5毫莫耳）如實施例1 3所述使用，獲得小標題化合物（28毫克，29%)。 ^NMR (500MHz)5 9.78 (s, 1H), 9.49 (s, 1H), 7.81 (d, 2H)? 7.47-7.43 (m, 6H), 7.25-7.17 (m, 5H), 2.45 (s, 3H)? 2.41 (s, 3H). MS m/z 380 (M+H)' 實施例1 5 N -笨基-5,6-^(4 -甲氧基苯基）-2 -吼哄叛3盘胺5,6-Di-p-tolyl-pyrphin-2-carboxylic acid (77 mg, 0.2 5 mmol) from step (c) of Preparation A was used as described in Example 13 to obtain the subtitle Compound (28 mg, 29%). ^ NMR (500MHz) 5 9.78 (s, 1H), 9.49 (s, 1H), 7.81 (d, 2H)? 7.47-7.43 (m, 6H), 7.25-7.17 (m, 5H), 2.45 (s, 3H )? 2.41 (s, 3H). MS m / z 380 (M + H) 'Example 1 5 N-benzyl-5,6-^ (4-methoxyphenyl) -2 Panamine

得自製備例A步驟（d)之5,6-貳- (4 -曱氧基苯基）-吡哄- 2-羧酸（8 5毫克，0.2 5毫莫耳）如實施例1 3所述使用，獲得小標題化合物（3 3毫克，3 2 % )。 lHNMR (3 00MHz) 5 9.74 (s, 1H), 9.42 (s, 1H), 7.79 (d, 2H), 7.5 0 (d, 4H)，7.42 (t，2H)，7.19 (t，1H), 6.94 (d，2H)，6·89 (d, 2H)，3.88 (s， 3H)，3.85 (s，3H). MS m/z 412 (M+H)' 實施例1 6 N-笨基-5，6-貳（4-氣苯基）-2-吡哄羧醯胺得自製備例A步驟（e)之5,6-貳- (4-氯笨基）-吡哄-2-羧酸 -23 - 200410693 (19) 發明說明續頁 (8 7毫克，0.2 5毫莫耳）如實施例1 3所述使用，獲得小標題化合物（6毫克，6 %)。 lHNMR (300ΜΗζ)ά 9.66 (s, 1H), 9.52 (s, 1H), 7.79 (d, 2H), 7.48-7.35 (m, 10H), 7.21 (t, 1H). MS m/z 420, 422, 424 (M + H) + . 實施例1 7 N -苯基-5,6 -貳（2 -氣苯基）-2 -吡哄羧醯胺得自製備例A步驟（f)之5，6 -氣-(2_氣-苯基）-¾哄·2 -叛酸（8 7毫克，0.2 5毫莫耳）如實施例1 3所述使用，獲得小標題化合物（2 7毫克，2 5 % )。 'HNMR (500ΜΗζ)5 9.73 (s? 1H), 9.66 (s, 1H), 7.81 (d, 2H), 7.46-7.22 (m, 1 1H). MS m/z 420, 422, 424 (M + H)' 實施例1 8 5-(4-氯苯基）-6-(2,4-二氣苯基）[I比哄-2-羧酸哌啶-1-基醯胺及6-(4 -氣苯基）-5-(2,4-二氣笨基）吡畊-2-羧酸哌啶-1- 基酿胺得自製備例A步驟（i)之5-(4-氣笨基）-6-(2,4-二氣笨基）吡哄-2-羧酸與6-(4 -氯笨基）-5-(2,4-二氯笨基）吡畊-2-羧酸之混合物（7 8毫克，0.2 0 5毫莫耳）及亞磺醯氣（1 4 7毫克， 1 · 2 3毫莫耳）於曱笨（2毫升）回流3小時。於減壓下蒸發去除溶劑及反應劑，中間物溶解於DCM (1毫升）。TEA (42毫克，〇 · 4 1毫莫耳）及1 -胺基哌啶（2 1毫克，0 · 2 0 5毫莫耳）溶解於D C Μ ( 1毫升）及加入反應混合物内。反應混合物於2 5 -24 - 200410693 (20) 發明說明續頁 °C攪拌隔夜，然後於減壓下蒸發。急速層析術（矽膠，灰 -烷：乙酸乙酯1 : 1)獲得標題化合物（45毫克，47%，異構物 -比 0.5:1)。WNMR (3 00MHz) (5 9.46 (s，1H)，8.3 9 (s，1H)，7.47-7.28 - (m，7H)，3.02-2.84 (m，4H)，1.89-1.73 (m，4H)，1.57-1.41 (m，2H)及 * 9.42 (s, 1H)，8·51 (s，1H), 7.47-7.28 (m，7H)，3.02-2.84 (m，4H), 1.89-1.73 (m? 4H)? 1.57-1.41 (m, 2H). 實施例1 8 (a) N(1囉°疋基）-5-(4 -氣苯基）-6-(2,4-二氯苯基）-2-吼哄叛 - i 醯胺標題化合物係藉製備性層析術由實施例1 8製備之混合物（33 毫克）單離（9毫克，26〇/〇)。(300MHz) <5 9.46 (s，1H)， 8·38 (s，1H)，7.46-7.24 (m，7H)，2·89 (t，4H)，1.78 (p, 4H)，1.52-1.40 (m，2H).5,6-fluorene- (4-methoxyphenyl) -pyridine-2-carboxylic acid (85 mg, 0.2 5 mmol) obtained in step (d) of Preparation A as in Example 13 This was used to obtain the subtitled compound (33 mg, 32%). lHNMR (3 00MHz) 5 9.74 (s, 1H), 9.42 (s, 1H), 7.79 (d, 2H), 7.5 0 (d, 4H), 7.42 (t, 2H), 7.19 (t, 1H), 6.94 (d, 2H), 6.89 (d, 2H), 3.88 (s, 3H), 3.85 (s, 3H). MS m / z 412 (M + H) 'Example 1 6 N-Benzyl-5 6,6-fluoren (4-Gaphenyl) -2-pyridinecarboxamide is obtained from 5,6-fluorene- (4-chlorobenzyl) -pyridine-2-carboxylic acid in step (e) of Preparation Example A -23-200410693 (19) Description of the invention Continuation sheet (87 mg, 0.2 5 mmol) was used as described in Example 13 to obtain the subtitled compound (6 mg, 6%). lHNMR (300ΜΗζ) ά 9.66 (s, 1H), 9.52 (s, 1H), 7.79 (d, 2H), 7.48-7.35 (m, 10H), 7.21 (t, 1H). MS m / z 420, 422, 424 (M + H) +. Example 1 7 N -Phenyl-5,6-pyrene (2-aerophenyl) -2 -pyridazine Carboxamide is obtained from steps 5 and 6 in Preparation Example A -Ga- (2_Ga-phenyl) -¾ co- 2 -metanoic acid (87 mg, 0.2 5 mmol) was used as described in Example 13 to obtain the subtitled compound (27 mg, 2 5 %). 'HNMR (500ΜΗζ) 5 9.73 (s? 1H), 9.66 (s, 1H), 7.81 (d, 2H), 7.46-7.22 (m, 1 1H). MS m / z 420, 422, 424 (M + H ) 'Example 1 8 5- (4-chlorophenyl) -6- (2,4-difluorophenyl) [I ratio of piperidin-1-ylhydrazine-2-carboxylic acid and 6- (4 -Phenylphenyl) -5- (2,4-diaminobenzyl) pyridine-2-carboxylic acid piperidin-1-ylpyrimidamine was obtained from 5- (4-aminobenzyl) in step (i) of Preparation Example A ) -6- (2,4-Difluorobenzyl) pyridine-2-carboxylic acid and 6- (4-chlorobenzyl) -5- (2,4-dichlorobenzyl) pyracin-2- A mixture of a carboxylic acid (78 mg, 0.2 05 mmol) and sulfinic acid (147 mg, 1.3 mg) was refluxed for 3 hours in a benzine (2 ml). The solvents and reactants were removed by evaporation under reduced pressure, and the intermediate was dissolved in DCM (1 mL). TEA (42 mg, 0.41 mmol) and 1-aminopiperidine (21 mg, 0.205 mmol) were dissolved in DC (1 ml) and added to the reaction mixture. The reaction mixture was stirred at 2 5 -24-200410693 (20) Description of the invention continued at ° C overnight and then evaporated under reduced pressure. Flash chromatography (silica gel, ash-alkane: ethyl acetate 1: 1) gave the title compound (45 mg, 47%, isomers-ratio 0.5: 1). WNMR (3 00 MHz) (5 9.46 (s, 1H), 8.39 (s, 1H), 7.47-7.28-(m, 7H), 3.02-2.84 (m, 4H), 1.89-1.73 (m, 4H), 1.57-1.41 (m, 2H) and * 9.42 (s, 1H), 8.51 (s, 1H), 7.47-7.28 (m, 7H), 3.02-2.84 (m, 4H), 1.89-1.73 (m? 4H)? 1.57-1.41 (m, 2H). Example 1 8 (a) N (1 啰 ° 疋) -5- (4-Gaphenyl) -6- (2,4-dichlorophenyl) -2- Howl Betrayal-i The title compound was isolated from the mixture (33 mg) prepared in Example 18 by preparative chromatography (9 mg, 26/0). (300 MHz) < 5 9.46 (s, 1H), 8.38 (s, 1H), 7.46-7.24 (m, 7H), 2.89 (t, 4H), 1.78 (p, 4H), 1.52-1.40 (m, 2H).

1(1-哌啶基）_6-(4-氯苯基）-5_(2,4_二氣苯基）_2-吡畊羧酿胺1 (1-piperidinyl) _6- (4-chlorophenyl) -5_ (2,4_difluorophenyl) _2-pyroxycarbamidine

標題化合物係藉製備性層析術由實施例1 8製備之混合物（3D 亳克）單離（1 1 毫克，31%)。iHNMR (300MHz) 5 9.42 (s，1H), 8·)0 (s，1H)，7.39-7.30 (m, 7H)，2.93 (t, 4H)，1.80 (p，4H), 1·54-1·43 (m, 2H).The title compound was isolated (11 mg, 31%) from a mixture prepared in Example 18 (3D g) by preparative chromatography. iHNMR (300MHz) 5 9.42 (s, 1H), 8 ·) 0 (s, 1H), 7.39-7.30 (m, 7H), 2.93 (t, 4H), 1.80 (p, 4H), 1.54--1 43 (m, 2H).

本發明化合物對C B I基因受體產物有活性。本發明化合物對於中樞***受體具有親和力述於Devane等人，分子藥理學’ 1988, 34,605或WO 01/70700或EP 656354所述方法驗證 -25 - 200410693 (21) 發明說明續頁。另外檢定分析進行如後。 ' 1 0微克由使用CB1基因穩定轉移感染細胞製備之細胞膜懸浮於200微升100mM氯化鈉，5mM氯化鎂，ImMEDTA， 50mM HEPES (pH 7.4)，lmM DTT ’ 0.1% BSA及 100 // M GDP。於其中加入EC80濃度之激動劑（CP55940)，需要濃度之試驗化合物以及0.1 e Ci [35S]-GTPt S。放反應於30°c進行45分鐘。然後樣本使用細胞收穫機移至GF/B過濾器上’以洗條缓衝液[5 0mM Tris (pH 7.4)，5mM氣化鎂，50mM氯化鈉]洗滌。然後過濾器上覆蓋閃爍劑，計數過濾器所保留之[35S]-GTP T S數量。於全部皆無配位子存在下（最低活性）或於E C 8 0濃度 CP55940存在下（最高活性）測定活性。此等活性分別設定為 0 %至1 0 0 %。於不等濃度之新穎配位子，計算出活性以占最高活性百分比表示且作圖。使用方程式y=A+((B-A)/l+((C/x) UD))匹配資料，IC50值係測定為於使用條件下獲得GTP τ S結合之半最大抑制需要的濃度。本發明化合物於CB1受體具有活性（〖C50<1微莫耳濃度）。最佳化合物具有IC50<200奈莫耳濃度。 -26-The compounds of the invention are active against the C B I gene receptor product. The compounds of the present invention have an affinity for central cannabis receptors, as described in Devane et al., Molecular Pharmacology '1988, 34,605 or WO 01/70700 or EP 656354. Method verification -25-200410693 (21) Description of the Invention Continued. In addition, the verification analysis was performed as follows. 10 micrograms of cell membrane prepared from CB1 gene stably transferred infected cells was suspended in 200 microliters of 100 mM sodium chloride, 5 mM magnesium chloride, ImMEDTA, 50 mM HEPES (pH 7.4), lmM DTT '0.1% BSA and 100 // M GDP. An agonist with an EC80 concentration (CP55940) is added to it, a concentration of the test compound and 0.1 e Ci [35S] -GTPt S are required. The reaction was allowed to proceed at 30 ° C for 45 minutes. The sample was then transferred to a GF / B filter using a cell harvester 'and washed with a strip buffer [50 mM Tris (pH 7.4), 5 mM magnesium vapor, 50 mM sodium chloride]. The filter was then covered with scintillator and the number of [35S] -GTP T S retained by the filter was counted. Activity was measured in the absence of all ligands (lowest activity) or in the presence of E C 80 0 concentration CP55940 (highest activity). These activities are set to 0% to 100%, respectively. For novel ligands of varying concentrations, the calculated activity is expressed as a percentage of the highest activity and plotted. Using the equation y = A + ((B-A) / l + ((C / x) UD)) to match the data, the IC50 value is determined as the concentration required to obtain half-maximal inhibition of GTP τ S binding under the conditions of use. The compounds of the present invention are active at the CB1 receptor (C50 < 1 micromolar concentration). The best compound has an IC50 < 200 nmole concentration. -26-

Claims

200410693 拾、申請專利範圍 1 . 一種式I化合物200410693 Patent application scope 1. A compound of formula I

其中- 及其醫藥可接受性鹽、溶劑合物及結晶形式 R1表示環己基、1-吡啶基或苯基； R2表示Η、氣、溴、甲基或曱氧基；以及當R3表示Η時，R4表示Η或氯；以及當R3表示C 1時，R4表示Η或氯。 2 .如申請專利範圍第1項之化合物，其中R1表示環己基。 3 .如申請專利範圍第1項之化合物，其中R1表示1 -吡啶基。 4 .如申請專利範圍第1項之化合物，其中R 1表示苯基。 5 . —種化合物，其係選自： Ν - ( 1 -哌啶基）-5，6 -二笨基-2 -吼畊羧醯胺； N-U-哌啶基）-5,6-貳（4-溴笨基）-2-吡哄羧醯胺； N-(l-哌啶基）-5,6-貳（4 -甲基笨基）-2-吡畊羧醯胺； N-(l-哌啶基）-5,6-貳（4 -甲氧基笨基）-2-吡哄羧醯胺； N-(l-哌啶基）-5,6-貳（4-氣苯基）-2-吡畊羧醯胺； N-(l-哌啶基）-5,6-貳（2<氣苯基）-2-吡哄羧醯胺； N - ( 1 -環己基）-5,6 -二笨基-2 - □比畊羧醯胺； N-( 1-環己基）-5,6-貳（4-溴笨基）-2-吡畊羧醯胺； 200410693 N-(l-環己基）-5,6-貳（4-曱基笨基）-2-吡畊羧醯胺； ' N-(l-環己基）-5,6-貳（4 -曱氧基苯基）-2-吡畊羧醯胺；己基）-5,6 -武（4-氣苯基）-2-D比哄緩酿胺； N-(l-環己基）-5,6-貳（2-氣笨基）-2·吡畊羧醯胺； N . 5，6 -三苯基-2 -哦畊羧醯胺； N-苯基-5,6-貳（4-甲基苯基）-2-吡畊羧醯胺； N -笨基-5,6-貳（4 -甲氧基苯基）-2-吡哄羧醯胺； N-笨基-5,6-貳（4-氣笨基）-2-吡哄羧醯胺； N-笨基-5,6-貳（2-氣笨基）-2-吡畊羧醯胺； 1^-(1-喊σ定基）-5-(4-氣笨基）-6-(2，4-二氯苯基）-2 -D比哄羧醯胺；以及 N-(l-哌啶基）-6-(4 -氣笨基）-5-(2,4-二氯笨基）-2-吡畊羧醯胺；以及當適用時，其光學異構物、互變異構物、立體異構物及外消旋混合物，以及其醫藥可接受性鹽類、溶劑合物及結晶形式。 6 .如前述申請專利範圍各項中任一項之式I化合物，其係用作為藥物。 7 - —種醫藥調配物，包含如申請專利範圍第1至5項中任一項定義之式I化合物及醫藥可接受性佐劑、稀釋劑或載劑。 8 . —種如申請專利範圍第1至5項中任一項定義之式I化合物之應用，其係用於製備治療肥胖、精神病症例如精神錯亂、精神***及兩極性躁#症、焦慮、焦慮-憂鬱症 200410693 、憂鬱症、認知障礙、記憶_礙、強迫症、厭食症、貪 ‘ r 食症、注意力障礙、癲癇及相關疾病、以及神經病症例，如癡呆、神經發炎病症、帕金森氏病、亨丁頓氏舞蹈症 · 及阿茲海默氏病、免疫、心血管、生殖及内分泌病症、 ‘ 敗血性休克、呼吸系統及胃腸系統相關疾病以及長期濫用、成癮及/或復發性適應症之治療或預防用藥物。Where-and its pharmaceutically acceptable salts, solvates, and crystalline forms R1 represents cyclohexyl, 1-pyridyl, or phenyl; R2 represents fluorene, gas, bromine, methyl, or fluorenyl; and when R3 represents fluorene R4 represents rhenium or chlorine; and when R3 represents C1, R4 represents rhenium or chlorine. 2. The compound according to item 1 of the scope of patent application, wherein R1 represents cyclohexyl. 3. The compound according to item 1 of the scope of patent application, wherein R1 represents 1-pyridyl. 4. The compound according to item 1 of the application, wherein R 1 represents a phenyl group. 5. A compound selected from the group consisting of: NH- (1-piperidinyl) -5,6-dibenzyl-2-carboxamidine; NU-piperidinyl) -5,6-fluorene ( 4-bromobenzyl) -2-pyridinecarboxamide; N- (l-piperidinyl) -5,6-fluorenyl (4-methylbenzyl) -2-pyridoxamine; N- ( l-piperidinyl) -5,6-fluorenyl (4-methoxybenzyl) -2-pyridinecarboxamide; N- (l-piperidinyl) -5,6-fluorenyl (4-gasbenzene) N- (l-piperidinyl) -5,6-fluorenyl (2 < phenyl) -2-pyridinecarboxamidine; N-(1-cyclohexyl) -5,6 -Dibenzyl-2-□ phenylcarboxamide; N- (1-cyclohexyl) -5,6-pyrene (4-bromobenzyl) -2-pyroxycarboxamide; 200410693 N -(l-cyclohexyl) -5,6-fluoren (4-fluorenylbenzyl) -2-pyridoxamine; 'N- (l-cyclohexyl) -5,6-fluoren (4 -fluorenyloxy Phenyl) -2-pyroxycarboxamidine; hexyl) -5,6-ammonium (4-phenyl) -2-D than amine; N- (l-cyclohexyl) -5,6 -Pyrene (2-aminobenzyl) -2 · pyroxycarboxamide; N. 5,6-triphenyl-2 -pyrocarboxamide; N-phenyl-5,6-pyrene (4-formyl) Phenyl) -2-pyridinecarboxamide; N-benzyl-5,6-fluorene (4-methoxyphenyl) -2-pyridinecarboxyl Fluorenylamine; N-benzyl-5,6-fluorenyl (4-airbenzyl) -2-pyridinecarboxamide; N-benzyl-5,6-fluorenyl (2-airbenzyl) -2-pyridine Carboxamide; 1 ^-(1-sigma stilbyl) -5- (4-aerobenzyl) -6- (2,4-dichlorophenyl) -2-D ratio carboxamide; and N -(l-piperidinyl) -6- (4-airbenzyl) -5- (2,4-dichlorobenzyl) -2-pyridoxamine; and, where applicable, its optical isomers , Tautomers, stereoisomers and racemic mixtures, as well as their pharmaceutically acceptable salts, solvates and crystalline forms. 6. A compound of formula I according to any one of the preceding claims, which is used as a medicament. 7-A pharmaceutical formulation comprising a compound of formula I as defined in any one of claims 1 to 5 of the patent application scope and a pharmaceutically acceptable adjuvant, diluent or carrier. 8. Use of a compound of formula I as defined in any one of claims 1 to 5 of the scope of the patent application, which is used for the preparation of the treatment of obesity, mental disorders such as insanity, schizophrenia and bipolar disorder, anxiety, Anxiety-depression 200410693, depression, cognitive impairment, memory disorders, obsessive-compulsive disorder, anorexia, greed's dysphagia, attention disorder, epilepsy and related diseases, and examples of neurological disorders such as dementia, neuroinflammatory disorders, Parkinson's 'S disease, Huntington's disease and Alzheimer's disease, immune, cardiovascular, reproductive and endocrine disorders,' septic shock, respiratory and gastrointestinal disorders and long-term abuse, addiction and / or relapse Drugs for the treatment or prevention of sexual indications.

9 . 一種治療肥胖、精神病症（例如精神錯亂）、精神***及兩極性躁鬱症、焦慮、焦慮-憂鬱症、憂鬱症、認知障礙、記憶障礙、強迫症、厭食症、貪食症、注意力障礙、癲癇及相關疾病、以及神經病症例如癡呆、神經發炎病症、帕金森氏病、亨丁頓氏舞蹈症及阿茲海默氏病、免疫、心血管、生殖及内分泌病症、敗血性休克、呼吸系統及胃腸系統相關疾病以及長期濫用、成癮及/或復發性適應症之方法，該方法包含對有需要之硬人投予藥理有效量之如申請專利範圍第1至5項中任一項之化合物。 10. 如申請專利範圍第1至5項中任一項之化合物，其係用於治療肥胖。 11. 一種製備式I化合物之方法，包含式11化合物9. A treatment for obesity, mental disorders (such as insanity), schizophrenia and bipolar disorder, anxiety, anxiety-depression, depression, cognitive impairment, memory disorder, obsessive-compulsive disorder, anorexia, bulimia, attention disorder , Epilepsy and related diseases, and neurological disorders such as dementia, neuroinflammatory disorders, Parkinson's disease, Huntington's disease and Alzheimer's disease, immune, cardiovascular, reproductive and endocrine disorders, septic shock, breathing System and gastrointestinal system related diseases and method of chronic abuse, addiction and / or relapsed indication, the method comprises administering a pharmacologically effective amount to a hard person in need as in any of claims 1 to 5 of the scope of patent application Of compounds. 10. The compound according to any one of claims 1 to 5, which is used for treating obesity. 11. A method for preparing a compound of formula I, comprising a compound of formula 11

200410693 其中R2、R3及R4定義如前與式111胺 RlNH 於惰性溶劑，於偶合劑存在下以及視需要地於催化劑存在下，於-25t至150°C溫度反應。 12.—種式II化合物200410693 where R2, R3, and R4 are as defined above and the amine of formula 111 RlNH is reacted in an inert solvent, in the presence of a coupling agent, and optionally in the presence of a catalyst, at a temperature of -25 to 150 ° C. 12.—Species of Formula II

其中 R1表示環己基、1-哌啶基或苯基； R2表示Η、氯、溴、曱基或甲氧基；以及當R3表示Η時，R4表示Η或氯；以及當R3表示C1時，R4表示Η或氯，但5,6-二笨基-2-□比哄羧酸及5,6-貳（4 -曱氧苯基）-2-吡哄羧酸除外。 200410693 陸、（一）、本案指定代表圖為：第_圖 (二）、本代表圖之元件代表符號簡單說明：柒、本案若有化學式時，請揭示最能顯示發明特徵的化學式：Wherein R1 represents cyclohexyl, 1-piperidinyl or phenyl; R2 represents fluorene, chlorine, bromine, fluorenyl or methoxy; and when R3 represents fluorene, R4 represents fluorene or chlorine; and when R3 represents C1, R4 represents fluorene or chlorine, except for 5,6-dibenzyl-2- □ carboxylic acid and 5,6-fluorene (4-oxophenyl) -2-pyridinecarboxylic acid. 200410693 Lu, (1), the designated representative of the case is: Figure _ (2), the representative symbols of the representative diagram are briefly explained: 柒, if there is a chemical formula in this case, please reveal the chemical formula that best shows the characteristics of the invention: