TW200823187A

TW200823187A - Benzodioxane derivatives and uses thereof

Info

Publication number: TW200823187A
Application number: TW096139848A
Authority: TW
Inventors: Gary Paul Stack; William Demaio; John Chuck Lem Erve; Karthick Vishwanathan; Jianyao Wang; Sarvesh Vashishtha
Original assignee: Wyeth Corp
Priority date: 2006-10-24
Filing date: 2007-10-24
Publication date: 2008-06-01
Also published as: AR063373A1; CL2007003065A1; WO2008052086A1

Abstract

Compounds of formula I are described herein which are agonists or partial agonists of the 2C subtype to brain serotonin receptors. or pharmaceutically acceptable salts thereof, wherein each of A, R1, R2, R3, R4, Ra, Rb, Rc, Rd, Re, Rx, Ry, m, n and each group are as defined herein. Such compounds, and compositions thereof, are useful for treating a variety of central nervous system disorders such as schizophrenia.

Description

200823187 九、發明說明：明所屬領^^ 發明領域本發明係有關5-HT2c受體激動劑或部分激動劑、其製 5 法及其用法。【先前技術：！發明背景精神***症患者約有5百萬人。目前最普及的精神*** 症之治療方法為「非典型」抗精神病劑，該非典型抗精神 10病劑組合多巴胺(〇2)及血清素(5-HT2A)受體拮抗作用。儘管已經報告非典型抗精神病劑相對於典型抗精神病劑之功效上的改良與副作用的傾向’但此等非典型抗精神病劑顯然不足以治療精神***症的全部症狀，伴隨有副作用問題，諸如體重增加(Allison，D. B.等人，美國精神病學期刊， 15 1M: 1686-1696 ; Masand，P· S·，Exp. Opin. Pharmac〇ther I : 377-389 ’ 2000 ; Whitaker ’ R.，頻譜生命科學，決策資源， 2 : 1-9 ， 2000)。非典型抗精神病劑也以高度親和力與5_HT2c受體結合，用作為5-HT2c受體拮抗劑或反激動劑。體重增加是非 2〇典型抗精神病劑堵如克羅札平（clozapine)及歐蘭札平 (olanzapine)所造成的副作用問題，曾經提示5_ΗΤ%神抗作用造成體重增加。相反地，已知刺激5-HT2C受體將導致食物攝取量的減少與體重的減輕(Walsh等人，精神藥理學 121:57-73’ 1996; Cowen’Rj·，等人，人類精神藥理學 5 200823187200823187 IX. INSTRUCTIONS: FIELD OF THE INVENTION Field of the Invention The present invention relates to 5-HT2c receptor agonists or partial agonists, methods for their preparation, and uses thereof. [Prior technology:! BACKGROUND OF THE INVENTION There are approximately 5 million people with schizophrenia. The most popular treatment for schizophrenia is the "atypical" antipsychotic, which combines dopamine (〇2) and serotonin (5-HT2A) receptor antagonism. Although the propensity of atypical antipsychotic agents to improve the efficacy and side effects of typical antipsychotic agents has been reported', these atypical antipsychotic agents are clearly insufficient to treat all symptoms of schizophrenia, with side effects such as body weight. Increase (Allison, DB et al., American Journal of Psychiatry, 15 1M: 1686-1696; Masand, P. S., Exp. Opin. Pharmac〇ther I : 377-389 ' 2000 ; Whitaker ' R., Spectrum Life Sciences , Decision Resources, 2: 1-9, 2000). Atypical antipsychotic agents also bind to the 5-HT2c receptor with high affinity and act as a 5-HT2c receptor antagonist or inverse agonist. Weight gain is a side effect caused by non-psychotic antipsychotic agents such as clozapine and olanzapine, which have been suggested to cause weight gain due to 5_ΗΤ% antipsychotic effects. Conversely, it is known that stimulating 5-HT2C receptors will result in a decrease in food intake and weight loss (Walsh et al., Psychopharmacology 121: 57-73' 1996; Cowen'Rj·, et al., Human Psychopharmacology 5 200823187

边：385-39卜 1995 ; R〇senzweig-Lipson，S·，等人ASPET 摘要，2000)。數項證據提示5-HT2c受體激動作用或部分激動作用可用於精神***症的治療上所扮演的角色。研究提示5-HT2C 5拮抗劑提高神經突觸之多巴胺濃度，用於巴金森氏症之動物研究模型中有效(Di Matteo，V.，等人，神經藥理學37 : 265-272，1998 ; Fox，S. H·，等人，實驗神經學U1: 35-49， 1998)。由於精神***症的正向症狀係與多巴胺濃度增高有關，故具有與5-HT2c拮抗劑之作用相反作用的化合物諸如 10 5-HT2c激動劑及部分激動劑，應該會降低神經突觸多巴胺濃度。晚近研究驗證5-HT2C激動劑增加前額葉皮質及前庭耳蜗神經核中之多巴胺濃度(Millan，M· J·，等人，神經藥理學II: 953-955，1998 ; Di Matteo，V·，等人，神經藥理學赵：1195-1205 ’ 1999 ; Di Giovanni，G·，等人，神經突 15觸35 : 53-61 ’ 2〇〇〇)，前額葉皮質及前庭耳蜗神經核為可媒介例如克羅札平等藥物之臨床抗精神病功效之腦區。但 5-HT2C激動劑不會降低紋狀體中之多巴胺濃度，紋狀體為與錐體外副作用最密切相關聯的腦區。此外，晚近研究驗證5-ΗΤπ激動劑可減少於腹側被蓋區（VTA)的發射，但不會 2〇減少黑質的發射。5-HT2c激動劑於腦中緣路徑相較於黑質紋狀體路徑的差異效應，提示5_HT2C激動劑有邊緣選擇性，較不可能產生與典型抗精神劑相關聯之錐體外副作用。【發明内容1 發明概要 6 200823187 本發明係有關5-11丁2〇激動劑及其用途。本發明化合物例如可用於治療精神***症及精神***症合併之情緒障礙及認知受損。於若干實施例中，本發明化合物較不可能造成目前非典型抗精神病藥所引發之體重增加。本發明化合 5 物也可用於治療肥胖及其合併症。 R2Side: 385-39b 1995; R〇senzweig-Lipson, S., et al. ASPET Abstract, 2000). Several lines of evidence suggest that 5-HT2c receptor agonism or partial agonism can be used for the treatment of schizophrenia. Studies suggest that 5-HT2C 5 antagonists increase dopamine concentration in synapses and are effective in animal studies models of Parkinson's disease (Di Matteo, V., et al., Neuropharmacology 37: 265-272, 1998; Fox , S. H., et al., Experimental Neurology U1: 35-49, 1998). Since the positive symptoms of schizophrenia are associated with increased dopamine concentrations, compounds that have an opposite effect on the action of 5-HT2c antagonists, such as 10 5-HT2c agonists and partial agonists, should reduce synaptic dopamine concentrations. Recent studies have demonstrated that 5-HT2C agonists increase dopamine concentrations in the prefrontal cortex and vestibular cochlear nucleus (Millan, MJ, et al, Neuropharmacology II: 953-955, 1998; Di Matteo, V., Et al, neuropharmacology Zhao: 1195-1205 '1999; Di Giovanni, G·, et al, neurite 15 touch 35 : 53-61 ' 2〇〇〇), prefrontal cortex and vestibular cochlear nucleus The brain area of the clinical antipsychotic efficacy of the drug such as Croza et al. However, 5-HT2C agonists do not reduce dopamine concentrations in the striatum, which is the brain region most closely associated with extrapyramidal side effects. In addition, recent studies have demonstrated that 5-ΗΤπ agonists can be reduced in the ventral tegmental area (VTA), but not in the reduction of substantia nigra. The differential effect of the 5-HT2c agonist on the midbrain pathway compared to the nigrostriatal pathway suggests that the 5-HT2C agonist is marginally selective and less likely to produce extrapyramidal side effects associated with typical antipsychotic agents. SUMMARY OF THE INVENTION Summary of the Invention 6 200823187 The present invention relates to a 5-11 butyl oxime agonist and use thereof. The compounds of the present invention are useful, for example, in the treatment of schizophrenia and schizophrenia combined with mood disorders and cognitive impairment. In several embodiments, the compounds of the invention are less likely to cause weight gain caused by current atypical antipsychotics. The compounds of the invention are also useful in the treatment of obesity and its comorbidities. R2

於若干實施例中，本發明提供一種式I化合物：或其藥學上可接受之鹽，其中： 10 各個=基分別表示單鍵或雙鍵； R1為氫、低碳烷基、-S(0)20H或-C(0)R、其中R為氫或視需要可經以-OH取代之低碳烷基； A為 _N(H)_、-N(OH)-或-0-; R2為氫或-OH ; 15 R3及R4各自分別為氫、鹵素、甲基、甲氧基或-OH ;In some embodiments, the invention provides a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: 10 each = group represents a single bond or a double bond, respectively; R1 is hydrogen, lower alkyl, -S(0) 20H or -C(0)R, wherein R is hydrogen or, if desired, a lower alkyl group substituted with -OH; A is _N(H)_, -N(OH)- or -0-; R2 Is hydrogen or -OH; 15 R3 and R4 are each hydrogen, halogen, methyl, methoxy or -OH;

Ra為氫或-OH&Rb為氫或-OH，或Ra&Rb與其附接之碳共同形成羰基部分；Ra is hydrogen or -OH& Rb is hydrogen or -OH, or Ra&Rb forms a carbonyl moiety together with the carbon to which it is attached;

Re為氫或-OH及Rd為氫或-OH，或與其附接之碳共同形成羰基部分； Re為氫或-OH ; 7 20 200823187 各個Rx分別為氫、鹵素、-CF3或低碳烷基，但兩個Rx 基非同時為氫；各個Ry分別為氫或-OH ; m為1、2或3 ;以及 5 η為1或2 ; 限制條件為適用下列條件中之至少一者：（a) R2、R3、 R4、Ra、Rb、Rc、Rd及Ry 中之一者為-OH ; (b) R1 為-C(0)R ; (c) R1為-S(0)20H;或(d) Ra與0或1^與Rd中之至少一對連同至其附接之碳共同形成為羰基部分。 10 於若干實施例中，本發明係關於一種治療患有下列疾病之病人之方法·精神***症、精神***樣病症、***情感病症、妄想症、物質誘發精神病症、左多巴(L-DOPA)誘發精神病、與阿茲海默氏痴呆所引發之精神病、巴金森氏症所引發之精神病、路易體病所引發之精神病、痴呆、記 15 憶力缺損、阿茲海默氏症所引發之智能缺損、躁鬱症、憂鬱症、情緒發作、焦慮症、調整障礙、飲食障礙、癲癇、睡眠障礙、偏頭痛、性功能障礙、物質濫用、酒精或多種其它藥物包括古柯鹼及尼古丁成瘾、胃腸病症、肥胖及其合併症、或因創傷、中風或脊索損傷所引發之中樞神經系 20 統缺陷，該方法包括對該病人投予治療有效量之式I化合物，或其藥學上可接受之鹽。於又有其它實施例中，本發明係關於包含式I化合物或其藥學上可接受之鹽，及一種或多種藥學上可接受之載劑、賦形劑或稀釋劑之組成物。 8 200823187 L· 較佳貫施例之詳細說明 1·化合物與定義本發明係關於腦血清素受體之2C爻蜇之激動劑或部分 5 激動劑。如此處使用，「低碳烷基」一詞係指含至多4個碳原子，較佳1至3個碳原子及更佳1至2個碳原子之烴鏈。「烷基」— 5司包括但非限於直鏈及分支鏈諸如曱基、乙基、正丙基、異丙基、正丁基、異丁基、第二丁基或第三丁基。 1〇如此處使用「鹵素」或「鹵原子」等詞係指氯、溴、氟或峨。「有效量」及「治療有效量」等詞用於此處係指當投予病人時，可有效至少部分治療病人所患有之病症之式^化合物之用量。此等病症包括但非限於精神***症、***情 15感病症、精神***樣病症、左多巴誘發精神病、躁鬱症、肥胖、強迫症、憂鬱症、恐慌症、睡眠障礙、飲食障礙及癲癇。「藥學上可接受之鹽類」或「藥學上可接受之鹽」等詞係指以有機酸或無機酸處理式I化合物所衍生之鹽，該等 20酸類諸如乙酸、乳酸、檸檬酸、桂皮醆、酒石酸、丁二酸、反丁烯二酸、順丁烯二酸、丙二酸、扁桃酸、蘋果酸、草酸、丙酸、鹽酸、氫溴酸、磷酸、硝酸、硫酸、乙醇酸、丙_酸、甲磺酸、乙磺酸、甲苯磺酸、水楊酸、苯甲酸、或類似之已知可接受之酸。於若干實施例中，本發明提供 9 200823187 式i化合物之鹽酸鹽。於其它實施例中，「藥學上可接受之鹽」一詞係指以有機鹼或無機鹼處理式I化合物所衍生之鹽。衍生自適當鹼之鹽類包括驗金屬鹽（例如鈉鹽及钟鹽）、驗土金屬鹽（例如鎮 5 鹽）、銨鹽及Ν+((^_4烷基)4鹽。「病人」一詞用於此處係指哺乳動物。於若干實施例中，「病人」一詞用於此處係指人類。「投予」或「投藥」於此處使用係指將化合物或組成物直接投予病人，或將化合物之前藥衍生物或類似物投予 10 病人，而於病人體内形成等量活性化合物或物質。「處理」或「治療」等詞用於此處係指部分或完全減輕、抑制、預防、改善及/或緩解病情。「患」或「患有」等詞，於此處用來指病人經過診斷或懷疑患有之一種或多種病症。 15 2.實例化合物之說明：於若干實施例中，本發明提供一種式I化合物：Re is hydrogen or -OH and Rd is hydrogen or -OH, or a carbon moiety attached thereto to form a carbonyl moiety; Re is hydrogen or -OH; 7 20 200823187 each Rx is hydrogen, halogen, -CF3 or lower alkyl , but the two Rx groups are not hydrogen at the same time; each Ry is hydrogen or -OH; m is 1, 2 or 3; and 5 η is 1 or 2; the constraint is that at least one of the following conditions applies: (a One of R2, R3, R4, Ra, Rb, Rc, Rd, and Ry is -OH; (b) R1 is -C(0)R; (c) R1 is -S(0)20H; d) Ra and at least one of 0 or 1 and Rd together with the carbon to which they are attached form a carbonyl moiety. In several embodiments, the present invention relates to a method of treating a patient suffering from the following diseases: schizophrenia, schizophrenic disorder, schizoaffective disorder, paranoia, substance-induced psychotic disorder, left dopa (L-DOPA) Inducing mental illness, psychosis caused by Alzheimer's dementia, mental illness caused by Parkinson's disease, psychosis caused by Lewy body disease, dementia, memory loss, Alzheimer's disease Intelligent defects, bipolar disorder, depression, mood episodes, anxiety disorders, adjustment disorders, eating disorders, epilepsy, sleep disorders, migraine, sexual dysfunction, substance abuse, alcohol or a variety of other drugs including ***e and nicotine addiction, A gastrointestinal disorder, obesity, and comorbidities thereof, or a central nervous system disorder caused by trauma, stroke, or spinal cord injury, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable compound thereof salt. In still other embodiments, the invention is directed to a composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients or diluents. 8 200823187 L. DETAILED DESCRIPTION OF PREFERRED EXAMPLES 1. Compounds and Definitions The present invention relates to an agonist or a partial 5 agonist of 2C爻蜇 of the brain serotonin receptor. As used herein, the term "lower alkyl" refers to a hydrocarbon chain containing up to 4 carbon atoms, preferably 1 to 3 carbon atoms and more preferably 1 to 2 carbon atoms. "Alkyl" - 5 includes, but is not limited to, straight and branched chains such as decyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl or t-butyl. 1〇 The words “halogen” or “halogen atom” as used herein mean chlorine, bromine, fluorine or antimony. The terms "effective amount" and "therapeutically effective amount" are used herein to mean the amount of the compound which is effective to at least partially treat the condition of the patient when administered to a patient. Such conditions include, but are not limited to, schizophrenia, a schizophrenic disorder, a schizophrenic disorder, levodopa-induced psychosis, bipolar disorder, obesity, obsessive-compulsive disorder, depression, panic disorder, sleep disorders, eating disorders, and epilepsy. The terms "pharmaceutically acceptable salts" or "pharmaceutically acceptable salts" refer to salts derived from the treatment of a compound of formula I with an organic or inorganic acid such as acetic acid, lactic acid, citric acid, cinnamon. Bismuth, tartaric acid, succinic acid, fumaric acid, maleic acid, malonic acid, mandelic acid, malic acid, oxalic acid, propionic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, glycolic acid, Propanic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, salicylic acid, benzoic acid, or a similarly known acceptable acid. In several embodiments, the invention provides the hydrochloride salt of the compound of formula 2008 200823187. In other embodiments, the term "pharmaceutically acceptable salt" refers to a salt derived from the treatment of a compound of formula I with an organic or inorganic base. Salts derived from appropriate bases include metal salts (eg, sodium salts and clock salts), soil metal salts (eg, town 5 salts), ammonium salts, and strontium + ((^_4 alkyl) 4 salts. "Patient" The term is used herein to mean a mammal. In several embodiments, the term "patient" is used herein to refer to a human. "Administration" or "administration" as used herein refers to the direct administration of a compound or composition. Give the patient, or a compound derivative or analog of the compound to 10 patients, and form an equivalent amount of the active compound or substance in the patient. The words "treatment" or "treatment" are used herein to mean partial or complete mitigation. , inhibit, prevent, ameliorate and/or alleviate the condition. The words "affected" or "affected" are used herein to refer to one or more conditions that a patient has been diagnosed or suspected of. 15 2. Description of the example compound: In several embodiments, the invention provides a compound of formula I:

或其藥學上可接受之鹽，其中：各個=基分別表示單鍵或雙鍵； 10 200823187 R1為氫、低碳烷基、-S(0)20H或-C(0)R、其中R為氫或視需要可經以-OH取代之低碳烷基； A為-N(H)-、-N(0H)_4-0-; R2為氫或-OH ; 5 r3及r4各自分別為氫、鹵素、甲基、甲氧基或-OH ;Or a pharmaceutically acceptable salt thereof, wherein: each = group represents a single bond or a double bond, respectively; 10 200823187 R1 is hydrogen, lower alkyl, -S(0)20H or -C(0)R, wherein R is Hydrogen or, if desired, a lower alkyl group substituted with -OH; A is -N(H)-, -N(0H)_4-0-; R2 is hydrogen or -OH; 5 r3 and r4 are each hydrogen respectively , halogen, methyl, methoxy or -OH;

Ra為氫或·ΟΗ及Rb為氫或-OH，或Ra及Rb與其附接之碳共同形成羰基部分；Ra is hydrogen or hydrazine and Rb is hydrogen or -OH, or Ra and Rb together with the carbon to which they are attached form a carbonyl moiety;

Re為氫或-OH&Rd為氫或-oh，或Re及Rd與其附接之碳共同形成羰基部分； 10 Re為氫或-OH ; 各個Rx分別為氫、鹵素、-CF3、或低碳烷基，但兩個 Rx基非同時為氫；各個Ry分別為氫或_〇H ; m為1、2或3 ;及 15 η為1或2 ; 限制條件為適用下列條件中之至少一者：（&) R2、R3、 R、R、R、R、Rd及Ry中之一者為 (c) R1為-S(0)20H;或(d) 1^與0或1^與Rd中之至少一對連同至其附接之碳共同形成為羰基部分。 20 大致上如先前定義，各個=基分別表示單鍵或雙鍵，但兩個=基並未同時表示雙鍵。當表示單鍵時，^及妒各自為氫或共同結合形成酮基部分；以及Re&Rd各自為氫或共同結合形成酮基部分。須瞭解當=基表示雙鍵時，則相對應之IT與Rb對或R、Rd對必須表示單一氯；以及Re基不 11 200823187 可存在。如此預期涵蓋價數所允許之式i化合物。於若干之實施例中，式基為1。於其它實施例中，式rin基為2。於若干實施例中，式基為1。 5 於若干實施例中，式I之m基為2。於又有其它實施例中，式I之πι基為3。大致上如前文定義，式I之R1基為R1為氫、低碳烷基、 -S(0)2〇H或-C(〇)R，其中尺為氫或低碳烷基。於若干實施例中，式1之以1基為氫。於其它之實施例中，式I之R1基為低碳 1〇烷基。於其它之實施例中，式I之Ri基為_s(0)2〇H。於又有其它實施例中，式RRl基為曱基。根據另一態樣，式r R1基為-c(o)r，其中R為氫、曱基或經羥基取代之丁基。式I之A基為_N(H)-、-N(OH)-或-〇_。於若干實施例中，式I之A基為_N(H)。於其它實施例中，式A基為_n(〇h)_。 15又有其它實施例中，式I之A基為·〇“ 於若干實施例中，式基為氟或氣。於其它實施例中’式I之R3基為氟。於若干實施例中，式RR2基為领此基為氯。於其它實施例中，R2基為氫及式〗之尺4基為_〇H。於又有其它實 2〇施例中，式I之R2基及R4基皆為_〇H。 ' 於若干實施例中，式I之各個RX基分別為幽素、碼或甲基。於其它實施例中，式jiRX基分別為齒基。於又有其它實施例中’式I之兩個基為氣。於若干實施例中，式、工之一個Rx基為氫，而另一個RX基為鹵素、_Ch或甲某。 12 200823187 於若干實施例中，式I之R2、R4及Ry基中之至少一者為 -OH，根據另一態樣，本發明提供式I-a、I-b、I-c、I-d及I-e 中之任一者之化合物：Re is hydrogen or -OH&dR is hydrogen or -oh, or Re and Rd together with the carbon to which they are attached form a carbonyl moiety; 10 Re is hydrogen or -OH; each Rx is hydrogen, halogen, -CF3, or low carbon An alkyl group, but two Rx groups are not hydrogen at the same time; each Ry is hydrogen or _〇H; m is 1, 2 or 3; and 15 η is 1 or 2; the restriction is that at least one of the following conditions is applicable :(&) One of R2, R3, R, R, R, R, Rd, and Ry is (c) R1 is -S(0)20H; or (d) 1^ and 0 or 1^ and Rd At least one of the pair together with the carbon to which it is attached forms a carbonyl moiety. 20 Roughly as previously defined, each = base represents a single or double bond, respectively, but two = bases do not simultaneously represent a double bond. When a single bond is indicated, ^ and oxime are each hydrogen or a common bond to form a keto moiety; and Re&Rd is each hydrogen or co-bonded to form a keto moiety. It should be understood that when the = base represents a double bond, then the corresponding IT and Rb pair or the R, Rd pair must represent a single chlorine; and the Re group does not exist. It is thus contemplated to cover the compounds of formula i as permitted by the valence. In several embodiments, the formula is one. In other embodiments, the formula rin is 2. In several embodiments, the formula is one. 5 In several embodiments, the m group of formula I is 2. In still other embodiments, the πι group of Formula I is 3. Roughly as defined above, the R1 radical of formula I is that R1 is hydrogen, lower alkyl, -S(0)2〇H or -C(〇)R, wherein the ruthenium is hydrogen or lower alkyl. In several embodiments, the 1 group of formula 1 is hydrogen. In other embodiments, the R1 group of formula I is a lower carbon 1 decyl group. In other embodiments, the Ri group of formula I is _s(0)2〇H. In still other embodiments, the formula RR1 is based on a fluorenyl group. According to another aspect, the formula r R1 is -c(o)r, wherein R is hydrogen, fluorenyl or hydroxy substituted butyl. The group A of formula I is _N(H)-, -N(OH)- or -〇. In several embodiments, the A group of formula I is _N(H). In other embodiments, the formula A is _n(〇h)_. In still other embodiments, the A group of formula I is "in some embodiments, the formula is fluorine or gas. In other embodiments, the R3 group of formula I is fluoro. In several embodiments, In the other embodiments, the R2 group is hydrogen and the quaternary 4 group of the formula is _〇H. In still other embodiments, the R2 group of the formula I and the R4 The radicals are all _〇H. ' In some embodiments, each RX group of formula I is a crypto, code or methyl group, respectively. In other embodiments, the jiRX groups are respectively a dentate group. Still other embodiments The two bases of Formula I are gas. In several embodiments, one Rx group of the formula, one is hydrogen, and the other RX group is halogen, _Ch or A. 12 200823187 In several embodiments, Formula I At least one of the R2, R4 and Ry groups is -OH. According to another aspect, the invention provides a compound of any of Formulas Ia, Ib, Ic, Id and Ie:

M 5 或其藥學上可接受之鹽，其中R2、R4及Rx各自係如前文定義，及於此處所述之類別及亞類定義。於若干實施例中，式I之各個基表示單鍵。於其它實施例中，本發明提供一種式I-f化合物，其中式I之基於化合物I-f中呈現雙鍵： R2M 5 or a pharmaceutically acceptable salt thereof, wherein each of R 2 , R 4 and R x is as defined above, and is defined by the classes and subclasses described herein. In several embodiments, each group of formula I represents a single bond. In other embodiments, the invention provides a compound of formula I-f wherein formula I exhibits a double bond based on compound I-f: R2

I-f 13 200823187 或其藥學上可接受之鹽，其中R1、R2、R3、R4、Rx、 Ry、m、n及A各自係如前文定義，及如此處戶斤述之類別及亞類定義。於其它實施例中，Ra及Rb與其附接之碳共同形成羰基 5 部分。根據另一態樣，Re&Rd與其附接之碳共同形成羰基部分。於若干實施例中，本發明提供一種式I-g或I-h化合物：I-f 13 200823187 or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, Rx, Ry, m, n and A are each as defined above, and as defined herein by the class and subclass. In other embodiments, Ra and Rb together with the carbon to which they are attached form a carbonyl moiety. According to another aspect, Re&Rd forms a carbonyl moiety with the carbon to which it is attached. In several embodiments, the invention provides a compound of Formula I-g or I-h:

或其藥學上可接受之鹽，其中R1、R2、R3、R4、、 10 Ry及m各自係如前文定義，及如此處所述之類別及亞類定義。於其它實施例中，本發明提供一種式Γ化合物：Or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, 10Ry and m are each as defined above, and the classes and subclasses as defined herein are defined. In other embodiments, the invention provides a hydrazine compound:

或其藥學上可接受之鹽，其中R1、R2、R3、R4、Rx、Or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, Rx,

Ry及m各自係如前文定義，及如此處所述之類別及亞類定 14 200823187 本發明化合物含有非對稱碳原子，如此產生立體異構物，包括對映異構物及非對映異構物。如此本發明意圖涵蓋全部此等立體異構物及立體異構物之混合物。於本案全 5案中，本發明產物名稱此處並未指示非對稱中心之絕對組態時，意圖涵蓋個別立體異構物及立體異構物之混合物。於若干實施例中，本發明提供一種式11_3或11七化合物：Ry and m are each as defined above, and as described herein, classes and subclasses 14 200823187 The compounds of the invention contain asymmetric carbon atoms, thus producing stereoisomers, including enantiomers and diastereoisomers Things. Thus, the invention is intended to cover all such stereoisomers and mixtures of stereoisomers. In the case of this case, the product name of the present invention is not intended to indicate the absolute configuration of the asymmetric center, and is intended to encompass mixtures of individual stereoisomers and stereoisomers. In several embodiments, the invention provides a compound of formula 11_3 or 11:

!〇或其藥學上可接受之鹽，其中R1、R2、R3、R4、Ra、〇 or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, Ra,

Rb、Re、Rd、RX、Ry及m各自係如前文式丨化合物之定義，及如此處所述之類別及亞類定義。於若千實施例中，本發明提供一種式ΙΙ-a化合物，顯示如上，或其藥學上可接受之鹽，其中R1、R2、R3、R4、Ra、 15 Rb、Rc、Rd、RX、^及㈤各自係如前文式I化合物之定義，及如此處所述之類別及亞類定義。根據男〆個實施例，本發明提供一種式Η-e或H-d化合物： 15 200823187Each of Rb, Re, Rd, RX, Ry, and m is as defined above for the compound of the formula, and as defined herein for the classes and subclasses. In the present invention, the present invention provides a compound of the formula a-a, as shown above, or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, Ra, 15 Rb, Rc, Rd, RX, ^ And (5) each being as defined in the compound of formula I above, and the definition of the class and subclass as described herein. According to an embodiment of the present invention, the present invention provides a compound of the formula Η-e or H-d: 15 200823187

或其藥學上可接受之鹽，其中尺2、114、1^、1^及111各自 f 係如文式i化合物之定義，及如此處所述之類別及亞類定 5義。若以對映異構物為較佳，則於若干實施例中，可提供實貝上不含相對應之對映異構物。如此，實質上不含相對應之對映異構物之一種對映異構物係指透過分離技術單離或分離或製備成不含相對應之對映異構物。如此處使用「實質上不含」表示該化合物係由顯著較大比例之對映異構物所、、且成於右干貫化例中，化合物係由至少約重量比較佳對映異構物所組成。於本發明之其它實施例中，化合 15 物係由至^約99/„重量比之較料映異構物所組成。較佳對映異構物可藉技藝界已知之任—種方法“㈣旋混合物分離’鱗方法包㈣m餘騎师PLC)及對掌鹽類之形成及結晶吱Μ 士老〆错此處所述方法製備。例如參考 Jacques等人，對映異構物、卜消旋物及光學分割（威利科技么司，紐約，1981); Wilen SH 望 χ ^ • ，5·Η•等人，四面體3:2725 (1977);Or a pharmaceutically acceptable salt thereof, wherein each of the scales 2, 114, 1^, 1^ and 111 is as defined for the compound of the formula i, and the classes and subclasses as defined herein. If enantiomers are preferred, in several embodiments, it is possible to provide no corresponding enantiomers on the shell. Thus, an enantiomer that is substantially free of the corresponding enantiomer refers to being isolated or isolated or prepared to be free of the corresponding enantiomer by separation techniques. As used herein, "substantially free" means that the compound is from a significantly larger proportion of the enantiomer, and is formed in a right-drying example, the compound being at least about the weight of the better enantiomer. Composed of. In other embodiments of the invention, the compound 15 is comprised of a comparative analogy to a weight ratio of about 99/30. The preferred enantiomer may be by any of the methods known to the art. (4) Spinning mixture separation 'scale method package (4) m Yu jockey PLC) and the formation and crystallization of palm salt class. See, for example, Jacques et al., Enantiomers, Racemates, and Optical Segmentation (Willie Technology, New York, 1981); Wilen SH χ ^ • , 5·Η• et al, tetrahedron 3: 2725 (1977);

Eliel，E.L.碳化合物之立體 1匕予（麥克羅希爾公司，紐約， 1962年）；Wilen，S.H 弁錢八—丨 •先予刀副劑及光學分割表268頁 Ehel，編輯，諾特丹大學予出版社，印第安那州諾特丹1972 16 20 200823187 年）。須瞭解可存在有本發明之滯轉異構物。如此本發明涵蓋如前文定義以及於前文定義及此處定義之類別及亞類之式I化合物之滯轉異構形式。 5 式I化合物之實例列舉於下表1。表1 :式I化合物之實例Eliel, EL Carbon Compound Stereo 1 匕 (McRowell, New York, 1962); Wilen, SH 弁八八丨先先先副副副副副副副副副副副副副副副副副副副副副副副副副副副副副副副副University Press, Nottdan, Indiana 1972 16 20 200823187). It will be appreciated that the atropisomers of the invention may be present. Thus, the invention encompasses the isomeric forms of the compounds of formula I as defined above and in the classes and subclasses defined above and herein. 5 Examples of compounds of formula I are listed in Table 1 below. Table 1: Examples of compounds of formula I

>/NH2>/NH2

17 20082318717 200823187

OHOH

1-16 1-17 1-181-16 1-17 1-18

OHOH

OH NH2OH NH2

1-19 1-20 1-21 18 2008231871-19 1-20 1-21 18 200823187

\ 或其藥學上可接受之鹽。 —W文定義之化合物之外，本發明也提供如此處所疋義之可用作為式I 5-HT2C激動劑或部八式m化合*。料化合㈣有姉U: 之前藥之 19 200823187 R2\ or a pharmaceutically acceptable salt thereof. In addition to the compounds defined by W, the invention also provides a 5-HT2C agonist or a formula ** compound* as defined herein. Compound (4) 姊U: Pre-medicine 19 200823187 R2

III 或其藥學上可接受之鹽，其中：各個基分別表示單鍵或雙鍵； 5 R1為氫、-〇H、-OGlu、-Glu、-C(0)Glu或-C(0)0Glu、 -C(0)R，其中R為氫或視需要可經以-OH取代之低碳烷基； A為-NH、-N(OH)-或; R2為氫、-OH 或-OGlu ; R3及R4各自分別為氫、鹵素、曱基、甲氧基、·〇Η或 10 -OGlu ;Or a pharmaceutically acceptable salt thereof, wherein: each group represents a single bond or a double bond; 5 R1 is hydrogen, -〇H, -OGlu, -Glu, -C(0)Glu or -C(0)0Glu And -C(0)R, wherein R is hydrogen or, if desired, a lower alkyl group substituted with -OH; A is -NH, -N(OH)- or; R2 is hydrogen, -OH or -OGlu; R3 and R4 are each hydrogen, halogen, fluorenyl, methoxy, hydrazine or 10-OGlu;

Ra&Rb各自為氫或與其附接之碳共同形成魏基部分； Rc&Rd各自為氫、-OGlu、-OH或與其附接之碳共同形成羰基部分；Ra&Rb is each hydrogen or a carbon attached thereto to form a Wei group; Rc&Rd is each hydrogen, -OGlu, -OH or a carbon moiety attached thereto to form a carbonyl moiety;

Re為氫、-Oglu或-OH ; 15 各個RX分別為氫、鹵素、-CF3，或低碳烷基，但限制條件為Rx基不可同時為氫；各個R5分別為氫、-Oglu或-OH ; m為1、2或3 ;以及 η為1或2 ; 20 但限制條件為R1、R2、R3、R4、R5、Rc、R^Re中之 20 200823187 至少一者含有Glu。大致上如先前定義，各個基分別表示單鍵或雙鍵，但兩個=基並未同時表示雙鍵。當表示單鍵時，Ra&Rb 各自為氫或共同結合形成酮基部分；以及RC&Rd各自為氕 5或共同結合形成酮基部分。須瞭解當=基表示雙鍵時，則相對應之Ra與Rb對或Re與Rd對必須表示單一氫；以及^基不可存在。如此預期涵蓋價數所允許之式丨化合物。本發明化合物也可用於5—HTm激動劑或部分激動劑於生物現象及病理現象之研究，以及用於5-ΗΤκ激動劑或部 10 分激動劑之比較性評估。由於5-HT2C激動劑或部分激動劑之代謝研究結果發現本化合物。不欲受理論所限，相信本化合物為5_HT2C激動劑或部分激動劑代謝產物，諸如說明於美國專利申請案 11/409,466,申請日2_年4月21日，全文以引用方式併入 15此處。如此，本化合物也可用於5_HT2C激動劑或部分激動劑於活體内或試管内之功效之研究。如此處使用，「前藥」一詞係指需要於體内經過轉換來釋放出活性藥物，且具有物理性質及/或遞送性質優於親代藥物分子之親代藥物分子之衍生物。例如，化合物可利用 20代謝手段(例如藉水解)轉換成式I化合物。前藥係設計來提升與親代藥物分子相關聯之基於藥學及/或藥力學性質。前藥之優點在於其物理性質，諸如比較親代藥物於生理pH 4，藉腸這外投藥之水溶性升高，或可促進由消化道之吸收，或可提升長期藥物安定性。近年來，已經探討數種不 21 200823187 同類性之生物可逆衍生物而用於設計前藥。使用酯類作為含有羧基或羥基官能基之藥物前藥類型為技藝界所已知，例如說明於「藥物設計及藥物交互作用之有機化學」，Re is hydrogen, -Oglu or -OH; 15 each RX is hydrogen, halogen, -CF3, or lower alkyl, but the restriction is that the Rx group cannot be hydrogen at the same time; each R5 is hydrogen, -Oglu or -OH m is 1, 2 or 3; and η is 1 or 2; 20 but the constraint is 20 of R1, R2, R3, R4, R5, Rc, R^Re 200823187 at least one contains Glu. Roughly as previously defined, each group represents a single bond or a double bond, respectively, but two = groups do not simultaneously represent a double bond. When a single bond is represented, Ra&Rb is each hydrogen or co-bonded to form a keto moiety; and RC&Rd is each 氕5 or co-bonded to form a keto moiety. It should be understood that when the = base represents a double bond, then the corresponding Ra and Rb pairs or the Re and Rd pairs must represent a single hydrogen; and the ^ group cannot exist. It is thus contemplated to cover the hydrazine compounds allowed by the valence. The compounds of the invention are also useful in the study of biological phenomena and pathological phenomena of 5-HTm agonists or partial agonists, as well as for comparative evaluation of 5-ΗΤκ agonists or partial agonists. This compound was found as a result of a metabolic study of a 5-HT2C agonist or a partial agonist. Without wishing to be bound by theory, it is believed that the present compound is a 5-HT2C agonist or a partial agonist metabolite, such as described in U.S. Patent Application Serial No. 11/409,466, filed on Apr. 21, the entire filing date of At the office. Thus, the present compounds are also useful for the study of the efficacy of 5-HT2C agonists or partial agonists in vivo or in vitro. As used herein, the term "prodrug" refers to a derivative of a parent drug molecule that is required to be converted in vivo to release the active drug and which has physical and/or delivery properties superior to the parent drug molecule. For example, a compound can be converted to a compound of formula I using 20 metabolic means (e.g., by hydrolysis). The prodrug line is designed to enhance the pharmaceutically and/or pharmacodynamic properties associated with the parent drug molecule. The advantage of the prodrug is its physical properties, such as the comparison of the parental drug at physiological pH 4, the increased water solubility of the parenteral administration, or the absorption of the digestive tract, or the improvement of long-term drug stability. In recent years, several bioreversible derivatives of the 200821187 congener have been explored for the design of prodrugs. The use of esters as drug prodrugs containing carboxyl or hydroxyl functional groups is known to the art, for example, in "Organic Chemistry for Drug Design and Drug Interaction,"

Richard Silverman，學術出版社出版（1992年）。多種形式之 5鈾藥為技藝界所已知，例如討論於Bundgaard編輯，前藥設計伊瑟微爾（Elsevier) (1985年）；Widder等人(編輯），酶學方法第4期’學術出版社（1985年）；Krogsgarrd-Larsen等人(編輯）「前藥之設計應用」，藥物設計與發展教科書第5章， 113-191 (1991)，Bimdgaard等人，藥物遞送綜論期刊， 10 8:1-38(1992)，Bundgaard，製藥科學期刊，77:285等（1988); 及Higuchi及Stella(編輯)前藥作為新穎藥物遞送系統，美國化學會（1975年）’各案全文以引用方式併入此處。如此處使用，「葡萄糖醛酸苷基部分」係可與縮寫「Glu」互換且具有結構式： ΟRichard Silverman, published by Academic Press (1992). Various forms of 5 uranium drugs are known to the art world, for example in Bundgaard's edition, Prodrug Design by Elsevier (1985); Widder et al. (ed.), Enzymology Method No. 4 'Academic Publishing Society (1985); Krogsgarrd-Larsen et al. (eds.) "Design and Application of Prodrugs", Textbook for Drug Design and Development, Chapter 5, 113-191 (1991), Bimdgaard et al., Journal of Drug Delivery, 10 8 : 1-38 (1992), Bundgaard, Journal of Pharmaceutical Sciences, 77: 285 et al (1988); and Higuchi and Stella (editor) prodrugs as novel drug delivery systems, American Chemical Society (1975) The way is incorporated here. As used herein, "glucuronide moiety" is interchangeable with the abbreviation "Glu" and has the structural formula:

OH 15 其中浪線係指附接至式III化合物之附接點。如此處使用’「葡萄糖基部分」係可與縮寫「Glucos」互換且具有結構式：OH 15 wherein the wave line refers to the attachment point attached to the compound of formula III. As used herein, the 'glucose-based moiety' is interchangeable with the abbreviation "Glucos" and has the structural formula:

OH 20 其中浪線係指附接至式III化合物之附接點。於若干實施例中，式III之η基為1。 22 200823187 於其它實施例中，式III之η基為2。於若干實施例中，式III之m基為1。於其它實施例中，式III之m基為2。於又有其它實施例中，式III之m基為3。 5 大致上如前文定義，式III之R1基為氫、-OH、-OGlu、 -Glu-、-C(0)Glu、-C(0)0Glu或-C(0)R。於若干實施例中，式III之R1基為氫。於其它實施例中，式in之r1基為_〇h或 OGhi〇於又有其它實施例中，式III之R1基為_Giu〇於又有其它實施例中，式III之R1基為-C(0)Ghi。於又有其它實施 10 例中，式III之R1基為-C(0)0Glu。於又有其它實施例中，式 III之R1基為-C(0)R，其中R為氫或視需要可經以·〇Η取代之低碳烧基。式III之A基為_N(H)_、_N(OH)_或-0·。於若干實施例中，式III之A基為-N(H)。於其它之實施例中，式in之A基 15 為-N(OH)-。又有其它實施例中，式III之A基為-0_。於若干實施例中，式III之A基為-0-。於若干實施例中，式III之R3基為氟或氯。於其它實施例中，式III之R3基為氟。於若干實施例中，式III之R2基為-OH及R4基為氫。於其 20 它實施例中，R2基為氫及式III之R4基為-OH。於又有其它實施例中，式III之R2基及R4基皆為_〇H。於若干實施例中，式III之R2基為-〇Ghi及R4基為氫。於其它實施例中，R2基為氫及式III之R4基為-OGhi。於若干實施例中，式III之各個Rx基分別為氫、鹵素、 23 200823187 -CF3或甲基。於其它實施例中，式III之一Rx基為鹵素。又有其它實施例中，式III之兩個Rx基為氣基。於若干實施例中，式III之一個Rx基為氯、-CF3或甲基，而另一個Rx基為氫。根據另一個實施例，本發明提供一種式IV化合物：OH 20 wherein the wave line refers to the attachment point to the compound of formula III. In several embodiments, the η group of formula III is one. 22 200823187 In other embodiments, the η group of formula III is 2. In several embodiments, the m group of formula III is one. In other embodiments, the m group of formula III is 2. In still other embodiments, the m group of formula III is 3. 5 Roughly as defined above, the R1 group of formula III is hydrogen, -OH, -OGlu, -Glu-, -C(0)Glu, -C(0)0Glu or -C(0)R. In several embodiments, the R1 group of formula III is hydrogen. In other embodiments, the r1 group of the formula in is _〇h or OGhi〇. In still other embodiments, the R1 group of the formula III is _Giu, and in still other embodiments, the R1 group of the formula III is - C(0)Ghi. In yet another embodiment, the R1 group of formula III is -C(0)0Glu. In still other embodiments, the R1 group of formula III is -C(0)R, wherein R is hydrogen or, if desired, a low carbon alkyl group substituted with ?. The group A of formula III is _N(H)_, _N(OH)_ or -0. In several embodiments, the A group of formula III is -N(H). In other embodiments, the A group 15 of the formula in is -N(OH)-. In still other embodiments, the A group of formula III is -0. In several embodiments, the A group of formula III is -0-. In several embodiments, the R3 group of formula III is fluoro or chloro. In other embodiments, the R3 group of formula III is fluoro. In several embodiments, the R2 group of formula III is -OH and the R4 group is hydrogen. In its embodiment, the R2 group is hydrogen and the R4 group of formula III is -OH. In still other embodiments, the R2 group and the R4 group of formula III are both 〇H. In some embodiments, the R2 group of formula III is -〇Ghi and the R4 group is hydrogen. In other embodiments, the R2 group is hydrogen and the R4 group of formula III is -OGhi. In several embodiments, each Rx group of formula III is independently hydrogen, halogen, 23 200823187 -CF3 or methyl. In other embodiments, one of the Rx groups of Formula III is a halogen. In still other embodiments, the two Rx groups of formula III are gas based. In several embodiments, one Rx group of formula III is chloro, -CF3 or methyl, and the other Rx group is hydrogen. According to another embodiment, the invention provides a compound of formula IV:

HOHO

或其藥學上可接受之鹽，其中RX'm'R1及R5各自大致上係如前文定義以及於前述及本文說明之類別及亞類中。 10 根據又另一個實施例，本發明提供一種式IV-a、IV-b 或IV-c化合物： Θ 02Or a pharmaceutically acceptable salt thereof, wherein RX'm'R1 and R5 are each substantially as defined above and in the classes and subclasses described above and herein. According to yet another embodiment, the invention provides a compound of formula IV-a, IV-b or IV-c: Θ 02

IV-b 24 200823187 R2IV-b 24 200823187 R2

IV-c 或其藥學上可接受之鹽，其中Rx、m、R2及R4及R5各自大致上係如前文定義以及於前述及本文說明之類別及亞類 5 中。根據又另一個實施例，本發明提供一種式V化合物： R2Or a pharmaceutically acceptable salt thereof, wherein Rx, m, R2 and R4 and R5 are each substantially as defined above and in the classes and subclasses 5 described above and herein. According to still another embodiment, the invention provides a compound of formula V: R2

V 或其藥學上可接受之鹽，其中Rx、R1、A、R2及R4各自 10 大致上係如前文定義以及於前述及本文說明之類別及亞類中〇 3.提供本化合物之大致方法：本發明化合物係使用熟諳技藝人士方便易得之方法，例如根據美國專利申請案11/409,466，申請日2006年4月21 15 曰（該案全文以引用方式併入此處）所詳細說明之方法製 25 200823187 備。本發明之立體異構物也可使用熟諳技藝人士方便易得之方法製備’例如根據美國臨時專利申請案6〇/792,830，申請日2006年4月18日（該案全文以引用方式併入此處）說明之立體選擇性方法製備。式IV化合物大致上係藉熟諳技藝人士已知方法製備，例如藉如下大致反應圖所述方法製備。反應圖1V or a pharmaceutically acceptable salt thereof, wherein each of Rx, R1, A, R2 and R4 is substantially as defined above and in the classes and subclasses described above and herein. 3. General methods for providing the present compound: The compounds of the present invention are those which are readily available to those skilled in the art, for example, as described in detail in U.S. Patent Application Serial No. 11/409,466, filed on Apr. 21, 2006, which is hereby incorporated by reference. System 25 200823187. The stereoisomers of the present invention can also be prepared by methods readily available to those skilled in the art, for example, in accordance with U.S. Provisional Patent Application No. 6/792,830, filed on Apr. 18, 2006. The preparation of the stereoselective method is described. The compounds of formula IV are prepared, generally, by methods known to those skilled in the art, for example, by the methods outlined in the Schemes below. Reaction diagram 1

X(R5)l-3 IV 如上反應圖1顯示製備式IV化合物之大致方法。如上所 10 示，羥基化合物1係以具有適當離去基之適當經保護之葡萄糖醛酸化物2處理來允許期望之偶合而形成化合物3。對式2 化合物而言，PG2、PG3及PG4各自為適當羥基保護基。適 26 200823187 當羥基保護基為技藝界眾所周知且包括其細節說明於有機合成保護基，T.W. Greene及P.G.M· Wuts，第3版，約輪威利父子公司，1999年（全文以引用方式併入此處)所述之經基保護基。適當羥基保護基之實例進一步包括但非限於酯類、 5 丙烯醚類、醚類、矽烷基醚類、烷基醚類、芳基烷基醚類及烷氧基烷基醚類。此等酯類之實例包括甲酸酯類、乙酸酯類、碳酸酯類、及磺酸酯類。特例包括甲酸酯、曱酸苯甲醯、氣乙酸酯、三氟乙酸酯、甲氧基乙酸酯、三苯基甲氧基乙酸酯、對氣苯氧基乙酸酯、3-苯基丙酸酯、4-酮基戊 10 酸酯、4,4-(伸乙基二硫基）戊酸酯、特戊酸酯（三甲基乙醯基）、巴豆酸酯、4-甲氧基-巴豆酸酯、苯甲酸酯、對苄基苯甲酸酯、2,4,6-(三甲基苯甲酸酯）；碳酸酯諸如碳酸甲酯、 9_戊基甲酯、乙酯、2,2,2-三氯乙酯、2-(三甲基矽烷基）乙醋、2_(苯基磺醯基）乙酯、乙烯酯、丙烯酯及對硝基苄酯。 15 此等石夕燒基醚類之實例包括三甲基矽烷基醚、三乙基矽烷基鱗、第三丁基二甲基矽烷基醚、第三丁基二苯基矽烷基謎、三異兩基矽烷基醚、及其它三烷基矽烷基醚。烷基醚類包括甲基醚、苄基醚、對甲氧基苄基醚、3,4_二甲氧基苄基鱗、三苯甲基醚、第三丁基醚、丙烯基醚、及丙烯氧羰 20基鱗或其衍生物。烷氧基烷基醚類包括縮醛類諸如甲氧基甲基喊、甲硫基甲基醚、（2-甲氧基乙氧基）甲基醚、苄氧基甲基鱗、(三甲基矽烷基）乙氧基甲基醚及四氫哌喃基鍵。芳基燒基醚類之實例包括节基醚、對甲氧基节基醚 (3,4-_甲氧基苄基醚、鄰石肖基苄基醚、對石肖基苄基 27 200823187 醚、對鹵苄基醚、2,6-二氯苄基醚、對氰基苄基醚、2-及4-吡啶曱基醚。須瞭解PG2、PG3及PG4各自可相異或相同。於若干實施例中，PG2、PG3及PG4各自為相同，故係藉相同條件移 5 除。此等保護基之移除也稱作為「脫去保護」係藉技藝界已知之方法達成，包括詳細說明於「有機合成保護基」，T.W. Greene及P.G.M· Wuts，第3版，約翰威利父子公司，1999年之該等保護基。對式2化合物而言，pg1基為適當羧酸保護基。此等保 10 護基為技藝界已知且包括於「有機合成保護基」，T.W. Greene及P.G.M. Wuts，第3版，約翰威利父子公司，1999年所6羊細ό兒明之保遵基’該案全文以引用方式併入此處。適當羧酸保護基進一步包括但非限於經取代之Cw脂肪族酯類、視需要可經取代之芳基酯類、矽烷基酯類、活化酯類、 15醯胺類、醯肼類等。此等酯基之實例包括甲酯、乙酯、丙酯、異丙酯、丁酯、異丁酯、苄酯、及苯酯，其中各個基團視需要可經取代。於葡萄糖醛酸化物2與化合物1偶合後，獲得經保護之化合物3。然後此化合物脫去保護形成式^化合物。 20 須瞭解於若干情況下，較佳係同時去除全部保護基。於此等情況下，PG1、PG2、PG3及PG4之選擇須讓各個保護基可於相同條件下被去除，例如經由以酸或鹼處理、經由還原或經由超紫外光(僅舉出少數實例）同時去除。此等保護基之選擇為熟諳技藝人士眾所周知。 28 200823187 式V化合物可以如上反應圖1所述之實質類似方式或藉热諳技藝人士已知方法製備。 4·用途、配方及投藥本發明化合物對腦血清素受體2C亞型具有親和力且具有激動劑或部分激動劑活性，如此令人感興趣地可用於治療多種病症及/或減輕一種或多種相關聯的症狀。此等與腦血清素受體2C亞型之調控相關聯之病症說明如下。本發明涵蓋本發明化合物關聯有快速作用起點。此外本發明化合物不具有性功能障礙之副作用。本發明化合物可用於治療如此處所述之一種或多種精神病症而不會造成糖尿病發生。糖尿病發生乃非典型抗精、申病某所引發之一種副作用。不欲受任何特定理論所限， 15 20 相k非典型抗精神病藥所引發之糠尿病發生係來自於該等樂物為5術2。拮抗劑。如此處所述，本化合物為5·ηί^激動劑或部分激動劑，因此不會造成糖尿病發生。 #八^發明化合物可用於治療〆種或多種精神病症諸如精、刀衣症包括妄想型精神***症、解離型精神***症、緊症1 ^神刀衣症及未分化型精神***症、精神***樣病之刀衣W紐、妄想症、物質誘發精神病症及未明示之=神病症，左多巴誘發精神病，·阿兹海默氏痴呆所引發 /中病’巴金森氏病所引發之病神病丨及路易體發之精神病。 29 200823187 向」症狀。此等症狀例如包括精神病病人之幻覺、妄想、偏執狂、焦慮、躁動不安、過度激動、緊張、思考障礙、情感遲鈍及社交退縮及情緒退縮。其它經常與精神病症相關聯之症狀包括認知障礙或缺陷諸如注意力不佳及功能受 5損、憂鬱、自殺、代謝症候群及物質濫用。如此，本發明之另一個實施例提供一種治療與精神病症相關聯之一種或多種症狀之方法。於其它實施例中’本化合物可用於治療焦慮病症諸如恐慌症發作、廣場恐懼症、恐慌症、特殊恐懼症、社交恐 10懼症、社交焦慮症、強迫症、創傷後壓力症、急性壓力症、綜合焦慮症、分離焦慮症、物質誘發焦慮症及未明示之焦慮症。根據另一個實施例，本化合物可用於治療躁鬱症。此等躁鬱症包括I型躁鬱症、II型躁鬱症及循環型躁鬱症；兩 15 極性躁症、痴呆症及帶有精神特徵之憂鬱症。本化合物也可用於治療（包括預防）兩極性鬱症與兩極性躁症間可能發生的循環。前述精神病症之更完整說明可參考精神病症之診斷及統計手冊第4版，華盛頓特區美國精神病學會（1994年），全 2〇文以引用方式併入此處。於若干實施例中，本發明化合物係與一種或多種抗精神病劑組合投予。此等抗精神病劑為技藝界眾所周知，且包括可雜平(clozapine)(例如可雜麗爾（Clozaril)、李斯霹靂東(risperidone)(例如李斯霹靂達(Risperidal))、歐藍雜平 30 200823187 (olanzapine)(例如吉普瑞沙(Zyprexa))、葵堤亞平(quetiapine) (例如斯柔葵爾（Seroquel))、吉普拉希東(ziprasidone)(例如喬東（Geodon))、阿麗皮拉左（aripiprazole)、阿米蘇皮德 (amisulpiride)、可洛瑪曾（chlorpromazine)、芙芬那曾 5 (fluphenazine)、哈羅皮麗度（haloperidol)(例如好度 (Haldol))、洛沙平(loxapine)、美索麗達曾（mesoridazine)、莫林東(molindone)、波芬那曾（perphenazine)、皮莫吉德 (pimozide)、塞洛葵爾（seroquel)、蘇麗德(sulpiride)、索麗達曾（thioridazine)、索希森（thiothixene)、崔芙皮拉曾 10 (trinuoPerazine)及碧夫普諾斯(bifeprunox)，只舉出若干實例0 15 么月化a物與一種或多種抗精神病劑之組合可用於 /口療精神刀放症包括妄想型精神***症、解離型精神*** 症、緊張型精神***症及未分化型精神***症、精神*** 木κ病症、***情感病症、妄想症、物質誘發精神病症及未月"I之精神病症；左多巴誘發精神病；阿兹海默氏痴呆所 X精神病，巴金森氏病所引發之病神病；及路易體病所引發之精神病；躁營症諸如包糾型躁營症、π型躁營症及循環型躁鬱症；兩極性 .^ ^ ^ ^ ^ ^ ’ 减、痴呆症及帶有精神病特徵 W⑨右干實關+，此等組合可肖於治療躁繫症，匕例如治療兩極性誉症與兩極性躁症間之循環。麻Γ其它實施财，料本發明化合物與抗精神病藥可 =精神病效果，同時去除或減少某些當抗精神病藥單獨使用時典型觀察得之不良㈣（例如靜坐不能、張2 31 200823187 常、巴金森氏運動困難及晚近運動困難等）。於其它實施例中，本發明化合物可用於治療_種或多種憂鬱症，諸如重度憂營症、季節性情感障礙、心情惡劣障礙、物質誘發心情障礙、未明示之憂#症及對治療有抗 5 性之憂誉症。本發明之另一態樣提供一種治療一種或多種心情障礙之方法，諸如重度憂鬱症、躁症、混合型發作及輕躁症；以及調整障礙諸如有焦慮心情及/或憂心情之調整障礙。本I月化合物也可用於治療與憂鬱症相關之症狀，包 10括身體症狀諸如神經病變性疼痛及性功能障礙。其它身體症狀匕括、、、邑J、無助、焦慮及擔憂、有或無認知受損客觀癥象之記憶主訴、喪失愉悅感（興趣缺乏）、行動緩慢、激動不安及對個人照顧缺乏興趣諸如對用藥計畫或膳食計晝之遵循不良。 15 於若干實施例中，本發明提供一種治療與憂鬱症相關聯之性功能障礙之方法。於其它實施例中，本發明提供一種治療與投予血清素再吸收抑制劑(SRI)用來治療憂繫症或其它病症所引發之性功能障礙之方法。此等性功能障礙之治療方法細節說明如下。力若干實施例中，本發明化合物係組合-種或多種抗鬱劑投予。適當抗鬱劑例如包括血清素再吸收抑制劑 (SRI) ’正腎上腺素再吸收抑制劑(NRI卜組合型血清素-正腎上腺素再吸收抑制劑（SNRI)、單胺氧化酶抑制劑 (MAOI)、單胺氧化酶之可逆性抑制劑(RIMA)、磷酸二酯酶 32 200823187 4 (PDE4)抑制劑、促腎上腺皮質激素釋放因子（CRF)拮抗劑、α腎上腺受體拮抗劑或包括非典型抗鬱劑之其它化合物。組合本發明化合物投予之其它抗鬱劑包括三重吸收抑制劑諸如DOV 216303及DOV 21947···;褪黑激素激動劑諸 5 如亞果美洛汀(agomelotine)、超神經傳遞物質吸收阻斷劑 (SNUB例如NS-2389得自葛蘭素史克公司（GlaxoSmithKline) 及神經研究公司（Neurosearch)之NS-2389 ;得自史普拉克公司（Sepracor)之(R)_DDMA)，及/或物質P/神經激廇受體拮抗劑（例如得自默克公司（Merck)之亞培皮坦 10 (aprepitant)/MK-869 ;得自諾華公司（Novartis)之NKP-608 ; 得自輝瑞公司（Pfizer)之CPI-122721 ;得自羅氏公司（Roche) 之R673 ;得自武田藥廠之TAK637 ;及得自葛蘭氏史密克公司之GW-97599)。組合本發明化合物投予之另一類抗鬱劑為正腎上腺素 15 抗鬱劑及特定血清素激性抗鬱劑(NaSSA^NaSSA之適當實例為米塔治平(mirtazepine)。組合本發明化合物投予之適當NRI包括第三胺三環化合物及第二胺三環化合物。第三胺三環化合物之適當實例包括：阿米崔林（amitriptyline)、克洛米拉明 20 (clomipramine)、朵西平(doxepin)、伊米普拉明（imipramine) (參考美國專利2,554,736,全文以引用方式併入此處）及崔米拉明（trimipramine)，及其藥學上可接受之鹽。第二胺三環化合物之適當實例包括：阿莫沙平(amoxapine)、迪斯普拉明（desipramine)、瑪柔堤林（maprotiline)、諾崔堤林 33 200823187 (nortriptyline)及普柔崔堤林(protriptyline)，及其藥學上可接受之鹽。組合本發明化合物投予之另一種NRI為麗伯西汀 (reboxetine)(伊卓那斯(Edronax) ; 2·[α·(2-乙氧基)苯氧基-5 苄基]咮啉，通常係呈外消旋形式投予；參考美國專利案 4,229,449，全文以引用方式併入此處。用來與本發明化合物組合投予之適當SSRI包括：西塔洛拉姆（citalopram) (1_[3-(二甲基胺基）丙基]-(4-氟苯基）-1，3 -二鼠-鄰-5-異苯弁咬喃甲骑；參考美國專利案 10 4，136,193 ; Christensen 等人，Eur. J. Pharmacol. 41:153, 1977;Dufour等人，Int. Clin. Psychopharmacol· 2:225，1987 ; Timmerman等人，同文，239，各案全文以引用方式併入此處）；夫洛西汀（fluoxetine) (N-甲基-3-(對三氟甲基苯氧基)-3-苯基丙基胺，以鹽酸鹽形式以及兩種同質異形體之外 15 消旋混合物形式出售；例如參考美國專利案4,314,081; Robertson等人，J. Med_ Chem. 31:1412, 1988，各文件以引用方式併入此處）；夫洛西汀/歐藍雜平之組合；夫露沃沙明 (fluvoxamine) (5-甲氧基-1-[4_(三氟甲基）苯基]小戊酮〇_(2_ 胺基乙基)肟；參考美國專利案4,085,225 ; Claassen等人， 20 Brit· J. Pharmacol. 60:505, 1977; De Wilde等人，情感障礙期刊4:249, 1982 ; Benfield等人，藥物32:313, 1986，各案全文以引用方式併入此處）；帕柔西、;丁(paroxetine)(反㈠-3-[(1，3_ 苯并二噚呃-5-基氧基）甲基]-4-(4-氟苯基)哌啶；參考美國專利案 3,912,743 ;美國專利案 4,007，196 ; Lassen Eur. J. 34 200823187X(R5)l-3 IV Reaction as above Figure 1 shows a general method for the preparation of a compound of formula IV. As indicated above, hydroxy compound 1 is treated with a suitably protected gluconate 2 having a suitable leaving group to allow the desired coupling to form compound 3. For the compound of formula 2, each of PG2, PG3 and PG4 is a suitable hydroxy protecting group.适26 200823187 When hydroxy protecting groups are well known to the art world and include details of their use in organic synthetic protecting groups, TW Greene and PGM· Wuts, 3rd edition, about the round of Willie & Sons, 1999 (full text incorporated by reference) Wherein the base protecting group is described. Examples of suitable hydroxy protecting groups further include, but are not limited to, esters, 5 propylene ethers, ethers, decyl ethers, alkyl ethers, aryl alkyl ethers, and alkoxyalkyl ethers. Examples of such esters include formates, acetates, carbonates, and sulfonates. Specific examples include formate, benzamidine phthalate, gaseous acetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, p-phenoxyacetate, 3 -Phenylpropionate, 4-ketopentaphthalate, 4,4-(ethylidenethio)valerate, pivalate (trimethylethenyl), crotonate, 4 -Methoxy-crotonate, benzoate, p-benzyl benzoate, 2,4,6-(trimethyl benzoate); carbonate such as methyl carbonate, 9-pentyl Ester, ethyl ester, 2,2,2-trichloroethyl ester, 2-(trimethyldecyl)ethyl acetate, 2-(phenylsulfonyl)ethyl ester, vinyl ester, propylene ester and p-nitrobenzyl ester . 15 Examples of such succinyl ethers include trimethyl decyl ether, triethyl decyl sulphate, tert-butyl dimethyl decyl ether, tert-butyl diphenyl fluorenyl, three different Bis-alkyl alkyl ethers, and other trialkyl decyl ethers. The alkyl ethers include methyl ether, benzyl ether, p-methoxybenzyl ether, 3,4-dimethoxybenzyl scale, trityl ether, tert-butyl ether, propylene ether, and Propyleneoxycarbonyl 20-based scale or a derivative thereof. Alkoxyalkyl ethers include acetals such as methoxymethyl sulfonate, methylthiomethyl ether, (2-methoxyethoxy)methyl ether, benzyloxymethyl scale, (trin) Esteryl)ethoxymethyl ether and tetrahydropyranyl linkage. Examples of the aryl alkyl ethers include a benzyl ether, a p-methoxy benzyl ether (3,4-methoxyphenyl ether, anthracenyl benzyl ether, p-Styshyl benzyl 27 200823187 ether, p-halobenzyl) Ether, 2,6-dichlorobenzyl ether, p-cyanobenzyl ether, 2- and 4-pyridinyl ether. It is to be understood that PG2, PG3 and PG4 may each be different or identical. In several embodiments, PG2, PG3, and PG4 are all the same, so they are removed by the same conditions. The removal of these protective groups is also referred to as "deprotection" by methods known to the art, including detailed description of "organic synthesis protection." TW Greene and PGM· Wuts, 3rd edition, John Wiley & Sons, the protective groups of 1999. For the compound of formula 2, the pg1 group is a suitable carboxylic acid protecting group. Known for the art world and included in the "Organic Synthesis Protection Base", TW Greene and PGM Wuts, 3rd Edition, John Wiley & Sons, 1999, 6th, Philippine, and the Guardian's Incorporated herein. Suitable carboxylic acid protecting groups further include, but are not limited to, substituted Cw aliphatic esters, as needed Substitutable aryl esters, decyl esters, activated esters, 15 guanamines, anthraquinones, etc. Examples of such ester groups include methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester And isobutyl ester, benzyl ester, and phenyl ester, wherein each group may be substituted as needed. After coupling of glucuronide 2 with compound 1, a protected compound 3 is obtained. The compound is then deprotected to form a formula ^ Compounds 20 It should be understood that in some cases it is preferred to remove all protecting groups simultaneously. In such cases, PG1, PG2, PG3 and PG4 are selected such that each protecting group can be removed under the same conditions, for example via Acid or base treatment, simultaneous reduction via reduction or via ultra-ultraviolet light (only a few examples). The choice of such protecting groups is well known to those skilled in the art. 28 200823187 The compound of formula V can be reacted in a substantially similar manner as described above in Figure 1. Or prepared by methods known to those skilled in the art. 4. Use, formulation and administration The compound of the present invention has affinity for the brain serotonin receptor 2C subtype and has agonist or partial agonist activity. Interestably, it can be used to treat a variety of conditions and/or alleviate one or more associated symptoms. Such conditions associated with the regulation of the brain serotonin receptor 2C subtype are described below. The present invention encompasses the rapid association of the compounds of the invention. Further, the compound of the present invention does not have side effects of sexual dysfunction. The compound of the present invention can be used for the treatment of one or more psychiatric conditions as described herein without causing diabetes. The occurrence of diabetes is caused by atypical anti-fertilization and a certain disease. A side effect. Without wishing to be bound by any particular theory, the occurrence of urinary tract disease caused by 15 20 phase k atypical antipsychotic drugs is derived from the 5 arteries of the music. Antagonist. As described herein, the present compound is a 5·ηί^ agonist or a partial agonist, and thus does not cause diabetes. #八^Inventive compounds can be used to treat warts or a variety of psychiatric conditions such as fine, scalpel disease including delusional schizophrenia, dissociative schizophrenia, tightness 1 ^ 刀衣及 and undifferentiated schizophrenia, spirit Syringe-like disease, W-news, delusions, substance-induced psychiatric disorders, and unspecified = God's disease, left dopa-induced psychosis, Alzheimer's dementia caused by / middle disease caused by Parkinson's disease Sickness and psychosis of Louis. 29 200823187 To the symptom. Such symptoms include, for example, hallucinations, delusions, paranoia, anxiety, restlessness, excessive excitement, stress, thinking disorders, emotional retardation, and social withdrawal and emotional withdrawal. Other symptoms often associated with psychiatric conditions include cognitive impairment or defects such as poor attention and functional impairment, depression, suicide, metabolic syndrome, and substance abuse. Thus, another embodiment of the present invention provides a method of treating one or more symptoms associated with a psychiatric condition. In other embodiments, the present compound can be used to treat anxiety disorders such as panic attacks, square phobias, panic attacks, special phobias, social fears, social anxiety disorders, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder. Comprehensive anxiety disorder, separation anxiety disorder, substance-induced anxiety disorder and unexplained anxiety disorder. According to another embodiment, the present compounds are useful in the treatment of bipolar disorder. Such bipolar disorder includes type I bipolar disorder, type II bipolar disorder, and circulatory bipolar disorder; two 15 polar snoring, dementia, and depression with mental characteristics. The compound can also be used to treat (including prevent) a cycle that may occur between bipolar depression and bipolar snoring. A more complete description of the aforementioned psychiatric disorders can be found in the Diagnostic and Statistical Manual of Psychiatric Disorders, 4th Ed., Washington, DC, American Psychiatric Association (1994), which is incorporated herein by reference. In several embodiments, the compounds of the invention are administered in combination with one or more antipsychotic agents. Such antipsychotic agents are well known to the artisan and include clozapine (e.g., Clozaril, risperidone (e.g., Risperidal), Ou Lanchaping 30 200823187 (olanzapine) (eg Zyprexa), quetiapine (eg Seroquel), ziprasidone (eg Geodon), Alipi Aripiprazole, amisulpiride, chlorpromazine, fluphenazine, haloperidol (eg Haldol), Luo Loxapine, mesoridazine, molindone, perphenazine, pimozide, seroquel, sulpiride , thioridazine, thiothixene, trinuoPerazine, and bifeprunox, to name a few examples. A combination of various antipsychotic agents can be used for / oral therapy, mental scalpel disease, including delusion Schizophrenia, dissociative schizophrenia, stress-type schizophrenia and undifferentiated schizophrenia, schizophrenia κ disease, schizoaffective disorder, paranoia, substance-induced psychosis, and unexplained mental illness; Dopa-induced psychosis; Alzheimer's dementia X mental illness, disease caused by Parkinson's disease; and psychosis caused by Lewy body disease; stagnation disease such as stagnation type camp, π type camp Symptoms and circulatory bipolar disorder; two polarities. ^ ^ ^ ^ ^ ^ ' reduction, dementia and W9 right-handedness with psychotic characteristics +, these combinations can be used to treat sputum, such as treatment of two polar Circulation between the disease and bipolar snoring. Other implementations of paralysis, the compound of the present invention and the antipsychotic drug can be used as a psychotic effect, while removing or reducing some of the typical observations when the antipsychotic drug is used alone (4) (for example) Sit-in can not, Zhang 2 31 200823187 often, Barkson's exercise difficulty and late exercise difficulty, etc.) In other embodiments, the compounds of the invention may be used to treat _ or more kinds of depression, such as severe Camp disease, seasonal affective disorder, mood disorder, substance-induced mood disorder, unrecognized worries, and anxiety about treatment. Another aspect of the present invention provides a treatment for one or more mood disorders Methods such as severe depression, snoring, mixed seizures, and palsy; and adjustment disorders such as adjustment disorders with anxiety and/or anxiety. This I month compound can also be used to treat symptoms associated with depression, including physical symptoms such as neuropathic pain and sexual dysfunction. Other physical symptoms include,,, 邑J, helplessness, anxiety and worry, memory complaints with or without cognitive impairment, loss of pleasure (lack of interest), slowness of movement, anxiety, and lack of interest in personal care Such as poor compliance with medication plans or meal plans. In some embodiments, the invention provides a method of treating sexual dysfunction associated with depression. In other embodiments, the invention provides a method of treating and administering a serotonin reuptake inhibitor (SRI) for the treatment of sexual dysfunction caused by a complication or other condition. Details of the treatment of these sexual dysfunctions are described below. In several embodiments, the compounds of the invention are administered in combination with one or more anti-depressants. Suitable anti-depressants include, for example, serotonin reuptake inhibitors (SRI) 'norepinephrine reuptake inhibitors (NRI combination serotonin-norepinephrine reuptake inhibitor (SNRI), monoamine oxidase inhibitor (MAOI), monoamine oxidase) Reversible inhibitors (RIMA), phosphodiesterase 32 200823187 4 (PDE4) inhibitors, corticotropin releasing factor (CRF) antagonists, alpha adrenoceptor antagonists or other compounds including atypical antidepressants Other antidepressants administered in combination with the compounds of the invention include triple absorption inhibitors such as DOV 216303 and DOV 21947...; melatonin agonists 5 such as agoomelotine, superneural transfer material absorption resistance Broken agents (SNUB such as NS-2389 are available from GlaxoSmithKline and Neurosearch, NS-2389; from Spracor (R)_DDMA), and/or substances P/neuroradatic receptor antagonists (eg, aprepitant 10/MK-869 from Merck; NKP-608 from Novartis; from Pfizer ( Pfizer) CPI-12 2721; R673 from Roche; TAK637 from Takeda Pharmaceutical Co., Ltd.; and GW-97599 from Glan Smith Co., Ltd.) Another type of anti-depressant that is administered by combining the compounds of the present invention is positive. Epinephrine 15 anti-depressant and a specific serotonin anti-depressant (a suitable example of NaSSA^NaSSA is mirtazepine. Suitable NRI for administration of a compound of the invention includes a third amine tricyclic compound and a second amine Tricyclic compounds. Suitable examples of third amine tricyclic compounds include: amitriptyline, clomipramine, doxepin, imipramine (reference to the United States) Patent 2,554,736, hereby incorporated by reference herein in its entirety herein in its entirety in its entirety in its entirety in its entirety in its entirety in its entirety in its entirety in its entirety in its entirety in its entirety in its entirety in its entirety in its entirety in its entirety in its entirety in Desipramine, maprotiline, notridine 33 200823187 (nortriptyline) and protriptyline, and pharmaceutically acceptable salts thereof. Another NRI is Reboxetine (Edronax); 2·[α·(2-ethoxy)phenoxy-5 benzyl]porphyrin, usually administered in racemic form; U.S. Patent No. 4,229,449, hereby incorporated by reference herein in entirety Suitable SSRIs for administration in combination with the compounds of the invention include: citalopram (1_[3-(dimethylamino)propyl]-(4-fluorophenyl)-1,3-di Rat-o--5-isobenzoquinone biting; see US Patent 10 4,136,193; Christensen et al, Eur. J. Pharmacol. 41: 153, 1977; Dufour et al, Int. Clin. Psychopharmacol. : 225, 1987; Timmerman et al., et al., 239, the entire contents of each of which is hereby incorporated by reference in its entirety; fluoxetine (N-methyl-3-(p-trifluoromethylphenoxy) 3-Phenylpropylamine, sold as the hydrochloride salt and as a 15 racemic mixture other than the two isoforms; for example, see U.S. Patent 4,314,081; Robertson et al., J. Med_Chem. 31:1412, 1988 , each of which is incorporated herein by reference); a combination of floxetine/ourapine; fluvoxamine (5-methoxy-1-[4_(trifluoromethyl)benzene) Pentyl ketone oxime _(2_aminoethyl) hydrazine; see U.S. Patent 4,085,225; Claassen et al, 20 Brit. J. Pharmacol. 60:505, 1977; De Wilde et al., Journal of Affective Disorder 4:249 , 1982 ; Benfield et al., Drugs 32: 313, 1986, the entire contents of each of which is hereby incorporated by reference in its entirety);;;;;;;;;;;;;;;;;;;;;; - methoxy)methyl]-4-(4-fluorophenyl)piperidine; see U.S. Patent No. 3,912,743; U.S. Patent No. 4,007,196; Lassen Eur. J. 34 200823187

Pharmacol. 47:351，1978 ; Hassan 等人，Brit. J. Clin. Pharmacol. 19:705，1985; Laursen4 人，Acta Psychiat. Scand. 71:249, 1985; Battegay等人，神經精神生物學 i3:3i，1985，各文件全文以引用方式併入此處）；塞查林(sertraiine)，（is_ 5順）·4·(3,4_二氯苯基）-1，2,3,4-四氫-：^-甲基-1-萘基胺鹽酸鹽；參考美國專利案4,536,518，全文以引用方式併入此處；伊西塔洛拉姆(escitalopram)(參考美國專利案re34,712); 及其藥學上可接受之鹽。組合本發明化合物投予之適當MAOI包括：伊索卡吉得 10 (lsocarboxazid)、芬尼曾（phenelzine)、塞拉吉林(selegiiine) 及川尼西普明（tranylcypromine)，及其藥學上可接受之鹽。與本發明化合物組合投予之適當可逆性MAOI包括：莫可洛邁德(moclobemide) (4-氣_N·[2-(4-咮啉基)-乙基]苄醯胺；參考美國專利案4,210,754，全文以引用方式併入此 15 處）、塞拉吉林及其藥學上可接受之鹽。供與本發明化合物組合投予之適當SNRI包括文拉法辛(venlafaxine)(參考美國專利案4,535，186，全文以引用方式併入此處；也參考美國專利案5,916,923、6,274，171、 6,403，120、6,419,958、6,444,708，各案全文以引用方式併 20入此處），及其藥學上可接受之鹽及類似物包括0-去甲基文拉法辛丁二酸鹽，米那西普藍(milnacipran) (N，N-二乙基-2-胺基甲基-1-苯基環丙烷羧醯胺；參考美國專利案 4,478,836 ; Moret等人，神經藥理學24:i21M9，1985，各文件全文以引用方式併入此處）；尼法左東(nefaz〇d〇ne)(得 35 200823187 自必治妥梅爾施貴寳公司（Bristol Myers Squibb)及瑞弟博士實驗室公司（〇1\1^(1(17 1^^111(：.));杜洛西汀(如1〇\6如6) 及其藥學上可接受之鹽。供與本發明化合物組合投予之適當CRF拮抗劑包括國 5 際專利說明書第 W0 94/13643、W0 94/13644、W0 94/13661、W0 94/13676及W0 94/13677號所述之該等化合物。供與本發明化合物組合投予之適當非典型抗鬱劑包括：布普柔皮昂（buproprion)(偉布春（Wellbutrin); 1〇 (.+-.)-1-(3-氯苯基)-2-[(l，l-二甲基乙基)胺基]-1-丙酮）、鋰、尼法左東、查左東(trazodone)及微洛沙曾（viloxazine)及其藥學上可接受之鹽。另一種適當非典型抗鬱劑為西布查明 (sibutramine) 〇供與本發明化合物組合投予之特定抗鬱劑包括但非限 15 於阿迪那左拉姆(adinazolam)、阿拉克雷特（alaproclate)、歐尼斯琵》容(&11^8卩丨1*〇116)阿米尼、;丁(amineptine)、阿米崔林、阿米崔林/可洛普西德（chlordiazepoxide)組合、阿莫沙平、阿普琵坦(aprepitant)、阿堤帕美左（atipamezole)、阿雜米塞林 (azamianserin)、巴吉那平（bazinaprine)、碧夫拉林 20 (befuraline)、比非美藍(bifemelane)、比諾達林(binodaline)、比普那莫(bipenamol)、布柔法明（brofaromine)、布普柔皮昂、卡柔沙中（caroxazone)、塞里克拉明（cericlamine)、西諾普拉明（cianopramine)、西莫沙同（cimoxatone)、西塔洛拉姆、克勒美柔（clemeprol)、克洛米拉明、克洛瓦沙明 36 200823187 (clovoxamine)、達治平尼（dazepinil)、迪諾(deanol)、德美西林(demexiptiline)、迪斯普拉明、〇-去甲基文拉法辛、迪賓治平（dibenzepin)、朵西平（dothiepin)、卓西朵帕（droxidopa、杜洛斯汀、伊雜松那（elzasonan)、伊那非辛（enefexine)、伊 5 塔琵容（eptapirone)、伊西塔洛藍姆、伊斯塔拉姆 (estazolam)、伊脫普麗東（etoperidone)、非莫西汀 (femoxetine)、芬嘉賓（fengabine)、非左拉明（fez〇iamine)、夫洛查森（fluotracen)、夫洛西汀、夫露瓦沙明 (fluvoxamine)、吉琵容(gepirone)、伊達左森(idazoxan)、伊 10 米普拉明、因達平(indalpine)、因德洛沙平(indeloxazine)、伊普林朵（iprindole)、伊索卡吉得、勒瓦普堤林 (levoprotiline)、里脫塞汀（litoxetine)、洛非普拉明 (lofepramine)、馬柔堤林、美迪發沙明（medifoxamine)、美塔普拉明（metapramine)、美查林朵（metralindole)、米安塞 15 林(mianserin)、米那西普藍、米那普林(minaprine)、米爾塔雜平(mirtazapine)、莫可洛邁德、曼堤麗林(montirelin)、尼布拉斯坦（nebracetam)、尼發喷（nefopam)、尼發左丁 (nefozodine)、尼米堤德（nemititide)、尼爾拉邁德 (nialamide)、諾米分辛（nomifensin)、正夫洛西塞汀 20 (norfluoxetine)、諾崔堤林、歐柔堤林(orotirelin)、歐沙夫洛曾（oxaflozane)、帕柔西汀、芬尼曾、皮那治喷(pinazepam)、皮爾林東(piflindone)、皮左堤林(pizotyline)、普柔崔堤林、麗伯西汀、麗坦塞林(ritanserin)、柔巴左坦(robalzotan)、柔麗普拉姆(rolipram)、塞拉吉林、塞克洛明（sercloremine)、 37 200823187 塞查林、塞堤堤林（setiptiline)、西布查明、蘇布堤明 (sulbutiamine)、蘇琵麗德（suipiride)、蘇尼琵容（sunepitron)、特尼洛沙冒（teniloxazine)、索查里農（thozalinone)、西莫里伯林（thymoliberin)、堤尼普汀（tianeptine)、堤夫卡賓 5 (tiflucarbine)、脫非那辛(t0fenacin)、脫夫索喷(t〇fisopam)、脫洛沙同（toloxatone)、脫莫塞丁 (tomoxetine)、川尼西普明、查左東、崔米普麗明（trimiprimine)、文拉法辛、微拉利得 (veralipride)、微拉左東(viiaz〇d〇ne)、微洛沙曾、微蔡林 (viqualine)、吉美利東(Zimelidine)及左美查平(z〇metrapine) 10及其藥學上可接受之鹽，及聖約翰草（St. John，s wort herb) 或穿孔角茴香（Hypencuin perforatum)或其萃取物。供與本發明化合物組合投予之適當抗焦慮劑類別包括 5-11丁1八激動劑或拮抗劑，特別為5_11丁以部分激動劑、神經激扇受體(NK)拮抗劑（例如沙麗杜坦（sare(jutant)及歐沙尼 15坦（osanetant))及促腎上腺皮質激素釋放因子（CRF)拮抗劑。可用於本發明之適當5-HTia受體激動劑或拮抗劑特別包括5-HT1A^體部分激動劑、布斯昆容(bUSpirone)、夫勒西諾山（flesinoxan)、吉琵容及伊沙琵容(ipsapirone)及其藥學上可接受之鹽。具有5-HT1A受體拮抗劑/部分激動劑活性之 20化合物之實例為平朵洛(Pindolol);新穎5HT1A激動劑微瑞雜 (vadza)、阿尼斯昆容、吉琵容、蘇尼昆容、MKC242、微拉左東、伊塔琵容及得自歐嘉農公司（〇rgan〇n)之 ORG12962 ;新穎5HU#抗劑諸如柔巴左坦；新穎5ht1b 激動劑諸如伊雜松那；新穎5HT2拮抗劑諸如ΥΜ-992(得自 38 200823187 山之内藥品公司（Yamanouchi Pharmaceuticals))及尼米德堤。根據本發明，本發明組合物可連同可用於治療憂鬱症或其它情緒障礙之一種或多種其它藥劑一起投藥。另外或 5此外，本發明組合物可與存在於哺乳動物體中治療任何其它症狀或醫療病情之一種或多種其它藥劑一起投藥，該藥劑係與哺乳動物之憂鬱症或情緒障礙相關或不相關。此等藥劑之實例例如包括抗血管生成劑、抗腫瘤劑、抗糖尿病劑、抗感染劑、疼痛緩解劑、抗精神病劑、胃腸道藥劑等 10或其組合。其它可用於本發明之實務之藥劑例如包括典型用於提升抗鬱劑功效之輔助治療。此等輔助治療劑例如包括情緒安定劑（例如鐘、微普柔伊克酸(valpr〇ic acid)、卡巴馬治平(carbamazepine)等）；平朵洛、興奮劑（例如美西芬尼德（methylphenidate)、右旋***（dextr〇amphetamine) 15等）；或甲狀腺素增強劑(例如I);抗精神病藥、抗焦慮劑(例如本并一叶坪類）及/或性功能障礙緩解劑（例如布斯昆容，也具有抗焦慮效果；多巴胺激性劑諸如阿曼塔丁 (amantadine)、普拉米索爾（pramipex〇ie)、布普皮昂 (bupropion)等）° 20 作為5-ΗΤ%調節劑，本發明化合物可用於治療多種病症。此等病症包括經前症候群(PMS)、經前煩躁症(PMDD)、行動障礙或運動障礙諸如巴金森氏症；慢性倦怠症候群、神經性厭食症、睡眠障礙(例如睡眠絕息）及緘默症。經前煩躁症或稱作為PMDD，是一種嚴重PMS形式。 39 200823187 類似PMS，PMDD典型係於月經來潮前一週開始，而於月經來潮後之數日消失。PMDD之特徵為每個月有嚴重的情緒起伏波動及生理症狀，干擾日常生活，特別係干擾女性與其家庭及友人間之關係。PMDD的症狀遠超過一般被視 5為可控制的或正常的經前症狀。 PMDD是多種症狀的組合，包括激動不安、憂營情緒、焦慮、睡眠障礙、難以集中注意力、憤怒爆發、***壓痛與漲痛。診斷的標準係強調憂鬱情緒、焦慮、情緒起伏或激動不安等症狀。受該病症影響之有規則月經期的美國婦 1〇女達20人中即有一人。根據另一個實施例，本發明提供一種治療PMDD相關聯之一種或多種症狀之方法。選擇性血清素再吸收抑制劑（SSRI)為目前治療PMDD 相關聯之症狀之較佳方法。根據另一態樣，本發明提供一種治療PMDD或PMDD相關聯之一種或多種症狀之方法，係 15經由投予式1化合物與SSRI之組合。於若干實施例中，SSRI 為夫洛西汀、文拉法辛、帕柔西汀、杜洛西汀、或塞查林。根據另一個實施例，本發明化合物可用於治療多種飲食障礙。於若干實施例中，飲食障礙為過食症、神經性貪食症或神經性厭食症。於若干實施例中，本發明化合物可 20用於治療胃腸病症，諸如胃腸蠕動或腸道推進功能異常。本發明化合物也可用來與體重減輕或體重控制結合（例如減少熱量或食物的攝取量及/或食欲的抑制）。此等方法特別可用於治療肥胖及隨後帶來的合併症包括糖尿病、第π型糖尿病、心血管病、高血壓、高血脂、中風、骨關節炎、睡 40 200823187 眠絕息、膽囊病、痛風、若干癌症、若干***症及早天。 5 10 15 於若干實施例中，本發明化合物係組合一種或多種抗肥胖劑投此等抗肥胖劑為技藝界所已知且包括阿朴脂蛋白B分泌/微粒體三酸甘油酿轉移蛋白質㈣Μ/·)抑制劑、^經基類固醇去氫梅㈣獅⑽抑制劑、ργγ3=及其類似物’ MCR_4激動劑、膽囊激扇A (CCK-A) 激動劑、單胺再吸收抑(諸如西布查明）、擬交感神經作用R3月上腺素激性受體激動劑、多巴胺激動劑(諸如布拉莫克利汀(bromocriptine))、黑素細胞刺激激素受體類似物、類***m受體拮抗劑(例如麗莫那班(rim〇nabant))、黑素濃縮激素拮抗劑、痩素_蛋白f)、瘦素類似物、瘦素叉體激動劑、甘丙胺素(galanin)拮抗劑、脂肪酶抑制劑（例如四氫抑脂素（tetrahydrolipstatin)，亦即歐麗史塔 (orlistat))、食欲抑制劑(諸如鈴蟾靡(b〇mbesin)激動劑）、神經胜廣Y受體拮抗劑、擬甲狀腺作用劑、去氫表睪固酮或其類似物、糖皮質激素受體激動劑或拮抗劑、食欲素(〇rexin) 受體拮抗劑、尿皮質素(urocortin)結合蛋白質抬抗劑、仿升糖素胜廇1受體激動劑、纖毛狀趨神經因子（諸如阿索金 (Axokine))、人刺鼠（agouti)相關蛋白質（AGRP)、葛麗林 20 (ghrelin)受體拮抗劑、組織胺3受體拮抗劑或反激動劑、及神經媒介素(neuromedin) U受體激動劑。於其它實施例中，本發明化合物係組合選自於歐麗史塔、西布查明、布拉莫克利汀、麻黃鹼、瘦素、麗莫那班、假麻黃鹼、PYY3.36或其類似物及2-酮基-N-(5-苯基吡啡基) 200823187 螺-[異苯并呋喃-1(3H)，4’-哌啶]-Γ-羧醯胺之抗肥胖劑組合投予。根據本發明之另一態樣，本發明化合物係與抗肥胖劑連同肥胖之典型治療例如運動及合理膳食組合投予。根據另一個實施例，本發明化合物係與一種或多種糖 5 尿病及相關病情之藥劑組合投予。於若干實施例中，本發明化合物係組合下列一種或多種藥劑投予，包括胰島素及胰島素類似物（例如李斯普羅胰島素（LysPro Insulin)); GLP-1 (7-37)(促胰島素激素)及GLP-1 (7-36)-NH2 ;石黃醯脲類及其類似物；克洛帕邁德(chlorpropamide)、吉利賓邁德 10 (glibenclamide)、脫布塔邁德（tolbutamide)、脫拉雜邁德 (tolazamide)、阿塞脫默德（acetohexamide)、吉利吉德 (Glypizide)、吉利美麗德（glimepiride)、瑞巴尼德 (repaglinide)、美吉利尼德（meglitinide)、雙脈類：美弗明 (metformin)、芬弗明（phenformin)、布弗明（buformin) ; “2-15 拮抗劑及咪唑啉類：咪唑麗左（midaglizole)、伊沙吉朵 (isaglidole)、狄 J而吉木（deriglidole)、伊達左山（idazoxan)伊柔山（efaroxan)、夫露帕山（fluparoxan);其它胰島素分泌類似物：林諾麗德（linogliride)、A-4166 ;吉利塔中 (glitazones):西格麗中（ciglitazone)、艾克脫斯(Actos)(^歐 20 吉麗中（Pioglitazone))、英利塔中（englitazone)、查吉麗塔中 (troglitazone)、達吉麗塔中（darglitazone)、阿文迪亞(Avandia) (BRL49653);脂肪酸氧化抑制劑：克洛莫塞(d〇m〇xir)、伊脫莫塞（etomoxir);葡萄糖苷酶抑制劑：阿卡伯斯 (acarbose) ' 米吉利脫(miglitol)、伊米吉利塔(emiglitate)、 42 200823187 瓦吉利伯斯（voglibose)、MDL-25,637、卡米吉伯斯 (camiglibose)、MDL-73,945 ; 13-激動劑：BRL 35135、BRL 37344、RO 16-8714、ICI D7114、CL 316,243 ;或磷酸二酯酶抑制劑：L-386,398。於其匕μ W例中’本發明化合物係組合一種或多種脂質下降劑投予：賓夫羅瑞斯(benfluorex):釩酸及釩錯合物 (例如那吉凡(Nagivan))及過氧釩錯合物；澱粉素拮抗劑；升糖素拮抗劑；糖新生抑制劑；生長抑制素類似物；抗脂肪分解劑：菸鹼酸、阿西琵莫斯(acipim〇x)、WAG 994、普 10 拉姆堤德(pramlintide)(西姆林(Symlin，，）、AC 2993、那特林德（nateghmde)、醛糖還原酶抑制劑（例如左巴瑞史塔 (zopolrestat))、肝醣磷酸化酶抑制劑、山梨糖醇去氫酶抑制劑、納-氯父換劑第一型(NNEq)抑制劑及/或膽固醇生物合 15 20 成抑制劑或膽固醇吸收抑·，特別糾觀心A還原酶抑制劑、或HMG-CoA合成晦抑亲j劑、或HMG_c〇A還原酶或合成酶基因表現抑制劑、CETp抑制劑、膽酸螯合劑、纖維 i^Cfibrate) . ACAT#flJ#J . . 化劑。於其它實_巾，本發明化合物雜合用來降低血水膽□醇/辰度之-種或多種天然化合物投予。此等天然化二物L稱為健康食品且例如包括大蒜萃取物、H。。灿植物萃取物及於鹼酸。於若干實_中，本發明化合物可用於哺乳動物誘 ^ I#持期望的膀胱控制。該方法特別可用於治療患有不穩定性膀胱或尿失禁或對其㈣之哺乳動物。本 43 200823187 發明方法包括預防、治療或抑制膀胱相關之尿路疾病及不穩定性膀胱，包括特發性不穩定性膀耽、尿床、夜尿、排工功月匕異$及尿失禁（例如包括應力型尿失禁、迫切型尿失不及/或此合型尿失禁）。也可藉投予本發明化合物治療或預 5防者為繼發於攝護腺肥大之不穩定性膀耽，作為於其它方面皆為健康者提升尿道張力減少非期望之漏尿之方法。舉例。之本發明方法可應用於緩和經常於產後第一年發生之漏尿。於其它實施例中，本發明可用於治療尿滯留或迫尿肌 10括約肌共濟失調。患有尿滞留之病人包括脊索損傷病人或有良性攝護腺肥大病人。根據本發明，本發明化合物也可用於促進於期望時暫時延遲排尿。根據本發明，此等化合物可用來於任何適用之丨月況下知疋膀脱。因此本發明化合物可用於允許接受者 15 控制排尿迫切性及頻次。於本發明之若干實施例中’本發明化合物投予有需要之哺乳動物來治療、預防、抑制及/或改善迫切型尿失禁（也稱作為不穩定性膀胱、神經性膀胱、排空功能異常、膀脱過激症、迫尿肌活性過高、迫尿肌過度反射或不受抑制的 20 膀胱）或混合型尿失禁。本發明用途包括但非限於其中排尿急迫係與攝護腺炎、攝護腺肥大、間質性膀胱炎、尿路感染或***炎所引發之膀胱活動性及膀胱不穩定性患者有關。本發明方法也可用於協助或矯正頻次-迫切症候群及懶惰性膀胱，也稱作為不頻繁排空症候群等疾病。 44 200823187 本=化合物也可用於治療、預防、抑制或限制由於投樂物所造錢料狀尿失禁、排料穩定、或排尿L刀轉藥物包_尿劑、血管增壓素拮抗劑、抗膽驗激性劑、鎮定劑或安眠劑、***品、α腎上腺素激性激動劑、α腎上腺素激性拮抗劑或舰道阻斷劑。 10 本發明化合物可用於需要緩解的病人包括成人及兒童，誘導或協助排尿膀胱的控制、或預防或治療此處所述之疾病。本發明化合物也可用於動物用藥用途，特別包括犬及貓之膀胱控制方法。若有所需，此處所述方法也可用於農場動物諸如羊群、牛群、豬群及馬群。根據本發明，本發明化合物可單獨用來調節膀胱活性’或另外’可組合（同時或循序）一種或多種其它可用於調郎膀胱活性之藥劑投予。另外或此外，本發明化合物可組合可用於治療或預防有需要膀胱活性調節個體所患有的一 15種或多種其它症狀、病症或疾病之一種或多種其它藥劑投〇其它可用於調節膀胱活性，特別係用於治療、預防、抑制及/或改善尿失禁之藥劑，例如包括狄斯莫普辛 (desmopressin)乙酸鹽（以DDAVP鼻喷霧劑及DDAVP疑劑得 20 自安萬特藥品公司（Aventis Pharmaceuticals))，以及狄斯莫普辛乙酸鹽鼻管（得自飛靈藥品公司（Ferring Pharmaceuticals))。其它產品例如包括托特柔定(tolterodine) 酒石酸鹽（以狄查姆(Detrltm)錠劑之名得自法瑪西亞普強公司（Pharmacia & Upjohn))、歐克斯布寧（oxybutinin)氯化物 45 200823187 (以狄查龐(Ditropan)錠劑及糖漿劑以及狄查龐XL延長釋放疑劑劑型得自阿爾雜藥品公司（ALZA Pharmaceuticals))、普柔龐塞林(Propanthaline)漠化物（以錠劑形式得自柔克山實驗室公司））、莨菪鹼及莨菪鹼硫酸鹽（分別以西斯脫帕茲 5 (Cystopaz)錠劑及西斯脫帕茲μ定時釋放膠囊劑得自波麗美弟卡藥品美國公司（PolyMedica Pharmaceuticals (U.S.A.) Inc·))、莨菪驗氫漠酸鹽、夫拉瓦沙(flavoxate)鹽酸鹽（以憂瑞帕斯(Urispas) 100毫克錠劑劑型得自阿爾雜藥品公司）、伊米普拉明（imipramine)鹽酸鹽（以1〇毫克、25毫克及50毫克 10 鍵劑劑型得自吉尼瓦藥品公司（Geneva Pharmaceuticals， Inc·))、苯基丙醇胺、米朵晶（midodrine)鹽酸鹽（以2.5毫克及 5毫克普羅曼亭（Proamatine)錠劑劑型得自席爾美國公司 (Shire US Inc.))、苯氧基苄胺鹽酸鹽（以狄賓茲林 (Dibenzyline)膠囊劑得自威爾史普靈藥品公司（WellSpring 15 Pharmaceuticals Corporation))、及普左辛（prazosin)鹽酸鹽 (以米你普瑞斯(Minipress)膠囊劑得自輝瑞公司）。各種藥品可以技藝界已知之藥學上有效量及用藥計畫取得，包括置師桌面手冊第55版2001年，醫藥經濟公司出版，紐澤西州蒙維爾07645-1742，所列舉之該等藥物，該文獻之相關部 20 分以引用方式併入此處。又有其它藥劑作用來調節膀胱活性，例如包括5HT2C 受體之其它調節劑。例如美國專利公告案第2004/0235856 號說明根據本發明可使用之多種5HT2C受體調節劑，該案全文以引用方式併入此處。額外5HT2C激動劑舉例說明於 46 200823187Pharmacol. 47: 351, 1978; Hassan et al, Brit. J. Clin. Pharmacol. 19: 705, 1985; Laursen 4, Acta Psychiat. Scand. 71: 249, 1985; Battegay et al., Neuropsychiatry i3: 3i, 1985, the full text of each document is incorporated herein by reference); sertrain, (is_ 5 cis)·4·(3,4_dichlorophenyl)-1,2,3,4- Tetrahydro-:^-methyl-1-naphthylamine hydrochloride; reference to U.S. Patent No. 4,536,518, hereby incorporated by reference herein in its entirety in the entire entire entire entire entire entire entire entire entire content And pharmaceutically acceptable salts thereof. Suitable MAOIs for administration of a compound of the invention include: lsocarboxazid, phenelzine, selegiiine, and tranylcypromine, and pharmaceutically acceptable salts thereof salt. Suitable reversible MAOI for administration in combination with a compound of the invention includes: moclobemide (4-gas_N.[2-(4-carbolinyl)-ethyl]benzylamine; reference to US patent Case 4,210,754, which is hereby incorporated by reference in its entirety herein in its entirety in its entirety in its entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire content Appropriate SNRI for administration in combination with a compound of the invention includes venlafaxine (cf. U.S. Patent No. 4,535,186, hereby incorporated by reference herein inco 120, 6, 419, 958, 6, 444, 708, the entire contents of each of which is hereby incorporated by reference in its entirety, and its pharmaceutically acceptable salts and analogs, including 0-desmethyl venlafaxine succinate, milacetem blue (milnacipran) (N,N-diethyl-2-aminomethyl-1-phenylcyclopropanecarboxamide; see U.S. Patent 4,478,836; Moret et al., Neuropharmacology 24: i21M9, 1985, each document The full text is incorporated herein by reference); Nefaz〇d〇ne (received 35 200823187 from Bristol Myers Squibb and Dr. Ruidi Laboratory (〇1) \1^(1(17 1^^111(:.)); duloxetine (eg 1〇\6 as 6) and pharmaceutically acceptable salts thereof. Suitable CRF for administration in combination with a compound of the invention The antagonists include those described in the National Patent Specification Nos. W0 94/13643, W0 94/13644, W0 94/13661, W0 94/13676, and W0 94/13677. Compounds Suitable atypical antidepressants for administration in combination with a compound of the invention include: buproprion (Wellbutrin; 1〇(.+-.)-1-(3-chloro) Phenyl)-2-[(l,l-dimethylethyl)amino]-1-propanone), lithium, nifazudung, trazodone and viloxazine A pharmaceutically acceptable salt. Another suitable atypical antidepressant is sibutramine, a specific antidepressant for administration in combination with a compound of the invention including, but not limited to, adinazolam (adinazolam) ), Alaproclate, Ounis 琵 (&11^8卩丨1*〇116) Amini, Ding (amineptine), Ami Cuilin, Ami Cuilin/Kolo Chlordiazepoxide combination, amoxapine, aprepitant, atipamezole, azamianserin, bazinaprine, Buffalo Forest 20 (befuraline), bifemelane, binodaline, bipenamol, bromaromine, buppe peon, carosa (carox Azone), cericlamine, cianopramine, cimoxatone, sitalam, clemrome, clomipramine, clova沙明36 200823187 (clovoxamine), dazepinil, deanol, demexiptiline, disspramin, 〇-desmethyl venlafaxine, dibenzepin , dothiepin, droxidopa, durostin, elzasonan, enefexine, eptapirone, ivaltolom, iss ESTazolam, etoperidone, femoxetine, fengabine, fez〇iamine, fluotracen, flo Westing, fluvoxamine, gepirone, idazoxan, 10m pramin, indalpine, indeloxazine, y Iprindole, Isokajid, levoprotiline, litoxetine , lofepramine, maretrine, medifoxamine, metapramine, metroindole, mianserin, Minasip blue, minaprine, mirtazapine, mokolomad, montirelin, nebracetam, nefopam , nefozodine, nemititide, nialamide, nomifensin, norfluoxetine, nordovician, ou Orotirelin, oxaflozane, paroxetine, fennelyl, pinazepam, piflindone, pizotyline, pulau Cui Dilin, Lie Bostin, Ritanserin, Robalzotan, Rolipram, Serra Jilin, Sercloremine, 37 200823187 Secha Forest, Setiptiline, West Bucharing, Sulbutiamine, Suipiride, Suni Sunepitron), teniloxazine, thozalinone, thymoliberin, tianeptine, tiflucarbine, fenfluramine T0fenacin), t〇fisopam, toloxatone, tomoxetine, chuanxi ximin, chazantong, trimiprimine, venlafaxine, Veralipride, viiaz〇d〇ne, micro-Lossian, viqualine, Zimelidine and z〇metrapine 10 and A pharmaceutically acceptable salt, and St. John, s wort herb or Hypencuin perforatum or an extract thereof. Suitable anti-anxiety agents for administration in combination with a compound of the invention include 5-11 butyl octagonal agonists or antagonists, particularly 5-11 conjugated to a partial agonist, a neurokinin receptor (NK) antagonist (eg, Sari Stan (jutant and osanetant) and corticotropin releasing factor (CRF) antagonists. Suitable 5-HTia receptor agonists or antagonists useful in the present invention include, inter alia, 5- HT1A body partial agonist, bUSpirone, flesinoxan, gibberium and ipsapirone and pharmaceutically acceptable salts thereof, having 5-HT1A receptor An example of a compound of the antagonist/partial agonist activity is Pindolol; a novel 5HT1A agonist, vadza, Anis Kunrong, Ji Rongrong, Suni Kunrong, MKC242, and micro-left East, Ita Rongrong and ORG12962 from Oujia Nong Company (〇rgan〇n); novel 5HU# anti-agents such as novobartan; novel 5ht1b agonists such as xoxazona; novel 5HT2 antagonists such as ΥΜ-992 ( From 38 200823187 Yamanouchi Pharmaceuticals and Nimid In accordance with the present invention, the compositions of the present invention may be administered in conjunction with one or more other agents useful in the treatment of depression or other mood disorders. Additionally or alternatively, the compositions of the present invention may be treated in the body of a mammal to treat any other The symptom or the medical condition is administered together with one or more other agents, which are related or not related to the depression or mood disorder of the mammal. Examples of such agents include, for example, an anti-angiogenic agent, an anti-tumor agent, an anti-diabetic agent, An anti-infective agent, a pain relieving agent, an antipsychotic agent, a gastrointestinal agent, etc. 10 or a combination thereof. Other agents useful in the practice of the invention include, for example, adjuvant therapies typically used to enhance the efficacy of anti-depressants. Including emotional stabilizers (such as clock, valpr〇ic acid, carbamazepine, etc.); Pindolo, stimulants (eg, methylphenidate, dextroamphetamine) (dextr〇amphetamine) 15;) or thyroxine enhancer (such as I); antipsychotics, anti-anxiety agents (such as this Yeping class) and / or sexual dysfunction mitigating agents (such as Busconundan, also have an anxiolytic effect; dopamine stimulants such as amantadine, pramipex〇ie, bup Bupropion, etc.) 20 As a 5-ΗΤ% modulator, the compounds of the invention are useful in the treatment of a variety of conditions, including premenstrual syndrome (PMS), premenstrual dysphoria (PMDD), mobility disorders or dyskinesias. Such as Parkinson's disease; chronic burnout syndrome, anorexia nervosa, sleep disorders (such as sleeplessness) and mutism. Premenstrual irritability or referred to as PMDD is a serious form of PMS. 39 200823187 Similar to PMS, PMDD typically begins one week before menstruation and disappears several days after menstruation. PMDD is characterized by severe emotional fluctuations and physical symptoms every month, which interfere with daily life, especially the relationship between women and their families and friends. The symptoms of PMDD far exceed the premenstrual symptoms that are generally considered to be controllable or normal. PMDD is a combination of symptoms, including agitation, anxiety, anxiety, sleep disorders, difficulty concentrating, anger outbursts, breast tenderness and pain. The criteria for diagnosis emphasize symptoms such as depression, anxiety, emotional ups and downs, and anxiety. One of the 20 women who have regular menstrual periods affected by the condition is one of 20 women. According to another embodiment, the invention provides a method of treating one or more symptoms associated with PMDD. Selective serotonin reuptake inhibitors (SSRIs) are currently the preferred method of treating the symptoms associated with PMDD. According to another aspect, the invention provides a method of treating one or more symptoms associated with PMDD or PMDD, by administering a combination of a compound of formula 1 and an SSRI. In several embodiments, the SSRI is flossoxine, venlafaxine, paroxetine, duloxetine, or cercharin. According to another embodiment, the compounds of the invention are useful in the treatment of a variety of eating disorders. In some embodiments, the eating disorder is overeating, bulimia, or anorexia nervosa. In several embodiments, the compounds of the invention may be used to treat gastrointestinal disorders, such as gastrointestinal motility or intestinal propulsion dysfunction. The compounds of the invention may also be used in conjunction with weight loss or weight management (e. g., reduced calorie or food intake and/or appetite suppression). These methods are particularly useful for the treatment of obesity and subsequent complications including diabetes, type π diabetes, cardiovascular disease, hypertension, hyperlipidemia, stroke, osteoarthritis, sleep 40 200823187 sleeplessness, gallbladder disease, gout , several cancers, several infertility and early days. 5 10 15 In several embodiments, the compounds of the invention are combined with one or more anti-obesity agents. Such anti-obesity agents are known to the art and include apolipoprotein B secretion/microsomal triglyceride-to-transfer protein (IV). /·) Inhibitors, steroid-based dehydrogenate (4) lion (10) inhibitors, ργγ3= and its analogues' MCR_4 agonists, gallbladder-induced fan A (CCK-A) agonists, monoamine reuptake (such as West Buchaming), sympathomimetic R3 adrenergic receptor agonist, dopamine agonist (such as bromocriptine), melanocyte stimulating hormone receptor analogue, cannabis m Body antagonists (eg rim〇nabant), melanin-concentrating hormone antagonists, alizarin-protein f), leptin analogues, leptin agonists, galanin antagonists , lipase inhibitors (such as tetrahydrolipstatin (orlistat), or appetite suppressants (such as 〇蟾靡 es 激动剂激动剂、、、、、、、、、、、、神经神经神经神经神经神经神经神经神经神经神经神经神经神经神经神经神经神经神经神经Antagonist, thyroid stimulating agent, dehydroepiantin or its analogue, sugar Corticosteroid receptor agonist or antagonist, orexin receptor antagonist, urocortin binding protein antagonist, mitosine 1 receptor agonist, ciliary neutrophil (such as Axokine), humanuti related protein (AGRP), ghrelin receptor antagonist, histamine 3 receptor antagonist or inverse agonist, and neuromedin (neuromedin) U receptor agonist. In other embodiments, the combination of compounds of the invention is selected from the group consisting of Olivia, Sibuchamin, Bramoclicin, Ephedrine, Leptin, Rimonabant, Pseudoephedrine, PYY3.36 Or an analog thereof and 2-keto-N-(5-phenylpyramyl) 200823187 spiro-[isobenzofuran-1 (3H), 4'-piperidine]-indole-carboxyguanamine anti-obesity The combination of agents is administered. According to another aspect of the invention, the compounds of the invention are administered in combination with an anti-obesity agent, along with a typical treatment for obesity, such as exercise and a reasonable diet. According to another embodiment, the compounds of the invention are administered in combination with one or more agents of the glucosuria and related conditions. In several embodiments, the compounds of the invention are administered in combination with one or more of the following agents, including insulin and insulin analogs (eg, LysPro Insulin); GLP-1 (7-37) (insulinotropic hormone) and GLP-1 (7-36)-NH2; sulphate and its analogues; chlorpropamide, glibenclamide, tolbutamide, delaide (tolazamide), acetohexamide, Glypizide, glimepiride, repaglinide, meglitinide, double veins: mephamine (metformin), phenformin, buformin; "2-15 antagonists and imidazolines: imidaglizole, isaglidole, di J and deriglidole ), idazoxan, efaroxan, fluparoxan; other insulin-sparing analogues: linogliride, A-4166; glitazones: sig Ciglitazone, Actos (^ Europe 20 Pioglitazone), englitazone, troglitazone, darglitazone, Avandia (BRL49653); fatty acid oxidation inhibitor: clomo Plug (d〇m〇xir), etomoxir; glucosidase inhibitor: acarbose 'miglitol, mimiglitate, 42 200823187 Vagely Voglibose, MDL-25,637, camiglibose, MDL-73, 945; 13-agonist: BRL 35135, BRL 37344, RO 16-8714, ICI D7114, CL 316, 243; or phosphodiesterase inhibition Agent: L-386, 398. In the case of 匕μ W, 'the compound of the invention is combined with one or more lipid-lowering agents: benfluex: vanadic acid and vanadium complex (such as Najifan ( Nagivan)) and peroxo-vanadium complex; amyloid antagonist; glycoside antagonist; sugar stimulating inhibitor; somatostatin analogue; anti-lipolytic agent: nicotinic acid, acitam x), WAG 994, Pu 10 pramlintide (Symlin,), AC 2993, Nat Nedghmde, aldose reductase inhibitor (eg zopolrestat), glycophosphorylase inhibitor, sorbitol dehydrogenase inhibitor, nano-gluco parental variant (NNEq) Inhibitors and/or Cholesterol Biosynthesis 15 20 Inhibitors or Cholesterol Absorption, Special Correction of Heart A Reductase Inhibitors, or HMG-CoA Synthetic Inhibitors, or HMG_c〇A Reductase or Synthetase gene expression inhibitor, CETp inhibitor, bile acid sequestrant, fiber i^Cfibrate). ACAT#flJ#J. In other embodiments, the compounds of the present invention are heterozygous for the administration of one or more natural compounds which reduce blood cholesterol/density. These naturalized substances L are referred to as healthy foods and include, for example, garlic extract, H. . Can plant extracts and alkali acids. In several embodiments, the compounds of the invention are useful in mammalian inducement of bladder control. This method is particularly useful for treating a mammal suffering from unstable bladder or urinary incontinence or for (4) it. Ben 43 200823187 The method of the invention comprises the prevention, treatment or inhibition of bladder-related urinary tract diseases and unstable bladder, including idiopathic unstable bladder, bedwetting, nocturia, labor failure, and urinary incontinence (eg Including stress-type urinary incontinence, urgent urinary incontinence and/or this type of urinary incontinence. It is also possible to treat or pre-treat the compound of the present invention as an unstable bladder secondary to the hypertrophy of the prostate, as a method for reducing urinary tract tension and reducing undesired leakage of urine in other aspects. For example. The method of the present invention can be applied to alleviate leakage of urine that often occurs in the first year after delivery. In other embodiments, the invention may be used to treat urinary retention or obsessive muscle 10 sphincter ataxia. Patients with urinary retention include patients with spinal cord injury or patients with benign prostatic hypertrophy. In accordance with the present invention, the compounds of the present invention are also useful for promoting temporary delay in urination when desired. In accordance with the present invention, such compounds can be used to detect convulsions in any suitable condition. Thus, the compounds of the invention can be used to allow the recipient 15 to control the urgency and frequency of urination. In several embodiments of the invention 'the compounds of the invention are administered to a mammal in need thereof for the treatment, prevention, inhibition and/or amelioration of urgent urinary incontinence (also referred to as unstable bladder, neurogenic bladder, abnormal emptying function) , bladder over-excitation, excessive urinary muscle activity, over-reflexive or unrestrained 20 bladder) or mixed urinary incontinence. Uses of the present invention include, but are not limited to, those in which urinary urgency is associated with bladder activity and bladder instability caused by mastitis, prostate hypertrophy, interstitial cystitis, urinary tract infection, or vaginitis. The method of the invention can also be used to assist or correct frequency-urgent syndromes and lazy inert bladders, also known as infrequent emptying syndromes. 44 200823187 This compound can also be used to treat, prevent, inhibit or limit the urinary incontinence, stable discharge, or urinary L-transfer drug packs due to the money produced by the music. 尿尿剂, angiotensin antagonist, anti-drug Biliary agonists, tranquilizers or hypnotics, narcotic drugs, alpha adrenergic agonists, alpha adrenergic antagonists or channel blockers. 10 The compounds of the invention are useful in patients in need of remission, including adults and children, in inducing or assisting in the control of urinary bladder, or in preventing or treating the diseases described herein. The compounds of the invention are also useful in animal applications, including, in particular, bladder control methods for dogs and cats. The methods described herein can also be used on farm animals such as flocks, herds, herds and horses, if desired. In accordance with the present invention, the compounds of the invention may be used alone to modulate bladder activity' or otherwise' may be combined (simultaneously or sequentially) with one or more other pharmaceutical agents useful for regulating bladder activity. Additionally or alternatively, the compounds of the invention may be used in combination with one or more other agents useful for the treatment or prevention of one or more other symptoms, disorders or diseases in a subject in need of modulation of bladder activity, and other agents useful for modulating bladder activity, Particularly for the treatment, prevention, inhibition and/or improvement of urinary incontinence, for example including desmopressin acetate (with DDAVP nasal spray and DDAVP suspect 20 from Aventis Pharmaceuticals ( Aventis Pharmaceuticals)), and Dessopsin Acetate Nasal Tube (available from Ferring Pharmaceuticals). Other products include, for example, tolterodine tartrate (from Pharmacia & Upjohn) and oxybutinin chloride in the name of Detrltm tablets. Compound 45 200823187 (Ditropan tablets and syrups and Dichapon XL extended release suspected dosage form from ALZA Pharmaceuticals), Propanthaline desertification Tablets are available from the Rick Hill Laboratory)), saponin and sulphate sulphate (Cystopaz tablets and Sistropaz μ time release capsules, respectively, from Bolimei Cardiac Pharmaceuticals (USA) Inc., Hydrochloroformate, Flavoxate Hydrochloride (Urispas 100 mg tablet) from Alza Pharmaceutical company), imipramine hydrochloride (available from Geneva Pharmaceuticals, Inc. in 1 mg, 25 mg, and 50 mg 10 bond formulations), phenylpropanol Amine, midodrine hydrochloride (According to 2.5 mg and 5 mg Proamatine tablet dosage form from Shire US Inc.), phenoxybenzylamine hydrochloride (derived from Dibenzyline capsules) WellSpring 15 Pharmaceuticals Corporation, and prazosin hydrochloride (available from Pfizer in the form of Minipress capsules). Various drugs can be obtained by pharmacy effective doses and medications known to the art world, including the 55th edition of the Desktop Handbook, 2001, published by the Pharmaceutical Economics Corporation, Monville, New Jersey 07645-1742, which lists the drugs. The relevant part of this document is hereby incorporated by reference. There are other agents that act to modulate bladder activity, such as other modulators including the 5HT2C receptor. A variety of 5HT2C receptor modulators that can be used in accordance with the present invention are described, for example, in U.S. Patent Publication No. 2004/0235856, which is incorporated herein in its entirety by reference. Additional 5HT2C agonists are exemplified in 46 200823187

Bishop 等人，Expert Opin· Ther· Patent 13:1691-1705, 2003，全文以引用方式併入此處。又有其它作用來調節膀胱活性之藥劑，例如包括一種或多種KCNQ鉀通道調節劑。於本發明之若干實施例中，本 5 發明化合物係連同一種或多種KCNQ 2/3或KCNQ3/5激動劑投予。此種KCNQ調節劑例如包括美國專利案第 5,384,330號所述化合物及美國專利案第5,565,483號所述化合物及美國專利公告案第2002/0183395號（現已放棄）所述化合物；及美國專利公告案第2004/0029949號，現在為美 10國專利案所述化合物。此等專利案及專利申請案併入此處以供參考。於本發明之若干實施例中，本發明化合物係與瑞堤嘉賓（retigabine)—起投予。於本發明之若干實施例中，本發明化合物係連同一種或多種作用為血管增壓素激動劑之化合物一起投予，包括 15但非限於美國專利案第6，194,407號(Failli等人）、美國專利案第6,090,803號(Failli等人）、美國專利案第6,〇96,736號 (Ogawa等人）、美國專利案第6,〇96,735號(〇§_等人)所述之化合物。通系根據本發明經常性期望投予一種或多種本發明化 20合物連同-種或多種α腎上腺素激性受體激動劑及/或一種或多種其它擬交感神經作用藥物。根據本發明，式!化合物可用於治療、預防或緩和對多種物貝中之壬者之依賴性、戒斷或其症狀，該等物質例如包括娱樂物質（例如酒精、終草[例如尼古丁])、藥理作用 47 200823187 劑（例如止痛劑[例如微可丁(vicodin)、樂塔伯（L〇rtab)、樂西特(L〇rcet)、波可西特(P⑽cet)、波可丹(p_dan)、堤洛克斯(Tylox)、經基可待因_、歐克斯騎(〇xyC〇ntin)、美沙東(methadone)、查馬朵（Tramad〇1)等]、安神劑興奮 5劑、或鎮定劑)及禁藥（例如***、海洛英、古柯鹼、快樂丸、 LSD、PCP、甲基***等。如此處使用「物質濫用」-詞可參考飽申病症之謗斷及統計手冊，第4版1994年（「DSM-IV」）所列舉之標準定義，該標準係由美國精神病學會命名與統計專案小組製備。物 10質濫用之特徵是一種適應不良之物質使用樣式，表現為重複使用物質引發重複出現顯著不良後果。如DSM-IV之引述，物質濫用為適應不良之物質濫用樣式，結果導致臨床上顯著之損害或窘迫，於12個月時間以内出現下列一種（或多種表徵）：（1)重複物質濫用結果導致無法滿足工作、上學 15或家庭之主要角色義務；（2)對肉體有害之情況下重複物質之使用；（3)重複物質相關之法律問題；以及(4)儘管由於物質的副作用所引起或加重而有持續性或復發性社交問題或人際問題仍然繼續使用該物質。此外DMS-IV要求物質濫用症狀不符合物質依賴性標準。 20 如此處使用「物質依賴性」一詞可參考精使病症之言兔斷及統計手冊，第4版1994年（「DSM_IV」）所列舉之標準定義，該標準係由美國精神病學會命名與統計專案小組製備。DSM-IV所陳述之物質依賴性標準是一種物質使用樣式，結果導致於同樣的十一個月時間以内之任何時間出現 48 200823187 臨床上顯著損害或窘迫，以選自於下列組群中之至少三項表現：（1)耐藥性，定義為(a)實質上需要增加物質劑量來達成期望的功效；或(b)持續使用等量物質功效實質上減低； (2)戒斷性，表現為(a)對特定物質之特徵性戒斷症候群；或 5 使用相同或類似相關物質來緩解或避免戒斷症狀；（3)物質經常使用更大量，或經歷一段長時間後意圖使用更大量；（4)持續期望減少或控制物質的使用但未能成功；（5)耗Bishop et al., Expert Opin, Ther. Patent 13: 1691-1705, 2003, which is incorporated herein in its entirety by reference. There are other agents which act to modulate bladder activity, for example, including one or more KCNQ potassium channel modulators. In several embodiments of the invention, the compounds of the invention are administered in combination with one or more KCNQ 2/3 or KCNQ3/5 agonists. Such KCNQ modulating agents include, for example, the compounds described in U.S. Patent No. 5,384,330, and the compounds described in U.S. Patent No. 5,565,483 and U.S. Patent Publication No. 2002/0183395 (now hereby assigned); No. 2004/0029949, which is now a compound described in the US 10 patents. These patents and patent applications are incorporated herein by reference. In several embodiments of the invention, the compounds of the invention are administered in conjunction with retiigaine. In several embodiments of the invention, the compounds of the invention are administered in conjunction with one or more compounds that function as an angiotensin agonist, including, but not limited to, U.S. Patent No. 6,194,407 (Failli et al.), Compounds described in U.S. Patent No. 6,090,803 (Failli et al.), U.S. Patent No. 6, pp. 96,736 (Ogawa et al.), U.S. Patent No. 6, 〇96,735 (〇§_ et al). It is often desirable in accordance with the present invention to administer one or more of the compounds of the invention together with one or more alpha adrenergic receptor agonists and/or one or more other sympathomimetic drugs. In accordance with the present invention, a compound of formula! can be used to treat, prevent, or alleviate dependence, withdrawal, or symptoms thereof in a variety of substances, including, for example, recreational substances (eg, alcohol, terminal grass [eg, nicotine]). Pharmacological action 47 200823187 Agents (eg analgesics [eg vidocin, L〇rtab, L〇rcet, Poxit (P)), bokdan (p_dan) ), Tylox, kekekeine _, xyxy ride (〇xyC〇ntin), meshadone (methadone), chamadu (Tramad〇1), etc. Or sedatives) and banned drugs (such as marijuana, heroin, ***e, happy pills, LSD, PCP, methamphetamine, etc. If used here, "substance abuse" - words can refer to the diagnosis and statistics of full-fledged diseases Manual, 4th edition of the standard definitions listed in 1994 ("DSM-IV"), which was prepared by the American Psychiatric Association's Nomenclature and Statistical Task Force. The substance abuse is characterized by a poorly adapted substance use pattern. Significant adverse consequences for repeated use of re-used substances, such as DSM-I According to V, substance abuse is a pattern of substance abuse that is maladaptive, resulting in clinically significant damage or distress. The following (or multiple characterizations) occur within 12 months: (1) Repeated substance abuse results in unsatisfactory work , school 15 or the main role of the family; (2) the use of repeated substances in the case of harmful to the flesh; (3) legal issues related to repeating substances; and (4) continued despite the cause or aggravation of the side effects of the substance Sexual or recurrent social or interpersonal problems continue to use the substance. In addition, DMS-IV requires that the substance abuse symptoms do not meet the substance dependence criteria. 20 If the term "substance dependence" is used here, refer to the words "sense dependence". And the statistical manual, 4th edition of the standard definitions listed in 1994 ("DSM_IV"), which was prepared by the American Psychiatric Association's Nomenclature and Statistical Task Force. The substance dependence standard stated by DSM-IV is a substance use pattern. The result is that at any time within the same eleven months, 48 200823187 clinically significant damage or paralysis Forced to be characterized by at least three of the following groups: (1) drug resistance, defined as (a) substantially increasing the dose of the substance to achieve the desired effect; or (b) continuing to use the same amount of substance Substantially reduced; (2) withdrawal, manifested as (a) characteristic withdrawal syndrome for a particular substance; or 5 using the same or similar substances to relieve or avoid withdrawal symptoms; (3) substances are often used more frequently Or, after a long period of time, intend to use a larger amount; (4) continue to expect to reduce or control the use of the substance but fail; (5) consumption

10 15 用大量時間來取得物質、使用物質或由其效應中回復；（6) 由於該物質的使用而放棄或減少重要的社交活動、職業活動或娛樂活動；以及(7)儘管瞭解由於該物質可能引發戈加重持績性或復發肉體或心理問題，儘管如此仍然持續^用該物質。物質依賴性可，有^雜難；存在有耐藥性或戒斷性證據，或不存在有心理依賴性，亦即不存在耐藥性或戒斷性證據。DSM-IV所列舉的條件中之四者包括減輕。此等減輕之麵包括由依賴性停止後所經歷之時間間隔’以及依賴性標準中所含括之症狀中之—者或多者^ 持續存在。 a於若干情況下’本發明化合物可用於治療_(例如酒精/凰用、成瘾及/或依賴性包括戒酒的治療、渴癌的減少以 2〇及預防飲酒的故態復萌）及/或於草细（例如終癌、戒终及/ 或依賴性包括對渴瘾減少的治療以及抽煙故態復伙、。 J頂於根據本發明評估物質的濫用中，例如可參考國家ρ 物使用與健康調查研究(NSDUH)，取得有關九種不同類^ 49 200823187 禁藥使用的資訊：***、古村驗、海洛英、逑幻藥b 劑，以及處方型止痛劑、安神劑、興奮劑及鎮定劑之= 療使用。於此等類別中，黑虛(hashish)含括有***而快I (crack)屬於计驗之-種形式。數㈣物被 5類別，包括LSD、PCP、琵亞特（peyote)、美斯卡林 (mescaline)、簟菇類及「快樂丸」（MDMA)。吸入劑包括多種物貝诸如亞石肖酸物質、清潔液、汽油、漆料及膠料四類處方型藥物（止痛劑、安神劑、興奮劑及鎮定劑）涵蓋多種可透過處方取得的藥物，偶而非法可於「衔頭上購得。甲 10基***屬於一類型興奮劑。要求被詢問者報告非對其處方藥物的使用，或經驗嘗試藥物的使用或藥物所造成的感覺。成藥以及處方藥的合法使用不包括在内。NSDUH報告將四者處方型藥物歸類成為一類「任何精神治療藥」。 NSDUH係透過問卷將酗酒問題歸類為含酒精飲料之 15使用頻次，諸如啤酒、葡萄酒、威士忌、白蘭地及混合飲品。有關涵蓋之飲料類別之綜合表單係於問卷之前給予被詢問者。「飲用」被定義為一罐啤酒或一瓶啤酒、一杯葡萄酒或一杯葡萄酒冷酒器、一小杯烈酒或混合有烈酒的混合型飲品。當被詢問者只有從一次飲用中吸取一小口或兩小 20 口時不被視為飲用。由此報告，對男性及女性以及對全部年齡分成三個層次報告酒精使用普及性之估值如下：目前使用一過去30日内至少飲用一次（包括狂熱使用及重度使用）狂熱使用一過去30日内於同一個場合飲用五杯或以上 50 200823187 至少一次（包括重度使用）。重度使用一過去30日内至少有5個不同日於同一個場合飲用五杯或以上。 NSDUH也歸類菸草製品的使用，包括香菸、咀嚼菸 5 草、鼻菸、雪茄、及管於。供分析目的，咀嚼菸草與鼻於之資料組合稱為「無煙菸草」。香菸的使用被定義為抽煙「一根香菸的一部分或全部」。NSDUH也包括判定目前抽煙者之尼古丁依賴性問卷。尼古丁依賴性係基於得自尼古丁依賴性症候群尺規（NDSS)或尼古丁依賴性費傑史壯 10 (Fagerstrom)試驗(FTND)之標準。於其它實施例中，本發明化合物可用於治療藥物成癮之戒斷，包括對尼古丁、酒精以及其它濫用物質成瘾的戒斷。由於停止使用任一種形式的菸草結果常出現尼古丁戒斷症候群，該等菸草形式包括但非限於抽香菸、雪茄或管 15菸，或口服或經鼻内攝取菸草或咀嚼菸草。此等經口或鼻内之菸草包括但非限於鼻菸及咀嚼菸草。停止尼古丁的使用或減少尼古丁的用量經常於24小時之内出現有症狀，症狀包括煩躁、情緒憂鬱·’頭昏眼花；失眠；激動、挫折感或憤怒；焦慮；神經性震顫、難以集中注意力；不安；心 2〇搏率減低；胃口增加或體重增加；以及對菸草或尼古丁的渴癌。此種症狀經常造成社交、職業或其它重要功能領域的臨床上顯著窘迫或危害。中斷或減少類牙鳥片劑的投予，典型係自我投予，透過注射或口服、透過抽煙或鼻内攝取而自我投予，經常導致 51 200823187 出現特徵性類鴉片劑戒斷現象。此等戒斷現象可藉於類鴉片劑使用後投予類鴉片劑拮抗劑諸如拿洛松(naloxone)或拿崔松(naltrexone)來誘發。類鴉片劑戒斷特徵為通常與類鴉片劑激動劑功效相反的症狀。戒斷症狀包括焦慮；不安； 5肌肉痛，經常背痛及腿痛；對類鴉片劑渴瘾；激動且對疼痛敏感度增高；情緒煩躁；噁心或嘔吐；流淚；鼻溢；乳頭膨脹；毛髮豎立、盜汗、腹瀉、打呵欠；發燒及失眠。當對短效作用之類鳩片劑諸如海洛英產生依賴性時，戒斷症狀常係在最末劑之後的6-24小時内出現；而使用長效作 10用之類鴉片劑諸如美沙東(methadone)，戒斷症狀經常需要 2-4日才出現。此等症狀經常造成社交、職業或其它重要功能領域的臨床上顯著窘迫或危害。本發明最佳係用來減輕類鳩片劑戒斷症狀，並非由於一般醫療也非因其它醫療病症時，由於類鴉片劑戒斷所導致的一種或多種症狀。 15 停止或減少乙醇（含乙醇飲料）的使用導致乙醇戒斷現象的發作。乙醇戒斷現象的特徵為於乙醇停止使用或減少使用後之4小時至12小時以内當血中乙醇濃度急劇下降時開始出現症狀。乙醇戒斷症狀包括對乙醇的渴瘾；自主神經系統過度活躍(例如盜汗或心搏率超過100);手顫抖；失 2〇目民；噁心；嘔吐；暫時性視覺、觸覺、或聽覺、幻覺或錯覺；心理運動激動；焦慮；及大發作。此等症狀經常造成社交、職業或其它重要功能領域的臨床上顯著窘迫或雇害。本發明最佳係用來減輕類鴉片劑戒斷症狀，並非由於一般醫療也非因其它醫療病症時，由於類鴉片劑戒斷所導 52 200823187 致的一種或多種症狀。根據另一個實施例，本發明化合物係組合一種或多種物質濫用治療劑一起投予。於若干實施例中，本發明化合物係組合一種或多種於草濫用治療劑一起投予。此等藥劑 5包括尼古丁受體部分激動劑布普皮昂鹽酸鹽（吉邦(zyban)) 及尼古丁替代治療。根據又另一個實施例，本發明化合物係組合一種或多種其它酗酒治療劑一起投予，諸如類鴉片劑拮抗劑（例如拿崔松、（瑞微亞(ReVia))、拿美芬(nalmefene)、狄蘇菲拉姆 10 (disulfiram)(安塔布斯（Antabuse))及阿坎普謝特 (acamprosate)(坎伯（Campra…。於若干實施例中，化合物係組合一種或多種酒精戒斷症狀減少劑一起投予，該等藥劑諸如苯并二吖呼類、万阻斷劑、可尼丁、卡巴治平、普瑞嘉巴林(pregaba㈣及嘉巴 15潘、/T(gabapentln)(紐容汀(Neurontin))。於本發明之其它實施例中，利用本發明化合物之治療係與教育計畫及/或行為修飾計畫同時、結合、及/或隨後投？來促進可持續戒掉物質依賴或物質濫用。本發明方法特別可用於治療於復健計畫或其它治療記畫中常觀察到之戒斷症狀。因此治療計畫 20的焦點集中在教育目的及行為修飾目的更為有效，可進一步減少未能完成戒斷計畫的發生。於若干實施例中，本發明化合物可用於治療一種或多種智能缺陷障礙，包含投予本發明化合物。於其它實施例中，此等智能缺陷障礙包括癡呆，諸如老年癌呆、血管性 53 200823187 痴呆、輕度認知雙損、老化相關聯之認知下降及輕度神經認知障礙；阿兹海默氏病及記憶力缺陷、包括於兒童及成人之注意力缺陷障礙(ADD，也稱作為注意力缺陷過動症或 ADHD)。於若干實施例巾，本發日月提供—種於小兒病人治 5 10 15 20 療ADD及/或ADHD之方法，包含對該病人投予式1化合物或其藥學組成物。立於其匕實靶例中，本發明提供一種治療一種或多種認决障礙之方法。根據另_個態樣，認知障礙為學習障礙。此種子P!礙為技藝界所已知，且包括緘默症、閱讀困難、亞、斤伯;^症候群’亞斯伯格症候群是—賴似緘默症的神經生物病症’係以社交技巧及溝通技巧有嚴重缺陷為特徵；特殊學習隍磁，s ^ μ 、礙疋一種涉及對於瞭解或使用語言或書寫的=子等基本。理處理程序中之—種或多種障礙，特殊早礙^現為聽、說、讀、S、思考、拼字或做數學 /的肖b力不佳，書寫困難，難以在一個經過界定的空子母或f寫之病症；計算困難，進行算數以及瞭問^上有問題之病症；運用障礙，身體運動系統的擾於給定情況下做出經過控制的或協調的肉體反的能i力；；J目^ ^ 兔缺卩曰，難以由視覺接收到及/或處理汛，但視力並益鬥e產· 接收到進、問^，以及聽覺缺陷，難以透過聽覺器官於:確資訊，但聽力上並無問題。動障’本㈣提供—種治療―種或多種衝制障礙之方、、、、礙）、破壞性行為障礙、或衝動控法。於若干實施例中，本發明提供一種治療妥 54 200823187 瑞氏症候群(ts)之方法，妥瑞氏症候群是一種遺傳的神經病症，以重複且不自主的身體移動（抽動）及/或無法控制的發出語音為特徵。根據另一個態樣，本發明提供一種治療一種或多種行 5為成瘾及成瘾病症之方法。行為成瘾及成瘾病症係來自於某些活動期間腦部釋放化學品（例如血清素、腎上腺素 (adrenaline)、腎上腺素(epinephrine)等）造成人類感覺的中毒所引起的病症。此等病症為技藝界已知，包括賭博、性成瘾、飲食障礙、花錢障礙、盛怒/憤怒、工作狂、運動成 10 癮、冒險成瘾以及完美主義者（只舉出少數實例）。於若干貫施例中’本發明化合物係組合一種或多種認知改善劑投予。此等認知改善劑為技藝界所已知且包括多尼普吉（donepezil)鹽酸鹽（愛憶欣(Aircept))及其它乙醯膽鹼酯酶抑制劑；葛蘭他命(galantainine)、神經保護劑（例如美 15曼汀(memantine)) ; ADD/ADHD藥劑(例如美西芬尼德）（利他林（Ritalin))、阿托莫西、;丁（at〇m〇xetine)(史查特拉 (Strattera))、美西芬尼德，持續釋放之美西芬尼德、康塞塔 (Concerta))及***/右旋***(阿德拉(AdderaU)。根據另一個態樣，本發明提供一種治療性功能異常之 20方法，包含投予本發明化合物。於若干實施例中，性功能異常係由於憂鬱症所引起。於其它實施例中，性功能異常係由於藉投予血清素再吸收抑制劑來治療病症所引起。本發明化合物可用於男性及女性治療性功能異常。此等病症包括男性***功能異常(MED)及女性性功能異常(FSD)，例 55 200823187 如女性性喚醒障礙(FSAD)。異常===中’本發明提供治療-種或多種性功能 , 沩;正之方法，包括HSDD，以性幻想及對性活於性^望缺卩㈢或不存在有欲望為特徵；FSAD，持續性或復 :座-法達核_至性活動完成、對性織的潤滑_膨服 ^應不足為特徵；咖於正常之性興奮期之後持續性或復 ▲〈遲潮或不存在有性高潮為特徵；性行為疼痛症古—丨又困難及***痙攣；及Z4Hsdd，女性極少有或無 10 亍為奴！，女性不存在有或極少有性行為念頭或性幻想為特徵。根據另一個實施例，本發明化合物係組合一種或多種男f生性功能障礙(例如男性***功能異常）治療劑投予。此等蕖刈為技藝界所已知且包括多巴胺激性劑（例如D2、D3或〇4激動劑及阿朴嗎啡）；Νργ(神經胜廇γ)(較佳為Νργ_ 1及 15 /*ΝΤΥ"5抑制劑）；黑皮質素受體激動劑或調節劑或黑皮質10 15 spends a great deal of time acquiring material, using substances or recovering from its effects; (6) giving up or reducing important social activities, professional activities or recreational activities due to the use of the substance; and (7) despite understanding of the substance It may trigger aggravation of the performance or recurrence of physical or psychological problems, although the substance continues to be used. Material dependence may be difficult; there is evidence of drug resistance or withdrawal, or there is no psychological dependence, that is, there is no evidence of drug resistance or withdrawal. Four of the conditions listed in DSM-IV include lightening. These mitigations include the time interval experienced by the cessation of dependence and the persistence of the symptoms included in the dependency criteria. a in some cases 'the compounds of the invention may be used for treatment _ (eg alcohol / phoenix, addiction and / or dependence including treatment of alcohol withdrawal, reduction of thirst cancer by 2 〇 and prevention of drinking relapse) and / or Grass fineness (eg, terminal cancer, cessation, and/or dependence include treatment for reduced thirst addiction and smoking refusal, J. in the assessment of substance abuse according to the present invention, for example, reference to national ρ use and health survey Study (NSDUH), obtained information on nine different categories of use: marijuana, ancient village test, heroin, scorpion medicinal b, and prescription analgesics, tranquilizers, stimulants and tranquilizers = therapy use. In these categories, hashish includes marijuana and I (crack) belongs to the test-type. The number (four) is classified into 5 categories, including LSD, PCP, and peyote. ), mescaline (mescaline), oyster mushrooms and "happy pills" (MDMA). Inhalants include a variety of prescription drugs such as yttrium acid, cleaning liquid, gasoline, paint and rubber ( Analgesics, tranquilizers, stimulants and tranquilizers) A variety of drugs that can be obtained through prescriptions can sometimes be purchased illegally. A 10 GMT is a type of stimulant. The respondent is required to report the use of the drug or the experience of the drug or the drug. The resulting sensation. The legal use of finished medicines and prescription drugs is not included. The NSDUH report classifies the four prescription drugs into one type of “any psychotherapeutic drug.” NSDUH uses the questionnaire to classify alcohol abuse as an alcoholic beverage. Frequencies such as beer, wine, whiskey, brandy and mixed drinks. The comprehensive form of the covered beverage category is given to the respondent before the questionnaire. “Drinking” is defined as a can of beer or a bottle of beer, a glass of wine or a glass of wine. A wine cooler, a small glass of spirits or a mixed drink with a strong spirit. When the respondent only takes a small mouth or two small 20 mouths from a single drink, it is not considered to be consumed. This report is for men and women. And the valuation of the popularity of alcohol use for all ages divided into three levels is as follows: Drink at least once in 30 days (including avid use and heavy use) Fanatic use of five cups or more on the same occasion in the past 30 days. 200823187 At least once (including heavy use). Heavy use at least 5 different in the past 30 days Drink five cups or more on the same occasion. NSDUH also categorizes the use of tobacco products, including cigarettes, chewing tobacco, grass, snuff, cigars, and tubes. For analysis purposes, the combination of chewing tobacco and nose is called "Smokeless tobacco." The use of cigarettes is defined as smoking "a part or all of a cigarette." NSDUH also includes a nicotine-dependent questionnaire that determines current smokers. Nicotine dependence is based on the rule from the nicotine-dependent syndrome (NDSS) Or the nicotine-dependent Fagerstrom test (FTND) standard. In other embodiments, the compounds of the invention are useful in the treatment of withdrawal from drug addiction, including withdrawal from nicotine, alcohol, and other substance abuse. Nicotine withdrawal syndrome often occurs as a result of cessation of use of any form of tobacco, including but not limited to smoking cigarettes, cigars or tube 15 cigarettes, or oral or intranasal ingestion of tobacco or chewing tobacco. Such oral or intranasal tobacco includes, but is not limited to, snuff and chewing tobacco. Stopping the use of nicotine or reducing the amount of nicotine often occurs within 24 hours. Symptoms include irritability, mood depression, 'dizziness; insomnia; agitation, frustration or anger; anxiety; neurological tremor, difficulty concentrating ; restless; heart 2 stroke rate decreased; increased appetite or weight gain; and thirst for tobacco or nicotine. Such symptoms often cause clinically significant distress or harm in social, occupational, or other important functional areas. Interruption or reduction of the administration of a dental bird tablet, typically self-administered, self-administered by injection or oral administration, by smoking or intranasal ingestion, often leads to the appearance of characteristic opioid withdrawals in May 2008. Such withdrawal can be induced by the administration of an opioid antagonist such as naloxone or naltrexone after the use of the crow tablet. Opioid withdrawal characteristics are symptoms that are generally contrary to the efficacy of opioid agonists. Abstinence symptoms include anxiety; restlessness; 5 muscle pain, frequent back pain and leg pain; thirst for opioids; increased sensitivity to pain; emotional irritability; nausea or vomiting; tearing; nasal overflow; nipple swelling; Erect, night sweats, diarrhea, yawning; fever and insomnia. When it is dependent on a short-acting such as sputum tablets such as heroin, withdrawal symptoms often occur within 6-24 hours after the last dose; while long-acting opiates such as 10 are used. East (methadone), withdrawal symptoms often take 2-4 days to appear. These symptoms often cause clinically significant distress or harm in social, professional, or other important functional areas. The present invention is preferably used to alleviate the symptoms of withdrawal of the plaque tablet, not because of general medical care or other medical conditions, due to one or more symptoms caused by opioid withdrawal. 15 Stopping or reducing the use of ethanol (alcoholic beverages) leads to the onset of ethanol withdrawal. Ethanol withdrawal is characterized by the onset of symptoms when ethanol is discontinued or reduced within 4 hours to 12 hours after use when the concentration of ethanol in the blood drops sharply. Ethanol withdrawal symptoms include alcohol addiction; autonomic nervous system hyperactivity (such as night sweats or heart rate over 100); hand shaking; loss of 2 eyes; nausea; vomiting; temporary vision, touch, or hearing, hallucinations Or illusion; psychological exercise; anxiety; and major seizures. These symptoms often cause clinically significant distress or employment in social, professional, or other important functional areas. The present invention is preferably used to alleviate the symptoms of opioid withdrawal, not because of general medical care or other medical conditions, due to one or more symptoms caused by opioid withdrawals. According to another embodiment, the compounds of the invention are administered in combination with one or more substance abuse therapeutic agents. In several embodiments, the compounds of the invention are administered in combination with one or more of the herbicide abuse therapeutic agents. These agents 5 include the nicotine receptor partial agonist, buppeine hydrochloride (zyban) and nicotine replacement therapy. According to yet another embodiment, the compounds of the invention are administered in combination with one or more other alcoholic therapeutic agents, such as opioid antagonists (e.g., Naxisui, ReVia, nalmefene). , Disulfiram (Antabuse) and Acamprosate (Campra.... In several embodiments, the compound is combined with one or more alcohol withdrawals. Symptom reducers are administered together, such as benzodiazepines, 10,000 blockers, cotinine, carbazine, pregabalin (pregaba), and gamma 15 pan, /T (gabapentln) In other embodiments of the invention, a therapeutic system utilizing a compound of the invention is simultaneously, combined, and/or subsequently administered with an educational program and/or behavioral modification program to promote sustainable cessation of the substance. Dependence or substance abuse. The method of the invention is particularly useful for treating withdrawal symptoms that are often observed in rehabilitation planning or other treatment recordings. Therefore, the focus of treatment plan 20 is more effective in educational purposes and behavioral modification purposes. Further reduction The occurrence of the withdrawal program can be accomplished. In several embodiments, the compounds of the invention can be used to treat one or more intelligent defect disorders, including administration of a compound of the invention. In other embodiments, such mental deficit disorders include dementia, such as Aged cancer, vascular 53 200823187 Dementia, mild cognitive impairment, cognitive decline associated with aging and mild neurocognitive impairment; Alzheimer's disease and memory impairment, including attention deficit disorder in children and adults ( ADD, also known as attention deficit hyperactivity disorder or ADHD. In several embodiments, the method provides for the treatment of ADD and/or ADHD in pediatric patients, including the method of ADD and/or ADHD. The compound of formula 1 or a pharmaceutical composition thereof. The present invention provides a method of treating one or more recognized disorders in its sputum target. According to another aspect, the cognitive disorder is a learning disorder. Obstacles are known to the art world, and include mutism, dyslexia, ya, jinbo; ^ syndrome group - Asperger syndrome is a neurobiological disorder that depends on mutism Skills and communication skills are characterized by serious defects; special learning 隍 magnetism, s ^ μ, 疋疋疋对于对于对于了解了解了解了解了解了解了解了解了解了解了解了解了解了解了解了解了解了解了解了解了解了解了解了解了解了解了解了解了解了解了解了解了解了解^It is difficult to write, speak, read, S, think, spell, or do mathematics. It is difficult to write, difficult to write in a defined empty child or f; calculation difficulties, arithmetic and Asking about the problematic condition; using the obstacle, the body movement system disturbs the ability to make a controlled or coordinated physical reflex in a given situation;; J eyes ^ ^ Rabbit lacks, difficult to receive by vision To and/or deal with sputum, but vision and benefit e-production · receiving incoming, asking ^, and hearing defects, difficult to pass through the auditory organs: accurate information, but there is no problem with hearing. The cataracts (4) provide a treatment, a type or a variety of mitigation obstacles, obstacles, impulsive behavior disorders, or impulse control. In several embodiments, the present invention provides a method of treating R. 54 200823187 Wright's syndrome (ts), a genetic neurological disorder with repeated and involuntary body movements (twitching) and/or uncontrollable The voice is characterized. According to another aspect, the invention provides a method of treating one or more of the lines 5 as an addictive and addictive condition. Behavioral addiction and addiction disorders arise from conditions caused by brain release chemicals (such as serotonin, adrenaline, epinephrine, etc.) that cause human sensation during certain activities. These conditions are known to the art world, including gambling, sexual addiction, eating disorders, spending disorders, anger/anger, workaholics, sports addiction, adventurous addiction, and perfectionists (only a few examples). In a number of embodiments, the compounds of the invention are administered in combination with one or more known enhancers. Such cognitive improvers are known to the artisan and include donepezil hydrochloride (Aircept) and other acetylcholinesterase inhibitors; galantainine, Neuroprotective agents (eg, Memantine); ADD/ADHD agents (eg, mexifenide) (Ritalin), Atomox, Ding (at〇m〇xetine) Strattera, Mesin Fenniide, Sustained release of Westphine, Concerta, and amphetamine/dextroamphetamine (AdderaU). According to another aspect, Ben The invention provides a method for treating aberrant dysfunction comprising administering a compound of the invention. In several embodiments, sexual dysfunction is caused by depression. In other embodiments, sexual dysfunction is due to administration of serotonin. Resorption inhibitors are used to treat conditions. The compounds of the invention are useful for the treatment of sexual dysfunction in men and women, including male erectile dysfunction (MED) and female sexual dysfunction (FSD), case 55 200823187 such as female sexual arousal Obstacle (FSAD). Abnormal ===中' The present invention provides a therapeutic-type or multiple sexual functions, 沩; positive methods, including HSDD, characterized by sexual fantasies and sexually active sexual deficiencies (3) or absence of desire; FSAD, persistence or complex: Fada nuclear _ to the completion of sexual activity, lubrication of sexual weaving _ swelling ^ should be insufficient; after the normal sexual excitement period, persistent or complex ▲ <late tide or no presence of sexual orgasm; sexual behavior pain Syndrome - sputum and difficulty and vaginal fistula; and Z4Hsdd, women with little or no 10 亍 slaves!, women do not have or rarely have sexual behavior or sexual fantasies. According to another embodiment, the compounds of the invention are combined One or more therapeutic agents for male sexual dysfunction (eg, male erectile dysfunction). These are known to the art and include dopamine agonists (eg, D2, D3 or 〇4 agonists and apomorphine). ); Νργ (nerve victory 廇 γ) (preferably Νργ_ 1 and 15 /*ΝΤΥ"5 inhibitors); melanocortin receptor agonist or modulator or black cortex

素促進劑；ΝΕΡ抑制劑；PDE抑制劑（較佳為CGMP PDE-5 抑制劑），鈴蟾素受體拮抗劑或調節劑，及可溶性分泌胜扇内切酶抑制劑（SEPi)。於若干實施例中，本發明化合物係組合一種或多種男性性功能異常治療劑諸如阿普史塔狄 20 (alpr〇stadil)或西登那非（sildenafil)投予。根據又另一個實施例，本發明化合物係組合一種或多種女性性功能異常治療劑投予。此等藥劑為技藝界所已知且包括***受體調節劑（例如***激動劑及/或*** 拮抗劑）；睪固酮補充劑、睪固酮(托史查爾（Tostrelle》、二 56 200823187 氫睪固酮、去氫表睪固酮(DHEA)、睪固酮植體；例如去氫雄烯二酮、***、***、美卓孕酮 (medroxyprogesterone)、美卓孕酮乙酸鹽（MPA)、雖激素與甲基睪固酮激素補充治療劑之組合；普馬林(Premarin)、塞 5 尼史汀（Cenestin)、歐斯查明拿（Oestrofeminal)、伊昆 (Equin)、伊斯查斯(Estrace)、伊斯查芬(Estrofem)、伊勒史特（Elleste)梭羅（Solo)、伊史村（Estring);伊史查登 (Eastraderm)TTS、伊史查登基體、德美史崔（Dermestril)、普瑞非斯（Premphase)、普瑞普羅（Preempro)、普瑞帕克 10 (Prempak)、普瑞米克(Premique)、伊史查特(Estratest)、伊史查特HS、堤伯隆(Tibolone)、多巴胺激性劑；例如阿朴嗎啡或選擇性D2、D3或D2/D3激動劑諸如普拉米索 (pramipexole)及柔琵瑞諾(ropirinol)、NPY(神經胜廇γ)抑制劑；例如NYP(神經胜廟Y)抑制劑諸如NPY1或NPY5抑制 15劑，較佳為NPY1抑制劑、黑皮質素受體調節劑或黑皮質素促進劑；例如美拉諾坦（melanotan) II、PT-14、PT-141、 NEP(中性胜廍内切酶)抑制劑；PDE(磷酸二酯酶)抑制劑；例如西登那非及/或鈴蟾素受體調節劑。根據本發明，本發明化合物可用於治療哺乳動物諸如 20人類之多種不同類型之疼痛中之任一者。例如，本發明化合物可用於治療急性疼痛（時間短）或慢性疼痛（常規重複發作疼痛或持續性疼痛），包括為中樞或周邊之疼痛。根據本發明方法可治療之急性疼痛或慢性疼痛之實例包括發炎痛、肌肉骨骼痛、骨痛、腰椎薦椎痛、頸痛或上 57 200823187 背痛、内臟痛、軀體痛、神經病變性疼痛、癌症痛、由於受傷或手術所引發的疼痛例諸如燒傷疼痛，或頭痛諸如偏頭痛或緊張性頭痛，或此等疼痛的組合。熟諳技藝人士瞭解，此等疼痛可能彼此重疊。例如發炎所引發的疼痛本質 5 上也可能為内臟痛或肌肉骨骼痛。於本發明之一個實施例中’一種或多種本發明化合物投予哺乳動物來治療慢性疼痛，諸如周邊神經系統或中樞神經系統損傷或病理變化所引發之神經病變性疼痛；腹部、骨盆區、及/或會陰區所引發之内臟痛或胰炎所引發之 10 内臟痛；例如因下背或上背、脊椎、纖維肌痛、顳顎關節或顏面肌肉痛症候群所引發之肌肉骨骼疼痛；例如由於骨骼或關節退化症諸如骨關節炎、類風濕性關節炎、或椎骨狹窄所引發之骨痛；頭痛諸如偏頭痛或緊張性頭痛；或因感染諸如HIV、鐮刀型血球貧血、自體免疫病、多發性硬化 15 或發炎諸如骨關節炎或類風濕性關節炎所引發之疼痛。於若干實施例中，本發明化合物可用於根據此處所述方法治療慢性疼痛，亦即神經病變性疼痛、内臟疼痛、肌肉骨骼痛、骨痛、頭痛、癌症痛或發炎痛或其組合。發炎痛可能由多種醫療情況注入骨關節炎、類風濕性關節炎、 20 手術或受傷所引起。神經病變性疼痛例如可能由於下列疾病所引起：糖尿病性神經病變、周邊神經病變、疱疹後神經痛、三叉神經痛、腰椎或頸椎神經根病變、纖維肌痛、舌咽神經痛、反射***感神經失養、偶發性疼痛、丘腦症候群、神經根撕裂或因受傷造成神經損傷所導致之周邊敏 58 200823187 化及/或中樞敏化諸如幻肢痛、反射***感神經失養或胸产切開術後疼痛、癌症、化學品傷害、毒素、營養缺陷戈疒毒感染或細菌感染諸如帶狀疱疹或HIV或其組合。本發明之治療方法進一步包括神經病變性疼痛係繼發於腫瘤轉移& 5潤之情況、痛性肥胖症、燒傷或與丘腦病症相關聯之中樞疼痛病症。前述神經病變性疼痛於某些情況下也可歸類，「、 ^ 痛性小纖維神經病變」諸如特發性小纖維痛覺神經病變或「痛性大纖維神經病變」諸如脫髓鞠神經病變或軸突神經病變 10或其組合。此等神經病變之進一步細節例如說明於了 Menddl等人，N· Engl j Med 2〇〇3, 348:1243 1255，全文以引用方式併入此處。於另-個實施例中，本發明化合物可投予來全然抑制或部分抑制神經病變性疼痛情況的發生。例如，本發明化 15合物可投予有出現神經病變性疼痛情況風險之嗔乳動物，諸如患有收縮性帶狀疱療之喷乳動物或接受癌症治療之續乳動物。於-個實施例中，本發明化合物可於手術之前或手術之中投予來部分㈣或完全抑制與手術發 20 生。如先前說明，本發明化合物可用於治_體本質及/或内臟本質之《。例如，_本發財法可治療之軀體痛匕括手術、牙科手術、毅傷、或外傷性身體受傷所遭遇之結構傷害或軟組織傷害所引發时痛。根據本發明方法 59 200823187 可治療之内臟痛之實例包括與内臟發之該型疼痛，該等疾病諸如潰癌性大或所引 =膀既、克隆氏病、風*_節痛二'㈣症、刺 s S感染絲道症或其組合胰炎、明方法可治療之疼痛也與痛覺過:::覺人^ =2。此外，根據本發明可治療之慢性疼^ f有周邊敏化或中樞敏化。了▼有或未之, 本發明也提供本發料合物驗急性疼痛及/或慢性疼痛，該等疼痛也心 1〇痛。此型疼痛包括單獨由女性或主要由女性所遭、= 包括月經痛、***痛、姑娠痛或產痛、流產、=位姑行經、滤'泡或黃體囊破裂、骨盆腔内臟刺激、子、腺肌症、子宮内膜異位、感染與發炎、骨盆腔器心血、梗阻、腹腔沾！έ、骨盆腔内臟解剖扭曲 15癌、骨盆喪失支撐、腫瘤、骨盆腔充血、或由於非婦科起因所引發的疼痛。於若干實施例中，本發明化合物係組合止痛劑投予。可組合本發明化合物投予之止痛劑實例包括但非限於止痛劑諸如非麻醉性止痛劑或麻醉性止痛劑；抗炎劑諸如非類 2〇固醇抗炎劑(NSAID)、類固醇或抗風濕劑；偏頭痛製劑諸如 β腎上腺素激性阻斷劑、麥角衍生物或伊索美坦 (isometheptene);三環抗鬱劑諸如阿米崔堤林、迪斯普拉明、或伊米普拉明；抗癲癇劑諸如嘉邦潘a(gabapentin)、卡巴馬治平、托琵拉美(topiramate)、微普柔特酸鈉（s〇dium 200823187 valproate)或癲通(phenytoin); Q：2激動劑；或選擇性血清素再吸收抑制劑/選擇性正腎上腺素吸收抑制劑或其組合。熟諳技藝人士瞭解此處所述若干藥劑可作用來解除多種病情，諸如疼痛與發炎，而其它藥劑可能只是解除一種 5症狀如疼痛。有多項性質之藥劑之特例為阿斯匹靈 (aspirin)，阿斯匹靈以高劑量投藥時為抗發炎，但低劑量時只能止痛。止痛劑可包括前述藥劑的組合，例如止痛劑可為非麻醉性止痛劑與麻醉性止痛劑的組合。本發明之實務上有用之非麻醉性止痛劑例如包括水楊 10酸鹽類諸如阿斯匹靈、伊布普芬（ibuprofen)(莫春 (Motrin)、阿微爾（Advil))、克脫普芬(ketoprofen)(歐如狄斯 (Orudis))、那普柔森(naproxen)(那普柔辛（Napr〇syn))、乙醯胺芬（acetaminophen)、因朵美森（indomethacin)或其組合。可組合本發明化合物使用之麻醉性止痛劑之實例包括 15類鴉片止痛劑諸如芬坦尼（fentenyl)、蘇芬坦尼 (sufentanil)、嗎啡、羥基嗎啡酮、可待因、羥基可待因酮、布普諾芬（buprenorphine)或其藥學上可接受之鹽或其組合。可組合本發明化合物使用之抗炎劑之實例包括但非限於阿斯匹靈；伊布普芬；克脫普芬；那普柔森；伊脫朵拉 20 (etodolac)(洛丁（Lodine)) ; COX-2抑制劑諸如希勒可西伯 (celecoxib)(希樂撰（Celebrex))、柔非可西伯（rofec〇xib)(偉克適（Vioxx))、偉德可西伯（valdec〇xib)(貝克斯查 (Bextra))、帕瑞西伯（parecoxib)、伊脫瑞西伯（et〇ric〇xib) (MK663)、德拉西伯（deracoxib)、2_(4_乙氧基-苯基)冬(4_ 61 200823187 甲磺醯基-苯基)-呢唾并[l，5-bp比讲、4-(2-酮基-3-苯基-2,3-二氫4°坐-4-基）本確醯胺、達布菲隆(darbufelone) '夫洛蘇麗德(flosulide)、4-(4-環己基-2-甲基-5-噚唑基)-2-氟苯磺醯胺）、美洛西卡姆(meloxicam)、尼美蘇麗德（nimesulide)、^ 5甲基磺醯基-4-(l，l-二甲基-4-(4-氟苯基)環戊-2,4-二烯_3_基) 苯、4-(1，5-二氫-6-氟-7-曱氧基_3-(三氟甲基)-(2)-笨并硫π辰喃并(4,3-c)吡唑-1-基）苯磺醯胺、4,4-二甲基-2-苯基-3-(4-甲基磺醯基）苯基）環丁烯酮、4-胺基-Ν-(4-(2·氟-5-三氣甲基)_噻唑-2-基)-苯磺醯胺、ι_(7_第三丁基_2,3·二氫-3,3-二甲 10 基-5-苯并呋喃基)-4-環丙基丁-1-酮、或其生理上可接受之鹽類、酯類或溶劑合物；蘇林達克（sulindac)(克林諾瑞 (Clinoril));狄克洛芬(diclofenac)(瓦塔仁(Voltaren));琵柔西卡姆(piroxicam)(復得健(Feldene));狄夫尼沙(diflimisal) (朵洛必（Dolobid))、那布美同（nabumetone)(瑞樂芬 15 (Relefen))、歐沙普曾（oxaprozin)(蝶普羅(Daypro))、因朵美森（因朵辛（Indocin));或類固醇諸如培狄亞培德(pediaped) (普尼松隆（prednisolone)磷酸鈉口服溶液劑、梭鹵-美卓 (Solu-Medro)甲基普尼松隆丁二酸鈉注射劑、普瑞隆 (Prelone)品牌普尼松隆糖漿劑。 20 根據本發明可用於治療疼痛諸如類風濕性關節炎所引發之疼痛之抗炎劑之額外實例包括拿普森，市面上可以EC 拿普森延遲釋放鍵、拿普森、安普柔克斯(Anaprox)及安普柔克斯DS錠及拿普森懸浮液得自羅氏公司、希樂葆品牌之希勒可西伯錠、偉克適品牌之柔非可西伯、希樂史東 62 200823187 (Celestone)品牌之貝它美沙松（betamethasone)、庫普拉明 (Cupramine)品牌之青黴胺（penicillamine)膠囊劑、滴潘 (Depen)品牌之可滴定青黴胺鍵、狄波美卓（Depo-Medrol) 品牌之甲基普尼松隆乙酸鹽注射懸浮液劑、阿拉瓦(Amva) 5 品牌之樂夫語邁德（leflunomide)錠、阿如費定（Azulfidine) EN-tab品牌之沙法沙拉曾（sulfasalazine)延遲釋放鍵劑、復得健品牌之琵柔西卡姆膠囊劑、卡塔拉姆(Cataflam)品牌之狄克洛芬鉀錠劑、瓦塔仁品牌之狄克洛芬鈉延遲釋放錠劑、瓦塔仁-XR品牌之狄克洛芬鈉延遲釋放錠劑、或英布瑞 10 爾（Enbrel)品牌之伊塔内西普（etanerecept)產品。其它可用於治療發炎特別為風濕性關節炎之藥劑之實例包括免疫抑制劑諸如剛葛拉夫(Gengraf)品牌之環孢靈 (cyclosporine)膠囊劑、紐拉爾（Neoral)品牌之環孢靈膠囊劑或口服溶液劑、或伊慕朗（Imuran)品牌之阿雜索林 15 (azathioprine)錠劑或IV注射劑；因朵辛品牌之因朵美沙辛膠囊劑、口服懸浮液劑或栓劑；普拉昆尼爾（Plaquen⑴品牌之.基氣奎寺硫酸鹽；或麗米卡德(Remica(Je)品牌之英夫利馬伯（infliximab)重組產物靜脈注射液；或金化合物諸如奥拉諾芬(auranofin)或米歐克利辛（My〇chrisyine)品牌之硫蘋 20 果酸金鈉注射液。作為5-HT2c調節劑，本發明化合物可用於治療多種病症。此等病症包括經前症候群、經前煩躁症、行動障礙或運動障礙諸如巴金森氏症；偏軸、慢性倦怠症候群、神經性厭食症、睡眠障礙(例如睡眠絕息）及緘默症。 63 200823187 於其它實施例中，本發明化合物可用於治療例如與創傷、中風及脊索受傷、神經退化病或毒性或感染<：1^3病（例如腦炎或腦膜炎）或巴金森氏病相關聯之一種或多種中樞神經系統缺陷。因此，本發明化合物可用於改良或抑制5亥 5等感興趣疾病或創傷期間或創傷後之中樞神鉍系統活性之進一步降級。此等改良包括運動及行動技巧、控制、協調及強度的維持或改善。 5·藥學上可接受之組成物於其它實施例中，本發明係有關包含至少一種式I或III 10 化合物或其藥學上可接受之鹽，及一種或多種藥學上可接受之載劑、賦形劑或稀釋劑之組成物。此等組成物包括用於治療或控制中樞神經系統疾病狀態或病情之藥學組成物。於若干實施例中，組成物包含一種或多種式I或III化合物之混合物。Promoters; sputum inhibitors; PDE inhibitors (preferably CGMP PDE-5 inhibitors), bombesin receptor antagonists or modulators, and soluble secreted end-spinase inhibitors (SEPi). In several embodiments, the compounds of the invention are administered in combination with one or more male sexual dysfunction therapeutics such as alp〇stadil or sildenafil. According to still another embodiment, the compound of the invention is administered in combination with one or more female sexual dysfunction therapeutic agents. Such agents are known to the art and include estrogen receptor modulators (e.g., estrogen agonists and/or estrogen antagonists); steroidal supplements, steroids (Tostrelle, ii 56 200823187 hydrogen) Testosterone, dehydroepiandroxone (DHEA), steroid vaccine; for example, dehydroandrostenedione, estrogen, estrogen, medroxyprogesterone, metoprolactone acetate (MPA), although hormones and nails Combination of ketamine-suppressing therapeutics; Premarin, Cenestin, Oestrofeminal, Equin, Estrace, Iss Estrofem, Elleste Solo, Estring, Eastraderm TTS, Ischraden, Dermestril, Premphase, Preempro, Prempak, Premique, Estratest, Ischacht HS, Tibolone a dopamine agonist; for example, apomorphine or a selective D2, D3 or D2/D3 agonist such as Lamipipexole and ropirinol, NPY inhibitors; for example, NYP inhibitors such as NPY1 or NPY5 inhibit 15 agents, preferably NPY1 inhibitors, Melanocortin receptor modulator or melanocortin promoter; for example, melanotan II, PT-14, PT-141, NEP (neutral endonuclease) inhibitor; PDE (phosphoric acid diester) An enzyme) inhibitor; for example, siddenafil and/or a bombesin receptor modulator. According to the invention, the compounds of the invention are useful for treating any of a number of different types of pain in a mammal, such as 20 humans. For example, The compounds of the invention are useful for the treatment of acute pain (short time) or chronic pain (conventional recurrent or persistent pain), including pain at the central or peripheral. Examples of acute or chronic pain treatable according to the methods of the invention include inflammation. Pain, musculoskeletal pain, bone pain, lumbar vertebrae, cervical pain or upper 57 200823187 Back pain, visceral pain, somatic pain, neuropathic pain, cancer pain, pain caused by injury or surgery such as burn pain Or headaches such as migraine or tension headaches, or a combination of such pains. Those skilled in the art understand that such pain may overlap with each other. For example, the nature of the pain caused by inflammation may also be visceral pain or musculoskeletal pain. In one embodiment of the invention 'one or more compounds of the invention are administered to a mammal to treat chronic pain, such as neuropathic pain caused by peripheral or central nervous system damage or pathological changes; abdominal, pelvic region, and/or 10 visceral pain caused by visceral pain or pancreatitis caused by the perineal area; for example, musculoskeletal pain caused by lower back or upper back, spine, fibromyalgia, ankle joint or facial muscle pain syndrome; Bone or joint degeneration such as osteoarthritis, rheumatoid arthritis, or bone pain caused by vertebral stenosis; headache such as migraine or tension headache; or infection such as HIV, sickle cell anemia, autoimmune disease, Multiple sclerosis 15 or inflammation caused by inflammation such as osteoarthritis or rheumatoid arthritis. In several embodiments, the compounds of the invention are useful for treating chronic pain, i.e., neuropathic pain, visceral pain, musculoskeletal pain, bone pain, headache, cancer pain, or inflammatory pain, or a combination thereof, according to the methods described herein. Inflammation can be caused by a variety of medical conditions that inject osteoarthritis, rheumatoid arthritis, 20 surgery or injuries. Neuropathic pain, for example, may be caused by: diabetic neuropathy, peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia, lumbar or cervical radiculopathy, fibromyalgia, glossopharyngeal neuralgia, reflex sympathetic loss Nutrients, sporadic pain, thalamic syndrome, nerve root tears, or peripheral damage caused by nerve damage caused by injury 58 200823187 and/or central sensitization such as phantom limb pain, reflex sympathetic dystrophy or thoracic surgery Pain, cancer, chemical damage, toxins, auxotrophy, or bacterial infections such as herpes zoster or HIV or a combination thereof. The method of treatment of the present invention further comprises a neuropathic pain secondary to the onset of tumor metastasis, painful obesity, burns or a central pain condition associated with a thalamic condition. The aforementioned neuropathic pain can also be classified in some cases, ", ^ painful fibrotic neuropathy" such as idiopathic fibrotic pain neuropathy or "painful fibrotic neuropathy" such as demyelinating neuropathy or axis Neuropathy 10 or a combination thereof. Further details of such neuropathies are described, for example, in Menddl et al., N. Engl j Med 2, 3, 348: 1243 1255, which is incorporated herein in its entirety by reference. In yet another embodiment, a compound of the invention can be administered to completely inhibit or partially inhibit the development of a neuropathic pain condition. For example, the compound of the present invention can be administered to a mammal having a risk of developing a neuropathic pain, such as a lactating animal having a contractile vesicular treatment or a recurrent animal receiving cancer treatment. In one embodiment, the compounds of the invention may be administered in part (d) or completely inhibited and surgically performed prior to or during surgery. As indicated previously, the compounds of the invention may be used to treat the essence of the body and/or the nature of the viscera. For example, the body pain that can be treated by this method of fat can cause pain caused by structural damage or soft tissue injury caused by surgery, dental surgery, pernicious injury, or traumatic physical injury. Examples of visceral pain treatable according to the method 59 200823187 of the present invention include this type of pain with the viscera, such as ulceration or sputum = bladder, Crohn's disease, wind * _ pain 2 (D) disease, s s S infection silk disease or a combination of pancreatitis, the method of treatment can also be treated with pain and painful::: conscious person ^ = 2. Furthermore, chronic pain treatable according to the present invention has peripheral sensitization or central sensitization. The invention also provides for the detection of acute pain and/or chronic pain, which is also a pain in the present invention. This type of pain includes female or mainly female, = including menstrual pain, ovulation pain, aching pain or labor pain, abortion, abortion, filtering 'bubble or corpus luteum rupture, pelvic visceral stimulation, Sub, adenomyosis, endometriosis, infection and inflammation, pelvic blood, obstruction, abdominal cavity! έ, pelvic visceral anatomical distortion 15 cancer, pelvic loss support, tumor, pelvic congestion, or pain caused by non-gynecological causes. In several embodiments, the compounds of the invention are administered in combination with an analgesic. Examples of analgesics which may be administered in combination with a compound of the invention include, but are not limited to, analgesics such as non-narcotic analgesics or narcotic analgesics; anti-inflammatory agents such as non-steroidal anti-inflammatory agents (NSAIDs), steroids or anti-rheumatic agents Migraine preparations such as beta-adrenergic blockers, ergot derivatives or isometheptene; tricyclic anti-depressants such as Amitricin, Dispramamine, or Imip Lamin; anti-epileptic agents such as gabapentin, carbamazepine, topiramate, s〇dium 200823187 valproate or phenytoin; Q:2 agonist Or a selective serotonin reuptake inhibitor/selective norepinephrine absorption inhibitor or a combination thereof. Skilled artisans understand that several agents described herein can act to relieve a variety of conditions, such as pain and inflammation, while other agents may simply relieve a 5 symptom such as pain. A special case of a multi-agent is aspirin. Aspirin is anti-inflammatory when administered at high doses, but it can only relieve pain at low doses. The analgesic may comprise a combination of the foregoing agents, for example the analgesic may be a combination of a non-narcotic analgesic and an anesthetic analgesic. Non-narcotic analgesics useful in the practice of the present invention include, for example, salicin 10 salts such as aspirin, ibuprofen (Motrin, Advil), ketamine. Ketoprofen (Orudis), naproxen (Napr〇syn), acetaminophen, indomethacin or combination. Examples of narcotic analgesics which can be used in combination with the compounds of the invention include 15 opioid analgesics such as fentenyl, sufentanil, morphine, hydroxymorphone, codeine, oxycodone , buprenorphine or a pharmaceutically acceptable salt thereof or a combination thereof. Examples of anti-inflammatory agents that can be used in combination with the compounds of the invention include, but are not limited to, aspirin; ibuprofen; clotfen; naproxen; etodolac (Lodine) COX-2 inhibitors such as celecoxib (Celebrex), rofec〇xib (Vioxx), viddec〇xib ) (Bextra), parecoxib, et〇ric〇xib (MK663), deracoxib, 2_(4_ethoxy-phenyl) Winter (4_ 61 200823187 methanesulfonyl-phenyl)-yespo-[l,5-bp ratio, 4-(2-keto-3-phenyl-2,3-dihydro 4° sitting-4 -Base) Benthamine, darbufelone 'flosulide, 4-(4-cyclohexyl-2-methyl-5-oxazolyl)-2-fluorobenzenesulfonamide ), meloxicam, nimesulide, ^5methylsulfonyl-4-(l,l-dimethyl-4-(4-fluorophenyl)cyclopentane-2 , 4-dienyl-3-yl) benzene, 4-(1,5-dihydro-6-fluoro-7-decyloxy-3-(trifluoromethyl)-(2)- benzothiazepine M-(4,3-c)pyrazol-1-yl)benzenesulfonamide, 4,4-di Benzyl-2-phenyl-3-(4-methylsulfonyl)phenyl)cyclobutenone, 4-amino-indole-(4-(2·fluoro-5-trimethylmethyl)-thiazole -2-yl)-benzenesulfonamide, ι_(7_t-butyl-2,3·dihydro-3,3-dimethyl-10-yl-5-benzofuranyl)-4-cyclopropyl 1-one, or a physiologically acceptable salt, ester or solvate thereof; sulindac (Clinoril); diclofenac (Vataren) (Voltaren)); piroxicam (Feldene); diflimisal (Dolobid), nabumetone (Rui Lefen 15) (Relefen)), oxaprozin (Daypro), Indosin (Indocin), or steroids such as pediaped (prednisolone) Sodium phosphate oral solution, Solu-Medro methylprednisolone sodium succinate injection, Prelonone brand prednisolone syrup. 20 According to the invention, it can be used for treating pain Additional examples of anti-inflammatory agents such as those caused by rheumatoid arthritis include Napson, which can be delayed in the market by EC. Keys, Napson, Anaprox and Ampox DS ingots and Napson suspension are available from Roche, the Hilke brand of Hilke, and the Flexor brand. Non-Keisbo, Xile Stone 62 200823187 (Celestone) brand of betamethasone, capricillamine brand penicillamine capsules, Depen brand of penicillin Amine bond, Depo-Medrol brand of methylprednisolone acetate suspension suspension, Avava 5 brand of leflunomide ingot, arufed ( Azulfidine) EN-tab brand sulfasalazine delayed release bond, Fujianjian brand 琵柔西卡姆胶囊, Cataflam brand of Dicloprofen potassium lozenge, tile Tallon's Dickloprofen Sodium Delay Release Lozenges, Vatarren-XR brand of Dicloprofen Sodium Delay Release Lozenges, or Enbrel's Entanecept product. Other examples of agents useful for the treatment of inflammation, particularly rheumatoid arthritis, include immunosuppressive agents such as the Gengraf brand of cyclosporine capsules, and the Neoral brand of cyclosporine capsules. Or oral solution, or Izamin brand azathioprine lozenge or IV injection; Indumethasin capsule, oral suspension or suppository; Neil (Plaquen (1) brand. Base gas Kui Temple sulfate; or Remica (Je) brand infliximab (infliximab) recombinant product intravenous injection; or gold compounds such as auranofen (auranofin) Or Myoschrisyine brand thiophene 20 fruit acid gold sodium injection. As a 5-HT2c modulator, the compounds of the invention can be used to treat a variety of conditions, including premenstrual syndrome, premenstrual irritability , mobility disorder or dyskinesia such as Parkinson's disease; off-axis, chronic burnout syndrome, anorexia nervosa, sleep disorders (eg sleep sleep) and mutism 63. The compounds of the invention are useful for treating one or more central nervous systems associated with, for example, trauma, stroke and spinal cord injuries, neurodegenerative diseases or toxic or infectious diseases such as encephalitis or meningitis or Parkinson's disease. Defects. Accordingly, the compounds of the present invention are useful for ameliorating or inhibiting further degradation of the activity of the central nervous system during or after trauma or trauma, such as exercise and mobility techniques, control, coordination, and intensity. Maintained or improved. 5. Pharmaceutically acceptable composition. In other embodiments, the invention relates to a compound comprising at least one compound of Formula I or III 10 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable salts a composition of a carrier, excipient or diluent. These compositions include a pharmaceutical composition for treating or controlling a disease state or condition of the central nervous system. In several embodiments, the composition comprises one or more Formula I or A mixture of III compounds.

15 於若干實施例中，本發明係關於包含至少一種式I或III 化合物或其藥學上可接受之鹽，及一種或多種藥學上可接文之載劑、賦形劑或稀釋劑之組成物。此等組成物可根據可接受之藥學程序製備，例如説明於雷明頓製藥科學第17 版，編者Alfonoso R· Gennar〇，默克出版公司，賓州伊斯頓 20 (1985年），全文則丨用方式併人此處。藥學上可接受之 =於配方中之其它成分可相容且為生物上可接受之該等^ ΆΙΙΙ化合物可經口或經腸道外投予習知藥學載劑投予才又予或、、且合通用之固體栽劑包括也可用作為綠味 64 200823187 劑、潤滑劑、增溶劑、懸浮劑、填充劑、滑動劑、壓縮助劑、黏結劑、錠劑、崩散劑或囊封材料之一種或多種物質。於散劑中，載劑為細分固體，固體混合經細分之活性成分。於錠劑中，活性成分以適當比例混合具有所需壓縮性質之 5 載劑，且緊壓成為期望之形狀及大小。散劑及錠劑較佳含有高達99%活性成分。適當固體載劑例如包括磷酸鈣、硬脂酸鎂、滑石、糖類、乳糖、糊精、澱粉、明膠、纖維素、甲基纖維素、羧甲基纖維素鈉、聚乙烯基吡咯啶、低熔蠟及離子交換樹脂。 10 液體載劑可用於製造溶液劑、懸浮液劑、乳液劑、糖漿劑及酏劑。活性成分可溶解於或懸浮於藥學上可接受之液體載劑，諸如水、有機溶劑、二者之混合物或藥學上可接受之油或脂肪。液體載劑可含有其它適當藥學添加劑諸如增溶劑、乳化劑、緩衝劑、保藏劑、甜味劑、矯味劑、 15 懸浮劑、增稠劑、色料、黏度調節劑、安定劑或滲透壓調節劑。供經口及經腸道外投藥之液體載劑之適當實例包括水(特別含有前述添加劑諸如纖維素衍生物、較佳為魏甲基纖維素鈉溶液）、醇類（包括一羥基醇類及多羥基醇類例如二醇類）及其衍生物及油類（例如分餾椰子油及花生油）。供腸 20 道外投予，載劑也可為油性醋，諸如油酸乙S旨及肉豆寇酸異丙酯。無菌液體載劑係呈無菌液體形式之組成物供腸道外投藥使用。加壓組成物之液體載劑可為i化烴或其它藥學上可接受之推進劑。屬於無菌溶液或無菌懸浮液之液體藥學組成物例如可 65 200823187 藉肌肉注射、腹内注射或皮下注射投予。無菌溶液劑也可經靜脈投予。口服投藥用組成物可呈液體形式或固體形式。式I或III化合物可呈習知栓劑劑型經直腸或經***投藥。供經由鼻内或支氣管内吸入投藥或吹入投藥’式I或III 5 化合物可調配成水性溶液或部分水性溶液，隨後呈噴霧劑劑型使用。式I化合物也可透過使用經皮貼片經皮投藥，該經皮貼片含有活性化合物及對活性化合物呈惰性之載劑，該載劑對皮膚為無毒，且允許將活性劑遞送透過皮膚做系統性吸收入血流。載劑可呈任一種劑型，諸如乳膏劑及軟 10膏劑、糊劑、膠漿劑及阻隔裝置。乳膏劑及軟膏劑可為水包油型或油包水型黏稠液體乳液或黏稠半固體乳液。也適合使用糊劑，糊劑包含吸收性粉末分散於含有活性成分之石蠟或親水石蠟。多種阻隔裝置可用來將活性成分釋放入血⑽，諸如半透膜覆蓋含有活性成分之有或無載劑之貯 15為，或含有活性成分之基體。其它阻隔裝置為技藝界所已知。幸又佳藥學組成物係呈單位劑型例如錠劑、膠囊劑、散 ^ /奋液劑、懸浮液劑、乳液劑、粒劑或栓劑劑型。於此等Μ型中，組成物被再劃分為含有適量活性成分之 20 位；i 乂里平 ^ 蜊型可為包裝組成物，例如包裝散劑、小瓶劑、、”預真充之注射夯或含有液體之藥包。單位劑型例二公囊劑或旋劑本身，或可為適當數目之任一種此等組成物呈包裝形式。提供予病人之式I或m化合物用量將依據投予病人之 66 200823187 t技藥目的、諸如預防或治療、病人狀態投藥方式等於治療應用中’式1化合物係以足夠治療或至少部分 rn症狀及其併發症之用量投予患有此種病情之病 “達成此項目的之用量為如前文說明之「冶療上有々里」m療特定關之劑量須由臨 ^變數包括病人及特定病情的病人身裁、年齡及反應形 ^。物質㈣之治療躲臨床料的指導之下遵循本藥物二1之相同方法。大致上，開始劑量為每日約5毫克，每日 10 *徐緩增加至約每日1紙克來對病人提供期望之劑量水平。 “於若干實施例中，本發明係針對式!化合物之前藥。「前桌」5司用於此處係如前文定義。實例生物檢定分析 15本發明化合物作為5媽说動似部分激動劑之能力係使用數種標準藥理試驗程序讀立；此等藥理試驗程序提供如下。於該試驗程序中5-HT表示5•羥基色胺，mcpp表示間氯苯基t井及D0I表示Ha:甲氧基_4_峨苯基)異丙基胺。 2〇 $ 了評估多種式1化合物對5-1受體活性之親和力，以可表現人5-經基色胺-2C(h5_HT2c)受體之cDNA轉移感染之CHO(中國倉鼠卵巢)細胞系維持於dmem(杜別克改性鷹式培養基），DMEM中補充胎牛血清、麵胺及標記··島嘌呤構酸核糖基轉移酶(GTP)及次黃嘌呤胸腺苷(HT)。讓細 67 200823187 胞於大型培養皿中生長至融合，中間改變培養基及進行分割。當細胞生長至融合時，藉刮取收穫細胞。收穫之細胞懸浮於半量體積新鮮生理磷酸緩衝食鹽水(PBS)溶液，以低速(900 xg)離心。此項操作重複一次。然後收集之細胞使用 5寶麗充(Polytron)設定為#7於十倍量之50 mM Tris.HCl，pH 7.4及0.5 mM EDTA中均化15秒。均化產物以900 x g離心i5 分4里來去除細胞核顆粒及其它細胞殘骸。抛棄丸粒，上清液以40,000 x g離心30分鐘。所得丸粒再懸浮於小量 Tris.HCl緩衝液，以整分1〇_25微升體積測定組織蛋白質含 10 量。牛血清白蛋白（BSA)用作為藉Lowry等人，（J· Biol Chem.，193:265 (1951))之方法測定蛋白質時之標準品。懸浮細胞膜之量以50 mM Tris.HCl緩衝液含有：0.1%抗壞血酸、10 mM帕吉林(pargyline)及4 mM CaCU調整來獲得每毫升懸浮液1-2毫克之組織蛋白質濃度。製備膜懸浮液(濃縮多 15 次)之體積為每份1毫升，儲存於-70°C直到隨後用於結合實驗。結合測定係於96孔微力價孔板格式，於總量200微升進行。於各孔内添加60微升培養緩衝液，培養緩衝液係於50 111]^丁1^.11(：1緩衝液，？117.4中製造且含有4 111]^〇3(：12;20 20 微升[125I] DOI (S.A·，2200西弗/毫莫耳(NEN科學生命公司)）。 [125I] DOI於人血清素體之解離常數KD經由以遞增濃度之[125I] DOI飽和結合測得為〇·4 nM。反應係藉最終添加100微升含50微克受體蛋白質組織懸浮液而引發反 68 200823187 應。於添加量20.0微升之1 // ]y[未加標記之d〇i存在下測定非特異性結合。試驗化合物係以2〇·〇微升添加。混合物於室溫培養60分鐘。藉快速過濾中止培養。結合配體_受體錯合物於96孔過濾、器上使用派克公司（packar^j)費特美特 5 (Filtermate) 196收穫器過濾出。於過濾器圓盤上所捕捉之結合錯合物於加熱至60°C之真空烤爐内乾燥，於裝配有6個光倍增器偵測器之派克公司脫普康（TopC〇unt)十，使用4〇微升麥克星特(Microscim)，閃爍計藉液體閃爍測定放射性。特異性結合定義為結合之總放射性減於丨# M未加標 10圮之D01存在下結合量。於不等濃度試驗藥物存在下之結合表示為於藥物不存在下之特異性結合百分比。然後將結果以結合log%相對於試驗藥物之1〇g濃度作圖。資料點之非線性迴歸分析，獲得試驗化合物之EC別值及&值，有95%信度極限。另外，貧料點下降之線性迴歸線作圖，由該圖中可 15由曲線讀取EC5G值，藉解除如下方程式測定Ki值。 κ(=」。50In some embodiments, the invention relates to a composition comprising at least one compound of Formula I or III, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients or diluents . Such compositions may be prepared according to acceptable pharmaceutical procedures, such as those described in Remington's Pharmaceutical Sciences, 17th edition, edited by Alfonoso R. Gennar, Merck Publishing Company, Easton, Pennsylvania 20 (1985), and full text. Use the way here. Pharmaceutically acceptable = other ingredients in the formulation are compatible and biologically acceptable. The compound can be administered orally or parenterally to a conventional pharmaceutical carrier before or after administration. General purpose solid seeding agents include one or more of which can also be used as a green flavor 64 200823187 agent, lubricant, solubilizer, suspending agent, filler, slip agent, compression aid, binder, lozenge, disintegrating agent or encapsulating material. substance. In the powder, the carrier is a finely divided solid, and the solid is mixed with the finely divided active ingredient. In the tablet, the active ingredient is mixed in a suitable ratio with 5 carriers having the desired compression properties and pressed into the desired shape and size. Powders and lozenges preferably contain up to 99% active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidine, low melting Wax and ion exchange resins. 10 Liquid carriers can be used in the manufacture of solutions, suspensions, lotions, syrups and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of the two or a pharmaceutically acceptable oil or fat. The liquid carrier may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, 15 suspending agents, thickening agents, colorants, viscosity regulators, stabilizers or osmotic pressure adjustments. Agent. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing the aforementioned additives such as cellulose derivatives, preferably sodium methylcellulose sodium), alcohols (including monohydric alcohols and polyhydric alcohols). Such as glycols and their derivatives and oils (such as fractionated coconut oil and peanut oil). The enteral is administered 20 times, and the carrier may also be oily vinegar, such as oleic acid B and isopropyl myristate. Sterile liquid carriers are compositions in sterile liquid form for parenteral administration. The liquid carrier of the pressurized composition can be a hydrocarbon or other pharmaceutically acceptable propellant. A liquid pharmaceutical composition which is a sterile solution or a sterile suspension can be administered, for example, by intramuscular injection, intraperitoneal injection or subcutaneous injection. Sterile solutions can also be administered intravenously. The oral pharmaceutical composition can be in liquid form or in solid form. The compound of formula I or III can be administered rectally or vaginally in the form of a conventional suppository formulation. For administration via intranasal or intrabronchial inhalation or insufflation, the compound of formula I or III 5 can be formulated into an aqueous solution or a partially aqueous solution, which is then used in a spray dosage form. The compounds of formula I can also be administered transdermally using a transdermal patch containing the active compound and a carrier inert to the active compound which is non-toxic to the skin and which allows delivery of the active agent through the skin. Systematic absorption into the bloodstream. The carrier can be in any of the dosage forms, such as creams and soft 10 pastes, pastes, pastes, and barrier devices. Creams and ointments may be in the form of oil-in-water or water-in-oil viscous liquid emulsions or viscous semi-solid emulsions. It is also suitable to use a paste containing an absorbent powder dispersed in a paraffin wax or a hydrophilic paraffin containing an active ingredient. A variety of barrier devices can be used to release the active ingredient into the blood (10), such as a semipermeable membrane covering the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other barrier devices are known to the art. Fortunately, the pharmaceutical composition is in a unit dosage form such as a tablet, a capsule, a dispersion, a suspension, a lotion, a granule or a suppository. In these types, the composition is subdivided into 20 positions containing an appropriate amount of the active ingredient; i 乂平 ^ 蜊 can be a package composition, such as a packaged powder, a vial, or a pre-filled injection or A liquid-containing pack, unit dosage form 2, a sachet or a rotatory agent itself, or a suitable number of any of these compositions in a packaged form. The amount of the compound of formula I or m provided to the patient will be based on administration to the patient. 66 200823187 t Technical purposes, such as prevention or treatment, patient state administration means equal to the therapeutic application of the compound of formula 1 with sufficient treatment or at least part of the rn symptoms and its complications to administer the disease The dosage of this item is as specified in the previous section. The dosage of the specific treatment must be determined by the patient's physique, age and reaction form. The treatment of substance (4) follows the same method as the drug II 1 under the guidance of the clinical material. Roughly, the starting dose is about 5 mg per day, and 10 x a day is slowly increased to about 1 gram per day to provide the patient with the desired dosage level. "In several embodiments, the present invention is directed to a compound of the formula! The "front table" 5 is used herein as defined above. EXAMPLES Bioassay Analysis 15 The ability of the compounds of the invention to act as a partial agonist for 5 mothers was read using several standard pharmacological test procedures; such pharmacological test procedures are provided below. In the test procedure, 5-HT represents 5 hydroxytryptamine, mcpp represents m-chlorophenyl t well and D0I represents Ha: methoxy _4_ phenyl) isopropylamine. 2〇$ evaluated the affinity of various compounds of formula 1 for 5-1 receptor activity, and the CHO (Chinese hamster ovary) cell line which can express the cDNA transfer of human 5- leucine-2C (h5_HT2c) receptor is maintained at Dmem (Dubec modified eagle medium), DMEM supplemented with fetal bovine serum, face amine and labeled · 嘌呤嘌呤嘌呤 ribosyltransferase (GTP) and hypoxanthine thymidine (HT). Let the fine 67 200823187 cells grow to a fusion in a large petri dish, change the medium and divide in the middle. When the cells are grown to confluence, the cells are harvested by scraping. The harvested cells were suspended in a half volume of fresh physiological phosphate buffered saline (PBS) solution and centrifuged at a low speed (900 x g). This operation is repeated once. The collected cells were then homogenized for 15 seconds using a Polytron set to #7 in ten times 50 mM Tris.HCl, pH 7.4 and 0.5 mM EDTA. The homogenized product was centrifuged at 900 x g for 5 minutes to remove nuclear particles and other cellular debris. The pellet was discarded and the supernatant was centrifuged at 40,000 x g for 30 minutes. The pellet obtained was resuspended in a small amount of Tris.HCl buffer, and the amount of tissue protein contained was measured in a volume of 1 〇 25 μl. Bovine serum albumin (BSA) was used as a standard for the determination of proteins by the method of Lowry et al. (J. Biol Chem., 193:265 (1951)). The amount of suspended cell membrane was adjusted in a 50 mM Tris.HCl buffer containing: 0.1% ascorbic acid, 10 mM pargyline, and 4 mM CaCU to obtain a tissue protein concentration of 1-2 mg per ml of the suspension. The membrane suspension (concentrated 15 times more) was prepared in a volume of 1 ml each and stored at -70 °C until subsequently used in the binding assay. Binding assays were performed in a 96-well microfluidic plate format at a total of 200 microliters. 60 μl of culture buffer was added to each well, and the culture buffer was prepared at 50 111 μm ^1.11 (:1 buffer, ?117.4 and contained 4 111]^〇3 (:12;20 20 Microliter [125I] DOI (SA·, 2200 sif/mole (NEN Scientific Life)). [125I] Dissociation constant KD of DOI in human serotonin via [125I] DOI saturation binding in increasing concentration The result is 〇·4 nM. The reaction is initiated by adding 100 μl of a suspension containing 50 μg of receptor protein tissue to initiate the inverse 68 200823187. The addition amount is 20.0 μl of 1 // ]y [unmarked d〇 The non-specific binding was determined in the presence of i. The test compound was added in 2 μL. The mixture was incubated at room temperature for 60 minutes. The culture was stopped by rapid filtration. The ligand-receptor complex was bound to a 96-well filter. It was filtered using a Packer^j Filtermate 196 harvester. The binding complex captured on the filter disc was dried in a vacuum oven heated to 60 ° C. Parker's TopC〇unt 10 equipped with six photomultiplier detectors, using 4 microliters of Microscim. The radioactivity is determined by liquid scintillation. The specific binding is defined as the total radioactivity of the binding minus the binding amount of D01 in the absence of 10 圮. The combination in the presence of the unequal concentration test drug is expressed as the drug does not exist. The percentage of specific binding is then plotted. The results are plotted against the log% of the test drug at a concentration of 1%. The non-linear regression analysis of the data points yields EC values and & values for the test compound, 95% In addition, the linear regression line of the lean point drop is plotted, and the EC5G value is read from the curve by the graph 15 in the figure, and the Ki value is determined by the following equation. κ (=".

l-hL/KD 此處L為所使用之放射性配體濃度，κ〇為受體之配體解離常數，乙及％皆以nM表示。對下表2之各種參考化合物提供K/s (95%信度間隔）如 20 下： 69 200823187 表2 :參考化合物之K;資料l-hL/KD where L is the concentration of the radioligand used, and κ〇 is the ligand dissociation constant of the receptor, and both B and % are expressed in nM. K/s (95% confidence interval) is provided for each of the reference compounds in Table 2 below, eg 20: 69 200823187 Table 2: K of reference compound; data

化合物 IQCompound IQ

麗坦塞林(Ritanserin) 2.0 (1.3-3.1) nM 克坦塞林(Ketanserin) 94.8 (70.7-127.0) nM 米恩塞林(Mianserin) 27(1.9-3.8) nM 克洛雜平(Clozapine) 23.2 (16.0-34.0) nM 美索塞平(Methiothepin) 4.6 (4.0-6.0) nM 美希塞吉德(Methysergide) 6.3 (4.6-8.6) nM 洛克沙平(Loxapine) 33.0 (24.0-47.0) nM mCPP 6.5 (4.8-9.0) nM DOI 6.2 (4.9-8.0) nMRitanserin 2.0 (1.3-3.1) nM Ketanserin 94.8 (70.7-127.0) nM Mianserin 27 (1.9-3.8) nM Clozapine 23.2 (16.0-34.0) nM Methiothepin 4.6 (4.0-6.0) nM Methysergide 6.3 (4.6-8.6) nM Loxapine 33.0 (24.0-47.0) nM mCPP 6.5 ( 4.8-9.0) nM DOI 6.2 (4.9-8.0) nM

式I化合物於腦部5-111^：產生激動劑反應之能力係經由使用下述程序測定其對鈣遷移之影響進行評估：穩定表現 5 人5-HT2C受體之CHO細胞於補充10%胎牛血清及非必須胺基酸之杜別克改性鷹式培養基（DMEM)中培養。於評估 5-HT2C受體刺激鈣遷移之前24小時，細胞以40K細胞/孔密度接種於96孔透明底黑壁孔板。用於鈣之研究，細胞以37 °C載荷鈣指示劑染料Fluo-3 - AM於漢克氏緩衝食鹽水(HB S) 10 經歷60分鐘時間。細胞於室溫以HBS洗滌，移至螢光計量成像板讀取器（FLIPR，分子裝置公司（Molecular Devices)，加州山尼維爾）來拍攝鈣影像。以氬離子雷射達成於488奈米之激光，使用510_560奈米發光濾光片。螢光影像及相對強度係以1秒間隔拍攝，於使用FLIPR之内部流體模組進行 15 10次基準線測定後，藉加入激動劑來刺激細胞。螢光計數 70 200823187 值增加係與胞内鈣的增加相對應。用於激動劑藥理學評估，使用原始螢光計數資料之最大值減最小值計算來測定回應於不同激動劑濃度之鈣變化。然後鈣變化係以使用最大有效濃度5_11丁觀察得之反應 5百分比表示。使用4參數邏輯函數，藉對數-濃度％最大5-HT 反應曲線之非線性迴歸分析估計£<^()值。於若干實施例中，本發明化合物獲得EC%小於等於約1〇〇〇 nM。於其它實知例中，本發明化合物獲得Ec5G小於等於約 100 nM，又有其匕實施例中小於等於約2〇 _，又有其它實施例中小於等於約5 nM，及於若干實施例中小於等於約2 nM。對下表3之各參考化合物提供如下Ec5〇表3 :參考化」⑺資料 __化如勿 —___ec5〇Compounds of formula I in the brain 5-111^: The ability to produce an agonist response is assessed by measuring the effect of calcium migration on CHO cells stably expressing 5 human 5-HT2C receptors in a supplement of 10% fetal Cultured in bovine serum and non-essential amino acid in Dubec modified eagle medium (DMEM). At 24 hours prior to the evaluation of 5-HT2C receptor-stimulated calcium migration, cells were seeded at 96K cells/well density in 96-well clear bottom black wall plates. For the study of calcium, the cells were loaded with calcium indicator dye Fluo-3 - AM at 37 ° C in Hank's buffered saline (HB S) 10 for 60 minutes. The cells were washed with HBS at room temperature and transferred to a fluorescence metrology imaging plate reader (FLIPR, Molecular Devices, Shanneville, CA) to capture calcium images. An argon ion laser was used to achieve a laser of 488 nm, using a 510-560 nm illuminating filter. Fluorescence images and relative intensities were taken at 1 second intervals. After 15 10 baseline measurements using FLIPR's internal fluid module, agonists were used to stimulate the cells. Fluorescence count 70 200823187 The increase in value corresponds to an increase in intracellular calcium. For agonist pharmacological evaluation, the maximum value minus the minimum value of the original fluorescence count data is used to determine the change in calcium in response to different agonist concentrations. The calcium change is then expressed as a percentage of the reaction observed using the maximum effective concentration of 5-11. The value of £<^() was estimated by a nonlinear regression analysis of the log-concentration % maximum 5-HT reaction curve using a 4-parameter logistic function. In several embodiments, the compounds of the invention achieve an EC% of less than or equal to about 1 〇〇〇 nM. In other embodiments, the compounds of the invention obtain an Ec5G of less than or equal to about 100 nM, and in other embodiments less than or equal to about 2 〇 _, and in other embodiments less than or equal to about 5 nM, and in some embodiments small It is equal to about 2 nM. For each of the reference compounds in Table 3 below, the following Ec5 is provided. Table 3: References (7) Information __化如勿____ec5〇

5"HT 0.5 nM5"HT 0.5 nM

D01 0.5 nMD01 0.5 nM

mCPP 5.4 nM 本文件中所引述或說明之各個專利案、專利申請案及 5公告案之全體揭示係以引用方式併入此處。雖然已經提示多個本發明之實施例，顯然本發明之基、、且成可經修改來提供利用本發明化合物及本發明方法之其匕實施例。因此須暸解本發明之範圍係由隨附之申請專利乾圍，而非由已經呈現供舉例說明之特定實施例所限。 71 200823187 I：圖式簡單說明3 (無）【主要元件符號說明】 (無） 72mCPP 5.4 nM The entire disclosures of each of the patents, patent applications and 5 publications cited or illustrated in this document are hereby incorporated by reference. While a plurality of embodiments of the invention have been shown, it is apparent that the invention may be modified and provided to exemplify the use of the compounds of the invention and the methods of the invention. Therefore, the scope of the invention is to be construed as being limited by the appended claims 71 200823187 I: Simple description of the diagram 3 (none) [Description of main component symbols] (none) 72

Claims

200823187 十、申請專利範圍： 1. 一種I化合物： R2200823187 X. Patent application scope: 1. A compound I: R2

5 或其藥學上可接受之鹽，其中：各個基分別表示單鍵或雙鍵； R1為氫、低碳烷基、-S(0)20H或-C(0)R、其中R為氫或視需要可經以-OH取代之低碳烷基； A為-N(H)_、-N(OH)-或-0-; 10 R2為氫或-OH ; R3及R4各自分別為氫、鹵素、甲基、甲氧基或-OH ; Re為氫或-OH&Rd為氫或-OH，或Re及Rd與其附接之碳共同形成羰基部分； Re為氫或-OH ; 15 各個Rx分別為氫、鹵素、-CF3或低碳烷基，但兩個 Rx基非同時為氫；各個Ry分別為氫或-OH ; m為1、2或3 ;以及 η為1或2 ; 20 限制條件為適用下列條件中之至少一者：（a) R2、 73 200823187 R3、R4、Ra、Rb、Rc、RjRy 中之一者為 _0H ;⑻ Rl 為-C(〇)R ; (c) R、-S(〇)2〇h ;或⑷ R、Rb或RlRd 中之至少一對連同至其附接之碳共同形成為羰基部分。 2·如申請專利範圍第i項之化合物，其中Ri為氫。 3·如申請專利範圍第2項之化合物，其中R3為氣或氟。 4·如申請專利範圍第3項之化合物，其中各個rx分為鹵素或-CF3。 5·如申請專利範圍第4項之化合物，其中R2及R4各自分別為-OH。 10 6 .申請專利範圍第1項之化合物，其中該化合物具有式 la、I-b、I-c、:Or a pharmaceutically acceptable salt thereof, wherein: each group represents a single bond or a double bond; R1 is hydrogen, lower alkyl, -S(0)20H or -C(0)R, wherein R is hydrogen or If desired, a lower alkyl group may be substituted with -OH; A is -N(H)_, -N(OH)- or -0-; 10 R2 is hydrogen or -OH; each of R3 and R4 is hydrogen, Halogen, methyl, methoxy or -OH; Re is hydrogen or -OH&dR is hydrogen or -OH, or Re and Rd together with the carbon to which they are attached form a carbonyl moiety; Re is hydrogen or -OH; 15 each Rx Respectively hydrogen, halogen, -CF3 or lower alkyl, but the two Rx groups are not hydrogen at the same time; each Ry is hydrogen or -OH; m is 1, 2 or 3; and η is 1 or 2; 20 The condition is that at least one of the following conditions is applicable: (a) R2, 73 200823187 One of R3, R4, Ra, Rb, Rc, RjRy is -0H; (8) Rl is -C(〇)R; (c) R, -S(〇)2〇h; or (4) at least one of R, Rb or RlRd together with the carbon to which it is attached form a carbonyl moiety. 2. A compound as claimed in claim i, wherein Ri is hydrogen. 3. A compound of claim 2, wherein R3 is gas or fluorine. 4. A compound of claim 3, wherein each rx is classified as halogen or -CF3. 5. The compound of claim 4, wherein each of R2 and R4 is -OH. 10 6. The compound of claim 1 wherein the compound has the formula la, I-b, I-c,:

或其藥學上可接受之鹽。如申請專利範圍第1項之化合物，其中該化合物具有式 Η 或 i-h : 74 200823187 R2 R2Or a pharmaceutically acceptable salt thereof. The compound of claim 1, wherein the compound has the formula i or i-h : 74 200823187 R2 R2

NHR1 或其藥學上可接受之鹽。NHR1 or a pharmaceutically acceptable salt thereof.

8.如申請專利範圍第1項之化合物，其中該化合物具有式 II-a、II-b、II-c、或 ΙΙ-d : R2 R28. The compound of claim 1, wherein the compound has the formula II-a, II-b, II-c, or ΙΙ-d: R2 R2

R2R2

NH2 R2NH2 R2

或其藥學上可接受之鹽。 9. 一種式III化合物： 75 10 200823187 R2Or a pharmaceutically acceptable salt thereof. 9. A compound of formula III: 75 10 200823187 R2

或其藥學上可接受之鹽，其中：各個=基分別表示單鍵或雙鍵； C 5 R1 為氫、-OH、-OGlu、-Glu、-C(0)Glu或-C(0)0Glu、 -C(〇)R，其中R為氫或視需要可經以_〇h取代之低碳烷基； A為-NH、-N(OH)-或-0-; R2為氮、-OH或-OGlu ; 10 R3及R4各自分別為氫、鹵素、甲基、甲氧基、-OH 或，OGlu ; C. R及^各自為氫、-OGlu、-OH或與其附接之碳共同形成羰基部分； Re為氫、-OGlu 或-OH ; 15 各個Rx分別為氫、鹵素、-CF3，或低碳烷基，但限制條件為Rx基不可同時為氫；各個R5分別為氫、-OGhi或-OH ; rn為1、2或3 ;以及 η為1或2 ; 2〇但限制條件為Rl、R2、R3、R4、R5、RC、Rd及" 76 200823187 之至少一者含有Glu或Glucos。 10. 如申請專利範圍第9項之化合物，其中R1為-Glu、 -C(o)Glu或-C(0)0Glu。 11. 如申請專利範圍第9項之化合物，其中R2為-OH及R4為 5 氫；R2為氫及R4為-OH ;或R2為-OGlu及R4為氫。 12. 如申請專利範圍第9項之化合物，其中該化合物具有式 IV ： HOOr a pharmaceutically acceptable salt thereof, wherein: each = group represents a single bond or a double bond, respectively; C 5 R1 is hydrogen, -OH, -OGlu, -Glu, -C(0)Glu or -C(0)0Glu , -C(〇)R, wherein R is hydrogen or, if desired, a lower alkyl group substituted with _〇h; A is -NH, -N(OH)- or -0-; R2 is nitrogen, -OH Or -OGlu ; 10 R3 and R4 are each hydrogen, halogen, methyl, methoxy, -OH or OGlu; C. R and ^ are each hydrogen, -OGlu, -OH or together with the carbon to which they are attached a carbonyl moiety; Re is hydrogen, -OGlu or -OH; 15 each Rx is hydrogen, halogen, -CF3, or lower alkyl, but the restriction is that the Rx group is not hydrogen at the same time; each R5 is hydrogen, -OGhi Or -OH; rn is 1, 2 or 3; and η is 1 or 2; 2〇, but the constraint is Rl, R2, R3, R4, R5, RC, Rd, and " 76 200823187 contains at least one of Glu or Glucos. 10. The compound of claim 9, wherein R1 is -Glu, -C(o)Glu or -C(0)0Glu. 11. A compound according to claim 9 wherein R2 is -OH and R4 is 5 hydrogen; R2 is hydrogen and R4 is -OH; or R2 is -OGlu and R4 is hydrogen. 12. A compound as claimed in claim 9 wherein the compound has the formula IV: HO

10 或其藥學上可接受之鹽。 13.如申請專利範圍第9項之化合物，其中該化合物具有式 IV、IV-a、IV_b 或 IV-c :10 or a pharmaceutically acceptable salt thereof. 13. A compound according to claim 9 wherein the compound has the formula IV, IV-a, IV_b or IV-c:

77 20082318777 200823187

或其藥學上可接受之鹽。 14.如申請專利範圍第9項之化合物，其中該化合物具有式Or a pharmaceutically acceptable salt thereof. 14. The compound of claim 9, wherein the compound has the formula

或其藥學上可接受之鹽。 15. —種組成物，含有如申請專利範圍第1項之化合物，及 10 —種或多種藥學上可接受之載劑、稀釋劑或賦形劑。 16. —種於一病人治療選自於下列中之至少一種病症之方法：精神病、焦慮症、躁鬱症、憂鬱症、經前症候群 (PMS)、經前煩躁症(PMDD)、飲食障礙、膀胱控制障礙、物質濫用或物質依賴性、認知障礙、ADD或ADHD、衝 15 動障礙、成瘾障礙、男性或女性性功能異常、疼痛、行 78 200823187 動障礙或運動障礙、巴金森氏病、癲癇、偏頭痛、慢性倦怠症候群、神經性厭食症、睡眠障礙、緘默症、或一種或多種中樞神經系統缺陷，該方法包含對該病人投予治療有效量之如申請專利範圍第1項之化合物或包含如 5 申請專利範圍第1項之化合物之組成物。 17. 如申請專利範圍第16項之方法，其中該精神病症為精神 ***、妄想型精神***症、解離型精神***症、緊張型精神***症及未分化型精神***症、精神***樣病症、 ***情感病症、妄想症、物質誘發精神病症、未明示之 10 精神病症；左多巴誘發精神病；阿茲海默氏痴呆所引發之精神病；巴金森氏病所引發之精神病；或路易體病所引發之精神病。 18. 如申請專利範圍第16項之方法，其中該病症為躁鬱症，且係選自於I型躁鬱症、II型躁鬱症、循環型躁鬱症；兩 15 極性躁症、痴呆、帶有精神特徵之鬱症、或於兩極性鬱症與兩極性躁症間循環。 19. 如申請專利範圍第16項之方法，其中該憂鬱症為重度憂鬱症、季節型情感症、心情惡劣症、物質誘發情緒障礙、未明示之憂鬱症、治療抗性憂鬱症、重度憂鬱發作。 20 20.如申請專利範圍第16項之方法，其中該認知障礙為學習障礙。 21. 如申請專利範圍第16項之方法，其中該病人係接受肥胖之治療。 22. 如申請專利範圍第16項之方法，其中該病人係接受ADD 79 200823187 或ADHD之治療。 23.如申請專利範圍第16項之方法，其中該物質濫用或物質依賴性係屬於娛樂性物質、藥理作用劑、安神劑、興奮劑、鎮定劑或禁藥之濫用或依賴性。 5 24.—種治療選自於精神***、肥胖、躁鬱症及憂鬱症中之至少一種病症之方法，包含對該病人投予治療有效量之如申請專利範圍第15項之組成物。 25.—種化合物，其係選自於下列所組成之組群：Or a pharmaceutically acceptable salt thereof. 15. A composition comprising a compound of claim 1 and 10 or more pharmaceutically acceptable carriers, diluents or excipients. 16. A method of treating a patient selected from at least one of the following: psychosis, anxiety, bipolar disorder, depression, premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD), eating disorder, bladder Control disorders, substance abuse or substance dependence, cognitive impairment, ADD or ADHD, dysfunction, addiction disorder, male or female sexual dysfunction, pain, line 78 200823187 dysmotility or movement disorder, Parkinson's disease, epilepsy a migraine, chronic burnout syndrome, anorexia nervosa, sleep disorder, mutism, or one or more central nervous system defects, the method comprising administering to the patient a therapeutically effective amount of a compound as claimed in claim 1 or A composition comprising a compound as in item 1 of the 5th patent application. 17. The method of claim 16, wherein the psychiatric condition is schizophrenia, delusional schizophrenia, dissociative schizophrenia, tense schizophrenia, and undifferentiated schizophrenia, a schizophrenic disorder, Splitting affective disorder, delusional disorder, substance-induced psychotic disorder, unspecified 10 mental illness; left dopa-induced psychosis; psychosis caused by Alzheimer's dementia; psychosis caused by Parkinson's disease; or Lewy body disease The mental illness caused. 18. The method of claim 16, wherein the condition is bipolar disorder and is selected from the group consisting of type I bipolar disorder, type II bipolar disorder, circulatory bipolar disorder; two 15 polar snoring, dementia, and spirit A characteristic depression, or a cycle between bipolar depression and bipolar snoring. 19. The method of claim 16, wherein the depression is severe depression, seasonal affective disorder, mood disorder, substance-induced mood disorder, unexplained depression, treatment-resistant depression, severe depression episode . 20 20. The method of claim 16, wherein the cognitive impairment is a learning disorder. 21. The method of claim 16, wherein the patient is treated for obesity. 22. The method of claim 16, wherein the patient is treated with ADD 79 200823187 or ADHD. 23. The method of claim 16, wherein the substance abuse or material dependence is an abuse or dependence of an entertaining substance, a pharmacological agent, a tranquilizer, a stimulant, a tranquilizer or a banned drug. 5 24. A method of treating at least one condition selected from the group consisting of schizophrenia, obesity, bipolar disorder, and depression, comprising administering to the patient a therapeutically effective amount of a composition as set forth in claim 15 of the patent application. 25. A compound selected from the group consisting of:

I \I \

1-4 ,ΝΗ1-4, ΝΗ

1-5 ,ΝΗ1-5, ΝΗ

,NHs 1-6 OH, NHs 1-6 OH

1-7 OH1-7 OH

1-8 ,ΝΗ1-8, ΝΗ

NH, 80 200823187NH, 80 200823187

1-20 1-21 1-19 81 2008231871-20 1-21 1-19 81 200823187

1-251-25

1-261-26

或其藥學上可接受之鹽。 82 200823187 七、指定代表圖： (一）本案指定代表圖為：第（）圖。（無) (二) 本代表圖之元件符號簡單說明：八、本案若有化學式時，請揭示最能顯示發明特徵的化學式：Or a pharmaceutically acceptable salt thereof. 82 200823187 VII. Designation of representative representatives: (1) The representative representative of the case is: (). (None) (2) A brief description of the symbol of the representative figure: 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: