200406207 五 經濟部智慧財產局員工消费合作社印製 Α7 Β7 發明說明（1) 本發明相關於已知5-HT6受體拮抗劑用於治療肥 胖之應用。 肥胖是一種慢性疼病’且被認為有許多併發症。 其特徵為體重有增加趨勢’此為缺乏運動與攝入過量 高脂肪食物所造成的。肥胖會增加許多疾病之風險， 如高血壓、糖尿病、心臟病、中風、膽囊病變、乳 癌、前列腺癌與結腸癌。肥胖疾病影響了至少390〇 萬美國人（超過四分之一的成人與五分之一的孩童）° 每年肥胖至少造成美國300,00死亡人口增加，並耗損 國家經費超過1000億。 美國肥胖協會認為最有效的治療肥胖方法便是結200406207 5 Printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 Description of the Invention (1) The present invention relates to the application of a known 5-HT6 receptor antagonist for the treatment of obesity. Obesity is a chronic pain 'and is considered to have many complications. It is characterized by a tendency to gain weight. This is caused by lack of exercise and excessive intake of high-fat foods. Obesity increases the risk of many diseases such as high blood pressure, diabetes, heart disease, stroke, gallbladder disease, breast cancer, prostate cancer, and colon cancer. Obesity affects at least 3.9 million Americans (more than a quarter of adults and one fifth of children) ° Obesity causes at least 300,000 deaths in the United States each year, and consumes more than 100 billion state funds. The American Obesity Association believes that the most effective way to treat obesity is to end
S 合行為治療（即，改善飲食並增加運動量）與藥物治 療。有數種治療肥胖的藥物已經美國奋品藥物管理局 核准上市，其中作用不是抑制食慾，便是阻斷飲食吸 收。然而，其中有些治療會有健康上的副作用，如芬 氟拉明（fenfluramine)與芬他命(phentermine)之合併藥 物療法。 WO 02/08179 (Biovitrum AB)揭示了 一系列作為血 清素拮抗劑之芳基磺醯胺藥物，用以治療肥胖；其中 特別提及先前於WO 98/27081與WO 99/42465 (SmithKline Beecham pic)所揭示的 5_HT6 受體拮抗 劑。 國際專利申請案PCT/EP01/09927揭示一種新穎 的磺醯胺基藥物Ν-(3,5·二氣_2_甲氧基_苯基)_4_甲氧 -3 - 200406207 A7 _ B7 五、發明說明（2) 基喻嗉-1-基-苯磺醯胺，其為一種強效的5-HT6受 體拮抗劑。此化合物於PCT/EPO1/09927中係作為一 種治療或預防某些中樞神經系統疾病之藥物，如焦 慮、憂鬱、癲癇、妄想強迫症、偏頭痛、認知記憶失 調（如阿茲海默症、與年齡有關之認知退化與輕微之認 知損傷）、帕金森氏症、ADHD(注意力不足/過動症）、 睡眠失調（包括全天候節律干擾）、進食失調如厭食症 或暴食症、恐慌攻擊症、戒毒症狀如可卡因、酒精、 尼古丁、苯并二氮雜苯（benzodiazepine)、精神分裂 症、與脊椎受傷及/或腦部受傷有關的疾病，如水腦、 或某些胃腸（GI)疾病，如IBS (Irritable Bowel症候）。 此外，PCT/EP01/09927亦指出，此化合物特別用於治 療阿茲海默症、與年齡有關之認知退化、ADHD、憂 鬱及/或焦慮。 我們發現N-(3,5-二氯-I甲氧基-苯基甲氧基_ 3-哌嗪-1-基-苯磺醯胺具有抑制食慾之功效，並經由後 面實驗數據證實此藥物具有治療肥胖之藥效。 經濟部智慧財產局員工消費合作社印製 因此，本發明提供，就第一觀點而言，一種使用 N-(3,5-二氯-2-甲氧基-苯基）-4-甲氧基_3-哌嗪_丨_基_苯 磺醯胺以製造治療肥胖藥物之用途，該化合物如\ (I): " -4- 200406207 A7 B7 五、發明說明（3) ΗS combined behavioral therapy (ie, improved diet and increased exercise) and medication. Several drugs for obesity have been approved for marketing by the US Drug Administration, and their role is either to suppress appetite or to block dietary intake. However, some of these treatments have health side effects, such as the combination of fenfluramine and phentermine. WO 02/08179 (Biovitrum AB) discloses a series of arylsulfonamide drugs as serotonin antagonists for the treatment of obesity; among them, special mention is made of WO 98/27081 and WO 99/42465 (SmithKline Beecham pic) Revealed 5-HT6 receptor antagonists. International patent application PCT / EP01 / 09927 discloses a novel sulfonamide drug N- (3,5 · digas_2_methoxy_phenyl) _4_methoxy-3-200406207 A7 _ B7 V. Description of the Invention (2) The metaphor fluoren-1-yl-benzenesulfenamide is a potent 5-HT6 receptor antagonist. This compound is used in PCT / EPO1 / 09927 as a drug to treat or prevent certain central nervous system diseases, such as anxiety, depression, epilepsy, paranoid obsessive-compulsive disorder, migraine, cognitive memory disorders (such as Alzheimer's disease, Age-related cognitive degradation and mild cognitive impairment), Parkinson's disease, ADHD (inattention / hyperactivity disorder), sleep disorders (including all-weather rhythm disturbances), eating disorders such as anorexia or binge eating disorder, panic attack, Detox symptoms such as cocaine, alcohol, nicotine, benzodiazepine, schizophrenia, diseases related to spinal injuries and / or brain injuries, such as the hydrocephalus, or certain gastrointestinal (GI) diseases, such as IBS (Irritable Bowel syndrome). In addition, PCT / EP01 / 09927 states that this compound is particularly useful in the treatment of Alzheimer's disease, age-related cognitive degradation, ADHD, depression and / or anxiety. We found that N- (3,5-dichloro-Imethoxy-phenylmethoxy_ 3-piperazin-1-yl-benzenesulfonamide has an appetite-suppressing effect, and the drug was confirmed by subsequent experimental data It has the effect of treating obesity. It is printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs. Therefore, the present invention provides, in the first aspect, a method using N- (3,5-dichloro-2-methoxy-phenyl ) -4-methoxy_3-piperazine_ 丨 _yl_benzenesulfonamide to use in the manufacture of drugs for treating obesity, the compounds such as \ (I): " -4- 200406207 A7 B7 V. Description of the invention ( 3) Η
經濟部智慧財產局貝工消費合作社印製 (I) 或其醫藥上可接受之鹽類。 該式（I)化合物可形成酸添加鹽類。應可認知到這 裡所用的式（I)化合物鹽類應為醫藥上可接受的。適用 之醫藥上可接受鹽類為熟習此技術領域者所知的，包 括那些於J. Pharm. Sci·，1977, 66, 1-19中所述的，例 如，由無機酸如氫氣酸、氫漠酸、硫酸、破酸或填 酸；以及有機酸如丁二酸、順-丁烯二酸、醋酸、反-丁烯二酸、檸檬酸、酒石酸、苯甲酸、對-甲苯磺酸、 甲基磺酸或萘基磺酸所形成之酸添加鹽類。 該式（I)化合物較佳係為氫氣酸鹽或對-甲苯磺酸 鹽。 本發明範圍包含所有化學計量或非化學計量形式 之化合物。 該式（I)化合物係可以晶體或非晶體形式製備，若 為晶體形式，則可選擇性地為水合物或媒合物。本發 明範圍包含具化學計量之水合物，以及含有各種水含 量之化合物。 200406207 A7 B7 五、發明說明（4) 本發明更提供一種治療肥胖之方法，包含對需要 主體投以有效劑量之式（I)化合物，或其醫藥上可接受 鹽類。 當用於治療時，該式（I)化合物通常配製為標準醫 藥組合物。此種組合物亦可以標準步驟製備。 ，因此，本發明更進一步提供一種用於治療肥胖之 醫藥組合物，包含式（I)化合物或其醫藥上可接受鹽 類，以及一醫藥上可接受之載體。 本發明之醫藥組合物，其係適於室溫與大氣壓力 下混合製備，通常用於口服、非口服或直腸投藥，如 以藥錠、膠囊、口服液體製劑、粉末、顆粒、錠劑、 可重組粉末、可注射或滲入溶液或懸浮液或栓劑。較 佳為口服投藥組合物。 用於口服投藥之藥錠或膠囊可為單位劑量形式， 且可含一般輔藥，如黏著劑、填充劑、製錠潤滑劑、 粉碎劑，以及可接受濕潤劑。該藥錠可以一般已知製 藥方法包覆外衣。 經濟部智慧財產局員工消费合作社印製 口服液體製劑可為，如水溶液或油狀懸浮液、溶 液、乳液、糖漿或酏劑，或在使用前可與水或其他適 用載劑重組之乾燥產物。此種液體製劑可含一般添加 物，如懸浮劑、乳化劑、非水性載劑（其可包含食用 油）、防腐劑，以及，若有需要，一般香料或增色劑。 用於非口服投藥，液體單位藥劑係利用本發明化 合物或其醫藥上可接受之鹽類，以及一無菌載劑。該 -6- 200406207 Α7Printed by (I) or its pharmaceutically acceptable salts from the Shellfish Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. The compound of formula (I) can form acid addition salts. It will be recognized that the salts of the compounds of formula (I) used herein should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts are known to those skilled in the art, including those described in J. Pharm. Sci., 1977, 66, 1-19, for example, by inorganic acids such as hydrogen acid, hydrogen Desert acid, sulfuric acid, broken acid or filling acid; and organic acids such as succinic acid, maleic acid, acetic acid, trans-butenedioic acid, citric acid, tartaric acid, benzoic acid, p-toluenesulfonic acid, formic acid Addition salts of acids formed from sulfonic acid or naphthylsulfonic acid. The compound of formula (I) is preferably a hydrochloride or a p-toluenesulfonate. The scope of the invention encompasses all compounds in stoichiometric or non-stoichiometric form. The compound of formula (I) can be prepared in a crystalline or amorphous form, and if it is in a crystalline form, it can optionally be a hydrate or a vehicle. The scope of the invention includes stoichiometric hydrates, as well as compounds containing various water contents. 200406207 A7 B7 V. Description of the invention (4) The present invention further provides a method for treating obesity, which comprises administering an effective dose of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need. When used in therapy, the compound of formula (I) is usually formulated as a standard pharmaceutical composition. Such compositions can also be prepared by standard procedures. Therefore, the present invention further provides a pharmaceutical composition for treating obesity, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The pharmaceutical composition of the present invention is suitable for preparation at room temperature and atmospheric pressure, and is usually used for oral, parenteral or rectal administration, such as tablets, capsules, oral liquid preparations, powders, granules, tablets, Reconstituted powder, injectable or infiltrated into solution or suspension or suppository. More preferred is an oral administration composition. Tablets or capsules for oral administration may be in unit dosage form and may contain general adjuvants such as adhesives, fillers, tableting lubricants, pulverizers, and acceptable wetting agents. This tablet can be coated with a coating by a generally known pharmaceutical method. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economics Oral liquid preparations can be, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or dried products that can be reconstituted with water or other suitable carriers before use. Such liquid preparations may contain general additives such as suspending agents, emulsifying agents, non-aqueous carriers (which may include edible oils), preservatives, and, if necessary, general flavors or colorants. For parenteral administration, the liquid unit medicament uses the compound of the present invention or a pharmaceutically acceptable salt thereof, and a sterile carrier. The -6- 200406207 Α7
化合物，取決於所使用之載劑與濃度，可懸浮或溶解 於該載劑中。製備該溶液時，該注射用化合物為完 全溶解，且在填裝至適合的藥水瓶或安瓿前經過濾除 菌，之後密封。較佳的使用情況為，輔藥，如局部麻 醉劑、防腐劑與緩衝試劑係溶解於該載劑中。為了加 強其穩定性，該組合物在填充至藥水瓶之後可冷凍， 且其水分可於真空下移除。非口服懸浮液實質上係以 相同方法製備，惟該化合物係懸浮於該載劑中，而非 溶解於其中；且不能用過濾方式除菌。該化合物可在 懸浮於該無菌載劑前，以與乙烯氧化物接觸方式滅 菌。較佳的情況為，一介面活性劑與或濕潤劑可包含 於該組合物中，以幫助該化合物之分布。 經濟部智慧財產局貝工消费合作社印製 該化合物可含0·1至99%重，較佳為10至60%重 之活性物質，取決於該投藥方式。用於治療前述疾病 之化合物劑量係依據疾病嚴重程度、病患體重以及其 他類似因素之常用方式而不同。然而，一般指標適用 單位劑量可為1至1000毫克，更佳為5至600毫 克’如5至300毫克；此種單位劑量每天可投藥一 次以上’例如每日兩次或三次，如此每日總劑量範圍 約為5至1〇〇〇毫克·，且此種療法可延長至數週或數 月。 於此說明書中所引用的所有文獻，包括但不侷限 於專利或專利申請案，皆附於參考資料中，每一篇文 獻皆獨立、完全地附於參考資料中。 本發明係以下列各實例進行詳細說明： 說明1 1- (2-甲氧基苯基）-4·三氣乙酸基娘嗓（D1) 含1_ (2-甲氧基苯基）哌嗪（7 〇克）之二氯甲烷溶液 (30毫升）於室溫氬氣環境下加入授拌中含有三氣乙 醯氣（4.06毫升）之二氣甲烷溶液(4〇毫升）〇 25小時 以上。之後加入二異丙基乙胺（5·95毫升），整體續授 拌18小時。該反應混合物係以水（2x100毫升）清洗， 乾燥（Na2S04)，並濃縮以得油狀如標題產物（Dl)(u.2 克，91%)，MS : m/z(MH+) 337/339。 說明2 3-(4-三氣乙醢基哌嗪-1_基)-4-甲氧基苯磺醢氣（!)2) 經濟部智慧財產局貝工消费合作社印製 含1- (2-甲氧基苯基）-4-三氣乙醯基哌嗪（D1) (1〇 克）之二氣甲烧溶液（115毫升）加入冰冷的氣化續酸 (52毫升）0.3小時以上。置於0°C0.5小時之後，再置 於室溫1小時，之後將該溶液倒入冰水(500克）與二氣 甲烷（500毫升）混合液中，快速攪拌。分層之後，該有 機層以水洗（2x800毫升），乾燥（MgS04)，並濃縮，得 泡洙狀如標題產物（D2)(6克，46%)，MS ： m/z(MH+) 435/437 〇 說明3 -8- 200406207 A7 B7 五、發明說明（7) 1，S-二氣-2-甲氧基_3_硝基苯（D3) 溶於N，N-二甲基甲醯胺（1L)之碳酸鉀（99·7克）、 碘化甲烷（89毫升）以及2,4-二氣-6-硝基酚（含20%水） 之攪拌中懸浮液係於60°C加熱18小時。冷卻該反應 混合物，過濾出固體產物，並以二氯甲烷清洗（2x500 毫升）。該濾液係於真空下蒸發，得一油狀固體，並溶 於二氣甲烷（1.5升）中。該結合之有機層係以1M氫氧 化鈉（1·5升）清洗，續以水（1升）清洗。該有機層經乾 燥（MgS04)，並濃縮，得固體狀如標題產物（D2)(35.7 克，42%)，MS : m/z(M-iT) 221/223 〇 說明4 3,5-二氣-2-甲氧基-苯胺（D4) 經濟部智慧財產局貝工消費合作杜印製 強力攪拌之鐵粉(42·5克）與1，5-二氣_2_甲氧基-3-硝基苯（D3)(65克）之甲醇懸浮液(500毫升），與飽和 水性氯化銨溶液（700毫升）係回流加熱3小時。該混合 物經過濾，所得固體以二氣甲烷/甲醇（1:1)(4χ 150毫 升）清洗，續以二氣甲烷（4x200毫升）清洗。該濾液以 水（500毫升）稀釋，搖晃後分層。該水相層續以二氣甲 烷（500毫升）萃取，結合之有機層經乾燥（MgS〇4)，並 濃縮成油狀。該油狀產物係經矽膠管柱層析法純化， 以二氣甲烷/己烷（4:1)沖提，之後再以二氣甲烷沖提， 得油狀如標題產物（D4)(41.8克，74%)，MS : m/z(M+) 191/192 〇 ㈣9- 200406207 A7 B7 五、發明說明（8) 說明5 N-(3,5-二氣-2-甲氧基-苯基）·4-甲氧基-3-[4_(2,2,2-三 氣-乙醇基）·哌嗪-1-基】-苯磺醯胺（D5) 3,5-二氣-2_甲氧基-苯胺（D4)(41克）、3_(4_三氣 乙醯基哌嗪-1-基)-4-甲氧基苯磺醯氣（D2)(93克）與無 水吡啶（51.7毫升）溶於無水1，2-二氯乙烷（1.5升）中， 於氬氣環境下回流40小時。該反應混合物冷卻至室 溫，以1M鹽酸（1·5升）、水（2χ1·5升）清洗，乾燥 (MgS04)，並於真空下濃縮成油狀。該油狀物係於熱 乙醇（400毫升）中攪拌，得一乳狀固體如標題化合物 (D5)，經過濾後以冰冷乙醇清洗，續以乙醚清洗 (104.8 克，83%) 〇 lH (400MHz, CDC13) δ 1.84-L87 (2H? m), 3.08-3.10 (4Η，m)，3·64 (3Η，s)，3·73-3·76 (2Η，m)，3·93 (3Η，s)， 6·91 (1H，d，J 8·4Ηζ)，7.04 (1H，d，J 2·4Ηζ)，7·14 (1H， s)，7·30 (1H，d，J 2·4Ηζ)，7·53-7.57 (2H，m); MS : m/z(MH+) 590/592/594。 經濟部智慧財產局員工消费合作社印製 該化合物D2亦可以下列方法得到： 說明2a 3- (4·二氣乙酸基旅嗓-1-基)-4-甲氧基苯續酸氣 (D2a) -D1/D2之另一方法 三氣乙醯氣(2.04當量）滴加入含1- (2-甲氧基苯基) 旅嗪氣化氫之二氣甲烧溶液中，於二異丙基乙胺（1.02 -10- 經濟部智慧財產局員工消費合作社印製 200406207 A7 B7 五、發明說明（9) 當量）存在下。該混合物於20至22°C下攪拌30分 鐘，直至經HPLC分析得知反應完全為止。所得之混 合物以水洗，且該水層繼之以二氣甲烷萃取。結合之 有機層以水洗，以硫酸鈉乾燥，並以Celite (DiatomaceousEarth)過;慮。所得渡液係於-9至13°C加 入氯化硫酸100分鐘以上，並於13至21°C攪拌17.5 小時。所得溶液加入預冷（-1°C)二氣甲烷與加工水混 合物中，於0至18°C經ca. 2.5小時。分層後，水層 以二氣甲烷清洗，結合之有機層以水清洗。以線上過 渡管（in-line filter)過瀘、澄清後，該有機層回流加熱， 並以進出式蒸餾法，將二氣乙烷替換成甲苯。該甲苯 溶液之後冷卻至18eC，並以正庚烷稀釋，沉澱出產 物，其以離心法收集並乾燥，得如標題產物。 該化合物D4亦可以下列方法獲得。 說明4a 3,5-二氣-2-甲氧基-苯胺（D4a)—D3/D4之另一方法 2,4-二氯·6-硝基苯溶於DMF中，並加入二甲基磺 酸鹽（3.3當量）55分鐘以上，於碳酸鉀（〜2.8當量）存在 下，之後於35至40°C攪拌3小時。該混合物冷卻至 25°C，之後以正庚烷與氨水分層。下方水層續以正庚 烷再萃取，該二有機層合併，隨後以10%碳酸鉀水 溶液與水清洗。之後，該有機溶液於含有1%始之 碳，156 型，於 50% 鉛質玻璃（paste)，15 至 25°C，40The compound, depending on the carrier and concentration used, can be suspended or dissolved in the carrier. In preparing this solution, the compound for injection is completely dissolved and sterilized by filtration before filling into a suitable vial or ampoule, and then sealed. The preferred use situation is that adjuvants such as topical narcotics, preservatives and buffering agents are dissolved in the vehicle. To enhance its stability, the composition can be frozen after filling into a vial, and its moisture can be removed under vacuum. Non-oral suspensions are prepared essentially in the same way, except that the compound is suspended in the vehicle, rather than dissolved in it; it cannot be sterilized by filtration. The compound can be sterilized by contact with ethylene oxide before being suspended in the sterile vehicle. Preferably, a surfactant and / or wetting agent may be included in the composition to help the distribution of the compound. Printed by Shelley Consumer Cooperatives, Bureau of Intellectual Property, Ministry of Economic Affairs The compound may contain from 0.1 to 99% by weight, preferably 10 to 60% by weight of active substance, depending on the method of administration. The dosage of the compound used to treat the aforementioned diseases will vary depending on the severity of the disease, the patient's weight and other similar factors commonly used. However, the general indicator applies to a unit dose of 1 to 1000 mg, more preferably 5 to 600 mg, such as 5 to 300 mg; such a unit dose can be administered more than once a day, such as two or three times a day, so that the total daily Doses range from about 5 to 1000 mg ·, and this therapy can be extended to weeks or months. All documents cited in this specification, including but not limited to patents or patent applications, are attached to the reference materials, and each article is independently and completely attached to the reference materials. The present invention is described in detail with the following examples: Description 1 1- (2-methoxyphenyl) -4 · triacetic acid (1) containing 1- (2-methoxyphenyl) piperazine ( 70 g) of dichloromethane solution (30 ml) was added to a mixture of digas methane solution (4.06 ml) of digas methane solution (40 ml) in argon at room temperature for more than 25 hours. After that, diisopropylethylamine (5.95 ml) was added, and the whole was continuously stirred for 18 hours. The reaction mixture was washed with water (2x100 ml), dried (Na2S04), and concentrated to give an oily product such as the title product (Dl) (u. 2 g, 91%), MS: m / z (MH +) 337/339 . Note 2 3- (4-Trigas ethinopiperazin-1_yl) -4-methoxybenzenesulfonium (!) 2) Printed by the Shelley Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs 1- (2 -Methoxyphenyl) -4-trifluoroacetamidinyl piperazine (D1) (10 g) in a digas solution (115 ml) was added to ice-cold gasified continuous acid (52 ml) for more than 0.3 hours. After being left at 0 ° C for 0.5 hour, and then at room temperature for 1 hour, the solution was poured into a mixture of ice water (500 g) and methane (500 ml) and stirred rapidly. After the layers were separated, the organic layer was washed with water (2x800 ml), dried (MgS04), and concentrated to give a foamy product like the title product (D2) (6 g, 46%). MS: m / z (MH +) 435 / 437 〇 Description 3 -8- 200406207 A7 B7 V. Description of the invention (7) 1, S-Digas-2-methoxy-3_nitrobenzene (D3) Soluble in N, N-dimethylformamide (1L) potassium carbonate (99 · 7 g), methyl iodide (89 ml) and 2,4-digas-6-nitrophenol (containing 20% water) in a stirred suspension were heated at 60 ° C 18 hours. The reaction mixture was cooled, the solid product was filtered off and washed with dichloromethane (2x500 ml). The filtrate was evaporated under vacuum to give an oily solid, which was dissolved in methane (1.5 liters). The combined organic layer was washed with 1M sodium hydroxide (1.5 liters), and then washed with water (1 liter). The organic layer was dried (MgS04) and concentrated to give a solid as the title product (D2) (35.7 g, 42%). MS: m / z (M-iT) 221/223. Explanation 4 3,5-Di Gas-2-methoxy-aniline (D4) Cooperate with shellfish consumer of Intellectual Property Bureau of Ministry of Economic Affairs to print strong stirring iron powder (42 · 5g) and 1,5-digas_2_methoxy-3 -A methanol suspension (500 ml) of nitrobenzene (D3) (65 g) was heated under reflux with a saturated aqueous ammonium chloride solution (700 ml) for 3 hours. The mixture was filtered, and the resulting solid was washed with methane / methanol (1: 1) (4 x 150 mL), and then washed with methane (4 x 200 mL). The filtrate was diluted with water (500 ml), and the layers were separated after shaking. The aqueous layer was extracted with dichloromethane (500 ml), and the combined organic layers were dried (MgS04) and concentrated to an oil. The oily product was purified by silica gel column chromatography, and was eluted with digas methane / hexane (4: 1), followed by digas methane to obtain the oily product as the title product (D4) (41.8 g , 74%), MS: m / z (M +) 191/192 〇9- 200406207 A7 B7 V. Description of the invention (8) Description 5 N- (3,5-Digas-2-methoxy-phenyl) · 4-methoxy-3- [4_ (2,2,2-trigas-ethanolyl) · piperazin-1-yl] -benzenesulfonamide (D5) 3,5-digas-2_methyl Oxy-aniline (D4) (41 g), 3- (4_tris-gasketylpiperazin-1-yl) -4-methoxybenzenesulfonium (D2) (93 g) and anhydrous pyridine (51.7 Ml) was dissolved in anhydrous 1,2-dichloroethane (1.5 liters) and refluxed under argon for 40 hours. The reaction mixture was cooled to room temperature, washed with 1 M hydrochloric acid (1.5 liters), water (2 x 1.5 liters), dried (MgS04), and concentrated under vacuum to an oil. The oil was stirred in hot ethanol (400 ml) to obtain a milky solid such as the title compound (D5). After filtration, it was washed with ice-cold ethanol, and then washed with ether (104.8 g, 83%). , CDC13) δ 1.84-L87 (2H? M), 3.08-3.10 (4Η, m), 3.64 (3Η, s), 3.73-3 · 76 (2Η, m), 3.93 (3Η, s), 6.91 (1H, d, J 8 · 4Ηζ), 7.04 (1H, d, J 2 · 4Ηζ), 7.14 (1H, s), 7.30 (1H, d, J 2 · 4Ηζ) ), 7.53-7.57 (2H, m); MS: m / z (MH +) 590/592/594. The compound D2 printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs can also be obtained by the following methods: Description 2a 3- (4-Diacetic acid acetone-l-yl) -4-methoxybenzoic acid (D2a) -D1 / D2 Another method of trigas acetamidine (2.04 equivalents) is added dropwise to a digas methyl bromide solution containing 1- (2-methoxyphenyl) travelazine hydrogenated hydrogen in diisopropylethyl Amine (1.02 -10- printed by the Intellectual Property Bureau of the Ministry of Economic Affairs, Consumer Cooperatives, 200606207 A7 B7 V. Description of Invention (9) Equivalent). The mixture was stirred at 20 to 22 ° C for 30 minutes until the reaction was completed by HPLC analysis. The resulting mixture was washed with water, and the aqueous layer was then extracted with methane gas. The combined organic layers were washed with water, dried over sodium sulfate, and dried over Celite (Diatomaceous Earth). The obtained fluid was added with chloric sulfuric acid at -9 to 13 ° C for more than 100 minutes, and stirred at 13 to 21 ° C for 17.5 hours. The resulting solution was added to a mixture of pre-cooled (-1 ° C) digas methane and processed water, and ca. 2.5 hours at 0 to 18 ° C. After layering, the aqueous layer was washed with methane, and the combined organic layer was washed with water. After passing through an in-line filter and clarifying, the organic layer was heated under reflux, and dioxane was replaced with toluene by an in-and-out distillation method. The toluene solution was then cooled to 18 eC and diluted with n-heptane to precipitate the product, which was collected by centrifugation and dried to give the title product. The compound D4 can also be obtained by the following method. Explain another method of 4a 3,5-digas-2-methoxy-aniline (D4a) -D3 / D4 2,4-dichloro · 6-nitrobenzene is dissolved in DMF, and dimethylsulfonic acid is added Acid salt (3.3 equivalents) for more than 55 minutes in the presence of potassium carbonate (~ 2.8 equivalents), followed by stirring at 35 to 40 ° C for 3 hours. The mixture was cooled to 25 ° C and then water was layered with n-heptane and ammonia. The lower aqueous layer was re-extracted with n-heptane, and the two organic layers were combined, followed by washing with a 10% potassium carbonate aqueous solution and water. Afterwards, the organic solution contains 1% carbon, type 156, 50% lead glass (paste), 15 to 25 ° C, 40
-11- 200406207 A7 B7 五、發明說明（10) 至47psig氫氣下進行氫化反應，至該反應以HPLC分 析反應完全為止。該混合物以Celite(Diatomaceous Earth)過濾，之後減壓抽氣乾燥，得油狀如標題產 物0 該化合物D5亦可以下列方法獲得。 說明5a N-(3,5-二氣-2-甲氧基·苯基)-4-甲氧基-3·[4-(2,2,2-三 氣-乙醇基）-旅嗓-1-基】-苯續釀胺（D5a)—D5之另一 方法 經 濟 部 智 慧 財 產 局 貝 X 消 费 合 作 社 3-(4-三氣乙酿基旅唤-1-基）-4-甲氧基苯績酿氣 (D2)(1.0當量）懸浮於二氣甲烷(0.9倍體積）中，並加入 3,5-二氣-2-甲氧基-苯胺（D4)(1.5當量）。異奎林（1·5 當量）之二氣甲烷（0.2倍體積）溶液分四部份加入，並 維持其溫度於17至26°C。該混合物加熱至回流2小 時15分鐘。該溶劑以進出式蒸餾法換成乙醇（3.9倍體 積）。該懸浮液冷卻至0至5°C，並攪拌1小時。該標 題產物過濾分離出，以乙醇（1.5倍體積）清洗，並於 30至35°C下真空乾燥。 實例1 N-(3,5-二氣-2-甲氧基-苯基)-4-甲氧基-3-旅嗓-1-基·苯 磺醢胺（E1) 1M氫氧化鉀（609毫升）於5分鐘以上，室溫下加 -12- 200406207 A7 B7 五、發明說明（11) 入快速攪拌之N-(3,5_二氣-2-甲氧基-苯基）-4-甲氧基-3-[4-(2，2,2-三氣-乙醇基）-旅嗓-1-基]•苯確酿胺 (D5)(103克）之四氫呋喃溶液（1·5升）。攪拌18小時 後，該經攪拌之冰冷混合物，以鹽酸將pH值調整至 7.0，得乳霜狀固體如標題產物（E1)，經過濾後以水 (3x100毫升）清洗並乾燥（72.9克，94%)。 lH (400MHz, DMSO-D6/CD3〇D 4:1) ^2.95-3.15 (8H，m)，3·63 (3H，m)，3·82 (3H，s)，6·88 (lH，br d)5 7·0 (1H，br dd)，7·18 (1H，br d)，7·29 (1H，br d)，7·40 (1H， br dd); MS : m/z(MH+) 446/448 ° m.p.189 至 1900 實例2 N-(3,5-二氣-2-甲氧基-苯基)-4-甲氧基·3-旅嗓-1-基-苯 磺醢胺氣化氫（Ε2) 經濟部智慧財產局員工消費合作社印製 Ν-(3,5-二氣-2-甲氧基-苯基）-4-曱氧基-3-哌嗪-1-基-苯磺醯胺（E1) (20克）於室溫下懸浮於乙醇（200毫 升）中，且該經攪拌之懸浮液加入濃鹽酸（密度為 1.18，4.3毫升，1.1當量）1分鐘以上。所得產物於0 °C靜置24小時，得白色固體如標題產物（E2)(16.4 克，76%) 〇 lH (400MHz, DMSO-D6) ^3.18 (8H, br s), 3.53 (3H, s), 3·86 (3H，s)，7·12 (1H，d3 J 8.4Hz)，7·32 (1H，d，J 2·4Ηζ)，7·36 (1H，d5 J 2·4Ηζ)，7·40 (1H，d5 J 2.4Hz)， 7.46 (1H，dd，J 2·4, 8·4Ηζ), 9·4 (2H, br s)，10.0 (1H，br -13- 200406207 A7 B7 五 經濟部智慧財產局員工消费合作社印製 發明說明（I2) s); MS ·· m/z(MH+) 446/448。m.p.207-9〇c ο 實例3 N-(3,5-二氣·2-甲氧基-苯基)-4-甲氧基-3-哌嗪-1-基-苯 磺醢胺-4-甲苯磺酸鹽（E3) 4-曱苯磺酸鹽單水合物（10.7克，56毫莫耳）之乙 醇（75毫升）溶液，於回流溫度下加入一攪拌中的 (3,5-二氣-2-甲氧基苯基）-4-甲氧基-3-哌嗪-1-基-苯磺 醯胺（E1) (25克，56亳莫耳）乙醇懸浮液(400毫升）中。 所得澄清淡黃色溶液係攪拌冷卻。以過濾法收集該固 體產物，於室溫下乾燥，並減壓至重量穩定，得白色 結晶固體如標題產物（E3)(28克，81%)。 iH (400MHz，DMSO-D6) 5 2·29 (3H，s)，3.13(4H，br s)， 3·36(4Η，br s)，3.53 (3H，s)5 3·86 (3H，s)，7·12 (3H，m)， 7·33 (1H，d5 J 2·4Ηζ)，7.37 (2H， m)，7·48 (3H，m)， 8.68 (1H，br s)，10·12 (1H，s)。m.p.207 至 209°C。 實例4 10天犬類試驗iV-(3，S-二氣-2-甲氧基·苯基)-4·甲氧基-3-哌嗪-1_基-苯磺醢胺氣化氫對食慾抑制的影響 包含一公與一母之小獵犬群組投以口服W(3,5-二 氣-2-甲氧基-苯基)-4-甲氧基-3-哌嗪_1-基_苯磺醯胺氣 化氫（E2)之明膠膠囊，劑量為30毫克/公斤/日，共8 天。在第9天，劑量由30毫克/公斤/曰降低為20毫 -14- 200406207 A7 B7 五、發明說明（13) 克/公斤/日，此劑量維持至第13天，以評估E2較低 劑量之影響。 結果顯示，當劑量為30毫克/公斤/日，公犬與母 犬在第3天食慾分別降至消耗基準線之63%與91%。 再經過五天，繼續由48%降至27%(公），以及由86% 降至12%(母）。此結果與在第1日至第9日之體重觀 察結果相一致。在第9天將劑量由30毫克/公斤/日降 至20毫克/公斤/曰後，此低劑量又持續投藥五天，公 犬與母犬之食物消耗量分別增加為63%與42%(消耗基 準線）。 實例5 28天犬類試驗iV-(3,5-二氣-2-甲氧基-苯基甲氧基-3-哌嗪-1_基_苯磺醯胺-4-甲苯磺酸鹽對食慾抑制的影 響 包含三公與三母之小獵犬群組一日一次投以^ (3,5-二氣-2-甲氧基-苯基)-4-甲氧基-3-旅唤-l-基-苯續 醯胺-4-甲苯磺酸鹽（E3)之明膠膠囊，劑量為20毫克/ 公斤/日，共28或29天。由於食物消耗量大減與體重 大量減輕，在第11天將E3劑量減至15毫克/公斤/ 日，並有兩天不投藥。 結果顯示，當劑量為20/15毫克/公斤/日食，大部 分動物體重減輕達12% 〇在不投藥期間，動物們體重 回升或維持當時體重（以維持正常食物消耗量）。所有 -15--11- 200406207 A7 B7 V. Description of the invention (10) The hydrogenation reaction is performed under 47 psig of hydrogen until the reaction is completed by HPLC analysis. The mixture was filtered through Celite (Diatomaceous Earth), and then dried under reduced pressure to obtain an oily product like the titled product. The compound D5 was also obtained by the following method. 5a N- (3,5-Digas-2-methoxy · phenyl) -4-methoxy-3 · [4- (2,2,2-trigas-ethanolyl) -Travel throat- 1-based] -Benzylamine (D5a)-Another method of D5, Intellectual Property Bureau of the Ministry of Economic Affairs, Shellfish X Consumer Cooperatives, 3- (4-Three Gas Ethyl Ethyl-1-Hexyl) -4-methoxy Benzene gas (D2) (1.0 equivalent) was suspended in digas methane (0.9 times volume), and 3,5-digas-2-methoxy-aniline (D4) (1.5 equivalent) was added. Isoquilin (1.5 equivalents) of two-gas methane (0.2 times volume) solution was added in four portions and the temperature was maintained at 17 to 26 ° C. The mixture was heated to reflux for 2 hours and 15 minutes. The solvent was replaced with ethanol (3.9 times volume) by in-and-out distillation. The suspension was cooled to 0 to 5 ° C and stirred for 1 hour. The title product was isolated by filtration, washed with ethanol (1.5 times the volume), and dried under vacuum at 30 to 35 ° C. Example 1 N- (3,5-Digas-2-methoxy-phenyl) -4-methoxy-3-bromo-1-yl · benzenesulfonamide (E1) 1M potassium hydroxide (609 Ml) over 5 minutes, add -12-200406207 A7 B7 at room temperature V. Description of the invention (11) Add N- (3,5_digas-2-methoxy-phenyl) -4- Tetrahydrofuran solution of methoxy-3- [4- (2,2,2-trifluoro-ethanol-based) -bran-1-yl] • Benzamine (D5) (103 g) (1.5 liters) ). After stirring for 18 hours, the stirred ice-cold mixture was adjusted to pH 7.0 with hydrochloric acid to obtain a cream-like solid such as the title product (E1). After filtration, it was washed with water (3x100 ml) and dried (72.9 g, 94 %). lH (400MHz, DMSO-D6 / CD3〇D 4: 1) ^ 2.95-3.15 (8H, m), 3.63 (3H, m), 3.82 (3H, s), 6.88 (lH, br d) 5 7 · 0 (1H, br dd), 7.18 (1H, br d), 7.29 (1H, br d), 7.40 (1H, br dd); MS: m / z (MH + ) 446/448 ° mp189 to 1900 Example 2 N- (3,5-Digas-2-methoxy-phenyl) -4-methoxy-3-propane-1-yl-benzenesulfonamide Hydrogen gas (E2) Printed by N- (3,5-Digas-2-methoxy-phenyl) -4-methoxy-3-piperazin-1-yl -Sulfasalazine (E1) (20 g) was suspended in ethanol (200 ml) at room temperature, and the stirred suspension was added with concentrated hydrochloric acid (density 1.18, 4.3 ml, 1.1 equivalents) for more than 1 minute. The obtained product was left to stand at 0 ° C for 24 hours, and a white solid such as the title product (E2) (16.4 g, 76%) was obtained. OH (400 MHz, DMSO-D6) ^ 3.18 (8H, br s), 3.53 (3H, s ), 3.86 (3H, s), 7.12 (1H, d3 J 8.4Hz), 7.32 (1H, d, J 2 · 4Ηζ), 7.36 (1H, d5 J 2 · 4Ηζ), 7 · 40 (1H, d5 J 2.4Hz), 7.46 (1H, dd, J 2 · 4, 8 · 4Ηζ), 9 · 4 (2H, br s), 10.0 (1H, br -13- 200406207 A7 B7 five Printed Invention Description (I2) s); MS ·· m / z (MH +) 446/448. mp207-9〇c ο Example 3 N- (3,5-Digas · 2-methoxy-phenyl) -4-methoxy-3-piperazin-1-yl-benzenesulfonamide-4 -Toluenesulfonate (E3) 4-Benzenebenzenesulfonate monohydrate (10.7 g, 56 mmol) in ethanol (75 ml), add a stirred (3,5-di) at reflux temperature Gas-2-methoxyphenyl) -4-methoxy-3-piperazin-1-yl-benzenesulfonamide (E1) (25 g, 56 mol) in ethanol suspension (400 ml) . The resulting clear light yellow solution was cooled with stirring. The solid product was collected by filtration, dried at room temperature, and decompressed to a stable weight to obtain a white crystalline solid such as the title product (E3) (28 g, 81%). iH (400MHz, DMSO-D6) 5 2 · 29 (3H, s), 3.13 (4H, br s), 3.36 (4Η, br s), 3.53 (3H, s) 5 3.86 (3H, s ), 7 · 12 (3H, m), 7.33 (1H, d5 J 2 · 4Ηζ), 7.37 (2H, m), 7.48 (3H, m), 8.68 (1H, br s), 10 · 12 (1H, s). m.p.207 to 209 ° C. Example 4 10-day canine test iV- (3, S-digas-2-methoxy · phenyl) -4 · methoxy-3-piperazine-1-yl-benzenesulfonamide The effects of appetite suppression include oral administration of W (3,5-digas-2-methoxy-phenyl) -4-methoxy-3-piperazine_1- Gelatin capsules based on benzylsulfazone hydrogenated hydrogen (E2) at a dose of 30 mg / kg / day for 8 days. On the ninth day, the dose was reduced from 30 mg / kg / day to 20 milliseconds. 2004-06207 A7 B7 V. Description of the invention (13) g / kg / day, this dose was maintained until the thirteenth day to evaluate the lower dose of E2 Influence. The results showed that when the dose was 30 mg / kg / day, the appetite of male dogs and female dogs decreased to 63% and 91% of the baseline consumption on the third day, respectively. After another five days, it continued to fall from 48% to 27% (male) and from 86% to 12% (parent). This result is consistent with the results of body weight observation on the 1st to 9th days. After the dose was reduced from 30 mg / kg / day to 20 mg / kg / day on the ninth day, the low dose was continued for another five days, and the food consumption of male and female dogs increased by 63% and 42%, respectively ( Consumption baseline). Example 5 28-day canine test iV- (3,5-Digas-2-methoxy-phenylmethoxy-3-piperazin-1_yl_benzenesulfonamide-4-toluenesulfonate pair The effects of appetite suppression include a group of three male and three female beagles administering (3,5-digas-2-methoxy-phenyl) -4-methoxy-3- brigade-l once a day -Gly-benzoxamine-4-toluenesulfonate (E3) gelatin capsules at a dose of 20 mg / kg / day for 28 or 29 days. Due to the significant reduction in food consumption and weight loss, The dose of E3 was reduced to 15 mg / kg / day and was not administered for two days. The results showed that when the dose was 20/15 mg / kg / day, most animals lost 12% of their body weight. Animals gain weight or maintain their current weight (to maintain normal food consumption). All -15-
經濟部智慧財產局員工消費合作社印製 200406207 A7 B7 五、發明說明（14) 投以20/15毫克/公斤/日之動物，在第一周食物正常供 給5小時情況下，食物消耗量皆減少（完全無食懲或低 攝食量，<50%)。而在未投藥期間食物消耗量為正 常。Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, 200406207 A7 B7 V. Description of the invention (14) The food consumption of animals that were fed at 20/15 mg / kg / day for 5 hours in the first week reduced food consumption (No food at all or low food intake, < 50%). Food consumption was normal during non-administration.
.經濟部智慧財產局貝工消費合作社印製Printed by the Shellfish Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs