TW200398B - - Google Patents
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- TW200398B TW200398B TW080102458A TW80102458A TW200398B TW 200398 B TW200398 B TW 200398B TW 080102458 A TW080102458 A TW 080102458A TW 80102458 A TW80102458 A TW 80102458A TW 200398 B TW200398 B TW 200398B
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- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
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- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
- C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
- C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D319/20—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring with substituents attached to the hetero ring
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Description
經濟部中夬標準局員工消费合作社印餐 200398 , A 6 ___B_6 五、發明説明(1 ) 本發明僳有開一些旋光性伸烷二氣基苯衍生物,此衍 生物充作抗焦廉劑之用途,以及含有一種衍生物作為主要 成份之藥學组成物。 f 由於目前社會條件及環境的快速變遷,人們對精神焦 慮更加關心重視,已知苯並二氮雜革可用作為治療此類精 神焦慮的抗焦盧劑,最近已發展出N — {4 一〔4 一 2_ 嘧啶基)一1一呢嗪基〕丁基}一1,1一環戊烷二乙醛 胺鹽酸鹽(Buspirone)作為新穎的抗焦慮劑,其具有獨特 的作用模式,與苯並二氮雜革並不相同。然而醫類領域仍 希望提供更多具更有效的抗焦盧活性的化合物。 當前已知化式1B所示之伸烷二氧基苯衍生物可作為抗 高血壓剤:
其中R是氫或低级烷基;X是氧或伸甲基;P是1至3的 整數;及q是3或4 (日本專利公告1 08088/ 1982, 219114/1983及 USP4, 684, 739),然而未知有上述化合物( Μ)之光學異構物的存在,且亦不知部份光學異構物具有 抗焦盧活性。 吾人發現待殊的一群化合物(B)之光學異構物及其 ...........-.......................................裝...........................訂........................線 (請先閲讀背面之注意事項再填寫本頁) 甲 4(21(1X297公贷)80· 5. 20,000張出) -3 - 200398 A 6 B 6 五、發明説明(2 ) 酸加成鹽具有優良的抗焦盧活性,所以,本發明係有關化 式(I)之化合物,及其酸加成鹽:
I) 其中m是整數2至5,且η是整數1至3。 本發明係有關一用以治療焦慮的藥學組成物,其含有 一種化式(I)之化合物及其鹽作為主要成份: 〆〇 (CH2)n -0(CH2)mNHCH2
:X) (II) 經濟部中央標準局員工消費合作社印製 其中m和n如上所定義。 本發明的另一目的是要提供治療焦慮症的方法,此方 法包含投服有效量之化式(I)及(I)的化合物及其鹽 Ο 化式(I)或(I)之化合物中較佳的是m為3, 4 或5,且η是1, 2或3者,更好的是n=l者。 代式(I)或(H)之化合物的酸加成鹽的例子是由 無機酸(如鹽酸,氫溴酸,硫酸,磷酸和硝酸)或有機酸 (如醋酸,琥珀酸,己二酸,丙酸,酒石酸,富馬酸,馬 來酸,草酸,檸樣酸,苯甲酸,甲苯磺酸及甲磺酸)形成 之酸加成鹽。 ............·.......................................裝................一..........訂....................…線- (請先閲讀背面之注意事項再填寫本頁) 中 4(210X297公釐)80_ 5. 20,000張出〉 4 200398 A6 B 6 五、發明説明(3 ) 化式(I)化合物可由任何一種習知的方法製得,例 如,化合物可依下列反應流程製得: 〇 (ch2)
—0(CH2)mNH2 (IV) 2〇s〇2^Q-ch: (CH2)n © +
(請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印51 其中m和n如上所定義。 起始化合物(IV)可由習知之合成一级胺的方法製 得,例如 Angewandte Chemie,8 0 986(1968 )所述之方法。另一個起始化合物(V)可依,例如,J_ 〇 u na1 of Medicinal Chemistry,2 0 8 8 0 ( 1977)的内容裂得。 本發明之化合物(I)可使用起始化合物(IV)及 (V)由習知之製備二级胺的方法製得。例如,化合物( V)與〇. 5_1 ◦莫耳當量化合物(IV)在一 10至 150¾下,在無或有溶劑(如芳族烴(如苯,甲苯,二 甲苯),醚(如乙醚,四氫呋喃(THF),二噁烷), 飽和烴(如正己烷),乙睛,二甲基甲醛胺,N —甲基吡 咯烷酮,二甲亞砜等)的存在下,在〇· 5至10莫耳當 量無機鹸(如碩酸鉀,碩酸納,氫氧化鉀,氫化納等)或 甲 4 ⑵0X297公釐)80. 5. 20,000張(H) - 5 - A6 B 6 200398 五、發明説明(4 ) 有機驗(如三乙胺,吡啶,二異丙基乙胺等)的存在下, 反應3 ◦分至28小時,接著純& (如矽謬層析或再結晶 )所得的産物。 化式(E)的化合物可輕易地依,例如, USP 4, 684, 739掲示的步驟製得。 本發明中,化合物(I)或(I)與5 —羥基色胺( 5 — HT)受體,待別是5 — ΗΤι λ受體結合,細節將詳 述於下文之實施例中。 吾人均知可與5—HTu受匾柑結合的化合物具有抗 焦慮活性.下列化合物是為已知之5 — HTu受體結合化 合物:N {4 -〔4 一(2 -嘧啶基)一 1 一哌嗪基基〕 丁基} 一1, 1 一環戊烷二乙醯胺鹽酸鹽(811”丨1*〇1^)(忖- aunyn-Schiniedeberg's Arch. Pharmako1 . , 3 2 8. 4 6 7, 1985) , 2 - {4一〔4 一 (2 - 嘧啶基) 一 1 一哌嗪基〕丁基} — 1, 2 —苯並異1«唑一 3 — (2 {1)酮一1,1一二氣基脱氛化氫(103&01'丨〇1^),及3& α , 4 β , 7 β , 7ayS — 六氫一2— (4 一 C 4 - (2 一嘧啶基)一 1 一哌嗪基〕丁基} 一4, 7 —甲烷一1H 一異吲跺一 1, 3 — (2H)二酮二樺樣酸鹽(314 — 3 9 9 7) (Naunyn-Schmiedeberg * s Arch. Pharmakol ., 3 2 8. 4 6 7 , 1 9 8 5; Japan. J· Pharmacol t 4 5 ,493, 1987)。本發明之化合物(I)或(I) 與上述的已知化合物類似亦具有5 — Η T ^受體活性,可 作為抗焦慮劑。因此•本發明之化合物(I)或(I)是 ......................-.............................裝...........................訂...................^......線 (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局貝工消費合作社印製 甲 4(21(丨X?97公犛)80· 5· 20,000張(H) -6 一 200398 A 6 B 6 經濟部中央標準局員工消費合作社印製 五、發明説明(5 ) 用於治療或預防急性或慢性焦盧症候群,包含與空曠恐懼 症有關之恐慌症,群居恐懼症,無知恐懼症,空曠恐懼症 ,強迫性失調症(強迫性精神官能症),及創傷後的抑壓 失調症;早發性裔呆症;躁管精神病厂偏頭痛等。 本發明之化合物可以任何一種習知的方法投服給患者 ,然而較佳的是經口投服_非經腸投服,例如,皮下,靜 脈内或肌下投服。 化合物的毎日劑量可依持定患者的年龄,體重或一般 健康狀況,是牵有其他一起投服之活性試劑,投服頻率, 預期的治療功效等而變化。 然而,通常可為0. 001 — 10. 0毫克/公(體 重),較佳的是0. 05 — 3. 0毫克/公斤(體重), 每曰藥劑可以單劑或多重劑型投服。 本發明之化合物傜調製成口服用錠劑,膠囊,粉劑, 溶液,酊劑,及非經腸投服用的無菌注射溶液或懸浮液。 本發明之藥學諝和物可含有無毒性,固體或液體之藥學上 可接受的載體。 本發明之一典型的調和物是硬或軟膠膠囊,調和物亦 可為含有活性成份以及有或型佐劑之錠劑或無菌包裝的粉 劑。 膠囊,錠劑或粉劑通常含有約5—95,宜為經25 一 9 ◦重量%本發明之活性化合物,較佳的是,諝和物製 成每個單位劑型含有約0. 5至500毫克,宜約1至 1 0 0毫克的活性化合物者。 .....................-.............................裝……....................訂...........................線 (請先閲讀背面之注意事項再填寫本頁) 甲 4(21(丨X297公蝥)80. 5. 20,000張(H) -7 - A 6 B 6 200398 五、發明説明(6 ) (請先閲讀背面之注意事項再填寫本頁) 液體載鼸的待殊例子包含無菌的水,石油,植物或動 物性合成或天然的油,例如,花生油,大豆油,礦油,或 芝蔴油。較佳的液體載體包含生理食鹽水,葡萄糖或蔗糖 類似物的水溶液,及甘醇,如丙二醇或乙二醇。使用生 理食鹽水製得的注射溶液可含有約0. 5至2 0,宜為約 1至1 0重量%活性成份。 當諝和物是為口服液型式時,其可為含有約0. 5至 1 0重董%活性成份以及液體助劑如香料,糖漿,藥學微 膠粒之懸浮液或糖漿。 以下之實例只用以說明本發明之範圍,決不用以限制 本發明的範圍。 奮例1 5 —〔3 — { (2S) — (1, 4 一苯並二噁烷一 2 —基 甲基)胺基}丙氣基〕一 1, 3 —苯並二噁醇鹽酸鹽(表 1中之化合物1 ) 經濟部中央標準局員工消費合作社印裝 5 —(3—胺基丙氣基)一 1,3 —苯並二嚼醇( 5. 86克)和(2R) — 2 —甲苯磺醛氧基甲基一 1, 4—苯並二稱院(Journal of Medicinal Chemistry,20 ,880,1977) (3. 2 ◦克)溶於乙腈( 100毫升)中,加入三乙胺(2. 77毫升)後混合物 在回流情況下加熱12小時,反應完成後,在反應混合物 中加水,並以氛仿萃取,以水沖洗氯仿萃取液,以無水硫 γ 4 (2丨丨丨><297公釐)80. 5_ 20,000張(H) -8 - 經濟部中央榣準局员工消费合作社印製 200398 Λ () 0 __Η () __ 五、發明説明7() 酸鈉乾燥,及濃縮,濃縮液進行矽膠層析(氮仿/甲醇) 得經純化之5 —〔3 — { (2s) — (1, 4 一苯並二噁 烷一 2 —基甲基)胺基)丙氣基〕—1, 3_苯並二噁醇 (2 . 6 8 克)0 上述産物溶於乙酸乙酯中,並加入26%鹽酸的異丙 醇溶液,過濾所得之沈澱物,得標題化合物,M . P . 2 12-218°C。〔 a〕f - 4 5 . 2 ° ( C 1 . ◦, CHC^3-MeOH 1:1) 2 Η - N M R ( D M S Ο - d 6 ) δ 9 . 16 ( 2 Η , m ), 6 . 8 9 ( 5 Η , m ), 6. 63 ( 1 Η , d , J = 2 . 4 H z ), 6 . 37 ( 1 H , d d , J = 7 . 5 , 2. 5 H z ) t 5 . 9 5 ( 2 H , s ), 4 . 6 5 ( 1 H , m ), 4. 37 (1H, dd, J = 1 2 . 5, 2 . 3 H z ). 4 . 0 2 ( 3 H , m ), 3 . 2 5 ( 4 H,m ), 2 . 10 ( 2 H,m ) 〇 在胺化上述光學異構物及外消旋物(依U S P 4,6 8 4,7 3 9所掲示之方法製得)後,在吡啶的存在下, 使用(S) —甲氣基三氟甲基一苯基乙酸氮,二種胺化物 本紙张尺度逍W中《國家標肀(CNS)*»M規格(210X29V公龙)_ Q _ (請先Μ讀背而之注总事項#项、?5木頁) 裝- 線- 200398 Λ (ί __Π G _ 五、發明説明沃) 均進行高壓液相層析(分離柱:Water Novapac C18),比 較分析二種化合物之層析圖發現光學異構物之光學密度達 90%e. e.以上。 啻例2 5 —〔4 一 {2 (S) — (1,4 一苯並二噁烷一2 —基 甲基)胺基} 丁氣基〕一1, 3 —苯並二噁醇鹽酸鹽(表 1中之化合物4 ) (請先閲讀背而之注意事項孙填¾木页) 經濟部中央楳準局貝工消#合作社印製 重覆實例1之步驟,惟使用5— (4一胺基丁氧基) 一 1, 3 —苯並二噁醇而非5 - (3 —胺基丙氣基)一 1 ,3 —苯並二噁醇,得標題化合物,M . P . 169-1 7 1 t: 〇 〔a〕f-41.70 (Cl.〇,CHCh-M e Ο Η 1 : 1 ) ^-NMR (DMS〇-d6) δ 9 . 2 0 ( 2 H , m ), 6 . 8 9 ( 5 H,m ), 6. 61 (2H, d , J = 2 . 5 Hz), 6. 35 ( 2 H , d d , J = 8 . 5, 2. 5 H z ) » 5 . 9 4 ( 2 H , s ), 4 . 6 5 ( 1 H , m ), 4. 36 ( 1 H , d d , J = 1 1 . 8,2. 3 H z ), 4 . 0 5 ( 1 H , m ) ,_____ 本紙張反度边川中《Η家櫺爭(CNS)T4規格(2丨0X25)7公龙L _ 裝. 訂 線. 200398 Λ (i ___Η (i _ 五、發明説明9() 3 . 9 0 ( 2 H , m ), 3 . 1 Ο ( 4 Η , m ), 1 . 7 5 ( 2 Η , m ) 〇 宮例3 5 —〔5— ( (2S) — (1, 4 —苯並二嚼院一 2 —基 甲基)胺基}戊氧基〕一 1, 3 —苯並二噁醇鹽酸鹽(表 1中之化合物7 ) 經濟部中央檁準局员工消t合作社印製 重覆實例1之步驟,惟使用5 - (5 —胺基戊氣基) 一 1,3 —苯並二嗯_以取代5 — (3 —胺基丙氧基)_ ,3 —苯並二噁醇,得標題化合物,Μ . Ρ . 1 6 9 — 1 7 3 t: 〇 〔α〕ΐ-4〇. I0 (Cl. 0 , C H C J? 3 -M e Ο Η 1 : 1 ) iH-NMR (DMS〇-d6) δ 9 . 1 0 ( 2 Η,m ), 6 . 8 8 ( 4 Η , m ), 6. 78 ( 1 Η , d m J = 8 . 5 Hz), 6. 6 0 ( 2 Η , d, J = 2 . 5 Η ζ ), 6. 34 ( 1 Η , d d , J = 8 . 3, 2. 5 Η ζ ) 5 . 9 3 ( 2 Η , s ), 4 . 6 5 ( 1 Η , m ), 4. 36 ( 1 Η , dd, J = 1 1 . 5, 2. 3 Η ζ _ 本紙張尺度边用中《«家«ί準(CNS) <丨Μ規格(210X297公Λ) 裝· -"a - 線- A 6 B 6 2〇〇3q8 五、發明説明(10) 4 . Ο 4 ( 1 Η , m ), 3. 88 ( 2 Η , t , J = 6 . 2 Η ζ ), 3 . 2 Ο ( 2 Η , m ), 2 . 9 8 ( 2 Η , m ), , 1.71 ( 4 Η , m ), 1 . 4 4 ( 2 Η,m ) 〇 本發明較佳的化合物(I)除了一述化合物1, 4和 7外尚包含表1所列示者。 f { .....................................................裝...........................訂............................線. (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消费合作社印«. 甲 4(210X297公嫠)80. 5. 20,000張(H〉 -12 - 200398 as B 6 五、發明説明(11) 表 1
經濟部中央標準局員工消費合作社印^ 化合物 位置 m n 1 m 3 1 2 m 3 2 3 .m 3 3 4 m 4 1 5 m 4 2 6 m 4 3 7 m 5 1 8 m 5 2 9 m 5 3 10 m 2 1 11 m 2 2 12 m 2 3 13 0 3 1 14 0 3 2 15 0 3 3 .....................-.............................^...........................•玎...........................¥ (請先閲讀背面之注意事項再填寫夂頁) 甲 4 (210X297公釐)80. 5. 20,000張(H) -13 - 200398 A 6 B 6 五、發明説明(12) (缜上頁) 16 0 4 1 17 0 4 f 2 18 0 4 3 19 0 5 1 2 0 〇 5 2 2 1 〇 5 3 2 2 0 2 1 2 3 0 2 2 2 4 0 2 3 經濟部中央標準局員工消費合作社印裝 奮例4 本發明之化合物(I)或(I)對5 — ΗΤ,λ受體的 親和力是依據結合分析使用8—羥基一2— (二正丙基胺 基)棻滿(下文中以〔3Η〕8 — OH — DPAT表示, 其為5-HTu受體之選擇性配位基)而測定的⑺^^口-harmacol . 2 6 . 1 39, 1987)。老鼠的大腦在 T r i s _ H C β缓衝液中攪勻並加以離心,所得之沈澱 物再以Tr i s — HC5緩衝液攪勻,並在37¾下培育 1 ◦分鐘,再次離心混合物,沈澱物以含有Perhline, 氣化鈣和抗壞血酸之Tr i s — HCi?缓衝液攆勻,得一 甲4(2丨丨以297公犛)80.5_20,000張汩) -14 - ...................................................#............................玎............................線. (請先閲讀背面之注意事項再填寫本頁) 200398 A6 B 6 五、發明説明(13) 可用於結合分析之薄膜製品。 此製品與〔3H〕8 - 0H - DPAT和待測試化合 物相混合,在3 7 1C下培育1 0分鐘,以Whatman GF/B滤 紙過濾,利用液相層析撿測留在濾紙上之放射活性。 测試化合物與5 — Η T 2 λ受體之親和力以K i值表示 ,Ki值是依下列方程式計算而得 K i = K d 其中〔L〕是〔3H〕8 — OH — DPAT 之濃度,Kd 是解離常數,而IC3。是測試化合物産生5 0%抑制〔3 H〕 8—0H—DPAT結合時之濃度。較低的Ki值表 示較高之測試化合物與5—HT受體的親和力,如此化合 物作為抗焦慮劑的用處較大。 (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 f 4(2川公嫠)80· 5. 20,000張出) -15 A 6 B 6 200398 五、發明説明(14) 測試結果總列於表2。 表 2 化合物 鹽 K i值 (η Μ ) 化合物1 ( d 1 ) H C 1 1 . 6 ( S ) H C 1 0 . 2 9 ( R ) H C 1 3 . 9 化合物2 ( d 1 ) H C 1 2 . 5 化合物3 ( d 1 ) H c 1 7 . 6 化合物4 ( d 1 ) H c 1 0 . 9 1 化合物6 ( d 1 ) H c 1 2 . 9 化合物7 ( d 1 ) H c 1 4 . 0 9 ( S ) H c 1 1 . 8 4 化物物1 3 ( d 1 ) H c 中 9 · 7 (請先閲讀背面之注意事項再填寫本頁) 經 濟 部 t 央 標 準 員 工 消 費 合 社 ΪΡ 製
Buspirone (活性控制組) 4 表2顯示本發明之化合物比已知的抗焦康劑Buspirone 具有更高之 5—ΗΤ/λ 受髏結合能力 ,因此 ,可預期的 是其應是優良抗焦慮劑。 f4(2lri><297&^)8a 5. 20,000*(H) 16 - 200398 A6 _B 6 五、發明説明(15) (請先閲讀背面之注意事項再填寫本頁) 奮例5 衝突試驗是用以檢査化合物的抗焦盧活性,所用之方 法像改良自 Vogel 等人(Psychopharmac01ogy2 1,1 , 1 9 7 1 )之方法。 在第一訓練期(不責罰期)前給老鼠飲水3 8小時, 每隻動物放在衝突試驗裝置内,由一嘴管給老鼠飲水,計 算10分鐘内飲水的次數,舔嘴次數超過100次上之老 鼠停止飲水24小時,在不責罰期後24小時,再次將老 鼠放在测試盒内,第二練習期(藥前責罰期)包含自老鼠 舔嘴20次後至受到第一値電擊之3分鐘期間,在毎20 個不責罰的舔嘴後,處罰後來的舔嘴動作只有在藥學責罰 期間受到電擊之次數減少至多2 5倍之老鼠才被留在測試 中。 測試化合物經口投服給每隻老鼠,在投服後1小時, 調換老鼠在測試裝置中的位置,計算3分鐘内的電擊次數 ,使用Buspirone (焦慮選擇性抗焦慮劑》作為陽性控制 組。 結果示於下表3。 當測試组中之霄擊次數高於控制組的次數時,評為具 有陽性抗衝突活性。 γ 4 (210X297公釐)80. 5. 20,000張(H) -17 - 200398 經濟部中央標準局員工消费合作社印51 A 6 B 6 五、發明説明(16) 表 3 化合物 劑量 f 接受電擊頻率 (毫克/公斤) (次/3分) 控制組 7.4 化合物 1 (d 1 ) 0 . 2 5 2 0 . 9 (S ) 0 . 0 5 2 0 . 1 (R ) 〇. 5 1 2 . '5 化合物 2 (S ) 0 . 2 2 1 . 8 化合物 3 (S ) 0 . 2 1 8 . 0
Buspirone 5.0 14.4 魚袢羞件 化合物(I)懸浮於0.5% CMC — Na水溶液 中,經口投服給雄性和雌性老鼠,觀察7天,化合物1之 ALD值(接近致死劑量)是100毫克/公斤(ρ. 〇 ...........,.......................................^...........................,玎..........................埠 (請先閲讀背面之注意事項再填寫本頁) 甲 4 (2丨(1X297公釐)80. 5. 20,000張(H〉 -18 - 200399 A6 B 6 五、發明説明(17) 奮例6 (1 )錠劑 混合下列成份並依習知方法壓成錠劑。 化合物1 ( S ) 結晶纖維素 玉米澱粉 乳糖 硬脂酸鎂 1 0毫克f 2 1毫克 3 3毫克 6 5毫克 .3毫克 (2 )軟膠囊 混合下列成份並依習知的方法填入膠囊中。 化合物1 ( S ) 橄攬油 卵磷脂 1 0毫克 1 ◦ 5毫克 6 . 5毫克 經濟部中央標準局員工消費合作社印製 (3 )注射液 化合物1 ( S ) N a C 5 注射蒸餾水 0 . 7毫克 3 . 5毫克 1 . 0毫升 ..................................................^.......P...................、玎...........................線. (請先閲讀背面之注意事項再填寫本頁) 甲 4(2川X297公釐)80. 5_ 20,000張出) -19 -
Claims (1)
- 經濟部屮央標準局员工消贽合作社印製 』 A7 B7 (’7^00^98_二_D7_ 六、中請專利範圓 附件: 第80102458號專利申請案 中文申請專利範圍修正本 民國81年9月修訂 1 . 一種用以治療焦慮之藥學組成物,其包含作為主 要成份之有效量的通式(Π)所示之化合物: (CH2), 、〇'°(CH2)mNHCH:(工工) 其中m是2至5之整數且η是1至3之整數,或其酸加成 鹽,以及適合之賦形劑或載體。 2 .如申請專利範圍第1項之藥學組成物,其中化合 物是如下式(11^)所示: (ch2)i 〇(CH2)]nNHCH2(II') 其中m和η如上所定義。 3 .如申請專利範圍第2項之藥學組成物,其中化合 物是如化式(It ’)所示者,且⑴是3,4或5。 4 .如申請專利範圍第3項之藥學組成物,其中化合 物是如化式(I /)所示者,且其為3構型。 (請先閱讀背面之:/i意事項再填荈本1Γ 本紙張尺度適用中Η 8家櫺準(CNS)甲4規格(210x297公釐) -1
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JP2063839A JPH03264528A (ja) | 1990-03-14 | 1990-03-14 | 抗不安薬 |
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EP (1) | EP0446921B1 (zh) |
JP (1) | JPH03264528A (zh) |
KR (1) | KR100240242B1 (zh) |
AT (1) | ATE171704T1 (zh) |
CA (1) | CA2038025C (zh) |
DE (1) | DE69130266T2 (zh) |
DK (1) | DK0446921T3 (zh) |
ES (1) | ES2122962T3 (zh) |
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US5391570A (en) * | 1993-10-14 | 1995-02-21 | Bristol-Myers Squibb | Aminomethyl-benzodioxane and benzopyran serotonergic agents |
FR2716680B1 (fr) * | 1994-02-25 | 1996-04-05 | Adir | Nouveaux dérivés de benzodioxane, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent. |
US5525347A (en) * | 1995-01-31 | 1996-06-11 | Medical University Of South Carolina | Composition and methods for treating performance anxiety |
US5998467A (en) * | 1995-10-25 | 1999-12-07 | Mitsubishi Chemical Corporation | Medicine for oculopathy |
ES2182175T3 (es) * | 1997-05-20 | 2003-03-01 | Mitsubishi Chem Corp | Utilizacion de un derivado del alquilenodioxibenceno para el tratamiento de los trastornos del ritmo circadiano del sueño. |
DE69822846T2 (de) * | 1997-08-19 | 2005-02-03 | Mitsubishi Chemical Corp. | Medikament zur Behandlung des Reizkolons |
EP1617838A4 (en) * | 2003-04-25 | 2011-07-06 | Mitsubishi Tanabe Pharma Corp | COMPOSITION FOR ORAL ADMINISTRATION CONTAINING AN ALKYLENE DIOXYBENZENE DERIVATIVE |
CN101619059B (zh) * | 2008-07-01 | 2011-09-14 | 江苏恩华药业股份有限公司 | 盐酸奥沙莫唑坦的制备方法 |
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US4684739A (en) * | 1980-12-15 | 1987-08-04 | Mitsubishi Chemical Industries Limited | Alkylenedioxybenzene derivatives and acid addition salts thereof |
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CA2038025A1 (en) | 1991-09-15 |
EP0446921B1 (en) | 1998-09-30 |
EP0446921A2 (en) | 1991-09-18 |
EP0446921A3 (en) | 1992-01-29 |
DK0446921T3 (da) | 1999-06-21 |
KR910016734A (ko) | 1991-11-05 |
ATE171704T1 (de) | 1998-10-15 |
KR100240242B1 (ko) | 2001-02-01 |
DE69130266T2 (de) | 1999-03-18 |
DE69130266D1 (de) | 1998-11-05 |
US5168099A (en) | 1992-12-01 |
CA2038025C (en) | 2005-12-20 |
JPH03264528A (ja) | 1991-11-25 |
ES2122962T3 (es) | 1999-01-01 |
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