TW509689B - Benzothiadiazoles and derivatives - Google Patents

Benzothiadiazoles and derivatives Download PDF

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TW509689B
TW509689B TW088102726A TW88102726A TW509689B TW 509689 B TW509689 B TW 509689B TW 088102726 A TW088102726 A TW 088102726A TW 88102726 A TW88102726 A TW 88102726A TW 509689 B TW509689 B TW 509689B
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Bernhard Peter Neumann
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Novartis Ag
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
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    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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Description

509689 五、發明說明（1) 本發明係有關新穎之苯并噻二哇及衍生物，其製法，其 使用作為醫藥之用途及含其之醫藥組合物。 . 詳言之，本發明提供一種呈游離鹼或酸加成鹽態之式I 化合物：
Het 其中 X 為0，S，N-CH3，CH = CH 或 CAlk = CAlk，其中 Aik 獨立為 ((^_4)烧基， K及1獨立為氫、鹵素、（C!_4)烷基、（C^)烷氧基或三氟甲 基；及
Het為具下式（a)至（p)之一之基：
第4頁 509689 五、發明說明.(2)
⑽ ⑻ ⑹ （p) 其中 R3&R8獨立為氮或（（^_4)烧基’ R4為氫、鹵素、（CV4)烷基、氰基、硝基、甲醯基或（CV4) 烷羰基， R5及1獨立為氫、（Ch)烷基、（c3_7)烯基、（c3_?)環烷基、 (c3_7)環烷基（Ch)院基、（(ν4)烷氧基（c2_5)烷基或1基， R7為氫、羥基、（(^_4)烷基或（Ch)烷氧基， W 為N，C-CN，C'N02，C-C0H 或 C-C〇-Alk，其中 Aik 如上述 定義’及 X如上述定義。 鹵素為氟、氣、漠或蛾，較好為氟或氣。
Het基較好位於與式I雜環部份鄰接之碳原子上。較好 Het為式（a)至（k)，尤其是式（a)。 進一步目的中，本發明提供一種製備式I化合物及其鹽
第5頁 509689
第6頁 509689 五、發明說明（4)
其中R3至1，W及X如前述定義及Hal為鹵素；與式II I化合 物反應：
HN\ III
Rs 其中R5及{?6如前述定義；及使所得化合物轉化成游離鹼態 或酸加成鹽態。 反應可以已知方式如實例1所述般進行。Ha 1較好為氣、-漠或蛾，尤其是氯。 上述方法所得反應混合物之結束反應操作及所得化合物 之純化可依據已知程序進行。 酸加成鹽可依已知方式自游離鹼製得或相反。用於本發 明之適宜醫藥可接受性酸加成鹽包含例如鹽酸鹽、馬來酸 氫鹽、富馬酸氫鹽及丙二酸氫鹽。 式I I起始物可如下製得： 其中Y為具式（a’）至（d’）之一之基之式II化合物之獲得 可藉使式IV化合物： ’
第7頁 509689
第8頁 509689 五、發明說明（6) 其中R3、R4、R7、r8及^如前述定義。 所有前述反應為習知。 ， 式I I I ’ I V ’ V a ’ V d及V I化合物為已知或可由已知化合 物使用習知程序製得。 式I化合物及其醫藥可接受性酸加成鹽（後文稱為本發明 藥劑）當使用促腎皮素釋出因子（CRF)受體表現細胞培養基 於體外測式及於動物中測試時，呈現有價值之醫藥性質， 且因此可作為醫藥。 尤其’本發明試藥結合至CRF受體上。詳言之，其呈現 以下列分析於活體外測定之對⑶匕受體之拮抗活性： 中國田鼠妒巢（CH0)細胞表現人類重組體CRF, (Chen等 人，Proc Natl Acad Sci USA 90， 8967-8971， 1993)於 補充有10%胎牛血清、非必需胺基酸、丨00 (]/毫升青黴 素、100毫克/升鏈黴素及1克/升基因素（genet i cin) (G418)之杜貝可（Dulbecco’s)改質之鷹培養基中繁殖。對 環狀AMP測定而言，細胞於2 4-洞盤中生長群集。如前述 (Schoeffter 等人，神經醫學 36， 42 9-437， 1 99 7 )使用 PH]腺嘌呤標記技術於完整細胞中測量由CRF (人類/大鼠 態）所刺激之環狀AMP累積。在假設拮抗劑（1 〇 # M)或载體^ (二曱基亞砚1%體積）存在下，架構CRF之濃度-反應曲線。 由式KB=[拮抗劑，Μ ]/濃度比例-1 )由對照面線之向右移動 計异ΚΒ值，其中濃度-比例表示存在有拮抗劑之EC枯 /不存在有拮抗劑之CRF £(：5{)值[?1_11^11§(^1:， In ··兒茶驗胺 (由 Blaschko Η 及 Muscholl E 編輯）第 283-335 頁，
第9頁 509689
Springer, Berlin， 1972]。 nM時顯.現 此測試中’本發明藥劑在K b C R F丨值約1至5 〇 〇 C F R!括抗活性。 因此本發明之藥劑可用以治療具增加CRF内源性旦 中ΗΡΑ (下丘腦垂體軸）失調之任何病況，或由二J/或 促成之各種疾病，包含發炎疾病如關節炎， 礼而及過敏； 焦慮包含晋遍性焦慮；恐怖及恐懼侵襲；抑 >r 影，疲勞症候 群；頭痛；疼痛如發炎性或神經性疼痛；病 、 广设姆 ^ ^ ^ , 么症，應激性腸 症候群’包3克隆氏疾病，痙擎性結腸及應激性钟腸· 疫官能障礙；人類免疫缺乏病毒（HI V)感染；抽 1經退化疾 病如老年癡呆、阿茲海默氏疾病及帕金森氏痂 - /六两，Τ風及 頭部外傷；癲癇；胃腸疾病；飲食及體重障礙如嗜食症及 神經性厭食症；出血性應力；藥物及醇戒除症候^ Τ =物 上癮；睡眠障礙；荷爾蒙失調；皮膚障礙；應力誘發^偶 發精神病；生育問題；性官能障礙及早產。 & 本發明藥劑於上述疾病之利用性可以數種測試證實： 例如本發明藥劑之解焦慮活性可以於老鼠升高之走迷宮 加以證實[例如參見Rodgers R.J·，Behavioural Pharmacology 8:4 77-49 6 ( 1 997 )，升高之走迷宮相關性 討論於第486頁；方法則參見Rodger s R· J·等人之 Ethology and Psychopharmacology (SJ Cooper 及CA Hendrie 編輯），第 9-44 頁（1994)，J· Wiley， C h i c h e s ΐ e r ]。此測試中，本發明藥劑在投與0 · 1至3 0毫克 /公斤p . 〇.時顯現似解焦慮活性。 509689 五、發明說明（8) 對上述指示而言，適宜劑量當然視例如所用化合物、宿 主、投藥模式及欲治療病況之性質及嚴重性等而變化 '但 通常對動物以約0 · 1至約1 0 0，較好約0 · 5至約1 0 0毫克/公 斤動物體重之日劑量可獲得令人滿意之結果。對較大哺乳 類中，例如人類中，所示之日劑量為約1至約5 0 0，較好約 1至約3 0 0毫克本發明藥劑，方便每曰分成達4次之劑量投 藥或以持續釋出狀態投藥。 本發明藥劑可以任何習知路徑投藥，尤其腸内，較好口 服例如錠劑或膠囊態，或以注射溶液或懸浮液態非經腸道 投藥。 · 對上述指示而言，較佳化合物為實例1化合物。上述結 合測試中，該化合物以36 nM之Kb CRFi呈現CRF:拮抗活 性。上述升高走迷宮中，0.1至10毫克/公斤p.o.劑量（最 大為3毫克/公斤）明顯影響焦慮相關行為參數。與標準曱 氨二氮草相反，並未影響與動作刺激有關之參數，其表示 所觀察到之解焦慮效果不會造成一般之動作刺激。 依據前述，本發明亦提供本發明藥劑作為醫藥例如用以 治療由CRF誘發或促成之疾病（如上述者）之醫藥用途。 本發明又提供一種含有本發明藥劑及至少一種醫藥載體 或稀釋劑之醫藥組合物。此種組合物可以習知方式製造。 單位劑型含有例如約0 · 2 5至約1 5 0，較好0 . 2 5至約2 5毫克 本發明化合物。 再者本發明提供本發明藥劑用以製造供治療上述任何病 況之醫藥之用途。
第11頁 本發明γ、 療上述住‘進一步目的係提供—種對需此治療之受療者治 本發明藥g病况之方法，包括對受療者投與治療有效量之 下歹眷> γ t 實例1 : 5 σ兒明本务明。溫度為攝氏度且未校正。 啶〜4〜Λί’ 7〜二甲基一4一[2, 5 —二甲基-6-(二正丙基）胺基嘧 含4:]胺基—H3—苯并噻二唑 2, 1，^〜、氣二2, 5一二曱基嘧啶—6—基）胺基-5, 7-二甲基-甲基叫f Β島二嗤（3 · 5克）及二正丙胺（5 · 3 5毫升）之絕對 小時。使°各燒嗣（35毫升）溶液於密封瓶中在157。攪拌96 5 〇毫升次用薄層層析法追蹤反應。冷卻反應混合物，添。加 升）。7 /且水相以曱基第三丁基醚萃取2次（ 2 x20 0毫一 三丁：μ：機相經脫水、蒸發並在石夕膠上使用環己烧/甲基第 醇再鈐曰V D : 1 )層析分離。蒸發適宜之區份且殘留物自甲 士 _ ’ 得標的產物。Mp = 117-119。。 4 7下逃製備起始物4-(4 -氯-2, 5 -二甲基嘧啶-6 -基）胺基 4>67/=二甲基-2，1，3-苯并噻二唑： 升）一甲基〜2, 1，3 —苯并噻二唑（7· 7克）溶於濃硫酸（20毫 ’攪拌下冷卻至0-5。並滴加硝酸（2. 5毫升； 1 · 5 2、 先· y。此透明溶液倒於冰上並濾出所得沉澱及以水， 所得5, 7 -二甲基-4 -硝基-2，1，3 -苯并噻二唑自環己烧 再結晶。Μρ=ι〇5-106。。 5’ 7—二甲·基-4 -硝基-2, 1，3-苯并噻二唑（20克）於水（2· 2 升）及乙醇（2.2升）中溫熱至沸騰並逐次添加連二硫酸 納（強烈放熱反應）。反應混合物立即於冰浴中冷卻及以乙
第12頁
O:\56\56961.PTD 509689 五、發明說明（ίο) 酸乙酯萃取。有機相經蒸發濃縮且殘留物自水中再結晶 得4 -胺基-5, 7 -二甲基-2, 1，3 -苯并噻二唑。 -
Mp-113»114 0 。 克）在氬氣下 喃（50毫升） 接著在3 0分 啶（4克）之絕 溫再授拌1 6小 甲醇洗。自甲 4 -胺基-5, 7-二甲基-2, 1，3 -苯并噻二唑（4 逐次添加至含氫化鈉（2 · 7 2克）之絕對四氫呋 55%分散液中。混合物在25- 30。攪拌3小時 鐘内於5。下滴加含4, 5-二氯-2, 5-二曱基嘧 對四氫呋喃（2 0毫升）溶液。反應混合物在室 時，小心添加冰水。所得沉澱以水洗及少量 基嘧啶_6-秦） 74- 1 77 0 。… 醇或環己烷再結晶後，得4-(4-氯-2, 5 -二甲 胺基-5,7-二曱基-2，1，3-苯并噻二唑。Mp = l 類似於實例1可製得下列式I化合物： a)下式化合物
R6 Rs \ / 5 N
實例 Ri Ri r3 R4 Rs R6 Mp 2 Me Me Me Me 正丙基 -ΟΗ2-環丙基 120-121° 3 Me Me Me H 正丙基 環丙基 124-127° * 4 Me Me Me H 正丙基 正丙基 177-179° * 5 Me Me Me Cl 正丙基 正丙基 106-108° 6 Me Me Me Cl 正丙基 -CHr環丙基 ， 111-113° 7 Me Me Me Me 正丙基_ Et 101-102° 第13頁
509689 五、發明說明（π) 8 Me Me Me Me 正丁基 Et 83-84° * 9 Me Me Me Me -CH2CH2OCH3 -CH2CH2OCH3 70-73° 10 Me Me Me Me -CH2-CH(CH3)-CH3 -CH2-CH(CH3)-CH3 104-105° 11 Me Me Me Me 3-戊基 Η 113-115° 12 Me Me Me Me 2- 丁基 Η 88° 13 Me Me Me CN 正丙基 正丙基 171-173° 14 Me Me Me CN 正丙基 •CHr環丙基 165-167° 15 Cl Cl Me Me Me Et 116° 16 Cl Cl Me Me Me 正丁基 105° 17 Cl Cl Me Me Et Et 189-193°* 18 Cl Cl Me Me Et 正丙基 107° 19 Cl Cl Me Me Et 正丁基 101° 20 Cl Cl Me Me 正丙基 正丙基 118-121° 21 Cl Cl Me Me 正丙基 -CH2」環丙基 120-123° 22 Cl Cl Me Me 正丁基 正丁基 56° 23 Cl Cl Me Me 烯丙基 烯丙基 112° 24 Cl Cl Me Me · Η 苄基 126° 25 Cl Cl Me Me Me 苄基 138° 26 Me Cl Me Me 正丙基 正丙基 102-104° 27 Me Cl Me Me 正丙基 -CHr環丙基 131-132° 28 Cl Me Me Me 正丙基 -CHr環丙基 110-112° 29 Cl Me Me Me 正丙基 正丙基 112-114° 30 Cl H Me Me 正丙基 正丙基 77-80° 31 Me H Me Me 正丙基 正丙基 95-98°
Me=甲基；4 Εΐ=乙基；* :富馬酸鹽 11·· 第14頁 509689 五、發明說明（12) b )下式化合物
R6 R. \ / 5 N
實例 Ri Ri r3 R4 Rs ^6 Mp 32 Me Me Me Me 正丙基 正丙基 123° 33 Cl Me Me Me 正丙基 正丙基 100° 34 Me Me Me Me 正丙基 -CH〗-環丙基 < 105° - 35 Cl Me Me Me 正丙基 -CHr環丙基 86° 36 Me Me Me Me 正丙基 Et 102〇 37 Me Me Me Me 正丁基 Et 71°
Me=曱基；Et=乙基 c )下式化合物
R6 R5 \ / 5 N
胥例 Ri Ri r3 R4 Rs r6 Mp 38 Me Me Me Me 丙基 正丙基 94-96° 39 Cl Cl Me Me 正丙基 _ 正丙基1 126-128° 40 Cl Me Me Me 正丙基 丨正丙基 ，. 107-109° 509689 五、發明說明（13) 41 C1 Me Me Me 正丙基 -CH2-環丙基 115-117° 42 Me Me Me Me 正丙基 -CHr環丙基 105406， 43 Cl Cl Me Me 正丙基 -CH2-環丙基 126-127° 44 Cl Cl Me Me Et 正丙基 120-123° 45 Me Me Me Me Et 正丙基 109-110° 46 Cl Cl Me Me Et 正丁墓· 117-119° 47 Me Me Me Me Et 主丁墓 106-107°
Me=甲基；Et二乙基 d )下式化合物 R5 \ / 5
實例 X Ri R3 r4 Rs R. Mp 48 S Cl Me Me Et 正丁基 85° 49 S Cl Me Me 正丙基 -CH〗-環丙基 84° 50 CH=CH Br Me Me Et 正丁基 110° 51 CH=CH Br Me Me 正丙基 -CH2-環丙基 135°
Me二甲基；Et=乙基
Hill 第16頁 509689 五、發明說明（14) e)下式化合物
r2 ^Ν、 V 實例 X Ri r2 R3 R5 R6 r7 Rb Mp 52 S Me Me Me Et 正丁基 Me Me 90-92° 53 CH=CH Me Me Me Et 正丁基 Me .， Me 106-108° 54 S Me Me Me 正丙基 正丙基 Me Me 126-128° · 55 CH=CH - Me Me Me 正丙基 正丙基 Me Me 156-158° 56 S Cl Me Me 正丙基 正丙基 Me Me 135-136° 57 CH=CH Cl Me Me 正丙基 正丙基 Me Me 130-131° 58 S Cl Me Me Et 正丁基 Me Me 90-92° 59 CH=CH Cl Me Me Et 正丁基 Me Me 177-178°
Me=曱基；Et=乙基 f )下式化合物 實例 Ri Ri Rs R6 Mp 60 Me Me 正丙基 -CHr環丙基 234-237° *
Me=甲基；* :富馬酸鹽
第17頁 509689 案號88102726 f年I月丨Ί曰 修正
O:\56\56961.ptc 第18頁

Claims (1)

  1. 509689 修正 案號 88102726 六、申請專利範圍 1 . 一種呈游離鹼或酸加成鹽態之式I化合物
    公1告象 其中 X 為0，S，或CH = CH， I及1獨立為氫、鹵素或（(^_4)烷基；及 Het為具下式（a)，（e)，及（m)之一之基 NH
    ^6 (a) R5
    (c) R6、
    (m) 其中 R3為（Ch)烧基， R4為氫、鹵素、（c^)烷基、鹵素或氰基， R5及^獨立為氫、（Ch)烷基、（c3_7)烯基、（c3_7)環烷 基（Ch)烷基或烷氧基（C2-5)烷基， R7為（Ch)烷基，及 R8為（Ch)烷基。
    O:\56\56961.ptc 第19頁 509689 案號 88102726 曰 修正 t、申請專利範圍 2. —種呈游離鹼或酸加成鹽態之5, 7 -二甲基_4-[ 2, 5-二 甲基-6-(二正丙基）胺基嘧啶-4 -基]胺基-2, 1，3-苯并噻二 口全 ° 3 · —種製備根據申請專利範圍第1項之式I化合物或其鹽 之方法，包括使式I I化合物： R,
    N. 其中X，Ri及1?2如申請專利範圍第1項之定義，及Y為具 下式（a’），（e’），及（m’）之一之基： NH
    (Ο Hal
    (Ο Hal
    (η〇 其中R3至1係如申請專利範圍第1項之定義及Hal為鹵 素；與式I I I化合物在有機溶劑中，溫度範圍在1 0 0至2 0 0 °C下反應，反應時間1至5天： in R<
    O:\56\5696l.ptc 第20頁 509689 _案號88102726_丨年I月1Ί日 修正_ 六、申請專利範圍 其中R5 &R6如申請專利範圍第1項之定義；及使所得化 合物轉化成游離驗態或酸加成鹽態。 4.根據申請專利範圍第1或2項之呈游離鹼或酸加成鹽態 之化合物，其係作為醫藥品。 5 .根據申請專利範圍第1或2項之呈游離鹼或酸加成鹽態 之化合物，其係用於治療具增加内源性量之CRF或其中ΗΡΑ 失調之任何狀態或治療由CRF誘發或促成之疾病。 6. —種用於治療具增加内源性量之CRF或其中ΗΡΑ失調之 任何狀態或治療由CRF誘發或促成之疾病之醫藥組合物， 其包括根據申請專利範圍第1或2項之呈游離鹼或酸加成鹽 態之化合物以及醫藥載體或稀釋劑。
    O:\56\5696i.ptc 第21頁
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IL139197A0 (en) * 1999-10-29 2001-11-25 Pfizer Prod Inc Use of corticotropin releasing factor antagonists and related compositions
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AR057035A1 (es) 2005-05-25 2007-11-14 Progenics Pharm Inc SíNTESIS DE (R)-N-METILNALTREXONA, COMPOSICIONES FARMACÉUTICAS Y USOS
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WO2007149938A2 (en) 2006-06-21 2007-12-27 The Salk Institute Biological Studies Methods for promoting hair growth
EP3263571B2 (en) 2007-03-29 2023-08-23 Progenics Pharmaceuticals, Inc. Crystal form of (r)-n-methylnaltrexone bromide and uses thereof
US8338446B2 (en) 2007-03-29 2012-12-25 Wyeth Llc Peripheral opioid receptor antagonists and uses thereof
PE20130480A1 (es) 2007-03-29 2013-05-08 Progenics Pharm Inc Compuestos heterociclicos como antagonistas del receptor opioide periferico
WO2009099411A1 (en) 2008-02-06 2009-08-13 Progenics Pharmaceuticals, Inc. Preparation and use of (r),(r)-2,2'-bis-methylnaltrexone
CA2676881C (en) 2008-09-30 2017-04-25 Wyeth Peripheral opioid receptor antagonists and uses thereof
US8349852B2 (en) 2009-01-13 2013-01-08 Novartis Ag Quinazolinone derivatives useful as vanilloid antagonists
US20120295942A1 (en) 2010-02-01 2012-11-22 Nicholas James Devereux Pyrazolo[5,1b]oxazole Derivatives as CRF-1 Receptor Antagonists
WO2011092293A2 (en) 2010-02-01 2011-08-04 Novartis Ag Cyclohexyl amide derivatives as crf receptor antagonists
ES2527849T3 (es) 2010-02-02 2015-01-30 Novartis Ag Derivados de ciclohexilamida como antagonistas del receptor de CRF
AR086554A1 (es) 2011-05-27 2014-01-08 Novartis Ag Derivados de la piperidina 3-espirociclica como agonistas de receptores de la ghrelina
CN104271579A (zh) 2012-05-03 2015-01-07 诺华股份有限公司 作为生长素释放肽受体激动剂的2,7-二氮杂-螺[4,5]癸烷-7-基衍生物的l-苹果酸盐及其结晶
CA3039026A1 (en) 2016-09-07 2018-03-15 The Regents Of The University Of California Allosteric corticotropin-releasing factor receptor 1 (crfr1) antagonists that decrease p-tau and improve cognition

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2499991A1 (fr) * 1981-02-19 1982-08-20 Sandoz Sa Nouveaux 2,1,3-benzothiadiazoles et 2,1,3-benzoxadiazoles, leur preparation et leur application comme medicaments
KR0163624B1 (ko) * 1992-04-28 1998-12-01 오노다 마사요시 신규의 치환된 3급 아미노 화합물 또는 이의 염
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