TW200900058A - N-(heteroaryl)-1-heteroaryl-1H-indole-2-carboxamide derivatives, their preparation and their therapeutic application - Google Patents
N-(heteroaryl)-1-heteroaryl-1H-indole-2-carboxamide derivatives, their preparation and their therapeutic application Download PDFInfo
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- TW200900058A TW200900058A TW097101049A TW97101049A TW200900058A TW 200900058 A TW200900058 A TW 200900058A TW 097101049 A TW097101049 A TW 097101049A TW 97101049 A TW97101049 A TW 97101049A TW 200900058 A TW200900058 A TW 200900058A
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Description
200900058 九、發明說明： 【發明所屬之技術領域】 本發明係有關由Ν·(雜芳基）-1-雜芳基-1H-吲哚-2-甲醯胺 所衍生的化合物，該化合物對於TRPV1(或VR1)型受體具 有活體外和活體内的拮抗劑活性。 【發明内容】 本發明第一個主題係關於如下通式（J)化合物。 本發明另一個主題係關於製備通式⑴化合物的方法。 本發明另一個主題係關於通式⑴化合物的應用，特定言 之用於藥劑或藥物組合物。 【實施方式】 本發明化合物如通式（j):
其中，Χι ' x2、χ3、 或 q-C6-烷基、c3-C基、Ci-c<- ϋ柃篡、 Χ4各自獨立地代表氫原子或鹵素原子
或Ci-C6-烧基、c3-C7-環烷基、 ' S02NR,R2 . NR3COR4 ' 擇性經一個或多個選自鹵素 、C3-C7-環烷基_Cl_c3-伸烷 127853.doc 200900058 基、CrCV氟烷基、CVCV燒氧基、q-cv氟烷氧基、硝美 或氰基中的取代基取代； w代表下列結構式的稠合二環基： 1
經由位置1、2、3或4與氮原子鍵合； A代表含有從〇、S或N中選取的一個至三個雜原子的5至 7員雜環； A中一個或多個碳原子可選擇性經一個或多個選自氯原子 或<^-(：6-烧基、c3_c7_環烧基、C3_C7_環炫基_Ci_c广伸烷 基 Ci-C6-鼠院基、C^-C^-烧氧基、C3-C7-環院氧基、匸3 C*7-環院基-CrC3-伸院氧基、芳基、芳基_c]-C6_伸烧基' 側氧基或硫代基中的基團取代； 當鄰接氮原子的碳原子經一個側氧基，或在其他情况下經 R7取代時’ A中一個或多個氮原子可選擇性經r6取代； y代表可選擇性經選自鹵素原子或Cl_C6_烷基、c3_C7_環 烧基、C3-C7-環烷基-Cl_c3_伸烷基、Cl-c6氟烷基、羥基、 c^-cv烧氧基、Ci-CV氟烷氧基、CVCV硫氟烷基、氰基、 CXCONH、硝基、NRlR2、Cl_c6_硫烷基、sH、_s(〇)_ Ci-C6-烷基、-8(0)2-(^-(36-烷基、-s(0)-c3-c7-環烷基、 -S(0)2-、c3-c7-環烷基、SC^NR^R^、NR3COR4、 NR3SO2R5、^基-Ci_C6-伸烧基或芳基中的一個或多個基 127853.doc 200900058 團取代的雜芳某. -個或〜 芳基_Cl-C6_伸烧基可選擇性經 3夕個選自鹵素或c c 、 環 烷基C3-cv%烷基、C3-C7- c6-氟院减、石肖基或氰基中的取代基取代； r二：R2各自獨立地代表齒素原子或cvc6-院基、c3_c7_ 广環院…3_伸烧基、芳基々C6，院基 , "々R2與其所附接之氮原子結合成氮雜環丁院
土、0比錢基"底咬基、氮雜環庚烯基、嗎琳基、硫代嗎 啉基、哌嗪基或高哌嗪基，該基團可選擇性經Cl_c6_烷 基c3 C7-i衣院基、c3_c7_環院基_Ci_c3·伸院基、芳基_Ci_ 匸6-伸院基或芳基取代； R3和R4各自獨立地代表氫原子或Ci_c6_烷基、芳基_Ci_ c0-伸烷基或芳基；
Rs代表C|-C6-烷基、芳基-Ci-C6-伸烷基或芳基； R6代表氫原子或Ci-C6·烷基、Cs-CV環烷基、C3-C7-環烷 基-Ci-C3-伸烷基、Ci_C6_氟烷基、芳基_Ci_C6_伸烷基或芳 基； R7代表氫原子或C〗-C6_烷基、Cs-CV環烷基、C3_C7-環烷 基-CVC3-伸院基、C|_C6_氟烷基、芳基_Ci_c6-伸烷基、 c6-烧基-C(o)-、c3_c7_環烷基 _Ci_c3_伸烷基 _(co)_、Ci_ c6-氟烷基-C(o)-、c3-C7-環烷基-C(o)-、芳基-C(O)-、芳 基-CVCV伸烷基·(：(；〇；)_、Cl-c6-烷基-s(0)2-、CVC6-氟燒 基-S(0)2-、c3-c7-環烷基-s(0)2-、c3-c7-環烷基-CVC3-伸 烧基-S(0)2-、芳基_S(；0)2_、芳基_Ci_c6_伸烷基_s(0)2-或芳 127853.doc -9- 200900058 基 在通式（I )化合物中： 雜環Α或雜芳基γ中一個或多個硫原子可呈氧化形式 (s(0)或 s(o)2); 雜環A或雜芳基γ中一個或多個氮原子可呈氧化形式（N_ 氧化物）。 f 4· κ.. 在本發明的全文中，W基團之實例可提及：十朵基、異 ^朵基、二氫«基、異二氫„基、苯#。夫喃基、二氫 本并°夫喃基、苯并喧吩基、二氫苯并嘆吩基、苯并鳴嗤 ^^氫笨并^坐基、異苯并°夫味基、二氫異苯并。夫喃 基、本并口米σ坐基、贫# 一虱本并味唑基、吲唑基、苯并噻唑 土異本开口塞唾基、二氣異苯并售唾基、苯并三嗤基、啥 啉基、二氫喹啉基、氯 Λ 卜 虱哩啉基、異喹啉基、二氫異喹啉 基、四虱異喹啉基、苯并。亞 友 噻嘻 故+ 〜•、一虱笨并噁嗪基、苯并 職土、—風本并嗟嗪基、嗜琳基、啥㈣基、二氫㈣ ::氯啥㈣基、啥。惡琳基、二…琳 氮雜環庚稀基、四二四氧駄嘻基、四氯苯并⑻ 氮雜環庚稀基、四氨苯并[⑷]庚縣四風本并⑷ 开Hie]二氮雜環庚稀基、 ▲四A本 基或四氫苯并Π 4 > 开[】，4_b】氧氮雜環庚烯 風本并[l，4-b]硫氮雜環庚烯基。 作為本發Μ題㈣切)化 群由下列化合物組成，其中·χ γ中化5物的第-個子 代表氣原子或齒素原子或Cl_C6；：A2、X3和I各自獨立地 1 h烷基、c3_c7•環貌基、 127853.doc 200900058 c7-環烧基-CVC3-伸烧基、Ci-CV氟烧基、q-CV燒氧基、 C1-C6-氟烷氧基、氰基、c(0)NRiR2、硝基、Nn、 C6-硫烷基、_S(0)_Cl_C6_ 烷基、•烷基' 、NR3COR4或 nr3so2r5基團。 作為本發明主題的通式⑴化合物中，化合物的第二個子 群由下列化合物組成，其中：Xl、X2、X3和&各自獨立地 代表氫原子或鹵素原子或Cl_C6_烷基或Ci_c6_氟烷基。 作為本發明主題的通式（I)化合物中，化合物的第三個子 群由下列化合物組成，其中：Xl、X3和X4代表氫原子。 作為本發明主題的通式⑴化合物中，化合物的第四個子 群由下列化合物組成n Xl、x#X4代表氫原子且X2 代表_素原子，特定言之氟原子。 作為本發明主題的通式⑴化合物中’化合物的第五個子 群由下列化合物組成，其中： W代表下列結構式的稠合二環基： 1
其經由位置1、2、3或4與氮原子鍵合； 係選自：w、異，朵基、二氫十朵基、異二㈣ 哚基、苯并呋喃基、二氫苯并呋喃基、苯并噻吩基、二氫 ί开售吩基、苯并㈣基、二氫苯并㈣基、異苯并t南 土、-風異苯并咬喃基、笨并蜂唑基、二氫笨并,唑基、 127853.doc 200900058
吲唑基、苯并噻唑基、異笨并噻唑基、二氫異苯并噻唑 基、苯并三唑基、喹啉基、二氫喹啉基、四氫喹啉基、異 喹啉基、二氫異喹啉基、四氫異喹啉基、苯并噁嗪基、二 氫苯并噁嗪基、苯并噻嗪基、二氫苯并噻嗪基、噌啉基、 喹唑啉基、二氫喹唑啉基、四氫喹唑啉基、喹噁啉基、二 虱喧嚼《、四氫㈣琳基、时基、H秦基、四氣 醜嗅基、四氫苯并[bm雜環庚烯基、四氫料[e]氮雜環庚 烯基、四氫苯并[d]氮雜環庚稀基、四氫苯并[M_b]二氮雜環 庚，基、四氫苯并[M_e]:氮雜環庚烯基、四氫苯并 b]氧氮雜環庚稀基或四氳苯并[Μ__氮雜環庚稀基中；’ 上述基團W中的-個或多個碳及/或氮原子可選擇性 ⑴所定義取代基取代。 ％ 作為本發明主題的通式⑴化合物中，化合物的第 群由下列化合物組成’其中：贾代
.^ I，上述基團W 中的一個或多個碳及/或氮原子 取代基取代。 ⑴所定義 化合物的第七個子 作為本發明主題的通式⑴化合物中 群由下列化合物組成，其中： ’且/或 經—個或多個Cl_c6_烷 w係選自苯並咪唑基和吲哚基中 A中一個或多個碳原子可選擇性 基取代，或特定言之爲甲基；且/或 A中一個或多個氮原子可選擇性經R7取代 CV烷基，或特定言之爲甲基。 I代表Cl- 作為本發明主題的通式⑴化合物中，化合物的第八個子 127853.doc -12- 200900058 群由下列化合物組成，其中：w係選自苯並味嗤_5_基和巧 13朵-5-基中選取；且/或 A中一個或多個碳原子可選擇性經一個或多個Cl_C6_烷 基取代，特定言之爲甲基；且/或 . A中一個或多個氮原子可選擇性經&取代，&代表Ci_
Cp烷基，特定言之爲甲基。 作為本發明主題的通式⑴化合物中，化合物的第九個子 (.....% 群由化下列合物組成，其中： γ代表可選擇性經一個或多個Ci_Ce_烷基（特定言之甲基） 取代的°比咬基。 化合物中的Xl、X2、X3、X4、WY同時如上述化合物 的個子群所定義，形成第十個子群。 本發明的全文中： -Ct-cz ’其中t和Z爲選自1至7的數值，咸了解，其係指有 t至z個碳原子的碳鏈，例如：Ci_C3指有1至3個碳原子的 / ; 碳鍵； V/ -烷基指飽和之直鏈或分支鏈脂系基團。其實例可提及甲 基、乙基、丙基、異丙基、丁基、異丁基、第三丁基或 ' 戊基，等； -伸烷基指飽和之直鏈或分支鏈的二價烷基；例如：Cw伸 烷基代表直鏈的或分支鏈的丨至3個碳原子的二價碳鏈，更 特定言之爲亞甲基、伸乙基、卜甲基伸乙基或伸丙基； -伸烷基氧指含氧原子的伸烷基； -環烷基指環狀碳基團。其實例可提及環丙基、環丁基、 127853.doc -13- 200900058 環戊基或環己基等； -氟烷基指烷基中一個或多個氫原子已經氟原子取代； -烧乳基指-〇 -烧基，其中烧基如上述定義； -環烧氧基指-0-環烧基’其中環烧基如上述定義. -氟烷氧基指烷氧基中一個或多個氫原子已經氟原子取 代； -硫烧基指-S-炫:基，其中院基如上述定義； -硫氟烷基指硫院基中一個或多個氫原子經氟原子取代. -芳基指含6至10個碳原子的芳香環基。芳基實例可提及 苯基或萘基； -雜環指含一至五個選自〇、S或N中的雜原子的芳香族部 分不飽和或飽和的5-至12-員基團；雜環實例可提及氮雜環 丁烷基、吡咯烷基、旅啶基、氮雜環庚烯基、嗎啉基、硫 代嗎啉基、派嗪基、高哌嗪基、二氫噁唑基、二氮售。坐 基、二氫咪唑基、二氫吼咯基、四氫吡啶基、味唾基、〇比 唑基、噻唑基、噁唑基、異噻唑基 '異噁唑基、咦喃基、 噻吩基、噁二唑基、噻二唑基、三唑基、四唑基、^比α定 基、°比D秦基、嘧啶基、噠唤基或三嗓基； -雜芳基指含有從0、S或N中選取的1至8個雜原子的芳香 族之5-至14-員單、雙或三環雜環基團；單環雜芳基的實例 可提及味°坐基、D比唾基、嘆峻基、α惡嗤基、異嗟唾基、異 噁唑基、呋喃基、噻吩基、噁二唑基、噻二唑基、三唾 基、四唑基、咣啶基、"比嗪基、嘧啶基、噠嗪基或三嘻 基； 127853.doc -14- 200900058 二環雜芳基實例可提及吲哚基、異吲哚基、苯并呋喃基、 笨并喧吩基、苯并11 惡也基、苯并咪嗤基、吲唾基、苯并嘆 唑基、異苯并呋喃基、異苯并噻唑基、異喹啉基、吡咯并 [2,3_C]吡啶、吡咯并[2,3-b]吡啶、吡咯并[3,2-b]吡啶、吡 咯并[3,2-c]吼啶、喹啉基、異喹啉基、噌啉基、喹唑啉基 或喹噁啉基； 作爲二環雜芳基的實例，可提及的爲°比啶并[1，2-a]苯并咪 坐基嗔°坐并U，2-a]苯并咪。坐基或咪嗤并[i,2-a]苯并咪唾 基； -鹵素原子指氟、氯、溴或碘； -側氧基”指”=〇，，； -"硫代基”指" = S”。 通式⑴化合物含有一個或多個不對稱碳原子。他們以對 映異構體或非對映異構體形式存在。這些對映異構體或非 對映異構體，和其混合物，包括消旋混合物，均成為本發 明的一部分。 通式（I)化合物可呈鹼形式或與酸形成的加成鹽形式存 在。這種加成鹽亦為本發明的一部分。 這些鹽宜使用醫藥上可接受的酸製得，但是其他例如用 於純化或分離通式（I)化合物的酸鹽類亦成為本發明的— 分。 X 峠 通式（I)化合物可呈水合物或溶劑化物 ^ 、 π形式存在，亦即 與一個或多個水分子或溶劑組合或結合
α的形式。這種水合 物和溶劑化物亦形成本發明的一部分。 Q 127853.doc -15- 200900058 下文中’術語”離去基團”指藉由裂解一個雜原子鍵使電 子對分離即可脫離分子的基團。例如，在取代反應中，這 種基團可輕易經其他基團取代。這種離去基團為例如：鹵 離子或活性氫氧根，如甲烷磺酸根、苯磺酸根、對甲苯磺 酸根、三氟f基磺酸根、乙酸根，等。離去基團實例和其 製法可參見"有機化學的發展··（Advanees in 〇Fganie Chemistry)，j· March，第五版，Wiley Interscience, 2〇〇ι。 根據本發明，通式⑴化合物可根據下列流程圖丨描述的 方法製備。 根據流程圖1，通式（IV)化合物可經由通式（11)化合物（其 中Χι、X2、X3和X4如通式⑴所定義且D代表c〗_c6_烷氧基） 和通式（III)化合物的反應得到，其中γ如通式⑴所定義且 LG代表離去基團或lg代表羥基。
該反應可在如碳酸鉀或磷酸三鉀的鹼之存在下進行，最 好在催化量的如碘化亞銅的金屬鹽，和如i，2-二甲基環己 胺的添加劑之存在下進行（BuehwaldS L，L 2004, 69， 5578-5587)。 1¾後在如甲苯的溶劑中，於回流下，由以上得到的通式 (IV)化合物和通式化合物的醯胺的反應，得到通式⑴ 化β物’其中w如通式⑴所定義。通式（V)化合物的醯胺 可先經由二甲基鋁與通式（V)的胺反應製得。 127853.doc -16- (II) 200900058
流程圖1
D = CfCe-烧氧基 r/LG (HI)
根據文獻中描述或習此相關技藝之人士習知之方法，可 由相應的通式（I)、（II)和（IV)化合物（其中Xl、X2、&及/或 X4代表離去基團’如溴）經如：鈀的金屬所催化偶聯反應 製得通式（I)、（II)和（IV)化合物（其中Χι、χ2、心及/或乂 Μ 表氰基或芳基）。 127853.doc 200900058 根據文獻中描述或習此相關技藝之人士習知之方法，可 從相應通式（I)、（II)和（IV)化合物（其中Χι、、Χ3及/戍χ4 代表氰基）得到通式（1)、（11)和（1¥)化合物（其中、& 及/或Χ4代表。 根據文獻中描述或習此相關技藝之人士習知之方法，可 從相應的通式（I)、（11)和（1¥)化合物（其中&、&、&及/或 X4代表CVC6-硫烷基）氧化得到通式（1)、（11)和（IV)化合物 (其中 Χι、x2、X3及 / 或 x4 代表-S(0)_Ci_C6•烷基或_8(〇)2_ Ci-Cf 烧基）。 根據文獻中描述或習此相關技藝之人士習知之方法，可 由相應的通式（I)、（II)和（IV)化合物（其中Χι、x2、&及/或 X4代表硝基），例如：經還原及隨後的醯化或磺醯化反 應，得到通式（I)、（II)和（IV)化合物（其中Χι、x2、&及/或 X4代表 NRiRs、NR3COR4或 NR3S02R5基團）。 根據文獻中描述或習此相關技藝之人士習知之方法，由 相應的通式（I)、（II)和（IV)化合物（其中X丨、χ2、&及/或χ4 代表例如：漢原子）分別在鹼、膦和以鈀為主之催化劑存 在下，和胺、醯胺或磺醯胺進行偶聯反應，得到通式（1)、 (II)和（IV)化合物（其中X!、Χ2、χ3及/或χ4代表NRiR2、 nr3cor4或nr3so2r5)。 通式（I)、（II)和（IV)化合物，其中Xl、χ2、XA，或χ4代 表 SC^NR!!^基團，可類似 Pharmazie 1990，45，346 中描述 的方法，或根據文獻中描述或習此相關技藝之人士習知之 方法得到。 127853.doc -18- 200900058 通式⑴化合物’其中R7代表氯原子， 通式（I)化合物（其中，例如： ^催化，虱化 文獻中描述或習此相關技蔽7本甲基)得到，或經由 前文中：^此相關技藝之人士習知之任何方法得到。 -通式（Π)化合物可自商品購得或依照文 方法製得⑶如D.Knittel，Synthesis，1985^的= JP2001151771A2) T.M. Williams, j. Med Chem., 1993, 36 (9), 1291；
-通式（III)化合物可自商品購得或使用習此相關技藝之人 士習知之方法得到。 -化合物（V)和其他反應物，若未說明其製備方法時，可 自商品購得或說明於文獻中（例如w〇〇3〇497〇2、 WO03068749) ° 以下實例描述了本發明化合物的製法。這些實例沒有限 制且只說明本發明。所例舉例化合物之編號可參見表1。 由元素微量分析、LC-MS分析（液相色譜-質譜分析）和IR及/ 或NMR光譜確定所得化合物結構。 實例1 (10號化合物） N-(l，2-二甲基-1H-苯并咪唑-5-基）-5 -氟- l-(4,6-二曱基吡 啶-2-基）-1Η-吲哚-2-曱醯胺 1.1 5-氟-1-(4,6-二甲基吡啶-2-基）-1Η-吲哚-2-甲酸乙酯 在加壓管中加入4.35 g (21 mmol) 5-氟-1H-吲哚-2-曱酸 乙酯，4.29 g (23.1 mmol) 2-溴-4,6-二曱基吡啶，9.36 g (44.1 mmol)磷酸三鉀，0.66 ml (4·2 mmol) 1，2-二甲基環己 127853.doc -19- 200900058 胺，0_2 g (1.05 mmol)单化 細 4 0 , J辦化亞銅和21 mi無水甲苯。密封試 管，於110°C授拌反庫湛人& ς 1 久應混合物5天。然後，將混合物倒入 100 ml水溶液中，添加醋酴, 0曰&調即介質pH至5。添加100 ml 乙酸乙醋。分離有機相，佑床 依·序用50 ml水和50 ml飽和氯化 鈉水溶液洗滌，然後於祐酿叙1 ρ β ^ 、 说％蜆鲛鈉上乾燥，過濾和減壓濃縮。 殘質經製備性色譜法純化(溶離液：二氯甲烷/乙酸乙酯卜 知到5·56 g所需産物’該產物即連續用於合成法。
1.2 N (1，2-一甲基_1H_苯并咪ϋ基）_5_氣小(4,6_二甲 基比义_2_基）-1Η-η引哚_2_甲醯胺（1〇號化合物） 在氬氣下，將1_54如三甲基銘（2 Μ甲苯溶液）加至含 〇·34 g (2.U mm〇1) 5_胺基_12·二曱基_ιη苯并咪唑 (彻2002059110)之19_2 ml無水甲苯溶液中。在5代下授 拌15分鐘後，加入〇.6g (1.92mmQl)步驟丄」中得到的5_氣_ 1-(4,6-二曱H定_2_基）_m令朵_2_曱酸乙醋。使反應混 合物回流4 h，然後於室溫下攪拌整夜。反應混合物倒入 150 g冰和70 ml乙酸乙酯中。分離水相且用3〇 w乙酸乙酿 提取2次。合併有機相並依序用5〇 n氫氧化鈉溶 液2人之50 ml水，及一次之5〇 mi飽和氣化納溶液洗滌。 最後取有機相於硫酸鈉上乾燥，過濾和減壓濃縮。殘質經 製備性色譜法純化（溶離液：二氯甲烷/甲醇）。得到〇·7ΐ g 固體’該固體於減壓下乾燥。
M.p.: 130-140〇C HNMR (CDC13), δ (ppm): 2.4 (s, 3H); 2.57 (s, 3H); 2.58 (s，3H); 3.71 (s，3H); 7.15 (m，7H); 7.6 (m，2H); 8·7 (s,可 127853.doc 200900058 交換之1H)。 類似實例1描述的方法製備以下化合物： • N - (1 -甲基-1Η -0引0朵-5 -基）-5 -氣-1-(π比唆-4 -基）-1H -0引 哚-2-曱醯胺（1號化合物） NMR (CDC13)，δ (ppm): 3.70 (s，3H); 6.33 (d, 1H); 6.99 (m, 2H); 7.18 (m, 4H); 7.32 (m, 3H); 7.78 (s, 1H); 7.89 (s, 1H); 8_70 (s, 2H)。 • N-(l -甲基-1H-吲哚-5-基）-5-氟-1-(吡啶-3-基）-1Η-吲 哚-2-甲醯胺（2號化合物） !H NMR (CDC13), δ (ppm): 3.79 (s, 3H); 6.41 (d, 1H); 7.09 (m, 3H); 7.21 (m, 3H); 7.42 (m, 2H); 7.82 (m, 3H); 8.7 (s, 2H)。 • N-(l-甲基-1H-吲哚-5-基）-5-氟-1-(吡啶-2-基）-1Η-吲 哚-2-甲醯胺（3號化合物） NMR (DMSO D6), δ (ppm): 3.73 (s, 3H); 6.31 (d, 1H); 7.12 (txd, 1H); 7.29 (d, 1H); 7.48 (m, 7H); 7.89 (s, 1H); 7.98 (txd, 1H); 8.52 (m，1H); 10.41 (s, 1H)。 • N-(l,2-二曱基-1H-苯并咪唑-5-基）-5 -氟-1-(吡啶-4-基）-1 Η-吲哚-2-甲醯胺（4號化合物） NMR (d6-DMSO), δ (ppm): 2.50 (s, 3H); 3.72 (s, 3H); 7.19 (txd, 1H); 7.38 (m, 2H); 7.51 (m, 4H); 7.62 (d, 1H); 7_88 (s, 1H); 8.20 (d, 2H); 10.51 (s，1H)。 • N-(l,2-二曱基-1H-苯并咪唑-5-基）-5-氟-1-(吡啶-2-基）-1 Η-吲哚-2-甲醯胺（5號化合物） 127853.doc -21 - 200900058 !H NMR (d6-DMSO), δ (ppm): 2.50 (s, 3H); 3.70 (s, 3H); 7.11 (txd, 1H); 7.45 (m, 7H); 7.84 (d, 1H); 8.02 (txd, 1H); 8.55 (d, 1H); 10.49 (s，1H)。 • 1^-(1，2-二甲基-111-苯并咪唑-5-基）-5-氟-1-(吡啶-3-基）-1H-吲哚-2-甲醯胺（6號化合物） !H NMR (CDC13), δ (ppm): 2.55 (s5 3H); 3.72 (s, 3H); 7.05 (m, 2H); 7.21 (m, 2H); 7.41 (m, 2H); 7.60 (m, 2H); 7.80 (m, 1H); 8_02 (s，1H); 8.72 (m, 2H)。 • N-(l-甲基-1H-吲哚-5-基）-5-氟-1-(4-甲基吡啶-2-基）-1H-吲哚-2-甲醯胺（7號化合物） !H NMR (d6-DMSO), δ (ppm): 2.40 (s, 3H); 3.75 (s, 3H); 6.32 (d, 1H); 7.11 (txd, 1H); 7.34 (m, 7H); 7.53 (dxd, 1H); 7.91 (s，1H); 8.39 (d，1H); 10.38 (s，1H)。 • N-(l，2-二甲基-1H-苯并咪唑-5-基）-5-氟-1-(4-曱基吡 啶-2-基）-1 Η-吲哚-2-曱醯胺（8號化合物） *H NMR (d6-DMSO), δ (ppm): 2.40 (s, 3H); 2.49 (s, 3H); 3.68 (s, 3H); 7.10 (txd, 1H); 7.24 (d, 1H); 7.40 (m, 6H); 7.82 (s，1H); 8.38 (d, 1H); 10.45 (s，1H)。 • N-(l-甲基-1H-吲哚-5-基）-5-氟-1-(2-甲基吡啶-4-基）-1H-吲哚-2-甲醯胺（9號化合物） !H NMR (d6-DMSO), δ (ppm): 2.55 (s, 3H); 3.72 (s, 3H); 6.34 (d, 1H); 7.20 (m, 8H); 7.59 (dxd, 1H); 7.89 (s, 1H); 8.56 (d, 1H); 10.34 (s, 1H)。 • N-(l -甲基-1H-吲哚-5-基）-5-氟-1-(4,6-二甲基吡啶-2- 127853.doc -22- 200900058 基）-lH-D弓卜朵-2-甲醯胺（11號化合物） !HNMR (CDCI3), δ (ppm). 2 1 (s, 3H); 2.58 (s, 3H); 3.78 (s, 3H); 6.41 (d，1H); 7.〇5 ( 1H); 8.58 (s, 1H) 1TJ、 （，4H); 7·3 (m, 5H); 7.86 (s, 之通式（I)化合物的化學結 "Μ·ρ.”攔出示產物熔點， 下表1中列出某些根據本發明 構和物理性質。在這個表格中， 單位爲攝氏溫度（°c )。
表1
編號 1 2 Y 吡啶-4-基 ϋ比咬-3-基 w --- 1-甲基。弓 1-甲基吲哚-5-¾ M.p. (°C) 189-194 203 -205 3 °比。定-2-基 1-甲基吲哚-5-某 210-211 4 °比唆-4-基 1,2-二甲基笨并咪唑-5_某 226-229 5 吼咬-2-基 1,2-二甲基苯并味吨_5_某 260-261 6 °比咬-3_基 1，2-一甲基笨并哺σ坐-5-某 139-141 7 4-甲基吡啶-2-基 1-甲基吲 276 - 279 8 4-甲基吡啶-2-基 1，2-二甲基苯并味嗤_5_某 270-278 9 2-曱基吡啶-4-基 1-甲基吲口 213-216 10 4,6-二甲基吡啶-2-基 1，2-二甲基笨并咪唑-5_基 130-140 11 4,6-二甲基吡啶-2-基 1-甲基吲哚-5-基 198-199 本發明的化合物已於活體外藥理學實驗中證實這些物質 具有治療活性的優點。 對辣椒素於大鼠DRGs上所誘發電流的抑制實驗 -大鼠背根神經節（DRG)細胞的初級培養物： 127853.doc -23- 200900058 DRG的神經元係天然表現TRPV1受體。 剛出生大鼠DRGs的初級培養物係從i天大的大鼠中製 得。簡略的講，在解剖後’以胰蛋白酶處理神經節，且採 用機械性溫和研碎解離其細胞。細胞再懸浮於含1 〇 %胎牛 血清、25 mM KC1、2 mM穀胺醢胺、1〇〇 μ§/ιηι健大黴素 (gentamicin)和 50 ng/ml NGF 的伊格氏（Eagle’s)基礎培養基 中’然後放置在塗有層粘蛋白的蓋玻片上（每片〇25χ1 〇6個 細胞），然後置於12孔康寧公司（Corning)之培養皿中。細 胞在37°C、含5°/。C〇2和95%空氣的濕潤條件下培養。在培 養48 h後’加入胞嘧啶β—D-阿拉伯糖苷（1 μΜ)，抑制非神 經元細胞的生長。在培養7-10天後，蓋玻片轉移至實驗室 中進行膜片鉗研究。 -電生理學： 取含細胞製備物的測量槽（體積800 μ1)置於配有Hoffman 鏡頭（紐約Modulation Contrast)的倒置顯微鏡（〇lympus IMT2)的載片臺上，並於400><放大倍數下觀察。該槽經溶 液分配器，靠重力（2.5 ml/min)持續灌注，該分配器有8個 進口和由一個由聚乙烯管（開口 5〇〇 μηι)組成的單一出口， 且距待研究的細胞至少3 mm。採用膜片鉗技術的"全細胞" 結構。採用3D壓電陶瓷微操縱器（Burieigh，pci〇〇〇)，將 矽酸硼玻璃吸液管（電阻爲5_1〇 Mohms)移近細胞。採用連 接到由Pclamp8軟體（Axon Instruments)控制的個人電腦 (PC)的Axopatch 1D放大器（加利福尼亞州，Foster城市，
Axon Instruments)，記錄總電流（膜電位設定在_60 mV)。 127853.doc -24- 200900058 於紙上描記電流圖，同時進行數字化記錄（抽樣頻率爲1 5-25 Hz) ’可於個人電腦（pc)的硬盤中的取得。 採用微莫耳濃度辣椒素溶液時，對DRG細胞產生輸入之 陽離子電流（電壓設爲-70 mV)。爲了使受體失去敏感性之 私度降至农低，在兩次使用辣椒素之間至少間隔1分鐘。 經過對照試驗期（僅穩定辣椒素單一反應）後，僅施用指定 濃度（濃度爲10 nM或0.1 nM)之試驗化合物，歷時4_5分 鐘’這段期間進行了多次辣椒素+化合物實驗（得到最大抑 制性）。其結果以相對於對照辣椒素反應的抑制％來表示。 在10 nM至0_1 nM濃度下測試的大多數本發明活性化合 物對辣椒素（1 μΜ)反應之抑制百分比在2〇%至1〇〇%之間 (見表2中的實例）。 本發明化合物因此是TRPV1型受體的有效活體外拮抗 劑。 表2 化合物編號 由DRG膜片甜技術測得的抑制0/。 10 70% (10 nM) 這些實驗的結果顯示大多數本發明化合物可阻斷TRpv【 受體的刺激。 本發明化合物因此可用於製備醫藥，特別用於製備供預 防或治療與TRPV1型受體相關的病理的醫藥。 ^ 因二’依據另-態樣，本發明主題爲含有通式⑴化合物 或醫藥上可接焚的0或上述化合物的纟合物或溶劑化物的 127853.doc •25- 200900058 醫藥。 运些醫樂係用於醫療’特定言之用於預防及/或治療長 期之神經性（外傷、糖尿病性、新陳代謝性、感染性、中 毒性、由抗癌劑治療法或醫生治療法所引起的）疼痛和發 炎、（骨）關節炎或風濕性之疼痛、纖維肌痛、背痛、與癌 症相關的疼痛、三又神經痛、頭痛、偏頭痛、牙痛、燒 傷、曬傷、咬傷或刺痛、疱疹後神經痛、肌肉痛、神經壓 追（中柩及/或周圍）、骨趫及/或腦外傷、局部缺血（骨髓及/ 或月旬）、神經退化、出血性血管病（骨趙及/或腦）或 疼痛。 本發明化合物亦用於預防及/或治療代謝失調，如 病。 本發明化合物可用於製備供預防及/或治療泌尿系統病 邊，如膀胱機能宄進、膀胱反射宄進、膀脱不穩定失 禁'急性撒尿、尿失禁、膀胱炎、腎絞痛、骨盆過敏和骨 盆疼痛的醫藥。 β 本發明化合物可用於製備供預防及/或治療婦科疾病， 如.外陰痛、與輪卵管炎相關的疼痛或痛經的醫藥。 這人些産物亦可用於製備供預防及/或治療胃腸病變，如 =道逆流疾病、胃潰癌、十二指腸潰癌、官能性消化 〈、結腸炎'IBS、克羅恩氏（Crohn，s)病、騰腺炎 道火或膽石絞痛的醫藥。 < 同樣’本發明產物可用於預防及/或治療 如峡# 次性疾病， 尋而、咳漱、COPD(慢性阻塞性肺病）、彡知一 又軋管收縮和 127853.doc -26- 200900058 炎症。這些產品亦可用於預防及/或治療乾癬、瘙癢、皮 膚、眼睛或粘膜的刺激、疱疹或帶狀疱疹。 本發明化合物亦可用於治療抑鬱症。 本發明化合物亦可用於治療中樞神經系統疾病，如多發 性硬化。 根據它的另一個態樣，本發明係關於含有根據本發明的 &物作爲有效成分的醫藥組合物。這些醫藥組合物含有
2效劑量的至少一種依據本發明化合物，或該化合物之醫 藥上可接党的鹽、水合物或溶劑化物’和至少一種醫藥上 可接受的賦形劑。 上述賦形劑可根據所需醫藥形態和投藥方法，從習此相 關技藝之人士習知之常用的賦形劑中選擇。
用於經口、舌下、由T Μ内 皮下、肌内、靜脈、外用、局部、氣 :、鼻内'穿透皮膚或經直腸投與本發明的醫藥組合物 物上述式⑴活性成分，或其視需要形成之鹽類、溶劑化 ::戈：合物可和常用之醫藥賦形劑形成混合物，以單位投 :。式投與動物和人類，供預防或治療上述的病變或疾 適當的單位投藥形式包括 戍硬性明®畚 。栝口服用型式，>:錠片、軟性 Α更！·生明膠囊、粉末、 〃 禾顆拉和口服用溶液或懸浮液，經舌 Γ頌内、氧管内、眼 外用、穿透皮“ 鼻内的投藥形式’經吸入、 牙透皮膚、皮下、肌内 腸投藥形式和植人物。根攄太旎㈣投㈣式，經直 膠、軟膏或洗液供外用投藥。X明的化合物可呈乳霜、凝 127853.doc •27· 200900058 舉例說明，根據本發明的錠片型單位投藥型式可含有以 下成分： 根據本發明的化合物 50.0 mg 甘露糖醇 223.7 5mg 交聯羧甲纖維素鈉 6.0 mg 玉米澱粉 15.0 mg 羥丙基甲基纖維素 2.25 mg 硬脂酸鎂 3.0 mg 上述單位劑型之所含劑量將根據醫藥劑型，使每公斤體 重之活性成份曰劑量爲 0.001 至 30 mg ° 可能有特殊的情况需要較高或較低的適當劑量；這種劑 量不偏離發明的範_。 根據慣例，可由醫師根據投藥方法 和遠病人的體重和反應 ，來决定適於每個病人的劑量。 根據另一態樣，本發明亦關於一種用於治療如上所述的 病理的方法，包括對患者投與有效劑量的根據本發明化合 物’或其醫藥上可接受的鹽或水合物或溶劑化物。 127853.doc -28-
Claims (1)
- 200900058 十、申請專利範圍： 1. 一種通式（I)化合物：χ»、χ2’ χ3’ χ4各自獨立地代表氫原子或函素原子或 CVCV烧基、c3_c7_環燒基、c3_c7•環烧基_Ci_C3_伸烧 基、q-CV氟烷基、CVC6-燒氡基、Ci_c6_敗烷氧基、氰 基、c(o)NRlR2、硝基、NRiR2、Ci_C6_硫烷基、_s(〇)_ q-CV 院基、_S ⑼ 2_Cl_C6.院基、s〇2nRiR2、NR;c〇R4 NR3S〇2R5或芳基，芳基可選擇性經一個或多個選自鹵 素或cvc6-烷基、c3_c7_環烷基、C3_C7_環烷基-伸 烷基、CVCV氟烷基、（^46_烷氧基、Ci_c6_氟烷氧基、 硝基或氰基的取代基取代； w代表下式的稠合二環基：其經由位置1、2、3或4與氮原子鍵合； A代表含有從〇、S或N中選取的一個至三個雜原子的 127853.doc 200900058 5-至7-員雜環； A中一個或多個碳原子可選擇性經一個或多個選自氳原 子或Ci-CV烷基、c3-C7-環烷基、C3-C7-環烷基-CVC3-伸 院基、G-CV氟烷基、Cl_c6·烧氧基、C3-C7-環烷氧基、 C3-C7-環烧基-CrCV伸烷氧基、芳基、芳基_Cl_c6_伸烷 基、側氧基或硫代基中的基團取代； 當鄰接氮原子的碳原子被側氧基，或在其他情况下經R7取代時’ A中一個或多個氮原子可選擇性經R6取代； γ代表可選擇性經一個或多個選自鹵素原子或Ci_c6_烷 基、c3-c7-環烧基、C3_C7_環烷基_Ci_C3,烷基、Ci_C6 氟烷基、羥基、cvcv烷氧基、Cl_c6_氟烷氧基、Ci_C6_ 硫氟烷基、氰基、c(0)NRiR2、硝基、NRiR2、Ci_c6_硫 烷基、SH、-8(0X1·。烷基、_s(〇)2_Ci C6_烷基、 ⑼-C3-CV 環燒基、-s(〇)2·、C3_C7•環烧基' s〇2NRlR2、皿3COR4、NR3S〇2R5、芳基 _Ci C6 伸烧基 或芳基中的㈣取代的”基；料基和U_Cl_C6伸 烧基可選擇性經一個戋容佃、g 6占 飞多個選自鹵素或C丨-C6-烷基、c3- C7-環烧基、C3-C7-環检糞r ρ认& 衣烷基-C丨-c3_伸烷基、Ci_C6_氟烷 基、CVCV烧氧基、p 6_氟烷氧基、硝基或氰基中的取 代基取代； Ri和R2各自獨立地代矣& π，丄、 r r 代表齒素原子或CK6-貌基、C3-C7· %烷基、c3-c7-環燒基夂义·伸烧基、 其十艺且.·VDin 々丞-C丨-C6-伸烧 基或务基，或¥R2與其所附接之氮原 雜環丁烷基、吡咯烷Λ、总& w _ /、门、、、。δ成氮 土0咬土、氮雜環庚烯基、嗎啉 127853.doc -2- 200900058 基、硫代嗎琳基、旅嗓基或高旅嘹基（homopiperazinyl)， 該基團可選擇性經CVC6-烷基、C3-C7-環烷基、C3-C7-環 烷基-CrC^-伸烷基、芳基-CrCe-伸烷基或芳基取代； R3和R·4各自獨立地代表氫原子或CrCr烷基、芳基-Q-Cr伸烷基或芳基； Rs代表CVCV烷基、芳基-CVCV伸烷基或芳基； R6代表氫原子或q-CV烷基、C3-C7-環烷基、c3-C7-環 烷基-Ci-CV伸烷基、CVC6·氟烷基、芳基-CkCV伸烷基 或芳基； R7代表氫原子或（VC6-烷基、Cs-C7-環烷基、c3_c7_環 烷基-CVCr伸烷基、Cl_C6_氟烷基、芳基_Ci_c6_伸烷 基、（VCV烷基-C(O)-、（VC7_環烷基_Ci_c3_伸烷基_ (CO)-、CVC6-敗院基-c(0)-、c3-c7-環烧基 _c(0)、芳 基-C(O)-、芳基-Cl-C6-伸烷基 _c(0)_、Ci_C6_ 烷基 _s(〇)2_ CrCV氟院基_s(0)2_、C3_C7_環烧基·s(〇)2_、CrC7_環 芳基_s(〇)2-、芳基-cvcv伸2. 烷基-CrCV伸烧基-S(〇)2_ 炫基-S ( Ο ) 2 -或芳基； 雜核A或雜芳基γ中的—個或多個硫原子可爲氧化形式； 雜環A或雜芳基γ中的—個或多個氮原子可爲氧化形式；’ 其係呈鹼形式或與酸形成加成鹽形式，且亦可呈水合 或溶劑化物形式。 σ 如請求項1之式⑴化合物，其特徵在於其中Χ1、Χ2、Χ 和Χ4各自獨立代表氫原子或- 2 Γ^^ 飞鹵素原子或Ci-C6-烷基或Cl_ 6-亂烷基；其係呈鹼形式或與酸形成加成鹽形式，且亦 127853.doc 200900058 呈水合物或溶劑化物形式。 3. 如請求们之式⑴化合物，其特徵在 代表氫原子；其係呈驗形式或與酸形^、Η3和X4 亦可呈水合物或溶劑化物形式。、V成鹽形式’且 4. 如請求項3之式⑴化合物，其特徵在 表氫®子丨X讲矣占表 ’、中χι、和X4代 t虱原子且X2代表_素原子；其係呈驗 加成鹽形式，且亦可呈水人 -/、酸形成 Χ σ物或溶劑化物形式。 I Sr:1至4中任一項之式⑴化合物，其特徵在於其中 w代表如下式的稠合環基： ΚΘ 4 其係經由位置1、2、3或4與氮原子鍵合； 且㈣係選自《基、異❹基、二氫”基、異二氣 °引嗓基、苯并吱D南基、二氫苯并咬喃基、苯并嗟吩基、 一氫苯并噻吩基、苯并噁唑基、二氫苯并噁唑基、異苯 并夫南基 '一氫異苯并呋喃基、苯并咪唑基、二氫苯并 米坐基、u引嗤基、苯并嚷。坐基、異苯并喧吐基、二氫異 笨并嗟唾基、苯并三嗤基、啥琳基、二氫啥淋基、四氫 喹啉基、異喹啉基、二氫異喹啉基、四氫異喹啉基、苯 并喔嘻基、二氫苯并噁嗪基、苯并噻嗪基、二氫苯并噻 秦基、嗜琳基（cinnoliny〗）、啥°坐淋基、二氫啥唾淋基、 四氫啥唾啉基、喹噁啉基、二氫喹噁啉基、四氫喹噁啉 127853.doc 200900058 基、酞嗪基、二氫酞嗪基、四氫 雜環庚縣、以料⑻氮 雜環庚稀、四氫苯并Γ14Μ .烯基、四氣苯并⑷氮 w四虱本开n，4_b]二氮雜環庚稀基、 ，-e]—氮雜環庚烯基、四氫苯朴，叫 基或四氫苯并π，4蜗氮雜環庚= 或氮原子(群)可選擇性如請求们二;::： '，生取代，其係呈鹼形式或與 呈水合物或溶劑化物形式:…-形式’且亦可 m項5之式⑴化合物’其特徵在於其中該w係選自 :咪唾基或十朵基中，.A中-個或多個碳原子可選擇 性經—個或多個〇1_(：6_烷美取符.于了選擇 可選擇性經r7取代二:表^ 或與酸形1 基，其係呈鹼形式 式。 成鹽形式，且亦可呈水合物或溶劑化物形 7.如請求項6之式（1)化合物，其特徵在 —、， …^ w丹甲该W係選自 本开''坐-5-基或吲哚_5_基；Α中一個或多個碳原子可選 擇生個或多個仏々烧基取代；人中一個或多個氮原 子可選擇性經r7取代，R7代表Ci_C6_烷基；其係呈鹼形 式或與馱形成加成鹽形式，且亦可呈水合物或溶劑化 形式。 _ 員1至7中任一項之式⑴化合物，其特徵在於其中 該y代表選擇性經一個或多個Ci_c6_烧基取代的吼咬基； 係呈鹼形式或與酸形成加成鹽形式，且亦可呈水合物 或溶劑化物形式。 127853.doc 200900058 9. 一種製備如請求項1至8中任一項之式（I)化合物之方法 其特徵在於由通式（IV)化合物：(其中X!、X2、X3、X4和γ係如請求項1的通式⑴中所定 義，且D代表CVC6-烷氧基）， 在溶劑回流下’與通式（V)化合物的醯胺反應： Η v\Tn、h (V) 其中W係如請求項1的通式⑴中所定義， 可先由二甲基鋁對於通式（V)的胺反應，製得通式（V)化 合物的酿胺。 10. —種藥劑，其特徵在於其含有如請求項丨至8中任一項之 式⑴化合物、或式⑴化合物的醫藥上可接受的鹽、或水 合物或溶劑化物。 11· -種醫藥組合物，其特徵在於其含有如請求項⑴中任 -項之式⑴化合物、或該化合物的醫藥上可接受的鹽、 或水合物或溶劑化物，和至少— ) 種醫樂上可接受的賦形 劑。 12 · —種如請求項1至8中任一項之彳 項之式（I)化合物之用途，其係 127853.doc 200900058 用於製造供預防或治療與TRPV丨型受體相關病症的醫 藥。 13.—種如請求項1至8中任一項之通式⑴化合物之用途，其 係用於製造供預防或治療疼痛；發炎；代謝失調；泌尿 系統病變；婦科疾病；胃腸病變；呼吸性疾病；乾癖； ’反廣、眼睛或粘膜的刺激；疱疹；帶狀疱疹；多 I性硬化症或抑鬱症之醫藥。127853.doc 200900058 七、指定代表圖： (一) 本案指定代表圖為：（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： /127853.doc
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| FR2926555B1 (fr) * | 2008-01-22 | 2010-02-19 | Sanofi Aventis | Derives bicycliques de carboxamides azabicycliques, leur preparation et leur application en therapeutique |
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| LT2986610T (lt) | 2013-04-19 | 2018-04-10 | Incyte Holdings Corporation | Bicikliniai heterociklai, kaip fgfr inhibitoriai |
| US10851105B2 (en) | 2014-10-22 | 2020-12-01 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
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| MA41551A (fr) | 2015-02-20 | 2017-12-26 | Incyte Corp | Hétérocycles bicycliques utilisés en tant qu'inhibiteurs de fgfr4 |
| AR111960A1 (es) | 2017-05-26 | 2019-09-04 | Incyte Corp | Formas cristalinas de un inhibidor de fgfr y procesos para su preparación |
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| WO2021067374A1 (en) | 2019-10-01 | 2021-04-08 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
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| EP2125787B1 (fr) | 2017-03-01 |
| CL2008000127A1 (es) | 2008-05-23 |
| FR2911604A1 (fr) | 2008-07-25 |
| AR064937A1 (es) | 2009-05-06 |
| US7868024B2 (en) | 2011-01-11 |
| JP5264773B2 (ja) | 2013-08-14 |
| EP2125787A1 (fr) | 2009-12-02 |
| US20090306143A1 (en) | 2009-12-10 |
| ES2624795T3 (es) | 2017-07-17 |
| PE20081689A1 (es) | 2008-12-31 |
| WO2008107544A1 (fr) | 2008-09-12 |
| UY30874A1 (es) | 2008-09-02 |
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