TW202214599A - 作為jak激酶抑制劑的小分子化合物及其應用之用途 - Google Patents
作為jak激酶抑制劑的小分子化合物及其應用之用途 Download PDFInfo
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- TW202214599A TW202214599A TW110137631A TW110137631A TW202214599A TW 202214599 A TW202214599 A TW 202214599A TW 110137631 A TW110137631 A TW 110137631A TW 110137631 A TW110137631 A TW 110137631A TW 202214599 A TW202214599 A TW 202214599A
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- compound
- cycloalkyl
- molecule compound
- small molecule
- heterocycloalkyl
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- 230000036961 partial effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 229940126703 systemic medication Drugs 0.000 description 1
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- 238000002626 targeted therapy Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
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- 230000001960 triggered effect Effects 0.000 description 1
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- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—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 three or more hetero rings
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
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- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
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- A61P37/00—Drugs for immunological or allergic disorders
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
本發明提供了一種小分子化合物,所述小分子化合物為由下式表示的
化合物,或其立體異構體、幾何異構體、互變異構體、水合物、溶劑化物、以及藥學上可接受的鹽或前藥,其中R1至R5各自獨立地選自C或N;並且其中R選自環烷基、取代的環烷基、雜環烷基、取代的雜環烷基、芳基、取代的芳基、雜芳基或取代的雜芳基。本發明的小分子化合物能夠抑制JAK激酶,更特別是作為JAK1/Tyk2雙抑制劑和Tyk2特異性抑制劑。
Description
本發明屬於小分子化合物領域,具體地,涉及一種能夠用於預防或治療緩解自身免疫性疾病如風濕性關節炎、潰瘍性結腸炎和系統性紅斑狼瘡等,或相關的炎症性皮膚病如銀屑病、濕疹、白癜風和斑禿等的小分子化合物。
JAK(Janus激酶,Janus Kinase)是細胞內非受體性酪氨酸蛋白激酶的一個家族,包括JAK1、JAK2、JAK3和Tyk2四個成員。JAK-STAT(轉錄蛋白的信號轉導和啟動劑,Signal Transducer and Activator of Transcription proteins)信號傳導通路是炎症性細胞因數和受體相結合之後激發的信號在細胞內傳導的主要通路。許多證據表明,JAK-STAT信號傳導通路在很多疾病的發病機理中起到不可或缺的驅動作用,特別是自身免疫性疾病如風濕性關節炎、紅斑狼瘡、炎症性腸病、多發性硬化、乾燥綜合征、銀屑病、斑禿和白癜風等;過敏性疾病如哮喘、過敏性鼻炎、過敏性結膜炎、特應性皮炎和濕疹等等。因此,利用高效的小分子對JAK激酶活性,特別是JAK1、TYK2激酶活性進行抑制可以阻斷參與炎症反應的細胞因數介導的信號通路,從而控制炎症,有效治療自身免疫性疾病和/或過敏性炎症性疾病。
不同炎症性疾病發病過程中T細胞會根據不同的炎症誘發因素如病毒或細菌感染而向不同的方向分化,形成Th1,Th2,Th17等T細胞亞群,這些T細胞相應地產生不同的細胞因數,如與病毒感染引起的急性炎症相關的Th1細胞產生IFNγ,IL-2;與過敏有關的Th2細胞產生IL-4,IL-5,IL-13;與自身免疫
有關的Th17細胞產生IL-17,IL-12,IL-21,IL-22,IL-23;這些細胞因數和細胞表面的受體結合後,通過細胞內的JAK傳遞炎症信號,驅動疾病的病理過程。更重要的是,很多病因不清楚的炎症性疾病發表機理複雜,在不同的階段甚至同一階段會涉及多種T細胞亞群,也就是會涉及多個JAK通路,這就對開發針對JAK的炎症性疾病治療藥物提出了新的要求。
雖然有研究報導JAK1抑制劑對Th2類過敏性炎症有特異性抑制,同時有效抑制JAK1和/或TYK2抑制劑的研究鮮有報導,尤其我們認為JAK1/Tyk2雙抑制劑和Tyk2抑制劑在臨床上有更廣泛的前途,尤其發病機制涉及到自身免疫異常的炎症性疾病。此外,更多的炎症性疾病尤其是炎症性皮膚病的發病機理可能涉及多個JAK,因此開發強效JAK1和Tyk2的單抑制劑或雙抑制劑具有重要意義,尤其用於皮膚病的外用治療,強效抑制劑在帶來很好的療效的同時又能避免系統用藥造成的副作用,但是這將同時需要很強的抑制活性才能實現。
本發明的目的旨在獲得高效的JAK1/Tyk2雙抑制劑和Tyk2特異性抑制劑,為不同的炎症性疾病提供有針對性的靶向治療,例如JAK1/Tyk2雙抑制劑可能適合於SLE、白癜風、IBD和濕疹等疾病,Tyk2特異性抑制劑可能更適合於治療類風濕性關節炎、銀屑病和斑禿等,同時克服由於抑制JAK2帶來的造血抑制和凝血異常。另外,選擇適合用於外用給藥途徑如針對炎症性皮膚病外用與疾病病因和症狀表現相關聯的不同性質的JAK家族成員抑制劑對疾病進行干預和症狀控制,能夠獲得好的治療效應。
為了實現上述目的,在一方面,本發明提供了一種小分子化合物,所述小分子化合物為由如下所示的式I表示的化合物,或其立體異構體、幾何異構體、互變異構體、水合物、溶劑化物、以及藥學上可接受的鹽或前藥:
其中,R1至R5各自獨立地選自C或N;並且
其中,R選自環烷基、取代的環烷基、雜環烷基、取代的雜環烷基、芳基、取代的芳基、雜芳基或取代的雜芳基。
在一個實施方式中,R1至R5中的至多兩個為N。
在另一個實施方式中,R具有如下所示的式II表示的結構:
其中,R6選自C或N;
其中,R7選自氫、鹵素、烷基、氨基、醯胺基、環烷基、雜環烷基、芳基或雜芳基;並且
R8選自氫、烷基、環烷基、雜環烷基、芳基或雜芳基。
在另一個實施方式中,R7和R8各自獨立地選自氫、烷基或環烷基。
在另一個實施方式中,R具有如下所示的式III表示的結構:
其中,R9選自C或N;
其中,R10選自氫、鹵素、烷基、氨基、醯胺基、環烷基、雜環烷基、芳基或雜芳基;並且
R11選自氫、烷基、環烷基、雜環烷基、芳基或雜芳基。
在另一個實施方式中,R10和R11各自獨立地選自氫、烷基或環烷基。
在另一個實施方式中,所述烷基為甲基、乙基、丙基或異丙基,所述環烷基為環丙基、環丁基或環丙基甲基。
在另一方面,本發明還提供了如上所述的小分子化合物在抑制JAK激酶中的用途。
在另一方面,本發明還提供了如上所述的小分子化合物在製備用於預防或治療JAK相關的自身免疫性疾病、以及與免疫有關的炎症性皮膚疾病的藥物中的用途。
在一個實施方式中,所述自身免疫性疾病選自類風濕性關節炎、強直性脊柱炎、潰瘍性結腸炎、克羅恩病、系統性紅斑狼瘡、皮肌炎、多發性硬化、I型糖尿病、乾燥綜合症和血管炎中的至少一種。
在另一個實施方式中,所述與免疫有關的炎症性皮膚疾病選自特應性皮炎、濕疹、斑禿、銀屑病、白癜風、扁平苔蘚、光澤苔蘚、硬化萎縮性苔蘚、脂膜炎、痤瘡和化膿性汗腺炎中的至少一種。
本發明的作用和效果:
本發明根據JAK激酶的蛋白結構,特別是Tyk2的蛋白結構,進行了小分子化合物有目的的合理設計,合成的化合物首先進行JAK的激酶生化活性檢測,根據IC50建立SAR(structure-activity relationship),對IC50在200nM以下的強效抑制劑再進行細胞學的測試,並確定化合物的選擇性。參見具體活性實驗資料可以發現,本發明涉及的化合物具有良好的JAK激酶活性和細胞生物學活性的抑制能力。
以下對本發明的具體實施方式進行詳細說明。應當理解的是,此處所描述的具體實施方式僅用於說明和解釋本發明,並不用於限制本發明。
在本文中所披露的範圍的端點和任何值都不限於該精確的範圍或值,這些範圍或值應當理解為包含接近這些範圍或值的值。對於數值範圍來說,各個範圍的端點值之間、各個範圍的端點值和單獨的點值之間,以及單獨的點值之間可以彼此組合而得到一個或多個新的數值範圍,這些數值範圍應被視為在本文中具體公開。
在詳細描述本發明前,應瞭解,在此使用的術語只在於描述特定的實施方式,而不希望限制本發明的範圍,本發明的範圍僅由所附權利要求書限定。為
了更完全地瞭解在此描述的本發明,採用以下術語,它們的定義如下所示。除非另外定義,在此使用的所有技術和科學術語具有與本發明所屬領域的普通技術人員所理解的相同的含義。
在一方面,本發明提供了一種小分子化合物,所述小分子化合物為由如下所示的式I表示的化合物,或其立體異構體、幾何異構體、互變異構體、水合物、溶劑化物、以及藥學上可接受的鹽或前藥:
其中,R1至R4各自獨立地選自C或N;並且
其中,R選自環烷基、取代的環烷基、雜環烷基、取代的雜環烷基、芳基、取代的芳基、雜芳基或取代的雜芳基。
也就是說,R1、R2、R3、R4和R5可以各自獨立地選自C或N。在一個優選的實施方式中,R1至R5中的至多三個(即0、1、2或3個)可以為N。在一個優選的實施方式中,R1至R5中的至多兩個(即0、1或2個)可以為N。在另一個優選的實施方式中,R1至R5中的至多一個(即0或1個)可以為N。
根據本發明,在一個優選的實施方式中,R可以具有如下所示的式II表示的結構:
其中,R6可以選自C或N;
其中,R7選自氫、鹵素、烷基、氨基、醯胺基、環烷基、雜環烷基、芳基或雜芳基;並且
R8選自氫、烷基、環烷基、雜環烷基、芳基或雜芳基。
在一個更優選的實施方式中,R7和R8可以各自獨立地選自氫、烷基或環烷基,進一步,所述烷基可以為甲基、乙基、丙基或異丙基,所述環烷基為環丙基、環丁基或環丙基甲基。
例如,在一個具體的實施方式中,R6為N,R7為甲基,且R8為甲基。在這種情況下,R可以具有如下所示的結構:。
例如,在一個具體的實施方式中,R6為C,R7為甲基,且R8為乙基。在這種情況下,R可以具有如下所示的結構:。
例如,在一個具體的實施方式中,R6為N,R7為甲基,且R8為氫。在
這種情況下,R可以具有如下所示的結構:。
根據本發明,在另一個優選的實施方式中,R可以具有如下所示的式III表示的結構:
其中,R9可以選自C或N;
其中,R10選自氫、鹵素、烷基、氨基、醯胺基、環烷基、雜環烷基、芳基或雜芳基;並且
R11選自氫、烷基、環烷基、雜環烷基、芳基或雜芳基。
在一個更優選的實施方式中,R10和R11可以各自獨立地選自氫、烷基或環烷基,進一步,所述烷基可以為甲基、乙基、丙基或異丙基,所述環烷基為環丙基、環丁基或環丙基甲基。
如本文所用,術語“藥學上可接受的”是指不影響本發明化合物的生物活性或性質的物質,並且相對無毒,即該物質可施用於個體而不造成不良的生物反應或以不良方式與組合物中包含的任意組分相互作用。在本發明中,“藥學上可接受的鹽”可以包括無機鹽和有機鹽,其中,所述有機鹽可以包括但不限於銨、鋰、鈉、鉀、銫、鈣、鎂、銅、鋁、鋅、鋇或季銨鹽,並且所述無機鹽可以包括但不限於精氨酸、叔丁胺、二甲胺、二乙醇胺、乙醇胺、乙二胺、咪唑、賴氨酸、甲胺、吡啶、吡啶甲酸酯、呱嗪、三乙胺、三乙醇胺、三甲胺或脲鹽。
在另一方面,本發明提供了上述小分子化合物在抑制JAK激酶中的用途,特別是作為JAK1/Tyk2雙抑制劑和Tyk2特異性抑制劑。
在另一方面,本發明還提供了上述小分子化合物在製備用於預防或治療自身免疫性疾病、以及與免疫有關的炎症性皮膚疾病的藥物中的用途。研究表明,這些疾病的發病機理均與JAK信號傳導的失調相關。
如本文所用,術語“治療”是指根據治療性方案的治療性試劑的任何施用,所述治療性方案達到所需效果,即部分或完全減輕、改善、緩解、抑制、延遲發作、降低嚴重程度和/或降低特定疾病、障礙和/或病症的一種或多種症狀或特徵的發生率;在一些實施方式中,根據治療性方案的治療性試劑的施用與所需效果的實現相關。這種治療可以針對沒有表現出相關疾病、障礙和/或病症的受試者和/或針對僅表現出疾病、障礙和/或病症的早期跡象的受試者。替代地或另外地,這種治療可以針對表現出相關疾病、障礙和/或病症的一種或多種所確定跡象的受試者。在一些實施方式中,治療可以針對已被診斷患有相關疾病、障礙和/或病症的受試者。在一些實施方式中,治療可以針對已知具有一種或多種易感因素
的受試者,所述易感因素在統計學上與相關疾病、障礙和/或病症發展的風險增加相關。
根據本發明,上述用途中制得的藥物可以包含有效量的本發明的小分子化合物,以及藥學上可接受的賦形劑、載體或稀釋劑。
如本文所用,術語“有效量”、“治療有效量”或“藥學有效量”是指對於治療的受試者以適用於任何藥物治療的合理受益/風險比賦予治療效果的治療性試劑的量。這樣的治療效果可以是客觀的(即可以通過某種測試或標記測量)或主觀的(即受試者給出指示或感覺到效果)。在一些實施方式中,“治療有效量”是指諸如通過改善與疾病有關的症狀、預防或延遲疾病發作和/或還減輕疾病症狀的嚴重性或頻率來有效治療、改善或預防(例如延遲發作)相關疾病或病症和/或表現出可檢測的治療或預防效果的治療性試劑或組合物的量。
本領域的技術人員將認識到,待施用的所述小分子化合物的治療有效量將根據以下各項而變化:受試者和疾病的性質和嚴重程度、受試者的身體狀況、治療方案(例如是否使用第二治療劑)、以及所選擇的施用途徑;合適的劑量可以由本領域的技術人員容易地確定。另外,該藥物的個體劑量的最佳數量和間隔將通過所治療的病狀的性質和程度、施用的形式、途徑和位置、以及所治療的特定受試者的年齡和病狀確定,並且醫師將最終確定待施用的合適劑量。此劑量可以視需要重複多次。如果出現副作用,則可以根據正常臨床實踐改變或減少劑量的量和/或頻率。
在本發明中,“藥學上可接受的賦形劑、載體或稀釋劑”包括但不限於任何被相關的政府管理部門許可為可接受供人類或家畜使用的佐劑、載體、賦形劑、助流劑、增甜劑、稀釋劑、防腐劑、染料/著色劑、矯味劑、表面活性劑、潤濕劑、分散劑、助懸劑、穩定劑、等滲劑、溶劑或乳化劑等。
根據本發明,進一步地,上述用途中制得的藥物除了可以包含本發明的
小分子化合物作為有效成分之外,還可以包含其他可用於預防或治療自身免疫性疾病、以及與免疫有關的炎症性皮膚疾病的藥劑作為另一種有效成分。所述藥劑的實例包括但不限於維生素D衍生物、維生素A衍生物、糖皮質激素、鈣調神經磷酸酶抑制劑或非甾體類抗炎藥等。當該藥物包含多種有效成分時,各有效成分可以根據醫師的判斷同時、依次或分開施用。
另外,本發明的小分子化合物可以通過多種途徑施用于患者,這些途徑諸如口服、透皮、皮下、鼻內、靜脈內、肌內、鞘內、區域或局部(例如粘膜)。在任何給定情況下最適合的施用途徑將取決於受試者和疾病的性質和嚴重程度、以及受試者的身體狀況等。在一個實施方式中,本發明的小分子化合物可以經靜脈內施用。在另一個實施方式中,本發明的小分子化合物可以口服施用。相應地,根據不同的施用方式,本發明的藥物可以製備為不同的劑型。例如,在一個實施方式中,所述藥物可以製備為片劑、膠囊劑、丸劑、顆粒劑、霧化劑、噴霧劑或注射劑。
經發明人研究發現,本發明的小分子化合物或其制得的藥物在用於預防或治療JAK相關的自身免疫性疾病、以及與免疫有關的炎症性皮膚疾病能夠發揮優異的效果。具體地,所述自身免疫性疾病可以包括但不限於類風濕性關節炎、強直性脊柱炎、潰瘍性結腸炎、克羅恩病、系統性紅斑狼瘡、皮肌炎、多發性硬化、I型糖尿病、乾燥綜合症和血管炎等;而所述與免疫有關的炎症性皮膚疾病可以包括但不限於特應性皮炎、濕疹、斑禿、銀屑病或白癜風、扁平苔蘚、光澤苔蘚、硬化萎縮性苔蘚、脂膜炎、痤瘡和化膿性汗腺炎等。
以下,將通過實施例對本發明的特定小分子化合物的效果進行詳細描述。
實施例
實施例1 合成化合物1的一般方法(TDM-180973)
步驟1:化合物1c(2-氯-4-(1H-吡咯-3-基)嘧啶)的製備
向250mL三口燒瓶中加入化合物1a(2g,13.43mmol),化合物1b(4.69g,13.43mmol),四(三苯基膦)鈀(940mg,1.08mmol),碳酸鉀(3.7g,26.85mmol),二氧六環(120mL)和水(120ml)。反應液氮氣置換數次,升溫至80℃反應45分鐘,LCMS[M+H]+=180,檢測反應完全。後處理:反應液濃縮拉幹,得到的粗品過柱,[洗脫劑:(EA/PE)=0-30%]得到黃色固體目標化合物(化合物1c,1.13g,收率46.86%),LCMS[M+1]+=180。
步驟2:化合物1e(3-(3-(2-氯嘧啶-4-基)-1H-吡咯-1-基)-3-(氰基甲基)氮雜環丁烷-1-羧酸叔丁酯)的製備
向化合物1c(1.23g,6.88mmol)的乙腈(100ml)溶液鐘加入化合物1d(1.47g,7.56mmol),1,8-二氮雜二環十一碳-7-烯(710mg,4.68mmol),反應液升溫至70℃攪拌2小時。LCMS[M+H]+=374,檢測反應完全。後處理:反應液濃縮拉幹,得到的粗品過柱,[洗脫劑:(EA/PE)=0-30%]得到黃色固體目標化合物(化合物1e,2.085g,收率81.09%),LCMS[M+H]+=374。
步驟3:化合物1f(2-(3-(3-(2-氯嘧啶-4-基)-1H-吡咯-1-基)氮雜環丁烷-3-基)乙腈)的製備
向化合物1e(1.6g,4.3mmol)的二氯甲烷(128ml)溶液中加入三氟乙
酸(25.6ml),反應液室溫攪拌一小時。LCMS[M+H]+=274,檢測反應完全。後處理:反應液在冰浴下用三乙胺中和,濃縮拉幹,得到的粗品過柱,[洗脫劑:(D/M=10/1):DCM=0-50%]得到黃色固體目標化合物(化合物1f,950mg,收率89.7%),LCMS[M+H]+=274。
步驟4:化合物1h((S)-2-(3-(3-(2-氯嘧啶-4-基)-1H-吡咯-1-基)-1-(2,2-二氟環丙烷-1-羰基)氮雜環丁-3-基))的製備
向化合物1f(1g,3.65mmol)的N,N-二甲基甲醯胺(100ml)溶液中加入2-(7-氮雜苯並三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(2.78g,7.3mmol),N,N-二異丙基乙胺(5g,7.3mmol)和化合物1g(450mg,3.65mmol)。反應液室溫攪拌1小時,LCMS[M+H]+=378,檢測反應完全。後處理:反應液濃縮拉幹,得到的粗品過柱,[洗脫劑:(EA/PE)=0-50%]得到黃色固體目標化合物(化合物1h,1120mg,收率81.16%),LCMS[M+H]+=378。
步驟5:化合物1((S)-4-((4-(1-(3-(氰基甲基)-1-(2,2-二氟環丙烷-1-羰基)氮雜環丁烷-3-基)-1H-吡咯-3-基)嘧啶-2-基)氨基)-N-乙基苯甲醯胺)的製備
向化合物1h(120mg,0.317mmol)的正丁醇(20ml)溶液中加入化合物1i(104mg,0.64mmol)和一水合對甲苯磺酸(120.8mg,0.64mmol)。反應液升溫至110℃攪拌2小時,LCMS[M+H]+=506,檢測反應完全。後處理:反應液濃縮拉幹,製備得到類白色固體目標化合物(化合物1,29mg,收率18.1%),LCMS[M+H]+=506.2。
1H NMR(400MHz,DMSO)δ 9.71(s,1H),8.41(d,J=5.3Hz,1H),8.25(t,J=5.5Hz,1H),7.95-7.86(m,3H),7.79(d,J=8.8Hz,2H),7.25-7.10(m,2H),6.84(dd,J=2.9,1.6Hz,1H),4.71(ddd,J=52.1,41.5,9.6Hz,2H),4.48-4.19(m,2H),3.60(s,2H),3.30-3.22(m,2H),2.79(dq,J=13.2,8.8Hz,1H),2.00-1.84(m,2H),1.12(t,J=7.2Hz,3H)。
實施例2 合成化合物2的一般方法(TDM-180975)
步驟1:化合物2b(3-甲基-5-硝基吡啶甲基醯胺)的製備
將化合物2a(3g,18.4mmol)和濃硫酸(18ml)的混合溶液升溫至80℃攪拌25分鐘。LCMS[M+H]+=182,檢測反應完全。後處理:將反應液冷卻至室溫,倒入冰水(100ml)中,隨後用碳酸鈉調PH至中性,混合液用乙酸乙酯(3*100ml)萃取三次,合併有機相,飽和食鹽水洗,無水硫酸鈉乾燥,抽濾,濃縮拉幹得到黃色目標化合物(化合物2b,3.33g,收率94.2%),LCMS[M+1]+=182。
步驟2:化合物2c(5-氨基-3-甲基吡啶甲基醯胺)的製備
在氮氣保護下向化合物2b(3.14g,17.33mmol)的甲醇(150ml)溶液中加入鈀碳(10%,300mg),用氫氣在真空下置換數次,反應液在氫氣球下室溫攪拌2小時。LCMS[M+H]+=152,檢測反應完全。後處理:將反應液過濾除去鈀碳,濾液濃縮拉幹,得到的粗品再重結晶得到白色固體目標化合物(化合物2c,2.3g,收率87.8%),LCMS[M+1]+=152。
步驟3:化合物2((S)-5-((4-(1-(3-(氰基甲基)-1-(2,2-二氟環丙烷-1-羰基)氮雜環丁烷-3-基)-1H-吡咯-3-基)嘧啶-2-基)氨基)-3-甲基吡啶啉醯胺)的製備
向化合物2d(150mg,0.397mmol)的正丁醇(15ml)溶液中加入化合物2c(120mg,0.79mmol)和一水合對甲苯磺酸(151mg,0.79mmol)。反應液升溫至110℃攪拌7小時,LCMS[M+H]+=493,檢測反應完全。後處理:反應液濃縮拉幹,殘留物加水和乙酸乙酯(3*30ml)萃取,合併有機相,並用飽和食鹽
水洗,無水硫酸鈉乾燥,抽濾,拉幹,粗品製備得到類白色固體目標化合物(化合物2,7.9mg,收率4.04%),LCMS[M+H]+=493.2。
1H NMR(400MHz,DMSO)δ 9.89(s,1H),8.80(s,1H),8.44(d,J=5.3Hz,1H),8.32(s,1H),7.89(d,J=21.0Hz,2H),7.26-7.15(m,3H),6.84(dd,J=2.9,1.6Hz,1H),4.71(ddd,J=53.5,41.8,9.6Hz,2H),4.46-4.24(m,2H),3.58(d,J=16.7Hz,2H),2.78(dt,J=11.7,8.9Hz,1H),2.61(s,3H),2.00-1.84(m,2H)。
實施例3 合成化合物3的一般方法(TDM-180976)
步驟1:化合物3b(3-甲基-5-硝基亞油酸乙酯)的製備
將濃硫酸(40ml)緩慢加入至0℃下的乙醇(160ml)溶液中,隨後向反應液中分批加入化合物3a(4g,24.5mmol),並將反應液升溫至回流攪拌72小時。LCMS[M+H]+=211,檢測反應完全。後處理:將反應液冷卻至室溫並倒入水(50ml)中,用乙酸乙酯(3*50mL)萃取三次,合併有機相,並用飽和食鹽水洗,無水硫酸鈉乾燥,抽濾,濃縮拉幹得到黃色目標化合物(化合物3b,3.73g,收率72.56%),LCMS[M+1]+=211。
步驟2:化合物3c(3-甲基-5-硝基亞油酸)的製備
向化合物3b(4.2g,20.03mmol)的四氫呋喃(200ml)溶液中加入1N的氫氧化鈉(120ml,120.16mmol)溶液,反應液室溫攪拌1小時,
LCMS[M+H]+=183,檢測反應完全。後處理:將反應液緩慢倒入冰水(30ml)中,水相用二氯甲烷(2*15mL)萃取兩次,水相用1N稀鹽酸調至pH=5-6,然後用乙酸乙酯(3*15mL)萃取三次,合併有機相,並用飽和食鹽水洗,無水硫酸鈉乾燥,抽濾,濃縮拉幹,粗品重結晶得到黃色固體目標化合物(化合物3c,3.0g,收率82.19%),LCMS[M+1]+=183。
步驟3:化合物3e(N,3-二甲基-5-硝基亞油醯胺)的製備
向化合物3c(3.0g,16.48mmol)的N,N-二甲基甲醯胺(100ml)溶液中加入2-(7-氮雜苯並三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(10.03g,26.37mmol),N,N-二異丙基乙胺(7.5g,57.68mmol)和化合物3d(2.26g,32.96mmol)。反應液室溫攪拌1小時,LCMS[M+H]+=196,檢測反應完全。後處理:反應液濃縮拉幹,得到的粗品過柱,[洗脫劑:(EA/PE)=0-30%],粗品再重結晶得到黃色固體目標化合物(化合物3e,3.0g,收率93.75%),LCMS[M+1]+=196。
步驟4:化合物3f(5-氨基-N,3-二甲基吡啶甲醯胺)的製備
在氮氣保護下向化合物3e(3.5g,17.9mmol)的甲醇(200ml)溶液中加入鈀碳(10%,350mg),用氫氣在真空下置換數次,反應液在氫氣球下室溫攪拌2小時。LCMS[M+H]+=166,檢測反應完全。後處理:將反應液過濾除去鈀碳,濾液濃縮拉幹,得到的粗品過柱,[洗脫劑:(D/M=10/1):DCM=0-10%],再重結晶得到黃色固體目標化合物(化合物3f,1.8g,收率60.87%),LCMS[M+1]+=166。
步驟5:化合物3((S)-5-((4-(1-(3-(氰基甲基)-1-(2,2-二氟環丙烷-1-羰基)氮雜環丁烷-3-基)-1H-吡咯-3-基)嘧啶-2-基)氨基)-N,3-二甲基吡啶甲酸醯胺)的製備
向化合物3g(150mg,0.40mmol)的正丁醇(35ml)溶液中加入化合物3f(131.2mg,0.79mmol)和一水合對甲苯磺酸(151.03mg,0.79mmol)。反應液升溫至110℃攪拌7小時,LCMS[M+H]+=507,檢測反應完全。後處理:反應液濃縮拉幹,殘留物加水和乙酸乙酯(3*30ml)萃取,合併有機相,並用飽和食鹽水洗,無水硫酸鈉乾燥,抽濾,拉幹,粗品製備得到類白色固體目標化合物(化合物3,6.8mg,收率3.38%),LCMS[M+1]+=507.2。
1H NMR(400MHz,DMSO)δ 9.88(s,1H),8.82(d,J=2.3Hz,1H),8.45(dd,J=8.9,4.8Hz,2H),8.30(s,1H),7.91(s,1H),7.32-7.10(m,2H),6.83(dd,J=2.9,1.6Hz,1H),4.71(ddd,J=53.5,41.7,9.6Hz,2H),4.48-4.19(m,2H),3.60(s,2H),2.82-2.70(m,4H),2.61(s,3H),1.97-1.85(m,2H)。
實施例4 合成化合物4的一般方法(TDM-180978)
步驟1:化合物4((S)-4-((4-(1-(3-(氰基甲基)-1-(2,2-二氟環丙烷-1-羰基)氮雜環丁烷-3-基)-1H-吡咯-3-基)嘧啶-2-基)氨基)-N-乙基-2-甲基苯甲醯胺)的製備
以相似的方法製備得到化合物4(類白色固體,16.8mg,收率4.3%)。
1H NMR(400MHz,DMSO)δ 9.52(s,1H),8.38(d,J=5.2Hz,1H),8.05(t,J=5.6Hz,1H),7.87(t,J=1.8Hz,1H),7.74(d,J=2.5Hz,1H),7.69(d,J=8.5Hz,1H),7.29(d,J=8.4Hz,1H),7.23-7.14(m,1H),7.10(dd,J=5.2,3.8Hz,1H),6.83(dd,J=2.9,1.6Hz,1H),4.71(ddd,J=53.1,42.0,9.6Hz,2H),4.48-4.19(m,2H),3.60(s,2H),3.26-3.17(m,2H),2.79(dd,J=12.3,9.6Hz,1H),2.34(d,J=13.1Hz,
3H),1.93(dd,J=17.3,9.3Hz,2H),1.11(t,J=7.2Hz,3H)。LCMS[M+H]+=520.2。
實施例5 合成化合物5的一般方法(TDM-180996)
步驟1:化合物5(2-(1-((S)-2,2-二氟環丙烷-1-羰基)-3-(3-(2-((6-(1-羥基丙烷-2-基)吡啶-3-基)氨基)嘧啶-4-基)-1H-吡咯-1-基)氮雜環丁烷-3-基)乙腈)的製備
以相似的方法製備得到化合物5(類白色固體,19.2mg,收率7.35%)。
1H NMR(401MHz,DMSO)δ 9.50(s,1H),8.81(d,J=2.5Hz,1H),8.36(d,J=5.3Hz,1H),8.21(d,J=8.5Hz,1H),8.15(s,1H),7.87(s,1H),7.17(dd,J=8.3,5.6Hz,2H),7.10(dd,J=5.2,4.0Hz,1H),6.81(dd,J=2.8,1.6Hz,1H),4.75(dt,J=18.0,9.6Hz,2H),4.58(d,J=9.5Hz,1H),4.42(dd,J=10.6,5.9Hz,1H),4.36-4.21(m,1H),3.68-3.57(m,3H),3.48(dd,J=10.2,7.0Hz,1H),2.90(dd,J=13.7,6.9Hz,1H),2.83-2.72(m,1H),1.99-1.81(m,2H),1.19(d,J=6.9Hz,3H)。LCMS[M+H]+=494.2。
實施例6 合成化合物6的一般方法(TDM-180982)
步驟1:化合物6c(3-(氰基甲基)-3-(4-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)-1H-吡唑-1-基)氮雜環丁-1-甲酸叔丁基酯)的製備
在室溫下,向化合物6a(2g,10.3mmol)的乙腈(40mL)混合物中加入化合物6b(2g,10.3mmol)和1,8-二氮雜二環十一碳-7-烯(1mL,10.3mmol),將混合物加熱至70℃,攪拌過夜。反應結束減壓濃縮混合物,殘餘物通過矽膠色譜法純化(石油醚/乙酸乙酯=0%-50%),得到白色固體目標化合物(化合物6c,2.42g,收率60.5%)。LCMS[M-C4H9]+=333.2。
步驟2:化合物6e(3-(4-(2-氯嘧啶-4-基)-1H-吡唑-1-基)-3-(氰甲基)氮雜環丁烷-1-羧酸叔丁酯)的製備
向化合物6d(2.13g,5.486mmol),化合物6c(1.31g,8.777mmol),碳酸鈉(1.16g,10.972mmol)和1,1'-雙二苯基膦二茂鐵二氯化鈀(401mg,0.549mmol)的混合物中加入二氧六環(120ml)和水(20ml),用氮氣置換幾次,然後加熱到80℃並攪拌1小時。將混合物在減壓下濃縮,殘餘物通過矽膠色譜法純化(石油醚/乙酸乙酯=0%-42%),得到淡黃色固體目標化合物(化合物6e,1.67g,收率81.2%)。LCMS[M+H]+=375。
步驟3:化合物6f(2-(3-(4-(2-氯嘧啶-4-基)-1H-吡唑-1-基)氮雜環丁-3-基)乙腈)的製備
向化合物6e(1.4g,3.735mmol)的二氯甲烷(80ml)溶液中滴加三氟乙酸(16ml),將混合物在室溫攪拌1小時。反應結束向混合物中加入水並用氫氧化鈉水溶液中和,然後用二氯甲烷(80ml*3)萃取,合併有機層,用鹽水(100ml)洗滌,用硫酸鈉乾燥,將濾液減壓濃縮,殘餘物通過矽膠色譜法純化(二氯甲烷/含10%甲醇的二氯甲烷溶液=0%-100%),得到白色固體目標化合物(化合物6f,571.1mg,收率55.7%)。LCMS[M+H]+=275。
步驟4:化合物6h((S)-2-(3-(4-(2-氯嘧啶-4-基)-1H-吡唑-1-基)-1-(2,2-二氟環丙烷-1-羰基)氮雜環丁-3-基)乙腈)的製備
向化合物6g(293.3mg,2.403mmol)的N,N-二甲基甲醯胺(30ml)溶液加入2-(7-氮雜苯並三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(913.7mg,2.403mmol)和N,N-二異丙基乙胺(776.2mg,3.003mmol),將混合物攪拌5分鐘,然後加入化合物6f(550mg,2.002mmol),將混合物在室溫攪拌1小時。反應結束向混合物中加入水並用乙酸乙酯(50ml*3)萃取,合併有機層,用水(50mL*3)和飽和鹽水(50ml)洗滌,用硫酸鈉乾燥,將濾液減壓濃縮,將殘餘物用矽膠色譜純化(石油醚/乙酸乙酯=0%-50%),得到白色固體目標化合物(化合物6h,566mg,收率74.6%)。LCMS[M+H]+=379。
步驟5:化合物6((S)-4-((4-(1-(3-(氰基甲基)-1-(2,2-二氟環丙烷-1-羰基)氮雜環丁烷-3-基)-1H-吡唑-4-基)嘧啶-2-基)氨基)-N-乙基苯甲醯胺)的製備
向化合物6h(50mg,0.132mmol)的正丁醇(5ml)溶液加入化合物6i(43.4mg,0.264mmol)和對甲苯磺酸一水合物(50.2mg,0.264mmol)。將所得混合物加熱至110℃並攪拌3小時。將混合物在減壓下濃縮,殘餘物通過製備型HPLC(甲酸)純化,以得到白色固體目標化合物TDM-180982(化合物6,11.4mg,收率17.1%)。LCMS[M+H]+=507.2。
1H NMR(400MHz,DMSO)δ 9.85(s,1H),8.86(d,J=4.6Hz,1H),8.51(d,
J=5.2Hz,1H),8.32(s,1H),8.27(t,J=5.5Hz,1H),7.90(d,J=8.8Hz,2H),7.81(d,J=8.8Hz,2H),7.23(dd,J=5.2,1.4Hz,1H),4.86(dd,J=35.3,9.6Hz,1H),4.67(dd,J=41.8,9.6Hz,1H),4.51(t,J=9.9Hz,1H),4.31(t,J=10.2Hz,1H),3.72(d,J=2.8Hz,2H),3.30-3.23(m,2H),2.90-2.74(m,1H),1.92(qd,J=11.0,7.4Hz,2H),1.12(t,J=7.2Hz,3H)。
實施例7 合成化合物7的一般方法(TDM-180983)
步驟1:化合物7((S)-5-((4-(4-(4-(2,2-二氟環丙烷-1-羧醯胺基)苯基)嘧啶-2-基)氨基)-N,3-二甲基吡啶啉醯胺)的製備
以相似的方法製備得到化合物7(白色固體,12.7mg,收率14.5%)。
1H NMR(400MHz,DMSO)δ9.66(s,1H),8.84(d,J=4.2Hz,1H),8.49(d,J=5.2Hz,1H),8.30(s,1H),8.06(t,J=5.6Hz,1H),7.73-7.65(m,2H),7.34-7.27(m,1H),7.19(dd,J=5.1,1.9Hz,1H),4.84(dd,J=34.2,9.6Hz,1H),4.66(dd,J=42.4,9.5Hz,1H),4.49(t,J=10.3Hz,1H),4.30(t,J=10.2Hz,1H),3.72(d,J=1.8Hz,2H),3.27-3.16(m,2H),2.82(ddd,J=19.2,12.0,9.0Hz,1H),2.36(s,3H),2.00-1.85(m,2H),1.11(t,J=7.2Hz,3H)。LCMS[M+H]+=521.1。
實施例8 合成化合物8的一般方法(TDM-180985)
步驟1:化合物8((S)-5-((4-(1-(3-(氰基甲基)-1-(2,2-二氟環丙烷-1-羰基)
氮雜環丁烷-3-基)-1H-吡唑-4-基)嘧啶-2-基)氨基)-N,3-二甲基吡啶甲酸醯胺)的製備
向化合物8a(80mg,0.258mmol)的正丁醇(8mL)溶液中加入化合物8b(85mg,0.517mmol)和對甲苯磺酸一水合物(98mg,0.517mmol)。將所得混合物加熱至115℃並攪拌過夜。反應結束將混合物冷卻至室溫,加水,然後用乙酸乙酯(30ml*3)萃取,合併有機層,用飽和鹽水(50ml)洗滌,用硫酸鈉乾燥,將濾液減壓濃縮,殘餘物通過製備型HPLC(甲酸)純化,得到類白色固體目標化合物TDM-180985(化合物8,10.2mg,收率6.2%)。LCMS[M+H]+=508.2。
1H NMR(400MHz,DMSO)δ 10.01(s,1H),8.88(d,J=4.5Hz,1H),8.81(d,J=2.3Hz,1H),8.55(d,J=5.2Hz,1H),8.46(d,J=4.8Hz,1H),8.30(s,1H),8.27(d,J=2.1Hz,1H),7.28(dd,J=5.2,1.9Hz,1H),4.85(dd,J=33.3,9.6Hz,1H),4.67(dd,J=42.3,9.6Hz,1H),4.49(t,J=10.4Hz,1H),4.31(t,J=10.3Hz,1H),3.72(s,2H),2.89-2.74(m,4H),2.61(s,3H),2.01-1.84(m,2H)。
實施例9 合成化合物9的一般方法(TDM-180986)
步驟1:化合物9((S)-5-((4-(1-(3-(氰基甲基)-1-(2,2-二氟環丙烷-1-羰基)氮雜環丁烷-3-基)-1H-吡唑-4-基)嘧啶-2-基)氨基)-3-甲基吡啶啉醯胺)的製備
以相似的方法製備得到化合物9(類白色固體,10.7mg,收率8.4%)。
1H NMR(400MHz,DMSO)δ 10.03(s,1H),8.88(d,J=4.4Hz,1H),8.80(d,J=2.0Hz,1H),8.55(d,J=5.2Hz,1H),8.29(d,J=11.4Hz,2H),7.87(s,1H),7.38-7.16(m,2H),4.85(dd,J=33.3,9.6Hz,1H),4.67(dd,J=42.5,9.6Hz,1H),4.49(t,J=10.4Hz,1H),4.31(t,J=10.2Hz,1H),3.72(s,2H),2.90-2.75(m,1H),
2.61(s,3H),1.94(d,J=8.0Hz,2H)。LCMS[M+H]+=494.3。
實施例10 合成化合物10的一般方法(TDM-180990)
步驟1:化合物10(2-(1-((S)-2,2-二氟環丙烷-1-羰基)-3-(4-(2-(((6-(1-羥基丙烷-2-基)吡啶-3-基)氨基)嘧啶-4-基)-1H-吡唑-1-基)氮雜環丁烷-3-基)乙腈)的製備
向化合物10a(190mg,0.502mmol),化合物10b(153mg,1.003mmol),醋酸鈀(11.4mg,0.050mmol),4,5-雙(二苯基膦)-9,9-二甲基氧雜蒽(58.1mg,0.1mmol)和碳酸銫(461mg,1.506mmol)的混合物中加入二氧六環(40mL),將混合物用氬氣置換幾次,將混合物加熱至100℃並攪拌1小時。反應結束向反應物中加入水(60mL),並用乙酸乙酯(60mL*3)萃取,合併有機層,然後用水(100mL)和飽和鹽水(100mL*2)洗滌,用硫酸鈉乾燥,將濾液減壓濃縮,殘餘物通過矽膠色譜法(石油醚/乙酸乙酯=0%-70%)和製備型HPLC(甲酸)純化,得到白色固體目標化合物TDM-180990(化合物10,76.6mg,收率30.9%)。LCMS[M+H]+=495.2。
1H NMR(400MHz,DMSO)δ 9.65(s,1H),8.85(d,J=4.3Hz,1H),8.79(s,1H),8.47(d,J=5.2Hz,1H),8.29(s,1H),8.21(dt,J=8.5,2.9Hz,1H),8.17(s,1H),7.19(dd,J=10.2,5.1Hz,2H),4.85(dd,J=33.3,9.6Hz,1H),4.66(dd,J=42.4,9.6Hz,2H),4.50(t,J=11.0Hz,1H),4.30(t,J=10.2Hz,1H),3.71(d,J=2.8Hz,2H),3.63(dd,J=10.2,6.6Hz,1H),3.49(dd,J=10.2,7.0Hz,1H),2.90(dt,J=12.7,6.4Hz,1H),2.81(ddd,J=13.2,10.4,6.2Hz,1H),2.00-1.86(m,2H),1.20(d,J=6.9
Hz,3H)。
測試例1 JAK激酶小分子抑制劑的酶活性抑制檢測
實驗方案
1、試劑準備
激酶反應緩衝液:配置激酶反應緩衝液,組分如下:50mM HEPES,pH 7.5,1mM EGTA,10mM MgCl2,2mM DTT,0.01% Tween20。1X檢測緩衝液:配置檢測緩衝液,去離子水9:1稀釋10X檢測緩衝液至1X。4X激酶溶液:激酶反應緩衝液稀釋JAK激酶至4X終濃度(JAK1:80nM,JAK2/JAK3/Tyk2:4nM)。4X底物溶液:激酶反應緩衝液稀釋ULightTM-JAK(Tyr1023)底物至200nM(終濃度:50nM)。4XATP溶液:激酶反應緩衝液稀釋ATP至4X終濃度(JAK1:160μM,JAK2/JAK3/Tyk2:40μM)。4X測試化合物溶液:DMSO溶解測試用化合物至10mM儲存液,3倍梯度稀釋配置成所需濃度,每個化合物設置10個濃度點,測試化合物終濃度範圍為:10μM-0.5nM。4X酶反應終止液:1X檢測緩衝液溶解EDTA至40mM(EDTA終濃度:10mM)。4X檢測抗體溶液:1X檢測緩衝液稀釋Eu標記檢測抗體(抗磷酸酪氨酸(PT66))至8nM(抗體終濃度:2nM)。
2、實驗過程
向384微孔板中依次加入2.5μL的4X激酶溶液和2.5μL已經稀釋好的不同濃度的4X測試化合物溶液,每個濃度設置2個複孔,同時設置酶溶液空白對照組和陰性對照組(DMSO組)。震盪384多孔板,混勻酶和化合物,1000轉,離心1分鐘,在室溫下孵育60分鐘。向384多孔板中加入2.5μL,4X底物溶液,1000轉離心1分鐘。向384多孔板中加入2.5μL,4XATP溶液,1000轉離心1分鐘,起始酶反應。JAK1室溫反應2小時,JAK2/JAK3/Tyk2室溫反應1
小時。JAK1反應的各組分終濃度分別為:JAK1:20nM,底物:50nM,ATP:40uM,測試化合物終濃度範圍為:10μM-0.5nM。JAK2/JAK3/Tyk2反應的各組分終濃度分別為:JAK2:1nM,底物:50nM,ATP:10μM,測試化合物終濃度範圍為:10μM-0.5nM。酶反應結束後,向384多孔板每孔中加入5μL,4X酶反應終止液,1000轉,離心1分鐘,在室溫下孵育5分鐘。向384多孔板每孔中加入5μL,4X檢測抗體溶液,(檢測抗體終濃度為2nM),1000轉,離心1分鐘,室溫條件下孵育1小時。抗體孵育結束後,在Envision讀板儀上測定各孔的信號值。
3、資料分析
以酶溶液空白對照組為100%抑制率和陰性對照組(DMSO組)為0%抑制率,計算檢測各個濃度對應的百分比抑制率。在GraphPad Prism軟體中對檢測化合物的濃度對數值和相對應的百分比抑制率進行非線性回歸分析,得到檢測化合物的半數抑制濃度(IC50),針對實施例1-10的化合物所測得的實驗結果列在下表1中。
從上表1的結果可以看出,本申請的化合物的酶活性資料優異,以上具體化合物測得的半數抑制濃度較低,特別是針對Tyk2、JAK1和JAK2時基本上達到0.01-0.1μM左右,尤其是化合物TDM-180973、TDM-180975、TDM-180976和TDM-180978,其半數抑制濃度均在0.01μM左右。因此,通過以上實驗已經證明了本申請的小分子化合物是一類針對JAK家族靶向性強、酶活性優異的化合物,能夠作為JAK1/Tyk2雙抑制劑和Tyk2特異性抑制劑。
以上詳細描述了本發明的優選實施方式,但是,本發明並不限於上述實施方式中的具體細節,在本發明的技術構思範圍內,可以對本發明的技術方案進行多種簡單變型,這些簡單變型均屬於本發明的保護範圍。
另外需要說明的是,在上述具體實施方式中所描述的各個具體技術特徵,在不矛盾的情況下,可以通過任何合適的方式進行組合,為了避免不必要的重複,本發明對各種可能的組合方式不再另行說明。
此外,本發明的各種不同的實施方式之間也可以進行任意組合,只要其不違背本發明的思想,其同樣應當視為本發明所公開的內容。
Claims (11)
- 如請求項1所述的小分子化合物,其中,R1至R5中的至多兩個為N。
- 如請求項3所述的小分子化合物,其中,R7和R8各自獨立地選自氫、烷基或環烷基。
- 如請求項5所述的小分子化合物,其中,R10和R11各自獨立地選自氫、烷基或環烷基。
- 如請求項4或6所述的小分子化合物,其中,所述烷基為甲基、乙基、丙基或異丙基,所述環烷基為環丙基、環丁基或環丙基甲基。
- 如請求項1-7中任一項所述的小分子化合物在抑制JAK激酶中的用途。
- 如請求項1-7中任一項所述的小分子化合物在製備用於預防或治療自身免疫性疾病、以及與免疫有關的炎症性皮膚疾病的藥物中的用途,其中,這些疾病的發病機理均與JAK信號傳導的失調相關。
- 如請求項9所述的用途,其中,所述自身免疫性疾病選自類風濕性關節炎、強直性脊柱炎、潰瘍性結腸炎、克羅恩病、系統性紅斑狼瘡、皮肌炎、 多發性硬化、I型糖尿病、乾燥綜合症和血管炎中的至少一種。
- 如請求項9所述的用途,其中,所述與免疫有關的炎症性皮膚疾病選自特應性皮炎、濕疹、斑禿、銀屑病、白癜風、扁平苔蘚、光澤苔蘚、硬化萎縮性苔蘚、脂膜炎、痤瘡和化膿性汗腺炎中的至少一種。
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