CN1166677C - 噻吩a2a受体激动剂 - Google Patents
噻吩a2a受体激动剂 Download PDFInfo
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- CN1166677C CN1166677C CNB008094608A CN00809460A CN1166677C CN 1166677 C CN1166677 C CN 1166677C CN B008094608 A CNB008094608 A CN B008094608A CN 00809460 A CN00809460 A CN 00809460A CN 1166677 C CN1166677 C CN 1166677C
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- Prior art keywords
- alkyl
- aryl
- substituted
- hydrogen
- compound
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- 101150051188 Adora2a gene Proteins 0.000 title abstract description 6
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 title description 5
- 229930192474 thiophene Natural products 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 71
- 230000024883 vasodilation Effects 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 105
- 229910052736 halogen Inorganic materials 0.000 claims description 49
- 150000002367 halogens Chemical class 0.000 claims description 49
- 229910052739 hydrogen Inorganic materials 0.000 claims description 42
- 239000001257 hydrogen Substances 0.000 claims description 42
- 125000001424 substituent group Chemical group 0.000 claims description 30
- 150000002431 hydrogen Chemical class 0.000 claims description 26
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 20
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 210000000440 neutrophil Anatomy 0.000 claims description 6
- CPTUWSZWVJPEBG-GJXNZEFLSA-N (2r,3r,4s,5r)-2-[6-amino-2-(5-phenylthiophen-2-yl)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C1=NC=2C(N)=NC(C=3SC(=CC=3)C=3C=CC=CC=3)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O CPTUWSZWVJPEBG-GJXNZEFLSA-N 0.000 claims description 5
- 230000004913 activation Effects 0.000 claims description 5
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- 238000002360 preparation method Methods 0.000 claims description 4
- ZSLYVKMIBBEJRS-RFOJGYJVSA-N (2r,3r,4s,5r)-2-[6-amino-2-(5-iodothiophen-2-yl)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C1=NC=2C(N)=NC(C=3SC(I)=CC=3)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O ZSLYVKMIBBEJRS-RFOJGYJVSA-N 0.000 claims description 2
- HFJRDLIFRKMEIL-YPKZDWGUSA-N (2r,3r,4s,5r)-2-[6-amino-2-(5-methylthiophen-2-yl)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound S1C(C)=CC=C1C1=NC(N)=C(N=CN2[C@H]3[C@@H]([C@H](O)[C@@H](CO)O3)O)C2=N1 HFJRDLIFRKMEIL-YPKZDWGUSA-N 0.000 claims description 2
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- 239000002126 C01EB10 - Adenosine Substances 0.000 abstract description 9
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- 125000003118 aryl group Chemical group 0.000 description 89
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- 125000000623 heterocyclic group Chemical group 0.000 description 36
- -1 thiophene compound Chemical class 0.000 description 26
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
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- 229910052717 sulfur Inorganic materials 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
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- 125000002252 acyl group Chemical group 0.000 description 5
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- 230000000694 effects Effects 0.000 description 5
- 125000005224 heteroarylcarbonylamino group Chemical group 0.000 description 5
- 125000005419 heteroarylsulfonylamino group Chemical group 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 238000012746 preparative thin layer chromatography Methods 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- 125000006413 ring segment Chemical group 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
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- 125000006260 ethylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])C([H])([H])[H] 0.000 description 4
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- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Diabetes (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Rheumatology (AREA)
- Pathology (AREA)
- Heart & Thoracic Surgery (AREA)
- Endocrinology (AREA)
- Gastroenterology & Hepatology (AREA)
- Toxicology (AREA)
- Urology & Nephrology (AREA)
- Epidemiology (AREA)
- Biomedical Technology (AREA)
- Cardiology (AREA)
- Pain & Pain Management (AREA)
- Surgery (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Saccharide Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
公开了具有通式(1)的2-腺苷噻吩化合物,和利用该化合物作为A2A受体激动剂以刺激哺乳动物冠状血管舒张的方法,以用于治疗目的和心脏显像的目的。
Description
发明领域
本发明包括可用作为A2A受体激动剂的噻吩化合物。
本发明的化合物是血管舒张因子,它可用于心脏成像以有助于鉴别患有指示冠状动脉疾病(CAD)的紊乱例如冠脉灌速不良的哺乳动物,特别是人类。本发明的化合物也可用作冠状动脉疾病的治疗剂。
现有技术的描述
在用T1闪烁法或超声波心动描记术成像之前用腺苷或双嘧达莫在怀疑含有CAD的患者中经常诱导药理学的应激反应。由于激活细胞表面A2受体两种药物影响冠状阻力血管的扩胀。虽然药理学应激反应最初诱导作为促进不能活动的患者的冠状扩胀的手段,但是一些研究已经证实给予腺苷或双嘧达莫产生药理学应激反应的患者201T1或回声心动描记成像的诊断价值相当于进行传统活动应激反应测试的患者。但是,用这些药物产生药理学应激反应时与药物—相关的副作用发生率高,例如头痛和恶心这可以用新的治疗剂加以改善。
腺甙A2B和A3受体参与肥大细胞的脱颗粒,因此,气喘没有给予非特异性腺苷激动剂以诱导药理学的应激反应测试。另外,在心房和A-V结中腺苷刺激A1受体将减少能够诱导AV阻滞的S-H间隙(N.C.Gupto等;J AmColl.Cardiol;(1992)19:248-257)。由腺苷刺激的腺苷A1受体可能与恶心的产生有关,因为在肠道发现A1受体(J.Nicholls等人;欧洲药物学杂志(1997)338(2)143-150)。
动物资料提示冠状阻力血管上的特异性腺苷A2A亚型受体介导对腺苷的冠状扩张反应,而A2B亚型受体刺激则松弛外周血管(注解:后者降低全身的血压)。因此需要寻求作为2A受体激动剂的药物化合物,它们不具有在体内刺激A1受体所引起的药理学作用。此外,需要寻求具有短半哀期的A2A受体激动剂,它们能被经受药理学冠脉应激反应评价的患者很好地耐受。
发明概述
一方面,本发明包括可用作为A2A受体激动剂的2-腺苷噻吩化合物。
另一个方面,本发明包括含有能够被耐受并且副作用极低的2-腺苷噻吩的药物组合物。
本发明的还有一个方面是易于与放射性显像剂联合使用以促进冠脉显像的噻吩化合物。
在一个实施方案中,本发明包括具有下列通式的噻吩化合物:
在另一个实施方案中,本发明包括使用本发明的化合物刺激哺乳动物尤其是人类的冠状血管舒张使心脏应激诱导窃血状态(steal situation)以达到心脏显像目的的方法。
在另一个实施方案中,本发明是重要的药物组合物,包括本发明的一个或多个化合物和一个或多个药物赋形剂。
当前的实施方案的描述
本发明的化合物包括具有下列通式的一类噻吩化合物:
其中X是S,O或NR5;R1是-CH2OH,和-C(=O)NR7R8;
R2,R3,R4和R5各自独自地选自于下列组:氢,卤素,NO2,CF3,CN,OR20,SR20,N(R20)2,S(O)R22,SO2R22,SO2N(R20)2,SO2NR20COR22,SO2NR20CO2R22,SO2NR20CON(R20)2,N(R20)2NR20COR22,NR20CO2R22,NR20CON(R20)2,NR20C(NR20)NHR23,COR20,CO2R20,CON(R20)2,CONR20SO2R22,NR20SO2R22,SO2NR20CO2R22,OCONR20SO2R22,OC(O)R20,C(O)OCH2OC(O)R20,OCON(R20)2,C1-15烷基,C1-15烷氧基,C2-15烯基,C2-15炔基,杂环基,芳基和杂芳基,其中烷基,烯基,炔基,烷氧基,芳基,杂环基和杂芳基可任选地用1-3的取代基取代,所述的取代基各自选自于下列组:卤素,NO2,杂环基,芳基,杂芳基,CF3,CN,OR20,SR20,N(R20)2,S(O)R22,SO2R22,SO2N(R20)2,SO2NR20CO2R22,SO2NR20CON(R20)2,N(R20)2,SO2NR20COR22,NR20CO2R22,NR20CON(R20)2,R20C(NR20)NHR23,COR20,CO2R20,CON(R20)2,CONR20SO2R22,NR20SO2R22,SO2NR20CO2R22,OCONR20SO2R23,OC(O)R20,C(O)OCH2OC(O)R20和OCON(R20)2,并且其中各个任选的杂芳基,芳基,杂环基取代的取代基可进一步任选地被卤素,NO2,烷基,CF3,氨基,单或二烷基氨基,烷基或芳基或杂芳基酰胺,NCOR22,NR20SO2R22,COR20,CO2R20,CON(R20)2,NR20CON(R20)2,OC(O)R20,OC(O)N(R20)2,SR20,S(O)R22,SO2R22,SO2N(R20)2,CN或OR20取代;
R7和R8各自独立地选自于下列组:H,和可任选地由1-2个取代基取代的C1-15烷基,取代基各自独立地选自于下列组:卤素,NO2,杂环基,芳基,杂芳基,CF3,CN,OR20,SR20,N(R20)2,S(O)R22,SO2R22,SO2N(R20)2SO2NR20COR22,SO2NR20CO2R22,SO2NR20CON(R20)2,(R20)2NR20COR22,NR20CO2R22,NR20CON(R20)2,NR20C(NR20)NHR23,COR20,CO2R20,CON(R20)2,CONR20SO2R22,NR20SO2R22,SO2NR20CO2R22,OCONR20SO2R22,OC(O)R20,C(O)OCH2OC(O)R20和OCON(R20)2,各个任选的杂芳基,芳基和杂环取代基可进一步任选地被卤素,NO2,烷基,CF3,氨基,单烷基氨基或二烷基氨基,烷基酰胺,芳基酰胺或杂芳基酰胺,NCOR22,NR20SO2R22,COR20,CO2R20,CON(R20)2,NR20CON(R20)2,OC(O)R20,OC(O)N(R20)2,SR20,S(O)R22,SO2R22,SO2N(R20)2,CN和OR20取代;
R20选自于H,C1-15烷基,C2-15烯基,C2-15炔基,杂环,芳基和杂芳基,其中烷基,烯基,炔基,杂环基,芳基和杂芳基分别可任选地被1-3个各自选自于下列组的取代基取代:卤素,烷基,单一或二烷基氨基,烷基或芳基或杂盒芳基酰胺,CN,O-C1-5烷基,CF3,芳基和杂芳基;和
R22选自于下列H,C1-15烷基,C2-15烯基,C2-15炔基,杂环基,芳基和杂芳基,其中烷基,烯基,炔基,杂环基,芳基和杂芳基分别可任选地被1-3个各自选自于下列组的取代基取代:卤素,烷基,单一或二烷基氨基,烷基或芳基或杂盒芳基酰胺,CN,O-C1-6烷基,CF3,芳基和杂芳基。
在一个优选的实施方案中,X是硫,R1是选自-CH2OH或-CONHEt;R2各自选自于下列组:氢,C1-10烷基和芳基,其中烷基和芳基取代基可任选地由1-2个取代基取代,所述的取代基各自选自于下列组:卤素,OR20,芳基,CF和CN,其中各个任选的芳基取代基可任选地由卤素,烷基,CF和CN取代;R3和R4各自选自于下列组:氢,C1-15烷基,芳基,卤素,CF3和CN,其中烷基和芳基取代基可任选地由各自选自卤素,CF3,和CN的取代基取代;和R20选自于H和C1-6烷基。
在一个更优选的实施方案中,R2各自选自于下列组:氢,C1-8烷基和芳基,其中烷基和芳基取代基可任选地由1-2个取代基取代,所述的取代基各自选自于下列组:卤素,OR20,芳基,CF3和CN,其中各个任选的芳基取代基可任选地由卤素,烷基,CF3和CN取代;R3和R4各自选自于下列组:氢,甲基和卤素;和R20选自于H和C1-6烷基。
在另一个还要优选的实施方案中,R2选自于下列组:氢,和可任选地由一个芳基取代基所取代的C1-8烷基,所述的取代基可任选地由卤素,烷基,CF3和CN取代;R3和R4各为氢。
在另一个优选的实施方案中,R1是-CONHEt;R2选自于下列组:氢,和可任选地被芳基取代基所取代的C1-6烷基,所述的取代基可任选地由烷基取代;R3和R4是氢。
在本发明的化合物中,含有R2,R3和R4取代基的环的上连结点可以是C-3,C-4或C-5。
在一个更优选的实施方案中,R2各自选自于下列组:氢,C1-8烷基和芳基,其中烷基和芳基取代基可任选地由1-2个取代基取代,所述的取代基各自选自于下列组:卤素,OR20,芳基,CF3,和CN,其中各个任选的芳基取代基可任选地由卤素,烷基,CF3和CN取代;R3和R4各自选自于下列组:氢,甲基和卤素;和R20选自于H,和C1-6烷基。
本发明的另一个实施方案是具有如上通式的化合物,其中R2各自选自于下列组:氢,C1-15烷基和芳基,其中烷基和芳基取代基可任选地由1-2个取代基取代,所述取代基各自选自于下列组:卤素,OR20,芳基,CF3,和CN,其中各个可任选的芳基取代基可任选地由卤素,烷基,CF3和CN取代;R3和R4各自选自于下列组:氢,C1-15烷基,芳基,卤素,CF3和CN,其中烷基和芳基取代基可任选地由1-3个取代基取代,所述取代基各自选自于下列组:卤素,芳基,CF3和CN;其中每个任选的芳基取代基可任选的被选自卤素,烷基,CF3和CN的取代基取代;和R20选自于H或C1-6烷基。
本发明的还有另一个实施方案是具有如上通式的化合物,其中R1是-CH2OH;X是S;R2选自于下列组:氢,C1-8烷基和芳基,其中烷基和芳基取代基可任选的由1-2个取代基取代,所述取代基各自选自于下列组:卤素,OR20,芳基,CF3和CN,其中各个可任选的芳基取代基可任选地由卤素,烷基,CF3和CN取代;R3和R4各自选自于下列组:氢,C1-3烷基和芳基,卤素,CF3和CN;和R20选自于H或C1-6烷基。
本发明的还有另一个实施方案是具有如上通式的化合物,其中R1是-CH2OH;X是S;R2选自于下列组:氢,C1-8烷基和芳基,其中烷基和芳基取代基可任选的由选自卤素,芳基,CF3和CN的1个取代基取代,其中各个可任选的芳基取代基可任选地由1个取代基取代,所述取代基选自下列组:卤素,烷基,CF3和CN;R3和R4各自选自于下列组:氢和甲基。
本发明的另一个进一步的实施方案是具有如上通式的化合物,其中R1是-CH2OH;X是S;R2各自选自于下列组:氢,C1-8烷基,其中烷基由任选自于下列组:芳基,CF3,和CN中的一个取代基取代,其中各个可任选的芳基取代基可任选地由选自于下列组:卤素,烷基,CF3和CN中的取代基取代;R3和R4各自选自于下列组:氢和甲基。
在进一步的实施方案中,本发明包括具有如上通式的化合物,其中R1是-CH2OH;X是S;R2是C1-6烷基,R3和R4各自为氢。
在另一个实施方案中,本发明包括具有如上通式的化合物,其中R1是-CONHEt;X是S;R2选自于下列组;氢和C1-8烷基,其中烷基由选自于芳基,CF3和CN中的一个取代基取代,其中各个可任选的芳基取代基可任选地由选自卤素,烷基,CF3和CN的一个取代基取代;R3和R4各自选自于下列组:氢和甲基。
在另一个优选的实施方案中,R1是-CONHEt;R2选自于下列组:氢,和可任选地被芳基取代基所取代的C1-6烷基,所述的取代基可任选地由烷基取代;R3和R4是氢。
在本发明的化合物中,含有R2,R3和R4取代基的环的上连结点可以是C-3,C-4或C-5。
本发明的化合物最优选的是选自于下列组的化合物:(4S,2R,3R,5R)-2-[6-氨基-2-(5-甲基(2-噻吩基))嘌呤-9-基]-5-(羟甲基)氧戊环-3,4-二醇,(4S,2R,3R,5R)-2-[6-氨基-2-(5-碘代(2-噻吩基))嘌呤-9-基]-5-(羟甲基)氧戊环-3,4-二醇和(4S,2R,3R,5R)-2-[6-氨基-2-(5-苯基(2-噻吩基))嘌呤-9-基]-5-(羟甲基)氧戊环-3,4-二醇。下面的定义应用于本文的术语。
″卤″或″卤素″-单独的或组合地指所有的卤素,即氯(Cl),氟(F),溴(Br),碘(I)。
″羟基″是指基团-OH。
″硫醇″或″巯基″是指基团-SH。
″烷基″-单独或结合地指源自含1-20个(优选1-15个)碳原子的链烷烃的基团(除非特别限定)。它是直链烷基,支链烷基或环烷基。优选地含有1-15个,更优选地1-8个,甚至更优选地1-6个,还要更优选地1-4个和最优选地1-2个碳原子的直链或支链烷基基团,例如甲基,乙基,丙基,异丙基,丁基,t丁基等等。术语“低级烷基”在本文用于描述上面刚描述的直链烷基基团。优选地,环烷基是单环的,二环的或三环的3-8个环原子,更优选地为3-6个环原子的体系,例如环丙基,环戊基,环己基,金刚烷基等等。烷基也包括含有环烷基或被环烷基部分间隔的直链或支链烷基。直链或支链烷基在有利的点连接以产生稳定的化合物。这样的例子包括(但不限于)4-(异丙基)-环己基乙基或2-甲基环丙基戊基。取代烷基是前面定义的直链,支链烷基或环烷基,各自被1-3个基团或取代基取代:卤素,羟基,烷氧基,烷硫基,烷基亚磺酰基,烷基磺酰基,酰氧基,芳氧基,杂芳氧基,可任选地由一个或二个烷基,芳基或杂芳基取代的氨基,脒基,可任选地由烷基,芳基,杂芳基或杂环基取代的脲,可任选地由烷基,芳基或杂芳基取代N-单取代或N,N-二取代的氨基磺酰基,烷基磺酰氨基,芳基磺酰氨基,杂芳基磺酰氨基,烷基羰基氨基,芳基羰基氨基,杂芳基羰基氨基等。
″烯基″-单独或结合地指含有2-20个,优选2-17个,更优选2-10个,甚至更优选2-8个,最优选2-4个碳原子和至少一个,优选1-3个,更优选1-2个,最优选一个碳-碳双键的直链、支链或环烃。对于环烷基,一个以上碳-碳双键共轭不至于赋予环芳香性。碳-碳双键可以包含于环烷基部分,但是环丙基除外,或包含于直链或支链部分。烯基的例子包括乙烯基,丙烯基,异丙烯基,丁烯基,环己烯基,环己烯烷基等等。取代的烯基是前面定义的直链烯基,支链烯基或环烯基,各自独立地被1-3个基团或取代基取代:卤,羟基,烷氧基,烷硫基,烷基亚磺酰基,烷基磺酰基,酰氧基,芳氧基,杂芳氧基,可任选地由一个或二个烷基,芳基或杂芳基取代的氨基,脒基,可任选地由烷基,芳基,杂芳基或杂环基取代的脲,可任选地被烷基,芳基或杂芳基N-单取代或N,N-二取代的氨基磺酰基,烷基磺酰氨基,芳基磺酰氨基,杂芳基磺酰氨基,烷基羰基氨基,芳基羰基氨基,杂芳基羰基氨基,羧基,烷氧基羰基,芳氧基羰基,杂芳氧基羰基等等,它们在有利的点连结以产生稳定的化合物。
″炔基″-单独的或组合地指含有2-20个,优选2-17个,更优选2-10个,甚至更优选2-8个,最优选2-4个碳原子和至少一个,优选1-3个,更优选1-2个,最优选一个碳-碳三键的直链,支链烃。炔基的例子包括乙炔基,丙炔基,丁炔基等等。取代的炔基是前面定义的直链炔基,或支链烯基,各自独立地由1-3个基团或取代基取代:卤,羟基,烷氧基,烷硫基,烷基亚磺酰,烷基磺酰基,酰氧基,芳氧基,杂芳氧基,可任选地由一个或二个烷基,芳基或氨基杂芳基取代的氨基,脒基,可任选地由烷基,芳基,杂芳基或杂环基取代的脲,可任选地由烷基,芳基或杂芳基N-单取代或N,N-二取代的氨基磺酰基,烷基磺酰氨基,芳基磺酰氨基,杂芳基磺酰氨基,烷基羰基氨基,芳基羰基氨基,杂芳基羰基氨基等,它们在可利用的点结合以产生稳定的化合物。
″烷基烯基″是指-R-CR’=CRR″″基,其中R是低级烷基,或取代的低级烷基,R’,R,R″″各自是氢,卤素,低级烷基,取代的低级烷基,酰基,芳基,取代的芳基,杂芳基,或取代的杂芳基,如下文定义。
″烷基炔基″是指-RC≡CR’,其中R是低级烷基或取代的低级烷基,R’是氢,低级烷基,取代的低级烷基,酰基,芳基,取代的芳基,杂芳基,或取代的杂芳基,如下文定义。
″烷氧基″是指-OR基,其中R是低级烷基,取代的低级烷基,酰基,芳基,取代的芳基,芳烷基,取代的芳烷基,杂烷基,杂芳基烷基,环烷基,取代的环烷基,环杂烷基,或取代的环杂烷基,如下文定义。
″烷硫基″是指-SR,-S(O)n=1-2-R,其中R是低级烷基,取代低级烷基,芳基,取代的芳基,芳烷基或取代的芳烷基,如下文定义。
″酰基″是指-C(O)R,其中R是氢,低级烷基取代的低级烷基,芳基,取代的芳基等等,如下文定义。
″芳氧基”是指-OAr,其中Ar是芳基,取代的芳基,芳烷基,取代的芳烷基,如下文定义。
″氨基″是指NRR’,其中R和R’可以各自为氢,低级烷基,取代的低级烷基,芳基,取代的芳基,杂芳基,或取代的杂芳基,如下文定义,或酰基。
″酰氨基″是指-C(O)NRR’,其中R和R’可以各自为氢,低级烷基,取代的低级烷基,芳基,取代的芳基,杂芳基,取代的杂芳基,如下文定义。
″羧基″是指-C(O)OR,其中R是氢,低级烷基,取代的低级烷基,芳基,取代的芳基,杂芳基,取代的杂芳基,如下文定义。
″芳基″-单独或组合地指其碳环可任选地与优选5-7个,更优选5-6个环原子的环烷基调合和/或可任选地由1-3个如下基团或取代基取代的苯基或萘基:卤,羟基,烷氧基,烷硫基,烷基亚磺酰基,烷基磺酰基,酰氧基,芳氧基,杂合芳氧基,可任选地由一个或二个烷基,芳基或杂芳基取代的氨基,脒基,可任选地由烷基,芳基,杂芳基或杂环基取代的脲,可任选地由烷基,芳基或杂芳基N-单取代或N,N-二取代的氨基磺酰基,烷基磺酰氨基,芳基磺酰氨基,杂芳基磺酰氨基,烷基羰基氨基,芳基羰基氨基,杂芳基羰基氨基等。
″取代的芳基″是指可任选地由一个或多个官能团例如卤素,低级烷基,低级烷氧基,烷硫基,亚乙基,氨基,酰氨基,羧基,羟基,芳基,芳氧基,杂环,杂芳基,取代的杂芳基,硝基,氰基,巯基,氨磺酰基等等。
″杂环″是指具有单环(例如吗啉代,吡啶基或呋喃基)或多个稠合环(例如萘吡啶基,喹喔啉基,喹啉基,吲嗪基或苯并[b]噻吩基)并且环内具有至少一个杂合原子(例如N,O或S)的饱和的,不饱和的或芳族碳环基团,它可任选地来被取代或可任选地由例如卤,低级烷基,低级烷氧基,烷硫基,亚乙基,氨基,酰氨基,羧基,羟基,芳基,芳氧基,杂环,杂芳基,取代的杂芳基,硝基,氰基,巯基,氨磺酰基等等取代。
″杂芳基″-单独或组合地指含有5或6个环原子的单环芳香环结构,或具有8-10原子的二环的芳基,所述芳基含有独立地选自:O,S和N的一个或多个,优选1-4个,更优选1-3个,甚至更优选1-2个杂原子,可任选地由1-3个以下基团或取代基取代:卤,羟基,烷氧基,烷硫基,烷基亚磺酰基,烷基磺酰基,酰氧基,芳氧基,杂芳氧基,可任选地由一个或二个烷基,芳基或杂芳基取代的氨基,脒基,可任选地由烷基,芳基,杂芳基或杂环基取代的脲,可任选地由烷基,芳基或杂芳基N-单取代或N,N-二取代的氨基磺酰基,烷基磺酰氨基,芳基磺酰氨基,杂芳基磺酰氨基,烷基羰基氨基,芳基羰基氨基,杂芳基羰基氨基等等。杂芳基是可以包括氧化S或N,例如亚硫酰基,磺酰基和环叔氮的N-氧化物。碳或氮原子是杂芳基环结构的连接点,这样保留稳定的芳香环。杂芳基的例子是吡啶基,哒嗪基,吡嗪基,喹唑啉基,嘌呤基,吲哚基,喹啉基,嘧啶基,吡咯基,噁唑基,噻唑基,噻吩基,异噁唑基,噁噻二唑基,异噻唑基,四唑基,咪唑基,三嗪基,呋喃基,苯并呋喃基,吲哚基等等。取代的杂芳基含有在可利用的碳或氮上连接的取代基以产生稳定的化合物。
″杂环″-单独或组合地指具有5-10个原子的非芳香性环烷基,其中环的1-3个碳原子被杂原子O,S或N取代,且可任选地苯并示周合或调合5-6个环原子的杂芳基和/或如环烷基的取代那样可任选地被取代。杂环也可以包括氧化的S或N,例如亚硫酰基,磺酰基和N-环的叔氮的N-氧化物。连接点是在碳或氮原子。杂环的例子是四氢呋喃基,二氢吡啶基,哌啶基,吡咯烷基,哌嗪基,二氢苯并呋喃基,二氢吲哚基等等。取代的杂环含有在可利用的碳或氮上连接取代基氮以产生稳定的化合物。
″取代的杂芳基″是指可任选的由一个或多个如下官能团单或多取代的杂环,例如卤素,低级烷基,低级烷氧基,烷硫基,亚乙基,氨基,酰氨基,羧基,羟基,芳基,杂氧基,杂环基,取代的杂环基,杂芳基,取代的杂芳基,硝基,氰基,巯基,氨磺酰基等等。
″芳烷基″是指-R-Ar,其中Ar是芳基,R是低级烷基或取代的低级烷基。芳基可以可任选地被或不被例如卤素,低级烷基,烷氧基,烷硫基,亚乙基,氨基,酰氨基,羧基,羟基,芳基,杂环,取代的杂环,杂芳基,取代的杂芳基,硝基,氰基,巯基,氨磺酰基等等取代。
″杂烷基″是指-R-Het,其中Het是杂环基团,R是低级烷基。杂烷基可以可任选地被或不被例如卤素,低级烷基,烷氧基,烷硫基,亚乙基,氨基,酰氨基,羧基,芳基,芳氧基,杂环,取代的杂环,杂芳基,取代的杂芳基,硝基,氰基,巯基,氨磺酰基等等取代。
″杂芳基烷基″是指-R-HetAr,其中HetAr是杂芳基,R是低级烷基或取代的低级烷基。杂芳基烷基可以可任选地被或不被例如卤素,低级烷基,取代的低级烷基,烷氧基,烷硫基,亚乙基,芳基,芳氧基,杂环,取代的杂环,杂芳基,取代的杂芳基,硝基,氰基,巯基,氨磺酰基等等取代。
″环烷基″是指含有3-15碳原子的二价环烷基或多环烷基。
″取代的环烷基″是指包括一个或多个取代基的环烷基,取代基包括卤素,低级烷基,取代的低级烷基,烷氧基,烷硫基,亚乙基,芳基,芳氧基,杂环,取代的杂环,杂芳基,或取代的杂芳基,硝基,氰基,巯基,氨磺酰基等等。
″环杂烷基″是指环烷基,其中一个或多个的环碳原子被杂原子(例如N,O,S或P)取代。
“取代的环杂烷基″是指本文定义的环杂烷基,含有一个或多个取代基,例如卤素,低级烷基,低级烷氧基,烷硫基,亚乙基,氨基,酰氨基,羧基,羟基,芳基,芳氧基,杂环,取代的杂环,杂芳基,取代的杂芳基,硝基,氰基,巯基,氨磺酰基等等。
″烷基环烷基″是指-R-环烷基,其中环烷基是环烷基团,R是低级烷基或取代的低级烷基。环烷基可任选地被或不被例如卤素,低级烷基,低级烷氧基,烷硫基,亚乙基,氨基,酰氨基,羧基,羟基,芳基,芳氧基,杂环,取代的杂环,杂芳基,取代的杂芳基,硝基,氰基,巯基,氨磺酰基等等取代。
″烷基环杂烷基″是指-R-环杂烷基,其中R是低级烷基或取代的低级烷基。环杂烷基可任选地被或不被例如卤素,低级烷基,低级烷氧基,烷硫基,氨基,酰氨基,羧基,亚乙基,羟基,芳基,芳氧基,杂环,取代的杂环,杂芳基,取代的杂芳基,硝基,氰基,巯基,氨磺酰基等等取代。
根据方案1-2所列的方法可以制备本发明的化合物。根据文献方法从商品化的6-氯嘌呤核糖甙按三个步骤制备2-甲锡烷基腺苷1(K.Kato等人.,J.Org.Chem.(1997),62,6833-6841)。
三TBDMS衍生物3是通过用TBDMSC1和咪唑在DMF中对式2化合物进行处理而获得的。通过用LTMP锂化随后用三氯化三正丁基锡猝灭唯一地得到2-甲锡烷基衍生物4。在2-丙醇中氨解得到2-甲锡烷基腺苷1。用商品化的2,5-二碘代噻吩在Pd(PPh3)4和CuI存在下进一步偶联1获得式5化合物(K.Kato等人.,J.Org.Chem.(1997),62,68336841)。将2’,3’和5’羟基上的甲硅烷基用0.5M氟化铵在甲醇中脱保护获得式6化合物(方案1)。
通过用商品化的三n-丁基苯基锡处理碘代噻吩衍生物5获得式7化合物,式7化合物用0.5M NH4F脱保护制得苯基噻吩衍生物8。
方案2
方案2举例说明化合物13的具体合成。将商品化的鸟苷9转化为以前描述的三醋酸盐10(M.J.Robins和B.Uznanski,Can.J.Chem.(1981),59,2601-2607)。将根据Cerster等人文献方法(J.F.Cerster,A.F.Lewis,和R.K.Robins,Org.Synthesis,242-243)制备的化合物11如前关于类似化合物所述的方法,以2个步骤转化为化合物13(Matsuda等人,Synthesis,(1984),963.)。
本发明的化合物可与放射性的显像剂联合使用,使冠脉状的活动显像。本发明的化合物是A2A激动剂,据认为A2A激动剂特异性激活冠脉腺苷A2A受体,与心房和AV结的腺苷A1受体和/或外周血管的A2B受体相反,从而避免不受欢迎的副作用。以治疗量给药,本发明的化合物引起冠状血管舒张以诱导冠脉窍血,其中健康的冠脉从不健康的血管窍血,导致血不能流到心脏组织。然后冠状进行成像鉴定具有健康和不健康血流的冠状区域。在慢性CAD的治疗时较低剂量的A2A激动剂可以提供有益的冠状血管舒张作用(不严重)。
作为A2A激动剂,本发明的化合物还可用于作为血管成形术的辅助治疗以诱导扩胀,抑制血小板凝集,及作为一般的抗炎剂。例如本发明的化合物A2A激动剂可以通过抑制嗜中性白细胞的活化提供了上面描述的治疗效果(实验的治疗学的嘌呤能途径,K.A.Jacobson和M.F.Jarvis 1997 Wiley,纽约)。本发明的化合物也可以有效地对抗称为无回流(noreflow)的状况,其中血小板和嗜中性白细胞聚集和阻塞血管。本发明的化合物如A2A激动剂通过防止嗜中性白细胞和血小板的活化可有效地抗无回流(例如,据认为它们防止过氧化物从嗜中性白细胞释放)。本发明的化合物如A2A激动剂还通过对嗜中性白细胞的抗炎作用用作心脏保护剂。因此在心脏经受缺血状态例如移植的情形,他们将是有用的。
本发明还包括上面鉴定的A2A激动剂的前药。前药是化学上修饰过的,在其作用部位是生物学失活的,但是经过一个或多个酶或体内过程将被降解或修饰为生物活性形式的药物。本发明的前药应与母体具有不同的药物动力学特征,使经粘膜上皮的吸收改良成盐和/或溶解度较好和全身稳定性改善。上面鉴定的化合物更好地在一个或多个羟基上修饰。修饰可以是(1)酯或氨基甲酸酯衍生物,例如可通过酯酶或脂肪酶裂解;(2)可用特异性或非特异性蛋白酶识别的肽;或(3)通过膜选择在作用部位累积的衍生物或前药形式或修饰的前药形式,或上面(1)至(3)的结合。
可以以口服、静脉注射、经皮或采用本领域内技术人员已知的已用于治疗剂给药的其他方式将该组合物给药。治疗方法包括以选定化合物的有效量给药,更好地被分散于药学载体中。通常活性成分的剂量单位选自0.01to 100mg/kg的范围,但是根据给药途径、患者年龄和病情,本领域内技术人员可轻易地决定。通常在冠脉,显像之前约5分钟到约1小时或更多的时间将该剂量以形式给药。当本发明的化合物以治疗量给药时没有不可预期的毒理学作用。
如果本发明的最后的化合物含有碱性基团,可以制成酸加成盐。以标准方式在合适的溶剂中从母体化合物和过量酸(例如盐酸,氢溴酸,硫酸,磷酸,乙酸,马来酸,琥珀酸或甲磺酸)制备化合物的酸加成盐。盐酸盐形式是尤其有用的。如果最后的化合物含有酸性基团,则可制成阳离子盐。通常用过量的碱性试剂(例如含有适当的阳离子的醇化物、氢氧化物,碳酸盐)母体化合物。阳离子例如Na+,K+,Ca+2和NH4 +是存在于药学上可接受的盐中的阳离子的例子。某些的化合物形成内盐或两性离子,也是可接受的。
包括本发明化合物的药物组合物,和/或其衍生物可以配制为溶液或冻干粉末用于非肠道给药。在使用之前加入合适的稀释剂或其他药学上可接受的载体可以重新构建粉末。如果以液体形式使用,较佳为将本发明的化合物掺入到缓冲的等渗的、水性溶液。合适的稀释剂的例子是生理等渗盐水溶液,标准5%葡萄糖在水中和缓冲的乙酸钠或乙酸铵中的溶液。这样的液体制剂适用于非肠道给药,但也可用于口服给药。将赋形剂例如聚乙烯吡咯烷酮,明胶,羟基纤维素,阿拉伯胶,聚乙二醇,甘露糖醇,氯化钠,柠檬酸钠或本领域技术人员已知的任何其他赋形剂加入到包含本发明的化合物的组合物是可取的。或者,可将药物化合物装胶囊或压片,或制成乳剂或糖浆,以便口服给药。可以加入药学上可接受的固体或液体载体以加强或稳定组合物,或利于组合物的制备。液体载体包括糖浆,花生油,橄榄油,甘油,盐水,醇类水。固体载体包括淀粉,乳糖,硫酸钙,二水合物,teffaalba,硬脂酸镁或硬脂酸,滑石,果胶,阿拉伯胶,琼脂或明胶。载体也可包括持续释放的材料,例如单独的或与蜡合用的甘油一硬脂酸酯或甘油二硬脂酸酯。固体载体的量可变化,但是优选的是每剂量单位约20mg到约1克。药物剂型采用常规技术制备例如研磨,混合,制粒法,和必要时对片剂形式采用压缩法;对于硬明胶胶囊形式采用研磨,混合和充填。
当使用液体载体时,制剂将是糖浆,酏剂,乳剂或水性或非水性悬浮液的形式。这样的液体制剂可以直接给药或填充到软明胶胶囊中给药。本发明的组合物以溶液形式口服或静脉注射是优选的。
下面的实施例用于举例说明本发明。这些实施例不以任何方式限制本发明的范围,而是用来说明如何制造和使用本发明的化合物的。在这些实施例中,所有的温度是摄氏度。
实施例1
乙酸{(2R,3R,4R,5R)-3,4-二乙酰氧基-5-[6-氯-2-(5-甲基(2-噻吩基))嘌呤-9基]氧戊环2基}甲酯(12)
向2-氨基-6-氯-9-(2’,3’,S’-tri-O-乙酰基)-D-呋喃核糖基嘌呤(11)(170.0mg,0.4mmol)的2毫升2-甲基噻吩悬浮液中加入亚硝酸盐异戊酯(250毫升),CuI(60mg),混合物在115℃加热3小时。过滤真空条件下,浓缩反应混合物,用制备型TLC(EtOAc∶己烷1∶1)将残渣纯化,获得化合物12。’HNMR(CDCl3)δ2.0(s,3H),2.05(s,3H),2.1(s,3H),2.5(s,3H),4.30(m,1H),4.40-4.55(m,2H),5.90(t,1H),6.0(t,1H),6.1(d,1H),6.8(d,1H),7.85(d,1H),8.1(s,1H)。
实施例2
(4S,2R,3R,5R)-2-[6-氨基-2-(5-甲基(2-噻吩基))嘌呤-9基1-5-(羟甲基)氧戊环-3,4-二醇(13)
将化合物12(50mg,0.1mmol)溶解于5mL氨的甲醇液(0℃饱和溶液),将混合物40℃加热24小时。真空浓缩后,用制备型TLC(10%MeOH/DCM)纯化残渣,获得化合物13’HNMR(CD30D)δ2.5(s,3H)3.75(d,1H),3.85(d,1H),4.15(d,2H)4.45(m,1H),4.85(m,1H),6.0(d,1H),6.75(d,1H),7.7(d,1H),8.25(s,1H)。
实施例3
分析本发明的化合物以测定在猪纹状体膜制剂上对A2A受体的亲合力。简言之,用腺苷脱氨基酶(2U/mL)和50mM Tris缓冲液(pH=7.4)处理0.2mg猪纹状体膜,随后混合。向猪膜加入2mL连续稀释的本发明化合物DMSO储备液,浓度范围为10nM到100μM或对照仅仅接受2mL的DMSO,然后加入Tris缓冲剂液配制的拮抗剂ZM 241385(50mM,pH为7.4)获得最后浓度为2nM。在23℃孵育2小时之后,然后用膜收集器过滤溶液多次洗涤膜(3x)。在闪烁混合液中将滤器皿计数以测定本发明化合物取代的*标记ZM的量。使用多于5点的曲线得到Ki值。化合物13的Ki在1,000和10,000nM之间。
实施例4
本发明的另外的化合物制备如下:
9-{(2R,3R,4R,5R)-3,4-双(1,1,2,2-四甲基-1-硅杂丙氧基)-5-[(1,1,2,2-四甲基-1-硅杂丙氧基)甲基]氧戊环-2基}-2-(5-碘代(2-噻吩基))嘌呤-6基胺(5)
在90℃将化合物4(50mg,0.056mmol),2,5-二碘代吡唑(50mg),Pd(PPh3)4(20mg,15mol%)和Cul(40mg,0.2mmol)在DMF(1ml)中的混合物在搅拌16小时。在真空中浓缩反应物,采用制备型薄层层析法(二氯甲烷∶甲醇10∶1)纯化残渣,获得化合物5:1HNMR(CDC13)0.00(s,3H,CH3),0.01(s,3H,CH3),0.04(s,3H,CH3),0.07(s,3H,CH3),0.11(s,3H,CH3),0.14(s,3H,CH3),0.78(s,9H,t-bu),0.83(s,9H,t-bu),0.91(s,9H,t-bu),3.80(d,1H),4.05(d,1H),4.11-4.12(m,1H),4.32-4.33(m,1H),4.80(d,1H),5.55(bs,2H,D20可交换的),5.95(d,1H),7.21(d,2H),7.50(d,2H),8.10(s,1H)。
(4S,2R,3R,5R)-2-[6-氨基-2-(5-碘代(2-噻吩基))嘌呤-9基]-5-(羟甲基)氧戊环-3,4-二醇(6)
将三TBDMS衍生物(5)(15mg)在甲醇0.5M NH4F(5mL)溶液中的溶液回流16小时。浓缩反应混合物,采用制备型TLC(甲醇-二氯甲烷9∶1)纯化残渣,获得化合物6;1HNMR(CD30D)3.65(d,J=11.2Hz,1H),3.81(d,J=11.2Hz,1H),4.15-4.16(m,1H),4.25-4.26(m,1H),4.78(dd,1H),5.72(d,1H),7.15(s,2H),7.45(d,2H),7.80(s,1H)。
9-{(2R,3R,4R,5R)-3,4-双(1,1,2,2-四甲基-1-硅杂丙氧基)-5-[(1,1,2,2-四甲基-1-硅杂丙氧基)甲基]氧戊环-2基}-2-(5-苯基(2-噻吩基))嘌呤-6基胺(7)。
将化合物5(20mg,0.056mmol),三正丁基苯基锡(50mg),Pd(PPh3)4(20mg,15mol%)和CuI(40mg,0.2mmol)在DMF(1mL)中的混合物90°搅拌16小时。真空浓缩反应液,采用制备型的薄层层析(二氯甲烷∶甲醇10∶1)纯化残渣,获得化合物7:1HNMR(CDCl3)0.00(s,3H,CH3),0.01(s,3H,CH3),0.04(s,3H,CH3),0.07(s,3H,CH3),0.11(s,3H,CH3),0.14(s,3H,CH3),0.78(s,9H,t-bu),0.83(s,9H,t-bu),0.91(s,9H,t-bu),3.80(d,1H),4.05(d,1H),4.11-4.12(m,1H),4.32-4.33(m,1H),4.80(d,1H),5.55(bs,2H,D20可交换的),5.95(d,1H),7.25-7.4(m,5H),7.65(d,2H),7.85(d,1H),8.12(s,1H)。
(4S,2R,3R,5R)-2-[6-氨基-2-(5-苯基 (2-噻吩基))嘌呤-9基]-5-(羟甲基)氧戊环-3,4-二醇(8)
将在NH4F的0.5M甲醇溶液中的三TBDMS衍生物7(5mg)的溶液(5mL)回流16小时。浓缩反应混合物,采用制备型的TLC(甲醇-二氯甲烷9∶1)纯化残渣,获得化合物8;1H NMR(CD30D)3.65(d,J=11.2Hz,1H),3.81(d,J=11.2Hz,1H),4.15-4.16(m,1H),4.22-4.26(m,1H),4.74(dd,1H),5.74(d,1H),7.10-7.25(m,5H),7.45(d,2H),7.74(d,2H),7.87(s,1H)。
Claims (13)
2.权利要求1所述的化合物,其中
R2独立地选自氢、C1-15烷基和苯基;并且
R3和R4各自独立地选自氢、C1-15烷基、苯基和卤素。
3.权利要求1所述的化合物,其中
R1是-CH2OH;X是S;
R2选自氢、C1-8烷基和苯基;并且
R3和R4各自独立地选自氢、C1-3烷基、苯基和卤素。
4.权利要求1所述的化合物,其中
R1是-CH2OH;X是S;
R2选自氢、C1-8烷基和苯基;并且
R3和R4各自独立地选自氢、甲基和卤素。
5.权利要求1所述的化合物,其中
R1是-CH2OH;X是S;
R2选自氢、C1-8烷基和苯基;并且
R3和R4各自独立地选自氢和甲基。
6.权利要求1所述的化合物,其中
R1是-CH2OH;X是S;
R2是C1-8烷基;并且
R3和R4都是氢。
7.权利要求1所述的化合物,其中
R1是-CH2OH;X是S;
R2是C1-6烷基;并且
R3和R4都是氢。
8.权利要求1所述的化合物,其中该化合物选自:
(4S,2R,3R,5R)-2-[6-氨基-2-(5-甲基(2-噻吩基))嘌呤-9-基]-5-(羟甲基)氧戊环-3,4-二醇,
(4S,2R,3R,5R)-2-[6-氨基-2-(5-碘(2-噻吩基))嘌呤-9-基]-5-(羟甲基)氧戊环-3,4-二醇,和
(4S,2R,3R,5R)-2-[6-氨基-2-(5-苯基(2-噻吩基))嘌呤-9-基]-5-(羟甲基)氧戊环-3,4-二醇。
9.权利要求1所述的化合物在制备能有效刺激哺乳动物冠状血管舒张的药物中的应用。
10.权利要求9所述的化合物的应用,其特征在于所述的哺乳动物是人。
11.一种药物组合物,其特征在于包含权利要求1的化合物和一种或多种药物赋形剂。
12.根据权利要求11所述的药物组合物,其中该药物组合物是溶液形式。
13.权利要求11所述的药物组合物在制备抗炎药、血管成形术的辅助治疗、血小板聚集抑制剂,以及血小板和嗜中性白细胞活化的抑制剂中的应用。
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TWI346109B (en) | 2004-04-30 | 2011-08-01 | Otsuka Pharma Co Ltd | 4-amino-5-cyanopyrimidine derivatives |
KR101267202B1 (ko) | 2004-05-26 | 2013-05-24 | 이노텍 파마슈티컬스 코포레이션 | 아데노신 a1 수용체 아고니스트로서의 퓨린 유도체 및 이것의 사용 방법 |
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BR112012017106A2 (pt) | 2010-01-11 | 2018-05-29 | Inotek Pharmaceuticals Corp | combinação, kit e método de redução de pressão intraocular. |
SG184221A1 (en) | 2010-03-26 | 2012-10-30 | Inotek Pharmaceuticals Corp | Method of reducing intraocular pressure in humans using n6 -cyclopentyladenosine (cpa), cpa derivatives or prodrugs thereof |
MX2014009086A (es) | 2012-01-26 | 2015-06-05 | Inotek Pharmaceuticals Corp | Polimorfos anhidros de nitrato de [ (2r,3s,4r,5r) -5- (6- (ciclopentilamino) -9h-purin-9-il) -3,4-dihidroxitetra-hidrofuran- 2-il) ] metilo y procesos para su preparación. |
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RU2742417C1 (ru) | 2017-01-13 | 2021-02-05 | Тобиси Фармасьютикал Ко., Лтд. | Регулятор активации нейтрофилов |
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