CN1151167C - 嘌呤衍生物 - Google Patents
嘌呤衍生物Info
- Publication number
- CN1151167C CN1151167C CNB008096287A CN00809628A CN1151167C CN 1151167 C CN1151167 C CN 1151167C CN B008096287 A CNB008096287 A CN B008096287A CN 00809628 A CN00809628 A CN 00809628A CN 1151167 C CN1151167 C CN 1151167C
- Authority
- CN
- China
- Prior art keywords
- compound
- general formula
- methyl
- group
- protecting group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 229940083251 peripheral vasodilators purine derivative Drugs 0.000 title 1
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- -1 1-naphthyl methyl Chemical group 0.000 claims description 41
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 32
- 125000006239 protecting group Chemical group 0.000 claims description 27
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 26
- 238000011282 treatment Methods 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 19
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- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical group C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 13
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 239000001587 sorbitan monostearate Substances 0.000 description 1
- 235000011076 sorbitan monostearate Nutrition 0.000 description 1
- 229940035048 sorbitan monostearate Drugs 0.000 description 1
- 235000019337 sorbitan trioleate Nutrition 0.000 description 1
- 229960000391 sorbitan trioleate Drugs 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 210000001562 sternum Anatomy 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- MHXBHWLGRWOABW-UHFFFAOYSA-N tetradecyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCC MHXBHWLGRWOABW-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 208000037816 tissue injury Diseases 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
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Abstract
本发明涉及通式(I)的化合物,药物上可接受的盐和溶剂化物,以及制备其的方法,和含有该化合物的组合物,该化合物可用作人腺嘌呤核苷A2a受体的激动剂。
Description
技术领域
本发明涉及嘌呤衍生物。更特别地,本发明涉及N-[(嘌呤-2-基)甲基]磺酰胺衍生物和涉及该衍生物、用于制备该衍生物的中间体、含有该衍生物的组合物三者的制备方法,和该衍生物的用途。这些衍生物是人腺嘌呤核苷A2a受体的选择性、功能性激动剂并可用作消炎剂尤其用于治疗呼吸道疾病。
背景技术
腺嘌呤核苷是在哺乳动物中间代谢中有中心作用的无所不在的分子。独立地,腺嘌呤核苷作用于多面的受体产生许多种响应。腺嘌呤核苷受体分类已经揭示了至少四个亚类的存在:A1,A2a,A2b和A3。腺嘌呤核苷A2受体在人嗜中性白细胞的表面上的刺激已经被报道能够潜在地抑制一定范围的嗜中性白细胞功能。活化的嗜中性白细胞能够通过释放反应活性氧物质例如过氧阴离子(O2 -)和粒状产物例如人嗜中性白细胞弹性蛋白酶(HNE)而损坏肺组织,它们属于炎症性的介质。另外,活化的嗜中性白细胞进行着全程合成和又释放花生四烯酸酯产品如白细胞三烯B4(LTB4)。LTB4是有效的化学吸引剂,为炎症性病灶补充附加的嗜中性白细胞,而释放的O2 -和HNE不利地影响肺的细胞外基质。媒介许多这些响应(O2 -和LTB4/HNE释放和细胞粘着)的A2受体亚类被确认为A2a。该A2亚类(A2a或A2b)媒介其它效果是仍然需要确认的。
在A2a受体上的选择性激动剂活性被认为提供了比使用非选择性腺嘌呤核苷受体激动剂时更高的治疗效果,因为在动物模型和人组织研究中与其它亚类的相互作用是与肺中的损害作用有关。例如,哮喘症,而不是非哮喘症,使支气管缩小,当抵抗吸入的腺嘌呤核苷时。这一响应至少部分地归因于A1受体亚类的活化。A1受体的活化还促进嗜中性白细胞趋药性和附着到内皮细胞上,因此加剧了肺伤害。而且,许多患有呼吸道疾病的病人将共同开处方指定β2-激动剂,并且已经在异丙基肾上腺素和负性偶合(negative interaction)到腺苷酸环化酶上的腺嘌呤核苷受体之间的动物研究中显示出负相互作用。人肥大细胞的脱粒因为腺嘌呤核苷A2b受体的活化而受到促进,因此,对A2b受体的选择性也是理想的。
发明内容
我们已经惊奇地发现,所述嘌呤衍生物抑制嗜中性白细胞功能并且是腺嘌呤核苷A2a受体的选择性的激动剂。它们还在腺嘌呤核苷A3受体上具有拮抗活性。本发明的化合物可用于治疗腺嘌呤核苷A2a受体激动剂所针对的任何疾病。它们能够用于治疗其中牵涉到白细胞(例如嗜中性白细胞,嗜曙红细胞,嗜碱细胞,淋巴细胞,巨噬细胞)-诱导的组织损伤的疾病。它们可用作消炎剂用于治疗呼吸道疾病,如成人呼吸窘迫综合征(ARDS),支气管炎,慢性支气管炎,慢性阻塞性肺病,囊性纤维化,哮喘,肺气肿,支气管扩张症,慢性窦炎和鼻炎。本化合物也可用于治疗脓毒性休克,雄性勃起障碍,高血压,中风,癫痫症,大脑局部缺血,周围性血管疾病,局部缺血后再灌注伤害,糖尿病,类风湿性关节炎,多发性硬化,干癣,皮炎,过敏性皮炎,湿疹,溃疡性结肠炎,克罗恩氏病,炎症性肠病,幽门部螺杆菌胃炎,非幽门部螺杆菌胃炎,非甾族的消炎药-诱发的对胃肠道的损害或精神障碍,或用于伤口愈合。
因此,本发明提供以下通式的化合物:
或它们的可药用盐或溶剂化物,其中
R1是氢或C1-C6烷基,该烷基任选被1或2个各自独立地选自苯基和萘基的取代基取代,该苯基和萘基任选被C1-C6烷基,C1-C6烷氧基,卤素或氰基所取代;
A是键或C1-C3亚烷基;
R2是(i)氢,C1-C6烷基,C3-C7环烷基,苯基或萘基,该C3-C7环烷基、苯基或萘基任选被C1-C6烷基、苯基、C1-C6烷氧基-(C1-C6)-烷基、R3R3N-(C1-C6)-烷基、氟-(C1-C6)-烷基、氟-(C1-C6)-烷氧基、C2-C5烷酰基、卤素、-OR3、氰基、-COOR3、C3-C7环烷基、-S(O)mR4、-NR3R3、-SO2NR3R3、-CONR3R3、-NR3COR4或-NR3SO2R4取代,前提条件是当A是键时R2不是氢,或(ii)当A是C2-C3亚烷基时,-NR7R8,-OR3,-COOR3,-OCOR4,-SO2R4,-CN,-SO2NR3R3,-NR3COR4或-CONR3R3,或(iii)C-连接的4-11元单或双环杂环,具有1-4个环中氮原子或1个或2个氮和1个氧或1个硫的环中原子,任选在C上被氧,C1-C6烷氧基-(C1-C6)-烷基,R3R3N-(C1-C6)-烷基,氟-(C1-C6)-烷基,氟-(C1-C6)-烷氧基,氟-(C2-C5)-烷酰基,卤素,氰基,-OR5,R6,-COR5,-NR5R5,-COOR5,-S(O)mR6,-SO2NR5R5,-CONR5R5,-NR5SO2R6或-NR5COR6取代和任选在N上被C1-C6烷氧基-(C1-C6)-烷基,R3R3N-(C2-C6)-烷基,氟-(C1-C6)-烷基,氟-(C2-C5)-烷酰基,R6,-COR5,-COOR5,-S(O)mR6,-SO2NR5R5或者-CONR5R5取代;
R3是H,C1-C6烷基,C3-C7环烷基或苯基;
R4是C1-C6烷基,C3-C7环烷基或苯基;
R5是H,C1-C6烷基,C3-C7环烷基,苯基,萘基或het;
R6是C1-C6烷基,C3-C7环烷基,苯基,萘基或het:
或者,R7和R8与它们所连接的氮原子一起表示氮杂环丁烷基,吡咯烷基,哌啶基,吗啉基,哌嗪基,高哌啶基,高哌嗪基或四氢异喹啉基,各自任选在环中碳原子上被C1-C6烷基,C3-C8环烷基,苯基,C1-C6烷氧基-(C1-C6)-烷基,R3R3N-(C1-C6)-烷基,氟-(C1-C6)-烷基,-CONR3R3,-COOR3或C2-C5烷酰基取代,并且任选在不邻近环中氮原子的环中碳原子上被氟-(C1-C6)-烷氧基,卤素,-OR3,氰基,-S(O)mR4,-NR3R3,-SO2NR3R3,-NR3COR4或-NR3SO2R4取代,并且该哌嗪-1-基和高哌嗪-1-基任选在不连接于A的环中氮原子上被C1-C6烷基,苯基,C1-C6烷氧基-(C2-C6)-烷基,R3R3N-(C2-C6)-烷基,氟-(C1-C6)-烷基,C2-C5烷酰基,-COOR4,C3-C8环烷基,-SO2R4,-SO2NR3R3或-CONR3R3取代,
或,R7是H,C1-C6烷基,C3-C8环烷基,苯基或苄基和R8是H,C1-C6烷基,C3-C8环烷基,苯基,苄基,氟-(C1-C6)-烷基,-CONR3R3,-COOR4,C2-C5烷酰基或-SO2NR3R3;
m是0,1或2;和
在R5和R6的定义中使用的“het”是指C-连接的吡咯基,咪唑基,三唑基,噻吩基,呋喃基,噻唑基,噁唑基,噻二唑,噁二唑基,吡啶基,嘧啶基,哒嗪基,吡嗪基,喹啉基,异喹啉基,苯并咪唑基,喹唑啉基,酞嗪基,苯并噁唑基或喹喔啉基,各自任选被C1-C6烷基,C1-C6烷氧基,氰基或卤素取代。
在以上定义中,卤素是指氟,氯,溴或碘以及含有所需数目的碳原子的烷基、亚烷基、烷酰基和烷氧基能够是非支化的或支化链。在以上的部分(iii)的R2中定义的杂环可以是芳族或完全或部分饱和的。在R2和“het”的定义中使用的表达短语“C-连接”是指该基团被环中碳原子连接于相邻的原子上。烷基的例子包括甲基,乙基,正-丙基,异丙基,正丁基,异丁基,仲丁基和叔丁基。烷氧基的例子包括甲氧基,乙氧基,正丙氧基,己丙氧基,正丁氧基,异丁氧基,仲丁氧基和叔丁氧基。亚烷基的例子包括亚甲基,1,1-亚乙基,1,2-亚乙基,1,3-亚丙基和1,2-亚丙基。环烷基的例子包括环丙基,环丁基,环戊基,环己基和环庚基。
通式(I)的化合物的可药用盐包括它的酸加合盐和碱性盐。
合适的酸加合盐是从可形成无毒盐的酸形成的,该盐的例子是盐酸盐,氢溴酸盐,氢碘酸盐,硫酸盐,硫酸氢盐,硝酸盐,磷酸盐,磷酸氢盐,乙酸盐,马来酸盐,富马酸盐,乳酸盐,酒石酸盐,柠檬酸盐,葡糖酸盐,丁二酸,蔗糖盐,苯甲酸酯,甲烷磺酸盐,乙烷磺酸盐,苯磺酸盐,对-甲苯磺酸盐和双羟萘酸盐。
合适的碱性盐是从可形成无毒盐的碱形成的和例子是钠,钾,铝,钙,镁,锌和二乙醇胺盐。
对于合适盐的评述参见Berge等人,J.Pharm.Sci.,66,1-19(1977)。
通式(I)的化合物的药学上可接受的溶剂化物包括它的水合物。
也包括在通式(I)的化合物的范围内的是它的多形体。
通式(I)的化合物可含有一种或多种附加的不对称碳原子,因此以两种或多种立体异构形式存在。本发明包括通式(I)的化合物的各立体异构体及其混合物。
非对映异构体的分离可通过传统方法来实现,例如通过通式(I)的化合物或它的合适盐或衍生物的立体异构体混合物的分步结晶,色层分离法或H.P.L.C.。通式(I)的化合物的各对映异构体也可从相应的旋光纯的中间体制备或通过拆分制备,如使用合适的手性载体对相应的外消旋物进行H.P.L.C.或如果合适,通过由相应外消旋物与合适的旋光活性酸或碱的反应所形成的非对映异构体盐的分步结晶方法。
优选,R1是C1-C6烷基,任选被1或2个取代基所取代,该取代基各自独立地选自苯基和萘基。
优选,R1是被1或2个取代基所取代的C1-C6烷基,该取代基各自独立地选自苯基和萘基。
优选,R1是被1或2个取代基所取代的C1-C4烷基,该取代基各自独立地选自苯基和萘基。
优选,R1是被1或2个取代基所取代的C1-C2烷基,该取代基各自独立地选自苯基和萘基。
优选,R1是苯基乙基,二苯基乙基或萘基甲基。
优选,R1是2-苯基乙基,2,2-二苯基乙基或1-萘基甲基。
优选,A是键。
优选,A是C1-C3亚烷基。
优选,A是C2-C3亚烷基。
优选,A是C2亚烷基。
优选,A是-CH2CH2-。
优选,R2是C1-C6烷基,苯基或NR7R8。
优选,R2是2-甲基丙-1-基,苯基或NR7R8。
优选,-A-R2是2-甲基丙-1-基,苯基或-CH2CH2NR7R8。
优选,R7是C1-C6烷基。
优选,R7是C1-C3烷基。
优选,R7是丙基。
优选,R7是丙-2-基。
优选,R8是C3-C8环烷基。
优选,R8是C3-C6环烷基。
优选,R8是环戊基。
包括在部分(iii)的R2的定义中的优选杂环是吡咯基,咪唑基,三唑基,噻吩基,呋喃基,噻唑基,噁唑基,噻二唑,噁二唑基,吡啶基,嘧啶基,哒嗪基,吡嗪基,喹啉基,异喹啉基,苯并咪唑基,喹唑啉基,酞嗪基,苯并噁唑基,喹喔啉基,1,2-二氢异喹啉基,3,4-二氢异喹啉基,1,2,3,4-四氢异喹啉基,氮杂环丁烷基,吡咯烷基,哌啶基,四氢吡喃基,四氢硫代吡喃基,吗啉基和哌嗪基。
通式(I)的化合物的优选例子包括以下实施例部分中的那些,包括它的任何可药用盐。
通式(I)的化合物能够通过普通方法制备,如通过在下面给出的一般方法中描述的程序或通过在实施例部分中描述的特定方法或与它们类似的方法。本发明还包括制备通式(I)的化合物的这些方法,以及其中所使用的任何新中间体。在所述的一般方法中,R1,R2和A与前面定义一样,除非另有说明。
所有通式(I)的化合物可以将下式的化合物脱保护来制备:
其中P1,P2和P3表示相同或不同的合适保护基,或P1和P2任选构成该同一保护基的一部分。合适保护基的例子对于所属领域中的技术人员来说是显而易见的[参见例如“有机合成中的保护基(第二版)”,Theodora W.Green and Peter G.M.Wuts,John Wiley and Sons,1991]。优选的各保护基是甲硅烷基(被三个独立地选自芳基和烷基的基团取代),烷酰基和芳酰基。其中P1和P2构成同一保护基的一部分的优选保护基是其中P1和P2连在一起是C1-C6亚烷基。特别优选的各保护基是乙酰基和苯甲酰基。去保护的合适条件是所属领域中的技术人员熟知的[参见例如“Protecting Groups in Organic Synthesis(Second Edition)”,Theodora W.Green and Peter G.M.Wuts,John Wiley and Sons,1991]。在典型的程序,其中P1、P2和P3各自是乙酰基,该保护基可通过典型在室温下用碱如碳酸钠处理通式(II)化合物在合适溶剂如水和甲醇的混合物中的溶液来除去。
该保护基P1,P2和P3可以在单个步骤一起除去或按任何顺序依次除去。另外,该保护基P1,P2和P3中的任何两个可在单个步骤中一起除去和剩余的基团可以在单独的步骤中除去,按任意的顺序。
通式(II)的化合物可以根据在反应历程1和2中所示的途径来制备,其中X是离去基团,优选氯以P1,P2和P3如以上所定义。
反应历程1
反应历程1(续)
在反应历程1中,通式(II)的化合物可以根据已知方法由通式(III)的化合物与通式(IV)的化合物反应来制备。在典型的程序中,通式(III)的化合物与N,O-双(三甲基乙酰胺)在惰性溶剂如1,1,1-三氯乙烷中一起加热,除去溶剂,然后将残余物在合适溶剂如甲苯中的溶液与通式(IV)的化合物和三甲基甲硅烷基三氟甲烷磺酸盐一起加热,优选在回流下。通式(IV)的化合物可以通过通式(V)的化合物的水解来制备。典型地,通式(V)的化合物溶于合适溶剂如乙醇中,然后用酸如盐酸处理。该反应优选在0到100℃,最优选20到50℃下进行。通式(V)的化合物可以通过用通式(VII)的化合物将通式(VI)的化合物加以磺酰化来制备。在典型的程序中,通式(VI)的化合物在合适惰性溶剂如二氯甲烷中的溶液用通式(VII)的化合物处理。任选添加吸酸剂如三乙胺。通式(VI)的化合物可以通过将通式(VIII)的化合物加以还原来制备。该还原反应可以用任何合适的氢化物还原剂或通过氢化来进行。在典型的程序中,通式(VIII)的化合物在合适溶剂如乙醇中的溶液用氨气饱和,用合适的加氢催化剂如Pearlmann催化剂处理并用氢气加压,优选加压至大约414kPa(60psi)。通式(VIII)的化合物可以通过通式(IX)的化合物与氰阴离子的源物质如氰化钾反应来制备。该反应典型地在溶剂如N,N-二甲基甲酰胺中在升高的温度下进行。通式(IX)的化合物可通过通式(X)的化合物的氧化来制备。在典型的程序中,将过硫酸钾的水溶液加入到通式(X)的化合物和碳酸氢钠在合适溶剂如水和丙酮的混合物中的溶液中。通式(X)的化合物可以通过用硫代甲氧基置换通式(XI)的化合物中的氯来制备。典型地,该反应是在极性溶剂如N,N-二甲基甲酰胺中,在升高的温度下和在氮气氛围中进行的。硫代甲氧基是作为碱金属盐如硫代甲醇钠形式使用。通式(XI)的化合物可通过通式(XII)的化合物与合适的伯胺反应来制备。典型地,二氯嘌呤(XII)在溶剂如异丙醇中的溶液用胺处理,并在回流下加热。任选添加吸酸剂如二苯基乙基胺。化合物(XII)可以通过2,6-二氯-9H-嘌呤(XIII)与二氢吡喃在合适溶剂如乙酸乙酯中和在酸催化剂如4-甲苯磺酸存在下,通常在升高的温度下进行反应来制备。
反应历程2
在反应历程2中,通式(II)的化合物可通过通式(XIV)的化合物用通式(VII)的化合物加以磺酰化来制备。在典型的程序中,通式(XIV)的化合物在合适惰性溶剂如二氯甲烷中的溶液用通式(VII)的化合物处理。任选添加吸酸剂如三乙胺。通式(XIV)的化合物可以通过将通式(XV)的化合物加以还原来制备。该还原反应可以用任何合适的氢化物还原剂或通过氢化来进行。在典型的程序中,通式(XV)的化合物在合适溶剂如乙醇中的溶液用氨气加以饱和,用适宜的加氢催化剂如5%w/w钯/炭处理,用氢气增压,优选增压到1034kPa(150psi)。通式(XV)的化合物可通过通式(XVI)的化合物与合适的伯胺反应来制备。典型地,化合物(XVI)在合适溶剂如乙腈中的溶液用该胺在室温下处理。任选添加吸酸剂如二苯基乙基胺。通式(XVI)的化合物可以通过用氰根取代通式(XVII)化合物中的碘基来制备。典型地,通式(XVII)的化合物在合适溶剂(例如N,N-二甲基甲酰胺)中的溶液用氰化铜(II)处理和然后加热,优选在超过100℃的温度下。通式(XVII)的化合物是现有技术中已知的(例如参见J.Med.Chem.,1992,35,248,其中P1,P2和P3各是乙酰基)。
另外,通式(I)的化合物可以根据反应历程3,其中X是离去基团(优选氯),利用通式(VII)的化合物将通式(XVIII)的化合物加以磺酰化来制备。
反应历程3
在典型的程序中,将通式(XVIII)的化合物溶于合适溶剂如1,4-二噁烷或四氢呋喃(如有必要的话可以加热)中,然后用通式(VII)的磺酰化剂处理,典型地在室温下和在氮气氛围中,任选在吸酸剂(例如三乙胺)存在下。通式(XVIII)的化合物可以通过将通式(XIX)的化合物加以还原来制备。该还原反应可以用任何合适的氢化物还原剂或通过氢化来进行。在典型的程序中,通式(XIX)的化合物在合适溶剂如乙醇中的溶液用氨气加以饱和,用适宜的加氢催化剂如5%w/w钯/炭处理,用氢气增压,优选增压到1034kPa(150psi)。通式(XIX)的化合物可以根据现有技术中已知的方法,将通式(XV)的化合物去保护来制备[参见例如“有机合成中的保护基团(第二版)”,Theodora W.Green and Peter G.M.Wuts,JohnWiley and Sons,1991]。这些保护基能够一起、单个或以两者的任何组合方式来除去。在典型的实例中,其中P1,P2和P3各自是乙酰基,通式(XV)的化合物在合适溶剂如乙醇中的溶液用碱如氨在室温下处理。在某些情况下,从通式(XV)化合物的去保护和还原得到通式(XVII)化合物的过程可以方便地在还原性条件下一起进行。在典型的实例中,将通式(XV)的化合物溶于合适的溶剂如乙醇中,接着,所获得的溶液用氨气保护,之后用合适的加氢催化剂如钯/碳处理和用氢气增压到1034kPa(150psi)。
其中A是-CH2CH2-和R2是-NR7R8的通式(I)化合物也能够由反应历程4中所示的路线合成。
反应历程4
在反应历程4中,其中A是-CH2CH2-和R2是-NR7R8的通式(I)化合物可通过通式(XX)的化合物与下式的化合物进行反应来制备:
R7R8NH (XXII)。
在典型的程序中,通式(XX)的化合物和通式(XXII)的化合物被混合,任选在合适的溶剂存在下。优选地,该反应混合物被加热,最优选在通式(XXII)化合物的回流温度下加热。通式(XXII)的化合物是可以从市场上可买到的或可以使用本技术领域中那些技术人员熟知的标准程序(例如胺与酮或醛的还原缩合)来容易地制备。通式(XX)的化合物可通过通式(XVII)的化合物与2-氯乙烷磺酰氯的缩合反应来制备。在典型的程序中,通式(XVIII)的化合物和碱(优选叔胺碱如三乙胺)在合适溶剂如二氯甲烷中的溶液用2-氯乙烷磺酰氯处理。通式(XVIII)的化合物可通过其中保护基P1、P2和P3如以上所定义的通式(XIV)化合物的去保护来制备。这些保护基能够一起、或以任何组合方式单个除去。去保护的合适条件是所属领域中的技术人员熟知的[参见例如“有机合成中的保护基团(第二版)”,Theodora W.Green and Peter G.M.Wuts,John Wiley and Sons,1991]。在典型的程序,其中P1、P2和P3各自是乙酰基,该保护基可通过典型在室温下用碱如碳酸钠处理通式(XIV)化合物在合适溶剂如水和甲醇的混合物中的溶液来除去。
通式(I)的化合物也可通过使用普通的官能团互转化技术来进行相互转变。
参考前面的文献和下面的实施例和制备部分,在前述方法中使用的新型起始原料的所有反应和制备过程是常用的,合适的试剂和反应条件以及分离所需产物的程序是本技术领域中的技术人员周知的。
通式(I)化合物的可药用盐能够容易地通过将通式(I)化合物的溶液和所需酸或碱(根据需要)混合在一起来制备。该盐可从溶液中沉淀和通过过滤收集或通过蒸发掉溶剂来回收。
通式(I)化合物的消炎性质可由它们抑制嗜中性白细胞功能的能力来验证,它表现A2a受体激动剂活性。这是通过在从fMLP活化的嗜中性白细胞测量过氧化物产生量的分析中通过测定化合物曲线模式(profile)来进行评价。通过使用葡聚糖沉降、随后通过Ficoll-Hypaque溶液的离心作用,从人的周围血液中分离嗜中性白细胞。在粒性白细胞颗粒中任何污染性红血球是通过用冰冷的蒸馏水消散来除去。嗜中性白细胞的过氧化物产生是在打底(priming)浓度的细胞松弛素B存在下由fMLP诱发的。腺苷脱氨酶被包括在该分析中以除去可能抑制过氧化物产生的任何内生的腺嘌呤核苷。该化合物对fMLP诱发的应答的效果是利用比色分析方法从细胞色素C在分析缓冲液中的还原来检测。化合物的效力是通过达到50%抑制(IC50)时的浓度,与对fMLP的对照应答进行对比来分析。
通式(I)的化合物能够单独给药,但是一般是与根据预定给药途径和标准药物实践经验所选择的合适药物赋形剂、稀释剂或载体一起混合来给药。
例如,通式(I)的化合物能够以片剂、胶囊剂、卵形剂、酏剂、溶液剂或悬浮剂形式口服、面颊或舌下给药,它们可含有调味剂或着色剂,用于中等速度-,延迟-,缓释-,脉冲-或受控-释放应用。
此类片剂可含有赋形剂如微晶纤维素,乳糖,柠檬酸钠,碳酸钙,磷酸氢钙和氨基乙酸,崩解剂如淀粉(优选玉米、土豆或木薯的淀粉),羟基乙酸淀粉钠,croscarmellose钠和某些复合硅酸盐,和造粒粘结剂如聚乙烯吡咯烷酮,羟丙基甲基纤维素(HPMC),羟丙基纤维素(HPC),蔗糖,明胶和阿拉伯胶。另外,脱模剂比如硬脂酸镁,硬脂酸,山俞酸甘油基酯和滑石可以包括在内。
类似类型的固体组合物也可用作胶囊中的填充物。在这点上优选的赋形剂包括乳糖,淀粉,纤维素,乳糖或高分子量聚乙二醇。对于含水悬浮体和/或酏剂,通式(I)的化合物可与各种甜味剂或调味剂,色素或染料,与乳化剂和/或悬浮剂和与稀释剂如水、乙醇、丙二醇或甘油以及它们的混合物并用。
通式(I)的化合物还可以通过胃肠外途径给药,例如,静脉内,动脉内,腹膜内,鞘内注射,心室内,胸骨内,颅内,肌内注射或皮下,或它们可通过灌输技术来给药。它们最好以无菌的水溶液形式使用,它可含有其它物质例如足够的盐或葡萄糖以使溶液与血液等渗压。如果需要,该水溶液应该适当地缓冲(优选到PH值3-9)。在无菌条件下的合适胃肠外配制剂的制备能够容易地通过本技术领域中那些技术周知的标准药物技术来完成。
若为人患者实施口服和肠胃外投药,通式(I)化合物的每天剂量水平通常是0.01到100mg/kg,优选0.1到100mg/kg(单次剂量或分剂量)。
因此通式(I)化合物的片剂或胶囊剂可含有5-500mg的活性化合物,每一次单批或分两批或多批给药,视情况而定。在任何情况下医生可以确定最适合于任何个体患者的实际剂量,并且剂量随具体病人的年龄、体重和响应能力来变化。上面的剂量是平均情况的范例。当然还有考虑更高或更低剂量的个别情况,并且也包括在本发明范围内。
通式(I)的化合物还能够鼻内给药或通过吸入给药,并且方便地以干粉吸入或气溶胶喷洒的形式从加压容器、泵、喷雾器、雾化器或喷洒器中分配出来,使用或不使用合适的推进剂,例如二氯二氟甲烷,三氯氟甲烷,二氯四氟乙烷,氢氟链烷烃如1,1,1,2-四氟乙烷(HFA 134A[商标])或1,1,1,2,3,3,3-七氟丙烷(HFA 227EA[商标]),二氧化碳或其它合适的气体。对于加压的气溶胶而言,该剂量单位可以通过提供一种用于分配计量用量的阀门来测定。加压容器,泵,喷雾器,雾化器或喷洒器可含有活性化合物的溶液或悬浮液,例如使用乙醇和推进剂的混合物作为溶剂,它另外含有润滑剂例如去水山梨糖醇三油酸酯。用于吸入器或吹药器的胶囊剂和药筒(例如从明胶制造)经过配制后使它含有通式(I)化合物和合适的粉末状底物如乳糖或淀粉的粉末状混合物。
气溶胶或干粉配方优选在经过排列后应使得每一计量的剂量或“一次喷射量(puff)”含有20到4000μg的通式(I)化合物,以供分配给患者。使用气溶胶的每天总剂量是在20μg至20mg的范围内,它能够以单个剂量或更通常,在整天中分剂量给药。
另外,通式(I)的化合物能够以栓剂或阴道环的形式给药,或它们以洗剂,溶液,霜剂,膏剂或细粉形式局部施用。通式(I)的化合物也能够经皮给药,例如通过使用皮肤贴片。
对于局部施用于皮肤,通式(I)的化合物能够配制成合成的膏剂,它含有悬浮或溶解在下面一种或多种物质的混合物中的活性化合物:矿物油,液体石蜡,白矿脂,丙二醇,聚氧化乙烯聚氧化丙烯化合物,乳化蜡和水。另外,它们能够配制成合适的洗剂或霜剂,被悬浮或溶解在例如下列一种或多种的混合物中:矿物油,脱水山梨糖醇单硬脂酸酯,聚乙二醇,液体石蜡,聚山梨酸酯60(polysorbate 60),十六烷基酯蜡,cetearyl醇,2-辛基十二醇,苯甲醇和水。
通式(I)的化合物也能够与环糊精并用。环糊精已知与药物分子形成包合和非包合型配合物。药物-环糊精配合物的形成可以改善药物分子的溶解度,溶解速率,生物利用率和/或稳定性。药物-环糊精配合物一般用于大多数剂型和给药途经。作为直接与药物配合的替代方案,环糊精可用作辅助添加剂,例如用作载体,稀释剂或增溶剂。α-,β-和γ-环糊精是最常用的并且合适的例子描述在WO-A-91/11172,WO-A-94/02518和WO-A-98/55148中。
可以认识到的是这里对治疗(treatment)的所有引用包括治疗,减轻和预防性治疗。
因此本发明提供:-
(i)通式(I)的化合物或它的可药用盐或溶剂化物;
(ii)制备通式(I)的化合物或它的可药用盐或溶剂化物的方法;
(iii)包括通式(I)的化合物或它的可药用盐或溶剂化物和药学上可接受的赋形剂、稀释剂或载体的药物组合物;
(iv)通式(I)的化合物或它的可药用盐、溶剂化物或组合物用作药物;
(v)通式(I)的化合物或它的可药用盐、溶剂化物或组合物用于制造药物的用途,该药物用于治疗指定用A2a受体激动剂的疾病;
(vi)通式(I)的化合物或它的可药用盐、溶剂化物或组合物用于制造消炎剂的用途;
(vii)通式(I)的化合物或它的可药用盐、溶剂化物或组合物用于制造供治疗呼吸道疾病用的药物的用途;
(viii)与(Vii)中同样的用途,其中疾病选自成人呼吸窘迫综合征(ARDS),支气管炎,慢性支气管炎,慢性阻塞性肺病,囊性纤维化,哮喘,肺气肿,支气管扩张症,慢性窦炎和鼻炎;
(ix)通式(I)的化合物或它的可药用盐、溶剂化物或组合物用于制造治疗下述疾病或使伤口愈合的药物的用途:脓毒性休克,雄性勃起障碍,高血压,中风,癫痫症,大脑局部缺血,周围性血管疾病,局部缺血后再灌注伤害,糖尿病,类风湿性关节炎,多发性硬化,干癣,过敏性皮炎,湿疹,溃疡性结肠炎,克罗恩氏病,炎症性肠病,幽门部螺杆菌胃炎,非幽门部螺杆菌胃炎,非甾族的消炎药物诱发的对胃肠道损害或精神障碍;
(x)治疗包括人在内的哺乳动物以治疗指定A2a受体激动剂的疾病的方法,该方法包括用有效量的通式(I)化合物或它的可药用盐、溶剂化物或组合物治疗该哺乳动物;
(xi)治疗包括人在内的哺乳动物以治疗炎症性疾病的方法,该方法包括用有效量的通式(I)化合物或它的可药用盐、溶剂化物或组合物治疗该哺乳动物;
(xii)治疗包括人在内的哺乳动物以治疗呼吸道疾病的方法,该方法包括用有效量的通式(I)化合物或它的可药用盐、溶剂化物或组合物治疗该哺乳动物;
(xiii)与(xii)中同样的方法,其中疾病选自成人呼吸窘迫综合征(ARDS),支气管炎,慢性支气管炎,慢性阻塞性肺病,囊性纤维化,哮喘,肺气肿,支气管扩张症,慢性窦炎和鼻炎;
(xiv)治疗包括人在内的哺乳动物以治疗下列疾病或使伤口愈合的方法,该疾病是:脓毒性休克,雄性勃起障碍,高血压,中风,癫痫症,大脑局部缺血,周围性血管疾病,局部缺血后再灌注伤害,糖尿病,类风湿性关节炎,多发性硬化,干癣,过敏性皮炎,湿疹,溃疡性结肠炎,克罗恩氏病,炎症性肠病,幽门部螺杆菌胃炎,非幽门部螺杆菌胃炎,非甾族的消炎药物诱发的对胃肠道的损害或精神障碍,该方法包括用有效量的通式(I)化合物或它的可药用盐、溶剂化物或组合物治疗该哺乳动物;和
(xv)这里所公开的某些新型中间体。
具体实施方式
以下实施例说明了结构式(I)的化合物的制备方法:
1H核磁共振(NMR)谱在所有情况下与所提出的结构一致。使用以下主峰名称的常用缩写,以在四甲基硅烷的低磁场一侧的百万分之一(ppm)给出特征化学位移(δ):例如,s,单峰;d,双峰;t,三重峰;q,四重峰;m,多重峰;br:宽阔部分。质谱(m/z)以热喷涂电离模式记录。以下缩写已用于普通溶剂:CDCl3,氘代氯仿;DMSO,二甲亚砜。缩写psi指磅/平方英寸。在使用薄层液相色谱法(TLC)时,它是指使用硅胶60 F254板的硅胶TLC,Rf是在TLC板上化合物向前移行的距离除以溶剂移行的距离。使用缩写Ac代替乙酰基,和TBDMS指叔丁基二甲基甲硅烷基。
实施例1:
N-({9-[(2R,3R,4S,5R)-3,4-二羟基-5-(羟甲基)四氢-2-呋喃基]-6-[(2,2-二苯基乙基)氨基]-9H-嘌呤-2-基}甲基)-2-甲基-1-丙烷磺酰胺
(2R,3R,4R,5R-)-4-(乙酰氧基)-2-[(乙酰氧基)甲基]-5-(6-[(2,2-二苯基乙基)氨基]-2-{[(异丁基磺酰基)氨基]甲基}-9H-嘌呤-9-基四氢-3-呋喃基乙酸酯(188mg,0.26mmol)(制备9)和碳酸钠(140mg,1.32mmol)在水(2ml)和甲醇(10ml)的混合物中的溶液在室温下搅拌6小时。在减压下除去溶剂,残余物在乙酸乙酯和盐水之间分开。分离有机相,再于减压下除去溶剂。然后通过硅胶柱色谱法,用二氯甲烷∶甲醇∶0.88氨水(95∶5∶0.5体积比)逐渐改变为二氯甲烷∶甲醇∶0.88氨水(90∶10∶1体积比)的梯度体系洗脱,来纯化残余物,获得了标题化合物(77mg)。
MS:597(MH+);619(MNa+)。
1H-NMR(CDCl3)δ:7.60(1H,br s),7.20-7.38(10H,m),6.02(1H,br s), 5.91(1H,br d),5.81(1H,t),5.70(1H,d),4.83(1H,brs),4.50(1H,d),4.07-4.40(7H,m),3.90(1H,d),3.75(1H,t),3.32(1H,s),2.95(2H,d),2.26(1H,m),4.06(6H,d)。
分析:测得C,57.54;H,6.10;N,13.76%;C29H36N6O6S.0.5H2O在计算上需要C,57.52;H,6.11;N,13.88%。
实施例2:
N-{[9-[(2R,3R,4S,5R)-3,4-二羟基-5-(羟甲基)-四氢-2-呋喃基]-6-(苯乙基氨基)-9H-嘌呤-2-基]甲基}苯磺酰胺
在0℃和在氮气氛围下,经过10分钟将苯磺酰氯(0.067g,0.38mmol)在干燥四氢呋喃(2ml)中的溶液加入到[(2R,3R,4S,5R)-2-[2-(氨基甲基)-6-(苯乙基氨基)-9H-嘌呤-9-基]-5-(羟甲基)四氢-3,4-呋喃二醇(0.19g,0.48mmol)(制备12)和三乙胺(0.14g,1.39mmol)在干燥四氢呋喃(10ml)的搅拌溶液中。该混合物在0℃下搅拌15分钟。然后在减压下除去溶剂,残余物与二氯甲烷(3×)共沸。通过硅胶柱色谱法,用二氯甲烷∶甲醇∶0.88氨水(92∶8∶0.4体积比)洗脱来纯化残余物,得到了产物,用二乙醚研磨,过滤,再干燥,获得固体状的标题化合物(200mg)。
MS:540(MH+)。
1H-NMR(CDCl3)δ:7.82(2H,d),7.63(1H,s),7.16-7.45(8H,m),6.02-6.22(2H,m),5.96(1H,br s),5.70(1H,d),4.82(1H,m),4.47(1H,d),4.02-4.34(4H,m),3.62-3.98(4H,m),3.37(1H,s),2.92(2H,t)。
实施例3:
N-({9-[(2R,3R,4S,5R)-3,4-二羟基-5-(羟甲基)四氢-2-呋喃基]-6-[(1-萘甲基)氨基]-9H-嘌呤-2-基}甲基)苯磺酰胺
温和地加热(2R,3R,4S,5R)-2-{2-(氨基甲基)-6-[(1-萘甲基)氨基]-9H-嘌呤-9-基}-5-(羟甲基)四氢-3,4-呋喃二醇(0.16g,0.37mmol)(制备15)在二噁烷(28ml)中的悬浮液,直到获得溶液为止。将溶液冷却到室温,再用三乙胺(0.12g,1.19mmol)处理,随后经10分钟加入苯磺酰氯(0.060g,0.34mmol)在二噁烷(2ml)中的溶液。混合物然后在室温下搅拌30分钟。在减压下除去溶剂,残余物与二氯甲烷共沸。通过硅胶柱色谱法,用二氯甲烷∶甲醇∶0.88氨水(92∶8∶0.4体积比)洗脱,获得了呈白色固体的标题化合物(150mg)。
MS:577(MH+)。
1H-NMR(DMSO-d6)δ:8.15-8.40(3H,m),7.20-7.98(12H,m),5.85(1H,d),5.38(1H,d),5.00-5.36(4H,m),4.52(1H,q),4.13(1H,m),4.00(2H,s),3.92(1H,d),3.42-3.72(2H,m)。
实施例4:
2-[环戊基(异丙基)氨基]N-({9-[(2R,3R,4S,5R)-3,4-二羟基-5-(羟甲基)四氢-2-呋喃基]-6-[(2,2-二苯基乙基)氨基]-9H-嘌呤-2-基}甲基)乙烷磺酰胺
N-({9-[(2R,3R,4S,5R)-3,4-二羟基-5-(羟甲基)四氢-2-呋喃基]-6-[(2,2-二苯基乙基)氨基]-9H-嘌呤-2-基}甲基)乙烯磺酰胺(60mg,0.11mmol)(制备16)溶解在N-异丙基环戊胺(2ml)(制备17),反应混合物再于回流状态下加热2小时。在减压下除去过量的试剂,和残余物在二氯甲烷(50ml)和水(30ml)之间分开。蒸发有机溶剂层,再干燥(无水硫酸镁),通过硅胶柱色谱法,用二氯甲烷∶甲醇∶氨水(92∶7∶1体积比)洗脱来纯化残余物,获得了呈油状物的标题化合物(13mg)。
MS:695(MH+)。
1H-NMR(CD3OD)δ:(1H,s),7.35-7.20(10H,m),6.00-5.95(1H,m),4.70-4.65(1H,m),4.55-4.50(1H,m),4.35-4.25(6H,m),4.15(1H,s),3.90-3.85(1H,m),3.75-3.70(1H,m),3.15-3.10(2H,m),3.00-2.90(2H,m),2.90-2.80(2H,m),1.70-1.60(2H,m),1.60-1.50(2H,m),1.50-1.40(2H,m),1.35-1.15(2H,m),0.9-0.85(6H,m)。
以下制备方法描述了在前述实施例中使用的某些中间体的制备方法。
制备1:2,6-二氯-9-四氢-2H-吡喃-2-基-9H-嘌呤
2,6-二氯-9H-嘌呤(20g,0.11mol)和4-甲苯磺酸一水合物(0.2g)溶解在乙酸乙酯(300ml)中,将混合物加热到50℃,再经30分钟缓慢加入2,3-二氢吡喃(12.6ml,0.14mol)在乙酸乙酯(50ml)中的溶液。然后将反应混合物冷却到室温,加入水(100ml),再用碳酸氢钠的饱和水溶液将溶液的pH调节到7。分离各层,有机层依次用水和盐水洗涤,用无水硫酸镁干燥,过滤,和在减压下蒸发。残余物从戊烷(×2)中共沸出来,获得了呈稍微不纯的白色固体的标题产物(30.9g)。
1H-NMR(CDCl3)δ:8.30(1H,s),5.75(1H,dd),4.25-4.15(1H,m),3.85-3.70(1H,m),2.20-1.60(6H,m)。
制备2:2-氯-N-(2,2-二苯基乙基)-9-四氢-2H-吡喃-2-基-9H-嘌呤-6-胺
2,6-二氯-9-四氢-2H-吡喃-2-基-9H-嘌呤(制备1)(30.9g,0.11mol)在异丙醇(600ml)中的溶液用N-乙基-N-异丙基-2-丙胺(47.5ml,0.27mol)和2,2-二苯基乙胺(24.8g,0.13mol)处理,然后所得混合物在回流下加热3小时。在减压下除去溶剂,残余物再从乙酸乙酯中共沸出来。通过硅胶柱色谱法,用乙酸乙酯∶己烷(40∶60体积比)逐渐改变为乙酸乙酯∶己烷(60∶40体积比)的梯度体系洗脱,以纯化残余物,获得了呈泡沫的标题化合物(49.7g)。
1H-NMR(CDCl3)δ:7.95-7.75(1H,br s),7.35-7.15(10H,m),5.80-5.70(1H,br s),5.65(1H,d),4.35(1H,m),4.30-4.18(1H,br.s),4.10(1H,d),3.70(1H,t),2.05-1.95(2H,m),1.95-1.80(1H,m),1.80-1.55(3H,m)。
制备3:N-(2,2-二苯基乙基)-2-(甲基硫烷基)-9-四氢-2H-吡喃-2-基-9H-嘌呤-6-胺
2-氯-N-(2,2-二苯基乙基)-9-四氢-2H-吡喃-2-基-9H-嘌呤-6-胺(制备2)(49.7g,0.11mol)在干燥N,N-二甲基甲酰胺(200ml)中的溶液用硫代甲醇钠(10g,0.14mol)处理,所得混合物在100℃和氮气氛围下加热90分钟。混合物在室温下搅拌72小时,然后预热到100℃,维持另外2小时。冷却反应混合物,用水(1000ml)稀释。形成悬浮液,再萃取到二乙醚(×2)中。合并的有机层依次用水和盐水洗,用无水硫酸镁干燥,过滤和在减压下蒸发。残余物从二乙醚中共沸出来,然后从戊烷中共沸出来,获得了呈泡沫的标题化合物(48.9g)。
1H-NMR(CDCl3)δ:7.80(1H,s),7.20-7.10(10H,m),5.70-5.55(2H,d),4.404.20(3H,m),4.20-4.05(1H,m),3.80-3.65(1H,m),2.60(3H,s),2.15-1.90(3H,m),1.90-1.60(3H,m)。
制备4:N-(2,2-二苯基乙基)-2-(甲基磺酰基)-9-四氢-2H-吡喃-2-基-9H-嘌呤-6-胺
Oxone(商品名)(过一硫酸钾)(44g,71.7mmol)在水中(200ml)的溶液经2小时滴加到N-(2,2-二苯基乙基)-2-(甲基硫烷基)-9-四氢-2H-吡喃-2-基-9H-嘌呤-6-胺(制备3)(25g,56.2mmol)和碳酸氢钠(20g,238mmol)在丙酮(1000ml)和水(250ml)中的溶液中。所得混合物在室温下搅拌24小时,过滤和残留物用丙酮洗涤。在减压下从滤液中除去丙酮,和所得含水残余物用乙酸乙酯萃取,然后用二氯甲烷萃取。合并的有机层用盐水洗,用无水硫酸镁干燥,过滤和在减压下蒸发。残余物用二乙醚研磨,过滤,用二乙醚和戊烷洗,然后干燥,获得了呈白色固体的标题产物(20.32g)。
1H-NMR(CDCl3)δ:8.00(1H,s),7.35-7.15(10H,m),6.05-5.95(1H,br s),5.75(1H,d),4.40-4.35(1H,m),4.35-4.20(2H,br s),4.15-4.05(1H,m),3.75(1H,t),3.30(3H,s),2.18-2.05(1H,m),2.05-1.98(1H,m),1.98-1.80(1H,m),1.80-1.60(3H,m)。
制备5:6-[(2,2-二苯基乙基)氨基]-9-四氢-2H-吡喃-2-基-9H-嘌呤-2-腈
N-(2,2-二苯基乙基)-2-(甲基磺酰基)-9-四氢-2H-吡喃-2-基-9H-嘌呤-6-胺(制备4)(20.1g,42.1mmol)在干燥N,N-二甲基甲酰胺(100ml)中的溶液用氰化钾(5.5g,84.6mmol)处理,和混合物在120℃和氮气氛围下加热24小时。然后将该混合物冷却到室温,倾倒于水(1000ml)中,再搅拌另外1小时。缓慢过滤所得固体,再用水洗涤几次。固体然后溶解在二氯甲烷中,所得溶液用水洗,用无水硫酸镁干燥,过滤和在减压下蒸发。残留物在二乙醚中进行共沸2次,获得了呈油状物的标题化合物(17g)。
1H NMR(CDCl3)δ:8.00(1H,s),7.40-7.20(10H,m),6.00-5.75(1H,br s),5.70(1H,d),4.40-4.20(3H,m),4.20-4.10(1H,m),3.80-3.70(1H,m),2.20-1.90(3H,m),1.90-1.60(3H,m)。
制备6:
N-[2-(氨基甲基)-9-四氢-2H-吡喃-2-基-9H-嘌呤-6-基]-N-(2,2-二苯基乙基)胺
6-[(2,2-二苯基乙基)氨基]-9-四氢-2H-吡喃-2-基-9H-嘌呤-2-腈(5.70g,13.18mmol)(制备5)在用氨气饱和的乙醇(200ml)中的溶液用Pearlmann’s催化剂(1.00g)处理,在密封的容器中用氢气加压到60psi,和在室温下搅拌30小时。混合物用Arbocel(商标)填充料过滤,和在减压下除去溶剂。残余物从二氯甲烷(×2)中共沸出来,然后通过硅胶柱色谱法,先用二氯甲烷∶甲醇(95∶5体积比),逐渐改变为用二氯甲烷∶甲醇∶0.88氨水(90∶10∶0.5体积比)进行洗脱来纯化,获得了标题化合物(4.34g)。
MS:429(MH+)。
1H-NMR(CDCl3)δ:7.84(1H,s),7.14-7.36(10H,m),5.70(1H,d),5.50-5.70(1H,br s),4.20-4.42(3H,m),4.14(1H,d),3.95(2H,s),3.78(1H,t),1.90-2.20(5H,m),1.50-1.88(3H,m)。
制备7:
N-({6-[(2,2-二苯基乙基)氨基]-9-四氢-2H-吡喃-2-基-9H-嘌呤-2-基}甲基)-2-甲基-1-丙烷磺酰胺
N-[2-(氨基甲基)-9-四氢-2H-吡喃-2-基-9H-嘌呤-6-基]-N-(2,2-二苯基乙基)胺(3.70g,8.63mmol)(制备6)和三乙胺(2.20g,21.78mmol)在干燥二氯甲烷(20ml)中的溶液用2-甲基-1-丙烷磺酰氯(1.48g,9.46mmol)进行处理,混合物再于室温下搅拌18小时。TLC显示,仍然保留了一些起始原料,所以加入另外的2-甲基-1-丙烷磺酰氯(0.2g,1.28mmol)和混合物在室温下搅拌1小时。在减压下除去溶剂,残余物通过硅胶柱色谱法用二氯甲烷∶甲醇(98∶2体积比)洗脱来纯化,获得了呈泡沫的的标题产物(4.4g)。
MS:549(MH+)。
1H-NMR(CDCl3)δ:7.86(1H,s),7.16-7.36(10H,m),5.74(1H,br s),5.64(1H,d),5.57(1H,t),4.18-4.46(5H,m),4.14(1H,d),3.77(1H,t),2.92(2H,d),2.28(1H,m)1.92-2.10(3H,m),1.58-1.88(3H,m),1.03(6H,d)。
制备8:
N-({6-[(2,2-二苯基乙基)氨基]-9H-嘌呤-2-基}甲基)-2-甲基-1-丙烷磺酰胺盐酸盐
N-({6-[(2,2-二苯基乙基)氨基]-9-四氢-2H-吡喃-2-基-9H-嘌呤-2-基}甲基)-2-甲基-1-丙烷磺酰胺(4.30g,7.84mmol)(制备7)在乙醇(100ml)中的溶液加热到37℃,然后用盐酸(2N,15ml)处理。让混合物在室温下放置18小时,此后滤去结晶沉淀,用乙醇(10ml)洗和干燥,获得了呈固体的标题化合物(3.0g)。
1H-NMR(DMSO-d6)δ:8.48(1H,br s),7.75(1H,br s),7.37(4H,d),7.27(4H,dd),7.16(2H,dd),4.56(1H,t),4.20-4.40(4H,m),2.95(2H,d),2.10(1H,m),0.95(6H,d)。
制备9:
(2R,3R,4R,5R)-4-(乙酰氧基)-2-[(乙酰氧基)甲基]-5-(6-[(2,2-二苯基乙基)氨基]-2-{[(异丁基磺酰基)氨基]甲基}-9H-嘌呤-9-基)四氢-3-呋喃基乙酸酯
N-({6-[(2,2-二苯基乙基)氨基]-9H-嘌呤-2-基}甲基)-2-甲基-1-丙烷磺酰胺盐酸盐(制备8)(0.21g,0.42mmol)在1,1,1-三氯乙烷(10ml)中的悬浮液用N,O-双(三甲基乙酰胺)(0.6ml,2.45mmol)处理,和混合物在回流下加热2小时。在减压下除去溶剂,残留物用甲苯(×2)共沸。残余物溶解在甲苯(10ml)中,再用β-D-呋喃核糖-1,2,3,5-四乙酸酯(0.16g,0.50mmol)和三甲基甲硅烷基三氟甲基磺酸酯(0.1ml,0.5mmol)处理。混合物然后在回流下加热4小时。混合物用乙酸乙酯稀释,依次用饱和碳酸氢钠水溶液和盐水洗,再于减压下蒸发。残余物通过硅胶柱色谱法用二氯甲烷∶甲醇(98∶2体积比)逐渐改变为二氯甲烷∶甲醇(95∶5体积比)的梯度体系纯化,获得了作为α-和β-端基异构体的1∶3混合物的标题化合物(188mg)。
MS:723(MH+);745(MNa+)。
1H-NMR(CDCl3)δ:7.97(0.25H,br s),7.76(0.75H,br s),7.15-7.37(10H,m),7.25(2.25H,m),5.88(1.75H,m),5.73(0.75H,m),5.51(0.25H,m),4.34-4.63(8H,m),2.95(2H,m),2.28(3H,s),2.06-2.20(4H,m),2.00(3H,s),1.05(6H,d)。
制备10:
(2R,3R,4R,5R)-4-(乙酰氧基)-2-[(乙酰氧基)甲基]-5-(6-氯-2-氰基-9H-嘌呤-9-基)四氢-3-呋喃基乙酸酯
(2R,3R,4R,5R)-4-(乙酰氧基)-2-[(乙酰氧基)甲基]-5-(6-氯-2-碘-9H-嘌呤-9-基)四氢-3-呋喃基乙酸酯(J.Med.Chem.,1992,35,248)(0.5g,0.93mmol)和氰化铜(II)(0.11g,1.23mmol)在N,N-二甲基甲酰胺中的混合物在115℃下加热90分钟。在减压下除去溶剂,和残余物通过硅胶柱色谱法用二氯甲烷∶乙酸乙酯(4∶1体积比)洗脱来纯化,获得了产物,然后依次用二氯甲烷和二乙醚共沸,获得了作为固体的标题化合物(0.22g)。
MS:438(MH+)。
1H-NMR(CDCl3)δ:8.50(1H,s),6.28(1H,d),5.78(1H,t),5.53(1H,m),4.52(1H,m),4.42(2H,m),2.20(3H,s),2.17(3H,s),2.10(3H,s)。
制备11:
(2R,3R,4R,5R)-4-(乙酰氧基)-2-[(乙酰氧基)甲基]-5-[2-氰基-6-(苯乙基氨基)-9H-嘌呤-9-基]四氢-3-呋喃基乙酸酯
(2R,3R,4R,5R)-4-(乙酰氧基)-2-[(乙酰氧基)甲基]-5-(6-氯-2-氰基-9H-嘌呤-9-基)四氢-3-呋喃基乙酸酯(1.96g,4.48mmol)(制备10)和三乙胺(1.8g,17.8mmol)在乙腈(20ml)中的溶液用苯乙基胺(0.60g,4.96mmol)处理,以及该混合物在室温和氮气氛围下搅拌2小时。在减压下除去溶剂,和残余物在二氯甲烷(75ml)和水(20ml)之间分开。分离有机相和在减压下除去溶剂。泡沫通过硅胶柱色谱法用二氯甲烷∶乙酸乙酯(4∶1体积比)洗脱来纯化,获得了产物,然后与二乙醚共沸,得到了呈泡沫的标题化合物(2.05g)。
MS:523(MH+)。
1H-NMR(CDCl3)δ:8.00(1H,s),7.17-7.35(5H,m),6.16(1H,d),6.03(1H,br s),5.77(1H,m),5.57(1H,m),4.34-4.47(3H,m),3.80-4.00(2H,br s),2.98(2H,m),2.16(3H,s),2.14(3H,s),2.08(3H,s)。
制备12:
(2R,3R,4S,5R)-2-[2-(氨基甲基)-6-(苯乙基氨基)-9H-嘌呤-9-基]-5-(羟甲基)四氢-3,4-呋喃二醇
(2R,3R,4R,5R)-4-(乙酰氧基)-2-[(乙酰氧基)甲基]-5-[2-氰基-6-(苯乙基氨基)-9H-嘌呤-9-基]四氢-3-呋喃基乙酸酯(1.0g,1.91mmol)(制备11)在用氨气饱和的乙醇(40ml)中的溶液用5%w/w钯/炭进行处理,在密封的容器中用氢气加压到1034Kpa(15opsi)和在室温下搅拌18小时。TLC分析显示,一些起始原料仍然保留,因此加入另外的5%w/w钯/炭(0.25g)和用氨气饱和的乙醇(20ml),混合物再次在密闭的容器中用氢气加压到1034kPa(150psi)和在室温下搅拌18小时。该混合物用Arbocel(商标)填充料过滤,滤液再于减压下蒸发。残余物从二氯甲烷中共沸出来,然后通过硅胶柱色谱法用二氯甲烷∶甲醇∶0.88氨水(90∶10∶0.5体积比)洗脱来纯化,获得了呈白色固体的标题化合物(340mg)。
MS:401(MH+)。
1H-NMR(DMSO-d6)δ:8.28(1H,br s),7.91(1H,br s),7.14-7.33(5H,m),5.90(1H,d),5.38(1H,br s),5.17(1H,br s),4.61(1H,br s),4.13(1H,br s),3.95(1H,s),3.73(5H,m),3.66(1H,dd),3.52(1H,dd),2.90(2H,t)。
制备13:
(2R,3R,4R,5R)-4-(乙酰氧基)-2-[(乙酰氧基)甲基]-5-{2-氰基-6-[(1-萘甲基)氨基]-9H-嘌呤-9-基)四氢-3-呋喃基乙酸酯
(2R,3R,4R,5R)-4-(乙酰氧基)-2-[(乙酰氧基)甲基]-5-(6-氯-2-氰基-9H-嘌呤-9-基)四氢-3-呋喃基乙酸酯(3.0g,6.86mmol)(制备10)、1-萘甲基胺(1.2g,7.63mmol)和三乙胺(2.8g,27.72mmol)在乙腈(30ml)中的溶液在室温下放置2小时,在这期间,慢慢形成了微细沉淀物。在减压下除去溶剂,和残余物在二氯甲烷(150ml)和水(50ml)之间分离。分离有机相,和在减压下除去溶剂。通过硅胶柱色谱法用二氯甲烷∶乙酸乙酯(4∶1体积比)洗脱来纯化残余物,获得产物,再用二氯甲烷共沸,得到了呈泡沫的标题化合物(3.6g)。
MS:559(MH+)。
1H-NMR(CDCl3)δ:7.78-8.10(4H,m),7.38-7.62(4H,m),6.22(1H,br s),6.16(1H,d),5.78(1H,t),5.56(1H,m),5.24(2H,br s),4.36-4.48(3H,m),2.18(3H,s),2.15(3H,s),2.10(3H,s)。
制备14:
9-[(2R,3R,4S,5R)-3,4-二羟基-5-(羟甲基)四氢-2-呋喃基]-6-[(1-萘甲基)氨基]-9H-嘌呤-2-腈
(2R,3R,4R,5R)-4-(乙酰氧基)-2-[(乙酰氧基)甲基]-5-{2-氰基-6-[(1-萘甲基)氨基]-9H-嘌呤-9-基)四氢-3-呋喃基乙酸酯(3.5g,6.27mmol)(制备13)在乙醇(120ml)中的溶液用氨气饱和,并在室温下搅拌4天。在减压下除去溶剂,和残余物用水(100ml)研磨,过滤,再干燥,获得了呈固体的标题化合物(2.4g)。
MS:433(MH+)。
1H-NMR(DMSO-d6)δ:9.12(1H,br s),8.67(1H,s),8.24(1H,d),7.94(1H,d),7.82(1H,m),7.34-7.63(4H,m),5.91(1H,d),5.50(1H,br s),4.90-5.30(4H,m),4.53(1H,m),4.14(1H,br s),3.95(1H,m),3.60(2H,m)。
制备15:
(2R,3R,4S,5R)-2-{2-(氨基甲基)-6-[(1-萘甲基)氨基]-9H-嘌呤-9-基}-5-(羟甲基)四氢-3,4-呋喃二醇
9-[(2R,3R,4S,5R)-3,4-二羟基-5-(羟甲基)四氢-2-呋喃基]-6-[(1-萘甲基)氨基]-9H-嘌呤-2-腈(0.75g,1.74mmol)(制备14)在乙醇(30ml)中的溶液用氨气饱和,用5%w/w钯/炭(0.50g)处理,在密闭容器中用氢气加压到1034kPa(150psi),以及在室温下搅拌42小时。TLC分析显示,一些起始原料依然保留,因此加入另外5%w/w钯/炭(0.30g)和用氨气饱和的乙醇(10ml)。混合物在密闭容器中用氢气预加压到1034kPa(150psi),并在室温下搅拌24小时。混合物用Arbocel(商标)的填充料过滤,滤液再于减压下蒸发。通过硅胶柱色谱法用二氯甲烷∶甲醇∶0.88氨水(90∶10∶0.5体积比)逐渐改变为二氯甲烷∶甲醇∶0.88氨水(85∶15∶0.75体积比)的梯度体系来纯化残余物,获得了标题化合物(0.18g)。
MS:437(MH+)。
1H-NMR(DMSO-d6)δ:8.42(1H,br s),8.28(2H,br s),7.93(1H,d),7.80(1H,d),7.36-7.60(4H,m),5.88(1H,d),5.38(1H,br s),5.18(3H,br s),4.60(1H,br m),4.13(1H,br s),3.95(1H,m),3.71(2H,s),3.63(1H,dd),3.57(1H,dd)。
制备16:
N-({9-[(2R,3R,4S,5R)-3,4-二羟基-5-(羟甲基)四氢-2-呋喃基]-6-[(2,2-二苯基乙基)氨基]-9H-嘌呤-2-基}甲基)乙烯磺酰胺
将2-氯乙烷磺酰氯(0.06ml,0.58mmol)加入到(2R,3R,4S,5R)-2-{2-(氨基甲基)-6-[(2,2-二苯基乙基)氨基]-9H-嘌呤-9-基}-5-(羟甲基)四氢-3,4-呋喃二醇(250mg,0.52mmol)(制备19)和三乙胺(0.15ml,1.1mmol)在二氯甲烷(5ml)中的溶液中。反应混合物在室温下搅拌2小时,然后用更多的二氯甲烷(50ml)稀释和用水(50ml)洗。干燥有机层(无水硫酸镁)和蒸发溶剂,产生了残余物,通过硅胶柱色谱法,用甲醇∶二氯甲烷(1∶19体积比)增加极性到甲醇∶二氯甲烷(1∶9体积比)的洗脱来纯化。在减压下除去溶剂,获得了呈油状物的标题化合物(65mg)。
1H-NMR(CD3OD)δ:8.15(1H,s),7.40-7.15(10H,m),6.70-6.55(1H,m),6.156.05(1H,m),6.00-5.95(1H,m),5.80-5.75(1H,m),4.75-4.70(1H,m),4.554.50(1H,m),4.35-4.15(6H,m),3.95-3.85(1H,m),3.80-3.70(1H,m)。
制备17:
N-异丙基环戊胺
把三乙酰氧基硼氢化钠(33.76g,0.16mol)加入到环戊基胺(15ml,0.15mol)在丙酮(500ml)中的溶液中。反应混合物在室温小搅拌24小时,然后除去溶剂和反应混合物在乙酸乙酯(400ml)和2M氢氧化钠水溶液(150ml)之间分离。分离有机层,干燥(无水硫酸镁)和在减压下蒸发,获得了呈液体的标题化合物(12g)。
1H-NMR(CD3OD)δ:3.20-3.10(1H,m),2.95-2.80(1H,m),1.95-1.80(2H,m),1.75-1.45(4H,m),1.35-1.20(2H,m),1.10-1.00(6H,m)。
制备18:
(2R,3R,4R,5R)-4-(乙酰氧基)-2-[(乙酰氧基)甲基]-5-{2-氰基-6-[(2,2-二苯基乙基)氨基]-9H-嘌呤-9-基}四氢-3-呋喃基乙酸酯
将N,O-双三甲基甲硅烷基乙酰胺(44ml,0.18mol)加入到6-[(2,2-二苯基乙基)氨基]-9H-嘌呤-2-腈(10.0g,0.03mol)(参见WO-A-00/23457)在1,1,1-三氯乙烷(250ml)中的悬浮液中。将悬浮液加热到回流状态。当所有悬浮固体已经溶解时,使反应混合物冷却到室温和在减压下除去溶剂。残余物两次溶解在甲苯(50ml)中,和溶剂在减压下除去。残余物然后溶解在甲苯(100ml)中,再加入(2R,3R,4R,5S)-4,5-双(乙酰氧基)-2-[(乙酰氧基)甲基]四氢-3-呋喃基乙酸酯(10.3g,0.032mol)。溶液在室温下搅拌,和小心加入三甲基甲硅烷基三氟甲基磺酸酯(16ml,0.088mol)。所得溶液在回流下加热2小时,然后冷却到室温。反应混合物通过添加乙酸乙酯(100ml)稀释,然后用饱和碳酸氢钠水溶液(10份的100ml)和饱和氯化钠水溶液(100ml)洗涤。合并含水萃取物,再用乙酸乙酯(三份的100ml)洗涤。干燥合并的有机层(无水硫酸镁),和在减压下除去溶剂,产生了固体,通过硅胶柱色谱法,用二氯甲烷∶甲醇∶0.88浓氨水(97∶3∶0.5体积比逐渐改变为80∶20∶3体积比)洗脱来纯化,获得了呈泡沫的标题化合物(8.5g)。
1H-NMR(CDCl3)δ:7.95(1H,s),7.35-7.20(10H,m),6.15-6.10(1H,m),5.955.90(1H,m),5.80-5.75(1H,m),5.60-5.55(1H,m),4.45-4.35(4H,m),4.354.25(2H,m),2.15(3H,s),2.10(3H,s),2.05(3H,s)。
制备19:
(2R,3R,4S,5R)-2-{2-(氨基甲基)-6-[(2,2-二苯基乙基)氨基]-9H-嘌呤-9-基}-5-(羟甲基)四氢-3,4-呋喃二醇
将10%w/w钯/炭(200mg)加入到(2R,3R,4R,5R)-4-(乙酰氧基)-2-[(乙酰氧基)甲基]-5-{2-氰基-6-[(2,2-二苯基乙基)氨基]-9H-嘌呤-9-基}四氢-3-呋喃基乙酸酯(制备18)(1.9g,3.2mmol)在用氨气饱和的乙醇(100ml)中的溶液中。反应混合物在室温和414kPa(60psi)氢气氛围下搅拌16小时。用Arbocel(商标)进行过滤来除去固体,再于减压下除去溶剂。通过硅胶柱色谱法,用二氯甲烷∶甲醇∶0.88浓氨水(90∶10∶1体积比逐渐改变为80∶20∶2体积比)洗脱来纯化残余物,得到了呈固体的标题化合物(770mg)。
MS:477(MH+)。
1H-NMR(CDCl3)δ:8.10(1H,s),7.35-7.20(8H,m),5.90-5.85(1H,m),4.754.70(1H,m),4.50-4.40(1H,m),4.30-4.20(2H,m),4.10(1H,m),3.90-3.80(2H,m),3.70-3.65(1H,m)。
药理活性
通过描述在15页中的方法由它们抑制嗜中性白细胞功能(表现A2a受体激动剂活性)的能力来测试实施例1-4的全部化合物的消炎活性,全部具有低于1微摩尔的IC50。
Claims (23)
1.以下通式的化合物:
或它们的可药用盐或溶剂化物,其中
R1是氢或C1-C6烷基,该烷基任选被1或2个各自独立地选自苯基和萘基的取代基取代;
A是键或C1-C3亚烷基;
R2是(i)氢,C1-C6烷基或苯基,或(ii)当A是C2-C3亚烷基时,为-NR7R8,其中R7为C1-C6烷基,并且R8为C3-C8环烷基。
2.权利要求1所要求的化合物,其中A是键。
3.根据权利要求1所要求的化合物,其中A是C1-C3亚烷基。
4.根据权利要求1中所要求的化合物,其中A是C2-C3亚烷基。
5.根据权利要求4的化合物,其中A是-CH2CH2-。
6.根据权利要求1的化合物,其中R2是C1-C6烷基或苯基。
7.根据权利要求6所要求的化合物,其中R2是2-甲基丙-1-基或苯基。
8.根据权利要求1所要求的化合物,其中R2是-NR7R8,其中R7为丙-2-基,并且R8为环戊基。
9.权利要求1所要求的化合物,其中R1是被1或2个各自独立地选自苯基和萘基的取代基所取代的C1-C6烷基。
10.根据权利要求9所要求的化合物,其中R1是2-苯乙基,2,2-二苯基乙基或1-萘基甲基。
11.根据权利要求1所要求的化合物,其中-A-R2是2-[(2-丙基)(环戊基)氨基]乙基,2-甲基丙-1-基或苯基。
12.根据权利要求1所要求的化合物,它选自:
N-({9-[(2R,3R,4S,5R)-3,4-二羟基-5-(羟甲基)四氢-2-呋喃基]-6-[(2,2-二苯基乙基)氨基]-9H-嘌呤-2-基}甲基)-2-甲基-1-丙烷磺酰胺;
N-{[9-[(2R,3R,4S,5R)-3,4-二羟基-5-(羟甲基)四氢-2-呋喃基]-6-(苯乙基氨基)-9H-嘌呤-2-基]甲基}苯磺酰胺;
N-({9-[(2R,3R,4S,5R)-3,4-二羟基-5-(羟甲基)四氢-2-呋喃基]-6-[(1-萘基甲基)氨基]-9H-嘌呤-2-基}甲基)苯磺酰胺;和
2-[环戊基(异丙基)氨基]-N-({9-[(2R,3R,4S,5R)-3,4-二羟基-5-(羟甲基)四氢-2-呋喃基]-6-[(2,2-二苯基乙基)氨基]-9H-嘌呤-2-基}甲基)乙烷磺酰胺;
和它的可药用盐和溶剂化物。
13.药物组合物,它包括权利要求1中的通式(I)的化合物或它的可药用盐或溶剂化物与药学上可接受的赋形剂、稀释剂或载体。
14.根据权利要求1所要求的通式(I)的化合物或它的可药用盐、溶剂化物或组合物用于制备治疗A2a受体激动剂针对的疾病的药物的用途。
15.根据权利要求14的用途,其中所述的药物为抗炎剂。
16.根据权利要求14的用途,其中所述的疾病为呼吸道疾病。
17.权利要求16的用途,其中疾病选自成人呼吸窘迫综合征,支气管炎,慢性支气管炎,慢性阻塞性肺病,囊性纤维化,哮喘,肺气肿,支气管扩张症,慢性窦炎和鼻炎。
18.根据权利要求14的用途,其中所述的疾病选自脓毒性休克,雄性勃起障碍,高血压,中风,癫痫症,大脑局部缺血,周围性血管疾病,局部缺血后再灌注伤害,糖尿病,类风湿性关节炎,多发性硬化,干癣,过敏性皮炎,湿疹,溃疡性结肠炎,克罗恩氏病,炎症性肠病,幽门螺杆菌胃炎,非幽门螺杆菌胃炎,非甾族的抗炎药物诱发的对胃肠道的损害,精神障碍或伤口愈合。
19.制备根据权利要求1的通式(I)的化合物,或它的可药用盐或溶剂化物的方法,该方法包括:
(a)将下式的化合物去保护
其中R1,R2和A如权利要求1中所定义,以及或者P1、P2和P3在单独存在时是保护基或者P1和P2一起是保护基并且P3是保护基,这些保护基可以一起或依次除去;或
(b)将下式的化合物去保护
其中R1,R2和A如权利要求1中所定义,以及或者P1和P2在单独存在时是保护基或者P1和P2一起是保护基,保护基P1和P2在单独存在时可以一起或依次除去;或
(c)将下式的化合物去保护
其中P3是保护基以及R1、R2和A如权利要求1中所定义;或(d)将下式的化合物
其中R1如权利要求1中所定义,用下式的化合物加以磺酰化:
R2-A-SO2X(VII)
其中X是离去基团,并且R2和A如权利要求1中所定义;
在该方法(a)-(d)中任何一个方法之后任选将通式(I)的化合物转化成它的可药用盐。
20.权利要求19所要求的方法,其中X为氯。
23.具有下式的化合物
基团R1如权利要求1中所定义。
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