CN101001833A - 有机化合物 - Google Patents
有机化合物 Download PDFInfo
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- CN101001833A CN101001833A CNA2005800272965A CN200580027296A CN101001833A CN 101001833 A CN101001833 A CN 101001833A CN A2005800272965 A CNA2005800272965 A CN A2005800272965A CN 200580027296 A CN200580027296 A CN 200580027296A CN 101001833 A CN101001833 A CN 101001833A
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- compound
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- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C275/30—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by halogen atoms, or by nitro or nitroso groups
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- C07C275/20—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
- C07C275/24—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
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Abstract
游离或盐形式的式I化合物,其中T、X、R1、R2、Ra、R3、R4、R5和U具有如说明书中所述的含义,其可用于治疗由CCR-3介导的病症、特别是炎性或过敏性病症如炎性或阻塞性气道疾病。还描述了含有该化合物的药物组合物以及制备该化合物的方法。
Description
本发明涉及有机化合物、其制备及作为药物的用途。
一方面,本发明提供了游离或盐形式的式I化合物,
其中
T是环状基团,其选自苯基和其中至少一个环原子选自氮、氧和硫的5-或6-元杂环,所述环状基团任选被如下基团取代:卤代、氰基、羟基、羧基、硝基、C1-C8-烷基或C1-C8-烷氧基;
X是-O-、羰基、亚甲基或键;
m是1至5的整数;
R1和R2独立地选自氢、氰基、羟基、羧基、硝基、C1-C8-烷基和C1-C8-烷氧基;
Ra是氢或者任选被如下基团取代的C1-C8-烷基:苯基、羟基或其中至少一个环原子选自氮、氧和硫的5-或6-元杂环;
n是2至8的整数;
R3和R4独立地选自氢、氰基、羟基、羧基、硝基、C1-C8-烷基和C1-C8-烷氧基;
R5是氢或C1-C8-烷基;且
U是环状基团,其选自苯基、C3-C8-环烷基和其中至少一个环原子选自氮、氧和硫的5-或6-元杂环,所述环状基团任选被如下基团取代:卤代、氰基、羟基、羧基、硝基、羟基、C1-C8-烷基或C1-C8-烷氧基。
本说明书中使用的术语具有以下含义:
“任选取代”表示所涉及的基团可以在一个或多个位置被其后所列基团的任意一个或任意组合取代。
如此处使用的“卤代”或“卤素”表示属于元素周期表的17族(以前的VII族)的元素,其可以是例如氟、氯、溴或碘。优选的卤代/卤素是氟、氯或溴。
如此处使用的“C1-C8-烷基”表示具有1至8个碳原子的直链或支链烷基。优选的C1-C8-烷基是C1-C4-烷基。
如此处使用的“C1-C8-烷氧基”表示具有1至8个碳原子的直链或支链烷氧基。优选的C1-C8-烷氧基是C1-C4-烷氧基。
“C3-C8-环烷基”表示具有3至8个环碳原子的环烷基,例如单环基团如环丙基、环丁基、环戊基、环己基、环庚基或环辛基,其中任意一个可被一个或多个、通常一个或两个C1-C4-烷基取代,或者双环基团如双环庚基或双环辛基。优选的“C3-C8-环烷基”是环丙基、环丁基、环戊基、环己基、环庚基或环辛基。
如此处使用的“含有至少一个选自氮、氧和硫的环杂原子的5-或6-元杂环”可以是例如吡咯、吡咯烷、吡唑、咪唑、三唑、四唑、噻二唑、异噻唑、噁二唑、吡啶、噁唑、异噁唑、吡嗪、哒嗪、嘧啶、哌嗪、吗啉代、三嗪、噁嗪或噻唑。优选的杂环基团包括异噁唑。
除非上下文另外要求,说明书及随后的权利要求书通篇中的术语“包含”或变体应理解为意指包括所述的整体或步骤或者整体或步骤的集合,但不排除其它任意整体或步骤或者整体或步骤的集合。
优选的游离或盐形式的式I化合物包括那些化合物,其中
T是任选被卤代取代的苯基;
X是键;
R1和R2都是氢;
m是1;
Ra是C1-C8-烷基;
R3和R4都是氢;
n是4;
R5是氢;且
U是环状基团,其选自苯基、C3-C8-环烷基和其中至少一个环原子是氮、氧和硫的5-或6-元杂环,所述环状基团任选被如下基团取代:卤代、硝基、C1-C8-烷基或C1-C8-烷氧基。
进一步优选的游离或盐形式的式I化合物包括那些化合物,其中
T是任选被卤代取代的苯基;
X是键;
R1和R2都是氢;
m是1;
Ra是C1-C4-烷基;
R3和R4都是氢;
n是4;
R5是氢;且
U是环状基团,其选自苯基、C3-C5-环烷基和其中至少一个环原子是氮、氧和硫的5-或6-元杂环,所述环状基团任选被如下基团取代:卤代、硝基、C1-C4-烷基或C1-C4-烷氧基。
由式I表示的许多化合物能形成酸加成盐,特别是药学可接受的酸加成盐。式I化合物的药学可接受的酸加成盐包括以下酸的盐:无机酸,例如氢卤酸如氢氟酸、盐酸、氢溴酸或氢碘酸、硝酸、硫酸、磷酸;和有机酸,例如脂族一元羧酸如甲酸、乙酸、三氟乙酸、丙酸和丁酸,脂族羟基酸如乳酸、柠檬酸、酒石酸或苹果酸,二元羧酸如马来酸或琥珀酸,芳族羧酸如苯甲酸、对氯苯甲酸、二苯乙酸或三苯乙酸,芳族羟基酸如邻羟基苯甲酸、对羟基苯甲酸、1-羟基萘-2-甲酸或3-羟基萘-2-甲酸,和磺酸如甲磺酸或苯磺酸。这些盐可通过已知的成盐方法由式I化合物制备。
含有酸性、例如羧基的式I化合物还能与碱形成盐,特别是药学可接受的碱如本领域已知的那些碱;适合的这类盐包括金属盐,特别是碱金属盐或碱土金属盐如钠盐、钾盐、镁盐或钙盐,或者与氨或药学可接受的有机胺或杂环碱例如乙醇胺、苄胺或吡啶成的盐。这些盐可通过已知的成盐方法由式I化合物制备。
在存在不对称碳原子的那些化合物中,化合物以单个的旋光活性异构体形式或其混合物例如外消旋或非对映体混合物存在。本发明同时包括单个的旋光活性R和S异构体以及其混合物例如外消旋或非对映体混合物。
具体的特别优选的本发明化合物是在下文实施例中描述的化合物。
本发明还提供了制备式I化合物的方法,其包括:
(i)使式II化合物
其中T、X、m、R1、R2、Ra、n、R3、R4和n如上文所定义,与式III化合物反应,
其中U如上文所定义;和
(ii)回收游离或盐形式的产物。
该方法可使用已知的胺与异氰酸酯反应的方法或者类似于例如下文实施例中所述的方法进行。该反应方便地使用有机溶剂如二甲基甲酰胺进行。适合的反应温度是10℃至40℃,例如室温。
式II化合物是新化合物,并且可通过使式IV化合物
其中T、X、m、R1、R2、Ra、n、R3、R4和R5如上文所定义且W表示以化学方法连接于所述亚甲基的固相底物,
与裂开所示-NH和-COOCH2-W之间的键的试剂反应而制备,由此使式II化合物脱离底物,以氢替换W。该反应可使用已知的使底物结合的氨基化合物脱离底物的方法或者类似于例如如下文实施例中所述的方法而实现。该反应方便地在酸性条件下进行,例如使用三氟乙酸(TFA)与有机溶剂如二氯甲烷(DCM)的混合物。适合的反应温度是10℃至40℃,例如室温。
式III化合物商购可得,或可通过已知的制备异氰酸酯的方法获得。
式IV化合物可使用已知的氨基化合物与烷基碘反应的方法或者类似于例如如下文实施例中所述的方法、通过使式V化合物
其中“Wang-碘化物树脂”中,n、R3、R4、R5和W如上文所定义,与式VI化合物反应而制备,
其中T、X、m、R1、R2和Ra如上文所定义。该反应方便地在非亲核性酸清除剂如二异丙基乙胺(DIPEA/Hünig′s碱)存在下、使用有机溶剂如二甲基甲酰胺(DMF)而进行。适合的反应温度是升高的温度,例如50℃至80℃,但是优选约55℃。
式V化合物可通过使式VII的相应伯醇
其中n、R3、R4、R5和W如上文所定义,与碘反应而制备,例如使用已知的方法,如在惰性有机溶剂如四氢呋喃(THF)和乙腈的混合物中、在三芳基膦和碱如咪唑存在下、方便地在10℃至40℃的温度、例如室温反应。
式VI化合物商购可得,或可使用已知方法制备。
式VII化合物可通过使式VIII化合物
其中n、R3、R4和R5如上文所定义,
与式IX化合物反应而制备,
其中W是固相底物,基于树脂的式IX化合物在下文中被称为“Wang对硝基苯酚树脂”或“Wang-PNP树脂”,或者类似于例如如下文实施例中所述制备。该反应方便地使用有机溶剂如二甲基甲酰胺(DMF)而进行。适合的反应温度是10℃至40℃,但优选室温。
式VIII化合物商购可得,或可使用已知方法制备。
式IX化合物可以通过使氯甲酸对硝基苯基酯与式X化合物反应、使用已知的卤代甲酸酯与醇反应的方法或者类似于例如如下文实施例中所述的方法而制备。
该反应方便地在有机碱如N-甲基吗啉存在下、使用有机溶剂如二氯甲烷(DCM)而进行。适合的反应温度是10℃至40℃,但是优选室温。
基于树脂的式X化合物商购可得,例如改性聚苯乙烯树脂,如Wang树脂,其具有连接于聚苯乙烯的骨架苯环上的对羟甲基取代的苯氧基烷基。
游离形式的式I化合物可以以常规方式转化成盐形式,反之亦然。该游离或盐形式的化合物可以以水合物或含有用于结晶的溶剂的溶剂合物的形式获得。式I化合物可以从反应混合物中回收,并以常规方式纯化。异构体如对映异构体可以以常规方式获得,例如通过分步结晶,或从相对不对称取代的例如旋光活性原料进行不对称合成。
游离或药学可接受盐形式的式I化合物在下文也被称为本发明的活性剂,可周作药物。相应地,本发明还提供了用作药物的游离或药学可接受盐形式的式I化合物。本发明的活性剂作为CCR-3受体拮抗剂,从而抑制炎性细胞、特别是嗜酸性粒细胞的浸润和激活,并抑制过敏反应。本发明活性剂的抑制特性可在以下测定中得以证明:
由麦胚凝集素(WGA)polyvinyltoluidene(PVT)SPA珠(可得自Amersham)、通过WGA与细胞表面糖蛋白的碳水化合物残基之间的特异性相互作用,将表达人CCR-3的重组细胞捕获。[125I]-人嗜酸性粒细胞趋化因子(eotaxin,可得自Amersham)特异性地与CCR-3受体结合,使[125I]-人嗜酸性粒细胞趋化因子紧密地靠近SPA珠。从[125I]-人嗜酸性粒细胞趋化因子释放的-微粒因其与珠粒接近而激活珠中的荧光基团并发光。溶液中的游离[125I]-人嗜酸性粒细胞趋化因子不靠近闪烁体,因此不发光。闪烁计数从而是试验化合物抑制嗜酸性粒细胞趋化因子与CCR-3结合的程度的量度。
测定缓冲溶液的制备:将5.96g HEPES和7.0g氯化钠溶于蒸馏水中,并加入1M CaCl2水溶液(1ml)和1M MgCl2水溶液(5ml)。用NaOH将pH调节至7.6,并用蒸馏水将溶液制成终体积1L。然后将5g牛血清白蛋白和0.1g叠氮化纳溶于该溶液中,将所得缓冲溶液贮存于4℃。在使用当天,每50mL缓冲溶液加一片COMPLETETM蛋白酶抑制剂合剂片剂(可得自Boehringer)。
均化缓冲溶液的制备:将Tris-碱(2.42g)溶于蒸馏水中,用盐酸将溶液的pH调节至7.6,并用蒸馏水将溶液稀释至终体积1L。将所得缓冲溶液贮存于4℃。在使用当天,每50mL缓冲溶液加一片COMPLETETM蛋白酶抑制剂盒剂片剂。
膜的制备:使用无酶的细胞分解液从组织培养瓶中分离稳定表达CCR3的融合大鼠嗜碱性白血病(RBL-2H3)细胞,并重悬于磷酸盐缓冲盐水中。将细胞离心(800g,5分钟),将沉淀物重悬于冰冷的均化缓冲溶液中,每克细胞用1ml均化缓冲溶液,并在冰上孵育30分钟。在玻璃研钵和研杵中以10次敲击将细胞在冰上匀化。将该匀浆离心(800g,5分钟,4℃),上清液再离心(48000g,30分钟,4℃),并将沉淀物重新溶解于含有10%(v/v)甘油的均化缓冲溶液中。膜制品的蛋白含量通过Bradford法(Anal.Biochem.(1976)72:248)测定,将等分试样快速冷冻并贮存于-80℃
该测定在每孔终体积250μl的OPTIPLATETM微量培养板(购自Canberra Packard)上进行。向微量培养板所选孔中加入50μl试验化合物在含5%DMSO的测定缓冲溶液中的溶液(浓度0.01nM至10μM)。向其它所选孔中加入含5%DMSO的50μl测定缓冲溶液,以测定总结合量。向另外所选孔中加入50μL 100nM人嗜酸性粒细胞趋化因子(购自R&DSystems)在含5%DMSO的测定缓冲溶液中的溶液,以测定非特异性结合。向所有孔中加入:浓度为250pM的50μl[125I]-人嗜酸性粒细胞趋化因子(购自Amersham)在含5%DMSO的测定缓冲溶液中的溶液(使终浓度为每孔50pM)、50μL WGA-PVT SPA珠在测定缓冲溶液中的溶液(使终浓度为每孔1.0mg珠)和100μl在测定缓冲溶液中100μg蛋白浓度的膜制品(使终浓度为每孔10μg蛋白)。然后在室温将培养板孵育4小时。根据制造商的说明书使用TOPSEAL-STM(购自Canberra Packard)将培养板密封。使用Canberra Packard TOPCOUNTTM闪烁计数器计数闪烁结果,每孔计数1分钟。发生50%抑制时的试验化合物浓度(IC50)以常规方法从浓度-抑制率曲线测得。
在上述测定中,下文实施例的化合物具有1.6μM或更小的IC50值。例如,实施例1、2、3和5的化合物的IC50值分别为1.54、0.049、0.181和0.197μM。
鉴于它们的CCR-3结合抑制作用,本发明活性剂可用于治疗由CCR-3介导的病症、特别是炎性或过敏性病症。根据本发明的治疗可以是症状性的或预防性的。
相应地,本发明的活性剂可用于治疗炎性或阻塞性气道疾病,例如减少组织损伤、支气管高反应性、重塑或疾病恶化。本发明适用的炎性或阻塞性气道疾病包括任何类型或起因的哮喘,包括内源性(非过敏性)哮喘和外源性(过敏性)哮喘、轻度哮喘、中度哮喘、重度哮喘、支气管性哮喘、运动诱发性哮喘、职业性哮喘和细菌感染后诱发的哮喘。哮喘的治疗还理解为包括治疗例如年龄低于4或5岁的个体,其表现喘息症状并已诊断或可诊断为“喘息婴儿”,这是一种已确定的医学上重点关注的患者类别,目前常常认定为初发或早期哮喘。(为方便起见,该特殊哮喘病症被称为“喘息性婴儿综合征”(wheezy-infant syndrome))。
在治疗哮喘中的预防功效可通过例如急性哮喘或支气管收缩发作的频度和严重性降低、肺功能改善或气道高反应性改善来证明。它还可进一步通过对其它症状性治疗的需求减少来证明,即用于或者预计用于限制或中止当其发生时的症状发作的疗法,例如抗炎(例如皮质类固醇)或支气管扩张。预防哮喘的益处在易于“晨僵(morning dipping)”的个体中是特别明显的。“晨僵”是一种公认的哮喘综合征,普遍见于相当比例的哮喘患者,特征是例如在约上午4至6时哮喘发作,即通常基本上远离任何以前施用的症状性哮喘治疗的时间。
本发明适用的其它炎性或阻塞性气道疾病和病症包括急性肺损伤(ALI)、急性/成人呼吸窘迫综合征(ARDS)、慢性阻塞性肺、气道或肺疾病(COPD、COAD或COLD),包括慢性支气管炎或与其伴发的呼吸困难、肺气肿,以及继发于其它药物治疗、特别是其它吸入性药物治疗的气道高反应性恶化。本发明还适用于治疗任何类型或起因的支气管炎,其包括例如急性的、花生仁吸入性的、卡他性的、格鲁布性的、慢性的或结核性的支气管炎。本发明适用的另外的炎性或阻塞性气道疾病包括任何类型或起因的尘肺病(一种炎性的、通常为职业性的肺疾病,通常伴随无论是慢性或急性的气道阻塞,且由反复吸入粉尘引起),包括例如矾土肺、炭肺、石棉肺、石末肺、驼鸟毛尘肺、肺尘病、矽肺、烟尘肺和棉尘肺。
鉴于它们的抗炎作用,特别关于嗜酸性粒细胞活化的抑制作用,本发明的活性剂还可用于治疗嗜酸性粒细胞相关疾病,例如嗜曙红细胞增多,特别是气道的嗜酸性粒细胞相关疾病(例如包括病态的肺部组织嗜酸性粒细胞性浸润),其包括影响气道和/或肺的嗜酸粒细胞增多症,以及例如继发于或伴发于Lffler’s综合征的嗜酸性粒细胞相关疾病、嗜酸细胞性肺炎、寄生性(特别是后生动物)感染(包括热带嗜酸粒细胞增多)、支气管肺曲霉病、结节性多动脉炎(包括Churg-Strauss综合征)、嗜酸细胞肉芽肿和由药物反应引起的影响气道的嗜酸性粒细胞相关疾病。
本发明的活性剂还可用于治疗皮肤的炎性或过敏性病症,例如银屑病、接触性皮炎、特应性皮炎、斑秃、多形性红斑、疱疹样皮炎、硬皮症、白斑病、变应性血管炎、风疹、大疱性类天疱疮、红斑狼疮、天疱疮、后天性大疱性表皮松解,以及其它皮肤炎性或过敏性病症。
本发明的活性剂还可用于治疗其它疾病或病症,特别是具有炎性成分的疾病或病症,例如治疗眼的疾病或病症,如结膜炎、干性性角膜结膜炎和春季结膜炎,影响鼻的疾病、包括过敏性鼻炎,以及胃肠道的炎性病症,例如炎性肠病如溃疡性结肠炎和局限性回肠炎。
本发明活性剂在抑制炎性病症例如炎性气道疾病中的功效可以在动物模型中证实,例如气道炎症或其它炎性病症的小鼠或大鼠模型,例如Szarka等,J.Immunol. Methods(1997)202:49-57;Renzi等,Am.Rev.Respir.Dis.(1993)148:932-939;Tsuyuki等,J.Clin.Invest.(1995)96:2924-2931;和Cernadas等(1999)Am.J.Respir.Cell Mol.Biol.20:1-8所述。
本发明的活性剂也可用作共同治疗剂,用于与其他药物物质联合,例如抗炎药、支气管扩张药、抗组胺药或镇咳药,特别是治疗如上文所述的阻塞性或炎性气道疾病,例如作为这类药物治疗活性的增效剂,或作为减少这类药物所需给药量或潜在副作用的手段。本发明的活性剂可与其它药物以固定的药物组合物混合,或者它可以与其它药物分别、之前、同时或之后施用。
这类抗炎药物有甾族化合物,特别是糖皮质激素如布地缩松、倍氯米松双丙酸酯、丙酸氟地松、环缩松或糠酸毛他松,或者描述于以下的甾族化合物:WO 02/88167、WO 02/12266、WO 02/100879、WO 02/00679(特别是实施例3、11、14、17、19、26、34、37、39、51、60、67、72、73、90、99和101中的那些)、WO 03/35668、WO 03/48181、WO 03/62259、WO 03/64445、WO 03/72592、WO 04/39827和WO 04/66920;非甾族糖皮质激素受体激动剂,例如描述于以下的那些:DE 10261874、WO00/00531、WO 02/10143、WO 03/82280、WO 03/82787、WO 03/86294、WO 03/104195、WO 03/101932、WO 04/05229、WO 04/18429、WO04/19935和WO 04/26248;LTB4拮抗剂例如BIIL 284、CP-195543、DPC11870、LTB4乙醇酰胺、LY 293111、LY 255283、CGS025019C、CP-195543、ONO-4057、SB 209247、SC-53228和US 5451700中描述的那些;LTD4拮抗剂如包括孟鲁司特、普仑司特、扎鲁司特、安可来(accolate)、SR2640、Wy-48,252、ICI 198615、MK-571、LY-171883、Ro24-5913和L-648051;多巴胺受体激动剂如卡麦角林、溴隐亭、累匹利洛和4-羟基-7-[2-[[2-[[3-(2-苯基乙氧基)丙基]磺酰基]乙基]-氨基]乙基]-2(3H)-苯并噻唑酮及其药学可接受的盐(盐酸盐为Viozan-AstraZeneca);PDE4抑制剂如西洛司特(cilomilast)(ArifloGlaxoSmithKline)、罗氟司特(Roflumilast)(Byk Gulden)、V-11294A(Napp)、BAY19-8004(Bayer)、SCH-351591(Schering-Plough)、阿罗茶碱(Arofylline)(Almirall Prodesfarma)、PD189659/PD168787(Parke-Davis)、AWD-12-281(Asta Medica)、CDC-801(Celgene)、SelCID(TM)CC-10004(Celgene)、VM554/UM565(Vernalis)、T-440(Tanabe)、KW-4490(KyowaHakko Kogyo),以及描述于以下的那些:WO 92/19594、WO 93/19749、WO 93/19750、WO 93/19751、WO 98/18796、WO 99/16766、WO 01/13953、WO 03/104204、WO 03/104205、WO 03/39544、WO 04/000814、WO04/000839、WO 04/005258、WO 04/01 8450、WO 04/01 8451、WO 04/018457、WO 04/018465、WO 04/018431、WO 04/018449、WO 04/018450、WO04/018451、WO 04/018457、WO 04/018465、WO 04/019944、WO 04/019945、WO 04/045607和WO 04/037805;A2a激动剂例如描述于以下的那些:EP409595A2、EP 1052264、EP 1241176、WO 94/17090、WO 96/02543、WO96/02553、WO 98/28319、WO 99/24449、WO 99/24450、WO 99/24451、WO 99/38877、WO 99/41267、WO 99/67263、WO 99/67264、WO 99/67265、WO 99/67266、WO 00/23457、WO 00/77018、WO 00/78774、WO 01/23399、WO 01/27130、WO 01/27131、WO 01/60835、WO 01/94368、WO 02/00676、WO 02/22630、WO 02/96462、WO 03/086408、WO 04/039762、WO04/039766、WO 04/045618、WO 04/046083;以及A2b拮抗剂例如描述于WO 02/42298中的那些。
这类支气管扩张药包括抗胆碱能药或抗毒蕈碱药,特别是异丙托溴铵、溴乙东莨菪碱、噻托盐(tiotropium salts)和CHF 4226(Chiesi),以及格隆溴铵,此外还有描述于以下的那些:EP 424021、US 3714357、US5171744、WO 01/04118、WO 02/00652、WO 02/51841、WO 02/53564、WO 03/00840、WO 03/33495、WO 03/53966、WO 03/87094、WO 04/018422和WO 04/05285;以及(β)-2-肾上腺素受体激动剂如β-2肾上腺素受体激动剂如沙丁胺醇(舒喘灵)、异丙喘宁、特布他林、沙美特罗、非诺特罗、丙卡特罗,并且特别地福莫特罗、卡莫昔罗(carmoterol)及其药学可接受的盐,和WO 0075114中的式I化合物(游离或盐或溶剂合物形式),该文献在此并入作为参考,优选其实施例的化合物,特别是下式化合物
及其药学可接受的盐,以及WO 04/16601中的式I化合物(游离或盐或溶剂合物形式),以及以下的化合物:EP 1440966、JP 05025045、WO 93/18007、WO 99/64035、US 2002/0055651、WO 01/42193、WO 01/83462、WO02/66422、WO 02/70490、WO 02/76933、WO 03/24439、WO 03/42160、WO 03/42164、WO 03/72539、WO 03/91204、WO 03/99764、WO 04/16578、WO 04/22547、WO 04/32921、WO 04/33412、WO 04/37768、WO 04/37773、WO 04/37807、WO 04/39762、WO 04/39766、WO 04/45618、WO 04/46083、WO 04/80964、EP1460064、WO 04/087142、WO 04/089892、EP 01477167、US 2004/0242622、US 2004/0229904、WO 04/108675、WO 04/108676、WO 05/033121、WO 05/040103和WO 05/044787。
共同治疗剂抗组胺药物包括盐酸西替利嗪、对乙酰胺基酚、富马酸氯马斯汀、异丙嗪、氯雷他定、地氯雷他定(desloratidine)、苯海拉明和盐酸非索非那定、activastine、阿司咪唑、氮斯丁、艾巴斯啶、依匹那丁、咪唑斯汀和特非那定,以及描述于以下的那些:WO 03/099807、WO04/026841、JP 2004107299。
本发明活性剂和一种或多种甾族化合物、β-2-激动剂、PDE4抑制剂或LTD4拮抗剂的组合可用于例如治疗COPD或者特别是哮喘。本发明活性剂和抗胆碱能药或抗毒蕈碱药、PDE4抑制剂、多巴胺受体激动剂或LTB4拮抗剂的组合可用于例如治疗哮喘或者特别是COPD。
其它有用的本发明活性剂与抗炎药的组合是与其它趋化因子受体的拮抗剂的组合,例如CCR-1、CCR-2、CCR-4、CCR-5、CCR-6、CCR-7、CCR-8、CCR-9和CCR10,CXCR1、CXCR2、CXCR3、CXCR4、CXCR5,特别是CCR-5拮抗剂如Sehering-Plough拮抗剂SC-351125、SCH-55700和SCH-D,Takeda拮抗剂如N-[[4-[[[6,7-二氢-2-(4-甲基苯基)-5H-苯并环庚烯-8-基]羰基]氨基]苯基]-甲基]四氢-N,N-二甲基-2H-吡喃-4-氯化铵(TAK-770),描述于以下的CCR-5拮抗剂:US 6166037(特别是权利要求18和19)、WO 00/66558(特别是权利要求8)以及WO 00/66559(特别是权利要求9)、WO 04/018425和WO 04/026873。
依照上述,本发明还提供了治疗由CCR-3介导的病症的方法,例如炎性或过敏性病症,特别是炎性或阻塞性气道疾病,其包括向有需要的个体、特别是人类个体施用有效量的如上所述游离或药学可接受盐形式的式I化合物。本发明另一方面提供了如上所述游离或药学可接受盐形式的式I化合物在制备用于治疗由CCR-3介导的病症的药物中的用途,该病症例如炎性或过敏性病症,特别是炎性或阻塞性气道疾病。
本发明的活性剂可通过任何适合的途径施用,例如经口,如以片剂或胶囊剂的形式;胃肠外,如静脉内;经吸入,如治疗炎性或阻塞性气道疾病;经鼻内,如治疗过敏性鼻炎;经局部至皮肤,如治疗特应性皮炎;或经直肠,如治疗炎性肠病。
再一方面,本发明还提供了药物组合物,其包含作为活性成分的游离或药学可接受盐形式的式I化合物,以及任选的药学可接受的稀释剂或载体。该组合物可含有共同治疗药,如如上述的抗炎药或支气管扩张药。该组合物可使用常规的稀释剂或赋形剂和盖仑医学领域已知的技术制备。因而口服剂型可包括片剂和胶囊剂。局部施用的制剂可以采取乳膏、软膏、凝胶或透皮递送系统如贴片的形式。供吸入的组合物可包含气雾剂或其它粉化的或干粉制剂。
当组合物包含气雾剂制剂时,其优选含有例如氢-氟-烷烃(HFA)抛射剂,如HFA134a或HFA227或它们的混合物,并可含有一种或多种本领域已知的共溶剂如乙醇(达20%重量),和/或一种或多种表面活性剂如油酸或失水山梨醇三油酸酯,和/或一种或多种填充剂如乳糖。当该组合物包含干粉制剂时,其优选含有例如粒径不超过10微米的式I化合物,以及任选的所需粒度分布的稀释剂或载体如乳糖,以及有助于保护防止产品因湿气而性能恶化的化合物例如硬脂酸镁,例如0.01至1.5%。当组合物包含喷雾制剂时,其优选含有例如溶解或混悬于载体中的式I化合物,该载体含有水、共溶剂如乙醇或丙二醇和可以是表面活性剂的稳定剂。
本发明包括(A)可吸入形式的本发明活性剂,如气雾剂或其它可粉化组合物或者可吸入微粒如微粉化形式,(B)可吸入药物,其包含可吸入形式的本发明活性剂;(C)药物产品,其包含可吸入形式的本发明活性剂与吸入装置;和(D)吸入装置,其含有可吸入形式的本发明活性剂。
在实施本发明中使用的本发明活性剂的剂量当然会依据例如治疗的特定病症、期望效果和施用方式而改变。通常,适合通过吸入施用的每日剂量是0.01至30mg/kg,而经口施用适合的每日剂量是0.01至100mg/kg。
本发明通过以下实施例进行阐述。
实施例
特别优选的式I化合物还可以是式XI化合物
其中X、Y、n和T如下表所示,制备方法描述于下文。该表还显示了特征性的质谱数据([MH]+)。
表I
原料的制备
Wang-PNP树脂
将氯甲酸4-硝基苯基酯(260g,1.30mmol)在500ml DCM中的溶液加至混悬于1000ml DCM和N-甲基吗啉(196ml,1.79mmol)中的Wang树脂(对-苄氧基苄醇树脂,Calbiochem-Novabiochem,350g,0.60mmol),在室温搅拌18小时。将该树脂过滤,接连用甲醇、DCM和醚洗涤,得到WANG对硝基苯酚树脂。[IR.1761.5cm-1;载荷1.20mmol/g]。
Wang-碘化物树脂
将1-氨基-3-丙醇(27ml,350mmol)加至WANG-PNP树脂(93g,116.4mmol)在DMF(100ml)中的混悬液中,在室温搅拌18小时。将该混合物过滤,接连用甲醇、DCM、最后用醚洗涤树脂,得Wang-氨基丙醇树脂(Wang-AP树脂)。向其中加入四氢呋喃(THF)和乙腈(1000ml,1∶1v/v)的混合物,接着加入三苯膦(91.8g,350mmol)、碘(88.83g,350mmol)和咪唑(23.83g,350mmol)。将该混悬液在室温搅拌24小时,过滤,然后用大量的DMF、DCM和甲醇洗涤,得到WANG-碘化物树脂。
实施例1
1-(3,5-二甲基-异噁唑-4-基)-3-{4-[(4-氟苄基)甲基氨基]-丁基}-脲
将4-(氟苄基)甲基胺(2.05g,14.73mmol)和DIPEA(2.6ml,14.73mmol)的溶液加至WANG-碘化物树脂(5.8g,7.37mmol)在100ml DMF中的混悬液中,在55℃搅拌60小时。将树脂冷却,用DMF(8×40ml)、甲醇(2×50ml)和DCM(12×40ml)洗涤,然后在室温用TFA和DCM(50ml,1∶1v/v)的混合物处理40分钟,过滤并蒸发滤液。残余物用碱性树脂(AMBERLYSTTMA-21)处理,得到式II的树脂中间体II。
将在DMF(5ml)中的3,5-二甲基异噁唑-4-基异氰酸酯(173mg,1.25mmol)加至树脂中间体II(300mg,1.25mmol)在DMF(10ml)中的溶液中,将该混合物在室温静置1小时。蒸发溶剂,残余物通过色谱纯化,得到标题产物,为白色固体。
实施例2
1-(3,4-二氟苯基)-3-{4-[(4-氟苄基)甲基氨基]-丁基}-脲
将2.6ml 14.73mmol DIPEA和4-(氟苄基)甲基胺与5.8g,7.37mmolWANG-碘化物树脂在100ml DMF中的混悬液混合,在55℃搅拌60小时。将该树脂冷却,用DMF(8×40ml)、甲醇(2×50ml)和DCM(12×40ml)洗涤,然后在室温用TFA和DCM(50ml,1∶1v/v)的混合物处理40分钟,过滤并蒸发滤液。残余物用碱性树脂(AMBERLYSTTM A-21)处理,得到式II的树脂中间体II。
将在DMF(5ml)中的3,4-二氟苯基异氰酸酯(188mg,1.25mmol)加至树脂中间体II(300mg,1.25mmol)在10ml DMF中的溶液中,该混合物在室温静置1小时。蒸发溶剂,残余物通过色谱纯化,得到标题产物,为白色固体[MH+366.1]。
使用类似与实施例2所用方法、使用适当的原料制备实施例3至7的化合物。
Claims (11)
1、游离或盐形式的式I化合物
其中
T是环状基团,其选自苯基和其中至少一个环原子选自氮、氧和硫的5-或6-元杂环,所述环状基团任选被如下基团取代:卤代、氰基、羟基、羧基、硝基、C1-C8-烷基或C1-C8-烷氧基;
X是-O-、羰基、亚甲基或键;
m是1至5的整数;
R1和R2独立地选自氢、氰基、羟基、羧基、硝基、C1-C8-烷基和C1-C8-烷氧基;
Ra是氢或者任选被如下基团取代的C1-C8-烷基:苯基、羟基或其中至少一个环原子选自氮、氧和硫的5-或6-元杂环;
n是2至8的整数;
R3和R4独立地选自氢、氰基、羟基、羧基、硝基、C1-C8-烷基和C1-C8-烷氧基;
R5是氢或C1-C8-烷基;且
U是环状基团,其选自苯基、C3-C8-环烷基和其中至少一个环原子选自氮、氧和硫的5-或6-元杂环,所述环状基团任选被如下基团取代:卤代、氰基、羟基、羧基、硝基、羟基、C1-C8-烷基或C1-C8-烷氧基。
2、根据权利要求1的化合物,其中
T是任选被卤代取代的苯基;
X是键;
R1和R2都是氢;
m是1;
Ra是C1-C8-烷基;
R3和R4都是氢;
n是4;
R5是氢;且
U是环状基团,其选自苯基、C3-C8-环烷基和其中至少一个环原子是氮、氧和硫的5-或6-元杂环,所述环状基团任选被如下基团取代:卤代、硝基、C1-C8-烷基或C1-C8-烷氧基。
3、根据权利要求2的化合物,其中
T是任选被卤代取代的苯基;
X是键;
R1和R2都是氢;
m是1;
Ra是C1-C4-烷基;
R3和R4都是氢;
n是4;
R5是氢;且
U是环状基团,其选自苯基、C3-C5-环烷基和其中至少一个环原子是氮、氧和硫的5-或6-元杂环,所述环状基团任选被如下基团取代:卤代、硝基、C1-C4-烷基或C1-C4-烷氧基。
4、基本上如本文任意一项实施例中所述的式I化合物。
5、用作药物的根据上述任意一项权利要求的化合物。
6、根据权利要求1至4任意一项的化合物与抗炎药、支气管扩张药、抗组胺药或镇咳药的组合,所述化合物和所述药物在相同或不同的药物组合物中。
7、药物组合物,其包含作为活性成分的根据权利要求1至4任意一项的化合物,任选还含有药学可接受的稀释剂或载体。
8、根据权利要求1至4任意一项的化合物在制备用于治疗由CCR-3介导的病症的药物中的用途。
9、根据权利要求1至4任意一项的化合物在制备用于治疗炎性或过敏性病症、特别是炎性或阻塞性气道疾病的药物中的用途。
11、游离或盐形式的式II化合物,
其中
T是环状基团,其选自苯基和其中至少一个环原子选自氮、氧和硫的5-或6-元杂环,所述环状基团任选被如下基团取代:卤代、氰基、羟基、羧基、硝基、C1-C8-烷基或C1-C8-烷氧基;
X是-O-、羰基、亚甲基或键;
m是1至5的整数;
R1和R2独立地选自氢、氰基、羟基、羧基、硝基、C1-C8-烷基和C1-C8-烷氧基;
Ra氢或者任选被如下基团取代的C1-C8-烷基:苯基、羟基或其中至少一个环原子选自氮、氧和硫的5-或6-元杂环;
n是2至8的整数;
R3和R4独立地选自氢、氰基、羟基、羧基、硝基、C1-C8-烷基和C1-C8-烷氧基;且
R5是氢或C1-C8-烷基。
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AU2012329098B2 (en) | 2011-10-26 | 2017-08-03 | Allergan, Inc. | Amide derivatives of N-urea substituted amino acids as formyl peptide receptor like-1 (FPRL-1) receptor modulators |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1455116A (en) * | 1972-12-15 | 1976-11-10 | Ici Ltd | Pharmaceutical compositions |
GB1460593A (en) * | 1973-06-22 | 1977-01-06 | Ici Ltd | Ethanolamine derivatives |
GB1468156A (en) * | 1973-07-19 | 1977-03-23 | Ici Ltd | Phenylethylamine derivatives |
GB8328489D0 (en) * | 1983-10-25 | 1983-11-23 | Fisons Plc | Aromatic amines |
EP0142283B1 (en) * | 1983-10-25 | 1991-01-30 | FISONS plc | Phenylethylamines, process for their preparation and compositions containing them |
JP2730135B2 (ja) * | 1989-02-13 | 1998-03-25 | 武田薬品工業株式会社 | 酸アミド誘導体 |
AU641394B2 (en) * | 1989-06-02 | 1993-09-23 | John Wyeth & Brother Limited | Amines |
US5106873A (en) * | 1990-06-26 | 1992-04-21 | Warner-Lambert Company | ACAT inhibitors |
GB9711122D0 (en) * | 1997-05-29 | 1997-07-23 | Leo Pharm Prod Ltd | Novel cyanoguanidines |
ATE321751T1 (de) * | 1999-07-28 | 2006-04-15 | Kirin Brewery | Harnstoffderivate als ccr-3 rezeptor-inhibitoren |
WO2002059081A2 (en) * | 2001-01-26 | 2002-08-01 | Kirin Beer Kabushiki Kaisha | Urea derivatives as inhibitors of ccr-3 receptor |
GB0303683D0 (en) * | 2003-02-18 | 2003-03-19 | Prolysis Ltd | Antimicrobial agents |
-
2004
- 2004-08-10 GB GBGB0417802.6A patent/GB0417802D0/en not_active Ceased
-
2005
- 2005-08-09 CA CA002574914A patent/CA2574914A1/en not_active Abandoned
- 2005-08-09 AU AU2005270306A patent/AU2005270306B9/en not_active Ceased
- 2005-08-09 CN CNA2005800272965A patent/CN101001833A/zh active Pending
- 2005-08-09 MX MX2007001645A patent/MX2007001645A/es not_active Application Discontinuation
- 2005-08-09 WO PCT/EP2005/008650 patent/WO2006015852A1/en active Application Filing
- 2005-08-09 EP EP05770044A patent/EP1778628A1/en not_active Withdrawn
- 2005-08-09 KR KR1020077003185A patent/KR20070047302A/ko not_active Application Discontinuation
- 2005-08-09 JP JP2007525244A patent/JP2008509184A/ja active Pending
- 2005-08-09 US US11/573,159 patent/US20080096943A1/en not_active Abandoned
- 2005-08-09 BR BRPI0514181-8A patent/BRPI0514181A/pt not_active IP Right Cessation
- 2005-08-09 RU RU2007108656/04A patent/RU2007108656A/ru not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
MX2007001645A (es) | 2007-04-10 |
JP2008509184A (ja) | 2008-03-27 |
GB0417802D0 (en) | 2004-09-15 |
WO2006015852A1 (en) | 2006-02-16 |
US20080096943A1 (en) | 2008-04-24 |
RU2007108656A (ru) | 2008-09-20 |
AU2005270306B9 (en) | 2009-11-05 |
EP1778628A1 (en) | 2007-05-02 |
AU2005270306B2 (en) | 2009-10-01 |
CA2574914A1 (en) | 2006-02-16 |
KR20070047302A (ko) | 2007-05-04 |
AU2005270306A1 (en) | 2006-02-16 |
BRPI0514181A (pt) | 2008-06-03 |
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