CN1368952A - 1,4-取代的4,4-二芳基环己烷 - Google Patents
1,4-取代的4,4-二芳基环己烷 Download PDFInfo
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- CN1368952A CN1368952A CN00811577A CN00811577A CN1368952A CN 1368952 A CN1368952 A CN 1368952A CN 00811577 A CN00811577 A CN 00811577A CN 00811577 A CN00811577 A CN 00811577A CN 1368952 A CN1368952 A CN 1368952A
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Classifications
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
- C07C45/29—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups
- C07C45/298—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups with manganese derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/56—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds
- C07C45/57—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom
- C07C45/58—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom in three-membered rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
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- C—CHEMISTRY; METALLURGY
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Abstract
本发明涉及式(I)的化合物,其中Z为胺,醇或其衍生物,及其酮类似物。
Description
发明领域
本发明涉及其为PDE4抑制剂,特别是治疗过敏和炎症疾病并抑制肿瘤坏死因子(TNF)产生的化合物。它们尤其适用于治疗肺部疾病,如各种形式的哮喘和慢性的阻塞性肺部疾病。
发明背景
本发明的化合物可用于治疗通过抑制PDE4来调节的疾病。它们在治疗过敏和炎症疾病以及抑制肿瘤坏死因子的产生中具有特别的应用。
关于抗炎活性,一种目标疾病是慢性阻塞性肺部疾病(COPD)。COPD是描述两种固定气道疾病—慢性支气管炎和肺气肿时经常使用的综合性术语(umbrella term)。造成慢性支气管炎和肺气肿的最常见的原因是吸烟;大约90%的COPD患者是吸烟者或曾经是吸烟者。大约50%的吸烟者发展成慢性支气管炎,约15%的吸烟者发展成丧失性气流阻塞。与COPD有关的气流阻塞是渐进性的,可能伴随气道机能亢进,也可能是部分可逆的。非特异性的气道高反应性还可能在COPD的发展中起一定的作用,也可能预示吸烟者的肺功能下降加速。
用PDE4抑制剂能够治疗的另一种疾病是哮喘,特别是由外来刺激物导致的哮喘。其为一种复杂的、多因子的疾病,其特征在于气道的可逆性变窄和呼吸道对外部刺激物的高反应性。很多媒介物是导致哮喘发展的原因。看来不大可能通过消除单一媒介物的作用就对慢性哮喘的三个成分产生实质性的影响。替换“媒介物途径”的是调节负责疾病病理的细胞的活性。这种方法之一是提高cAMP(环3′,5′-单磷酸腺苷)的水平。已经表明环AMP是介导很多激素、神经递质和药物的生物学应答的第二信使[KrebsEndocrinology Proceedings of the 4th International Congress Excerpta Medica,17-29,1973]。当适宜的激动剂与特异细胞表面受体结合时,腺苷酸环酶被活化,其加速将Mg+2-ATP转化成cAMP。
环AMP调节即使不是全部也是大部分的造成外因性(过敏性)哮喘病理的细胞的活性。正因如此,提高cAMP会产生有益的效果,这些效果包括;1)气道平滑肌松弛,2)抑制肥大细胞媒介物释放,3)抑制嗜中性粒细胞脱粒,4)抑制嗜碱细胞脱粒,和5)抑制单核细胞和巨噬细胞活化。因此,活化腺苷酸环酶或抑制磷酸二酯酶的化合物应该有效地抑制气道平滑肌和各种炎性细胞的不适当活化。cAMP的钝化作用的主要细胞机理是3′-磷酸二酯键被称作环核苷酸磷酸二酯酶(PDEs)的同工酶族中的一种或多种水解。
现已发现,独特的环核苷酸磷酸二酯酶(PDE)同工酶,PED4,导致气道平滑肌和炎性细胞中的cAMP故障[Torphy,“Phosphodiesterase Isozymes:Potential Targets for Novel Anti-asthma Agents”in New Drugs for Asthma,Barnes,ed.IBC Technical Services Ltd.,1989]。研究表明,这种酶的抑制不仅导致气道平滑肌松弛,而且抑制肥大细胞、嗜碱细胞和嗜中性粒细胞的脱粒,同时抑制单核细胞和嗜中性粒细胞的活化。此外,在靶细胞的腺苷酸环酶活性被适当的激素或内分泌物提高时,PDE4抑制剂的有益效果得到显著的加强,正如在体内的情况。因而,PDE4抑制剂在哮喘肺中将是有效的,其中前列腺素E2和环前列腺素(腺苷酸环酶的活化剂)的水平升高了。这种化合物将为支气管哮喘的药物治疗提供一种独特的方法,并且比目前市场上的药物具有显著的治疗优点。
本发明的化合物还抑制肿瘤坏死因子(TNF)-血清糖蛋白的产生。过度或未经调节的TNF产生意味着介导或加剧很多疾病,这些疾病包括风湿性关节炎,类风湿性脊椎炎,骨关节炎,痛风性关节炎和其它关节炎疾病;脓毒病,脓毒性休克,内毒素性休克,革兰氏阴性脓毒病,毒性休克综合症,成人呼吸窘迫综合症,脑型疟,慢性肺炎疾病,硅肺,肺肉质变,骨吸收疾病,多次灌注液伤害,移植的宿主反应,同种异体移植的排斥作用,感染导致的发烧和肌肉痛,如流感,感染或恶性肿瘤后继发的恶性体质,人类获得性免疫缺陷综合症(AIDS)之后继发的恶性体质,ARC(与AIDS有关的综合症),瘢痕瘤的形成,疤痕组织的形成,克罗恩氏(Crohn)病,溃疡性结肠炎,或者pyresis,以及大量的自身免疫疾病,如多发性硬化,自身免疫糖尿病和全身性红斑狼疮。
可利用本发明提供的化合物,通过抑制各种PDE4异形体(isoform)中的一种或多种来治疗这些疾病和其它受PDE4调节的疾病。
发明概述
其中:
R1为-(CR4R5)nC(O)O(CR4R5)mR6,-(CR4R5)nC(O)NR4(CR4R5)mR6,-(CR4R5)nO(CR4R5)mR6或-(CR4R5)rR6,其中的烷基部分被一个或多个卤素取代或未取代;
m为0~2;
n为1~4;
r为0~6;
R4和R5独立地选自氢或C1~2烷基;
R6为氢,甲基,羟基,芳基,卤代芳基,芳氧基C1~3烷基,卤代芳氧基C1~3烷基,2,3-二氢化茚基,茚基,C7~11多环烷基,四氢呋喃基,呋喃基,四氢吡喃基,吡喃基,四氢噻吩基,噻吩基,四氢噻喃基,噻喃基,C3~6环烷基,或者包含一个或两个不饱和键的C4~6环烷基,其中该环烷基或杂环部分是未取代的或被1~3个甲基、一个乙基或羟基所取代;
条件是:
a)R6为羟基时,m为2;或者
b)R6为羟基时,r为2~6;或者
c)R6为2-四氢吡喃基、2-四氢噻喃基、2-四氢呋喃基或2-四氢噻吩基时,m为1或2;或者
d)R6为2-四氢吡喃基、2-四氢噻喃基、2-四氢呋喃基或2-四氢噻吩基时,r为1~6;
e)当n为1且m为0时,-(CR4R5)nO(CR4R5)mR6中的R6不为H;
X为YR2,氟,NR4R5或甲酰胺;
Y为O或S(O)m′;
m′为0,1或2;
X2为O或NR8;
X4为H,R9,OR8,CN,C(O)R8,C(O)OR8,C(O)NR8R8或NR8R8;
R2独立地选自任选被一个或多个卤素取代的-CH3或-CH2CH3;
s为0~4;
Ar为未取代的或被R7取代的苯基;
Z为OR14,OR15,SR14,S(O)m′R7,S(O)2NR10R14,NR10R14,NR14C(O)R9,NR10C(Y′)R14,NR10C(O)OR7,NR10C(Y′)NR10R14,NR10S(O)2NR10R14,NR10C(NCN)NR10R14,NR10S(O)2R7,NR10C(CR4NO2)NR10R14,NR10C(NCN)SR9,NR10C(CR4NO2)SR9,NR10C(NR10)NR10R14,NR10C(O)C(O)NR10R14或NR10C(O)C(O)OR14;
Y′为O或S;
R7为-(CR4R5)qR12或C1~6烷基,其中该R12或C1~6烷基是未取代的或被甲基或乙基取代一次或多次,所述的甲基或乙基是未取代的或被1~3个氟所取代;-F;-Br;-Cl;-NO2;-NR10R11;-C(O)R8;-CO2R8;-O(CH2)2~4OR8;-O(CH2)qR8;-CN;-C(O)NR10R11;-O(CH2)qC(O)NR10R11;-O(CH2)qC(O)R9;-NR10C(O)NR10R11;-NR10C(O)R11;-NR10(O)OR9;-NR10C(O)R13;-C(NR10)NR10R11;-C(NCN)NR10R11;-C(NCN)SR9;-NR10C(NCN)SR9;-NR10C(NCN)NR10R11;-NR10S(O)2R9;-S(O)m′R9;-NR10C(O)C(O)NR10R11;-NR10C(O)C(O)R10或R13;
q为0,1或2;
R12为R13,OR14,OR15,SR14,S(O)m′R7,S(O)2NR10R14,NR10R14,NR14C(O)R9,NR10C(Y′)R14,NR10C(O)OR7,NR10C(Y′)NR10R14,NR10S(O)2NR10R14,NR10C(NCN)NR10R14,NR10S(O)2R7,NR10C(CR4NO2)NR10R14,NR10C(NCN)SR9,NR10C(CR4NO2)SR9,NR10C(NR10)NR10R14,NR10C(O)C(O)NR10R14或NR10C(O)C(O)OR14;或者为C3~7环烷基或2-,3-或4-吡啶基,嘧啶基,吡唑基,1-或2-咪唑基,吡咯基,哌嗪基,哌啶基,吗啉基,呋喃基,2-或3-噻吩基,喹啉基,萘基或苯基,其中2,3-或4-吡啶基,嘧啶基,吡唑基,1-或2-咪唑基,吡咯基,哌嗪基,哌啶基,吗啉基,呋喃基,2-或3-噻吩基、喹啉基,萘基,或苯基可以被OR14,OR15,SR14,S(O)m′R7,S(O)2NR10R14,NR10R14,NR14C(O)R9,NR10C(Y′)R14,NR10C(O)OR7,NR10C(Y′)NR10R14,NR10S(O)2NR10R14,NR10C(NCN)NR10R14,NR10S(O)2R7,NR10C(CR4NO2)NR10R14,NR10C(NCN)SR9,NR10C(CR4NO2)SR9,NR10C(NR10)NR10R14,NR10C(O)C(O)NR10R14或NR10C(O)C(O)OR14所取代;
R8独立地选自氢或R9;
R9为任选被1~3个氟取代的C1~4烷基;
R10为OR8或R11;
R11为氢或被1~3个氟取代或未取代的烷基;或者当R10与R11为NR10R11时,它们可以与氮一起形成5~7元环,该环由碳或碳与一个或多个选自O、N或S的另外的杂原子组成;
R13为噁唑烷基,噁唑基,噻唑基,吡唑基,三唑基,四唑基,咪唑基,咪唑烷基,噻唑烷基,异噁唑基,噁二唑基或噻二唑基,这些杂环的每一个通过碳原子连接,并且每一个均可被一个或两个C1~2烷基取代或未取代,所述C1~2烷基的甲基可以被1~3个氟原子取代或未取代;
R14为氢或R7;或者当R8与R14为NR8R14时,它们可以与氮一起形成5~7元环,该环由碳或碳与一个或多个选自O、N或S的另外的杂原子组成;
R15为C(O)R14,C(O)NR8R14,S(O)qNR8R14或S(O)qR7,其中q为0,1或2;
条件是:
f)R7不是被1~3个氟取代或未取代的C1~4烷基。
发明详述
本发明涉及介导或抑制哺乳动物中PDE IV的酶活性(或催化活性)的方法,并且涉及抑制哺乳动物中TNF的产生,该方法包括给药于所述哺乳动物以有效量的式(I)和式(II)的化合物。
磷酸二酯酶4抑制剂可用于治疗多种过敏性和炎性疾病,这些疾病包括:哮喘,慢性支气管炎,特异性皮炎,荨麻疹,过敏性鼻炎,过敏性结膜炎,春季卡他,嗜酸粒细胞肉芽肿,牛皮癣,风湿性关节炎,脓毒性休克,溃疡性结肠炎,克罗恩氏病,心肌和大脑的多次灌注液伤害,慢性肾小球肾炎,毒性休克和成人呼吸窘迫综合症。另外,PDE4抑制剂可用于治疗尿崩症和中枢神经系统紊乱,如抑郁和多梗塞性痴呆。
本发明试图治疗的病毒是那些因感染而产生TNF的病毒,或者那些对抑制敏感的病毒,例如通过直接或间接降低复制,通过式(I)的TNF抑制剂。这种病毒包括但不限于HIV-1、HIV-2和HIV-3,细胞肥大病毒(CMV),流感,腺病毒和疱疹病毒族,如但不限于带状疱疹和单纯疱疹。
本发明更具体地涉及治疗患有人类免疫缺陷病毒(HIV)引起疾病的哺乳动物的方法,该方法包括将有效抑制TNF量的式(I)和式(II)的化合物给药于这种哺乳动物。除了用于人类之外,本发明的化合物还可以与需要抑制TNF产生的哺乳动物的兽医治疗结合起来使用。在哺乳动物中,需要治疗或预防的TNF介导的疾病包括各种疾病,如上面所述的疾病,特别是病毒感染。这些病毒的实例包括但不限于猫科免疫缺陷病毒(FIV)或逆转录感染,如马感染的贫血病毒,公山羊关节炎病毒,绵羊髓鞘脱落病毒,maedi病毒和其它lentiviruses。
本发明的化合物还可用于治疗酵母和真菌感染,其中这种酵母和真菌对TNF向上调节敏感或在体内引导TNF的产生。优选的治疗疾病状态是真菌性脑膜炎。另外,式(I)和式(II)的化合物可以与全身性酵母和真菌感染时所选择的其它药物一起给药。对于真菌感染所选择的药物包括但不限于称作多粘菌素类的化合物,如多链丝霉素B;称作咪唑类的化合物,如克霉唑、益康唑、双氯苯咪唑和酮康唑;称作三唑类的化合物,如氟康唑和itranazole;以及称作两性霉素类的化合物,特别是两性霉素B和脂质体两性霉素B。
式(I)的化合物还可以通过将有效量的式(I)和式(II)的化合物给药于需要这种治疗的哺乳动物来抑制和/或降低抗真菌、抗细菌或抗病毒剂的毒性。优选给药式(I)和式(II)的化合物,以抑制或降低两性霉素类化合物、特别是两性霉素B的毒性。
“抑制IL-1的产生”或“抑制TNF的产生”是指:
a)通过抑制体内所有细胞释放IL-1,分别降低人体内过量的IL-1或TNF水平至正常水平或低于正常水平,所述细胞包括但不限于单核细胞和巨噬细胞;
b)在翻译或转录水平上,分别向下调节人体内过量的IL-1或TNF水平至正常水平或低于正常水平;或
c)作为翻译的结果,通过抑制IL-1或TNF的直接合成来向下调节IL-1或TNF的水平。
短语“TNF介导的疾病或疾病状态”是指其中TNF起作用的任何疾病,或者是因为TNF本身的产生而导致的疾病,或者是因为TNF致使另外细胞因子如但不限于IL-1或IL-6的释放而导致的疾病。例如,其中的IL-1为主要因素而且IL-1的产生和作用加剧或隐藏对TNF的应答的疾病,因此被认为是TNF介导的疾病状态。由于TNF-β(也称淋巴毒素)与TNF-α(也称恶病质素)具有相近的结构同源性,并且因为每一种都诱导相类似的生物学应答并结合到相同的细胞受体上,因此,不论TNF-α还是TNF-β均受到本发明化合物的抑制,因而在本发明中总体上称为“TNF”,除非另外具体说明。优选TNF-α受到抑制。
“细胞因子”是指所影响细胞功能的任何分泌的多肽,并且是调节细胞间免疫、炎性或造血应答的相互作用。细胞因子包括但不限于单核因子和淋巴因子,而不管是什么细胞产生的。
受本发明抑制的用于治疗HIV-感染病人的细胞因子必须是这样的细胞因子,该细胞因子涉及(a)起始作用(initiation)和/或保持T细胞活化和/或活化T-细胞介导的HIV基因表达和/或复制,和/或(b)任何细胞因子介导的疾病相关的问题如恶病体质或肌肉变性。优选该细胞因子为TNF-α。
可以制备的本发明化合物的可药用的盐也包括在本发明中。这些盐在药物应用中是可以接受的。这意味着该盐将保持其母化合物的生物活性,而且该盐在其治疗疾病的应用和使用中不会具有不适当的或有害的作用。
可药用的盐是按标准方法制备的。用过量的有机或无机酸处理溶解于适当溶剂中的母化合物,这种情况下为碱的酸加成盐,或者用过量的有机或无机碱处理溶解于适当溶剂中的母化合物,这种情况下分子中包含COOH。
本发明的药物组合物包含药物载体或稀释剂以及一定数量的式(I)和式(II)的化合物。该化合物以产生生理应答的量加入,或者以低于使用者为进行治疗所需要的2或更多单位的组合物的量加入。这些组合物可以制成固体、液体或气体形式。这三种形式之一在给药时可以转化成另一种形式,如当固体通过气溶胶给药时,或液体通过喷剂或气溶胶给药时。
该组合物以及药物载体或稀释剂的种类取决于预定的给药途径,如不经胃肠给药,局部给药,通过口腔给药或通过吸入给药。
对于局部给药,该药物组合物将为乳剂、药膏、擦剂、洗剂、糊剂、气溶胶,和滴剂,适用于给药于皮肤、眼、耳或鼻。
对于不经胃肠给药,该药物组合物将为无菌注射液的形式,例如安瓿剂或者含水或不含水的液体悬浮液。
对于通过口腔给药,该药物组合物将为药片、胶囊、粉剂、丸剂、atroche、锭剂、糖浆、液体或乳液的形式。
当该药物组合物以溶液或悬浮液形式使用时,适宜药物载体或稀释剂的实例包括:对于含水体系,为水;对于不含水体系,为乙醇、甘油、丙二醇、玉米油、棉籽油、花生油、芝麻油、液体石蜡及其与水的混合物;对于固体体系,为乳糖、高岭土和甘露糖醇;而对于气溶胶体系,为二氯二氟甲烷、氯三氟乙烷和压缩的二氧化碳。同时,除药物载体或稀释剂之外,本发明的组合物还可以包含其它的成分,如稳定剂、抗氧剂、防腐剂、润滑剂、悬浮剂、粘度调节剂等,只要这些额外成分对本发明化合物的治疗作用没有有害的的影响。
如此描述的药物制剂是根据药剂师认为合适的常规技术制成所需要的最终产品的。
在这些组合物种,载体或稀释剂的用量将是变化的,但优选其占活性成分悬浮液或溶液的较大的比例。当稀释剂为固体时,它可以小于、等于或大于固体活性成分的量加入。
通常以组合物的形式将式(I)的化合物给药于患者,该组合物包含无毒的其用量足以产生抑制白细胞三烯为因子的疾病的症状的式(I)的化合物。局部制剂将包含约0.01~5.0%重量的活性成分,并按预防或治疗药物的要求应用于受侵袭的部位。当以口服或者其它吞咽或注射的摄取形式使用时,组合物的剂量范围为每次给药1~1000mg的活性成分。为了方便,每天给药1~5次相等的剂量,且选择日摄取剂量为约1~5000mg。
优选的式(I)或(II)的化合物如下:
当R1为被一个或多个卤素取代的烷基时,该卤素优选为氟和氯,更优选被一个或多个氟取代的C1~4烷基。优选的卤素取代的烷基链的长度为一个或两个碳,并且最优选的是-CF3,-CH2F,-CHF2,-CF2CHF2,-CH2CF3和-CH2CHF2。优选式(I)化合物的R1取代基为CH2-环丙基,CH2-C5~6环烷基,羟基取代或未取代的C4~6环烷基,C7~11多环烷基,3-或4-环戊烯基,苯基,四氢呋喃-3-基,被一个或多个氟取代或未取代的苄基或C1~2烷基,-(CH2)1~3C(O)O(CH2)0~2CH3,-(CH2)1~3O(CH2)0~2CH3及-(CH2)2~4OH。
当术语R1包含(CR4R5)部分时,术语R4和R5独立地为氢或烷基。这允许各亚甲基单元支化成(CR4R5)n或(CR4R5)m;每个重复的亚甲基单元独立于其它的亚甲基单元,例如,其中n为2的(CR4R5)n可以是-CH2CH(CH3)-。该重复亚甲基单元或支链烃的各氢原子可以被互相独立的氟所取代,以产生如上所述的优选的R1取代。当R1为C7~11多环烷基时,其实例为双环[2.2.1]-庚基,双环[2.2.2]-辛基,双环[3.2.1]-辛基,三环[5.2.1.02,6]-癸基等,另外的实例见1987年11月5日出版的Saccamano等人的WO 87/06576。
Z优选为OR14,OR15,SR14,S(O)m′R7,S(O)2NR10R14,NR10R14,NR14C(O)R9,NR10C(O)R14,NR10C(O)OR7,NR10C(O)NR10R14,NR10S(O)2NR10R14,NR10C(NCN)NR10R14,NR10S(O)2R7,NR10C(CR4NO2)NR10R14,NR10C(NCN)SR9,NR10C(CR4NO2)SR9,NR10C(NR10)NR10R14,NR10C(O)C(O)NR10R14或NR10C(O)C(O)OR14。
式(I)的X基团优选为那些其中的X为YR2和Y为氧的基团。式(I)的X2基团优选其中X2为氧的基团。优选可应用的R2基团为被一个或多个卤素取代的C1~2烷基。该卤原子优选为氟和氯,更优选为氟。更优选的R2是那些其中R2为甲基或氟代烷基的基团,特别是C1~2烷基,例如-CF3,-CH2F或-CH2CHF2。最优选-CH2F和-CH3。
优选的R7部分包括取代或未取代的-(CH2)1~2(环丙基),-(CH2)0~2(环丁基),被OH取代或未取代的-(CH2)1~2(环戊基),-(CH2)0~2(环己基),-(CH2)0~2(2-,3-或4-吡啶基),-(CH2)1~2(2-咪唑基),-(CH2)2(4-吗啉基),-(CH2)2(4-哌嗪基),-(CH2)1~2(2-噻吩基),-(CH2)1~2(4-噻唑基)和-(CH2)0~2苯基。
当-NR10R11中的R10和R11与它们所连接的氮一起形成5~7元的包含碳或者碳和至少一个选自O、N或S的杂原子的环时,优选该环包括但不限于1-咪唑基,2-(R8)-1-咪唑基,1-吡唑基,3-(R8)-1-吡唑基,1-三唑基,2-三唑基,5-(R8)-1-三唑基,5-(R8)-2-三唑基,5-(R8)-1-四唑基,5-(R8)-2-四唑基,1-四唑基,2-四唑基,吗啉基,哌嗪基,4-(R8)-1-哌嗪基,或吡基。
当-NR10R14中的R10和R14与它们所连接的氮一起形成5~7元的包含碳或者碳和至少一个选自O、N或S的杂原子的环时,优选该环包括但不限于1-咪唑基,1-吡唑基,1-三唑基,2-三唑基,1-四唑基,2-四唑基,吗啉基,哌嗪基和吡咯基。可能时,各环在合适的氮或碳原子上可以另外被式(I)中所描述的R7部分所取代。这种碳取代的例子包括但不限于2-(R7)-1-咪唑基,4-(R7)-1-咪唑基,5-(R7)-1-咪唑基,3-(R7)-1-吡唑基,4-(R7)-1-吡唑基,5-(R7)-1-吡唑基,4-(R7)-2-三唑基,5-(R7)-2-三唑基,4-(R7)-1-三唑基,5-(R7)-1-三唑基,5-(R7)-1-四唑基和5-(R7)-2-四唑基。可应用的氮被R7取代的例子包括但不限于1-(R7)-2-四唑基,2-(R7)-1-四唑基,4-(R7)-1-哌嗪基。如果可能,该环可以被R7取代一次或多次。
包含杂环的NR10R14基团优选为5-(R14)-2-四唑基,2-(R14)-1-咪唑基,5-(R14)-2-四唑基,4-(R14)-1-哌嗪基或4-(R15)-1-哌嗪基。
优选R13的环包括2-,4-或5-咪唑基,3-,4-或5-吡唑基,4-或5-三唑基[1,2,3],3-或5-三唑基[1,2,4],5-四唑基,2-,4-或5-恶唑基,3-,4-或5-异恶唑基,3-或5-恶二唑基[1,2,4],2-恶二唑基[1,3,4],2-噻二唑基[1,3,4],2-,4-或5-噻唑基,2-,4-或5-恶唑烷基,2-,4-或5-噻唑烷基或2-,4-或5-咪唑烷基。
当R7基团被杂环如咪唑基、吡唑基、三唑基、四唑基或噻唑基等取代或未取代时,该杂环本身在合适的氮或碳原子上可以被R8取代或未取代,如1-(R8)-2-咪唑基,1-(R8)-4-咪唑基,1-(R8)-5-咪唑基,1-(R8)-3-吡唑基,1-(R8)-4吡唑基,1-(R8)-5-吡唑基,1-(R8)-4-三唑基或1-(R8)-5-三唑基。如果合适,该环可以被R8取代一次或多次。
优选其中R1为-CH2-环丙基,CH2-C5~6环烷基,被羟基取代或未取代的C4~6环烷基,四氢呋喃-3-基,3-或4-环戊烯基,被一个或多个氟取代或未取代的苄基或C1~2烷基,及-(CH2)2~4OH;R2为甲基或氟代烷基,且X为YR2的那些式(I)的化合物。
最优选其中R1为-CH2-环丙基,环戊基,3-羟基环戊基,甲基或CF2H;X为YR2;Y为氧;X2为氧;且R2为CF2H或甲基的那些化合物。
最优选的化合物为:
4-[4-(2-氨基嘧啶-5-基)苯基]-4-(3-环戊氧基-4-甲氧基苯基)-环己酮;
顺-4-[4-(2-氨基嘧啶-5-基)苯基]-4-(3-环戊氧基-4-甲氧基苯基)-环己醇;
反-4-[4-(2-氨基嘧啶-5-基)苯基]-4-(3-环戊氧基-4-甲氧基苯基)-环己基-1-胺;
顺-4-[4-(2-氨基嘧啶-5-基)苯基]-4-(3-环戊氧基-4-甲氧基苯基)-环己基-1-胺;及
反-4-[4-(2-氨基嘧啶-5-基)苯基]-4-(3-环戊氧基-4-甲氧基苯基)-环己基-1-胺。
给出下面的实施例,以进一步说明本发明。这些实施例只是用来说明本发明的,不应以任何方式将其当作是对本发明的限制。发明人所保留的请参照下文中的权利要求书。
当给药本发明的这些化合物时,没有发现不可接受的毒理作用。
式(I)的化合物可以按方案1中所描述的方法制备。
(a)K2CO3,DMF;
(b)4-溴苯基锂,THF;
(c)MnO2,CH2Cl2;
(d)(CH3)3SiCH2Cl;
(d)仲丁基锂,TMEDA,THF;(e)25%TFA/CH2Cl2;
(f)甲基乙烯基酮,10%KOH/C2H5OH;
(g)2-(2-氨基嘧啶-5-基)-4,4,5,5-四甲基-1,3-二氧硼己环(borolane),Pd(PPh3)4,甲苯,Na2CO3;
(h)Pd-C/H2;(i)NaBH4,CH3OH;
(j)邻苯二甲酰亚胺,PPh3,DIAD;
(k)N2H4·H2O,EtOH。
根据已公开的方法(J.Med.Chem.1999,41,821-835;US 4012495,3/15/97),3-环戊基氧基-4-甲氧基苯甲醛,3-方案-1,可以由3-羟基-4-甲氧基苯甲醛,1-方案-1,通过与环戊基溴化物,2-方案-1,在碳酸钾或其它适宜的碱与若干适宜溶剂之一的DMF共同存在下烷基化而制备。利用如TMF中的4-溴苯基锂(通过用丁基锂处理1,4-二溴苯而制备)芳基化3-方案-1,得到4′-溴-4-环戊基氧基-3-甲氧基二苯基甲醇,4-方案-1,其可利用二氯甲烷中的二氧化锰氧化成4′-溴-4-环戊基氧基-3-甲氧基二苯酮,5-方案-1。可以通过用α-氯-α-三甲基甲硅烷基甲基锂(用THF中的仲丁基锂和四甲基乙二胺处理氯甲基三甲基硅烷而制备)处理进行5-方案-1的同系物化,得到α,β-环氧硅烷,6-方案-1。通过用二氯甲烷中的TFA处理,使6-方案-1水解,得到2-(4-溴苯基)-2-(3-环戊基氧基-4-甲氧基苯基)乙醛,7-方案-1。使用甲基乙烯基酮和乙醇中的氢氧化钾对7-方案-1进行Robinson环化,得到4-(4-溴苯基)-4-(3-环戊氧基-4-甲氧基苯基)环己-2-烯-1-酮,8-方案-1。使用四(三苯基膦)合钯(O)与甲苯中的碳酸钠,使8-方案-1与2-(2-氨基吡啶-5-基)-4,4,5,5-四甲基-1,3-二氧硼己环[由2-氨基-5-碘吡啶通过用二(pinacolato)二硼和1,1′-二(二苯基膦基)二茂铁]二氯钯(II)处理而制备]进行Suzuki偶联,得到4-[4-(2-氨基嘧啶-5-基)苯基]-4-(3-环戊氧基-4-甲氧基苯基)-环己-2-烯-1-酮,9-方案-1。首先利用催化剂钯/碳氢化,将9-方案-1还原成4-[4-(2-氨基嘧啶-5-基)苯基]-4-(3-环戊氧基-4-甲氧基苯基)-环己酮,10-方案-1。随后再利用甲醇中的硼氢化钠将该酮还原成4-[4-(2-氨基吡啶-5-基)苯基]-4-(3-环戊氧基-4-甲氧基苯基)-环己醇的顺式和反式的混合物,11-方案-1。该顺式和反式异构体可以通过快速色谱进行分离,然后独立地进行合成的剩余步骤。利用邻苯二甲酰亚胺,使顺-11-方案-1和反-11-方案-1与三苯基膦和偶氮二羧酸二异丙酯独立地进行Mitsunobu反应,然后用乙醇中的肼单水合物进行水解,分别得到反-和顺-4-[4-(2-氨基吡啶-5-基)苯基]-4-(3-环戊氧基-4-甲氧基苯基)-环己基-1-胺,反-12-方案-1和顺-12-方案-1。
下面给出的实施例是对本发明的解释,无论如何不应将其当作是对本发明的限制。
实施例
[实施例1]3-环戊氧基-4-甲氧基苯甲醛
将3-羟基-4-甲氧基苯甲醛(30g,0.2mol),环戊基溴(35.77g,0.24mol)和碳酸钾(38.6g,0.24mol)在N,N-二甲基甲酰胺(200ml)中的悬浮液剧烈搅拌3天。加水(300ml)并用乙酸乙酯萃取该混合物4次。用10%的氢氧化钠水溶液洗涤合并后的有机萃取物3次,用水洗涤1次,用盐水洗涤1次,干燥(硫酸钠)并蒸发,得到澄清的桔黄色油状的标题化合物(36.47g,83%)。1H-NMR(400MHz,CDCl3):δ9.84(s,1H),7.43(dd,1H,J=8.3Hz,1.8Hz),7.39(d,1H,J=1.8Hz),6.96(d,1H,J=8.3Hz),4.86(m,1H),3.93(s,3H),2.0(m,2H),1.8-1.95(m,4H),1.63(m,2H)。
[实施例2]4′-溴-4-环戊氧基-3-甲氧基二苯基甲醇
于异丙醇/干冰浴温度和氩气氛下,向1,4-二溴苯(25.72g,109mmol)在干燥四氢呋喃(50ml)的溶液中,滴加正丁基锂(43.6ml 2.5M的己烷溶液,109mmol)。将该混合物搅拌1小时,并在搅拌期间形成浆液。在异丙醇/干冰浴温度下,通过套管将该浆液加到3-环戊氧基-4-甲氧基苯甲醛的干燥四氢呋喃(140ml)溶液中。1小时之后,使反应混合物逐步加热至室温,并再搅拌4小时。用水使反应淬灭,然后用乙醚萃取3次。合并后的有机萃取物用1%的盐酸、水、盐水连续洗涤,然后干燥并蒸发。通过快速色谱(硅胶,17%乙酸乙酯/83%己烷)进行纯化,得到灰白色固体的标题化合物(36.78g,100%粗产率)。MS(m/e):359[(M+1-H2O)+]
[实施例3]4′-溴-4-环戊氧基-3-甲氧基二苯酮
向4′-溴-4-环戊氧基-3-甲氧基二苯基甲醇(10g,0.5mmol)的二氯甲烷(50ml)溶液中加入二氧化锰(IV)(24.0g,267mmol)。将该混合物在室温下搅拌2天,然后通过塞利特硅藻土过滤,并用二氯甲烷洗涤剩余物。蒸发滤液,剩余物从乙醇中结晶,得到白色固体的标题化合物(8.2g,83%)。MS(m/e):375[(M+1)+]
[实施例4]2-(4-溴苯基)-2-(3-环戊氧基-4-甲氧基苯基)乙醛
-78℃下,用仲丁基锂(13.0ml 1.3M的环己烷溶液,16.88mmol)处理干燥四氢呋喃(45ml)中的氯甲基三甲基硅烷(1.875g,15.37mmol),然后用TMEDA(2.4ml,16.1mmol)处理。将该混合物搅拌40分钟,然后加热至-55℃。加入4′-溴-4-环戊氧基-3-甲氧基二苯酮(4.0g,10.6mol)的THF(20ml)溶液,并将该混合物在-40℃下搅拌0.5小时。然后将其逐步加热至室温,并再搅拌18小时。用氯化铵水溶液将反应淬灭,并用乙酸乙酯萃取所得到的混合物3次。依次用水和盐水洗涤合并后的萃取物,然后干燥(硫酸钠)并蒸发。剩余物通过快速色谱(硅胶,4%乙酸乙酯/96%己烷)进行纯化。将所得到的黄色油状物在50ml 20%三氟乙酸的二氯甲烷溶液中搅拌1小时,然后用水洗涤3次,用稀的碳酸氢钠溶液洗涤1次,用水洗涤2次,用盐水洗涤1次并干燥(硫酸钠)。蒸除溶剂,得到黄色油状的标题化合物(1.757g,42.5%)。1H-NMR(400MHz,CDCl3):δ9.87(s,1H),7.49(d,2H,J=8.4),7.07(d,2H,J=8.4),6.87(d,1H,J=8.2),6.70(dd,1H,J=2.2,J=8.3),6.68(d,1H,J=2.2)。
[实施例5]4-[4-溴苯基]-4-(3-环戊氧基-4-甲氧基苯基)-2-环己烯-1-酮
向2-(4-溴苯基)-2-(3-环戊氧基-4-甲氧基苯基)乙醛(2.60g,6.7mmol)的四氢呋喃(10ml)的溶液中,加入甲基乙烯基酮(670μl,8.4mmol)。在-10℃下搅拌该溶液,并慢慢加入10%氢氧化钾乙醇(480μl)。0.5小时之后,将该混合物加热至室温并再搅拌1小时。加入水和乙酸乙酯,并用3N盐酸中和该混合物。将水层和有机层分离,并用乙酸乙酯洗涤水层2次。用水然后用盐水洗涤合并后的有机萃取物,干燥(硫酸钠)并蒸发。通过快速色谱(硅胶,12%乙酸乙酯/82%己烷)进行纯化,得到灰白色蜡状固体的标题化合物(1.39g,47%)。MS(m/e):441[(M+1)+],443[(M+3)+]。
[实施例6]4-[4-(2-氨基嘧啶-5-基)苯基]-4-(3-环戊氧基-4-甲氧基苯基)-2-环己烯-1-酮
向4-[4-溴苯基]-4-(3-环戊氧基-4-甲氧基苯基)-2-环己烯-1-酮(1.39g,3.17mmol)的甲苯(50ml)的溶液中,加入四(三苯基膦)合钯(O)(417mg,0.36mmol),然后加入2-(2-氨基嘧啶-5-基)-4,4,5,5-四甲基-1,3-二氧硼己环(2.02g,6.1mmol,按Tatsuo Ishiyama;Miki Murata and Miyaura,J.Org.Chem.1995,60,7508-7510中所描述的方法制备),乙醇(8ml)和2M的碳酸钠(8ml)。将反应混合物在80℃和氩气氛下搅拌18小时。加水并用乙酸乙酯萃取该混合物3次,合并后的有机萃取物依次用水和盐水洗涤,干燥(硫酸钠)并蒸发。通过快速色谱(硅胶,73%乙酸乙酯/27%己烷)进行纯化,得到白色固体的标题化合物(1.2g,83%粗产率)。MS(m/e):456[(M+1)+]。
[实施例7]4-[4-(2-氨基嘧啶-5-基)苯基]-4-(3-环戊氧基-4-甲氧基苯基)-环己酮
在大气压和氢气氛下,将4-[4-(2-氨基嘧啶-5-基)苯基]-4-(3-环戊氧基-4-甲氧基苯基)-2-环己烯-1-酮(1.2g,2.63mmol)与钯/活性碳(360mg,30%w/w)的乙酸乙酯(20ml)浆液搅拌3天然后过滤,剩余物用二氯甲烷洗涤。蒸发合并后的有机溶液,得到灰色固体的标题化合物(1.05g,88%的粗产率)。1H-NMR(400MHz,CDCl3):δ8.51(s,2H),7.44(d,2H,J=8.4),7.38(d,2H,J=8.4),6.89(dd,1H,J=8.4,J=2.2),6.84(d,1H,J=8.4),6.83(d,1H,J=2.2),5.21(s,2H),4.69(m,1H),3.83(s,3H),2.64(m,4H),2.48(m,4H),1.81(m,6H),1.57(m,2H)。
[实施例8]4-[4-(2-氨基嘧啶-5-基)苯基]-4-(3-环戊氧基-4-甲氧基苯基)-环己醇
将硼氢化钠(86.6mg,2.29mmol)加到4-[4-(2-氨基吡啶-5-基)苯基]-(3-环戊氧基-4-甲氧基苯基)-环己酮(1.05g,2.29mmol)的甲醇(50ml)与四氢呋喃(12.5ml)浆液中。将该混合物搅拌1.5小时(10分钟后该浆液变清)。加入丙酮以破坏过量的硼氢化钠并除去全部溶剂。剩余物从甲醇中蒸发2次,然后溶解于乙酸乙酯中,依次用水和盐水洗涤并干燥(硫酸钠)。蒸除溶剂之后,通过快速色谱(硅胶,5%甲醇/95%二氯甲烷)进行纯化,得到顺-4-[4-(2-氨基嘧啶-5-基)苯基]-4-(3-环戊氧基-4-甲氧基苯基)-环己醇白色固体(485mg,46%),MS(m/e):460[(M+1)+];及反-4-[4-(2-氨基嘧啶-5-基)苯基]-4-(3-环戊氧基-4-甲氧基苯基)-环己醇白色固体(485mg,43%),MS(m/e):460[(M+1)+]。
[实施例9]反-4-[4-(2-氨基嘧啶-5-基)苯基]-4-(3-环戊氧基-4-甲氧基苯基)-环己基-1-胺
向顺-4-[4-(2-氨基嘧啶-5-基)苯基]-4-(3-环戊氧基-4-甲氧基苯基)-环己醇(462mg,1.01mmol)的THF(15ml)溶液中,加入三苯基膦(1.318g,5.58mmol),邻苯二甲酰亚胺(740mg,5.58mmol)和偶氮二羧酸二异丙酯(1.0ml,5.58mmol)。将该混合物搅拌18小时,然后除去溶剂。剩余物通过快速色谱(硅胶,3%甲醇/97%二氯甲烷)进行纯化,而所得到的反-4-[4-(2-氨基嘧啶-5-基)苯基]-4-(3-环戊氧基-4-甲氧基苯基)-1-邻苯二甲酰亚胺基-环己烷粗产物[MS(m/e):598(M+1)+]无须进一步纯化即可使用。
向反-4-[4-(2-氨基嘧啶-5-基)苯基]-4-(3-环戊氧基-4-甲氧基苯基)-1-邻苯二甲酰亚胺基-环己烷(前述步骤的粗产物)的乙醇(20ml)溶液中加入单水合肼(2.0ml),并将所得溶液加热回流4小时。除去溶剂并将剩余物溶解在乙酸乙酯中,然后用3N盐酸洗涤3次。合并之后的含水萃取物用乙酸乙酯洗涤1次,然后用10%的氢氧化钠水溶液中和,并用乙酸乙酯萃取4次。合并之后的有机萃取物依次用水和盐水洗涤,然后干燥(硫酸钠)并在真空下除去溶剂。通过快速色谱(硅胶,5%甲醇/94%二氯甲烷/1%氢氧化铵)进行纯化,然后通过制备HPLC进行纯化,得到白色固体的标题化合物(120mg,26%)。MS(m/e):459[(M+1)+]。
[实施例10]顺-4-[4-(2-氨基嘧啶-5-基)苯基]-4-(3-环戊氧基-4-甲氧基苯基)-环己基-1-胺
按(9)中的方法制备标题化合物,只是用反-4-[4-(2-氨基嘧啶-5-基)苯基]-4-(3-环戊氧基-4-甲氧基苯基)-环己醇代替顺-4-[4-(2-氨基嘧啶-5-基)苯基]-4-(3-环戊氧基-4-甲氧基苯基)-环己醇。通过快速色谱(硅胶,5%甲醇/94%二氯甲烷/1%氢氧化铵)进行纯化,然后通过制备HPLC进行纯化,得到顺-4-[4-(2-氨基嘧啶-5-基)苯基]-4-(3-环戊氧基-4-甲氧基苯基)-环己基-1-胺白色固体(120mg,41%)。MS(m/e):459[(M+1)+]。
用途实例
实例A:式(I)和(II)化合物在体外对人类单核细胞产生的TNF的抑制作用
式(I)和(II)化合物在体外对人类单核细胞产生的TNF的抑制作用,可以根据1991年2月6日公开的Badger等人的EPO申请0411754A2以及1990年12月27日公开的Hanna的WO 90/15534中所描述的方法进行测定。
实例B:使用两种模式的内毒素性休克来测定式(I)和(II)化合物在体内的TNF活性。这些模式中所使用的方法见1991年2月6日公开的Badger等人的EPO申请0411754A2以及1990年12月27日公开的Hanna的WO90/15534。
本发明实施例1的化合物证实,在降低由注射内毒素而诱导的TNF的血清水平方面为体内阳性反应。
实例C:PDE同工酶的分离
式(I)和(II)化合物的磷酸二酯酶抑制活性及选择性,可以利用一组5种不同的PDE同工酶来测定。用作不同同工酶来源的组织如下:1)PDE Ib,猪的主动脉;2)PDE Ic,几内亚猪的心脏;3)PDE III,几内亚猪的心脏;4)PDE IV,人类单核细胞;和5)PDE V(也称“Ia”),犬的气管。PDEs Ia,Ib,Ic和III用标准色谱技术部分纯化[Torphy and Cieslinsky,Mol.Pharmacol.,37:206-214,1990]。通过连续使用阴离子交换,然后通过肝-琼脂糖凝胶色谱将PDE IV纯化至动力学上是均匀的[Torphy等人,J.Biol.Chem.,267:1798-1804,1992]。
按Torphy和Cieslinski,Mol.Pharmacol.,37:206-214,1990的方法中所描述的对磷酸二酯酶活性进行评价。已证实,本发明中所描述的式(I)和(II)的实施例的化合物在纳摩尔至微摩尔的范围中IC50是积极的。
Claims (11)
其中:
R1为-(CR4R5)nC(O)O(CR4R5)mR6,-(CR4R5)nC(O)NR4(CR4R5)mR6,-(CR4R5)nO(CR4R5)mR6或-(CR4R5)R6,其中的烷基部分被一个或多个卤素取代或未取代;
m为0~2;
n为1~4;
r为0~6;
R4和R5独立地选自氢或C1~2烷基;
R6为氢,甲基,羟基,芳基,卤代芳基,芳氧基C1~3烷基,卤代芳氧基C1~3烷基,2,3-二氢化茚基,茚基,C7~11多环烷基,四氢呋喃基,呋喃基,四氢吡喃基,吡喃基,四氢噻吩基,噻吩基,四氢噻喃基,噻喃基,C3~6环烷基,或者包含一个或两个不饱和键的C4~6环烷基,其中该环烷基或杂环部分是未取代的或被1~3个甲基、一个乙基或羟基所取代;
条件是:
a)R6为羟基时,m为2;或者
b)R6为羟基时,r为2~6;或者
c)R6为2-四氢吡喃基、2-四氢噻喃基、2-四氢呋喃基或2-四氢噻吩基时,m为1或2;或者
d)R6为2-四氢吡喃基、2-四氢噻喃基、2-四氢呋喃基或2-四氢噻吩基时,r为1~6;
e)当n为1且m为0时,-(CR4R5)nO(CR4R5)mR6中的R6不为H;
X为YR2,氟,NR4R5或甲酰胺;
Y为O或S(O)m′;
m′为0,1或2;
X2为O或NR8;
X4为H,R9,OR8,CN,C(O)R8,C(O)OR8,C(O)NR8R8或N8R8;
R2独立地选自任选被一个或多个卤素取代的-CH3或-CH2CH3;
s为0~4;
Ar为未取代的或被R7取代的苯基;
Z为OR14,OR15,SR14,S(O)m′R7,S(O)2NR10R14,NR10R14,NR14C(O)R9,NR10C(Y′)R14,NR10C(O)OR7,NR10C(Y′)NR10R14,NR10S(O)2NR10R14,NR10C(NCN)NR10R14,NR10S(O)2R7,NR10C(CR4NO2)NR10R14,NR10C(NCN)SR9,NR10C(CR4NO2)SR9,NR10C(NR10)NR10R14,NR10C(O)C(O)NR10R14或NR10C(O)C(O)OR14;
Y′为O或S;
R7为-(CR4R5)qR12或C1~6烷基,其中该R12或C1~6烷基是未取代的或被甲基或乙基取代一次或多次,所述的甲基或乙基是未取代的或被1~3个氟所取代;-F;-Br;-Cl;-NO2;-NR10R11;-C(O)R8;-CO2R8;-O(CH2)2~4OR8;-O(CH2)qR8;-CN;-C(O)NR10R11;-O(CH2)qC(O)NR10R11;-O(CH2)qC(O)R9;-NR10C(O)NR10R11;-NR10C(O)R11;-NR10(O)OR9;-NR10C(O)R13;-C(NR10)NR10R11;-C(NCN)NR10R11;-C(NCN)SR9;-NR10C(NCN)SR9-NR10C(NCN)NR10R11;-NR10S(O)2R9;-S(O)m′R9;-NR10C(O)C(O)NR10R11;-NR10C(O)C(O)R10或R13;
q为0,1或2;
R12为R13,OR14,OR15,SR14,S(O)m′R7,S(O)2NR10R14,NR10R14,NR14C(O)R9,NR10C(Y′)R14,NR10C(O)OR7,NR10C(Y′)NR10R14,NR10S(O)2NR10R14,NR10C(NCN)NR10R14,NR10S(O)2R7,NR10C(CR4NO2)NR10R14,NR10C(NCN)SR9,NR10C(CR4NO2)SR9,NR10C(NR10)NR10R14,NR10C(O)C(O)NR10R14或NR10C(O)C(O)OR14;或者为C3~7环烷基或2-,3-或4-吡啶基,嘧啶基,吡唑基,1-或2-咪唑基,吡咯基,哌嗪基,哌啶基,吗啉基,呋喃基,2-或3-噻吩基,喹啉基,萘基或苯基,其中2-,3-或4-吡啶基,嘧啶基,吡唑基,1-或2-咪唑基,吡咯基,哌嗪基,哌啶基,吗啉基,呋喃基,2-或3-噻吩基,喹啉基,萘基;或苯基可以被OR14,OR15,SR14,S(O)m′R7,S(O)2NR10R14,NR10R14,NR14C(O)R9,NR10C(Y′)R14,NR10C(O)OR7,NR10C(Y′)NR10R14,NR10S(O)2NR10R14,NR10C(NCN)NR10R14,NR10S(O)2R7,NR10C(CR4NO2)NR10R14,NR10C(NCN)SR9,NR10C(CR4NO2)SR9,NR10C(NR10)NR10R14,NR10C(O)C(O)NR10R14或NR10C(O)C(O)OR14所取代;
R8独立地选自氢或R9;
R9为任选被1~3个氟取代的C1~4烷基;
R10为OR8或R11;
R11为氢或被1~3个氟取代或未取代的烷基;或者当R10与R11为NR10R11时,它们可以与氮一起形成5~7元环,该环由碳或碳与一个或多个选自O、N或S的另外的杂原子组成;
R13为噁唑烷基,噁唑基,噻唑基,吡唑基,三唑基,四唑基,咪唑基,咪唑烷基,噻唑烷基,异噁唑基,噁二唑基或噻二唑基,这些杂环的每一个通过碳原子连接,并且每一个均可被一个或两个C1-2烷基取代或未取代,所述C1~2烷基的甲基可以被1~3个氟原子取代或未取代;
R14为氢或R7;或者当R8与R14为NR8R14时,它们可以与氮一起形成5~7元环,该环由碳或碳与一个或多个选自O、N或S的另外的杂原子组成;
R15为C(O)R14,C(O)NR8R14,S(O)qNR8R14或S(O)qR7,其中q为0,1或2;
条件是:
f)R7不是被1~3个氟取代或未取代的C1~4烷基。
2.权利要求1的化合物,其中R1为-CH2-环丙基,-CH2-C5~6环烷基,被羟基取代或未取代的-C4~6环烷基,四氢呋喃-3-基,(3-或4-环戊烯基),苄基或被一个或多个氟取代的或未取代的-C1~2烷基,及-(CH2)2~4OH;R2为甲基或氟代烷基,且X为YR2。
3.权利要求1或2的化合物,其中R1为-CH2-环丙基,环戊基,3-羟基环戊基,甲基或CF2H;X为YR2;X2为氧;且R2为CF2H或甲基。
4.权利要求1的化合物,该化合物为
顺-4-[4-(2-氨基嘧啶-5-基)苯基]-4-(3-环戊氧基-4-甲氧基苯基)-环己醇;
反-4-[4-(2-氨基嘧啶-5-基)苯基]-4-(3-环戊氧基-4-甲氧基苯基)-环己基-1-胺;
顺-4-[4-(2-氨基嘧啶-5-基)苯基]-4-(3-环戊氧基-4-甲氧基苯基)-环己基-1-胺;及
反-4-[4-(2-氨基嘧啶-5-基)苯基]-4-(3-环戊氧基-4-甲氧基苯基)-环己基-1-胺。
其中:
R1为-(CR4R5)nC(O)O(CR4R5)mR6,-(CR4R5)nC(O)NR4(CR4R5)mR6,-(CR4R5)nO(CR4R5)mR6或-(CR4R5)rR6,其中的烷基部分被一个或多个卤素取代或未取代;
m为0~2;
n为1~4;
r为0~6;
R4和R5独立地选自氢或C1~2烷基;
R6为氢,甲基,羟基,芳基,卤代芳基,芳氧基C1~3烷基,卤代芳氧基C1~3烷基,2,3-二氢化茚基,茚基,C7~11多环烷基,四氢呋喃基,呋喃基,四氢吡喃基,吡喃基,四氢噻吩基,噻吩基,四氢噻喃基,噻喃基,C3~6环烷基,或者包含一个或两个不饱和键的C4~6环烷基,其中该环烷基或杂环部分是未取代的或被1~3个甲基、一个乙基或羟基所取代;
条件是:
a)R6为羟基时,m为2;或者
b)R6为羟基时,r为2~6;或者
c)R6为2-四氢吡喃基、2-四氢噻喃基、2-四氢呋喃基或2-四氢噻吩基时,m为1或2;或者
d)R6为2-四氢吡喃基、2-四氢噻喃基、2-四氢呋喃基或2-四氢噻吩基时,r为1~6;
e)当n为1且m为0时,-(CR4R5)nO(CR4R5)mR6中的R6不为H;
X为YR2,氟,NR4R5或甲酰胺;
Y为O或S(O)m′;
m′为0,1或2;
X2为O或NR8;
X4为H,R9,OR8,CN,C(O)R8,C(O)OR8,C(O)NR8R8或NR8R8;
R2独立地选自任选被一个或多个卤素取代的-CH3或-CH2CH3;
s为0~4;
Ar为未取代的或被R7取代的苯基;
R7为-(CR4R5)qR12或C1~6烷基,其中该R12或C1~6烷基是未取代的或被甲基或乙基取代一次或多次,所述的甲基或乙基是未取代的或被1~3个氟所取代;-F;-Br;-Cl;-NO2;-NR10R11;-C(O)R8;-CO2R8;-O(CH2)2~4OR8;-O(CH2)qR8;-CN;-C(O)NR10R11;-O(CH2)qC(O)NR10R11;-O(CH2)qC(O)R9;-NR10C(O)NR10R11;-NR10C(O)R11;-NR10(O)OR9;-NR10C(O)R13;-C(NR10)NR10R11;-C(NCN)NR10R11;-C(NCN)SR9;-NR10C(NCN)SR9;-NR10C(NCN)NR10R11;-NR10S(O)2R9;-S(O)m′R9;-NR10C(O)C(O)NR10R11;-NR10C(O)C(O)R10或R13;
q为0,1或2;
R12为R13,OR14,OR15,SR14,S(O)mR7,S(O)2NR10R14,NR10R14,NR14C(O)R9,NR10C(Y′)R14,NR10C(O)OR7,NR10C(Y′)NR10R14,NR10S(O)2NR10R14,NR10C(NCN)NR10R14,NR10S(O)2R7,NR10C(CR4NO2)NR10R14,NR10C(NCN)SR9,NR10C(CR4NO2)SR9,NR10C(NR10)NR10R14,NR10C(O)C(O)NR10R14或NR10C(O)C(O)OR14;或者为C3~7环烷基或2-,3-或4-吡啶基,嘧啶基,吡唑基,1-或2-咪唑基,吡咯基,哌嗪基,哌啶基,吗啉基,呋喃基,2-或3-噻吩基,喹啉基,萘基或苯基,其中2,3-或4-吡啶基,嘧啶基,吡唑基,1-或2-咪唑基,吡咯基,哌嗪基,哌啶基,吗啉基,呋喃基,2-或3-噻吩基,喹啉基,萘基,或苯基可以被OR14,OR15,SR14,S(O)m′R7,S(O)2NR10R14,NR10R14,NR14C(O)R9,NR10C(Y′)R14,NR10C(O)OR7,NR10C(Y′)NR10R14,NR10S(O)2NR10R14,NR10C(NCN)NR10R14,NR10S(O)2R7,NR10C(CR4NO2)NR10R14,NR10C(NCN)SR9,NR10C(CR4NO2)SR9,NR10C(NR10)NR10R14,NR10C(O)C(O)NR10R14或NR10C(O)C(O)OR14所取代;
R8独立地选自氢或R9;
R9为任选被1~3个氟取代的C1~4烷基;
R10为OR8或R11;
R11为氢或被1~3个氟取代或未取代的烷基;或者当R10与R11为NR10R11时,它们可以与氮一起形成5~7元环,该环由碳或碳与一个或多个选自O、N或S的另外的杂原子组成;
R13为噁唑烷基,噁唑基,噻唑基,吡唑基,三唑基,四唑基,咪唑基,咪唑烷基,噻唑烷基,异噁唑基,噁二唑基或噻二唑基,这些杂环的每一个通过碳原子连接,并且每一个均可被一个或两个C1~2烷基取代或未取代,所述C1~2烷基的甲基可以被1~3个氟原子取代或未取代;
R14为氢或R7;或者当R8与R14为NR8R14时,它们可以与氮一起形成5~7元环,该环由碳或碳与一个或多个选自O、N或S的另外的杂原子组成;
R15为C(O)R14,C(O)NR8R14,S(O)qNR8R14或S(O)qR7,其中q为0,1或2;
条件是:
f)R7不是被1~3个氟取代或未取代的C1~4烷基。
6.权利要求5的化合物,其中R1为-CH2-环丙基,-CH2-C5~6环烷基,被OH取代或未取代的-C4~6环烷基,四氢呋喃-3-基,(3-或4-环戊烯基),苄基或被一个或多个氟取代的或未取代的-C1~2烷基,及-(CH2)2~4OH;R2为甲基或氟代烷基,且X为YR2。
7.权利要求5或6的化合物,其中R1为-CH2-环丙基,环戊基,3-羟基环戊基,甲基或CF2H;X为YR2;X2为氧;且R2为CF2H或甲基。
8.权利要求5的化合物,该化合物为4-[4-(2-氨基嘧啶-5-基)苯基]-4-(3-环戊氧基-4-甲氧基苯基)-环己酮。
9.一种药物组合物,其包含权利要求1~4中任一项的化合物和可药用的赋形剂。
10.一种药物组合物,其包含权利要求5~8中任一项的化合物和可药用的赋形剂。
11.一种治疗炎症疾病的方法,该方法包括将权利要求1~8中任一项的化合物和可药用的赋形剂共同给药于需要的病人。
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US14803499P | 1999-08-10 | 1999-08-10 | |
US60/148,034 | 1999-08-10 |
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US (1) | US6518306B1 (zh) |
EP (1) | EP1202955A4 (zh) |
JP (1) | JP2003522129A (zh) |
KR (1) | KR20020022102A (zh) |
CN (1) | CN1368952A (zh) |
AU (1) | AU6763900A (zh) |
BR (1) | BR0013230A (zh) |
CA (1) | CA2378990A1 (zh) |
CO (1) | CO5190716A1 (zh) |
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NO (1) | NO20020597L (zh) |
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WO2002088079A2 (en) * | 2001-05-01 | 2002-11-07 | Bristol-Myers Squibb Company | Dual inhibitors of pde 7 and pde 4 |
US20040001895A1 (en) * | 2002-06-17 | 2004-01-01 | Pfizer Inc. | Combination treatment for depression and anxiety |
UA83266C2 (en) * | 2003-12-08 | 2008-06-25 | Уайет | Oxazole derivatives of tetracyclines |
JP4869221B2 (ja) * | 2004-04-08 | 2012-02-08 | ワイス・エルエルシー | プロゲステロン受容体調節剤としてのチオアミド誘導体 |
BRPI0509159B1 (pt) * | 2004-04-08 | 2014-08-26 | Wyeth Llc | Processo para preparar um composto de fenoxicicloalquila |
US7825265B2 (en) | 2004-05-04 | 2010-11-02 | Acadia Pharmaceuticals Inc. | Compounds with activity at estrogen receptors |
WO2005108337A2 (en) * | 2004-05-04 | 2005-11-17 | Acadia Pharmaceuticals Inc. | Compounds with activity at estrogen receptor |
KR100694873B1 (ko) * | 2005-05-26 | 2007-03-13 | 주식회사 대인정밀 | 정수기 |
TW200716536A (en) * | 2005-06-09 | 2007-05-01 | Chugai Pharmaceutical Co Ltd | Vitamin D compounds |
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JPH07278038A (ja) * | 1994-04-01 | 1995-10-24 | Sumitomo Chem Co Ltd | 多官能ビニルエーテル化合物 |
AU708349B2 (en) * | 1994-12-23 | 1999-08-05 | Smithkline Beecham Corporation | 4,4-(disubstituted)cyclohexan-1-one monomers and related compounds |
NZ301096A (en) * | 1994-12-23 | 1999-01-28 | Smithkline Beecham Corp | 4,4-(disubstituted)cyclohexan-1-ol monomer and related derivatives; medicaments containing them |
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HUP0202936A3 (en) | 2003-11-28 |
HUP0202936A2 (hu) | 2002-12-28 |
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AU6763900A (en) | 2001-03-05 |
PL353360A1 (en) | 2003-11-17 |
CA2378990A1 (en) | 2001-02-15 |
EP1202955A4 (en) | 2004-02-11 |
TR200200347T2 (tr) | 2002-06-21 |
WO2001010385A3 (en) | 2001-08-16 |
US6518306B1 (en) | 2003-02-11 |
WO2001010385A2 (en) | 2001-02-15 |
EP1202955A2 (en) | 2002-05-08 |
ZA200201036B (en) | 2003-04-30 |
MXPA02001471A (es) | 2002-07-02 |
NO20020597L (no) | 2002-04-03 |
NZ516620A (en) | 2004-03-26 |
NO20020597D0 (no) | 2002-02-06 |
BR0013230A (pt) | 2002-04-23 |
CO5190716A1 (es) | 2002-08-29 |
JP2003522129A (ja) | 2003-07-22 |
CZ2002460A3 (cs) | 2002-06-12 |
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