CN1067244A - Pyrrolidones - Google Patents

Pyrrolidones Download PDF

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CN1067244A
CN1067244A CN 92104385 CN92104385A CN1067244A CN 1067244 A CN1067244 A CN 1067244A CN 92104385 CN92104385 CN 92104385 CN 92104385 A CN92104385 A CN 92104385A CN 1067244 A CN1067244 A CN 1067244A
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formula
compound
cyclopentyloxy
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P·E·本德
S·B·克里斯滕森
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史密丝克莱恩比彻姆公司
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D207/00Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24Oxygen or sulfur atoms
    • C07D207/262-Pyrrolidones

Abstract

新的吡咯烷酮化合物,它能抑制PEDIV及TNF。 New pyrrolidone compound which inhibits PEDIV and TNF.

Description

本发明涉及新的吡咯烷酮、含有这些化合物的药物组合物和它们在治疗过敏性及炎性疾病中和抑制产生肿瘤坏死因子(TNF)中的应用。 The present invention relates to novel pyrrolidinones, pharmaceutical compositions containing these compounds and the composition thereof in the treatment and inhibition of allergic and inflammatory diseases applications tumor necrosis factor production (TNF) in.

支气管哮喘是一种复杂的,多因素的疾病,它的特点是当受到外部刺激时,发生气管可逆性狭窄及呼吸道的过度反应。 Bronchial asthma is a complex, multifactorial disease, which is characterized by when subjected to external stimuli, overreaction reversible airway narrowing and respiratory tract occurs.

现已明确慢性哮喘综合症表现为三种不同的过程:1)对抗原的早期反应,2)对抗原的延迟的和晚期的反应,和3)慢性炎症和气管的过度反应(Cockcroft,Ann.Allergy 55∶857-862,1985;Larsen,Hosp.Practice 22∶113-127,1987)。 Syndrome, chronic asthma has been clearly showed three different processes: 1) an early response to antigen, 2) a delayed response to the antigen and late, and 3) chronic inflammation and airway overreaction (Cockcroft, Ann. Allergy 55:857-862,1985; Larsen, Hosp.Practice 22:113-127,1987).

目前为控制这种疾病所采用的各种药物(β-肾上腺素能受体兴奋剂,类固醇,甲基黄嘌呤,色甘酸二钠盐)都是不能达到目的的。 Is currently controlling various drugs used in this disease ([beta] -adrenergic receptor agonists, steroids, methylxanthines, disodium cromoglycate) are not achieve the purpose. 它们中无一能减缓哮喘的三个阶段并且几乎全都有一定的付作用。 None of them can slow down the three stages of asthma and almost all have certain side effects. 并且更重要的是,上述药物中没有一个(类固醇可能是个例外)能改变慢性哮喘病的进程。 And more importantly, none of these drugs (steroids may be an exception) can change the course of chronic asthma.

发现新的哮喘治疗剂是有困难的,这是因为许多介体和该病的进程有关。 The discovery of new asthma therapeutic agent is difficult, because many mediators and processes related to the disease. 因之消除单一介体的作用似乎不可能对慢性哮喘的所有三个过程产生重大影响。 Consequent elimination of a single mediator role seems unlikely to have a significant impact on all three of chronic asthma. 代替“介体处理”的另一种方法是调节和该病的病理生理学有关的细胞的活性。 Another method instead of the "mediator process" is to regulate the activity of cells involved in the pathophysiology of the disease.

方法之一是提高cAMP(腺苷环状3′,5′-单磷酸酯)的量。 One method is to increase the amount of cAMP (adenosine cyclic 3 ', 5'-monophosphate) is. 环状AMP被证明是传递各类激素、神经介质和药物的生物学反应的另一个信使(Robison等,Cyclic AMP,Academic Press,New York,Pgs.17-47,1971;Krebs,Endocrinology Proceedings of the 4th International Congress Excerpta Medica,Pgs.17-29,1973)。 Cyclic AMP proved to be transmitted all types of hormones, biological response messenger another neurotransmitters and drugs (Robison et, Cyclic AMP, Academic Press, New York, Pgs.17-47,1971; Krebs, Endocrinology Proceedings of the 4th International Congress Excerpta Medica, Pgs.17-29,1973). 当适当的兴奋剂结合到特定的细胞表面受体上时,腺苷酸环化酶就被活化,这能加速把Mg2+-ATP转化成cAMP。 When the appropriate agonist binding to specific cell surface receptors, adenylate cyclase was activated, which can accelerate the conversion of Mg2 + -ATP into cAMP. cAMP的作用会被环状核苷酸磷酸二酯酶(PDEs)中止,后者水解3′-磷酸二酯键形成5′-AMP-一种无活性的代谢产物。 Role of cAMP will be cyclic nucleotide phosphodiesterases (The PDEs) suspension, which is hydrolyzed 3'-phosphodiester bond formation 5'-AMP- an inactive metabolite.

环状AMP能调节大部分的(即使不是全部)对外源的(过敏性的)哮喘病的病理生理学起作用的细胞的活性。 Cyclic AMP can regulate the activity of most cells in the pathophysiology function (if not all) of the external source (allergic) asthma. 因之,提高cAMP的量可能产生好的效果,包括:1)气管平滑肌松弛,2)抑制乳头细胞介体释放,3)抑制中性白细胞脱粒,4)抑制嗜碱细胞脱粒,及5)抑制单核细胞和巨噬细胞活化。 Consequent, the amount of elevation of cAMP may produce good results, including: 1) airway smooth muscle relaxation, 2) inhibition of mediator release papilla cells, 3) suppression of neutrophil degranulation, 4) inhibition of basophil degranulation, and 5) inhibition monocyte and macrophage activation. 因之,活化腺苷酸环化酶或抑制PDE的化合物能有效地抑制气管平滑肌及各种炎性细胞的不恰当的激活。 Consequent, the compound activating adenylate cyclase or inhibiting PDE is effective to inhibit the inappropriate activation of airway smooth muscle and a wide variety of inflammatory cells. cAMP失活的主要的细胞学机理是3′-磷酸二酯键被一族或多族被称为环状核苷酸磷酸二酯酶(PDEs)的同功酶所水解。 The main cellular mechanism of the inactivation of cAMP is hydrolysis of the 3'-phosphodiester isozyme family or aromatic ester bonds are referred to as cyclic nucleotide phosphodiesterases (The PDEs) are.

已经证明,特殊的环状核苷酸磷酸二酯酶(PDE)同功酶PDE IV使气管平滑肌及炎性细胞中的环状AMP断裂(Torphy,“Phosphodiesterase Isozymes:Potential Targets for Novel Antiasthmatic Agents”,New Drugs forAsthma,Barnes,等,IBC Technical Services Ltd.(1989))。 We have demonstrated that specific cyclic nucleotide phosphodiesterase (PDE) isoenzyme PDE IV trachea smooth muscle and inflammatory cells break cyclic AMP (Torphy, "Phosphodiesterase Isozymes: Potential Targets for Novel Antiasthmatic Agents", New Drugs forAsthma, Barnes, etc., IBC Technical Services Ltd. (1989)). 研究指出,这种酶的抑制作用不仅能使气管平滑肌松弛,也能抑制乳头细胞,嗜碱细胞及中性白细胞的脱粒,同时抑制单核细胞和中性白细胞的活化作用。 Research indicates that inhibition of this enzyme not only relax tracheal smooth muscle can be suppressed papilla cells, basophils and neutrophils degranulation, while inhibiting the activation of monocytes and neutrophils. 而且,如在体内试验中,当靶细胞的腺苷酸环酯酶活性被适当的激素或内分泌物提高时,PDE IV抑制剂的有益作用是十分有效的。 Further, as in vivo tests, when adenylate esterase activity of target cells is increased or the appropriate hormone secretion, the beneficial effects of PDE IV inhibitors is very effective. 因之,PDE IV抑制剂对治疗哮喘肺是有效的,此时,前列腺素E2和前列腺环素(腺苷酸环化酶的活化剂)的量被提高了。 Consequent, PDE IV inhibitors are effective for the treatment of asthmatic, this time, the amount of prostaglandin E2 and prostacyclin (activators of adenylate cyclase) are improved. 这类化合物对于支气管哮喘的药物治疗提供了唯一的方法,并且比市场上通用的药物具有极大的治疗优点。 Such compounds offer a unique approach for the treatment of bronchial asthma, and has great therapeutic advantages over generic drugs on the market.

本发明的化合物也抑制产生肿瘤坏死因子(TNF)-一种血清糖蛋白。 Compounds of the invention also inhibit the production of tumor necrosis factor (TNF) - one serotype glycoprotein. 过量的或无规律的产生TNF与引起或者加重许多疾病有关系。 The excessive or irregular TNF to cause or exacerbating a number of diseases are. 这些疾病包括类风湿关节炎,类风湿脊椎炎,骨关节炎,痛风关节炎及其它关节炎症;脓毒病,脓毒性休克,内毒素休克,革兰阴性脓毒病,毒性休克综合症,成人呼吸痛苦综合症,大脑疟,慢性肺炎,硅肺,肺Sacroidosis,骨吸收病,reperfusion损伤,对宿主移植的反应,同种排异反应,由于感染(如流感)引起的高烧和肌痛,感染或恶性癌的继发性恶病质,获得性免疫缺陷综合症(AIDS)的继发性恶病质,AIDS,ARC(AIDS相关综合症),瘢痕瘤,伤疤组织生成,节段性回肠炎,溃疡性结肠炎或peresis。 These diseases include rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic disorders; sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pneumonia, silicosis, pulmonary Sacroidosis, bone resorption diseases, reperfusion injury, graft versus host reaction, and the same kind of rejection, due to infection (such as influenza) fever and myalgias due to infection cachexia secondary to malignancy or cancer, acquired immune deficiency syndrome (AIDS) of cachexia secondary to evil, AIDS, ARC (AIDS related complex), keloid, scar tissue formation, Crohn's disease, ulcerative colitis inflammation or peresis.

TNF以各种方式和人体获得性免疫缺陷综合症(AIDS)有关系。 TNF in various ways and human acquired immune deficiency syndrome (AIDS) have a relationship. AIDS是由于T淋巴细胞感染上了人体免疫缺陷病毒(HIV)所致。 AIDS is due to T-lymphocytes infected with the human immunodeficiency virus (HIV) due. 已经发现,单核因子(特别是TNF)是通过起着维持T淋巴细胞活性的作用而与T淋巴细胞被HIV感染有关的。 It has been found, monokines (especially TNF) play by maintaining T lymphocyte activity is related to the HIV infection of T-lymphocytes. 而且,一旦活化的T淋巴细胞被HIV感染,T淋巴细胞就必须继续维持在活化状态以便允许HIV基因表达和/或HIV复制。 Moreover, once activated T lymphocyte is infected with HIV, T lymphocyte must continue to be maintained at an activated state to permit HIV gene expression and / or HIV replication. 也已经发现,单核因子(特别是TNF)是通过起着维持T淋巴细胞活性的作用而和被活化了的T-细胞调解的HIV蛋白质表达和/或病毒复制有关。 Has also been found, monokines (especially TNF) by T lymphocyte function to maintain the activity of the HIV and activated T- cells mediate protein expression and / or viral replication. 因此,在HIV-感染的个体中,干扰单核因子的活性,如通过抑制单核因子(特别是TNF)的产生,有助于限制T-细胞活性的维持,因之可减少还未被感染细胞感染HIV的程度,这样就可以减慢或消除由于HIV感染引起的免疫机能障碍的进程。 Thus, in HIV- infected individuals, interference with monokine activity such as by inhibition of monokine generation (in particular TNF) and help limit T- cell activity is maintained, has not been infected with consequent reduction may the extent of HIV-infected cells, so that you can slow down or eliminated due to immune dysfunction caused by HIV infection process. 单核细胞,巨噬细胞及其它有关细胞(如枯否细胞和神经胶质细胞)也和维持HIV感染有关系。 Monocytes, macrophages and other related cells (such as Kupffer cells and glial cells) and also to maintain a relationship HIV infection. 这些细胞(如T细胞)是病毒复制的目标,并且病毒复制的水平依赖于这些细胞的活化状态。 These cells (e.g. T cells) is the target viral replication and the level of viral replication is dependent on the activation state of these cells. 〔见Rosenberg等,The Immunopathogenesis of HIV Infection,Advances in Immunology,Vol 57,(1989)〕。 [See Rosenberg et al., The Immunopathogenesis of HIV Infection, Advances in Immunology, Vol 57, (1989)]. 已经证明,单核因子(如TNF)在单核细胞和/或巨噬细胞中能活化HIV的复制〔见Poli等,Proc.Natl.Acad.Sci.,87∶782-784,(1990)〕,因之,如上文对于T细胞所述,抑制单核因子的产生或活性有助于限制HIV的发展。 Has been demonstrated, monokines (e.g., TNF) and the like [See Poli, Proc.Natl.Acad.Sci., 87:782-784, (1990)] in monocytes and / or macrophages can activate HIV replication , consequent, as described above for the T-cells, inhibition of monokine production or activity helps to limit the development of HIV.

现在已经发现,单核因子与某些疾病有关的难题如恶病质及肌肉退化有关。 Has now been found that a single nuclear factor problems associated with certain diseases, such as cachexia and muscle degeneration. 因之,例如通过抑制TNF产生,干扰单核因子的活性,在HIV-感染的个体中将有助于通过减少与单核因子引起的疾病有关的难题(如恶病质和肌肉退化)的严重程度,来提高HIV-感染的病人的生命力。 Consequent, for example, by inhibiting TNF production, interference with monokine activity, in HIV- infected individuals will contribute to the severity of the disease by reducing the monokine induced problems (such as cachexia and muscle degeneration) of HIV- infected patients to increase vitality.

TNF也和酵母菌及真菌感染有关。 TNF also and yeast and fungal infections. 特别是在体外试验中已证明,白色念珠菌(Candida Albicans)能在人体单核细胞及天然杀伤细胞中诱发TNF的产生〔见Riipi等,Infection and Immunity,Vol 58,No.9,p2750-54,(1990);Jafari等,Journal of Infectious Diseases,Vol164,P.389-95(1991);Wasan等,Antimicrobial Agents and Chemotherapy,Vol.35,No.10,P.2046-48(1991);Luke等,Journal of Infecfious Diseases,Vol.162,P.211-214(1990)〕。 Has proven especially in vitro, Candida albicans (Candida Albicans) can induce TNF production [See Riipi in human monocytes and natural killer cells, etc., Infection and Immunity, Vol 58, No.9, p2750-54 , (1990); Jafari et, Journal of Infectious Diseases, Vol164, P.389-95 (1991); Wasan et, Antimicrobial Agents and Chemotherapy, Vol.35, No.10, P.2046-48 (1991); Luke etc., Journal of Infecfious Diseases, Vol.162, P.211-214 (1990)].

抑制TNF产生的一类化合物的发现将提供一种治疗与过量的或不规则的产生TNF有关的疾病的方法。 Discovered a class of compounds to inhibit TNF production provides a method of treating with an excess or irregular production of TNF-related diseases.

本发明包括式(Ⅰ)表示的苄基吡咯烷酮及含这类化合物的药物组合物。 Benzyl pyrrolidinone represented by the formula of the present invention comprises (Ⅰ) and pharmaceutical compositions containing such compounds.

本发明还包括抑制动物体内(包括人体)的磷酸二酯酶IV的方法,该方法是对需要治疗的动物给有效量的式(Ⅰ)化合物。 The present invention further comprises a method of inhibiting an animal (including human) of phosphodiesterase IV, which is given to an animal in need of treatment an effective amount of Formula (Ⅰ) compound. 磷酸二酯酶IV抑制剂用于治疗各种过敏性及炎性疾病,包括:哮喘,慢性支气管炎,特异反应性皮炎,荨麻疹,过敏性鼻炎,过敏性结肠炎,春季(卡他性)结膜炎,嗜曙红细胞肉芽瘤,牛皮癣,类风湿关节炎,脓毒性休克,溃疡性结肠炎,节段性回肠炎,心肌和脑的reperfusion损伤,慢性肾小球性肾炎,内毒素休克,成年人呼吸痛苦综合症,除此,PDE IV抑制剂还用于治疗尿崩症(Kidney Int,37∶362,1990;Kidney Int.35∶494,1989)及中枢神经系统失调如抑郁症及多一梗死性痴呆。 Phosphodiesterase IV inhibitors for the treatment of a variety of allergic and inflammatory diseases including: asthma, chronic bronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergic colitis, spring (catarrh) conjunctivitis, eosinophilic granuloma, psoriasis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock, adult human respiratory distress syndrome, In addition, PDE IV inhibitors are useful in the treatment of diabetes insipidus (Kidney Int, 37:362,1990; Kidney Int.35:494,1989) and central nervous system disorders such as depression and multi-one infarct dementia.

本发明还包括抑制在动物体中(包括人体)产生TNF的方法,它包括对需要治疗的动物给有效量的式(Ⅰ)化合物。 The present invention further includes a method of inhibiting TNF production in an animal (including human), which comprises administering to an animal in need of treatment an effective amount of a formula (Ⅰ) compound.

本发明还涉及治疗被人体免疫缺陷病毒(HIV),AIDS综合症(ARC)及任何其它与HIV感染有关的疾病折磨的病人的方法,它包括对患者给有效TNF抑制量的式(Ⅰ)化合物。 The present invention is further directed to the treatment of human immunodeficiency virus (HIV), syndrome of AIDS (ARC), and any other HIV-infected patients with a disease associated afflicted a method which comprises administering to a patient an effective TNF inhibiting amount of a compound of formula (Ⅰ) .

本发明还提供了一种通过预防性地给有效量的式(Ⅰ)化合物,预防动物(包括人)的TNF-引起的疾病的方法。 A disease of the present invention also provides a compound of formula an effective amount of a (Ⅰ) by prophylactically to prevent animals (including humans) caused a TNF-.

本发明的化合物还可用于治疗其它的病毒感染,这些病毒是对TNF的增加敏感的,或是在体内将引起TNF产生。 Compounds of the invention may also be used to treat other viral infections, where such viruses are sensitive to increased TNF, or TNF production induced in vivo. 这种治疗所关注的病毒是通过施用式(Ⅰ)的TNF抑制剂,直接或渐接地,如通过减少复制作用,对抑制作用敏感的那些病毒,这些病毒包括,但不限于:HIV-1,HIV-2及HIV-3,巨细胞病毒(CMV),流感病毒,腺病毒及疱疹类的病毒如带状疱疹病毒和单纯疱疹病毒。 Such treatment is concerned virus by administering TNF inhibitors of Formula (Ⅰ) directly or gradually ground as indicated by decreased replication of, those viruses sensitive to inhibition, such viruses include, but are not limited to: HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza virus, adenovirus, and the herpes group of viruses, such as herpes zoster virus and herpes simplex virus.

式(Ⅰ)化合物也可用于治疗酵母菌和真菌感染,这些酵母菌和真菌是对TNF的增加敏感的或者将引起TNF在体内的产生。 The compounds of formula (Ⅰ) also useful in treating yeast and fungal infections, where such yeast and fungi are sensitive to increased TNF or TNF production induced in vivo.

推荐治疗的疾病是真菌脑膜炎。 Recommended treatment is a fungal disease of meningitis. 另外,对于全身的酵母菌及真菌感染,可以将式(Ⅰ)化合物和选择的其它药物或者同时,或者相继地联合给药。 Further, other drugs for systemic yeast and fungal infections, the compound of formula (Ⅰ) and selection or simultaneously, jointly or sequentially administered. 对于真菌感染所选择的药物包括(但不限于)被称为多粘菌素的一类化合物,如多链丝霉素B;被称为咪唑的一类化合物,如克霉唑,益康唑,霉康唑及酮康唑;称为三唑的一类化合物,如氟康唑及itranazole以及称为两性霉素的一类化合物,特别是两性霉素B及脂质两性霉素B。 For fungal infections selected drugs include (but are not limited to) a class of compounds known as polymyxin, amphotericin B multi-filament strand; a class of compounds called the imidazoles, such as clotrimazole, econazole , miconazole, and ketoconazole; the class of compounds called the triazoles, such as fluconazole, and itranazole, and the class of compounds known as amphotericin B, amphotericin B, and in particular amphotericin B. lipid

推荐治疗的微生物是念珠菌属微生物。 Microbial treatment is recommended Candida organisms. 式(Ⅰ)化合物可以类似的方式与抗病毒剂或抗菌剂联合给药。 The compounds of formula (Ⅰ) can be a similar manner as antiviral or antibacterial agents administered in combination.

通过对需要治疗的哺乳动物给有效量的式(Ⅰ)化合物,式(Ⅰ)化合物还可用于抑制和/或减少抗真菌剂、抗菌剂或抗病毒剂的毒性。 Compound (Ⅰ) a compound of formula (Ⅰ) by a mammal in need of treatment an effective amount of a formula can also be used to inhibit and / or reduce the toxicity of the antifungal agent, antibacterial or antiviral agents. 式(Ⅰ)化合物被用来抑制或减低两性霉素类化合物的毒性较好,特别是两性霉素B。 The compounds of formula (Ⅰ) are preferably used to inhibit or reduce the toxicity of the Amphotericin class of compounds, in particular Amphotericin B.

本发明的化合物用式(Ⅰ)表示: The compounds of this invention are represented by formula (Ⅰ):

其中R1是未取代的或被1个或多个卤素取代的C1-12烷基,未取代的或被1-3个甲基或1个乙基取代的C3-6环烷基,含1或2个不饱和键的C4-6环烷基,C7-11的多环烷基,(CR14R14)nC(O)-O-(CR14R14)m-R10,(CR14R14)nC(O)-O-(CR14R14)r-R11,(CR14R14)xOH,(CR14R14)sO(CR14R14)m-R10,(CR14R14)sO(CR14R14)r-R11,(CR14R14)n-(C(O)NR14)-(CR14R14)m-R10,(CR14R14)n-(C(O)NR14)-(CR14R14)r-R11,(CR14R14)y-R11,或(CR14R14)z-R10; Wherein R1 is unsubstituted or substituted by one or more halogen-substituted C1-12 alkyl, unsubstituted or substituted with a methyl or ethyl group substituted by C3-6 cycloalkyl containing one or two unsaturated bonds C4-6 cycloalkyl, C7-11 polycyclic group, (CR14R14) nC (O) -O- (CR14R14) m-R10, (CR14R14) nC (O) -O- ( CR14R14) r-R11, (CR14R14) xOH, (CR14R14) sO (CR14R14) m-R10, (CR14R14) sO (CR14R14) r-R11, (CR14R14) n- (C (O) NR14) - (CR14R14) m -R10, (CR14R14) n- (C (O) NR14) - (CR14R14) r-R11, (CR14R14) y-R11, or (CR14R14) z-R10;

X1是O或S; X1 is O or S;

X2是O或NR14; X2 is O or NR14;

X3是H或X; X3 is H or X-;

X是YR2,卤素,硝基,NR14R14或甲酰氨基; X is YR2, halogen, nitro, carboxamido, or NR14R14;

Y是O或S(O)m; Y is O or S (O) m;

R2是-CH3或-CH2CH3,每个是未取代的或被1-5个氟取代; R2 is -CH3 or -CH2CH3, each of which is unsubstituted or substituted with 1-5 fluoro;

R3是氢,卤素,CN,C1-4烷基,卤代的C1-4烷基,未取代的或被R9取代的环丙烷基,OR5,-CH2OR5,-NR5R16,-CH2NR5R16,-C(O)OR5,-C(O)NR5R16,-CH=CR9R9,-C≡CR9或-C(=Z)H; R3 is hydrogen, halo, the CN, C1-4 alkyl, halogenated C1-4 alkyl, unsubstituted or substituted cyclopropyl R9, OR5, -CH2OR5, -NR5R16, -CH2NR5R16, -C (O ) OR5, -C (O) NR5R16, -CH = CR9R9, -C≡CR9 or -C (= Z) H;

R3′是氢,卤素,C1-4烷基,卤-代C1-4烷基,未取代的或被R9取代的环丙烷基,-CH2OR5,-CH2NR5R16,-C(O)OR5,-C(O)NR5R16或-C(=Z)H; R3 'is hydrogen, halo, C1-4 alkyl, halo - Generation C1-4 alkyl, unsubstituted or R9-substituted cyclopropyl, -CH2OR5, -CH2NR5R16, -C (O) OR5, -C ( O) NR5R16 or -C (= Z) H;

A是 A is

(C)未取代的或被1个或多个氟或1个或2个R4基取代的C1-3烷基; (C) unsubstituted or substituted by one or more fluoro, or 1 or 2 C1-3 alkyl substituted with R4;

m是0-2的整数; m is an integer of 0 to 2;

n是1-4的整数; n is an integer of 1-4;

q是0-1的整数; q is an integer of 0-1;

r是1-2的整数; r is an integer of 1-2;

s是2-4的整数; s is an integer of 2-4;

x是2-6的整数; x is an integer from 2-6;

y是1-6的整数; y is an integer from 1 to 6;

z是0-6的整数; z is an integer of 0-6;

R4分别是氢,Br,F,Cl,-NR5R6,-NR6R16,NO2,-C(Z)R7,-S(O)mR12,CN,OR16,-OC(O)NR5R16,1-或2-咪唑基,-C(=NR16)NR5R16,-C(=NR5)-SR12,-OC(O)CH3,-C(=NCN)NR5R16,-C(S)NR5R16,-NR16-C(O)-R15,C(O)R15,噁唑基,噻唑基,吡唑基,三唑基或四唑基;或者当R5和R16是NR5R16时,它们可以和氮一起形成任意含至少一个另外选自O,N或S杂原子的5-7元环。 R4 each is hydrogen, Br, F, Cl, -NR5R6, -NR6R16, NO2, -C (Z) R7, -S (O) mR12, CN, OR16, -OC (O) NR5R16,1- 2-imidazolyl, or groups, -C (= NR16) NR5R16, -C (= NR5) -SR12, -OC (O) CH3, -C (= NCN) NR5R16, -C (S) NR5R16, -NR16-C (O) -R15 , C (O) R15, oxazolyl, thiazolyl, pyrazolyl, triazolyl or tetrazolyl; or R5 and R16 are as NR5R16, they may be formed together with the nitrogen and optionally containing at least one further selected from O, 5-7 membered ring N or S heteroatom.

R5分别是氢,或未取代的或被1-3个氟取代的C1-4烷基; R5 is independently hydrogen, unsubstituted or substituted with 1-3 fluoro C1-4 alkyl;

R6是H,R12,-C(O)R12,-C(O)C(O)R7,-C(O)NR5R16,-S(O)mR12,-S(O)mCF3,-C(=NCN)SR12,-C(=NCN)R12,-C(=NR16)R12,-C(=NR16)SR12或-C(=NCN)NR5R16; R6 is H, R12, -C (O) R12, -C (O) C (O) R7, -C (O) NR5R16, -S (O) mR12, -S (O) mCF3, -C (= NCN ) SR12, -C (= NCN) R12, -C (= NR16) R12, -C (= NR16) SR12, or -C (= NCN) NR5R16;

R7是OR5,-NR5R16或R12; R7 is OR5, -NR5R16 or R12;

R8是氢,C(O)R7,2-,4-或5-咪唑基,3-,4-,或5-吡唑基,4-,或5-〔1,2,3〕三唑基,3-或5-〔1,2,4〕三唑基,5-四唑基,2-,4-,或5-噁唑基,3-,4-,或5-异噁唑基,3-或5-〔1,2,4〕噁二唑基,2-〔1,3,4〕噁二唑基,2-〔1,3,4〕噻二唑基,2-,4-,或5-噻唑基,2-,4-,或5-噁唑烷基,2-,4-或5-噻唑烷基或2-,4-或5-咪唑烷基; R8 is hydrogen, C (O) R7,2-, 4- or 5-imidazolyl, 3-, 4-, or 5-pyrazolyl, 4-, or 5-triazolyl [1,2,3] , 3- or 5- [1,2,4] triazolyl, 5-tetrazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or 5- [1,2,4] oxadiazolyl, 2- [1,3,4] oxadiazolyl, 2- [1,3,4] thiadiazolyl, 2-, 4- , or 5-thiazolyl, 2-, 4-, or 5-oxazolidinyl, 2-, 4-, or 5-thiazolidinyl or 2-, 4-, or 5-imidazolidinyl;

R9是氢,F,或R12; R9 is hydrogen, F, or R12;

R10是氢,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,呋喃基,吡喃基,噻吩基,噻喃基,C3-6环烷基,或含1或2个不饱和键的C4-6环烷基,其中的环烷基或杂环烷基部分可以是未取代的或被1-3个甲基或1个乙基取代。 R10 is hydrogen, methyl, hydroxyl, aryl group, halogenated aryl group, C1-3 aryloxy group, a halogenated aryloxy C1-3 alkyl, indanyl, indenyl, C7 -11 polycycloalkyl, furanyl, pyranyl, thienyl, thiopyranyl, a C3-6 cycloalkyl group or containing 1 or 2 unsaturated bonds C4-6 cycloalkyl, wherein cycloalkyl or heterocycloalkyl moiety may be unsubstituted or substituted with 1 to 3 methyl or an ethyl.

R11是2-四氢吡喃基,或2-四氢噻喃基,2-四氢呋喃基或2-四氢噻吩基,可以是未取代的或是被1-3个甲基或1个乙基取代; R11 is a 2-tetrahydropyranyl, or 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, may be unsubstituted or substituted with 1-3 methyl or an ethyl group replace;

R12是未取代的或被1-3个氟取代的C1-4烷基; R12 is unsubstituted or substituted with 1-3 fluoro C1-4 alkyl;

R14分别是氢或未取代的或被氟取代的C1-2烷基; Each R14 is hydrogen or unsubstituted or fluorine-substituted C1-2 alkyl group;

R15是未取代的或被1或多个卤素取代的C1-4烷基; R15 is unsubstituted or substituted by one or more halogen-substituted C1-4 alkyl;

-C(O)C1-4烷基,它是未取代的或被1或多个卤素取代;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,噻二唑基,吗啉基,哌啶基,哌嗪基或吡咯基,上述每个杂环可以是未取代的或被1-2个C1-2烷基取代; -C (O) C1-4 alkyl, which is unsubstituted or substituted by 1 or more halogens; oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazole group, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, morpholinyl, piperidinyl, piperazinyl, or pyrrolyl, each of said heterocyclic ring may be unsubstituted or C1-2 alkyl substituted with 1-2;

R16是OR5或R5; R16 is OR5 or R5;

Z是O,-NR12,-NOR5,NCN,-C(-CN)2, Z is O, -NR12, -NOR5, NCN, -C (-CN) 2,

-CR5NO2,-CR5C(O)OR12,-CR5C(O)NR5R5,-C(-CN)NO2,-C(-CN)C(O)OR12或-C(-CN)C(O)NR5R5; -CR5NO2, -CR5C (O) OR12, -CR5C (O) NR5R5, -C (-CN) NO2, -C (-CN) C (O) OR12 or -C (-CN) C (O) NR5R5;

本发明化合物也可是式(Ⅰ)化合物的药学上可接受的盐。 The compounds of this invention may also be a compound of formula a pharmaceutically acceptable (Ⅰ) salts. 其限定条件是:当(CR14R14)nC(O)O-(CR14R14)m-R10,(CR14R14)n-(C(O)NR14)-(CR14R14)m-R10或(CR14R14)sO(CR14R14)mR10中的R10是OH时,m是2;并且进一步的限定条件是当q是O,R3,R3′,R8和X3是H,X是OR2,X2是O及X1是O或S时,(a)或(b)中的R4或R14中至少一个不是氢。 Which is defined with the proviso that: when (CR14R14) nC (O) O- (CR14R14) mR10, (CR14R14) n- (C (O) NR14) - (CR14R14) mR10, or (CR14R14) sO (CR14R14) mR10 the R10 is OH, m is 2; and with the further proviso that when q is O, R3, R3 ', R8 and X3 are H, X is OR2, X2 is O and X1 is O or S, (a ) or (b) in at least one of R4 or R14 is not hydrogen.

能形成盐的本发明化合物的药学上可接受的盐的复合物也属于本发明的范围。 Pharmaceutically acceptable compounds of the present invention can form a salt complex salts within the scope of the present invention.

所有定义的烷基可以是直链的或支链的。 All defined alkyl groups can be linear or branched.

本发明的化合物可以含有1或多个不对称碳原子并能以外消旋体及光学活性体形式存在。 The compounds of this invention may contain one or more asymmetric carbon atoms and can exist in racemic form and optically active forms. 所有这些化合物都属于本发明的范围,“卤素”一词指氯,氟,溴或碘;烷基可以被1或多个卤素取代,直至是全卤代的。 All of these compounds are within the scope of the present invention, the term "halogen" refers to chloro, fluoro, bromo or iodo; alkyl group may be substituted with one or more halo, until a perhalogenated.

此处所用“环烷基”一词是指3-6个碳原子的基团,如环丙基,环丙甲基,环戊基或环己基。 As used herein, "cycloalkyl" refers to a group of 3-6 carbon atoms, such as cyclopropyl, cyclopropylmethyl, cyclopentyl or cyclohexyl.

此处所用“芳基”或“芳烷基”一词,除另有说明以外,是指6-10个碳原子的芳环或环体系,如苯基,苄基,苯乙基或萘基。 As used herein, "aryl" or "aryl alkyl", unless otherwise noted, it refers to an aromatic ring of 6-10 carbon atoms or ring system, such as phenyl, benzyl, phenethyl or naphthyl group . 优选的芳基是单环芳基,即苯基。 Preferred aryl groups are monocyclic aryl, i.e., phenyl.

C7-11多环烷基的例子是双环〔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。 Examples of C7-11 cycloalkyl groups are multi-bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl, tricyclo [5.2.1.0 2,6] decyl and the like. 这种取代基的其它实例公开在Saccamano等人的专利中(WO87/06576,1987.11.5公开),此处作为参考。 Other examples of such substituents are disclosed in Saccamano et al patent (WO87 / 06576,1987.11.5 disclosed), herein incorporated by reference.

当-NR5R16中的R5和R16和其所连的氮原子一起形成任意含有至少一个选自O,N和S杂原子的5-7元环时,该环的实例包括,(但不限于):1-咪唑基,1-吡唑基,1-三唑基,2-三唑基,四唑基,2-四唑基,吗啉基,哌嗪基或吡咯基。 When -NR5R16 R5 and R16 and the nitrogen atom to which they are attached together form optionally containing at least one heteroatom selected from O, N and S heteroatoms 5-7 membered ring, examples of the ring include, (but are not limited to): 1-imidazolyl, 1-pyrazolyl, 1-triazolyl, 2-triazolyl, tetrazolyl, 2-tetrazolyl, morpholinyl, piperazinyl, or pyrrolyl.

本发明还提供了新的式(Ⅰ)化合物的药物组合物。 The present invention also provides novel pharmaceutical compositions comprising a compound of formula (Ⅰ).

本发明提供了抑制PDE IV的方法,它包括对需要治疗的对象施用式(Ⅰ)化合物。 The present invention provides a method of inhibiting PDE IV which comprises the compound administered to a subject in need of treatment of formula (Ⅰ).

本发明进一步提供了治疗过敏性和炎性疾病的方法,它包括对需要治疗的对象给有效量的式(Ⅰ)化合物。 The present invention further provides a method of treating allergic and inflammatory disease which comprises a compound of a subject in need of treatment an effective amount of a formula (Ⅰ) to.

本发明还提供了一种治疗哮喘病的方法,它包括对需要治疗的对象给有效量的式(Ⅰ)化合物。 The present invention also provides a method of treating asthma, which comprises administering to a subject in need of treatment an effective amount of a formula (Ⅰ) compound.

式(Ⅰ)化合物在预防学和治疗学上用于治疗人体由于过量地或不规律地产生TNF引起的或加重的疾病。 Formula (Ⅰ) compound in the prevention and therapeutics for the treatment of the human or generated due to an excessive or increased TNF mediated disease erratically.

因此,本发明还提供了一种抑制动物体(包括人)中产生肿瘤坏死因子(TNF)的方法,该方法是对需要治疗的动物给有效量的式(Ⅰ)化合物。 Accordingly, the present invention also provides a method of inhibiting an animal (including human) method of tumor necrosis factor (TNF) is generated in the method is to an animal in need of treatment an effective amount of a formula (Ⅰ) compound.

术语“抑制TNF产生”是指:a)在体内减少人体中过剩的TNF的量,在体内通过抑制所有细胞(包括但不限于单核细胞或巨噬细胞)释放TNF,使其达到正常水平或正常水平以下; The term "inhibiting the production of TNF" means: a) reducing the amount of TNF in the body of excess body in vivo by suppressing all cells (including but not limited to monocytes or macrophages) release TNF, to reach the normal level or below normal levels;

b)在翻译和转录水平上,在体内将人体中过剩的TNF下调到正常水平或正常水平以下;或c)在翻译之后,通过抑制TNF的直接合成将其下调。 b) at the level of transcription and translation, in vivo human TNF excess down to normal levels or below normal levels; or c) after the translation, the direct synthesis of TNF by inhibiting its lowered.

术语“TNF引起的疾病”是指任何及所有或者是通过产生TNF本身,或者是通过TNF引起的其它细胞活素(如但不限于IL-1或IL-6)的释放,而其中是TNF起作用的疾病。 The term "TNF mediated disorder" refers to any and all or released by production of TNF itself, or other cytokines by TNF-induced (e.g., but not limited to IL-1 or IL-6), and wherein TNF, from the effects of the disease. 例如,一种疾病,其中IL-1是主要因素,并且在对TNF的反应中它的产生和作用被加重或者其被分泌,因此,我们把这种疾病看作TNF引起的疾病。 For example, a disorder in which IL-1 is a major factor, and its production and action is aggravated in response to TNF, or which is secreted, therefore, we have considered the disease caused by TNF disease.

此处所用“细胞活素”一词是指任何被分泌的多肽,它影响其它细胞的功能,并且在免疫和炎性反应中是一种调解细胞之间相互作用的分子。 As used herein, the term "cytokine" refers to any secreted polypeptide that affects the functions of other cells in the immune and inflammatory responses and interactions between cells is a molecule with mediation. 细胞活素包括但不限于单核因子和淋巴因子,不管什么细胞产生它们。 Cytokines include, but are not limited to, monokines and lymphokines, regardless of which cells produce them. 例如,一般认为单核因子是由单核细胞(如巨噬细胞和/或单核细胞)产生和分泌出来的,但是许多其它细胞也产生单核因子,如中性杀伤细胞,成纤细胞,嗜碱细胞,中性白细胞,内皮细胞,脑星形细胞,骨髓基质细胞,表皮角质化细胞和β-淋巴细胞。 For example, a monokine is generally believed that production and secreted by monocytes (e.g., macrophages and / or monocytes), but many other cells also produce monokines, such as neutral killer cells, fibroblasts, basophils, neutrophils, endothelial cells, brain astrocytes, bone marrow stromal cells, epidermal keratinocytes, and β- lymphocytes. 淋巴因子一般被认为是由淋巴细胞产生的。 It is generally considered a lymphokine produced by lymphocytes. 本发明中细胞活素的实例包括(但不限定于):白细胞介素-1(IL-1),白细胞介素-6(IL-6),肿瘤坏死因子-α(TNFα)和肿瘤坏死因子-β(TNF-β)。 Examples of the present invention cytokines include (but are not limited to): Interleukin -1 (IL-1), interleukin -6 (IL-6), tumor necrosis factor -α (TNFα) and tumor necrosis factor -β (TNF-β).

优选的一小类式(Ⅰ)化合物是式(Ib)化合物或其药学上可接受的盐: The compound or a pharmaceutically acceptable salt of the compound preferred subclass of formula (Ⅰ) is of formula (Ib):

其中:R1是未取代的或被1-3个甲基或乙基取代的C4-6环烷基;未取代的或被1-3个氟取代的C1-7烷基; Wherein: R1 is unsubstituted or substituted by 1 to 3 methyl or ethyl substituted by C4-6 cycloalkyl; unsubstituted or substituted with 1-3 fluoro substituted C1-7 alkyl;

-(CH2)sC(O)O-(CH2)mCH3;-(CH2)sO(CH2)mCH3; - (CH2) sC (O) O- (CH2) mCH3 ;-( CH2) sO (CH2) mCH3;

-(CH2)sOH;-CH2-环戊基;-CH2-环丙基或3-四氢呋喃基; - (CH2) sOH; -CH2- cyclopentyl; -CH2- cyclopropyl or 3-tetrahydrofuranyl;

s是2-4; s is 2-4;

m是0-2; m is 0-2;

X是-YR2,卤素,硝基,氨基,C1-2二烷基氨基,C1-2单烷基氨基或甲酰氨基; X is -YR2, halo, nitro, amino, C1-2 dialkylamino, C1-2 monoalkylamino, or carboxamido;

Y是O或S(O)m; Y is O or S (O) m;

R2是-CH3或-CH2CH3,每个可以是未取代的或被1-4个氟取代; R2 is -CH3 or -CH2CH3, each may be unsubstituted or substituted with 1-4 fluoro;

R3是H,CH3,CN,F,OH,-C≡CR9或CF3; R3 is H, CH3, CN, F, OH, -C≡CR9 or CF3;

X1是O或S; X1 is O or S;

q是0或1; q is 0 or 1;

R4分别是H,Br,F,Cl,-NR5R16,NO2,-C(Z)R7,-S(O)mC1-3烷基,CN,OR16, R4 are each independently H, Br, F, Cl, -NR5R16, NO2, -C (Z) R7, -S (O) mC1-3 alkyl, CN, OR16,

-OC(O)NR5R16,1-或2-咪唑基,-C(=NR16)NR5R16,-C(=NR5)-SR12,-C(O)R15,-OC(O)CH3,-C(=NCN)NR5R16,-C(S)NR5R16或-NH-C(O)-R15; -OC (O) NR5R16,1- or 2-imidazolyl, -C (= NR16) NR5R16, -C (= NR5) -SR12, -C (O) R15, -OC (O) CH3, -C (= NCN) NR5R16, -C (S) NR5R16 or -NH-C (O) -R15;

R5分别是H或未取代的或被1-3个氟取代的C1-4烷基; R5 is independently H or substituted or unsubstituted C1-4 alkyl substituted with fluoro;

R6是H,R12,-C(O)R12,-C(O)C(O)R7,-C(O)NR5R16,S(O)mCR12,-S(O)mCF3,-C(=NCN)SR12,-C(=NCN)NR5R16,-C(=NCN)R12,或-C(=NR16)R12; R6 is H, R12, -C (O) R12, -C (O) C (O) R7, -C (O) NR5R16, S (O) mCR12, -S (O) mCF3, -C (= NCN) SR12, -C (= NCN) NR5R16, -C (= NCN) R12, or -C (= NR16) R12;

R7是OR5,NR5R16或R12; R7 is OR5, NR5R16 or R12;

R8是H或-C(O)R7; R8 is H or -C (O) R7;

R9是H,F或R12; R9 is H, F or R12;

R12是未取代的或被1-3个氟取代的C1-4烷基; R12 is unsubstituted or substituted with 1-3 fluoro C1-4 alkyl;

R14是H或未取代的或被1或多个氟取代的C1-2烷基; R14 is H or unsubstituted or substituted by 1 or more fluorine substituents of C1-2 alkyl;

R15是未取代的或被1或多个卤素取代的C1-4烷基,-C(O)C1-4烷基,它是未取代的或被1或多个卤素取代,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,噻二唑基,吗啉基,哌啶基,哌嗪基或吡咯基,每个杂环可以是未取代的或被1或2个C1-2烷基取代; R15 is unsubstituted or substituted with 1 or more halogen C1-4 alkyl, -C (O) C1-4 alkyl, which is substituted by unsubstituted or substituted 1 or more halogens, oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, morpholinyl, piperazine piperidinyl, piperazinyl, or pyrrolyl, each heterocyclic ring may be unsubstituted or substituted with 1 or 2 C1-2 alkyl substituents;

R16是OR5或R5。 R16 is OR5 or R5.

优选的化合物是下列化合物:其中的R1是-CH2-环丙基,-CH2-C5-6环烷基,C4-6环烷基,四氢呋喃基,环戊烯基,任意被一或多个氟或氯取代的C1-7烷基以及-(CH2)2-4OH;X1和X2是氧,X是YR2及Y是氧;R2是任意被1或多个卤素(优选氟或氯)取代的C1-2烷基;一个R3是氢且另一个R3是氢,-C≡CR9,CN,C(=Z)H,CH2OH,CH2F,CF2H,或CF3;Z是O,NCN,或NOR5;R3′是氢;X3是氢;A是(a);R4是H,Br,OR16,CN,NR5R6,NO2,C(O)R7,S(O)mR12,1-或2-咪唑基,-OC(O)CH3或NHC(O)R15;R8是C(O)OH,H或C(O)OEt;R14是氢,CH3,NH2或NHC(O)CH3。 Preferred compounds are the following compounds: wherein R1 is -CH2- cyclopropyl, -CH2-C5-6 cycloalkyl, C4-6 cycloalkyl, tetrahydrofuranyl, cyclopentenyl, optionally substituted by one or more fluorine or chlorine-substituted C1-7 alkyl, and - (CH2) 2-4OH; X1 and X2 are oxygen, X is YR2 and Y is oxygen; R2 is optionally substituted with 1 or more halogen (preferably fluoro or chloro) a C1 -2 alkyl; R3 is a hydrogen and the other R3 is hydrogen, -C≡CR9, CN, C (= Z) H, CH2OH, CH2F, CF2H, or CF3; Z is O, NCN, or NOR5; R3 ' It is hydrogen; X3 is hydrogen; A is (a); R4 is H, Br, OR16, CN, NR5R6, NO2, C (O) R7, S (O) mR12,1- or 2-imidazolyl, -OC ( O) CH3 or NHC (O) R15; R8 is C (O) OH, H or C (O) OEt; R14 is hydrogen, CH3, NH2 or NHC (O) CH3.

更优选的是下列化合物,其中的R1是被1或多个氟取代的C1-4烷基,CH2-环丙烷基,CH2-环戊烷基,环戊烷基或环戊烯基;R2是甲基或氟取代的C1-2烷基;R3是氢,C≡CH或CN;R4是氢,Br,NH2,-NHC(O)CH3,C(O)OH,-NHC(NCN)SCH3,-NHC(O)NH2,-N(CH3)2,NHC(O)C(O)OCH3,-NHC(O)C(O)OH,-NHS(O)2CH3,-C(O)OCH3,S(O)2CH3,SCH3,-NHC(O)C(O)CH3,S(O)CH3,-NHC(O)C(O)NH2,CN,C(O)NH2,NHS(O)2CF3,C(NH)NH2,OC(O)CH3,-C(O)N(CH3)2,1-或2-咪唑基,-NHC(O)CH2Cl,-NHC(O)-噁唑烷基,-NHC(O)-4,4-二甲基噁唑烷基或OH。 More preferred are the following compounds, wherein R1 is phenyl substituted with 1 or more fluorine C1-4 alkyl, CH2- cyclopropyl, CH2- cyclopentyl, cyclopentyl or cyclopentenyl; R2 is methyl or fluoro-substituted C1-2 alkyl group; R3 is hydrogen, C≡CH or CN; R4 is hydrogen, Br, NH2, -NHC (O) CH3, C (O) OH, -NHC (NCN) SCH3, -NHC (O) NH2, -N (CH3) 2, NHC (O) C (O) OCH3, -NHC (O) C (O) OH, -NHS (O) 2CH3, -C (O) OCH3, S (O) 2CH3, SCH3, -NHC (O) C (O) CH3, S (O) CH3, -NHC (O) C (O) NH2, CN, C (O) NH2, NHS (O) 2CF3, C (NH) NH2, OC (O) CH3, -C (O) N (CH3) 2,1- or 2-imidazolyl, -NHC (O) CH2Cl, -NHC (O) - oxazolidinyl, -NHC (O) -4,4- dimethyl-oxazolidinyl or OH.

最优选的是下列化合物,其中的R1是环戊烷基,CF3,CH2F,CHF2,CF2CHF2,CH2CF3,CH2CHF2,CH3,CH2-环戊烷基,CH2-环丙烷基,或环戊烯基;R2是CF3,CHF2,或CH2CHF2;一个R3是氢而另一个R3是氢,C≡CH,或CN并且是在4一位;一个R4是氢而另一个是NHC(O)CH3,NH2,NH-C(=NCN)SCH3,NHC(O)CO2CH3,C(O)OCH3,NHC(O)NH2,NHC(O)C(O)CH3或NHC(O)C(O)NH2;或者其中两个R4都是NH2或NHC(O)CH3;R8是氢;R14是氢。 Most preferred are the following compounds, wherein R1 is cyclopentyl, CF3, CH2F, CHF2, CF2CHF2, CH2CF3, CH2CHF2, CH3, CH2- cyclopentyl, CH2- cyclopropyl, cyclopentyl or alkenyl group; R2 is CF3, CHF2, or CH2CHF2; R3 is a hydrogen and the other R3 is hydrogen, C≡CH, or CN and is in a 4; R4 is a hydrogen and the other is NHC (O) CH3, NH2, NH- C (= NCN) SCH3, NHC (O) CO2CH3, C (O) OCH3, NHC (O) NH2, NHC (O) C (O) CH3 or NHC (O) C (O) NH2; or wherein two R4 It is NH2 or NHC (O) CH3; R8 is hydrogen; R14 is hydrogen.

特别优选的是下列化合物:1-(4-氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮; Particularly preferred are the following compounds: 1- (4-aminobenzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone;

1-(4-乙酰氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮; 1- (4-acetylamino-benzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone;

1-(4-草酰氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮; 1- (4-oxamido-yl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone;

4-(3-环戊氧基-4-甲氧基苯基)-1-(2,4-二乙酰氨基苄基)-2-吡咯烷酮; 4- (3-cyclopentyloxy-4-methoxyphenyl) -1- (2,4-diacetoxy-aminobenzyl) -2-pyrrolidinone;

4-(3-环戊氧基-4-甲氧基苯基)-1-(2,4-二氨基苄基)-2-吡咯烷酮; 4- (3-cyclopentyloxy-4-methoxyphenyl) -1- (2,4-aminobenzyl) -2-pyrrolidinone;

1-(4-甲氧羰基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮; 1- (4-methoxycarbonyl benzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone;

4-(3-环戊氧基-4-甲氧基苯基)-1-(4-N′-〔N-2-氰基-S-甲基-异硫脲基〕苄基)-2-吡咯烷酮; 4- (3-cyclopentyloxy-4-methoxyphenyl) -1- (4-N '- [N-2- cyano -S- methyl - isothiourea-yl] benzyl) -2 - pyrrolidone;

1-(4-N-甲氧羰基脲基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮; 1- (4-N- methoxycarbonyl-benzyl-ureido) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone;

4-(3-(环戊氧基-4-甲氧基苯基)-1-(4-N-〔脲基〕苄基)-2-吡咯烷酮;和 4- (3- (cyclopentyloxy-4-methoxyphenyl) -1- (4-N- [ureido] benzyl) -2-pyrrolidinone; and

4-(3-环戊氧基-4-甲氧基苯基)-1-(4-丙酮酸酰氨基苄基)-2-吡咯烷酮; 4- (3-cyclopentyloxy-4-methoxyphenyl) -1- (4-benzyl pyruvate amido) -2-pyrrolidinone;

最特别优选的化合物是:(S)-1-(4-氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮; Most particularly preferred compounds are: (S) -1- (4- aminobenzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone;

(R)-1-(4-乙酰氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮; (R) -1- (4- acetylamino-benzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone;

(S)-1-(4-乙酰氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮; (S) -1- (4- acetylamino-benzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone;

一般的合成方法:式(Ia)化合物 The compound of formula (Ia): General method for the synthesis of

能用下述方法制备,该方法包括:a)对于其中R3是H,R12或未取代的或被R9取代的环丙基;X及X3是除了S(O)mR2(其中m=1或2),Br,I,NO2或甲酰氨基以外的其它基团的式(Ia)化合物,使式(2)化合物: Can be prepared by a method, the method comprising: a) for which R3 is H, R12 or R9 is substituted or unsubstituted cyclopropyl; and X3 is in addition to X-S (O) mR2 (wherein m = 1 or 2 ), the compound of formula (Ia) other groups other than Br, I, NO2 or carboxamido of the formula (2) compound:

(其中X2R1,X及X3分别代表如式(Ⅰ)中所定义的X2R1、X和X3或者代表能转化成X2R1,X和X3的基团,X1是H)在适当溶剂如苯和甲苯中,在有或无适当的催化剂(例如四氯化钛或带或不带加成酸的叔胺碱)存在下,与合适的丙二酸酯衍生物,如丙二酸二甲酯一起回流,和/或于惰性气氛下共沸去水,得到式(3)化合物: (Wherein X2R1, X and X3 represent the formula X2R1 in (Ⅰ) as defined, X and X3 or represent energy into X2R1, X and X3 group, the X1 is H) in a suitable solvent such as benzene and toluene, in the absence or presence of a suitable catalyst, with a suitable malonic ester derivative, such as reflux (e.g. titanium tetrachloride or acid with or without a tertiary amine base-addition) with dimethyl malonate, and / or under an inert atmosphere to the water azeotropically, to give a compound of formula (3):

(其中R17是烷基或芳基,R18是COOR17)。 (Where R17 is alkyl or aryl, R18 is COOR17).

在适当溶剂如含水乙醇中,于25-90℃下,将上述式(3)化合物与氰化物如氰化钠,氰化钾或四烷基氰化铵反应,得到式(4)化合物: In a suitable solvent such as aqueous ethanol, at 25-90 deg.] C, the compound (3) the formula with a cyanide such as sodium cyanide, potassium cyanide or tetra-alkyl ammonium reaction of formula (4) compounds:

(其中R3′是H或COOR17,通常是一混合物)。 (Wherein R3 'is H or COOR17, typically a mixture).

另一方法是,使式(2)化合物和例如烷氧羰基或芳氧羰基-亚甲基三烷基或三芳基正膦反应,得到其中R18是H的式(3)化合物,再将这个式(3)化合物于合适溶剂如含水乙醇中,于25-90℃下和氰化物如氰化钠,氰化钾或四烷基氰化铵反应得到其中R3′是H的式(4)化合物。 Another method is the formula (2) compound e.g. alkoxycarbonyl group or an aryloxycarbonyl group - methylene trialkyl or triaryl phosphine positive reaction, to give a compound wherein R18 is H in formula (3), then the formula (3) compound in a suitable solvent such as aqueous ethanol, at 25-90 deg.] C and cyanides such as sodium cyanide, potassium cyanide or tetra-alkyl ammonium reaction wherein R3 'is H, a compound of formula (4).

另一方法是,其中R18是H的式(3)化合物与由适当碱或在适当催化剂(如醇盐,四烷基胍或季铵卤化物)存在下产生的硝基甲烷阴离子,在适当溶剂如乙醇或硝基甲烷中进行反应,得到式(5)的酯类化合物。 Another method is wherein R18 is H in formula (3) is reacted with the anion of nitromethane in a suitable base or a suitable catalyst (e.g., alkoxide, tetraalkyl guanidine or quaternary ammonium halide) generated by the presence, in a suitable solvent the reaction was carried out in ethanol or nitromethane, to give the ester compound of formula (5).

(其中R3′是COOR17),该化合物被水解或脱羧,可得到其中R3′是H的式(5)化合物。 (Wherein R3 'is COOR17), the compound is hydrolysis or decarboxylation obtained wherein R3' is H, a compound of formula (5). 同样,其中R3′是H的式(5)化合物可用下述方法得到:1)首先使式(2)化合物和如上所述的硝基甲烷反应,得到式(6)化合物: Similarly, where R3 'is H, a compound of formula (5) can be obtained as follows: 1) first reacting the formula (2) and a compound of nitromethane as described above to obtain formula (6) compounds:

2)然后将式(6)化合物进一步和在适当温度(如-78℃)下产生的乙酸烷基酯或乙酸芳基酯阴离子在适当溶剂(如四氢呋喃)中反应,在反应中使用适当的碱(如二异丙基氨基化锂或六甲基二硅叠氮化锂)。 2) then the formula (6) compound and an alkyl acetate or a further aryl ester of acetic acid anions generated at an appropriate temperature (e.g., -78 ℃), using an appropriate base in the reaction in a suitable solvent (e.g. tetrahydrofuran) reaction (such as lithium diisopropylamide or hexamethyldisilazide lithium azide).

另一方法是,式(9)化合物(如下文所述,其中R20是H;R3是H,R12,未取代的或被R9取代的环丙基)和强碱反应,随后和适当的烷基或芳基α-卤化羧酸酯(如α-溴代乙酸甲酯)反应,得到式(4)化合物(其中R3是H,R12或未取代的或被R9取代的环丙基)。 Another method is, the compound (as described below, where R20 is H; R3 is H, R12, unsubstituted or substituted cyclopropyl R9) of formula (9) and a strong base, and then the appropriate alkyl α- or aryl carboxylic acid ester halide (e.g., α- methyl bromoacetate) to give the formula (4) (wherein R3 is H, R12 or R9 is substituted or unsubstituted cyclopropyl). 使上述式(4)化合物的氰基或者上述类似式(5)化合物的硝基进行反应,得其中R19是H的式(7)化合物: The compound of the formula (4) is a cyano group or a nitro compound similar to the above formula (5) is reacted to give a compound wherein R19 is H in formula (7):

将其中R19是H的式(7)的胺和醛在合适溶剂如氯仿中,于回流温度下反应,随后用例如氰基硼氢钠,在有酸的甲醇溶液存在下还原上述亚胺,得到其中R19是CH2(CH2)mA的式(7)化合物。 In which R19 is H in Formula (7) of the amines and aldehydes in a suitable solvent such as chloroform, at the reflux temperature, followed by sodium cyanoborohydride e.g., reduction of the above methanol solution of the imine in the presence of an acid to give a compound wherein R19 is CH2 (CH2) mA of formula (7). 然后环化上述的式(7)化合物得到相应的式(Ia)化合物。 Is then cyclized in the above formula (7) to give Compound corresponding compound of formula (Ia). 另外,在有或无催化剂存在下,在适当溶剂中,用适当活化的烷基化剂(如烷基卤化物,甲磺酸酯或甲苯磺酸酯)处理其中R19是H的式(7)化合物,可得到R19是CHR3(O)q(CH2)mA的式(7)化合物,它可以如上述那样被环化,得到相应的式(Ia)化合物。 Further, in the presence or absence of a catalyst, in a suitable solvent, treated with an appropriate activated alkylating agent (e.g. alkyl halide, mesylate or tosylate) of formula wherein R19 is H (7) compound, is a compound obtained R19 CHR3 (O) q (CH2) mA of formula (7), which can be cyclized as described above to give the corresponding compound of formula (Ia). 除此,环化R19是H的上述式(7)化合物,可得到R19是H的式(8)化合物。 In addition, R19 is H, cyclizing a compound of the formula (7), R19 to obtain a compound of the formula H (8).

R19是H的适当的式(8)化合物和强碱如氢化钠反应,随后将得到的酰胺阴离子和适当活化的烷基化剂(如烷基卤化物,甲磺酸酯,甲苯磺酸酯)反应,也可得到式(Ia)化合物。 R19 is H, the appropriate formula (8) compounds and a strong base such as sodium hydride reaction, the resulting amide is then suitably activated anion and alkylating agent (e.g. alkyl halide, mesylate, tosylate) The reaction, also compounds of formula (Ia).

b)对于R3是CN,X和X3是除了S(O)mR2(m=1或2),Br,I,NO2或甲酰氨基以外的其它基团的式(Ia)化合物,将其中R3是H的式(2)化合物在适当溶剂中连续地与卤化锂和甲硅烷基卤化物反应,然后用适当的还原剂如硅氧烷还原,得到式(9)化合物, b) for R3 is CN, X and X3 is in addition to S (O) mR2 (m = 1 or 2), the compound of formula (Ia) other groups other than Br, I, NO2, or carboxamido, and R3 is in which compound H of the formula (2) is continuously reacted in a suitable solvent with a lithium halide and a silyl halide, followed by reduction of an appropriate reducing agent such as silicone, to give a compound of formula (9),

(其中X4是氯或溴,R3和R20是H);另一方法是,R3是H的式(2)化合物用例如氢硼化钠在甲醇中还原,得到X4是OH,并且R3和R20是H的式(9)化合物。 (Wherein X4 is chloro or bromo, R3 and R20 are H); another method, R3 is H in Formula (2) compounds, for example sodium borohydride in methanol to reduction, to give X4 is OH, and R3 and R20 are compound H of the formula (9). 后者和例如三氯化磷,亚硫酰氯,三溴化磷,溴化铜或三苯基膦-四溴化碳反应,也得到X4是氯或溴及R3和R20是H的式(9)化合物。 The latter and, for example phosphorus trichloride, thionyl chloride, phosphorus tribromide, cupric bromide or triphenylphosphine - carbon tetrabromide reaction, also X4 is chloro or bromo and R3 and R20 are H, the formula (9 ) compound. 然后卤素被氰基取代得X4是CN及R3和R20是H的式(9)化合物,后者与强碱如丁基锂在低温及惰性气氛下反应,随后可以a)例如用无水溴化镁处理,然后与例如三甲基甲硅烷基异氰酸酯反应并适当处置,得到其中R3是CONH2,R20是H及X4是CN的式(9)化合物,或者b)例如与烷基或芳基卤代甲酸酯例如氯代甲酸甲酯反应,得到其中R3是COOR17,R20是H及X4是CN的式(9)化合物。 Then substituting the halo by cyano X4 is CN and R3 and R20 are compounds of formula (9) H, the latter with a strong base such as butyllithium in an inert atmosphere at a low temperature and the reaction may then be a), for example over anhydrous bromide magnesium treatment, then, for example trimethylsilyl isocyanate group is reacted with and appropriate disposal afford wherein R3 is CONH2, R20 is H and X4 is CN a compound of formula (9), or b) for example, halogenated alkyl or aryl carboxylic esters such as methyl chloroformate there was obtained wherein R3 is COOR17, R20 is H and X4 is CN a compound of formula (9). 上述化合物中的COOR17基团可以在此步或后续步骤中,通过本技术领域中任何已知的标准技术方法,如和浓氢氧化铵反应,将其转变成CONH2基团。 The above compounds can be COOR17 group In this step, or subsequent step, by any art standard techniques known methods, such as concentrated ammonium hydroxide, and the reaction, which was converted to CONH2 group.

另外,R3是COOR17,R20是H及X4是CN的式(9)化合物也可以通过使R3和R20是H及X4是CN的式(9)化合物和金属氢化物例如氢化钠,在二烷基或二芳基碳酸酯例如碳酸二甲酯的存在下反应而被制得。 Further, R3 is COOR17, R20 is H and X4 is CN in the formula (9) may also be prepared by reacting a compound R3 and R20 are H and X4 are compounds and metal hydrides such as sodium hydride CN in formula (9), dialkyl or diaryl carbonates such as dimethyl carbonate in the presence of reaction is obtained. 同时,这种化合物也可通过任何已知方法,如和甲基亚磺酰甲基硫化甲基及碱例如氢氧化钠反应,随后用醇酸处理,使R3是H的式(2)化合物同系化成R3是COOR17及X4和R20是H的式(9)化合物而得到。 Meanwhile, such a compound may be by any known method, such as sulfide and methyl methylsulfinyl-methyl and a base such as sodium hydroxide, followed by treatment with an alkyd, R3 is H, so that the formula (2) compound homolog Chemical R3 is COOR17 and X4 and R20 are H, a compound of formula (9) obtained. 产生的式(9)化合物的阴离子和适当的碱,随后再和例如氯化氰或2-氯苄基硫氰酸酯反应,得到R3是COOR17,R20是H及X4是CN的式(9)化合物。 Of formula (9) produced by the anion of the compound and a suitable base, followed by, for example, cyanogen chloride and 2-chloro-benzyl ester or thiocyanate to give R3 is COOR17, R20 is H and X4 is CN in the formula (9) compound. 产生的式(9)化合物(其中R20是H,X4是CN及R3是CONH2或COOR17)的阴离子,在适当的溶剂中和合适的碱反应,随后再和烷基或芳基α-卤代羧酸酯反应得到其中R3是CONH2或COOR17的式(4)化合物。 The compound of formula (9) produced (where R20 is H, X4 is CN and R3 is CONH2 or COOR17) anion, a base in a suitable solvent and appropriate, followed by alkyl or aryl, and halocarboxylic acid α- esters obtained by reacting a compound wherein R3 is CONH2 or COOR17 of formula (4). 还原这个化合物的氰基部分,例如用贵金属或阮内镍催化氢化,得到R19是H及R3是CONH2或COOR17的式(7)化合物。 The reducing a cyano moiety of the compound, for example, hydrogenation with a noble metal or Raney nickel catalyst, to give R19 is H and R3 is a compound of formula (7) CONH2 or COOR17 of. 式(7)化合物的氨基部分(式(7)化合物中R19是H及R3是CONH2)被保护得到其中R19是保护基例如叔丁氧羰基和R3是CONH2的式(7)化合物。 Formula (7) an amino moiety of the compound (compound of formula (7) wherein R19 is H and R3 is CONH 2) is protected to give wherein R19 is a protecting group such as tert-butoxycarbonyl group and R3 is a compound of formula (7) is CONH 2. 酰胺用例如三氟乙酸酐脱水,随后除去保护基,得到R19是H及R3是CN的式(7)化合物,然后后者如上文对式(7)的其它化合物所述,可以被转化成式(Ia)化合物,其中的R3是CN,X和X3是除了S(O)mR2(其中m=1或2),Br,I,NO2或甲酰氨基以外的基团。 Amide dehydration with, for example trifluoroacetic anhydride, followed by removal of the protecting group R19 is H and R3 is CN a compound of formula (7), and said other compound which above formula (7) may be converted to the formula (Ia) compounds in which R3 is CN, X and X3 is in addition to S (O) mR2 (wherein m = 1 or 2), other than Br, I, NO2, or carboxamido group.

c)式(Ⅰ)化合物(其中R3是OR5或F,X和X3是除了S(O)mR2(其中m=1或2),Br,I,NO2或甲酰氨基以外的基团)可从氰醇(其中的羟基被适当保护为甲硅烷基醚,乙缩醛或酯例如t-BOC)开始进行反应而制备。 (Compound Ⅰ) (OR5 or wherein R3 is F, X, and X3 are in addition to S (O) c) Formula mR2 (wherein m = 1 or 2), other than Br, I, NO2 groups or carboxamido) from cyanohydrin (wherein the hydroxy group is suitably protected as a silyl ether, acetal or an ester e.g. t-BOC) is prepared to start the reaction. 式(2)化合物(其中R3是H,R12或未取代的或被R9取代的环丙基)用例如氢氰酸衍生物处理得到其中R3是H,R20是OH及X4是CN的式(9)的氰醇。 (2) a compound of formula (wherein R3 is H, R12 or R9 is substituted or unsubstituted cyclopropyl) treated with hydrocyanic acid to give a derivative, for example, where R3 is H, R20 is OH and X4 is CN in the formula (9 ) cyanohydrin. 随后用合适的保护试剂(如三甲基甲硅烷基氯化物,二叔丁基碳酸酯)及合适的碱或甲基乙烯醚处理式(9)化合物,或者用三甲基甲硅烷基氰化物和路易斯酸直接处理式(2)化合物,可得到式(9)的被保护的氰醇化合物,其中R3是H,R20是被保护的羟基,X4是CN。 Followed by a suitable protecting agent (e.g. trimethylsilyl chloride, di-tert-butyl carbonate) and a suitable base, or methyl vinyl ether compound of formula (9), or with trimethylsilyl cyanide and Lewis acids directly with the formula (2) compound, the protected cyanohydrin obtained compound of formula (9) wherein R3 is H, R20 is a protected hydroxy group, X4 is CN. 该被保护的氰醇用强的受阻碱如LDA,于低温及惰气氛下处理,随后和例如溴代乙酸酯反应,并适当处置,可得到其中R3是被保护的羟基,R3′是H的式(4)化合物。 The protected cyanohydrin with a strong hindered base such as LDA, in an inert atmosphere and at low temperature process, for example, and then the reaction bromoacetate, and appropriate disposal obtained where R3 is a protected hydroxy group, R3 'is H the compound of formula (4). 例如用阮内镍催化剂加氢将上述化合物的氰基部分还原,可得R19是H及R3是保护的或未保护的羟基的式(7)化合物。 E.g. hydrogenation with Raney nickel catalyst cyano portion of the reduction of a compound, R19 is H can be obtained, and R3 is a compound of formula (7) hydroxyl group is protected or unprotected. 这些式(7)化合物在氮原子上被烷基化并如上文所述环化,然后用二乙氨基三氟化硫处理,得到R3是F的式(Ia)化合物。 These compounds are alkylated Formula (7) on the nitrogen atom and cyclized as described above, then treated with diethylaminosulfur trifluoride to give compound F R3 is of formula (Ia).

d)R3代表式(Ia)中其余R3基团的式(Ia)化合物,可以通过保护酰氨基和其它敏感的官能团,并转化CN官能团,例如还原CN(R3)部分为CHO,并且用本技术领域中已知的任何标准方法将CHO进行官能团转换,从式(8)化合物或其中R3是CN的式(Ia)化合物得到。 d) a compound wherein R3 represents formula (Ia) Formula (Ia) remaining R3 groups can be protected amido, and other sensitive functional group, and transformed CN functional groups, e.g. reduction CN (R3) moiety is CHO, and with present technology any standard method known in the art CHO functional group conversion from formula (8) or the compound wherein R3 is CN, the compound of formula (Ia) obtained.

某些式(Ia)化合物可以从另一些式(Ia)化合物通过适当处理存在于A,X,X1,X2R1,R3或R3′部分中的官能团或其本身来制备。 Certain compounds of formula (Ia) may be X, X1, X2R1, R3 or R3 'or a functional group portion itself be prepared from other formula (Ia) compound is present in a suitable process A,.

R3是CF3,CHF2或CH2F的式(Ia)化合物可以从相应的式(2)化合物使用上述方法制备。 R3 is CF3, CHF2 or CH2F compound of formula (Ia) from the corresponding compound of formula (2) compound was prepared using the method described above. 其中R3是CF3的式(2)化合物可通过Shono等人所述电化学方法(J.Org.Chem.Vol.56,P.204(1991))从R3是H的式(2)化合物得到。 Wherein R3 is the compound of formula (2) CF3 may be prepared by the electrochemical method of Shono et al (J.Org.Chem.Vol.56, P.204 (1991)) H from a compound of formula R3 (2) obtained.

R3是CF3或CF2H的式(2)化合物可以于-78℃用金属化试剂,随后用三氟乙酸或二氟乙酸处理式(10)化合物的方法制得(Nad等,Izvest,(1959)P71;Chem.Abstr.Vol.53,No.14977;及Vol.53,No.17933(1959))。 R3 is CF3 or CF2H of formula (2) can be at -78 deg.] C with a metal reagent, and then prepared compound with trifluoroacetic acid or difluoro acetic acid of formula (10) to give (Nad et, Izvest, (1959) P71 ; Chem.Abstr.Vol.53, No.14977; and Vol.53, No.17933 (1959)).

R3是CH2F的式(2)化合物可按照Rozen等人的方法(Synthesis(6)665(1985)),通过处理R3是CH3的式(2)化合物制备。 R3 is CH2F of a compound of formula (2) in accordance with the method of Rozen et al (Synthesis (6) 665 (1985)), R3 is prepared by treating a compound of formula (2) is a CH3.

对于X是S(O)mR12及m是0或1的化合物,最终化合物是在合成步骤中的适当的CONH2部分经脱水成为氰基以后,通过在本领域技术人员已知的条件下氧化中间体-SR12,而由-SR12部分制备的。 For X is S (O) mR12, and m is 0 or 1, a compound, the final compound is suitable CONH2 portion after the synthesis step cyano become dehydrated, by oxidation under the present conditions known to those skilled Intermediate -SR12, prepared from -SR12 portion. 对于其中X和/或X3是Br,I,硝基,氨基或甲酰氨基的化合物,这些化合物的合成是通过任何上述步骤,使用被适当保护的氨基作为X和/或X3来完成的。 For wherein X and / or X3 is a compound Br, I, nitro, amino or formylamino, these compounds are synthesized by any of the above-described steps, using the suitably protected amino group as X and / or X3 accomplished. 这种保护基是本领域的技术人员已知的并且是充分公开的(Greene,T.,Protective Groups in Organic Synthesis,Wiley Publishers,NY(1981)其内容收编在此作为参考)。 Such protecting groups are known to those skilled in the art and are fully disclosed (Greene, T., Protective Groups in Organic Synthesis, Wiley Publishers, NY (1981) the contents of which incorporated herein by reference). 脱去保护基的氨基然后适当被酰化成甲酰氨基,氧化成NO2,或用本领域技术人员熟知的方法重氮化并取代,得到所需的Br或I取代基。 Removal of amino-protecting group is then appropriately acylated to the formyl group, is oxidized to NO2, or by diazotization methods well known to the skilled person and substituted, Br, or I to give the desired substituents.

适当地处理并保护任何化学官能团,其它式(Ⅰ)化合物的合成可按照类似于上述的方法及实施例部分所述的方法来完成。 Suitably processed and protection of any chemical functionality, synthesis of compounds of the other formula (Ⅰ) may be accomplished according to a method similar to the method described above and in the Examples section.

为了用式(Ⅰ)化合物或其药学上可接受的盐治疗病人和其它哺乳动物,通常要按照标准药物学方法,将其配制成药物组合物。 In order to use a compound of formula (Ⅰ) or a pharmaceutically acceptable salt thereof to treat patients and other mammals, typically according to standard pharmaceutical methods, formulated into a pharmaceutical composition.

式(Ⅰ)化合物及其药学上可接受的盐对于治疗上述指出的疾病能以标准方式给药。 Formula (Ⅰ) and pharmaceutically acceptable salts of the compounds can be administered in standard manner for the treatment of diseases indicated above. 例如口服,非肠道给药,舌下给药,表皮下给药,直肠给药,通过吸入或通过口腔给药。 E.g., oral, parenteral, sublingual administration, rectal administration under the skin, or by inhalation through the mouth.

式(Ⅰ)化合物及其药学上可接受的盐(当口服给药时,它们是有活性的)能配制成糖浆,片剂,胶囊及锭剂。 (Ⅰ) a compound of formula and pharmaceutically acceptable salts thereof (when administered orally, they are active) can be formulated as syrups, tablets, capsules and lozenges. 糖浆制剂通常是该化合物或其盐在液体载体如乙醇,花生油、橄榄油,甘油或水中的悬浮液或溶液,并加入调味剂或着色剂。 A syrup formulation generally a suspension or a liquid carrier such as ethanol, peanut oil, olive oil, glycerine or water the compound or a salt thereof, and adding flavoring or coloring agents. 当组合物是片剂时,可以采用通常制备固体制剂的任何药物载体。 When the composition is a tablet, any pharmaceutical carrier preparing solid formulations generally may be employed. 这些载体的例子包括:硬脂酸镁,白土,滑石粉,明胶,琼脂,果胶,阿拉伯胶,硬脂酸,淀粉,乳糖及蔗糖。 Examples of such carriers include: magnesium stearate, terra alba, talc, gelatin, agar, pectin, acacia, stearic acid, starch, lactose and sucrose. 当组合物是胶囊形式时,任何常用的胶囊化方法都是适用的。 When the composition is in the form of capsules, any conventional method of encapsulation is suitable. 例如,在硬的明胶胶囊壳中,使用上述载体;当组合物被制备成软明胶壳胶囊形式时,可考虑使用制备分散液或悬浮液时通常采用的任何药物载体,例如可将含水树胶,纤维素,硅酸盐或油类加入到软胶囊壳中。 For example, in a hard gelatin capsule shells using the above support; When the composition is prepared in the form of a soft gelatin shell capsule, any pharmaceutical carrier may be considered when preparing dispersions or suspensions generally employed, for example aqueous gums, celluloses, silicates or oils added to a soft capsule shell.

典型的非肠道给药组合物是该化合物或其盐在无菌的水或非水载体中的溶液或悬浮液,上述载体选择性地含有药学上可接受的油类,例如聚乙二醇,聚乙烯吡咯烷酮,卵磷脂,花生油或芝麻油。 Typical parenteral administration the composition is a compound or a salt thereof in a sterile aqueous or non-aqueous carrier in a solution or suspension of the carrier optionally comprises a pharmaceutically acceptable oils, such as polyethylene glycol , polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.

典型的吸入剂形式的组合物可采用溶液,悬浮液或乳液的形式,它们能以干粉形式给药,或采用常规气化剂如二氯二氟甲烷或三氯一氟甲烷的气雾剂形式给药。 Typical compositions for inhalation may take the form of solutions, suspensions or emulsions, they can be administered in the form of a dry powder, or aerosol form using a conventional gasifying agent such as dichlorodifluoromethane or trichlorofluoromethane of administration.

典型的栓剂制剂是式(Ⅰ)化合物或其药学上可接受的盐(当以此种方式给药时,它们是有活性的),并加入粘合剂和/或润滑剂,例如聚合的二元醇,明胶,可可油,其它低熔点植物蜡或脂肪或其它合成的类似物。 The compound or a pharmaceutically acceptable salt thereof typical suppository formulation is of formula (Ⅰ) (when administered in this way, they are active), and adding a binder and / or lubricants such as polymeric di- alcohols, gelatin, cocoa butter, other low melting vegetable waxes or fats or other synthetic analogs.

典型的皮下给药制剂包括常规的水或非水赋形剂,例如乳膏,油膏,洗剂或糊剂,或者是药用的硬膏剂,膏药或药膜的形式。 A typical formulation comprises subcutaneous administration of a conventional aqueous or non-aqueous vehicles, such as creams, ointments, lotions or pastes, or in the form of a pharmaceutical plaster, the plaster or pellicles.

这些组合物的单位剂量形式是优选的,例如片剂,胶囊剂或计量的气雾剂,以便患者可以自己给药。 Unit dosage forms of these compositions are preferred, e.g. an aerosol tablet, capsule or metered, may be administered to the patient himself.

对于口服给药,每个剂量单位适宜含0.001mg-100mg/kg,优选0.01mg-30mg/kg;对于非肠道给药,每个剂量单位适宜含0.001mg-40mg/kg的式(Ⅰ)化合物或其药学上可接受的盐(依游离基底计算)。 For oral administration, each dosage unit contains suitably 0.001mg-100mg / kg, preferably 0.01mg-30mg / kg; For parenteral administration, each dosage unit contains suitably 0.001mg-40mg / kg of Formula (Ⅰ) compound or a pharmaceutically acceptable salt thereof (calculated as the free base). 对于鼻内给药或口服吸入剂,每个剂量单位适宜为每一患者1-400mg,优选每个患者10-200mg。 For intranasal administration or oral inhalation, each dosage unit is suitably 1-400 mg per patient, per patient preferably 10-200mg. 表皮给药制剂适宜含0.01-1.0%的式(Ⅰ)化合物。 Formulations suitable for topical administration containing 0.01 to 1.0% of a compound of formula (Ⅰ). 直肠给药的每个剂量单位适宜含0.01mg-100mg的式(Ⅰ)化合物。 Each dosage unit for rectal administration suitable compounds (Ⅰ) containing 0.01mg-100mg formula.

对于口服给药,日剂量规定适宜为约0.01-40mg/kg的式(Ⅰ)化合物或其药学上可接受的盐(依游离基底计算),对于非肠道给药,日剂量规定适宜为约0.001mg/kg-40mg/kg的式(Ⅰ)化合物或其药学上可接受的盐(依游离基底计算)。 For oral administration, suitable daily dose of a compound from about predetermined 0.01-40mg / kg of Formula (Ⅰ) or a pharmaceutically acceptable salt thereof (calculated as the free base) for parenteral administration, the daily dose is suitably from about predetermined the compound or a pharmaceutically acceptable salt thereof 0.001mg / kg-40mg / kg of formula (ⅰ) (calculated as the free base). 对于鼻内给药及口腔内吸入给药,日剂量规定适宜为约10-1200mg/每个患者。 For intranasal administration and inhalation administration orally, a daily dosage of about predetermined 10-1200mg / suitable to each patient. 活性组份可每日给药1-6次,即足以表现出抗炎活性。 The active ingredient may be administered 1 to 6 times a day, sufficient to exhibit antiinflammatory activity. 假如作为TNF抑制剂使用,活性组份以足以抑制产生TNF的量给药,以便其达到足以改善或预防疾病的正常或稍低于正常的水平。 If used as a TNF inhibitor, the active ingredient administered in an amount sufficient to inhibit the production of TNF, so that sufficient to ameliorate or prevent normal or slightly below normal levels diseases.

式(Ⅰ)化合物作为PDE IV抑制剂的生物学活性用以下试验说明。 The compounds of formula (Ⅰ) as the biological activity of PDE IV inhibitors is illustrated by the following tests.

式(Ⅰ)化合物对PDE IV的抑制作用Ⅰ PDE同功酶的离析用一组五种不同的PDE同功酶测定化合物的磷酸二酯酶抑制活性和选择性。 The compounds of formula (Ⅰ) isolated PDE IV to PDE isoenzyme inhibition Ⅰ enzyme phosphodiesterase assay compound with a different set of five kinds of PDE isoenzyme inhibiting activity and selectivity. 这些PDEs的特性见表1。 Table 1 characteristics of these PDEs. 各种同功酶取自下述组织:1)PDE Ia,犬的气管肌;2)PDE Ib,猪的主动脉;3)PDE Ic,几内亚猪的心脏;4)PDE III,几内亚猪的心脏;及5)PDE IV,人体单核细胞。 Various isoenzymes from the following tissues: 1) PDE Ia, canine tracheal muscle; 2) PDE Ib, porcine aorta; 3) PDE Ic, guinea pig heart; 4) PDE III, guinea pig heart ; and 5) PDE IV, human monocytes. PDE Ia,Ib,Ic和Ⅲ部分地用标准色谱技术提纯(Torphy and Cieslinski,Mol.Pharmacol.37:206-214,1990);PDE IV是通过连续采用阴离子交换及肝素-Sepharose层析法(Torphy等,J.Biol.Chem.,267:1798-1804,1992)提纯的,使达到动力学均一性。 PDE Ia, Ib, Ic and Ⅲ partially purified using standard chromatographic techniques (Torphy and Cieslinski, Mol.Pharmacol.37: 206-214,1990); PDE IV by successive anion exchange chromatography and heparin -Sepharose (Torphy etc., J.Biol.Chem, 267:. 1798-1804,1992) purified the kinetics reach homogeneity.

表1 PED同功酶的特性aPeak 同功酶 Km(mM)cAMP cGMPⅠa cGMP-特异的 135 4Ⅰb Ca2+/钙调蛋白质- 50 5刺激的Ⅰc Ca2+/钙调蛋白质- 1 2刺激的Ⅲ cGMP-抑制的 0.4 8Ⅳ Ro 20-1724-抑制的 4 38 Table 1 PED isozymes characteristic aPeak isozyme Km (mM) cAMP cGMPⅠa cGMP- specific 135 4Ⅰb Ca2 + / calmodulin protein --505 stimulated Ⅰc Ca2 + / calmodulin protein - 1 2 stimulated Ⅲ cGMP- inhibited 0.4 8Ⅳ Ro 20-1724- 438 suppression

a 数据摘自Torphy和Cieslinski,同上; a data is extracted from Torphy and Cieslinski, supra;

b 术语来自Beavo,Adv.Second Messenger Phosphoprotein Res.22:1-38,1988Ⅱ PDE试验如Torphy和Cieslinski所述方法(Mol.Pharmacol.37:206-214,1990)检测磷酸二酯酶的活性。 The term b from Beavo, Adv.Second Messenger Phosphoprotein Res.22: 1-38,1988Ⅱ PDE Torphy and Cieslinski, such as the test methods: Activity (Mol.Pharmacol.37 206-214,1990) detecting phosphodiesterase. 本发明化合物的IC50值为25nM-500uM。 IC50 value of the compounds of the present invention 25nM-500uM.

Ⅲ 在U-937细胞中cAMP的积累检测选择的PDE IV抑制剂增加完整组织中cAMP蓄集的能力是采用U-937细胞-一种人体单核细胞株,它含有大量的PDE IV。 Ⅲ U-937 cells in cAMP accumulation detecting selected PDE IV inhibitors to increase cAMP accumulation in intact tissues capability set is the use of U-937 cells - one kind of human monocytic cell line, which contains a large amount of PDE IV. 为了检测在完整细胞中PDE IV抑制活性,相同的U-937细胞(nondifferentiated U-937 cells)(大约每个试管105细胞)同各种浓度(0.01-100μM)的PDE抑制剂一起孵化1分钟,并且用1μM前列腺素E2再孵化4分钟。 In intact cells in order to detect PDE IV inhibitory activity, the same U-937 cells (nondifferentiated U-937 cells) (about 105 cells per tube) together with various concentrations Incubation (0.01 to 100) of PDE inhibitors for 1 minute, and treated with 1μM prostaglandin E2 further incubation for 4 minutes. 开始反应后5分钟加入1M碳酸钾使细胞溶解,并用RIA检测cAMP含量。 5 minutes after the start of the reaction was added 1M potassium carbonate cells were lysed and cAMP content was detected by RIA. 该试验的一般方法已被报导(Brooker等,Radioimmunassag of Cyelic AMP and Cyclic GMP,Adv.Cyclic Nucleotide Res.10:1-33,1979)。 General Procedure The tests have been reported (Brooker et, Radioimmunassag of Cyelic AMP and Cyclic GMP, Adv.Cyclic Nucleotide Res.10: 1-33,1979). 数据被表示为两个EC50,用对由10mM试验化合物产生的环戊苯吡酮的最大反应的百分比说明cAMP积蓄的增加。 Data are expressed as two EC50, a percentage of the maximum response to rolipram produced by 10mM test compound indicating an increase in cAMP accumulation. 本发明化合物的EC50值为0.030μM至大于10μM。 EC50 value of the compounds of the present invention is greater than 0.030μM to 10μM.

式(Ⅰ)化合物对TNF产生的抑制作用Ⅰ.在体外试验中,式(Ⅰ)化合物通过人体单核细胞对TNF产生的抑制作用。 Inhibitory effect in vitro, the compound of formula (Ⅰ) on TNF production by human monocytes The compounds of formula (Ⅰ) inhibition of TNF production Ⅰ.

式(Ⅰ)化合物在体外试验中通过人体单核细胞对TNF产生的抑制作用可通过Badger等人及Hanna所述的方法进行测定(EPO公开的申请,0411754A2,1991,2,6;WO 90/15534,1990,12,27)。 Compound (Ⅰ) of formula in vitro by inhibition of human monocytes to produce TNF can be measured (EPO published application, 0411754A2,1991,2,6 Badger et al., And by a method according to Hanna; WO 90 / 15534,1990,12,27).

Ⅱ.体内活性:采用两个内毒素休克模型测定式(Ⅰ)化合物在体内的TNF活性。 Ⅱ activity in vivo: endotoxin shock model was measured using TNF active compound of formula (Ⅰ) in two in vivo. 这些模型中使用的试验方案已经发表(Badger等,EPO公开的申请,0411754A2,1991,2,6;Hanna,WO 90/15534,1990,12,27)。 The protocol used in the model have been published (Badger et, EPO published application, 0411754A2,1991,2,6; Hanna, WO 90 / 15534,1990,12,27).

当按照本发明的方法施用本发明化合物时,未发现不能接受的毒理学效应。 When compounds of the present invention, the method according to the present invention, unacceptable toxicological effects were found.

本发明的化合物用下述实施例说明,但不构成对本发明的限制。 Examples illustrate compounds of the invention by the following embodiments, but not limit the present invention.

实施例1R-(+)-和S-(-)-1-(4-溴代苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮a)3-环戊氧基-4-甲氧基苯甲醛氩气氛、100℃下,将3-羟基-4-甲氧基苯甲醛(40g,0.26mol),碳酸钾(40g,0.29mol)和溴代环戊烷(32ml,0.31mol)于二甲基甲酰胺(0.25l)中的混合物加热。 Example embodiments 1R - (+) - and S - (-) - 1- (4- bromobenzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone a) 3-cyclopentyloxy-4-methoxybenzaldehyde an argon atmosphere at 100 deg.] C, 3-hydroxy-4-methoxybenzaldehyde (40g, 0.26mol), potassium carbonate (40g, 0.29mol) and bromine substituting cyclopentane (32ml, 0.31mol) was heated in the mixture (0.25L) dimethylformamide. 4小时后,再加入另一部分溴代环戊烷(8ml,0.08mol)并继续加热4小时。 After 4 hours, then another portion of bromocyclopentane (8ml, 0.08mol) and continued heating for 4 hours. 使混合物冷却并过滤。 The mixture was cooled and filtered. 减压下将滤液浓缩,使剩余物在乙醚和碳酸钠水溶液之间分配。 The filtrate was concentrated under reduced pressure, the residue was partitioned between diethyl ether and aqueous sodium carbonate. 有机萃取物用碳酸钠水溶液洗涤并干燥(碳酸钾)。 The organic extract was washed with aqueous sodium carbonate and dried (potassium carbonate). 真空下除去溶剂,剩余物用闪式色谱提纯,用2∶1的己烷/乙醚洗脱,得到浅黄色油状物的3-环戊氧基-4-甲氧基苯甲醛(52g,89%)。 The solvent was removed under vacuum, and the residue was purified by flash chromatography, eluting with 2:1 hexane / diethyl ether to give a pale yellow oil of 3-cyclopentyloxy-4-methoxybenzaldehyde (52g, 89% ).

元素分析:C13H16O3计算值:C:70.89;H:7.32实验值:C:70.71;H:7.33b)(3-环戊氧基-4-甲氧基亚苄基)丙二酸二甲酯氩气氛下,将3-环戊氧基-4-甲氧基苯甲醛(22.3g,101mmol),丙二酸二甲酯(17ml,101mmol),哌啶(0.5ml,0.861mmol)和乙酸(0.3ml,0.861mmol)的混合物在苯(50ml)中的溶液在回流下搅拌,共沸除去水。 Elemental analysis for: C13H16O3 Calcd: C: 70.89; H: 7.32 Found: C: 70.71; H: 7.33b) (3- cyclopentyloxy-4-methoxybenzylidene) malonate argon atmosphere, 3- cyclopentyloxy-4-methoxybenzaldehyde (22.3 g, 101 mmol), dimethyl malonate (17ml, 101mmol), piperidine (0.5ml, 0.861mmol) and acetic acid (0.3 the mixture ml, 0.861mmol) was stirred in benzene (solution, 50ml) was refluxed under azeotropic removal of water. 6小时后,真空下除去溶剂,剩余物在乙醚和饱和碳酸钠溶液之间分配并萃取。 After 6 hours, the solvent was removed in vacuo, and the residue was partitioned between ether and extracted with saturated sodium carbonate solution. 将有机萃取物干燥(碳酸钾)并浓缩,得到一橙色油状物的标题化合物(33.5g,100%),不需进一步纯化即可使用。 The organic extract was dried (potassium carbonate) and concentrated to give the title compound as an orange oil (33.5g, 100%), used without further purification.

c)3-氰基-3-(3-环戊氧基-4-甲氧基苯基)丙酸甲酯将(3-环戊氧基-4-甲氧基亚苄基)丙二酸二甲酯(33.5g,101mmol)溶于甲醇(250ml)中,并用氰化钾(6.7g,101mmol)的水溶液(5ml)处理。 c) 3- cyano-3- (3-cyclopentyloxy-4-methoxyphenyl) propanoate (3-cyclopentyloxy-4-methoxybenzylidene) malonate dimethyl ester (33.5g, 101mmol) was dissolved in methanol (250ml) and treated with aqueous potassium cyanide (6.7g, 101mmol) in (5ml). 将混合物加热至回流。 The mixture was heated to reflux. 5小时后,真空下除去溶剂,剩余物在乙醚和碳酸氢钠(5%)间分配并萃取三次。 After 5 hours, the solvent was removed in vacuo, and the residue was partitioned between diethyl ether and extracted three times with sodium bicarbonate (5%). 将有机萃取物干燥(碳酸钾),真空下除去溶剂。 The organic extract was dried (potassium carbonate) and the solvent removed in vacuo. 剩余的油状物经闪式色谱提纯,用25-40%的乙酸乙酯/己烷洗脱,得到白色固体状的标题化合物(13.2g,43%)。 The remaining oil was purified by flash chromatography, eluting with 25-40% ethyl acetate / hexane to give the title compound as a white solid (13.2g, 43%).

d)4-氨基-3-(3-环戊氧基-4-甲氧基苯基)丁酸甲酯将3-氰基-3-(3-环戊氧基-4-甲氧基苯基)丙酸甲酯(6.0g,19.8mmol)和70%的高氯酸(1.95ml)加入到10%钯碳催化剂(0.9g)的甲醇(100ml)悬浮液中。 d) 4- amino-3- (3-cyclopentyloxy-4-methoxyphenyl) butanoate A solution of 3-cyano-3- (3-cyclopentyloxy-4-methoxybenzyl yl) propanoate (6.0g, 19.8mmol) and 70% perchloric acid (1.95ml) was added to 10% palladium on carbon catalyst (0.9 g) in methanol (100ml) suspension. 在50psi压力下将混合物氢化1.5小时,用二氯甲烷稀释,通过硅藻土过滤,然后蒸发。 The mixture was hydrogenated for 1.5 hours at 50psi pressure was diluted with dichloromethane, filtered through Celite, and then evaporated. 剩余物在二氯甲烷和稀的碳酸氢钠水溶液间分配并萃取三次。 And the residue was partitioned between methylene chloride and extracted three times with dilute aqueous sodium bicarbonate. 将有机层干燥(碳酸钾)。 The organic layer was dried (potassium carbonate). 蒸去溶剂后得到胺(6.0g,100%),是一黄色油状物。 After evaporation of the solvent to give the amine (6.0g, 100%), a yellow oil.

e)4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮将4-氨基-3-(3-环戊氧基-4-甲氧基苯基)丁酸甲酯(6.0g,19.8mmol)的甲苯(100ml)溶液和催化量的氰化钠一起回流20小时。 E) 4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone A mixture of 4-amino-3- (3-cyclopentyloxy-4-methoxyphenyl) butanoic acid methyl ester (6.0g, 19.8mmol) in toluene (100ml) was refluxed with a catalytic amount of sodium cyanide and 20 hours. 真空下除去溶剂,令得到的剩余物在二氯甲烷和水间分配并萃取二次。 The solvent was removed in vacuo, and so the residue was partitioned between methylene chloride and extracted twice with water. 将有机层干燥(碳酸钾)并蒸发,得到一固体。 The organic layer was dried (potassium carbonate) and evaporated to give a solid. 经闪式色谱纯化,用95∶5的氯仿/甲醇洗脱得到一固体(3.7g,67%):mp130℃。 Purification by flash chromatography eluting with 95:5 chloroform / methanol to give a solid (3.7g, 67%): mp130 ℃.

f)R-(+)-和S-(-)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮用制备HPLC完成4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮的手性分离,条件是用1.0kg E.Merck三乙酸纤维素(15-25m)装填的8cm×55cm柱,室温下以1g/30ml的量注射,流动相是95∶5乙醇/水,以20ml/分的流速洗脱。 f) R - (+) - and S - (-) - 4- (3- cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone completion of 4- (3-cyclopentyloxy by preparative HPLC 4-methoxyphenyl) -2-pyrrolidinone chiral separation conditions with 1.0kg E.Merck cellulose triacetate (15-25m) column packed 8cm × 55cm, an amount of 1g / 30ml at room temperature injection, the mobile phase 95:5 ethanol / water eluted at 20ml / min flow rate. 在254nm处进行,洗脱物的紫外检测。 Performed at 254nm, UV detection was eluted. S-(+)异构体的保留时间是68分钟,R-(-)异构体的保留时间是86分钟,其回收率分别是88%(>99%ee)和87%(>98%ee)。 S - (+) isomer retention time is 68 minutes, R - (-) isomer retention time of 86 minutes, and the recovery rate was 88% (> 99% ee) and 87% (> 98% ee).

g)R-(+)-和S-(-)-1-(4-溴代苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮在分离反应中,在氩气氛及室温下,用氢化钠(62mg的80%分散体,2.04mmol)将具有手性的4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮(510mg,1.85mmol)的无水二甲基甲酰胺(10ml)溶液处理45分钟。 g) R - (+) - and S - (-) - 1- (4- bromobenzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone in the separation in the reaction, at room temperature under an argon atmosphere and treated with sodium hydride (62 mg of 80% dispersion, 2.04 mmol) having a chiral 4- (3-cyclopentyloxy-4-methoxyphenyl) -2- pyrrolidinone (510mg, 1.85mmol) in anhydrous dimethylformamide (10ml) over 45 minutes. 向混合物中加入对一溴代苄基溴(509mg,2.04mmol)的二甲基甲酰胺(1ml)溶液并搅拌3小时。 Was added (1ml) solution of a-bromo benzyl bromide (509mg, 2.04mmol) in dimethylformamide and the mixture was stirred for 3 hours. 加入水,用乙醚萃取混合物三次。 Water was added, the mixture was extracted three times with ether. 将合并的萃取物干燥(碳酸钾),并真空下除去溶剂。 The combined extracts were dried (potassium carbonate) and the solvent removed in vacuo. 剩余物经闪式色谱纯化,用9∶1的乙醚/二氯甲烷洗脱,得到固体的标题化合物(630mg,76.5%):mp100-102℃。 The residue was purified by flash chromatography, eluting with 9:1 ether / dichloromethane to give the title compound as a solid (630mg, 76.5%): mp100-102 ℃.

元素分析:C23H26NO3Br计算值:C:62.17;H:5.90;N:3.15;Br:17.98实验值:R-(+):C:62.01;H:5.88;N:3.16; Elemental analysis: C23H26NO3Br Calcd: C: 62.17; H: 5.90; N: 3.15; Br: 17.98 Found: R - (+): C: 62.01; H: 5.88; N: 3.16;

S-(-):C.62.14;H.5.96;N.3.16;Br.18.21〔a〕25D(Cl,甲醇)=+50.4℃〔a〕25D(Cl,甲醇)=-48.1℃实施例2 S - (-): C.62.14; H.5.96; N.3.16; Br.18.21 [a] 25D (Cl, methanol) = + 50.4 ℃ [a] 25D (Cl, methanol) = - 48.1 ℃ Example 2

1-苄基-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮氩气氛下,将4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮(689mg,2.5mmol)加入到氢化钠(90mg,3.0mmol的80%分散体,用己烷洗涤过3次)的无水二甲基甲酰胺(12ml)悬浮液中并搅拌。 1-benzyl-4- (3-cyclopentyloxy-4-methoxyphenyl) 2-pyrrolidinone under an atmosphere of argon, 4- (3-cyclopentyloxy-4-methoxyphenyl) 2-pyrrolidinone (689mg, 2.5mmol) was added to a suspension of sodium hydride (90mg, 3.0mmol 80% dispersion, washed 3 times with hexane) in dry dimethylformamide (12ml) and the suspension stirred. 2.5小时后,加入苄基溴(360ml,3.03mmol),并在室温下将反应混合物搅拌16小时。 After 2.5 hours, benzyl bromide (360ml, 3.03mmol), and the reaction mixture was stirred for 16 hours at room temperature. 将水加入到反应混合物中,用二氯甲烷萃取。 Water was added to the reaction mixture, and extracted with dichloromethane. 将有机萃取物干燥(碳酸钾)并浓缩。 The organic extract was dried (potassium carbonate) and concentrated. 经闪式色谱提纯,用9∶1的乙醚/二氯甲烷洗脱,得到浅黄色油状物的标题化合物(548mg,60.0%)。 Purification by flash chromatography, eluting with 9:1 ether / dichloromethane to give the title compound as a pale yellow oil (548mg, 60.0%).

元素分析:C23H27NO3·1/2 H2O计算值:C.73.77;H.7.54;N.3.74实验值:C.73.52;H.7.18;N.3.72。 Elemental analysis: C23H27NO3 · 1/2 H2O Calcd: C.73.77; H.7.54; N.3.74 Found: C.73.52; H.7.18; N.3.72.

实施例31-(4-羧基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮将如实施例1制备的4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮(200mg,0.73mmol)加入到含有15-冠-5醚(100ml)的氢化钠(90mg的80%分散体,3mmol)的无水二甲基甲酰胺(5ml)悬浮液中。 Example 31- (4-carboxybenzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidone 4- (3-cyclopentyloxy-prepared as described in Example 1 4-methoxyphenyl) -2-pyrrolidinone (200mg, 0.73mmol) was added to a suspension of sodium hydride containing 15-crown-5 ether (100ml) of (80% 90mg dispersion, 3mmol) in anhydrous dimethyl formamide (5ml) suspension. 在氩气氛室温下搅拌悬浮液直到气体的放出减慢,然后将其加热到50℃持续5分钟,得到一钠盐溶液。 Was stirred at room temperature under argon gas suspension until it slowed, then heated to 50 deg.] C for 5 minutes to obtain a sodium salt solution. 在另一烧瓶中,将氯代甲基苯甲酸(183mg,1.08mmol)溶于无水四氢呋喃(3ml)中并冷却到-78℃。 In another flask, chloro methylbenzoic acid (183mg, 1.08mmol) was dissolved in dry tetrahydrofuran (3ml) and cooled to -78 ℃. 将正丁基锂(440ml的2.5N溶液,1.08mmol)滴加到酸中并使溶液温热至0℃。 N-Butyl lithium (440ml of 2.5N solution, 1.08mmol) was added dropwise to the acid and the solution was allowed to warm to 0 ℃. 将钠盐溶液慢慢加到酸的锂盐中,并使混合物温热至室温。 The sodium salt solution was slowly added to the lithium salt of the acid, and the mixture was allowed to warm to room temperature. 将得到的溶液倾入冰水中,用3M盐酸酸化,并用二氯甲烷萃取。 The resulting solution was poured into ice water, and extracted with methylene chloride and acidified with 3M hydrochloric acid. 有机萃取物用水洗涤两次并干燥(硫酸钠)。 The organic extracts were washed twice with water and dried (sodium sulfate). 剩余物经闪式色谱提纯,用含有1%乙酸的1∶1的乙醚/二氯甲烷洗脱。 The residue was purified by flash chromatography, eluting with 1:1 ether / methylene chloride containing 1% acetic acid. 用乙醇/乙醚重结晶得到标题化合物(94mg,32%),是一固体:mp173.5-175.5℃。 From ethanol / diethyl ether to obtain the title compound (94mg, 32%), a solid: mp173.5-175.5 ℃.

元素分析:C24H27NO5计算值:C.70.40;H.6.65;N.3.42实验值:C.70.26;H.7.63;N.3.40。 Elemental analysis: C24H27NO5 Calcd: C.70.40; H.6.65; N.3.42 Found: C.70.26; H.7.63; N.3.40.

实施例4S-(-)-1-(4-氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮a)S-(-)-1-(4-硝基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮将如实施例1中制备的S-(+)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮(1.8g,6.5mmol)加入到含有15-冠-5醚(1.28ml)的氢化钠(196mg,6.53mmol的80%分散体)的无水二甲基甲酰胺(65ml)悬浮液中。 Example 4S - (-) - 1- (4- aminobenzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone a) S - (-) - 1- (4-nitrobenzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2- prepared as in Example 1 pyrrolidinone S - (+) - 4- (3- cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone (1.8g, 6.5mmol) was added to sodium (196 mg containing 15-crown-5 ether (1.28 ml) is hydrogenated, 6.53mmol 80% dispersion ) in dry dimethylformamide (65 ml of) the suspension. 在氩气氛室温下将悬浮液搅拌过夜,然后加热到50-60℃持续90分钟,得到一钠盐溶液。 Under an argon atmosphere at room temperature the suspension was stirred overnight, then heated to 50-60 deg.] C for 90 minutes to obtain a sodium salt solution. 将4-硝基苄基溴(2.79g,12.9mmol)溶于无水四氢呋喃(70ml)中并加入钠盐溶液。 A solution of 4-nitrobenzyl bromide (2.79g, 12.9mmol) was dissolved in dry tetrahydrofuran (70ml) and added to a solution of the sodium salt. 将反应混合物搅拌过夜,在真空下除去四氢呋喃。 The reaction mixture was stirred overnight, the tetrahydrofuran was removed in vacuo. 将得到的溶液倾入冰水中,用3M盐酸酸化,并用乙酸乙酯萃取。 The resulting solution was poured into ice water, and extracted with ethyl acetate, acidified with 3M hydrochloric acid. 有机萃取物用水洗涤六次,干燥(硫酸钠)并在真空下蒸发。 The organic extracts were washed six times with water, dried (sodium sulfate) and evaporated in vacuo. 剩余物经两次闪式色谱纯化,第一次用1-2%的甲醇/氯仿洗脱,然后用3∶1的乙酸乙酯/己烷洗脱,得到黄色树脂状的标题化合物(505mg,19%)。 Purification of the residue by flash chromatography twice, first eluting with 1-2% methanol / chloroform and then 3:1 eluting with ethyl acetate / hexanes to give a yellow resin of the title compound (505mg, 19%).

〔a〕25D(0.61,甲醇)=-48.5℃。 [A] 25D (0.61, methanol) = - 48.5 ℃.

b)S-(-)-1-(4-氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮用甲酸铵(1.04g,16.4mmol)和10%钯碳催化剂(127mg)的甲醇(25ml)悬浮液处理S-(-)-1-(4-硝基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮(450mg,1.1mmol)的无水四氢呋喃(9ml)溶液。 b) S - (-) - 1- (4- aminobenzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone with ammonium formate (1.04g, 16.4mmol) methanol (25ml) and 10% palladium on carbon catalyst (127 mg of) treated with a suspension of S - (-) - 1- (4- nitrobenzyl) -4- (3-cyclopentyloxy-4-methoxybenzyl yl) -2-pyrrolidinone (450mg, 1.1mmol) in dry tetrahydrofuran (9ml) was added. 将悬浮液搅拌3小时,然后反应物通过硅藻土过滤,并用甲醇洗涤。 The suspension was stirred for 3 hours and then the reaction was filtered through celite, and washed with methanol. 真空下除去溶剂,剩余物在二氯甲烷和水间分配。 The solvent was removed in vacuo, the residue was partitioned between methylene chloride and water. 萃取后,有机层用水洗涤两次,干燥(碳酸钾)并真空浓缩。 After extraction, the organic layer was washed twice with water, dried (potassium carbonate) and concentrated in vacuo. 树脂状物经闪式色谱提纯,用50-75%的乙酸乙酯/二氯甲烷梯度液洗脱,得到无色树脂状的标题化合物(342mg,81%)。 Resin was purified by flash chromatography, eluting with 50-75% ethyl acetate / dichloromethane gradient to afford the title compound as a colorless resin (342mg, 81%).

元素分析:C23H28N2O3·1/5 H2O计算值:C.71.92;H.7.45;N.7.29实验值:C.71.97;H.7.60;N.7.28〔a〕25D(0.63,甲醇)=-72.5℃。 Elemental analysis: C23H28N2O3 · 1/5 H2O Calcd: C.71.92; H.7.45; N.7.29 Found: C.71.97; H.7.60; N.7.28 [a] 25D (0.63, methanol) = - 72.5 ℃ .

实施例5 Example 5

R-(+)-1-(4-氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮,sb201158a)R-(+)-1-(4-硝基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮将如实施例1中制备的R-(-)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮(1.81mg,6.57mmol)加入到含有15-冠-5醚(1.28ml)的氢化钠(202mg的80%分散体)的无水二甲基甲酰胺(65ml)悬浮液中。 R - (+) - 1- (4- aminobenzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone, sb201158a) R - (+) - 1- ( 4-nitrobenzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone prepared as in Example 1 of R - (-) - 4- (3- ring pentyloxy-4-methoxyphenyl) -2-pyrrolidinone (1.81mg, 6.57mmol) was added to a dry 15-crown-5 ether (1.28 ml) containing sodium hydride (202mg of 80% dispersion) dimethylformamide (65 ml of) the suspension. 在氩气氛室温下将悬浮液搅拌过夜,然后加热到50-60℃持续90分钟,得到一钠盐溶液。 Under an argon atmosphere at room temperature the suspension was stirred overnight, then heated to 50-60 deg.] C for 90 minutes to obtain a sodium salt solution. 将4-硝基苄基溴(2.79g,12.9mmol)溶于无水四氢呋喃(70ml)中,并加入钠盐溶液。 A solution of 4-nitrobenzyl bromide (2.79g, 12.9mmol) was dissolved in dry tetrahydrofuran (70ml) and added a solution of the sodium salt. 将反应混合物搅拌过夜并在真空下除去四氢呋喃。 The reaction mixture was stirred overnight and tetrahydrofuran was removed in vacuo. 将得到的溶液倾入冰水中,用3M盐酸酸化,并用乙酸乙酯萃取。 The resulting solution was poured into ice water, and extracted with ethyl acetate, acidified with 3M hydrochloric acid. 有机萃取物用水洗涤六次,干燥(硫酸钠)并在真空下蒸发。 The organic extracts were washed six times with water, dried (sodium sulfate) and evaporated in vacuo. 剩余物经闪式色谱提纯,用1-3%的甲醇/氯仿洗脱,得到一黄色树脂状物(570mg,21%)。 The residue was purified by flash chromatography, eluting with 1-3% methanol / chloroform to give a yellow resin (570mg, 21%).

〔a〕25D(0.63,甲醇)=+43.8°。 [A] 25D (0.63, methanol) = + 43.8 °.

b)R-(+)-1-(4-氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮用甲酸铵(1.2g,19mmol)和10%钯碳催化剂(120mg)的甲醇(18ml)悬浮液处理R-(+)-1-(4-硝基苄基氨基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮(503mg,1.23mmol)的无水四氢呋喃(6ml)溶液。 b) R - (+) - 1- (4- aminobenzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone with ammonium formate (1.2g, 19mmol) and 10% palladium on carbon catalyst (120 mg of) in methanol (18ml) treated with a suspension R - (+) - 1- (4- nitrobenzyl) -4- (3-cyclopentyloxy-4-methoxybenzyl yl) -2-pyrrolidinone (503mg, 1.23mmol) in dry tetrahydrofuran (6ml) was added. 在氩气氛将悬浮液搅拌2小时。 The suspension was stirred in an argon atmosphere for 2 hours. 反应物通过硅藻土过滤并用甲醇洗涤。 The reaction was filtered through celite and washed with methanol. 真空下除去溶剂,剩余物用冷水处理后用二氯甲烷萃取两次。 The solvent was removed in vacuo, the residue was treated with cold water and extracted twice with dichloromethane. 有机层用水洗涤两次,干燥(碳酸钾)并真空浓缩。 The organic layer was washed twice with water, dried (potassium carbonate) and concentrated in vacuo. 树脂状物经闪式色谱提纯,用50-100%的乙酸乙酯/二氯甲烷梯度液洗脱,得到无色油状物的标题化合物(396mg,82%)。 Resin was purified by flash chromatography, eluting with 50-100% ethyl acetate / dichloromethane gradient to afford the title compound as a colorless oil (396mg, 82%).

元素分析:C23H28N2O3·1/5 H2O计算值:C.71.92;H.7.45;N.7.29实验值:C.71.99;H.7.54;N.7.31。 Elemental analysis: C23H28N2O3 · 1/5 H2O Calcd: C.71.92; H.7.45; N.7.29 Found: C.71.99; H.7.54; N.7.31.

〔a〕25D(0.56,甲醇)=+72.5°。 [A] 25D (0.56, methanol) = + 72.5 °.

实施例61-(4-乙酰氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮在氩气氛下,将4-氨基-3-(3-环戊氧基-4-甲氧基苯基)丁酸甲酯(650mg,2.12mmol)和4-乙酰氨基苯甲醛(346mg,2.12mmol)在氯仿(35ml)中的溶液加热回流30分钟。 Example 61- (4-acetylamino-benzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone Under an argon atmosphere, 4-amino-3- (3- cyclopentyloxy-4-methoxyphenyl) butanoate (650mg, 2.12mmol) and 4-acetylamino-benzaldehyde (346mg, 2.12mmol) in chloroform (35 ml of) was heated at reflux for 30 minutes. 蒸馏出10ml氯仿,补加新鲜的溶剂。 10ml chloroform was distilled off, fed with fresh solvent. 再回流1小时后重复上述过程。 After refluxing for 1 hour and then repeat the process. 将混合物冷却,真空下除去溶剂,将剩余物再溶于四氢呋喃中,并加入无水盐酸的乙醚溶液(1.0M,1.6ml),将溶液蒸发至干,剩余物再溶于无水甲醇中,在冰浴上冷却,并加入氰基硼氢化钠(200mg,3.2mmol)的甲醇溶液。 The mixture was cooled, the solvent was removed in vacuo, the residue was redissolved in tetrahydrofuran, and diethyl ether was added a solution of anhydrous hydrochloric acid (1.0M, 1.6ml), the solution was evaporated to dryness, the residue was redissolved in absolute methanol, was cooled in an ice bath, was added sodium cyanoborohydride (200mg, 3.2mmol) in methanol. 室温下将混合物搅拌2小时,令其在10%乙酸乙酯/乙醚和冰冷却的5%氢氧化钠之间分配,然后将有机层干燥(硫酸钠)。 The mixture was stirred at room temperature for 2 hours, allowed to partitioned between 10% ethyl acetate / ether and ice-cold 5% sodium hydroxide, and the organic layer was dried (sodium sulfate). 真空下除去溶剂,剩余物在乙酸乙酯和水之间分配,并萃取两次。 The solvent was removed, the residue was partitioned between ethyl acetate and water under vacuum and extracted twice. 将有机层干燥(硫酸钠)并蒸发。 The organic layer was dried (sodium sulfate) and evaporated. 经闪式色谱提纯,用0-1%的甲醇/乙酸乙酯洗脱,从乙酸乙酯/乙醚中结晶,得到一灰白色固体状的标题化合物(415mg,46%):mp116-118℃。 Purification by flash chromatography, eluting with 0-1% methanol / ethyl acetate, crystallized from ethyl acetate / ether to give the title compound as an off-white solid (415mg, 46%): mp116-118 ℃.

元素分析:C25H30N2O4·1/8 H2O计算值:C.70.69;H.7.18;N.6.59实验值:C.70.52;H.6.95;N.6.53。 Elemental analysis: C25H30N2O4 · 1/8 H2O Calcd: C.70.69; H.7.18; N.6.59 Found: C.70.52; H.6.95; N.6.53.

实施例7S-(-)-1-(4-乙酰氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮在0℃下,逐滴用乙酸酐(90ml,0.95mmol)处理如实施例4中制备的S-(-)-1-(4-氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮(77mg,0.2mmol)的无水吡啶(3ml)溶液。 Example 7S - (-) - 1- (4- acetylamino-benzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidone at 0 ℃, treated dropwise with B anhydride (90ml, 0.95mmol) prepared in process S as described in Example 4 - (-) - 1- (4-aminobenzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) - 2-pyrrolidinone (77mg, 0.2mmol) in dry pyridine (3ml) was added. 氩气氛下将反应物搅拌过夜,并在真空下除去溶剂。 The reaction was stirred overnight under argon, and the solvent removed in vacuo. 剩余物溶于乙酸乙酯,用冷盐酸,水,5%的碳酸氢钠水溶液洗涤,最后再用水洗涤。 The residue was dissolved in ethyl acetate, washed with cold hydrochloric acid, water, 5% aqueous sodium bicarbonate solution, and finally washed with water. 将有机层干燥(硫酸钠)并真空蒸发,得到的剩余物经闪式色谱提纯,用0-2%的甲醇/乙酸乙酯梯度液洗脱,得到树脂状的标题化合物(85.5mg,100%)。 The organic layer was dried (sodium sulfate) and evaporated in vacuo, the resulting residue was purified by flash chromatography, eluting with methanol / ethyl acetate gradient elution with 0-2%, to give the title compound as a resin (85.5mg, 100% ).

元素分析:C25H30N2O4·1/H2O计算值:C.70.32;H.7.20;N.6.56实验值:C.70.14;H.7.22;N.6.51。 Elemental analysis: C25H30N2O4 · 1 / H2O Calcd: C.70.32; H.7.20; N.6.56 Found: C.70.14; H.7.22; N.6.51.

〔α〕25D(0.49,甲醇)=-56.8℃。 [Α] 25D (0.49, methanol) = - 56.8 ℃.

实施例8 Example 8

R-(+)-1-(4-乙酰氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮在0℃下,逐滴用乙酸酐(125ml,1.3mmol)处理如在实施例5中制备的R-(+)-1-(4-氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮(115mg,0.3mmol)的无水吡啶(3ml)溶液。 R - (+) - 1- (4- acetylamino-benzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidone at 0 ℃, treated dropwise with acetic anhydride ( 125ml, 1.3mmol) prepared in Example 5 treated as R in the embodiment - (+) - 1- (4-aminobenzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2 - pyrrolidinone (115mg, 0.3mmol) in dry pyridine (3ml) was added. 氩气氛下将反应物搅拌过夜,真空下除去溶剂得到剩余物,经闪式色谱提纯,用0-2%的甲醇/乙酸乙酯梯度液洗脱,得到一树脂状的标题化合物(59.5mg,47%)。 The reaction was stirred overnight under argon, the solvent was removed under vacuum to give a residue which was purified by flash chromatography, using 0-2% methanol / ethyl acetate gradient elution, to give a resin of the title compound (59.5 mg, 47%).

元素分析:C25H30N2O4·1/4 H2O计算值:C.70.32;H.7.20;N.6.56实验值:C.70.28;H.7.17;N.6.44。 Elemental analysis: C25H30N2O4 · 1/4 H2O Calcd: C.70.32; H.7.20; N.6.56 Found: C.70.28; H.7.17; N.6.44.

〔α〕25D(0.46,甲醇)=+56.9℃。 [Α] 25D (0.46, methanol) = + 56.9 ℃.

实施例91-〔4-N-(N′-氰基-S-甲基-异硫脲基)苄基〕-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮氩气氛下,将1-(4-氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮(219mg,0.59mmol)和N-氰基二硫代亚氨基碳酸二甲酯(90%,194mg,1.19mmol)的吡啶(2.5ml)溶液加热回流3小时。 Example 91- [4-N- (N'- cyano -S- methyl - isothiourea-yl) benzyl] -4- (3-cyclopentyloxy-4-methoxyphenyl) -2 - pyrrolidone under an atmosphere of argon, 1- (4-aminobenzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone (219mg, 0.59mmol) and N- cyano dithio-imino dimethyl carbonate (90%, 194mg, 1.19mmol) in pyridine (2.5ml) was refluxed for 3 hours. 将混合物冷却,真空下除去溶剂,剩余物经闪式色谱提纯,用40-75%的乙酸乙酯/二氯甲烷洗脱标题化合物,得到浅黄色油状物(139mg,49%)。 The mixture was cooled, the solvent was removed in vacuo, the residue was purified by flash chromatography, eluting with 40-75% ethyl acetate / dichloromethane to afford a pale yellow oil (139mg, 49%).

元素分析:C26H30N4O3S·1/2 H2O计算值:C.64.04;H.6.41;N.11.49;S.6.57实验值:C.64.09;H.6.39;N.11.15;S.6.57。 Elemental analysis: C26H30N4O3S · 1/2 H2O Calcd: C.64.04; H.6.41; N.11.49; S.6.57 Found: C.64.09; H.6.39; N.11.15; S.6.57.

实施例101-〔4-N-(N′-氰基胍基)苄基〕-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮氩气氛下,将1-〔4-N-(N′-氰基-S-甲基-异硫脲基)苄基〕-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮(100mg,0.21mmol)的乙醇溶液用氨饱和并在95℃加热24小时。 Example 101 at [4-N- (N'- cyano-guanidino) benzyl] -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone argon atmosphere, 1 - [4-N- (N'- cyano -S- methyl - isothiourea-yl) benzyl] -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone ( 100mg, 0.21mmol) in ethanol was saturated with ammonia and heated at 95 ℃ 24 hours. 将混合物冷却,真空下除去溶剂,剩余物经闪式色谱提纯,用加有0-5%的甲醇的5%异丙醇/二氯甲烷洗脱,得到玻璃状固体的标题化合物(48.5mg,51.7%)。 The mixture was cooled, the solvent was removed in vacuo, the residue was purified by flash chromatography, supplemented with 0-5% methanol in 5% isopropanol / dichloromethane to give the title compound as a glassy solid (48.5 mg, 51.7%).

元素分析:C25H29N5O3·1/2 CDCl3计算值:C.62.39;H.5.99;N.14.36实验值:C.62.48;H.6.06;N.14.26。 Elemental analysis: C25H29N5O3 · 1/2 CDCl3 calcd: C.62.39; H.5.99; N.14.36 Found: C.62.48; H.6.06; N.14.26.

实施例111-〔4-N-(脲基)苄基〕-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮氩气氛下,逐滴用氰化钠的水溶液(223mg,3.4mmol溶于4ml水中)处理1-(4-氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮(350mg,1.05mmol)的乙酸水溶液(1∶1的冰醋酸/水)。 Example 111- [4-N- (ureido) benzyl] -4- (3-cyclopentyloxy-4-methoxyphenyl) 2-pyrrolidinone under an argon atmosphere was treated dropwise with sodium cyanide aqueous solution (223mg, 3.4mmol was dissolved in 4ml of water) of 1- (4-aminobenzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone (350mg, 1.05mmol) aqueous solution (1:1 glacial acetic acid / water) acetic acid. 室温下搅拌30分钟后,将反应物倾入冰水中,用二氯甲烷萃取,用水洗涤三次并干燥(硫酸钠)。 After stirring at room temperature for 30 minutes, the reaction was poured into ice water, extracted with methylene chloride, washed three times with water and dried (sodium sulfate). 真空下除去溶剂,剩余物经闪式色谱提纯,用含有7-10%甲醇的80%乙酸乙酯/二氯甲烷洗脱,得到固体状的标题化合物,令其从二氯甲烷/乙醚中重结晶(258mg,58%):mp113-115.5℃。 The solvent was removed in vacuo, the residue was purified by flash chromatography, eluting with 80% ethyl acetate / dichloromethane containing 7-10% methanol to afford the title compound as a solid, so that it re from dichloromethane / diethyl ether crystals (258mg, 58%): mp113-115.5 ℃.

元素分析:C24H29N3O4计算值:C.68.06;H.6.90;N.9.92; Elemental analysis: C24H29N3O4 Calcd: C.68.06; N.9.92; H.6.90;

实验值:C.67.70;H.6.89;N.9.95。 Found: C.67.70; H.6.89; N.9.95.

实施例121-(4-二甲基氨基苄基)-4-(3,4-二甲氧基苯基)-2-吡咯烷酮a)氩气氛下,将3,4-二甲氧基苯甲醛(20.0g,120mmol),丙二酸二甲酯(16.4g,120mmol),哌啶(0.3ml,0.517mmol)和乙酸(3.0ml,0.861mmol)的混合物溶于甲苯溶液(100ml),搅拌回流共沸除去水。 Under argon embodiment Example 121- (4-Dimethylamino-benzyl) -4- (3,4-dimethoxyphenyl) -2-pyrrolidinone a), 3,4-dimethoxybenzaldehyde (20.0g, 120mmol), dimethyl malonate (16.4g, 120mmol), a mixture of piperidine (0.3ml, 0.517mmol) and acetic acid (3.0ml, 0.861mmol) was dissolved in toluene (100ml), stirred at reflux azeotropic removal of water. 回流2小时后,于室温下过夜,加入环己烷,将混合物冷却到5℃并过滤。 After refluxing for 2 hours, overnight at room temperature, cyclohexane was added, the mixture was cooled to 5 ℃ and filtered. 从氯仿/己烷中重结晶,得到一固体(11.9g,35%),不需进一步纯化即可使用。 Recrystallized from chloroform / hexane to give a solid (11.9g, 35%), used without further purification.

b)3-氰基-3-(3,4-二甲氧基苯基)丙酸甲酯将(3,4-二甲氧基亚苄基)丙二酸二甲酯(11.7g,42mmol)溶于甲醇(70ml)中,并用氰化钾(2.7g,42mmol)和水(10ml)处理。 b) 3- cyano-3- (3,4-dimethoxyphenyl) propanoate (3,4-methoxybenzylidene) malonate (11.7g, 42mmol ) was dissolved in methanol (70ml) and treated with potassium cyanide (2.7g, 42mmol) and water (10ml). 氩气下将混合物搅拌18小时。 Under argon and the mixture was stirred for 18 hours. 真空下除去溶剂,剩余物在乙醚和碳酸氢钠(5%)间分配,并用乙酸乙酯萃取六次。 The solvent was removed in vacuo, and the residue between ether and sodium bicarbonate (5%) is assigned, and extracted six times with ethyl acetate. 将有机萃取物干燥(硫酸钠),真空下除去溶剂,得到一黄色油状物(3g,29%)。 The organic extracts were dried (sodium sulfate), the solvent was removed in vacuo to give a yellow oil (3g, 29%).

c)4-氨基-3-(3,4-二甲氧基苯基)丁酸甲酯将3-氰基-3-(3,4-二甲氧基苯基)丙酸甲酯(3.0g,12mmol)和70%的高氯酸(1.9g)加入到10%钯碳催化剂(0.6g)的甲醇(100ml)悬浮液中。 c) 4- amino-3- (3,4-dimethoxyphenyl) butanoate 3-cyano-3- (3,4-dimethoxyphenyl) propanoate (3.0 g, 12mmol) and 70% perchloric acid (1.9g) was added methanol (suspension 100ml) and 10% palladium on carbon catalyst (0.6g) in. 50psi压力下将混合物氢化1.25小时,用二氯甲烷稀释,通过硅藻土过滤并蒸发。 The mixture was hydrogenated under 50psi pressure of 1.25 hours, diluted with dichloromethane, filtered through Celite and evaporated. 剩余物在二氯甲烷和稀的碳酸氢钠水溶液间分配,并加入碳酸钠调PH大于9。 The residue was partitioned between methylene chloride and dilute aqueous sodium bicarbonate, and sodium carbonate was added to adjust PH is greater than 9. 水相用二氯甲烷萃取三次,将有机相合并干燥(碳酸钾)。 The aqueous phase was extracted three times with dichloromethane, the organic phases were combined dried (potassium carbonate). 蒸发溶剂后得到一胺(3.0g,100%),是一黄色油状物。 The solvent was evaporated to give an amine (3.0g, 100%) after a yellow oil.

d)1-(4-二甲基氨基苄基)-4-(3,4-二甲氧基苯基)-2-吡咯烷酮氩气氛下,将4-氨基-3-(3,4-二甲氧基苯基)丁酸甲酯(1.0g,4.0mmol)和4-二甲基氨基苯甲醛(0.6g,4.0mmol)的氯仿溶液加热回流,蒸馏出几乎所有的溶剂。 Under d) 1- (4- dimethylamino-benzyl) -4- (3,4-dimethoxyphenyl) -2-pyrrolidone argon atmosphere, 4-amino-3- (3,4- methoxyphenyl) butanoate (1.0g, 4.0mmol) and 4-dimethylaminobenzaldehyde (0.6g, 4.0mmol) in chloroform was heated under reflux, distilling off almost all of the solvent. 再加入氯仿并继续回流,蒸馏出大部分的溶剂。 Chloroform was added and reflux was continued, most of the solvent was distilled off. 将混合物冷却,真空下除去溶剂,将剩余物再溶于四氢呋喃中,加入无水盐酸的乙醚溶液(1.0M,4.0ml)。 The mixture was cooled, the solvent was removed in vacuo, the residue was redissolved in tetrahydrofuran, was added a solution of anhydrous hydrochloric acid in ether (1.0M, 4.0ml). 将溶液蒸发至干,剩余物再溶于无水甲醇中,在冰浴上冷却,并加氰基硼氢化钠(0.5g,8.0mmol)的溶液。 The solution was evaporated to dryness, the residue was redissolved in absolute methanol, cooled in an ice bath, and add sodium cyanoborohydride (0.5g, 8.0mmol) was added. 在0℃时将混合物搅拌1小时,温热至20℃,真空下浓缩,剩余物在25%乙酸乙酯/乙醚和稀的冷的氢氧化钠溶液之间分配。 The mixture was stirred at 0 ℃ 1 h, warmed to 20 ℃, concentrated in vacuo, the residue was partitioned between 25% ethyl acetate / ether and dilute, cold sodium hydroxide solution. 萃取水层,合并了的有机相用水洗涤并干燥(硫酸钠)。 The aqueous layer was extracted, the combined organic phases were washed with water and dried (sodium sulfate). 真空下除去溶剂,将剩余物溶于甲苯并加入催化量的氰化钠,回流7小时。 The solvent was removed in vacuo, the residue was dissolved in toluene and a catalytic amount of sodium cyanide at reflux for 7 hours. 真空下除去溶剂,将剩余物溶于乙酸乙酯中,用水洗涤两次。 The solvent was removed, the residue was dissolved in ethyl acetate, washed twice with water under vacuum. 将有机层干燥(硫酸钠)并蒸发。 The organic layer was dried (sodium sulfate) and evaporated. 经闪式色谱提纯,用75-100%的乙酸乙酯/己烷洗脱,得到树脂状的标题化合物(572mg,40%)。 Purification by flash chromatography, eluting with 75-100% ethyl acetate / hexane, to give the title compound resinous (572mg, 40%).

元素分析:C21H26N2O3·1/3 H2O计算值:C.69.98;H.7.46;N.7.77实验值:C.70.08;H.7.34;N.7.72。 Elemental analysis: C21H26N2O3 · 1/3 H2O Calcd: C.69.98; H.7.46; N.7.77 Found: C.70.08; H.7.34; N.7.72.

实施例131-(4-乙酰氨基苄基)-4-(3,4-二甲氧基苯基)-2-吡咯烷酮氩气氛下,将4-氨基-3-(3,4-二甲氧基苯基)丁酸甲酯(1.01g,4.0mmol)和4-乙酰氨基苯甲醛(0.65g,4.0mmol)的氯仿溶液加热回流2.5小时。 2-pyrrolidone Under an atmosphere of argon Example 131- (4- acetylamino-benzyl) -4- (3,4-dimethoxyphenyl), 4-amino-3- (3,4- phenyl) butanoate (1.01g, 4.0mmol) and 4-acetylamino-benzaldehyde (0.65g, 4.0mmol) in chloroform was heated at reflux for 2.5 hours. 将混合物冷却,真空下除去溶剂,将剩余物再溶于四氢呋喃中并加入无水盐酸的乙醚溶液(1.0M,4.1ml)。 The mixture was cooled, the solvent was removed in vacuo, the residue was redissolved in tetrahydrofuran and anhydrous hydrochloric acid in ether (1.0M, 4.1ml). 将溶液蒸发至干,剩余物再溶于无水甲醇中并加入氰基硼氢化钠(0.50g,8.0mmol)。 The solution was evaporated to dryness, the residue was redissolved in absolute methanol and sodium cyanoborohydride (0.50g, 8.0mmol). 在0℃时将混合物搅拌1小时,温热至20℃,真空浓缩,使剩余物在10%乙酸乙酯/乙醚和稀的冷的氢氧化钠之间分配。 The mixture was stirred at 0 ℃ 1 h, warmed to 20 ℃, concentrated in vacuo and the residue was partitioned between 10% ethyl acetate / ether and dilute, cold sodium hydroxide. 将水层萃取,合并的有机相用水洗涤并干燥(硫酸钠)。 The washed aqueous layer was extracted, the combined organic phases were washed with water and dried (sodium sulfate). 真空下除去溶剂,将剩余物溶于甲苯并加入催化量的氰化钠,回流6小时。 The solvent was removed in vacuo, the residue was dissolved in toluene and a catalytic amount of sodium cyanide and refluxed for 6 hours. 真空下除去溶剂,将剩余物溶于乙酸乙酯,用水洗涤两次。 The solvent was removed, the residue was dissolved in ethyl acetate, washed twice with water under vacuum. 将有机层干燥(硫酸钠)并蒸发。 The organic layer was dried (sodium sulfate) and evaporated. 经闪式色谱提纯,用0.5-8%的甲醇于1∶1乙酸乙酯/氯仿中的梯度液洗脱,得到固体状的标题化合物,其从乙酸乙酯/乙醚中重结晶(445mg,30%):mp88.5-90.5℃。 Purification by flash chromatography, eluting with 0.5-8% methanol / chloroform gradient elution 1:1 in ethyl acetate to give the title compound as a solid, which from ethyl acetate / ether and recrystallized (445mg, 30 %): mp88.5-90.5 ℃.

元素分析:C21H23N2O4·1/2 H2O计算值:C.67.01;H.6.43;N.7.44实验值:C.67.20;H.6.59;N.7.53。 Elemental analysis: C21H23N2O4 · 1/2 H2O Calcd: C.67.01; H.6.43; N.7.44 Found: C.67.20; H.6.59; N.7.53.

实施例141-(4-硝基苄基)-4-(3,4-二甲氧基苯基)-2-吡咯烷酮氩气氛下,将4-氨基-3-(3,4-二甲氧基苯基)丁酸甲酯(1.01g,4.0mmol)和4-硝基苯甲醛(0.60g,4.0mmol)的氯仿溶液加热回流2.5小时。 The following example embodiments 141- (4-nitrobenzyl) -4- (3,4-dimethoxyphenyl) -2-pyrrolidone argon atmosphere, 4-amino-3- (3,4- phenyl) butanoate (1.01g, 4.0mmol) and 4-nitrobenzaldehyde (0.60g, 4.0mmol) in chloroform was heated at reflux for 2.5 hours. 将混合物冷却,真空下除去溶剂,剩余物再溶于四氢呋喃中,并加入无水盐酸的乙醚溶液(1.0M,4ml)。 The mixture was cooled, the solvent was removed in vacuo, the residue was redissolved in tetrahydrofuran, and anhydrous hydrochloric acid in ether (1.0M, 4ml). 将溶液蒸发至干,剩余物再溶于无水甲醇中,在冰浴中冷却,并加入氰基硼氢化钠(0.50g,8.0mmol)的甲醇溶液。 The solution was evaporated to dryness, the residue was redissolved in absolute methanol, chilled in an ice bath, was added sodium cyanoborohydride (0.50g, 8.0mmol) in methanol. 在0℃时将混合物搅拌1小时,温热至20℃,真空浓缩,使剩余物在10%乙酸乙酯/乙醚和稀的冷的氢氧化钠之间分配。 The mixture was stirred at 0 ℃ 1 h, warmed to 20 ℃, concentrated in vacuo and the residue was partitioned between 10% ethyl acetate / ether and dilute, cold sodium hydroxide. 将水层萃取,合并的有机相用水洗涤并干燥(硫酸钠)。 The washed aqueous layer was extracted, the combined organic phases were washed with water and dried (sodium sulfate). 真空下除去溶剂,剩余物经闪式色谱提纯,用40-80%乙酸乙酯/二氯甲烷洗脱,得到固体状的标题化合物(560mg,39%):mp100-101℃。 The solvent was removed in vacuo, the residue was purified by flash chromatography, eluting with 40-80% ethyl acetate / dichloromethane, to give the title compound as a solid (560mg, 39%): mp100-101 ℃.

元素分析:C19H20N2O5计算值:N.7.86实施例151-(4-氨基苄基)-4-(3,4-二甲氧基苯基)-2-吡咯烷酮用甲酸铵(1.06g,16.8mmol)和10%钯碳催化剂(140mg)处理1-(4-硝基苄基)-4-(3,4-二甲氧基苯基)-2-吡咯烷酮(500mg,1.40mmol)的甲醇(20ml)和无水四氢呋喃(10ml)溶液。 Elemental analysis: C19H20N2O5 Calcd: N.7.86 Example 151- (4-aminobenzyl) -4- (3,4-dimethoxyphenyl) -2-pyrrolidone with ammonium formate (1.06g, 16.8mmol) and 10% palladium on carbon catalyst (140 mg of) of 1- (4-nitrobenzyl) -4- (3,4-dimethoxyphenyl) -2-pyrrolidinone (500mg, 1.40mmol) in methanol (20ml) and anhydrous tetrahydrofuran (10ml) was added. 氩气下将悬浮液搅拌2小时。 Under argon suspension was stirred for 2 hours. 然后反应物通过硅藻土过滤并用甲醇洗涤。 The reaction was then filtered through celite and washed with methanol. 真空下除去溶剂,剩余物在二氯甲烷和水间分配。 The solvent was removed in vacuo, the residue was partitioned between methylene chloride and water. 萃取后将有机层干燥(硫酸钠)并真空浓缩,得到标题化合物(303mg,64%)。 After the organic layer was extracted, dried (sodium sulfate) and concentrated in vacuo to give the title compound (303mg, 64%).

元素分析:C19H22N2O3·5/8 H2O计算值:C.67.59;H.6.94;N.8.29实验值:C.67.48;H.6.90;N.8.19。 Elemental analysis: C19H22N2O3 · 5/8 H2O Calcd: C.67.59; H.6.94; N.8.29 Found: C.67.48; H.6.90; N.8.19.

实施例161-(4-二甲基氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮氩气氛下,将4-氨基-3-(3-环戊氧基-4-甲氧基苯基)丁酸甲酯(0.5g,1.5mmol)和4-二甲基氨基苯甲醛(0.27g,1.8mmol)的氯仿溶液加热回流2.5小时。 The following example embodiments 161- (4-Dimethylamino-benzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone argon atmosphere, 4-amino-3- (3 - cyclopentyloxy-4-methoxyphenyl) butanoate (0.5g, 1.5mmol) and 4-dimethylaminobenzaldehyde (0.27g, 1.8mmol) in chloroform was heated at reflux for 2.5 hours. 将混合物冷却,真空下除去溶剂,剩余物再溶于四氢呋喃中,在冰浴中冷却,并加入无水盐酸的乙醚溶液(1.0M,3.8ml)。 The mixture was cooled, the solvent was removed in vacuo, the residue was redissolved in tetrahydrofuran, cooled in an ice bath, and anhydrous hydrochloric acid in ether (1.0M, 3.8ml). 将溶液蒸发至干,剩余物再溶于无水甲醇中,并加入氰基硼氢化钠(0.43g,6.9mmol)。 The solution was evaporated to dryness, the residue was redissolved in absolute methanol, was added sodium cyanoborohydride (0.43g, 6.9mmol). 在0℃时将混合物搅拌3小时,在5℃时搅拌16小时,然后温热至20℃,真空下浓缩,使剩余物在10%乙酸乙酯/乙醚和稀的冷的氢氧化钠之间分配。 The mixture between the residue in 10% ethyl acetate / ether and dilute, cold sodium hydroxide was stirred at 0 ℃ 3 hours, stirred at 5 ℃ 16 hours and then allowed to warm to 20 ℃, concentrated in vacuo, to make distribution. 将水层萃取,合并的有机相用水洗涤并干燥(硫酸钠)。 The washed aqueous layer was extracted, the combined organic phases were washed with water and dried (sodium sulfate). 真空下除去溶剂,将剩余物溶于甲苯并加入催化量的氰化钠,回流过夜。 The solvent was removed in vacuo, the residue was dissolved in toluene and a catalytic amount of sodium cyanide and refluxed overnight. 真空下除去溶剂,将剩余物溶于乙酸乙酯并用水洗涤两次。 The solvent was removed in vacuo, the residue was dissolved in ethyl acetate and washed twice with water. 将有机层干燥(硫酸钠)并蒸发。 The organic layer was dried (sodium sulfate) and evaporated. 经闪式色谱提纯,用67-75%的乙酸乙酯/己烷洗脱,得到树脂状的标题化合物(366mg,60%)。 Purification by flash chromatography, eluting with 67-75% ethyl acetate / hexane, to give the title compound resinous (366mg, 60%).

元素分析:C25H32N2O3·1/4 H2O计算值:C.72.70;H.7.93;N.6.78实验值:C.72.76;H.7.80;N.6.74。 Elemental analysis: C25H32N2O3 · 1/4 H2O Calcd: C.72.70; H.7.93; N.6.78 Found: C.72.76; H.7.80; N.6.74.

实施例171-(4-N-甲酯基脲基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮在0℃下,逐滴用甲基草酰氯(54ml,0.58mmol)处理1-(4-氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮(0.2g,0.53mmol)的无水二氯甲烷和N-甲基吗啉(70ml,0.64mmol)的溶液。 Example 171- (4-N- ureido carbomethoxy) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidone at 0 ℃, treated dropwise with methyl oxalyl chloride (54ml, 0.58mmol) of 1- (4-aminobenzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone (0.2g, 0.53mmol) free dry dichloromethane and N- methylmorpholine (70ml, 0.64mmol) was morpholine. 搅拌过夜后,再加入甲基草酰氯(108ml),令反应混合物在冰冷的碳酸氢钠水溶液和二氯甲烷之间分配,有机相用水洗涤,并在真空下浓缩,得到标题化合物的粗产物固体,将其从乙酸乙酯/乙醚中重结晶(210mg,85%);mp134-136℃。 After stirring overnight, then was added methyl oxalyl chloride (108 ml), the reaction mixture is partitioned between ice cold aqueous sodium bicarbonate and dichloromethane, the organic phase was washed with water, and concentrated in vacuo to give crude solid title compound which was crystallized from ethyl acetate / ether and recrystallized (210mg, 85%); mp134-136 ℃.

元素分析:C26H30N2O6·1/8 H2O计算值:C.66.62;H.6.50;N.5.98实验值:C.66.54;H.6.57;N.5.95。 Elemental analysis: C26H30N2O6 · 1/8 H2O Calcd: C.66.62; H.6.50; N.5.98 Found: C.66.54; H.6.57; N.5.95.

实施例181-(4-羧基脲基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮用粉沫状的氢氧化锂-水合物(26mg,0.6mmol)处理如实施例17中制备的1-(4-N-甲酯基脲基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮(95mg,0.2mmol)的甲醇溶液,并在氩气氛下搅拌1.5小时。 Example 181- embodiment lithium hydroxide (4-carboxy-benzyl-ureido) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone with the pulverulent - monohydrate (26mg, 0.6 mmol) treated as 1- (4-N- methyl-benzyl-ureido group prepared in embodiment 17) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone ( 95mg, 0.2mmol) in methanol and stirred under argon for 1.5 hours. 真空下除去溶剂,将剩余物加入到冰和3N盐酸的混合物中,沉淀出白色固体状的标题化合物(73mg,81%):mp167.5-170℃(分解)。 The solvent was removed in vacuo, the residue was added to a mixture of ice and 3N hydrochloric acid, the precipitated title compound as a white solid (73mg, 81%): mp167.5-170 ℃ (decomposition).

元素分析:C25H28N2O6·5/8 H2O计算值:C.64.75;H.6.36;N.6.04实验值:C.64.83;H.6.43;N.6.02。 Elemental analysis: C25H28N2O6 · 5/8 H2O Calcd: C.64.75; H.6.36; N.6.04 Found: C.64.83; H.6.43; N.6.02.

实施例191-(4-甲基磺酰氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮氩气氛下,逐滴用甲基磺酰氯(60ml,0.79mmol)处理1-(4-氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮(200mg,0.53mmol)的无水吡啶(3ml)溶液,将溶液在60℃加热30分钟,然后回流2小时。 The following example embodiments 191- (4-methylsulfonyl aminobenzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone under argon was treated dropwise with methanesulfonyl chloride ( 60ml, 0.79mmol) of 1- (4-aminobenzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone (200mg, 0.53mmol) in dry pyridine (3ml ) was added, and the solution was heated for 30 minutes at 60 ℃, then refluxed for 2 hours. 使反应物在冰冷的酸水溶液和乙酸乙酯之间分配,并将有机层干燥(硫酸钠)。 The reaction was partitioned between ice cold aqueous acid and ethyl acetate, and the organic layer was dried (sodium sulfate). 真空下除去溶剂,剩余物经闪式色谱提纯,用75-90%的乙酸乙酯/己烷洗脱,得到乳色泡沫状的标题化合物(107mg,44%)。 The solvent was removed in vacuo, the residue was purified by flash chromatography, eluting with 75-90% ethyl acetate / hexane, to give the title compound as a cream-colored foam (107mg, 44%).

元素分析:C24H30N2O2S·1/3 H2O计算值:C.62.05;H.6.65;N.6.03实验值:C.62.11;H.6.62;N.6.04实施例201-(4-甲酯基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮氩气氛室温下,将4-氨基-3-(3-环戊氧基-4-甲氧基苯基)丁酸甲酯(1.57g,4.9mmol)和4-甲酯基苯甲醛(0.82g,5.0mmol)的氯仿溶液搅拌过夜,第二天加热回流2小时。 Elemental analysis: C24H30N2O2S · 1/3 H2O Calcd: C.62.05; H.6.65; N.6.03 Found: C.62.11; H.6.62; N.6.04 Example 201- (4-methyl benzyl) under -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone an argon atmosphere at room temperature, 4-amino-3- (3-cyclopentyloxy-4-methoxyphenyl ) butanoate (1.57g, 4.9mmol) and 4-methyl-benzaldehyde (0.82g, 5.0mmol) in chloroform solution was stirred overnight, refluxed for 2 hours the next day. 将混合物冷却,真空下除去溶剂,将剩余物再溶于四氢呋喃中,并加入无水盐酸的乙醚溶液(1.0M,6.5ml)。 The mixture was cooled, the solvent was removed in vacuo, the residue was redissolved in tetrahydrofuran, and anhydrous hydrochloric acid in ether (1.0M, 6.5ml). 将溶液蒸发至干,剩余物再溶于在冰浴中冷却的无水甲醇中,并加入氰基硼氢化钠(0.47g,7.4mmol)。 The solution was evaporated to dryness, the residue redissolved in an ice-bath cooled anhydrous methanol, was added sodium cyanoborohydride (0.47g, 7.4mmol). 在0℃时将混合物搅拌2小时,5℃时保持16小时,然后温热至20℃,在真空下浓缩,剩余物在二氯甲烷和稀的冷的氢氧化钠之间分配。 The mixture was stirred at 0 ℃ 2 hours for 16 hours 5 ℃, then warmed to 20 ℃, concentrated in vacuo, the residue was partitioned between methylene chloride and dilute, cold sodium hydroxide. 水层用二氯甲烷萃取,合并的有机相用水洗涤并干燥(硫酸钠)。 The aqueous layer was extracted with dichloromethane, washed with water and the combined organic phases were dried (sodium sulfate). 真空下除去溶剂,将剩余物溶于甲苯中加入催化量的氰化钠,回流过夜。 The solvent was removed in vacuo, the residue was dissolved in toluene was added a catalytic amount of sodium cyanide and refluxed overnight. 真空下除去溶剂,将剩余物溶于乙酸乙酯中,用水洗涤两次。 The solvent was removed, the residue was dissolved in ethyl acetate, washed twice with water under vacuum. 将有机层干燥(硫酸钠)并蒸发。 The organic layer was dried (sodium sulfate) and evaporated. 经闪式色谱提纯,用40-75%的乙酸乙酯/己烷洗脱,得到固体状的标题化合物(1.1g,53%):mp98-99℃。 Purification by flash chromatography, eluting with 40-75% ethyl acetate / hexane, to give the title compound as a solid (1.1g, 53%): mp98-99 ℃.

元素分析:C25H29NO5计算值:C.70.90;H.6.90;N.3.31实验值:C.70.69;H.6.89;N.3.35实施例211-(4-甲基磺酰基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮将1-(4-甲硫基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮(0.5g,123mmol)的二氯甲烷溶液冷却到0℃,并用间-氯代过氧苯甲酸(80%,0.43g,2.4mmol)处理。 Elemental analysis: C25H29NO5 Calcd: C.70.90; H.6.90; N.3.31 Found: C.70.69; H.6.89; N.3.35 Example 211- (4-methylsulfonylphenyl) -4- ( 3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone 1- (4-methylthio-benzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) 2-pyrrolidinone (0.5g, 123mmol) in dichloromethane was cooled to 0 ℃, and with m - (, 2.4mmol 80%, 0.43g) chloroperoxybenzoic acid treatment. 氩气氛下将反应物搅拌3.5小时。 The reaction was stirred under argon for 3.5 hours. 反应物用二氯甲烷稀释,并用饱和的碳酸氢钠水溶液洗涤二次,再用水和盐水各洗涤一次。 The reaction was diluted with dichloromethane and washed twice with saturated sodium bicarbonate solution, washed with water and brine once each. 将有机层干燥(碳酸钾),真空下除去溶剂,得到标题化合物(0.5g,92%),该物在真空下呈泡沫状。 The organic layer was dried (potassium carbonate), solvent was removed in vacuo to afford the title compound (0.5g, 92%), as a foam which was under vacuum.

元素分析:C24H29NO5S·1/2 H2O计算值:C.63.69;H.6.68;N.3.09; Elemental analysis: C24H29NO5S · 1/2 H2O Calcd: C.63.69; H.6.68; N.3.09;

S.7.08实验值:C.63.69;H.6.42;N.3.12; S.7.08 Found: C.63.69; H.6.42; N.3.12;

S.6.91。 S.6.91.

实施例221-(3,4-二甲氧基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮氩气氛下,将4-氨基-3-(3-环戊氧基-4-甲氧基苯基)丁酸甲酯(1.5g,4.9mmol)和3,4-二甲氧基苯甲醛(0.85g,5.1mmol)的氯仿溶液加热回流2小时,然后在室温下搅拌过夜。 Example 221- (3,4-dimethoxybenzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) 2-pyrrolidinone under an atmosphere of argon, 4-amino-3- (3-cyclopentyloxy-4-methoxyphenyl) butanoate (1.5g, 4.9mmol) and 3,4-dimethoxybenzaldehyde (0.85g, 5.1mmol) was heated at reflux in chloroform 2 hours and then stirred at room temperature overnight. 真空下除去溶剂,将剩余物再溶于四氢呋喃中,并加入无水盐酸的乙醚溶液(1.0M,5ml)。 The solvent was removed in vacuo, the residue was redissolved in tetrahydrofuran, and anhydrous hydrochloric acid in ether (1.0M, 5ml). 将溶液蒸发至干,剩余物再溶于无水甲醇中,并加入氰基硼氢化钠(0.5g,8.0mmol)。 The solution was evaporated to dryness, the residue was redissolved in absolute methanol, was added sodium cyanoborohydride (0.5g, 8.0mmol). 室温下将混合物搅拌4.5小时,使其在1∶1乙酸乙酯/乙醚和5%的氢氧化钠之间分配,将有机层干燥(硫酸钠)。 The mixture was stirred at room temperature for 4.5 hours and partitioned between 1 ethyl acetate / ether and 5% sodium hydroxide, and the organic layer was dried (sodium sulfate). 真空下除去溶剂,向油状物中加入甲苯和催化量的氰化钠。 The solvent was removed under vacuum, toluene was added and a catalytic amount of sodium cyanide to the oil. 室温下将反应物搅拌过夜,然后加热回流6小时。 The reaction was stirred at room temperature overnight and then heated at reflux for 6 hours. 减压下除去甲苯,剩余的油状物在二氯甲烷和水之间分配。 Toluene was removed under residual oil was partitioned between methylene chloride and water under reduced pressure. 将有机层干燥(硫酸钠)。 The organic layer was dried (sodium sulfate). 剩余物经闪式色谱提纯,用95∶5氯仿/甲醇洗脱,得到油状的标题化合物(1.6g,75%)。 The residue was purified by flash chromatography, eluting with methanol 95:5 chloroform / afford the title compound as an oil (1.6g, 75%).

元素分析:C24H31NO5·1/4 SiO2计算值:C.68.16;H.7.09;N.3.18实验值:C.68.12;H.6.96;N.3.05。 Elemental analysis: C24H31NO5 · 1/4 SiO2 calcd: C.68.16; H.7.09; N.3.18 Found: C.68.12; H.6.96; N.3.05.

实施例231-(4-甲硫基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮氩气氛下,将4-氨基-3-(3-环戊氧基-4-甲氧基苯基)丁酸甲酯(1.5g,4.9mmol)和4-甲硫基苯甲醛(0.78g,5.1mmol)的氯仿溶液加热回流2小时,然后在室温下搅拌过夜。 2-pyrrolidone Under an atmosphere of argon Example 231- (4-methylthio-benzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl), 4-amino-3- (3- cyclopentyloxy-4-methoxyphenyl) butanoate (1.5g, 4.9mmol) and 4-methylthio-benzaldehyde (0.78g, 5.1mmol) in chloroform was refluxed for 2 hours, then at room temperature with stirring overnight. 真空下除去溶剂,将剩余物再溶于四氢呋喃中,并加入无水盐酸的乙醚溶液(1.0M,5ml)。 The solvent was removed in vacuo, the residue was redissolved in tetrahydrofuran, and anhydrous hydrochloric acid in ether (1.0M, 5ml). 将溶液蒸发至干,剩余物再溶于无水甲醇中,并加入氰基硼氢化钠(0.5g,8.0mmol)。 The solution was evaporated to dryness, the residue was redissolved in absolute methanol, was added sodium cyanoborohydride (0.5g, 8.0mmol). 室温下将混合物搅拌4.5小时,使其在1∶1乙酸乙酯/乙醚和5%的氢氧化钠之间分配,并将有机层干燥(硫酸钠)。 The mixture was stirred at room temperature for 4.5 hours, allowed to between 1 ethyl acetate / ether and 5% sodium hydroxide was partitioned, and the organic layer was dried (sodium sulfate). 真空下除去溶剂,向油状物中加入甲苯和催化量的氰化钠。 The solvent was removed under vacuum, toluene was added and a catalytic amount of sodium cyanide to the oil. 将反应物在回流温度下搅拌过夜,然后在室温下搅拌6小时。 The reaction was stirred at reflux temperature overnight and then stirred at room temperature for 6 hours. 减压下除去甲苯,剩余的油状物在二氯甲烷和酸水溶液之间分配,将有机层干燥(硫酸钠)。 Toluene was removed, the remaining oil was partitioned between dichloromethane and an aqueous acid under reduced pressure distribution, and the organic layer was dried (sodium sulfate). 剩余物经闪式色谱提纯,用98∶3的氯仿/甲醇洗脱,得到油状物的标题化合物(1.7g,85%)。 The residue was purified by flash chromatography, eluting with chloroform / methanol 98:3 to give the title compound as an oil (1.7g, 85%).

元素分析:C24H29NO3S·1/4 SiO2计算值:C.67.57;H.6.85;N.3.28实验值:C.67.42;H.6.82;N.3.19。 Elemental analysis: C24H29NO3S · 1/4 SiO2 calcd: C.67.57; H.6.85; N.3.28 Found: C.67.42; H.6.82; N.3.19.

实施例241-(4-甲基亚硫酰基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮氩气氛下,向冰冷却的高碘酸钠(201mg,0.94mmol)和水的溶液中加入1-(4-甲硫基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮(352mg,0.86mmol)的甲醇(8ml)溶液。 2-pyrrolidone Under an atmosphere of argon Example 241- (4-methylsulfinyl-benzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) to ice-cooled sodium periodate (201mg, 0.94mmol) and water solution of 1- (4-methylthio-benzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone (352mg, 0.86 mmol) in methanol (8ml) was added. 使反应混合物温热至室温,然后搅拌过夜。 The reaction mixture was allowed to warm to room temperature and then stirred overnight. 真空下除去溶剂,剩余物在二氯甲烷和水之间分配。 The solvent was removed, the residue was partitioned between methylene chloride and water under vacuum. 并萃取三次。 And extracted three times. 将有机层干燥(碳酸钾),除去溶剂后得到油状的标题化合物(370mg,71%)。 The title compound The organic layer was dried (potassium carbonate) and the solvent removed to give an oil (370mg, 71%).

元素分析:C24H29NO4S·1/4SiO2计算值:C.65.13;H.6.60;N.3.16实验值:C.65.26;H.6.66;N.3.14。 Elemental analysis: C24H29NO4S · 1 / 4SiO2 calcd: C.65.13; H.6.60; N.3.16 Found: C.65.26; H.6.66; N.3.14.

实施例251-(2-乙酰氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮a)1-(2-硝基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮氩气氛下,将4-氨基-3-(3-环戊氧基-4-甲氧基苯基)丁酸甲酯(0.5g,1.65mmol)和2-硝基苯甲醛(0.26g,1.72mmol)的氯仿溶液加热回流9小时。 Example 251- (2-acetylamino-benzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone a) 1- (2- nitrobenzyl) -4- the (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone a solution of 4-amino-3- (3-cyclopentyloxy-4-methoxyphenyl) butanoic acid methyl ester (0.5g, 1.65mmol) and 2-nitrobenzaldehyde (0.26g, 1.72mmol) in chloroform was heated under reflux for 9 hours. 将混合物冷却,真空下除去溶剂,剩余物再溶于四氢呋喃中,并加入无水盐酸的乙醚溶液(1.0M,1.72ml)。 The mixture was cooled, the solvent was removed in vacuo, the residue was redissolved in tetrahydrofuran, and anhydrous hydrochloric acid in ether (1.0M, 1.72ml). 将溶液蒸发至干,剩余物再溶于无水甲醇,用冰浴冷却,并加入氰基硼氢化钠(0.21g,3.3mmol)的甲醇溶液。 The solution was evaporated to dryness, the residue was redissolved in absolute methanol, cooled with an ice bath, was added sodium cyanoborohydride (0.21g, 3.3mmol) in methanol. 混合物在5℃下保持18小时,然后温热至20℃,真空下浓缩,剩余物在含有乙酸乙酯的乙醚和冷的稀氢氧化钠溶液之间分配,并将有机层干燥(碳酸钾)。 The mixture was kept at 5 ℃ 18 hours, then allowed to warm to 20 ℃, concentrated in vacuo, the residue was partitioned between ether containing ethyl acetate and a cold dilute sodium hydroxide solution, and the organic layer was dried (potassium carbonate) . 真空下除去溶剂,剩余物溶于甲苯中,加入催化量的氰化钠,并回流15小时。 The solvent in vacuo, the residue was dissolved in toluene was removed, a catalytic amount of sodium cyanide and refluxed for 15 hours. 真空下除去溶剂,剩余物在乙酸乙酯和水之间分配,有机层用水洗涤两次。 The solvent was removed in vacuo, the residue was partitioned between ethyl acetate and water, the organic layer was washed twice with water. 将有机层干燥(硫酸钠)并蒸发。 The organic layer was dried (sodium sulfate) and evaporated. 剩余物经闪式色谱提纯,用1∶1的乙酸乙酯/己烷洗脱,得到产物(468mg,69%)。 The residue was purified by flash chromatography, / 1:1 eluting with ethyl acetate-hexane to give the product (468mg, 69%).

b)1-(2-氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮用甲酸铵(0.95g,15.1mmol)和10%钯碳催化剂(110mg)处理1-(2-硝基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮(0.47g,1.14mmol)的甲醇(20ml)和无水四氢呋喃(5ml)溶液。 b) 1- (2- aminobenzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone palladium on carbon catalyst is treated with ammonium formate (0.95g, 15.1mmol) and 10% (110 mg) of 1- (2-nitrobenzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone (0.47g, 1.14mmol) in methanol (20ml) and in dry tetrahydrofuran (5ml) was added. 氩气下将悬浮液搅拌18小时。 Under argon suspension was stirred for 18 hours. 然后使反应物通过硅藻土过滤并用甲醇洗涤。 The reaction was then filtered through celite and washed with methanol. 真空下除去溶剂,剩余物在二氯甲烷和冰水之间分配。 The solvent was removed, the residue was partitioned between methylene chloride and ice water under vacuum. 萃取后,有机层用水洗涤,干燥(硫酸钠)并真空浓缩,得到一无色油状物(434mg,100%)c)1-(2-乙酰氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮逐滴用乙酸酐(216ml,2.28mmol)处理冷却到0℃的1-(2-氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮(0.43g,1.14mmol)的无水吡啶溶液。 After extraction, the organic layer was washed with water, dried (sodium sulfate) and concentrated in vacuo to give a colorless oil (434mg, 100%) c) 1- (2- acetylamino-benzyl) -4- (3-oxo-cyclopentyl yl-4-methoxy-phenyl) -2-pyrrolidinone was treated dropwise with cooling to a 1- 0 ℃ (2-aminobenzyl) -4- (3-cyclopentyloxy-treated with acetic anhydride (216ml, 2.28mmol) 4-methoxyphenyl) -2-pyrrolidinone (0.43g, 1.14mmol) in dry pyridine solution. 搅拌过夜后,使反应混合物在冰冷的盐酸水溶液和乙酸乙酯之间分配,将水相萃取,合并的有机层用盐酸水溶液,水和碳酸氢钠水溶液洗涤并干燥(硫酸钠)。 After stirring overnight, the reaction mixture was partitioned between ice cold aqueous hydrochloric acid and ethyl acetate, the aqueous phase was extracted, the organic layers were washed with aqueous hydrochloric acid, aqueous sodium bicarbonate and washed with water and dried (sodium sulfate). 真空下浓缩溶液,得到泡沫状的标题化合物(293mg,60%)。 The title compound (293mg, 60%) the solution was concentrated under vacuum to give a foam.

元素分析:C25H30N2O4计算值:C.70.07;H.7.21;N.6.54实验值:C.70.07;H.7.02;N.6.40。 Elemental analysis: C25H30N2O4 Calcd: C.70.07; H.7.21; N.6.54 Found: C.70.07; H.7.02; N.6.40.

实施例26 Example 26

1-(3-乙酰氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮a)1-(3-硝基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮氩气氛下,将4-氨基-3-(3-环戊氧基-4-甲氧基苯基)丁酸甲酯(0.5g,1.65mmol)和3-硝基苯甲醛(270mg,1.79mmol)的氯仿溶液加热回流9小时。 1- (3-acetylamino-benzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone A) 1- (3-nitrobenzyl) -4- (3 - cyclopentyloxy-4-methoxyphenyl) 2-pyrrolidinone under an atmosphere of argon, 4-amino-3- (3-cyclopentyloxy-4-methoxyphenyl) butyrate ( 0.5g, 1.65mmol) and 3-nitrobenzaldehyde (270mg, 1.79mmol) in chloroform was heated under reflux for 9 hours. 将混合物冷却,真空下除去溶剂,将剩余物再溶于四氢呋喃中,并加入无水盐酸的乙醚溶液(1.0M,1.65ml)。 The mixture was cooled, the solvent was removed in vacuo, the residue was redissolved in tetrahydrofuran, and anhydrous hydrochloric acid in ether (1.0M, 1.65ml). 将溶液蒸发至干,剩余物再溶于无水甲醇中,在冰浴中冷却,并加入氰基硼氢化钠(0.24g,3.8mmol)的甲醇溶液。 The solution was evaporated to dryness, the residue was redissolved in absolute methanol, chilled in an ice bath, was added sodium cyanoborohydride (0.24g, 3.8mmol) in methanol. 将混合物在5℃下保持18小时,然后温热至20℃,真空下浓缩,使剩余物在含有乙酸乙酯的乙醚和冷的稀氢氧化钠溶液之间分配,并将有机层干燥(碳酸钾)。 The mixture was kept at 5 ℃ 18 hours, then allowed to warm to 20 ℃, concentrated in vacuo and the residue partitioned between ether containing ethyl acetate and a cold dilute sodium hydroxide solution, and the organic layer was dried (carbonate potassium). 真空下除去溶剂,将剩余物溶于甲苯中,加入催化量的氰化钠并回流40小时。 The solvent was removed in vacuo, the residue was dissolved in toluene, was added a catalytic amount of sodium cyanide and refluxed for 40 hours. 真空下除去溶剂,剩余物在乙酸乙酯和水之间分配,有机层用水洗涤两次。 The solvent was removed in vacuo, the residue was partitioned between ethyl acetate and water, the organic layer was washed twice with water. 将有机层干燥(硫酸钠)并蒸发。 The organic layer was dried (sodium sulfate) and evaporated. 剩余物经闪式色谱提纯,用40-66%的乙酸乙酯/己烷洗脱,得到黄色油状物(0.44g,64%)。 The residue was purified by flash chromatography, eluting with 40-66% ethyl acetate / hexane to give a yellow oil (0.44g, 64%).

b)1-(3-氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮用甲酸铵(1.0g)和10%钯碳催化剂(110mg)处理1-(3-硝基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮(0.44g,1.06mmol)的甲醇(20ml)和无水四氢呋喃(5ml)的溶液。 b) 1- (3- aminobenzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone with ammonium formate (1.0g) and 10% palladium on carbon (110 mg) of 1- (3-nitrobenzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone (0.44g, 1.06mmol) in methanol (20ml) and anhydrous tetrahydrofuran (5ml) was added. 氩气氛下将悬浮液搅拌2小时。 Under an argon atmosphere and the suspension was stirred for 2 hours. 然后使反应物通过硅藻土过滤并用甲醇洗涤。 The reaction was then filtered through celite and washed with methanol. 真空下除去溶剂,剩余物在二氯甲烷和水之间分配。 The solvent was removed, the residue was partitioned between methylene chloride and water under vacuum. 萃取后,将有机层干燥(硫酸钠)并真空浓缩,得到一无色油状的标题化合物(403mg,100%)。 After extraction, the organic layer was dried (sodium sulfate) and concentrated in vacuo to give the title compound as a colorless oil (403mg, 100%).

c)1-(3-乙酰氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮在0℃下,逐滴用乙酸酐(200ml,2.12mmol)处理1-(3-氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮(0.40g,1.06mmol)的无水吡啶溶液。 c) 1- (3- acetylamino-benzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidone at 0 ℃, dropwise with acetic anhydride (200ml, 2.12mmol ) of 1- (3-aminobenzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone (0.40g, 1.06mmol) in dry pyridine solution. 搅拌过夜后,使反应混合物在冰冷的盐酸水溶液和乙酸乙酯之间分配,将水层萃取,合并的有机层用盐酸水溶液,水和碳酸氢钠水溶液洗涤并干燥(硫酸钠)。 After stirring overnight, the reaction mixture was partitioned between ice cold aqueous hydrochloric acid and ethyl acetate, the aqueous layer was extracted, the organic layers were washed with aqueous hydrochloric acid, water and aqueous sodium bicarbonate and dried (sodium sulfate). 真空下将溶液浓缩,得到固体状的标题化合物(332mg,69%):mp145-146.5℃。 The solution was concentrated in vacuo to afford the title compound as a solid (332mg, 69%): mp145-146.5 ℃.

元素分析:C25H30N2O4·1/8 H2O计算值:C.70.69;H.7.18;N.6.59实验值:C.70.72;H.7.27;N.6.49实施例271-(4-三氟甲基磺酰氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮逐滴用三氟甲磺酸酐(triflic anhydride)(106ml,0.63mmol)处理冷却到-78℃的1-(4-氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮(224mg,0.57mmol)和三乙胺(160ml,1.15mmol)的无水二氯甲烷(4ml)溶液。 Elemental analysis: C25H30N2O4 · 1/8 H2O Calcd: C.70.69; H.7.18; N.6.59 Found: C.70.72; H.7.27; N.6.49 Example 271- (4-trifluoromethylsulfonyloxy aminobenzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone was cooled to -78 and treated dropwise with trifluoromethanesulfonic anhydride (triflic anhydride) (106ml, 0.63mmol) 1- (4-aminobenzyl) ℃ 4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone (224mg, 0.57mmol) and triethylamine (160ml, 1.15mmol) in dry dichloromethane (4ml) was added. 5分钟后,因还有部分原料物,所以再加入一些三氟甲磺酸酐(35ml,0.21mmol)。 After 5 minutes, as well as part of the feed material, some of it is added trifluoromethanesulfonic anhydride (35ml, 0.21mmol). 真空下除去溶剂,使树脂状物在碳酸氢钠水溶液和乙酸乙酯之间分配,并萃取。 The solvent was removed in vacuo, the resin was partitioned between aqueous sodium bicarbonate and ethyl acetate and extracted. 有机层用稀的冷酸水溶液,水洗涤并干燥(硫酸钠)。 The organic layer was washed with dilute cold aqueous acid, water and dried (sodium sulfate). 真空下除去溶剂,剩余物经闪式色谱提纯,用75∶25的乙酸乙酯/己烷洗脱,得到泡沫状的标题化合物(133mg,46%)。 The solvent was removed in vacuo, the residue was purified by flash chromatography, eluting with 75:25 ethyl acetate / hexane, to give the title compound as a foam (133mg, 46%).

元素分析:C24H27N2O5F3S计算值:C.56.24;H.5.31;N.5.47实验值:C.56.54;H.5.62;N.5.47。 Elemental analysis: C24H27N2O5F3S calcd: C.56.24; H.5.31; N.5.47 Found: C.56.54; H.5.62; N.5.47.

实施例281-(4-羧基氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮将1-(4-甲酯基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮(如实施例20中制备,300mg,0.71mmol)的甲醇溶液与氰化钠(13mg,0.27mmol)一起在一个封闭的玻璃弹中被冷却到0℃,然后用氨饱和。 Example 281- (4-carboxy-aminobenzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone 1- (4-carbomethoxy-yl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone (prepared as described in embodiment 20, 300mg, 0.71mmol) in methanol with sodium cyanide (13mg, 0.27mmol) in a closed together glass bomb was cooled to 0 ℃, then saturated with ammonia. 在50-55℃时将反应物慢慢加热6天。 At 50-55 deg.] C the reaction was slowly heated for 6 days. 真空下除去溶剂,得到粗产物,其经闪式色谱提纯,用4-6%的甲醇/二氯甲烷洗脱,得到白色固体状的标题化合物(174mg,60%)mp164-165℃。 The solvent was removed in vacuo to give the crude product, which was purified by flash chromatography, eluting with 4-6% methanol / dichloromethane, to give the title compound as a white solid (174mg, 60%) mp164-165 ℃.

元素分析:C24H28N2O4计算值:C.70.57;H.6.91;N.6.86实验值:C.70.47;H.6.81;N.6.90。 Elemental analysis: C24H28N2O4 Calcd: C.70.57; H.6.91; N.6.86 Found: C.70.47; H.6.81; N.6.90.

实施例291-(2,4-二氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮a)1-(2,4-二硝基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮氩气氛下,将4-氨基-3-(3-环戊氧基-4-甲氧基苯基)丁酸甲酯(1.52g,4.95mmol)和2,4-二硝基苯甲醛(0.98g,5.0mmol)的氯仿溶液加热回流2小时。 Example 291- (2,4-aminobenzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone a) 1- (2,4- dinitro-benzyl under-yl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone a solution of 4-amino-3- (3-cyclopentyloxy-4-methoxybenzyl yl) butanoate (1.52g, 4.95mmol) and 2,4-nitrobenzaldehyde (0.98g, 5.0mmol) in chloroform was refluxed for 2 hours. 将混合物冷却,真空下除去溶剂,剩余物再溶于四氢呋喃中,并加入无水盐酸的乙醚溶液(1.0M,6.5ml)。 The mixture was cooled, the solvent was removed in vacuo, the residue was redissolved in tetrahydrofuran, and anhydrous hydrochloric acid in ether (1.0M, 6.5ml). 将溶液蒸发至干,剩余物再溶于无水甲醇中,然后向这个冷却在冰浴中的溶液中加入氰基硼氢化钠(0.44g,7.0mmol)。 The solution was evaporated to dryness, the residue was redissolved in absolute methanol and sodium cyanoborohydride (0.44g, 7.0mmol) To this solution was cooled in an ice bath was added. 室温下将混合物搅拌15小时,真空下浓缩,使剩余物在含有乙酸乙酯的乙醚和冷的稀氢氧化钠溶液之间分配,并将有机层干燥(碳酸钾)。 The mixture was stirred at room temperature for 15 hours and concentrated in vacuo and the residue partitioned between ether containing ethyl acetate and a cold dilute sodium hydroxide solution, and the organic layer was dried (potassium carbonate). 真空下除去溶剂,剩余物溶于甲苯中,加入催化量的氰化钠,并回流15小时。 The solvent in vacuo, the residue was dissolved in toluene was removed, a catalytic amount of sodium cyanide and refluxed for 15 hours. 真空下除去溶剂,剩余物溶于乙酸乙酯中,并用水洗涤两次。 The solvent was removed in vacuo, the residue was dissolved in ethyl acetate, and washed twice with water. 将有机层干燥(硫酸钠)并蒸发。 The organic layer was dried (sodium sulfate) and evaporated. 剩余物经闪式色谱提纯,用40-60%的乙酸乙酯/己烷洗脱,并从乙酸乙酯中重结晶,得到褐色固体(1.09g,48%):mp125.5-127℃。 The residue was purified by flash chromatography, eluting with 40-60% ethyl acetate / hexanes, and recrystallized from ethyl acetate to give a brown solid (1.09g, 48%): mp125.5-127 ℃.

b)1-(2,4-二氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮用甲酸铵(0.4g)和10%钯碳催化剂(40mg)处理1-(2,4-二硝基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮(0.1g,0.22mmol)的甲醇(7ml)和无水四氢呋喃(2.5ml)溶液,氩气氛下将悬浮液搅拌2小时。 b) 1- (2,4- diamino-benzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone palladium on carbon catalyst (0.4g) and 10% ammonium formate (40mg) of 1- (2,4-nitrobenzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone (0.1g, 0.22mmol) in methanol ( 7ml) and anhydrous tetrahydrofuran (2.5ml) was under argon and the suspension was stirred for 2 hours. 然后使反应物通过硅藻土过滤并用甲醇洗涤。 The reaction was then filtered through celite and washed with methanol. 真空下除去溶剂,剩余物在氯仿和水之间分配。 The solvent was removed in vacuo, the residue was partitioned between chloroform and water. 萃取后,将有机层干燥(碳酸钾)并真空下浓缩。 After extraction, the organic layer was dried (potassium carbonate) and concentrated under vacuum. 剩余物经闪式色谱提纯,用0-2%的甲醇/乙酸乙酯洗脱,得到树脂状的标题化合物(70mg,79%)。 The residue was purified by flash chromatography, eluting with 0-2% methanol / ethyl acetate to give the title compound as a resinous (70mg, 79%).

元素分析:C23H29N3O3·0.29 H2O计算值:C.68.97;H.7.44;N.10.49实验值:C.69.26;H.7.36;N.10.09。 Elemental analysis: C23H29N3O3 · 0.29 H2O Calcd: C.68.97; H.7.44; N.10.49 Found: C.69.26; H.7.36; N.10.09.

实施例301-(4-草酰氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮用氯代甲酸异丁基酯230ml,1.8mmol)处理1-(4-羧基脲基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮(458mg,0.99mmol)的二甲氧基乙二醇和N-甲基吗啉(200ml,1.82mmol)溶液。 Example 301 (4-oxamido-yl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone with isobutyl chloroformate 230ml, 1.8mmol) process 1- (4-carboxy-benzyl-ureido) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone (458mg, 0.99mmol) and ethylene glycol dimethoxy N- methylmorpholine (200ml, 1.82mmol) was added. 在一分离瓶中将液氨(5ml)冷凝,并向其中加入二甲氧基乙二醇(10ml)。 In a separate vial of liquid ammonia (5ml) condensed thereto Dimethoxy glycol (10ml). 向瓶中加入氯代甲酸异丁基酯后约10分钟,再向反应瓶中加入部分氨/乙二醇二甲醚溶液(约2-5ml)。 After addition of isobutyl chloroformate ester To a flask for about 10 minutes to the reaction flask was added part of the ammonia / ethylene glycol dimethyl ether solution (approx. 2-5ml). 45分钟后,真空下除去溶剂,剩余物溶于氯仿中,并用冷的酸水溶液洗涤两次,再用水洗涤两次。 After 45 minutes, the solvent was removed in vacuo, the residue was dissolved in chloroform, and washed twice with cold aqueous acid, and then washed twice with water. 将有机层干燥(硫酸钠)并真空下浓缩,得到一树脂状物,经闪式色谱提纯,用70-100%的乙酸乙酯/二氯甲烷梯度液洗脱,最后用99∶1的乙酸乙酯/甲醇洗脱。 The organic layer was dried (sodium sulfate) and concentrated in vacuo to give a resin which was purified by flash chromatography eluting with 70-100% ethyl acetate / dichloromethane gradient elution, and finally with 99 acetic acid ethyl ester / methanol. 标题化合物(190mg,43%)是一白色固体:mp180-182℃。 The title compound (190mg, 43%) as a white solid: mp180-182 ℃.

元素分析:C25H29N3O5计算值:C.66.50;H.6.47;N.9.31实验值:C.66.66;H.6.47;N.9.57。 Elemental analysis: C25H29N3O5 Calcd: C.66.50; H.6.47; N.9.31 Found: C.66.66; H.6.47; N.9.57.

实施例311-(2,4-二乙酰氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮0℃下,逐滴用乙酸酐(209ml,2.20mmol)处理1-(2,4-二氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮(如实施例29中制备,0.22g,0.55mmol)的无水吡啶溶液。 Example 311- (2,4-acetylamino-benzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) 2-pyrrolidinone at 0 ℃, treated dropwise with acetic anhydride (209ml, 2.20 mmol) of 1- (2,4-aminobenzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone (prepared as in Example 29 in the embodiment, 0.22g, 0.55 mmol) in dry pyridine solution. 搅拌过夜后,反应混合物在冰冷的盐酸水溶液和乙酸乙酯之间分配,将水层萃取,合并的有机层用盐酸水溶液,水和碳酸氢钠水溶液洗涤并干燥(硫酸钠)。 After stirring overnight, the reaction mixture was partitioned between ice cold aqueous hydrochloric acid and ethyl acetate, the aqueous layer was extracted, the organic layers were washed with aqueous hydrochloric acid, aqueous sodium bicarbonate and washed with water and dried (sodium sulfate). 真空下将溶液浓缩,得到一树脂状物,其经闪式色谱提纯,用1∶99的甲醇/乙酸乙酯洗脱,得到树脂状的标题化合物(167mg,63%)。 The solution was concentrated in vacuo to give a resin that was purified by flash chromatography, eluting with 1:99 methanol / ethyl acetate, to give the title compound as a resin (167mg, 63%).

元素分析:C27H33N3O5·1/4 H2O计算值:C.66.99;H.6.98;N.8.68实验值:C.66.73;H.6.93;N.8.52。 Elemental analysis: C27H33N3O5 · 1/4 H2O Calcd: C.66.99; H.6.98; N.8.68 Found: C.66.73; H.6.93; N.8.52.

实施例321-(4-氰基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮氩气氛下,将4-氨基-3-(3-环戊氧基-4-甲氧基苯基)丁酸甲酯(2.1g,6.8mmol)和4-氰基苯甲醛(1.1g,8.2mmol)的氯仿溶液在室温下搅拌72小时,然后加热回流1.25小时。 2-pyrrolidone Under an atmosphere of argon Example 321 (4-cyanobenzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl), 4-amino-3- (3- pentyloxy-4-methoxyphenyl) butanoate (2.1g, 6.8mmol) and 4-cyanobenzaldehyde (1.1g, 8.2mmol) in chloroform was stirred for 72 hours at room temperature and then heated to reflux 1.25 hours. 将混合物冷却,真空下除去溶剂,将剩余物再溶于四氢呋喃中,并加入无水盐酸的乙醚溶液(1.0M,9.0ml)。 The mixture was cooled, the solvent was removed in vacuo, the residue was redissolved in tetrahydrofuran, and anhydrous hydrochloric acid in ether (1.0M, 9.0ml). 将溶液蒸发至干,剩余物再溶于无水甲醇中,并向该冷却到0℃的溶液中加入氰基硼氢化钠(0.6g,9.5mmol)。 The solution was evaporated to dryness, the residue was redissolved in absolute methanol, and the solution was cooled to 0 ℃ was added sodium cyanoborohydride (0.6g, 9.5mmol). 室温下将混合物搅拌过夜,使其在二氯甲烷和稀的冷的氢氧化钠之间分配。 The mixture was stirred overnight at room temperature, partitioned between methylene chloride and dilute, cold sodium hydroxide. 将水层萃取,合并的有机层用水洗涤并干燥(碳酸钾)。 The organic layer was washed aqueous layer was extracted with water, combined and dried (potassium carbonate). 真空下除去溶剂,剩余物溶于乙酸乙酯中,并用水洗涤两次。 The solvent was removed in vacuo, the residue was dissolved in ethyl acetate, and washed twice with water. 将有机层干燥(硫酸钠)并蒸发。 The organic layer was dried (sodium sulfate) and evaporated. 经闪式色谱提纯,用75%的乙酸乙酯/己烷洗脱,得到固体状的标题化合物(1.4g,44%):mp92-93℃。 Purification by flash chromatography, eluting with 75% ethyl acetate / hexane, to give the title compound as a solid (1.4g, 44%): mp92-93 ℃.

元素分析:C24H26N2O3计算值:C.73.82;H.6.71;N.7.17实验值:C.73.78;H.6.95;N.7.12。 Elemental analysis: C24H26N2O3 Calcd: C.73.82; H.6.71; N.7.17 Found: C.73.78; H.6.95; N.7.12.

实施例331-〔4-(1-咪唑基)苄基〕-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮氩气氛下,将4-氨基-3-(3-环戊氧基-4-甲氧基苯基)丁酸甲酯(0.46g,1.4mmol)和4-(1-咪唑基)苯甲醛(0.29g,1.7mmol)的氯仿溶液加热回流1小时。 2-pyrrolidone Under an atmosphere of argon Example 331- [4- (1-imidazolyl) benzyl] -4- (3-cyclopentyloxy-4-methoxyphenyl), 4- amino-3- (3-cyclopentyloxy-4-methoxyphenyl) butanoate (0.46g, 1.4mmol) and 4- (1-imidazolyl) benzaldehyde (0.29g, 1.7mmol) was heated at reflux in chloroform 1 hour. 将混合物冷却,真空下除去溶剂,剩余物再溶于四氢呋喃中,并加入无水盐酸的乙醚溶液(1.0M,2.0mmol)。 The mixture was cooled, the solvent was removed in vacuo, the residue was redissolved in tetrahydrofuran, and anhydrous hydrochloric acid in ether (1.0M, 2.0mmol). 将溶液蒸发至干,剩余物再溶于无水甲醇中,在冰浴中冷却,并加入氰基硼氢化钠(0.15g,2.3mmol)的甲醇溶液。 The solution was evaporated to dryness, the residue was redissolved in absolute methanol, chilled in an ice bath, was added sodium cyanoborohydride (0.15g, 2.3mmol) in methanol. 将混合物温热至20℃持续1.5小时,然后在5℃保持16小时,并真空浓缩。 The mixture was warmed to 20 ℃ for 1.5 hours and then kept at 5 ℃ 16 hours and concentrated in vacuo. 剩余物在二氯甲烷和稀的冷的氢氧化钠之间分配。 The residue was partitioned between methylene chloride and dilute, cold sodium hydroxide. 有机层用水洗涤并干燥(碳酸钾)。 The organic layer was washed with water and dried (potassium carbonate). 浓缩后将剩余物溶于甲苯,加入催化量的氰化钠并回流24小时。 And concentrated. The residue was dissolved in toluene, a catalytic amount of sodium cyanide and refluxed for 24 hours. 真空下除去溶剂,剩余物溶于乙酸乙酸并用水洗涤两次。 The solvent was removed in vacuo and the residue dissolved in ethyl acetate and washed twice with water. 将有机层干燥(硫酸钠)并蒸发。 The organic layer was dried (sodium sulfate) and evaporated. 经连续闪式色谱提纯,先用2-10%甲醇/氯仿的梯度液洗脱,然后用-=2%甲醇于氯仿中的梯度液(用氢氧化铵平衡并经碳酸钾干燥)洗脱,得到脆性树脂状的标题化合物(159mg,26%)。 Continuous by flash chromatography, eluting first with a gradient of 2-10% methanol / chloroform elution, followed by - = 2% methanol gradient in chloroform (dried over potassium carbonate and ammonium hydroxide balance) as eluent, to give a brittle resin of the title compound (159mg, 26%).

元素分析:C26H29N3O3·1/2 H2O计算值:C.70.89;H.6.86;N.9.53实验值:C.70.91;H.7.12;N.9.29。 Elemental analysis: C26H29N3O3 · 1/2 H2O Calcd: C.70.89; H.6.86; N.9.53 Found: C.70.91; H.7.12; N.9.29.

实施例341-(4-羟基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮氩气氛下,将4-氨基-3-(3-环戊氧基-4-甲氧基苯基)丁酸甲酯(2.1g,6.6mmol)和4-羟基苯甲醛(0.94g,7.5mmol)的氯仿溶液加热回流1.5小时。 2-pyrrolidone Under an atmosphere of argon Example 341- (4-hydroxybenzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl), 4-amino-3- (3-cyclopentyl oxy-4-methoxyphenyl) butanoate (2.1g, 6.6mmol) and 4-hydroxybenzaldehyde (0.94g, 7.5mmol) in chloroform was heated at reflux for 1.5 hours. 将混合物冷却,真空下除去溶剂,剩余物再溶于四氢呋喃中,并加入无水盐酸的乙醚溶液(1.0M,7.4ml)。 The mixture was cooled, the solvent was removed in vacuo, the residue was redissolved in tetrahydrofuran, and anhydrous hydrochloric acid in ether (1.0M, 7.4ml). 将溶液蒸发至干,剩余物再溶于无水甲醇中,在冰浴中冷却,并加入氰基硼氢化钠(0.55g,8.7mmol)。 The solution was evaporated to dryness, the residue was redissolved in absolute methanol, chilled in an ice bath, was added sodium cyanoborohydride (0.55g, 8.7mmol). 将混合物温热至室温过夜,真空下浓缩,剩余物在二氯甲烷和稀的冷的氢氧化钠之间分配,有机层用水洗涤并干燥(硫酸钠)。 The mixture was allowed to warm to room temperature overnight, concentrated in vacuo, the residue was partitioned between methylene chloride and dilute, cold sodium hydroxide, the organic layer was washed with water and dried (sodium sulfate). 将剩余物溶于甲苯中,加入催化量的氰化钠并回流1.5小时。 The residue was dissolved in toluene, was added a catalytic amount of sodium cyanide and refluxed for 1.5 hours. 真空下除去溶剂,剩余物溶于二氯甲烷中并用水洗涤两次。 The solvent was removed in vacuo, the residue was dissolved in dichloromethane and washed twice with water. 将有机层干燥(碳酸钾)并蒸发。 The organic layer was dried (potassium carbonate) and evaporated. 经闪式色谱提纯,用50-90%的乙酸乙酯/己烷洗脱,并从乙醚中结晶,得到固体状的标题化合物(934mg,37%):mp118-120℃。 Purification by flash chromatography, eluting with 50-90% ethyl acetate / hexanes, and crystallized from ether to give the title compound as a solid (934mg, 37%): mp118-120 ℃.

元素分析:C23H27NO4计算值:C.72.42;H.7.13;N.3.67实验值:C.72.33;H.7.17;N.3.59。 Elemental analysis: C23H27NO4 Calcd: C.72.42; H.7.13; N.3.67 Found: C.72.33; H.7.17; N.3.59.

实施例351-〔2-(4-氨基苯基)乙酸乙酯基〕-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮a)4-〔N-(4-叔丁氧基羰基氨基-1-乙酯基苄基)氨基〕-3-(3-环戊氧基-4-甲氧基苯基)丁酸甲酯向3-氰基-3-(3-环戊氧基-4-甲氧基苯基)丙酸甲酯(484mg,1.6mmol)的甲醇(20ml)溶液中加入70%的高氯酸(155ml,1.7mmol)和10%的钯碳催化剂(12mg)。 Embodiment Example 351- [2- (4-aminophenyl) ethyl] -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone a) 4- [N- ( 4-tert-butoxycarbonyl-amino-1-ethyl benzyl) amino] -3- (3-cyclopentyloxy-4-methoxyphenyl) butanoate to 3-cyano-3- (3-cyclopentyloxy-4-methoxyphenyl) propanoate (484mg, 1.6mmol) in methanol (20ml) was added 70% perchloric acid (155ml, 1.7mmol) and 10% palladium on carbon catalyst (12mg). 在50psi压力下将得到的混合物氢化2小时,然后通过硅藻土垫板过滤。 Under 50psi pressure resulting mixture was hydrogenated for 2 hours and then filtered through a pad of celite. 真空下将滤液浓缩,使固体剩余物在二氯甲烷和碳酸钠水溶液之间分配,用碳酸氢钠水溶液再洗一遍,将有机层干燥(硫酸钠)。 The filtrate was concentrated in vacuo, the solid residue was partitioned between methylene chloride and aqueous sodium carbonate solution, wash again with aqueous sodium bicarbonate, and the organic layer was dried (sodium sulfate). 真空下除去溶剂,将剩余物溶于二甲基甲酰胺(5ml)中,并用2-氯代-2-(4-叔丁氧基羰基氨基苯基)乙酸乙酯(503mg,1.6mmol),碘化钠(240mg,0.32mmol)和三乙胺(225ml,1.6mmol)处理。 The solvent was removed in vacuo, the residue was dissolved in dimethylformamide (5ml) and treated with 2-chloro-2- (4-tert-butoxycarbonyl-aminophenyl) acetate (503mg, 1.6mmol), sodium iodide (240mg, 0.32mmol) and triethylamine (225ml, 1.6mmol) process. 氩气氛室温下搅拌1小时后,剩余物在乙醚和水之间分配,并萃取几次。 After stirring under an argon atmosphere at room temperature for 1 hour and the residue between ether and water, and extracted several times. 将有机萃取物干燥(硫酸镁)并蒸发。 The organic extracts were dried (magnesium sulfate) and evaporated. 经闪式色谱提纯,用3∶7的乙酸乙酯/己烷洗脱,得到产物(718mg,77%)。 Purification by flash chromatography, eluting with 3:7 ethyl acetate / hexane, to give the product (718mg, 77%).

b)1-〔2-(4-叔丁氧基羰基氨基苯基)乙酸乙酯基〕-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮用催化量的氰化钠和二甲基氨基吡啶(378mg,3.1mmol)处理4-〔N-(4-叔丁氧基羰基氨基-1-乙酯基苄基)氨基〕-3-(3-环戊氧基-4-甲氧基苯基)丁酸甲酯(1.8g,309mmol)的二甲基甲酰胺(30ml)溶液,并在95-100℃下加热20小时。 b) 1- [2- (4-tert-butoxycarbonyl-aminophenyl) ethyl] -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone with a catalytic amount of sodium cyanide and dimethylaminopyridine (378mg, 3.1mmol) treating 4- [N- (4- tert-butoxycarbonylamino-l-yl methacrylate benzyl) amino] -3- (3-cyclopentyl oxy-4-methoxyphenyl) butanoate (1.8g, 309mmol) in dimethylformamide (30ml) was added and heated at 95-100 ℃ 20 hours. 使反应混合物在乙醚和水之间分配几次,将有机萃取物干燥(硫酸镁)并蒸发。 Reaction mixture was partitioned between ether and water several times, and the organic extracts were dried (magnesium sulfate) and evaporated. 经闪式色谱提纯,用4∶6的乙酸乙酯/己烷洗脱,得到黄色泡沫体(840mg,49%)。 Purification by flash chromatography, eluting with 4/6 ethyl acetate / hexane, to give a yellow foam (840mg, 49%).

c)1-〔2-(4-氨基苯基)乙酸乙酯基〕-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮将1-〔2-(4-叔丁氧基羰基氨基苯基)乙酸乙酯基〕-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮(920mg,1.67mmol)的二氯甲烷(20ml)溶液冷却到0℃,用三氟乙酸(20ml)处理,并在室温下搅拌24小时。 c) 1- [2- (4-aminophenyl) ethyl] -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidone 1- [2- (4 - tert-butoxycarbonyl-aminophenyl) ethyl] -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone (920mg, 1.67mmol) in dichloromethane (20ml ) was cooled to 0 ℃, treated with trifluoroacetic acid (20ml), and stirred at room temperature for 24 hours. 加入固体碳酸氢钠使反应停止,令反应混合物在二氯甲烷和水之间分配。 Solid sodium bicarbonate was added to stop the reaction, the reaction mixture was partitioned between methylene chloride and water. 将有机萃取物干燥(碳酸钾)并蒸发。 The organic extract was dried (potassium carbonate) and evaporated. 经闪式色谱提纯,用4∶6的乙酸乙酯/己烷洗脱,得到产物(647mg,86%)。 Purification by flash chromatography, eluting with 4/6 ethyl acetate / hexane, to give the product (647mg, 86%).

元素分析:C26H32N2O5·1 H2O计算值:C.66.36;H.7.28;N.5.95实验值:C.66.11;H.6.89;N.5.66。 Elemental analysis: C26H32N2O5 · 1 H2O Calcd: C.66.36; H.7.28; N.5.95 Found: C.66.11; H.6.89; N.5.66.

实施例361-〔2-(4-乙酰氨基苯基)乙酸乙酯基〕-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮逐滴用乙酸酐(35ml,0.36mmol)的二氯甲烷(1ml)和吡啶(3滴)的溶液处理1-〔2-(4-氨基苯基)乙酸乙酯基〕-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮(53.4mg,0.12mmol)的二氯甲烷(0.25ml)溶液。 Example 361- [2- (4-acetamidophenyl) ethyl] -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone was treated dropwise with acetic anhydride (35ml embodiment , (1ml) and pyridine (3 drops) was 0.36 mmol) in methylene chloride 1- [2- (4-aminophenyl) ethyl] -4- (3-cyclopentyloxy-4 methoxyphenyl) -2-pyrrolidinone (53.4mg, 0.12mmol) in dichloromethane (0.25 ml of) solution. 氩气氛下搅拌3小时后,反应混合物经闪式色谱提纯,用7∶3的乙酸乙酯/己烷洗脱,得到油状物的标题化合物(55.1mg,94%)。 After stirring under an argon atmosphere for 3 hours, the reaction mixture was purified by flash chromatography, eluting with 7:3 ethyl acetate / hexane, to give the title compound as an oil (55.1mg, 94%).

元素分析:C28H34N2O6计算值:C.68.00;H.6.93;N.5.66实验值:C.67.91;H.7.18;N.5.54。 Elemental analysis: C28H34N2O6 Calcd: C.68.00; H.6.93; N.5.66 Found: C.67.91; H.7.18; N.5.54.

实施例371-〔2-(4-乙酰氨基苯基)乙酸〕-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮用氢氧化锂-水合物(55mg,1.29mmol)处理1-〔2-(4-氨基苯基)乙酸乙酯基〕-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮(212mg,0.43mmol)的乙醇(5ml)溶液,并搅拌1小时。 Example 371- [2- (4-acetamidophenyl) acetate] -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone with lithium hydroxide - hydrate (55mg, 1.29 mmol) of 1- [2- (4-aminophenyl) ethyl] -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone (212mg, 0.43mmol) in ethanol (5ml) was added and stirred for 1 hour. 真空下除去溶剂,树脂状物溶于水中,并用10%的盐酸水溶液酸化。 The solvent was removed in vacuo, the resin was dissolved in water and acidified with 10% aqueous hydrochloric acid. 用95∶5的二氯甲烷/甲醇萃取产物,将有机层干燥(硫酸镁)并蒸发,得到标题化合物(174mg,88%)。 95:5 with dichloromethane / methanol product was extracted and the organic layer was dried (magnesium sulfate) and evaporated to give the title compound (174mg, 88%).

元素分析:C26H30N2O6·3/8 H2O计算值:C.65.98;H.6.55;N.5.92实验值:C.65.94;H.6.54;N.5.79。 Elemental analysis: C26H30N2O6 · 3/8 H2O Calcd: C.65.98; H.6.55; N.5.92 Found: C.65.94; H.6.54; N.5.79.

实施例381-(4-氨基硫代羰基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮将1-(4-氰基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮(如实施例32中制备,850mg,2.18mmol)的甲醇(25ml)溶液置于一高压容器中,用亚硫酸铵(15ml,53mmol的23.9%溶液)处理。 Example 381 (4-benzyl-thio-carbonyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone 1- (4-cyanobenzyl) -4 - (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone (prepared as in Example 32, 850mg, 2.18mmol) in methanol (25ml) was placed in a pressure vessel, with sulfurous acid ammonium (15ml, 53mmol of 23.9% solution). 将容器封闭,并在65-75℃下将反应物搅拌1小时。 The vessel was sealed, and the reaction was stirred at 65-75 ℃ 1 hour. 真空下将反应混合物浓缩,加入水,并用二氯甲烷将水相萃取三次。 The reaction mixture was concentrated in vacuo, water was added, and the aqueous phase was extracted with dichloromethane three times. 萃取物用水洗涤两次,干燥(硫酸钠)并蒸发,得到一黄色剩余物。 The extract was washed twice with water, dried (sodium sulfate) and evaporated to give a yellow residue. 该物用乙醇/水结晶。 This was crystallized from ethanol / water. 经闪式色谱提纯,用60-75%的乙酸乙酯/二氯甲烷洗脱,然后再从乙酸乙酯/乙醚中结晶,得到黄色固体(682mg,74%):mp85.5-87.5℃。 Purification by flash chromatography, eluting with 60-75% ethyl acetate / dichloromethane and then recrystallized from ethyl acetate / diethyl ether to give a yellow solid (682mg, 74%): mp85.5-87.5 ℃.

元素分析:C25H28N2O3S计算值:C.67.90;H.6.65;N.6.60实验值:C.67.63;H.6.81;N.6.38。 Elemental analysis: C25H28N2O3S Calcd: C.67.90; H.6.65; N.6.60 Found: C.67.63; H.6.81; N.6.38.

实施例391-(4-甲硫基碳酰亚氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮氢碘化物用甲基碘(100ml,1.61mmol)处理1-(4-氨基硫代羰基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮(由实施例38制备,290mg,0.68mmol)的丙酮(4ml)溶液。 Embodiment Example 391- (4-methylthio-imino carbonyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidone with hydrogen iodide, methyl iodide (100ml, 1.61 mmol) of 1- (4-amino-thiocarbonyl benzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone (prepared as in Example 38, 290mg, 0.68mmol ) in acetone (4ml) was added. 将反应物封闭,并在室温下搅拌18小时。 The reaction was sealed and stirred at room temperature for 18 hours. 加入乙醚,以形成乳色固体,过滤分离出该固体并用乙醚洗涤(336mg,87%):mp170-172℃。 Ether was added to form a cream-colored solid, the solid was isolated by filtration and washed with ether (336mg, 87%) with: mp170-172 ℃.

元素分析:C25H30N2O3S·HI计算值:C.53.01;H.5.52;N.4.95实验值:C.52.99;H.5.51;N.4.68。 Elemental analysis: C25H30N2O3S · HI Calculated: C.53.01; H.5.52; N.4.95 Found: C.52.99; H.5.51; N.4.68.

实施例401-(4-甲脒鎓苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮乙酸盐在氩气氛、90-95℃下,将1-(4-甲硫基碳酰亚氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮氢碘化物(如实施例39中制备,350mg,0.62mmol)和乙酸铵(151mg,1.95mmol)的乙醇(1.8ml)悬浮液加热1小时。 , The Example 401 (4-amidinium benzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone acetate 90-95 deg.] C in an argon atmosphere, to 1- (4-methylthio-imino carbonyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone hydroiodide (prepared as in Example 39, 350mg , 0.62mmol) and ammonium acetate (151mg, 1.95mmol) in ethanol (1.8ml) was heated for 1 hour. 使反应混合物冷却,收集白色晶体并依次用甲醇和乙醚洗涤(234mg,78%):mp186-188℃。 The reaction mixture was cooled and white crystals were collected and washed with methanol and diethyl ether (234mg, 78%) with: mp186-188 ℃.

元素分析:C24H29N3O3·C2H4O·H2O计算值:C.64.31;H.7.26;N.8.65实验值:C.64.63;H.7.32;N.8.56。 Elemental analysis: C24H29N3O3 · C2H4O · H2O Calcd: C.64.31; H.7.26; N.8.65 Found: C.64.63; H.7.32; N.8.56.

实施例41 Example 41

1-〔4-(2-咪唑基)苄基〕-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮用10%的氢氧化钠和冰处理实施例40的1-(4-甲脒鎓苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮乙酸盐(183mg,0.38mmol)的氯仿溶液。 1- [4- (2-imidazolyl) benzyl] -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-Example 40 10% sodium hydroxide and ice handling pyrrolidinone 1- (4-amidinium benzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone acetate (183mg, 0.38mmol) in chloroform. 混合物用氯仿萃取,将有机层干燥(碳酸钾)并蒸发,得到剩余物甲脒。 The mixture was extracted with chloroform, and the organic layer was dried (potassium carbonate) and evaporated to give a residue formamidine. 氩气氛下将该剩余物溶于氯仿(20ml)中,并用氯代乙醛(113ml,0.28mmol的50%水溶液)和三乙胺(119ml,0.86mmol)处理,将混合物加热回流5小时,然后在室温下搅拌86小时。 The residue was dissolved under argon in chloroform (20ml) and treated with chloroacetaldehyde (113ml, 0.28mmol 50% aqueous solution) and triethylamine (119ml, 0.86mmol), and the mixture was heated at reflux for 5 hours, then It was stirred at room temperature for 86 hours. 真空下除去溶剂,剩余物经闪式色谱提纯,用0.5-1%的甲醇/氯仿洗脱。 The solvent was removed in vacuo, the residue was purified by flash chromatography eluting with 0.5-1% methanol / chloroform. 将剩余物溶于乙酸乙酯/乙醇中,并用冷的10%盐酸水溶液萃取。 The residue was dissolved in ethyl acetate / ethanol and extracted with cold 10% aqueous hydrochloric acid. 酸萃取物用乙酸乙酯洗涤4次,用碳酸钠水溶液使水层呈碱性,并用二氯甲烷萃取三次。 Acid extracts were washed 4 times with ethyl acetate, the aqueous layer with aqueous sodium carbonate solution was made basic, and extracted three times with dichloromethane. 将合并的二氯甲烷相干燥(碳酸钾)并蒸发,得到脆性树脂状物(44mg,27%)。 The combined dichloromethane phases were dried (potassium carbonate) and evaporated to give a brittle resin was (44mg, 27%).

元素分析:C26H29N3O3·1/2 H2O计算值:C.70.89;H.6.86;N.9.54实验值:C.70.95;H.6.75;N.9.21。 Elemental analysis: C26H29N3O3 · 1/2 H2O Calcd: C.70.89; H.6.86; N.9.54 Found: C.70.95; H.6.75; N.9.21.

实施例421-(4-二甲基氨基羰基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮氩气氛下,逐滴加入N-甲基吗啉(112ml,1.02mmol)处理实施例3的1-(4-羧基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮(225mg,0.62mmol)的四氢呋喃(15ml)溶液。 Example 421- (4-methylaminocarbonyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) 2-pyrrolidinone under an argon atmosphere, was added dropwise N- methylmorpholine morpholine (112ml, 1.02mmol) of 1- (4-carboxybenzyl) Example 3 4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone (225mg, 0.62mmol) in tetrahydrofuran (15ml) was added. 在第二个烧瓶中,使二甲胺(15ml)鼓泡进入-78℃的无水四氢呋喃溶液(15ml)中。 In a second flask, dimethylamine (15ml) was bubbled into anhydrous tetrahydrofuran (15ml) in a -78 deg.] C. 然后在氩气氛下用氯代甲酸异丁基酯(135ml,10.2mmol)处理该酸和N-甲基吗啉溶液,并搅拌7分钟。 Under argon atmosphere and then treating the acid and N- methylmorpholine was treated with isobutyl chloroformate (135ml, 10.2mmol), and stirred for 7 min. 通过套管将混酐悬浮液转移到含有胺的烧瓶中,并移去冷浴。 The mixed anhydride suspension was transferred via cannula to a flask containing the amine and the cold bath was removed. 15分钟后,将反应物在真空下浓缩,并在乙酸乙酯和碳酸钠水溶液之间分配。 After 15 minutes, the reaction was concentrated in vacuo, and partitioned between ethyl acetate and aqueous sodium carbonate. 水相用乙酸乙酯萃取,合并的有机萃取物用水洗涤,干燥(硫酸钠)并蒸发。 The aqueous phase was extracted with ethyl acetate, washed the combined organic extracts were washed with water, dried (sodium sulfate) and evaporated. 经闪式色谱提纯,用4-6%甲醇的乙酸乙酯液洗脱,得到一树脂状物(104mg,38%)。 Purification by flash chromatography, eluting with 4-6% methanol in ethyl acetate to give a resin bar (104mg, 38%).

元素分析:C26H32N2O4·1/5 H2O计算值:C.70.95;H.7.42;N.6.36实验值:C.70.94;H.7.26;N.6.31。 Elemental analysis: C26H32N2O4 · 1/5 H2O Calcd: C.70.95; H.7.42; N.6.36 Found: C.70.94; H.7.26; N.6.31.

实施例431-(4-乙酰氧基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮氩气氛下,0℃时,逐滴加入乙酸酐(160ml,1.7mmol)处理1-(4-羟基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮(如实施例34中制备,239mg,0.63mmol)的吡啶(2ml)溶液并搅拌72小时。 Under Example 431- (4-acetoxy-benzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone A solution when 0 deg.] C, was added dropwise acetic anhydride ( 160ml, 1.7mmol) of 1- (4-hydroxybenzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone (prepared as described in embodiment 34, 239mg, 0.63mmol ) in pyridine (2ml) was added and stirred for 72 hours. 将反应物倾入到冰冷的盐酸水溶液中,用乙酸乙酯萃取两次。 The reaction was poured into ice-cold aqueous hydrochloric acid and extracted twice with ethyl acetate. 有机萃取物用冷的稀盐酸,冷水和冷的碳酸氢钠水溶液洗涤。 The organic extract was washed with cold dilute hydrochloric acid, cold water and cold aqueous sodium bicarbonate. 将萃取物干燥(硫酸钠)并蒸发。 The extracts were dried (sodium sulfate) and evaporated. 经闪式色谱提纯,用60%的乙酸乙酯/己烷洗脱,得到树脂状物(148mg,55.5%)。 Purification by flash chromatography, eluting with 60% ethyl acetate / hexane, to obtain a resin substance (148mg, 55.5%).

元素分析:C25H29NO5计算值:C.70.90;H.6.90;N.3.31实验值:C.70.71;H.7.00;N.3.25。 Elemental analysis: C25H29NO5 Calcd: C.70.90; H.6.90; N.3.31 Found: C.70.71; H.7.00; N.3.25.

实施例441-(4-乙酰氨基-2-氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮a)1-(4-氨基-2-硝基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮和1-(2-氨基-4-硝基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮用亚硫酸铵(共1.67g,23.9%的乙醇溶液,共5.9mmol)分三次处理实施例29的1-(2,4-二硝基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮(426mg,0.94mmol)的乙醇(60ml)悬浮液,每次加完后加热至回流10分钟,接着在室温及氩气氛下搅拌18小时。 Example 441- (4-acetamido-2-aminobenzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone a) 1- (4- amino-2- nitrobenzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone and 1- (2-amino-4-nitrobenzyl) -4- (3- pentyloxy-4-methoxyphenyl) -2-pyrrolidinone (total 1.67g, 23.9% in ethanol, 5.9 mmol total) in three portions treatment Example 29 1- (2,4-alkylene with ammonium nitrobenzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone (426mg, 0.94mmol) in ethanol (60ml) suspension was heated to reflux after each addition 10 minutes, followed by stirring at room temperature under an argon atmosphere for 18 hours. 真空下除去溶剂,剩余物经闪式色谱提纯,用50~60%的乙酸乙酯/己烷洗脱,得到2-氨基-4-硝基异构体(140mg,35%),继续用70-90%的乙酸乙酯/己烷洗脱,得到4-氨基-2-硝基异构体(180mg,45%)。 The solvent was removed in vacuo, the residue was purified by flash chromatography, eluting with 50-60% ethyl acetate / hexane to give 2-amino-4-nitro isomer (140mg, 35%), 70 continue to use -90% ethyl acetate / hexane to give 4-amino-2-nitro isomer (180mg, 45%).

b)1-(4-乙酰氨基-2-硝基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮逐滴用乙酸酐(105ml,1.1mmol)处理冷却到0℃的1-(4-氨基-2-硝基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮(180mg,0.42mmol)的吡啶溶液。 b) 1- (4- acetylamino-2-nitrobenzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone was treated dropwise with acetic anhydride (105ml, 1.1mmol ) was cooled to treatment of 1- (4-amino-2-nitrobenzyl 0 ℃) of 4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone (180mg, 0.42mmol) in pyridine. 在氩气氛室温下,将反应物搅拌18小时。 Under an argon atmosphere at room temperature, the reaction was stirred for 18 hours. 将反应物倾入冰冷的盐酸水溶液中并用乙酸乙酯萃取两次。 The reaction was poured into ice-cold aqueous hydrochloric acid and extracted with ethyl acetate twice. 有机萃取物用冷的稀盐酸,冷水和冷的碳酸氢钠水溶液洗涤。 The organic extract was washed with cold dilute hydrochloric acid, cold water and cold aqueous sodium bicarbonate. 将萃取物干燥(硫酸钠)并蒸发。 The extracts were dried (sodium sulfate) and evaporated. 经闪式色谱提纯,用60%的乙酸乙酯/己烷洗脱,得到一树脂状物(200mg,100%)。 Purification by flash chromatography, eluting with 60% ethyl acetate / hexane, to give a resin bar (200mg, 100%).

c)1-(4-乙酰氨基-2-氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮用10%钯碳催化剂(43mg)和甲酸铵(400mg,6.35mmol)处理1-(2-硝基-4-乙酰氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮(814mg,0.42mmol)的甲醇(4ml)和四氢呋喃(3ml)溶液。 c) 1- (4- acetamido-2-aminobenzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidone with 10% palladium on carbon catalyst (43mg) and formic acid ammonium (400mg, 6.35mmol) of 1- (2-nitro-4-acetylamino-benzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone (814mg, 0.42 mmol) in methanol (4ml) and tetrahydrofuran (3ml) was added. 氩气下将反应物搅拌5小时,然后通过硅藻土过滤。 The reaction was stirred under argon for 5 hours and then filtered through celite. 真空下除去溶剂,并使剩余物在冷的碳酸钠水溶液和氯仿之间分配。 The solvent was removed in vacuo, and the residue was partitioned between cold aqueous sodium carbonate and chloroform. 有机萃取物用水洗涤,干燥(碳酸钾)并蒸发。 The organic extract was washed with water, dried (potassium carbonate) and evaporated. 经闪式色谱提纯,用75-100%的乙酸乙酯/二氯甲烷洗脱,接着用温热的乙酸乙酯重结晶并用乙醚洗涤,得到橙色晶体(35mg,20%):mp184-186℃。 Purification by flash chromatography, eluting with 75-100% ethyl acetate / dichloromethane, followed by recrystallization from warm ethyl acetate and washed with ether to give orange crystals (35mg, 20%): mp184-186 ℃ .

元素分析:C25H31N3O4·1/4 H2O计算值:C.67.93;H.7.18;N.9.51实验值:C.68.08;H.7.13;N.9.22。 Elemental analysis: C25H31N3O4 · 1/4 H2O Calcd: C.67.93; H.7.18; N.9.51 Found: C.68.08; H.7.13; N.9.22.

实施例451-(2-乙酰氨基-4-氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮逐滴用乙酸酐(100μl,1.1mmol)处理冷却到0℃的实施例44的1-(2-氨基-4-硝基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮(140mg,0.33mmol)的吡啶溶液。 Example 451- (2-acetylamino-4-aminobenzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone was treated dropwise with acetic anhydride (100μl, 1.1mmol) was cooled to 0 ℃ process of Example 44, 1- (2-amino-4-nitrobenzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone (140mg, 0.33 mmol) in pyridine. 氩气氛室温下将反应混合物搅拌24小时,并再用乙酸酐(200μl,2.2mmol;400μl,4.4mmol)进行两次重复性处理。 The reaction mixture was stirred under an argon atmosphere at room temperature for 24 h and then acetic anhydride (200μl, 2.2mmol; 400μl, 4.4mmol) twice repetitive process. 将反应物倾入冰冷的盐酸水溶液中并用二氯甲烷萃取两次。 The reaction was poured into ice-cold aqueous hydrochloric acid and extracted twice with dichloromethane. 有机萃取物用冷的稀盐酸,冷水和10%的氢氧化钠水溶液洗涤。 The organic extracts were washed with cold dilute hydrochloric acid, washed with cold water and an aqueous solution of 10% sodium hydroxide. 将萃取物干燥(碳酸钾)并蒸发,得到一油状物(114mg,74%)。 The extract was dried (potassium carbonate) and evaporated to give an oil (114mg, 74%). 1-(2-乙酰氨基-4-氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮。 1- (2-acetamido-4-aminobenzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidone. 用10%钯碳催化剂(32mg)和甲酸铵(246mg,3.9mmol)处理1-(4-硝基-2-乙酰氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮(114mg,0.24mmol)的甲醇(10ml)和四氢呋喃(1.5ml)溶液。 With 10% palladium on carbon catalyst (32 mg of) and ammonium formate (246mg, 3.9mmol) of 1- (4-nitro-2-acetylamino-benzyl) -4- (3-cyclopentyloxy-4-methoxy phenyl) -2-pyrrolidinone (114mg, 0.24mmol) in methanol (10ml) and tetrahydrofuran (1.5ml) was added. 氩气下将反应物搅拌4小时,然后通过硅藻土过滤。 The reaction was stirred under argon for 4 hours and then filtered through celite. 真空下除去溶剂,剩余物在冷的碳酸钠水溶液和二氯甲烷之间分配。 The solvent was removed in vacuo, the residue was partitioned between cold aqueous sodium carbonate and dichloromethane. 有机萃取物用水洗涤,干燥(碳酸钾)并蒸发,得到一玻璃体(75mg,71%)。 The organic extract was washed with water, dried (potassium carbonate) and evaporated to give a glass body (75mg, 71%).

元素分析:C25H31N3O4计算值:C.68.63;H.7.14;N.9.60实验值:C.68.63;H.7.25;N.9.40。 Elemental analysis: C25H31N3O4 Calcd: C.68.63; H.7.14; N.9.60 Found: C.68.63; H.7.25; N.9.40.

实施例461-〔3-(2-氯代乙酰氨基)苄基〕-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮在氩气氛室温下,向1-(3-氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮(0.23g,0.6mmol)和粉沫状碳酸钠(0.13g,1.21mmol)于无水丙酮(4ml)中的混合物中滴加氯代乙酰氯(0.09ml,1.13mmol)。 Example 461- [3- (2-chloro-acetylamino) benzyl] -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone Under an argon atmosphere a solution of 1- (3-aminobenzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone (0.23g, 0.6mmol), and sodium carbonate powder form (0.13g, 1.21mmol) in a mixture of dry acetone (4ml) was added dropwise chloroacetyl chloride (0.09ml, 1.13mmol). 搅拌4小时后,在氩汽流下除去溶剂,并使剩余物在二氯甲烷和含有稀盐酸的冰水之间分配。 After stirring for 4 hours, the solvent was removed under a stream of argon vapor, and the residue was partitioned between methylene chloride and ice water containing dilute hydrochloric acid. 水层用二氯甲烷萃取三次,将合并的有机萃取物干燥(硫酸钠)并在真空下除去溶剂。 The aqueous layer was extracted three times with dichloromethane, and the combined organic extracts were dried (sodium sulfate) and the solvent removed in vacuo. 剩余物分两部分经闪式色谱提纯,一半用1∶1的乙醚/二氯甲烷洗脱,另一半用45-60%的乙酸乙酯/二氯甲烷洗脱,得到泡沫状的标题化合物(0.22g,80%)。 The residue was divided into two parts by flash chromatography, eluting with half 1:1 ether / methylene chloride, the other half with 45-60% ethyl acetate / dichloromethane, to give the title compound as a foam ( 0.22g, 80%).

元素分析:C25H29ClN2O4计算值:C.65.71;H.6.40;N.6.13实验值:C.65.72;H.6.40;N.5.99。 Elemental analysis: C25H29ClN2O4 Calcd: C.65.71; H.6.40; N.6.13 Found: C.65.72; H.6.40; N.5.99.

实施例471-〔4-(2-氯代乙酰氨基)苄基〕-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮在氩气氛室温下,向1-(4-氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮(0.35g,0.92mmol)和粉沫状碳酸钠(0.195g,1.84mmol)于无水丙酮(8ml)中的混合物中滴加氯代乙酰氯(0.132ml,1.66mmol)。 EXAMPLE 471- [4- (2-chloro-acetylamino) benzyl] -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone Under an argon atmosphere a solution of 1- (4-aminobenzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone (0.35g, 0.92mmol) and sodium carbonate powder form (0.195g, 1.84mmol) in a mixture of dry acetone (8ml) was added dropwise chloroacetyl chloride (0.132ml, 1.66mmol). 搅拌1.5小时后,除去溶剂,使剩余物在二氯甲烷和含有稀盐酸的冰水之间分配。 After stirring for 1.5 hours, the solvent removed and the residue was partitioned between methylene chloride and ice water containing dilute hydrochloric acid. 有机萃取物用水洗涤两次,干燥(硫酸钠)并在真空下除去溶剂。 The organic extracts were washed twice with water, dried (sodium sulfate) and the solvent removed in vacuo. 剩余物经闪式色谱提纯,用45-60%的乙酸乙酯/二氯甲烷洗脱,并用乙醚研磨产物,得到白色固体状的标题化合物(0.35g,83%):mp138-139℃。 The residue was purified by flash chromatography, eluting with 45-60% ethyl acetate / dichloromethane, and the product triturated with ether to give the title compound as a white solid (0.35g, 83%): mp138-139 ℃.

元素分析:C25H29ClN2O4计算值:C.65.71;H.6.40;N.6.13实验值:C.65.74;H.6.36;N.6.06。 Elemental analysis: C25H29ClN2O4 Calcd: C.65.71; H.6.40; N.6.13 Found: C.65.74; H.6.36; N.6.06.

实施例484-(3-环戊氧基-4-甲氧基苯基)-1-〔4-(4,4-二甲基-2-噁唑啉-2-基羰基氨基)苄基〕-2-吡咯烷酮a)4-(3-环戊氧基-4-甲氧基苯基)-1-〔4-(N-1-羟基-2-甲基-2-丙基脲基脲基苄基〕-2-吡咯烷酮向1-(4-N-甲酯基脲基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮(0.125g,0.27mmol)的经氧化铝处理的氯仿(10ml)溶液中加入2-氨基-2-甲基丙醇(0.051ml,0.54mmol),并在氩气氛下将混合物搅拌过夜。再加入一些2-氨基-2-甲基丙醇(0.037ml,0.27mmol)并继续搅拌8小时。氯仿液用稀盐酸萃取,用水洗涤并干燥(硫酸钠)。算空下除去溶剂,剩余物经闪式色谱提纯,用2%的甲醇氯仿液洗脱,得到一油状物(0.106g,79%)。 Example 484- (3-cyclopentyloxy-4-methoxyphenyl) -1- [4- (4,4-dimethyl-2-oxazolin-2-yl-carbonyl amino) benzyl] 2-pyrrolidinone a) 4- (3- cyclopentyloxy-4-methoxyphenyl) -1- [4- (N-1- hydroxy-2-methyl-2-propyl-ureido ureido benzyl] -2-pyrrolidinone to 1- (4-N- ureido carbomethoxy) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone (0.125g, 0.27 mmol) in chloroform was treated alumina (10ml) was added 2-methyl-propanol (0.051ml, 0.54mmol), and the mixture was stirred under argon atmosphere overnight. Some added 2-amino -2-methyl-propanol (0.037ml, 0.27mmol) and stirring was continued for 8 hours. chloroform solution was extracted with dilute hydrochloric acid, washed with water and dried (sodium sulfate). the solvent was removed under operator empty, the residue was purified by flash chromatography, with 2% methanol in chloroform as eluent to give an oil (0.106g, 79%).

b)4-(3-环戊氧基-4-甲氧基苯基)-1-〔4-(4,4-二甲基-2-噁唑啉-2-基羰基氨基)苄基〕-2-吡咯烷酮在氩气氛、-45℃下,用40分钟向二乙基氨基三氟化硫(0.054ml,0.4mmol)的无水二氯甲烷(15ml)溶液中滴加4-(3-环戊氧基-4-甲氧基苯基)-1-〔4-(N-1-羟基-2-甲基-2-丙基脲基脲基)苄基〕-2-吡咯烷酮(0.106g,0.2mmol)的无水二氯甲烷(2.5ml,然后用6ml洗)的溶液。 b) 4- (3- cyclopentyloxy-4-methoxyphenyl) -1- [4- (4,4-dimethyl-2-oxazolin-2-yl-carbonyl amino) benzyl] 2-pyrrolidone an argon atmosphere at -45 deg.] C, over 40 minutes (15ml) was added dropwise a solution of 4- (3- to diethylaminosulfur trifluoride (0.054ml, 0.4mmol) in dry dichloromethane cyclopentyloxy-4-methoxyphenyl) -1- [4- (N-1- hydroxy-2-methyl-2-ureido-propyl-ureido) benzyl] -2-pyrrolidinone (0.106 g , 0.2mmol) in dry dichloromethane (2.5ml, then washed with 6ml) was added. 在-45℃下0.75小时后,加入5%的碳酸钠水溶液(5ml),使混合物温热至室温,分出有机层,干燥(碳酸钾)并蒸发。 After 0.75 hours at -45 ℃, addition of 5% aqueous sodium carbonate solution (5ml), the mixture was allowed to warm to room temperature, the organic layer was separated, dried (potassium carbonate) and evaporated. 剩余物经闪式色谱提纯,用2%的甲醇氯仿液洗脱,得到树脂状的标题化合物(0.071g,70%)。 The residue was purified by flash chromatography, eluting with 2% methanol in chloroform, to give the title compound as a resin (0.071g, 70%).

元素分析:C29H35N3O5计算值:C.68.89;H.6.98;N.8.31实验值:C.68.56;H.6.94;N.8.18。 Elemental analysis: C29H35N3O5 Calcd: C.68.89; H.6.98; N.8.31 Found: C.68.56; H.6.94; N.8.18.

实施例494-(3-环戊氧基-4-甲氧基苯基)-1-〔4-(2-噁唑啉-2-基羰基氨基)苄基〕-2-吡咯烷酮a)4-(3-环戊氧基-4-甲氧基苯基-1-〔4-(N-2-羟基乙基脲基脲基苄基〕-2-吡咯烷酮向1-(4-N-甲酯基脲基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮(0.185g,0.4mmol)的经氧化铝处理的氯仿(10ml)溶液中加入乙醇胺(0.049ml,0.81mmol),并在氩气氛下将混合物搅拌过夜。真空下除去溶剂,剩余物经闪式色谱提纯,用2-3%的甲醇氯仿液洗脱,产物用乙醚研磨,得到一白色固体(0.175g,89%);mp133-134℃。 Example 494- (3-cyclopentyloxy-4-methoxyphenyl) -1- [4- (2-oxazolin-2-yl-carbonyl) benzyl] -2-pyrrolidinone a) 4- (3-cyclopentyloxy-4-methoxyphenyl-1- [4- (N-2- hydroxyethyl ureido-benzyl-ureido] -2-pyrrolidinone to 1- (4-N- methyl ester ureido-yl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone (0.185g, 0.4mmol) in chloroform was treated alumina (10ml) was added ethanolamine (0.049ml, 0.81mmol), and the mixture was stirred overnight under argon. the solvent was removed in vacuo, the residue was purified by flash chromatography, eluting with 2-3% methanol in chloroform, the product was triturated with ether to give a as a white solid (0.175g, 89%); mp133-134 ℃.

b)4-(3-环戊氧基-4-甲氧基苯基)-1-〔4-(2-噁唑啉-2-基羰基氨基)苄基〕-2-吡咯烷酮在氩气氛、-40℃下,向二乙基氨基三氟化硫(0.052ml,0.39mmol)的无水二氯甲烷(15ml)溶液中用40分钟滴加4-(3-环戊氧基-4-甲氧基苯基)-1-〔4-(N-2-羟基乙基脲基脲基)苄基〕-2-吡咯烷酮(0.13g,0.26mmol)的无水二氯甲烷(10ml)溶液。 b) 4- (3- cyclopentyloxy-4-methoxyphenyl) -1- [4- (2-oxazolin-2-yl-carbonyl) benzyl] -2-pyrrolidinone in an argon atmosphere, at -40 ℃, the diethylamino sulfur trifluoride (0.052ml, 0.39mmol) in dry dichloromethane (15ml) was added dropwise 40 minutes with a solution of 4- (3-cyclopentyloxy-4- ) -1- [4- (N-2- hydroxyethyl ureido ureido) benzyl] -2-pyrrolidinone (0.13g, 0.26mmol) in dry dichloromethane (10ml) was added. 1小时后,在-40℃下,再加入一些二乙基氨基三氟化硫(0.02ml,0.15mmol)。 After 1 hour at -40 deg.] C, then add some diethylaminosulfur trifluoride (0.02ml, 0.15mmol). 1小时后,加入5%的碳酸钠水溶液(4ml)使混合物温热至室温,分离出有机层,干燥(碳酸钾)并蒸发。 After 1 h, 5% aqueous sodium carbonate (4ml) and the mixture allowed to warm to rt, organic layer was separated, dried (potassium carbonate) and evaporated. 剩余物经闪式色谱提纯,第一次用20%的丙酮二氯甲烷液洗脱,第二次用2.5%的甲醇氯仿液洗脱,得到白色固体状的标题化合物(0.05g,40%):mp164-165℃。 The residue was purified by flash chromatography, eluting first with 20% acetone in methylene chloride, the second with 2.5% methanol in chloroform as eluent to give the title compound as a white solid (0.05g, 40%) : mp164-165 ℃.

元素分析:C27H31N3O5计算值:C.67.91;H.6.54;N.8.80实验值:C.67.75;H.6.53;N.8.62。 Elemental analysis: C27H31N3O5 Calcd: C.67.91; H.6.54; N.8.80 Found: C.67.75; H.6.53; N.8.62.

实施例504-(3-环戊氧基-4-甲氧基苯基)-1-(4-丙酮酰氨基苄基)-2-吡咯烷酮氩气氛室温下,向1-(4-氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮(0.183g,0.48mmol)的无水二氯甲烷(7ml)溶液中滴加丙酮酰氯溶液(39.1%的四氯化碳溶液,0.1ml,0.48mmol)。 Example 504- (3-cyclopentyloxy-4-methoxyphenyl) -1- (4-benzyl acetone amido) 2-pyrrolidinone under an argon atmosphere at room temperature, a solution of 1- (4-aminobenzyl ) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone (0.183g, 0.48mmol) in anhydrous dichloromethane (7ml) was added dropwise the acetone solution of acid chloride (39.1% in carbon tetrachloride, 0.1ml, 0.48mmol). 搅拌4小时后,将混合物倾入冰冷的5%的碳酸氢钠水溶液中,并用二氯甲烷萃取三次,将有机萃取物干燥(硫酸钠),并在真空下除去溶剂。 After stirring for 4 hours, the mixture was poured into ice-cold 5% aqueous sodium bicarbonate, and extracted three times with dichloromethane, the organic extracts were dried (sodium sulfate) and the solvent removed in vacuo. 将剩余物与另一批处理1-(4-氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮(54mg,0.12mmol)类似反应的产物合并,经闪式色谱提纯,用20-25%的乙酸乙酯/二氯甲烷洗脱。 The residue was another batch of 1- (4-aminobenzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone (54mg, 0.12mmol) in a similar reaction product combined and purified by flash chromatography, eluting with 20-25% ethyl acetate / dichloromethane. 产物用乙醚研磨,得到固体状的标题化合物(0.20g,72%):mp95-97℃。 The product was triturated with diethyl ether to give the title compound as a solid (0.20g, 72%): mp95-97 ℃.

元素分析:C26H30N2O5计算值:C.69.31;H.6.71;N.6.22实验值:C.69.02;H.6.59;N.6.29。 Elemental analysis: C26H30N2O5 Calcd: C.69.31; H.6.71; N.6.22 Found: C.69.02; H.6.59; N.6.29.

用上文给出的方法,制备下列化合物:实施例51S-(-)-1-(4-氨基-3,5-二甲氧基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮一树脂状物:元素分析C25H32N2O3·1/2 H2O计算值:C.71.91;H.7.97;N.6.71实验值:C.71.88;H.7.92;N.6.57。 The method given above, the following compounds were prepared: EXAMPLE embodiment 51S - (-) - 1- (4-amino-3,5-dimethoxybenzyl) -4- (3-cyclopentyloxy-4 - methoxyphenyl) -2-pyrrolidinone a resin: elemental analysis for C25H32N2O3 · 1/2 H2O Calcd: C.71.91; H.7.97; N.6.71 Found: C.71.88; H.7.92; N .6.57.

实施例52S-(-)-1-(4-乙酰氨基-3,5-二甲氧基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮一固体,mp166-169℃。 Example 52S - (-) - 1- (4- acetylamino-3,5-dimethoxy-benzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone a solid, mp166-169 ℃.

元素分析:C27H34N2O4·1/4 H2O Elemental analysis: C27H34N2O4 · 1/4 H2O

计算值:C.71.26;H.7.64;N.6.16实验值:C.71.27;H.7.54;N.6.04。 Calcd: C.71.26; H.7.64; N.6.16 Found: C.71.27; H.7.54; N.6.04.

实施例531-(4-氨基苄基)-4-(3,4-双一二氟甲氧基苯基)-2-吡咯烷酮一树脂状物:元素分析C19H18F4N2O3·1/4 H2O计算值:C.56.65;H.4.63;N.6.95实验值:C.56.71;H.4.62;N.6.80。 Example 531- (4-aminobenzyl) -4- (3,4-bis twelve difluoromethoxyphenyl) -2-pyrrolidinone a resin: Elemental analysis for C19H18F4N2O3 · 1/4 H2O Calcd: C .56.65; H.4.63; N.6.95 Found: C.56.71; H.4.62; N.6.80.

实施例541-(4-乙酰氨基苄基)-4-(3,4-双-二氟甲氧基苯基)-2-吡咯烷酮一固体,mp131-132℃。 Example 541- (4-acetylamino-benzyl) -4- (3,4-bis - difluoromethoxy-phenyl) -2-pyrrolidinone as a solid, mp131-132 ℃.

元素分析:C21H20F4N2O4计算值:C.57.27;H.4.58;N.6.36实验值:C.57.15;H.4.64;N.6.21。 Elemental Analysis: C21H20F4N2O4 Calcd: C.57.27; H.4.58; N.6.36 Found: C.57.15; H.4.64; N.6.21.

实施例551-(4-氨基-3,5-二甲氧基苄基)-4-(3,4-双-二氟甲氧基苯基)-2-吡咯烷酮一树脂状物:元素分析C21H22F4N2O3·1/2 H2O计算值:C.57.93;H.5.32;N.6.48实验值:C.58.15;H.5.16;N.6.31。 Example 551- (4-amino-3,5-dimethoxybenzyl) -4- (3,4-bis - difluoromethoxy-phenyl) -2-pyrrolidinone a resin: Elemental analysis for C21H22F4N2O3 · 1/2 H2O Calcd: C.57.93; H.5.32; N.6.48 Found: C.58.15; H.5.16; N.6.31.

实施例561-(4-乙酰氨基-3,5-二甲氧基苄基)-4-(3,4-双-二氟甲氧基苯基)-2-吡咯烷酮一树脂状物:元素分析C23H24F4N2O4·1/2 H2O计算值:C.57.85;H.5.28;N.5.87实验值:C.58.03;H.5.23;N.5.69。 Example 561 (4-acetylamino-3,5-dimethoxybenzyl) -4- (3,4-bis - difluoromethoxy-phenyl) -2-pyrrolidinone a resin: Elemental analysis C23H24F4N2O4 · 1/2 H2O Calcd: C.57.85; H.5.28; N.5.87 Found: C.58.03; H.5.23; N.5.69.

实施例574-(3-环戊氧基-4-甲氧基苯基)-1-甲氧基甲基-2-吡咯烷酮一油状物。 EXAMPLE 574- (3-cyclopentyloxy-4-methoxyphenyl) -1-methoxy-2-pyrrolidinone an oil. 元素分析:C18H25NO4计算值:C.67.69;H.7.89;N.4.39实验值:C.67.50;H.7.77;N.4.34。 Elemental analysis: C18H25NO4 Calcd: C.67.69; H.7.89; N.4.39 Found: C.67.50; H.7.77; N.4.34.

实施例581-苄氧基甲基-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮一油状物。 Example 581- benzyloxymethyl-4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone embodiment of an oil. 元素分析:C24H29NO4·1/4 H2O计算值:C.72.07;H.7.43;N.3.50实验值:C.71.93;H.7.28;N.3.40。 Elemental analysis: C24H29NO4 · 1/4 H2O Calcd: C.72.07; H.7.43; N.3.50 Found: C.71.93; H.7.28; N.3.40.

实施例59含有本发明化合物的药用组合物可以与多种赋形剂一起制成各种剂型。 Pharmaceutical compositions containing the compounds of the present invention can be made into various dosage forms embodiment 59 with a variety of excipients. 下文给出了这类组合物的实例。 Examples are given below of such compositions.

吸入剂一种式Ⅰ化合物(1μg-100mg)从一计量剂量吸入器中呈烟雾状散出,施放出每次使用所需的药量。 A compound of formula inhalants Ⅰ (1μg-100mg) as a smoke-like shed, cast the amount required for each use of the drug from a metered dose inhaler.

片剂成分 每片1.活性成分(式Ⅰ化合物) 40mg2.谷物淀粉 20mg3.藻酸 20mg4.藻酸钠 20mg5.硬脂酸镁 1.3mg101.3mg片剂的制备:步骤1:将第1,2,3,4号成分在一适当的混合器中混合。 ... Tablets Ingredients Per tablet 1. Active ingredient (compound of Formula Ⅰ) 40mg2 20mg3 alginic acid, corn starch, sodium alginate 20mg5 20mg4 magnesium stearate 1.3mg101.3mg tablets prepared: Step 1: 1,2 , 3,4 ingredients were mixed in a suitable mixer.

步骤2:向步骤1得到的混合物中分批加入足够量的水,每次加完后要进行小心的混合。 Step 2: Add sufficient water portionwise to the mixture obtained in step 1, after each addition to be careful mixing. 这些水的加入和混和要直到使物料呈粘稠状以使其能转化成湿的颗粒。 The water was added to and mixed until the material was so viscous that it can be converted to wet granules.

步骤3:令该湿物料通过一个8号目(2.38mm)筛子的振动成粒器,转化成颗粒。 Step 3: The wet mass through a mesh to make a number 8 (2.38mm) sieve granulator vibration, is converted into granules.

步骤4:然后将该湿颗粒在一烘炉中,在140°F(60℃)下干燥至干。 Step 4: The wet granules are then in an oven at 140 ° F (60 ℃) was dried to dryness.

步骤5:用第5号成分使干颗粒润滑。 Step 5: No. 5 and the dry granules can be lubricated component.

步骤6:在一适当的压片机上将润滑的颗粒压片。 Step 6: on a suitable tablet machine lubricating tableting granules.

肠胃外用药剂型肠胃外施用的药物组合物可以这样制备:将适当量的一种式Ⅰ化合物加热溶于聚乙二醇,然后用欧洲药典(Ph Eur.)注射剂用水将溶液稀释(至100ml),最后令溶液通过一个0.22微米的薄膜过滤器过滤灭菌并密封在无菌容器中。 Parenteral pharmaceutical compositions for parenteral administration may be prepared dosage forms for external use: an appropriate amount of a compound of formula Ⅰ dissolved in warm polyethylene glycol, water for injection and then the solution was diluted with European Pharmacopoeia (Ph Eur.) (To 100ml) , so that the final solution was sterilized by filtration through a 0.22 micron membrane filter and sealed in sterile containers.

Claims (8)

1.制备式(Ⅰ)化合物及其药学上可接受的盐的方法 The compound (Ⅰ) and pharmaceutically acceptable salts of formula 1. Preparation method
其中:R1是未取代的或被1或多个卤素取代的C1-12烷基,未取代的或被1-3个甲基或1个乙基取代的C3-6环烷基,含1或2个不饱和键的C4-6环烷基,C7-11多环烷基,(CR14R14)nC(O)-O-(CR14R14)m-R10,(CR14R14)nC(O)-O-(CR14R14)r-R11,(CR14R14)xOH,(CR14R14)sO(CR14R14)m-R10,(CR14R14)sO(CR14R14)r-R11,(CR14R14)n-(C(O)NR14)-(CR14R14)m-R10,(CR14R14)n-(C(O)NR14)-(CR14R14)r-R11,(CR14R14)y-R11,或(CR14R14)z-R10;X1是O或S;X2是O或NR14;X3是H或X;X是YR2,卤素,硝基,NR14R14或甲酰氨基;Y是O或S(O)m;R2是-CH3或-CH2CH3,每个可以是未取代的或被1-5个氟取代;R3是氢,卤素,CN,C1-4烷基,卤素取代的C1-4烷基,未取代的或被R9取代的环丙基,OR5,-CH2OR5,NR5R16,-CH2NR5R16,-C(O)OR5,C(O)NR5R16,-CH=CR9R9,-C≡CR9,或-C(=Z)H;R3′是氢,卤素,C1-4烷基,卤代C1-4烷基,未取代的或被R9取代的环丙基,-CH2OR5,-CH2NR5R16,-C(O)OR5,-C(O)NR5R16或-C(=Z)H;A Wherein: R1 is unsubstituted or substituted by one or more halogen-substituted C1-12 alkyl, unsubstituted or substituted with a methyl or ethyl group substituted by C3-6 cycloalkyl containing one or two unsaturated bonds C4-6 cycloalkyl, C7-11 polycycloalkyl, (CR14R14) nC (O) -O- (CR14R14) m-R10, (CR14R14) nC (O) -O- (CR14R14 ) r-R11, (CR14R14) xOH, (CR14R14) sO (CR14R14) m-R10, (CR14R14) sO (CR14R14) r-R11, (CR14R14) n- (C (O) NR14) - (CR14R14) m- R10, (CR14R14) n- (C (O) NR14) - (CR14R14) r-R11, (CR14R14) y-R11, or (CR14R14) z-R10; X1 is O or S; X2 is O or NR14; X3 is H or X; X is YR2, halogen, nitro, NR14R14, or carboxamido; Y is O or S (O) m; R2 is -CH3 or -CH2CH3, each may be unsubstituted or substituted by 1-5 fluoro substituent; R3 is hydrogen, halo, the CN, C1-4 alkyl, halo-substituted C1-4 alkyl, unsubstituted or substituted cyclopropyl R9, OR5, -CH2OR5, NR5R16, -CH2NR5R16, - C (O) OR5, C (O) NR5R16, -CH = CR9R9, -C≡CR9, or -C (= Z) H; R3 'is hydrogen, halo, C1-4 alkyl, halo C1-4 alkoxy group, unsubstituted or R9-substituted cyclopropyl, -CH2OR5, -CH2NR5R16, -C (O) OR5, -C (O) NR5R16 or -C (= Z) H; a
(C)未取代的或被1或多个氟或1或2个R4基团取代的C1-3烷基;m是0-2的整数;n是1-4的整数;q是0-1的整数;r是1-2的整数;s是2-4的整数;x是2-6的整数;y是1-6的整数;z是0-6的整数;R4分别是氢,Br,F,C1,NR5R6,NR6R16,NO2,-C(Z)R7,-S(O)mR12,CN,OR16,-OC(O)NR5R16,1-或2-咪唑基,-C(=NR16)NR5R16,-C(=NR5)-SR12,-OC(O)CH3,-C(=NCN)NR5R16,-C(S)NR5R16,-NR16-C(O)-R15,C(O)R15,噁唑基,噻唑基,吡唑基,三唑基或四唑基;或者当R5和R16是以NR5R16出现时,它们可以和氮原子一起形成任意含至少1个选自O,N或S的另一个杂原子的5-7元环;R5分别是氢或未取代的或被1-3个氟取代的C1-4烷基;R6是H,R12,-C(O)R12,-C(O)C(O)R17,-C(O)NR5R16,-S(O)mR12,-S(O)mCF3,-C(=NCN)SR12,-C(=NCN)R12,-C(=NR16)R12,-C(=NR16)SR12,或-C(=NCN)NR5R16;R7是OR5,-NR5R16或R12;R8是氢,C(O)R7,2-,4-或5-咪唑基,3-,4-或5-吡唑基,4-或5-[1,2,3] (C) unsubstituted or substituted with one or more fluoro, or 1 or 2 R4 groups substituted by a C1-3 alkyl group; m is an integer of 0-2; n is an integer of 1-4; Q is 0-1 integer; is an integer from 1 to 2 R & lt; S is an integer of 2 to 4; x is an integer from 2-6; Y is an integer from 1-6; Z is an integer of 0-6; each R4 is hydrogen, Br, F, C1, NR5R6, NR6R16, NO2, -C (Z) R7, -S (O) mR12, CN, OR16, -OC (O) NR5R16,1- or 2-imidazolyl, -C (= NR16) NR5R16 , -C (= NR5) -SR12, -OC (O) CH3, -C (= NCN) NR5R16, -C (S) NR5R16, -NR16-C (O) -R15, C (O) R15, oxazole yl, thiazolyl, pyrazolyl, triazolyl or tetrazolyl; or R5 and R16 are as NR5R16 occurs when, they may be of any other nitrogen atom and containing at least one selected from O, N or S, with 5-7 membered ring heteroatoms; each R5 is hydrogen or unsubstituted or substituted with 1-3 fluoro C1-4 alkyl; R6 is H, R12, -C (O) R12, -C (O) C (O) R17, -C (O) NR5R16, -S (O) mR12, -S (O) mCF3, -C (= NCN) SR12, -C (= NCN) R12, -C (= NR16) R12 , -C (= NR16) SR12, or -C (= NCN) NR5R16; R7 is OR5, -NR5R16 or R12; R8 is hydrogen, C (O) R7,2-, 4- or 5-imidazolyl, 3- , 4- or 5-pyrazolyl, 4- or 5- [1,2,3] 三唑基,3-或5-[1,2,4]三唑基,5-四唑基,2-,4-,或5-噁唑基,3-,4-,或5-异噁唑基,3-或5-[1,2,4]噁二唑基,2-[1,3,4]噁二唑基,2-[1,3,4]噻二唑基,2-,4-或5-噻唑基,2-,4-或5-噁唑烷基,2-,4-或5-噻唑烷基,或2-,4-或5-咪唑烷基;R9是氢,F或R12;R10是氢,甲基,羟基,芳基,卤代芳基,芳氧基C1-3烷基,卤代的芳氧基C1-3烷基,2,3-二氢化茚基,茚基,C7-11多环烷基,呋喃基,吡喃基,噻吩基,噻喃基,C3-6环烷基,或含1或2个不饱和键的C4-6环烷基,其中的环烷基或杂环烷基部分可以是未取代的或被1-3个甲基或1个乙基取代;R11是2-四氢呋喃基,2-四氢噻喃基,2-四氢呋喃基或2-四氢噻吩基,可以是未取代的或被1-3个甲基或1个乙基取代;R12是未取代的或被1-3个氟取代的C1-4烷基;R14分别是氢或未取代的或被氟取代的C1-2烷基;R15是未取代的或被1或多个卤 Triazolyl, 3- or 5- [1, 2,4] triazolyl, 5-tetrazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl oxazolyl, 3- or 5- [1,2,4] oxadiazolyl, 2- [1,3,4] oxadiazolyl, 2- [1,3,4] thiadiazolyl, 2- , 4- or 5-thiazolyl, 2-, 4- or 5-oxazolyl group, 2-, 4- or 5-thiazolyl group, or 2-, 4-, or 5-imidazolidinyl; R9 is hydrogen , F or R12; R10 is hydrogen, methyl, hydroxyl, aryl group, halogenated aryl group, aryloxy C1-3 alkyl, C1-3 halogenated aryloxy group, indane group, indenyl group, a C7-11 polycycloalkyl, furanyl, pyranyl, thienyl, thiopyranyl, a C3-6 cycloalkyl group or containing 1 or 2 unsaturated bonds C4-6 cycloalkyl wherein the cycloalkyl or heterocycloalkyl moiety may be unsubstituted or substituted with 1 to 3 methyl or an ethyl group; R11 is 2-tetrahydrofuryl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl yl or 2-tetrahydrothienyl, may be unsubstituted or substituted with 1 to 3 methyl or an ethyl group; R12 is unsubstituted or substituted with 1-3 fluoro C1-4 alkyl; R14 are hydrogen or unsubstituted or fluorine-substituted C1-2 alkyl; R15 is unsubstituted or substituted by one or more halogen 素取代的C1-4烷基,未取代的或被1或多个卤素取代的-C(O)C1-4烷基,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,噻二唑基,吗啉基,哌啶基,哌嗪基或吡咯基,每个杂环基或以是未取代的或被1或2个C1-2烷基取代;R16是OR5或R5;Z是O,-NR12,-NOR5,NCN,-C(-CN)2,-CR5NO2,-CR5C(O)OR12,-CR5C(O)NR5R5,-C(-CN)NO2,-C(-CN)C(O)OR12,或-C(-CN)C(O)NR5R5;其条件是:当(CR14R14)nC(O)O-(CR14R14)m-R10,(CR14R14)n-(C(O)NR14)-(CR14R14)m-R10,或(CR14R14)sO(CR14R14)mR10中的R10是OH时,m是2;另一个条件是当q是o,R3,R3′,R8和X3是H,X是OR2,X2是O及X1是O或s时,(a)或(b)上的R4或R14至少一个不是氢;该方法包括:a)使式(7)化合物 Su substituted C1-4 alkyl, unsubstituted or substituted with 1 or more halogen substituents of -C (O) C1-4 alkyl, oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl yl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, morpholinyl, piperidinyl, piperazinyl, or pyrrolyl, each heteroaryl be a cyclic group or a unsubstituted or substituted with 1 or 2 C1-2 alkyl substituents; R16 is OR5 or R5; Z is O, -NR12, -NOR5, NCN, -C (-CN) 2, -CR5NO2, -CR5C (O) OR12, -CR5C (O) NR5R5, -C (-CN) NO2, -C (-CN) C (O) OR12, or -C (-CN) C (O) NR5R5; with the proviso that : when the (CR14R14) nC (O) O- (CR14R14) mR10, (CR14R14) n- (C (O) NR14) - (CR14R14) mR10, or (CR14R14) sO (CR14R14) mR10 of R10 is OH, m is 2; provided further that when q is o, R3, R3 ', R8 and X3 are H, X is OR2, X2 is O and X1 is O or s when, (a) or (b) R4, or R14 on at least one is not hydrogen; the method comprising: a) of formula (7) compound
其中R19是H,R17是烷基或芳基,R3′是H或C(O)OR17,R3是H,R12或未取代的或被R9取代的环丙烷基,R1,X2,X和X3如式(Ⅰ)所定义或者是能转化成这种基团的基团;和适当的醛反应,随后还原该亚胺得到其中R19是CH2(CH2)mA的式(7)化合物,后者进一步环化得式(Ⅰ)化合物;或(b)R19是H的式(7)化合物在有或无催化剂存在下用适当活化的烷基化剂处理,得R19是CHR8(O)q(CH2)mA的式(7)化合物,后者被环化成式(Ⅰ)化合物;或者(c)R19是H的式(7)化合物环化成R19是H的式(8)化合物 Wherein R19 is H, R17 is an alkyl or aryl group, R3 'is H or C (O) OR17, R3 is H, R12 or R9 is substituted or unsubstituted cyclopropyl, R1, X2, X and X3 as formula (ⅰ) is defined or a group convertible to such groups; and an appropriate aldehyde, followed by reduction of the resulting imine compound wherein R19 is CH2 (CH2) mA of formula (7), which is further ring of formula (ⅰ) compound; or (B) R19 is H in formula (7) compound in the presence or absence of a catalyst treated alkylating agent with a suitably activated, to give R19 is cHR8 (O) q (CH2) mA compound, the latter being the compound of formula (7) is cyclized of formula (ⅰ); or (C) R19 is H in formula (7) is cyclized to a compound of the formula R19 is H, (8) the compound
后者进一步和强碱反应,再和适当活化的烷基化剂反应,得到式(Ⅰ)化合物,或者(d)对于R19是H及R3是C(O)NH2的式(7)化合物,首先用合适的保护基保护R19,随后进行酰胺脱水,再除去保护基,得到R19是H及R3是CN的式(7)化合物,后者环化可得R3是CN,X和X3是除了S(O)mR2,Br,I,NO2或甲酰氨基以外的其它基团的式(Ⅰ)化合物,或者(e)对于R3是OR5的式(Ⅰ)化合物,R19是H及R3是被保护的或未被保护的羟基的式(7)化合物在氮上烷基化并环化;或(f)对于R3是F的化合物,(e)中的化合物用二乙氨基三氟化硫处理,得所需的化合物;或(g)其中R3代表式(Ⅰ)中其余R3基的式(Ⅰ)化合物,可以通过保护酰氨基及其它敏感官能团从其中R3是CN的式(Ⅰ)或式(8)化合物得到,然后还原R3的CN基团为CHO,再进一步将CHO转变成所需的基团,得式(Ⅰ)化合物。 And a strong base which is further reacted with an alkylating agent and then suitably activated, to give formula (Ⅰ) compound, or (d) R19 is H, and R3 for the compound is C (O) NH2 in the formula (7), first with a suitable protecting group R19, followed by amide dehydration, followed by removal of the protecting group R19 is H and R3 is CN, a compound of formula (7), which can be cyclized to give R3 is CN, and X3 is in addition to X-S ( O) a compound of formula than the other groups mR2, Br, I, NO2 or carboxamido (ⅰ), or (e) R3 is a formula for (ⅰ) OR5 compounds, R19 is H, and R3 is a protected or formula (7) unprotected hydroxy compounds alkylated on nitrogen and cyclized; or (f) for compounds R3 is F, compound (e) was treated with diethylaminosulfur trifluoride, to give the compound required; or (g) wherein in R3 represents formula (ⅰ) the remainder of formula (ⅰ) R3 group-containing compound, can be protected acylamino and other sensitive functional groups from which R3 is (ⅰ) or formula (8) CN formula obtained compound, followed by reduction of the R3 CN group to CHO, CHO further converted into the desired groups, the compound of formula (ⅰ).
2.按照权利要求1制备式(Ⅰ)化合物的方法,其中X1和X2是氧;A是(a);X是Y R2;Y是O及R1是CH2-环丙烷基,CH2-C5-6-环烷基,C4-6环烷基,四氢呋喃基,环戊烯基,未取代的或被1或多个氟或氯取代的C1-7烷基,或-(CH2)2-4OH;R2是任意被1或多个卤素,优选氟和氯取代的C1-2烷基;一个R3是氢;另一个R3是氢,C≡CR9,CN,C(=Z)H,CH2OH,CH2F,CF2H,或CF3;R3′是氢;Z是O,NCN或NOR5;X3是氢;R4是H,Br,OR16,CN,NR5R6,NO2,C(O)R7,S(O)mR12,1-或2-咪唑基,-OC(O)CH3,或NHC(O)R15;R3是C(O)OH,H或C(O)OEt及R14是氢,CH3,NH2或NHC(O)CH3。 2. The method according to claim 1 preparing a compound of formula (Ⅰ), wherein X1 and X2 are oxygen; A is (a); X is Y R2; Y is O and R1 is CH2- cyclopropyl, CH2-C5-6 - cycloalkyl, C4-6 cycloalkyl, tetrahydrofuranyl, cyclopentenyl group, unsubstituted or substituted with 1 or more fluorine or chlorine-substituted C1-7 alkyl, or - (CH2) 2-4OH; R2 It is optionally substituted with 1 or more halogen, preferably fluorine and chlorine, C1-2 alkyl; R3 is a hydrogen; the other R3 is hydrogen, C≡CR9, CN, C (= Z) H, CH2OH, CH2F, CF2H , or CF3; R3 'is hydrogen; Z is O, NCN or NOR5; X3 is hydrogen; R4 is H, Br, OR16, CN, NR5R6, NO2, C (O) R7, S (O) mR12,1- or 2-imidazolyl, -OC (O) CH3, or NHC (O) R15; R3 is C (O) OH, H or C (O) OEt, and R14 is hydrogen, CH3, NH2 or NHC (O) CH3.
3.按照权利要求1的方法,其中R1是被1或多个氟取代的C1-4烷基,CH2-环丙烷基,CH2-环戊烷基,环戊烷基或环戊烯基;R2是甲基或氟取代的C1-2烷基;R3是氢,C≡CH或CN;R4是氢,Br,NH2,NHC(O)CH3,C(O)OH,NHC(NCN)SCH3,NHC(O)NH2,N(CH3)2,NHC(O)CO2CH3,NHC(O)C(O)OH,NHS(O)2CH3,C(O)OCH3,S(O)2CH3,SCH3,NHC(O)C(O)CH3,SOCH3,NHC(O)C(O)NH2,CN,C(O)NH2,NHS(O)2CF3,C(NH)NH2,O-OC(O)CH3,-C(O)N(CH3)2,1-或2-咪唑基,-NHC(O)CH2Cl,-NHC(O)-噁唑烷基,-NHC(O)-4,4-二甲基噁唑烷基或OH。 3. The method according to claim 1, wherein R1 is phenyl substituted with 1 or more fluorine C1-4 alkyl, CH2- cyclopropyl, CH2- cyclopentyl, cyclopentyl or cyclopentenyl; R2 is methyl or fluoro-substituted C1-2 alkyl group; R3 is hydrogen, C≡CH or CN; R4 is hydrogen, Br, NH2, NHC (O) CH3, C (O) OH, NHC (NCN) SCH3, NHC (O) NH2, N (CH3) 2, NHC (O) CO2CH3, NHC (O) C (O) OH, NHS (O) 2CH3, C (O) OCH3, S (O) 2CH3, SCH3, NHC (O ) C (O) CH3, SOCH3, NHC (O) C (O) NH2, CN, C (O) NH2, NHS (O) 2CF3, C (NH) NH2, O-OC (O) CH3, -C ( O) N (CH3) 2,1- or 2-imidazolyl, -NHC (O) CH2Cl, -NHC (O) - oxazolidinyl, -NHC (O) -4,4- dimethyl-oxazolidine group or OH.
4.按照权利要求1的方法,其中R1是环戊烷基,CF3,CH2F,CHF2,CF2CHF2,CH2CF3,CH2CHF2,CH3,CH2-环戊烷基,CH2-环丙烷基或环戊烯基;R2是CF3,CHF2,CH2CHF2;一个R3是氢;另一个R3是氢,C≡CH,或CN,并且处在4-位;一个R4是氢;另一个是NHC(O)CH3,NH2,NH-C(NCN)SCH3,NHC(O)C(O)OCH3,C(O)OCH3,NHC(O)NH2,NHC(O)C(O)CH3,NHC(O)C(O)NH2;或者其中两个R4基团是NH2或NHC(O)CH3;R8是氢及R14是氢。 The method according to claim 1, wherein R1 is cyclopentyl, CF3, CH2F, CHF2, CF2CHF2, CH2CF3, CH2CHF2, CH3, CH2- cyclopentyl, CH2- cyclopropyl or cyclopentenyl; R2 is CF3, CHF2, CH2CHF2; R3 is a hydrogen; the other R3 is hydrogen, C≡CH, or CN, and in the 4-position; R4 is a hydrogen; and the other is NHC (O) CH3, NH2, NH- C (NCN) SCH3, NHC (O) C (O) OCH3, C (O) OCH3, NHC (O) NH2, NHC (O) C (O) CH3, NHC (O) C (O) NH2; or wherein two R4 groups are NH2 or NHC (O) CH3; R8 is hydrogen and R14 is hydrogen.
5.按照权利要求1的方法制备下述化合物:(S)-1-(4-氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮;(R)-1-(4-乙酰氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮;(S)-1-(4-乙酰氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮;(R)-1-(4-乙酰氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮;1-(4)-草酰氨基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮;4-(3-环戊氧基-4-甲氧基苯基)-1-(2,4-二乙酰氨基苄基)-2-吡咯烷酮;4-(3-环戊氧基-4-甲氧基苯基)-1-(2,4-二氨基苄基)-2-吡咯烷酮;1-(4-甲氧羰基苄基)-4-(3-环戊氧基-4-甲氧基苯基)-2-吡咯烷酮;4-(3-环戊氧基-4-甲氧基苯基)-1-(4-N′-〔N-2-氰基-S-甲基-异硫脲基〕苄基)-2-吡咯烷酮;1-(4-N-甲氧羰基脲基苄基)-4-(3-环戊氧基-4-乙氧基苯基)-2-吡咯烷酮;4-(3-环戊氧基- The following compounds were prepared according to the method of claim 1 wherein: (S) -1- (4- aminobenzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone; (R) -1- (4- acetylamino-benzyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone; (S) -1- (4- acetylamino-benzyl yl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone; (R) -1- (4- acetylamino-benzyl) -4- (3-cyclopentyloxy- 4-methoxyphenyl) -2-pyrrolidinone; 1- (4) - oxamido-yl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone; 4- (3-cyclopentyloxy-4-methoxyphenyl) -1- (2,4-diacetoxy-aminobenzyl) -2-pyrrolidinone; 4- (3-cyclopentyloxy-4- ) -1- (2,4-aminobenzyl) -2-pyrrolidinone; 1- (4-methoxycarbonyl benzyl) -4- (3-cyclopentyloxy-4-methoxy phenyl) -2-pyrrolidinone; 4- (3-cyclopentyloxy-4-methoxyphenyl) -1- (4-N '- [N-2- cyano -S- methyl - isothiourea ureido] benzyl) -2-pyrrolidinone; 1- (4-N- methoxycarbonyl-benzyl-ureido) -4- (3-cyclopentyloxy-4-ethoxyphenyl) -2-pyrrolidinone; 4- (3-cyclopentyloxy - 4-甲氧基苯基)-1-(4-N-〔脲基〕苄基)-2-吡咯烷酮;及4-(3-环戊氧基-4-甲氧基苯基)-1-(4-丙酮酸酰氨基苄基)-2-吡咯烷酮。 4-methoxyphenyl) -1- (4-N- [ureido] benzyl) -2-pyrrolidone; and 4- (3-cyclopentyloxy-4-methoxyphenyl) -1- (4-pyruvate amido benzyl) -2-pyrrolidinone.
6.使用如权利要求1定义的式(Ⅰ)化合物制备用于抑制产生肿瘤坏死因子(TNF)或预防TNF引起的疾病的药物。 6. Use as claimed in claim 1 of formula (Ⅰ) for inhibiting compounds defined generation of tumor necrosis factor (TNF) or prophylaxis of a disease caused by TNF.
7.使用如权利要求1定义的式(Ⅰ)化合物制备用于抑制磷酸二酯酶Ⅳ的药物。 7. The use of a compound as claimed in claim 1 of formula (Ⅰ) for inhibiting phosphodiesterase Ⅳ medicament.
8.使用如权利要求1定义的式(Ⅰ)化合物制备用于治疗过敏性或炎性疾病的药物。 8. Use as claimed in claim 1 of formula (Ⅰ) preparation of a compound as defined medicament for the treatment of allergic or inflammatory disease.
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