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    • 2. 发明授权
      US07705019B2 Piperidinyl piperidine derivatives useful as inhibitors of chemokine receptors 失效
    • Piperidinyl piperidine derivatives useful as inhibitors of chemokine receptors
    • 可用作趋化因子受体抑制剂的哌啶基哌啶衍生物
    • US07705019B2
    • 2010-04-27
    • US11358248
    • 2006-02-21
    • Tze-Ming Chan , Kathleen Cox , Wenqing Feng , Michael W. Miller , Daniel Weston , Stuart W. McCombie
    • Tze-Ming Chan , Kathleen Cox , Wenqing Feng , Michael W. Miller , Daniel Weston , Stuart W. McCombie
    • A61K31/4545 , C07D403/14
    • C07D401/14
    • In its many embodiments, the present invention provides a novel class of compounds of structural formula IA or IB where R1-R8 are as disclosed herein as inhibitors of the CCR5 receptors, methods of preparing such compounds, pharmaceutical compositions containing one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition, or amelioration of one or more diseases associated with CCR5 using such compounds or pharmaceutical compositions. The invention also relates to the use of a combination of a compound of this invention and one or more antiviral or other agents useful in the treatment of Human Immunodeficiency Virus (HIV). The invention further relates to the use of a compound of this invention, alone or in combination with another agent, in the treatment of solid organ transplant rejection, graft v. host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis.
    • 在其许多实施方案中，本发明提供了一类新颖结构式IA或IB的化合物，其中R 1 -R 8如本文所公开的CCR5受体的抑制剂，制备此类化合物的方法，含有一种或多种此类化合物的药物组合物， 制备包含一种或多种此类化合物的药物制剂的方法，以及使用这些化合物或药物组合物治疗，预防，抑制或改善与CCR5相关的一种或多种疾病的方法。 本发明还涉及本发明化合物与一种或多种可用于治疗人类免疫缺陷病毒（HIV）的抗病毒剂或其它药剂的组合的用途。 本发明还涉及本发明化合物单独或与另一种药剂组合用于治疗实体器官移植排斥，移植物抗宿主病，关节炎，类风湿性关节炎，炎症性肠病，特应性皮炎，牛皮癣 ，哮喘，过敏或多发性硬化。
    • 基本信息 添加关注 加入工作空间 PDF全文 PDF下载 全文下载 相似专利 双屏查看 权利要求书 说明书全文 Espacenet 法律信息 同族专利 专利引用
    • 3. 发明授权
      US07659275B2 Piperidinyl piperazine derivatives useful as inhibitors of chemokine receptors 失效
    • Piperidinyl piperazine derivatives useful as inhibitors of chemokine receptors
    • 可用作趋化因子受体抑制剂的哌啶基哌嗪衍生物
    • US07659275B2
    • 2010-02-09
    • US11358520
    • 2006-02-21
    • Tze-Ming Chan , Kathleen Kox , Wenqing Feng , Michael W. Miller , Daniel Weston , Stuart W. McCombie
    • Tze-Ming Chan , Kathleen Kox , Wenqing Feng , Michael W. Miller , Daniel Weston , Stuart W. McCombie
    • A61K31/497 , C07D401/00
    • C07D211/96 , C07D401/06 , C07D401/14
    • In its many embodiments, the present invention provides a novel class of compounds of structural formula IA or IB where R1-R8 are as disclosed herein as inhibitors of the CCR5 receptors, methods of preparing such compounds, pharmaceutical compositions containing one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition, or amelioration of one or more diseases associated with CCR5 using such compounds or pharmaceutical compositions. The invention also relates to the use of a combination of a compound of this invention and one or more antiviral or other agents useful in the treatment of Human Immunodeficiency Virus (HIV). The invention further relates to the use of a compound of this invention, alone or in combination with another agent, in the treatment of solid organ transplant rejection, graft v. host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis.
    • 在其许多实施方案中，本发明提供了一类新颖结构式IA或IB的化合物，其中R 1 -R 8如本文所公开的CCR5受体的抑制剂，制备此类化合物的方法，含有一种或多种此类化合物的药物组合物， 制备包含一种或多种此类化合物的药物制剂的方法，以及使用这些化合物或药物组合物治疗，预防，抑制或改善与CCR5相关的一种或多种疾病的方法。 本发明还涉及本发明化合物与一种或多种可用于治疗人类免疫缺陷病毒（HIV）的抗病毒或其它药剂的组合的用途。 本发明还涉及本发明化合物单独或与另一种药剂组合用于治疗实体器官移植排斥，移植物抗宿主病，关节炎，类风湿性关节炎，炎症性肠病，特应性皮炎，牛皮癣 ，哮喘，过敏或多发性硬化。
    • 基本信息 添加关注 加入工作空间 PDF全文 PDF下载 全文下载 相似专利 双屏查看 权利要求书 说明书全文 Espacenet 法律信息 同族专利 专利引用
    • 8. 发明授权
      US4237051A Stereospecific production of 6- or 7-carbon-substituted-.beta.-lactams 失效
    • Stereospecific production of 6- or 7-carbon-substituted-.beta.-lactams
    • 6-或7-碳取代的β-内酰胺的立体特异性生产
    • US4237051A
    • 1980-12-02
    • US031286
    • 1979-04-19
    • Stuart W. McCombie
    • Stuart W. McCombie
    • C07D499/00 , C07D501/04 , C07D501/02
    • C07D499/00
    • Reaction of 6- or 7-diazo-.beta.-lactams with allylic halides in the presence of a catalytic amount of metallic copper or a copper salt affords 6- or 7-carbon-substituted-.beta.-lactams with the desired stereochemical configuration at the 6- or 7-position. Subsequent reduction with a trialkyl stannane affords useful intermediates for further syntheses affording 6- or 7-carbon-substituted-.beta.-lactams.The present invention relates to a process for the production of 6- or 7-carbon-substituted-.beta.-lactams having the desired stereochemical configuration at the 6- or 7-position. More particularly, this invention provides a process for the preparation of a .beta.-lactam of the formula ##STR1## wherein R.sub.1 is cyano or COOR.sub.2 wherein R.sub.2 is a readily removable ester-forming moiety, hydrogen or an alkali-metal cation;R.sub.3 and R.sub.4 are independently hydrogen, lower alkyl, aryl or aralkyl;Z is a group of the formula ##STR2## wherein R.sub.5 is hydrogen, lower alkyl or aralkyl; and the dotted line indicates the optional presence of a double bond; which comprises(1) reacting a diazo-.beta.-lactam of the formula ##STR3## wherein Y is a sulfur or an oxygenated sulfur atom and Z, R.sub.1, R.sub.3, and R.sub.4 are as hereinbefore defined; with an allyl halide of the formula ##STR4## wherein R.sub.3 and R.sub.4 are as hereinbefore defined andX is bromo or iodo;in the presence of a catalytic amount of metallic copper or a copper salt; and where Y is an oxygenated sulfur atom, followed by transformation of the resultant oxygenated sulfur intermediate to a compound wherein Y is a sulfur atom; and(2) subjecting the resultant intermediate of the formula ##STR5## wherein X, Z, R.sub.1, R.sub.3, and R.sub.4 are as hereinabove defined, to reduction with a trialkyl stannane to afford the compound of formula I.The lower alkyl groups referred to contain 1 to 6 carbon atoms and are exemplified by methyl, ethyl, propyl, butyl, pentyl, hexyl and the corresponding branched-chain isomers thereof.The lower alkoxy groups referred to above likewise contain 1 to 6 carbon atoms and are exemplified by methoxy, ethoxy, propoxy, and the like.The term "aryl" as used herein refers to phenyl substituted by one or more substituent groups selected from among chloro, bromo, fluoro, lower alkyl, hydroxy, nitro, amino, aminomethyl, lower monoalkylamino, lower dialkylamino, lower alkoxy and carboxy. Such aryl groups represented by R.sub.1 can be, for example, 4-hydroxyphenyl, 3,4-dichlorophenyl, 2,6-dimethoxyphenyl, 4-methylphenyl, 2-fluorophenyl, 4-carboxyphenyl, 3-nitrophenyl, 4-aminophenyl, 3-aminophenyl, 4-dimethylaminophenyl, 4-aminomethylphenyl and 4-ethoxyphenyl.The term "aralkyl" encompasses aryl-substituted lower alkyl groups such as benzyl, phenethyl, p-fluorobenzyl, o-tolylethyl and m-hydroxy-phenethyl.The process of this invention initially involves the reaction of a diazo-.beta.-lactam of formula II and the allyl halide of formula III in the presence of a catalytic amount of metallic copper or a copper salt to induce the decomposition of the diazo-.beta.-lactam at temperatures of about 0.degree.-50.degree. C. to provide the intermediate of formula IV. The diazo-.beta.-lactam utilizable in this step of the invention may be any type of readily removable ester-blocked acid, i.e., the compound of formula II wherein R.sub.1 is COOR.sub.2 or a nitrile, i.e., the compound of formula II wherein R.sub.1 is cyano. Preferably, benzyl or benzhydryl esters are employed in the reaction wherein R.sub.1 is COOR.sub.2. The starting materials of formula II wherein Y is oxygenated sulfur are preferred due to the stability of the starting compound. However, the reaction using the equivalent sulfide also proceeds with good yields and avoids the need for a subsequent deoxygenation step.The allyl halides of formula III utilizable in the present invention are those wherein the halogen is iodine or bromine with iodine being most particularly preferred. The allyl halide of formula III may be substituted by lower alkyl, aryl or aralkyl groups. Those compounds wherein R.sub.3 and R.sub.4 are methyl or phenyl are preferred.The copper compound utilizable as a catalyst for this step of the instant invention may be almost any copper salt or finely divided elemental copper. Preferably, 1-10 mole percent of the copper or copper salt is utilized. The most preferred catalysts are cuprous chloride and copper (II)-2,4-pentanedioate.In order to maximize the yield for this step of the instant invention, it is preferable to use a large excess of the allyl halide of formula III. Most preferably, allyl bromide or allyl iodide is used as the reaction medium. Substituted allyl halides of formula III are preferably diluted with a non-polar co-solvent such as methylene chloride. Polar solvents may also be used, e.g., dimethylformamide, dimethylsulfoxide or acetonitrile, but these provide poorer yields.The reaction is preferably carried out at room temperature; however, depending on the nature of the starting materials, the reaction temperatures may range from about 0.degree. to 50.degree. C. Occasionally, warming to about 40.degree. C. is utilized to initiate the reaction which is then continued without further heating.The stereochemistry at C-6 or C-7 of the intermediate of formula IV is generally a mixture of alpha and beta compounds. Generally, use of the bromides gives a higher ratio of beta to alpha compounds, i.e., 5 to 6:1. Use of the iodides gives more approximately equal amounts of the alpha and beta isomers.The reduction of step 2 to afford the cis product of formula I is accomplished using trialkyl stannane (trialkyl tin hydride). Preferably, tri-n-butyl stannane is utilized. The intermediate of formula IV is heated at about 60.degree.-100.degree. C. with 1-2 equivalents of the tin hydride in an inert solvent. Preferred solvents are tetrahydrofuran, benzene and toluene. Typically, the product is separated by chromatography in yields of greater than 80%.The compounds of formula II wherein Y is an oxygenated sulfur atom may be obtained from the corresponding compounds wherein Y is sulfur by any of the conventional oxidation procedures, e.g., ozone, iodobenzene dichloride in aqueous pyridine, etc. An oxygenated sulfur penicillin compound, i.e., wherein Z is ##STR6## may then be converted to the corresponding cephalosporin, i.e., wherein Y is S and Z is ##STR7## by various literature methods. See, for instance, Flynn, "Cephalosporins and Penicillins", Academic Press, pp. 193-199 and 670-673 (1972). By such methods benzyl 6.beta.-allyl-6.alpha.-bromopenicillanate-1.beta.-oxide may be converted to benzyl 7.beta.-allyl-6.alpha.-bromo-3-methyl-3-cephem-4-carboxylate. The sulfoxide compound is also particularly useful wherein it is desired to convert a mixture of 2- and 3-cephem compounds to a pure 3-cephem compound.The 6- or 7-diazo starting materials of formula II are preparable via a variety of literature methods or variations thereof. A preferred method involves degradation of the penicillin or cephalosporin side chain via the N-nitroso derivative as described by Hausler and Sigg, Helv. Chim. Acta., 1327 (1967); and Sheehan, J. Org. Chem., 39, 1444 (1974). This process involves treatment of the penicillin or cephalosporin, e.g., benzylpenicillin benzyl ester or benzhydryl ester, to form the N-nitroso derivative, followed by decomposition of the nitroso amide side chain with methylene chloride-pyridine or methylene chloride at about 40.degree. C. to afford the diazo compound. An improvement of this process, omitting the pyridine and allowing the reaction to proceed at room temperature in a polar solvent, e.g., dimethylsulfoxide or dimethylformamide, affords a cleaner reaction and better conversion, i.e., >90%. This reaction sequence may be represented by the following scheme: ##STR8## wherein Y, Z and R.sub.1 are as hereinbefore defined.Preferable by this route are the following:benzyl 6-diazopenicillanate;benzhydryl 6-diazopenicillanate;6-diazopenicillanonitrile; andbenzyl 7-diazo-3-methylcephalosporanate.Another modification of the decomposition step in the preparation of the starting materials of formula II is to utilize triphenylphosphine and water in place of the methylene chloride and pyridine according to the method of Sheehan, J. Org. Chem., 42, 1012 ( 1977) to afford the hydrazone of the formula: ##STR9## Oxidation of this hydrazone by the method of U.S. Pat. No. 3,880,837 affords the desired diazo compound. This route is particularly preferred for the cephalosporin starting materials of this invention. Preparable by this route are the following:benzhydryl 7-diazo-3-methylcephalosporinate;benzhydryl 7-diazo-3-acetoxymethylcephalosporinate; andbenzhydryl 6-diazopenicillanate.An additional method for preparing the 6- or 7-diazo compounds of formula II involves diazotisation of the corresponding amino compounds using nitrous acid according to the procedure originally carried out by Hausler and Sigg, Helv. Chim. Acta., 1327 (1967) and further delineated in J. Amer. Chem. Soc., 94, 1408 (1972) and J. Org. Chem., 41, 1578 (1976).Once prepared, the compounds of formula I are utilizable to prepare various 6- or 7-substituted-.beta.-lactams having useful antimicrobial activity, many of which are known in the art. For instance, ozonolysis of 6.beta.-(allyl)penicillanonitrile, benzyl 6.beta.-(allyl)penicillanate or benzhydryl 6.beta.-allylpenicillanate affords 6.beta.-(formylmethyl)-penicillanonitrile, benzyl 6.beta.-(formylmethyl)penicillanate and benzhydryl 6.beta.-(formylmethyl)penicillanate, respectively. This ozonolysis is carried out according to standard methodology.The aldehyde obtained by the ozonolysis described in the preceding paragraph may then be subjected to reduction utilizing a mild reducing agent such as sodium borohydride to afford the corresponding alcohol. For instance, obtainable by this reaction is 6.beta.-(2-hydroxyethyl)penicillanonitrile, benzyl 6.beta.-(2-hydroxyethyl)penicillanate and benzhydryl 6.beta.-(2-hydroxyethyl)penicillanate. The ester group of the preceding two compounds may, of course, be removed utilizing standard hydrogenolysis typically with a palladium catalyst to afford the resulting free acids. Workup with a weak base, e.g., potassium carbonate or sodium carbonate, will afford the potassium or sodium salts, e.g., potassium 6.beta.-(2-hydroxyethyl)penicillanate or sodium 6.beta.-(2-hydroxyethyl)penicillanate.Oxidation of the aldehydes obtainable by the ozonolysis procedure affords the corresponding carboxylic acids. For instance, benzhydryl 6.beta.-(formylmethyl)penicillanate treated with chromic acid in acetone and water affords benzhydryl 6.beta.-(carboxymethyl)penicillanate.Reaction of the foregoing carboxylic acids with suitable azides provides various homo-penicillanates. For instance, benzhydryl 6.beta.-(carboxymethyl)penicillanate treated with diphenylphosphoryl azide and triethylamine at a reaction temperature of about 80.degree. C. according to the method of Ninomiya, et. al., Chem. Pharm. Bull. Japan, 22, 1398 (1974), affords benzhydryl 6.beta.-(carbonylaminomethyl)penicillanate which is typically not isolated. Treatment of this intermediate with the desired acid or alcohol provides homopenicillanates which then may be optionally deblocked. Obtainable in this method are potassium 6.beta.-(phenylacetamidomethyl)penicillanate and potassium 6.beta.-(ethoxycarbonylaminomethyl)penicillanate.Treatment of benzhydryl 6.beta.-(carbonylaminomethyl)penicillanate with trichloroethanol followed by a zinc/acetic acid reduction affords benzhydryl 6.beta.-(aminomethyl)penicillanate. Conventional deblocking of this compound then affords 6.beta.-(aminomethyl)penicillanic acid.Several of the foregoing compounds are described by Sheehan, et. al. as having useful and interesting antimicrobial activity in German Pat. Nos. 2,416,492 and 2,643,085. However, 6.beta.-(aminomethyl)penicillanic acid has not heretofore been described in any publication and is therefore a novel compound.The 6.beta.-(aminomethyl)penicillanic acid produced by the process of this invention possesses antibacterial activity. Additionally, it is a penicillinase inhibitor which may be used concomitantly with other penicillin-type antibiotics in infection therapy.Thus, when tested in standardized microbiological assays, this compound exhibits activity vis-a-vis such organisms as Staphylococcus aureus, Klebsiella, Bacillus subtilis, and Pseudomonas aeruginosa at test levels of 0.1 to 100 .mu.cg/ml. Thus, as antibacterial agents this compound is conventionally formulated for oral, intramuscular, intravenous or topical therapy.Thus, the present invention includes within its scope pharmaceutical compositions comprising an antibacterially effective amount of the novel 6.beta.-(aminomethyl)penicillanic acid with a compatible pharmaceutical carrier therefor, and a method of using such compositions for the treatment of microbial infections.The dosage administered of this compound is dependent upon the age and weight of the animal species being treated, the mode of administration, and the type and severity of bacterial infection being prevented or reduced. Typically, the dosage administered per day will be in the range of 100-5000 mg with 500-1000 mg being preferred.For oral administration, this compound may be formulated in the form of tablets, capsules, elixirs or the like. For parenteral administration it may be formulated into solutions or suspensions for intramuscular injection. Topical formulations include creams, ointments, gels and the like.
    • 在催化量的金属铜或铜盐存在下，6-或7-重氮-β-内酰胺与烯丙基卤化物的反应，得到6-或7-碳取代的β-内酰胺，其具有所需的立体化学构型 - 或7位。 随后用三烷基锡烷还原，为进一步合成提供6-或7-碳取代的β-内酰胺提供了有用的中间体。
    • 基本信息 添加关注 加入工作空间 PDF全文 PDF下载 全文下载 相似专利 双屏查看 权利要求书 说明书全文 Global Dossier Espacenet 法律信息 同族专利 专利引用
    • 9. 发明授权
      US06451797B1 Muscarinic antagonists 失效
    • Muscarinic antagonists
    • 毒蕈碱拮抗剂
    • US06451797B1
    • 2002-09-17
    • US09514935
    • 2000-02-28
    • Joseph A. Kozlowski , Stuart W. McCombie , Jayaram R. Tagat , Susan F. Vice
    • Joseph A. Kozlowski , Stuart W. McCombie , Jayaram R. Tagat , Susan F. Vice
    • A61K31501
    • C07D401/12 , C07D211/58 , C07D405/14 , C07D409/12
    • Heterocyclic derivatives of di-N-substituted piperazine or 1,4 di-substituted piperidine compounds in accordance with formula I (including all isomers, salts and solvates) wherein wherein one of Y and Z is —N— and the other is —N— or —CH—; X is —O—, —S—, —SO—, —SO2— or —CH2—; Q is R is alkyl, cycloalkyl, optionally substituted aryl or heteroaryl; R1, R2 and R3 are H or alkyl; R4 is alkyl, cyclolalkyl or R5 is H, alkyl, —C(O)alkyl, arylcarbonyl, —SO2alkyl, aryl-sulfonyl —C(O)Oalkyl, aryloxycarbonyl, —C(O)NH-alkyl or aryl-aminocarbonyl, wherein the aryl portion is optionally substituted; R6 is H or alkyl; and R7 is H, alkyl, hydroxyalkyl or alkoxyalkyl; are muscarinic antagonists useful for treating cognitive disorders such as Alzheimer's disease. Pharmaceutical compositions and methods of treatment are also disclosed.
    • 根据式I的二-N-取代哌嗪或1,4-二取代的哌啶化合物的杂环衍生物（包括所有异构体，盐和溶剂合物），其中Y和Z之一是-N-，另一个是-N-或 -CH-; X是-O - ， - S-，-SO-，-SO 2 - 或-CH 2 - ; Q是R是烷基，环烷基，任选取代的芳基或杂芳基; R 1和R 2是H或烷基; R 4 是烷基，环烷基或R 5是H，烷基，-C（O）烷基，芳基羰基，-SO 2烷基，芳基 - 磺酰基-C（O）O烷基，芳氧基羰基，-C（O）NH-烷基或芳基 - 氨基羰基， 部分任选被取代; R 6是H或烷基; 和R 7是H，烷基，羟基烷基或烷氧基烷基; 是可用于治疗认知障碍如阿尔茨海默氏病的毒蕈碱拮抗剂。 还公开了药物组合物和治疗方法。
    • 基本信息 添加关注 加入工作空间 PDF全文 PDF下载 全文下载 相似专利 双屏查看 权利要求书 说明书全文 Espacenet 法律信息 同族专利 专利引用
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