- Diverse functionalization of strong alkyl C–H bonds by undirected borylation
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The selective functionalization of strong, typically inert carbon-hydrogen (C–H) bonds in organic molecules is changing synthetic chemistry. However, the undirected functionalization of primary C–H bonds without competing functionalization of secondary C–H bonds is rare. The borylation of alkyl C–H bonds has occurred previously with this selectivity, but slow rates required the substrate to be the solvent or in large excess. We report an iridium catalyst ligated by 2-methylphenanthroline with activity that enables, with the substrate as limiting reagent, undirected borylation of primary C–H bonds and, when primary C–H bonds are absent or blocked, borylation of strong secondary C–H bonds. Reactions at the resulting carbon-boron bond show how these borylations can lead to the installation of a wide range of carbon-carbon and carbon-heteroatom bonds at previously inaccessible positions of organic molecules.
- Oeschger, Raphael,Su, Bo,Yu, Isaac,Ehinger, Christian,Romero, Erik,He, Sam,Hartwig, John
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Read Online
- Sustainable Route Toward N-Boc Amines: AuCl3/CuI-Catalyzed N-tert-butyloxycarbonylation of Amines at Room Temperature
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N-tert-butoxycarbonyl (N-Boc) amines are useful intermediates in synthetic/medicinal chemistry. Traditionally, they are prepared via an indirect phosgene route with poor atom economy. Herein, a step- and atom-economic synthesis of N-Boc amines from amines, t-butanol, and CO was reported at room temperature. Notably, this N-tert-butyloxycarbonylation procedure utilized ready-made substrates, commercially available AuCl3/CuI as catalysts, and O2 from air as the sole oxidant. This catalytic system provided unique selectivity for N-Boc amines in good yields. More significantly, gram-scale preparation of medicinally important N-Boc amine intermediates was successfully implement, which demonstrated a potential application prospect in industrial syntheses. Furthermore, this approach also showed good compatibility with tertiary and other useful alcohols. Investigations of the mechanisms revealed that gold catalyzed the reaction and copper acted as electron transfer mediator in the catalytic cycle.
- Cao, Yanwei,Huang, Yang,He, Lin
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- Enantioselective reduction of heterocyclic ketones with low level of asymmetry using carrots
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A whole spectrum of biocatalysts for asymmetric reduction of prochiral ketones is well known including the Daucus carota root. However, this type of reaction is still challenging when pro-chiral ketones present low level of asymmetry, like heterocyclic ketones. In this work, 4,5-dihydro-3(2H)-thiophenone (1), 2-methyltetrahydrofuran-3-one (2), N-Boc-3-pyrrolidinone (3), 1-Z-3-pyrrolidinone (4) and 1-benzyl-3-pyrrolidinone (5) were studied in order to obtain the respective enantioselective heterocyclic secondary alcohols. Except for 5, the corresponding alcohols were obtained in high values of conversion and with high selectivity. In order to circumvent the low isolated yield of the corresponding chiral alcohol from 2, we observed that the use of carrots in the absence of water is feasible. Addition of co-solvents was needed to the water-insoluble ketones 3 and 4. Comparatively, baker’s yeast was used for bio reductions of 1, 3 and 4. And in terms of conversion, selectivity and work-up, the use of carrots were a more efficient biocatalyst, as well as a viable method for obtaining 5-member heterocyclic secondary alcohols.
- Machado, Naira Vieira,Omori, álvaro Takeo
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p. 475 - 480
(2021/09/27)
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- Erbium-Catalyzed Regioselective Isomerization-Cobalt-Catalyzed Transfer Hydrogenation Sequence for the Synthesis of Anti-Markovnikov Alcohols from Epoxides under Mild Conditions
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Herein, we report an efficient isomerization-transfer hydrogenation reaction sequence based on a cobalt pincer catalyst (1 mol %), which allows the synthesis of a series of anti-Markovnikov alcohols from terminal and internal epoxides under mild reaction conditions (≤55 °C, 8 h) at low catalyst loading. The reaction proceeds by Lewis acid (3 mol % Er(OTf)3)-catalyzed epoxide isomerization and subsequent cobalt-catalyzed transfer hydrogenation using ammonia borane as the hydrogen source. The general applicability of this methodology is highlighted by the synthesis of 43 alcohols from epoxides. A variety of terminal (23 examples) and 1,2-disubstituted internal epoxides (14 examples) bearing different functional groups are converted to the desired anti-Markovnikov alcohols in excellent selectivity and yields of up to 98%. For selected examples, it is shown that the reaction can be performed on a preparative scale up to 50 mmol. Notably, the isomerization step proceeds via the most stable carbocation. Thus, the regiochemistry is controlled by stereoelectronic effects. As a result, in some cases, rearrangement of the carbon framework is observed when tri-and tetra-substituted epoxides (6 examples) are converted. A variety of functional groups are tolerated under the reaction conditions even though aldehydes and ketones are also reduced to the respective alcohols under the reaction conditions. Mechanistic studies and control experiments were used to investigate the role of the Lewis acid in the reaction. Besides acting as the catalyst for the epoxide isomerization, the Lewis acid was found to facilitate the dehydrogenation of the hydrogen donor, which enhances the rate of the transfer hydrogenation step. These experiments additionally indicate the direct transfer of hydrogen from the amine borane in the reduction step.
- Liu, Xin,Longwitz, Lars,Spiegelberg, Brian,T?njes, Jan,Beweries, Torsten,Werner, Thomas
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p. 13659 - 13667
(2020/11/30)
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- NOVEL COMPOUNDS FOR INHIBITION OF JANUS KINASE 1
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An object of the invention is to provide compounds as selective JAK1 inhibitor, a process for preparation of the inhibitors, a composition containing the compounds and utility of the compounds.
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Page/Page column 89
(2020/12/11)
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- NON-FUSED TRICYCLIC COMPOUNDS
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Provided herein are compounds and pharmaceutical compositions comprising said compounds that are useful for treating cancers. Specific cancers include those that are mediated by YAP/TAZ or those that are modulated by the interaction between YAP/TAZ and TEAD.
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Paragraph 00685
(2018/11/26)
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- NAPHTHYRIDINES AS INHIBITORS OF HPK1
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Naphthyridine compounds and their use as inhibitors of HPK1 are described. The compounds are useful in treating HPK1-dependent disorders and enhancing an immune response. Also described are methods of inhibiting HPK1, methods of treating HPK1-dependent disorders, methods for enhancing an immune response, and methods for preparing the naphthyridine compounds.
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Paragraph 1143; 1144
(2018/10/21)
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- Alkenyl compound and its method and use thereof
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The invention provides a new substituted alkenyl compound, pharmaceutically acceptable salts of the new substituted alkenyl compound, a medicinal preparation of the new substituted alkenyl compound, and application of the new substituted alkenyl compound, the pharmaceutically acceptable salts and the medicinal preparation of the new substituted alkenyl compound in aspects of regulating the activity of protein kinase and regulating the intercellular or intracellular signal response. The invention also relates to a medicament composition containing the compound at the same time, and relates to a method for treating high-proliferative diseases of mammals especially the human by using the medicament composition.
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Paragraph 0763; 0765; 0766
(2018/03/01)
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- BIARYL DERIVATIVE AS GPR120 AGONIST
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The present invention relates to a biaryl derivative expressed by the chemical formula 1, a method for producing the biaryl derivative, a pharmaceutical composition comprising same, and use of same, the biaryl derivative expressed by the chemical formula 1, as a GPR120 agonist, promoting GLP-1 generation in the gastro-intestinal tract, reducing insulin resistance in the liver, muscles and the like from anti-inflammatory activity in the macrophage, pancreatic cells and the like, and allowing effective use in prevention or treatment of inflammation or metabolic diseases such as diabetes, complications from diabetes, obesity, non-alcoholic fatty liver disease, fatty liver disease, and osteoporosis.
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Paragraph 0265
(2017/11/17)
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- Glutaminase inhibitors as well as compositions and applications thereof
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The invention provides a series of heterocyclic compounds expressed in a formula I. The compound comprises glutaminase inhibition activity, and can be used for treating diseases and symptoms related to dysfunction of glutaminase or raising activity of glutaminase.
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Paragraph 0385; 0386; 0387; 0388
(2018/01/09)
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- Trisubstituted Pyridinylimidazoles as Potent Inhibitors of the Clinically Resistant L858R/T790M/C797S EGFR Mutant: Targeting of Both Hydrophobic Regions and the Phosphate Binding Site
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Inhibition of the epidermal growth factor receptor represents one of the most promising strategies in the treatment of lung cancer. Acquired resistance compromises the clinical efficacy of EGFR inhibitors during long-term treatment. The recently discovered EGFR-C797S mutation causes resistance against third-generation EGFR inhibitors. Here we present a rational approach based on extending the inhibition profile of a p38 MAP kinase inhibitor toward mutant EGFR inhibition. We used a privileged scaffold with proven cellular potency as well as in vivo efficacy and low toxicity. Guided by molecular modeling, we synthesized and studied the structure-activity relationship of 40 compounds against clinically relevant EGFR mutants. We successfully improved the cellular EGFR inhibition down to the low nanomolar range with covalently binding inhibitors against a gefitinib resistant T790M mutant cell line. We identified additional noncovalent interactions, which allowed us to develop metabolically stable inhibitors with high activities against the osimertinib resistant L858R/T790M/C797S mutant.
- Günther, Marcel,Lategahn, Jonas,Juchum, Michael,D?ring, Eva,Keul, Marina,Engel, Julian,Tumbrink, Hannah L.,Rauh, Daniel,Laufer, Stefan
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p. 5613 - 5637
(2017/07/22)
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- Substituted heteroaryl compounds and composition thereof, and applicaitons of compounds and composition
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The invention provides substituted heteroaryl compounds and a composition thereof, and applicaitons of the compounds and the composition. The compounds are compounds represented by the formula (I) or the formula (II) or stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of the compounds represented by the formula (I) or the formula (II). The invention also provides the pharmaceutical composition comprising the compounds; the compounds and the pharmaceutical composition can adjust the activity of protein kinase, and are used for prevention, processing, treatment and remission of diseases or disorders mediated by the protein kinase.
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Paragraph 1036; 1037; 1038; 1039
(2017/07/31)
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- NEW ANTIBACTERIAL COMPOUNDS
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The present invention relates to novel antibacterial compounds, pharmaceutical compositions containing them and their use as antimicrobials.
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Page/Page column 59
(2018/01/19)
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- Stereo-complementary bioreduction of saturated N-heterocyclic ketones
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The asymmetric bioreduction of several saturated N-heterocyclic ketones is demonstrated in a stereo-complementary fashion using the ketoreductases READH and ChKRED20 for the production of (S)- and (R)-alcohols, respectively. The reaction accepts substrates with a five-, six- or seven-membered ring, and exhibits excellent stereoselectivity when using 2-propanol as both the ultimate reducing agent and cosolvent, achieve >99% ee in the majority of cases for both enantiomers.
- Li, Chao,Liu, Yan,Pei, Xiao-Qiong,Wu, Zhong-Liu
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- SUBSTITUTED HETEROARYL COMPOUNDS AND METHODS OF USE
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The present invention provides novel heteroaryl compounds, pharmaceutical acceptable salts and formulations thereof. They are useful in preventing, managing, treating or lessening the severity of a protein kinase-mediated disease. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of protein kinase-mediated disease.
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Paragraph 0488
(2017/03/28)
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- SUBSTITUTED 1,2,3,4-TETRAHYDROPYRIDO[3,4-E] PYRROLO[1,2-A]PYRIMIDINES AS KINASE INHIBITORS
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The present invention relates to organic molecules capable of modulating tyrosine kinase signal transduction in order to regulate, modulate and/or inhibit abnormal cell proliferation.
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Paragraph 0137; 0138
(2016/05/02)
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- Preparation method of 1-BOC-3-hydroxymethyl pyrrolidine
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The invention discloses a preparation method of 1-Boc-3-hydroxymethyl pyrrolidine. The preparation method uses epichlorohydrin as a raw material, 3-hydroxymethyl pyrrolidine is obtained through reduction and cyclization reaction, then the 1-Boc-3-hydroxymethyl pyrrolidine is prepared through Boc protection reaction, then 1-BOC-3-methyl formate pyrrolidine is prepared through carboxylation reaction and esterification reaction, and finally the 1-BOC-3-methyl formate pyrrolidine and lithium aluminum hydride are catalyzed by a catalyst to prepare the 1-BOC-3-hydroxymethyl pyrrolidine. The preparation method is high in product synthesis rate, high in product purity and low in production cost, and the raw materials are cheap and easy to obtain.
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Paragraph 0021; 0025
(2017/05/10)
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- ALKENYL COMPOUNDS AND METHODS OF USE
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The present invention provides novel substituted alkenyl compounds, pharmaceutical acceptable salts and formulations thereof useful in modulating the protein tyrosine kinase activity, and in modulating cellular activities such as proliferation, differentiation, apoptosis, migration and invasion. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of hyperproliferative disorders in mammals, especially humans.
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Paragraph 0270
(2014/12/12)
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- IMIDAZO [1, 2 - B] PYRIDAZINE DERIVATIVES AS CDPK1 INHIBITORS
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A first aspect of the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt or ester thereof, (Formula (I)) wherein: R1 is -(CH2)nNR3R4, -OR5 or -(CH2)n-heterocycloalkyl, wherein said heterocycloalkyl group is optionally substituted by one or more R7 groups; R2 is selected from aryl, heteroaryl, fused aryl-heterocycloalkyl and fused hetero aryl-heterocycloalkyl each of which is substituted by at least one R8 group; R3 is H or alkyl; R4 is: (i) cycloalkyl optionally substituted by one or more -NR11R12 or NHCOR11 groups; or (ii) -(CH2)n-heterocycloalkyl, wherein said heterocycloalkyl is a 4, 5 or 6-membered nitrogen-containing group optionally containing one or more CO groups, wherein said heterocycloalkyl is optionally substituted by one or more one or more (CH2)nR7 groups; or (iii) alkyl substituted by one or more -NR11R12groups; or R3 and R4 are linked together with the nitrogen to which they are attached to form a 4, 5, 6 or 7-membered monocyclic heterocycloalkyl group or a bicyclic heterocyclic group, each of which optionally contains one or two further groups selected from CO, O, N and S, and which is optionally further substituted by one or more R7 groups; R5 is selected from alkyl, -(CH2)n-heteroaryl and - (CH2)n-heterocycloalkyl, wherein said heteroaryl and heterocycloalkyl groups are each optionally substituted by one or more R7 groups; each R8 is independently selected from - NR16R17, -OR17 and -(CH2)nR17 where each R16 is H and each R17 is independently - (CHR10)n-heteroaryl, wherein said heteroaryl group is in turn optionally substituted by one or more R7 groups; each R10, R11 and R12 is independently H or alkyl; or in the case of an - NR11R12 group, R11 and R12 may be linked together with the nitrogen to which they are attached to form a 4, 5, 6 or 7-membered monocyclic or bicyclic heterocycloalkyl group optionally containing one or two further groups selected from CO, O, N and S, and which is optionally further substituted by one or more R7 groups; each m is independently an integer from 1 to 6; and each n is independently an integer from 0 to 6. Further aspects relate to the use of said compounds in the treatment of various therapeutic disorders, and more particularly as inhibitors of PfCDPK1.
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Page/Page column 87
(2012/10/08)
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- NOVEL HETEROCYCLIC ACRYLAMIDES AND THEIR USE AS PHARMACEUTICALS
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The invention relates to novel heterocyclic acrylamide compounds (I), to the preparation of the compounds and intermediates used therein, to the use of the compounds as antibacterial medicaments and pharmaceutical compositions containing the compounds.
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Page/Page column 47
(2011/06/19)
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- HETEROCYCLOALKYL-CONTAINING THIENOPYRIMIDINES FOR PHARMACEUTICAL COMPOSITIONS
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The present invention relates to novel pharmaceutical compositions comprising thienopyrimidine compounds. Moreover, the present invention relates to the use of the thienopyrimidine compounds of the invention for the production of pharmaceutical compositio
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Page/Page column 29
(2011/09/20)
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- HETEROCYCLIC COMPOUND
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The present invention relates to wherein each symbol is as defined in the specification. The compound of the present invention has a superior RBP4-lowering action, and is useful as a medicament for the prophylaxis or treatment of disease and condition mediated by increased RBP4.
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Page/Page column 63-64
(2010/07/08)
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- Pleuromutilin derivatives having a purine ring. Part 2: Influence of the central spacer on the antibacterial activity against Gram-positive pathogens
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Structural modification of the 4-piperidinethio moiety, as a spacer of the first pleuromutilin analogues 2A and 2B having a purine ring, led to discovery of the novel pleuromutilin derivatives 14B and 17B. These compounds with good solubility in water showed promising in vitro antibacterial activity against various Gram-positive bacteria including MRSA, PRSP, and VRE and have potent in vivo efficacy.
- Hirokawa, Yoshimi,Kinoshita, Hironori,Tanaka, Tomoyuki,Nakamura, Takanori,Fujimoto, Koichi,Kashimoto, Shigeki,Kojima, Tsuyoshi,Kato, Shiro
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scheme or table
p. 170 - 174
(2009/05/07)
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- Heterocyclic lithium amides as chiral ligands for an enantioselective hydroxyalkylation with n-BuLi
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(Chemical Equation Presented) Chiral heterocyclic structures based on 3-aminopyrrolidines (3APs), 3-aminotetrahydrothiophens (3ATTs), and 3-aminotetrahydrofurans (3ATFs) have been synthesized. The corresponding lithium amides have been evaluated as chiral ligands in the condensation of n-BuLi on o-tolualdehyde. The returned levels of induction were in the 46-80% ee range. The cheap and easily prepared 3ATFLi's turned out to be also the best ligands, giving access to the expected R or S alcohols in a same 80% level of induction at -78°C in THF. In all cases, the sense of induction depends on the absolute configuration of C8 on the 3-amino appendage. A general concept is proposed to rationalize the process of induction in the presence of organolithium species.
- Duguet, Nicolas,Petit, Sylvain M.,Marchand, Philippe,Harrison-Marchand, Anne,Maddaluno, Jacques
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p. 5397 - 5409
(2008/12/21)
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- PROCESS FOR PRODUCTION OF ARALKYLOXYPYRROLIDINE DERIVATIVE
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The present invention provides a process for producing a 3-aralkyloxypyrrolidine derivative which is important for production of pharmaceutical products and the like. In the present invention, a N-protected-3-hydroxypyrrolidine is converted into a N-protected-3-aralkyloxypyrrolidine by allowing an aralkyl halide to act in the presence of a base and at least one of a metal halide and a phase-transfer catalyst followed by deprotecting a N-protecting group to convert it to a 3-aralkyloxypyrrolidine derivative and subsequently treating the derivative in a solvent containing a polar solvent, thereby obtaining the 3-aralkyloxypyrrolidine derivative as a crystal. According to the present invention, a 3-aralkyloxypyrrolidine derivative of high purity can be produced conveniently and efficiently on an industrial scale.
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Page/Page column 13
(2008/12/07)
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- QUINAZOLINE DERIVATIVES AS A MULTIPLEX INHIBITOR AND METHOD FOR THE PREPARATION THEREOF
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The present invention relates to a novel quinazoline derivative and a pharmaceutically acceptable salt thereof as a multiplex inhibitor, a method for the preparation thereof, and a pharmaceutical composition and a therapeutic composition comprising same as an active ingredient. The inventive quinazoline derivative as a multiplex inhibitor can selectively and effectively inhibit diseases caused by the overactivity of a tyrosine kinase.
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Page/Page column 106
(2008/06/13)
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- AZAHETEROCYCLYL DERIVATIVES OF ANDROSTANES AND ANDROSTENES AS MEDICAMENTS FOR CARDIOVASCULAR DISORDERS
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Compounds of formula (I) wherein: the groups are as defined in the description, are useful for the preparation of medicaments for the treatment of cardiovascular disorders, in particular heart failure and hypertension. The compounds are inhibitors of the enzymatic activity of the Na+,K+-ATPase. They are useful for the preparation of a medicament for the treatment of a disease caused by the hypertensive effects of endogenous ouabain, such as renal failure progression in autosomal dominant polycystic renal disease (ADPKD), preeclamptic hypertension and proteinuria and renal failure progression in patients with adducin polymorphisms.
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Page/Page column 92
(2008/06/13)
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- 2-(CYCLIC AMINO)-PYRIMIDONE DERIVATIVES AS TPK1 INHIBITORS
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A compound represented by the formula (I), an optically active isomer thereof, or a pharmaceutical acceptable salt thereof (I) wherein R2 represents a hydrogen or the like; R3 represents methyl group or the like; R20 represents a halogen atom or the like; q represents an integer of 0 to 3; Z represent nitrogen atom, CH, or the like; R4 represents hydrogen or the like; R5 represents hydrogen or the like; R6 represents a substituted alkyloxy and the like; p represents an integer of 0 to 3; X represents bond, CH2, oxygen atom, NH, or the like; any one or more of R5 and R6, R5 and R4, R6 and R4, X and R5, X and R4, X and R6, and R6 and R6 may combine to each other to form a ring, which is used for preventive and/or therapeutic treatment of a disease caused by tau protein kinase 1 hyperactivity such as a neurodegenerative diseases (e.g. Alzheimer disease).
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Page/Page column 206
(2008/06/13)
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- Design and synthesis of rho kinase inhibitors (III)
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The structure-activity relationship of Rho kinase inhibitors bearing an isoquinoline scaffold was studied. N-(1-Benzyl-3-pyrrolidyl)-N-(5-isoquinolyl)amine analogues were optimized with respect to their inhibitory potencies for the enzyme and for chemotaxis. The potent analogues were further evaluated by an ex vivo test in which the selected compounds were orally administered to rats, and the Rho kinase inhibitory potency observed in the rat serum was evaluated 3 h after the administration. Compound 23g showed a high level of Rho kinase inhibitory activity in the rat serum and was stable in an in vitro metabolic test using a microsomal cytochrome preparation. The (R)-isomer of 23g displayed a higher level of inhibitory potency than the (S)-isomer in a cell-free kinase assay and in the cell migration assay (IC50ENZ = 25 nM and IC50MCP = 1 μ M). The (R)-isomer successfully inhibited the phosphorylation of MBS (myosin-binding subunit) in cells.
- Iwakubo, Masayuki,Takami, Atsuya,Okada, Yuji,Kawata, Takehisa,Tagami, Yoshimichi,Sato, Motoko,Sugiyama, Terumi,Fukushima, Kayoko,Taya, Shinichiro,Amano, Mutsuki,Kaibuchi, Kozo,Iijima, Hiroshi
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p. 1022 - 1033
(2007/10/03)
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- THIENOPYRIMIDINES FOR PHARMACEUTICAL COMPOSITIONS
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The present invention relates to novel pharmaceutical compositions of general formula (I) comprising thienopyrimidine compounds. Moreover, the present invention relates to the use of the thienopyrimidine compounds of the invention for the production of pharmaceutical compositions for the prophylaxis and/or treatment of diseases which can be influenced by the inhibition of the kinase activity of Mnk1 and/or Mnk2 (Mnk2a or Mnk2b) and/or variants thereof.
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Page/Page column 107
(2010/11/25)
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- INHIBITORS OF TRYPTASE
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The present invention related to certain inhibitors of tryptase that are inhibitors of tryptase, pharmaceutical composition comprising these compounds and method of treating asthma, allergic rhinitis, and/or Chronic Obstructive Pulmonary Disease utilizing these compounds.
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Page/Page column 158
(2008/06/13)
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- PYRROLIDYL DERIVATIVES OF HETEROAROMATIC COMPOUNDS AS PHOSPHODIESTERASE INHIBITORS
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The invention pertains to new pyrrolidyl derivatives of benzo-fused aza heteroaromatic compounds that serve as effective phosphodiesterase (PDE) inhibitors. The invention also relates to compounds that are selective inhibitors of PDE-IO. The invention fur
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Page/Page column 45
(2008/06/13)
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- Synthesis of racemic and enantiomeric 3-pyrrolidinyl derivatives of nucleobases
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The synthesis of novel 3-pyrrolidinyl derivatives of nucleobases is described. Starting from malic acid, we improved the synthesis of both racemic and optically active N-benzyl-3-hydroxypyrrolidine-2,5-diones, which were transformed in four steps into N-tert-butyloxycarbonyl-3-mesyloxypyrrolidines, the key synthons for the alkylation of purine and pyrimidine nucleobases. Alkylations of cesium salts of purines and sodium salts of pyrimidines with N-tert-butyloxycarbonyl-3-mesyloxypyrrolidines proceeded smoothly, giving high yields of 9-substituted purine derivatives and moderate yields of 1-substituted pyrimidine derivatives. Using (S)-N-tert-butyloxycarbonyl-3-mesyloxypyrrolidine as the same intermediate for the synthesis of both enantiomeric N-Boc-3-pyrrolidinyladenines, and considering the results obtained on chiral HPLC analysis of the products, we proved that nucleophilic displacement of the mesyloxy group proceeded with inversion and not with retention of the configuration. Prepared compounds were tested for cytostatic and antiviral properties, but no significant activity was found.
- Ko?alka, Petr,Pohl, Radek,Rejman, Dominik,Rosenberg, Ivan
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p. 5763 - 5774
(2007/10/03)
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- NON-ANILINIC DERIVATIVES OF ISOTHIAZOL-3(2H)-ONE 1,1-DIOXIDES AS LIVER X RECEPTOR MODULATORS
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The present invention relates to certain novel compounds of the formula (I) to processes for preparing such compounds, to their the utility in modulation of nuclear hormone receptors Liver X Receptor (LXR) α (NR1H3) and/or β (NR1H2) and in treating and/or preventing clinical conditions including cardiovascular diseases such as atherosclerosis; inflammatory diseases, Alzheimer's disease, lipid disorders (dyslipidemias) whether or not associated with insulin resistance, type 2 diabetes and other manifestations of the metabolic syndrome, to methods for their therapeutic use and to pharmaceutical compositions containing them.
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Page/Page column 184-185
(2008/06/13)
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- 7-PHENYL-ISOQUINOLINE-5-SULFONYLAMINO DERIVATIVES AS INHIBITORS OF AKT (PROTEINKINASE B)
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The present invention relates to compounds Formula (I) as inhibitors of AKT activity, which are useful for the treatment of susceptible neoplasms and viral infections.
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Page/Page column 31
(2010/02/12)
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- 6-AZAINDOLE COMPOUND
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A compound represented by the formula (I) wherein R1, R2, R3 and R6 are the same or different and each is a hydrogen atom or a substituent; one of R4 and R5 is a hydrogen atom and the other is a group represented by the formula: -C(=X)-R7 wherein X is N-O-R8 or N-NH-R9 wherein R8 and R9 are the same or different and each is a hydrogen atom or a group bonded via a carbon atom; and R7 is a hydrogen atom or a substituent, and the like and a salt thereof have a superior IκB kinase inhibitory activity, and useful as pharmaceutical agents such as agents for preventing or treating diabetes and the like.
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Page/Page column 78-79
(2008/06/13)
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- Pyrazolopyrimidines as therapeutic agents
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The present invention is directed to pyrazolopyrimidine derivatives of formula (I) wherein the substituents are defined herein, which are useful as kinase inhibitors and as such are useful for affecting angiogenesis and diseases and conditions associated with angiogenesis.
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- BENZAMIDE DERIVATIVES
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A compound represented by formula (1): wherein X is a single bond or a substituted or unsubstituted lower alkylene group; Z is a saturated or unsaturated monocyclic hydrocarbon ring group or the like; and each of R1, R2, R3 and R4, which may be the same or different, is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a carboxyl group, a substituted or unsubstituted alkyl group, or the like, a prodrug of said compound, or a pharmaceutically acceptable salt of said compound or prodrug has inhibitory effect on Rho kinase and hence is useful for treating diseases which are such that morbidity due to them is expected to be improved by inhibition of Rho kinase and secondary effects such as inhibition of the Na+/H+ exchange transport system caused by the Rho kinase inhibition, for example, hypertension.
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- Pyrazolyl derivatives, preparation process and intermediates of this process as medicinal products and pharmaceutical compositions containing them
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The present invention relates to the novel derivatives of formula (I) in which A is, if it is present, a (C1-C6) alkyl, a (C3-C6) alkenyl, a (C3-C6) alkynyl, a (C3-C7) cycloalkyl or a (C5-C7) cycloalkenyl, R1 is an NR6R7, (C4-C7) azacycloalkyl, (C5-C7) azacycloalkenyl, (C5-C9) azabicycloalkyl or (C5-C9) azabicycloalkenyl group; A-R1 is such that the nitrogen of R1 and the nitrogen in the 1-position of the pyrazole are necessarily separated by at least two carbon atoms, R3 is an H, halogen, OH, SH, NH2, ORc, SRc, SORa, SO2Ra, NHCHO, NRaRb, NHC(O)Ra, NHC(S)Ra or NHSO2Ra, R4 is an aryl or heteroaryl; and R5 is an H, halogen, CF3, CHF2, CH2F, linear or branched (C1-C6) alkyl or (C3-C7) cycloalkyl to their racemates, enantiomers and diastereoisomers and to their mixtures, their tautomers and to their pharmaceutically acceptable salts.
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Page/Page column 58
(2008/06/13)
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- ORGANIC COMPOUNDS
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Compounds of formula (I) in free or salt form, wherein T, X, Y, U, R1, R2,m, n and p have the meanings as indicated in the specification, are useful for treating conditions mediated by CCR3. Pharmaceutical compositions that con
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Page/Page column 19
(2008/06/13)
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- Pharmaceutical compositions as inhibitors of dipeptidyl peptidase-IV (DPP-IV)
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The present invention relates to compounds of formula (I), which inhibit dipeptidyl peptidase IV (DPP-IV) and are useful for the prevention or treatment of diabetes, especially type II diabetes, as well as hyperglycemia, syndrome X, hyperinsulinemia, obesity, atherosclerosis, and various immunomodulatory diseases.
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Page/Page column 38
(2010/02/14)
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- PHARMACEUTICAL COMPOSITIONS AS INHIBITORS OF DIPEPTIDYL PEPTIDASE-IV (DPP-IV)
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The present invention relates to compounds of formula (I), which inhibit dipeptidyl peptidase IV (DPP-IV) and are useful for the prevention or treatment of diabetes, especially type II diabetes, as well as hyperglycemia, syndrome X, hyperinsulinemia, obesity, atherosclerosis, and various immunomodulatory diseases.
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Page/Page column 38-39
(2010/02/14)
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- INHIBITORS OF PHOSPHODIESTERASE TYPE-IV
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The present invention relates to isoxazoline derivatives, which can be used as selective inhibitors of phosphodiesterase (PDE) type IV. In particular, compounds disclosed herein can be useful in the treatment of AIDS, asthma, arthritis, bronchitis, chronic obstructive pulmonary disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis and other inflammatory diseases in a patient, particularly in humans. The present invention also relates to processes for the preparation of disclosed compounds, as well as pharmaceutical compositions thereof, and their use as phosphodiesterase (PDE) type IV inhibitors.
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Page/Page column 75
(2010/02/11)
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- NOVEL BENSOPHENONE DERIVATIVES OR SALTS THEREOF
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A benzophenone derivative represented by the following formula: whereinR1 represents, for example, an optionally substituted heterocyclic group, or a substituted phenyl group; Z represents, for example, an alkylene group; R2 represents, for example, a carboxyl group optionally protected with alkyl;R3 represents, for example, an optionally protected hydroxyl group; R4 represents, for example, an optionally substituted cycloalkyloxy group; and R5 represents, for example, a hydrogen atom, ???or a salt thereof has anti-arthritic activity, inhibits bone destruction caused by arthritis, and provides high safety and excellent pharmacokinetics and thus is useful as therapeutic agent for arthritis. These compounds have inhibitory effect on AP-1 activity and are useful as preventive or therapeutic agent for diseases in which excessive expression of AP-1 is involved.
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Page 131-132
(2010/02/07)
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- Pyrazolopyrimidines as therapeutic agents
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The present invention provides compounds of Formula I, including pharmaceutically acceptable salts and/or prodrugs thereof, where G, Ra, R2, and R3 are defined as described herein.
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Page/Page column 98
(2010/11/30)
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- PYRIDYL ETHERS AND THIOETHERS AS LIGANDS FOR NICOTINIC ACETYLCHOLINE RECEPTOR AND ITS THERAPEUTIC APPLICATION
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The present invention provides compounds of the formula:wherein m is 0, 1 or 2; p is 0 or 1; Y is O, S, S(O) or S(O)2 and R1 to R7 are various substituents as selective modulators of the nicotinic acetylcholine receptor useful in the treatment of pain, Al
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- Design and synthesis of Rho kinase inhibitors (I)
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Several structurally unrelated scaffolds of the Rho kinase inhibitor were designed using pharmacophore information obtained from the results of a high-throughput screening and structural information from a homology model of Rho kinase. A docking simulation using the ligand-binding pocket of the Rho kinase model helped to comprehensively understand and to predict the structure-activity relationship of the inhibitors. This understanding was useful for developing new Rho kinase inhibitors of higher potency and selectivity. We identified several potent platforms for developing the Rho kinase inhibitors, namely, pyridine, 1H-indazole, isoquinoline, and phthalimide.
- Takami, Atsuya,Iwakubo, Masayuki,Okada, Yuji,Kawata, Takehisa,Odai, Hideharu,Takahashi, Nobuaki,Shindo, Kazutoshi,Kimura, Kaname,Tagami, Yoshimichi,Miyake, Mika,Fukushima, Kayoko,Inagaki, Masaki,Amano, Mutsuki,Kaibuchi, Kozo,Iijima, Hiroshi
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p. 2115 - 2137
(2007/10/03)
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- Discovery of N-propylurea 3-benzylpiperidines as selective CC chemokine receptor-3 (CCR3) antagonists
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The discovery of novel and selective small molecule antagonists of the CC Chemokine Receptor-3 (CCR3) is presented. Simple conversion from a 4- to 3-benzylpiperidine gave improved selectivity for CCR3 over the serotonin 5HT2A receptor. Chiral resolution and exploration of mono- and disubstitution of the N-propylurea resulted in several 3-benzylpiperidine N-propylureas with CCR3 binding IC50s under 5 nM. Data from in vitro calcium mobilization and chemotaxis assays for these compounds ranged from high picomolar to low nanomolar EC50s and correlated well with antagonist binding IC50s.
- Varnes, Jeffrey G.,Gardner, Daniel S.,Santella III, Joseph B.,Duncia, John V.,Estrella, Melissa,Watson, Paul S.,Clark, Cheryl M.,Ko, Soo S.,Welch, Patricia,Covington, Maryanne,Stowell, Nicole,Wadman, Eric,Davies, Paul,Solomon, Kimberley,Newton, Robert C.,Trainor, George L.,Decicco, Carl P.,Wacker, Dean A.
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p. 1645 - 1649
(2007/10/03)
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- Novel compounds
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The invention provides compounds of general formula (I) wherein Q, R, R2, R4, R5, R6, R7 and R8 are as defined in the specification, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
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