- Cobalt-Catalyzed C(sp2)-C(sp3) Suzuki-Miyaura Cross-Coupling Enabled by Well-Defined Precatalysts with L,X-Type Ligands
-
Cobalt(II) halides in combination with phenoxyimine (FI) ligands generated efficient precatalysts in situ for the C(sp2)-C(sp3) Suzuki-Miyaura cross-coupling between alkyl bromides and neopentylglycol (hetero)arylboronic esters. The protocol enabled efficient C-C bond formation with a host of nucleophiles and electrophiles (36 examples, 34-95%) with precatalyst loadings of 5 mol %. Studies with alkyl halide electrophiles that function as radical clocks support the intermediacy of alkyl radicals during the course of the catalytic reaction. The improved performance of the FI-cobalt catalyst was correlated with decreased lifetimes of cage-escaped radicals as compared to those of diamine-type ligands. Studies of the phenoxyimine-cobalt coordination chemistry validate the L,X interaction leading to the discovery of an optimal, well-defined, air-stable mono-FI-cobalt(II) precatalyst structure.
- Mills, L. Reginald,Gygi, David,Ludwig, Jacob R.,Simmons, Eric M.,Wisniewski, Steven R.,Kim, Junho,Chirik, Paul J.
-
p. 1905 - 1918
(2022/02/07)
-
- A general N-alkylation platform via copper metallaphotoredox and silyl radical activation of alkyl halides
-
The catalytic union of amides, sulfonamides, anilines, imines, or N-heterocycles with a broad spectrum of electronically and sterically diverse alkyl bromides has been achieved via a visible-light-induced metallaphotoredox platform. The use of a halogen abstraction-radical capture (HARC) mechanism allows for room temperature coupling of C(sp3)-bromides using simple Cu(II) salts, effectively bypassing the prohibitively high barriers typically associated with thermally induced SN2 or SN1 N-alkylation. This regio- and chemoselective protocol is compatible with >10 classes of medicinally relevant N-nucleophiles, including established pharmaceutical agents, in addition to structurally diverse primary, secondary, and tertiary alkyl bromides. Furthermore, the capacity of HARC methodologies to engage conventionally inert coupling partners is highlighted via the union of N-nucleophiles with cyclopropyl bromides and unactivated alkyl chlorides, substrates that are incompatible with nucleophilic substitution pathways. Preliminary mechanistic experiments validate the dual catalytic, open-shell nature of this platform, which enables reactivity previously unattainable in traditional halide-based N-alkylation systems.
- Cabré, Albert,Dow, Nathan W.,MacMillan, David W. C.
-
supporting information
p. 1827 - 1842
(2021/07/07)
-
- Merging Halogen-Atom Transfer (XAT) and Cobalt Catalysis to Override E2-Selectivity in the Elimination of Alkyl Halides: A Mild Route towardcontra-Thermodynamic Olefins
-
We report here a mechanistically distinct tactic to carry E2-type eliminations on alkyl halides. This strategy exploits the interplay of α-aminoalkyl radical-mediated halogen-atom transfer (XAT) with desaturative cobalt catalysis. The methodology is high-yielding, tolerates many functionalities, and was used to access industrially relevant materials. In contrast to thermal E2 eliminations where unsymmetrical substrates give regioisomeric mixtures, this approach enables, by fine-tuning of the electronic and steric properties of the cobalt catalyst, to obtain high olefin positional selectivity. This unprecedented mechanistic feature has allowed access tocontra-thermodynamic olefins, elusive by E2 eliminations.
- Zhao, Huaibo,McMillan, Alastair J.,Constantin, Timothée,Mykura, Rory C.,Juliá, Fabio,Leonori, Daniele
-
supporting information
p. 14806 - 14813
(2021/09/18)
-
- Copper-Catalyzed Cross-Coupling between Alkyl (Pseudo)halides and Bicyclopentyl Grignard Reagents
-
The development of a copper-catalyzed cross-coupling between primary and secondary (pseudo)halides and bicyclopentyl Grignard reagents is reported. Highly strained bicyclopentanes can be cross-coupled with a large panel of primary alkyl mesylates and secondary alkyl iodides. The catalytic system is simple and cheap, and the reaction is general and chemoselective.
- Andersen, Claire,Bernardelli, Patrick,Cossy, Janine,Daumas, Marc,Ferey, Vincent,Guérinot, Amandine
-
supporting information
(2020/08/05)
-
- Nickel-Catalyzed Formal Aminocarbonylation of Unactivated Alkyl Iodides with Isocyanides
-
Herein, we disclose a Ni-catalyzed formal aminocarbonylation of primary and secondary unactivated aliphatic iodides with isocyanides to afford alkyl amide, which proceeds via the selective monomigratory insertion of isocyanides with alkyl iodides, subsequent β-hydride elimination, and hydrolysis process. The reaction features wide functional group tolerance under mild conditions. Additionally, the selective, one-pot hydrolysis of reaction mixture under acid conditions allows for expedient synthesis of the corresponding alkyl carboxylic acid.
- Chen, Yifeng,Huang, Wenyi,Qu, Jingping,Shrestha, Mohini,Wang, Yun,Weng, Yangyang
-
supporting information
p. 3245 - 3250
(2020/04/21)
-
- Palladium-Catalyzed Visible-Light-Driven Carboxylation of Aryl and Alkenyl Triflates by Using Photoredox Catalysts
-
A visible-light-driven carboxylation of aryl and alkenyl triflates with CO2 is developed by using a combination of Pd and photoredox catalysts. This reaction proceeds under mild conditions and can be applied to a wide range of substrates including acyclic alkenyl triflates.
- Shimomaki, Katsuya,Nakajima, Tomoya,Caner, Joaquim,Toriumi, Naoyuki,Iwasawa, Nobuharu
-
supporting information
p. 4486 - 4489
(2019/06/24)
-
- Synthesis, molecular modeling and evaluation of α-glucosidase inhibition activity of 3,4-dihydroxy piperidines
-
Biological evaluation of 3,4-dihydroxy piperidines as α-glucosidase inhibitors is being reported for the first time. Forty-five derivatives (amides, di-amides and sulfonamides) were made using cis and trans 3,4-dihydroxy piperidines to evaluate their α-glucosidase inhibition activity. Polar groups (-OH, -NH2) on phenyl ring having derivatives 5i, 5l, 7g, 7i & 12j showed excellent activity compared to standard references. Acarbose, Voglibose and Miglitol were used as standard references. Molecular docking simulations were done for compounds to identify important binding modes responsible for inhibition activity of α-glucosidase.
- Kasturi, Siva Prasad,Surarapu, Sujatha,Uppalanchi, Srinivas,Dwivedi, Shubham,Yogeeswari, Perumal,Sigalapalli, Dilep Kumar,Bathini, Nagendra Babu,Ethiraj, Krishna S.,Anireddy, Jaya Shree
-
-
- A N - Boc - 4 - piperidine formaldehyde preparation method (by machine translation)
-
The invention discloses a N - Boc - 4 - piperidine formaldehyde preparation method, which belongs to the technical field of organic chemistry. From the N - Boc - 4 - piperidone as the starting point, and the toluene shPs reaction generating diethylketohydrazone, then add the butyl lithium/tetramethyl ethylenediamine/formylation reagent reaction to obtain the 1 - Boc - 4 - formyl - 3, 6 - dihydro - 2 H - pyridine, then palladium carbon to catalyze hydrogenation to obtain N - Boc - 4 - piperidine formaldehyde. The invention has simple operation, higher yield, use of the starting raw material is cheap, is preparing N - Boc - 4 - piperidine formaldehyde suitable method. (by machine translation)
- -
-
Paragraph 0023-0024
(2018/03/26)
-
- Method for preparing N-substituted-1,2,3,6-tetrahydropyridine
-
The invention discloses a method for preparing N-substituted-1,2,3,6-tetrahydropyridine and belongs to the technical field of organic chemistry. N-substituted-4-piperidinol as a raw material reacts with triphenylphosphine and azodicarbonic acid diester, alcoholic hydroxyl groups are converted into alkenyl groups, and N-substituted-1,2,3,6-tetrahydropyridine is prepared. The method has the advantages that the raw materials are easily available, the operation is simple and convenient, the product purity is high, demands of the conventional method for high-temperature condition and highly toxic chemicals are avoided, and the method has potential route advantage.
- -
-
Paragraph 0023; 0024; 0025; 0026; 0030
(2018/05/16)
-
- Saturated Heterocyclic Aminosulfonyl Fluorides: New Scaffolds for Protecting-Group-Free Synthesis of Sulfonamides
-
Cyclic saturated aminosulfonyl fluorides were synthesized as their HCl salts. The compounds were found to be stable upon storage and could be used for the protecting-group-free synthesis of sulfonamides. In the presence of the ?SO2F group, the nitrogen atom could be modified by means of acylation, arylation, or reductive amination to give products that have high potential for the synthesis of bioactive compounds.
- Zhersh, Sergey A.,Blahun, Oleksandr P.,Sadkova, Iryna V.,Tolmachev, Andrey A.,Moroz, Yurii S.,Mykhailiuk, Pavel K.
-
supporting information
p. 8343 - 8349
(2018/06/04)
-
- Multimetallic Ni- and Pd-Catalyzed Cross-Electrophile Coupling to Form Highly Substituted 1,3-Dienes
-
The synthesis of highly substituted 1,3-dienes from the coupling of vinyl bromides with vinyl triflates is reported for the first time. The coupling is catalyzed by a combination of (5,5′-bis(trifluoromethyl)-2,2′-bipyridine)NiBr2 and (1,3-bis(diphenylphosphino)propane)PdCl2 in the presence of a zinc reductant. This method affords tetra- and penta-substituted 1,3-dienes that would otherwise be difficult to access and tolerates electron-rich and -poor substituents, heterocycles, an aryl bromide, and a pinacol boronate ester. Mechanistically, the reaction appears to proceed by an unusual zinc-mediated transfer of a vinyl group between the nickel and palladium centers.
- Olivares, Astrid M.,Weix, Daniel J.
-
supporting information
p. 2446 - 2449
(2018/02/28)
-
- Decarboxylative Olefination of Activated Aliphatic Acids Enabled by Dual Organophotoredox/Copper Catalysis
-
Herein, we demonstrate a dual organophotoredox/copper catalytic strategy toward challenging decarboxylative olefination processes proceeding in high yields and selectivities. This operationally simple method uses photoactive organic molecules and Cu(II)-complexes as catalysts to provide rapid access to a wide variety of olefins from inexpensive synthetic and biomass-derived carboxylic acids under mild light-mediated conditions. Mechanistic investigations suggest that the reaction rate for this process is controlled solely by the incident photon flux.
- Tlahuext-Aca, Adrian,Candish, Lisa,Garza-Sanchez, R. Aleyda,Glorius, Frank
-
p. 1715 - 1719
(2018/03/13)
-
- Identification of Ligand Binding Hot Spots of the Histamine H1 Receptor following Structure-Based Fragment Optimization
-
Developments in G protein-coupled receptor (GPCR) structural biology provide insights into GPCR-ligand binding. Compound 1 (4-(2-benzylphenoxy)piperidine) with high ligand efficiency for the histamine H1 receptor (H1R) was used to design derivatives to investigate the roles of (i) the amine-binding region, (ii) the upper and lower aromatic region, and (iii) binding site solvation. SAR analysis showed that the amine-binding region serves as the primary binding hot spot, preferably binding small tertiary amines. In silico prediction of water network energetics and mutagenesis studies indicated that the displacement of a water molecule from the amine-binding region is most likely responsible for the increased affinity of the N-methylated analog of 1. Deconstruction of 1 showed that the lower aromatic region serves as a secondary binding hot spot. This study demonstrates that an X-ray structure in combination with tool compounds, assessment of water energetics, and mutagenesis studies enables SAR exploration to map GPCR-ligand binding hot spots.
- Kuhne, Sebastiaan,Kooistra, Albert J.,Bosma, Reggie,Bortolato, Andrea,Wijtmans, Maikel,Vischer, Henry F.,Mason, Jonathan S.,De Graaf, Chris,De Esch, Iwan J.P.,Leurs, Rob
-
p. 9047 - 9061
(2016/10/22)
-
- PYRROLO[2,3-D]PYRIMIDINYL, PYRROLO[2,3-B]PYRAZINYL AND PYR-ROLO[2,3-D]PYRIDINYL ACRYLAMIDES
-
The present invention provides pharmaceutically active pyrrolo[2,3-d]pyrimidinyl and pyrrolo[2,3-d]pyridinyl acrylamides and analogues thereof. Such compounds are useful for inhibiting Janus Kinase (JAK). This invention also is directed to compositions comprising methods for making such compounds, and methods for treating and preventing conditions mediated by JAK.
- -
-
Paragraph 0469
(2015/06/17)
-
- Cobalt-Catalyzed Cross-Coupling of 3- and 4-Iodopiperidines with Grignard Reagents
-
A cobalt-catalyzed cross-coupling between 3- and 4-iodopiperidines and Grignard reagents is disclosed. The reaction is an efficient, cheap, chemoselective, and flexible way to functionalize piperidines. This coupling was used as the key step to realize a short synthesis of (±)-preclamol. Some mechanistic investigations were conducted that highlight the formation of radical intermediates. Scaffold synthesis: A cobalt-catalyzed cross-coupling between iodopiperidines and Grignard reagents is reported (see scheme; PG=protecting group). A large variety of 3- and 4-substituted piperidines were synthesized and the method was applied to a short synthesis of (±)-preclamol. This work constitutes one of the rare examples of cross-couplings involving 3-halogeno piperidines.
- Gonnard, Laurine,Gurinot, Amandine,Cossy, Janine
-
p. 12797 - 12803
(2015/09/01)
-
- Synthesis of the stabilized active metabolite of clopidogrel
-
The convergent synthesis of the stabilized active metabolite of clopidogrel was achieved in eleven steps from commercially available 1,2,3,6- tetrahydropyridine and 2-bromo-3′-methoxy acetophenone (MPBr). This synthetic route used a standard Horner-Wadsworth-Emmons reaction allowing the introduction of a Z exocyclic double bond. A selective hydrolysis of an acrylic methyl ester moiety, isolated by an efficient and reliable preparative chiral chromatography at gram scale, released the title compound with a 98% LC purity and d.e. >99%.
- Bluet, Guillaume,Blankenstein, Jorg,Brohan, Eric,Prévost, Céline,Chevé, Michel,Schofield, Joseph,Roy, Sébastien
-
p. 3893 - 3900
(2014/06/09)
-
- PIPERIDINYLCARBAZOLE AS ANTIMALARIAL
-
The present invention provides compounds of Formula (I) for the treatment of parasitic diseases including malaria, as well as neurodegenerative diseases. Formula (I) wherein R3, R4, X and Y have the meaning given in claim 1.
- -
-
Page/Page column 71; 72
(2014/07/23)
-
- IMIDAZOLE DERIVATIVES AND METHODS OF USE THEREOF FOR IMPROVING THE PHARMACOKINETICS OF A DRUG
-
The present invention relates to Imidazole Derivatives of Formula (I), and pharmaceutically acceptable salts thereof, wherein A, B, Y, R1 and R2 are as defined herein. The present invention also relates to compositions comprising at least one Imidazole Derivative, and and methods of using the Imidazole Derivatives for inhibiting CYP450 3A. Inhibition of CYP450 3A can be used to improve the pharmacokinetics of a drug that is metabolized by CYP450 3A4.
- -
-
Page/Page column 64
(2015/01/06)
-
- Substituted Imidazopyridines as HDM2 Inhibitors
-
The present invention provides substituted imidazopyridines as described herein or a pharmaceutically acceptable salt or solvate thereof. The representative compounds are useful as inhibitors of the HDM2 protein. Also disclosed are pharmaceutical compositions comprising the above compounds and potential methods of treating cancer using the same.
- -
-
Paragraph 0742
(2014/07/08)
-
- IMIDAZOLE DERIVATIVES AND METHODS OF USE THEREOF FOR IMPROVING PHARMACOKINETICS OF DRUG
-
Imidazole derivatives of formula (I), pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising at least one imidazole derivative are disclosed. The imidazole derivatives are effective to inhibit CYP450 3A and can be used to improve the pharmacokinetics of a drug that is metabolized by CYP450 3A4.
- -
-
Page/Page column 58
(2015/01/06)
-
- RUTHENIUM-BASED METATHESIS CATALYSTS, PRECURSORS FOR THEIR PREPARATION AND THEIR USE
-
The invention is directed to ruthenium-based metathesis catalysts of the Grubbs-Hoveyda type. The new 2-aryloxy-substituted ruthenium catalysts described herein reveal rapid initiation behavior. Further, the corresponding styrene-based precursor compounds are disclosed. The catalysts are prepared in a cross-metathesis reaction starting from styrene-based precursors which can be prepared in a cost- effective manner. The new Grubbs-Hoveyda type catalysts are suitable to catalyze ring- closing metathesis (RCM), cross metathesis (CM) and ring- opening metathesis polymerization (ROMP). Low catalyst loadings are necessary to convert a wide range of substrates including more complex and critical substrates via metathesis reactions at low to moderate temperatures in high yields within short reaction times.
- -
-
Page/Page column 30; 31; 32
(2014/05/24)
-
- AMINOQUINAZOLINE DERIVATIVES AND THEIR SALTS AND METHODS OF USE
-
The present invention relates to the field of medicine. Provided herein are aminoquinazoline derivatives, their salts and pharmaceutical formulations useful in modulating the protein tyrosine kinase activity, and in modulating inter- and/or intra-cellular signaling. Also provided herein are pharmaceutically acceptable compositions comprising the aminoquinazoline compounds and methods of using the compositions in the treatment of hyperproliferative disorders in mammals, especially humans.
- -
-
Paragraph 0598-0599
(2014/08/19)
-
- SUBSTITUTED CYCLIC COMPOUNDS AND METHODS OF USE
-
The present invention provides novel substituted cyclic 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.
- -
-
Paragraph 0242
(2013/09/26)
-
- Fast olefin metathesis: Synthesis of 2-aryloxy-substituted Hoveyda-type complexes and application in ring-closing metathesis
-
Four 1-(4-R-phenoxy)-2-ethenylbenzenes (R=NMe2, H, Cl, NO 2) 4a, 4b, 4c and 4d were reacted with the ruthenium complexes [RuCl2(NHC)(3-phenylindenylidene)(py)] in the presence of a protic resin to result in the formation of the respective Hoveyda-type complexes 5a-d {NHC=SIMes [1,3-bis(2,4,6-trimethylphenylimidazolin)-2-ylidene]} and 6a-d {NHC=SIPr [1,3-bis(2,6-diisopropylphenylimidazolin)-2-ylidene]} in 66-84% yield. The lower steric bulk and the decreased donation of the diaryl ether oxygen atoms in complexes 5 and 6 led to rapidly initiating precatalysts. The Ru(II/III) redox potentials of complexes 6 were determined (6a-d: ΔE=0.89-1.08 V). In the crystal structure of 5b two independent molecules were observed in the unit cell, displaying Ru-O distances of 226.6(4) and 230.5(3) pm. The catalytic performance of complexes 5 and 6 in various ring-closing metathesis (RCM) reactions was studied. Catalyst loadings of between 15-200 ppm are sufficient for the formation of >90% yield of the respective cyclic products. Complex 6b catalyzes the formation of N-protected 2,5-dihydropyrroles with up to TON 64,000 and TOF 256,000 h-1, of the N-protected 1,2,3,6- tetrahydropyridines with up to TON 18,200 and TOF 73,000 h-1 and of the N-protected 2,3,6,7-tetrahydroazepines with up to TON 8,100 and TOF 32,000 h-1 with yields ranging between 77 and 96%.
- Kos, Pavlo,Savka, Roman,Plenio, Herbert
-
p. 439 - 447
(2013/05/21)
-
- AMINOQUINAZOLINE DERIVATIVES AND THEIR SALTS AND METHODS OF USE
-
The present invention relates to the field of medicine. Provided herein are aminoquinazoline derivatives, their salts and pharmaceutical formulations useful in modulating the protein tyrosine kinase activity, and in modulating inter-and/or intra-cellular signaling. Also provided herein are pharmaceutically acceptable compositions comprising the aminoquinazoline compounds and methods of using the compositions in the treatment of hyperproliferative disorders in mammals, especially humans.
- -
-
Paragraph 00374
(2013/06/05)
-
- Ring-closing metathesis reactions: Interpretation of conversion-time data
-
Conversion-time data were recorded for various ring-closing metathesis (RCM) reactions that lead to five- or six-membered cyclic olefins by using different precatalysts of the Hoveyda type. Slowly activated precatalysts were found to produce more RCM product than rapidly activated complexes, but this comes at the price of slower product formation. A kinetic model for the analysis of the conversion-time data was derived, which is based on the conversion of the precatalyst (Pcat) into the active species (Acat), with the rate constant kact, followed by two parallel reactions: 1) the catalytic reaction, which utilizes Acat to convert reactants into products, with the rate k cat, and 2) the conversion of Acat into the inactive species (Dcat), with the rate kdec. The calculations employ two experimental parameters: the concentration of the substrate (c(S)) at a given time and the rate of substrate conversion (-dc(S)/dt). This provides a direct measure of the concentration of Acat and enables the calculation of the pseudo-first-order rate constants kact, kcat, and kdec and of k S (for the RCM conversion of the respective substrate by Acat). Most of the RCM reactions studied with different precatalysts are characterized by fast kcat rates and by the kdec value being greater than the kact value, which leads to quasistationarity for Acat. The active species formed during the activation step was shown to be the same, regardless of the nature of different Pcats. The decomposition of Acat occurs along two parallel pathways, a unimolecular (or pseudo-first-order) reaction and a bimolecular reaction involving two ruthenium complexes. Electron-deficient precatalysts display higher rates of catalyst deactivation than their electron-rich relatives. Slowly initiating Pcats act as a reservoir, by generating small stationary concentrations of Acat. Based on this, it can be understood why the use of different precatalysts results in different substrate conversions in olefin metathesis reactions. Copyright
- Thiel, Vasco,Wannowius, Klaus-Juergen,Wolff, Christiane,Thiele, Christina M.,Plenio, Herbert
-
p. 16403 - 16414
(2013/12/04)
-
- Fast olefin metathesis at low catalyst loading
-
Reactions of the Grubbs 3rd generation complexes [RuCl2(NHC) (Ind)(Py)] (N-heterocyclic carbene (NHC)=1,3-bis(2,4,6- trimethylphenylimidazolin)-2-ylidene (SIMes), 1,3-bis(2,6- diisopropylphenylimidazolin)-2-ylidene (SIPr), or 1,3-bis(2,6- diisopropylphenylimidazol)-2-ylidene (IPr); Ind=3-phenylindenylid-1-ene, Py=pyridine) with 2-ethenyl-N-alkylaniline (alkyl=Me, Et) result in the formation of the new N-Grubbs-Hoveyda-type complexes 5 (NHC=SIMes, alkyl=Me), 6 (SIMes, Et), 7 (IPr, Me), 8 (SIPr, Me), and 9 (SIPr, Et) with N-chelating benzylidene ligands in yields of 50-75 %. Compared to their respective, conventional, O-Grubbs-Hoveyda complexes, the new complexes are characterized by fast catalyst activation, which translates into fast and efficient ring-closing metathesis (RCM) reactivity. Catalyst loadings of 15-150 ppm (0.0015-0.015 mol %) are sufficient for the conversion of a wide range of diolefinic substrates into the respective RCM products after 15 min at 50 °C in toluene; compounds 8 and 9 are the most catalytically active complexes. The use of complex 8 in RCM reactions enables the formation of N-protected 2,5-dihydropyrroles with turnover numbers (TONs) of up to 58 000 and turnover frequencies (TOFs) of up to 232 000 h-1; the use of the N-protected 1,2,3,6-tetrahydropyridines proceeds with TONs of up to 37 000 and TOFs of up to 147 000 h-1; and the use of the N-protected 2,3,6,7-tetrahydroazepines proceeds with TONs of up to 19 000 and TOFs of up to 76 000 h-1, with yields for these reactions ranging from 83-92 %. The tortoise and the hare: The use of diphenylalkylamino-based instead of phenyldialkylamino-based styrenes (see figure) leads to rapidly initiating precatalysts that enable very fast ring-closing metathesis reactions with turnover numbers of up to 58 000 and turnover frequencies of up to 232 000 h-1. Copyright
- Peeck, Lars H.,Savka, Roman D.,Plenio, Herbert
-
p. 12845 - 12853
(2012/11/06)
-
- Chimeric self-sufficient P450cam-RhFRed biocatalysts with broad substrate scope
-
A high-throughput screening protocol for evaluating chimeric, self-sufficient P450 biocatalysts and their mutants against a panel of substrates was developed, leading to the identification of a number of novel biooxidation activities.
- Robin, Aelig,Koehler, Valentin,Jones, Alison,Ali, Afruja,Kelly, Paul P.,O'Reilly, Elaine,Turner, Nicholas J.,Flitsch, Sabine L.
-
supporting information; experimental part
p. 1494 - 1498
(2012/01/13)
-
- PIPERIDINYL SUBSTITUTED 1,3-DIHYDRO-BENZOIMIDAZOL-2-YLIDENEAMINE DERIVATIVES
-
The invention relates to new derivatives of formula (I) wherein the substituents are as defined in the specification; to processes for the preparation of such derivatives; pharmaceutical compositions comprising such derivatives; such derivatives as a medicament; such derivatives for the treatment of one or more IGF-1R mediated disorders or diseases
- -
-
Page/Page column 86
(2012/01/06)
-
- The synthesis of piperidine nucleoside analogs - A comparison of several methods to access the introduction of nucleobases
-
This work deals with the synthesis of piperidine and hydroxypiperidine analogs of nucleosides. Starting from commercially available 3-hydroxypiperidine, proline or 4-hydroxyproline, a series of piperidine derivatives of both purine and pyrimidine nucleobases was prepared. Various methods of nucleobase attachment were evaluated. The prepared compounds were tested for cytostatic, antibacterial, and antiviral properties but no significant activity was found.
- Kova?ková, Soňa,Dra?ínsky, Martin,Rejman, Dominik
-
scheme or table
p. 1485 - 1500
(2011/04/15)
-
- 2-Aryl-4,5,6,7-tetrahydro-1,3-benzothiazol-7-ols as a class of antitumor agents selectively active in securin-/- cells
-
A series of 2-(4-aminophenyl)-4,5,6,7-tetrahydro-1,3-benzothiazol-7-ols have been developed as antitumor agents that showed high selectivity against aneuploid cell lines (vs diploid cell lines). Structure-activity relationship studies showed that a hydroxymethyl group at the 2-position of the phenyl ring increased potency and selectivity. A pyrrolidinyl group at the 4-position of the phenyl ring was comparable to a dimethylamino group. The corresponding 5-aza analogs, 2-(4-aminophenyl)-4,5,6,7-tetrahydro[1,3]thiazolo[4,5-c]pyridin-7-ols, retained potency and high level of selectivity against aneuploid cell growth (vs diploid cells). These 5-aza compounds exhibited higher water solubility and higher metabolic stability than the corresponding carba analogs. Compound 19 showed the highest potency against MCF-7 and MDA-MB-361 lines and was selected for further evaluation.
- Zhang, Nan,Ayral-Kaloustian, Semiramis,Niu, Chuansheng,Nguyen, Thai,Upeslacis, Erik,Mansour, Tarek S.,Ragunathan, Shoba,Rosfjord, Edward
-
scheme or table
p. 3903 - 3905
(2010/09/03)
-
- Low catalyst loadings in olefin metathesis: Synthesis of nitrogen heterocycles by ring-closing metathesis
-
(Chemical Equetion Presentation) A series of ruthenium catalysts have been screened under ring-closing metathesis (RCM) conditions to produce five-, six-, and seven-membered carbamate-protected cyclic amines. Many of these catalysts demonstrated excellent RCM activity and yields with as low as 500 ppm catalyst loadings. RCM of the five-membered carbamate series could be run neat, the six-membered carbamate series could be run at 1.0 M, and the seven-membered carbamate series worked best at 0.2-0.05 M.
- Kuhn, Kevin M.,Champagne, Timothy M.,Hong, Soon Hyeok,Wei, Wen-Hao,Nickel, Andrew,Lee, Choon Woo,Virgil, Scott C.,Grubbs, Robert H.,Pederson, Richard L.
-
supporting information; experimental part
p. 984 - 987
(2010/06/15)
-
- THIENOPYRIMIDIENE DERIVATIVES AS PI3K INHIBITORS
-
Thienopyrimidines of formula (I) wherein W and R1 to R4 are as defined in the claims, and the pharmaceutically acceptable salts thereof are inhibitors of PI3K and are selective for the p110δ isoform, which is a class Ia PI3 kinase, over both other class Ia and class Ib kinases. The compounds may be used to treat diseases and disorders arising from abnormal cell growth, function or behaviour associated with PI3 kinase such as cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine function disorders and neurological disorders.
- -
-
Page/Page column 103-104
(2009/05/28)
-
- MINERALOCORTICOID RECEPTOR ANTAGONISTS AND METHODS OF USE
-
The present invention provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof; pharmaceutical compositions comprising a compound of Formula (I) in combination with a suitable carrier, diluent, or excipient; and methods for treating physiological disorders, particularly congestive heart failure, hypertension, diabetic nephropathy, or chronic kidney disease, comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
- -
-
Page/Page column 27
(2009/07/10)
-
- Practical synthesis of 5-Fluoro-2-(piperidin-4-yloxy)pyrimidin-4-amine, a key intermediate in the preparation of potent deoxycytidine kinase inhibitors
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A practical synthesis of 5-fluoro-2-(piperidin-4-yloxy)pyrimidin-4-amine, a key intermediate in the preparation of a new class of potent deoxycytidine kinase (dCK) inhibitors, is described. The commercially available 2,4-dichloro-5-fluoropyrimidine (12) i
- Wenxue, Wu,Keyes, Philip,Haiming, Zhang,Jie, Yan,Kanamarlapudi, Ramanaiah C.
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scheme or table
p. 807 - 811
(2010/04/22)
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- Design, synthesis, and biological activity of piperidine diamine derivatives as factor Xa inhibitor
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Previously, we identified cyclohexane diamine derivative 1 as orally bioavailable factor Xa inhibitor. We have investigated two racemic cis-piperidine diamine derivatives 2 and 3 based on 1. Compounds 2a-e showed higher fXa inhibitory activity, anticoagulant activity, and aqueous solubility than 3a-e having same substituent. Compounds 2a, 2c, 2e, and 2g-m having sp2 nitrogen, especially amide and urea derivatives, showed potent anticoagulant activity. Compounds 2h and 2k showed high oral activities in rats.
- Mochizuki, Akiyoshi,Nakamoto, Yumi,Naito, Hiroyuki,Uoto, Kouichi,Ohta, Toshiharu
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p. 782 - 787
(2008/09/19)
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- Potent, selective MCH-1 receptor antagonists
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This paper describes the lead optimization of a new series of potent, selective, orally bioavailable, brain-penetrant MCH-1 receptor antagonists. A major focus of the work was to achieve a selectivity profile appropriate for in vivo efficacy studies and safety.
- Erickson, Shawn D.,Banner, Bruce,Berthel, Steven,Conde-Knape, Karin,Falcioni, Fiorenza,Hakimi, Irina,Hennessy, Bernard,Kester, Robert F.,Kim, Kyungjin,Ma, Chun,McComas, Warren,Mennona, Francis,Mischke, Steven,Orzechowski, Lucy,Qian, Yimin,Salari, Hamid,Tengi, John,Thakkar, Kshitij,Taub, Rebecca,Tilley, Jefferson W.,Wang, Hong
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p. 1402 - 1406
(2008/12/21)
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- Convenient preparation of optically pure 3-aryloxy-pyrrolidines
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Chiral 3-methanesulfonyl-1-Boc-pyrrolidine and piperidine were reacted with sodium phenolates, resulting in a mixture of displacement and elimination products. Following carbamate deprotection and pH adjustment, the 3-pyrroline and tetrahydropyridine by-products resulting from elimination were easily removed through aqueous partitioning and/or concentration. Although the pyrrolidines were formed with a high degree of optical purity, slight racemization was observed for the piperidine case because elevated temperatures were required to effect displacement. Copyright Taylor & Francis Group, LLC.
- Benard, Christophe,Mohammad, Rahim,Saraswat, Neerja,Shan, Rudong,Maiti, Samarendra N.,Wuts, Peter G. M.,Stier, Michael,Lints, Teresa,Bradow, James,Schwarz, Jacob B.
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p. 517 - 524
(2008/04/12)
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- Pd-catalyzed cross-coupling reactions with carbonyls: Application in a very efficient synthesis of 4-aryltetrahydropyridines
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A method is proposed to prepare 4-aryltetrahydropyridines by a Pd-catalyzed cross-coupling reaction by using tosylhydrazone as the nucleophilic coupling agent without stoichiometric organometallic reagent. Palladium-catalyzed couplings can be used for the formation of C-C linkages. It was observed during study that tosylhydrazone can be generated by employing 4-piperidones directly in the cross-coupling reaction with tetrahydropyridines in very high yields. It was also found during study that the ketones and aldehydes can be employed as nucleophilic coupling partners in a reaction without using stoichiometric organometallic reagent. The study concluded that the method can be used to prepare different types of di- and trisubstituted olefins at large scale.
- Barluenga, Jose,Tomas-Gamasa, Maria,Moriel, Patricia,Aznar, Fernando,Valdes, Carlos
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supporting information; body text
p. 4792 - 4795
(2009/05/07)
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- Synthesis and antibacterial activity of novel fluoroquinolones containing substituted piperidines
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The design and synthesis of new fluoroquinolone antibacterial agents having substituted piperidine rings at the C-7 position are described. Most of the new compounds demonstrated high in vitro antibacterial activity. Several of them exhibited significant activities against Gram-positive organisms, which were more potent than those of gemifloxacin, Linezolid, and vancomycin.
- Dang, Zhao,Yang, Yushe,Ji, Ruyun,Zhang, Shuhua
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p. 4523 - 4526
(2008/02/12)
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- MCH receptor antagonists
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Provided herein are compounds of the formula (I): as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of obesity, hyperphagia, anxiety, depression and related disorders and diseases.
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(2008/06/13)
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- DIPEPTIDYL PEPTIDASE-IV INHIBITING COMPOUNDS, METHODS OF PREPARING THE SAME, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME AS AN ACTIVE AGENT
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The present invention relates to novel compounds exhibiting good inhibitory activity versus Dipeptidyl Peptidase-IV(DPP-IV), methods of preparing the same and pharmaceutical compositions containing the same as an active agent.
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Page/Page column 90
(2010/11/24)
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- Thienopyrimidines useful as Aurora kinase inhibitors
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The present invention provides compounds having the formula: wherein R1, R2, X1, X2, L1, L2, Y and Z are as defined in classes and subclasess herein, and pharmaceutical compositions thereof, as described generally and in subclasses herein, which compounds are useful as inhibitors of protein kinase (e.g., Aurora), and thus are useful, for example, for the treatment of Aurora mediated diseases.
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Page/Page column 111
(2008/06/13)
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- COMPOUNDS
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Piperidine derivatives and pharmaceutically acceptable derivatives thereof useful in methods of treatment of bacterial infections in mammals, particularly in man.
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Page/Page column 46
(2008/06/13)
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- LACTAM-CONTAINING CYCLIC DIAMINES AND DERIVATIVES AS FACTOR XA INHIBITORS
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The present application describes lactam-containing cyclic diamines and derivatives thereof of Formula I: or pharmaceutically acceptable salt forms thereof, wherein M is a non-aromatic carbocycle or heterocycle. Compounds of the present invention are useful as inhibitors of trysin-like serine proteases, specifically factor Xa.
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Page/Page column 166
(2010/02/08)
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- Identifying specific conformations by using a carbohydrate scaffold: Discovery of subtype-selective LPA-receptor agonists and an antagonist
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Stable and potent subtype-selective lysophosphatidic acid (LPA) analogues (agonists and an antagonist) were developed by using carbohydrates as a core structure (see scheme). An array of molecules with the recognition motifs of LPA (a phosphate anion, an oleoyl group, and a hydrogen-bond acceptor) attached to carbohydrate isomers in different three-dimensional arrangements were tested for LPA-receptor activation or inhibition. R = alkyl.
- Tamaruya, Yoko,Suzuki, Masato,Kamura, Goshu,Kanai, Motomu,Hama, Kotaro,Shimizu, Kumiko,Aoki, Junken,Arai, Hiroyuki,Shibasaki, Masakatsu
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p. 2834 - 2837
(2007/10/03)
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- DIAMINE DERIVATIVES
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A compound represented by the general formula (1):Q1-Q2-T0-N(R1)-Q3-N(R2)-T1-Q4 wherein R1 and R2 are hydrogen atoms or the like; Q1 is a saturated or unsaturated, 5- or 6- membered cyclic hydrocarbon group which may be substituted, or the like; Q2 is a single bond or the like; Q3 is a group in which Q5 is an alkylene group having 1 to 8 carbon atoms, or the like; and T0 and T1 are carbonyl groups or the like; a salt thereof, a solvate thereof, or an N-oxide thereof. The compound is useful as an agent for preventing and/or treating cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary infarction, pulmonary embolism, Buerger's disease, deep venous thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after valve or joint replacement, thrombus formation and reocclusion after angioplasty, systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), thrombus formation during extracorporeal circulation, or blood clotting upon blood drawing.
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- 1-PHENYLPIPERIDIN-3-ONE DERIVATIVES AND PROCESSES FOR THE PREPARATION THEREOF
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The present invention provides 1-phenylpiperidin-3-one derivatives and pharmaceutically acceptable saltsthereof, having cysteine protease inhibitory activity, pharmaceutical compositions containing the sameas an active ingredient, and processes for the preparation thereof.
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- γ-amino-substituted analogues of 1-[(S)-2,4-diaminobutanoyl]piperidine as highly potent and selective dipeptidyl peptidase II inhibitors
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Using 1-[(S)-2,4-diaminobutanoyl]piperidine as lead compound, we developed a large series of highly potent and selective dipeptidyl peptidase II (DPP II) inhibitors. γ-Amino substitution with arylalkyl groups, for example, a 2-chlorobenzyl moiety, resulted in a DPP II inhibitor with an IC50 = 0.23 nM and a high selectivity toward DPP IV (IC50 = 345 μM). Furthermore, it was shown that the basicity of the γ-amino is important and that α-amino substitution is not favorable. Piperidine-2-nitriles did not show an increase in potency but rather reduced the selectivity. Introduction of a 4-methyl or a 3-fluorine on piperidine improved selectivity and preserved the high potency.
- Senten, Kristel,Van Der Veken, Pieter,De Meester, Ingrid,Lambeir, Anne-Marie,Scharpé, Simon,Haemers, Achiel,Augustyns, Koen
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p. 2906 - 2916
(2007/10/03)
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- Pyrazolopyridine adenosine antagonists
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The present invention relates to a novel pyrazolopyridine compound of the following formula: whereinR1 is aryl, andR2 is cyclo(lower)alkyl which may have one or more suitable substituent(s), etc;and a pharmaceutically acceptable salt thereof, which is useful as a medicament; the processes for the preparation of said pyrazolopyridine compound or a salt thereof; a pharmaceutical composition comprising said pyrazolopyridine compound or a pharmaceutically acceptable salt thereof; etc.
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(2008/06/13)
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