- Pharmacological characterization of a new series of carbamoylguanidines reveals potent agonism at the H2R and D3R
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Even today, the role of the histamine H2 receptor (H2R) in the central nervous system (CNS) is widely unknown. In previous research, many dimeric, high-affinity and subtype-selective carbamoylguanidine-type ligands such as UR-NK22 (5, pKi = 8.07) were reported as H2R agonists. However, their applicability to the study of the H2R in the CNS is compromised by their molecular and pharmacokinetic properties, such as high molecular weight and, consequently, a limited bioavailability. To address the need for more drug-like H2R agonists with high affinity, we synthesized a series of monomeric (thio)carbamoylguanidine-type ligands containing various spacers and side-chain moieties. This structural simplification resulted in potent (partial) agonists (guinea pig right atrium, [35S]GTPγS and β-arrestin2 recruitment assays) with human (h) H2R affinities in the one-digit nanomolar range (pKi (139, UR-KAT523): 8.35; pKi (157, UR-MB-69): 8.69). Most of the compounds presented here exhibited an excellent selectivity profile towards the hH2R, e.g. 157 being at least 3800-fold selective within the histamine receptor family. The structural similarities of our monomeric ligands to pramipexole (6), a dopamine receptor agonist, suggested an investigation of the binding behavior at those receptors. The target compounds were (partial) agonists with moderate affinity at the hD2longR and agonists with high affinity at the hD3R (e.g. pKi (139, UR-KAT523): 7.80; pKi (157, UR-MB-69): 8.06). In summary, we developed a series of novel, more drug-like H2R and D3R agonists for the application in recombinant systems in which either the H2R or the D3R is solely expressed. Furthermore, our ligands are promising lead compounds in the development of selective H2R agonists for future in vivo studies or experiments utilizing primary tissue to unravel the role and function of the H2R in the CNS.
- Biselli, Sabrina,Bresinsky, Merlin,Buschauer, Armin,Forster, Lisa,Honisch, Claudia,Pockes, Steffen,Tropmann, Katharina,Bernhardt, Günther
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supporting information
(2021/02/12)
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- Design, synthesis and antifungal activity of threoninamide carbamate derivatives via pharmacophore model
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Thirty-six novel threoninamide carbamate derivatives were designed and synthesised using active fragment-based pharmacophore model. Antifungal activities of these compounds were tested against Oomycete fungi Phytophthora capsici in vitro and in vivo. Interestingly, compound I-1, I-2, I-3, I-6 and I-7 exhibited moderate control effect (>50%) against Pseudoperonospora cubensis in greenhouse at 6.25 μg/mL, which is better than that of control. Meanwhile most of these compounds exhibited significant inhibitory against P. capsici. The other nine fungi were also tested. More importantly, some compounds exhibited remarkably high activities against Sclerotinia sclerotiorum, P. piricola and R. solan in vitro with EC50 values of 3.74–9.76 μg/mL. It is possible that the model is reliabile and this method can be used to discover lead compounds for the development of fungicides.
- Dong, Wei-Li,Du, Xiu-Jiang,Liu, Xing-Hai,Peng, Xing-Jie,Zhao, Rui-Qi,Zhao, Wei-Guang
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p. 682 - 691
(2020/03/19)
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- Rh(III)-catalyzed synthesis of isoquinolines using the N-Cl bond of N-chloroimines as an internal oxidant
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The Rh(III)-catalyzed coupling of N-chloroimines with alkynes for the efficient synthesis of isoquinolines is reported. This represents the first use of the N-Cl bond of N-chloroimines as an internal oxidant for construction of the isoquinoline skeleton. The synthesis features atom and step economy, a green solvent (EtOH), mild reaction conditions, and a broad substrate scope.
- Chu, Benfa,Fang, Lili,Guo, Shan,Qi, Bing,Shi, Pengfei,Wang, Qi,Zhu, Jin
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supporting information
(2020/03/10)
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- A Comprehensive Quantitative Assay for Amine Transaminases
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The development of effective high-throughput screening assays has contributed greatly to the wealth of designer enzymes available, by enabling rapid identification of desired variants from large mutant libraries. Here, we report a general and operationally simple end-point assay for transaminases that enables the screening of both amine donors and acceptors in liquid phase. The spectrophotometric-based screen exploits the amine donor 2-aminoethylaniline (2-AEA) and relies on reaction of in situ generated indole with Ehrlich's reagent. The assay has also been adapted to allow screening in the reverse direction by addition of indole and subsequent spectrophotometric analysis. Importantly, the screen provides qualitative information on the enantio-preference of the individual biocatalysts. To increase the assay throughput, an engineered expression strain (E. coli BL21(DE3) ΔtnaA) lacking tryptophanase activity, was generated to enable reliable and direct evaluation of individual colonies arrayed on agar plates.
- Cairns, Ryan,Gomm, Andrew,Peel, Christopher,Sharkey, Michael,O'Reilly, Elaine
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p. 4738 - 4743
(2019/11/05)
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- Carbon Dioxide-Mediated C(sp2)-H Arylation of Primary and Secondary Benzylamines
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C-C bond formation by transition metal-catalyzed C-H activation has become an important strategy to fabricate new bonds in a rapid fashion. Despite the pharmacological importance of ortho-arylbenzylamines, however, effective ortho-C-C bond formation of free primary and secondary benzylamines using PdII remains an outstanding challenge. Presented herein is a new strategy for constructing ortho-arylated primary and secondary benzylamines mediated by carbon dioxide (CO2). The use of CO2 with Pd is critical to allowing this transformation to proceed under relatively mild conditions, and mechanistic studies indicate that it (CO2) is directly involved in the rate-determining step. Furthermore, the milder temperatures furnish free amine products that can be directly used or elaborated without the need for deprotection. In cases where diarylation is possible, an interesting chelate effect is shown to facilitate selective monoarylation.
- Kapoor, Mohit,Chand-Thakuri, Pratibha,Young, Michael C.
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supporting information
p. 7980 - 7989
(2019/05/22)
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- Substituent effects on chiral resolutions of derivatized 1-phenylalkylamines by heptakis(2,3-di-O-methyl-6-O-tert-butyldimethylsilyl)-β-cyclodextrin GC stationary phase
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Chiral resolutions of trifluoroacetyl-derivatized 1-phenylalkylamines with different type and position of substituent were investigated by capillary gas chromatography by using heptakis(2,3-di-O-methyl-6-O-tert-butyldimethylsilyl)-β-cyclodextrin diluted in OV-1701 as a chiral stationary phase. The influence of column temperature on retention and enantioselectivity was examined. All enantiomers of meta-substituted analytes as well as fluoro-substituted analytes could be resolved. Temperature had a favorable influence on enantioselectivity for small amines with substituents at the ortho-position. The type of substituent at the stereogenic center of amines also had a crucial effect as the ethyl group led to poor enantioseparation. Among all analytes studied, trifluoroacetyl-derivatized 1-(2′-fluorophenyl)ethylamine exhibited baseline resolution with the shortest analysis time.
- Issaraseriruk, Natthapol,Sritana-anant, Yongsak,Shitangkoon, Aroonsiri
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supporting information
p. 900 - 906
(2018/05/08)
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- A su ammonia amide carbamate derivative and application thereof
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The invention belongs to the field of plant bactericide, and relates to a threonyl amine carbamate derivative shown as the general formula (I) and salt capable of being accepted pharmaceutically. Substituent groups R1, R2 and R3 have the definitions given by a specification. The invention further relates to a preparation method of the compound of the general formula (I), a midbody specially developed for preparing the threonyl amine carbamate derivative and an application of the threonyl amine carbamate derivative in plant disease prevention and control. The formula is shown in the specification.
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Paragraph 0090; 0094; 0130
(2017/09/02)
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- Stereoselective amination of racemic sec-alcohols through sequential application of laccases and transaminases
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A one-pot/two-step bienzymatic asymmetric amination of secondary alcohols is disclosed. The approach is based on a sequential strategy involving the use of a laccase/TEMPO catalytic system for the oxidation of alcohols into ketone intermediates, and their following transformation into optically enriched amines by using transaminases. Individual optimizations of the oxidation and biotransamination reactions have been carried out, studying later their applicability in a concurrent process. Therefore, 17 racemic (hetero) aromatic sec-alcohols with different substitutions in the aromatic ring have been converted into enantioenriched amines with good to excellent selectivities (90-99% ee) and conversion values (67-99%). The scalability of the process was also demonstrated when two different amine donors were used in the transamination step, such as isopropylamine and cis-2-buten-1,4-diamine. Satisfyingly, both sacrificial amine donors can shift the equilibrium toward the amine formation, leading to the corresponding isolated enantioenriched amines with good to excellent results.
- Martínez-Montero, Lía,Gotor, Vicente,Gotor-Fernández, Vicente,Lavandera, Iván
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p. 474 - 480
(2017/06/23)
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- CATALYST COMPOUNDS
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The present invention relates to an iridium-based catalyst compound for hydrogenating reducible moieties, especially imines and iminiums, the catalyst compounds being defined by the formulas: where ring B is either itself polycyclic, or ring B together with R is polycyclic. The catalysts of the invention are particularly effective in reductive amination procedures 10 which involve the in situ generation of the imine or iminium under reductive hydrogenative conditions.
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Paragraph 0314; 0321
(2015/03/28)
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- Primary amines by transfer hydrogenative reductive amination of ketones by using cyclometalated IrIII catalysts
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Cyclometalated iridium complexes are found to be versatile catalysts for the direct reductive amination (DRA) of carbonyls to give primary amines under transfer-hydrogenation conditions with ammonium formate as both the nitrogen and hydrogen source. These complexes are easy to synthesise and their ligands can be easily tuned. The activity and chemoselectivity of the catalyst towards primary amines is excellent, with a substrate to catalyst ratio (S/C) of 1000 being feasible. Both aromatic and aliphatic primary amines were obtained in high yields. Moreover, a first example of homogeneously catalysed transfer-hydrogenative DRA has been realised for β-keto ethers, leading to the corresponding β-amino ethers. In addition, non-natural α-amino acids could also be obtained in excellent yields with this method. Reduce the work! A broad range of ketones have been successfully aminated to afford primary amines under transfer-hydrogenation conditions by using ammonium formate as the amine source and 0.1 mol % of a cyclometalated IrIII catalyst (see scheme). Copyright
- Talwar, Dinesh,Salguero, Noemi Poyatos,Robertson, Craig M.,Xiao, Jianliang
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supporting information
p. 245 - 252
(2014/01/17)
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- Transaminases applied to the synthesis of high added-value enantiopure amines
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Critical parameters affecting the stereoselective amination of (hetero)aromatic ketones using transaminases have been studied, such as temperature, pH, substrate concentration, cosolvent, and source and percentage of amino donor, to further optimize the production of enantiopure amines using both (S)- and (R)-selective biocatalysts from commercial suppliers. Interesting enantiopure amino building blocks have been obtained, overcoming some limitations of traditional chemical synthetic methods. Representative processes were scaled up, affording halogenated and heteroaromatic amines in enantiomerically pure form and good isolated yields.
- Paul, Caroline E.,Rodriguez-Mata, Maria,Busto, Eduardo,Lavandera, Ivan,Gotor-Fernandez, Vicente,Gotor, Vicente,Garcia-Cerrada, Susana,Mendiola, Javier,De Frutos, Oscar,Collado, Ivan
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supporting information
p. 788 - 792
(2014/07/08)
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- Liquid chromatographic resolution of fendiline and its analogues on a chiral stationary phase based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid
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Fendiline, an effective anti-anginal drug for the treatment of coronary heart diseases, and its sixteen analogues were resolved on a CSP based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid. Fendiline was resolved quite well with the separation factor (α) of 1.25 and resolution (RS ) of 1.55 when a mobile phase consisting of methanol-acetonitrile-trifluoroacetic acid-triethylamine at a ratio of 80/20/0.1/0.5 (v/v/v/v) was used. The comparison of the chromatographic behaviors for the resolution of fendiline and its analogues indicated that the 3,3-diphenylpropyl group bonded to the secondary amino group of fendiline is important in the chiral recognition and the difference in the steric bulkiness between the phenyl group and the methyl group at the chiral center of fendiline is also important in the chiral recognition.
- Lee, Ga Ram,Hyun, Myung Ho
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p. 21386 - 21397
(2015/02/19)
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- CATALYST COMPOUNDS
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The present invention relates to an iridium-based catalyst compound for hydrogenating reducible moieties, especially imines and iminiums, the catalyst compounds being defined by the formulas: where ring B is either itself polycyclic, or ring B together with R is polycyclic. The catalysts of the invention are particularly effective in reductive amination procedures 10 which involve the in situ generation of the imine or iminium under reductive hydrogenative conditions.
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Paragraph 00163; 00170
(2013/11/05)
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- Sequential reductive amination-hydrogenolysis: A one-pot synthesis of challenging chiral primary amines
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Difficult-to-access chiral primary amines were formed in good to high yield and ee using a rare example of a one-pot synthesis from prochiral ketones (sequential reductive amination-hydrogenloysis). As a highlight we also demonstrate a one-pot reductive amination-hydrogenolysis-reductive amination (five reactions) of ortho-methoxyacetophenone resulting in the chiral diamine 1-(2-methoxyphenyl)ethyl-(2-pyridylmethyl)-amine (4) (58% overall yield, >99% ee), a new organocatalyst for aqueous enantioselective aldol reactions. Copyright
- Nugent, Thomas C.,Negru, Daniela E.,El-Shazly, Mohamed,Hu, Dan,Sadiq, Abdul,Bibi, Ahtaram,Umar, M. Naveed
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supporting information; experimental part
p. 2085 - 2092
(2011/10/19)
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- OXAZOLONE AND PYRROLIDINONE-SUBSTITUTED ARYLAMIDES AS P2X3 AND P2X2/3 ANTAGONISTS
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Compounds of the formula 1: or a pharmaceutically acceptable salt thereof, wherein, X, Y, R1, R2, R3, R4, R5, R6 and R7 are as defined herein. Also disclosed are methods of using the compounds for treating diseases associated with P2X3 and/or a P2X2/3 receptor antagonists and methods of making the compounds.
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Page/Page column 24
(2010/12/31)
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- INDOLE, INDAZOLE AND BENZIMIDAZOLE ARYLAMIDES AS P2X3 AND P2X2/3 ANTAGONISTS
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Compounds of the formula I: or a pharmaceutically acceptable salt thereof, wherein, X, Y, Z, R1, R2, R3, R4 and R5 are as defined herein. Also disclosed are methods of using the compounds for treating diseases associated with P2X3 and/or a P2X2/3 receptor antagonists and methods of making the compounds.
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Page/Page column 20
(2010/12/31)
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- Identification and SAR of squarate inhibitors of mitogen activated protein kinase-activated protein kinase 2 (MK-2)
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A novel series of inhibitors for mitogen activated protein kinase-activated protein kinase 2 (MK-2) are reported. These squarate based inhibitors were identified via a high-throughput screen. An MK2 co-structure with the starting ligand was obtained and a structure based approach was followed to optimize potency and selectivity.
- Lovering, Frank,Kirincich, Steve,Wang, Weiheng,Combs, Kerry,Resnick, Lynn,Sabalski, Joan E.,Butera, John,Liu, Julie,Parris, Kevin,Telliez
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experimental part
p. 3342 - 3351
(2009/09/08)
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- A highly efficient resolution protocol for 2′-halo-α-methylbenzylamines
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A highly efficient resolution protocol for 2′-halo-α-methylbenzylamines is reported. Commercially available and inexpensive mandelic acid can be used for the resolution of the Br, Cl, and F derivatives to >99% de in a single crystallization. In addition, the reduction of acetophenone oximes using borane-dimethylsulfide is presented as a method for the preparation of racemic amine precursors.
- Klingensmith, Liane M.,Nadeau, Kelly A.,Moniz, George A.
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p. 4589 - 4593
(2008/02/06)
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- Process for producing optically active 3,3,3-Trifluoro-2-Hydroxy-2-Methylpropionic acid, and salt thereof
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There are disclosed are a diastereomer salt of formula (1): a process for producing the same, a process for producing optically active 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid of formula (2′): a novel optically active amine compound of formula (4): a novel optically active amine compound of formula (8): an imine compound of formula (7) or (11):
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- N-(α-alkylbenzylidene)-α-phenylalkylamine, its use and process for producing the same and process for producing intermediate therefor
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There is disclosed an N-(α-alkylbenzylidene)-α-phenylalkylamine represented by the general formula (1): STR1 wherein R1 represents a lower alkyl group, R2 represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group and X represents a halogen atom or a lower alkoxy group, its use and a process for producing the same and processes for producing intermediates therefor.
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