- Chirality sensing and size discrimination of anions by macrotricyclic cyclen-disodium complexes
-
Two macrotricyclic ligands composed of two face-to-face octadentate metal chelates were synthesized. These cage-shaped disodium complexes had special recognition ability for various counter anions. Specific chiral dicarboxylates bound to the complexes within the cavity and exhibited chirality induction properties. For instance, N-Boc-Asp dianion strongly induced circular dichroism (CD) signals, but N-Boc-Glu dianion, which is one carbon longer, did not. Chirality on Na+: The first example of chirality sensing on Na+ was achieved by a macrotricyclic host composed of two octadentate cyclen-Na+ complexes. Chiral N-Boc-Asp dianions coordinated to the Na+ at the cavity, resulting in the chirality induction of the cage molecule, but N-Boc-Glu dianion, which is one carbon longer, did not.
- Ito, Hiroshi,Shinoda, Satoshi
-
-
Read Online
- Palladium-Catalyzed β-C(sp3)-H Arylation of Aliphatic Ketones Enabled by a Transient Directing Group
-
The direct arylation of aliphatic ketones has been developed via Pd-catalyzed β-C(sp3)-H bond functionalization with 2-(aminooxy)-N,N-dimethylacetamide as a novel transient directing group (TDG), which showed remarkable directing ability to generate arylated products in moderate to good yields. Furthermore, the reaction can tolerate abundant substrate of ketones and aryl iodides. This study expands the scope of applications for TDGs.
- Wang, Yangyang,Wu, Gaorong,Xu, Xiaobo,Pang, Binghan,Liao, Shaowen,Ji, Yafei
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p. 7296 - 7303
(2021/05/29)
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- 4-Arylthieno[2,3-b]pyridine-2-carboxamides Are a New Class of Antiplasmodial Agents
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Malaria causes hundreds of thousands of deaths every year, making it one of the most dangerous infectious diseases worldwide. Because the pathogens have developed resistance against most of the established anti-malarial drugs, new antiplasmodial agents are urgently needed. In analogy to similar antiplasmodial ketones, 4-arylthieno[2,3-b]pyridine-2-carboxamides were synthesized by Thorpe-Ziegler reactions. In contrast to the related ketones, these carboxamides are only weak inhibitors of the plasmodial enzyme PfGSK-3 but the compounds nevertheless show strong antiparasitic activity. The most potent representatives inhibit the pathogens with IC50values in the two-digit nanomolar range and exhibit high selectivity indices (>100).
- Alder, Arne,Gilberger, Tim,Kunick, Conrad,Schwed, Sandra I.
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- PROCESS FOR PREPARATION OF ERDAFITINIB, ITS PURIFICATION AND AMORPHOUS SOLID DISPERSION
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An aspect of the present application provides a process for the preparation of Erdafitinib and its pharmaceutically acceptable salts. Another aspect of the present application relates to amorphous solid dispersions of Erdafitinib, process for the preparation thereof and pharmaceutical composition comprising amorphous solid dispersions of Erdafitinib. Another aspect of the present application provides process for purification of Erdafitinib.
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Page/Page column 20
(2020/10/21)
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- GLUCOSE UPTAKE INHIBITORS
-
this invention provides compounds that modulate glucose uptake activity and cellular transport/uptake of glucose, and particularly GLUTS3, but also including but not limited to GLUT1-14 (SLC2A1-SLC2A14). Compounds of the invention are useful for treating diseases, including cancer, autoimmune diseases and inflammation, infectious diseases, and metabolic diseases.
- -
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Paragraph 0196; 0199-0201
(2020/01/24)
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- Novel vanillin derivatives containing a 1,3,4-thiadiazole moiety as potential antibacterial agents
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In this study, thirty-four novel vanillin derivatives containing a 1,3,4-thiadiazole structure were obtained and their antibacterial activities were evaluated. The results indicate that most of the title compounds displayed inhibitory effects on Xanthomonas oryzae pv. oryzae (Xoo) and Xanthomonas oryzae pv. oryzicola (Xoc). Among them, compound 29 exhibited excellent antibacterial activities against Xoo and Xoc in vitro, with the EC50 values of 3.14 and 8.83 μg/mL, respectively, much superior to thiodiazole copper (87.03 and 108.99 μg/mL) and bismerthiazol (67.64 and 79.26 μg/mL). Under greenhouse condition, the protective efficiency of compound 29 against rice bacterial leaf blight was 49.34%, and curative efficiency was 40.96%. In addition, compound 29 can reduce the exopolysaccharides production of Xoo, increase the permeability of cell membrane and damage cell membrane.
- Cai, Hui,Gan, Xiuhai,Li, Shaoyuan,Song, Baoan,Wu, Qiong,Yuan, Ting
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supporting information
(2020/03/24)
-
- Design, Synthesis, and Bioactivity of α-Ketoamide Derivatives Bearing a Vanillin Skeleton for Crop Diseases
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A series of novel α-ketoamide derivatives bearing a vanillin skeleton were designed and synthesized. Bioactivity tests on virus and bacteria were performed. The results indicated that some compounds exhibited excellent antitobacco mosaic virus (TMV) activities, such as compound 34 exhibited an inactivation activity of 90.1percent and curative activity of 51.8percent and compound 28 exhibited a curative activity of 54.8percent at 500 μg mL-1, which is equivalent to that of the commercial ningnanmycin (inactivation of 91.9percent and curative of 51.9percent). Moreover, the in vitro antibacterial activity test illustrated that compounds 2, 22, and 33 showed much higher activities than commercial thiodiazole copper, which could be used as lead compounds or potential candidates. The findings of transmission electron microscopy and molecular docking indicated that the synthesized compounds exhibited strong and significant binding affinity to the TMV coat protein and could obstruct the self-assembly and increment of TMV particles. This study revealed that α-ketoamide derivatives bearing a vanillin skeleton could be used as a novel potential pesticide for controlling the plant diseases.
- Chen, Shunhong,Dai, Ali,Guo, Shengxin,He, Feng,Luo, Dexia,Wu, Jian,Zhang, Renfeng
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p. 7226 - 7234
(2020/08/06)
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- Continuous-Flow Electrosynthesis of Benzofused S-Heterocycles by Dehydrogenative C?S Cross-Coupling
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Reported herein is the synthesis of benzofused six-membered S-heterocycles by intramolecular dehydrogenative C?S coupling using a modular flow electrolysis cell. The continuous-flow electrosynthesis not only ensures efficient product formation, but also obviates the need for transition-metal catalysts, oxidizing reagents, and supporting electrolytes. Reaction scale-up is conveniently achieved through extended electrolysis without changing the reaction conditions and equipment.
- Huang, Chong,Qian, Xiang-Yang,Xu, Hai-Chao
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supporting information
p. 6650 - 6653
(2019/04/26)
-
- RHO-ASSOCIATED PROTEIN KINASE INHIBITOR, PHARMACEUTICAL COMPOSITION COMPRISING THE SAME, AS WELL AS PREPARATION METHOD AND USE THEREOF
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The present invention relates to a Rho-associated protein kinase inhibitor of Formula (I), a pharmaceutical composition comprising the same, a preparation method thereof, and use thereof for the prevention or treatment of a disease mediated by the Rho-associated protein kinase (ROCK).
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Paragraph 0306; 0307; 0311; 0312
(2019/01/11)
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- Discovery of 4-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one derivatives as potent and orally active PI3K/mTOR dual inhibitors
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PI3K/Akt/mTOR signaling pathway plays an important role in cancer cell growth and survival. In this study, a new class of molecules with skeleton of 4-phenyl-2H-benzo[b] [1,4]oxazin-3(4H)-one were designed and synthesized targeting this pathway. Bioassays showed that, among all the molecules, 8d-1 was a pan-class I PI3K/mTOR inhibitor with an IC50 of 0.63 nM against PI3Kα. In a wide panel of protein kinases assays, no off-target interactions of 8d-1 were identified. 8d-1 was orally available, and displayed favorable pharmacokinetic parameters in mice (oral bioavailability of 24.1%). In addition, 8d-1 demonstrated significant efficiency in Hela/A549 tumor xenograft models (TGI of 87.7% at dose of 50 mg/kg in Hela model) without causing significant weight loss and toxicity during 30 days treatment. Based on the bioassays, compound 8d-1 could be used as an anti-cancer drug candidate.
- Yan, Guoyi,Pu, Chunlan,Lan, Suke,Zhong, Xinxin,Zhou, Meng,Hou, Xueyan,Yang, Jie,Shan, Huifang,Zhao, Lifeng,Li, Rui
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p. 667 - 686
(2019/06/24)
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- Ether acetamide derivative containing alpha-carbonyl amide structure and application of ether acetamide derivative
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The invention discloses application of an ether acetamide derivative containing an alpha-carbonyl amide structure in an aspect of resisting plant diseases. The structure is shown in a general formulaI. Limitation of groups such as R and R is shown as the specification. A compound shown in the general formula I has a function of preventing and treating the plant diseases, and TMV, rice bacterial blight, citrus canker, ralstonia solanacearum and other plant virus diseases can be prevented and treated.
- -
-
Paragraph 0056; 0058
(2019/11/12)
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- HETEROCYCLIC COMPOUNDS AS CLASS II PHOSPHOINOSITIDE 3-KINASE INHIBITORS
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The present application relates to compounds of formula (1) and their use as medicament, in particular for the treatment of a medical condition associated with defective PI3K signalling.
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Page/Page column 83; 117
(2019/12/28)
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- Design, Synthesis, and SAR Studies of Heteroarylpyrimidines and Heteroaryltriazines as CB2R Ligands
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Herein we describe the design and synthesis of a new series of heteroarylpyrimidine/heteroaryltriazine derivatives on the basis of quinazoline-2,4(1H,3H)-diones as CB2R-selective ligands using a bioisosterism strategy. An acetamide group was explored to displace the enamine linker of the lead compound for the purpose of stereoisomerism elimination and hydrophilicity increase. As a result, some of the synthesized compounds showed high bioactivity and selectivity for CB2R in calcium mobilization assays, and four displayed CB2R agonist activity, with EC50 values below 30 nm. The compound exhibiting the highest agonist activity toward CB2R (EC50=7.53±3.15 nm) had a selectivity over CB1R of more than 1328-fold. Moreover, structure–activity relationship (SAR) studies indicated that the substituents on the nucleus play key roles in the functionality of a ligand, with one such example demonstrating CB2R antagonist activity. Additionally, molecular docking simulations were conducted with the aim of better understanding of these new derivatives in relation to the structural requirements for agonists/antagonists binding to CB2R.
- Qian, Hai-Yan,Wang, Zhi-Long,Chen, Li-Li,Pan, You-Lu,Xie, Xiao-Yu,Xie, Xin,Chen, Jian-Zhong
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supporting information
p. 2455 - 2463
(2018/11/23)
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- Rational Design, Synthesis, and Biological Activity of N-(1,4-Benzoxazinone)Acetamide Derivatives as Potent Platelet Aggregation Inhibitors
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Inappropriate thrombus formation within blood vessels is the leading cause of mortality in the industrialized world. Platelet aggregation activated by thrombin may have close relationship with thrombosis. Based on our studies on the pharmacophoric role of 1,4-benzoxazine-3(4H)-one for desirable platelet aggregation inhibitory activity, we identified N-(4-ethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-2-(4-methylpiperazin-1-yl)acetamide (BOAP-AM6) and N-(4-butyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-2-(4-(4-fluorophenyl)piperazin-1-yl)acetamide (BOAP-AM21) as platelet aggregation inhibitors with an IC50 of 8.93 and 8.67 μM, respectively, as potent as the positive control aspirin. A combination of structure–activity relationships studies and molecular modeling revealed that the molecule BOAP-AM6 interacted with the amino acid residue TYR166 and ARG214 in the binding site of GPIIb/IIIa receptor through hydrogen bond and compound BOAP-AM21 acted on the amino acid residue ASN215 and ALA218, both through the same approach as the reported potent molecules 7a and 7b.
- Xiang, Yi,Wang, Xiu-Hua,Yang, Quan,Tan, Jia-Lian,Jang, Hee-Jae,Zuo, Hua,Shin, Dong-Soo
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supporting information
p. 146 - 155
(2018/01/27)
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- Synthesis and acaricidal activities of scopoletin phenolic ether derivatives: Qsar, molecular docking study and in silico Adme predictions
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Thirty phenolic ether derivatives of scopoletin modified at the 7-hydroxy position were synthesized, and their structures were confirmed by IR,1H-NMR,13C-NMR, MS and elemental analysis. Preliminary acaricidal activities of these compounds against female adults of Tetranychus cinnabarinus (Boisduval) were evaluated using the slide-dip method. The results indicated that some of these compounds exhibit more pronounced acaricidal activity than scopoletin, especially compounds 32, 20, 28, 27 and 8 which exhibited about 8.41-, 7.32-, 7.23-, 6.76-, and 6.65-fold higher acaricidal potency. Compound 32 possessed the the most promising acaricidal activity and exhibited about 1.45-fold higher acaricidal potency against T. cinnabarinus than propargite. Statistically significant 2D-QSAR model supports the observed acaricidal activities and reveals that polarizability (HATS5p) was the most important parameter controlling bioactivity. 3D-QSAR (CoMFA: q2 = 0.802, r2 = 0.993; CoMSIA: q2 = 0.735, r2 = 0.965) results show that bulky substituents at R4, R1, R2 and R5 (C6, C3, C4, and C7) positions, electron positive groups at R5 (C7) position, hydrophobic groups at R1 (C3) and R2 (C4), H-bond donors groups at R1 (C3) and R4 (C6) will increase their acaricidal activity, which provide a good insight into the molecular features relevant to the acaricidal activity for further designing novel acaricidal agents. Molecular docking demonstrates that these selected derivatives display different bide modes with TcPMCA1 from lead compound and they interact with more key amino acid residues than scopoletin. In silico ADME properties of scopoletin and its phenolic ether derivatives were also analyzed and showed potential to develop as good acaricidal candidates.
- Luo, Jinxiang,Lai, Ting,Guo, Tao,Chen, Fei,Zhang, Linli,Ding, Wei,Zhang, Yongqiang
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- Development of Quinazoline/Pyrimidine-2,4(1H,3H)-diones as Agonists of Cannabinoid Receptor Type 2
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Starting from a prototypical structure 1, we describe our efforts to design and obtain novel quinazoline/pyrimidine-2,4(1H,3H)-diones with high CB2 agonist potency and selectivity as well as improved physicochemical characteristics, mainly hydrophilicity. The most potent and selective CB2 agonists, 8 and 36, in this series were also endowed with lower logP values than that of GW842166X and lead compound 1. These derivatives appear to be promising lead compounds for the development of future CB2 agonists.
- Qian, Hai-Yan,Wang, Zhi-Long,Pan, You-Lu,Chen, Li-Li,Xie, Xin,Chen, Jian-Zhong
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supporting information
p. 678 - 681
(2017/06/13)
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- Quinazoline dione derivatives and preparation method and application thereof
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The invention provides novel quinazoline dione derivatives and a preparation method and application thereof. The compounds include compounds with the structure shown in the general formula V in the description and pharmaceutically acceptable salts or hydrates thereof. The compounds are active ligands of novel cannabinoid II receptors (CB2) and can be used for preparing medicine for treating, preventing and relieving CB2 receptor-mediated diseases, wherein the medicine is an agonist or partial agonist or inverse agonist or antagonist of CB2 receptors.
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Paragraph 0472; 0473; 0474
(2017/07/19)
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- TREATMENT OF INFECTIOUS DISEASES WITH GLUCOSE UPTAKE INHIBITORS
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Provided are methods of treating infectious diseases in mammals comprising administering a compound that inhibits glucose uptake. Particular infectious diseases that may be treated include malaria, leishmaniasis, African trypanosomiasis, tuberculosis, HIV, HCMV or herpes virus. In a first aspect, the invention features a method of treating infectious diseases in a mammal, comprising administering to a mammalian subject in need thereof a therapeutically effective amount of a compound or prodrug thereof, or pharmaceutically acceptable salt or ester of said compound or prodrug, wherein the compound is an inhibitor of glucose uptake.
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Paragraph 0089; 0090
(2017/01/09)
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- GLUCOSE UPTAKE INHIBITORS
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Provided hererin are compounds that modulate glucose uptake activityand are useful for treating cancer, autoimmune diseases, inflammation, infectious diseases, and metabolic diseases. In certain embodiments, the compounds modulate glucose uptake activity by modulating cellular components, including, but not limited to those related to glycolysis and known transporters/co-transporters of glucose such as GLUT1 and other GLUT family members/alternative hexose transporters. In certain embodiments, the compounds have the structure of formula I: Formula (I) wherein the variables have the values disclosed herein.
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Paragraph 0093-0094
(2017/01/09)
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- Heteroarylpyrimindinedione derivative and use thereof
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The invention provides a heteroarylpyrimindinedione derivative and use thereof. The heteroarylpyrimindinedione derivative comprises a compound with a structure shown as general formula I, and a pharmaceutically acceptable salt or hydrate thereof. The derivative is obtained by chemical synthesis, and pharmacological experiments prove that the active ligand with cannabinoid type II receptor CB2 can be used for preparation of drugs for prevention and mitigation of CB2 receptor-mediated diseases, and the drug is cannabinoid CB2 receptor agonist's agonist, partial agonist, inverse agonist or antagonist. And the general structural formula I is shown as the specification.
- -
-
Paragraph 0119; 0120
(2017/04/03)
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- Chloroquinoline-acetamide hybrids: A promising series of potential antiprotozoal agents
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In an endeavour to develop efficacious antiprotozoal agents 2-[4-(7-chloroquinolin-4-yl)piperazin-1-yl]acetamide derivatives were synthesized and screened in vitro against the HM1:IMSS strain of E. histolytica and 3D7 strain of P. falciparum. Among the twenty-seven synthesized compounds, eleven evinced propitious anti-amoebic activity with IC50 values ranging from 0.41 to 1.80 μM) lower than the standard drug metronidazole (IC50 1.80 μM). All the compounds inhibited the in vitro growth of P. falciparum (IC50 range: 0.30-33.52 μM). Compounds A22 and A25 were found to be the most active antimalarial derivatives, and compound A16 the most active in inhibiting β-haematin formation; however compound A25 displayed the more favourable safety profile. The crystal structure for the compounds A7, A8, A12 and A21 was also determined. The molecular docking of crystal resolved inhibitors with PfDHFR allowed identification of stabilizing interactions within enzyme active sites. These compounds affirm the potential for further derivatives to enhance antiprotozoal activity whilst retaining their safety profile.
- Inam, Afreen,Van Zyl, Robyn L.,Van Vuuren, Natasha J.,Chen, Chien-Teng,Avecilla, Fernando,Agarwal, Subhash M.,Azam, Amir
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p. 48368 - 48381
(2015/06/16)
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- The synthesis of 4,7-disubstituted-2H-benzo[b][1,4]-oxazin-3(4H)-ones using Smiles rearrangement and their in vitro evaluation as platelet aggregation inhibitors
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A series of novel benzo[b][1,4]oxazin-3(4H)-one derivatives were synthesized as platelet aggregation inhibitors for structure-activity relationships (SAR) analysis. The synthetic pattern, involved Smiles rearrangement for the preparation of benzoxazine, was proven to be more efficient than the conventional methods. Biological evaluation demonstrated that among all the synthesized compounds, compound 9u (IC50 = 9.20 μM) exhibited the most potent inhibition activity compared with aspirin, the positive control (IC50 = 7.07 μM). Molecular docking revealed that these set of compounds could be the GPIIb/IIIa antagonist for that they could be situated in the binding site of GPIIb/IIIa receptor quite well.
- Xia, Shuai,Liu, Ji-Qiang,Wang, Xiu-Hua,Tian, Ye,Wang, Yu,Wang, Jing-Huan,Fang, Liang,Zuo, Hua
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supporting information
p. 1479 - 1483
(2014/03/21)
-
- A 1,4-diphenyl-1,2,3-triazole-based β-turn mimic constructed by click chemistry
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A series of 1,4-diphenyl-1,2,3-triazole-incorporated amide derivatives have been designed and prepared. X-ray crystallographic and (1D and 2D) 1H NMR studies reveal that these compounds fold into stable U-shaped conformations driven by three-center intramolecular C-H???O hydrogen-bonding formed between the triazole C-5 H atom and the two ether O atoms. Such folded structures make this 1,4-diphenyl-1,2,3-triazole skeleton a good candidate to be used as β-turn mimic. To prove this, the formation of a β-hairpin structure induced by this β-turn motif has been further demonstrated.
- Wu, Chun-Fang,Zhao, Xin,Lan, Wen-Xian,Cao, Chunyang,Liu, Jin-Tao,Jiang, Xi-Kui,Li, Zhan-Ting
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experimental part
p. 4261 - 4270
(2012/06/18)
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- Modulating the development of E. coli biofilms with 2-aminoimidazoles
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The synthesis of a 20 member 2-aminoimidazole/triazole pilot library is reported. Each member of the library was screened for its ability to inhibit or promote biofilm development of either Escherichia coli and Acinetobacter baumannii. From this screen, E. coli-selective 2-aminoimidazoles were discovered, with the best inhibitor inhibiting biofilm development with an IC50 of 13 μM. The most potent promoter of E. coli biofilm formation promoted biofilm development by 321% at 400 μM.
- Reed, Catherine S.,Huigens III, Robert W.,Rogers, Steven A.,Melander, Christian
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supporting information; experimental part
p. 6310 - 6312
(2010/11/18)
-
- New macrocyclic terbium(III) complex for use in RNA footprinting experiments
-
Reaction of terbium triflate with a heptadentate ligand derivative of cyclen, L1 = 2-[7-ethyl-4,10-bis(isopropylcarbamoylmethyl)-1,4,7,10- tetraazacyclododec-1-yl]-N-isopropyl-acetamide, produced a new synthetic ribonuclease, [Tb(L1)(OTf)(OH2)](OTf)2? MeCN (C1). X-ray crystal structure analysis indicates that the terbium(III) center in C1 is 9-coordinate, with a capped square-anf/prism geometry. While the terbium(III) center is tightly bound by the L1 ligand, two of the coordination sites are occupied by labile water and triflate ligands. In water, the triflate ligand is likely to be displaced, forming [Tb(L1)(OH2)2] 3+, which is able to effectively promote RNA cleavage. This complex greatly accelerates the rate of intramolecular transesterification of an activated model RNA phosphodiester, uridine-3'-p-nitrophenylphos- phate (UpNP), with kobs = 5.5(1) × 10-2 s-1 at 21 °C and pH 7.5, corresponding to an apparent second- order rate constant of 277(5) M-1s-1. By contrast, the analogous complex of an octadentate derivative of cyclen featuring only a single labile coordination site, [Tb(L2)(OH2)](OTf)3 (C2), where L2 = 2-[4,7,10-tris(isopropylcarbamoylmethyl)-1,4,7,10-tetraazacyclododec-1-yl] -N-isopropyl-acetamide, is inactive. [Tb(L1)(OH2)2] 3+ is also capable of hydrolyzing short transcripts of the HIV-1 transactivation response (TAR) element, HIV-1 dimerization initiation site (DIS) and ribosomal A-site, as well as formyl methionine tRNA (tRNAfMet), albeit at a considerably slower rate than UpNP transesterification (k obs = 2.78(8) × 10-5 s-1 for TAR cleavage at 37 °C, pH 6.5, corresponding to an apparent second-order rate constant of 0.56(2) M-1s-1). Cleavageis concentrated at the single-stranded "bulge" regions of these RNA mot ifs. Exploiting this selectivity, [Tb(L1)(OH2)2]3+ was successfully employed in footprinting experiments, in which binding of the Tat peptide and neomycin B to the bulge region of theTAR stem-loop was confirmed.
- Belousoff, Matthew J.,Ung, Phuc,Forsyth, Craig M.,Tor, Yitzhak,Spiccia, Leone,Graham, Bim
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experimental part
p. 1106 - 1114
(2009/06/27)
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- Synthesis of 3-alkyloxazolidin-2,4-diones using 2-chloroacetamides, carbon dioxide and 1,8-diazabicyclo[5.4.0]undecene (DBU)
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Diazabicyclo[5.4.0]undecene (DBU) reacts with carbon dioxide and N-subsititued-2-chloroacetoamides in a very simple one-step procedure, to give the corresponding 3-substituted oxazolidin-2,4-diones in excellent yields.
- Galliani, Guido,Rindone, Bruno,Saliu, Francesco
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experimental part
p. 5123 - 5125
(2009/11/30)
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- PYRROLOPYRIMIDINE DERIVATIVES USEFUL AS MODULATORS OF MULTIDRUG RESISTANCE
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A compound which is a pyrrolopyrimidine of formula (I) wherein: R1 is selected from R9 and halogen; R2 is NR6R7; R3 is selected from H, C1-C6 alkyl which is unsubstituted or substituted and -(CH2) nAr; R4 is selected from H, C1-C6 alkyl and -(CH2)? Ar; or R3 and R4 form, together with the N and C atoms to which they are attached, a fused five-, six-, seven- or eight-membered N-containing saturated ring which is unsubstituted or substituted; R5 is selected from CN, C02R9,C(O)NR10R11, -(CH2)nOH, -(CH2)nR10Rn, -C=CH, -C(S)NR10R11, -C(NH2)=NOR9, -C(R9)=NOR9, -C(NH2)NH, -C(O)R9 and an unsaturated 5- or 6-membered heterocyclic group which contains 1, 2 or 3 heteroatoms selected from N, O and S and which is unsubstituted or substituted; R6 and R7, which are the same or different, are selected from C1-C6 alkyl which is unsubstituted or substituted, -(CH2)nX and -(CH2)nAr; or R6 and R7 form, together with the nitrogen atom to which they are attached, a saturated five-, six-, seven- or eight-membered heterocyclic group which contains one nitrogen atom and 0 or from 1 to 3 additional heteroatoms selected from N, O and S, which is unsubstituted or substituted and which optionally contains one or two bridgehead atoms; R10and R11,which are the same or different, are selected from H, C1-C6 alkyl which is unsubstituted or substituted, -(CH2)nC3-C10 cycloalkyl and -(CH2)nAr; or R10 and R11 form, together with the nitrogen atom to which they are attached, a saturated five or six membered heterocyclic group which contains a nitrogen atom and 0 or from to 3 additional heteroatoms selected from O, S and N, which is unsubstituted or substituted and which is optionally fused to a benzene ring which is unsubstituted or substituted; n is the same or different when more than one is present within a given substituent group and is 0 or an integer of from 1 to 6; X is selected from -CN, -C02R9 and -NR10R11; R9 is the same or different when more than one is present within a given substituent group and is selected from -H, -QAr, -(CH2) nAr, C1-C6 alkyl which is unsubstituted or substituted and -(CH2) nC3-C10cycloalkyl, wherein the cycloalkyl moiety is optionally fused to a benzene ring which is unsubstituted or substituted; Q is C2-C6 alkenylene or alkynylene; and Ar is an unsaturated C6-C10 membered carbocyclic group or an unsaturated 5-11 membered heterocyclic group, which groups are unsubstituted or substituted; or a pharmaceutically acceptable salt thereof. These compounds have activity as inhibitors of MRP (multidrug resistant protein) and may thus be used to modulate multidrug resistance, for instance in potentiating the cytotoxicity of a chemotherapeutic agent.
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- Compounds for the management of aging-related and diabetic vascular complications, process for their preparation and therapeutic uses thereof
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Novel compounds of the pyridinium series useful for the management of diabetes and aging-related vascular and neurovascular complications, including kidney disease, nerve damage, atherosclerosis, retinopathy, inflammatory disorders, immunological disorders, oxidative stress, dermatological disorders and discoloration of teeth, by breaking preformed AGE, of the general formula I, or pharmaceutically acceptable salts thereof, wherein, R1, R2, R3, X and m are as defined in the specification. Also disclosed is a method for preparation of the compounds of general formula (I) and pharmaceutical composition containing one or more compounds as defined above as active ingredients. Also disclosed is a method of treatment of a diabetic patient by administering the compounds as defined above, either singly or in combination with drugs for antidiabetic therapy.
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- REACTIONS OF DICHLOROACETYLENE WITH PRIMARY ALIPHATIC AMINES
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Primary aliphatic amines are good nucleophilic reagents which easily react with dichloroacetylene (DCA).The reactions of DCA with primary aliphatic amines have been studied and a mechanism of these reactions has been proposed and discussed.
- Pielichowski, Jan,Czub, Piotr
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p. 407 - 410
(2007/10/02)
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- BENZODIOXANYL-HYDROXYETHYLENEAMINO-PIPERIDINYL ACETANILIDES, KETONES, ESTERS AND CARBAMATES WHICH EFFECT IMMUNITY AND CALCIUM ENTRY AND BETA-BLOCKADE
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Novel compounds of the general formula: STR1 and the pharmaceutically acceptable acid addition salts thereof, wherein: R 1, R 2, R 3 and R 4 are each independently hydrogen, lower alkyl, lower alkoxy, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl or lower alkyl sulfonyl;R 5 is hydrogen or lower alkyl;m is 0 or 1;W is alkylene,--CH=CH--,--O--, or--N(R 6)--, where R 6 is lower alkyl or hydrogen;n is 0 or 1; andQ is lower alkyl, cycloalkyl or optionally substituted phenyl. These compounds combine β-blockade and calcium entry blockade properties in the same compound and therefore are useful in therapy in the treatment of cardiovascular diseases, including myocardial infarction, hypertension, arrhythmia and variant and exercise induced angina. The compounds are also useful in immunosuppressant therapy for immune diseases, such as rheumatoid arthritis.
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