- Method for preparing 2-amino-4-aminomethyl methyl benzoate and hydrochloride thereof
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The invention relates to the field of organic synthesis, and discloses a method for preparing 2-amino-4-aminomethyl methyl benzoate and hydrochloride thereof. The method comprises the following steps:1) sequentially contacting dimethyl terephthalate with a nitration reagent and acetic acid to obtain 3-nitro-4-methoxycarbonyl benzoic acid; (2) converting the 3-nitro-4-methoxycarbonyl benzoic acidinto 2-nitro-4-methoxycarbonyl benzoyl chloride, and enabling the 2-nitro-4-methoxycarbonyl benzoyl chloride to be in contact with ammonia gas so as to obtain methyl 2-nitro-4-formylaminobenzoate; 3)performing dehydration reaction on the 2-nitro-4-formylaminobenzoic acid methyl ester to obtain 2-nitro-4-cyanobenzoic acid methyl ester, and 4) performing reduction reaction on the 2-nitro-4-cyanobenzoic acid methyl ester to obtain 2-amino-4-aminomethyl benzoate. The preparation method has the advantages of high yield, high purity and environmental protection.
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Paragraph 0051-0053; 0060-0062; 0069-0072
(2020/09/08)
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- Design, synthesis, and evaluation of compounds capable of reducing Pseudomonas aeruginosa virulence
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Anti-virulence approaches in the treatment of Pseudomonas aeruginosa (PA)-induced infections have shown clinical potential in multiple in vitro and in vivo studies. However, development of these compounds is limited by several factors, including the lack of molecules capable of penetrating the membrane of gram-negative organisms. Here, we report the identification of novel structurally diverse compounds that inhibit PqsR and LasR-based signaling and diminish virulence factor production and biofilm growth in two clinically relevant strains of P. aeruginosa. It is the first report where potential anti-virulent agents were evaluated for inhibition of several virulence factors of PA. Finally, co-treatment with these inhibitors significantly reduced the production of virulence factors induced by the presence of sub-inhibitory levels of ciprofloxacin. Further, we have analyzed the drug-likeness profile of designed compounds using quantitative estimates of drug-likeness (QED) and confirmed their potential as hit molecules for further development.
- Hossain, Mohammad Anwar,Sattenapally, Narsimha,Parikh, Hardik I.,Li, Wei,Rumbaugh, Kendra P.,German, Nadezhda A.
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supporting information
(2019/11/26)
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- PROCESS FOR PREPARATION OF 1-NITROBENZENE-2-ALKYLOXYCARBONYL-5-CARBOXYLIC ACID
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The present invention relates to processes for preparation of 1 -nitrobenzene-2- alkyloxycarbonyl-5-carboxylic acid. In particular, the present invention relates to preparation of 1 -nitrobenzene-2-alkyloxycarbonyl-5-carboxylic acid by partial hydrolysis of diester of 1 -nitrobenzene 2,5-dicarboxylic acid in presence of hydrogen chloride.
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Page/Page column 7
(2019/08/29)
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- Synthesis of a new fluorine-18-labeled bexarotene analogue for PET imaging of retinoid X receptor
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The reference standard 2-fluoro-4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)vinyl)ben-zoic acid was synthesized from 2,5-dimethyl-2,5-hexanediol and 2-fluoro-4-methylbenzoic acid in 10 steps with 3% overall chemical yield. The precursor 2-nitro-4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetra-hydronaphthalen-2-yl)vinyl)benzoic acid was synthesized from 2,5-dimethyl-2,5-hexanediol and dimethyl-2-nitroterephthalate in seven steps with 2% overall chemical yield. The target tracer 2-[18F]flu-oro-4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)vinyl)benzoic acid was synthesized from its nitro-precursor by the nucleophilic substitution with K[18F]F/Kryptofix 2.2.2 and isolated by HPLC combined with solid-phase extraction (SPE) purification in 20-30% radiochemical yield with 37-370 GBq/μmol specific activity at end of bombardment (EOB).
- Wang, Min,Davis, Toni,Gao, Mingzhang,Zheng, Qi-Huang
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p. 1742 - 1747
(2015/03/14)
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- Synthesis of a new fluorine-18-labeled bexarotene analogue for PET imaging of retinoid X receptor
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The reference standard 2-fluoro-4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8- tetrahydronaphthalen-2-yl)vinyl)benzoic acid was synthesized from 2,5-dimethyl-2,5-hexanediol and 2-fluoro-4-methylbenzoic acid in 10 steps with 3% overall chemical yield. The precursor 2-nitro-4-(1-(3,5,5,8,8-pentamethyl-5, 6,7,8-tetrahydronaphthalen-2-yl)vinyl)benzoic acid was synthesized from 2,5-dimethyl-2,5-hexanediol and dimethyl-2-nitroterephthalate in seven steps with 2% overall chemical yield. The target tracer 2-[18F]fluoro-4-(1- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)vinyl)benzoic acid was synthesized from its nitro-precursor by the nucleophilic substitution with K[18F]F/Kryptofix 2.2.2 and isolated by HPLC combined with solid-phase extraction (SPE) purification in 20-30% radiochemical yield with 37-370 GBq/μmol specific activity at end of bombardment (EOB).
- Wang, Min,Davis, Toni,Gao, Mingzhang,Zheng, Qi-Huang
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p. 1742 - 1747
(2014/04/17)
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- DERIVATIZED 3-STYRYL-CEPHALOSPORINS
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Broad spectrum beta-lactamase inhibitors. Certain inhibitors also exhibit potent antibiotic activity in addition to beta-lactamase inhibition. Compounds of the invention are designed such that on cleavage of the beta-lactam ring reactive moieties are generated which can inactivate beta-lactamase. Also provided are methods of making betalactamase inhibitors and beta-lactam antibiotics exhibiting such inhibition. Additionally provided are pharmaceutical compositions for treatment or prevention of bacterial infections and methods of treatment of such infections.
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Paragraph 00151
(2014/10/18)
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- NOVEL BEXAROTENE ANALOGS
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The present invention relates to analogs of bexarotene and methods of use thereof.
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Page/Page column 21-22
(2011/09/19)
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- Modeling, synthesis and biological evaluation of potential Retinoid X Receptor (RXR) selective agonists: Novel analogues of 4-[1-(3,5,5,8,8- pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene)
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This report describes the synthesis of analogues of 4-[1-(3,5,5,8,8- pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (1), commonly known as bexarotene, and their analysis in acting as retinoid X receptor (RXR)-specific agonists. Compound 1 has FDA approval to treat cutaneous T-cell lymphoma (CTCL); however, its use can cause side effects such as hypothyroidism and increased triglyceride concentrations, presumably by disruption of RXR heterodimerization with other nuclear receptors. The novel analogues in the present study have been evaluated forRXR activation in an RXR mammalian-2-hybrid assay as well as an RXRE-mediated transcriptional assay and for their ability to induce apoptosis as well as for their mutagenicity and cytotoxicity. Analysis of 11 novel compounds revealed the discovery of three analogues that best induce RXR-mediated transcriptional activity, stimulate apoptosis, have comparable Ki and EC50 values to 1, and are selective RXR agonists. Our experimental approach suggests that rational drug design can develop new rexinoids with improved biological properties. 2009 American Chemical Society.
- Wagner, Carl E.,Jurutka, Peter W.,Marshall, Pamela A.,Groy, Thomas L.,Van Der Vaart, Arjan,Ziller, Joseph W.,Furmick, Julie K.,Graeber, Mark E.,Matro, Erik,Miguel, Belinda V.,Tran, Ivy T.,Kwon, Jungeun,Tedeschi, Jamie N.,Moosavi, Shahram,Danishyar, Amina,Philp, Joshua S.,Khamees, Reina O.,Jackson, Jevon N.,Grupe, Darci K.,Badshah, Syed L.,Hart, Justin W.
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experimental part
p. 5950 - 5966
(2010/02/28)
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- Further optimization of sulfonamide analogs as EP1 receptor antagonists: Synthesis and evaluation of bioisosteres for the carboxylic acid group
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4-{[2-[(2-Furylsulfonyl)(isobutyl)amino]-5-(trifluoromethyl)phenoxy]methyl}benzoic acid analogs 2a and b and a series of the acid analogs, in which the carboxylic acid residue of 2b was replaced with various kinds of carboxylic acid bioisosteres, were synthesized and evaluated as EP1 receptor antagonists. Compound 2b and its monocyclic acid analogs, in which the carboxylic acid residue of 2b was replaced with monocyclic acid bioisosteres, were found to show potent EP1 receptor antagonist activity. Optimization of the linker Y between the phenyl moiety and the carboxylic acid residue of 2b was also carried out (Table 5). Compounds 2b and 16 and 17 possessing conformationally restricted linker Y were found to show the most optimized potency among the tested compounds. Cytochrome P450 inhibition of optimized compounds was also investigated. Details of the structure-activity relationship study are presented.
- Naganawa, Atsushi,Matsui, Toshiaki,Ima, Masaki,Saito, Tetsuji,Murota, Masayuki,Aratani, Yoshiyuki,Kijima, Hideomi,Yamamoto, Hiroshi,Maruyama, Takayuki,Ohuchida, Shuichi,Nakai, Hisao,Toda, Masaaki
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p. 7121 - 7137
(2007/10/03)
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- Amino (oxo) acetic acid protein tyrosine phosphatase inhibitors
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Compounds of formula (I) or therapeutically acceptable salts thereof, are protein tyrosine kinase PTP1B inhibitors. Preparation of the compounds, compositions containing the compounds, and treatment of diseases using the compounds are disclosed.
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- Conformational preferences in a benzodiazepine series of potent nonpeptide fibrinogen receptor antagonists
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Previously, we reported the direct design of highly potent nonpeptide 3- oxo-1,4-benzodiazepine fibrinogen receptor antagonists from a constrained, RGD-containing cyclic semipeptide. The critical features incorporated into the design of these nonpeptides were the exocyclic amide at the 8-position which overlaid the Arg carbonyl, the phenyl ring which maintained an extended Gly conformation, and the diazepine ring which mimicked the γ-turn at Asp. In this paper, we investigate conformational preferences of the 8-substituted benzodiazepine analogues by examining structural modifications to both the exocyclic amide and the seven-membered diazepine ring and by studying the conformation of the benzodiazepine ring using molecular modeling, X-ray crystallography, and NMR. We found that the directionality of the amide at the 8-position had little effect on activity and the (E)-olefin analogue retained significant potency, indicating that the trans orientation of the amide, and not the carbonyl or NH groups, made the largest contribution to the observed activity. For the diazepine ring, with the exception of the closely analogous 3-oxo-2-benzazepine ring system described previously, all of the modifications led to a significant reduction in activity compared to the potent 3-oxo-1,4-benzodiazepine parent ring system, implicating this particular type of ring system as a desirable structural feature for high potency. Energy minimizations of a number of the modified analogues revealed that none could adopt the same low-energy conformation as the one shared by the active (S)-isomer of the 3-oxo-1,4-benzodiazepines and 3-oxo-2- benzazepines. The overall data suggest that the features contributing to the observed high potency in this series are the orientation of the 3-4 amide and the conformational constraint imposed by the seven-membered ring, both of which position the key acidic and basic groups in the proper spatial relationship.
- Keenan, Richard M.,Callahan, James F.,Samanen, James M.,Bondinell, William E.,Calvo, Raul R.,Chen, Lichong,DeBrosse, Charles,Eggleston, Drake S.,Haltiwanger, R. Curtis,Hwang, Shing Mei,Jakas, Dalia R.,Ku, Thomas W.,Miller, William H.,Newlander, Kenneth A.,Nichols, Andrew,Parker, Michael F.,Southhall, Linda S.,Uzinskas, Irene,Vasko-Moser, Janice A.,Venslavsky, Joseph W.,Wong, Angela S.,Huffman, William F.
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p. 545 - 559
(2007/10/03)
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- Bicyclic fibrinogen antagonists
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This invention relates to compounds of the formula: STR1 wherein A1 to A5 form an accessible substituted seven-membered ring, which may be saturated or unsaturated, optionally containing up to two heteroatoms chosen from the group of O, S and N wherein S and N may be optionally oxidized; D1 to D4 form an accessible substituted six membered ring, optionally containing up to two nitrogen atoms; R is at least one substituent chosen from the group of R7, or Q--C1-4 alkyl, Q--C2-4 alkenyl, Q--C2-4 alkynyl, preferably substituted by an acidic function; R* is H, Q--C1-6 alkyl, Q--C1-6 oxoalkyl, Q--C2-6 alkenyl or Q--C2-4 alkynyl, C3-6 cycloalkyl, Ar or Het, optionally substituted by one or more substitutents; and R6 is preferably a substituent containing a basic nitrogen moiety; or a pharmaceutically acceptable salt thereof, which are effective for inhibiting platelet aggregation, pharmaceutical compositions for effecting such activity, and a method for inhibiting platelet aggregation.
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