- Three xanthones from Poeciloneuron pauciflorum and Mammea acuminata
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From the stem of Poeciloneuron pauciflorum, two new xanthones (1,6- dihydroxy-7-methoxyxanthone and 1,6-dihydroxy-7-methoxyxanthone 6-O-β-D- glucoside) in addition to 12 known compounds (1,5-dihydroxy-, 1,5-dihydroxy- 3-methoxy-, 1,7-dihydroxy-, 1-hydroxy-7-methoxy-, 2-methoxy-, 4-methoxy-, 1,4,5-trihydroxy-, 1,3,5-trihydroxy-, 1,3,6-trihydroxy-7-methoxy-, 1,3,7- trihydroxy-, 3-hydroxy-2-methoxyxanthone and (-)-epicatechin) were isolated. From the aerial paris (stems and bark) of Mammea acuminata, a new xanthone (2,7-dihydroxyxanthone) was isolated in addition to two known xanthones (1,5- dihydroxy- and 5-hydroxy-1-methoxyxanthone) and (-)-epicatechin. The structures were established by spectral analysis and total synthesis in case of 1,6-dihydroxy-7-methoxyxanthone.
- Tosa, Hideki,Iinuma, Munekazu,Murakami, Koh-Ichi,Ito, Tetsuro,Tanaka, Toshiyuki,Chelladurai, Veliah,Riswan, Soedarsono
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Read Online
- Two xanthones from roots of Cratoxylum formosanum
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From the roots of Cratoxylum formosanum, two new xanthones, 2,7- dihydroxy-1,8-dimethoxyxanthone and 1,4,7-trihydroxy-8-methoxyxanthone, were isolated, in addition to seven known xanthones and two flavonoids. Among the xanthones, 1,4,7-trihydroxyxanthone was the first isolation from the natural sources. Structures were determined by spectral analyses.
- Iinuma, Munekazu,Tosa, Hideki,Ito, Tetsuro,Tanaka, Toshiyuki,Madulid, Domingo A.
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Read Online
- TRPV3 small molecule allosteric inhibitor and preparation method thereof
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The present invention discloses a TRPV3 small molecule allosteric inhibitor and a preparation method thereof. The small molecule inhibitor comprises compounds represented by a general formula (I) anda general formula (II) shown in the specification or pharmaceutically acceptable salts thereof, wherein X is selected from N or C, Y is selected from (CH2) or (CO); R2 is selected from hydrogen and halogen; R4 is selected from C1-C8 alkyl groups, C3-C8 cycloalkyl groups, a naphthalene ring, an adamantyl group, morpholine, 4-(methylsulfonyl) piperazine and 4-(trifluoromethyl)pyridine-2-amine; and R1 and R3 are respectively and independently selected from hydrogen, deuterium, halogen, hydroxyl, sulfydryl, cyano, nitro, C1-C8 alkyl, halogenated C1-C8 alkyl, C1-C8 alkoxy, C3-C8 naphthenic bases, C3-C8 cycloalkenyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C10 aryl, C3-C10 heteroaryl and C4-C8 heterocyclic radical.
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Paragraph 0047; 0048-0051
(2021/03/13)
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- Computational discovery, structural optimization and biological evaluation of novel inhibitors targeting transient receptor potential vanilloid type 3 (TRPV3)
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Transient receptor potential vanilloid type 3 (TRPV3) is a Ca2+ permeable nonselective cation channel and expressed abundantly in skin keratinocytes. TRPV3 emerges as an attractive target for treatment of pruritic, inflammatory, pain and skin-related diseases. However, only a few reports of TRPV3 inhibitors exist at present besides some patents. Therefore, TRPV3 research has always been fraught with challenges. Through a combination of virtual screening and biological evaluation, compound P1 (10 μM) was identified as a top hit with 34.5% inhibitory effect on 2-APB (1 mM)-evoked currents of mTRPV3-WT. Further structural optimization provided the inhibitor PC5 with the best activity (IC50 = 2.63 ± 0.28 μM), and point mutation assays indicated that amino acids V629 and F633 are crucial for the binding of PC5 and TRPV3. In summary, these newly discovered inhibitors could serve as promising lead compounds for the development of TRPV3 inhibitors in the future.
- Zhang, Fang,Lin, Yiyu,Min, Wenjian,Hou, Yi,Yuan, Kai,Wang, Jin,Yang, Peng
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- Synthesis of 3-aryl-1-phosphinoimidazo[1,5-a]pyridine ligands for use in Suzuki-Miyaura cross-coupling reactions
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3-Aryl-1-phosphinoimidazo[1,5-a]pyridine ligands were synthesized from 2-aminomethylpyridine as the initial substrateviatwo complementary routes. The first synthetic pathway underwent the coupling of 2-aminomethylpyridine with substituted benzoyl chlorides, followed by cyclization, iodination and palladium-catalyzed cross-coupling phosphination reactions sequence to give our phosphorus ligands. In the second route, 2-aminomethylpyridine was cyclized with aryl aldehydes, followed by the iodination and palladium-catalyzed cross-coupling phosphination reactions to yield our phosphorus ligands. The 3-aryl-1-phosphinoimidazo[1,5-a]pyridine ligands were evaluated in palladium-catalyzed sterically-hindered biaryl and heterobiaryl Suzuki-Miyaura cross-coupling reactions.
- Dinh, Long P.,Harris, Nekoda W.,Jacoby, Seth A.,Semsey, Rebecca Y.,Swann, William A.,Tran, Ryan Q.,Williamson, Savannah N.,Yet, Larry
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p. 28347 - 28351
(2021/09/15)
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- Late-Stage β-C(sp3)-H Deuteration of Carboxylic Acids
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Carboxylic acids are highly abundant in bioactive molecules. In this study, we describe the late-stage β-C(sp3)-H deuteration of free carboxylic acids. On the basis of the finding that C-H activation with our catalysts is reversible, the de-deuteration process was first optimized. The resulting method uses ethylenediamine-based ligands and can be used to achieve the desired deuteration when using a deuterated solvent. The reported method allows for the functionalization of a wide range of free carboxylic acids with diverse substitution patterns, as well as the late-stage deuteration of bioactive molecules and related frameworks and enables the functionalization of nonactivated methylene β-C(sp3)-H bonds for the first time.
- Mal, Sourjya,Uttry, Alexander,Van Gemmeren, Manuel
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supporting information
p. 10895 - 10901
(2021/08/03)
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- Preparation method of 2,4,6-trimethylbenzoyl chloride and acyl chloride co-production technology
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The invention relates to the field of new materials of fine chemicals, in particular to 2,4,6-trimethylbenzoyl chloride (also known as trimesoyl chloride) and an environment-friendly and economical novel preparation process technology for co-producing series acyl chloride products.
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Paragraph 0030-0032
(2020/11/25)
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- 6,7-Dimethoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinoline amides and corresponding ester isosteres as multidrug resistance reversers
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Aiming to deepen the structure–activity relationships of the two P-glycoprotein (P-gp) modulators elacridar and tariquidar, a new series of amide and ester derivatives carrying a 6,7-dimethoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinoline scaffold linked to different methoxy-substituted aryl moieties were synthesised. The obtained compounds were evaluated for their P-gp interaction profile and selectivity towards the two other ABC transporters, multidrug-resistance-associated protein-1 and breast cancer resistance protein, showing to be very active and selective versus P-gp. Two amide derivatives, displaying the best P-gp activity, were tested in co-administration with the antineoplastic drug doxorubicin in different cancer cell lines, showing a significant sensitising activity towards doxorubicin. The investigation on the chemical stability of the derivatives towards spontaneous or enzymatic hydrolysis, showed that amides are stable in both models while some ester compounds were hydrolysed in human plasma. This study allowed us to identify two chemosensitizers that behave as non-transported substrates and are characterised by different selectivity profiles.
- Bartolucci, Gianluca,Braconi, Laura,Colabufo, Nicola Antonio,Contino, Marialessandra,Dei, Silvia,Giampietro, Roberta,Manetti, Dina,Perrone, Maria Grazia,Riganti, Chiara,Romanelli, Maria Novella,Teodori, Elisabetta,Chiaramonte, Niccolò
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p. 974 - 992
(2020/04/24)
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- Preparation method of 2,6-dimethoxybenzoyl chloride
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The invention discloses a preparation method of 2,6-dimethoxybenzoyl chloride and belongs to the technical field of medicine techniques. The technical problem to be solved by the invention is to relate to a more advanced preparation method of 2,6-dimethoxybenzoyl chloride. The main point of the technical scheme for solving the technical problem by the invention is a new preparation method of the compound.
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Paragraph 0007-0010
(2018/12/03)
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- Electrochemical C-H cyanation of electron-rich (Hetero)arenes
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A straightforward method for the electrochemical C-H cyanation of arenes and heteroarenes that proceeds at room temperature in MeOH, with NaCN as the reagent in a simple, open, undivided electrochemical cell is reported. The platinum electrodes are passivated by ad-sorbed cyanide, which allows conversion of an exceptionally broad range of electron-rich substrates all the way down to dialkyl arenes. The cyanide electrolyte can be replenished with HCN, opening opportunities for salt-free industrial C-H cyanation.
- Hayrapetyan, Davit,Rit, Raja K.,Kratz, Markus,Tschulik, Kristina,Goo?en, Lukas J.
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supporting information
p. 11288 - 11291
(2018/10/20)
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- Synthesis, carbonic anhydrase inhibitory activity and antioxidant activity of some 1,3-oxazine derivatives
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(Table presented.). A series of 1-(6-methyl-2-substituted phenyl-4-thioxo-4H-1,3-oxazin-5-yl)ethanones (3a-n) were synthesized by the reaction of benzoyl isothiocyanates with active methylene compound acetylacetone in the presence of triethyl amine in a one-pot process. The structures of the products were elucidated by elemental analyses, FT-IR, 1H NMR, 13C NMR, and mass spectroscopy. These new 1,3-oxazine derivatives were evaluated for their inhibitory activity against carbonic anhydrase II. Results for in vitro assay revealed that compound 3b having 4-methoxy phenyl moiety was the most potent inhibitor with IC50 value of 0.144 ± 0.008 μM. It exhibited higher enzyme inhibitory activity as compared to the standard acetazolamide (IC50 = 0.997 ± 0.061 μM). The compounds 3c, 3h, and 3n also displayed superior inhibitory activities compared to the rest of the synthesized oxazine derivatives. The radical scavenging activity of oxazine derivatives was also performed and it was found that compounds showed moderate antioxidant activity. Lipinski rule confirmed the therapeutic potential of the synthesized compounds. Molecular docking studies were also performed to further understand the binding affinity of these compounds with PDBID 1V9E which confirmed that the synthesized derivatives bind in the active binding site of the target protein. Based upon our results, it is proposed that compound 3b may serve as a lead structure to design more potent carbonic anhydrase inhibitors.
- Qamar, Rabia,Saeed, Aamer,Saeed, Maria,Ashraf, Zaman,Abbas, Qamar,Hassan, Mubashir,Albericio, Fernando
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p. 352 - 361
(2018/10/20)
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- Synthesis of 4-Quinolones: N,O-Bis(trimethylsilyl)acetamide-Mediated Cyclization with Cleavage of Aromatic C-O Bond
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The synthesis of 1,4-dihydro-4-oxoquinoline derivatives (4-quinolones) based on a BSA [N,O-bis(trimethylsilyl)acetamide]-mediated cyclization of substituted 1-(2-methoxyphenyl)-3-(alkyl/arylamino)prop-2-en-1-ones is described. The reaction belongs to a rare set of cyclizations in which a methoxy group serves as the leaving group. Reaction takes place by the action of silylating agent under mild conditions and provides high yields of pure products following simple aqueous work-up. The versatility of the approach is exemplified by a wide range of 1-alkyl/aryl 3-carboxylates and 3-nitriles that have been prepared. A crucial advantage of this approach is the facile availability of starting methoxy compounds enabling new synthetic possibilities as well as improved cost efficiency. A new approach to the synthesis of 1,4-dihydro-4-oxoquinoline (4-quinolone) derivatives using a BSA-mediated reaction was developed; this entails an example of rare cyclizations in which an OMe group serves as a leaving group. This transformation has great synthetic potential due to the phenolic framework of starting materials and the mildness of the reagent.
- Pí?a, Ond?ej,Rádl, Stanislav
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p. 2336 - 2350
(2016/05/19)
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- CYCLOPENTYLBENZAMIDE DERIVATIVES AND THEIR USE FOR THE TREATMENT OF PSYCHOTIC AND COGNITIVE DISORDERS
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The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein n, L, X, Ra, Rb, R1, R2 and R3 their preparation, pharmaceutical compositions containing them and their use in therapy.
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Page/Page column 152; 153
(2015/05/05)
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- Beyond directed ortho metalation: Ru-catalyzed CAr-O activation/cross-coupling reaction by amide chelation
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Disclosed is a new, catalytic, and general methodology for the chemical synthesis of biaryl, heterobiaryl, and polyaryl molecules by the cross-coupling of o-methoxybenzamides with aryl boroneopentylates. The reaction is based on the activation of the unreactive C-OMe bond by the proximate amide directing group using catalytic RuH2(CO)(PPh3)3 conditions. A one-step, base-free coupling process is thereby established that has the potential to supersede the useful two-step directed ortho metalation/cross- coupling reaction involving cryogenic temperature and strong base conditions. High regioselectivity, orthogonality with the Suzuki-Miyaura reaction, operational simplicity, minimum waste, and convenient scale-up make these reactions suitable for industrial applications.
- Zhao, Yigang,Snieckus, Victor
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supporting information
p. 11224 - 11227
(2014/09/29)
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- A-ring oxygenation modulates the chemistry and bioactivity of caged Garcinia xanthones
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Natural products of the caged Garcinia xanthones (CGX) family are characterized by a unique chemical structure, potent bioactivities and promising pharmacological profiles. We have developed a Claisen/Diels-Alder reaction cascade that, in combination with a Pd(0)-catalyzed reverse prenylation, provides rapid and efficient access to the CGX pharmacophore, represented by the structure of cluvenone. To further explore this pharmacophore, we have synthesized various A-ring oxygenated analogues of cluvenone and have evaluated their bioactivities in terms of growth inhibition, mitochondrial fragmentation, induction of mitochondrial-dependent cell death and Hsp90 client inhibition. We found that installation of an oxygen functionality at various positions of the A-ring influences significantly both the site-selectivity of the Claisen/Diels-Alder reaction and the bioactivity of these compounds, due to remote electronic effects.
- Elbel, Kristyna M.,Guizzunti, Gianni,Theodoraki, Maria A.,Xu, Jing,Batova, Ayse,Dakanali, Marianna,Theodorakis, Emmanuel A.
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supporting information
p. 3341 - 3348
(2013/06/26)
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- Synthesis and biological activities of new halophenols
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A series of new halophenols were synthesized, and their structures were established on the basis of 1H, 13C NMR and mass spectral data. All of the prepared compounds were screened for their in vitro protein tyrosine kinase (PTK) and vascular smooth muscle cell (VSMC) proliferation inhibitory activity. Twelve halophenols showed significant PTK inhibitory activity, most of them exhibited stronger activities than that of genistein, a positive reference compound. Several halophenols also displayed moderate VSMC proliferation inhibitory activity, compound 8c showed higher activity than that of tetrandrine, a positive reference compound. The preliminary structure-activity relationships of these compounds were investigated and discussed. The results provided a foundation for the action mechanism study and further structure optimization of the halophenols.
- Zheng, Fei Lang,Ban, Shu Rong,Feng, Xiu E.,Zhao, Cheng Xiao,Du, Guan Hua,Li, Qing Shan
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p. 303 - 311
(2013/07/28)
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- GARCINIA DERIVATIVE, ITS PREPARING METHOD AND MEDICINAL USE
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The present invention relates to a field of pharmaceutical chemistry, more specifically, the present invention relates to a garcinia derivative Formula (I), its preparing method, and medicinal use. Wherein the definitions of R1 and R2 are disclosed in the specification of the present invention, and the derivative of the present invention is a structurally simplified analogue of the gambogic acid compound; wherein the gambogic acid compound possesses anti-cancer characteristics, and could be used for preparation of anti-tumor drugs.
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Page/Page column 6
(2012/03/26)
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- Synthesis and evaluation of boronic acids as inhibitors of Penicillin Binding Proteins of classes A, B and C
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In response to the widespread use of β-lactam antibiotics bacteria have evolved drug resistance mechanisms that include the production of resistant Penicillin Binding Proteins (PBPs). Boronic acids are potent β-lactamase inhibitors and have been shown to display some specificity for soluble transpeptidases and PBPs, but their potential as inhibitors of the latter enzymes is yet to be widely explored. Recently, a (2,6-dimethoxybenzamido) methylboronic acid was identified as being a potent inhibitor of Actinomadura sp. R39 transpeptidase (IC50: 1.3 μM). In this work, we synthesized and studied the potential of a number of acylaminomethylboronic acids as inhibitors of PBPs from different classes. Several derivatives inhibited PBPs of classes A, B and C from penicillin sensitive strains. The (2-nitrobenzamido)methylboronic acid was identified as a good inhibitor of a class A PBP (PBP1b from Streptococcus pneumoniae, IC50 = 26 μM), a class B PBP (PBP2xR6 from Streptococcus pneumoniae, IC50 = 138 μM) and a class C PBP (R39 from Actinomadura sp., IC50 = 0.6 μM). This work opens new avenues towards the development of molecules that inhibit PBPs, and eventually display bactericidal effects, on distinct bacterial species.
- Zervosen, Astrid,Bouillez, Andre,Herman, Alexandre,Amoroso, Ana,Joris, Bernard,Sauvage, Eric,Charlier, Paulette,Luxen, Andre
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experimental part
p. 3915 - 3924
(2012/08/28)
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- Studies on chemical modification and biology of a natural product, gambogic acid (III): Determination of the essential pharmacophore for biological activity
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Caged 4-oxa-tricyclo[4.3.1.03,7]dec-2-one structural motifs are found in Garcinia natural products that demonstrate anti-tumor activity. Gambogic acid (GA, 1), the most abundant caged Garcinia xanthones, has been reported to be a promising anti-cancer agent. To identify the essential pharmacophore for its anti-tumor activity, a series of GA analogues that address potential key structural features for biological activity were synthesized, among which compound 11a displayed comparable in vitro anti-tumor activity as GA. Mechanistic studies on 11a determined that the compound induces apoptosis as well as arrests the G2/M phase of the cell cycle in HepG2 cells. The determination of the essential part of the scaffold found in GA to maintain anti-tumor effects, and the SAR based on the caged pharmacophore are reported and will provide key information for future anti-cancer drug development studies.
- Wang, Xiaojian,Lu, Na,Yang, Qian,Gong, Dandan,Lin, Changjun,Zhang, Shenglie,Xi, Meiyang,Gao, Yuan,Wei, Libing,Guo, Qinglong,You, Qidong
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experimental part
p. 1280 - 1290
(2011/04/22)
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- Synthesis and in vitro protein tyrosine kinase inhibitory activity of furan-2-yl(phenyl)methanone derivatives
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A series of novel furan-2-yl(phenyl)methanone derivatives were synthesized, and their structures were established on the basis of 1H-NMR, 13C-NMR and mass spectral data. All the prepared compounds were screened for their in vitro protein tyrosine kinase inhibitory activity and several new derivatives exhibited promising activity, which, in some cases, was identical to, or even better than that of genistein, a positive reference compound. The preliminary structure-activity relationships of these compounds were investigated and are discussed.
- Zheng, Fei Lang,Ban, Shu Rong,Feng, Xiu E,Zhao, Cheng Xiao,Lin, Wenhan,Li, Qing Shan
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experimental part
p. 4897 - 4911
(2011/08/10)
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- Preparation of non-peptide, highly potent and selective antagonists of arginine vasopressin V1a receptor by introduction of alkoxy groups
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A series of compounds structurally related to 4′-[(4,4-difluoro-5- methylidene-2,3,4,5-tetrahydro-1H-1-benzoazepin-1-yl)carbonyl]benzanilide were synthesized and evaluated for arginine vasopressin (AVP) antagonistic activity. Compounds with alkoxy groups (especially ethoxy group) at the 2′-position of benzanilide possessed potent affinity and selectivity for the V1A receptor versus V2 receptor. Further study has shown that the introduction of 4,4-dimethylaminopiperidino and morpholino groups at carbonylmethylene exhibited more potent affinity and selectivity for V 1A receptors. Consequently, we found that the (Z)-4′-({4,4- Difluoro-5-[(4-dimethylaminopiperidino) carbonylmethylene]-2,3,4,5-tetrahydro- 1H-1-benzoazepin-1-yl}carbonyl)-2-ethoxybenzanilide monohydrochloride (8d) and the (Z)-4′-[(4,4-Difluoro-5-morpholinocarbamoylethylene-2,3,4,5- tetrahydro-1H-1-benzoazepin-1-yl)carbonyl]-2-ethoxybenzanilide (8q) exhibited potent and selective V1A receptor antagonist activity. The synthesis and pharmacological properties of these compounds are detailed in this paper.
- Shimada, Yoshiaki,Taniguchi, Nobuaki,Matsuhisa, Akira,Yatsu, Takeyuki,Tahara, Atsuo,Tanaka, Akihiro
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p. 1075 - 1080
(2007/10/03)
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- Vibrational and theoretical study of the 2',6'-dimethoxyflavone cis-formic acid inclusion compound.
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The FT-infrared and Raman microscopy spectra of the 2',6'-dimethoxyflavone and its 1:1 complex with formic acid in solid state have been recorded and analysed. Some vibrational components appear as specific to the cis-rotamer of formic acid in the crystalline sample, especially the CH group stretching vibration feature. The broad and intense infrared absorption observed in the range 3400-1900 cm(-1) and assigned to the hydrogen bonded OH group stretching vibration exhibits the characteristic ABC structure of strong hydrogen bonded complexes. This ABC pattern corroborates previous X-ray crystallographic data showing that cis-formic acid is strongly hydrogen bonded to the flavonic compound. The inclusion complex is quite unstable and the infrared spectrum clearly shows that formic acid disappears after a period of a few months. In order to get some information on the stability criterions of the intermolecular hydrogen bonded complex, semiempirical AM1 calculations have been investigated. The comparison of the calculated heats of complexation (deltacH) for chelates involving the cis- and trans-conformers of formic acid suggests that the reaction of hydrogen bonding complexation with the cis-rotamer is surely favoured.
- Vrielynck,Wallet,Merlin
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p. 2439 - 2450
(2007/10/03)
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- Synthesis and microbiological activity of some N-(o-hydroxyphenyl)benzamides and phenylacetamides as the possible metabolites of antimicrobial active benzoxazoles: Part II
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The synthesis of some N-(o-hydroxyphenyl)benzamides and benzacetamides (2a-2p) in order to determine their in vitro antimicrobial activity against two Gram-positive bacteria, three Gram-negative bacteria and the fungus Candida albicans is described. The new compounds were compared with several control drugs. The derivative 2g, 4-amino-N-(o-hydroxyphenyl)benzamide, was found active at an MIC value of 25 μg/ml against the Gram-negative microorganism Klebsiella pneumoniae. Most of the compounds exhibited antibacterial activity at an MIC value of 25 μg/ml against Pseudomonas aureginosa. For the antifungal activity against C. albicans, compounds 2e, 2h and 2m were found more active than the other derivatives (MIC 12.5 μg/ml). The antimicrobial activity of some of these benzamide and phenylacetamide derivatives (2a, 2b, 2f, 2g, 2h and 2k), possible metabolites of benzoxazoles, was also compared with that of the cyclic analogues 3-8. Compound 2f possesses two dilutions better antifungal activity than its cyclic analogue the benzoxazole derivative 5 against C. albicans, while having one dilution better antibacterial activity against Streptococcus faecalis and K. pneumoniae. (C) 2000 Elsevier Science S.A.
- Sener, Esin Aki,Bingoel, Kamuran K.,Oeren, Ilkay,Arpaci, Oezlem Temiz,Yalcin, Ismail,Altanlar, Nurten
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p. 469 - 476
(2007/10/03)
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- Synthesis and preliminary pharmacological investigation of N-lupinyl-2-methoxybenzamides
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A set of eleven N-lupinyl-2-methoxybenzamides, variously substituted on the benzene ring, together with two related compounds, were prepared and subjected to a large pharmacological screening, though not all compounds were tested in each assay. Compounds 1-10 displaced [125I]iodosulpride from D2 receptors only at very high concentration (IC50 > 5μM). At micromolar concentrations, compounds 1, 12, and 13 inhibited the binding of [3H]-pirenzepine and of [3H]-di-o-tolylguanidine respectively on M1 and sigma receptors; in the last case comp. 13 was more active (IC50 = 0.3 μM) than the epimeric 1. Compounds 1-10 at 10-25 mg/kg p.o. protected mice against electroshock induced seizures; l-sulpiride was inactive in this test. Compound 1 exhibited in three tests antiarrhythmic activity superior to that of quinidine and lidocaine. The same antagonized, in vitro, guinea pig ileum contractile response induced by several agents, and enhanced the intestinal transit rate in mice (charcoal bolus test). The last activity (shown in lower degree also by comp. 5) could be related to agonism with 5HT4 receptors, as could be expected for orthopramides with conformationally restricted side chains. This possibility is presently under investigation.
- Iusco,Boido,Sparatore
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p. 159 - 174
(2007/10/03)
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- Synthesis, gastrointestinal prokinetic activity and structure-activity relationships of novel N-[[2-(dialkylamino)ethoxy]benzyl]benzamide derivatives
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Novel N-[[2-(dialkylamino)ethoxy]benzyl]benzamide derivatives (II-1-51), derived from the structural modification of metoclopramide (1), were synthesized and examined for their pharmacological activities. Among them, N-[4-[2-(dimethylamino)ethoxy]benzyl]-3,4-dimethoxybenzamide (II-34) which exhibited well balanced gastrointestinal prokinetic and antiemetic activities was selected as a new type of gastrointestinal prokinetic agent.
- Sakaguchi,Nishino,Ogawa,Iwanaga,Yasuda,Kato,Ito
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p. 202 - 211
(2007/10/02)
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- Potential antipsychotic agents. 6. Synthesis and antidopaminergic properties of substituted N-(1-benzyl-4-piperidinyl)salicylamides and related compounds. QSAR based design of more active members
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A number of substituted 2-methoxybenzamides, with and without 6-hydroxy groups, with 4-piperidinyl side-chains have been synthesized and evaluated for their antidopaminergic properties. The salicylamides were found to require a lipophilic N-substituent, like a benzyl group, for high affinity for the dopamine D-2 binding site in contrast to salicylamides with 2-pyrrolodinylmethyl side-chains. Furthermore, the influence of the aromatic substituents on the activity in the 2 series, ie 4-piperidinyl and 2-pyrrolidinylmethyl side-chains, was different. This was supported by a Hansch analysis, which could accomodate both phenolic and non-phenolic benzamides with 1-benzyl-4-piperidinyl side-chains. The activity is primarily dictated by electronic features rather than by steric and lipophilic properties. The QSAR equations were validated by the design and synthesis of a new 10-fold more active derivative. The 2 classes of benzamides with different side-chains are suggested to act on different binding sites or on different subtypes of the dopamine D-2 receptor.
- De Paulis,Hall,Kumar,Ramsby,Ogren,Hogberg
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p. 507 - 517
(2007/10/02)
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- A Complex Induced Proximity Effect in the Anionic Fries Rearrangement of o-Iodophenyl Benzoates: Synthesis of Dihydro-O-methylsterigmatocystin and Other Xanthones
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The success of an anionic Fries rearrangement, used to synthesise dihydro-O-methylsterigmatocystin and other xanthones, is dependent on the presence of a remote methoxyl substituent.
- Horne, Stephen,Rodrigo, Russell
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p. 4520 - 4522
(2007/10/02)
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- Dopamine D-2 receptor imaging radiopharmaceuticals: Synthesis, radiolabeling, and in vitro binding of (R)-(+)- and (S)-(-)-3-iodo-2-hydroxy-6 methoxy-N-[(1-ethyl-2-pyrrolidinyl)methyl]benzamide
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In developing central nervous system (CNS) dopamine D-2 receptor imaging agents, enantiomers, R-(+) and S-(-) isomers, of 3-[125I]iodo-2-hydroxy-6-methoxy-N-[(1-ethyl-2-pyrrolidinyl)methyl]d benzamide, [125I]IBZM, were synthesized, and their in vitro binding characteristics were evaluated in rat striatum tissue preparation. The (S)-(-)-[125I]IBZM showed high specific dopamine D-2 receptor binding (K(d) = 0.43 nM, B(max) = 0.48 pmol/mg of protein). Competition data of various ligands for IBZM binding displayed the following rank order of potency: spiperone > (S)-(-)-IBZM > (+)-butaclamol >> (R)-(+)-IBZM > (S)-(-)-BZM > dopamine > ketanserin > SCH23390 >> propranolol. The results indicate that [125I]IBZM binds specifically to the dopamine D-2 receptor with stereospecificity. The [123I][IBZM is potentially useful as an imaging agent for the investigation of dopamine D-2 receptors in humans.
- Kung,Kasliwal,Pan,Kung,Mach,Guo
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p. 1039 - 1043
(2007/10/02)
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- THE INVENTION OF RADICAL REACTIONS. PART XVI. RADICAL DECARBOXYLATIVE BROMINATION AND IODINATION OF AROMATIC ACIDS
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Thiohydroxamic esters of aromatic carboxylic acids undergo clean decarboxylative bromination or iodination on treatment with bromotrichloromethane, iodoform or diiodomethane in the presence of a radical initiator.
- Barton, Derek H.R.,Lacher, Brigitte,Zard, Samir Z.
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p. 4321 - 4328
(2007/10/02)
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- Potential neuroleptic agents. 3. Chemistry and antidopaminergic properties of substituted 6-methoxysalicylamides
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A series of substituted 6-methoxysalicylamides were synthesized from their corresponding 2,6-dimethoxybenzamides by demethylation of one methoxy group with boron tribromide. Substituted 6-methoxysalicylamides having a lipophilic aromatic substituent in the 3-position para with respect to the methoxy group, e.g. a bromo or an iodo atom or an ethyl or a propyl group, and having an (S)-N-(1-alkyl-2-pyrrolidinyl)methyl moiety as the side chain were found to be potent blockers of [3H]spiperone binding in vitro and potent inhibitors of the apomorphine syndrome in the rat. Similar to remoxipride but in contrast to haloperidol, some of the substituted salicylamides show a 10-20 fold separation between the dose that inhibits hyperactivity and that which inhibits stereotypy. It was concluded that, besides the requirement of a lipophilic substitutent in the position para to the methoxy group for antidopamine activity in vivo, the formation of a coplanar six-membered pseudoring involving the amide moiety and the methoxy group is a structural requirement for activity in vitro.
- de Paulis,Kumar,Johansson,Raemsby,Florvall,Hall,Angeby-Moeller,Ogren
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p. 1263 - 1269
(2007/10/02)
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- Benzamides, compositions and agricultural method
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N-Aryl benzamides wherein the aryl group is a nitrogen containing heterocycle are useful as selective herbicidal agents. Compositions containing the novel benzamides and a herbicidal method of selective weed control are disclosed.
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- Potential Neuroleptic Agents. 2,6-Dialkoxybenzamide Derivatives with Potent Dopamine Receptor Blocking Activities
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A series of some novel N-(1-ethyl-2-pyrrolidinylmethyl)benzamides was synthesized and tested for dopamine receptor blockade in vivo by the ability to block the apomorphine syndrome in the rat.Several compounds were considerably more potent than sulpiride as dopamine receptor blockers and displayed low liability to induce extrapyramidal side effects (catalepsy) in the rat.The blockade of dopamine receptor activity in vivo was mainly confined to the levorotatory isomers having the S absolute configuration.The structure-activity relationships are discussed.
- Florvall, Lennart,Oegren, Sven-Ove
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p. 1280 - 1286
(2007/10/02)
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- REAGENTS AND SYNTHETIC METHODS 21. THIONYL CHLORIDE/4-(N,N-DIMETHYLAMINO)PYRIDINE COMPLEX. A SIMPLE ONE-POT METHOD FOR ESTERIFICATION OF CARBOXYLIC ACIDS.
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Esters are obtained by a one-pot method, in which the carboxylic acid is first converted into its acyl chloride by means of thionyl chloride/4-(N,N-dimethylamino)pyridine complex as a new activating reagents.
- Arrieta, A.,Garcia, T.,Palomo, C.
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p. 1139 - 1146
(2007/10/02)
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