- Synthesis of N-trifluoromethyl amides from carboxylic acids
-
Found in biomolecules, pharmaceuticals, and agrochemicals, amide-containing molecules are ubiquitous in nature, and their derivatization represents a significant methodological goal in fluorine chemistry. Trifluoromethyl amides have emerged as important functional groups frequently found in pharmaceutical compounds. To date, there is no strategy for synthesizing N-trifluoromethyl amides from abundant organic carboxylic acid derivatives, which are ideal starting materials in amide synthesis. Here, we report the synthesis of N-trifluoromethyl amides from carboxylic acid halides and esters under mild conditions via isothiocyanates in the presence of silver fluoride at room temperature. Through this strategy, isothiocyanates are desulfurized with AgF, and then the formed derivative is acylated to afford N-trifluoromethyl amides, including previously inaccessible structures. This method shows broad scope, provides a platform for rapidly generating N-trifluoromethyl amides by virtue of the diversity and availability of both reaction partners, and should find application in the modification of advanced intermediates.
- Flavell, Robert R.,Liu, Jianbo,Parker, Matthew F. L.,Toste, F. Dean,Wang, Sinan,Wilson, David M.
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supporting information
p. 2245 - 2255
(2021/08/12)
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- Palladium-Catalyzed Migratory Insertion of Carbenes and C-C Cleavage of Cycloalkanecarboxamides
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A palladium catalyzed reaction of cycloalkanecarboxamides and diazomalonates or bis(phenylsulfonyl)diazomethane has been developed. The reaction proceeds via carbene migratory insertion and cascade C-C cleavage pathways. Cycloalkanecarboxamides with four to seven membered rings are applicable in the transformation. A series of ring opening products were prepared with moderate yields. The finding provides valuable clues for the development of new reactions involving carbene migratory insertion and the cleavage of unstrained C(sp3)-C(sp3) bonds.
- Pan, Ping,Yan, Ming,Zeng, Jia,Zhang, Peng,Zhang, Xue-Jing
-
supporting information
(2022/01/20)
-
- Isoalantolactone derivative, pharmaceutical composition and application thereof
-
The invention relates to an isoalantolactone derivative, a pharmaceutical composition and application thereof, especially use of the isoalantolactone derivative shown as formula (I) or a salt pharmaceutical compound thereof in preparation of adjuvant drugs treating cancer, a pharmaceutical composition containing a therapeutically effective amount of isoalantolactone derivative (I) or its salt anda pharmaceutically acceptable carrier or a composition with other anticancer drugs.
- -
-
Paragraph 0014
(2019/02/02)
-
- Electrochemical [4+2] Annulation-Rearrangement-Aromatization of Styrenes: Synthesis of Naphthalene Derivatives
-
We report the first electrochemical strategy to synthesize functionalized naphthalene derivatives through [4+2] annulation—rearrangement–aromatization from styrenes under mild conditions. The electrolysis does not require metals, oxidants and high valence substrates, indicating the atom and step-economy ideals. The dehydrodimer produced through [4+2] cycloaddition of 4-methoxy α-methyl styrene is isolated and proved to be the key intermediate for the following oxydehydrogenation to form carbon cation, which undergoes rearrangement–aromatization to afford the final products. This reaction represents a powerful access to construct multi-substituted naphthalene blocks in a single step.
- Ma, Yueyue,Lv, Jufeng,Liu, Chengyu,Yao, Xiantong,Yan, Guoming,Yu, Wei,Ye, Jinxing
-
supporting information
p. 6756 - 6760
(2019/04/17)
-
- CHROMENOPYRIDINE DERIVATIVES AS PHOSPHATIDYLINOSITOL PHOSPHATE KINASE INHIBITORS
-
The invention relates to inhibitors of PI5P4K inhibitors useful in the treatment of cancers, neurodegenerative diseases, inflammatory disorders, and metabolic diseases, having the Formula (I); where A1, A2, G, R1, R2, R3, R4, and W are described herein.
- -
-
Paragraph 0432
(2019/07/13)
-
- AMINOPYRIDINE DERIVATIVES AS PHOSPHATIDYLINOSITOL PHOSPHATE KINASE INHIBITORS
-
The invention relates to inhibitors of PI5P4K inhibitors useful in the treatment of cancers, neurodegenerative diseases, inflammatory disorders, and metabolic diseases, having the Formula: (I) where A, B, R1, X1, X2, and W are described herein.
- -
-
Paragraph 0614
(2019/07/13)
-
- THIOPHENE DERIVATIVES FOR THE TREATMENT OF DISORDERS CAUSED BY IGE
-
Thiophene derivatives of formula (I) and a pharmaceutically acceptable salt thereof are provided. These compounds have utility for the treatment or prevention of disorders caused by IgE, such as allergy, type 1 hypersensitivity or familiar sinus inflammation.
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Page/Page column 161; 162
(2020/01/11)
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- Visible Light-Mediated Decarboxylative Alkylation of Pharmaceutically Relevant Heterocycles
-
A net redox-neutral method for the decarboxylative alkylation of heteroarenes using photoredox catalysis is reported. Additionally, this method features the use of simple, commercially available carboxylic acid derivatives as alkylating agents, enabling the facile alkylation of a variety of biologically relevant heterocyclic scaffolds under mild conditions.
- Sun, Alexandra C.,McClain, Edward J.,Beatty, Joel W.,Stephenson, Corey R. J.
-
supporting information
p. 3487 - 3490
(2018/06/26)
-
- BICYLIC COMPOUNDS AND METHODS OF USE
-
The present invention provides compounds that modulate protein function, specifically phosphodiesterase 4 (PDE4). The invention provides methods of treating, ameliorating, and/or preventing diseases, disorders, and conditions associated with PDE4. Compositions, including in combination with other inflammatory mediators, are also provided.
- -
-
Paragraph 0226; 0230
(2019/01/04)
-
- Pd(II)-Catalyzed Enantioselective C(sp3)-H Borylation
-
Pd(II)-catalyzed enantioselective borylation of C(sp3)-H bonds has been realized for the first time using chiral acetyl-protected aminomethyl oxazoline ligands. This reaction is compatible with carbocyclic amides containing α-tertiary as well as α-quaternary carbon centers. The chiral β-borylated amides are useful synthons for the synthesis of chiral β-hydroxylated, β-fluorinated, and β-arylated carboxylic acids.
- He, Jian,Shao, Qian,Wu, Qingfeng,Yu, Jin-Quan
-
supporting information
p. 3344 - 3347
(2017/03/15)
-
- Total Synthesis of Cardiolipins Containing Chiral Cyclopropane Fatty Acids
-
Cardiolipin (CL) is a phospholipid located in both the eukaryotic mitochondrial inner membrane and the bacterial cell membrane. Some bacterial CLs are known to contain cyclopropane moieties in their acyl chains. Although the CLs are thought to be involved in the innate immune response, there have been few attempts at chemical synthesis of the CLs, and detailed studies of their biological activities are scarce. Thus, we have developed a synthetic route to CLs containing chiral cyclopropane moieties.
- Inuki, Shinsuke,Ohta, Ippei,Ishibashi, Shunichi,Takamatsu, Masayuki,Fukase, Koichi,Fujimoto, Yukari
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p. 7832 - 7838
(2017/08/14)
-
- Ni-Al Bimetallic Catalyzed Enantioselective Cycloaddition of Cyclopropyl Carboxamide with Alkyne
-
A Ni-Al bimetallic catalyzed enantioselective cycloaddition reaction of cyclopropyl carboxamides with alkynes has been developed. A series of cyclopentenyl carboxamides were obtained in up to 99% yield and 94% ee. The bifunctional-ligand-enabled bimetallic catalysis proved to be an efficient strategy for the C-C bond cleavage of unreactive cyclopropanes.
- Liu, Qi-Sheng,Wang, De-Yin,Yang, Zhi-Jun,Luan, Yu-Xin,Yang, Jin-Fei,Li, Jiang-Fei,Pu, You-Ge,Ye, Mengchun
-
supporting information
p. 18150 - 18153
(2017/12/27)
-
- Constrained bithiazoles: Small molecule correctors of defective δf508-CFTR protein trafficking
-
Conformationally constrained bithiazoles were previously found to have improved efficacy over nonconstrained bithiazoles for correction of defective cellular processing of the δF508 mutant cystic fibrosis transmembrane conductance regulator (CFTR) protein. In this study, two sets of constrained bithiazoles were designed, synthesized, and tested in vitro using δF508-CFTR expressing epithelial cells. The SAR data demonstrated that modulating the constraining ring size between 7-versus 8-membered in these constrained bithiazole correctors did not significantly enhance their potency (IC50), but strongly affected maximum efficacy (Vmax), with constrained bithiazoles 9e and 10c increasing Vmax by 1.5-fold compared to benchmark bithiazole corr4a. The data suggest that the 7-and 8-membered constrained ring bithiazoles are similar in their ability to accommodate the requisite geometric constraints during protein binding.
- Coffman, Keith C.,Nguyen, Huy H.,Phuan, Puay-Wah,Hudson, Brandi M.,Yu, Gui J.,Bagdasarian, Alex L.,Montgomery, Deanna,Lodewyk, Michael W.,Yang, Baoxue,Yoo, Choong L.,Verkman,Tantillo, Dean J.,Kurth, Mark J.
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p. 6729 - 6738
(2014/10/15)
-
- Synthesis of functionalized spiroindolines via palladium-catalyzed methine C-H arylation
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The synthesis of cyclopropyl spiroindolines is described using an intramolecular palladium(0)-catalyzed C-H functionalization of a methine C(sp3)-H bond. This transformation can be coupled with intermolecular Suzuki couplings or direct arylations of heteroaromatics to access functionalized indoline scaffolds in a single step.
- Saget, Tanguy,Perez, David,Cramer, Nicolai
-
supporting information
p. 1354 - 1357
(2013/05/09)
-
- Bromination of enamines from tertiary amides using the petasis reagent: A convenient one-pot regioselective route to bromomethyl ketones
-
An original one-pot synthesis of bromomethyl ketones is achived using the Petasis reagent (dimethyltitanocene) as a key for enamine generation. Several amides were used to test the limits of the procedure by changing either the alkyl chain R or the amino portion of the starting materials. The enamines generated in situ were allowed to react with bromine at low temperature followed by hydrolysis to yield bromomethyl ketones in excellent yields (85 to 95%). Mechanistic details and optimum conditions for the reaction are briefly discussed. The present approach offers several advantages such as regioselectivity in enamine formation, good yields, mild reaction conditions, and ease of experimentation.
- Kobeissi, Marwan,Cherry, Khalil,Jomaa, Wissam
-
supporting information
p. 2955 - 2965
(2013/09/02)
-
- Synthesis, crystal structure and bioactivity of N-(5-propyl-1,3,4- thiadiazol-2-yl)cyclopropanecarboxamide
-
A new 1,3,4-thiadiazole compound with m.f. C9H 13N3OS, has been synthesized and confirmed by 1H NMR and HRMS. The single crystal structure of the 1,3,4-thiadiazole compound was determined by a single crystal X-ray diffraction study. The crystal belongs to the triclinic system, space group P-1 with a = 10.238(2), b = 10.325(2), c = 10.560(2) ?, α = 104.09(3), β = 109.50(3), γ = 93.40(3)°, Z = 4, V = 1008.4(3)?3, Mr = 211.28, Dc = 1.392 g/cm3, S = 0.98, μ = 0.29 mm-1, F(000) = 448, the final R1 = 0.0970 and wR2 = 0.2147 for 1776 were observed with I > 2Σ(I). X-ray indicated that two intermolecular hydrogen bonds N1-H1···N5, N4-H4···N2 were observed. The preliminary biological test shown that the synthesized compound has moderate herbicidal activity against Brassica campestris.
- Sun, Na-Bo,Jin, Jian-Zhong,Lei, Chao,He, Fang-Yue
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p. 7820 - 7822
(2013/09/23)
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- Synthesis, crystal structure and biological activity of N-(5-(o-tolyl)-1,3,4-thiadiazol-2-yl)cyclopropanecarboxamide
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A new 1, 3, 4-thiadiazole compound, N-(5-(o-tolyl)-1,3,4-thiadiazol-2-yl) cyclopropanecarboxamide, was synthesized and its structure was confirmed by 1H NMR, MS and HRMS. The single crystal structure of the title compound was determined by X-ray diffraction. The preliminary biological test showed that the synthesized compound has moderate herbicidal activity against Brassica campestris and fungicidal activities against Sclerotinia sclerotiorum(Lib.) de Bary, Rhizoctonia solanii, Fusarium oxysporum, Corynespora cassiicola, and Botrytis cinerea.
- Tong, Jian-Ying,Sun, Na-Bo,Wu, Hong-Ke,Liu, Xing-Hai
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p. 1349 - 1353
(2014/01/06)
-
- Synthesis and evaluation of novel monosubstituted sulfonylurea derivatives as antituberculosis agents
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A series of novel monosubstituted sulfonylurea derivatives 10a-y were synthesized and characterized by 1H NMR, 13C NMR and HRMS. These compounds were evaluated against Mycobacterium tuberculosis H37Rv in vitro. The results showed compounds 10f, 10k and 10s exhibited moderate antituberculosis activities with MIC values in the range of 20-100 mg/L. Compounds 10b and 10o displayed good antituberculosis activities (MIC 10 mg/L), which were comparable with that of the sulfometuron methyl. Both of the two compounds showed little cytotoxicities, with an IC50 against THP-1 cells greater than 100 mg/L.
- Pan, Li,Jiang, Ying,Liu, Zhen,Liu, Xing-Hai,Liu, Zhuo,Wang, Gang,Li, Zheng-Ming,Wang, Di
-
scheme or table
p. 18 - 26
(2012/07/01)
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- Design and synthesis of novel DFG-out RAF/vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors: 3. Evaluation of 5-amino-linked thiazolo[5,4-d]pyrimidine and thiazolo[5,4-b]pyridine derivatives
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Our aim was to discover RAF/vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors that possess strong activity and sufficient oral absorption, and thus, we selected a 5-amino-linked thiazolo[5,4-d]pyrimidine derivative as the lead compound because of its potential kinase inhibitory activities and its desired solubility. The novel tertiary 1-cyano-1-methylethoxy substituent was designed to occupy the hydrophobic region of 'back pocket' of BRAF on the basis of the X-ray co-crystal structure data of BRAF. In addition, we found that N-methylation of the amine linker could control the twisted molecular conformation leading to improved solubility. These approaches produced N-methyl thiazolo[5,4-b]pyridine-5-amine derivative 5. To maximize the in vivo efficacy, we attempted salt formation of 5. Our result indicated that the besylate monohydrate salt form (5c) showed significant improvement of both solubility and oral absorption. Owing to the improved physicochemical properties, compound 5c demonstrated regressive antitumor efficacy in a HT-29 xenograft model.
- Hirose, Masaaki,Okaniwa, Masanori,Miyazaki, Tohru,Imada, Takashi,Ohashi, Tomohiro,Tanaka, Yuta,Arita, Takeo,Yabuki, Masato,Kawamoto, Tomohiro,Tsutsumi, Shunichirou,Sumita, Akihiko,Takagi, Terufumi,Sang, Bi-Ching,Yano, Jason,Aertgeerts, Kathleen,Yoshida, Sei,Ishikawa, Tomoyasu
-
p. 5600 - 5615
(2012/10/29)
-
- Ligand-enabled methylene C(sp3)-H bond activation with a Pd(II) catalyst
-
Pd(II) insertion into β-methylene C(sp3)-H bonds was enabled by a mutually repulsive and electron-rich quinoline ligand. Ligand tuning led to the development of a method that allows for installation of an aryl group on a range of acyclic and cyclic amides containing β-methylene C(sp3)-H bonds.
- Wasa, Masayuki,Chan, Kelvin S. L.,Zhang, Xing-Guo,He, Jian,Miura, Masanori,Yu, Jin-Quan
-
supporting information
p. 18570 - 18572
(2013/01/15)
-
- Palladium(0)-catalyzed enantioselective C-H arylation of cyclopropanes: Efficient access to functionalized tetrahydroquinolines
-
Activated: The title reaction proceeds efficiently with 1 mol % of palladium and gives tetrahydroquinolines in excellent enantioselectivities (see scheme). The enantiodiscriminating concerted metalation-deprotonation step occurs via a rare seven-membered palladacycle. The cyclopropyl-substituted tetrahydroquinolines can be regioselectively and enantiospecifically reduced to chiral tetrahydrobenzoazepines. Copyright
- Saget, Tanguy,Cramer, Nicolai
-
supporting information
p. 12842 - 12845
(2013/02/22)
-
- HETEROCYCLIC COMPOUND AND USE THEREOF
-
A compound represented by formula (I) or a salt thereof, which has a potent Raf inhibitory activity. In formula (I), R1 represents an optionally substituted C1-6 alkyl, etc.; X represents —O— or —NR2— (wherein R2 represents a hydrogen atom or a C1-6 alkyl); Y represents a group represented by formula 2 (2ii or 2ii) (wherein ring A represents an optionally substituted benzene ring; Z represents a group represented by (1) —NR3CO—W1—, (2) —NR3CO—W1—O—, (3) —NR3CO—W1—O—W2—, (4) —NR3CO—W1—S—, (5) —NR3CO—W1—NR4—, (6) —NR3COO—, (7) —NR3COO—W1—, (8) —NR3CO—CO—, or (9) —NR3CONR4— (wherein R3 and R4 each represents a hydrogen atom, etc., and W1 and W2 each represents an optionally substituted C1-6 alkylene, etc.); and R5 represents an optionally substituted five- or six-membered ring group.
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Page/Page column 37-38
(2011/10/12)
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- PROCESS FOR PREPARATION OF NITROPYRIDINE DERIVATIVES
-
Disclosed here is a process for the preparation of nitropyridine derivatives of Formula (I) and its salt and precursors such as halogenated amino pyridines; Wherein; R1 is selected from amino group, hydroxyl group, acyl group, alkyl amino group, halogen atom, -NH - C (O) - R3; Where R3 is branched or linear alkyl group having 1 - 6 carbon atoms, or cycloalkyl group having 3 - 6 carbon atoms; R2 is selected from hydroxyl group, halogen atom, alkoxy group,
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-
Page/Page column 17
(2010/08/18)
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- Pd(II)-catalyzed carbonylation of C(sp3)-H bonds: A new entry to 1,4-dicarbonyl compounds
-
Pd(II)-catalyzed β-C(sp3)-H carbonylation of N-arylamides under CO (1 atm) has been achieved. Following amide-directed C(sp3)-H cleavage and insertion of CO into the resulting [Pd(II)-C(sp3)] bond, intramolecular C-N reductive elimination gave the corresponding succinimides, which could be readily converted to 1,4-dicarbonyl compounds. This method was found to be effective with substrates containing α-hydrogen atoms and could be applied to effect methylene C(sp3)-H carbonylation of cyclopropanes.
- Yoo, Eun Jeong,Wasa, Masayuki,Yu, Jin-Quan
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supporting information; experimental part
p. 17378 - 17380
(2011/02/24)
-
- Synthesis, antifungal activities and 3D-QSAR study of N-(5-substituted-1,3,4-thiadiazol-2-yl)cyclopropanecarboxamides
-
A series of cyclopropanecarboxamide were prepared and tested for antifungal activity in vivo. The preliminary bioassays indicated that some compounds are comparable to the commercial fungicides. To further explore the comprehensive structure-activity relationship on the basis of fungicidal activity data, comparative molecular field analysis (CoMFA) was performed, and a statistically reliable model with good predictive power (r2 = 0.8, q2 = 0.516) was achieved. Based on the CoMFA, compound 7p was designed and synthesized, which was found to display a good antifungal activity (79.38%) as 7g and 7h.
- Liu, Xing-Hai,Shi, Yan-Xia,Ma, Yi,Zhang, Chuan-Yu,Dong, Wei-Li,Pan, Li,Wang, Bao-Lei,Li, Bao-Ju,Li, Zheng-Ming
-
scheme or table
p. 2782 - 2786
(2009/10/19)
-
- 2,4-Diaminopyridine δ-opioid receptor agonists and their associated hERG pharmacology
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A number of libraries were produced to explore the potential of 2,4-diaminopyridine lead 1. The resulting diaminopyridines proved to be potent and selective δ-opioid receptor agonists. Several rounds of lead optimisation using library chemistry identified compound 17 which went on to show efficacy in an electromyography model of neuropathic pain. The structure-activity relationship of the series against the hERG ion channel proved to be a key selectivity hurdle for the series.
- Owen, Dafydd R.,Rodriguez-Lens, Margarita,Corless, Martin D.,Gaulier, Steven M.,Horne, Valerie A.,Kinloch, Ross A.,Maw, Graham N.,Pearce, David W.,Rees, Huw,Ringer, Tracy J.,Ryckmans, Thomas,Stammen, Blanda L.C.
-
scheme or table
p. 1702 - 1706
(2009/12/03)
-
- ANTIOXIDANT INFLAMMATION MODULATORS: OLEANOLIC ACID DERIVATIVES WITH AMINO AND OTHER MODIFICATIONS AT C-17
-
This invention provides, but is not limited to, novel oleanolic acid derivatives having the formula: wherein the variables are defined herein. Also provided are pharmaceutical compositions, kits and articles of manufacture comprising such compounds, methods and intermediates useful for making the compounds, and methods of using the compounds and compositions.
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-
Page/Page column 114-115; 126
(2009/12/02)
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- NOVEL BENZOFURAN DERIVATIVE, MEDICINAL COMPOSITION CONTAINING THE SAME, AND USES OF THESE
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[From equivalent EP1710233A1] The present invention provides compounds represented by general formula (I): or pharmaceutical acceptable salts thereof, wherein R1 is hydrogen or lower alkyl; R2 is lower alkyl, halo-lower alkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, arylalkenyl, aryloxy-lower alkyl, heteroaryl, heteroaryl-lower alkyl, etc; R3, R4, R5 and R6 are each hydrogen, halogen, cyano, lower alkyl, halo-lower alkyl, lower alkoxy, hydroxy, aryl, etc; provided that at least one of R3, R4, R5 and R6 is other than hydrogen. Compound (I) of the present invention shows a potent adenosine A2A receptor antagonistic activity, and are useful for treating or preventing a disease mediated by adenosine A2A receptors such as motor function disorders, depression, anxiety disorders, cognitive function disorders, cerebral ischemia disorders, restless legs syndrome and the like.
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Page/Page column 39
(2008/06/13)
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- α-Aminoalkylphosphonates as a tool in experimental optimisation of P1 side chain shape of potential inhibitors in S1 pocket of leucine- and neutral aminopeptidases
-
The synthesis and biological activity studies of the series of structurally different α-aminoalkylphosphonates were performed in order to optimise the shape of the side chain of the potential inhibitors in S1 pocket of leucine aminopeptidase [E.C.3.4.11.1]. Analysis of a series of compounds with aromatic, aliphatic and alicyclic P1 side chains enabled to find out the structural features, optimal for that fragment of inhibitors of LAP. The most active among all investigated compounds were the phosphonic analogues of homo-tyrosine (Ki = 120:nM) and homo-phenylalanine (Ki = 140:nM), which even as racemic mixtures were better inhibitors in comparison with the best till now-phosphonic analogue of l-leucine (230 nM). Additional comparison of the inhibitory activity obtained for aminopeptidase N (APN, E.C.3.4.11.2) give insight into structural preferences of both enzymes.
- Drag, Marcin,Grembecka, Jolanta,Pawelczak, Malgorzata,Kafarski, Pawel
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p. 764 - 771
(2007/10/03)
-
- IMIDAZO(1,2-a)PYRIDINE DERIVATIVE
-
A compound reprsented by the following formula (I), its salts or nsolvates thereof capable of specifically or selectively expressig an antifungal activity in a broad spectrum based on the novel mechanism thereof of 1,6-β-glucan synthesis inhibition, and an antifungal agent containing any of them.
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-
-
- Pyran-2-ones and 5,6-dihydropyran-2-ones useful for treating hyperplasia and other diseases
-
Certain 2H-pyran-2-ones are useful for treating benign prostatic hypertrophy or hyperplasia, prostatic cancer, alopecia, hirsutism, acne vulgaris and seborrhea.
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-
-
- Synthesis and structure-activity relationships of potential anticonvulsants based on 2-piperidinecarboxylic acid and related pharmacophores
-
Using N-(2,6-dimethyl)phenyl-2-piperidinecarboxamide (1) and N-(α-methylbenzyl)-2-piperidinecarboxamide (2) as structural leads, a variety of analogues were synthesised and evaluated for anticonvulsant activity in the MES test in mice. In the N-benzyl series, introduction of 3-Cl, 4-Cl, 3,4-Cl2, or 3-CF3 groups on the aromatic ring led to an increase in MES activity. Replacement of the α-methyl group by either i-Pr or benzyl groups enhanced MES activity with no increase in neurotoxicity. Substitution on the piperidine ring nitrogen led to a decrease in MES activity and neurotoxicity, while reduction of the amide carbonyl led to a complete loss of activity. Movement of the carboxamide group to either the 3- or 4-positions of the piperidine ring decreased MES activity and neurotoxicity. Incorporation of the piperidine ring into a tetrahydroisoquinoline or diazahydrinone nucleus led to increased neurotoxicity. In the N-(2,6-dimethyl)phenyl series, opening of the piperidine ring between the 1- and 6-positions gave the active norleucine derivative 75 (ED50 = 5.8 mg kg-1, TD50 = 36.4 mg kg-1, PI = 6.3). Replacement of the piperidine ring of 1 by cycloalkane (cyclohexane, cyclopentane, and cyclobutane) resulted in compounds with decreased MES activity and neurotoxicity, whereas replacement of the piperidine ring by a 4-pyridyl group led to a retention of MES activity with a comparable PI. Simplification of the 2-piperidinecarboxamide nucleus of 1 into a glycinecarboxamide nucleus led to about a six-fold decrease in MES activity. The 2,6-dimethylanilides were the most potent compounds in the MES test in each group of compounds evaluated, and compounds 50 and 75 should be useful leads in the development of agents for the treatment of tonic-clonic and partial seizures in man.
- Ho, Bin,Michael Crider,Stables, James P
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p. 265 - 286
(2007/10/03)
-
- Lactam metalloprotease inhibitors
-
The present application describes novel lactams and derivatives thereof of formula I: or pharmaceutically acceptable salt forms thereof, wherein rings ring B is a 4-8 membered cyclic amide containing from 0-3 additional heteroatoms selected from N, O, and S, which are useful as metalloprotease inhibitors.
- -
-
-
- 5-HT1F AGONISTS
-
This invention provides 5-HT 1F agonists of Formula I: STR1 where A--B, X, and R are as defined in the specification. The invention also encompasses pharmaceutical formulations employing compounds of Formula I as well as methods of treating conditions associated with 5-HT. sub.1F activation employing these compounds or compositions. The invention also provides intermediates useful for the preparation of the compounds of Formula I.
- -
-
-
- Imidazopyridines as pharmaceutical agents
-
Described herein are novel imidazopyridine derivatives of the formula I STR1 wherein R is STR2 and R1, R2, R3 and R4 are as defined in Patent Claim 1, and their salts, which exhibit antagonistic properties towards angiotensin II and can be used for the treatment of hypertension, aldosteronism, cardiac insufficiency and increased intraocular pressure, and of disorders of the central nervous system.
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-
- Potent and subtype-selective CCK-B/gastrin receptor antagonists: 2,4-dioxo-1,5-benzodiazepines with a plane of symmetry
-
A series of CCK-B/gastrin receptor antagonists, 2,4-dioxo-1,5-benzodiazepine derivatives with a plane of symmetry, were designed, synthesized, and evaluated for antagonistic activity. Structure-activity relationship studies revealed that carbonylmethyl groups at both N-1 and N-5 positions and hydrophilic groups, such as the carboxyl group on the benzene ring attached to the ureido group at the C-3 position, brought about potent affinity and subtype selectivity for CCK-B/gastrin receptors. Several compounds showed excellent in vivo inhibition of gastric acid secretion induced by pentagastrin in anesthetized rats.
- Hagishita, Sanji,Seno, Kaoru,Kamata, Susumu,Haga, Nobuhiro,Ishihara, Yasunobu,Ishikawa, Michio,Shimamura, Mayumi
-
p. 1433 - 1446
(2007/10/03)
-
- Synthesis of Alkyl and Aryl Cyclopropyl Ketones
-
A series of cyclopropyl ketones are prepared by reactions of organometallic compounds with cyclopropanecarboxylic acid derivatives and also by cyclization of γ-chloro ketones.
- Matveeva,Kvasha,Kurts
-
-
- Biosynthesis of the indolizidine alkaloid cyclizidine: incorporation of singly and doubly labelled precursors
-
Incorporation of CH313C18O2Na and CD3CH213CO2Na into the indolizidine alkaloid cyclizidine 1, produced by Streptomyces species NCIB 11649, shows that the oxygen attached to C-2 is derived intact from acetate and that the cyclopropyl ring is derived from a single intact propionate unit.However, the level and stereochemistry of the incorporation of deuteriated sodium propionate indicates that it undergoes unexpected modification during incorporation into the cyclopropyl ring.
- Leeper, Finian J.,Shaw, Susan E.,Satish, Padma
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p. 131 - 141
(2007/10/02)
-
- Synthesis and spectral properties of cyclopropyl-substituted phosphaalkenes
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Cyclopropanecarboxylic acid chlorides 5a-d react with tris(trimethylsilyl)phosphane 6 in benzene at -2 deg C to form cyclopropylcarbonyl-bis(trimethylsilyl)phosphanes 7.These products undergo silylic rearrangement at 25 deg C to yield phosphoalkenes 8.Compounds 8a,b,d are formed as mixtures of Z- and E-isomers where the latter predominante.In the case of 8c, the Z-isomer is formed exclusively. - Key words: phosphaalkenes, cyclopropyl-substituted, E/Z-isomerism.
- Kostitsyn, A. B.,Ruzek, H.,Heydt, H.,Regitz, M.,Nefedov, O. M.
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p. 635 - 640
(2007/10/02)
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- Selective κ-opioid agonists: Synthesis and structure-activity relationships of piperidines incorporating an oxo-containing acyl group
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This study describes the synthesis and the structure-activity relationships (SARs) of the (S)-(-)-enantiomers of a novel class of 2- (aminomethyl)piperidine derivatives, using κ-opioid binding affinity and antinociceptive potency as the indices of biological activity. Compounds incorporating the 1-tetralon-6-ylacetyl residue (30 and 34-45) demonstrated an in vivo antinociceptive activity greater than predicted on the basis of their κ-binding affinities. In particular, (2S)-2-[(dimethylamino)methyl]- 1-[(5,6,7,8-tetrahydro-5-oxo-2-naphthyl)acetyl]piperidine (34) was found to have a potency similar to spiradoline in animal models of antinociception after subcutaneous administration, with ED50s of 0.47 and 0.73 μmol/kg in the mouse and in the rat abdominal constriction tests, respectively. Further in vivo studies in mice and/or rats revealed that compound 34, compared to other selective κ-agonists, has a reduced propensity to cause a number of κ-related side effects, including locomotor impairment/sedation and diuresis, at antinociceptive doses. For example, it has an ED50 of 26.5 μmol/kg sc in the rat rotarod model, exhibiting a ratio of locomotor impairment/sedation vs analgesia of 36. Possible reasons for this differential activity and its clinical consequence are discussed.
- Giardina,Clarke,Dondio,Petrone,Sbacchi,Vecchietti
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p. 3482 - 3491
(2007/10/02)
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- Pyrrolo [1,2A] thieno [3,2-F] [1,4] diazepines
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The invention relates to pyrrolo [1,2-a] thieno [3,2-f][1,4]diazepine compounds of the formula (I) STR1 in which: R1 is hydrogen; alkyl optionally substituted with alkoxy, hydroxy, cycloalkyl, or phenyl; or alkyl- or arylsulfonyl; R2 is hydrogen, phenyl, or phenylalkyl; alkyl optionally substituted with hydroxyl, alkoxy, oxo, cycloalkyl or phenyl; or optionally substituted amino; R3 represents hydrogen or alkyl, and R4 and R5 independently represent: hydrogen, alkyl optionally substituted with alkoxy, cycloalkyl, or phenyl; or phenyl; their isomers, diastereoisomers and enantiomers as well as their addition salts with pharmaceutically-acceptable acids. The compounds are useful for treating cerebral ischemia, hypertriglyceridemia, hypercholesterolemia, hyperlipidemia, and hyperglycemia and are obtained in a few steps from the corresponding substituted 2-(1-pyrrolyl)thiophenes STR2 Y=--CHO or H; X= CN, CONH2, CH2 NHCOR2, or CH2 NH2.
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- STEREOSPECIFIC NUCLEOPHILIC RING-OPENING OF A DEUTERIATED CYCLOPROPYLCARBINOL
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The cyclopropyl phenyl carbinol (3) was obtained by degradation in the course of biosynthetic studies on the unique cyclopropane alkaloid cyclizidine (1).The stereochemistry of the ring-opening to the homoallylic alcohol (4) was investigated by synthesis of chirally deuteriated (3) followed by 1H n.m.r. spectroscopy of the ring-opened product with a chiral shift reagent.It was found to proceed with inversion of configuration.
- Leeper, Finian J.,Padmanabhan, Padma
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p. 5017 - 5020
(2007/10/02)
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- Amino acid amide derivatives of 2-[3-(aminomethyl)-4H-1,2,4-triazol-4-yl]benzophenones, a novel class of annelated peptidoaminobenzophenones
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A series of the title compounds was prepared via condensation of the 3-(aminomethyl)triazolylbenzophenone with N-protected amino acids, followed by deprotection, amination of the 3-[(chloroacetamido)methyl]triazolylbenzophenone, or reduction of the relevant azide derivative. Some of the title compounds were also derived directly from the quinazolines by acid-induced rearrangement, followed by deprotection. These new amino acid amide derivatives of the triazolylbenzophenones were evaluated for central nervous system (CNS) activity. Members of this class of compounds exhibited a high level of CNS activities. For example, 2',5-dichloro-2-[3-[(glycylamino)methyl]-5-methyl-4H-1,2,4-triazol-4-yl ]benzophenone was as active as triazolam, with an ED50 of 0.58 mg/kg (mice, po), against antifighting activity in the foot shock-induced fighting test. Other triazolylbenzophenone derivatives showed similar pharmacological activities.
- Hirai,Fujishita,Ishiba,Sugimoto,Matsutani,Tsukinoki,Hirose
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p. 1466 - 1473
(2007/10/02)
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- Pyridine esters of cyclopropane-carboxylic acid
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Heterocyclic organic esters and thioesters characterized by the presence of one or two cyclopropane moieties, synthesis thereof, and compositions thereof for the control of mites and ticks.
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- 2-Acyl-3-substituted cyclopentan-1-ones and process for their preparation
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1,3-Dicarbonyl compounds useful as medicines, agricultural chemicals, perfumes, and their intermediates are prepared by reacting a specific α,β-unsaturated carbonyl compound with a specific organic copper lithium compound in the presence of an aprotic inert organic solvent, and then reacting the reaction product with an organic carboxylic acid halide or anhydride. In particular, novel 2-acyl-3-substituted cyclopentan-1-ones and 2-acyl-3-substituted cyclohexan-1-ones having important physiological activities are provided.
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