- Total synthesis of hydroxy-α- and hydroxy-β-sanshool using Suzuki-Miyaura coupling
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Here, we describe the first total synthesis of hydroxyl-α- and hydroxyl-β-sanshool, which involves Suzuki-Miyaura coupling (SMC). Hydroxy-α-sanshool (1) was synthesized by SMC of bromoalkyne 4 with boronate 3 followed by (Z)-selective reduction of the triple bond in the coupling product. Hydroxy-β-sanshool (2) was synthesized by regio- and (E)-selective conversion of 4 to iodoalkene 11 followed by SMC with 3.
- Igarashi, Yasushi,Aoki, Katsuyuki,Nishimura, Hiroaki,Morishita, Isao,Usui, Kimitoshi
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- BICYCLIC PHOSPHANES. PART 2. SPONTANEOUS DIMERIZATION OF A CONSTRAINED BICYCLIC PHOSPHANE. THE CRYSTAL AND MOLECULAR STRUCTURE OF A TRICYCLIC COMPOUND CONTAINING THE DIOXADIAZADIPHOSPHECINE RING
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The dimerization of 3,3,7,7-tetramethyl-2,8-dioxa-5-aza-1-phosphaIIIbicyclooctane (1) leads to octahydro-2,2,6,6,10,10,14,14-octamehylbis-1,2,3-oxazaphospholo-1,6,3,8,2,7-dioxadiazadiphosphecine (2), a tricyclic compound with sixteen atoms around the periphery.The preparation, identification, and the X-ray structure are described.A pathway for the formation of the dimer is suggested by the trans-position of the two phosphorus ione pairs.
- Bonningue, Corine,Houalla, Douraid,Wolf, Robert,Jaud, Joel
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- Synthesis and evaluation of new alkylamides derived from α-hydroxysanshool, the pungent molecule in szechuan pepper
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Szechuan pepper is widely used in Asia as a spice for its pleasant pungent and tingling sensations, produced by natural alkylamides called sanshools. R-Hydroxysanshool, the main alkylamide found in the pericarp of the fruit, stimulates sensory neurons innervating the mouth by targeting two chemosensitive members of the transient receptor potential (TRP) channels, TRPV1 and TRPA1. As it was previously found that configuration of the unsaturations in the R-hydroxysanshool alkyl chain is required for TRPA1 but not TRPV1 selectivity, this study aimed at obtaining more potent and selective TRPA1 agonists using R-hydroxysanshool as a starting material. This paper reports the preparation of new alkylamides derived from sanshool and their efficacy in stimulating TRPA1 and TRPV1 receptors. The data provide knowledge of the main sanshool chemical functionalities required for TRP channel activation, but they also evidence new selective and potent TRPA1 agonists based on α-hydroxysanshool.
- Menozzi, Candice,Riera, Celine E.,Munari, Caroline,Coutre, Johannes Le,Robert, Fabien
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- IMIDAZOQUINOLINE-TYPE COMPOUNDS AND USES THEREOF
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Provided in the present disclosure are imidazoquinoline-type compounds, methods for their preparation, pharmaceutical compositions thereof and their use, wherein the imidazoquinoline-type compounds, upon local administration, form depots inducing cell mediated immune response while mitigating a systemic proinflammatory immune response.
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Paragraph 0010; 0083; 0088
(2021/10/11)
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- LOCALLY ACTING TOLL-LIKE RECEPTOR 7 (TLR7) AND/OR TLR8 AGONIST IMMUNOTHERAPY COMPOUNDS AND THEIR USES
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Provided in the present disclosure are immunotherapy compounds, pharmaceutical compositions thereof and their use, wherein the immunotherapy compounds, upon local administration, form depots inducing cell mediated immune response while mitigating a systemic proinflammatory immune response.
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Paragraph 0029; 00163-00164; 00169
(2020/10/19)
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- Intermediate compound used for synthesizing valnemulin hydrochloride, and preparation method of valnemulin hydrochloride
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The invention discloses an intermediate compound used for synthesizing valnemulin hydrochloride. The chemical structure of the intermediate compound used for synthesizing valnemulin hydrochloride is represented by a formula in the invention. A preparation method of the intermediate compound comprises following steps: beta-hydroxyisovaleric acid is subjected to Curtius rearrangement reaction so as to obtain 2-methyl-2-hydroxy propylamine; 2-methyl-2-hydroxy propylamine and D-valine Dane salt are subjected to mixed anhydride method reaction so as to obtain an amide product; the amide product is subjected to hydroxy activation under alkaline conditions with methylsulfonyl chloride, and then is reacted with potassium thioacetate. The preparation method of valnemulin hydrochloride comprises following steps: pleuromutilin is reacted with paratoluensulfonyl chloride so as to obtain pleuromutilin p-tosylate; pleuromutilin p-tosylate is reacted with the intermediate compound, and hydrochloric acid deprotection is carried out so as to obtain valnemulin hydrochloride. In the preparation method of valnemulin hydrochloride, no dimethyl cysteamine hydrochloride is needed, production conditions are mild, no environment pollution is caused, and the preparation method is suitable for industrialized production.
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Paragraph 0018; 0019; 0023
(2017/08/02)
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- Remote C(sp3)-H Oxygenation of Protonated Aliphatic Amines with Potassium Persulfate
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This letter describes the development of a method for selective remote C(sp3)-H oxygenation of protonated aliphatic amines using aqueous potassium persulfate. Protonation serves to deactivate the proximal C(sp3)-H bonds of the amine substrates and also renders the amines soluble in the aqueous medium. These reactions proceed under relatively mild conditions (within 2 h at 80 °C with amine as limiting reagent) and do not require a transition metal catalyst. This method is applicable to a variety of types of C(sp3)-H bonds, including 3°, 2°, and benzylic C-H sites in primary, secondary, and tertiary amine substrates.
- Lee, Melissa,Sanford, Melanie S.
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supporting information
p. 572 - 575
(2017/02/10)
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- INDANYLOXYPHENYLCYCLOPROPANECARBOXYLIC ACIDS
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A compound of formula I, wherein the groups R1, R2, R3, X, m, and n are defined as in claim 1, which have valuable pharmacological properties, in particular bind to the GPR40 receptor and modulate its activity. The compounds are suitable for treatment and prevention of diseases which can be influenced by this receptor, such as metabolic diseases, in particular diabetes type 2. Furthermore, the invention relates to novel intermediates, useful for the synthesis of compounds of formula I.
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Paragraph 0427-0428
(2015/06/03)
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- NEW INDANYLOXYPHENYLCYCLOPROPANECARBOXYLIC ACIDS
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The present invention relates to compounds of general formula (I), wherein the groups R1, R2, R3, X, m and n are defined as in claim 1, wich have valuable pharmacological properties, in particular bind to the GPR40 receptor and modulate its activity. The compounds are suitable for treatment and prevention of diseases which can be influenced by this receptor, such as metabolic diseases, in particular diabetes type 2. Furthermore, the invention relates to novel intermediates, useful for the synthesis of compounds of formula I.
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Page/Page column 71; 72
(2015/06/11)
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- IMMUNOMODULATORY CONJUGATES
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The present invention provides an immunomodulatory compound comprising a carbohydrate polymer comprising mannose, wherein the carbohydrate polymer is conjugated to at least one immune modulator. The present invention also provides for the use of this compound in immunomodulatory compositions for vaccination and gene therapy methods, together with processes for its preparation.
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Page/Page column 77
(2013/05/23)
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- Synthesis of hydroxy-α-sanshool
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The amide hydroxy-α-sanshool is responsible for the mild numbing sensation experienced when Sichuan (or Szechuan) peppercorns (huajiao) are eaten. It has been synthesized in six steps from simple commercially available starting materials using Wittig reactions as the key transformations for construction of the carbon skeleton. The penultimate synthetic intermediate was 2E,6Z,8E,10E-dodecatetraenoic acid, and its crystalline nature allowed it, and thus hydroxy-α-sanshool, to be purified to a very high level of stereochemical homogeneity.
- Wu, Bo,Li, Kun,Toy, Patrick H.
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p. 2564 - 2566,3
(2012/12/11)
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- Synthesis, structure-activity relationship, and pharmacological studies of novel melanin-concentrating hormone receptor 1 antagonists 3- aminomethylquinolines: Reducing human ether-a-go-go-related gene (hERG) associated liabilities
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Recently, we discovered 3-aminomethylquinoline derivative 1, a selective, highly potent, centrally acting, and orally bioavailable human MCH receptor 1 (hMCHR1) antagonist, that inhibited food intake in F344 rats with diet-induced obesity (DIO). Subsequent investigation of 1 was discontinued because 1 showed potent hERG K+ channel inhibition in a patch-clamp study. To decrease hERG K+ channel inhibition, experiments with ligand-based drug designs based on 1 and a docking study were conducted. Replacement of the terminal p-fluorophenyl group with a cyclopropylmethoxy group, methyl group introduction on the benzylic carbon at the 3-position of the quinoline core, and employment of a [2-(acetylamino)ethyl]amino group as the amine portion eliminated hERG K+ channel inhibitory activity in a patch-clamp study, leading to the discovery of N-{3-[(1R)-1-{[2-(acetylamino)ethyl]amino} ethyl]-8-methylquinolin-7-yl}-4-(cyclopropylmethoxy)benzamide (R)-10h. The compound (R)-10h showed potent inhibitory activity against hMCHR1 and dose-dependently suppressed food intake in a 2-day study on DIO-F344 rats. Furthermore, practical chiral synthesis of (R)-10h was performed to determine the molecule's absolute configuration.
- Kasai, Shizuo,Kamata, Makoto,Masada, Shinichi,Kunitomo, Jun,Kamaura, Masahiro,Okawa, Tomohiro,Takami, Kazuaki,Ogino, Hitomi,Nakano, Yoshihide,Ashina, Shuntarou,Watanabe, Kaoru,Kaisho, Tomoko,Imai, Yumi N.,Ryu, Sunghi,Nakayama, Masaharu,Nagisa, Yasutaka,Takekawa, Shiro,Kato, Koki,Murata, Toshiki,Suzuki, Nobuhiro,Ishihara, Yuji
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supporting information; experimental part
p. 4336 - 4351
(2012/07/01)
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- Substituted Fused Imidazole Derivatives, Pharmaceutical Compositions, and Methods of Use Thereof
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Substituted fused imidazole derivatives, methods of their preparation, pharmaceutical compositions comprising a substituted fused imidazole derivative, and methods of use in treating inflammation are provided. The substituted fused imidazole derivatives may control the activity or the amount or both the activity and the amount of heme-oxygenase.
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Page/Page column 115-116; 123
(2011/09/14)
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- N-SUBSTITUTED SATURATED HETEROCYCLIC SULFONE COMPOUNDS WITH CB2 RECEPTOR AGONISTIC ACTIVITY
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This invention relates to compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein X, R1, R2,R3, R4, R5, R6, R7, k, m, n, p, q, r and s are each as described herein, and compositions containing such compounds, and the use of such compounds in the treatment of a condition mediated by CB2 receptor activity.
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Page/Page column 50-51
(2010/08/08)
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- PYRIDAZINONE DERIVATIVES AND USE THEREOF AS P2X7 RECEPTOR INHIBITORS
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Novel pyridazinone compounds of formula (I), which inhibit the purinergic P2X7 receptor and are useful for prevention, therapy and improvement of inflammatory and immunological diseases.
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Page/Page column 171
(2009/06/27)
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- Regioisomerism-dependent TLR7 agonism and antagonism in an imidazoquinoline
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Chronic immune activation is a hallmark of progressive HIV infection. Recent reports point to the engagement of toll-like receptor 7 (TLR7) and -9 by viral RNA as contributing to the activation of innate immune responses, which drive viral replication leading to immune exhaustion. The only known class of TLR7 antagonists is single-stranded phosphorothioate oligonucleotides, which has been demonstrated to inhibit immune activation in human and Rhesus macaque in vitro models. The availability of a selective and potent small-molecule TLR7 antagonist should allow the evaluation of potential benefits of suppression of TLR7-mediated immune activation in HIV/AIDS. Gardiquimod is a known N1-substituted 1H-imidazoquinoline TLR7 agonist, the synthesis of which has not been published. We show that the 3H regioisomer is completely inactive as a TLR7 agonist and is weakly antagonistic. A des-amino precursor of the 3H regioisomer is more potent as a TLR7 antagonist, with an IC50 value of 7.5 μM. This class of compound may serve as a starting point for the development of small-molecule inhibitors of TLR7.
- Shukla, Nikunj M.,Kimbrell, Matthew R.,Malladi, Subbalakshmi S.,David, Sunil A.
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supporting information; experimental part
p. 2211 - 2214
(2009/12/07)
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- DIPHENYL SUBSTITUTED CYCLOALKANES
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The present invention provides compounds of Formula I which are FLAP inhibitors useful as anti-atherosclerotic, anti-asthmatic, anti-allergic, anti-inflammatory and cytoprotective agents.
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Page/Page column 59-60
(2009/05/28)
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- N-HALOGENATED AMINO ACIDS AND N, N-DIHALOGENATED AMINO ACIDS IN COMBINATION WITH HYPOHALOUS ACIDS
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The present invention relates to active bactericidal, antibacterial, anti-infective, antimicrobial, sporicidal, disinfectant, antifungal and antiviral compounds and compositions and to new uses of these compositions in therapy. This specification also describes methods of use for the new compounds and compositions. The specification further describes methods for preparing these compounds.
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Page/Page column 51
(2008/06/13)
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- Thiazolinone unsubstituted quinolines
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Thiazolinone quinoline derivatives having no substitution on the quinoline ring active as CDK1 inhibitors which are useful as anti-proliferation agents such as for treating solid tumors.
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Page/Page column 21
(2010/02/15)
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- THIENOPYRIMIDINE COMPOUNDS AND USE THEREOF
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The present invention provides a compound represented by the formula: wherein R1 is a C1-4 alkyl; R2 is (1) a 5- to 7-membered nitrogen-containing heterocyclic group which may have a substituent selected from the group consisting of (1') a halogen, (2') a hydroxy group, (3') a C1-4 alkyl and (4') a C1-4 alkoxy, (2) a phenyl which may have a substituent selected from the group consisting of (1') a halogen, (2') a C1-4 alkoxy-C1-4 alkyl, (3') a mono-C1-4 alkyl-carbamoyl-C1-4 alkyl, (4') a C1-4 alkoxy and (5') a mono-C1-4 alkylcarbamoyl-C1-4 alkoxy, or the like; R3 is a C1-4 alkyl; R4 is a C1-4 alkoxy, or the like; n is an integer of 1 to 4; or a salt thereof, as a thienopyrimidine compound having gonadotropin-releasing hormone antagonistic activity.
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Page/Page column 96
(2010/02/14)
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- DERIVATIVES OF [6,7-DIHYDRO-5H-IMIDAZO[1,2-A]IMIDAZOLE-3-SULFONYL]-PYRROLIDINE-2-CARBOXYLIC ACID AMIDE
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Derivatives of 6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-sulfonyl]-pyrrolidine-2-carboxylic acid amide which exhibit good inhibitory effect upon the interaction of CAMs and Leukointegrins and are thus useful in the treatment of inflammatory disease
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(2008/06/13)
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- Synthesis, physicochemical properties, and evaluation of N-substituted- 2-alkyl-3-hydroxy-4(1H)-pyridinones
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The synthesis of a range of 3-hydroxy-4(1H)-pyridinones with potential for the chelation of iron(III) is described. The pK(a) values of respective ligands and the stability constants of their iron(III) complexes are presented. The distribution coefficient values of a range of 48 hydroxypyridinones and their corresponding iron(III) complexes between 1- octanol and MOPS buffer (pH 7.4) are reported. The range of log D(complex) values covers 7 orders of magnitude. The results suggest the existence of a biphasic relationship between the distribution coefficient values of the chelator and the corresponding iron(III) complexes. For ligands with a log D(ligand) = -1, a linear relationship exists with a value of the slope 2.53, whereas with ligands with a log D(ligand) 59Fe]ferritin-loaded rat model. Both systems compare the ability of chelators to remove iron from the liver, the prime target organ in thalassemia. The N-(hydroxyalkyl)-3-hydroxypyridin-4-ones are demonstrated to be orally active under the in vivo conditions adopted. Thus both 1- (hydroxyalkyl)- and 1-(carboxyalkyl)pyridinones are able to remove iron from the liver. Although 1-(carboxyalkyl)hydroxypyridinones are: active, they do not demonstrate any clear advantage over Deferiprone (1,2-dimethyl-3- hydroxypyridin-4-one). Indeed 1-(hydroxyalkyl)hydroxypyridinones which are known to be rapidly converted to 1-(carboxYalkyl)hydroxypyridinones are also marginally superior to Deferiprone. In contrast, 2-ethyl-1-(2'- hydroxyethyl)3-hydroxypyridin-4-one, which is not metabolized to the corresponding (carboxyalkyl)hydroxypyridinone, was found to be superior to Deferiprone and therefore deserves further consideration as an orally active iron chelator with potential for the treatment of iron overload associated with transfusion-dependent thalassemia.
- Rai, Bijaya L.,Dekhordi, Lotfollah S.,Khodr, Hicham,Jin, Yi,Liu, Zudong,Hider, Robert C.
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p. 3347 - 3359
(2007/10/03)
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- New methods for the preparation of 2-amino-2-methylpropanesulfonic acid
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2-Amino-2-methylpropanesulfonic acid 3 was prepared either from 2-N-[(1,1-dimethylethoxy)carbonyl]amino-2-methyl-1-propanol 4 or from 1-N-[(1,1-dimethylethoxy)carbonyl]amino-2-methyl-2-propanol 5 in good overall yields.
- Braghiroli, Daniela,Di Bella, Maria
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p. 7319 - 7322
(2007/10/03)
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- Alkylation of chiral phosphonoglycine equivalents: Asymmetric synthesis of diethyl α-amino-α-alkyl-phosphonates
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A model was developed to rationalize the experimental results of the alkylation of chiral phosphonoglycine equivalents yielding α-amino-α-alkyl-phosphonates. The model studies, carried out using semiempirical calculations, have emphasized the role of the chelating effects in influencing the diastereoselectivity of the alkylation step. Chelation can be optimized by tuning the functionality of the substituent at carbon C-1 of the camphor skeleton. By employing 2d, as suggested by the modelling, a major improvement in the enantiomeric excesses of compounds 5 (R = CH3, C2H5) was obtained.
- Cabella, Giulia,Jommi, Giancarlo,Pagliarin, Roberto,Sello, Guido,Sisti, Massimo
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p. 1817 - 1826
(2007/10/02)
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- 3-Amino or 3-nitro quinoline compounds which are intermediates in preparing 1H-imidazo[4,5-c]quinolines
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A process for the preparation of 1-substituted, 4-substituted-1H-imidazo[4,5-c]quinolines, intermediates in the preparation of such compounds, and processes for the preparation of such intermediates.
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- Chemical compounds
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The invention provides a compound of formula I STR1 where R1 represents hydrogen, lower alkanoyl or aryol, or tri-lower alkyl silyl, or a group R3 --O--CO-- (where R3 represents lower alkyl); R2 represents hydrogen, hydroxyl or fluorine and X represents --S--, --SO--, --SO2 --, --O--or --NR4 -- (where R4 represents hydrogen, lower alkyl or lower alkanoyl); the compounds are useful in the prophylaxis or management of cardiovascular disease through the regulation of serum cholesterol and a particularly useful compound is 23-thia-25-hydroxy-cholesterol.
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- Anodic Oxidation of Amines. VII. Oxidation of β-Alkanolamines in Aqueous Buffer of pH 10
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The anodic oxidation of several different types of β-alkanolamines, R1R2C(OH)CR3R4NR5R6, was studied by cyclic voltammetry and controlled potential electrolysis in an aqueous carbonat buffer of pH 10 at a glassy carbon electrode.Upon oxidation, both the (α)C-(β)C and the C-N bonds are cleaved.Substituents R1-R4 affect the first oxidation potential and product distribution.The relative rates of the bond cleavages were estimated from the oxidation products.It was found that most of the amine cleaves through the (α)C-(β)C bond when at least one of the R groups is phenyl, nearly half cleaves through this bond when R is alkyl, and only about a tenth does so when R1-R4 are all hydrogen.The stability of the transient intermediates at the e-c step of the e-c-e process seems to affect the oxidation potentials and to govern the relative rates of the (α)C-(β)C bond cleavage.A scheme for the reaction processes is proposed.Keywords---β-alkanolamines; anodic oxidation; (α)C-(βC) bond fission; C-N bond fission; carbonate buffer; aldehyde; acetone; glycolaldehyde
- Masui, Masaichiro,Kamada, Yoshiyuki,Sasaki, Etuko,Ozaki, Shigeko
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p. 1234 - 1243
(2007/10/02)
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