- A by 3 - phenyl -1 - methylacetylene preparation quickly disintegrating process method (by machine translation)
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A by 3 - phenyl - 1 - propyne preparation quickly disintegrating process method, which belongs to the technical field of pharmaceutical intermediates. In the preparation quickly disintegrating in the process, intermediate benzyl acrylic acid yield and purity of the most important, this method first using 3 - phenyl - 1 - propyne as the raw material, in the palladium catalyst Pd2 (Dba)3 And the ligand dppp with ethyl carbonate under the catalysis of the reaction to the one-step synthesis of benzyl acrylic acid, its advantage lies in atmospheric pressure to complete the addition reaction, functional group tolerance is good, high efficiency, high purity, the production process is greatly simplified, and to obtain the target product preparation process of yield and purity than the traditional process much higher. The method has the advantages of greatly improve the productivity, reduce the cost, improve the safety, energy saving and the like, in accordance with the green reaction of modern chemical production requirement. (by machine translation)
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- New orally active dual enkephalinase inhibitors (DENKIs) for central and peripheral pain treatment
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Protecting enkephalins, endogenous opioid peptides released in response to nociceptive stimuli, is an innovative approach for acute and neuropathic pain alleviation. This is achieved by inhibition of their enzymatic degradation by two membrane-bound Zn-metallopeptidases, neprilysin (NEP, EC 3.4.24.11) and aminopeptidase N (APN, EC 3.4.11.2). Selective and efficient inhibitors of both enzymes, designated enkephalinases, have been designed that markedly increase extracellular concentrations and half-lives of enkephalins, inducing potent antinociceptive effects. Several chemical families of Dual ENKephalinase Inhibitors (DENKIs) have previously been developed but devoid of oral activity. We report here the design and synthesis of new pro-drugs, derived from co-drugs combining a NEP and an APN inhibitor through a disulfide bond with side chains improving oral bioavailability. Their pharmacological properties were assessed in various animal models of pain targeting central and/or peripheral opioid systems. Considering its efficacy in acute and neuropathic pain, one of these new DENKIs, 19-IIIa, was selected for clinical development.
- Poras, Hervé,Bonnard, Elisabeth,Dangé, Emilie,Fournié-Zaluski, Marie-Claude,Roques, Bernard P.
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supporting information
p. 5748 - 5763
(2014/08/05)
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- "A PROCESS FOR THE PREPARATION OF N-[2-[(ACETYLTHIO) METHYL]-1-OXO-3-PHENYLPROPYL] GLYCINE PHENYL METHYL ESTER AND INTERMEDIATES THEREOF"
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The present invention provides a process for the preparation of N-[2-[(acetylthio) methyl]-1-oxo-3-phenylpropyl] glycine phenyl methyl ester and intermediates thereof.
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Page/Page column 10
(2013/07/19)
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- SN2-type nucleophilic opening of β-thiolactones (thietan-2-ones) as a source of thioacids for coupling reactions
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β-Thiolactones monosubstituted in the 3-position by alkyl and carbamoyl groups undergo nucleophilic ring opening by arenethiolates through a process involving an SN2-type attack at the 4-position leading to 3-arylthiopropionates substituted in the 2-position. These thiocarboxylates can be trapped in situ by Mukaiyama's reagent or Sanger's reagent through a nucleophilic aromatic substitution process leading to highly activated thioesters that are then allowed to react further with primary or secondary amines leading, overall, to one-pot, three-component syntheses of 3-arylthiopropionamides carrying various substituents in the 2-position. Alternatively, the trapping combination of an electron deficient aryl halide and an amine may be replaced by a 2,4-dinitrobenzenesulfonamide, resulting in the formation of the same products overall with the incorporation of the latent amine in the sulfonamide into the final amide product. In another embodiment, the thiocarboxylate intermediate is allowed to react with a sulfonyl azide, resulting overall in N-arenesulfonyl 3-arylthiopropionamide derivatives.
- Crich, David,Sana, Kasinath
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scheme or table
p. 3389 - 3393
(2009/10/02)
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- Dual-acting antihypertensive agents
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The invention is directed to compounds of formula I: wherein Ar, r, R3, X, and R5-7 are as defined in the specification, and pharmaceutically acceptable salts thereof. The compounds of formula I have AT1 receptor antagonist activity and neprilysin inhibition activity. The invention is also directed to pharmaceutical compositions comprising such compounds; methods of using such compounds; and a process and intermediates for preparing such compounds.
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Page/Page column 44
(2008/12/07)
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- Design and synthesis of non-cytotoxic tetrahydrothieno[3,2-c]pyridine derivatives exhibiting complement inhibition activity
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A series of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine derivatives have been synthesized and evaluated for their activity on the activation of human complement (classical pathway) and their intrinsic haemolytic activity. The in vitro assay results of these analogues for inhibition of complement activity reveals improved inhibitory activity for some of the analogues over existing tetrahydrothienopyridine derivatives like Ticlopidine and Clopidogrel. Significantly, these analogues did not exhibit any haemolytic activity and are non-cytotoxic to human cell lines.
- Master, Hoshang E.,Khan, Shabana I.,Poojari, Krishna A.
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- Discovery of potent HIV-1 protease inhibitors incorporating sulfoximine functionality
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Based on the unique property of sulfoximine and the homodimeric C2 structural symmetry of HIV-1 protease, a novel class of sulfoximine-based pseudosymmetric HIV-1 protease inhibitors was designed and synthesized. The sulfoximine moiety was demonstrated to be important for HIV-1 protease inhibitor potency. The most active stereoisomer (2S,2′S) displays a potency of 2.5 nM (IC50) against HIV-1 protease and an anti-HIV-1 activity of 408 nM (IC50). A possible mode of action is proposed.
- Lu, Ding,Vince, Robert
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p. 5614 - 5619
(2008/03/13)
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- Structural studies of racecadotril and its process impurities by NMR and mass spectroscopy
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Three unknown impurities in racecadotril bulk drug at levels below 0.5% were detected by simple reverse phase isocratic high performance liquid chromatography (HPLC). Structures for these impurities were proposed by molecular ion information and their fragmentation pattern obtained by LC-MS and these impurities were confirmed by NMR spectroscopy. The impurities I, II and III were characterized as benzyl 2-methyl carboximido acetate, benzyl 2-phenyl ethyl carboximido acetate, and benzyl 2-(1-benzyl vinyl carboximido) acetate. These structures were further confirmed by co-injecting of synthetic standards of impurities with racecadotril. The mechanism of the formation of these process related impurities is discussed.
- Mallikarjun Reddy,Moses Babu,Sudhakar,Sharma,Sudershan Reddy,Vyas
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p. 994 - 998
(2007/10/03)
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- Novel compounds that inhibit dipeptidyl peptidase (DPP-IV) and neprilysin (NEP) and/or angiotensin converting enzyme (ACE)
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This invention relates to novel compounds, compositions containing the compounds, that inhibit dipeptidyl peptidase (especially DPP-IV) and neprilysin (NEP, neutral endopeptidase) as well as dipeptidyl peptidase (especially DPP-IV) and angiotensin converting enzyme (ACE) and/or dipeptidyl Peptidase (especially DPP-IV) and vasopeptidases (especially ACE and NEP). These compounds and pharmaceutical compositions thereof are useful for the treatment as well as the prevention of type 2 diabetes mellitus.
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Page/Page column 6
(2010/10/20)
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- PROCESS FOR PRODUCING 2-ARALKYLPROPIONIC ACID DERIVATIVE
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A process for easily and industrially advantageously producing a high-purity 2-aralkyl-3-acetylthiopropionic acid and a high-purity 2-aralkylpropionic acid having a leaving group in the 3-position from easily available compounds. A 2-aralkyl-1-propanol ha
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- New asymmetric synthesis of dexecadotril and ecadotril starting from a single precursor
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We describe herein a method providing access to both enantiomers of 3-acetylthio-2-benzylpropionic acid via enzymatic desymmetrization of 2-benzyl-1,3-propanediol. These compounds are respectively the starting materials for the synthesis of ecadotril, and dexecadotril, which are powerful inhibitors of NEP (EC 3.4.24.11) and have been developed as therapeutic agents.
- Monteil,Danvy,Plaquevent,Duhamel,Duhamel,Gros,Schwartz,Lecomte
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p. 211 - 218
(2007/10/03)
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- PROCESS FOR THE ASYMMETRIC SYNTHESIS OF S-ACYL DERIVATIVES OF 2-MERCAPTOMETHYL -3- PHENYL PROPANOIC ACID, APPLICATION TO THE SYNTHESIS OF N-(MERCAPTOACYL) AMINO ACID DERIVATIVES
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Process for the asymmetric synthesis of S-acyl derivatives of 2-mercaptomethyl-3-phenylpropanoic acid of formula (I): characterized in that it comprises the steps consisting in:a) preparing the diol (VI) by reduction of a malonic ester (V) in the presence of a hydride; b) preparing the monoacetates (VII R) or (VII S) respectively; c) subjecting these monoacetates to an oxidation in order to form the acids (IX S) or (IX R);d) saponifying the compounds (IX S) or (IX R) in order to form the hydroxy acids (X S) or (X R);e) thioacylating the hydroxy acids (X S) or (X R) with a mercapto acid R. sub.1 SH (XI), according to a Mitsunobu-type reaction, in order to lead to the desired acids (I R) (I S) respectively and application to the synthesis of N-(mercaptoacyl)amino acid derivatives (II). STR1
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- Downfield chemical shifts at α-protons and carbons of β-propiothiolactones
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Both the α-protons and carbons of β-propiothiolactones exhibit atypical downfield chemical shifts. The α-protons of β-propiothiolactones with no heteroatom at the α-position appear at 3.53-5.35ppm, whereas the α-carbons appear at 56.9-86.2 ppm. The major cause of the unexpected deshielding effect was rationalized by assuming a through-space interaction between the occupied orbital of the α-carbon and the vacant orbital of sulfur. Copyright
- Lee, Hee Bong,Park, Hyung-Yeon,Lee, Bon-Su,Kim, Young Gyu
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p. 468 - 471
(2007/10/03)
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- The synthesis of (S)-3-acetylthio-2-benzylpropionic acid from (Z)-2-chloromethyl-3-phenylprop-2-enoic acid by asymmetric hydrogenation: A chiral building block of an enkephalinase inhibitor
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(S)-2-Benzyl-3-chloropropionic acid (7) was synthesized from (Z)-2-(chloromethyl)-3-phenylprop-2-enoic acid (5) by asymmetric hydrogenation with a ruthenium 2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl complex in the presence of triethylamine. Acetylthio
- Yuasa, Yoko,Yuasa, Yoshifumi,Tsuruta, Haruki
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p. 511 - 514
(2007/10/03)
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- Thiol inhibitors of endothelin-converting enzyme
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Synthesis and structure activity relationships of a series of thiol inhibitors of the endothelin-converting enzyme (ECE) are presented. Optimisation of the stereochemistry as well as of the P'1 and P'2 residues led to inhibitors with similar potency to that of phosphoramidon.
- Deprez, Pierre,Guillaume, Jacques,Dumas, Jacques,Vevert, Jean-Paul
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p. 2317 - 2322
(2007/10/03)
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- Mercaptoacyl amino acid inhibitors of atriopeptidase. 1. Structure- activity relationship studies of methionine and S-alkylcysteine derivatives
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A broad series of N-(3-mercaptoacyl) amino acid derivatives was evaluated for their ability to inhibit atriopeptidase (neutral endopeptidase, EC 3.4.24.11) in vitro and in vivo. Structural parameters studied were (i) the substituent on the 2-position of the 3-mercaptopropionyl moiety, (ii) the amino acid component, (iii) the S-terminal derivative, and (iv) the C- terminal derivative. Optimum activity was observed for derivatives of methionine and S-alkylcysteines. N-[3-Mercapto-2(S)-[(2- methylphenyl)methyl]-1-oxopropyl]-L-methionine was identified as a highly effective inhibitor of atriopeptidase meriting evaluation as a potential cardiovascular therapeutic agent.
- Neustadt,Smith,Nechuta,Bronnenkant,Haslanger,Watkins,Foster,Sybertz
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p. 2461 - 2476
(2007/10/02)
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- A novel class of enkephalinase inhibitors containing a C-terminal sulfo group
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A new series of sulfonic acids were synthesized and tested for their enkephalinase inhibitory activity. Among them, the most potent was N-(2- benzyl-3-mercaptopropionyl)metanilic acid 10i with an IC50 value of 0.27 nM. Several other analogues (10a,b,j,n,o,gg,hh) showed the inhibitory activity comparable to or greater than thiorphan (IC50 = 2.6 nM), a C- terminal carboxyl-containing inhibitor of enkephalinase. Thus compounds containing a C-terminal sulfo group, instead of the C-terminal carboxyl group, were found to show a remarkably high level of inhibition of enkephalinase. The analgesic activity of 10b, (S)-10b, and (R)-10b was also evaluated by the phenylbenzoquinone writhing test.
- Mimura,Nakamura,Nishino,Sawayama,Komiya,Deguchi,Kita,Nakamura,Matsumoto
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p. 602 - 608
(2007/10/02)
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- Process for the preparation of amino acid-derived enatiomeric compounds
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The (R) or (S) isomer of acetorphan or N-12-acetylthiomethyl-1-oxo-3-phenyl propyl/(S) alanine methyl ester is prepared by splitting of racemic 3-acetylthio-2-benzyl propanoic acid by reaction with ephedrin, separation of the enantiomeric salt obtained, then freeing of the acid and coupling with the corresponding amino acid ester. The obtained preparations possess remarkable therapeutic activities and can notably be used as drugs.
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