- IMPROVED METHODS, KITS, COMPOSITIONS AND DOSING REGIMENS FOR THE USE OF HETEROCYCLIC INHIBITORS OF ERK1 AND ERK2
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The present application provides improved compositions, methods, kits and dosing regimens for the use of heterocyclic compounds and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, or stereoisomers thereof. These compositions, methods, kit
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Page/Page column 86-87
(2021/05/07)
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- METHODS OF TREATING LIVER FIBROSIS USING CALPAIN INHIBITORS
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Disclosed herein are methods of treating liver fibrosis by administering calpain inhibitors to subjects in need thereof.
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Paragraph 0350
(2020/01/24)
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- CALPAIN MODULATORS AND THERAPEUTIC USES THEREOF
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Small molecule calpain modulator compounds, including their pharmaceutically acceptable salts, can be included in pharmaceutical compositions. The compounds can be useful in inhibiting calpain, or competitive binding with calpastatin, by contacting them with CAPN1, CAPN2, and/or CAPN9 enzymes residing inside a subject. The compounds and composition can also be administered to a subject in order to treat a fibrotic disease or a secondary disease state or condition of a fibrotic disease.
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Paragraph 0406
(2019/10/23)
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- Gold-catalyzed oxidative couplings of two indoles with one aryldiazo cyanide under oxidant-free conditions
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Gold-catalyzed oxidative couplings of two indoles and one α-cyano gold carbene to form bis(indolyl)methane derivatives are described. Two different indoles are compatible with these reactions to provide reasonable yields. A plausible mechanism is postulated to rationalize the experimental data including product distributions, D2O labeling, and the significant effects of gold catalysts and cyano groups.
- Singh, Rahulkumar Rajmani,Liu, Rai-Shung
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supporting information
p. 4593 - 4596
(2017/04/28)
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- A Sustainable, Semi-Continuous Flow Synthesis of Hydantoins
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Hydantoins are an important class of heterocycles with applications in pharmacy, agriculture, and as intermediates in organic synthesis. Traditional synthetic procedures to access hydantoins are target oriented with multiple synthetic steps and often use reagents that are not commercially available or sustainable. Herein, an efficient process is described for accessing hydantoins starting from commercially available amines using consecutive gas–liquid transformations (oxygen, carbon dioxide). This semi-continuous process produced ten benzylic/aliphatic hydantoins in good overall yields (52–84 %).
- Vukeli?, Stella,Koksch, Beate,Seeberger, Peter H.,Gilmore, Kerry
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supporting information
p. 13451 - 13454
(2016/09/13)
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- HETEROCYCLIC INHIBITORS OF ERK1 AND ERK2 AND THEIR USE IN THE TREATMENT OF CANCER
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The present application provides novel heterocyclic compounds and pharmaceutically acceptable salts thereof. Also provided are methods for preparing these compounds. These compounds are useful for inhibiting ERK1/2. By administering to a patient in need a
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Paragraph 0411-0412
(2017/01/02)
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- Continuous-flow oxidative cyanation of primary and secondary amines using singlet oxygen
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Primary and secondary amines can be rapidly and quantitatively oxidized to the corresponding imines by singlet oxygen. This reactive form of oxygen was produced using a variable-temperature continuous-flow LED-photoreactor with a catalytic amount of tetraphenylporphyrin as the sensitizer. α- Aminonitriles were obtained in good to excellent yields when trimethylsilyl cyanide served as an insitu imine trap. At 25°C, primary amines were found to undergo oxidative coupling prior to cyanide addition and yielded secondary α-aminonitriles. Primary α-aminonitriles were synthesized from the corresponding primary amines for the first time, by an oxidative Strecker reaction at -50 °C. This atom-economic and protecting-group-free pathway provides a route to racemic amino acids, which was exemplified by the synthesis of tert-leucine hydrochloride from neopentylamine. The mild synthesis of imines paves the way to aminonitriles and amino acids. Aerobic oxidation of primary and secondary amines in a continuous photoreactor with singlet oxygen generated insitu led to the rapid formation of imines, which were quantitatively trapped as α-aminonitriles (see scheme; TMS=trimethylsilyl). Benzylic and primary α-aminonitriles, precursors for amino acids, could be efficiently produced in three minutes.
- Ushakov, Dmitry B.,Gilmore, Kerry,Kopetzki, Daniel,McQuade, D. Tyler,Seeberger, Peter H.
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supporting information
p. 557 - 561
(2014/01/23)
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- Method of making imidazole-2-thiones
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The present invention provides a method of making an imidazole-2-thione which comprises the steps of reacting a vicinal diamine with a compound having a thiocarbonyl moiety and oxidizing the resulting reaction product to obtain said imidazole-2-thione.
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Page/Page column 3; 7
(2008/06/13)
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- PROCESS FOR THE RACEMISATION OF ENANTIOMERICALLY ENRICHED ALPHA-AMINO NITRILES
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Process for the racemisation of an enantiomerically enriched α-amino nitrile characterized in that the enantiomerically enriched α-amino nitrile is contacted with a lewis acid catalyst. Preferably an aprotic solvent is used. The lewis acid catalyst preferably comprises a metal chosen from main group elements IA-IVA of the Periodic Table (CAS version), the transition metals and the lanthanides, in particular Al, Ti, Zr, or lanthanides. The catalsyt for example has the general structure MnXpSqLr, and preferably is chosen from the group of aluminum alkoxides, aluminum alkyls, lanthanide alkoxydes and lanthanocenes. The racemisation may be performed in combination with a resolution process, for instance in combination with an enzymatic or a crystallization induced resolution process, preferably in situ, for instance in situ in a crystallization induced asymmetric transformation process.
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- Process for the preparation of enantiomerically enriched compounds
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1. Process for the preparation of enantiomerically enriched amino aldehydes and amino alcohols, wherein a corresponding enantiomerically enriched amino nitrile is subjected to hydrogenation in the presence of hydrogen, a hydrogenation catalyst, preferably a Pd-catalyst and a mineral acid. For the preparation of an amino aldehyde hydrogen preferably is present at a hydrogen-pressure between 0.1 and 2 MPa, in particular between 0.5 and 1 MPa. The amino aldehyde preferably is isolated in the form of a chemically and configurationally stable derivative. For the preparation of an amino alcohol, preferably at least during part of the hydrogenation hydrogen is present at a hydrogen-pressure between 2 and 10 MPa, in particular between 4 and 6 MPa. In a preferred embodiment the hydrogen-pressure initially is between 0,5 and 2 MPa and subsequently, after most of the nitrile starting material is converted, the hydrogen pressure is increased to a value between 2 and 10 MPa. The enantiomerically enriched nitrile starting material may a.o. be prepared by enzymatic resolution, classical resolution, resolution via preferential crystallization, diastereomeric synthesis, catalytic asymmetric synthesis or dehydratation of amino acid amides.
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Page/Page column 5
(2010/11/29)
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- α-Aminonitrile hydration in the presence of hydrogen peroxide in aqueous basic medium
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α-Aminonitriles are hydrated into α-aminoamides in the presence of hydrogen peroxide in sodic or ammoniacal basic medium. While the hydration mechanism is close to the mechanism described previously in the case of aromatic nitrites, we showed that, in weakly basic conditions, the amine function of α-aminonitrile is competitively oxidized via a peroxyimidic acid by an intramolecular process. In the case of 2-aminopropanenitrile, this reaction leads to pyruvamide oxime. Furthermore, the study of structurereactivity relationships in the hydration of aliphatic and aromatic monofunctional nitriles and α-aminonitriles showed that the reactivity of the substrates towards hydroperoxide onion, which mostly depends on inductive effects of the substituents, is sufficiently enhanced to allow hydration of tertiary α-aminonitriles with low steric hindrance and regioselective hydration of dissymmetric α-aminodinitriles. Eisevier,.
- Taillades, Jacques
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- Preparation of N-H aziridines in high enantiomeric excess by in situ aziridine-azirine-aziridine interconversion
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Aziridine 6 is produced highly diastereoselectively by treatment of enantiopure 3-acetoxyaminoquinazolinone 4 (Q*NHOAc) with β-trimethylsilylstyrene: desilylative elimination of Q* and in situ addition of cyanide to the intermediate azirine gives the NH-a
- Atkinson, Robert S.,Coogan, Michael P.,Lochrie, Ian S. T.
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p. 789 - 790
(2007/10/03)
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- La pronase immobilisee sur poly(N-acryloylpiperidin-4-one): un catalyseur d'hydrolyse L-enantiospecifique des α-aminonitriles
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Pronase immobilized on poly(N-acryloylpiperidin-4-one) : a L-enantiospecific hydrolysis of α-aminonitriles with immobilized amidase. α-Aminonitriles are not substrates for pronase (an amidase) in the homogeneous phase but become substrates for pronase when it is immobilized on polymer matrix with ketonic sites (piperidin-4-one).In this paper we show that under low basic aqueous conditions (pH 10-11), the hydration of α-aminonitriles can be efficiently catalyzed by poly(N-acryloylpiperidin-4-one) crosslinked with 1,4-bis acryloylpiperazine (A(80:20)) in the presence of phosphate or borate buffers.These conditions comply with the hydrolysis of α-aminoamides by pronase immobilized on poly(N-acryloylpiperidin-4-one)crosslinked with 1,4-bis(acryloyl)piperazine (A(80:20/p).Thus, in a buffered borate solution at pH 10.5, α(DL)-aminonitrile is enantiospecifically hydrolyzed into α(D)-aminoamide and α(L)-amino acid. Key words: α-aminonitriles / α amino acids / L-enantiospecific hydrolysis / polymer-supported catalysis / nitrilasic activity
- Taillades, Jacques,Garrel, Laurence,Guillen, Franck,Collet, Helene,Commeyras, Auguste
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p. 119 - 127
(2007/10/02)
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- Influence of a Hydroalcoholic Solvent on the Enantioselectivity of α-Amino nitrile Hydration Catalysed by Chiral Ketones
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The enantioselective hydration of α-aminonitriles 1, RCH(CN)NH2 i; 1c: R = Ph> has been achieved in an alkaline hydroalcoholic medium in the presence of chiral ketonic catalysts.Of the different ketones used, (-)-(5R,3R,2R)-5-(methylethenyl)-3-cyano-2-methylcyclohexanone (8) gives rise to significant enantioselectivity D/kL = 2.1; T = 10 deg C; solvent, water-propan-2-ol (45:55,v/v)>.Although the structure of the catalyst could probably be improved, we show in this paper that the efficiency and especiallythe enantioselectivity of the catalyst are not only under steric control but also depend on the nature and composition of the hydroalcoholic solvent.Thus, for the three aminonitriles studied in the presence of the catalyst 8, the increase in percentage of propan-2-ol favours the hydration of the D α-aminonitrile as shown for the hydration of 1c for which the ratio kD/kL increases threefold when the percentage of propan-2-ol increases from 10 to 95percent.
- Lagriffoul, Pierre-Henri,Tadros, Ziad,Taillades, Jacques,Commeyras, Auguste
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p. 1279 - 1285
(2007/10/02)
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- Hydratation enantioselective d'α-aminonitriles en presence de catalyseurs cetoniques chiraux supportes
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Enantioselective hydration of α-aminonitriles with chiral ketonic immobilized catalyst.In a previous publication, we showed that the hydration of α-aminonitriles under basic aqueous conditions was efficiently catalyzed by a poly(N-acryloylpiperidin-4-one) crosslinked with 20percent N,N'-bisacryloylpiperazine.In this paper, we show that lowering the degree of crosslinking and diluting piperidone sites inside the polymeric matrix by copolymerisation with an inactive comonomer (N-acryloylmrpholine), decrease catalyst degradation and improve average reactivity ofcatalytic sites.The best results were obtained with a 5percent crosslinked resin containing 15percent piperidin-4-one sites.With the same proportions, we prepared a polymer-supported chiral ketone 14 which catalyzes the enantioselective hydration of α-aminobenzylacetonitrile. Key words: α-aminonitrile / α-aminoamide / enantioselective hydration / polamer-supported catalysis / ketonic resins
- Taillades, J,Garrel, L.,Lagriffoul, P. H.,Commeyras, A.
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p. 191 - 198
(2007/10/02)
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- Process for obtaining α-amino nitriles and their applications to organic synthesis
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The present invention relates to the synthesis of nitriles having an amine function on the adjacent carbon.
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- SYSTEMES DE STRECKER ET APPARENTES-XII. CATALYSE PAR LES ALDEHYDES DE L'HYDRATATION INTRAMOLECULAIRE DES α-AMINONITRILES
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Aqueous basic hydration of α-aminopropionitrile is first order either in acetaldehyde (formed by decomposition of α-aminopropionitrile) or different aldehydes added in the medium.The rate determining step involves a rapid preequilibrium in which the catal
- Pascal, R.,Taillades, J.,Commeyras, A.
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p. 2999 - 3008
(2007/10/02)
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