- Bioisosteric Modification of To042: Synthesis and Evaluation of Promising Use-Dependent Inhibitors of Voltage-Gated Sodium Channels
-
Three analogues of To042, a tocainide-related lead compound recently reported for the treatment of myotonia, were synthesized and evaluated in vitro as skeletal muscle sodium channel blockers possibly endowed with enhanced use-dependent behavior. Patch-clamp experiments on hNav1.4 expressed in HEK293 cells showed that N-[(naphthalen-1-yl)methyl]-4-[(2,6-dimethyl)phenoxy]butan-2-amine, the aryloxyalkyl bioisostere of To042, exerted a higher use-dependent block than To042 thus being able to preferentially block the channels in over-excited membranes while preserving healthy tissue function. It also showed the lowest active transport across BBB according to the results of P-glycoprotein (P-gp) interacting activity evaluation and the highest cytoprotective effect on HeLa cells. Quantum mechanical calculations and dockings gave insights on the most probable conformation of the aryloxyalkyl bioisostere of To042 in solution and the target residues involved in the binding, respectively. Both approaches indicated the conformations that might be adopted in both the unbound and bound state of the ligand. Overall, N-[(naphthalen-1-yl)methyl]-4-[(2,6-dimethyl)phenoxy]butan-2-amine exhibits an interesting toxico-pharmacological profile and deserves further investigation.
- Milani, Gualtiero,Cavalluzzi, Maria Maddalena,Altamura, Concetta,Santoro, Antonella,Perrone, Mariagrazia,Muraglia, Marilena,Colabufo, Nicola Antonio,Corbo, Filomena,Casalino, Elisabetta,Franchini, Carlo,Pisano, Isabella,Desaphy, Jean-Fran?ois,Carrieri, Antonio,Carocci, Alessia,Lentini, Giovanni
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p. 3588 - 3599
(2021/10/07)
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- BICYCLIC COMPOUNDS
-
Provided herein are compounds and pharmaceutical compositions comprising said compounds that are useful for treating cancers. Specific cancers include those that are mediated by YAP/TAZ or those that are modulated by the interaction between YAP/TAZ and TEAD.
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Paragraph 00505
(2020/10/28)
-
- BICYCLIC COMPOUNDS
-
Provided herein are compounds and pharmaceutical compositions comprising said compounds that are useful for treating cancers. Specific cancers include those that are mediated by YAP/TAZ or those that are modulated by the interaction between YAP/TAZ and TEAD.
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Paragraph 00518
(2020/06/01)
-
- APOPTOSIS SIGNAL-REGULATING KINASE INHIBITORS AND USES THEREOF
-
Described herein are ASK1 inhibitors and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for the treatment of blood disease, autoimmune disorders, pulmonary disorders, hypertension, inflammatory diseases, fibrotic diseases, diabetes, diabetic nephropathy, renal diseases, respiratory diseases, cardiovascular diseases, acute lung injuries, acute or chronic liver diseases, and neurodegenerative diseases.
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Paragraph 00597
(2019/04/09)
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- MACROCYCLIC COMPOUNDS AS TRK KINASE INHIBITORS AND USES THEREOF
-
The present disclosure describes novel TRK kinase inhibitors and methods for preparing them. The pharmaceutical compositions comprising such TRK kinase inhibitors and methods of using them for treating cancer, infectious diseases, and other disorders are also described.
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Paragraph 258
(2019/05/30)
-
- TETRADENTATE LIGAND, AND PRODUCTION METHOD THEREFOR, SYNTHETIC INTERMEDIATE THEREOF, AND TRANSITION METAL COMPLEX THEREOF
-
The present invention relates to: a compound as a ligand in a variety of catalytic organic synthetic reactions; a method for producing the compound; a synthetic intermediate of the compound; and a transition metal complex which has the compound as a ligand. The compound includes a compound represented by the following general formula (1A):
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Paragraph 0281-0283
(2019/05/15)
-
- PYRROLOTRIAZINE COMPOUNDS AND METHODS OF INHIBITING TAM KINASES
-
Described herein are compounds, methods of making such compounds, pharmaceutical compositions, and medicaments comprising such compounds, and methods of using such compounds to treat cancer. (II), or a pharmaceutically acceptable salt thereof, wherein: R1 is pyridin-3-yl, pyridin-4-yl, pyrazol-4-yl, cyclohexyl, or 8-azabicyclo[3.2.1]oct-2- ene-3-yl, wherein R1 is optionally substituted with up to four independently selected substituents; R2 is cyclohexyl substituted with hydroxy and optionally substituted with one or two additional substituents independently selected from C1-C4 alkyl and fluoro, or is 4,5,6,7- tetrahydro-lH-indazolyl optionally substituted with one to three substituents independently selected from C1-C4 alkyl and fluoro; and R3 is -C3-C8 alkyl, -(C2-C6 alkylene)-0-(C1-C6 alkyl), C3-C6 cycloalkyl, or -(C2-C6 alkylene)-C3-C6 cycloalkyl, wherein R3 is optionally substituted with 1-5 substituents inde endentl selected from deuterium, halo, and -OH.
- -
-
Paragraph 0160; 0214
(2019/05/06)
-
- Preparation method for R-3-aminobutanol
-
The invention relates to a preparation method for R-3-aminobutanol. The preparation method specifically comprises the following steps: (a) reacting R-3-aminobutyric acid with di-tert-butyl carbonate in the presence of a polar solvent so as to form N-Boc-(R)-3-aminobutyric acid; (b) reducing N-Boc-(R)-3-aminobutyric acid in the presence of a reducing agent and Lewis acid so as to form N-Boc-(R)-3-aminobutanol; and (c) subjecting N-Boc-(R)-3-aminobutanol to a Boc removal in the presence of an acid solvent so as to form R-3-aminobutanol. The preparation method of the invention is simple in process, low in cost, friendly to environment, easier for industrial production and worth promotion.
- -
-
Paragraph 0090; 0091
(2018/09/08)
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- Preparation method of (R)-3-aminobutanol
-
The invention relates to the technical field of synthesis of drug intermediates and particularly relates to a preparation method of dolutegravir intermediate (R)-3-aminobutanol, comprising: using 3-(Boc-amino)butyric acid as a starting material, chirally splitting to obtain a compound of formula I; reducing with sodium borohydride and Lewis acid to obtain a compound of formula II; performing amino deprotection to obtain (R)-3-aminobutanol. The materials used herein are low in price and easy to obtain, the reaction conditions are mild, the safety is reliable, process stability is high, the yield is high, optical purity is high, and the preparation method is green and suitable for industrial production.
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Paragraph 0022; 0023; 0024
(2017/08/29)
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- MOLECULES HAVING PESTICIDAL UTILITY, AND INTERMEDIATES, COMPOSITIONS, AND PROCESSES, RELATED THERETO
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This disclosure relates to the field of molecules having pesticidal utility against pests in Phyla Arthropoda, Mollusca, and Nematoda, processes to produce such molecules, intermediates used in such processes, compositions containing such molecules, and processes of using such molecules and compositions against such pests. These molecules and compositions may be used, for example, as acaricides, insecticides, miticides, molluscicides, and nematicides. This document discloses molecules having the following formula (“Formula One”).
- -
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Paragraph 0537-0538
(2017/09/02)
-
- Continuous Flow Synthesis of Morpholines and Oxazepanes with Silicon Amine Protocol (SLAP) Reagents and Lewis Acid Facilitated Photoredox Catalysis
-
Photocatalytic coupling of aldehydes and silicon amine protocol (SLAP) reagents enables the simple, scalable synthesis of substituted morpholines, oxazepanes, thiomorpholines, and thiazepanes under continuous flow conditions. Key to the success of this process is the combination of an inexpensive organic photocatalyst (TPP) and a Lewis acid additive, which form an amine radical cation that is easily reduced to complete the catalytic cycle. Di- and trisubstituted SLAP reagents are formed in one step by an iron-catalyzed aminoetherification of olefins.
- Jackl, Moritz K.,Legnani, Luca,Morandi, Bill,Bode, Jeffrey W.
-
supporting information
p. 4696 - 4699
(2017/09/11)
-
- NOVEL COMPOUNDS
-
The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein n, X1, X2, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12and R13 are as defined in the specification, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
- -
-
Page/Page column 50; 51
(2018/04/12)
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- MULTICYCLIC COMPOUNDS AND METHODS OF USING SAME
-
The invention generally relates to compounds represented by Structural Formula I: or a pharmaceutically acceptable salt thereof, wherein the variables are as defined and described herein. The invention also includes the synthesis and use of a compound of
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Paragraph 00528
(2015/04/15)
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- BICYCLIC PYRIMIDONE COMPOUNDS AS INHIBITORS OF LP-PLA2
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The present invention relates to novel pyrimido[1,6-a]pyrimidin-6(2H)-one compounds that inhibit Lp-PLA2 activity, processes for their preparation, to compositions containing them and to their use in the treatment of diseases associated with the activity of Lp-PLA2, for example atherosclerosis, Alzheimer's disease.
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-
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- NOVEL RUTHENIUM CARBONYL COMPLEX HAVING TRIDENTATE LIGAND, ITS PRODUCTION METHOD AND USE
-
The present invention relates to a ruthenium carbonyl complex that is represented by the following Formula (1): [in-line-formulae]RuXY(CO)(L)??(1)[/in-line-formulae](in the Formula (1), X and Y, which may be the same or different from each other, represent an anionic ligand and L represents a tridentate aminodiphosphine ligand which has two phosphino groups and a —NH— group), its production method, and a method for production of alcohols by hydrogenation-reduction of ketones, esters, and lactones using the complex as a catalyst. The ruthenium carbonyl complex of the invention has a high catalytic activity and it can be easily prepared and handled.
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Page/Page column 11
(2011/10/12)
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- HETEROCYCLIC COMPOUNDS CONTAINING AN INDOLE CORE
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Disclosed are novel compounds which inhibit RSK, methods of making such compounds and pharmaceutical compositions comprising such compounds. Also disclosed are methods of treating RSK2 regulated disorders using compounds of the invention.
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Page/Page column 89
(2011/06/26)
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- A homogeneous catalyst for reduction of optically active esters to the corresponding chiral alcohols without loss of optical purities
-
A ruthenium complex was found to catalyze the hydrogen reduction of esters under mild and neutral conditions. A variety of optically active esters can be reduced to the corresponding alcohols in excellent yield without loss of their optical purity or causing undesirable side reactions. Hydrogen reduction needs such simple operations - reaction, concentration, and purification - that the violent quench step and extraction step, which accompany conventional sodium borohydride or lithium aluminum hydride reduction, can be omitted.
- Kuriyama, Wataru,Ino, Yasunori,Ogata, Osamu,Sayo, Noboru,Saito, Takao
-
supporting information; experimental part
p. 92 - 96
(2010/06/17)
-
- Stereoselective synthesis of 2,6-disubstituted piperidines using the iridium-catalyzed allylic cyclization as configurational switch: Asymmetric total synthesis of (+)-241 D and related piperidine alkaloids
-
Total stereoselective synthesis of the dendrobate alkaloid (+)-241D, its C6-epimer, and a spruce alkaloid, was presented. The configurational switch allows preparation of each of the eight stereoisomers with high selectivity, due to availability of enanti
- Gnamm, Christian,Krauter, Caroline M.,Broedner, Kerstin,Helmchen, Guenter
-
scheme or table
p. 2050 - 2054
(2009/09/06)
-
- A configurational switch based on iridium-catalyzed allylic cyclization: Application in asymmetric total syntheses of prosopis, dendrobate, and spruce alkaloids
-
A method for the stereoselective synthesis of 2,6-disubstituted piperidines has been developed that is based on the use of an intramolecular iridium-catalyzed allylic substitution as a configurational switch. The procedure allows the preparation of 2-viny
- Gnamm, Christian,Broedner, Kerstin,Krauter, Caroline M.,Helmchen, Guenter
-
scheme or table
p. 10514 - 10532
(2010/04/29)
-
- Method for producing alcohols
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A method for producing alcohols which comprises reducing esters or lactones with hydrogen gas in the presence of a catalyst comprising (i) a ruthenium compound, (ii) a monodentate monophosphine or a bidentate bisphosphine, and (iii) an amine. Examples of the catalyst include a ruthenium (Ru) complex represented by the formula:RuX1X2(LP)m(LN)n [X1 and X2 each represent an anionic ligand, LP represents a phosphine ligand, m is 1 when LP is bidentate, while m is 2 when LP is monodentate, LN represents an amine ligand, and n is 1 when LN is bidentate, while n is 2 when LN is monodentate.] and a catalyst comprising an amine and a ruthenium (Ru) complex of the formula: RuX1X2 (LP1)r [LP1 represents a monophosphine ligand and r is 3 or 4.].
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Page/Page column 20
(2008/12/08)
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- INHIBITORS OF AKT ACTIVITY
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Invented are novel 1 H-imidazo[4,5-c]pyridin-2-yl compounds, the use of such compounds as inhibitors of protein kinase B activity and in the treatment of cancer and arthritis.
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Page/Page column 49
(2008/06/13)
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- 1,3-DISUBSTITUTED AZETIDINE DERIVATIVES FOR USE AS CCR-3 RECEPTOR ANTAGONISTS IN THE TREATMENT OF INFLAMMATORY AND ALLERGIC DISEASES
-
Compounds of formula Ia or Ib in free or salt form, wherein Ar, X1, X2, m, R1, Q, Y, R2 and R3 have the meanings as indicated in the specification, are useful for treating conditions that are mediated by CCR-3, for example an inflammatory or allergic cond
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-
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- CHK-1 INHIBITORS
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Disclosed are novel inhibitors of Chk-1 and methods of using the same for therapy.
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Page/Page column 214
(2010/02/11)
-
- Substituted imidazole compounds
-
The present invention relates to novel 1,4,5-substituted imidazole compounds and compositions for use in therapy as CSBP/p38 inhibitors.
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-
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- Preparation and structure of homochiral tetrahydro-2H-l,3-oxazines
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The synthesis, and structural elucidation using NMR and X-ray crystallography, of homochiral N-tert-butoxycarbonyl-tetrahydro-2H-1,3-oxazines are described.
- Rae, Alastair,Aliev, Abil E.,Edgar Anderson,Castro, Jose L.,Ker, James,Parsons, Simon,Stchedroff, Marc,Tabor, Alethea B.
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p. 1933 - 1941
(2007/10/03)
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- Ornithine decarboxylase inhibiting branched aminooxy amino alkane derivatives
-
Compounds of formula (I) in which (a) four of the radicals R1, R2, R3, R4, R5 and R6 are hydrogen and the others independently of one another are in each case C1 -C2 alkyl, these groups being bonded to the same carbon atom or to two different carbon atoms, or (b) five of the radicals R1, R2, R3, R4, R5 and R6 are hydrogen and the other radical is C1 -C2 alkyl or hydroxymethyl, or salts thereof, are described. The compounds of formula (I) and their salts are ornithine decarboxylase inhibitors.
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-
-
- A Concise Enantioselective Synthesis of Allylamines and N-Boc-β-Amino Acids
-
A new and efficient enantioselective synthesis of allylamines and N-Boc-β-amino acids has been developed.Starting from enantiomerically enriched N-diphenylmethyl-3-amino-1,2-diols, allylamines are easily obtained by a Corey-Hopkins deoxygenative protocol.After a change in the nitrogen protecting group, the resulting N-Boc allylamines are converted into β-amino acids by hydroboration with 9-BBN followed by oxidation with PDC in DMF.
- Alcon, Montserrat,Canas, Marc,Poch, Marta,Moyano, Albert,Pericas, Miquel A.,Riera, Antoni
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p. 1589 - 1592
(2007/10/02)
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- Lithiation of N-Boc-2-methyltetrahydro-1,3-oxazine: A Synthetic Equivalent for 1-Lithio-3-hydroxy-1-propylamine
-
A α-metalo amine synthetic equivalent of an unactivated primary amine, 1-lithio-3-hydroxy-1-propylamine (7) is provided by the lithiation of N-Boc-2-methyltetrahydro-1,3-oxazine (8) to give 9 which on reaction with electrophiles and hydrolysis gives derivatives of 1-substituted 3-hydroxy-1-propylamines 10-24.
- Beak, Peter,Yum, Eul Kgun
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p. 823 - 824
(2007/10/02)
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- Stereospecific Synthesis of (2R,5R)-Hept-6-yne-2,5-diamine: A Potent and Selective Enzyme-activated Irreversible Inhibitor of Ornithine Decarboxylase (ODC)
-
Hept-6-yne-2,5-diamine (2) and 2-methylhept-6-yne-2,5-diamine (3), while structurally related to the potent ornithine decarboxylase (ODC) inhibitor hex-5-yne-1,4-diamine (1), are stable to in vivo oxidation by monoamine oxidase (MAO).Although the methyl substitution is at a carbon relatively remote from the site of metabolic attack by ornithine decarboxylase (ODC), it has a critical influence on the potencies of these compounds as inhibitors of the enzyme.Of the four stereoisomers, (2R,5R)-(2) is the most active.Unambiguous syntheses of each isomer of (2) from the dianion of 3-trimethylsilyl-N-butoxycarbonylprop-2-ynylamine (5) are presented.
- Casara, Patrick,Danzin, Charles,Metcalf, Brian,Jung, Michel
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p. 2201 - 2208
(2007/10/02)
-