- From off-to on-target: New BRAF-inhibitor-template-derived compounds selectively targeting mitogen activated protein kinase kinase 4 (MKK4)
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The mitogen-activated protein kinase (MAP) kinase 4 (MKK4) was found to be a major regulator of liver regeneration and could be a valuable drug target addressing liver related diseases by restoring its intrinsic regenerative capacity. We report on the synthesis and optimization of novel MKK4 inhibitors following a target-hopping strategy from the FDA-approved BRAFV600E inhibitor PLX4032 (8). Applying an iterative multi-parameter optimization process we carved out essential structural features yielding in compounds with a low nanomolar affinity for MKK4 and excellent selectivity profiles against the main off-targets MKK7 and JNK1, which, upon relevant inhibition, would totally abrogate the pro-regenerative effect of MKK4 inhibition, as well as against the off-targets MAP4K5, ZAK and BRAF with selectivity factors ranging from 40 to 430 for our best-balanced compounds 70 and 73.
- Kl?vekorn, Philip,Pfaffenrot, Bent,Juchum, Michael,Selig, Roland,Albrecht, Wolfgang,Zender, Lars,Laufer, Stefan A.
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supporting information
(2020/11/20)
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- Inhibitor for dipeptidyl peptidase-IV
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The invention provides an aminotetrahydropyran derivative with a general formula (I) as described in the specification, pharmaceutically acceptable salts, hydrates, solvates and stereoisomers thereof, a preparation method for the aminotetrahydropyran derivative, and a pharmaceutical composition containing the aminotetrahydropyran derivative. The aminotetrahydropyran derivative provided by the invention can inhibit the activity of dipeptidyl peptidase-IV(DPP-IV), and can be used for treatment of diseases related to dipeptidyl peptidase-IV, especially for treatment of diabetes.
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Paragraph 0137-0140
(2017/08/28)
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- THIAZOLIDINONE COMPOUNDS AND USE THEREOF
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A pharmaceutical composition containing a compound of Formula (I) for treating an opioid receptor-associated condition. Also disclosed is a method for treating an opioid receptor-associated condition using such a compound. Further disclosed are two sets of thiazolidinone compounds of formula (I): (i) compounds each having an enantiomeric excess greater than 90% and (ii) compounds each being substituted with deuterium.
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Paragraph 1248-1248
(2017/09/21)
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- NOVEL INHIBITORS OF PROTEIN KINASES
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Protein kinases are regulators of cellular signaling and their functional dysregulation is common in carcinogenesis and many other disease states or disorders. The present invention relates to novel chemical entities that have biological activity to modulate mammalian protein kinase enzymes. In particular, compounds of the invention display potent inhibition of breast tumor related kinase (BRK).
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Paragraph 0093; 0135; 0137
(2017/09/08)
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- Aminotetrahydropyran derivative used as dipeptidyl peptidase-IV inhibitor
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The invention provides an aminotetrahydropyran derivative as shown in the general formula (I), pharmaceutically acceptable salt, hydrate, solvate and stereisomer of the derivative, a preparation method thereof, and a pharmaceutical composition containing the compound. The compound can inhibit activity of dipeptidyl peptidase IV (DPP-IV) and can be used in treating diseases related to dipeptidyl peptidase IV.
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Paragraph 0171; 0172
(2016/10/09)
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- NITROGENATED HETEROCYCLIC COMPOUND
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A nitrogen-containing heterocyclic compound represented by formula (I-A): (wherein R1A represents lower alkyl which may be substituted with lower alkoxy, R3A represents lower alkyl substituted with fluorine atom(s), and RqA represents an optionally substituted aromatic heterocyclic group) or the like, or a pharmaceutically acceptable salt thereof; and the like, are provided.
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Paragraph 0093
(2014/11/27)
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- Clean and economic synthesis of alkanesulfonyl chlorides from S-alkyl isothiourea salts via bleach oxidative chlorosulfonation
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A simple procedure for clean and economic synthesis of alkanesulfonyl chlorides via bleach-mediated oxidative chlorosulfonation of S-alkyl isothiourea salts is disclosed. This procedure is environment- and worker-friendly with the advantages of readily accessible materials and reagents, simple and safe operations, easy purification without chromatography, and affords high yields of up to 99%.
- Yang, Zhanhui,Zhou, Bingnan,Xu, Jiaxi
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p. 225 - 229
(2014/03/21)
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- NITROGEN-CONTAINING HETEROCYCLIC COMPOUND HAVING INHIBITORY EFFECT ON PRODUCTION OF KYNURENINE
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The present invention provides a nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof having an inhibitory effect on the production of kynurenine, represented by formula (I): (wherein R6 and R7 may be the same or different and each represent a hydrogen atom or the like, R8, R9, R19, and R11 may be the same or different and each represent a hydrogen atom or the like, R1 represents lower alkyl which may be substituted with cycloalkyl, or the like, and R3 represents optionally substituted aryl or an optionally substituted heterocyclic group).
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Paragraph 0234
(2013/03/28)
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- Convenient and environment-friendly synthesis of sulfonyl chlorides from S -alkylisothiourea salts via N-chlorosuccinimide chlorosulfonation
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A convenient, practical, and environmentally friendly method for the synthesis of sulfonyl chlorides has been developed. Structurally diverse sulfonyl chlorides were synthesized in moderate to excellent yields from S-alkylisothiourea salts, which can be easily prepared from readily accessible alkyl halides or mesylates and inexpensive thiourea, via N-chlorosuccinimide chlorosulfonation. In large-scale syntheses, the byproduct succinimide from 'waste water' can be conveniently converted into the starting reagent N-chlorosuccinimide with sodium hypochlorite (bleach) to make the method sustainable. Georg Thieme Verlag Stuttgart, New York.
- Yang, Zhanhui,Xu, Jiaxi
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p. 1675 - 1682
(2013/07/27)
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- Simple synthesis of sulfonyl chlorides from thiol precursors and derivatives by NaClO2-mediated oxidative chlorosulfonation
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A simple method to synthesize diverse sulfonyl chlorides through NaClO 2-mediated oxidative chlorosulfonation of S-alkyl isothiourea salts is presented. The approach features safe operation, environmental friendliness, convenient purification procedures, and delivers high yields of up to 96%. The procedure is also applicable to substrates such as thiols, disulfides, thioacetates, and xanthates. It is a versatile and convenient method for the synthesis of various sulfonyl chlorides from different thiol precursors and derivatives. Georg Thieme Verlag Stuttgart, New York.
- Yang, Zhanhui,Zheng, Yongpeng,Xu, Jiaxi
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supporting information
p. 2165 - 2169
(2013/10/22)
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- INDOLE DERIVATIVES AS IKK2 INHIBITORS
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The invention is directed to a certain novel compound whioh is an inhibitor of kinase activity, in particular IKK2 activity of Formula (I): or a salt thereof. for use in the treatment of disorders such as inflammatory bowel disease, COPD (chronic obstructive pulmonary disease), asthma, rhinitis, fibrotic diseases, psoriasis, atopic dermatitis and ultraviolet radiation (UV)-induced skin damage.
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Page/Page column 39
(2010/10/03)
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- Pyrrolopyrazinyl Urea Kinase Inhibitors
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The present invention relates to the use of novel pyrrolopyrazinyl urea derivatives of Formula I, wherein the variables R1, R2, R3, R4, and R5 are defined as described herein, which inhibit JAK and are useful for the treatment of auto-immune and inflammatory diseases.
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Page/Page column 49
(2010/06/19)
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- PYRAZOLE DERIVATIVES FOR THE INHIBITION OF CDK' S AND GSK' S
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The invention provides compounds of the formula (I), or salts, tautomers, N-oxides or solvates thereof wherein: R1 is selected from: (a) 2,6-dichlorophenyl; (b) 2,6-difluorophenyl; (c) a 2,3,6-trisubstituted phenyl group wherein the substituents for the phenyl group are selected from fluorine, chlorine, methyl and methoxy; (d) a group R0; (e) a group R a; (f) a group Rlb; (g) a group Rlc; (h) a group Rld; and 0) 2,6-difluorophenylamino ; wherein R )0υ, r R> llaa, T Rj I1bD, T R) I1cC, r R> Iidα, r R?2zaa, r R>22bD and RJ are as defined in the claims. The compounds have activity as inhibitors of cdk kinase (such as cdkl or cdk2) and glycogen synthase kinase-3 activity.
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Page/Page column 158-159
(2008/06/13)
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- Mechanisms of hydrolysis and related nucleophilic displacement reactions of alkanesulfonyl chlorides: pH dependence and the mechanism of hydration of sulfenes
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pH-rate profiles, primary kinetic isotope effects, deuterium substitution patterns, and pH-product ratios in the presence of added nucleophiles provide evidence for the following overlapping set of mechanisms for the hydrolysis of methanesulfonyl chloride (1) (in 0.1 M KCl at 25 °C): (a) pH ≤ 1-6.7, reaction with water by direct nucleophilic attack on the sulfonyl chloride; (b) pH ≥ 6.7-11.8, rate-determining attack by hydroxide anion to form sulfene (2), which is then trapped by water in a fast step; and (c) pH ≥ 11.8, sulfene formation and sulfene trapping by hydroxide anion; careful inspection showed no sign of sulfene formation in the reaction with water or of direct displacement by hydroxide anion. This pattern, with appropriate variations in the values of pHi (the pH at which two competing mechanisms have the same rate), is apparently general for simple alkanesulfonyl chlorides having at least one hydrogen on the carbon bearing the sulfonyl group. Azide and acetate anions react with 1 below pHi for 1 (6.7) by direct nucleophilic substitution at the sulfur, but above pHi by trapping of the sulfene. 2-Chlorophenoxide anion reacts with 1 below pH 6.7 by both (a) direct displacement to form the ester and (b) elimination to form the sulfene. Above pH 6.7, sulfene is formed from the sulfonyl chloride by reaction with either 2-chlorophenoxide or hydroxide ion; this is followed by trapping of the sulfene with 2-chlorophenoxide, water, or hydroxide. The possibility of the 2-chlorophenoxide anion acting as a general base promoting the reaction of water with either 1 and 2 was examined, but no sign of either process was detected.
- King,Lam,Skonieczny
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p. 1743 - 1749
(2007/10/02)
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- Fungicidal N-cyanoalkyl-N-haloalkylthio sulfonamides
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Compounds of the formula: STR1 wherein R is aryl of 6 to 12 carbon atoms or aralkyl of 7 to 14 carbon atoms either optionally substituted with 1 to 3 substituents independently selected from lower alkyl of 1 to 6 carbon atoms, lower alkoxy of 1 to 6 carbon atoms, lower alkylthio of 1 to 6 carbon atoms, lower alkylsulfinyl of 1 to 6 carbon atoms, lower alkylsulfonyl of 1 to 6 carbon atoms, halogen, trihalomethyl, nitro, cyano or carboxyl; alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, lower alkenyl of 2 to 6 carbon atoms, or lower alkynyl of 2 to 6 carbon atoms, all optionally substituted with 1 to 3 halogen atoms; lower alkoxyalkylene; lower alkylene carbalkoxy; lower alkylthioalkylene; lower alkylsulfinylalkylene; or lower alkylsulfonylalkylene; R1 and R2 are independently hydrogen, lower alkyl of 1 to 6 carbon atoms, aryl of 6 to 12 carbon atoms, or thienyl, or taken together form an alkylene bridge to give a cycloalkyl group of 3 to 10 carbon atoms; and R3 is alkyl of 1 to 3 carbon atoms substituted with 3 to 6 halogen atoms or trihalovinyl are fungicidal.
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- Anthraquinone disperse dyestuffs
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1-Amino-4-hydroxy 2-p-alkoxy-benzenesulfonyloxy anthraquinone disperse dyestuffs have been prepared.
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